PMID- 12401127
TI  - Albumin synthesis in humans increases immediately following the administration of
      endotoxin.
AB  - In order to investigate the immediate (i.e. within 3 h) response of albumin
      synthesis to the administration of endotoxin, as a model of a moderate and well
      controlled catabolic insult, two measurements employing L-[(2)H(5)]phenylalanine
      were performed in 16 volunteers. One group ( n =8) received an intravenous
      injection of endotoxin (4 ng/kg; lot EC-6) immediately after the first
      measurement of albumin synthesis, whereas the other group received saline. A
      second measurement was initiated 1 h later. In the endotoxin group, the
      fractional synthesis rate of albumin was 6.9+/-0.6%/day (mean+/-S.D.) in the
      first measurement. In the second measurement, a significant increase was observed
      (9.6+/-1.2%/day; P <0.001). The corresponding values in the control group were
      were 6.6+/-0.6%/day and 7.0+/-0.6%/day respectively (not significant compared
      with first measurement and P <0.001 compared with the second measurement in the
      endotoxin group). The absolute synthesis rates of albumin were 148+/-35 and 201+/
      49 mg x kg(-1) x day(-1) before and after endotoxin ( P <0.01). In the control
      group, the corresponding values were 131+/-21 and 132+/-20 mg x kg(-1) x day(-1)
      (not significant compared with the first measurement and P <0.01 compared with
      the second measurement in the endotoxin group). In conclusion, these results
      indicate that albumin synthesis increases in the very early phase after a
      catabolic insult, as represented by the administration of endotoxin.

PMID- 12401128
TI  - Elucidation of acute regulation of protein synthesis in man in vivo using stable
      isotopes.

PMID- 12401129
TI  - Role of cdc2 kinase phosphorylation and conserved N-terminal proteolysis motifs
      in cytoplasmic polyadenylation-element-binding protein (CPEB) complex
      dissociation and degradation.
AB  - Cytoplasmic polyadenylation-element-binding protein (CPEB) is a well
      characterized and important regulator of translation of maternal mRNA in early
      development in organisms ranging from worms, flies and clams to frogs and mice.
      Previous studies provided evidence that clam and Xenopus CPEB are
      hyperphosphorylated at germinal vesicle breakdown (GVBD) by cdc2 kinase, and
      degraded shortly after. To examine the conserved features of CPEB that mediate
      its modification during meiotic maturation, we microinjected mRNA encoding wild
      type and mutated clam CPEB into Xenopus oocytes that were subsequently allowed to
      mature with progesterone. We observed that (i) ectopically expressed clam CPEB is
      phosphorylated at GVBD and subsequently degraded, mirroring the fate of the
      endogenous Xenopus CPEB protein, (ii) mutation of nine Ser/Thr Pro-directed
      kinase sites prevents phosphorylation and degradation and (iii) deletion of the
      PEST box, and to a lesser extent of the putative cyclin destruction box,
      generates a stable and phosphorylated version of CPEB. We conclude that
      phosphorylation of both consensus and non-consensus sites by cdc2 kinase targets
      clam CPEB for PEST-mediated destruction. We also show that phosphorylation of
      CPEB mediates its dissociation from ribonucleoprotein complexes, prior to
      degradation. Our findings reinforce results obtained in Xenopus, and have
      implications for CPEB from other invertebrates including Drosophila,
      Caenorhabditis elegans and Aplysia, which lack PEST boxes.

PMID- 12401130
TI  - Calcium triggers the refolding of Bacillus subtilis chitosanase.
AB  - We characterized the reversible folding-unfolding transition of Bacillus subtilis
      exocellular chitosanase from either thermal or urea denaturation of the protein.
      The transitions were monitored in each case by intrinsic fluorescence changes and
      resistance to proteolysis. Unfolding and refolding kinetics and differential
      scanning calorimetry analysis suggested a two-state equilibrium. The equilibrium
      between the folded and unfolded states was rapidly displaced towards the folded
      state in the presence of a low concentration of calcium (2-20 mM). The binding
      titration curve indicated that chitosanase possesses one weak Ca(2+)-binding site
      (with an equilibrium affinity constant, K (A), of 0.3x10(3) M(-1)). These results
      support the hypothesis that this metal ion, which is accumulated in the cell wall
      environment of B. subtilis, is an effector that influences folding and stability
      of newly translocated proteins.

PMID- 12401131
TI  - Molecular cloning and characterization of a novel carboxylesterase-like protein
      that is physiologically present at high concentrations in the urine of domestic
      cats (Felis catus).
AB  - Normal mammals generally excrete only small amounts of protein in the urine, thus
      avoiding major leakage of proteins from the body. Proteinuria is the most
      commonly recognized abnormality in renal disease. However, healthy domestic cats
      ( Felis catus ) excrete proteins at high concentrations (about 0.5 mg/ml) in
      their urine. We investigated the possible cause of proteinuria in healthy cats,
      and discovered a 70 kDa glycoprotein, which was excreted as a major urinary
      protein in cat urine, irrespective of gender. To elucidate the biochemical
      functions and the excretion mechanism of this protein, we cloned the cDNA for
      this protein from a cat kidney cDNA library. The deduced amino acid sequence
      shared 47% identity with the rat liver carboxylesterase (EC 3.1.1.1), and both
      the serine hydrolase active site and the carboxylesterase-specific sequence were
      conserved. Therefore we named this protein cauxin (carboxylesterase-like urinary
      excreted protein). In contrast to the mammalian carboxylesterases, most of which
      are localized within the cells of various organs, cauxin was expressed
      specifically in the epithelial cells of the distal tubules, and was secreted
      efficiently into the urine, probably because it lacked the endoplasmic reticulum
      retention sequence (HDEL). Based on our finding that cauxin is not expressed in
      the immature cat kidney, we conclude that cauxin is involved in physiological
      functions that are specific for mature cats. Recently, cauxin-like cDNAs were
      found from human brain and teratocarcinoma cells. These data suggest that cauxin
      and cauxin-like human proteins are categorized as a novel group of
      carboxylesterase multigene family.

PMID- 12401132
TI  - Ubiquitination of tissue transglutaminase is modulated by interferon alpha in
      human lung cancer cells.
AB  - The addition of 2500 i.u./ml interferon alpha (IFNalpha) for 48 h induced
      apoptosis, and caused an approx. 4-fold increase in the activity and expression
      of tissue transglutaminase (tTG), in human lung cancer H1355 cells. However, the
      increase in mRNA levels for tTG was just 1.6-fold. On the basis of these data, we
      investigated whether tTG levels may be regulated through regulation of its
      degradation via ubiquitination. It was found that 2500 i.u./ml IFNalpha induced a
      time-dependent decrease in tTG ubiquitination. On the other hand, addition of the
      proteasome inhibitor lactacystin led to accumulation of the ubiquitinated form of
      the enzyme and to a consequent increase in its expression. Treatment of the cells
      with the two agents combined antagonized the accumulation of the ubiquitinated
      isoforms of tTG induced by lactacystin and caused a potentiation of tTG
      expression. Moreover, the tTG inducer retinoic acid was also able to cause
      increased expression and ubiquitination of tTG in H1355 cells. The addition of
      monodansylcadaverine (a tTG inhibitor) to IFNalpha-treated H1355 cells completely
      antagonized growth inhibition and apoptosis induced by the cytokine. In
      conclusion, we demonstrate for the first time that tTG is ubiquitinated and
      degraded by a proteasome-dependent pathway. Moreover, IFNalpha can, at least in
      part, induce apoptosis through the modulation of this pathway.

PMID- 12401133
TI  - Rapid degradation of dominant-negative Rab27 proteins in vivo precludes their use
      in transgenic mouse models.
AB  - BACKGROUND: Transgenic mice have proven to be a powerful system to study normal
      and pathological gene functions. Here we describe an attempt to generate a
      transgenic mouse model for choroideremia (CHM), a slow-onset X-linked retinal
      degeneration caused by mutations in the Rab Escort Protein-1 (REP1) gene. REP1 is
      part of the Rab geranylgeranylation machinery, a modification that is essential
      for Rab function in membrane traffic. The loss of REP1 in CHM patients may
      trigger retinal degeneration through its effects on Rab proteins. We have
      previously reported that Rab27a is the Rab most affected in CHM lymphoblasts and
      hypothesised that the selective dysfunction of Rab27a (and possibly a few other
      Rab GTPases) plays an essential role in the retinal degenerative process.
      RESULTS: To investigate this hypothesis, we generated several lines of dominant
      negative, constitutively-active and wild-type Rab27a (and Rab27b) transgenic mice
      whose expression was driven either by the pigment cell-specific tyrosinase
      promoter or the ubiquitous beta-actin promoter. High levels of mRNA and protein
      were observed in transgenic lines expressing wild-type or constitutively active
      Rab27a and Rab27b. However, only modest levels of transgenic protein were
      expressed. Pulse-chase experiments suggest that the dominant-negative proteins,
      but not the constitutively-active or wild type proteins, are rapidly degraded.
      Consistently, no significant phenotype was observed in our transgenic lines. Coat
      colour was normal, indicating normal Rab27a activity. Retinal function as
      determined by fundoscopy, angiography, electroretinography and histology was also
      normal. CONCLUSIONS: We suggest that the instability of the dominant-negative
      mutant Rab27 proteins in vivo precludes the use of this approach to generate
      mouse models of disease caused by Rab27 GTPases.

PMID- 12401134
TI  - SeqHound: biological sequence and structure database as a platform for
      bioinformatics research.
AB  - BACKGROUND: SeqHound has been developed as an integrated biological sequence,
      taxonomy, annotation and 3-D structure database system. It provides a high
      performance server platform for bioinformatics research in a locally-hosted
      environment. RESULTS: SeqHound is based on the National Center for Biotechnology
      Information data model and programming tools. It offers daily updated contents of
      all Entrez sequence databases in addition to 3-D structural data and information
      about sequence redundancies, sequence neighbours, taxonomy, complete genomes,
      functional annotation including Gene Ontology terms and literature links to
      PubMed. SeqHound is accessible via a web server through a Perl, C or C++ remote
      API or an optimized local API. It provides functionality necessary to retrieve
      specialized subsets of sequences, structures and structural domains. Sequences
      may be retrieved in FASTA, GenBank, ASN.1 and XML formats. Structures are
      available in ASN.1, XML and PDB formats. Emphasis has been placed on complete
      genomes, taxonomy, domain and functional annotation as well as 3-D structural
      functionality in the API, while fielded text indexing functionality remains under
      development. SeqHound also offers a streamlined WWW interface for simple web-user
      queries. CONCLUSIONS: The system has proven useful in several published
      bioinformatics projects such as the BIND database and offers a cost-effective
      infrastructure for research. SeqHound will continue to develop and be provided as
      a service of the Blueprint Initiative at the Samuel Lunenfeld Research Institute.
      The source code and examples are available under the terms of the GNU public
      license at the Sourceforge site http://sourceforge.net/projects/slritools/ in the
      SLRI Toolkit.

PMID- 12401137
TI  - Left ventricular contrast echocardiography: role for evaluation of function and
      structure.
AB  - Despite the recent introduction of tissue harmonic imaging in echocardiography,
      in 10%-15% of patients endocardial borders of the left ventricle are poorly
      defined. This may lead to erroneous assessment of regional and global left
      ventricular (LV) function or further diagnostic imaging with another modality
      leading to increased cost to the healthcare system. The recent development of
      second generation contrast echocardiography agents such as SonoVue has resulted
      in several studies showing the value of these agents to outline endocardium
      clearly, thereby improving assessment of LV function. The use of these contrast
      agents has also opened the possibility of automated and qualitative LV function
      assessment, resulting in more accurate and reproducible assessment. Other major
      clinical uses of these contrast agents are evaluation of LV masses such as
      thrombus and tumors, and better definition of LV structure such as delineating LV
      aneurysm, pseudoaneurysm; and noncompaction of LV and apical cardiomyopathy.
      Thus, it is clear that contrast-enhanced LV assessment at rest will play an
      important role in echocardiography.

PMID- 12401138
TI  - Usefulness of ultrasound contrast for image enhancement during stress
      echocardiography.
AB  - Although stress echocardiography has been established as a diagnostic technique
      for the detection and assessment of ischemia, there are still a number of
      limitations to the technique. These are related to suboptimal image quality with
      poor visualization of endocardial borders. Because assessment of wall motion is
      fundamental to the diagnostic value of stress echocardiography (both
      pharmacologic and exercise), endocardial border visualization is of utmost
      importance. Furthermore, interinstitutional observer agreement of 100% in highest
      image quality patients to a cumbersome 43% in low image quality patients is
      present. Therefore, improvements of image quality during stress are essential.
      One of the recent improvements is harmonic imaging, which improves visualization
      of endocardial borders at rest and during dobutamine stress. However, there is
      room for improvement. Since the introduction of ultrasound contrast agents,
      contrast has been increasingly used for better endocardial border visualization.
      Data from centers with a large number of stress echocardiography tests have shown
      that the addition of contrast agents decreases the number of more redundant
      diagnostic testing. Data obtained in our center in a subset of patients
      administered with SonoVue, a new generation contrast agent made of stabilized
      microbubbles containing sulfur hexafluoride, an inert gas, showed an improvement
      in the number of evaluable segments with fundamental and harmonic imaging and in
      the endocardial border detection during dobutamine stress echocardiography.
      Contrast also enables future quantitative analysis using acoustic quantification
      (AQ), and color kinesis. These studies should be carried out now that contrast
      has been approved for introduction to the market.

PMID- 12401139
TI  - Tailored reperfusion strategies in acute myocardial infarction: role of
      intravenous myocardial contrast echocardiography.
AB  - After many years of study and research, the noninvasive assessment of myocardial
      perfusion by echo contrast agents is becoming a clinical reality. The fast
      technological progress of echocardiographic imaging and the approval for human
      use in Europe and the United States of some first and second generation contrast
      agents explains the growing interest in this new methodology. Recently, a new
      second generation contrast agent, SonoVue, made of microbubbles stabilized by
      phospholipids and containing sulphur hexafluoride, has been introduced on the
      European market. We describe the role of intravenous myocardial contrast
      echocardiography with second-generation contrast agents such as SonoVue in the
      tailored reperfusion strategies in acute myocardial infarction.

PMID- 12401140
TI  - Clinical value of myocardial contrast echocardiography in chronic coronary artery
      disease.
AB  - Myocardial contrast echocardiography (MCE) has become a major field of clinical
      research in echocardiography in the last decade. The introduction of new contrast
      agents was accompanied by a large variety of new contrast specific imaging
      techniques. Recent experimental and clinical studies demonstrate that MCE is now
      ready for clinical applications. We report our clinical experience for diagnosis
      of coronary artery disease (CAD) and in particular, first experimental and
      clinical results with SonoVue, a new echo contrast agent.

PMID- 12401135
TI  - Replicate high-density rat genome oligonucleotide microarrays reveal hundreds of
      regulated genes in the dorsal root ganglion after peripheral nerve injury.
AB  - BACKGROUND: Rat oligonucleotide microarrays were used to detect changes in gene
      expression in the dorsal root ganglion (DRG) 3 days following sciatic nerve
      transection (axotomy). Two comparisons were made using two sets of triplicate
      microarrays, naive versus naive and naive versus axotomy. RESULTS: Microarray
      variability was assessed using the naive versus naive comparison. These results
      support use of a P < 0.05 significance threshold for detecting regulated genes,
      despite the large number of hypothesis tests required. For the naive versus
      axotomy comparison, a 2-fold cut off alone led to an estimated error rate of 16%;
      combining a >1.5-fold expression change and P < 0.05 significance reduced the
      estimated error to 5%. The 2-fold cut off identified 178 genes while the combined
      >1.5-fold and P < 0.05 criteria generated 240 putatively regulated genes, which
      we have listed. Many of these have not been described as regulated in the DRG by
      axotomy. Northern blot, quantitative slot blots and in situ hybridization
      verified the expression of 24 transcripts. These data showed an 83% concordance
      rate with the arrays; most mismatches represent genes with low expression levels
      reflecting limits of array sensitivity. A significant correlation was found
      between actual mRNA differences and relative changes between microarrays (r2 =
      0.8567). Temporal patterns of individual genes regulation varied. CONCLUSIONS: We
      identify parameters for microarray analysis which reduce error while identifying
      many putatively regulated genes. Functional classification of these genes suggest
      reorganization of cell structural components, activation of genes expressed by
      immune and inflammatory cells and down-regulation of genes involved in
      neurotransmission.

PMID- 12401142
TI  - Antioxidants do not prevent heart disease in high-risk individuals.

PMID- 12401141
TI  - The time is right to unite.

PMID- 12401143
TI  - Arthroscopic surgery ineffective for osteoarthritis of the knee.

PMID- 12401144
TI  - Beta-blocker survival benefit outweighs side-effect risks.

PMID- 12401145
TI  - B-type natriuretic peptide is an accurate predictor of heart failure in the
      emergency department.

PMID- 12401146
TI  - Hair apposition technique is better than suturing scalp lacerations.

PMID- 12401147
TI  - Do the risks of estrogen plus progestin outweigh the benefits in healthy post
      menopausal women?

PMID- 12401148
TI  - DEET is the most effective mosquito repellent.

PMID- 12401149
TI  - Topical steroids more effective than antifungals for chronic paronychia.

PMID- 12401150
TI  - Is a history of trauma associated with a reduced likelihood of cervical cancer
      screening?
AB  - OBJECTIVE: We tested the hypothesis that a history of trauma (especially sexual
      trauma) was associated with a reduced likelihood of having had medically
      appropriate cervical cancer screening. STUDY DESIGN: A case-control study using
      mailed self-report questionnaires. POPULATION: The questionnaires were completed
      by an age-stratified random sample of adult women members of a large health
      maintenance organization. The sample included 364 women who had received
      medically appropriate cervical cancer screening and 372 who had not. OUTCOMES
      MEASURED: We defined cases as women who, according to their medical record, had
      not had cervical cancer screening within 2 years before the study. Controls were
      defined as women who had been screened. We evaluated exposures to trauma that we
      hypothesized to be associated with the case/control state. RESULTS: Women who had
      been sexually abused in childhood were less likely to have had a Pap smear within
      the past 2 years (36.0% vs. 50.4%, P =.050). Other traumatic events were
      associated with Pap testing in bivariate analyses but not when demographic
      characteristics and clinic location were controlled. Childhood sexual abuse
      remained associated with reduced odds of Pap screening in logistic regression
      analyses that controlled for clinic location, demographics, attitudes about Pap
      screening, and posttraumatic stress disorder symptoms (adjusted OR = 0.56, 95% CI
      0.34 to 0.91). CONCLUSIONS: These findings suggest that childhood sexual abuse
      may lead to decreased probability of screening for cervical cancer, potentially
      contributing to the poorer health seen in other studies of women who have been
      sexually abused.

PMID- 12401151
TI  - Relationships between physician practice style, patient satisfaction, and
      attributes of primary care.
AB  - OBJECTIVES: Style of physician-patient interaction has been shown to have an
      impact on patient outcomes. Although many different interaction styles have been
      proposed, few have been empirically tested. This study was conducted to
      empirically derive physician interaction styles and to explore the association of
      style with patient reports of specific attributes of primary care, satisfaction
      with care received, and duration of the visit. STUDY DESIGN: A cross-sectional
      observational study. POPULATION: We observed 2881 patients visiting 138 family
      physicians for outpatient care in 84 community family practice offices in
      northeast Ohio. OUTCOMES MEASURED: Components of Primary Care Instrument (CPCI),
      patient satisfaction, and duration of the visit. RESULTS: A cluster analysis of
      variables derived from qualitative field notes identified 4 physician interaction
      styles: person focused, biopsychosocial, biomedical, and high physician control.
      Physicians with the person-focused style rated highest on 4 of 5 measures of the
      quality of the physician-patient relationship and patient satisfaction. In
      contrast, physicians with the high-control style were lowest or next to lowest on
      the outcomes. Physicians with a person-focused style granted the longest visits,
      while high-control physicians held the shortest visits-a difference of 2 minutes
      per visit on average. The associations were not explained away by patient and
      physician age and gender. CONCLUSIONS: In community-based practices, we found
      that the person-focused interaction style appears to be the most congruent with
      patient reported quality of primary care. Further investigation is needed to
      identify ways to support and encourage person-focused approaches and the time
      needed to provide such care.

PMID- 12401152
TI  - Do written action plans improve patient outcomes in asthma? An evidence-based
      analysis.
AB  - OBJECTIVE: Current guidelines recommend use of written action plans and peak flow
      monitoring as key components of asthma care. Our study assesses whether written
      action plans, with or without peak flow monitoring, have an independent effect on
      outcomes when used as a component of asthma self-management. STUDY DESIGN: This
      was a systematic review of published studies. Two independent reviewers followed
      a prospective protocol for study selection and data abstraction. Outcome data
      were synthesized qualitatively; they were not appropriate for quantitative meta
      analysis. Our comprehensive literature search used MEDLINE, EMBASE, the Cochrane
      Library, and a hand search of recent bibliographies. The search was limited to
      full-length, peer-reviewed articles with abstracts in English. The studies were
      randomized controlled trials that compared the outcomes of an asthma self
      management intervention with and without the use a written action plan. The
      primary outcomes of interest are utilization measures, such as hospitalizations
      and ER visits. Other outcomes of interest include measures of symptom control and
      lung function. POPULATION: There were 1501 evaluable patients with asthma; 1410
      adults and 91 children. OUTCOMES MEASURED: We measured the frequency of waiting
      and examination room companions, the reasons for accompaniment, the influence on
      the encounter, and the overall helpfulness of the companion as assessed by
      patients and companions. We also determined the physicianamprsquos assessment of
      the companionamprsquos influence, helpfulness, and behavior during the encounter.
      RESULTS: Nine randomized controlled trials enrolling a total of 1501 patients met
      selection criteria. The majority of comparisons in these studies do not
      demonstrate improved outcomes associated with a written action plan. There are
      notable methodologic limitations: studies reporting negative findings lack
      sufficient power, and studies reporting positive findings demonstrate systematic
      bias. CONCLUSIONS: Although written action plans are widely used, there is
      insufficient evidence to determine whether their use, with or without peak flow
      monitoring, improves outcomes.

PMID- 12401153
TI  - Management of the low-grade abnormal Pap smear: What are women's preferences?
AB  - OBJECTIVE: To evaluate preferences among ethnically diverse women for the
      management of a low-grade abnormal Pap smear result: early colposcopy or
      observation with repeat Pap smears. STUDY DESIGN: Structured interviews were
      conducted with 170 women of diverse ethnic backgrounds to assess their
      preferences. Trained personnel conducted standardized interviews. A standard
      description of all tests and procedures was read to participants. The
      participants were presented with scenarios of contrasting management approaches
      for a hypothetical low-grade abnormal Pap smear result-observation with repeat
      Pap smear vs. immediate colposcopy. POPULATION: Study participants were recruited
      from the waiting rooms of 5 family planning clinics in Northern
      Californiaamprsquos Central Valley. OUTCOMES MEASURED: The primary outcome
      measures for each scenario were utilities (quantified preferences for specific
      health states) measured by the Standard Gamble. RESULTS: The range in utilities
      was large for all scenarios. Mean utilities (SD) for observation: 0.96 (  0.13)
      followed by resolution; 0.93 (  0.17) followed by cryotherapy; 0.91 (  0.21)
      followed by cone biopsy. Mean utilities for early colposcopy: 0.93 (  0.20)
      followed by resolution; 0.95 (  0.14) followed by cryotherapy; and 0.92 (  0.16)
      followed by cone biopsy. Subject characteristics explained less than 20% of the
      variance in utilities. Decision analysis gave a slightly higher overall utility
      for early colposcopy (0.940 vs 0.932 for observation), but was sensitive to small
      changes in branch utilities. CONCLUSIONS: Womenamprsquos preferences for
      management of a low-grade abnormal Pap result vary widely. Clinicians should
      adopt a flexible approach to the management of low-grade abnormal Pap smears to
      incorporate individual preferences.

PMID- 12401156
TI  - Information about tests for breast cancer: what are we telling people?
AB  - We reviewed publications currently available about breast cancer screening to
      assess what information was provided about test accuracy and pretest and posttest
      disease probabilities, as this information is needed by consumers to make
      informed decisions about whether to undergo testing and to fully understand test
      results. A rating form was developed and used to assess 54 publications about
      their reports of breast cancer tests. A description of how the test is done was
      provided by almost all publications (93%). About half (48%) provided some
      information about possible adverse effects of the test. Eighteen percent of
      publications provided some (generally qualitative) information about test
      accuracy, and none provided quantitative information about the probability of
      disease given normal and abnormal test results.

PMID- 12401157
TI  - Effectiveness of sibutramine.

PMID- 12401158
TI  - Effectiveness and safety of lidocaine patch 5%.

PMID- 12401159
TI  - Snake oil or sound medicine.

PMID- 12401160
TI  - Electronic solutions to implementing lipid guidelines.

PMID- 12401161
TI  - Prevention and treatment of osteoporosis in postmenopausal women.

PMID- 12401162
TI  - Evaluation and treatment of the patient with allergic rhinitis.

PMID- 12401163
TI  - Clinical inquiries. What are the most effective interventions to reduce childhood
      obesity?

PMID- 12401164
TI  - Clinical inquiries. What is the target for low-density lipoprotein cholesterol in
      patients with heart disease?

PMID- 12401165
TI  - Clinical inquiries. What medications are effective for treating symptoms of
      premenstrual syndrome (PMS)?

PMID- 12401166
TI  - EXS, a putative LRR receptor kinase, regulates male germline cell number and
      tapetal identity and promotes seed development in Arabidopsis.
AB  - BACKGROUND: Plant germlines arise late in development from archesporial initials
      in the L2 layer of the anther and ovule primordia. These cells generate a
      radially symmetrical array of tissues that, in the Arabidopsis anther, comprises
      a core of sporogenous cells (meiocytes) and the enveloping tapetum, middle cell,
      and endothecium layers. The putative transcription factor NZZ/SPL is required for
      the specification of archesporial cells, but nothing is known of how their number
      is regulated, or what controls cell fate in the lineages they generate. Here, we
      report detailed characterization of extra sporogenous cells (exs), a male sterile
      mutant that generates extra meiocytes but lacks tapetal and middle cell layers.
      RESULTS: We identified the EXS locus by map-based cloning and found it to encode
      a putative LRR receptor kinase. In the anther, an increased number of L2 layer
      cells assume an archesporial fate and divide to generate a larger number of
      sporogenous cells. In seeds, the exs mutation results in smaller embryonic cells,
      delayed embryo development, and smaller mature embryos. Consistent with the
      observed phenotype, EXS is expressed in the inflorescence meristem, floral
      apices, anthers, and in developing seeds. CONCLUSIONS: EXS regulates the number
      of cells that divide in the L2 layer of the anther, and thus the number of
      functional male archesporial initials. In the young seed, EXS affects cell size
      in the embryo and the rate at which it develops. The apparently contrasting roles
      of EXS in the anther and embryo suggest that signaling through the EXS receptor
      kinase is a feature of a number of regulatory pathways in Arabidopsis.

PMID- 12401167
TI  - A ubiquitin-proteasome pathway represses the Drosophila immune deficiency
      signaling cascade.
AB  - BACKGROUND: The inducible production of antimicrobial peptides is a major immune
      response in Drosophila. The genes encoding these peptides are activated by NF
      kappaB transcription factors that are controlled by two independent signaling
      cascades: the Toll pathway that regulates the NF-kappaB homologs, Dorsal and DIF;
      and the IMD pathway that regulates the compound NF-kappaB-like protein, Relish.
      Although numerous components of each pathway that are required to induce
      antimicrobial gene expression have been identified, less is known about the
      mechanisms that either repress antimicrobial genes in the absence of infection or
      that downregulate these genes after infection. RESULTS: In a screen for factors
      that negatively regulate the IMD pathway, we isolated two partial loss-of
      function mutations in the SkpA gene that constitutively induce the antibacterial
      peptide gene, Diptericin, a target of the IMD pathway. These mutations do not
      affect the systemic expression of the antifungal peptide gene, Drosomycin, a
      target of the Toll pathway. SkpA encodes a homolog of the yeast and human Skp1
      proteins. Skp1 proteins function as subunits of SCF-E3 ubiquitin ligases that
      target substrates to the 26S proteasome, and mutations affecting either the
      Drosophila SCF components, Slimb and dCullin1, or the proteasome also induce
      Diptericin expression. In cultured cells, inhibition of SkpA and Slimb via RNAi
      increases levels of both the full-length Relish protein and the processed Rel
      homology domain. CONCLUSIONS: In contrast to other NF-kappaB activation pathways,
      the Drosophila IMD pathway is repressed by the ubiquitin-proteasome system. A
      possible target of this proteolytic activity is the Relish transcription factor,
      suggesting a mechanism for NF-kappaB downregulation in Drosophila.

PMID- 12401168
TI  - Serotonin promotes G(o)-dependent neuronal migration in Caenorhabditis elegans.
AB  - BACKGROUND: The directed migration of neurons during development requires
      attractive and repulsive cues that control the direction of migration as well as
      permissive cues that potentiate cell motility and responsiveness to guidance
      molecules. RESULTS: Here, we show that the neurotransmitter serotonin functions
      as a permissive signal for embryonic and postembryonic neuronal migration in the
      nematode C. elegans. In serotonin-deficient mutants, the migrations of the ALM,
      BDU, SDQR, and AVM neurons were often foreshortened or misdirected, indicating a
      serotonin requirement for normal migration. Moreover, exogenous serotonin could
      restore motility to AVM neurons in serotonin-deficient mutants as well as induce
      AVM-like migrations in the normally nonmotile neuron PVM; this indicates that
      serotonin was functioning as a permissive cue to enable neuronal motility. The
      migration defects of serotonin-deficient mutants were mimicked by ablations of
      serotonergic neuroendocrine cells, implicating humoral release of serotonin in
      these processes. Mutants defective in G(q) and G(o) signaling, or in N-type
      voltage-gated calcium channels, showed migration phenotypes similar to serotonin
      deficient mutants, and these molecules appeared to genetically function
      downstream of serotonin in the control of neuronal migration. CONCLUSIONS: Thus,
      serotonin is important for promoting directed neuronal migration in the
      developing C. elegans nervous system. We hypothesize that serotonin may promote
      cell motility through G protein-dependent modulation of voltage-gated calcium
      channels in the migrating cell.

PMID- 12401169
TI  - Immunoglobulin isotype switching is inhibited and somatic hypermutation perturbed
      in UNG-deficient mice.
AB  - BACKGROUND: We have previously proposed that deamination of cytosine to uracil at
      sites within the immunoglobulin loci by activation-induced deaminase (AID)
      triggers antibody diversification. The pattern of diversification (phase 1 or 2
      hypermutation, gene conversion, or switch recombination) is viewed as depending
      on the mode of resolution of the dU/dG lesion. A major resolution mode involves
      excising the uracil, an activity that at least four different enzymes can
      accomplish in the mouse. RESULTS: Deficiency in UNG uracil-DNA glycosylase alone
      is sufficient to distort the pathway of hypermutation in mice. In ung(-/-)
      animals, mutations at dC/dG pairs are dramatically shifted toward transitions
      (95%), indicating that the generation of abasic sites (which can induce
      transversions) has been inhibited. The pattern of substitutions at dA/dT pairs is
      unaffected. Class-switch recombination is substantially, but not totally,
      inhibited. CONCLUSIONS: The results provide strong support for the DNA
      deamination model for antibody diversification with respect to class-switching as
      well as hypermutation and, in the context of this model, suggest that (i) UNG is
      the major mouse DNA glycosylase responsible for processing the programmed dU/dG
      lesions within the immunoglobulin locus; (ii) the second (dA/dT-biased) phase of
      mutation is probably triggered by recognition of the initiating dU/dG lesion; and
      (iii) switch recombination largely proceeds via formation of an abasic site,
      although (iv) an UNG-independent pathway of switch recombination exists, which
      could reflect action by another uracil-DNA glycosylase but might alternatively be
      explained by a distinct pathway of resolution, for example, one involving
      MSH2/MSH6 recognition of the dU/dG lesion.

PMID- 12401170
TI  - A ubiquitous and conserved signal for RNA localization in chordates.
AB  - During oogenesis in Xenopus laevis, several RNAs that localize to the vegetal
      cortex via one of three temporally defined pathways have been identified.
      Although individual mRNAs utilize only one pathway, there is functional overlap
      and apparent continuity between them, suggesting that common cis-acting sequences
      may exist. Because previous work with the Vg1 mRNA revealed that short nontandem
      repeats are important for localization, we developed a new computer program,
      called REPFIND, to expedite the identification of repeated motifs in other
      localized RNAs. Here we show that clusters of short CAC-containing motifs
      characterize the localization elements (LEs) of virtually all mRNAs localized to
      the vegetal cortex of Xenopus oocytes. A search for this signal in GenBank [9]
      resulted in the identification of new localized mRNAs, demonstrating the
      applicability of REPFIND to predict localized RNAs. CAC-rich LEs are also found
      in ascidians and other vertebrates, indicating that these cis regulatory elements
      are conserved in chordates. Interestingly, biochemical evidence shows that
      distinct CAC-containing motifs have different functions in the localization
      process. Thus, clusters of CAC-containing motifs are a ubiquitous signal for RNA
      localization and can signal localization in a variety of pathways through slight
      variations in sequence composition.

PMID- 12401171
TI  - Atypical protein kinase C-zeta is essential for delayed phagocytosis of
      Helicobacter pylori.
AB  - Phagocytosis is a rapid actin-dependent endocytic process used by macrophages and
      neutrophils to ingest and kill microorganisms. Perturbation of phagocytosis is
      central to the ability of some pathogenic microbes to cause disease, and we
      demonstrated previously that the ulcerogenic bacterium Helicobacter pylori (Hp)
      actively retards its uptake by macrophages and subsequently persists inside novel
      vacuoles called megasomes. Neither the receptor that mediates Hp binding nor the
      signaling pathways that regulate bacterial engulfment have been defined.
      Nevertheless, the fact that other phagocytic stimuli do not exhibit delayed
      phagocytosis suggests that Hp may be ingested by a unique mechanism. We now show
      that Hp transiently activated protein kinase C (PKC) in macrophages and that
      atypical PKCzeta and novel PKC(epsilon), but not conventional PKC(alpha),
      accumulated on forming phagosomes. Pharmacologic agents, isoform-selective
      pseudosubstrate peptides, and antisense oligonucleotides demonstrated that
      PKC(zeta) regulated local actin polymerization and bacterial engulfment, whereas
      other PKC isoforms did not. In contrast, opsonization of Hp with immunoglobulin G
      (IgG) induced rapid PKC(zeta)-independent uptake and enhanced killing of ingested
      bacteria. A role for atypical PKCs in phagocytosis has not been described. We
      conclude that Hp defines a new phagocytic pathway in macrophages that is
      regulated by PKC(zeta).

PMID- 12401172
TI  - Dinoflagellate-cyanobacterium communication may determine the composition of
      phytoplankton assemblage in a mesotrophic lake.
AB  - The reasons for annual variability in the composition of phytoplankton
      assemblages are poorly understood but may include competition for resources and
      allelopathic interactions. We show that domination by the patch-forming
      dinoflagellate, Peridinium gatunense, or, alternatively, a bloom of a toxic
      cyanobacterium, Microcystis sp., in the Sea of Galilee may be accounted for by
      mutual density-dependent allelopathic interactions. Over the last 11 years, the
      abundance of these species in the lake displayed strong negative correlation.
      Laboratory experiments showed reciprocal, density-dependent, but nutrient
      independent, inhibition of growth. Application of spent P. gatunense medium
      induced sedimentation and, subsequently, massive lysis of Microcystis cells
      within 24 hr, and sedimentation and lysis were concomitant with a large rise in
      the level of McyB, which is involved in toxin biosynthesis by Microcystis. P.
      gatunense responded to the presence of Microcystis by a species-specific pathway
      that involved a biphasic oxidative burst and activation of certain protein
      kinases. Blocking this recognition by MAP-kinase inhibitors abolished the
      biphasic oxidative burst and affected the fate (death or cell division) of the P.
      gatunense cells. We propose that patchy growth habits may confer enhanced defense
      capabilities, providing ecological advantages that compensate for the aggravated
      limitation of resources in the patch. Cross-talk via allelochemicals may explain
      the phytoplankton assemblage in the Sea of Galilee.

PMID- 12401174
TI  - Auditory chronostasis: hanging on the telephone.
AB  - The perception of time can be illusory: we have all waited anxiously for
      important seconds to tick away slowly at the end of a football game and have
      experienced the truth of the adage "time flies when you're having fun." One
      illusion of time experience that has recently been investigated, the apparent
      slowing of the movement of the second hand on the clock when one first looks at
      it, has been termed "chronostasis," and it has been suggested that the effect is
      unique to vision and is dependent on eye movements. We sought to test whether the
      effect is really unique to vision or whether it can also be produced with
      auditory stimuli. Subjects were asked to judge the length of a silent gap between
      two tones presented through headphones. When the tones were presented to one ear,
      subjects judged the duration of the gap veridically. When subjects were required
      to shift concentration from one ear to the other, however, the judgement of time
      showed that the auditory system is also susceptible to chronostasis. We suggest
      that this generalization of chronostasis to another sensory system is consistent
      with theories of time perception that emphasize a single, multimodal clock for
      duration estimation rather than a mechanism that is dependent on motor acts.

PMID- 12401173
TI  - The closest unicellular relatives of animals.
AB  - Molecular phylogenies support a common ancestry between animals (Metazoa) and
      Fungi, but the evolutionary descent of the Metazoa from single-celled eukaryotes
      (protists) and the nature and taxonomic affiliation of these ancestral protists
      remain elusive. We addressed this question by sequencing complete mitochondrial
      genomes from taxonomically diverse protists to generate a large body of molecular
      data for phylogenetic analyses. Trees inferred from multiple concatenated
      mitochondrial protein sequences demonstrate that animals are specifically
      affiliated with two morphologically dissimilar unicellular protist taxa: Monosiga
      brevicollis (Choanoflagellata), a flagellate, and Amoebidium parasiticum
      (Ichthyosporea), a fungus-like organism. Statistical evaluation of competing
      evolutionary hypotheses confirms beyond a doubt that Choanoflagellata and
      multicellular animals share a close sister group relationship, originally
      proposed more than a century ago on morphological grounds. For the first time,
      our trees convincingly resolve the currently controversial phylogenetic position
      of the Ichthyosporea, which the trees place basal to Choanoflagellata and Metazoa
      but after the divergence of Fungi. Considering these results, we propose the new
      taxonomic group Holozoa, comprising Ichthyosporea, Choanoflagellata, and Metazoa.
      Our findings provide insight into the nature of the animal ancestor and have
      broad implications for our understanding of the evolutionary transition from
      unicellular protists to multicellular animals.

PMID- 12401175
TI  - DNA topoisomerase VI is essential for endoreduplication in Arabidopsis.
AB  - Endoreduplication is a common process in eukaryotes that involves DNA
      amplification without corresponding cell divisions. Cell size in various
      organisms has been linked to endoreduplication, but the molecular mechanisms are
      poorly understood. We have used a genetic strategy to identify molecules involved
      in endocycles in Arabidopsis. We isolated two extreme dwarf mutants, hypocotyl6
      (hyp6) and root hairless2 (rhl2) [3], and cells of these mutants successfully
      complete only the first two rounds of endoreduplication and stall at 8C. In both
      mutants, large cell types, such as trichomes and some epidermal cells, that
      normally endoreduplicate their DNA are much reduced in size. We show that HYP6
      encodes AtTOP6B, a plant homolog of the archaeal DNA topoisomerase VI subunit B,
      and that RHL2 encodes AtSPO11-3, one of the three Arabidopsis subunit A homologs.
      We propose that this topoisomerase VI complex is essential for the decatenation
      of replicated chromosomes during endocycles and that successive rounds of
      endoreduplication are required for the full growth of specific cell types.

PMID- 12401176
TI  - An archaebacterial topoisomerase homolog not present in other eukaryotes is
      indispensable for cell proliferation of plants.
AB  - Plants, in contrast to other eukaryotes, possess not only homologs of subunit A
      (AtSPO11-1, 2, 3) but also of subunit B (AtTOP6B) of the archaebacterial
      topoisomerase VI. AtTOP6B and AtSPO11-3 are strongly expressed in somatic tissue
      of Arabidopsis and are able to interact with each other in vitro. A T-DNA
      insertion in AtTOP6B results in deficient cell proliferation; plants stop growing
      at the rosette stage, have small crinkled leaves, and die about 4 weeks after
      germination. Cultured root cells die after a limited number of cell divisions.
      The mitotic index of the root meristems is strongly reduced. Flow cytometric
      analysis demonstrates that endoreplication in mutant plants is stopped at the 8C
      stage; the last cycle is not completed in most cases. Mutant plants show a
      significant increase in nuclear DNA strand breaks. A T-DNA insertion mutant of
      AtSPO11-3 has a phenotype that is almost to that of AtTOP6B and the double
      mutant. Thus, both genes seem to act in vivo as subunits of a functional entity.
      A loss of this function most likely results in a defect in DNA replication,
      leading directly, or via the activation of a DNA damage checkpoint, to an arrest
      of cell division and endoreduplication. The dependence on an archaebacterial
      topoisomerase VI homolog distinguishes plants from the other eukaryotic kingdoms.

PMID- 12401177
TI  - The Rab6 GTPase regulates recruitment of the dynactin complex to Golgi membranes.
AB  - Dynactin is a multisubunit protein complex required for the activity of dynein in
      diverse intracellular motility processes, including membrane transport. Dynactin
      can bind to vesicles and liposomes containing acidic phospholipids, but general
      properties such as this are unlikely to explain the regulated recruitment of
      dynactin to specific sites on organelle membranes. Additional factors must
      therefore exist to control this process. Candidates for these factors are the Rab
      GTPases, which function in the tethering of vesicles to their target organelle
      prior to membrane fusion. In particular, Rab27a tethers melanosomes to the actin
      cytoskeleton. Other Rabs have been implicated in microtubule-dependent organelle
      motility; Rab7 controls lysosomal transport, and Rab6 is involved in microtubule
      dependent transport pathways through the Golgi and from endosomes to the Golgi.
      We demonstrate that dynactin binds to Rab6 and shows a Rab6-dependent recruitment
      to Golgi membranes. Other Golgi Rabs do not bind to dynactin and are unable to
      support its recruitment to membranes. Rab6 therefore functions as a specificity
      or tethering factor controlling the recruitment of dynactin to membranes.

PMID- 12401178
TI  - New champion for basic research.

PMID- 12401179
TI  - Pursuing the puzzle of autism.

PMID- 12401180
TI  - More than just big ears.

PMID- 12401181
TI  - Cannabinoid receptors.

PMID- 12401182
TI  - Computational theories of vision.

PMID- 12401183
TI  - Antibiotic-resistant sub-populations of the pathogenic bacterium Staphylococcus
      aureus confer population-wide resistance.

PMID- 12401184
TI  - MicroRNAs: something new under the sun.
AB  - MicroRNAs are plentiful in plants, as in animals. The effects of mutations which
      disrupt their processing imply that miRNAs have important roles in plant
      development. Although the targets of these miRNAs are still not known, excellent
      candidates have been identified based on sequence similarity to the miRNAs.

PMID- 12401185
TI  - Eukaryotic evolution: getting to the root of the problem.
AB  - Comparative analyses of multiple genes suggest most known eukaryotes can be
      classified into half a dozen 'super-groups'. A new investigation of the
      distribution of a fused gene pair amongst these 'super-groups' has greatly
      narrowed the possible positions of the root of the eukaryote tree, clarifying the
      broad outlines of early eukaryote evolution.

PMID- 12401186
TI  - Chromatin methylation: who's on first?
AB  - Two recent studies have exploited Arabidopsis mutants and chromatin
      immunoprecipitation to reveal the complexity of the interaction between histone
      H3 methyl K9 and cytosine methylation, two epigenetic marks that characterize
      silent chromatin.

PMID- 12401187
TI  - Plant meristems: the interplay of KNOX and gibberellins.
AB  - KNOX proteins are required for meristem activity in plants. Recent studies have
      identified potential targets of KNOX proteins, and in doing so suggested a
      possible mechanism for the generation of different leaf morphologies.

PMID- 12401188
TI  - Vertebrate segmentation: lunatic transcriptional regulation.
AB  - Vertebrate segmentation relies on a molecular oscillator, the segmentation clock,
      which controls the periodic expression of genes such as lunatic fringe in the
      presomitic mesoderm. Oscillations of lunatic fringe transcripts have now been
      shown to be controlled at the transcriptional level by clock elements in the
      lunatic fringe promoter.

PMID- 12401189
TI  - Multifactorial diseases: asthma genetics point the way.
AB  - A recent study has identified the variation in the ADAM33 gene as an important
      risk factor for asthma. This is not only good news for asthma sufferers,
      suggesting new directions for diagnostics and treatment, but also provides
      encouragement that unravelling the genetics of common diseases may not be quite
      as hard as had been feared.

PMID- 12401190
TI  - Embryonic stem cells: taming the fountain of youth.
AB  - Embryonic stem cells readily generate neurons in vitro, but steering their
      differentiation into specific neuronal subtypes is a major challenge. It has now
      been shown that mechanisms that regulate neuronal specification during
      development can be applied to embryonic stem cells in vitro; this may lead to new
      ways of generating cells for therapy.

PMID- 12401191
TI  - Pattern formation: swimming in retinoic acid.
AB  - The metabolite retinoic acid has been implicated as a key player during anterior
      posterior patterning in vertebrate embryos. Recent studies in zebrafish extend
      this model by demonstrating the influence of retinoic acid on endoderm
      regionalization.

PMID- 12401192
TI  - Workshop on lipid signalling: cellular events and their biophysical mechanisms.
      Madrid, Spain. May 20-22, 2002.

PMID- 12401193
TI  - Phospholipase A(2) regulation of arachidonic acid mobilization.
AB  - Phospholipase A(2) (PLA(2)) constitutes a growing superfamily of lipolytic
      enzymes, and to date, at least 19 distinct enzymes have been found in mammals.
      This class of enzymes has attracted considerable interest as a pharmacological
      target in view of its role in lipid signaling and its involvement in a variety of
      inflammatory conditions. PLA(2)s hydrolyze the sn-2 ester bond of cellular
      phospholipids, producing a free fatty acid and a lysophospholipid, both of which
      are lipid signaling molecules. The free fatty acid produced is frequently
      arachidonic acid (AA, 5,8,11,14-eicosatetraenoic acid), the precursor of the
      eicosanoid family of potent inflammatory mediators that includes prostaglandins,
      thromboxanes, leukotrienes and lipoxins. Multiple PLA(2) enzymes are active
      within and surrounding the cell and these enzymes have distinct, but
      interconnected roles in AA release.

PMID- 12401194
TI  - Biological effects of group IIA secreted phosholipase A(2).
AB  - Group IIA secreted phospholipase A(2) (sPLA(2)-IIA) is the most abundant element
      in human tissues of a large family of low molecular weight phospholipases A(2),
      which shows properties different from those displayed by the cytosolic
      phospholipase A(2) involved in the release of arachidonic acid. sPLA(2)-IIA
      behaves as a ligand for a group of receptors inside the C-type multilectin
      mannose receptor family and also interacts with heparan sulfate proteoglycans
      such as glypican, the dermatan/chondroitin sulfate-rich decorin, and the
      chondroitin sulfate-rich versican, thus being able to internalize to specific
      compartments within the cell and producing biological responses. This review
      provides a short summary of the biological actions of sPLA(2)-IIA on
      intracellular signaling pathways.

PMID- 12401195
TI  - Expression and function of phospholipase A(2) in brain.
AB  - Phospholipase A(2) (PLA(2)) appears to play a fundamental role in cell injury in
      the central nervous system. We have investigated PLA(2) expression in the
      astrocytoma cell line 1231N1, and found that GIVA, GIVB, GIVC and GVI PLA(2)
      messages are expressed. PLA(2) activity is increased by inflammatory/injury
      stimuli such as interleukin-1beta and lipopolysaccharide in these cells but with
      very different time courses. The arachidonic acid liberated is converted to
      prostaglandin E(2), possibly by cyclooxygenase-2, which is induced by
      inflammatory stimuli. This cell system emerges as a model to study
      injury/inflammation-related activation of the new PLA(2) forms GIVB and GIVC.

PMID- 12401196
TI  - Role of caspases in TNF-mediated regulation of cPLA(2).
AB  - A major part of the proinflammatory activity of tumor necrosis factor (TNF) is
      brought about by cytosolic phospholipase A(2) (cPLA(2)) that generates
      arachidonic acid, the precursor for the production of leukotrienes and
      prostaglandins. The activation of cPLA(2) and induction of proinflammatory lipid
      mediators is in striking contrast to the teleologic meaning of apoptosis, which
      is to avoid an inflammatory reaction. In this review we highlight the evidence
      for a caspase-mediated cleavage and inactivation of cPLA(2), which seems to be an
      important mechanism by which TNF downregulates cPLA(2) activity in cells
      undergoing apoptosis.

PMID- 12401197
TI  - Biophysical mechanisms of phospholipase A2 activation and their use in liposome
      based drug delivery.
AB  - Secretory phospholipase A2 (PLA2) is a ubiquitous water-soluble enzyme found in
      venom, pancreatic, and cancerous fluid. It is also known to play a role in
      membrane remodeling processes as well as in cellular signaling cascades. PLA2 is
      interfacially active and functions mainly on organized types of substrate, e.g.
      micelles and lipid bilayers. Hence the activity of the enzyme is modulated by the
      lateral organization and the physical properties of the substrate, in particular
      the structure in the nanometer range. The evidence for nano-scale structure and
      lipid domains in bilayers is briefly reviewed. Results obtained from a variety of
      experimental and theoretical studies of PLA2 activity on lipid-bilayer substrates
      are then presented which provide insight into the biophysical mechanisms of PLA2
      activation on lipid bilayers and liposomes of different composition. The insight
      into these mechanisms has been used to propose a novel principle for liposomal
      drug targeting, release, and absorption triggered by secretory PLA2.

PMID- 12401198
TI  - Multiple roles of pleckstrin homology domains in phospholipase Cbeta function.
AB  - Since their discovery almost 10 years ago pleckstrin homology (PH) domains have
      been identified in a wide variety of proteins. Here, we focus on two proteins
      whose PH domains play a defined functional role, phospholipase C (PLC)-beta(2)
      and PLCdelta(1). While the PH domains of both proteins are responsible for
      membrane targeting, their specificity of membrane binding drastically differs.
      However, in both these proteins the PH domains work to modulate the activity of
      their catalytic core upon interaction with either phosphoinositol lipids or G
      protein activators. These observations show that these PH domains are not simply
      binding sites tethered onto their host enzyme but are intimately associated with
      their catalytic core. This property may be true for other PH domains.

PMID- 12401199
TI  - Membrane properties of sphingomyelins.
AB  - Sphingomyelin and phosphatidylcholine are important components in the external
      leaflet of cellular plasma membranes. In this review we compare the structure of
      these lipid molecules, with emphasis on the differences in hydrogen bonding
      capacity and membrane properties that arise from the small but significant
      differences in molecular structure. The membrane properties of sphingomyelins and
      the implications that these have, or might have, in biological membranes and for
      raft function are further discussed.

PMID- 12401200
TI  - Sphingomyelinases: enzymology and membrane activity.
AB  - This paper reviews our present knowledge of sphingomyelinases as enzymes, and as
      enzymes acting on a membrane constituent lipid, sphingomyelin. Six types of
      sphingomyelinases are considered, namely acidic, secretory, Mg(2+)-dependent
      neutral, Mg(2+)-independent neutral, alkaline, and bacterial enzymes with both
      phospholipase C and sphingomyelinase activity. Sphingomyelinase assay methods and
      specific inhibitors are reviewed. Kinetic and mechanistic studies are summarized,
      a kinetic model and a general-base catalytic mechanism are proposed.
      Sphingomyelinase-membrane interactions are considered from the point of view of
      the influence of lipids on the enzyme activity. Moreover, effects of
      sphingomyelinase activity on membrane architecture (increased membrane
      permeability, membrane aggregation and fusion) are described. Finally, a number
      of open questions on the above topics are enunciated.

PMID- 12401201
TI  - Role of sphingomyelinase and ceramide in modulating rafts: do biophysical
      properties determine biologic outcome?
AB  - Recent biophysical data suggest that the properties of ceramide observed in model
      membranes may apply to biological systems. In particular, the ability of ceramide
      to form microdomains, which coalesce into larger platforms or macrodomains,
      appears to be important for some cellular signaling processes. Several
      laboratories have now demonstrated similar reorganization of plasma membrane
      sphingolipid rafts, via ceramide generation, into macrodomains. This event
      appeared necessary for signaling upon activation of a specific set of cell
      surface receptors. In this article, we review the properties and functions of
      rafts, and the role of sphingomyelinase and ceramide in the biogenesis and re
      modeling of these rafts. As clustering of some cell surface receptors in these
      domains may be critical for signal transduction, we propose a new model for
      transmembrane signal transmission.

PMID- 12401202
TI  - Sphingosine-1-phosphate: dual messenger functions.
AB  - The sphingolipid metabolite sphingosine-1-phosphate (S1P) is a serum-borne lipid
      that regulates many vital cellular processes. S1P is the ligand of a family of
      five specific G protein-coupled receptors that are differentially expressed in
      different tissues and regulate diverse cellular actions. Much less is known of
      the intracellular actions of S1P. It has been suggested that S1P may also
      function as an intracellular second messenger to regulate calcium mobilization,
      cell growth and suppression of apoptosis in response to a variety of
      extracellular stimuli. Dissecting the dual actions and identification of
      intracellular targets of S1P has been challenging, but there is ample evidence to
      suggest that the balance between S1P and ceramide and/or sphingosine levels in
      cells is an important determinant of cell fate.

PMID- 12401203
TI  - Regulation of phospholipase D.
AB  - Structural studies of plant and bacterial members of the phospholipase D (PLD)
      superfamily are providing information about the role of the conserved HKD domains
      in the structure of the catalytic center and the catalytic mechanism of mammalian
      PLD isozymes (PLD1 and PLD2). Mutagenesis and sequence comparison studies have
      also defined the presence of pleckstrin homology and phox homology domains in the
      N-terminus and have demonstrated that a conserved sequence at the C-terminus is
      required for catalysis. The N- and C-terminal regions of PLD1 also contain
      interaction sites for protein kinase C, which can directly activate the enzyme
      through a non-phosphorylating mechanism. Small G proteins of the Rho and ADP
      ribosylation factor families also directly regulate the enzyme, with RhoA binding
      to a sequence in the C-terminus. Certain tyrosine kinases and members of the Ras
      subfamily of small G proteins can activate the enzyme, but the mechanisms appear
      to be indirect. The mechanisms by which agonists activate PLD in vivo probably
      involve multiple pathways.

PMID- 12401204
TI  - The regulation of phospholipase D by inositol phospholipids and small GTPases.
AB  - Phospholipase D1 and D2 (PLD1, PLD2) both have PX and PH domains in their N
      terminal regions with these inositol lipid binding domains playing key roles in
      regulating PLD activity and localisation. The activity of PLD1 is also regulated
      by protein kinase C and members of the Rho and Arf families of GTPases. Each of
      these proteins binds to unique sites; however, there appears to be little in
      vitro discrimination between individual family members. In agonist-stimulated
      cells, however, there is specificity, with, for example in RBL-2H3 cells, antigen
      stimulating the activation of PLD1 by association with Arf6, Rac1 and protein
      kinase Calpha. PLD2 appears to be less directly regulated by GTPases and rather
      is primarily controlled through interaction with phosphatidylinositol 4-phosphate
      5-kinase that generates the activating phosphatidylinositol 4,5-bisphosphate.

PMID- 12401205
TI  - The role of phosphatidic acid in the regulation of the Ras/MEK/Erk signaling
      cascade.
AB  - Phosphatidic acid (PA) is an important second messenger produced by the
      activation of numerous cell surface receptors. Recent data have suggested that PA
      regulates multiple cellular processes. This review addresses primarily the role
      of PA in the regulation of the Erk1/2 cascade pathway. A model for the regulation
      of Erk1/2 phosphorylation by cell surface receptors is presented. According to
      this model, agonists stimulate the binding of GTP to Ras and the activation of
      phospholipase D to generate phosphatidic acid. PA promotes the binding of cRaf-1
      kinase to the membrane, where it interacts with Ras.GTP and other regulatory
      components of the pathway. Ras-Raf complexes remain bound to the surface of
      endosomes, where scaffolding complexes involving Ras, cRaf-1, MEK and Erk are
      formed. Complete activation and coupling of the cascade requires endocytosis, a
      process that is also modulated by PA.

PMID- 12401206
TI  - The structure of phosphatidylinositol transfer protein alpha reveals sites for
      phospholipid binding and membrane association with major implications for its
      function.
AB  - Elucidation of the three-dimensional structure of phosphatidylinositol transfer
      protein alpha (PI-TPalpha) void of phospholipid revealed a site of membrane
      association connected to a channel for phospholipid binding. Near the top of the
      channel specific binding sites for the phosphorylcholine and phosphorylinositol
      head groups were identified. The structure of this open form suggests a mechanism
      by which PI-TPalpha preferentially binds PI from a membrane interface. Modeling
      predicts that upon association of PI-TPalpha with the membrane the inositol
      moiety of bound PI is accessible from the medium. Upon release from the membrane
      PI-TPalpha adopts a closed structure with the phospholipid bound fully
      encapsulated. This structure provides new insights as to how PI-TPalpha may play
      a role in PI metabolism.

PMID- 12401207
TI  - Current thoughts on the phosphatidylinositol transfer protein family.
AB  - Monomeric transport of lipids is carried out by a class of proteins that can
      shield a lipid from the aqueous environment by binding the lipid in a hydrophobic
      cavity. One such group of proteins is the phosphatidylinositol transfer proteins
      (PITP) that can bind phosphatidylinositol and phosphatidylcholine and transfer
      them from one membrane compartment to another. PITPs are found in both
      unicellular and multicellular organisms but not bacteria. In mice and humans, the
      PITP domain responsible for lipid transfer is found in five proteins, which can
      be classified into two classes based on sequence. Class I PITPs comprises two
      family members, alpha and beta, small 35 kDa proteins with a single PITP domain
      which are ubiquitously expressed. Class IIA PITPs (RdgBalphaI and II) are larger
      proteins possessing additional domains that target the protein to membranes and
      are only able to bind lipids but not mediate transfer. Finally, Class IIB PITP
      (RdgBbeta) is similar to Class I in size (38 kDa) and is also ubiquitously
      expressed. Class III PITPs, exemplified by the Sec14p family, are found in yeast
      and plants but are unrelated in sequence and structure to Class I and Class II
      PITPs. In this review we discuss whether PITP proteins are passive transporters
      or are regulated proteins that are able to couple their transport and binding
      properties to specific biological functions including inositol lipid signalling
      and membrane turnover.

PMID- 12401208
TI  - Dynamics of plasma membrane microdomains and cross-talk to the insulin signalling
      cascade.
AB  - The critical role of the heterogeneous nature of cellular plasma membranes in
      transmembrane signal transduction has become increasingly appreciated during the
      past decade. Areas of relatively disordered, loosely packed phospholipids are
      disrupted by hydrophobic detergent/carbonate-insoluble glycolipid-enriched raft
      microdomains (DIGs) of highly ordered (glyco)sphingolipids and cholesterol. DIGs
      exhibit low buoyant density and are often enriched in
      glycosylphosphatidylinositol-anchored plasma membrane proteins (GPI proteins),
      dually acylated signalling proteins, such as non-receptor tyrosine kinases
      (NRTKs), and caveolin. At least two types of DIGs, hcDIGs and lcDIGs, can be
      discriminated on basis of higher and lower content, respectively, of these
      typical DIGs components. In quiescent differentiated cells, GPI proteins and
      NRTKs are mainly associated with hcDIGs, however, in adipose cells certain
      insulin-mimetic stimuli trigger redistribution of subsets of GPI proteins and
      NRTKs from hcDIGs to lcDIGs. Presumably, these stimuli induce displacement of GPI
      proteins from a GPI receptor located at hcDIGs whereas simultaneously NRTKs
      dissociate from a complex with caveolin located at hcDIGs, too. NRTKs are thereby
      activated and, in turn, modulate intracellular signalling pathways, such as
      stimulation of metabolic insulin signalling in insulin-sensitive cells. The
      apparent dynamics of DIGs may provide a target mechanism for regulating the
      activity of lipid-modified signalling proteins by small drug molecules, as
      exemplified by the sulfonylurea, glimepiride, which lowers blood glucose in an
      insulin-independent fashion, in part.

PMID- 12401209
TI  - Glycosphingolipid-dependent cross-talk between glycosynapses interfacing tumor
      cells with their host cells: essential basis to define tumor malignancy.
AB  - Status of tumor progression (either remaining in situ, or becoming
      invasive/metastatic) may be defined largely by subtle interactions ('cross-talk')
      in a microenvironment formed by interfacing tumor cell and host cell membrane
      domains (termed 'glycosynapses') involved in glycosylation-dependent cell
      adhesion and signaling. Functional roles of tumor-associated gangliosides,
      organized in glycosynapses of three types of tumor cell lines, are discussed.
      Gangliosides function as adhesion receptors or as 'sensors' that can be
      stimulated by antibodies, with consequent activation of signal transducers
      leading to enhanced motility and invasiveness.

PMID- 12401210
TI  - Monosialyl-Gb5 organized with cSrc and FAK in GEM of human breast carcinoma MCF-7
      cells defines their invasive properties.
AB  - Two human mammary carcinoma cell variants, MCF-7/AZ and MCF-7/6, show the same
      composition in their glycosphingolipid-enriched microdomain (GEM) with regard to
      globo-series structures Gb3, Gb4, Gb5, monosialyl-Gb5, GM2, and cSrc and FAK.
      Both variants are non-invasive into collagen gel layer, and showed similar
      motility in wound migration assay. Whereas invasiveness and motility of MCF-7/AZ
      cells were enhanced greatly by treatment with mAb RM1 directed to monosialyl-Gb5,
      the same RM1 treatment had no effect on MCF-7/6. cSrc and FAK of MCF-7/AZ, but
      not MCF-7/6, were activated by RM1 treatment. Thus, malignancy of MCF-7 is highly
      dependent on monosialyl-Gb5, and its activation of cSrc and FAK in GEM.

PMID- 12401211
TI  - Tandem genomic arrangement of a G protein (Gna15) and G protein-coupled receptor
      (s1p(4)/lp(C1)/Edg6) gene.
AB  - A genomic analysis of the s1p(4)/lp(C1)/Edg6 mouse sphingosine-1-phosphate (S1P)
      G protein-coupled receptor gene revealed it to be located on central chromosome
      10 and to consist of two exons with an intronless coding region. Surprisingly, we
      found the gene encoding the promiscuously coupling G(alpha15) protein (Gna15)
      located in tandem just upstream, an arrangement conserved in the human genome (on
      chromosome 19p13.3). Given that Northern blots demonstrated similar tissue
      distributions of the mouse s1p(4) and Gna15 transcripts, we propose that
      transcription of the two genes may be under control of the same enhancer elements
      and that their protein products may couple in vivo.

PMID- 12401213
TI  - Accessibility of phosphates in domain I of 23 S rRNA in the ribosomal 50 S
      subunit as detected by R(P) phosphorothioates.
AB  - Recent atomic models of ribosomal structure emphasize the need for new
      biochemical methods, suitable for fine-scale studies of ribosomal structure and
      function. We have used the phosphorothioate approach to probe iodine
      accessibility of 23 S rRNA domain I phosphates inside functional 50 S ribosomal
      subunits. Five percent of R(P) isomers of nucleoside phosphorothioate were
      incorporated into Thermus aquaticus 23 S rRNA during in vitro transcription.
      Ribosomal large subunits were reconstituted from 23 S rRNA and 5 S rRNA
      transcripts and ribosomal large subunit proteins. The resulting particles
      sedimented as 50 S and were active in a peptide bond formation assay. Iodine
      induced cleavage sites were determined for domain I of 23 S rRNA by reverse
      transcriptase-directed primer extension. Specific signals were detected at 360
      positions, 80 of which were protected in reconstituted 50 S subunits. We argue
      that most observed protections are caused by shielding of phosphates by ribosomal
      proteins. The phosphorothioate approach can be extended to analyze dynamic
      structural changes during translation and the functional roles of individual
      chemical groups in rRNA.

PMID- 12401212
TI  - Embryonic brain expression analysis of lysophospholipid receptor genes suggests
      roles for s1p(1) in neurogenesis and s1p(1-3) in angiogenesis.
AB  - In a comparison of embryonic brain expression patterns of lysophosphatidic acid
      and sphingosine 1-phosphate receptor genes (lpa(1-3) and s1p(1-5), respectively),
      transcripts detected by Northern blot were subsequently localized using in situ
      hybridization. We found striking s1p(1) expression adjacent to several
      ventricles. Near the lateral ventricle, s1p(1) expression was temporally and
      spatially coincident with neurogenesis and overlapped with lpa(1) in the
      neocortical area. We also observed a widespread diffuse pattern for lpa(2-3) and
      a scattered punctate pattern for s1p(1-3). The punctate pattern colocalized with
      vascular endothelial markers. Together, these results suggest that s1p(1)
      influences neurogenesis and s1p(1-3) influence angiogenesis in the developing
      brain.

PMID- 12401214
TI  - Two light-responsive elements of pea chloroplastic fructose-1,6-bisphosphatase
      gene involved in the red-light-specific gene expression in transgenic tobaccos.
AB  - The pea chloroplast fructose-1,6-bisphosphatase (FBPase) gene was cloned from a
      pea genomic library and sequenced. The gene contained three introns and four
      exons. Both in vitro and in vivo analyses of the promoter region of the gene were
      carried out simultaneously to elucidate the mechanisms of light-mediated gene
      expression. Two light-responsive elements were identified in gel mobility shift
      assays: a GT-1-like sequence for the binding of a GT-1-like factor (termed pea
      factor 1; PF1) and a binding site for a dark-specific factor (termed pea factor
      2; PF2). The binding affinity of PF1 was higher in light-grown peas than in dark
      grown peas and was affected by phosphorylation. The binding site was located at
      nucleotides (nt) -326 to -341. PF2 binding was dark-specific and the binding
      region was located upstream of the PF1-binding site (nt -492 to -412). In vivo
      experiments with transgenic tobacco plants suggested that the region between nt 
      411 and -272 contained a PF1-binding site that promoted light-mediated expression
      of the pea chloroplast FBPase. In contrast, the 81-bp region between nt -492 and 
      412, which is located further upstream than the PF1-binding site, negatively
      regulated light-mediated expression of FBPase. Moreover, activation of gene
      expression by the region (nt -411 to -272) contained a PF1-binding site that was
      sensitive to red-light irradiation, suggesting that the expression of the
      chloroplast FBPase was regulated by the phytochrome system. Interestingly, the
      binding region for the dark-specific factor (PF2; nt -492 to -412) not only
      repressed gene expression in the dark, but also acted as a light-dependent
      activating element of the chloroplast FBPase gene.

PMID- 12401215
TI  - Cloning and characterization of WDR17, a novel WD repeat-containing gene on
      chromosome 4q34.
AB  - As part of our project to generate a catalogue of genes with potential relevance
      to human retinal disease, we have cloned a transcript abundantly expressed in the
      human retina and testis. Analysis of the deduced 1322 amino acid protein sequence
      demonstrates that it encodes a novel WD repeat protein, termed WDR17. The N
      terminal moiety of the WDR17 protein is predicted to consist of at least 12
      conserved WD repeats that likely adopts a beta-propeller-like structure. Homology
      searches with the C-terminal region revealed no similarity to known or
      hypothetical proteins. However, putative orthologous ESTs with 82-91% identity to
      the human cDNA were found in several mammalian species including rodents, pig and
      cattle, suggesting that WDR17 represents an evolutionarily novel subtype of WD
      repeat proteins with unique function(s) in higher eukaryotes. Temporal expression
      analysis in the murine eye showed that transcription of WDR17 begins prenatally,
      suggesting a functional role of the protein in the early stages of retinal
      development. Human WDR17 maps to the same chromosomal interval as the locus for
      autosomal recessive retinitis pigmentosa (RP29) on 4q34, making it a candidate
      for this disease gene. Sequencing of the entire coding region of WDR17 in an
      affected patient of the original RP29 pedigree has not revealed any disease
      causing sequence variations likely excluding WDR17 as the gene underlying RP29.

PMID- 12401216
TI  - Regulation of carotenoid biosynthesis genes in response to light in Chlamydomonas
      reinhardtii.
AB  - Carotenoids are ubiquitous and essential components of photosynthetic tissues in
      plants, algae and cyanobacteria. They participate in the light harvesting process
      and prevent photooxidative damage of the photosynthetic apparatus. Although de
      etiolation and growth under different light conditions were reported to have
      pronounced effects on carotenoid contents in higher plants and algae, very little
      is known about the light regulation of carotenogenesis on a molecular level. In
      the present study, we chose the unicellular green alga Chlamydomonas reinhardtii
      to investigate the regulation of carotenoid biosynthesis genes in response to
      light. The carotenoid genes phytoene synthase and phytoene desaturase were
      selected for gene expression studies. Both phytoene synthase and phytoene
      desaturase revealed a fast up-regulation in response to light, which seemed to be
      due to transcriptional control. Only blue light was effective whereas
      illumination with red light did not lead to elevated transcript levels of
      phytoene synthase and phytoene desaturase. The inhibition of photosynthesis did
      not abolish the light induction of carotenoid genes. Comparison with published
      results showed that the carotenoid genes are simultaneously expressed with other
      genes involved in chlorophyll biosynthesis and light harvesting. This
      simultaneous expression may represent one mechanism for the coordinated
      biosynthesis of carotenoids, chlorophylls and the proteins of the photosynthetic
      apparatus.

PMID- 12401217
TI  - Gluconeogenic enzyme gene expression is decreased by dietary carbohydrates in
      common carp (Cyprinus carpio) and gilthead seabream (Sparus aurata).
AB  - Our objective is to understand the low metabolic utilization of dietary
      carbohydrates in fish. We compared the regulation of gluconeogenic enzymes at a
      molecular level in two fish species, the common carp (Cyprinus carpio) and
      gilthead seabream (Sparus aurata), known to be relatively tolerant to dietary
      carbohydrates. After cloning of partial cDNA sequences for three key
      gluconeogenic enzymes (glucose-6-phosphatase (G6Pase), fructose biphosphatase
      (FBPase) and phosphoenolpyruvate carboxykinase (PEPCK) in the two species, we
      analyzed gene expressions of these enzymes 6 and 24 h after feeding with (20%) or
      without carbohydrates. Our data show that there is at least one gluconeogenic
      enzyme strongly regulated (decreased expression after feeding) in the two fish
      species, i.e. the PEPCK for common carp and G6Pase/FBPase for gilthead seabream.
      In these fish species, the regulation seems to be similar to the mammals at least
      at the molecular level.

PMID- 12401218
TI  - Effects of phosphate deficiency and sugars on expression of rab18 in Arabidopsis:
      hexokinase-dependent and okadaic acid-sensitive transduction of the sugar signal.
AB  - The lack of phosphorus in the nutrient medium increased the expression of rab18,
      an abscisic acid (ABA)-responsive gene, in leaves of Arabidopsis thaliana. The
      expression of this gene was also upregulated after feeding the excised leaves
      with D-mannose and sucrose for both wild-type (wt) and aba1 (ABA-deficient)
      mutant plants. For aba1 mutants, both the phosphate deficiency and sugar effects
      on rab18 were weaker than in wt plants, suggesting possible involvement of both
      ABA-dependent and ABA-independent components in signalling. Transgenic
      Arabidopsis plants with increased hexokinase (HXK) expression had a much higher
      sucrose-dependent level of rab18 mRNA, implying the HXK involvement in
      sensing/transmitting the sugar signal. Sucrose-related induction of rab18 was
      completely inhibited by okadaic acid (OKA), suggesting the involvement of
      specific protein phosphatase(s) in transduction of the sugar signal. The results
      suggest that rab18 is regulated via interaction of a plethora of signals,
      including ABA, sugar and phosphate deficiency, and that the sugar effect is
      transmitted via a HXK-pathway, involving OKA-sensitive component(s). The findings
      prompt caution in linking the expression of rab18 solely to ABA signalling.

PMID- 12401219
TI  - Isolation and characterization of chicken GA-binding protein.
AB  - We have purified and characterized chicken liver nuclear proteins that bind to
      Ets binding sites (EBSs) of ribosomal protein (r-protein) gene promoters. We
      employed supershift assays and antibodies to mouse GA binding protein (GABP), to
      show that the proteins were similar to alpha and beta subunits of GABP. Western
      blot analysis identified 54- and 38-kDa proteins as the alpha type, and a 46-kDa
      protein as the beta type. When compared with nuclear extracts (NEs) of other
      species, we observed that the 38-kDa protein was unique to chicken, and appears
      to be derived from the 54-kDa protein. The 54- and 46-kDa proteins were highly
      expressed in chicken tissues and were major components through higher animals,
      indicating that both proteins have a conserved role.

PMID- 12401220
TI  - Characterization of the flgG operon of Rhodobacter sphaeroides WS8 and its role
      in flagellum biosynthesis.
AB  - In this work, we show evidence regarding the functionality of a large cluster of
      flagellar genes in Rhodobacter sphaeroides. The genes of this cluster, flgGHIJKL
      and orf-1, are mainly involved in the formation of the basal body, and flgK and
      flgL encode the hook-associated proteins HAP1 and HAP3. In general, these genes
      showed a good similarity as compared with those reported for Salmonella enterica.
      However, flgJ and flgK showed particular features that make them unique among the
      flagellar sequences already reported. flgJ is only a third of the size reported
      for flgJ from Salmonella; whereas flgK is about three times larger than any other
      flgK sequence previously known. Our results indicate that both genes are
      functional, and their products are essential for flagellar assembly. In contrast,
      the interruption of orf-1, did not affect motility suggesting that this sequence,
      if functional, is not indispensable for flagellar assembly. Finally, we present
      genetic evidence suggesting that the flgGHIJKL genes are expressed as a single
      transcriptional unit depending on the sigma-54 factor.

PMID- 12401221
TI  - AhSL28, a senescence- and phosphate starvation-induced S-like RNase gene in
      Antirrhinum.
AB  - Several species of higher plants have been found to contain S-like ribonucleases
      (RNases), which are homologous to S-RNases controlling self-incompatibility. No S
      like RNase genes have been isolated from self-incompatible Antirrhinum. To
      investigate the relationship between S- and S-like RNases, we cloned a gene named
      AhSL28 encoding an S-like RNase in Antirrhinum. Amino acid sequence, genomic
      structure and phylogenetic analyses indicated that AhSL28 is most similar to
      RNS2, an S-like RNase from Arabidopsis thaliana and formed a distinct subclass
      together with several other S-like RNases within the S-RNase superfamily. Unlike
      S-RNase genes in Antirrhinum, AhSL28 is not only expressed in pistils but also in
      leaves, petals, sepals and anthers, in particular, showing a strong expression in
      vascular tissues and transmitting track. Moreover, its RNA transcripts were
      induced during leaf senescence and phosphate (Pi) starvation but not by wounding,
      indicating that AhSL28 plays a role in remobilizing Pi and other nutrients,
      particularly when cells senesce and are under limited Pi conditions in
      Antirrhinum. Possible evolutionary relations of S- and S-like RNases as well as
      signal transduction pathways related to S-like RNase action are discussed.

PMID- 12401222
TI  - Purification strategies for microbial lipases.
AB  - Microbial lipases today occupy a place of prominence among biocatalysts owing to
      their ability to catalyze a wide variety of reactions in aqueous and non-aqueous
      media. The chemo-, regio- and enantio-specific behaviour of these enzymes has
      caused tremendous interest among scientists and industrialists. Lipases from a
      large number of bacterial, fungal and a few plant and animal sources have been
      purified to homogeneity. This has enabled their successful sequence determination
      and their three-dimensional structure leading to a better understanding of their
      unique structure-function relationships during various hydrolytic and synthetic
      reactions. This article presents a critical review of different strategies which
      have been employed for the purification of bacterial, yeast and fungal lipases.
      Since protein purification is normally done in a series of sequential steps
      involving a combination of different techniques, the effect of sequence of steps
      and the number of times each step is used is analyzed. This will prove to be of
      immense help while planning lipase purification. Novel purification technologies
      now available in this field are also reviewed.

PMID- 12401223
TI  - Direct estimate of active bacteria: CTC use and limitations.
AB  - During the last 10 years, the dye 5-cyano-2,3-ditolyl tetrazolium chloride (CTC)
      has been used to determine the in situ number of "active" bacteria in different
      ecosystems. A part of this success is due to a simple protocol, which does not
      require sophisticated equipment. However, it has not been established whether the
      method determines viable cells, e.g. those capable of growth and cell division,
      as opposed to cells that are active in the sense of having some detectable
      metabolic activity. In this study, the number of CTC-positive cells through the
      growth stages of Escherichia coli was estimated and compared to counts of the
      total number of bacteria, the culturability (CFU counts) and respiratory activity
      (CO(2) evolution). There was a good correlation between the number of CTC
      positive cells and the CFU count, regardless of the growth phase. However, CTC
      could still be reduced by a large part of the population during the first hours
      of stationary phase even if the bacteria were no longer releasing CO(2). Thus,
      the reduction of CTC is a good estimator for cell viability, rather than cell
      activity. Additionally, a review of the literature showed that there is presently
      no standardized protocol for using CTC, which makes difficult at present the
      comparison of active bacterial numbers in different samples from different sites.

PMID- 12401224
TI  - Competitive touchdown PCR for estimation of Escherichia coli DNA recovery in soil
      DNA extraction.
AB  - Competitive approaches have shown promise for overcoming some of the difficulties
      in the use of PCR for assessment of specific bacterial species in soil. A
      competitive touchdown PCR (cTD-PCR) protocol specific for the rrsB gene of
      Escherichia coli was developed for tracking the organism in environments impacted
      by human wastes. Regression of product ratios from co-amplification of varying
      amounts of analyte and competitor DNA templates was linear. To test the
      robustness of the method, reactions were titrated with an extract of sterilized
      soil; no significant effect was detected. The cTD-PCR was used to assay recovery
      of E. coli DNA from soil. Stock DNA was spiked onto two sterilized soils during
      extraction, and the purified extracts were analyzed by cTD-PCR. Recovery of DNA
      spiked at a rate of 180 ng g(-1) was 34+/-7% (mean+/-S.D.) for an agricultural
      silt loam. DNA spiked at 1.8 pg g(-1) was recovered at a mean rate of 6.1+/-1.3%.
      DNA in these extracts was not directly quantifiable by image analysis. The cTD
      PCR method provides a useful means of quantifying small amounts of E. coli DNA,
      and could be modified for other specific targets in a mixture of DNA from a
      variety of organisms.

PMID- 12401225
TI  - Optimization of direct cell counting in sediment.
AB  - This study reports a method for optimizing direct counts of bacteria in sediment,
      designed to reduce the masking by sediment particles. The protocol was designed
      to determine appropriate dilution factors by incorporating counting statistics
      and was used to measure depth-associated changes in microbial abundance in metal
      impacted freshwater sediments. We demonstrated a direct method to determine
      appropriate sample dilution for accurate counting by adding a known amount of
      cells to the sediment. For accurate counting in our sediment samples, we
      determined that the average number of bacteria per microscope ocular field must
      be between 8.5 and 10. This is well below the 30 bacteria/field previously
      suggested for accurate counting. These results indicate that an optimal dilution
      rate must be determined before accurate direct counts in sediment can be
      achieved.

PMID- 12401226
TI  - Applicability of tetrazolium salts for the measurement of respiratory activity
      and viability of groundwater bacteria.
AB  - A study was undertaken to measure aerobic respiration by indigenous bacteria in a
      sand and gravel aquifer on western Cape Cod, MA using tetrazolium salts and by
      direct oxygen consumption using gas chromatography (GC). In groundwater and
      aquifer slurries, the rate of aerobic respiration calculated from the direct GC
      assay was more than 600 times greater than that using the tetrazolium salt 2-(4
      iodophenyl)-3-(4-nitrophenyl)-5-phenyl tetrazolium chloride (INT). To explain
      this discrepancy, the toxicity of INT and two additional tetrazolium salts,
      sodium 3'-[1-(phenylamino)-carbonyl]-3,4-tetrazolium]-bis(4-methoxy-6-nitro)
      benzenesulfonic acid hydrate (XTT) and 5-cyano-2,3-ditolyl tetrazolium chloride
      (CTC), to bacterial isolates from the aquifer was investigated. Each of the three
      tetrazolium salts was observed to be toxic to some of the groundwater isolates at
      concentrations normally used in electron transport system (ETS) and viability
      assays. For example, incubation of cells with XTT (3 mM) caused the density of
      four of the five groundwater strains tested to decline by more than four orders
      of magnitude. A reasonable percentage (>57%) of cells killed by CTC and INT
      contained visible formazan crystals (the insoluble, reduced form of the salts)
      after 4 h of incubation. Thus, many of the cells reduced enough CTC or INT prior
      to dying to be considered viable by microscopic evaluation. However, one
      bacterium (Pseudomonas fluorescens) that remained viable and culturable in the
      presence of INT and CTC, did not incorporate formazan crystals into more than a
      few percent of cells, even after 24 h of incubation. This strain would be
      considered nonviable based on traditional tetrazolium salt reduction assays. The
      data show that tetrazolium salt assays are likely to dramatically underestimate
      total ETS activity in groundwater and, although they may provide a reasonable
      overall estimate of viable cell numbers in a community of groundwater bacteria,
      some specific strains may be falsely considered nonviable by this assay due to
      poor uptake or reduction of the salts.

PMID- 12401227
TI  - 5-Cyano-2,3-ditolyl tetrazolium chloride (CTC) reduction in a mesophilic
      anaerobic digester: measuring redox behavior, differentiating abiotic reduction,
      and comparing FISH response as an activity indicator.
AB  - The tetrazolium salt 5-cyano-2,3-ditolyl tetrazolium chloride (CTC) has been
      widely applied to assess microbiological activity in environmental samples. CTC
      reduction has previously been quantified in a variety of anaerobic systems (i.e.,
      fermentative, nitrate reducing, sulfate reducing) using direct microscopy,
      solvent extraction, and flow cytometry. In this work, extracellular CTC reduction
      was observed and distinguished from its intercellular counterparts by the
      amorphous character and near uniform fluorescence of the resulting formazan
      precipitates (CTF). Fluorescence yielded by non-cellular-associated formazan
      precipitates bleached much more rapidly than CTF formed within cells under
      identical UV exposure (<2 min). Dehydrogenase activity assays and fluorescent in
      situ hybridization (FISH) were simultaneously carried out in microcosms
      containing active anaerobic digester biomass, propylene glycol, and settled
      sewage centrate for direct comparison. In substrate limited microcosms,
      quantitative FISH measurements remained well above their detection limit
      indicating sustained intercellular ribosomal RNA concentrations over a 5-day
      period, while dehydrogenase assays (CTC) decreased to background levels within 14
      h of substrate limitation. Results from this work suggest that CTC reduction in
      cell-free samples may impede accurate enzyme activity measurements, particularly
      when quantification involves solvent extraction, flow cytometry, or software
      aided counting. In addition, activity assessment in anaerobic digesters using
      FISH and CTC reduction assays may be comparable until substrate becomes limited.

PMID- 12401228
TI  - Quantitative determination of pneumococcal capsular polysaccharide serotype 14
      using a modification of phenol-sulfuric acid method.
AB  - The capsular polysaccharide of Streptococcus pneumoniae, serotype 14, is part of
      every pneumococcal vaccine presently in the market or under development. A
      strategy for the quantitative determination of this polysaccharide by the phenol
      sulfuric acid method is described. The modality of acid addition is shown to be
      the critical step for obtaining reproducible test results between different
      technicians. Raising the incubation temperature above 80 degrees C increased the
      consistency of the method by more than 60% regardless of the acid addition
      modality, but at the expense of some loss of sensitivity. Incubation at 110
      degrees C was found necessary to obtain reproducible results within 3% for this
      technique, which was used to follow the enrichment of the polysaccharide during
      the last steps of purification. A model mixture of the component polysaccharide
      sugars provided an adequate and economic standard to construct the calibration
      curve for this assay, with absorbance reading either in the reaction tubes or in
      a microplate. A similar procedure may be applied to the determination of other
      bacterial polysaccharides as well.

PMID- 12401229
TI  - CTC staining and counting of actively respiring bacteria in natural stone using
      confocal laser scanning microscopy.
AB  - A method was established for staining and counting of actively respiring bacteria
      in natural stone by using the tetrazolium salt 5-cyano-2,3-ditolyltetrazolium
      chloride (CTC) in combination with confocal laser scanning microscopy (CLSM).
      Applying 5 mM CTC for 2 h to pure cultures of representative stone-inhabiting
      microorganisms showed that chemoorganotrophic bacteria and fungi-in contrast to
      lithoautotrophic nitrifying bacteria-were able to reduce CTC to CTF, the red
      fluorescing formazan crystals of CTC. Optimal staining conditions for
      microorganisms in stone material were found to be 15 mM CTC applied for 24 h. The
      cells could be visualized on transparent and nontransparent mineral materials by
      means of CLSM. A semi-automated method was used to count the cells within the
      pore system of the stone. The percentage of CTC-stained bacteria was dependent on
      temperature and humidity of the material. At 28 degrees C and high humidity
      (maximum water holding capacity) in the laboratory, about 58% of the total
      bacterial microflora was active. On natural stone exposed for 9 years at an urban
      exposure site in Germany, 52-56% of the bacterial microflora was active at the
      east, west, and north side of the specimen, while only 18% cells were active at
      the south side. This is consistent with microclimatic differences on the south
      side which was more exposed to sunshine thus causing UV and water stress as well
      as higher temperatures on a microscale level. In combination with CLSM, staining
      by CTC can be used as a fast method for monitoring the metabolic activity of
      chemoorganotrophic bacteria in monuments, buildings of historic interest or any
      art objects of natural stone. Due to the small size of samples required, the
      damage to these objects and buildings can be minimized.

PMID- 12401230
TI  - A TaqMan-PCR protocol for quantification and differentiation of the
      phytopathogenic Clavibacter michiganensis subspecies.
AB  - Real-time TaqMan-PCR assays were developed for detection, differentiation and
      absolute quantification of the pathogenic subspecies of Clavibacter michiganensis
      (Cm) in one single PCR run. The designed primer pair, targeting intergenic
      sequences of the rRNA operon (ITS) common in all subspecies, was suitable for the
      amplification of the expected 223-nt DNA fragments of all subspecies. Closely
      related bacteria were completely discriminated, except of Rathayibacter iranicus,
      from which weak PCR product bands appeared on agarose gel after 35 PCR cycles.
      Sufficient specificity of PCR detection was reached by introduction of the
      additional subspecies specific probes used in TaqMan-PCR. Only Cm species were
      detected and there was clear differentiation among the subspecies C.
      michiganensis sepedonicus (Cms), C. michiganensis michiganensis (Cmm), C.
      michiganensis nebraskensis (Cmn), C. michiganensis insidiosus (Cmi) and C.
      michiganensis tessellarius (Cmt). The TaqMan assays were optimized to enable a
      simultaneous quantification of each subspecies. Validity is shown by comparison
      with cell counts.

PMID- 12401231
TI  - Direct random insertion mutagenesis of Helicobacter pylori.
AB  - Random insertion mutagenesis is a widely used technique for the identification of
      bacterial virulence genes. Most strategies for random mutagenesis involve cloning
      in Escherichia coli for passage of plasmids or for phenotypic selection. This can
      result in biased selection due to restriction or instability of the cloned DNA,
      or toxicity of the encoded products. We therefore created two mutant libraries in
      the human pathogen Helicobacter pylori using a simple, direct mutagenesis
      technique, which does not require E. coli as intermediate. H. pylori total DNA
      was digested, circularized and digested again with a frequently cutting
      restriction enzyme, and the resulting fragments were ligated to a kanamycin
      antibiotic resistance cassette. Subsequently, the ligation mixture was
      transformed into the parental H. pylori strain 1061. Insertion of the kanamycin
      cassette by double homologous recombination into the genome of H. pylori 1061
      resulted in approximately 2500 kanamycin resistant colonies. Heterogeneity of
      kanamycin cassette insertion was confirmed by Southern blotting. The isolation of
      two independent H. pylori mutants defective in production of urease from this
      library underlines the potential of this mutagenesis strategy.

PMID- 12401232
TI  - Assessment of fluorescent-labeled bacteria for evaluation of in vivo uptake of
      bacteria (Vibrio spp.) by crustacean larvae.
AB  - Available methods to study crustacean digestive tract colonization by bacteria
      are laborious, time-consuming, and do not permit in vivo assays and observation.
      This paper reports on a rapid and consistent technique to apply a fluorescent
      label to bacteria, which can then be presented to filter-feeding crustacea such
      as Artemia and penaeid larvae for later in situ bacterial distribution
      observation. Three luminescent Vibrio spp. were stained and observed inside
      Artemia nauplii, shrimp zoea and mysis stages, Vibrio harveyi type strain ATCC
      14126, M(1) (pathogenic) and Ea (non-pathogenic). Factors such as dye (DTAF)
      concentration, exposure time/temperature and sonication time were evaluated.
      Viability of the dye and stained bacteria were tested at 4, -20 and -70 degrees C
      storage temperatures for up to 81 days. Results show that 4 and -20 degrees C
      storage temperatures are not recommended. At -70 degrees C, both bacteria and dye
      are optimally preserved. Monodispersed fluorescent-labeled bacterial cells can be
      observed inside the digestive tract of crustacean larvae at a density of
      inoculation as high as 5.2 x 10(6) CFU ml(-1). After 2 to 4 h, some leaching
      occurs, increasing difficulty in observation, although after 24 h, it is still
      possible to observe monodispersed FLB inside the digestive tract of crustacean
      larvae. Autofluorescence may complicate observation when filter-feeding
      crustacean larvae are co-fed with microalgae.

PMID- 12401233
TI  - Evaluation of exudates by solid phase microextraction-gas chromatography.
AB  - Head-space solid phase microextraction combined with gas chromatography (SPME-GC)
      was used for the determination of bacterial volatile fatty acid (VFA) patterns.
      The method was validated with cultures of reference bacterial strains. It was
      confirmed that VFA production depends on the composition of the cultivation
      medium, which limits accurate characterisation of particular bacterial species. A
      set of 195 clinical exudates of various origin and consistence was analysed using
      SPME-GC and compared with 73 samples extracted using tert-butyl methyl ether.
      Approximate agreement of VFA profiles with cultivation findings was found in most
      cases. However, 20.5% of clinical exudates with distinct VFA profiles appeared to
      be false-negative by cultivation. Using SPME-GC of exudates, the frequency of
      false-negative cultivations was higher than that of solvent extraction of
      exudates or blood cultures found previously. The described method is suitable for
      preliminary detection of bacteria, particularly non-sporulating anaerobes, in
      clinical samples. It can reveal false-negative findings due to cultivation.
      Analysis can be performed in 30 min without the need for cultivation.

PMID- 12401234
TI  - Application of the fluorogenic probe technique (TaqMan PCR) to the detection of
      Enterococcus spp. and Escherichia coli in water samples.
AB  - A recent PCR detection technique (TaqMan) based on the 5'-3'-exonuclease activity
      of the Taq DNA polymerase was applied to the detection of indicator organisms in
      water samples. In this technique, an increasing fluorescence signal is measured
      online which enables direct assessment of results after PCR without additional
      detection steps. The test is completed within about 5 h. Two sets of primers and
      probes were designed and tested: a genus-specific assay for the detection of
      Enterococcus spp. based on 23S rRNA sequence and an Escherichia coli-specific
      assay based on the uidA gene sequence. Specificity of the assays was confirmed by
      testing strains of target bacteria and potential interfering microorganisms.
      Application of the tests to 55 natural water samples showed the need of an
      overnight enrichment step to achieve compliance with detection limits of existing
      regulations. Compared with a parallel microbiological examination of the samples,
      agreement was 96% with the Enterococcus assay and 98% with the E. coli assay. The
      rapidity and feasibility of the method point to benefits in drinking water
      analysis, particularly in emergency situations and, thus, to improved public
      health management.

PMID- 12401235
TI  - Application of the novel fluorescent dye Beljian red to the differentiation of
      Giardia cysts.
AB  - Beljian red (BR) is a novel long Stokes shift fluorescent dye that fluoresces
      orange when illuminated with UV or blue light. Due to its long Stokes shift, and
      the fact that it is excitable at 488 nm, BR has particular utility in multi
      colour applications with short Stokes shift fluorophores such as fluorescein.
      Here we have demonstrated that BR can be used to discriminate Giardia cysts
      seeded into water samples from those naturally present in the sample. We show
      that the dye does not interfere with other staining methods such as DAPI, and is
      compatible with mAb-FITC staining in a multi-colour fluorescence technique. This
      should be useful in determining the specific recovery of protozoan parasites from
      environmental samples.

PMID- 12401236
TI  - Combined use of the fully automated Bactec MGIT 960 system and a PCR-restriction
      fragment length polymorphism analysis for routine detection and identification of
      mycobacteria from clinical samples.
AB  - The combined use of Bactec MGIT 960 system and a PCR-Restriction Fragment Length
      Polymorphism (PCR-RFLP) analysis was assessed for the rapid detection and
      identification of mycobacteria from clinical samples. The diagnostic sensitivity
      and the time of detection of MGIT 960 system were significantly higher than of
      Lowenstein-Jensen medium. PCR-RFLP identification analysis results were in
      concordance with those obtained by the conventional biochemical tests.

PMID- 12401237
TI  - Generation of disruption cassettes in vivo using a PCR product and Saccharomyces
      cerevisiae.
AB  - A method to obtain disruption cassettes based on the homologous recombination in
      Saccharomyces cerevisiae is described. The disruption marker is amplified by PCR
      using oligonucleotides containing 50 bp homologous to the disruptable gene and 20
      bp from the marker. The PCR product is cotransformed into yeast with a plasmid
      containing the gene. After recombination, a plasmid that carries the disruption
      cassette for the gene is produced.

PMID- 12401238
TI  - New leadership for the FDA.

PMID- 12401239
TI  - Cardiopulmonary mortality and air pollution.

PMID- 12401240
TI  - Gene therapy for SCID--a complication after remarkable progress.

PMID- 12401241
TI  - Barriers to HIV testing--where next?

PMID- 12401242
TI  - Measuring microvascular blood flow in sepsis--a continuing challenge.

PMID- 12401243
TI  - From Demetrius to Serageldin.

PMID- 12401244
TI  - Early administration of intravenous magnesium to high-risk patients with acute
      myocardial infarction in the Magnesium in Coronaries (MAGIC) Trial: a randomised
      controlled trial.
AB  - BACKGROUND: The benefits of supplemental administration of intravenous magnesium
      in patients with ST-elevation myocardial infarction (STEMI) are controversial.
      Despite promising results from work in animals and the ready availability of this
      simple, inexpensive treatment, conflicting results have been reported in clinical
      trials. Our aim was to compare short-term mortality in patients with STEMI who
      received either intravenous magnesium sulphate or placebo. METHODS: We did a
      randomised, double-blind trial in 6213 patients with acute STEMI who were
      assigned a 2 g intravenous bolus of magnesium sulphate administered over 15 min,
      followed by a 17 g infusion of magnesium sulphate over 24 h (n=3113), or matching
      placebo (n=3100). Our primary endpoint was 30-day all-cause mortality. At
      randomisation, patients were stratified by their eligibility for reperfusion
      therapy. The first stratum included patients who were aged 65 years or older and
      eligible for reperfusion therapy, and the second stratum included patients of any
      age who were not eligible for reperfusion therapy. Analysis was by intention-to
      treat. FINDINGS: At 30 days, 475 (15.3%) patients in the magnesium group and 472
      (15.2%) in the placebo group had died (odds ratio 1.0, 95% CI 0.9-1.2, p=0.96).
      No benefit or harm of magnesium was observed in eight prespecified subgroup
      analyses of patients and in 15 additional exploratory subgroup analyses. After
      adjustment for factors shown to effect mortality risk in a multivariate
      regression model, no benefit of magnesium was observed (1.0, 0.8-1.1, p=0.53).
      INTERPRETATION: Early administration of magnesium in high-risk patients with
      STEMI has no effect on 30-day mortality. In view of the totality of the available
      evidence, in current coronary care practice there is no indication for the
      routine administration of intravenous magnesium in patients with STEMI.

PMID- 12401245
TI  - Incidence of Henoch-Schonlein purpura, Kawasaki disease, and rare vasculitides in
      children of different ethnic origins.
AB  - BACKGROUND: The frequency and ethnic variation of Henoch-Schonlein purpura,
      Kawasaki disease, and rarer vasculitides during childhood are not well
      characterised. Our aim was to ascertain the incidence and ethnic distribution of
      these conditions in children resident in a region of the UK with a diverse ethnic
      mix. METHODS: 1.1 million children younger than age 17 years live in the West
      Midlands. Between Sept 1, 1996, and Aug 31, 1999, we surveyed this population
      with monthly questionnaires sent to 321 consultants, a single questionnaire sent
      to 2860 family doctors, and review of 406 case notes with diagnostic codes for
      vasculitis. We included in the analyses children who fulfilled established
      criteria for vasculitis with disease onset during the study, and calculated
      incidence rates from population rates derived from the census of 1991. FINDINGS:
      We identified 586 new instances of vasculitis and connective tissue disease. The
      estimated annual incidence of Henoch-Schonlein purpura was 20.4 per 100000, and
      was highest between the ages of 4 years and 6 years (70.3 per 100000). The
      estimated annual incidence of Kawasaki disease was 5.5 per 100000 in children
      younger than 5 years, and was highest in Indian subcontinent Asian children (14.6
      per 100000). Indian subcontinent Asian and black children had the highest
      incidence of systemic lupus erythematosus, juvenile dermatomyositis, and other
      primary systemic vasculitides. INTERPRETATION: Childhood Henoch-Schonlein purpura
      is more frequent in the West Midlands than previously reported, and Kawasaki
      disease has a higher incidence than previously indicated in the UK, with the
      highest incidence in Indian subcontinental Asian children. Other vasculitis is
      rare in childhood.

PMID- 12401246
TI  - Association between mortality and indicators of traffic-related air pollution in
      the Netherlands: a cohort study.
AB  - BACKGROUND: Long-term exposure to particulate matter air pollution has been
      associated with increased cardiopulmonary mortality in the USA. We aimed to
      assess the relation between traffic-related air pollution and mortality in
      participants of the Netherlands Cohort study on Diet and Cancer (NLCS), an
      ongoing study. METHODS: We investigated a random sample of 5000 people from the
      full cohort of the NLCS study (age 55-69 years) from 1986 to 1994. Long-term
      exposure to traffic-related air pollutants (black smoke and nitrogen dioxide) was
      estimated for the 1986 home address. Exposure was characterised with the measured
      regional and urban background concentration and an indicator variable for living
      near major roads. The association between exposure to air pollution and (cause
      specific) mortality was assessed with Cox's proportional hazards models, with
      adjustment for potential confounders. FINDINGS: 489 (11%) of 4492 people with
      data died during the follow-up period. Cardiopulmonary mortality was associated
      with living near a major road (relative risk 1.95, 95% CI 1.09-3.52) and, less
      consistently, with the estimated ambient background concentration (1.34, 0.68
      2.64). The relative risk for living near a major road was 1.41 (0.94-2.12) for
      total deaths. Non-cardiopulmonary, non-lung cancer deaths were unrelated to air
      pollution (1.03, 0.54-1.96 for living near a major road). INTERPRETATION: Long
      term exposure to traffic-related air pollution may shorten life expectancy.

PMID- 12401247
TI  - Effect of air-pollution control on death rates in Dublin, Ireland: an
      intervention study.
AB  - BACKGROUND: Particulate air pollution episodes have been associated with
      increased daily death. However, there is little direct evidence that diminished
      particulate air pollution concentrations would lead to reductions in death rates.
      We assessed the effect of air pollution controls--ie, the ban on coal sales--on
      particulate air pollution and death rates in Dublin. METHODS: Concentrations of
      air pollution and directly-standardised non-trauma, respiratory, and
      cardiovascular death rates were compared for 72 months before and after the ban
      of coal sales in Dublin. The effect of the ban on age-standardised death rates
      was estimated with an interrupted time-series analysis, adjusting for weather,
      respiratory epidemics, and death rates in the rest of Ireland. FINDINGS: Average
      black smoke concentrations in Dublin declined by 35.6 mg/m(3) (70%) after the ban
      on coal sales. Adjusted non-trauma death rates decreased by 5.7% (95% CI 4-7,
      p<0.0001), respiratory deaths by 15.5% (12-19, p<0.0001), and cardiovascular
      deaths by 10.3% (8-13, p<0.0001). Respiratory and cardiovascular standardised
      death rates fell coincident with the ban on coal sales. About 116 fewer
      respiratory deaths and 243 fewer cardiovascular deaths were seen per year in
      Dublin after the ban. INTERPRETATION: Reductions in respiratory and
      cardiovascular death rates in Dublin suggest that control of particulate air
      pollution could substantially diminish daily death. The net benefit of the
      reduced death rate was greater than predicted from results of previous time
      series studies.

PMID- 12401248
TI  - Pre-eclampsia and expression of heparin-binding EGF-like growth factor.
AB  - BACKGROUND: Pre-eclampsia is a disorder of pregnancy associated with poor
      extravillous cytotrophoblast invasion and above-normal rates of apoptosis in the
      trophoblast. Heparin-binding epidermal-growth-factor-like growth factor (HB-EGF)
      has strong cytoprotective activity and is an important signalling protein that
      regulates trophoblast invasion during early placentation. We aimed to establish
      whether HB-EGF expression is altered in placentae of pre-eclamptic women.
      METHODS: We assessed the expression of HB-EGF mRNA and protein by in-situ
      hybridisation and immunohistochemical techniques, respectively, in archived
      placental tissues from pregnancies terminated at around 20 weeks of gestation,
      and from women delivering between weeks 19 and 35 of gestation with preterm
      labour, small for gestational age infants, or pre-eclampsia. FINDINGS: HB-EGF
      mRNA and protein were expressed in villous and extravillous cytotrophoblast cells
      up to week 35 of gestation in placentae from women who delivered preterm. Similar
      levels of HB-EGF protein were found in the placentae of women who were not in
      labour. HB-EGF expression was reduced about five-fold (p=0.0001) in pre-eclamptic
      pregnancies. Fetal growth retardation, which has been linked with shallow
      trophoblast invasion and moderate apoptosis, was associated with placentae
      expressing intermediate levels of HB-EGF. INTERPRETATION: In pre-eclampsia,
      deficient HB-EGF signalling during placental development could impair trophoblast
      survival, differentiation, and invasion, leading to poor placental perfusion and
      hypertension.

PMID- 12401249
TI  - A blinding combination.

PMID- 12401250
TI  - Peritoneal fluid, endometriosis, and ciliary beat frequency in the human
      fallopian tube.
AB  - Endometriosis and infertility are known to be associated, but it is unclear
      whether endometriosis causes infertility. We used contrast analogue enhancement
      to study the effect of peritoneal fluid from women with early stage endometriosis
      on the ciliary beat frequency of human fallopian tube epithelium. We obtained
      peritoneal fluid from six women with early stage endometriosis and from six
      fertile women with no evidence of endometriosis to use as controls. Fallopian
      tubes from hysterectomy specimens were collected from 17 women. The difference in
      ciliary beat frequency between fallopian tubes exposed to peritoneal fluids of
      women with and without endometriosis increased with the duration of incubation
      (mean difference at 24 h 1.35 Hz, 95% CI 0.94-1.75, p=0.01). At 24 h, ciliary
      beat frequency was significantly lower in the incubations with peritoneal fluid
      from women with endometriosis than controls (4.29 [0.15] vs 5.64 Hz [0.15],
      respectively, p=0.001). Impairment of ciliary action in women with endometriosis
      might reduce fertility.

PMID- 12401251
TI  - Effects of transmission of Y chromosome AZFc deletions.
AB  - Deletions of specific regions on the Y chromosome cause male infertility. Recent
      advances in infertility treatment allow Y chromosome deletions to be transmitted
      to male offspring with the assumption that there will be no clinical consequences
      other than infertility in adult life. We screened 12 patients, who had a 45X/46XY
      karyotype and presented with Turner stigmata or sexual ambiguities, or both, for
      Y chromosome microdeletions with PCR. A third of these patients had Y chromosome
      microdeletions of distal Yq, the most common microdeletion seen in infertile men
      with azoospermia or severe oligozoospermia. Transmission of Y chromosome
      microdeletions could potentially have severe clinical consequences other than
      male infertility, such as the development of sexual ambiguities and Turner
      stigmata.

PMID- 12401252
TI  - Global Fund faces uncertain future as cash runs low.

PMID- 12401257
TI  - Civilian health: the new target of conflict.

PMID- 12401258
TI  - UK political parties roll out health policies.

PMID- 12401261
TI  - Canadian scientists urge government to develop antibiotic plan.

PMID- 12401262
TI  - Brundtland pleas for tough tobacco treaty meet reality.

PMID- 12401263
TI  - Thailand court forces reversal of drug firm antiretroviral patent.

PMID- 12401267
TI  - South Africa hints at HIV/AIDS policy rethink.

PMID- 12401268
TI  - Air pollution and health.
AB  - The health effects of air pollution have been subject to intense study in recent
      years. Exposure to pollutants such as airborne particulate matter and ozone has
      been associated with increases in mortality and hospital admissions due to
      respiratory and cardiovascular disease. These effects have been found in short
      term studies, which relate day-to-day variations in air pollution and health, and
      long-term studies, which have followed cohorts of exposed individuals over time.
      Effects have been seen at very low levels of exposure, and it is unclear whether
      a threshold concentration exists for particulate matter and ozone below which no
      effects on health are likely. In this review, we discuss the evidence for adverse
      effects on health of selected air pollutants.

PMID- 12401269
TI  - Uncertainty.

PMID- 12401270
TI  - The future of dengue vaccines.

PMID- 12401271
TI  - Breastmilk erythropoietin and mother-to-child HIV transmission through
      breastmilk.
AB  - A third to a half the 1.5 million HIV-positive children in the world today
      acquired their infection via breastfeeding. However, what protects the 85% of
      breastfed babies of HIV-infected mothers who do not become infected? We postulate
      that erythropoietin (EPO), a hormone in human milk, has a role in the prevention
      of HIV transmission during breastfeeding. EPO might maintain mammary epithelium
      integrity, thereby reducing viral loads in milk, or maintain intestinal
      epithelial integrity in the breastfed neonate, and thus preventing ingested milk
      borne virus being infective. This hypothesis could be tested by administration of
      recombinant human EPO parenterally to HIV-infected mothers or enterally to
      breastfed babies, or both, and assessment of the effect on mammary permeability,
      viral load in milk, and intestinal permeability in babies. If our hypothesis is
      correct, EPO treatment for mother or baby, or both might help prevent
      transmission of HIV.

PMID- 12401272
TI  - Nutrition, physical activity, and obesity.

PMID- 12401273
TI  - Nutrition, physical activity, and obesity.

PMID- 12401274
TI  - Nutrition, physical activity, and obesity.

PMID- 12401275
TI  - Nutrition, physical activity, and obesity.

PMID- 12401276
TI  - Terlipressin for haemodynamic support in septic patients: a double-edged sword?

PMID- 12401278
TI  - Screening for and treatment of left-ventricular abnormalities in diabetes
      mellitus.

PMID- 12401280
TI  - Outcomes after off-pump and on-pump heart surgery.

PMID- 12401281
TI  - Multiple sclerosis and type 1 diabetes in Sardinia.

PMID- 12401282
TI  - Multiple sclerosis and type 1 diabetes in Sardinia.

PMID- 12401283
TI  - Avoid hormones in gastrointestinal angiodysplasia.

PMID- 12401284
TI  - Opioid prescription in Italy: new law, no effect.

PMID- 12401285
TI  - Continuing influence of tobacco industry in Germany.

PMID- 12401287
TI  - Visibility of research: FUTON bias.

PMID- 12401291
TI  - Help from ISABEL for paediatric diagnoses.

PMID- 12401295
TI  - Perinatal infection: detection and prevention.

PMID- 12401296
TI  - Infection and prematurity and the role of preventive strategies.
AB  - This article reviews the role of infection in spontaneous premature parturition,
      the pathways of ascending intrauterine infection, microbiology, and the frequency
      of intra-amniotic infection in obstetrical complications leading to premature
      delivery. The evidence that infection is causally linked to premature birth is
      critically examined, as is the relationship between urogenital tract
      infection/colonization with microorganisms and the risk of preterm birth. The
      effect of antibiotic administration in perinatal outcome in patients with preterm
      labor and intact membranes, preterm premature rupture of membranes, asymptomatic
      bacteriuria, Group B streptococcus and genital mycoplasmas of the lower genital
      tract, and bacterial vaginosis are critically examined.

PMID- 12401297
TI  - The role of breastfeeding in prevention of neonatal infection.
AB  - The immune system of the human newborn is of very limited size. It expands
      rapidly, especially due to the exposure to the gut microflora. Normally the
      newborn is colonized with microbes from the mother's intestinal flora at and
      after delivery. The many defence factors of the mother's milk include large
      amounts of secretory IgA antibodies produced by lymphocytes which have migrated
      from the mother's gut to the mammary glands. Therefore the SIgA antibodies are
      mainly directed against the mother's previous and recent gut microflora. Thus
      breastfeeding modulates the early exposure of the neonate's intestinal mucosa to
      microbes and limits bacterial translocation through the gut mucosa. This may be a
      major reason why breastfeeding protects efficiently against neonatal septicaemia,
      as well as several other infections. The defence factors of the milk prevent
      infections already at the mucosal level. The transplacentally obtained maternal
      IgG antibodies protect primarily in tissues and do so at the cost of cytokine
      induced clinical symptoms, tissue engagement and high energy consumption.

PMID- 12401298
TI  - Neonatal herpes infection: diagnosis, treatment and prevention.
AB  - Approximately 2000 neonates contract infection due to herpes simplex virus each
      year in the United States. Although herpes simplex virus type 2 is responsible
      for most neonatal infections, approximately 30% of infections are caused by
      herpes simplex virus type 1. Infections are categorized by extent of disease into
      skin/eye/mouth, central nervous system and disseminated disease categories. Each
      disease category is responsible for roughly one third of neonatal infections.
      Mortality is highest in disseminated disease. Morbidity is highest for survivors
      of central nervous system infection. Treatment with high dose parenteral
      acyclovir (60 mg/kg/day) for 14-21 days improves outcome. Since most neonatal
      infections are acquired from contact with infected maternal genital tract
      secretions, potential preventative strategies include: Caesarean delivery,
      serologic screening of pregnant women, prophylactic acyclovir and vaccination.
      The two strategies currently accepted by most obstetricians are Caesarean
      delivery for women with active lesions or prodromal symptoms and prophylactic
      acyclovir for women with gestational herpes.

PMID- 12401299
TI  - Strategies to prevent CMV infection in the neonate.
AB  - Congenital cytomegalovirus (CMV) infection is a major cause of sensorineural
      hearing loss and mental retardation, whose annual healthcare costs in the USA
      approximate to one billion dollars. Only a minority of neonates with this
      infection has symptoms present at birth and some of the damage to ear and brain
      occurs in the first few months of life. Extensive studies of CMV infection have
      been conducted in pregnant women and their children to define the natural history
      of this infection. What is required now is a concerted commitment to tackle this
      clinical problem using one or more of the following strategies: avoid iatrogenic
      transmission; advise those at risk how to avoid acquisition; provide diagnosis in
      an individual neonate or pregnant woman and offer treatment; develop and deploy a
      CMV vaccine.

PMID- 12401300
TI  - Perinatal treatment to prevent early onset group B streptococcal sepsis.
AB  - Implementation of the 1996 consensus recommendations for perinatal antibiotic
      prophylaxis has produced a remarkable reduction in the rate of early-onset group
      B streptococcal sepsis.

PMID- 12401301
TI  - Vaccines to prevent neonatal GBS infection.
AB  - Group B Streptococcus (GBS) remains the leading bacterial cause of neonatal
      sepsis and meningitis in the United States. Although antibiotic prophylaxis has
      decreased the infection rate, the best long-term solution lies in the development
      of effective vaccines. The GBS capsular polysaccharide (CPS) is a major target of
      antibody-mediated immunity. While antibody to CPS is protective, uncoupled CPS is
      variably immunogenic in humans, a finding that led to the development of GBS CPS
      protein conjugate vaccines. GBS CPS-protein conjugate vaccines of all clinically
      important serotypes have been produced and tested in animals. Mice and baboons
      immunized with CPS conjugates transplacentally transferred functionally active
      GBS-specific IgG to their offspring. Phase 1 and phase 2 clinical trials have
      shown that GBS conjugate vaccines are safe, well-tolerated and immunogenic in
      healthy adults. Moreover, human antibodies elicited by the conjugate vaccines are
      functionally active both in vitro and in animal models of invasive GBS disease.

PMID- 12401302
TI  - Preventing nosocomial bloodstream infection in very low birth weight infants.
AB  - Nosocomial sepsis is a frequent complication of caring for very low birth weight
      infants and incidence varies substantially among centres. Many cases are
      preventable. An organized approach to understanding the epidemiology of
      nosocomial sepsis within a unit, and implementing evidence-based practices can
      successfully reduce the incidence. Diagnostic accuracy is important to limit
      excess empiric antibiotic therapy. Instituting a hand hygiene program of
      education, monitoring, and consideration of waterless hand disinfectants to avoid
      hand transmission of organisms is essential. An emphasis on early achievement of
      enteral nutrition, preferably with human milk is important to reduce unnecessary
      exposure to central catheters and parenteral nutrition. Use of maximum sterile
      barrier precautions by personnel trained and skilled in central catheter
      insertion, followed by meticulous care in preventing catheter hub contamination
      will reduce the incidence of catheter related sepsis. Ultimately, the culture of
      the NICU needs to shift from a focus on early detection of infection to one of
      prevention.

PMID- 12401303
TI  - The current role of colony-stimulating factors in prevention and treatment of
      neonatal sepsis.
AB  - OBJECTIVES: To review the role of colony-stimulating factors as adjuncts in the
      therapy of neonatal sepsis. DATA SUMMARY: Data provided by animal experiments and
      in vitro experiments in human neonates demonstrate the inability of newborn
      infants to significantly upregulate colony-stimulating factor expression during
      infectious challenge. In a few clinical trials, exogenous administration of
      colony-stimulating factors has been associated with reduced neonatal morbidity
      and mortality. However, reviewing the existing data on colony-stimulating factor
      administration in neonates, evidence for efficacy and benefit of these adjuncts
      in treating neonatal sepsis still appears to be poor. CONCLUSION: Further
      randomized, placebo-controlled clinical trials, particularly for the subgroups of
      premature infants or infants with neutropenia, are urgently warranted before
      routine application of these cytokines can be recommended.

PMID- 12401305
TI  - Clinical implications of changes in the modern diet: iron intake, absorption and
      status.
AB  - The modern British diet contains less red meat and is lower in iron than that
      consumed 30 years ago. This is in spite of the fact that fortification of foods,
      particularly breakfast cereals, with iron has become more widespread. Although
      there is no clear relationship between dietary iron intake and iron status,
      isotope studies have identified multiple dietary factors that influence iron
      absorption, such as ascorbic acid, animal tissue, phytates and polyphenols. There
      is no evidence to suggest that current dietary changes will have a major impact
      on iron status in the general population; however, effects on the incidence of
      iron overload in individuals with HFE mutations and iron deficiency in children
      and premenopausal women remain to be determined.

PMID- 12401306
TI  - Iron transport across cell membranes: molecular understanding of duodenal and
      placental iron uptake.
AB  - Iron is an essential element playing a vital role in many cellular processes.
      This requirement is complicated by the fact that environmental iron is invariably
      present as insoluble Fe(3+) leading to poor bioavailability and toxicity, since
      even low concentrations of iron catalyse the production of damaging reactive
      oxygen species. As a result organisms have evolved efficient uptake and transport
      systems to extract iron from their environment as well as ferritins that store
      iron in a non-toxic form. In higher organisms, the first membrane barrier
      encountered is the apical surface of the duodenal enterocyte, a specialized
      absorptive cell of the intestinal epithelium that undertakes vectorial transport
      of iron. Iron is initially solubilized by reduction and Fe(2+) is transported
      across the cell membrane by a carrier-mediated transport process. This is
      followed by intracellular transfer of iron to the basolateral enterocyte membrane
      with subsequent transfer and release of iron to transferrin in the portal blood.
      A second site of iron transport is at the placento-fetal barrier where similar
      principles operate. In this review we describe recently identified transmembrane
      transporters and associated accessory proteins responsible for iron transport at
      these two sites.

PMID- 12401307
TI  - Genetic haemochromatosis: genes and mutations associated with iron loading.
AB  - Haemochromatosis is an autosomal recessive disorder common among Caucasians that
      leads to iron overload. Molecular studies have shown that the disease is
      prevalently due to a mutation in the HFE gene. Although C282Y in the homozygous
      state remains the most common patient's genotype, other genes and genetic
      mutations are associated with haemochromatosis. Haemochromatosis type 2, a severe
      form with juvenile onset, is due to mutations in an unidentified gene on
      chromosome 1q. Haemochromatosis type 3 is linked to a locus on 7q22 and is due to
      mutations in the transferrin receptor 2. Haemochromatosis type 4, the only
      autosomal dominant form, is caused by mutations in ferroportin 1 on 2q32. The
      genes responsible for African and neonatal forms of iron overload are still
      unknown. The identification of all of the genes associated with haemochromatosis
      is critical for molecular-based diagnosis and central to our understanding of the
      regulation of iron homeostasis.

PMID- 12401308
TI  - Diagnosis and management of genetic haemochromatosis.
AB  - Haemochromatosis may be inherited or acquired. The commonest inherited form is
      HFE-related genetic haemochromatosis (GH). This is associated with homozygosity
      for the C282Y mutation in the HFE gene. Individuals with GH present in several
      ways depending upon the severity of iron overload. However, only a small
      proportion of genetically susceptible individuals develop disease. Diagnosis of
      GH is based on measurement of transferrin saturation, serum ferritin levels and
      mutation analysis of HFE. Liver biopsy is not necessary for diagnosis. It is used
      to establish the severity of liver disease in selected patients. Other
      complications of iron overload are identified by specific tests. Initial
      management of GH is by weekly venesection until borderline iron deficiency is
      achieved. The serum ferritin is then maintained at 50 microg/l by 3-6 monthly
      venesection. Specific organ damage is managed appropriately. Early diagnosis and
      treatment before irreversible damage has occurred gives a normal life expectancy.
      Non-HFE related inherited iron overload may be due to mutations in other iron
      related genes. Management is along the same lines as for GH, although if
      venesection is not tolerated, other approaches may be necessary.

PMID- 12401309
TI  - HFE Mutations as risk factors in disease.
AB  - Iron deficiency is the most common disorder of iron metabolism worldwide, but
      there is concern that iron accumulation resulting from enhanced iron absorption
      may also be a cause of morbidity. In patients with genetic haemochromatosis the
      clinical manifestations of iron overload are well-known. In northern Europe 90%
      of such patients are homozygous for the C282Y mutation of the HFE gene and this
      genotype is found in 1 in 200 of the population. Heterozygosity for C282Y occurs
      in 15% of the population and 25% carry another mutation, H63D. Population studies
      have revealed (i) the serum transferrin saturation is strongly influenced by HFE
      genotype, being lowest in subjects lacking mutations and highest in those
      homozygous for C282Y; (ii) most subjects homozygous for C282Y accumulate iron but
      do not present with the clinical manifestations of iron overload. Testing for HFE
      mutations in clinics for diabetes, liver disease and cardiovascular disease has
      shown that homozygosity for C282Y is not commonly found. Heterozygosity for
      either C282Y or H63D does not appear to be a risk factor for these common
      conditions.

PMID- 12401310
TI  - Hereditary haemochromatosis: a realistic approach to prevention of iron overload
      disease in the population.
AB  - Iron overload in body tissues can cause complications such as cirrhosis,
      cardiomyopathy, diabetes, hypogonadism and arthritis. In populations of northern
      European descent, most iron overload is due to hereditary haemochromatosis (HHC),
      a genetic condition that causes increased iron absorption. HHC can be treated or
      prevented by regular phlebotomy treatments. Some experts have called for
      population screening for HHC, so that early phlebotomy treatment can be
      initiated. Two screening tests are available: measurement of the serum iron
      transferrin saturation (Tf%) and genetic testing for HFE mutations. However, both
      methods have low positive predictive values. Current data suggest that most
      people at risk are unlikely to develop clinical symptoms and that the population
      prevalence of clinical complications of HHC is low, arguing against population
      screening. Two other prevention strategies are available. (1) Health provider
      education, to heighten awareness of HHC as an explanation for symptoms and signs
      seen in early iron overload including unexplained fatigue, joint pain,
      palpitations, abdominal pain, elevated liver function tests, hepatomegaly and
      elevated serum ferritin. (2) Family-based testing after a diagnosis of HHC, to
      ensure that relatives are evaluated for evidence of iron overload. More research
      is also needed to identify the factors that increase risk for disease in persons
      with excess iron uptake, to determine whether moderate iron overload is a health
      risk and to evaluate the causes of iron overload other than HHC.

PMID- 12401311
TI  - Monitoring chelation therapy to achieve optimal outcome in the treatment of
      thalassaemia.
AB  - Effective management of iron overload in thalassaemia requires monitoring both
      for iron toxicity and the effects of excessive chelation. Careful monitoring
      together with adherence to established regimens using desferrioxamine (DFO)
      results in a 78% survival rate at 40 years of age at UCLH, with steadily
      improving survival as progressive cohorts receive chelation earlier in life. By
      contrast, survival is considerably below this in non-specialist centres. The
      prognostic significance of the measures being used in monitoring should be known
      so that decisions about chelation management are evidence-based. Serum ferritin
      measurement, although easy to perform frequently, is subject to variability and
      falsely high or falsely low values in relation to body iron are frequently
      obtained. However, there is evidence that persistently high ferritin values above
      2500 microg/l have poor prognostic significance in patients treated with DFO.
      Liver iron predicts total body iron in a more predictable way than serum ferritin
      in thalassaemia. Liver iron concentrations of 15 mg/g dry weight appear to
      predict those patients who develop heart failure in subjects treated with DFO.
      The prognostic significance of this measurement or indeed other measurements of
      iron overload in patients treated with other chelation regimens is not known.
      Recent advances with MRI imaging have aroused interest in its use for monitoring
      patients with thalassaemia. A recent publication suggests a relationship between
      left ventricular ejection fraction and cardiac T2*, the value of which shortens
      with increasing iron concentrations in the liver and hence by inference in the
      heart. The prognostic value of this technique has not yet been demonstrated in
      prospective studies and hence changes in therapy based on this measurement alone
      should be considered with caution at this time. The value of monitoring to
      decrease morbidity from iron overload is also discussed, particularly with
      reference to the estimation of iron deposition in the pituitary.

PMID- 12401312
TI  - Oral iron chelators--development and application.
AB  - Iron chelation therapy is the only therapeutic approach that leads to enhanced
      iron excretion in beta-thalassaemia major and other transfusion-dependent
      patients. Although desferrioxamine has been used in such treatment over the last
      three decades, it is not an ideal drug due to its poor oral availability.
      Consequently extensive research effort has been directed towards the
      identification of non-toxic, orally active iron chelators. An ideal candidate
      must possess a range of critical physicochemical and biological properties, such
      as high selectivity and affinity for iron(III), tightly controlled distribution
      and metabolic profiles and low toxicity. Unfortunately, hexadentate ligands are
      generally associated with poor oral bioavailability, whereas many tridentate and
      bidentate molecules are orally active. The tridentate triazoles have been
      investigated for clinical potential; they are readily absorbed from the
      gastrointestinal tract and promote iron excretion with high efficacy. In similar
      fashion, several bidentate hydroxypyridinones have been demonstrated to possess
      potential as oral chelating agents.

PMID- 12401313
TI  - Hereditary hyperferritinaemia/ cataract syndrome.
AB  - In mammalian cells, cellular iron homeostasis is maintained by the co-ordinated
      regulation of transferrin receptor and ferritin synthesis that occurs at the
      translational level. This regulation is mediated by iron-responsive elements
      (IREs) that are found within the untranslated regions (UTRs) of mRNA and by
      cytoplasmic mRNA-binding proteins, known as iron regulatory proteins (IRPs). When
      cellular iron is scarce, IRPs are available for binding the 5' IRE of ferritin
      mRNA, initiation of translation is prevented and ferritin synthesis is inhibited.
      By contrast, the presence of abundant intracellular iron prevents binding of the
      IRPs to the 5' IRE and allows efficient mRNA translation to proceed. Hereditary
      hyperferritinaemia/cataract syndrome (HHCS) arises as a result of various point
      mutations or deletions within a protein binding sequence in the 5'-UTR of the L
      ferritin mRNA, which results in increased efficiency of L-ferritin translation.
      Each unique mutation confers a characteristic degree of hyperferritinaemia and
      severity of cataract in affected individuals. This exemplifies a new paradigm in
      which mutations in mRNA cis-acting elements may be responsible for phenotypic
      variability in disease states.

PMID- 12401314
TI  - Erythropoiesis and iron.
AB  - Iron and erythropoiesis are inextricably linked. Erythropoiesis is a dynamic
      process that requires 30-40 mg of iron per day. In normal circumstances this is
      met from red cell destruction but in anaemia this will not be the case. Reduced
      iron stores will limit iron supply to erythroblasts but normal or raised iron
      stores may not be able to supply iron fast enough. This is particularly true when
      the marrow is stimulated by erythropoietin therapy; the most common cause of
      failure to respond is "functional iron deficiency"'. This entity can only be
      effectively addressed by intravenous iron therapy. While haemoglobin and serum
      ferritin concentrations reflect the major iron pools, iron supply to erythroid
      cells can only be assessed by measuring effective haemoglobinization through the
      percentage of hypochromic red cells in the circulation.

PMID- 12401315
TI  - Iron and infection: competition between host and microbes for a precious element.
AB  - During infection microbes attack host tissues, causing damage to specific organs,
      sepsis or even death. For proliferation microbes desperately need iron for which
      they have to compete with the host. Micro-organisms have developed an abundant
      number of strategies to acquire iron from their specific environment and to
      transport the element to sites of incorporation into biologically important
      molecules. As part of the non-specific defence mechanisms against infection, the
      body modifies iron metabolism in order to make iron less available for micro
      organisms. Such processes have a profound effect on the immune system and are
      also expressed in other forms of inflammation. Microbial iron transport systems
      are explored as targets for antibiotic treatment and vaccines. In particular,
      iron chelators, used for the treatment of iron overload may become important
      drugs for fighting bacterial and viral infections.

PMID- 12401316
TI  - Coexpression of alpha 9 and alpha 10 nicotinic acetylcholine receptors in rat
      dorsal root ganglion neurons.
AB  - Previous binding studies have suggested the presence of a so far unknown
      nicotinic acetylcholine receptor subunit in dorsal root ganglia (Pugh et al.,
      1995). Here, we investigated whether the most recently identified subunit,
      alpha10, and its potential interaction partner, alpha9 (Elgoyhen et al., 2001),
      are expressed in these ganglia. All neurons of rat dorsal root ganglia, but no
      glial cells, expressed both alpha9 and alpha10 mRNA in in situ hybridization, and
      exhibited alpha10 immunoreactivity using a newly raised antibody. These findings
      were confirmed by RT-PCR and western blotting. The data show that dorsal root
      ganglion neurons coexpress alpha9 and alpha10 nicotinic receptor subunits,
      thereby providing the first example of neuronal expression of this receptor
      subunit pair.

PMID- 12401317
TI  - Projection neurons and interneurons in the lateral geniculate nucleus undergo
      distinct forms of degeneration ranging from retrograde and transsynaptic
      apoptosis to transient atrophy after cortical ablation in rat.
AB  - The cytological responses of thalamic interneurons to selective degeneration of
      thalamocortical projection neurons after cortical damage in the adult brain are
      poorly understood. We used a unilateral neocortical lesion model (occipital
      cortex ablation) in the adult rat to test the hypothesis that interneurons and
      projection neurons in the lateral geniculate nucleus undergo distinct forms of
      degeneration. In situ nuclear DNA fragmentation in neurons in the lateral
      geniculate occurs maximally at 7 days postlesion. Geniculocortical projection
      neurons that are identified by the retrograde tracer Fluorogold die primarily
      with a morphology of endstage apoptosis prominent at 7 days postlesion. In
      contrast, interneurons, identified by their particular nuclear ultrastructure and
      by glutamic acid decarboxylase immunoreactivity, undergo an atrophic vacuolar
      pathology starting early during the period of projection neuron death and peaking
      after the projection neuron death is complete. This degeneration of interneurons
      is transient, because these neurons exhibit structural recovery and their numbers
      are not changed significantly postlesion. A rare subset of interneurons (less
      than one in 100 interneurons and less than one in 100 apoptotic cells) undergoes
      apoptosis concurrently with the projection neurons. We conclude that different
      types of neurons within the same thalamic nucleus respond differently to focal
      cortical target deprivation. Unlike the apoptosis-prone projection neurons, most
      interneurons undergo transient transsynaptic atrophy and recovery rather than
      cell death. Nevertheless, a small subset of lateral geniculate interneurons
      undergoes transsynaptic apoptosis in response to projection neuron apoptosis. The
      pathological responses of thalamic neurons to cortical trauma vary depending on
      cell type.

PMID- 12401318
TI  - Chemical responsiveness and histochemical phenotype of electrophysiologically
      classified cells of the adult rat dorsal root ganglion.
AB  - Whole cell patch recordings were obtained from medium diameter (35-45 microm)
      dorsal root ganglion neurons. Using electrophysiological parameters, we were able
      to subclassify acutely dissociated dorsal root ganglion cells into three uniform
      (types 5, 6 and 9) and one mixed class (type 8) of neurons. All subtypes (types
      5, 6, 8 and 9) had broad action potentials (7.0+/-0.2, 5.2+/-0.4, 7.3+/-0.5 and
      6.0+/-0.4 ms) and exceptionally long afterhyperpolarizations (112+/-9, 178+/-19,
      124+/-31 and 204+/-33 ms). Long afterhyperpolarizations have been linked to
      mechanically insensitive (silent) nociceptors by other laboratories [Djouhri et
      al., J. Physiol. 513 (1998) 857-872]. Chemosensitivity varied among cell classes.
      Cell types 5, 8 and 9 were capsaicin sensitive (45+/-13, 87+/-30 and 28+/-13
      pA/pF; 5 microM) groups, while the type 6 cell was capsaicin insensitive. All
      cell types expressed ASIC-like (acid sensing ion channel) amiloride sensitive,
      proton-activated currents with a threshold of pH 6.8 and a peak near pH 5.0. All
      medium sized cells were sensitive to ATP (50 microM) and exhibited the 'mixed'
      form of ATP-gated current [Burgard et al., J. Neurophysiol. 82 (1999) 1590-1598;
      Grubb and Evans, Eur. J. Neurosci. 11 (1999) 149-154]. Immunohistochemistry
      performed on individual cells indicated the expression of both P2X(1) and P2X(3)
      subunits. Electrophysiologically defined classes were histochemically uniform.
      All types were examined for the presence of substance P (SP), calcitonin gene
      related peptide (CGRP) and binding of isolectin B4 (IB4). All subtypes expressed
      CGRP immunoreactivity. Types 5 and 8 co-expressed SP and CGRP immunoreactivity
      and also bound IB4. Subtypes 6 and 9 were positive for neurofilament m. It is
      likely that these cells represent major classes of myelinated and unmyelinated
      peptide expressing nociceptors.

PMID- 12401319
TI  - An investigation of neurones that possess the alpha 2C-adrenergic receptor in the
      rat dorsal horn.
AB  - The function of the alpha(2C) subclass of adrenergic receptor in the spinal cord
      is unclear at present. Immunoreactivity for this receptor is found predominantly
      on axon terminals of the superficial dorsal horn but limited information is
      available about the properties and origin of these axons. The aim of this study
      was to determine which classes of neurone give rise to axons that possess this
      receptor and to investigate the synaptic organisation of these terminals. A
      series of double-labelling experiments was performed to investigate the
      relationship between the alpha(2C) receptor and each one of 14 chemical markers
      that label various types of axon terminal in the dorsal horn. Tissue was examined
      with two-colour confocal laser scanning microscopy. Quantitative analysis
      revealed that alpha(2C)-adrenergic receptors are not present on terminals of
      unmyelinated or peptidergic primary afferents and descending noradrenergic or
      serotoninergic axons. They were found on a proportion of terminals belonging to a
      mixed population of excitatory and inhibitory spinal interneurones, including
      those that contain neurotensin, somatostatin, enkephalin, GABA and neuropeptide
      Y. However, a greater proportion of terminals originating from excitatory
      interneurones were found to possess the receptor. Electron microscopic analysis
      revealed that alpha(2C)-adrenergic receptor immunoreactivity is predominantly
      associated with axon terminals that are presynaptic to dendrites but a small
      proportion of immunoreactive terminals formed axo-axonic synaptic arrangements.
      These studies indicate that noradrenaline can modulate transmission in the dorsal
      horn by acting through alpha(2C)-adrenergic receptors on terminals of spinal
      interneurones.

PMID- 12401320
TI  - Protective effects of the alpha 2-adrenoceptor antagonist, dexefaroxan, against
      degeneration of the basalocortical cholinergic system induced by cortical
      devascularization in the adult rat.
AB  - It has been hypothesized [Colpaert, F.C., 1994. In: Briley, M., Marien, M.
      (Eds.), Noradrenergic Mechanisms in Parkinson's Disease. CRC Press, Boca Raton,
      FL, pp. 225-254] that a deficiency in the noradrenergic system originating from
      the locus coeruleus is a decisive factor in the progression of central
      neurodegenerative disorders including Alzheimer's disease, and that treatments
      which boost noradrenergic transmission (e.g. via blockade of alpha(2)
      adrenoceptors) could provide both symptomatic and trophic benefits against the
      disease. Studies in the rat in vivo demonstrating that the selective alpha(2)
      adrenoceptor antagonist dexefaroxan increases acetylcholine release in the
      cortex, improves measures of cognitive performance and protects against
      excitotoxin lesions, support this concept. As a further test of the hypothesis,
      we investigated the effect of dexefaroxan in a rat model of unilateral cortical
      devascularization that induces a loss of the cortical cholinergic terminal
      network and a retrograde degeneration of the cholinergic projections that
      originate in the nucleus basalis magnocellularis. Lesioned and sham-operated rats
      received a 28-day subcutaneous infusion of dexefaroxan (0.63 mg/rat/day) or
      vehicle, delivered by osmotic minipumps implanted on the day of the cortical
      devascularization procedure. In lesioned rats, the dexefaroxan treatment was
      associated with a significantly higher number and size of vesicular acetylcholine
      transporter-immunoreactive boutons in comparison to the vehicle treatment; this
      effect was most marked within cortical layer V. Dexefaroxan also significantly
      reduced the atrophy of cholinergic neurons within the nucleus basalis
      magnocellularis. Dexefaroxan had no observable effect on any of these parameters
      in sham-operated cohorts. These results show that systemically administered
      dexefaroxan mitigates cholinergic neuronal degeneration in vivo, and provide
      further evidence for a therapeutic potential of the drug in neurodegenerative
      diseases such as Alzheimer's disease, where central cholinergic function is
      progressively compromised.

PMID- 12401321
TI  - Massive cell death of cerebellar granule neurons accompanied with caspase-3-like
      protease activation and subsequent motor discoordination after
      intracerebroventricular injection of vincristine in mice.
AB  - Vincristine, a microtubule-depolymerizing agent, is known to induce neuronal cell
      damage. Biochemical, histological and behavioral alterations were investigated
      after intracerebroventricular injection of vincristine in mice.
      Intracerebroventricular injection of vincristine caused caspase-3-like protease
      activation followed by nucleosomal release in the cerebellum. Histological
      examinations showed that vincristine-induced damage was relatively specific to
      granule cells in the cerebellum, and terminal deoxynucleotidyl transferase
      mediated dUTP-biotin nick-end labeling-positive cells were observed among these
      cells. Chromatin condensation, one of the criteria for apoptosis, was seen on
      electron microscopy. Behavioral changes, namely head movements, pivoting and
      backward walking, were observed in parallel with the increase of caspase-3-like
      protease activity and nucleosomal release. Furthermore, motor function tests
      (bulb balance test and rotating rod test) showed deficits of motor coordination
      ability. These observations suggest that intracerebroventricular vincristine
      causes massive apoptosis of cerebellar granule cells accompanied with caspase-3
      like protease activation, leading to motor dysfunction, in this model. These
      vincristine-treated mice should be a useful in vivo model for examination of
      neuronal apoptosis, which might be involved in a variety of neurodegenerative
      diseases.

PMID- 12401322
TI  - Distinct pattern of c-fos mRNA expression after systemic and intra-accumbens
      amphetamine and MK-801.
AB  - Pharmacological manipulation of both dopamine and glutamate systems affects motor
      responses in laboratory animals. The two systems, however, seem to act in
      opposite ways, since direct or indirect activation of dopamine receptors induces
      similar stimulatory effects to those seen following blockade of N-methyl-D
      aspartate receptors. In the present study we compared the pattern of c-fos
      activation induced by systemic and intra-accumbens administration of the non
      competitive N-methyl-D-aspartate antagonist MK-801 and the indirect dopamine
      agonist amphetamine. Systemic MK-801 induced c-fos mRNA expression in the motor
      cortex and preferentially in the motor thalamus, i.e. ventrolateral nucleus.
      Systemic amphetamine, on the other hand, enhanced c-fos mRNA expression in the
      shell of the accumbens and in limbic thalamic nuclei such as the anteroventral
      and anterodorsal nuclei. The main effect observed after intra-accumbens
      administrations of either drug was enhanced c-fos expression in the thalamus,
      somewhat similar to what seen following systemic administration. In fact also in
      this case there was a preferential activation of the limbic thalamus by
      amphetamine and the motor thalamus by MK-801. The present results confirm that
      different neural substrates underlie behavioral effects induced by systemic
      administrations of N-methyl-D-aspartate receptor antagonists and dopamine
      agonists. Further they suggest that intra-accumbens manipulation of the two
      neural systems could affect different efferent pathways from this structure
      activating different thalamic targets.

PMID- 12401323
TI  - Procaine into the VMH inhibits IBAT activation caused by frontal cortex
      stimulation in urethane-anesthetized rats.
AB  - This experiment tested the effect of procaine injection into the ventromedial
      hypothalamus on the sympathetic and thermogenic activation induced by frontal
      cortex stimulation. Oxygen consumption, firing rate of the sympathetic nerves to
      interscapular brown adipose tissue (IBAT), along with IBAT and colonic
      temperatures were monitored in fasted male Sprague-Dawley rats before and during
      25 min after an electrical stimulation of the frontal cortex. The same variables
      were monitored in rats with administration of procaine into the ventromedial
      hypothalamus. The results show that cortical stimulation increases oxygen
      consumption, sympathetic firing rate, IBAT and colonic temperatures. The increase
      in sympathetic firing rate was reduced by procaine injection, and the increase in
      IBAT and colonic temperatures as well as oxygen consumption was fully inhibited
      by procaine. These findings suggest that the ventromedial nucleus plays an
      important role in the sympathetic and thermogenic changes induced by cortical
      stimulation.

PMID- 12401324
TI  - Induction of rapid eye movement sleep by neurotrophin-3 and its co-localization
      with choline acetyltransferase in mesopontine neurons.
AB  - Because neurotrophin-3 (NT-3), a neurotrophic factor closely related to nerve
      growth factor, is capable of modulating neuronal activity [Yamuy et al.,
      Neuroscience 95 (2000a) 1089-1100], we sought to examine if the microinjection of
      NT-3 into the nucleus reticularis pontis oralis (NPO) of chronically prepared
      cats also induced changes in behavior. In contrast to vehicle administration, NT
      3 injection induced, with a mean latency of 4.7 min, long-duration episodes
      (mean, 21.6 min) of a state that was polygraphically indistinguishable from
      naturally occurring REM sleep. If NT-3 plays a physiologic role in the generation
      of REM sleep, then an endogenous source for this neurotrophin that is capable of
      controlling the activity of NPO neurons should exist. We therefore determined
      whether cholinergic neurons in the latero-dorsal and pedunculo-pontine tegmental
      (LDT and PPT) nuclei, which are involved in the initiation of REM sleep and
      project to the NPO, contained NT-3. Most, if not all, of the LDT-PPT cholinergic
      neurons exhibited NT-3 immunoreactivity. A portion (10%) of the NT-3+ neurons in
      the LDT-PPT were not cholinergic. The present data indicate that NT-3 rapidly
      modulates the activity of NPO neurons involved in REM sleep and that cholinergic
      neurons in the LDT and PPT contain NT-3. Taken together, these results support
      the hypothesis that NT-3 may be involved in the control of naturally occurring
      REM sleep.

PMID- 12401325
TI  - Spatial segregation within the sacral parasympathetic nucleus of neurons
      innervating the bladder or the penis of the rat as revealed by three-dimensional
      reconstruction.
AB  - The purpose of the present investigations was (1) to examine the spatial
      organization of preganglionic neurons of the sacral parasympathetic nucleus in
      the lumbosacral spinal cord of male adult rats and (2) to search, in this
      nucleus, for a possible segregation of sub-populations of neurons innervating the
      penis or the bladder, respectively. To estimate their spatial organization,
      neurons of the sacral parasympathetic nucleus were retrogradely labeled by wheat
      germ agglutinin coupled to horseradish peroxidase applied to the central end of
      the sectioned pelvic nerve. The sub-populations of lumbosacral neurons
      innervating the corpus cavernosum of the penis or the dome of the bladder were
      identified using transsynaptic retrograde labeling by pseudorabies virus injected
      into these organs in different rats. In both wheat germ agglutinin-labeled and
      pseudorabies virus-labeled rats, serial coronal sections were cut through the
      spinal L5-S1 segments. Labeled neurons were revealed by histochemistry
      (peroxidase experiments) or immunohistochemistry (pseudorabies virus
      experiments). By means of a three-dimensional reconstruction software developed
      in our laboratory, three-dimensional models were calculated from each spinal
      section image series. They revealed the spatial organization of (i) preganglionic
      neurons and (ii) neurons innervating the bladder or the penis. The different
      three-dimensional models were subsequently merged into a single one which
      revealed the segregation, within the sacral parasympathetic nucleus, of the sub
      populations of neurons. Neurons labeled by virus injected into the penis extended
      predominantly from the rostral part of the L6 segment to the rostral part of the
      S1 segment while those labeled by bladder injections were distributed
      predominantly from the caudal part of the L6 segment to the caudal part of the S1
      segment. These results support the hypothesis of a viscerotopic organization of
      sacral neurons providing the spinal control of pelvic organs.

PMID- 12401326
TI  - Short-term (Fos) and long-term (FRA) protein expression in rat locus coeruleus
      neurons during the neurolab mission: contribution of altered gravitational
      fields, stress, and other factors.
AB  - Changes in immediate-early gene (IEG) expression during and after space flight
      were studied in the rat locus coeruleus (LC) during the NASA Neurolab mission.
      The LC sends widespread projections throughout the brain and releases the
      neuromodulator norepinephrine. LC neurons respond to natural vestibular
      stimulation; their firing rate also increases during waking and decreases or
      ceases during sleep. LC neurons express IEGs such as c-fos after activation.
      Adult male albino Fisher 344 rats were killed at four mission time points, and
      the number of Fos- and Fos-related antigen (FRA)-positive LC cells were counted
      in flight and ground-based control rats. Half of the subjects at each time point
      were exposed to light for 60 min prior to killing to standardize their sleep
      waking state. FRA-expressing cells were more numerous than Fos-expressing cells
      in both flight- and ground-based subjects. The difference between FRA- and Fos
      expressing cells within individuals was significantly larger 24 h after landing
      in subjects exposed to both space flight and light pulse than in all other
      subjects at any mission time point. Fos and FRA responses scaled in proportion to
      the maximum response observed in any single individual showed similar patterns of
      variation. Analysis of the scaled and combined responses showed that LC IEG
      levels responded to both gravity changes and light pulses. Subjects exposed to
      either single stimulus had equivalent responses, significantly greater than those
      of control subjects maintained in dim light. The combination of gravity change
      and light pulse gave significantly higher LC responses than either stimulus alone
      24 h after takeoff, and to a lesser extent after 12 days in space; the highest
      responses were obtained 24 h after landing. By 14 days after landing, animals
      exposed to space flight and light pulse responded no differently than ground
      based subjects. No difference in LC IEG expression was clearly attributable to
      changes in the sleep-waking state of subjects. Activity of noradrenergic LC
      neurons has been previously shown to modulate IEG expression in target
      structures. The increased IEG LC activity (seen most especially 24 h after
      landing) may reflect large-scale activation of noradrenergic neurons that may
      serve as a trigger for molecular changes in target structures, and be critical
      for adaptation to gravity changes.

PMID- 12401327
TI  - Immunohistochemical and biochemical assessment of caspase-3 activation and DNA
      fragmentation following transient focal ischemia in the rat.
AB  - In the present study, we evaluated the time-course of caspase-3 activation, and
      the evolution of cell death following focal cerebral ischemia produced by
      transient middle cerebral artery occlusion in rats. Ischemia-induced active
      caspase-3 immunoreactivity in the striatum but not the cortex at 3 and 6 h time
      points post-reperfusion. Furthermore, using a novel approach to visualize
      enzymatic activity, deltaC-APP, a C-terminal cleavage product of APP generated by
      caspase-3, was found to immunolocalize to the same areas as active caspase-3.
      Double-labeling studies demonstrated co-localization of these two proteins at the
      cellular level. Further double-labeling experiments revealed that active caspase
      3 was confined to neuronal cells which were still viable and thus immunoreactive
      for NeuN. DNA fragmentation, assessed histologically by terminal dUTP nick-end
      labeling (TUNEL), was observed in a small number of cells in the striatum as
      early as 3 h, but only began to appear in the cortex by 6 h. DNA fragmentation
      was progressive, and by 24 h post-reperfusion, large portions of both the
      striatum and cortex showed TUNEL positive cells. However, double-labeling of
      active caspase-3 with TUNEL showed only minimal co-localization at all time
      points. Thus, caspase-3 activation is an event that appears to occur prior to DNA
      fragmentation. As a confirmation of the histological TUNEL data, 24 h ischemia
      also induced the generation of nucleosome fragments, evidenced by cell death
      enzyme-linked immunosorbent assay. Using a novel ischemia-induced substrate
      cleavage biochemical approach, spectrin P120 fragment, a caspase-specific
      cleavage product of alpha II spectrin, a cytoskeletal protein, was shown to be
      elevated by western blotting. Brain concentrations of both nucleosomes and
      spectrin P120 correlate with the degree of injury previously assessed by
      triphenyltetrazolium chloride staining and infarct volume calculation. Together,
      our findings suggest a possible association between caspase-3 activation and
      ischemic cell death following middle cerebral artery occlusion brain injury.

PMID- 12401328
TI  - Nicotinic receptors mediate increased GABA release in brain through a
      tetrodotoxin-insensitive mechanism during prolonged exposure to nicotine.
AB  - The effects of nicotine on the spontaneous release of GABA from nerve terminals
      in the chick lateral spiriform nucleus were examined using whole cell patch-clamp
      recording in brain slices. Exposure to 1 microM nicotine produced an early
      immediate increase in the frequency of spontaneous postsynaptic GABAergic
      currents. This effect was blocked in the presence of 0.5 microM tetrodotoxin.
      However, a prolonged application of 0.1-1 microM nicotine (>3 min) caused a
      tetrodotoxin-insensitive increase in the frequency of spontaneous GABAergic
      currents. This late tetrodotoxin-insensitive effect was blocked by the nicotinic
      antagonists dihydro-beta-erythroidine (30 microM) and mecamylamine (10 microM),
      but not by methyllycaconitine (50-100 nM), indicating that activation of high
      affinity nicotine receptors was mainly responsible for this effect. This
      enhancement was inhibited by the high threshold Ca(2+) channel blocker Cd(2+)
      (100 microM), but not by dantrolene or ryanodine. The tetrodotoxin-insensitive
      enhancement of the frequency of GABA currents by nicotine was reduced by
      inhibition of cAMP-dependent protein kinase with HA1004 (30 microM), but not by
      inhibition of protein kinase C with staurosporine (1 microM), and was facilitated
      by forskolin (10 microM) or bromo-cAMP (50 microM). The results indicate that
      nicotine-enhanced GABA release can operate through both tetrodotoxin-sensitive
      and -insensitive mechanisms in a single brain region and that a second messenger
      cascade may be involved in the tetrodotoxin-insensitive enhancement by nicotine.

PMID- 12401329
TI  - Expression of caveolin-1 in human brain microvessels.
AB  - Caveolae are microinvaginations of the cell plasma membrane involved in cell
      transport and metabolism as well as in signal transduction; these functions
      depend on the presence of integral proteins named caveolins in the caveolar
      frame. In the brain, various caveolin subtypes have been detected in vivo by
      immunocytochemistry: caveolin-1 and -2 were found in rat brain microvessels,
      caveolin-3 was revealed in astrocytes. The aim of this study was to identify the
      site(s) of cellular expression of caveolin-1 in the microvessels of the human
      cerebral cortex by immunofluorescence confocal microscopy and immunogold electron
      microscopy. Since in the barrier-provided brain microvessels tight relations
      occur between the endothelium-pericyte layer and the surrounding vascular
      astrocytes, double immunostaining with caveolin-1 and the astroglia marker, glial
      fibrillary acidic protein, was also carried out. Immunocytochemistry by confocal
      microscopy revealed that caveolin-1 is expressed by endothelial cells and
      pericytes in all the cortex microvessels; caveolin-1 is also expressed by cells
      located in the neuropil around the microvessels and identified as astrocytes.
      Study of the cortex microvessels carried out by immunoelectron microscopy
      confirmed that in the vascular wall caveolin-1 is expressed by endothelial cells,
      pericytes, and vascular astrocytes, and revealed the association of caveolin-1
      with the cell caveolar compartment. The demonstration of caveolin-1 in the cells
      of the brain microvessels suggests that caveolin-1 may be involved in blood-brain
      barrier functioning, and also supports co-ordinated activities between these
      cells.

PMID- 12401330
TI  - Cocaine mechanisms: enhanced cocaine, fluoxetine and nisoxetine place preferences
      following monoamine transporter deletions.
AB  - Cocaine blocks uptake by neuronal plasma membrane transporters for dopamine,
      serotonin and norepinephrine, producing subjective effects in humans that are
      both euphoric/rewarding and also fearful, jittery and aversive. Mice with gene
      knockouts of each of these transporters display cocaine reward, manifest by
      cocaine place preferences that are at least as great as wildtype values.
      Norepinephrine and serotonin receptor knockouts even display enhanced cocaine
      reward. One explanation for these observations could be that cocaine produces
      aversive or anhedonic effects by serotonin or norepinephrine receptor blockade in
      wildtype mice that are removed in serotonin or norepinephrine receptor knockouts,
      increasing net cocaine reward. Adaptations to removing one transporter could also
      change the rewarding valence of blocking the remaining transporters. To test
      these ideas, drugs that block serotonin transporter (fluoxetine), norepinephrine
      transporter (nisoxetine) or all three transporters (cocaine) were examined in
      single- or multiple-transporter knockout mice. Fluoxetine and nisoxetine acquire
      rewarding properties in several knockouts that are not observed in wildtype mice.
      Adding serotonin transporter knockout to norepinephrine transporter knockouts
      dramatically potentiates cocaine reward. These and previous data provide evidence
      that serotonin and norepinephrine transporter blockade can contribute to the net
      rewarding valence of cocaine. They identify neuroadaptations that may help to
      explain the retention of cocaine reward by dopamine and serotonin transporter
      knockout mice. They are consistent with emerging hypotheses that actions at the
      three primary brain molecular targets for cocaine each provide distinct
      contributions to cocaine reward and cocaine aversion in wildtype mice, and that
      this balance changes in mice that develop without dopamine, norepinephrine or
      serotonin transporters.

PMID- 12401331
TI  - Presynaptic effects of group III metabotropic glutamate receptors on excitatory
      synaptic transmission in the retina.
AB  - Metabotropic glutamate receptors (mGluRs) are located in both plexiform layers in
      the retina and may modulate transmission between photoreceptors and bipolar cells
      and between bipolar and ganglion cells. We investigated whether mGluR activation
      modulates excitatory synaptic input to bipolar cells and ganglion cells in the
      salamander retinal slice preparation. The group III mGluR agonist L-2-amino-4
      phosphonobutyric acid (AP4) inhibited monosynaptic excitatory postsynaptic
      currents (EPSCs) in ganglion cells evoked by electrical stimuli, whereas group I
      and group II agonists had no significant effect. AP4 reduced the frequency but
      not the amplitude of ganglion cell miniature EPSCs, suggesting a presynaptic
      action at bipolar cell terminals. AP4 also reduced ganglion cell EPSCs evoked by
      the offset of a light stimulus, suggesting that group III mGluRs modulate release
      from OFF bipolar cells. Comparison of light-evoked EPSCs in OFF bipolar cells and
      ganglion cells indicated that AP4 reduced ganglion cell EPSCs by acting primarily
      at bipolar cell terminals, and to a lesser extent at photoreceptor terminals. The
      group II/III mGluR antagonist (RS)-alpha-cyclopropyl-4-phosphonophenylglycine
      (CPPG) blocked the effect of AP4 at bipolar cell terminals, consistent with
      localization of group III mGluRs at these sites. However, CPPG did not increase
      EPSCs at light offset, indicating that activation of group III mGluRs by synaptic
      glutamate does not play a large role in modulating transmission from bipolar
      cells to ganglion cells.

PMID- 12401332
TI  - Preconditioned resistance to oxygen-glucose deprivation-induced cortical neuronal
      death: alterations in vesicular GABA and glutamate release.
AB  - Central neurons exposed to several types of sublethal stress, including ischemia,
      acquire resistance to injury induced by subsequent ischemic insults, a phenomenon
      called ischemic preconditioning. We modeled this phenomenon in vitro, utilizing
      exposure to 45 mM KCl to reduce the vulnerability of cultured murine cortical
      neurons to subsequent oxygen-glucose deprivation. Twenty-four hours after
      preconditioning, cultures exhibited enhanced depolarization-induced, tetanus
      toxin-sensitive GABA release and a modest decrease in glutamate release. Total
      cellular GABA levels were unaltered. Inhibition of GABA degradation with the GABA
      transaminase inhibitor (+/-)-gamma-vinyl GABA, or addition of low levels of GABA,
      muscimol, or chlormethiazole to the bathing medium, mimicked the neuroprotective
      effect of preconditioning against oxygen-glucose deprivation-induced death.
      However, neuronal death was enhanced by higher levels of these manipulations, as
      well as by prior selective destruction of GABAergic neurons by kainate. Finally,
      selective blockade of GABA(A) receptors during oxygen-glucose deprivation or
      removal of GABAergic neurons eliminated the neuroprotective effects of prior
      preconditioning. Taken together, these data predict that presynaptic alterations,
      specifically enhanced GABA release together with reduced glutamate release, may
      be important mediators of ischemic preconditioning, but suggest caution in regard
      to interventions aimed at increasing GABA(A) receptor activation.

PMID- 12401333
TI  - Ventral tegmental area region governs GABA(B) receptor modulation of ethanol
      stimulated activity in mice.
AB  - Locomotor stimulation in response to ethanol in mice may model human ethanol
      induced euphoria. The associated neural substrates, possibly relevant to
      alcoholism, have not been fully elucidated. Systemic injection of baclofen, a
      GABA(B) receptor agonist, attenuates ethanol's stimulant effects. GABA(B)
      receptors on dopamine cell bodies in the ventral tegmental area (VTA) may
      modulate ethanol-induced dopamine release, a postulated mechanism for ethanol's
      stimulant effects. However, baclofen's attenuating effects could be associated
      with peripheral receptor actions. Baclofen was injected i.c.v. or into the VTA of
      FAST mice, bred for extreme sensitivity to ethanol-induced locomotor stimulation,
      to test the hypotheses that (1) central GABA(B) receptors influence baclofen's
      effects on ethanol-stimulated activity, and (2) VTA GABA(B) receptors
      specifically modulate ethanol's stimulant effects. I.c.v. baclofen dose
      dependently attenuated ethanol stimulation, supporting a central locus for
      baclofen's effects. Anterior VTA baclofen also attenuated ethanol stimulation.
      However, more posterior VTA infusions unexpectedly potentiated ethanol
      stimulation. In SLOW mice, bred for resistance to ethanol stimulation, posterior
      intra-VTA baclofen did not alter EtOH response. However, anterior VTA baclofen
      alone produced a locomotor depressant effect in SLOW mice, not seen in FAST mice.
      GABA(B) receptor autoradiography using [(3)H]CGP 54626, a potent GABA(B) receptor
      antagonist, did not reveal line differences in binding density in the VTA, or in
      the substantia nigra pars compacta, a nearby brain structure associated with
      motor control. These results suggest that anterior VTA GABA(B) receptors play a
      role in baclofen's attenuation of ethanol's stimulant effects, and that posterior
      VTA GABA(B) receptors serve an opposite role that is normally masked. Selection
      for differential ethanol stimulant sensitivity has altered VTA GABA(B) systems
      that influence locomotor behavior. However, differences in GABA(B) receptor
      densities in the VTA or substantia nigra pars compacta cannot explain the
      selected line difference.

PMID- 12401334
TI  - Amyloid beta peptide induces tau phosphorylation and loss of cholinergic neurons
      in rat primary septal cultures.
AB  - The neuropathological features associated with Alzheimer's disease (AD) brain
      include the presence of extracellular neuritic plaques composed of amyloid beta
      protein (Abeta), intracellular neurofibrillary tangles containing phosphorylated
      tau protein and the loss of basal forebrain cholinergic neurons which innervate
      regions such as the hippocampus and the cortex. Studies of the pathological
      changes that characterize AD and several other lines of evidence indicate that
      Abeta accumulation in vivo may initiate phosphorylation of tau protein, which by
      disrupting neuronal network may trigger the process of neurodegeneration observed
      in AD brains. However, the underlying cause of degeneration of the basal
      forebrain cholinergic neurons and their association, if any, to Abeta peptides or
      phosphorylated tau remains mostly unknown. In the present study, using rat
      primary septal cultures, we have shown that aggregated Abeta peptides, in a time
      (18-96 h)- and concentration (0.7-60 microM)-dependent manner, induce toxicity
      and decrease choline acetyltransferase enzyme activity in cultured neurons. Using
      immunocytochemistry and immunoblotting, we have also demonstrated that Abeta
      treatment can significantly increase the phosphorylation of tau protein in septal
      cultures. At the cellular level, hyperphosphorylated tau is mostly apparent in
      the somatodendritic compartment of the neurons. Abeta peptide (10 microM), in
      addition to tau phosphorylation, also activates mitogen-activated protein kinase
      and glycogen synthase kinase-3beta, the two kinases which are known to be
      involved in the formation of hyperphosphorylated tau in the AD brain. Exposure to
      specific inhibitors of the mitogen-activated protein kinase (i.e. PD98059) or
      glycogen synthase kinase-3beta (i.e. LiCl) attenuated the hyperphosphorylation of
      the tau protein in cultured neurons. Given the evidence that tau phosphorylation
      can induce cell loss by disrupting neuronal cytoskeleton, it is likely that
      aggregated Abeta peptide triggers degeneration of septal neurons, including those
      expressing the cholinergic phenotype, by phosphorylation of the tau protein
      activated by mitogen-activated protein kinase and glycogen synthase kinase-3beta.
      These results, taken together, suggest that cultured septal cholinergic neurons
      are vulnerable to Abeta-mediated toxicity and tau phosphorylation may play an
      important role in Abeta-induced neurodegeneration.

PMID- 12401335
TI  - Identification and localization of multiple classic cadherins in developing rat
      limbic system.
AB  - Classic cadherins are multifunctional adhesion proteins that play roles in tissue
      histogenesis, neural differentiation, neurite outgrowth and synapse formation.
      Several lines of evidence suggest that classic cadherins may establish regional
      or laminar recognition cues by virtue of their differential expression and tight,
      and principally homophilic, cell adhesion. As a first step toward investigating
      the role this family plays in generating limbic system connectivity, we used RT
      PCR to amplify type I and type II classic cadherins present in rat hippocampus
      during the principal period of synaptogenesis. We identified nine different
      cadherins, one of which, cadherin-9, is novel in hippocampus. Using in situ
      hybridization, we compared the cellular and regional distribution of five of the
      cadherins (N, 6, 8, 9 and 10) during the first two postnatal weeks in
      hippocampus, subiculum, entorhinal cortex, cingulate cortex, anterior thalamus,
      hypothalamus and amygdala. We find that each cadherin is differentially
      distributed in distinct, but highly overlapping fields that largely correspond to
      known anatomical boundaries and are often coordinately expressed in
      interconnected regions. For example, cadherin-6 expression defines CA1 and its
      principal target, the subiculum; cadherin-10 is differentially expressed in CA1
      and CA3 in a manner correlating with the organization of interconnecting Schaffer
      collateral axons; and cadherin-9 shows a striking concentration in CA3. Some
      cadherin mRNAs are highly restricted to particular anatomical fields over the
      entire time course, while others are more broadly expressed and become
      concentrated within particular domains coincident with the timing of afferent
      ingrowth. Our data indicate that classic cadherins are sufficiently diverse and
      differentially distributed to support a role in cell surface recognition and
      adhesion during the formation of limbic system connectivity.

PMID- 12401336
TI  - Stress reactivity of the brain noradrenergic system in three rat strains
      differing in their neuroendocrine and behavioral responses to stress:
      implications for susceptibility to stress-related neuropsychiatric disorders.
AB  - The brain noradrenergic system is activated by stress, modulating the activity of
      forebrain regions involved in behavioral and neuroendocrine responses to stress.
      In this study, we characterized brain noradrenergic reactivity to acute
      immobilization stress in three rat strains that differ in their neuroendocrine
      stress response: the inbred Lewis (Lew) and Wistar-Kyoto (WKY) rats, and outbred
      Sprague-Dawley (SD) rats. Noradrenergic reactivity was assessed by measuring
      tyrosine hydroxylase mRNA expression in locus coeruleus, and norepinephrine
      release in the lateral bed nucleus of the stria terminalis. Behavioral measures
      of arousal and acute stress responsivity included locomotion in a novel
      environment, fear-potentiated startle, and stress-induced reductions in social
      interaction and open-arm exploration on the elevated-plus maze. Neuroendocrine
      responses were assessed by plasma adrenocorticotropic hormone. Compared to SD,
      adrenocorticotropic hormone responses of Lew rats were blunted, whereas those of
      WKY were enhanced. The behavioral effects of stress were similar in Lew and SD
      rats, despite baseline differences. Lew had similar elevations of tyrosine
      hydroxylase mRNA, and initially greater norepinephrine release in the lateral bed
      nucleus of the stria terminalis during stress, although both noradrenergic
      responses returned toward baseline more rapidly than in SD rats. WKY rats showed
      depressed baseline startle and lower baseline exploratory and social behavior
      than SD. However, unlike the Lew or SD rats, WKY exhibited a lack both of fear
      potentiation of the startle response and of stress-induced reductions in
      exploratory and social behavior, indicating attenuated stress responsivity. Acute
      noradrenergic reactivity to stress, measured by either tyrosine hydroxylase mRNA
      levels or norepinephrine release, was also attenuated in WKY rats. Thus, reduced
      arousal and behavioral responsivity in WKY rats may be related to deficient brain
      noradrenergic reactivity. This deficit may alter their ability to cope with
      stress, resulting in the exaggerated neuroendocrine responses and increased
      susceptibility to stress-related pathology exhibited by this strain.

PMID- 12401337
TI  - Extracortical descending projections to the rat inferior colliculus.
AB  - Feedback controlling is an important element in the sensory processing in the
      auditory system. It has been long recognized that the inferior colliculus (IC)
      sends direct ascending projections to the medial geniculate body (MGB), but
      receives feedback regulation from the auditory cortex. In the present study we
      probed the shorter extracortical projections to the IC, including the direct
      descending pathway from the MGB. In the rat, the fluorescence retrograde tracers
      Fluorogold, True Blue or Rhodamine latex microspheres were injected into the IC,
      and the auditory thalamus and surrounding regions were examined for fluorescent
      neurones. We did not find any retrograde labelling in the ventral division of the
      MGB. However, retrogradely labelled neurones were found in the medial and
      suprageniculate nuclei of the MGB. We also observed densely packed groups of
      fluorescent neurones in the peripeduncular nucleus and numerous labelled neurones
      in the nucleus of the brachium of the IC. The existence of a direct descending
      pathway to the IC from at least some auditory thalamic nuclei challenges the
      perception of the colliculo-thalamic relationship as one-way traffic and suggests
      more direct involvement of the auditory thalamus in the feedback regulation of
      the incoming acoustic signals.

PMID- 12401338
TI  - Quinine suppresses extracellular potassium transients and ictal epileptiform
      activity without decreasing neuronal excitability in vitro.
AB  - The effect of quinine on pyramidal cell intrinsic properties, extracellular
      potassium transients, and epileptiform activity was studied in vitro using the
      rat hippocampal slice preparation. Quinine enhanced excitatory post-synaptic
      potentials and decreased fast- and slow-inhibitory post-synaptic potentials.
      Quinine reduced the peak potassium rise following tetanic stimulation but did not
      affect the potassium clearance rate. Epileptiform activity induced by either low
      Ca(2+) or high-K(+) artificial cerebrospinal fluid (ACSF) was suppressed by
      quinine. The frequency of spontaneous inter-ictal bursting induced by picrotoxin,
      high-K(+), or 4-aminopyridine was significantly increased. In normal ACSF,
      quinine did not affect CA1 pyramidal cell resting membrane potential, input
      resistance, threshold for action potentials triggered by intracellular or
      extracellular stimulation, or the orthodromic and antidromic evoked population
      spike amplitude. The main effects of quinine on intrinsic cell properties were to
      increase action potential duration and to reduce firing frequency during
      sustained membrane depolarizations, but not at normal resting membrane
      potentials. This attenuation was enhanced at increasingly depolarized membrane
      potentials. These results suggest that quinine suppresses extracellular potassium
      transients and ictal activity and modulates inter-ictal activity by limiting the
      firing rate of cells in a voltage-dependent manner. Because quinine does not
      affect 'normal' neuronal function, it may merit consideration as an
      anticonvulsant.

PMID- 12401339
TI  - Lithium modulates expression of TRH receptors and TRH-related peptides in rat
      brain.
AB  - Lithium is an established mood stabilizer and neuroprotective agent frequently
      used in the treatment of bipolar disorder and as an adjuvant in drug-resistant
      unipolar depression. The mechanisms underlying both the therapeutic efficacy of
      lithium and the exacerbation of symptoms following rapid withdrawal are not
      understood. From previous studies showing antidepressant and neuroprotective
      activities of thyrotropin releasing hormone (TRH) and TRH-related neuropeptides
      we hypothesized that lithium may have substantial effects on the expression and
      secretion of these peptides and/or their receptors in various rat brain regions
      involved in the regulation of mood. Chronic lithium effect on TRH receptor
      binding studies: The effect of 1 and 2 weeks of dietary lithium on [(3)H]3-Me-His
      TRH binding to plasma membranes of nucleus accumbens, amygdala and pituitary of
      young adult male Wistar and the endogenously 'depressed' Wistar Kyoto (WKY) rats
      was measured by the method of Burt and Taylor [Burt, D.R., Taylor, R.L.,
      Endocrinology 106 (1980) 1416-1423]. Acute, chronic and withdrawal effect of
      lithium on TRH and TRH-like peptide levels in young, adult male Sprague-Dawley
      rats: Rats were divided into four lithium treatment groups. Control animals
      received a standard laboratory rodent chow. The acute group received a single
      i.p. injection of 1.5 milli-equivalents of LiCl 2 h prior to killing. The chronic
      and withdrawal groups received standard rodent chow containing 1.7 g/kg LiCl for
      2 weeks. Withdrawal rats were returned to standard chow 48 h prior to killing
      while the chronic animals continued on the LiCl diet. TRH, TRH-Gly (pGlu-His-Pro
      Gly, a TRH precursor), EEP (pGlu-Glu-Pro-NH(2), a TRH-like peptide with
      antidepressant activity) and Ps4 (a prepro-TRH-derived TRH-enhancing decapeptide)
      immunoreactivity (IR) were measured in 13 brain regions. The remaining samples
      were pooled and fractionated by high-pressure liquid chromatography followed by
      EEP radioimmunoassay. Chronic lithium treatment increased [(3)H]3Me-TRH binding
      in the nucleus accumbens and amygdala about two-fold in both Wistar and WKY rats
      but no change was observed in pituitary binding. The most widespread changes in
      TRH and TRH-related peptide levels were observed in the withdrawal group compared
      to the controls. The direction of change for the total IR was consistent for all
      TRH-IR and TRH-related peptide-IR within a given tissue. For example, withdrawal
      increased all peptide levels in the pyriform cortex and striatum but decreased
      these levels in the anterior cingulate and lateral cerebellum. Both acute
      injection and chronic treatment with LiCl decreased TRH and TRH-related peptide
      levels in the entorhinal cortex. Acute injection and withdrawal both increased
      EEP-IR in striatum by more than two-fold. The acute effects are most likely due
      to changes in the release of these peptides since 2 h is not sufficient time for
      alterations in peptide biosynthesis. Chronic treatment increased levels of pGlu
      Phe-Pro-NH(2) levels in hippocampus, pGlu-Leu-Pro-NH(2), and peak '2' in septum
      by more than four-fold. The present results are consistent with a component role
      for TRH and related peptides in the mood-altering effects of lithium
      administration and withdrawal frequently observed during treatment for depression
      and bipolar disorder.

PMID- 12401340
TI  - Sources of endothelin-1 in hippocampus and cortex following traumatic brain
      injury.
AB  - Endothelin 1 (ET-1) exerts normally a powerful vasoconstrictor role in the
      control of the brain microcirculation. In altered states, such as following
      traumatic brain injury (TBI), it may contribute to the development of ischemia
      and/or secondary cell injury. Because little is known of ET-1's cellular
      compartmentalization and its association to vulnerable neurons after TBI, we
      assessed its expression (both mRNA and protein) in cerebral cortex and
      hippocampus using correlative in situ hybridization and immunocytochemical
      techniques.Sprague-Dawley male rats were killed at 4, 24 or 48 h after TBI (450 g
      from 2 m, Marmarou's model). Semiquantitative analysis of our in situ
      hybridization results indicated a 2.5- and a 2.0-fold increase in ET-1 mRNA
      content in the hippocampus and cortex respectively which persisted up to 48 h
      post TBI. At 4 and 24 h after TBI enzyme-linked immunosorbent assay showed a
      tendency for increased ET-1 synthesis. In animals subjected to TBI, qualitative
      immunocytochemical analysis revealed a shift in ET-1 expression from astrocytes
      (in control animals) to endothelial cells, macrophages and neurons. Astrocytes
      and macrophages were identified unequivocally by using double immunofluorescence
      revealing ET-1 and glial fibrillary acidic protein or ED-1, respectively, the
      markers being specific for these cellular types. While this redistribution was
      most prominent at 4 and 24 h post TBI, at 48 h the endothelial cells remained
      strongly ET-1 immunopositive. The results suggest that cellular types which in
      the intact animal synthesize little or no ET-1 provide novel sources of the
      peptide after TBI. These sources may contribute to the sustained cerebrovascular
      hypoperfusion observed post TBI.

PMID- 12401341
TI  - Ventrolateral preoptic nucleus contains sleep-active, galaninergic neurons in
      multiple mammalian species.
AB  - The ventrolateral preoptic nucleus (VLPO) is a group of sleep-active neurons that
      has been identified in the hypothalamus of rats and is thought to inhibit the
      major ascending monoaminergic arousal systems during sleep; lesions of the VLPO
      cause insomnia. Identification of the VLPO in other species has been complicated
      by the lack of a marker for this cell population, other than the expression of
      Fos during sleep. We now report that a high percentage of the sleep-active (Fos
      expressing) VLPO neurons express mRNA for the inhibitory neuropeptide, galanin,
      in nocturnal rodents (mice and rats), diurnal rodents (degus), and cats. A
      homologous (i.e. galanin mRNA-containing cell group) is clearly distinguishable
      in the ventrolateral region of the preoptic area in diurnal and nocturnal
      monkeys, as well as in humans. Galanin expression may serve to identify sleep
      active neurons in the ventrolateral preoptic area of the mammalian brain. The
      VLPO appears to be a critical component of sleep circuitry across multiple
      species, and we hypothesize that shrinkage of the VLPO with advancing age may
      explain sleep deficits in elderly humans.

PMID- 12401342
TI  - Stromal cell-derived factor 1 is secreted by meningeal cells and acts as
      chemotactic factor on neuronal stem cells of the cerebellar external granular
      layer.
AB  - The cerebellar external granular layer (EGL) is an unusually long-lasting neural
      proliferative zone positioned immediately beneath the pial surface. Its position
      and stability critically depend on meningeal cells, as their selective
      destruction leads to its rapid dispersal, creating massive cortical ectopia.
      Similar ectopias have recently been described as a side effect of deficiency for
      stromal cell-derived factor 1 (SDF-1), a chemoattractant for haematopoietic
      precursor cell migration. Here we show that SDF-1 is present in meningeal cells
      in vivo and in vitro, where it is secreted in functionally relevant
      concentrations into the medium. Correspondingly, the SDF-1 receptor (termed
      CXCR4) can be demonstrated on stem cells of the external granular layer, but is
      absent on postmitotic cells commencing their final inward migration. We show that
      SDF-1 is concentrated by heparan sulphate proteoglycans highly expressed in the
      EGL in a laminar fashion, which thus might act to locally restrict SDF-1 action
      to the EGL in a kind of step gradient. In vitro, SDF-1 chemotactically attracts
      neuronal cells isolated from the external, but not from the internal granular
      layer, in a Boyden chamber assay in concentrations found in meningeal cell
      conditioned medium. Selective removal of SDF-1 from conditioned media by
      immunoprecipitation abolishes their chemoattractive action, which can be
      reconstituted again by the addition of recombinant SDF-1. Meningeal cells are
      thus an important source for the expression of SDF-1 during brain development,
      which--comparable to its role in haematopoiesis--appears to be a key factor
      attracting precursor cells to their proliferative compartment.

PMID- 12401343
TI  - Chemically induced neuronal damage and gliosis: enhanced expression of the
      proinflammatory chemokine, monocyte chemoattractant protein (MCP)-1, without a
      corresponding increase in proinflammatory cytokines(1).
AB  - Enhanced expression of proinflammatory cytokines and chemokines has long been
      linked to neuronal and glial responses to brain injury. Indeed, inflammation in
      the brain has been associated with damage that stems from conditions as diverse
      as infection, multiple sclerosis, trauma, and excitotoxicity. In many of these
      brain injuries, disruption of the blood-brain barrier (BBB) may allow entry of
      blood-borne factors that contribute to, or serve as the basis of, brain
      inflammatory responses. Administration of trimethyltin (TMT) to the rat results
      in loss of hippocampal neurons and an ensuing gliosis without BBB compromise. We
      used the TMT damage model to discover the proinflammatory cytokines and
      chemokines that are expressed in response to neuronal injury. TMT caused
      pyramidal cell damage within 3 days and a substantial loss of these neurons by 21
      days post dosing. Marked microglial activation and astrogliosis were evident over
      the same time period. The BBB remained intact despite the presence of multiple
      indicators of TMT-induced neuropathology. TMT caused large increases in whole
      hippocampal-derived monocyte chemoattractant protein (MCP)-1 mRNA (1,000%) by day
      3 and in MCP-1 (300%) by day 7. The mRNA levels for tumor necrosis factor (TNF)
      alpha, interleukin (IL)-1beta and IL-6, cytokines normally expressed during the
      earliest stage of inflammation, were not increased up to 21 days post dosing.
      Lipopolysaccharide, used as a positive control, caused large inductions of
      cytokine mRNA in liver, as well as an increase in IL-1beta in hippocampus, but it
      did not result in the induction of astrogliosis. The data suggest that enhanced
      expression of the proinflammatory cytokines, TNF-alpha, IL-1beta and IL-6, is not
      required for neuronal and glial responses to injury and that MCP-1 may serve a
      signaling function in the damaged CNS that is distinct from its role in
      proinflammatory events.

PMID- 12401344
TI  - In vivo proliferation, migration and phenotypic changes of Schwann cells in the
      presence of myelinated fibers.
AB  - Following injury to a peripheral nerve, changes in the behavior of Schwann cells
      help to define the subsequent microenvironment for regeneration. Such changes,
      however, have almost exclusively been considered in the context of Wallerian
      degeneration distal to an injury, where loss of axonal contact or input is
      thought to be critical to the changes that occur. This supposition, however, may
      be incorrect in the proximal stumps where axons are still in contact with their
      cell bodies. In this work, we studied aspects of in vivo Schwann cell behavior
      after injury within the microenvironment of proximal stumps of transected rat
      sciatic nerves, where axons are preserved. In particular we studied this
      microenvironment proximal to the outgrowth zone, in an area containing intact
      myelinated fibers and a perineurial layer, by using double immunolabelling of
      Schwann cell markers and 5-bromo-2'-deoxyuridine (BrdU) labeling of proliferating
      cells. In normal sciatic nerve, Schwann cells were differentiated, in an orderly
      fashion, into those associated with unmyelinated fibers that labeled with glial
      fibrillary acidic protein (GFAP) and those associated with myelinated fibers that
      could be identified by individual axons and myelin sheaths. After sciatic nerve
      transection, there was rapid and early expansion in the population of GFAP
      labeled cells in proximal stumps that was generated in part, by de novo
      expression of GFAP in Schwann cells of myelinated fibers. Schwann cells from this
      population also underwent proliferation, indicated by progressive rises in BrdU
      and GFAP double labeling. Finally, this Schwann cell pool also developed the
      property of migration, traveling to the distal outgrowth zone, but also with
      lateral penetration into the perineurium and epineurium, while in intimate
      contact with new axons. The findings suggest that other signals, in the injured
      proximal nerve stumps, beyond actual loss of axons, induce 'mature' Schwann cells
      of myelinated axons to dedifferentiate into those that up-regulated their GFAP
      expression, proliferate and migrate with axons.

PMID- 12401345
TI  - Monolithic silica rod liquid chromatography with ultraviolet or fluorescence
      detection for metabolite analysis of cytochrome P450 marker reactions.
AB  - In vitro cytochrome P450 assays are used in metabolism studies in support of
      early phases of drug discovery to investigate, e.g., metabolic stability, enzyme
      inhibition and induction by new chemical entities. LC-UV and LC-fluorescence are
      traditional analytical tools in support of such studies. However, these tools
      typically comprise different methods of relatively low throughput for the various
      metabolites of probe reactions. In recent years, LC-MS methods have been
      developed to increase throughput. Increased throughput can also be achieved by
      means of modern chromatographic tools in combination with UV and fluorescence
      detection. This approach is especially suitable when cytochrome P450 isoforms are
      investigated by means of single probe incubations. Here, an LC-UV/fluorescence
      system based on a monolithic porous silica column is described for the analysis
      of metabolites of nine cytochrome P450 marker reactions [phenacetin to
      paracetamol (CYP1A2), coumarin to 7-hydroxycoumarin (CYP2A6), paclitaxel to
      6alpha-hydroxypaclitaxel (CYP2C8), diclofenac to 4-hydroxydiclofenac (CYP2C9),
      mephenytoin to 4-hydroxymephenytoin (CYP2C19), bufuralol to 1-hydroxybufuralol
      (CYP2D6), chlorzoxazone to 6-hydroxychlorzoxazone (CYP2E1), midazolam to 1
      hydroxymidazolam (CYP3A4), and testosteron to 6beta-hydroxytestosteron (CYP3A4)].
      While offering sensitivities and linear ranges comparable to previously reported
      methods, the set-up described here provides ease of use and increased throughput
      with maximum cycle times of 4.5 min.

PMID- 12401346
TI  - Determination of chloral hydrate and its metabolites in blood plasma by capillary
      gas chromatography with electron capture detection.
AB  - A sensitive, accurate, and reliable method is described for the quantitative
      determination of chloral hydrate (CH) and its metabolites in blood plasma of mice
      and rats. Metabolites of CH include trichloroacetic acid (TCA), trichloroethanol
      (TCE), and trichloroethanol glucuronide (TCE-Glu). This new method uses capillary
      gas chromatography with electron-capture detection (GC/ECD). Procedures for
      improving sample stability and quality assurance are also described that were not
      mentioned in previous literature. Rat or mouse plasma (50 microl) is acidified
      (or treated enzymatically for TCE-Glu determination) and extracted with peroxide
      free methyl t-butyl ether. Distilled diazomethane (CH(2)N(2)) is added to
      derivatize TCA to its methyl ester. Detection limits were estimated at 0.2
      microg/ml for CH and TCE, and 0.1 microg/ml for TCA. Detector response to TCA and
      TCE were shown to be linear in the range of 3.125-200 microg/ml (r> or =0.9996).
      For CH, the response fits a second-order equation in this same range (r=0.99994)

PMID- 12401347
TI  - Sensitive biomonitoring of monoterpene exposure by gas chromatographic-mass
      spectrometric measurement of hydroxy terpenes in urine.
AB  - A gas chromatographic method with mass selective detection was developed which
      enables the simultaneous determination of the urinary hydroxy terpenes cis
      verbenol, alpha-terpineol, myrtenol, carveol, perillyl alcohol and trans
      sobrerol. The sample preparation consisted of enzymatic hydrolysis, solid phase
      extraction (SPE) with RP-C(18) SPE material and clean up with silica gel
      cartridges. Large volume injection was used and the mass selective detection was
      done in the single ion modus. Low detection limits in the range of 1.0-4.5
      microg/l for the terpene metabolites in urine and mean recoveries of 100% were
      achieved.

PMID- 12401348
TI  - Affinity chromatography of bull seminal proteins on mannan-Sepharose.
AB  - The interaction of bull seminal plasma proteins and sperm with mannan was
      investigated using an enzyme-linked binding assay (ELBA). A high mannan-binding
      activity was found in the protein fraction interacting with heparin. Mannan
      binding to seminal plasma proteins was inhibited by D-mannose and D-fructose, but
      not by D-mannose-6-phosphate, D-glucose-6-phosphate, ovalbumin and ovomucoid.
      Mannan inhibited the binding of bovine zona pellucida glycoproteins both to bull
      sperm and seminal plasma proteins. Yeast mannan immobilized to divinyl sulfone
      activated Sepharose was used for the isolation of mannan-binding proteins. The
      protein components of this fraction were identified on the basis of relative
      molecular mass determination and N-terminal amino acid sequencing: RNAase dimer,
      PDC-109 and a protein homologous to BSP-30K (relative molecular mass 14,500). The
      isolated proteins were characterized by a high zona pellucida binding activity.

PMID- 12401349
TI  - Direct injection micellar liquid chromatographic determination of benzodiazepines
      in serum.
AB  - A simple micellar liquid chromatographic (MLC) procedure is reported for the
      determination of several benzodiazepines in serum: bromazepam, diazepam,
      flunitrazepam, halazepam, medazepam, nitrazepam, oxazepam and tetrazepam. The
      optimization studies have been made in C(18) and C(8) columns, using solutions
      containing sodium dodecyl sulphate (SDS) modified with butanol or pentanol as
      mobile phases. The method proposed for the determination of the benzodiazepines
      uses a hybrid micellar mobile phase of 0.06 M SDS-5% butanol-0.01 M phosphate
      buffer (pH 7) at 25 degrees C, and UV detection (230 nm) in a C(18) column. The
      serum samples were injected directly, without any pretreatment, and eluted in
      less than 22 min, in accordance with their relative polarities, as indicated by
      their octanol-water partition coefficients. The limits of detection (ng ml(-1))
      were within the ranges of 2-6 and 4-18 for aqueous and serum samples,
      respectively. Repeatability and intermediate precision were tested for three
      different concentrations of the drugs, and RSD (%) was below 10 for most of the
      assays. The MLC results were compared with those obtained from a conventional
      HPLC method using methanol-water 5:5 (v/v) which requires a previous extraction
      procedure.

PMID- 12401350
TI  - Determination of methylnaltrexone in clinical samples by solid-phase extraction
      and high-performance liquid chromatography for a pharmacokinetics study.
AB  - A high-performance liquid chromatographic (HPLC) method with electrochemical
      detection and solid-phase extraction (SPE) using cartridges of weak cation
      exchange capacity as the primary retention mechanism is described for the
      separation and determination of methylnaltrexone (MNTX) in small clinical samples
      of plasma or urine. The procedure was performed using a Phenomenex Prodigy ODS-2,
      5 microm, 150x3.2 mm analytical column and 50 mM potassium acetate buffer, with
      11% methanol as organic modifier at pH* 4.5 at a flow-rate of 0.5 ml/min. The
      detection potential was 700 mV. The six-point standard calibration curves were
      linear over three consecutive days in the range from 2 to 100 ng/ml. The average
      goodness of fit (r) was 0.9993. The lower limit of detection (LOD) and limit of
      quantification (LOQ) were found to be 2.0 and 5.0 ng/ml, respectively. At the
      LOQ, the coefficient of variation for the entire method was 8.0% and the accuracy
      was 10.0% (n = 10). Recovery of the drug from plasma was in the region of 94%.
      The method was applied to a pharmacokinetics study of methylnaltrexone after
      subcutaneous administration and in numerous assays of analytes in blood plasma
      and urine. The pharmacokinetics parameters for a single dose of 0.1 or 0.3 mg/kg
      in plasma were C(max) = 110 (+/-55) and 287 (+/-101) ng/ml and t(max) = 16.7 (+/
      10.8) and 20.0 (+/-9.5) min, respectively. The method is simple, yet sensitive
      for the detection and determination of methylnaltrexone in biological samples at
      the level of the physiological response.

PMID- 12401351
TI  - Development and validation of a fast and sensitive chromatographic assay for all
      trans-retinol and tocopherols in human serum and plasma using liquid-liquid
      extraction.
AB  - A sensitive HPLC assay for all-trans-retinol, alpha-tocopherol, and gamma
      tocopherols in human serum and plasma is reported. Sample preparation is
      performed in one step and involves precipitation of proteins and extraction of
      lipids with two volumes of an ethanol-chloroform mixture (3:1, v/v) without I.S.
      addition. After removal of the precipitated protein, 20 microl aliquots of the
      supernatant (equivalent to 6.7 microl of serum or plasma) were injected into the
      HPLC system and analyzed using fluorometric detection. RP-HPLC was performed
      using a C(18) S3 ODS2 column with a methanol-water step gradient (97:3 to 100) at
      1.0 ml/min. The quantification limit expressed as nanograms of analyte per
      milliliter of serum or plasma was approximately 30 ng for all-trans-retinol, 300
      ng for alpha-tocopherol and 250 ng for gamma- and delta-tocopherol. The method
      was validated and applied to human serum and plasma from a total of 120 subjects.
      This procedure requires a small volume of serum or plasma and can therefore be a
      valuable tool for measuring low concentrations of these vitamins in preterm
      infants with sensitivity, precision and accuracy.

PMID- 12401352
TI  - Quantitative analysis of a model opioid peptide and its cyclic prodrugs in rat
      plasma using high-performance liquid chromatography with fluorescence and tandem
      mass spectrometric detection.
AB  - Two analytical methods were developed for quantitative determination of DADLE
      (H(2)N-Tyr-D-Ala-Gly-Phe-D-Leu-COOH) and its two cyclic prodrugs in rat plasma.
      For high-performance liquid chromatography with fluorescence detection (LC-FLU),
      precolumn derivatization of DADLE was accomplished by labeling the N-terminal
      amino group with the reagent naphthalene-2,3-dicarboxaldehyde in the presence of
      cyanide (NDA/CN) to form a highly fluorescent 1-cyanobenz[f]isoindole (CBI)
      derivative. A multi-dimensional LC system was employed to improve selectivity,
      and solid-phase extraction (SPE) was used for plasma sample preparation. The
      cyclic prodrugs were converted to DADLE prior to their derivatization. With
      fluorescence detection after derivatization, the limit of quantitation (LOQ) was
      6 ng ml(-1) for the analysis of DADLE, and good linearity was observed up to 6000
      ng ml(-1) in rat plasma. Quantitative analysis of DADLE and its cyclic prodrugs
      was also performed using liquid chromatography interfaced to electrospray
      ionization tandem mass spectrometry (LC-ESI-MS-MS). Chromatographic separation
      was achieved on a C(18) column using gradient elution in a water-acetonitrile
      system containing 0.1% (v/v) formic acid. The tandem mass spectrometric analysis
      was performed in the multiple reaction monitoring mode using internal
      standardization to improve assay precision and accuracy. For plasma sample
      pretreatment, acetonitrile was added first to precipitate proteins and SPE was
      used to minimize matrix effects. Using LC-ESI-MS-MS, the LOQ was 0.5 ng ml(-1)
      for DADLE and 2 to 5 ng ml(-1) for its prodrugs. Good linearity was observed from
      the LOQ up to 1000 ng ml(-1) for all compounds. For the analysis of DADLE, both
      analytical methods showed good precision, accuracy and stability. However, for
      prodrug analysis, LC-FLU showed some sensitivity and accuracy problems, while the
      LC-ESI-MS-MS method provided consistent and satisfactory results. In conclusion,
      LC-ESI-MS-MS is the method of choice for the analysis of DADLE and its cyclic
      prodrugs in rat plasma samples due to its good selectivity, high sensitivity, and
      fast analysis. Its application was demonstrated through biodisposition and
      bioconversion studies of the coumarinic acid-based prodrug after intravenous
      administration in rats.

PMID- 12401353
TI  - Heterogeneity of protein labeling with a fluorogenic reagent, 3-(2
      furoyl)quinoline-2-carboxaldehyde.
AB  - Fluorogenic reagents are used for protein labeling when high-sensitivity
      fluorescence detection is required. Similar to traditional labeling with
      activated fluorescent dyes, such as fluorescein isothiocyanate, a fluorogenic
      reaction is expected to change the physical-chemical properties of proteins.
      Knowledge of these changes may be essential for efficient separation and
      identification of labeled proteins. Here we studied the effect of labeling of
      myoglobin with a fluorogenic reagent on the acid-base properties of the protein.
      The fluorogenic reagent used was 3-(2-furoyl)quinoline-2-carboxaldehyde (FQ). In
      slab-gel isoelectric focusing, we found that the labeling reaction generated at
      least six species with pI values lower than that of non-labeled myoglobin. These
      species can be identified as products of progressive labeling of myoglobin with
      one to six FQ molecules. The same series of FQ-labeled species were observed when
      the reaction products were analyzed by capillary zone electrophoresis. The
      comparison of experimental and theoretical pI values allowed us to elucidate the
      labeling pattern--the number of FQ molecules corresponding to each labeled
      product detected by isoelectric focusing.

PMID- 12401354
TI  - Liquid chromatographic method for the determination of ganciclovir and/or
      acyclovir in human plasma using pulsed amperometric detection.
AB  - We have developed a simple, rapid and highly sensitive method for determining
      plasma concentrations of ganciclovir and/or acyclovir by using reversed-phase
      chromatography followed by pulsed amperometric detection. A linear relationship
      between the amount of ganciclovir (0.05-10 microg/ml plasma) or acyclovir (0.1-20
      microg/ml plasma) and peak height ratio was obtained. The relative standard
      deviations of all standard curves were greater than or equal to 0.999. The limits
      of detection for ganciclovir and acyclovir quantitation were 10 ng/ml and 50
      ng/ml (signal/noise >3), respectively. Daily fluctuations of plasma standard
      curves (n=5) for the ganciclovir and acyclovir samples were small, with relative
      standard deviations (RSD) of 3.3 and 4.5% (n=5), respectively. The intra-assay
      precision for the ganciclovir and acyclovir samples were 6.9 (n=5) and 5.5%
      (n=5), respectively. Inter-assay precision of ganciclovir (n=3) and acyclovir
      (n=3) ranged from 2.6 to 6.8% and 3.5 to 5.0%, respectively. Using this method,
      the pharmacokinetics and removal of ganciclovir during continuous
      hemodiafiltration (CHDF) in a liver transplant recipient being treated for severe
      cytomegalovirus infection was investigated. The mean (+/-SD) ratio of ganciclovir
      concentrations at the inlet and outlet of the dialyzer (C(outlet)/C(inlet)) was
      0.56+/-0.09. The areas under the curves of ganciclovir up to 12 h postdosing
      (AUC(0-->12)) at the inlet and outlet of the dialyzer were 12.54 microg h/ml and
      7.16 microg h/ml, respectively. The ultrafiltrate of ganciclovir was 16.6 mg. The
      terminal elimination half-life (T(1/2)) of ganciclovir during CHDF was 3.6 h.
      These results demonstrate that CHDF effectively removes ganciclovir. Until formal
      guidelines have been established, ganciclovir or acyclovir dosage should be
      adjusted according to the results of monitoring of plasma drug concentration. The
      method described here is suitable for clinical monitoring of plasma ganciclovir
      or acyclovir levels in solid organ transplant recipients and for use in studies
      involving pharmacokinetics.

PMID- 12401355
TI  - High-performance liquid chromatography-mass spectrometry method for the
      determination of paroxetine in human plasma.
AB  - A rapid and specific liquid chromatographic mass spectrometric (LC-MS-MS) method
      has been developed for the determination of paroxetine in human plasma. The
      procedure involves a liquid-liquid extraction of paroxetine and fluoxetine
      (internal standard) with cyclohexane-ethyl acetate. The standard curve was linear
      over a working range of 0.2-50 ng/ml. The lower limit of quantitation was 0.2
      ng/ml. No endogenous compounds were found to interfere with the analysis. The
      absolute recovery was 70.8% for paroxetine and 84.1% for the internal standard.
      The accuracy of inter-assay and intra-assay accuracy was in the ranges -4.8 to 
      0.5% and -3.4 to 4.8%, respectively. This method proved to be suitable for
      bioequivalence studies by being simple, selective and reproducible.

PMID- 12401356
TI  - High-performance liquid chromatographic separation of renin-angiotensin system
      peptides and most of their metabolic fragments.
AB  - We describe here a gradient HPLC procedure for the separation, and quantification
      by UV absorption of renin tri- and tetradecapeptide substrates, angiotensins I,
      II, III, IV and V, angiotensin-derived peptides, and peptidase inhibitors
      including amastatin, bestatin, pepstatin, lisinopril, a renin peptide inhibitor,
      Z-Pro-prolinal, N-[1-(R,S)-carboxy-2-phenylethyl]-L-Ala-L-Ala-L-Phe-p
      aminobenzoate, and phosphoramidon. Most peptides and peptidase inhibitors were
      baseline-resolved within 32 min. The overall intra- and inter-assay precisions
      ranged from 0.8 to 5.9 (n=6) and 2 to 13% (n=6), respectively. There was a linear
      relationship (correlation coefficients> or =0.9660) between peak height and
      peptide amount injected. In conclusion, the present method when combined with a
      peptidase-inhibitor paradigm can lead to the identification of renin-angiotensin
      system metabolizing enzymes, and when combined with radioimmunoassay can enhance
      the specificity of angiotensin measurement.

PMID- 12401357
TI  - Liquid chromatography analysis of enrofloxacin and ciprofloxacin in chicken blood
      spotted on filter-paper disks.
AB  - A simple, low-cost, sensitive and selective LC method was developed for the
      determination of enrofloxacin and ciprofloxacin in chicken blood. The method was
      applied to whole blood from a chicken using dried blood spots on filter paper
      disks. The detection limits of enrofloxacin and ciprofloxacin (100 microl of
      whole blood on a disk) were 0.005 and 0.01 microg/ml, respectively. The whole
      procedure was verified in intra-laboratory studies (recoveries of both compounds
      were above 90%), and its applicability was tested with blood from the chicken
      receiving enrofloxacin in a single oral dose at a level of 10 mg/kg body mass.
      The method permits the use of a small volume of blood from a chicken and should
      be useful for pharmacokinetic studies.

PMID- 12401358
TI  - Stable isotope dilution high-performance liquid chromatography-electrospray
      ionization mass spectrometry method for endogenous 2- and 4-hydroxyestrones in
      human urine.
AB  - A sensitive, precise and accurate stable isotope dilution high-performance liquid
      chromatography-electrospray ionization mass spectrometry method has been
      developed for measuring endogenous 2- and 4-hydroxyestrones, the main catechol
      estrogens in human urine. Compared to the published methods using gas
      chromatography-mass spectrometry, this approach simplifies sample preparation and
      increases the throughput of analysis. The unique part of our method is the use of
      a simple and rapid derivatization step that forms a hydrazone at the C-17
      carbonyl group of catechol estrogens. This derivatization step has greatly
      enhanced method sensitivity as well as HPLC separability of 2- and 4
      hydroxyestrones. Standard curves were linear over a 100-fold calibration range
      with correlation coefficients for the linear regression curves typically greater
      than 0.996. The lower limit of quantitation for each catechol estrogen is 1 ng
      per 10-ml urine sample, with an accuracy of 97-99% and overall precision,
      including the hydrolysis, extraction and derivatization steps, of 1-3% for
      samples prepared concurrently and 2-11% for samples prepared in several batches.
      This method is adequate for measuring the low endogenous levels of catechol
      estrogens in urine from postmenopausal women.

PMID- 12401359
TI  - Determination of histamine in the whole blood of colon cancer patients.
AB  - The aim of the present work is to investigate whether histamine assay could be
      useful in detecting the presence of primary cancer. The high-performance liquid
      chromatographic (HPLC)-based o-phthalaldialdehyde (OPA) histamine derivatization
      assay was investigated with respect to several variables, dramatization reagent
      concentration, organic solvent requirement, derivatization time and counter-ion
      effect on chromatographic separation. The OPA histamine assay, in the absence of
      added -SH groups, was found to detect histamine in whole blood samples with
      relative standard deviations <14% and recoveries not less than 90%. The assay
      showed high selectivity towards other aminic-containing compounds and a detection
      limit of 18 nM of histamine was evaluated. Calibration curves in the range 50-500
      nM were obtained by using histamine standards in 0.1 M HCl with a regression
      coefficient value (r(2)) of 0.9969. In order to assess the usefulness of this
      assay in primary tumor monitoring, two groups of individuals, 29 controls and 29
      colon cancer patients were selected, and serum levels of histamine, carcinogen
      embrionary antigen (CEA), carcinogen antigen 19.9 (CA19.9), and tumor staging,
      were determined. A significant histamine reduction (P=0.028) between controls
      (180.12+/-70.4 nM) and patients (134.5+/-90.3 nM) was found, and a cut-off value
      of 157.5 nM was extrapolated as intercept point of sensitivity and specificity
      curves. Fifty percent of patients showed a histamine value below the cut-off,
      while 45.8 and 8.3% of patients were positive for CEA and CA19.9, respectively.
      No correlation was found between Tumor Node Metastasis staging and histamine
      amount, indicating that this marker is not related to the tumor mass. Our data
      suggest that histamine level, together with other classical tumor markers, could
      be a potentially interesting tumor marker in colon cancer monitoring.

PMID- 12401360
TI  - Validation of a liquid chromatographic method for the determination of ibuprofen
      in human plasma.
AB  - A simple, rapid method of determining the ibuprofen concentration in small
      volumes of human plasma (50 microl) by HPLC was developed. The sample was
      prepared for injection using a solid-phase extraction method, with naproxen as
      the internal standard. A 96-well extraction plate was used, easing sample
      preparation and allowing the simultaneous extraction of multiple plasma samples
      directly into the HPLC injection vials. Samples were stable at room temperature
      for at least 48 h prior to injection. The HPLC method used an ultraviolet
      detector with a 5-min run time and measured concentrations across the range
      typically seen with the clinical use of this drug. The calibration curve was
      linear across the concentration range of 0.78-100 microg/ml with a limit of
      quantitation (LOQ) of 1.56 microg/ml. The coefficient of variation for intra-day
      and inter-day precision was 6% or less with accuracies within 2% of the nominal
      values for low (4.5 microg/ml), medium (40 microg/ml) and high (85 microg/ml)
      ibuprofen concentrations. For ibuprofen concentrations at the LOQ, the intra-day
      and inter-day precision and accuracy were within 10 and 15%, respectively.
      Recovery was 87% or greater for ibuprofen. This method was used to analyze plasma
      samples for unknown ibuprofen concentrations in bioequivalence and limited food
      effect studies of different formulations of ibuprofen. Thus, this method has been
      fully validated and used in the analysis of unknown plasma samples for ibuprofen.

PMID- 12401361
TI  - Trace analysis of tobramycin in human plasma by derivatization and high
      performance liquid chromatography with ultraviolet detection.
AB  - A simple and sensitive high-performance liquid chromatographic (HPLC) method is
      established for the trace determination of tobramycin in human plasma by
      derivatization. The method is based on the chemical derivatization of
      aminoglycoside antibiotic, tobramycin in human plasma, with 1-naphthyl
      isothiocyanate (NITC) in pyridine at 70 degrees C. After derivatization reaction,
      a methylamine/acetonitrile solution was added to the reaction mixture to
      eliminate the excess derivatizing agent and shorten the analysis time. The
      resulting derivative was separated using a Purospher STAR RP-18e column and a
      water-acetonitrile (50:50, v/v) mobile phase (detection at 230 nm). Optimization
      conditions for the derivatization of tobramycin were investigated by HPLC. The
      linear range for the quantitation of tobramycin in spiked plasma was over 0.93
      9.34 mg/l; the detection limit (signal-to-noise ratio=3; injection volume, 10
      microl) was about 0.23 mg/l. The relative standard deviation was less than 2.1%
      for intra-day assay (n=6) and 5.2% for inter-day assay (n=6) and relative
      recoveries were found greater than 99%.

PMID- 12401362
TI  - Evaluation of lipophilicity and antitumour activity of parallel carboxamide
      libraries.
AB  - Searching for molecules possessing antitumour activity, a parallel molecule
      library of aromatic carboxamides has been designed and synthesised. This work
      resulted in a "thiophene" sub-library containing a thiophene core and of a
      "furoyl" sub-library with a furoyl core, respectively. In both sub-libraries
      substitutions were carried out with six different groups resulting in six pairs
      of compounds differing in only the heteroatom of aromatic ring of the cores. To
      study the importance of the type of cores and the specific substitutions in
      relation to their lipophilicity and antitumour activity, lipophilicity of
      carboxamides was determined by chromatographical data (log k') and by software
      calculated parameters (CLOGP). Pairs of compounds were tested for their ability
      to inhibit the proliferation of the A431 cells by MTT assay. The isosteric
      molecule pairs were successfully separated. Our results showed that the
      experimentally determined (log k') and the calculated (CLOGP) lipophilicity
      parameters correlated well with each other. Furthermore, lipophilicity values of
      the thiophene sub-library were always higher than those in the furoyl sub
      library. Moreover, compounds of the thiophene sub-library were more active than
      their respective furoyl pairs in our MTT antiproliferative assay. From these
      observations we can conclude that the higher the lipophilicity values the higher
      the antitumour activity of the carboxamides synthesised. Therefore, determination
      of lipophilicity by measuring the log k' or by calculating the CLOGP values of
      the carboxamide sub-libraries may help to predict their biological activities.

PMID- 12401363
TI  - Measurement of bisphenol A in human urine using liquid chromatography with multi
      channel coulometric electrochemical detection.
AB  - Environmental exposure levels of bisphenol A (BPA) in human were investigated by
      measuring BPA glucuronide (BPA-G) in urine. After enzymatic hydrolysis of
      glucuronide substances in urine, BPA was extracted with diethyl ether. The
      extract was analyzed using a column-switching HPLC system employing a C(8) and a
      C(18) column with multi-channel coulometric electrochemical detection (ECD). The
      sensitivity and selectivity provided with redox mode of ECD allowed measurement
      of low level BPA in hydrolyzed urine. The quantification limit of BPA-G in urine
      was 0.2 ng/ml. RSDs of the intraassay precision were less than 3% and recoveries
      of the method were over 96% when analyzing BPA spiked urine samples (1.0 and 10
      ng/ml). In a group of 48 women students, the level of BPA-G in urine ranged from
      0.2 to 19.1 ng/ml with a median concentration of 1.2 ng/ml. Normalized against
      urinary creatinine, BPA-G ranged from 0.1 to 11.9 ng/mg creatinine with a median
      of 0.77 ng/mg creatinine.

PMID- 12401364
TI  - Rapid and quantitative determination of metabolites from multiple cytochrome P450
      probe substrates by gradient liquid chromatography-electrospray ionization-ion
      trap mass spectrometry.
AB  - A rapid quantitative assay method, developed by combining fast gradient liquid
      chromatography and electrospray ionization-ion trap mass spectrometry, is
      described for the simultaneous determination of CYP450 probe substrate
      metabolites (4-aminophenol for CYP2E1, acetaminophen for CYP1A2, dextrorphan for
      CYP2D6, 4'-hydroxymephenytoin for CYP2C19, 4-hydroxytolbutamide for CYP2C9 and
      6beta-hydroxytestosterone for CYP3A4) in microsomal incubations. Using this
      method Michaelis-Menten kinetic parameters K(m) and V(max) for the probe
      substrates in human liver microsomes were obtained. This LC-MS-MS method,
      developed with the use of LC-ESI-ion trap MS instrumentation, can efficiently be
      used to improve the throughput and cost-effectiveness in the preclinical drug
      metabolism studies.

PMID- 12401365
TI  - Quantitation of tryptophan, kynurenine and kynurenic acid in human plasma by
      capillary liquid chromatography-electrospray ionization tandem mass spectrometry.
AB  - Concentrations of tryptophan and its metabolites in plasma are of great interest
      in determining proper diagnosis and medication of several neurological diseases
      like, for example, Alzheimer's disease. A method of standard addition was
      developed to determine total level of tryptophan and two of its metabolites,
      kynurenine and kynurenic acid, in human plasma by capillary liquid chromatography
      electrospray ionization tandem mass spectrometry. Plasma samples were simply
      deproteinized by addition of diluted perchloric acid. Samples were then mixed
      with trichloroacetic acid and injected onto a capillary column. Analytes were
      separated by a fast gradient elution of the injected samples. Detection was
      performed by sheathless electrospray tandem mass spectrometry in the multiple
      reaction monitoring mode. Linear calibration curves were obtained for spiked
      plasma sample with up to 100% of the expected analytes concentrations. The
      determined concentrations were well within ranges previously reported (i.e., 6 nM
      95 microM) and limit of detections were around 3 nM for each analyte.

PMID- 12401366
TI  - Isolation of alpha-1-antitrypsin from human plasma by partitioning in aqueous
      biphasic systems of polyethyleneglycol-phosphate.
AB  - The partitioning of alpha-1-antitrypsin was assayed in biphasic aqueous systems
      containing potassium phosphate and two polyethyleneglycols of molecular mass 600
      and 1000, respectively. In order to isolate the alpha-1-antitrypsin from serum
      plasma, the partitioning behaviour of human serum albumin, its principal
      contaminant, was also studied. Several aqueous two-phase systems with different
      partitioning properties were obtained by varying the PEG1000/PEG600 mass
      proportion. In systems with PEG1000/PEG600 mass ratio of 8, the optimal
      difference between the partition coefficients of both proteins was found. Under
      such conditions, a satisfactory purification was carried out by a three-step
      extraction procedure. By applying this method the alpha-1-antitrypsin specific
      activity increased severalfold (nearly 10 times) with a yield of 43%.

PMID- 12401367
TI  - Application of solid-phase microextraction to the quantitative analysis of 1,8
      cineole in blood and expired air in a Eucalyptus herbivore, the brushtail possum
      (Trichosurus vulpecula).
AB  - We have developed two solid-phase microextraction (SPME) methods, coupled with
      gas chromatography, for quantitatively analysing the major Eucalyptus leaf
      terpene, 1,8-cineole, in both expired air and blood from the common brushtail
      possum (Trichosurus vulpecula). In-line SPME sampling (5 min at 20 degrees C room
      temperature) of excurrent air from an expiratory chamber containing a possum
      dosed orally with 1,8-cineole (50 mg/kg) allowed real-time semi-quantitative
      measurements reflecting 1,8-cineole blood concentrations. Headspace SPME using 50
      microl whole blood collected from possums dosed orally with 1,8-cineole (30
      mg/kg) resulted in excellent sensitivity (quantitation limit 1 ng/ml) and
      reproducibility. Blood concentrations ranged between 1 and 1380 ng/ml.
      Calibration curves were prepared for two concentration ranges (0.05-10 and 10-400
      ng/50 microl) for the analysis of blood concentrations. Both calibration curves
      were linear (r(2)=0.999 and 0.994, respectively) and the equations for the two
      concentration ranges were consistent.

PMID- 12401368
TI  - Gas chromatography-mass spectrometry method for determination of phenylalanine
      and tyrosine in neonatal blood spots.
AB  - In this paper we developed a simple, rapid and sensitive method for the
      quantitative analysis of phenylalanine (Phe) and tyrosine (Tyr) in dried blood
      spots of newborns by gas chromatography-mass spectrometry (GC-MS). Phe and Tyr in
      blood samples were reacted with N-methyl-N-(tert.
      butyldimethylsilyl)trifluoroacetamide at 120 degrees C for 30 min and their
      corresponding single derivatives were obtained. Phe and Tyr were determined by
      measurement of their derivatives by GC-MS in the selected ion monitoring mode.
      Contents of Phe and Tyr in blood spots were calculated by external standard
      method. The ratio of Phe to Tyr was used for neonatal screening for
      phenylketonuria. The present method only took a few minutes to perform and
      required minimal sample preparation. In addition it provided low detection limits
      of 1.2 micromol l(-1) for Phe and 1.6 micromol l(-1)for Tyr.

PMID- 12401369
TI  - Separation and selective detection of lipoprotein particles of patients with
      coronary artery disease by frit-inlet asymmetrical flow field-flow fractionation.
AB  - An analytical method to improve the characterization of lipoprotein fractions is
      presented. Human plasma samples were treated with Sudan Black B to stain the
      lipid component in lipoproteins, then the stained lipoproteins were separated by
      frit inlet asymmetrical flow field-flow fractionation (FI-AFlFFF), according to
      the lipoprotein particle sizes, with the selective detection of eluting
      lipoprotein fractions, high-density lipoproteins (HDL), low-density lipoproteins
      (LDL) and very-low-density lipoproteins (VLDL), at 610 nm. The capability of this
      technique has been evaluated with plasma samples obtained from patients with
      coronary artery disease (CAD), and it showed that the retention profile of
      patients' lipoprotein samples was clearly distinct from those of healthy persons.
      The potential of this technique comes with the direct injection of a stained
      lipoprotein sample without a prior procedure such as ultracentrifugation for
      sample preparation, and the size calculation of lipoprotein particles from the
      experimental retention time by theory. Since sample relaxation was achieved
      hydrodynamically in an FI-AFlFFF channel, sample injection and separation
      processes were continuously made without stopping the separation flow. This study
      demonstrated the potential of the FI-AFlFFF technique to be utilized as a
      powerful tool for the determination of the LDL profiles of patients with CAD.

PMID- 12401370
TI  - Isocratic ion-exchange chromatographic assay for the nucleotide gemcitabine
      triphosphate in human white blood cells.
AB  - An isocratic bio-analytical assay for the nucleotide gemcitabine triphosphate
      (2',2'-difluorodeoxycytidine 5'-triphosphate, dFdCTP) in human white blood cells
      (leukocytes) has been developed and validated. The method is based on ion
      exchange liquid chromatography and ultraviolet detection (275 nm). dFdCTP is
      isolated from the matrix by extraction with perchloric acid while the sample is
      chilled on ice. After neutralization with potassium hydroxide and removal of the
      potassium perchlorate precipitate, with the sample still chilled on ice, the
      mixture is injected into the chromatograph. The method has been validated in the
      range 0.4-20 microM, 0.4 microM (approximately 20 pmol/10(6) cells) being the
      lower limit of quantification, using erythrocytes as a substitute for leukocytes.
      Precisions and accuracies both meet the current requirements for a bioanalytical
      assay. The stability of dFdCTP in intact mononuclear blood cells on ice is
      strongly limited (half-life approximately 100 min) and after freezing the half
      life of the analyte in the cellular lysate is approximately 30 min. On the other
      hand, no degradation was observed for dFdCTP for at least approximately 24 h in
      perchloric acid extracts on ice or in neutralized extracts at ambient
      temperature. The applicability of the assay was demonstrated in white blood cells
      of a patient with advanced non-small cell lung cancer receiving i.v. gemcitabine.

PMID- 12401371
TI  - Determination of organophosphorus pesticide residues in human tissues by
      capillary gas chromatography-negative chemical ionization mass spectrometry
      analysis.
AB  - We describe an analytical method that allows the determination of
      organophosphorus pesticides (OPs) in different human tissues. It involves an
      extraction procedure with ethanol-ethyl acetate, followed by gel permeation
      chromatography clean-up step and analysis by capillary gas chromatography
      negative chemical ionization mass spectrometry in the selected ion monitoring
      mode. The method was tested for 37 OPs and the recoveries obtained vary between
      60 and 106% with standard deviations ranging between +/-2 and +/-10. These values
      are independent of the analyzed tissue. Peak area repeatability as RSD for some
      OPs was < or =4.8% while a good linear relationship in the range 1.0-500 pg
      microl(-1) with r(2)> or =0.9878 was obtained. The limit of detection for the 37
      OPs falls between 0.01 and 0.09 ng g(-1) with an RSD< or =9.5%. The analytical
      set up in this paper has been used to analyze different samples of human tissues
      (liver, healthy kidney, cancer kidney and adipose tissue) of 24 patients. The
      number of the identified OPs in the tissue samples is different (max. 20)
      according to the sample while their concentration ranges between the limit of
      detection and 28.0 ng g(-1). The highest concentrations have been determined in
      liver samples without any pathology (0.4-28.0 ng g(-1)) while the lowest
      concentrations have been determined in healthy kidney samples (0.01-1.50 ng g(
      1)). In the cancer kidney samples OP concentrations vary between 0.03 and 4.6 ng
      g(-1): these concentrations are more elevated than those determined in healthy
      kidney samples. The comparison between the concentration of OPs determined in the
      healthy part, when possible, and those determined in the cancer part of the same
      kidney sample are very interesting: in fact, in the latter the OP concentration
      is generally 1-2-times higher than that in the former, an index of lower
      enzymatic activity in the cancer tissue.

PMID- 12401372
TI  - Improved procedure for the separation of major stratum corneum lipids by means of
      automated multiple development thin-layer chromatography.
AB  - The separation of the major stratum corneum lipids, i.e., ceramides, fatty acids,
      cholesterol and its esters by means of high-performance thin-layer chromatography
      is hereby presented. The used automated multiple development technique allows the
      reproducible development of a 17-step solvent gradient also capable of separating
      seven ceramide classes in the same run. Reliable quantification has been
      performed after visualisation and densitometric scanning. The present approach is
      less time and solvent-consuming than previously described procedures. The
      application to samples obtained by in vivo skin surface extraction with hexane
      ethanol (2:1) demonstrates that the method can be routinely used for diagnostic
      purposes.

PMID- 12401373
TI  - Semi-automated determination of plasma stability of drug discovery compounds
      using liquid chromatography-tandem mass spectrometry.
AB  - A simple procedure for the measurement of stability of drug candidates in plasma
      was developed to eliminate the traditional labor-intensive and time-consuming
      sample preparation procedures that are typically used for these studies. The
      procedure makes use of a thermostatic autosampler as an incubator combined with
      the direct plasma injection method based on high-performance liquid
      chromatography (HPLC) coupled to tandem mass spectrometry (MS-MS). Untreated
      human, monkey, mouse and rat plasma containing the test compound was directly
      injected into a mixed-function column for on-line protein removal and
      chromatography. The test compound and its biotransformation product were
      separated via HPLC and monitored using the tandem mass spectrometer. The need for
      adequate chromatographic separation of the test compound (M) from its carboxylic
      acid metabolite (M+1) is demonstrated. Plasma samples from four different species
      at specified incubation temperatures were sequentially assayed in one analytical
      procedure. The injection-to-injection time was about 6 min. The peak responses of
      the test compound in individual plasma samples were repeatedly determined every
      24 min. The retention times and peak shape of all analytes were found to be
      consistent throughout the experiments. The stability of the test compound in
      plasma was found to be a function of animal species, incubation time and
      temperature. The test compound was rapidly degraded in rat plasma at 37 degrees
      C, but it could be stabilized by adding sodium thiosulfate.

PMID- 12401374
TI  - Phenotype of CYP2C19 and CYP3A4 by determination of omeprazole and its two main
      metabolites in plasma using liquid chromatography with liquid-liquid extraction.
AB  - We present a new simple and reliable HPLC method for measuring omeprazole and its
      two main metabolites in plasma. This can be used for studying CYP2C19 and CYP3A4
      genetic polymorphisms using omeprazole as the probe drug. Omeprazole,
      hydroxyomeprazole and omeprazole sulfone were extracted from plasma samples with
      phosphate buffer and dichloromethane-ether (95:5). HPLC separation was achieved
      using an Ultrasphere ODS C(18) (Beckman) column. The mobile phase was
      acetonitrile-phosphate buffer (24:76, pH 8), containing nonylamine at 0.015%.
      Retention times were 9.5 min for omeprazole, 3.25 min for hydroxyomeprazole, 7.4
      min for omeprazole sulfone and 6.27 min for internal standard (phenacetine).
      Detection (UV at 302 nm) of analytes was linear in the range from 96 to 864
      ng/ml. This is useful for calculating metabolic index for CYP2C19 and CYP3A4 in
      adults and children. This method is stable, reproducible, improves resolution and
      has practical advantages such as low cost.

PMID- 12401375
TI  - Triazine-human serum albumin association: thermodynamic approach and sodium
      effect.
AB  - Human serum albumin (HSA) serves as a carrier protein to transport triazine
      herbicides to molecular targets. In this paper, a theoretical treatment was
      developed to describe the HSA-triazine herbicides association. A determination of
      the association constant, K, as well as the degree of complexation n(c) (the
      percent of complex guest) was carried out. Enthalpy-entropy compensation was also
      analyzed in relation to this mathematical model to confirm the herbicide
      complexation behavior with HSA. The role of the sodium cation (Na(+)) on this
      association was investigated. It was expected that the sodium ion would act on
      the herbicide-HSA association process by modifying the surface tension of the
      bulk solvent and increase the K and n(c) values. The results showed that for
      patients who suffer from Na(+) desequilibrium, the triazine-HSA binding would
      change and as well the toxicological effect of these herbicides.

PMID- 12401376
TI  - Measurement of resiniferatoxin in cerebrospinal fluid by high-performance liquid
      chromatography.
AB  - A sensitive and simple high-performance liquid chromatographic (HPLC) assay was
      developed for the quantification of resiniferatoxin (RTX) in canine cerebrospinal
      fluid (CSF). A reversed-phase C(18) column and acetonitrile in 0.02 M NaH(2)PO(4)
      as mobile phase provided satisfactory resolution for RTX analysis. Direct HPLC
      analysis of the CSF samples without sample extraction or preparation improves the
      accuracy and detection limits of this assay. This assay was applied to measure
      CSF RTX content to test this method for research and clinical applications
      related to studies examining its analgesia effects.

PMID- 12401377
TI  - High-performance liquid chromatographic method with fluorescence detection for
      the screening and quantification of oxolinic acid, flumequine and sarafloxacin in
      fish.
AB  - A previously published liquid chromatographic method for determining residues of
      nine quinolones in chicken, porcine, bovine and ovine muscle was adapted and
      applied to fish tissue for simultaneous determination of three quinolones
      (flumequine, oxolinic acid and sarafloxacin). The analytes were extracted from
      homogenised muscle using an acetonitrile basic solution. After centrifugation,
      partial evaporation and cleaning with hexane, direct injection was possible.
      Separation was achieved on PLRP-S column and detection was performed with a
      programmable fluorescence detector. Chromatographic conditions were optimised to
      be compatible with the determination of the three quinolones in a single run. The
      linearity, recovery, accuracy and precision of the method were evaluated from
      fortified tissue samples at concentration levels ranging from 15 to 120 microg
      kg(-1) for sarafloxacin and 75 to 600 microg kg(-1) for oxolinic acid and
      flumequine according to the EU maximum residue limit of each quinolone. The
      limits of detection were estimated to be 2, 5 and 7 microg kg(-1), respectively,
      for sarafloxacin, oxolinic acid and flumequine. The limits of quantification were
      validated at 15 microg kg(-1) for sarafloxacin and 75 microg kg(-1) for oxolinic
      acid and flumequine. Mean extraction recoveries of quinolones in fish ranged from
      56.9 to 71.0%. This simple and rapid method is suitable for residue control.

PMID- 12401378
TI  - Real-time three-dimensional fetal echocardiography--optimal imaging windows.
AB  - A total of 15 fetuses were scanned using 2-D array volumetric ultrasound (US).
      Acquired cardiac data were converted for rendering dynamic 3-D surface views and
      reformatting cross-sectional views. The image usefulness was compared between the
      data obtained from subcostal/subxiphoid and other imaging windows; the former are
      usually free of acoustic shadowing. Of 60 data sets recorded, 12 (20%) were
      acquired through subcostal windows in 6 (40%) patients. Subcostal windows were
      unavailable from the remaining patients due to unfavourable fetal positions. Of
      the 12 sets, 6 (50%) provided the dynamic 3-D and/or cross-sectional views of
      either the entire fetal heart or a great portion of it for sufficient assessments
      of its major structures and their spatial relationships. Of 48 data sets from
      other windows, only 9 (19%) provided such 3-D and/or cross-sectional views; the
      lower rate being due to acoustic shadowing. Real-time 3-D US is a convenient
      method for volumetric data acquisition. Through subcostal windows, useful
      information about the spatial relationships between major cardiac structures can
      be acquired. However, to offer detailed information, considerable improvement in
      imaging quality is needed.

PMID- 12401379
TI  - Volume blood flow estimation in the normal and growth-restricted fetus.
AB  - The objective was to compare volume blood flow (VBF) in the descending aorta
      (DAo) of gestational age and weight-matched growth restricted (GR) and normal (N)
      fetuses. A longitudinal study of 20 N was compared with 11 GR in two analyses
      matched for weight and gestation. DAo dimensions and flow velocity were measured
      simultaneously using a new technique combining an ultrasonic phase-locked echo
      tracking system synchronized with a pulsed Doppler velocimeter. Cardiac output
      was estimated using standard echocardiographic views. DAo and semilunar valve
      diameters increased linearly in N and indexed cardiac output was similar in N and
      GR, although GR showed reduced DAo relative pulse amplitude, mean flow velocity
      and VBF. This synchronized technique permits calculation of VBF in human fetuses.
      Growth restriction is associated with reduced aortic wall pulsations and lower
      mean blood flow velocities and VBF in DAo secondary to increased placental
      impedance.

PMID- 12401380
TI  - New method of sentinel node identification with ultrasonography using albumin as
      contrast agent: a study in pigs.
AB  - The purpose of our study was to verify in animals the possibility of using
      albumin-enhanced ultrasonography as a modality for sentinel node detection. The
      nine pigs were injected subcutaneously in the neck with albumin, five with 5%
      solution and four with 25% solution, and then the regional lymph nodes were
      observed over time. It was found that, where the 5% solution had been injected,
      the lymph nodes showed no change, but where the 25% solution had been used, a
      high echo 1 to 5 mm in size was seen at the hilus of the nearest lymph node.
      Examination of the excised pathologic specimens of lymph nodes demonstrated that
      this echo was due to albumin accumulated in the efferent lymphatics. This finding
      suggested that this technique of ultrasonography using albumin as a contrast
      agent was an effective new method of identifying sentinel nodes.

PMID- 12401381
TI  - Carotid ultrasound backscatter analysis in hypertensive and in healthy subjects.
AB  - The purpose of this study was to evaluate, by integrated backscatter (IBS)
      analysis, the influence of arterial hypertension on the carotid ultrasound (US)
      reflectivity and the age-related changes of this parameter. We recruited 20
      middle-aged hypertensive patients free from other major cardiovascular risk
      factors and 20 gender- and age-matched healthy control subjects. An additional 30
      healthy subjects, 15 younger than 30 years old and 15 older than 65 years old
      were also recruited. The "calibrated" IBS (C-IBS) of the left carotid "distant"
      wall, calculated as the difference between the IBS mean value (62 measurements)
      of intima-media (IM) complex and the IBS mean value of adventitia (62
      measurements), was significantly higher in those with hypertension than in the
      age-matched controls, but similar between those with hypertension and the elderly
      subjects. In the 50 healthy subjects, the C-IBS was positively related to age (r
      = 0.40; p < 0.01) and to carotid IM thickness (r = 0.33; p < 0.05). Our study
      shows an increased US reflectivity of carotid wall in hypertensive patients and a
      positive relation of this parameter to age in the healthy population, suggesting
      that IBS analysis can be an useful tool to detect a vascular change related to
      hypertension and to aging.

PMID- 12401382
TI  - Fractal dimension estimation of carotid atherosclerotic plaques from B-mode
      ultrasound: a pilot study.
AB  - In this paper, a pilot study regarding carotid atherosclerotic plaque instability
      using B-mode ultrasound (US) images was carried out. The fractal dimension of
      plaques obtained from ten symptomatic subjects (i.e., subjects having experienced
      neurological symptoms) as well as from nine asymptomatic subjects, was estimated
      using a novel method, called the kth nearest neighbour (KNN) method. The results
      indicated a significant difference, as per the fractal dimension, between the two
      groups, providing a significantly lower value for the asymptomatic group.
      Moreover, the phase of the cardiac cycle (systole/diastole) during which the
      fractal dimension was estimated had no systematic effect on the calculations. The
      fractal dimension of the plaques was also estimated using a well-known method,
      namely the box-counting (BC) method. No significant differences between the two
      groups, as per the fractal dimension, were observed using the BC method. The
      presented pilot study suggests that the fractal dimension, estimated by the
      proposed method, could be used as a single determinant for the discrimination of
      symptomatic and asymptomatic subjects.

PMID- 12401383
TI  - Assessment of zebrafish cardiac performance using Doppler echocardiography and
      power angiography.
AB  - The zebrafish (Danio rerio) has become a new animal model for cardiac researches.
      Although it is equipped with a prototypical vertebrate heart, the zebrafish
      studies for cardiac mutations and genetic control of development can reveal some
      hints for solving human problems. Despite the simplicity of the zebrafish heart,
      the objective parameters of cardiac performance are not easily available, except
      for the morphological description, due to its small size. Because the four
      components (sinus venosus, atrium, ventricle and bulbus arteriosus) of the
      zebrafish heart are connected in series, we studied it by applying ultrasonic
      imaging methods for the vascular system. A total of 20 fishes that were ages of 3
      to 4 months were studied. Their mean body weight and height were 562 +/- 173 mg
      and 4.6 +/- 0.7 cm, respectively. Power angiography and routine Doppler
      echocardiography were used to evaluate the cardiac performance of zebrafish at 25
      degrees C and 15 degrees C. The zebrafish hearts could be easily identified with
      color Doppler (8.5 MHz) or power angiography (7 MHz). The ventricular filling
      flow contained two components (E and A-flow). The E-flow velocities were lower
      than the A-flow velocities at both 25 and 15 degrees C. The cycle length was
      prolonged (p < 0.05) and the velocities of ventricular filling and bulbus
      arteriosus decreased significantly at 15 degrees C (p < 0.05). A significant
      decrease in early diastolic deceleration slope and significant prolongation in
      early diastolic and late-diastolic deceleration times were found at a lower
      temperature (15 degrees C). The acceleration:deceleration ratio for early and
      late diastole also showed a significant difference at 15 degrees C. In
      conclusion, the cardiac performance of the zebrafish could be approached using
      commercially available clinical instruments equipped with Doppler
      echocardiography and power angiography.

PMID- 12401384
TI  - Elasticity of human vocal folds measured in vivo using color Doppler imaging.
AB  - Noninvasive measurement of human vocal fold (VF) vibratory length was made during
      normal phonation to calculate the corresponding elasticity. A fixed-ends rubber
      string phantom that was driven by a vibrating motor was built to simulate the
      horizontal VF movement. The vibratory artefact of color Doppler imaging (CDI) was
      used to characterize and quantify the high-frequency tissue vibration with small
      amplitude. Because the frequency and the length of vibrating VFs were obtained
      simultaneously, the stress-strain relation and the Young's moduli of the VFs
      could be calculated. For the six vocally normal adult volunteers (3 M, 3 F, ages
      from 19 to 51 years old), the effective vibrating lengths of the vocal fold in
      low pitch were about 1.4 to 1.6 cm and 1.3 to 1.5 cm for men and women,
      respectively. The VFs lengths extended to about 1.7 to 1.8 cm in pitch over an
      octave higher and the stress-strain relation was nonlinear. However, in the range
      of lower pitch, the VF stress was relatively linear with respect to the strains
      and the Young's moduli were about 30 to 120 kPa in men and 120 to 300 kPa in
      women.

PMID- 12401385
TI  - Quantitative ultrasound at the hand phalanges in monozygotic twins: a preliminary
      report.
AB  - The aim of this study was to assess the contribution of genetic and environmental
      factors on ultrasound (US) values within hand phalanges in monozygotic (MZ)
      twins. A total of 83 pairs of MZ twins (54 pairs of females, mean age 14.9 +/-
      8.3 years, SD, and 29 pairs of males, mean age 14.1 +/- 7.1 years) and a control
      group consisting of 21 pairs of dizygotic (DZ) twins (14 pairs of females, mean
      age 13.9 +/- 6.9 years and 7 pairs of males, mean age 13.0 +/- 5.6 years) with no
      reasons for potential influence on bone metabolism were studied. Skeletal status
      was assessed using DBM Sonic 1200 (IGEA, Carpi, Italy) which measures at the hand
      phalanges amplitude-dependent speed of sound (Ad-SoS, m/s). The intrapair
      correlation coefficients of Ad-SoS values were in MZ pairs 0.96 for males, 0.98
      for females and, in DZ pairs, 0.92 and 0.93, respectively (p < 0.0001). The
      intrapair correlation coefficients for Ad-SoS were significantly stronger in MZ
      pairs in comparison to DZ pairs (Fisher's test, p < 0.05). To study the
      hypothesis that the intrapair differences in Ad-SoS are connected with
      environmental factors, a simple linear regression analyses of absolute
      differences in Ad-SoS values with age were performed. In MZ pairs, increasing age
      was connected with significantly greater intrapair differences in Ad-SoS (for
      males r = 0.37, p < 0.05 and, for females, r = 0.32, p < 0.05). The results of
      multivariate linear analysis by using intrapair differences in Ad-SoS in MZ pairs
      as a dependent variable and age, weight and height as independent variables,
      showed that intrapair difference in Ad-SoS was influenced only by age, and not by
      weight, height, or intrapair differences in weight or height, for both males and
      females. The study provides the support for a significant contribution of
      heredity to skeletal status in MZ twins, although significantly greater intrapair
      differences in Ad-SoS with age suggest also the importance of environmental
      factors.

PMID- 12401386
TI  - Displacement sequence and elastic properties of anterior prostate/urethral
      interface during micturition of spinal cord injured men.
AB  - The management of complex micturition problems frequently encountered in patients
      with spinal cord injury (SCI) may be facilitated by characterization of the
      elastic properties of the prostate. To this end, we have developed a method of
      evaluating changes in prostate biomechanics using ultrasound (US) images obtained
      during routine diagnostic urodynamic evaluations. Ultrasound video sequences of
      the prostate and urethra during voiding were digitized simultaneously with
      bladder pressure measurement on 76 patients with spinal cord injury, having a
      mean age of 47 +/- 16 years. Computer enhancement of the
      bladder/prostate/urethral interface from sequences of 2-D US images facilitated
      measurement of midprostatic urethral displacement during micturition. Of 76
      patients, 21 were able to initiate voiding. Maximum urethral diameter was 12.0 +/
      1.3 mm, with corresponding maximum voiding pressure of 61.6 +/- 1.9 cmH(2)O.
      Urethral/prostatic pressure strain elastic modulus (Ep) was 960 +/- 624 N/m(2)
      and stiffness (beta) calculated as the inverse of compliance was 2.8 +/- 0.1. The
      diameter of the urethra at P(det50+), during the opening phase, was 0.4 +/- 0.1
      mm and, during the closing phase, was 0.7 +/- 0.1 mm. During voiding, the
      anterior prostate was displaced to a greater extent than the posterior prostate.
      These observations suggest that distension of the prostate/urethra during
      micturition is hysteretic and nonuniform and indicates regional differences in
      compliance within the prostate/urethra interface. These regional differences lend
      support to the concept that the posterior prostate is implicated in the active
      process of micturition involving the fibromuscular stroma. Clinical application
      of this method could include quantification of the biomechanics of micturition
      consequent to spinal injury, prostatic enlargement, and the impact of targeted
      evaluation of pharmacological interventions.

PMID- 12401387
TI  - A new ultrasound instrument for in vivo microimaging of mice.
AB  - We report here on the design and evaluation of the first high-frequency
      ultrasound (US) imaging system specifically designed for microimaging of the
      mouse. High-frequency US or US biomicroscopy (UBM) has the advantage of low cost,
      rapid imaging speed, portability and high resolution. In combination with the
      ability to provide functional information on blood flow, UBM provides a powerful
      method for the investigation of development and disease models. The new UBM
      imaging system is demonstrated for mouse development from day 5.5 of
      embryogenesis through to the adult mouse. At a frequency of 40 MHz, the
      resolution voxel of the new mouse scanner measures 57 microm x 57 microm x 40
      microm. Duplex Doppler provides blood velocity sensitivity to the mm per s range,
      consistent with flow in the microcirculation, and can readily detect blood flow
      in the embryonic mouse heart, aorta, liver and placenta. Noninvasive UBM
      assessment of development shows striking similarity to invasive atlases of mouse
      anatomy. The most detailed noninvasive in vivo images of mouse embryonic
      development achieved using any imaging method are presented.

PMID- 12401388
TI  - Transdermal delivery of poly-l-lysine by sonomacroporation.
AB  - A feasibility study of using high-amplitude ultrasound (US) to deliver large
      molecules transdermally was undertaken. US (20 kHz) of intensity in the range
      between 2 to 50 W/cm(2) was used to increase the permeability of skin in vitro to
      large size molecules. For example, when 20-kHz, 5% duty cycle US at the spatial
      average and pulse-average intensity I(SAPA) = 19 W/cm(2) was applied for 10 min
      and the distance between the US source and the surface of a skin specimen was 2
      mm, the skin permeability was calculated to be 0.5 +/- 0.2 cm/h and 8.5 +/- 4.2
      cm/h, respectively, for poly l-lysine-fluorescein isothiocyanate (FITC) (51 kDa)
      and octa-1-lysine-FITC (2.5 kDa). Without application of US, the skin
      permeability of the above-mentioned molecules would be essentially zero. A
      transdermal flux enhancement occurring during the process reported here was much
      higher than that due to sonophoresis (I(SAPA) < 2 W/cm(2)) as reported in the
      literature. For comparison, for example, the skin permeability for delivering
      erythropoeitin (48 kDa) and insulin (6 kDa) reached 9.8 x 10(-6) and 3.3 x10(-3)
      cm/h, respectively, by using sonophoresis for 1 h US exposure. Experimental
      results from transdermal flux kinetics, and confocal microscopic cross-sectional
      and optical images, suggested that the formation of pores in the stratum corneum,
      whose size varies with skin samples, may be in the range of 1 to 100 microm. The
      confocal images also suggest the formation of microm-size pathways in epidermis
      during US exposure.

PMID- 12401389
TI  - In vitro thrombolysis enhanced by standing and travelling ultrasound wave fields.
AB  - Success of thrombolytic therapy depends on penetration of recombinant tissue
      plasminogen activator (rt-PA) into clots. Ultrasound (US) of therapeutic quality
      accelerates thrombolysis in vitro. As yet, only the effects of travelling
      acoustic waves on thrombolysis have been investigated, and the impact of standing
      acoustic waves has been neglected. In the present study, we examined the effects
      of standing and travelling US wave fields applied continuously for 1 h (frequency
      2 MHz, acoustic intensity 1.2 W/cm(2)) on thrombolysis enhancement by measuring
      clot weight reduction and concentration of fibrin degradation product D-dimer
      (FDP-DD) produced from clots subjected to rt-PA. The level of FDP-DD was 1.8
      times greater in travelling than in standing acoustic waves. Thrombolysis
      enhancement was 46.0 +/- 20.8% in standing and 116.8 +/- 23.1% in travelling
      acoustic waves. Travelling waves enhanced thrombolysis significantly more (p <
      0.0001) than did standing waves.

PMID- 12401390
TI  - Ultrasound nucleolysis: an in vitro study.
AB  - Thermal intradiscal therapy for chronic low back pain, using a catheter inserted
      into the intervertebral disc, is becoming more popular in the treatment of low
      back pain. The aim of this study was to investigate the possibility of heating
      the nucleus pulposus of the intervertebral disc with high-intensity focused
      ultrasound (US) or HIFU. Two specific situations were considered, invasive
      transducers that would be in contact with the annulus fibrosus of the disc, and
      noninvasive transducers that could be used externally. Theoretical simulations
      were performed to find the optimal parameters of US transducers and then
      experimental studies were done using transducers made to these specifications.
      These experiments confirmed that it was possible to heat the discs with HIFU. Two
      orthogonal transducers resulted in a superior temperature distribution than using
      just one transducer. It is, therefore, feasible to consider thermal treatment of
      the nucleus pulposus of the disc using noninvasive US.

PMID- 12401391
TI  - In vitro sonoluminescence and sonochemistry studies with an electrohydraulic
      shock-wave lithotripter.
AB  - Sonoluminescence and sonochemistry from a cavitation field generated by an
      electrohydraulic shock-wave lithotripter were investigated as functions of spark
      discharge voltage (13 to 21 kV) and pulse-repetition frequency (PRF) (0.5 to 2.0
      Hz). Sonochemical activity, measured with an iodide dosimeter, increased with
      both voltage and PRF. Sonoluminescence was measured in an acoustically matched
      light-tight box. The envelope of the light intensity was measured in a temporally
      gated region extending from the initial arrival of the shock wave (resulting in
      bubble compression) to the final inertial collapse of the bubble cloud, which
      follows hundreds of micros after passage of the shock wave. The initial
      compression resulted in greater sonoluminescence emissions, suggesting that the
      initial bubble compression due to the leading positive pressure spike from the
      lithotripter generated higher temperatures than the inertial collapse of the
      bubble. These unexpected results are consistent with some recent calculations in
      which the vapor pressure of the liquid limits compressional heating.

PMID- 12401392
TI  - Acoustic attenuation properties of the lung: an open question.
AB  - Between 1961 and 1986, a number of investigators studied the propagation
      properties of ultrasound (US) in the lungs. These studies revealed high
      attenuation levels in the lung tissue at all levels of lung inflation. In
      contrast, some clinical investigators have, in the past decade, used US at 5 to
      7.5 MHz to penetrate the collapsed lung effectively during intraoperative
      thoracic ultrasonography. There is a discrepancy between these clinical imaging
      results and the high attenuation levels found in the earlier studies of US
      propagation in the lungs. We studied the attenuation of US in the lungs with an
      ultrasonic analyzer, designed for highly attenuating materials, and utilizing
      linear sweep-based transmission measurements. Our data also revealed high
      attenuation levels at various low levels of lung inflation, inconsistent with the
      findings of intraoperative thoracic ultrasonography. These results imply that the
      US attenuation properties of the lung are far from accurately established.

PMID- 12401393
TI  - Models and regulatory considerations for transient temperature rise during
      diagnostic ultrasound pulses.
AB  - A new diagnostic ultrasound (US) technique, sometimes called radiation force
      imaging, produces and detects motion in solid tissue or acoustic streaming in
      fluids via a high-intensity beam. Current models for estimating temperature rise
      during US exposure calculate the steady-state rise, using time-averaged acoustic
      output, as the worst case for safety consideration. Although valid for very short
      pulses, this analysis might not correspond to a worst-case scenario for the
      longer pulses or pulse bursts, up to hundreds of ms, used by this newer method.
      Models are presented to calculate the transient temperature rise from these pulse
      bursts for both the bone at focus and soft tissue situation. It is shown, based
      on accepted time-temperature dose criteria, that, for the bone at focus case and
      pulse lengths and intensities utilized by these methods, temperature may increase
      to levels that raise safety concerns. Also, regulatory aspects of this modality
      are analyzed in terms of the current FDA acoustic output limits for diagnostic US
      devices.

PMID- 12401394
TI  - Endogenous ligands of Toll-like receptors: implications for regulating
      inflammatory and immune responses.
AB  - Toll-like receptors (TLRs) have a crucial role in regulating immunity against
      microbial agents. Recent studies indicate that these receptors might also have an
      important role in regulating responses to endogenous stimuli, such as necrotic
      cells, heat-shock proteins and extracellular matrix breakdown products.
      Specifically, TLR2 and TLR4 were shown to mediate expression of inflammatory
      genes and trigger dendritic-cell 'maturation' by these agents. These intriguing
      findings suggest that the ancient family of TLRs are involved in the recognition,
      not only of microbes, but also of endogenous harmful stimuli. However, potential
      complications associated with microbial contamination of endogenous agents and
      the specific nature of in vivo responses induced by these agents remain to be
      determined.

PMID- 12401395
TI  - Growth factor treatment of demyelinating disease: at last, a leap into the light.
AB  - Researchers seeking treatments for multiple sclerosis (MS) have long dreamed of
      using neurotrophic factors to enhance remyelination. Previous attempts to apply
      trophic support for oligodendrocytes in experimental demyelination uniformly
      produced complicated outcomes that reflected unexpected effects on immune or
      inflammatory responses and could be interpreted only with caution. Now, two
      recent publications have demonstrated convincingly that cytokines of the
      interleukin (IL)-6 superfamily can ameliorate experimental autoimmune
      encephalomyelitis and promote oligodendrocyte survival, without demonstrable
      effect on inflammation or immune responses.

PMID- 12401396
TI  - Distinct subsets of human Valpha24-invariant NKT cells: cytokine responses and
      chemokine receptor expression.
AB  - CD1d-restricted T-cell receptor Valpha-invariant natural killer T (NKT) cells are
      important regulators of immune responses through their efficient secretion of T
      helper 1 (Th1) and Th2 cytokines. Recently, it has been shown that this NKT-cell
      population contains functionally distinct subsets, producing different sets of
      cytokines and cytotoxic effector molecules. NKT-cell subsets are also distinct
      from each other in their expression of adhesion molecules and chemokine
      receptors, suggesting that they might be targeted to different tissues and
      perform different immune functions.

PMID- 12401404
TI  - Is selection for TCR affinity a factor in cytokine polarization?
AB  - Many factors influence polarization of CD4 T cells to Th1 or Th2, including those
      collectively termed 'strength of stimulation', such as peptide dose and duration
      of T-cell receptor (TCR) engagement. When other factors dictate the need for a
      Th1 or Th2 response, there might be selection from the TCR pool, selecting for
      those with optimal affinity for the desired cytokine profile. In a Th2
      environment, this would entail selection from the bulk population of lower
      affinity receptors, causing differential signaling and favoring transcription of
      Th2 cytokines. Reliance on experiments using a single, transgenic TCR polarized
      into either subset might have obscured the fact that, under physiological
      conditions, there is selection for differential TCRs on the basis of affinity.

PMID- 12401405
TI  - Autoimmunity on alert: naturally occurring regulatory CD4(+)CD25(+) T cells as
      part of the evolutionary compromise between a 'need' and a 'risk'.
AB  - Autoimmunity, at least in the central nervous system (CNS), is not only an
      outcome of immune system malfunction, but is the body's own protective mechanism
      against destructive self-compounds. Likewise, the naturally occurring regulatory
      CD4(+)CD25(+) T cells have a physiological function, and are not merely an
      evolutionary adaptation to suppress self-reactive T-cell clones that escaped
      deletion in the thymus. We postulate that the regulatory T (Tr) cells are the
      product of an evolutionary compromise between the need for autoimmunity on alert
      for tissue maintenance and the need to control autoimmunity to avoid autoimmune
      disease. In the event of an insult to the CNS, the balance between self-reactive
      (effector) T cells and Tr cells determines the time of onset, the intensity and
      the duration of the autoimmune response. This response might thus represent an
      adaptive mechanism, which is optimal for day-to-day maintenance, but insufficient
      in extreme cases of CNS damage or failure of regulation. Downregulation or
      upregulation of CD4(+)CD25(+) Tr cells might be a way to achieve better
      protection from neurodegenerative conditions induced by self-destruction or avoid
      autoimmune inflammatory disease development, respectively.

PMID- 12401406
TI  - Inflammation and immune responses in atherosclerosis.
AB  - Recent studies have highlighted the role of inflammatory mediators and the cells
      of the innate and adaptive immune response in the initiation, growth and rupture
      of atherosclerotic plaques. Viewing this form of vascular pathology as a modified
      form of chronic inflammation suggests new avenues for therapeutic intervention in
      cardiovascular disease.

PMID- 12401407
TI  - Formyl-peptide receptors revisited.
AB  - Leukocytes accumulate at sites of inflammation and microbial infection in direct
      response to locally produced chemotactic factors, which signal through specific G
      protein-coupled receptors. The first chemotactic factors to be structurally
      defined were the N-formyl peptides. Unlike other leukocyte chemoattractants, N
      formyl peptides could originate from either an endogenous source, such as the
      mitochondrial proteins of ruptured host cells, or an exogenous source, such as
      the proteins of invading pathogens. This suggests that the formyl-peptide
      receptor (FPR) and its variant FPRL1 (FPR-like 1) are involved in host defense
      against bacterial infection and in the clearance of damaged cells. Recently,
      additional, more complex, roles for these receptors have been proposed because
      FPR, and to a greater extent FPRL1, have been found to interact with a menagerie
      of structurally diverse pro- and anti-inflammatory ligands associated with
      different diseases, including amyloidosis, Alzheimer's disease, prion disease and
      HIV. How these receptors recognize such diverse ligands, which are the most
      important in vivo, and how they contribute to disease pathogenesis and host
      defense are basic questions currently under investigation that could lead to new
      therapeutic targets.

PMID- 12401408
TI  - Macrophage polarization: tumor-associated macrophages as a paradigm for polarized
      M2 mononuclear phagocytes.
AB  - Mononuclear phagocytes are versatile cells that can express different functional
      programs in response to microenvironmental signals. Fully polarized M1 and M2 (or
      alternatively activated) macrophages are the extremes of a continuum of
      functional states. Macrophages that infiltrate tumor tissues are driven by tumor
      derived and T cell-derived cytokines to acquire a polarized M2 phenotype. These
      functionally polarized cells, and similarly oriented or immature dendritic cells
      present in tumors, have a key role in subversion of adaptive immunity and in
      inflammatory circuits that promote tumor growth and progression.

PMID- 12401411
TI  - Who cares about recruitment anyway?

PMID- 12401412
TI  - If you build it, will they come?. Reach and Adoption associated with a
      comprehensive lifestyle management program for women with type 2 diabetes.
AB  - This paper describes recruitment and participation of physicians and patients in
      a randomized study to evaluate the effects of a moderately intensive (2-year)
      lifestyle management intervention for post-menopausal women with type 2 diabetes
      at risk for coronary heart disease (CHD). The purpose of this report is to answer
      two practical public health questions: (1) "Will physicians refer their patients
      with type 2 diabetes to such an intensive lifestyle change program?" and, if so,
      (2) "Will these patients participate?" Results showed high (70%) acceptance among
      physicians. About 51% of eligible patients agreed to participate, which was
      encouraging given the substantial time commitment involved. Main reasons for
      refusal were lack of eligible patients (among physicians) and lack of time (among
      patients). Patient participants and non-participants did not differ significantly
      on age, body mass, and other demographic and medical variables. Based on these
      results, it appears that appropriate recruitment procedures will yield a
      representative sample of women willing to participate in intensive lifestyle
      management programs.

PMID- 12401413
TI  - Integrating patient teaching into bedside patient care: a participant-observation
      study of hospital nurses.
AB  - Today's patients are quickly discharged from hospitals and often continue complex
      treatments at home. Patient teaching is critical and hospital nurses are
      encouraged to use "every teachable moment." This study explored and described the
      nature of integrating patient teaching into daily patient care and the factors
      influencing the delivery of teaching. A fieldwork method, conducted over 12
      months, used participant-observation (PO) and a focus group session to answer the
      research questions. Three experienced registered nurses working on the oncology
      unit of an acute care community hospital served as informants. Critical
      attributes and patterns of observed teaching events were described.

PMID- 12401414
TI  - Implementation, generalization and long-term results of the "choosing well"
      diabetes self-management intervention.
AB  - Prerequisites for translating intervention research findings into practice are
      maintenance of results, generalization of effects and consistency of
      implementation. This report presents 12 months follow-up information on a
      randomized 2x2 factorial trial evaluating the incremental effects of adding (1)
      telephone follow-up or (2) a community resources utilization component to a basic
      touchscreen computer-assisted dietary goal-setting intervention for 320 type 2
      diabetes patients. All conditions evidenced significant improvement from baseline
      to the 12 months follow-up across behavioral, biological and psychosocial
      measures. There were few consistent differences between conditions, but results
      were robust across interventionists and clinics. The telephone follow-up
      component appeared to enhance long-term results on some measures. When considered
      along with earlier results from a randomized trial that included a control
      condition without goal setting, it is concluded that this basic goal-setting
      intervention can be consistently implemented by a variety of interventionists and
      produce lasting improvements.

PMID- 12401415
TI  - Hospitalized patients' views on in-ward psychological counseling.
AB  - This qualitative study explores the feelings and beliefs of patients hospitalized
      in an orthopedic rehabilitation ward for receiving psychological help in that
      setting. Semi-structured interviews with 10 hospitalized patients were
      audiotaped, transcribed verbatim, and analyzed using interpretative
      phenomenological analysis (IPA). Themes of an approach-avoidance conflict towards
      receiving psychological help were identified, some of them unique to the hospital
      setting. Approach tendencies were associated with high psychological distress,
      awareness of free accessibility, and beliefs in body-mind relationship. Avoidance
      tendencies were associated with fears of psychotherapy, misconceptions, and
      perceived threats to one's independence and self-esteem. The implications of
      these findings for the provision of psychological counseling in hospital settings
      are discussed.

PMID- 12401416
TI  - Provision of information and advice in cardiovascular care: clinical performance
      of general practitioners.
AB  - The aim of this study was to assess the provision of information and advice by
      general practitioners (GPs) with respect to patients with hypertension,
      hypercholesterolaemia, or cardiovascular disease. The study relied on the
      prospective recording of patient encounters by GPs. Performance indicators were
      selected from the Dutch national guidelines for general practice. The GPs (n=195)
      completed 5330 encounter forms. High levels of performance were found with regard
      to advice on smoking cessation and the provision of information (e.g. information
      about alarm symptoms or the aim of treatment). Low levels of performance were
      found with regard to advice on salt consumption, alcohol consumption, weight
      reduction and physical exercise for patients with hypertension. Discussion of
      compliance with the therapy in case of hypercholesterolaemia, advice on physical
      exercise in case of angina pectoris and advice on foot care in case of peripheral
      arterial disease also showed a substantial gap between recommended and actual
      care. Performance rates varied considerably across GPs. The patient and GP
      characteristics examined in this study contributed very little to the clinical
      performance.

PMID- 12401417
TI  - Gender differences in the psychological adjustment to type 1 diabetes mellitus:
      an explorative study.
AB  - This study examined gender differences in (1) the psychological adjustment to
      diabetes and (2) the relation between psychological adjustment and metabolic
      control in patients with type 1 diabetes. The 280 adult patients attending the
      outpatient diabetes clinic completed psychological self-rating questionnaires
      evaluating coping, depression, marital satisfaction, cognitive and emotional
      adjustment to diabetes. Glycaemic control was measured with HbA(1c)-values. This
      study revealed that men used significantly more active coping, less avoiding,
      less social support seeking and less depressive coping. Despite these
      differences, glycaemic control was not significantly better in men than in women.
      Women reported more depressive symptomatology than men did and more women were
      depressed. Significant gender differences were also found in psychological
      adjustment to diabetes. The psychological factors negatively related with the
      psychological adjustment to diabetes in men and women are depressive coping and
      depressive symptomatology.

PMID- 12401418
TI  - Program development for promoting adherence during and after exercise therapy for
      urinary incontinence.
AB  - This paper presents the development process of a health education program to
      promote adherence to a pelvic floor muscle exercise (PFME) therapy for women with
      urinary incontinence (UI). The development process started with a needs
      assessment phase in which the health problem, health-related quality of life, and
      behavioral and environmental determinants were assessed. Guided by the
      intervention mapping (IM) approach, program objectives were formulated and, on
      the basis of both empirical and theoretical data, intervention methods for
      influencing determinants of adherence to PFME therapy were chosen and translated
      into practical strategies. This information was assimilated to a transparent
      description of the program design. The theoretical rationale of the program was
      based on the transtheoretical model, the self-regulation theory and principles of
      targeted communication and sex-specific health care.

PMID- 12401419
TI  - Cross-cultural differences in lay attitudes and utilisation of antibiotics in a
      Belgian and a Dutch city.
AB  - Cultural differences are probably an important factor in the considerable
      variation in antibiotic use between countries. The objective of this study was to
      explore local cultural differences in the lay perspective on coping with URTD and
      using antibiotics. We interviewed 30 persons in a Dutch and a Belgian city.
      Twenty-one were interviewed a second time after 3 months. Between the first and
      second interview, they noted in a diary all URTD episodes experienced by
      themselves and their family members (N=69) and how they coped with them. The
      Dutch participants labelled most URTD episodes as "common cold" or "flu". The
      Flemish participants labelled most of their URTD episodes as "bronchitis" and
      used more antibiotics. Four categories of antibiotic users could be
      distinguished. Participants with a Protestant background were more sceptical
      about medicines than those with a Catholic background. A thorough understanding
      of the cultural context is necessary to design effective campaigns to promote
      rational antibiotic use.

PMID- 12401420
TI  - Doctors expressions of uncertainty and patient confidence.
AB  - Although recent work has encouraged doctors to express their uncertainty to
      patients as a means to improve communication the potential impact of this on
      patients remains unclear. The present study first explored the impact of the way
      in which uncertainty was expressed (behaviourally versus verbally) on doctor's
      and patient's beliefs about patient confidence. Second the study examined the
      role of the patient's personal characteristics and knowledge of their doctor as a
      means to address the broader context. Matched questionnaires were completed by
      GPs (n=66, response rate=92%) and patients (n=550, response rate=88%) from
      practices in the south-east of England. The results showed that the majority of
      GPs and patients viewed verbal expressions of uncertainty such as 'Let's see what
      happens' as the most potentially damaging to patient confidence and both GPs and
      patients believed that asking a nurse for advice would have a detrimental effect.
      In contrast, behaviours such as using a book or computer were seen as benign or
      even beneficial activities. When compared directly, GPs and patients agreed about
      behavioural expressions of uncertainty, but the patients rated the verbal
      expressions as more detrimental to their confidence than anticipated by the
      doctors. In terms of the context, patients who indicated that both verbal and
      behavioural expressions of uncertainty would have the most detrimental impact
      upon their confidence were younger, lower class and had known their GP for less
      time. To conclude, patients' reactions to uncertainty occur within the context of
      the patient's own background and experience, however, some consistent responses
      can be found. In particular, whilst behavioural expressions of uncertainty may
      have a positive impact upon patient confidence, verbal expressions have a
      consistently detrimental effect which is underestimated by GPs.

PMID- 12401421
TI  - Self-management approaches for people with chronic conditions: a review.
AB  - The purpose of this paper is to provide an overview of self-management approaches
      for people with chronic conditions. The literature reviewed was assessed in terms
      of the nature of the self-management approach and the effectiveness. Findings are
      discussed under the headings of: chronic conditions targeted, country where
      intervention was based, type of approach (e.g. format, content, tutor, setting),
      outcomes and effectiveness. The last of these focused on reports of randomised
      controlled studies.

PMID- 12401422
TI  - Perceptions of asthma in South Asians and their views on educational materials
      and self-management plans: a qualitative study.
AB  - Asians with asthma have higher hospital admission rates than whites without any
      evidence of increased asthma severity. There is limited information as to whether
      these differences are due to language or communication difficulties, variable
      knowledge and cultural attitudes to asthma or deficiencies of medical care. A
      qualitative study with 60 participants (12 participants with asthma for semi
      structured interviews and 48 participants for focus groups) was designed to
      explore knowledge about asthma, attitudes, perceptions, health beliefs and health
      needs of those from Pakistan and India (South Asians). Overall, most of the
      patients with asthma were aware of the symptoms and trigger factors of asthma and
      were well informed about the 'reliever' and 'preventer' properties of their
      inhalers. They were also well informed about alternative/complementary therapies
      and were willing to try them should the treatment provided by their general
      practitioner (GP) fail to resolve their symptoms. Most were dissatisfied with the
      asthma care provided by their GPs e.g. delays in making the diagnosis and
      deficiencies in providing both verbal and written information on asthma. There
      was lack of awareness about self-management plans although when explained, the
      concept of self management was well received and there was approval for the
      concept of written action plans. All the focus group participants seemed to know
      something about asthma and amongst those with the condition (or with relatives
      with the condition), knowledge of the disease and its treatment seemed to be
      good. It was concluded that improved dissemination of written and verbal
      information on all aspects of asthma and increased awareness, training and
      support for adoption of written self-management (action) plans is needed to
      provide a more efficient and effective service for South Asian patients with
      asthma.

PMID- 12401423
TI  - Steering between weight extremes.

PMID- 12401424
TI  - Coping with sports injuries: an examination of the adolescent athlete.
AB  - Forty-eight injured adolescent athletes completed questionnaires over 3 months
      after injury to assess psychosocial outcomes. Depressive symptoms decreased over
      time, and the lack of positive stress and high athletic identity were associated
      with early depressive symptoms after accounting for injury severity. Increased
      social support was associated with lower initial depressive symptoms.

PMID- 12401425
TI  - Dimensions of adolescent health behavior.
AB  - PURPOSE: To determine dimensions of healthy and unhealthy behaviors of young
      people aged 12 to 21 years to better inform measures of adolescent health
      behavior and assist in targeting appropriate strategies to promote health.
      METHODS: The study sample (N = 8730), derived from a U.S. national probability
      sample; 52.3% were female, 67% white, 15% African-American, 18% Hispanic, 22.2%
      aged 12-13 years, 38.4% aged 14-17 years, and 39.4% aged 18-21 years. Principal
      components analysis was done to examine the covariance structure of 42 healthy
      and unhealthy behaviors selected from the behavioral questions of the Youth Risk
      Behavior Survey (YRBS). RESULTS: A four-factor oblique rotation, comprised of 18
      variables with factor loadings of.50 or greater, resulted in interpretable and
      meaningful health behavior factors. Sexual activity, substance use (e.g.,
      alcohol, marijuana, and other drugs), smoking, and exercise factors accounted for
      74% of the variance in the composite of healthy and unhealthy behaviors. These
      four factors were subsequently reproduced on random samples as well as on samples
      defined by age (12-13 years [excluding sexual activity variables], 14-17 years,
      18-21 years), gender, and race (white, African-American, Hispanic). CONCLUSIONS:
      These results provide new information about the consistent structure of sexual
      activities and exercise behaviors across subgroups defined by age, gender, and
      racial/ethnic origins, and about differences in clusters of substance use
      behaviors across ethnic groups. Further study of diverse population-based samples
      and multiple health-promoting and health-negating behaviors should profile
      developmental variations and health protective factors in adolescents.

PMID- 12401426
TI  - Religiousness and sexual responsibility in adolescent girls.
AB  - OBJECTIVE: To investigate a potential association between religiousness and
      sexual responsibility in a nationally representative sample of adolescent girls.
      METHODS: Subjects were 3356 adolescent girls (mean age 15.97 years, SD = 1.77;
      59.4% Euro-American, 23.3% African-American, 6.0% Hispanic, and 11.4% of other
      ethnic backgrounds) from the Wave I, In-Home section of the National Longitudinal
      Study of Adolescent Health (Add Health Study) who responded to items on four
      dimensions of religiousness (frequent attendance of religious events, personal
      conservatism, personal devotion, and religious denomination) and three dimensions
      of sexual responsibility (sexual activity, perception of risk in unprotected
      intercourse, and birth control use). Data were analyzed using a series of
      regression analyses with religiousness as the predictor and sexual responsibility
      as the outcome. RESULTS: Personal devotion was positively associated with fewer
      sexual partners outside a romantic relationship. Frequent attendance of religious
      events was positively associated with greater perception of risk of contracting
      human immunodeficiency virus (HIV) or pregnancy from unprotected intercourse,
      greater foresight of suffering from HIV or pregnancy, and a responsible and
      planned use of birth control. Personal conservatism was positively associated
      with unprotected sex. CONCLUSION: Sexual responsibility was positively associated
      with personal devotion and frequent attendance of religious events but inversely
      associated with personal conservatism.

PMID- 12401427
TI  - How to reach sexual minority youth in the health care setting: the teens offer
      guidance.
AB  - PURPOSE: To explore factors sexual minority youth believe make them feel safe in
      a health care setting. METHODS: Participants in three urban programs serving
      lesbian/gay/bisexual/transgendered and questioning (LGBTQ) youth engaged in a
      four-stage process to generate, prioritize, and explain their own ideas. In Stage
      III, 94 youth, aged 14 to 23 years, completed a survey comprised of the 34
      highest rated items generated in earlier stages. Using a Likert scale, they
      answered, "How important are each of the following ideas in making you feel safe
      as an LGBTQ youth when you go for health care?" In Stage IV, youth discussed the
      results in focus groups. The Marginal Homogeneity Test divided the items into
      priority ranks and the Kruskal-Wallis test explored subgroup differences in item
      ratings. RESULTS: The 34 items were divided into six ranks. Five items shared the
      top rank: the clinician maintaining privacy, demonstrating cleanliness, offering
      respect, being well-educated, and being honest. The second rank was shared by the
      following: the clinician not talking down to patients, being a good listener, not
      downplaying patients' fears, being professional, holding a nonjudgmental stance
      of the LGBTQ lifestyle, and not assuming every LGBTQ youth has HIV. Interspersed
      among other ranks were items specific to the needs of sexual minority youth: the
      clinician not assuming LGBTQ sexual behavior was painful or dangerous; the
      clinician being educated about the gay lifestyle; clinician sensitivity to the
      needs of same-sex partners; staff sensitivity to the needs of closeted youth;
      having a choice of an LGBTQ provider; and the clinician not assuming
      heterosexuality. Youth who had not publicly disclosed their sexuality rated
      health information being offered in a private place higher (p =.01). CONCLUSIONS:
      LGBTQ youth value the same clinician characteristics desired by all adolescents:
      privacy, cleanliness, honesty, respect, competency, and a nonjudgmental stance.
      They clearly describe what attracts them (e.g., clinicians educated about their
      lifestyle) and what offends them (e.g., equating their sexuality with HIV).
      Clinicians need to achieve and convey a higher comfort level in addressing the
      special needs of sexual minority youth.

PMID- 12401428
TI  - Smoking reduction among high school seniors: a test of selected indicators.
AB  - PURPOSE: To examine differences in the explanatory power of variables thought to
      discriminate between students who smoke and students who have reduced (or quit).
      METHOD: The design is a two-group test of differences on 33 variables identified
      from previous studies of adolescent smoking and cessation as potential
      discriminators, which represent a variety of perceptual, behavioral, social, and
      psychological factors. Data are from a national survey of U.S. high school
      students administered in 1997 by the Monitoring the Future project. RESULTS: The
      most effective variables involve smoking-related beliefs and perceptions,
      particularly in anticipated future smoking status, attempted quitting, number of
      smoking friends, and perceptions of other smokers. Personality and psychological
      variables were not effective at discriminating between the two groups.

PMID- 12401429
TI  - Perceived legitimacy of parental authority and tobacco and alcohol use during
      early adolescence.
AB  - PURPOSE: To assess the likelihood that young adolescents perceive that parents
      have legitimate authority regarding cigarette smoking and alcohol consumption; to
      test whether perceived parental authority predicts adolescents' use of tobacco
      and alcohol, and to test the association between parenting style and the
      legitimacy of parental authority regarding tobacco and alcohol. METHODS: Survey
      data were obtained in 1997 from 1220 sixth and eighth grade adolescents enrolled
      in a central North Carolina school district. The sample comprised 72.3% of 1687
      eligible students and 92.3% of 1321 students with parental consent; 83.8% of the
      sample was European-American and 16.2% African-American. Students completed self
      report questionnaires administered in classrooms. Logistic regression models were
      used to test the study hypotheses. RESULTS: Adolescents were significantly more
      likely to legitimize parental authority regarding tobacco and alcohol than
      parental authority regarding conventional or contemporary issues. Failure to
      legitimize parental authority was associated with significantly greater odds of
      current smoking (OR = 4.06; p <.000) or drinking (OR = 3.81; p <.000) among all
      respondents, and significantly greater odds of intending to smoke (OR = 3.38; p
      <.000) or drink (OR = 3.38; p <.000) among abstinent respondents. Adolescents'
      perceptions of parental authority regarding tobacco and alcohol varied
      significantly by parenting style. CONCLUSIONS: The results discredit the myth
      that adolescents uniformly disregard parental values and rules regarding tobacco
      and alcohol. The results also showed that general parenting style covaried
      strongly with adolescents' perceptions of parental authority regarding substance
      use. Additional research is warranted to test for causal relations between
      general parenting style, adolescents' perceptions of parental authority regarding
      substance use, and adolescents' risk of substance use.

PMID- 12401430
TI  - Smoking and other substance use as distinct features of teenage subcultures.
AB  - To analyze whether subcultures play a part in shaping the smoking behavior and
      other substance use among teenagers. We expected that teenagers affiliated with
      counter-cultural styles are more likely to have a positive attitude toward the
      use of substances than members of teenage subcultures that embrace the dominant
      culture.

PMID- 12401431
TI  - Self-reported organic and nonorganic sleep problems in schoolchildren aged 11 to
      15 years in Vienna.
AB  - PURPOSE: To estimate the prevalence of self-reported sleep problems, to examine
      associations among demographic characteristics, familial factors, and sleep
      problems, and to investigate the association between the symptoms of obstructive
      sleep apnea (OSA) and nonorganic sleep disorders. METHODS: An anonymous
      questionnaire with 22 questions was designed. 332 schoolchildren (aged 11-15
      years, mean age 12 years and 9 months; median, 12 years; 56% female, 44% male)
      from two high schools in Vienna were investigated with regard to self-reported
      symptoms characteristic for obstructive sleep apnea and for parasomnia/insomnia.
      Data were analyzed by definition of three groups (problem, occasional problem,
      and nonproblem sleepers, and by calculation of an insomnia/parasomnia sum score).
      Statistical analysis included nonparametric tests (Mann Whitney-U and Kruskal),
      Pearson correlation test, and multiple regression analysis. RESULTS: Twelve
      percent reported at least one sleep problem every night, 76% reported occasional
      sleep problems, and 12% had no sleep problems. Girls were affected more
      frequently than boys (p <.01). Children with sleep problems suffered more often
      from concentration difficulties (p <.05), daytime fatigue (p <.001), and daytime
      naps (p <.05). Children who snored had nightmares (10% vs. 2%, p <.01), night
      terrors (4% vs. 1.5%, p <.001), sleepwalking (1.4% vs. 1%, p <.05), and nocturnal
      awakening (16% vs. 5%, p <.01) more frequently. On multiple regression analysis,
      23% of the variability of a defined parasomnia/insomnia sum score had the
      characteristic OSA symptoms of nocturnal sweating, dryness of the mouth, snoring,
      hyperactivity, and daytime fatigue. CONCLUSION: 12% of schoolchildren aged 11-15
      years reported sleep problems almost every night. The children suffer from
      daytime fatigue, naps, and concentration difficulties. Nearly one-fourth of the
      symptoms of parasomnia/insomnia were associated with characteristic signs of OSA,
      suggesting the importance of a routine clinical investigation in children with so
      called nonorganic sleep disorders.

PMID- 12401432
TI  - Longitudinal prostaglandin E(2) generation in various organs during evolution of
      experimental portal hypertension.
AB  - It has been suggested that the arteriolar vasodilatation and hyperdynamic
      circulation observed in rats with partial portal vein ligation (PPVL) is caused
      by increased splanchnic and systemic delivery of vasodilator substances. The aims
      of our study were to determine organ-specific generation of prostaglandin E(2)
      (PGE(2)) in rats with PPVL during the evolution of portal hypertension. Rats with
      PPVL and sham-operated (S) rats were studied in the first, third, fourth and 14th
      postoperative days. They were anesthetized and splenic pulp pressure and blood
      pressure were measured. Spleen, colon and lungs were removed and the splenic,
      pulmonary and mucosal colonic PGE(2) were determined. All PPVL rats developed
      sequential hemodynamic changes compatible with evolving portal hypertension.
      Splenic pulp pressure was higher in PPVL rats compared with S rats during all
      days of the study. Within the group of PPVL the splenic pulp pressure was higher
      in the first postoperative day and decreased in the ensuing days. No changes in
      splenic and colonic PGE(2) generation were noted during the study period.
      Pulmonary PGE(2) generation increased significantly in the first postoperative
      day in PPVL rats compared with S rats. However, similar increase was observed on
      the third postoperative day in S rats. PGE(2) probably has no role in splanchnic
      hemodynamic changes during evolution of portal hypertension. Pulmonary PGE(2)
      generation may increase as a response to increased portal pressure, or to
      abdominal surgery.

PMID- 12401433
TI  - Polyunsaturated fatty acids in plasma and erythrocyte membrane lipids of diabetic
      children.
AB  - While insulin is a potent activator of essential fatty acid metabolism, portal
      hypoinsulinemia is common in Type 1 diabetes. Fatty acids were determined by high
      resolution capillary gas-liquid chromatography in plasma and erythrocyte membrane
      lipids in diabetic children (n = 40) and in age-matched healthy controls (n =
      40). In plasma phospholipids, values of linoleic acid (23.00 [2.35] vs. 18.13
      [2.54], % by wt, median [range from the first to the third quartile], P<0.000l)
      and alpha-linolenic acid (0.12 [0.06] vs. 0.07 [0.07], P<0.05) were significantly
      higher in diabetic children than in controls. In contrast, values of arachidonic
      acid (10.73 [2.34] vs. 11.53 [2.50], P<0.05) and docosahexaenoic acid (2.23
      [0.63] vs. 2.77 [0.98], P<0.01) were significantly lower in diabetic children
      than in controls. Reduced availability of long-chain polyunsaturates in diabetic
      children suggests that an enhanced dietary supply of long-chain polyunsaturates
      may be beneficial.

PMID- 12401434
TI  - Defibrotide modulates prostaglandin production in the rat mesenteric vascular
      bed.
AB  - Defibrotide 1 microM, a polydeoxyribonucleotide extracted from mammalian organs,
      reduced the contractile responses to noradrenaline (NA) in the rat isolated and
      perfused mesenteric vascular bed, in intact as well as in de-endothelialized
      preparations. Defibrotide was without effect on the acetylcholine-induced
      relaxations of U-46619-precontracted mesenteric vascular beds. Moreover,
      defibrotide increased 6-keto prostaglandin (PG) F(2alpha) (stable metabolite of
      prostacyclin) release sixfold in the presence, but not in the absence of the
      endothelium, with no modification on the release of other prostanoids.
      Defibrotide also inhibited the NA-induced increase in PGF(2alpha) release, in
      both intact and de-endothelialized mesenteric vascular beds. In conclusion, the
      present results show that defibrotide modulates PG production in the mesenteric
      bed and that the observed inhibition of the contractile responses should be due
      to the impairment of the NA-induced increase in PGF(2alpha) release.

PMID- 12401435
TI  - The fatty acid composition of the serum phospholipids of children with sickle
      cell disease in Nigeria.
AB  - The purpose of this study was to determine the fatty acid composition of the
      serum phospholipids of children with sickle cell disease (SCD) in Nigeria and to
      compare the relative fluidity of the acyl chains of the serum phospholipids of
      controls versus the subjects with SCD. It is widely accepted that the fatty acid
      composition of an individual's serum phospholipids reflects that of their tissue
      phospholipids. An alteration in the fatty acid composition of membrane
      phospholipids could affect critical membrane-dependent enzymes and processes
      (e.g., ion and solute transport, hormone-receptor interactions, signal
      transduction pathways). We found a significant reduction in the content of
      polyunsaturated n-3 fatty acids in the phospholipids of subjects with SCD which
      could result in a reduction of the fluidity of their tissue membranes.
      Specifically, there was a 40-50% reduction in the proportion of total n-3 fatty
      acids in subjects with SCD. On the basis of calculated melting points and double
      bond indices of the acyl chains of the serum phospholipids, the phospholipids of
      the children with SCD are less fluid relative to those of their healthy
      counterparts. In addition, we determined that linoleic acid, arachidonic acid,
      and stearic acid were the major determinants of the fluidity of the acyl chains
      of the serum phospholipids of the healthy controls and children with SCD.

PMID- 12401436
TI  - Influence of conjugated vs. conventional linoleic acid on liver metastasis and
      hepatic lipidperoxidation in BOP-induced pancreatic cancer in Syrian hamster.
AB  - While conjugated linoleic acid (CLA) is regarded as an essential fatty acid with
      anticarcinogenic effects, conventional linoleic acid (LA) is reported to promote
      tumour growth in various experimental studies probably caused by high sensitivity
      to non-enzymatic lipid peroxidation. In order to evaluate the impact of dietary
      LA and CLA on liver metastasis and lipidperoxidation (LPO), 60 Syrian hamsters
      were injected with 10 mg N -nitrosobis-2-oxopropylamine (BOP)/kg body weight s.c.
      for 12 weeks. Animals were fed a special diet containing LA or CLA. The
      experiment was terminated after 24 weeks. Incidence, number and size of liver
      metastases were histologically determined. Furthermore, the activities of
      antioxidative enzymes and concentration of hepatic lipidperoxidation were
      measured intra- and extrametastatically. Incidence, number and size of liver
      metastases did not differ between the tumour groups. Otherwise, antioxidative
      enzyme activity of GSH-Px was higher in non-metastatic liver, while SOD activity
      and lipidperoxidation were increased in liver metastases. Conclusively there was
      no difference between the groups fed with LA and CLA according to the impact on
      liver metastasis in ductal pancreatic cancer.

PMID- 12401437
TI  - The effect of prostaglandin E(2) (PGE(2)) and long-chain polyunsaturated fatty
      acids (LC PUFA) on bone formation in piglets: a model for bone growth in
      nutritional investigation.
AB  - This research investigates the effects of exogenous prostaglandin E(2) (PGE(2))
      treatment and arachidonic acid supplementation on the rate of growth in modelling
      bone of piglets. The piglet is a good model for the study of infant nutrition and
      bone growth. PGE(2) and long-chain polyunsaturated fatty acid (LC PUFA)
      supplementation, alone and in combination, are shown to have little or no effect
      on cortical bone thickness. Though exogenous PGE(2) supplementation and LC PUFA
      supplementation may both be effective in promoting bone growth and mass in
      adults, they do not appear to have the same positive effect on bone growth in
      infancy over a short term. A dynamic model for bone growth in piglets is proposed
      here for the first time. This research adds to our knowledge of the relationship
      between the dynamic histology of bone, the rate of osteogenesis, and the link
      between nutrition and bone growth.

PMID- 12401438
TI  - NS-398: cyclooxygenase-2 independent inhibition of leukocyte priming for lipid
      body formation and enhanced leukotriene generation.
AB  - Because the induction of new lipid body formation in leukocytes correlates with
      and likely contributes to their enhanced 'primed' prostaglandin and leukotriene
      formation, we evaluated two selective cyclooxygenase (COX)-2 inhibitors. Three
      types of stimuli, cis -unsaturated fatty acids, platelet activating factor and
      protein kinase C activators, stimulate lipid body formation. NS-398 (0.1-10
      microM), but not another COX-2 inhibitor, SC58125 (0.1- 10 microM), blocked
      leukocyte lipid body formation elicited by all three types of stimuli and also
      blocked priming for enhanced LTB(4) production and PGE(2) production. The effect
      of NS-398 on lipid body formation was independent of its inhibitory effects on
      COX-2 since arachidonate-induced lipid body formation in COX-2-deficient mouse
      leukocytes was also inhibited by NS-398. By means of its ability to inhibit
      leukocyte lipid body formation, NS-398 may exert actions independent of its COX-2
      inhibition and more broadly contribute to the suppression of formation of COX-1
      and lipoxygenase-derived eicosanoids.

PMID- 12401439
TI  - Effect of peroxisome proliferator-activated receptor gamma on thromboxane A(2)
      and prostaglandin E(2) production in macrophage cell lines.
AB  - We studied the effect of peroxisome proliferator-activated receptor gamma
      (PPARgamma) activation on thromboxane A(2)(TXA(2)) and prostaglandin E(2)(PGE(2))
      production in monocyte/macrophage cell lines. In present experiment, we used
      human peripheral blood monocyte (PBMC), monocyte-cell line THP-1 and mouse
      macrophage-like cell line RAW264.7. The expression of PPARgamma is reported in
      PBMC and THP-1. Synthetic PPARgamma ligands (troglitazone or BRL49653) inhibited
      TXA(2) production and enhanced PGE(2) production of PBMC and THP-1. When treated
      with 0.5-10 microM of troglitazone, there were no significant changes of TXA(2)
      and PGE(2) production of RAW264.7 cells, which express very low levels of
      PPARgamma. When RAW264.7 cells was transfected with PPARgamma expression plasmid
      and treated with troglitazone, PPARgamma was activated in a dose-dependent
      manner. In PPARgamma-transfected RAW264.7, TXA(2) production was decreased and
      PGE(2) production was increased by troglitazone treatment. But it needs high
      concentration of troglitazone (10 microM) for increasing PGE(2) production. These
      results suggest that PPARgamma may have negative effect on TXA(2) production, and
      also have slightly positive effect on PGE(2) production of macrophage.

PMID- 12401440
TI  - Inhibitory effects of eicosapentaenoic acid (EPA) on the hypoxia/reoxygenation
      induced tyrosine kinase activation in cultured human umbilical vein endothelial
      cells.
AB  - We have previously reported that the n-3 polyunsaturated fatty acid
      eicosapentaenoic acid (EPA) inhibited the abnormal gap junctional intercellular
      communication (GJIC) induced by hypoxia/reoxygenation (H/R) via suppressing
      tyrosine kinase (TK) activation (Zhang et al., Prostaglandins Leukot Essent Fatty
      Acids, 1999; 61: 33-40). However, the mechanisms by which EPA-inhibited TK
      activation remained unidentified. In this study we investigated whether reactive
      oxygen species (ROS) and growth factor-receptor systems would contribute to the
      H/R-induced TK activation or not. The results showed that H/R-induced ROS
      production, which reached the peak after 30 min of reoxygenation. Pretreatment
      with 10 microM EPA significantly inhibited this ROS production. However, the TK
      inhibitor genistein (10 microM) failed to inhibit the generation of ROS, although
      it completely inhibited TK activation. On the other hand, the ROS inhibitor DMSO
      (0.5% v/v) showed little effect on TK activation while it significantly blocked
      ROS production. Further EPA and genistein, but not DMSO and superoxide dismutase
      (SOD, 300 U/ml), prevented cells from GJIC injury induced by H/R. Moreover, EPA
      protected against VEGF-induced reduction in GJIC and phosphorylation of connexin
      43. These data suggest that growth factor, but not ROS, might be involved in the
      EPA-inhibited TK activation induced by H/R.

PMID- 12401441
TI  - Low-dose desmopressin infusion: renal action in healthy women in moderate salt
      retention and depletion, and interactions with prostanoids.
AB  - Studies were carried out to evaluate the influence of variations in sodium
      balance on the renal response to low-dose infusion of 1-desamino-8- D -arginine
      vasopressin (dDAVP), and the functional interaction between dDAVP and renal
      prostanoids. The studies were performed on healthy women in conditions of
      extracellular fluid volume expansion (SR group, n =9) and depletion (SD2 group,
      n=6), respectively. The study protocol included hypotonic polyuria (induced by
      oral water load) and subsequent antidiuresis (induced by low-dose infusion of
      dDAVP). Three 60-min clearance (cl.) periods were performed during polyuria (cl.
      P), early (cl. A1) and late (cl. A2) antidiuresis. The urinary concentrations of
      prostaglandin (PG) E(2) and the stable metabolites of PGI(2) and thromboxane (Tx)
      A(2), 6-keto-PGF(1alpha) (6KPGF) and TxB(2), were estimated. Paired renal
      functional explorations were performed in salt retention and salt depletion both
      in absence and presence of indomethacin (SR.I and SD2.I groups). In both paired
      and unpaired studies, the early and late effects of dDAVP on the functional
      excretory variables and the excretion of prostanoids were assessed as percentage
      variations, (A1-P)% P and (A2-A1)% A1. (I) dDAVP in salt retention and depletion.
      During early infusion dDAVP produced in both conditions a significant reduction
      in urinary flow rate, creatinine cl., absolute and fractional excretions of
      sodium, chloride and potassium; during late infusion dDAVP was effective in
      inducing a further significant reduction in urinary flow rate. In salt retention
      compared to depletion the early reductions in sodium and chloride (absolute and
      fractional) excretions were significantly lower. (II) Indomethacin pretreatment.
      During early infusion the dDAVP-induced reductions in the urinary flow rate and
      6KPGF excretion were enhanced in both conditions. In salt depletion the dDAVP
      effects in reduction of creatinine cl. and urinary electrolyte excretions were
      also enhanced. During late infusion the antidiuretic effect of dDAVP was
      suppressed in salt retention, while in salt depletion creatinine cl., the urinary
      excretions of electrolytes and both 6KPGF and TxB(2) showed increases
      significantly different from the dDAVP effects in the absence of indomethacin. In
      conclusion, (a) the salt-retaining effect of dDAVP was less effective in salt
      retention compared to depletion. (b) Indomethacin pretreatment affected the renal
      action of dDAVP in a time-dependent pattern. The early effects in both conditions
      were consistent with an inhibited synthesis of modulator PGs. On the contrary,
      the late effects were consistent with the occurrence, at least in salt depletion,
      of an escape from dDAVP renal action. This escape phenomenon probably depended on
      a partial regression of the pharmacological inhibition of the modulating PGs.

PMID- 12401442
TI  - Developmental expression of ZnT3 in mouse brain: correlation between the
      vesicular zinc transporter protein and chelatable vesicular zinc (CVZ) cells.
      Glial and neuronal CVZ cells interact.
AB  - We examine the expression pattern of ZnT3 in the cerebral and cerebellar areas of
      mouse brain throughout development. During embryogenesis and early postnatal
      stages, ZnT3 transcripts were detected in several areas. Label was clear in areas
      related to proliferation and differentiation. As development proceeded, the label
      gradually disappeared in these areas and increased in the chelatable vesicular
      zinc (CVZ) system. To assess whether ZnT3 was expressed in all CVZ cells, its
      distribution pattern was studied through postnatal stages using a retrograde zinc
      transport method. While the ZnT3 expression pattern and the distribution of CVZ
      cells coincided from P12 to adulthood, this coincidence was not detected in early
      postnatal days. Moreover, immunohistochemical procedures highlighted a
      differential phenotype within CVZ cells throughout postnatal development. These
      findings suggest the presence of different CVZ cell subpopulations throughout
      brain development and, consequently, the existence of distinct chelatable
      vesicular zinc pools.

PMID- 12401443
TI  - Persephin-overexpressing neural stem cells regulate the function of nigral
      dopaminergic neurons and prevent their degeneration in a model of Parkinson's
      disease.
AB  - Persephin (PSP) is a neurotrophic factor of the GDNF family that has been found
      to promote the survival of multiple populations of neurons. In the present study
      we have examined: (1) the mechanism of action and the function of PSP on
      nigrostriatal dopamine neurons and (2) the therapeutic potential of PSP,
      delivered by neural stem cells (NSCs) in a model of Parkinson's disease.
      Interestingly we found that the prenatal ventral mesencephalon and the newborn
      striatum express high levels of PSP mRNA. Moreover, midbrain dopamine neurons
      express its preferred receptor GFRalpha4, allowing a cis type of action of PSP on
      dopamine neurons. Primary culture studies showed that PSP is as potent and
      efficacious as GDNF at promoting both survival and neuritogenesis of midbrain
      dopamine neurons. To study the function and therapeutic potential of PSP in vivo
      we engineered NSCs to overexpress PSP. PSP-c17.2 cells were found to stably
      express PSP mRNA and protein for at least 3 months in vivo, to disperse within
      the striatum, and to give rise to neurons, astrocytes, and a large proportion of
      oligodendrocytes that integrated within white matter tracts in the striatum.
      Moreover, PSP-c17.2 cells enhanced dopamine-dependent behavioral parameters in
      unlesioned mice and prevented the loss of dopamine neurons and the behavioral
      impairment of mice receiving intrastriatal 6-OHDA injections. Thus, our findings
      are consistent with a direct action of PSP on developing and adult midbrain
      dopamine neurons and suggest that the delivery of PSP by NSCs may constitute a
      very useful strategy in the treatment of Parkinson's disease.

PMID- 12401444
TI  - Proteasomal inhibition-induced inclusion formation and death in cortical neurons
      require transcription and ubiquitination.
AB  - Increasing evidence suggests that proteasomal dysfunction plays a role in the
      pathogenesis of Lewy body diseases. We have used pharmacological inhibitors of
      the proteasome to model proteasomal dysfunction in cultured rat cortical neurons.
      Proteasomal inhibition induced apoptotic death and formation of cytoplasmic
      ubiquitinated inclusions, which were present only in viable neurons. Actinomycin
      D, but not a caspase inhibitor, prevented inclusion formation, whereas both
      agents inhibited cell death. alpha-Synuclein and thioflavin S staining were found
      within the inclusions. alpha-Synuclein, however, did not appear to be
      ubiquitinated or aggregated. A dominant-negative mutant of an E2 ubiquitin
      conjugating enzyme, cdc34, prevented inclusion formation and attenuated cell
      death. Our results suggest that in cortical neurons: (a) proteasomal dysfunction
      plays a role in formation of ubiquitin/alpha-synuclein-positive inclusions, (b)
      inclusion formation is an active cell process requiring transcription, and (c)
      ubiquitination of certain proteins is required for inclusion formation and may
      participate in neuronal death.

PMID- 12401445
TI  - Developmental regulation and possible alternative cleavage of presenilin 1 in the
      rat retina.
AB  - Presenilin 1 (PS1) is a multitransmembrane protein well known for being mutated
      in most cases of familial Alzheimer's disease. Although its pathological effect
      is clear, its biological functions are not yet fully understood, but it appears
      to be involved in development and apoptosis. To investigate the role of PS1 in
      developmental processes we have studied the expression and proteolytic processing
      of this protein in the developing rat retina. PS1 appears to be developmentally
      regulated in the retina, and the pattern of PS1 immunoreactivity is consistent
      with a role in retinal lamination and pattern formation. Interestingly, no
      correlation was observed between PS1-positive cells and cells undergoing
      programmed cell death, suggesting that PS1 does not play a role in apoptosis
      occurring during this period. Moreover, we observed a change in the pattern of
      PS1 proteolytic fragments suggestive of a novel alternative cleavage site in the
      PS1 molecule.

PMID- 12401446
TI  - Slit promotes branching and elongation of neurites of interneurons but not
      projection neurons from the developing telencephalon.
AB  - Proper neuronal migration and establishment of circuitry are key processes for
      laying down the functional network of cortical neurons. A variety of
      environmental guidance cues, attractive or repulsive, have been shown to guide
      cell migration and axon arborization. One of these, Slit, appears to possess
      contrarian properties; it can either inhibit axon outgrowth or promote branching
      and elongation. The object of the present study was to assess the effect of Slit
      on MGE and neocortical neurons in culture and in the developing ventricle. When
      cocultured with a Slit source, E13.5 MGE explants displayed inhibited neurite
      outgrowth while GABA neuron dispersion away from Slit was increased. Similar
      inhibition of neurite outgrowth was seen in dissociated cells from E13.5 MGE,
      these cells were identified to be interneurons based upon their GABA staining. In
      contrast, E13.5 interneurons, after culture for another 5 days, were responsive
      to Slit by neurite branching and elongation. Projection neurons, identified by
      lack of GABA staining, did not respond to Slit, either by branching or
      elongation. Furthermore, GABA interneurons but not pyramidal neurons, appeared to
      avoid neocortical areas close to an implanted source of Slit in the ventricular
      wall. These results lead us to suggest that interneurons but not projection
      neurons are responsive to the chemorepellant effect of Slit. However, more mature
      interneurons appear to respond to Slit by neurite arborization. These results
      demonstrate a selective response to Slit by GABAergic neurons during neocortical
      development.

PMID- 12401447
TI  - Pontocerebellar axon guidance: neuropilin-1- and semaphorin 3A-sensitivity
      gradients across basilar pontine nuclei and semaphorin 3A variation across
      cerebellum.
AB  - To assess the role of semaphorin 3A (Sema3A) and its receptor component
      neuropilin-1 (Npn-1) in pontocerebellar axon guidance, we compared the
      distributions of Sema3A, Npn-1, and DiI-labeled pontocerebellar axons in neonatal
      mouse cerebellum. Between embryonic day 18 and birth there was a large increase
      in Npn-1 expression in the basilar pontine nuclei (BPN), the major source of
      pontocerebellar axons. Sema3A expression in cerebellum also increased at this
      time. In the BPN, Npn-1 and the response of axons to Sema3A were graded with high
      Npn-1 and Sema3A responsiveness rostrally and lower levels caudally. The Npn-1
      gradient was not smooth and cells with higher and lower expression were
      interspersed. Between birth and postnatal day 5, pontocerebellar axons projected
      to lobules of the hemispheres, including those with low to moderate levels of
      Sema3A, but did not enter regions with high levels of Sema3A, including the
      flocculus and much of the vermis. These results suggest that varying neuropilin
      levels on BPN axons, which correlated with their varying responses to Sema3A,
      combined with varying Sema3A levels across cerebellum, may contribute to guiding
      subsets of BPN axons to their distinct target regions within cerebellum.

PMID- 12401448
TI  - Interkinetic nuclear movement may provide spatial clues to the regulation of
      neurogenesis.
AB  - During the transition from S phase to mitosis, vertebrate neuroepithelial cells
      displace their nuclei and subsequently migrate from the basal membrane to the
      apical surface of the neuroepithelium, a phenomenon termed interkinetic nuclear
      movement (INM). Here we provide evidence that cycling neuroepithelial cells pass
      through a neurogenic state in which they are situated apically, as defined by the
      capacity to express Notch1, Delta1, and Neurogenin2 (Ngn2). Based on this
      scenario, we have developed a mathematical model to analyze the influence of INM
      on neurogenesis. In the absence of INM, the model predicted an increase in the
      rate of neurogenesis due to the reduction in the influence of inhibitory signals
      on cells in the neurogenic state. This exacerbation in neurogenesis led to the
      diminished growth of the neuroepithelium and a reduction in the later production
      of neurons. Pharmacological perturbation of the stereotypical distribution of
      precursors along the orthogonal axis of the neuroepithelium resulted in an excess
      of neurogenesis, as seen by the expression of Ngn2, and of the neuronal marker
      RA4 in the retina. These findings suggest that INM might be important for the
      efficient and continued production of neurons in G0, since it is involved in
      defining a proneural cluster in the ventricular part of the neuroepithelium that
      contains precursors at stages of the mitotic cycle compatible with neuronal
      differentiation.

PMID- 12401449
TI  - Effect of lens lesion on neurite outgrowth of retinal ganglion cells in vitro.
AB  - Recent studies have shown that lens lesion promotes axonal regeneration in the
      optic nerve of adult rats. In the present investigations, dissociated retinal
      ganglion cells (RGC) from intact postnatal (P) 9-11 rats showed spontaneous
      neurite outgrowth on laminin-1, in contrast to RGC from intact P14-adult rats.
      Neurite outgrowth from P9-14 RGC on laminin-1 was promoted by prior lens lesion
      and also during coculture with lesioned lenses. Neurite outgrowth from adult RGC
      following prior lens lesion, or in cocultures with lesioned lenses, required the
      presence of laminin-2. In media conditioned by lesioned lenses, the stimulatory
      effect on neurite outgrowth was still observed in the presence of K252a (trk
      receptor blocker) and mAb 228 (which blocks the effects of leukemia inhibitory
      factor and ciliary neurotrophic factor). Together, these results suggest the
      existence of a neuritogenic factor(s) associated with the lesioned lens that
      belongs to neither the neurotrophin nor the gp130 cytokine family.

PMID- 12401450
TI  - Impaired adult neurogenesis in mice lacking the transcription factor E2F1.
AB  - During nervous system development the fate of neural stem cells-whether to
      undergo proliferation, differentiation, or apoptosis-is controlled by various
      signals, such as growth factors. Here, we demonstrate that the transcription
      factor E2F1, which is targeted by several signaling cascades that are activated
      by growth factors, is involved in neurogenesis in the adult brain. When analyzing
      the brains of E2F1-deficient mice, we found significantly decreased stem cell and
      progenitor division in the proliferative zones of the lateral ventricle wall and
      the hippocampus. As a consequence, the production of newborn neurons in the adult
      olfactory bulb and dentate gyrus was decreased. Neuronal cell counts of the adult
      cerebellum revealed a mild but significant cerebellar atrophy, whereas
      neocortical neurons were unaffected, suggesting that E2F1 deficiency produces a
      predominantly postnatal phenotype. The results indicate an involvement of E2F1 in
      controlling proliferation and neuronal cell numbers in the postnatal and adult
      brain.

PMID- 12401451
TI  - Synaptic anchoring of glycine receptors in developing collicular neurons under
      control of metabotropic glutamate receptor activity.
AB  - The role of GlyRs in supramedullar neurons is still enigmatic: although present
      in the plasma membrane, they seem to be excluded from synaptic transmission. Two
      distinct stages of inhibitory synaptogenesis in cultured collicular neurons were
      defined on the basis of strychnine sensitivity of IPSCs, presence of EPSCs, KCC2
      expression, and transmitter-induced Ca(2+) responses. In the absence of KCC2 and
      glutamatergic transmission, newborn VIAAT-labeled boutons contained GlyT2,
      released glycine, and accumulated postsynaptic gephyrin and GlyRs. With ongoing
      maturation, when neurons expressed KCC2 and displayed glutamatergic activity,
      inhibitory synapses contained GAD65, released GABA, and accumulated postsynaptic
      gephyrin and GABA(A)Rs, but not GlyRs. This activity- and transmitter-specific
      regulation of GlyR distribution could be challenged by chronic blockade of group
      I mGluRs. It is thus concluded that glutamatergic transmission can contribute to
      the regulation of synaptic GlyR stabilization during inhibitory synapse
      development.

PMID- 12401452
TI  - E-cadherin is required for the correct formation of autotypic adherens junctions
      of the outer mesaxon but not for the integrity of myelinated fibers of peripheral
      nerves.
AB  - The calcium-dependent adhesion protein E-cadherin is present in noncompacted
      regions of myelin sheaths in the peripheral nervous system. There, it is
      localized to electron-dense structures between membranes of the same Schwann cell
      referred to as autotypic adherens junctions. It has been suggested that the
      failure of E-cadherin-mediated adhesion might cause demyelination that proceeds
      in certain pathological states. To test the requirement of E-cadherin in
      peripheral nerves, we used tissue-specific gene ablation techniques based on the
      Cre/LoxP system. We show that E-cadherin deficiency does not cause significant
      demyelination up to the age of 15 months. Immunostainings for nodal sodium
      channels, the paranodal protein Caspr1, and the juxtaparanodal potassium channels
      Kv1.1 and Kv1.2 revealed that E-cadherin is not necessary to maintain the general
      functional architecture of the nodal region. On the ultrastructural level, we
      detected a widening of the outer mesaxon accompanied by a loss of electron-dense
      cytoplasmic areas. We conclude that E-cadherin is required for the proper
      establishment and/or the maintenance of the outer mesaxon in myelinated PNS
      fibers but is dispensable for proper nerve function.

PMID- 12401453
TI  - Alternate splicing in the cytosolic II-III loop and the carboxy terminus of human
      E-type voltage-gated Ca(2+) channels: electrophysiological characterization of
      isoforms.
AB  - There is growing evidence that Ca(v)2.3 (alpha1E, E-type) transcripts may encode
      the ion-conducting subunit of a subclass of R-type Ca(2+) channels, a
      heterogeneous group of channels by definition resistant to blockers of L-, N-,
      and P/Q-type Ca(2+) channels. To understand whether splice variation of Ca(v)2.3
      contributes to the divergence of R-type channels, individual variants of Ca(v)2.3
      were constructed and expressed in HEK-293 cells. With Ba(2+) as charge carrier,
      the tested biophysical properties were similar. In Ca(2+), the inactivation time
      course was slower and the recovery from short-term inactivation was faster;
      however, this occurred only in variants containing a 19-amino-acid-long
      insertion, which is typical for neuronal Ca(v)2.3 Ca(2+) channel subunits. This
      different Ca(2+) sensitivity is not responsible for the major differences between
      various R-type channels, and future studies might clarify its importance for in
      vivo synaptic or dendritic integration and the reasons for its loss in endocrine
      Ca(v)2.3 splice variants.

PMID- 12401454
TI  - A short protocol for muscle MRI in children with muscular dystrophies.
AB  - The use of muscle magnetic resonance imaging in patients with muscular
      dystrophies or congenital myopathies has been limited. We describe the
      development of a short protocol to be used in young patients with neuromuscular
      disorders. The protocol includes transverse T1-weighted spin echo sequence images
      of thighs and calves. The total scanning time is less than 30 minutes, and can be
      easily applied to patients over the age of 4 years without any need for sedation.
      Although only the leg muscles are imaged, the images obtained can still help to
      identify specific patterns of muscle involvement and provide additional help in
      the differential diagnosis of muscle disorders with overlapping clinical
      features.

PMID- 12401455
TI  - Muscle MRI findings in a three-generation family affected by Bethlem myopathy.
AB  - We report clinical and muscle magnetic resonance imaging (MRI) findings in three
      individuals (aged 6, 26 and 73 years) from a three-generation family with Bethlem
      myopathy, confirmed by molecular genetic analysis which showed an exon skipping
      mutation in the COL6A1 gene. The clinical severity ranged from mild proximal
      weakness and distal laxity in the younger patients, to inability to stand or walk
      and severe contractures in the 76-year-old grandmother. The pattern of muscle
      involvement showed variable severity in parallel with the severity of motor
      function impairment. Although there was a marked variability in the severity of
      the MRI findings, it was possible to recognize a specific pattern of muscle
      involvement in all three patients. This consisted of involvement of the
      peripheral region of the vastus lateralis and hamstrings muscles with relative
      sparing of their central part. This was best appreciated in the third decade of
      life, but could also be identified both in the younger patient with minimal MRI
      changes and in the oldest patient, despite her more severe and diffuse muscle
      involvement. This report suggests that muscle MRI could be used as an additional
      tool to establish the pattern and the degree of muscle involvement in patients
      with Bethlem myopathy. Further studies in a larger cohort are needed to evaluate
      the specificity of these findings.

PMID- 12401456
TI  - Diagnostic significance of Wada procedure in very young children and children
      with developmental delay.
AB  - Localization of vital components of neurological functioning has to be performed
      before epilepsy surgery can be considered in children with intractable epilepsy.
      This study reports the experience with the Wada procedure in very young children
      and/or developmentally delayed children with an a priori considerable chance of
      failing the procedure. The aim of this study was to indicate the applicability of
      this procedure in this patient group. The Wada procedure is described in 16
      children under 10 years of age and/or have intelligence quotient scores below 50
      and/or are critically ill and/or are behaviourally disturbed. Information on
      motor, language and memory functioning is obtained in respectively 13/15, 9/13,
      and 5/11 children. Nine children underwent epilepsy surgery without postoperative
      impairment of neurological functioning. In five children epilepsy surgery was not
      performed because of the results of the Wada procedure or the lack of information
      during the Wada procedure. One child became seizure-free before surgery. Even in
      very young, developmentally delayed or behaviourally disturbed children, the Wada
      test can provide important information with respect to the decision pro or contra
      epilepsy surgery.

PMID- 12401457
TI  - Plantar response in infancy.
AB  - The objective of the study was to characterize the plantar response at various
      ages in infancy in Indian children. The subjects were 1281 apparently healthy
      children born at term and without any history suggestive of neurological disease,
      enrolled between the ages of 1 and 12 months. The plantar response was elicited
      in both feet by thumbnail drag method and graded as flexor, extensor and
      equivocal. The percentage of extensor, flexor and equivocal responses was
      compared between right and left foot and the average of these two responses was
      compared between the age categories [1-3 months (n=389), 3.1-6 months (n=332),
      6.1-9 months (n=354) and 9.1-12 months (n=206)]. Frequency (%) of various
      combinations of bilateral responses was also calculated for different age
      categories. Results showed that the extensor plantar response was the predominant
      response till 6 months of age. Bilateral extensor response was seen in 79.4%,
      67.8%, 32.5% and 31.1% in the four age categories respectively; bilateral flexor
      response in the corresponding age groups was 0.3%, 5.1%, 26.6% and 39.3%
      respectively. The percentage of asymmetrical responses was 20.7%, 25.3%, 40.3%,
      and 28.7% in different age categories. We concluded that normal plantar response
      is predominantly extensor in early infancy; the transition to flexor response
      starts occurring after 6 months of age. A fairly high number of infants continue
      to have an extensor response even after 6 months; and the transition may be
      advanced in one foot leading to asymmetrical plantar response.

PMID- 12401458
TI  - Multiphasic disseminated encephalomyelitis associated with streptococcal
      infection.
AB  - Multiphasic disseminated encephalomyelitis (MDEM) is a rare peculiar diagnosis
      which is defined as acute demyelinating central nervous system disease with
      relapses occurring only within 4 weeks of initial manifestation. This report
      describes the case of a 6-year-old boy with MDEM diagnosed by clinical findings
      and magnetic resonance imaging. The disease had a biphasic evolution, and with a
      second course of high-dose corticosteroids a complete recovery without further
      relapse was obtained during the following 18 months. Serological evidence of
      streptococcal infection as specific trigger for MDEM was given. Thus this report
      raises the question whether an additional penicillin prophylaxis could be
      valuable for prevention of streptococcus-associated MDEM relapses.

PMID- 12401459
TI  - Focal cerebral vasculitis and stroke after chickenpox.
AB  - Cerebral infarcts are rather rare in children and can be caused by a number of
      diverse conditions. We report a case of cerebral infarct associated with a recent
      varicella infection. A 5-year old girl presented with an acute central facial
      palsy 1 month after a chickenpox infection. The infarction was revealed by
      magnetic resonance imaging and laboratory studies ruled out all known causes of
      stroke. Cerebral angiogram demonstrated segmental narrowing and irregularity of
      the wall of the right internal carotid artery, compatible with focal vasculitis.
      With the presumed diagnosis of varicella-associated focal angiitis, the patient
      was treated with high-dose methylprednisolone, acyclovir and aspirin. Magnetic
      resonance angiogram performed 6 weeks after the stroke demonstrated the
      resolution of the vasculitis. Varicella infection should be considered one of the
      possible causes of acute ischaemic strokes in children.

PMID- 12401463
TI  - Cytokines and depression: an update.

PMID- 12401464
TI  - Effects of sleep and sleep loss on immunity and cytokines.
AB  - Sleep is hypothesized to be a restorative process that is important for the
      proper functioning of the immune system. Severity of disordered sleep in
      depressed- and alcoholic subjects correlates with declines in natural- and
      cellular immunity and is associated with alterations in the complex cytokine
      network. Sleep loss has a role in mediating these immune changes as
      experimentally induced partial night sleep deprivation replicates the kind of
      sleep loss found in clinical samples and induces a pattern of immune alterations
      similar to that found in depressed- and alcoholic patients. Despite evidence that
      sleep and sleep loss have effects on immune processes and nocturnal secretion of
      cytokines, the clinical significance of these immune changes is not known.
      Moreover, in view of basic evidence of a reciprocal interaction between sleep and
      cytokines, further research is needed to understand whether alterations in
      cytokines contribute to disordered sleep in patient populations.

PMID- 12401465
TI  - Cytokines, stress, and depressive illness.
AB  - It has been suggested that immune activation, and particularly increased activity
      of several cytokines, notably interleukin-1, interleukin-2, interleukin-6, tumor
      necrosis factor-alpha as well as their soluble receptors is characteristic of
      depression. Normalization of cytokine activity does not necessarily occur
      following successful antidepressant, suggesting that cytokines may be trait
      markers of depression, or simply represent bystander effects of the illness. The
      relationship between cytokines and depression is complicated as a variety factors
      could directly or indirectly influence cytokine activity. While cytokine
      elevations are most pronounced in severe (melancholic) depression, their activity
      may also be related to chronicity of illness, neurovegetative features of
      depression (altered sleep patterns, food intake, weight changes, fatigue or
      general activity), or the high stress perception characteristic of depression.
      Although, studies assessing cytokines in depressive populations are basically
      correlational in nature, patients receiving cytokine immunotherapy frequently
      show depressive symptoms, which may be attenuated by antidepressant medication,
      supporting a causal role for cytokines in depressive disorders. The processes
      underlying such outcomes remain to be established, but the affective changes may
      stem from the neuroendocrine and central neurochemical changes elicited by
      cytokines, as these are reminiscent of those associated thought to subserve
      depression.

PMID- 12401466
TI  - Low levels of circulating inflammatory cytokines--do they affect human brain
      functions?
AB  - Animal studies provide consistent evidence for the pivotal role of inflammatory
      cytokines in inducing sickness behavior during systemic infection and
      inflammation. Because depression in humans shows a considerable symptomatic
      overlap with sickness behavior, it has been hypothesized that cytokines are also
      involved in affective disorders. This view is supported by studies showing that
      therapeutic administration of inflammatory cytokines can induce typical major
      depression and by evidence that stimulated cytokine-release during experimental
      endotoxemia provokes transient deterioration in mood and memory. However, in
      these conditions, similar to the animal models of acute infections, huge amounts
      of cytokines produced in the periphery act on the brain. In contrast, during most
      clinical conditions where depression might involve cytokine actions, such as
      chronic infection and inflammation, only low amounts of cytokines are
      circulating. The present paper addresses the question whether and how low amounts
      of circulating cytokines act on the human brain. Evidence is presented that very
      low amounts of circulating cytokines are likely to influence brain functions,
      even under baseline conditions. It is also likely that low levels of cytokines
      affect the same brain function as high levels do. However, it is uncertain
      whether these effects go in the same direction. NonREM sleep, for example, is
      promoted by a slight increase in cytokine levels, but suppressed by prominent
      increases. Because no comparable data are available for mood and other brain
      functions, the answer to the question whether and how low circulating amounts of
      cytokines affect mood depends on further experimental studies.

PMID- 12401467
TI  - Experimental autoimmune encephalomyelitis-associated behavioral syndrome as a
      model of 'depression due to multiple sclerosis'.
AB  - Many medical conditions, including inflammatory diseases such as multiple
      sclerosis (MS), are often accompanied by a high prevalence of depressive
      episodes. Inflammatory mediators, such as cytokines, were implicated in illness
      associated depressive conditions, both in humans and in animals. For example, MS
      associated depression (MSD) was attributed to pathophysiological processes such
      as immune dysregulation and cerebral inflammation. We have recently documented a
      depressive-like behavioral syndrome in mice with experimental autoimmune
      encephalomyelitis (EAE), an established model of MS. In the present paper, we
      discuss the similarities between the EAE-associated behavioral syndrome (EBS) and
      MSD, in terms of phenomenology, putative mechanisms and responsiveness to anti
      depressive therapy. In particular, we show that: (1) EAE and depression are
      associated not only with similar behavioral symptomatology, but also with common
      physiological alterations, including impaired serotonergic neurotransmission, and
      activation of neuroendocrine (e.g., adrenocortical) and inflammatory cytokine
      systems; (2) the EBS precedes any neurological deficit during the initial EAE
      attack, as well as further exacerbations, and remits during recovery and between
      relapses. Similarly, in many MS patients depression precedes and accompanies the
      attacks and wanes during remissions; (3) females show increased susceptibility to
      EBS. Similarly, depression is much more prevalent in women than in men; (4)
      chronic treatment with the tricyclic anti-depressant imipramine reduced EAE
      induced mortality, body-weight loss and behavioral suppression. Similarly, anti
      depressant drugs have been used effectively in treating MSD. These findings
      suggest that the EBS may serve as an animal model for MSD.

PMID- 12401468
TI  - Further evidence for the depressive effects of cytokines: anhedonia and
      neurochemical changes.
AB  - Although human studies have emphasized a role for IL-2 in depressive illness,
      limited attention has been devoted to the behavioral and neurochemical effects of
      this cytokine in animal studies. The present review assesses the behavioral
      effects of IL-2 in rodents, in counterpoint to the effects of interleukin-1beta
      (IL-1beta), necrosis factor-alpha (TNF-alpha) and endotoxin challenge. Unlike IL
      1beta, systemic IL-2 provokes modest effects on hypothalamic-pituitary-adrenal
      (HPA) functioning, and does not provoke marked signs of illness or anxiety. In
      some respects, however, IL-2 elicits effects reminiscent of traditional
      stressors, including anhedonia (diminished pleasure gained from otherwise
      rewarding stimuli). Additionally, when chronically administered, IL-2 may impact
      on cognitive processes, including spatial working memory. While IL-2 may induce
      depressive-like symptoms, the available data are sparse, have hardly considered
      the impact of chronic cytokine treatment, only assessed behavior in a narrow
      range of tests, and it remains to be established whether the effects of IL-2 are
      modifiable by antidepressant treatments. Finally, as the effects of IL-2 on CNS
      processes vary in a biphasic fashion, and may also engender neurotoxic effects,
      further analyses are necessary to discern under what conditions this cytokine
      provokes depressive-like behavioral outcomes.

PMID- 12401469
TI  - The effect of thymectomy and IL-1 on memory: implications for the relationship
      between immunity and depression.
AB  - Macrophages produced proinflammatory cytokines and inflammatory responses can
      cause many symptoms of depression, including direct stimulation of the HPA axis
      and secretion of cortisol. In depressed patients, hypercortisolism has been well
      described as one of the major symptoms and also as the cause for hippocampal
      atrophy and memory impairment. In this paper, the relationships between
      thymectomy, increased IL-1 levels, and changes in corticosterone and
      neurotransmitter concentrations in rats are discussed, as well as their
      implications for memory impairments and depression. In thymectomized rats,
      deficits in both spatial and fear conditioned memory have been observed.
      Thymectomy decreases noradrenaline and dopamine levels, and increases
      serotonergic neurotransmission in limbic areas, without affecting corticosterone
      concentrations. In a depression model, thymopeptides or IL-2 treatment
      significantly attenuated changes in behavior, lymphocyte proliferation and
      neurotransmitters caused by bulbectomy. The reduction of thymic functions may
      increase IL-1 synthesis. Central IL-1beta administration impairs rat's spatial
      memory in the Morris water maze and 8 arms radial maze, but enhances conditioned
      memory in the passive avoidance. These changes can be reversed by either IL-1
      receptor antagonist or a glucocorticoid receptor antagonist (RU 486).
      Furthermore, IL-1-induced changes in some neurotransmitter systems are similar to
      those observed in thymectomized rats. However, both acute and sub-chronic IL-1
      administration increases plasma corticosterone concentrations. Together, these
      findings suggest that changes in the function of the thymus gland may play an
      important role in the unbalance between macrophages, cytokines, and lymphocytes,
      which induces neurotransmitter and neuroendocrine changes, and memory
      disturbances in depressive illness.

PMID- 12401470
TI  - Effects of antidepressants on cytokine production and actions.
AB  - There are intriguing analogies between many features of depression and
      physiological and behavioral responses to infection, which are mediated by the
      brain effects of cytokines. These observations suggest that depression can be
      considered as a psychoneuroimmunological disorder where a central increase of pro
      inflammatory cytokines, may have adverse consequences on the functional activity
      of the neurochemical and neuroendocrine systems implicated in the symptoms of the
      disorder. According to this hypothesis, the therapeutic effects of
      antidepressants should be at least partly exerted by attenuating the brain
      expression and/or actions of pro-inflammatory cytokines. Despite their inherent
      limitations, animal models of depression that are based on behavioral and
      pharmacological analogies with the symptoms observed in humans, represent the
      best available tool to test this hypothesis and to investigate the action
      mechanisms of the immune effects of antidepressants. Treatment with different
      classes of antidepressants indeed conferred protection against cytokine-induced
      depressive-like biological and behavioral changes. This 'anti-inflammatory'
      profile may be due to alterations of the pro-/anti-inflammatory cytokine balance.
      The mechanisms underlying these effects of antidepressants are presently unknown,
      but the available literature suggests several possibilities, including actions on
      different molecules representing potential mediators of mood disorders induced by
      cytokines. The studies summarized in this review have opened up new vistas in
      both the pathophysiology of depression and the pharmacology of antidepressants.
      Whether their demonstrated immune effects are a side effect or a significant part
      of their clinical activity still remains to be elucidated.

PMID- 12401471
TI  - Treatment of cytokine-induced depression.
AB  - A high proportion of cancer and hepatitis C patients who receive cytokine
      immunotherapy develop symptoms of depression that are indistinguishable from
      those found in major depressive disorders. These symptoms are alleviated by anti
      depressant treatment. Moreover, preventive treatment with anti-depressants, in
      particular selective serotonin reuptake inhibitors (SSRIs) attenuates IFN-alpha
      associated symptoms of depression, anxiety, and neurotoxicity. The intermediate
      mechanisms of these effects are still unclear. Studies suggest that the state of
      depression is associated with an increase in plasma levels of various cytokines
      and soluble cytokine receptors. Furthermore, anti-depressants have been shown to
      shift the cytokine network towards a decreased production of pro-inflammatory
      cytokines and an increased production of anti-inflammatory cytokines. Other
      studies suggest that anti-depressants can also modify immune reactivity by acting
      on neural structures involved in neuroimmunomodulation. It is possible that anti
      depressants could help to normalize the serotoninergic neurotransmission that is
      likely disrupted during immunotherapy due to the potent effects of cytokines on
      the metabolism of the amino acid precursor tryptophan. Further work is needed to
      optimize strategies for preventing neuropsychiatric side effects of cytokine
      immunotherapy, to clarify the mechanisms involved in the alleviating effects of
      anti-depressants on cytokine-induced depression, as well as to assess the
      possible consequences of anti-depressant therapy on the efficacy of immunotherapy
      on the disease process.

PMID- 12401472
TI  - Tryptophan, mood, and cognitive function.
AB  - In separate experiments we investigated the duration of the effects of acute
      tryptophan depletion (ATD) on mood and cognition. The results showed that ATD's
      effects consist of lowering of mood only in subjects with a family history of
      unipolar depression. A specific impairment of memory consolidation was seen in
      all subjects. In subjects without any vulnerability for mood disorders,
      performance on so-called 'frontal tasks,' measuring higher attentional functions
      tended to improve after ATD. The effects of ATD on mood and cognition were
      manifest as long as biochemical indices of low tryptophan remained low. In
      conclusion, ATD is a model for impairment of memory, next to being a model of
      mood disorders in vulnerable subjects. Moreover, ATD could be used as a challenge
      to demonstrate individual vulnerability of the serotonergic system.

PMID- 12401473
TI  - Neopterin production, tryptophan degradation, and mental depression--what is the
      link?
AB  - The cytokine interferon-gamma stimulates human monocytes/macrophages to release
      large amounts of neopterin. Increased neopterin concentrations in body fluids of
      patients are observed during diseases with activated cellular (=TH1-type) immune
      response such as allograft rejection, virus infections, autoimmune disorders, or
      malignant tumors but also in neurodegenerative diseases or during pregnancy. In
      various cells interferon-gamma induces indoleamine 2,3-dioxygenase (IDO) which
      degrades tryptophan via the kynurenine pathway. Therefore like increased
      neopterin formation, enhanced tryptophan degradation is observed in diseases
      concomitant with cellular immune activation. Disturbed metabolism of tryptophan
      affects biosynthesis of neurotransmitter 5-hydroxytryptamine (serotonin), and it
      appears to be associated with an increased susceptibility for depression. In
      fact, enhanced neopterin concentrations together with increased degradation of
      tryptophan and low serum levels of tryptophan correlate with neuropsychiatric
      abnormalities like cognitive decline and depressive symptoms especially in long
      lasting and chronic diseases. Activation of IDO could represent an important link
      between the immunological network and the pathogenesis of depression.

PMID- 12401474
TI  - The enzyme indoleamine 2,3-dioxygenase is induced in the mouse brain in response
      to peripheral administration of lipopolysaccharide and superantigen.
AB  - The essential amino-acid, L-tryptophan, is the precursor of serotonin. Its
      availability in the brain is controlled by indoleamine 2,3-dioxygenase (IDO).
      This enzyme is inducible by cytokines such as interferon-gamma (IFN-gamma) and is
      the first and rate-limiting enzyme of the catabolism pathway of tryptophan. Since
      induction of IDO has been proposed to mediate the influence of cytokines on mood
      in patients with various somatic disorders, the present study aimed at analyzing
      the relationships between changes in brain IDO activity and serum IFN-gamma
      levels in response to peripheral immune stimulation by lipopolysaccharide (LPS)
      and superantigen in mice. Each of these treatments induced an increase in serum
      IFN-gamma at 6 h post-treatment followed 24 h later by a two-fold increase in IDO
      activity in the brain. These results support the involvement of peripheral IFN
      gamma in the control of L-tryptophan catabolism in the brain.

PMID- 12401475
TI  - Adult brain neurogenesis and depression.
AB  - The waning and waxing of neurogenesis in brain areas such as the dentate gyrus is
      proposed as a key factor in the descent into and recovery from clinical
      depression, respectively. A decrease in neurogenesis could occur due to genetic
      factors, stress (especially because of the involvement of adrenal corticoids),
      and/or a decline in serotonergic neurotransmission. An increase in neurogenesis
      could be brought about by several factors, but especially those that activate the
      serotonin 5-HT(1A) receptor. The possible interaction of immune system factors,
      especially the proinflammatory cytokines, with adult brain neurogenesis is
      discussed.

PMID- 12401476
TI  - Questions raised by the cytokine hypothesis of depression.
AB  - The cytokine hypothesis of depression raises a certain number of questions. These
      questions include: the inability of the theory to account for the classical
      (Freudian) psychodynamics of depression; the role of sensitization in cytokine
      induced depression; the compatibility of some of the effects of cytokines (on
      sleep, on cognition, on the HPA) with the hypothesis; the possibility of
      occurrence of depression in the absence of an increase in circulating cytokines;
      the nature of the relationships between cytokines, stress, and depression; the
      compatibility of the effects of cytokines on brain monoamines with the current
      monoamine hypothesis of depression; the inability of antidepressants to fully
      abrogate the brain effects of individual cytokines in animal experiments. Based
      on these limitations of the theory, it is proposed to define a new clinical
      entity designated as "the cytokine-associated depressive syndrome."

PMID- 12401478
TI  - Regulation of lymphoid homeostasis by interleukin-15.
AB  - Interleukin (IL)-15 is a member of the common gamma chain family of cytokines,
      and is closely related to IL-2. While these two cytokines share several important
      biological functions in vitro, recent mouse models have demonstrated unique roles
      for these two cytokines in supporting lymphoid homeostasis in vivo. IL-15 has
      been shown to regulate the homeostasis of both innate and adaptive immune cells,
      and this review will discuss several ways in which this pleiotropic cytokine may
      support lymphoid homeostasis.

PMID- 12401479
TI  - The role of IFN-gamma in immune responses to viral infections of the central
      nervous system.
AB  - Interferon (IFN)-gamma, is not only a marker of T(H)1 CD4, CD8 and natural killer
      (NK) cells, it is also a critical antiviral mediator which is central to the
      elimination of viruses from the CNS. In this review, we describe IFN-gamma, its
      receptor, signal transduction from receptor engagement, and antiviral downstream
      mediators. We demonstrate that although neurons are post-mitotic and non
      renewing, they respond to IFN-gamma in a fashion similar to peripheral
      fibroblasts or lymphocytes. We have illustrated this review with details about
      studies on the role(s) of IFN-gamma in the pathogenesis of measles virus (MV),
      herpes simplex virus (HSV) type 1, and vesicular stomatitis virus (VSV)
      infections of the CNS. For VSV infection, IFN-gamma signals through Jaks 1 and 2
      and STAT1 to activate (interferon regulatory factor) IRF-1; although viral
      protein synthesis is inhibited, PKR is not a critical mediator in the antiviral
      response to VSV in murine neurons. In contrast, induction of nitric oxide
      synthase (NOS) type 1 and its production of nitric oxide is essential in the
      elimination of viruses from neurons.

PMID- 12401480
TI  - Macrophage inflammatory protein-1.
AB  - Macrophage inflammatory protein-1alpha (MIP-1alpha) and MIP-1beta are highly
      related members of the CC chemokine subfamily. Despite their structural
      similarities, MIP-1alpha and MIP-1beta show diverging signaling capacities.
      Depending on the MIP-1 subtype and its NH(2)-terminal processing, one or more of
      the CC chemokine receptors CCR1, CCR2, CCR3 and CCR5 are recognized. Since both
      human MIP-1alpha subtypes (LD78alpha and LD78beta) and MIP-1beta signal through
      CCR5, the major co-receptor for M-tropic HIV-1 strains, these chemokines are
      capable of inhibiting HIV-1 infection in susceptible cells. In this review,
      different aspects of human and mouse MIP-1alpha and MIP-1beta are discussed,
      including their protein and gene structures, their regulated production, their
      receptor usage and biological activities and their role in several pathologies
      including HIV-1 infection.

PMID- 12401481
TI  - Evolution of interleukin-1beta.
AB  - All jawed vertebrates possess a complex immune system, which is capable of
      anticipatory and innate immune responses. Jawless vertebrates possess an equally
      complex immune system but with no evidence of an anticipatory immune response.
      From these findings it has been speculated that the initiation and regulation of
      the immune system within vertebrates will be equally complex, although very
      little has been done to look at the evolution of cytokine genes, despite well
      known biological activities within vertebrates. In recent years, cytokines, which
      have been well characterised within mammals, have begun to be cloned and
      sequenced within non-mammalian vertebrates, with the number of cytokine sequences
      available from primitive vertebrates growing rapidly. The identification of
      cytokines, which are mammalian homologues, will give a better insight into where
      immune system communicators arose and may also reveal molecules, which are unique
      to certain organisms. Work has focussed on interleukin-1 (IL-1), a major mediator
      of inflammation which initiates and/or increases a wide variety of non
      structural, function associated genes that are characteristically expressed
      during inflammation. Other than mammalian IL-1beta sequences there are now full
      cDNA sequences and genomic organisations available from bird, amphibian, bony
      fish and cartilaginous fish, with many of these genes having been obtained using
      an homology cloning approach. This review considers how the IL-1beta gene has
      changed through vertebrate evolution and whether its role and regulation are
      conserved within selected non-mammalian vertebrates.

PMID- 12401482
TI  - A social validation assessment of the use of microswitches with persons with
      multiple disabilities.
AB  - The purpose of this two-part study was to conduct a social validation assessment
      of microswitches versus interaction/stimulation conditions used with persons with
      multiple disabilities. In Part I, 32 teacher-assistant trainees were shown video
      tapes reporting the use of microswitches versus interaction conditions for six
      children. In Part II, 40 teacher-assistant trainees or classroom aides and 44
      rehabilitation staff were presented with video-tapes showing the use of
      microswitches versus systematic stimulation strategies for four adults. Raters
      scored the microswitch and the interaction or stimulation conditions on a 7-item
      questionnaire covering social/emotional and practical aspects. The microswitch
      condition was viewed as generally more positive than or comparable to the
      interaction or stimulation conditions. Main features of the findings and their
      implications are discussed.

PMID- 12401483
TI  - Investigation of a reinforcement-based toilet training procedure for children
      with autism.
AB  - Independent toileting is an important developmental skill which individuals with
      developmental disabilities often find a challenge to master. Effective toilet
      training interventions have been designed which rely on a combination of basic
      operant principles of positive reinforcement and punishment. In the present
      study, the effectiveness of a reinforcement-based toilet training intervention
      was investigated with three children with a diagnosis of autism. Procedures
      included a combination of positive reinforcement, graduated guidance, scheduled
      practice trials and forward prompting. Results indicated that all procedures were
      implemented in response to urination accidents. A three participants reduced
      urination accidents to zero and learned to spontaneously request use of the
      bathroom within 7-11 days of training. Gains were maintained over 6-month and 1
      year follow-ups. Findings suggest that the proposed procedure is an effective and
      rapid method of toilet training, which can be implemented within a structured
      school setting with generalization to the home environment.

PMID- 12401484
TI  - Early intensive behavioral intervention for children with autism: parental
      therapeutic self-efficacy.
AB  - Several authors have suggested that the quality of therapist performance accounts
      for some of the variability in outcomes observed in early intensive behavioral
      intervention for children with autism. However, there is a distinct lack of
      theoretical and empirical work addressing therapist performance in this context.
      In the present study, we explored predictors of one variable, beliefs about one's
      efficacy in the therapeutic role, that may be related to therapist performance.
      Eighty-five UK mothers who were acting as therapists for their child's program
      completed a questionnaire survey. Results showed that program variables (e.g.,
      number of hours of therapy each week, time since program started) were unrelated
      to maternal therapeutic self-efficacy. However, support received from the
      program, the severity of the child's autism, and maternal stress were significant
      predictors. Regression analysis also showed that maternal stress mediated the
      impact of support from the program and autism severity on maternal therapeutic
      self-efficacy. Limitations of the study, suggestions for future research, and
      practical implications are briefly discussed. In particular, we advocate a role
      for supervisors in analyzing and developing interventions for therapist behavior.

PMID- 12401485
TI  - Engagement in meaningful activity and "active support" of people with
      intellectual disabilities in residential care.
AB  - Forty-nine adults with learning disabilities living in 13 small staffed homes in
      England were studied as part of larger projects in 1997 and again in 2000. A pre
      test/post-test comparison group design was used to assess differences in staff
      implementation of "active support," service user engagement in meaningful
      activities and adaptive behaviour. Homes which adopted active support showed
      significantly increased engagement in meaningful activity and adaptive behaviour
      between 1997 and 2000. A comparison group showed no significant change.

PMID- 12401486
TI  - Effect of resident and direct-care staff training on responding during social
      interactions.
AB  - The effectiveness of a multifaceted training package was evaluated for
      inappropriate social behavior of five children with mild mental retardation and
      attention deficit hyperactivity disorder (ADHD), who resided in a facility. The
      procedure encompassed resident training with video feedback and self-management
      and direct-care staff training with video and graphic feedback. Resident training
      occurred on an individual basis; feedback to staff was presented during routine
      staff meetings. Results showed increases of appropriate staff responses to
      residents' behavior. However, the effect of the package on residents'
      inappropriate social responses proved to be ineffective. Differences with
      previous studies as well as the need for research into procedural variables that
      affect social behavior of children with ADHD and mild mental retardation are
      discussed.

PMID- 12401488
TI  - Genta incorporated. Gallium therapeutics: take two.

PMID- 12401489
TI  - siRNA. A guide for RNA silencing.
AB  - RNAi is routinely used to eliminate gene activity for experimental purposes.
      However, the precise molecular mechanism of RNAi is unknown. Recent papers
      partially illuminate this mechanism in human cells, advancing the potential
      application of RNAi toward the treatment of human disease.

PMID- 12401490
TI  - Sensing nickel. NikRs with two pockets.
AB  - NikR represses expression of a nickel transporter in response to elevated levels
      of Ni(II). Recent results suggest that repression is elicited by binding of
      nickel to a high-affinity site, but a low-affinity binding pocket may also play a
      role.

PMID- 12401491
TI  - The chemical biology of apoptosis. Exploring protein-protein interactions and the
      life and death of cells with small molecules.
AB  - Apoptosis, a fundamental process for both human health and disease, is initiated
      and regulated by protein-protein interactions, notable examples of which are the
      interactions involving Bcl-2 and IAP protein families. This article discusses
      recent advances in the use of chemical approaches in discovering and studying
      small molecules targeted to proteins of the Bcl-2 and IAP families. These small
      molecules and their complexes with receptors provide the tools and model systems
      to probe the basic mechanism of molecule recognition underling the life and death
      of cells and develop novel strategies for therapeutic intervention of the
      dysregulated apoptotic process. The review of these studies highlights the
      opportunity and challenge in this emerging area of chemical and chemical
      biological research.

PMID- 12401492
TI  - Targeted nucleotide exchange in Saccharomyces cerevisiae directed by short
      oligonucleotides containing locked nucleic acids.
AB  - Locked nucleic acids (LNAs) are novel base modifications containing a methylene
      bridge uniting the 2'-oxygen and the 4'-carbon. In this study, LNA-modified
      single-stranded molecules directed the repair of single base mutations in a yeast
      chromosomal gene. Using a genetic assay involving a mutant hygromycin-resistance
      gene, correction of point and frameshift mutations was facilitated by vectors
      containing an LNA residue on each terminus. Increasing the number of LNA bases on
      each terminus reduced the correction frequency progressively. When the LNA vector
      is used in combination with a phosphorothioate-modified vector (74-mer), however,
      a high level of gene-repair activity occurs; hence, short LNA-based vectors can
      augment the activity of other types of targeting vectors. These data suggest that
      oligonucleotides containing locked nucleic acid residues can be used to direct
      single nucleotide exchange reactions in vivo.

PMID- 12401493
TI  - Small molecule affinity fingerprinting. A tool for enzyme family
      subclassification, target identification, and inhibitor design.
AB  - Classifying proteins into functionally distinct families based only on primary
      sequence information remains a difficult task. We describe here a method to
      generate a large data set of small molecule affinity fingerprints for a group of
      closely related enzymes, the papain family of cysteine proteases. Binding data
      was generated for a library of inhibitors based on the ability of each compound
      to block active-site labeling of the target proteases by a covalent activity
      based probe (ABP). Clustering algorithms were used to automatically classify a
      reference group of proteases into subfamilies based on their small molecule
      affinity fingerprints. This approach was also used to identify cysteine protease
      targets modified by the ABP in complex proteomes by direct comparison of target
      affinity fingerprints with those of the reference library of proteases. Finally,
      experimental data were used to guide the development of a computational method
      that predicts small molecule inhibitors based on reported crystal structures.
      This method could ultimately be used with large enzyme families to aid in the
      design of selective inhibitors of targets based on limited structural/function
      information.

PMID- 12401494
TI  - Exclusive interaction of the 15.5 kD protein with the terminal box C/D motif of a
      methylation guide snoRNP.
AB  - Box C/D small nucleolar RNAs (snoRNAs) direct site-specific methylation of ribose
      2'-hydroxyls in ribosomal and spliceosomal RNAs. To identify snoRNA functional
      groups contributing to assembly of an active box C/D snoRNP in Xenopus oocytes,
      we developed an in vivo nucleotide analog interference mapping procedure.
      Deleterious substitutions consistent with requirements for binding the 15.5 kD
      protein clustered within the terminal box C/D motif only. In vitro analyses
      confirmed a single interaction site for recombinant 15.5 kD protein and
      identified the exocyclic amine of A89 in box D as essential for binding. Our
      results argue that the 15.5 kD protein interacts asymmetrically with the two sets
      of conserved box C/D elements and that its binding is primarily responsible for
      the stability of box C/D snoRNAs in vivo.

PMID- 12401495
TI  - Multisite and multivalent binding between cyanovirin-N and branched
      oligomannosides: calorimetric and NMR characterization.
AB  - Binding of the protein cyanovirin-N to oligomannose-8 and oligomannose-9 of gp120
      is crucially involved in its potent virucidal activity against the human
      immunodeficiency virus (HIV). The interaction between cyanovirin-N and these
      oligosaccharides has not been thoroughly characterized due to aggregation of the
      oligosaccharide-protein complexes. Here, cyanovirin-N's interaction with a
      nonamannoside, a structural analog of oligomannose-9, has been studied by nuclear
      magnetic resonance and isothermal titration calorimetry. The nonamannoside
      interacts with cyanovirin-N in a multivalent fashion, resulting in tight
      complexes with an average 1:1 stoichiometry. Like the nonamannoside, an alpha1-
      >2-linked trimannoside substructure interacts with cyanovirin-N at two distinct
      protein subsites. The chitobiose and internal core trimannoside substructures of
      oligomannose-9 are not recognized by cyanovirin-N, and binding of the core
      hexamannoside occurs at only one of the sites on the protein. This is the first
      detailed analysis of a biologically relevant interaction between cyanovirin-N and
      high-mannose oligosaccharides of HIV-1 gp120.

PMID- 12401496
TI  - Crystal structures of Candida albicans N-myristoyltransferase with two distinct
      inhibitors.
AB  - Myristoyl-CoA:protein N-myristoyltransferase (Nmt) is a monomeric enzyme that
      catalyzes the transfer of the fatty acid myristate from myristoyl-CoA to the N
      terminal glycine residue of a variety of eukaryotic and viral proteins. Genetic
      and biochemical studies have established that Nmt is an attractive target for
      antifungal drugs. We present here crystal structures of C. albicans Nmt complexed
      with two classes of inhibitor competitive for peptide substrates. One is a
      peptidic inhibitor designed from the peptide substrate; the other is a
      nonpeptidic inhibitor having a benzofuran core. Both inhibitors are bound into
      the same binding groove, generated by some structural rearrangements of the
      enzyme, with the peptidic inhibitor showing a substrate-like binding mode and the
      nonpeptidic inhibitor binding differently. Further, site-directed mutagenesis for
      C. albicans Nmt has been utilized in order to define explicitly which amino acids
      are critical for inhibitor binding. The results suggest that the enzyme has some
      degree of flexibility for substrate binding and provide valuable information for
      inhibitor design.

PMID- 12401497
TI  - Rational structure-based design of a novel carboxypeptidase R inhibitor.
AB  - A novel carboxypeptidase R (CPR) inhibitor, related to potato carboxypeptidase
      inhibitor (PCI), was designed using rational structure-based strategies,
      incorporating two principle facts: CPR has a strong affinity for basic amino
      acids, and the two lysine and arginine residues of PCI are orientated in the same
      direction and held in close spatial proximity by three disulfide bonds.
      Initially, a disulfide-bonded fragment of PCI was synthesized showing weak
      competitive inhibitory activity against CPR. Subsequently, a smaller linear 9-mer
      peptide, designated CPI-2KR, was designed/synthesized and found to be a more
      efficient competitive inhibitor of CPR, without affecting the activity of the
      other plasma carboxypeptidase, carboxypeptidase N. In vitro studies showed that,
      together with tissue plasminogen activator, CPI-2KR synergistically accelerated
      fibrinolysis, representing a lead compound for the design of smaller organic
      molecules for use in thrombolytic therapy.

PMID- 12401498
TI  - NikR repressor: high-affinity nickel binding to the C-terminal domain regulates
      binding to operator DNA.
AB  - E. coli NikR repressor binds operator DNA in a nickel-dependent fashion. The pM
      affinity of NikR for nickel is mediated by its C-terminal 86 residues. Nickel
      binding induced additional secondary structure, decreased the compactness, and
      increased the stability of NikR. Tetramer formation by the C-terminal domain and
      intact NikR did not require nickel. High-affinity nickel binding decreased the
      NikR concentration needed to half maximally protect operator DNA from
      undetectable levels to 30 nM. The intracellular concentration of NikR in E. coli
      is high enough that saturation of the high-affinity nickel sites should lead to
      substantial occupancy of the nik operator. Nickel binding to a set of low
      affinity NikR sites resulted in an additional large increase in operator affinity
      and substantially increased the size of the NikR footprint on the operator.

PMID- 12401499
TI  - Chemistry-based functional proteomics reveals novel members of the
      deubiquitinating enzyme family.
AB  - The ubiquitin (Ub)-proteasome system includes a large family of deubiquitinating
      enzymes (DUBs). Many members are assigned to this enzyme class by sequence
      similarity but without evidence for biological activity. A panel of novel DUB
      specific probes was generated by a chemical ligation method. These probes allowed
      identification of DUBs and associated components by tandem mass spectrometry, as
      well as rapid demonstration of enzymatic activity for gene products whose
      functions were inferred from primary structure. We identified 23 active DUBs in
      EL4 cells, including the tumor suppressor CYLD1. At least two DUBs tightly
      interact with the proteasome 19S regulatory complex. An OTU domain-containing
      protein, with no sequence homology to any known DUBs, was isolated. We show that
      this polypeptide reacts with the C terminus of Ub, thus demonstrating DUB-like
      enzymatic activity for this novel superfamily of proteases.

PMID- 12401500
TI  - Maternal serum and amniotic fluid bisphenol A concentrations in the early second
      trimester.
AB  - To assess human exposure to bisphenol A (BPA) over a 10-year period, BPA
      concentrations in maternal serum (MS) and amniotic fluid (AF) obtained at early
      second trimester were determined. ELISA was used to measure BPA in 200 MS/AF
      pairs in women carrying fetuses with normal karyotypes (Group I) and in 48 pairs
      with abnormal karyotypes (Group II). In Group I, BPA concentrations in AF
      (median: 0.26 ng/ml) were lower (P<0.01) than in MS (2.24 ng/ml). Over a 10-year
      period, yearly BPA concentrations in MS decreased from 5.62 to 0.99 ng/ml
      (P<0.001). Eight of the Group I AF samples had relatively high concentrations of
      BPA (2.80-5.62 ng/ml). In Group II, BPA concentrations in AF (0 ng/ml) were lower
      (P<0.01) than in MS (2.97 ng/ml). MS BPA concentrations in Group II were higher
      (P<0.01) than in Group I.

PMID- 12401501
TI  - Increased susceptibility to retinoid-induced teratogenesis in TGF-beta2 knockout
      mice.
AB  - Transforming growth factor-beta (TGF-beta) and retinoic acid (RA) have been
      implicated in normal and abnormal embryonic development. The aim of this study
      was to investigate the effect of TGF-beta2 gene deletion on susceptibility to RA
      induced teratogenesis in a mouse model. TGF-beta2 heterozygous or wild-type mice
      were mated and the dams dosed with a teratogenic dose of RA, or with control
      vehicle. The incidence of RA-induced cleft palate (CP) was 48% in wild-type
      embryos from wild-type dams, increasing to 71% in TGF-beta2 heterozygous
      littermates. Wild-type and TGF-beta2 heterozygous embryos from heterozygous dams
      exhibited a CP incidence of 74 and 77% respectively, following treatment with RA.
      Ninety-one percent of littermates nullizygous for TGF-beta2 were dead when
      examined; the remainder exhibited a CP. We conclude that the genotype of the dam
      and embryo with respect to TGF-beta2 affects the incidence of RA-induced
      teratogenesis.

PMID- 12401502
TI  - Effects of metronidazole, ipronidazole, and dibromochloropropane on rabbit and
      human sperm motility and fertility.
AB  - Treatment of protozoal pathogens in the reproductive system with chemical agents
      exposes flagellated sperm cells to potential toxicants. A widely used
      antiprotozoal agent is metronidazole. Its effect on rabbit and human sperm was
      compared with a more soluble 5-nitroazole compound, ipronidazole, and with a
      systemic environmental toxicant, dibromochloropropane (DBCP). The percentages of
      motile rabbit and human sperm incubated with the compounds, the velocity of
      sperm, migration of sperm in polyacrylamide gel, young born in rabbits, and
      penetration of hamster oocytes by treated human sperm were measured in seven
      experiments. Up to 10mg/ml metronidazole and 1mg/ml DBCP had little effect on
      most sperm characteristics. However, 10mg/ml metronidazole and 5mg/ml of
      ipronidazole increased attachment of human sperm to hamster oocytes, but oocyte
      penetration was unaffected. Rabbit sperm exposed to 5mg/ml ipronidazole were
      infertile. No oocytes were penetrated by DBCP-treated human sperm.

PMID- 12401503
TI  - Impairment of male fertility induced by muscarinic receptor antagonists in rats.
AB  - Male rats were treated with a muscarinic receptor antagonist at 3, 10, and
      100mg/kg/day for 4 weeks prior to mating with untreated females and their
      reproductive status was determined on gestation days (GD) 15-17. Treatment
      related decreases in the pregnancy rate were observed at 100mg/kg/day without any
      effects on mating performance. Impairment of male fertility by this compound was
      also observed after treatment for 1 week, but there were no effects after a 1
      week withdrawal period suggesting reversibility of the effect. There were no
      treatment-related effects on sperm production or motility, or testicular
      histopathology in any group. In order to determine whether the reduced fertility
      was a class effect of muscarinic receptor antagonists, atropine was examined.
      Males received atropine for 1 week at 62.5 and 125 mg/kg/day and were mated with
      untreated females. A low pregnancy rate associated with a decrease in the number
      of implantations was observed at 125 mg/kg/day. The effect on implantation was
      also observed at 62.5mg/kg/day. These findings suggest that the impairment of
      fertility in male rats induced by muscarinic receptor antagonists is a class
      effect, and has a relatively short onset of effect and is quickly reversible.

PMID- 12401504
TI  - Effects of chronic valproate treatment on reproductive endocrine hormones in
      female and male Wistar rats.
AB  - Valproate (VPA) has been claimed to induce endocrine disorders in both sexes in
      humans. There is sparse information regarding the mechanisms behind these
      disturbances. By using an animal model, we wanted to study the effect of
      valproate on hormonal function in non-epileptic rats. Female rats were given 0
      (vehicle control, n=15), 200mg/kg (n=15), or 300 mg/kg (n=20) valproate twice
      daily by gavage for 90 days, resulting in mean valproate concentrations within
      the therapeutic range 4-6h after the last dose given. Serum testosterone
      concentrations remained unchanged, while estradiol levels were significantly
      reduced in both treatment groups, leading to significantly increased
      testosterone/estradiol ratios. Follicle stimulating hormone (FSH) levels remained
      unaltered in valproate treated rats, whereas the luteinizing hormone (LH)
      concentrations were reduced at the lowest valproate dose. Male rats received 0
      (vehicle control, n=15), 200mg/kg (n=15), or 400mg/kg (n=20) valproate twice
      daily by gavage for 90 days, resulting in mean valproate concentrations within
      the therapeutic range 4-6h after the last dose. Serum testosterone levels were
      not significantly changed, but there was a highly significant increase in FSH and
      LH concentrations at the high dose. In conclusion, the study demonstrates a drug
      induced effect of valproate on endocrine function in both male and female rats.
      The results indicate that the drug exerts its effect primarily at the gonadal
      level, although a centrally mediated effect cannot be ruled out.

PMID- 12401505
TI  - Long-term effects of ovarian follicular depletion in rats by 4-vinylcyclohexene
      diepoxide.
AB  - 4-Vinylcyclohexene diepoxide (VCD) destroys preantral ovarian follicles in rats.
      Female 28-day Fisher 344 (F344) rats were dosed (30 days) with VCD (80 mg/kg per
      day, i.p.) or vehicle, and animals were evaluated for reproductive function at
      subsequent time points for up to 360 days. At each time point animals were
      killed, and ovaries and plasma collected. VCD reduced (P<0.05) the number of
      preantral follicles by day 30 relative to control. There were no ultrastructural
      differences in morphology between VCD-treated and control ovaries. Circulating
      FSH levels in VCD-treated animals were greater (days 120, 240, and 360, P<0.05)
      than in controls. Cyclicity was disrupted in the VCD-treated group by day 360.
      These results show that VCD-induced follicular destruction in rats is associated
      with a sequence of events (loss of preantral follicles, increased plasma FSH, and
      cyclic disruption) preceding premature ovarian senescence that is similar to
      events that occur during the onset of menopause in women.

PMID- 12401506
TI  - Effect of endosulfan on ovarian compensatory hypertrophy in hemicastrated albino
      mice.
AB  - Endosulfan, a chlorinated cyclodiene insecticide, was administered orally at 1.5,
      3, 6, and 9 mg/kg per day to normal hemicastrated virgin mice for 15 consecutive
      days to examine the effect on ovarian function. Sham-operated and hemicastrated
      control mice were administered a similar volume of olive oil. The vaginal smear
      and body weight of the mice were recorded daily and mice were sacrificed on day
      16. The remaining left ovary, uterus, kidney, adrenal, liver, thymus, and thyroid
      were removed and weighed. The left ovary from each animal was serially sectioned
      and stained for histologic studies. The hemicastrated control mice had a 40.5%
      increase in weight of the remaining left ovary and a significant increase in
      healthy and atretic follicles when compared with sham-operated controls. The
      remaining left ovaries of mice treated with 1.5mg endosulfan had a 37.2% increase
      in weight with no significant difference in ovarian weight and or in the healthy
      and atretic follicles when compared with hemicastrated olive oil-treated
      controls. However, treatment with 3, 6, and 9 mg endosulfan resulted in weight
      increases in the remaining left ovary of only 14.9, 7.4, and 0.8% and a
      significant decrease in healthy follicles with a concomitant increase in the
      number of atretic follicles compared to the olive oil-treated controls. There was
      no significant change in the number of estrous cycles or the duration of each
      phase of the estrous cycle with 1.5 and 3mg/kg per day endosulfan. However, there
      was a significant decrease in the number of estrous cycles, and the duration of
      estrus and metestrus with a concomitant significant increase in the duration of
      the diestrus phase with 6 and 9 mg/kg per day endosulfan treatment when compared
      with hemicastrated olive oil-treated controls. There were no significant change
      in body weight or the weights of the uterus, kidney, adrenal, liver, thymus, or
      thyroid after endosulfan treatment. These observations show that endosulfan
      treatment caused a significant decrease in compensatory ovarian hypertrophy. An
      increase in the number of atretic follicles and disruption of the estrous cycle
      may have been due to a direct effect on the ovary or to effects on the
      hypothalamo-hypophysial-ovarian axis.

PMID- 12401507
TI  - Pregnancy outcome after cabergoline treatment in early weeks of gestation.
AB  - We collected information on 61 pregnancies in 50 women treated with cabergoline.
      These pregnancies resulted in 12 (19.7%) early terminations (five induced
      abortions, six spontaneous abortions, one hydatidiform mole) and 49 (80.3%) live
      births. In one case, malformations were suspected by a gynecologist based on
      ultrasound at 12 gestational weeks and the pregnancy was terminated; additional
      information was not available. There was one case of trisomy 18. The frequency of
      spontaneous and induced abortions and major congenital malformations was
      comparable with rates in the general population. The data did not indicate any
      potential adverse effect of the drug on pregnancy. The data from this study in
      combination with previous reports can exclude a congenital malformation risk
      greater than 10% associated with pregnancy exposure to cabergoline.

PMID- 12401508
TI  - Effects of nicotine and cotinine on bovine theca interna and granulosa cells.
AB  - The purpose of this study was to determine if nicotine or cotinine inhibits
      steroidogenesis in the ovarian follicle. Theca interna and granulosa cells were
      isolated from bovine follicles, cultured with nicotine or cotinine for 24h, and
      culture media were assayed for androstenedione or estradiol. Treatment of theca
      interna with 6, 60, and 600 micro M nicotine decreased (P<or=0.002) production of
      androstenedione to 55, 53, and 24% of control levels, respectively. Levels of
      androstenedione in theca interna treated with cotinine were not different from
      control values. In granulosa cells, nicotine inhibited production of estradiol at
      the highest dose tested. Treatment with 600 micro M nicotine decreased
      (P<or=0.001) estradiol concentration to 12% of control values, attributable to a
      general cytotoxic effect. Cotinine had no effect on estradiol production by
      granulosa cells. These results provide novel evidence for inhibitory effects of
      nicotine on androgen production by theca interna.

PMID- 12401509
TI  - Alteration of pregnancy related hormones and fetal survival in F-344 rats exposed
      by inhalation to benzo(a)pyrene.
AB  - The objective of this study was to evaluate the effect of subacute exposure to
      inhaled benzo(a)pyrene (BaP) on fetal survival and luteal maintenance using timed
      pregnant Fisher 344 rats. Prior to assignment of pregnant rats to treatment and
      control groups, numbers of implantation sites were determined on gestation day
      (GD) 8 via midventral laparotomy. Subsequently, animals were assigned randomly to
      three treatment groups and two control groups. Treatment consisted of subacute
      exposure of rats via inhalation to BaP 25, 75, and 100 micro g/m(3), 4h daily for
      10 days (GD-11-20). Control animals were either sham exposed to carbon black (CB)
      to control for inert BaP carrier or remained unexposed (UNC). Blood samples were
      collected on days 15 and 17 of gestation via sinus orbital veini-puncture for
      plasma. Number of pups per litter was determined postpartum and fetal survival
      rate was expressed as a percentage of the corresponding implantation sites.
      Radioimmunoassays were used to determine plasma progesterone, estrogen, and
      prolactin (indirect measurement of decidual luteotropin) concentrations. Fetal
      survival among BaP-treated rats declined in a dose-dependent manner (25 micro
      g/m(3), 78.3% per litter; 75 micro g/m(3), 38.0% per litter; 100 micro g/m(3),
      33.8% per litter; P<0.05) compared with CB (96.7% per litter) and UNC (98.9% per
      litter). Plasma progesterone, estrogen, and prolactin concentrations also
      declined as a result of subacute exposure of rats to BaP compared to controls.
      These data suggest that inhaled BaP compromised fetal survival and consequently
      luteotropic activity in the exposed animals.

PMID- 12401510
TI  - Effect of L-arginine on arginase activity in male accessory sex glands of alloxan
      treated rats.
AB  - Arginase activity has been identified in the prostate, and may be important in
      the synthesis of polyamines in accessory sex glands in the male. Polyamines in
      turn may mediate the action of androgens. Diabetic patients have disordered
      androgen synthesis. The purpose of this work was to evaluate the effect of L
      arginine on arginase activity in accessory sex glands of male rats under normal
      and diabetic conditions (alloxan 120 mg/kg, i.p.). Normal and diabetic male rats
      were untreated or were treated with insulin or L-arginine for 96 h, and
      sacrificed. Arginase activity was measured in serum and in accessory sex glands.
      Arginase activity in accessory glands did not change significantly with induction
      of diabetes. Arginase activity was increased in diabetic insulin-treated rats,
      but there was no arginase response to L-arginine administration in diabetic
      animals. These findings stand in contrast to beneficial effects of L-arginine
      previously observed when this amino acid was administered for a long time (at
      least 10 days). We suspect that altered arginase activity in accessory sex glands
      may play a role in the reproductive dysfunction caused by diabetes, inasmuch as
      arginase activity can be increased in experimentally diabetic rats by the
      administration of insulin.

PMID- 12401511
TI  - Comparative study of sodium valproate-induced skeletal malformations using single
      or double staining methods.
AB  - The teratogenic activity of xenobiotics is usually investigated by examining
      visceral and skeletal abnormalities of term fetuses. Although the rodent fetal
      skeleton is only partially ossified, the single stain for bone is the most
      commonly used method in routine teratology testing, while the double stain for
      evaluation of both bone and cartilage is often used only in basic research. The
      present work compares data obtained from rat fetuses using the two methods after
      exposure to the teratogenic agent sodium valproate at specific embryonic stages
      of development. Pregnant rats were treated with 400mg/kg sodium valproate and
      sacrificed at term of pregnancy. Even if both methods were able to identify
      sodium valproate as a teratogenic molecule, correct and complete interpretation
      of data was possible only by using the double stain. Our results show the
      inability of the single stain to correctly discriminate between major and minor
      abnormalities.

PMID- 12401512
TI  - Neural crest cell motility in valproic acid.
AB  - Neural crest cells (NCCs) exit the dorsal neural tube and migrate to sites where
      they form diverse tissues. Valproic acid (VPA) is an anticonvulsant drug that
      induces neural tube and related defects. Altered NCC migration and proliferation
      have been proposed as mechanisms of teratogenicity. We cultured neural tube
      segments from chick embryos in 0.75-3.0mM VPA. We used image analysis,
      proliferation assays, and fluorescence localization to investigate NCCs during
      VPA exposure. VPA inhibited attachment of explants and the number that produced
      migrating cells. VPA markedly decreased the proportion of cells migrating
      individually, promoting migration as epithelial sheets. VPA at 3mM decreased
      cellular spreading. Area and perimeter change per minute were reduced, but
      migration velocity was not. VPA at 2mM reduced proliferation 11% and 3mM arrested
      proliferation. Immunostaining of VPA-exposed explants revealed N-cadherin
      positive cell boundaries within sheets, but independent NCCs did not stain. F
      actin staining was reduced in independent NCCs. The data support a VPA mechanism
      involving interference with epithelial-mesenchymal transition.

PMID- 12401513
TI  - Diclofenac-induced embryotoxicity is associated with increased embryonic 8
      isoprostaglandin F2alpha level in rat whole embryo culture.
AB  - Diclofenac is embryotoxic in animals but the mechanism of its embryotoxicity is
      not fully understood. We postulated that diclofenac-induced embryotoxicity might
      be related to free oxygen radical damage. Rat embryos were explanted at 9.5 days
      gestation and cultured in medium containing various concentrations of diclofenac.
      The direct effect of diclofenac on embryonic free oxygen radical content was
      evaluated by measuring the 8-isoprostaglandin F2alpha level. We found that
      embryos exposed to high concentrations of diclofenac (7.5 and 15.0 micro g/ml)
      had significantly higher levels of 8-isoprostaglandin F2alpha (2.85 and 3.50
      pg/mm embryonic crown-rump length, respectively) than the control group (1.73
      pg/mm, P<0.05), while the 8-isoprostaglandin F2alpha level in embryos exposed to
      low concentration of diclofenac (1.5 micro g/ml) was 2.54 pg/mm, which was not
      significantly different from the control group. Median embryo morphologic score
      was also lower in the high concentration group compared to the control group
      (39.0 versus 44.0, P<0.05). These results suggest that diclofenac-induced
      embryopathy may be related to free oxygen radical damage.

PMID- 12401514
TI  - Involvement of NF-kappaB signalling in skin physiology and disease.
AB  - Transcription factors of the nuclear factor-kappaB (NF-kappaB)/Rel family play a
      crucial role in gene regulation during a variety of different cellular processes.
      This review focuses on the increasing knowledge of the role of NF-kappaB in skin
      physiology and pathology. Several studies demonstrate that NF-kappaB, or
      components of the system such as IkappaB kinase (IKK)-alpha, seem to be involved
      in epidermal development and differentiation. Furthermore, a dysregulation of NF
      kappaB is suggested to play an important role in skin pathology, including
      proliferative disorders, e.g. psoriasis, inflammatory processes such as
      incontinentia pigmenti (IP), sunburn, Lyme disease, allergic contact dermatitis
      and autoimmune diseases, as well as also in skin carcinogenesis. However,
      although the knowledge concerning the role of NF-kappaB in the homeostasis of the
      skin is steadily increasing, many more questions need to be answered.

PMID- 12401515
TI  - CD40 and its viral mimic, LMP1: similar means to different ends.
AB  - CD40 is an important regulator of diverse aspects of the immune response
      including the T-cell-dependent humoral immune response, the development of
      antigen-presenting cells (APCs) and inflammation. Latent membrane protein 1
      (LMP1), a protein encoded by Epstein-Barr Virus (EBV), appears to mimic CD40 in
      multiple ways. CD40 and LMP1 bind similar sets of cellular signalling proteins
      and activate overlapping signalling pathways. Despite many similarities shared
      between CD40 and LMP1, they also differ substantively. In this review, we will
      compare and contrast the signalling mediated by CD40 and LMP1.

PMID- 12401516
TI  - Regulation of corticotropin-releasing factor receptor type 2beta mRNA via cyclic
      AMP pathway in A7r5 aortic smooth muscle cells.
AB  - Corticotropin-releasing factor receptor type 2beta (CRF R2beta) is a member of
      the Class B heptahelical G protein-coupled receptors. This receptor is positively
      coupled to adenylate cyclase and is bound preferentially by the CRF-related
      peptides, urocortin (Ucn), Ucn II and Ucn III. In the rodent, CRF R2beta
      messenger RNA (mRNA) is expressed in the cardiovascular system, where its levels
      can be modulated by Ucn. In the present study, we investigated regulation of CRF
      R2beta levels by Ucn in A7r5 aortic smooth muscle cells. Ribonuclease protection
      assays show that A7r5 cells expressed the CRF R2beta subtype, which had two
      isoforms differing in one codon at the junction of exons 3 and 4. Ucn induced
      accumulation of intracellular cAMP via CRF R2beta in this cell line. In addition
      to the treatment with Ucn, cAMP agonists or analogues themselves caused a
      significant decrease in CRF R2beta mRNA levels. Blockade of Ucn- or cAMP-induced
      decreases in CRF R2beta mRNA levels by H7, a broad protein kinase inhibitor,
      suggested that a protein kinase pathway might be involved in this regulation.
      H89, a protein kinase A inhibitor, partially blocked Ucn- or cAMP-induced
      decreases in CRF R2beta mRNA levels. Thus, Ucn induces intracellular cAMP to
      downregulate CRF R2beta mRNA expression in A7r5 cells.

PMID- 12401517
TI  - Forskolin suppresses insulin gene transcription in islet beta-cells through a
      protein kinase A-independent pathway.
AB  - This work was designed to evaluate the effect of cAMP on insulin gene regulation.
      We studied the effects of forskolin on insulin gene transcription in the INS-1
      beta-cell line, confirming key results in primary cultures of human islet cells.
      Forskolin increased intracellular cAMP and cAMP-responsive element-binding
      activity. Insulin gene transcription was studied using a reporter construct in
      which the human insulin promoter was fused to luciferase. When cells were treated
      with forskolin for 12 h, insulin promoter activity was decreased 2- to 3-fold,
      whereas islet amyloid polypeptide promoter activity was significantly increased.
      This effect of forskolin on the insulin gene was time- and concentration
      dependent, and was mimicked by 8-bromo-cAMP. Mutagenesis of the CRE-like elements
      in the insulin promoter had no effect on the forskolin-induced suppression, but
      dramatically decreased basal insulin promoter activity. Inhibition of PKA with H
      89 also did not reverse the forskolin-induced suppression of insulin
      transcription. However, this effect was completely reversed by inhibition of
      cellular MAP kinase activity with PD98059 or U0126. These results demonstrate
      that forskolin suppresses insulin transcription in INS-1 cells through a PKA
      independent mechanism that probably involves MAP kinase signalling.

PMID- 12401518
TI  - Negative regulation of phosphatidylinositol 3-kinase and Akt signalling pathway
      by PKC.
AB  - Although substantial studies have begun to explore the regulation of
      phosphatidylinositol 3-kinase/Akt cascade by different signalling pathways,
      whether protein kinase C (PKC) activity plays a crucial role remains as yet
      unclear. In this study, we found that in A549 and HEK293 cells non-selective PKC
      inhibitors Ro 31-8220 and bisindolylmaleimide VIII, and PKCbeta inhibitor LY
      379196, caused Akt/PKB phosphorylation at Ser 473 and increased the upstream
      activator, integrin-linked kinase (ILK) activity. The increased Akt
      phosphorylation was blocked by phosphatidylinositol 3-kinase inhibitor wortmannin
      and the newly identified PIP(3)-dependent kinases (PDK) inhibitor SB 203580. In
      contrast to the Akt stimulation caused by PKC inhibitors, PMA attenuated Akt/PKB
      phosphorylation. We also found that this stimulating effect on Akt
      phosphorylation by PKC inhibitors was not the result of phosphatase inhibition,
      since treatment with PP2A, PP2B and tyrosine phosphatase inhibitors (okadaic
      acid, FK506 and sodium orthovanadate, respectively) had no effect. We conclude
      that phosphatidylinositol 3-kinase/Akt signalling pathway is regulated by PKC in
      a negative manner.

PMID- 12401519
TI  - Jak2 and proteasome activities control the availability of cell surface growth
      hormone receptors during ligand exposure.
AB  - Several mechanisms participate in the down-regulation of growth hormone receptor
      (GHR) signalling under ligand exposure. In CHO cells expressing GHR, we show that
      ligand stimulation induces degradation of the total cell GHR content. Experiments
      with 125I-hGH indicate that ligand-bound internalized receptors are not
      immediately replaced. Using cell surface biotinylation, we demonstrate for the
      first time that, concomitantly with the degradation of cell surface receptors,
      GHRs from the intracellular compartments are also degraded. We thus suggest that
      under prolonged ligand exposure, some GHRs are targeted to the cell surface,
      while others are routed to degradation compartments. Inhibitors of Jak2 and of
      the proteasome partially inhibited degradation of cell surface receptors, while
      these compounds completely inhibit the degradation of intracellular GHRs,
      resulting in their accumulation. We therefore propose that Jak2 and proteasome
      activities control the amount of intracellular GHRs, and thus the availability of
      receptors at the cell surface, during ligand exposure.

PMID- 12401520
TI  - Mitochondrial calcium-mediated reactive oxygen species are essential for the
      rapid induction of the grp78 gene in 9L rat brain tumour cells.
AB  - The glucose-regulated protein grp78 gene is rapidly transactivated in 9L rat
      brain tumour (RBT) cells treated with okadaic acid (OA) followed by heat shock
      (HS) (termed OA-->HS treatment). By Northern blotting analyses and transient
      transfection assays, we herein show that transactivation of grp78 by OA-->HS is
      abolished by an intracellular calcium chelator, bis(aminophenoxy)ethane N,N'
      tetraacetic acid (BAPTA), and an inhibitor of mitochondrial Ca(2+) uniporter,
      ruthenium red (RR), while unaffected by cyclosporin A (CsA), an inhibitor of
      mitochondrial permeability transition pore (MTP). The inhibitory effects of BAPTA
      and RR also present in OA-->HS induction of transient elevation of intracellular
      hydrogen peroxide. The requirement of reactive oxygen intermediates (ROIs) is
      confirmed by substitutional addition of antioxidants, N-acetyl cysteine (NAC) and
      pyrrolidinedithiocarbamate (PDTC) during OA-->HS treatment, mimicking these
      inhibitory effects of BAPTA and RR. Western blotting analyses show that
      phosphorylation of transcription factor CREB is diminished only by BAPTA but not
      by RR, while phosphorylation of ATF-2 is unaffected by either agent.
      Conclusively, we present that both the disturbances of mitochondrial calcium
      homeostasis and reactive oxygen intermediates are essential for rapid
      transactivation of grp78, and this pathway is separate from protein kinase A
      (PKA)-dependent CREB activation or p38 mitogen-activated protein kinase
      (p38(MAPK))-dependent ATF-2 activation and signalling.

PMID- 12401521
TI  - A subdomain of MEKK1 that is critical for binding to MKK4.
AB  - Mitogen-activated protein kinase (MAPK) cascades are central components of signal
      transduction pathways induced by mitogens and stresses. They consist of a three
      kinase module in which a mitogen-activated protein kinase kinase kinase (MAP3K)
      activates a mitogen-activated protein kinase kinase (MAP2K), which in turn
      activates MAPK. The molecular determinants that underlie specific MAP3K-MAP2K
      interactions are poorly understood. In this study, we examined the interaction
      between the MAP3K MEKK1 and MKK4, a MAP2K of the JNK pathway. Select point
      mutations in subdomain X of the catalytic domain of MEKK1 (MEKK1delta) were found
      to impair the ability of MEKK1delta to bind to and activate MKK4. Such mutations
      were also found to impair MEKK1delta-induced activation of an AP1 reporter gene.
      These studies point to a critical role for subdomain X in the interaction of
      MEKK1 with MKK4.

PMID- 12401522
TI  - Engagement of the NG2 proteoglycan triggers cell spreading via rac and p130cas.
AB  - Cells that express the NG2 proteoglycan will spread on surfaces coated with
      monoclonal antibodies against this membrane-spanning protein. On surfaces coated
      with the N143 monoclonal antibody, this cell spreading occurs by extension of
      lamellipodia, suggesting that activation of the small GTPase rac is involved in
      the observed morphological change. Support for this hypothesis comes from the
      finding of increased levels of GTP-bound rac in cells spreading on N143-coated
      surfaces. Furthermore, lamellipodia extension is blocked by transfection of cells
      with the dominant negative rac construct N17rac, but not by transfection with
      N17cdc42. Formation of lamellipodia on the N143-coated surfaces is also inhibited
      by transfection of the dominant negative CasdeltaSD construct. This result
      implicates p130cas as an additional functional player in NG2-mediated cell
      spreading.

PMID- 12401523
TI  - Modulation of the electrophoretic mobility of the linker for activation of T
      cells (LAT) by the calcineurin inhibitors CsA and FK506: LAT is a potential
      substrate for PKC and calcineurin signaling pathways.
AB  - The linker for activation of T cells (LAT) is essential for T cell activation.
      Cyclosporin A (CsA) and FK506, inhibitors of T cell proliferation, have been very
      useful for preventing autoimmune and inflammatory disease and graft rejection.
      However, both compounds are associated with side effects. We show that TCR
      ligation in the presence of FK506 or CsA induced rapid modifications in LAT that
      modulate the electrophoretic mobility of the molecule in SDS-PAGE. Calcineurin, a
      target for CsA and FK506, dephosphorylated LAT in vitro and restored its
      electrophoretic mobility. Stimulating T cells with the protein kinase C (PKC)
      activator PMA induced a shift in the mobility of LAT, whereas inhibitors of PKC
      blocked the effect of PMA. Thus, manipulating calcineurin or PKC activation
      alters the electrophoretic mobility of LAT. These results shed light on the
      molecular actions of CsA and FK506 in T cells and implicate LAT in mediating the
      drugs' actions.

PMID- 12401524
TI  - p53 and MDM2 are regulated by PI-3-kinases on multiple levels under stress
      induced by UV radiation and proteasome dysfunction.
AB  - p53 is a key stress responsive cellular component. It is negatively regulated by
      MDM2, which is also its transcriptional target. Here we have studied the
      involvement of phosphatidylinositol-3-kinases (PI-3-kinase) in the regulation of
      p53-MDM2 pathway following cellular stress induced by UV damage and proteasomal
      downregulation. We show that p53 stabilized both by proteasome inhibition and UV
      damage is transcriptionally active. However, p53 in proteasomally downregulated
      cells differs from UV-stabilized p53 in its interaction with MDM2,
      posttranslational modifications and subnuclear localization. It is known that
      members of PI-3-kinase family are able to directly phosphorylate p53 and MDM2. We
      show that these kinases regulate p53 accumulation after UV radiation, but
      accumulation of MDM2 after proteasome inhibition. Both proteins have earlier been
      shown to translocate into nucleoli after downregulation of the proteasome. We
      found this effect to be dependent on PI-3-kinase activity but not on any
      suggested PI-3-kinase phosphorylation site on MDM2. In conclusion, we show here
      that PI-3-kinases regulate p53-MDM2 pathway on multiple, earlier unknown levels.

PMID- 12401525
TI  - Regulation of phospholipase D by muscarinic receptors in rat submandibular ductal
      cells.
AB  - The muscarinic agonist carbachol stimulated phospholipase D (PLD) in rat
      submandibular gland (RSMG) ductal cells in a time and concentration-dependent
      manner. This effect was inhibited by chelation of extracellular calcium with
      ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA). PLD
      could also be activated by epinephrine and AlF(4)(-), two polyphosphoinositide
      specific phospholipase C (PPI-PLC) activators, and by the phorbol ester o
      tetradecanoylphorbol 13-acetate (TPA) which activates protein kinase C (PKC).
      Ionomycin and thapsigargin only slightly increased PLD activity. Ortho-vanadate,
      a tyrosine phosphatase inhibitor, also stimulated PLD activity. Both carbachol
      and o-vanadate increased the formation of inositol phosphates and the tyrosine
      phosphorylation of at least two proteins (55-60 and 120 kDa). Calphostin C (a PKC
      inhibitor), U73122 (a PPI-PLC inhibitor) and genistein (a tyrosine kinase
      inhibitor) blocked the activation of PLD, of PLC and the phosphorylation of
      tyrosyl residues in response to carbachol and vanadate. Taken together, these
      results suggest that rat submandibular gland ductal cells express a calcium
      dependent PLD activity. This enzyme is regulated by carbachol via a PLC-PKC
      tyrosine kinase pathway.

PMID- 12401526
TI  - Activation of P2Y2 purinoceptor inhibits the activity of the Na+/K+-ATPase in
      HeLa cells.
AB  - The role of ATP on regulation of the Na(+)/K(+)-ATPase activity in the human
      cancerous HeLa cells was investigated. HeLa cells stimulated with increasing ATP
      concentrations showed a dose-dependent inhibition of the Na(+)/K(+)-ATPase
      activity. These effects were also obtained by UTP. ATP and UTP provoked a rise in
      intracellular calcium concentration ([Ca(2+)](i)) persisting for at least 4 min.
      The inhibitor of phospholipase C, U73122, blocked the elevation of [Ca(2+)](i)
      provoked by ATP/UTP. The expression of mRNA for P2Y2 and P2Y6 receptors was
      demonstrated by RT-PCR. ATP/UTP activated PKC-alpha, -betaI and -epsilon
      isoforms, but not PKC-delta and -zeta. The inhibition of the Na(+)/K(+)-ATPase
      activity by ATP/UTP was blocked by Go6976, a specific inhibitor of the calcium
      dependent PKCs. In conclusion, our results suggest that ATP/UTP modulate
      Na(+)/K(+)-ATPase activity in HeLa cells through the P2Y2 purinoceptor via
      calcium mobilisation and activation of calcium-dependent PKCs.

PMID- 12401527
TI  - An epsilonPKC-selective inhibitor attenuates back phosphorylation of a low
      molecular weight protein in cardiac myocytes.
AB  - We have studied epsilon PKC-mediated phosphorylation events in neonatal cardiac
      myocytes using back phosphorylation. 3 nM 4-beta 12-myristate-13-acetate (PMA)
      intact cell treatment preferentially activates epsilon PKC in these cells (Circ.
      Res. 76 (1995) 654) and caused decreased 32P incorporation (back phosphorylation)
      into an approximately 18-kDa protein. This response required physiological levels
      of free Mg(2+) and short (3-5 min) incubation periods in back phosphorylation
      assays. Introduction of a selective epsilon PKC translocation inhibitor (epsilon
      V1) into these cells attenuated the 3 nM PMA-induced back phosphorylation
      response while translocation inhibitors to the classical PKC or deltaPKC isozymes
      were without effect. Pretreatment of our cells with endothelin-1 (ET1) had
      similar effects to 3 nM PMA albeit the magnitude of the ET1 back phosphorylation
      response was about one-half that of 3 nM PMA. Our results suggest that epsilon
      PKC phosphorylates an approximately 18-kDa protein found in the particulate cell
      fraction of neonatal cardiac myocytes. Epsilon PKC modulates diverse cardiac
      responses including contraction, ion channel functions, hypertrophy, and ischemic
      preconditioning. Characterization of epsilon PKC-selective phosphotransferase
      events may reveal novel regulatory mechanisms for this enzyme in neonatal cardiac
      myocytes.

PMID- 12401528
TI  - Cholesterol cell content modulates GTPase activity of G proteins in GH4C1 cell
      membranes.
AB  - Previous results from our laboratory showed that GH(4)C(1) cells with low
      cholesterol cell content had increased adenylyl cyclase (AC) activity with a
      parallel increase in G protein alpha subunits associated to the plasma membrane.
      This effect was directly related to mevalonate availability. In the present
      report, we characterized the high-affinity GTPase activity present in GH(4)C(1)
      cell membranes and studied its regulation by cholesterol cell content. The high
      affinity GTPase activity, measured as the [gamma32P]GTP hydrolysis rate, was both
      time-dependent and protein concentration-dependent. Cultured cells with
      lipoprotein-deficient serum (LPDS) showed decreased cholesterol cell content and
      decreased GTPase activity. The kinetic analysis, as interpreted by Lineweaver
      Burk plots, indicated that low-cholesterol cell content had no effect on the
      apparent affinity for GTP, but resulted in a 47% decrease in the maximal velocity
      of the reaction. Addition of 25-hydroxycholesterol (25-HC), an inhibitor of the
      expression of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and
      synthetase to cells in LPDS, further decreased GTPase activity in a dose
      dependent manner. This effect was reverted by exogenous cholesterol, but not by
      mevalonate. Studies with bacterial toxins revealed that neither cholera toxin
      (CTX) nor pertussis toxins (PTX) were able to revert the inhibition produced by
      low-cholesterol cell content. These results allowed us to postulate that
      cholesterol modulates GTPase activity in both Gs and Gi protein families. To
      analyse further the mechanism of modulation of GTPase activity by cholesterol
      cell content, [35S]GTPgammaS binding in membranes of GH(4)C(1) cells was studied.
      Changes in cholesterol cell content did not have any effect on GTP binding. Data
      demonstrated that high-affinity GTPase activity in plasma membrane of GH(4)C(1)
      cells is direct stimulated by cholesterol cell content and not by mevalonate
      availability. This example provides a mechanism by which cholesterol cell content
      can modulate signal transduction mediating by G proteins.

PMID- 12401529
TI  - A population-based study of the long-term risks associated with atrial
      fibrillation: 20-year follow-up of the Renfrew/Paisley study.
AB  - PURPOSE: To describe the effect of atrial fibrillation on long-term morbidity and
      mortality. SUBJECTS AND METHODS: The Renfrew/Paisley Study surveyed 7052 men and
      8354 women aged 45-64 years between 1972 and 1976. All hospitalizations and
      deaths occurring during the subsequent 20 years were analyzed by the presence or
      absence of atrial fibrillation at baseline. Lone atrial fibrillation was defined
      in the absence of other cardiovascular signs or symptoms. Cox proportional
      hazards models were used to adjust for age and cardiovascular conditions.
      RESULTS: After 20 years, 42 (89%) of the 47 women with atrial fibrillation had a
      cardiovascular event (death or hospitalization), compared with 2276 (27%) of the
      8307 women without this arrhythmia. Among men, 35 (66%) of 53 with atrial
      fibrillation had an event, compared with 3151 (45%) of 6999 without atrial
      fibrillation. In women, atrial fibrillation was an independent predictor of
      cardiovascular events (rate ratio [RR] = 3.0; 95% confidence interval [CI]: 2.1
      4.2), fatal or nonfatal strokes (RR = 3.2; 95% CI: 1.0-5.0), and heart failure
      (RR = 3.4; 95% CI: 1.9-6.2). The rate ratios among men were 1.8 (95% CI: 1.3-2.5)
      for cardiovascular events, 2.5 (95% CI: 1.3-4.8) for strokes, and 3.4 (95% CI:
      1.7-6.8) for heart failure. Atrial fibrillation was an independent predictor of
      all-cause mortality in women (RR = 2.2; 95% CI: 1.5-3.2) and men (RR = 1.5; 95%
      CI: 1.2-2.2). However, lone atrial fibrillation (which occurred in 15 subjects)
      was not associated with a statistically significant increase in either
      cardiovascular events (RR = 1.5; 95% CI: 0.6-3.6) or mortality (RR = 1.8; 95% CI:
      0.9-3.8). CONCLUSIONS: Atrial fibrillation is associated with an increased long
      term risk of stroke, heart failure, and all-cause mortality, especially in women.

PMID- 12401530
TI  - A population-based study of mortality among patients with atrial fibrillation or
      flutter.
AB  - PURPOSE: To determine the mortality associated with atrial flutter and atrial
      fibrillation in the general population. SUBJECTS AND METHODS: Using the
      Marshfield Epidemiologic Study Area, a database that captures nearly all medical
      care and deaths among its 58,820 residents, we identified patients diagnosed with
      atrial flutter or atrial fibrillation from July 1, 1991, through June 30, 1995.
      Patients were followed prospectively and compared with a group of controls
      without these arrhythmias. RESULTS: A total of 4775 person-years of follow-up
      were completed in 577 patients and 577 controls. Compared with controls,
      mortality among patients with atrial fibrillation or flutter was nearly 7.8-fold
      higher at 6 months (95% confidence interval [CI]: 4.1 to 15) and 2.5-fold higher
      (95% CI: 2.0 to 3.1; P < 0.0001) at the last follow-up (mean [+/- SD] of 3.6 +/-
      2.3 years; range, 1 day to 7.3 years). At 6 months, mortality among patients with
      atrial flutter alone was somewhat greater than in controls and less than one
      third that of those with atrial fibrillation (with or without atrial flutter) (P
      = 0.02). At the last follow-up, however, mortality was greater among patients
      with atrial flutter (hazard ratio [HR] = 1.7; 95% CI: 1.2 to 2.6; P = 0.007),
      atrial fibrillation (HR = 2.4; 95% CI: 1.9 to 3.1; P < 0.0001), or both atrial
      arrhythmias (HR = 2.5; 95% CI: 1.9 to 3.3; P < 0.0001) when compared with
      controls in models that adjusted for cardiovascular risk factors. CONCLUSION: In
      the general population, both atrial flutter and atrial fibrillation are
      independent predictors of increased late mortality. The relatively benign course
      during the 6-month period after the initial diagnosis of atrial flutter suggests
      that early diagnosis and treatment of these patients may improve their long-term
      survival.

PMID- 12401531
TI  - A prospective multicenter study of factors associated with hospital admission
      among adults with acute asthma.
AB  - PURPOSE: We sought to determine patient characteristics associated with hospital
      admission after emergency treatment for asthma, and whether disposition
      guidelines are followed. SUBJECTS AND METHODS: We performed a prospective
      multicenter cohort study involving 64 emergency departments in the United States
      and Canada. Consecutive adult patients with asthma exacerbations were
      interviewed, and their charts were reviewed using standardized protocols.
      Telephone follow-up at 2 weeks determined relapse. RESULTS: Of 1805 patients, 363
      (20%; 95% confidence interval [CI]: 18% to 22%) were hospitalized. Among patients
      with severe exacerbations (final peak flow <50% of predicted), 122 (49%; 95% CI:
      43% to 55%) were hospitalized. Admission was associated with final peak flow,
      female sex, nonwhite race, severity of chronic illness, and severity of
      exacerbation. Admission predictors were similar regardless of hospital funding,
      region, or size. Among patients with mild or moderate exacerbations of asthma
      (peak flow >or=50% predicted), the likelihood of admission was associated
      significantly with the number of predefined risk factors for death from asthma.
      Of patients who were discharged from the emergency department, 62 (5%; 95% CI: 4%
      to 6%) relapsed within 72 hours. Relapse was not associated with final peak flow
      (P = 0.39). CONCLUSION: Associations between patient characteristics and
      disposition were similar across sites. Despite guidelines to the contrary, half
      of patients with final peak flow <50% were discharged. After emergency department
      treatment and discharge, short-term relapse was uncommon among patients with
      asthma, suggesting that strict peak flow cutoffs may be unnecessary if risk
      factors in patients with mild or moderate exacerbations are considered.

PMID- 12401532
TI  - Improving the quality of pneumonia care that patients experience.
AB  - PURPOSE: Although many hospitals have reported attempts to reduce length of stay
      for patients hospitalized with community-acquired pneumonia, few have included
      efforts to educate patients to prepare them for earlier discharges. We aimed to
      improve patients' knowledge about pneumonia and their experiences with inpatient
      care as part of a multifaceted intervention that included attempts to reduce
      unnecessary time on intravenous antibiotics and length of hospital stay. METHODS:
      We developed guidelines for the appropriate duration of intravenous antibiotics
      in patients with community-acquired pneumonia and collected baseline data
      retrospectively on patients discharged from October 1996 through April 1997. We
      surveyed these patients to assess knowledge and experience with care. Beginning
      in July 1997, we conducted a series of physician and nurse educational
      interventions (lectures, feedback of performance data, one-on-one education by
      peers). Patients received education about pneumonia from their nurses and a
      specially developed educational brochure. Following the interventions, we
      collected clinical and survey data on patients with pneumonia discharged from
      October 1997 through April 1998. RESULTS: Among patients who responded to the
      survey (163 in the preintervention period; 114 in the postintervention period),
      fewer reported that no one went out of the way to help them (preintervention, 37%
      [n = 60]; postintervention, 6% [n = 7]; P = 0.001), more reported that they
      received all the information they needed to recover (75% [n = 122] vs. 94% [n =
      107], P = 0.02), and more reported that they were told about danger signals of
      relapse (46% [n = 75] vs. 60% [n = 68], P = 0.03). Mean (+/- SD) time on
      intravenous antibiotics decreased from 5.0 +/- 3.7 days to 4.3 +/- 3.3 days (P =
      0.04). CONCLUSION: The interventions improved patients' knowledge and experiences
      with care, while decreasing time on intravenous antibiotics.

PMID- 12401533
TI  - Compliance with National Cholesterol Education Program dietary and lifestyle
      guidelines among older women with self-reported hypercholesterolemia. The Women's
      Health Initiative.
AB  - PURPOSE: Dietary therapy remains the first line of treatment for patients with
      high blood cholesterol levels. Among free-living persons, compliance with
      National Cholesterol Education Program (NCEP) dietary recommendations is
      uncertain. SUBJECTS AND METHODS: We performed a cross-sectional, baseline
      analysis of 91,627 postmenopausal women enrolled in the Women's Health Initiative
      Observational Study. Among women with self-reported hypercholesterolemia, we
      ascertained factors associated with compliance with National Cholesterol
      Education Program dietary recommendations, defined for the Step II diet as
      <or=30% of total calories from fat, <7% of calories from saturated fat, and daily
      dietary cholesterol <200 mg. RESULTS: Of the 13,777 participants who reported
      having high cholesterol levels requiring drug therapy, only 20% reported total
      fat, saturated fat, and dietary cholesterol consumption consistent with Step II
      dietary goals. Factors associated with Step II dietary compliance included having
      a college degree (odds ratio [OR] = 1.26; 95% confidence interval [CI]: 1.14 to
      1.40), a prior cardiovascular event (OR = 1.48; 95% CI: 1.28 to 1.70), and
      consumption of five or more daily servings of fruits or vegetables (OR = 3.0; 95%
      CI: 2.7 to 3.3). Being married, smoking, a sedentary lifestyle, and a higher body
      mass index were all associated with reduced compliance (all P <0.0001). In the
      subsample in which plasma lipid levels were measured, dietary compliance was
      associated with higher levels of low-density lipoprotein cholesterol (P = 0.02).
      CONCLUSION: Since the inception of the NCEP in 1985, health care providers,
      public health programs, and patients have not successfully implemented the
      dietary recommendations.

PMID- 12401534
TI  - Long-term financial implications of specialty training for physicians.
AB  - PURPOSE: Given the recent changes in physician reimbursement and managed care
      penetration, we examined the financial returns that might be anticipated when
      considering different medical careers. METHODS: We used survey data from the
      American Medical Association and standard financial techniques to calculate the
      return on educational investment (as the discounted, annual hours-adjusted, net
      present value of additional training) over a working lifetime for six different
      specialties (family practice, pediatrics, general internal medicine,
      gastroenterology, cardiology, and general surgery). RESULTS: From 1992 to 1998,
      the annual yield on specialty training (hours-adjusted internal rate of return)
      declined for all specialty groups, especially for primary care specialties. The
      difference in the average income between a given specialty and general practice
      decreased for general internal medicine, from $5400 (95% confidence interval
      [CI]: $5000 to $5800) in 1992 to $1180 (95% CI: $1160 to $1205) in 1998, and
      became negative for family practice (from $5200 [95% CI: $1000 to $9500] to 
      $2500 [95% CI: -$5800 to $800]) and pediatrics (from $4000 [95% CI: $1200 to
      $6800] to -$6300 [95% CI: -$9700 to -$2900]). Values for surgery decreased from
      $33,100 (95% CI: $29,400 to $36,400) in 1992 to $27,200 (95% CI: $21,700 to
      $32,100) in 1998, whereas there were increases for cardiology, from $35,100 (95%
      CI: $30,000 to $39,700) to $36,700 (95% CI: $26,500 to $45,700), and for
      gastroenterology, from $30,000 (95% CI: $21,800 to $37,200) to $34,700 (95% CI:
      $22,700 to $45,300). CONCLUSION: Our analysis suggests that recent efforts to use
      financial incentives to make primary care fields more attractive have not been
      effective. Financial returns and the incentives they create should be carefully
      considered as part of health care reform.

PMID- 12401535
TI  - Estimating the cost-effectiveness of 54 weeks of infliximab for rheumatoid
      arthritis.
AB  - PURPOSE: To estimate the cost-effectiveness of infliximab plus methotrexate for
      active, refractory rheumatoid arthritis. METHODS: We projected the 54-week
      results from a randomized controlled trial of infliximab into lifetime economic
      and clinical outcomes using a Markov computer simulation model. Direct and
      indirect costs, quality of life, and disability estimates were based on trial
      results; Arthritis, Rheumatism, and Aging Medical Information System (ARAMIS)
      database outcomes; and published data. Results were discounted using the standard
      3% rate. Because most well-accepted medical therapies have cost-effectiveness
      ratios below $50,000 to $100,000 per quality-adjusted life-year (QALY) gained,
      results below this range were considered to be "cost-effective." RESULTS: At 3
      mg/kg, each infliximab infusion would cost $1393. When compared with methotrexate
      alone, 54 weeks of infliximab plus methotrexate decreased the likelihood of
      having advanced disability from 23% to 11% at the end of 54 weeks, which
      projected to a lifetime marginal cost-effectiveness ratio of $30,500 per
      discounted QALY gained, considering only direct medical costs. When applying a
      societal perspective and including indirect or productivity costs, the marginal
      cost-effectiveness ratio for infliximab was $9100 per discounted QALY gained. The
      results remained relatively unchanged with variation of model estimates over a
      broad range of values. CONCLUSIONS: Infliximab plus methotrexate for 54 weeks for
      rheumatoid arthritis should be cost-effective with its clinical benefit providing
      good value for the drug cost, especially when including productivity losses.
      Although infliximab beyond 54 weeks will likely be cost-effective, the economic
      and clinical benefit remains uncertain and will depend on long-term results of
      clinical trials.

PMID- 12401536
TI  - Vascular and cardiac benefits of angiotensin receptor blockers.
AB  - Angiotensin II not only is a vasoconstrictor, but it also affects cell growth and
      apoptosis, inflammation, fibrosis, and coagulation. Blockade of the renin
      angiotensin system, either with inhibitors of the generation of angiotensin
      (angiotensin-converting enzyme [ACE] inhibitors) or with blockers of angiotensin
      receptors, reduces blood pressure and inhibits other pathophysiological actions.
      These other effects provide benefits in coronary heart disease, heart failure,
      diabetic nephropathy, and stroke beyond blood pressure reduction. These benefits
      were first demonstrated with ACE inhibitors. However, the mechanism of action of
      angiotensin receptor blockers, which block angiotensin II stimulation at the
      angiotensin type 1 receptor but not at the type 2 receptor, may have advantages,
      particularly for endothelial dysfunction and vascular remodeling, as well as
      cardiac and renal protection. Recent multicenter trials suggest that ACE
      inhibitors and angiotensin receptor blockers may reduce morbidity and mortality
      associated with cardiovascular and renal disease beyond blood pressure reduction.
      Several studies with different angiotensin receptor blockers, including
      comparisons with ACE inhibitors, are under way, and should provide further
      guidance for their clinical use.

PMID- 12401537
TI  - Myocarditis in systemic lupus erythematosus.
AB  - Although clinical manifestations of myocarditis in systemic lupus erythematosus
      are uncommon, noninvasive cardiac testing may detect subclinical cases. The
      pathogenesis of myocarditis in systemic lupus erythematosus has been ascribed to
      many factors, including autoimmunity, medications, and coexisting diseases. Lupus
      myocarditis merits urgent clinical attention because of the likely progression to
      arrhythmias, conduction disturbances and heart block, dilated cardiomyopathy, and
      heart failure. Endomyocardial biopsy can be used to identify the underlying
      inflammatory histopathology. Usual therapy includes high-dose corticosteroids, in
      addition to standard cardiac medications.

PMID- 12401538
TI  - An outbreak of web sites selling ciprofloxacin following an outbreak of anthrax
      by mail.

PMID- 12401539
TI  - Effects of splenomegaly and splenic macrophage activity in hypersplenism due to
      cirrhosis.

PMID- 12401540
TI  - Atrial fibrillation: an old disease, a new epidemic.

PMID- 12401541
TI  - Cases from the Osler Medical Service at Johns Hopkins University.

PMID- 12401542
TI  - Diarrhea and hypokalemia as primary manifestations of medullary carcinoma of the
      thyroid.

PMID- 12401543
TI  - Hemophagocytic syndrome in association with visceral leishmaniasis.

PMID- 12401544
TI  - Endocarditis and extrinsic coronary compression.

PMID- 12401545
TI  - Respecting the lifecycle: rational workforce planning for a section of general
      internal medicine.

PMID- 12401546
TI  - Effect of temperature on synaptic transmission between identified neurones of the
      mollusc Lymnaea stagnalis.
AB  - The mollusc, Lymnaea stagnalis, has been used as a model to study the mechanisms
      of temperature-dependent processes in the central nervous system. Effects of
      temperature changes on transmission in monosynaptic connections, made by the
      FMRFamide-containing neurone VD4 and the giant dopaminergic neurone RPeD1 with
      follower neurones, were recorded with intracellular microelectrodes. In the
      temperature range of 4-6 degrees C, inhibitory postsynaptic potentials (IPSP) in
      response to VD4 stimulation were not observed in postsynaptic cells while the
      IPSPs persisted in the RPeD1 followers. A temperature rise resulted in a sharp
      increase in the IPSP amplitude in followers of both VD4 and RPeD1. In isolated
      nervous systems taken from molluscs which have been kept at 4-6 degrees C for 2
      weeks and more, no coupling between VD4, RPeD1 and synaptically connected cells
      was seen in the full experimental temperature range. The synaptic coupling
      recovered only after maintaining the molluscs at a water temperature of 14-16
      degrees C for at least 2 days. The changes observed in synaptic responses to
      temperature alterations correspond to the behaviour of the molluscs.

PMID- 12401547
TI  - Chrysamine G and its derivative reduce amyloid beta-induced neurotoxicity in
      mice.
AB  - The neurotoxicity of amyloid beta (Abeta) is widely believed to play a seminal
      role in neurodegeneration in Alzheimer's disease. We examined the effect of
      Chrysamine G (CG) on such neurotoxicity using the specific measurement of
      surviving neurons. CG was found to reduce the neurodegeneration induced by both
      the active short fragment of Abeta(25-35) and full-sized Abeta(1-40). In this
      study, we synthesized a new chemical compound from a monovalent structure of CG
      (hCG), with a lower affinity for Abeta, and compared its activity with that of
      CG. Both CG and hCG were found to be equally efficacious in reducing Abeta
      induced neuronal death at a concentration of 0.1-1 microM, indicating that the
      mechanism of action for CG was not due to its chelating activity, but rather due
      to its anti-oxidant activity.

PMID- 12401548
TI  - Identification of a single nucleotide polymorphism in the choline
      acetyltransferase gene associated with Alzheimer's disease.
AB  - The dysfunction of the cholinergic system in Alzheimer's disease (AD) supports
      the hypothesis that a decline in choline acetyltransferase (ChAT) activity in
      memory as well as in cognitive functions in AD might be functionally linked. To
      assess the physiological relevance of an allelic variation in the ChAT gene we
      investigated the presence of a possible polymorphism in AD patients and in
      elderly non-demented subjects as controls. By using polymerase chain reaction,
      single stranded conformation polymorphism or the LightCycler analysis we detected
      a single nucleotide polymorphism in the first common coding exon of the ChAT
      gene. We found a G --> A transition which occurred at position +4 of the coding
      sequence. The association between AD and the AA genotype or A alleles were found
      to be significant (odds ratio 3.7 and 2.4, respectively). The frequency of the AA
      genotype was three times higher in AD patients than in age-matched controls. This
      G --> A change raises the possibility that it may influence ATG usage resulting
      in attenuation of translation efficacy of ChAT messenger RNA. We suggest that
      such a polymorphism might be one of the events conferring an increased risk for
      deterioration of memory and cognition functions in AD.

PMID- 12401549
TI  - Gender differences in neural correlates of recognition of happy and sad faces in
      humans assessed by functional magnetic resonance imaging.
AB  - To examine the effect of gender on the volume and pattern of brain activation
      during the viewing of alternating sets of faces depicting happy or sad
      expressions, 24 volunteers, 12 men and 12 women, participated in this functional
      magnetic resonance imaging study. The experimental stimuli were 12 photographs of
      Japanese adults selected from Matsumoto and Ekman's Pictures of Facial Affect.
      Four of these pictures depicted happy facial emotions, four sad, and four
      neutral. Half of the photographs were of men and the other half were of women.
      Consistent with previous findings, distinct sets of neural correlates for
      processing happy and sad facial emotions were noted. Furthermore, it was observed
      that male and female subjects used a rather different set of neural correlates
      when processing faces showing either happy or sad expressions. This was more
      noticeable when they were processing faces portraying sad emotions than happy
      emotions. Our findings provide some preliminary support for the speculation that
      the two genders may be associated with different areas of brain activation during
      emotion recognition of happy or sad facial expressions. This suggests that the
      generalizability of findings in regard to neural correlates of facial emotion
      recognition should consider the gender of the subjects.

PMID- 12401550
TI  - Metabolic abnormality in the cerebellum in patients with essential tremor: a
      proton magnetic resonance spectroscopic imaging study.
AB  - The pathological basis for essential tremor (ET) is unknown. We used proton
      magnetic resonance spectroscopic imaging (1H MRSI) in 16 ET patients and 11
      controls to measure levels of intracellular metabolites, including N-acetyl-L
      aspartate (NAA) and total choline, relative to total creatine (tCR), in several
      brain regions (cerebellum, thalamus, basal ganglia). Multislice 1H MRSI data were
      acquired on a 1.5 T GE Signa Scanner by prescribing four 15-mm axial-oblique
      slices. The mean (standard deviation) cerebellar cortical NAA/tCR was reduced in
      cases compared to controls (1.53 [0.36] versus 1.91 [0.49], P = 0.03). There was
      an inverse association between cerebellar cortical NAA/tCR and dominant arm
      tremor severity (r = -0.59, P = 0.02). The reduction in cerebellar cortical
      NAA/tCR indicates that there is neuronal damage or loss in ET, suggesting that ET
      may be a neurodegenerative disease.

PMID- 12401551
TI  - Transient postnatal thyroxine treatment leads to variation in transmitter binding
      site densities in the hippocampus of rats.
AB  - Newborn rats were treated daily with thyroid hormone (TH) until postnatal day 12.
      In the adult animals we measured the densities of glutamatergic (N-methyl-D
      aspartate (NMDA), amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA),
      kainic acid (KA)), cholinergic (muscarinic subtype 1 and 2 (M1, M2)), gamma
      aminobutyric acid (GABA)ergic (GABA(A)) and serotonergic (5-hydroxytryptamine (5
      HT(1A))) binding sites using quantitative receptor-autoradiography with tritiated
      ligands. In the TH-treated rats the KA binding site density was increased in the
      stratum oriens of cornu ammonis (CA)3, the terminal field of the infrapyramidal
      mossy fibers (IPMF). Densities of M2 and 5-HT(1A) were increased in the CA1
      region. In contrast, binding site densities for NMDA in the entire hippocampus
      and for AMPA in the dentate gyrus were reduced, whereas binding site densities
      for M2 and GABA(A) remained unchanged. From this study we conclude that
      concomitant with the increase of the IPMF zone the density of the KA binding
      sites is specifically enhanced. In addition, we found a general shift from
      binding sites receiving cortical to those receiving subcortical input in the
      hippocampus.

PMID- 12401552
TI  - Possible involvement of both mitochondria- and endoplasmic reticulum-dependent
      caspase pathways in rotenone-induced apoptosis in human neuroblastoma SH-SY5Y
      cells.
AB  - Recently, it has been shown that rotenone, a specific inhibitor of mitochondrial
      complex I, is a useful tool in animal models of Parkinson's disease, but the
      mechanism of rotenone-induced neuronal death is not fully understood. In human
      neuroblastoma SH-SY5Y cells, rotenone induced the degradation of procaspases-12, 
      9 and -3, followed by cleavage of poly (adenosine diphosphate-ribose) polymerase,
      DNA fragmentation and cell death. Pretreatment with phorbol-12-myristate-13
      acetate inhibited the rotenone-induced decrease in procaspases-9 and -3, but not
      that in procaspase-12. In contrast, benzyloxycarbonyl-Val-Ala-Asp(OCH(3))-CH(2)F
      inhibited the decrease in procaspase-12, but not those in procaspases-9 and -3 in
      this study. These results suggest that rotenone may induce activation of both
      mitochondria- and endoplasmic reticulum-dependent caspases in human SH-SY5Y
      cells.

PMID- 12401553
TI  - Abnormal brain processing of cutaneous pain in migraine patients during the
      attack.
AB  - We examined cutaneous pain thresholds using CO(2) laser stimuli during migraine
      attacks, and defined the evoked cortical potential characteristics. Ten patients
      without aura were studied during attacks and for at least 72 h subsequently. Pain
      stimuli were generated on the dorsum of both hands and the right and left
      supraorbital zones, using pulses from a CO(2) laser. Absolute latencies of scalp
      potentials were measured at the highest peak of each response component, and the
      peak-to-peak amplitudes of N2a-P2 components were recorded. Cutaneous pain
      thresholds were significantly reduced on both the symptomatic and non-symptomatic
      sides during the attack, in comparison with the headache-free phase. The N2a-P2
      complexes also increased in amplitude during attacks in comparison with the pain
      free side. Thus, cutaneous hyperalgesia occurs during migraine attack, and is
      subtended by central sensitization phenomena, probably involving the cortex.

PMID- 12401555
TI  - Changes in superoxide dismutase and catalase activities of rat brain regions
      during early global transient ischemia/reperfusion.
AB  - It has been widely recognized that the hippocampus and striatum are clearly more
      susceptible to oxidative stress than the remaining brain regions. However, the
      mechanism involved is not known. The activities of the antioxidant enzymes CuZn
      superoxide dismutase (SOD), Mn-SOD and catalase were measured in the hippocampus
      and striatum and the results were compared to cortex and cerebellum (less
      susceptible to oxidative stress) after 3 h of a global transient
      ischemia/reperfusion. CuZn-SOD activities were reduced in all brain regions, but
      mainly in the hippocampus and striatum. Mn-SOD activity was lowered in the
      striatum, whereas catalase activity was reduced in the hippocampus and striatum.
      Our findings indicate that in the earlier phase of ischemia/reperfusion the decay
      in activities of catalase and SOD may be related with the high susceptibility of
      the hippocampus and striatum to oxidative damage.

PMID- 12401554
TI  - Abeta peptide 1-42, Tau protein and S-100B protein level in cerebrospinal fluid
      of three patients with primary progressive aphasia.
AB  - Primary progressive aphasia (PPA) is a clinical syndrome characterized by a
      slowly progressive aphasia in the absence of accompanying signs of generalized
      dementia. While non-fluent PPA tends to progress frontally and is usually linked
      to frontotemporal degeneration, fluent PPA might be associated with both,
      frontotemporal degeneration or Alzheimer's disease. Although recent reports
      suggest that PPA belongs neuropathologically to the group of tauopathias,
      cerebrospinal fluid analysis has not been established as a means of diagnosis in
      PPA so far. In this paper we investigated Abeta peptide(1-42) (Abeta(1-42)), Tau
      protein and S-100B protein level in the cerebrospinal fluid of three patients
      with PPA. In all patients Tau protein and S-100B level were slightly elevated,
      however, Abeta(1-42) was found to be in normal range. Thus, our first results
      point to PPA being neurochemically linked to frontotemporal degeneration.

PMID- 12401556
TI  - Norepinephrine transporter gene (NET) variants in patients with panic disorder.
AB  - Several lines of evidence suggest that catecholamines, especially norepinephrine,
      are implicated in the etiology and/or symptomatology of panic disorder (PD). At
      the cellular level, functional noradrenergic neurotransmission depends on
      synaptic reuptake of norepinephrine as mediated by the norepinephrine transporter
      (NET). A pharmacological target of agents with an established anti-panic
      efficacy, e.g. tricyclic antidepressants, the NET is of particular interest in
      PD. We investigated the NET gene for the presence of 6 naturally occurring exonic
      sequence variants, 5 of which give rise to amino acid substitutions (Val69Ile,
      Thr99Ile, Val245Ile, Val449Ile and Gly478Ser) in a population of 87 patients with
      PD and 89 healthy controls. Except for a silent substitution (G1287A), overall
      frequencies of variant alleles were low (< or =0.016). None of the variants under
      study was found to be associated with PD regardless of an additional diagnosis of
      agoraphobia.

PMID- 12401557
TI  - Evidence for the importance of the human dopamine transporter gene for withdrawal
      symptomatology of alcoholics in a German population.
AB  - Two new polymorphisms in the 3' untranslated region (3'UTR) of the dopamine
      transporter (DAT1) gene, adjacent to the known variable number of tandem repeats
      (VNTR) polymorphism, have been investigated in the present population-based
      association study including 351 alcoholics and 336 controls. The DraI restriction
      site was not polymorphic in our population. The G2319A polymorphism was not
      significantly different with respect to genotype or allele distribution between
      alcoholics and controls. Subsequently, in individuals with VNTR homozygosity for
      the ten repeat allele, we found a higher prevalence of A/A homozygosity in
      patients with seizure history (P = 0.001, odds ratio (OR) = 7.913), with delirium
      history (P = 0.032, OR = 4.707), and with an alcoholic mother (P = 0.021, OR =
      5.250), compared to homozygote 10/10 controls. Our findings provide further
      evidence that the 3'UTR of the DAT1 gene affects vulnerability to severe alcohol
      withdrawal.

PMID- 12401558
TI  - Differential regulation of gene expression of neurotensin and prohormone
      convertases PC1 and PC2 in the bovine ocular ciliary epithelium: possible
      implications on neurotensin processing.
AB  - Prohormone convertases PC1 and PC2 are enzymes involved in the intracellular
      processing of pro-neurotensin/neuromedin N (pro-NT/NN) through the regulated
      secretory pathway. In this study, we present evidence of the differential gene
      expression of pro-NT/NN, pro-PC1 and pro-PC2 in two cell lines established from
      the neuroendocrine ocular ciliary epithelium. Dexamethasone and forskolin were
      found to synergistically up-regulate NT/NN mRNA expression in both cell types.
      The pigmented cells released NT, and this release was enhanced by agents that
      induced its biosynthesis. In contrast, nonpigmented cells exhibited a
      significantly reduced neurotensin secretion in response to inducers, leading to
      an accumulation of the peptide. PC1 and PC2 mRNA expression was induced in a cell
      specific manner by the same agents that enhanced pro-NT/NN biosynthesis. These
      results demonstrate cell-specific processing of pro-NT/NN by the ciliary
      epithelium.

PMID- 12401559
TI  - Interleukin-1 receptor immunoreactivity in sympathetic vascular and non-vascular
      neurons in guinea-pig coeliac ganglion.
AB  - Immunoreactivity (IR) for the interleukin-1 receptor type I (IL1RI) was examined
      in sympathetic neurons in guinea-pig coeliac ganglion using multiple-labelling
      immunofluorescence. IL1RI-IR was present in 8% of sympathetic neurons in
      untreated preparations. The proportion of neurons with IL1RI-IR increased
      significantly after incubation in interleukin-6 (200 ng/ml) for 2-4 h (16-26%
      neurons), or after incubation for 4 h without cytokine (16%), with interleukin
      1beta (IL1beta, 200 ng/ml; 18%) or tumour necrosis factor-alpha (200 ng/ml; 16%).
      This increase occurred predominantly in neuropeptide Y-IR, vasoconstrictor
      neurons. IL1RI-IR also was present in varicose axons, some of which projected
      from the gut, and in vascular smooth muscle cells and endothelium. These
      potential binding sites for the proinflammatory cytokine, IL1beta, on
      vasoconstrictor neurons and blood vessels may modulate sympathetic regulation of
      intestinal blood flow in inflammatory conditions.

PMID- 12401560
TI  - Autophosphorylated calcium/calmodulin-dependent protein kinase II alpha induced
      by cerebral ischemia immediately targets and phosphorylates N-methyl-D-aspartate
      receptor subunit 2B (NR2B) in hippocampus of rats.
AB  - In this article, we investigated the autophosphorylation and translocation of
      calcium/calmodulin-dependent protein kinase II alpha (CaMKII alpha) in
      hippocampus during global ischemia. The following results were observed: (1)
      CaMKII alpha immediately became autophosphorylated after 3 min ischemia, at the
      same time, there is a dramatic and sustained translocation of CaMKII alpha from
      cytosolic fraction to synaptic fraction; (2) CaMKII alpha translocated to post
      synaptic density and targeted N-methyl-D-aspartate receptor subunit 2B (NR2B)
      which was serine-phosphorylated by active CaMKII alpha; (3) serine
      phosphorylation of NR2B could not only inhibit the formation of CaMKII alpha-NR2B
      complexes but also promote the dissociation of the preformed complexes when
      ischemic time was prolonged. These results suggest that phosphorylation of NR2B
      can influence the channel properties of NR2B, and the dissociation of the CaMKII
      alpha-NR2B complexes may be a negative feedback mechanism during longer time
      cerebral ischemia.

PMID- 12401561
TI  - Cerebellar slice cultures from mice lacking the P/Q calcium channel:
      electroresponsiveness of Purkinje cells.
AB  - To investigate the role of P/Q type Ca(2+) channels in determining the firing
      pattern of Purkinje cells (PCs) we compared the somatically evoked discharge of
      action potentials (APs) in PCs from 3 to 4 week old cerebellar slice cultures
      obtained with ataxic mice lacking alpha(1A)-subunit (alpha(-/-)) and with normal
      mice (non-ataxic alpha(+/-) or alpha(+/+)) using the whole-cell configuration of
      the patch-clamp recording method. Whereas evoked responses of PCs in normal mice
      were mainly fast APs, those of PCs from ataxic mice were mainly low-threshold
      Ca(2+) spikes (LTS). Furthermore, a sustained plateau potential due to the
      activation of cadmium sensitive Ca(2+) conductances was not observed in PCs from
      ataxic mice by blocking K(+) channels. These results confirm that P/Q Ca(2+)
      channels elicit Ca(2+)-dependent plateau potentials and control the propagation
      of the dendritic LTS to the soma.

PMID- 12401562
TI  - Simultaneous electroencephalography and functional magnetic resonance imaging of
      primary and secondary somatosensory cortex in humans after electrical
      stimulation.
AB  - Simultaneous electroencephalography (EEG) and functional magnetic resonance
      imaging (fMRI) measurements were performed in six healthy subjects to determine
      the representation of stimulation of the right thumb in somatosensory cortex. In
      all subjects EEG-based dipole locations could be determined in primary (S1) and
      secondary (S2) somatosensory cortex. The stimulus-induced blood oxygenation level
      dependent response of the fMRI showed deviations of 23.5 mm (standard deviation,
      SD = 6.9) for S1 and 15.7 mm (SD = 3.5) for S2 cortex. fMRI constrained dipole
      searches lead to higher residual variances. The data show that simultaneous EEG
      and fMRI measurements of somatosensory activity are feasible and yield reliable
      and valid results.

PMID- 12401563
TI  - Overexpression of midbrain-specific transcription factor Nurr1 modifies
      susceptibility of mouse neural stem cells to neurotoxins.
AB  - Nurr1 is a member of the nuclear receptor superfamily of transcription factors
      that is highly expressed in midbrain dopaminergic (DA) neurons, the cells
      primarily lost in human Parkinson's disease (PD), and in Nurr1-null mice
      selective agenesis of midbrain DA neurons is found. To investigate possible
      correlation between the expression of Nurr1 gene and neurotoxin-induced cell
      death of DA neurons, a neural stem cell line (NSC, A3) and Nurr1-overexpressing
      NSC (A3.Nurr1) were exposed to DA neurotoxins 6-hydroxydopamine (6-OHDA) and
      methyl phenylpyridinium (MPP(+)). Although both neurotoxins were shown to induce
      cell death in A3 and A3.Nurr1 cells, patterns of cell deaths were different.
      A3.Nurr1 cells showed increased vulnerability to 6-OHDA cytotoxicity, but
      increased resistance to MPP(+)-induced cell death when compared to A3 cells. To
      investigate the differential vulnerability to neurotoxins by Nurr1 protein
      correlates with biochemical features that discriminate between apoptosis and
      necrosis, we carried out a nucleosomal DNA fragmentation assay and electron
      microscopy. While 6-OHDA treatment induced shrinkage of cytoplasmic membrane,
      condensation of nuclei and generation of apoptotic bodies in both cell lines,
      cells treated with MPP(+) showed mitochondrial swelling, indicating that 6-OHDA-
      but not MPP(+)-mediated cell death was apoptotic. These results suggest that DA
      neuronal cell death in response to 6-OHDA and MPP(+) may progress through
      separate signaling pathways differentially regulated by the Nurr1 protein. Our
      observations indicated that Nurr1 may play a role in the manifestation of DA
      neurotoxicity and that variations in Nurr1 expression might be a susceptibility
      factor for DA neurodegeneration in PD.

PMID- 12401565
TI  - DNA-lipid interactions in vitro and in vivo.
AB  - The data on lipid-nucleic interactions and their role in vitro and in vivo are
      presented. The results of study of DNA-lipid complexes in absence and in presence
      of divalent metal cations (triple complexes) are discussed. The triple complexes
      represent the generation of cellular structures such as pore complexes of
      eucaryotes and "Bayer's junctions" of procaryotes. The participation of triple
      complexes in the formation of structure of bacterial and eucaryotic nucleoid and
      nuclear matrix is analysed. A model of formation of triple complexes and cellular
      structures and their role in DNA-lipid interactions are discussed.

PMID- 12401566
TI  - Functional role of phospholipids in the nuclear events.
AB  - This review presents the structural and functional role of phospholipids in
      chromatin and nuclear matrix as well as the difference in composition and
      turnover compared to those present in the nuclear membrane. Nuclei have a very
      active lipid metabolism which seems to play an important role in the transduction
      of the signals to the genome in response to agonists acting at the plasma
      membrane level. The evidence on the presence of phospholipid-calcium-dependent
      protein kinase C (PKC) in nuclei and enzymes of phospholipids turnover is given.
      Protein kinase C interacts with nuclear phosphoinositol and sphingomyelin cycles
      products. This fact evidences about possibility that signal transduction events
      could also occur at the nuclear level during induction of cell proliferation,
      differentiation and apoptosis.

PMID- 12401567
TI  - DNA-bound lipids of normal and tumor cells: retrospective and outlooks for
      functional genomics.
AB  - By very soft phenol method, the high-molecular-mass natural DNA complexes (10(8)
      10(9) Da), which contain 1-3% specific lipids, were isolated from different
      eukaryotic and prokaryotic cells. Two pools of DNA-bound lipids were isolated:
      loosely bound (extracted with 35% ethanol) and tightly bound lipids (extracted
      after additional treatment DNAse I). The composition of these two lipid pools of
      different sources (rat thymus, liver, regenerating liver, loach sperm, pigeon
      erythrocytes, Zajdel ascites hepatoma, Ehrlich ascites carcinoma, sarcoma 37,
      Escherichia coli B, T2 phage) was studied. The DNA-bound lipid pools consist of
      neutral lipids (NL) and phospholipids (PL), moreover NL is always in a few fold
      more than PL. The composition of these lipid pools of eukaryotes distinguishes
      between themselves, mainly, by free cholesterol (minor fraction), cardiolipin
      (major fraction), and by phosphatidylcholine. Only the tightly bound lipid pool
      was present in T2 phage DNA. The dramatic redistribution effect between all
      fractions of NL pools (free and ester cholesterol, free fatty acids,
      diglycerides) was observed in DNA synthesis phase of cell cycle on the background
      of the unchanged composition of PL pools. Comparative analysis of DNA-bound lipid
      pools of normal and cancer cells was carried out. The DNA-bound lipid pools of
      transformed cells significantly differ from the same normal cells both by PL
      composition (cardiolipin) and by the presence of additional fractions (mono- and
      triglycerides) as well. The possible functions of DNA-bound lipid pools,
      especially of cardiolipin and cholesterol at the attachment of DNA loops to the
      nuclear matrix, DNA replicon organization, replication, and transcription are
      discussed.

PMID- 12401568
TI  - Nuclear and chromatin lipids: metabolism in normal and gamma-irradiated rats.
AB  - The data on nuclear and chromatin lipid metabolism are reviewed. The amount of
      neutral lipids and phospholipids in nuclei of rat thymus, liver and neocortex
      neuron as well as the amount of lipids in rat thymus and liver chromatin are
      described. The metabolic responses of nuclear and chromatin lipids from thymus to
      different doses and dose rates of gamma-irradiation of rats are discussed. In
      most cases, the nuclear and chromatin lipid responses are distinct. Changes in
      nuclear and chromatin lipid metabolism in response to gamma-irradiation are
      suggested to connect with the signal transduction pathway and the regulation of
      the transcriptional and replicative chromatin activity. The influence of beta
      carotene and picrotoxin on rat liver nuclear lipids and neocortex neuronal
      nuclear lipids, respectively, was analyzed. The possible involvement of the lipid
      traffic in the chromatin lipid responses to gamma-irradiation and other agents is
      suggested.

PMID- 12401569
TI  - Role of lipid membrane-nucleic acid interactions, DNA-membrane contacts and metal
      (II) cations in origination of initial cells and in evolution of prokaryotes to
      eukaryotes.
AB  - The problems of the origin of primary cells and eukaryotic cells are discussed in
      terms of possible role of interactions between nucleic acids with lipid membrane
      according to corresponding original hypothesis. We propose that there are two
      main hypotheses of the origin of primary cells: (a). RNA appeared before proteins
      and DNA [Nature 213 (1967) 119]; (b). it is needed for the appearance of a
      primary cell, the volume closed by the lipid membrane. There was no information
      about the ways on how RNA appeared inside that volume for saving the reaction
      products around. Our hypothesis suggests that one of the starting points in the
      origination of primary cells was the interaction of nucleic acid and lipid
      membrane bubbles in the presence of metal (II) ions (which existed in high
      concentrations in prebiotic conditions), and this resulted in the enclosing of
      the pro-RNAs inside the lipid membrane. This hypothesis is formulated by us on
      the basis of experimental biochemical and biophysical studies of the DNA/RNA
      phospholipid vesicles interactions in the presence of metal ions (II) fulfilled
      in the Institute of Biomedical Chemistry, RAMS, Moscow and Institute of
      Biophysics, RAS, Pushchino. Our belief is that DNA-membrane contacts (DNA-MCs)
      played an important role in the prokaryotes-to-eukaryotes transition. The model
      of the confluence of four prokaryotic cells may explain the prokaryotes-to
      eukaryotes transition by the way of eukaryotic nuclear pore formation from
      prokaryotic Bayer' contacts. The main requirement for the following fusion of
      prokaryotic cells must be their mutual orientation. After possible association,
      the division of the formed cell is begun. The great advantage of the model of
      four prokaryotic cells is the profit in the metabolism and the possibility of the
      intensive growth of intercellular membrane structures.

PMID- 12401570
TI  - DNA-phospholipid recognition: modulation by metal ion and lipid nature. Complexes
      structure and stability calculated by molecular mechanics.
AB  - The structures and formation energies of nucleic acid-phospholipid complexes both
      in the absence and in the presence of Mg(2+) ions were calculated taking double
      stranded trinucleoside diphosphates NpNpN or heptanucleotides ApAp(NpNpN)pApA,
      composed of 64 possible combinations of genetic code, and phosphatidylcholine
      (PC) and sphingomyelin (SM) as model compounds. The dependence of intramolecular
      interactions on the primary structure of nucleic acid molecules and on the
      presence of a cationic bridge was revealed. The formation energies and structure
      of oligonucleotides were found by molecular mechanics calculations with the AMBER
      force field. The structures of phospholipid and MgCl(2) molecules were calculated
      by the semiempirical PM3 method, while the energies of phospholipid
      oligonucleotide complexes were calculated by the molecular mechanics method.
      Calculations of complexes were carried out with consideration of solvation
      effects. Considerable gain in the formation energy of triple complexes is
      achieved due to the presence of the electroneutral metal bridge. A tendency
      toward increasing the stability of "triple" PC complexes (but not SM ones),
      containing guanosine- and cytidine-enriched triplets was revealed. Depending on
      the structure of NpNpN trinucleotides, the formation energy values of NpNpN
      MgCl(2)-PC and ApAp(NpNpN)pApA-MgCl(2)-PC complexes differ by 1.7-2.6 kcal mol(
      1), which can be considered as the atomic-scale manifestation of the recognition
      phenomenon. Presence of metal (II) ion bridge results in a greater stabilization
      of the phospholipid-nucleic acid complexes for SM in comparison to PC (the total
      energy difference equals to 4-16 kcal mol(-1)). Depending on the structure of
      NpNpN trinucleotides, the formation energies of NpNpN-MgCl(2)-SM and
      ApAp(NpNpN)pApA-MgCl(2)-SM complexes differ by 1.7-2.1 kcal.mol(-1), which is
      essential at physiological conditions and can also be considered as the
      recognition effect.

PMID- 12401571
TI  - Cationic lipid-DNA complexes-lipoplexes-for gene transfer and therapy.
AB  - Cationic lipid-mediated gene transfer and delivery still attract great attention
      of many gene therapy laboratories. From the point of view of the most important
      characteristics of lipoplex particles, e.g. its charge and size, we reviewed
      recent studies available. In general, the paper deals with non-viral systems of
      gene transfer into eukaryotic cell based on various lipids. Having usually less
      efficiency in gene transfer, lipid-based gene transfer vehicles
      (lipoplexes/genosomes) are characterized with certain advantages even over viral
      ones: they are less toxic and immunogenic, could be targetable and are easy for
      large-scale production, a size of transferred DNA being quite high. Conditions of
      DNA condensation during interactions with lipids are described. Results of the
      studies of mechanism of DNA-lipid complex interactions with the cell membrane and
      their transport into the nucleus are summarized. Dependence of efficiency of gene
      transfer on lipoplex structure and physical-chemical properties is reviewed.
      Advantages and disadvantages of different macromolecule complexes from the point
      of view of transfection efficiency, possibility of use in vivo, cytotoxicity and
      targeted gene transfer in certain organs and tissues are also discussed. Results
      of transfection of different cells using neutral, anion and cation liposomes are
      reviewed. The conclusion reached was that efficiency and specificity of gene
      transfer may grow considerably when mixed macromolecule lipid systems including
      polycations and glycolipids are used.

PMID- 12401572
TI  - An experimental approach for direct observation of the interaction of polyanions
      with sphingosine-containing giant vesicles.
AB  - A new approach for direct optical microscopy observation of polyanion
      interactions with bilayers of giant cationic liposomes (GUVs) was suggested.
      Polyanions as DNA, dextran sulfate (DS), heparin (H) and polyacrylic acids (PA)
      were locally delivered by a micropipette to a part of a giant unilamellar vesicle
      membrane. The phenomena were directly observed under optical microscope. GUVs,
      about 100 micro m in diameter, formed of phosphatidylcholines and up to 33 mol%
      of the natural bioactive cationic amphiphile sphingosine (Sph), were prepared by
      electroformation. The effects of water-soluble molecules with high negative
      linear charge density as dextran sulfate (DS), heparin (H) polyacrylic acids (PA)
      and adenosine-5'-triphosphoric acid (ATP) were compared with those of DNAs. The
      resulting membrane topology transformations were monitored in phase contrast,
      while the DNA distribution was followed in fluorescence. DNA-induced endocytosis
      like membrane morphology transformation due to the DNA/lipid membrane local
      interactions was observed. The DS, H and PA induced membrane topology
      transformations similar to those of the DNAs, while ATP did not cause any
      detectable ones. The endocytosis mechanism involves the formation of ordered
      domains in the GUV membrane where some surface and charge asymmetries between the
      two membrane monolayers were created. The sizes of created polyanionic/cationic
      membrane domains depend on the form, length and elasticity of the adsorbed highly
      charged molecules. Endosome-including capacities of polyanionic molecules depend
      heavily on the high linear negative charge at a certain length. An original
      method for direct studying of the DNA/membrane interactions in autoadaptable
      giant liposome system imitating biological membrane interactions was forwarded.
      The model observations could also help for understanding events associated with
      cationic liposome/DNA complex formation in gene transfer processes.

PMID- 12401573
TI  - Structural and thermodynamic features of complexes formed by DNA and synthetic
      polynucleotides with dodecylamine and dodecyltrimethylammonium bromide.
AB  - Complex formation of native and denatured DNA, single-stranded
      polyribonucleotides poly(A) and poly(U), as well as double-stranded
      poly(A).poly(U) with dodecylamine (DDA) and dodecyltrimethylammonium bromide
      (DTAB) has been studied by UV-, CD-, IR-spectroscopy and fluorescence analysis of
      hydrophobic probe pyrene. DDA and DTAB were shown to bind cooperatively with DNA
      and polyribonucleotides, resulting in the formation of complexes containing
      hydrophobic micelle-like clusters. Critical aggregation concentration (CAC) of
      DDA and DTAB shifts sharply to lower values (30-50 times) in the presence of DNA
      and polynucleotides as compared to critical micelle concentration (CMC) of free
      DDA and DTAB in solution. The analysis of binding isotherms within the frame of
      the model of cooperative binding of low-molecular ligands to linear polymers
      allowed us to determine the thermodynamic parameters of complex formation and
      estimate the contribution of electrostatic interaction of positively charged
      heads of amphiphiles with negatively charged phosphate groups of DNA and
      polyribonucleotides, and hydrophobic interaction of aliphatic chains to complex
      stability. Electrostatic interaction was shown to make the main contribution to
      the stability of DNA complexes with DDA, while preferential contribution of
      hydrophobic interactions is characteristic of DTAB complexes with DNA. The
      opposite effect of DDA and DTAB on the thermal stability of DNA double helix was
      demonstrated from UV-melting of DNA-while DTAB stabilizes the DNA helix, DDA, to
      the contrary, destabilizes it. The destabilizing effect of DDA seems to originate
      from the displacement of intramolecular hydrogen bonds in complementary Watson
      Crick A.T and G.C base pairs with intermolecular H-bonds between unsubstituted
      DDA amino groups and proton-accepting sites of nucleic bases.

PMID- 12401574
TI  - Condensed lamellar phase in ternary DNA-DLPC-cationic gemini surfactant system: a
      small-angle synchrotron X-ray diffraction study.
AB  - We report on a small-angle synchrotron X-ray diffraction study of
      dilauroylphosphatidylcholine (DLPC) liposomes aggregated with high molecular DNA
      in the presence of 1,4-butanediammonium-N,N'-dilauryl-N,N,N',N'-tetramethyl
      gemini surfactant cations (C12GS). The aggregates prepared at the DLPC/C12GS/DNA
      phosphate group=2:1:1.6 molar ratio in 0.0015 mol x l(-1) NaCl aqueous solution
      exhibit Bragg reflections due to lamellar lipid bilayer stacking and the Bragg
      reflection typical of one-dimensional DNA lattice with parallel strands
      intercalated between lipid bilayers. In this condensed fluid lamellar L(alpha)(c)
      phase, the interactions between DNA and charged bilayers damp the thermally
      induced bilayer undulations. The diffraction data obtained with the mixture of
      DLPC liposomes and DNA (at DNA phosphate group/DLPC=0.8:1 molar ratio) indicate a
      DNA-lipid interaction in the absence of C12GS.

PMID- 12401575
TI  - Electrostriction of supported lipid films at presence of cationic surfactants,
      surfactant-DNA and DNA-Mg(2+) complexes.
AB  - The method of electrostriction has been applied to study the physical properties
      of supported lipid membranes (sBLM) during membrane formation at application of
      negative potential. Application of negative potential -350 mV to the sBLM during
      its formation resulted in more compact membrane structure as revealed by higher
      elastic modulus in comparison with sBLM formed without application of this
      potential. We also studied interaction with sBLM cationic surfactant
      hexadecylamine (HDA), HDA-DNA and DNA-Mg(2+) complexes. Interaction of HDA with
      sBLM resulted in decrease of membrane capacitance and two-directional effect on
      elasticity modulus (increase or decrease), which can be caused by different
      aggregation state of surfactant at the surface of sBLM. In contrast with effect
      of HDA, the complexes of HDA-DNA resulted, in most cases, increase of elasticity
      modulus and increase of membrane capacitance, which can be caused by
      incorporation of these complexes into the hydrophobic interior of the membrane.
      Certain part of these complexes can, however, be adsorbed on the sBLM surface.
      DNA itself does not cause substantial changes of physical properties of sBLM;
      however, addition of bivalent cations Mg(2+) to the electrolyte-contained DNA
      caused substantial increase of elasticity modulus and surface potential. These
      changes are, however, much slower than that observed for HDA-DNA complexes, which
      can be caused by slow competitive exchange between Na(+) and Mg(2+) ions.

PMID- 12401576
TI  - A minisensor for the rapid screening of atenolol in pharmaceutical preparations
      based on surface-stabilized bilayer lipid membranes with incorporated DNA.
AB  - This work describes an electrochemical technique that is suitable for the rapid
      and sensitive screening of atenolol based on surface-stabilized bilayer lipid
      membranes (s-BLMs) composed from egg phosphatidylcholine (PC). The interactions
      of atenolol with s-BLMs produced electrochemical ion current increases that
      reproducible appeared within a few seconds after the exposure of the membranes to
      the drug. The current signal increase was related to the concentration of
      atenolol in bulk solution in the micromolar range. The present lipid film-based
      sensor provided fast response (i.e. on the order of a few seconds) to alterations
      of atenolol concentration (20 to 200 micro M) in electrolyte solution. ssDNA
      incorporated into s-BLMs can interact with atenolol, and decreased the detection
      limit of this drug by one order of magnitude. The oligomers used were single
      stranded deoxyribonucleic acids: thymidylic acid icosanucleotide terminated with
      a C-16 alkyl chain to assist incorporation into s-BLMs (5'-hexadecyl
      deoxythymidylic acid icosanucleotide, dT(20)-C(16)). The electrochemical
      transduction of the interactions of atenolol with s-BLMs was applied in the
      determination of these compounds in pharmaceutical preparations by using the
      present minisensor.

PMID- 12401577
TI  - Electrochemical DNA biosensor for analysis of wastewater samples.
AB  - The application of a disposable electrochemical DNA biosensor to wastewater
      samples is reported. The DNA biosensor is assembled by immobilising double
      stranded calf thymus DNA on the surface of a disposable, carbon screen-printed
      electrode (SPE). The oxidation signal of the guanine base, obtained by a square
      wave voltammetric scan, is used as analytical signal. The presence of compounds
      with affinity for DNA is measured by their effect on the guanine oxidation. The
      comparison of the results with a toxicity test based on bioluminescent bacteria
      has confirmed the applicability of the method to real samples.

PMID- 12401578
TI  - DNA and PNA sensing on mercury and carbon electrodes by using methylene blue as
      an electrochemical label.
AB  - Described here are the electrochemical parameters for MB on binding to DNA at
      hanging mercury drop electrode (HMDE), glassy carbon electrode (GCE), and carbon
      paste electrode (CPE) in the solution and at the electrode surface. MB, which
      interacts with the immobilized calf thymus DNA, was detected by using single
      stranded DNA-modified HMDE or CPE (ssDNA-modified HMDE or CPE), bare HMDE or CPE,
      and double-stranded DNA-modified HMDE or CPE (dsDNA-modified HMDE or CPE) in
      combination with adsorptive transfer stripping voltammetry (AdTSV), differential
      pulse voltammetry (DPV), and alternating current voltammetry (ACV) techniques.
      The structural conformation of DNA and hybridization between synthetic peptide
      nucleic acid (PNA) and DNA oligonucleotides were determined by the changes in the
      voltammetric peak of MB. The PNA and DNA probes were also challenged with
      excessive and equal amount of noncomplementary DNA and a mixture that contained
      one-base mismatched and target DNA. The partition coefficient was also obtained
      from the signal of MB with probe, hybrid, and ssDNA-modified GCEs. The effect of
      probe, target, and ssDNA concentration upon the MB signal was investigated. These
      results demonstrated that MB could be used as an effective electroactive
      hybridization indicator for DNA biosensors. Performance characteristics of the
      sensor are described, along with future prospects.

PMID- 12401579
TI  - Lidocaine for neuroprotection: more evidence of efficacy.

PMID- 12401580
TI  - The effect of lidocaine on early postoperative cognitive dysfunction after
      coronary artery bypass surgery.
AB  - We investigated the effect of lidocaine on the incidence of cognitive dysfunction
      in the early postoperative period after cardiac surgery. One-hundred-eighteen
      patients undergoing elective coronary artery bypass surgery with cardiopulmonary
      bypass (CPB) were randomized to receive either lidocaine (1.5 mg/kg bolus
      followed by a 4 mg/min infusion during operation and 4 mg/kg in the priming
      solution of CPB) or placebo. A battery of nine neuropsychological tests was
      administered before and 9 days after surgery. A postoperative deficit in any test
      was defined as a decline by more than or equal to the preoperative SD of that
      test in all patients. Any patient showing a deficit in two or more tests was
      defined as having postoperative cognitive dysfunction. Eighty-eight patients
      completed pre- and postoperative neuropsychological tests. Plasma lidocaine
      concentrations (microg/mL) were 4.78 +/- 0.52 (mean +/- SD), 5.38 +/- 0.95, 4.52
      +/- 0.39, 5.82 +/- 0.76, and 7.10 +/- 1.09 at 10 min before CPB; 10, 30, and 60
      min of CPB; and at the end of operation, respectively. The proportion of patients
      showing postoperative cognitive dysfunction was significantly reduced in the
      lidocaine group compared with that in the placebo group (18.6% versus 40.0%; P =
      0.028). We conclude that intraoperative administration of lidocaine decreased the
      occurrence of cognitive dysfunction in the early postoperative period.
      IMPLICATIONS: Postoperative cognitive dysfunction is a commonly recognized
      complication after cardiac surgery. Intraoperative cerebral microembolism and
      hypoperfusion have been proposed to be the major mechanisms. The results of this
      study show that intraoperative administration of lidocaine decreased the
      occurrence of early postoperative cognitive dysfunction, perhaps because of its
      neuroprotective effects.

PMID- 12401581
TI  - The impact of newly diagnosed patent foramen ovale in patients undergoing off
      pump coronary artery bypass grafting: case series of eleven patients.
AB  - The increased use of transesophageal echocardiography (TEE) by anesthesiologists
      may lead to an increase in the intraoperative detection of previously undiagnosed
      patent foramen ovale (PFO). The impact of heart manipulation on interatrial
      shunting through a PFO during off-pump coronary artery bypass graft (CABG) has
      not been studied. We retrospectively studied 11 patients with PFOs who underwent
      off-pump CABG. TEE contrast studies and blood gas analyses were performed at
      baseline, during heart elevation for distal coronary arteries anastomoses, and at
      the end of the surgery. At baseline, 5 of 11 patients had left-to-right shunting
      and 2 of 11 had right-to-left shunting. Heart elevation did not result in oxygen
      desaturation in any patient; however, it caused the disappearance of a right-to
      left shunt (n = 1), persistence of this shunt (n = 1), and the development of a
      new right-to-left shunt (n = 2). Return of the heart to its original position
      resulted in a return of TEE findings to the baseline state in all patients. This
      series suggests that off-pump CABG can be performed safely in the majority of
      patients with PFOs; however, additional investigation is needed to assure that
      adverse effects do not occur in a subset of patients undergoing off-pump CABG in
      the presence of a PFO. IMPLICATIONS: This case series suggests that coronary
      artery bypass graft surgery can be safely performed in most patients with patent
      foramen ovale without the use of a cardiopulmonary bypass.

PMID- 12401582
TI  - Halothane, isoflurane, and fentanyl increase the minimally effective
      defibrillation threshold of an implantable cardioverter defibrillator: first
      report in humans.
AB  - Placing an implantable cardioverter defibrillator (ICD) involves the induction of
      ventricular fibrillation, whereupon the minimally effective defibrillation energy
      threshold (DFT) is determined. We evaluated the effects of 0.7% halothane, 1%
      isoflurane, or 1.5 micro g/kg of IV fentanyl during N(2)O/oxygen-based general
      anesthesia (GA) or those of subcutaneous 1.5% lidocaine plus IV 0.35 mg/kg of
      propofol on the DFT during ICD implantation in humans (n = 20 per group). Thirty
      minutes after the first set of DFT measurements under such conditions, the
      inhaled anesthetics were withdrawn, and all three GA groups received fentanyl 1
      microg/kg IV (second set). A third set was taken 30 min later, before the GA
      patients awakened and when only N(2)O/oxygen was delivered for GA. The lidocaine
      plus propofol patients were given the same IV propofol bolus 1 min before each
      fibrillation/defibrillation trial and at the same time points as the three GA
      groups. The first DFTs were 16.1 +/- 2.2 J (halothane), 17.7 +/- 2.7 J
      (isoflurane), 16.4 +/- 2.9 J (fentanyl), and 12.9 +/- 3.8 J (lidocaine plus
      propofol) (P = 0.01). The second set of DFTs were significantly lower than the
      first sets for the halothane (P = 0.01) and isoflurane (P = 0.02), but not the
      fentanyl or lidocaine plus propofol, regimens. The third DFTs were significantly
      (P < 0.01) lower than the first ones for the three GA groups, but not for the
      lidocaine plus propofol patients. Thus, halothane, isoflurane, and fentanyl
      increased DFT values during ICD implantation in humans, whereas lidocaine plus
      intermittent small-dose IV propofol minimized these thresholds. IMPLICATIONS:
      Halothane, isoflurane, and IV fentanyl added to N(2)O/oxygen-based general
      anesthesia similarly increase minimal defibrillation threshold energy
      requirements (DFT) during cardioverter defibrillator implantation in humans.
      Subcutaneous lidocaine plus intermittent small-dose IV propofol minimizes DFT
      compared with these general anesthetics while providing equal patient
      satisfaction.

PMID- 12401583
TI  - A prospective randomized study comparing two techniques of perioperative blood
      conservation: isovolemic hemodilution and hypervolemic hemodilution.
AB  - We compared hypervolemic hemodilution (HVH) and isovolemic hemodilution (IVH) as
      means of perioperative blood conservation under standardized conditions. Thirty
      ASA status I/II adults slated for orthopedic, ear-nose-throat, or general surgery
      with expected blood loss of >500 mL underwent either IVH (n = 15) or HVH (n =
      15). They were hemodiluted to a hematocrit (Hct) of 25% by blood withdrawal and
      simultaneous polygeline (Hemaccel((R))) infusion (IVH) or by infusing polygeline
      without blood withdrawal, thus creating hypervolemia (HVH). Further blood loss to
      a Hct of 20% was allowed before autologous/allogeneic blood transfusion to aim
      for a 24-h postoperative Hct of > or =25%. Systolic blood pressure (P = 0.0107)
      and central venous pressure (P = 0.0281) were significantly higher during HVH.
      The mean difference (MD) between the target postdilution Hct of 25% and the Hct
      achieved was not statistically significant in either group (MD [95% confidence
      interval; CI], 0% [-0.7% to 0.7%] for IVH and 0.6% [-0.1% to 1.3%] for HVH). The
      actual amount of allogeneic blood used was similar in the two groups, with an MD
      (95% CI) of -7 (-326 to 312), and was significantly less than the corresponding
      projected amount (MD [95% CI], -581 mL [-753 to -409 mL] in IVH; -376 mL [-531 to
      -221] in HVH). The two techniques were similar in time taken (MD [95% CI] = 7 min
      [-0.5 to 14.5 min]), cost incurred (MD [95% CI] = $1.7 (-$4.10 to $7.50]), and
      volumes of polygeline used (MD [95% CI] = -6 mL/kg body weight [-16 to 4 mL/kg
      body weight]). This study found IVH and HVH comparable in significantly reducing
      perioperative allogeneic blood requirements, time needed, and cost incurred. The
      formula used for achieving the desired HVH appears promising. IMPLICATIONS: Both
      hypervolemic hemodilution (HVH) and isovolemic hemodilution (IVH) claim to reduce
      red blood cell loss during surgery by diluting the patient's blood. This study
      found both comparable in significantly reducing the exposure to bank blood in the
      perioperative period, the time needed, and the cost incurred. HVH, being simpler,
      because it does not involve blood withdrawal, appeared superior to IVH in the
      healthy adults studied. Larger studies are needed to substantiate the results.

PMID- 12401584
TI  - Isoflurane does not produce a second window of preconditioning against myocardial
      infarction in vivo.
AB  - The administration of a volatile anesthetic shortly before a prolonged ischemic
      episode exerts protective effects against myocardial infarction similar to those
      of ischemic preconditioning. A second window of preconditioning (SWOP) against
      myocardial infarction can also be elicited by brief episodes of ischemia when
      this occurs 24 h before prolonged coronary artery occlusion. Whether remote
      exposure to a volatile anesthetic also causes delayed myocardial protection is
      unknown. We tested the hypothesis that the administration of isoflurane 24 h
      before ischemia produces a SWOP against infarction. Barbiturate-anesthetized dogs
      (n = 25) were instrumented for measurement of hemodynamics, including aortic and
      left ventricular (LV) pressures and LV +dP/dt(max), and subjected to a 60-min
      left anterior descending coronary artery occlusion followed by 3 h of
      reperfusion. Myocardial infarct size and coronary collateral blood flow were
      assessed with triphenyltetrazolium chloride staining and radioactive
      microspheres, respectively. Two groups of dogs received 1.0 minimum alveolar
      anesthetic concentration isoflurane for 30 min or 6 h that was discontinued 30
      min (acute) or 24 h (delayed) before ischemia and reperfusion, respectively. A
      control group of dogs did not receive isoflurane. Infarct size was 27% +/- 3% of
      the LV area at risk in the absence of pretreatment with isoflurane. Acute, but
      not remote, administration of isoflurane reduced infarct size (12% +/- 1% and 31%
      +/- 3%, respectively). No differences in hemodynamics or transmural myocardial
      perfusion during or after occlusion were observed between groups. The results
      indicate that isoflurane does not produce a SWOP when administered 24 h before
      prolonged myocardial ischemia in vivo. IMPLICATIONS: Isoflurane mimics the
      beneficial effects of ischemic preconditioning by protecting myocardium against
      infarction when it is administered shortly before a prolonged ischemic episode.
      However, unlike ischemic preconditioning, isoflurane does not produce a second
      window of protection 24 h after administration in dogs.

PMID- 12401585
TI  - The effect of hypernatremia on liver allografts in rats.
AB  - Hypernatremia in the donor organ is one of the most dangerous risk factors that
      may cause primary graft loss after orthotopic liver transplantation (OLT).
      However, the viability of donor grafts from acute hypernatremic donors, which is
      likely to occur during resuscitation of trauma patients with hypertonic saline
      solution, has not been studied precisely. In the present study, we sought to
      evaluate whether the hypernatremia, per se, induced by hypertonic saline
      solution, affects the outcome of liver transplantation in the normal rat. Thirty
      minutes after the induction of hypernatremia (>160 mEq/L), the livers of nine
      Wistar rats were removed under ether anesthesia. Six livers were immediately
      transplanted into normal Wistar rats, whereas the other three were preserved in 4
      degrees C University of Wisconsin solution for 6 h before transplantation in the
      recipients. Liver function variables of the donor rats at graft procurement and
      of the recipients at Day 7 after OLT were compared with a control group. The
      water content of the graft at procurement and the survival of the recipients at 7
      days after OLT were, likewise, compared with the untreated control group. Results
      showed that there were no significant differences in the liver function tests of
      the donors and recipients, as well as in the water content of the grafts, between
      groups. All the rats survived the observation period of 7 days. This study showed
      that acute hypernatremia induced by the infusion of 10% saline solution before
      graft procurement in a nonbrain-dead donor rat model did not lead to a
      deterioration of liver graft viability after OLT. IMPLICATIONS: Hypernatremia in
      cadaveric donors may be detrimental to the graft in clinical liver
      transplantation, but acute donor hypernatremia induced by an IV infusion of 10%
      saline solution before graft procurement in nonbrain-dead rats did not affect the
      survival of the recipient rats in an experimental liver transplantation model.

PMID- 12401586
TI  - Hemodynamic and hormonal responses to the sudden interruption of caval flow:
      insights from a prospective study of hepatic vascular exclusion during major
      liver resections.
AB  - Hepatic vascular exclusion (HVE) combines portal triad clamping and occlusion of
      the inferior vena cava. Although HVE has been performed for major liver
      resections during the last 2 decades, little is known about the mechanisms that
      explain its satisfactory hemodynamic tolerance. Consequently, we performed a
      comprehensive study of both hemodynamic and hormone responses to HVE. Twenty-two
      patients who underwent liver resection for secondary tumors developed in
      noncirrhotic livers were prospectively studied. Heart rate, arterial blood
      pressure, pulmonary artery pressure, mixed venous saturation, cardiac output, and
      left ventricular dimensions determined by transesophageal echocardiography were
      monitored in HVE patients. Blood concentrations of arginine vasopressin (AVP),
      epinephrine, norepinephrine, dopamine, and atrial natriuretic peptide and plasma
      renin activity (PRA) were measured before clamping; 5, 15, and 30 min after
      clamping; and 15 min after unclamping. Hemodynamic response to HVE was
      characterized by a significant (P < 0.05) decrease in left ventricular
      dimensions, fractional area change, and pulmonary artery pressure. We also
      observed a marked decrease in cardiac output (50%) and an increase in heart rate
      and systemic vascular resistance. After unclamping, there was peripheral
      vasodilation, assessed by a significant decrease in systemic vascular resistance
      from the preclamping value to unclamping. An acute and sustained increase in AVP
      and norepinephrine that returned to baseline after unclamping and the absence of
      modification in PRA concentrations were noted. The marked decrease in venous
      return that characterizes HVE is compensated for by an increase in vascular
      resistance secondary to an important activation of the AVP and sympathetic
      systems. The PRA system does not play an important role in maintaining arterial
      blood pressure during HVE. IMPLICATIONS: Hemodynamic and hormonal responses to
      the acute interruption of caval venous return to the heart were investigated in
      patients undergoing liver resection with hepatic vascular exclusion. A
      compensatory role for arginine vasopressin and sympathetic systems that provoked
      increased vascular resistance was demonstrated.

PMID- 12401587
TI  - Epidural anesthesia and analgesia in liver resection.
AB  - IMPLICATIONS: In patients undergoing major liver resection, the decision to
      introduce an epidural catheter and the timing of its removal should be made with
      care because of the prolonged changes in platelet count and in prothrombin time
      that develop in some patients.

PMID- 12401588
TI  - Elimination of indocyanine green in the perioperative evaluation of donor liver
      function.
AB  - IMPLICATIONS: The authors describe the intraoperative use of indocyanine green
      dye elimination to detect critical reductions in donor liver function.

PMID- 12401589
TI  - Acute postoperative pulmonary thromboembolism as a result of intravascular
      migration of a pigtail ureteral stent.
AB  - IMPLICATIONS: The symptomatic obstruction of a pulmonary arterial branch
      secondary to the intravascular migration of a pigtail ureteral stent is reported.
      This iatrogenic complication may cause dyspnea, chest pain, or both after
      uneventful urologic procedures involving ureteral stents.

PMID- 12401590
TI  - Bronchial stenting and high-frequency percussive ventilation treatment of
      descending aortic aneurysm-induced atelectasis of the left lung.
AB  - IMPLICATIONS: This case report shows that atelectasis of the left lung-induced by
      extrinsic compression of the left main bronchus by an aortic aneurysm and
      persisting despite aggressive conservative treatment-may be effectively treated
      by bronchial stenting and high-frequency percussive ventilation.

PMID- 12401591
TI  - Arterial catheter pressure cable corrosion leading to artifactual diagnosis of
      hypotension.
AB  - IMPLICATIONS: Arterial pressure cable corrosion leads to artifactual hypotension
      despite a normally appearing waveform.

PMID- 12401592
TI  - Supine hypertension during general anesthesia in a patient taking midodrine.
AB  - IMPLICATIONS: Midodrine, a drug used to treat symptomatic orthostatic
      hypotension, may cause or exacerbate supine hypertension. We describe a case of a
      patient taking midodrine who exhibited severe hypertension during general
      anesthesia. Possible preventive measures to avoid this complication are
      discussed.

PMID- 12401593
TI  - Aortic valve fibroelastomas as an incidental intraoperative transesophageal
      echocardiographic finding.
AB  - IMPLICATIONS: We report incidental findings of aortic valve fibroelastomas during
      routine intraoperative transesophageal echocardiography examination in cardiac
      surgery. Preoperative echocardiography failed to identify this potentially
      devastating pathology. The echocardiographic features of this lesion are
      reviewed, and the importance of diligence and complete examination are
      emphasized.

PMID- 12401595
TI  - Intrathecal versus IV fentanyl in pediatric cardiac anesthesia.
AB  - Systemic large-dose opioids are widely used in pediatric cardiac anesthesia, but
      there are no randomized, prospective studies regarding the use of intrathecal
      (IT) opioids for these procedures. In this randomized, prospective study, we
      compared cardiovascular and neurohumoral responses during IT or IV fentanyl
      anesthesia for pediatric cardiac surgery. Thirty children aged 6 mo to 6 yr were
      anesthetized with an IV fentanyl bolus of 10 micro g/kg. This was followed by a
      fentanyl infusion of 10 micro g. kg(-1). h(-1) (Group IV; n = 10), 2 micro g/kg
      of IT fentanyl (Group IT; n = 10), or combined IV and IT protocols (Group IV +
      IT; n = 10). Heart rate, mean arterial blood pressure, additional fentanyl doses,
      time to first analgesic requirement, COMFORT and Children's Hospital of Eastern
      Ontario Pain Scale scores, and extubation time were recorded. Blood cortisol,
      insulin, glucose, and lactate levels were measured presurgery, poststernotomy,
      during the rewarming phase of cardiopulmonary bypass (CPB), and 6 and 24 h after
      surgery. The patients' urinary cortisol excretion rates were also measured during
      the first postoperative day. The findings in all three groups were statistically
      similar, except for higher blood glucose levels during CPB in Group IT compared
      with Group IV (P < 0.004). Group IV + IT was the only group in which the
      increases in heart rate and mean arterial blood pressure from presurgery to
      poststernotomy were not significant. The 24-h urinary cortisol excretion rates (
      micro g. kg(-1). d(-1)) were 61.51 +/- 39, 92.54 +/- 67.55, and 40.15 +/- 29.69
      for Groups IV, IT, and IV + IT, respectively (P > 0.05). A single IT injection of
      fentanyl 2 micro g/kg offers no advantage over systemic fentanyl (10 micro g/kg
      bolus and 10 micro g. kg(-1). h(-1)) with regard to hemodynamic stability or
      suppression of stress response. The combination of these two regimens may provide
      better hemodynamic stability during the pre-CPB period and may be associated with
      a decreased 24-h urinary cortisol excretion rate. IMPLICATIONS: In this
      prospective, randomized study, we investigated the adequacy of a single
      intrathecal injection of fentanyl for intraoperative analgesia, compared the
      effects of IT and IV fentanyl on stress response, and assessed for an additive
      effect of IT and IV fentanyl administration in pediatric cardiac anesthesia. The
      results with these three different anesthetic regimens were similar regarding
      anesthesia depth and level of stress response. However, the combination of IT and
      IV routes may provide better hemodynamic stability and a less pronounced stress
      response, as reflected by 24-h urinary cortisol excretion.

PMID- 12401594
TI  - Pulmonary-to-systemic blood flow ratio effects of sevoflurane, isoflurane,
      halothane, and fentanyl/midazolam with 100% oxygen in children with congenital
      heart disease.
AB  - The cardiovascular effects of volatile anesthetics in children with congenital
      heart disease have been studied, but there are limited data on the effects of
      anesthetics on pulmonary-to-systemic blood flow ratio (Qp:Qs) in patients with
      intracardiac shunting. In this study, we compared the effects of halothane,
      isoflurane, sevoflurane, and fentanyl/midazolam on Qp:Qs and myocardial
      contractility in patients with atrial (ASD) or ventricular (VSD) septal defects.
      Forty patients younger than 14 yr old scheduled to undergo repair of ASD or VSD
      were randomized to receive halothane, sevoflurane, isoflurane, or
      fentanyl/midazolam. Cardiovascular and echocardiographic data were recorded at
      baseline, randomly ordered 1 and 1.5 mean alveolar anesthetic concentration (MAC)
      levels, or predicted equivalent fentanyl/midazolam plasma levels. Ejection
      fraction (using the modified Simpson's rule) was calculated. Systemic (Qs) and
      pulmonary (Qp) blood flow was echocardiographically assessed by the velocity-time
      integral method. Qp:Qs was not significantly affected by any of the four regimens
      at either anesthetic level. Left ventricular systolic function was mildly
      depressed by isoflurane and sevoflurane at 1.5 MAC and depressed by halothane at
      1 and 1.5 MAC. Sevoflurane, halothane, isoflurane, or fentanyl/midazolam in 1 or
      1.5 MAC concentrations or their equivalent do not change Qp:Qs in patients with
      isolated ASD or VSD. IMPLICATIONS: Sevoflurane, halothane, isoflurane, and
      fentanyl/midazolam do not change pulmonary-to-systemic blood flow ratio in
      children with atrial and ventricular septal defects when administered at standard
      anesthetic doses with 100% oxygen.

PMID- 12401596
TI  - Caudal neostigmine, bupivacaine, and their combination for postoperative pain
      management after hypospadias surgery in children.
AB  - In a randomized, double-blinded study, we examined the analgesic efficacy of
      caudal neostigmine, bupivacaine, or a mixture of both drugs in 60 children. After
      the induction of general anesthesia, children were allocated randomly into three
      groups (n = 20) to receive a caudal injection of either 0.25% bupivacaine 1
      mL/kg, with or without neostigmine 2 micro g/kg, or neostigmine 2 micro g/kg in
      normal saline 1 mL/kg. Intraoperatively, children receiving caudal bupivacaine or
      a bupivacaine/neostigmine mixture maintained hemodynamic stability, required less
      inhaled anesthetics, and had a shorter recovery time compared with the caudal
      neostigmine alone. Postoperatively, the caudal bupivacaine/neostigmine mixture
      resulted in superior analgesia compared with the other two groups. Recovery to
      first rescue analgesic times were (mean +/- SD) 22.8 +/- 2.9 h, 8.1 +/- 5.9 h,
      and 5.2 +/- 2.1 h in the bupivacaine/neostigmine, bupivacaine, and neostigmine
      groups, respectively (P < 0.001). In addition, the bupivacaine and neostigmine
      groups received more doses of paracetamol than the bupivacaine/neostigmine group
      to maintain adequate analgesia in the first 24 postoperative h. Postoperative
      vomiting occurred in 25%, 10%, and 30% in the caudal bupivacaine/neostigmine,
      bupivacaine, and neostigmine groups, respectively (P < 0.01). We conclude that
      caudal neostigmine 2 micro g/kg provides postoperative analgesia comparable to
      caudal bupivacaine in children undergoing hypospadias repair surgery.
      IMPLICATIONS: Caudal neostigmine 2 micro g/kg provides postoperative analgesia
      comparable to caudal bupivacaine in children undergoing hypospadias repair
      surgery. Co-administration of the two drugs is associated with extended
      postoperative analgesia and reduced need for supplementary analgesics.

PMID- 12401597
TI  - Caudal anesthesia in children: effect of volume versus concentration of
      bupivacaine on blocking spermatic cord traction response during orchidopexy.
AB  - In this study we compared the intensity and level of caudal blockade when two
      different volumes and concentrations of a fixed dose of bupivacaine were used.
      Fifty children, 1-6 yr old, undergoing unilateral orchidopexy received a caudal
      block with a fixed 2 mg/kg dose of bupivacaine immediately after the induction.
      Group 1 (n = 23) received 0.8 mL/kg of 0.25% bupivacaine, whereas Group 2 (n =
      27) received 1.0 mL/kg of 0.2% bupivacaine. Epinephrine 1:400,000 and 0.1 mL of
      sodium bicarbonate per 10 mL of local anesthetic solution were added. There were
      no statistically significant differences between the two groups in their
      anesthesia, surgery, recovery, and discharge times. Fifteen patients (65.2%) in
      Group 1 required an increase in inspired halothane concentration to block
      hemodynamic and/or ventilatory response during spermatic cord traction, as
      compared with 8 patients (29.6%) in Group 2 (P = 0.022). In the recovery room,
      four (17.4%) patients in Group 1 required rescue treatment with fentanyl, versus
      two (7.4%) in Group 2 (P = 0.372). In children undergoing orchidopexy, a caudal
      block with a larger volume of dilute bupivacaine is more effective than a smaller
      volume of the standard 0.25% solution in blocking the peritoneal response during
      spermatic cord traction, with no change in the quality of postoperative
      analgesia. IMPLICATIONS: In children undergoing orchidopexy, a caudal block with
      a larger volume of dilute bupivacaine is more effective than a smaller volume of
      the more concentrated solution in blocking the peritoneal response during
      spermatic cord traction, with no change in the quality of postoperative
      analgesia.

PMID- 12401598
TI  - The reliability and validity of the Face, Legs, Activity, Cry, Consolability
      observational tool as a measure of pain in children with cognitive impairment.
AB  - Pain assessment remains difficult in children with cognitive impairment (CI). In
      this study, we evaluated the validity and reliability of the Face, Legs,
      Activity, Cry, Consolability (FLACC) tool for assessing pain in children with CI.
      Each child's developmental level and ability to self-report pain were evaluated.
      The child's nurse observed and scored pain with the FLACC tool before and after
      analgesic administration. Simultaneously, parents scored pain with a visual
      analog scale, and scores were obtained from children who were able to self-report
      pain. Observations were videotaped and later viewed by nurses blinded to
      analgesics and pain scores. One-hundred-forty observations were recorded from 79
      children. FLACC scores correlated with parent scores (P < 0.001) and decreased
      after analgesics (P = 0.001), suggesting good validity. Correlations of total
      scores (r = 0.5-0.8; P < 0.001) and of each category (r = 0.3-0.8; P < 0.001), as
      well as measures of exact agreement (kappa = 0.2-0.65), suggest good reliability.
      Test-retest reliability was supported by excellent correlations (r = 0.8-0.883; P
      < 0.001) and categorical agreement (r = 0.617-0.935; kappa = 0.400-0.881; P <
      0.001). These data suggest that the FLACC tool may be useful as an objective
      measure of postoperative pain in children with CI. IMPLICATIONS: The FLACC pain
      assessment tool may facilitate reliable and valid observational pain assessment
      in children with cognitive impairment who cannot self-report their pain.
      Objective pain assessment is important to facilitate effective postoperative pain
      management in these vulnerable children.

PMID- 12401599
TI  - Ondansetron and dolasetron provide equivalent postoperative vomiting control
      after ambulatory tonsillectomy in dexamethasone-pretreated children.
AB  - In this prospective, randomized, double-blinded, placebo-controlled study, we
      compared the incidence of emesis and 48-h recovery profiles after a single dose
      of preoperative ondansetron versus dolasetron in dexamethasone-pretreated
      children undergoing ambulatory tonsillectomy. One-hundred-forty-nine children, 2
      12 yr old, ASA physical status I and II, completed the study. All children
      received standardized perioperative care, including premedication, surgical and
      anesthetic techniques, IV fluids, analgesics, and rescue antiemetic medications.
      Patients were randomized to receive ondansetron 0.15 mg/kg, maximum 4 mg (Group
      1); dolasetron 0.5 mg/kg, maximum 25 mg (Group 2); or saline placebo (Group 3) IV
      before the initiation of surgery. In addition, all patients received
      dexamethasone 1 mg/kg (maximum 25 mg). Rescue antiemetics were administered for
      two or more episodes of retching/vomiting. The incidence of retching/vomiting
      before home discharge did not differ between the ondansetron and dolasetron
      groups and was significantly less frequent compared with the placebo group (10%,
      Group 1; 8%, Group 2; 30%, Group 3). Similar results were obtained at 24-48 h
      after discharge (6%, Groups 1 and 2; 18%, Group 3). The need for rescue
      antiemetics administered after the second retching/vomiting episode was
      significantly less in Groups 1 (4%) and 2 (6%) compared with Group 3 (22%) before
      home discharge. The complete response rate, defined as no retching/vomiting and
      no antiemetic for 48 h, was significantly increased in Groups 1 (76%) and 2 (74%)
      compared with Group 3 (44%). The antiemetic efficacy of prophylactic ondansetron
      and dolasetron was comparable in dexamethasone-pretreated children undergoing
      ambulatory tonsillectomy. IMPLICATIONS: The efficacy of a single dose of
      prophylactic ondansetron versus dolasetron in conjunction with dexamethasone was
      studied on posttonsillectomy retching/vomiting and 48-h recovery in children 2-12
      yr old. Compared with placebo, ondansetron and dolasetron produced comparable
      reductions in the incidence of retching/vomiting and the need for rescue
      antiemetics.

PMID- 12401600
TI  - Arterial carbon dioxide markedly increases during diagnostic laparoscopy in
      portal hypertensive children.
AB  - Several factors are responsible for hypercarbia during laparoscopic procedures.
      This study was undertaken because we observed a sudden increase in PaCO(2) in
      children with portal hypertension (PHT), which was unusual in healthy children
      undergoing laparoscopic procedures. Fifty-seven children underwent laparoscopic
      procedures under general anesthesia and were mechanically ventilated. Arterial
      blood samples were obtained 5 min after intubation (T(0)), 15 min and 30 min
      after CO(2) pneumoperitoneum (T(15) and T(30)), 5 min after desufflation
      (T(end)), and 10 min after extubation (T(ext)) for blood gas analysis. The
      changes in PaCO(2), pH, and ETCO(2) were statistically significant during the
      study periods in both groups (P < 0.05). The percentage of PaCO(2) increase
      between T(0) and T(15) was 11.5% and 20.1%, respectively, in the control group
      and the PHT group (P < 0.05). This increase reached 36.8% at T(30) in the PHT
      group, whereas the control group had a 17.2% increase (P < 0.05). ETCO(2)
      presented similar changes. The variability in base excess, bicarbonate, PaO(2),
      arterial oxygen saturation, and SpO(2) was not significant in either group (P >
      0.05). The PaCO(2) increased remarkably in children with PHT undergoing
      laparoscopy, with no difference in intrahepatic or extrahepatic origin. Limiting
      the duration of CO(2) pneumoperitoneum and intraabdominal pressure and adjusting
      ventilatory variables to accommodate hypercarbia are of the utmost importance for
      such cases. IMPLICATIONS: We compared children with portal hypertension with
      systemically healthy children during laparoscopy. The increase in arterial and
      end-tidal CO(2) was remarkable in children with portal hypertension, regardless
      of bicarbonate changes. Managing ventilation to accommodate hypercarbia is of the
      utmost importance for such cases.

PMID- 12401601
TI  - Fiberoptic-guided Fogarty catheter placement using the same diaphragm of an
      adapter within the single-lumen tube in children.
AB  - IMPLICATIONS: We describe successful placement of a Fogarty catheter for one-lung
      ventilation through a single-lumen tube using a single diaphragm of an adapter
      for both the fiberoptic bronchoscope and the Fogarty catheter.

PMID- 12401602
TI  - An effective use of magnesium sulfate for intraoperative management of
      laparoscopic adrenalectomy for pheochromocytoma in a pediatric patient.
AB  - IMPLICATIONS: This report concerns a case for which the intraoperative use of
      magnesium sulfate as an adjunct to the conventional use of nicardipine was
      effective for managing a pediatric patient with pheochromocytoma who was
      undergoing a laparoscopic operation.

PMID- 12401603
TI  - Cardiac arrest from tension pneumopericardium in a premature infant.
AB  - IMPLICATIONS: This case report describes a rare and potentially fatal anesthetic
      complication. It occurred during the care of a small premature infant as a result
      of improper use of medical equipment.

PMID- 12401604
TI  - Vallecular cyst and laryngomalacia in infants: report of six cases and airway
      management.
AB  - IMPLICATIONS: This report describes difficulties encountered in the airway
      management of six infants with concurrent vallecular cyst and laryngomalacia. It
      is hoped that our experience will assist others in the management of such
      patients.

PMID- 12401605
TI  - Bilateral pneumothoraces in a pediatric patient undergoing Hickman catheter
      placement.
AB  - IMPLICATIONS: The laryngeal mask airway (LMA) is often used for airway management
      in pediatric patients. We report bilateral pneumothoraces in a patient who
      underwent neck surgery whose airway was managed with a LMA. We recommend that the
      LMA be used with caution in small children undergoing deep-neck dissection.

PMID- 12401606
TI  - Small-dose intrathecal lidocaine versus ropivacaine for anorectal surgery in an
      ambulatory setting.
AB  - Spinal anesthesia with the local anesthetic lidocaine has come under scrutiny
      because it is associated with transient neurologic symptoms (TNS). We designed
      this study to prospectively compare the efficacy of ropivacaine as an alternative
      to lidocaine in patients undergoing elective outpatient anorectal procedures.
      Seventy-two patients were randomized to receive either hyperbaric lidocaine 25 mg
      with fentanyl 20 microg (n = 37) or hyperbaric ropivacaine 4 mg with fentanyl 20
      microg (n = 35). Patients were examined for motor block, sensory block, and block
      duration. Patients were contacted at 24, 48, 72, and 168 h and questioned about
      their perceptions of pain after the spinal with specific questions designed to
      diagnose TNS. There were no patients with TNS in either group. There was no
      significant difference between the lidocaine and ropivacaine groups in any of the
      outcomes studied. In conclusion, intrathecal hyperbaric small-dose ropivacaine
      with fentanyl is an acceptable anesthetic for anorectal surgery. IMPLICATIONS: In
      this prospective trial, small-dose ropivacaine with fentanyl was as effective as
      small-dose lidocaine with fentanyl for anorectal procedures in the ambulatory
      setting.

PMID- 12401607
TI  - Acute postoperative pain management at home after ambulatory surgery: a French
      pilot survey of general practitioners' views.
AB  - IMPLICATIONS: We assessed the views of French general practitioners concerning
      pain relief at home after ambulatory surgery in a cross-sectional prospective
      survey. The results revealed that there is need for improvement, mainly in
      prescribing more suitable analgesic protocols and optimizing postdischarge
      relationships between physicians.

PMID- 12401608
TI  - The effects of lidocaine on the activity of glutamate transporter EAAT3: the role
      of protein kinase C and phosphatidylinositol 3-kinase.
AB  - Using two electrode voltage clamps, we investigated the effects of lidocaine on
      one type of glutamate transporter, EAAT3, and the role of protein kinase C (PKC)
      and phosphatidylinositol 3-kinase (PI3K) in mediating the lidocaine effects.
      EAAT3 was expressed in Xenopus oocytes, and membrane currents were recorded after
      the application of L-glutamate (30 microM). Lidocaine increased glutamate-induced
      inward currents significantly at 2 concentrations (100 microM and 1 mM), but not
      at other concentrations. Lidocaine (100 microM) significantly increased the
      V(max), but not the K(m), of EAAT3 for glutamate compared with control. The
      action sites of lidocaine on EAAT3 seem to be intracellular, because only
      intracellularly injected QX314 (permanently charged lidocaine analog) increased
      the response. The combination of phorbol-12-myrisate-13-acetate, an activator of
      PKC, and lidocaine did not further increase the responses compared with phorbol
      12-myrisate-13-acetate or lidocaine alone, although each of these three groups
      showed significantly bigger responses than controls. Three PKC inhibitors
      (staurosporine, calphostin C, and chelerythrine) did not affect the basal EAAT3
      activity but abolished lidocaine-enhanced EAAT3 activity. Wortmannin (a specific
      PI3K inhibitor) inhibited EAAT3 basal activity and lidocaine-enhanced EAAT3
      activity. Our results suggest that lidocaine enhances EAAT3 activity at certain
      concentrations and that PKC and PI3K may mediate these lidocaine effects.
      IMPLICATIONS: By using the Xenopus oocyte expression system, we investigated the
      effects of lidocaine on a glutamate transporter (EAAT3). Our findings suggest
      that lidocaine enhances EAAT3 activity at certain concentrations and that protein
      kinase C and phosphatidylinositol 3-kinase may mediate these lidocaine effects.

PMID- 12401609
TI  - The inhibitory effects of tramadol on muscarinic receptor-induced responses in
      Xenopus oocytes expressing cloned M(3) receptors.
AB  - Tramadol is a widely used analgesic, but its mechanism of action is not
      completely understood. Muscarinic receptors are involved in neuronal function in
      the brain and autonomic nervous system, and much attention has been paid to these
      receptors as targets of analgesic drugs in the central nervous system. In this
      study, we investigated the effects of tramadol on type-3 muscarinic (M(3))
      receptors using the Xenopus oocyte expression system. Tramadol (10 nM-100 micro
      M) inhibited acetylcholine-induced currents in oocytes expressing M(3) receptor.
      Although GF109203X, a protein kinase C inhibitor, increased the basal current, it
      had little effect on the inhibition of acetylcholine-induced currents by
      tramadol. Moreover, tramadol inhibited the specific binding sites of
      [(3)H]quinuclidinyl benzilate. These findings suggest that tramadol at clinically
      relevant concentrations inhibits M(3) function via quinuclidinyl benzilate
      binding sites. This may explain the modulation of neuronal function and the
      anticholinergic effects of tramadol. IMPLICATIONS: Muscarinic receptors are
      involved in neuronal function and are targets of analgesic drugs. We here report
      that tramadol inhibits type-3 muscarinic receptors function via quinuclidinyl
      benzilate-binding sites at clinically relevant concentrations. These findings may
      explain the modulation of neuronal function and the anticholinergic effects of
      tramadol.

PMID- 12401610
TI  - The effects of general anesthetics on norepinephrine release from isolated rat
      cortical nerve terminals.
AB  - Intravenous and volatile general anesthetics inhibit norepinephrine (NE) release
      from sympathetic neurons and other neurosecretory cells. However, the actions of
      general anesthetics on NE release from central nervous system (CNS) neurons are
      unclear. We investigated the effects of representative IV and volatile
      anesthetics on [(3)H]NE release from isolated rat cortical nerve terminals
      (synaptosomes). Purified synaptosomes prepared from rat cerebral cortex were
      preloaded with [(3)H]NE and superfused with buffer containing pargyline (a
      monoamine oxidase inhibitor) and ascorbic acid (an antioxidant). Basal
      (spontaneous) and stimulus-evoked [(3)H]NE release was evaluated in the
      superfusate in the absence or presence of various anesthetics. Depolarization
      with increased concentrations of KCl (15-20 mM) or 4-aminopyridine (0.5-1.0 mM)
      evoked concentration- and Ca(2+)-dependent increases in [(3)H]NE release from rat
      cortical synaptosomes. The IV anesthetics etomidate (5-40 microM), ketamine (5-30
      microM), or pentobarbital (25-100 microM) did not affect basal or stimulus-evoked
      [(3)H]NE release. Propofol (5-40 microM) increased basal [(3)H]NE release and, at
      larger concentrations, reduced stimulus-evoked release. The volatile anesthetic
      halothane (0.15-0.70 mM) increased basal [(3)H]NE release, but did not affect
      stimulus-evoked release. These findings demonstrate drug-specific stimulation of
      basal NE release. Noradrenergic transmission may represent a presynaptic target
      for selected general anesthetics in the CNS. Given the contrasting effects of
      general anesthetics on the release of other CNS transmitters, the presynaptic
      actions of general anesthetics are both drug- and transmitter-specific.
      IMPLICATIONS: General anesthetics affect synaptic transmission both by altering
      neurotransmitter release and by modulating postsynaptic responses to transmitter.
      Anesthetics exert both drug-specific and transmitter-specific effects on
      transmitter release: therapeutic concentrations of some anesthetics stimulate
      basal, but not evoked, norepinephrine release, in contrast to evoked glutamate
      release, which is inhibited.

PMID- 12401611
TI  - Changes of propofol concentration in cerebrospinal fluid during continuous
      infusion.
AB  - We studied the changes in the propofol concentration in the cerebrospinal fluid
      (CSF) in 14 patients, undergoing elective intracranial procedures, who were
      anesthetized with propofol administered by target-controlled infusion. During
      anesthesia, fentanyl and cisatracurium were administered as required. After
      intubation of the trachea, the lungs of the patients were ventilated to
      normocapnia with an oxygen-air mixture (FIO(2) = 0.33). Arterial blood and CSF
      samples (from an intraventricular drain) were collected between 90-180 min after
      the induction of anesthesia. Blood propofol concentrations were stable, between
      5.0 +/- 1.89 and 4.5 +/- 1.7 microg/mL (mean +/- SD). There was a significant
      decrease in the CSF propofol concentration, from 52.2 +/- 35.01 ng/mL at 90 min
      to 28.6 +/- 21.9 ng/mL at 150 min (P < 0.05). The CSF propofol concentration at
      180 min (21.4 +/- 14.0 ng/mL) was not significantly different from the
      concentration at 150 min. Some possible reasons for this decrease after
      commencing continuous intraventricular drainage are discussed. IMPLICATIONS:
      Propofol concentrations in the cerebrospinal fluid in neurosurgical patients
      Propofol concentration in cerebrospinal fluid of investigated patients decreased
      significantly after starting intraventricular drainage, despite relatively steady
      blood propofol concentrations. These results supplement the limited information
      about propofol pharmacokinetics in the human central nervous system.

PMID- 12401612
TI  - Propofol phosphate, a water-soluble propofol prodrug: in vivo evaluation.
AB  - After a single IV injection of the water-soluble propofol prodrug propofol
      phosphate (PP) in mice, rats, rabbits, and pigs, propofol was produced rapidly (1
      15 min), inducing dose-dependent sedative effects. In mice, the hypnotic dose
      (HD(50)), lethal dose (LD(50)), and safety index (defined as a ratio:
      LD(50)/HD(50)) were 165.4 mg/kg, 600.6 mg/kg, and 3.6, respectively. Propofol was
      produced with half-lives of 5.3 +/- 0.6 min in rats, 2.1 +/- 0.6 min in rabbits,
      and 4.4 +/- 2.4 min in pigs. The maximal concentration was dose and species
      dependent. The elimination half-life was 24 +/- 12 min in rats, 21 +/- 16 min in
      rabbits, and 225 +/- 56 min in pigs. Propofol generated from PP produced
      pharmacological effects similar to those described in the literature. We found a
      correlation between PP dose and duration of sedation with propofol concentrations
      larger than 1.0 microg/mL, which produced somnolence and sedation in rats and
      pigs. Adequate sedation and, at large enough doses, anesthetic-level sedation
      were produced after the administration of PP. Overall, PP, the water-soluble
      prodrug of propofol, seems to be a viable development candidate for sedative and
      anesthetic applications. IMPLICATIONS: Propofol phosphate, a water-soluble
      prodrug of the widely used IV anesthetic propofol, was developed and evaluated in
      mice, rats, rabbits, and pigs after IV injection. The results of the study
      clearly demonstrate the feasibility of the prodrug approach to achieve sedative
      and anesthetic levels of propofol in laboratory animals; this warrants further
      evaluation in humans.

PMID- 12401613
TI  - Ephedrine reduces the pain from propofol injection.
AB  - One hundred seventy-six patients (ASA physical status I or II) presenting for
      elective surgery were randomly allocated into six study groups to compare the
      incidence of propofol-induced pain after pretreatment with different doses of
      ephedrine as compared with lidocaine. Patients in Group P (n = 30) received
      saline placebo; patients in Group L (n = 30) received 2% lidocaine 40 mg;
      patients received ephedrine 30 microg/kg (Group E30, n = 28), 70 microg/kg (Group
      E70, n = 30), 110 microg/kg (Group E110, n = 30), and 150 microg/kg (Group E150,
      n = 28), respectively, followed 30 s later by propofol 2.5 mg/kg. A blinded
      anesthesiologist asked the patient to evaluate the pain score (verbal rating
      scale and face pain scale). The incidence and intensity of pain was less in the
      lidocaine and ephedrine groups than in the placebo group (P < 0.01). Before
      tracheal intubation, the arterial blood pressure was decreased in the P and L
      groups, and after intubation, hemodynamics were increased in the E110 and E150
      groups, respectively (P < 0.05). We concluded that pretreatment with a small dose
      of ephedrine (30 and 70 microg/kg) reduced the incidence and intensity of
      propofol-induced pain with a lesser decrease in arterial blood pressure than from
      propofol alone in lidocaine pretreatment. IMPLICATIONS: Propofol is a widely used
      IV anesthetic for the induction of anesthesia, but it often causes local pain
      when administered into peripheral veins. A small dose of ephedrine reduces the
      incidence and intensity of the pain without significant adverse hemodynamic
      effects during induction.

PMID- 12401614
TI  - A comparison of metoclopramide and lidocaine for preventing pain on injection of
      diazepam.
AB  - We compared the ability of metoclopramide with IV lidocaine pretreatment to
      abolish pain from a diazepam injection. In a randomized, prospective, double
      blinded, placebo-controlled clinical trial, 159 patients (ASA physical status I
      and II), aged 20-70 yr old, were allocated to one of three groups. Placebo and
      study drugs were injected IV immediately before 0.1 mg/kg of diazepam into a
      dorsal hand vein. Patients in Groups 1, 2, and 3 received 2 mL of placebo, 2 mL
      of lidocaine 1%, and 2 mL of metoclopramide (10 mg), respectively. The patient's
      response was graded using a 4-point scale. Any score other than 0 represented
      pain on injection. We observed that the incidence of pain on diazepam injection
      was 83% in the placebo group, which was decreased to 70% and 39% in patients
      pretreated with metoclopramide and lidocaine, respectively. Although there was no
      significant difference in the incidence of pain in Groups 1 and 3 (P > 0.05),
      Group 3 showed significantly less patients with severe pain scores than Group 1
      as diazepam was injected (P < 0.000). Group 2 showed a significantly less
      frequent incidence of pain than the saline (P < 0.000) and the metoclopramide (P
      < 0.002) groups as diazepam was injected. The intensity of pain in Group 2 was
      significantly less than Group 3 (P = 0.012). The intensity of diazepam injection
      pain was intense with placebo as compared with other groups (P < 0.000).
      Metoclopramide, rather than lidocaine pretreatment, may be a reasonable analgesic
      alternative for painful injections. IMPLICATIONS: Metoclopramide, rather than
      lidocaine pretreatment, may be a reasonable analgesic alternative to decrease
      pain from a diazepam injection, especially when there is a medical condition in
      which lidocaine should be used very cautiously.

PMID- 12401615
TI  - The analgesic effect of xenon on the formalin test in rats: a comparison with
      nitrous oxide.
AB  - To investigate the analgesic effects of xenon, we performed formalin tests in
      rats under 0.5 minimum alveolar anesthetic concentration xenon or nitrous oxide
      and stained the lumbar spinal cord for c-fos (n = 18) and the phosphorylated N
      methyl-D-aspartate (NMDA) receptor (n = 24) by using the avidin-biotin-peroxidase
      method. After 20 min of 79% xenon, 68% nitrous oxide, or 100% inhaled oxygen, 10%
      formalin (100 microL) was injected into the left rear paw of the animals except
      for a control group. Nociceptive behavior was observed for 1 h. The rats were
      killed 2 h after the formalin injection, and the lumbar spinal cord was stained
      for c-fos or the phosphorylated NMDA receptor immunohistochemically. Animals in
      the xenon and nitrous oxide groups showed less nociceptive behavior than did the
      oxygen group. Although the number of c-fos-positive cells in the lumbar spinal
      cord in the nitrous oxide group was not decreased, that in the xenon group
      decreased. The number of phosphorylated NMDA receptor-positive cells in the xenon
      group was significantly less than in the nitrous oxide and oxygen groups. Inhaled
      xenon suppressed nociceptive behaviors, c-fos expression, and activation of the
      NMDA receptor during the formalin test in rats. These results confirm that
      xenon's analgesic effects result from inhibition of the NMDA receptor.
      IMPLICATIONS: Inhaled xenon suppressed nociceptive behaviors, c-fos expression,
      and activation of the N-methyl-D-aspartate receptor during the formalin test in
      rats. Xenon's analgesic effect was speculated to result from the inhibition of
      the N-methyl-D-aspartate receptor in vivo.

PMID- 12401616
TI  - In vitro remifentanil metabolism: the effects of whole blood constituents and
      plasma butyrylcholinesterase.
AB  - We designed this in vitro study to determine whether the half-life of
      remifentanil was altered in butyrylcholinesterase-deficient patients. Test tubes
      containing Krebs buffered solution, whole blood, plasma, or red cells from both
      normal and butyrylcholinesterase-deficient patients were incubated with
      remifentanil. Remifentanil concentrations were determined by using gas
      chromatography and mean half-lives were calculated by using a nonlinear
      regression analysis. There were no differences in whole blood, red cells, or
      plasma half-life between normal and butyrylcholinesterase-deficient volunteers.
      In both normal and butyrylcholinesterase-deficient volunteers, whole blood and
      plasma had a significantly longer half-life than the red cell component.
      Extrapolation to the in vivo setting would suggest that a butyrylcholinesterase
      deficient patient should not have altered remifentanil kinetics. IMPLICATIONS:
      This was a test-tube-designed study to determine whether an enzyme deficiency
      (butyrylcholinesterase deficiency) changes the way remifentanil is metabolized.
      It seems that remifentanil dosage does not need to be changed in patients with
      butyrylcholinesterase deficiency.

PMID- 12401617
TI  - Analgesic effects of rofecoxib in ear-nose-throat surgery.
AB  - In this study we evaluated the analgesic efficacy and the opioid-sparing effect
      of rofecoxib in ear-nose-throat surgery patients. Patients undergoing nasal
      septal or sinus surgery were randomized to receive either oral placebo or
      rofecoxib 50 mg 1 h before surgery. All patients received propofol 0.8 mg/kg,
      fentanyl 1 microg/kg, and local anesthesia at the operative site. Sedation was
      maintained by a continuous infusion of propofol adjusted to maintain sedation at
      a 2-3 level on the Ramsey scale. Additional fentanyl 0.5-1 microg/kg was
      administered at the patient's request or if the verbal rating scale score was >4.
      Patient sedation and pain scores were obtained at 5, 15, 30 45, and 60 min during
      surgery and 30 min and 2, 4, 6, 12, and 24 h after completion of the procedure.
      During the postoperative period, diclofenac 75 mg IM was administered for
      analgesia at the patient's request or if the visual analog scale (VAS) rating for
      pain was more than 4. VAS pain scores, intraoperative fentanyl, and postoperative
      diclofenac requirements were significantly smaller in the rofecoxib group
      compared with the placebo group (P < 0.001). The times to first analgesic request
      were also significantly less in the rofecoxib group. We conclude that the
      preoperative administration of oral rofecoxib provided a significant analgesic
      benefit and decreased the need for opioids in patients undergoing nasal septal
      and nasal sinus surgery. IMPLICATIONS: The aim of this study was to evaluate the
      analgesic efficacy and opioid-sparing effect of rofecoxib, a new selective
      cyclooxygenase-2 inhibitor drug, in ear-nose-throat surgery patients.
      Preoperative administration of oral rofecoxib provided a significant analgesic
      benefit and decreased the need for opioids in patients undergoing nasal septal
      and nasal sinus surgery.

PMID- 12401618
TI  - A mathematical model of cell salvage efficiency.
AB  - Cell salvage (CS) is one of the modalities that can be used during surgery to
      decrease the use of allogeneic blood. Unlike acute normovolemic hemodilution, the
      efficiency of CS has not been mathematically modeled. In this article, we
      hypothesized that a mathematical model could predict the decline of hematocrit
      during CS. The model that was developed accounts for both the effect of
      decreasing the hematocrit because of blood loss and the effect of increasing
      hematocrit because of the readministration of washed blood in an isovolemic
      patient. The efficiency of CS is defined to be the maximum allowable blood loss
      (MABL) for a fixed blood volume and a fixed transfusion trigger. For
      demonstration purposes, variables used for a hypothetical patient included an
      estimated blood volume of 5000 mL, a presurgery hematocrit of 45%, and a
      transfusion trigger of 21%. The MABL in a typical case was 9600 mL, with a CS red
      cell recovery rate of 60%. Patient records from a convenience sample showed an
      average recovery rate of 57% with 20% variability. This mathematical model
      suggests that CS can be a highly effective blood conservation method when red
      blood cell collection is optimal. IMPLICATIONS: In this study, a mathematical
      model of cell salvage was developed. The model was then matched against real
      clinical cases to gain an understanding of the variables that modify cell salvage
      efficiency. The model illustrates that cell salvage can be a highly effective
      method of avoiding blood transfusion.

PMID- 12401619
TI  - The auditory steady-state response is not a suitable monitor of anesthesia.
AB  - Previous studies show that the human 40-Hz auditory steady-state response (ASSR)
      disappears on induction of general anesthesia, suggesting that it may be a good
      candidate for a monitor of anesthesia. In this study, we aimed to learn whether
      all normal alert adults display ASSRs with adequate signal-to-noise ratio. Clicks
      were presented at a series of frequencies between 35 and 70 Hz and
      electroencephalographic records taken at the vertex were Fourier transformed.
      ASSRs were observable as sharp peaks in the electroencephalograph spectrum at the
      frequency of the clicks. Initial results showed that a discernible ASSR could not
      be obtained from about half the subjects studied at any click frequency used.
      Further investigation revealed that in subjects whose ASSR was undetectable in
      the alert state, induction of a drowsy mental state resulted in appearance of an
      observable ASSR. This was attributable to an increase in signal in the drowsy
      state, not to a decrease in noise. We conclude that, because a significant
      proportion of subjects do not display easily recordable ASSRs when alert, it is
      not practical to use disappearance of the ASSR as a routine test for adequacy of
      anesthesia. IMPLICATIONS: Auditory steady-state responses (ASSRs) are brain waves
      evoked by auditory stimuli. Because they reportedly disappear under general
      anesthesia, they have been suggested as potential indicators of anesthetic depth.
      However, in this study, we show that about half our normal adult subjects did not
      produce measurable ASSRs when awake. This suggests that ASSRs are not good
      candidates for use in monitoring anesthetic depth during surgery.

PMID- 12401620
TI  - Narcotrend, bispectral index, and classical electroencephalogram variables during
      emergence from propofol/remifentanil anesthesia.
AB  - The aim of this study was to investigate modern and classical
      electroencephalographic (EEG) variables in response to remifentanil and propofol
      infusions. We hypothesized that modern EEG variables may indicate the effects of
      propofol but not of remifentanil. Twenty-five patients were included in the study
      after the end of elective spine surgery without any surgical stimulation.
      Baseline values were defined with remifentanil 0.3 microg. kg(-1). min(-1) and
      target-controlled infusion of propofol 3.0 microg/mL. EEG changes were evaluated
      1, 3, 5, 7, and 9 min after the stop of remifentanil infusion, followed by a step
      by-step reduction (0.2 microg/mL) every 3 min of target-controlled infusion
      propofol. Narcotrend (NT; classifying EEG stages from awake to deep anesthesia),
      bispectral index (BIS), EEG spectral frequency bands (%), 50% (Median) and 95%
      percentiles (spectral edge frequency), mean arterial blood pressure, heart rate,
      and oxygen saturation were detected at every time point. The end of remifentanil
      application resulted in significant increases in %alpha, spectral edge frequency,
      mean arterial blood pressure, and %theta and decreases in %delta (P < 0.05). NT,
      BIS, Median, heart rate, and oxygen saturation were unchanged. Decreases in
      propofol concentration were associated with statistically significant increases
      in NT and BIS (P < 0.05). Thus, the sedative-hypnotic component of propofol could
      be estimated by modern EEG variables (NT and BIS), whereas the analgesic
      component provided by remifentanil was not indicated. However, during conditions
      without surgical stimulation, neither NT nor BIS provided an adequate assessment
      of the depth of anesthesia when a remifentanil infusion was used. IMPLICATIONS:
      We investigated modern and classical electroencephalographic (EEG) variables
      during emergence from propofol/remifentanil anesthesia. Modern EEG variables
      indicate changes of infusion in propofol, but not in remifentanil. Thus, modern
      EEG variables did not provide an adequate assessment of depth of anesthesia when
      remifentanil was used.

PMID- 12401621
TI  - The delivery rate accuracy of portable infusion pumps used for continuous
      regional analgesia.
AB  - Portable pumps used for local anesthetic infusion during continuous regional
      analgesia are gaining acceptance. These pumps are often used for ambulatory
      patients who are medically unsupervised throughout most of the infusion. However,
      the performance of these pumps, which infuse potentially toxic medication, has
      not been independently investigated. We investigated the flow rate accuracy,
      consistency, and profiles of various portable pumps often used for local
      anesthetic infusion during continuous regional analgesia. By using a
      computer/scale combination within a laboratory to record infusion rates, 6 pumps
      were tested with their flow regulators at expected (30 degrees-32 degrees C) and
      increased (34 degrees-36 degrees C) temperatures. Infusion rate accuracy differed
      significantly among the pumps, exhibiting flow rates within +/-15% of their
      expected rate for 18%-100% of their infusion duration. An increase in temperature
      also affected pumps to differing degrees, with infusion rates increasing from 0%
      to 25% for each model tested. These results suggest that factors such as flow
      rate accuracy and consistency, infusion profile, and temperature sensitivity
      should be considered when choosing and using a portable infusion pump for local
      anesthetic administration. IMPLICATIONS: Portable pumps often used for local
      anesthetic infusion during continuous regional analgesia exhibit varying degrees
      of delivery rate accuracy and consistency. Furthermore, increases in temperature
      result in an increased infusion rate for various pumps investigated. These
      factors should be taken into consideration when choosing and using a portable
      infusion pump.

PMID- 12401622
TI  - Irritant contact dermatitis after use of Bispectral Index sensor in prone
      position.
AB  - IMPLICATIONS: Because the Bispectral Index monitor is placed on the forehead,
      skin reactions such as dermatitis have more than cosmetic implications for the
      physician and patient.

PMID- 12401623
TI  - The effect of guanethidine and local anesthetics on the electrically stimulated
      mouse vas deferens.
AB  - Complex regional pain syndrome is often treated with the sympatholytic
      guanethidine and a local anesthetic in a Bier's block. The efficacy of this
      treatment has been questioned. Because local anesthetics inhibit the
      norepinephrine uptake transporter, we hypothesized that this variable efficacy
      results from the local inhibiting the uptake of guanethidine. In this study, we
      tested this hypothesis by using a sympathetically innervated mouse vas deferens
      preparation. Organ bath-mounted mouse vasa deferentia were electrically
      stimulated in the absence and presence of guanethidine, prilocaine, procaine, and
      cocaine in various combinations. Prilocaine (1 mM) induced an immediate
      inhibition of twitch response (maximum 100% after 2 min) that fully reversed
      after washing. Guanethidine (3 microM) also inhibited twitching by 95% +/- 3% in
      15 min, but this effect was only partially reversed after 1 h of washing (33% +/-
      12% of control). When prilocaine and guanethidine were added in combination, a
      reversal of 80% +/- 13% (at 1 h) was observed. Procaine (300 micro M) produced a
      transient increase (152% +/- 14%) in response. When co-incubated with
      guanethidine (3 microM), the twitch was reduced to 24% +/- 4% of control and was
      reversed to 77% +/- 7% after 1 h. Cocaine (30 microM) inhibited the twitch
      response to 53% +/- 8%, which was fully reversed by 1 h of washing. When co
      incubated with guanethidine, the response was reduced to 39% +/- 6% of control
      and was reversed to 86% +/- 10% after 1 h. In all cases, the reversal produced by
      the combination was significantly more intense (P < 0.05) than that produced by
      guanethidine alone. Local anesthetics reduce the sympatholytic actions of
      guanethidine, and this may explain the variable efficacy of guanethidine in the
      treatment of complex regional pain syndrome. IMPLICATIONS: In this study, with a
      sympathetically innervated vas deferens preparation, local anesthetics reduced
      the efficacy of the sympatholytic guanethidine, questioning its co-administration
      in the pain clinic.

PMID- 12401624
TI  - A randomized, double-blinded comparison of thoracic epidural ropivacaine,
      ropivacaine/fentanyl, or bupivacaine/fentanyl for postthoracotomy analgesia.
AB  - Epidural ropivacaine has not been compared with bupivacaine for postthoracotomy
      analgesia. Eighty patients undergoing elective lung surgery were randomized in a
      double-blinded manner to receive one of three solutions for high thoracic
      epidural analgesia. A continuous epidural infusion of 0.1 mL. kg(-1). h(-1) of
      either 0.2% ropivacaine, 0.15% ropivacaine/fentanyl 5 micro g/mL, or 0.1%
      bupivacaine/fentanyl 5 micro g/mL was started at admission to the intensive care
      unit. We assessed pain scores (rest and spirometry), IV morphine consumption,
      spirometry, hand grip strength, PaCO(2), heart rate, blood pressure, respiratory
      rate, and side effects (sedation, nausea, vomiting, and pruritus) for 48 h.
      Thoracic epidural ropivacaine/fentanyl provided adequate pain relief similar to
      bupivacaine/fentanyl during the first 2 postoperative days after posterolateral
      thoracotomy. The use of plain 0.2% ropivacaine was associated with worse pain
      control during spirometry, larger consumption of IV morphine, and increased
      incidence of postoperative nausea and vomiting. Morphine requirements were larger
      in the ropivacaine group, with no differences between bupivacaine/fentanyl and
      ropivacaine/fentanyl groups. Patients in the ropivacaine group experienced more
      pain and performed worse in spirometry than patients who received epidural
      fentanyl. There was no significant difference in motor block. We conclude that
      epidural ropivacaine/fentanyl offers no clinical advantage compared with
      bupivacaine/fentanyl for postthoracotomy analgesia. IMPLICATIONS: Thoracic
      epidural ropivacaine/fentanyl provided adequate pain relief and similar analgesia
      to bupivacaine/fentanyl during the first 2 postoperative days after
      posterolateral thoracotomy. Plain 0.2% ropivacaine was associated with worse pain
      control and an increased incidence of postoperative nausea and vomiting. We
      conclude that epidural ropivacaine/fentanyl offers no clinical advantage compared
      with bupivacaine/fentanyl for postthoracotomy analgesia.

PMID- 12401625
TI  - Attenuation of pain in a randomized trial by suppression of peripheral
      nociceptive activity in the immediate postoperative period.
AB  - Peripheral neuronal barrage from tissue injury produces central nervous system
      changes that contribute to the maintenance of postoperative pain. The therapeutic
      approaches to blocking these central changes remain controversial, because
      previous studies have not differentiated presurgical interventions from those
      administered after tissue injury, yet before pain onset. In this study, we
      evaluated the relative contributions of blockade of nociceptive input during
      surgery or during the immediate postoperative period on pain suppression.
      Subjects were randomly allocated to one of four groups: preoperative 2%
      lidocaine, postoperative 0.5% bupivacaine, both, or placebo injections. General
      anesthesia was induced and third molars extracted. Pain was assessed over 4 h and
      at 24 and 48 h. The beta-endorphin in blood samples increased twofold during
      surgery, which is indicative of activation of the peripheral nociceptive barrage
      in response to painful stimuli. Pain was decreased in the immediate postoperative
      period in the bupivacaine groups, whereas it increased in the lidocaine group
      over time. Pain intensity was less 48 h after surgery in the groups whose
      postoperative pain was blocked by the administration of bupivacaine, but no
      effect was demonstrated for the preoperative administration of lidocaine alone.
      These results in the oral surgery pain model suggest that minimizing the
      peripheral nociceptive barrage during the immediate postoperative period
      decreases pain at later time periods. In contrast, blocking the intraoperative
      nociceptive barrage does not appear to contribute significantly to the subsequent
      reduction in pain. IMPLICATIONS: Suppression of postoperative pain immediately
      after surgery attenuates the pain experienced 1 to 2 days after surgery. These
      findings suggest that pain after minor surgery can be prevented by blocking the
      development of pain processes that amplify pain for days after surgery.

PMID- 12401626
TI  - Venous malformations associated with central pain: report of a case.
AB  - IMPLICATIONS: The authors describe an unusual case of central pain (CP) that
      resulted from giant venous hemangiomas. The patient was treated with a variety of
      medications, including the N-methyl-D-aspartate antagonist dextromethorphan. We
      report the first known association between venous malformations and CP and
      briefly describe why the use of dextromethorphan in this disorder requires
      further evaluation.

PMID- 12401627
TI  - Does an acute pain service improve postoperative outcome?

PMID- 12401628
TI  - Evaluating intraoperative therapeutic and diagnostic interventions.
AB  - A cost-conscious health care system requires detailed measures of its activities,
      including measurements of care provided to perioperative patients. Because there
      are no scoring systems that quantify the extent of intraoperative care
      interventions, we developed an intraoperative therapeutic intensity score (I
      TIS). Physiological/biochemical monitoring and therapeutic interventions were
      assigned one to four points on the basis of the resource utilization and/or
      intensity of care they each reflect. Scoring was performed on actual patients,
      and the results were compared with ASA classification and surgical complexity. A
      78-item scoring system was developed and assessed by using two patient groups.
      Group 1 (n = 307) entered the postanesthesia care unit (PACU) for short
      postoperative stays and had an I-TIS of 7.3 +/- 5.0; Group 2 patients (n = 443)
      were either admitted to the surgical, cardiothoracic, or neurosurgical intensive
      care units or had extended PACU stays, and they had an I-TIS of 25.2 +/- 12.4 (P
      < 0.001 versus Group 1). The correlation of I-TIS with the surgical complexity
      classification was r = 0.77, with ASA base relative value units was r(s) = 0.75,
      and with the ASA physical status classification was r(s) = 0.49. The score
      correlated well with surgical complexity and was able to differentiate between
      the intensity of care during various surgical procedures. IMPLICATIONS: A scoring
      system to quantify the extent of nonsurgical intraoperative care was developed.
      The scoring system was validated and correlated well with surgical complexity; it
      was able to differentiate between the intensity of care provided during various
      surgical procedures.

PMID- 12401629
TI  - Preoperative risk factors of intraoperative hypothermia in major surgery under
      general anesthesia.
AB  - Preoperative factors, such as age and body habitus, affect intraoperative
      hypothermia during general anesthesia. In a preliminary study, we developed a
      logistic model to retrospectively evaluate predictors of intraoperative
      hypothermia in patients who received major surgery. The following factors were
      selected to develop the model: Z = -15.014 + 0.097 x (Age) + 0.263 x (Height) -
      0.323 x (Weight) - 0.055 x (Preoperative systolic blood pressure) - 0.121 x
      (Preoperative heart rate). By using this model, the probability of hypothermia
      can be estimated by applying the following formula: Probability = 1/(1 + e(
      )(Z)). If an estimated probability of hypothermia was >0.5, the sensibility of
      prediction was 81.5% and the specificity was 83%. In the second study, the model
      was applied prospectively to other patients, and the validity of the logistic
      model was evaluated. The core temperature showed a significant decrease in
      patients with a probability >0.7, who were predicted to be hypothermic, and their
      thermoregulatory vasoconstriction threshold also showed a significant decrease,
      compared with the patients with a probability <==0.3, who were predicted to be
      normothermic. We concluded that intraoperative hypothermia could be predicted
      from preoperative characteristics such as age, height, weight, systolic blood
      pressure, and heart rate. IMPLICATIONS: Increases in age and height and decreases
      in weight systolic blood pressure and heart rate are major preoperative risk
      factors of intraoperative hypothermia during major surgery.

PMID- 12401630
TI  - Sevoflurane provides faster recovery and postoperative neurological assessment
      than isoflurane in long-duration neurosurgical cases.
AB  - Sevoflurane (SEVO) provides faster emergence than isoflurane (ISO). This
      advantage is thought to magnify with increased duration of exposure. In addition,
      SEVO has several of the characteristics of an ideal neuroanesthetic. We designed
      a prospective, randomized, double-blinded study to compare the recovery profile
      of SEVO versus ISO in neurosurgery. Sixty patients undergoing intracranial
      surgery were enrolled. They were randomized to receive SEVO or ISO in 40% oxygen
      as part of a balanced anesthetic regimen. The anesthetic concentration (0.5 to
      1.0 minimum alveolar anesthetic concentration [MAC]) was adjusted to maintain
      mean arterial blood pressure within 20% of the preinduction baseline. At the end
      of the surgery, neuromuscular blockade was reversed, anesthetics were
      discontinued without prior tapering, and fresh gas flow was increased to 10
      L/min. Recovery end-points were measured as the time from closure of the
      anesthetic vaporizer. Mean MAC-hours were identical in both groups (4.7).
      Patients in the SEVO group demonstrated a shorter time to emergence (P = 0.02)
      and for response to command (squeeze hand, P = 0.03; move feet, P = 0.01).
      Patients in the SEVO group obtained a Glasgow coma scale score of >/=10 5 min
      before patients in the ISO group (P = 0.04). Obtaining an early neurological
      examination can be critical in neurosurgical patients. The observed difference in
      emergence between SEVO and ISO could therefore be of clinical importance.
      IMPLICATIONS: The low-solubility anesthetic, sevoflurane, provides faster
      recovery and postoperative neurological assessment than isoflurane after long
      duration (4.7 MAC-h) intracranial surgery.

PMID- 12401631
TI  - The effect of gamma-aminobutyric acid (GABA) receptor drugs on morphine-induced
      spastic paraparesis after a noninjurious interval of spinal cord ischemia in
      rats.
AB  - We have previously demonstrated that intrathecal morphine given after a
      noninjurious interval of spinal cord ischemia induced transient spastic
      paraparesis in a rodent model. However, the mechanism of this paraparesis is
      unknown. We hypothesized that morphine inhibits gamma-aminobutyric acid
      (GABA)ergic interneurons that control the tonus of spinal cord alpha-motoneurons
      and that inhibition of spinal cord interneurons may cause spastic paraparesis. In
      this study, we investigate interactions between morphine and GABAergic agonists
      or antagonists on motor function after spinal cord ischemia and then clarified
      the mechanism of the spastic paraparesis induced by intrathecal morphine. Spinal
      cord ischemia was induced by aortic occlusion lasting 6 min. We first determined
      whether intrathecally administered GABA agonists (muscimol or baclofen) improve
      the spastic paraparesis in this model. GABA agonists did not improve the
      paraparesis. Next, we examined the effect of GABA antagonists (bicuculline or 5
      aminovaleric acid) and determined the interaction between morphine and GABA
      antagonists. In an isobolographic analysis, the 50% effective dose decreased
      below the theoretical additive line, indicating a synergistic interaction between
      morphine and GABA antagonists. These results indicate that the spastic
      paraparesis induced by intrathecal morphine may be mediated in part by GABA
      receptors. IMPLICATIONS: The purpose of this study was to investigate
      interactions between morphine and GABAergic agonists or antagonists on motor
      function after spinal cord ischemia and then clarify the mechanism of the spastic
      paraparesis induced by intrathecal morphine. The spastic paraparesis induced by
      intrathecal morphine may be mediated in part by GABA receptors.

PMID- 12401632
TI  - A randomized, double-blinded trial of subarachnoid bupivacaine and fentanyl, with
      or without clonidine, for combined spinal/epidural analgesia during labor.
AB  - Subarachnoid clonidine may increase the duration of spinal opioid and local
      anesthetic analgesia during labor, but it may also increase hypotension and
      sedation, and the therapeutic range is unclear. We studied 110 term parturients
      of mixed parity having combined spinal/epidural analgesia during labor in this
      randomized, double-blinded trial. All received subarachnoid fentanyl 20 micro g
      and bupivacaine 2.5 mg, plus either saline or clonidine (15, 30, or 45 micro g).
      Of 101 per-protocol parturients (n = 25, 24, 26, and 26 in Groups C0, C15, C30,
      and C45, respectively), 22 delivered before the cessation of spinal analgesia.
      Group demographics and pain scores from Time 0 to 120 min were similar. There was
      no significant difference among groups in the duration of spinal analgesia (P =
      0.09) or in the duration of clonidine groups combined compared with control
      (median, 120 min [interquartile range, 96-139 min] versus 98 min [80-120 min]; P
      = 0.07). Systolic blood pressure was significantly lower in all clonidine groups
      between 40 and 90 min (P = 0.001). Hypotension (P = 0.05) and the requirement for
      ephedrine (P = 0.02) were dose dependent, but groups had a similar incidence of
      hypotension. The addition of clonidine 15-45 micro g to subarachnoid fentanyl and
      bupivacaine reduced blood pressure and did not significantly increase the
      duration of spinal analgesia. IMPLICATIONS: The addition of 15-45 micro g of
      clonidine to subarachnoid fentanyl plus bupivacaine did not significantly
      increase the duration of spinal analgesia but did decrease maternal blood
      pressure. The results of this study do not support the use of subarachnoid
      clonidine to prolong the action of spinal labor analgesia when fentanyl plus
      bupivacaine are administered.

PMID- 12401633
TI  - The effect of the addition of epinephrine on early systemic absorption of
      epidural ropivacaine in humans.
AB  - The addition of epinephrine to ropivacaine has not been recommended because
      ropivacaine has intrinsic vasoconstrictor properties. However, few
      pharmacokinetic data are available on the addition of epinephrine to epidural
      ropivacaine in humans. In this prospective, double-blinded study, we randomized
      patients having elective abdominal hysterectomy to receive epidural ropivacaine
      1.5 mg/kg, diluted in 15 mL, either with (epinephrine group, n = 12) or without
      (plain group, n = 12) epinephrine 5 microg/mL and then measured arterial and
      venous plasma concentrations of ropivacaine at intervals up to 180 min. We found
      that arterial and venous plasma ropivacaine concentrations were smaller in the
      epinephrine group compared with the plain group in the first 60 min after the
      drug administration (P < 0.01). Mean (+/- SD) maximum total plasma ropivacaine
      concentration was smaller in the epinephrine group (arterial, 0.92 +/- 0.32
      microg/mL; venous, 0.82 +/- 0.33 microg/mL) compared with the plain group (1.31
      +/- 0.39 microg/mL and 1.31 +/- 0.50 microg/mL, respectively; P = 0.01). Time to
      maximum total plasma ropivacaine concentration was not significantly different
      between groups (mean +/- SD; arterial, 16 +/- 2 min; venous, 23 +/- 2 min in the
      epinephrine group versus 9 +/- 2 min and 12 +/- 3 min, respectively, in the plain
      group; P = 0.08). Arterial plasma ropivacaine concentrations were larger than
      venous concentrations during the first hour (P < 0.01); the arterio-venous
      difference decreased exponentially, and the rate and magnitude of this decrease
      was unaffected by epinephrine. We conclude that the addition of epinephrine 5
      microg/mL to ropivacaine reduced the early systemic plasma concentrations of
      ropivacaine after epidural injection and may be useful for decreasing the risk of
      toxicity from systemic absorption of epidural ropivacaine. IMPLICATIONS: The
      addition of epinephrine 5 microg/mL to epidural ropivacaine reduced the systemic
      arterial and venous plasma concentrations of ropivacaine in the first hour and
      the maximum plasma concentration of ropivacaine. Epinephrine may be a useful
      additive for reducing the risk of systemic toxicity when large doses of
      ropivacaine are given epidurally.

PMID- 12401634
TI  - Does the choice of electrocardiography lead affect the efficacy of the T-wave
      criterion for detecting intravascular injection of an epinephrine test dose?
AB  - Accidental intravascular injection of an epinephrine-containing test dose
      decreases the T-wave amplitude of a Lead II electrocardiogram (EKG) with 100%
      sensitivity and specificity on the basis of the T-wave criterion (positive if
      there is a > or =25% decrease in amplitude). We designed this study to test
      whether the choice of EKG lead would affect the efficacy of the simulated
      intravascular test dose in anesthetized patients. After an 8-h fast and no
      premedication, 35 healthy patients were anesthetized with end-tidal 2%
      sevoflurane and nitrous oxide after endotracheal intubation. When hemodynamic
      stability was obtained, all subjects received 3 mL of normal saline IV, followed
      4 min later by 1.5% lidocaine 3 mL plus 15 microg of epinephrine (1:200,000) IV.
      Heart rate, systolic blood pressure, Leads II (n = 35) and V(5) (n = 35), and
      either Lead I (n = 17) or III (n = 18), whichever had the greater T-wave
      amplitude, were continuously recorded for 4 min after the saline and test-dose
      injections. An IV test dose produced significant increases in heart rate and
      systolic blood pressure and produced decreases in the T-wave amplitude of all EKG
      leads studied in all subjects, whereas IV saline elicited no changes in these
      variables. The maximum percentage decreases in T-wave amplitude of Leads II, I,
      III, and V(5) were -87% +/- 13%, -88% +/- 8%, -94% +/- 15%, and -86% +/- 16%,
      respectively (mean +/- SD; P > 0.05). There was no significant difference in
      temporal changes in T-wave amplitude among the 4 leads, and sensitivity and
      specificity were 100% on the basis of the T-wave criterion, irrespective of the
      lead examined. Our results indicate that Leads II, I, III, and V(5) of the EKG
      are equally effective for detecting intravascular injection of the epinephrine
      containing test dose in sevoflurane-anesthetized adults. IMPLICATIONS: To
      determine whether an epidural catheter is in a blood vessel, an epidural test
      dose containing 15 microg of epinephrine is used. We found that decreases in the
      T-wave amplitude of Leads I, II, III, and V(5) of the electrocardiogram were
      equally sensitive and specific for detecting intravascular injection of the test
      dose in sevoflurane-anesthetized adult patients.

PMID- 12401635
TI  - Isoflurane dosage for equivalent intraoperative electroencephalographic
      suppression in patients with and without epidural blockade.
AB  - We conducted a prospective, randomized, controlled trial to establish the effect
      of epidural blockade on isoflurane requirements for equivalent intraoperative
      electroencephalographic (EEG) suppression. Fifty patients undergoing abdominal
      hysterectomy received combined epidural and general anesthesia or general
      anesthesia alone with isoflurane and alfentanil. Isoflurane was administered by
      computer-controlled closed-loop feedback to maintain an EEG 95% spectral edge
      frequency of 17.5 Hz, a target chosen on the basis of a pilot study. In epidural
      patients, end-tidal isoflurane concentration (FE'(ISO)) was 0.19% smaller (95%
      confidence interval [CI], -0.32% to -0.06%; P < 0.01), mean arterial blood
      pressure was 17 mm Hg lower (95% CI, -24 to -9 mm Hg; P < 0.0001), and body
      temperature was 0.4 degrees C lower (95% CI, -0.7 to 0 degrees C; P < 0.05) than
      in controls. EEG bispectral index (BIS) was 4 points higher (95% CI, 1 to 7; P <
      0.05). EEG median frequency and heart rate were similar in both groups. Epidural
      patients were 76% more likely (95% CI, 58% to 94%; P < 0.001) to require
      metaraminol for hypotension and were 28% more likely (95% CI, 3% to 53%; P <
      0.05) to require glycopyrrolate for bradycardia. After surgery, the time to eye
      opening in epidural patients was 2.3 min shorter (95% CI, -4.2 to -0.5 min; P <
      0.05). Time to eye opening correlated better with FE'(ISO) in the last 30 s of
      anesthesia (FE'(ISO) = 0.07 x time to eye opening + 0.31; r(2) = 0.59; P <
      0.0001) than with BIS from the same period (BIS = 64 - 1.25 x time to eye
      opening; r(2) = 0.22; P < 0.001) (P < 0.0001). To maintain similar intraoperative
      spectral edge frequency, patients receiving combined epidural and general
      anesthesia require 21% less isoflurane than those receiving general anesthesia
      alone. This smaller isoflurane dose is associated with faster emergence from
      anesthesia. IMPLICATIONS: The dose of general anesthetic required to maintain
      similar intraoperative suppression of brain electrical activity is 21% less in
      patients with nerve blockade than in those without. This dose reduction results
      in faster waking times in patients with nerve blockade, which may reflect lighter
      intraoperative anesthesia. The dose of general anesthetic required to maintain
      similar intraoperative suppression of brain electrical activity is 21% less in
      patients with nerve blockade than in those without. This dose reduction results
      in faster waking times in patients with nerve blockade, which may reflect lighter
      intraoperative anesthesia.

PMID- 12401636
TI  - Intravenous regional anesthesia using prilocaine and neostigmine.
AB  - Neostigmine has been added to local anesthetics for central and peripheral nerve
      blocks resulting in prolonged, increased anesthesia and improved analgesia. We
      conducted this study to evaluate the effects of neostigmine when added to
      prilocaine for IV regional anesthesia (IVRA). Thirty patients undergoing hand
      surgery were randomly assigned to two groups to receive IVRA. The control group
      received 1 mL of saline plus 3 mg/kg of prilocaine diluted with saline to a total
      dose of 40 mL; the study group received 0.5 mg of neostigmine plus 3 mg/kg of
      prilocaine diluted with saline to a total dose of 40 mL. Sensory and motor block
      onset and recovery, anesthesia quality determined by an anesthesiologist,
      anesthesia quality determined by a surgeon, and dryness of the operative field
      were noted. Heart rate, mean arterial blood pressure, and oxygen saturation
      values were noted at 1, 5, 10, 20, and 40 min before surgery and after tourniquet
      release. Time to first analgesic requirement was also noted. Shortened sensory
      and motor block onset times, prolonged sensory and motor block recovery times,
      improved quality of anesthesia, and prolonged time to first analgesic requirement
      were found in the neostigmine group. We conclude that neostigmine as an adjunct
      to prilocaine improves quality of anesthesia and is beneficial in IVRA.
      IMPLICATIONS: Neostigmine has been added to local anesthetics for central and
      peripheral nerve blocks. This study was conducted to evaluate the effects of
      neostigmine when added to prilocaine for IV regional anesthesia (IVRA).
      Neostigmine as an adjunct to prilocaine improves quality of anesthesia and is
      beneficial in IVRA.

PMID- 12401637
TI  - A new teaching model for resident training in regional anesthesia.
AB  - The adequacy of resident education in regional anesthesia is of national concern.
      A teaching model to improve resident training in regional anesthesia was
      instituted in the Anesthesiology Residency in 1996 at Duke University Health
      System. The key feature of the model was the use of a CA-3 resident in the
      preoperative area to perform regional anesthesia techniques. We assessed the
      success of the new model by comparing the data supplied by the Anesthesiology
      Residency to the Residency Review Committee for Anesthesiology for the training
      period July 1992-June 1995 (pre-model) and the training period July 1998-June
      2001 (post-model). During the 3-yr training period, the pre-model CA-3 residents
      (n = 12) performed a cumulative total of 80 (58-105) peripheral nerve blocks
      (PNBs), 66 (59-74) spinal anesthetics, and 133 (127-142) epidural anesthetics.
      The CA-3 post-model residents (n = 10) performed 350 (237-408) PNBs, 107 (92-123)
      spinal anesthetics, and 233 (221-241) epidural anesthetics (P < 0.0001). All
      results are reported as median (interquartile range). We conclude that our new
      teaching model using our CA-3 residents as block residents in the preoperative
      area has increased their clinical exposure to PNBs. IMPLICATIONS: Inadequate
      exposure to peripheral nerve blocks has been a national problem. A teaching model
      instituted at Duke University Health System has resulted in a fourfold increase
      in exposure to peripheral nerve blocks compared with the national averages.

PMID- 12401638
TI  - Lumbar plexus posterior approach: a catheter placement description using
      electrical nerve stimulation.
AB  - IMPLICATIONS: The authors describe a modified technique of posterior approach to
      the lumbar plexus in the psoas compartment which allows nerve stimulation for the
      location of the plexus and catheter placement for extended-duration surgery and
      postoperative patient-controlled regional analgesia. A frequent incidence of
      total lumbar plexus block was observed.

PMID- 12401639
TI  - Nasotracheal intubation: a simple and effective technique to reduce
      nasopharyngeal trauma and tube contamination.
AB  - Our hypothesis was that nasopharyngeal passage of an endotracheal tube can be
      facilitated by a nasopharyngeal airway (Wendl tube) acting as a "pathfinder."
      Accordingly, we performed a randomized, controlled trial with blinded assessment
      of nasopharyngeal bleeding and contamination of the tip of the endotracheal tube.
      After the induction of anesthesia, a Wendl tube (28 Ch) was inserted into the
      more patent nostril. In the control group (n = 30), the Wendl tube was retrieved
      before nasopharyngeal passage was attempted with an endotracheal tube (inner
      diameter, 7.0 mm). In the intervention group (n = 30), the Wendl tube was kept in
      position and only its adjustable flange was removed. Then, we inserted the tip of
      the endotracheal tube into the trailing end of the Wendl tube. Subsequently, the
      endotracheal tube was advanced under visual control to the oropharynx guided by
      the Wendl tube. After the endotracheal tube was positioned in the oropharynx, the
      Wendl tube was removed and intubation completed. Six hours after surgery, we
      determined the patients' nasal pain. The "pathfinder" technique reduced the
      incidence (P < 0.001) and severity (P = 0.001) of bleeding, decreased tube
      contamination with blood and mucus (P < 0.001), and diminished postoperative
      nasal pain (P = 0.036). IMPLICATIONS: Nasopharyngeal passage of an endotracheal
      tube can be facilitated by a flexible Wendl tube (nasopharyngeal airway) covering
      and guiding the rigid tube tip. This technique is helpful in reducing the
      incidence and severity of nosebleeds and in minimizing contamination of the tip
      of the endotracheal tube with blood and mucus.

PMID- 12401640
TI  - The reliability of the Bellhouse test for evaluating extension capacity of the
      occipitoatlantoaxial complex.
AB  - We examined the reliability of an airway evaluation test to assess the
      occipitoatlantoaxial (OAA) extension capacity described by Bellhouse et al.
      (Bellhouse test) in 20 adult volunteers with normal cervical spines. Each subject
      sat upright with the head in the neutral position and was then asked to extend
      the head maximally while attempting to move the neck as little as possible. The
      angle from the neutral position to the extreme extension was measured using the
      goggle-goniometer. Lateral cervical radiographs were taken in these positions,
      and the OAA extension angle was radiographically measured. Median values for OAA
      extension measured radiographically and extension of the head measured with the
      Bellhouse test were 21.5 degrees and 30 degrees, respectively. Extension of 9.5
      degrees occurred at the subaxial regions, which could not be detected by
      inspecting surface contours of the neck. The extent of the subaxial extension was
      almost consistent with the degree of overestimation of the OAA extension capacity
      by the Bellhouse test. Because the subaxial extension occurred independent of the
      degree of the OAA extension, a strong relationship between the angle measured
      with the goggle-goniometer and the OAA extension angle measured radiographically
      was not established (P < 0.01, r(2) = 0.44). These findings mean that the test is
      not always accurate to evaluate the OAA extension capacity and will fail to
      detect a reduction of the OAA extension capacity if the subaxial regions are
      normal. Therefore, these problems derived from the Bellhouse test offer a
      potential for missing a prediction of difficult tracheal intubations because
      reduced OAA extension is one of the important factors that make intubation
      difficult. IMPLICATIONS: The Bellhouse test was not always accurate to evaluate
      the actual occipitoatlantoaxial extension capacity because of the inevitable
      occurrence of the subaxial extension. This may mean that some difficult
      endotracheal intubations will be unpredictable.

PMID- 12401641
TI  - Prevention of nausea and vomiting with tandospirone in adults after
      tympanoplasty.
AB  - We have hypothesized that the 5-hydroxytrypta-mine-1A receptor agonist
      tandospirone reduces postoperative nausea and vomiting (PONV). In a double
      blinded, randomized design, 3 groups of 30 patients each received 1 of the
      following oral medications 90 min before arrival in the operating room, together
      with famotidine 20 mg: 1) placebo (P group), 2) tandospirone 10 mg (T10 group),
      or 3) tandospirone 30 mg (T30 group). Standard anesthetic regimens and techniques
      were applied for all patients. All episodes of PONV were recorded during the
      following time intervals: 0-3 h and 3-24 h after the end of general anesthesia.
      The incidence of a complete response, defined as no PONV and no need for other
      rescue antiemetics, was significantly more frequent in the T30 group than in the
      P group during 0-24 h (P = 0.019), especially during 3-24 h (P = 0.007) after
      general anesthesia. In conclusion, premedication with oral tandospirone is
      effective against PONV in patients undergoing tympanoplasty under general
      anesthesia. IMPLICATIONS: Oral tandospirone reduced the incidence of
      postoperative nausea and vomiting without significant adverse effects in adults
      undergoing tympanoplasty under general anesthesia.

PMID- 12401642
TI  - Physiological and psychological influences on postoperative fatigue.
AB  - Fatigue is common after major surgery and delays recovery. We studied the role of
      physiological and psychological factors in determining fatigue and physical well
      being after surgery in 102 patients undergoing primary hip arthroplasty. Self
      administered questionnaires were used to measure the intensity of feelings of
      fatigue, vigor, depression, and subjective physical well being on the day before
      surgery, on the third and seventh postoperative days, and 1 and 6 mo after
      surgery. The physiological response to surgery was determined by sequential
      measurements of circulating norepinephrine, epinephrine, cortisol, interleukin-6,
      and C-reactive protein during the 7 days after surgery. The peak value of each
      variable was used for statistical analysis. Physical well being decreased
      significantly at 3 and 7 days but increased significantly at 1 and 6 mo. Fatigue
      decreased significantly at 1 and 6 mo. Multiple regression analysis showed that
      the main predictor of worse physical well being at 3 days was the size of the C
      reactive protein response. Subsequently, the main predictor was the level of
      preoperative well being. The severity of fatigue and vigor after surgery were
      predicted mostly by the preoperative levels of the respective variable. We
      conclude that fatigue after hip arthroplasty was not predicted by physiological
      variables but was largely predicted by preoperative levels of fatigue.
      IMPLICATIONS: Fatigue is common after major surgery and delays recovery. It is
      usually attributed to the physiological response to surgery. We studied patients
      undergoing hip arthroplasty and found that the severity of postoperative fatigue
      was not predicted by physiological changes. Instead, it was predicted by the
      preoperative level of fatigue.

PMID- 12401643
TI  - Lateral medullary syndrome after prone position for general surgery.
AB  - IMPLICATIONS: We describe postoperative lateral medullary syndrome with myoclonic
      spasm. Improper head rotation during positioning in the anesthetized patient
      might obstruct the flow of the vertebral artery at the neck and result in
      diminished perfusion of the associated regions in patients with a history of
      cervical spinal trauma.

PMID- 12401644
TI  - The upside-down intubating laryngeal mask airway: a technique for cases of fixed
      flexed neck deformity.
AB  - IMPLICATIONS: When the neck is fixed in extreme flexion, access to the windpipe
      becomes very difficult. The intubating laryngeal mask airway (ILMA) appears
      unsuitable for guiding the breathing tube into the windpipe in such cases because
      of its rigid, preformed shape. However, the ILMA introduced upside down may
      provide the answer, even if the mouth opening is smaller than normal.

PMID- 12401645
TI  - Propofol, nitrous oxide, and jugular bulb oxygen saturation.

PMID- 12401646
TI  - The potency of new muscle relaxants on recombinant muscle-type acetylcholine
      receptors.

PMID- 12401647
TI  - The effect of clonidine on peribulbar block.

PMID- 12401648
TI  - A rapid infusion system using a three-way stopcock with two no-return valves.

PMID- 12401649
TI  - Optimizing the benefits of outpatient preoperative anesthesia evaluation.

PMID- 12401650
TI  - Diagnosis of acute glaucoma in the postoperative period.

PMID- 12401651
TI  - A single lobal inflation technique using bronchofiberoptic jet ventilation during
      video-assisted thoracoscopic surgery for bullae.

PMID- 12401652
TI  - Assessing drug effects on cerebral autoregulation using the static rate of
      autoregulation.

PMID- 12401653
TI  - Supplemental oxygen versus latent alcohol vapors as surgical fire precursors.

PMID- 12401654
TI  - A case of frozen succinylcholine encountered during emergency Cesarean delivery.

PMID- 12401655
TI  - Venous air embolism during changes in patient position or ventilation: an
      etiology for postoperative cardiovascular collapse?

PMID- 12401656
TI  - Droperidol-treated PONV and bilateral mandibular fracture after maxillofacial
      surgery.

PMID- 12401657
TI  - Postoperative bleeding after coronary artery bypass surgery with cardiopulmonary
      bypass.

PMID- 12401658
TI  - Gastric cancer: staging and surgery.

PMID- 12401660
TI  - Therapy of localized gastric cancer: preoperative and postoperative approaches.

PMID- 12401661
TI  - New drugs for treatment of gastric cancer.

PMID- 12401662
TI  - An update of new targets for cancer treatment: vessels and matrix.

PMID- 12401663
TI  - An update of new targets for cancer treatment: receptor-mediated signals.

PMID- 12401664
TI  - Cell cycle regulators: role in etiology, prognosis and treatment in cancer.

PMID- 12401665
TI  - New developments and treatment in multiple myeloma: new insights on molecular
      biology.

PMID- 12401666
TI  - High-dose therapy in multiple myeloma.

PMID- 12401667
TI  - New developments and treatment in multiple myeloma: new drugs in the treatment of
      multiple myeloma.

PMID- 12401668
TI  - Endocrine therapy of breast cancer.

PMID- 12401669
TI  - New directions in hormone therapy for metastatic breast cancer.

PMID- 12401670
TI  - Hormonal replacement therapy in breast cancer.

PMID- 12401671
TI  - Management of early prostate cancer.

PMID- 12401672
TI  - Prostate cancer: management of advanced disease.

PMID- 12401673
TI  - Treatment options in hormone resistant prostate cancer.

PMID- 12401674
TI  - The clinical impact of the Human Genome Project: inherited variants in cancer
      care.

PMID- 12401676
TI  - The impact of chip technology on cancer medicine.

PMID- 12401677
TI  - The impact of genomic and proteomic technologies on the development of new cancer
      drugs.

PMID- 12401678
TI  - Evaluation of response: new and standard criteria.

PMID- 12401679
TI  - Designing randomised trials: both large and small trials are needed.

PMID- 12401680
TI  - Novel endpoints and design of early clinical trials.

PMID- 12401681
TI  - Epidemiology and etiology of Hodgkin's lymphoma.

PMID- 12401682
TI  - Primary treatment of Hodgkin's disease.

PMID- 12401683
TI  - Hodgkin's disease: treatment of relapsed disease.

PMID- 12401684
TI  - Psycho-oncology and cancer: psychoneuroimmunology and cancer.

PMID- 12401685
TI  - Psycho-oncology and cancer: linking psychosocial factors with cancer development.

PMID- 12401687
TI  - Improving the recognition of concerns and affective disorders in cancer patients.

PMID- 12401688
TI  - Cancer screening for medical oncologists: definitions and aims.

PMID- 12401689
TI  - Current situation of screening for cancer.

PMID- 12401690
TI  - Cancer screening for medical oncologists: importance of quality control and
      audit.

PMID- 12401691
TI  - Progress in the treatment of breast cancer in the elderly.

PMID- 12401693
TI  - Advances in the treatment of non-Hodgkin's lymphoma.

PMID- 12401694
TI  - Pleura mesothelioma: combined modality treatments.

PMID- 12401695
TI  - The value of positron emission tomography (PET) imaging in disease staging and
      therapy assessment.

PMID- 12401696
TI  - Molecular and biochemical markers in colorectal cancer.

PMID- 12401697
TI  - Interventional palliative treatment options for lung cancer.

PMID- 12401698
TI  - Optimal staging and treatment of localised rectal cancer.

PMID- 12401699
TI  - Palliative care in hospital, hospice, at home: results from a systematic review.

PMID- 12401700
TI  - Extragonadal germ cell tumors.

PMID- 12401701
TI  - Neo-adjuvant and adjuvant chemotherapy of bladder cancer: Is there a role?

PMID- 12401702
TI  - The role of mini-allotransplants in the treatment of solid tumors.

PMID- 12401703
TI  - Gastrointestinal stromal tumours (GIST): biology and treatment.

PMID- 12401704
TI  - While tinkering with the beta-cell...metabolic regulatory mechanisms and new
      therapeutic strategies: American Diabetes Association Lilly Lecture, 2001.
AB  - A common feature of the two major forms of human diabetes is the partial or
      complete loss of insulin secretion from beta-cells in the pancreatic islets of
      Langerhans. In this article, we review the development of a set of tools for
      studying beta-cell biology and their application to understanding of fuel
      mediated insulin secretion and enhancement of beta-cell survival. Insights into
      these basic issues are likely to be useful for the design of new drug and cell
      based diabetes therapies.

PMID- 12401705
TI  - Effects of insulin deficiency or excess on hepatic gluconeogenic flux during
      glycogenolytic inhibition in the conscious dog.
AB  - The direct acute effects of insulin on the regulation of hepatic gluconeogenic
      flux to glucose-6-phosphate (G6P) in vivo may be masked by the hormone's effects
      on net hepatic glycogenolytic flux and the resulting changes in glycolysis. To
      investigate this possibility, we used a glycogen phosphorylase inhibitor (BAY
      R3401) to inhibit glycogen breakdown in the overnight-fasted dog, and the effects
      of complete insulin deficiency or a fourfold rise in the plasma insulin level
      were assessed during a 5-h experimental period. Hormone levels were controlled
      using somatostatin with portal insulin and glucagon infusion. After the control
      period, plasma insulin infusion 1) was discontinued, creating insulin deficiency;
      2) increased fourfold; or 3) was continued at the basal rate. During insulin
      deficiency, glucose production and the plasma level and net hepatic uptake of
      nonesterified free fatty acids increased, whereas during hyperinsulinemia they
      decreased. Net hepatic lactate uptake increased sixfold during insulin deficiency
      and 2.5-fold during hyperinsulinemia. Net hepatic gluconeogenic flux increased
      more than fourfold during insulin deficiency but was not reduced by
      hyperinsulinemia. We conclude that in the absence of appreciable glycogen
      breakdown, an acute gluconeogenic effect of hypoinsulinemia becomes manifest,
      whereas inhibition of the process by a physiologic rise in insulin was not
      evident.

PMID- 12401706
TI  - Altered myocellular and abdominal fat partitioning predict disturbance in insulin
      action in HIV protease inhibitor-related lipodystrophy.
AB  - HIV protease inhibitor-related lipodystrophy is characterized by peripheral fat
      loss, hyperlipidemia, and insulin resistance. Increased availability of lipid to
      muscle may be one of the mechanisms that induce insulin resistance. Regional fat,
      intramyocellular lipid (by (1)H-magnetic resonance spectroscopy), serum lipids,
      and insulin-stimulated glucose disposal (by hyperinsulinemic-euglycemic clamp)
      were quantified in 10 men who had HIV-1 infection with moderate to severe
      lipodystrophy and a control group of 10 nonlipodystrophic men who had HIV-1
      infection and were naive to protease inhibitors to examine the effects of
      lipodystrophy on glucose and lipid metabolism. Lipodystrophic subjects showed
      lower insulin-stimulated glucose disposal than control subjects (P = 0.001) and
      had increased serum triglycerides (P = 0.03), less limb fat (P = 0.02), increased
      visceral fat as a proportion of total abdominal fat (P = 0.003), and increased
      intramyocellular lipid (1.90 +/- 0.15 vs. 1.23 +/- 0.16% of water resonance peak
      area; P = 0.007). In both groups combined, visceral fat related strongly to
      intramyocellular lipid (r = 0.83, P < 0.0001) and intramyocellular lipid related
      negatively to insulin-stimulated glucose disposal (r = -0.71, P = 0.0005).
      Fasting serum cholesterol and triglycerides related positively to
      intramyocellular lipid and visceral fat in lipodystrophic subjects only. The data
      indicate that lipodystrophy is associated with increased lipid content in muscle
      accompanying impaired insulin action. The results do not establish causation but
      emphasize the interrelationships among visceral fat, myocyte lipid, and insulin
      action.

PMID- 12401707
TI  - Impact of duration of infusion and choice of isotope label on isotope recycling
      in glucose homeostasis.
AB  - The purposes of this study were to quantify the impact of the duration of
      infusion and choice of stable isotope of glucose on measures of glucose rate of
      appearance (glucose R(a)) and to determine whether the differences observed were
      due to tracer recycling via the glycogen pool (direct pathway) or gluconeogenesis
      (indirect pathway). Six healthy adult volunteers were studied on four occasions
      in the postabsorptive state during infusions of [1-(13)C]glucose and [6,6
      (2)H(2)]glucose: 2.5-h infusion of both (A), and 2.5-h infusion of one (B) and
      14.5-h infusion of the other isotope (C), and 5-h infusion of [6,6
      (2)H(2)]glucose and 2.5-h infusion of [1-(13)C]glucose (D). Infusion of both
      isotopes for 2.5 h resulted in similar glucose R(a) values. When compared with a
      14.5-h infusion, the 2.5-h glucose tracer infusion overestimated glucose R(a) by
      26-35%. Glucose (13)C recycled via the Cori cycle, resulting in slower decay from
      the plasma pool and longer half-life of [1-(13)C]glucose compared with [6,6
      (2)H(2)]glucose. There was no detectable release of [(13)C]glucose or
      [(2)H(2)]glucose tracer into the plasma pool after administration of glucagon.
      These data demonstrate that glucose R(a) varies not as a result of isotope
      cycling but as a result of differences in duration of isotope infusion regardless
      of the isotope used. This is most likely due to incomplete isotope and substrate
      equilibration with the 2.5-h infusion. The potential error was reduced by nearly
      80% using a 5-h infusion of [6,6-(2)H(2)]glucose. These studies demonstrate that
      the duration of isotope infusion has significantly greater impact on quantitation
      of glucose R(a) than does the selection of isotope.

PMID- 12401708
TI  - Profiling gene transcription in vivo reveals adipose tissue as an immediate
      target of tumor necrosis factor-alpha: implications for insulin resistance.
AB  - Despite extensive studies implicating tumor necrosis factor (TNF)-alpha as a
      contributing cause of insulin resistance, the mechanism(s) by which TNF-alpha
      alters energy metabolism in vivo and the tissue specificity of TNF-alpha action
      are unclear. Here, we investigated the effects of TNF-alpha infusion on gene
      expression and energy metabolism in adult rats. A 1-day TNF-alpha treatment
      decreased overall insulin sensitivity and caused a 70% increase (P = 0.005) in
      plasma levels of free fatty acids (FFAs) and a 46% decrease (P = 0.01) in ACRP30.
      A 4-day TNF-alpha infusion caused insulin resistance and significant elevation of
      plasma levels of FFAs and triglycerides and reduction of ACRP30. Plasma glucose
      concentration was not altered following TNF-alpha infusion for up to 4 days. As
      revealed by oligonucleotide microarrays, TNF-alpha evoked major and rapid changes
      in adipocyte gene expression, favoring FFA release and cytokine production, and
      fewer changes in liver gene expression, but favoring FFA and cholesterol
      synthesis and VLDL production. There was only a moderate repressive effect on
      skeletal muscle gene expression. We demonstrate that TNF-alpha antagonizes the
      actions of insulin, at least in part, through regulation of adipocyte gene
      expression including reduction in ACRP30 mRNA and induction of lipolysis
      resulting in increased plasma FFAs. TNF-alpha later alters systemic energy
      homeostasis that closely resembles the insulin resistance phenotype. Our data
      suggest that blockade of TNF-alpha action in adipose tissue may prevent TNF-alpha
      induced insulin resistance in vivo.

PMID- 12401709
TI  - Dissociation of obesity and impaired glucose disposal in mice overexpressing acyl
      coenzyme a:diacylglycerol acyltransferase 1 in white adipose tissue.
AB  - Acyl coenzyme A:diacylglycerol acyltransferase 1 (DGAT1) is one of two DGAT
      enzymes known to catalyze the final step in mammalian triglyceride synthesis.
      Mice deficient in DGAT1 are resistant to obesity and have enhanced insulin
      sensitivity. To understand better the relationship between triglyceride synthesis
      and energy and glucose metabolism, we generated transgenic (aP2-Dgat1) mice in
      which expression of murine DGAT1 in the white adipose tissue (WAT) was twofold
      higher than normal. aP2-Dgat1 mice that were fed a regular diet had larger
      adipocytes and greater total fat pad weight than wild-type (WT) mice. In response
      to a high-fat diet, aP2-Dgat1 mice became more obese ( approximately 20% greater
      body weight after 15 weeks) than WT mice. However, the increase in adiposity in
      aP2-Dgat1 mice was not associated with impaired glucose disposal, as demonstrated
      by glucose and insulin tolerance tests. Correlating with this finding,
      triglyceride deposition in the liver and skeletal muscle, two major target
      tissues of insulin, was similar in aP2-Dgat1 and WT mice. Thus, DGAT1
      overexpression in murine WAT provides a model in which obesity does not impair
      glucose disposal. Our findings support the lipotoxicity hypothesis that the
      deposition of triglycerides in insulin-sensitive tissues other than adipocytes
      causes insulin resistance.

PMID- 12401710
TI  - Comparison of central and peripheral administration of C75 on food intake, body
      weight, and conditioned taste aversion.
AB  - Mice respond to fatty acid synthase (FAS) inhibitors by profoundly reducing their
      food intake and body weight. Evidence indicates that the central nervous system
      (CNS) may be the critical site of action; however, a peripheral contribution
      cannot be ruled out. We compared doses of the FAS inhibitor C75 in the CNS (third
      ventricle [i3vt]) and periphery (intraperitoneal [IP]) to reduce food intake and
      body weight in rats. Centrally, the threshold dose was 3 micro g, whereas a dose
      of 10 mg/kg was required peripherally. Such data argue for FAS activity in the
      CNS as a potent target for the actions of C75. To control for nonspecific effects
      of FAS inhibition, we compared C75 administration in two models of illness,
      conditioned taste aversion and need-induced sodium appetite. Our results suggest
      the anorexia produced by IP C75 is accompanied by visceral illness, whereas the
      anorexia produced by i3vt is not. In addition, we placed animals in an indirect
      calorimeter after an IP injection of C75. We found that consistent with
      behavioral measures of visceral illness, peripheral C75 reduced heat expenditure
      and resulted in animals losing less weight than fasted control animals,
      suggesting that peripherally administered C75 has aversive properties.
      Understanding the mechanisms by which FAS inhibition in the CNS reduces food
      intake could lead to specific targets for the manipulation of energy balance and
      the treatment of obesity.

PMID- 12401711
TI  - The role of autoimmunity in islet allograft destruction: major histocompatibility
      complex class II matching is necessary for autoimmune destruction of allogeneic
      islet transplants after T-cell costimulatory blockade.
AB  - Although it has often been assumed that transplanted allogeneic islets can be
      destroyed by recurrent autoimmunity in recipients with type 1 diabetes,
      definitive evidence is lacking and the settings in which this may occur have not
      been defined. To address these issues, we compared the survival of islet
      transplants (subject to tissue-specific autoimmunity) with cardiac transplants
      (not subject to tissue-specific autoimmunity) from various major
      histocompatibility complex (MHC)-matched and -mismatched donors transplanted into
      autoimmune NOD recipients. We found that when recipients were treated with
      combined B7 and CD154 T-cell costimulatory blockade, hearts survived best with
      better MHC matching, whereas islets survived worst when the donor and recipient
      shared MHC class II antigens. In the absence of full or MHC class II matching,
      there was no difference in the survival of islet and cardiac allografts. We also
      found that the tendency of NOD mice to resist tolerance induction by
      costimulation blockade is mediated by both CD4+ and CD8+ T-cells, not directly
      linked to the presence of autoimmunity, and conferred by non-MHC background
      genes. These findings have clinical importance because they suggest that under
      some circumstances, avoiding MHC class II sharing may provide better islet
      allograft survival in recipients with autoimmune diabetes, since mismatched
      allogeneic islets may be resistant to recurrent autoimmunity. Our results may
      have implications for the design of future clinical trials in islet
      transplantation.

PMID- 12401712
TI  - Uncoupling protein 2 knockout mice have enhanced insulin secretory capacity after
      a high-fat diet.
AB  - Uncoupling protein 2 (UCP2) may act as an important regulator of insulin
      secretion. In this study, beta-cell function in UCP2-deficient mice was examined
      after a 45% high-fat diet (HFD) to assess its role during the development of diet
      induced type 2 diabetes. HFD-fed UCP2 (-/-) mice have lower fasting blood glucose
      and elevated insulin levels when compared with wild-type (WT) mice. UCP2 (-/-)
      mice also have enhanced beta-cell glucose sensitivity compared with WT mice after
      HFD, a result that is due in part to the deterioration of glucose responsiveness
      in WT mice. HFD-fed UCP2 (-/-) mice have increased insulin secretory capacity as
      a result of increased pancreatic beta-cell mass and insulin content per islet.
      Islets from WT mice exposed to 0.5 mmol/l palmitate for 48 h have significantly
      reduced mitochondrial membrane potential, ATP concentrations, and glucose
      responsiveness compared with UCP2 (-/-) islets, suggesting that elevated UCP2 in
      WT mice increases proton leak and decreases mitochondrial ATP production. Highly
      increased carnitine palmitoyl transferase-1 gene expression in UCP2 (-/-) mice is
      suggestive of enhanced fatty acid oxidizing capacity, particularly after HFD
      stress. These results further establish UCP2 as a component in glucose sensing
      and suggest a possible new aspect of UCP2 function during the progression of type
      2 diabetes.

PMID- 12401713
TI  - Vascularized islet cell transplantation in miniature Swine: islet-kidney
      allografts correct the diabetic hyperglycemia induced by total pancreatectomy.
AB  - We have previously reported the preparation of vascularized islet-kidneys (IKs)
      by transplantation of islets under the autologous kidney capsule. Here, we
      compare the efficacy of transplanting vascularized versus nonvascularized islets
      into diabetic allogeneic swine recipients. In the vascularized islet
      transplantation (5,000 islet equivalents [IE]/kg), recipients received minor
      mismatched (n = 4) or fully-mismatched (n = 2) IKs after pancreatectomy, with a
      12-day course of cyclosporine A (CyA) or FK506, respectively. For the
      nonvascularized islet transplantation (7,000 IE/kg), three recipients received
      minor-mismatched islets alone and two recipients received minor-mismatched donor
      islets placed in a donor kidney on the day of transplantation. All recipients of
      nonvascularized islets were treated with a 12-day course of CyA. With
      vascularized islet transplantation, pancreatectomized recipients were markedly
      hyperglycemic pretransplant (fasting blood glucose >300 mg/dl). After composite
      IK transplantation, all recipients developed and maintained normoglycemia (<120
      mg/dl) and stable renal function indefinitely (>3 months), and insulin therapy
      was not required. Major histocompatibility complex-mismatched recipients
      demonstrated in vitro donor-specific unresponsiveness. In contrast, recipients of
      nonvascularized islets remained hyperglycemic. In conclusion, IK allografts cured
      surgically induced diabetes across allogeneic barriers, whereas nonvascularized
      islet transplants did not. These data indicate that prevascularization of islet
      allografts is crucial for their subsequent engraftment and that composite IKs may
      provide a strategy for successful islet transplantation.

PMID- 12401714
TI  - Glucagon is required for early insulin-positive differentiation in the developing
      mouse pancreas.
AB  - The embryonic pancreas is thought to develop from pluripotent endodermal cells
      that give rise to endocrine and exocrine cells. A key guidance mechanism for
      pancreatic development has previously been found to be epithelial-mesenchymal
      interaction. Interactions within the epithelium, however, have not been well
      studied. Glucagon is the earliest peptide hormone present at appreciable levels
      in the developing pancreatic epithelium (embryonic day [E]-9.5 in mouse). Insulin
      accumulation begins slightly later (E11 in mouse), followed by a rapid
      accumulation during the "second wave" of insulin differentiation ( approximately
      E15). Here we found that blocking early expression and function of glucagon, but
      not GLP-1, an alternate gene product of preproglucagon mRNA, prevented insulin
      positive differentiation in early embryonic (E11) pancreas. These results suggest
      a novel concept and a key role for glucagon in the paracrine induction of
      differentiation of other pancreatic components in the early embryonic pancreas.

PMID- 12401715
TI  - Induction of autoimmune diabetes through insulin (but not GAD65) DNA vaccination
      in nonobese diabetic and in RIP-B7.1 mice.
AB  - Insulin has been used to modify T-cell autoimmunity in experimental models of
      type 1 diabetes. In a large clinical trial, the effect of insulin to prevent type
      1 diabetes is currently investigated. We here show that insulin can adversely
      trigger autoimmune diabetes in two mouse models of type 1 diabetes, using
      intramuscular DNA vaccination for antigen administration. In female nonobese
      diabetic (NOD) mice, diabetes development was enhanced after preproinsulin
      (ppIns) DNA treatment, and natural diabetes resistance in male NOD mice was
      diminished by ppIns DNA vaccination. In contrast, GAD65 DNA conferred partial
      diabetes protection, and empty DNA plasmid was without effect. In RIP-B7.1
      C57BL/6 mice (expressing the T-cell costimulatory molecule B7.1 in pancreatic
      beta-cells), autoimmune diabetes occurred in 70% of animals after ppIns
      vaccination, whereas diabetes did not develop spontaneously in RIP-B7.1 mice or
      after GAD65 or control DNA treatment. Diabetes was characterized by diffuse
      CD4(+)CD8(+) T-cell infiltration of pancreatic islets and severe insulin
      deficiency, and ppIns, proinsulin, and insulin DNA were equally effective for
      disease induction. Our work provides a new model of experimental autoimmune
      diabetes suitable to study mechanisms and outcomes of insulin-specific T-cell
      reactivity. In antigen-based prevention of type 1 diabetes, diabetes acceleration
      should be considered as a potential adverse result.

PMID- 12401716
TI  - SERCA3 ablation does not impair insulin secretion but suggests distinct roles of
      different sarcoendoplasmic reticulum Ca(2+) pumps for Ca(2+) homeostasis in
      pancreatic beta-cells.
AB  - Two sarcoendoplasmic reticulum Ca(2+)-ATPases, SERCA3 and SERCA2b, are expressed
      in pancreatic islets. Immunocytochemistry showed that SERCA3 is restricted to
      beta-cells in the mouse pancreas. Control and SERCA3-deficient mice were used to
      evaluate the role of SERCA3 in beta-cell cytosolic-free Ca(2+) concentration
      ([Ca(2+)](c)) regulation, insulin secretion, and glucose homeostasis. Basal
      [Ca(2+)](c) was not increased by SERCA3 ablation. Stimulation with glucose
      induced a transient drop in basal [Ca(2+)](c) that was suppressed by inhibition
      of all SERCAs with thapsigargin (TG) but unaffected by selective SERCA3 ablation.
      Ca(2+) mobilization by acetylcholine was normal in SERCA3-deficient beta-cells.
      In contrast, [Ca(2+)](c) oscillations resulting from intermittent glucose
      stimulated Ca(2+) influx and [Ca(2+)](c) transients induced by pulses of high
      K(+) were similarly affected by SERCA3 ablation or TG pretreatment of control
      islets; their amplitude was increased and their slow descending phase suppressed.
      This suggests that, during the decay of each oscillation, the endoplasmic
      reticulum releases Ca(2+) that was pumped by SERCA3 during the upstroke phase.
      SERCA3 ablation increased the insulin response of islets to 15 mmol/l glucose.
      However, basal and postprandial plasma glucose and insulin concentrations in
      SERCA3-deficient mice were normal. In conclusion, SERCA2b, but not SERCA3, is
      involved in basal [Ca(2+)](c) regulation in beta-cells. SERCA3 becomes operative
      when [Ca(2+)](c) rises and is required for normal [Ca(2+)](c) oscillations in
      response to glucose. However, a lack of SERCA3 is insufficient in itself to alter
      glucose homeostasis or impair insulin secretion in mice.

PMID- 12401717
TI  - The iddm4 locus segregates with diabetes susceptibility in congenic WF.iddm4
      rats.
AB  - Viral antibody-free BBDR and WF rats never develop spontaneous diabetes. BBDR
      rats, however, develop autoimmune diabetes after perturbation of the immune
      system, e.g., by viral infection. We previously identified a disease
      susceptibility locus in the BBDR rat, iddm4, which is associated with the
      development of autoimmune diabetes after treatment with
      polyinosinic:polycytidylic acid and an antibody that depletes ART2(+) regulatory
      cells. We have now developed lines of congenic WF.iddm4 rats and report that in
      an intercross of N5 generation WF.iddm4 rats, approximately 70% of animals either
      homozygous or heterozygous for the BBDR origin allele of iddm4 became
      hyperglycemic after treatment to induce diabetes. Fewer than 20% of rats
      expressing the WF origin allele of iddm4 became diabetic. Testing the progeny of
      various recombinant N5 WF.iddm4 congenic rats for susceptibility to diabetes
      suggests that iddm4 is centered on a small segment of chromosome 4 bounded by the
      proximal marker D4Rat135 and the distal marker D4Got51, an interval of <2.8 cM.
      The allele at iddm4 has 79% sensitivity and 80% specificity in prediction of
      diabetes in rats that are segregating for this locus. These characteristics
      suggest that iddm4 is one of the most powerful non-major histocompatibility
      complex determinants of susceptibility to autoimmune diabetes described to date.

PMID- 12401718
TI  - Prevention of hypoglycemia using risk assessment with a continuous glucose
      monitoring system.
AB  - Due to the lag between sugar intake and the beginning of recovery from
      hypoglycemia, it is necessary to intervene in an anticipatory way if one wants to
      prevent, not only detect, hypoglycemia. This article presents the principle of a
      hypoglycemia prevention system based on risk assessment. The risk situation can
      be defined as the moment when the system estimates that the glucose concentration
      is expected to reach a hypoglycemia threshold in less than a given time (e.g., 20
      min). Since there are well-known discrepancies between blood and interstitial
      glucose concentrations, the aim of this experimental study performed in
      nondiabetic rats was first to validate this strategy, and second to determine
      whether it can work when the glucose concentration is estimated by a glucose
      sensor in subcutaneous tissue rather than in blood. We used a model of controlled
      decrease in blood glucose concentration. A glucose infusion, the profile of which
      mimicked the appearance of glucose from an intragastric load, was administered
      either when hypoglycemia was detected or on the basis of risk recognition.
      Despite the lag between the beginning of the load and that of the increase in
      blood glucose concentration, which was in all experiments 15-20 min, hypoglycemia
      was fully prevented without overshoot hyperglycemia in the groups of rats in
      which the glucose load was started when the hypoglycemia risk was detected, on
      the basis of either blood or interstitial glucose concentration. This was, of
      course, not the case when the same glucose load was infused at the detection of
      the hypoglycemia threshold.

PMID- 12401719
TI  - Reduction of the accumulation of advanced glycation end products by ACE
      inhibition in experimental diabetic nephropathy.
AB  - The effect of ACE inhibition on the formation of advanced glycation end products
      (AGEs) and oxidative stress was explored. Streptozocin-induced diabetic animals
      were randomized to no treatment, the ACE inhibitor ramipril (3 mg/l), or the AGE
      formation inhibitor aminoguanidine (1 g/l) and followed for 12 weeks. Control
      groups were followed concurrently. Renal AGE accumulation, as determined by
      immunohistochemistry and both serum and renal fluorescence, were increased in
      diabetic animals. This was attenuated by both ramipril and aminoguanidine to a
      similar degree. Nitrotyrosine, a marker of protein oxidation, also followed a
      similar pattern. The receptor for AGEs, gene expression of the membrane-bound
      NADPH oxidase subunit gp91phox, and nuclear transcription factor-kappaB were all
      increased by diabetes but remained unaffected by either treatment regimen. Two
      other AGE receptors, AGE R2 and AGE R3, remained unchanged for the duration of
      the study. The present study has identified a relationship between the renin
      angiotensin system and the accumulation of AGEs in experimental diabetic
      nephropathy that may be linked through oxidative stress

PMID- 12401720
TI  - ALT-946 and aminoguanidine, inhibitors of advanced glycation, improve severe
      nephropathy in the diabetic transgenic (mREN-2)27 rat.
AB  - The severe diabetic nephropathy that develops in the hypertensive transgenic
      (mRen-2)27 rat with streptozotocin (STZ) diabetes has previously been considered
      angiotensin II-dependent. Because metabolic pathways are also activated in the
      diabetic kidney, the present study aimed to determine whether renoprotection
      could be afforded with inhibitors of advanced glycation end products (AGEs), ALT
      946, and aminoguanidine (AG). At 6 weeks of age, nondiabetic control and STZ
      diabetic Ren-2 rats were randomized to receive vehicle, ALT-946 (1 g/l), or AG (1
      g/l) and were studied for 12 weeks. Systolic blood pressure was unchanged with
      diabetes, ALT-946, or AG. Both kidney weight and glomerular filtration rate were
      increased with diabetes and unchanged with ALT-946 or AG. ALT-946 and AG equally
      ameliorated glomerulosclerosis and medullary pathology; however, ALT-946 did
      reduce cortical tubular degeneration to a greater extent than AG. Albumin
      excretion rate, which was elevated with diabetes, was reduced with ALT-946 but
      not AG. AGE immunolabeling was increased in glomeruli and reduced with ALT-946
      and AG. These findings indicate that even in the context of renal injury presumed
      to be primarily blood pressure- and/or angiotensin II-dependent, approaches that
      interfere with metabolic pathways such as inhibitors of AGE formation can confer
      renal protection in experimental diabetes.

PMID- 12401721
TI  - Activation of cyclin D1-Cdk4 and Cdk4-directed phosphorylation of RB protein in
      diabetic mesangial hypertrophy.
AB  - To determine the role of cell-cycle proteins in regulating pathological renal
      hypertrophy, diabetes was induced in mice expressing a human retinoblastoma (RB)
      transgene and in wild-type littermates. Whole-kidney and glomerular hypertrophy
      caused by hyperglycemia was associated with specific G1 phase cell-cycle events:
      early and sustained increase in expression of cyclin D1 and activation of cyclin
      D1-cdk4 complexes, but no change in expression of cyclin E or cdk2 activity.
      Overexpression of RB alone likewise caused hypertrophy and increased only cyclin
      D1-cdk4 activity; these effects were not further augmented by high glucose.
      Identical observations were made when isolated mesangial cells conditionally
      overexpressing RB from a tetracycline-repressible system hypertrophied in
      response to high glucose. A mitogenic signal in the same cell-culture system, in
      contrast, transiently and sequentially activated both cyclin D1-cdk4 and cyclin E
      cdk2. In vivo and in cultured mesangial cells, high glucose resulted in
      persistent partial phosphorylation of RB, an event catalyzed specifically by
      cyclin D1-cdk4. These data indicate that mesangial hypertrophy caused by
      hyperglycemia in diabetes results in sustained cyclin D1-cdk4-dependent
      phosphorylation of RB and maintenance of mesangial cells in the early-to-middle
      G1 phase of the cell cycle.

PMID- 12401722
TI  - Relationship of phospholipid transfer protein activity to HDL and apolipoprotein
      B-containing lipoproteins in subjects with and without type 1 diabetes.
AB  - Patients with type 1 diabetes have greatly increased phospholipid transfer
      protein (PLTP) activity and have an altered HDL subclass distribution. In 195
      patients with type 1 diabetes and in 194 men and women aged 30-55 years, we
      examined the relationship of PLTP activity to HDL and examined whether PLTP
      activity contributes to differences in HDL found in type 1 diabetes. PLTP
      activity was measured using an exogenous substrate assay. Average HDL particle
      size and HDL subclasses were measured using nuclear magnetic resonance
      spectroscopy. Apolipoprotein AI (apoAI) and apoAII were measured by
      immunoturbidimetry. The amount of apoAI present in LpAI was measured using a
      differential electroimmunoassay, and the amount of apoAI in LpAIAII was inferred
      from the apoAI and LpAI data. Higher PLTP activity was associated with more large
      HDL (P < 0.001) and less small HDL (P < 0.01), more apoAI and apoAII (both at P <
      0.001), and more apoAI in both LpAI and LpAIAII (P = 0.02 and P < 0.001,
      respectively). These associations were independent of other lipids and enzyme
      activities. Adjusting for PLTP activity halved the difference between subjects
      with and without diabetes in apoA1 (from 10.1 mg/dl higher in subjects with
      diabetes to 4.6 mg/dl higher) and large HDL (2.4 micro mol/l higher to 1.2 micro
      mol/l higher) and reduced the difference in HDL size (from 0.31 nm higher to 0.26
      nm higher). PLTP activity was also positively associated with apoB, total VLDL
      and LDL particle number, and IDL level in subjects with diabetes. These data
      support the idea that PLTP is a major factor in HDL conversion and remodeling in
      humans and that higher PLTP activity makes an important contribution to the
      higher apoAI levels and altered HDL subclass distribution in type 1 diabetes.
      They also support a role for PLTP in the metabolism of apoB-containing
      lipoproteins.

PMID- 12401723
TI  - Decreased myocardial perfusion reserve in diabetic autonomic neuropathy.
AB  - The pathophysiological mechanisms responsible for increased cardiovascular
      mortality in diabetic autonomic neuropathy are unknown. To investigate the effect
      of autonomic neuropathy on myocardial function, we performed dynamic contrast
      enhanced magnetic resonance perfusion imaging during baseline conditions and
      after Dipyridamole-induced vasodilatation in nine type 1 diabetic patients with
      autonomic neuropathy (AN+), defined by cardiovascular tests, as well as in 10
      type 1 diabetic patients without autonomic neuropathy (AN-) and 10 healthy
      control subjects. Baseline myocardial perfusion index (K(i)) was similar in the
      three groups (AN+ 88.6 +/- 8.7 ml. 100 g(-1). min(-1), AN- 82.6 +/- 7.2, control
      subjects 93.7 +/- 9.0) (means +/- SE). K(i) during Dipyridamole vasodilatation
      was significantly lower in the patients with autonomic neuropathy (P < 0.001)
      than in the other groups (AN+ 131.1 +/- 13.0 ml. 100 g(-1). min(-1), AN- 177.3 +/
      8.6, control subjects 197.2 +/- 8.9). Mean blood pressure was unchanged during
      Dipyridamole infusion in AN- and control subjects, whereas a significant blood
      pressure decrease was found in AN+ (15.6 +/- 2.6 mmHg, P < 0.025). There was a
      significant correlation between blood pressure response to Dipyridamole and
      myocardial perfusion reserve index. We conclude that type 1 diabetic patients
      with autonomic neuropathy have a decreased myocardial perfusion reserve capacity
      when challenged with a vasodilatator, a finding that may in part be the
      pathophysiological substrate for the increase in mortality in these patients. The
      underlying mechanism may be defective myocardial sympathetic vasodilatation, a
      lack of ability to maintain blood pressure during vasodilatation, or both.

PMID- 12401724
TI  - STAT5 activation induced by diabetic LDL depends on LDL glycation and occurs via
      src kinase activity.
AB  - Advanced glycation end products (AGEs) have been implicated in the accelerated
      vascular injury occurring in diabetes. We recently reported that LDL prepared
      from type 2 diabetic patients (dm-LDL), but not normal LDL (n-LDL) triggered
      signal transducers and activators of transcription STAT5 activation and p21(waf)
      expression in endothelial cells (ECs). The aims of the present study were to
      investigate the role of LDL glycation in dm-LDL- mediated signals and to analyze
      the molecular mechanisms leading to STAT5 activation. We found that glycated LDL
      (gly-LDL) triggered STAT5 activation, the formation of a prolactin inducible
      element (PIE)-binding complex containing STAT5, and increased p21(waf) expression
      through the activation of the receptor for AGE (RAGE). We also demonstrated that
      dm-LDL and gly-LDL, but not n-LDL treatment induced the formation of a stable
      complex containing the activated STAT5 and RAGE. Moreover, gly-LDL triggered src
      but not JAK2 kinase activity. Pretreatment with the src kinase inhibitor PP1
      abrogated both STAT5 activation and the expression of p21(waf) induced by gly
      LDL. Consistently, gly-LDL failed to activate STAT5 in src(-/-) fibroblasts.
      Collectively, our results provide evidence for the role of glycation in dm-LDL
      mediated effects and for a specific role of src kinase in STAT5-dependent
      p21(waf) expression.

PMID- 12401725
TI  - Linkage and association with type 1 diabetes on chromosome 1q42.
AB  - Type 1 diabetes is a complex disorder with multiple genetic loci and
      environmental factors contributing to disease etiology. In the current study, a
      human type 1 diabetes candidate region on chromosome 1q42 was mapped at high
      marker density in a panel of 616 multiplex type 1 diabetic families. To
      facilitate the identification and evaluation of candidate genes, a physical map
      of the 7-cM region surrounding the maximum logarithm of odds (LOD) score (2.46, P
      = 0.0004) was constructed. Genes were identified in the 500-kb region surrounding
      the marker yielding the peak LOD score and evaluated for polymorphism by
      resequencing. Single-nucleotide polymorphisms (SNPs) identified in these genes as
      well as other anonymous markers were tested for allelic association with type 1
      diabetes by both family-based and case-control methods. A haplotype formed by
      common alleles at three adjacent markers (D1S225, D1S2383, and D1S251) was
      preferentially transmitted to affected offspring in type 1 diabetic families
      (nominal P = 0.006). These findings extend the evidence supporting the existence
      of a type 1 diabetes susceptibility locus on chromosome 1q42 and identify a
      candidate region amenable to positional cloning efforts.

PMID- 12401726
TI  - No association between lck gene polymorphisms and protein level in type 1
      diabetes.
AB  - We previously described a reduced expression of the protein tyrosine kinase Lck
      in T-cells from type 1 diabetic patients, the origin of which is still unknown.
      The human lck gene, located on chromosome 1p35-34.3, was evaluated as a candidate
      susceptibility gene for type 1 diabetes. A molecular scan of the sequence
      variations in the coding, the relevant promoter, and most of the intronic
      sequences of the lck gene (representing a total of 10.5 kb fragment) was
      performed in 187 Caucasian subjects including 91 type 1 diabetic patients and 96
      normoglycemic control subjects. We identified 35 sequence variations, including
      one deletion and 34 single nucleotide polymorphisms (SNPs), 33 of them being new.
      Four variants were frequent but not significantly associated with diabetes or Lck
      protein level. Of the SNP variants, 11 were only found within the diabetic
      population and some were associated with low Lck protein levels. The low
      frequency of these polymorphisms did not permit any statistically significant
      correlations with the disease status, suggesting that the lck gene probably does
      not contribute to genetic susceptibility to type 1 diabetes.

PMID- 12401727
TI  - A functional polymorphism in the promoter of UCP2 enhances obesity risk but
      reduces type 2 diabetes risk in obese middle-aged humans.
AB  - Obesity is frequently associated with type 2 diabetes. We previously observed an
      association of a functional G/A polymorphism in the uncoupling protein 2 (UCP2)
      promoter with obesity. The wild-type G allele was associated with reduced adipose
      tissue mRNA expression in vivo, reduced transcriptional activity in vitro, and
      increased risk of obesity. On the other hand, studies in animal and cell culture
      models identified pancreatic beta-cell UCP2 expression as a main determinant of
      the insulin secretory response to glucose. We therefore ascertained associations
      of the -866G/A polymorphism with beta-cell function and diabetes risk in obesity.
      We show here that the pancreatic transcription factor PAX6 preferentially binds
      to and more effectively trans activates the variant than the wild-type UCP2
      promoter allele in the beta-cell line INS1-E. By studying 39 obese nondiabetic
      humans, we observed genotype differences in beta-cell function; wild-type
      subjects displayed a greater disposition index (the product of insulin
      sensitivity and acute insulin response to glucose) than subjects with the variant
      allele (P < 0.03). By comparing obese subjects with and without type 2 diabetes,
      we observed genotype-associated differences in diabetes prevalence that
      translated into a twofold age-adjusted risk reduction in wild-type subjects.
      Thus, the more common UCP2 promoter G allele, while being conducive for obesity,
      affords relative protection against type 2 diabetes.

PMID- 12401728
TI  - Association of IL4R haplotypes with type 1 diabetes.
AB  - We have investigated, in 282 multiplex Caucasian families (the Human Biological
      Data Interchange Repository), the association of type 1 diabetes with
      polymorphisms in the IL4R gene. IL4R encodes a subunit of the interleukin-4
      receptor, a molecule critical to T-helper cell development. By genotyping eight
      different IL4R single-nucleotide polymorphisms (SNPs) and identifying haplotypes
      (complex alleles) in the multiplex type 1 diabetic families who were stratified
      for HLA genotype, we have observed significant evidence of linkage and
      association of the IL4R gene to type 1 diabetes. In particular, we have
      identified a specific haplotype that appears to be protective and observed that
      this protective effect is strongest among individuals not carrying the HLA
      DR3/DR4 genotype (which confers the strongest genetic risk for type 1 diabetes).
      These findings suggest an important role for the IL4R gene in immune-related
      disease susceptibility and illustrate the value of using multi-SNP haplotype
      information in association studies.

PMID- 12401729
TI  - Molecular analysis of KCNJ10 on 1q as a candidate gene for Type 2 diabetes in
      Pima Indians.
AB  - The KCNJ10 gene is located within a region on chromosome 1q linked to type 2
      diabetes in the Pima Indians and six other populations. We therefore investigated
      this gene as a potential type 2 diabetes candidate gene in Pima Indians. KCNJ10
      consists of two exons, spans approximately 33 kb, and we identified eight single
      nucleotide polymorphisms (SNPs), including one (SNP2) in the coding region
      leading to a Glu359Lys substitution. Association studies were carried out in a
      case-control group composed of 149 affected and 150 unaffected Pimas, and the
      linkage analysis was performed in a linkage set of 1,338 Pimas. SNP1 in the
      promoter and SNP2 in the intron, which were in a complete linkage disequilibrium,
      and SNP5 in the 3' untranslated region showed association with diabetes in the
      case-control group (P = 0.02 and P = 0.01, respectively). When genotyped in the
      linkage set, only the KCNJ10-SNP1 variant showed a modest association with type 2
      diabetes (P = 0.01). KCNJ10-SNP1 is in a strong linkage disquilibrium with SNP14
      of the adjacent KCNJ9 locus, which we previously found to be associated with type
      2 diabetes. After adjustment for KCNJ10-SNP1, the original linkage score at this
      locus was marginally reduced from 3.1 to 2.9. We conclude that these variants in
      KCNJ10 are unlikely to be the cause of linkage of type 2 diabetes with 1q in Pima
      Indians.

PMID- 12401730
TI  - Interleukin-18 promoter polymorphisms in type 1 diabetes.
AB  - Type 1 diabetes is believed to be a Th1 lymphocyte-mediated disease, and both
      environmental and genetic factors play a role in its pathogenesis. It was
      recently found that interleukin (IL)-18 acts as a proinflammatory cytokine and,
      in synergy with IL-12, promotes development of Th1 lymphocyte response by
      induction of gamma-interferon production. The aim of our study was to evaluate
      the frequency of known polymorphisms in the IL-18 promoter in patients with type
      1 diabetes in comparison with healthy control subjects, since higher levels of IL
      18 were recently reported in the subclinical stage of type 1 diabetes. We studied
      two recently described single-nucleotide polymorphisms of the promoter of IL-18
      gene at the position -137 and -607, which have been suggested to cause
      differences in transcription factor binding and have an impact on IL-18 gene
      activity. The genotype distribution differed significantly between patients with
      type 1 diabetes and control subjects. The difference reflected an increase in the
      GC genotypes and a decrease in GG genotypes at position -137 in the promoter of
      IL-18 gene. AA genotype at position -607 was found only in the control group. The
      results also demonstrated that the contribution of -137GC genotypes to genetic
      susceptibility to type 1 diabetes differs depending on the combination of IL-18
      promotor gene haplotypes. Our study suggests the first evidence of an association
      between type 1 diabetes and polymorphisms in the promoter of IL-18 gene.

PMID- 12401731
TI  - Irbesartan reduces the albumin excretion rate in microalbuminuric type 2 diabetic
      patients independently of hypertension: a randomized double-blind placebo
      controlled crossover study.
AB  - OBJECTIVE: ACE inhibitors delay the progression from incipient to overt diabetic
      nephropathy and reduce albumin excretion rate (AER), independently of blood
      pressure. Angiotensin II type 1 receptor antagonists produce similar effects on
      microalbuminuria and mean arterial pressure. The aim of this study was to
      evaluate the effect of irbesartan on microalbuminuria and blood pressure in
      hypertensive and normotensive type 2 diabetic patients. RESEARCH DESIGN AND
      METHODS: Sixty-four microalbuminuric hypertensive (group 1) and 60
      microalbuminuric normotensive (group 2) type 2 diabetic male patients, matched
      for age, BMI, HbA(1c), and diabetes duration, were enrolled. Each group was
      divided into two subgroups receiving either irbesartan (150 mg b.i.d. orally) or
      placebo for 60 days. After 15 days of washout, irbesartan was given to the
      subgroups who had received the placebo, and vice versa, in a randomized double
      blind crossover study. RESULTS: In microalbuminuric hypertensive type 2 diabetic
      subjects, irbesartan reduced 24-h mean systolic and diastolic pressure and AER.
      In microalbuminuric normotensive type 2 diabetic patients, irbesartan reduced
      AER. CONCLUSIONS: These results indicate the beneficial effects of irbesartan on
      AER in type 2 diabetic subjects, independently of its antihypertensive effects.

PMID- 12401732
TI  - Comparison of a homogeneous assay with a precipitation method for the measurement
      of HDL cholesterol in diabetic patients.
AB  - OBJECTIVE: To compare direct-measured HDL cholesterol with HDL cholesterol
      measured by a precipitation method. RESEARCH DESIGN AND METHODS: We compared a
      homogeneous assay for direct HDL cholesterol analysis with the phosphotungstic
      acid magnesium chloride precipitation method in 55 type 1 diabetic patients, 70
      type 2 diabetic patients, and 82 nondiabetic normal control subjects with plasma
      triglyceride levels <4.6 mmol/l. The cholesterol content of HDL determined by the
      direct assay was overall 0.1 mmol/l higher in all three groups than HDL
      cholesterol measured after precipitation, but the two methods were closely
      correlated (r(2) = 0.98, P < 0.001). RESULTS: HbA(1c), blood glucose, serum
      albumin, serum bilirubin, or triglyceride did not influence the differences of
      the two HDL cholesterol measurements. Because we have previously shown HDL
      cholesterol isolated by phosphotungstic acid precipitation to be lower than that
      by ultracentrifugation, the positive bias found in this study was expected. It
      seems that the direct HDL cholesterol assay reacts with apolipoprotein (apo) B
      containing lipoproteins in the fraction with a density of >1.063; these apo B
      containing lipoproteins are suggested to be coprecipitated with the
      phosphotungstic acid method. We also measured LDL cholesterol directly by a LDL
      cholesterol plus method and found no significant differences between this method
      and LDL cholesterol calculated from Friedewald's formula. CONCLUSIONS: Direct
      homogeneous assay for HDL cholesterol determination in diabetic patients seems
      not to exhibit a negative bias, in contrast to the precipitation method, when
      compared with the ultracentrifugation method. In addition, the direct assay saves
      time and is not influenced by type of diabetes or degree of metabolic control.

PMID- 12401733
TI  - Effects of vitamin E on cardiovascular and microvascular outcomes in high-risk
      patients with diabetes: results of the HOPE study and MICRO-HOPE substudy.
AB  - OBJECTIVES: Experimental and observational studies suggest that vitamin E may
      reduce the risk of cardiovascular (CV) events and of microvascular complications
      in people with diabetes. However, data from randomized clinical trials are
      limited. Therefore, we evaluated the effects of vitamin E supplementation on
      major CV outcomes and on the development of nephropathy in people with diabetes.
      RESEARCH DESIGN AND METHODS: The Heart Outcomes Prevention Evaluation (HOPE)
      trial is a randomized clinical trial with a 2 x 2 factorial design, which
      evaluated the effects of vitamin E and of ramipril in patients at high risk for
      CV events. Patients were eligible for the study if they were 55 years or older
      and if they had CV disease or diabetes with at least one additional coronary risk
      factor. The study was designed to recruit a large number of people with diabetes,
      and the analyses of the effects of vitamin E in this group were preplanned.
      Patients were randomly allocated to daily treatment with 400 IU vitamin E and
      with 10 mg ramipril or their respective placebos and were followed for an average
      of 4.5 years. The primary study outcome was the composite of myocardial
      infarction, stroke, or CV death. Secondary outcomes included total mortality,
      hospitalizations for heart failure, hospitalizations for unstable angina,
      revascularizations, and overt nephropathy. RESULTS: There were 3,654 people with
      diabetes. Vitamin E had a neutral effect on the primary study outcome (relative
      risk = 1.03, 95% CI 0.88-1.21; P = 0.70), on each component of the composite
      primary outcome, and on all predefined secondary outcomes. CONCLUSIONS: The daily
      administration of 400 IU vitamin E for an average of 4.5 years to middle-aged and
      elderly people with diabetes and CV disease and/or additional coronary risk
      factor(s) has no effect on CV outcomes or nephropathy.

PMID- 12401734
TI  - Meal-related structured self-monitoring of blood glucose: effect on diabetes
      control in non-insulin-treated type 2 diabetic patients.
AB  - OBJECTIVE: To investigate the effect of meal-related self-monitoring of blood
      glucose on glycemic control and well-being in non-insulin-treated type 2 diabetic
      patients. RESEARCH DESIGN AND METHODS: This 6-month study, which included 6
      months of follow-up, adopted a prospective, multicenter, randomized controlled
      design. Subjects were randomized to two groups: one group used a blood glucose
      monitoring device, kept a blood glucose/eating diary, and received standardized
      counseling; the control group received nonstandardized counseling on diet and
      lifestyle. The primary efficacy parameter was the change in HbA(1c). Secondary
      efficacy variables included changes in body weight, lipids, and microalbumin and
      changes in treatment satisfaction and well-being. RESULTS: In the per-protocol
      analysis, the use of a self-monitoring blood glucose device significantly reduced
      HbA(1c) levels by 1.0 +/- 1.08% compared with 0.54 +/- 1.41% for the control
      group (P = 0.0086); subgroup analysis showed three types of responders. Body
      weight, total cholesterol, and microalbumin improved when using a glucometer, but
      there was no statistically significant difference between the two groups.
      Treatment satisfaction increased in both groups to a similar extent (P = 0.9).
      Self-monitoring resulted in a marked improvement of general well-being with
      significant improvements in the subitems depression (P = 0.032) and lack of well
      being (P = 0.02). CONCLUSIONS: Meal-related self-monitoring of blood glucose
      within a structured counseling program improved glycemic control in the majority
      of non-insulin-treated type 2 diabetic patients in this study. The finding of
      three types of responders will be important for future planning of counseling and
      educational interventions.

PMID- 12401735
TI  - Inside guidelines: comparative analysis of recommendations and evidence in
      diabetes guidelines from 13 countries.
AB  - OBJECTIVE: To compare guidelines on diabetes from different countries in order to
      examine whether differences in recommendations could be explained by use of
      different research evidence. RESEARCH DESIGN AND METHODS: We analyzed 15 clinical
      guidelines on type 2 diabetes from 13 countries using qualitative methods to
      compare the recommendations and bibliometric methods to measure the extent of
      overlap in citations used by different guidelines. A further qualitative analysis
      of recommendations and cited evidence for two specific issues in diabetes care
      explored the apparent discrepancy between recommendations and evidence. RESULTS:
      The recommendations made in the guidelines were in agreement about the general
      management of type 2 diabetes, with some important differences in treatment
      details. There was little overlap in evidence cited by the guidelines, with 18%
      (185/1,033) of citations shared with any other guideline, and only 10 studies
      (1%) appearing in six or more guidelines. The measurable overlap in evidence
      between guidelines increases if multiple publications from the same study and the
      use of reviews are taken into account. Research originating from the U.S.
      predominated (40% of citations); however, nearly all (11/12) guidelines were
      significantly more likely to cite evidence originating from their own countries.
      CONCLUSIONS: Despite the variation in cited evidence and preferential citation of
      evidence from a guideline's country of origin, we found a high degree of
      international consensus in recommendations made for the clinical care of type 2
      diabetes. The influence of professional bodies such as the American Diabetes
      Association may be an important factor in explaining international consensus.
      Globalization of recommended management of diabetes is not a simple consequence
      of the globalization of research evidence.

PMID- 12401736
TI  - Projected impact of implementing the results of the diabetes prevention program
      in the U.S. population.
AB  - OBJECTIVE: To determine the feasibility of using either fasting plasma glucose or
      HbA(1c) to identify individuals in the U.S. population who meet the Diabetes
      Prevention Program (DPP) criteria for intervention, defined as BMI >/=24 kg/m(2),
      fasting plasma glucose level 96-125 mg/dl, and 2-h glucose level 140-199 mg/dl in
      an oral glucose tolerance test (OGTT). RESEARCH DESIGN AND METHODS: Analysis of a
      representative sample of U.S. adults aged 40-74 years with no medical history of
      diabetes for whom data on height, weight, fasting plasma glucose, HbA(1c), and 2
      h plasma glucose during an OGTT were obtained. Sensitivity, specificity, positive
      predictive value (PPV), and receiver operator characteristic (ROC) curves for
      fasting glucose and HbA(1c) were determined. RESULTS: Using BMI <24 kg/m(2) as an
      initial criterion eliminated 27.2% of U.S. adults from further testing. Of the
      remaining group, 41.1% did not have to be considered for an OGTT because their
      fasting glucose level was below or above 96-125 mg/dl. Overall, 10.6% of adults
      aged 40-74 years without medical history of diabetes met the DPP eligibility
      criteria for intervention. Among individuals with BMI >/=24 kg/m(2) and fasting
      glucose level 96-125 mg/dl, applying a fasting plasma glucose cutoff of >/=105
      mg/dl excluded 62.5% of this group and resulted in 56.0% of those with 2-h
      glucose level 140-199 mg/dl in this group being identified, with a specificity of
      72.0% and a PPV of 17.1%. Similar values were obtained for an HbA(1c) cutoff
      value of >/=5.5%. CONCLUSIONS: Using data on BMI and setting cutoff values for
      fasting glucose and HbA(1c) would greatly reduce the number of individuals who
      would need to undergo an OGTT while achieving adequate sensitivity, specificity,
      and PPV.

PMID- 12401737
TI  - Impact of a program to improve adherence to diabetes guidelines by primary care
      physicians.
AB  - OBJECTIVES: Previous studies have shown that primary care physician (PCP)
      adherence to diabetes guidelines is suboptimal. We sought to determine the state
      of diabetes care given by independently practicing PCPs in a rural county in
      Indiana and whether a multifaceted intervention targeting PCPs, patients, and the
      health care system would improve adherence to diabetes guidelines. RESEARCH
      DESIGN AND METHODS: Baseline audits to assess adherence to diabetes guidelines
      were done on charts of the seven PCPs in the county. Audits were repeated after
      development of local consensus guidelines and feedback of baseline performance
      and after implementation of various interventions (practice aids, physician
      detailing, patient education sessions, and implementation of computerized
      individual meal planning). RESULTS: Before any intervention, rates of adherence
      to guidelines were low (15% for foot exams, 20% for HbA(1c) measurement, 23% for
      eye exam referrals, 33% for urine protein screening, 44% for lipid profiles, 73%
      for home glucose monitoring, and 78% for blood pressure measurements). One year
      after development of local consensus guidelines and feedback of baseline
      performance, significant improvements were seen in blood pressure measurements
      (71 vs. 83%; P = 0.002), foot exams (19 vs. 42%; P < 0.001), HbA(1c) measurements
      (26 vs. 37%; P = 0.012), and PCP eye exams (38 vs. 46%; P = 0.043); a trend
      toward improvement was seen in referral to eye specialists (25 vs. 33%; P =
      0.059). After a second year of multiple interventions, only blood pressure
      measurements (70 vs. 92%; P < 0.001) and foot exams (22 vs. 47%; P < 0.001)
      remained significantly improved; all other areas returned to rates
      indistinguishable from baseline. CONCLUSIONS: In busy primary care practices
      lacking organizational support and computerized tracking systems, sustained
      improvements in diabetes care are difficult to attain using traditional physician
      targeted approaches.

PMID- 12401738
TI  - The impact of planned care and a diabetes electronic management system on
      community-based diabetes care: the Mayo Health System Diabetes Translation
      Project.
AB  - OBJECTIVE: The Mayo Health System Diabetes Translation Project sought to assess
      models of community-based diabetes care and use of a diabetes electronic
      management system (DEMS). Planned care is a redesigned model of chronic disease
      care that involves guideline implementation, support of self-management, and use
      of clinical information systems. RESEARCH DESIGN AND METHODS: We studied adult
      diabetic patients attending three primary care practice sites in Wisconsin and
      Minnesota. We implemented planned care at all sites and DEMS in the practice of
      16 primary care providers. We assessed quality of diabetes care using standard
      indicators for 200 patients randomly selected from each site at baseline and at
      24 months of implementation. We used multivariable analyses to estimate the
      association between planned care and DEMS and each quality indicator. RESULTS:
      Planned care was associated with improvements in measurement of HbA(1c) (odds
      ratio 7.0 [95% CI 4.2-11.6]), HDL cholesterol (5.6 [4.1-7.5]), and
      microalbuminuria (5.3 [3.5-8.0]), as well as the provision of tobacco advice (6.9
      [4.7-10.1]), among other performance measures. DEMS use was associated with
      improvements in all indicators, including microalbuminuria (3.2 [1.9-5.2]),
      retinal examination (2.4 [1.5-3.9]), foot examinations (2.3 [1.2-4.4]), and self
      management support (2.6 [1.7-3.8]). Although planned care was associated with
      improvements in metabolic control, we observed no additional metabolic benefit
      when providers used DEMS. CONCLUSIONS: Planned care was associated with improved
      performance and metabolic outcomes in primary care. DEMS use augmented the impact
      of planned care on performance outcomes but not on metabolic outcomes. Optimal
      identification of the best translation of evidence to diabetes practice will
      require longer follow-up or new care-delivery models.

PMID- 12401739
TI  - Attributing inpatient medicare costs to diabetes among the Texas elderly.
AB  - OBJECTIVE: This study compares alternative methods for attributing hospital
      utilization and costs to diabetes. Findings from five "numerator" methods, found
      in the literature and based on presence of certain diagnoses or combinations of
      diagnoses in the billing records, were compared to benchmark findings derived
      from attributable risk calculations. RESEARCH DESIGN AND METHODS: Estimates of
      non-HMO, short-term, nonspecialized hospital stays, hospital days, and costs
      attributable to diabetes in Texas were derived from the 1995 Medicare inpatient
      database (MEDPAR) for persons aged at least 65 years at the end of 1994.
      Attributable risk calculations applied age-, sex-, and ethnicity-specific
      estimates of diabetes prevalence, based on the combined 1987-1994 National Health
      Interview Surveys, to 1995 Medicare non-HMO, Part A (hospital insurance)
      enrollment among the Texas elderly. Alternative prevalence estimates were based
      on the 1994-1996 Texas Behavioral Risk Factor Surveillance System. RESULTS: The
      five numerator methods yielded cost estimates that were 10, 10, 75, 144, and 172%
      of the benchmark estimate. CONCLUSIONS: This study documents great variation in
      diabetes cost estimates that might result from alternative methods for selecting
      diagnoses or combinations of diagnoses as criteria for attributing costs to
      diabetes. Whereas no method that ignores population prevalence yielded an
      accurate cost estimate, I suggest that further empirical study may be helpful in
      selecting those combinations of diagnoses that might, on average, reasonably
      estimate diabetes costs in situations where population denominators are
      unavailable or prevalence is unknown.

PMID- 12401740
TI  - Diabetes in employer-sponsored health insurance.
AB  - OBJECTIVE: To examine medical and mental health care expenditures for large
      numbers of individuals with diabetes enrolled in employment-sponsored insurance
      plans. RESEARCH DESIGN AND METHODS: Health insurance billing data for
      approximately 1.3 million individuals enrolled in health insurance plans
      sponsored by 862 large self-insured employers nationwide were used to examine
      employer expenditures and consumer out-of-pocket payments for 20,937 people
      identified with diabetes. These expenditures were compared with expenditures for
      individuals with other chronic illnesses. Main outcome measures were covered
      charges, insurance plan reimbursements, and estimated consumer out-of-pocket
      payments for both medical and mental health services. RESULTS: A total of 1.7% of
      enrollees were identified as having diabetes and approximately 11% of those used
      at least one mental health service during 1996. Health care expenditures were
      three times higher for those with diabetes compared with all health care
      consumers in these insurance plans, but when compared with individuals with other
      chronic illnesses such as heart disease, HIV/AIDS, cancer, and asthma, those with
      diabetes were not more expensive for employers' insurance plans. Diabetes
      accounts for 6.5% of total health plan expenditures. CONCLUSIONS: Diabetes is not
      more expensive for either consumers or their employer-sponsored insurance plans
      than other chronic illnesses.

PMID- 12401741
TI  - The epidemiology of type 1 diabetes in children in Philadelphia 1990-1994:
      evidence of an epidemic.
AB  - OBJECTIVE: To determine the epidemiology of type 1 diabetes in children in
      Philadelphia from 1990 to 1994, and to identify whether an epidemic occurred
      during that time period. RESEARCH DESIGN AND METHODS: This is a descriptive
      epidemiological study using a retrospective population-based registry in
      Philadelphia, PA, a city with large white, African-American, and Hispanic (Puerto
      Rican) populations. All hospitals in Philadelphia that admit children were
      identified. All charts meeting the following criteria were reviewed: 1) newly
      diagnosed type 1 diabetes, 2) children 0-14 years of age, 3) children residing in
      Philadelphia at the time of diagnosis, and 4) those diagnosed from 1 January 1990
      to 31 December 1994. Standard type 1 diabetes registry data were abstracted from
      the charts. Ascertainment of the completeness of the hospital registry was
      validated by data from the Philadelphia School District. Communicable disease
      records were reviewed to identify epidemics from 1987 to 1995. RESULTS: A total
      of 209 cases were identified, and the combined hospital and school registry was
      determined to be 96% complete. The overall age-adjusted incidence rate in
      Philadelphia was 13.3/100,000/year. The highest rate by race continues to be in
      the Hispanic population (15.5). The incidence in African-American children has
      increased markedly (12.8), particularly in the 10- to 14-year age-group (22.9).
      An epidemic of type 1 diabetes occurred from January to June 1993, approximately
      2 years after a measles epidemic in Philadelphia. CONCLUSIONS: The overall
      incidence of type 1 diabetes in Philadelphia is similar to other U.S. registries.
      The incidence in the Hispanic population continues to be among the highest of any
      U.S. ethnic group. The marked increase in incidence in the African-American
      population may be due in part to misclassification of cases actually having type
      2 diabetes. The 1993 epidemic may have been due to beta-cell autoimmunity
      triggered by the measles virus.

PMID- 12401742
TI  - Neighborhood characteristics and components of the insulin resistance syndrome in
      young adults: the coronary artery risk development in young adults (CARDIA)
      study.
AB  - OBJECTIVE: To examine associations of neighborhood characteristics with six
      components of the insulin resistance syndrome (IRS) in young adults. RESEARCH
      DESIGN AND METHODS: Cross-sectional data from the Coronary Artery Risk
      Development in Young Adults (CARDIA) Study were used to examine associations of
      neighborhood characteristics with the IRS in 3,093 nondiabetic adults aged 28-40
      years. Measures of BMI, fasting HDL cholesterol, triglycerides, insulin, glucose,
      and systolic blood pressure were combined into an IRS score. U.S. Census-derived
      neighborhood characteristics were summarized into a neighborhood socioeconomic
      score, with an increasing score signifying increasing socioeconomic advantage.
      RESULTS: Among white men and women, the IRS score was inversely related to
      neighborhood socioeconomic score. Neighborhood characteristics remained
      associated with the IRS score after controlling for personal income and education
      (adjusted mean differences for 95th vs. 5th percentile of neighborhood score: 
      0.24 standard deviation units [SE = 0.12] in men and -0.56 standard deviation
      units [SE = 0.10] in women). Among black participants, neighborhood score was
      inversely associated with IRS score in persons of high income and education (mean
      differences 95th vs. 5th percentile -0.54 [SE 0.26] in men and -0.52 [SE 0.26] in
      women) but positively associated or not associated with IRS score in persons of
      low income and education (mean differences 0.60 [SE 0.21] in men and 0.00 [SE
      0.16] in women). CONCLUSIONS: The IRS score is associated with neighborhood
      characteristics as early as young adulthood. Features of residential environments
      may be related to the development of insulin resistance.

PMID- 12401743
TI  - Incidence of falls, risk factors for falls, and fall-related fractures in
      individuals with diabetes and a prior foot ulcer.
AB  - OBJECTIVE: To describe the incidence of falls, risk factors for falls, and the
      frequency of fall-related fractures in a cohort of individuals with diabetes and
      a prior foot ulcer. RESEARCH DESIGN AND METHODS: A total of 400 individuals with
      diabetes and a prior foot ulcer were recruited from two western Washington State
      health care organizations and followed prospectively for 2 years. Diabetes,
      demographic, and health information was collected at baseline, 1 year, and 2
      years. Data on falls were collected at baseline, 4 weeks, and every 17 weeks
      thereafter. Medical records were abstracted to confirm fall-related morbidity.
      RESULTS: The average age of the study population was 62 years, with 77% male and
      23% female. Approximately 32% had fixed foot deformities, 58% had insensate feet,
      and 76% had comorbid conditions. Of the participants, 252 (64%) reported at least
      one fall during the 2-year study period. The overall incidence of falls in this
      cohort was 1.25 falls/person-year (95% CI 1.17-1.33). For the 164 participants
      (41%) who reported two or more falls, a BMI >/=30 kg/m(2), the presence of one or
      more comorbid conditions, and insensate feet increased the risk. Two or more
      falls of any type were associated with a higher fracture risk. Although women
      were not at significantly greater risk for falls than men, their fracture
      incidence was 3.6 times higher. CONCLUSIONS: Falls are very common in individuals
      with diabetes and prior foot ulcers. A small percentage of falls resulted in
      fractures. The risk of a fall-related fracture was significantly higher in women
      than in men. Increased attention to falls and fall prevention is indicated for
      diabetes care providers.

PMID- 12401744
TI  - Personal control and disordered eating in female adolescents with type 1
      diabetes.
AB  - OBJECTIVE: The onset and subsequent management of diabetes can challenge one's
      sense of control. Sense of control can also be affected by the biological changes
      accompanying normal pubertal development. The negative impact on one's sense of
      control may be further exacerbated when both events (i.e., diabetes and puberty)
      occur in relatively close temporal proximity. RESEARCH DESIGN AND METHODS: This
      study examined the relationship between sense of control and disordered eating
      and glycemic control in 45 female adolescents with type 1 diabetes. RESULTS: A
      lower sense of overall control and a lower sense of bodily control were both
      directly related to more severe eating-disordered symptoms. However, a lower
      sense of overall control and lower bodily control were related to poorer
      metabolic control primarily when the diagnosis of diabetes occurred closer to the
      onset of puberty. CONCLUSIONS: Clinicians should assess and monitor perceptions
      of control and also consider the temporal proximity of disease onset and onset of
      puberty when managing type 1 diabetes in female adolescents.

PMID- 12401746
TI  - A multivariate logistic regression equation to screen for diabetes: development
      and validation.
AB  - OBJECTIVE: To develop and validate an empirical equation to screen for diabetes.
      RESEARCH DESIGN AND METHODS: A predictive equation was developed using multiple
      logistic regression analysis and data collected from 1,032 Egyptian subjects with
      no history of diabetes. The equation incorporated age, sex, BMI, postprandial
      time (self-reported number of hours since last food or drink other than water),
      and random capillary plasma glucose as independent covariates for prediction of
      undiagnosed diabetes. These covariates were based on a fasting plasma glucose
      level >/=126 mg/dl and/or a plasma glucose level 2 h after a 75-g oral glucose
      load >/=200 mg/dl. The equation was validated using data collected from an
      independent sample of 1,065 American subjects. Its performance was also compared
      with that of recommended and proposed static plasma glucose cut points for
      diabetes screening. RESULTS: The predictive equation was calculated with the
      following logistic regression parameters: P = 1/(1 - e(-x)), where x = -10.0382 +
      [0.0331 (age in years) + 0.0308 (random plasma glucose in mg/dl) + 0.2500
      (postprandial time assessed as 0 to >/=8 h) + 0.5620 (if female) + 0.0346 (BMI)].
      The cut point for the prediction of previously undiagnosed diabetes was defined
      as a probability value >/=0.20. The equation's sensitivity was 65%, specificity
      96%, and positive predictive value (PPV) 67%. When applied to a new sample, the
      equation's sensitivity was 62%, specificity 96%, and PPV 63%. CONCLUSIONS: This
      multivariate logistic equation improves on currently recommended methods of
      screening for undiagnosed diabetes and can be easily implemented in a inexpensive
      handheld programmable calculator to predict previously undiagnosed diabetes.

PMID- 12401747
TI  - Clinical usefulness of cystatin C for the estimation of glomerular filtration
      rate in type 1 diabetes: reproducibility and accuracy compared with standard
      measures and iohexol clearance.
AB  - OBJECTIVE-Assessment and follow-up of early renal dysfunction is important in
      diabetic nephropathy. Plasma creatinine is insensitive for a glomerular
      filtration rate (GFR) >50 ml/min and creatinine clearance is unwieldy and subject
      to collection inaccuracies. We aimed to assess the reproducibility, reliability,
      and accuracy of plasma cystatin C as a measure of GFR ranging from normal to
      moderate impairment due to type 1 diabetes in the presence of a normal plasma
      creatinine concentration. RESEARCH DESIGN AND METHODS-A sensitive
      immunoturbidimetric cystatin C assay was examined in 29 subjects with type 1
      diabetes and 11 nondiabetic subjects. Duplicate measurements of the following
      were collected from each subject, 2 weeks apart: cystatin C, enzymatic plasma
      creatinine, 24-h creatinine clearance, GFR estimated from plasma creatinine by
      the Cockcroft-Gault equation, and iohexol clearance as a gold standard. RESULTS
      Iohexol clearance ranged from 35 to 132 ml. min(-1). 1.73 m(-2). Plasma cystatin
      C compared well with the other clinically used tests. The reliability of cystatin
      C, as assessed by the discriminant ratio, was superior to creatinine clearance
      (3.4 vs. 1.5, P < 0.001) and the correlation of cystatin C with iohexol clearance
      (Rs -0.80) was similar to that of creatinine clearance (Rs -0.74) and superior to
      that of plasma creatinine and the Cockcroft-Gault estimate (Rs -0.54 and 0.66,
      respectively). Duplicate estimations were used to provide an unbiased equation to
      convert plasma cystatin C to GFR. CONCLUSIONS-Based on this study, cystatin C is
      a more reliable measure of GFR than creatinine clearance, is more highly
      correlated with iohexol clearance than plasma creatinine, and is worthy of
      further investigation as a clinical measure of GFR in type 1 diabetes.

PMID- 12401745
TI  - Psychological and behavioral correlates of baseline BMI in the diabetes
      prevention program (DPP).
AB  - OBJECTIVE: To determine psychological and behavioral correlates of baseline BMI
      in the Diabetes Prevention Program (DPP). RESEARCH DESIGN AND METHODS: Of 1,079
      DPP lifestyle intervention participants, 274 completed validated questionnaires
      at baseline assessing weight loss history, stage of change, self-efficacy,
      dietary restraint, emotional eating, binge eating, perceived stress, depression,
      and anxiety. RESULTS: The mean age of subjects was 52.5 years, 65% were women,
      and their mean BMI was 33.9 kg/m(2). Higher BMI correlated with more frequent
      weight cycling (r = 0.50, P < 0.0001) and efforts at weight loss (r = 0.34, P <
      0.0001); younger age when first overweight (r = -0.42, P < 0.0001); lower
      exercise efficacy (r = -0.15, P = 0.015); lower weight loss efficacy (r = -0.21,
      P < 0.001); a less advanced stage of change for weight loss (r = -0.12, P =
      0.04); more perceived stress (r = 0.14, P = 0.02); emotional eating (r = 0.19, P
      = 0.001); poor dietary restraint (r = -0.14, P = 0.02); binge eating frequency (r
      = 0.18, P = 0.004) and severity (r = 0.30, P < 0.0001); feeling deprived, angry,
      or upset while dieting (r = 0.27, P </= 0.0001); and food cravings while dieting
      (r = 0.31, P < 0.0001). Correlations did not differ as a function of sex;
      however, correlations of BMI with anxiety and low-fat diet and weight loss self
      efficacy differed as a function of ethnicity. In multivariate models, binge
      eating severity, poor dietary restraint, and food craving were independent
      correlates of baseline BMI. CONCLUSIONS: Many psychological and behavioral
      factors are associated with higher BMI in this ethnically diverse group of men
      and women. Whether strategies that help patients increase levels of dietary
      restraint and reduce binge eating and food craving lead to long-term weight loss
      maintenance needs longitudinal study.

PMID- 12401748
TI  - Can motor nerve conduction velocity predict foot problems in diabetic subjects
      over a 6-year outcome period?
AB  - OBJECTIVE: This study examined motor nerve conduction velocity (MNCV) and other
      peripheral nerve and vascular tests as predictors for foot ulceration,
      amputation, and mortality in diabetes over a 6-year follow-up period. RESEARCH
      DESIGN AND METHODS: We recruited 169 diabetic subjects (without significant
      peripheral vascular disease with an ankle brachial pressure index [ABPI] >/=0.75)
      for the study and separated them into groups (to ensure diversity of nerve
      function). The control group consisted of 22 nondiabetic people. At baseline, all
      subjects underwent assessment of MNCV; vibration, pressure, and temperature
      perception thresholds; peripheral vascular function; and other diabetes
      assessments. RESULTS: Over the 6-year outcome period, 37.3% of the diabetic
      subjects developed at least one new ulcer, 11.2% had a lower-limb amputation
      (LLA) (minor or major), and 18.3% died. Using multivariate Cox's regression
      analysis (RR [95% CI] and removing previous ulcers as a confounding variable,
      MNCV was found to be the best predictor of new ulceration (0.90 [0.84-0.96], P =
      0.001) and the best predictors of amputation were pressure perception threshold
      (PPT) (5.18 [1.96-13.68], P = 0.001) and medial arterial calcification (2.88
      [1.13-7.35], P = 0.027). Creatinine (1.01 [1.00-1.01], P < 0.001), MNCV (0.84
      [0.73-0.97], P = 0.016), and skin oxygen levels (14.32 [3.04-67.52], P = 0.001)
      were the best predictors of mortality. CONCLUSIONS: This study shows that MNCV,
      which is often assessed in clinical trials of neuropathy, can predict foot
      ulceration and death in diabetes. In addition, tests of PPT and medial arterial
      calcification can be used in the clinic to predict LLA in diabetic subjects.

PMID- 12401749
TI  - Prospective study of C-reactive protein in relation to the development of
      diabetes and metabolic syndrome in the Mexico City Diabetes Study.
AB  - OBJECTIVE: Recent evidence suggests that C-reactive protein (CRP) may predict
      development of diabetes in Caucasian populations. We evaluated CRP as a possible
      risk factor of the development of diabetes and metabolic syndrome in a 6-year
      study of 515 men and 729 women from the Mexico City Diabetes Study. RESEARCH
      DESIGN AND METHODS: Baseline CRP, indexes of adiposity, and insulin resistance
      (homeostasis model assessment [HOMA-IR]) were used to predict development of the
      metabolic syndrome, defined as including two or more of the following: 1)
      dyslipidemia (triglyceride >/=2.26 mmol/l or HDL cholesterol </=0.91 mmol/l in
      men and </=1.17 mmol/l in women; <35 and 40 mg/dl for men and women); 2)
      hypertension (blood pressure >140/90 mmHg or on hypertensive medication); or 3)
      diabetes (1999 World Health Organization criteria). RESULTS: At baseline, CRP
      correlated significantly (P < 0.001) with all metabolic indexes in women, but
      less so in men. After 6 years, 14.2% of men and 16.0% of women developed the
      metabolic syndrome. Compared with tertile 1, women with CRP in the highest
      tertile had an increased relative risk of developing the metabolic syndrome by
      4.0 (95% CI 2.0-7.9) and diabetes by 5.5 (2.2-13.5); these risks changed
      minimally after adjusting for BMI or HOMA-IR. The area under receiver-operating
      characteristic (ROC) curve for the prediction of the development of the syndrome
      was 0.684 for CRP, increasing to 0.706 when combined with BMI and to 0.710 for a
      complex model of CRP, BMI, and HOMA-IR. CONCLUSIONS: CRP was not a significant
      predictor of the development of the metabolic syndrome in men. Our data strongly
      support the notion that inflammation is important in the pathogenesis of diabetes
      and metabolic disorders in women.

PMID- 12401750
TI  - Biological variation of homeostasis model assessment-derived insulin resistance
      in type 2 diabetes.
AB  - OBJECTIVE: Individuals with type 2 diabetes are particularly vulnerable to
      cardiovascular disease. Insulin resistance is a major determinant of this
      increased risk and is a potential therapeutic target. This study was undertaken
      to establish the natural biological variation of insulin resistance in
      individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS: The biological
      variation of insulin resistance was assessed by measuring insulin resistance at 4
      day intervals on 10 consecutive occasions in 12 postmenopausal women with diet
      controlled type 2 diabetes and in 11 weight- and age-matched postmenopausal women
      without type 2 diabetes. Insulin resistance was derived using the homeostasis
      model assessment for insulin resistance (HOMA-IR) method. RESULTS: The
      distribution of HOMA-IR was log Gaussian in the type 2 diabetic study group and
      Gaussian in the control group. The HOMA-IR in the type 2 diabetic group was
      significantly greater than that of the control group (mean +/- SD: 4.33 +/- 2.3
      vs. 2.11 +/- 0.79 units, P = 0.001). After accounting for analytical variation,
      the mean intraindividual variation was also substantially greater in the type 2
      diabetic group than in the control group (mean 1.05 vs. 0.15, P = 0.001).
      Consequently, at any level of HOMA-IR, a subsequent sample must increase by >90%
      or decrease by >47% to be considered significantly different from the first.
      CONCLUSIONS: HOMA-IR is significantly greater and more variable for individuals
      with type 2 diabetes. Therefore, this inherent variability needs to be accounted
      for in studies evaluating therapeutic reduction of HOMA-IR in this group.

PMID- 12401751
TI  - Concomitance of diabetic retinopathy and proteinuria accelerates the rate of
      decline of kidney function in type 2 diabetic patients.
AB  - OBJECTIVE: To evaluate the rate of progression of renal disease in proteinuric
      type 2 diabetic patients with and without retinopathy. RESEARCH DESIGN AND
      METHODS: Thirty-eight proteinuric type 2 diabetic patients with diabetic
      retinopathy and 27 without were enrolled in an observational study for the
      evaluation of rate of glomerular filtration rate (GFR) decline and followed up
      for a median period of 6 years. GFR was determined at least once per year, and
      blood pressure, glycated hemoglobin, and proteinuria were determined every 4
      months. RESULTS: Although the two groups had comparable GFR, albuminuria, blood
      pressure, and HbA(1c) at entry of the study, the rate of decline of GFR was
      higher in type 2 diabetic patients with retinopathy (-6.5 +/- 4.4 ml/year) than
      in those without (-1.8 +/- 4.8 ml/year; P < 0.0001). Protein and albumin
      excretion rate increased significantly in patients with retinopathy, while they
      did not change in those without. Mean blood pressure between the two groups of
      patients were similar both at entry and during the follow-up, although the
      proportion of patients treated with at least two antihypertensive drugs was
      higher in patients with retinopathy. On a multiple regression analysis, only mean
      blood pressure and proteinuria were significant determinants of progression of
      renal disease in type 2 diabetic patients with retinopathy. CONCLUSIONS: The rate
      of progression of renal disease in proteinuric type 2 diabetic patients with
      retinopathy is faster than that observed in those without retinopathy. The
      screening for retinopathy identifies patients at high risk for rapid
      deterioration of kidney function.

PMID- 12401752
TI  - Cardiac events in 735 type 2 diabetic patients who underwent screening for
      unknown asymptomatic coronary heart disease: 5-year follow-up report from the
      Milan Study on Atherosclerosis and Diabetes (MiSAD).
AB  - OBJECTIVE: To report the cardiac events in type 2 diabetic outpatients screened
      for unknown asymptomatic coronary heart disease (CHD) and followed for 5 years.
      RESEARCH DESIGN AND METHODS: During 1993, 925 subjects aged 40-65 years underwent
      an exercise treadmill test (ETT). If it was abnormal, the subjects then underwent
      an exercise scintigraphy. Of the 925 subjects, 735 were followed for 5 years and
      cardiac events were recorded. RESULTS: At the entry of the study, 638 of the 735
      followed subjects had normal ETT, 45 had abnormal ETT with normal scintigraphy,
      and 52 had abnormal ETT and abnormal scintigraphy. The 52 subjects with abnormal
      scintigraphy and ETT underwent a cardiological and diabetological follow-up; the
      subjects with just abnormal ETT had a diabetological follow-up only. During the
      follow-ups, 42 cardiac events occurred: 1 fatal myocardial infarction (MI), 20
      nonfatal MIs, and 10 cases of angina in the 638 subjects with normal ETT; 1 fatal
      MI in the 45 subjects with normal scintigraphy; and 1 fatal MI and 9 cases of
      angina in the 52 subjects with abnormal scintigraphy. In these 52 subjects all
      cardiac events were significantly more frequent (chi(2) = 21.40, P < 0.0001) but
      the ratio of major (cardiac death and MI) to minor (angina) cardiac events was
      significantly lower (P = 0.002). Scintigraphy abnormality (hazard ratio 5.47; P <
      0.001; 95% CI 2.43-12.29), diabetes duration (1.06; P = 0.021; 1.008-1.106), and
      diabetic retinopathy (2.371; P = 0.036; 1.059-5.307) were independent predictors
      of cardiac events on multivariate analysis. CONCLUSIONS: The low ratio of major
      to minor cardiac events in the positive scintigraphy group may suggest, although
      it does not prove, that the screening program followed by appropriate management
      was effective for the reduction of risk of major cardiac events.

PMID- 12401753
TI  - Proteinuria as a predictor of total plasma homocysteine levels in type 2 diabetic
      nephropathy.
AB  - OBJECTIVE: Patients with diabetes who manifest proteinuria are at increased risk
      for cardiovascular events. Some studies suggest that proteinuria exerts its
      cardiovascular effects at least partly through a positive association with total
      plasma homocysteine (tHcy). Modestly sized but better designed contrary studies
      find no such link through a limited range of serum creatinine and proteinuria. We
      tested the hypothesis that proteinuria independently predicts tHcy levels in a
      larger cohort of type 2 diabetic patients with nephropathy throughout a much
      broader range of kidney disease and proteinuria. RESEARCH DESIGN AND METHODS:
      Baseline data for the cross-sectional study were obtained from 717 patients
      enrolled in the multicenter Irbesartan Diabetic Nephropathy Trial. All subjects
      had type 2 diabetes, hypertension, and proteinuria and were between 29 and 78
      years of age. Data included age, sex, BMI, serum creatinine and albumin, LDL and
      HDL cholesterol, triglyceride, proteinuria and albuminuria, plasma folate, B12,
      and pyridoxal 5'-phosphate (PLP) (the active form of B6), HbA(1c), and tHcy
      levels. Unadjusted and multivariable models were used in the analysis. RESULTS:
      Crude analyses revealed significant associations between tHcy and age (r = 0.074;
      P = 0.008), creatinine (r = 0.414; P < 0.001), PLP (r = -0.105; P = 0.021), B12
      (r = -0.216; P < 0.001), folate (r = -0.241; P < 0.001), and HbA(1c) (r = -0.119;
      P = 0.003), with serum albumin approaching significance (r = 0.055; P = 0.072).
      Only serum creatinine, plasma folate, B12, serum albumin, sex, HbA(1c), and age
      were independent predictors of tHcy after controlling for all other variables.
      CONCLUSIONS: By finding no independent correlation between proteinuria (or
      albuminuria) and tHcy levels, this study improves the external validity of
      previous negative findings. Therefore, it is unlikely that the observed positive
      association between proteinuria and cardiovascular disease is directly related to
      hyperhomocysteinemia.

PMID- 12401754
TI  - Influence of metabolic control on splanchnic glucose uptake, insulin sensitivity,
      and the time required for glucose absorption in patients with type 1 diabetes.
AB  - OBJECTIVE: The relationship between splanchnic glucose uptake (SGU) after oral
      glucose administration and metabolic control in type 1 diabetic patients is
      controversial. We estimated SGU as well as peripheral glucose uptake and the time
      required for glucose absorption by a validated method, the oral glucose (OG)
      clamp, in type 1 diabetic patients with different levels of long-term glycemic
      control. RESEARCH DESIGN AND METHODS: An OG clamp (which combines a
      hyperinsulinemic clamp [120 mU. m(-2). min(-1)] with an OR load [75 g] during
      steady-state glucose uptake) was performed in eight type 1 diabetic patients with
      good metabolic control (DG) (HbA(1c) 6.1 +/- 0.2%, BMI 23.1 +/- 0.7 kg/m(2)),
      eight type 1 diabetic patients with poor metabolic control (DP) (HbA(1c) 8.5 +/-
      0.3%, BMI 25.4 +/- 1.4 kg/m(2)), and eight healthy matched control subjects (C)
      (HbA(1c) 5.1 +/- 0.1%, BMI 25 +/- 1.3 kg/m(2)) to determine SGU, glucose uptake,
      and glucose absorption. RESULTS: Glucose uptake calculated from 120 to 180 min
      during the clamp was 9.13 +/- 0.55 mg. kg(-1). min(-1) in C, 8.18 +/- 0.71 mg.
      kg(-1). min(-1) in DG, and 7.42 +/- 0.96 mg. kg(-1). min(-1) in DP (NS). Glucose
      absorption was 140 +/- 6 min in C, 156 +/- 4 min in DG, and 143 +/- 7 min in DP
      (NS). The respective calculated SGU was 14.5 +/- 5.6% in C, 17.8 +/- 3.1% in DG,
      and 18.8 +/- 4.2% in DP (NS) and did not correlate with HbA(1c) values.
      CONCLUSIONS: Peripheral glucose uptake, SGU after oral glucose administration,
      and the glucose absorption time were not different in type 1 diabetic patients
      independent of glycemic control when compared with healthy subjects.

PMID- 12401755
TI  - Validation of the Toronto Clinical Scoring System for diabetic polyneuropathy.
AB  - OBJECTIVE: The aim of the current study was to determine the validity of the
      Toronto Clinical Scoring System (CSS) in reflecting the presence and severity of
      diabetic peripheral sensorimotor polyneuropathy (DSP) as determined by myelinated
      fiber density (FD) on sural nerve biopsy. RESEARCH DESIGN AND METHODS: Eighty
      nine patients with both type 1 and type 2 diabetes, ascertained from a large
      therapeutic randomized controlled trial, were included in this cross-sectional,
      observational cohort study. Morphological severity of DSP was expressed as the FD
      in the sural nerve biopsy. The Toronto CSS was applied to all patients to
      determine a clinical neuropathy score. General linear regression models were used
      to assess the relationship between the morphological severity of DSP and the
      Toronto CSS. RESULTS: The Toronto CSS showed a significant negative correlation
      with sural nerve FD (R(2) = 0.256, P < 0.0001). The Toronto CSS was lower in
      those with better glycemic control (HbA(1c) </=8%). Sural nerve FD and the
      Toronto CSS showed strong correlations with electrophysiology, by both summed
      amplitude and summed conduction velocity values. CONCLUSIONS: The Toronto CSS is
      a valid instrument to reflect the presence and severity of DSP as measured by
      sural nerve morphology and electrophysiology. The results of the current study
      underscore the interrelationships between clinical deficits, electrophysiological
      findings, and morphological changes in DSP. This evidence suggests that the
      Toronto CSS may prove useful in documenting and monitoring DSP in the clinic and
      in clinical research trials.

PMID- 12401756
TI  - A direct comparison of insulin aspart and insulin lispro in patients with type 1
      diabetes.
AB  - OBJECTIVE: Both rapid-acting insulin analogs, insulin aspart and lispro,
      attenuate prandial glucose excursion compared with human soluble insulin. This
      trial was performed to study the pharmacokinetic and pharmacodynamic profiles of
      insulin aspart and insulin lispro in type 1 diabetic patients in a direct
      comparison and to investigate whether the administration of one analog results in
      favorable effects on prandial blood glucose control. RESEARCH DESIGN AND METHODS:
      A total of 24 type 1 diabetic patients (age 36 +/- 8 years, 16 men and 8 women,
      BMI 24.3 +/- 2.6 kg/m(2), diabetes duration 17 +/- 11 years, HbA(1c) 7.9 +/-
      0.8%) on intensified insulin therapy were recruited into a single-center,
      randomized, double-blind, two-period, cross-over, glucose clamp trial. The
      subjects were given an individual need-derived dose of prandial insulin lispro or
      aspart immediately before a standard mixed meal. RESULTS: With respect to blood
      glucose excursions from time 0 to 6 h (Exc(glu(0-6 h))) and from time 0 to 4 h
      (Exc(glu(0-4 h))), the pharmacodynamic effect of insulin aspart and insulin
      lispro can be declared equivalent. This was supported by comparison with maximum
      postprandial blood glucose excursions (C(max(glu))) (estimated ratio
      aspart/lispro ANOVA [90% CI]: 0.95 [0.80-1.13], 0.97 [0.82-1.17], and 1.01 [0.95
      1.07] for Exc(glu(0-6 h)), Exc(glu(0-4 h)), and C(max(glu)), respectively). For
      pharmacokinetic end points (maximum postprandial insulin excursions and area
      under the curve for insulin from time 0 to 6 h and from time 0 to 4 h),
      equivalence was indicated. No difference concerning absorption or elimination for
      time to maximal insulin concentration, time to half-maximum insulin
      concentration, and time to decrease to 50% of maximum insulin concentration was
      observed. CONCLUSIONS: These data suggest that in type 1 diabetic patients, both
      insulin analogs are equally effective for control of postprandial blood glucose
      excursions.

PMID- 12401757
TI  - A comparison of the effects of rosiglitazone and glyburide on cardiovascular
      function and glycemic control in patients with type 2 diabetes.
AB  - OBJECTIVE: This open-label, active-controlled study investigated the cardiac
      safety and antihyperglycemic effect of rosiglitazone (RSG) in patients with type
      2 diabetes. RESEARCH DESIGN AND METHODS: Of the 203 patients randomly assigned to
      RSG (4 mg b.i.d.) or glyburide (GLB) (titrated to achieve optimal glycemic
      control for the first 8 weeks only to limit the risk of hypoglycemia; mean 10.5
      mg/day), 118 had an echocardiogram performed at week 52. Left ventricular (LV)
      mass index, ejection fraction, and left ventricular end-diastolic volume were
      assessed by M-mode echocardiography at baseline and weeks 12, 28, and 52; 24-h
      ambulatory blood pressure was assessed at baseline and at weeks 28 and 52.
      Glycemic control was assessed by measuring fasting plasma glucose (FPG) and
      HbA(1c). RESULTS: Neither treatment produced an increase in LV mass index that
      exceeded 1 SD. Ejection fraction did not change in either group. Both groups had
      clinically insignificant increases in LV end-diastolic volume. RSG, but not GLB,
      caused a statistically significant reduction in ambulatory diastolic blood
      pressure. Both treatments reduced HbA(1c) and FPG. CONCLUSIONS: A total of 52
      weeks of therapy with RSG (4 mg b.i.d.) did not adversely affect cardiac
      structure or function in patients with type 2 diabetes and produced significant
      and sustained reductions in hyperglycemia. Decreases in ambulatory diastolic
      blood pressure with RSG were superior to those with GLB.

PMID- 12401758
TI  - Acute effect of glimepiride on insulin-stimulated glucose metabolism in glucose
      tolerant insulin-resistant offspring of patients with type 2 diabetes.
AB  - OBJECTIVE: This study addressed whether acute infusion of glimepiride influences
      glucose metabolism independent of its effect on insulin secretion. RESEARCH
      DESIGN AND METHODS: Ten healthy, glucose-tolerant but insulin-resistant probands
      were subjected to a placebo-controlled, double-blind, cross-over study. Each
      individual received infusions of either 0.15 mol/l saline or glimepiride in
      randomized order on two separate occasions. A three-step hyperinsulinemic (0.5,
      1.0, and 1.5 mU. kg(-1). min(-1))-euglycemic glucose clamp was performed on both
      occasions to determine insulin sensitivity. Glimepiride-induced insulin secretion
      was inhibited by octreotide. Endogenous glucose production and glucose
      elimination were measured with the "hot" glucose infusion method using U
      [(13)C]glucose as tracer. Glucose oxidation was determined from indirect
      calorimetry. Lipolysis was evaluated by measurements of nonesterified fatty acid
      (NEFA) and glycerol concentration and measurement of glycerol production.
      RESULTS: Plasma glucose and insulin concentrations were not significantly
      different between glimepiride or saline infusions. There was a significant
      increase in the rate of glucose infusion necessary to maintain euglycemia during
      infusion of glimepiride during the low- (12.2 +/- 1.1 vs. 16.1 +/- 1.7 micro mol.
      kg(-1). min(-1)) and intermediate-dose insulin infusion (24.4 +/- 1.7 vs. 30.0 +/
      2.8 micro mol. kg(-1). min(-1)). This was explained by an increased rate of
      glucose elimination and to a lesser degree by a decrease in glucose production.
      Glucose oxidation rate was not different. NEFA and glycerol concentration and
      glycerol production were equally suppressed. CONCLUSIONS: Glimepiride improves
      peripheral glucose uptake and decreases endogenous glucose production independent
      of its insulin secretagogue action. The effects shown in this acute study are,
      however, too small to be considered therapeutically beneficial for the individual
      patient.

PMID- 12401759
TI  - A randomized trial of continuous subcutaneous insulin infusion and intensive
      injection therapy in type 1 diabetes for patients with long-standing poor
      glycemic control.
AB  - OBJECTIVE: To assess in a randomized crossover trial the efficacy of continuous
      subcutaneous insulin infusion in improving glycemic control and health-related
      quality of life in type 1 diabetic patients with long-standing poor glycemic
      control. RESEARCH DESIGN AND METHODS: A total of 79 patients in 11 Dutch centers
      were randomized to 16 weeks of continuous subcutaneous insulin infusion followed
      by 16 weeks intensive injection therapy or the reverse order. Glycemic control
      was assessed by HbA(1c), self-reported hypoglycemic events, and blood glucose
      memory meter read outs. Changes in quality of life were assessed by self-report
      questionnaires administered at baseline and 16 weeks. RESULTS: As the drop-out
      rate after crossover was high (17 of 79 patients [22%]), we analyzed the trial as
      a parallel clinical trial, using data of the first half of the crossover phase
      only. At 16 weeks, mean HbA(1c) was 0.84% (95% CI -1.31 to -0.36) lower in the
      continuous subcutaneous insulin infusion group compared with the insulin
      injection group (P = 0.002). Stability of blood glucose self-measurement values,
      expressed as SD of the nine-point blood glucose profiles, improved in the insulin
      pump group by 29.3 +/- 41.1 vs. 8.2 +/- 36.5% in the injection group (P = 0.039).
      The number of mild hypoglycemic episodes per patient-week was 0.99 (95% CI 0.11
      1.87) higher in the insulin pump group (P = 0.028). Weight gain was similar in
      both groups. Scores on the Short-Form 36-Item subscales 'general health' and
      'mental health' improved in the continuous subcutaneous insulin infusion group,
      compared with stable values in the injection group (P = 0.048 and 0.050,
      respectively). CONCLUSIONS: Continuous subcutaneous insulin infusion improves
      glycemic control and some aspects of health-related quality of life in patients
      with a history of long-term poor glycemic control.

PMID- 12401761
TI  - Obesity, hypertension, and insulin resistance.

PMID- 12401760
TI  - Indices of insulin action, disposal, and secretion derived from fasting samples
      and clamps in normal glucose-tolerant black and white children.
AB  - OBJECTIVE: To validate fasting indices of insulin sensitivity and secretion in a
      diverse pediatric population against gold standard estimates from euglycemic and
      hyperglycemic clamps. RESEARCH DESIGN AND METHODS: A total of 31 children (mean
      BMI 25.1 +/- 4.9 kg/m(2), mean age 8.7 +/- 1.4 years, 15 girls and 16 boys, 12
      black and 19 white) underwent euglycemic and hyperglycemic clamps 2-6 weeks apart
      to derive insulin sensitivity indices (SI (Eug clamp) and SI (Hyper clamp)).
      Fasting samples were used to derive the homeostasis model assessment of insulin
      resistance index (HOMA-IR), HOMA of percent beta-cell function (HOMA-B%),
      quantitative insulin sensitivity check index (QUICKI), insulinogenic index,
      antilipolytic insulin sensitivity index (ISI-FFA), and C-peptide-to-insulin
      ratio. RESULTS: The QUICKI correlated best with SI (Eug clamp) (r = 0.69, P <
      0.05) and had greater correlations to SI (Eug clamp) than did either SI (Hyper
      clamp) (r = 0.45, P < 0.05) or the HOMA-IR (r = -0.51, P < 0.05). Both fasting
      insulin and the insulinogenic index correlated well with first- and steady-phase
      insulin secretion (r's from 0.79 to 0.86, P < 0.05). HOMA-B% was not as highly
      correlated (r = 0.69-0.72, P < 0.05). Fasting C-peptide-to-insulin ratio was not
      significantly correlated with clamp-derived metabolic clearance rate of insulin.
      ISI-FFA was not correlated with the degree of free fatty acid suppression
      obtained from the clamps. CONCLUSIONS: The QUICKI, fasting insulin, and the
      insulinogenic index all closely correlate with corresponding clamp-derived
      indices of insulin sensitivity and secretion in this diverse pediatric cohort.
      These results, if replicated in similarly diverse populations, suggest that
      estimates based on fasting samples can be used to rank order insulin secretion
      and sensitivity in pediatric cohorts.

PMID- 12401762
TI  - Identifying the target population for primary prevention: the trade-offs.

PMID- 12401763
TI  - To pump or not to pump.

PMID- 12401764
TI  - Cost-effectiveness of two screening programs for microalbuminuria in type 2
      diabetes.

PMID- 12401765
TI  - Self-monitored blood glucose in pregnant women without gestational diabetes
      mellitus.

PMID- 12401766
TI  - Pulmonary mucormycosis in a diabetic patient with HIV.

PMID- 12401767
TI  - A mitochondrial genotype associated with the development of autoimmune-related
      type 1 diabetes.

PMID- 12401769
TI  - The prevalence of hypertension and utilization of antihypertensive therapy in a
      district diabetes population.

PMID- 12401768
TI  - Cockcroft's formula underestimates glomerular filtration rate in diabetic
      subjects treated by lipid-lowering drugs.

PMID- 12401770
TI  - A case of recurrent and fatal hypothermia in a man with diabetic neuropathy.

PMID- 12401771
TI  - Incidence and costs of severe hypoglycemia.

PMID- 12401772
TI  - Psychological impact of changing the scale of reported HbA(1c) results affects
      metabolic control.

PMID- 12401773
TI  - The role of hemochromatosis C282Y and H63D gene mutations in type 2 diabetes:
      findings from the Rotterdam Study and meta-analysis.

PMID- 12401774
TI  - Forgot to fast?: The importance on plasma glucose values.

PMID- 12401775
TI  - The use of alkali therapy in severe diabetic ketoacidosis.

PMID- 12401776
TI  - Alternative-site blood glucose measurement at the abdomen.

PMID- 12401777
TI  - The long-term effects of self-management education for patients with type 2
      diabetes on glycemic control: response to Norris et al.

PMID- 12401778
TI  - Editor's comment: "It ain't necessarily so".

PMID- 12401779
TI  - Repair of dihydrouracil supported by base excision repair in mNTH1 knock-out cell
      extracts.
AB  - In mammalian cells, thymine glycols and other oxidized pyrimidines such as 5,6
      dihydrouracil are removed from DNA by the NTH1 protein, a bifunctional DNA-N
      glycosylase. However, mNTH1 knock-out mice in common with other DNA glycosylase
      deficient mice do not show any severe abnormalities associated with accumulation
      of DNA damage and mutations. In the present study we used an in vitro repair
      system to investigate the mechanism for the removal of 5,6-dihydrouracil from DNA
      by mNTH1-deficient cell-free extracts derived from testes of mNTH1 knock-out
      mice. We found that these extracts are able to support the removal of 5,6
      dihydrouracil from DNA at about 20% of the efficiency of normal extracts.
      Furthermore, we also found that single-nucleotide patch base excision repair is
      the major pathway for removal of 5,6-dihydrouracil in mNTH1-deficient cell
      extracts, suggesting the involvement of other DNA glycosylase(s) in the removal
      of oxidized pyrimidines.

PMID- 12401780
TI  - Inhibition of Tat-mediated transactivation and HIV-1 replication by human anti
      hCyclinT1 intrabodies.
AB  - Human immunodeficiency virus, type 1 (HIV-1) replication requires the interaction
      of Tat protein with the human cyclinT1 (hCyclinT1) subunit of the positive
      transcription elongation factor (P-TEFb) complex, which then cooperatively binds
      to transactivation response element (TAR) RNA to transactivate HIV transcription.
      In this report, a non-immune human single-chain antibody (sFv) phage display
      library was used to isolate anti-hCyclinT1 sFvs that could disrupt hCyclinT1-Tat
      interactions. The N-terminal 272 residues of hCyclinT1, including the entire
      cyclin domains and the Tat.TAR recognition motif (TRM), that fully support Tat
      transactivation was used for panning, and of the five unique anti-hCyclinT1 sFvs
      that were obtained, three bound to the cyclin box domains and two bound to TRM.
      All sFvs could be expressed as intrabodies at high levels in transiently
      transfected 293T and in stable Jurkat and SupT1 transfectants and could
      specifically co-immunoprecipitate co-expressed hCyclinT1 in 293T cells with
      varying efficacy without disrupting hCyclinT1-Cdk9 interactions. In addition, two
      sFv clones (3R6-1 and 2R6-21) that mapped to the cyclin box domains markedly
      inhibited Tat-mediated transactivation in several transiently transfected cell
      lines without inhibiting basal transcription or inducing apoptosis. When HIV-1
      challenge studies were performed on stable 3R6-1-expressing Jurkat T cells, near
      complete inhibition of viral replication was obtained at a low challenge dose,
      and 74-88% inhibition to HIV-1 replication was achieved at a high infection dose
      in SupT1 cells. These results provide proof-in-principle that anti-hCyclinT1
      intrabodies can be designed to block HIV-1 replication without causing cellular
      toxicity, and as a result, they may be useful agents for "intracellular
      immunization"-based gene therapy strategies for HIV-1 infection/AIDS.

PMID- 12401781
TI  - Differential effects of peroxynitrite on human mitochondrial creatine kinase
      isoenzymes. Inactivation, octamer destabilization, and identification of involved
      residues.
AB  - Creatine kinase isoenzymes are very susceptible to free radical damage and are
      inactivated by superoxide radicals and peroxynitrite. In this study, we have
      analyzed the effects of peroxynitrite on enzymatic activity and octamer stability
      of the two human mitochondrial isoenzymes (ubiquitous mitochondrial creatine
      kinase (uMtCK) and sarcomeric mitochondrial creatine kinase (sMtCK)), as well as
      of chicken sMtCK, and identified the involved residues. Inactivation by
      peroxynitrite was concentration-dependent and similar for both types of MtCK
      isoenzymes. Because peroxynitrite did not lower the residual activity of a sMtCK
      mutant missing the active site cysteine (C278G), oxidation of this residue is
      sufficient to explain MtCK inactivation. Mass spectrometric analysis confirmed
      oxidation of Cys-278 and further revealed oxidation of the C-terminal Cys-358,
      possibly involved in MtCK/membrane interaction. Peroxynitrite also led to
      concentration-dependent dissociation of MtCK octamers into dimers. In this study,
      ubiquitous uMtCK was much more stable than sarcomeric sMtCK. Mass spectrometric
      analysis revealed chemical modifications in peptide Gly-263-Arg-271 located at
      the dimer/dimer interface, including oxidation of Met-267 and nitration of Trp
      268 and/or Trp-264, the latter being a very critical residue for octamer
      stability. These data demonstrate that peroxynitrite affects the octameric state
      of MtCK and confirms human sMtCK as the generally more susceptible isoenzyme. The
      results provide a molecular explanation of how oxidative damage can lead to
      inactivation and decreased octamer/dimer ratio of MtCK, as seen in
      neurodegenerative diseases and heart pathology, respectively.

PMID- 12401782
TI  - Functional analysis of cdc42 residues required for Guanine nucleotide exchange.
AB  - Guanine nucleotide exchange factors (GEFs) directly engage small GTPases to
      facilitate the exchange of bound GDP for GTP, leading to GTPase activation.
      Several recent crystal structures of GEFs in complex with Rho family GTPases
      highlight the conserved interactions and conformational alterations necessary for
      catalyzing exchange. In the present study, functional roles were defined for
      specific residues within Cdc42 implicated by the crystal structures as important
      for physiological exchange of guanine nucleotides within Rho GTPases. In
      particular, this study highlights the paramount importance of the phosphate
      binding loop and interactions with the magnesium co-factor as critical for proper
      regulation of RhoGEF-catalyzed exchange. Other conformational alterations of the
      GTPases affecting interactions with the sugar and base of guanine nucleotides are
      also important but are secondary. Of particular note, substitution of alanine for
      cysteine at position 18 of Cdc42 leads to a fast cycling phenotype for Cdc42 with
      heightened affinity for RhoGEFs and produces a dominant negative form of Cdc42
      capable of inhibiting RhoGEFs both in vitro and in vivo.

PMID- 12401783
TI  - Nitric oxide-dependent generation of reactive species in sickle cell disease.
      Actin tyrosine induces defective cytoskeletal polymerization.
AB  - The intermittent vascular occlusion occurring in sickle cell disease (SCD) leads
      to ischemia-reperfusion injury and activation of inflammatory processes including
      enhanced production of reactive oxygen species and increased expression of
      inducible nitric-oxide synthase (NOS2). Appreciating that impaired nitric oxide
      dependent vascular function and the concomitant formation of oxidizing and
      nitrating species occur in concert with increased rates of tissue reactive oxygen
      species production, liver and kidney NOS2 expression, tissue 3-nitrotyrosine
      (NO(2)Tyr) formation and apoptosis were evaluated in human SCD tissues and a
      murine model of SCD. Liver and kidney NOS2 expression and NO(2)Tyr
      immunoreactivity were significantly increased in SCD mice and humans, but not in
      nondiseased tissues. TdT-mediated nick end-label (TUNEL) staining showed
      apoptotic cells in regions expressing elevated levels of NOS2 and NO(2)Tyr in all
      SCD tissues. Gas chromatography mass spectrometry analysis revealed increased
      plasma protein NO(2)Tyr content and increased levels of hepatic and renal protein
      NO(2)Tyr derivatives in SCD (21.4 +/- 2.6 and 37.5 +/- 7.8 ng/mg) versus wild
      type mice (8.2 +/- 2.2 and 10 +/- 1.2 ng/mg), respectively. Western blot analysis
      and immunoprecipitation of SCD mouse liver and kidney proteins revealed one
      principal NO(2)Tyr-containing protein of 42 kDa, compared with controls.
      Enzymatic in-gel digestion and MALDI-TOF mass spectrometry identified this
      nitrated protein as actin. Electrospray ionization and fragment analysis by
      tandem mass spectrometry revealed that 3 of 15 actin tyrosine residues are
      nitrated (Tyr(91), Tyr(198), and Tyr(240)) at positions that significantly modify
      actin assembly. Confocal microscopy of SCD human and mouse tissues revealed that
      nitration led to morphologically distinct disorganization of filamentous actin.
      In aggregate, we have observed that the hemoglobin point mutation of sickle cell
      disease that mediates hemoglobin polymerization defects is translated, via
      inflammatory oxidant reactions, into defective cytoskeletal polymerization.

PMID- 12401784
TI  - Biochemical and genetic evidence for the involvement of yeast Ypt6-GTPase in
      protein retrieval to different Golgi compartments.
AB  - Yeast Ypt6p, the homologue of the mammalian Rab6 GTPase, is not essential for
      cell viability. Based on previous studies with ypt6 deletion mutants, a
      regulatory role of the GTPase either in protein retrieval to the trans-Golgi
      network or in forward transport between the endoplasmic reticulum (ER) and early
      Golgi compartments was proposed. To assess better the primary role(s) of Ypt6p,
      temperature-sensitive ypt6 mutants were generated and analyzed biochemically and
      genetically. Defects in N-glycosylation of proteins passing the Golgi and of
      Golgi-resident glycosyltransferases as well as protein sorting defects in the
      trans-Golgi were recorded shortly after functional loss of Ypt6p. ER-to-Golgi
      transport and protein secretion were delayed but not interrupted. Mis-sorting of
      the vesicular SNARE Sec22p to the late Golgi was also observed. Combination of
      the ypt6-2 mutant allele with a number of mutants in forward and retrograde
      transport between ER, Golgi, and endosomes led to synthetic negative growth
      defects. The results obtained indicate that Ypt6p acts in endosome-to-Golgi, in
      intra-Golgi retrograde transport, and possibly also in Golgi-to-ER trafficking.

PMID- 12401785
TI  - Regulation of the farnesoid X receptor (FXR) by bile acid flux in rabbits.
AB  - We investigated the roles of hydrophobic deoxycholic acid (DCA) and hydrophilic
      ursocholic acid (UCA) in the regulation of the orphan nuclear farnesoid X
      receptor (FXR) in vivo. Rabbits with bile fistula drainage (removal of the
      endogenous bile acid pool), rabbits with bile fistula drainage and replacement
      with either DCA or UCA, and intact rabbits fed 0.5% cholic acid (CA) (enlarged
      endogenous bile acid pool) were studied. After bile fistula drainage, cholesterol
      7alpha-hydroxylase (CYP7A1) mRNA and activity levels increased, FXR-mediated
      transcription was decreased, and FXR mRNA and nuclear protein levels declined.
      Replacing the enterohepatic bile acid pool with DCA restored FXR mRNA and nuclear
      protein levels and activated FXR-mediated transcription as evidenced by the
      increased expression of its target genes, SHP and BSEP, and decreased CYP7A1 mRNA
      level and activity. Replacing the bile acid pool with UCA also restored FXR mRNA
      and nuclear protein levels but did not activate FXR-mediated transcription,
      because the SHP mRNA level and CYP7A1 mRNA level and activity were unchanged.
      Feeding CA to intact rabbits expanded the bile acid pool enriched with the FXR
      high affinity ligand, DCA. FXR-mediated transcription became activated as shown
      by increased SHP and BSEP mRNA levels and decreased CYP7A1 mRNA level and
      activity but did not change FXR mRNA or nuclear protein levels. Thus, both
      hydrophobic and hydrophilic bile acids are effective in maintaining FXR mRNA and
      nuclear protein levels. However, the activating ligand (DCA) in the enterohepatic
      flux is necessary for FXR-mediated transcriptional regulation, which leads to
      down-regulation of CYP7A1.

PMID- 12401786
TI  - G1 cyclin/cyclin-dependent kinase-coordinated phosphorylation of endogenous
      pocket proteins differentially regulates their interactions with E2F4 and E2F1
      and gene expression.
AB  - Mitogenic stimulation leads to activation of G(1) cyclin-dependent kinases
      (CDKs), which phosphorylate pocket proteins and trigger progression through the
      G(0)/G(1) and G(1)/S transitions of the cell cycle. However, the individual role
      of G(1) cyclin-CDK complexes in the coordinated regulation of pocket proteins and
      their interaction with E2F family members is not fully understood. Here we report
      that individually or in concert cyclin D1-CDK and cyclin E-CDK complexes induce
      distinct and coordinated phosphorylation of endogenous pocket proteins, which
      also has distinct consequences in the regulation of pocket protein interactions
      with E2F4 and the expression of p107 and E2F1, both E2F-regulated genes. The up
      regulation of these two proteins and the release of p130 and pRB from E2F4
      complexes allows formation of E2F1 complexes not only with pRB but also with p130
      and p107 as well as the formation of p107-E2F4 complexes. The formation of these
      complexes occurs in the presence of active cyclin D1-CDK and cyclin E-CDK
      complexes, indicating that whereas phosphorylation plays a role in the abrogation
      of certain pocket protein/E2F interactions, these same activities induce the
      formation of other complexes in the context of a cell expressing endogenous
      levels of pocket and E2F proteins. Of note, phosphorylated p130 "form 3," which
      does not interact with E2F4, readily interacts with E2F1. Our data also
      demonstrate that ectopic overexpression of either cyclin is sufficient to induce
      mitogen-independent growth in human T98G and Rat-1 cells, although the effects of
      cyclin D1 require downstream activation of cyclin E-CDK2 activity. Interestingly,
      in T98G cells, cyclin D1 induces cell cycle progression more potently than cyclin
      E. This suggests that cyclin D1 activates pathways independently of cyclin E that
      ensure timely progression through the cell cycle.

PMID- 12401787
TI  - Mutations of bacterial RNA polymerase leading to resistance to microcin j25.
AB  - A mutation in the conserved segment of the rpoC gene, which codes for the largest
      RNA polymerase (RNAP) subunit, beta', was found to make Escherichia coli cells
      resistant to microcin J25 (MccJ25), a bactericidal 21-amino acid peptide active
      against Gram-negative bacteria (Delgado, M. A., Rintoul, M. R., Farias, R. N.,
      and Salomon, R. A. (2001) J. Bacteriol. 183, 4543-4550). Here, we report that
      mutant RNAP prepared from MccJ25-resistant cells, but not the wild-type RNAP, is
      resistant to MccJ25 in vitro, thus establishing that RNAP is a true cellular
      target of MccJ25. We also report the isolation of additional rpoC mutations that
      lead to MccJ25 resistance in vivo and in vitro. The new mutations affect beta'
      amino acids in evolutionarily conserved segments G, G', and F and are exposed
      into the RNAP secondary channel, a narrow opening that connects the enzyme
      surface with the catalytic center. We also report that previously known rpoB
      (RNAP beta subunit) mutations that lead to streptolydigin resistance cause
      resistance to MccJ25. We hypothesize that MccJ25 inhibits transcription by
      binding in RNAP secondary channel and blocking substrate access to the catalytic
      center.

PMID- 12401788
TI  - The NF-YB/NF-YC structure gives insight into DNA binding and transcription
      regulation by CCAAT factor NF-Y.
AB  - The heterotrimeric transcription factor NF-Y recognizes with high specificity and
      affinity the CCAAT regulatory element that is widely represented in promoters and
      enhancer regions. The CCAAT box acts in concert with neighboring elements, and
      its bending by NF-Y is thought to be a major mechanism required for transcription
      activation. We have solved the structure of the NF-YC/NF-YB subcomplex of NF-Y,
      which shows that the core domains of both proteins interact through histone fold
      motifs. This histone-like pair is closely related to the H2A/H2B and
      NC2alpha/NC2beta families, with features that are both common to this class of
      proteins and unique to NF-Y. The structure together with the modeling of the
      nonspecific interaction of NF-YC/NF-YB with DNA and the full NF-Y/CCAAT box
      complex highlight important structural features that account for different and
      possibly similar biological functions of the transcriptional regulators NF-Y and
      NC2. In particular, it emphasizes the role of the newly described alphaC helix of
      NF-YC, which is both important for NF-Y trimerization and a target for regulatory
      proteins, such as MYC and p53.

PMID- 12401789
TI  - In situ conversion of protochlorophyllide b to protochlorophyllide a in barley.
      Evidence for a novel role of 7-formyl reductase in the prolamellar body of
      etioplasts.
AB  - We recently put forth a model of a protochlorophyllide (Pchlide) light-harvesting
      complex operative during angiosperm seedling de-etiolation (Reinbothe, C.,
      Lebedev, N., and Reinbothe, S. (1999) Nature 397, 80-84). This model, which was
      based on in vitro reconstitution experiments with zinc analogs of Pchlide a and
      Pchlide b and the two NADPH:protochlorophyllide oxidoreductases (PORs), PORA and
      PORB, of barley, predicted a 5-fold excess of Pchlide b, relative to Pchlide a,
      in the prolamellar body of etioplasts. Recent work (Scheumann, V., Klement, H.,
      Helfrich, M., Oster, U., Schoch, S., and Rudiger, W. (1999) FEBS Lett. 445, 445
      448), however, contradicted this model and reported that Pchlide b would not be
      present in etiolated plants. Here we demonstrate that Pchlide b is an abundant
      pigment in barley etioplasts but is rather metabolically unstable. It is rapidly
      converted to Pchlide a by virtue of 7-formyl reductase activity, an enzyme that
      had previously been implicated in the chlorophyll (Chl) b to Chl a reaction
      cycle. Our findings suggest that etiolated plants make use of 7-formyl reductase
      to fine tune the levels of Pchlide b and Pchlide a and thereby may regulate the
      steady-state level of light-harvesting POR-Pchlide complex.

PMID- 12401790
TI  - In vitro reconstitution of light-harvesting POR-protochlorophyllide complex with
      protochlorophyllides a and b.
AB  - NADPH:protochlorophyllide oxidoreductase (POR; EC ) is a key enzyme for the light
      induced greening of angiosperms. In barley, two POR proteins exist, termed PORA
      and PORB. These have previously been proposed to form higher molecular weight
      light-harvesting complexes in the prolamellar body of etioplasts (Reinbothe, C.,
      Lebedev, N., and Reinbothe, S. (1999) Nature 397, 80-84). Here we report the in
      vitro reconstitution of such complexes from chemically synthesized
      protochlorophyllides (Pchlides) a and b and galacto- and sulfolipids. Low
      temperature (77 K) fluorescence measurements revealed that the reconstituted,
      lipid-containing complex displayed the same characteristics of photoactive
      Pchlide 650/657 as the presumed native complex in the prolamellar body. Moreover,
      Pchlide F650/657 was converted to chlorophyllide (Chlide) 684/690 upon
      illumination of the reconstituted complex with a 1-ms flash of white light.
      Identification and quantification of acetone-extractable pigments revealed that
      only the PORB-bound Pchlide a had been photoactive and was converted to Chlide a,
      whereas Pchlide b bound to the PORA remained photoinactive. Nondenaturing PAGE of
      the reconstituted Pchlide a/b-containing complex further demonstrated a size
      similar to that of the presumed native complex in vivo, suggesting that both
      complexes may be identical.

PMID- 12401791
TI  - The extra loop distinguishing POR from the structurally related short-chain
      alcohol dehydrogenases is dispensable for pigment binding but needed for the
      assembly of light-harvesting POR-protochlorophyllide complex.
AB  - We have recently discovered a protochlorophyllide (Pchlide)-based light
      harvesting complex involved in chlorophyll a biosynthesis. This complex consists
      of the two previously identified NADPH:protochlorophyllide oxidoreductases
      (PORs), PORA and PORB, their natural substrates (Pchlide b and Pchlide a,
      respectively), plus NADPH. These are all held together in a stoichiometry of five
      PORA-Pchlide b-NADPH complexes and one PORB-Pchlide a-NADPH complex in the
      prolamellar body of etioplasts. The assembly of this novel light-harvesting POR
      Pchlide complex (LHPP) requires both the proper interaction of the PORA and PORB
      with their cognate substrates as well as the oligomerization of the resulting POR
      pigment-NADPH ternary complexes into the native, lipid-containing structure of
      the etioplast. In this study, we demonstrate that the conserved extra sequence
      that distinguishes PORA and PORB from the structurally related short-chain
      alcohol dehydrogenases, is dispensable for pigment binding but needed for the
      assembly of LHPP. As shown by in vitro mutagenesis, deleting this extra sequence
      gave rise to assembly-incompetent but pigment-containing PORA and PORB
      polypeptides.

PMID- 12401792
TI  - Adipocyte-specific gene expression and adipogenic steatosis in the mouse liver
      due to peroxisome proliferator-activated receptor gamma1 (PPARgamma1)
      overexpression.
AB  - Peroxisome proliferator activated-receptor (PPAR) isoforms, alpha and gamma,
      function as important coregulators of energy (lipid) homeostasis. PPARalpha
      regulates fatty acid oxidation primarily in liver and to a lesser extent in
      adipose tissue, whereas PPARgamma serves as a key regulator of adipocyte
      differentiation and lipid storage. Of the two PPARgamma isoforms, PPARgamma1 and
      PPARgamma2 generated by alternative splicing, PPARgamma1 isoform is expressed in
      liver and other tissues, whereas PPARgamma2 isoform is expressed exclusively in
      adipose tissue where it regulates adipogenesis and lipogenesis. Since the
      function of PPARgamma1 in liver is not clear, we have, in this study,
      investigated the biological impact of overexpression of PPARgamma1 in mouse
      liver. Adenovirus-PPARgamma1 injected into the tail vein induced hepatic
      steatosis in PPARalpha(-/-) mice. Northern blotting and gene expression profiling
      results showed that adipocyte-specific genes and lipogenesis-related genes are
      highly induced in PPARalpha(-/-) livers with PPARgamma1 overexpression. These
      include adipsin, adiponectin, aP2, caveolin-1, fasting-induced adipose factor,
      fat-specific gene 27 (FSP27), CD36, Delta(9) desaturase, and malic enzyme among
      others, implying adipogenic transformation of hepatocytes. Of interest is that
      hepatic steatosis per se, induced either by feeding a diet deficient in choline
      or developing in fasted PPARalpha(-/-) mice, failed to induce the expression of
      these PPARgamma-regulated adipogenesis-related genes in steatotic liver. These
      results suggest that a high level of PPARgamma in mouse liver is sufficient for
      the induction of adipogenic transformation of hepatocytes with adipose tissue
      specific gene expression and lipid accumulation. We conclude that excess
      PPARgamma activity can lead to the development of a novel type of adipogenic
      hepatic steatosis.

PMID- 12401793
TI  - Piccolo, a Ca2+ sensor in pancreatic beta-cells. Involvement of cAMP-GEFII.Rim2.
      Piccolo complex in cAMP-dependent exocytosis.
AB  - We have previously shown that cAMP-binding protein cAMP-guanidine nucleotide
      exchange factor II (GEFII) (or Epac2) interacting with Rim2 is involved in cAMP
      dependent, protein kinase A-independent exocytosis in pancreatic beta-cells. The
      action of the cAMP-GEFII.Rim2 complex requires both intracellular cAMP and
      Ca(2+). Although Rim2 has C(2) domains, its role as a Ca(2+) sensor has remained
      unclear. In the present investigation, we have discovered that Piccolo, a CAZ
      (cytoskeletal matrix associated with the active zone) protein in neurons that is
      structurally related to Rim2, also binds to cAMP-GEFII and that it forms both
      homodimer and heterodimer with Rim2 in a Ca(2+)-dependent manner, whereas Rim2
      alone does not form the homodimer. The association of Piccolo.Rim2
      heterodimerization is stronger than Piccolo. Piccolo homodimerization. Treatment
      of pancreatic islets with antisense oligodeoxynucleotides against Piccolo
      inhibits insulin secretion induced by cAMP analog 8-bromo-cyclic AMP plus high
      glucose stimulation. These results suggest that Piccolo serves as a Ca(2+) sensor
      in exocytosis in pancreatic beta-cells and that the formation of a cAMP
      GEFII.Rim2. Piccolo complex is important in cAMP-induced insulin secretion. In
      addition, this study suggests that CAZ proteins similar to those in neurons are
      also function in pancreatic beta-cells.

PMID- 12401794
TI  - Interfacial basic cluster in annexin V couples phospholipid binding and trimer
      formation on membrane surfaces.
AB  - Annexin V is an abundant eukaryotic protein that binds phospholipid membranes in
      a Ca(2+)-dependent manner. In the present studies, site-directed mutagenesis was
      combined with x-ray crystallography and solution liposome binding assays to probe
      the functional role of a cluster of interfacial basic residues in annexin V. Four
      mutants were investigated: R23E, K27E, R61E, and R149E. All four mutants
      exhibited a significant reduction in adsorption to phospholipid membranes
      relative to the wild-type protein, and the R23E mutation was the most
      deleterious. Crystal structures of wild-type and mutant proteins were similar
      except for local changes in salt bridges involving basic cluster residues. The
      combined data indicate that Arg(23) is a major determinant for interfacial
      phospholipid binding and participates in an intermolecular salt bridge that is
      key for trimer formation on the membrane surface. Together, crystallographic and
      solution data provide evidence that the interfacial basic cluster is a locus
      where trimerization is synergistically coupled to membrane phospholipid binding.

PMID- 12401795
TI  - A lysine substitute for K+. A460K mutation eliminates K+ dependence in H+
      pyrophosphatase of Carboxydothermus hydrogenoformans.
AB  - The H(+) proton-translocating inorganic pyrophosphatase (H(+)-PPase) family is
      composed of two phylogenetically distinct types of enzymes: K(+)-dependent and
      K(+)-independent. However, to date, the sequence criteria governing this
      dichotomy have remained unknown. In this study, we describe the heterologous
      expression and functional characterization of H(+)-PPase from the thermophilic
      bacterium Carboxydothermus hydrogenoformans. Both PP(i)-hydrolyzing and PP(i)
      energized H(+) translocation activities of the recombinant enzyme in Escherichia
      coli inner membrane vesicles are strictly K(+)-dependent. Here we deduce the K(+)
      requirement of all available H(+)-PPase sequences based on the K(+) dependence of
      C. hydrogenoformans H(+)-PPase in conjunction with phylogenetic analyses. Our
      data reveal that K(+)-independent H(+)-PPases possess conserved Lys and Thr that
      are absent in K(+)-dependent H(+)-PPases. We further demonstrate that a A460K
      substitution in C. hydrogenoformans H(+)-PPase is sufficient to confer K(+)
      independence to both PP(i) hydrolysis and PP(i)-energized H(+) translocation. In
      contrast, a A463T mutation does not affect the K(+) dependence of H(+)-PPase.

PMID- 12401796
TI  - Translesion synthesis past acrolein-derived DNA adduct, gamma 
      hydroxypropanodeoxyguanosine, by yeast and human DNA polymerase eta.
AB  - gamma-Hydroxy-1,N(2)-propano-2'deoxyguanosine (gamma-HOPdG) is a major
      deoxyguanosine adduct derived from acrolein, a known mutagen. In vitro, this
      adduct has previously been shown to pose a severe block to translesion synthesis
      by a number of polymerases (pol). Here we show that both yeast and human pol eta
      can incorporate a C opposite gamma-HOPdG at approximately 190- and approximately
      100-fold lower efficiency relative to the control deoxyguanosine and extend from
      a C paired with the adduct at approximately 8- and approximately 19-fold lower
      efficiency. Although DNA synthesis past gamma-HOPdG by yeast pol eta was
      relatively accurate, the human enzyme misincorporated nucleotides opposite the
      lesion with frequencies of approximately 10(-1) to 10(-2). Because gamma-HOPdG
      can adopt both ring closed and ring opened conformations, comparative replicative
      bypass studies were also performed with two model adducts, propanodeoxyguanosine
      and reduced gamma-HOPdG. For both yeast and human pol eta, the ring open reduced
      gamma-HOPdG adduct was less blocking than gamma-HOPdG, whereas the ring closed
      propanodeoxyguanosine adduct was a very strong block. Replication of DNAs
      containing gamma-HOPdG in wild type and xeroderma pigmentosum variant cells
      revealed a somewhat decreased mutation frequency in xeroderma pigmentosum variant
      cells. Collectively, the data suggest that pol eta might potentially contribute
      to both error-free and mutagenic bypass of gamma-HOPdG.

PMID- 12401797
TI  - Ubiquitination-independent trafficking of G protein-coupled receptors to
      lysosomes.
AB  - Ubiquitination of cytoplasmic lysine residues can target G protein-coupled
      receptors (GPCRs) to proteasomes and has recently been shown to also be required
      for sorting of certain GPCRs to lysosomes following ligand-induced endocytosis.
      We addressed the generality of this mechanism by examining regulated proteolysis
      of the murine delta opioid receptor (DOR) expressed in human embryonic kidney 293
      cells, a well characterized model system in which receptors are sorted to
      lysosomes. Incubation of cells in the presence of the highly specific proteasome
      inhibitor lactacystin did not detectably affect ligand-induced proteolysis of DOR
      but significantly delayed ligand-induced proteolysis of epidermal growth factor
      receptors. Mutation of all cytoplasmic lysine residues in DOR, creating a mutant
      opioid receptor that is unable to be ubiquitinated, did not detectably inhibit
      either ligand-induced endocytosis or proteolytic degradation of endocytosed
      receptors. Furthermore, the lysine-mutated DOR, like its wild type counterpart,
      colocalized extensively with lysosomes after ligand-induced endocytosis. These
      results demonstrate that ubiquitination of DOR is not required either for its
      ligand-induced endocytosis or for postendocytic trafficking to lysosomes.

PMID- 12401799
TI  - Dihydroxyacetone kinases in Saccharomyces cerevisiae are involved in
      detoxification of dihydroxyacetone.
AB  - The genes YML070W/DAK1 and YFL053W/DAK2 in the yeast Saccharomyces cerevisiae
      were characterized by a combined genetic and biochemical approach that firmly
      functionally classified their encoded proteins as dihydroxyacetone kinases
      (DAKs), an enzyme present in most organisms. The kinetic properties of the two
      isoforms were similar, exhibiting K(m)((DHA)) of 22 and 5 microm and K(m)((ATP))
      of 0.5 and 0.1 mm for Dak1p and Dak2p, respectively. We furthermore show that
      their substrate, dihydroxyacetone (DHA), is toxic to yeast cells and that the
      detoxification is dependent on functional DAK. The importance of DAK was clearly
      apparent for cells where both isogenes were deleted (dak1 Delta dak2 Delta),
      since this strain was highly sensitive to DHA. In the opposite case,
      overexpression of either DAK1 or DAK2 made the dak1 Delta dak2 Delta highly
      resistant to DHA. In fact, overexpression of either DAK provided cells with the
      capacity to grow efficiently on DHA as the only carbon and energy source, with a
      generation time of about 5 h. The DHA toxicity was shown to be strongly dependent
      on the carbon and energy source utilized, since glucose efficiently suppresses
      the lethality, whereas galactose or ethanol did so to a much lesser extent.
      However, this suppression was found not to be explained by differences in DHA
      uptake, since uptake kinetics revealed a simple diffusion mechanism with similar
      capacity independent of carbon source. Salt addition strongly aggravated the DHA
      toxicity, independent of carbon source. Furthermore, the DHA toxicity was not
      linked to the presence of oxygen or to the known harmful agents methylglyoxal and
      formaldehyde. It is proposed that detoxification of DHA may be a vital part of
      the physiological response during diverse stress conditions in many species.

PMID- 12401798
TI  - Prostaglandin E2 induces hypoxia-inducible factor-1alpha stabilization and
      nuclear localization in a human prostate cancer cell line.
AB  - Hypoxia-induced up-regulation of vascular endothelial growth factor (VEGF)
      expression is a critical event leading to tumor neovascularization. Hypoxia
      stimulates hypoxia-inducible factor-1alpha (HIF-1alpha), a transcriptional
      activator of VEGF. Cyclooxygenase (COX)-2, an inducible enzyme that catalyzes the
      formation of prostaglandins (PGs) from arachidonic acid, is also induced by
      hypoxia. We reported previously that COX-2 inhibition prevents hypoxic up
      regulation of VEGF in human prostate cancer cells and that prostaglandin E(2)
      (PGE(2)) restores hypoxic effects on VEGF. We hypothesized that PGE(2) mediates
      hypoxic effects on VEGF by modulating HIF-1alpha expression. Addition of PGE(2)
      to PC-3ML human prostate cancer cells had no effect on HIF-1alpha mRNA levels.
      However, PGE(2) significantly increased HIF-1alpha protein levels, particularly
      in the nucleus. This effect of PGE(2) largely results from the promotion of HIF
      1alpha translocation from the cytosol to the nucleus. PGE(2) addition to PC-3 ML
      cells transfected with a GFP-HIF-1alpha vector induced a time-dependent nuclear
      accumulation of the HIF-1alpha protein. Two selective COX-2 inhibitors, meloxicam
      and NS398, decreased HIF-1alpha levels and nuclear localization, under both
      normoxic and hypoxic conditions. Of several prostaglandins tested, only PGE(2)
      reversed the effects of a COX-2 inhibitor in hypoxic cells. Finally, PGE(2)
      effects on HIF-1alpha were specifically inhibited by PD98059 (a MAPK inhibitor).
      These data demonstrate that PGE(2) production via COX-2-catalyzed pathway plays a
      critical role in HIF-1alpha regulation by hypoxia and imply that COX-2 inhibitors
      can prevent hypoxic induction of HIF-mediated gene transcription in cancer cells.

PMID- 12401800
TI  - Protection from pancreatitis by the zymogen granule membrane protein integral
      membrane-associated protein-1.
AB  - Pancreatitis is a common disease with substantial morbidity and mortality. To
      better understand the mechanisms conferring sensitivity or resistance to
      pancreatitis, we have initiated the analysis of novel acinar cell proteins.
      Integral membrane-associated protein-1 (Itmap1) is a CUB (complement
      subcomponents C1r/C1s, sea urchin Uegf protein, bone morphogenetic protein-1) and
      zona pellucida (ZP) domain-containing protein we find prominently expressed in
      pancreatic acinar cells. Within the acinar cell, Itmap1 localizes to zymogen
      granule membranes. Although roles in epithelial polarity, granule assembly, and
      mucosal protection have been postulated for CUB/ZP proteins, in vivo functions
      for these molecules have not been proven. To determine the function of Itmap1, we
      generated Itmap1-deficient mice. Itmap1(-/-) mice demonstrate increased severity
      of secretagogue- and diet-induced pancreatitis in comparison to Itmap1(+/+) mice.
      In contrast to previous animal models exhibiting altered severity of
      pancreatitis, Itmap1 deficiency results in impaired activation of trypsin, an
      enzyme believed critical for initiating a cascade of digestive zymogen activation
      during pancreatitis. Itmap1 deficiency does not alter zymogen granule size,
      appearance, or the composition of zymogen granule contents. Our results
      demonstrate that Itmap1 plays an essential role in trypsinogen activation and
      that both impaired and augmented trypsinogen activation can be associated with
      increased severity of pancreatitis.

PMID- 12401801
TI  - Mechanisms for inhibition of hepatitis B virus gene expression and replication by
      hepatitis C virus core protein.
AB  - We have demonstrated previously that the core protein of hepatitis C virus (HCV)
      exhibits suppression activity on gene expression and replication of hepatitis B
      virus (HBV). Here we further elucidated the suppression mechanism of HCV core
      protein. We demonstrated that HCV core protein retained the inhibitory effect on
      HBV gene expression and replication when expressed as part of the full length of
      HCV polyprotein. Based on the substitution mutational analysis, our results
      suggested that mutation introduced into the bipartite nuclear localization signal
      of the HCV core protein resulted in the cytoplasmic localization of core protein
      but did not affect its suppression ability on HBV gene expression. Mutational
      studies also indicated that almost all dibasic residue mutations within the N
      terminal 101-amino acid segment of the HCV core protein (except Arg(39)-Arg(40))
      impaired the suppression activity on HBV replication but not HBV gene expression.
      The integrity of Arg residues at positions 101, 113, 114, and 115 was found to be
      essential for both suppressive effects, whereas the Arg residue at position 104
      was important only in the suppression of HBV gene expression. Moreover, our
      results indicated that the suppression on HBV gene expression was mediated
      through the direct interaction of HCV core protein with the trans-activator HBx
      protein, whereas the suppression of HBV replication involved the complex
      formation between HBV polymerase (pol) and the HCV core protein, resulting in the
      structural incompetence for the HBV pol to bind the package signal and
      consequently abolished the formation of the HBV virion. Altogether, this study
      suggests that these two suppression effects on HBV elicited by the HCV core
      protein likely depend on different structural context but not on nuclear
      localization of the core protein, and the two effects can be decoupled as
      revealed by its differential targets (HBx or HBV pol) on these two processes of
      the HBV life cycle.

PMID- 12401802
TI  - Structure and dynamics of thioguanine-modified duplex DNA.
AB  - Mercaptopurine and thioguanine, two of the most widely used antileukemic agents,
      exert their cytotoxic, therapeutic effects by being incorporated into DNA as
      deoxy-6-thioguanosine. However, the molecular mechanism(s) by which incorporation
      of these thiopurines into DNA translates into cytotoxicity is unknown. The
      solution structure of thioguanine-modified duplex DNA presented here shows that
      the effects of the modification on DNA structure were subtle and localized to the
      modified base pair. Specifically, thioguanine existed in the keto form, formed
      weakened Watson-Crick hydrogen bonds with cytosine and caused a modest
      approximately 10 degrees opening of the modified base pair toward the major
      groove. In contrast, thioguanine significantly altered base pair dynamics,
      causing an approximately 80-fold decrease in the base pair lifetime with cytosine
      compared with normal guanine. This perturbation was consistent with the
      approximately 6 degrees C decrease in DNA melting temperature of the modified
      oligonucleotide, the 1.13 ppm upfield shift of the thioguanine imino proton
      resonance, and the large increase in the exchange rate of the thioguanine imino
      proton with water. Our studies provide new mechanistic insight into the effects
      of thioguanine incorporation into DNA at the level of DNA structure and dynamics,
      provide explanations for the effects of thioguanine incorporation on the activity
      of DNA-processing enzymes, and provide a molecular basis for the specific
      recognition of thioguanine-substituted sites by proteins. These combined effects
      likely cooperate to produce the cellular responses that underlie the therapeutic
      effects of thiopurines.

PMID- 12401803
TI  - The link module from human TSG-6 inhibits neutrophil migration in a hyaluronan-
      and inter-alpha -inhibitor-independent manner.
AB  - TSG-6 protein (the secreted product of the tumor necrosis factor-stimulated gene
      6), a hyaluronan-binding protein comprised mainly of a Link and CUB module
      arranged in a contiguous fashion, has been shown previously to be a potent
      inhibitor of neutrophil migration in an in vivo model of acute inflammation
      (Wisniewski, H. G., Hua, J. C., Poppers, D. M., Naime, D., Vilcek, J., and
      Cronstein, B. N. (1996) J. Immunol. 156, 1609-1615). It was hypothesized that
      this activity of TSG-6 was likely to be mediated by its potentiation of inter
      alpha-inhibitor anti-plasmin activity (causing a down-regulation of the protease
      network), which was reliant on these proteins forming a stable, probably covalent
      approximately 120-kDa complex. Here we have shown that the recombinant Link
      module from human TSG-6 (Link_TSG6; expressed in Escherichia coli) has an
      inhibitory effect on neutrophil influx into zymosan A-stimulated murine air
      pouches, equivalent to that of full-length protein (which we produced in a
      Drosophila expression system). The active dose of 1 microg of Link_TSG6 per mouse
      (administered intravenously) also resulted in a significant reduction in the
      concentrations of various inflammatory mediators (i.e. tumor necrosis factor
      alpha, KC, and prostaglandin E(2)) in air pouch exudates. Link_TSG6, although
      unable to form a stable complex with inter-alpha-inhibitor (under conditions that
      promote maximum complex formation with the full-length protein), could potentiate
      its anti-plasmin activity. This demonstrates that formation of an approximately
      120-kDa TSG-6.inter-alpha-inhibitor complex is not required for TSG-6 to enhance
      the serine protease inhibitory activity of inter-alpha-inhibitor. Six single-site
      Link_TSG6 mutants (with wild-type folds) were compared for their abilities to
      inhibit neutrophil migration in vivo, bind hyaluronan, and potentiate inter-alpha
      inhibitor. These experiments indicate that all of the inhibitory activity of TSG
      6 resides within the Link module domain, and that this anti-inflammatory property
      is not related to either its hyaluronan binding function or its potentiation of
      the anti-plasmin activity of inter-alpha-inhibitor.

PMID- 12401804
TI  - PAX3-FKHR transformation increases 26 S proteasome-dependent degradation of
      p27Kip1, a potential role for elevated Skp2 expression.
AB  - PAX3-FKHR is an oncogenic form of the developmental regulator Pax3 transcription
      factor. PAX3-FKHR results from a t(2,13) chromosomal translocation, a unique
      genetic marker of alveolar rhabdomyosarcoma. In this study, we showed that
      ectopic expression of PAX3-FKHR, but not Pax3, in fibroblasts altered cell cycle
      control and accelerated G(0)/G(1) to S cell cycle transition. PAX3-FKHR
      expressing cells had reduced expression of p27(Kip1) protein, a key cell cycle
      regulator. The reduction in p27(Kip1) levels by PAX3-FKHR resulted from
      destabilization of p27(Kip1) as shown by cycloheximide treatment and in vivo
      pulse-chase labeling experiments. The reduced p27(Kip1) protein level in PAX3
      FKHR-expressing cells was restored to the level of control cells by treatment
      with chemical inhibitors that specifically blocked 26 S proteasome activity.
      Along with the reduction in p27(Kip1) protein, PAX3-FKHR-expressing cells
      exhibited elevated expression of F-box Skp2 protein, a substrate-specific
      component of SCF (Skp1-Cullin-F box protein) ligase involved in the cell cycle
      dependent control of p27(Kip1) ubiquitination and 26 S proteasome dependent
      degradation. Finally, we showed that ectopic expression of p27(Kip1) in PAX3-FKHR
      expressing cells significantly reduced the proliferation and colony-forming
      potential of these cells, implicating that down-regulation of p27(Kip1) protein
      played an active role in the PAX3-FKHR-directed cell transformation.

PMID- 12401805
TI  - Structural comparisons of empty and full cytoplasmic polyhedrosis virus. Protein
      RNA interactions and implications for endogenous RNA transcription mechanism.
AB  - Viruses in the family Reoviridae are capable of transcription within the intact
      capsids. As the only single-shelled and thus the simplest member of the
      Reoviridae, cytoplasmic polyhedrosis virus (CPV) provides an attractive system
      for studying endogenous transcription. We report the structures of the full and
      empty CPV determined at 13-A resolution by electron cryomicroscopy. The structure
      of the empty CPV reveals a density attributed to the transcription enzyme
      complex, which is attached to the internal surface of the capsid shell below each
      of the 12 turrets. The full capsid has an identical capsid shell but contains
      additional internal densities contributed by the genomic double-stranded (ds)
      RNA. The RNA densities proximal to the capsid shell are organized into layers
      with a dodecahedral appearance, suggesting a genome organization of dsRNA
      segments each having a cone shape spooling around a transcription enzyme complex.
      Our structures also suggest that the capsid shell serves as a scaffold for
      appropriate positioning of the RNA genome, whereas nascent mRNA release takes
      place through the constricted central channel of the turret. Based on these
      observations, a detailed moving template transcription mechanism is proposed that
      may provide insight into the well coordinated and highly efficient endogenous RNA
      transcription of dsRNA viruses.

PMID- 12401806
TI  - Both acidic and basic amino acids in an amphitropic enzyme, CTP:phosphocholine
      cytidylyltransferase, dictate its selectivity for anionic membranes.
AB  - Amphitropic proteins are regulated by reversible membrane interaction. Anionic
      phospholipids generally promote membrane binding of such proteins via
      electrostatics between the negatively charged lipid headgroups and clusters of
      basic groups on the proteins. In this study of one amphitropic protein, a
      cytidylyltransferase (CT) that regulates phosphatidylcholine synthesis, we found
      that substitution of lysines to glutamine along both interfacial strips of the
      membrane-binding amphipathic helix eliminated electrostatic binding.
      Unexpectedly, three glutamates also participate in the selectivity for anionic
      membrane surfaces. These glutamates become protonated in the low pH milieu at the
      surface of anionic, but not zwitterionic membranes, increasing protein positive
      charge and hydrophobicity. The binding and insertion into lipid vesicles of a
      synthetic peptide containing the three glutamates was pH-dependent with an
      apparent pK(a) that varied with anionic lipid content. Glutamate to glutamine
      substitution eliminated the pH dependence of the membrane interaction, and
      reduced anionic membrane selectivity of both the peptide and the whole CT enzyme
      examined in cells. Thus anionic lipids, working via surface-localized pH effects,
      can promote membrane binding by modifying protein charge and hydrophobicity, and
      this novel mechanism contributes to the membrane selectivity of CT in vivo.

PMID- 12401807
TI  - Ubiquitin conjugation is not required for the degradation of oxidized proteins by
      proteasome.
AB  - Oxidatively modified proteins that accumulate in aging and many diseases can form
      large aggregates because of covalent cross-linking or increased surface
      hydrophobicity. Unless repaired or removed from cells, these oxidized proteins
      are often toxic, and threaten cell viability. Most oxidatively damaged proteins
      appear to undergo selective proteolysis, primarily by the proteasome. Previous
      work from our laboratory has shown that purified 20 S proteasome degrades
      oxidized proteins without ATP or ubiquitin in vitro, but there have been no
      studies to test this mechanism in vivo. The aim of this study was to determine
      whether ubiquitin conjugation is necessary for the degradation of oxidized
      proteins in intact cells. We now show that cells with compromised ubiquitin
      conjugating activity still preferentially degrade oxidized intracellular
      proteins, at near normal rates, and this degradation is still inhibited by
      proteasome inhibitors. We also show that progressive oxidation of proteins such
      as lysozyme and ferritin does not increase their ubiquitinylation, yet the
      oxidized forms of both proteins are preferentially degraded by proteasome.
      Furthermore, rates of oxidized protein degradation by cell lysates are not
      significantly altered by addition of ATP, excluding the possibility of an energy
      requirement for this pathway. Contrary to earlier popular belief that most
      proteasomal degradation is conducted by the 26 S proteasome with ubiquitinylated
      substrates, our work suggests that oxidized proteins are degraded without
      ubiquitin conjugation (or ATP hydrolysis) possibly by the 20 S proteasome, or the
      immunoproteasome, or both.

PMID- 12401808
TI  - Tissue transglutaminase mediates activation of RhoA and MAP kinase pathways
      during retinoic acid-induced neuronal differentiation of SH-SY5Y cells.
AB  - All-trans-retinoic acid (RA) plays a crucial role in survival and differentiation
      of neurons. For elucidating signaling mechanisms involved in RA-induced neuronal
      differentiation, we have selected SH-SY5Y cells, which are an established in
      vitro cell model for studying RA signaling. Here we report that RA-induced
      neuronal differentiation of SH-SY5Y cells is coupled with increased
      expression/activation of TGase and in vivo transamidation and activation of RhoA.
      In addition, RA promotes formation of stress fibers and focal adhesion complexes,
      and activation of ERK1/2, JNK1, and p38alpha/beta/gamma MAP kinases. Using C-3
      exoenzyme (RhoA inhibitor) or monodansylcadaverine (TGase inhibitor), we show
      that transamidated RhoA regulates cytoskeletal rearrangement and activation of
      ERK1/2 and p38gamma MAP kinases. Further, by using stable SH-SY5Y cell lines
      (overexpressing wild-type, C277S mutant, and antisense TGase), we demonstrate
      that transglutaminase activity is required for activation of RhoA, ERK1/2, JNK1,
      and p38gamma MAP kinases. Activated MAP kinases differentially regulate RA
      induced neurite outgrowth and neuronal marker expression. The results of our
      studies suggest a novel mechanism of RA signaling, which involves activation of
      TGase and transamidation of RhoA. RA-induced activation of TGase is proposed to
      induce multiple signaling pathways that regulate neuronal differentiation.

PMID- 12401809
TI  - Identification of natural ligands for the orphan G protein-coupled receptors GPR7
      and GPR8.
AB  - GPR7 and GPR8 are two structurally related orphan G protein-coupled receptors,
      presenting high similarities with opioid and somatostatin receptors. Two
      peptides, L8 and L8C, derived from a larger precursor, were recently described as
      natural ligands for GPR8 (Mori, M., Shimomura, Y., Harada, M., Kurihara, M.,
      Kitada, C., Asami, T., Matsumoto, Y., Adachi, Y., Watanabe, T., Sugo, T., and
      Abe, M. (December, 27, 2001) World Patent Cooperation Treaty, Patent Application
      WO 01/98494A1). L8 is a 23-amino acid peptide, whereas L8C is the same peptide
      with a C terminus extension of 7 amino acids, running through a dibasic motif of
      proteolytic processing. Using as a query the amino acid sequence of the L8
      peptide, we have identified in DNA databases a human gene predicted to encode
      related peptides and its mouse ortholog. By analogy with L8 and L8C, two
      peptides, named L7 and L7C could result from the processing of a 125-amino acid
      human precursor through the alternative usage of a dibasic amino acid motif. The
      activity of these four peptides was investigated on GPR7 and GPR8. In binding
      assays, L7, L7C, L8, and L8C were found to bind with low nanomolar affinities to
      the GPR7 and GPR8 receptors expressed in Chinese hamster ovary (CHO)-K1 cells.
      They inhibited forskolin-stimulated cAMP accumulation through a pertussis toxin
      sensitive mechanism. The tissue distribution of prepro-L7 (ppL7) and prepro-L8
      (ppL8) was investigated by reverse transcription-PCR. Abundant ppL7 transcripts
      were found throughout the brain as well as in spinal cord, spleen, testis, and
      placenta; ppL8 transcripts displayed a more restricted distribution in brain,
      with high levels in substantia nigra, but were more abundant in peripheral
      tissues. The ppL7 and ppL8 genes therefore encode the precursors of a class of
      peptide ligands, active on two receptor subtypes, GPR7 and GPR8. The distinct
      tissue distribution of the receptor and peptide precursors suggest that each
      ligand and receptor has partially overlapping but also specific roles in this
      signaling system.

PMID- 12401810
TI  - Preliminary characterization and crystal structure of a thermostable cytochrome
      P450 from Thermus thermophilus.
AB  - The second structure of a thermophile cytochrome P450, CYP175A1 from the
      thermophilic bacterium Thermus thermophilus HB27, has been solved to 1.8-A
      resolution. The overall P450 structure remains conserved despite the low sequence
      identity between the various P450s. The CYP175A1 structure lacks the large
      aromatic network found in the only other thermostable P450, CYP119, thought to
      contribute to thermal stability. The primary difference between CYP175A1 and its
      mesophile counterparts is the investment of charged residues into salt-link
      networks at the expense of single charge-charge interactions. Additional factors
      involved in the thermal stability increase are a decrease in the overall size,
      especially shortening of loops and connecting regions, and a decrease in the
      number of labile residues such as Asn, Gln, and Cys.

PMID- 12401811
TI  - Protein kinase A phosphorylation of the cardiac calcium release channel
      (ryanodine receptor) in normal and failing hearts. Role of phosphatases and
      response to isoproterenol.
AB  - The cardiac ryanodine receptor/calcium release channel (RyR2) on the sarcoplasmic
      reticulum (SR) comprises a macromolecular complex that includes a kinase and two
      phosphatases that are bound to the channel via targeting proteins. We previously
      found that the RyR2 is protein kinase A (PKA)-hyperphosphorylated in end-stage
      human heart failure. Because heart failure is a progressive disease that often
      evolves from hypertrophy, we analyzed the RyR2 macromolecular complex in several
      animal models of cardiomyopathy that lead to heart failure, including
      hypertrophy, and at different stages of disease progression. We now show that
      RyR2 is PKA-hyperphosphorylated in diverse models of heart failure and that the
      degree of RyR2 PKA phosphorylation correlates with the degree of cardiac
      dysfunction. Interestingly, we show that RyR2 PKA hyperphosphorylation can be
      lost during perfusion of isolated hearts due to the activity of the endogenous
      phosphatases in the RyR2 macromolecular complex. Moreover, infusion of
      isoproterenol resulted in PKA phosphorylation of RyR2 in rat, indicating that
      systemic catecholamines can activate phosphorylation of RyR2 in vivo. These
      studies extend our previous analyses of the RyR2 macromolecular complex, show
      that both the kinase and phosphatase activities in the macromolecular complex are
      regulated physiologically in vivo, and suggest that RyR2 PKA hyperphosphorylation
      is likely a general feature of heart failure.

PMID- 12401812
TI  - Modulation of the cardiac sodium channel Nav1.5 by fibroblast growth factor
      homologous factor 1B.
AB  - We have previously shown that fibroblast growth factor homologous factor 1B
      (FHF1B), a cytosolic member of the fibroblast growth factor family, associates
      with the sensory neuron-specific channel Na(v)1.9 but not with the other sodium
      channels present in adult rat dorsal root ganglia neurons. We show in this study
      that FHF1B binds to the C terminus of the cardiac voltage-gated sodium channel
      Na(v)1.5 and modulates the properties of the channel. The N-terminal 41 amino
      acid residues of FHF1B are essential for binding to Na(v)1.5, and the conserved
      acidic rich domain (amino acids 1773-1832) in the C terminus of Na(v)1.5 is
      sufficient for association with this factor. Binding of the growth factor to
      recombinant wild type human Na(v)1.5 in human embryonic kidney 293 cells produces
      a significant hyperpolarizing shift in the voltage dependence of channel
      inactivation. An aspartic acid to glycine substitution at position 1790 of the
      channel, which underlies one of the LQT-3 phenotypes of cardiac arrythmias,
      abolishes the interaction of the Na(v)1.5 channel with FHF1B. This is the first
      report showing that interaction with a growth factor can modulate properties of a
      voltage-gated sodium channel.

PMID- 12401813
TI  - Evidence for a Trypanosoma brucei lipoprotein scavenger receptor.
AB  - African trypanosomes are lipid auxotrophs that live in the bloodstream of their
      human and animal hosts. Trypanosomes require lipoproteins in addition to other
      serum components in order to multiply under axenic culture conditions.
      Delipidation of the lipoproteins abrogates their capacity to support trypanosome
      growth. Both major classes of serum lipoproteins, LDL and HDL, are primary
      sources of lipids, delivering cholesterol esters, cholesterol, and phospholipids
      to trypanosomes. We show evidence for the existence of a trypanosome lipoprotein
      scavenger receptor, which facilitates the endocytosis of both native and modified
      lipoproteins, including HDL and LDL. This lipoprotein scavenger receptor also
      exhibits selective lipid uptake, whereby the uptake of the lipid components of
      the lipoprotein exceeds that of the protein components. Trypanosome lytic factor
      (TLF1), an unusual HDL found in human serum that protects from infection by
      lysing Trypanosoma brucei brucei, is also bound and endocytosed by this
      lipoprotein scavenger receptor. HDL and LDL compete for the binding and uptake of
      TLF1 and thereby attenuate the trypanosome lysis mediated by TLF1. We also show
      that a mammalian scavenger receptor facilitates lipid uptake from TLF1 in a
      manner similar to the trypanosome scavenger receptor. Based on these results we
      propose that HDL, LDL, and TLF1 are all bound and taken up by a lipoprotein
      scavenger receptor, which may constitute the parasite's major pathway mediating
      the uptake of essential lipids.

PMID- 12401814
TI  - A single c-Jun N-terminal kinase isoform (JNK3-p54) is an effector in both
      neuronal differentiation and cell death.
AB  - The c-Jun N-terminal kinases (JNKs) mediate degeneration and apoptosis in the
      brain. Particularly, JNK3 is considered to be a degenerative enzyme with c-Jun as
      a relevant substrate. The contribution of individual JNK isoforms, however, to
      pathological as well as to physiological processes remains to be defined. To
      analyze the effects of a single JNK isoform on neuronal cell death and
      differentiation, we transfected PC12 cells, which normally express only JNK1 and
      JNK2, with JNK3-p54. Transfected JNK3 significantly enhanced cell death after UV
      irradiation (0.5-6 J/cm(2)) and paclitaxel/taxol treatment (1-10 microm). In
      contrast, in the context of nerve growth factor-induced (10 or 50 ng/ml)
      differentiation of PC12 cells, JNK3 expression significantly increased the number
      and length of neurites. This functional dichotomy of JNK3 was mirrored by
      differential activation and induction of nuclear JNK substrates; although
      activating transcription factor-2 phosphorylation was enhanced by death signaling
      in response to UV and taxol, c-Jun protein expression and N-terminal
      phosphorylation were increased during nerve growth factor-induced
      differentiation. The absence of significant JNK activation or target
      phosphorylation in response to H(2)O(2) (60 microm) further supports the
      hypothesis that JNK isoforms are not merely injury- or stress-specific kinases
      but also have context-specific physiological functions.

PMID- 12401815
TI  - X-ray diffraction patterns of crystalline tobacco mosaic proteins.

PMID- 12401817
TI  - British Andrology Society guidelines for the assessment of post vasectomy semen
      samples (2002).
AB  - The British Andrology Society guidelines for the assessment of post vasectomy
      semen samples recommend that initial assessment is undertaken 16 weeks post
      vasectomy and after the patient has produced at least 24 ejaculates. The
      laboratory should examine a freshly produced seminal fluid specimen by direct
      microscopy and if no sperm are seen the centrifugate should be examined for the
      presence of motile and non-motile spermatozoa. It is recommended that the
      clinician should give clearance after the production of two consecutive sperm
      free ejaculates. In cases of persistent identification of non-motile spermatozoa
      the referring clinician should advise the patient regarding the cessation of
      other contraceptive precautions. Surgeons are responsible both preoperatively and
      postoperatively for the counselling of couples regarding complications and the
      possibility of late recanalisation after clearance.

PMID- 12401816
TI  - Apoptosis in myocardial ischaemia and infarction.
AB  - Recent studies indicate that, in addition to necrosis, apoptosis also plays a
      role in the process of tissue damage after myocardial infarction, which has
      pathological and therapeutic implications. This review article will discuss
      studies in which the role and mechanisms of apoptosis in myocardial infarction
      were analysed in vivo and in vitro in humans and in animals.

PMID- 12401818
TI  - Imaging bacterial infection with (99m)Tc-ciprofloxacin (Infecton).
AB  - AIMS: The diagnosis of deep seated bacterial infections, such as intra-abdominal
      abscesses, endocarditis, and osteomyelitis, can be difficult and delayed, thereby
      compromising effective treatment. This study assessed the efficacy of a new
      radioimaging agent, Tc-99m ciprofloxacin (Infecton), in accurately detecting
      sites of bacterial infection. METHODS: Eight hundred and seventy nine patients
      with suspected bacterial infection underwent Infecton imaging and microbiological
      evaluation. The sensitivity and specificity of Infecton in detecting sites of
      bacterial infection were determined with respect to Centres of Disease Control,
      World Health Organisation, and Dukes's criteria. RESULTS: Five hundred and
      seventy four positive and 295 negative images were produced. These included 528
      true positives, 46 false positives, 205 true negatives and 90 false negatives,
      giving an overall sensitivity of 85.4% and a specificity of 81.7% for detecting
      infective foci. Sensitivity was higher (87.6%) in microbiologically confirmed
      infections. CONCLUSIONS: Infecton is a sensitive technique, which aids in the
      earlier detection and treatment of a wide variety of deep seated bacterial
      infections. The ability to localise infective foci accurately is also important
      for surgical intervention, such as drainage of abscesses. In addition, serial
      imaging with Infecton might be useful in monitoring clinical response and
      optimising the duration of antimicrobial treatment.

PMID- 12401819
TI  - DNA fingerprinting analysis of coagulase negative staphylococci implicated in
      catheter related bloodstream infections.
AB  - AIMS: The epidemiological assessment of cases of coagulase negative
      staphylococcal catheter related bloodstream infection. METHODS: Two hundred and
      thirty patients with suspected catheter related bloodstream infection were
      evaluated over a two year period. Central venous catheters were cultured both
      endoluminally and extraluminally. Peripheral blood, catheter hubs, skin entry,
      and skin control sites were also cultured. Pulsed field gel electrophoresis
      (PFGE) was used to DNA fingerprint coagulase negative staphylococci isolated from
      patients with presumptive catheter related bloodstream infection. RESULTS: Sixty
      cases of catheter related bloodstream infection were identified, 21 of which were
      attributed to coagulase negative staphylococci. Two hundred and ninety four
      separate isolates of coagulase negative staphylococci from the 21 cases of
      catheter related bloodstream infection were subjected to PFGE (mean of 14 for
      each case). Catheter related bloodstream infection was only confirmed by PFGE
      analysis in 16 of the 21 cases because in the remaining five cases peripheral
      blood and central venous catheter coagulase negative staphylococci isolates were
      different. Skin entry, control skin, and central venous catheter hub isolates
      matched peripheral blood isolates in six, four, and seven cases, respectively.
      Coagulase negative staphylococci isolates could not be cultured from the
      patients' own skin in seven cases of catheter related bloodstream infection.
      Central venous catheter lumens were colonised in all cases of catheter related
      bloodstream infection compared with 44-81% of cases that had positive external
      surface catheter tip cultures, depending on the threshold used to define
      significant growth. CONCLUSIONS: Catheter related bloodstream infection as a
      result of coagulase negative staphylococci may be over stated in about a quarter
      of cases, unless a discriminatory technique is used to fingerprint isolates. No
      single, simplistic route of bacterial contamination of central venous catheters
      was identified, but endoluminal catheter colonisation is invariably present in
      cases of catheter related bloodstream infection.

PMID- 12401820
TI  - Comparison of the expression of p53, p21, Bax and the induction of apoptosis
      between patients with basal cell carcinoma and normal controls in response to
      ultraviolet irradiation.
AB  - AIM: Ultraviolet light (UV) is known to cause DNA damage in the epidermis. The
      damaged DNA is repaired or deleted by apoptosis to prevent the generation of
      cancer. It has been suggested that a deficient apoptotic mechanism may predispose
      individuals to skin cancer. Therefore, the response of normal controls and
      patients with basal cell carcinoma (BCC) to UV irradiation was investigated.
      METHODS: The buttock skin from normal volunteers and patients with BCC was
      irradiated using solar simulated radiation (SSR). SSR mimics the effect of
      natural sunlight. Skin biopsies were excised and examined for p53, p21, and Bax
      protein expression and for the induction of apoptosis. RESULTS: At 33 hours after
      UV irradiation, the induction of apoptosis was significantly higher (p = 0.04) in
      patients with BCC than in normal volunteers (Mann Whitney test). A trend towards
      higher p21 expression was found at 33 hours in patients with BCC (mean, 18.69
      positive cells/field) than in normal volunteers (mean, 9.89), although this
      difference was not significant (p = 0.05 positive cells/field). CONCLUSION: These
      results may imply that patients with BCC have enhanced sensitivity to UV
      irradiation or that there is some defect in the cell arrest or repair pathways,
      which results in damaged cells been pushed into apoptosis rather than repair.

PMID- 12401821
TI  - Specific p53 immunostaining patterns are associated with smoking habits in
      patients with oral squamous cell carcinomas.
AB  - AIMS: To identify immunostaining patterns that are predictive for p53 mutations
      and to investigate whether p53 mutations are associated with established risk
      factors for oral squamous cell carcinoma (OSCC). METHODS: Fifty five OSCCs were
      investigated for p53 protein expression by immunohistochemistry (IHC). Ten of
      these cases, including five p53 immunopositive and five p53 immunonegative cases,
      were subjected to microdissection of representative tumour areas followed by
      sequence analysis for the detection of TP53 mutations. RESULTS: Paired IHC and
      sequence analysis revealed that p53 immunoexpression in more than 25% of tumour
      cells was indicative of TP53 mutations, whereas p53 immunonegativity was not
      informative. Therefore, for p53 immunohistochemical interpretation, p53
      immunonegative cases were excluded from the analysis and the cut off value for
      p53 immunoexpression was set at 25%. Of the OSCCs showing any p53
      immunoexpression, 64% revealed staining in more than 25% of the tumour cells. p53
      immunoexpression in more than 25% of the neoplastic cells was significantly
      associated with smoking but not with alcohol consumption. No significant
      association with smoking habits was found when OSCCs were dichotomised into p53
      immunonegative and p53 immunopositive. CONCLUSIONS: In OSCCs the following
      conclusions can be made: (1) p53 immunonegativity is not informative for TP53
      mutations; (2) 25% p53 immunopositive cells appears to be a good cut off value to
      predict TP53 mutations; (3) p53 immunostaining patterns that appeared to be
      predictive for TP53 mutations were associated with the smoking habits of the
      patients.

PMID- 12401822
TI  - The clinical relevance of an isolated increase in the number of circulating
      hyperchromic red blood cells.
AB  - AIMS: To search for laboratory evidence of hereditary spherocytosis (HS) among
      apparently healthy children with the chance finding of an isolated increase in
      hyperchromic red cells (cells with intracellular haemoglobin concentration > 410
      g/litre). METHODS: Blood and reticulocyte counts and Pink tests were performed on
      successive children found on routine counts to have > 4% hyperchromic red cells,
      and compared with age and mean cell haemoglobin concentration (MCHC) matched
      controls and children known to have HS. RESULTS: Thirty four patients with > 4%
      hyperchromic red cells had significantly higher absolute numbers of such cells (p
      < 0.0001) and higher reticulocyte counts (p < 0.01) than age matched controls,
      together with higher MCHC (p < 0.0001) and haemoglobin distribution width (p <
      0.0001) values and lower mean cell volume (p < 0.02) values. Significant
      differences were also found among hyperchromic red blood cell, reticulocyte, and
      haemoglobin distribution width values when subjects were compared with MCHC
      matched controls. Pink test values were higher in children with increased
      hyperchromic red blood cells, but not significantly so. In patients with HS, most
      variables measured were significantly different both from those of children with
      > 4% hyperchromic cells and controls. Despite the differences found, few MCHC,
      HDW, reticulocyte, or Pink test values were outside of the normal limits, and
      only one child with increased hyperchromic cells had both a mild reticulocytosis
      and a slightly raised Pink test value. CONCLUSIONS: Subjects with an isolated
      increase in hyperchromic red blood cells have a profile of red blood cell changes
      similar to that of patients with HS, but to a lesser degree. They may carry a
      recessive form of the disease but lack the laboratory features of clinically
      manifest HS.

PMID- 12401823
TI  - A randomised controlled trial of patient self management of oral anticoagulation
      treatment compared with primary care management.
AB  - BACKGROUND: The increase in numbers of patients receiving warfarin treatment has
      led to the development of alternative models of service delivery for oral
      anticoagulant monitoring. Patient self management for oral anticoagulation is a
      model new to the UK. This randomised trial was the first to compare routine
      primary care management of oral anticoagulation with patient self management.
      AIM: To test whether patient self management is as safe, in terms of clinical
      effectiveness, as primary care management within the UK, as assessed by
      therapeutic international normalised ratio (INR) control. METHOD: Patients
      receiving warfarin from six general practices who satisfied study entry criteria
      were eligible to enter the study. Eligible patients were randomised to either
      intervention (patient self management) or control (routine primary care
      management) for six months. The intervention comprised two training sessions of
      one to two hours duration. Patients were allowed to undertake patient self
      management on successful completion of training. INR testing was undertaken using
      a Coaguchek device and regular internal/external quality control tests were
      performed. Patients were advised to perform INR tests every two weeks, or weekly
      if a dose adjustment was made. Dosage adjustment was undertaken using a simple
      dosing algorithm. RESULTS: Seventy eight of 206 (38%) patients were eligible for
      inclusion and, of these, 35 (45%) declined involvement or withdrew from the
      study. Altogether, 23 intervention and 26 control patients entered the study.
      There were no significant differences in INR control (per cent time in range:
      intervention, 74%; control, 77%). There were no serious adverse events in the
      intervention group, with one fatal retroperitoneal haemorrhage in the control
      group. Costs of patient self management were significantly greater than for
      routine care (pound 90 v pound 425/patient/year). CONCLUSION: These are the first
      UK data to demonstrate that patient self management is as safe as primary care
      management for a selected population. Further studies are needed to elucidate
      whether this model of care is suitable for a larger population.

PMID- 12401824
TI  - Proactive management of histopathology workloads: analysis of the UK Royal
      College of Pathologists' recommendations on specimens of limited or no clinical
      value on the workload of a teaching hospital gastrointestinal pathology service.
AB  - AIMS: To investigate the effect on the workload of a gastrointestinal pathology
      service of implementing the recommendations of the Royal College of Pathologists'
      (RCPath) working party on specimens of limited or no clinical value (LONCV).
      METHODS: All endoscopic gastrointestinal pathology reports for the first three
      months of 2001 at a large teaching hospital were reviewed against the RCPath
      recommendations. Specimens in the category of LONCV were recorded and the final
      histopathology diagnosis noted. RESULTS: The biopsies in the LONCV category were
      30% of oesophageal, 61% of gastric, 0.5% of duodenal, and 7% of colorectal
      origin. CONCLUSIONS: Implementing the RCPath recommendations would reduce the
      number of requests for the examination of gastrointestinal endoscopic specimens
      by 3500 specimens each year in this department. None of the specimens in the
      LONCV category showed an abnormality that could not have been detected by a more
      efficient and less invasive method. In the UK, where there is a severe shortage
      of trained histopathologists, the implementation of these recommendations would
      ensure that these scarce resources are not misused.

PMID- 12401825
TI  - Frequent expression of smooth muscle markers in malignant fibrous histiocytoma of
      bone.
AB  - BACKGROUND/AIMS: Malignant fibrous histiocytoma (MFH) of bone, a relatively rare
      primary malignant bone tumour, is a distinct clinicopathological entity as
      opposed to MFH derived from soft tissue. Although the true histogenesis of this
      condition is still controversial, a considerable number of cases of MFH in soft
      tissue show positive immunohistochemical reactivity for muscle markers such as
      desmin, common muscle actin (HHF35), and alpha smooth muscle actin (SMA),
      suggesting that MFH cells are myofibroblastic in nature. METHODS: This study
      investigated immunoreactivity for several different muscle markers in 19 cases of
      MFH of bone together with reverse transcription polymerase chain reaction (RT
      PCR) analysis on frozen tissue samples that were available in four cases, and
      compared the data with those found in 11 cases of osteosarcoma and 11 cases of
      soft tissue MFH treated over the same period. RESULTS: Immunohistochemistry
      revealed that MFH of bone showed relatively frequent expression of smooth muscle
      markers, including calponin (nine cases), alpha-SMA (nine cases), and SM22alpha
      (18 cases), and this was confirmed by RT-PCR analysis. However, only one, two,
      and three cases of MFH of bone showed positive staining for desmin, MyoD1, and
      HHF35, respectively. Similarly, 11 osteosarcoma cases were relatively frequently
      positive for alpha-SMA (five cases), calponin (four cases), and SM22alpha (seven
      cases), and less frequently positive for desmin (one case), MyoD1 (none), and
      HHF35 (none). In contrast, very few MFH of soft tissue cases (n = 11) showed
      positive reactivity for all of these muscle markers. It has recently been
      reported that human bone marrow stromal cells also express various kinds of
      smooth muscle markers including alpha-SMA and calponin. CONCLUSIONS: These
      results suggested that MFH of bone may derive from mesenchymal stromal cells in
      bone marrow and has a more myofibroblastic differentiation than soft tissue MFH.

PMID- 12401826
TI  - Specificity of the commonly used enzymatic assay for plasma cholesterol
      determination.
AB  - AIM: To assess the specificity and sensitivity of the commonly used enzymatic
      colorimetric test for plasma cholesterol determination. METHODS: Interference
      with an enzymatic method for cholesterol measurement by several non-cholesterol
      sterols (beta sitosterol, campesterol, stigmasterol, stigmastanol, desmosterol,
      and lathosterol) was assessed. Some of these compounds are present in plasma at
      higher than normal concentrations either in rare genetic disorders, such as
      phytosterolaemia, or after the consumption of phytosterol enriched foods.
      RESULTS: The non-cholesterol sterols were detected by the assay in a linear
      manner. There was no competitive interference in the presence of cholesterol.
      CONCLUSIONS: This crossreactivity may affect the diagnosis and treatment of non
      cholesterol dyslipidaemias, including phytosterolaemia and cerebrotendinous
      xanthomatosis. Similarly, changes in plasma lipid compositions after the
      consumption of phytosterol enriched foods cannot be specifically determined by
      this enzymatic assay. Until a more specific enzymatic assay is developed,
      alternative methods such as gas chromatography should be used to differentiate
      between cholesterol and non-cholesterol sterols.

PMID- 12401827
TI  - Chronic neutrophilic leukaemia: 14 new cases of an uncommon myeloproliferative
      disease.
AB  - BACKGROUND: Chronic neutrophilic leukaemia (CNL) is a distinct BCR/ABL negative
      myeloproliferative disorder of elderly patients characterised by sustained
      neutrophilia and splenomegaly. The bone marrow shows expansion of neutrophilic
      granulopoiesis, without excess of myeloblasts. To date, only 129 cases of CNL
      have been reported in the literature. AIMS: To report the findings from a large
      group of 14 new cases of CNL, consisting of eight women and six men (mean age,
      64.7 years). METHODS: A review of the 14 new cases of CNL and the investigation
      of BCR/ABL translocations in these patients. RESULTS: Three quarters of the
      patients died within two years after diagnosis, mostly as a result of severe
      cerebral haemorrhage. Two younger patients were successfully treated with
      allogeneic bone marrow transplantation or interferon, which resulted in
      haematological remission for years. CONCLUSION: CNL is a rare myeloproliferative
      disease mostly taking a fatal clinical course, despite the presence of mature
      neutrophils as leukaemic cells in the blood. Thus, it is important to recognise
      CNL to develop appropriate therapeutic strategies for affected patients.

PMID- 12401828
TI  - A reliable method for total RNA extraction from frozen human bone marrow samples
      taken at diagnosis of acute leukaemia.
AB  - This report describes a newly developed method using Trizol LS reagent that can
      reliably extract high quality total RNA from frozen human leukaemic bone marrow
      samples. Extraction of total RNA from 71 frozen leukaemic bone marrow samples
      obtained at the time of diagnosis produced a median yield of 145 micro g/ml
      leukaemic bone marrow. Total RNA samples could be reverse transcribed into cDNA
      and used successfully in the reverse transcription polymerase chain reaction
      amplification of B2M transcripts in 68 of 71 cases. A multivariate linear
      regression analysis revealed that significant predictors of RNA yield were both
      sample volume (< 1 ml v > 1 ml; p = 0.003) and peripheral blood white cell count
      (< 5 x 10(9) v >or= 5 x 10(9) white blood cells/litre; p = 0.011). The percentage
      of blasts present, leukaemia subtype, and sample storage period at -80 degrees C
      (up to 945 days) were not predictors of total RNA yield. This method of total RNA
      extraction should be of interest to diagnostic and research staff using frozen
      bone marrow samples for molecular analyses. Similarly, the lack of association
      between sample storage period at -80 degrees C and total RNA yield should be of
      interest to the administrators of tumour banks housing frozen bone marrow
      samples.

PMID- 12401829
TI  - Anaplastic lymphoma kinase (ALK) protein expressing lymphoma after liver
      transplantation: case report and literature review.
AB  - Most post transplantation lymphoproliferative disorders (PTLDs) are Epstein-Barr
      virus (EBV) associated B cell proliferations. We report a case of aggressive
      anaplastic large cell lymphoma expressing the anaplastic lymphoma kinase (ALK)
      protein in a 58 year old man who had previously undergone liver transplantation.
      A definite diagnosis was not possible on histopathological examination.
      Immunostaining clearly showed a predominant population of small irregular
      lymphocytes, admixed with large cells strongly positive for CD30, epithelial
      membrane antigen, and the ALK protein. Neoplastic cells were of the T/cytotoxic
      phenotype. In situ hybridisation with EBV encoded early RNA probes showed only a
      few scattered positive non-neoplastic small lymphocytes. Polymerase chain
      reaction analysis of immunoglobulin and T cell receptor rearrangements was
      negative. The NPM-ALK fusion transcript associated with the t(2;5) translocation
      was detected by reverse transcription polymerase chain reaction. A review of the
      literature revealed 76 cases of T cell PTLD, showing a broad spectrum of
      morphological features and clinical behaviour. Most of these cases were EBV
      negative (61 of 76) and occurred after renal transplantation (48 of 76). To our
      knowledge, this is the first case of ALK positive lymphoma occurring in the
      setting of organ transplantation. This observation stresses the need for accurate
      immunostaining for diagnosing this rare, apparently aggressive, lymphoma in
      immunosuppressed patients.

PMID- 12401830
TI  - Atypical (bizarre) leiomyoma of the nasal cavity with prominent myxoid change.
AB  - A 72 year old woman presented complaining of nasal obstruction, rhinorrea, and
      epistaxis. At examination, a polypoid mass on the right posterior choana was
      revealed and subsequently removed. Light microscopic findings consisted of a
      diffuse proliferation of spindle shaped, pleomorphic cells with eosinophilic
      cytoplasm and blunt ended nuclei in a prominent myxoid background. The presence
      of numerous plurinucleate, bizarre cells made it very difficult to determine the
      malignant potential. Immunohistochemical evidence for leiomyogenic markers
      coupled with the low mitotic rate, the lack of an infiltrating growth pattern,
      and the indolent clinical course led to the diagnosis of atypical leiomyoma with
      prominent myxoid change. A literature survey confirmed that such a tumour is
      extremely rare at this site, but the biological behaviour seems to be similar to
      its uterine counterpart. Clinicians should be aware of this occurrence to prevent
      misdiagnosis because a conservative therapeutic approach is necessary in this
      disease.

PMID- 12401831
TI  - Sensitivity to Quorn mycoprotein (Fusarium venenatum) in a mould allergic
      patient.

PMID- 12401832
TI  - Rare presentation of intestinal amyloidosis with acute intestinal pseudo
      obstruction and perforation.

PMID- 12401833
TI  - Tumour cells produce receptor activator of NF-kappaB ligand (RANKL) in skeletal
      metastases.

PMID- 12401834
TI  - Are coroners' necropsies necessary? A prospective study examining whether a "view
      and grant" system of death certification could be introduced into England and
      Wales.

PMID- 12401835
TI  - Androgen receptor expression in ductal carcinoma in situ of the breast: relation
      to oestrogen and progesterone receptors.

PMID- 12401836
TI  - Megalin and cubilin--the story of two multipurpose receptors unfolds.

PMID- 12401837
TI  - Halting progression of renal failure: consideration beyond angiotensin II
      inhibition.

PMID- 12401838
TI  - Vitamin D deficiency: a neglected aspect of disturbed calcium metabolism in renal
      failure.

PMID- 12401839
TI  - Peritoneal-dialysis-related peritonitis: the art of rope-dancing.

PMID- 12401840
TI  - Cystinosis: from gene to disease.

PMID- 12401841
TI  - Sixth symposium of the Japan-France Nephrology Exchange Association.

PMID- 12401842
TI  - Report from the Second International Congress on Quality of Life in End-stage
      Renal Disease, Thessaloniki, Greece, March 8-9, 2002.

PMID- 12401843
TI  - Urinary N-acetyl-beta-glucosaminidase excretion is a marker of tubular cell
      dysfunction and a predictor of outcome in primary glomerulonephritis.
AB  - BACKGROUND: The urinary excretion of N-acetyl-beta-glucosamynidase (NAG) is
      increased in subjects exposed to substances toxic for renal tubular cells. In
      experimental and human glomerular diseases, its increased excretion is probably
      due to the dysfunction of tubular epithelial cells induced by increased traffic
      of proteins in the tubular lumen. The first aim of this study was to evaluate
      whether NAG excretion is correlated not only with the amount of proteinuria but
      also with some proteinuric components which reflect both glomerular capillary
      wall damage (IgG) and an impairment of tubular reabsorption of microproteins
      (alpha(1) microglobulin). The second aim was to assess whether NAG excretion has
      a predictive value on functional outcome and response to therapy. METHODS: In 136
      patients with primary glomerulonephritis [74 with idiopathic membranous
      nephropathy (IMN), 44 with primary focal segmental glomerulosclerosis (FSGS) and
      18 with minimal change disease (MCD)] urinary NAG excretion was measured by a
      colorimetric method and expressed in units per gram of urinary creatinine.
      RESULTS: Using univariate linear regression analysis NAG excretion in all 136
      patients was significantly dependent on IgG excretion, 24-h proteinuria,
      fractional excretion of alpha(1) microglobulin (FE alpha(1)m) and diagnosis.
      Using multiple linear regression analysis, NAG excretion was significantly
      dependent only on IgG excretion and 24-h proteinuria. Limiting the analysis to 67
      patients with nephrotic syndrome (NS) and baseline normal renal function, by
      multiple linear regression, NAG excretion was significantly dependent on IgG
      excretion (P=0.0004), 24-h proteinuria (P=0.0067) and FE alpha(1)-m (P=0.0032)
      (R(2)=0.63). In 66 patients with NS and normal baseline renal function (MCD 10
      patients; FSGS 20 patients; IMN 36 patients), according to values below or above
      defined cut-offs (IMN, </= or >18 U/g urinary Cr; FSGS and MCD, </= or >24 U/g
      urinary Cr), NAG excretion predicted remission in 86 vs 27% of IMN patients
      (P=0.0002) and 77 vs 14% of FSGS patients (P=0.005). Progression to chronic renal
      failure (CRF) was 0 vs 47% in IMN patients (P=0.001) and 8 vs 57% in FSGS
      patients (P=0.03). Using Cox model, in IMN patients only NAG excretion (P=0.01,
      RR 5.8), but not 24-h proteinuria, predicted progression to CRF. All MCD patients
      had NAG excretion values below the chosen cut-off, and 90% of them developed
      remission. Response to immunosuppressive therapy was significantly different in
      patients with NAG excretion values below or above the cut-offs. CONCLUSION:
      Urinary NAG excretion can be considered as a reliable marker of the tubulo
      toxicity of proteinuria in the early stage of IMN, FSGS and MCD; the excretion
      values show a significant relationship with 24-h proteinuria, IgG excretion and
      FE alpha(1)m. Its determination may be a non-invasive, useful test for the early
      identification of patients who will subsequently develop CRF or clinical
      remission and responsiveness to therapy.

PMID- 12401844
TI  - Correlation of histopathological features and renal impairment in autosomal
      dominant Alport syndrome in Bull terriers.
AB  - BACKGROUND: Bull terrier hereditary nephritis represents a model for autosomal
      dominant Alport syndrome, as affected dogs have the characteristically lamellated
      glomerular basement membrane and demonstrate vertical male-to-male disease
      transmission. METHODS: This study compared the histopathological features in
      kidneys from affected Bull terrier neonates, puppies, and adult dogs with normal
      or impaired renal function, with the histopathological appearance of kidneys from
      age- and size-matched normal dogs. RESULTS: There were fewer glomeruli per unit
      area of cortex in kidneys from affected neonatal kidneys (P<0.05), increased
      numbers of fetal glomeruli in affected puppy kidneys (P<0.05), and a separate
      population of glomeruli with larger renal corpuscles and glomerular tufts in
      kidneys from affected adult dogs with normal renal function (both P<0.0001)
      compared with normal dogs. Other histological features that are characteristic of
      human X-linked and autosomal recessive Alport syndrome and that were present
      included hypercellular glomeruli, occasional crescents, segmental and global
      glomerular sclerosis, periglomerular fibrosis, interstitial fibrosis without
      significant cellular infiltrates and cystic dilatation of Bowman's capsular space
      and tubules. In dogs with renal impairment, the tubular index was the best
      predictor of increased urinary protein:creatinine (r=0.92) compared with
      glomerular, interstitial and vascular indices (r=0.77, 0.88 and 0.81), and
      medullary fibrosis correlated best with serum creatinine (r=0.72, P=0.0002).
      CONCLUSIONS: The demonstration in Bull terrier kidneys of fewer nephrons in
      neonates increased fetal glomeruli, and a separate population of glomeruli with
      larger corpuscles and tufts reflects the effects of the underlying genetic
      mutation that are first manifest antenatally. The major determinant of renal
      impairment in adult affected Bull terriers is, however, progressive
      tubulointerstitial damage after birth.

PMID- 12401845
TI  - Assessment of glomerular filtration rate in healthy subjects and normoalbuminuric
      diabetic patients: validity of a new (MDRD) prediction equation.
AB  - BACKGROUND: Based on the data derived from the Modification of Diet in Renal
      Disease (MDRD) study, a new equation was developed for the estimation of
      glomerular filtration rate (GFR). This equation, which takes into account body
      weight, age, sex, serum creatinine, race, serum urea, and serum albumin, provided
      a more accurate estimation of GFR in patients with renal insufficiency. However,
      this prediction equation has not been validated in subjects with normal or supra
      normal GFR. METHODS: In a cross-sectional study, we measured GFR by inulin
      clearance in 46 healthy controls and 46 non-complicated type 1 diabetic patients.
      In this study population, GFR was predicted by measured creatinine clearance, the
      Cockcroft-Gault formula, and the MDRD equation. RESULTS: In the healthy subjects,
      mean GFR (+/-SD) was 107+/-11 as compared to 122+/-18 ml/min per 1.73 m(2) in the
      diabetic patients. This difference in GFR was reflected by a lower serum
      creatinine (76+/-8 vs 71+/-8 micro mol/l) in the diabetic patients. In the
      healthy controls, median absolute differences (and the 50th-75th-90th percentile
      of percentage absolute differences) between predicted and measured GFR were 5.2
      ml/min per 1.73 m(2) (4.9-9.8-18.5%) for creatinine clearance, 9.0 ml/min per
      1.73 m(2) (8.6-14.3-24.6%) for the Cockcroft-Gault formula, and 10.7 ml/min per
      1.73 m(2) (10.9-16.3-25.5%) for the MDRD equation. In the diabetic patients,
      these differences were 8.3 ml/min per 1.73 m(2) (7.6-9.3-13.0%) for creatinine
      clearance; 11.8 ml/min per 1.73 m(2) (10.1-16.0-22.5%) for the Cockcroft-Gault
      formula, and 18.8 ml/min per 1.73 m(2) (16.0-24.2-31.9%) for the MDRD equation.
      CONCLUSIONS: In subjects with a normal or increased GFR, the new MDRD-prediction
      equation of GFR is less accurate than creatinine clearance or the Cockcroft-Gault
      formula, and offers no advantage.

PMID- 12401846
TI  - Karyomegalic nephropathy: an uncommon cause of progressive renal failure.
AB  - BACKGROUND: Karyomegalic nephropathy, first identified in 1974, represents an
      increasingly recognized, but perhaps underdiagnosed condition associated with
      interstitial nephritis. It undoubtedly leads to end-stage renal disease requiring
      renal support. METHODS AND RESULTS: We present a series of six cases of
      karyomegalic nephropathy. The age at diagnosis was 9-51 years, median 33 years.
      Impaired renal function, proteinuria, and haematuria were present in the majority
      of cases. Non-specific elevated liver enzymes were present in three cases. Two
      patients died soon after transplantation from overwhelming respiratory sepsis.
      The classical histological features of large, abnormal hyperchromatic nuclei with
      irregular outlines within epithelial cells were present in renal epithelial
      cells. Abnormality of DNA ploidy distributions compared with age- and sex-matched
      controls, and characterized by the presence of significant numbers of cells with
      high ploidy values was present in cases but not in controls. Mitotic figures were
      absent. Proliferation markers, Ki-67 and proliferating cell nuclear
      antigen/cyclin were not significantly elevated in those cases examined. Human
      leukocyte antigen analysis did not support the clustering of A9 or B35, in the
      cases or their families. CONCLUSIONS: The presence of significant renal
      impairment, positive urine sediment, abnormal liver enzymes, and early age of
      onset should alert one to the presence of karyomegalic nephropathy. It represents
      an underdiagnosed disorder with a high degree of ploidy indicative of karyotypic
      abnormality.

PMID- 12401847
TI  - MEFV gene mutations in familial Mediterranean fever phenotype II patients with
      renal amyloidosis in childhood: a retrospective clinicopathological and molecular
      study.
AB  - BACKGROUND: Familial Mediterranean fever (FMF) is an autosomal recessive disease
      characterized by recurring attacks of fever and serositis. The definition of the
      mutated gene has allowed molecular diagnosis of the disease. The most important
      complication of FMF is the development of AA type secondary amyloidosis. In a
      group of patients clinically designated as phenotype II amyloidosis patients,
      renal amyloidosis develops without being preceded by typical attacks of the
      disease. In this study, the mutations of the MEFV gene were analysed in a group
      of patients clinically recognized as phenotype II. METHODS: DNA samples were
      obtained from tissue samples of the subjects. PCR-RFLP methods were used to
      analyse the M694V, M680I, V726A and E148Q mutations that have been previously
      defined by us to be the most common mutations in our Turkish cohort. RESULTS: The
      distribution of the four most common mutations among phenotype II patients was
      38% for M694V, 8% for M680I, 4% for V726A and 4% for E148Q. CONCLUSIONS: In
      phenotype II amyloidosis patients, the distribution of the four common MEFV
      mutations was not significantly different from that found in all FMF patients
      with typical symptoms who do or do not develop amyloidosis. We therefore suggest
      that secondary genetic or environmental factors are operative in the development
      of secondary amyloidosis in patients with FMF.

PMID- 12401848
TI  - Effect of combination therapy (ribavirin and interferon) in HCV-related
      glomerulopathy.
AB  - BACKGROUND: Hepatitis C virus (HCV) is a major cause of acute and chronic
      hepatitis throughout the world. Several extrahepatic manifestations, including
      glomerulonephritis, have been reported to be associated with this type of
      infection. Cryoglobulinaemic and non-cryoglobulinaemic membranoproliferative
      glomerulonephritis (MPGN) and membranous nephropathy (MN) are the commonest
      lesions associated with HCV. Results of treatment of these patients with
      interferon therapy have been disappointing, since relapse of the viraemia and
      subsequent relapse of the renal disease are major problems. Combination of
      interferon with ribavirin in patients with chronic liver disease has been shown
      to increase the rate of sustained response. METHODS: In this work, 20 patients
      with HCV-associated glomerulopathy were subjected to an in-depth evaluation of
      their kidney lesions and HCV involvement. Laboratory, histopathological,
      immunohistochemical, and electron-microscopy techniques were used. The patients
      received interferon therapy for 12 months; in interferon-resistant subjects,
      interferon was combined with ribavirin. RESULTS: MPGN was the commonest kidney
      lesion, being reported in 85% of these cases, followed by MN and
      mesangioproliferative glomerulonephritis (10 and 5% respectively). Mixed
      cryoglobulinaemia was encountered in 60% of the cases. Twelve months' anti-viral
      treatment resulted in aviraemia in 25% of cases, while liver enzymes were
      normalized in 75%, 24-h proteinuria significantly decreased (from median 4 g to
      1.10 g, P=0.001), serum albumin increased (from median 2.50 to 3.55 g/dl,
      P=0.012), lower viral titres (from median 1.15 to 0.53 mega-Eq/ml, P=0.049), and
      C3 and C4 concentrations returned to normal. Basal serum creatinine and viral
      titres were important determinants of response to treatment. CONCLUSION: This
      study supports the relationship between HCV and glomerulonephritis, especially
      MPGN, and the use of a combination of interferon and ribavirin in the treatment
      of selected cases of HCV-related glomerulopathy.

PMID- 12401849
TI  - Cumulative prior dose of cisplatin as a cause of the nephrotoxicity of high-dose
      chemotherapy followed by autologous stem-cell transplantation.
AB  - BACKGROUND: Nephrotoxicity is one of the most frequent dose-limiting factors of
      high-dose chemotherapy to create tolerance of autologous peripheral blood stem
      cell transplantation (PBSCT) for the treatment of malignant diseases. The
      relative importance of factors that may be responsible for the development of
      nephrotoxicity varied in different trials. METHODS: The factors affecting
      nephrotoxicity in the early period of high-dose ifosfamide, carboplatin and
      etoposide treatment (ICE) followed by autologous PBSCT was investigated in 47
      patients. ICE was given as a conditioning regimen for 6 days. Nephrotoxicity was
      defined as an increase in the serum creatinine concentration of 0.5 mg/dl or more
      over individual baseline levels. RESULTS: Eleven patients developed
      nephrotoxicity (23.4%). There was no significant difference in baseline renal
      function between patients with nephrotoxicity and those without. No differences
      were found between the two groups in terms of average total doses of ICE,
      infections and antibiotic use. The age of patients was higher in those with
      nephrotoxicity (37+/-3.7 vs 26+/-1.7 years, P=0.019). The cumulative cisplatin
      dose administered prior to this regimen was higher in the group that developed
      nephrotoxicity (470 vs 227 mg/m(2), P=0.02). The overall mortality rate was 17%,
      but the transplant-related deaths were higher in the presence of nephrotoxicity
      (54.5 vs 5.5%, P=0.001). CONCLUSIONS: The cumulative dose of cisplatin is a
      strong risk factor for the development of nephrotoxicity in patients who receive
      high doses of ICE followed by PBSCT. Nephrotoxicity may occur with much lower
      doses than the currently recommended maximum doses.

PMID- 12401850
TI  - The role of theophylline in contrast-induced nephropathy: a case-control study.
AB  - BACKGROUND: Various strategies for the prevention of contrast-induced nephropathy
      (CN) have been studied, with conflicting results. Adenosine may play an important
      role in the pathogenesis of CN. This study prospectively assessed the role of
      oral theophylline in the prevention of CN. METHODS: We randomized into two groups
      70 patients with diabetes mellitus who were undergoing coronary angiography (CAG)
      with high-osmolar contrast media. Group I (n=35) underwent routine CAG, and group
      II (n=35) received oral theophylline 200 mg b.d. 24 h before and for 48 h after
      CAG. Serum Na(+), K(+), blood urea nitrogen (BUN), creatinine, osmolality,
      glomerular filtration rate (GFR) and urinalysis were performed before and after
      CAG. The (99m)Tc-DTPA-clearance method was used to assess GFR. RESULTS: Following
      angiography, patients in the control group showed a significant rise in serum
      creatinine (1.19+/-0.23 vs 1.44+/-0.32 mg/dl, P=0.003) and BUN (13.95+/-2.61 vs
      17.55+/-3.9 mg/dl, P=0.01) along with a fall in GFR (85.4+/-14.7 vs 66.85+/-14.8
      ml/min, P=0.008). The mean percentage fall in GFR was 35.8%. There was no
      significant change in serum creatinine (1.16+/-0.18 vs 1.24+/-0.21 mg/dl), BUN
      (12.8+/-3.36 vs 14.8+/-2.5 mg/dl) and GFR (86.8+/-15.8 vs 80.3+/-16.0 ml/min) in
      those receiving theophylline. No patient in the theophylline group had a >25%
      rise in serum creatinine, compared with 7/35 in the control group (P=0.017). In
      the control group, 11/35 (31%) developed CN, as demonstrated by a >/=25% fall in
      GFR, while only one patient in the theophylline group had a fall in GFR
      (P=0.004). None of the pre-angiographic variables could predict the development
      of CN. CONCLUSIONS: Following the use of high-osmolar contrast media for routine
      CAG, CN may develop in 31% of diabetic patients. Patients who received
      prophylactic oral theophylline had a significantly lower risk of CN than those
      who did not.

PMID- 12401851
TI  - Clinical findings in the renal victims of a catastrophic disaster: the Marmara
      earthquake.
AB  - BACKGROUND: The clinical course of acute renal failure (ARF) related to crush
      syndrome is very complex, because of co-existing surgical and/or medical
      complications. After the devastating Marmara earthquake that struck Turkey in
      August 1999, 639 patients were identified with nephrological problems, whose
      clinical findings have been the subject of this analysis. METHODS: Specific
      questionnaires asking about 63 variables were sent to 35 reference hospitals that
      treated the victims. Clinical findings of the renal victims were analysed.
      RESULTS: At admission, high fever was noted in 31.8% of the patients; the
      temperature of non-survivors was higher (P=0.027). Mean blood pressure was higher
      in survivors (P=0.004) and dialysed victims (P <0.001). Most (61.4%) patients
      were oligo-anuric; oliguria lasted for 10.8+/-7.2 days. Thoracic and abdominal
      traumas were associated with a higher risk of mortality. 397 fasciotomies and 121
      amputations were performed in 790 traumatized extremities. Fasciotomies were
      associated with sepsis (P<0.001) and dialysis needs (P<0.0001), while amputations
      were associated with mortality (P<0.0001). Medical complications, which were
      associated with dialysis needs (P<0.0001) and mortality (P<0.0001), were observed
      in 51.5% of patients. In a multivariate analysis model of medical complications,
      disseminated intravascular coagulation (DIC) (P<0.0001, OR=5.81), and adult
      respiratory distress syndrome (ARDS) (P=0.0001, OR=4.53) were predictors of
      mortality. CONCLUSIONS: In the aftermath of catastrophic earthquakes, clinical
      findings of the renal victims can predict the final outcome. While fasciotomies
      indicate dialysis needs, extremity amputations, abdominal and thoracic traumas
      are associated with higher rates of mortality in addition to DIC and ARDS.

PMID- 12401852
TI  - The effect of coupled haemofiltration and adsorption on inflammatory cytokines in
      an ex vivo model.
AB  - BACKGROUND: The objective of this study was to evaluate the ex vivo removal of
      cytokines with an extracorporeal circuit using coupled large-pore haemofiltration
      and sorbent adsorption. METHODS: The setting for this study was a laboratory
      attached to the Intensive Care Unit of a tertiary hospital. Six healthy
      volunteers donated blood, which was incubated with endotoxin. Control blood was
      left at room temperature. Treatment blood was recirculated for 6 h through a
      closed circuit with a large-pore polysulfone haemofilter (average pore size 150
      kDa) and an activated charcoal cartridge. Blood and ultrafiltrate were sampled
      hourly from three sites (pre-haemofilter for the circulating concentration, at
      cartridge inlet and cartridge outlet) to measure the concentrations of
      interleukins (IL)-1beta, -6, -8 and -10, and tumour necrosis factor (TNF).
      RESULTS: Control cytokine concentrations remained the same or increased slightly.
      Most of the preformed circuit cytokines were removed, with the exception of IL
      10. The average sieving coefficients were 0.61 for IL-1beta, 1.34 for IL-6, 0.30
      for IL-8, and 0.56 for TNF. Average single-pass clearances were 49, 107, 24 and
      45 ml/min, respectively. The cartridge adsorbed 90% of IL-1beta, 72% of IL-6,
      100% of IL-8, and 7% of TNF during each pass. CONCLUSION: The combination of a
      large-pore haemofilter and charcoal cartridge removed several cytokines
      efficiently under ex vivo conditions. This technique can now be tested for
      cytokine removal in vivo.

PMID- 12401853
TI  - In vitro studies on hirudin elimination by haemofiltration: comparison of three
      high-flux membranes.
AB  - BACKGROUND: Recombinant hirudin (r-hirudin) is a highly selective thrombin
      inhibitor used for anticoagulation in heparin-induced thrombocytopenia type II. R
      hirudin is increasingly applied to patients with renal failure and on renal
      replacement therapy. Since kidney function impairment strongly prolongs r-hirudin
      elimination half-life, severe accumulation and bleeding complications may occur.
      Data on the r-hirudin permeability and elimination capacity of different
      haemofilters are limited. METHODS: Three haemofilter types were investigated:
      high-flux polysulphone (Fresenius), AN69 (Hospal), and polyamide (Gambro). We
      used two in vitro haemofiltration models: (i) an open post-dilution
      haemofiltration model with ultrafiltration and fluid substitution (model 1)
      simulating hirudin intoxication, and (ii) a closed model with ultrafiltrate
      reinfusion (model 2) to determine steady-state sieving coefficients (SC). Fresh
      human heparinized blood (2 IU unfractionated heparin/ml blood) was used. In model
      2, SC obtained with human whole blood were compared with isotonic saline.
      RESULTS: In model 1, r-hirudin levels decreased significantly faster with
      polysulphone than with AN69 or polyamide (P<0.05). In accordance with this, in
      model 2 the observed SC in whole blood were 1.11+/-0.28 (polysulphone), 0.61+/
      0.15 (AN69) and 0.33+/-0.13 (polyamide), and clearances were 28+/-7
      (polysulphone), 15+/-4 (AN69) and 8+/-3 ml/min (polyamide) (P<0.001 for all
      comparisons). The SC in saline were slightly but significantly lower for
      polysulphone (0.88+/-0.12), similar for AN69 (0.59+/-0.1), and significantly
      improved for polyamide (0.83+/-0.1). CONCLUSIONS: Elimination of r-hirudin by
      haemofiltration strongly depended on the membrane material. Using human blood, we
      observed large differences between the three high-flux membranes. The saline
      experiments suggest a membrane-dependent impact of plasma proteins and pH on
      hirudin sieving. Our findings have implications for r-hirudin dosage in
      haemofiltration, for treatment of overdosage, and for future in vitro
      haemofiltration studies.

PMID- 12401854
TI  - IL-1beta, TNF-alpha and IL-6 release from monocytes in haemodialysis patients in
      relation to dialytic age.
AB  - BACKGROUND: It has been suggested that changes in immune response to infectious
      agents in patients on haemodialysis might be due to impaired monocyte function;
      uraemic and haemodialysed patients overproduce proinflammatory cytokines, such as
      interleukin-1 beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha) and
      interleukin-6 (IL-6). METHODS: We quantitated the cytokines released into the
      plasma and into the supernatants of 24-h cultured purified monocytes, under basal
      conditions and after stimulation by lipopolysaccharide from Escherichia coli, in
      15 healthy subjects (CON), 20 uraemic patients who had not yet started dialysis
      (CRF) and 60 haemodialysed patients (HD), who were divided into three groups of
      20 patients corresponding to short-, medium- and long-term dialysis. RESULTS:
      Monocytes from HD patients spontaneously secreted significantly higher levels of
      cytokines than those from controls and uraemic patients who had not yet started
      dialysis. After stimulation with lipopolysaccharide (LPS), cytokine levels in
      culture supernatants of cells from HD patients were significantly lower than
      those from controls and uraemic patients. Moreover, levels of cytokines in
      monocyte supernatants and plasma from short-, medium- and long-term haemodialysed
      patients decreased progressively with dialytic age. Monocytes from haemodialysed
      patients tended to be constitutively active, but their ability to secrete
      proinflammatory cytokines was inversely correlated with dialytic age.
      CONCLUSIONS: These results indicate that prolonged treatment with dialysis can be
      considered a form of chronic stress that causes the progressive activation of
      monocytes, which ultimately leads to monocyte exhaustion and dysfunction.

PMID- 12401855
TI  - Caspase-3-dependent pathway mediates apoptosis of human mononuclear cells induced
      by cellulosic haemodialysis membranes.
AB  - BACKGROUND: Mononuclear cells from patients dialysed with cellulosic membranes
      undergo rapid apoptosis in vitro. The aim of the present study was to determine
      whether the apoptosis associated with cellulosic haemodialysis membrane shares
      similar features with the spontaneous apoptosis described in normal monocytes.
      Thus, we determined whether apoptosis is dependent on caspase-3 activity and is
      inhibited by lipopolysaccharide (LPS), which are two features of spontaneous
      apoptosis in normal monocytes. METHODS: We examined mononuclear cells from
      healthy subjects and from 14 end-stage renal failure patients on haemodialysis
      with cellulosic membranes (n=7) and non-cellulosic membranes (n=7). Isolated
      mononuclear cells were cultured for 48 h. To determine the effect of
      haemodialysis membrane exposure on caspase-3 activity, on mononuclear apoptosis,
      or both, cells from healthy subjects were cultured in mini-dialysers with the
      same membrane types that were used in the haemodialysis patients. Caspase-3
      active form was determined by flow cytometric analysis using anti-human-active
      caspase-3 antibodies. The effect of LPS and Ac-DEVD-CHO, a specific inhibitor of
      active caspase-3, was also evaluated. Cell apoptosis was assessed by the terminal
      deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labelling method.
      RESULTS: After 48 h of culture, the percentage of mononuclear cells expressing
      the active form of caspase-3 was greater in patients dialysed with cellulosic
      membranes than in patients using non-cellulosic membranes and in healthy
      subjects. This increase in caspase-3 activity was associated with a high rate of
      apoptosis, which was prevented by Ac-DEVD-CHO, an inhibitor of caspase-3
      activity. LPS decreased both apoptosis and caspase-3 activity in mononuclear
      cells from patients dialysed with cellulosic membranes. Finally, in cells from
      healthy subjects, both caspase-3 activation and apoptosis were induced after
      incubation with cellulosic membranes. In contrast, the active form of caspase-3
      was not increased in cells cultured with non-cellulosic membranes and was
      significantly lower than with cellulosic membranes. CONCLUSION: These findings
      suggest that the apoptosis of mononuclear cells induced by cellulosic
      haemodialysis membranes occurs through a pathway that is similar to the
      spontaneous apoptosis of normal monocytes. They additionally suggest that LPS
      regulates the proteolytic activation of caspase-3.

PMID- 12401856
TI  - Creatine monohydrate treatment alleviates muscle cramps associated with
      haemodialysis.
AB  - BACKGROUND: Muscle cramp is a common complication of haemodialysis. The exact
      mechanism of this complication is still unknown. Many approaches have been used
      to relieve the muscle cramping but have had variable effects. One of the possible
      mechanisms of haemodialysis-associated muscle cramps (HAMC) is the disturbance of
      muscle energy metabolism. Creatine monohydrate can enhance muscle metabolism. We
      evaluated the clinical effect of creatine monohydrate on HAMC. METHODS: Ten
      patients with frequent muscle cramps during haemodialysis were randomly selected
      into two groups, control and placebo. In a double-blind manner, 12 mg of creatine
      monohydrate or placebo was given to each patient before each dialysis session for
      4 weeks. The incidence of muscle cramp during haemodialysis was compared between
      the two groups. Dialysis adequacy, haemodynamic status, and side-effects were
      also evaluated. We continued to observe and compare the patients during a 4-week
      washout period to verify the effect of creatine monohydrate. RESULTS: The
      frequency of symptomatic muscle cramps decreased by 60% in the creatine
      monohydrate treatment group (6.2+/-0.8 vs 2.6+/-1.8 times/4 weeks, P<0.05) during
      the treatment period. This decreasing incidence of muscle cramps disappeared in
      the washout period in the creatine group (6.6+/-1.1 times/4 weeks). There was no
      difference in the incidence of muscle cramps in the placebo group. The
      haematocrit, Kt/V, serum albumin, and haemodynamics remained unchanged in both
      groups during the treatment and washout periods. Serum creatinine increased
      slightly after creatine monohydrate treatment (10.7+/-3.2 vs 12.4+/-3.2 mg/dl,
      P<0.05). No adverse effect was found in either group during the treatment and
      washout periods. CONCLUSION: These data suggest that creatine monohydrate can
      reduce the incidence of HAMC and that it may be a safe agent.

PMID- 12401857
TI  - Efficacy of the accelerated hepatitis B vaccination schedule used in
      haemodialysis patients post-exposure to virus: a single-centre experience.
AB  - BACKGROUND: The hepatitis B (HB) vaccination regime currently recommended for use
      in the UK for both preventative and post-exposure purposes is the accelerated
      regime, although there have been no recent reports of its efficacy. This
      observational study reports on the response rate achieved and longevity of
      protection conferred with this regime in a large number of haemodialysis patients
      following an episode of HB exposure. METHODS: One-hundred and five patients
      received primary vaccination (vaccine administered at 0, 1 and 2 months). Eighty
      six completed the regime, receiving a booster dose at month 12. Measuring
      antibodies to HB surface antigen (anti-HBS) 6 weeks after receiving the third and
      fourth doses assessed patients' response. Seventy-seven patients subsequently had
      anti-HBs measured at month 24. RESULTS: The response rate (anti-HBS >10 mIU/ml)
      to primary vaccination and the complete regime was 33 and 73%, respectively. Non
      European patients responded better to primary vaccination than Europeans
      (P=0.014). Those receiving steroids responded less well to the complete
      vaccination regime (P=0.007). Patient's age, sex, renal diagnosis, diabetes
      mellitus, time on dialysis, dialysis adequacy, erythropoietin dose, hepatitis C
      or body weight did not affect response rates. By month 24, 24 responders (44%)
      had lost seroprotection. Antibody levels achieved with vaccination by transient
      responders was significantly lower than persistent responders. No patients became
      HB surface antigen positive during the 2-year study. CONCLUSION: Reserving the
      accelerated vaccination to the post-exposure scenario will expose many more
      patients to the risk of HB cross-infection than if used prophylactically. Regular
      monitoring is required if seroprotection is to be maintained.

PMID- 12401858
TI  - Dialysis with icodextrin interferes with measurement of serum alpha-amylase
      activity.
AB  - BACKGROUND: The glucose polymer icodextrin has gained a widespread use in
      peritoneal dialysis especially in patients with low ultrafiltration and high
      peritoneal transport properties. In patients using a once-daily exchange with
      icodextrin, a decreased serum amylase activity has been reported. We explored the
      potential underlying mechanisms of this effect. METHODS: Using standard
      chromolytic methods, serum amylase activity was measured in blood samples from 11
      patients on icodextrin treatment and from 11 patients on conventional glucose
      treatment. Samples were additionally supplemented with alpha-amylase and unused
      icodextrin dialysis fluid. Potential complex formation between icodextrin and
      alpha-amylase was studied by SDS-gel electrophoresis with protein silver staining
      and fluorophore-assisted carbohydrate staining with the AMAC (FACE) method, which
      provides oligosaccharide labelling. Lipase activity was measured in parallel in
      all samples by two standard methods. RESULTS: Amylase activity was reduced by 90%
      in serum from patients using icodextrin for the long dwell (15.9+/-10.9 U/l) vs
      patients using standard glucose (157.1+/-23.7 U/l; P<0.001). Addition of
      icodextrin to serum samples from patients using conventional glucose solutions
      induced a dose-dependent decrease in amylase activity. The assay results
      indicated a substrate competition between ET7-G7PNP and icodextrin. AMAC
      fluorophore staining of icodextrin and subsequent gel electrophoresis failed to
      demonstrate complex formation between icodextrin and alpha-amylase. Unlike the
      amylase findings, icodextrin did not affect lipase activity. CONCLUSIONS: The
      present findings indicate that icodextrin competitively interacts as a substrate
      in the amylase assay. In support of this, fluorophore-assisted oligosaccharide
      electrophoresis on SDS gel failed to reveal the formation of an
      'amylase/icodextrin complex'. Lipase measurement should provide an alternative
      and unconfounded method for diagnosing pancreatitis in icodextrin patients.

PMID- 12401859
TI  - Interstitial expression of alpha-SMA: an early marker of chronic renal allograft
      dysfunction.
AB  - BACKGROUND: Renal myofibroblast infiltration has been shown to be strongly
      associated with renal function decline in several chronic renal diseases. The
      purpose of the present study was to investigate whether early detection of
      myofibroblast infiltration using alpha-smooth-muscle actin (alpha-SMA) expression
      in time-zero biopsies predicts renal allograft dysfunction. METHODS: We studied
      renal tissue from 38 renal transplant patients from whom biopsies had been taken
      after vascular anastomosis during transplantation to ascertain whether
      myofibroblasts infiltration predicts renal graft survival. Immunohistochemistry
      was performed on time-zero biopsies to determine alpha-SMA expression, and this
      was compared to annual glomerular filtration rate (GFR) variation and other
      parameters including cold ischaemic time (CIT), donor and recipient age, number
      of acute rejections, and delayed graft function (DGF). GFR was measured by inulin
      clearance during of 3 years of follow-up after the transplantation. Progressors
      were defined as patients with an annual GFR decline >5 ml/min/year. RESULTS: We
      found a significant correlation between interstitial alpha-SMA expression in time
      zero biopsies and GFR evolution during the post-transplantation course (r=0.60,
      P<0.001). Although progressors had greater interstitial alpha-SMA expression than
      non progressors (7.9+/-0.7 vs 4.3+/-0.4%), they showed only a tendency towards
      higher glomerular alpha-SMA expression. In addition, progressors had more
      interstitial fibrosis in time-zero biopsies than non-progressors. There was no
      relationship between alpha-SMA expression and CIT, donor and recipient ages,
      number of acute rejections, and occurrence of DGF. CONCLUSION: This study
      suggests that alpha-SMA evaluation in time-zero biopsies, especially the
      combination of alpha-SMA expression and interstitial fibrosis, can strongly
      predict chronic renal allograft dysfunctions.

PMID- 12401860
TI  - Net renal extraction of asymmetrical (ADMA) and symmetrical (SDMA)
      dimethylarginine in fasting humans.
AB  - BACKGROUND: Recently, the potential importance of dimethylarginines as
      endogenously produced inhibitors of nitric oxide synthase has become clearer.
      Interestingly, elevated levels have been reported in patients with vascular
      disease, but especially in patients suffering end-stage renal disease. Although
      the kidney obviously seems to play a key role in the elimination of
      dimethylarginines, clear insight into the renal handling of these compounds is
      lacking. Thus, our aim was to investigate the renal extraction of
      dimethylarginines. METHODS: Plasma concentrations of dimethylarginines were
      determined in both arterial and renal venous blood in 20 fasting patients with
      normal renal function. Renal extraction was calculated as the arteriovenous
      concentration difference divided by the arterial concentration times 100%.
      RESULTS: A significant renal extraction was found for both dimethylarginines.
      Renal extraction was significantly higher for asymmetrical dimethylarginine
      (ADMA) when compared with symmetrical dimethylarginine (SDMA) (16.2 vs 10.5%
      respectively, P=0.001). In addition, arterial SDMA concentration, but not ADMA
      concentration, significantly correlated with arterial creatinine concentration.
      CONCLUSIONS: In healthy humans, the kidney contributes to the regulation of
      plasma levels of dimethylarginines, since both ADMA and SDMA were significantly
      extracted from the arterial supply. Interestingly, a higher renal extraction of
      ADMA was found when compared to SDMA extraction, which strongly suggests the
      presence of an additional catabolic pathway for ADMA in the kidney.

PMID- 12401861
TI  - A retrospective analysis for aetiology and clinical findings of 287 secondary
      amyloidosis cases in Turkey.
AB  - BACKGROUND: Secondary amyloidosis is the most frequent of the various types of
      systemic amyloidosis, the epidemiology of which is not yet fully known. The aim
      of our study was to evaluate retrospectively the collective data for the
      aetiological distribution, clinical findings and approaches to the management of
      secondary amyloidosis in Turkey. METHODS: Data from a simple questionnaire
      addressing aetiology, and demographic and clinical characteristics of patients
      with biopsy-proven secondary amyloidosis was retrospectively analysed. Eleven
      nephrology clinics contributed data for this study. RESULTS: The 11 contributing
      centres provided a total of 287 cases (102 female, 185 male). The aetiological
      distribution was as follows: familial Mediterranean fever (FMF) 64%, tuberculosis
      10%, bronchiectasis and chronic obstructive lung disease 6%, rheumatoid arthritis
      4%, spondylarthropathy 3%, chronic osteomyelitis 2%, miscellaneous 4%, unknown
      7%. Oedema accompanied by proteinuria was present in 88% of the cases,
      hepatomegaly in 17%, and splenomegaly in 11%. The mean systolic and diastolic
      blood pressures were 115+/-26 and 73+/-15 mmHg respectively. The family history
      was positive in 16%; 73% of the cases were on colchicine treatment when the
      questionnaire was administered. Thirty-eight per cent of the cases had progressed
      to ESRD and were on renal replacement therapy. CONCLUSIONS: FMF is the leading
      cause of secondary amyloidosis in Turkey, followed by tuberculosis. Oedema
      accompanied by proteinuria is the most prominent presenting finding, and
      hypotension seems to be common among these patients.

PMID- 12401862
TI  - Must metabolic acidosis be associated with malnutrition in haemodialysed
      patients?
AB  - BACKGROUND: Metabolic acidosis was evaluated in the past as an independent
      variable of catabolism in haemodialysis (HD) patients. Nevertheless, it could in
      theory reflect a higher acid production from protein oxidation. The aim of this
      study was to evaluate the incidence and basis of metabolic acidosis in
      conjunction with a nutritional assessment in a HD population (n=120). METHODS:
      Three groups were identified based on three consecutive monthly predialysis
      plasma bicarbonate concentrations (P(HCO3)) and pH values. The effect of
      correction of metabolic acidosis on nutritional parameters was also studied in
      acidotic patients. RESULTS: The mean P(HCO3) ranged from 19.2+/- 0.4 mmol/l in
      group A (n=21) to 24.4+/-0.3 mmol/l in group B (n=80) and 27.5+/-0.4 mmol/l in
      group C (n=19). The adequency of dialysis (Kt/V) and ultrafiltration rates was
      comparable in the three groups. When compared with group B, group A had
      significantly higher body mass index (BMI), triceps skin fold thickness (TSF),
      dietary protein intake (DPI), normalized protein catabolic rate (nPCR) as well as
      serum creatinine, K(+) and intact parathyroid hormone (I-PTH). In contrast, when
      compared with group B, group C had a significantly lower DPI, nPCR, plasma
      creatinine and albumin. There was no significant difference in plasma
      inflammatory markers such as C-reactive protein (CRP) and interleukin 6 (IL-6)
      among all three groups. There was a significant negative correlation between
      P(HCO3) and nPCR (P<0.001), DPI (P<0.001), creatinine (P<0.001). Over a period of
      6 months, the correction of metabolic acidosis in the HD patients did not affect
      nutritional parameters. CONCLUSION: These findings suggest that metabolic
      acidosis as a result of a higher protein intake does not detrimentally affect
      nutritional status.

PMID- 12401863
TI  - Mycophenolate mofetil in the treatment of resistant idiopathic nephrotic
      syndrome.
AB  - BACKGROUND: A small proportion of patients with initially steroid-sensitive
      nephrotic syndrome relapse frequently, despite treatment with cyclophosphamide
      and/or cyclosporin. We investigated the efficacy of mycophenolate mofetil (MMF)
      in this group. METHODS: Seven patients with nephrotic syndrome due to minimal
      change nephropathy (MCN) or classical focal segmental glomerulosclerosis (FSGS)
      who had suffered multiple relapses over many years despite treatment with several
      different agents were commenced on MMF 1 g twice daily, together with a reducing
      dose of corticosteroids. RESULTS: Six patients went into complete remission and
      the seventh into partial remission. At 1 year, five remained in complete
      remission. The median (range) serum albumin concentration rose from 19 g/l (16-42
      g/l) pre-MMF to 42 g/l (25-45 g/l) after 12 months (P=0.023), and the median
      (range) dose of prednisolone fell from 40 mg/day (30-60 mg/day) to 7.5 mg/day (0
      40 mg/day) at 12 months (P=0.0008). CONCLUSION: MMF appears to be of benefit in
      the treatment of multiply relapsing nephrotic syndrome caused by MCN or FSGS.
      Controlled trials are required to establish the role of MMF in these disorders.

PMID- 12401864
TI  - Two different glomerular diseases in the same patient at an interval of 7 years.

PMID- 12401865
TI  - The successful treatment of renal-vein thrombosis by low-molecular-weight heparin
      in a steroid-sensitive nephrotic patient.

PMID- 12401866
TI  - Renal failure following cardiac transplantation-think of the arteries.

PMID- 12401867
TI  - Treatment of polyomavirus infection with cidofovir in a renal-transplant
      recipient.

PMID- 12401868
TI  - An unusual cause of nephrotic syndrome and hypertension in a young woman.

PMID- 12401869
TI  - Giant cells and pneumonia in a transplant patient. What is the link?

PMID- 12401870
TI  - Steroid therapy in chronic interstitial renal fibrosis: the case of Chinese-herb
      nephropathy.

PMID- 12401871
TI  - Fish oils and glomerulonephritis.

PMID- 12401872
TI  - Comment on Dr Canaud's editorial.

PMID- 12401873
TI  - Aldactone therapy in a peritoneal dialysis patient with decreased left
      ventricular function.

PMID- 12401874
TI  - MDRD equation estimates of glomerular filtration rate in potential living kidney
      donors and renal transplant recipients with impaired graft function.

PMID- 12401876
TI  - Endothelial lipase: a new lipase on the block.
AB  - Endothelial lipase (EL) is a newly described member of the triglyceride lipase
      gene family. It has a considerable molecular homology with lipoprotein lipase
      (LPL) (44%) and hepatic lipase (HL) (41%). Unlike LPL and HL, this enzyme is
      synthesized by endothelial cells and functions at the site where it is
      synthesized. Furthermore, its tissue distribution is different from that of LPL
      and HL. As a lipase, EL has primarily phospholipase A1 activity. Animals that
      overexpress EL showed reduced HDL cholesterol levels. Conversely, animals that
      are deficient in EL showed a marked elevation in HDL cholesterol levels,
      suggesting that it plays a physiologic role in HDL metabolism. Unlike LPL and HL,
      EL is located in the vascular endothelial cells and its expression is highly
      regulated by cytokines and physical forces, suggesting that it may play a role in
      the development of atherosclerosis. However, there is only a limited amount of
      information available about this enzyme. Some of our unpublished data in addition
      to previously published data support the possibility that the enzyme plays a role
      in the formation of atherosclerotic lesion.

PMID- 12401877
TI  - Angiopoietin-like protein 4 is a potent hyperlipidemia-inducing factor in mice
      and inhibitor of lipoprotein lipase.
AB  - Studies with KK/San, obese and diabetic model mice having a unique
      hypotriglyceridemia phenotype, revealed that angiopoietin-like protein 3
      (ANGPTL3) regulates lipid metabolism in mice. To determine the lipid-modulating
      role of other ANGPTLs, we focused on ANGPTL4, which overall shows a significant
      similarity to ANGPTL3. Surprisingly, an intravenous injection of the ANGPTL4
      protein in KK/San mice rapidly increased the circulating plasma lipid levels at a
      higher rate than ANGPTL3 protein. Furthermore, the ANGPTL4 protein inhibited the
      lipoprotein lipase activity in vitro.

PMID- 12401878
TI  - Gene expression regulation by retinoic acid.
AB  - Over the last quarter century, more than 532 genes have been put forward as
      regulatory targets of retinoic acid. In some cases this control is direct, driven
      by a liganded heterodimer of retinoid receptors bound to a DNA response element;
      in others, it is indirect, reflecting the actions of intermediate transcription
      factors, non-classical associations of receptors with other proteins, or even
      more distant mechanisms. Given the broad range of scientific questions
      continually under investigation, researchers do not always have occasion to
      classify target genes along these lines. However, our understanding of the
      genetic role of retinoids will be enhanced if such a distinction can be made for
      each regulated gene. We have therefore evaluated published data from 1,191 papers
      covering 532 genes and have classified these genes into four categories according
      to the degree to which an hypothesis of direct versus indirect control is
      supported overall. We found 27 genes that are unquestionably direct targets of
      the classical pathway in permissive cellular contexts (Category 3 genes), plus
      105 genes that appear to be candidates, pending the results of specific
      additional experiments (Category 2). Data on another 267 targets are not
      evocative of direct or indirect regulation either way, although control by
      retinoic acid through some mechanism is clear (Category 1). Most of the remaining
      133 targets seem to be regulated indirectly, usually through a transcriptional
      intermediary, in the contexts studied so far (Category 0).

PMID- 12401879
TI  - Lipid metabolome-wide effects of the PPARgamma agonist rosiglitazone.
AB  - Successful therapy for chronic diseases must normalize a targeted aspect of
      metabolism without disrupting the regulation of other metabolic pathways
      essential for maintaining health. Use of a limited number of single molecule
      surrogates for disease, or biomarkers, to monitor the efficacy of a therapy may
      fail to predict undesirable side effects. In this study, a comprehensive
      metabolomic assessment of lipid metabolites was employed to determine the
      specific effects of the peroxisome proliferator-activated receptor gamma
      (PPARgamma) agonist rosiglitazone on structural lipid metabolism in a new mouse
      model of Type 2 diabetes. Dietary supplementation with rosiglitazone (200 mg/kg
      diet) suppressed Type 2 diabetes in obese (NZO x NON)F1 male mice, but chronic
      treatment markedly exacerbated hepatic steatosis. The metabolomic data revealed
      that rosiglitazone i) induced hypolipidemia (by dysregulating liver-plasma lipid
      exchange), ii) induced de novo fatty acid synthesis, iii) decreased the
      biosynthesis of lipids within the peroxisome, iv) substantially altered free
      fatty acid and cardiolipin metabolism in heart, and v) elicited an unusual
      accumulation of polyunsaturated fatty acids within adipose tissue. These
      observations suggest that the phenotypes induced by rosiglitazone are mediated by
      multiple tissue-specific metabolic variables. Because many of the effects of
      rosiglitazone on tissue metabolism were reflected in the plasma lipid metabolome,
      metabolomics has excellent potential for developing clinical assessments of
      metabolic response to drug therapy.

PMID- 12401880
TI  - 15-Deoxy-delta12,14-prostaglandin J2-induced apoptosis does not require PPARgamma
      in breast cancer cells.
AB  - Naturally occurring derivatives of arachidonic acid are potent agonists for the
      nuclear hormone receptor peroxisome proliferator-activated receptor gamma
      (PPARgamma) and block cancer cell proliferation through the induction of
      apoptosis. We have previously reported that induction of apoptosis using
      cyclopentenone prostaglandins of the J series, including
      15deoxydelta(12,14)PGJ(2) (15dPGJ(2)), is associated with a high degree of PPAR
      response element (PPRE) activity and requires early de novo gene expression in
      breast cancer cells. In the current study, we used pharmacologic and genetic
      approaches to test the hypothesis that PPARgamma is required for 15dPGJ(2)
      induced apoptosis. The PPARgamma agonists 15dPGJ(2), trogliltazone (TGZ), and
      GW7845, a synthetic and highly selective tyrosine-based PPARgamma agonist, all
      increased transcriptional activity of PPARgamma, and expression of CD36, a
      PPARgamma-dependent gene. Transcriptional activity and CD36 expression was
      reduced by GW9662, a selective and irreversible PPARgamma antagonist, but GW9662
      did not block apoptosis induced by 15dPGJ(2). Moreover, dominant negative
      expression of PPARgamma blocked PPRE transcriptional activity, but did not block
      15dPGJ(2)-induced apoptosis. These studies show that while 15dPGJ(2) activates
      PPRE-mediated transcription, PPARgamma is not required for 15dPGJ(2)-induced
      apoptosis in breast cancer cells. Other likely mechanisms through which
      cyclopentenone prostaglandins induce apoptosis of cancer cells are discussed.

PMID- 12401881
TI  - Class A scavenger receptors mediate cell adhesion via activation of G(i/o) and
      formation of focal adhesion complexes.
AB  - Class A macrophage scavenger receptors (SR-A) are multifunctional receptors with
      roles in modified lipoprotein uptake, innate immunity, and macrophage adhesion.
      Our previous studies conducted in mouse peritoneal macrophages demonstrated that
      pertussis toxin (PTX) mediated inhibition of G(i/o) attenuated SR-A-dependent
      uptake of modified lipoprotein. The finding that SR-A-mediated lipoprotein
      internalization was PTX-sensitive led us to hypothesize that SR-A-mediated cell
      adhesion might be similarly regulated by G(i/o)-dependent signaling pathways. To
      test this hypothesis, SR-A was expressed in HEK cells under inducible control.
      Relative to HEK cells that lack SR-A, SR-A expressing cells displayed enhanced
      adhesion to tissue culture dishes. SR-A-mediated adhesion was significantly
      reduced following PTX treatment and was insensitive to chelating divalent cations
      with EDTA. SR-A-expressing cells exhibited a distinct cell morphology
      characterized by fine filopodia-like projections. Both polymerized actin and
      vinculin were codistributed with SR-A in the filopodia-like projections
      indicating the formation of focal adhesion complexes. Overall, our results
      indicate that the ability of SR-A to enhance cell adhesion involves G(i/o)
      activation and formation of focal adhesion complexes.

PMID- 12401882
TI  - Glucosylceramide modulates membrane traffic along the endocytic pathway.
AB  - Glycosphingolipids are endocytosed and targeted to the Golgi apparatus, but are
      mistargeted to lysosomes in numerous sphingolipidoses. Substrate reduction
      therapy utilizes imino sugars to inhibit glucosylceramide synthase and
      potentially abrogate the effects of storage. Gaucher disease is a hereditary
      deficiency in glucocerebrosidase leading to glucosylceramide accumulation;
      however, Gaucher fibroblasts exhibited normal Golgi transport of
      lactosylceramide. To better understand the effects of glycosphingolipid
      accumulation on intracellular trafficking and the use of imino sugar inhibitors,
      we studied sphingolipid endocytosis in fibroblast and macrophage models for
      Gaucher disease. Treatment of fibroblasts or RAW macrophages with conduritol B
      epoxide, an inhibitor of lysosomal glucocerebrosidase, resulted in a change in
      the endocytic targeting of lactosylceramide from the Golgi to the lysosomes. Co
      treatment of macrophages with conduritol B-epoxide and 12-25 microM N
      butyldeoxygalactonojirimycin, an inhibitor of glycosphingolipid biosynthesis,
      prevented the mistargeting of lactosylceramide to the lysosomes and restored
      trafficking to the Golgi. Surprisingly, higher doses (>25 microM) of NB-DGJ
      induced targeting of lactosylceramide to the lysosomes, even in the absence of
      conduritol B-epoxide. These data demonstrate that both increases and decreases in
      glucosylceramide levels can dramatically alter the endocytic targeting of
      lactosylceramide and suggest a role for glucosylceramide in regulation of
      membrane transport.

PMID- 12401883
TI  - Familial combined hyperlipidemia plasma stimulates protein secretion by HepG2
      cells: identification of fibronectin in the differential secretion proteome.
AB  - The aim of this study was to evaluate whether soluble factors in plasma of
      familial combined hyperlipidemia (FCHL) patients affect hepatic protein
      secretion. Cultured human hepatocytes, i.e., HepG2 cells, were incubated with
      fasting plasma (20%, v/v, in DMEM) from untreated FCHL patients or normolipidemic
      controls. Overall protein secretion was 10-15% higher after incubation with FCHL
      plasma. This was specifically caused by an increase in four secreted proteins,
      with estimated sizes of 240, 180, 120, and <40 kD (P < 0.001, P < 0.006, P <
      0.002, P < 0.02, respectively). The 240 kD protein in the secretion proteome was
      identified as fibronectin by mass spectrometry. Plasma fibronectin concentrations
      were elevated in FCHL patients, confirming biological relevance of these data.
      Overall protein secretion by HepG2 cells correlated with concentrations of
      triglycerides (r = 0.61, P < 0.001) in the applied plasma samples. VLDL+IDL
      isolated from FCHL patients, induced a higher protein secretion than lipoproteins
      isolated from controls (P < 0.001). Remarkably, secretion of apoB, the structural
      protein of VLDL, was stimulated to a similar extent by FCHL and control plasma.
      FCHL plasma did not induce excess secretion of apoB by HepG2 cells compared with
      control plasma. FCHL plasma did stimulate secretion of several distinct hepatic
      proteins, among which fibronectin was identified.

PMID- 12401884
TI  - AZ 242, a novel PPARalpha/gamma agonist with beneficial effects on insulin
      resistance and carbohydrate and lipid metabolism in ob/ob mice and obese Zucker
      rats.
AB  - Abnormalities in fatty acid (FA) metabolism underlie the development of insulin
      resistance and alterations in glucose metabolism, features characteristic of the
      metabolic syndrome and type 2 diabetes that can result in an increased risk of
      cardiovascular disease. We present pharmacodynamic effects of AZ 242, a novel
      peroxisome proliferator activated receptor (PPAR)alpha/gamma agonist. AZ 242 dose
      dependently reduced the hypertriglyceridemia, hyperinsulinemia, and hyperglycemia
      of ob/ob diabetic mice. Euglycemic hyperinsulinemic clamp studies showed that
      treatment with AZ 242 (1 micromol/kg/d) restored insulin sensitivity of obese
      Zucker rats and decreased insulin secretion. In vitro, in reporter gene assays,
      AZ 242 activated human PPARalpha and PPARgamma with EC(50) in the micro molar
      range. It also induced differentiation in 3T3-L1 cells, an established PPARgamma
      effect, and caused up-regulation of liver fatty acid binding protein in HepG-2
      cells, a PPARalpha-mediated effect. PPARalpha-mediated effects of AZ 242 in vivo
      were documented by induction of hepatic cytochrome P 450-4A in mice. The results
      indicate that the dual PPARalpha/gamma agonism of AZ 242 reduces insulin
      resistance and has beneficial effects on FA and glucose metabolism. This effect
      profile could provide a suitable therapeutic approach to the treatment of type 2
      diabetes, metabolic syndrome, and associated vascular risk factors.

PMID- 12401885
TI  - Inhibition of cholesterol absorption by SCH 58053 in the mouse is not mediated
      via changes in the expression of mRNA for ABCA1, ABCG5, or ABCG8 in the
      enterocyte.
AB  - Intestinal cholesterol absorption is a major determinant of plasma low density
      lipoprotein-cholesterol (LDL-C) concentrations. Ezetimibe (SCH 58235) and its
      analogs SCH 48461 and SCH 58053 are novel potent inhibitors of cholesterol
      absorption whose mechanism of action is unknown. These studies investigated the
      effect of SCH 58053 on cholesterol metabolism in female 129/Sv mice. In mice fed
      a low cholesterol rodent diet containing SCH 58053, cholesterol absorption was
      reduced by 46% and fecal neutral sterol excretion was increased 67%, but biliary
      lipid composition and bile acid synthesis, pool size, and pool composition were
      unchanged. When the dietary cholesterol content was increased either 10- or 50
      fold, those animals given SCH 58053 manifested lower hepatic and biliary
      cholesterol concentrations than did their untreated controls. Cholesterol feeding
      increased the relative mRNA level for adenosine triphosphate-binding cassette
      transporter A1 (ABCA1), ABC transporter G5 (ABCG5), and ABC transporter G8
      (ABCG8) in the jejunum, and of ABCG5 and ABCG8 in the liver, but the magnitude of
      this increase was generally less if the mice were given SCH 58053. We conclude
      that the inhibition of cholesterol absorption effected by this new class of
      agents is not mediated via changes in either the size or composition of the
      intestinal bile acid pool, or the level of mRNA expression of proteins that
      facilitate cholesterol efflux from the enterocyte, but rather may involve
      disruption of the uptake of luminal sterol across the microvillus membrane.

PMID- 12401886
TI  - Elevation of plasma phospholipid transfer protein in transgenic mice increases
      VLDL secretion.
AB  - Two lipid transfer proteins are active in human plasma, cholesteryl ester
      transfer protein (CETP), and phospholipid transfer protein (PLTP). Mice by nature
      do not express CETP. Additional inactivation of the PLTP gene resulted in reduced
      secretion of VLDL and subsequently in decreased susceptibility to diet-induced
      atherosclerosis. The aim of this study is to assess possible effects of
      differences in PLTP expression on VLDL secretion in mice that are proficient in
      CETP and PLTP. We compared human CETP transgenic (huCETPtg) mice with mice
      expressing both human lipid transfer proteins (huCETPtg/huPLTPtg). Plasma
      cholesterol in huCETPtg mice was 1.5-fold higher compared with huCETPtg/huPLTPtg
      mice (P < 0.001). This difference was mostly due to a lower HDL level in the
      huCETPtg/huPLTPtg mice, which subsequently could lead to the somewhat decreased
      CETP activity and concentration that was found in huCETPtg/huPLTPtg mice (P <
      0.05). PLTP activity was 2.8-fold increased in these animals (P < 0.001). The
      human PLTP concentration was 5 microg/ml. Moderate overexpression of PLTP
      resulted in a 1.5-fold higher VLDL secretion compared with huCETPtg mice (P <
      0.05). The composition of nascent VLDL was similar in both strains. These results
      indicate that elevated PLTP activity in huCETPtg mice results in an increase in
      VLDL secretion. In addition, PLTP overexpression decreases plasma HDL cholesterol
      as well as CETP.

PMID- 12401887
TI  - Evidence for differential effects of apoE3 and apoE4 on HDL metabolism.
AB  - We present a murine model that examines the effects of macrophage-produced
      apolipoprotein E3 (apoE3) and apoE4 on VLDL and high density lipoprotein (HDL)
      metabolism. Mice expressing apoE3 on the Apoe(-/-) background had substantially
      lower VLDL levels than mice expressing apoE4. In addition, there were differences
      between the HDL of apoE3- and apoE4-expressing mice. Apoe(-/-) mice have low
      levels of HDL. Low level expression of either apoE3 or apoE4 was able to restore
      near-normal HDL levels, which increased dramatically when the mice were
      challenged with a high-fat diet. ApoE4-expressing mice had smaller HDL than apoE3
      expressing mice on both chow and high-fat diets. In addition, plasma from apoE4
      expressing mice was less efficient at transferring apoA-I from VLDL to HDL and at
      generating HDL in vitro than that from apoE3-expressing mice. Thus, we present
      experimental evidence for differential effects of apoE3 and apoE4 on HDL
      metabolism that supports epidemiological observations made in humans, which
      suggested that individual homozygous for the epsilon 4 allele had lower HDL than
      others.

PMID- 12401888
TI  - The fate of HDL particles in vivo after SR-BI-mediated selective lipid uptake.
AB  - Scavenger receptor class B type I (SR-BI) delivers cholesterol ester from HDL to
      cells via a selective uptake mechanism, whereby lipid is transferred from the
      core of the particle without concomitant degradation of the protein moiety. The
      precise metabolic fate of HDL particles after selective lipid uptake is not
      known. To characterize SR-BI-mediated HDL processing in vivo, we expressed high
      levels of this receptor in livers of apoA-I(-/-) mice by adenoviral vector gene
      transfer, and then injected the mice with a bolus of human HDL(2) traced with
      (125)I-dilactitol tyramine. HDL recovered from apoA-I(-/-) mice over-expressing
      SR-BI was significantly smaller than HDL recovered from control mice as measured
      by non-denaturing gel electrophoresis. When injected into C57BL/6 mice, these HDL
      "remnants" were rapidly converted to HDL(2)-sized lipoprotein particles, and were
      cleared from the plasma at a rate similar to HDL(2). In assays in cultured cells,
      HDL remnants did not stimulate ATP-binding cassette transporter A1-dependent
      cholesterol efflux. When mixed with mouse plasma ex vivo, HDL remnants rapidly
      converted to larger HDL particles. These studies identify a previously ill
      defined pathway in HDL metabolism, whereby SR-BI generates small, dense HDL
      particles that are rapidly remodeled in plasma. This remodeling pathway may
      represent a process that is important in determining the rate of apoA-I
      catabolism and HDL-mediated reverse cholesterol transport.

PMID- 12401889
TI  - Relationship between stearoyl-CoA desaturase activity and plasma triglycerides in
      human and mouse hypertriglyceridemia.
AB  - Stearoyl-CoA desaturase (SCD) is expressed at high levels in several human
      tissues and is required for the biosynthesis of oleate (18:1) and palmitoleate
      (16:1). These monounsaturated fatty acids are the major components of
      phospholipids, triglycerides, wax esters, and cholesterol esters. Mice with a
      targeted disruption of the SCD1 gene have very low levels of VLDL and impaired
      triglyceride and cholesterol ester biosynthesis. In the HYPLIP mouse, a model of
      hyperlipidemia, there was a 4-fold increase in hepatic SCD activity, a 1.8-fold
      increase in the desaturation index, and a 2-fold increase in plasma
      triglycerides. We used the plasma ratio of 18:1/18:0 (the "desaturation index")
      as an in vivo measure of SCD activity in human subjects. In human subjects with
      triglycerides ranging from 0.3 to 20 mM, the desaturation ratio accounted for one
      third of the variance in plasma triglyceride levels. A 2-fold increase in the
      desaturation index was associated with a 4-fold increase in plasma triglycerides.
      In human subjects exposed to a high carbohydrate diet, the desaturation index
      explained 44% of the variance in triglycerides. We propose that many of the
      factors that influence plasma triglyceride levels do so by converging upon the
      regulation of SCD activity.

PMID- 12401890
TI  - Niemann-Pick type C disease: mutations of NPC1 gene and evidence of abnormal
      expression of some mutant alleles in fibroblasts.
AB  - We analyzed Niemann-Pick type C disease 1 (NPC1) gene in 12 patients with Niemann
      Pick type C disease by sequencing both cDNA obtained from fibroblasts and genomic
      DNA. All the patients were compound heterozygotes. We found 15 mutations, eight
      of which previously unreported. The comparison of cDNA and genomic DNA revealed
      discrepancies in some subjects. In two unrelated patients carrying the same
      mutations (P474L and nt 2972del2) only one mutant allele (P474L), was expressed
      in fibroblasts. The mRNA corresponding to the other allele was not detected even
      in cells incubated with cycloheximide. The promoter variants (-1026T/G and 
      1186T/C or -238 C/G), found to be in linkage with 2972del2 allele do not explain
      the lack of expression of this allele, as they were also found in control
      subjects. In another patient, (N1156S/Q922X) the N1156S allele was expressed in
      fibroblasts while the expression of the other allele was hardly detectable. In a
      fourth patient cDNA analysis revealed a point mutation in exon 20 (P1007A) and a
      56 nt deletion in exon 22 leading to a frameshift and a premature stop codon. The
      first mutation was confirmed in genomic DNA; the second turned out to be a T-->G
      transversion in exon 22, predicted to cause a missense mutation (V1141G). In
      fact, this transversion generates a donor splice site in exon 22, which causes an
      abnormal pre-mRNA splicing leading to a partial deletion of this exon. In some
      NPC patients, therefore, the comparison between cDNA and genomic DNA may reveal
      an unexpected expression of some mutant alleles of NPC1 gene.

PMID- 12401891
TI  - Altered adrenal gland cholesterol metabolism in the apoE-deficient mouse.
AB  - Previous studies suggest the hypothesis that apoE produced by adrenocortical
      cells modulates cellular cholesterol metabolism to enhance the storage of
      esterified cholesterol (EC) at the expense of cholesterol delivery to the
      steroidogenic pathway. In the present study, parameters of adrenal cholesterol
      metabolism and corticosteroid production were examined in wild type and apoE
      deficient (apoe(-/-)) mice. Adrenal gland EC content and the EC/free cholesterol
      (FC) ratio in mice stressed by adrenocorticotropin (ACTH) treatment or saline
      injection were reduced in apoe(-/-) compared to apoe(+/+) mice. Relative to
      apoe(+/+) mice, apoE deficiency also resulted in increased levels of plasma
      corticosterone in the basal state, in response to acute or long-term ACTH
      treatment, and after a swim-induced neuroendocrine-directed stress test.
      Measurements of adrenal gland scavenger receptor class B, type I (SR-BI), LDL
      receptor, and LDL receptor related protein (LRP) levels and the activities of
      ACAT or HMG-CoA reductase showed no difference between genotypes. Apoe(-/-) and
      apoe(+/+) mice showed similar quantitative increases in LDL receptors, SR-BI,
      adrenal weight gain, and ACAT activities in response to ACTH, and both genotypes
      had similar basal plasma ACTH concentrations. These results suggest that the
      effects of apoE deficiency reflect events at the level of the adrenal gland and
      are specific to changes in cholesterol accumulation and corticosterone
      production. Further, these findings support the hypothesis that apoE acts to
      enhance adrenocortical EC accumulation and diminish corticosterone production.

PMID- 12401892
TI  - Alpha-tocopherol protects against diet induced atherosclerosis in New Zealand
      white rabbits.
AB  - In this study, we asked the question "does alpha-tocopherol supplementation
      prevent an increase in total plasma cholesterol (TPC) concentration and reduce
      the deposition of cholesterol in arterial plaques of rabbits fed atherogenic
      diets?" Isocaloric diets containing 0.1% cholesterol to induce atherosclerosis
      were enriched in one of three fats: saturated fats (SAT), monounsaturated fats
      (MONO), or n-6 polyunsaturated fats (POLY). Half of each of the three diets were
      supplemented with 2,500 IU alpha-tocopherol/kg-diet. Unsupplemented diets
      contained 25 IU alpha-tocopherol/kg-diet. Rabbits supplemented with alpha
      tocopherol had plasma alpha-tocopherol concentrations 10-fold higher and an
      average TPC concentration 31% lower, P = 0.017, than rabbits fed unsupplemented
      diets. Among the three fat-fed groups, the difference was greatest for the POLY
      fat fed group (54%, P = 0.041). POLY fat-fed rabbits without alpha-tocopherol
      supplementation had plasma HDL cholesterol concentrations that were less than
      half that of rabbits fed other fats, P < or = 0.0001. In general, differences in
      mean esterified artery cholesterol concentrations among the three fat-fed groups,
      with and without alpha-tocopherol supplementation, paralleled differences in TPC
      concentration among the groups. This study suggests that for rabbits fed high
      pharmacological doses of alpha-tocopherol, atherosclerosis can be diminished in
      situations where the plasma cholesterol concentrations are also significantly
      lower.

PMID- 12401893
TI  - Truncation mutations in ABCA1 suppress normal upregulation of full-length ABCA1
      by 9-cis-retinoic acid and 22-R-hydroxycholesterol.
AB  - Mutations in ABCA1 uniformly decrease plasma HDL-cholesterol (HDL-C) and reduce
      cholesterol efflux, yet different mutations in ABCA1 result in different
      phenotypic effects in heterozygotes. For example, truncation mutations result in
      significantly lower HDL-C and apoliprotein A-I (apoA-I) levels in heterozygotes
      compared with nontruncation mutations, suggesting that truncation mutations may
      negatively affect the wild-type allele. To specifically test this hypothesis, we
      examined ABCA1 protein expression in response to 9-cis-retinoic acid (9-cis-RA)
      and 22-R-hydroxycholesterol (22-R-OH-Chol) in a collection of human fibroblasts
      representing eight different mutations and observed that truncation mutations
      blunted the response to oxysterol stimulation and dominantly suppressed induction
      of the remaining full-length allele to 5-10% of wild-type levels. mRNA levels
      between truncation and nontruncation mutations were comparable, suggesting that
      ABCA1 expression was suppressed at the protein level. Dominant negative activity
      of truncated ABCA1 was recapitulated in an in vitro model using transfected Cos-7
      cells. Our results suggest that the severe reduction of HDL-C in patients with
      truncation mutations may be at least partly explained by dominant negative
      suppression of expression and activity of the remaining full-length ABCA1 allele.
      These data suggest that ABCA1 requires a physical association with itself or
      other molecules for normal function and has important pharmacogenetic
      implications for individuals with truncation mutations.

PMID- 12401894
TI  - Aging per se is an independent risk factor for cholesterol gallstone formation in
      gallstone susceptible mice.
AB  - Cholesterol gallstones occur rarely in childhood and adolescence and increase
      linearly with age in both genders. To explore whether aging per se increases
      cholesterol saturation of bile and gallstone prevalence, and to investigate age
      related changes in hepatic and biliary lipid metabolism, we studied gallstone
      susceptible C57L mice and resistant AKR mice of both genders fed 8 weeks with a
      lithogenic diet containing 1% cholesterol, 0.5% cholic acid, and 15% butter fat
      starting at (young adult) 8, (older adult) 36, and (aged) 50-weeks-of-age. After
      the 8-week feeding, gallstone prevalence, gallbladder size, biliary lipid
      secretion rate, and HMG-CoA reductase activity were significantly greater but
      cholesterol 7alpha-hydroxylase activity was lower in C57L mice of both genders
      compared with AKR mice. Increasing age augmented biliary secretion and intestinal
      absorption of cholesterol, reduced hepatic synthesis and biliary secretion of
      bile salts, and decreased gallbladder contractility, all of which increased
      susceptibility to cholesterol cholelithiasis in C57L mice. We conclude that aging
      per se is an independent risk factor for cholesterol gallstone formation. Because
      aging increases significantly biliary cholesterol hypersecretion and gallstone
      prevalence in C57L mice carrying Lith genes, it is highly like that Longevity
      (aging) genes can enhance lithogenesis of Lith (gallstone) genes.

PMID- 12401895
TI  - Effect of beta-muricholic acid on the prevention and dissolution of cholesterol
      gallstones in C57L/J mice.
AB  - This study investigated whether beta-muricholic acid, a natural trihydroxy
      hydrophilic bile acid of rodents, acts as a biliary cholesterol-desaturating
      agent to prevent cholesterol gallstones and if it facilitates the dissolution of
      gallstones compared with ursodeoxycholic acid (UDCA). For gallstone prevention
      study, gallstone-susceptible male C57L mice were fed 8 weeks with a lithogenic
      diet (2% cholesterol and 0.5% cholic acid) with or without 0.5% UDCA or beta
      muricholic acid. For gallstone dissolution study, additional groups of mice that
      have formed gallstones were fed chow with or without 0.5% beta-muricholic acid or
      UDCA for 8 weeks. One hundred percent of mice fed the lithogenic diet formed
      cholesterol gallstones. Addition of beta-muricholic acid and UDCA decreased
      gallstone prevalence to 20% and 50% through significantly reducing biliary
      secretion rate, saturation index, and intestinal absorption of cholesterol, as
      well as inducing phase boundary shift and an enlarged Region E that prevented the
      transition of cholesterol from its liquid crystalline phase to solid crystals and
      stones. Eight weeks of beta-muricholic acid and UDCA administration produced
      complete gallstone dissolution rates of 100% and 60% compared with the chow
      (10%). We conclude that beta-muricholic acid is more effective than UDCA in
      treating or preventing diet-induced or experimental cholesterol gallstones in
      mice.

PMID- 12401896
TI  - ApoC-III content of apoB-containing lipoproteins is associated with binding to
      the vascular proteoglycan biglycan.
AB  - Retention of apolipoprotein (apo)B and apoE-containing lipoproteins by
      extracellular vascular proteoglycans is critical in atherogenesis. Moreover, high
      circulating apoC-III levels are associated with increased atherosclerosis risk.
      To test whether apoC-III content of apoB-containing lipoproteins affects their
      ability to bind to the vascular proteoglycan biglycan, we evaluated the impact of
      apoC-III on the interaction of [(35)S]SO(4)-biglycan derived from cultured
      arterial smooth muscle cells with lipoproteins obtained from individuals across a
      spectrum of lipid concentrations. The extent of biglycan binding correlated
      positively with apoC-III levels within VLDL (r = 0.78, P < 0.01), IDL (r = 0.67,
      P < 0.01), and LDL (r = 0.52, P < 0.05). Moreover, the biglycan binding of VLDL,
      IDL, and LDL was reduced after depletion of apoC-III-containing lipoprotein
      particles in plasma by anti-apoC-III immunoaffinity chromatography. Since apoC
      III does not bind biglycan directly, enhanced biglycan binding may result from a
      conformational change associated with increased apo C-III content by which apoB
      and/or apoE become more accessible to proteoglycans. This may be an intrinsic
      property of lipoproteins, since exogenous apoC-III enrichment of LDL and VLDL did
      not increase binding. ApoC-III content may thus be a marker for lipoproteins
      characterized as having an increased ability to bind proteoglycans.

PMID- 12401897
TI  - Analysis of plasma tocopherols alpha, gamma, and 5-nitro-gamma in rats with
      inflammation by HPLC coulometric detection.
AB  - Reactive nitrogen oxide species (RNOS) have been implicated as effector molecules
      in inflammatory diseases. There is emerging evidence that gamma-tocopherol
      (gammaT), the major form of vitamin E in the North American diet, may play an
      important role in these diseases. GammaT scavenges RNOS such as peroxynitrite by
      forming a stable adduct, 5-nitro-gammaT (NGT). Here we describe a convenient HPLC
      method for the simultaneous determination of NGT, alphaT, and gammaT in blood
      plasma and other tissues. Coulometric detection of NGT separated on a deactivated
      reversed-phase column was linear over a wide range of concentrations and highly
      sensitive (approximately 10 fmol detection limit). NGT extracted from blood
      plasma of 15-week-old Fischer 344 rats was in the low nM range, representing
      approximately 4% of gammaT. Twenty-four h after intraperitoneal injection of
      zymosan, plasma NGT levels were 2-fold higher compared to fasted control animals
      when adjusted to gammaT or corrected for total neutral lipids, while alpha- and
      gammaT levels remained unchanged. These results demonstrate that nitration of
      gammaT is increased under inflammatory conditions and highlight the importance of
      RNOS reactions in the lipid phase. The present HPLC method should be helpful in
      clarifying the precise physiological role of gammaT.

PMID- 12401898
TI  - The differential apoA-I enrichment of prebeta1 and alphaHDL is detectable by gel
      filtration separation.
AB  - The aim of the study was to assess the isolation of HDL by fast protein liquid
      chromatography (FPLC) to perform kinetics studies of apolipoprotein (apo)A-I-HDL
      labelled with a stable isotope. Comparison between FPLC and ultracentrifugation
      has been made. ApoA-I-HDL kinetics were studied by infusion of [5.5.5
      (2)H(3)]leucine for 14 h in five subjects. Using FPLC, prebeta(1) HDL and
      alphaHDL (HDL(2) and HDL(3)) were separated from 200 microl of plasma samples.
      Total HDL was isolated by sequential ultracentrifugation (HDL-UC). The tracer-to
      tracee ratio was higher in prebeta(1) HDL than in total HDL-UC. The higher
      leucine enrichment found in total HDL-UC compared to alphaHDL suggested the
      existence of a mixture of apoA-I-HDL sub-classes. From this difference in
      enrichments, the turnover rate of total HDL-UC, usually assumed to be alphaHDL,
      was probably overestimated in previous studies. To our knowledge, this study is
      the first report which provides a convenient tool to distinguish enrichments of
      apoA-I in prebeta(1) HDL and alphaHDL from total HDL previously used for kinetic
      measurements. This original and new method should help to understand the kinetics
      of HDL in humans and the reverse cholesterol transport dynamics.

PMID- 12401900
TI  - Gleevec for the treatment of chronic myelogenous leukemia: US. Food and Drug
      Administration regulatory mechanisms, accelerated approval, and orphan drug
      status.
AB  - Gleevec (imatinib mesylate), a highly promising new drug for the treatment of
      chronic myelogenous leukemia in blast crisis, in accelerated phase, and in
      chronic phase after interferon failure or intolerance, received orphan drug
      status from the U.S. Food and Drug Administration (FDA) Office of Orphan Products
      Development on January 31, 2001, and accelerated approval from the FDA for the
      above three indications on May 10, 2001. The purpose of this report is to
      summarize FDA regulatory mechanisms, i.e., accelerated approval and orphan drug
      regulations, that have permitted patients to receive this drug as rapidly as
      possible.

PMID- 12401901
TI  - U.S. Food and Drug Administration drug approval summaries: imatinib mesylate,
      mesna tablets, and zoledronic acid.
AB  - The purpose of this report is to summarize information on drugs recently approved
      by the U.S. Food and Drug Administration. Three drugs have recently been
      approved: Gleevec (imatinib mesylate) at a starting dose of 400 or 600 mg daily
      for the treatment of malignant unresectable and/or metastatic gastrointestinal
      stromal tumors; Mesnex (mesna) tablets as a prophylactic agent to reduce the
      incidence of ifosfamide-induced hemorrhagic cystitis, and Zometa (zoledronic
      acid) for the treatment of patients with multiple myeloma and for patients with
      documented bone metastases from solid tumors, in conjunction with standard
      antineoplastic therapy. Prostate cancer should have progressed after treatment
      with at least one hormonal therapy. The recommended dose and schedule is 4 mg
      infused over 15 minutes every 3-4 weeks. These three drugs represent three
      different types of drug approval: Gleevec is an accelerated approval and
      supplemental new drug application (NDA); Mesnex tablets represent an oral
      formulation of a drug approved 14 years ago as an intravenous formulation, and
      Zometa represents a standard NDA for a noncytotoxic, supportive-care drug.
      Information provided includes rationale for drug development, study design,
      efficacy and safety results, and pertinent literature references.

PMID- 12401902
TI  - Clinical trial design for target-based therapy.
AB  - Anticancer drug discovery has shifted from an empiric random screening directed
      approach to a more rational and mechanistic, target-based approach, which
      reflects our rapidly expanding knowledge of the pathogenesis of a variety of
      forms of cancer at the molecular level, providing new targets for drug discovery
      and development. The clinical development of target-based anticancer drugs will
      require fundamental changes to the traditional clinical trial design and end
      points that have been used for conventional cytotoxic drugs. In the phase I and
      II settings, traditional end points (toxicity and response) may not be suitable
      for more selective, cytostatic target-based agents, and these end points may be
      replaced by biological or pharmacokinetic end points to define the optimal doses
      and the therapeutic effects of these drugs on their targets. For phase III
      trials, measurable clinical benefit will continue to be the primary end point. As
      our understanding of the complex pathways and networks controlling cell
      signaling, proliferation, and cell death expands, we must learn how and when to
      use agents to target specific steps in malignant transformation and
      proliferation, and we must adapt clinical trial design to test the clinical
      utility of this promising new class of anticancer drugs.

PMID- 12401903
TI  - Phase II trial of weekly vinorelbine and trastuzumab as first-line therapy in
      patients with HER2(+) metastatic breast cancer.
AB  - PURPOSE: Human epidermal growth factor receptor 2 (HER2) overexpression is
      associated with a more aggressive form of breast cancer that responds well to
      trastuzumab therapy. Trastuzumab-based combination regimens have shown greater
      antitumor activity than chemotherapy alone. These findings, coupled with the
      favorable antitumor activity and tolerability profile of vinorelbine in breast
      cancer, provided the rationale for investigating the novel combination of
      vinorelbine and trastuzumab. PATIENTS AND METHODS: A phase II, open-label trial
      of intravenous vinorelbine (30 mg/m(2) on day 1, then weekly) and trastuzumab (4
      mg/kg on day 0, then 2 mg/kg weekly) was conducted in previously untreated
      HER2(+) metastatic breast cancer patients. Vinorelbine dose was adjusted for
      grade 3/4 neutropenia; patients remained on combination therapy until disease
      progression or patient withdrawal due to adverse events. RESULTS: Of 40 enrolled
      patients (median age 51 years, range 30-82), 37 were evaluable for response.
      Overall response rate was 78% (29/37, 95% confidence interval [CI] 62%-90%),
      including four (11%, 95% CI 3%-25%) complete and 25 (68%) partial responses.
      Objective tumor response correlated with degree of HER2 positivity:
      immunohistochemistry (IHC) 3(+) = 82% (18/22) response and IHC 2(+) = 58% (7/12)
      response. Median time to progression was 72 weeks (95% CI 37-138 weeks); median
      survival has not been reached. Grade 3/4 neutropenia was the most frequent
      serious toxicity and cause of dose reductions (9% of courses) and omissions (10%
      of courses). No patient experienced serious cardiac toxicity. CONCLUSIONS: Weekly
      vinorelbine/trastuzumab offers a high therapeutic index as initial therapy in
      patients with HER2(+) metastatic breast cancer. Further investigation of this
      novel regimen is planned.

PMID- 12401904
TI  - Efficacy of a primary chemotherapy regimen combining vinorelbine, epirubicin, and
      methotrexate (VEM) as neoadjuvant treatment in 89 patients with operable breast
      cancer.
AB  - PURPOSE: In order to improve the breast conservation rate for noninflammatory
      operable breast cancer stage II and IIIa, neoadjuvant chemotherapy containing
      vinorelbine, 25 mg/m(2), epirubicin, 35 mg/m(2), and methotrexate, 20 mg/m(2),
      VEM, was administered days 1 and 8 every 28 days for six cycles. METHODS: From
      October, 1991 to April, 1996, 89 patients (median age 52 years, range 31-72; 68
      stage II and 19 stage IIIa) received 519 cycles (median six) of VEM chemotherapy.
      RESULTS: Hematotoxicity was mild (World Health Organization grade 3-4 neutropenia
      in 28% of cycles for 22 patients, and anemia or thrombocytopenia >grade 2) when
      it occurred, and there were no toxic deaths. The clinical objective response was
      90% (28% complete response and 62% partial response). All patients underwent
      surgery: 77 (87%) had conservative and 12 (13%) had modified radical mastectomy,
      and 12 (14%) reached pathological complete response. At December, 2000, with a
      median follow-up of 86 months (39-100), 13 patients had relapsed, and five had
      died of metastatic disease. Median disease-free survival was 100 months (8.4
      years) and median survival had not yet been reached.

PMID- 12401905
TI  - 5-HT(3)-receptor antagonists for the treatment of nausea and vomiting: a
      reappraisal of their side-effect profile.
AB  - Nausea and vomiting can cause considerable distress and discomfort to patients
      undergoing chemotherapy, radiotherapy, or surgery. Several classes of antiemetic
      agents exist to combat these side effects, though the 5-HT(3)-receptor
      antagonists have become the first-line treatment choice for many cancer patients
      and are considered the "gold standard" in antiemetic therapy. Compared with the
      older generation antiemetic drugs, 5-HT(3)-receptor antagonists are effective,
      well tolerated, and associated with few side effects. However, emerging
      differences among these agents suggest that the incidence and/or intensity of
      adverse events should not be regarded as a class effect. The side-effect profile
      of any supportive care therapy is particularly important in certain subgroups of
      patients, including pediatric patients and the elderly, as well as those
      suffering comorbid conditions, such as cardiovascular disease and renal or
      hepatic impairment. Indeed, dolasetron is associated with cardiovascular effects,
      and thus, should be used with extreme caution in patients who suffer from or may
      develop prolongation of cardiac conduction intervals. Ondansetron, on the other
      hand, is associated with a greater incidence of central nervous system side
      effects than either dolasetron or ondansetron, and pharmacokinetic parameters are
      affected in patients with hepatic impairment, thereby requiring dose adjustments.
      Clinicians are encouraged to evaluate patients on an individual basis when
      choosing which 5-HT(3)-receptor antagonist to prescribe.

PMID- 12401906
TI  - CA125 response: can it replace the traditional response criteria in ovarian
      cancer?
AB  - CA125 is well established as an accurate and reliable means of monitoring
      response to treatment and confirming relapse in ovarian cancer patients. Its role
      in follow-up after initial treatment is less certain and the subject of a current
      clinical trial. Measuring response with computerized tomography scans is futile
      in the majority of patients, as disease is often nonmeasurable at presentation,
      e.g., ascites or peritoneal deposits, or all measurable disease has been removed
      at the time of surgery. Serial changes in CA125 can be used as a reliable
      indicator of disease response or progression so that patients can be classified
      as responding or progressing according to either standard or CA125 criteria.
      These precise definitions are currently being prospectively validated in
      conjunction with the new response evaluation criteria in solid tumor response
      guidelines and are being incorporated into all future clinical trials.

PMID- 12401907
TI  - A phase I trial of weekly paclitaxel plus prolonged oral eniluracil/5
      fluorouracil in patients with refractory malignancies.
AB  - PURPOSE: This phase I study was conducted to determine the dose-limiting toxicity
      (DLT), maximum-tolerated doses, and recommended phase II doses of the combination
      of weekly intravenous paclitaxel and oral eniluracil/5-fluorouracil (5-FU).
      PATIENTS AND METHODS: Patients received paclitaxel i.v. over 1 hour weekly for
      four consecutive weeks of each cycle. Oral eniluracil/5-FU was administered
      orally twice daily for 28 consecutive days starting on day 1 of each cycle.
      Cycles were repeated every 35 days. Patients were accrued at six different dosing
      combinations. Weekly paclitaxel doses ranged from 60 mg/m(2) to 80 mg/m(2), and
      oral eniluracil/5-FU doses ranged from 8.0/0.8 mg/m(2) to 11.5/1.15 mg/m(2) twice
      daily. RESULTS: Thirty-seven patients received 126 cycles of therapy.
      Myelosuppression was minimal at all dose levels, with no grade 4 neutropenia or
      thrombocytopenia reported. DLT was reported in three out of six patients enrolled
      at the highest dose level and consisted of grade 3 diarrhea (two patients) and
      grade 3 mucositis (one patient). No DLTs were reported in patients enrolled at
      lower dose levels. One complete response and three partial responses were
      reported in patients with taxane-resistant metastatic breast cancer. CONCLUSION:
      The combination of paclitaxel and eniluracil/5-FU was generally well tolerated.
      The recommended doses for further phase II testing are paclitaxel 80 mg/m(2) i.v.
      weekly for 4 weeks plus eniluracil/ 5-FU 10.0/1.0 mg/m(2) orally twice daily on
      days 1-28 with cycles repeated every 35 days.

PMID- 12401908
TI  - Aberrant DNA methylation in lung cancer: biological and clinical implications.
AB  - Genetic abnormalities of proto-oncogenes and tumor suppressor genes are well
      known changes that are frequently involved in lung cancer pathogenesis. However,
      another mechanism for inactivation of tumor suppressor genes is coming more and
      more into focus. Epigenetic inactivation of certain tumor suppressor genes by
      aberrant promoter methylation is frequently observed in lung carcinomas and seems
      to play an important role in the pathogenesis of this tumor type. While genetic
      abnormalities are associated with changes in DNA sequence, epigenetic events may
      lead to changes in gene expression that occur without changes in DNA sequence.
      Recent findings demonstrate that aberrant methylation can also be detected in the
      smoking-damaged bronchial epithelium from cancer-free heavy smokers, suggesting
      that aberrant methylation might be an ideal candidate biomarker for lung cancer
      risk assessment and monitoring of chemoprevention trials. Moreover, in vitro
      studies demonstrate that methylation can be reversed by demethylating agents
      resulting in gene re-expression. This concept is currently under investigation in
      clinical trials. In summary, recent studies demonstrate that aberrant methylation
      may be the most common mechanism of inactivating cancer-related genes in lung
      cancer, occurs already in smoking-damaged bronchial epithelium from cancer-free
      individuals, can be reversed in vitro by demethylating agents, and may be a
      useful biomarker for lung cancer risk assessment.

PMID- 12401910
TI  - The molecular perspective: cadherin.

PMID- 12401909
TI  - Combining radiotherapy with gene therapy (from the bench to the bedside): a novel
      treatment strategy for prostate cancer.
AB  - Combined radiotherapy and gene therapy is a novel therapeutic approach for
      prostate cancer. There are various potential benefits in combining ionizing
      radiation with gene therapy to achieve enhanced antitumor effects: A) ionizing
      radiation improves transfection/ transduction efficiency, transgene integration,
      and possibly, the "bystander effect" of gene therapy; B) gene therapy, on the
      other hand, may interfere with repair of radiation-induced DNA damage and
      increase DNA susceptibility to radiation damage in cancer cells, and C)
      radiotherapy and gene therapy target at different parts of the cell cycle.
      Preclinical data have demonstrated the enhanced antitumor effects of this
      combined approach in local tumor control, prolongation of survival, as well as
      systemic control. This combined radio-gene therapy is under study in an ongoing
      clinical trial in prostate cancer. Our study adds gene therapy to the standard of
      care therapy (radiotherapy). These treatment modalities have different toxicity
      profiles. The goal of this combined approach is to enhance cancer cure without an
      increase in treatment-related toxicity. This approach also offers a new paradigm
      in spatial cooperation, whereby two local therapies are combined to elicit both
      local and systemic effects. Early clinical results showed the safety of this
      approach.

PMID- 12401914
TI  - Comparative study of iliac bone graft and carbon cage with local bone graft in
      posterior lumbar interbody fusion.
AB  - We performed a comparative study of iliac bone graft (the iliac bone group) and
      carbon cage with local bone graft (the cage group) in PLIF to evaluate the
      clinical results of both methods. We examined both groups about the operating
      time, the estimated blood loss, the operative results using the score rating
      system of Japanese Orthopaedic Association (JOA score), and the presence of bone
      union on radiography. The operating time and the estimated blood loss of the cage
      group were statistically less than those of the iliac bone group. There were no
      significant differences between both groups about the operative results. The
      radiographic evaluation on bone union showed that half of the iliac bone group
      had collapsed union, but all cases of the cage group revealed union without
      collapse.

PMID- 12401915
TI  - Fractures of the distal end of radius in elderly patients: a comparative study of
      anatomical and functional results.
AB  - The functional and anatomical results of distal end of radius fractures with
      severe displacement in 22 elderly patients are reviewed in this retrospective
      study. The mean age of the patients was 69.4 years (range, 60-88 years) and the
      mean follow-up period was 24 months (range, 12-53 months). According to the sum
      of demerit points (Saito, 1983), the latest follow-up functional end results were
      excellent  in 64% of fractures and  good  in 36%. As for the anatomical results
      at follow-up, the average radial tilt was 20.7 degrees, ulnar variance was 4.0
      mm, and palmar tilt was -2.7 degrees respectively. Though most of the patients
      had satisfactory outcome and the functional results did not correlate with the
      radiographic evidence of minor deformities, the functional results of the
      patients with radial shortening of 6 mm or over were poor. Furthermore, the grip
      power was the most significant factor related to subjective evaluation and did
      not improve significantly in patients with the non-dominant hand injured.

PMID- 12401916
TI  - Retrograde femoral interlocking nail in complex fractures.
AB  - Retrograde interlocking nail was used as the method of fixation in 35 different
      cases of combination of complex femoral fractures. We performed this procedure in
      fractures of femoral shaft associated with fracture neck femur, pathological
      fractures of proximal third of femur with trochanteric pathology, ipsilateral
      fracture of femur and tibia in polytrauma cases with multiple other injuries, in
      highly obese patients with fracture shaft femur. This technique was also used in
      cases of pregnancy with fracture shaft femur and in unstable pelvic fracture or
      dislocation hip associated with fracture shaft femur. Operative technique
      involved with retrograde insertion of un-reamed, non-cannulated custom made nail
      through entrance portal in intercondylar notch was applied for fixation of the
      shaft femur fracture. The other associated fracture around hip was stabilized
      separately using suitable implant according to type of fracture. In cases of
      ipsilateral fracture of femur and tibia, femur was stabilized by retrograde
      interlocking nail and tibia was stabilized by antigrade interlocking nail through
      same incision at the same sitting. The case was followed up for three years; the
      average union time was 12 to 18 weeks. Out of 35 cases, 31 cases regained full
      knee movement. Out of the remaining 4 cases, 2 cases could regain up to 90
      degrees of movement, these were old fractures and non-cooperative patients. In
      one case, patellofemoral arthritis was developed because of an operative error
      where a nail was not put inside the articular surface. Mal-union was observed in
      an early case of the series and implant failure was nil. Retrograde interlocking
      nail was used as the method of fixation in complex fracture problems. Multiple
      fractures of long bones can be stabilized in one stage, preventing multiple
      operations at different stages in polytraumatized patients. This resulted in
      early recovery, lesser hospital stay, and early rehabilitation of patient with
      good results and is economical also.

PMID- 12401917
TI  - Clinical evaluation of aged patients who underwent surgery for femoral neck
      fractures -- comparative study of clinical results according to age.
AB  - The objective was to assess mortality and ambulatory ability for elderly patients
      over 90 years of age with femoral neck fractures treated surgically. From January
      1998 to March 1999, 60 patients aged over 80 years were chosen for the study. The
      patients had a mean age of 87.1 years. The mean follow-up period was 12.9 months.
      The patients were classified into three groups according to age: group A (80-84
      years old), group B (85-89 years old) and group C (over 90 years old). The rates
      of recovered postoperative walking ability were 72.2% (13/18) of group A, 65.2%
      (15/23) of group B and 84.2% (16/19) of group C. These patients were followed up
      until death or for at least one year. The overall mortality rates were 11.1%
      (2/18) of group A, 17.4% (4/23) of group B and 10.5% (2/19) of group C.

PMID- 12401918
TI  - Total hip arthroplasty for arthrodesed hips.
AB  - The benefits of converting an ankylosed or arthrodesed hip to total hip
      arthroplasty have been reported in the literature as have the technical
      difficulties associated with this procedure. This review, however, outlines the
      experience of a single surgeon (WJMB) at a single institution using uncemented
      prostheses. Between November 1991 and June 1996, 5 arthrodesed hips underwent
      uncemented total hip arthroplasty in 4 males and 1 female. Clinical and
      radiological follow-up review was for at least three years in all patients. In
      general, patients were satisfied with the outcome of their surgery with Harris
      Hip scores improving from an average of 62 preoperatively to an average of 72
      postoperatively. The surgical outcome in these difficult cases was not as
      satisfactory as for routine total hip arthroplasty. Meticulous preoperative
      planning is required to aim toward leg length restoration and restoration of the
      abductor moment arm. A modular prosthesis allows versatility at surgery.

PMID- 12401919
TI  - A modified direct lateral approach in total hip arthroplasty.
AB  - A modified lateral approach of Hardinge allows adequate access for orientation of
      the implant was described. Although this approach is more difficult than the
      posterior approach, there is a learning curve, when mastered, it ll definitely
      reduce the incidence of dislocation. In the Author s opinion, this approach
      should be used routinely for total hip arthroplasty for fractured neck of femur
      where the incidence of dislocation is unacceptably high using the posterior
      approach.

PMID- 12401920
TI  - Correlation between the acetabular diameter and thickness in Thais.
AB  - We conducted a study on dried cadaveric pelvic bones to determine the relation
      between acetabular diameter and thickness of the acetabular wall. The acetabulum
      was divided into four quadrants: antero-superior, postero-superior, postero
      inferior, and antero-inferior. The diameters of the acetabulum were measured for
      152 pelvic bones. The thickness of the center of the acetabulum was measured with
      the use of a caliper at four quadrants of the acetabulum. The average acetabular
      diameter was found to be 51.8224 mm for all the acetabuli. The average thickness
      in the posterior quadrant has been calculated to be about 50% of the acetabular
      diameter, which is about 26 mm. The acetabular diameter and the thickness of the
      acetabulum correlated very well though there was very little significance
      statistically (0.099) due to the lack of full data for all the individual bones.
      Linear correlation between the thickness and the diameter is definitely collinear
      but the correlation is not statistically significant. Some additional factors
      such as bone density, body mass, etc, are required to correlate the thickness and
      the diameter. Further study is required in this field.

PMID- 12401921
TI  - Profile of congenital transverse deficiencies among cases of congenital
      orthopaedic anomalies.
AB  - The authors showed the data of congenital amputation in 36 cases among the
      physically handicapped individuals (who attended a district level hospital for
      the purpose of obtaining a handicap certificate) during the period from 1 January
      1999 to 31 December 2000. Out of 3550 individuals, we found 612 with congenital
      orthopaedic anomalies, which accounted for 17.2%. Of these 612 individuals, we
      noted 36 cases with congenital amputation (amputation through digits and toes
      were not included). Both unilateral and bilateral congenital amputations were
      much more common in the upper extremity as compared to lower extremity. Not a
      single case of simultaneous upper and lower extremity involvement was seen. The
      most common transverse deficiency in the upper limb was through the forearm, and
      in the lower limb it was through the foot. Congenital amputation was common in
      males with a gender ratio of 3.5:1. Left limb involvement was twice as much as
      right limb involvement, and it was common in both sexes. Bilateral limb
      involvement was seen only in males.

PMID- 12401922
TI  - The treatment of chronic osteomyelitis with a biodegradable antibiotic
      impregnated implant.
AB  - The use of local antibiotics from a biodegradable implant for chronic
      osteomyelitis is an attractive alternative. The implant delivers high tissue
      levels, obliterates dead space, aids bone repair and does not need to be removed.
      The purpose of this paper is to review our early clinical experience with custom
      made calcium sulfate (Osteoset bone void filler) antibiotic-impregnated implants.

PMID- 12401923
TI  - Calcium absorption measured by stable calcium isotopes ((42)Ca & (44)Ca) among
      Northern Chinese adolescents with low vitamin D status.
AB  - An adequate calcium intake and vitamin-D status is important for bone
      mineralization in adolescents. In Northern China, calcium intake and plasma
      vitamin-D level of adolescents is low due to low consumption of dairy foods and
      inadequate sunshine exposure. True fractional calcium absorption (TFCA) in
      Chinese adolescents has never been performed. This study aims to evaluate
      nutritional adaptation namely, TFCA and urinary calcium excretion among Chinese
      adolescents in northern China.

PMID- 12401924
TI  - Power spectrum analysis of compound muscle action potential in carpal tunnel
      syndrome patients.
AB  - The objective of using wave-form analysis to assess compound muscle action
      potential (CMAP) in entrapment neuropathy had not been fully developed. We
      applied the power spectrum analysis to patients with carpal tunnel syndrome (CTS)
      for this purpose. 24 patients with CTS were divided into three stages according
      to Mackinnon s classification, and 50 normal volunteers were examined. CMAP was
      obtained from the abductor pollicis brevis with supramaximal stimulation to
      median nerve. Mean and peak frequencies were measured by power spectrum analysis.
      The distal latencies of CMAP and the sensory nerve conduction velocities showed
      some prolongation in CTS patients. Integral values of CMAP were also decreased in
      CTS patients. Mean and peak frequencies of power spectrum of CMAP in volunteers
      were 134 Hz and 98 Hz, respectively. These values shifted into lower frequencies
      in CTS patients, namely 102 Hz and 61 Hz. Regardless of clinical stage, distal
      latency of CTS patients correlated with mean frequency.

PMID- 12401925
TI  - Osteophyte at the sacroiliac joint as a cause of sciatica: a report of four
      cases.
AB  - Four cases of sciatica due to osteophytes impinging on the sciatic nerve at the
      sacroiliac joint are reported. Of these 4 cases, 2 were treated conservatively
      and the other 2 required surgical excision of the osteophyte. The report
      highlights the importance of keeping this uncommon etiology in the differential
      diagnosis of sciatica.

PMID- 12401926
TI  - Retroperitoneal giant schwannomas: report on two cases and review of the
      literature.
AB  - The occurrence of massive retroperitoneal schwannomas is extremely rare and their
      presence may only be expressed by insidious onset of non-specific and misleading
      symptoms with a predominance of lower back pain. MRI scan as the imaging
      procedure of choice will demonstrate the tumour location and its relation to the
      surrounding structures, but due to heterogeneity and degeneration in some
      tumours, it may mimic malignancy. Hence tissue sampling through needle biopsies
      are essential to verify the diagnosis prior to surgery. Tumour excision in toto
      is considered the treatment of choice, but it can be hazardous especially if the
      tumour is adherent to the presacral venous plexus. Severe bleeding complications
      due to the damage of venous structures have to be encountered, and establishing
      lasting haemostasis may pose considerable difficulties. Hence surgery should be
      attempted with full precautions, and preoperative counseling of the patient. If
      malignancy can safely be excluded, laparoscopic  piecemeal  excision should be
      considered as an alternative treatment as recurrence is unlikely. Definition of
      the originating nerve might not always be possible and a minor degree of
      neurological impairment has therefore to be anticipated.

PMID- 12401927
TI  - Skeletal angiomatosis in association with gastro-intestinal angiodysplasia and
      paraproteinemia: a case report.
AB  - Skeletal-extraskeletal angiomatosis is defined as a benign vascular proliferation
      involving the medullary cavity of bone and at least one other type of tissue. It
      has also been known as cystic angiomatosis in which multiple cystic lesions are
      scattered diffusely throughout the skeleton often with similar angiomatous
      changes in other tissues, usually the spleen. A case of skeletal angiomatosis in
      association with gastro-intestinal angiodysplasia and paraproteinemia is
      reported.

PMID- 12401928
TI  - True aneurysm of a thumb digital artery in a radiographer: a case report.
AB  - True aneurysms of the digital artery are very rare. We report a case of true
      aneurysm of a proper digital artery of the right thumb in a radiographer.
      Treatment by ligation and excision resulted in complete relief of symptoms.

PMID- 12401929
TI  - Rehabilitation services in the Asia-Pacific region.

PMID- 12401931
TI  - Pathogenesis and diagnosis of hyponatremia.
AB  - This discussion emphasizes two aspects of hyponatremia: classification according
      to effective osmolality of the body fluid, and distinction between appropriate
      and inappropriate ADH secretion. Assessment of the effective osmolality is
      important because the main deleterious effect of hyponatremia is cell
      overhydration, which occurs only when the effective osmolality is reduced. Since
      most cases of hyponatremia are associated with low effective osmolality, cell
      overhydration is a hallmark of acute hyponatremia. On the other hand, one must be
      aware of other types of hyponatremia in which effective osmolality is either
      normal or even increased. Inappropriateness of ADH secretion is defined as ADH
      secretion that occurs despite low effective osmolality and normal or expanded
      effective vascular volume. ADH secretion that occurs in hyponatremia is deemed
      appropriate if the effective vascular volume is low. The use of laboratory
      parameters is much more reliable in determining effective vascular volume than is
      careful physical examination.

PMID- 12401932
TI  - Therapeutic approach to hyponatremia.
AB  - Hyponatremia is a relatively common disorder occurring in up to 6% of
      hospitalized patients and can occur through any mechanism that produces a
      relative excess of body water to body sodium. Although most hyponatremia patients
      are asymptomatic, severe symptomatic hyponatremia is a medical emergency that may
      lead to cerebral edema, tentorial herniation and death. More aggressive therapy
      is indicated in these patients. However, in some patients, the treatment itself
      may result in central nervous system demyelination that may be associated with
      permanent neurologic sequelae. The therapeutic strategy that should guide optimal
      treatment of hyponatremia requires attention to the following four factors: the
      patient's volume status, the presence or absence of symptoms, duration of hypo
      osmolality, and the presence or absence of risk factors for the development of
      neurologic complication. An initial categorization according to the clinical ECF
      volume status of the patient will allow a determination of the appropriate
      initial therapy in the majority of cases. The importance of duration of
      hyponatremia and the presence or absence of symptoms relates to how well the
      brain has adapted to the hyponatremia. The severity of hyponatremia is also an
      important consideration because osmotic demyelination is rarely seen in patients
      with the initial serum sodium greater than 120 mEq/l. Clinical surveys have
      identified subgroups of patients at greatest risk for developing neurologic
      complication of hyponatremia. Optimal therapy of these patients must consider
      balancing the risks of hyponatremia against the risks of correction for each
      patient individually. Although individual variability in response to treatment is
      considerable, consensus guidelines for treating hyponatremic patients allow a
      rational and safe therapeutic approach to minimize the neurologic complications.

PMID- 12401933
TI  - Pathogenesis and treatment of hypernatremia.
AB  - Two aspects of hypernatremia are emphasized in this discussion: pathogenesis and
      treatment. Hypernatremia rarely develops with increased water loss alone; there
      must be a mechanism that interferes with water intake. In treating hypernatremia,
      the speed of correction is important because the volume regulation mechanisms
      restore the brain volume to normal when hypernatremia is chronic. Thus, too rapid
      correction of chronic hypernatremia results in brain edema. The calculation of
      fluid volume needed to correct hypernatremia can be obtained with use of various
      formulae described here for the fluid that contains dextrose in water or for
      hypotonic saline solution. Accurate prediction of the fluid volume requirement
      demands the knowledge of urine output and its electrolyte content, but when the
      information is not available, urine may be assumed to be isotonic in its
      electrolyte content.

PMID- 12401934
TI  - Bartter's, Gitelman's, and Gordon's syndromes. From physiology to molecular
      biology and back, yet still some unanswered questions.
AB  - The molecular basis of many of the inherited disorders of potassium homeostasis
      has become much clearer in the last two decades. Despite these new insights into
      the physiology of renal potassium handling, a number of questions remain to be
      answered. The examples we use to illustrate these issues are Gordon's syndrome,
      Bartter's syndrome, and Gitelman's syndrome. Our objective is to integrate these
      new insights into an understanding of the pathophysiology of renal potassium
      handling. We also propose different ways to think about some of the unresolved
      issues in this area.

PMID- 12401935
TI  - Therapeutic approach to hypokalemia.
AB  - For successful potassium replacement, one should consider the optimal potassium
      preparation, route of administration, and the appropriate speed of
      administration. In the absence of an independent factor causing transcellular
      potassium shifts, the plasma potassium concentration can be used as a rough index
      to estimate body potassium stores. Oral KCl replacement therapy is preferable if
      there are bowel sounds, except in the setting of life-threatening abnormalities
      such as ventricular arrhythmias, digitalis intoxication, or paralysis. In
      patients with impaired renal function or those treated with intravenous
      potassium, the risk of hyperkalemia should be monitored. Since potassium
      depletion rarely occurs as an isolated phenomenon, associated fluid and
      electrolyte disorders should be corrected, and the causes of potassium loss
      should be sought and eliminated to complete the treatment of hypokalemia.

PMID- 12401936
TI  - Therapeutic approach to hyperkalemia.
AB  - The foremost step in the initial clinical management of hyperkalemia is to decide
      whether a hyperkalemic patient requires immediate treatment to avoid a life
      threatening situation (serum potassium concentration >6.0 mEq/l and EKG changes).
      When the decision for urgent treatment of hyperkalemia is based on EKG changes,
      an important caveat for clinicians is that absent or atypical EKG changes do not
      exclude the necessity for immediate intervention. Once an urgent situation has
      being handled with intravenous push of a 10% calcium salt, the initiation of
      short-term measures can be launched by either a single or combined regimen of the
      three agents that cause a transcellular shift of potassium - insulin with
      glucose, beta(2)-agonist (albuterol), and NaHCO(3). As the first choice among
      these available options, we favor an intravenous bolus of 10 units of insulin
      with 50 ml of 50% glucose alone or in combination with 10-20 mg of albuterol by
      nebulizer. These can be repeated as required until the institution of
      hemodialysis. The combination of insulin with glucose and NaHCO(3) as an another
      option needs further clarification for its additive effects. However, NaHCO(3)
      has lost its favor because of its poor efficacy as a potassium-lowering agent
      when used alone. The next step is to remove potassium from the body - diuretics
      (furosemide), cation exchange resin (kayexelate) with sorbitol, and dialysis
      (preferably hemodialysis). The final important step for the managements of
      hyperkalemia is a long-term plan to prevent its recurrence or worsening. In
      addition to every effort to elucidate underlying causes and pathophysiologic
      mechanisms for hyperkalemia, an extensive search must be made to uncover overt or
      sometimes covert medications that may have led to the development of
      hyperkalemia. Furthermore, one must obtain detailed dietary and medical history
      of hyperkalemic patients.

PMID- 12401937
TI  - A conceptual approach to the patient with metabolic acidosis. Application to a
      patient with diabetic ketoacidosis.
AB  - We shall illustrate that management of patients with an acid-base disorder could
      be improved if the acid-base analysis was based on a better understanding of
      basic concepts of physiology. Three concepts of acid-base physiology and their
      clinical implications are emphasized in a patient with diabetic ketoacidosis.
      First, when an acid is produced from neutral precursors in the body, there is a
      net increase in the number of hydrogen ions (H(+)) and new anions. The corollary
      is that H(+) will be removed when the accompanying anion is metabolized to a
      neutral end-product or is excreted in the urine with H(+) or ammonium (NH(4)(+)).
      Second, buffering of H(+) is beneficial if H(+) are removed by bicarbonate rather
      than being able to bind to proteins. This latter function depends on having a low
      tissue PCO(2), due to a combination of hyperventilation plus an adequate blood
      flow rate to vital organs. Third, the kidneys add new bicarbonate to the body
      when NH(4)(+) is excreted with chloride ions.

PMID- 12401938
TI  - Basic rules of parenteral fluid therapy.
AB  - The following basic rules of parenteral fluid therapy are formulated with the aim
      of alleviating concern and confusion about i.v. fluid orders that are experienced
      by most physicians: Don't be generous with fluid; in determining the water
      intake, one must know the usual water output through the kidney, skin and lung;
      one must know the quantities of the electrolytes and nutrients that are being
      given, and know the initial volume of distribution (usually the ECF); one must
      know the aim of fluid therapy; one must not give and remove the same substance at
      the same time; one must be aware that hypertonic saline contains less water for a
      given amount of Na than isotonic saline; one must be familiar with different i.v.
      solutions and i.v. additives; one must be aware that the kidney does not
      manufacture water or electrolytes except for bicarbonate; for short-term fluid
      therapy, divalent ions (Ca, Mg, and P) do not need replacement; one should think
      about COP-wedge gradient in determining the type of fluid to be given.

PMID- 12401939
TI  - Long-term effects of growth hormone therapy on bone mineral density, body
      composition, and serum lipid levels in growth hormone deficient children: a 6
      year follow-up study.
AB  - AIM: To study the effects of growth hormone (GH) deficiency (GHD) and GH
      replacement therapy (GHRx) on bone mineral density (BMD) and body composition.
      METHODS: 59 GHD children participated (age range 0.4-16.9 years); the follow-up
      period was 6 years. Lumbar spine BMD (BMD(LS)), total-body BMD (BMD(TB)), and
      body composition were measured prospectively using dual-energy X-ray
      absorptiometry. RESULTS: Mean BMD(LS )and BMD(TB) were significantly reduced at
      the time of the diagnosis. The bone mineral apparent density of the lumbar spine
      (BMAD(LS)) was reduced to a lesser degree. The BMAD(LS) increased to normal
      values after 1 year; BMD(LS) and BMD(TB) normalized 1 year later. At the time of
      the diagnosis, the lean body mass was reduced and steadily increased during GHRx.
      Percentage of body fat was increased at baseline and normalized within 6 months.
      The severity of GHD was not associated with the BMD at diagnosis or the response
      to GHRx. CONCLUSION: Areal BMD(LS) and BMD(TB) and, to a lesser extent, BMAD(LS)
      are decreased in GHD children, but normalize within 1-2 years.

PMID- 12401940
TI  - Increased adrenal androgen levels in patients with Prader-Willi syndrome are
      associated with insulin, IGF-I, and leptin, but not with measures of obesity.
AB  - BACKGROUND/AIM: Since hyperandrogenism in simple obesity is assumed to arise from
      hyperinsulinism and/or increased insulin-like growth factor I (IGF-I) or leptin
      levels, we examined how in patients with Prader-Willi syndrome (PWS), the most
      frequent form of syndromal obesity, the accelerated adrenarche can be explained
      despite hypothalamic-pituitary insufficiency with low levels of insulin and IGF
      I. METHODS: In 23 children with PWS and a mean age of 5.6 years, height, weight,
      fat mass, fasting insulin concentration, insulin resistance (by HOMA-R; see
      text), and leptin and IGF-I levels were determined to test whether they explain
      the variance of the levels of dehydroepiandrosterone (DHEA) and its sulfate
      (DHEAS), of androstenedione, and of cortisol before and during 42 months of
      therapy with growth hormone. RESULTS: The baseline DHEAS, DHEA, and
      androstenedione concentrations were increased as compared with age-related
      reference values, whereas the cortisol level was always normal. During growth
      hormone treatment, the DHEA concentration further rose, and the cortisol level
      decreased significantly. The insulin and IGF-I concentrations were low before
      therapy, while fat mass and leptin level were elevated. The hormonal covariates
      provided alone or together between 24 and 60% of the explanation for the variance
      of adrenal androgen levels, but the anthropometric variables did not correlate
      with them. CONCLUSIONS: In children with PWS, elevated androgen levels correlate
      with hormones that are usually associated with adiposity. However, the lack of
      direct correlations between disturbed body composition and androgen levels as
      well as the increased sensitivity to insulin and IGF-I are abnormalities specific
      to PWS, potentially caused by the underlying hypothalamic defect.

PMID- 12401941
TI  - Mucosal cytology in the determination of the pubertal status in girls.
AB  - AIM: To assess and validate the diagnostic value of buccal and vaginal smears in
      the ambulatory care of girls with potential disorders of puberty. METHODS: Smears
      were obtained from 77 girls who presented for assessment of their pubertal
      status, stained as described by Papanicolaou, examined for signs of
      estrogenization according to the method of Schmitt, and compared with the
      clinical status. RESULTS: Vaginal but not buccal smears reflect accurately the
      changes of sexual maturation, even more sensitive than single serum hormone
      measurements. CONCLUSIONS: Vaginal smears represent a valid, reproducible, and
      well-tolerated diagnostic tool in the ambulatory care of peripubertal girls to
      identify their estrogen status with high sensitivity and specificity. The
      decision to perform confirmative but invasive diagnostic procedures can be based
      on auxology, physical examination, bone age determination, and analysis of
      vaginal smears.

PMID- 12401942
TI  - Insulin resistance (HOMA) in relation to plasma cortisol, IGF-I and IGFBP-3. A
      study in normal short-statured and GH-deficient children.
AB  - OBJECTIVE: To investigate the possible contribution of plasma cortisol and growth
      hormone (GH) as reflected by insulin-like growth factor-I (IGF-I)/insulin-like
      growth factor-binding protein-3 (IGFBP-3) on insulin action in short-statured
      children. METHODS: In this study, insulin resistance (HOMA) was determined in 34
      normal short-statured (age 9.4 +/- 3.5 years) and in 19 GH-deficient children
      (age 10.4 +/- 2.2 years). HOMA was examined in relation to fasting plasma
      cortisol, IGF-I, IGFBP-3 and in addition to birthweight and body mass index
      (BMI). RESULTS: Birthweight was not correlated to insulin resistance. In GH
      deficient children, BMI was significantly augmented and was associated with HOMA
      (p < 0.02). In both groups of patients, fasting plasma cortisol was related to
      HOMA (normal: r = 0.295, p < 0.05, GH-deficient: r = 0.495, p < 0.02). Only in
      normal short-statured children IGF-I (r = 0.338, p < 0.03) and IGFBP-3 (r =
      0.493, p < 0.002) were associated with insulin resistance. CONCLUSION: The
      results indicated that at a young age cortisol contributed to insulin resistance
      in short-statured children. In normal short-statured children HOMA was associated
      with IGF-I and IGFBP-3. Possibly GH, a known cause of insulin resistance,
      contributed to HOMA as IGF-I and IGFBP-3 do not mediate insulin resistance but
      reflect growth hormone secretion. The results in GH-deficient children supported
      this conclusion as in the absence of GH insulin resistance was not associated
      with IGF-I/IGFBP-3.

PMID- 12401943
TI  - European audit of current practice in diagnosis and treatment of childhood growth
      hormone deficiency.
AB  - BACKGROUND: The present survey among members of the ESPE on current practice in
      diagnosis and treatment of growth hormone (GH) deficiency (GHD) is of great
      clinical relevance and importance in the light of the recently published
      guidelines for diagnosis and treatment of GHD by the Growth Hormone Research
      Society. We have found much conformity but also numerous discrepancies between
      the recommendations of the Growth Hormone Research Society and the current
      practice in Europe. RESULTS: We found that 80% of the pediatric endocrinologists
      included insulin-like growth factor I (IGF-I) in their initial evaluation of a
      short child suspected of having GHD, whereas only 22% used GH provocative testing
      alone in the initial evaluation of a short child. Sixty-eight percent confirmed
      the diagnosis of GHD using two separate provocative tests. In the present survey
      cutoff values for GH provocative testing clustered around two values; 10 ng/ml
      and 20 mU/l. Interestingly, these two values, differing by a factor of 2, were
      also the most prevalent cutoff values among those who reported their assay to be
      calibrated against the WHO International Reference Preparation 80/505 where the
      conversion factor between milligrams and milliunits is 2.6. This suggests that
      the selection of cutoff values is based on tradition rather than on specific GH
      assay characteristics. In addition, only 63% of the respondents actually knew
      what GH assay they were using, and only 57% knew how their GH assay was
      calibrated. Dosing of GH at the start of treatment was reported according to body
      surface by 39%, whereas 59% were dosing according to body weight. GH dose
      adjustment was primarily based on growth response and height during auxological
      assessment every 3-4 months (height velocity, change in height velocity or change
      in height standard deviation scores) as indicated by almost 70% of the
      respondents. However, dose adjustment according to body surface (38%) and body
      weight (44%) was also quite common. Sixty-five percent measures IGF-I regularly
      (at least once a year) during GH therapy in children, and to our surprise 17%
      reported that they adjust the GH dose according to the IGF-I levels. SUMMARY: In
      summary, we have found large heterogeneity in the current practice of diagnosis
      and treatment of childhood GHD among European pediatric endocrinologists.
      Especially standardizations of GH assays and cutoff values are urgently required
      to ensure a uniform and correct diagnosis and therapy of GHD in the future.

PMID- 12401946
TI  - Distribution of ferroportin1 protein in different regions of developing rat
      brain.
AB  - Ferroportin1 is a newly discovered transmembrane iron export protein. It plays a
      key role in Fe(2+) transport across the basal membrane of enterocytes in the gut.
      It has been suggested that this protein might have the same role in Fe(2+)
      transport across the abluminal membrane of the blood-brain barrier as it works in
      enterocytes. However, the presence of ferroportin1 in the brain has not been well
      determined. In the present study, we investigated expression of ferroportin1
      protein in different brain regions, including cortex, hippocampus, striatum and
      substantia nigra, in developing male Sprague-Dawley rats. The results provided
      direct evidence for the existence of ferroportin1 protein in the rat brain. All
      brain areas examined have the ability to synthesize ferroportin1 protein. The
      findings also showed that age has a significant effect on the expression of
      ferroportin1 protein in the cortex, hippocampus, striatum and substantia nigra of
      the rat brain.

PMID- 12401947
TI  - A morphological study of the developmentally regulated transport of iron into the
      brain.
AB  - The distribution of transferrin, transferrin receptor, ferritin and ferric iron
      was studied in the developing rat brain. Transferrin immunoreactivity (IR) was
      observed diffusely in the brain from E16 until P10 from where it gradually
      decreased. The subcellular distribution of transferrin-IR in neurons was
      compatible with receptor-mediated uptake from P21 and onwards. Transferrin
      receptor-IR was observed prenatally on cells of neuroectodermal origin in the
      ventricular zone and in brain capillary endothelial cells (BCECs). In postnatal
      rats, transferrin receptor-IR in BCECs was most pronounced in rats aged P10-P21
      but thereafter decreased in intensity. The neuronal transferrin-receptor IR in
      postnatal brains was not consistently expressed on neurons until from P21 and
      onwards. Transferrin receptor-IR was not observed in astrocytes, oligodendrocytes
      or ramified microglial cells at any age. Ferric iron and ferritin were present in
      BCECs already from E16, declined from P3-P5, and was absent by P10. There results
      are discussed with emphasis on the age-dependent transport of transferrin into
      the developing brain. The upregulated expression of transferrin receptors on
      BCECs in the second and third postnatal week is compatible with a high need for
      iron at this age. The neuronal transferrin receptor expression by P21 coincides
      with a drop in transferrin-IR and iron transport into the brain at this age,
      suggesting that neuronal transferrin receptor mRNA is posttranscriptionally
      regulated by the lowered iron availability from this developmental stage onwards.

PMID- 12401948
TI  - Mechanism and developmental changes in iron transport across the blood-brain
      barrier.
AB  - Transferrin and iron uptake by the brain were measured using [(59)Fe
      (125)I]transferrin injected intravenously in rats aged from 15 days to 22 weeks.
      The values for both decreased with age. In rats aged 18 and 70 days the uptake
      was measured at short time intervals after the injection. When expressed as the
      volume of distribution (Vd), which represents the volume of plasma from which the
      transferrin and iron were derived, the results for iron were greater than those
      of transferrin as early as 7 min after injection and the difference increased
      rapidly with time, especially in the younger animals. A very similar time course
      was found for uptake by bone marrow (femurs) where iron uptake involves receptor
      mediated endocytosis of Fe-transferrin, release of iron in the cell and recycling
      of apo-transferrin to the blood. It is concluded that, during transport of
      transferrin-bound plasma iron into the brain, a similar process occurs in brain
      capillary endothelial cells (BCECs) and that transcytosis of transferrin into the
      brain interstitium is only a minor pathway. Also, the high rate of iron transport
      into the brain in young animals, when iron requirements are high due to rapid
      growth of the brain, is a consequence of the level of expression and rate of
      recycling of transferrin receptors on BCECs. As the animal and brain mature both
      decrease.

PMID- 12401950
TI  - Zinc status of human IMR-32 neuroblastoma cells influences their susceptibility
      to iron-induced oxidative stress.
AB  - The current work tested the hypothesis that the zinc status of a cell influences
      its sensitivity to iron-induced oxidative stress. Human IMR-32 neuroblastoma
      cells were cultured for 24 h in nonchelated control media (5 microM zinc; 4.5
      microM iron), or in media that was treated with DTPA to reduce its zinc content
      (chelated media). Chelated media was supplemented with zinc to achieve
      concentrations of 1.5-50 microM Zn. The media was then replaced with serum-free
      complex media (0.9 microM Zn) with either no added iron (0.6 microM Fe), or iron
      (FeCl(3)) added at concentrations ranging from 15 to 100 microM. Cells were
      cultured for an additional 3- to 24-hour period. Over the 24-hour period, cells
      cultured in the control iron media had good viability, and they displayed the
      gross morphology typical of these cells in culture. With 100 microM iron, cell
      viability was low in all groups. After 24 h and at iron concentrations between 15
      50 microM, cells that had been cultured in the low zinc-chelated media (1.5
      microM Zn) showed a concentration-dependent increase in 5 (or 6)-carboxy-2'7'
      dichlorodihydrofluorescein diacetate (DCDCDHF) fluorescence (oxidative stress)
      and decrease in cell viability. A positive correlation between both parameters
      was observed (r = 0.92). These cells had altered morphology and high level of
      nucleosomes suggestive of cell death by apoptosis. These results support the
      concept that the zinc status of IMR-32 neuroblastoma cells modulates their
      sensitivity to iron overload.

PMID- 12401949
TI  - Numerous proteins in Mammalian cells are prone to iron-dependent oxidation and
      proteasomal degradation.
AB  - The mechanisms that underlie iron toxicity in cells and organisms are poorly
      understood. Previous studies of regulation of the cytosolic iron sensor, iron
      regulatory protein 2 (IRP2), indicate that iron-dependent oxidation triggers
      ubiquitination and proteasomal degradation of IRP2. To determine if oxidization
      by iron is involved in degradation of other proteins, we have used a carbonyl
      assay to identify oxidized proteins in lysates from RD4 cells treated with either
      an iron source or iron chelator. Protein lysates from iron-loaded or iron
      depleted cells were resolved on two-dimensional gels and these iron manipulations
      were also repeated in the presence of proteasomal inhibitors. Eleven abundant
      proteins were identified as prone to iron-dependent oxidation and subsequent
      proteasomal degradation. These proteins included two putative iron-binding
      proteins, hNFU1 and calreticulin; two proteins involved in metabolism of hydrogen
      peroxide, peroxiredoxin 2 and superoxide dismutase 1; and several proteins
      identified in inclusions in neurodegenerative diseases, including HSP27, UCHL1,
      actin and tropomyosin. Our results indicate that cells can recognize and
      selectively eliminate iron-dependently oxidized proteins, but unlike IRP2, levels
      of these proteins do not significantly decrease in iron-treated cells. As iron
      overload is a feature of many human neurological diseases, further
      characterization of the process of degradation of iron-dependently oxidized
      proteins may yield insights into mechanisms of human disease.

PMID- 12401951
TI  - Interactions of iron with reactive intermediates of oxygen and nitrogen.
AB  - Iron not only functions as a cofactor for various enzymes, but it is also a
      source of potentially cytotoxic molecules produced through interactions with
      certain reactive intermediates of oxygen (ROI) and nitrogen (RNI). Protection
      from such iron-mediated damage results in large part from homeostatic mechanisms
      that regulate the sequestration of iron. Perturbations in iron homeostasis can
      result in an array of adverse cellular manifestations including oxidative and
      nitrosative stress, enhanced production of free radicals, macromolecular damage,
      and cell death. This brief review focuses on some of the potentially adverse
      reactions of iron with ROI and RNI.

PMID- 12401952
TI  - Deferoxamine attenuates iron-induced oxidative stress and prevents mitochondrial
      aggregation and alpha-synuclein translocation in SK-N-SH cells in culture.
AB  - One of the defining characteristics of neurodegenerative diseases, including
      Parkinson's disease, is an abnormal accumulation of iron in the affected brain
      areas. By using SK-N-SH, a dopaminergic cell line, we have found that iron (100
      250 microM FeSO(4)) decreased cell viability, increased lipid peroxidation, and
      the said effects were blocked by deferoxamine (DFO: 10 microM). Furthermore, DFO,
      in the absence of iron, enhanced the level of adenosine triphosphate (ATP), but
      caused chromatin condensation and cell death. Morphological studies revealed that
      iron (50-100 microM) altered mitochondrial morphology, disrupted nuclear
      membrane, and translocated alpha-synuclein from perinuclear region into the
      disrupted nucleus. The results of these studies suggest that DFO is able to block
      and attenuate iron-mediated oxidative stress. However, in the absence of excess
      iron, DFO itself may have deleterious effects on the morphology and hence
      integrity of dopaminergic neurons.

PMID- 12401953
TI  - Protein oxidation and heme oxygenase-1 induction in porcine white matter
      following intracerebral infusions of whole blood or plasma.
AB  - Spontaneous or traumatic intracerebral hemorrhage (ICH) in the white matter of
      neonates, children and adults causes significant mortality and morbidity. The
      detailed biochemical mechanisms through which blood damages white matter are
      poorly defined. Presently, we tested the hypothesis that ICH induces rapid
      oxidative stress in white matter. Also, since clot-derived plasma proteins
      accumulate in white matter after ICH and these proteins can induce oxidative
      stress in microglia in vitro, we determined whether the blood's plasma component
      alone induces oxidative stress. Lastly, since heme oxygenase-1 (HO-1) induction
      is highly sensitive to oxidative stress, we also examined white matter HO-1 gene
      expression. We infused either whole blood or plasma (2.5 ml) into the frontal
      hemispheric white matter of pentobarbital-anesthetized pigs ( approximately 1 kg)
      over 15 min. We monitored and controlled physiologic variables and froze brains
      in situ between 1 and 24 h after ICH. White matter oxidative stress was
      determined by measuring protein carbonyl formation and HO-1 gene expression by RT
      PCR. Protein carbonyl formation occurred rapidly in the white matter adjacent to
      both blood and plasma clots with significant elevations (3- to 4-fold) already 1
      h after infusion. This increase remained through the first 24 h. HO-1 mRNA was
      rapidly induced in white matter with either whole blood or plasma infusions.
      These results demonstrate that not only whole blood but also its plasma component
      are capable of rapidly inducing oxidative stress in white matter. This rapid
      response, possibly in microglial cells, may contribute to white matter damage not
      only following ICH, but also in pathophysiological states in which blood-brain
      barrier permeability to plasma proteins is increased.

PMID- 12401954
TI  - Heme oxygenase-1 induction and dependent increase in ferritin. A protective
      antioxidant stratagem in hemin-treated rat brain.
AB  - The in vivo effect of hemin on both brain oxidative stress and heme oxygenase-1
      (HO-1) induction was studied. A marked increase in lipid peroxidation was
      observed 1 h after hemin administration and antioxidant enzymes significantly
      decreased 3 h after hemin injection. HO-1 activity appeared 6 h after treatment,
      peaking 9 h after hemin administration. Such induction was preceded by a decrease
      in GSH pool and an increase in hydrogen peroxide concentration. Iron ferritin
      levels and ferritin content began to increase 6 h after HO-1 induction, and these
      increases remained high for at least 24 h after hemin injection. Administration
      of bilirubin entirely prevented HO-1 induction as well as the generation of
      oxidative stress parameters. These results indicate that the induction of heme
      oxygenase by hemin may be a general response to oxidant stress, by increasing
      bilirubin and ferritin levels and could therefore provide a major cellular
      defense mechanism against oxidative damage.

PMID- 12401955
TI  - Role of porphyrin sequestration in the biogenesis of iron-laden astrocytic
      inclusions in primary culture.
AB  - Astrocytes in subcortical regions of the mammalian brain progressively accumulate
      iron-rich, autofluorecent cytoplasmic inclusions as a function of aging.
      Cysteamine (CSH) accelerates the appearance of this senescent glial phenotype in
      situ and in primary rat astroglial cultures. Porphyrins have been implicated as
      the source of orange-red autofluorescence in these glial inclusions. Yet, CSH has
      been shown to suppress porphyrin-heme biosynthesis in cultured astroglia. To
      determine whether porphyrin biosynthesis or sequestration participates in the
      biogenesis of these glial inclusions, the porphyrin precursor, (3)H-delta
      aminolevulinic acid ((3)H-ALA) was administered to CSH-exposed and control rat
      astroglial cultures followed by light and electron microscopic autoradiography.
      Control cultures exhibited faint orange-red autofluorescence, intense (3)H-ALA
      labeling, numerous normal mitochondria and few cytoplasmic inclusions. In these
      cells, (3)H-ALA labeling largely occurred over normal mitochondria. The CSH
      treated astroglia exhibited diminished (3)H-ALA labeling and contained numerous
      orange-red autofluorescent inclusions. The latter manifested internal
      compartments delimited by double membranes characteristic of damaged
      mitochondria. The complement of normal mitochondria in the CSH-exposed cells was
      markedly reduced. In the CSH-treated cells, (3)H-ALA labeling predominated over
      the large multi-compartmental inclusions. CSH attenuates de novo porphyrin-heme
      biosynthesis in astroglia but may induce punctate orange-red autofluorescence in
      the cytoplasm of these cells by promoting large numbers of damaged, porphyrin
      containing mitochondria to form tight aggregates within the nascent gliosomes.

PMID- 12401956
TI  - Apoferritin attenuates experimental allergic encephalomyelitis in SJL mice.
AB  - Ferritin has been shown to attenuate iron-catalyzed oxidative damage in several
      experimental conditions. Since oxidative damage has been implicated in the
      pathogenesis of multiple sclerosis (MS) and experimental allergic
      encephalomyelitis (EAE), an animal model of MS, we tested the hypothesis that
      ferritin would act to attenuate disease. The experimental design was to increase
      plasma ferritin levels during the active stage of EAE by giving systemic
      injections of apoferritin and then compare disease activity between these mice
      and EAE mice administered vehicle. Additional mice received systemic injections
      of iron, which induces ferritin synthesis, in order to test the effects of
      exogenous iron on the disease course. Although plasma levels of ferritin were
      found to be elevated in both apoferritin and iron-injected EAE mice, only
      apoferritin treatment resulted in a reduction in disease activity compared to EAE
      mice given vehicle. The suppressive effects of apoferritin administration suggest
      that the increase in endogenous ferritin levels that have been previously
      observed in the cerebrospinal fluid of chronic progressive MS patients with
      active disease might be functioning to limit the severity and spread of tissue
      damage.

PMID- 12401957
TI  - Iron: a pathological mediator of Alzheimer disease?
AB  - Brains from patients with Alzheimer disease (AD) show a disruption in the
      metabolism of iron, such that there is an accumulation of iron in senile plaques,
      and an altered distribution of iron transport and storage proteins. One of the
      earliest events in AD is the generation of oxidative stress, which may be related
      to the generation of free radicals by the excess iron that is observed in the
      disease. Iron has also been shown to mediate the in vitro toxicity of amyloid
      beta peptide, and the presence of iron in most in vitro systems could underlie
      the toxicity that is normally attributed to amyloid-beta in these studies. In
      contrast, several recent studies have suggested that amyloid-beta may decrease
      oxidative stress and decrease the toxicity of iron. Continued examination of the
      complex interactions that occur between iron and amyloid-beta may assist in the
      elucidation of the mechanisms that underlie the neurodegeneration that leads to
      dementia in AD.

PMID- 12401958
TI  - Brain iron metabolism and neurodegenerative disorders.
AB  - Iron, an essential element for central nervous system (CNS) function, has
      frequently been found to accumulate in brain regions that undergo degeneration in
      neurological diseases such as Alzheimer disease, Parkinson disease, Friedreich
      ataxia and other disorders. However, the precise role of iron in the cause of
      many neurodegenerative diseases is unclear. To assist in understanding the
      potential importance of iron in CNS disease, this review summarizes the present
      knowledge in the areas of CNS iron metabolism, homeostasis and disregulation of
      iron balance caused by mutations in genes encoding proteins involved in iron
      transport, storage and metabolism. This review encompasses neurodegenerative
      disorders associated with both iron overload and deficiency to highlight areas
      where iron misregulation is likely to be important in the pathophysiology of
      several human brain diseases.

PMID- 12401959
TI  - Iron deficiency during embryogenesis and consequences for oligodendrocyte
      generation in vivo.
AB  - One of the hallmarks of the pathology of iron deficiency in children is
      neurological disabilities that are often associated with hypomyelination. It has
      been hypothesized that this amyelination is mainly due to a disruption of myelin
      generation during the early postnatal stages when oligodendrocytes mature to
      generate myelin producing cell. In addition to these suggestions, we have
      previously provided in vitro data showing that iron affects both the
      proliferation and differentiation of glial precursor cells leading to a
      disruption in the generation of oligodendrocytes. We now present evidence
      demonstrating in vivo that iron deficiency during pregnancy affects the iron
      levels of various brain tissues in the developing fetus and disrupts not only the
      proliferation of their glial precursor cells but also disturbs the generation of
      oligodendrocytes from these precursor cells. In addition, we show that iron
      deficiency during embryogenesis affects glial lineage cells in a tissue-specific
      manner. Our studies offer the possibility to begin to comprehend whether any
      effects that occur during embryogenesis might have an influence on the
      establishment of the pathological defects that occur as a consequence of iron
      deficiency.

PMID- 12401960
TI  - Ferritin binding in the developing mouse brain follows a pattern similar to
      myelination and is unaffected by the jimpy mutation.
AB  - We have previously provided evidence that ferritin binds selectively to white
      matter tracts in adult mouse and human brains. In cell culture experiments,
      ferritin binding is specifically localized to oligodendrocytes. The goal of the
      present study is to test the hypothesis that the developmental pattern for
      ferritin binding will coincide with the onset and progression of myelination. The
      first evidence of ferritin binding in the mouse brain is at 12 days of age and
      occurs within the brainstem. Ferritin binding persisted in the brainstem and
      expanded to the corpus callosum by 15-16 days of age. By 23-24 days of age
      ferritin binding had further extended to the striatal white matter. By adulthood,
      ferritin binding was strongly and selectively expressed throughout all white
      matter tracts. To begin to identify which factors may be involved in the
      induction of ferritin-binding proteins on oligodendrocytes, brains from the
      myelin mutant jimpy mice and unaffected littermates were examined at postnatal
      days 16-18. Jimpy mice were chosen because their oligodendrocytes fail to produce
      myelin or accumulate iron. Thus, using jimpy mice would elucidate whether these
      factors are necessary for ferritin-binding protein expression. Both the jimpy
      mutants and their controls exhibited saturable ferritin binding with similar
      binding densities and dissociation constants. Dissociation constants for ferritin
      binding in the unaffected littermates and jimpy mutant mice were 0.38 +/- 0.04
      and 0.32 +/- 0.06 nM, respectively and binding densities were similar (1.1 +/-
      0.09 and 0.96 +/- 0.12 fmol/mg, respectively). Our results demonstrate that
      expression of ferritin binding is dependent on the age of the oligodendrocytes
      and not dependent upon iron accumulation by oligodendrocytes or myelin
      production. We propose that iron delivery to oligodendrocytes is predominantly
      via ferritin and this method of iron uptake is unique to oligodendrocytes in the
      brain.

PMID- 12401961
TI  - HoloTransferrin but not ApoTransferrin prevents Schwann cell de-differentiation
      in culture.
AB  - Schwann cells (SCs) in culture, without the presence of axons, become de
      differentiated, reaching a condition similar to that of their precursor cells.
      The cytoplasmic accumulation of transferrin (Tf) in the myelinated peripheral
      nerve has been reported and data in the literature support a role for apoTf in
      myelination in the CNS. In the present report, we used SC cultures to evaluate
      the capacity of apoTf and holoTf to prevent cell de-differentiation promoted by
      fetal calf serum deprivation. SCs incubated in a serum-free medium showed a
      decrease in the expression of myelin basic protein (MBP) and P(0), markers of
      mature myelin-forming SCs, together with an increase in the levels of p75NTR and
      glial fibrillary acidic protein, markers of immature SCs. Treatment with holoTf
      prevented the decrease in expression of MBP and P(0) and the increase in p75NTR.
      ApoTf was unable to prevent these changes except when iron was added to the
      cultures. These results suggest a role for holoTf in the regulation of myelin
      formation by SCs.

PMID- 12401962
TI  - Regulation of the tissue-specific expression of transferrin gene.
AB  - Transferrin (Tf), the plasma protein involved in iron transport, seems to play
      complex physiological roles related to cell function, differentiation and
      proliferation. The protein is essentially synthesized in hepatocytes, but also in
      Sertoli cells, in the epithelial cells of the choroid plexus in rodents and in
      oligodendrocytes in all species analyzed. In this manuscript, we review the
      results obtained on Tf gene expression in the different cellular systems in which
      the protein is synthesized. In vitro and ex vivo experiments indicate that
      different combinations of transcription factors are necessary in different
      subsets of cells to achieve Tf tissue-specific expression. Several lines of
      transgenic mice were generated in which the expression of reporter genes is under
      the control of different Tf regulatory regions. More recently, transgenic mice
      were obtained using the complete human Tf gene and its 5' and 3' flanking
      sequences. These mice constitute the first model in which the physiological
      consequences of a specific Tf over expression in oligodendrocytes can be studied.
      Although much information is now available, further work is still necessary for a
      full understanding of the in vivo mechanisms responsible for the regulation of Tf
      gene expression.

PMID- 12401963
TI  - Transferrin regulates transcription of the MBP gene and its action synergizes
      with IGF-1 to enhance myelinogenesis in the md rat.
AB  - Myelin-deficient (md) rats and their unaffected littermates were injected at
      postnatal day 4 either with a single dose of transferrin (Tf) or insulin-like
      growth factor one (IGF-1) singly or combined. Two weeks later, their brains were
      perfused and coronal sections were analyzed for MBP by in situ hybridization and
      for transferrin and myelin basic protein (Tf and MBP) by double
      immunofluorescence. Each of the factors separately had an effect on mutant
      animals as seen by both increased OL maturation, and MBP mRNA and protein
      synthesis. The combination of factors resulted in a profound enhancement of the
      myelinogenic properties of oligodendrocytes (OL) with a consequent increase in
      the number of MBP-labeled fibers. The brains of unaffected littermates also
      responded to growth factor(s) injection either by increasing myelination in some
      brain areas or by regulating the synthesis of MBP in OL. Using rat OL cultures we
      studied the site of transferrin action for the expression of MBP gene. We found
      by run off transcription that the MBP mRNA was significantly increased at the
      nuclear level but the PLP message was unaffected. Thus, transferrin selectively
      regulates MBP at the transcriptional level and together with IGF-1 synergizes to
      increase both the maturation and myelinogenic properties of md and normal OL.

PMID- 12401964
TI  - Changes in the expression of cytoskeletal proteins in the CNS of transferrin
      transgenic mice.
AB  - Apotransferrin injected intracranially into young rats has been shown in our
      laboratories to induce an early differentiation of oligodendroglial cells and an
      increased deposition of myelin. The expression of some myelin-specific proteins
      such as myelin basic protein (MBP) and 2',3'-cyclic nucleotide 3'
      phosphodiesterase (CNPase) and of their mRNAs were significantly increased in
      these animals. Also, in the cytoskeleton obtained from isolated myelin, it was
      found that several microtubule associated proteins (MAPs), particularly the
      stable tubule only peptide (STOP) and MAP 1B, as well as actin and tubulin were
      markedly increased. In the present paper, we compare the changes in expression of
      brain and myelin cytoskeletal proteins in a newly generated transferrin
      transgenic mouse (Tg), overexpressing the human transferrin gene, with the
      results obtained in aTf-injected rats. In the myelin cytoskeletal fraction of Tg
      mice there was a significant increase in the expression of MBP, tubulin, tau and
      STOP, similarly to what was previously found in the aTf-injected rats.
      Immunohistochemical studies showed that a variance with what occurs in the aTf
      injected model, in which the above mentioned changes were limited to the corpus
      callosum, in the Tg mice the changes in expression of cytoskeletal proteins were
      observed in the various anatomical areas studied such as cerebral cortex, brain
      stem and cerebellum. There was also an increased expression of neurofilaments in
      the Tg animals, in contrast with results obtained in aTf-injected rats,
      suggesting that in the Tg mice, the continuous overexpression of Tf might also
      induce some neuronal changes. Changes in tau, total and acetylated tubulin and
      MAP 1B were observed in both neurons and OLGc. The increase in STOP was more
      significant in OLGc while the changes in MAP2 were exclusively found in neurons.

PMID- 12401965
TI  - Speech perception in nucleus CI24M cochlear implant users with processor settings
      based on electrically evoked compound action potential thresholds.
AB  - Adjusting the speech processor of a cochlear implant, per electrode, to the
      individual's response is a laborious task that may interfere with a user-friendly
      start of implant-mediated hearing, particularly in children. This research
      concerns the possibility of processor adjustment based on a profile derived from
      measurements of the electrically evoked compound action potential (ECAP)
      thresholds across the electrode array, followed by adjustment of the overall
      level of the profile to the hearing threshold and maximum comfortable loudness
      level using live voice. The results for CVC word lists show that speech
      perception is quite insensitive to the threshold setting of the speech processor.
      On average, the speech score does not decrease by more than 10% when, with the
      new method, the threshold setting comes out so much lower that the dynamic range
      has doubled. In contrast, the speech score appears to be sensitive to an increase
      of the maximum high-frequency stimulation settings for the basal electrodes,
      resulting in lower scores at these higher settings. The correlation between the
      overall ECAP thresholds and conventionally measured subjective thresholds is weak
      (r = 0.64). However, the correlation between the slopes of these threshold curves
      is satisfactory (r = 0.82). The correlation between the ECAP thresholds and the
      maximum stimulation levels is poor, both with respect to overall level and slope
      (r = 0.39 and 0.36, respectively). Applicability of the ECAP threshold in
      processor adjustment could not be demonstrated in this study. Prediction of the
      most critical factor in speech perception, the slope of the maximum stimulation
      curve, from the ECAP thresholds is poor. However, considering habituation to the
      initial processor setting of at least 6 months, the small decrease in the CVC
      scores with the new setting suggests that a more user-friendly adjustment
      procedure can be developed.

PMID- 12401966
TI  - Effects of age on contralateral suppression of distortion product otoacoustic
      emissions in human listeners with normal hearing.
AB  - The auditory efferent system presumably plays a role in enhancing signals in
      noise and, in particular, speech perception in background noise. This study
      measured the age-related changes of the medial olivocochlear (MOC) system by
      comparing distortion product otoacoustic emissions (DPOAEs) with and without
      contralateral white noise stimulation. Otoacoustic emissions were typically
      reduced in level (magnitude) when white noise was presented to the contralateral
      ear. This contralateral suppression (CS) is attributed to activation of the MOC
      system, which has an inhibitory effect on the outer hair cell (OHC) system. By
      studying CS on cochlear output in human listeners of different ages, it is
      possible to describe aging effects on the MOC system. Human subjects were young
      adult, middle aged and old (n = 10/group). All subjects had normal hearing and
      middle-ear function based upon standard audiometric criteria. The present study
      recorded 2f(1)-f(2) DPOAE-grams in response to moderate primary tones (L1 = 75,
      L2 = 65 dB SPL), from 1 to 6.3 kHz. The principal findings were that DPOAE levels
      were smaller in the old compared to the young group and that CS declined with age
      for the middle-aged and old groups. In addition, CS in the 1- to 2-kHz range was
      greater than in the 4- to 6-kHz range for all ages, but especially for the old
      group. These findings suggest that a functional decline of the MOC system with
      age precedes OHC degeneration. Moreover, the MOC system maintains better function
      in the 1- to 2-kHz range than in the 4- to 6-kHz range as a function of age.

PMID- 12401967
TI  - Psychoacoustic characterization of the tinnitus spectrum: implications for the
      underlying mechanisms of tinnitus.
AB  - In this study, an original psychometric procedure was used in order to
      characterize in more detail than in previous studies the different perceptual
      components of tinnitus, i.e. auditory sensations which are perceived in the
      absence of a corresponding external acoustic stimulus. Ten subjects with chronic
      tinnitus were asked to rate on a numeric scale the contribution of elementary
      pitch sensations evoked by isolated frequency components to their overall
      tinnitus sensation. The resulting 'internal tinnitus spectra', which represented
      the estimated perceptual contribution to the tinnitus sensation as a function of
      frequency over a large range of frequencies, were found to occupy a wide
      frequency range corresponding largely to that at which hearing thresholds were
      abnormally elevated. In most cases, they exhibited a broad peak falling within
      the hearing loss range. This pattern of result suggests that in subjects with
      high-frequency hearing loss, tinnitus sensations, when present, resemble those
      evoked by high-frequency noise bands with, in some cases, a superimposed tonal
      like pitch. These results confirm and extend earlier results in the literature
      and agree with the patients' reports; their practical implications for the design
      of future studies on tinnitus and theoretical implications for the understanding
      of the neurophysiological mechanisms underlying tinnitus are discussed. The
      results of an additional experiment showed that the internal tinnitus spectrum
      could be altered by perceptual training in a fine frequency discrimination task
      with tones in the frequency range of the main peak of the tinnitus spectrum.

PMID- 12401968
TI  - The influence of voluntary muscle contractions upon the onset and modulation of
      tinnitus.
AB  - OBJECTIVE: To evaluate the frequency of tinnitus onset (in normal subjects) and
      modulation (in tinnitus patients) during muscle contractions, estimating possible
      risk factors. MATERIAL AND METHOD: This case-control study enrolled 121 tinnitus
      patients and 100 healthy volunteers who underwent medical history, ENT
      examination and 16 maneuvers of muscular contraction (head, neck and limbs).
      Modulation data were compared between patients with and without normal
      audiometry, well-defined diagnosis and symptoms of craniomandibular disorders.
      RESULTS: The ability to modulate tinnitus (65.3%) was significantly higher than
      that to originate tinnitus (14.0%). The head and neck musculature was
      significantly more efficient than that of the limbs. Audiometric pattern, well
      defined etiology and symptoms of craniomandibular disorders showed no relation to
      tinnitus modulation. CONCLUSIONS: Somatic modulation is a characteristic aspect
      of tinnitus.

PMID- 12401969
TI  - Congenital absence of the vagina: in search of the perfect solution. When, and by
      what technique, should a vagina be created?
AB  - PURPOSE OF REVIEW: To review the Mayer-von Rokitansky-Kuster-Hauser syndrome and
      to address means of diagnosis, patient education and counselling. The timing of,
      and vast options for, creation of a functional vaginal are also discussed. RECENT
      FINDINGS: The diagnosis of Mayer-von Rokitansky-Kuster-Hauser usually occurs
      during an evaluation of primary amenorrhea. Counselling and support are of great
      importance for affected young women and their families. Educational materials
      have increased with the availability of Internet web sites and there is a vast
      number of options for creation of a functional vagina; most international centers
      promote the utilization of vaginal dilators. SUMMARY: Young girls, adolescents
      and women with Mayer-von Rokitansky-Kuster-Hauser should be offered a
      comprehensive evaluation, and presented with information regarding all options
      for management and support. Ongoing psycho-social and educational support is
      extremely important. International centers that focus on congenital anomalies of
      the reproductive tract should be developed. These centers of excellence will
      facilitate long-term follow up studies to improve patient care and evidence based
      medical options.

PMID- 12401970
TI  - Adolescent androgen abnormalities.
AB  - PURPOSE OF REVIEW: Polycystic ovary syndrome is one of the most common
      endocrinopathies affecting premenopausal women. This review focuses on this major
      cause of hyperandrogenism in adolescents and young women, highlighting new
      diagnostic and therapeutic strategies that are under investigation. The
      pathophysiologic role in the disorder are the subject of several recent reports.
      RECENT FINDINGS: Recent studies have found a 33% prevalence of abnormal glucose
      tolerance in a cohort of affected adolescents, higher fasting insulin levels and
      lower insulin sensitivity, and that glucose tolerance testing appears to be
      necessary for routine screening. The effects of hyperinsulinism may be
      counteracted by insulin sensitizing agents. In adult women with polycystic ovary
      syndrome, metformin treatment reduced hyperinsulinemia and hyperandrogenemia. In
      some obese adolescents, metformin therapy resulted in declines in body mass
      index, insulin, and glucose. Restoration of regular menses may also occur after
      metformin treatment. Thus, data is accumulating that insulin-sensitizing agents
      may be helpful in decreasing the pathophysiologic effects of hyperinsulinism and
      insulin resistance associated with polycystic ovary syndrome. Other hormonal
      alterations in polycystic ovary syndrome have also been the subject of recent
      reports. Leptin secretion was found to be markedly irregular in these women.
      Elevated LH secretion may be secondary to accelerated gonadotropin-releasing
      hormone pulse generator activity, although the etiology of the pulse alterations
      is unclear. SUMMARY: Although polycystic ovary syndrome is the most common
      endocrine disorder affecting young women, it is one of the least understood,
      reflected by the wealth of research in this area. One area of focus has been the
      pathophysiologic link between insulin resistance and this disorder, including the
      effects of promising new agents to counteract these effects.

PMID- 12401972
TI  - Ovarian cysts in neonates, children and adolescents.
AB  - PURPOSE OF REVIEW: This review is intended to increase the understanding of
      normal ovarian physiology in neonates, prepubescent girls and adolescents and to
      outline management guidelines for ovarian cysts at each age. RECENT FINDINGS:
      Ultrasound has increased the level of understanding regarding the development of
      ovarian cysts. With ultrasound, ovarian cysts are recognized as a consequence of
      follicular growth and atresia that can be a normal developmental occurrence at
      all ages. Clinical experience has taught us that ovarian cysts are common,
      frequently regress without treatment and are seldom associated with malignancy.
      New management schemes are developing which rely on increased recognition of
      torsion and prompt intervention to untwist the adnexa and leave it in situ. In
      addition, new operative techniques are being developed that are less invasive and
      morbid, as well as being more conservative of ovarian tissue. SUMMARY: With the
      understanding of normal ovarian follicular growth in girls prior to full
      maturity, the normal development of ovarian cysts can be appreciated.
      Conservative therapies with observation can often replace surgical management.
      When treatment is necessary, knowledge of less invasive and morbid techniques can
      improve ovarian preservation rates.

PMID- 12401971
TI  - Fertility options for HIV patients.
AB  - PURPOSE OF REVIEW: This paper reviews the latest reproductive options for HIV
      infected couples. In light of the new treatment options and improved prognosis
      for HIV patients, policymakers have issued recent statements to guide physicians
      in the care of HIV patients desiring fertility. We will review the advances in
      reproductive technologies and ethical considerations that have led to these most
      recent statements. RECENT FINDINGS: Millions of young adults of reproductive age
      are afflicted with the HIV virus. With the improvement in treatment options for
      HIV patients and the increase in their life expectancy it is not surprising that
      many HIV patients desire children. Assisted reproductive technologies can assist
      serodiscordant couples in achieving pregnancy while at the same time minimizing
      risk of HIV transmission to the uninfected partner. Several European fertility
      clinics have a great deal of experience in providing both intrauterine
      inseminations and in-vitro fertilization to serodiscordant couples without
      seroconversion of the uninfected female partners. This is both a medical and an
      ethical issue. Guidelines from policymakers regarding this issue have changed
      over the years as a result of both changes in disease prognosis and the
      reproductive technologies. SUMMARY: Reproductive technologies provide a logical
      way to minimize HIV transmission for HIV couples desiring pregnancy. Although the
      most recent research is compelling, much more needs to be performed in order to
      establish the safety of these techniques. Protocols need to be put in place in
      order to assist physicians in better serving these patients. In addition, many
      ethical and legal issues need to be addressed before these treatments can become
      standard of care in the United States.

PMID- 12401973
TI  - Adolescent endometriosis.
AB  - PURPOSE OF REVIEW: Endometriosis can exist in the adolescent female. It can be a
      very disruptive disease and cause significant dysfunction at a time in life when
      self-esteem, school attendance, and school performance are critical to
      achievement of life goals. Approaches to diagnosis and management in the recent
      literature are reviewed, focusing on those that apply directly to the adolescent
      or indirectly, by extrapolation from work done in the adult population. Practical
      strategies for adolescent patient care are presented. RECENT FINDINGS: Recent
      research has focused on the efficacy of current treatment modalities and
      management of potential adverse side effects. Possible etiologies of
      endometriosis have been proposed, and therapies directed at those causes are
      being explored. Methods of diagnosis, both invasive and noninvasive, have been
      studied in order to determine the most effective way of diagnosing the disease.
      SUMMARY: A better understanding of the etiology of endometriosis would probably
      assist in determining the most suitable treatment strategies. Future work in
      adolescent endometriosis should focus on developing safe, minimally invasive, yet
      definitive options for diagnosis and treatment.

PMID- 12401974
TI  - Update on female pubertal development.
AB  - PURPOSE OF REVIEW: To elucidate recent findings regarding female puberty. The
      successful completion of puberty is a prerequisite for reproduction. Many later
      disorders of fertility and metabolism may develop during puberty. New more
      sensitive and specific assays provided us with possibilities for a better
      understanding of the process of puberty, and the discovery of new factors such as
      leptin evoked the hope of finding key regulators of the onset of puberty. RECENT
      FINDINGS: The secular trend towards earlier menarche appears now to have come to
      an end, but discussions about changes in the age of pubertal onset still
      continue. In a few detected cases of leptin mutations puberty has not occurred
      spontaneously. The intact secretion of leptin seems to be a necessary
      prerequisite for the onset of puberty. Apart from that, recent research has
      indicated that leptin levels mainly reflect body composition. Leptin as well as
      gonadotropins, steroids and growth hormone shows specific circadian patterns. The
      24 h pattern of leptin is similar before and after puberty, but the 24 h pattern
      of the other hormones changes. The serum concentration of inhibin B increases in
      the years preceding puberty and in early puberty, whereas inhibin A increases in
      mid to late puberty. SUMMARY: The biological significance of the changing
      circadian patterns remains to be determined. Inhibin B serum concentrations
      together with follicle-stimulating hormone may indicate remaining potential
      ovarian activity during childhood in, for example, patients with Turner syndrome,
      but more information and other possible markers are needed.

PMID- 12401975
TI  - Developments in vulvovaginal care.
AB  - Clinical studies on the myriad benign diseases of the vulva and vagina have long
      been outnumbered by emphasis on other areas of obstetrics and gynecology. The
      complexity of vulvovaginal diseases emerges in the recent literature. As
      clinicians embrace available knowledge, women's health will improve. This review
      encompasses current developments in candida, bacterial vaginosis, lichen
      sclerosus and vulvodynia.

PMID- 12401976
TI  - Adolescent sexuality and sexual behavior.
AB  - PURPOSE OF REVIEW: Adolescence is a time of self-discovery and physical, as well
      as cognitive, development. It is within this context that adolescent sexual
      development and sexual behavior occur. While curiosity and experimentation are
      normal, sexual behaviors, both coital and non-coital, place adolescents at risk
      for undesired consequences including sexually transmitted disease acquisition and
      pregnancy. Trends in adolescent sexual behavior are changing, and health care
      professionals must be aware of these trends to provide necessary medical care and
      education to this population. RECENT FINDINGS: While the sexual activity of
      teenagers garners much attention, attention must also be directed at non-coital
      activities such as masturbation, mutual masturbation and oral sex, as the riskier
      of these behaviors appear to be increasing. The trends in sexual activity and
      contraceptive use are encouraging with a decrease in the proportion of
      adolescents reporting sexual activity, and an increase in the proportion
      reporting using contraception. These trends, however, are not shared equally
      among racial groups with the greatest decline reported in the in lowest risk
      groups. Sexual minority youth continue to report a higher prevalence of high-risk
      behaviors, both sexual and non-sexual, as compared to their heterosexual peers.
      SUMMARY: These findings highlight the multiple roles health care professionals
      can play in caring for this unique population: firstly as health care providers,
      offering age appropriate, confidential health care; secondly, as reproductive
      health care educators providing factual, balanced, and realistic information to
      both teenagers and the community; and thirdly, as advocates lobbying for greater
      education and services for this at-risk population.

PMID- 12401977
TI  - Adolescent dating violence and date rape.
AB  - PURPOSE OF REVIEW: In this review we intend to examine recent literature on
      dating violence among female adolescents, including prevalence, risk factors,
      sequelae, screening practices, and potential interventions. RECENT FINDINGS:
      Dating violence is perpetrated by both males and females and occurs frequently
      within heterosexual dating relationships. Attitudes toward physical aggression,
      including those of peers, and abuse by siblings predict later violence as victim
      and perpetrator. Victims of childhood or dating violence may be at greater risk
      of developing eating disorders. New strategies and measures to promote screening
      are available. SUMMARY: Dating violence occurs among all groups of adolescents
      with common and unique risk factors for dating violence found across adolescents
      grouped by race/ethnicity, sex, and prior victimization. Efforts to decrease
      dating violence should (1) increase the use of screening tools that measure
      victimization as well as attitudes and contextual parameters that promote dating
      violence; (2) increase self-efficacy to negotiate safer sex; (3) reduce the
      use/abuse of alcohol and other drugs that facilitate dating violence; and (4)
      eliminate the influence of negative peer behavior. Interventions to prevent
      dating violence will likely also reduce rates of unintended pregnancies, HIV, and
      sexually transmitted diseases among adolescents.

PMID- 12401979
TI  - Current opinion on the classification and definition of genital tract prolapse.
AB  - PURPOSE OF REVIEW: There are few issues in obstetrics and gynecology that seem so
      readily apparent but are in actuality replete with confusion than the diagnosis
      of genital tract prolapse. This stems from the difficulties in defining genital
      tract prolapse and from the long history of turmoil regarding how to classify and
      describe it. In the past 5-10 years our specialty has begun to make inroads into
      these issues. Finally, there is an accepted classification system and because of
      this we are beginning to recognize what represents normal vaginal support versus
      genital tract prolapse. RECENT FINDINGS: In 1993 the confusion regarding the
      classification of genital tract prolapse was documented by a very thorough review
      of the literature; in response, the Pelvic Organ Prolapse Quantification system
      was developed. Subsequent to this, several articles have begun to define the
      epidemiology of genital tract prolapse and this is providing a glimpse of what
      differentiates pathologic genital tract prolapse from normal support. SUMMARY: We
      can now reliably classify and describe genital tract relaxation and imply what is
      normal support versus pathological genital tract prolapse. However, we still have
      not defined genital tract prolapse, determined its prevalence or provided the
      clinician with a simple and reliable means of testing for its presence or
      absence.

PMID- 12401980
TI  - The role of electrophysiology in the evaluation of incontinence and prolapse.
AB  - PURPOSE OF REVIEW: Apart from histopathology, electrophysiological methods are
      the only tests to reveal neuromuscular involvement in the absence of gross
      anatomical lesions. They have played a major role in establishing the
      neuromuscular lesion due to vaginal delivery as a risk factor for incontinence
      and pelvic organ prolapse, but there is no consensus on the usefulness of
      different methods. It is timely to reevaluate their validity, and their role in
      urogynecology. RECENT FINDINGS: The most important development is the move
      towards standardization of the diagnostic approach, based on computer assisted
      quantified techniques of concentric needle electromyography. Studies using less
      operator biased techniques have confirmed subtle pelvic floor muscle changes in
      parous women. Reports on usefulness of different tests as predictors of treatment
      outcome are controversial. SUMMARY: Standardization of concentric needle
      electromyography strengthened the position of this test as practical and
      informative. Neuromuscular changes following vaginal delivery have been
      reconfirmed, but the usefulness of particular electrophysiological tests in the
      individual patient needs to be further researched. Valid clinical
      neurophysiological methods remain valuable as research tools for incontinence and
      prolapse pathophysiology.

PMID- 12401981
TI  - Complications of urethral sling procedures.
AB  - PURPOSE OF REVIEW: To review the current literature on complications of
      suburethral slings used to treat stress urinary incontinence in the female.
      RECENT FINDINGS: The surgical treatment of female urinary incontinence has
      changed considerably since the development of the tension-free vaginal tape
      procedure, introduced by Ulmsten in 1995. As the follow-up for the first studies
      is now more than 5 years, the 'long-term' results of the technique can be
      evaluated. Furthermore, now that the learning phase has been completed and the
      technique can be considered to be well mastered, it is interesting to review the
      complications inherent in this technique, their frequency, including those rarer
      complications that are sometimes associated with severe morbidity, and to
      consider the ways in which these complications can be prevented or treated. The
      development of the tension-free vaginal tape procedure has not prevented the
      development of other types of suburethral sling, but on the contrary, has
      promoted the development of these alternatives by the use of various sling
      insertion techniques, and especially various types of materials. There has even
      been a renewed interest in materials that have been known for a long time
      (heterologous and autologous materials) in some recent papers, and new synthetic
      suburethral slings have been proposed with the objectives of combining low
      morbidity, safety and efficacy. SUMMARY: Monofilament polypropylene meshes can be
      used safely to perform suburethral slings and seems to be the most suitable
      material in this indication according to the existing literature.

PMID- 12401982
TI  - Sacral neuromodulation: new applications in the treatment of female pelvic floor
      dysfunction.
AB  - PURPOSE OF REVIEW: The first sacral nerve stimulators implanted by Tanagho and
      Schmidt (1981) were performed for the indications of urinary urge incontinence,
      urgency-frequency, and nonobstructive urinary retention. Since that time,
      observations have been made for benefits beyond voiding disorders. These
      additional benefits have included re-establishment of pelvic floor muscle
      awareness, resolution of pelvic floor muscle tension and pain, decrease in
      vestibulitis and vulvadynia, decrease in bladder pain (interstitial cystitis),
      and normalization of bowel function. RECENT FINDINGS: Therapy for fecal
      incontinence in patients with a structurally intact sphincter mechanism appears
      to be very promising. Investigators agree that there is a role for sacral nerve
      stimulation in patients with urge fecal incontinence that have failed
      conservative efforts. Objective manovolumetric testing shows an increase in
      resting pressure, an increase in voluntary contraction pressure, a decrease in
      rectal volumes which cause first urge, a decrease in rectal volume to initiate
      first urge to defecate, and an increase in duration of maximum squeeze pressure.
      Intractable interstitial cystitis is defined as patients that have failed
      conventional therapy. Historically, the only option remaining was extirpative
      surgery or diversion. Maher et al. reported on patients with intractable
      interstitial cystitis who had undergone sacral nerve stimulation. They found that
      73% of these patients had a reduction in pelvic pain, daytime frequency,
      nocturnal urgency and an increase in average voided volumes. The final area of
      interest concerns refractory pelvic pain. Siegal et al. reported a decrease in
      severity, number of hours of pain, and improved quality of life measures in
      patients who underwent transforamenal sacral nerve stimulations. These patients
      had all failed conventional pain therapy. SUMMARY: While the data are encouraging
      in these new arenas of pelvic floor disorders, investigators acknowledge the need
      for multicenter, statistically powered studies to evaluate the validity of these
      findings.

PMID- 12401984
TI  - Recurrent urinary tract infection in the female.
AB  - PURPOSE OF REVIEW: Recurrent urinary tract infection is a common problem and can
      affect women of all ages, particularly the elderly and pregnant women.
      Obstetricians and gynaecologists need to have up-to-date knowledge of the
      diagnosis, pathophysiology and management of this condition. RECENT FINDINGS: The
      diagnosis of urinary tract infection is made on the basis of symptoms and
      bacteriuria of more than 103 bacteria per ml. Host and bacterial virulence
      factors are important in the pathogenesis of recurrent urinary tract infections.
      General host factors predisposing to recurrent infection are genetic factors,
      ageing, the menopause, urogenital dysfunction, sexual behaviour, and previous
      pelvic surgery. Urinary tract infection is common in pregnancy, and recent
      studies have suggested an association with mental retardation and developmental
      delay. Women with recurrent urinary tract infection in pregnancy should be
      considered for long-term antibiotic prophylaxis. Intravaginal oestrogens and
      cranberry juice have been found to be effective for prevention, although more
      research is required. Women with recurrent urinary tract infection should have at
      least a 3-day course of trimethoprim or cotrimoxazole, or a 5-day course of beta
      lactams or nitrofurantoin, with perhaps a 10-day course in the elderly. Women
      with frequent urinary tract infection (more than three episodes per year) should
      be offered prophylactic antibiotics, which can be patient-initiated, postcoital,
      or long-term low-dose therapy. In the future, vaccines against specific
      uropathogenic bacteria may be useful in urinary tract infection prophylaxis.
      SUMMARY: More research is required, by all medical disciplines, on various
      aspects of urinary tract infection.

PMID- 12401983
TI  - The role of synthetic and biological prostheses in reconstructive pelvic floor
      surgery.
AB  - PURPOSE OF REVIEW: Uterovaginal prolapse and urinary incontinence are common
      problems whose pathogenesis remains unclear. As life expectancy increases,
      significantly greater numbers of women will present with pelvic floor prolapse
      and incontinence requiring surgical intervention. Currently, the lifetime risk of
      undergoing prolapse or continence surgery in the USA is one in 11, and up to 30%
      of patients will require repeat prolapse and 10% repeat continence surgery. In an
      attempt to improve surgical outcomes and to preserve vaginal capacity and coital
      function, a number of synthetic and biological prostheses have been developed.
      This review aims to look at the controversies that exist as the 'ideal'
      prosthetic material is developed. RECENT FINDINGS: The recent literature has
      reflected the increasing interest in the use of biological prostheses
      (Allograft/Xenograft) and synthetic absorbable meshes. There has been a focus on
      the risk factors for erosion seen with the use of synthetic non-absorbable
      material and a review of techniques for the reduction and management of this
      complication. The advent of mesh placement in minimally invasive continence
      surgery (tension-free vaginal tape, intravaginal sling, and Supra Public ARC) is
      now seeing surgical success to 5 years, but the reporting of complications
      remains inconsistent. SUMMARY: The use of prosthetics in pelvic floor and
      continence surgery is an evolving field. Further randomized controlled trials are
      required to evaluate the role of both biological and synthetic prostheses in
      reconstructive surgery, to determine which type of prosthesis is most suitable
      for specific procedures. Prosthetic reinforcement should not be used to replace
      good surgical techniques.

PMID- 12401985
TI  - Surgical intervention for faecal incontinence in women: an update.
AB  - PURPOSE OF REVIEW: In this review we intend to overview the operations available
      for faecal incontinence with particular reference to recently published articles.
      RECENT FINDINGS: Operations benefiting faecal incontinence in women are direct
      sphincter repair, dynamic graciloplasty, artificial anal sphincter and sacral
      nerve stimulation. Considerable benefit was demonstrated with these operations
      but not without complications. Studies with longer follow-up are required for
      better assessment of these operations. SUMMARY: Surgery for faecal incontinence
      is indicated after failure of non-operative measures. Good results may be
      achieved.

PMID- 12401986
TI  - Split hand/split foot, iris/choroid coloboma, hypospadias and subfertility: a new
      developmental malformation syndrome?
AB  - This paper presents a patient with the following malformations: split hand and
      split foot on the left side, a hypoplastic fifth ray of the right hand and a
      hypoplastic first ray of the right foot with a small cleft between the first and
      second ray; eye abnormalities which consist of a complete iris coloboma of the
      left eye in an atypical position (cranio-temporal) and a coloboma of the choroid
      in the right eye; a glandular hypospadias and terato-zoospermia. Since split
      hand/split foot can be caused by mutations in the p63 gene, mutation analysis of
      this gene was performed. However, sequencing analysis did not reveal a mutation.
      This malformation complex may represent a new syndrome.

PMID- 12401988
TI  - Guadalajara camptodactyly type III: a new probably autosomal dominant syndrome.
AB  - A Mexican family is presented with the main clinical features of camptodactyly, a
      distinctive facial appearance because of ocular hypertelorism, telecanthus,
      symblepharon and spinal defects. Other clinical manifestations included: multiple
      nevi, simplified ears, retrognathia, congenital shortness of the
      sternocleidomastoid muscle, thin hands and feet, a small penis and mild mental
      retardation. Radiographic studies revealed spina bifida occulta at cervical and
      dorso-lumbar levels, increased bone trabeculae, cortical thickening and delayed
      bone age. The presence of five affected members through four generations suggests
      autosomal dominant inheritance although no male-to-male transmission was
      documented. The authors propose this as a new entity, and have designated it
      Guadalajara camptodactyly type III.

PMID- 12401987
TI  - Dominant inheritance of cleft palate, microstomia and micrognathia--possible
      linkage to the fragile site at 16q22 (FRA16B).
AB  - We report a family in which a father and his three children are affected with
      microstomia, micrognathia and partial or complete cleft of the hard and soft
      palate. The probands were non-identical twins, a boy and a girl, both noted to
      have the above features soon after birth. Their father was diagnosed with a
      submucous cleft of the palate at the age of 4 years and their older brother has
      milder facial features and a bifid uvula. All affected family members were
      demonstrated to have a fragile site on chromosome 16q22 but otherwise normal
      karyotypes. Of interest is a previously described family with autosomal dominant
      inheritance of U-shaped cleft palate, microstomia, micrognathia and oligodontia
      where all affected members were shown to have the fragile site at 16q22 in a
      proportion of their cells [Bettex et al. (1998) Eur J Pediatr Surg 8:4-8]. We
      propose that these two conditions are the same and represent a distinctive
      syndrome involving aberrant orofacial development that may be linked to the
      fragile site at 16q22.

PMID- 12401989
TI  - Food aversion and facial dysmorphism--a newly described syndrome?
AB  - We report three children with food aversion and characteristic facial
      dysmorphism, long digits and genitourinary abnormality. Interrogation of the
      London Dysmorphology Database suggests that this is a previously unreported
      syndrome.

PMID- 12401990
TI  - A variant microcephalic osteodysplastic slender-bone disorder with growth hormone
      deficiency and a pigmentary retinopathy.
AB  - We present the case of a 3-year-old boy with post-natal growth failure,
      microcephaly, developmental delay, facial dysmorphism, an evolving pigmentary
      retinopathy, pituitary hypoplasia, micropenis, and growth hormone (GH)
      deficiency. He has a microcephalic osteodysplastic slender-bone disorder with
      disharmonic delayed osseous maturation, most closely resembling patients with
      microcephalic osteodysplastic primordial dwarfism type II (MOPD II). Intrauterine
      growth retardation, a universal finding in the MOPD II, was absent in our
      patient.

PMID- 12401991
TI  - Apparently new autosomal dominant Spondyloepimetaphyseal dysplasia: gonadal
      mosaicism onset.
AB  - We report a family in which an apparently previously undescribed form of
      Spondyloepimetaphyseal dysplasia (SEMD) presented after probable gonadal
      mosaicism occurred and is inherited in an autosomal dominant mode. The other
      autosomal dominant SEMDs are compared.

PMID- 12401992
TI  - Dysplastic cortical hyperostosis (Kozlowski-Tsuruta syndrome): report of a second
      case.
AB  - We report a fetus from a pregnancy that was terminated at 26 weeks gestation for
      hydrops and short limb skeletal dysplasia. The parents were first cousins. Post
      mortem examination showed pulmonary hypoplasia and hepatomegaly. The radiographs
      showed shortening and cortical thickening of all long bones. The cortical
      thickening was most marked in the long bones, ribs, clavicles and scapulae but
      spared the skull vault, facial bones and pelvis. There were coronal clefts in the
      lower lumbar vertebrae. The clinical and radiological features of this fetus
      conform to those reported in a stillborn male by Kozlowski and Tsuruta in 1989
      (Br J Radiol 62:376-378). This is the second reported case of this condition and
      confirms that it is a distinct and recognisable, lethal skeletal dysplasia. The
      parental consanguinity in our patient suggests that this condition may be
      inherited in an autosomal recessive manner.

PMID- 12401993
TI  - A Schinzel-Giedion-like syndrome--a milder version or a separate condition?
AB  - We report two 12-year-old monozygotic twins followed from birth. Their features
      include midface hypoplasia, a prominent forehead, coarse features, sensorineural
      deafness, short stature with thoracic kyphosis and lumbar lordosis and
      intellectual delay. As they have developed, their features have been reminiscent
      of a storage disorder but mucopolysaccharidoses, mucolipidoses and gangliosidoses
      have been excluded by biochemical testing. We discuss the phenotypic overlap with
      the Schinzel-Giedion syndrome but highlight the important differences.
      Individuals with Schinzel-Giedion syndrome tend to have renal and cardiac
      malformations and to have a very poor outlook, often dying in the first 3 years
      of life. We suggest that these twins have a previously undescribed Schinzel
      Giedion like syndrome.

PMID- 12401994
TI  - A male with polysyndactyly, linear skin defects and sclerocornea. Goltz syndrome
      versus MIDAS.
AB  - Focal dermal hypoplasia (FDH) or Goltz syndrome is a rare clinical syndrome
      presenting with cutaneous, skeletal, dental, ocular, central nervous system and
      soft-tissue defects. We report on a male infant with characteristic skin defects
      of the face, trunk and extremities, polysyndactyly and unusual ocular and brain
      findings. He had sclerocornea of the right eye, anterior persistent hyperplastic
      primary vitreous of the left eye and hydrocephalus. Clinical findings support the
      diagnosis of Goltz syndrome. The clinical picture of Goltz syndrome is compared
      with that of MIDAS syndrome.

PMID- 12401995
TI  - VATER--tibia aplasia association: report on two patients.
AB  - We report two patients with oesophageal atresia, tracheo-oesophageal fistula and
      unilateral tibial aplasia. The karyotype in both patients was normal and both
      cases were sporadic. The congenital defects of the children can be regarded as an
      uncommon variant of VA(C)TER(L) association. Recently Basel and Goldblatt [(2000)
      Clin Dysmorphol 9:205-208] reported a similar patient with a VATER-tibia aplasia
      association.

PMID- 12401996
TI  - Mental retardation, ptosis and polydactyly: a new autosomal recessive syndrome?
AB  - Three affected sibs in a consanguineous family with short stature, mental
      retardation, downslanting palpebral fissures, ptosis and polydactyly are
      described. There was no hypogonadism or pigmentary retinopathy. They were thin in
      childhood and while two of the postpubertal sibs have a stocky build none is
      obese. We propose that this could be a previously unreported autosomal recessive
      syndrome.

PMID- 12401997
TI  - A possible relationship between Beckwith-Wiedemann syndrome and prune belly
      syndrome.
AB  - A new case of the association of the Beckwith-Wiedemann and prune belly syndrome
      is reported and the aetiology of the syndromes discussed.

PMID- 12401998
TI  - Distal aphalangia, an extra metatarsal, short stature and microcephaly: a second
      case.
AB  - A 17-year-old male with distal aphalangia, an extra metatarsal, short stature and
      microcephaly is described. This is the second case with these features to be
      reported. In addition this case has scolios and megaureter. There was
      consanguinity of the parents suggesting the possibility of autosomal recessive
      inheritance.

PMID- 12401999
TI  - Spontaneous chylothorax in a case of cardio-facio-cutaneous syndrome.
AB  - A patient is reported who fulfills the diagnostic criteria for severe cardio
      facio-cutaneous syndrome who developed a chylothorax. Lymphatic abnormalities
      have previously only been reported in Noonan syndrome.

PMID- 12402000
TI  - A fetus suggesting an extension of theXK-aprosencephaly spectrum phenotype.
AB  - We report a fetus with atelencephaly, bilateral radial aplasia/hypoplasia,
      ventriculoseptal defect and megacolon, this combination of anomalies being
      consistent with the diagnosis of XK-aprosencephaly syndrome. The facial
      dysmorphology of this fetus differs from that previously reported and together
      with reports on overlapping phenotypes suggests an extension of the XK
      aprosencephaly spectrum.

PMID- 12402001
TI  - Cost-effective diagnosis of acoustic neuromas: a philosophical, macroeconomic,
      and technological decision.
AB  - OBJECTIVE: Our goals were to define the most sensitive techniques of acoustic
      neuroma diagnosis, to examine their relative costs, and to propose diagnostic
      modality selection given the rarity of acoustic neuroma incidence and given the
      other costs that society faces in more commonly encountered diseases. METHODS: We
      conducted a MEDLINE search of the English language from 1966 to 2001 using the
      following keywords: acoustic neuroma, acoustic tumor, vestibular schwannoma,
      diagnosis, cost effectiveness, MRI, auditory brainstem response, brainstem
      audiometric evoked response, incidence, and prevalence. RESULTS: Although
      magnetic resonance imaging with gadolinium remains the most sensitive diagnostic
      modality in the discovery of acoustic neuromas, its cost may be prohibitive for
      some societies. CONCLUSION: Which modality to use in acoustic neuroma diagnosis
      is just as much a philosophical and macroeconomic question as a technological
      one. CLINICAL SIGNIFICANCE: The cost of a timely diagnosis of acoustic neuromas
      must be weighed against using resources for other, more pressing, health
      concerns.

PMID- 12402002
TI  - Histopathologic changes in the vestibule after cochlear implantation.
AB  - OBJECTIVE: The study goal was to determine the histopathologic changes of the
      vestibular end organs after cochlear implantation and to relate them to clinical
      performance. STUDY DESIGN: To differentiate the effect of implantation from the
      disease process that originally destroyed the hearing, 11 pairs of temporal bones
      from unilateral implantees were studied with light microscopy to compare the
      vestibular damage in the implanted ears with that in the nonimplanted ears.
      RESULTS: Significant histopathologic damage of the vestibular end organs was
      noted in 6 patients (54.5%). The major histopathologic findings were fibrosis in
      the vestibule, saccule membrane distortion, new bone formation, and reactive
      neuromas. The scala vestibuli involvement, as a result of damage to the osseous
      spiral lamina or basilar membrane in cochlear basal turn, was highly correlated
      with vestibular damage (75%). CONCLUSIONS: Although the clinical incidence of
      balance disturbance after cochlear implantation is low, damage of the vestibular
      end organs may occur and be asymptomatic. Keeping the electrode array in the
      scala tympani will minimize vestibular damage.

PMID- 12402003
TI  - Chondrocyte repopulation of allograft cartilage: a preliminary investigation and
      strategy for developing cartilage matrices for reconstruction.
AB  - OBJECTIVE: To evaluate the ability of devitalized cartilage to sustain
      repopulation by allogenic chondrocytes and to use 2-photon microscopy to assess
      cultured chondrocyte viability. STUDY DESIGN AND SETTING: At an academic medical
      center, we conducted experimental analysis of lagomorph nasal septa devitalized
      by subjecting them to either 1) chemical dehydration in ethanol, 2)
      lyophilization (freeze dry), or 3) repeated freeze-thaw (12 cycles) in liquid
      nitrogen. The processed cartilages were seeded with chondrocytes isolated from
      the septa of either the same rabbit or another rabbit and cultured for 4 weeks.
      They were assessed with a variety of techniques. RESULTS: The seeded chondrocytes
      maintained viability on the devitalized cartilage throughout the study period.
      Two-photon microscopy was effective in assessing the viability of cultured
      chondrocytes. CONCLUSION: Isolated lagomorph chondrocytes can be maintained in
      allogenic cartilage grafts devitalized using conventional physicochemical
      techniques. SIGNIFICANCE: This is the first experimental study to demonstrate
      that cultured chondrocytes can be maintained on devitalized cartilage.

PMID- 12402004
TI  - Hepatocyte growth factor/scatter factor stimulates mitogenesis and migration of a
      head and neck squamous cell carcinoma cell line.
AB  - OBJECTIVE: We sought to assess the effect of extracellular matrix and hepatocyte
      growth factor/scatter factor (HGF/SF) on the growth and motility of cultured
      squamous cell carcinoma of the head and neck (SCCHN) cells. METHODS: Cultured
      cells were incubated in the presence of HGF/SF. The effect of HFG/SF on cell
      growth, motility, and phosphorylation of the signaling proteins FAK and Erk was
      determined. RESULTS: HGF/SF is both mitogenic and motogenic to the human SCCHN
      cell line FaDu. Incubation of FaDu cells in the presence of HGF/SF led to a rapid
      increase in phosphorylation of both FAK and the growth-promoting kinase Erk.
      HGF/SF-induced phosphorylation of FAK and Erk was observed in both detached and
      attached SCCHN cells. However, phosphorylation was much greater in attached
      cells. CONCLUSIONS AND SIGNIFICANCE: The mitogenic and motogenic activities of
      HGF/SF may contribute to the pathogenesis of SCCHN in vivo.

PMID- 12402005
TI  - Efficacy of selective lymph node dissection in clinically negative neck.
AB  - OBJECTIVE: The purpose of this study was to evaluate the efficacy of selective
      neck dissection (SND) for elective treatment of the clinically negative neck in
      head and neck squamous cell carcinoma (SCC). METHODS: A retrospective review was
      undertaken on 91 previously untreated patients with T1-4 SCC of oral cavity (23),
      oropharynx (5), hypopharynx (7), larynx (56), and clinically negative neck (N0),
      undergoing 126 SND from January 1990 to March 1999 at a single institution.
      Twenty-five patients received postoperative radiation therapy on the basis of
      histologic evidence of >2 positive nodes, extracapsular spread (ECS), and/or the
      presence of advanced primary lesion. RESULTS: On pathologic examination the
      average number of lymph nodes was 20.5 per neck, occult disease was detected in
      14 (11.11%) of 126 necks; of necks with positive nodes, 6 (42.85%) of 14 had ECS.
      The median follow-up was 36 months. Overall recurrence rate (local, regional, and
      distant) was 12.8% (11 of 91). Recurrent disease developed in the neck of one
      patient, outside the dissected field. There was no difference in recurrence rate
      between pN0 and pN+ patients, as well as between pN+ with or without ECS. Overall
      survival rate was 84% (77 of 91), with a statistically significant difference
      between pN0 and pN+ necks. CONCLUSION: SND seems to be a pragmatic approach that
      is as effective as comprehensive procedures for staging and treating the
      clinically negative neck.

PMID- 12402006
TI  - Thyroidectomy using the harmonic scalpel: analysis of 105 consecutive cases.
AB  - OBJECTIVE: The purpose of this report was to evaluate the technical benefits, if
      any, of thyroidectomy using the harmonic scalpel versus conventional
      thyroidectomy. STUDY DESIGN: One hundred five consecutive patients underwent
      thyroidectomy over 1 year with use of the harmonic scalpel. They were compared
      with a group of 20 patients who underwent thyroidectomy 1 year earlier using
      conventional techniques. RESULTS: The incision length for those undergoing
      thyroidectomy with the harmonic knife averaged 4.5 cm compared with 5.5 cm for
      the conventional thyroidectomy group. The operating time for a hemithyroidectomy
      averaged 50 minutes for the harmonic scalpel group versus 80 minutes for the
      conventional technique. The operating time for a total thyroidectomy averaged 80
      minutes for the harmonic scalpel group versus 120 minutes for the conventional
      thyroidectomy group. CONCLUSION: The use of the harmonic scalpel in thyroid
      surgery offers several advantages over the conventional technique. The incision
      length is shorter and the operating time is reduced. Bleeding is negligible and
      complications are few. SIGNIFICANCE: The harmonic scalpel, whose use was
      pioneered in laparoscopic surgery, offers the thyroid surgeon the ability to
      safely and expeditiously control the feeding vessels through a limited field.

PMID- 12402007
TI  - Predicting calcium status post thyroidectomy with early calcium levels.
AB  - OBJECTIVE: The study goals were to predict postoperative normocalcemia and
      hypocalcemia after total thyroidectomy using calcium levels and to assess the
      value of a standardized protocol in managing the total thyroidectomy patient.
      STUDY DESIGN: We conducted a prospective study encompassing 68 patients
      undergoing a total thyroidectomy using a standardized protocol. Blood to measure
      postoperative calcium levels was drawn at 6, 12, and 20 hours and then twice
      daily thereafter. Calcium slope was calculated from the 6- and 12-hour serum
      corrected calcium levels. RESULTS: Logistic regression analysis allowed the
      comparison of the 6- and 12-hour calcium slope versus proportion of normocalcemic
      patients postoperatively. A slope of +0.02 had a 97% chance of remaining
      normocalcemic (p = 0.0007). CONCLUSION: Successful prediction of calcium status
      post total thyroidectomy can be achieved using the slope of the 6- and 12-hour
      calcium levels. The risk of developing severe hypocalcemia can also be predicted
      with these slope values. Implementation of the protocol resulted in a significant
      reduction in the duration of hospital stay for patients who remain normocalcemic.

PMID- 12402008
TI  - Cystic cervical metastases: incidence and diagnosis using fine needle aspiration
      biopsy.
AB  - BACKGROUND: Seventeen patients presenting with a cystic cervical metastasis were
      identified after either having undergone excision of a cyst, initially diagnosed
      as a branchial cyst but subsequently found to be malignant, or after having had
      fluid aspirated from a neck mass that ultimately proved to be malignant while
      undergoing fine needle aspiration biopsy. METHODS: Patients had primary cancer
      documented at a variety of primary sites, including hypopharynx (3 patients),
      oropharynx (2 patients), lower lip (2 patients), nasopharynx, supraglottis, oral
      cavity, and prostate (1 patient each). Six cases (35%) remained occult. RESULTS:
      In nearly half of the cases (8 of 17), there was no evidence of the primary
      cancer at presentation. In the same period, 25 branchial cysts were encountered,
      giving an incidence of unsuspected carcinoma in cervical cysts of 24% (8 of 33).
      CONCLUSION: In contrast to previous studies in which smaller numbers of patients
      underwent the procedure, we found fine needle aspiration to be very helpful in
      the assessment of these lesions, having a sensitivity of 73% in diagnosing
      malignancy.

PMID- 12402009
TI  - Comparison of methods for determining cricopharyngeal intrabolus pressure in
      normal patients as possible indicator for cricopharyngeal myotomy.
AB  - OBJECTIVE: We sought to compare methods for determining intrabolus
      cricopharyngeal pressure as a possible indicator for cricopharyngeal myotomy.
      STUDY DESIGN: We determined multiple intrabolus pressures in the cricopharyngeal
      region of 20 normal volunteers, of whom 12 were 20 to 35 years old and 8 were
      older than 75 years. Data were collected using a commercially available
      manofluorography system and a 6-sensor unidirectional solid-state 2- x 4-mm
      catheter. Each subject underwent 5 5-mL and 5 10-mL liquid barium swallows. Data
      were analyzed, and young subjects were compared with old subjects. RESULTS: The
      mean mid-bolus pressures in young subjects were 5.2 +/- 4.9 mm Hg and 7.2 +/- 6.5
      mm Hg for the 5-mL and 10-mL swallows, respectively, and in older subjects, 10.8
      +/- 8.8 mm Hg and 12.3 +/- 7.4 mm Hg. The mean gradient pressures across the 3-cm
      cricopharyngeal region in young subjects were 2.02 +/- 5.0 mm Hg, and -0.91 +/-
      4.8 mm Hg for the 5-mL and 10-mL swallows, respectively, and for older subjects,
      4.38 +/- 3.1 mm Hg and 2.82 +/- 3.4 mm Hg. CONCLUSIONS: Cricopharyngeal
      intrabolus pressures were lower in young than in older subjects. The mid-bolus
      pressure and the gradient pressure across the cricopharyngeal region appeared to
      be the most consistent methods for evaluating intrabolus pressures. SIGNIFICANCE:
      Intrabolus pressure anomalies in the cricopharyngeal region have been proposed as
      an indicator for selecting patients who would benefit from cricopharyngeal
      myotomy. The methods of determining intrabolus pressures vary, with resulting
      variations in recommendations.

PMID- 12402010
TI  - Endoscopic treatment of Zenker's diverticulum using CO2 laser.
AB  - OBJECTIVES: The objective of the present study was to review the technique of
      endoscopic laser-assisted esophagodiverticulostomy (ELAED) for the treatment of
      Zenker's diverticulum. METHODS: We reviewed 83 cases of ELAED performed for the
      treatment of Zenker's diverticuli during the past decade. RESULTS: ELAED-treated
      patients had a reduced hospital stay and were able to start an oral diet earlier
      than were patients who underwent other surgical procedures. Two (2.4%) of our
      patients developed small fistulas, which closed spontaneously. An additional 2
      (2.4%) of our patients required conversion to an open approach due to inadequate
      endoscopic exposure, and 5 (6%) required a revision endoscopic procedure for
      persistent symptoms. CONCLUSIONS: Our series of 83 patients treated at 2 large
      academic centers during the past decade with an average follow-up of 4 years
      demonstrates that ELAED is a safe and effective procedure for the management of
      Zenker's diverticulum.

PMID- 12402011
TI  - Preliminary findings from a prospective, randomized trial of two palatal
      operations for sleep-disordered breathing.
AB  - OBJECTIVES: We compared the efficacy of 2 palatal surgical procedures in the
      treatment of patients with mild sleep-disordered breathing (SDB). STUDY DESIGN
      AND SETTING: We conducted a prospective, randomized, crossover surgical trial at
      a university hospital. METHODS: Twenty patients with mild SDB for whom
      conservative treatment failed were identified and consecutively enrolled into an
      institutional review board-approved surgical protocol. They were randomly
      assigned to undergo either radiofrequency ablation of the palate (RFAP) for a
      planned 3-stage treatment or laser-assisted uvulopalatoplasty (LAUP), also for 3
      stages of treatment, using a CO(2) laser. Parameters assessed included severity
      of SDB (polysomnography), subjective and objective loudness of snoring (visual
      analog scale and SNAP recording), sleepiness (Epworth Sleepiness Scale), and
      anatomic changes (upper airway endoscopy), as well as demographic factors.
      Patients not achieving satisfactory improvement in their condition were crossed
      over to the alternative surgical therapy for attempted salvage. RESULTS:
      Seventeen of the enrolled patients have completed the protocol. Ten of these were
      randomized to the RFAP group, and 7 to the LAUP group. Six of the RFAP patients
      (60%) achieved a satisfactory resolution of their snoring, and 4 failed and were
      salvaged with LAUP. Six of the LAUP patients (86%) achieved a satisfactory
      resolution of their snoring, and 1 patient failed and was salvaged with nasal
      surgery. One patient who was initially cured had a relapse after 9 months and was
      successfully salvaged with RFA. CONCLUSION: Prospective, randomized trials of
      surgery for SDB are possible. Preliminary findings from the current protocol
      reveal a slight advantage of LAUP over RFAP but with a greater degree of
      discomfort postoperatively.

PMID- 12402012
TI  - Fungus-specific IgG and IgE in allergic fungal rhinosinusitis.
AB  - OBJECTIVE: Our study goal was to study fungus-specific immunoglobulins G (sIgG)
      and E (sIgE) in polypoid rhinosinusitis with and without evidence of allergic
      fungal rhinosinusitis (AFS). STUDY DESIGN AND SETTING: A prospective analysis was
      conducted of fungal sIgG and sIgE using a 9-mold RAST panel in 13 AFS, 11 AFS
      like, and 27 non-AFS polypoid rhinosinusitis patients. Nonpolyp controls included
      17 volunteers with allergic rhinitis and 11 with no atopic history. RESULTS: All
      groups had elevated fungal sIgG levels. Polyps, increasing polyp severity, and
      AFS were associated with elevated fungal sIgG to a greater number of molds. The
      AFS group had sIgE elevations (>or=class II) to an average of 5 molds versus only
      0.1 in the non-AFS polyp group. Total IgE was 971 U/mL versus 64 U/mL,
      respectively. CONCLUSIONS: Multiple elevations of fungal sIgE are adequate
      diagnostic evidence of these fungi when fungal cultures and histologic
      examinations are negative in diagnosing AFS. The significance of increased fungal
      sIgG remains unclear. SIGNIFICANCE: Early recognition of AFS may be facilitated
      by screening polypoid rhinosinusitis patients with total serum IgE and RAST
      testing.

PMID- 12402013
TI  - A comparison of tonsillectomy with the harmonic scalpel versus electrocautery.
AB  - OBJECTIVE: We sought to test whether the use of the harmonic scalpel would cause
      less pain and more rapid recovery in tonsillectomy patients versus the use of
      electrocautery. DESIGN AND SETTING: In a private practice community hospital, we
      conducted a prospective nonrandomized comparison of 156 pediatric tonsillectomy
      cases. Local anesthetic infiltrations and steroids were used at the discretion of
      the surgeon. Outcome variables consisted primarily of immediate- and mid-term
      pain, pain medications required, time to eating, morbidities and charges.
      RESULTS: There were no differences between the groups on an intention-to-treat
      basis except for costs, which were higher in the harmonic scalpel group. When
      rescue use of electrocautery was required to control bleeding in the in the
      harmonic scalpel patients, more pain and longer times to taking food were noted.
      CONCLUSIONS: Used with discretion the harmonic scalpel is equivalent to
      electrocautery for tonsillectomy. SIGNIFICANCE: The harmonic scalpel does not
      provide a major benefit over more conventional methods of tonsillectomy.

PMID- 12402014
TI  - Broken glass mercury thermometer: a difficult airway foreign body.

PMID- 12402015
TI  - Stapedotomy above the facial nerve in a congenitally malformed ear: a case
      report.

PMID- 12402016
TI  - Congenital cholesteatoma of the mastoid region.

PMID- 12402017
TI  - Wegener's granulomatosis presenting in the sinus and orbit.

PMID- 12402018
TI  - Intrathyroidal parathyroid carcinoma presenting with only hypercalcemia.

PMID- 12402019
TI  - Bullous pemphigoid associated with parotid carcinoma.

PMID- 12402020
TI  - Benign mesenchymoma of the tongue.

PMID- 12402021
TI  - Congenital cholesteatoma of the tympanic membrane.

PMID- 12402022
TI  - A new experimental murine aspergillosis model to identify strains of Aspergillus
      fumigatus with reduced virulence.
AB  - Experimental animals are an obligate screen to investigate microorganism
      pathogenicity. Numerous animal models have been used to analyse the virulence of
      the opportunistic human pathogen Aspergillus fumigatus but none of the
      experimental models used previously have been satisfactory. This report discuss
      these models and presents a murine model of pulmonary aspergillosis that is very
      easy and the most adapted to compare the pathogenicity of A. fumigatus strains.
      Strains to be tested are inoculated intranasally and synchronously to mice and
      strains isolated from the lung of mice killed by the infection are typed. The
      number of colonies recovered is directly correlated to the virulence of the
      strain.

PMID- 12402023
TI  - [Advances in serological systems for diagnosis of systemic fungal infections,
      particularly those caused by Candida and Aspergillus].
AB  - Invasive fungal infections have emerged as important causes of morbidity and
      mortality in neutropenicand some other immunocompromised hosts; Candida and
      Aspergillus are among the major pathogens in this patient population. The
      clinical diagnosis of these infections is not specific and the traditional
      mycological methods for them not sensitive, with limits in the early detection of
      the pathogen. The potential additives or complements to the laboratory diagnosis
      of invasive candidiasis and aspergillosis are two non-culture-based methods,
      serodiagnostic methods and molecular ones. The former methods include the
      detection of pathogen-specific antigens, antibodies, metabolites and cell wall
      components. Several have already become standard laboratory tools and some others
      are under active investigation for developing new, more accurate detection
      systems. In this review, I will discuss the current status and future potential
      of serodiagnostic methods, highlighting both their technical and clinical
      implications.

PMID- 12402024
TI  - [Serodiagnosis for deep-seated mycoses].
AB  - Early diagnosis and treatment for an immunocompromised patient with a deep-seated
      mycosis are very important for the prognosis of the patient. Several methods of
      serodiagnosis for deep-seated mycosis have been developed and are clinically
      available. Detection of (1,3)-beta-D-glucan from serum samples of a patient can
      be evaluated with high sensitivity and specificity. Antigens detection test for
      fungi is another useful method for this serodiagnosis. A novel sandwich ELISA to
      detect galactomannan has higher sensitivity than the latex agglutination test.
      The cryptococcus capsular antigen detection technique is also very useful for
      patients with cryptococcosis. Thus, serodiagnosis for deep-seated mycosis appears
      to be a useful tool for treatment of immunocompromised patients.

PMID- 12402025
TI  - [Issues in the development of drugs for treating deep-seated mycosis].
AB  - This review is a collection of abstracts of seven papers presented at the panel
      discussion Issues in the Development of Drugs for Treating Deep-Seated Mycosis -
      From Drug Discovery to Clinical Studies held at the 45th Annual Meeting of the
      Japanese Society of Medical Mycology. The first three presentations concerned the
      discovery of new drugs. The first discussed the screening, analysis of chemical
      structure and elucidation of the mechanism of action of new antifungal agents
      focusing on aureobasidin A. The second was on the search for and development of
      novel agents with selective targets of action, specifically FK463 (micafungin)
      which inhibits (1-3)-beta-glucan synthase. The third described the development of
      novel derivatives based on the structure-activity correlation of triazole agents,
      with CS-758 as an example. The remaining four presentations discussed the status
      and issues of clinical studies targeting hematological disorders and respiratory
      diseases, as well as various problems from the company point of view on new drug
      development and those from the government side concerning the approval of new
      drugs. This type of meeting which provides an opportunity for discussion of
      various multi-faceted issues from the discovery of a new drug to its preclinical
      and clinical studies can contribute greatly to progress in the future development
      of new antifungal agents.

PMID- 12402026
TI  - An isolate of Arthroderma benhamiae with Trichophyton mentagrophytes var.
      erinacei anamorph isolated from a four-toed hedgehog (Atelerix albiventris) in
      Japan.
AB  - A female four-toed hedgehog probably imported from Africa and kept as a pet by a
      family suffered from depilation and mite (Caparinia tripilis) infection.
      Depilated quills were inoculated on a commercially available medium and an
      isolate of the dermatophytes was obtained. A giant colony after 14 days
      incubation on yeast extract Sabourauds agar had a central umbo with white
      granular surface and a yellow pigment ring in the reverse. The hedgehog isolate
      produced numerous elongated microconidia singly attached along the sides of
      hyphae. Macroconidia were somewhat irregular in shape and size and 2-6 septa.
      Abundant intermediate sized spores between micro- and macro conidia and few
      spirals were observed. Hair perforation and urease activity tests were positive.
      Maximum growth temperature was 40 C. In the mating tests using the tester strains
      of both African and Americano-European races of Arthroderma benhamiae, the strain
      produced numerous gymnothecia only when paired with the African race mating type
      minus(-). In addition, 591 bases of the internal transcribed spacer region of the
      ribosomal RNA gene including the 5.8S region (ITS1-5.8S-ITS2) were sequenced and
      corresponded to those of T. mentagrophytes var. erinacei (DDBJ/EMBL/GenBank
      accession numbers Z97996 and Z97997) by more than 99.7%. Therefore, our case is
      the first isolation of A. benhamiae with T. mentagrophytes var. erinacei anamorph
      in Japan.

PMID- 12402027
TI  - [Environmental Isolates of Sporothrix schenckii in China].
AB  - Restriction fragment length polymorphism (RFLP) in mitochondrial DNA (mtDNA) from
      25 environmental isolates of Sporothrix schenckii from northeastern China was
      investigated. Based on the mtDNA-RELP patterns with Hae III, 6 isolates were
      confirmed to be S. schenckii, while the other 19 isolates were confirmed to be
      species distinct from S. schenckii. The mtDNA RFLP patterns of the 19 non-S.
      schenckii were identical to each other. The non-S. schenckii isolates could not
      be discriminated from S. schenckii by their macro- or micro-morphological
      features, and were not pathogenic in guinea pigs. Serological and delayed
      hypersensitivity cross-reactions were found between S. schenckii and the non-S.
      schenckii species, suggesting antigenic similarity. These results indicate that
      RFLP analysis of mtDNA is essential for the identification of environmental
      isolates of S. schenckii.

PMID- 12402028
TI  - Histopathological examination of in vitro bone degeneration caused by a black
      yeast, Exophiala spinifera.
AB  - Exophiala spinifera, a black yeast, rarely causes systemic infection, and only a
      very few cases of its infection by the invasion of internal organs or bones have
      been reported. We examined the ability of E. spinifera to invade bone tissues in
      vitro. The fungus was inoculated on the surface of murine bones, and then these
      bones were incubated at 30 C for 2, 4, and 12 weeks on water agar plates and on
      brain heart infusion agar supplemented with 1%glucose (BHIA) plates.
      Histopathological examination demonstrated that the fungus was initially found in
      the non-calcified parts of the bone tissue, such as the growth plate and
      articular cartilage. Thereafter, the fungus invaded the calcified parts:
      cancellous and cortical bones. Our experiments showed that the capability of E.
      spinifera to invade bone tissue is higher than that of Candida albicans or other
      black fungi. E. spinifera grew in the mycelial form and C. albicans in the yeast
      form in these experiments. Our results suggest that E. spinifera may have a high
      potential to invade bone tissues, and that the mycelial form can invade bone more
      deeply than the yeast form. Therefore, bone degeneration should/ must be
      carefully monitored in any systemic infection with E. spinifera.

PMID- 12402029
TI  - Modeling and experiment yields the structure of acireductone dioxygenase from
      Klebsiella pneumoniae.
AB  - Here we report the structure of acireductone dioxygenase (ARD), the first
      determined for a new family of metalloenzymes. ARD represents a branch point in
      the methionine salvage pathway leading from methylthioadenosine to methionine and
      has been shown to catalyze different reactions depending on the type of metal ion
      bound in the active site. The solution structure of nickel-containing ARD (Ni
      ARD) was determined using NMR methods. X-ray absorption spectroscopy, assignment
      of hyperfine shifted NMR resonances and conserved domain homology were used to
      model the metal-binding site because of the paramagnetism of the bound Ni2+.
      Although there is no structure in the Protein Data Bank within 3 A r.m.s
      deviation of that of Ni-ARD, the enzyme active site is located in a conserved
      double-stranded b-helix domain. Furthermore, the proposed Ni-ARD active site
      shows significant post-facto structural homology to the active sites of several
      metalloenzymes in the cupin superfamily.

PMID- 12402030
TI  - Structural characterization of a proline-driven conformational switch within the
      Itk SH2 domain.
AB  - Interleukin-2 tyrosine kinase (Itk) is a T cell-specific kinase required for a
      proper immune response following T cell receptor engagement. In addition to the
      kinase domain, Itk is composed of several noncatalytic regulatory domains,
      including a Src homology 2 (SH2) domain that contains a conformationally
      heterogeneous Pro residue. Cis-trans isomerization of a single prolyl imide bond
      within the SH2 domain mediates conformer-specific ligand recognition that may
      have functional implications in T cell signaling. To better understand the
      mechanism by which a proline switch regulates ligand binding, we have used NMR
      spectroscopy to determine two structures of Itk SH2 corresponding to the cis and
      trans imide bond-containing conformers. The structures indicate that the
      heterogeneous Pro residue acts as a hinge that modulates ligand recognition by
      controlling the relative orientation of protein-binding surfaces.

PMID- 12402032
TI  - Nuclear coupling: RNA processing reaches back to transcription.

PMID- 12402033
TI  - Folding plasticity.

PMID- 12402034
TI  - Getting hotter with RNA.

PMID- 12402035
TI  - Spotlight on receptor/transducer interaction.

PMID- 12402036
TI  - Picture story. And the Nobel goes to...

PMID- 12402037
TI  - Acetylation inactivates the transcriptional repressor BCL6.
AB  - The proto-oncogene BCL6 encodes a BTB/POZ-zinc finger transcriptional repressor
      that is necessary for germinal-center formation and has been implicated in the
      pathogenesis of B-cell lymphomas. Here we show that the co-activator p300 binds
      and acetylates BCL6 in vivo and inhibits its function. Acetylation disrupts the
      ability of BCL6 to recruit histone deacetylases (HDACs), thereby hindering its
      capacity to repress transcription and to induce cell transformation. BCL6 is
      acetylated under physiologic conditions in normal germinal-center B cells and in
      germinal center-derived B-cell tumors. Treatment with specific inhibitors shows
      that levels of acetylation of BCL6 are controlled by both HDAC-dependent and SIR2
      dependent pathways. Pharmacological inhibition of these pathways leads to the
      accumulation of the inactive acetylated BCL6 and to cell-cycle arrest and
      apoptosis in B-cell lymphoma cells. These results identify a new mechanism of
      regulation of the proto-oncogene BCL6 with potential for therapeutic
      exploitation. Furthermore, these findings provide a new mechanism by which
      acetylation can promote transcription not only by modifying histones and
      activating transcriptional activators, but also by inhibiting transcriptional
      repressors.

PMID- 12402038
TI  - A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic
      lupus erythematosus in humans.
AB  - Systemic lupus erythematosus (SLE, OMIM 152700) is a complex autoimmune disease
      that affects 0.05% of the Western population, predominantly women. A number of
      susceptibility loci for SLE have been suggested in different populations, but the
      nature of the susceptibility genes and mutations is yet to be identified. We
      previously reported a susceptibility locus (SLEB2) for Nordic multi-case
      families. Within this locus, the programmed cell death 1 gene (PDCD1, also called
      PD-1) was considered the strongest candidate for association with the disease.
      Here, we analyzed 2,510 individuals, including members of five independent sets
      of families as well as unrelated individuals affected with SLE, for single
      nucleotide polymorphisms (SNPs) that we identified in PDCD1. We show that one
      intronic SNP in PDCD1 is associated with development of SLE in Europeans (found
      in 12% of affected individuals versus 5% of controls; P = 0.00001, r.r. (relative
      risk) = 2.6) and Mexicans (found in 7% of affected individuals versus 2% of
      controls; P = 0.0009, r.r. = 3.5). The associated allele of this SNP alters a
      binding site for the runt-related transcription factor 1 (RUNX1, also called
      AML1) located in an intronic enhancer, suggesting a mechanism through which it
      can contribute to the development of SLE in humans.

PMID- 12402039
TI  - Superficial NK1-expressing neurons control spinal excitability through activation
      of descending pathways.
AB  - The increase in pain sensitivity that follows injury is regulated by
      superficially located projection neurons in the dorsal horn of the spinal cord
      that express the neurokinin-1 (NK1) receptor. After selective ablation of these
      neurons in rats, we identified changes in receptive field size, mechanical and
      thermal coding and central sensitization of deeper dorsal horn neurons that are
      important for both pain sensations and reflexes. We were able to reproduce these
      changes by pharmacological block of descending serotonergic facilitatory
      pathways. Using Fos histochemistry, we found changes in the activation of
      serotonergic neurons in the brainstem as well as evidence for a loss of
      descending control of spinal excitability. We conclude that NK1-positive spinal
      projection neurons, activated by primary afferent input, project to higher brain
      areas that control spinal excitability--and therefore pain sensitivity--primarily
      through descending pathways from the brainstem.

PMID- 12402040
TI  - State-related and item-related neural correlates of successful memory encoding.
AB  - Neuroimaging studies show that the efficacy of long-term memory encoding of a
      stimulus is indexed by transient neural activity elicited by that stimulus. Here,
      we show that successful memory encoding is also indexed by neural activity that
      is tonically maintained throughout a study task. Using functional magnetic
      resonance imaging (fMRI), transient and sustained neural activity were
      dissociated with a mixed event-related and blocked design. In a series of short
      task blocks, human subjects made semantic or phonological decisions about
      visually presented words. After statistically removing item-related activity, we
      found that the mean level of activity across a task block was correlated with the
      number of words subsequently remembered from that block. These correlations were
      found in inferior medial parietal and left prefrontal cortex for the semantic
      task, and in superior medial parietal cortex for the phonological task. Our
      findings suggest that state-related activity in these brain regions is involved
      in memory encoding.

PMID- 12402041
TI  - Role of CD40 ligand in amyloidosis in transgenic Alzheimer's mice.
AB  - We have shown that interaction of CD40 with CD40L enables microglial activation
      in response to amyloid-beta peptide (Abeta), which is associated with Alzheimer's
      disease (AD)-like neuronal tau hyperphosphorylation in vivo. Here we report that
      transgenic mice overproducing Abeta, but deficient in CD40L, showed decreased
      astrocytosis and microgliosis associated with diminished Abeta levels and beta
      amyloid plaque load. Furthermore, in the PSAPP transgenic mouse model of AD, a
      depleting antibody against CD40L caused marked attenuation of Abeta/beta-amyloid
      pathology, which was associated with decreased amyloidogenic processing of
      amyloid precursor protein (APP) and increased circulating levels of Abeta.
      Conversely, in neuroblastoma cells overexpressing wild-type human APP, the CD40
      CD40L interaction resulted in amyloidogenic APP processing. These findings
      suggest several possible mechanisms underlying mitigation of AD pathology in
      response to CD40L depletion, and validate the CD40-CD40L interaction as a target
      for therapeutic intervention in AD.

PMID- 12402042
TI  - BID regulation by p53 contributes to chemosensitivity.
AB  - The role of the p53 protein (encoded by TP53) in tumour suppression relies partly
      on the ability of p53 to regulate the transcription of genes that are important
      in cell-cycle arrest and in apoptosis. But the apoptotic pathway mediated by p53
      is not fully understood. Here we show that BID, a member of the pro-apoptotic Bcl
      2 family of proteins, is regulated by p53. BID mRNA is increased in a p53
      dependent manner in vitro and in vivo, with strong expression in the splenic red
      pulp and colonic epithelium of gamma-irradiated mice. Both the human and the
      mouse BID genomic loci contain p53-binding DNA response elements that bind p53
      and mediate p53-dependent transactivation of a reporter gene. In addition, BID
      null mouse embryonic fibroblasts are more resistant than are wild-type
      fibroblasts to the DNA damaging agent adriamycin and the nucleotide analogue 5
      fluorouracil, both of which stabilize endogenous p53. Our results indicate that
      BID is a p53-responsive 'chemosensitivity gene' that may enhance the cell death
      response to chemotherapy.

PMID- 12402043
TI  - Sprouty1 and Sprouty2 provide a control mechanism for the Ras/MAPK signalling
      pathway.
AB  - Sprouty (Spry) inhibits signalling by receptor tyrosine kinases; however, the
      molecular mechanism underlying this function has not been defined. Here we show
      that after stimulation by growth factors Spry1 and Spry2 translocate to the
      plasma membrane and become phosphorylated on a conserved tyrosine. Next, they
      bind to the adaptor protein Grb2 and inhibit the recruitment of the Grb2-Sos
      complex either to the fibroblast growth factor receptor (FGFR) docking adaptor
      protein FRS2 or to Shp2. Membrane translocation of Spry is necessary for its
      phosphorylation, which is essential for its inhibitor activity. A tyrosine
      phosphorylated octapeptide derived from mouse Spry2 inhibits Grb2 from binding
      FRS2, Shp2 or mouse Spry2 in vitro and blocks activation of the extracellular
      signal-regulated kinase (ERK) in cells stimulated by growth factor. A non
      phosphorylated Spry mutant cannot bind Grb2 and acts as a dominant negative,
      inducing prolonged activation of ERK in response to FGF and promoting the FGF
      induced outgrowth of neurites in PC12 cells. Our findings suggest that Spry
      functions in a negative feedback mechanism in which its inhibitor activity is
      controlled rapidly and reversibly by post-translational mechanisms.

PMID- 12402044
TI  - PML-dependent apoptosis after DNA damage is regulated by the checkpoint kinase
      hCds1/Chk2.
AB  - The promyelocytic leukaemia (PML) gene is translocated in most acute
      promyelocytic leukaemias and encodes a tumour suppressor protein. PML is involved
      in multiple apoptotic pathways and is thought to be pivotal in gamma irradiation
      induced apoptosis. The DNA damage checkpoint kinase hCds1/Chk2 is necessary for
      p53-dependent apoptosis after gamma irradiation. In addition, gamma irradiation
      induced apoptosis also occurs through p53-independent mechanisms, although the
      molecular mechanism remains largely unknown. Here, we report that hCds1/Chk2
      mediates gamma irradiation-induced apoptosis in a p53-independent manner through
      an ataxia telangiectasia-mutated (ATM)-hCds1/Chk2-PML pathway. Our results
      provide the first evidence of a functional relationship between PML and a
      checkpoint kinase in gamma irradiation-induced apoptosis.

PMID- 12402045
TI  - The Doc1 subunit is a processivity factor for the anaphase-promoting complex.
AB  - Ubiquitin-mediated proteolysis of securin and mitotic cyclins is essential for
      exit from mitosis. The final step in ubiquitination of these and other proteins
      is catalysed by the anaphase-promoting complex (APC), a multi-subunit ubiquitin
      protein ligase (E3). Little is known about the molecular reaction resulting in
      APC-dependent substrate ubiquitination or the role of individual APC subunits in
      the reaction. Using a well-defined in vitro system, we show that highly purified
      APC from Saccharomyces cerevisiae ubiquitinates a model cyclin substrate in a
      processive manner. Analysis of mutant APC lacking the Doc1/Apc10 subunit
      (APC(doc1 Delta)) indicates that Doc1 is required for processivity. The specific
      molecular defect in APC(doc1 Delta) is identified by a large increase in apparent
      K(M) for the cyclin substrate relative to the wild-type enzyme. This suggests
      that Doc1 stimulates processivity by limiting substrate dissociation. Addition of
      recombinant Doc1 to APC(doc1 Delta) fully restores enzyme function. Doc1-related
      domains are found in mechanistically distinct ubiquitin-ligase enzymes and may
      generally stimulate ubiquitination by contributing to substrate-enzyme affinity.

PMID- 12402046
TI  - Membrane microviscosity regulates endothelial cell motility.
AB  - Endothelial cell (EC) movement is an initiating and rate-limiting event in the
      neogenesis and repair of blood vessels. Here, we explore the hypothesis that
      microviscosity of the plasma membrane (PM) is a key physiological regulator of
      cell movement. Aortic ECs treated with membrane-active agents, such as alpha
      tocopherol, cholesterol and lysophospholipids, exhibited a biphasic dependency on
      membrane microviscosity, in which moderate increases enhanced EC migration, but
      increases beyond a threshold markedly inhibited migration. Surprisingly,
      angiogenic growth factors, that is, basic fibroblast growth factor (bFGF) and
      vascular endothelial growth factor (VEGF), also increased membrane
      microviscosity, as measured in live cells by fluorescence recovery after
      photobleaching (FRAP). The localization of Rac to the PM was modified in cells
      treated with membrane-active agents or growth factors, suggesting a molecular
      mechanism for how membrane microviscosity influences cell movement. Our data show
      that angiogenic growth factors, as well as certain lipophilic molecules, regulate
      cell motility through alterations in membrane properties and the consequent
      relocalization of critical signalling molecules to membranes.

PMID- 12402047
TI  - A novel Epac-specific cAMP analogue demonstrates independent regulation of Rap1
      and ERK.
AB  - cAMP is involved in a wide variety of cellular processes that were thought to be
      mediated by protein kinase A (PKA). However, cAMP also directly regulates Epac1
      and Epac2, guanine nucleotide-exchange factors (GEFs) for the small GTPases Rap1
      and Rap2 (refs 2,3). Unfortunately, there is an absence of tools to discriminate
      between PKA- and Epac-mediated effects. Therefore, through rational drug design
      we have developed a novel cAMP analogue, 8-(4-chloro-phenylthio)-2'-O
      methyladenosine-3',5'-cyclic monophosphate (8CPT-2Me-cAMP), which activates Epac,
      but not PKA, both in vitro and in vivo. Using this analogue, we tested the
      widespread model that Rap1 mediates cAMP-induced regulation of the extracellular
      signal-regulated kinase (ERK). However, both in cell lines in which cAMP inhibits
      growth-factor-induced ERK activation and in which cAMP activates ERK, 8CPT-2Me
      cAMP did not affect ERK activity. Moreover, in cell lines in which cAMP activates
      ERK, inhibition of PKA and Ras, but not Rap1, abolished cAMP-mediated ERK
      activation. We conclude that cAMP-induced regulation of ERK and activation of
      Rap1 are independent processes.

PMID- 12402048
TI  - Wound healing recapitulates morphogenesis in Drosophila embryos.
AB  - The capacity to repair a wound is a fundamental survival mechanism that is
      activated at any site of damage throughout embryonic and adult life. To study the
      cell biology and genetics of this process, we have developed a wounding model in
      Drosophila melanogaster embryos that allows live imaging of rearrangements and
      changes in cell shape, and of the cytoskeletal machinery that draws closed an in
      vivo wound. Using embryos expressing green fluorescent protein (GFP) fusion
      proteins, we show that two cytoskeletal-dependent elements -- an actin cable and
      dynamic filopodial/lamellipodial protrusions -- are expressed by epithelial cells
      at the wound edge and are pivotal for repair. Modulating the activities of the
      small GTPases Rho and Cdc42 demonstrates that these actin-dependent elements have
      differing cellular functions, but that either alone can drive wound closure. The
      actin cable operates as a 'purse-string' to draw the hole closed, whereas
      filopodia are essential for the final 'knitting' together of epithelial cells at
      the end of repair. Our data suggest a more complex model for epithelial repair
      than previously envisaged and highlight remarkable similarities with the well
      characterized morphogenetic movement of dorsal closure in Drosophila.

PMID- 12402049
TI  - Anal manometric predictors of significant rectocele in constipated patients.
AB  - The diagnosis of significant rectocele is currently made on the basis of
      cinedefecographic findings. Clinical examination alone will only allow assessment
      of the presence but not the significance of a rectocele. Therefore, the aim of
      this study was to determine if anal manometric findings can predict the
      significance of a rectocele. All patients with a diagnosis of constipation and
      rectocele confirmed on cinedefecography between 1992 and 1998 were
      retrospectively reviewed. Significant rectocele was defined as the presence of
      three of the following five parameters: rectocele >4 cm in diameter as measured
      during the evacuatory phase of cinedefecography, rectal and/or vaginal symptoms
      present for longer than 12 months, persistence of rectal or vaginal symptoms for
      at least four weeks, despite increased dietary fiber (up to 35 g/day), need for
      rectal and/or vaginal digitation or perineal support maneuvers for rectal
      evacuation. Statistical analysis was performed using the Mann-Whitney test and
      Fisher's exact test. A logistic regression model with stepwise selection was used
      to determine significant prognostic factors. A total of 305 patients (31 men)
      with rectocele, with a median age of 68 years (range, 12-89) were identified. Of
      these, 89 (29.2%) had significant rectoceles. There was no difference in the
      frequency of significant and non-significant rectoceles with respect to gender or
      age. However, patients with a significant rectocele compared to those with a non
      significant rectocele had higher median first sensation volume (45 vs. 30 ml,
      p=0.0005), median capacity (160 vs. 120 ml, p<0.0001), and median compliance (10
      vs. 8 ml H(2)O/mmHg, p=0.05). Calculations based on a logistic regression model
      determined that with a first sensation of 100 ml, a capacity of 400 ml, and a
      compliance of 50 ml/mmHg, the probability of a significant rectocele would be
      85%. In conclusion, anal manometric findings may be useful in predicting
      significant rectocele in constipated patients.

PMID- 12402050
TI  - Oral lacidipine in the treatment of anal fissure.
AB  - The aim of this prospective study was to assess the effectiveness in healing anal
      fissure (AF) of lacidipine, a calcium channel blocker with a better tolerability
      in comparison to other calcium antagonists. Twenty-one consecutive patients (16
      women, 76.2%) with AF (16 chronic, situated posteriorly in 17 patients (81.0%),
      anteriorly in 4) with a mean age of 37.1 years (SD, 13.6, range, 20-6) were
      treated with oral lacidipine (6 mg daily) and warm sitz baths for 28 days, adding
      only stool softeners for patients with constipation. Blood pressure, pain scores
      (assessed from 0 to 10 on a visual analogue scale) and fissure healing were
      monitored at 14 days, 28 days and 2 months. At the 14-day and 28-day follow-ups,
      the mean systolic and diastolic pressures were not significantly different from
      pre-treatment levels. Seven patients (33.3%) developed side effects, but only
      one, who developed dyplopia, withdrew from the study at the 14-day control (non
      compliance rate with treatment, 4.8%). Pain scores were significantly reduced
      after 14 days and continued to show a significant reduction throughout the
      treatment period. Three fissures (14.3%) healed by 14 days and a total of 19
      (90.4%) after 28 days: among the healed AF no recurrences were seen at the 2
      month control. Among the two treatment failures, one was the patient who withdrew
      from the study at the 14-day control due to dyplopia and the other was a patient
      who failed to heal up to the 2-month follow-up, although completely asymptomatic.
      Both patients underwent left lateral sphincterotomy and healed. In conclusion,
      oral lacedipine is quite well tolerated and may offer a promising alternative
      treatment for AF.

PMID- 12402051
TI  - Complications after stapled hemorrhoidectomy: can they be prevented?
AB  - Stapled hemorrhoidectomy (SH), a new approach to the treatment of hemorrhoids,
      removes a circumferential strip of mucosa about four centimeters above the
      dentate line. A review of 1,107 patients treated with SH from twelve Italian
      coloproctological centers has revealed a 15% (164/1,107) complication rate.
      Immediate complications (first week) were: severe pain in 5.0% of all patients,
      bleeding (4.2%), thrombosis (2.3%), urinary retention (1.5%), anastomotic
      dehiscence (0.5%), fissure (0.2%), perineal intramural hematoma (0.1%), and
      submucosal abscess (0.1%). Bleeding was treated surgically in 24%, with Foley
      insertion 15%; and by epinephrine infiltration in 2%; 53% of patients with
      bleeding received no treatment and 6% needed transfusion. One patient with
      anastomotic dehiscence needed pelvic drainage and colostomy formation. The most
      common complication after 1 week was recurrence of hemorrhoids in 2.3% of
      patients, severe pain (1.7%), stenosis (0.8%), fissure (0.6%), bleeding (0.5%),
      skin tag (0.5%), thrombosis (0.4%), papillary hypertrophy (0.3%) fecal urency
      (0.2%), staples problems (0.2%), gas flatus and fecal incontinence (0.2%),
      intramural abscess, partial dehiscence, mucosal septum and intussusception (each
      <0.1%). Recurrent hemorrhoids were treated by ligation in 40% and by Milligan
      Morgan procedure in 32%. All hemorrhoidal thromboses were excised. Anal stenoses
      were treated by dilatation in 55% and by anoplasty in 45%. Fissure was treated by
      dilatation in 57%. Most complications (65%) occurred after the surgeon had more
      than 25 case experiences of stapled hemorrhoidectomy. The most common
      complication in the first 25 cases of the surgeon's experience was bleeding
      (48%). Even though SH appears to be promising, we feel that a multicenter
      randomized study with a long-term follow-up comparing SH and banding is necessary
      before recommending the procedure. Most complications can be avoided by
      respecting the rectal wall anatomy in the execution of the procedure.

PMID- 12402052
TI  - Harmonic scalpel hemorrhoidectomy: preliminary results of a new alternative
      method.
AB  - Surgical treatment is considered to be the best therapeutic modality for severe
      hemorrhoidal disease. Different surgical methods of hemorrhoidectomy aim to
      decrease pain, bleeding, stenosis and discharge. The aim of this study was to
      evaluate the efficacy of harmonic scalpel hemorrhoidectomy. During a period of
      seven months, 54 consecutive patients with third- and fourth-degree hemorrhoids
      were prospectively randomized for harmonic scalpel hemorrhoidectomy (HS) or
      Milligan-Morgan procedure (MM). These patients were examined at one, two, and six
      weeks after the operation. All patients had a lower gastrointestinal
      investigation prior to operation to exclude other colorectal pathologies. All
      patients had the same kind of preoperative preparation and analgesia during the
      postoperative course. Pain was assessed using a visual analog scale from 0 to 10.
      Patient satisfaction was defined as decrease or absence of symptoms and return to
      normal daily activities. HS groups included 29 patients, while the MM group had
      25 patients. There as no difference between the groups in terms of age, gender,
      hemorrhoidal degree and indication for operation. The types of intra-operative
      anesthesia administered to the two groups were similar. Duration of surgery was
      significantly higher in the MM group ( p<0.0001). Postoperative hospitalization
      was longer in the MM group ( p<0.0001), and the pain degree was higher in MM
      group ( p<0.0001). No significant difference was noted in the overall amount of
      analgesics used in the two groups at week 1, although it was significantly higher
      in the MM group 2 and 3 weeks after the operation. Early complication occurred
      more frequently in the MM group but overall the difference was not statistically
      significant. In conclusion, harmonic scalpel hemorrhoidectomy is virtually a
      bloodless operation with minimal tissue damage. It is associated with significant
      less postoperative pain and a fast return to normal activity.

PMID- 12402053
TI  - Anatomical rationale for spleen salvage by lobe/segment dearterialization in
      inferior pole spleen injury during left hemicolectomy: a post-mortem study.
AB  - The aim of this study was to determine the rationale for spleen salvage by
      lobe/segment dearterialization without resection for inferior pole injury during
      left hemicolectomy. One hundred and two consecutive human cadavers were
      dissected. Corrosion case and post-mortem arteriography with computerized
      planimetry were employed. Lobe/segment size, artery diameter and length and
      anastomoses between arteries were measured. The mean inferior terminal splenic
      artery had a significantly smaller diameter than the superior (2.8 vs. 3.4 mm,
      p<0.01). An inferior polar artery was found in 22.5% of the specimens (mean
      diameter, 1.9 mm; mean length, 33 mm). The inferior lobe and inferior polar
      segment comprised 41.3% and 12.6% of the spleen, respectively. Anastomoses were
      detected in 34 of 102 spleens (3% extraparenchymal, 88% intraparenchymal, 9%
      combined). The mean diameter and length of intrasplenic anastomoses were 0.3 mm
      and 20 mm, respectively. In conclusion, there was a positive correlation between
      diameters of lobar/segmental arteries and vascular zones ( p<0.05). The rationale
      for splenic lobe/segment dearterialization without resection is found in the
      presence of intrasplenic anastomoses.

PMID- 12402054
TI  - Results of resection for volvulus of the right colon.
AB  - The aim of the present study was to retrospectively evaluate the results of
      resection for volvulus of the right colon. Over a 17-year period, 45 patients (33
      women) of mean age 64 years were admitted with acute right colon volvulus.
      Preoperative diagnosis was obtained in 53% of the cases. A right hemicolectomy
      was performed in all the cases, with primary anastomosis in 43 cases and double
      ileal and transverse stomy in 2 cases. Gangrene was observed in 23 patients
      (51%). Postoperative mortality was 6.6% (3 patients) due to septic shock and
      multi-organ failure in 2 cases, and respiratory failure in the other cases.
      Postoperative morbidity was 20% (9 patients), including 2 cases of anastomotic
      leaks. On the basis of this study and a review of the literature, it appears that
      right hemicolectomy is the treatment of choice for volvulus of the right colon,
      as it avoids all risk of recurrence and mortality is lower than that obtained
      with conservative treatment.

PMID- 12402055
TI  - Anorectal function after modern conformal radiation therapy for prostate cancer:
      a pilot study.
AB  - We evaluated whether, and if so to what extent, radiotherapy applied on a series
      of patients with prostate cancer influenced the patient's bowel habits and
      anorectal function. Ten consecutive patients participated in the study. The
      median age of the patients was 74 years (range, 61-71) and the average follow-up
      period was 22 (range, 15-28) months. Four patients were irradiated using external
      beam radiotherapy (2 Gy/day for a total of 70 Gy); 6 patients were irradiated
      with a combination of external beam radiotherapy (50 Gy, 2 Gy/day) and high dose
      rate brachytherapy (two 10-Gy fractions). Upon interview, patients disclosed
      characteristic functional disturbances such as urgency with occasional accidents,
      faecal soiling and spotting of underwear. Involuntary release of gas was another
      embarrassing problem. One or more of these problems were present in half of the
      patients. Endoscopy disclosed signs of mild proctitis. Sphincter pressure, rectal
      capacity and the volume threshold for appreciation of defecation urge were all
      significantly lower in patients than in 10 age-matched controls. In conclusion,
      disturbances of anorectal function with imperfection of incontinence still occur
      so some extent despite improved precision, and reduced margins offered by the
      modern conformal radiation therapy of prostate cancer. Anal sphincter function,
      the reservoir capacity of the rectum and its sensory function are adversely
      affected and radiation proctitis with rectal fibrosis and damage of the extrinsic
      innervations of the anal sphincters appear to be the principal causative factors.
      Although conformal radiotherapy together with better positioning may be two
      substantial improvements of modern radiotherapy, further improvements are needed.

PMID- 12402056
TI  - Two-quadrant semiclosed hemorrhoidectomy. A preliminary report.
AB  - Bleeding and delayed healing may affect the postoperative course following
      hemorrhoidectomy and cause discomfort to the patient. The present report deals
      with a modification of the Milligan-Morgan operation: the upper part of the
      surgical wound is covered with rectal mucosa and the distal edge is stitched with
      a running suture, with the aim of decreasing both the risk of bleeding and the
      healing time. The operation has been performed in 12 consecutive patients with
      two quadrant internal and external piles. The median operative time was 32
      minutes (range, 21-30). The mean postoperative pain after 12 hours, measured from
      1 to 10 on a visual analogue scale, was 4.4 (SEM, 1.4). All patients but three
      had their wounds healed within 3 weeks and none of them had postoperative
      bleeding requiring treatment. Acute urinary retention occurred in one case. All
      patients were discharged after 48 hours. None had anal incontinence or short-term
      recurrence. In conclusion, two-quadrant semiclosed hemorrhoidectomy provided good
      results in terms of both bleeding rate and healing process with an acceptable
      operative time and postoperative pain.

PMID- 12402057
TI  - Perineal rectosigmoidectomy (Altemeier's procedure): a review of physiology,
      technique and outcome.
AB  - Perineal rectosigmoidectomy (Altemeier's procedure), as used for the surgical
      treatment of full-thickness rectal prolapse, has a long history. The
      physiological derangement in patients with rectal prolapse is complex, frequently
      showing impairment of the rectoanal inhibitory reflex, intermittent high-pressure
      rectal motor activity, disturbances in anorectal sampling and attendant pudendal
      neuropathy. There are currently few defined preoperative factors in patients
      presenting with rectal prolapse and fecal leakage which predict for the
      restoration of continence after surgery. This review describes our technique of
      Altemeier's procedure and analyzes the reported results of this operation,
      presenting those studies which assessed postoperative continence and prolapse
      recurrence in particular. The lack of prospective randomized data regarding this
      perineal approach makes clinical interpretation difficult at the present time.

PMID- 12402058
TI  - Perianal acquired tufted angioma associated with pregnancy: case report.
AB  - Tufted angiomas are rare lesions described as slowly growing/spreading
      erythematous macules especially located in the upper trunk and neck. Herein we
      report the case of perianal location of a tufted angioma in a young pregnant
      woman. She came to our observation complaining of perianal pain accompanied by
      bleeding at defecation. A lesion resembling a perianal fissure was observed. Mild
      hypertonia of the internal sphincter was confirmed at manometry. After one week
      of ineffective medical treatment, surgery was planed at the end of the sixteenth
      week under local anaesthesia. The lesion was excised and a minimal sphincterotomy
      was performed; histopathology report described features of a tufted angioma. The
      pregnancy proceeded regularly, without anal symptoms, followed by normal vaginal
      delivery at the thirty-eighth week. This case showed three peculiar features: the
      association of tufted angioma and pregnancy, the perianal location, and the
      clinical appearance suggestive of an anal fissure. The clinical manifestation of
      a perianal tufted angioma, mimicking an anal fissure, is of utmost importance to
      the differential diagnosis and treatment plan, especially in a pregnant woman.

PMID- 12402059
TI  - Endosonographic diagnosis of pneumatosis cystoides intestinalis in infancy.
AB  - We report pneumatosis cystoides intestinalis in a 10-month-old girl who developed
      bloody diarrhea following chemotherapy for leukemia. The diagnosis was made only
      by colonic endoscopic ultrasonography, whereas the abdominal plain radiogram and
      computed tomography failed to elucidate the diagnosis. She was successfully
      treated with hyperbaric oxygen therapy. Wider application of endoscopic
      ultrasonography may lead to the more frequent detection of pneumatosis cystoides
      intestinalis, currently a rare disorder.

PMID- 12402060
TI  - The evolving role of aromatase inhibitors in breast cancer.
AB  - Anti-aromatase agents inhibit the cytochrome p-450 component of the aromatase
      enzyme complex responsible for the final step of estrogen biosynthesis in
      peripheral tissues. These drugs can be classified into first-generation (e.g.,
      aminoglutethimide), second-generation (e.g., formestane and fadrazole), and third
      generation (e.g., anastrozole, letrozole, and exemestane) agents. Anti-aromatase
      agents can also be divided into type I and type II inhibitors. Type I inhibitors
      have a steroidal structure similar to androgens and inactivate the enzyme
      irreversibly by blocking the substrate-binding site, and are therefore known as
      aromatase inactivators. Type II inhibitors are nonsteroidal and their action is
      reversible. This article reviews the recent evidence regarding the role of third
      generation aromatase inhibitors in the management of breast cancer. Relevant
      PubMed listed articles and presentations at recent international symposia were
      reviewed. There is a growing body of evidence supporting the role of third
      generation aromatase inhibitors (anastrozole, letrozole, and exemestane) as first
      line and second-line therapy for estrogen receptor (ER)- and/or progesterone
      receptor (PgR)-positive advanced breast cancer in postmenopausal women, and as a
      neoadjuvant therapy in postmenopausal women with hormone receptor-positive
      invasive breast cancer unsuitable for breast-conserving surgery. Furthermore, the
      preliminary results of the ATAC (Arimidex, Tamoxifen, Alone and in Combination)
      study have shown that adjuvant anastrozole is superior to tamoxifen in terms of
      disease-free survival (DFS), adverse effects, and prevention of contralateral
      breast cancer in postmenopausal women with early, ER-positive breast cancer.
      However, longer follow-up is required to assess the long-term effects of these
      agents on bone mineral density, cognitive function, and overall survival prior to
      considering their routine use in the adjuvant setting instead of tamoxifen. The
      potential role of these drugs in the management of ductal carcinoma in situ
      (DCIS), premenopausal breast cancer, and breast cancer prevention is worth
      investigating.

PMID- 12402061
TI  - Short-course palliative radiotherapy for airway stenosis in non-small cell lung
      cancer.
AB  - BACKGROUND: The majority of patients with non-small cell lung cancer have
      inoperable disease that is already too advanced for radical treatment at the
      initial diagnosis. But patients who suffer from symptoms caused by intrathoracic
      tumor often require palliative treatment to relieve the symptoms. We
      investigated, retrospectively, the outcome of short-course palliative
      radiotherapy for airway stenosis in non-small cell lung cancer. METHODS: Between
      October 1997 and June 2001, 24 patients were treated by palliative radiotherapy
      to relieve airway stenosis caused by intrathoracic tumor. The short-course
      radiotherapy consisted of a total dose of 30 Gy given in ten fractions over 2
      weeks. The effect of treatment was assessed by improvement of radiographic
      findings. The duration of palliation and this duration as a percentage of the
      remaining survival time were also investigated. RESULTS: Palliation of airway
      stenosis was achieved in 13 (54.2%) patients. The time until palliation was
      achieved ranged from 11 to 44 days (median, 24 days). The duration of palliation
      ranged from 44 to 351 days (median, 116 days). In the palliated patients, the
      median survival time was 192 days, while that of the non-responders was 43 days.
      The duration of palliation as a percentage of the remaining lifetime ranged from
      41% to 96% (median, 66%). CONCLUSIONS: Short-course palliative radiotherapy of 30
      Gy in ten fractions over 2 weeks achieved good palliation without severe acute
      toxicities in over half of the patients. It is suggested that, in the palliated
      patient, the airway can be, potentially, maintained over the long term.

PMID- 12402062
TI  - Complications of bacillus Calmette-Guerin therapy in superficial urothelial
      cancer: clinical analysis and implications.
AB  - BACKGROUND: Intravesical bacillus Calmette-Guerin (BCG) therapy has been proven
      to be effective in the prophylaxis and treatment of superficial bladder cancer.
      However, several complications of BCG therapy have been reported. The aim of this
      study was to clarify the impact of BCG treatment-related side effects on the
      clinical outcome of patients with superficial urothelial cancer. METHODS: We
      reviewed the medical records of 33 patients who underwent BCG instillation
      therapy in our department. After complete endoscopic tumor resection,
      intravesical or intrapelvic instillation of BCG (80 mg of the Tokyo strain) was
      performed every week for 8 weeks. BCG treatment-related side effects were
      classified as minor (persistence of symptoms or low-grade fever for less than 48
      h) or major (persistence of symptoms or low-grade fever for more than 48 h, or
      high fever). Risk factors for major side effects and relationships between the
      occurrence of major side effects and subsequent tumor progression were evaluated.
      RESULTS: In total, there were 43 courses of intravesical and intrapelvic
      instillations of BCG in 33 patients, 20 (46%) of which were associated with major
      side effects. Risk factors associated with the occurrence of major side effects
      could not be detected. Subsequent tumor progression was observed in 3 of the 16
      patients (19%) with major side effects and in 10 of the 17 patients (59%) without
      them. Nine patients who discontinued BCG therapy because of major side effects
      experienced no tumor progression. Progression-free survival was significantly
      higher in patients with major side effects than in those without them.
      CONCLUSIONS: These results suggest that BCG therapy should be discontinued
      whenever major side effects occur, because this does not necessarily lead to an
      unfavorable outcome regarding tumor progression.

PMID- 12402063
TI  - Survival prediction using artificial neural networks in patients with uterine
      cervical cancer treated by radiation therapy alone.
AB  - BACKGROUND: We evaluated the usefulness of artificial neural networks (ANNs) for
      survival prediction in patients with uterine cervical cancer treated by
      radiotherapy. METHODS: We used data from 134 patients with uterine cervical
      cancer treated by combined external and high-dose-rate remote afterloading
      intracavitary radiotherapy between 1978 and 1993. The ANNs were trained using the
      data from 67 randomly selected patients. Using the trained ANNs, we predicted the
      5-year survival in the remaining 67 patients, and compared it with the known 5
      year survival. The performance of the ANNs was evaluated using a receiver
      operating characteristic (ROC) curve and was compared using the area under the
      ROC curve (Az). RESULTS: When fundamental factors, such as age, performance
      status, hemoglobin, total protein, International Federation of Gynecology and
      Obstetrics (FIGO) stage, and histological type were used as inputs in the ANNs,
      Az was 0.5483 +/- 0.0145 (mean +/- SD). When the histological grading of
      radiation effect determined by periodic biopsy examination was used in addition
      to the fundamental factors, Az was highest (0.7782 +/- 0.0105). When the
      cytological grading of radiation effect by the periodic smear was used in
      addition to the fundamental factors, Az was 0.5523 +/- 0.0135, which was not
      significantly different from that when only the fundamental factors were used.
      CONCLUSION: ANNs allow us to evaluate the importance of prognostic factors, and
      make it possible to predict the survival of each patient. Using ANNs, the
      combination of histological grading of radiation effect determined by periodic
      biopsy examination, in addition to the fundamental factors, is the most effective
      for prediction of survival in patients with uterine cervical cancer.

PMID- 12402064
TI  - Autopsy findings of patients with urological neoplasms.
AB  - BACKGROUND: A study was carried out to gain extensive understanding of the
      disease status in patients who had suffered and died of urological neoplasms.
      METHODS: The subjects were 524 patients who had died at the Department of Urology
      of Gunma Cancer Center. The autopsy rate for each urological, neoplasm, the
      extent of the disease, and incidental diseases were analyzed. RESULTS: Autopsies
      were performed in 27.1% (142/524) of the patients. Frequent metastatic sites were
      the lymph nodes, bone, and lung in prostate neoplasms; the lymph nodes, liver,
      and lung in bladder neoplasms; and the lymph nodes, lung, and bone in kidney
      neoplasms. In the 116 patients with these three major urological neoplasms, the
      autopsy findings of all patients were compatible with progression of the disease,
      except for 5 cases (acute myocardial infarction in 2 and liver failure in 3).
      Multiple primary cancers were seen in 21.6% (25/116), and other cancers that
      caused death, apart from those at urological sites, were confirmed in 7 patients
      (pancreas in 2, and esophagus, lung, gallbladder, liver, and uterus in 1 patient
      each). CONCLUSION: Autopsies revealed the macroscopic and microscopic extent of
      the disease and the presence of incidental disease beyond the diagnosis made in
      the patient's lifetime.

PMID- 12402065
TI  - Development of Japanese version of the UCLA Prostate Cancer Index: a pilot
      validation study.
AB  - METHODS: The Japanese version (version 1.2) of the UCLA PCI was developed through
      a process of translation, back-translation, and refinement after interviewing
      patients. Reliability and validity were examined for 125 Japanese patients with
      localized prostate cancer. The patients simultaneously responded to the Japanese
      version of the RAND 36-Item Health Survey (SF-36) and five representative
      questions from the International Index of Erectile Function (IIEF). RESULTS:
      Internal consistency reliability was very high for both urinary and sexual
      function scales, and lower for bowel function. The test-retest reliability of the
      urinary and sexual function scales and the urinary bother scales was stable,
      while that of the bowel function and bother scales was relatively unstable.
      Sexual function scores did not correlate highly with sexual bother scores.
      Furthermore, poor sexual function and bother had little association with the SF
      36 scores. Missing data as to urinary and bowel function/bother scales were
      minimal (0.8%-2.4%), while those for sexual function and bother were relatively
      high (4.8%-11.2%). CONCLUSIONS: The results of this pilot study, together with
      the previous American study, suggest ethnic or cultural difference in how
      impaired sexual function is integrated into overall QOL. A future cross-cultural
      comparative study using the UCLA PCI and SF-36 will provide useful information
      about the influence of cultural or ethnic differences on health-related QOL in
      prostate cancer patients.

PMID- 12402066
TI  - Serum soluble interleukin-2 receptor (IL-2R) and immunohistochemical staining of
      IL-2R/Tac antigen in colorectal cancer.
AB  - BACKGROUND: In the present study, we investigated the significance of serum
      soluble interleukin-2 receptor (IL-2R) as a tumor marker, and examined the
      existence and localization of cells positive for IL-2R/Tac antigen in colorectal
      cancer tissues and their regional lymph nodes. METHODS: The study included 155
      patients with colorectal cancer. Levels of serum soluble IL-2R were measured by
      an enzyme-linked immunosorbent assay. In the tissues obtained from 18 patients,
      immunohistochemical staining was performed, with the use of the avidin-biotin
      peroxidase complex technique, in which mouse anti-human IL-2R antibody was used.
      RESULTS: The preoperative levels of serum soluble IL-2R in patients with
      colorectal cancer were significantly higher than those of normal controls ( P =
      0.0065). The levels of serum soluble IL-2R in patients with metastatic lymph
      nodes were also significantly higher than the levels in those without metastatic
      lymph nodes ( P = 0.0258). Concerning tumor markers, there were significant
      differences in serum soluble IL-2R levels between patients who were positive and
      those who were negative for carcinoembryonic antigen (CEA) and between these who
      were positive and those who were negative for immunosuppressive acidic protein
      (IAP). In the immunohistochemical staining of IL-2R, 16 of the 18 patients
      (88.8%) showed IL-2R-positive cells in the colorectal cancer tissues. In regard
      to the metastatic lymph nodes, all of 5 patients (100%) showed IL-2R-positive
      cells. On the other hand, IL-2R-positive cells were not recognized in normal
      colorectal tissues and non-metastatic lymph nodes. CONCLUSION: These results
      suggest that activated T lymphocytes infiltrating into cancer tissues to play an
      antitumor role may release a large amount of the alpha-chain of IL-2R, resulting
      in the high levels of serum soluble IL-2R in patients with colorectal cancer.

PMID- 12402067
TI  - Osteosarcoma after bone marrow transplantation for acute lymphoblastic leukemia.
AB  - A male patient initially diagnosed with acute lymphoblastic leukemia at age 9
      years received chemotherapy (total body irradiation, 12 Gy) followed by
      allogeneic bone marrow transplantation. Since then, he had been in complete
      remission. Three years after the bone marrow transplantation, he complained of
      increasing pain in the right knee. Radiological and histological examinations led
      to a diagnosis of conventional osteosarcoma. We performed intensive chemotherapy
      and wide local excision of the osteosarcoma. Intensive chemotherapy was
      accomplished as planned, although recovery from myelosuppression was delayed
      during some cycles. Polymerase chain reaction-single-strand conformation
      polymorphism analysis revealed a p53 gene mutation in exon 7 in the tumor cells,
      but not in skin or blood cells. This is an extremely rare case of osteosarcoma
      after bone marrow transplantation.

PMID- 12402068
TI  - Experience of intravenous digital subtraction angiography (IV-DSA) in evaluation
      of neoadjuvant chemotherapy for advanced breast cancer.
AB  - Intravenous digital subtraction angiography (IV-DSA) was performed before and
      after neoadjuvant chemotherapy (NACT) in five patients with locally advanced
      breast cancer, and the efficacy of NACT was evaluated on the basis of the results
      of IV-DSA and histopathological examination. Following NACT, the maximum density
      of tumor enhancement (MAX) in the IV-DSA image decreased by 61.6% in case 1, 50%
      in case 2, 58.1% in case 3, 90.8% in case 4, and 97.2% in case 5. In all five
      patients, the efficacy of chemotherapy was rated as a partial response in terms
      of tumor size, while histological efficacy was rated as slightly effective in
      cases 1-4 and moderately effective in case 5. The pathological efficacy of NACT
      was highest in case 5, which showed the greatest decrease in MAX. These results
      indicate that variations in MAX reflect clinical efficacy, and, to some extent,
      also permit prediction of pathological efficacy.

PMID- 12402069
TI  - Advanced gastric cancer with liver metastases successfully treated with S-1.
AB  - S-1 is an anticancer drug in which tegafur is combined with modulators, gimeracil
      and oteracil potassium. We encountered a patient with gastric cancer for whom
      oral administration of S-1 was effective, and we report this case. A 79-year-old
      woman visited our hospital with a major complaint of anorexia. Tests revealed
      severe anemia, with a hemoglobin (Hb) level of 6.5 g/dl, and the patient was
      admitted to the hospital for treatment. The primary lesion was a large type-1
      gastric cancer (poorly differentiated adenocarcinoma) in the middle gastric body.
      In addition, a lesion with a diameter of 50 mm was observed in the left hepatic
      lobe and small metastatic lesions were also scattered in the right lobe. When a
      performance status (PS) of 0 was obtained after her systemic condition had been
      improved, S-1 was started, at a dose of 80 mg/day (with one course consisting of
      administration for 4 weeks, followed by 2 weeks' rest). No severe adverse drug
      reaction was observed. After one course of administration was completed, the
      patient received administrations at the outpatient clinic. Upon the completion of
      two courses, computed tomography (CT) showed disappearance of the metastatic
      lesions and marked regression of the primary lesion. At present, upon completion
      of the sixth course, no hepatic metastasis is observed and the primary gastric
      lesion shows a tendency to regress. Her PS is maintained at 0.

PMID- 12402070
TI  - Platelet-sparing effect of paclitaxel in heavily pretreated ovarian cancer
      patients.
AB  - Carboplatin has proven to be effective in the treatment of patients with
      recurrent ovarian cancer who have responded to platinum-based first-line
      chemotherapy. However, thrombocytopenia is a problem in heavily pretreated
      patients. Paclitaxel has a so-called platelet-sparing effect, but until now it
      was unknown whether this effect could be obtained in heavily pretreated patients.
      We treated four patients with recurrent epithelial ovarian cancers who had
      previously undergone heavy chemotherapy. Because these patients had responded to
      platinum-based first-line therapy, single carboplatin administration was
      employed. Although satisfactory tumor marker responses were obtained,
      thrombocytopenia occurred. When paclitaxel was administered before the
      carboplatin infusion in the subsequent treatments, the thrombocytopenia became
      milder. It was concluded that a platelet-sparing effect was also observed in
      patients who had undergone heavy prior chemotherapy.

PMID- 12402071
TI  - Is Dr. Satava voicing genuine concerns?

PMID- 12402072
TI  - Pulmonary function after laparoscopic and open cholecystectomy.

PMID- 12402073
TI  - Foreign bodies of the gastrointestinal tract: when to wait and which to extract?

PMID- 12402074
TI  - Laparoscopic repair of incisional hernia: which prosthesis to choose?

PMID- 12402076
TI  - Modulation of the cell-surface proteinase activity of thermophilic lactobacilli
      by the Peptide supply.
AB  - The proteolytic system of thermophilic lactobacilli is considered important for
      bacterial nutrition as well as for the formation of flavor and texture in
      fermented products. We investigated the influence of peptide content on the cell
      surface proteinase and intracellular aminopeptidase activities from seven
      thermophilic lactobacilli strains. The proteinase activities were remarkably
      reduced in cells grown in the peptide-rich medium MRS or in a chemically defined
      medium supplemented with Casitone compared with those found in a synthetic
      medium. The degree of inhibition observed was strain dependent. When proteinase
      activities were analyzed by their hydrolytic patterns of alpha- and beta-casein
      degradation, four types of P(III)-caseinolytic cleavage specificity were
      distinguished. Lactobacillus helveticus strains possessed aminopeptidase
      activities with broader specificity than those found in L. delbrueckii subsp.
      lactis strains. However, the aminopeptidase activities were not influenced by the
      peptide content of the medium.

PMID- 12402077
TI  - Cloning of a gene encoding acetate kinase from Methanosarcina mazei 2-P isolated
      from a Japanese paddy field soil.
AB  - The ack gene encoding acetate kinase from the mesophilic Methanosarcina mazei 2
      P, isolated from a paddy field soil in Japan, was cloned, sequenced, and
      functionally expressed in Escherichia coli. The terminal region of the putative
      pta gene, probably encoding phosphotransacetylase, was found upstream of the ack
      gene. The deduced amino acid sequence of the acetate kinase is 86.5% identical to
      that of the Methanosarcina thermophila acetate kinase. The activity of the His(6)
      tagged acetate kinase purified from E. coli JM109 was optimal at 35 degrees C.

PMID- 12402078
TI  - Sodium azide reduces the thermotolerance of respiratively grown yeasts.
AB  - The effect of sodium azide in heat shock-induced cell death was studied in
      Debaryomyces vanrijiae, Candida albicans, and Saccharomyces cerevisiae yeasts.
      The results presented demonstrate that the azide addition induced a drastic
      decrease in the thermotolerance of glucose-grown D. vanrijiae. In contrast,
      glucose-grown S. cerevisiae and C. albicans cells treated with NaN(3) became more
      resistant to heat shock than control cells. Nevertheless, in galactose medium the
      decrease of thermotolerance of S. cerevisiae and C. albicans cells was observed
      in the presence of sodium azide. It was suggested that the decreasing effect of
      sodium azide on thermotolerance takes place only when the yeast cell is incapable
      of using fermentation for ATP synthesis and obtains energy via oxidative
      phosphorylation.

PMID- 12402079
TI  - Genotype analyses of Campylobacter isolated from distinct segments of the
      reproductive tracts of broiler breeder hens.
AB  - Campylobacter isolated from feces and from the oviduct of six broiler breeder
      hens were genotyped by using flaA SVR DNA sequence analyses. A diversity of
      genotypes was observed among fecal and oviduct isolates. Comparison of isolates
      from the oviducts of individual hens revealed variable results. In three cases
      (hen 2, hen 3, and hen 6), analyses indicated that isolates from all regions of
      the individual hen's reproductive tract were closely related; isolates from hen 1
      and hen 4 were diverse. Comparison of the Campylobacter isolates between hens
      revealed that in two cases, hens 1 and 3 and hens 4 and 6, certain isolates
      possessed identical flaA SVR sequence types. Comparisons of Campylobacter
      isolates recovered from a distinct region of the oviduct were found to have
      increased diversity as sampling progressed down the oviduct. This study further
      demonstrates that Campylobacter is present within the reproductive tract of
      breeder hens and that this presence may enable vertical transmission of
      Campylobacter from the breeder hen to the broiler offspring.

PMID- 12402080
TI  - Intracellular proteases of Bacillus thuringiensis subsp. kurstaki and a protease
      deficient mutant Btk-q.
AB  - The commencement of intracellular protease synthesis was studied by gelatin
      zymography in Bacillus thuringiensis ( Btk) HD1, Btk HD73, and a protease
      deficient mutant Btk-q derived from the former strain. By gelatin zymography, a
      92-kDa protease was detected first at 3 h of sporulation, which continued until
      48 h, whereas two other proteases of mol wt 78 and 69 kDa were detectable from 6
      h onwards and continued until 48 h of growth in Btk HD1. Similar studies revealed
      the presence of two major intracellular proteases in Btk HD73 by gelatin
      zymography, which first appeared at 6 h of sporulation and continued until 48 h
      of growth. The quantitative azocasein assay confirmed that the total protease
      activity increases from 3 to 21 h, thereafter reaching a plateau up to 48 h of
      growth examined, in HD1 and HD73 strains. Btk-q, a protease-deficient mutant,
      showed traces of protease activity by azocasein analysis that could not be
      detected by gelatin zymography. The free amino acid pool content was also
      increased parallel to the way that the protease activity increased in all three
      strains. However, this increase was found to be low (16-fold) in Btk-q when
      compared with Btk HD1 and HD73 strains. The following amino acids were detected
      by paper chromatography in Btk HD1: DL-alanine, L-glutamic acid, L-aspartic acid,
      tyrosine, tryptophan/methionine/valine, arginine, leucine/norleucine/isoleucine,
      and glycine, whereas only DL-alanine, L-glutamic acid, and L-aspartic acid were
      in Btk-q at 24 and 48 h, when the protease activity was maximum.

PMID- 12402081
TI  - Mechanism of copper resistance in a copper mine isolate Pseudomonas putida strain
      S4.
AB  - The mechanism of copper resistance in a multiple-metal-resistant natural isolate
      Pseudomonas putida strain S4 is based on inducible efflux. Active extrusion of
      copper ions occurs from the cytoplasm during the exponential phase of growth.
      Involvement of ATPase in the efflux of copper ions has been demonstrated by
      employing specific inhibitors. The effluxed copper is not thrown out of the cell,
      but remains in a bound form (to a protein) in the periplasm. Thus, a balance
      between the intracellular level, to fulfill the metabolic requirements, and the
      periplasmic sequestration, to evade toxicity, is maintained by this isolate.

PMID- 12402083
TI  - An evolutionary perspective of Pierce's disease of grapevine, citrus variegated
      chlorosis, and mulberry leaf scorch diseases.
AB  - Xylella fastidiosa causes diseases on a growing list of economically important
      plants. An understanding of how xylellae diseases originated and evolved is
      important for disease prevention and management. In this study, we evaluated the
      phylogenetic relationships of X. fastidiosa strains from citrus, grapevine, and
      mulberry through the analyses of random amplified polymorphic DNAs (RAPDs) and
      conserved 16S rDNA genes. RAPD analysis emphasized the vigorous genome-wide
      divergence of X. fastidiosa and detected three clonal groups of strains that
      cause Pierce's disease (PD) of grapevine, citrus variegated chlorosis (CVC), and
      mulberry leaf scorch (MLS). Analysis of 16S rDNA sequences also identified the PD
      and CVC groups, but with a less stable evolutionary tree. MLS strains were
      included in the PD group by the 16S rDNA analysis. The Asiatic origins of the
      major commercial grape and citrus cultivars suggest the recent evolution of both
      PD and CVC disease in North and South America, respectively, since X. fastidiosa
      is a New World organism. In order to prevent the development of new diseases
      caused by X. fastidiosa, it is important to understand the diversity of X.
      fastidiosa strains, how strains of X. fastidiosa select their hosts, and their
      ecological roles in the native vegetation.

PMID- 12402082
TI  - Physiological and cellular responses of the 2,4-D degrading bacterium,
      Burkholderia cepacia YK-2, to the phenoxyherbicides 2,4-D and 2,4,5-T.
AB  - Our previous research has demonstrated that novel 43-kDa DnaK and 41-kDa GroEL
      proteins are synthesized in Burkholderia sp. YK-2 in response to sublethal
      concentrations of 2,4-D stress [Cho et al. (2000) Curr Microbiol 41:33-38]. In
      this study, we have extended this work to examine the cellular responses of
      strain YK-2 to stresses induced in response to the phenoxyherbicides 2,4-D or
      2,4,5-T. Strain YK-2 exhibited a more sensitive response to 2,4,5-T stress than
      to 2,4-D stress, as shown in physiological and morphological changes, suggesting
      a greater cytotoxic effect of 2,4,5-T. SEM analyses revealed the presence of
      perforations and irregular rod forms with wrinkled surfaces for cells treated
      with either herbicide. These irregularities were found more frequently for 2,4,5
      T-treated cells than for 2,4-D-treated cells. Analysis of cellular fatty acids
      showed similar effects in the shifts of total cellular fatty acid composition in
      response to 2,4-D and 2,4,5-T. Strain YK-2 could degrade 2.25 m M 2,4-D
      completely during 28 h of incubation with transient production of 2,4
      dichlorophenol as a metabolite; however, 2,4,5-T was not catabolized at any of
      the concentrations tested. BIOLOG and 16S rDNA analyses revealed that strain YK-2
      was 98% similar to the Burkholderia cepacia species cluster; therefore, we have
      designated this strain as B. cepacia YK-2.

PMID- 12402084
TI  - Isolation of spectinomycin resistance mutations in the 16S rRNA of Salmonella
      enterica serovar Typhimurium and expression in Escherichia coli and Salmonella.
AB  - Two single-base mutations in 16S rRNA conferring high-level resistance to
      spectinomycin were isolated on a plasmid-borne copy of the rrnD operon from
      Salmonella enterica serovar Typhimurium. Neither of the mutations (C1066U and
      C1192U) had appreciable effects on cell growth, but each had differential effects
      on resistance to spectinomycin and fusidic acid. Both mutations also conferred
      resistance to spectinomycin in Escherichia coli strains containing deletions of
      all seven chromosomal rrn operons and expressing plasmid-encoded Salmonella rRNA
      exclusively. In contrast, when expressed in E. coli strains containing intact
      chromosomal rrn operons, the strains were sensitive to spectinomycin. However,
      chromosomal mutations arose that allowed expression of the rRNA-dependent
      spectinomycin resistance phenotype. It is proposed that in heterogeneous rRNA
      populations, the native E. coli rRNA out-competes the heterologous Salmonella
      rRNA for binding to ribosomal proteins, translation factors, or ribosome
      assembly, thus limiting entry of the antibiotic-resistant 30S subunits into the
      functioning ribosome pool.

PMID- 12402085
TI  - Isolation and characterization of bile salts-sensitive mutants of Enterococcus
      faecalis.
AB  - A library of insertional mutants of Enterococcus faecalis was constructed; it
      allowed the isolation and the characterization of 10 mutants affected in
      resistance to bile salts. Insertion loci of two mutants corresponded to genes of
      unknown function, while the amino acid sequences deduced from the other loci were
      homologous to proteins related to DNA repair, oxidative response, transcriptional
      regulation, dGTP hydrolysis, membrane composition, or cell wall synthesis.
      Further characterization of one mutant revealed that the insertion within the E.
      faecalis sagA gene led to a decrease of the resistance towards numerous
      independent physicochemical stresses, to modifications of the cell wall
      integrity, and to perturbations of cell division with septation anomalies.

PMID- 12402086
TI  - Overexpression of the cgtA (yhbZ, obgE) gene, coding for an essential GTP-binding
      protein, impairs the regulation of chromosomal functions in Escherichia coli.
AB  - GTPases belonging to the Obg/Gtp1 subfamily are essential proteins in most
      bacterial species and are evolutionarily conservative from bacteria to humans.
      However, their specific functions in the regulation of cellular processes are
      largely unknown. Here we demonstrate that overproduction of a member of the
      Obg/Gtp1 subfamily, cgtA ( yhbZ, obgE) gene product, in Escherichia coli is
      deleterious for bacterial growth. However, syntheses of DNA, RNA, and proteins
      were not significantly affected under these conditions as measured by efficiency
      of incorporation of radioactive precursors. On the other hand, flow cytometry
      studies revealed that cgtA-overexpressing bacteria form enlarged cells with
      significantly changed distribution of chromosomal DNA. These results strongly
      suggest that overproduction of a GTP-binding protein from the Obg/Gtp1 subfamily
      impairs regulation of some chromosomal functions in E. coli, especially
      synchronization of DNA replication initiation and possibly also partitioning of
      daughter chromosomes after a replication round.

PMID- 12402087
TI  - Diffusion of beta-lactam antibiotics through oligomeric or monomeric porin
      channels of some gram-negative bacteria.
AB  - The penetration of anionic beta-lactam antibiotics through porins was evaluated
      as a mechanism of drug resistance. The major proteins with porin activity were
      purified from the outer membranes of six bacteria. Three of the six porins were
      oligomeric porins. The molecular weights of their monomers were 37 kDa from
      Photobacterium damsela, 42 kDa from Serratia liquefaciens, and 36 kDa from E.
      coli B. The other three porins were heat-modifiable monomeric porins with
      molecular weights of 43 kDa from Porphyromonas asaccharolytica and Acinetobacter
      baumannii, and 37 kDa from Escherichia coli K12. Comparison of the six porin
      proteins revealed that, independent of their aggregation state, their amino acid
      content is similar but not identical. All have double the amount of negatively
      charged amino acids compared with positively charged amino acids. They have a
      similar polarity and polarity index. Two of the six tested bacteria do not
      produce beta-lactamase. These two bacteria were sensitive to the different beta
      lactams tested. The other four bacteria were resistant to all or to several beta
      lactams.A modified liposome swelling method was used for determining the rate of
      penetration of charged beta-lactam antibiotics. Zwitterionic beta-lactams were
      found to penetrate into liposomes at a rate that more or less fits their
      molecular weight, whether the porins are monomeric or oligomeric. The penetration
      rates of negatively charged beta-lactams are different for oligomeric and
      monomeric porins. Negatively charged beta-lactams penetrate through oligomeric
      porins better than estimated by their molecular weight, whereas monomeric porins
      are less penetrable to negatively charged beta-lactams than estimated by their
      molecular weight. The contribution of all types of porins to the susceptibility
      of bacteria to beta-lactam antibiotics (zwitterionic or negatively charged) is
      apparently doubtful. The porins may decrease or increase bacterial penetration
      rates to beta-lactams, and only the existence of a potential beta-lactamase that
      can destroy the penetrating drug will cause resistance.

PMID- 12402088
TI  - Cloning and expression of Chlorobium vibrioforme uroporphyrinogen decarboxylase
      gene in a Salmonella heme auxotroph.
AB  - To study the post-uroporphyrin steps in heme and chlorophyll biosynthesis in
      Chlorobium, we attempted to clone the uroporphyrinogen decarboxylase ( hemE)
      gene. A Chlorobium genomic library was used to transform a restriction-minus
      Salmonella typhimurium strain. The recombinant DNA molecules were transduced into
      an auxotrophic Salmonella double mutant ( hemA(-) hemE(-)) by phage P22. Faster
      growing colonies indicated complementation of the hemE mutation. Each clone was
      tested by backcross transduction of the mutant. Growth rates of the confirmed
      clones in LB medium were comparable to wild-type Salmonella. HPLC analysis of the
      substrate (uroporphyrinogen) and the product (coproporphyrinogen) of the
      decarboxylase activity was performed in one such clone. This clone showed an
      active hemE gene within a 4-kb insert.

PMID- 12402089
TI  - Isolation and characterization of the genes encoding delta(8)-sphingolipid
      desaturase from Saccharomyces kluyveri and Kluyveromyces lactis.
AB  - Saccharomyces kluyveri IFO 1685 and Kluyveromyces lactis IFO 1090 synthesize
      cerebroside containing 9-methyl- trans-4, trans-8-sphingadienine as a sphingoid
      base. From the genome of the two strains, the regions encompassing Delta(8)
      sphingolipid desaturase were amplified and sequenced. The nucleotide sequences of
      these regions revealed single open reading frames of 1707 bp for S. kluyveri and
      1722 bp for K. lactis, encoding polypeptides of 568 and 573 amino acids with
      molecular weights of 66.5 and 67.1 kDa, respectively. Conversion of 4
      hydroxysphinganine to 4-hydroxy- trans-8-sphingenine in the cells of
      Saccharomyces cerevisiae was observed by the expressed gene from K. lactis and
      not by that from S. kluyveri. These findings may be explained by the difference
      in substrate specificity for the sphingoid base moiety between Delta(8)
      sphingolipid desaturases of S. kluyveri and K. lactis.

PMID- 12402090
TI  - Avanca Brasil: environmental and social consequences of Brazil's planned
      infrastructure in Amazonia.
AB  - "Avanca Brasil" (Forward Brazil) is a package of 338 projects throughout Brazil;
      the portion of the plan to be carried out in Brazil's Legal Amazon region totals
      US$43 billion over 8 years, US$20 billion of which would be for infrastructure
      causing environmental damage. Brazil's environmental impact assessment system is
      not yet capable of coping with the challenge presented by Avanca Brasil. Generic
      problems with the licensing process include stimulation of a lobby in favor of
      construction before decisions are made on the advisability of the projects, the
      "dragging effect" of third parties, whereby economic activity is attracted to the
      infrastructure but escapes the environmental impact assessment system, a tendency
      for consulting firms to produce favorable reports, a bureaucratic emphasis on the
      existence of steps without regard to the content of what is said, and the
      inability to take account of the chain of events unleashed when a given project
      is undertaken. The environmental and social costs of forest loss are high; among
      them is loss of opportunities for sustainable use of the forest, including loss
      of environmental services such as biodiversity maintenance, water cycling, and
      carbon storage. The benefits of export infrastructure are meager, especially from
      the point of view of generating employment. Much of the transportation
      infrastructure is for soybeans, while the hydroelectric dams contribute to
      processing aluminum. The example of Avanca Brasil makes clear the need to rethink
      how major development decisions are made and to reconsider a number of the plan's
      component projects.

PMID- 12402091
TI  - Involving indigenous peoples in protected area management: comparative
      perspectives from Nepal, Thailand, and China.
AB  - Despite over two decades of efforts towards involving indigenous and traditional
      peoples in protected area management, there are few successful examples. Several
      international principles and guidelines on indigenous peoples' involvement in
      protected areas exist. However, because of the lack of evaluation of whether or
      not these principles and guidelines have been put into practice, there is hardly
      any information that indicates the actual involvement of indigenous peoples in
      protected areas. This paper attempts to compare efforts in partnership between
      indigenous peoples and protected area authority in three Asian countries: Nepal,
      Thailand, and China. It shows that the involvement of indigenous peoples is more
      successful where park planning is participatory and where political and
      socioeconomic reforms are underway. Indigenous peoples are in conflict with park
      authorities where park management is centralized and nonparticipatory. Unless
      concrete efforts are made to address livelihood issues of indigenous peoples
      living in and around protected areas, park management aimed to protect wildlife
      will rarely succeed. Participatory park management that involves indigenous
      peoples and that addresses livelihood issues of indigenous communities will
      ultimately succeed in its efforts toward wildlife conservation.

PMID- 12402092
TI  - Technology, managerial, and policy initiatives for improving environmental
      performance in small-scale gold mining industry.
AB  - This paper reviews a series of strategies for improving environmental performance
      in the small-scale gold mining industry. Although conditions vary regionally, few
      regulations and policies exist specifically for small-scale gold mining activity.
      Furthermore, because environmental awareness is low in most developing countries,
      sites typically feature rudimentary technologies and poor management practices. A
      combination of policy-, managerial- and technology-related initiatives is needed
      to facilitate environmental improvement in the industry. Following a broad
      overview of these initiatives, a recommended strategy is put forth for
      governments keen on improving the environmental conditions of resident small
      scale gold mines.

PMID- 12402093
TI  - Observations on the workshop as a means of improving communication between
      holders of traditional and scientific knowledge.
AB  - Traditional ecological knowledge (TEK) and the information and insights it offers
      to natural resource research and management have been given much attention in
      recent years. On the practical question of how TEK is accessed and used together
      with scientific knowledge, most work to date has examined documentation and
      methods of recording and disseminating information. Relatively little has been
      done regarding exchanges between scientific and traditional knowledge. This paper
      examines three workshop settings in which such exchanges were intended outcomes.
      The Barrow Symposium on Sea Ice, the Exxon Valdez Oil Spill Restoration Program
      Synthesis/Information Workshops, and the Alaska Beluga Whale Committee illuminate
      certain features of the preparation, format, and context of workshops or series
      of workshops and their eventual outcomes and influence. The examples show the
      importance of long-term relationships among participants and thorough preparation
      before the actual workshop. Further research should look more systematically at
      the factors that influence the success of a given workshop and the various ways
      in which participants perceive success.

PMID- 12402094
TI  - Measuring positive, negative, and null impacts of forest disturbances: a case
      study using dwarf mistletoe on Douglas fir.
AB  - Not all disease activity causes an impact. Not all impacts are negative. The aim
      of this study was to examine a method that could conceptually specify when
      impacts occur and that could quantify both negative and positive disease impacts.
      For this study, dwarf mistletoe ( Arceuthobium douglasi) of Douglas fir (
      Pseudotsuga menziesii) in southwestern Oregon was used as a case study. The
      method uses six variables for forest growth, mortality, and stand structure, and
      six categorical disease severity scores. The impact model displays stands as
      points in multidimensional scaling space, where relative position is determined
      by values of the six stand variables. Positions in this two-dimensional space
      change when stand characteristics change. Differences associated with disease
      severity could be traced as trajectories, and impact was quantified using the
      length and direction of these trajectories. This multivariate impact assessment
      method was contrasted to impact assessments based on single variables. Methods
      based on multiple variables offer a useful way of characterizing impact on
      multiple objectives. The model indicates that dwarf mistletoe has positive,
      negative, and neutral impacts and that these could be illustrated and quantified
      using this method.

PMID- 12402095
TI  - Impact of selective herbicide right-of-way vegetation treatment on birds.
AB  - Power line rights-of-way provide a major portion of the shrub habitat in New
      York. Since this habitat type is on the decline, many of the birds dependent on
      shrub habitat are also declining. The methods used to control right-of-way
      vegetation could therefore have serious impacts on several birds of conservation
      concern. Since New York is increasingly using selective herbicide treatments in
      vegetation management, we sought to investigate the potential impacts of these
      treatments on nesting birds. The study looked at plots in two adjacent rights-of
      way before and after a selective herbicide treatment in one of the rights-of-way.
      We investigated three bird species: alder flycatcher (Empidonax alnorum),
      chestnut-sided warbler (Dendroica pensylvanica), and gray catbird (Dumetella
      carolinensis). All three species exhibited a preference for shrub vegetation
      around nest sites. The selective herbicide treatment did not significantly
      decrease that shrub vegetation, and neither the density nor the nesting success
      of the three species declined following the treatment. We conclude that selective
      herbicide vegetation management encourages the development of shrub habitat
      without negatively impacting the birds nesting in the habitat.

PMID- 12402096
TI  - A technicoeconomic approach for the selection of a site remediation strategy-
      part A: theory.
AB  - A technicoeconomic model is developed to select an optimal strategy for the
      remediation of a contaminated site and to determine the value of this remediation
      strategy. The model is an extension of actual cost-benefit analysis, with
      consideration of "irreversible" remediation technology choices, technology
      effectiveness, and uncertainty on the site's level of contamination. The model
      considers the possibility of reducing uncertainty by both acquiring more and
      better information on the level of contamination and by offering the decision
      maker the opportunity to reevaluate his decision and switch to a more appropriate
      technology. It is believed that this model will help decision-makers in the
      selection of a remediation strategy by presenting all potentially feasible
      strategies, and how uncertainty on the site's level of contamination affects
      these strategies.

PMID- 12402097
TI  - Fuzzy multiple-criteria decision-making approach for industrial green
      engineering.
AB  - This paper describes a fuzzy hierarchical analytic approach to determine the
      weighting of subjective judgments. In addition, it presents a nonadditive fuzzy
      integral technique to evaluate a green engineering industry case as a fuzzy
      multicriteria decision-making (FMCDM) problem. When the investment strategies are
      evaluated from various aspects, such as economic effectiveness, technical
      feasibility, and environmental regulation, it can be regarded as an FMCDM
      problem. Since stakeholders cannot clearly estimate each considered criterion in
      terms of numerical values for the anticipated alternatives/strategies, fuzziness
      is considered to be applicable. Consequently, this paper uses triangular fuzzy
      numbers to establish weights and anticipated achievement values. By ranking fuzzy
      weights and fuzzy synthetic utility values, we can determine the relative
      importance of criteria and decide the best strategies. This paper applies what is
      called a lambda fuzzy measure and nonadditive fuzzy integral technique to
      evaluate the synthetic performance of green engineering strategies for aquatic
      products processors in Taiwan. In addition, we demonstrate that the nonadditive
      fuzzy integral is an effective evaluation and appears to be appropriate,
      especially when the criteria are not independent.

PMID- 12402098
TI  - A morphological comparison of narrow, low-gradient streams traversing wetland
      environments to alluvial streams.
AB  - Twelve morphological features from research on alluvial streams are compared in
      four narrow, low-gradient wetland streams located in different geographic regions
      (Connecticut, Indiana, and Wisconsin, USA). All four reaches differed in
      morphological characteristics in five of the features compared (consistent bend
      width, bend cross-sectional shape, riffle width compared to pool width, greatest
      width directly downstream of riffles, and thalweg location), while three reaches
      differed in two comparisons (mean radius of curvature to width ratio and axial
      wavelength to width ratio). The remaining five features compared had at least one
      reach where different characteristics existed. This indicates the possibility of
      varying morphology for streams traversing wetland areas further supporting the
      concept that the unique qualities of wetland environments might also influence
      the controls on fluvial dynamics and the development of streams. If certain
      morphological features found in streams traversing wetland areas differ from
      current fluvial principles, then these varying features should be incorporated
      into future wetland stream design and creation projects. The results warrant
      further research on other streams traversing wetlands to determine if streams in
      these environments contain unique morphology and further investigation of the
      impact of low-energy fluvial processes on morphological development. Possible
      explanations for the morphology deviations in the study streams and some
      suggestions for stream design in wetland areas based upon the results and field
      observations are also presented.

PMID- 12402099
TI  - Impacts of man-made landscape features on numbers of estuarine waterbirds at low
      tide.
AB  - The potential impact of human disturbance on wintering waterbirds using
      intertidal mudflats was considered by relating their numbers to the presence of
      nearby footpaths, roads, railroads, and towns. Data were obtained for six English
      estuaries from the Wetland Bird Survey Low Tide Count scheme. Counts were
      undertaken monthly from November to February, and data were available for an
      average of 2.8 years per estuary for the period 1992-1993 to 1999-2000. Count
      sections and the positions of man-made landscape features were mapped using a
      GIS. Generalized linear models tested whether bird numbers varied according to
      the estuary, month, area, whether or not the section bordered water, and the
      proportion of each section within a specified distance of each landscape feature.
      In addition, the proximity of sections to the nearest footpath access point was
      considered. Numbers of six of nine species, northern shelduck (Tadorna tadorna),
      red knot (Calidris canutus), dunlin (Calidris alpina), black-tailed godwit
      (Limosa limosa), Eurasian curlew (Numenius arquata) and common redshank (Tringa
      totanus), were significantly lower where a footpath was close to a count section,
      while those of brant (Branta bernicla) were greater. Northern shelduck, black
      bellied plover (Pluvialis squatarola), dunlin, and black-tailed godwit numbers
      were reduced close to railroads and those of common ringed plover (Charadrius
      hiaticula), black-bellied plover, and Eurasian curlew close to roads. Common
      ringed plover numbers were greater close to towns. The relative distances to
      which species were affected by footpaths corresponded to published information
      concerning their flight distances in response to human disturbance. The study
      provided evidence that sustained disturbance associated with footpaths, roads,
      and railroads reduced local habitat quality for waterbirds and the carrying
      capacity of estuaries.

PMID- 12402100
TI  - Impacts of disturbance from construction work on the densities and feeding
      behavior of waterbirds using the intertidal mudflats of Cardiff Bay, UK.
AB  - The impact of disturbance from construction work around Cardiff Bay, south Wales,
      on the densities and feeding behavior of seven waterbird species was studied over
      an 11-year period. Construction of a barrage across the mouth of the bay has
      subsequently resulted in its impoundment; other major works included the
      construction of a bridge carrying a divided highway. Construction work
      disturbance significantly reduced the densities of five species--green-winged
      teal (Anas crecca), Eurasian oystercatcher (Haematopus ostralegus), dunlin
      (Calidris alpina), Eurasian curlew (Numenius arquata), and common redshank
      (Tringa totanus)--on adjacent intertidal mudflats, and thus the overall carrying
      capacity of the bay. Construction work also reduced the feeding activity of
      Eurasian oystercatcher, dunlin, and common redshank on these mudflats. The
      possible impact of the loss of birds from these mudflats upon the populations
      that the bay supported is discussed. Evidence from other local studies suggests
      that the displacement of common redshank from these mudflats did not contribute
      to a decline in this species.

PMID- 12402101
TI  - Sydney tar ponds: some problems in quantifying toxic waste.
AB  - Information on the type and amount of hazardous and toxic waste is required to
      develop a meaningful strategy and estimate a realistic cost for clean up of the
      Sydney Tar Pond site which is located on Cape Breton, in the province of Nova
      Scotia, Canada. The site covers the area of the decommissioned Sysco (Sydney
      Steel Corporation) plant. The materials of concern include BTEX (benzene,
      toluene, ethylbenzene, and xylenes), PAH (polycyclic aromatic hydrocarbons), PCB
      (polychlorinated biphenyl), and particulates laden with toxic metals, such as
      arsenic, lead, and others. The originally nontoxic materials such as soil, blast
      furnace slag, and vegetation, as well as surface and ground waters, which were
      subsequently contaminated, must also be included if they fail tests prescribed by
      environmental regulations. An extensive sampling program must be undertaken to
      obtain data for an accurate estimate of the waste to be cleaned and disposed of.
      Apparently, 700,000 tons of toxic waste, which is believed to be present on the
      site, may represent only a fraction of the actual amount. The clean-up of the
      site is only part of the solution. Toxic waste has to be disposed of in
      accordance with environmental regulations.

PMID- 12402104
TI  - [Pathophysiology of overuse tendon injury].
AB  - Overuse tendon injury is one of the most common injuries in sports. The etiology
      as well as the pathophysiological mechanisms leading to tendinopathy are of
      crucial medical importance. At the moment intrinsic and extrinsic factors are
      assumed as mechanisms of overuse tendon injury. Except for the acute, extrinsic
      trauma, the chronic overuse tendon injury is a multifactorial process. There are
      many other factors, such as local hypoxia, less of nutrition, impaired metabolism
      and local inflammatory that may also contribute to the development of tissue
      damage. The exact interaction of these factors cannot be explained entirely at
      the moment. Further studies will be necessary in order to get more information.

PMID- 12402103
TI  - Cocaine-seeking behavior after extended cocaine-free periods in rats: role of
      conditioned stimuli.
AB  - RATIONALE: Cocaine abstinence symptoms and conditioned stimuli (CSs) previously
      associated with cocaine administration are postulated to contribute to relapse to
      drug taking in humans. OBJECTIVE: The present study assessed the role of both non
      contingent CS presentation and experimenter-imposed extended cocaine-free periods
      on cocaine-seeking behavior in rats. METHODS: A fixed interval (FI) second-order
      schedule of intravenous cocaine (0.5 mg/infusion) reinforcement of the type FI 15
      min (fixed ratio 8:S) was used. RESULTS: Non-contingent CS presentation before
      exposure to a cocaine binge had no effect on responding under the second-order
      schedule of reinforcement for cocaine after 23 h of no access to cocaine. By
      contrast, six non-contingent presentations of the CS during a 1-min period before
      the test session increased the number of responses in both no-binge (daily 2-h
      sessions, five infusions) and binge (two 12-h overnight sessions; maximum 48
      infusions) exposed rats on day 7 of the cocaine-free period compared to no-binge-
      and binge-exposed rats that were not presented with the CSs. On day 30 of the
      cocaine-free period, only binge-exposed rats presented with the CSs exhibited a
      tendency for increased level of responding. CONCLUSIONS: The results indicated
      that non-contingent CS presentation had no effect after 23 h of no access to
      cocaine, increased drug-seeking behavior on day 7 of the cocaine-free period
      independent of binge exposure, and a strong tendency to increase drug-seeking
      behavior only in binge-exposed rats, on day 30 of the cocaine-free period,
      illustrating the interactive effects of conditioned stimuli with the extended
      cocaine-free period.

PMID- 12402105
TI  - [Stress fractures in athletes].
AB  - Stress fractures may pose a diagnostic dilemma for radiologists since they are
      sometimes difficult to demonstrate on plain films and may simulate a tumour. They
      were first described in military personnel and professional athletes. Recently,
      there is an increasing incidence in the general population due to increasing
      sportive activities. Stress fractures occur most often in the lower extremities,
      especially in the tibia, the tarsal bone, the metatarsal bone, the femur and the
      fibula. In the upper extremities, they are commonly found in the humerus, the
      radius and the ulna. Some fractures of the lower extremities appear to be
      specific for particular sports, for example, fractures of the tibia affect mostly
      distance runners. Whereas stress fractures of the upper extremities are generally
      associated with upper limb-dominated sports. A correct diagnosis requires a
      careful clinical evaluation. The initial plain radiography may be normal. Further
      radiological evaluation could be performed by means of computerised tomography,
      magnetic resonance imaging and bone scanning. The latter two techniques are
      especially helpful for establishing a correct initial diagnosis.

PMID- 12402106
TI  - [Diagnostic imaging of injuries and overuse in soccer players].
AB  - Soccer is one of the most popular sports worldwide. There is a high incidence of
      injuries in soccer in which several intrinsic and extrinsic factors play a part.
      Most injuries are minor, self-limiting and do not need extensive medical
      treatment or imaging. Imaging can be required for several reasons e.g. when the
      clinical findings are doubtful, to replace arthroscopy (i. e. of the knee) or for
      prognostic reasons. All imaging modalities available to the radiologist can be
      used but MRI is the most valuable imaging modality with its superior contrast
      resolution and multiplanar capabilities. Basically, injuries in the soccer player
      can occur anywhere in the body like in every sport. The lower extremities, more
      specific the knee and ankle, are however the most injured parts.

PMID- 12402102
TI  - The reinstatement model of drug relapse: history, methodology and major findings.
AB  - RATIONAL AND OBJECTIVES: The reinstatement model is currently used in many
      laboratories to investigate mechanisms underlying relapse to drug seeking. Here,
      we review briefly the history of the model and describe the different procedures
      that have been used to study the phenomenon of reinstatement of drug seeking. The
      results from studies using pharmacological and neuroanatomical techniques to
      determine the neuronal events that mediate reinstatement of heroin, cocaine and
      alcohol seeking by acute priming injections of drugs, drug-associated cues and
      environmental stressors are summarized. In addition, several issues are
      discussed, including (1) the concordance between the neuronal mechanisms involved
      in drug-induced reinstatement and those involved in drug reward and
      discrimination, (2) the role of drug withdrawal states and periods in
      reinstatement of drug seeking, (3) the role of neuronal adaptations induced by
      exposure to drugs in relapse, and (4) the degree to which the rat reinstatement
      model provides a suitable preclinical model of relapse to drug taking.
      CONCLUSIONS: The data derived from studies using the reinstatement model suggest
      that the neuronal events that mediate drug-, cue- and stress-induced
      reinstatement of drug seeking are not identical, that the mechanisms underlying
      drug-induced reinstatement are to some degree different from those mediating drug
      discrimination or reward, and that the duration of the withdrawal period
      following cocaine and heroin self-administration has a profound effect on
      reinstatement induced by drug cues and stress. Finally, there appears to be a
      good correspondence between the events that induce reinstatement in laboratory
      animals and those that provoke relapse in humans.

PMID- 12402107
TI  - [Diagnosis of climbing related overuse injuries].
AB  - Sport climbing shows an enormous increase in participation, evolving to more
      popularity, including even school sport activity on high standards. Therefore the
      number of climbing related injuries is increasing and becomes a more frequently
      encountered medical problem. Typical climbing associated injuries involve
      predominantly the upper limb. Overuse injuries are the most common climbing
      related injuries. The clinical examination is the first line investigation, which
      is often limited especially in the acute phase. However, an exact diagnosis is
      desirable for therapeutic management. Imaging modalities have shown to be capable
      for detection of climbing related injuries. An overview about the current use of
      x-ray, ultrasound and magnetic resonance imaging in different climbing related
      overuse injuries is presented.

PMID- 12402108
TI  - [Sport injuries of the extensor mechanism of the knee].
AB  - Injuries of the extensor mechanism of the knee occur frequently during sport
      activity. For a successful treatment they must be diagnosed early. Besides
      osseous structures the patellar tendon, the patella, the quadriceps muscle and
      tendon, retinacula and bursae can be affected. After initial clinical examination
      there are different noninvasive imaging modalities available for assessment of
      bone, cartilage, ligaments, tendons and soft tissue. Conventional radiographs are
      still the basic imaging tool for the clinician. Additional information about the
      osseous status is provided by computed tomography, whereas sonography plays an
      important role concerning diagnosis of soft tissue injuries. For the detection of
      cartilagenous, ligamentous or tendon lesions MRI is the superior non-invasive
      imaging modality.

PMID- 12402109
TI  - [Achilles tendon and sports].
AB  - Because of the rising popularity of recreational sports activities achillodynia
      is an often associated symptom with running, soccer and athletics. Therefore
      radiologist are frequently asked to image this tendon. The origin of the damage
      of the Achilles tendon is explained by numerous hypothesis, mainly a decreased
      perfusion and a mechanical irritation that lead to degeneration of the tendon.
      High-resolution technics such as sonography and magnetic resonance imaging show
      alterations in the structure of the tendon which can be graduated and classified.
      Manifestations like tendinosis, achillobursitis, rupture and Haglunds disease can
      summarized as the tendon overuse syndrome. A rupture of a tendon is mostly the
      result of a degeneration of the collagen fibers. The task of the radiologist is
      to acquire the intrinsic factors for a potential rupture.

PMID- 12402110
TI  - [Apophyseal damage in adolescent athlete].
AB  - The increasing demands on the adolescent athlete in high performance sports puts
      high biomechanical stress on the growing structures of the active and passive
      locomotor system. The "growing factor" itself increases stretching forces on
      tendon insertions, which are often overloaded when a physical demanding sport is
      performed additionally. The apophysis is an ossification nucleus near the tendon
      insertion, which appears before the growing age resumes and these apophysis
      finally fuses with the adjacent bone. The tensile forces from vigorous sports
      activity leads to a chronic or acute avulsion of the ossifying tendon insertion.
      The radiological appearance of this apophyseal damage with ossification and
      osteolytic processes is sometimes difficult with respect to differential
      diagnoses. Apophyseal impairment is associated with pain, tenderness to palpation
      and decreased muscle function. If it is not diagnosed and treated properly it can
      lead to end of career in many adolescent athletes.

PMID- 12402111
TI  - [Sports-related injuries of the spine].
AB  - Different sports show different patterns and frequencies of injuries, which are
      discussed in this paper. About 3% of all sports accidents relate to the spine.
      These injuries often have far-reaching consequences for the patients. A very
      early and extensive diagnosis of all changes is decisive for the start of an
      adequate therapy and thus for the prognosis of the injury. Radiological diagnosis
      is also of decisive importance for the documentation of late injuries and in the
      question of rehabilitation. Here special focus is put on MRT and CT diagnostics.A
      healthy spine of humans is normally able to resist all static and dynamic strains
      of the usual sports. However, anomalies and dysfunctions of the spine can reduce
      its capacity to resist strain. The recommendations of sporting activities are
      given according to the extent of deflection and the expected growth. The
      importance of radiology in primary diagnosis and in the follow-up due to typical
      changes like scoliosis, Morbus Scheuerman, spondylolysis and spondylolisthesis is
      discussed here as well.

PMID- 12402112
TI  - [Congenial seminal vesicle cyst with an intracystic papillary adenoma associated
      with ipsilateral renal agenesis].
AB  - We report on a case of a 67 year old male who had a cyst in the seminal vesicle
      region on sonography. The computed tomography and magnetic resonance imaging
      findings included a seminal vesical cyst with an intracystic tumor associated
      with an ipsilateral renal agenesis and are demonstrated. Postoperatively the
      diagnosis of an intracystic papillary adenoma in a seminal vesicle cyst was made
      histologically.

PMID- 12402113
TI  - [Intracerebral tumors in adulthood. 2: Extra-axial tumors].

PMID- 12402114
TI  - [Continuing medical education. Voluntary commitment to competence--no federal
      control system].

PMID- 12402115
TI  - [DRGs/case fee schedules. The 2003 option model is coming].

PMID- 12402116
TI  - [2002 hospital barometer. High investment inertia and "on-call schedules"].

PMID- 12402117
TI  - [Guidelines of the Federal Physician Council. New quality control in the nuclear
      medicine laboratory].

PMID- 12402119
TI  - [Out of scope].

PMID- 12402118
TI  - [Evidence based medicine hit list 2000. Mammography update--sequelae for
      screening. 1].

PMID- 12402120
TI  - [Stuttgart district court. Radiologist may confine himself to examination order].

PMID- 12402121
TI  - [Great damage event of the Dutch Enschede on May 13th, 2000].
AB  - The mass casualty of injured confronts the rescue service with a special
      challenge again and again. An immediate need arises besides the emergency medical
      help for the coordination of use strengths moving up differently than at the
      individual emergency. Executives of the rescue service in Germany are leading
      emergency doctor and organizational leader. If the damage event takes place,
      however, outside the country borders or country general, then one feels compared
      with a situation which offers next to sizes in addition unknown to a great damage
      situation of the country by different use of tactics. It is interesting from this
      aspect to look at the great damage event of the Dutch Enschede on May 13th, 2000
      and to examine the accident expiry by different points of view.

PMID- 12402122
TI  - [Analysis of the incidence and causes of mass casualty events in a southern
      Germany medical rescue area].
AB  - The growing number of mass casualty events during the early 1990s led, in January
      1996, to the foundation of an honorary group of specially trained emergency
      physicians for dealing primarily with the management of large-scale emergency
      events and mass casualties. The incidence and quantity of these casualties was
      analysed in order to be better prepared for such events in the future. METHODS:
      All calls prospectively registered by the Augsburg Rescue Co-ordination Centre
      (ARCC) in the 5 years from July 1997 to June 2002 were analysed, distinguishing
      between the different types of damage, number of patients involved, and time of
      occurrence (time of day/season). The area served by the ARCC includes the city of
      Augsburg with its surrounding counties. An estimated 850,000 inhabitants live in
      this area of 4,100 square kilometers (1,600 square miles). Since 1998, more than
      145,000 calls a year have been dealt with of which 28,000 were covered by
      emergency physicians. In the 5 year period discussed here, 75 large-scale-calls
      were registered, giving an average incidence of 1.25 calls/month. Most of the
      calls were fire alarms, followed by car accidents. In total, we were able to
      serve more than 800 patients. The lowest number per event was two people during
      an emergency landing of a sport aircraft; the largest number was about 150
      patients during a large open-air event in the city. While there was no difference
      in the time of day at which the event happened, most occurred in November and
      December. Taking these results into account, the authors, supported by the
      members of the emergency physician team of the German Trauma Society, developed
      an algorithm describing the optimal procedure for mass casualty events. This is
      presented here. In mass casualty or large-scale emergency events, an experienced
      emergency physician is necessary to co-ordinate the rescue brigades on site.

PMID- 12402123
TI  - [Preclinical care of trauma patients in air rescue. Results of the medical
      quality management for patients with severe head injury and polytrauma in the
      years 2000 and 2001].
AB  - In a retrospective study of mission data of ADAC Air Rescue of the years 2000 and
      2001 the quality of preclinical care of 1,946 patients with severe head injuries
      and 1,878 polytraumatized patients was examined. The actual preclinical care of
      these patients was compared with a catalogue of eleven thesis-like
      recommendations. These recommendations were previously derived from corresponding
      publications of national and international specialist companies and were
      introduced in a binding manner by the senior doctors of the participating air
      rescue centres. The results of the study show that 73.3% of the severe head
      injuries were preclinically intubated and 94.4% were supplied with oxygen, 82.2%
      were analgosedated. 94.8% could be delivered to the hospital of destination.
      65.9% had a systolic blood pressure of >120 mmHg upon admission to the hospital.
      71.4% of severe head injury victims were equipped with a cervical support, 23.3%
      had the blood pressure documented. 47.3% reached the hospital of destination in
      less than 60 minutes. Among polytraumatic patients the intubation was performed
      in 75.7%, the supply with oxygen in 90.7%, 88.6% of the patients were
      analgosedated. 78.7% of patients suffering from concomitant head injuries were
      provided with a cervical support and only 22.8% had a blood sugar measurement
      documented. A concomitant severe thorax trauma was treated by a thorax drainage
      in 59.2%. 35.6% of the polytraumata reached the hospital of destination in less
      than 60 minutes. The work describes the preclinical patient care of severe head
      injuries and polytraumata, pointing out deficits and presenting optimization
      possibilities, particularly in the area of training. Furthermore, the work shows
      the concept of the medical quality management in an air rescue enterprise. The
      total evaluation of all air rescue centres participating in data collection forms
      the basis of an external quality comparison. The data evaluation of a single
      station makes regional strengths and weaknesses visible, deficits can be proven
      and proposals for optimization be developed. The presentation of the time history
      of data yields continuous standard information on the state of the patient care
      at the relevant air rescue location and enables the analysis of improvement
      concepts based on the updated data.

PMID- 12402124
TI  - [Optimized management of polytraumatized patients by prehospital ultrasound].
AB  - AIM: The purpose of the study was to evaluate the practicability and the benefit
      of focused abdominal sonography for trauma (FAST) on scene. METHODS: Prehospital
      ultrasound was performed on 61 patients being suspicious for abdominal trauma.
      Free fluid in the Koller's and Morison's pouch, pelvis and pleural space was
      investigated. After admission routine ultrasound and computer tomography scan was
      obtained to control prehospital findings. RESULTS: The mean investigation time
      was 2.8+/-1.2 min. In 16 patients (26.2%) free fluid was detected with 7 massive
      and 9 moderate findings. 3 patients died on the scene due to their abdominal
      injuries. 4 patients underwent laparotomy immediately after admission with 3
      splenectomies performed. There was one false positive but no negative FAST
      resulting in a specificity of 97.5% and sensitivity of 100%. In 37% of the cases
      the prehospital management was modified and hospital selection was influenced in
      21% of the cases due to the findings of the FAST. CONCLUSION: In the present
      study the data have shown that the prehospital ultrasound is a useful and
      reliable tool for diagnostic procedure on the scene. The data are the basis for a
      multicenter study in the helicopter rescue service. This study will try to answer
      the question whether prehospital ultrasound may be generally recommended in
      trauma patients suspicious for abdominal trauma.

PMID- 12402125
TI  - [Emergency treatment of penetrating, combined thoracic- and abdominal injury. Pre
      hospital i.v. fluid therapy].
AB  - We report the rare case of a penetrating, combined thoracic- and abdominal injury
      as a consequence of a farm work accident. During the recent years, a "treat and
      run" approach has been increasingly advocated as a time-saving way of treating
      penetrating injuries, constituting a compromise between the existing strategies
      of "scoop and run" (used mainly in the USA) and "stay and treat" (preferred in
      Central Europe). A prolonged rescue response time makes the treat and run
      approach impossible here. Immediate treatment at the accident site requires an
      appropriate provision of i.v. fluids. We examine the course of pre-hospital
      treatment of a trauma patient to illustrate the various approaches to i.v. fluid
      therapy in relation to rescue response time. However there are only a few studies
      with a real evidence. If "treat and run" is not possible, the outcome of patients
      with penetrating trauma can be influenced positively by moderate fluid therapy
      under continuous monitoring after having reached a constant, low mean arteria
      pressure (so called permissive hypotension).

PMID- 12402126
TI  - [Pediatric prehospital trauma care. A retrospective comparison of air and ground
      transportation].
AB  - OBJECTIVE: In contrast to prehospital care of adult trauma victims, prehospital
      care providers have only limited clinical experience of pediatric trauma cases as
      these are relatively infrequent. Literature reports on prehospital pediatric
      trauma care given by paramedics are frequently found in the literature, but there
      are few publications analyzing the quality of prehospital trauma care provided by
      emergency physicians in the care of injured children. It was the goal of this
      study to analyze the prehospital care of the pediatric trauma victims transported
      to a trauma center by physician-staffed ambulances and helicopters. METHODS: The
      study took the form of a retrospective 5-year review of pediatric trauma patients
      admitted to a trauma center. The inclusion criteria were age younger than 13
      years and a NACA score higher than 3. In all, 104 patients were included, and
      these were divided into two groups, those transported to hospital by helicopter
      (RTH, n=87) and those taken to hospital by road ambulance (NEF, n=17). RESULTS:
      With a mean NACA score of 4.6 and a mean ISS of 15, no significant differences
      were found between the two groups in either severity of injury or length of
      hospital stay. The mortality of the total patient population was 15.4%, with no
      evidence of preventable deaths in patients who were admitted to the trauma center
      with vital signs. Analysis of prehospital therapy showed no differences in the
      volume of intravenous fluids administered (RTH 636 ml vs NEF 476 ml) or in the
      proportion of children with a GCS<9 in whom endotracheal intubation was
      implemented (RTH 39/44 vs NEF 7/7). Placement of more than one i.v. line and
      endotracheal intubation were associated with longer times at the scene of the
      accident before patients were taken to hospital (>one i.v. corresponded to 9 min
      longer, and endotracheal intubation, to 10 min longer). CONCLUSIONS: Prehospital
      pediatric trauma care delivered by physician-staffed ambulances or rescue
      helicopters is associated with a high rate of i.v. line placement (92%) and high
      intubation rates (90%) in patients with an altered level of consciousness
      (GCS<9). The prehospital care provided by helicopter or ground ambulance
      personnel was not different and was not associated with longer stays in the
      intensive care unit or longer overall stays in hospital. Scene times became
      longer with increasing number of i.v. line placements and with endotracheal
      intubation, but was not prolonged by a greater severity of injury as determined
      by the ISS. Preventable deaths were not observed in the patient population. In
      summary, owing to the the local infrastructure, pediatric trauma patients are
      more frequently transported to the trauma center by air (87 by air vs. 17 by road
      per 5-year time period). However, despite being less frequently involved in the
      case of pediatric trauma, the quality of care provided by road ambulance staff is
      similar to that in air ambulances.

PMID- 12402127
TI  - [Algorithm for prehospital blunt trauma management].
AB  - Clinical algorithms can divide sophisticated treatment concepts for blunt trauma
      care into logical, systematic and easy to follow sequences. The presented
      algorithm for prehospital management of major and suspected blunt trauma will
      assure appropriate trauma care within narrow time windows. The risk of over- or
      undertreatment is reduced for both, the suspected and confirmed diagnosis of
      polytrauma. Due to the lack of evident data the algorithm was confirmed via
      consent expert opinion of trauma surgeons, incorporating the ABC priorities and
      also the concept of the ATLS((R))-programme. The algorithm was validated in
      simulated scenarios and was by affirmed by the German Trauma Surgeons Task Force
      on Emergency Care under the regulations of a nominal group process via
      resolution.

PMID- 12402128
TI  - [Algorithm for extrication and medical care in vehicular trauma].
AB  - The rescue and treatment of trapped persons in car accidents requires a close
      cooperation and coordination between firefighters and medical personnel.
      Priorities of medical care as well as aspects of extrication should be considered
      equally. Procedures on scene should follow a sequence securing life support and
      careful rescue of the trapped patient.The developed algorithm allows for
      prioritized and coordinated management and represents a transparent guide for
      both teams, during training as well as practical application. The concept
      incorporates the ABC priorities for polytrauma management and also the structure
      of the ATLS((R))-programme. The algorithm was validated in simulated scenarios
      and was by affirmed by the German Trauma Surgeons Task Force on Emergency Care
      under the regulations of a nominal group process via resolution.

PMID- 12402129
TI  - [Systematic literature searches for clinical guideline development in the field
      of out-of-hospital and early in-hospital care of multiply injured patients].
AB  - QUESTION: To what extent does the scientific literature have an impact on current
      clinical practice guidelines (CPGs) in trauma surgery? METHODS: We searched for
      CPGs on the initial management of multiply injured patients and assessed the
      quality of literature search and appraisal within these CPGs. Secondly, we
      compiled a list of all medical journal with relevance to prehospital trauma care.
      Lastly, we performed a hand search for randomised controlled trials (RCTs) in
      some of the German not in Medline indexed traumatological journals. RESULTS: We
      identified 22 CPGs of varying methodological quality. The American guidelines
      scored highest. Only 21 of the 38 journals (55%) in the field of prehospital
      trauma surgery were indexed in Medline, while 6 were covered only by Embase and
      11 were indexed in neither of both databases. Hand searching four non-indexed
      German journals identified nearly 200 RCTs. CONCLUSION: Information flow between
      clinical research and CPG development remains difficult. Thoroughly performed
      literature searches have an important role in CPG development.

PMID- 12402130
TI  - [Innovative training for enhancing patient safety. Safety culture and integrated
      concepts].
AB  - INTRODUCTION: Patient safety is determined by the performance safety of the
      medical team. Errors in medicine are amongst the leading causes of death of
      hospitalized patients. These numbers call for action. Backgrounds, methods and
      new forms of training are introduced in this article. METHOD: Concepts from
      safety research are transformed to the field of emergency medical treatment.
      Strategies from realistic patient simulator training sessions and innovative
      training concepts are discussed. RESULTS: The reasons for the high numbers of
      errors in medicine are not due to a lack of medical knowledge, but due to human
      factors and organisational circumstances. A first step towards an improved
      patient safety is to accept this. We always need to be prepared that errors will
      occur. A next step would be to separate "error" from guilt (culture of blame)
      allowing for a real analysis of accidents and establishment of meaningful
      incident reporting systems. Concepts with a good success record from aviation
      like "crew resource management" (CRM) training have been adapted my medicine and
      are ready to use. These concepts require theoretical education as well as
      practical training. Innovative team training sessions using realistic patient
      simulator systems with video taping (for self reflexion) and interactive
      debriefing following the sessions are very promising. CONCLUSION: As the need to
      reduce error rates in medicine is very high and the reasons, methods and training
      concepts are known, we are urged to implement these new training concepts widely
      and consequently. To err is human - not to counteract it is not.

PMID- 12402131
TI  - [Costs for acute, stationary treatment of polytrauma patients].
AB  - Are the costs required for a polytraumatised patient sufficiently paid by the
      health care companies?The study population consisted of 71 polytrauma patients.
      The treatment-costs were calculated and compared with the reimbursements. The
      mean patient age was 38.0 years with a mean injury severity score (ISS) of 23.0
      points. The mean duration of hospitalisation was 25.9 days and the mean
      calculated cost per patient was Euro 21,866.30. The reimbursement was only Euro
      16,863.03/patient. This leads to a financial deficit of approximately Euro
      5,000/patient (Euro 167/polytrauma patient/hospital day) and nearly Euro 355,000
      for all patients during the period of 1 year. The introduction of the DRG system
      endangers the high standard of polytrauma treatment because of insufficient
      reimbursement.It is necessary to consider the implementation of an additional
      polytrauma-reimbursement based on the injury severity and duration of
      hospitalisation. The concentration of the patients in trauma centres, where the
      optimum of therapy is guarantied, leads in these hospitals to a continuously
      increasing deficit. The latter may be deleterious for the concept of "trauma
      centers" in the future.

PMID- 12402132
TI  - [Fractures and instability of the cervical spine].

PMID- 12402133
TI  - [The role of oxidative stress in the pathogenesis and therapy of chronic wounds].
AB  - Molecular oxygen plays a central role in the pathogenesis and therapy of chronic
      wounds. When reactive oxygen species are overproduced, oxidative stress results,
      with detrimental cytotoxic effects causing delayed wound healing. Therefore,
      elimination of reactive oxygen species could be an important strategy to improve
      healing of chronic wounds. Currently first therapeutic strategies targeting
      reactive oxygen species by antioxidants are being introduced into the treatment
      of chronic wounds.

PMID- 12402134
TI  - [Triclosan, a topical dermatologic agent. In vitro- and in vivo studies on the
      effectiveness of a new preparation in the New German Formulary].
AB  - BACKGROUND AND OBJECTIVE: Triclosan (2,4,4'-trichloro-2'-hydroxydiphenyl ether)
      is an antiseptic suitable for formulation as a W/O emulsion. The objective of the
      present study was to explore its potential utility in atopic dermatitis and
      prophylactic skin care following leg eczema and leg ulcer treatment. SUBJECTS AND
      METHODS: We performed in vitro susceptibility testing using the agar diffusion
      test on 602 isolates from swabs of our institution's Division of Dermatology.
      Additionally in an in vivo study with 15 healthy volunteers, the occlusion test
      and the expanded flora test were performed following the application of
      Hydrophobic Triclosan Cream 2% NRF (New German Formulary) 11.122. (TC) versus
      untreated, triclosan-free vehicle, 1% chlorhexidine digluconate solution, and
      ethanol 70%. RESULTS: In vitro susceptibility testing showed excellent activity
      against Staphylococcus aureus, Klebsiella species, and Proteus species. TC had
      little or no effect on Pseudomonas, beta-hemolytic streptococci, enterococci, and
      Candida species. In the in vivo study, TC produced a highly significant,
      quantitatively substantial reduction in aerobic bacterial counts versus untreated
      and versus vehicle. The 1% chlorhexidine digluconate solution was significantly
      more effective than TC in the expanded flora test. CONCLUSIONS: As S. aureus is a
      relevant pathogen in atopic dermatitis, and gram-negative organisms, including
      Klebsiella and Proteus species, as well as S. aureus play a major role in the
      prophylactic skin care after leg eczema and leg ulcer treatment, TC appears to be
      suitable for maintenance therapy in these indications.

PMID- 12402135
TI  - [ANCA-positive vasculitis of the skin and kidneys associated with acne
      conglobata].
AB  - A 19 year old man with severe acne conglobata and ulcerated pyoderma gangraenosum
      like skin lesions on the face was first treated with isotretinoin
      (Roaccutan((R))), then immunosuppressively with prednisolone,
      diaminodiphenylsulfone (Dapson-Fatol((R))) and mycophenolate mofetil
      (Cellcept((R))). Under a daily maintenance dose of immunosuppressive treatment
      with 2.5 mg prednisolone and 1 g mycophenolate mofetil, weakness, muscle and
      joint aches appeared. Due to proteinuria, haematuria and an elevated
      antineutrophil cytoplasmic antibody (cANCA) and the histological detection of a
      leukocytoclastic vasculitis, the diagnosis of cANCA positive vasculitis of the
      skin and kidneys was established. Therapy with cyclophosphamide (Endoxan((R)))
      along with prednisolone was effective. An exact classification of this disease
      process was not possible.

PMID- 12402136
TI  - [Arteriovenous fistula: an uncommon cause of leg ulcers].
AB  - A 69-year-old woman presented with a therapy-resistant ulcer on the medial aspect
      of her left ankle present for 2 years. Previously there had been a blood vessel
      tumor at the same site, but it had regressed almost completely in adolescence
      following a bacterial infection. A whirring flow sound was e heard over the
      ulcer. Numerous arteriovenous connections in the area of the ulcer were shown in
      the form of vascular convolutions with duplex sonography and angiography. The
      diagnosis of arteriovenous fistula was made. In addition, there was calcinosis
      around the ulcer. Successful therapy consisted of excision of the ulcer and the
      underlying calcinosis, and of ligature of the multiple arteriovenous connections.
      Our patient demonstrates that smaller arteriovenous fistulas may exist for
      decades without symptoms. The classification, clinical patterns, diagnostic
      approach, possible complications (bleeding, ulceration) and therapy of the rare
      arteriovenous fistulas are discussed.

PMID- 12402138
TI  - [Thalidomide therapy of cutaneous lupus erythematosus].
AB  - Immunosuppressive and immune-modulating substances such as corticosteroids,
      chloroquin, hydroxychloroquin, azathioprin, methotrexate, and others are
      standards in therapy of cutaneous lupus erythematosus. However, alternative
      substances are necessary when standard therapy regimens fail or are associated
      with side effects. Describing the course of disease in five female patients, we
      demonstrate alternative treatment of subacute cutaneous lupus erythematosus with
      thalidomide, showing good symptom response and possible side effects. By careful
      patient selection, we observed no polyneuropathy as it is most commonly
      described. In two cases, maculopapulous exanthema induced by medication was seen.
      The teratogeny of the substance must be taken into account in prescription. In
      selected cases, thalidomide can be a highly effective therapeutic option in the
      treatment of subacute cutaneous lupus erythematosus.

PMID- 12402137
TI  - [Bullous pemphigoid manifesting as dyshidrotic eczema and prurigo nodularis].
AB  - A 63-year-old woman presented simultaneously with two rare forms of bullous
      pemphigoid. Initially she had a dyshidrotic palmoplantar eczema. Repeated
      epicutaneous patch tests ruled out a type IV allergic reaction to common
      allergens. Six months later the patient developed disseminated pruritic nodules.
      After 4.5 years she then demonstrated scattered bullae within erythematous
      plaques indicative of bullous pemphigoid. A skin biopsy showed linear IgG and IgM
      as well as C3 deposits at the dermo-epidermal junction and circulating
      autoantibodies against the basement membrane could be found in serum.
      Accordingly, the diagnosis of bullous pemphigoid was made. In retrospect, the
      vesicular palmoplantar eczema and pruritic nodules could be interpreted in this
      case as early manifestations of bullous pemphigoid. We recommend that in patients
      with persistent pruritic skin lesions, which are resistant to standard therapy,
      bullous pemphigoid should be excluded by adequate immunological examinations.

PMID- 12402139
TI  - [From wound healing to modern tissue engineering of the skin. A historical review
      on early techniques of cell and tissue culture].
AB  - The early precursors of modern techniques of keratinocyte transplantation and
      tissue engineering of the skin are reviewed, starting with histological research
      into the processes of wound healing and of skin transplantation in the 19th
      century and continuing with the introduction of cell and tissue culture
      techniques in early 20th century medicine. The later experimental and clinical
      application of this research in dermatology and plastic surgery is also explored.

PMID- 12402140
TI  - ["Skin and crime"].

PMID- 12402141
TI  - [Meeting report of the "Analytic Morphology and Experimental Dermato-Oncology"
      Study Group, 28 February 2002].

PMID- 12402143
TI  - Treatment-induced anaemia and its potential clinical impact in patients receiving
      sequential high dose chemotherapy for metastatic testicular cancer.
AB  - First-line sequential high dose chemotherapy is under investigation in patients
      with "poor prognosis" metastatic germ cell tumours in order to improve survival.
      Despite the use of autologous peripheral blood stem cell transplantation and
      granulocyte colony stimulating factor chemotherapy dose intensification is
      associated with severe haematotoxicity including anaemia, which may significantly
      affect quality of life and tolerability of chemotherapy. This study investigates
      the frequency and degree of anaemia in patients receiving first-line sequential
      high dose chemotherapy for metastatic testicular cancer and the impact of anaemia
      on treatment outcome. A total of 101 newly diagnosed patients with "poor
      prognosis" metastatic nonseminomatous germ cell tumours were treated with one
      cycle of standard VIP followed by three cycles of HD-VIP-chemotherapy (etoposide,
      ifosfamide, cisplatin) within a large phase I/II study. Differential blood cell
      counts were taken prior, during and after every cycle of chemotherapy.
      Additionally, the numbers of red blood cell and platelet transfusions were
      recorded. Kaplan-Meier analyses were performed to correlate pre-treatment and
      post-treatment haemoglobin values to response and overall survival. Forty-eight
      per cent of the patients were classified anaemic (haemoglobin <12 g dl(-1)) prior
      to the start of chemotherapy. The application of sequential HD-VIP resulted in
      median haemoglobin nadirs between 7.8 g dl(-1) (range 5.5-11.1 g dl(-1)) in the
      first cycle and 7.6 g dl(-1) (range 6.0-11.4 g dl(-1)) in the third cycle despite
      the frequent use of red blood cell transfusions. Almost all patients (99%) had
      haemoglobin levels <10 g dl(-1) at some timepoint during first-line sequential
      high dose chemotherapy. Overall, 97 patients received red blood cell transfusions
      with a median of 10 units (range 2-25) per patient during the four consecutive
      cycles of therapy. The time to first transfusion was shortest in patients with
      the lowest initial haemoglobin values. While there was no prediction of response
      or outcome by baseline haemoglobin-levels, a significant survival difference in
      favour of patients with a haemoglobin value >10.5 g dl(-1) after completion of
      four cycles of therapy (at leukocyte recovery after the last cycle) compared to
      those with haemoglobin values <10.5 g dl(-1) was found with 3-year overall
      survival rates of 87% vs 68%, respectively (P<0.05). Severe anaemia is a very
      frequent side effect of sequential dose intensive therapy in patients with germ
      cell cancer, with almost all patients becoming transfusion dependent. Despite the
      frequent use of red blood cell transfusions, median haemoglobin nadirs remained
      about 7.5-8 g dl(-1) during therapy. A correlation of haemoglobin-values after
      completion of therapy to overall treatment outcome was found.

PMID- 12402142
TI  - Role of genetic polymorphisms in tumour angiogenesis.
AB  - Angiogenesis plays a crucial role in the development, growth and spread of solid
      tumours. Pro- and anti-angiogenic factors are abnormally expressed in tumours,
      influencing tumour angiogenesis, growth and progression. Polymorphisms in genes
      encoding angiogenic factors or their receptors may alter protein expression
      and/or activity. This article reviews the literature to determine the possible
      role of angiogenesis-related polymorphisms in cancer. Further research studies in
      this potentially crucial area of tumour biology are proposed.

PMID- 12402144
TI  - Phase I study of docetaxel in combination with cyclophosphamide as first-line
      chemotherapy for metastatic breast cancer.
AB  - This phase I was study conducted to establish the maximum tolerated dose, dose
      limiting toxicity, and recommended dose of docetaxel in combination with
      cyclophosphamide as first-line chemotherapy for metastatic breast cancer. Twenty
      six patients were treated with cyclophosphamide (600 mg m(-2), intravenous bolus)
      followed by docetaxel (60, 75 or 85 mg m(-2), 1-h intravenous infusion) every 3
      weeks. The maximum tolerated dose was docetaxel 85 mg m(-2) with cyclophosphamide
      600 mg m(-2), the dose-limiting toxicity being febrile neutropenia. Grade 4
      neutropenia was experienced by all patients, but was generally brief. Otherwise,
      the combination was well tolerated with few acute and no chronic non
      haematological toxicities of grade 3/4. Activity was observed at all dose levels
      and disease sites, and the overall response rate was 42% (95% confidence interval
      22-61%). The pharmacokinetics of docetaxel were not modified by cyclophosphamide
      coadministration. These findings establish a recommended dose of docetaxel 75 mg
      m(-2) in combination with cyclophosphamide 600 mg m(-2) every three weeks for
      phase II evaluation.

PMID- 12402145
TI  - A phase I/II study of 4 monthly courses of high-dose cyclophosphamide and
      thiotepa for metastatic breast cancer patients.
AB  - This pilot phase I/II study intended to determine the maximum tolerated dose of
      cyclophosphamide and thiotepa administered on four consecutive courses with
      peripheral blood progenitor cell and granulocyte-colony stimulating factor
      support, as first-line therapy for hormone-refractory metastatic breast cancer
      patients. Twenty-eight patients were entered in the study. After two courses of
      epirubicin (120 mg m(-2)) and cyclophosphamide (2 g m(-2)) followed by
      granulocyte-colony stimulating factor injection and leukaphereses, patients
      received four cycles of cyclophosphamide and thiotepa. Each cycle was followed by
      peripheral blood progenitor cell and granulocyte-colony stimulating factor
      supports, then repeated every 28 to 35 days. Six escalating dose levels of
      cyclophosphamide and thiotepa were planned, beginning at cyclophosphamide 1.5 g
      m(-2) and thiotepa 200 mg m(-2). At least three patients were enrolled for each
      dose level. Eighteen patients completed the study. The maximum tolerated dose was
      3000 mg m(-2) cyclophosphamide and 400 mg m(-2) thiotepa per course.
      Haematological toxicity was manageable on an outpatient basis and did not
      increase significantly with dose escalation. Dose-limiting toxicity was
      chemotherapy-induced immunosuppression, which resulted in one toxic death and two
      life-threatening infections. Median times to treatment failure and survival were
      11 and 26 months, respectively. Three patients were alive, free of disease 30
      months after completion of the study. Such therapy allows for high-dose intensity
      and high cumulative doses on a short period of time with manageable toxicity.

PMID- 12402146
TI  - Choroid plexus tumours.
AB  - Choroid plexus tumours are rare epithelial brain tumours and limited information
      is available regarding their biology and the best treatment. A meta-analysis was
      done to determine prognostic factors and the influence of various treatment
      modalities. A thorough review of the medical literature (1966-1998) revealed 566
      well-documented choroid plexus tumours. These were entered into a database, which
      was analysed to determine prognostic factors and treatment modalities. Most
      patients with a supratentorial tumour were children, while the most common sites
      in adults were the fourth ventricle and the cerebellar pontine angle. Cerebellar
      pontine angle tumours were more frequently benign. Histology was the most
      important prognostic factor, as one, five, and 10-year projected survival rates
      were 90, 81, and 77% in choroid plexus-papilloma (n=353) compared to only 71, 41,
      and 35% in choroid plexus-carcinoma respectively (P<0.0005). Surgery was
      prognostically relevant for both choroid plexus-papilloma (P=0.0005) and choroid
      plexus-carcinoma (P=0.0001). Radiotherapy was associated with significantly
      better survival in choroid plexus-carcinomas. Eight of 22 documented choroid
      plexus-carcinomas responded to chemotherapy. Relapse after primary treatment was
      a poor prognostic factor in choroid plexus-carcinoma patients but not in choroid
      plexus-papilloma patients. Treatment of choroid plexus tumours should start with
      radical surgical resection. This should be followed by adjuvant treatment in case
      of choroid plexus-carcinoma, and a "wait and see" approach in choroid plexus
      papilloma.

PMID- 12402148
TI  - Social problems in oncology.
AB  - A study was undertaken to describe, evaluate and categorise the social problems
      experienced by cancer patients. Ninety-six adult cancer patients at all stages of
      disease participated in either a telephone focus group discussion, a face to face
      focus group or an individual interview which were tape recorded and transcribed.
      Six experts analysed the transcripts. A total of 32 social problems were
      identified categorized under eight headings plus four single items. The
      categories were: problems with (1) managing in the home, (2) health and welfare
      services, (3) finances, (4) employment, (5) legal matters, (6) relationships, (7)
      sexuality and body image and (8) recreation. Problems with relationships and
      communication were the most frequently reported with financial, employment, body
      image and domestic problems also being widely endorsed. Female groups, younger
      patient groups and groups where the aim of treatment was palliative reported more
      social problems than other groups. Social problems are common and important to
      cancer patients. The social problems identified in this study will contribute to
      an item pool generated for developing a Social Problems Inventory that may be
      included in patient centred assessment as part of routine oncology practice.

PMID- 12402147
TI  - Nephrotoxicity in survivors of Wilms' tumours in the North of England.
AB  - One aspect of concern for survivors of Wilms' tumour has been the late outcome in
      terms of renal function. Previous studies have documented low glomerular
      filtration rate and high blood pressure in some patients. Furthermore, disorders
      in tubular function (especially urinary concentration defects) have been
      suggested but not confirmed in small studies. The aim of this study was to
      determine the prevalence and nature of subclinical and overt glomerular, proximal
      and distal renal tubular toxicity in a population based cohort of survivors of
      Wilms' tumour. Forty patients (24 female) with a median age of 4.3 years (3
      months-11.8 years) at diagnosis were studied. Median follow-up was 8.8 (range
      0.06-27.5) years. Glomerular filtration rate was measured by (51)Cr-EDTA plasma
      clearance, proximal tubular function by electrolyte fractional excretions, urine
      excretion of low molecular weight proteins (retinol-binding protein) and renal
      tubular enzymes (alanine aminopeptidase; N-acetylglucosaminidase) and distal
      tubular function by the osmolality of the first two urines of the day on 3
      consecutive days. Renal size (ultrasound) and blood pressure were also measured.
      Mean (range) glomerular filtration rate was 100 (61-150) ml min(-1) 1.73 m(-2).
      Nine were below the reference range for healthy individuals with two kidneys.
      Most serum electrolyte concentrations (sodium, potassium, chloride, calcium,
      magnesium and phosphate) fell within the normal range for age, as did the
      fractional excretions. The values that fell outside the normal range were only
      marginally abnormal. Subclinical measures of tubular toxicity (retinal-binding
      protein, alanine aminopeptidase, N-acetylglucosaminidase) were abnormal in only
      four patients. Thirty-seven patients achieved maximal urine osmolalities > or
      =800 mOsm kg(-1), but three failed to achieve this value even after DDAVP
      administration. Two patients had evidence of increased urinary albumin excretion.
      Compensatory renal hypertrophy was seen in all but two patients, but blood
      pressure was within normal limits in all patients. Current and past treatment for
      Wilms' tumour does not have any clinically important nephrotoxic effect in the
      majority of patients. This finding will enable paediatric oncologists to reassure
      patients and parents that treatment for Wilms' tumour rarely causes long-term
      renal impairment.

PMID- 12402149
TI  - Infiltrating ductal and lobular breast carcinomas are characterised by different
      interrelationships among markers related to angiogenesis and hormone dependence.
AB  - To obtain a more integrated understanding of the different breast cancer
      phenotypes and to investigate whether bio-molecular profiles can distinguish
      between specific histotypes, we explored the interrelations among several
      biologic variables indicative of, or related to, hormone dependence,
      proliferation and apoptosis control, and angiogenesis in ductal and lobular
      carcinomas, the most common histotypes. Oestrogen and progesterone receptors,
      tumour proliferative activity, the expression of cyclin A, p16(ink4A), p27(kip1),
      p21(waf1), p53, bcl-2, and levels of vascular endothelial growth factor and
      hypoxia-inducible factor-1alpha (HIF-1alpha) were evaluated in 190 in ductal and
      67 lobular carcinomas. Our findings support the hypothesis that in ductal and
      lobular carcinomas are two distinct, partially phenotypically unrelated entities,
      the latter being characterised by the presence of features indicative of
      differentiation such as oestrogen receptors, low proliferation and lack of p53
      expression and associated with low vascular endothelial growth factor content
      compared to angiogenesis in ductal carcinomas. Conversely, no significant
      difference was found between lobular carcinomas and in ductal carcinomas
      considering the frequency distribution of PgR-positive cases, cyclin-dependent
      kinase inhibitors acting at the G1/S boundary, bcl-2 and HIF-1alpha protein
      expression. Although both generally defined as hormone responsive, in ductal and
      lobular carcinomas are also characterised by biologic patterns in which proteins
      related to hormone responsiveness, cell-cycle control, apoptosis and angiogenesis
      were differently associated. This finding suggests the need to refine breast
      cancer characterisation in order to provide detailed information about individual
      tumours, or subsets of tumours, that will help in defining optimal treatment
      approaches.

PMID- 12402150
TI  - Lung tumour markers in oncology practice: a study of TPA and CA125.
AB  - Several substances mark the course of lung cancer and may reliably help the
      clinician in decision-making. This is the first clinical study specifically
      designed to compare tissue polypeptide antigen and CA 125 tumour associated
      antigen. Three hundred and eighty-four new lung cancer patients (309 males) were
      studied at their first clinical presentation and then strictly followed-up.
      Anthropometric, clinical and laboratory data - including tissue polypeptide
      antigen and CA 125 tumour associated antigen serum levels - were prospectively
      recorded. A total of 1000 tissue polypeptide antigen and CA 125 tumour associated
      antigen serum assays (384 pre-treatment and 616 posttreatment assays) were
      performed. Both tissue polypeptide antigen and CA 125 tumour associated antigen
      correlated significantly with the T, N and M stage descriptors at diagnosis (Rho:
      0.200, 0.203, 0.263 and 0.181, 0.240, 0.276, respectively), and then with the
      objective response to treatment (Rho: 0.388 and 0.207, respectively). A pleural
      neoplastic involvement was mainly associated to an increase of CA 125 tumour
      associated antigen (Rho: 0.397). Both tissue polypeptide antigen and CA 125
      tumour associated antigen were strongly predictive of the patients' outcome, as
      assessed by the univariate analysis of survival (log-rank test: 37.24 and 29.01)
      and several Cox' proportional hazards regression models. The two marker tests are
      similarly helpful and appear complementary, given the low inter-marker
      correlation and their independent prognostic capability.

PMID- 12402151
TI  - Secretion of soluble complement inhibitors factor H and factor H-like protein
      (FHL-1) by ovarian tumour cells.
AB  - We observed that the soluble complement regulators factor H and factor H-like
      protein were abundantly present in ascites samples as well as in primary tumours
      of patients with ovarian cancer. RT-PCR and immunoblotting analyses showed that
      the two complement inhibitors were constitutively produced by the ovarian tumour
      cell lines SK-OV-3 and Caov-3, but not PA-1 or SW626 cells. The amounts of factor
      H-like protein secreted were equal to those of factor H. This is exceptional,
      because e.g. in normal human serum the concentration of factor H-like protein is
      below 1/10th of that of factor H. In ascites samples the mean level of factor H
      like protein (130+/-55 microg ml(-1)) was 5.5-fold higher than in normal human
      serum (24+/-3 microg ml(-1)). Ovarian tumour cells thus preferentially synthesise
      factor H-like protein, the alternatively spliced short variant of factor H. The
      tumour cells were found to bind both (125)I-labelled factor H and recombinant
      factor H-like protein to their surfaces. Surprisingly, the culture supernatants
      of all of the ovarian tumour cell lines studied, including those of PA-1 and
      SW626 that did not produce factor H/factor H-like protein, promoted factor I
      mediated cleavage of C3b to inactive iC3b. Subsequently, the PA-1 and SW626 cell
      lines were found to secrete a soluble form of the membrane cofactor protein
      (CD46). Thus, our studies reveal two novel complement resistance mechanisms of
      ovarian tumour cells: (i) production of factor H-like protein and factor H and
      (ii) secretion of soluble membrane cofactor protein. Secretion of soluble
      complement inhibitors could protect ovarian tumour cells against humoral immune
      attack and pose an obstacle for therapy with monoclonal antibodies.

PMID- 12402152
TI  - Elevated c-Src is linked to altered cell-matrix adhesion rather than
      proliferation in KM12C human colorectal cancer cells.
AB  - Elevated expression and/or activity of c-Src, the prototype of the Src family of
      protein tyrosine kinases, is associated with the development of human colon
      cancer. However, despite the known pleiotropic effects of these kinases in
      promoting (a) cell growth downstream of growth factor receptors, and (b) the
      dynamic regulation of integrin adhesions in fibroblast model systems, their
      precise role in epithelial cancer cells is unknown. Here we addressed whether
      elevated expression and activity of cellular Src alters cell proliferation and/or
      cell-matrix adhesion in cancer cells from the Fidler model of colorectal
      metastasis. Although elevated Src correlates with ability to metastasise to the
      liver after intrasplenic injection, we found that this was not linked to enhanced
      growth, either in vitro or in vivo as sub-cutaneous tumours. However, elevated
      Src was associated with enhanced attachment to extracellular matrix. In addition,
      adhesion to fibronectin, was suppressed by agents that inhibited Src activity,
      while enforced elevation of Src in non-metastatic cells was sufficient to
      stimulate adhesion to fibronectin and enhanced assembly of adhesion complexes,
      without influencing cell growth. Thus, we conclude that one role of elevated Src
      in human colon cancer cells is to modulate integrin-dependent cell-matrix
      attachment and formation of adhesion structures, which may, in turn, influence
      cell motility and integrin-dependent cellular responses.

PMID- 12402153
TI  - Nuclear BAG-1 expression reflects malignant potential in colorectal carcinomas.
AB  - BAG-1 is a recently identified Bcl-2-interacting anti-apoptotic protein. The aim
      of our study was to investigate the immunohistochemical staining pattern of BAG-1
      protein in patients with colorectal cancer and examine associations of BAG-1
      expression with various clinicopathological factors and patient survival. Tumour
      samples were collected from 86 patients diagnosed with colorectal cancer. There
      was significant variation in the immunohistochemical staining patterns for BAG-1,
      including absent staining and staining of either the cytoplasm, nucleus or both.
      Twenty-one colorectal carcinomas (24.4%) exhibited a nuclear staining pattern
      whilst 56 (65.1%) exhibited cytoplasmic staining. The percentage of cases
      exhibiting nuclear BAG-1 positivity was significantly higher in distant
      metastasis-positive cases (55.6%) than in distant metastasis-negative cases
      (20.8%; P=0.036). Overall survival was significantly shorter for patients with
      tumours exhibiting BAG-1 positive nuclei than those with absent nuclear BAG-1
      staining (P=0.011). In addition, the multivariate cox proportional hazard models
      indicated that nuclear BAG-1 expression was the only independent prognostic
      variable for mortality (P=0.013). These studies demonstrate that nuclear BAG-1
      expression is a useful predictive factor for distant metastasis and a poor
      prognosis in patients with colorectal cancer.

PMID- 12402154
TI  - Impact of caveolin-1 expression on prognosis of pancreatic ductal adenocarcinoma.
AB  - Caveolin-1 is a major component of caveolae and plays a regulatory role in
      several signalling pathways. Caveolin-1 was recently identified as a metastasis
      related gene in prostate cancer. The clinical effects of caveolin-1 expression in
      pancreatic carcinoma, however, remain unknown. In this study, we have
      investigated the relationship between caveolin-1 expression and the
      clinicopathologic variables and clinical outcome in 79 patients with pancreatic
      adenocarcinoma undergoing surgical resection. Caveolin-1 expression was
      determined by immunohistochemistry, using a polyclonal anti-caveolin-1 antibody.
      Patients were divided into two groups based on the extent of caveolin-1
      expression: a negative expression group (immunoreactivity in less than 50% of
      cells) and a positive expression group. Positive caveolin-1 immunostaining was
      detected in 32 cases (40.5% of total), while non-neoplastic ductal epithelium
      showed little or no staining. Positive caveolin-1 expression was correlated with
      tumour diameter (P=0.0079), histopathologic grade (P=0.0272) and poor prognosis
      (P=0.0008). Upon multivariate analysis with Cox's proportional hazards model,
      positive caveolin-1 expression was shown to be an independent negative predictor
      for survival (P=0.0358). These results suggest that caveolin-1 overexpression is
      associated with tumour progression, thereby indicating a poor prognosis for
      certain patients undergoing surgical resection for pancreatic carcinoma.

PMID- 12402155
TI  - Expression of cyclooxygenase-2 (COX-2) in tumour and stroma compartments in
      cervical cancer: clinical implications.
AB  - This study aims at investigating the relationship between cyclooxygenase-2
      expression in tumour vs stroma inflammatory compartment and its possible clinical
      role. The study included 99 stage IB-IV cervical cancer patients: immunostaining
      of tumour tissue sections was performed with rabbit antiserum against
      cyclooxygenase-2. CD3, CD4, CD8, CD25, Mast Cell Tryptase monoclonal antibodies
      were used to characterise stroma inflammatory cells in nine cervical tumours. An
      inverse relation was found between cyclooxygenase-2 levels (cyclooxygenase-2 IDV)
      of tumour vs stroma compartment (r=-0.44, P<0.0001). The percentage of cases
      showing high tumour/stromal cyclooxygenase-2 IDV ratio was significantly higher
      in patients who did not respond to treatment (93.3%) with respect to patients
      with partial (60.5%), and complete (43.7%) response (P= 0.009). Cases with a high
      tumour/stroma cyclooxygenase-2 IDV ratio had a shorter overall survival rate than
      cases with a low tumour/stroma cyclooxygenase-2 IDV (P<0.0001). In the
      multivariate analysis advanced stage and the status of tumour/stroma
      cyclooxygenase-2 IDV ratio retained an independent negative prognostic role. The
      proportion of CD3(+), CD4(+), and CD25(+) cells was significantly lower in
      tumours with high tumour/stroma cyclooxygenase-2 IDV ratio, while a higher
      percentage of mast cells was detected in tumours showing high tumour/stroma
      cyclooxygenase-2 IDV ratio. Our study showed the usefulness of assessing
      cyclooxygenase-2 status both in tumour and stroma compartment in order to
      identify cervical cancer patients endowed with a very poor chance of response to
      neoadjuvant therapy and unfavourable prognosis.

PMID- 12402156
TI  - Differential gene expression profiles of gastric cancer cells established from
      primary tumour and malignant ascites.
AB  - Advanced gastric cancer is often accompanied by metastasis to the peritoneum,
      resulting in a high mortality rate. Mechanisms involved in gastric cancer
      metastasis have not been fully clarified because metastasis involves multiple
      steps and requires a combination of altered expressions of many different genes.
      Thus, independent analysis of any single gene would be insufficient to understand
      all of the aspects of gastric cancer peritoneal dissemination. In this study, we
      performed a global analysis of the differential gene expression of a gastric
      cancer cell line established from a primary main tumour (SNU-1) and of other cell
      lines established from the metastasis to the peritoneal cavity (SNU-5, SNU-16,
      SNU-620, KATO-III and GT3TKB). The application of a high-density cDNA microarray
      method made it possible to analyse the expression of approximately 21 168 genes.
      Our examinations of SNU-5, SNU-16, SNU-620, KATO-III and GT3TKB showed that 24
      genes were up-regulated and 17 genes down-regulated besides expression sequence
      tags. The analysis revealed the following altered expression such as: (a) up
      regulation of CD44 (cell adhesion), keratins 7, 8, and 14 (epitherial marker),
      aldehyde dehydrogenase (drug metabolism), CD9 and IP3 receptor type3 (signal
      transduction); (b) down-regulation of IL2 receptor gamma, IL4-Stat (immune
      response), p27 (cell cycle) and integrin beta4 (adhesion) in gastric cancer cells
      from malignant ascites. We then analysed eight gastric cancer cell lines with
      Northern blot and observed preferential up-regulation and down-regulation of
      these selected genes in cells prone to peritoneal dissemination. Reverse
      transcriptase-polymerase chain reaction confirmed that several genes selected by
      DNA microarray were also overexpressed in clinical samples of malignant ascites.
      It is therefore considered that these genes may be related to the peritoneal
      dissemination of gastric cancers. The results of this global gene expression
      analysis of gastric cancer cells with peritoneal dissemination, promise to
      provide a new insight into the study of human gastric cancer peritoneal
      dissemination.

PMID- 12402157
TI  - Mutation analysis of CBP and PCAF reveals rare inactivating mutations in cancer
      cell lines but not in primary tumours.
AB  - In this study we screened the histone acetyltransferases CBP and PCAF for
      mutations in human epithelial cancer cell lines and primary tumours. We
      identified two CBP truncations (both in cell lines), seven PCAF missense variants
      and four CBP intronic microdeletions. These data suggest that neither gene is
      commonly inactivated in human epithelial cancers.

PMID- 12402158
TI  - Novel thalidomide analogues display anti-angiogenic activity independently of
      immunomodulatory effects.
AB  - The anti-tumour effects of thalidomide have been associated with its anti
      angiogenic properties. Second generation thalidomide analogues are distinct
      compounds with enhanced therapeutic potential. Although these compounds are
      beginning to enter trials for the treatment of cancer there is very little
      information regarding the anti-angiogenic activity of these clinically relevant
      compounds. Furthermore, it is not known how the various immunomodulatory
      activities of these compounds relate to anti-angiogenic activity. In this study
      we assessed the anti-angiogenic activity of compounds from both IMiD and SelCID
      classes of analogues using a novel in vitro multicellular human assay system and
      the established rat aorta assay. Our results show that both the IMiDs and SelCIDs
      tested are significantly more potent than thalidomide. The anti-angiogenic
      potency of the analogues was not related to inhibition of endothelial cell
      proliferation, nor their TNF-alpha/PDE type 4 inhibitory properties. However,
      anti-migratory effects in vitro and inhibition of tumour growth in vivo was
      observed with the analogue IMiD-1 (clinically known as REVIMID). Our results show
      that anti-angiogenic activity spans both currently defined classes of thalidomide
      analogue and is not related to their previously described immunomodulatory
      properties. Identification of the differential effects of these compounds will
      enable targeting of such compounds into the appropriate clinical setting.

PMID- 12402159
TI  - Regulation of a rat VL30 element in human breast cancer cells in hypoxia and
      anoxia: role of HIF-1.
AB  - Novel approaches to cancer gene therapy currently exploit tumour hypoxia to
      achieve transcriptional targeting using oxygen-regulated enhancer elements called
      hypoxia response elements. The activity of such elements in hypoxic cells is
      directly dependent on upregulation of the hypoxia-inducible transcription factor
      1 However tumours also contain areas of anoxia, which may be considered a more
      tumour-selective transcriptional stimulus than hypoxia for targeting gene therapy
      to tumours. Another element, from the rat virus-like retrotransposon, VL30
      (termed the "secondary anoxia response element") has been reported to be more
      highly inducible in rat fibroblasts under anoxia than hypoxia. To investigate
      anoxia as a potential transcriptional target in human tumours, we have examined
      secondary anoxia response element inducibility in two human breast cancer cell
      lines, MCF-7 and T47D, under anoxia, hypoxia and normoxia. In both cell types,
      the trimerised secondary anoxia response element showed greater inducibility in
      anoxia than hypoxia (1% and 0.5% O(2)). The anoxic response of the secondary
      anoxia response element was shown to be dependent on hypoxia-inducible
      transcription factor-1 and the presence of a hypoxia-inducible transcription
      binding site consensus (5'-ACGTG-3'). Mutational analysis demonstrated that the
      base immediately 5' to this modulates the anoxic/hypoxic induction of the
      secondary anoxia response element, such that TACGTG>GACGTG>>CACGTG. A similar
      correlation was found for erythropoietin, phosphoglycerate kinase 1, and aldolase
      hypoxia response elements, which contain these respective 5' flanking bases.

PMID- 12402160
TI  - Angiopoietin-1 inhibits tumour growth and ascites formation in a murine model of
      peritoneal carcinomatosis.
AB  - Angiopoietin-1 is an important regulator of endothelial cell survival.
      Angiopoietin-1 also reduces vascular permeability mediated by vascular
      endothelial growth factor. The effects of angiopoietin-1 on tumour growth and
      angiogenesis are controversial. We hypothesised that angiopoietin-1 would
      decrease tumour growth and ascites formation in peritoneal carcinomatosis. Human
      colon cancer cells (KM12L4) were transfected with vector (pcDNA) alone (control)
      or vector containing angiopoietin-1 and injected into the peritoneal cavities of
      mice. After 30 days, the following parameters were measured: number of peritoneal
      nodules, ascites volume, and diameter of the largest tumour. Effects of
      angiopoietin-1 on vascular permeability were investigated using an intradermal
      Miles assay with conditioned media from transfected cells. Seven of the nine mice
      in the pcDNA group developed ascites (1.3+/-0.5 ml (mean+/-s.e.m.)), whereas no
      ascites was detectable in the angiopoietin-1 group (0 out of 10) (P<0.01). Number
      of peritoneal metastases (P<0.05), tumour volume, (P<0.05), vessel counts
      (P<0.01), and tumour cell proliferation (P<0.01) were significantly reduced in
      angiopoietin-1-expressing tumours. Conditioned medium from angiopoietin-1
      transfected cells decreased vascular permeability more than did conditioned
      medium from control cells (P<0.05). Our results suggest that angiopoietin-1 is an
      important mediator of angiogenesis and vascular permeability and thus could
      theoretically serve as an anti-neoplastic agent for patients with carcinomatosis
      from colorectal cancer.

PMID- 12402161
TI  - Anisomycin activates JNK and sensitises DU 145 prostate carcinoma cells to Fas
      mediated apoptosis.
AB  - Treatment of the hormone refractory prostate cancer cell line DU 145 with
      sublethal concentrations of chemotherapeutic drugs has been reported to sensitise
      these cells to Fas mediated apoptosis. However, the mechanism by which this
      occurs has not been determined. Our group has shown that inhibition of JNK
      activity completely abrogates the effects of chemotherapeutic drugs. Using
      anisomycin, a potent JNK agonist, we have demonstrated a role for JNK in Fas
      mediated apoptosis in DU 145 cells. Inhibition of Caspase 8 and Caspase 9
      completely inhibits this process which suggests that DU 145 cells require
      mitochondrial amplification of the Fas apoptotic signal. Furthermore, we have
      shown that inhibition of Fas mediated apoptosis is an early event in DU 145
      cells, occurring upstream of Caspase 8 cleavage. It is hoped that identifying the
      target of JNK will allow novel therapies to be developed for the treatment of
      hormone refractory prostate cancer. Such therapies are especially important
      because no single or combined treatment to date has significantly prolonged
      survival in patients with hormone refractory prostate cancer.

PMID- 12402162
TI  - Pathological mechanisms of human T-cell lymphotropic virus type I-associated
      myelopathy (HAM/TSP).
AB  - The recent studies have greatly improved our understanding of the pathological
      mechanisms of human T cell lymphotropic virus type I (HTLV-I)-associated
      myelopathy/tropical spastic paraparesis (HAM/TSP). The pathological mechanisms of
      HAM/TSP based on the histopathological, immunological, and molecular analysis
      with emphasis on the longitudinal alterations of the disease will be discussed.
      Immunohistological examination revealed the existence and the activation both of
      HTLV-I-infected CD4+ cells and HTLV-I-specific CD8+ cytotoxic T lymphocytes in
      the spinal cord lesions, which suggest that they play an important role in the
      pathogenesis. Increased expression of several cytokines, Fas/Fas ligand, adhesion
      molecules, and molecules influencing T cell migration in the lesions have been
      reported. These cell infiltrates and cytokines they secrete in the lesions may
      damage bystander neural tissue. Furthermore, longitudinal alterations in the
      affected spinal cords suggest that the inflammatory process is gradually
      decreased. Epidemiological studies show that less than 5% of infected individuals
      develop HAM/TSP and indicate that increased proviral load of HTLV-I is a strong
      predictor for the development of HAM/TSP. A recent study has shown that the
      autoantibody for the ribonuclear protein-A1 can cross-react with HTLV-I Tax
      protein and inhibit neuronal firing ex vivo, indicating that a molecular mimicry
      of the humoral immune response may be involved in the pathogenesis of HAM/TSP.
      Based on these studies, two hypotheses can be proposed for the pathogenesis of
      HAM/TSP, where cellular and humoral immune responses both play important roles.

PMID- 12402163
TI  - Reovirus-induced neuronal apoptosis is mediated by caspase 3 and is associated
      with the activation of death receptors.
AB  - Reovirus infection of the central nervous system (CNS) is an important
      experimental system for understanding the pathogenesis of neurotropic viral
      infection. Infection of neonatal mice with T3 reoviruses causes lethal
      encephalitis in which injury results from virus-induced apoptosis. We now show
      that this apoptosis in vivo is associated with activation of caspase 3, and use
      neuroblastoma and primary neuronal cultures to identify the cellular pathways
      involved. Reovirus-induced apoptosis in neuronal cultures is initiated by
      activation of the tumor necrosis factor (TNF) receptor superfamily death
      receptors and is inhibited by treatment with soluble death receptors (DRs). The
      DR-associated initiator caspase, caspase 8, is activated following infection,
      this activation is inhibited by a cell-permeable peptide inhibitor (IETD-CHO). In
      contrast to our previous findings in non-neuronal cell lines, reovirus-induced
      neuronal apoptosis is not accompanied by significant release of cytochrome c from
      the mitochondria or with caspase 9 activation following infection. This suggests
      that in neuronal cells, unlike their non-neuronal counterparts, the mitochondria
      mediated apoptotic pathway associated with cytochrome c release and caspase 9
      activation does not play a significant role in augmenting reovirus-induced
      apoptosis. Consistent with these results, peptide caspase inhibitors show a
      hierarchy of efficacy in inhibiting reovirus-induced apoptosis, with inhibitors
      of caspase 3 > caspase 8 >>> caspase 9. These studies provide a comprehensive
      profile of the pattern of virus-induced apoptotic pathway activation in neuronal
      culture.

PMID- 12402164
TI  - Enhanced green fluorescent protein expression may be used to monitor murine
      coronavirus spread in vitro and in the mouse central nervous system.
AB  - Targeted recombination was used to select mouse hepatitis virus isolates with
      stable and efficient expression of the gene encoding the enhanced green
      fluorescent protein (EGFP). The EGFP gene was inserted into the murine
      coronavirus genome in place of the nonessential gene 4. These viruses expressed
      the EGFP gene from an mRNA of slightly slower electrophoretic mobility than mRNA
      4. EGFP protein was detected on a Western blot of infected cell lysates and EGFP
      activity (fluorescence) was visualized by microscopy in infected cells and in
      viral plaques. Expression of EGFP remained stable through at least six passages
      in tissue culture and during acute infection in the mouse central nervous system.
      These viruses replicated with similar kinetics and to similar final extents as
      wild-type virus both in tissue culture and in the mouse central nervous system
      (CNS). They caused encephalitis and demyelination in animals as wild-type virus;
      however, they were somewhat attenuated in virulence. Isogenic EGFP-expressing
      viruses that differ only in the spike gene and express either the spike gene of
      the highly neurovirulent MHV-4 strain or the more weakly neurovirulent MHV-A59
      strain were compared; the difference in virulence and patterns of spread of viral
      antigen reflected the differences between parental viruses expressing each of
      these spike genes. Thus, EGFP-expressing viruses will be useful in the studies of
      murine coronavirus pathogenesis in mice.

PMID- 12402165
TI  - Differential induction of apoptosis in demyelinating and nondemyelinating
      infection by mouse hepatitis virus.
AB  - The role of apoptosis in mouse hepatitis virus (MHV) infection is still
      controversial. To better assess the role of apoptosis in MHV infection, we used
      three different biologic phenotypes of MHV to examine their differential effect
      on the induction of apoptosis. MHV-A59 produces acute hepatitis,
      meningoencephalitis, and chronic demyelination. MHV-2 causes only acute hepatitis
      and meningitis, whereas Penn98-1 produces acute hepatitis and meningoencephalitis
      without demyelination. We detected TdT-mediated dUTP nick-end labeling (TUNEL)
      staining in the livers and meninges of MHV-A59-, MHV-2-, and Penn98-1-infected
      mice. TUNEL staining in brain parenchyma was only detected in MHV-A59- and Penn98
      1-infected mice. We detected apoptosis by electronmicroscopy in olfactory neurons
      during acute infection with MHV-A59. The kinetics and distribution of TUNEL
      staining correlated with the pathologic damage and colocalized with viral antigen
      in some cells. At 1 month, TUNEL staining was found exclusively in areas of
      demyelination in the spinal cord of MHV-A59-infected mice; however, it was not
      found in nondemyelinated mice infected with MHV-2 or Penn98-1, or in mock
      infected mice. TUNEL-positive cells were identified as macrophage/microglial
      cells, some astrocytes, and some oligodendrocytes, by colabeling with cell
      specific markers. The presence of TUNEL staining in oligodendrocytes suggests
      that apoptosis may play an important role in MHV-induced demyelination.

PMID- 12402166
TI  - The virulence of mouse hepatitis virus strain A59 is not dependent on efficient
      spike protein cleavage and cell-to-cell fusion.
AB  - The cleavage and fusion properties of recombinant murine hepatitis viruses (MHV)
      were examined to assess the role of the cleavage signal in determining the extent
      of S protein cleavage, and the correlation between cleavage and induction of cell
      to-cell fusion. Targeted recombination was used to introduce amino acid
      substitutions into the cleavage signal of the fusion glycoprotein (spike or S
      protein) of MHV strain A59. The recombinants were then used to address the
      question of the importance of S protein cleavage and viral-mediated cell-to-cell
      fusion on pathogenicity. Our data indicate that cleavage of spike is not solely
      determined by the amino acid sequence at the cleavage site, but may also depend
      on sequences removed from the cleavage site. In addition, efficient cell-to-cell
      fusion is not necessary for virulence.

PMID- 12402167
TI  - Functional CXCR4 receptor development parallels sensitivity to HIV-1 gp120 in
      cultured rat astroglial cells but not in cultured rat cortical neurons.
AB  - The alpha chemokine receptor CXCR4 is used as the major coreceptor for the cell
      entry of T-cell-tropic human immunodeficiency virus-1 (HIV-1) isolates.
      Activation of this coreceptor by its natural ligand SDF1alpha is associated with
      an intracellular Ca(2+) increase. Because the HIV-1 glycoprotein 120 (gp120) is
      shedded from the surface of HIV-1-infected cells and is regarded as an injurious
      molecule in the pathogenesis of HIV-1-associated encephalopathy (HIVE), we
      investigated the effects of gp120 on the intracellular Ca(2+) regulation of
      astrocytes and neurons. After 5 days in vitro (DIV), SDF1alpha (50 nM) elicited a
      pertussis toxin-sensitive intracellular Ca(2+) increase due to Ca(2+) release
      from internal stores that was reduced by a blocking monoclonal antibody against
      the CXCR4 receptor in astrocytes and neurons. Parallel with the development of
      the SDF1alpha response, cells became sensitive to direct application of gp120
      (1.25 microg/ml), which, similarly to SDF1alpha, elicited a transient
      intracellular Ca(2+) increase. However, short-term incubation with gp120 for 60
      to 120 min induced a reduction of glutamate- or ATP-evoked intracellular Ca(2+)
      responses only in astrocytes and not in neurons, although functional CXCR4
      receptors were expressed in both cell types. Therefore, our data strongly suggest
      that the CXCR4 receptor-mediated intracellular signaling pathway of gp120 differs
      in astrocytes and neurons.

PMID- 12402168
TI  - Neurovirulence depends on virus input titer in brain in feline immunodeficiency
      virus infection: evidence for activation of innate immunity and neuronal injury.
AB  - Lentiruses cause neurological disease depending on the virus strain and its
      neurotropism, yet it remains uncertain to what the impact of infectious virus
      quantity in the brain early in infection is on the subsequent development of
      neurological disease or neurovirulence. We investigated the relationship between
      infectious virus input titer and the resulting neurovirulence, using ex vivo and
      in vivo assays of feline immunodeficiency virus (FIV)-induced neurovirulence. FIV
      infection of cell cultures and neonatal cats was performed using 10(2.5) (low
      titer) or 10(4.5) (high-titer) 50% tissue culture infectious doses (TCID(50))/ml
      of the neurovirulent FIV strain, V1CSF. Ex vivo neurotoxicity assays revealed
      that conditioned medium (CM) from feline macrophages infected with high-titer (P
      <.001) or low-titer (P <.01) V1CSF induced greater neuronal death than CM from
      mock-infected cells. In vivo, animals infected intracranially with high-titer
      V1CSF showed neurodevelopmental delays compared to mock-infected animals (P
      <.001) and animals infected with low-titer V1CSF (P <.02), concurrent with
      reduced weight gains and greater depletion of CD4+ cells over a 12-week period.
      Neuropathological changes, including astrogliosis, macrophage activation, and
      neuronal damage, were evident in V1CSF-infected animals and were viral titer
      dependent. In vivo magnetic resonance (MR) spectroscopy and proton nuclear
      magnetic resonance ((1)H-NMR) spectroscopy of tissue extracts revealed evidence
      of neuronal injury, including reduced N-acetyl aspartate/creatine (P <.05) and
      increased trimethylamine/creatine (P <.05) ratios, in the frontal cortex of high
      titer V1CSF-infected animals compared to the other groups. T2-weighted MR imaging
      detected increased signal intensities in the frontal cortex and white matter of
      V1CSF-infected animals relative to controls, which was more evident as viral
      titer increased (P <.01). The present findings indicate that lentivirus
      infectious titers in the brain during the early stages of infection determine the
      severity of neurovirulence, reflected by neurobehavioral deficits, together with
      neuroradiological and neuropathological findings of activation of innate immunity
      and neuronal injury.

PMID- 12402169
TI  - Epstein-Barr virus DNA load in cerebrospinal fluid and plasma of patients with
      AIDS-related lymphoma.
AB  - Detection of Epstein-Barr virus (EBV) DNA in the cerebrospinal fluid (CSF) is
      associated with acquired immunodeficiency syndrome (AIDS)-related brain lymphoma.
      Real-time polymerase chain reaction (PCR) was performed to quantify EBV DNA in
      CSF and plasma from 42 patients with AIDS-related non-Hodgkin's lymphoma (NHL).
      Twenty patients had primary central nervous system lymphoma (PCNSL) and 22
      systemic NHL, including 12 with central nervous system involvement (CNS-NHL). As
      controls, 16 HIV-infected patients with other CNS disorders were examined. EBV
      DNA was detected in the CSF from 16/20 (80%) patients with PCNSL, 7/22 (32%) with
      systemic NHL, 8/12 (67%) with CNS-NHL, and 2/16 (13%) of the controls. The viral
      EBV DNA levels were significantly higher in the CSF from patients with PCNSL or
      CNS-NHL compared to patients with systemic NHL or controls. EBV DNA was detected
      in plasma from 5/16 (31%) patients with PCNSL, 9/16 (56%) with systemic NHL, 4/9
      (44%) with CNS-NHL, and 4/15 (27%) controls. No difference in plasma viral load
      was found between patient groups. From the patients with CNS-NHL, plasma samples
      drawn prior to CNS involvement contained significantly higher EBV DNA levels than
      those from systemic NHL patients without subsequent CNS involvement. EBV DNA
      levels in the CSF, but not in plasma, from patients treated with antiherpes drugs
      were significantly lower than in untreated patients. High CSF EBV DNA levels were
      found in HIV-associated brain lymphomas and the viral load can be clinically
      useful. High plasma EBV DNA levels might predict CNS involvement in systemic NHL.

PMID- 12402170
TI  - Detection of infectious agents in brain of patients with acute hemorrhagic
      leukoencephalitis.
AB  - Acute hemorrhagic leukoencephalitis (AHL) is a rare and usually fatal disorder
      characterized clinically by an acute onset of neurologic abnormalities. It may
      occur in association with a viral illness or vaccination. Radiology and brain
      biopsy are essential for the diagnosis. The etiology of AHL is unclear. We
      postulated that viral/bacterial infection might be responsible, directly or
      through an immune-mediated mechanism, for this acute inflammatory myelinopathy.
      Fifteen cases of AHL were studied. Infectious agents, including varicella zoster
      virus (VZV), herpes simplex virus (HSV), human herpes virus-6 (HHV-6),
      cytomegalovirus, Epstein-Barr virus, and Mycoplasma, were investigated in brain
      specimens using the polymerase chain reaction (PCR), reverse transcriptase (RT)
      PCR, and immunohistochemistry. Using PCR, HSV DNA was found in four cases, VZV
      DNA in two, and HHV-6 DNA in one. Among the control cases, two were HSV DNA
      positive. Further investigation to detect HSV RNA and antigens in HSV DNA
      positive cases revealed that two cases with AHL were both HSV RNA and antigen
      positive. AHL is a hyperacute disease, which is considered the most acute form of
      acute disseminated encephalomyelitis (ADEM). Our findings suggests that a viral
      infection may be implicated in its pathogenesis, most likely through an indirect
      mechanism; however, as only a few cases of this rare disease were examined,
      statistical significance was not achieved. As a number of patients with disorders
      of the ADEM group may progress to develop multiple sclerosis (MS), we argue that
      an organism that has produced the former may remain in the brain tissue and be
      subsequently involved in the production of a self-sustained disorder such as MS.

PMID- 12402171
TI  - High incidence of JC viruria in JC-seropositive older individuals.
AB  - The prevalence of the human JC virus (JCV) in the general population at various
      ages was investigated. Polymerase chain reaction was employed to detect viral DNA
      in the urine. The results showed that the incidence of JC viruria was low in the
      young population, but it was high in the elderly. Hemagglutination inhibition
      assay was performed for JCV seroprevalence study. The results showed that the
      seropositive rate of JCV was lower in children than that in adults. The ratio of
      viruria to seropositive for JCV increased with age and reached 79.7% for those
      older than 70 years. The results indicated that aging immunity may correlate with
      JCV reactivation.

PMID- 12402172
TI  - ICAM-1 is crucial for protection from TMEV-induced neuronal damage but not
      demyelination.
AB  - Previous work has suggested that the factors protecting mice from Theiler's
      murine encephalomyelitis virus (TMEV)-induced spinal cord demyelination are
      distinct from those involved in protection of the brain during the acute
      encephalitic phase. In this study, we examined the requirement for intercellular
      adhesion molecule-1 (ICAM-1) in both of these processes. During the acute phase
      of infection (days 7 to 10 after intracerebral infection with TMEV), no
      differences in brain or spinal cord pathology or virus burdens were observed
      between ICAM-1-knockout mice and the infected immunocompetent control mice of a
      similar background. Examination of brain pathology later in infection (that is,
      day 45 post infection [p.i.]) revealed that ICAM-1-deficient mice experienced
      increased levels of pathology in gray matter regions of the brain. We observed an
      increase in striatal damage and meningeal inflammation in the brains of TMEV
      infected ICAM-1-knockout mice compared to C57BL/6J mice. Despite the increase in
      brain pathology, no immunoreactivity to viral antigens was detected, suggesting
      that the virus had been cleared by this time. Resistance to demyelination was
      similar in both groups, indicating that the resulting immune response was
      sufficient for protection of the spinal cord white matter.

PMID- 12402173
TI  - Defective NF-kappaB activation in virus-infected neuronal cells is restored by
      genetic complementation.
AB  - The interferon-beta (IFNbeta) gene is not inducible in neuronal cells in response
      to measles virus (MV) due to lack of nuclear factor kappa B (NF-kappaB)
      activation. NF-kappaB is normally sequestered in the cytoplasm by an inhibitor
      (IkappaBalpha). Previously, the authors demonstrated that the failure to activate
      neuronal NF-kappaB by MV was due to the inability to phosphorylate and degrade
      its inhibitor, IkappaBalpha. Here the authors demonstrate that transient
      transfection of a brain cDNA library into neuronal cells restores the ability of
      MV to activate NF-kappaB. In addition, tumor necrosis factor-alpha (TNFalpha),
      but not interleukin-1 (IL-1) or lipopolysaccharide (LPS), stimulation resulted in
      IkappaBalpha phosphorylation and degradation in two neuronal cell lines. These
      results indicate that failure of MV to activate neuronal NF-kappaB is due to a
      signaling defect and that MV utilizes an NF-kappaB signaling pathway distinct
      from that of TNFalpha, but may overlap with that for IL-1 and LPS.

PMID- 12402174
TI  - Viral pathogenesis and immune control.

PMID- 12402175
TI  - 1st SIV International Workshop on Neurovirology.

PMID- 12402176
TI  - Total daily energy expenditure and incidence of upper respiratory tract infection
      symptoms in young females.
AB  - A group of 31 young females, tennis players and non-athletes, aged 16 +/- 2 years
      (range: 14 - 21 years), with a wide range of physical activity levels was used to
      investigate the relationship between total daily energy expenditure and the
      incidence of upper respiratory tract infection symptoms. METHODS: During a 12
      week winter period, habitual daily activity (excluding training) was evaluated
      using a 3-day physical activity record. Tennis training was quantified using a
      validated method of estimating energy expenditure during play. Total daily energy
      expenditure was calculated from the sum of daily training plus mean habitual
      daily activity energy expenditures. The total group of subjects was divided in
      quartiles for total daily energy expenditure. A validated symptom checklist was
      used to assess the incidence and severity of upper respiratory tract infections,
      on a daily basis. RESULTS: The girls in the highest quartile of total daily
      energy expenditure (> or = 17,322 kJ/day) and in the lowest quartile (< or =
      10,047 kJ/day) had the greatest incidence of URTI symptomatology, although the
      moderately active girls in quartile three (12,290 - 16,410 kJ/day) presented the
      lowest incidence. Significant differences in number of upper respiratory tract
      infection episodes, sickness days and symptomatology index were found between
      quartiles three and one (p < 0.05) and quartiles three and four (p < 0.01). Peak
      severity of symptoms was significantly lower in quartile three compared with all
      other quartiles (p < 0.05).

PMID- 12402177
TI  - Identical twins are discordant for markers of eccentric exercise-induced muscle
      damage.
AB  - This study investigated whether the variability observed in the markers of
      exercise-induced muscle damage (EIMD) has a genetic etiology. Sixteen pairs of
      identical twins performed 24 maximal eccentric contractions (24MAX) using the
      elbow flexors. EIMD indicators were measured pre-24MAX and three days post-24MAX
      and included: post-exercise force deficit, maximal isometric force (ISO), plasma
      creatine kinase (CK), myoglobin (Mb), and joint range of motion. Force-time
      curves were recorded throughout the 24MAX. Twin siblings were alike for pre
      exercise ISO (intraclass R = 0.89) and CK (R = 0.76) (p < 0.001), but were
      discordant for post-exercise force deficit (R = 0.29), CK (R = 0.15), and Mb (R =
      0.17) (p > 0.05). In comparison with individuals minimally affected by the 24MAX,
      those who experienced the greatest force deficit 3 days post-exercise (> 50 %)
      were characterised by the greater application of eccentric force at longer muscle
      lengths (23.1 % vs 17.3 %) (p < 0.05). This study demonstrates that twins do not
      experience the same level of EIMD following identical exercise bouts. This
      suggests that the individual variability following high-force eccentric exercise
      cannot be attributed to genetic differences, refuting the idea that an inherited
      subclinical predisposition is responsible. From these results, a potential
      mechanism for the repeated bout effect is discussed.

PMID- 12402178
TI  - Combination of estrogen replacement and exercise protects against HDL oxidation
      in post-menopausal women.
AB  - The incidence of atherosclerosis and cardiovascular disease (CVD) in women
      increases following menopause and has been associated with a reduction in
      circulating estrogen. Increased CVD risk is also perpetuated by sedentary
      lifestyle. Growing evidence indicates that oxidation of lipoproteins leads to a
      powerful immune response, disruption of normal lipoprotein function, and
      deposition of atherosclerotic plaques. For example, once high-density
      lipoproteins (HDL) are oxidized, they lose the ability to a) participate in
      reverse transport of cholesterol to the liver, and b) protect low-density
      lipoproteins (LDL) against oxidation. The purpose of this study was to determine
      the effects of combining estrogen replacement and exercise upon lipid
      peroxidation of the HDL fraction (HDL-ox). Blood samples were drawn from 34 post
      menopausal women from four groups: women who were not receiving estrogen
      replacement and who were sedentary (NSD) (n = 9); women who were not receiving
      estrogen replacement and who were participating in regular exercise (NEX) (n =
      8); women who were receiving estrogen replacement and who were sedentary (ESD) (n
      = 8); and women who were receiving estrogen replacement and who were
      participating in regular exercise (EEX) (n = 9). Total-HDL cholesterol was
      significantly higher (p<0.05) in EEX when compared with NEX, NSD, and ESD. HDL-ox
      was assessed via malondialdehyde (MDA). Mean (+/- SEM) values for HDL MDA
      expressed in nM are as follows: NSD = 903.3 +/- 118.4; NEX = 1226.7 +/- 247.7;
      ESD = 876.7 +/- 116.3; EEX = 537.4 +/- 74.8. EEX lipid peroxidation was
      significantly (p = 0.02) lower than NEX. Lipid peroxidation tended to be lower in
      EEX than in NSD and ESD (p = 0.07). These data indicate that the combination of
      estrogen replacement and regular exercise in post-menopausal women may be most
      effective in reducing oxidation of HDL in vivo.

PMID- 12402179
TI  - Myosin heavy chain composition of single muscle fibers in male distance runners.
AB  - The purpose of this study was to characterize the myosin heavy chain (MHC)
      composition of single muscle fibers from the gastrocnemius of male collegiate
      distance (DIST; n = 7), middle-distance (MID; n = 6), and recreational runners
      (REC; n = 6). Additionally, mATPase histochemistry was used to serve as a
      comparison to previous studies and the single fiber MHC technique. SDS-PAGE of
      single muscle fibers revealed a higher proportion of MHC I in DIST compared to
      MID and REC (74.9 +/- 4.3 vs 54.4 +/- 2.8 vs 56.2 +/- 2.9 %, respectively; p <
      0.05), less MHC IIa/IIx in DIST compared to MID and REC (0.0 +/- 0.0 vs 6.0 +/-
      2.4 vs 15.9 +/- 4.2 %, respectively; p < 0.05), and more total hybrids
      (I/IIa+IIa/IIx+I/IIa/IIx) in REC than both run groups, DIST and MID (23.0 +/- 3.3
      vs 6.2 +/- 1.1 vs 13.2 +/- 2.6 %, respectively; p < 0.05). ATPase histochemistry
      (pH 4.54) revealed a higher percentage of type I fibers in DIST compared to MID
      and REC (71.1 +/- 3.1 vs 56.3 +/- 2.5 vs 59.8 +/- 2.3 %, respectively; p < 0.05),
      a higher percentage of type IIa in MID compared to DIST and REC (43.3 +/- 2.7 vs
      28.5 +/- 3.1 vs. 30.2 +/- 3.1 %, p < 0.05), and a higher distribution of type IIb
      in REC than both run groups (10.0 +/- 2.7 vs 0.4 +/- 0.2 vs 0.4 +/- 0.2 %, p <
      0.05). These results suggest that distance running leads to an increase in MHC I
      expression, training for mid-distance events leads to a prevalence of MHC IIa,
      and run training leads to a decrease in hybrid fibers.

PMID- 12402180
TI  - Evidence of exercise-induced cardiac dysfunction and elevated cTnT in separate
      cohorts competing in an ultra-endurance mountain marathon race.
AB  - Cardiac damage has recently been implicated in the aetiology of "exercise induced
      cardiac dysfunction". The humoral markers of cardiac damage that have been
      utilised to date are not sufficiently cardio-specific to investigate this
      hypothesis. The aim of the present study was to examine cardiac function
      following prolonged exercise, and investigate the contention of cardiac damage
      utilising a new highly cardio-specific marker. Thirty-seven competitors in the 2
      day Lowe Alpine Mountain Marathon 2000 volunteered for the study. Competitors
      were sub-divided into 2 groups. Group 1 (n = 11) were examined using
      echocardiography pre and post the event, examining left ventricular diastolic and
      systolic function. Group 2 (n = 26) had venous blood samples drawn prior to the
      event and immediately following day-1 and day-2. Blood samples were analysed for
      total creatine kinase activity (CK), creatine kinase isoenzyme MB(mass) (CK
      MB(mass)), and cardiac troponin T. Echocardiographic results indicated left
      ventricular diastolic and systolic dysfunction following cessation of exercise.
      CK and CK-MB(mass) were both elevated following day-1, and immediately following
      race completion. Cardiac troponin T levels were below the 99th percentile (0.01
      microg/L) in all subjects prior to the event, following day-1 cTnT was elevated
      above 0.01 microg/L in 13 subjects, but returned to below 0.01 microg/L following
      race completion on day-2. However, no individual data reached clinical cut-off
      levels for acute myocardial infarction (AMI) (0.1 microg/L). Two days arduous
      exercise over mountainous terrain resulted in cardiac dysfunction, and
      significant skeletal muscular degradation. The elevation of cTnT above the 99th
      percentile in the present study is suggestive of minimal myocardial damage. The
      clinical significance of and exact mechanism responsible for such damage remains
      to be elucidated.

PMID- 12402181
TI  - Markers of coagulation, fibrinolysis and angiogenesis after strenuous short-term
      exercise (Wingate-test) in male subjects of varying fitness levels.
AB  - It was the aim of the study to analyse the haemostatic system during a high
      standardized intensive short-term (30 s) exercise (anaerobic Wingate test). Blood
      samples were taken from 15 male subjects before (t0 ), and within 2 (t1 ), 9 (t2
      ) and 30 min (t3 ) after the test. We found that the partial thromboplastin time
      was markedly shortened, whereas the prothrombin time increased slightly from t0
      to t1 (p < 0.002) and remained elevated (t3, p < 0.046). Factor VIII increased
      from t0 to t1 (p < 0.001) and remained elevated as well (t3, p < 0.001). Fibrin
      monomers were approximately 15 times higher immediately post-exercise (t1, p <
      0.001) and continued to be elevated (t3, p < 0.004). The tissue plasminogen
      activator increased by 4 times after exercise (t1, p < 0.001) and remained
      elevated (t3, p < 0.002). The d-dimers increased from t0 to t1 (p < 0.001) as
      well and remained elevated (t3, p < 0.005). Thrombopoietin concentrations were
      unchanged, whereas the vascular endothelial growth factor increased immediately
      post-exercise (t0 to t1, p < 0.011 resp. at t2 p < 0.019) and returned to the
      control level at t3 (p < 0.878). In conclusion, it was found that prothrombotic
      markers and, even more pronounced, those of the fibrinolytic system were
      increased. The study provides evidence that due to intensive short-term exercise
      the balance of the haemostatic system is shifted to a higher equilibrium.
      Theoretically, the data show that in the case of a subject with risk factors such
      as impaired fibrinolysis, unfavourable conditions cannot be excluded.

PMID- 12402182
TI  - Thrombin potential and thrombin generation after exhaustive exercise.
AB  - Exhaustive exercise leads to an activation of blood coagulation, but the
      implications of this activation are still unclear. The aim of this study was to
      investigate if a hypercoagulant stage exists after exhaustive treadmill- or cycle
      exercise; intrinsic and extrinsic endogenous thrombin potential (ETP) were
      measured by using the method of Hemker et al. Thirteen healthy male subjects
      underwent an exhaustive treadmill (TR) or cycle (CY) ergometer test and a control
      day in random order. Blood samples were taken, repeatedly, after a 30 min rest,
      immediately before and after, and 1 h after exercise for measuring intrinsic and
      extrinsic total thrombin potential (TTPin, TTPex) (including free and alpha 2 
      macroglobulin-bound thrombin) and endogenous thrombin potential (ETPin, ETPex),
      aPTT, PT, F1 + 2 and TAT. In comparison to the pre-value taken immediately before
      the exercise, the intrinsic TTP was significantly (p < 0.05) increased directly
      after exercise (TR-TTPin, + 11.6 %; CY-TTPin, + 11.5 %). In contrast, ETPin
      remained unchanged after both exercises. Additionally for TTPex and ETPex, no
      changes after exercise were detectable. aPTT was significantly (p < 0.05) shorter
      after exercise (TR-aPTT, - 16.2 %; CY-aPTT - 17.5 %), F1 + 2-concentrations were
      higher (p < 0.05) (TR-F1 + 2, + 21.2 %; CY-F1 + 2, + 9.8 %), but TAT remained
      unchanged. Differences between TR or CY could not be determined. These results
      show the expected shortening of aPTT and the increase of F1 + 2 indicating an
      activation of the coagulation system during exercise. However, the unchanged
      intrinsic and extrinsic ETP lead to the conclusion that in healthy young male
      subjects the potential for thrombin generation is insignificant, is directly
      counterbalanced by alpha 2-macroglobulin and is independent of the type of
      exhaustive exercise done.

PMID- 12402183
TI  - Exercise intensity of cycle-touring events.
AB  - The aim of the study was to analyze the exercise intensity of recreational
      cyclists participating in a cycling-touring event. In 14 male healthy
      recreational cyclists heart rate (HR) monitoring was performed during the Otztal
      Radmarathon 1999 (distance: 230 km; altitude difference: 5500 m) in order to
      evaluate the HR response and to estimate the cardiopulmonary strains for the less
      trained athlete confronted with such a marathon. Four different exercise
      intensities were defined as percentages of maximal HR (HR(max)) as follows:
      recovery HR (HR(re)) < 70 % of HR max; moderate aerobic HR (HR(ma)) = 70 - 80 %;
      intense aerobic HR (HR(ia)) = 80 - 90 %; and anaerobic HR (HR(an)) > 90 %. All
      athletes finished the competition successfully. The mean racing time was 10 h 14
      min, the average speed 22.5 km/h. The mean HR(max) was 188 bpm, the average value
      of the measured HRs (HR(average)) was 145 bpm resulting in a mean
      HR(average)/HR(max) ratio of 0.77. Athletes spent 18.5 % (1 h 54 min) of total
      race time within HR(re), 28 % (2 h 52 min) within HR(ma), 39.5 % (4 h 02 min)
      within HR(ia), and 14 % (1 h 26 min) within HR(an). The vast majority of exercise
      was done under "aerobic conditions" (HR(re) + HR(ma) + HR(ia) = 86 % or 8 h 48
      min) - confirming the knowledge that the aerobic energy supply is crucial for the
      performance of long-term exercise. The large amount of high exercise intensities
      (HR(ia) + HR(an) = 53.5 % or 5 h 30 min), however, features the intense
      cardiopulmonary strains evoked by such competitions. The HR response was related
      to the course profile with HRs significantly declining in all subjects to an
      extent of 10 % during the course of race. Our findings show that the exercise
      intensity borne by recreational cyclists during a cycle-touring event is high and
      very similar to that of professionals. With respect to the high cardiovascular
      strains a thorough medical screening is advisable for any participant of such an
      event combining both high volume and high intensity loads.

PMID- 12402184
TI  - Cortisol, DHEA, performance and training in elite swimmers.
AB  - Salivary cortisol (C) and DHEA concentrations were measured in 9 elite swimmers
      (4 female and 5 male) over a 37-week period, 5 to 12 times per swimmer, before 68
      competitions. For female and male swimmers, no significant relationship was found
      between C, DHEA and performance. For the whole group, C was negatively correlated
      with week number of training (r = -0.31, p < 0.01). The incorporation of the
      cumulated distance swum as a second variable in the regression increased r to
      0.56 (p < 0.01). The higher the cumulated distance swum, the higher C. No
      significant relationship was found between DHEA and distance swum. For individual
      swimmers, 3 of 4 females showed a significant negative relationship between C and
      cumulated dry-land training. No equivalent relationship was found for DHEA. The 2
      males practicing dry-land training showed a significant and negative relationship
      between DHEA and cumulated dry-land training. No equivalent relationship was
      found for C. Thus, C and DHEA were not good predictors of swimming performance. C
      for individual females, and DHEA for individual males were considered useful
      markers for dry-land training stress.

PMID- 12402185
TI  - Carbohydrate dependence during hard-intensity exercise in trained cyclists in the
      competitive season: importance of training status.
AB  - To test the hypothesis that intensive endurance training increases CHO
      utilisation during hard-intensity exercise, seven competitive road cyclists (Cy)
      performed three 50-min steady-state exercise tests on a cycle ergometer above
      their ventilatory threshold (+ 15 %) over the course of a cycling season (January
      [ET1], May [ET2] and September [ET3]). We compared the data with the baseline
      values of seven sedentary controls (Sed). CHO oxidation in Cy was higher in ET2
      and ET3 than in ET1 (p < 0.05), was lower in ET3 than in ET2 (p < 0.05) and was
      higher in Cy than in Sed only in ET2 (p < 0.05). Lactate kinematics were lower in
      Cy than in Sed in all conditions (p < 0.05), but in Cy they were lower in ET2
      than in ET1 and higher in ET3 than in ET2 (p < 0.05). Race performance was
      impaired and the overtraining score was increased at ET3 in comparison with ET2
      (p < 0.05). We conclude that competitive cyclists increase CHO oxidation during
      hard-intensity exercise over the course of a season, but show a decline by the
      end of the season in association with the appearance of an overtraining state.
      Thus, well-trained cyclists develop a CHO dependence, which is modified with
      training status.

PMID- 12402186
TI  - Qualified rescue by ski patrols -- safety for the skier.
AB  - This study aims to determine whether the training of ski-patrol teams is still
      adequate in view of a marked change in injury patterns. All accidents which
      occurred during two winter seasons (n = 579, 583 patients) in the Oberwallis ski
      area in Switzerland are analysed retrospectively. As the analysis of the
      accidents' data are similar to other studies and first aid training is
      standardised throughout Switzerland, the results of this study can be viewed as
      representative for other areas of Switzerland. The generally high level of
      training is reflected by the accuracy of "on-scene" diagnoses: 77.5 % were
      "correct", 12 % "mainly correct". In the remainder, the most frequent problems
      were underestimation or failure of recognition of multiple injuries (n = 25),
      head injury (n = 10), injuries to the trunk (n = 9) and to the spine (n = 7).
      Special emphasis on these topics during the training of ski patrols should result
      in the further improvement in on-scene first aid and rescue.

PMID- 12402187
TI  - Self-release of ski-binding.
AB  - We investigated whether twenty-five male and female downhill skiers of different
      ages (11 - 63 years) and skiing skills were able to self-release their ski
      binding by an inward twist of the foot and leg. We also studied possible
      correlations between thigh muscle torques and the ability to release the binding.
      All subjects used the same ski and binding, Marker Titanum M48, individually set
      according to weight, height, skiing skill, age, and boot sole length. Prior to
      the test we used a special torque wrench, the Vermont Release Calibrator, to
      verify that the settings of the binding corresponded to the appropriate torque
      (Nm) to produce a release. Isokinetic concentric and eccentric quadriceps and
      hamstring torques were measured. EMG was used to study which muscles are engaged
      in this self-test. Nineteen skiers were able to release the binding, while four
      children and the two muscularly weakest skiers were not. The medial hamstrings
      produced the highest degree of muscle activity during the inward twist release of
      the binding. There was a highly significant correlation between thigh muscle
      torques and the ability to release the binding.

PMID- 12402188
TI  - Respiratory syncytial virus-induced activation of nuclear factor-kappaB in the
      lung involves alveolar macrophages and toll-like receptor 4-dependent pathways.
AB  - The transcription factor nuclear factor (NF)-kappaB controls the expression of
      numerous respiratory syncytial virus (RSV)-inducible inflammatory and
      immunomodulatory genes. Using a BALB/c mouse model, the present article shows
      that RSV potently and specifically activates NF-kappaB in vivo, a process that
      involves nuclear translocation of the subunits RelA, p50, and c-Rel in the lung.
      By depletion of alveolar macrophages (AMs) in BALB/c mice and use of C3H/HeJ mice
      lacking a functional Toll-like receptor (TLR)-4 signaling pathway, we demonstrate
      the existence of distinct but sequentially integrated RSV-inducible early NF
      kappaB responses in the lung. The first response occurs early after RSV
      inoculation, is AM and TLR4 dependent, and is viral replication independent,
      whereas the second response involves epithelial cells and/or inflammatory cells,
      is TLR4 independent, and requires viral replication. NF-kappaB may be considered
      a central activator of not only inflammatory but also innate immune responses to
      RSV.

PMID- 12402189
TI  - A common haplotype of interleukin-4 gene IL4 is associated with severe
      respiratory syncytial virus disease in Korean children.
AB  - Respiratory syncytial virus (RSV) is a major health problem in young children,
      and host response to severe disease favors a Th2 immune response. To investigate
      the genetic basis for RSV disease severity, linked variants of 3 Th2 cytokine
      genes, IL4, IL13, and IL5 (which are clustered on chromosome 5q31.1) were
      characterized in 105 children who were hospitalized with severe RSV infection and
      315 Korean control subjects in a pilot study. A common IL4 haplotype defined at 5
      loci, which includes the -589T promoter variant, previously shown to be
      associated with increased interleukin (IL)-4 transcriptional activity and
      predisposition to asthma, was overrepresented in patients with severe RSV disease
      (odds ratio, 1.63; P=.02). These results support the hypothesis that severe RSV
      disease might be related to increased Th2 response, which is perhaps mediated by
      overexpression of IL-4, and provide preliminary evidence for a genetic link
      between severe RSV disease and subsequent wheezing.

PMID- 12402190
TI  - A genetic analysis of hepatitis C virus transmission between injection drug
      users.
AB  - Hepatitis C virus (HCV) genotype 1a and 3a partial NS5B gene segment sequences
      obtained from 154 HCV-infected injection drug users were studied to determine the
      extent to which HCV transmission occurs between injection drug user communities
      in London, Edinburgh, Glasgow (United Kingdom), Marseilles (France), and
      Melbourne. Phylogenetic relationships between sequences were analyzed by
      conventional methods and by a recently developed method that numerically scores
      the extent of sequence segregation between groups through calculation of
      association indices. The association indices revealed that none of the cities
      sampled support an HCV population that is completely isolated from that
      circulating in the other cities. Sequences from Melbourne were most isolated,
      whereas those from London were most dispersed. This suggests that HCV
      transmission between these cities occurs, with London playing a pivotal role. The
      degree of city-specific segregation of HCV subtype 1a sequences was linearly
      related to that of subtype 3a, indicating that these subtypes have spread through
      similar transmission networks.

PMID- 12402191
TI  - Prevention of influenza pneumonitis by sialic Acid-conjugated dendritic polymers.
AB  - Influenza A viral infection begins by hemagglutinin glycoproteins on the viral
      envelope binding to cell membrane sialic acid (SA). Free SA monomers cannot block
      hemagglutinin adhesion in vivo because of toxicity. Polyvalent, generation 4 (G4)
      SA-conjugated polyamidoamine (PAMAM) dendrimer (G4-SA) was evaluated as a means
      of preventing adhesion of 3 influenza A subtypes (H1N1, H2N2, and H3N2). In
      hemagglutination-inhibition assays, G4-SA was found to inhibit all H3N2 and 3 of
      5 H1N1 influenza subtype strains at concentrations 32-170 times lower than those
      of SA monomers. In contrast, G4-SA had no ability to inhibit hemagglutination
      with H2N2 subtypes or 2 of 5 H1N1 subtype strains. In vivo experiments showed
      that G4-SA completely prevented infection by a H3N2 subtype in a murine influenza
      pneumonitis model but was not effective in preventing pneumonitis caused by an
      H2N2 subtype. Polyvalent binding inhibitors have potential as antiviral
      therapeutics, but issues related to strain specificity must be resolved.

PMID- 12402192
TI  - Molecular analysis of T cell clonotypes in muscle-infiltrating lymphocytes from
      patients with human T lymphotropic virus type 1 polymyositis.
AB  - Epidemiological studies have shown that a correlation may exist between human T
      cell lymphotropic virus type 1 (HTLV-1) infection and a form of polymyositis
      (PM). To characterize muscle-infiltrating lymphocytes (MILs) from patients with
      HTLV-1 PM, we examined the T cell receptor (TCR) beta-chain variable region
      repertoire and clonotype of MILs and peripheral blood mononuclear cells (PBMC)
      from 3 patients, using TCR complementarity-determining region 3 (CDR3) length
      spectratyping and DNA sequencing. Immunohistochemical studies showed that MILs
      from patients with HTLV-1 PM contain both CD4(+) and CD8(+) T cells. Although
      some clonotypes observed in PBMC were also found in MILs in all patients
      examined, MILs consisted predominantly of locally expanded clones. One clonotype
      in MILs was derived from human leukocyte antigen (HLA)-A*02/Tax11-19 tetramer
      positive cells, the CDR3 motif of which contains amino acid residues for HLA
      A*02/Tax peptide-TCR interaction. We conclude that certain T cell clones
      proliferate in the muscle lesions of HTLV-1 PM and may contribute to the
      pathogenesis of the disease.

PMID- 12402193
TI  - Preparation of clinical-grade recombinant canarypox-human immunodeficiency virus
      vaccine-loaded human dendritic cells.
AB  - Preclinical data are reported that support a human immunodeficiency virus (HIV)
      vaccine strategy using recombinant canarypox-HIV vectors (ALVAC-HIV) to load
      human dendritic cells (DCs) with HIV antigens. Clinical-grade DCs were infected
      with good manufacturing practice-grade ALVAC-HIV vaccine constructs. ALVAC
      infection, HIV gene expression, and DC viability and function were monitored by
      use of immunohistochemistry, flow cytometry, blastogenesis assays, antigen
      specific interferon (IFN)-gamma enzyme-linked immunospot assay, and enzyme-linked
      immunosorbent assay protein detection. The vaccines infected both immature and
      mature DCs, and intracellular HIV-1 Gag protein was detected within hours. ALVAC
      HIV induced DC maturation that was mediated by tumor necrosis factor-alpha and
      induced DC apoptosis that was directly related to the length of vaccine exposure.
      Of importance, the infected DCs remained functional in T cell stimulation assays
      and induced HIV antigen-specific CD8(+) T cell production of IFN-gamma from cells
      of HIV-1-infected individuals. These data support an ongoing HIV vaccine trial
      comparing conventional vaccine delivery routes with ex vivo vaccine-loaded
      autologous DCs for immunogenicity in HIV-1-uninfected volunteers.

PMID- 12402194
TI  - Choline-binding protein A of Streptococcus pneumoniae elicits chemokine
      production and expression of intercellular adhesion molecule 1 (CD54) by human
      alveolar epithelial cells.
AB  - Recruitment of neutrophils into alveolar air spaces is an early event in the
      pathogenesis of pneumonia due to Streptococcus pneumoniae. This results from
      chemokines released by activated endothelial and epithelial cells and alveolar
      macrophages. Culture supernatants of 6 wild-type strains of S. pneumoniae, shown
      to contain choline-binding protein A (CbpA; clades A and B), induced release of
      chemokine CXCL8 from the human alveolar epithelial cell line A549, whereas a CbpA
      deletion mutant elicited significantly reduced CXCL8 release, compared with that
      of its isogenic parent (P<.01). Recombinant CbpA up-regulated expression of
      messenger RNA of CXCL8 and CCL2 but not of XCL1, CXCL10, CCL1, CCL3, CCL4, or
      CCL5 in A549 cells and induced increased secretion of CXCL8, CCL2, CXCL1, and
      CXCL5 in a dose- and time-dependent manner. CbpA also increased the expression of
      intercellular adhesion molecule 1 (CD54) by A549 cells. Thus, CbpA of S.
      pneumoniae induces the transcription and release of proinflammatory molecules by
      human alveolar epithelial cells.

PMID- 12402195
TI  - A nontoxic chimeric enterotoxin adjuvant induces protective immunity in both
      mucosal and systemic compartments with reduced IgE antibodies.
AB  - A novel nontoxic form of chimeric mucosal adjuvant that combines the A subunit of
      mutant cholera toxin E112K with the pentameric B subunit of heat-labile
      enterotoxin from enterotoxigenic Escherichia coli was constructed by use of the
      Brevibacillus choshinensis expression system (mCTA/LTB). Nasal immunization of
      mice with tetanus toxoid (TT) plus mCTA/LTB elicited significant TT-specific
      immunoglobulin A responses in mucosal compartments and induced high serum
      immunoglobulin G and immunoglobulin A anti-TT antibody responses. Although TT
      plus native CT induced high total and TT-specific immunoglobulin E responses, use
      of the chimera molecule as mucosal adjuvant did not. Furthermore, all mice
      immunized with TT plus mCTA/LTB were protected from lethal systemic challenge
      with tetanus toxin. Importantly, the mice were completely protected from
      influenza virus infection after nasal immunization with inactivated influenza
      vaccine together with mCTA/LTB. These results show that B. choshinensis-derived
      mCTA/LTB is an effective and safe mucosal adjuvant for the induction of
      protective immunity against potent bacterial exotoxin and influenza virus
      infection.

PMID- 12402196
TI  - Effect of factor X inhibition on coagulation activation and cytokine induction in
      human systemic inflammation.
AB  - Anticoagulants have gained increasing attention in the treatment of sepsis. This
      study used danaparoid to investigate the role of factor Xa in endotoxin-induced
      coagulation and inflammation and its effectiveness when coagulation activation
      has already occurred. Thirty healthy volunteers were enrolled in the randomized,
      placebo-controlled trial. Subjects received 2 ng/kg endotoxin and danaparoid 10
      min or 3 h thereafter or placebo. Endotoxin increased prothrombin fragment 1+2
      (F(1+2)) levels from 0.5 to 7.0 nmol/L at 5 h in the placebo group. Early
      danaparoid infusion inhibited endotoxin-induced thrombin formation: maximum
      F(1+2) levels reached only 1.8 nmol/L (P<.01, vs. baseline or placebo). Delayed
      danaparoid infusion effectively blocked further thrombin formation. However,
      danaparoid did not alter endotoxin-induced changes in the fibrinolytic system,
      cytokine levels, activation of leukocytes, or tissue factor expression on
      monocytes. Danaparoid therefore selectively attenuates endotoxin-induced
      coagulopathy, even with delayed administration when coagulation activation is
      well under way.

PMID- 12402197
TI  - Proinflammatory cytokines in the course of Mycobacterium tuberculosis-induced
      apoptosis in monocytes/macrophages.
AB  - Mycobacterium tuberculosis (MTB) can induce apoptosis in monocytes/macrophages
      both in vitro and in vivo, and this phenomenon is associated with mycobacterial
      survival. The present study addresses the possibility that apoptotic and
      inflammatory pathways could coexist through a caspase-1-mediated mechanism. In
      this context, a caspase-1 inhibitor (YVAD), but not caspase-3 (DEVD) or caspase-4
      (LEVD) inhibitors, was able to strongly inhibit MTB-induced apoptosis. Moreover,
      caspase-1 activity was confirmed by the increased maturation of interleukin (IL)
      1beta. Of interest, IL-1beta and tumor necrosis factor (TNF)-alpha were produced
      massively in the course of infection, and both were inhibited by YVAD
      pretreatment. To determine whether TNF-alpha was produced actively by apoptotic
      cells, the intracytoplasmatic cytokine content and apoptotic phenotype were
      analyzed at the single-cell level. Results showed a progressive increase of TNF
      alpha production in annexin V-positive cells. These results indicate that MTB
      induced apoptosis is associated with proinflammatory cytokine production.

PMID- 12402198
TI  - A new model for studying the effects of Mycobacterium leprae on Schwann cell and
      neuron interactions.
AB  - Millions of patients with leprosy suffer from nerve damage resulting in
      disabilities as a consequence of Mycobacterium leprae infection. However,
      mechanisms of nerve damage have not been elucidated because of the lack of a
      model that maintains M. leprae viability and mimics disease conditions. A model
      was developed using viable M. leprae, rat Schwann cells, and Schwann cell-neuron
      cocultures incubated at 33 degrees C. M. leprae retained 56% viability in Schwann
      cells for 3 weeks after infection at 33 degrees C, compared with 3.6% viability
      at 37 degrees C. Infected Schwann cells had altered morphology and expression of
      genes encoding cellular adhesion molecules at 33 degrees C but were capable of
      interacting with and myelinating neurons. Cocultures, infected after myelination
      occurred, showed no morphological changes in myelin architecture after 1 month of
      incubation at 33 degrees C, and M. leprae retained 53% viability. This article
      describes a new model for studying the effects of M. leprae on Schwann cells.

PMID- 12402199
TI  - Use of circulating galactomannan screening for early diagnosis of invasive
      aspergillosis in allogeneic stem cell transplant recipients.
AB  - Screening for galactomannan (GM) has been adopted by many European centers as
      part of the management plan for allogeneic stem cell transplant recipients.
      However, the temporal onset of GM antigenemia remains unknown. A series of
      allogeneic stem cell transplant recipients were monitored prospectively, and the
      relationship between antigenemia and other diagnostic triggers for initiation of
      antifungal therapy was analyzed. GM detection had a sensitivity of 94.4% and a
      specificity of 98.8%. Positive and negative predictive values were 94.4% and
      98.8%, respectively. This statistical profile was better than that of other
      triggers, including unexplained fever, new pulmonary infiltrates, isolation of
      Aspergillus species, and abnormalities seen on computed tomography. Antigenemia
      preceded diagnosis on the basis of radiologic examination or Aspergillus
      isolation by 8 and 9 days in 80% and 88.8% of patients, respectively. Antigenemia
      preceded therapy in 83.3% of patients. Detection of GM was especially useful when
      patients were receiving steroid treatment or when coexisting conditions masked
      the diagnosis of invasive aspergillosis. Prospective screening for GM allows
      earlier diagnosis of aspergillosis than do conventional diagnostic criteria.

PMID- 12402200
TI  - Association of transient dermal mastocytosis and elevated plasma tryptase levels
      with development of adverse reactions after treatment of onchocerciasis with
      ivermectin.
AB  - To investigate the role of mast cells in treatment-associated adverse reactions
      in patients with onchocerciasis, changes in plasma tryptase levels and skin mast
      cell counts were examined in 2 groups of Onchocerca volvulus-infected subjects
      after ivermectin treatment. After treatment, an increase in tryptase levels was
      observed concurrent with the onset of blood eosinopenia and preceding the
      appearance of plasma eosinophil-derived neurotoxin (EDN) and interleukin-5.
      Tryptase levels were correlated with development of peripheral eosinopenia and
      markers of eosinophil activation and degranulation. Dermal mast cell numbers
      increased transiently at 24 h after treatment, preceding the onset of dermal
      eosinophil infiltration and the development of clinically apparent inflammation.
      Local reactions were strongly correlated with levels of plasma tryptase and EDN,
      and the severity of systemic reactions was correlated with levels of tryptase,
      EDN, and interleukin-5. The data indicate that mast cells play a role in
      initiation of tissue inflammatory reactions after ivermectin treatment of
      onchocerciasis.

PMID- 12402201
TI  - Infectiousness in a cohort of brazilian dogs: why culling fails to control
      visceral leishmaniasis in areas of high transmission.
AB  - The elimination of seropositive dogs in Brazil has been used to control zoonotic
      visceral leishmaniasis but with little success. To elucidate the reasons for
      this, the infectiousness of 50 sentinel dogs exposed to natural Leishmania
      chagasi infection was assessed through time by xenodiagnosis with the sandfly
      vector, Lutzomyia longipalpis. Eighteen (43%) of 42 infected dogs became
      infectious after a median of 333 days in the field (105 days after
      seroconversion). Seven highly infectious dogs (17%) accounted for >80% of sandfly
      infections. There were positive correlations between infectiousness and anti
      Leishmania immunoglobulin G, parasite detection by polymerase chain reaction, and
      clinical disease (logistic regression, r2=0.08-0.18). The sensitivity of enzyme
      linked immunosorbent assay to detect currently infectious dogs was high (96%) but
      lower in the latent period (<63%), and specificity was low (24%). Mathematical
      modeling suggests that culling programs fail because of high incidence of
      infection and infectiousness, the insensitivity of the diagnostic test to detect
      infectious dogs, and time delays between diagnosis and culling.

PMID- 12402202
TI  - Opsonin-independent phagocytosis: an effector mechanism against acute blood-stage
      Plasmodium chabaudi AS infection.
AB  - Opsonin-independent macrophage phagocytosis was investigated as a possible
      mechanism of controlling early blood-stage Plasmodium chabaudi AS infection.
      Early during infection, peritoneal macrophages from resistant C57BL/6 (B6) mice
      exhibited increased phagocytosis of parasitized red blood cells (pRBCs) and free
      merozoites, which was absent in mice with deficient interferon (IFN)-gamma
      production during infection, including susceptible A/J, interleukin (IL)-12 p40,
      and IFN-gamma gene knockout mice. IFN-gamma treatment of macrophages collected
      from B6 and A/J mice early during infection enhanced phagocytosis of pRBCs, but
      IL-10 treatment inhibited this function. In vitro and in vivo studies in which
      type I and II class A scavenger receptor-deficient mice and inhibitors of
      scavenger and mannose receptors were used revealed that scavenger receptors other
      than class A type I and II and mannose receptors may play a role in malaria
      parasite uptake. These results indicate that opsonin-independent phagocytosis
      contributes to the IFN-gamma-dependent control of acute blood-stage malaria
      infection.

PMID- 12402203
TI  - Virological features and clinical manifestations associated with human
      metapneumovirus: a new paramyxovirus responsible for acute respiratory-tract
      infections in all age groups.
AB  - The virological features and clinical findings associated with the new human
      metapneumovirus (HMPV) were examined retrospectively in Canadian patients
      hospitalized for various respiratory conditions since 1993. Thirty-eight
      previously unidentified respiratory viruses isolated from rhesus monkey kindey
      (LLC-MK2) cells were found to be positive for HMPV by reverse-transcription
      polymerase chain reaction, and those strains clustered in 2 phylogenetic groups.
      Children aged <5 years and elderly subjects aged >65 years represented 35.1% and
      45.9% of the HMPV-infected cases, respectively. In hospitalized children, the
      most frequent diagnoses were pneumonitis (66.7%) and bronchiolitis (58.3%),
      whereas bronchitis and/or bronchospasm (60%) and pneumonitis (40%) were most
      commonly seen in elderly subjects. Of the 15 patients with pneumonitis, 4 (26.7%)
      had immunosuppressive conditions and 6 (40%) were infants aged <15 months. These
      findings suggest that HMPV can be associated with severe lower-respiratory-tract
      infections in very young children, the elderly, and immunocompromised patients.

PMID- 12402204
TI  - Relationship between the development of precore and core promoter mutations and
      hepatitis B e antigen seroconversion in patients with chronic hepatitis B virus.
AB  - Chinese patients with chronic hepatitis B virus (332 with and 44 without
      cirrhosis-related complications) were studied. Fifty percent of patients <30
      years old had precore mutations. The prevalence of precore mutations among
      hepatitis B e antigen (HBeAg)-positive patients, although lower than that among
      anti-HBe-positive patients (P=.031), was already high (44.2%). Median HBV DNA
      level in anti-HBe-positive patients was 1.5 x 10(6)-1.55 x 10(6) copies/mL,
      irrespective of the presence or absence of precore mutations. There was no
      difference in the prevalence of precore mutations between patients with and
      without complications (P, not significant). However the prevalence of core
      promoter mutations was higher among patients with complications than among those
      without complications (90.5% vs. 69.3%, respectively; P=.003). In conclusion,
      precore mutations occurred in a large proportion of Chinese patients with chronic
      hepatitis B virus before HBeAg seroconversion. The development of complications
      was not related to precore mutations but was probably due to the persistence of
      significant viremia after HBeAg seroconversion.

PMID- 12402206
TI  - A novel methicillin-resistance cassette in community-acquired methicillin
      resistant Staphylococcus aureus isolates of diverse genetic backgrounds.
AB  - Until recently, it has been unclear whether community-acquired (CA) methicillin
      resistant Staphylococcus aureus (MRSA) isolates represent the spread of hospital
      MRSA isolates into the community. In 2 CA-MRSA isolates, a novel genetic element,
      designated staphylococcal cassette chromosome mec (SCCmec) type IV, was found; it
      differs from SCCmec types I-III in its small size and absence of non-beta-lactam
      genetic-resistance determinants. To study the prevalence of type IV SCCmec,
      polymerase chain reaction characterization of SCCmec was performed on DNA from 12
      CA-MRSA isolates. The 12 CA-MRSA isolates were from diverse genetic backgrounds,
      as evidenced by their stratification into 5 pulsed-field gel electrophoresis
      types, 4 coagulase types, and 2 ribotypes. Eleven of the 12 isolates contained
      the novel SCCmec type IV element. Ten were resistant only to beta-lactam
      antibiotics. SCCmec type IV is present on the genome of CA-MRSA isolates. Its
      relatively small size and presence in isolates of diverse genetic backgrounds
      suggest that it may spread among S. aureus isolates.

PMID- 12402205
TI  - Pharmacokinetic and pharmacodynamic investigation of efavirenz in the semen and
      blood of human immunodeficiency virus type 1-infected men.
AB  - Therapeutic concentrations of antiretroviral agents in seminal plasma (SP) may
      reduce virus burden and influence sexual transmission of human immunodeficiency
      virus (HIV) type 1. This study compared the pharmacokinetic, pharmacodynamic, and
      dose responses of efavirenz (EFV) in SP versus those in blood plasma (BP). A
      total of 431 BP samples and 157 SP samples were obtained over a period of 40
      days, from 9 EFV-naive men (i.e., men about to receive EFV for the first time)
      and from 12 EFV-experienced men (i.e., men already receiving EFV as part of an
      antiretroviral regimen). Overall, median EFV exposure in SP was 3.4% (range, 2.0%
      5.0%) of that in BP. However, all EFV concentrations in SP were >/=40-fold higher
      than the wild-type IC(90) (IC(90)(WT)) for HIV-1. During the dosing interval, no
      single SPrcolon;BP EFV-concentration ratio was significantly predictive of the
      absolute measure of exposure in SP. By day 40, HIV-1 RNA in SP was undetectable
      in 8 (89%) of 9 EFV-naive men and remained undetectable in 10 (83%) of 12 EFV
      experienced men. In SP, EFV reaches concentrations above the HIV-1 IC(90)(WT)
      throughout the dosing interval. EFV-containing regimens effectively suppress HIV
      1 RNA in SP.

PMID- 12402207
TI  - Gastric Helicobacter species infection in murine and gerbil models: comparative
      analysis of effects of H. pylori and H. felis on gastric epithelial cell
      proliferation.
AB  - C57BL/6 mice and Mongolian gerbils were infected with Helicobacter felis and
      Helicobacter pylori SS1 strain to investigate the effects of different
      Helicobacter species on gastric inflammation and epithelial cell proliferation in
      different animal models. At 4 weeks, gerbils infected with H. pylori or H. felis
      developed antral gastritis. Onset of gastritis varied between the models, with
      mice infected with H. pylori having minimal inflammation at 8 weeks. In mice, H.
      felis, but not H. pylori, induced significantly increased epithelial cell
      proliferation in the cardia and corpus at 8 weeks, but no changes were observed
      at 4 weeks. In gerbils, both H. pylori and H. felis significantly increased
      antral epithelial cell proliferation at 4 weeks. Epithelial cell proliferation
      induced by H. felis in gerbils was twice that stimulated by H. pylori. These
      studies demonstrate host differences in the development of Helicobacter species
      induced gastric inflammation and a marked difference in epithelial cell
      proliferation induced by H. pylori and H. felis in 2 animal models.

PMID- 12402208
TI  - Antibody persistence and immunological memory at age 4 years after meningococcal
      group C conjugate vaccination in children in the United kingdom.
AB  - Antibody persistence and immunological priming for 2 formulations of a
      meningococcal group C (menC) conjugate (MCC) vaccine (containing 2 or 10 microg
      of menC polysaccharide) administered at 2, 3, and 4 months of age was
      investigated by boosting vaccine recipients at age 13-16 months or 4 years with
      10 microg of unconjugated menC polysaccharide. At age 4 years, geometric mean
      titers (GMTs) and concentrations of menC-specific immunoglobulin G and serum
      bactericidal antibody (SBA) had decreased to prevaccination levels. Geometric
      mean avidity indices increased after the primary vaccination until age 13-16
      months and then remained constant until age 4 years. One month after boosting at
      age 4 years, menC immunoglobulin G and SBA levels increased significantly. The
      postbooster SBA GMT for the 2-microg vaccination (2181.2; 95% confidence interval
      [CI], 975.9-4875.1) was 2-fold higher than that for the 10-microg vaccination
      (931.6; 95% CI, 338.0-2568.1). This is the first demonstration of immunological
      memory at 4 years of age in children receiving MCC vaccine on the United
      Kingdom's 2/3/4-month immunization schedule.

PMID- 12402209
TI  - Combinations of protein polysaccharide conjugate vaccines for intranasal
      immunization.
AB  - The ability of 2 mutants of heat-labile Escherichia coli enterotoxin (LTK63 and
      LTR72) to enhance the immunogenicity of 2 protein polysaccharide conjugate
      vaccines, Neisseria meningitidis group C (MenC) and Haemophilus influenzae type B
      (Hib), both of which are conjugated to the nontoxic mutant of diphtheria toxin
      (CRM197), after intranasal (inl) immunization in mice was evaluated. In addition,
      the question of whether combining both vaccines in a single formulation with heat
      labile E. coli enterotoxin mutants reduced the response to either vaccine was
      investigated. The results showed that potent serum antibody responses against
      MenC and Hib could be elicited by inl immunization in combination with the
      mucosal adjuvants. Moreover, IgA mucosal responses were induced only in animals
      immunized through the inl route. Finally, the coadministration of 2 conjugate
      vaccines simultaneously did not adversely affect the responses against either.
      These studies support the rationale for developing mucosal vaccines, based on
      combining protein polysaccharide conjugates with heat-labile E. coli enterotoxin
      mutants, for infants and young children.

PMID- 12402210
TI  - Does antimicrobial resistance cluster in individual hospitals?
AB  - Factors that affect the resistance rates for an organism-drug combination in a
      given hospital also might influence resistance rates for other organism-drug
      combinations. We examined correlations between resistance prevalence in non
      intensive care inpatient areas of 41 hospitals participating in phase 3 (1998
      1999) of Project ICARE (Intensive Care Antimicrobial Resistance Epidemiology). We
      focused on statistically significant (P<.05) Pearson correlation coefficients for
      methicillin-resistant Staphylococcus aureus, coagulase-negative staphylococci,
      vancomycin-resistant enterococci, and resistance to third-generation
      cephalosporins, imipenem, and fluoroquinolones in Escherichia coli, Klebsiella
      pneumoniae, Enterobacter species, and Pseudomonas aeruginosa. Resistance
      prevalence rates in individual hospitals were not strongly correlated among gram
      positive organisms, and few correlations were seen between rates in gram-positive
      and gram-negative organisms. More frequent significant associations were found
      among resistance rates for gram-negative organisms. Resistance to third
      generation cephalosporins in K. pneumoniae was significantly correlated with the
      majority of other sentinel antimicrobial-resistant organisms. High prevalence of
      this organism may serve as a marker for more generalized resistance problems in
      hospital inpatient areas.

PMID- 12402211
TI  - Impact of highly active antiretroviral therapy on the incidence of visceral
      leishmaniasis in a French cohort of patients infected with human immunodeficiency
      virus.
AB  - The incidence of human immunodeficiency virus (HIV)-Leishmania coinfections in
      France was estimated on the basis of the French Hospital Database on HIV, and
      risk factors for the occurrence of visceral leishmaniasis (VL) were analyzed by a
      multivariate Cox model. VL was diagnosed in 165 of 55,626 HIV-infected patients
      followed since 1992. The incidence of VL decreased from 11.6+/-1.2 per 10,000
      persons-years before 1996 to 6.3+/-0.7 per 10,000 persons-years after 1996, the
      year when highly active antiretroviral therapy (HAART) was initiated in France.
      The relative hazard (RH) for development of VL was higher in (1) intravenous drug
      users versus other transmission groups (RH=1.56; 95% CI, 1.13-2.15), (2) patients
      living in southern France versus those living in northern France (RH=3.36; 95%
      CI, 2.44-4.61), and (3) patients who had a CD4 cell count of </=50/mm(3) during
      their follow-up versus those who did not (RH=6.45; 95% CI, 4.27-9.75) but was
      lower in (4) patients who received antiretroviral therapy including >/=3 drugs
      versus those who did not (RH=0.41; 95% CI, 0.26-0.65). We found a significant
      decrease in the incidence of HIV-Leishmania coinfections after 1996, associated
      with the introduction of HAART in France.

PMID- 12402212
TI  - Immunity to placental malaria. IV. Placental malaria is associated with up
      regulation of macrophage migration inhibitory factor in intervillous blood.
AB  - Macrophage migration inhibitory factor (MIF) may play a role in immune responses
      to malaria during pregnancy by virtue of its ability to activate macrophages and
      to overcome the immunosuppressive effect of glucocorticoids. The present study
      investigated whether plasma MIF levels are altered in pregnant women with
      placental malaria (PM) and/or human immunodeficiency virus (HIV) infection. For
      the first time it is demonstrated that MIF levels in the intervillous blood (IVB)
      plasma were significantly elevated, compared with that in both peripheral plasma
      ( approximately 500-fold) and cord plasma (4.6-fold; P<.01). IVB mononuclear
      cells also produced significantly higher levels of MIF, compared with that of
      peripheral blood mononuclear cells. PM was associated with increased levels of
      MIF in the IVB plasma (P<.02). Primigravid and secundigravid women had
      significantly higher levels of MIF in their IVB plasma than did multigravid women
      (P<.05). HIV infection did not significantly alter MIF levels in any site
      examined.

PMID- 12402213
TI  - Relationship between respiratory syncytial virus load and illness severity in
      children.

PMID- 12402214
TI  - Role of the toll-like receptor 4 Asp299Gly polymorphism in susceptibility to
      Candida albicans infection.

PMID- 12402218
TI  - [Bioethical considerations of genetic engineering].
AB  - Recombinant DNA technology, popularly known as genetic engineering, has numerous
      applications which have both fascinated and alarmed the public. Since the mid
      70s, the benefits of this technology, generally speaking, outnumber the risks.
      These benefits, which take the shape of an increase in knowledge and in the
      improvement of diagnostic and therapeutic products, have had widespread
      repercussions, not only in the laboratory but also in our day-to-day lives.
      Scientific progress and the new scientific directions in Biology make it
      necessary for scientists to have an advanced philosophical concept of the world
      so as to be able to properly evaluate the results and perspectives of any
      biological science, including those of genetic engineering. It is very important
      for it to have a biosocial approach: there must be an unrelenting battle against
      pseudoscientific ideas and attempts to use the recent advances in Biology for
      reactionary, antihuman purposes.

PMID- 12402217
TI  - A highly significant association between a COMT haplotype and schizophrenia.
AB  - Several lines of evidence have placed the catechol-O-methyltransferase (COMT)
      gene in the limelight as a candidate gene for schizophrenia. One of these is its
      biochemical function in metabolism of catecholamine neurotransmitters; another is
      the microdeletion, on chromosome 22q11, that includes the COMT gene and causes
      velocardiofacial syndrome, a syndrome associated with a high rate of psychosis,
      particularly schizophrenia. The interest in the COMT gene as a candidate risk
      factor for schizophrenia has led to numerous linkage and association analyses.
      These, however, have failed to produce any conclusive result. Here we report an
      efficient approach to gene discovery. The approach consists of (i) a large sample
      size-to our knowledge, the present study is the largest case-control study
      performed to date in schizophrenia; (ii) the use of Ashkenazi Jews, a well
      defined homogeneous population; and (iii) a stepwise procedure in which several
      single nucleotide polymorphisms (SNPs) are scanned in DNA pools, followed by
      individual genotyping and haplotype analysis of the relevant SNPs. We found a
      highly significant association between schizophrenia and a COMT haplotype
      (P=9.5x10-8). The approach presented can be widely implemented for the genetic
      dissection of other common diseases.

PMID- 12402219
TI  - [Guillain-Barre syndrome in the northern area of Gran Canaria and the island of
      Lanzarote].
AB  - AIMS: The objective of this study is to analyse the incidence and clinical
      characteristics of Guillain Barre syndrome (GBS) in the Canary Islands. PATIENTS
      AND METHODS: We conducted a retrospective study of GBS patients (according to
      diagnostic criteria from the National Institute of Neurological and Communicative
      Disorders and Stroke) treated in the Ntra. Sra. del Pino Hospital in Gran Canaria
      between 1983 and 1998. Annual incidence, seasonal distribution, preceding
      infection, clinical and electrophysiological data, and evolution were all
      evaluated. Prognostic factors were studied by means of a univariate analysis.
      RESULTS: A total of 81 patients were selected for the study. The raw incidence
      was 1.04/100,000 inhab./year (CI 95%: 0.83 1.29; adjusted for age to the European
      population: 1.5). The rates of incidence were higher in men and increased
      lineally with age in both sexes. We observed an upward tendency during the winter
      months. 48% of the patients displayed serious motor deficits in the nadir of the
      disease, and 17.8% required assisted ventilation. After one year s evolution 74%
      were seen to experience an excellent recovery. The mortality rate was 8.2% and
      37% received immunomodulatory treatment. The main variables associated with a bad
      prognosis at 3 and 12 months were: serious deficits in muscular balance, the need
      for assisted ventilation and very reduced amplitude of evoked motor potential.
      CONCLUSIONS: GBS incidence in the Canary Islands is similar to that found in
      other countries. An increase with age and an upward tendency during the winter
      months was observed. No differences were found in the clinical data as compared
      with other series.

PMID- 12402221
TI  - [Silent cerebral infarct in patients with sickle cell anemia].
AB  - INTRODUCTION: Ictus is a complication in patients with Sickle Cell Anemia (SCA),
      in these is of importance the precocious diagnosis of Silent Cerebral Infarcts
      (SCI). OBJECTIVE: To determine the incidence of ICS in patients with SCA without
      neurological symptoms but with images in Cerebral Magnetic Resonance (RMC).
      PATIENTS: A total of 18 patients (13 males, 5 females) with ages between 5 and 24
      years (11.5 4,9), without history of neurological alterations, taken care at the
      Instituto Hematol gico de Occidente Banco de Sangre, Estado Zulia Venezuela.
      Methods. A clinical history was made to each patient in addition to detailed
      physical and neurological examinations that included the state of mind,
      conscience, language, sensitivity, cranial pairs, muscular force, reflexes,
      cerebella tests, neck and march. Later, RMC studies were carried out. RESULTS: It
      was found that 2/18 (11,1%) patients without neurological manifestations showed
      alterations in the RMC and they were diagnosed as ICS. The findings by images
      showed asymmetry of lateral ventricles and one of them showed gliosis as well.
      CONCLUSION: 11,1% of the all the studied cases (2/18) showed SCI, for what is
      suggested to carry out neurological evaluation and images, once a year, and to
      offer opportune therapies, for their impact in the function neurocognitive

PMID- 12402220
TI  - [A study of some indirect biochemical markers in the evaluation of enzymatic
      induction caused by antiepileptic drugs].
AB  - A comparative study was carried out to examine urinary excretion of D glucaric
      acid (DGA), g glutamyltransferase (GGT) activity and the concentration of serum
      bilirubin as enzymatic induction markers in 89 adult patients (56 men and 33
      women) who were receiving chronic treatment with phenobarbital, phenytoin,
      carbamazepine and valproate. As in most cases, these drugs were administered as a
      polytherapy; drugs doses were expressed in units/day, in accordance with a
      previously described system of scoring, which would reflect the induction
      capacity of the combination of drugs administered. We found a high prevalence of
      results that were above the upper reference limit for urinary DGA (93.2%) and
      serum GGT (80.6%). Bilirubin and its conjugate and non conjugate fractions were
      found to offer values that to a large extent matched those of the control group.
      The levels of the different biochemical variables presented significant
      correlations with the daily doses of the drugs administered, above all in the
      case of DGA (r= 0.773, p< 0.001). When we split the data according to sex, the
      correlations improved in men but were significantly worse in women. This fact
      could be due to a greater inter individual variability in the response to
      inducers of the phenobarbital type in female patients. Urinary DGA seems to be a
      better enzymatic induction marker than GGT and bilirubin and its serum fractions,
      the value of which appeared to be very limited in these cases. Separating GGT
      into its isoforms provided no further information of practical interest as
      regards the enzymatic activity as a whole.

PMID- 12402222
TI  - [Changes in episodic and semantic memory associated with temporal lobectomy].
AB  - INTRODUCTION: Temporal lobectomy (TL) is an effective treatment for drug
      refractory temporal lobe epilepsy. The main neuropsychological consequences of
      the intervention are changes in episodic and semantic memory. Aim. To study the
      consequences of right temporal lobectomy (RTL) and left temporal lobectomy (LTL)
      on episodic and semantic mnemonic functioning. PATIENTS AND METHOD: 27 patients
      who had undergone TL in the Hospital Universitario Virgen de las Nieves in
      Granada were submitted to pre and post surgical evaluation by means of a battery
      of neuropsychological tests that included episodic and semantic memory tests for
      both verbal and visual material. RESULTS AND CONCLUSIONS: ANOVA analysis was
      employed to analyse the pre and post surgical changes for the whole group of
      patients, and Student s t and Wilcoxon s non parametric test were used for each
      group of RTL and LTL. No deterioration was found in ipsilateral memory after the
      intervention, that is to say, in the verbal memory of the patients submitted to
      LTL and in the visual memory of RTL patients. With regard to contralateral
      memory, that is, the visual memory of patients submitted to LTL and the verbal
      memory of RTL patients, the ANOVA analyses of the whole group revealed a
      statistically significant improvement. The analyses performed for the whole group
      (LTL and RTL), however, did not reveal any statistically significant changes.

PMID- 12402223
TI  - [A study of psychomotor development in premature patients during their first
      year].
AB  - INTRODUCTION: It is necessary to differentiate neurological evaluation in the
      different stages of development, which include the premature newborn infant
      (PNI), the full term newborn, the unweaned baby, the child and the teenager.
      Several studies have shown the importance of using the corrected age when
      exploring the psychomotor development of premature babies. CASUISTICS AND METHOD:
      The population we studied was made up of a cohort of PNI who were born in the
      Hospital de Cl nicas de Porto Alegre and were monitored until they reached the
      age of 12 months. Motricity, sociability and speech were all considered. RESULTS
      AND CONCLUSIONS: It was possible to establish the frameworks of neurological
      development at the corrected ages of 3, 6, 9 and 12 months. The development of
      static balance was the only item among the motor aspects that did not agree with
      what was to be expected for the corrected age. The PNIs development was uniform,
      with regard to the perceptive and language functions for each corrected age. Such
      results reinforce the importance of studies like the one we present in this
      paper, since it is a period that can provide us with information that is useful
      for the early diagnosis of development disorders. It is also the best time to
      indicate psychomotor and affective stimulation, if we bear in mind the importance
      of the brain s plasticity during the first year of life.

PMID- 12402224
TI  - [Encephalitis caused by Rickettsia conorii without exanthema].
AB  - INTRODUCTION: Mediterranean boutonneuse fever, caused by Rickettsia conorii, is
      an endemic disease in the Mediterranean area. The serious forms of the disease,
      which include encephalitis, are infrequent but are associated with a high
      mortality rate. Diagnostic suspicion is backed up by the development of
      exanthema. We report the case of a patient who developed encephalitis caused by
      Rickettsia conorii without exanthema. Clinical case. A 27 year old woman who had
      nauseas, headache, fever, abdominal upset and generalised pain during the days
      before being admitted to hospital. On the day she was admitted, she noticed
      reduced strength in the left limbs, together with numbness and pins and needles
      in the left side of the body. In the casualty department she presented tonic
      seizures in the left extremities and later generalised tonic clonic seizures.
      Exploration showed facial paresis and 4/5 hemiparesis on the left side.
      Complementary tests carried out in casualty, including cerebrospinal fluid (CSF),
      did not reveal any significant findings. She was admitted after a loading dose of
      phenytoin. After 48 hours she presented fever and repeated complex partial
      seizures. A new CSF analysis was normal. She was treated with valproate,
      clonazepam, ceftriaxone, doxycycline and acyclovir. An electroencephalogram (EEG)
      showed theta activity in the left centroparietal areas and slow delta waves in
      the right temporal regions. Magnetic resonance imaging (MRI) of the brain showed
      contrast enhancement in the meninges. 24 later, due to the frequency of the
      seizures, phenobarbital and methylprednisolone were added, which enabled the
      seizures to be controlled. The posterior brain MRI revealed a right parasylvian
      lesion. Serological Rickettsia conorii IgM +, IgG 1/256 was administered. After
      eight months, she has presented no seizures or neurological deficit. CONCLUSIONS:
      There are cases of encephalitis from Rickettsia conorii that can present without
      exanthema. This means that in endemic areas early treatment with doxycycline
      could be advisable when faced with encephalitis of unknown aetiology, bearing in
      mind the high mortality rate that occurs when no early treatment is administered
      and the good tolerance to doxycycline.

PMID- 12402225
TI  - [Periodic lateralised epileptiform discharges as a form of presentation of
      neurosyphilis].
AB  - INTRODUCTION: Neurosyphilis is a recognised cause of epileptic seizures, but its
      association with periodic lateralised epileptiform discharges (PLED) has been
      described only rarely, in spite of the fact that it gives rise to acute vascular
      lesions. CLINICAL CASE: We report the case of a male patient who was diagnosed as
      having meningovascular syphilis after the onset of tonic clonic epileptic
      seizures and PLED in the left frontotemporal region. The initial neurological
      exploration revealed a syndrome of confusion and mild mixed, but predominantly
      motor, dysphasia. In complementary tests, the most noteworthy features were
      positive luetic serology in the blood and in cerebrospinal fluid (CSF), which was
      confirmed by means of treponemic assays. The patient was treated with penicillin
      for two weeks. The study was completed with a magnetic resonance (MR) brain scan
      that showed a small left temporal infarction, which was the origin of the
      clinical and electrical convulsive activity. The patient s evolution was
      satisfactory, with an improvement in the language disorder, and the seizures were
      controlled after the administration of phenytoin. The control
      electroencephalogram (EEG) that was performed later only showed a slowing in the
      known injured area. CONCLUSIONS: PLED are an infrequent electroencephalographic
      pattern whose appearance has been linked with acute brain lesions, mainly with
      strokes, tumours and meningoencephalitis. When, exceptionally, they appear as a
      consequence of an ischemia secondary to meningovascular syphilis their
      significance, clinical features and prognosis do not differ from other causes of
      a cerebrovascular disease.

PMID- 12402226
TI  - [Hypokalemic periodic paralysis: exercise test].
AB  - INTRODUCTION: Periodic paralyses are illnesses related with the dysfunction of
      the ionic pathways of the muscle fibre membrane. Neurophysiological diagnosis by
      means of a conventional electromyogram (EMG) is rather unsatisfactory when
      exploring patients in the asymptomatic phase, since they often display unspecific
      changes. Furthermore, it does not identify the alterations in muscular
      excitability. The exercise test consists in determining the variation in the area
      or the amplitude of the muscular action potential, which is obtained through
      electrical stimuli that are repeated periodically for several minutes after
      having carried out local exercise with the explored muscles. It is a simple
      technique that enables us to achieve a significant reduction in the area or
      amplitude of the action potential (more than 40% or 50% with regard to the basal
      value) in certain diseases produced by ionic pathway dysfunction, while the
      patient is in the asymptomatic phase. CLINICAL CASES: We report the cases of
      three patients diagnosed as suffering from hypokalemic periodic paralysis. During
      the asymptomatic phase, the EMG revealed characteristic myopathic changes in only
      one case and unspecific alterations in the other two. Nevertheless, the exercise
      test that was also performed during the asymptomatic phase showed a
      characteristic pathological response in the three patients. CONCLUSION: The
      exercise test is a technique that indirectly shows up the progressive loss of
      muscle fibre membrane excitability and helps diagnosis in asymptomatic patients.

PMID- 12402227
TI  - [Hypothyroidism concealed by Parkinson's disease].
AB  - AIMS: Although it is commonly recognised that diseases of the thyroids can
      simulate extrapyramidal disorders, a review of the causes of Parkinsonism in the
      neurology literature shows that they are not usually mentioned or, if so, only
      very briefly. The development of hypothyroidism in a patient with Parkinson s
      disease can go undetected, since the course of both diseases can involve similar
      clinical features. Generally speaking there is always an insistence on the need
      to conduct a thyroidal hormone study in any patient with symptoms of Parkinson,
      but no emphasis is put on the need to continue to rule out dysthyroidism
      throughout the natural course of the disease, in spite of the fact that the
      concurrence of both pathological conditions can be high and that, in the same way
      hypothyroidism can simulate Parkinson s disease, the latter can also conceal
      hypothyroidism. CASE REPORT: We report the case of a female patient who had been
      suffering from Parkinson s disease for 17 years and started to present on off
      fluctuations that did not respond to therapy. Hypothyroidism was observed and the
      hormone replacement therapy used to resolve the problem allowed the Parkinsonian
      fluctuations to be controlled. CONCLUSIONS: We believe that it is very wise to
      suspect hypothyroidism in patients known to be suffering from Parkinson s
      disease, and especially so in cases where the clinical condition worsens and
      symptoms no longer respond properly to antiparkinsonian treatment. These
      observations stress the possible role played by thyroid hormones in dopaminergic
      metabolism and vice versa.

PMID- 12402228
TI  - [Origin of cortical interneurons: basic concepts and clinical implications].
AB  - Introduction and development. GABAergic interneurons play a prominent role in the
      function of the cerebral cortex, since they allow the synchronization of
      pyramidal neurons and greatly influence their differentiation and maturation
      during development. Until recently it has been thought that cortical interneurons
      and pyramidal neurons originate from progenitor cells located in the dorsal
      region of the telencephalon, the pallium. Recent studies, however, have
      demonstrated that a large number of cortical GABAergic neurons arise from
      progenitors located in the subpallium the region of the telencephalon that gives
      rise to the basal ganglia, and that they arise in the cerebral cortex after a
      long tangential migration. Aims. In this review I have summarized our current
      knowledge of the factors that control the specification of cortical interneurons,
      as well as the mechanisms that direct their migration to the cortex.

PMID- 12402229
TI  - [Neurobiology and molecular biology of Alzheimer's disease].
AB  - INTRODUCTION AND DEVELOPMENT: The neuropathological characteristics of
      Alzheimer's disease (AD) include the presence of neurofibrillary tangles (NFT),
      senile plaques (SP), neuronal death, and amyloid angiopathy. However, it is
      accepted that the accumulation of beta amyloid proteins, which are the main
      constituent of the SP, is the central neuropathological lesion in AD. All
      mutations that known to cause AD are related to an increase production of beta
      amyloid. An inflammatory process usually surrounds the SP, and it is though to
      contribute to the formation of the SP, and to the metabolic cascade that leads to
      neuronal death. There is seveltive vulnerability of the limbic system and
      heteromodal areas to AD pathology, and it is in these areas where amyloid
      deposits can induce a greater inflammatory response. The most affected
      neurotransmitter is acetylcholine, and it is associated with the loss of enzymes
      that are part of ots normal metabolism, and with loss of a presynaptic receptors
      (e.g. Muscarinic 2), and with a relative preservation of postsynaptic receptors
      (e.g. Muscarinic1). There is significant loss of nicotinic receptors.
      CONCLUSIONS: Significant advances have been made with transgenic mice that
      enhanced our understanding of AD pathology. It has been identified enzymes that
      participate in the metabolism of amyloid, and the possible mechanisms of
      interaction between amyloid deposits and NFT. These advances are the starting
      point for future treatments that could interfere with amyloid formation

PMID- 12402230
TI  - [Dementia with Lewy bodies. Pure and mixed forms].
AB  - INTRODUCTION AND METHOD: Dementia with Lewy bodies is a generative brain disease
      of unknown origin, characterised clinically by progressive mental deterioration,
      with striking fluctuations and transitory episodes of confusion, hallucinations
      and psychotic symptoms (hallucinations and paranoid deliria), extrapyramidal
      signs and hypersensitivity to neuroleptic drugs. The main pathological finding
      was the abundance of Lewy bodies in the neurons of the cortex, brain stem and
      other subcortical nuclei. In many cases, however, varying amounts of Alzheimer
      like degenerative lesions are associated. CONCLUSION: This study analyses the
      anatomopathological, clinical, diagnostic and therapeutic aspects of this
      disease.

PMID- 12402231
TI  - [Recent advances in the neuropathological evaluation of Alzheimer's disease: the
      importance of alpha-synuclein].
AB  - INTRODUCTION AND METHOD: The uncertainty regarding the nosology and significance
      of Lewy bodies (LB) in dementia is still very present in current research. It is
      an acknowledged fact that an important number of cases of Alzheimer s disease
      (AD) also present LB. These can be detected by a synuclein immunohistochemistry
      in most of the sporadic cases of AD and is most frequently detected in the
      amygdala. CONCLUSIONS: Although the role of LB and the filaments of Lewy in the
      pathogenesis of dementia has still to be determined, it is clear that alphya
      synuclein immunohistochemistry represents an important advance in the evaluation
      of the neuropathological changes in AD and in associated dementias.

PMID- 12402232
TI  - [Neuropharmacology and receptor studies in the elderly].
AB  - Functional brain imaging has provided unique and exciting opportunities to
      strengthen our knowledge of the biological substrate of the aging brain and
      neuropsychiatric disorders. Positron emission tomography (PET) is a particularly
      powerful tool for quantifying the neurobiological correlates of cognition, mood
      and behavior. Initial PET studies of aging, psychiatric disorders and
      neurodegenerative disease focused primarily on generalized physiological
      parameters such as cerebral blood flow and metabolism, and early neuroreceptor
      imaging studies relied on relatively non selective markers. New, selective
      receptor radioligands now offer a previously inaccessible means to investigate
      the dynamic relationships among neurochemistry, aging and psychopathology in
      vivo. This approach has substantial advantages over peripheral (platelet and
      cerebrospinal fluid) markers, neuroendocrine challenge studies, animal models,
      and postmortem receptor binding assays. Advances in tracer kinetic modeling,
      magnetic resonance imaging (MRI) to PET registration, radiochemistry techniques,
      instrumentation and image processing have helped pave the way for increased
      emphasis on functional imaging studies of neuropsychiatric disorders of the
      elderly. The capability to correct PET image data for the confounding effect of
      cerebral atrophy permits relationships among age related brain changes and
      neurobiological disease mechanisms to be more accurately examined in the course
      of normal aging and in elderly patient populations.

PMID- 12402233
TI  - [The semantic memory deficit in Alzheimer's disease].
AB  - INTRODUCTION AND DEVELOPMENT: Although the loss of episodic memory is considered
      one of the the hallmarks of Alzheimer s disease (AD), it is by no means the only
      memory dysfunction suffered by these patients. Perhaps equally important in terms
      of functional adaptation is the loss of, what Tulving referred, semantic memory.
      Semantic memory is that information necessary for language, a mental diccionary
      including not only lexical information (i.e., word meaning and concepts) but also
      facts and general world knowledge. There is a debate in the field of cognitive
      psychology regarding semantic memory, deficits in AD; whether there is an actual
      defect in semantic memory, or this is related to a disruption of the information
      accessing process. Neuroimaging studies have shown that the basis of the semantic
      memory defect is localized in the temporal and frontal lobes. CONCLUSIONS: The
      inferior temporal lobe, and perhaps more importantly, the parahippocampal gyrus,
      is critical for the ability to successfully name objects. However, the ability to
      retrieve name of objects appears to be associated with the frontal lobes.

PMID- 12402235
TI  - [Neurotrophin therapy. Some bioethical considerations].
AB  - Bioethics , which provides a new ethical outlook on human life, is a term used in
      public health and biomedical research issues. It is for this reason that, in this
      paper, we decided to analyse certain aspects associated with the ethical
      considerations we must bear in mind when conducting research in humans, although
      the purpose of doing so is to cure or to improve the quality of life of people
      who suffer from certain diseases, many of which are fatal. Reasons are put
      forward to make it necessary to doubt which is the strategy with the most
      favourable benefit/risk relation for those who will undergo such interventions.
      We describe Alzheimer s disease and discuss the possible use of neurotrophic
      drugs in the treatment of this disorder (NGF therapy). We also emphasise the care
      that will have to be taken in each of the stages of development of the research.
      That is why we are witnessing the emergence of a new culture that is needed to
      regulate the multiple interventions that can be performed on life, and to
      guarantee the primacy of what is good, both for the human being of today and
      those of generations to come.

PMID- 12402236
TI  - [Onset of slowed P300 potential prior to N2 wave genesis in cognitive
      deterioration].

PMID- 12402234
TI  - [Physiology of the neuropeptides].
AB  - In the present review, the characteristics of mammalian neuropeptides have been
      studied. Neuropeptides are widely distributed not only in the nervous system but
      also in the periphery. They are synthesised by neurons as large precursor
      molecules (pre propeptides) which have to be cleaved and modified in order to
      form the mature neuropeptides. Neuropeptides may exert actions as
      neurotransmitters, neuromodulators and/or neurohormones. In the neurons, they
      coexist with classic transmitters and often with other peptides. After their
      releasing, they bind to especific receptors to exert their action in the target
      cell. Most of these receptors belongs to a family of G protein coupled receptors.
      Finally, peptidases are the enzymes involved in the degradation of neuropeptides.
      Conclusions. In the last years, the number of known neuropeptides and the
      understanding of their functions have been increased. With these data, present
      investigations are looking for the treatment of different pathologies associated
      with alterations in the physiology of neuropeptides.

PMID- 12402237
TI  - [Meningitis due to Streptococcus salivarius and spontaneous fistula: a case
      report].

PMID- 12402238
TI  - [Hyponatremia in subarachnoid haemorrhage].

PMID- 12402239
TI  - Overexpressed yeast mitochondrial putative RNA helicase Mss116 partially restores
      proper mtRNA metabolism in strains lacking the Suv3 mtRNA helicase.
AB  - RNA helicase, encoded by the Saccharomyces cerevisiae nuclear gene SUV3, is a
      subunit of the mitochondrial (mt) degradosome: an enzyme complex that takes part
      in turnover of mtRNAs. Deletion of the SUV3 gene leads to a variety of
      disturbances in mtRNA metabolism and results in respiratory incompetence of yeast
      cells. Here we show that the nuclear gene MSS116, which codes for a mitochondrial
      putative RNA helicase necessary for splicing of several mt introns, can suppress
      the lack of the SUV3 gene. Overexpression of the Mss116 putative helicase from a
      multicopy plasmid present in the SUV3-deleted strains partially restores
      respiratory competence, brings the steady-state levels of COB and ATP6/8 mRNA
      back almost to normal and lowers the accumulation of 21S rRNA and ATP6/8 RNA
      precursors to the wild-type levels. To the best of our knowledge, this is the
      first reported case of a substitution of one RNA helicase by another, belonging
      to a different class of RNA helicases.

PMID- 12402240
TI  - Simultaneous determination of potassium and rubidium content in yeast.
AB  - Rubidium is widely used as a potassium analogue in transport studies in yeast and
      other organisms. As rubidium (potassium) uptake is modulated by the internal
      potassium concentration, it is often necessary to determine both Rb(+) and K(+)
      concentrations in the same cell extract. Current methods based on atomic
      absorption/emission spectroscopy require separate analysis for each cation.
      Alternatively, unsafe radioactive isotopes can be used. Here we report a
      convenient, non-radioactive, HPLC/conductivity-based method that allows a
      complete analysis of both cations with a single injection from a cell extract.
      The increase in Rb(+) uptake during K(+) starvation in yeast is easily
      demonstrated with this method.

PMID- 12402241
TI  - Non-respiratory oxygen consumption pathways in anaerobically-grown Saccharomyces
      cerevisiae: evidence and partial characterization.
AB  - Despite the absence of an alternative mitochondrial ubiquinol oxidase,
      Saccharomyces cerevisiae consumes oxygen in an antimycin A- and cyanide-resistant
      manner. Cyanide-resistant respiration is typically used when the classical
      respiratory chain is impaired or absent (i.e in anaerobically-grown cells shifted
      to normoxia or in respiratory-deficient cells). We characterized the non
      respiratory oxygen consumption pathways operating during anoxic-normoxic
      transitions in glucose-repressed resting cells. High-resolution oxygraphy
      confirmed that the cellular non-respiratory oxygen consumption pathway is
      sensitive to high concentrations of cyanide, azide, SHAM and TTFA, and revealed
      several new characteristics. First, the use of sterol biosynthesis inhibitors
      showed that this pathway makes a considerable contribution (about 25%) to both
      endogenous and glucose-dependent oxygen consumption. Anaerobically-grown glucose
      repressed cells exhibited high apparent oxygen affinities (K(m) for oxygen = 0.5
      1 micro M), even in mutants deficient in respiration or sterol synthesis.
      Exogeneously added glucose and endogenous stored carbohydrates were the only
      substrates that were efficient for cellular oxygen consumption (apparent K(m) for
      exogenous glucose = 2-3 mM). On the other hand, fluorimetric measurements of the
      cellular NAD(P)H pool showed that the cellular oxygen consumption (sterol
      biosynthesis and unknown pathways) was dependent more on the intracellular level
      of NADPH than of NADH. High oxygen affinity NADPH-dependent oxygen consumption
      systems were thought to be mainly localized in microsomal membranes, and several
      data indicated a significant contribution made by uncoupled p450 systems,
      together with still uncharacterized systems. Such activities are associated in
      vitro with a massive production of O(2) (.-) and, to a lower extent, H(2)O(2) and
      a likely concomitant production of H(2)O.

PMID- 12402242
TI  - Proteins interacting with Lin 1p, a putative link between chromosome segregation,
      mRNA splicing and DNA replication in Saccharomyces cerevisiae.
AB  - Proteins involved in chromosome segregation during mitosis are likely to
      participate in other cell cycle-coordinated processes. Using a two-hybrid screen
      we identified a novel nuclear protein, Lin1, interacting with Irr1p/Scc3p, a
      component of the cohesin complex. The second round of two-hybrid assay with Lin1p
      as the bait resulted in the identification of six proteins: Prp8, Slx5, Siz2,
      Wss1, Rfc1 and YIL149w. These proteins have previously been shown to participate
      in mRNA splicing, DNA replication, chromosome condensation, chromatid separation
      and alternative cohesion. We propose that Lin1p may constitute a link among these
      processes.

PMID- 12402244
TI  - Metabolic physiology of aroma-producing Kluyveromyces marxianus.
AB  - Kluyveromyces marxianus has a high potential for industrial production of aroma
      compounds, such as 2-phenylethanol, which is derived in a bioconversion from L
      phenylalanine. In the present work the product yield of K. marxianus in batch
      cultivation was estimated as 0.65 mol 2-phenylethanol/mol L-phenylalanine and
      thus significantly below the theoretical optimum of 1 mol/mol. By a comprehensive
      approach of stoichiometric balancing and GC-MS analysis of various substrates and
      products of K. marxianus a detailed insight into its metabolism was gained. For
      this purpose ring-labelled ((13)C(6)) L-phenylalanine and naturally labelled
      glucose were applied as substrates in tracer studies in batch culture. The
      produced aroma compounds 2-phenylethanol and 2-phenylethylacetate stem
      exclusively from the supplied L-phenylalanine, whereas glucose was not converted
      into these products because of efficient feed-back inhibition of prephenate
      dehydratase in the L-phenylalanine biosynthetic pathway. It could be further
      shown that the supplied L-phenylalanine completely covers the anabolic cellular
      demand for this amino acid. Quantification of (13)CO(2) in the exhaust gas
      provided clear evidence for catabolic breakdown of L-phenylalanine during
      cultivation. Metabolic balancing around the pool of free intracellular L
      phenylalanine revealed a significant loss of L-phenylalanine into catabolic and
      anabolic pathways. While 73.3% of L-phenylalanine was converted into 2
      phenylethanol or 2-phenylethylacetate, 22.4% was catabolized through the
      cinnamate pathway and 4.3% was directed towards protein biosynthesis. Catabolic
      breakdown of L-phenylalanine via hydroxylation to L-tyrosine could be excluded.
      In addition to an insight into metabolic functioning and regulation of 2
      phenylethanol-producing K. marxianus, the approach presented here provides
      important information on potential targets for genetic optimization of 2
      phenylethanol-producing yeasts.

PMID- 12402243
TI  - Molecular and structural characterization of the spindle pole bodies in the
      fission yeast Schizosaccharomyces japonicus var japonicus.
AB  - The structure and localization of the microtubule organization centres (MTOCs) of
      the fission yeast Schizosaccharomyces japonicus var. japonicus were examined by
      fluorescence microscopy and electron microscopy. Spindle pole bodies (SPBs),
      which are the fungal equivalent of centrosomes, of Sz. japonicus were visualized
      by immunofluorescent staining using a monoclonal anti-gamma-tubulin antibody. The
      behaviour of the SPBs during the cell cycle mostly coincided with previous
      reports on the most widely used fission yeast Schizosaccharomyces pombe. We
      cloned the gamma-tubulin gene from Sz. japonicus by PCR using redundant sets of
      primers corresponding to conserved regions of known gamma-tubulins. The predicted
      amino acid sequence of Sz. japonicus gamma-tubulin was most similar to the Sz.
      pombe gamma-tubulin. Under the electron microscope, the SPBs of Sz. japonicus
      were detected as electron-dense multilayered structures located just outside the
      nuclear envelope. The SPBs of Sz. japonicus were composed of three electron-dense
      layers and were surrounded by fuzzy material. Each layer showed structural
      changes according to the progression of the cell cycle. In mitotic cells, the
      SPBs were located on the fenestrae of the nuclear envelopes through which the
      mitotic spindle microtubules ran into the nucleoplasm. Our results show that Sz.
      japonicus is a very potent and attractive organism for the investigation of the
      microtubule nucleation system and morphogenesis in yeasts. The Accession No. for
      the nucleotide sequence of the Sz. japonicus gtb1(+) gene is AF159163.

PMID- 12402245
TI  - Cation/H+ antiporters mediate potassium and sodium fluxes in Pichia sorbitophila.
      Cloning of the PsNHA1 and PsNHA2 genes and expression in Saccharomyces
      cerevisiae.
AB  - Pichia sorbitophila grows rapidly in the presence of very high NaCl
      concentrations. Under these conditions, even when the K(+) concentration is low,
      P. sorbitophila cells can maintain low Na(+) and high K(+) contents. This
      remarkable capacity of P. sorbitophila fails when the external pH is not acidic.
      This indicates that Na(+) efflux is mediated by an electroneutral Na(+)/H(+)
      antiporter. We have cloned and sequenced two genes designated as PsNHA1 and
      PsNHA2, which probably encode two antiporters of this type. The genes present
      high similarity with the corresponding genes from other yeasts. The heterologous
      expression of PsNHA1 or PsNHA2 in a Saccharomyces cerevisiae mutant lacking the
      Na(+) efflux systems and sensitive to high concentrations of Na(+) and K(+)
      rescued the tolerance and the ability to extrude both cations. The Accession Nos
      of the sequenced DNA fragments are: PsNHA1, AJ496431; PsNHA2, AJ496432. (TC
      2.A.36)

PMID- 12402246
TI  - Leber hereditary optic neuropathy: a nuclear solution of a mitochondrial problem.

PMID- 12402247
TI  - What does it mean to be a carrier for a metabolic disease?

PMID- 12402248
TI  - Polar bear liver, vitamin A, aquaporins, and pseudotumor cerebri.

PMID- 12402249
TI  - Rescue of a mitochondrial deficiency causing Leber Hereditary Optic Neuropathy.
AB  - A G to A transition at nucleotide 11778 in the ND4 subunit gene of complex I was
      the first point mutation in the mitochondrial genome linked to a human disease.
      It causes Leber Hereditary Optic Neuropathy, a disorder with oxidative
      phosphorylation deficiency. To overcome this defect, we made a synthetic ND4
      subunit compatible with the "universal" genetic code and imported it into
      mitochondria by adding a mitochondrial targeting sequence. For detection we added
      a FLAG tag. This gene was inserted in an adeno-associated viral vector. The
      ND4FLAG protein was imported into the mitochondria of cybrids harboring the
      G11778A mutation, where it increased their survival rate threefold, under
      restrictive conditions that forced the cells to rely predominantly on oxidative
      phosphorylation to produce ATP. Since assays of complex I activity were normal in
      G11778A cybrids we focused on changes in ATP synthesis using complex I
      substrates. The G11778A cybrids showed a 60% reduction in the rate of ATP
      synthesis. Relative to mock-transfected G11778A cybrids, complemented G11778A
      cybrids showed a threefold increase in ATP synthesis, to a level
      indistinguishable from that in cybrids containing normal mitochondrial DNA.
      Restoration of respiration by allotopic expression opens the door for gene
      therapy of Leber Hereditary Optic Neuropathy.

PMID- 12402250
TI  - Quantitative CSF PCR in Epstein-Barr virus infections of the central nervous
      system.
AB  - Acute Epstein-Barr virus (EBV) infection of the central nervous system (CNS) is
      associated with meningoencephalitis and other neurological syndromes and with CNS
      lymphomas (CNSLs). Diagnosis is based on serological studies and more recently on
      detection of EBV DNA in cerebrospinal fluid (CSF) by polymerase chain reaction
      (PCR). We measured EBV DNA by quantitative PCR and EBV mRNA by RT-PCR in the CSF
      in patients with EBV-associated neurological disorders. EBV was identified as the
      cause of CNS infection in 28 patients: 14 with CNSL, 10 with encephalitis, and 4
      with postinfectious neurological complications. CSF analysis showed that patients
      with CNSL had high EBV load (mean +/- standard error of 4.8 +/- 0.2 log(10) DNA
      copies/ml) and low leukocyte counts (22 +/- 7 cells/microl); encephalitis was
      characterized by high EBV load (4.2 +/- 0.3 log(10) DNA copies/ml) and high
      leukocyte counts (143 +/- 62 cells/microl); and patients with postinfectious
      complications showed low EBV load (3.0 +/- 0.2 log(10) DNA copies/ml) with high
      leukocyte counts (88 +/- 57 cells/microl). Lytic cycle EBV mRNA, a marker of
      viral replication, was identified in 10 CSF samples from patients with CNSL and
      encephalitis. These studies demonstrate the utility of quantitative CSF PCR and
      establish the presence of lytic cycle EBV mRNA in CSF of patients with EBV
      associated neurological disease.

PMID- 12402251
TI  - A susceptibility gene for late-onset idiopathic Parkinson's disease.
AB  - Eight regions of the genome (PARK1-8) have been implicated in autosomal dominant
      and autosomal recessive forms of early-onset Parkinson's disease. These forms
      constitute a few of all cases. However, except for a haplotype in six families
      (PARK3), no study has successfully mapped a gene or described mutations that
      contribute to the common late-onset Parkinson's disease. Some have even suggested
      that a genetic component does not exist. We cross-matched our nationwide
      genealogy database with a population-based list of Icelandic Parkinson's disease
      patients to search for families with more than one patient. We performed a
      genomewide scan on 117 patients and 168 of their unaffected relatives within 51
      families using 781 microsatellite markers. Allele-sharing, model-independent
      analysis of the results showed linkage to a region on chromosome 1p32 with a
      logarithm of odds score of 3.9 (Z(lr) = 4.2). By increasing the information
      content with additional microsatellite markers in this region, we found that the
      logarithm of odds score increased to 4.9 (Z(lr) = 4.8). This result corresponds
      to an unadjusted p value of 1.0 x 10(-6) and p < 0.005 after adjusting for a
      genomewide search. We designate this region PARK10. We therefore have
      successfully mapped, to genomewide significance, a susceptibility gene for late
      onset Parkinson's disease using multiple families drawn across a whole
      population. Identification of the susceptibility gene in this region may pave the
      way for a better understanding of the disease process, which, in turn, may lead
      to improved diagnostics and therapeutics.

PMID- 12402252
TI  - Long-term amygdalohippocampal stimulation for refractory temporal lobe epilepsy.
AB  - Short-term deep brain stimulation (DBS) recently has been shown to be efficacious
      in refractory temporal lobe epilepsy. We (1) evaluated long-term DBS in medial
      temporal lobe structures in patients with normal magnetic resonance imaging (MRI)
      findings and (2) investigated the use of chronic DBS electrodes for the
      localization of the ictal onset zone before DBS. In three patients with complex
      partial seizures (CPSs), DBS electrodes were implanted in the amygdalohippocampal
      region to identify and subsequently stimulate the ictal onset zone. CPSs were
      compared before and after chronic DBS. Side effects were carefully monitored. DBS
      electrodes yielded high-quality electroencephalogram recordings showing
      unilateral seizure onset in medial temporal lobe structures. For all patients,
      unilateral amygdalohippocampal stimulation was performed. After a mean follow-up
      of 5 months (range, 3-6 months), all patients had a greater than 50% reduction in
      seizure frequency. In two patients, antiepileptic drugs could be tapered. None of
      the patients reported side effects. This open study demonstrates the feasibility
      of consecutive electroencephalographic recordings and DBS in medial temporal lobe
      structures using DBS electrodes. These results prompt further studies in a larger
      patient population to establish the efficacy and safety of chronic DBS as an
      alternative treatment for refractory temporal lobe epilepsy.

PMID- 12402253
TI  - Eubaric hyperoxemia and experimental cerebral infarction.
AB  - We explore three questions concerning arterial hyperoxygenation and focal
      ischemia. (1) Does greater benefit accrue with higher levels of arterial
      hyperoxemia? (2) Is the net effect of continuous (intraischemic plus
      postischemic) oxygen therapy toxic, or beneficial to middle cerebral artery
      infarction? (3) In view of free radical theories of reperfusion injury, does
      hyperoxia isolated to the reperfusion period damage tissue? Rats subjected to
      transient, focal, normothermic, normoglycemic ischemia were assessed at 2 weeks'
      survival. Arterial hyperoxygenation from 98.9 +/- 4.0 to 312.2 +/- 48.4mm Hg
      during ischemia improved (p < 0.05) neurological function, as did isolated
      reperfusion hyperoxemia, but treatment with continuous hyperoxemia both during
      and after ischemia yielded greatest benefit (p < 0.001). Cortical infarcts
      constituted 6.5 +/- 1.8% of the hemisphere at normoxia, but 2.3 +/- 0.9% at
      hyperoxic levels (p < 0.01). Hyperoxia isolated to the reperfusion period also
      reduced cortical necrosis, from 6.5% to 2.7 +/- 1.2%. However, continuous
      intraischemic and reperfusion hyperoxemia led to only 0.2 +/- 0.1% cortical
      necrosis (p = 0.0005). Increasing the degree of hyperoxemia did not augment the
      benefit. We conclude that (1) eubaric hyperoxemia improves neurological and
      neuropathological outcome, (2) continuous oxygen therapy offers the greatest
      benefit, and (3) reperfusion hyperoxemia is beneficial. The findings should allay
      clinical concerns regarding oxygen-induced reperfusion injury, and, by obviating
      hyperbaric chambers, encourage clinical trials studying arterial hyperoxemia in
      treating stroke.

PMID- 12402254
TI  - The structural consequences of newly diagnosed seizures.
AB  - Intractable epilepsy may be associated with widespread structural cerebral
      damage. We determined whether structural damage occurs to the hippocampus,
      cerebellum and neocortex in the first few years following a diagnosis of
      seizures. Sixty-eight patients over the age of 14 years with newly diagnosed
      seizures and 90 matched controls underwent serial magnetic resonance imaging
      (MRI) brain scans 3.5 years apart. Using quantitative analysis of serial scans,
      we determined changes in hippocampal volume, hippocampal T2 relaxometry and total
      and regional brain volumes. Thirty-four (50%) patients had recurrent unprovoked
      seizures between baseline and follow-up scans. One patient with pre-existing
      hippocampal sclerosis (HS) did not develop progressive hippocampal damage. Group
      analyses found no difference in change in cerebral measures between patients and
      controls or between patients with and without recurrent seizures. Significant
      quantitative changes in individuals were largely attributable to pre-existing
      cerebral lesions or alcohol abuse. Subtle changes detected in individuals over
      3.5 years but were not related to a history of overt seizures. Our results show
      patients with newly diagnosed seizures are not generally at increased risk of
      seizure-induced structural cerebral damage as detected with MRI. Cerebral damage
      may occur before the onset of seizures or develop insidiously over a more
      prolonged period.

PMID- 12402255
TI  - Disruption of the proprioceptive mapping in the medial wall of parkinsonian
      monkeys.
AB  - Parkinsonian patients present an impairment of proprioceptor-guided movement that
      could imply abnormal processing in the frontal mesial cortex. To test this
      hypothesis, we compared neuronal response to joint displacement in the
      supplementary and presupplementary motor areas of two monkeys, before and after
      the progressive establishment of an 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
      (MPTP)-induced parkinsonian syndrome. After MPTP administration, neurons were
      activated by the passive movement of numerous joints in various directions and no
      longer simply by one or two joints in one direction. This impairment of the
      focused selection of proprioceptive inputs, imputable to dopamine depletion,
      could impede motor planning and thus contribute to akinesia.

PMID- 12402256
TI  - Abnormal asymmetry in language association cortex in autism.
AB  - Autism is a neurodevelopmental disorder affecting cognitive, language, and social
      functioning. Although language and social communication abnormalities are
      characteristic, prior structural imaging studies have not examined language
      related cortex in autistic and control subjects. Subjects included 16 boys with
      autism (aged 7-11 years), with nonverbal IQ greater than 80, and 15 age- and
      handedness-matched controls. Magnetic resonance brain images were segmented into
      gray and white matter; cerebral cortex was parcellated into 48 gyral-based
      divisions per hemisphere. Asymmetry was assessed a priori in language-related
      inferior lateral frontal and posterior superior temporal regions and assessed
      post hoc in all regions to determine specificity of asymmetry abnormalities. Boys
      with autism had significant asymmetry reversal in frontal language-related
      cortex: 27% larger on the right in autism and 17% larger on the left in controls.
      Only one additional region had significant asymmetry differences on post hoc
      analysis: posterior temporal fusiform gyrus (more left-sided in autism), whereas
      adjacent fusiform gyrus and temporooccipital inferior temporal gyrus both
      approached significance (more right-sided in autism). These inferior temporal
      regions are involved in visual face processing. In boys with autism, language and
      social/face processing-related regions displayed abnormal asymmetry. These
      structural abnormalities may relate to language and social disturbances observed
      in autism.

PMID- 12402257
TI  - p53 inhibitors preserve dopamine neurons and motor function in experimental
      parkinsonism.
AB  - Drugs currently used for patients with Parkinson's disease provide temporary
      relief of symptoms but do not halt or slow the underlying neurodegenerative
      disease process. Increasing evidence suggests that neurons die in Parkinson's
      disease by a process called apoptosis, which may be triggered by mitochondrial
      impairment and oxidative stress. We report that two novel synthetic inhibitors of
      the tumor suppressor protein p53, pifithrin-alpha (PFT-alpha) and Z-1-117, are
      highly effective in protecting midbrain dopaminergic neurons and improving
      behavioral outcome in a mouse model of Parkinson's disease. Mice given
      intraperitoneal injections of PFT-alpha or Z-1-117 exhibited improved motor
      function, reduced damage to nigrostriatal dopaminergic neurons and reduced
      depletion of dopamine and its metabolites after exposure to the toxin 1-methyl-4
      phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP caused an increase in the level of
      the proapoptotic protein Bax, which was prevented by giving mice PFT-alpha and Z
      1-117. PFT-alpha and Z-1-117 also suppressed Bax production and apoptosis in
      cultured dopaminergic cells exposed to MPP(+). Our findings demonstrate a pivotal
      role for p53 in experimental parkinsonism and identify a novel class of synthetic
      p53 inhibitors with clinical potential.

PMID- 12402258
TI  - Motor cortex activation is preserved in patients with chronic hemiplegic stroke.
AB  - Many central nervous system conditions that cause weakness, including many
      strokes, injure corticospinal tract but leave motor cortex intact. Little is
      known about the functional properties of surviving cortical regions in this
      setting, in part because many studies have used probes reliant on the
      corticospinal tract. We hypothesized that many features of motor cortex function
      would be preserved when assessed independent of the stroke-affected corticospinal
      tract. Functional MRI was used to study 11 patients with chronic hemiplegia after
      unilateral stroke that spared regions of motor cortex. Activation in stroke
      affected hemisphere was evaluated using 3 probes independent of affected
      corticospinal tract: passive finger movement, a hand-related visuomotor stimulus,
      and tapping by the nonstroke index finger. The site and magnitude of cortical
      activation were similar when comparing the stroke hemisphere to findings in 19
      control subjects. Patients activated each of 8 cortical regions with similar
      frequency as compared to controls, generally with a smaller activation volume. In
      some cases, clinical measures correlated with the size or the site of stroke
      hemisphere activation. The results suggest that, despite stroke producing
      contralateral hemiplegia, surviving regions of motor cortex actively participate
      in the same proprioceptive, visuomotor, and bilateral movement control processes
      seen in control subjects.

PMID- 12402259
TI  - Intravenous TAT-Bcl-Xl is protective after middle cerebral artery occlusion in
      mice.
AB  - The delivery of proteins across the blood-brain barrier is severely limited by
      the proteins' size and biochemical properties. Eleven-amino acid human
      immunodeficiency virus TAT protein is able to cross cell membranes even when
      coupled with larger peptides. We evaluated whether TAT-Bcl-X(L) fusion protein is
      protective in focal ischemia. Mice underwent 30 or 90 minutes of intraluminal
      middle cerebral artery thread occlusion. TAT-Bcl-X(L), TAT-beta-galactosidase, or
      TAT-GFP (0.6 nmol each) were applied intravenously over 10 minutes either 1 hour
      before or immediately after ischemia. Additional animals received no TAT protein
      infusions. We show that the brain tissue is progressively transduced with TAT
      proteins within 3 to 4 hours after intravenous delivery. We provide evidence that
      TAT-Bcl-X(L) treatment reduces infarct volume and neurological deficits after
      long ischemic insults lasting 90 minutes, when applied both before and after
      ischemia. After short insults, lasting only 30 minutes, TAT-Bcl-X(L) further
      diminishes the number of caspase-3-reactive and DNA fragmented cells and
      increases the number of viable neurons in the striatum. Our results indicate that
      TAT fusion proteins are elegant and powerful tools that might be of clinical
      interest for stroke treatment, because factors may be intravenously applied.
      Thus, fusion proteins may open fascinating perspectives for future research.

PMID- 12402260
TI  - Mitochondrial respiratory chain function in skeletal muscle of ALS patients.
AB  - Evidence implicating mitochondrial dysfunction in the central nervous system of
      patients with sporadic amyotrophic lateral sclerosis (SALS) has recently been
      accumulating. In contrast, data on mitochondrial function in skeletal muscle in
      SALS are scarce and controversial. We investigated the in situ properties of
      muscle mitochondria in patients with early-stage SALS and sedentary (SED)
      controls using the skinned fiber technique to determine whether respiration of
      muscle tissue is altered in early-stage SALS in comparison with SED. Musculus
      vastus lateralis biopsies were obtained from 7 SED group members and 14 patients
      with early-stage SALS (mean disease duration, 9 months). Muscle fibers were
      permeabilized with saponine and then skinned and placed in an oxygraphic chamber
      to measure basal (V(0)) and maximal (V(max)) adenosine diphosphate-stimulated
      respiration rates and to assess mitochondrial regulation by adenosine
      diphosphate. Muscle oxidative capacity, evaluated with V(max), was identical in
      patients in the SALS and SED groups (V(0): SALS, 1.1 +/- 0.1; SED, 0.8 +/- 0.1,
      micromol 0(2). min(-1). gm(-1)dw and V(max): SALS, 3.1 +/- 0.3; SED, 2.5 +/- 0.3,
      micromol 0(2). min(-1). gm(-1)dw). This study shows an absence of large
      mitochondrial damage in skeletal muscle of patients with early-stage SALS,
      suggesting that mitochondrial dysfunction in the earlier stages of SALS is almost
      certainly not systemic.

PMID- 12402261
TI  - Dyskinesia after fetal cell transplantation for parkinsonism: a PET study.
AB  - Persistent dyskinesias in the absence of or with only minimal amounts of
      dopaminergic medication have been reported after dopamine cell implantation for
      Parkinson's disease. In this study, we used [(18)F]fluorodopa (FDOPA) and
      positron emission tomography to determine whether this complication resulted from
      specific alterations in dopamine function after transplantation. Caudate and
      putamen FDOPA uptake values in these patients (DYS+, n = 5) were compared with
      those obtained in a cohort of age- and disease duration-matched transplant
      recipients who did not develop this complication (DYS-, n = 12). PET signal for
      both groups was compared at baseline and at 12 and 24 months after
      transplantation. We found that putamen FDOPA uptake was significantly increased
      (p < 0.005) in DYS+ transplant recipients. These increases were predominantly
      localized to two zones within the left putamen. In addition to the posterodorsal
      zone in which a prominent reduction in FDOPA uptake was present at baseline, the
      DYS+ group also displayed a relative increase ventrally, in which preoperative
      dopaminergic input was relatively preserved. Postoperative FDOPA uptake did not
      reach supranormal values over the 24-month follow-up period. These findings
      suggest that unbalanced increases in dopaminergic function can complicate the
      outcome of neuronal transplantation for parkinsonism.

PMID- 12402262
TI  - Neuronal and glial metabolite content of the epileptogenic human hippocampus.
AB  - Mesial temporal lobe epilepsy is characterized by hippocampal atrophy,
      hypometabolism, and decreased N-acetylaspartate, often attributed to neuron loss
      and gliosis. Twenty hippocampal specimens were obtained during temporal lobectomy
      and frozen quickly. Perchloric acid extracts of the small metabolites were
      analyzed by proton magnetic resonance spectroscopy. There were no significant
      associations between hippocampal neuron loss and the cellular content of N
      acetylaspartate, glutamate, GABA, glutamine, or aspartate. The mean metabolite
      content of hippocampi with less than 30% of neurons remaining was the same as
      those with greater than 65% of neurons surviving. Mean N-acetylaspartate levels
      were below those reported by in vivo studies of control subjects. The highest and
      the lowest glutamate concentrations were seen in specimens with the worst neuron
      loss. A highly significant association between hippocampal N-acetylaspartate and
      glutamate content was seen with weak associations between N-acetylaspartate and
      aspartate and glutamate and aspartate. The hippocampal content of N
      acetylaspartate, glutamate, GABA, glutamine, and aspartate is altered minimally
      by severe neuron loss in mesial temporal lobe epilepsy. The epileptic human
      hippocampus has increased intracellular glutamate content that may contribute to
      the epileptogenic nature of hippocampal sclerosis.

PMID- 12402263
TI  - Heterozygous GLDC and GCSH gene mutations in transient neonatal hyperglycinemia.
AB  - Transient neonatal hyperglycinemia is clinically or biochemically
      indistinguishable from nonketotic hyperglycinemia at onset. In the case of
      transient neonatal hyperglycinemia, the elevated plasma and cerebrospinal fluid
      glycine levels are normalized within 2 to 8 weeks. To elucidate the pathogenesis
      of transient neonatal hyperglycinemia, we studied three patients by screening
      mutations in the genes that encode three components of the glycine cleavage
      system. Heterozygous mutations were identified in all of the three patients,
      suggesting that transient neonatal hyperglycinemia develops in some heterozygous
      carriers for nonketotic hyperglycinemia.

PMID- 12402264
TI  - Vitamin A in the cerebrospinal fluid of patients with and without idiopathic
      intracranial hypertension.
AB  - We quantified vitamin A in the cerebrospinal fluid of patients with idiopathic
      intracranial hypertension, elevated intracranial pressure of other causes and
      normal intracranial pressure. Vitamin A could be detected by high-pressure liquid
      chromatography in most of the specimens. There was a significantly higher level
      of vitamin A in the cerebrospinal fluid of some patients with idiopathic
      intracranial hypertension. Vitamin A toxicity may play a role in the pathogenesis
      of idiopathic intracranial hypertension.

PMID- 12402265
TI  - Thalamic neurodegeneration in multiple sclerosis.
AB  - Multiple sclerosis is still regarded primarily as a disease of the white matter.
      However, recent evidence suggests that there may be significant involvement of
      gray matter. Here, we have used magnetic resonance imaging and magnetic resonance
      spectroscopy in vivo and histopathology postmortem to estimate thalamic neuronal
      loss in patients with multiple sclerosis. Our results show that neuronal loss in
      multiple sclerosis can be substantial (30-35% reduction). We conclude that a
      neurodegenerative pathology may make a major contribution to the genesis of
      symptoms in multiple sclerosis.

PMID- 12402266
TI  - A nonsense mutation of the MASS1 gene in a family with febrile and afebrile
      seizures.
AB  - A naturally occurring mutation of the mass1 (monogenic audiogenic seizure
      susceptible) gene recently has been reported in the Frings mouse strain, which is
      prone to audiogenic seizures. The human orthologous gene, MASS1, was mapped to
      chromosome 5q14, for which we previously have reported significant evidence of
      linkage to febrile seizures (FEB4). We screened for MASS1 mutations in
      individuals from 48 families with familial febrile seizures and found 25 DNA
      alterations. None of nine missense polymorphic alleles was significantly
      associated with febrile seizures; however, a nonsense mutation (S2652X) causing a
      deletion of the C-terminal 126 amino acid residues was identified in one family
      with febrile and afebrile seizures. Our results suggest that a loss-of-function
      mutation in MASS1 might be responsible for the seizure phenotypes, though it is
      not likely that MASS1 contributed to the cause of febrile seizures in most of our
      families.

PMID- 12402267
TI  - Saccadic lateropulsion and upbeat nystagmus: disorders of caudal medulla.
AB  - A patient developed a primary position upbeat nystagmus and a left saccadic
      lateropulsion. Magnetic resonance imaging demonstrated a probable cavernoma at
      right caudal paramedian medullary level. Anatomical correlations are discussed.
      Saccadic lateropulsion is attributed to olivocerebellar pathway impairment but
      usually is described in more rostral medullar lesions. Our case would still
      support this hypothesis because the lesion could have involved the
      olivocerebellar pathway at its very caudal level. Upbeat nystagmus could be
      attributed to impairment of the nucleus intercalatus and/or cell groups of the
      paramedian tract.

PMID- 12402268
TI  - Herpes vector-mediated expression of proenkephalin reduces bone cancer pain.
AB  - We examined whether a herpes simplex virus vector that expresses human
      proenkephalin could be used to attenuate nociception in a model of bone cancer
      pain in mice. Osteolytic sarcoma cells were implanted into the medullary space of
      the right femur, followed by a subcutaneous inoculation of a replication
      defective herpes simplex virus vector expressing human proenkephalin (vector
      SHPE) or a lacZ-expressing control vector (vector SHZ). SHPE-inoculated mice
      demonstrated a significant, naltrexone-reversible decrease in pain-related
      behavior assessed during open-field motor activity. These results suggest that
      gene transfer with an enkephalin-expressing vector may be used to treat pain
      resulting from cancer in bone.

PMID- 12402269
TI  - A new locus for spinocerebellar ataxia (SCA21) maps to chromosome 7p21.3-p15.1.
AB  - We investigated a French family with a new type of autosomal dominant
      spinocerebellar ataxia that was excluded from all previously identified genes and
      loci. The patients exhibited a slowly progressive gait and limb ataxia variably
      associated with akinesia, rigidity, tremor, and hyporeflexia. A mild cognitive
      impairment also was observed in some cases. We performed a genomewide search and
      found significant evidence for linkage to chromosome 7p21.3-p15.1. Analysis of
      key recombinants and haplotype reconstruction traced this novel spinocerebellar
      ataxia locus to a 24cM interval flanked by D7S2464 and D7S516.

PMID- 12402270
TI  - Oligodendrocytic polyglutamine pathology in dentatorubral-pallidoluysian atrophy.
AB  - White matter degeneration is one of the pathological conditions of dentatorubral
      pallidoluysian atrophy. Autopsy brains exhibited a reduced number of glial cells
      in the lesions and an involvement of oligodendrocytes in nuclear inclusion
      formation, which previously has been recognized only as a pathological hallmark
      in neurons. Dentatorubral-pallidoluysian atrophy transgenic mice showed an
      increased number of affected glias with increasing age and with larger expansions
      of CAG repeats. These findings suggest that glial cells in dentatorubral
      pallidoluysian atrophy also are involved in the polyglutamine pathogenesis.

PMID- 12402271
TI  - Epsilon-sarcoglycan mutations found in combination with other dystonia gene
      mutations.
AB  - Myoclonus-dystonia is a movement disorder associated with mutations in the
      epsilon-sarcoglycan gene (SGCE) in most families and in the DRD2 and DYT1 genes
      in two single families. In both of the latter families, we also found a mutation
      of SGCE. The molecular mechanisms through which the detected mutations may
      contribute to myoclonus-dystonia remain to be determined.

PMID- 12402272
TI  - "True" sporadic ALS associated with a novel SOD-1 mutation.
AB  - Mutations in the Cu/Zn superoxide dismutase gene (SOD-1) are reported in 20% of
      familial amyotrophic lateral sclerosis (ALS) cases, but no definite report of a
      mutation in a "truly" sporadic case of ALS has been proved. We present the first
      case of a novel SOD-1 mutation in a patient with genetically proven sporadic ALS.
      This mutation (H80A) is believed to alter zinc ligand binding, and its functional
      significance correlates well with the aggressive clinical course and postmortem
      findings observed in this patient.

PMID- 12402273
TI  - Symptoms in carriers of adrenoleukodystrophy relate to skewed X inactivation.
AB  - Skewing of X inactivation may contribute to the manifestation of symptoms in
      adrenoleukodystrophy carriers. We observed highly skewed X inactivation in 32% of
      22 symptomatic and asymptomatic carriers but not in 7 related and 35 unrelated
      controls. Skewing of X inactivation correlated with clinical neurological scores
      but not with the extent of very long-chain fatty acid accumulation. Transcript
      analysis in cultured fibroblasts revealed that skewing could occur both in favor
      of the mutant and the wild-type allele. Adrenoleukodystrophy carriers are more
      susceptible to develop skewing of X inactivation in favor of the mutant allele
      being associated with the manifestation of symptoms.

PMID- 12402274
TI  - Effect of minocycline in experimental autoimmune encephalomyelitis.

PMID- 12402275
TI  - No evidence for an association between Saitohin Q7R polymorphism and Alzheimer's
      disease.

PMID- 12402277
TI  - c954C-->T polymorphism in the Fe65L2 gene is associated with early-onset
      Alzheimer's disease.

PMID- 12402280
TI  - Quantitative sensation testing in small-diameter sensory fiber neuropathy.

PMID- 12402281
TI  - Mitochondrial abnormalities in muscle and other aging cells: classification,
      causes, and effects.
AB  - The involvement of mitochondria and of mitochondrial DNA (mtDNA) in the aging
      process has generated much interest and even more controversy. The mitochondrial
      theory of aging considers a vicious circle consisting of: (1) accumulation of
      somatic mtDNA mutations; (2) impairment of respiratory chain function; (3)
      increased production of reactive oxygen species (ROS) in mitochondria; and (4)
      further damage to mtDNA. We review the evidence for and against the belief that
      these steps occur in aging muscle and brain, considering separately
      morphological, biochemical, and molecular data. The relationship between
      mitochondrial aging and late-onset neurodegenerative diseases is briefly
      reviewed. We conclude that mitochondrial dysfunction does play a crucial role in
      the aging process of both muscle and brain, but it remains unclear whether
      mitochondria are the culprits or mere accomplices.

PMID- 12402282
TI  - Dejerine-Sottas disease and hereditary demyelinating polyneuropathy of infancy.
AB  - Dejerine-Sottas disease (DSD) was originally described as a hypertrophic
      polyneuropathy characterized by onset in infancy or early childhood in patients
      born to unaffected parents. The clinical features included distal sensory changes
      with ataxia; pes cavus, at times with kyphoscoliosis; motor deficit and atrophy
      predominating in the distal lower limbs and progressing toward the proximal limbs
      following a length-dependent pattern; palpable nerve hypertrophy; and Argyll
      Robertson pupils. The morphological hallmark was the extensive nerve and root
      hypertrophy associated with demyelination-remyelination of surviving, originally
      myelinated axons and profuse Schwann-cell proliferation forming onion bulbs. Wide
      variations in clinical manifestations of chronic demyelinating polyneuropathies
      of early onset in children born to unaffected parents have now been reported,
      with only some of the characteristics required in the original study, and at
      least seven genes encoding the myelin proteins P0, PMP22, the transcriptional
      factor EGR2, and others have been implicated. Thus, DSD is now a component of the
      hereditary demyelinating polyneuropathies of infancy that also include subsets of
      the recently individualized CMT4 neuropathies. The presumed recessive
      transmission of patients with DSD should be confirmed by molecular genetic
      analysis, which is still negative in a significant proportion of patients. The
      nerve biopsy can be useful in patients in whom genealogical or DNA abnormalities
      in favor of a genetic disorder are missing, because in a few patients with a
      progressive or relapsing course the diagnosis of early-onset chronic inflammatory
      demyelinating polyneuropathy must be considered.

PMID- 12402283
TI  - Physiological characterization of neuropathy in Fabry's disease.
AB  - Fabry's disease is commonly associated with a painful, debilitating neuropathy.
      Characterization of the physiological abnormalities is an important step in
      evaluating response to specific therapies. Twenty-two patients with Fabry's
      disease, and with relatively preserved renal function, underwent conventional and
      near-nerve conduction studies, electromyography, sympathetic skin responses, and
      quantitative sensory testing (QST). Nerve conduction studies were mostly normal
      except for an increased frequency of median nerve entrapment at the wrist in 6
      (27%) patients. Sympathetic skin responses were preserved in 19 of 20 (95%) of
      the patients. The QST showed increased or immeasurable cold and warm detection
      thresholds in patients, significantly different from controls (n = 28) in the
      hand (P < 0.001, P = 0.04, respectively) and foot (P < 0.001 for both). Cold
      thresholds were more often abnormal than were warm thresholds. Vibration
      thresholds were normal in the feet and, in some patients, elevated in the hand
      only, probably due to frequent median nerve entrapment at the wrist. Our findings
      suggest that the neuropathy of Fabry's disease is characterized by an increased
      prevalence of median nerve entrapment at the wrist and by thermal afferent fiber
      dysfunction in a length-dependent fashion, with greater impairment of cold than
      warm sensation.

PMID- 12402284
TI  - Motion of the foot and ankle during the stance phase in rats.
AB  - Computerized analysis of rat gait is becoming an invaluable technique used by
      some peripheral nerve investigators for the evaluation of function. In this
      article we describe the use of a biomechanical model of the foot and ankle that
      allows a quantitative assessment and description of the ankle angle, reflecting
      plantarflexion and dorsiflexion during the stance phase of gait. Kinematic data
      of 144 trial walks from 36 normal rats were recorded with a high-speed digital
      image camera at 225 images per second. The ankle angular changes associated with
      the specific temporal events of foot placement on the ground through the stance
      phase were assessed. The information obtained was used to propose a new
      subdivision of the stance phase in the rat into three major components. This
      approach will provide a helpful research tool to analyze gait data that rely on
      the accurate determination of spatiotemporal foot events.

PMID- 12402285
TI  - Skeletal muscle fiber function and rate of disease progression in amyotrophic
      lateral sclerosis.
AB  - The contractile properties of single muscle fibers reflect the functional status
      of muscle at the cellular level and have not been described in amyotrophic
      lateral sclerosis (ALS). Chemically skinned single muscle fibers (n = 173),
      obtained by needle biopsy from six men with ALS, were activated with Ca(2+),
      allowing maximal force measurements and specific force (SF) estimates. Maximum
      unloaded shortening velocity (V(o)) was determined using the slack test. The
      results were compared with muscle from healthy controls. Markers of disease
      progression included rate of change of ALS functional rating scale score, rate of
      change of forced vital capacity, and disease duration. Compared with controls,
      ALS patients had decreased whole muscle SF (measured by a combination of
      computerized tomography and isokinetic testing) but normal single fiber SF. The
      V(o) was greater for type I fibers in ALS. Patients with slower disease
      progression had increased single fiber size and a high percentage of hybrid
      fibers (expressing multiple myosin heavy chain isoforms). A needle biopsy
      obtained at the time of ALS diagnosis may assist with predicting rate of disease
      progression.

PMID- 12402287
TI  - Near-nerve needle sensory conduction study of the medial calcaneal nerve: New
      method and report of four cases of medial calcaneal neuropathy.
AB  - There has been one previously published antidromic method for studying medial
      calcaneal nerve (MCN) conduction. However, the origin of the compound nerve
      action potentials (CNAPs) with this technique is uncertain because of the
      antidromic nature of stimulation. We report a new orthodromic method for MCN
      conduction study using the near-nerve needle technique. In 35 normal controls,
      maximum nerve conduction velocity (NCV) and negative-peak NCV of MCN were 42.4 +/
      3.9 m/s and 33.6 +/- 3.0 m/s, respectively. The amplitude of the CNAP was 4.1 +/
      2.2 micro V. We also report four cases of medial calcaneal neuropathy, three of
      which were confirmed by this technique. We conclude that the present technique is
      capable of recording the sensory nerve action potentials of MCN in isolation and
      confirming the diagnosis of medial calcaneal neuropathy electrophysiologically.

PMID- 12402286
TI  - Inhibition of dystroglycan binding to laminin disrupts the PI3K/AKT pathway and
      survival signaling in muscle cells.
AB  - Dystroglycan is a component of the dystrophin-glycoprotein complex (DGC) in
      muscle and a cell surface receptor for laminin. Numerous muscular dystrophies are
      the result of disruption of proteins comprising the DGC, but the underlying
      pathogenetic mechanisms are unknown. Because apoptosis is an early feature of
      muscular dystrophy in vivo, and perturbation of cell-extracellular matrix
      associations is known to induce apoptosis, we investigated the role of
      dystroglycan-laminin interactions in the propagation and maintenance of cell
      survival signals in muscle cells. We found that disrupting the interaction
      between alpha-dystroglycan and the extracellular matrix protein laminin induces
      apoptosis in muscle cells. This increase in apoptosis is mediated in part by
      caspase activation and can be blocked by a caspase-3 inhibitor. We demonstrate a
      role for the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway in
      muscle cell-survival signaling using a pharmacological inhibitor of PI3K.
      Treatment with this inhibitor resulted in decreased phosphorylation of AKT and
      its downstream effector glycogen synthase kinase (GSK)-3beta and induced
      apoptosis in muscle cell cultures. Disruption of dystroglycan-laminin
      interactions resulted in decreased phosphorylation of AKT and GSK-3beta.
      Furthermore, activation of AKT prior to the disruption of dystroglycan-laminin
      protected the muscle cells from the induction of apoptosis. These results support
      a role for the PI3K/AKT pathway in the propagation of cell-survival signals
      mediated by the DGC and provide new insight into the molecular pathogenesis
      associated with the development of muscular dystrophies.

PMID- 12402288
TI  - Wave properties of action potentials from fast and slow motor units of rats.
AB  - The purpose of this study was to identify the frequency, conduction velocity, and
      wavelength of fast and slow motor unit action potentials (MUAPs) from mixed
      mammalian muscle. Stimulation and blocking pulses to the sciatic nerve produced
      varying recruitment patterns (confirmed by force measurements) of fast and slow
      motor units of the medial gastrocnemius of six rats. Myoelectric signals from the
      muscle were resolved into their intensity in time and frequency space. Slow MUAPs
      had a mean frequency (+/- SEM) of 183 +/- 8 Hz, conduction velocity of 3.5 +/-
      0.6 m s(-1), and wavelength of 19 mm. Fast MUAPs had a mean frequency of 369 +/-
      11 Hz, conduction velocity of 6.7 +/- 0.5 m s(-1), and wavelength of 18 mm.
      Frequency and conduction velocity, but not wavelength, were significantly
      different between the fast and slow MUAPs. The distinct wave properties of fast
      and slow MUAPs can thus be used to distinguish action potentials from these motor
      units, and could be used to determine patterns of motor unit recruitment during
      locomotion.

PMID- 12402289
TI  - Cardiovascular autonomic function and sympathetic skin response in chronic
      inflammatory demyelinating polyradiculoneuropathy.
AB  - Quantitative cardiovascular autonomic function tests (AFTs) and sympathetic skin
      response (SSR) were performed in 12 patients with chronic inflammatory
      demyelinating polyradiculoneuropathy (CIDP). Parasympathetic autonomic function
      was examined by Valsalva ratio and R-R interval variation during rest and deep
      breathing. Sympathetic autonomic function was evaluated by blood pressure
      responses to sustained handgrip and active standing. Using quantitative AFTs,
      subclinical autonomic dysfunction was demonstrated in three (25%) patients.
      Abnormal SSR was seen in six (50%) patients. Thus, mild autonomic dysfunction is
      present in many CIDP patients. The autonomic abnormalities involve
      parasympathetic or sympathetic components; in the sympathetic nervous system,
      both vasomotor and sudomotor fibers may be involved.

PMID- 12402290
TI  - Within-train neuromuscular propagation varies with torque in paralyzed human
      muscle.
AB  - Electromyographic (EMG) recordings may serve an important role in predicting
      torque during repetitive activation of paralyzed muscle. We compared the initial
      M-wave to the subsequent M-waves of the same train under fatigued and recovered
      conditions in the paralyzed human soleus muscle. Sixteen individuals with chronic
      (n = 13) or acute paralysis (n = 3) had the tibial nerve activated before and
      after a repetitive supramaximal stimulation protocol. The mean within-train M
      wave amplitude and median frequency increased approximately 20%, whereas the
      duration decreased approximately 15% compared with the initial M-wave of each
      train. During fatigue, there was a linear decrease in the difference between the
      initial M-wave amplitude and subsequent train ( approximately 20% to 8%).
      Following fatigue, this difference recovered to approximately 12%. The difference
      between the M-wave train average and the initial M-wave for amplitude, duration,
      and median frequency closely followed torque (Pearson correlations = 0.99, 0.94,
      and 0.98, respectively) during fatigue. We conclude that the difference between
      the later-occurring M-waves (average of the train) and initial M-wave is large
      when muscle torque is high and less when torque is low and, therefore, predicts
      torque during activation of paralyzed muscle. This difference in the within-train
      M-wave amplitude, duration, and median frequency may reflect a mechanical change,
      such as muscle shortening and increased muscle cross-sectional area during
      isometric contractions. Electromyographic feedback may assist in the optimization
      of neuromuscular electrical stimulation of paralyzed muscle.

PMID- 12402291
TI  - Surface EMG crosstalk between knee extensor muscles: experimental and model
      results.
AB  - Surface electromyographic (EMG) crosstalk between vastus lateralis, vastus
      medialis, and rectus femoris muscles was evaluated by selective electrical
      stimulation of one muscle and recording from the stimulated and another muscle
      with linear surface arrays of eight electrodes. The ratio between the amplitude
      of the signals recorded over nonstimulated and stimulated muscles and their
      correlation coefficient were used as indices to quantify crosstalk. Single
      differential and double-differential detection systems were used with
      interelectrode distances in the range 10-40 mm. The multichannel EMG signals
      clearly showed that crosstalk is largely due to nonpropagating potentials that
      correspond in time to the end of the propagation of the action potentials
      generated by the stimulated muscle. The crosstalk signal increased with
      increasing interelectrode distance and was statistically higher for single- than
      for double-differential recordings. The correlation-based indices of crosstalk
      were poorly correlated with the amplitude-based indices. Moreover, the
      characteristic spectral frequencies of the signals detected over the
      nonstimulated muscles were statistically higher than those from the stimulated
      muscles. A mathematical model of signal generation was used to explain the
      experimental findings. This study clarifies many controversial findings of past
      investigations and creates the basis for crosstalk interpretation, simulation,
      and reduction.

PMID- 12402292
TI  - Fibronectin receptor reduction in skin and fibroblasts of patients with Ullrich's
      disease.
AB  - Ullrich's disease is a congenital muscular dystrophy characterized clinically by
      generalized muscle weakness, multiple contractures of the proximal joints, and
      hyperextensibility of the distal joints. Recent studies have demonstrated that
      collagen VI is deficient in the muscles of patients with Ullrich's disease, and
      some cases result from recessive mutations of the collagen VIalpha2 gene
      (COL6A2). Fibronectin is one of the main components of the extracellular matrix
      (ECM) and associates with a variety of other matrix molecules including collagen.
      The behavior of fibronectin on cells is mediated by fibronectin receptors,
      members of the integrin family. We studied the expression of fibronectin
      receptors and fibronectin in patients with Ullrich's disease, and found a marked
      reduction of fibronectin receptors in the ECM of skin and cultured fibroblasts of
      these patients. These results suggest that collagen VI deficiency may lead to the
      reduction of fibronectin receptors and that an abnormality of cell adhesion may
      be involved in the pathogenesis of Ullrich's disease.

PMID- 12402293
TI  - Ion channel and striational antibodies define a continuum of autoimmune
      neuromuscular hyperexcitability.
AB  - Neuromuscular hyperexcitability is a characteristic of Isaacs' syndrome.
      Autoantibodies specific for voltage-gated potassium channels (VGKC) or ganglionic
      nicotinic acetylcholine receptors (AChR) are markers of this disorder. To
      determine the frequency of these ion channel antibodies and of related neuron-
      and muscle-specific antibodies in patients with acquired neuromuscular
      hyperexcitability, we tested serum specimens from 77 affected patients (35
      neuromyotonia, 32 cramp-fasciculation syndrome, 5 rippling muscle syndrome, and 5
      focal neuromuscular hyperexcitability) and 85 control subjects. Among study
      patients, 14% had coexisting myasthenia gravis, and 16% had an associated
      neoplasm. We found that 35% had VGKC antibodies, 12% ganglionic AChR antibodies,
      16% muscle AChR antibodies, and 10% striational antibodies. Overall, 55% had
      serological evidence of neurological autoimmunity compared to 2% of control
      subjects. Patients with neuromyotonia were more frequently seropositive (71%)
      than patients with cramp-fasciculation syndrome (31%). We conclude that acquired
      neuromuscular hyperexcitability consists of a continuum of clinical disorders
      with a common autoimmune pathogenesis.

PMID- 12402294
TI  - Inhibition of maximal voluntary contraction force by experimental muscle pain: a
      centrally mediated mechanism.
AB  - Muscle weakness frequently accompanies conditions with musculoskeletal pain. It
      is not clear if this attenuation of force is due to peripheral or central
      processes. The effect of experimental muscle pain on maximal voluntary
      contraction torque and peripheral contractile properties was therefore assessed.
      Experimental muscle pain reduced the torque produced by isometric knee extension,
      but the contractile properties assessed by twitch interpolation were not
      affected. This indicates that force inhibition by muscle pain is centrally
      mediated. This has clinical implications for rehabilitation and training of
      patients with musculoskeletal pain.

PMID- 12402295
TI  - Anti-heparan sulfate antibodies in neurological disease.
AB  - Antibodies to heparan sulfate (HS) have previously been found in association with
      peripheral neuropathy. We tested sera from patients with neuropathies and with
      other neurological diseases for antibodies to HS using an avidin-biotin enzyme
      linked immunosorbent assay (ELISA) system. Increased titers of anti-HS antibodies
      were found in 3.4% of patients with neuropathy, and in 3% of patients with other
      neurological diseases. In all cases, however, an inflammatory disease was
      present, including chronic inflammatory neuropathy, cerebral vasculitis, or
      multiple sclerosis. Antibodies to HS appear not to be specific for neuropathy, as
      they occur in several inflammatory diseases. They might contribute to the
      associated breakdown of the blood-brain or blood-nerve barrier.

PMID- 12402296
TI  - Anomalous superficial radial nerve: a patient with probable autosomal dominant
      inheritance of the anomaly.
AB  - The sensory symptoms due to lesions of the superficial branch of the radial nerve
      are usually limited to the dorsolateral area of the hand. We describe a 40-year
      old woman who presented with numbness of the dorsomedial aspect of the right hand
      following arthroplasty of the wrist. Clinically, the sensory loss suggested a
      lesion of the dorsal branch of the ulnar nerve. However, nerve conduction studies
      showed that the sensory loss was due to a lesion of a branch of the superficial
      branch of the radial nerve. The patient had bilateral, anomalous innervation of
      the dorsum of the hand-the dorsal branch of the ulnar nerve could not be
      demonstrated with nerve conduction techniques and the superficial branch of the
      radial nerve innervated most of the dorsum of the hand. Antidromic stimulation of
      the dorsal branch of the ulnar nerve and superficial branch of the radial nerve
      with paired surface recording of sensory nerve action potentials from the
      dorsolateral (radial side) and dorsomedial (ulnar side) hand is useful for
      evaluating this anomaly. Our patient had two children, one of them with a similar
      anomaly. This suggests an autosomal dominant inheritance of the anomaly.

PMID- 12402298
TI  - Oxidative DNA damage by a common metabolite of carcinogenic nitrofluorene and N
      acetylaminofluorene.
AB  - Both carcinogenic NF and AAF are metabolized to a common N-hydroxy metabolite, N
      OH-AF. We investigated oxidative DNA damage by N-OH-AF, using (32)P-labeled human
      DNA fragments from the human p53 and p16 tumor-suppressor genes and the c-Ha-ras
      1 protooncogene. N-OH-AF caused Cu(II)-mediated DNA damage, and endogenous
      reductant NADH markedly enhanced this process. Catalase and bathocuproine, a
      Cu(I)-specific chelator, decreased the DNA damage, suggesting the involvement of
      H(2)O(2) and Cu(I). N-OH-AF induced piperidine-labile lesions frequently at
      thymine and cytosine residues. With formamidopyrimidine-DNA glycosylase
      treatment, N-OH-AF induced cleavage at guanine residues, especially of the ACG
      sequence complementary to codon 273, a well-known hot spot of the p53 gene. N-OH
      AF dose-dependently induced 8-oxodG formation in the presence of Cu(II) and NADH.
      Treatment with N-OH-AF increased amounts of 8-oxodG in HL-60 cells compared to
      the H(2)O(2)-resistant clone HP100, supporting the involvement of H(2)O(2). The
      present study demonstrates that the N-hydroxy metabolite of NF and AAF induces
      oxidative DNA damage through H(2)O(2) in both a cell-free system and cultured
      human cells. We conclude that oxidative DNA damage may play an important role in
      the carcinogenic process of NF and AAF in addition to previously reported DNA
      adduct formation.

PMID- 12402299
TI  - Specific ligands of the peripheral benzodiazepine receptor induce apoptosis and
      cell cycle arrest in human esophageal cancer cells.
AB  - Esophageal cancer is the most markedly increasing tumor entity in Western
      countries. Due to very poor 5-year-survival, new therapeutic approaches are
      mandatory. Peripheral benzodiazepine receptors (PBR) have been implicated in
      growth control of various tumor models, but they have not been studied yet in
      esophageal cancer. We used esophageal cancer cell lines and primary cell cultures
      of human esophageal cancers and evaluated (i) expression and localization of PBR;
      (ii) PBR-ligand-induced inhibition of cell growth; (iii) induction of apoptosis;
      and (iv) alterations in cell cycle. Expression of PBR was detected both in cell
      lines and in primary cell cultures of human esophageal cancers. PBR was localized
      in the mitochondria. The PBR-specific ligands FGIN-1-27 and PK 11195, but not the
      centrally acting benzodiazepine clonazepam or the indolacetamide FGIN-1-52,
      neither of which displaying any affinity to the PBR, inhibited cell
      proliferation. FGIN-1-27 and PK 11195, but not clonazepam, potently induced
      apoptosis. FGIN-1-27 was shown to sequentially decrease the mitochondrial
      membrane potential, then to activate caspase-3 and finally to cause DNA
      fragmentation. In addition, PBR-specific ligands induced cell cycle arrest in the
      G1/G0 phase. Our data qualify PBR-specific ligands as innovative proapoptotic and
      antiproliferative substances. They might prove suitable for the treatment of
      esophageal cancer.

PMID- 12402300
TI  - Ectopic expression of herpes simplex virus-thymidine kinase gene in human non
      small cell lung cancer cells conferred caspase-activated apoptosis sensitized by
      ganciclovir.
AB  - Human non-small cell lung cancer (NSCLC) cells were transfected with recombinant
      prodrug herpes simplex virus type I thymidine kinase (HSV-tk) cDNA, and the
      selected clones underwent apoptosis in response to induction by antiviral
      ganciclovir (GCV). The efficiency of GCV-induced growth inhibition and the extent
      of the bystander effect were associated with the expression level of HSV-TK in
      stable transfectants. Development in the HSV-tk/GCV system toward cell death was
      initiated with cell-cycle accumulation at S and G(2)/M phases, immediately
      followed by the appearance of sub-G(0)/G(1) cells after drug exposure. To
      investigate the regulation of cell-cycle modulators during drug treatment, we
      analyzed release of the apoptosis initiator cytochrome c and activation of the
      downstream effectors caspase-9, caspase-3 and poly(ADP-ribose)polymerase 16 hr
      after GCV sensitization, followed by transient escalation of tumor-suppressor p53
      and cell-cycle modulators cyclin A and B(1) before committing to programmed cell
      death. Furthermore, tumor regression was proportional to the degree of ectopic
      expression of the transferred HSV-tk gene. Our results demonstrate that the HSV
      tk/GCV system effectively inhibits the proliferation of NSCLC cells in vitro and
      in vivo through potent induction of apoptosis, thus providing a rationale for
      further development.

PMID- 12402301
TI  - Estrogen receptor alpha expression in normal human breast epithelium is
      consistent over time.
AB  - If increased expression of estrogen receptor alpha (ER) in benign breast
      epithelium increases susceptibility to breast cancer, such overexpression should
      be stable over time. There are no published data regarding this important aspect
      of ER expression in breast epithelium. We examined the temporal consistency of ER
      expression in the normal breast tissue of 28 women who had 2 separate breast
      surgical procedures, at least 6 months apart (mean interval, 2.8 years). Paraffin
      embedded breast tissue blocks containing an adequate sample of normal breast
      epithelium and no cancer, were sectioned and processed using the 6F11 antibody
      and standard immunohistochemical techniques. The ER labelling index (ER LI) was
      calculated by counting a mean of 2,000 epithelial cells. The median ER LI at
      first sampling was 13.6 and at second sample 15.5, with R(2) = 0.34 and p =
      0.001. The ER LI was categorized into high and low values, using a threshold of
      10. Twenty-four women (85.7%) showed concordance of high and low expression
      between the 2 samples (p = 0.002). There were 11 women who were premenopausal at
      both time points. Among them, much of the variation in ER LI was explained by
      differences in the menstrual cycle day at the time of sampling and adding the day
      of cycle to the regression model substantially improved the correlation between
      first and second labeling indices. These data suggest that ER expression of
      normal breast tissue is fairly consistent over time and support the notion that
      overexpression of ER in normal epithelium is a constant feature of the high risk
      breast.

PMID- 12402302
TI  - Cytoplasmic and/or nuclear accumulation of the beta-catenin protein is a frequent
      event in human osteosarcoma.
AB  - The molecular events that precede the development of osteosarcoma, the most
      common primary malignancy of bone, are unclear, and concurrent molecular and
      genetic alterations associated with its pathogenesis have yet to be identified.
      Recent studies suggest that activation of beta-catenin signaling may play an
      important role in human tumorigenesis. To investigate the potential role of beta
      catenin deregulation in human osteosarcoma, we analyzed a panel of 47
      osteosarcoma samples for beta-catenin accumulation using immunohistochemistry.
      Potential activating mutations were investigated by sequencing exon 3 of the beta
      catenin gene in genomic DNA isolated from tumor samples. Our findings revealed
      cytoplasmic and/or nuclear accumulation of beta-catenin in 33 of 47 samples
      (70.2%); however, mutation analysis failed to detect any genetic alterations
      within exon 3, suggesting that other regulatory mechanisms may play an important
      role in activating beta-catenin signaling in osteosarcoma. In our survival
      analysis, beta-catenin deregulation conferred a hazard ratio of 1.05, indicating
      that beta-catenin accumulation does not appear to be of prognostic value for
      osteosarcoma patients. When analyzed against other clinicopathologic parameters,
      beta-catenin accumulation correlated only with younger age at presentation (26.4
      vs. 39.8 years). Nevertheless, our results demonstrate that the deregulation of
      beta-catenin signaling is a common occurrence in osteosarcoma that is implicated
      in the pathogenesis of osteosarcoma.

PMID- 12402303
TI  - Submicromolar doses of alkyl-lysophospholipids induce rapid internalization, but
      not activation, of epidermal growth factor receptor and concomitant MAPK/ERK
      activation in A431 cells.
AB  - Synthetic ALPs, e.g., Et-18-OCH(3) and HePC, are anticancer agents that
      accumulate in cell membranes, where they interfere with lipid-mediated signal
      transduction. We previously reported that ALPs, when added at micromolar
      concentrations (5-25 microM), inhibit growth factor-induced MAPK/ERK activation
      and enhance radiation-induced apoptosis. We now show that, at nanomolar doses (10
      500 nM), ALPs activate the MAPK/ERK pathway in A431 cells without stimulating
      cell proliferation. Strikingly, ALPs (500 nM) also trigger rapid clustering and
      internalization of the EGFR in A431 cells. Tyrphostin AG1478, an EGFR tyrosine
      kinase inhibitor, blocks ALP-induced MAPK/ERK activation but not EGFR
      internalization. We found no evidence for ALPs acting via G protein-coupled
      receptors and/or transactivation of EGFRs, as determined by calcium mobilization,
      EGFR phosphorylation and Grb2 binding assays. Since ALPs readily intercalate into
      the plasma membrane, our data suggest that they induce subtle changes in the
      lipid microenvironment of the EGFR, resulting in clustering and internalization
      of the EGFR and concomitant MAPK/ERK activation.

PMID- 12402304
TI  - In vivo angiogenic activity of neuroblastoma correlates with MYCN oncogene
      overexpression.
AB  - Neuroblastoma (NB) is the most common malignant solid tumor in early childhood.
      Amplification of the MYCN oncogene is associated with a more malignant course of
      disease and poor outcome. The role that MYCN plays in the regulation of
      angiogenesis in NB remains unclear. To better elucidate this matter, fresh biopsy
      samples from 21 patients, 10 with MYCN-amplified tumors (defined as having >10
      copies of the oncogene) and 11 with nonamplified tumors, were tested for their
      angiogenic capacity using the chick embryo chorioallantoic membrane assay, a
      useful model for such investigation. Moreover, using the same experimental model,
      conditioned media obtained from 5 different human NB cell lines MYCN-amplified
      (HTLA-230, LAN-5 and GI-LI-N) or nonamplified (ACN and SH-SY5Y) and biopsy
      fragments obtained from xenografts derived from 4 NB cell lines (HTLA-230, GI-LI
      N, ACN and SH-SY5Y) injected in nude mice were assayed for angiogenic potential.
      Our results clearly demonstrated that MYCN amplification parallels angiogenesis
      in NB. When fresh biopsy samples from patients, CM derived from NB cell lines and
      biopsy fragments derived from xenografts of the same cell lines injected in nude
      mice were tested, the response was univocal: the angiogenic response, evaluated
      both macroscopically and microscopically, was significantly higher in the MYCN
      amplified specimens compared to the nonamplified ones.

PMID- 12402305
TI  - Genetic imbalances revealed by comparative genomic hybridization in
      osteosarcomas.
AB  - Osteosarcomas are the most frequent bone sarcomas. The molecular chromosomal
      aberrations in osteosarcomas were analyzed by comparative genomic hybridization
      (CGH). We studied 47 frozen tumors (41 primary samples, 6 relapses) in
      osteosarcoma patients registered in the Cooperative Osteosarcoma Study (COSS)
      protocol. Genomic imbalances were detected in 40 of 41 primary tumors and 6 of 6
      relapsed tumors. Gains were more frequent than losses (ratio of 1.3:1). The
      median number of changes was 16 and 12 in primary and relapsed osteosarcomas,
      respectively. The median number of aberrations in primary high-grade
      osteosarcomas (17.0) was significantly higher than in low- or intermediate-grade
      osteosarcoma subtypes (3.0) (p = 0.038). The most frequent gains included 8q,
      1p21-p31 and 1q21-q24, and the most frequent losses were 10q, 5q and 13q. High
      level gains were observed on 8q23-q24, 17p13 and 1q21-q24. A gain of 19p (p <
      0.001) or loss of 9p (p = 0.027) was more frequent in poor responders than in
      good responders. Univariate analysis revealed that patients with primary
      metastases (p = 0.002), poor histologic responses (p = 0.005), high-level gains
      of 19p (p = 0.012) or losses of 13q14 (p = 0.042) had significantly lower event
      free survival (EFS), whereas patients with a loss of 5q (p = 0.007) or a loss of
      10q21-22 (p = 0.017) had significantly higher EFS than patients without these
      aberrations. Multivariate analysis demonstrated that primary metastasis, loss of
      13q14 and loss of 5q were independent prognostic factors. The findings of our
      study seem to be useful for evaluating the prognosis of patients and may finally
      lead to treatment strategies based on genetic background of osteosarcoma.

PMID- 12402306
TI  - Microsatellite instability in thorotrast-induced human intrahepatic
      cholangiocarcinoma.
AB  - Thorotrast, a colloidal suspension of radioactive (232)ThO(2) that emits alpha
      particles, was used as a radiographic contrast during World War II. It is known
      to induce liver cancers, most frequently ICC, decades after injection. Since
      radiation induces genomic instability, we analyzed MSI in Thorotrast-induced ICC.
      The frequency of MSI(+) cases was 62.5% in Thorotrast ICC, whereas it was 22.7%
      in non-Thorotrast ICC. However, frameshift mutations of mononucleotide repeats
      were not observed in Thorotrast ICC. In addition, the MSI(+) phenotype was not
      associated with the quantity of Thorotrast deposited or the latency period of ICC
      induction. Promoter regions of both the hMLH1 and the hMSH2 MMR genes tended to
      be hypermethylated in the tumor part compared to the adjacent nontumor part in
      Thorotrast ICC. Methylation of the hMLH1 promoter was associated with the MSI(+)
      phenotype in Thorotrast ICC. In contrast, methylation status of these promoter
      regions was not related to MSI in non-Thorotrast ICC cases. These findings
      suggest that MSI induced by exposure to Thorotrast mainly reflects clonal
      expansion of cancer cells and is partly due to inactivation of hMLH1 by
      hypermethylation.

PMID- 12402307
TI  - Toward a more complete recognition of immunoreactive antigens in squamous cell
      lung carcinoma.
AB  - There is very limited knowledge about the antibody response against tumor
      expressed antigens in lung cancer. To arrive at a more complete picture of lung
      cancer antigens, we generated 2 cDNA libraries from squamous cell lung carcinoma
      and isolated 15 immunogenic antigens using autologous sera. Among the antigens
      most frequently identified were the lymphoid blast crisis oncogene (LBC), an
      unknown hypothetical protein and the p53-binding protein (TP53 BP), which have
      already been associated with tumor development. Of the immunogenic antigens, 6
      map to chromosomes that are frequently altered in squamous cell lung carcinoma.
      SEREX database analysis showed that 7 of the identified immunogenic antigens have
      been associated with the humoral immune response in other human tumors. Screening
      with heterologous sera of patients with lung carcinoma identified 4 antigens,
      including human protein kinase C and TP53 BP, which have also been found by
      autologous screening. Only 1 of the 15 identified antigens reacted with any of
      the 36 control sera, which were taken from individuals without known disease.
      Sera from adenocarcinoma and large cell carcinoma of the lung were not reactive
      for the antigens. In summary, using 2 newly established cDNA libraries, we
      isolated 15 novel antigens, which were subsequently evaluated for the frequency
      of their corresponding antibodies in autologous, normal and heterologous sera;
      their chromosomal localization; and their correlation with survival after
      surgery.

PMID- 12402308
TI  - CD44 stimulation by fragmented hyaluronic acid induces upregulation of urokinase
      type plasminogen activator and its receptor and subsequently facilitates invasion
      of human chondrosarcoma cells.
AB  - It has been established that fragmented hyaluronic acid (HA), but not native high
      molecular weight HA, can induce angiogenesis, cell proliferation and migration.
      We have studied the outside-in signal transduction pathways responsible for
      fragmented HA-mediated cancer cell invasion. In our study, we have studied the
      effects of CD44 stimulation by ligation with HA upon the expression of matrix
      metalloproteinases (MMPs)-2 and -9 as well as urokinase-type plasminogen
      activator (uPA), its receptor (uPAR) and its inhibitor (PAI-1) and the subsequent
      induction of invasion of human chondrosarcoma cell line HCS-2/8. Our study
      indicates that (i) CD44 stimulation by fragmented HA upregulates expression of
      uPA and uPAR mRNA and protein but does not affect MMPs secretion or PAI-1 mRNA
      expression; (ii) the effects of HA fragments are critically HA size dependent:
      high molecular weight HA is inactive, but lower molecular weight fragmented HA
      (Mr 3.5 kDa) is active; (iii) cells can bind avidly Mr 3.5 kDa fragmented HA
      through a CD44 molecule, whereas cells do not effectively bind higher Mr HA; (iv)
      a fragmented HA induces phosphorylation of MAP kinase proteins (MEK1/2, ERK1/2
      and c-Jun) within 30 min; (v) CD44 is critical for the response (activation of
      MAP kinase and upregulation of uPA and uPAR expression); and (vi) cell invasion
      induced by CD44 stimulation with a fragmented HA is inhibited by anti-CD44 mAb,
      MAP kinase inhibitors, neutralizing anti-uPAR pAb, anti-catalytic anti-uPA mAb or
      amiloride. Therefore, our study represents the first report that CD44 stimulation
      induced by a fragmented HA results in activation of MAP kinase and, subsequently,
      enhances uPA and uPAR expression and facilitates invasion of human chondrosarcoma
      cells.

PMID- 12402309
TI  - Prostate stem cell antigen: Identification of immunogenic peptides and assessment
      of reactive CD8+ T cells in prostate cancer patients.
AB  - Identification of TAAs recognized by CD8(+) CTLs paved the way for new concepts
      in cancer therapy. In view of the heterogeneity of tumors and their diverse
      escape mechanisms, CTL-based cancer therapy largely depends on an appropriate
      number of TAAs. In prostate cancer, the number of antigens defined as suitable
      targets of CTLs remains rather limited. PSCA is widely distributed in prostate
      cancer. In this report, we define immunogenic peptides of PSCA which are
      recognized by circulating CD8(+) T cells from prostate cancer patients and able
      to activate CTLs in vitro. Screening the amino acid sequence of PSCA for peptides
      containing a binding motif for HLA-A*0201 resulted in 8 candidate peptides.
      Specificity and affinity of peptide binding were verified in a competition assay.
      Frequencies of CD8(+) T lymphocytes reactive against selected epitopes were
      determined in the blood of prostate cancer patients using the ELISPOT assay.
      Increased frequencies were revealed for CD8(+) T cells recognizing the peptides
      ALQPGTALL and AILALLPAL. CTLs from prostate cancer patients were raised against
      these 2 peptides in vitro when presented by autologous DCs. They specifically
      recognized peptide-pulsed T2 target cells and prostate cancer cells that were HLA
      A*0201- and PSCA-positive, indicating that these peptides were naturally
      generated by tumor cells. These data suggest that PSCA is a promising target for
      the immunotherapy of prostate cancer.

PMID- 12402310
TI  - Possible involvement of hMLH1, p16(INK4a) and PTEN in the malignant
      transformation of endometriosis.
AB  - Endometriosis is a common gynecologic disease, which generally follows a benign
      course. Notwithstanding, several clinical and histologic studies as well as
      molecular data show that endometriosis could be a precursor of sporadic
      endometrioid and clear cell carcinomas at extrauterine loci. Several reports have
      implicated alterations of the hMLH1 and p16(ink4a) (p16) genes, in particular
      hypermethylation of the promoter region, and of the PTEN gene, principally
      genetic mutations, in endometrial and ovarian cancers and have indicated that
      these alterations are already present in precancer conditions. In this report, we
      analyzed the methylation status of hMLH1 and p16 and the protein expression of
      PTEN and hMLH1 in 46 cases of endometriosis stages III and IV to better define
      the possible involvement of these genes in the malignant transformation of
      endometriosis. We found abnormal methylation of hMLH1 in 4 of the 46 cases
      (8.6%). In addition, these cases had no detectable hMLH1 protein expression.
      Regarding patients with hMLH1 alterations, 2 were classified as stage IV and 2
      showed coexistent endometriosis and carcinoma. Only 1 case of endometriosis
      (2.17%), classified as atypical, showed abnormal methylation of p16. Reduced PTEN
      protein expression was detected in 7 of 46 cases (15.21%): 5 were clinically
      classified as stage IV, and the other 2 presented both cancer and hypermethylated
      hMLH1. Our preliminary study suggests that reduced expression of both hMLH1 and
      PTEN may be involved in the malignant evolution of endometriosis and should be
      used as markers of neoplastic transformation in aggressive endometriosis with
      elevated tumor markers.

PMID- 12402311
TI  - Association of chili pepper consumption, low socioeconomic status and
      longstanding gallstones with gallbladder cancer in a Chilean population.
AB  - We explored the risk factors for gallbladder cancer and explanations for its
      sharp and constant incidence increase in Chile since the 1970s. We compared 114
      consecutive patients with verified gallbladder cancer, diagnosed 1992-1995, to
      114 matched hospital patients with gallstones, using conditional logistic
      regression analysis. Low education showed a nonsignificant positive relationship
      with gallbladder cancer [odds ratio (OR) = 2.3, 95% confidence interval (CI) 0.8
      6.2], and low socioeconomic level showed a significant relationship (OR = 5.0,
      95% CI 1.5-17.3). A very long history of gallstone disease was significantly more
      prevalent among cases (OR = 11.0, 95% CI 1.4-85.2). Significant red chili pepper
      consumption was observed in gallbladder cancer patients (OR = 2.9, 95% CI 1.6
      5.2). Low intake of both fresh fruit and sugar as soft drinks was associated with
      gallbladder cancer, with ORs of 6.4 (95% CI 1.4-30.3) and 3.6 (95% CI 1.3-10.1),
      respectively. Multivariate analysis kept only a very low socioeconomic status and
      red chili pepper consumption as significant independent risk factors for
      gallbladder cancer, ORs of 6.3 (95% CI 1.7-23.0) and 3.2 (95% CI 1.7-5.9).
      Longstanding gallstone cases were removed from the multivariate model because all
      were in the low and very low socioeconomic groups, reinforcing the association.
      Patients with gallbladder cancer differed from matched controls by exhibiting
      lower socioeconomic levels, having a much longer history of gallstone disease and
      presenting a dietary pattern characterized by high red chili pepper consumption
      and low fresh fruit intake.

PMID- 12402312
TI  - Cancer incidence patterns among Vietnamese in the United States and Ha Noi,
      Vietnam.
AB  - Nearly 600,000 persons have immigrated to the United States from Vietnam since
      the end of the Vietnam War. Despite the rapid growth of the U.S. Vietnamese
      population, little is known about cancer incidence in this migrant group. Using
      population-based data from the Surveillance, Epidemiology and End Results
      program, California Cancer Registry and International Agency for Research on
      Cancer, we compared cancer incidence rates for Vietnamese in the United States
      (1988-1992) to rates for residents of Ha Noi, Vietnam (1991-1993); non-Hispanic
      whites were included to serve as the U.S. reference rates. Lung and breast
      cancers were the most common among Vietnamese males and females, respectively,
      regardless of geographic region. Rates of cancers more common to U.S. whites,
      such as breast, prostate and colon cancers, were elevated for U.S. Vietnamese
      compared to residents in Ha Noi but still lower than rates for U.S. whites. Rates
      of cancers more common to Asian countries, such as stomach, liver, lung and
      cervical cancers, were likewise elevated for U.S. Vietnamese compared to
      residents of Ha Noi and exceeded corresponding rates for whites. Incidence
      patterns for stomach, liver, lung and cervical cancers may reflect increased risk
      of exposures in this migrant population and should be further explored to uncover
      the relative contributions of environmental and genetic factors to cancer
      etiology.

PMID- 12402313
TI  - Association of genotypes of carcinogen-activating enzymes, phenol
      sulfotransferase SULT1A1 (ST1A3) and arylamine N-acetyltransferase NAT2, with
      urothelial cancer in a Japanese population.
AB  - Carcinogenic aromatic amines such as 4-aminobiphenyl, which is contained in
      tobacco smoke, are one of the causal factors of urothelial epithelial cancers. 4
      Aminobiphenyl has been shown to be bioactivated through N-hydroxylation by
      hepatic cytochrome (CYP) 1A2 and subsequently through O-sulfation and O
      acetylation by phenol sulfating sulfotransferase, ST1A3 (SULT1A1), and arylamine
      N-acetyltransferase, NAT2, respectively. In a case-control study for urothelial
      epithelial cancers, low activity alleles of NAT2 are overall high-risk alleles
      (OR 2.11; 95% CI 1.08-4.26). Wild-type ST1A3*1 ((213)Arg) alleles were slightly
      overrepresented in nonsmoking urothelial cancer patients (82.6% vs. 69.7%) and in
      smoking cancer patients (76.7% and 74.3%) compared to a variant ST1A3*2
      ((213)His) allele. In combination of ST1A3 and NAT2 genotypes for analyses of
      urothelial cancer risk, the highest OR of 2.45 (95% CI 1.04-5.98) was obtained
      with ST1A3*1 and NAT2 slow genotype among the 4 combinations. Recombinant ST1A3*1
      enzyme showed a tendency of catalyzing higher in vitro 3'-phosphoadenosine 5'
      phosphosulfate-dependent DNA adduct formation than ST1A3*2 (2.84 +/- 0.49 and
      2.22 +/- 0.11 adducts/10(8) nucleotides). Combined analyses of different alleles
      of carcinogenic aromatic amine-activating phase II enzymes were applied to
      urothelial cancer risk for the first time and showed the highest risk combination
      of ST1A3 and NAT2 alleles.

PMID- 12402314
TI  - Continuing rising trend in oesophageal adenocarcinoma.
AB  - Our study provides an update of the incidence of oesophageal cancer in the West
      Midland region of England and Wales from 1992-96. A total of 2,671 cases of
      oesophageal cancer were identified during the 5-year study period, with an age
      standardised annual incidence (ASR) of 5.24 per 100,000 (95% CI: 5.02, 5.45).
      Similar numbers of adenocarcinoma and squamous cell carcinoma were found. Only
      152 (5.6%) had no histology. There was a 5-fold difference in age-standardised
      annual incidence rates between males and females for adenocarcinoma of
      oesophagus, but no gender difference for squamous cell carcinoma. The parallel
      but higher ASR in males compared to females for adenocarcinoma of both oesophagus
      and cardia merits further investigation. The similarities in the patterns of age-
      and sex-specific rates and in the socioeconomic profiles could indicate a common
      aetiology for adenocarcinoma of oesophagus and gastric cardia. Quality control in
      Cancer Registries needs to focus on the accuracy and consistency of subsite
      classification to ensure that trends in incidence are identified. In the absence
      of accurate subsite classification of stomach cancers, the proportions of
      adenocarcinoma and squamous cell carcinoma of oesophagus (or the absolute rate of
      adenocarcinoma of oesophagus) may provide a useful tool in indicating whether
      adenocarcinoma of gastric cardia is likely to be increasing in incidence.

PMID- 12402315
TI  - Both the epitope specificity and isotype are important in the antitumor effect of
      monoclonal antibodies against Her-2/neu antigen.
AB  - The Her-2/neu oncogene, which encodes a growth factor receptor, was implicated in
      the malignancy of human adenocarcinomas. Antibodies directed to this molecule
      have been previously shown to have an antitumor effect in vivo. In an attempt to
      understand the mechanisms of the antitumor activity, we generated 2 monoclonal
      antibodies (mAbs), HRO G1 and HRT G1, that recognize different epitopes on Her
      2/neu. Both of the mAbs bound HER2/neu on the tumor surface, resulting in
      phosphorylation of HER2/neu. We also generated IgG2a and IgG2b mAbs from these 2
      mAbs, respectively. The results of in vitro studies showed that these anti-Her
      2/neu mAbs could not inhibit the growth of the tumor cells that express Her-2/neu
      molecules by themselves. However, in an antibody-dependent cellular cytotoxicity
      study using mouse splenocytes as effector cells, HRT mAbs had antitumor
      activities superior to those of HRO mAbs, indicating that the epitope specificity
      may also partake in antibody-dependent cellular cytotoxicity with antibody
      isotype. In a complement-dependent cytotoxicity study, the IgG2a and IgG2b mAbs
      showed stronger effects than IgG1 isotype mAbs irrespective of the epitope
      specificities. The results of in vivo studies also showed that HRT mAbs had
      superior antitumor activity to those of HRO mAbs. The antitumor activity was most
      prominent in the HRT G2b isotype among HRT mAbs. HRT G1 also showed a moderate
      antitumor effect, while HRT G2a showed only slight inhibition effect. These data
      indicate that both the epitope specificity and the differences in Fc region of
      mAbs could play important roles in the antitumor activities.

PMID- 12402316
TI  - Alcohol drinking outside meals and cancers of the upper aero-digestive tract.
AB  - In our integrated series of case-control studies conducted in Italy and
      Switzerland (324 oral, 397 pharyngeal, 271 oesophageal, 506 laryngeal cancers and
      3,263 controls), individuals who also drank alcoholic beverages outside meals
      showed an increased risk compared to those who drank at meals only. At any
      alcohol intake level, subjects also drinking between meals showed a more elevated
      risk of developing an upper aero-digestive tract cancer than subjects drinking
      only at meals. After adjustment for potential covariates, and, after allowance
      for the number of daily drinks to adjust for different alcohol-intake levels, the
      odds ratios for subjects reporting drinking outside meals were 1.5 (95%
      confidence interval [CI]: 1.0-2.2) for oral, 1.8 (95% CI: 1.3-2.5) for
      pharyngeal, 1.7 (95% CI: 1.2-2.5) for oesophageal and 1.2 (95% CI: 0.9-1.7) for
      laryngeal cancers. Our findings show that drinking pattern with respect to food
      consumption may influence alcohol carcinogenesis in the upper digestive and
      respiratory tract. An "alcohol washing effect" by chewing and swallowing is
      suggested.

PMID- 12402318
TI  - Analysis of the role of GADD153 in the control of apoptosis in NS0 myeloma cells.
AB  - Apoptosis can limit the maximum production of recombinant protein expression from
      cultured mammalian cells. This article focuses on the links between nutrient
      deprivation, ER perturbation, the regulation of (growth arrest and DNA damage
      inducible gene 153) GADD153 expression and apoptosis. During batch culture,
      decreases in glucose and glutamine correlated with an increase in apoptotic
      cells. This event was paralleled by a simultaneous increase in GADD153
      expression. The expression of GADD153 in batch culture was suppressed by the
      addition of nutrients and with fed-batch culture the onset of apoptosis was
      delayed but not completely prevented. In defined stress conditions, glucose
      deprivation had the greatest effect on cell death when compared to glutamine
      deprivation or the addition of tunicamycin (an inhibitor of glycosylation), added
      to generate endoplasmic reticulum stress. However, the contribution of apoptosis
      to overall cell death (as judged by morphology) was smaller in conditions of
      glucose deprivation than in glutamine deprivation or tunicamycin treatment.
      Transient activation of GADD153 expression was found to occur in response to all
      stresses and occurred prior to detection of the onset of cell death. These
      results imply that GADD153 expression is either a trigger for apoptosis or offers
      a valid indicator of the likelihood of cell death arising from stresses of
      relevance to the bioreactor environment.

PMID- 12402319
TI  - Cumulative bondomers: a new concept in flux analysis from 2D [13C,1H] COSY NMR
      data.
AB  - A well-established way of determining metabolic fluxes is to measure 2D
      [(13)C,(1)H] COSY NMR spectra of components of biomass grown on uniformly (13)C
      labeled carbon sources. When using the entire set of measured data to
      simultaneously determine all fluxes in a proposed metabolic network model, the
      (13)C-labeling distribution in all measured compounds has to be simulated. This
      requires very large sets of isotopomer or cumomer balances. This article
      introduces the new concept of bondomers; entities that only vary in the numbers
      and positions of C-C bonds that have remained intact since the medium substrate
      molecule entered the metabolism. Bondomers are shown to have many analogies to
      isotopomers. One of these is that bondomers can be transformed to cumulative
      bondomers, just like isotopomers can be transformed to cumomers. Similarly to
      cumomers, cumulative bondomers allow an analytical solution of the entire set of
      balances describing a metabolic network. The main difference is that cumulative
      bondomer models are considerably smaller than corresponding cumomer models. This
      saves computational time, allows easier identifiability analysis, and yields new
      insights in the information content of 2D [(13)C,(1)H] COSY NMR data. We
      illustrate the theoretical concepts by means of a realistic example of the
      glycolytic and pentose phosphate pathways. The combinations of 2D [(13)C,(1)H]
      COSY NMR data that allow identification of all metabolic fluxes in these pathways
      are analyzed, and it is found that the NMR data contain less information than was
      previously expected.

PMID- 12402320
TI  - Process control for enhanced L-phenylalanine production using different
      recombinant Escherichia coli strains.
AB  - A novel fed-batch approach for the production of L-phenylalanine (L-Phe) with
      recombinant E. coli is presented concerning the on-line control of the key
      fermentation parameters glucose and tyrosine. Two different production strains
      possessing either the tyrosine feedback resistant aroF(fbr) (encoding tyrosine
      feedback resistant DAHP-synthase (3-desoxy-D-arabino-heptusonate-7-phosphate)) or
      the wild-type aroF(wt) were used as model systems to elucidate the necessity of
      finding an individual process optimum for each genotype. With the aid of tyrosine
      control, wild-type aroF(wt) could be used for L-Phe production achieving higher
      final L-Phe titers (34 g/L) than the aroF(fbr) strain (28 g/L) and providing
      higher DAHP-synthase activities. With on-line glucose control, an optimum glucose
      concentration of 5 g/L could be identified that allowed a sufficient carbon
      supply for L-Phe production while at the same time an overflow metabolism leading
      to acetate by-product formation was avoided. The process approach is suitable for
      other production strains not only in lab-scale but also in pilot-scale
      bioreactors.

PMID- 12402321
TI  - Laboratory-scale continuous reactor for soluble selenium removal using selenate
      reducing bacterium, Bacillus sp. SF-1.
AB  - A model continuous flow bioreactor (volume 0.5 L) was constructed for removing
      toxic soluble selenium (selenate/selenite) of high concentrations using a
      selenate-reducing bacterium, Bacillus sp. SF-1, which transforms selenate into
      elemental selenium via selenite for anaerobic respiration. Model wastewater
      contained 41.8 mg-Se/L selenate and excess lactate as the carbon and energy
      source; the bioreactor was operated as an anoxic, completely mixed chemostat with
      cell retention time between 2.2-95.2 h. At short cell retention times selenate
      was removed by the bioreactor, but accumulation of selenite was observed. At long
      cell retention times soluble selenium, both selenate and selenite, was
      successfully reduced into nontoxic elemental selenium. A simple mathematical
      model is proposed to evaluate Se reduction ability of strain SF-1. First-order
      kinetic constants for selenate and selenite reduction were estimated to be 2.9 x
      10(-11) L/cells/h and 5.5 x 10(-13) L/cells/h, respectively. The yield of the
      bacterial cells by selenate reduction was estimated to be 2.2 x 10(9) cells/mg
      Se.

PMID- 12402322
TI  - Effect of gene location, mRNA secondary structures, and RNase sites on expression
      of two genes in an engineered operon.
AB  - The effects of endoribonuclease sites, secondary structures in mRNA, and gene
      placement on protein production and mRNA stability and steady-state levels were
      tested in a dual-gene operon containing the genes encoding beta-galactosidase
      (lacZ) from Escherichia coli and green fluorescent protein (gfp) from Aequorea
      victoria. Two previously identified RNase E sites were placed separately between
      the coding regions to direct cleavage in this area and produce two secondary
      transcripts, each containing a single-gene coding region. Novel secondary
      structures were engineered into the 3' and 5' ends of each of the coding regions
      to protect the transcript from inactivation by endoribonucleases (5' hairpins)
      and degradation by exoribonucleases (3' hairpins). In addition, the effects of
      relative gene placement were examined by switching the locations of the two
      coding regions. Depending on the particular secondary structures and RNase E
      sites placed between the genes the relative steady-state transcript and protein
      levels encoded by the two reporter genes could be changed up to 2.5-fold and 4
      fold, respectively. By changing gene location and incorporating secondary
      structures and RNase E sites the relative steady-state transcript and protein
      levels encoded by the two reporter genes could be changed up to 100-fold and 750
      fold, respectively.

PMID- 12402323
TI  - Hydrogen production by cyanobacteria in an automated outdoor photobioreactor
      under aerobic conditions.
AB  - The possibility of hydrogen production by a hydrogenase impaired mutant strain of
      Anabaena variabilis in outdoor culture was studied. A computer-controlled rooftop
      (outdoor) tubular photobioreactor (4.35 L) was assembled. H(2) production rates
      by A. variabilis PK84 grown in CO(2) + air in the photobioreactor were measured
      together with other parameters such as temperature, irradiance, pH, dry biomass
      weight, and pO(2), and Chl a concentrations during summer months of 1998 and
      1999. Efficiencies of light energy bioconversion to H(2) energy and energy
      accumulated in biomass were calculated. The influence of irradiance, temperature,
      and mode of cultivation on H(2) production and efficiency of light energy
      bioconversion were evaluated. The culture produced up to 1.1 L H(2) day(-1) PhBR(
      1). The efficiency of light energy to H(2) energy bioconversion on some days was
      0.094%. However, the conditions for maximum H(2) photoproduction and for maximum
      efficiency of light energy to H(2) energy bioconversion were not the same. A.
      variabilis PK84 could produce hydrogen for prolonged periods (up to 40 days)
      without injection of fresh inoculum. During this period photobioreactor produced
      24.5 L of H(2). Possibilities for increasing the efficiency of light energy
      conversion are discussed.

PMID- 12402324
TI  - Structural and catalytic response to temperature and cosolvents of
      carboxylesterase EST1 from the extremely thermoacidophilic archaeon Sulfolobus
      solfataricus P1.
AB  - The interactive effects of temperature and cosolvents on the kinetic and
      structural features of a carboxylesterase from the extremely thermoacidophilic
      archaeon Sulfolobus solfataricus P1 (Sso EST1) were examined. While
      dimethylformamide, acetonitrile, and dioxane were all found to be deleterious to
      enzyme function, dimethyl sulfoxide (DMSO) activated Sso EST1 to various extents.
      This was particularly true at 3.5% (v/v) DMSO, where k(cat) was 20-30% higher
      than at 1.2% DMSO, over the temperature range of 50-85 degrees C. DMSO
      compensated for thermal activation in some cases; for example, k(cat) at 60
      degrees C in 3.5% DMSO was comparable to k(cat) at 85 degrees C in 1.2% DMSO. The
      relationship between DMSO activation and enzyme structural characteristics was
      also investigated. Nuclear magnetic resonance spectroscopy and circular dichroism
      showed no gross change in enzyme conformation with 3.5% DMSO between 50 and 80
      degrees C. However, low levels of DMSO were shown to have a small yet significant
      change in enzyme conformation. This was evident through the reduction of Sso
      EST1's melting temperature and changes in the microenvironment of the enzyme's
      tyrosine and tryptophan residues at 3.5% versus 1.2% (v/v) solvent. Finally,
      activation parameter analysis based on kinetic data, at 1.2% and 3.5% DMSO,
      implied an increase in conformational flexibility with additional cosolvent.
      These results suggest the activating effect of DMSO was related to small changes
      in the enzyme's structure resulting in an increase in its conformational
      flexibility. Thus, in addition to their use for solubilizing hydrophobic
      substrates in water, cosolvents may also serve as activators in applications
      involving thermostable biocatalysts at sub-optimal temperatures.

PMID- 12402325
TI  - Modeling, optimization and experimental assessment of continuous L-(-)-carnitine
      production by Escherichia coli cultures.
AB  - In a previous paper Canovas et al. (Biotechnol Bioeng 2002;77:764-775) presented
      a model for L-(-)-carnitine production using Escherichia coli O44 K74, in a cell
      recycle bioreactor for the biotransformation of crotonobetaine into L-carnitine.
      In this work we optimize this biotechnological setup and experimentally verify
      the predicted optimal parameter profiles. Provided with a reliable and robust S
      system description of the cell-bioreactor combined system, we applied the
      Indirect Optimization Method described by Torres et al. (Biotechnol Bioeng
      1997;55(5):758-772; Food Technol Biotechnol 1998;36(3):177-184). This
      optimization approach provides different parameter value profiles, all of which
      are compatible with the cell physiology and the bioreactor operating conditions,
      that yield increased rates of L-(-)-carnitine production. Three parameters were
      seen to be of critical importance for maximizing L-(-)-carnitine production: the
      dilution rate, the initial crotonobetaine concentration, and the carnitine
      dehydratase activity. When the first two were changed in the experimental setup,
      there was a 74% increase in the L-(-)-carnitine production rate, performance that
      was in close agreement with the predictions of the model. In accordance with the
      optimized solution, a further improvement (90% increase in the L-(-)-carnitine
      production rate) could be attained by over-expressing up to 5 times the carnitine
      dehydratase basal activity. Thus the optimization approach shown herein provides
      experimental evidence of a new strategy which demonstrates the possible variables
      that can be subjected to modifications compatible with the cell physiology and
      bioreactor operating conditions, and which are able to yield increased rates of L
      (-)-carnitine production.

PMID- 12402326
TI  - Characterization of electrostatic binding sites of extracellular polymers by
      linear programming analysis of titration data.
AB  - Electrostatic binding sites of extracellular polymeric substances (EPS) were
      characterized from titration data using linear programming analysis. Test results
      for three synthetic solutions of given solutes comprising amino, carboxyl, and
      phenolic groups indicated that this method was able to identify the electrostatic
      binding sites. For the six sites with pK(a) between 3 and 10, the estimated pK(a)
      deviated 0.11 +/- 0.09 from the theoretical values, and the estimated
      concentrations deviated 3.0% +/- 0.9% from the actual concentrations. Two EPS
      samples were then extracted from a hydrogen-producing sludge (HPS) and a sulfate
      reducing biofilm (SRB). Analysis of charge excess data in titration from pH 3 to
      11 indicated that the EPS of HPS comprised of five electrostatic binding sites
      with pK(a) ranging from 3 to 11. The pK(a) values of these binding sites and the
      possible corresponding functional groups were pK(a) 4.8 (carboxyl), pK(a) 6.0
      (carboxyl/phosphoric), pK(a) 7.0 (phosphoric), pK(a) 9.8 (amine/phenolic), and
      pK(a) 11.0 (hydroxyl). EPS of the SRB comprised five of similar binding sites
      (with corresponding pK(a) values of 4.4, 6.0, 7.4, 9.4, and 11.0), plus one extra
      site at pK(a) 8.2, which was likely corresponding to the sulfhydryl group. The
      total electrostatic binding site concentration of EPS extracted from HPS were
      10.88 mmol/g-EPS, of which the highest concentration was from the site of pK(a)
      11.0. The corresponding values for the EPS extracted from SRB were 16.44 mmol/g
      EPS and pK(a) 4.4. The total concentrations of electrostatic binding sites found
      in this study were 20- to 30-fold of those reported for bacterial cell surface,
      implying that EPS might be more crucial in biosorption of metals than bacterial
      cell surface in wastewater treatment and in bioremediation.

PMID- 12402327
TI  - Hepatitis B surface antigen (HBsAg) expression in plant cell culture: Kinetics of
      antigen accumulation in batch culture and its intracellular form.
AB  - The production of edible vaccines in transgenic plants and plant cell culture may
      be improved through a better understanding of antigen processing and assembly.
      The hepatitis B surface antigen (HBsAg) was chosen for study because it undergoes
      substantial and complex post-translational modifications, which are necessary for
      its immunogenicity. This antigen was expressed in soybean (Glycine max L. Merr.
      cv Williams 82) and tobacco NT1 (Nicotiana tabacum L.) cell suspension cultures,
      and HBsAg production in batch culture was characterized. The plant-derived
      antigen consisted predominantly of disulfide cross-linked HBsAg protein (p24(s))
      dimers, which were all membrane associated. Similar to yeast, the plant-expressed
      HBsAg was retained intracellularly. The maximal HBsAg titers were obtained with
      soybean suspension cultures (20-22 mg/L) with titers in tobacco cultures being
      approximately 10-fold lower. For soybean cells, electron microscopy and
      immunolocalization demonstrated that all the HBsAg was localized to the
      endoplasmic reticulum (ER) and provoked dilation and proliferation of the ER
      network. Sucrose gradient analysis of crude extracts showed that HBsAg had a
      complex size distribution uncharacteristic of the antigen's normal structure of
      uniform 22-nm virus-like particles. The extent of authentic epitope formation was
      assessed by comparing total p24(s) synthesized to that reactive by polyclonal and
      monoclonal immunoassays. Depending on culture age, between 40% and 100% of total
      p24(s) was polyclonal antibody reactive whereas between 6% and 37% was recognized
      by a commercial monoclonal antibody assay. Possible strategies to increase HBsAg
      production and improve post-translational processing are discussed.

PMID- 12402328
TI  - Effect of rate of chemical or thermal renaturation on refolding and aggregation
      of a simple lattice protein.
AB  - We used dynamic Monte Carlo simulation to investigate how changing the rate of
      chemical or thermal renaturation affects the folding and aggregation behavior of
      a system of simple, two-dimensional lattice protein molecules. Four renaturation
      methods were simulated: infinitely slow cooling; slow but finite cooling;
      quenching; and pulse renaturation. The infinitely slow cooling method, which is
      equivalent to dialysis or diafiltration, provides refolding yields that are
      relatively high and aggregates that are relatively small (mostly dimers or
      trimers). The slow but finite cooling method, which is equivalent to multiple
      step dilution, provides refolding yields that are almost as high as those
      observed in the infinitely slow cooling case, but in a relatively short period of
      time. Quenching, which is equivalent to one-step dilution or quick quenching, is
      extremely slow and has low re- folding yields. A maximum appears in the refolding
      yield as a function of denaturant concentration in the simulation but disappears
      after a very long duration. Finally, the pulse renaturation method provides
      refolding yields that are substantially higher than those observed in the other
      three methods, even at high packing fractions. As in the early stages of
      quenching, there is a maximum in the refolding yield as a function of denaturant
      concentration when relatively large numbers of denatured chains are added to the
      refolding solution at each step.

PMID- 12402329
TI  - The detection of large deletions or duplications in genomic DNA.
AB  - While methods for the detection of point mutations and small insertions or
      deletions in genomic DNA are well established, the detection of larger (>100 bp)
      genomic duplications or deletions can be more difficult. Most mutation scanning
      methods use PCR as a first step, but the subsequent analyses are usually
      qualitative rather than quantitative. Gene dosage methods based on PCR need to be
      quantitative (i.e., they should report molar quantities of starting material) or
      semi-quantitative (i.e., they should report gene dosage relative to an internal
      standard). Without some sort of quantitation, heterozygous deletions and
      duplications may be overlooked and therefore be under-ascertained. Gene dosage
      methods provide the additional benefit of reporting allele drop-out in the PCR.
      This could impact on SNP surveys, where large-scale genotyping may miss null
      alleles. Here we review recent developments in techniques for the detection of
      this type of mutation and compare their relative strengths and weaknesses. We
      emphasize that comprehensive mutation analysis should include scanning for large
      insertions and deletions and duplications.

PMID- 12402330
TI  - The human SHOX mutation database.
AB  - The human SHOX database has recently been established to provide clinicians and
      scientists access to a central source of information about all known SHOX
      mutations associated with short stature phenotypes such as idiopathic short
      stature, Leri-Weill dyschondrosteosis, Langer syndrome, and Turner syndrome. So
      far, the database contains 29 unique intragenic mutations of the SHOX gene. These
      mutations were detected in a total of 39 patients from different families.
      Fourteen of these mutations have been found from the SHOX research group at the
      Institute of Human Genetics in Heidelberg, Germany; 25 mutations are from data
      reported in the literature. Not included in this database are complete SHOX gene
      deletions which represent the majority of all detectable SHOX mutations [Rappold
      et al., 2002]. The database is accessible via the website www.shox.uni-hd.de. It
      contains general information about the SHOX gene, and allows remote users to
      search the data and to submit new mutations to the database.

PMID- 12402331
TI  - Novel PEX1 mutations and genotype-phenotype correlations in Australasian
      peroxisome biogenesis disorder patients.
AB  - The peroxisome biogenesis disorders (PBDs) are a group of neuronal
      migration/neurodegenerative disorders that arise from defects in PEX genes. A
      major subgroup of the PBDs includes Zellweger syndrome (ZS), neonatal
      adrenoleukodystrophy (NALD), and infantile Refsum disease (IRD). These three
      disorders represent a clinical continuum with Zellweger syndrome the most severe.
      Mutations in the PEX1 gene, which encodes a protein of the AAA ATPase family
      involved in peroxisome matrix protein import, account for the genetic defect in
      more than half of the patients in this PBD subgroup. We report here on the
      results of PEX1 mutation detection in an Australasian cohort of PEX1-deficient
      PBD patients. This screen has identified five novel mutations, including nonsense
      mutations in exons 14 and 19 and single nucleotide deletions in exons 5 and 18.
      Significantly, the allele carrying the exon 18 frameshift mutation is present at
      moderately high frequency (approx. 10%) in this patient cohort. The fifth
      mutation is a missense mutation (R798G) that attenuates, but does not abolish
      PEX1 function. We have evaluated the cellular impact of these novel mutations,
      along with that of the two most common PEX1 mutations (c.2097-2098insT and
      G843D), in PBD patients by determining the levels of PEX1 mRNA, PEX1 protein, and
      peroxisome protein import. The findings are consistent with a close correlation
      between cellular phenotype, disease severity, and PEX1 genotype.

PMID- 12402332
TI  - A low frequency of non-founder BRCA1 mutations in Ashkenazi Jewish breast-ovarian
      cancer families.
AB  - The 185delAG and 5382insC founder mutations account for the majority of mutations
      identified in BRCA1 in Ashkenazi Jewish breast and breast-ovarian cancer
      families. Few non-founder BRCA1 mutations have been identified to date in these
      families. We initially screened a panel of 245 Ashkenazi Jewish breast-ovarian
      cancer families with an affected proband and at least one other case of breast or
      ovarian cancer for founder mutations in BRCA1 and BRCA2. Founder mutations were
      identified in 85 families (185delAG in 44 families, 5382insC in 16 families, and
      the BRCA2 6174delT in 25 families). The 160 negative families were then screened
      for the entire BRCA1 gene by a combination of DGGE and PTT. We identified one
      novel frameshift mutation in BRCA1 in exon 14 (4572del22) that truncated the
      protein at codon 1485. The family contained three cases of early-onset ovarian
      cancer (41 years, 43 years, and 52 years) and one case of breast cancer (at age
      54 years subsequent to an ovarian cancer). In addition, three missense variants
      of unknown significance (exon 11 C3832T (P1238L), exon 15 G4654T (S1512I), and
      exon 15 G4755A (D1546N)) were found in single families. These missense variants
      have been previously identified in other families [BIC Database] and are
      considered to be "unclassified variants, favoring polymorphism." Non-founder
      BRCA1 mutations are rare in Ashkenazi Jewish breast/ovarian cancer families.

PMID- 12402333
TI  - Epidemiology of the delta globin alleles in southern Italy shows complex
      molecular, genetic, and phenotypic features.
AB  - We characterized mutations and haplotypes of the delta-globin gene (HBD, MIM#
      142000) in two regions of southern Italy. Mutations were discovered by screening
      for individuals with Hb A2<2%. In Basilicata, about 10,000 students were screened
      and 53 carriers in 43 unrelated families were diagnosed; in Campania, cases were
      referred through a routine thalassemia counseling service. Twelve alleles were
      detected. Four were novel variants [Hb A2-Metaponto (g.238C>A), Hb A2-Campania
      (g.302C>A), Hb A2-Lucania (g.393C>G), and Hb A2-Capri (g.443G>T)]. Hb A2-Lucania
      was not inherited but had arisen in the propositus. Two were novel mutations in
      the noncoding regions: the substitutions IVS2+6T>A, presumably affecting the
      splicing, and g.-126A>T in the GATA motif presumably affecting transcription. All
      novel alleles were found associated with haplotypes common in the Mediterranean
      area. The remaining six were alleles already described. The Hb A2-Yialousa
      (g.82G>T) was the most prevalent (42/63 families). Recurrent homologous crossing
      over events have, most likely, linked this allele to Haplotypes IX (24 families),
      IV (10 families), or III (seven families). The ratio of Haplotypes IX:IV:III was
      about the same in the two regions. The rare allele Hb A2-NYU (g.39T>A) was found
      in 11 families from Basilicata associated with Haplotype I. All the 11 families
      lived in a restricted area extending from the Ionian Coast for 15 km along the
      Angri and Sinni Rivers. A founder effect most probably gave origin to this
      isolated group. The remaining four alleles were rare: the 7.2-kb deletion Corfu
      type (HBD g.-5946_1262del), Hb A2-Mitsero (g.14C>T), Hb A2-Etolia (g.385T>C), Hb
      A2-Coburg (g.1376G>A). Correlation between genotype and phenotype was established
      in 103 carriers.

PMID- 12402334
TI  - Different molecular mechanisms underlie genomic deletions in the MLH1 Gene.
AB  - In this study we examined a series of 52 patients belonging to hereditary
      nonpolyposis colorectal cancer (HNPCC) or HNPCC-related families, all who had
      previously tested negative for mismatch repair (MMR) gene point mutations.
      Southern blot mutational screening of MLH1 and MSH2 genes was carried out with
      the aim of detecting large genomic rearrangements and of identifying the
      molecular mechanisms underlying the inactivation of the MMR genes. Three patients
      had abnormal restriction patterns and were found to carry distinct MLH1 internal
      deletions. Long-range PCRs identified the loss of DNA tracts spanning exon 6
      (about 2.4 kb in proband A-AV20 and 0.8 kb in proband A-PD5) and exon 3 (about
      2.5 kb in proband R-RM2). In A-AV20 the breakpoints occurred into identical 33-bp
      regions in introns 5 and 6 and a mechanism of classical Alu-mediated homologous
      recombination was evident. Also, in patient A-PD5 the breakpoints were located in
      these introns, but without direct involvement of repetitive sequences. In patient
      R-RM2 the breakpoints were located within repetitive L1 elements with poor
      homology in intron 2 and 3 and the rearranged allele was characterized by a
      complex insertion deletion (delCCinsACATAGTA), giving rise to a palindromic
      CTTAACATAGTATGTTAAG sequence in proximity of the fusion site. This study confirms
      that genomic rearrangements are an important component of the spectrum of MMR
      mutations. Although Alu repeats are likely to be implicated in the majority of
      cases, different molecular mechanisms may also be responsible for the observed
      MLH1 intragenic deletions. In particular, HNPCC resulting from L1-mediated
      recombination has been identified as a novel mechanism for MMR inactivating
      mutation.

PMID- 12402336
TI  - DHPLC analysis of potassium ion channel genes in congenital long QT syndrome.
AB  - Congenital long QT syndrome (LQTS) is electrocardiographically characterized by a
      prolonged QT interval and polymorphic ventricular arrhythmias (torsade de
      pointes). As a result of these arrhythmias, patients suffer from recurrent
      syncopes, seizures, or sudden death as the most dramatic event. Mutations in five
      genes, encoding cardiac ion channels, have been identified in LQTS. Two potassium
      channel genes, KCNQ1 (LQT1) and KCNH2 (LQT2 or HERG), are frequently involved in
      LQTS. Potassium-channel defects account for approximately 50-60% of LQTS. As
      patients benefit from preventive medication, early detection of a genetic defect
      is desired to identify the family members at risk. Speed and sensitivity of
      mutation detection was improved by applying the denaturing high performance
      liquid chromatography (DHPLC) technique for analysis of the entire KCNQ1 and
      KCNH2 genes and the protein encoding part of the KCNE1 and KCNE2 genes. By using
      this methodology, seven missense mutations in the KCNQ1 gene and nine mutations
      (four missense, two nonsense, one insertion, and two deletions) in the KCNH2 gene
      have been identified in a total number of 32 index patients diagnosed with LQTS
      syndrome. We conclude that this method is suitable for rapid identification of
      LQT gene defects due to the combination of automation, high throughput,
      sensitivity, and short time of analysis.

PMID- 12402335
TI  - Five novel SLC7A7 variants and y+L gene-expression pattern in cultured
      lymphoblasts from Japanese patients with lysinuric protein intolerance.
AB  - Two distinct human light subunits of the heteromeric amino acid transporter,
      y+LAT-1 coded by SLC7A7 and y+LAT-2 coded by SLC7A6, are both known to induce
      transport system y+L activity. SLC7A7 has already been identified as the gene
      responsible for lysinuric protein intolerance (LPI). We successfully identified
      five novel SLC7A7 variants (S238F, S489P, 1630delC, 1673delG, and IVS3
      IVS5del9.7kb) in Japanese patients with LPI by PCR amplification and direct DNA
      sequencing. In addition, we performed a semi-quantitative expression analysis of
      SLC7A7 and SLC7A6 in human tissue. In normal tissue, the gene-expression ratio of
      SLC7A6 to SLC7A7 was high in the brain, muscle, and cultured skin fibroblasts;
      low in the kidneys and small intestine; and at an intermediate level in
      peripheral blood leukocytes, the lungs, and cultured lymphoblasts. The gene
      expression ratio of SLC7A6 to SLC7A7 in cultured lymphoblasts was significantly
      different between normal subjects and LPI patients with R410X and/or S238F, where
      the relative amount of SLC7A7 mRNA was significantly lower and the relative
      amount of SLC7A6 mRNA was statistically higher in affected lymphoblasts than in
      normal cells. Expression of SLC7A7 and SLC7A6 may thus be interrelated in
      cultured lymphoblasts.

PMID- 12402337
TI  - Molecular analysis in Japanese patients with Charcot-Marie-Tooth disease: DGGE
      analysis for PMP22, MPZ, and Cx32/GJB1 mutations.
AB  - Charcot-Marie-Tooth disease (CMT) is a heterogeneous disorder and is
      traditionally classified into two major types, CMT type 1 (CMT1) and CMT type 2
      (CMT2). Most CMT1 patients are associated with the duplication of 17p11.2-p12
      (CMT1A duplication) and small numbers of patients have mutations of the
      peripheral myelin protein 22 (PMP22), myelin protein zero (MPZ), connexin 32
      (Cx32/GJB1), and early growth response 2 (EGR2) genes. Some mutations of MPZ and
      Cx32 were also associated with the clinical CMT2 phenotype. We constructed
      denaturing gradient gel electrophoresis (DGGE) analysis as a screening method for
      PMP22, MPZ, and Cx32 mutations and studied 161 CMT patients without CMT1A
      duplication. We detected 27 mutations of three genes including 15 novel
      mutations; six of PMP22, three of MPZ, and six of Cx32. We finally identified 21
      causative mutations in 22 unrelated patients and five polymorphic mutations.
      Eighteen of 22 patients carrying PMP22, MPZ, or Cx32 mutations presented with
      CMT1 and four of them with MPZ or Cx32 mutations presented with the CMT2
      phenotype. DGGE analysis was sensitive for screening for those gene mutations,
      but causative gene mutation was not identified in many of the Japanese patients
      with CMT, especially with CMT1. Other candidate genes should be studied to
      elucidate the genetic basis of Japanese CMT patients.

PMID- 12402338
TI  - Association of a homozygous (TA)8 promoter polymorphism and a N400D mutation of
      UGT1A1 in a child with Crigler-Najjar type II syndrome.

PMID- 12402341
TI  - Clustering of variations and haplotype analysis in the highly variable region of
      exon 11 of BRCA1 in Chinese women with sporadic breast cancer.
AB  - Studies on mutations of BRCA1 gene in Oriental populations, especially in Chinese
      are sparse. To evaluate the contribution of BRCA1 mutations to sporadic breast
      cancer in Chinese, mutations in exon 11 from nucleotide positions 3533 to
      3682(U14680), a highly variable region of BRCA1 gene, were screened by single
      strand conformation polymorphism (SSCP) and DNA sequencing in 329 genomic DNAs
      from 95 Chinese women with sporadic breast cancer, 29 with benign breast disease
      and 50 controls. As results, 6 single nucleotide changes were found, and 5 of
      them (3545A>G, 3551G>T, 3607C>T, 3646T>A and 3661T>C) were newly discovered. The
      3545A>G and 3607C>T were germline variations, and the other 3 were somatic
      variations. In addition, four new haplotypes were defined. Since these newly
      discovered nucleotide changes were only detected in patients, our results suggest
      that BRCA1 may also play a role in the development of sporadic breast cancer in
      Chinese populations.

PMID- 12402342
TI  - The LDL receptor-related protein (LRP1/A2MR) and coronary atherosclerosis--novel
      genomic variants and functional consequences.
AB  - The LDL receptor-related protein/alpha 2-macroglobulin receptor (LRP1/A2MR) is a
      multifunctional cell-surface glycoprotein that endocytoses several structurally
      and functionally distinct ligands. In clinical studies different genomic variants
      of the LRP1/A2MR and its role in the development of degenerative diseases like
      atherosclerosis or Alzheimer's disease were studied. We screened for novel
      genomic variants of LRP1/A2MR and investigated the importance of these variants
      in 214 coronary patients suffering from myocardial infarction as well as in 224
      healthy controls. We detected a novel C>G polymorphism at position -25 in the
      functionally important promoter region of LRP1/A2MR. This polymorphism (c.1
      25C>G) leads to the creation of a new GC-box, recognized by the constitutively
      expressed SP 1 transcription factor. Investigating the LRP1/A2MR gene expression
      with respect to this polymorphism, carriers of the mutant G-allele were found to
      have a higher mRNA expression level. A novel polymorphism in exon 22 (c.4012C>T),
      and two novel polymorphisms in intron 24 (IVS24+123C>A and IVS24+690G>A)
      associated with a previously described polymorphism in exon 61 (c.10249G>A), were
      related to the development of myocardial infarction. Two novel rare genetic
      variants of exon 88 (c.13933C>T) and intron 88 (IVS88+15G>A) were identified in
      four patients with severe coronary symptoms. However, the LRP1/A2MR gene
      expression was found to be independent of all identified novel genomic variants
      as well as other previously described changes (A217V, A775P, D2080N, D2632E,
      G4379S) except the promoter polymorphism.

PMID- 12402343
TI  - Ten novel ORF15 mutations confirm mutational hot spot in the RPGR gene in
      European patients with X-linked retinitis pigmentosa.
AB  - RGPR was the first gene found to be mutated in XLRP, the subtype of RP displaying
      the most severe form of retinal degeneration with partial or complete blindness
      in the third or fourth decade of life. Despite the RP3 locus on Xp21.1 accounting
      for 60-90% of XLRP, only 10-20% of identified RPGR mutations were reported in
      earlier analyses. This discrepancy appeared to be resolved when Vervoort et al.
      identified a mutational hot spot in a new purine-rich 3' exon (ORF15) that
      accounted for 60% of their XLRP patients [Vervoort et al., 2000]. In our mutation
      screening of 37 unrelated European XLRP patients we identified two recently
      described deletions and 10 novel mutations in exon ORF15 of RPGR, 4 of which were
      nonsense and 6 frameshift mutations. The latter included one duplication and 5
      deletion mutations, all of which lead to a downstream premature termination. No
      mutations were detected in the additionally screened new exon ORF14. The data
      reported here, together with previous findings, document a significant clustering
      of mutations as well as polymorphisms in ORF15 of RPGR. In our unselected XLRP
      patient population, ORF15 mutations constitute 32% of cases, a finding that
      contradicts the results of Vervoort and coworkers [Vervoort et al., 2000] but is
      in agreement with a more recent study on North American XLRP patients [Breuer et
      al., 2002]. The observed prevalence is sufficient to justify an initial mutation
      screening of ORF15 in the genetically heterogeneous group of XLRP.

PMID- 12402344
TI  - Detection of C1 inhibitor (SERPING1/C1NH) mutations in exon 8 in patients with
      hereditary angioedema: evidence for 10 novel mutations.
AB  - Hereditary angioedema (HAE) is caused by mutations in the C1 inhibitor gene
      (SERPING1, C1NH) and the result is C1 inhibitor deficiency, either in levels or
      function. We have searched exon 8 for mutations by direct sequencing and analyzed
      the rest of the exons by SSCP in 87 Spanish families affected by HAE. Out of 87
      screened families, we have detected exon 8 mutations in 26. Among these, 17
      different mutations were identified: 14 point mutations and 3 frameshift. Seven
      of the point mutations and the three frameshift were not previously reported.
      Mutations were: S438P; R444P; V451G; W460X; V468D; G471E; X479R; S417fsX427;
      I440fsX450; E429fsX450. The rest of the families presented previously reported
      mutations, 5 missense and two nonsense. In none of the 26 families was an
      additional change identified in the rest of the exons by SSCP, and, in 20 out of
      the 22 families with point mutation, we verified that the mutation did not affect
      a healthy relative. Seven of these families had no history of the disease, and in
      five of them we were able to verify that the progenitors did not have the
      mutation. Therefore, they were de novo mutations.

PMID- 12402345
TI  - Molecular studies in mutase-deficient (MUT) methylmalonic aciduria:
      identification of five novel mutations.
AB  - Mutase-deficient (MUT) methylmalonic aciduria (MMA) is an autosomal recessive
      inborn error of organic acid metabolism, resulting from a functional defect in
      the nuclear encoded mitochondrial enzyme methylmalonyl-CoA mutase (MCM)
      (EC.5.4.99.2). The enzyme requires 5'-deoxyadenosylcobalamin as a cofactor.
      Isolated MMA results from either apoenzyme or cofactor defects, and is classified
      into several genotypic classes and complementation groups. These are designated
      mut(-) or mut(0) (together termed mut), depending on minimal or no apoenzyme
      activity respectively and cobalamin A or B (cbl A/B) for cofactor defects. To
      date various studies have identified over 53 disease-causing mutations from
      patients with mut(0/-) MMA. These are predominantly missense/nonsense nucleotide
      substitutions. In this study, we report the genotype analysis on 7 patients
      diagnosed with mut MMA. Five novel mutations were identified (R403stop, 497delG,
      P615T, 208delG and R467stop) and one novel polymorphism (c712A->G). The
      previously reported R228Q mutation was found in one patient, who is a compound
      heterozygote for this mutation and the R467stop mutation. A recently reported
      N219Y mutation was found in one patient. The 497delG mutation was detected as a
      homozygous deletion. The remaining mutations were observed in compound
      heterozygotes, with the second mutation yet to be identified. Many of the
      unidentified mutations may occur within the promotor or intronic regions.

PMID- 12402346
TI  - Mutation screening of the fibrillin-1 (FBN1) gene in 76 unrelated patients with
      Marfan syndrome or Marfanoid features leads to the identification of 11 novel and
      three previously reported mutations.
AB  - Mutations in the gene encoding fibrillin-1 (FBN1) cause Marfan syndrome (MFS) and
      other related connective tissue disorders. In this study we performed SSCP to
      analyze all 65 exons of the FBN1 gene in 76 patients presenting with classical
      MFS or related phenotypes. We report 7 missense mutations, 3 splice site
      alterations, one indel mutation, one nonsense mutation and two mutations causing
      frameshifts: a 16bp deletion and a single nucleotide insertion. 5 of the missense
      mutations (Y1101C, C1806Y, T1908I, G1919D, C2251R) occur in calcium-binding
      Epidermal Growth Factor-like (EGFcb) domains of exons 26, 43, 46 and 55,
      respectively. One missense mutation (V449I) substitutes a valine residue in the
      non-calcium-binding epidermal growth factor like domain (EGFncb) of exon 11. One
      missense mutation (G880S) affects the "hybrid" motif in exon 21 by replacing
      glycine to serine. The 3 splice site mutations detected are: IVS1-1G>A in intron
      1, IVS38-1G>A in intron 38 and IVS46+5G>A in intron 46. C628delinsK was
      identified in exon 15 leading to the substitution of a conserved cysteine
      residue. Furthermore two frameshift mutations were found in exon 15 (1904-1919del
      ) and exon 63 (8025insC) leading to premature termination codons (PTCs) in exon
      17 and 64 respectively. Finally we identified a nonsense mutation (R429X) located
      in the proline rich domain in exon 10 of the FBN1 gene. Y1101C, IVS46+5G>A and
      R429X have been reported before.

PMID- 12402347
TI  - H intragenic polymorphisms and haplotype analysis in the ornithine
      transcarbamylase (OTC) gene and their relevance for tracking the inheritance of
      OTC deficiency.
AB  - The "private" nature of most mutations causing ornithine transcarbamylase (OTC)
      deficiency makes mutation identification in the patients difficult. Further, the
      PCR-amplification technology generally used for the genetic diagnosis of the
      deficiency misses large deletions in carrier females. Intragenic OTC
      polymorphisms may allow detection of these deletions and may represent an
      alternative to mutation detection for prenatal diagnosis and carrier
      identification in families with a history of inherited OTC deficiency. A new
      highly informative polymorphism (allele frequencies, 0.66/0.34) in intron 3 of
      the OTC gene (IVS3-39_40insT) is reported here, and allelic frequencies of 16
      additional intragenic OTC polymorphisms are determined in 133-35 (average per
      polymorphism, 72) unrelated chromosomes. In addition to the novel polymorphism,
      only three of the studied polymorphisms (Lys46Arg, allelic frequency 0.68/0.32;
      IVS3-8A>T, 0.34/0.66; Gln270Arg, 0.97/0.03) are confirmed to be informative.
      These provide, together with another reported polymorphism (IVS4-7A>G; reported
      allelic frequency 0.71/0.29; Plante and Tuchman, 1998), a set of highly valuable
      markers of the OTC gene. Nevertheless, the combined informativity of the studied
      polymorphisms is limited by their distribution in only four haplotypes with one
      of them predominating (65% of the sampled chromosomes). Although this haplotype
      composition may be restricted to the Iberian peninsula (the origin of the
      samples), more informative polymorphisms are required to increase the diagnostic
      potential and, particularly, to identify large deletions affecting OTC gene exons
      5-10, where only one polymorphism of weak diagnostic value is known.

PMID- 12402348
TI  - Loss of heterozygosity and mutations are the major mechanisms of RB1 gene
      inactivation in Chinese with sporadic retinoblastoma.
AB  - We investigated sequence alternation, promoter methylation, and loss of
      heterozygosity (LOH) of the RB1 gene as possible mechanisms of its inactivation
      in retinoblastoma. In 42 Chinese patients with sporadic retinoblastoma, the
      promoter and entire coding region of RB1 were examined for sequence changes.
      Status of methylation of the CpG-rich island at the 5'end was determined by
      methylation specific PCR assay. We detected 15 RB1 mutations in 38% (16/42) of
      the retinoblastoma patients, among them 19% (8/42) were germ-line mutations. A
      total of nine novel mutations were identified: E54X, S114X, I126S, g73779insG,
      D718N, IVS2+1G>C, IVS14+1G>C, IVS21+1G>C, and a complex alteration
      g78177G>T/g78176insTT leading to 543X. Most of them are likely to affect the
      RB1large pocket domain through the production of truncated gene products. None of
      the DNA samples showed methylation at the RB1promoter. In 15 cases where both
      normal and cancerous retinoblastoma tissue specimens were available, allelic loss
      according to microsatellite markers within or distal to the RB1 locus was
      analyzed and immunohistological staining for RB1 expression performed. Among
      them, frequency of LOH at 13q14 was found to be high at 60% (9/15) with no
      segregation with unilateral tumors. All these nine tumors did not express RB1
      protein, showing an association of LOH at the RB1 locus with its loss of
      expression in retinoblastoma. Our results indicate that the RB1 gene in sporadic
      retinoblastoma is commonly inactivated because of loss-of-function mutations and
      loss of heterozygosity but not by the epigenetic phenomenon of promoter
      hypermethylation.

PMID- 12402349
TI  - Novel O6-methylguanine-DNA methyltransferase SNPs: a frequency comparison of
      patients with familial melanoma and healthy individuals in Sweden.
AB  - The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) is involved
      in the cellular defense against alkylating agents. Genetic alterations in the
      MGMT gene may impair the protein's ability to remove alkyl groups from the O6
      position of guanine, thereby raising the mutation rate and increasing the risk of
      cancer. We assessed polymorphisms in the promoter region and the 5 exons of the
      MGMT gene by PCR/SSCP and nucleotide sequence analysis of DNA extracted from
      blood samples. The population studied consisted of 89 melanoma patients, each
      belonging to a different family with a hereditary predisposition for melanoma,
      and 76 healthy individuals (blood donors). A total of 11 single nucleotide
      polymorphisms (SNPs) were detected, five in the promoter region, one in exon 1,
      two in exon 3 and three in exon 5. Six of the alterations were novel
      polymorphisms, of which five were located in the promoter region and one in exon
      5. When the distribution of specific SNPs in cases and controls with only one
      variant was calculated; C575A was present only in melanoma patients (p=0.072).
      Moreover, while 20% of the healthy individuals had no SNPs this was the case in
      only 12.4% of the melanoma patients. However, no statistically significant
      differences were seen between cases and controls for any of the 11 SNPs.

PMID- 12402350
TI  - A collection of 33 novel human mtDNA homoplasmic variants.
AB  - Mitochondria are involved in cellular energy production via oxidative
      phosphorylation and this function may be damaged by any mutation in mitochondrial
      DNA (mtDNA). To identify novel mtDNA mutations, we have developed a program to
      systematically screen the entire mitochondrial genome in a large number of
      individuals with clinical and/or morphological features of mitochondrial
      dysfunction, but still no genetic diagnosis. The sequence-data were obtained with
      an automated rapid system, which gave us a series of information: in the eleven
      mitochondrial genomes analyzed we observed the presence of 33 differences from
      the revised Cambridge Reference Sequence (Andrews et al., 1999), but they were
      all homoplasmic in the patients' tissues analyzed (skeletal muscle and blood),
      suggesting that they are unlikely to be primarily pathogenic though they may be
      co-responsible in the determination of the disease. This work can therefore help
      complete the already ample mtDNA polymorphism existent database.

PMID- 12402351
TI  - Cyclooxygenase 1 (COX1) polymorphisms in African-American and Caucasian
      populations.
AB  - Cyclooxygenases (COXs) are the primary targets of aspirin and other non-steroidal
      anti-inflammatory drugs (NSAIDs), and thus enzymes of major interest to
      pharmacology, pharmacogenetics, and epidemiology. Genetic variants that affect
      enzyme function, or the interaction with NSAIDs, could alter drug response. We
      have screened the human COX1 gene coding regions of 48 African-American and 47
      Caucasian individuals using DNA sequencing. We identified 13 coding-region
      variants, of which seven were amino-acid substitutions, and further five intronic
      polymorphisms within 60bp of an exon. All nonsynonymous variants were confirmed
      in an independent Caucasian population (n=94 unrelated individuals). Most of the
      discovered polymorphisms were rare, although some variants resulting in amino
      acid changes occurred at appreciable frequency in at least one population (> or
      =4%: R8W, P17L, L237M). We used two sequence-homology-based software programs to
      predict the potential impact of these polymorphisms on COX1 function. The L237M
      substitution was predicted as most likely to alter protein function, whereas the
      glycine at position 230 may be specific to COX1 function. More detailed
      phenotypic characterizations of these COX1 polymorphisms remain to be undertaken.

PMID- 12402352
TI  - HIVdb: a database of the structures of human immunodeficiency virus protease.

PMID- 12402353
TI  - Influence of induced fit in the interaction of Bacillus subtilis trp RNA-binding
      attenuator protein and its RNA antiterminator target oligomer.
AB  - In the presence of excess tryptophan, tryptophan-activated TRAP (trp RNA-binding
      attenuator protein) binds to a specific target in the trp-leader transcript,
      which induces the formation of a transcription terminator and transcription halts
      in the leader region. In the absence of tryptophan, TRAP does not bind RNA, an
      antiterminator forms, and the operon is expressed. Although the ternary complex
      involving TRAP (Bacillus stearothermophilus), tryptophan, and the RNA target has
      recently been crystallized, efforts to obtain structural data for the apo-form of
      TRAP (in any species) have not been successful. We have used
      multidimensional/multinuclear nuclear magnetic resonance (NMR) spectroscopy to
      probe the structure-function relationship in the TRAP-activated system, and have
      obtained high-resolution multidimensional/multinuclear NMR spectra of TRAP in all
      three of its functional states: tryptophan-free or apo-TRAP, tryptophan-activated
      TRAP, and tryptophan-activated TRAP-RNA ternary complex. Chemical shift
      perturbation analysis of the NMR data clarifies the interpretation of results
      obtained from previous crystal studies. Results presented herein demonstrate that
      tryptophan binding induces an essential structural change in TRAP that supports
      high-affinity binding of the RNA target oligonucleotide.

PMID- 12402354
TI  - All-atom fast protein folding simulations: the villin headpiece.
AB  - We provide a fast folding simulation using an all-atom solute, implicit solvent
      method that eliminates the need for treating solvent degrees of freedom. The
      folding simulations for the 36-residue villin headpiece exhibit close
      correspondence with the landmark all-atom explicit solvent molecular dynamics
      simulations by Duan and Kollman (Duan & Kollman, Science 1998;282:740-744; Duan,
      Wang, & Kollman, Proc Natl Acad Sci USA 1998;95:9897-9902). Our implicit solvent
      approach uses only an entry-level single CPU PC with comparable throughput (
      approximately 4 nsec/day) to the DK supercomputer simulation. The native state is
      shown to be stable. Our 200-nsec folding trajectory agrees with the DK simulation
      in displaying a burst phase, a rapid initial shrinkage, a highly native-like
      binding site structure, and more.

PMID- 12402355
TI  - Nonatomic solvent-driven Voronoi tessellation of proteins: an open tool to
      analyze protein folds.
AB  - A three-dimensional Voronoi tessellation of folded proteins is used to analyze
      geometrical and topological properties of a set of proteins. To each amino acid
      is associated a central point surrounded by a Voronoi cell. Voronoi cells
      describe the packing of the amino acids. Special attention is given to
      reproduction of the protein surface. Once the Voronoi cells are built, a lot of
      tools from geometrical analysis can be applied to investigate the protein
      structure; volume of cells, number of faces per cell, and number of sides per
      face are the usual signatures of the protein structure. A distinct difference
      between faces related to primary, secondary, and tertiary structures has been
      observed. Faces threaded by the main-chain have on average more than six edges,
      whereas those related to helical packing of the amino acid chain have less than
      five edges. The faces on the protein surface have on average five edges within 1%
      error. The average number of faces on the protein surface for a given type of
      amino acid brings a new point of view in the characterization of the exposition
      to the solvent and the classification of amino acid as hydrophilic or
      hydrophobic. It may be a convenient tool for model validation.

PMID- 12402356
TI  - A new test set for validating predictions of protein-ligand interaction.
AB  - We present a large test set of protein-ligand complexes for the purpose of
      validating algorithms that rely on the prediction of protein-ligand interactions.
      The set consists of 305 complexes with protonation states assigned by manual
      inspection. The following checks have been carried out to identify unsuitable
      entries in this set: (1) assessing the involvement of crystallographically
      related protein units in ligand binding; (2) identification of bad clashes
      between protein side chains and ligand; and (3) assessment of structural errors,
      and/or inconsistency of ligand placement with crystal structure electron density.
      In addition, the set has been pruned to assure diversity in terms of protein
      ligand structures, and subsets are supplied for different protein-structure
      resolution ranges. A classification of the set by protein type is available. As
      an illustration, validation results are shown for GOLD and SuperStar. GOLD is a
      program that performs flexible protein-ligand docking, and SuperStar is used for
      the prediction of favorable interaction sites in proteins. The new CCDC/Astex
      test set is freely available to the scientific community
      (http://www.ccdc.cam.ac.uk).

PMID- 12402357
TI  - Equilibrium and kinetic folding of hen egg-white lysozyme under acidic
      conditions.
AB  - The equilibrium and kinetic folding of hen egg-white lysozyme was studied by
      means of circular dichroism spectra in the far- and near-ultraviolet (UV) regions
      at 25 degrees C under the acidic pH conditions. In equilibrium condition at pH
      2.2, hen lysozyme shows a single cooperative transition in the GdnCl-induced
      unfolding experiment. However, in the GdnCl-induced unfolding process at lower pH
      0.9, a distinct intermediate state with molten globule characteristics was
      observed. The time-dependent unfolding and refolding of the protein were induced
      by concentration jumps of the denaturant and measured by using stopped-flow
      circular dichroism at pH 2.2. Immediately after the dilution of denaturant, the
      kinetics of refolding shows evidence of a major unresolved far-UV CD change
      during the dead time (<10 ms) of the stopped-flow experiment (burst phase). The
      observed refolding and unfolding curves were both fitted well to a single
      exponential function, and the rate constants obtained in the far- and near-UV
      regions coincided with each other. The dependence on denaturant concentration of
      amplitudes of burst phase and both rate constants was modeled quantitatively by a
      sequential three-state mechanism, U<-->I<-->N, in which the burst-phase
      intermediate (I) in rapid equilibrium with the unfolded state (U) precedes the
      rate-determining formation of the native state (N). The role of folding
      intermediate state of hen lysozyme was discussed.

PMID- 12402358
TI  - Stability scale and atomic solvation parameters extracted from 1023 mutation
      experiments.
AB  - The stability scale of 20 amino acid residues is derived from a database of 1023
      mutation experiments on 35 proteins. The resulting scale of hydrophobic residues
      has an excellent correlation with the octanol-to-water transfer free energy
      corrected with an additional Flory-Huggins molar-volume term (correlation
      coefficient r = 0.95, slope = 1.05, and a near zero intercept). Thus, hydrophobic
      contribution to folding stability is characterized remarkably well by transfer
      experiments. However, no corresponding correlation is found for hydrophilic
      residues. Both the hydrophilic portion and the entire scale, however, correlate
      strongly with average burial accessible surface (r = 0.76 and 0.97,
      respectively). Such a strong correlation leads to a near uniform value of the
      atomic solvation parameters for atoms C, S, O/N, O(-0.5), and N(+0.5,1). All are
      in the range of 12-28 cal x mol(-1) A(-2), close to the original estimate of
      hydrophobic contribution of 25-30 cal x mol(-1) A(-2) to folding stability.
      Without any adjustable parameters, the new stability scale and new atomic
      solvation parameters yielded an accurate prediction of protein-protein binding
      free energy for a separate database of 21 protein-protein complexes (r = 0.80 and
      slope = 1.06, and r = 0.83 and slope = 0.93, respectively).

PMID- 12402359
TI  - FROST: a filter-based fold recognition method.
AB  - To assess the reliability of fold assignments to protein sequences, we developed
      a fold recognition method called FROST (Fold Recognition-Oriented Search Tool)
      based on a series of filters and a database specifically designed as a benchmark
      for this new method under realistic conditions. This benchmark database consists
      of proteins for which there exists, at least, another protein with an extensively
      similar 3D structure in a database of representative 3D structures (i.e., more
      than 65% of the residues in both proteins can be structurally aligned). Because
      the testing of our method must be carried out under conditions similar to those
      of real fold recognition experiments, no protein pair with sequence similarity
      detectable using standard sequence comparison methods such as FASTA is included
      in the benchmark database. While using FROST, we achieved a coverage of 60% for a
      rate of error of 1%. To obtain a baseline for our method, we used PSI-BLAST and
      3D-PSSM. Under the same conditions, for a 1% error rate, coverages for PSI-BLAST
      and 3D-PSSM were 33 and 56%, respectively.

PMID- 12402360
TI  - Data mining the protein data bank: residue interactions.
AB  - The protein databank contains a vast wealth of structural and functional
      information. The analysis of this macromolecular information has been the subject
      of considerable work in order to advance knowledge beyond the collection of
      molecular coordinates. This article presents a method that determines local
      structural information within proteins using mathematical data mining techniques.
      The mine program described returns many known configurations of residues such as
      the catalytic triad, metal binding sites and the N-linked glycosylation site; as
      well as many other multiple residue interactions not previously categorized.
      Because mathematical constructs are used as targets, this method can identify new
      information not previously known, and also provide unbiased results of typical
      structure and their expected deviations. Because the results are defined
      mathematically, they cannot indicate the biological implications of the results.
      Therefore two support programs are described that provide insight into the
      biological context for the mine results. The first allows a weighted RMSD search
      between a template set of coordinates and a list of PDB files, and the second
      allows the labeling of a protein with the template results from mining to aid in
      the classification of this protein.

PMID- 12402361
TI  - Docking of non-nucleoside inhibitors: neotripterifordin and its derivatives to
      HIV-1 reverse transcriptase.
AB  - The docking of small molecules to proteins has played an important role in the
      understanding of drug/receptor interactions. An important drug/receptor
      interaction is between non-nucleoside inhibitors of HIV-1 RT and the non
      nucleoside binding pocket. We report the results of docking calculations in which
      we have docked known and proposed non-nucleoside reverse transcriptase inhibitors
      to the type 1 virus. The proposed NNRTIs dock in a similar position and
      orientation as known inhibitors. In addition, we observe a linear correlation
      between the calculated interaction energy and EC50 for the inhibitors, suggesting
      that the docked structure orientation and the interaction energies are
      reasonable. Two hydrogen bonds between nevirapine and RT (3HVT and 1VRT) are
      observed and are reproduced across different docking schemes. Since we used two
      different HIV-1 RT crystal structures (3HVT and 1VRT), which are at different
      levels of resolution (2.9 and 2.2 A, respectively), we propose that structures
      with resolutions better than 3 A can be used to produce reasonable docking
      results.

PMID- 12402362
TI  - Solution structure of the DNA-binding domain of interleukin enhancer binding
      factor 1 (FOXK1a).
AB  - Interleukin enhancer binding factor (ILF) binds to the interleukin-2 (IL-2)
      promoter and regulates IL-2 gene expression. In this study, the 3D structure of
      the DNA-binding domain of ILF was determined by multidimensional NMR
      spectroscopy. NMR structure analysis revealed that the DNA-binding domain of ILF
      is a new member of the winged helix/forkhead family, and that its wing 2 contains
      an extra alpha-helix. This is the first study to report the presence of a C
      terminal alpha-helix in place of a typical wing 2 in a member of this family.
      This structural difference may be responsible for the different DNA-binding
      specificity of ILF compared to other winged helix/forkhead proteins. Our deletion
      studies of the fragments of ILF also suggest that the C-terminal region plays a
      regulatory role in DNA binding.

PMID- 12402363
TI  - Ligand specificity and ligand-induced conformational change in gal repressor.
AB  - Gal repressor (GalR) binds D-galactose, which is responsible for lifting of
      repression of the gal operon. Proton T1 measurements of alpha- and beta-anomers
      of galactose as a function of gal repressor show preferential binding of the beta
      anomer. The beta-anomer was isolated by high-performance liquid chromatography
      and was shown to bind tightly to GalR. Calorimetry was used to determine enthalpy
      changes at several temperatures. Heat capacity change was found to be positive,
      indicating that a significant amount of hydrophobic surface area was exposed upon
      galactose binding. Bis-ANS binding to GalR is significantly enhanced in the
      presence of a saturating amount of galactose, indicating additional exposure of
      hydrophobic surfaces. We propose that the galactose-induced conformational change
      involves the opening of the two subdomains, which may disrupt protein-protein
      interactions responsible for repression.

PMID- 12402365
TI  - Kinase inhibitors and the case for CH...O hydrogen bonds in protein-ligand
      binding.
AB  - Although the hydrogen bond is known to be an important mediator of intermolecular
      interactions, there has yet to be an analysis of the role of CH...O hydrogen
      bonds in protein-ligand complexes. In this work, we present evidence for such
      nonstandard hydrogen bonds from a survey of aromatic ligands in 184 kinase
      crystal structures and 358 high-resolution structures from the Protein Data Bank.
      CH groups adjacent to the positively charged nitrogen of nicotinamide exhibit
      geometric preferences strongly suggestive of hydrogen bonding interactions, as do
      heterocyclic CH groups in kinase ligands, while other aromatic CH groups do not
      exhibit these characteristics. Ab initio calculations reveal a considerable range
      of CH...O hydrogen bonding potentials among different aromatic ring systems, with
      nicotinamide and heterocycles preferred in kinase inhibitors showing particularly
      favorable interactions. These results provide compelling evidence for the
      existence of CH...O hydrogen bonds in protein-ligand interactions, as well as
      information on the relative strength of various aromatic CH donors. Such
      knowledge will be of considerable value in protein modeling, ligand design, and
      structure-activity analysis.

PMID- 12402364
TI  - Origins of protein denatured state compactness and hydrophobic clustering in
      aqueous urea: inferences from nonpolar potentials of mean force.
AB  - Free energies of pairwise hydrophobic association are simulated in aqueous
      solutions of urea at concentrations ranging from 0-8 M. Consistent with the
      expectation that hydrophobic interactions are weakened by urea, the association
      of relatively large nonpolar solutes is destabilized by urea. However, the
      association of two small methane-sized nonpolar solutes in water has the opposite
      tendency of being slightly strengthened by the addition of urea. Such size
      effects and the dependence of urea-induced stability changes on the configuration
      of nonpolar solutes are not predicted by solvent accessible surface area
      approaches based on energetic parameters derived from bulk-phase solubilities of
      model compounds. Thus, to understand hydrophobic interactions in proteins, it is
      not sufficient to rely solely on transfer experiment data that effectively
      characterize a single nonpolar solute in an aqueous environment but not the
      solvent-mediated interactions among two or more nonpolar solutes. We find that
      the m-values for the rate of change of two-methane association free energy with
      respect to urea concentration is a dramatically nonmonotonic function of the
      spatial separation between the two methanes, with a distance-dependent profile
      similar to the corresponding two-methane heat capacity of association in pure
      water. Our results rationalize the persistence of residual hydrophobic contacts
      in some proteins at high urea concentrations and explain why the heat capacity
      signature (DeltaC(P)) of a compact denatured state can be similar to DeltaC(P)
      values calculated by assuming an open random-coil-like unfolded state.

PMID- 12402366
TI  - Crystal structure of phosphoglucose isomerase from pig muscle and its complex
      with 5-phosphoarabinonate.

PMID- 12402367
TI  - Rapid prenatal detection of down and edwards syndromes by fluorescent polymerase
      chain reaction with short tandem repeat markers.
AB  - Chromosome analysis is the main tool for the prenatal diagnosis of trisomies but
      requires great technical expertise and time consuming manual procedures.
      Recently, alternative methods, which provide rapidity and accuracy, without
      culture, have been developed for pregnant women requiring rapid decisions for
      termination. In this study, multiplex fluorescent polymerase chain reactions (F
      PCRs) were performed by the concurrent use of short tandem repeat (STR) markers
      specific for the chromosomes 18 and 21. The aims of this investigation were to
      evaluate the clinical usefulness of this assay for rapid prenatal detection of
      Down and Edwards syndromes and then to accumulate the basic data for clinical
      application. F-PCRs were carried out using DNA extracted from amniotic fluid and
      peripheral blood derived from 47 normal karyotypes, 23 Down and 8 Edwards
      syndrome patients. Fluorescent intensities of the PCR products were then
      calculated. Normal samples displayed diallelic peaks for each STR marker.
      Reference ranges of peak area ratios were 1.0 - 1.4 for D21S11, 1.0 - 1.5 for
      D21S1412 and 1.0 - 1.3 for D18S535 and D18S51. Down and Edwards syndromes showed
      characteristic triallelic peaks of similar intensity corresponding to 3 different
      alleles or characteristic diallelic peaks. The sensitivity, specificity and
      efficiency of the assay for detecting Down and Edwards syndromes were 96.7%,
      93.6% and 94.8%, respectively. In conclusion, these results show that F-PCR
      rapidly detects Down and Edwards syndromes with high accuracy and provides normal
      reference ranges of peak area ratios. However, the presence of false results (4
      out of 77 cases) and the possibility of anomalies other than trisomies 21 and 18
      do not permit F-PCR to substitute for chromosome analysis.

PMID- 12402368
TI  - Tocolytic Effect of Morphine via Increased Metabolic Clearance of Oxytocin in the
      Baboon.
AB  - Morphine is known to inhibit nocturnal uterine contractions in several animal
      models, and oxytocin is known to be a primary causative factor of uterine
      contractions. The purpose of the present study was to determine the tocolytic
      effect of morphine in relation to the pharmacokinetics of oxytocin, after a bolus
      injection of oxytocin. The metabolism of oxytocin was investigated during the
      third trimester in baboons. Four animals were placed on a tether system with
      venous and arterial access, including continuous uterine monitoring. Plasma
      oxytocin levels were determined by radioimmunoassay after extraction with
      petroleum ether/acetone. Morphine consistently increased the metabolic clearance
      rate of oxytocin in all four animals (p < 0.05) and this was in accordance with
      suppressed uterine contractions. We conclude that morphine could be used as an
      inhibitor of nocturnal uterine contractions, and that this is caused by the
      morphine induced increased metabolic clearance rate of oxytocin.

PMID- 12402369
TI  - Acute bacterial meningitis as a complication of otitis media and related
      mortality factors.
AB  - The aim of this study was to evaluate the characteristics of patients with acute
      bacterial meningitis (ABM) developed secondary to acute and chronic otitis media
      (OM). Between 1991 and 2001, among 269 adult patients with ABM, 56 who were
      secondary to OM were included in the study. We reviewed the charts of patients
      who were diagnosed as ABM following acute or chronic OM. Risk factors associated
      with mortality were determined by using a logistic regression model. The mean age
      of the patients, 38 male and 18 female, was 25.8 +/- 10.8 years (range 14 - 65).
      Forty-four of these cases (79%) have had chronic OM, of whom 19 (43% of the 44)
      have also had chronic mastoiditis and 12 (27% of the 44) acute OM. Twenty-three
      patients (41%) died, during either hospitalization or the follow-up period.
      Univariate analysis revealed comatose mental status on admission, inappropriate
      antibiotic treatment before admission, and elevated erythrocyte sedimentation
      rate (ESR) as significant risk factors for mortality. In multifactorial analysis,
      comatose mental status (OR=42.5, CI=6.4-280.1, p=0.001) and elevated ESR (OR=1.0,
      CI=1.01-1.07; p=0.005) remained as significant predictors for mortality. In
      conclusion, the primary sources of infection leading to the development of ABM
      should be investigated carefully to reduce the morbidity and mortality rates. It
      is hoped that this study will raise awareness among general practitioners and
      otolaryngologists concerning the role of ABM as one of the most important
      complications of OM.

PMID- 12402370
TI  - Medication and symptom management education program for the rehabilitation of
      psychiatric patients in Korea: the effects of promoting schedule on self-efficacy
      theory.
AB  - An effective rehabilitation program was developed for psychiatric patients' self
      management of medication and symptoms. The rehabilitation program was designed to
      allow the patients to understand their illness, cope with their medical regimen,
      and prevent a relapse by recognizing any of the symptoms when they recur. This
      study consisted of three phases. The first phase was to explore the extent and
      the specific mental health needs of psychiatric patients. Data was obtained from
      82 subjects who had symptoms of a mental illness including schizophrenia, bipolar
      disorders, and delusional disorder. They had received medication instruction
      during their hospitalization. The subjects were at the time outpatients in a
      psychiatric hospital. In the second phase, the researchers developed an
      educational program focused on coping with the residual and relapse warning
      signs, managing the drug side effects, medication compliance, and daily routines,
      according to the information acquired in the first step. The developed program
      includes the self-efficacy method reported by Bandura, including manuals and
      videotapes focusing on real life situations, small group discussions, and
      telephone coaching. Finally, the researchers investigated the effects of this
      program. Thirty-eight patients were selected for this study, 18 in the
      experimental program and 20 as controls. The diagnoses were same as those with
      the first step. The results showed that the subjects who attended this
      educational program reported significantly more improvement in self-efficacy
      (p=0.014) and medication compliance (p= 0.005), and significantly less relapse
      warning symptom scores (p=0.000) than the controls. In conclusion, these
      instructional materials will be beneficial for medication and symptom management
      in rehabilitating psychiatric patients in Korea. In addition, the materials may
      be a useful psychoeducational resource for professionals in the field of clinical
      psychiatry.

PMID- 12402371
TI  - Hemodynamic analysis of coronary circulation in angulated coronary stenosis
      following stenting.
AB  - The present study in angulated coronary stenosis used human in vivo hemodynamic
      parameters and computed simulation, both qualitatively and qualitatively, to
      evaluate the influence of flow velocity and wall shear stress (WSS) on coronary
      atherosclerosis, the changes of hemodynamic indices following coronary stenting,
      and their effect on evolving in-stent restenosis. Initial and follow-up coronary
      angiographies in patients with angulated coronary stenosis were performed (n=60).
      The optimal degree of coronary stenting for angulated coronary stenosis had two
      models, the less than 50% angle changed group (model 1, n=33) and the more than
      50% angle changed group (model 2, n=27). This angle change was based on the
      percentage change of vascular angle between pre- and post-intracoronary stenting.
      The flow-velocity wave obtained from in vivo intracoronary Doppler study data was
      used for in vitro numerical simulation. Spatial and temporal patterns of the flow
      velocity vector and recirculation area were drawn throughout the selected segment
      of coronary models. WSS of pre- and post-intracoronary stenting was calculated
      from three-dimensional computer simulation. As results, follow-up coronary
      angiogram demonstrated significant difference in the percentage of diameter
      stenosis between the two groups (group 1: 40.3 +/- 30.2 vs. group 2: 25.5 +/-
      22.5%, p < 0.05). Negative shear area on 3D simulation, which is consistent with
      the re-circulation area of flow vector, was noted on the inner wall of the post
      stenotic area before stenting. The negative WSS disappeared after stenting. High
      spatial and temporal WSS before stenting fell within the range of physiologic WSS
      after stenting. This finding was more prominent in model 2 (p < 0.01). The
      present study suggests that hemodynamic forces exerted by pulsatile coronary
      circulation, termed WSS, might affect the evolution of atherosclerosis within the
      angulated vascular curvature. Moreover, geometric characteristics, such as the
      angular difference between pre- and post- intracoronary stenting might define
      optimal rheologic properties for vascular repair after stenting.

PMID- 12402372
TI  - Low grade MALT lymphoma of the stomach: treatment outcome with radiotherapy
      alone.
AB  - In order to evaluate the role of radiation therapy in the management of low-grade
      mucosa-associated lymphoid tissue lymphoma of the stomach (MLS), in patients with
      no evidence of Helicobacter pylori (H. pylori) or who had not responded to H.
      pylori eradication treatment, we analyzed the treatment outcome of patients who
      had received radiotherapy alone. Between Jan 1995 and May 2001, 6 patients with
      low- grade MLS were treated with radiotherapy alone. The median radiation dose
      was 30.6 Gy (range; 30 - 39 Gy) in a daily fractions of 1.5 - 1.8 Gy. Each
      patient had an endoscopic esophago-gastro-duodenoscopy with biopsy, 4 weeks after
      the completion of radiotherapy and every 6 months thereafter. A complete response
      was obtained in all patients. All patients were followed-up without evidence of
      disease, and no patient suffered a relapse. There was neither perforation nor
      hemorrhage of the stomach in any of the patients. No renal or hepatic toxicity
      were noted, and no secondary malignancies developed. In conclusion, radiotherapy
      should be considered as the preferred treatment method for low-grade MLS, in
      patients with no evidence of H. pylori infection, or who do not respond to
      antibiotic therapy, due to the significant benefits in gastric preservation and
      low morbidity.

PMID- 12402373
TI  - Instillation of normal saline before suctioning in patients with pneumonia.
AB  - This study was conducted to investigate the effects of a no saline, a 2 ml and a
      5 ml saline instillation prior to endotracheal suctioning on oxygen saturation in
      patients with pneumonia. The subjects in this study were 16 pneumonic patients
      with a tracheotomy tube, who had been admitted to the neuro-surgical intensive
      care unit at a university hospital in Seoul Korea. All three (0, 2 and 5 ml)
      saline instillation methods were applied to the 16 patients. The methods were
      randomly assigned to each patient. Each of the instillation methods was applied
      in a four-step sequence: 1) recording the level of oxygen saturation (baseline
      levels), 2) instilling normal saline, 3) supplying oxygen and suctioning, and 4)
      recording the level of oxygen saturation. The oxygen saturation was evaluated
      using pulse oximetry. The recovery times for oxygen saturation to return to
      baseline levels following suctioning were, just after suctioning, 45 seconds
      after suctioning and in excess of 5 minutes with 0, 2 and 5 ml saline
      instillations, respectively. Instillation of normal saline before suctioning
      could have an adverse effect on oxygen saturation, and should be used carefully
      as a routine intervention in patients who have pneumonia.

PMID- 12402374
TI  - Comparison of skin prick test results between crude allergen extracts from foods
      and commercial allergen extracts in atopic dermatitis by double-blind placebo
      controlled food challenge for milk, egg, and soybean.
AB  - Skin Prick Test (SPT's) are performed to identify the causes of allergy. However,
      low diagnostic accuracy is a limitation to SPT, for which many possible causes
      have been suggested. The protein composition and allergenicity of crude allergen
      extracts from foods and commercial allergen extracts for SPT were analyzed.
      Clinical significances of SPT using crude allergen extracts from foods were
      compared with those using commercial allergen extracts. A total of 292 atopic
      dermatitis patients were involved in this study. Crude allergen extracts were
      prepared from milk, egg white, egg yolk, and soybean. The protein composition of
      food allergen extracts and commercial allergen extracts of milk, whole egg,
      white, egg yolk, and soybean were compared by SDS-PAGE. The allergenicity was
      tested by the immunoblotting method using immune sera. SPTs were performed using
      crude and commercial allergen. Double-blind placebo- controlled food challenge
      (DBPCFC) was performed to verify the SPT results and to compare the clinical
      significance of crude and commercial allergen extracts. Protein composition
      differed markedly between crude and commercial allergen extracts. By
      immunoblotting, crude and commercial allergen extracts showed different
      allergenicity. The SPT results using crude and commercial allergen extracts
      showed significant differences. The prevalence of milk, egg and soybean allergy
      was over 35% in atopic dermatitis. The accuracy of SPT using crude allergen
      extracts from foods was significantly higher than that using commercial allergen
      extracts. In the case of soybeans, the result of SPT using commercial allergen
      extract was clinically insignificant for the prediction of soybean allergy. The
      source of allergen extract was very important for the appropriate SPT in food
      allergy. The accuracy of SPT might be improved using the appropriate allergen
      source for food allergy.

PMID- 12402375
TI  - The effect of cold air application on intra-articular and skin temperatures in
      the knee.
AB  - The present study was performed to investigate the effect on the skin and the
      intra-articular structures of 5-minutes of cold air application. During and after
      5 minutes of cold air application on 20 healthy subjects, the skin and intra
      articular temperatures were measured by means of an infrared thermogram and a
      digital k-wire probe, respectively. The results showed that 1) Skin temperature
      dropped very rapidly by a total of 22.1 degrees C after 5 minutes of cold air
      application. 2) Intra-articular temperature dropped by 3.9 degrees C after 5
      minutes of cold air application. 3) Two hours after the start of treatment with
      cold air, intra-articular temperatures had still not returned to their baseline
      values (p < 0.01). 4) The baseline skin temperature and the baseline intra
      articular temperature were significantly correlated r=0.51 (p < 0.05). However,
      there was no significant correlation between the skin temperature change and the
      intra-articular temperature change after 5 minutes and after two hours of cold
      air application. Finally, 5) a significant correlation r=-0.72 (p < 0.01) between
      the body mass index and the baseline skin temperatures was found. There was no
      significant correlation between the body mass index and the temperature changes,
      at the skin or in the knee joint, either during or after cryotherapy (p > 0.05).

PMID- 12402376
TI  - Anatomic motor point localization for the treatment of gastrocnemius muscle
      spasticity.
AB  - The location of the motor point of the gastrocnemius muscle was accurately
      defined relative to surrounding bony landmarks to facilitate the approach to the
      nerve of the gastrocnemius muscle during treatment for gastrocnemius muscle
      spasticity. Anatomic dissection of 40 cadaver knees was undertaken for
      morphometric measurement. The distances from the epicondyle of the femur to the
      motor branch, and from the motor branch to the motor point of the nerve to the
      medial head of the gastrocnemius muscle were 3.68 +/- 11.44 mm, and 37.79 +/-
      7.80 mm, respectively; while those of the nerve to lateral head of the
      gastrocnemius muscle were 4.45 +/- 11.96 mm, and 32.16 +/- 4.64 mm, respectively.
      The tibial nerve lay 44.57 +/- 5.45% and 56.30 +/- 4.73% from the lateral margins
      of the epicondyle and the fibular head, respectively. Careful consideration of
      the morphometry of the motor point of the gastrocnemius muscle may provide
      accurate anatomical guidance, and hence reduce complications during the chemical
      blockage of these nerves.

PMID- 12402377
TI  - Operative treatment for isolated distal ulnar shaft fracture.
AB  - This study retrospectively evaluated the effectiveness of an open reduction and
      internal fixation of a tension band wiring technique for treating displaced or
      unstable comminuted distal ulnar shaft fractures without a radial fracture. Ten
      patients were treated for an isolated distal ulnar shaft fracture. There were 6
      cases of a fracture 2.5 cm below the lower end of the ulna, and 4 cases with the
      fracture being 2.5 cm to 5 cm away from the lower end of the ulna. The authors
      classified the fractures of the distal ulnar into 3 types: a type I-simple
      fracture, a type II-comminuted fracture without a distal radioulnar joint (DRUJ)
      involvement, and a type III- comminuted fracture with DRUJ involvement. There
      were 3 cases of a type I fracture, 4 of type II and 3 of type III. The open
      reduction and internal fixation using tension band wiring were performed in 10 of
      these cases. After the operation, the wrist was placed in a cast for six weeks
      before active movement was allowed. The clinical results were excellent in 7
      cases, good in 2 and poor in 1. In conclusion, tension band wiring surgery is
      recommended for treating an isolated distal ulnar with unreduced displaced
      fractures, in a comminuted fracture that cannot be maintained by a closed
      reduction and when there is the potential encroachment of fracture fragments in
      the DRUJ.

PMID- 12402378
TI  - Evaluation of a bio-impedance method for measuring human arm movement.
AB  - This study proposes a new method for measuring upper limb movement using a bio
      impedance technique. Bio-impedance and joint angle were simultaneously measured
      during the wrist and elbow movements of 12 normal subjects. The joint angles of
      the wrist and elbow were estimated by measuring the bio-impedances of the forearm
      and upper arm, respectively. Although the measured bio-impedances on upper limbs
      varied among individuals, changes in the bio-impedances and joint angles of the
      wrist and elbow during their extension and flexion were very highly correlated,
      having correlation coefficients of 0.96 +/- 0.04 and -0.98 +/- 0.02,
      respectively. The reproducibilities of wrist and elbow bio-impedance changes were
      2.1 +/- 1.0% and 1.8 +/- 1.0%, respectively. Since the proposed method is not
      restricted by size or the duration of measurements, it is expected to be useful
      for the analysis of athletic movement.

PMID- 12402379
TI  - Treatment of female urethral syndrome refractory to antibiotics.
AB  - Various methods of treatment, other than antibiotic therapy, have been proposed
      for the treatment of female urethral syndrome; however, the results of these
      treatment methods are disappointing, due perhaps to the use of the wrong
      treatment approach. The aim of this study was to evaluate the effectiveness of
      external sphincter relaxant and biofeedback (BFB) with electrical stimulation
      therapy (EST) in patients who do not respond well to antibiotics. One hundred and
      five patients with a diagnosis of female urethral syndrome were entered into this
      study. Antibiotics were given as a first-line therapy for about 3 months. In
      cases of recurrent or incurable urethral syndrome, antibiotic therapy combined
      with external sphincter relaxant or BFB with EST were performed. External
      sphincter relaxant group was composed of 31 patients (29.5%) who showed
      functional urethral obstruction. Biofeedback group was composed of 41 patients
      (39.0%) who had severe pain or discomfort with irritative voiding symptoms.
      Subjective symptom was measured before and after therapy using the Bristol Female
      Lower Urinary Tract Symptoms questionnaire. Thirty-three patients (31.4%) were
      treated with antibiotic therapy alone and 7 (21.2%) of these patients recurred.
      The symptom score of this group changed from 10.51 to 2.85. In the antibiotics
      plus external sphincter relaxant group (N=31), the symptom score changed from
      12.39 to 3.96. Five (16.1%) of these patients recurred and 3 of these 5 underwent
      urethral dilatation. In the antibiotics plus biofeedback group (N=41), the
      average urinary frequency changed from 12.2 to 7.7 times a day and nocturia
      changed from 2.4 to 0.6 times a night. The symptom score improved from 15.22 to
      4.69 and the overall satisfaction rate was 87.8% (41.5%: very satisfied, 46.3%:
      satisfied, 12.2%: no response). Female urethral syndrome is not due to a single
      factor but is a complex disease due to various combined symptoms and mechanisms.
      This condition needs to be treated with an appropriate treatment protocol. We
      believe that satisfactory results could be obtained in female urethral syndrome,
      which has shown poor prognosis until now, by appropriately combining treatment
      methods, which include the use of external sphincter relaxants, biofeedback
      therapy and bladder training, according to indication, and depending on whether
      symptoms continue after initial antibiotic therapy.

PMID- 12402380
TI  - Sensory neuronal change after intravesical electrical stimulation in spinailized
      rat.
AB  - The clinical benefits of intravesical electrical stimulation (IVES) in patients
      with increased residual urine or reduced bladder capacity have been reported.
      However, studies on the underlying mechanism of IVES has been limited to the
      Adelta afferent and parasympathetic neurons. This study investigated the changes
      in the calcitonin gene-related peptide (CGRP), substance P (SP), and nitric oxide
      synthase (NOS) expression in the thoracolumbar and lumbosacral dorsal root
      ganglia (DRG) of spinalized rats to determine the effect of IVES on the C fiber
      afferent nerve. Forty Sprague-Dawley rats were divided into normal controls
      (n=10); IVES treated normal rats (n=10), spinalized rats (n=10), and IVES treated
      spinalized rats (n=10). IVES was performed for 2 weeks (5 days a week). IVES was
      started 3 weeks after spinalization in the spinalized animals. All animals had
      the DRG removed at the thoracolumbar (T13-L2) and lumbosacral (L5-S1) level.
      Changes in the CGRP, SP and n-NOS levels at the DRG were measured by western-blot
      analysis. The relative density of the CGRP and SP following spinalization was
      significantly higher compared to the controls in both the T13-L2 and L5-S1 DRG.
      However, IVES in the spinalized rat significantly decreased the relative density
      of the CGRP and SP compared to the rats with spinalization alone. A significant
      increase in the relative density of n-NOS was detected in the L5-S1 DRG following
      spinalization. However, the density of n-NOS was significantly lower after IVES
      in both the T13-L2 and L5-S1 DRGs. In conclusion, IVES significantly reduced the
      CGRP, SP and n-NOS levels in the DRG of spinalized rats. CGRP, SP and n-NOS are
      the main factors that contribute to the hyperexcitability of the micturition
      reflex after spinal cord injury. These results suggest that the bladder C fiber
      afferent is also involved in modulating the micturition reflex by IVES.

PMID- 12402381
TI  - Expression patterns of cytokines and chemokines genes in human hepatoma cells.
AB  - Various cytokines and chemokines play a role in carcinogenesis. However, no study
      has previously been undertaken to investigate comprehensively the expressions of
      cytokines and chemokines in hepatoma cells. In this study, we determined which
      cytokines and chemokines are expressed in hepatoma cells. Recently, it was
      reported that the expressions of several chemokines could be increased by Fas
      stimulus in many normal and cancer cells. Therefore, we also investigated whether
      chemokines expression is regulated by Fas ligation. To address this issue, we
      performed RNase protection assays upon 13 cytokines and 8 chemokines genes in 10
      human hepatoma cell lines, comprising 8 hepatitis B virus (HBV)-associated
      hepatoma cell lines. Transforming growth factor-beta2 (TGF-beta2) was found to be
      expressed in 8 HBV-associated hepatoma cell lines, and to be potently expressed
      in 5 cell lines; however, the mRNA expressions of interleukin-10 (IL-10), IL-12,
      interferon-gamma(IFN-gamma) and tumor necrosis factor-alpha(TNF-alpha) were not
      detected in any cell lines examined. Among the chemokines investigated in this
      study, IL-8 was expressed by 8 HBV- associated hepatoma cell lines, and monocyte
      chemoattractant protein-1 (MCP-1) by 7 HBV-associated hepatoma cell lines.
      However, the mRNA expressions of macrophage inflammatory protein-1alpha(MIP
      1alpha), MIP-1beta, interferon-inducible protein-10 (IP-10), RANTES, lymphotactin
      and I-309 were either very weak or undetectable. Fas ligation did not increase
      chemokines expression in hepatoma cells. Conclusively, TGF-beta2, IL-8 and MCP-1
      were overexpressed in HBV-associated hepatoma cells, and the expressions of
      chemokines were not increased by Fas ligation in human hepatoma cells.

PMID- 12402382
TI  - Metastatic follicular thyroid carcinoma to the thymus in a 35-year-old woman.
AB  - Clinically detectable metastatic follicular thyroid carcinoma to the thymus is
      very rare in the literature and sometimes confused with false positive uptake of
      Iodine(131) (I(131)) in the normal thymus or hilar lymph node. The authors report
      a 35-year-old woman with metastatic follicular carcinoma to the thymus. She
      underwent total thyroidectomy and I(131) ablation with 200 mCi. Six months later,
      a follow-up I(131) whole body scan showed continued radioactive iodine uptake in
      the retrosternal area and the serum thyroglobulin level remained continuously
      elevated with levothyroxine suppression therapy (22.3 and 36.4 ng/ml, 6 and 10
      months after total thyroidectomy, respectively). CT scan of the chest revealed
      several aggregated cystic lesions in the retrosternal mediastinum, suspected to
      represent mediastinal metastasis. The surgically resected retrosternal mass was
      confirmed as a metastatic follicular carcinoma to the thymus. After surgical
      excision, the serum thyroglobulin level was below 1.0 ng/ml and I(131) whole body
      scan showed no radioactive iodine uptake in the mediastinum. The patient showed
      no evidence of recurrence after excision of thymic metastasis during one year of
      0.2 mg levothyroxine suppression therapy. We report a case of metastatic
      follicular thyroid carcinoma to the thymus without bone or pulmonary involvement.

PMID- 12402383
TI  - Stress-induced cardiomyopathy presenting as acute myocardial infarction.
AB  - Stress-induced cardiomyopathy is described as an acute cardiomyopathy that occurs
      under the influence of an excessive level of catecholamine related to intense
      emotional stress. A 64-year-old woman presented with symptoms of acute myocardial
      infarction after emotional upset, but her coronary angiographic findings were
      revealed to be normal. Diffuse T wave inversions were observed in her
      electrocardiograms with akinetic wall motions sparing the basal segments in her
      left ventriculography. After four months, her electrocardiogram and
      echocardiogram findings had completely returned to normal. The precise diagnosis
      of this acute cardiomyopathy must be emphasized because it can initially be
      misdiagnosed as acute coronary syndromes. However in complete contrast to acute
      myocardial infarction, it has a rapid and favorable recovery with hardly any
      sequelae after a few months.

PMID- 12402384
TI  - Congenital fibrous epulis in the infant.
AB  - Congenital fibrous epulis is an extremely rare tumor of infancy. It is a benign
      gingival tumor and generally seen in maxillary alveolar crest and its etiology
      remains the subject of debate. Congenital fibrous epulis could be considered a
      hamartomatous lesion. Histologically it does not show the closely packed large
      granular cells necessary for the diagnosis of an ordinary congenital epulis.
      Instead, it consists of irregular bundles of collagenous connective tissue,
      varying numbers of fusiform cells with oval or fusiform shaped nuclei and mild
      subepithelial inflammatory infiltration with tiny blood vessels and in this case
      a woven bone spicule in the deep area. Recommended treatment for this tumor is
      simple excision. We report upon a case of congenital fibrous epulis in a male
      infant and discuss the clinical features, histopathologic findings, and surgical
      treatment.

PMID- 12402385
TI  - Benign peripheral nerve sheath tumor of the tongue.
AB  - Peripheral nerve sheath tumors rarely occur in the oral cavity and include
      neurofibroma, schwannoma, and palisaded encapsulated neuroma. We report a rare
      case of benign peripheral nerve sheath tumor of the tongue. This tumor was a 0.8
      X 0.5 cm sized, firm mass on the left lateral surface of the tongue.
      Histologically, this mass was composed of well- circumscribed variable sized
      nodules, which consisted of moderately cellular spindle cells with vague nuclear
      palisading and a small amount of fibrous tissue. Most of the tumor cells were
      strongly positive for S-100 protein, but negative for epithelial membrane antigen
      on immunohistochemistry. No axons were found by immunostaining for neurofilament
      and Bodian stains. In addition, the surrounding, compressed, fibrous tissue
      showed rare EMA- positive cells. The present case might be a rare case of
      neurofibroma arising in the tongue, although immunohistochemical and special
      stains did not support such a diagnosis.

PMID- 12402386
TI  - Spinal cord compression by primary amyloidoma of the spine.
AB  - In this report, we presented a case of solitary spine amyloidoma, its clinical
      and radiological findings and management, and a review of the literature on
      vertebral amyloidosis.

PMID- 12402388
TI  - Dinara   the mountain of extraordinary beauty.

PMID- 12402387
TI  - Pneumatosis intestinalis associated with immune-suppressive agents in a case of
      minimal change disease.
AB  - We report treatment of a 38-year-old man with minimal change disease (MCD) who
      developed pneumatosis intestinalis (PI) during administration of immune
      suppressive agents. His immunosuppressive medication had been tapered to 15
      mg/day of prednisolone. MCD was steroid-resistant type. Abdominal examination and
      laboratory studies were not clinically remarkable. Radiologic findings were
      consistent with PI. Abnormal air accumulation was noted in the bowel, peritoneum,
      mediastinum and retroperitoneum. Conservative therapy with oxygen and
      metronidazole improved the PI symptoms. In 1993, a case of PI with nephrotic
      syndrome following steroid treatment was reported in Japan. However this is only
      the second case reported in the literature, and the first in English.

PMID- 12402389
TI  - Molecular and genetic mechanisms of lymphomagenesis.
AB  - The analysis of the molecular characteristics of immunoglobulin or T-cell
      receptor genes of lymphomas allows us to determine the cell origin in terms of
      pre- or postgerminal center cells. Most molecular oncogenic events are associated
      with the activity of otherwise physiologically active enzymatic and protein
      machinery for Ig/TCR gene modeling, where normal molecular sequence of events can
      be disrupted, leading to pathogenic molecular lesion and neoplastic cell
      transformation. Our current knowledge on the molecular and genetic basis of
      neoplastic transformation of lymphoid cells resulting in clinical phenotype of
      malignant lymphoma is further reviewed, and basic specific molecular mechanisms
      of Ig/TCR gene deregulation are presented, as well as recent achievements in
      molecular genetic profiling of malignant lymphoma.

PMID- 12402390
TI  - The World Health Organization classification of lymphomas.
AB  - The Revised European-American Classification of Lymphoid Neoplasms (REAL)
      classification has been validated by a multi-institutional study, and project
      data showed that it is both reproducible and clinically relevant. The new World
      Health Organization (WHO) Classification of Neoplastic Diseases of Hematopoietic
      and Lymphoid Tissues, as a joint project of the Society of Hematopathology and
      European Association of Hematopathologists, is an update of the REAL
      classification, with minor changes based on newly available information. We
      analyzed the incidence of different histological types of non-Hodgkin s lymphomas
      diagnosed in Zagreb University Hospital Center, which were reclassified according
      to the WHO classification. Furthermore, we present a conceptual grouping of
      lymphomas into four categories (indolent, aggressive, highly aggressive, and
      localized indolent).

PMID- 12402391
TI  - Diffuse large B-cell lymphoma and its variants.
AB  - According to the World Health Organization classification of neoplastic diseases
      of the hematopoietic and lymphoid tissues, diffuse large B-cell lymphoma
      comprises about 40% of adult cases of non-Hodgkin s lymphoma. It consists of the
      following morphological variants: 1) centroblastic (with or without
      multilobulated nuclei); 2) immunoblastic (>90% of immunoblasts); 3) T
      cell/histiocytes rich; and 4) anaplastic. Rare morphological variants  
      plasmablastic type, mediastinal (thymic) diffuse large B-cell lymphoma,
      intravascular, and primary effusion B-cell lymphoma   are considered distinct
      variants of diffuse large B-cell lymphoma due to their unique topographic
      presentation and clinical behavior, as well as immunophenotypic and genetic
      characteristics. T-cell/histiocyte-rich B-cell lymphoma is morphologically
      characterized by up to 25% of large neoplastic B cells and 75-90% of reactive,
      non-neoplastic T cells. Mediastinal (thymic) diffuse large B-cell lymphoma is
      considered a subtype of diffuse large B-cell lymphoma arising in the mediastinum,
      with distinctive morphological, immunohistochemical, genotypic, and clinical
      features. Mediastinal diffuse large B-cell lymphoma is an aggressive disease with
      poor outcome, which probably originates from thymic B cells at the terminal stage
      of differentiation. During the 1997-2001 period, 720 patients were diagnosed with
      non-Hodgkin s lymphoma in our institution. Out of 101 (14%) patients with diffuse
      large B-cell lymphoma, 17 had T-cell-rich B-cell lymphoma and their median
      survival was less than 20 months, with no difference regarding sex, bone marrow
      involvement, CD30 positivity, or histiocytic component of the tumor. Twenty out
      of 101 patients had mediastinal B-cell lymphoma and their median survival was 21
      months, with sex or degree of necrosis of the involved lymph node having no
      impact on survival. We studied the frequency of bcl-2 gene rearrangement in
      fusion with immunoglobulin receptor gene of t(14;18) and found no such event
      among 20 of our patients with mediastinal diffuse large B-cell lymphoma. Despite
      extensive efforts and constant progress in our understanding of non-Hodgkin s
      lymphoma pathogenesis, the diffuse large B-cell lymphoma group remains
      heterogeneous entity awaiting further pathological and clinical stratification.

PMID- 12402392
TI  - Fluorine-18-fluorodeoxyglucose positron emission tomography metabolic imaging in
      patients with lymphoma.
AB  - Fluorine-18-fluorodeoxyglucose (FDG) positron emission tomography (PET) provides
      unique information about the metabolic behavior of the malignant tumors,
      independent of morphological criteria. This technique is more sensitive in
      imaging lymphoma prior to therapy than conventional computed tomography (CT)
      imaging and Ga-67 scintigraphy. FDG-PET performed in patients with lymphoma
      offers important additional information on the presence of viable disease in
      residual masses of the tumor. It is also of great value in assessing therapy
      response in patients with Hodgkin s disease and non-Hodgkin s lymphoma, because
      of its ability to differentiate between fibrosis and active tumor. More studies
      are needed to assess the value of this method in long-term follow-up. In our
      institution this method is mostly used for clarification of residual post-therapy
      abnormalities that fall under the category of unconfirmed/uncertain complete
      remission. Our preliminary data on 14 patients indicate that this non-invasive,
      metabolic imaging is superior to CT and other conventional diagnostic methods in
      the post-therapy staging of lymphoma.

PMID- 12402393
TI  - Therapy for stage I aggressive non-Hodgkin's lymphoma.
AB  - Although radiotherapy was considered sufficient for stage I and limited stage II
      aggressive non-Hodgkin s lymphoma in the past, new data from randomized studies
      have shown that intensified chemotherapy or combined modality therapy (multiagent
      chemotherapy followed by involved field radiotherapy) can result in complete
      remission in 75-90% of the cases, with 5-year overall survival ranging between
      82% and 89%. However, not all patients benefit from this management. Patients
      above 60 years of age, with high lactate dehydrogenase concentration, poor
      performance, or extranodal disease localized in the testis or central nervous
      system have a much worse outcome. Therefore, typical extranodal character of this
      disease (40-57% of the patients show a primary extranodal localization) needs to
      be recognized and therapy adapted to these subcategories.

PMID- 12402394
TI  - Combination of ifosfamide, methotrexate, and etoposide (IMVP) as a salvage
      therapy for relapsed and refractory aggressive non-Hodgkin lymphoma:
      retrospective study.
AB  - AIM: There are contradictory reports on the outcomes of IMVP (ifosfamide,
      methotrexate, and etoposide) treatment in patients with aggressive non-Hodgkin s
      lymphomas. Our aim was to evaluate retrospectively the results of this treatment
      in our institution. METHODS: Twenty eight patients with refractory or relapsed
      aggressive non-Hodgkin s lymphomas received IMVP between April 1997 and June
      2001. Median follow-up of the survivors was 24 months. There were 15 women and 13
      men, aged 15-68 years. Twelve patients were refractory to primary treatment. The
      number of previous treatment lines varied between one and five. The overall
      response rate to IMVP treatment was 39%, with 6 patients achieving complete and 5
      partial response/remission. Eleven patients received a subsequent hematopoietic
      stem cell transplant after IMVP therapy. RESULTS: Median duration of the survival
      for all patients was 6 months, and the response duration for responders 6 months.
      Nine patients had grade 3 hematologic toxicity or higher, 5 developed significant
      infectious complications, and one developed the tumor lysis syndrome. There was
      one treatment-related death due to infection. The patients with a low or low
      intermediate international prognostic index at the start of IMVP had a
      significantly better survival and progression-free survival rates than those with
      high or high-intermediate score. Seven patients with hematopoietic stem cell
      transplant were alive in December 2001. CONCLUSION: IMVP is an active regimen
      with acceptable level of toxicity in patients with relapsed or refractory
      aggressive non-Hodgkin s lymphoma. However, outcomes of this treatment are
      unsatisfactory and better treatment is still needed.

PMID- 12402395
TI  - Surgical resection in the treatment of primary gastrointestinal non-Hodgkin's
      lymphoma: retrospective study.
AB  - AIM: To evaluate the role of surgical resection in the treatment of patients with
      primary gastrointestinal non-Hodgkin s lymphoma in our institution. METHOD: The
      retrospective study included 79 patients with a histologically confirmed primary
      gastrointestinal lymphoma, who were diagnosed and treated for the disease in the
      1978-1997 period. According to the treatment modality, the patients were divided
      into surgically treated and surgically non-treated group. Data were analyzed with
      Fisher s exact test, long-rank test, and Kaplan-Meier method. RESULTS: The
      stomach was the primary site of non-Hodgkin s lymphoma in 45 (57%) patients,
      small intestine in 19 (24%), and colon in 9 (11%) patients. Six patients (8%) had
      multifocal disease. There were 56 (71%) patients with stages IE and IIE, and 23
      (29%) with stages III and IV. Aggressive histology was found in 51 cases (65%),
      and low grade mucosa-associated lymphoid tissue (MALT) lymphoma in 28 (35%).
      Helicobacter pylori infection was registered in 20 out of 45 patients with
      gastric lymphoma. Twenty-six (33%) patients underwent surgical resection followed
      by chemotherapy, 47 (59%) were treated with chemotherapy alone, and 6 (8%)
      received antibiotics plus chemotherapy. Fifteen patients needed urgent surgical
      intervention. The overall response rate was 77%. Complete remission was achieved
      in 54 (68%) patients and partial remission in 7 (9%). Eighteen patients (23%)
      experienced progressive disease. A 10-year overall survival (OS) was 63% and
      event-free survival (EFS) was 52% for all patients. Patients with gastric
      lymphoma had better OS and EFS than patients with primary lymphoma at other sites
      (65% vs 42%, and 62 vs 28%, respectively) (p=0.005). A 10-year EFS rates were 58%
      and 52% for surgically treated and non-treated group, respectively. There was no
      significant difference between patients with resected and non-resected tumors
      (p=0.855). Patients with early-stage disease had significantly better OS and PFS
      than patients with advanced-stage disease (p=0.048). CONCLUSION: Primary
      gastrointestinal lymphoma can be successfully treated with chemotherapy alone but
      surgery remains an important therapeutic option for emergency problems. The main
      prognostic factors were primary tumor site and extent of the disease.

PMID- 12402396
TI  - Autologous stem cell transplantation in treatment of aggressive non-Hodgkin's
      lymphoma.
AB  - There is no doubt that autologous stem cell transplantation is useful for
      patients with relapsed aggressive non-Hodgkin s lymphoma if they are responsive
      to the chemotherapy given before the transplantation. A small subset of patients
      with primary refractory disease still profits from this high dose chemotherapy
      regimen, but only if chemosensitive and if presenting with favorable risk factors
      at the moment of transplant eligibility. Autologous stem cell transplantation as
      upfront first line therapy for patients with aggressive non-Hodgkin s lymphoma
      does not contribute to a better outcome, most certainly not if it concerns
      patients with a favorable risk profile. There is still some doubt whether there
      is any place for autologous stem cell transplantation as first line therapy for
      patients with an unfavorable risk profile. Most randomized studies do not show an
      advantage, but more data are needed to definitely assess the place for this
      therapy option.

PMID- 12402397
TI  - Allogeneic stem cell transplantation in treatment of aggressive lymphomas: case
      series.
AB  - AIM: To assess the outcome of allogeneic stem cell transplantation in patients
      with aggressive lymphoma. METHODS: Between 1991 and 2002, 22 patients with
      aggressive lymphoma in advanced phase of the disease underwent allogeneic stem
      cell transplantation at the Division of Hematology, Zagreb University Hospital
      Center. Seventeen patients received stem cells from the bone marrow. Eighteen
      patients underwent total body irradiation and received cyclophosphamide for
      conditioning, whereas the rest of the patients received busulfan and
      cyclophosphamide (n=2) or chemotherapeutic protocol combining carmustine,
      melphalan, etoposide, and cytarabine (BEAM regimen) (n=2). All patients received
      cyclosporin and short methotrexate for the prophylaxis of graft-versus-host
      disease (GVHD). RESULTS: Three months after allotransplantation, 17 patients had
      complete remission, 3 patients had active disease, and the outcome in 2 patients
      was early death. Nine patients were alive and in complete remission for 4 to 124
      months, whereas 13 patients died (8 because of disease progression and 3 because
      of GVHD and infection). The probability of overall survival at 4 years was 47%.
      CONCLUSION: Allogeneic transplantation is an effective therapy for advanced
      aggressive lymphoma. Because of high treatment-related toxicity and mortality,
      prospective trials are needed to asses the best time when to apply this
      treatment.

PMID- 12402398
TI  - Radiotherapy of stage IEA primary breast lymphoma: case report.
AB  - A 47-year-old woman was referred for the treatment to our Hospital because of a
      palpable nodule in the upper medial quadrant of her right breast. After tumor
      excision, pathohistological examination showed a follicular center cell lymphoma
      grade 2, B-cell type (CD20+, bc16+, CD10+, bcl2+). The final diagnosis was stage
      IEA primary extranodal non-Hodgkin s breast lymphoma. The involved breast was
      irradiated isocentrically with two opposite 6-megavolt (MeV) photon beams
      delivered from the linear accelerator (tangential fields) using asymmetric
      collimator opening. Radiation volume, inclinations of the medial and lateral
      field, and the part of the underlying chest wall and lung parenchyma were
      determined during the radiotherapy simulation process. The total irradiation dose
      was 44 Gy delivered in single daily doses of 2 Grays (Gy). After breast photon
      irradiation, a boost to the tumor bed was performed by a direct 12 MeV electron
      beam, with a total dose of 6 Gy delivered over three days. Since primary non
      Hodgkin lymphoma of the breast is rather rare, there has been no uniform approach
      to its treatment. The advantage of applying the asymmetric collimator jaw opening
      in breast radiotherapy is the instant reduction of the dose at margin fields,
      resulting in both the protection of neighboring lung parenchyma and the good
      coverage of planned target volume.

PMID- 12402399
TI  - Hodgkin s disease with nephrotic syndrome as a complication of ulcerative
      colitis: case report.
AB  - We describe a case of a 32-year-old patient with ulcerative colitis complicated
      by Hodgkin s disease who presented with nephrotic syndrome. The patient had
      suffered from relapsing ulcerative colitis for 6 years before he developed
      Hodgkin s lymphoma. He was treated for Hodgkin s disease with 9 cycles of
      combined chemotherapy (COPP/ABV) and achieved the stabile remission of lymphoma,
      nephrotic syndrome, and ulcerative colitis. To the best of our knowledge, this is
      the first report on ulcerative colitis associated with Hodgkin s disease and
      nephrotic syndrome.

PMID- 12402400
TI  - Dinara - new natural focus of hemorrhagic fever with renal syndrome in Croatia.
AB  - AIM: To investigate the characteristics and determine risk factors for
      hantanvirus infection in natural focus of hemorrhagic fever with renal syndrome
      (HFRS) on the Dinara Mountain, where outbreak of disease emerged among Croatian
      soldiers in 1995, and to describe the features of HFRS acquired on the Dinara
      mountain and determine the scale of the largest HFRS epidemic so far in Croatia.
      METHODS: During 1996, small mammals were captured in the region of Dinara
      Mountain where infected Croatian soldiers had sojourned. By taxonomic
      classification of 42 captured small mammals, three species were determined: 23
      yellow-necked mouse, 9 wood mouse, and 5 bank vole. Hantavirus antigen was
      determined in the lungs of the captured animals by means of direct
      immunofluorescence assay. The most important features of HFRS were
      retrospectively determined in 37 soldiers with HFRS treated in the Department for
      Infectious Diseases of the Split University Hospital. The degree of inapparent
      exposure to infection was determined by indirect immunofluorescence in 103
      soldiers sojourning in this region of natural focus with no apparent signs of
      HFRS. Epidemiological questionnaire included 50 soldiers with negative serum
      antibodies, as well as 33 available out of total 37 soldiers with HFRS. Chi
      square test was used to determine risk factors. RESULTS: Hantavirus was found in
      the lungs of 5/42 (12%) captured animals. Mild form of the disease, with few
      hemorrhagic symptoms and pronounced renal insufficiency, was present in 19/37
      patients. The epidemiological questionnaire determined the following risk factors
      for hantanvirus infection in this focus: service in artillery corps (p=0.040),
      sleep in wooden barracks (p=0.004), station in forest biotope (p=0.037), usage of
      natural camouflage (p=0.024), smoking (p=0.010), and the presence of rodents in
      the place of housing (p<0.001). CONCLUSION: A new natural focus of HFRS in
      Croatia, and the first one in Dalmatia, was defined by seroepidemiologic,
      mamologic, and virologic analysis. The risk factors for infection in the new
      focus have been identified. Our patients suffered from a mild form of HFRS, which
      predominates in south-eastern Europe, without lethal outcome.

PMID- 12402401
TI  - Epidemiologic characteristics and military implications of hemorrhagic fever with
      renal syndrome in croatia.
AB  - AIM: To analyze epidemiologic characteristics of hemorrhagic fever with renal
      syndrome in Croatia, including military implications of the disease and measures
      for its prevention. METHOD: We analyzed data from obligatory infectious disease
      reports and notification of deaths due to infectious diseases, data on the
      hemorrhagic fever with renal syndrome epidemics in Croatia, and data collected by
      survey of the population, serological findings, and studies of wild rodents
      serving as reservoirs of the infection. RESULTS: During the 1987-2001 period, 235
      cases of hemorrhagic fever with renal syndrome were recorded in Croatia, with 147
      (62.6%) of them among Croatian Army soldiers. Mortality rate was up to 15.4%
      (mean 2.2%) (5/235). The highest number of cases was recorded in months of June
      and July, ie, during the warm season characterized by increased activity of both
      the animals acting as infection reservoirs and humans as hosts. The known natural
      foci of hemorrhagic fever with renal syndrome have been Plitvice and Slunj areas,
      Velika and Mala Kapela mountains, Zagreb area (Velika Gorica and Jastrebarsko),
      west Slavonia, Novska area, and Dinara Mountain. The disease has not been
      recorded in the littoral area and Adriatic islands. The identified causative
      agents include Dobrava and Puumala viruses of the genus Hantavirus, whereas
      rodents Clethrionomys glareolus, Apodemus flavicollis, Apodemus agrarius, and
      Apodemus sylvaticus serve as the main reservoirs of the infection. Typical
      biotopes of the infection in Croatia are deciduous woods. The measures of
      prevention in Croatia include pest control, disinfection, hygienic waste
      disposal, preventing rodent access to food and water, proper choice of camping
      sites, and health education. CONCLUSION: Hemorrhagic fever with renal syndrome
      occurs predominantly in soldiers, in a sporadic or epidemic form. Because of the
      course of disease and potentially lethal outcome, the disease has a considerable
      impact on the field task performance and combat readiness of military units, and
      is of great importance for a military community. Accommodation in permanent
      buildings with appropriate common and personal hygiene standards is recommended.

PMID- 12402402
TI  - Immune parameters in hemorrhagic fever with renal syndrome during the incubation
      and acute disease: case report.
AB  - We describe immune parameters in a Croatian soldier who presented with mild flu
      like symptoms and interstitial inflammatory infiltrate in the lungs on an X-ray
      during the incubation phase of hemorrhagic fever with renal syndrome (HFRS).
      Enzyme-linked immunosorbent assay (ELISA) IgM and polymerase chain reaction (PCR)
      were negative. Two weeks later, he developed HFRS caused by the Puumala virus. We
      performed two-color immunofluorescence cytometry with monoclonal antibodies
      identifying the activation markers on T cells. Serum samples were also examined
      by enzyme immunoassay (EIA) for the presence of interleukins IL-2 and IL-6 and
      their soluble receptors (sR). The analysis of early and late activation markers
      during the period of incubation revealed a small increase in the percentage of
      helper (CD4+CD25+) T cells and no significant increase in total activated (HLA
      DR+TCR+) and cytotoxic (CD8+CD71+) T cells as compared with healthy controls. In
      the serum, only the concentration of soluble IL-6 receptor was increased.
      However, when the patient developed HFRS, all activation markers on T cells
      increased. Concentrations of sIL-2Ralpha and IL-6 remained increased two and six
      days after HFRS onset, respectively, whereas sIL-6R increased six days after HFRS
      onset. IL-2 concentration did not change. Our case indicates that rapid, modern
      diagnostic tools are necessary in the diagnosis of infectious diseases and their
      differential diagnosis. Immunological tests, which provide information on the
      patient immune status and especially on early changes in immune parameters, may
      contribute to the improvement of the diagnosis, prognosis, and therapy of HFRS.

PMID- 12402403
TI  - Human immunodeficiency virus-1 tat- and tat/nef-defective genomes containing HIV
      regulated diphtheria toxin A chain gene inhibit HIV replication.
AB  - AIM: To assess the ability of human immunodeficiency virus-1 (HIV-1) tat- and
      tat/nef-defective genomes containing diphtheria toxin A chain gene (DTA) to
      inhibit replication of HIV in human cells. METHODS: Plasmids were constructed to
      contain the HIV-1 genome disabled by tat and tat/nef deletions, and sequences
      coding for the A subunit of diphtheria toxin gene were inserted into one of these
      deletions. An infectious clone of HIV-1 (pBRU-3) was cotransfected into HeLa-CD4
      cells, together with plasmids carrying the modified DTA-containing genomes. Cell
      culture supernatants were collected and titrated for the virus by multinuclear
      activation of beta-galactosidase (MAGI) assay. RESULTS: Each of the DTA
      containing plasmids suppressed HIV production by no less than 96%, whereas the
      defective non-DTA containing plasmids did not interfere with the virus growth.
      Plasmids containing wild-type DTA inhibited HIV replication slightly more than
      its moderately attenuated mutant form, probably by limiting the synthesis of
      viral proteins. These modified DTA-containing HIV constructs gave no evidence of
      virus growth in HIV susceptible cells that supported the multiplication of the
      parent plasmid. None of the modified DTA-containing plasmids was toxic to cells
      cotransfected with a selectable marker, as shown by the ability of
      cotransfectants to multiply and form colonies at rates identical to controls
      exposed to non-specific DNA. This suggested that DTA was probably not expressed
      in the absence of activating wild-type HIV plasmid. CONCLUSION: HIV-regulated DTA
      in the background of a HIV replication and expression of defective provirus may
      be taken into consideration as a therapy approach to the treatment of HIV
      infection, based on its selective and specific toxicity only to HIV infected CD4
      positive cells.

PMID- 12402404
TI  - Temporal trends in demographic profiles and stress levels in medieval (6th-13th
      century) population samples from continental Croatia.
AB  - AIM: To analyze and compare the demographic profiles and disease frequencies of
      early (6th-9th century) and late (10th-13th century) medieval skeletal series
      from continental Croatia. METHODS: Age and sex distributions in three early
      (n=277) and six late (n=175) medieval skeletal series were compared. All
      skeletons were analyzed for the presence of dental enamel hypoplasia,
      periostitis, trauma, and presence of Schmorl s depressions in vertebral bodies.
      RESULTS: Data collected from the skeletal series suggested significantly higher
      stress in the late medieval period. This stress may have affected mortality, as
      evidenced by significantly higher subadult mortality and shorter adult average
      life span. Men in the late medieval series, in particular, seem to have been
      under greater stress. They exhibited significantly higher mortality in the 21-25
      years age category, and significantly higher frequencies of periosteal lesions,
      cranial and postcranial trauma, and Schmorl s depressions. CONCLUSION: The
      frequencies of all skeletal indicators of stress increased significantly during
      the late medieval period. This was accompanied by a significant increase in
      subadult mortality and shortening of the average life span of adult men and
      women.

PMID- 12402405
TI  - Diagnostic relevance of fine needle aspiration cytology for follicular lesions of
      the thyroid: retrospective study.
AB  - AIM: To determine diagnostic relevance of cytologic subclassification of
      follicular lesions of the thyroid and its role in the therapeutic approach.
      METHODS: We performed a retrospective analysis of the data of patients who
      underwent thyroid surgery at the Sisters of Mercy University Hospital, Zagreb,
      between March 1995 and February 2001, and had a report of preoperative fine
      needle aspiration (FNA) biopsy of thyroid follicular lesion, which comprises
      cellular follicular lesion, suspicious for follicular neoplasm, or follicular
      neoplasm. RESULTS: Out of 110 patients with preoperative FNA biopsy diagnosis of
      follicular lesion, 86 (78%) had a lesion corresponding histologically to a
      neoplasm. However, a malignant tumor was found in only 6% of the patients. In the
      diagnostic categories of cellular follicular lesion and lesion suspicious for
      follicular neoplasm, the rate of malignancy was even lower, 3% and 4%,
      respectively. We found significant difference between FNA and histologic findings
      in distinguishing non-neoplastic from neoplastic thyroid lesions in the category
      of cellular follicular lesion and follicular neoplasm. CONCLUSION: Due to the low
      malignancy rate in patients with FNA biopsy diagnoses of cellular follicular
      lesion or lesion suspicious for follicular neoplasm of the thyroid, we suggest
      close clinical follow-up of such patients, rather than immediate surgical
      intervention.

PMID- 12402406
TI  - New modification of transurethral incision of the prostate in surgical treatment
      of bladder outlet obstruction: prospective study.
AB  - AIM: To analyze long-term effects of short and shallow incision of the prostate,
      a new modification of transurethral incision of the prostate (TUIP), as a method
      of resolving bladder outlet obstruction and preserving anterograde ejaculation
      and potency. METHOD: Fifty patients with symptoms of bladder outlet obstruction
      caused by a small benign prostate tumor of less than 30 g estimated weight were
      included in a nonrandomized, prospective study and underwent transurethral
      incision of the prostate. In the patients with normal sexual activity (n=28),
      short and shallow incisions were made, limited to the prostatic urethra and
      reaching to the fibrous capsule. In sexually inactive men (n=22), longer and
      deeper incisions were made, extending from below the urethral orifice upward to
      the verumontanum and in depth to the perivesical and periprostatic fat. All
      incisions were made at 5 and 7 o clock. Preoperative and postoperative
      evaluations performed 1, 3, 6, 12, 18, 24, 30, 36, 40, 48, 54, 60, 66, and 72
      months after surgery were based on the International Prostate Symptom Scores (I
      PSS), uroflowmetry, patients overall assessment of surgery outcome, and a sexual
      function questionnaire. RESULTS: Median follow-up was 42 months (6-72 months).
      There was a significant improvement in urinary peak flow rates and I-PSS
      decreased significantly during the follow-up period in both groups (p<0.05).
      Surgery outcome was rated satisfactory by all patients, with no difference
      between the groups. All 28 patients sexually active before the surgery retained
      their sexual activity after surgery; only one developed retrograde ejaculation.
      Two patients, one from each group, underwent further urologic treatment
      (transurethral resection of the prostate) 36 and 42 months after transurethral
      incision of the prostate, respectively. CONCLUSION: Transurethral short and
      shallow incision at 5 and 7 o clock is an effective method for long-term relief
      of bladder outlet obstruction in patients with small, benign prostate tumor. It
      has equally good long-term outcome as the classic long and deep transurethral
      incision but with fewer complications. None of the patients operated by this new
      method had lost potency and only a single one developed retrograde ejaculation.

PMID- 12402408
TI  - Value of life.

PMID- 12402407
TI  - Acquired coagulopathy due to anticoagulant rodenticide poisoning.
AB  - A 35-year-old woman was admitted to hospital because of epistaxis, hematomas, and
      metrorrhagia. Laboratory data indicated severe coagulopathy with prolonged
      prothrombin time and decreased serum concentrations of vitamin K-dependent
      clotting factors II, VII, IX, and X. The patient denied taking any oral
      anticoagulants. She was given transfusions of red blood cells, fresh frozen
      plasma (1,180 mL) and phytomenadione daily for 6 weeks (total dose 550 mg), which
      normalized the coagulation factors concentration. After all other possible causes
      of acquired coagulopathy had been excluded, rodenticide poisoning was suspected
      on the basis of her epidemiologic history. The patient was a war refugee from
      Bosnia and Herzegovina. During her absence, the troops of United Nations
      Protection Force performed rodent extermination in and around her house. History
      data and therapeutic effects suggested that the coagulopathy had been caused by
      prolonged exposure to long-acting anticoagulant rodenticide. This could also
      explain the need for protracted phytomenadione therapy.

PMID- 12402409
TI  - Quality of care in the management of lymphomas.

PMID- 12402410
TI  - Are cardiovascular diseases a subspeciality of clinical immunology?

PMID- 12402411
TI  - Cardiac involvement in systemic autoimmune diseases.
AB  - The heart and the vascular system are frequent and characteristic targets of
      several systemic autoimmune diseases, in particular Systemic Lupus Erythematosus
      (SLE), Rheumatoid Arthritis (RA) and Systemic Sclerosis (SSc). In this chapter we
      review the classic cardiac abnormalities and the more recent data about
      cardiovascular involvement as part of a major disease complication determining a
      substantial morbidity and mortality. In addition to the classic cardiac
      abnormalities involving the heart structures, acute and chronic ischemic heart
      disease and cerebrovascular accidents are threatening clinical manifestations of
      SLE and RA associated to an early accelerated atherosclerosis. Immune-mediated
      inflammation is now recognized as an important factor involved in the
      pathogenesis of atherosclerosis. Ongoing clinical studies are being devised to
      find specific risk factors associated with systemic autoimmune diseases and/or
      treatment regimens. Hopefully, prophylactic measures should be available within
      the next few years.

PMID- 12402413
TI  - Neonatal lupus.
AB  - Congenital heart block (CHB), defined as an atrioventricular block diagnosed in
      utero, at birth, or within the neonatal period (0-27 d after birth), is a rare
      disorder closely linked to transplacental transport of maternal antibodies anti
      Ro/SSA and anti-La/SSB. These antibodies may induce a myocarditis, or interact
      directly with calcium channel proteins with disturbance of transmembrane
      signaling at the level of the conduction tissue, or interfere with apoptosis.
      Depending on the severity of the process, the fetus may die in utero or a few
      days after birth or survive to the perinatal period and have a near-normal life;
      in most survivors a pace-maker must be implanted. Skin lesions, haematological
      disorders, and hepatic cholestasis are other transient clinical features of the
      syndrome. Sinus bradycardia and QT interval prolongation may be observed as well
      in babies born from anti-Ro/SSA positive mothers. The risk of recurrence of
      complete block ranges from 10-17%. Most of the mothers are asymptomatic at
      delivery and are identified only by the birth of an affected child. Their long
      term outcome generally is more reassuring than previously assumed and arthralgias
      and dry eyes are the most common symptoms. A standard therapy for blocks detected
      in utero still does not exist. The prevalence of complete CHB in newborns of anti
      Ro/SSA positive women and with known connective-tissue disease was 2%. Serial
      echocardiograms and obstetric sonograms, performed at least every 2 wk starting
      from the 16 wk gestation, are recommended in anti-Ro/SSA positive pregnant women.

PMID- 12402412
TI  - Anti-inflammatory and immunomodulating properties of statins. An additional tool
      for the therapeutic approach of systemic autoimmune diseases?
AB  - Cardiovascular diseases secondary to accelerated atherosclerosis are now accepted
      as a cause of mortality and morbidity in patients suffering from systemic lupus
      erythematosus and rheumatoid arthritis. More recently, atherosclerosis is
      emerging as one of the most serious complications in the anti-phospholipid
      syndrome, although large epidemiological studies, such as those performed in
      lupus and rheumatoid arthritis patients, have not been performed up to now.
      Classical risk factors (dislipidemia, hypertension, diabetes, smoking, etc.) and
      steroid therapy cannot completely explain the high prevalence of cardiovascular
      complications in systemic autoimmune diseases. Since the modern view defines
      atherosclerosis as a chronic inflammatory disorder, it has been suggested that
      systemic inflammation and soluble immune mediators (circulating autoantibodies,
      immune-complexes, complement activation products) might play a role in
      accelerating vessel pathology. The main target appears to be the endothelium
      because of its ability to switch to a pro-adhesive, pro-inflammatory and pro
      coagulant surface in response to these mediators. Recent advances in the
      knowledge of the pharmacology of statins have indicated that these drugs rather
      than to be simple cholesterol lowering molecules display a pleiotropic effects on
      several mechanisms involved in the atherosclerotic plaque formation. Their anti
      inflammatory activity and particularly their ability to downregulate endothelial
      cell activation induced by different stimuli strongly suggest their possible use
      in conditions in which the systemic inflammation and the endothelial
      activation/damage are thought to represent key pathogenic mechanisms.

PMID- 12402414
TI  - Autoimmune mechanisms as the basis for human peripartum cardiomyopathy.
AB  - The etiology and mechanisms of pathogenesis of human peripartum cardiomyopathy
      (PPCM) remain unknown. The incidence and prevalence of this disease is rare in
      some parts of the world and more common in others. The purpose of this review is
      to summarize our current knowledge of the factors that have been entertained
      which may contribute to the pathogenesis of PPCM with special emphasis on more
      recent data from our laboratory that provide support to the view that this
      disease is an autoimmune disease with multiple contributing factors and effector
      mechanisms. This is supported by the fact that sera from PPCM patients contain
      high titers of auto-antibodies against normal human cardiac tissue proteins of
      37, 33, and 25 kD that was not present in the sera of patients with idiopathic
      cardiomyopathy (IDCM), indicating for the first time that PPCM is distinct from
      IDCM. In addition to the autoantibodies, the PBMC's from PPCM patients
      demonstrate a heightened level of fetal microchimerism, an abnormal cytokine
      profile, decreased levels of CD4+ CD25lo regulatory T cells, and a significant
      reduction in the plasma levels of progesterone, estradiol and relaxin in PPCM
      patients as compared with other normal pregnant non-PPCM patients. A potential
      role for reduced plasma levels of selenium in the pathogenesis of select PPCM
      patients was also noted. These findings for the first time suggest that such
      abnormalities may in concert lead to the initiation and perpetuation of an
      autoimmune process, which leads to cardiac failure and disease. Identification of
      the precise nature of the cardiac tissue autoantigens (currently in progress)
      will pave the way for the delineation of mechanism of this autoimmune disease. A
      working model for the pathogenesis of this disease is also described herein.

PMID- 12402416
TI  - Cardiac valvulopathy in the antiphospholipid syndrome.
AB  - The Libman and Sacks non bacterial endocarditis was reported in 1924 in patients
      with SLE. Its relation to the anti cardiolpin syndrome has only been described as
      recently as the last decade. In this paper we review the deposition of these
      antibodies on the valve with complement components initiating the deformation of
      the valve. The valvulopathy in APS is quite common and may lead to valve
      replacement. In addition, a diversity of manifestations are detailed. More
      awareness should be drawn to this new complication of APS.

PMID- 12402417
TI  - [Meta-analysis and evidence based medicine].
AB  - Meta-analysis is a statistical method for combining the results of available
      research studies to increase statistical power. The steps of meta-analysis are
      identification of question, search and selection of trials and analysis. Evidence
      based medicine (EBM) is integrating individual clinical expertise with the best
      available external clinical evidence from systematic research. The practice of
      EBM consists of formulated clinical question, systematic review, critical
      appraisal, application for patients and performance review. We must notice the
      results of meta-analysis and evidence are keeping up to date. We should use them
      with critical appraisal skill and should not criticize without good
      understanding.

PMID- 12402419
TI  - [Clinical significance for detection of circulating cancer cells in renal cell
      carcinoma].
AB  - Renal cell carcinoma has a very poor prognosis since various therapeutic
      modalities other than radical operation are not effective. Early detection and
      treatment are of considerable importance to cure the patients; however, early
      diagnosis of renal cell carcinoma is not easy because no specific tumor marker,
      like PSA for prostate cancer, is available. MN/CA9 is considered to be one of the
      carbonic anhydrase isoenzymes, and is expressed in approximately 90% of renal
      cell carcinomas. Expression of MN/CA9 in normal tissues is very limited. Using
      optimal RT-PCR with specific primers, MN/CA9 positive cells were clearly detected
      in the blood. The sensitivity and specificity were found to be approximately 40%
      and 90% respectively. The detection of circulating renal cell carcinoma cells
      using RT-PCR for MN/CA9 mRNA is useful for diagnosis of the presence of renal
      cell carcinomas. This RT-PCR assay may also be able to provide information with
      which to predict the prognosis of the patients.

PMID- 12402415
TI  - Chronic heart failure and the immune system.
AB  - Several lines of evidence support a role of immune mechanisms in the pathogenesis
      of chronic heart failure (CHF). Proinflammatory cytokines (interleukin-1, -2, -6,
      and tumor necrosis factor) and chemokines are involved in cardiac depression and
      in the progression of heart failure. Other components believed to be relevant to
      the pathogenesis of CHF are adhesion molecules, autoantibodies, nitric oxide
      (NO), and endothelin-1. The origin of the immune activation in patients with CHF
      is still unknown, however two hypotheses have been proposed on the basis of
      experimental and clinical data. One suggests that the bowel wall edema leads to
      bacterial translocation with subsequent endotoxin release and immune activation.
      The second suggests that the heart in CHF is the main source of cytokines, as is
      shown by the fact that TNF alpha is produced by the failing myocardium but not by
      a normal one. No single source of cytokine production (gut or heart) seems
      sufficient to fully explain the multiple organ involvement and the systemic
      inflammation of CHF, which is probably related to systemic hypoxia, a potent
      stimulus for activation of the immune system and for cytokine production. The
      effort of define the immune system's role has opened new perspectives of
      therapeutic strategies, such as anti-cytokine drugs, to treat CHF.

PMID- 12402420
TI  - [Development of human renal cell carcinoma (RCC)--the responsible genes for the
      development of hereditary and sporadic human RCCs].
AB  - Renal Cell Carcinoma (RCC) is classified into six cell pathological types by the
      Thoenes classification (5). Deletion of DNA (loss of heterozeigosity: LOH) is
      seen with a high frequency in human RCC of all 6 types at chromosome 3p 14-25.
      The presence of at least three tumor suppressor genes at this domain has been
      pointed out. The VHL gene, one of the tumor suppressor genes (TSG), was
      identified in 1993 at chromosome 3p25-26 as the gene responsible for VHL disease.
      As a consequence, it was demonstrated that inactivation of the von Hippel-Lindau
      (VHL) gene is responsible for sporadic clear cell RCC. Activating mutations of c
      Met receptor type tyrosine kinase has been demonstrated in papillary renal cell
      carcinoma families. Possible involvement of the FHIT tumor suppressor gene,
      located at the fragile site (FRA3B) of chromosome 3p14, has been detected in
      sporadic RCC. Recently, methylation of RASSF1A at chromosome 3p21.3 was pointed
      out in sporadic RCC. Thus, it has become apparent that chromosome 3p14-25 3 has
      possible TSGs for RCC. Furthermore, it was pointed out in April that germline
      mutation of fumarate hydratase, a Krebs cycle enzyme (FH), is present in multiple
      cutaneous and uterine leiomyomatosis families that develop papillary RCC. The
      functional significance in these genes for the development of RCC is still not
      apparent, except for the VHL gene. Thus, there is still a long way to go before
      we find all responsible TSGs in all pathological subtypes in sporadic RCC.

PMID- 12402421
TI  - [Recent advances in nephron-sparing surgery for renal cell carcinoma].
AB  - Although radical nephrectomy is a "standard" surgery for management of renal cell
      carcinoma, nephron-sparing surgery has become accepted for selected patients:
      those with solitary kidney, bilateral renal cell carcinoma or small renal cell
      carcinoma. Recently laparoscopic surgery has gradually come to include nephron
      sparing surgery with minimum invasiveness. Furthermore, new methodologies such as
      cryoablation and radiowave ablation enable percutaneous management of nephron
      sparing surgery. Thus, nephron-sparing surgery is becoming less invasive.
      However, its efficacy in controlling cancer needs to be discussed further.

PMID- 12402422
TI  - [What is the impact of cytoreductive nephrectomy in patients with metastatic
      renal cell carcinoma?].
AB  - The impact of cytoreductive nephrectomy in patients with metastatic renal cell
      carcinoma (RCC) is discussed herein with consideration of prolonged survival and
      quality of life. A nephrectomy can be indicated in a patient with good
      performance status and pulmonary metastases when adjuvant immunotherapy is an
      option. In contrast, in a patient with poor performance status and/or metastases
      including multiple organs, a nephrectomy is not indicated. To relieve symptoms,
      options other than nephrectomy should be considered.

PMID- 12402423
TI  - [Cytokine therapy for metastatic renal cell carcinoma].
AB  - Cytokine therapy for patients with metastatic renal cancer is based on
      observations suggesting this neoplasm may be responsive to immunotherapy. Two
      cytokines, interferon-alpha (IFN-alpha) and interleukin 2 (IL-2) induce tumor
      regression in 10% to 15% of patients with metastatic disease. Randomized trials
      demonstrate a modest survival advantage for patients treated with IFN-alpha, as
      compared with chemotherapy. The combination of IL-2 and IFN-alpha appears to be
      associated with improved response rates, but has no demonstrable effect on
      survival. The addition of other cytokines (e.g., GM-CSF) or chemotherapy to this
      combination has been investigated, but results do not suggest that they enhance
      the outcome. Patient selection remains an important issue in this patient
      population. Individuals who are asymptomatic and have limited pulmonary or soft
      tissue disease are most likely to benefit. The addition of novel cytostatic
      agents to these regimens is now under way.

PMID- 12402424
TI  - [Cell therapy for renal cell carcinoma].
AB  - Renal cell carcinoma (RCC) is an immunogenic tumor that has shown some response
      to cytokine-therapy and other types of immune-based treatment. Since the advent
      of lymphocyte culture techniques in the 1980s, clinical trials of lymphokine
      activatedkiller cells and tumor infiltrating lymphocytes have been conducted.
      Although these approaches have not shown apparent benefit compared to the
      standard cytokine therapy, further trials are ongoing using dendritic cell or
      gene-modified tumor vaccines in order to induce a tumor-specific cytotoxic T cell
      response in vivo. Recently, several investigators have indicated that RCC is
      susceptible to a graft-versus-tumor effect promoted by allogeneic stem-cell
      transplantation. This article reviews the clinical results of these cell
      therapies for metastaic RCC.

PMID- 12402425
TI  - [Benefit of screening for gastric cancer--a comparison of symptomatic and
      screened patients who underwent gastrectomy].
AB  - We compared the clinicopathological factors and treatment results with regard to
      symptoms and screening in patients who underwent gastrectomy for primary gastric
      cancer. PATIENTS: The subjects included 797 patients with asymptomatic gastric
      cancer (SCG) and 1090 patients with symptomatic cancer (SYG) who had undergone
      gastrectomy for gastric cancer from 1989 to 2000. RESULTS: The proportion of
      early gastric cancer, N0 cases, and curative cases in the SCG and SYG patients
      were 70% & 33%, 77% & 44%, and 98% & 80%, respectively (p = 0.000, for each).
      Five-year survival rates of the SCG and SYG patients were 87% and 63% (p =
      0.000). CONCLUSION: Screening for gastric cancer in order to detect asymptomatic
      disease may contribute to patient survival.

PMID- 12402426
TI  - [Pharmacologic study of intraperitoneal docetaxel in gastric cancer patients with
      peritoneal dissemination].
AB  - This study was designed to evaluate the pharmacokinetics and toxicity of
      docetaxel administered via an intraperitoneal (i.p.) route for patients with
      gastric cancer. Eleven patients with peritoneal dissemination were entered into
      this trial. Patients were treated with 45 mg/m2 of i.p. docetaxel administration
      in 1 l of saline. Peak peritoneal concentration was 40.0 +/- 14.5 micrograms/ml
      and peritoneal concentration at 24 hours after drug administration was 4.3 +/-
      3.9 micrograms/ml. The median pharmacokinetic advantage (AUC peritoneal/AUC
      plasma) was 515 (range 22-1, 770). Grade 2 and 3 toxicities included 5 episodes
      of diarrhea; 3 of abdominal pain; 3 of ascites; 2 of alopecia; and 1 of
      neutropenia. We conclude that intraperitoneal docetaxel administration is well
      tolerated and provides a peritoneal pharmacokinetic advantage for the treatment
      of peritoneal dissemination.

PMID- 12402427
TI  - [Final results of a randomized clinical trial of adjuvant intraportal
      chemotherapy for colorectal cancer: Intraportal Chemotherapy for Colorectal
      Cancer Group].
AB  - The purpose of the present multi-center collaborative study was to elucidate the
      efficacy of intraportal chemotherapy with the combination of 5-FU and MMC for the
      prevention of liver recurrence after resection for colorectal cancer. A total of
      125 patients with Stage II, III, and IV colorectal cancer were enrolled in this
      study between June 1993 and December 1995. Of them, 45 patients were randomized
      to a portal group: 10 mg/body of mitomycin one shot portal infusion, before and
      after 500 mg/m2 of 5-FU per 24 h for 7 days portal infusion followed by
      administration of oral 5-FU. Fifty-three patients were randomized to a control
      group: oral administration of 5-FU. Twelve patients suffered from temporary mild
      liver damage. One patient (2%) in the portal group and 6 patients (11%) in the
      control group developed liver metastases; there was not a significant difference
      between these two groups regarding development of liver metastases. There was
      also no significant difference by tumor stage between the portal and control
      groups regarding development of liver metastases. The 5-year survival rate and 5
      year disease-free survival were 84.3% and 81.9%, respectively, in the portal
      group, and 70.7% and 72.4%, respectively, in the control group; the difference
      was not significant. Although there was not a significant difference between the
      portal and control groups regarding the prognosis in stage II, there was a
      significant difference between the portal and control groups regarding the 5-year
      disease free survival in stage III (81.1% vs 54.2%). These results suggest that
      intraportal chemotherapy is effective for stage III colorectal cancer.

PMID- 12402428
TI  - [Low-dose cisplatin and UFT for hormone refractory prostate cancer].
AB  - OBJECTIVES: Biochemical modulation (BM) was initially used to enhance the effect
      of 5-fluorouracil (5-FU) by modulating its pharmacological action with the
      addition of other drugs. BM with low-dose cisplatin and 5-FU or UFT has been
      examined in cases of advanced gastric or pancreas cancer and 30 to 40% response
      rates have been reported. In the present study, the effect of BM on hormone
      refractory prostate cancer (HRPC) patients was examined. METHODS: BM consisting
      of 5 mg/body of cisplatin 3 times per week and 300-450 mg of UFT/day was given to
      30 HRPC patients (median and range of age: 66 and 52-72, respectively). The ECOG
      performance status was 0 to 1. Gleason score was 7 in 8 patients, 8 in 10
      patients and 9 in 12 patients, respectively. The metastatic site was bone in 29
      patients (extent of disease on bone scan [EOD] grade 1: 10, 2: 10, 3: 8, 4: 1),
      lymph node in 8 and liver in 1. RESULTS: Among the 29 patients assessable for
      bone metastasis, 5 (17%) obtained marked improvement on bone scan. One was EOD
      grade 4 (super bone scan) and 4 were EOD grade 1-3. Eight (28%) were stable and
      16 (55%) progressed on bone scan. Among 8 patients with lymph node metastasis, 4
      (50%) showed partial response and 4 (50%) progression. One patient with liver
      metastasis showed complete response. Fourteen (47%) out of 30 patients showed a
      PSA decline of 50% or greater. Their median response duration was 8 months
      (range; 2 to 44 months). Among the 25 patients assessable for bone pain, 7 (28%)
      improved, 12 (48%) remained stable and 6 (24%) progressed. A side effect of Grade
      II anemia was seen in one patient. CONCLUSION: BM is effective in almost half of
      hormone refractory prostate cancer patients.

PMID- 12402429
TI  - [Serum lactate dehydrogenase and CD4+/CD8+ lymphocyte ratio predict survival in
      terminally ill cancer patients].
AB  - Accurate estimation of survival is important for effective palliative medicine of
      patients with cancer. In most clinical practice, however, the life expectancy has
      been predicted based on subjective evaluations. The purpose of this study was to
      find objective biological markers that can contribute to accurate prediction of
      survival in terminally ill cancer patients. Consecutive terminally ill cancer
      patients admitted to the Palliative Care Center in Tohoku University hospital
      from January to May 2001 were approached for this study. Forty-eight blood
      samples were obtained from 25 patients who provided a written informed consent.
      Common serum enzyme markers were determined using standard hospital laboratory
      methods. Cellular immunity status was evaluated by peripheral blood lymphocyte
      subset analysis using flow cytometry. Mean patient survival was 33.5 +/- 21.6 (1
      80) days. Multiple regression analysis revealed that lactate dehydrogenase (LDH)
      and the CD4+/CD8+ ratio were significantly associated with survival (r = 0.64, p
      < 0.0001). Further prospective studies are warranted to validate the usefulness
      of these determinants for accurate prediction of survival.

PMID- 12402430
TI  - [A case of large-cell lung cancer with liver metastasis successfully treated
      using combination chemotherapy with CDDP and vinorelbine].
AB  - A 38-year-old woman presented to our hospital with the chief complaint of
      dyspnea. A chest radiograph showed pleural effusion of the right lung and a CT
      scan revealed liver metastasis. A tumor biopsy done under bronchoscopy revealed
      large-cell carcinoma of the lungs. She was given 4 courses of a combination
      therapy consisting of CDDP (80 mg/m2) and vinorelbine (25 mg/m2). The primary
      tumor in the right lung and liver metastasis were markedly reduced in size and a
      partial response was obtained. The combination therapy of CDDP and vinorelbine
      may become a standard chemotherapy for advanced non-small cell lung cancer.

PMID- 12402431
TI  - [A case of preoperative concurrent chemoradiotherapy and curative resection for
      locally advanced non-small-cell lung cancer].
AB  - We report the case of a 58-year-old man who underwent complete resection for
      locally advanced non-small-cell lung cancer (cT4N2M0). The patient received UFT
      (400 mg/m2 orally on days 1-14 and 22-35) and cisplatin (80 mg/m2 intravenously
      on days 8, 29) with a total 40 Gy, delivered in 20 fractions on days 1-26. The
      tumor reduction rate was 76%, and no remarkable toxicities were observed. The
      patient underwent complete resection and a pathologic complete response was
      observed. This induction concurrent chemoradiotherapy (followed by surgery) is
      considered to be effective and safe.

PMID- 12402432
TI  - [A case of effective bisphosphonate therapy for bone metastasis from breast
      cancer with multiorganic metastases].
AB  - A 50-year-old woman with a past history of breast cancer was referred to our
      department of radiology for detailed examination after abnormal shadows on chest
      x-ray were detected following a routine medical examination. After lung biopsy
      via thoracotomy, segmental resection of the lung was performed and mediastinal
      lymph nodes were dissected. A histopathological diagnosis of breast cancer with
      lung metastasis and mediastinal lymph-node metastases was made. Later, the
      patient complained of pain in the left lower extremity. A diagnosis of a left
      tibial metastasis was made according to bone scintigraphy and MRI. Radiation
      therapy at 50 Gy was then initiated. Chemotherapy and hormone therapy combined
      with bisphosphonate therapy (Bisphonal, once in 2 weeks), was also begun. During
      the treatment, the patient had multiple organ metastases including multiple brain
      metastases, and metastases to submental lymph nodes and the left adrenal gland.
      However, her bone metastasis was limited to the left tibial bone and no other
      bone lesions were detected by bone scintigraphy and MRI. She did not experience
      adverse effects from the bisphosphonate therapy. We consider that the inhibition
      of extension and further metastases of the tibial bone metastasis noted in this
      patient reflected the efficacy of bisphosphonate therapy, and that bisphosphonate
      therapy might become an essential treatment in patients with bone metastasis of
      breast cancer.

PMID- 12402433
TI  - [A case of recurrent hepatocellular carcinoma successfully treated with a
      combination therapy of interferon-alpha and intravenous continuous infusion of 5
      fluorouracil].
AB  - We report a case of recurrent hepatocellular carcinoma (HCC) successfully treated
      with a combination therapy of interferon-alpha (IFN-alpha) and 5-fluorouracil (5
      FU), which was administered intravenously. A 49-year-old Japanese man who
      underwent a right hepatectomy for HCC developed tumor recurrence in the liver 19
      months after surgery. Abdominal CT revealed multiple metastatic lesions in the
      liver. He received a combination therapy of 500 mg/day of 5-FU that was given
      intravenously by continuous infusion and 5 x 10(6) units of IFN-alpha, given
      three times weekly. The treatment resulted in a fall in serum PIVKA-II (protein
      induced by vitamin K antagonism) levels from 337 mAU/ml to 65 mAU/ml and
      disappearance of tumor stain in enhanced CT. 5-FU is usually administered by
      arterial infusion in a combination therapy of IFN-alpha and 5-FU. However, 5-FU
      infusion may be possible intravenously in the combination therapy of IFN-alpha
      and 5-FU for the treatment of advanced HCC.

PMID- 12402434
TI  - [Angina attack caused by 5-fluorouracil infusion--report of a case and review of
      the literature].
AB  - Cardiac toxicity of 5-fluorouracil (5-FU) has been rarely reported. We
      encountered a case of angina attack caused by 5-FU. A 58-year-old Japanese woman
      underwent sigmoidectomy for a sigmoid colon carcinoma with multiple liver
      metastases. Two months after surgery, she received chemotherapy comprising
      hepatic arterial infusion of 5-FU. During the 2nd chemotherapy session 7 days
      after the first, she complained of anterior chest pain. Her electrocardiograms
      showed elevations of the ST segment in almost all leads, confirming the diagnosis
      of angina pectoris. Soon after the third chemotherapy session the same type of
      attack occurred again. The close association of the attacks with 5-FU
      administration suggested that the angina might have been induced by 5-FU. Further
      attacks were avoided by discontinuing the 5-FU thereafter. The incidence of
      cardiac toxicity 5-FU has been reported to be 1.6-7.6%. Labianca et al. found 17
      cases of 5-FU-associated cardiopathy, 15 of which were angina pectoris, out of
      1,083 patients treated with the drug for various kinds of neoplasm. Analysis of 6
      domestic cases including ours revealed that all patient lacked a previous history
      of cardiac disease except one who had an arrhythmia. There seemed to be no dose
      dependent correlation with 5-FU-induced angina. Cardiac events were found even in
      the earlier phase of chemotherapy. Since 5-FU is widely used in the treatment of
      a number of gastrointestinal malignancies, one should bear in mind its cardiac
      toxicity, manifested as angina pectoris.

PMID- 12402435
TI  - [A trial of continuous and biweekly low-dose cisplatin and 5-FU with UFT
      chemotherapy for esophageal cancer].
AB  - A 77-year-old man with advanced esophageal cancer with tracheal and esophageal
      obstruction underwent continuous low-dose FP chemotherapy for a total of seven
      weeks, resulting in a complete response (CR) and disappearance of the esophago
      tracheal fistula. Since discharge from the hospital, he has maintained a stable
      good condition for about two years while receiving biweekly low dose FP
      chemotherapy and oral UFT. Eight patients who had post-operative recurrence and
      underwent noncurative operation for esophageal cancer were given low-dose FP
      chemotherapy. The results of this chemotherapy for those 8 patients and the
      present patient, for a total of 9 patients were 2 CR, 2 PR, 3 NC and 2 PD, with
      an overall response rate of 44%, and overall one-year and two-year survival rates
      of 44% and 22%, respectively.

PMID- 12402436
TI  - [Complete response in a case of advanced scirrhous type 3 gastric cancer of with
      bulky N2 para-aorta lymph node metastases treated by combined chemotherapy of TS
      1 and CDDP].
AB  - A 54-year-old patient with scirrhous type 3 gastric cancer having bulky N2 and
      para-aorta lymph node metastases was treated by combined chemotherapy of TS-1 and
      CDDP. Before treatment, CEA was 28.4 mg/ml. TS-1 (120 mg/day) administered for 14
      days followed by 14 days rest was one course. CDDP (80 mg/m2) was administered by
      24 hour continuous intravenous infusion at day 8 after the start of TS-1. After 2
      courses of treatment, the level of CEA decreased to 1.4 mg/ml and the primary
      legion with lymph node metastases had decreased significantly. After 5 courses,
      endoscopic examination revealed complete disappearance of the primary tumor with
      no cancer cells detected by endoscopic biopsy. A CT scan also showed complete
      disappearance of all lymph node metastases. No severe adverse effects (NCI-CTC
      grade 3 of 4) were observed with this therapy. TS-1/CDDP chemotherapy is
      considered very effective for scirrhous gastric cancer with far advanced lymph
      node metastases.

PMID- 12402437
TI  - [TS-1/CDDP therapy for advanced gastric cancer as neoadjuvant chemotherapy].
AB  - Five patients with inoperable advanced gastric cancer were treated with
      combination chemotherapy of TS-1 and cisplatin (CDDP). TS-1 of 80-120 mg/body/day
      was orally administered for 3 weeks followed by 2 drug-free weeks, and 60
      mg/m2/day of CDDP was venally administered on Day 8. It was possible to evaluate
      all 5 patients for response and toxicity. Only low grade toxicities (Grade 1 or
      2) of leukocytopenia, neutrocytopenia, anemia, nausea, diarrhea and stomatitis
      were seen. Four of 5 patients achieved a partial response, for a response rate of
      80.0%. Stomach, liver, lymph node and peritoneal tumors responded to TS-1/CDDP.
      TS-1/CDDP therapy produces a high response in cases of gastric cancer, and it is
      useful as a neoadjuvant chemotherapy.

PMID- 12402438
TI  - [Effective use of TS-1 in a case of advanced gastric cancer, both in treating the
      tumor and in maintaining the patient's quality of life].
AB  - A 60-year-old man was admitted to our hospital suffering from discomfort in the
      epigastrium. Endoscopic examination revealed stenosis from the fornix to the body
      of the stomach. The lesion had invaded the lower esophagus. Biopsy specimens
      confirmed poorly differentiated adenocarcinoma. An abdominal CT scan showed the
      lesion was a single mass in the stomach and swollen lymph nodes at the fornix,
      and revealed slight ascites and left hydronephrosis. The patient received oral
      administration of TS-1. No adverse effect was seen after 3 courses of treatment,
      and the lesion was reduced so that it was only found in the fornix. During the 1
      year and 3 months of treatment with TS-1, this patient worked as mountain guide
      in the Hida area and was able to travel to the Himalayas in Nepal for the New
      Year of 2001. To preserve the quality of life of cancer patients, it is worth
      considering outpatient treatment with TS-1.

PMID- 12402439
TI  - [A case of gastric cancer with multiple liver metastases responding to combined
      hepatic arterial and aortic infusion chemotherapy with cisplatinum, 5
      fluorouracil, and levofolinate calcium].
AB  - A 64-year-old man who had type IIc-like advanced gastric cancer with multiple
      liver metastases was admitted to our hospital. He underwent combined hepatic
      arterial and aortic infusion chemotherapy with cisplatinum (CDDP), 5-fluorouracil
      (5-FU), and levofolinate calcium (l-LV). After 4 weeks (2 courses) of
      chemotherapy, a partial response was achieved for the hepatic metastasis.
      Therefore, distal gastrectomy, right hepatectomy combined with caudate lobectomy,
      partial resection of the hepatic right lobe, and microwave coagulation therapy of
      the residual tumor of the hepatic right lobe were performed. With this operation,
      all tumor cells were removed or killed. Histopathologically, almost all of the
      primary tumor was fibrous tissue, and only a few sections of moderately
      differentiated adenocarcinoma observed in the subserosal layer. In the periphery
      of the metastatic lesion, residual well to moderately differentiated
      adenocarcinomas were observed, and in the center, only necrotic tissue was seen.
      The postoperative course was uneventful. Now, one year and seven months after the
      operation, he is followed as an outpatient. Combined hepatic arterial and aortic
      infusion chemotherapy with CDDP, 5-FU, and l-LV is thought to be an effective
      regimen for advanced gastric cancer with multiple liver metastases.

PMID- 12402440
TI  - [A case of postoperative liver metastasis from gastric cancer which responded
      well to weekly chemotherapy with paclitaxel].
AB  - We report a case of postoperative liver metastasis from gastric cancer showing a
      remarkable response to weekly administration of paclitaxel (TXL). The patient was
      a 50-year-old woman who underwent total gastrectomy. One month later, liver
      metastasis and a small amount of ascites were detected by CT scan. Therefore, the
      patient was administered weekly TXL. TXL (80 mg/m2) was infused over 1 hour after
      short premedication on an outpatient basis. Administration was continued for 3
      weeks followed by 1 week rest. Liver metastasis and ascites disappeared 3 months
      after administration. The toxic events were leukopenia (grade 1) and alopecia
      (grade 1). No major adverse effects were observed.

PMID- 12402441
TI  - [A case of colon metastasis to the lung treated successfully with combined
      chemotherapy of CPT-11 and 5'-DFUR].
AB  - We administered pharmacokinetic modulating chemotherapy (PMC, oral tegafur/uracil
      [UFT] plus fluorouracil infusion) together with irinotecan hydrochloride (CPT-11)
      in a patient with rectal cancer, who had multiple lung metastases at 2 years and
      7 months after surgery. However, because the patient showed resistance, we
      attempted combination therapy with CPT-11 and doxifluridine (5'-DFUR) on an
      outpatient basis, which resulted in NC after 9 months. During this period, the
      therapy was performed safely without any observable adverse reactions such as
      diarrhea or myelosuppression. This case suggests the efficacy of combination
      therapy with CPT-11 and 5'-DFUR, which was expected since this is an established
      treatment for progressive recurrent colon cancer.

PMID- 12402442
TI  - [A study of usefulness of chemotherapy in long-term survival choroid plexus
      carcinoma case of childhood].
AB  - We report a girl who was diagnosed with choroid plexus carcinoma at the age of 7
      and has had an active daily life in the 11 years after onset. She underwent two
      tumor excision operations and received radiotherapy followed by intensive
      chemotherapy using cisplatin, carboplatin, and etoposide. In general, the
      prognosis of choroid plexus carcinoma is very poor, especially in the childhood
      cases, since no optimal treatment for choroid plexus carcinoma has yet been
      established. However, the results of analyses of the present long-term survival
      case, and similar long-term survival cases in the literature, strongly suggest
      the usefulness of chemotherapy in the treatment of choroid plexus carcinoma in
      children.

PMID- 12402443
TI  - [A case of hypopharyngeal carcinoma in which a complete response to chemotherapy
      was achieved with docetaxel, cisplatin, 5-FU and levofolinate].
AB  - We treated a patient with hypopharyngeal carcinoma who achieved a complete
      response following three cycles of chemotherapy with docetaxel, cisplatin, 5-FU
      and levofolinate. A 77-year-old Japanese male with hypopharyngeal carcinoma had
      undergone a radical esophageal operation and subsequent radiation therapy in the
      lower neck and upper mediastinum in 1991 because of esophageal carcinoma. He
      refused radical total laryngopharyngotomy, and agreed to chemotherapy. Three
      cycles of chemotherapy with docetaxel, CDDP, 5-FU and l-LV were then administered
      and no other therapy was given. Sixteen months after this chemotherapy he had no
      recurrence and no metastasis. We conclude that chemotherapy using docetaxel,
      cisplatin, 5-FU, and levofolinate will be useful for treating head and neck
      cancer.

PMID- 12402444
TI  - [Theory for identification of disease-related genes using genetic polymorphisms].
AB  - There are 2 different approaches to search for disease-related genes: a knowledge
      based approach using the functions of molecules, and a statistics-based approach
      using polymorphisms. In the latter approach, researchers search for disease
      related sequences or test the association between the sequence and the disease
      using statistics. Statistical methods are classified into 2 subdivisions: a
      linkage-based method and a linkage-disequilibrium-based method. For the former
      method, Mendel's laws are directly applied and the samples should be families,
      while for the latter method, Mendel's laws are only indirectly applied and the
      samples do not have to be families. As an example of the former method, an
      algorithm of linkage analysis based on the Lander-Green algorithm in which hidden
      Markov model is used is explained herein. As an example of the latter method, a
      program inferring haplotype frequencies and diplotype configurations of
      individuals is explained.

PMID- 12402445
TI  - Regulation of cerebral blood flow in patients with autonomic dysfunction and
      severe postural hypotension.
AB  - BACKGROUND: Whether cerebral blood flow (CBF) autoregulation is maintained in
      autonomic dysfunction has been debated for a long time, and the rather sparse
      data available are equivocal. The relationship between CBF and mean arterial
      blood pressure (MABP) was therefore tested in eight patients with symptoms and
      signs of severe cardiovascular autonomic dysfunction. PATIENTS AND METHODS: Eight
      patients were included, three of whom had Parkinson's disease, three diabetes,
      one pure autonomic failure and the last one had multiple system atrophy. By the
      use of two techniques, the arteriovenous oxygen [(a-v)O2] method and xenon
      inhalation with single photon emission tomography, 15 measurements (range 10-20)
      and three to four CBF measurements, respectively, were obtained in each patient.
      Following CBF measurements during baseline, MABP was raised gradually using
      intravenous noradrenaline infusion, and then lowered by application of lower body
      negative pressure. From the (a-v)O2 samples the CBF response to changes in MABP
      was evaluated using a computer program fitting one or two regression lines
      through the plot. RESULTS AND CONCLUSION: Preserved autoregulation was observed
      in three patients, while the remaining five patients showed a linear relationship
      between CBF and MABP. Comparison of the results of the tomographic CBF
      measurements to the (a-v)O2 data demonstrated that it is not possible to assess
      whether CBF is autoregulated or not with only three to four pairs of data.

PMID- 12402446
TI  - The validity of the Computer Science and Applications activity monitor for use in
      coronary artery disease patients during level walking.
AB  - The principal aim of the present study was to examine the validity of the
      Computer Science and Applications (CSA) activity monitor during level walking in
      coronary artery disease (CAD) patients. As a secondary aim, we evaluated the
      usefulness of two previously published energy expenditure (EE) prediction
      equations. Thirty-four subjects (29 men and five women), all with diagnosed CAD,
      volunteered to participate. Oxygen uptake (VO2) was measured by indirect
      calorimetry during walking on a motorized treadmill at three different speeds
      (3.2, 4.8 and 6.4 km h-1). Physical activity was measured simultaneously using
      the CSA activity monitor, secured directly to the skin on the lower back (i.e.
      lumbar vertebrae 4-5) with an elastic belt. The mean (+/- SD) activity counts
      were 1208 +/- 429, 3258 +/- 753 and 5351 +/- 876 counts min-1, at the three
      speeds, respectively (P < 0.001). Activity counts were significantly correlated
      to speed (r = 0.92; P < 0.001), VO2 (ml kg-1 min-1; r = 0.87; P < 0.001) and EE
      (kcal min-1; r = 0.85, P < 0.001). A stepwise linear regression analysis showed
      that activity counts and body weight together explained 75% of the variation in
      EE. Predicted EE from previously published equations differed significantly when
      used in this group of CAD patients. In conclusion, the CSA activity monitor is a
      valid instrument for assessing the intensity of physical activity during
      treadmill walking in CAD patients. Energy expenditure can be predicted from body
      weight and activity counts.

PMID- 12402447
TI  - Ventilatory efficiency and rate of perceived exertion in obese and non-obese
      children performing standardized exercise.
AB  - Sixty children, in the age span 6-17 years originally divided into two groups,
      matched by age, sex and height--30 obese subjects [15 girls/15 boys; body mass
      index (BMI) = 27.4 +/- 4.5 m kg-2; ideal body weight (IBW) range = 122-185%] and
      30 controls (BMI = 18.8 +/- 2.7 m kg-2) performed incremental treadmill exercise
      test. Perceived exertion was assessed by means of Category-Ratio Borg scale. The
      duration of the exercise for the children in the obesity group was significantly
      shorter than controls (P = 0.010) but obese children have greater absolute values
      for oxygen uptake (VO2peak ml min-1 = 1907 +/- 671 versus 1495 +/- 562; P =
      0.013) and ventilatory variables (VE, VT), which adjusted for body mass decrease
      significantly (VO2/kg ml min-1 kg-1 = 29.2 +/- 3.8 versus 33.6 +/- 3.5; P <
      0.001). Among the various methods for 'normalizing' absolute values of VO2peak
      for body size, dividing it by body surface area (BSA) yielded the best results
      (VO2/BSA ml min-1 m-2 = 43.5 +/- 4.6 versus 44.7 +/- 5.6; P = 0.335). The
      ventilatory efficiency determined either as a slope of VE versus VCO2 or as a
      simple ratio at anaerobic threshold did not differ between obese and non-obese
      children in the incremental and recovery periods of exercise. There was a
      negative correlation of VE/VCO2 slope with age and anthropometric parameters.
      Obese children rated perceived exertion significantly higher than controls
      despite the standard workload (Borg score = 6.2 +/- 1.2 versus 5.2 +/- 1.1; P =
      0.001). In conclusion, the absolute metabolic cost of exercise is higher in the
      obesity group compared with the control subjects. Both groups have similar
      ventilatory efficiency but an increased awareness of fatigue that furthermore
      limits their physical capacity.

PMID- 12402448
TI  - Repeatability of measurements of oxygen consumption, heart rate and Borg's scale
      in men during ergometer cycling.
AB  - The coefficient of repeatability (COR), expressed as 2-SD of differences, was
      calculated between two measurements of oxygen consumption (V O2), heart rate (HR)
      and rating of perceived exertion (RPE) during ergometer cycling by men. The two
      sets of measurements were performed 5 to 6 weeks apart. Nineteen healthy men
      performed an incremental maximal exercise test on an ergometer cycle. The load
      started at 50 W and increased by 5 W 20 s-1 until exhaustion was reached. At 40%
      of the individual maximum load of the pretest, the load was kept constant for 4
      min in order to reach steady state. Gas measurements were recorded continuously
      by computerized instrumentation. The HR was monitored with electrocardiography
      (ECG) and the perceived exertion was evaluated using Borg's scale. The COR of V
      O2 at sub-maximal load was 14% and at maximum load 11%. The values in absolute
      figures were 209 and 332 ml min-1. The corresponding COR of the HR was 16% at sub
      maximum load and 6% at maximum load, and an evaluation of the perceived exertion
      yielded CORs in absolute values of 4.8 and 1.3, respectively. The COR for V O2,
      HR and ratings of perceived exertion when cycling on an ergometer cycle thus
      indicate a better agreement between the measurements at maximum load. The COR of
      the heart at sub-maximal loads must be kept in mind when using HR for estimation
      of V O2max. The reported findings should be considered when using tests on an
      ergometer cycle for evaluating exercise capacity.

PMID- 12402449
TI  - Measurement of the whole body clearance of infused glycerol as a test of liver
      function after major hepatectomy.
AB  - Major liver resection can be used in the treatment of liver cancer. The
      functional capacity of liver parenchyma needs to be evaluated preoperatively
      because it conditions the outcome. We assessed whether the whole body clearance
      of glycerol, a substrate essentially metabolized in liver cells, may be suitable
      as a simple test of liver function. Seven patients after major hepatectomy, six
      patients after colectomy and 12 healthy subjects were studied. Patients were
      investigated on the first day after surgery. All participants were studied during
      a 150-min basal period followed by a 120-min infusion of 16 mumol kg-1 min-1 13C
      labelled glycerol. Whole body glycerol clearance was calculated from the change
      in plasma glycerol concentration. Whole body glucose production was measured with
      6,6 2H2 glucose infused as a tracer in the basal state and during glycerol
      infusion. In addition, 13C glucose synthesis was monitored to quantitate
      gluconeogenesis from glycerol. Patients after liver resection had higher plasma
      glycerol concentrations and lower whole body glycerol clearance than healthy
      subjects and patients after colectomy. They also had higher plasma glucagon
      concentrations. Their fasting glucose production was mildly elevated in the
      fasting state and did not change after glycerol infusion, indicating a normal
      hepatic autoregulation of glucose production. These results indicate that whole
      body glycerol clearance can be simply determined from plasma glycerol
      concentrations during exogenous glycerol infusion. It is significantly reduced in
      patients after major hepatectomy, suggesting that it constitutes a sensitive test
      of hepatic function. Its use as a preoperative testing procedure remains to be
      evaluated.

PMID- 12402450
TI  - Cardiovascular effects of ophthalmic 0.5% timolol aqueous solution and 0.1%
      timolol hydrogel.
AB  - The objective of this randomized, double-masked, cross-over study was to compare
      the cardiovascular effects of two glaucoma formulations, ophthalmic 0.5% timolol
      aqueous solution and 0.1% timolol hydrogel. Twenty-four young healthy subjects
      received for 2 weeks either twice daily 0.5% timolol solution or once daily 0.1%
      timolol hydrogel. Heart rate (HR), blood pressure, atrio-ventricular conduction
      (PR interval), corrected QT time (QTc) and heart rate variability (HRV) were
      measured in supine position and during head-up tilted position. The mean peak
      concentrations of timolol in plasma were significantly higher after
      administration of 0.5% aqueous solution than after 0.1% hydrogel. A 0.5% timolol
      aqueous solution decreased HR on average by 3 bpm in supine position and by 7 bpm
      in head-up tilted position while no significant effects were observed with 0.1%
      timolol hydrogel. During tilt test HR was significantly lower after
      administration of timolol aqueous solution than after timolol hydrogel (mean +/-
      SD, 77 +/- 11 bpm versus 86 +/- 13 bpm, P < 0.05). Timolol aqueous solution
      slightly decreased QTc during tilt (5.9 +/- 5.6 ms, P < 0.01). During tilt tests,
      timolol aqueous solution slightly increased atrio-ventricular conduction (7.2 ms,
      P = 0.02). No significant differences were found in HRV. These results indicate
      that in healthy volunteers, ophthalmic 0.5% timolol aqueous solution produces
      more pronounced cardiac beta-blocking effects than 0.1% timolol hydrogel.

PMID- 12402451
TI  - Effects of athletic training on heart rate variability triangular index.
AB  - The purpose of this study was to assess the heart rate variability triangular
      index (HRVI) in elite track and field athletes. Sixty healthy males (mean aged
      22.1 +/- 3.5 years) -15 long distance runners (group A), 15 speed runners (Group
      B), 15 throwers (Group C) and 15 non-trained subjects (Group D) were submitted to
      spiroergometric test, m-mode echocardiography and 24-h ambulatory ECG monitoring.
      The HRVI, mean heart rate, mean interval between two consecutive R waves of the
      QRS complexes (R-R interval) and standard deviation of the R-R (SDRR) were
      assessed through time domain method on computed 24-h Holter recordings. The HRVI
      and the SDRR were 62.2 +/- 9.6 and 220 +/- 40 ms correspondingly in group A, 52.7
      +/- 6.0 and 210 +/- 40 ms in B, 44.5 +/- 5.3 and 180 +/- 40 ms in C, 39.3 +/- 6.4
      and 180 +/- 30 ms in D. The HRVI and the mean R-R were found to differ
      statistically between groups A, B and C versus D (P < 0.05). However, the higher
      value in HRVI was found in group A. Maximal oxygen consumption (VO2max) was 62.0
      +/- 4.4 ml kg-1 min-1 in group A, 52.7 +/- 6.0 in group B, 44.6 +/- 5.3 in C and
      41.6 +/- 6.0 in D. The higher value in VO2max was also found in group A. The left
      ventricular mass index (LVMI) and end-diastolic volume index (EDVI) were 136 g m
      2 and 83 ml m-2 correspondingly in group A, 136 and 79 in B, 124 and 56 in C and
      88 and 55 in group D. The HRVI was found to have a significant relationship with
      VO2max and EDVI only in group A. On the other hand, no significant relationships
      were found between HRVI and LVMI in all groups. It is concluded, that the
      enhanced HRVI in athletes is affected by exercise training pattern. Moreover,
      HRVI depends on the level of VO2max in endurance-trained, but is independent from
      the extent of myocardial hypertrophy in all types of training.

PMID- 12402452
TI  - Intracellular free calcium in the neutrophils of maintenance haemodialysis
      patients.
AB  - Chronic renal failure has on occasion been referred to as a state of calcium
      toxicity. The aim of this study was to investigate the status of intracellular
      free Ca2+ in the neutrophils of chronic renal failure patients on maintenance
      haemodialysis treatment. Factors previously suggested to influence intracellular
      free Ca2+ were investigated including PTH levels, oxidative stress and
      recombinant human erythropoietin administration. The study involved 14 chronic
      renal failure patients on the haemodialysis programme of the Pretoria Academic
      hospital. Intracellular free Ca2+ and transmembrane Ca2+ fluxes were investigated
      by fluorescence spectrophotometry. Increases above control values were found in
      intracellular free Ca2+ (P-value 0.0242) and in the transmembrane Ca2+ flux upon
      fMLP stimulation (P-value 0.0002). The results showed significant differences in
      intracellular free Ca2+ between patients on rHuEPO and patients not on rHuEPO.
      The apparently rHuEPO-induced increase in intracellular free Ca2+ persisted in
      the presence of calcium channel blockers. No overt indications of oxidative
      stress could be detected by the antioxidant vitamin levels. It is concluded that
      factors other than those associated with uraemia, such as rHuEPO administration,
      might contribute to the often reported increase in intracellular free Ca2+ in
      these patients. Further studies to investigate the relationship between
      intracellular free Ca2+, rHuEPO and calcium channel blockers are suggested.

PMID- 12402453
TI  - Neural networks--a diagnostic tool in acute myocardial infarction with
      concomitant left bundle branch block.
AB  - The prognosis of acute myocardial infarction (AMI) improves by early
      revascularization. However the presence of left bundle branch block (LBBB) in the
      electrocardiogram (ECG) increases the difficulty in recognizing an AMI and
      different ECG criteria for the diagnosis of AMI have proved to be of limited
      value. The purpose of this study was to detect AMI in ECGs with LBBB using
      artificial neural networks and to compare the performance of the networks to that
      of six sets of conventional ECG criteria and two experienced cardiologists. A
      total of 518 ECGs, recorded at an emergency department, with a QRS duration > 120
      ms and an LBBB configuration, were selected from the clinical ECG database. Of
      this sample 120 ECGs were recorded on patients with AMI, the remaining 398 ECGs
      being used as a control group. Artificial neural networks of feed-forward type
      were trained to classify the ECGs as AMI or not AMI. The neural network showed
      higher sensitivities than both the cardiologists and the criteria when compared
      at the same levels of specificity. The sensitivity of the neural network was 12%
      (P = 0.02) and 19% (P = 0.001) higher than that of the cardiologists. Artificial
      neural networks can be trained to detect AMI in ECGs with concomitant LBBB more
      effectively than conventional ECG criteria or experienced cardiologists.

PMID- 12402454
TI  - [Metabolism and receptors of leukotriene B4].

PMID- 12402455
TI  - [Reorganization of the actin cytoskeleton by WASP family proteins].

PMID- 12402456
TI  - [Three-dimensional structures and dimerization of alpha-amylases hydrolyzing a
      polysaccharide, pullulan].

PMID- 12402457
TI  - [Peroxisomal ABC proteins and adrenoleukodystrophy].

PMID- 12402458
TI  - [Heparan sulfate and axon guidance].

PMID- 12402459
TI  - [Abnormal glycosylation and muscular dystrophy].

PMID- 12402460
TI  - [Tissue expression of the tropomyosin gene of Caenorhabditis elegans--enhancer
      modification of the promoter control].

PMID- 12402461
TI  - [Identification of a novel substrate of Alzheimer's beta-secretase: beta
      secretase dependent cleavage of alpha 2,6 sialyltransferase].

PMID- 12402462
TI  - [Stress management for office workers].
AB  - The environment which surrounds office workers has undergone a big transformation
      with the collapse of lifetime employment, the shift from the long employment
      principle to meritocracy, the results principle, the introduction of flexible
      work hours, outsourcing and dispatch work. Today's office worker stressor include
      1. VDT work, 2. meritocracy, 3. management by objective, 4. excessive load on the
      middle and advanced age generations, 5. the collapse of the lifetime employment
      system and 6. non-employee changes. (1) VDT work management, (2) the use of
      Information technology, (3) Improvement of office environments, (4) Management of
      long overtime work and (5) Support of superiors and colleagues are thought as
      stress management.

PMID- 12402463
TI  - [Evaluation of a swiveling seat to reduce the physical load on forklift drivers].
AB  - Many forklift drivers have musculoskeletal disorders such as low back pain
      related to poor work posture and whole-body vibration. With a forklift operator's
      seat capable of 45-degree swiveling, we evaluated the physical reduction in the
      load in 10 subjects working in a back-looking position by means of surface
      electromyography (EMG) and the angle of rotation of the trunk and neck regions.
      The amplitude of surface EMG on the trapezius, erector spinae, and latissimus
      dorsi muscles in looking back or maintaining a back-looking position decreased
      with a swiveling seat compared to the stationary seat. Nevertheless, there was
      little alleviation of the amplitude of surface EMG on the sternocleidomastoid
      muscle in maintaining a back-looking posture and no decrease in looking back. The
      angle of rotation of the trunk maintaining a back-looking position was decreased
      greatly with the swiveling seat, but no decrease in the rotation angle of the
      neck was seen. Our study suggests that a swiveling seat is effective in reducing
      the physical load on the forklift driver during back-looking operations, and this
      may lead to the prevention of low back pain.

PMID- 12402464
TI  - [A survey of utilization of and problems with the MSDS in chemical substances
      management at workplaces in Kanagawa Prefecture].
AB  - Kanagawa Occupational Health Promotion Center conducted a survey on how the MSDS
      is utilized at workplaces with more than 50 employees handling chemical
      substances, and what measures are taken to help employees to thoroughly
      understand information in the Material Safety Data Sheet (MSDS). Questionnaires
      were sent out to 265 enterprises in Kanagawa prefecture, putting questions to
      industrial physicians and industrial hygiene supervisors. The objective of the
      survey was to find out how MSDS is adopted in the system to manage occupational
      health, what improvements the survey respondents want in MSDS and what
      expectations the respondents have of our center. 193 enterprises (72.8%) returned
      answers to the questionnaire. The major findings are as follows. (1) In many
      companies, information on hazardous/toxic materials is "controlled by a division
      using such materials", and roughly half of the companies have compiled a common
      list shared throughout the company. (2) For the most part suppliers submit to the
      MSDS. Larger companies have a higher rate of posting up or filing the MSDS at
      their workplaces. Only 25.8% of the companies "rewrite the MSDS so that workers
      can understand it." (3) Companies that carry out a hazard/toxicity assessment
      before introducing a new chemical substance account for 72.1%, which is higher
      than we expected. It indicates that even though the companies don't manage the
      MSDS adequately, they are highly concerned about hazard control of chemical
      substances. (4) The rate of answering that "the current MSDS is not easy to
      understand" is higher among large-sized enterprises and lower among enterprises
      with fewer than 300 employees. (5) Asked what improvement needs to be made on the
      MSDS, the industrial physicians and industrial hygiene supervisors gave same
      answers such as "Workers find the terminology difficult to understand." and
      "Levels of toxicity can't be clearly identified." (6) The respondents expect our
      center to provide information for the MSDS. In conclusion, it is considered that
      in order to prepare understandable MSDSs to workers in enterprises, the role of
      our center to provide information and education on the MSDS to respondents was
      important.

PMID- 12402465
TI  - [Willingness to implement mental health measures among small-scale enterprise
      employers in Ohta ward, Tokyo, Japan].
AB  - Due to the increase in mental health problems among Japanese workers in recent
      years, effective approaches to address these problems are of growing concern.
      Although such an effort is now under way in largescale enterprises (LSEs), small
      scale enterprises (SSEs) are lagging behind LSEs for a number of reasons. In the
      present study, to know the reason, the presidents of 263 SSEs (fewer than 50
      employees) in the Ohta ward of Tokyo were surveyed with a self-administered
      questionnaire from October 1999 to March 2000 (response rate, 51.0%). The main
      business types were manufacturing (71.2%), transportation & storage (6.1%), and
      construction (5.3%). The results revealed that employers attribute the mental
      health problems of employees to "Job content/Aptitude for job (78.6%)",
      "Communication among employees (71.0%)", "Physical problems/Illness (50.4%)",
      "Family problems (33.6%)". These results are very similar to those obtained in
      the same enterprises employees survey in 1996, suggesting that employers perceive
      the factors responsible for employees' mental health problems with substantial
      accuracy. Sixty-nine point five percent of the employers answered that they need
      mental health measures for employees. And 62.7% of employers agreed to take
      mental health measures in their enterprises. Taken together, it is considered
      that employers are willing to improve their employees' mental health problems.
      Nevertheless, 95% of employers are doing nothing to improve the situation. The
      major reasons cited were 1) Cannot obtain a consultant or counselor (44.8%), 2)
      Lack of time (43.1%), 3) Manpower shortage (41.4%), 4) Difficulty in ensuring
      employees' privacy (36.2%), and 5) Lack of financial resources (30.2%). The
      results of the present study suggest that perception of the mental health
      problems among employers and employees of SSEs in the Ohta area were close to
      each other. Effective strategies are needed to improve mental health problems in
      SSEs.

PMID- 12402466
TI  - [Academic program on behavioral sciences in the National Institute of Public
      Health].

PMID- 12402467
TI  - [Analysis of factors affecting breakfast skipping by male students undergoing
      hard training for sports].
AB  - PURPOSE: The purpose of this survey was to find factors affecting breakfast skip
      rates for male students participating in sports, and to determine how to improve
      their nutrition. METHODS: The survey was conducted on 86 male students (58 who
      played sports and 28 who did not). A questionnaire was supplied to all,
      containing questions concerning daily food eating behavior. The student's answers
      were evaluated according to the guidelines of the Ministry of Health and Welfare.
      In addition, blood pressure, body mass index, and serum levels of uric acid,
      triglycerides and ferritin were measured in all subjects. RESULTS: The breakfast
      skip rate was 36% for the sports club affiliation group, and 46.4% for the non
      affiliation group. Students who were not supplied with meals from their mothers
      or dormitory food service had more irregular meal times, skipped breakfast more,
      and drank less milk and miso soup often than the students supplied with meals.
      Students playing sports, but not supplied with meals, had a lower evaluation
      regarding eating habits and higher serum levels of serum uric acid and ferritin,
      compared to the students supplied with meals. CONCLUSIONS: The eating habits of
      male students are affected by whether they receive meals or not. It is considered
      that the higher levels of serum uric acid and ferritin in the students not
      supplied with meals is due to their irregular eating habits and heavy exercise.
      It is suggested that nutritional guidance is needed for such students.

PMID- 12402468
TI  - [Differences in subject needs between nursing home residents' and residential
      care professional's perspectives].
AB  - OBJECTIVE: Considerable attention has been directed toward the quality of nursing
      home care, with a more recent focus on residents' perspectives concerning bio
      psychosocial needs. Several researchers have reported professional and patients'
      perspectives to be consistently different regarding biopsychosocial needs. The
      objective of this study was to examine such differences. METHODS: A cross
      sectional survey was conducted, with interviews of nursing home residents and a
      self-administered questionnaire for residential care professions. The data were
      obtained from 85 matched pairs in 6 nursing homes. The measures for subjective
      needs of the residents had three dimensions (physical, psychological, and social)
      covering 8 sub-categories. Analyses of the data offered good evidence of
      reliability (internal consistency) and content validity. RESULTS: In an agreement
      statistic analysis using Cohen's kappa, the residents' and care professional
      perspectives significantly differed regarding subject needs. In another analysis
      using t-tests, measures for subject needs derived from residential care
      professionals were consistently greater than those with nursing home residents.
      This tendency was generally consistent across sub-categories by ADL levels.
      However, the ranking order for the 7 sub-categories for subject needs was very
      similar with both raters. CONCLUSION: Assessing nursing home residents' subject
      needs represents an important and essential component of quality of care.
      However, needs assessment by the residential care profession is still its infancy
      and includes failure to consider the residents' perspective. The future research
      challenge is to find reasons for the gap in subjective thinking between the
      groups. In addition, researchers can perform a critical function on behalf of
      nursing home residents when they suggest improvements to the methodology for
      assessing residential care professionals views on residents' needs.

PMID- 12402469
TI  - [Nutrient intake of elderly people with care need and caregivers based on data of
      the Comprehensive Survey of the Living Conditions of People on Health and Welfare
      and the National Nutrition Survey in Japan].
AB  - OBJECTS: This study examined the nutritional intakes of elderly people with care
      needs and of the caregivers, using data of the Comprehensive Survey of the Living
      Conditions of People on Health and Welfare and the National Nutrition Survey in
      1995. METHODS: Four groups were categorized: elderly people with care needs (65
      and older, n = 83), female caregivers (40 and older, n = 95), other elderly
      people (65 and older, n = 1,818), and other women (40 and older, n = 3,477). The
      ratios of intakes to dietary reference intakes (DRIs) for energy and 8 nutrients
      (protein, fat, calcium, iron, vitamin A/B1/B2/C), as well as salt, were compared
      among those four groups. RESULTS: Mean ratios to DRIs in elderly people with care
      needs were 108% for energy, 85% for calcium, and 101-224% for the other 7
      nutrients. Mean salt intake in this group was 11.0 g/day. For many nutrients,
      ratios to DRIs were significantly lower than those in other elderly people. Mean
      ratios to DRIs in caregivers were 104-294% for energy and the 8 nutrients, and
      mean salt intake was 12.8 g/day, with no significant differences from date for
      other women. CONCLUSION: This study cast light on the status of the nutrient
      intake in elderly people with care needs and their caregivers. It was suggested
      that calcium intake was insufficient in the former.

PMID- 12402470
TI  - ["Neoceader" contains nicotine. A report of two user's nicotine addiction].
AB  - "Neoceader smoking" is widely marketed in drug stores as an over the counter
      expectorant for cigarette smokers in Japan. Using high-pressure liquid
      chromatography, we determined that one piece of Neoceader (3 cm) contains 0.79 mg
      of nicotine, which is equivalent to one-sixth of the amount of nicotine in one
      Japanese cigarette (Mildseven extra-light, Mildseven super-light, or Sevenstar).
      Two patients who had switched from cigarette smoking to Neoceader smoking,
      subsequently became addicted to nicotine. The continine concentration in their
      urine were 937 ng/ml and 2,724 ng/ml, respectively. These findings demonstrate
      that Neoceader contains nicotine and that its use can lead to nicotine addiction.

PMID- 12402471
TI  - [A report of emergency counter-move at a local health center against the "heavy
      rain disaster on west-southern area of Kochi Prefecture].

PMID- 12402472
TI  - [Body lice measure in Toshima City strategy with a combination health and welfare
      department].

PMID- 12402473
TI  - [Factors influencing the utilization of visiting nursing and home-help services].
AB  - PURPOSE: To identify the respective characteristics of clients using visiting
      nursing service and home-help service. Since the past, research on the
      utilization of in-home care services has usually focused on different services
      collectively. METHODS: Interviews using structured questionnaires were carried
      out with 134 elderly individuals who were selected in October 1997 from the list
      for home visit of public health nurses in a town with a population of 36,000.
      With regard to the utilization of visiting nursing as well as home-help service,
      the relationship with three factors of the conceptual Andersen's model
      (predisposing factor, needs factor, enabling factor) were examined. RESULTS AND
      DISCUSSION: Of the 134 subjects, 38.1% utilized visiting nursing service and
      36.6% used home-help services. Use of visiting nursing service was significantly
      associated with variables such as declining ADL in the elderly, hospitalization
      within the past two years, less caregiving by family members, and less resistance
      to service-use by caregivers. On the other hand, use of home help service was
      related to less caregiving by family members and resources of visiting nursing.
      The clients who used both visiting nursing and home-help service had more
      difficulty with caregiving by family members compared to those who used only
      nursing service, and the latter were inferior in them of physical conditions,
      including ADL, to those who employed only home-helpers. CONCLUSION: The factors
      promoting the use of visiting nursing are different to some extent from those for
      home-help service. Clients using both are characterized by the presence of a
      broader variety needs.

PMID- 12402474
TI  - [Patients' evaluation of information provided by medical doctors on the invasive
      ventilator for amyotrophic lateral sclerosis. An analysis of a survey of patients
      and their families in Japan].
AB  - OBJECTIVE: The study aim was to evaluate by ALS patients' satisfaction regarding
      information about invasive ventilators provided by medical doctors. METHODS: Semi
      structural interviews were conduced for 12 cases (11 patients and 9 family
      members provided information) at three areas in Japan. RESULTS: 1) Most patients
      were unsatisfied with the information by doctors; 2) some cases felt strong
      distrust of doctors' attitudes; 3) more than half of the cases complained of
      insufficient information. CONCLUSION: This study suggests that in the informed
      consent for ALS patients, doctors' negative attitudes to life prolongation
      adversely impact on ALS patients. Roles of service providers, patients and family
      members should be reconsidered for cases of ALS and other incurable diseases.

PMID- 12402476
TI  - [Evaluation of a community-based preventive care program for elderly living at
      home].
AB  - PURPOSE: The purpose of this study was to evaluate a community-based preventive
      care program focused on physical and psychosocial status of frail elderly living
      at home. METHOD: The study had a prospective cohort design. Community-dwelling
      frail elderly not applying for the long-term insurance system care were assigned
      to a participant group (n = 71), wishing to participate in the community-based
      preventive care program, and a non-participant group (n = 40) who did not have
      the intention. The care program included activities and health education for
      elderly to promote their social contacts. Outcome variables were Activities of
      Daily Living (FIM), upper extremity function, time required for a 1.5 meter walk,
      health complaints, cognitive function (MMSE), psychological Quality of Life
      (QOL), depression (GDS), modified fall-related self efficacy (MFES), self
      efficacy for health promotion (SEHP), and social network. Data were collected
      prior to and at 6 months and 12 months after the intervention. RESULTS: 1. At the
      baseline, the number of female (P = .033) and B day service use (P = .001) in the
      participant group was significantly greater, and the number reporting falls (P =
      .017) and A day service use (P = .014) was lower than the non-participant group.
      MMSE (P = .032), MFES (P = .001), and SEHP scores (P = .017) as well as the
      social network values (P = .022) in the participant group were significantly
      higher than for the non-participant group. 2. The participants demonstrated
      significant effectiveness in the MMSE scores (P = .002) during the follow-up
      period, values after both 6-months (P = .002) and 12-months (P = .005) follow-up,
      being lower than in the non-participant group. 3. The participant group also
      demonstrated significant effectiveness in the GDS score (P = .033) during the
      study period, their values being lower after 12-months (P = .070) than in the
      other group. CONCLUSION: The results indicated that the community-based
      preventive care program to the elderly could effect on cognitive function and
      depression.

PMID- 12402475
TI  - [A survey of infants requiring long-term neonatal intensive care in Tokyo: 1989
      1998].
AB  - In order to grasp the characteristics and outcomes with infants hospitalized long
      term in NICUs, we reviewed all summary charts of 18 perinatal medical centers in
      Tokyo for the period from January 1989 to December 1998. We sampled 3,000 infants
      who required neonatal intensive care over 90 consecutive days out of 46,309
      registered cases during the decade. The duration of hospital stay, making a
      comparative analysis of the number of days for the 50 percentile, was as follows.
      As a whole the infants required 125 days until discharge. Infants with 29-30
      weeks gestation and infants with birth weights 1,000-1,499 g required shorter
      stays (106 days in both cases). The "discharge with complications" group required
      136 days, and the "discharge on remission" group 119 days. Within the 31-32 weeks
      gestation group, those with "discharge with complications" required 107 days.
      Within the 29-30 weeks gestation group, those with "discharge on remission"
      required 104 days. Infants with 1,000-1,499 g birth weights for the "discharge
      with complications" and "discharge on remission" groups required 116 and 104 days
      respectively. Focusing on birthplace, the group of "inside-born" (born at
      perinatal medical centers) infants required 124 days, and the "outside-born"
      (born at non-perinatal medical centers) required 127 days. Respiratory distress
      syndrome (RDS), bronchopulmonary dysplasia (BPD) and chronic lung disease (CLD)
      were often seen in patients under 29 weeks gestation and under 1,000 g birth
      weight. Hypoxic ischemic encephalopathy (HIE), convulsions, congenital
      malformations and chromosomal abnormalities were frequent in the groups over 31
      weeks and over 1,500 g. Apnoea and transient tachypnoea of newborn (TTN) often
      occurred in these at 29-30 weeks and 1,000-1,499 g. Also, apnoea and TTN were
      often seen in the "discharge on remission" group. RDS, apnoea and TTN occurRed
      frequently in the "inside-born" infants with over 31 weeks of gestation and over
      1,500 g birth weight. There were many cases of HIE and convulsions in the
      "outside-born" infants of these groups. We found infants who required long-term
      intensive care to comprise three main groups. The first group consisted of
      infants of 29-30 weeks gestation and 1,000-1,499 g birth weight and demonstrated
      mild or few complications. The second consisted of under 29 weeks and under 1,000
      g and exhibited complications of chronic lung diseases caused by immaturity of
      respiratory organs. The third was the group of over 31 weeks and over 1,500 g who
      had complications due to central nervous system disease, congenital malformations
      and chromosomal abnormalities.

PMID- 12402477
TI  - [A case of erythropoietin-producing renal cell carcinoma with polycythemia].
AB  - The patient was a 46-year-old man with gross hematuria and left lumbar pain.
      Computed tomography revealed a large left renal tumor with hemorrhage.
      Serological examination revealed polycythemia and a high erythropoietin level.
      After left radical nephrectomy, polycythemia and serologically high level of
      erythropoietin disappeared. Histopathological findings showed renal cell
      carcinoma composed of spindle cells. Based on the above mentioned clinical
      course, we diagnosed this case as erythropoietin-producing renal cell carcinoma
      with polycythemia. It is suggested that erythropoietin not only causes
      polycythemia but also stimulates proliferation of the tumor, because the majority
      of erythropoietin-producing renal cell carcinomas have been reported to be highly
      advanced. This patient had no evidence of disease one year after the operation.

PMID- 12402478
TI  - [A case of bilateral multiple ureteral diverticula].
AB  - The patient was a 73-year-old man who was referred to our hospital for
      examination of asymptomatic gross hematuria. Urine cytology was negative. Drip
      infusion pyelography and retrograde pyelography revealed bilateral multiple out
      patchings of both ureters. Multiple ureteral diverticula is generally considered
      to be rare. There have been 20 reported cases in the Japanese literature. We
      present the 21st case of multiple ureteral diverticula.

PMID- 12402479
TI  - [Idiopathic retroperitoneal fibrosis with large vessel thrombosis].
AB  - A 53-year-old female was hospitalized for evaluation of swelling in the bilateral
      lower extremities. A computed tomography (CT) scan of the abdomen revealed
      bilateral hydronephrosis and features consistent with retroperitoneal fibrosis.
      Transfemoral venography and magnetic resonance angiography (MRA) showed
      thrombosis of both the left common iliac vein and inferior vena cava, and filling
      of numerous collateral veins in the retroperitoneal area. A diagnosis of
      idiopathic retroperitoneal fibrosis with central venous thrombosis was made.
      Ureteral stenting, medication with corticosteroids and subsequent warfarin were
      started, resulting in marked improvement of renal function and the lower
      extremities. Diagnosis and follow-up of deep venous thrombosis can be aided by
      MRA. Administration of steroids with anticoagulation was considered to be
      successful in the case presenting with deep venous thrombosis caused by
      retroperitoneal fibrosis.

PMID- 12402480
TI  - [Emphysematous perinephric abscess with diabetes mellitus: a case report].
AB  - A 48-year-old woman was referred to our hospital with high fever and left flank
      pain. She was diagnosed with diabetes mellitus (DM), and abdominal computed
      tomography (CT) revealed left perinephric abscess with much emphysema. She
      underwent drainage of the abscess by left flank incision after treatment with
      antibiotics and insulin. The pus culture revealed Escherichia coli. Immediately
      after drainage, the symptoms began to subside. At three months after drainage,
      abdominal CT revealed no emphysema around the left kidney. At 18 months after the
      discharge, left perinephric abscess was not seen and DM was well controlled with
      insulin.

PMID- 12402481
TI  - [A case of spermatic granuloma difficult to differentiate from malignant tumor].
AB  - A 33-year-old man visited our hospital with complaint of painless left
      intrascrotal mass. A hard and rough induration in contact with the left testis
      was palpable. The laboratory data including beta-human churionic gonadotropin,
      alpha fetoprotein and lactate dehydrogenase were normal. Ultrasound sonography
      showed a large hypoechoic lesion at the left epididymis. Surgical exploration of
      this lesion indicated a malignant tumor of the epididymis or spermatic cord, and
      left high orchiectomy was performed. A milk-white nodule 6 cm in diameter was
      found in the resected specimen. Pathological diagnosis was spermatic granuloma.
      Fourteen cases of spermatic granuloma have been reported in the last twenty years
      in Japan. All of them were relatively small nodules and epididymectomy was
      performed for most of them. We selected radical orchiectomy because of a large
      nodule with suspicion of malignant lesion.

PMID- 12402482
TI  - [A case of carcinosarcoma of the urinary bladder].
AB  - We report a case of carcinosarcoma of the urinary bladder. A 68-year-old man
      visited our hospital with complaints of asymptomatic macroscopic hematuria, cold
      sweat and general malaise. Excretory urography revealed a filling defect in the
      left wall of the bladder, and subsequent cystoscopy revealed a non-papillary
      sessile tumor. The tumor was transurethrally resected and its histology showed
      carcinosarcoma which was characteristics of a mixture of transitional cell
      carcinoma with spindle cell sarcoma. The patient underwent total cystectomy and
      his bladder was reconstructed with the ileum. Nevertheless, he died of multiple
      organ metastases 3 months after the surgery.

PMID- 12402483
TI  - [Ductal carcinoma of the prostate with multilocular cystic formation].
AB  - A 72-year-old man was admitted to our department with the complaint of nocturia.
      PSA was elevated to 18.2 ng/ml. Transrectal ultrasonography, CT scan and MRI
      showed multilocular cystic lesions at the posterior site of the prostate, with
      rectal and bladder invasion and lymph node metastasis. Transrectal needle biopsy
      of the prostate and fluid aspiration of the prostatic cyst were performed. The
      aspirated fluid was bloody, but the result of cytology was negative.
      Histopathological examination of the needle biopsy specimen revealed ductal
      carcinoma of the prostate. We diagnosed this case as a T4N1M0 prostatic cancer,
      and started endocrine therapy. Thirty-nine cases of adenocarcinoma of the
      prostate with cystic formation in the Japanese literature are reviewed.

PMID- 12402484
TI  - [A case of primary malignant lymphoma of the pararectal space].
AB  - A 16-year-old man presented with lumbago, perianal pain and constipation. A large
      tumor was palpable by digital rectal examination. Then, transrectal needle
      biopsies of the tumor were performed. Histopathological diagnosis was non
      Hodgkin's malignant lymphoma (diffuse large B-cell type according to the new WHO
      classification). The results of some examinations were compatible with the
      diagnosis of primary lymphoma of the pararectal space. The patient underwent 2
      courses of combination chemotherapy CHOP (consisting of cyclophosphamide,
      doxorubichin, vincristine, and prednisolone), and high-dose chemotherapy
      (ranimustine, etoposide, ifosfamide) with peripheral blood stem cell
      transplantation. After high-dose chemotherapy, radiation therapy was performed
      since there was a possibility of residual tumor, and complete remission was
      achieved. Now, 12 months after completion of the radiation, he remains free of
      the disease. This is probably the first clinical case of malignant lymphoma of
      the pararectal space ever reported in the Japanese literature.

PMID- 12402485
TI  - [A case of pyoderma gangrenosum involving the prostate gland after radiation
      therapy for prostate cancer].
AB  - A 76-year-old man complained of difficulty in urination and miction pain with
      abacterial pyuria after radiation therapy for prostate cancer. Transurethral
      resection of the prostate was performed and histopathologically widespread
      necrosis was observed in the prostate. Thereafter retention of urine and fever
      occurred and computed tomography scan revealed an abscess of the penile corpus.
      The abscess was drained, but the fever continued. He developed an abacterial lung
      abscess and abacterial necrotic ulcerating lesions on his back, his left leg and
      his lower abdomen. Macroscopic findings demonstrated typical features of pyoderma
      gangrenosum. Steroid treatment was initiated and the response to steroid therapy
      was dramatic. Finally urinary diversion using an ileal conduit was performed. We
      found few cases of pyoderma gangrenosum involving lesions other than those of the
      skin in the literature. This is the first report of pyoderma gangrenosum
      involving the prostate gland after radiation therapy for prostate cancer.

PMID- 12402486
TI  - [Recurrent epididymitis in a child without genitourinary malformations: a case
      report].
AB  - The patient was a 12-year-old boy, who was brought to our hospital with a chief
      complaint of swelling and pain in the right scrotum. Color Doppler
      ultrasonography showed blood flow in the right testis and increased blood flow at
      the right epididymis. Our diagnosis was right epididymitis, and the swelling of
      the scrotum was improved by antibiotics. Since there was recurrence, right
      epididymectomy was performed. Histological diagnosis was chronic epididymitis.
      Postoperative, screening for abnormalities in the urinary tract revealed no
      malformations. Recurrent epididymitis in a child without genitourinary
      malformations is a very rare pathology.

PMID- 12402487
TI  - [Evidence of otospongiosis obtained by computerized tomography. Does it
      compromise the post-stapedectomy auditory gain?].
AB  - To study the influence of tomographic otospongiosis/otosclerosis on the
      audiometric gain after stapedectomy, we evaluated 34 patients (mean age 39.9
      years, S.D. 9.8) with otosclerosis and mixed hearing loss. We performed Computed
      Tomography (CT) with densitometry before stapedectomy and audiometry before and 4
      weeks after the surgery. CT results were classified as compatible or not for
      otospongiosis (< 1000 UH) or for otosclerosis (> 2000 UH). According to the
      affected turns of the cochlea, the studies were classified in 3 groups. In 43% of
      the patients the CT showed otospongiosis. After stapedectomy, air conduction
      thresholds of the low (125-500 Hz), middle (500-2000 Hz) and high frequency bands
      (2000-8000 Hz) and for the air/bone gap were similar for the ears with or without
      otospongiosis (p > 0.05, ANOVA). However, patients with otospongiosis in all the
      cochlea showed the lowest audiometric gain for the high frequency band (p < 0.05
      ANOVA). Evidence of otospongiosis evaluated just by CT has a low impact on the
      audiometric outcome after stapedectomy.

PMID- 12402488
TI  - [Sino-nasal endoscopic surgery in fungal sinusitis. Our experience].
AB  - Fungal sinusitis is a rare entity which has increased amongst immunocompromised
      individuals. Records of thirteen patients treated of fungal sinus disease between
      1995 and 2001 were reviewed. Histopathological studies demonstrated infection due
      to Aspergillus in eight patients and due to Mucormycosis in five patients. The
      surgical debridement via endoscopic sinus surgery was the essential part of the
      management. The follow-up is 12-72 months (mean 29.08). The main clinical
      findings and a review of the literature are presented. We conclude that
      endoscopic sinus surgery is the treatment of choice for fungal sinusitis except
      in advanced cases of mucormycosis in which a combined approach is still necessary
      together with intravenous antifungal drugs (amphotericin B).

PMID- 12402489
TI  - [Oxidative profile of tonsil infection. Study of antioxidant enzymes in tonsil
      and blood].
AB  - In order to investigate the effect of oxidative damage due to free radicals on
      ENT infectious diseases, levels of superoxide dismutase (SOD), glutathione
      peroxidase (GPx) and reductase (GRt) and the total antioxidant status (TAS) were
      measured by spectrophotometry on tonsillar tissue obtained from tonsillectomy in
      538 patients, who were divided in three groups according to their surgical
      indication: tonsillar hypertrophy (n = 235), recurrent tonsillitis (n = 280) or
      peritonsillar abscess (n = 23). SOD concentration were also measured on adenoid
      tissue and middle ear exudate in 75 patients from the first two groups.
      Erythrocyte and tonsillar SOD levels were significantly greater in the abscess
      group, and lower in the hypertrophic one. These differences were similar for GPx
      and TAS. For GRt, its level in abscess were lower than in the other two groups in
      a statistically significant way. There were strong correlations between
      erythrocyte and tonsillar SOD, tonsillar SOD and GPx, tonsillar SOD and TAS, and
      tonsillar GPx and TAS. SOD concentrations from adenoid tissue and middle ear
      exudate did not affect its blood level. So, we can conclude that tonsillar
      oxidative damage is determined by the frequency or the severity of local
      infections, and it can be evaluated by measuring the SOD concentration in the
      tonsillar tissue or in the peripheral blood. So, it can be considered a good
      marker of tonsillar damage.

PMID- 12402490
TI  - [Cost-benefit analysis of the anatomo-pathological study of tonsillectomy
      specimens in the pediatric population].
AB  - To study the cost-benefit of the histological examination of tonsilar samples, we
      evaluated 567 cases (547 routine and 20 nonroutine cases) of patients under 14
      years of age, operated between 1st January 1996 and 30th November 2000. There
      were 2 routine cases (0.3%), and 6 nonroutine cases (30%) with a diagnosis
      different to follicular hyperplasia. In this way, our clinical preoperative
      sensitivity was 75% and specificity 97%. The average cost per case at our Centro
      to study the tonsilar samples was 30$. We conclude that the histological
      examination of tonsilar specimens is economically worth only in nonroutine cases,
      although additional factors (e.g. training of residents of Pathology and the
      quality control of the institution must be taken into consideration.

PMID- 12402491
TI  - [Possible factors influencing rehabilitation of the total laryngectomy patient
      using esophageal speech].
AB  - One of the handicaps of patients that have had a total laryngectomy is the loss
      of oral speech. There are three possibilities to rehabilitate these patients;
      surgery, voice prosthesis or esophageal speech. This last one appears as an
      inexpensive, non-invasive rehabilitation method; it does not need a complex
      learning and in spite of new technics, it continues to be an effective method in
      the social rehabilitation of laryngectomized patients. We have made a
      retrospective study of patients who underwent TL between 1992-1998 and that were
      rehabilitated by esophageal voice learning. Three factors have been evaluated:
      first, those related to the patient (gender, age, study level...); second, those
      related to the treatment itself [TL, pharyngolaryngectomy (PTL), TL plus
      radiotherapy...] and third, those related to the rehabilitation (technics,
      delayed on starting, number of sessions...). Data were compared with
      rehabilitation outcome: good (usually using esophageal voice), medium (speaking
      sometimes) and bad (not speaking). 74.1% had an acceptable outcome and they use
      esophageal voice with more or less difficulty to communicate, and this outcome
      increases to 95.8% when we do not take into account 7 patients who gave-up
      rehabilitation before finishing the first five sessions.

PMID- 12402492
TI  - [Surgery for secondary and tertiary hyperparathyroidism: 11 years' experience].
AB  - From 1990 to september 2001, we have performed surgery in 22 patients diagnosed
      as Secondary hyperparathyroidism and three patients diagnosed as Tertiary, that
      were sent to our clinic from the Nephrology Department. These pathologies are
      rare in clinical practice but they mean a lot for the patient and his family. In
      17 cases we performed a subtotal parathyroidectomy, in 2 cases a total
      parathyroidectomy and in another 2 an adenoma was found and excised. In one of
      these 22 cases and following a careful exam we did not final pathological
      parathynoids. We present and analysed here our results with an obvious
      improvement in all patients but one. Finally we carry out a revision of the
      literature comparing our results to other similar published series.

PMID- 12402493
TI  - [Subdural empyema of sinus origin caused by Gemella morbillorum, a strange
      etiology].
AB  - We present a case of frontal sinusitis complicated with a subdural empyema, in
      which the identified microorganism was Gemella morbillorum, a frequent host of
      the aerodigestive tract and occasionally related to infections. The problem was
      resolved successfully using endoscopic surgery and an external approach of the
      sinus. Afterwards it was completed with a subdural drainage through craniotomy.
      Subdural empyema is a rare complication of sinusitis although very severe. We
      want to emphasize the importance of early diagnosis of intracranial
      complications, the need of a detailed microbiology test the method used to obtain
      samples, and the convenience of a combined approach by the otolaryngologists and
      the neurosurgeons for its complete drainage.

PMID- 12402494
TI  - [Paraglottic laryngeal abscesses].
AB  - We present 2 cases of laryngeal abscesses in the paraglottic space. We revise the
      existing literature in relation with this nowadays rare entity that requires a
      quick diagnosis and treatment as it is a fast life threatening disease.

PMID- 12402495
TI  - [Chronic pharyngitis and macrolides].
AB  - We have noticed that macrolides can improve the main symptoms of many patients
      with chronic pharyngitis. We feel that the efficacy of macrolides for chronic
      pharyngitis can be due to the anti-inflammatory effect of this group of
      antibiotics. However, we think that at present the use of macrolides is not the
      therapy of choice for chronic pharyngitis.

PMID- 12402496
TI  - New resources on the Horizon.

PMID- 12402497
TI  - Value of novelty?

PMID- 12402498
TI  - New tools and concepts for modern organic synthesis.
AB  - The increasing need to efficiently assemble small molecules as potential
      modulators of therapeutic targets that are emerging from genomics and proteomics
      is driving the development of novel technologies for small-molecule synthesis.
      Here, we describe some of the general applications and approaches to synthesis
      using one such technology--solid-supported reagents--that has been shown to
      significantly improve productivity in the generation of combinatorial libraries
      and complex target molecules.

PMID- 12402499
TI  - CDKs and CKIs: molecular targets for tissue remodelling.
AB  - Effective tissue remodelling is essential to the survival of adult organs. Many
      of the signalling pathways that control these cellular decisions are regulated by
      nuclear interactions of cell-cycle proteins. Molecules that target cyclin
      dependent kinases (CDKs) or CDK inhibitors (CKIs) represent a new class of
      therapeutic agents that influence tissue remodelling in several organ systems. An
      understanding of their cell-specific functions is leading to the development of
      exciting and bold approaches to the treatment cancer, cardiovascular disease and
      other diseases.

PMID- 12402500
TI  - The use of constitutively active GPCRs in drug discovery and functional genomics.
AB  - The complete sequencing of the human genome has afforded researchers the
      opportunity to identify novel G-protein-coupled receptors (GPCRs) that are
      expressed in human tissues. The successful identification of hundreds of GPCRs
      represents the single greatest opportunity for novel drug development today.
      However, the lack of identified ligands for these GPCRs has limited their utility
      for traditional drug discovery approaches that focus on ligand-based assay
      methods to discover and pharmacologically characterize drug candidates. Here, we
      review the use of constitutively activated GPCRs in the discovery pathway, both
      as a means to overcome the limitations of traditional drug discovery at novel
      GPCRs and as a tool to investigate the functionality of these receptors.

PMID- 12402501
TI  - Endogenous kynurenines as targets for drug discovery and development.
AB  - The kynurenine pathway is the main pathway for tryptophan metabolism. It
      generates compounds that can modulate activity at glutamate receptors and
      possibly nicotinic receptors, in addition to some as-yet-unidentified sites. The
      pathway is in a unique position to regulate other aspects of the metabolism of
      tryptophan to neuroactive compounds, and also seems to be a key factor in the
      communication between the nervous and immune systems. It also has potentially
      important roles in the regulation of cell proliferation and tissue function in
      the periphery. As a result, the pathway presents a multitude of potential sites
      for drug discovery in neuroscience, oncology and visceral pathology.

PMID- 12402502
TI  - Drugs targeting the renin-angiotensin-aldosterone system.
AB  - Effective antihypertensive therapy has made a major contribution to the
      reductions in the morbidity and mortality of cardiovascular disease that have
      been achieved since the 1960s. However, blood-pressure control with conventional
      drugs has not succeeded in reducing cardiovascular disease risks to levels seen
      in normotensive persons. Drugs that inhibit or antagonize components of the renin
      angiotensin-aldosterone system are addressing this deficiency by targeting both
      blood pressure and related structural and functional abnormalities of the heart
      and blood vessels, thus preventing target-organ damage and related cardiovascular
      events.

PMID- 12402503
TI  - The emergence of the drug receptor theory.
AB  - Today, the concept of specific receptors for drugs and transmitters lies at the
      very heart of pharmacology. Less than one hundred years ago, this novel idea met
      with considerable resistance in the scientific community. To mark the 150th
      anniversary of the birth of John Newport Langley, one of the founders of the
      receptor concept, we highlight his most important observations, and those of Paul
      Ehrlich and Alfred Joseph Clark, who similarly helped to establish the receptor
      theory of drug action.

PMID- 12402504
TI  - A proposal for FDA reform.
AB  - Since the current system for the regulation of drugs in the United States was
      established in 1962, the FDA has steadily increased the scope of its
      responsibilities and activities, and, concomitantly, the regulatory burden on
      drug developers. The costs and time that are required for drug development have
      spiralled upwards. Reform of drug regulation is necessary; it must be fundamental
      in nature, and it must come from outside the agency through new legislation.

PMID- 12402505
TI  - Mass spectrometry in drug discovery and development.

PMID- 12402506
TI  - CCR5 and HIV infection.
AB  - Chemokines and chemokine receptors play a crucial role in the trafficking of
      leukocyte populations across the body, and are involved in the development of a
      large variety of human diseases. CCR5 is the main coreceptor used by macrophage
      (M)-tropic strains of human immunodeficiency virus type 1 (HIV-1) and HIV-2,
      which are responsible for viral transmission. CCR5 therefore plays an essential
      role in HIV pathogenesis. A number of inflammatory CC-chemokines, including MIP-1
      alpha, MIP-1 beta, RANTES, MCP-2, and HCC-1[9-74] act as CCR5 agonists, while MCP
      3 is a natural antagonist of the receptor. CCR5 is mainly expressed in memory T
      cells, macrophages, and immature dendritic cells, and is upregulated by
      proinflammatory cytokines. It is coupled to the Gi class of heterotrimeric G
      proteins, and inhibits cAMP production, stimulates Ca2+ release, and activates
      PI3-kinase and MAP kinases, as well as other tyrosine kinase cascades. A mutant
      allele of CCR5, CCR5 delta 32 is frequent in populations of European origin, and
      encodes a nonfunctional truncated protein that is not transported to the cell
      surface. Homozygotes for the delta 32 allele exhibit a strong, although
      incomplete, resistance to HIV infection, whereas heterozygotes display delayed
      progression to acquired immunodeficiency syndrome (AIDS). Many other alleles,
      affecting the primary structure of CCR5 or its promoter have been described, some
      of which lead to nonfunctional receptors or otherwise influence AIDS progression.
      CCR5 is considered as a drug target in the field of HIV, but also in a growing
      number of inflammatory diseases. Modified chemokines, monoclonal antibodies and
      small chemical antagonists, as well as a number of gene therapy approaches have
      been developed in this frame.

PMID- 12402507
TI  - Rhodopsin and retinitis pigmentosa: shedding light on structure and function.
AB  - Rhodopsin is the dim-light activated photoreceptor located in the rod cells of
      the eye. It belongs to the large superfamily of G-protein-coupled receptors
      (GPCRs). Many consider it the proto-typical GPCR as numerous studies since its
      cloning in 1983 (Nathans and Hogness 1983) have established many fundamental
      principles of seven transmembrane-spanning GPCRs. Abundant expression in the
      rod's outer segment, constituting about 90% of the total membrane protein in the
      discs, and the development of techniques to purify large quantities of functional
      protein has facilitated this process. Another distinct feature is rhodopsin's
      ligand, 11-cis-retinal, which is covalently bound via a Schiff base to
      transmembrane seven (TM VII), allowing extensive spectroscopic studies. Exciting
      recent developments include the discovery of naturally occurring mutations that
      lead to retinal degeneration, the determination of transmembrane movements using
      electron paramagnetic resonance (EPR) and biochemical techniques, and the
      discovery of its 3D X-ray crystal structure, the first among GPCRs. The impact of
      these major advances will be discussed in this review.

PMID- 12402508
TI  - V2R structure and diabetes insipidus.
AB  - For most audiences, the term "diabetes" conjures thoughts of high levels of blood
      glucose and of the symptoms that characterize diabetes mellitus. In the last few
      years, a spirited campaign spear-headed by the families of affected individuals
      has made progress in educating nonprofessional and medical communities about
      diabetes insipidus (DI), the other disease characterized by polyuria (i.e.,
      diabetes). Much work lies ahead to find better treatments for this affliction,
      but the progress in molecular biology over the last years made possible the
      identification of the genetic defects underlying the inherited forms of the
      disease. Numerous cases of adult-onset DI are triggered by toxic damage to the
      kidneys that impairs the concentrating capacity of the nephrons by a nonspecific
      mechanism. In these pages I shall deal mostly with the inherited forms of the
      disease. Diabetes insipidus is characterized by the inability of the kidneys of
      affected individuals to produce concentrated urine (Morello and Bichet 2001). The
      elimination of large volumes of diluted urine (polyuria) and excessive thirst
      (polydipsia) are the chief symptoms of the disease. Although this condition and
      the hints that it was a hereditary disease were described at the end of the 19th
      century, it took almost 100 years to gain molecular knowledge about its etiology.
      A brief review of the important role played by vasopressin in the maintenance of
      body fluids will help the reader understand the severity of this disease.

PMID- 12402509
TI  - Polymorphic G-protein-coupled receptors and associated diseases.
AB  - Polymorphisms are quite common in the human population. Most likely every gene
      could be polymorphic. Most of these variations are common and have no functional
      consequence. However, as we learn more about the function of G-protein-coupled
      receptors (GPCRs) and how amino acid differences can modulate the function enough
      to measure, especially in a compromised physical state, the importance of
      characterizing these variations becomes substantial. This review will focus on
      polymorphisms in receptors that bind biogenic amines, calcium, opioids,
      endothelin, and those that also regulate taste, skin pigmentation, and oogenesis
      that have been suggested to cause variations of physiology.

PMID- 12402510
TI  - Effects of nitric oxide synthase inhibitors and melatonin on the hyperglycemic
      response to streptozotocin in rats.
AB  - Recent studies evidence that peroxynitrite is spontaneously formed when nitric
      oxide (NO) and superoxide coexist and suggest that it is likely to be involved in
      the destruction of the pancreatic beta cells. We examined whether drugs that
      inhibit nitric oxide synthase (NOS) or scavenge peroxynitrite could abrogate STZ
      induced hyperglycemia in rats. Blood glucose levels were measured before (0 h)
      and 24, 48, and 72 h following intraperitoneal administration of 60 mg/kg
      streptozotocin (STZ). The levels of blood sugar in STZ-treated control animals
      were significantly elevated at all time points of observation with a peak
      increase at 48 h. The hyperglycemic response of STZ was found to be significantly
      reduced in animals pretreated with aminoguanidine (50 mg/kg i.p.), an inducible
      isoform-selective NOS (iNOS) inhibitor with antioxidant property, and by
      melatonin (6 mg/kg i.p.), an antioxidant that also prevents peroxynitrite
      formation but not by Nw-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg i.p.),
      and 7-nitroindazole (7-NI, 50 mg/kg i.p.), the constitutive inhibitors of
      endothelial and neuronal NOS, respectively. These findings indicate the possible
      participation of iNOS-derived NO as well as oxygen free radicals in STZ-induced
      pancreatic beta cell destruction and compounds that act as scavengers of
      peroxynitrite may offer protection against such a damage.

PMID- 12402511
TI  - Analysis of moricizine block of sodium current in isolated guinea-pig atrial
      myocytes. Atrioventricular difference of moricizine block.
AB  - The effects of moricizine on Na+ channel currents (INa) were investigated in
      guinea-pig atrial myocytes and its effects on INa in ventricular myocytes and on
      cloned hH1 current were compared using the whole-cell, patch-clamp technique.
      Moricizine induced the tonic block of INa with the apparent dissociation constant
      (Kd,app) of 6.3 microM at -100 mV and 99.3 microM at -140 mV. Moricizine at 30
      microM shifted the h infinity curve to the hyperpolarizing direction by 8.6 +/-
      2.4 mV. Moricizine also produced the phasic block of INa, which was enhanced with
      the increase in the duration of train pulses, and was more prominent with a
      holding potential (HP) of -100 mV than with an HP of -140 mV. The onset block of
      INa induced by moricizine during depolarization to -20 mV was continuously
      increased with increasing the pulse duration, and was enhanced at the less
      negative HP. The slower component of recovery of the moricizine-induced INa block
      was relatively slow, with a time constant of 4.2 +/- 2.0 s at -100 mV and 3.0 +/-
      1.2 s at -140 mV. Since moricizine induced the tonic block of ventricular INa
      with Kd,app of 3.1 +/- 0.8 microM at HP = -100 mV and 30.2 +/- 6.8 microM at HP =
      -140 mV, and cloned hH1 with Kd,app of 3.0 +/- 0.5 microM at HP = -100 mV and
      22.0 +/- 3.2 microM at HP = -140 mV, respectively, either ventricular INa or
      cloned hH1 had significantly higher sensitivity to moricizine than atrial INa.
      The h infinity curve of ventricular INa was shifted by 10.5 +/- 3.5 mV by 3
      microM moricizine and that of hH1 was shifted by 5.0 +/- 2.3 mV by 30 microM
      moricizine. From the modulated receptor theory, we have estimated the
      dissociation constants for the resting and inactivated state to be 99.3 and 1.2
      microM in atrial myocytes, 30 and 0.17 microM in ventricular myocytes, and 22 and
      0.2 microM in cloned hH1, respectively. We conclude that moricizine has a higher
      affinity for the inactivated Na+ channel than for the resting state channel in
      atrial myocytes, and moricizine showed the significant atrioventricular
      difference of moricizine block on INa. Moricizine would exert an antiarrhythmic
      action on atrial myocytes, as well as on ventricular myocytes, by blocking Na+
      channels with a high affinity to the inactivated state and a slow dissociation
      kinetics.

PMID- 12402512
TI  - Serum antibodies to collagen type IV and development of diabetic vascular
      complications in children with type 1 (insulin-dependent) diabetes mellitus. A
      longitudinal study.
AB  - Thickening of basement membrane in capillaries and small vessels is a well-known
      finding and important in the progression of diabetic microangiopathy. To monitor
      the metabolism of the basement membrane protein collagen type IV (CIV) in
      diabetes mellitus, serum levels of IgG, IgM and IgA to CIV were measured using an
      ELISA method in 28 children with Type 1 diabetes mellitus over a period of 6
      years. These values were compared to serum antibodies to CIV in 24 age- and sex
      matched controls. At the end of the study, 11 children had diabetic
      microangiopathy. IgG to CIV was associated with age (r = .33, P = .026), diabetes
      duration (r = .32, P = .021), HbA1c (r = .31, P = .019), microalbuminuria (r =
      .32, P = .022) and anti-AGE antibodies (r = .47, P = .0007). IgM to CIV
      correlated with age (r = .46, P = .001), diabetes duration (r = .45, P = .001),
      HbA1c (r = .26, P = .038) and anti-AGE antibodies (r = .26, P = .038) and IgA to
      CIV with triglycerides (r = .29, P = .038) and anti-AGE antibodies (r = .44, P =
      .0025). We suggest that serum levels of IgG to CIV can be used as a marker for
      the development of diabetic microalbuminuria.

PMID- 12402513
TI  - Effect of hypothyroidism on beta-adrenoceptor-mediated relaxation in the rat
      thoracic aortae. A time-dependent study.
AB  - We investigated the time dependency of hypothyroid-induced changes in beta
      adrenoceptor-mediated relaxation of vascular smooth muscle. Methimazole (0.03%)
      was administered to male Wistar-Imamichi rats for 3 days, 1, 2 or 6 weeks. This
      treatment led to significant increases in thyroid weight while inhibiting growth
      rate. Tension in isolated rings of thoracic aortae from control and hypothyroid
      rats was measured isometrically. Responses of aortic rings to cumulative doses of
      acetylcholine (ACh) and sodium nitroprusside (SNP) were not significantly
      different between control and hypothyroid groups. After 3 days and 1 week of
      treatment, isoprenaline (ISO)-induced relaxation was unchanged, but after 2 and 6
      weeks, a marked increase was observed as compared to controls. Removal of the
      endothelium and pretreatment with NG-nitro-L-arginine (L-NOARG) inhibited the ISO
      induced relaxation in both groups; but whereas this degree of inhibition was the
      same for both groups after 3 days and 1 week, it was significantly less
      pronounced in hypothyroid rats after 2 and 6 weeks as compared to their controls.
      These results suggest that hypothyroidism has a time-dependent influence on beta
      adrenoceptor-mediated relaxation in the rat thoracic aortae and that the
      enhancement after 2 and 6 weeks of methimazole treatment may be due to a
      hypothyroid-induced alteration in arterial smooth muscle function.

PMID- 12402514
TI  - Microtubule depolymerization facilitates contraction of rat aorta via activation
      of Rho-kinase.
AB  - This study tests the hypothesis that microtubule (MT) depolymerization
      facilitates contraction of rat aorta via activation of Rho-kinase. Aortic rings
      from Sprague-Dawley rats were placed in a muscle bath for the measurement of
      isometric force generation. Bath temperature was decreased from 37 to 10-20
      degrees C (30 min), inducing MT depolymerization. Some vessels were treated with
      nocodazole (10(-5) M) or colchicine (10(-8)-10(-5) M) to stabilize the MTs in the
      depolymerized state, and the remaining vessels were treated with dimethyl
      sulfoxide (DMSO: vehicle). Warming of vessels to 37 degrees C induced a
      significantly greater contraction in nocodazole- and colchicine-treated vessels
      as compared with controls, and this increase was blocked by pretreatment with
      taxol (10(-5) M; a MT stabilizing agent) [force (mg): NOC 1159 +/- 93; COL 1138
      +/- 69; DMSO 578 +/- 14; TAX + NOC 526 +/- 43; TAX + COL 538 +/- 90]. Following
      the sustained contraction in response to rewarming, Rho-kinase inhibition with Y
      27632 (10(-5) M) relaxed nocodazole- and colchicine-treated rings to a
      significantly greater extent as compared to DMSO-treated vessels (percent
      relaxation: NOC 64 +/- 2; COL 65 +/- 5; DMSO 33 +/- 5). These results support the
      hypothesis that MT depolymerization facilitates contraction of rat aorta via
      activation of Rho-kinase.

PMID- 12402515
TI  - Inhibition of ATPases by Cleistocalyx operculatus. A possible mechanism for the
      cardiotonic actions of the herb.
AB  - The water extract of the buds of Cleistocalyx operculatus, Roxb. (CO), a herb
      commonly used as an ingredient for tonic drinks in southern China, was shown to
      increase the contractility and decrease the frequency of contraction in an
      isolated rat heart perfusion system. CO was found to inhibit Na+/K(+)-ATPase
      activities in rat heart sarcolemma, as well as in a purified enzyme from porcine
      cerebral cortex. CO also inhibited Ca(2+)-dependent ATPase in mouse heart
      homogenate and in mouse heart sarcoplasmic reticulum at a similar dose. These
      enzyme inhibitory actions provide a possible explanation for the positive
      inotropic and negative chronotropic actions of CO on the perfused rat heart. This
      study suggests the presence of ATPase inhibitory compounds in CO with
      specificities different from that of ouabain.

PMID- 12402516
TI  - Does segmental difference in alpha 1-adrenoceptor subtype explain contractile
      difference in rat abdominal and thoracic aortae?
AB  - The cyclooxygenase inhibitor, indomethacin, depresses adrenergic agonist
      constriction of endothelium-denuded rat abdominal, but not thoracic, aorta. In
      order to explain this finding, we explored the possibility of segmental
      differences in the population of alpha 1-adrenoceptor (AR) subtypes. In
      endothelium-denuded tissues, phenylephrine elicited concentration-dependent
      contractions in the thoracic and abdominal aortic rings with potencies and
      maximal effects that, respectively, did not differ significantly (P > .05).
      Indomethacin (1 x 10(-5) M) inhibited phenylephrine-induced contractions only in
      abdominal aorta. The subtype-selective alpha 1D-AR antagonist, BMY 7378, was
      found to antagonize contractions to phenylephrine competitively in abdominal (pA2
      8.44) and thoracic (pA2 8.56) aortic rings. These data are consistent with
      published alpha 1D-AR functional potency and clonal alpha 1D-AR binding affinity.
      In addition, cumulative concentration-contraction curves for phenylephrine were
      competitively antagonized in the rat abdominal and thoracic aortae by prazosin, 5
      methylurapidil and WB 4101, with pA2 values of 9.39 and 9.61, 7.64 and 7.85, and
      9.43 and 9.58, respectively. These compounds with varying degrees of subtype
      selectivity inhibited contractions of the thoracic and abdominal aortae with
      affinities consistent with those determined at the alpha 1D-AR subtype. The
      results of this study suggest that the contraction to phenylephrine of the rat
      abdominal and thoracic aorta is mediated via the same alpha 1D-AR subtype.

PMID- 12402517
TI  - Beneficial effect of pentaerythrityl tetranitrate on functional and morphological
      changes in the rat thoracic aorta evoked by long-term nitric oxide synthase
      inhibition.
AB  - The present study examined whether pentaerythrityl tetranitrate (PETN), a
      tolerance-devoid exogenous donor of nitric oxide (NO), could attenuate functional
      and morphological changes in the rat thoracic aorta evoked by 6-week NO synthase
      inhibition by NG-nitro-L-arginine methyl ester (L-NAME). Systolic blood pressure
      in L-NAME + PETN-treated rats (163 +/- 1 mm Hg) was significantly lower than in L
      NAME-treated rats (172 +/- 2 mm Hg) but was still higher than in age-matched
      controls (126 +/- 2 mm Hg). Six weeks of treatment of rats with L-NAME
      significantly inhibited endothelium-dependent relaxation of the isolated thoracic
      aorta induced by acetylcholine. The inhibitory effect of L-NAME was entirely
      reversed by the simultaneous treatment with PETN. The enhancing effect of L-NAME
      on noradrenaline-induced contraction was antagonised by long-term treatment with
      PETN. Wall thickness, cross-sectional area and wall/diameter ratio of the
      thoracic aorta in L-NAME-treated rats were markedly increased. In the L-NAME +
      PETN-treated rats, the increment of these parameters was significantly lower. The
      results suggest that PETN administered to rats during development of NO-deficient
      hypertension prevented functional impairment and at the same time reduced
      structural changes in the thoracic aorta induced by long-term inhibition of NO
      synthase.

PMID- 12402518
TI  - Influence of nitric oxide on the in vitro antiaggregant effect of ticlopidine.
AB  - The aim of this study was to evaluate the influence of leukocyte nitric oxide
      (NO) production on the antiplatelet aggregant effect of aspirin and ticlopidine.
      This in vitro study was done with platelets (platelet-rich plasma, PRP) and
      polymorphonuclear leukocytes (PMNLs) separated from samples of human blood.
      Collagen-induced platelet aggregation and calcium-dependent NO production by PMNL
      were quantified. The inhibition of NO production in PRP significantly reduced the
      antiaggregant affect of aspirin (IC50 2.64-fold greater), whereas it had no
      significant effect on the effect of ticlopidine (IC50 1.03-fold greater).
      Incubating PMNL in PRP increased the antiaggregant effect of both aspirin (IC50
      5.09-fold lower) and ticlopidine (IC50 10.16-fold lower). The inhibition of NO
      production in PMNL significantly reduced the antiaggregant effect of both aspirin
      (IC50 2.21-fold greater) and ticlopidine (IC50 3.26-fold greater). Both drugs
      increased leukocyte NO production. The concentration of aspirin that raised NO
      production by 50% was greater than 1000 microM, whereas the concentration of
      ticlopidine that led to this effect was 9.14 +/- 0.87 microM. We conclude that
      the effect of ticlopidine on leukocyte NO production may constitute an addition
      mechanism to the IIb/IIIa glycoprotein complex inactivation in the inhibition of
      platelet activation.

PMID- 12402519
TI  - Invasive pneumococcal infection in first nations children in northern Alberta.

PMID- 12402520
TI  - New geographical records of parasitic nematodes from Bufo bufo in Italy.
AB  - To provide information on parasites of Bufo bufo (toad), eyes, skin, lungs, gut
      and urinary bladder of individuals collected near lakes Endine and Segrino
      (Northern Italy) from March to April 1999 were recorded in laboratory. A total of
      five nematode species were classified: Oswaldocruzia filiformis, Oxysomatium
      brevicaudatum, Cosmocerca ornata, Neyraplectana schneideri were found in the
      intestine and rectum and Rhabdias sphaerocephala in the lungs. Of these species,
      the last three are new geographical records for Italy.

PMID- 12402521
TI  - A new stable focus of canine leishmaniasis in northern Italy.
AB  - A new stable focus of canine leishmaniasis (CanL) was identified in a coastal
      Adriatic area of the Emilia-Romagna Region in Northern Italy. Following the first
      clinical cases observed starting from 1998, a seroepidemiological survey was
      carried out on owned dogs from two communes and on animals housed in dog pounds
      of the Rimini province. Sixteen out of 612 dogs (2.6%) resulted positive to the
      IFA test. The 16 positive dogs all came from the two communes, with
      seroprevalences of 3 and 6%, respectively. The autochthonous origin of the
      infection was confirmed in all the cases. The parasitological investigation led
      to the isolation and identification of the parasite as Leishmania infantum
      Zymodeme MON 1. An entomological survey showed that Phlebotomus perniciosus and
      P. perfiliewi are present in this area and that P. perfiliewi was very abundant
      in one collection site. The risk of the establishment of a permanent transmission
      of the infection in the area, previously considered CanL-free, must be analysed
      in view of further investigations to be extended also to neighbouring areas.

PMID- 12402522
TI  - Single strand conformational polymorphism evaluation for the identification of
      TH3R alleles of the circumsporozoite protein gene of Plasmodium falciparum.
AB  - Highly polymorphic regions of the circumsporozoite protein (CSP) of Plasmodium
      falciparum are associated with cellular immune responses. One of these regions,
      the TH3R polymorfic region of the csp gene codes for known T-cell epitopes. The
      present study tested the use of SSCP to determine sequence variations of the TH3R
      regions of four clones of P. falciparum (3D7, HB3, Dd2 and K1) which are known to
      have different TH3R regions. Single-strand conformation polymorphism (SSCP)
      technique was performed on amplified products labelled with fluorescent primer
      (both strands) and electrophoresed in an automated sequencer. Various gel
      compositions and electrophoresis conditions were tested. Even if some
      electrophoretogram differences were observed between clones, they could not
      distinguish between the alleles.

PMID- 12402523
TI  - Cloning and phylogenetic analysis of the ribosomal internal transcribed spacer-1
      (ITS1) of Cryptosporidium wrairi and its relationship to C. parvum genotypes.
AB  - We have cloned and sequenced the ribosomal internal transcribed spacer-1 (ITS1)
      of Cryptosporidium wrairi. Phylogenetic analysis of this region provided further
      support to the validity of C. wrairi as a distinct species and also to the
      concept that many of the genotypes recently identified within C. parvum are in
      fact separate species. Analysis placed the "cattle" and "mouse" genotypes of C.
      parvum as each other's closest relatives and C. wrairi as a sister group to these
      two genotypes, followed by the "human" genotype.

PMID- 12402524
TI  - Lacerta bilineata (Reptilia, Lacertidae) as a host of Ixodes ricinus (Acari,
      Ixodidae) in a protected area of northern Italy.
AB  - A survey on the importance of Lacerta bilineata as host of Ixodes ricinus was
      conducted in Northern Italy over a three-year period. A total of 202 western
      green lizards were captured and a total of 2349 ticks were collected. All ticks
      were identified as I. ricinus; 53.2% and 46.7% were at the larval and nymphal
      stages, respectively. Tick number and prevalence were higher in males than in
      females, especially from April to June during the host breeding period. The level
      of tick infestation increased with lizard age and size. The number of ticks
      collected on adult lizards peaked in June and in August. Infestation levels
      appear to be related to lizard activity patterns and behaviour. Tick number and
      prevalence also varied in relation to host habitat, infestation being higher in
      lizards from areas with hard vegetation cover.

PMID- 12402525
TI  - Diptera Brachycera horse parasites in a stable/manege in northern Italy.
AB  - The presence of tabanids and muscoid fly (Diptera Brachycera) parasites of horses
      in a stable/manege near Verona (Northern Italy) is reported. Tabanus
      quatuornotatus, T. glaucopis, T. exclusus, Hybomitra muehlfeldi, Haematopota
      pandazisi, Stomoxys calcitrans and Haematobia irritans were the blood-sucking
      species directly found on horses. Musca domestica, Ophyra sp. and Fannia
      canicularis were the flies most frequently collected by sticky traps in the
      stable.

PMID- 12402526
TI  - Real-time PCR for quantification of the bacterial endosymbionts (Wolbachia) of
      filarial nematodes.
AB  - Filarial nematodes harbour intracellular symbiotic bacteria belonging to the
      genus Wolbachia. Wolbachia is thought to play an important role in the biology of
      the nematode. Moreover, Wolbachia appears to be involved in the
      immunopathogenesis of filariasis and in the onset of the side-effects of
      antifilarial therapy. Investigations in these research areas require reliable
      methods to quantify Wolbachia both in nematodes and in vertebrate tissues. To
      this purpose, we designed a quantitative real-time PCR targeted on the ftsZ gene
      of the Wolbachia of Brugia pahangi, a model filarial species maintained in
      gerbils. The method was applied to quantify Wolbachia in Brugia pahangi, from
      animals with or without tetracycline treatment. Our results show that
      tetracycline treatment leads to dramatic reduction or clearance of Wolbachia from
      the nematode. Results obtained from different replicates were reproducible and
      the method appeared very sensitive compared to other PCR protocols for Wolbachia
      detection. Real-time PCR is thus an appropriate method for investigations on the
      biological role of Wolbachia and on the implication of these bacteria in the
      pathogenesis of filariasis. With slight modifications of the primers and probe,
      the protocol we have developed could be applied in studies of the human pathogen
      Brugia malayi and on the model filarial species Litomosoides sigmodontis.

PMID- 12402527
TI  - Preliminary lack of evidence for simian odour preferences of savanna populations
      of Anopheles gambiae and other malaria vectors.
AB  - The behavioural response to several culicine and anopheline mosquitoes to the
      odour of alternative hosts (human vs monkey) arranged in a choice set-up using
      odour-baited entry traps (OBETs) was assessed in a field experiment in south
      eastern Senegal. The experimental protocol followed procedures analogous to those
      adopted in olfactometer laboratory tests. Two adult Cercopithecus aethiops and a
      child of similar mass slept inside separate tents and their odours were drawn to
      each one of two paired OBETs so that approaching mosquitoes could experience both
      odour-laden streams before "choosing" to fly against one of the two air currents
      and into the trap. The traps were set up in a riverine forest clearing near the
      town of Kedougou, where primates (Papio papio, Cercopithecus aethiops, and
      Erythrocebus patas) are common. A total of 192 mosquitoes belonging to 4 genera
      was captured during 8 trap nights. All major human malaria vectors including
      Anopheles gambiae sensu lato, An. funestus, and An. nili, which constituted the
      bulk of the trap catch (N = 153), clearly expressed a preference for human odour,
      with > 90% of captured mosquitoes caught in the human-baited trap. A sub-sample
      of specimens belonging to the An. gambiae complex caught in both traps was
      identified by rDNA-PCR and RFLP as An. gambiae sensu stricto molecular form S
      (7/10), and An. arabiensis (3/10). The only species that did not show a
      preference for the alternative odour-laden air streams, among those caught in
      significant numbers, were mosquitoes of the genus Mansonia, with both Ma.
      uniformis and Ma. africana weakly preferring human odour, but not at a
      statistically significant level. These results are in accordance with the
      hypothesis that the strongly anthropophilic feeding preferences of An. gambiae
      did not evolve from an ancestral association with non-human primates.

PMID- 12402528
TI  - Prostate carcinoma metastasis to the mandible: report of a case.

PMID- 12402529
TI  - Patient musings.

PMID- 12402530
TI  - When your patients try to sell you....

PMID- 12402531
TI  - Chemical dependency ... there is help.

PMID- 12402532
TI  - Oral pathology quiz #36. Case 1. Chronic diffuse sclerosing osteomyelitis.

PMID- 12402533
TI  - Oral pathology quiz #36. Case 2. Irritation fibroma.

PMID- 12402534
TI  - Oral pathology quiz #36. Case 3. Epidermoid cyst.

PMID- 12402535
TI  - Oral pathology quiz #36. Case 4. Odontogenic keratocyst.

PMID- 12402536
TI  - Hormonal control of folliculogenesis: the key to successful reproduction.

PMID- 12402537
TI  - Activation of primordial follicles.
AB  - The activation of primordial follicles appears to be regulated by a myriad of
      factors, and the current evidence suggests that whether an individual follicle
      stays in the resting pool or initiates growth may depend on the balance of
      stimulatory and inhibitory factors impinging on the follicle at a particular
      point in time. Although it is particularly difficult to study the factors
      involved in the initiation of follicle growth in large mammals, my laboratory has
      developed two experimental models for studying the regulation of follicular
      activation and growth. In one model, using organ cultures of small pieces of
      ovarian cortex, almost all primordial follicles activate. This model may thus be
      useful for testing putative inhibitors of activation. In contrast, the second
      model, using grafts of ovarian cortical pieces beneath the CAM of chick embryos,
      provides an environment in which no or little activation occurs, and this
      situation may be used in the future to test potential stimulators of follicular
      activation. Our results thus far indicate that there may be significant species
      differences in the regulation of follicle activation and the initial growth of
      activated follicles. Although encouraging progress has been made in identifying
      potential regulators of follicular activation in rodents, there is much to be
      learned and this first critical transition of follicular development is still
      very poorly understood in larger mammals.

PMID- 12402538
TI  - Follicular development and apoptosis.

PMID- 12402539
TI  - Delivery of the oocyte from the follicle to the oviduct: a time of vulnerability.
AB  - The multiplicity of genes regulated by the actions of LH in specific granulosa
      cell and cumulus cell microenvironments of the follicle during ovulation has now
      revealed how complex and finely tuned the ovulation process is. Although many
      proteases are expressed in the ovary and are hormonally regulated, the novel
      proteases ADAMTS-1 and cathepsin L, rather than the MMPs, have gained particular
      recognition. These may play critical roles in the eventual rupture of the
      follicle at the ovarian surface. Rupture is only one part of ovulation. Another
      important aspect is the actual release of the oocyte from the ovulation pore.
      Several recent studies have shown that the production of the matrix that is
      evidenced by cumulus expansion is somehow critical for extrusion to occur and for
      the oocyte to travel into the oviduct. At any point the oocyte may be trapped
      within a non-ovulating structure. Lastly, if the events of ovulation fail to
      occur before the events of luteinization are complete, oocytes are destined to
      degenerate within the non-ovulating structures.

PMID- 12402540
TI  - Phenotypic effects of knockout of oocyte-specific genes.

PMID- 12402541
TI  - The biochemistry of oocyte maturation.

PMID- 12402542
TI  - The structural basis of oocyte-granulosa cell communication.

PMID- 12402543
TI  - Ageing and aneuploidy in oocytes.

PMID- 12402544
TI  - Ovarian infertility--reasons and treatment paradigms.

PMID- 12402545
TI  - Can stimulation protocols improve oocyte quality?

PMID- 12402546
TI  - FF-MAS and its role in mammalian oocyte maturation.

PMID- 12402547
TI  - [The 40th anniversary of RAMS institute of human morphology].
AB  - Institute of Human Morphology of Russian Academy of Medical Sciences was
      established in 1961 and united efforts of morphologists of various profile-
      pathologists, cytologists, embryologists. The role of outstanding Russian
      morphologists and the first Institute heads is shown. Basic achievements in four
      research fields are characterized: in geographic pathology; structural basis of
      immune homeostasis in health and pathology; pathologic anatomy and pathogenesis
      of basic human diseases; human morpho- and embriogenesis in health and disease.

PMID- 12402548
TI  - [Current views on the biology of the stem cell].
AB  - Stem cells (SC) represent a unique cell population capable of self renewing and
      differentiation. Embryonal SC, represented in the internal cell mass blastocyst,
      give rise to cells of all three germ leaves. SC are also represented in many
      tissues of the adult organism. Their physiological function consists in renewing
      or restoration of the differentiated cells pool during the life span of the
      organism. The majority of regional SC of the adults differentiate into the
      limited number of cell types though some regional SC have a wider differential
      potential. Perfection of SC investigation methods at the molecular genetic level
      will help to reveal subtle mechanisms of these cells functioning.

PMID- 12402549
TI  - [Embryonic mechanisms of human holoprosencephaly development].
AB  - 12 human embryos (stages 14-18) with different form of holoprosencephaly were
      studied. Spatial organization of the brain was reproduced with graphic
      reconstructions. It is demonstrated that the cause of different forms of
      holoprosencephaly is disturbed or delayed movement of the neurulation wave coming
      through the hemispheres of the forebrain. The cause of the defect may be an
      unspecific teratogenic factor or some cytogenetic damage. Severity and type of
      holoprosencephaly are associated not with the etiological factor but with the
      time of the action on the neurulation wave. Alobar holoprosencephaly results from
      the impact on neuralation for 22 days, semilobar--for 23 days and lobar--for 24
      days.

PMID- 12402550
TI  - [Ultrastructure of the heart conduction system in diphtheria].
AB  - Cytoarchitectonics and ultrastructure of the node and conducting myocardiocytes
      of the conducting system of the heart and surrounding blood capillaries and
      nervous fibers are described. In diphtheria, metabolic and destructive changes
      were found in the node myocytes, conducting myocardiocytes and surrounding
      structures. The most noticeable changes were seen in the left pedicle of the
      atrioventricular fascicle and later others components of the conducting heart
      system. These changes are more pronounced in clear cells of conducting
      myocardiocytes as compared to the node myocytes.

PMID- 12402551
TI  - [Morphology of immune system organs in drug addiction].
AB  - The autopsy material from the thymus, spleen and bifurcation tracheal lymph nodes
      from 34 drug addicts who died because of heroin overdosing were studied. Morphin
      and heroin components were found in all tissues and fluids investigated. The
      enzyme immunoassay identified antibodies to hepatitis C virus in blood serum. The
      control group consisted of 12 cases who died of mechanic asphyxia and severe
      trauma. Morphologically, the livers from all cases were affected with chronic
      viral hepatitis of minimal-moderate activity. Accidental involution of the
      thymus, depletion of the cortical layer, hyperplasia of lymphoid follicles in the
      lymph nodes; prevailing follicles of type 1 in the spleen were found.

PMID- 12402552
TI  - [Morphology of the kidneys in arterial hypertension of adrenal genesis (according
      to biopsy findings)].
AB  - 67 renal biopsies obtained in the course of adrenalectomy from patients with
      primary hyperaldosteronism, hypercorticism and pheochromocytoma were studied.
      Sclerotic affection of the arterioles and renal interstitium were found in long
      lasting adrenal arterial hypertension. This may cause residual postoperative
      hypertension. Endocrine nephropathy in primary hyperaldosteronism due to
      hypopotassemia and alcalosis manifests with vacuolar distrophy and atrophy of the
      epithelium, dilatation of tubular lumen, intratubular calcinosis and
      tubulointerstitial nephritis. Primary hyperaldosteronism was characterized by
      hypoplasia of the juxtaglomerular apparatus (JGA) but in massive spironolacton
      therapy signs of enhanced renin-secreting function of the glomerular efferent
      arteriola may be observed. In hypercorticism pyelonephritis is rather frequent.
      In patients with pheochromocytoma hypercatecholaminemia may result in JGA
      activation this being particularly evident in renal artery stenosis. Recurrent
      hypertension after pheochromocytoma removal in the absence of renal pathology may
      indicate recurrent tumor or missed second tumor.

PMID- 12402553
TI  - [Influence of immunosuppressors on remodeling of extracellular matrix in
      experimental nephropathies].
AB  - Influence of methylprednisolone (MP) and cyclosporine A (CsA) on the
      extracellular matrix and growth factors was studied on the model of rapid
      nephrotoxic nephritis (RNN) and puromycin-aminonucleoside nephrosis (PAN). MP
      decreased accumulation of type IV collagen in RNN and increased the content of
      laminine in both models. CsA decreased deposits of type IV collagen but increased
      accumulation of fibronectin in both models. CsA reduced the content of a free
      form of oPRP in both models but MP did so in RNN only. CsA and MP decreased the
      level of active PRP in both models but MP did so in RNN only. CsA and MP
      decreased the level of active TPR-beta and increased the content of latent forms
      but CsA was more active in PAN. In experimental models of inflammatory RNN and
      non-inflammatory CPAN nephropathy CsA raised fibronectin production, MP increased
      deposition of laminine. CsA in both models suppressed production of basic
      fibrogenic factor TPR-beta while MP inhibited this in RNN only.

PMID- 12402554
TI  - [Etiological diagnosis of isolated stenosis of the aortic valve].
AB  - We tried to objectivize etiologic diagnosis of isolated aortic stenosis. We
      studied 950 valves removed during operation on the heart and 15 valves of the
      dead patients without cardiac pathology using automatic semi-quantitative
      microscopic description of the valve pathology with further calculation of
      informative value of the signs. As a result of our investigation the list of the
      most important signs for the differential diagnosis was compiled. We found out
      that most often causes of aortic stenosis are calcinosis of bicuspid aortic valve
      and senile calcinosis. Silvering of the nucleolus organiser in endotheliocytes
      and fibroblasts in various pathology of the aortic valve showed an increase in
      the metabolism level and plastic possibilities of the cells in aortic calcinosis.

PMID- 12402555
TI  - [Clinico-morphological and molecular-genetic correlations in the stomach
      pathology associated with Helicobacter pylori].
AB  - Some clinicomorphological correlations are made in Helicobacter pylori (H.
      pylori) associated diseases of the gastroduodenal zone. Genes vacA and cagA in
      the H. pylori genome were revealed by PCR in stomach biopsies of infected
      patients and the results were compared with histological changes in the patients'
      mucous membrane. Specific IgG antibodies to some H. pylori antigens were detected
      in the serum and a comparative analysis of serological and histological data was
      performed. The findings suggest that H. pylori associated gastroduodenal
      pathology is determined by interaction between macro- and microorganisms taking
      account of genetic characteristics of the infective microorganism, its phenotypic
      variations and properties of inflammatory and immune response of the host.

PMID- 12402556
TI  - [Correlation between expression of androgen receptors and the degree of cell
      differentiation in human prostate cancer].
AB  - Immunohistochemical examination was carried out to investigate androgen receptor
      antigen expression in epithelial cells of benign or malignant tumors in the
      prostate of aged men. The benign tumors were characterized by homogeneous
      distribution of androgen receptors in all nuclei of secretory epithelial cells.
      In malignant cells there was partial or complete loss of the androgen receptors
      to androgens in parallel with decreased cell differentiation.

PMID- 12402557
TI  - [Hemorrhagic pseudocyst of the pancreas with spontaneous rupture of the spleen].
AB  - A case of hemorrhagic pseudocyst of the pancreas in a young male, 33 years of
      age, heavy drinker is reported. The cyst was closely attached to the posterior
      wall of the stomach. Partial damage of the stomach wall resulted in subserosa
      hematoma. There was also rupture of the spleen, on its diaphragma surface there
      were many small vesicles like herpetic eruption. This indicates that the rupture
      took place slowly for several days.

PMID- 12402558
TI  - [Professor Nikolai Matveevich Liubimov (the 150th birth anniversary].

PMID- 12402559
TI  - [Professor Ivan Petrovich Vasil'ev (1879-1949)].

PMID- 12402560
TI  - [Pathogenesis and clinical morphology of congenital disorders of sex
      differentiation].
AB  - Bisexual structure of genitalia presents difficulties for clinical diagnosis.
      Therefore, knowledge of pathogenesis and clinical morphology of congenital
      disturbances of sexual differentiation helps to establish earlier hermaphroditism
      variant, appropriate surgery for complete social-psychological adaptation of this
      group of patients.

PMID- 12402561
TI  - [Human and animal vomeronasal systems in health and disease].
AB  - The vomeronasal organ (VO) or the second olfactory organ has the form of paired
      epithelial pockets at the base of the nasal septum. In animals it has various
      functions including reception of pheromones mediating sexual, parental and social
      behavior. Human VO was considered to be rudimental until the last decade of the
      XXth century. Since then it was found to be present almost in every adult
      individual and was proved to be functional. The paper provides new facts on the
      occurrence of VO in man and animals, analyzes possible consequences of plastic
      surgery of the nose and considers some vomeronasal abnormalities, their diagnosis
      and treatment.

PMID- 12402562
TI  - Early problem behavior among children from low-income, mother-headed families: a
      multiple risk perspective.
AB  - Examined proximal and contextual factors most strongly related to externalizing
      behavior among young children growing up in low-income, mother-headed families.
      Participants were 50 low-income single mothers and their preschool-age children
      who were visited twice in the home setting. Measures of proximal (low levels of
      supportive parenting, high levels of punitive disciplinary practices, low levels
      of maternal emotional well-being) and contextual (low maternal support, high
      levels of family stress) risk were assessed in relation to maternal reports of
      child externalizing behavior and an index of negative child behavior during a
      clean-up task. Child defiance during the clean-up task was highly associated with
      punitive maternal control in the same situation but had no other direct
      correlates. However, multiple risk factors representing both proximal and
      contextual variables were associated with variations in children's behavior
      problem scores. Mothers of children with high behavior problem scores reported
      lower feelings of self-efficacy in handling child care and emotional stressors,
      more frequent use of punitive child disciplinary practices, and lower feelings of
      satisfaction with the quality of their supportive resources than others. Maternal
      self-evaluations of coping efficacy mediated the relation between perceived
      support and child behavior problems, suggesting that constructs of personal
      control are important to represent in future studies of highly stressed parents.

PMID- 12402563
TI  - The role of separation-individuation experiences and personality in predicting
      externalizing and internalizing dimensions of functional impairment in a rural
      preadolescent and adolescent sample.
AB  - Studied 4th- through 8th-grade students in a rural school district (N = 382, 201
      girls; M age = 12.48) who, at the end of the academic year, completed self-report
      measures assessing functional impairment, self-concept, reactance, and autonomy
      experiences in relation to parents. Confirmatory factor analysis supported a
      distinction between 2 aspects of autonomy: mutuality (perceptions of parents as
      encouraging of autonomy) and conflictual dependence (negative representations of
      "self-in-relation-to-parent" and related feelings of anger and shame). Path
      analysis findings mostly were consistent with a mediated model predicting
      personality from autonomy experiences and functional impairment from personality.
      However, conflictual dependence rather than negative self-feelings directly
      predicted girls' emotional difficulties. Comparisons of total effects suggested
      that conflictual dependence may have stronger and more consistent implications
      for adolescent psychopathology than mutuality. In general, significant relations
      between conflictual dependence and psychopathology remained significant even
      after controlling for a measure of negative affectivity (NA).

PMID- 12402564
TI  - The social behaviors and peer expectation of girls with attention deficit
      hyperactivity disorder and comparison girls.
AB  - Investigated self-described social goals, self-generated actions, and perceived
      peer responses to hypothetical vignettes, as well as observed social behavior and
      peer sociometric status, in an ethnically and socioeconomically diverse sample of
      girls with attention deficit hyperactivity disorder (ADHD; n = 49) and comparison
      girls (n = 30). Although we found no differences between the social goals of
      girls with ADHD and comparison participants, girls with ADHD generated higher
      rates of aggressive responses to the hypothetical vignettes than did comparison
      girls, whereas comparison girls generated a larger number of negotiating
      behaviors than did the ADHD sample. The ADHD participants anticipated negative
      peer responses, whereas comparison girls predicted positive reactions from peers.
      Importantly, these perceived peer responses showed associations with girls'
      naturalistic social behaviors and peer sociometric status. Several pertinent
      predictions held with control of ADHD versus comparison status. Social cognitions
      appear to be relevant in the investigation of ADHD in girls.

PMID- 12402565
TI  - Sex differences in young children who meet criteria for attention deficit
      hyperactivity disorder.
AB  - Examined sex differences in a mostly clinic-referred sample of 127 children (22
      girls, 105 boys) who met Diagnostic and Statistical Manual of Mental Disorders
      (4th ed.; [DSM-IV], American Psychiatric Association, 1994) criteria for
      attention deficit hyperactivity disorder (ADHD) and 125 comparison children (24
      girls, 101 boys) matched on age, sex, and race-ethnicity. Children in both groups
      ranged in age from 3 years, 10 months to 7 years, 0 months. Both girls and boys
      who met criteria for ADHD were more impaired than same-sex controls on a variety
      of measures when intelligence and other types of psychopathology were controlled.
      Teachers reported that boys with ADHD were more inattentive and more
      hyperactive/impulsive than girls with ADHD. These findings suggest that the
      diagnosis of ADHD is valid for both girls and boys in this young age range. Young
      girls and boys who meet DSM-IV criteria for ADHD are more similar than different,
      but boys tend to display more symptoms of ADHD, particularly in school.

PMID- 12402566
TI  - Positive and negative affectivity in children: a multitrait-multimethod
      investigation.
AB  - Examined the validity of the tripartite model of anxiety and depression and its
      internal structure in children. Measures of positive affect/surgency (PA/S) and
      negative affect/neuroticism (NA/N) and self-report and peer nominations of
      symptoms of depression and anxiety were completed by 104 children (mean age =
      14.9 years, SD = 1.9). Parents completed measures of temperament and anxious and
      depressive symptoms. Multitrait-multimethod and confirmatory factor analyses
      (CFA) supported a 3-factor model that included separate Child and Parent NA/N
      factors and a joint PA/S factor. Child and Parent NA/N were related to symptoms
      of both depression and anxiety, but neither parent nor peer symptom ratings
      related to Child NA/N. PA/S was primarily related to symptoms of depression.
      These results support aspects of the tripartite model in children and suggest
      caution in the use of multimethod assessment of children's temperament and
      internalizing symptoms.

PMID- 12402567
TI  - An affect-based, hierarchical model of temperament and its relations with
      internalizing symptomatology.
AB  - Examined the tripartite model of personality, which emphasizes negative
      affectivity (NA) and positive affectivity (PA) as central organizing dimensions
      of personality that are useful for discriminating psychopathologies.
      Conceptualizations of youth temperament also include second-order, organizing
      factors of negative emotionality/neuroticism and positive
      emotionality/extroversion that may differentially predict psychopathologies. A
      community sample of 290 10- to 17-year-old youth completed the Emotionality,
      Activity, and Sociability Temperament Survey (EAS), Positive and Negative
      Affectivity Schedule, and measures of symptoms of anxiety and depression. Factor
      analysis replicated the 5-factor structure of the EAS and revealed 2 independent
      second-order factors, negative temperament (NT) and positive temperament (PT). NT
      and PT demonstrated convergent and discriminant relations with NA and PA.
      Consistent with the tripartite model, NT was associated with both anxiety and
      depression scores, but PT was related to depression scores only.

PMID- 12402568
TI  - Measuring cognitive vulnerability to depression in adolescence: reliability,
      validity, and gender differences.
AB  - Evaluated the psychometric properties of a newly created measure of cognitive
      vulnerability to depression for use with adolescents. Previous measures have
      shown poor internal consistency reliability and have not completely assessed all
      hypothesized components of cognitive vulnerability. High school students
      completed questionnaires assessing cognitive vulnerability to depression,
      negative life events, depressive symptoms, and general internalizing and
      externalizing symptoms. The Adolescent Cognitive Style Questionnaire (ACSQ)
      demonstrated excellent internal consistency reliability and good test-retest
      reliability. Confirmatory factor analysis showed there were 3 latent factors to
      the ACSQ. Construct validity was supported by significant correlations with
      another attributional style questionnaire, as well as with depressive and
      internalizing symptoms. The interaction of ACSQ with negative events
      significantly predicted concurrent depressive and internalizing symptoms but not
      externalizing problems. Last, cognitive vulnerability mediated the gender
      difference in depressive symptoms. Overall, results suggest that the ACSQ is a
      highly reliable and valid measure of cognitive vulnerability to depression in
      adolescence.

PMID- 12402569
TI  - Out of the picture: a study of family drawings by children from step-, single
      parent, and non-step families.
AB  - Investigated the family drawings of 180 children ages 5 to 7 years in various
      family settings, including stepfather, single-parent, complex stepfamilies, and 2
      parent control families. The relations of family type and biological relatedness
      to omission of family members and grouping of parents were examined. Children
      from step- and single-parent families were more likely to exclude family members
      than children from "control" non-step families, and exclusion was predicted from
      biological relatedness. Children who were biologically related to both resident
      parents were also more likely to group their parents together. Omission of family
      members was found to be associated with children's adjustment (specifically more
      externalizing and internalizing behavior) as reported by teachers and parents.
      The results indicate that biological relatedness is a salient aspect of very
      young children's representations of their families. The association between
      adjustment and exclusion of family members and grouping of parents indicates that
      family drawings may be useful research and clinical tools, when used in
      combination with other methods of assessment.

PMID- 12402570
TI  - Further evidence of reliability and validity of the Child Symptom Inventory-4:
      parent checklist in clinically referred boys.
AB  - Examined reliability and validity of the parent version of the Child Symptom
      Inventory (CSI-4) in 247 boys between 6.0 and 10 years 11 months old referred for
      evaluation of behavioral and emotional problems. The CSI-4 is a behavior rating
      scale whose items correspond to the symptoms of disorders defined by the
      Diagnostic and Statistical Manual of Mental Disorders (4th ed. [DSM-IV]; American
      Psychiatric Association, 1994). Results indicated satisfactory internal
      consistency reliability, test-retest reliability, and temporal stability over a 4
      year period for most symptom categories. CSI-4 ratings converged and diverged in
      a theoretically consistent pattern with respective scales of the Child Behavior
      Checklist (CBCL; Achenbach, 1991a) and the Diagnostic Interview for Children and
      Adolescents-Revised-Parent Version (DICA-P; Reich, Shayka, & Taibleson, 1991).
      Discriminant validity was established in that boys with specific DICA-P diagnoses
      received significantly higher corresponding CSI-4 parent symptom ratings than
      boys not so diagnosed. Clinical utility (sensitivity, specificity, positive
      predictive power, negative predictive power) was evaluated for screening cutoffs
      based on categorical (DSM-IV) and dimensional (normative distribution of Symptom
      Severity scores) scoring methods.

PMID- 12402571
TI  - Development and validation of a Q-sort procedure to assess temperament and
      behavior in preschool-age children.
AB  - Few broad observational measures of preschool-age children's temperament and
      behavior currently exist. Studied the Child Temperament and Behavior Q-Set (CTBQ
      Set) as a naturalistic observation measure to tap the major domains of
      temperament and behavior in preschoolers. Pairs of observers rated the behavior
      of a community sample of preschoolers during 2 independent home visits using q
      sort methodology. The CTBQ-Set scales displayed good levels of internal
      consistency and convergent and discriminant content saturation. The scales
      displayed good interrater reliability at each observation and moderate test
      retest stability between observations. The construct validity of the CTBQ-Set
      scales was supported by correlations with mothers' ratings of their children's
      behavior using the Child Behavior Checklist for 2- and 3-year-olds (CBCL/2-3) and
      the Children's Behavior Questionnaire. The CTBQ-Set shows promise as an observer
      reated measure of preschoolers' behavior and temperament in their natural home
      environment.

PMID- 12402572
TI  - Initial validation of the Emotion Expression Scale for Children (EESC).
AB  - The Emotion Expression Scale for Children (EESC) is a new self-report scale
      designed to examine 2 aspects of deficient emotion expression: lack of emotion
      awareness and lack of motivation to express negative emotion. Validity was
      assessed using self-report measures of emotion regulation and self- and peer
      report of internalizing and externalizing symptoms. Using a community sample of
      208 fourth- and fifth-grade children, reliability analyses revealed high internal
      consistency and moderate test-retest reliability of the EESC. The results provide
      initial support for concurrent validity for the EESC factors evidenced by
      relations with measures of emotion management. Associations were found between
      the EESC and measures of internalizing symptoms.

PMID- 12402573
TI  - Parent-child interactions in clinically anxious children and their siblings.
AB  - Observed 57 children (37 anxiety-disordered and 20 non-clinic-referred children)
      and their siblings interacting with their parents while completing a complex
      puzzle task. Consistent with previous findings, mothers were more involved and
      more intrusive during the task with their anxiety-disordered child than mothers
      of non-clinic-referred children. Mothers in the clinic-referred group were also
      significantly more involved and more intrusive during interactions with the
      anxious child's sibling than mothers of non-clinic-referred children. Although
      fathers were more involved during the task than mothers overall, no significant
      differences in overinvolvement were found between fathers of anxiety-disordered
      children and fathers of non-clinic-referred children. Both mothers and fathers
      were equally involved with the anxious child and the sibling of the anxious
      child. Although this study provides support for the association between maternal
      overinvolvement and the anxiety disorders, it suggests that overinvolvement does
      not occur exclusively in the context of relationships with the anxiety-disordered
      child.

PMID- 12402574
TI  - Examining cognitive models of externalizing and internalizing problems in
      subgroups of juvenile delinquents.
AB  - Examined cognitive content and processes, from models of externalizing and
      internalizing problems, in incarcerated delinquents (N = 177). Four groups were
      defined by multiple criteria (with 41 youth not able to be classified):
      aggressive-internalizing (AI, n = 22); aggressive-noninternalizing (AN, n = 14);
      nonaggressive-internalizing (NI, n = 27); and nonaggressive-noninternalizing (NN,
      n = 73). Groups did not differ on self-centered and minimizing types of self
      serving processing distortions, although the comorbid group endorsed more self
      serving distortions of assuming the worst and blaming others than the NN group.
      Aggressive, in comparison to nonaggressive, delinquents reported more self
      serving distortions in reference to overt behavior content. In contrast, self
      debasing cognitive content was related to internalizing problems, as both the AI
      and NI groups had more negative beliefs about self than both the AN and NN
      groups, and more negative beliefs about the world and the future than the NN
      group. The AI group also had more negative beliefs about the world than the AN
      group. Self-debasing processing distortions were not specifically related to
      internalizing problems, as no differences emerged between the AN and NI groups;
      however, the AI group differed from the NN group on 3 of 4 types of these
      distortions. Both of the internalizing groups had a more negative attributional
      style than the NN group. Theoretical and treatment implications are highlighted.

PMID- 12402575
TI  - Factor structure of the Young Mania Rating Scale for use with youths ages 5 to 17
      years.
AB  - Assessed the factor structure of the Young Mania Rating Scale (YMRS). Youths
      presenting to a research program specializing in the pharmacological treatment of
      mood and disruptive behavioral disorders (N = 612) were administered a
      semistructured diagnostic interview. Based on the interview, youths were placed
      into diagnostic groups. Highly trained raters completed the YMRS for each youth.
      YMRS ratings were internally consistent (alpha = .91), and exploratory and
      confirmatory factor analyses yielded a 1-factor solution for boys and girls in
      both young (5 to 11 years) and older (12 to 17 years) subsamples. However, the
      young male group showed higher scores on several items as well as the total YMRS
      score. Results suggest that the YMRS total score can be meaningfully interpreted
      in child and adolescent samples.

PMID- 12402576
TI  - Kinetics of carboxy-terminal propeptide of type I procollagen in pediatric
      patients undergoing peritoneal dialysis.
AB  - Carboxy-terminal propeptide of type I procollagen (PICP) is used as a marker of
      bone formation and, presumably, also peritoneal fibrosis. The aim of the present
      study was to assess the effect of dialysate PICP level (PICPd) on serum PICP
      level (PICPs). The study group consisted of 20 patients divided into two groups:
      group A consisted of 10 children without peritonitis, mean age 13.6 +/- 5 years,
      3 on continuous ambulatory peritoneal dialysis (CAPD) and 7 on automated
      peritoneal dialysis (APD); and group B consisted of 10 children with peritonitis
      (last episode having occurred at least 2 months before the study), mean age 13.9
      +/- 2 years, 8 on CAPD and 2 on APD. Osmolarity of the dialysate fluid in groups
      A and B was similar (375.7 +/- 42 mOsm/L and 363.1 +/- 16 mOsm/L respectively).
      The PICPs and PICPd levels, PICP index (PICPd/PICPs), PICP peritoneal clearance
      (ClPICP), and PICP mass transfer (MTPICP) were measured in both groups. Mean
      PICPs was higher in group B, but the difference was not significant. No
      significant differences were seen in the mean values of PICPd, PICP index,
      ClPICP, and MTPICP between groups. Levels of PICPd correlated positively with
      ClPICP (r = 0.75, p < 0.001) and negatively with MTPICP (r = -0.89, p < 0.0001).
      No associations were seen between PICPs and PICPd, ClPICP, and MTPICP. No
      associations were observed between osmolarity and ClPICP and MTPICP. Serum PICP
      level in children undergoing peritoneal dialysis does not depend on peritoneal
      PICP level.

PMID- 12402577
TI  - Lymphocyte subset counts in continuous ambulatory peritoneal dialysis patients in
      relation to administration of recombinant human erythropoietin and angiotensin
      converting enzyme inhibitors.
AB  - Estimation of lymphocyte subset counts (SLCs) is a useful tool in diagnosing
      nutrition and immune changes in continuous ambulatory peritoneal dialysis (CAPD)
      patients. Administration of recombinant human erythropoietin (rHuEPO) or
      angiotensin-converting enzyme inhibitors (ACEIs) can influence SLCs. Our aim was
      to evaluate the relationship between rHuEPO and ACEI doses and SLCs in the course
      of CAPD. In the group of studied patients (n = 55), 34 patients were taking
      rHuEPO and 38 patients were taking ACEIs. In 35 patients, enalapril was the ACEI
      used. Seven patients were taking rHuEPO, but not ACEIs; 11 patients were taking
      ACEIs, but not rHuEPO; 27 patients were taking rHuEPO and ACEIs both; and 10
      patients were receiving neither rHuEPO nor ACEIs. Flow cytometry was used to
      estimate CD3, CD4, CD8, CD19, and CD16 + 56 antigens. In the study group, a
      correlation was seen between dialysis duration and rHuEPO dose (r = 0.395). No
      correlation was seen between CAPD duration and ACEI dose, but it was seen for
      total rHuEPO and ACEI doses (r = 0.327). A negative correlation was also seen
      between dialysis duration and CD19 cell count (r = -0.313). In patients taking
      only ACEIs (n = 11), a negative correlation was seen between total ACEI doses and
      CD16 + 56 cell count (r = -0.710). In patients who were not receiving rHuEPO or
      ACEIs, negative correlations were seen between dialysis duration and total
      lymphocyte count (r = -0.727), CD3 cell count (r = -0.706), CD4 cell count (r = 
      0.636), and CD8 cell count (r = -0.764). In conclusion, rHuEPO and ACEIs can
      influence the total lymphocyte count or lymphocyte subset counts--the natural
      changes being disturbed with prolongation of CAPD treatment. The possibility of
      this influence should be taken into account when evaluating lymphocyte counts as
      indices of nutrition and immune status.

PMID- 12402578
TI  - Chronic alteration of subperitoneal tissue and peritoneal transport.
AB  - Based on previous work, we hypothesized that the alterations in tissue hyaluronan
      concentration ([HA]) brought about by chronic treatment of the peritoneum would
      result in corresponding changes in solute and water transport. To address that
      hypothesis, we carried out daily intraperitoneal (i.p.) injections for 2 months
      in 200-300 g rats of 30-40 mL of a sterile solution via peritoneal catheter
      tunneled to a subcutaneous port in the neck. Solutions used were: 4% N
      acetylglucosamine (NAG), 4% mannitol (M), 4% glucose (G), and control group (C).
      After 2 months, each animal underwent transport studies, using plastic chambers
      affixed to the parietal peritoneum of the abdominal wall, to determine: small
      solute mass, osmotic filtration, and albumin flux in response to 450-500 mOsm/kg.
      After each animal was humanely killed, the tissue below the chamber was removed
      and analyzed for [HA]. A 50% enhancement in [HA] in tissue was seen in NAG
      treated animals as compared with animals in the other groups. Results for small
      solute transport (one-way ANOVA, p > 0.6) and osmotic filtration (one-way ANOVA,
      p > 0.2) both demonstrated no significant differences among groups. The albumin
      flux (mean +/- standard error of the mean) in the control group (C) was
      significantly higher (0.36 +/- 0.03 microL/min/cm2) than in the three treatment
      groups, but no difference was seen among the treatment groups (NAG: 0.25 +/- 0.03
      microL/min/cm2; M: 0.26 +/- 0.03 microL/min/cm2; G: 0.29 +/- 0.03 microL/min/cm2;
      one-way ANOVA, p = 0.064). We conclude that increasing [HA] by 50% in parietal
      peritoneal tissue does not bring about major changes in transperitoneal
      transport.

PMID- 12402579
TI  - Protein oxidative stress in dialysis patients.
AB  - Inflammatory status is observed in patients with chronic renal failure (CRF). The
      relationship between oxygen free radical production and dialysis could play an
      important role in protein oxidation. Carbonyl protein plasma level is an
      important tool in the study of protein stress, and it is related to the arterial
      intima thickness in the atherosclerosis process. We studied protein oxidative
      stress in 21 peritoneal dialysis (PD) patients and 42 hemodialysis (HD) patients
      as compared with 32 undialyzed patients with CRF. Carbonyl protein plasma levels
      were measured in nanomoles per milligram protein by the ELISA method (Winterbourn
      et al). Dialysis patients had a higher protein carbonyl content than did CRF
      patients (0.1265 +/- 0.04 nmol/mg vs. 0.1594 +/- 0.03 nmol/mg, p < 0.0002).
      Patients on PD had a lower level than patients on HD (0.1452 +/- 0.03 nmol/mg vs.
      0.1665 +/- 0.04, p < 0.004). Glucose administration in PD is known to be able to
      increase glucose degradation products (GDPs) and advanced glycosylation end
      products (AGEs) with high carboxylic and oxidative stress. In our study, the
      carbonyl protein level was higher in HD patients than in PD patients, perhaps
      because more protein oxidative stress is associated with hemodialysis technique
      or because the PD patients had greater residual renal function.

PMID- 12402580
TI  - Endothelial nitric oxide synthase gene polymorphism in dialysis patients.
AB  - Nitric oxide is an important factor in the regulation of vasodilator tone. In
      vascular cells, NO is synthesized by endothelial nitric oxide synthase, a key
      enzyme of the endogenous vasodilator system. Some studies have described the
      interaction between NO and the other factors that promote vasodilatation in
      vascular smooth muscular cells. Some of those factors are angiotensin-converting
      enzyme (ACE), transforming growth factor beta (TGF beta), and endothelial oxide
      nitric synthase (eNOS). Polymorphism that can alter the expression or the
      function of the eNOS protein has been identified in the eNOS gene in the promoter
      and codification zones. We studied the Glu298Asp variant of the eNOS gene in 52
      hemodialysis (HD) patients, 22 peritoneal dialysis (PD) patients, and 93 healthy
      controls. Identification of the Glu298Asp variant in exon 7 was performed by
      enzymatic amplification and restriction fragment length polymorphism (RFLP)
      analysis. The frequencies of eNOS genotypes in the control group were GG, 39.8%;
      GT, 43%; and TT, 17.2%. In HD patients, the frequencies were GG, 40.3%; GT,
      38.7%; and TT, 21.7%. In PD patients, they were GG, 41.6%; GT, 50%; and TT, 8.6%.
      No significant differences were seen between the control group and the dialysis
      patients, or between the HD and the PD patients.

PMID- 12402581
TI  - Glucose suppresses peritoneal inflammatory reactions and mesothelial hyperplasia
      caused by intraperitoneal saline infusion.
AB  - In the past, we had observed that infusion of normal saline into the peritoneal
      cavity stimulates an inflammatory response. In the present study, we examined
      what effect the addition of glucose to normal saline would have on the peritoneal
      inflammatory response and change in peritoneal morphology. After catheter
      implantation, rats were infused intraperitoneally (i.p.) for 3 days with Dianeal
      1.36% (Baxter Healthcare Corporation, Deerfield, IL, U.S.A.). Dialysate samples
      were collected on day 3 after a 4-hour dwell. Next, rats were exposed to either
      NaCl (n = 7) or NaCl with glucose 250 mmol/L (Glu, n = 7) twice daily for 4
      weeks. After 2 weeks and 4 weeks of the study, dialysate samples were collected
      after a 4-hour dwell to analyze the activity of inflammatory reaction. At the end
      of the experiment, imprints of peritoneal mesothelium were taken. Control animals
      (C, n = 6) did not undergo catheter implantation or the dialysis procedure. The
      inflammatory reaction--cell count, cell differentiation, nitric oxide production,
      protein loss, and monocyte chemoattractant protein-1 (MCP-1) concentration in
      dialysate expressed as a percentage of the initial value--did not change during
      the study in rats exposed to NaCl. On the other hand, in Glu-treated animals, the
      protein concentration was decreased after 4 weeks of the study (74% +/- 23%, p <
      0.05), as was MCP-1 (24% +/- 12%, p < 0.05). The nitrites concentration was
      decreased after 2 weeks (72% +/- 19%; p < 0.05). Intraperitoneal adhesions were
      found in 6 rats of the NaCl group (86%) and in only 4 rats (57%) of Glu group. In
      the NaCl rats, a higher density of mesothelial cells was observed (2792 +/- 510
      cells/mm2) as compared with Glu rats (2028 +/- 561 cells/mm2; p < 0.05) and with
      control rats (1629 +/- 422 cells/mm2, p < 0.05). The NaCl group also showed a
      higher nucleus: cytoplasm surface ratio (0.25 +/- 0.03) as compared with the Glu
      group (0.18 +/- 0.02, p < 0.01) and with the control group (0.14 +/- 0.01, p <
      0.01). Addition of glucose to normal saline suppresses the peritoneal
      inflammatory response and mesothelial hyperplasia occurring with intraperitoneal
      infusion of NaCl solution alone.

PMID- 12402582
TI  - Small-solute and middle-molecule clearances during continuous flow peritoneal
      dialysis.
AB  - Previous theoretic and clinical studies have shown that continuous flow
      peritoneal dialysis (CFPD) provides a high dose of small-solute removal; however,
      the dose of middle-molecule removal with CFPD therapy has not been evaluated. We
      used a variable-volume, two-compartment model to calculate theoretical steady
      state solute kinetic profiles during CFPD, continuous ambulatory peritoneal
      dialysis (CAPD), and hemodialysis using a high-flux dialyzer (HFHD), for an
      anuric 70-kg patient and two measures of dose: equivalent renal clearance (EKR)
      and standard Kt/V (stdKt/V). Dose measures during each therapy were calculated
      for five solutes: urea, creatinine, vitamin B12, inulin, and beta 2
      microglobulin. Fluid (1 L daily) was assumed to accumulate in and to be removed
      from the extracellular space, and non renal clearance was assumed to be zero for
      all solutes except beta 2-microglobulin. Calculated doses for CFPD were higher
      than for CAPD or HFHD when assessed by either EKR or stdKt/V. Dose enhancements
      for CFPD were highest for small solutes, but were still considerable for middle
      molecules. We conclude that CFPD achieves higher doses than CAPD or HFHD for both
      small-solute and middle-molecule removal.

PMID- 12402583
TI  - Differences in peritoneal equilibration test results in patients aged above or
      below 60 years.
AB  - Peritoneal permeability, evaluated using the peritoneal equilibration test (PET),
      indicates that, in an adult population not selected for age, an increase in the
      transport rate of small solutes usually occurs in the course of peritoneal
      dialysis (PD) treatment. We evaluated the dialysate-to-plasma ratio of urea (D/P
      urea), the D/P creatinine, the ratio of dialysate glucose at a designated dwell
      time to dialysate glucose at 0 dwell time (D/D0 glucose), and the mass transfer
      area coefficients (KBDs) of those solutes in PETs performed in patients aged
      above or below 60 years who were matched for sex, PD duration, and outcome. The
      single-center, retrospective study was carried out in a peritoneal dialysis unit
      in a university hospital. Two groups of PD patients were chosen. Mean age of
      patients in group I (n = 21; 9 women, 12 men) was 67.7 +/- 4.5 years; PD duration
      was 20.1 +/- 12.1 months. In group II, the patients (n = 21; 9 women, 12 men) had
      a mean age of 42.8 +/- 9.1 years, and had been treated with PD for 20.7 +/- 12.1
      months. A standard PET was performed according to Twardowski et al every 3 months
      from PD start to PD end. The first results, the mean results representing the
      entire PD course, and the last results were compared between groups. In addition,
      the first and the last results were compared within each group. No significant
      differences were seen between the groups in peritoneal transport in the first
      PET. In the last PET, the curves for D/P urea and D/P creatinine, and the KBD for
      urea, were significantly lower in the older patients than the curves obtained at
      PD start. In consequence, a tendency toward lower D/P ratios or KBDs for urea and
      creatinine in the last and mean PETs was observed in group I as compared with
      group II. No significant changes were seen in the peritoneal transfer of glucose
      in the course of PD or between groups. Older patients may show a reduction in
      peritoneal permeability from the vascular to the mesothelial side of the membrane
      in the course of PD treatment; peritoneal transport in the opposite direction
      remains unchanged during approximately 20 months from the start of PD treatment.
      The patients under 60 years of age maintain stable bi-directional permeability
      under a comparable PD duration.

PMID- 12402584
TI  - Small solute clearances and nutrition indices in obese patients on continuous
      peritoneal dialysis.
AB  - To investigate the relationship between obesity, small-solute clearances, and
      nutrition in continuous peritoneal dialysis (CPD), we compared clearances and
      nutrition indices between 270 obese and 502 normal-weight CPD patients. Degree of
      obesity was classified by the ratio of body weight (W) to desired weight (DW) at
      the first clearance study. The DWs were obtained from the tables of the
      Metropolitan Life Insurance Company, assuming a medium skeletal frame. The obese
      patients (group I) had W/DW > 1.2 (1.38 +/- 0.17), and the normal-weight patients
      (group II) had 0.9 < or = W/DW < or = 1.2 (1.05 +/- 0.08). Nutrition indices
      derived from urea nitrogen and creatinine excretion were normalized by both W and
      DW. The following variables differed between group I (first value) and group II:
      sex (women: 48.2% vs. 33.9%), W (87.6 +/- 14.4 kg vs. 68.2 +/- 8.7 kg), body
      surface area (1.95 +/- 0.22 m2 vs. 1.77 +/- 0.16 m2), body water by method of
      Watson (41.2 +/- 7.7 L vs. 36.3 +/- 5.5 L), body mass index (31.8 +/- 3.9 vs 24.3
      +/- 2.0), protein nitrogen appearance (PNA: 62.9 +/- 17.6 kg in 24 h vs. 57.7 +/-
      15.7 kg in 24 h), PNA normalized to DW (1.08 +/- 0.29 g/kg in 24 h vs. 0.96 +/-
      0.26 g/kg in 24 h), creatinine excretion (CrEx: 1111 +/- 396 mg in 24 h vs. 991
      +/- 348 mg in 24 h), CrEx/W (12.6 +/- 3.7 g/kg in 24 h vs. 15.4 +/- 4.5 g/kg in
      24 h), CrEx/DW (17.3 +/- 5.3 g/kg in 24 h vs. 15.1 +/- 4.8 g/kg in 24 h), lean
      body mass (LBM: 49.3 +/- 13.8 kg vs. 43.6 +/- 11.9 kg), LBM/W (0.56 +/- 0.12 vs.
      0.64 +/- 0.15), and LBM/DW (0.77 +/- 0.18 vs 0.67 +/- 0.16), all at p < or =
      0.034. Marginal differences (0.10 > p > 0.05) were found in the diabetes
      prevalence (53.0% vs. 40.8%), height (165.9 +/- 11.7 cm vs. 167.4 +/- 9.8 cm),
      and serum albumin (3.64 +/- 0.55 g/dL vs. 3.53 +/- 0.62 g/dL). No differences
      were found in age, duration of CPD until the first clearance study, percent of
      subjects with anuria, Kt/V urea, creatinine clearance, blood urea nitrogen, serum
      creatinine, and PNA normalized to W. Obese CPD patients tend to have better
      nutrition indices than do normal-weight CPD patients with similar small-solute
      clearances. In obese subjects, normalization by W creates inappropriately low
      values for nutrition indices derived from urea nitrogen and creatinine excretion.
      Normalization of those indices by DW appears preferable.

PMID- 12402585
TI  - The impact of healthy start peritoneal dialysis on the evolution of residual
      renal function and nutrition parameters.
AB  - The optimal time to start renal replacement therapy remains controversial.
      Residual renal function (RRF) and nutrition status being important prognostic
      factors, the present study evaluates the impact of timely start of peritoneal
      dialysis (PD) on their evolution. Our study used a prospective database on pre
      end-stage renal disease patients at a tertiary care center. We included 18
      patients who were planned to start PD at a GFR > 8 mL/min between 1 January and
      31 December 1999. At the start of PD (month 0), creatinine clearance (CCr) was
      11.3 +/- 3.9 mL/min, actual glomerular filtration rate (GFR) was 8.6 +/- 3.3
      mL/min, and Kt/V was 1.56 +/- 0.65. The monthly declines of GFR and CCr before
      and after the start of PD were -0.47 +/- 0.64 mL/min (GFR) and -0.59 +/- 0.46
      mL/min (CCr), and -0.06 +/- 0.30 mL/min (GFR) and -0.05 +/- 0.39 mL/min (CCr)
      respectively (p = 0.034 and 0.001, respectively). Before the start of PD, CCr was
      21.9 +/- 4.6 mL/min (month -12) and 18.1 +/- 4.8 mL/min (month -6, p < 0.001).
      After the start of PD, CCr was 12.0 +/- 4.3 mL/min (month 3), 11.5 +/- 4.9 mL/min
      (month 6), and 13.1 +/- 5.4 mL/min (month 12, p = 0.9). Serum albumin dropped
      until just before the start of PD: 3.89 +/- 0.59 g/dL (month -6) and 3.78 +/-
      0.51 g/dL (month -3) versus 2.56 +/- 1.60 g/dL (month 0, p = 0.04). Serum albumin
      then increased to 3.42 +/- 0.95 mg/dL (month 3 after the start of PD) and 3.35 +/
      0.86 mg/dL (month 6 after the start of PD, p = 0.04). In the months preceding
      the start of PD, the normalized protein catabolic rate (nPCR) dropped from 1.41
      +/- 0.36 g/kg daily (month -6) and 1.34 +/- 0.46 g/kg daily (month -3) to 1.12 +/
      0.25 g/kg daily (month 0). It then stabilized at 1.17 +/- 0.25 g/kg daily (month
      3) and 1.18 +/- 0.17 g/kg daily (months 6). One patient died owing to a
      cerebrovascular accident after 18 months of PD, and one was transferred to
      hemodialysis because of ultrafiltration failure after 19 months of PD. During 264
      patient-months, 14 peritonitis episodes occurred. Of the 14 episodes, 12 resolved
      without complication, and the catheter was replaced in 2 episodes. After timely
      start of PD, the rate of RRF decline decreases. Already, at a GFR > 8 mL/min,
      uremia has a negative impact on nutrition parameters. Timely initiation of PD
      could reverse the negative evolution of albumin and stop the decline of nPCR. No
      severe complications related to PD were seen. In view of the important impact of
      RRF and nutrition on patient outcome, our data may favor an early start of PD.

PMID- 12402586
TI  - Hypotension in patients on chronic peritoneal dialysis: etiology, management, and
      outcome.
AB  - We retrospectively evaluated the phenomenon of arterial hypotension in peritoneal
      dialysis (PD) in a large cohort of 633 PD patients from two centers (Toronto
      Western Hospital, Toronto, Canada, and Division of Nephrology, Democritus
      University of Thrace, Greece), thus extending our previously reported experience
      for an additional 6 years (1995-2000). Together, the units had 81 hypotensive
      patients (12.8%), whose mean age was 63.8 +/- 14.2 years and whose mean duration
      of peritoneal dialysis was 49.3 +/- 30 months. Based on the underlying
      pathophysiology, the hypotensive PD patients were divided into four groups: (A)
      hypovolemia, 32 patients (39.5%); (B) congestive heart failure (CHF), 15 patients
      (18.5%); (C) receiving antihypertensive medications, 11 patients (13.6%); and (D)
      "unknown" etiology, 23 patients (28.4%). All patients in the hypovolemic and
      antihypertensive groups responded well to treatment (volume expansion and
      discontinuation of antihypertensive medication, respectively), but in the CHF and
      "unknown" groups, only 40% improved with the appropriate intervention. Patients
      in the latter two groups showed the poorest prognosis, with an approximate death
      rate of 65%. The hypovolemic group had better outcomes, which might reflect
      prompt response to fluid replacement in that group. We conclude that, in PD
      patients, careful use of antihypertensive medication, the right evaluation of
      target weight (especially in patients with cardiac failure), and judicious use of
      hypertonic exchanges may prevent the severe complication of arterial hypotension.

PMID- 12402587
TI  - Comparison of quality-of-life assessment in Russia and the United States in
      chronic peritoneal dialysis patients.
AB  - Numerous reports of quality-of-life data in chronic peritoneal dialysis (CPD)
      patients in the United States and Western Europe use the short form questionnaire
      (SF-36). Few centers in Europe have reported data examining the incidence of
      depression in CPD patients. Depression has been shown to correlate with morbidity
      and mortality in dialysis patients. A high incidence of clinical depression is
      seen in end-stage renal disease patients in the United States. We thought it
      could be important to compare depression measurements between the United States
      and European countries. Quality-of-life data of the peritoneal dialysis patients
      from the New Haven continuous ambulatory peritoneal dialysis (CAPD) unit and from
      the New Technology Center at Hospital #31 in St. Petersburg were compared. The
      Beck Depression Inventory (BDI) and the SF-36, which includes the mental
      component score (MCS) and the physical component score (PCS), were administered
      to the patients. The study participants included 147 Russian and 96 U.S.
      patients. The BDI, PCS, and MCS scores were similar in both groups. The BDI
      scores in the Russian patients indicated that a high incidence of clinical
      depression likely exists in that patient population. The utility of the BDI in
      assessing quality-of-life issues in Europe and Russia requires further
      evaluation.

PMID- 12402588
TI  - Review of health information Web sites for peritoneal dialysis information for
      patients.
AB  - We performed a review of United States-based, English-language Web sites to
      evaluate the information on peritoneal dialysis (PD) available to patients via
      the Internet. The "hits" obtained after using the search term "peritoneal
      dialysis" on a series of health care Web sites were listed and reviewed.
      Information was classified as limited, brief summary, detailed, or extensive, in
      order of increasing information. Professional organizations dedicated to kidney
      disease provided extensive information on PD, but Web sites for consumers
      generally provided little information. Information regarding PD is available to
      patients on the Internet, but for the most detailed and accurate information,
      patients should be directed to sites provided by professional organizations that
      specialize in kidney disease.

PMID- 12402589
TI  - Five years' experience of combination therapy: peritoneal dialysis with
      hemodialysis.
AB  - The fundamental objective of dialysis is to maintain the dose of solute clearance
      and ultrafiltration (UF). When peritoneal dialysis (PD) patients cannot maintain
      the target dose of clearance [weekly Kt/V > 2.0, weekly creatinine clearance
      (CCr) > 60 L/1.73 m2], the dialysis dose needs to be increased. But the means of
      increasing the dose only by PD are limited, especially for patients with UF
      failure (UFF). Combination therapy--PD with hemodialysis (PD + HD)--is the
      simplest way to solve the problem. The purpose of PD + HD therapy is to support
      solute clearance and UF when PD alone cannot meet the necessary targets. Acute
      and transient dialysis cases should be excluded. The general prescription for PD
      + HD should be 5-6 days of PD weekly and 1 session of HD weekly. For determine
      the adequacy of PD + HD, we adopted the equivalent renal clearance (EKR),
      transforming the PD weekly Kt/V and then evaluating total clearance from both
      modalities. Of our 238 dialysis patients, 31 (13%) use combined therapy. Except
      for 1 patient that transferred from long-term HD, all of patients had been on PD
      for more than 60 months, and were experiencing uremic symptoms after decline of
      residual renal function. In 12 cases, the problem was lack of solute clearance;
      in 5 cases, it was UFF. High permeability was involved in 5 cases: 4 after long
      term PD and 1 from the start of PD. Poor self-management occurred in 9 cases.
      Contributing factors included hernia, diaphragmatic intercourse, and severe heart
      failure with strict fluid control. Among the 31 patients, 8 used HD twice weekly.
      After combination therapy was started, the dialysis dose increased and body
      fluids became controllable. As a result, uremic symptoms improved and the
      patients' quality of life increased.

PMID- 12402590
TI  - Influence of pH-neutral peritoneal dialysis solution.
AB  - We evaluated the influence of a neutral peritoneal dialysis solution (PDS) on the
      peritoneum. The subjects were 10 stable PD patients using conventional PDS. We
      substituted pH-neutral PDS (PD Solita A: Shimizu Medical, Tokyo, Japan) for
      conventional PDS (Gambrosol A: Shimizu Medical). Effluent from 4-hour dwells was
      collected, and the appearance rate of cancer antigen 125 (CA125-AR) was
      calculated using the method of Pannekeet et al and corrected to body surface
      area. The dialysate-to-plasma creatinine (D/P Cr) was obtained, and personal
      dialysis capacity (PDC) was evaluated at 3-month intervals. Mean daily
      ultrafiltration volumes did not significantly change when pH-neutral PDS was
      used. The mean CA125-AR obtained 1 month after substitution was twice as high as
      that before substitution (139.2 +/- 47.3 U/min/1.73 m2 before substitution vs.
      286 +/- 126.2 U/min/1.73 m2 1 month later). However, mean values of CA125-AR were
      maintained at higher levels and did not significantly vary for 7 months after PD
      fluid substitution. When the change in CA125-AR (delta CA125-AR) was calculated
      as the ratio of the CA125-AR value before substitution to that after substitution
      at the respective measurement points, delta CA125-AR negatively correlated with
      D/P Cr. However, none of % area, % absorption, or % plasma loss significantly
      correlated with the delta CA125-AR obtained 6 months later. Although mesothelial
      cell viability may increase with the use of pH-neutral PDS, the level of the
      increase may differ depending on the severity of peritoneal damage. In addition,
      the use of a neutral PD fluid did not improve the endothelial cell system. In the
      future, development of a novel osmotic pressure-regulating substance substituting
      for glucose is essential to the development of PD fluids with higher
      biocompatibility.

PMID- 12402591
TI  - Compliance in automated peritoneal dialysis.
AB  - In peritoneal dialysis (PD), compliance with the dialytic prescription is an
      important element in achieving adequate dialysis. Using the questionnaire or
      inventory method, a rate of noncompliance between 10% and 20% has been reported
      for automated peritoneal dialysis (APD). The recent introduction of APD equipment
      capable of recording dialytic treatments (DTs) means that compliance can be
      assessed more precisely. In the present study, the PDLink software program
      (Baxter Healthcare Corporation, Deerfield, IL, U.S.A.) was used to
      retrospectively analyze 3 consecutive months of DTs in 19 APD patients (15 men, 4
      women; age: 67.9 +/- 10.2 years; duration of PD: 36.3 +/- 30.0 months) who were
      treated with the HomeChoice Pro [HCpro (Baxter Healthcare Corporation, Deerfield,
      IL, U.S.A.)]. In 12 patients (63%), the treatment was self-administered; for the
      other 7 patients (37%), treatment was handled by a partner (spouse: 5; family
      member: 2). Of 1673 recorded DTs, 20 (1.2%) were not performed. In the period
      taken into consideration (90 consecutive days), 9 patients underwent all the
      prescribed sessions, 4 patients missed 1 session, 3 patients missed 2 sessions, 2
      patients missed 3 sessions, and 1 patient missed 4 sessions. No irregularities
      were observed in relation to the prescribed volumes, and session length was 60
      120 minutes shorter in only 0.12% of the recorded sessions. In conclusion, the
      HCpro system proved effective in assessing compliance. In our experience,
      noncompliance occurred in a lower percentage of cases than has previously been
      reported, notwithstanding the present method's greater sensitivity and lesser
      specificity.

PMID- 12402592
TI  - Influence of the preceding exchange on peritoneal equilibration test results.
AB  - The present study evaluates the influence of the preceding exchange on peritoneal
      equilibration test (PET) results in patients on automated peritoneal dialysis
      (APD). A standard PET was performed following a 24-hour CAPD period with a
      preceding long overnight dwell of 8-10 hours (PETST), and following the usual APD
      regimen with short overnight dwell (PETAPD). We evaluated 9 patients of mean age
      59 +/- 18 years. Mean time on peritoneal dialysis was 31 +/- 17 months, and mean
      APD duration was 15 +/- 11 months. Mean D/P creatinine at 4 hours was 0.77 +/-
      0.12 (PETST) and 0.77 +/- 0.13 (PETAPD, p = 0.901). Mean D/D0 glucose was 0.33 +/
      0.07 (PETST) and 0.36 +/- 0.09 (PETAPD, p = 0.347). A significant correlation
      was seen between the D/P creatinine ratios (r = 0.946, p < 0.001) for the two PET
      methods and the D/D0 glucose ratios (r = 0.554, p = 0.017) for the two PET
      methods. Transport classification did not change in any patient. The current data
      support the use of the PET for peritoneal membrane evaluation immediately after
      cycler therapy in APD patients. We suggest that there is no need to change the
      dialysis regimen to a long dwell for the preceding exchange to evaluate
      peritoneal membrane characteristics when D/P creatinine and D/D0 glucose ratios
      are measured.

PMID- 12402593
TI  - Peritoneal rest may successfully recover ultrafiltration in patients who develop
      peritoneal hyperpermeability with time on continuous ambulatory peritoneal
      dialysis.
AB  - Temporary transfer to hemodialysis, as a peritoneal rest, may be a rescue therapy
      to recover ultrafiltration (UF) in patients who develop peritoneal
      hyperpermeability as a complication of continuous ambulatory peritoneal dialysis
      (CAPD). However, peritoneal sclerosis has been reported after peritoneal pause.
      Since the beginning of our CAPD program in 1985, 12 elective peritoneal pauses
      have been performed in 11 patients who developed type I ultrafiltration failure
      (D/P240 creatinine: 0.88 +/- 0.09) after 42 +/- 14 months on CAPD. Eight patients
      recovered UF and remained on CAPD with standard solutions for 10 +/- 9 months
      more (minimum: 5 months; maximum: 29 months). Only 3 of those patients were later
      switched to hemodialysis because of recurring UF failure. One patient remains on
      CAPD (62 months of follow-up). Four patients failed to respond and were
      permanently transferred to hemodialysis, without signs of developing
      encapsulating peritoneal sclerosis. The failed pauses were performed later after
      the detection of UF failure than were the successful ones (483 +/- 574 days vs.
      54 +/- 52 days). In our study, 8 of 12 peritoneal pauses (66.6%) successfully
      treated type I UF failure and prolonged CAPD retention. If a pause is initiated
      soon after diagnosis of UF failure, results may improve further. We urge
      prospective studies to better determine the best and timely therapeutic approach
      in patients with loss of ultrafiltration.

PMID- 12402594
TI  - Peritoneal equilibration test at home.
AB  - The peritoneal equilibration test (PET) has been widely used as a standardized
      means for estimating solute transport. However, the procedure is rather complex,
      and patients must spend more than half a day in the hospital. The fast PET is an
      alternative method, but the results are not reliable in patients whose peritoneal
      catheters drain poorly. We postulated that patients could perform the PET at home
      if educated well about the procedure. To that purpose, we prepared three types of
      visual aids that introduce the PET procedure: a VCR tape, a DVD disc, and a
      brochure with photographs. Equilibration tests were performed using the twin-bag
      system. For making fluid level indicator lines (200 mL and 10 mL), patients are
      given a guide sheet on which the fresh dialysate bag is placed. After an 8- to 12
      hour overnight dwell, the dwelled dialysate is drained completely into the empty
      bag. Immediately after the patient infuses 2 L of fresh 2.5% glucose dialysis
      solution, 200 mL of that solution is drained into the bag on which the two fluids
      levels were previously marked. After mixing, about 190 mL of the dialysate is re
      infused, and the remaining 10 mL (the amount indicated by a guide mark at the
      corner) is left within the bag. After a 4-hour dwell, the dialysate is completely
      drained into another twin-bag. A standard PET was also performed on a different
      day, and the data were compared with those from the home PET. Significant
      correlations were seen in D/D0 and in drain volume between the home PET and the
      standard PET (n = 10; D/D0: 0.385 +/- 0.054 vs. 0.371 +/- 0.052 respectively, r =
      0.872, p = 0.0004; drain volume: 2340 +/- 123 mL vs. 2372 +/- 90 mL respectively,
      r = 0.788, p = 0.0048). We conclude that the home PET is a clinically useful
      alternative to the standard PET, saving time and labor while maintaining
      accuracy.

PMID- 12402595
TI  - Streaming, mixing, and recirculation: role of the peritoneal access in continuous
      flow peritoneal dialysis (clinical considerations).
AB  - Continuous flow peritoneal dialysis (CFPD) is a very promising modality of PD in
      terms of high rates of solute removal and ultrafiltration (UF). The published
      clinical data are characterized by marked variability in terms of clearances and
      UF. Analysis of those data suggest significant streaming and recirculation with
      the available double-lumen catheters. A new double lumen catheter is described.
      It has wide separation between the limbs to minimize streaming and recirculation,
      and a novel geometric configuration to maximize internal cross-sectional luminal
      area with the lowest external diameter. Preliminary in vitro studies have shown
      flow rates consistent with those required for CFPD, satisfactory mixing of the
      fluid, and minimal streaming and recirculation. Clinical validation with long
      term studies are needed to assess the viability of CFPD as a chronic renal
      replacement therapy.

PMID- 12402596
TI  - A rapid assay for icodextrin determination in plasma and dialysate.
AB  - Icodextrin is a glucose polymer osmotic agent used to achieve sustained
      ultrafiltration during long peritoneal dialysis dwells. Previous assays for
      icodextrin in plasma and dialysate samples involved laborious methods, such as
      gel permeation chromatography with post-column derivatization of the eluted
      glucose polymers. We developed and validated a simple and more rapid assay for
      icodextrin using amyloglucosidase to hydrolyze all glucose polymers to glucose.
      Glucose was determined pre- and post-hydrolysis using a glucose hexokinase assay,
      and icodextrin concentration was calculated as the difference between glucose
      levels before and after hydrolysis. The complete hydrolysis of icodextrin to
      glucose was confirmed using anion exchange chromatography. Recovery studies using
      icodextrin powder added to plasma or dialysate showed 100% +/- 15% recovery for
      plasma concentrations from 10 mg/dL to 800 mg/dL and for dialysate concentrations
      from 50 mg/dL to 800 mg/dL. The percent relative standard deviation (%RSD) based
      on multiple replicates was within 6%, except at plasma icodextrin concentrations
      of 10 mg/dL and below. This simple and reliable assay has been used routinely in
      our laboratory to analyze thousands of plasma and dialysate samples from patients
      using Extraneal peritoneal dialysis solution (Baxter Healthcare Corporation,
      Deerfield, IL, U.S.A.).

PMID- 12402597
TI  - Kinetic analysis of icodextrin interference with serum amylase assays.
AB  - Patients treated with Extraneal peritoneal dialysis solution (Baxter Healthcare
      Corporation, Deerfield, IL, U.S.A.) have a significant decrease in serum amylase
      activity. The decline is reported to be due to interference of icodextrin in a
      routinely used laboratory assay. The present study was designed to investigate
      the kinetics of icodextrin interference in the amylase activity assay and to
      determine whether assay interference can account for the total decline in amylase
      activity. Plasma obtained from healthy volunteers was spiked with 0, 0.21, 0.71,
      and 3.6 mg/mL icodextrin. Amylase activity was determined using Sigma kit 577-10
      (Sigma Diagnostics, St. Louis, MO, U.S.A.). Amylase activity in plasma samples
      spiked with 3.6 mg/mL icodextrin was also monitored while varying the
      concentration of the substrate (ET-G7-PNP) from the assay kit. Amylase activity
      decreased with increasing amounts of icodextrin and decreasing amounts of assay
      substrate. A 72.6% decrease in amylase activity was observed in samples spiked
      with 3.6 mg/mL icodextrin as compared with samples without icodextrin at a
      substrate level similar to that in the assay kit (0.71 mmol/L). Double reciprocal
      and Dixon plots indicate competitive inhibition of amylase activity by
      icodextrin. Icodextrin functions as a competitive inhibitor in the assay for
      amylase activity, as predicted by the structural similarities between icodextrin
      and the amylase assay substrate. The degree of icodextrin interference suggests
      that the entire decline in amylase activity observed in patients using Extraneal
      can be accounted for qualitatively by icodextrin interference. The amylase
      activity decline in patients treated with Extraneal is an artifact attributable
      to assay interference.

PMID- 12402598
TI  - Declining trend of peritoneal dialysis: a single-center experience.
AB  - Peritoneal dialysis (PD), despite being advantageous to patient, physician, and
      society, has failed to show the growth it deserves. On the contrary, PD
      utilization has declined. Over the past several years, we have noticed a decline
      in the number of our home dialysis patients. When compared to the national trend,
      we find our trend to be not significantly different from other centers across the
      country. A similar trend has also been noticed in Canada. Although several
      reasons may exist for the decline, we intend to concentrate on local factors. In
      the first quarter of 1996, we had a total of 46 adult and pediatric end-stage
      renal disease (ESRD) patients on PD. That number decreased to 23 at the end of
      fourth quarter of the year 2001. The losses in our program far exceeded the
      gains. We lost our patients mainly to in-center hemodialysis (ICHD) and to
      transplantation. Peritonitis and membrane failure remained the major grounds for
      the loss to ICHD. In our center, geographic location and a lack of structured pre
      ESRD education probably played a major role in the decline. Many of our patients
      are from distant counties that have a contract with University of Texas Medical
      Branch for providing health care to their indigent population. However, once
      those patients develop complications, the counties rely on the expertise of local
      physicians and nephrologists.

PMID- 12402599
TI  - High peritoneal transport: a blessing or curse?
AB  - High transporters are defined based on the peritoneal equilibration test.
      Peritoneal transport rate changes over time, inflammation and angiogenesis
      affecting the total pore area. Factors influencing the neovascularization process
      are described. High transporters have distinctive clinical and laboratory
      features. The incidence of high transporters varies among different populations.
      Unfortunately, high transporters have the worst clinical outcomes. Mechanisms
      proposed to explain the adverse prognosis--including hypoalbuminemia, chronic
      fluid overload, malnutrition, and chronic inflammation--are discussed. We suggest
      dividing baseline high transporters into two groups: "sick" and "healthy" high
      transporters. The two types of high transporters have different baseline
      characteristics and different clinical outcomes. Hopefully, further studies will
      better define the appearance of the two groups of high transporters.

PMID- 12402600
TI  - Antibiotic prophylaxis before peritoneal dialysis catheter insertion.
AB  - The use of antibiotic prophylaxis before peritoneal dialysis (PD) catheter
      insertion has been a matter of great interest for both the surgical and the
      nephrology community. No uniform consensus exists on the timing, duration, or
      choice of antibiotic prophylaxis. The exact incidence of early postoperative
      peritonitis is unknown. The impact of the use of antibiotic prophylaxis in the
      prevention of early PD peritonitis and in long-term catheter survival is not
      clear. In that respect, many retrospective and prospective studies have been
      undertaken in the past, and they have shown conflicting results. Based on
      extensive data from the surgical and nephrology literature, and also based on our
      experience, we present a review of the use of antibiotic prophylaxis before
      peritoneal dialysis catheter insertion.

PMID- 12402601
TI  - Racial differences and peritonitis in an urban peritoneal dialysis center.
AB  - Racial differences have been reported among various groups with end-stage renal
      disease maintained on dialysis. In particular, patient survival on dialysis has
      been reported to be better in African-American patients than in Caucasian
      patients. Peritonitis rates and dropout from chronic peritoneal dialysis (CPD)
      have been reported to be higher in African-American patients. We decided to
      review our experience with peritonitis rates in African-American and Caucasian
      patients. From 1994 to 2000, 403 patients were maintained on CPD in the New Haven
      continuous ambulatory peritoneal dialysis (CAPD) unit. Peritonitis rates were 1
      episode in 14 patient-months in Caucasian patients and 1 episode in 13.6 patient
      months in African-American patients. Mean ages at the start of dialysis were 52.4
      +/- 16.2 years in the Caucasian patients and 62.6 +/- 14.9 years in the African
      American patients. African-American patients were older. African-American and
      Caucasian patients had similar peritonitis rates. Time of first episode of
      peritonitis was not different in the two groups.

PMID- 12402602
TI  - Encapsulating peritoneal sclerosis in patients undergoing continuous ambulatory
      peritoneal dialysis in Japan.
AB  - Encapsulating peritoneal sclerosis (EPS) is recognized as a serious complication
      in patients on continuous ambulatory peritoneal dialysis (CAPD). We
      retrospectively studied the management of CAPD patients who developed EPS in 157
      CAPD centers in Japan. Among 11,549 patients undergoing CAPD between 1980 and
      2000 in 157 centers, 256 patients developed EPS. The EPS developed between 10 and
      168 months (average: 99.6 months) after the start of CAPD. Of the 256 patients
      who developed EPS, 104 (40.6%) were using high glucose CAPD solution; however,
      135 (52.7%) were not. Only 27 patients who developed EPS (10.5%) were using beta
      blockers; many other patients were not. A history of peritonitis was seen in 232
      patients (90.6%), but not in 11 other patients (4.3%). The average frequency of
      peritonitis before development of EPS was 3.3 times higher in patients who
      developed EPS than in those who did not. Various therapeutic approaches were
      tried with 101 of the patients who developed EPS. Steroid therapy, including
      pulse therapy, was used to treat 84 patients (83.2%), and total parenteral
      nutrition was used to treat 80 patients (79.2%). Total intestinal enterolysis was
      performed in 31 patients (30.7%). Immunosuppressive agents were used in only 8
      patients (7.9%). After 2 years, 100 patients (39.1%) were known to have died; 143
      (55.9%) patients were known to still be alive. The most important problem for the
      living EPS patients was their mental condition, especially depressive state.
      However, only 22 of 133 patients (16.5%) were able to consult with a counselor in
      the hospital. A mental health support system should be provided to EPS patients
      in Japan.

PMID- 12402603
TI  - Glucocorticoid protects against the development of encapsulating peritoneal
      sclerosis on peritoneal dialysis.
AB  - Encapsulating peritoneal sclerosis (EPS) is an important complication of
      peritoneal dialysis in which all or part of the intestine is enveloped in a
      fibrous ball resulting in a cocoon. Previously, we reported that acid dialysis
      solution (DS) induces peritoneal fibrosis. In the present study, we examined the
      effect of treatment with glucocorticoid (GC) in a model of EPS in rats. We
      divided 20 male Wistar-Kyoto rats into four groups and dialyzed them with various
      solutions for 40 days as follows: (1) pH 3.5 DS, 10 mL (pH 3.5, containing 1.35%
      glucose, n = 5); (2) pH 3.5 DS, 10 mL + GC (0.1 mg dexamethasone daily, n = 5);
      (3) pH 7.0 DS, 10 mL (n = 5); and (4) pH 7.0 DS, 10 mL + GC (n = 5). At the end
      of 40 days, all rats were humanely killed by decapitation. Expression of mRNA of
      aquaporins (AQPs) and glucose transporters (GLUTs) were studied by reverse
      transcriptase polymerase chain reaction. In rats treated with pH 3.5 DS, necropsy
      findings showed evidence of EPS. The typical appearance was multiple surfaces
      covered with granulation tissue or fibrotic tissue or both. Multiple adhesions
      were present. Microscopic findings revealed that low-pH DS induced peritoneal
      fibrosis and loss of mesothelium. In the dialyzed rats, mRNA of AQP-1, AQP-4,
      GLUT-1, GLUT-4, and GLUT-5 was expressed in peritoneum. In rats treated with pH
      3.5 DS, expression of AQPs was significantly suppressed and expression of GLUTs
      was significantly enhanced. However, glucocorticoid treatment prevented the
      progression of peritoneal fibrosis and adhesion of peritoneum. In rats treated
      with pH 7.0 DS, no signs of EPS were seen. Our study suggests that low-pH DS
      induced the development of EPS. Glucocorticoid protects against the development
      of EPS on peritoneal dialysis.

PMID- 12402604
TI  - High-transport membrane is a risk factor for encapsulating peritoneal sclerosis
      developing after long-term continuous ambulatory peritoneal dialysis treatment.
AB  - Increased peritoneal function has been suggested to be a risk factor for
      developing encapsulating peritoneal sclerosis (EPS); however, clinical evidence
      is scarce. The present study aimed to clarify the specific character of
      peritoneal function in patients who developed EPS after withdrawal from
      peritoneal dialysis (PD). We studied 12 patients who developed EPS after PD
      withdrawal [(EPS group) mean PD duration: 109 months; mean period of EPS
      development: 7.0 months after withdrawal] and 128 patients who did not develop
      EPS (non EPS group). All 140 patients were withdrawn from continuous ambulatory
      peritoneal dialysis (CAPD) and were observed for the following 24 months. Based
      on the records of the annual peritoneal equilibration tests (PETs), we analyzed
      (1) the patients' dialysate-to-plasma (D/P) creatinine at various durations on
      PD, and (2) the accumulative appearance incidence of high-transport (HT) state of
      peritoneal membrane. The mean D/P creatinine in EPS group was significantly
      higher than that in the non EPS group in the course of PD from the 6th to the
      10th year. The accumulative incidence of HT was significantly higher in the EPS
      group than in the non EPS group, indicating early development of HT membrane in
      EPS group. Early development of increased D/P creatinine, classified as HT state,
      was observed during certain periods on PD in patients who developed EPS after PD
      withdrawal. That finding may indicate that HT state of peritoneal membrane is an
      early marker for EPS, and that the PET is useful to detect patients at high risk
      of EPS.

PMID- 12402605
TI  - Fifteen cases of encapsulating peritoneal sclerosis related to peritoneal
      dialysis: a single-center experience in Japan.
AB  - To evaluate the incidence and characteristics of encapsulating peritoneal
      sclerosis (EPS), we analyzed 111 patients who had been transferred to
      hemodialysis and had been periodically monitored using the peritoneal
      equilibration test. Encapsulating peritoneal sclerosis was diagnosed in 11
      patients. All patients had high-transport peritoneum, and 10 patients had been
      treated with continuous ambulatory peritoneal dialysis (CAPD) for more than 72
      months. Incidence of EPS increased according to prolongation of CAPD. To evaluate
      outcome, we analyzed 15 cases of EPS. All patients were treated with total
      parenteral nutrition (TPN). Five patients improved with TPN alone. However, the
      remaining 10 patients showed deterioration. Of those 10, 4 patients died. They
      had not been treated with corticosteroids (CSs). The remaining 6 patients were
      treated with CSs, but they did not improve. Those cases required surgical
      treatment. The postoperative course in 4 patients was satisfactory, but 2
      patients died. In our center, the EPS survival rate was 60%. In patients treated
      with TPN alone, the remission rate was only 33.3%. Administration of CSs could
      not improve that rate. In 6 patients treated with surgery, the mortality rate was
      33.3%. When EPS symptoms are not ameliorated by CS and TPN, surgical treatment
      should be considered. To prevent EPS, high-risk patients who have more than 72
      months on CAPD and who have a high-transport peritoneum should discontinue CAPD.

PMID- 12402606
TI  - Surgical treatment for encapsulating peritoneal sclerosis.
AB  - Although encapsulating peritoneal sclerosis (EPS) is feared as a fatal
      complication of peritoneal dialysis (PD), several recent studies have reported
      that many cases of EPS can be completely cured by appropriate methods of
      prevention and treatment. In this study, we describe therapeutic tactics for EPS
      and discuss methods of prevention. To begin, appropriate management of
      peritonitis and use of a biocompatible dialysis fluid are important to prevent
      the development of EPS. After the development of EPS is confirmed, the basic
      therapeutic tactics should be chosen according to the disease stage. That is,
      immediately after onset (inflammatory stage), EPS should be initially treated by
      steroid administration. If steroid therapy is ineffective, the steroid dose
      should be decreased immediately, and followed (encapsulating stage) by management
      with total parenteral nutrition (TPN). If ileus symptoms remain (ileus stage),
      active laparotomy and total intestinal enterolysis should be performed. During
      surgical treatment of EPS, it is important to perform total enterolysis without
      damaging the capsule-covered intestine. We believe that EPS is no longer an
      incurable disease, and that it can be completely cured by active diagnosis and
      treatment.

PMID- 12402607
TI  - Risk factors and preventive measures for encapsulating peritoneal sclerosis-
      Jikei experience 2002.
AB  - A growing incidence of encapsulating peritoneal sclerosis (EPS) has been reported
      recently in Japan, and it is now urgent to establish preventive measures against
      EPS development. In the present paper, we describe our observational results
      regarding the risk of EPS development and the characteristic features of patients
      with EPS, in terms of peritoneal morphology and peritoneal function as determined
      by peritoneal equilibration test. The ongoing working protocol for EPS prevention
      at Jikei University Hospital is also discussed. Our findings have revealed that
      long-term continuous ambulatory peritoneal dialysis (CAPD) is a risk factor for
      EPS development after transfer to hemodialysis from peritoneal dialysis (PD), and
      that, in most patients with EPS, peritoneal function is characterized by a
      longstanding high-transport state. The striking alterations in peritoneal
      morphology between patients with EPS and those with simple long-term CAPD
      hyperplasia include, in EPS patients, a prominent thickening of the collagenous
      layer of the peritoneum with neoangiogenesis and myofibroblastic transformation.
      Based on our findings, we established a withdrawal protocol for long-term CAPD
      patients, with the goal of preventing EPS. Those who have been on PD treatment
      for more than 72 months with high-transport state are candidates for withdrawal
      from PD, with performance of peritoneal lavage thereafter for a certain period of
      time. The clinical benefit of post-PD lavage has not yet been determined;
      however, the maneuver could be precluded in patients at low risk of EPS, because
      it was found that some patients can recover to average transport state during the
      period of PD withdrawal. Patients who remain high transporters with inflammatory
      reaction might require pharmacologic intervention, including prednisolone
      therapy. Further observations are required to validate our approach.

PMID- 12402608
TI  - Preservation of peritoneal catheter for prevention of encapsulating peritoneal
      sclerosis.
AB  - We evaluated the usefulness of periodic abdominal irrigation through the
      peritoneal catheter preserved after termination of peritoneal dialysis (PD) to
      prevent encapsulating peritoneal sclerosis (EPS). The study group included 8
      patients in whom PD had been terminated (mean age: 53.1 +/- 7.1 years; mean PD
      duration: 119.6 +/- 37.8 months). The abdominal cavity was periodically irrigated
      through the peritoneal catheter preserved after PD discontinuation. The
      appearance rate of cancer antigen 125 (CA125-AR), corrected by body surface area,
      was obtained every 3 months from 4-hour dwells. Based on the creatinine levels in
      4-hour dwells and plasma, the dialysate-to-plasma creatinine (D/P Cr) was also
      obtained. Following abdominal irrigation for more than 12 months, the peritoneal
      catheter was removed and a biopsy specimen was taken from the peritoneum. The
      CA125-AR increased 3 months after PD discontinuation, but decreased thereafter.
      Encapsulating peritoneal sclerosis developed in 3 of 4 patients who lacked
      parietal mesothelial cells (PMCs) in a peritoneal specimen. In contrast, a good
      prognosis was obtained in 4 patients who had PMCs. The maximum value of the
      change in CA125-AR (delta CA125-AR, as compared with the value at PD
      discontinuation) was significantly greater in the PMC+ group than in the PMC-
      group (8.0 +/- 2.7 vs. 3.4 +/- 3.1, p < 0.001). The D/P Cr at catheter removal
      was lower in the PMC+ group than in the PMC- group (0.45 +/- 0.21 vs. 0.85 +/-
      0.18, p < 0.05). Our findings suggest that periodic abdominal irrigation through
      the peritoneal catheter preserved after PD enhances the recovery of peritoneal
      damage. The CA125-AR value is a useful marker of viability and proliferation of
      PMCs.

PMID- 12402609
TI  - Rapid diagnosis of Mycobacterium tuberculous peritonitis in two continuous
      ambulatory peritoneal dialysis patients, using DNA amplification by polymerase
      chain reaction.
AB  - Tuberculous peritonitis is not an uncommon cause of continuous ambulatory
      peritoneal dialysis (CAPD) peritonitis in endemic countries. The diagnosis is
      usually delayed because peritoneal fluid smears for acid-fast bacilli (AFB) are
      insensitive, and cultures for Mycobacterium tuberculosis require weeks. The
      present paper reports two cases of tuberculous CAPD peritonitis that were rapidly
      diagnosed using gene amplification for M. tuberculosis DNA complex by polymerase
      chain reaction with the commercial Amplicor M. tuberculosis nucleic acid
      amplification test (Roche Diagnostic Systems, Branchburg, NJ, U.S.A.). A 18-year
      old man and a 50-year-old man, both on CAPD, developed culture-negative
      peritonitis. Empirical therapy with intraperitoneal vancomycin and gentamicin
      failed. Peritoneal fluid AFB smears were negative. In both patients, M.
      tuberculosis DNA complex was detected by nucleic acid amplification using the
      Amplicor test. Anti-tuberculosis treatment was unsuccessful and their catheters
      were removed. Six weeks later, their peritoneal fluid cultures isolated M.
      tuberculosis. The use of molecular techniques to assist in the diagnosis of
      pulmonary tuberculosis is well accepted. Little information exists regarding the
      use of molecular techniques in the diagnosis of tuberculous CAPD peritonitis. The
      diagnosis of tuberculous peritonitis in CAPD patients is frequently delayed and
      may cause increased morbidity and mortality. Molecular diagnosis of tuberculous
      peritonitis using nucleic acid amplification tests may allow more rapid
      diagnosis. Further studies are required to determine the sensitivity and
      specificity of the technique in CAPD patients with tuberculous peritonitis.

PMID- 12402610
TI  - Keeping the catheter exit site clean by sealing with a dressing film in patients
      under continuous ambulatory peritoneal dialysis.
AB  - In patients on continuous ambulatory peritoneal dialysis (CAPD), exit-site care
      is troublesome. We developed a new method for exit-site care, using a dressing
      film. We investigated the possibility of keeping the exit site clean for up to 6
      weeks, using seven protocols: Control group (n = 24)--the exit site was cleaned
      with a povidone iodine solution daily and a gauze dressing was applied. Group A
      (n = 120)--the exit site was cleaned with a povidone iodine solution once weekly,
      was covered with a small piece of gauze, and was completely sealed using a
      dressing film. Group B (n = 181)--as with Group A, except once every 2 weeks.
      Group C (n = 64)--as with Group A, except once every 3 weeks. And so on: Group D
      (n = 45)--once every 4 weeks. Group E (n = 8)--once every 5 weeks. Group F (n =
      2)--once every 6 weeks. At each session, we examined the small gauze
      bacteriologically. In groups A-F, the patients were asked to bathe every day and
      not to do anything about the exit site for 1-6 weeks, as applicable. In the
      control group, the rate of positive bacterial culture was 87.5%. In the other
      groups, the rates were group A, 15%; group B, 6.6%; group C, 6.3%; group D, 2.2%;
      and groups E and F, 0%. In the film-method groups, the rates of positive
      bacterial culture were significantly low. We thought that the film method kept
      the exit site clean.

PMID- 12402611
TI  - Peritonitis in continuous cycling peritoneal dialysis.
AB  - The increased use of automated peritoneal dialysis (APD) has generated interest
      in potential differences in the incidence and causes of peritonitis between APD
      and continuous ambulatory peritoneal dialysis (CAPD). Several seldom-considered
      factors may influence peritonitis rates in those patient groups. Patient
      selection and sequence of therapies, reuse practices, effect of solutions on host
      defenses, and promptness of diagnosis may have an effect on peritonitis rates.
      Those factors are reviewed in light of recent literature and technologic
      advances.

PMID- 12402612
TI  - Comparison of immunophenotypes in the blood of patients on continuous ambulatory
      peritoneal dialysis, asymptomatic and with peritonitis.
AB  - Peritonitis is a complication of continuous ambulatory peritoneal dialysis (CAPD)
      that often causes fibrosis. Understanding the role played by the immune system is
      required if we are to understand the mechanisms of defense and tissue lesion
      triggered by germs. We compared the characteristics of the blood immunophenotypes
      of patients on CAPD, with and without peritonitis. This descriptive, prospective
      study was carried out in the dialysis unit of San Jose University Hospital, a
      tertiary care institution in Popayan, Colombia. In blood samples from 46 patients
      on CAPD (26 with peritonitis and 20 without peritonitis), we used flow cytometry
      to measure cytokine production at the single-cell level. The diagnosis of
      peritonitis was made by standard clinical and laboratory criteria. We noted
      general clinical characteristics of the patients; percentages of lymphocytes,
      monocytes, neutrophils, and eosinophils; and cell counts of lymphocytes (CD4
      cells, CD8 cells) and their subsets [B1, B2, and natural killer (NK) cells]. We
      also determined the CD4:CD8 ratio. We found significant differences in the levels
      of serum albumin (p < 0.001), the percentages of lymphocytes (p < 0.04) and
      neutrophils (p < 0.04), and the counts of B1 and B2 cells, especially in patients
      whose CD4:CD8 ratio was below 1.2. Those patients also had more intense CD4
      lymphopenia, more CD8 cells (principally T-suppressor cells), and more expansion
      of NK cells. In patients on CAPD, an important immune activation and rise in the
      percentage of B1 cells occurs that increases with peritonitis. Among the general
      clinical characteristics, albumin was the only one to show a statistically
      significant difference between patients with and without peritonitis. An
      important CD4 lymphopenia occurred in patients with a CD4:CD8 ratio below 1.2.

PMID- 12402614
TI  - Peritonitis in continuous ambulatory peritoneal dialysis: cytokines in peritoneal
      fluid and blood.
AB  - Cytokines are soluble mediators of the immune system that regulate the response
      to antigens and microorganisms. In patients on continuous ambulatory peritoneal
      dialysis (CAPD) who have peritonitis, an inflammatory process exists that must be
      understood if susceptibility to, and the mechanisms of, complications such as
      fibrosis and others are to be understood. To that end, we studied 9 CAPD patients
      with peritonitis. The case series was conducted in Popayan, Colombia, at the RTS
      Cauca dialysis unit and the University of Cauca hospital, a tertiary health care
      facility. Peritonitis was diagnosed by standard clinical and laboratory criteria.
      Using flow cytometry, we measured the percentage production of intracellular
      cytokines [interleukin-1 alpha (IL-1 alpha), IL-6, IL-12, tumor necrosis factor
      alpha (TNF alpha), IL-4, and interferon-gamma (IFN-gamma) in T lymphocytes from
      blood and peritoneal fluid. Among the studied patients, all (100%) produced high
      levels of IL-1, IL-6, TNF alpha, IL-12, and IL-4 in both fluids (blood: 89% +/-
      63% of cells; peritoneal fluid: 81.6% +/- 10.1% of cells). In blood, 25% of
      patients produced IFN-gamma (mean: 15.7% of cells), showing that 75% of patients
      had the TH2 pattern, and 25% were close to TH0. In peritoneal fluid, 34% of
      patients produced IFN-gamma spontaneously (mean: 24.5% of cells), indicating that
      66% of patients were TH2, and 34% were close to TH0. After stimulation,
      expression of cytokines, including IFN-gamma (39% of T cells), was increased, and
      high production of IL-4 indicated that 25% of patients were TH2, and 75% were
      TH0. In peritoneal fluid, production of cytokines, including IFN-gamma, was
      increased, with high production of IL-4, indicating switching from TH2 (34% of
      patients) to TH0 (66% of patients). Of the studied patients, 35% had a CD4:CD8
      ratio < 1.1 in blood, and also produced IL-12 (94.5% of cells) and IFN-gamma (30%
      of cells), as compared with patients in whom the CD4:CD8 ratio was > 1.2.
      Patients on CAPD who have peritonitis produce large amounts of pro-inflammatory
      and TH2 cytokines. More IFN-gamma is produced in peritoneal fluid than in blood,
      which suggests more inflammation. Immunodeviation TH2 is seen in blood and
      peritoneal fluid of CAPD patients with peritonitis. Patients with a CD4:CD8 ratio
      < 1.1 produce more IFN-gamma and IL-12, and are more able to switch from TH2 to
      TH0.

PMID- 12402613
TI  - Cytokines and peritonitis in continuous ambulatory peritoneal dialysis:
      immunodeviation and immunodeficiency.
AB  - Cytokines are soluble mediators of the immune system, which regulate the immune
      response to antigenic stimuli. In continuous ambulatory peritoneal dialysis
      (CAPD) patients with peritonitis, an inflammatory process occurs, but the
      patterns of cytokine secretion have not yet been clarified. We compared the
      characteristics of the intracellular production of cytokines and looked for the
      immunophenotypes T helper 1 (TH1), T helper 2 (TH2), and T helper 0 (TH0) in CAPD
      patients with and without peritonitis. Our descriptive, prospective study was
      carried out in the dialysis unit of the San Jose University Hospital, a tertiary
      health care center in Popayan, southwest Colombia. We obtained 28 peripheral
      blood samples from CAPD patients (8 with peritonitis and 20 without peritonitis)
      and processed them by flow cytometry for intracellular detection of cytokines.
      The peritonitis diagnosis was made based using established clinical and
      laboratory criteria. We measured the general clinical characteristics and
      percentage of intracellular production of interleukin-1 (IL-1), interleukin-6 (IL
      6), interleukin-12 (IL-12), tumor necrosis factor alpha (TNF alpha), interleukin
      4 (IL-4), and interferon-gamma (INF-gamma) in T lymphocytes. Diabetic nephropathy
      and chronic glomerulonephritis were the most frequent primary pathologies in both
      groups of patients. The patients on CAPD without peritonitis expressed high
      levels of CD69 and the pro-inflammatory cytokines IL-1, IL-6, IL-12, TNF alpha,
      and IL-4, indicating in vivo immune activation similar to the group with
      peritonitis. In the group without peritonitis, 95% of samples displayed
      immunodeviation TH2. Just 5% of samples approached TH0, producing IFN-gamma.
      After mitogen activation, 45% of the samples stayed in TH2; 55% approached TH0.
      Patients with peritonitis produced high levels of IL-4 and little IFN-gamma,
      which indicates immunodeviation TH2 in 75% of samples; 25% approached TH0. When
      cells were stimulated by ionomicin and phorbol 12-myristate 13-acetate (PMA),
      more IFN-gamma appeared and high levels of IL-4 persisted in 75% of the samples,
      which looked like intent to correct the TH2 immunodeviation toward TH0. Patients
      on CAPD with and without peritonitis showed immune activation per se and high
      production of pro-inflammatory cytokines accompanied by a strong pattern of
      cytokine TH2 and a deficiency of IFN-gamma production, suggesting heavy
      immunodeviation TH2 and immunodeficiency TH1 (owing to the deficit of IFN-gamma).
      Finally, with in vitro immune stimulation, the TH2 pattern tried to approach TH0.

PMID- 12402615
TI  - Immunophenotyping by flow cytometry of peritoneal fluid of patients with
      peritonitis on continuous ambulatory peritoneal dialysis.
AB  - Our project identified, by flow cytometry, the immunophenotypes and activation
      state of the immune cells in the peritoneal dialysis fluid from patients with
      peritonitis on continuous ambulatory peritoneal dialysis. The results showed that
      all kinds of cells of the immune system were present in the peritoneal fluid in
      percentages and activation states similar to those seen in blood. Also, two
      subgroups of patients were noted, according to CD4:CD8 ratio. Patients whose
      ratio was < 1.1 had more expansion of CD8 and NK cells, and a higher percentage
      of B1 cells in both fluids than were seen in healthy people.

PMID- 12402616
TI  - The relationship between residual renal function, protein catabolic rate, and
      phosphate and magnesium levels in peritoneal dialysis patients.
AB  - Residual renal function (RRF) is an important factor in the well-being of
      peritoneal dialysis (PD) patients. Serum phosphate has been correlated with long
      term morbidity and mortality. We wished to determine if RRF contributes to a
      lower level of serum phosphate and magnesium. We also investigated the
      relationship between protein catabolic rate (PCR) and phosphate and magnesium. We
      collected data related to serum phosphate, serum magnesium, PCR, and RRF in 100
      PD patients. The Pearson correlation coefficient was used to study the
      correlation between RRF and magnesium, RRF and phosphate, PCR and magnesium, and
      PCR and phosphate. No relationship were seen between PCR and serum phosphate, and
      RRF and serum magnesium. Significant relationships were seen between PCR and
      serum magnesium and phosphate. The very good inverse correlation between RRF and
      serum phosphate highlights the importance of RRF in the control of serum
      phosphate. A very good relationship was also seen between PCR and serum
      magnesium.

PMID- 12402617
TI  - Correlation between oxidized low-density lipoprotein and other factors in
      patients on peritoneal dialysis.
AB  - Oxidized low-density lipoprotein (Ox-LDL) has been related with progression of
      atherosclerosis. Some studies reported increased Ox-LDL levels in hemodialysis
      (HD) patients. The levels of Ox-LDL in peritoneal dialysis (PD) patients have not
      yet been clarified. We measured Ox-LDL in PD patients and investigated the
      related factors. We measured plasma Ox-LDL, total cholesterol (TC), triglycerides
      (TG), and LDL-cholesterol (LDL-c) levels in 18 PD patients (mean age: 55.5 +/-
      9.8 years; mean duration of dialysis: 2.7 +/- 1.4 years) and in 24 HD patients as
      controls. We compared Ox-LDL levels in patients with diabetes mellitus (DM) and
      ischemic heart disease (IHD). And we looked at the correlation between Ox-LDL
      levels and adequacy of PD. Levels of Ox-LDL were significantly higher in the PD
      patients (2.24 +/- 1.14 ng/microgram LDL protein) than in the HD patients (1.43
      +/- 0.90 ng/microgram LDL protein), and other lipids were higher in the PD
      patients. The Ox-LDL did not correlate with other lipids. The Ox-LDL levels of
      the PD patients with DM or IHD were higher than those of non DM or non IHD
      patients. The adequacy of PD did not correlate with Ox-LDL. Patients on PD,
      especially those with DM or IHD, showed elevated Ox-LDL levels. Special attention
      should be paid to the level of Ox-LDL and atherosclerosis in PD patients.

PMID- 12402618
TI  - Usefulness of bioelectrical impedance analysis in monitoring nutrition status and
      survival of peritoneal dialysis patients.
AB  - Malnutrition is highly prevalent in peritoneal dialysis (PD) patients and is
      associated with higher mortality. Lower serum levels of markers of nutrition-
      such as albumin, creatinine, prealbumin, and total cholesterol--are important
      risk factors in PD patients. Usefulness of bioimpedance analysis (BIA) in
      hemodialysis (HD) patients has been reported. In the present study, we
      prospectively examined the relationship of bioimpedance indexes to the nutrition
      status and survival of 45 PD patients who were followed for more than 1 year. On
      patient enrollment, a BIA was performed (Bioelectrical Impedance Analyzer, Model
      BIA-101: RJL Systems, Clinton Township, MI, U.S.A.). Monthly blood was analyzed
      for biochemical markers. The mean age of the study group was 50 +/- 15 years. Of
      the 45 patients, 56% were female and 24% were diabetic. Mean body mass index was
      25.7 +/- 5.1. Mean resistance, reactance, capacitance, and phase angle were 524
      +/- 106 omega 57 +/- 20 omega, 678 +/- 223 pF, and 6.2 +/- 1.7 degrees
      respectively. Patients with diabetes had lower capacitance (555 pF vs. 713 pF, p
      = 0.007) and phase angle (5.35 degrees vs. 6.4 degrees, p = 0.05) than patients
      without diabetes. During the study period, 4 patients died. Patients who survived
      had higher capacitance (486 +/- 163 pF vs. 697 +/- 218 pF, p = 0.07) and phase
      angle (4.65 +/- 0.73 degrees, vs. 6.34 +/- 1.67 degrees, p = 0.008) than those
      who did not survive. The Kaplan-Meier method was used to compute observed
      survival. The cumulative observed survival of PD patients with an enrollment
      phase angle > or = 6 degrees was significantly (p = 0.01) higher than that of
      patients with an enrollment phase angle < 6 degrees. Reactance was directly
      correlated with albumin (r = 0.52, p < 0.0001) and total protein (r = 0.44, p <
      0.05). Capacitance was directly correlated with body mass index (r = 0.35, p <
      0.05), albumin (r = 0.32, p < 0.05), and blood urea nitrogen (BUN) (r = 0.44, p <
      0.01), and inversely correlated with body weight (r = -0.51, p < 0.0001). Phase
      angle was directly correlated with all of the biochemical markers of nutrition,
      such as albumin (r = 0.54, p < 0.01), total protein (r = 0.38, p < 0.05),
      creatinine (r = 0.28, p < 0.01), and BUN (r = 0.39, p < 0.05). By stepwise
      multivariate regression analysis, body weight (beta = -0.60, p < 0.0001) and
      total protein (beta = 0.32, p = 0.012) were significant determinants of
      resistance. Body weight (beta = -0.31, p = 0.02) and albumin (beta = 0.59, p <
      0.0001) were significant predictors of reactance. Serum albumin (beta = 0.53, p <
      0.0001) was the only best predictor of phase angle in PD patients. The BIA
      indices reflect nutrition status in PD patients, and may be useful in monitoring
      nutrition interventions.

PMID- 12402619
TI  - Effects of human recombinant erythropoietin on inflammatory status in peritoneal
      dialysis patients.
AB  - Treatment with recombinant human erythropoietin (rHuEPO) in dialysis patients has
      been associated with improvement of nutritional and immune status through an
      increase of cytokine production [such as tumor necrosis factor alpha (TNF
      alpha)]. The high cytokine production can be a double-edged sword owing to the
      relationship of cytokines with the systemic inflammatory process, which has been
      associated with many complications of uremic status. Our aim was to analyze the
      medium-long term effects of rHuEPO treatment on uremic inflammatory markers. We
      studied 45 peritoneal dialysis (PD) patients divided in two groups: a rHuEPO
      group (40-70 subcutaneous units/kg weekly) and a control group (no rHuEPO). The
      treated group was analyzed in four periods. Period 1 (rHuEPO-1) included 24
      patients who had been using rHuEPO at long-term. Period 2 (rHuEPO-2; n = 21)
      looked at the patients 2 months after rHuEPO withdrawal. Period 3 (rHuEPO-3; n =
      19) looked at the patients after 2 months under rHuEPO therapy. Period 4 (rHuEPO
      4; n = 17) looked at the patients after 4 months on rHuEPO treatment. With the
      reintroduction of rHuEPO, we observed a progressive, statistically significant (p
      < 0.05), and temporary increase in TNF alpha plasma levels, from 44 +/- 24 pg/mL
      (rHuEPO-2) to 76.8 +/- 25 pg/mL (rHuEPO-3), and then to 83 +/- 27 pg/mL (rHuEPO
      4). But in the long term, TNF alpha decreased [33.5 +/- 10 pg/mL (rHuEPO-1)].
      Similarly, albumin increased in the short term (3.73 +/- 0.5 g/dL to 4 +/- 0.5
      g/dL, and then to 4 +/- 0.43 g/dL), and then decreased (3.8 +/- 0.44 g/dL). The
      normalized protein catabolic rate (nPCR) increased from 1 +/- 0.2 g/kg daily to
      1.12 +/- 0.3 g/kg daily (rHuEPO-4). Long term, nPCR decreased to 1.06 +/- 0.3
      g/kg daily. Leptin initially increased (60.1 +/- 48 ng/mL to 42.8 +/- 22 ng/mL,
      and then to 38 +/- 18.2 ng/mL); it also increased in the long term (62 +/- 50.9,
      p < 0.05). At baseline, we found a significant positive linear correlation (p <
      0.05) between TNF alpha and leptin (r = 0.52), TNF alpha and C-reactive protein
      [(CRP) r = 0.4], CRP and leptin (r = 0.49), fibrinogen and CRP (r = 0.78, p <
      0.01), fibrinogen and leptin (r = 0.37), and leptin and body mass index [(BMI) r
      = 0.67]. In conclusion, rHuEPO induces a temporary, non inflammatory immune
      hyperactivity mediated by TNF alpha, without the adverse effects associated with
      that cytokine. By decreasing leptin, rHuEPO could increase food intake and
      improve the nutritional status of PD patients. At baseline, we confirm the
      existence of a chronic inflammatory process in uremia.

PMID- 12402620
TI  - True deficiency of antioxidant vitamins E and A in dialysis patients.
      Relationship with clinical patterns of atherosclerosis.
AB  - Atherosclerosis is an important cause of morbidity and mortality in peritoneal
      dialysis (PD) patients. Oxidative stress plays a role in the pathogenesis of
      uremic atherosclerosis. Although antioxidant substances (vitamins A and E) are
      elevated in the plasma of dialysis patients, intracellular and clinical signs of
      hypovitaminosis are frequently found. Recently, the importance of vitamin/carrier
      complexes as a marker of vitamin bioavailability has been demonstrated. In the
      present study, we analyzed vitamin A and E bioavailability, measured as
      vitamin/carrier complexes, and the relationship of those measurements with
      clinical atherosclerosis status in PD patients. We studied 45 patients (15 men,
      30 women), who were divided into four groups according to clinical
      atherosclerotic score (CAS). Five cases were scored as CAS grade 1 (low CAS); 9
      as CAS-2; 18 as CAS-3; and 13 as CAS-4. Vitamins A and E and their carriers
      [prealbumin and retinol binding protein (vitamin A), and cholesterol and
      triglycerides (vitamin E)] were determined. Plasma levels of vitamin A were low
      in 5 patients, normal in 7 patients, and high in 33 patients. By correcting the
      values for the carrier levels, we created three groups: 24 patients showed low
      vitamin A/carrier complex (5 from the low plasma vitamin A group, 6 from the
      normal-value group, and 13 from the high-value group); 11 patients were in the
      group with normal vitamin A/carrier (1 from the normal plasma vitamin A group,
      and 10 from the high-value group); and 10 patients were in the group with high
      vitamin A/carrier. The vitamin A/carrier complex showed a statistically
      significant, negative linear correlation with CAS and with serum iron. Low
      vitamin E plasma levels were found in 1 patient, normal levels in 28 patients,
      and high levels in 16 patients. When those values were corrected using the
      carrier values, three groups were also created. The group with low vitamin
      E/carrier complex contained 24 patients (1 from the low-value group, 22 from the
      normal-value group, and 1 from the high-value group). The group with normal
      vitamin E/carrier complex contained 21 patients (15 from the group with high
      vitamin E values, and 6 from the normal-value group). By univariate logistic
      regression analysis, significant associations between CAS and vitamin E plasma
      levels, vitamin E/carrier, age, and serum albumin were found. In the multiple
      logistic regression analysis, we confirmed that vitamin E/carrier complex, age,
      and serum albumin showed independent associations with CAS, but not with vitamin
      only plasma levels. Our results in PD patients show a vitamin/carrier complex
      disorder that results in elevated vitamin mobilization from pool and target
      cells. Our results and the findings of other researchers about intracellular
      vitamin A and E deficiencies may change the traditional concept of
      hypervitaminosis A and E in uremic patients.

PMID- 12402621
TI  - Leptin as a marker of nutrition and cardiovascular risk in peritoneal dialysis
      patients.
AB  - Anorexia and protein malnutrition, occasionally associated with obesity, are
      frequently observed in peritoneal dialysis (PD) patients. Both are recognized
      risk factors for cardiovascular (CV) morbidity and mortality. Leptin is produced
      by adipocytes and regulates body-fat mass through a satiety central effect.
      Leptin accumulates in the uremic state. We analyzed the relationship between
      plasma leptin levels, nutritional status, obesity, CV risk factors, and
      atherosclerosis in PD patients. Leptin was determined using a polyclonal antibody
      [radioimmunoassay: Linco Research, St. Louis, MO, U.S.A.]. The normal range was 1
      7.8 ng/mL. We studied 38 PD patients. Mean leptin levels were 59.1 +/- 57.5 ng/mL
      (elevated in 32 patients). Women (n = 21) showed higher leptin levels than did
      men (80.4 +/- 60 ng/mL vs. 32.3 +/- 43.3 ng/mL, p < 0.01), in spite of both
      groups having a similar body mass index (BMI). A statistically significant direct
      correlation was found between leptin and BMI (r = 0.7, p < 0.01) and triceps skin
      fold measurement (r = 0.77, p < 0.01). Leptin levels and renal creatinine
      clearance (CCr) showed no significant correlation. Independent of BMI, higher
      leptin levels were associated with parameters considered to be CV risk factors
      (Framingham study), such as serum triglycerides < 150 mg/dL (n = 29) as compared
      with > 150 mg/dL (44.2 +/- 53.2 ng/mL vs. 80 +/- 58.4 ng/mL, p < 0.05),
      cholesterol < 250 mg/dL (n = 28) as compared with > 250 mg/dL, (50 +/- 55.6 mg/dL
      vs. 84.7 +/- 57.7 mg/dL, p < 0.05), uric acid < 7 mg/dL (n = 28) as compared with
      > 7 mg/dL (47 +/- 53.7 mg/dL vs. 93.1 +/- 56.6 mg/dL, p < 0.05), and the presence
      or lack of presence of left ventricular hypertrophy [68.8 +/- 60 (n = 30) vs.
      29.5 +/- 23.7 (n = 5), p < 0.05]. The patients were classified into two groups
      according to a clinical atherosclerosis score (CAS). Nineteen patients had low
      CAS scores, and they showed higher plasma leptin values than did the other
      patients (82.4 +/- 65.7 ng/mL vs 35.8 +/- 36.6 ng/mL, p < 0.05). Twelve patients
      with anorexia had lower leptin values than did patients with normal appetite
      (19.2 +/- 15.8 ng/mL vs. 91.3 +/- 58.8 ng/mL, p < 0.001). In non obese patients
      (BMI < 25 and CCr < 3 mL/min, n = 14), leptin had a statistically significant
      direct linear correlation with markers of nutrition, including albumin (r = 0.63,
      p < 0.05), transferrin (r = 0.4, p < 0.05), cholesterol (r = 0.65, p < 0.05), and
      triglycerides (r = 0.6, p < 0.05). Finally, plasma leptin levels were notably
      increased in the PD population, indicating increased production (possibly by
      chronic hyperinsulinism), or uremic retention, or both. By multivariate analysis,
      we confirmed the association between leptin levels and sex, leptin and BMI, and
      leptin levels > 40 ng/mL and sex and LVH. All of those features suggest that
      plasma leptin levels could be considered a marker of CV risk and food intake in
      non obese PD patients without inflammation.

PMID- 12402622
TI  - New England's short list. Survey shows RNs struggling to cope.

PMID- 12402623
TI  - Nurse Reinvestment Act: show us the money!

PMID- 12402624
TI  - North America, Inc. NAFTA chips away at Canadian health care.

PMID- 12402625
TI  - All in a day's work.

PMID- 12402626
TI  - The ultimate sacrifice.
AB  - One hundred seventy-three people died in the outbreak, including a doctor and 12
      nurses. Belluz said more people were saved from infection or death because of the
      extraordinary job of containing the disease and educating people about what they
      should and shouldn't do.

PMID- 12402627
TI  - Seoul searching.

PMID- 12402628
TI  - Make a fist for me.

PMID- 12402629
TI  - Oh! My aching back!

PMID- 12402630
TI  - Electronic document management systems: an overview.
AB  - For over a decade, most health care information technology (IT) professionals
      erroneously learned that document imaging, which is one of the many component
      technologies of an electronic document management system (EDMS), is the only
      technology of an EDMS. In addition, many health care IT professionals erroneously
      believed that EDMSs have either a limited role or no place in IT environments. As
      a result, most health care IT professionals do not understand documents and
      unstructured data and their value as structured data partners in most aspects of
      transaction and information processing systems.

PMID- 12402631
TI  - How to produce EDMS requirements and cost-benefit data.
AB  - Electronic document management systems (EDMS) have a profound impact on
      administrative operations of health care provider organizations. Thorough yet
      conservative system requirements and cost-benefit data can prove the necessity
      and priority of the EDMS. This case study-based article provides a methodology
      for all EDMS implementations, including the preparation of the vision and scope,
      business analysis, cost-benefit analysis, and system specification and project
      plan. These are illustrated with EDMS examples. To successfully minimize project
      risk, the article reviews the importance of phasing, standards, and integration,
      and it provides six detailed examples of this methodology.

PMID- 12402632
TI  - Saying goodbye to optical storage technology.
AB  - The days of using optical disk based mass storage devices for high volume
      applications like health care document imaging are coming to an end. The
      price/performance curve for redundant magnetic disks, known as RAID, is now more
      positive than for optical disks. All types of application systems, across many
      sectors of the marketplace are using these newer magnetic technologies, including
      insurance, banking, aerospace, as well as health care. The main components of
      these new storage technologies are RAID and SAN. SAN refers to storage area
      network, which is a complex mechanism of switches and connections that allow
      multiple systems to store huge amounts of data securely and safely.

PMID- 12402633
TI  - Creating and managing a paperless health information management department.
AB  - Over the last 10 to 15 years, the health care industry has experienced dramatic
      changes in health care delivery, consumer needs, and demands. The medical record,
      a recapitulation of the care patients receive, continues to be one of the most
      vital components of the health care delivery system. It serves as a crucial
      administrative, clinical, financial, and research tool. Health information
      managers, striving to meet ever-changing requirements, have turned to electronic
      record processing to meet these changes. The following article describes one
      hospital's journey from a cumbersome paper environment to an electronic
      environment that not only resulted in improved customer service but also provided
      employees with renewed job satisfaction and increased skill levels.

PMID- 12402634
TI  - EDMS implementation challenge.
AB  - The challenges faced by facilities wishing to implement an electronic medical
      record system are complex and overwhelming. Issues such as customer acceptance,
      basic computer skills, and a thorough understanding of how the new system will
      impact work processes must be considered and acted upon. Acceptance and active
      support are necessary from Senior Administration and key departments to enable
      this project to achieve measurable success. This article details one hospital's
      "journey" through design and successful implementation of an electronic medical
      record system.

PMID- 12402635
TI  - EDMS: what it was, is, and could be.
AB  - The decision to implement an Electronic Document Management System (EDMS) should
      not be made lightly. Such is the advice of a health are provider organization
      that pioneered the technology a decade ago. University Health Systems of Eastern
      Carolina's largest facility, Pitt County Memorial Hospital (PCMH), implemented an
      EDMS in February 1992 and converted to its current EDMS in December 1999. This
      article describes PCMH's transition from paper to automation, the many trials
      along the way, and the advantages an EDMS offers.

PMID- 12402636
TI  - Transforming health information management through technology.
AB  - No one would deny the need to transform health care. Information technology is
      capable of transforming health care organizations and delivering measurable
      value. However, these organizations will have to deploy effective, proactive
      strategies for managing information and adapting to the opportunities the
      technology offers. If, for example, an organization wants to become paperless,
      its information strategy must include appropriate tools to store and access
      unstructured data components of the medical record as well as structured data. An
      Electronic Document Management System (EDMS) is a critical element of this
      strategy. Also, a plan for managing change must be developed to mitigate
      technology risks. This can be realized through the development of a clear vision
      of the future and strong leadership, among other key items.

PMID- 12402637
TI  - An overview of Electronic Document Management System product offerings.
AB  - The goal of this article is to provide insight in the evaluation of Electronic
      Document Management Systems (EDMSs) and the current EDMS vendors and their
      product offerings. Comparisons are made between the vendors and the products over
      the past decade. Appendix A and Appendix B outline many of today's key vendor
      offerings. Issues such as HIPAA and medical errors are discussed as it becomes
      clearer that the quality of patient care can be positively impacted with the
      application of information technology such as EDMSs.

PMID- 12402638
TI  - [Culture-sensitive nurses].

PMID- 12402639
TI  - [If you are tense--relax].

PMID- 12402640
TI  - [Getting old among the unfamiliar].

PMID- 12402641
TI  - [Departure from all principles. Culture-sensitive nurses as learning volunteers-
      a practical example].

PMID- 12402642
TI  - [...volunteer helpers can correct many problems].

PMID- 12402643
TI  - [New continuing education for psychiatric nursing].

PMID- 12402644
TI  - [When the nurse becomes a family member].

PMID- 12402645
TI  - [Development in six modules].

PMID- 12402646
TI  - Health care 2002: the State of the Nation.
AB  - Over the last decade in Michigan, as in other states, health care has emerged as
      a significant public policy issue. One of the striking characteristics of the
      health care debate is that, because it is a relatively new issue compared to
      others such as education or civil rights, we are still uncertain as to what it
      means or how we should address it.

PMID- 12402647
TI  - Health care matters.
AB  - A landmark election year is an ideal time to remind the public about the critical
      role that health care plays in our quality of life. As candidates for office
      publicly debate the issues the matter most to Michiganders, it is imperative that
      we tell our story and elevate health care to the very pinnacle of the state's
      priority list. In short, we need to explain clearly why health care matters.

PMID- 12402648
TI  - New districts--old results?
AB  - On Nov. 5, Michigan voters will elect legislators in each of Michigan's 15 new
      congressional districts to serve in Washington, DC, as well as state senators and
      representatives from newly drawn districts. But will the new districts change the
      makeup of the congressional delegation and the Republican's decade-long hold on
      majorities in the state House and Senate?

PMID- 12402649
TI  - Gubernatorial candidates respond.

PMID- 12402650
TI  - Finalization of rule removes uncertainty.
AB  - Although the deadline for compliance with the Health Insurance Portability and
      Accountability Act Privacy Rule is only a few months away, some hospitals and
      other covered entities have essentially placed HIPAA compliance efforts on hold
      for the past several months because of the perceived uncertainty surrounding the
      rule's requirements. A new final rule was released on Aug. 9, removing this
      uncertainty and maintaining the April 14, 2003, deadline.

PMID- 12402651
TI  - Shape up your community.
AB  - Looking for a new way to strengthen your community's health? Active community
      environments (ACEs) is a new approach to public health, which also serves to
      boost economic vitality in communities and is being used by some companies to
      attract a great employee team.

PMID- 12402652
TI  - Proposal 4 is only right.

PMID- 12402653
TI  - 3-to-1: public supports proposal 4.

PMID- 12402654
TI  - Grassroots advocacy network. Growing agents of change.

PMID- 12402655
TI  - Saving lives after death.
AB  - With more than 78,000 people on the waiting list, organ and tissue donation has
      become a national priority. Last year, the Department of Health and Human
      Services launched a nationwide campaign to create a "donation friendly America,"
      calling upon everyone from corporations to health care systems to help increase
      awareness about the need for organ and tissue donors.

PMID- 12402656
TI  - Building relationships: the key to successful health care philanthropy.
AB  - Creating and maintaining a vigorous philanthropy program has seldom been more
      challenging to health care organizations. To our communities that are discontent
      with changed health care management and practices, we have now added economic
      insecurity and global unrest.

PMID- 12402657
TI  - How to improve executive-physician relationships.

PMID- 12402658
TI  - Patient safety leadership fellowship.

PMID- 12402659
TI  - Do we have the will for change?

PMID- 12402660
TI  - Anaplastic large cell lymphoma and acquired angioedema: a novel association?

PMID- 12402661
TI  - [Rhabdomyolysis].

PMID- 12402662
TI  - [Growth hormone deficiency in the adult: only an endocrinologic problem?].
AB  - In the literature published during the last decade an increased risk of death due
      to cerebrovascular and cardiovascular events in growth hormone deficient adults
      has been reported. A partial reversibility of the syndrome following recombinant
      growth hormone treatment has also been described. Both these factors have
      contributed to the proposal of growth hormone therapy not only for children but
      also for adults. Following the initial enthusiasm, the scientific community is
      now evaluating various clinical experiences held over recent years and weighing
      up the results. Present day medicine has to take the economic impact of
      prescribed therapeutic regimens into consideration; in other words the ratio
      between cost and benefits must be calculated. The relatively recent issuance of
      the license for the treatment of growth hormone deficiency in adults using
      recombinant growth hormone does not allow us to evaluate a possible reduction in
      the risk of death due to cerebrovascular and cardiovascular events in treated
      subjects. A much longer observational period will be required. Besides the
      partial reversibility of the syndrome as a consequence of treatment, it is
      necessary to single out the selection criteria for the choice of treatment. These
      could also be useful as indicators of the efficacy of the same treatment.

PMID- 12402663
TI  - [Probiotics: history, definition, requirements and possible therapeutic
      applications].
AB  - The ingestion of probiotics is associated with various beneficial effects on
      human health and modifies the physiological homeostasis of the intestinal flora.
      Probiotics are microorganisms with some particular characteristics: human origin,
      safety in human use, bile and acid resistance, survival in the intestine, at
      least temporary colonization of the human gut, adhesion to the mucosa and
      bacteriocine production. Thanks to these characteristics, probiotics block the
      invasion of human intestinal cells by the enteroinvasive bacteria. Furthermore,
      they should be able to stimulate and modulate the intestinal immune response, and
      to protect and stabilize the mucosal barrier. Finally, the efficacy of probiotics
      should be evident and documented with valid studies. All their properties should
      be maintained during processing and storage. Probiotics are usually used to
      protect the host from pathogens. With regard to this, they are useful in the
      prevention of antibiotic and traveler's diarrhea and they may play a role in the
      management of gastric Helicobacter pylori infection. Furthermore, their efficacy
      in the treatment of infectious diarrhea, in inflammatory bowel diseases, in
      pouchitis and in food allergy has been shown. Probiotics can improve the symptoms
      of irritable bowel syndrome and of lactose malabsorption. Finally, it has been
      suggested that such microorganisms may play a role in the prevention of
      carcinogenesis and of tumor growth.

PMID- 12402664
TI  - [Staphylococcus aureus sepsis in hospitalized non neutropenic patients:
      retrospective clinical and microbiological analysis].
AB  - Staphylococcus aureus is one of the leading agents of nosocomial infection among
      adult patients. The aim of this study was to determine the predisposing factors
      and secondary complications of Staphylococcus aureus septicemia (SAS) in non
      neutropenic patients, as well as the predictors of the outcome in non neutropenic
      patients with SAS. We performed a retrospective study of 56 cases of SAS that
      occurred from January 1997 through June 2001 in patients hospitalized in medical
      wards at the Policlinico Umberto I, "La Sapienza" University of Rome; we excluded
      surgical patients and those admitted to the intensive care unit. The median age
      was 61.9 years (range 24-89 years), 29 (51%) patients were male, and infection
      was hospital-acquired in 83.5% of cases. Metastatic infections were found in 12
      patients (21.4%), with 6 (10.7%) developing infectious endocarditis; the relapse
      rate was 8.9%; 30.3% of Staphylococcus aureus isolates were methicillin
      resistant. The overall mortality was 41% and the attributable mortality 28.5%.
      Twenty-nine patients who developed metastatic infections or died for sepsis were
      compared with 27 patients who did not develop complications. At univariate
      analysis, the following factors were associated with a complicated course: delay
      to adequate antibiotic therapy (2.46 vs 1.15 days, p < 0.03), persistent
      Staphylococcus aureus bacteremia during antibiotic therapy (3.56 vs 1.51 days, p
      = 0.01), septic shock (58.6 vs 3.7%, p < 0.002), bacteremic pneumonia as the
      source of bacteremia (17.2 vs 0%, p = 0.02), and the increased severity of
      illness at the onset of SAS as evaluated using an "illness score" (4.2 vs 2.1, p
      < 0.002). At multivariate analysis, septic shock (p < 0.01) and delay to adequate
      antibiotic therapy (p = 0.05) were confirmed as associated with a complicated
      outcome. SAS in non neutropenic patients is associated with significant morbidity
      consequent to a high rate of metastatic infectious disease and with a
      considerable related mortality.

PMID- 12402665
TI  - Rendu-Osler-Weber disease: experience with 56 patients.
AB  - Rendu-Osler-Weber disease, or hereditary hemorrhagic telangiectasia (HHT), is an
      autosomal dominant disease characterized by systemic vascular dysplasia. The
      prevalence varies and ranges, according to region, from 1/3500 to 1/5000. Data
      concerning Italy are not available. The diagnosis is based on the following
      criteria: family history, epistaxis, telangiectases and visceral arteriovenous
      malformations. The diagnosis is to be considered definite if three criteria are
      present and suspected if two criteria are present. From September 2000 to March
      2002, 100 patients (63 males, 37 females, mean age 45.5 +/- 17.3 years)
      potentially affected by HHT were evaluated in the HHT Center of the "Augusto
      Murri" Internal Medicine Section at the University of Bari (on a day-hospital or
      hospitalization basis). The diagnosis of HHT was confirmed in 56 patients and
      suspected in 10. Magnetic resonance imaging revealed cerebral arteriovenous
      malformations in 8.5% of patients. In 14.6% of patients contrast echocardiography
      revealed pulmonary arteriovenous malformations subsequently confirmed at
      multislice computed tomography in all cases but one. In 48.2% of subjects hepatic
      vascular malformations were revealed by echo color Doppler ultrasonography,
      whereas abdominal multislice computed tomography was positive in 63.8% of
      patients. In 64% of the 25 patients, who underwent endoscopy, gastric
      telangiectases were found. In 3 out of 6 patients presenting with pulmonary
      arteriovenous malformations, embolotherapy was performed with success. In our
      patients, the use of tranexamic acid caused a reduction in the frequency of
      epistaxis. The future objectives of the HHT Center of Bari are to increase
      knowledge of the disease, to cooperate with other centers with the aim of
      increasing the number of patients studied and to avoid the limits of therapeutic
      and diagnostic protocols of a rare disease such as HHT.

PMID- 12402666
TI  - Three cases of severe acute hepatitis after parenteral administration of
      amiodarone: the active ingredient is not the only agent responsible for
      hepatotoxicity.
AB  - Amiodarone is one of the most effective antiarrhythmic drugs available and is
      widely prescribed despite several potentially life-threatening side-effects.
      Hepatotoxicity is the most frequent one during long-term oral therapy:
      occasionally acute hepatitis necessitates the suspension of treatment but
      monitoring of a transient increase in serum aminotransferases is usually
      sufficient; the clinical-morphological pictures of liver cirrhosis have also been
      reported. Fulminant hepatitis soon after a parenteral load of the drug is far
      less well described in the literature. Most published cases were reversible after
      the suspension of treatment. A negative challenge after oral amiodarone exposure
      suggested that polysorbate 80, a solvent added to the intravenous infusion and
      already implied in the pathogenesis of a similar syndrome observed in infants, is
      a more likely cause of this complication. The occurrence of acute hepatitis
      complicating parenteral amiodarone treatment does not preclude subsequent oral
      use of the drug: an evidence-based therapeutic behavior now definitively
      consolidated. Because of the rarity of this diagnosis, we report 3 cases of short
      term hepatotoxicity secondary to amiodarone treatment for supraventricular
      tachyarrhythmias: in 2 male patients with dilated cardiomyopathy and in a female
      with liver disease. The diagnosis was presumptive and based on a thorough drug
      history, the temporal relationship, the time-course of liver dysfunction, the
      exclusion of other causes and on the rapid improvement observed after parenteral
      amiodarone withdrawal in 2 cases; in no case could we find any other explanation
      for the liver damage. Since amiodarone is sometimes still an irreplaceable
      antiarrhythmic drug, we raise the question of whether careful and continuous
      vigilance should be mandatory in patients receiving the drug or whether it is
      possible to introduce a pharmaceutical preparation not containing the vehicle
      that induces acute liver toxicity.

PMID- 12402667
TI  - [Angioedema: first manifestation of non-Hodgkin's lymphoma].
AB  - Angioedema can be hereditary or acquired. Hereditary angioedema is a genetic
      disease transmitted with an autosomal dominant mechanism. Acquired angioedema
      usually occurs after the second decade of life and is often related to an
      underlying disease. In a 48-year-old male patient a diagnosis of a non-Hodgkin
      lymphoma was made after two episodes of angioedema. No previously documented
      cases of angioedema in his family were reported; physical examination and routine
      blood samples were normal whereas the serum levels of C1-esterase inhibitor were
      reduced. Three months later he presented with epigastric pain after meals and
      weight loss. Abdominal ultrasonography and computed tomography showed two solid
      splenic masses infiltrating the greater curvature of the stomach and a 2 cm
      aortic lymph node. Digestive endoscopy confirmed the neoplastic infiltration. A
      diagnosis of anaplastic large-cells lymphoma CD30+, anaplastic lymphoma kinase
      negative was made. The disappearance of the neoplastic gastric infiltration and
      the decrease in size of the aortic lymph node and splenic mass were achieved
      after chemotherapy. Serum levels of C1-esterase inhibitor returned to normal. An
      adult onset not associated with a family history of angioedema should lead the
      physician to suspect the presence of a major disease.

PMID- 12402668
TI  - Salmonella enteritidis pericarditis: case report and review of the literature.
AB  - A 65-year-old male patient with primary idiopathic dermatomyositis and on regular
      immunosuppressive therapy was admitted to our Department for fever and dyspnea. A
      diagnosis of hemorrhagic Salmonella enteritidis pericarditis was made. Treatment
      necessitated aggressive medical/surgical supervision. A review of the pertinent
      literature revealed that during the last decade Salmonella enteritidis has been
      identified as the most frequent agent of pericarditis caused by Salmonella
      species apart from Salmonella typhi. This, possibly as a consequence of the
      widespread contamination of poultry foods by this Salmonella species and/or owing
      to a possible peculiar affinity of Salmonella enteritidis to the pericardium.

PMID- 12402669
TI  - [Safeguarding quality of life: a promise for the future].

PMID- 12402670
TI  - [Megaloblastic anemia: an increasing pathology?].

PMID- 12402671
TI  - Learning to keep balance.

PMID- 12402672
TI  - Sexual selection and human life history.

PMID- 12402673
TI  - Developments in early recall memory: normative trends and individual differences.

PMID- 12402674
TI  - Intersensory redundancy guides early perceptual and cognitive development.

PMID- 12402675
TI  - Children's emotion-related regulation.

PMID- 12402676
TI  - Maternal sensitivity and attachment in atypical groups.

PMID- 12402677
TI  - Influences of friends and friendships: myths, truths, and research
      recommendations.

PMID- 12402678
TI  - Inositol phosphates in foods.

PMID- 12402679
TI  - Pyrrolizidine alkaloids in foods.

PMID- 12402680
TI  - Ultrasonic sensors for the food industry.

PMID- 12402681
TI  - Ozone and its current and future application in the food industry.
AB  - The food industry is interested considerably in using ozone to enhance the shelf
      life and safety of food products and in exploring new applications of the
      sanitizer. This interest was recently accompanied by a US governmental approval
      of ozone for the safe use, in gaseous and aqueous phases, as an antimicrobial
      agent on food, including meat and poultry. Ozone has a strong microbicidal action
      against bacteria, fungi, parasites and viruses when these microorganisms are
      present in low ozone-demand media. Readily available organic constituents in
      food, however, compete with microorganisms for applied ozone and thus efficacy of
      the treatment is minimized. Ozone is suitable for washing and sanitizing solid
      food with intact and smooth surfaces (e.g., fruits and vegetables) and ozone
      sanitized fresh produce has recently been introduced in the US market. Use of
      ozone to sanitize equipment, packaging materials, and processing environment is
      currently investigated. Efforts to decontaminate bean sprouts and remove biofilm
      with ozone have not been successful. The antimicrobial efficacy can be enhanced
      considerably when ozonation is combined with other chemical (e.g., hydrogen
      peroxide) or physical (e.g., ultraviolet radiation) treatments. Mechanical action
      is also needed as a means to dislodge microorganisms from the surface of food and
      expose them to the action of the sanitizer. The food industry also is interested
      in using ozone to decontaminate processing water and decrease its chemical and
      biological oxygen demand. This application improves the reusability of processing
      water and allows for environment-friendly processing operations.

PMID- 12402682
TI  - The high molecular weight subunits of wheat glutenin and their role in
      determining wheat processing properties.

PMID- 12402683
TI  - [Lasers in dentistry 7. The use of 3D imaging in dentistry].
AB  - Optical surface scanning accurately records the 3D nature of the face non
      invasively and quantitatively. Programmes to analyse the data now enable the
      clinician to compare the changes in the face as the result of growth or of
      treatment and also to average groups of patients to provide an assessment of
      treatment. An average face has been obtained from groups of patients each year
      from 5 to 18 years. Growth of an individual can be compared with the norm for
      that age to determine which areas of the face show abnormal growth. Prediction of
      facial form for forensic and surgical purposes is possible. Programmes have been
      developed that analyse shape and curvature of areas of the facial surface. Such
      an analysis can be used to determine the changes in the facial surface as the
      result of growth, treatment, or drug therapy and to study genetic effects.

PMID- 12402684
TI  - [The response of bone cells to shear stress].
AB  - Loading-induced flow of fluid is a signal for bone cell adaptive responses, but
      the nature of the flow-derived stimulus which activates the cell is debated.
      Candidate stimuli include shear stress, streaming potentials and chemotransport.
      In this study the nature of the cell stimulus was addressed by varying the shear
      stress, using nitric oxide (NO) and prostaglandin E2 (PGE2) production as a
      parameter of bone cell activation. Mouse bone cell cultures were treated for 15
      minutes with or without pulsating fluid flow (PFF). In a few experiments, dextran
      was added to the fluid to increase the shear stress without affecting streaming
      potentials or chemotransport. NO and PGE2 production were dose-dependently
      stimulated by PFF. Application of dextran in the flow medium enhanced both NO and
      PGE2 production by bone cells. It was demonstrated that the production of NO and
      PGE2 by bone cells is enhanced by fluid flow of increasing shear stress.
      Therefore, the stimulus leading to NO and PGE2 production is shear stress rather
      than streaming potentials or chemotransport.

PMID- 12402685
TI  - [Factors involved in the etiology of hypomineralized first permanent molars].
AB  - Severe hypomineralized first permanent molars (cheese molars) can be found in
      children. The aetiology of this phenomenon is unknown. The aim of this study is
      to collect more information about the causes of such molars. Parents of 24
      children with severe cheese molars and of 21 controls without cheese molars,
      matched for age, living area and sex were interviewed. The mean age of the 45
      children was 9.9 year (; ssd: 2.02). A questionnaire about the medical data from
      birth to four years of age and the medical situation of the mother during
      pregnancy was sent to the parents. No significant differences were found
      concerning weight and length at the time of birth between the two groups. Also no
      significant differences were found for the period of breast-/and bottle-feeding
      and for problems of the mother during pregnancy and child delivery. The mothers
      were healthy during pregnancy. Compared to the control group the children with
      cheese molars were ill more often Significant differences were found for
      pneumonia, high fever and inflammation of the middle ear.

PMID- 12402686
TI  - [Lip carcinoma. A review].
AB  - Lip cancer develops in the vermilion border of the lip. The great majority of
      these malignancies are squamous cell carcinomas. Lip cancer predominantly affects
      the lower lip and particularly occurs in males. The main risk factors involved
      are cumulative lifetime exposure to sunlight and the use of tobacco. It usually
      presents at an early stage. In the Netherlands (16 million inhabitants),
      approximately 190 new cases are registered annually. Since lip cancers in most
      instances are easily recognized, they may be diagnosed at an early stage. Lip
      cancer is best cured when it is diagnosed early. Dental examination should
      routinely include clinical examination of the lips and, on indication, palpation.
      This article reviews the clinical presentation, diagnosis and management of lip
      cancer.

PMID- 12402687
TI  - [New guidelines for primary resuscitation in adults].
AB  - The European Resuscitation Council (ERC) has recommended changes in the
      guidelines for adult basic life support. This paper describes these new
      guidelines in detail.

PMID- 12402688
TI  - [A blister on the palate].

PMID- 12402689
TI  - [Incontinence].

PMID- 12402690
TI  - Managing emergencies in general practice. How can we do even better?

PMID- 12402691
TI  - Information technology.

PMID- 12402692
TI  - HRT advice.

PMID- 12402693
TI  - Aboriginal health.

PMID- 12402694
TI  - Adult cardiac arrest in general practice.
AB  - BACKGROUND: Out of hospital cardiac arrest victims contribute significantly to
      adult mortality figures but are encountered infrequently by most general
      practitioners and their staff. A number of scientific organisations produce
      guidelines for the basic and advanced management of cardiac arrest. OBJECTIVE: To
      review the management principles for basic and advanced adult cardiac life
      support measures for cardiac arrest. DISCUSSION: General practitioners are
      required to manage cardiac arrest victims infrequently. The initiation of
      bystander cardiopulmonary resuscitation and the rapid defibrillation of suitable
      cardiac rhythms determine a favourable outcome. All staff working at a surgery
      must be skilled in basic life support. The GP needs an understanding of advanced
      life support principles.

PMID- 12402695
TI  - Emergency management of acute asthma.
AB  - BACKGROUND: Life threatening asthma is not an uncommon emergency and all doctors
      need to have an ordered approach to managing this problem both in the surgery and
      the home. OBJECTIVE: To develop a plan for the rapid assessment and management of
      a patient with asthma. The main focus is on severe life threatening asthma and
      management is based on the equipment and medication a doctor is likely to have
      available in the surgery. CONCLUSION: The key to successful treatment of life
      threatening asthma is a rapid assessment of severity, an early emergency call for
      an ambulance, oxygen, continuous nebulised beta 2 agonist, corticosteroids and
      the use of parenteral adrenaline for the patient in extremis.

PMID- 12402696
TI  - Anaphylaxis. The GP perspective.
AB  - BACKGROUND: Anaphylaxis is not uncommon in Australia, representing the most
      severe form of allergy. It is most likely to be triggered by food with the most
      common allergen being peanuts. It constitutes a medical emergency that requires a
      rapid medical response. OBJECTIVE: This article aims to provide an overview of
      anaphylaxis--its prevalence, causes, diagnosis and treatment both acutely and in
      relation to long term management. It also aims to highlight the importance of
      having a protocol established for the management of this condition in the
      emergency situation. DISCUSSION: With the increased prevalence of allergy in the
      community, it is likely that at some stage most general practitioners will have
      to treat a case of acute anaphylaxis. It is imperative that GPs are prepared for
      such an event as failure to recognise the condition or to follow a validated
      protocol can have fatal consequences.

PMID- 12402697
TI  - Patient education. Management of anaphylaxis at school.

PMID- 12402698
TI  - Patient education. How to use an EpiPen.

PMID- 12402699
TI  - Treating the acutely psychotic patient.
AB  - BACKGROUND: Acute psychosis is a medical emergency that is responsive to medical
      treatment and has a significant risk of morbidity and mortality if untreated. It
      is a common presentation both in general practice and hospital emergency
      departments. With the shift of long term management of mental illness from
      psychiatric hospitals to the community in the past 20 years, general
      practitioners are increasingly involved in the short and long term management of
      psychotic patients. OBJECTIVE: To review contemporary assessment and management
      of acute psychosis with the emphasis on patient and practitioner safety, and the
      resources that are available for the management of psychotic patients.
      DISCUSSION: General practitioners should be able to safely assess acutely
      disturbed patients and diagnose acute psychosis and its potential causes. They
      should be aware of the alternatives for acute treatment. They should be
      conversant with the Mental Health Act and its use to ensure patient safety and
      with the medications that are used to treat acutely psychotic patients.

PMID- 12402700
TI  - Practical management of the suicidal patient.
AB  - BACKGROUND: Suicide is nearly always due to untreated depression, causes
      widespread distress, and is a waste of life years. Eighty percent of suicides are
      male, mainly in the age range of 25-44 years. Nearly every person who commits
      suicide has talked about it before the event. OBJECTIVE: This article focusses on
      teaching some 'tricks of the trade' used by the author in treating suicidal
      patients. DISCUSSION: General practitioners should ask the patient to indicate on
      a scale of 0-10, the stresses, emotional suffering and suicidal intensity they
      are feeling. They should offer understanding, very frequent contact,
      antidepressants, discussion, guarantees of improvement, and benzodiazepines for
      relief from pain during the process.

PMID- 12402701
TI  - Genital herpes. An approach for general practitioners in Australia.
AB  - BACKGROUND: Genital herpes is a common sexually transmitted infection that is
      most often asymptomatic and remains largely undiagnosed. OBJECTIVE: To discuss
      the diagnosis, management and treatments available for genital herpes infections.
      DISCUSSION: Genital herpes is a common infection with significant associated
      morbidity. Along with diagnosis and appropriate treatment, patient education,
      counselling and support are essential for effective management.

PMID- 12402702
TI  - Who cares for the carer? The often forgotten patient.
AB  - BACKGROUND: Dementia not only affects the patient but also those nearest the
      patient most notably the carer. It is known that caring for a patient with
      dementia can adversely affect one's psychological, physical, social and financial
      health. OBJECTIVE: To highlight the needs of the carer of a patient with dementia
      and suggest means by which general practitioners may provide the necessary
      support for these carers. DISCUSSION: The GP has a key role in providing support
      to the carer of the patient with dementia. General practitioners and carers can
      work as partners in the long term management of dementia thereby reducing the
      adverse health effects on the carer.

PMID- 12402703
TI  - Failure to diagnose acute myocardial infarction.
AB  - Case histories are based on actual medical negligence claims, however, certain
      facts have been omitted or changed by the author to ensure the anonymity of the
      parties involved. An allegation of failure to diagnose acute myocardial
      infarction is a relatively common cause of medical negligence claims against
      general practitioners. The main factors contributing to these claims are failure
      to order appropriate investigations (including electrocardiograms), failure to
      suspect myocardial infarction, failure or delay in hospital admission and/or
      referral and misinterpretation of investigations. This article outlines risk
      management strategies for GPs to minimise the possibility of a claim arising from
      the failure to diagnose acute myocardial infarction.

PMID- 12402704
TI  - Test your knowledge.  A rare cause of breathlessness.

PMID- 12402705
TI  - Practice tip. Diabetes register and recall.
AB  - The majority of general practices now have their patients' details entered on a
      computer database. These details often include a patient's age, sex, allergies,
      medications, diagnoses and dates of visits. Accessing this information by the
      general practitioner can prove useful for a variety of purposes including audits,
      notifications and research. Most medical software available has the capacity to
      search a database using specified criteria. The following practice tip is a guide
      to setting up this search process using the commonly used Medical Director
      software.

PMID- 12402706
TI  - Test your knowledge.  A child with acute onset of neurological signs.

PMID- 12402707
TI  - Test your knowledge. A young man with dysuria and discharge.

PMID- 12402708
TI  - The tasks of general practice. A new kind of GP?
AB  - BACKGROUND: The Department of Health and Aging is driving a reform of general
      practice to encompass primary care and population health. Although these new
      ideas are quite old they have rarely been comprehensively applied. OBJECTIVE: To
      develop an up-to-date conceptual framework of the comprehensive tasks of general
      practice. DISCUSSION: This framework can help the 'new kind of general
      practitioner' (and those in training) in deciding which elements of the 'new
      primary health care' they can, or will, encompass.

PMID- 12402709
TI  - Reward before effort? Is the cart before the horse?

PMID- 12402710
TI  - GPs' perceived competence and comfort in managing medical emergencies in
      southeast Queensland.
AB  - INTRODUCTION: Little is known about general practitioners' confidence and
      competence in managing medical emergencies, yet these qualities are vital to
      maximise patients' chances of survival. AIM: To document the distribution and
      determinants of GPs' self reported levels of comfort and competence in managing
      medical emergencies, and GPs' interest in attending an emergency skills update
      course. METHODS: We conducted a random sample survey of 900 GPs in current
      clinical practice in southeast Queensland. RESULTS: Five hundred and twelve (57%)
      GPs responded to the questionnaire. An association between perceived levels of
      competence and the amount of training GPs received was demonstrated (P < 00.05
      for 14 of 16 listed emergency skills), as was an association between level of
      comfort in managing emergencies and the frequency with which such emergency types
      are encountered in practice (P < 0.05 for 8 of 18 listed emergencies). Sixty-nine
      percent of GPs expressed interest in attending a specifically designed emergency
      medicine update course. CONCLUSION: Postgraduate training in and experience with
      medical emergencies is important for GPs' confidence and competence in dealing
      with such emergencies. A proposed update course designed specifically for GPs was
      strongly supported.

PMID- 12402711
TI  - Time for care. Length of general practice consultations in Australia.
AB  - BACKGROUND: Past estimates of the length of Australian general practice
      consultations have been based on Medicare item numbers claimed, which carries
      probable serious inaccuracies. AIMS: To describe the length of general
      practitioner consultations. METHODS: A random sample of 926 GPs recorded the
      start and finish times in minutes of their consultations for which a Medicare
      item number was claimed between April 2000 and March 2001, within a continuous
      cross sectional national study of general practice activity. RESULTS: Mean length
      of the consultations was 14.8 minutes (range 1-106). Mean length per GP varied
      widely (mean of means 14.8, range 3-39, mode 15.0 minutes). Female GPs had
      significantly longer consultations than males. Younger (< 45 years) male
      metropolitan GPs had the shortest mean length. Most attendances (85.7%) were
      designated Level B, 1.5% as Level A, 11.7% Levels C and 1.1% as level D. Mean
      length of Level A was 7.1 minutes, Level B-13.0, Level C-26.1, and Level D-44.9
      minutes. CONCLUSION: This study suggests that the majority of GPs are not
      practising 'six minute medicine', and may assist cost projections of any changes
      to the Medicare Schedule.

PMID- 12402712
TI  - Confidential enquiries into maternal deaths, 1997-1999.

PMID- 12402713
TI  - Pressure support ventilation and the critically ill patient with muscle weakness.

PMID- 12402714
TI  - Impaired explicit memory after recovery from propofol/sufentanil anaesthesia is
      related to changes in the midlatency auditory evoked response.
AB  - BACKGROUND: Midlatency auditory evoked responses (MLAER) can distinguish
      different stages of anaesthesia. We studied MLAER during emergence from
      propofol/sufentanil anaesthesia in relation to recovery of explicit memory.
      METHODS: MLAER were recorded in 29 healthy patients before and during anaesthesia
      and during emergence until the patients opened their eyes spontaneously. After a
      structured interview the next day, patients were classified into those with and
      without explicit memory of the recovery period. Latencies Na, Pa and Nb and the
      peak-to-peak amplitudes NaPa and PaNb were compared between the groups by
      multivariate analysis of variance. Results are mean (SD). RESULTS: At eye opening
      (37 (12) min after the end of anaesthesia) the latency Nb (47 (5) compared with
      41 (5) ms; P < 0.001) was prolonged and the amplitude PaNb (1.3 (0.8) compared
      with I (0.5) ms; P = 0.012) was greater than the baseline value, respectively.
      The Nb latency was significantly shorter in patients with explicit memory (49 (2)
      ms compared with 45 (I); P = 0.041). CONCLUSIONS: Large intra- and inter
      individual variability in the MLAER values limited their ability to predict
      memory responses in individual patients during emergence from propofol/sufentanil
      anaesthesia.

PMID- 12402715
TI  - Effect of propofol anaesthesia on the event-related potential mismatch negativity
      and the auditory-evoked potential N1.
AB  - BACKGROUND: Studies on the effects of anaesthesia on event-related potentials and
      long latency auditory-evoked potentials (AEP) are sparse. Both provide
      information on cortical processing and may have potential as monitors of
      awareness. We studied the effect of propofol on the event-related potential
      mismatch negativity (MMN) and the long-latency AEP NI. METHODS: Twenty-one
      patients received 1 microgram ml-1 stepped increases in the target concentration
      of propofol using Diprifusor until a maximum of 6 micrograms ml-1 was achieved or
      the patient had lost consciousness. Neurophysiological responses (MMN and N1) and
      the patients' level of consciousness were recorded before the administration of
      propofol and at a target effector site concentration of propofol of 1, 2, 3, 4,
      and 6 micrograms ml-1. Grand average evoked potentials were computed at baseline,
      before the administration of propofol (A); at the highest propofol concentration
      at which each patient was responsive (B); and at the concentration of propofol at
      which the patient became unconscious (C). RESULTS: Patients lost consciousness at
      different target concentrations of propofol, all being unresponsive by 4
      micrograms ml-1. The response to the deviant stimuli used to elicit duration
      shift MMN was significantly more negative than to the standard stimuli at A (mean
      difference 2.58 microV, P = 0.0011) but this difference was virtually abolished
      at point B, before the patients lost consciousness (mean difference 0.63 microV,
      P = ns). The amplitude of N1 evoked by standard stimuli was negative compared
      with electrical baseline at both point A (mean amplitude -3.81 microV, P < 0.001)
      and at point B (mean amplitude -2.2 microV, P = 0.002), but was no longer
      significantly different to baseline at point C (mean amplitude 0.51 microV, P =
      ns). The change in the mean amplitude of N1 from last awake (point B) to first
      unconscious (point C) was also significant (mean difference in amplitude 1.69
      microV, P = 0.02). CONCLUSIONS: MMN is unlikely to be a clinically useful tool to
      detect awareness in surgical patients. In contrast, the loss of N1 may identify
      the transition from consciousness to unconsciousness and deserves further study.

PMID- 12402716
TI  - Prediction of the haemodynamic response to tracheal intubation: comparison of
      laser-Doppler skin vasomotor reflex and pulse wave reflex.
AB  - BACKGROUND: The laser-Doppler skin vasomotor reflex (SVmR) caused by tetanic
      stimulation of the ulnar nerve may be a test that can predict the haemodynamic
      response to tracheal intubation. A decrease in pulse wave amplitude (pulse wave
      reflex, PWR) may be an alternative index of this response. We compared the
      abilities of PWR and SVmR to predict the haemodynamic response to tracheal
      intubation and studied how alfentanil, muscle relaxation, stimulation site and
      stimulation pattern affected the two reflexes. METHODS: Anaesthesia was induced
      and maintained with 2% sevoflurane and 50% nitrous oxide in two groups of 10 ASA
      status 1 patients. Tetanic stimuli were applied to the flexor muscles of the
      forearm and the ulnar nerve before and after administration of vecuronium. The
      change in skin blood flow (laser-Doppler) and pulse wave amplitude (pulse
      oximetry) after a 5 and 10 s stimulation was measured on the opposite hand. If
      skin blood flow (laser-Doppler) decreased by more than 10%, a computer-controlled
      infusion of alfentanil was started and the target plasma concentration was
      increased in steps until this response was suppressed (< 10%). The trachea was
      intubated and arterial pressure and heart rate responses were recorded. Plasma
      alfentanil concentration was measured. RESULTS: When PWR and SVmR were
      suppressed, the haemodynamic response to tracheal intubation was reduced in 100
      and 53% of patients respectively. PWR and SVmR responses decreased with
      increasing plasma alfentanil concentration. The SVmR response to muscle
      stimulation was reduced by muscle relaxants. The pulse wave response to both
      muscle and neural stimulation was reduced by relaxants. The responses to 5 and 10
      s stimulations were similar. CONCLUSION: An absent SVmR does not predict a
      blunted arterial pressure or heart rate response to tracheal intubation. The PWR
      may be a better predictor.

PMID- 12402717
TI  - Incidence and risk calculation of inotropic support in patients undergoing
      cardiac surgery with cardiopulmonary bypass using an automated anaesthesia record
      keeping system.
AB  - BACKGROUND: This retrospective study analysed the effects of preoperative and
      intraoperative factors on the occurrence of inotropic support after
      cardiopulmonary bypass (CPB). METHODS: The data sets of 1471 adult patients
      having received elective cardiac surgery with CPB were recorded using an online
      anaesthesia record-keeping system. Patients were judged to have required
      inotropic drug support if they had received one or a combination of the positive
      inotropic drugs, epinephrine, dobutamine and enoximone. The effects of age,
      height, weight, body mass index, gender, chronic heart failure, documented
      preoperative myocardial infarction, left main coronary artery disease,
      preoperative history of hypertension, chronic renal failure, diabetes mellitus,
      chronic obstructive pulmonary disease (COPD), preoperative medical treatment,
      type of surgical procedure, duration of CPB, duration of aortic clamping and
      reperfusion time were analysed by logistic regression for predictive power of the
      need for positive inotropic drugs. RESULTS: Of the patients, 32.4% received
      positive inotropic drugs in the operating theatre after weaning from CPB. The
      overall 30-day mortality was 2.2%. Of non-survivors, 81.8% received inotropes
      compared with 18.2% of survivors (P < 0.01). The numbers of previous myocardial
      infarctions (odds ratio (OR), 2.01), congestive heart failures New York Heart
      Association class > 2 (OR, 1.85), COPD (OR, 1.85) and age > 65 yr (OR, 1.62),
      aortic cross clamping time of > 90 min (OR, 2.32) and coronary artery bypass
      surgery (OR, 0.43) all represented influential factors within the logistic
      regression model. CONCLUSION: The knowledge of these risk factors should be
      useful in increasing the anaesthetist's vigilance in those patients most at risk
      for inotropic support and in providing for more timely therapeutic intervention
      and optimizing anaesthesia management.

PMID- 12402718
TI  - Delays in defibrillation: influence of different monitoring techniques.
AB  - BACKGROUND: Rapid defibrillation is the most important intervention required for
      a patient in cardiac arrest due to ventricular fibrillation or ventricular
      tachycardia. Isolated case reports of spurious asystole may have seen a change in
      practice, moving away from monitoring through defibrillator paddles and gel pads
      in favour of attaching electrocardiograph (ECG) leads for the initial monitoring
      of a collapsed patient. We surveyed current preferences for initial monitoring
      and estimated the difference in time taken to deliver the first shock with the
      following three monitoring techniques: defibrillator paddles and gel pads, ECG
      leads and hands-free adhesive pads. METHODS: Sixty Advanced Life Support (ALS)
      course directors, selected at random, were questioned to establish their current
      practice. Twenty ALS providers received 5 min revision in the three techniques
      for the initial monitoring of a collapsed patient and were then randomly tested
      to measure the time from confirmation of arrest to the first shock. RESULTS:
      Forty-two directors indicated their preferred methods for initial monitoring as
      74% leads, 21% paddles and 5% hands-free adhesive pads. Before testing, 10
      providers preferred paddles and 10 preferred leads. Monitoring through leads 54
      (range 49-65) s was significantly slower than paddles 28 (24-31) s, P < 0.01 and
      adhesive pads 23 (19-27) s, P < 0.01. There was no significant difference in the
      time taken between paddles and adhesive pads. CONCLUSION: The current practice of
      monitoring through leads delays the time to deliver the first shock. We recommend
      that initial monitoring through leads be discontinued in favour of hands-free
      adhesive pads or defibrillator paddles/gel pads.

PMID- 12402719
TI  - Effectiveness of acute postoperative pain management: I. Evidence from published
      data.
AB  - BACKGROUND: This review examines the evidence from published data concerning the
      incidence of moderate-severe and of severe pain after major surgery, with three
      analgesic techniques; intramuscular (i.m.) analgesia, patient controlled
      analgesia (PCA), and epidural analgesia. METHODS: A MEDLINE search of the
      literature was conducted for publications concerned with the management of
      postoperative pain. Over 800 original papers and reviews were identified. Of
      these 212 papers fulfilled the inclusion criteria but only 165 provided usable
      data on pain intensity and pain relief. Pooled data on pain scores obtained from
      these studies, which represent the experience of a total of nearly 20,000
      patients, form the basis of this review. RESULTS: Different pain measurement
      tools provided comparable data. When considering a mixture of three analgesic
      techniques, the overall mean (95% CI) incidence of moderate-severe pain and of
      severe pain was 29.7 (26.4-33.0)% and 10.9 (8.4-13.4)%, respectively. The overall
      mean (95% CI) incidence of poor pain relief and of fair-to-poor pain relief was
      3.5 (2.4-4.6)% and 19.4 (16.4-22.3)%, respectively. For i.m. analgesia the
      incidence of moderate-severe pain was 67.2 (58.1-76.2)% and that of severe pain
      was 29.1 (18.8-39.4)%. For PCA, the incidence of moderate-severe pain was 35.8
      (31.4-40.2)% and that of severe pain was 10.4 (8.0-12.8)%. For epidural analgesia
      the incidence of moderate-severe pain was 20.9 (17.8-24.0)% and that of severe
      pain was 7.8 (6.1-9.5)%. The incidence of premature catheter dislodgement was 5.7
      (4.0-7.4)%. Over the period 1973-1999 there has been a highly significant (P <
      0.0001) reduction in the incidence of moderate-severe pain of 1.9 (1.1-2.7)% per
      year. CONCLUSIONS: These results suggest that the UK Audit Commission (1997)
      proposed standards of care might be unachievable using current analgesic
      techniques. The data may be useful in setting standards of care for Acute Pain
      Services.

PMID- 12402720
TI  - Comparison of morphine alone with morphine plus clonidine for postoperative
      patient-controlled analgesia.
AB  - BACKGROUND: Clonidine is an alpha 2 adrenergic agonist with analgesic properties.
      This study aimed to see if the addition of clonidine to morphine when given by
      patient-controlled analgesia (PCA) would improve analgesia beyond the first 12 h
      after surgery. METHODS: Sixty patients undergoing lower abdominal surgery were
      recruited into a randomized double blind study. At the end of surgery Group C
      received an infusion of clonidine 4 micrograms kg-1 over 20 min, PCA clonidine 20
      micrograms and morphine 1 mg bolus. Group M received an infusion of saline and
      then PCA morphine 1 mg bolus. Pain, sedation and nausea and vomiting were
      assessed after 12, 24 and 36 h, and satisfaction with analgesia was assessed at
      36 h. RESULTS: Pain scores were significantly lower in Group C between 0 and 12
      h, but thereafter there was no difference. Morphine consumption was the same for
      both groups until 24-36 h. Nausea and vomiting was significantly reduced in Group
      C between 0 and 24 h. Patients in Group C were significantly happier with their
      pain relief (four-point scale).

PMID- 12402721
TI  - Contribution of midazolam and its 1-hydroxy metabolite to preoperative sedation
      in children: a pharmacokinetic-pharmacodynamic analysis.
AB  - BACKGROUND: Oral midazolam is widely used for preoperative sedation in children.
      We have studied the pharmacokinetics (PK) of both midazolam and its active 1
      hydroxy metabolite and their contributions to sedative effect in 45 children
      attending for day surgery. METHODS: Blood samples (two per individual) were
      collected at the beginning and end of the surgical procedure. Plasma midazolam
      and 1-hydroxymidazolam (1-OHMDZ) were measured by HPLC. Sedation score (score: 1
      = awake, 2 = drowsy/asleep) was recorded at the same time as the first blood
      sample. The population-PK software P-Pharm was used to analyse the data. Age,
      weight, sex, concomitant drugs, and the metabolic ratio, 1-OHMDZ/midazolam were
      investigated as co-variates of the PK of midazolam and 1-OHMDZ. The
      pharmacokinetic-pharmacodynamic (PK-PD) modelling of the score in relation to
      plasma midazolam and 1-OHMDZ was performed using logistic regression analysis.
      RESULTS: A median dose of 0.5 mg kg-1 was given to the children, median age 5 yr
      (range from 9 months to 12 yr) and weight 21 kg (range 8-75 kg). Average
      concentrations of midazolam 150 ng ml-1 and 1-OHMDZ 90 ng ml-1 were observed in
      the first plasma samples. These concentrations resulted in an odds ratio of 4 in
      favour of score 2 vs 1. The best PK-PD model included both midazolam and 1-OHMDZ
      as active moieties and predicted correct scores in 86% of cases. CONCLUSION:
      Studies of midazolam should evaluate the contribution of 1-OHMDZ to the overall
      PD effect. The metabolite 1-OHMDZ has approximately half the activity of the
      parent drug and can compensate for at least part of the decreased effect due to
      increased midazolam metabolism.

PMID- 12402723
TI  - Evaluation of S1 motor block to determine a safe, reliable test dose for epidural
      analgesia.
AB  - BACKGROUND: Accidental intrathecal injection of bupivacaine during epidural
      analgesia in labour remains a hazard, with the potential to cause total spinal
      anaesthesia and maternal collapse. Sacral block appears early after intrathecal
      injections compared with epidural ones, and we therefore used SI motor block to
      determine a safe and reliable test dose for epidural catheter misplacement.
      METHODS: Mothers booked for elective Caesarean section were given various
      intrathecal doses of bupivacaine with fentanyl during routine combined spinal
      epidural anaesthesia. RESULTS: Using sequential allocation we found that the ED50
      for SI motor block 10 min after intrathecal injection was bupivacaine 7 mg with
      fentanyl 14 micrograms (95% CI, 6.2-7.8 mg). We then used intrathecal bupivacaine
      13 mg to look for the ED95. We found the calculated ED97.5 to be bupivacaine 9.7
      mg with fentanyl 19.4 micrograms (95% CI, 8.7-11.4). CONCLUSION: We conclude that
      testing for SI motor block 10 min after epidural injection of bupivacaine 10 mg
      is a reliable test to detect accidental intrathecal injection in the obstetric
      population.

PMID- 12402722
TI  - Pharmacokinetics of 0.75% ropivacaine and 0.5% bupivacaine after ilioinguinal
      iliohypogastric nerve block in children.
AB  - BACKGROUND: Blockade of the ilioinguinal and iliohypogastric nerves is a useful
      procedure in paediatric patients undergoing inguinal surgery. Bupivacaine 2 mg kg
      1 has been recommended for this block. We compared the plasma concentrations of
      ropivacaine and bupivacaine following an ilioinguinal-iliohypogastric block.
      METHODS: Forty children scheduled for elective inguinal surgery were randomized
      to receive 2 mg kg-1 of either 0.75% ropivacaine or 0.5% bupivacaine. Surgical
      anaesthesia was maintained with mask inhalation of oxygen, nitrous oxide and
      sevoflurane. Venous blood samples were drawn at regular intervals for up to 2 h
      and plasma was separated. Total venous plasma concentrations were determined by
      gas chromatography. RESULTS: The groups were similar with respect to age, weight
      and dose of local anaesthetic. The peak plasma concentration achieved was
      significantly higher in the bupivacaine group compared with the ropivacaine group
      (2.2 vs 1.2 micrograms ml-1, P = 0.025). The time to peak plasma concentration
      was significantly shorter in the bupivacaine group (24 vs 35 min, P = 0.024). The
      initial distribution half time of bupivacaine was significantly shorter (3.6 vs
      6.5 min, P = 0.020) compared with that of ropivacaine. CONCLUSIONS: Bupivacaine
      is more rapidly absorbed from the injection site and leads to higher plasma
      concentrations than ropivacaine.

PMID- 12402724
TI  - Effect of thoracic epidural anaesthesia on colonic blood flow.
AB  - BACKGROUND: The effect of thoracic epidural block on splanchnic blood flow is
      unclear. It remains to be resolved if sympathetic block, increases or decreases
      regional splanchnic blood flow and whether regional splanchnic flow becomes
      dependent on cardiac output or perfusion pressure. A clear understanding of the
      regional haemodynamic consequences of an epidural block may modify practice with
      respect to epidural anaesthesia. METHODS: Fifteen patients, who underwent
      anterior resection for rectal cancer, had invasive intraoperative monitoring of
      arterial pressure, central venous pressure, cardiac output, inferior mesenteric
      artery flow (Doppler flow probe), and colonic serosal red cell flux (laser
      Doppler probe), while an epidural block was established with local anaesthetic.
      In three consecutive time periods, arterial pressure was first allowed to fall
      (to a mean arterial pressure of 60 mm Hg), then treated with colloid fluid
      resuscitation and finally by vasopressors until the pre-epidural arterial
      pressure had been restored. RESULTS: On induction of epidural block, there was a
      reduction in mean colonic serosal red cell flux to 65% and inferior mesenteric
      artery flow to 80% (mean) of pre-epidural levels. There was a strong association
      between mean arterial pressure and both measured inferior mesenteric artery blood
      flow (P < 0.004) and colonic serosal red cell flux (P < 0.0001). Changes in
      cardiac output were poorly associated with either inferior mesenteric artery
      blood flow (P = 0.638) or colonic serosal red cell flux (P = 0.265). Inferior
      mesenteric artery blood flow and colonic serosal red cell flux were restored to
      pre-epidural levels after arterial pressure had been improved with a vasopressor.
      CONCLUSION: Once intraoperative epidural block has been established, colonic
      serosal red cell flux and inferior mesenteric artery flow are more closely
      associated with changes in mean arterial pressure than changes in cardiac output.
      The measured reduction in colonic flow does not respond to an increase in cardiac
      output with fluid resuscitation, but requires the use of a vasopressor to
      increase arterial pressure, before colonic blood flow is improved.

PMID- 12402725
TI  - Comparison of intrathecal fentanyl and diamorphine in addition to bupivacaine for
      caesarean section under spinal anaesthesia.
AB  - BACKGROUND: Co-administration of small doses of opioids and bupivacaine for
      spinal anaesthesia reduces intraoperative discomfort and may reduce postoperative
      analgesic requirements in patients undergoing Caesarean section. Fentanyl and
      diamorphine are the two most frequently used agents in UK obstetric anaesthetic
      practice. METHODS: Seventy-five healthy parturients scheduled for elective
      Caesarean section under spinal anaesthesia using hyperbaric 0.5% bupivacaine,
      were randomly allocated to additionally receive intrathecal fentanyl 20
      micrograms, diamorphine 300 micrograms or 0.9% saline. Patients also received
      i.v. cyclizine and rectal diclofenac. RESULTS: Less supplementary intraoperative
      analgesia was required by patients in either opioid group (4%) compared with the
      control (32%) (P < 0.05). Twenty four hours after spinal injection, total mean
      (SD) postoperative morphine requirement was significantly lower if diamorphine
      was administered (31 (21) mg), in comparison with the other two groups (control
      68 (26) mg; fentanyl 62 (26) mg) (P < 0.05). Reduced visual analogue pain scores
      were evident 12 h following diamorphine, but observed only for 1 h after fentanyl
      when compared with the control (P < 0.05). Mild pruritus was more common for 2 h
      after either spinal opioid (P < 0.05), but no inter-group differences were
      observed for the remainder of the first 24 h. Patients displayed deeper levels of
      sedation both acutely and 12 h after administration of intrathecal fentanyl (P <
      0.05). CONCLUSIONS: Both intrathecal opioids reduce intraoperative discomfort,
      but only diamorphine reduced postoperative analgesic requirement beyond the
      immediate postoperative period.

PMID- 12402726
TI  - Patient-controlled epidural analgesia versus continuous infusion for labour
      analgesia: a meta-analysis.
AB  - BACKGROUND: Patient-controlled epidural analgesia (PCEA) is a relatively new
      method of maintaining labour analgesia. There have been many studies performed
      that have compared the efficacy of PCEA with continuous epidural infusion (CEI).
      The purpose of this systematic review is to compare the efficacy and safety of
      PCEA and CEI. METHODS: All randomized controlled trials that compared PCEA,
      without background infusion, with CEI were sought from the literature. These were
      rated for quality using a validated, five-point scale. The primary outcome was
      the number of patients who received anaesthetic interventions. Secondary outcomes
      included the dose of local anaesthetic, incidence of motor block, quality of
      analgesia, obstetric and safety outcomes. Where feasible, the data were combined
      using meta-analytical techniques. For dichotomous data, the risk difference (RD)
      and 95% confidence intervals (CI) were calculated. For continuous data, the
      weighted mean differences (WMD) were calculated. The differences were
      statistically significant when the 95% CI excluded 0. RESULTS: Nine studies
      comprised of 640 patients were found. There were fewer anaesthetic interventions
      in the PCEA group (RD, 27%; 95% CI, 18-36%; P < 0.00001). This group also
      received less local anaesthetic (WMD, -3.92; 95% CI, -5.38 to -2.42; P < 00001)
      and less motor block (RD, 18%; 95% CI, 6-31%; P = 0.003). Both methods were safe
      for mother and newborn. CONCLUSION: Patients who receive PCEA are less likely to
      require anaesthetic interventions, require lower doses of local anaesthetic and
      have less motor block than those who receive CEI. Future research should be
      directed at determining differences in maternal satisfaction and obstetric
      outcome.

PMID- 12402727
TI  - Epidural analgesia and backache: a randomized controlled comparison with
      intramuscular meperidine for analgesia during labour.
AB  - BACKGROUND: Concern has been expressed that epidural analgesia for labour may be
      associated with a higher incidence of backache. METHODS: A prospective randomized
      trial investigating the effect of epidural analgesia on the outcome of labour in
      nulliparae, mothers were randomized to receive either epidural analgesia or
      meperidine. A questionnaire on postnatal symptoms was sent to them 6 months after
      delivery. RESULTS: In all, 611 mothers were studied; 310 were randomly allocated
      to receive i.m. meperidine up to 300 mg and 301 to receive epidural bupivacaine.
      The response rate to our questionnaire was 83%. Intention-to-treat analysis
      showed similar prevalence rates of postpartum backache in the epidural (48%) and
      meperidine groups (50%), with an observed difference (epidural-meperidine) of -2%
      (95% CI, -11 to +6%). After excluding mothers with backache before delivery,
      there were also similar incidence rates of postpartum backache in the epidural
      (29%) and meperidine groups (28%), observed difference 1% (95% CI, -8 to +10%).
      CONCLUSIONS: Epidural analgesia in labour was not associated with an increase in
      the prevalence or incidence of backache.

PMID- 12402728
TI  - Management of post-strabismus nausea and vomiting in children using ondansetron:
      a value-based comparison of outcomes.
AB  - BACKGROUND: This study evaluated the clinical efficacy and cost-effectiveness of
      prophylactic ondansetron versus early ondansetron treatment in the management of
      postoperative nausea and vomiting (PONV) in children undergoing strabismus repair
      using clinically meaningful outcomes and value-based principles. METHODS: One
      hundred and fifty children were randomly assigned to either prophylactic (P) or
      early symptomatic treatment only (T) group (n = 75). Children in group P received
      ondansetron 100 micrograms kg-1 i.v. and those in group T received placebo at the
      end of the procedure. After surgery, at the earliest sign of nausea or vomiting,
      children in both groups received ondansetron 100 micrograms kg-1 i.v. Besides the
      incidence of PONV, non-surrogate (fast tracking time, duration of stay in the
      postanaesthesia care unit (PACU) and parental satisfaction scores), therapeutic
      (numbers needed to prevent and treat) and pharmacoeconomic (cost to benefit a
      child and cost per PONV-free child) outcome measures were evaluated. RESULTS: The
      incidences of PONV in the immediate, early, late and first 24-h periods were
      significantly less in group P (20, 12, 19 and 35% respectively) than in group T
      (37, 29, 47 and 72%, P < 0.05). Time to achieve fast-track eligibility and
      duration of PACU stay were significantly shorter in group P (P < 0.001). Children
      in group P had superior mean (SD) parental satisfaction scores (8.2 (1.8))
      compared with those in group T (6.8 (1.7), P < 0.001). The number needed to
      prevent PONV was 2 and the number needed to treat PONV was 9. The cost to benefit
      a child was more than fourfold less and the cost per PONV-free child was 35% less
      in group P. CONCLUSIONS: Compared with early symptomatic treatment with
      ondansetron, prophylactic ondansetron shortened fast-tracking time and duration
      of PACU stay and improved parental satisfaction and therapeutic outcomes at a
      lower direct cost.

PMID- 12402729
TI  - Effects of halothane and isoflurane on the contraction, relaxation and energetics
      of rat diaphragmatic muscle.
AB  - BACKGROUND: The inotropic effects of halogenated anaesthetics on diaphragmatic
      muscle remain a matter of debate. Their effects on its relaxation are poorly
      understood, although diaphragmatic relaxation is recognized as an important
      physiological process that may interfere with diaphragmatic performance, fatigue
      and arterial blood flow. METHODS: The effects of halothane and isoflurane (1 or 2
      x minimum alveolar concentration [1 or 2 MAC]) on contraction and relaxation of
      rat diaphragm muscle strips (n = 40) were studied in vitro from force-velocity
      curves obtained at various loads from isotonic to isometric conditions. From
      these curves we determined the peak power output and the curvature. Data are mean
      (SD) percentage of baseline values. RESULTS: At I MAC, isoflurane and halothane
      induced no significant inotropic and lusitropic effects. At 2 MAC, isoflurane
      induced a negative inotropic effect (active force, 93(5)% of baseline). Halothane
      and isoflurane induced a significant decrease in the peak power output at 2 MAC
      (88(8) and 86(9)% of baseline; P < 0.05), without significant changes in the
      curvature of the force-velocity curve. At 2 MAC isoflurane under high loads and
      halothane under low loads induced moderate negative lusitropic effects.
      CONCLUSION: Halothane and isoflurane induced very moderate inotropic and
      lusitropic effects, suggesting that the decrease in diaphragm function observed
      in vivo is not related to a direct effect on diaphragmatic contractility.

PMID- 12402730
TI  - Pharmacological preconditioning: comparison of desflurane, sevoflurane,
      isoflurane and halothane in rabbit myocardium.
AB  - BACKGROUND: Recent investigations showed that isoflurane can induce
      pharmacological preconditioning. The present study aimed to compare the potency
      of four different halogenated anaesthetics to induce preconditioning. METHODS:
      Anaesthetized open-chest rabbits underwent 30 min of coronary artery occlusion
      followed by 3 h of reperfusion. Before this, rabbits were randomized into one of
      five groups and underwent a treatment period consisting of either no intervention
      for 45 min (control; n = 10), or 30 min of 1 MAC halogenated anaesthetic
      inhalation followed by 15 min of washout. End-tidal concentrations of halogenated
      agents were 3.7% for sevoflurane (n = 11), 1.4% for halothane (n = 9), 2.0% for
      isoflurane (n = 11), and 8.9% for desflurane (n = 11). Area at risk and infarct
      size were assessed by blue dye injection and tetrazolium chloride staining.
      RESULTS: Mean (SD) infarct size was 54 (18)% of the risk area in untreated
      controls and 40 (18)% in the sevoflurane group (P > 0.05, ns). In contrast, mean
      infarct size was significantly smaller in the halothane, isoflurane, and
      desflurane groups: 26 (18)%, 32 (18)% and 16 (17)%, respectively (P < 0.05 vs
      control). CONCLUSIONS: Halothane, isoflurane and desflurane induced
      pharmacological preconditioning, whereas sevoflurane had no significant effect.
      In this preparation, desflurane was the most effective agent at preconditioning
      the myocardium against ischaemia.

PMID- 12402731
TI  - Role of propofol and its solvent, intralipid, in nitric oxide-induced peripheral
      vasodilatation in dogs.
AB  - BACKGROUND: The commercial propofol preparation in an intralipid solution causes
      marked vasodilatation. Both propofol and its solvent seem to stimulate the nitric
      oxide (NO) pathway. The role of intralipid in cardiac and regional haemodynamic
      changes induced by propofol and their respective interactions with the NO pathway
      was assessed. METHODS: Dogs were instrumented to record arterial pressure, heart
      rate, cardiac output, dP/dt (the first derivative of left ventricular pressure)
      and vertebral, carotid, coronary, mesenteric, hepatic, portal and renal blood
      flows. Experimental groups were as follows. Group 1 (control; n = 11): N-methyl-L
      arginine (L-NMA) 20 mg kg-1 i.v.; Group 2 (n = 8): propofol (10 mg ml-1) 4 mg kg
      1 i.v. bolus followed by 0.6 mg kg-1 min-1; Group 3 (n = 6): intralipid 0.25 ml
      kg-1 bolus followed by 0.06 ml kg-1 min-1. After 60 min, L-NMA was injected in
      Groups 2 and 3. RESULTS: Propofol induced increases in heart rate, coronary and
      carotid blood flows, and decreases in systemic vascular resistance and dP/dt.
      Intralipid increased renal blood flow, carotid vascular resistance and mesenteric
      vascular resistance. In the presence of intralipid, L-NMA-induced pressor
      response and systemic, carotid and renal vasoconstriction were more pronounced
      than in control dogs. CONCLUSIONS: Except for the coronary and carotid
      circulations, intralipid modulates the NO pathway in cardiac and regional blood
      flow.

PMID- 12402732
TI  - Maternal deaths from anaesthesia. An extract from Why mothers die 1997-1999, the
      Confidential Enquiries into Maternal Deaths in the United Kingdom.
AB  - This article is reprinted from Why Mothers Die 1997-1999, the fifth report of the
      Confidential Enquiries into Maternal Deaths in the United Kingdom.

PMID- 12402733
TI  - Effect of a single dose of esmolol on the bispectral index scale (BIS) during
      propofol/fentanyl anaesthesia.
AB  - BACKGROUND: Esmolol, a short-acting beta 1-antagonist, can reduce anaesthetic
      requirements and decrease seizure activity during electroconvulsive therapy even
      after a single dose of 80 mg. We studied the effect of esmolol on the bispectral
      index scale (BIS), which is a processed EEG recently introduced to monitor depth
      of anaesthesia. METHODS: We gave esmolol 80 mg to 30 healthy male patients after
      induction of anaesthesia using propofol, with either fentanyl (group 1) or
      placebo (group 2). Patients were ventilated mechanically through a laryngeal mask
      airway and anaesthesia was maintained using propofol to keep the BIS value
      between 55 and 60. RESULTS: Esmolol did not affect the BIS index value in either
      group. In group 1, the areas (mean (SD)) under the BIS vs time curve 3 min before
      and 3 min after esmolol administration were 145 (9) and 146 (8) respectively (P =
      0.116). In group 2 values were 147 (8) and 146 (7) respectively (P = 0.344). In
      contrast, in group 1 the area under the systolic arterial pressure (SAP) curve
      was 299 (31) before and 270 (29) after esmolol (P < 0.001), and 156 (17) and 141
      (17) respectively for heart rate (P < 0.001). In group 2 values were 326 (36) and
      302 (41) for SAP (P < 0.001) and 182 (25) and 155 (22) for heart rate (P <
      0.001). CONCLUSIONS: The results suggest that a single dose of esmolol affects
      the SAP and heart rate but does not affect BIS values.

PMID- 12402734
TI  - Flow-by induced hypoventilation in high spinal cord lesions--report of two cases.
AB  - Flow triggering in ventilators is an alternative to pressure triggering.
      Differences between these two trigger mechanisms may not be clinically
      significant in most patients. We report two patients with high spinal cord
      lesions in whom the use of flow triggering was unsuccessful. Severe muscle
      weakness in these patients made them sensitive to small changes in ventilator
      trigger characteristics.

PMID- 12402735
TI  - Posterior spinal ligament rupture associated with laryngeal mask insertion in a
      patient with undisclosed unstable cervical spine.
AB  - A case of posterior spinal ligament rupture associated with a general anaesthetic
      for a laparoscopic cholecystectomy is reported. The role of the general
      anaesthetic in this case is discussed and a review of the literature is
      presented.

PMID- 12402736
TI  - Complete airway obstruction in a ventilated patient after oesophageal dilatation.
AB  - A case of instrumental perforation of the oesophagus is presented. This caused
      systemic sepsis, requiring tracheal intubation and positive pressure ventilation.
      Sudden unexpected life-threatening airway obstruction was caused by distal
      tracheal compression by a peritracheal abscess. The aetiology and management of
      distal tracheal obstruction is discussed.

PMID- 12402737
TI  - Coronary artery spasm and non-Q-wave myocardial infarction following intravenous
      ephedrine in two healthy women under spinal anaesthesia.
AB  - Vasovagal episodes occur frequently in young healthy patients undergoing venous
      cannulation and loco-regional anaesthesia. We report two cases of severe coronary
      vasospasm and non-Q-wave infarction in healthy young women after administration
      of ephedrine for vasovagal symptoms at the onset of spinal anaesthesia. In the
      light of unopposed vagal predominance pre-disposing patients to coronary
      vasospasm, even in young healthy patients, atrophine and not ephedrine should be
      the first line treatment for bradycardia with or without hypotension under spinal
      anaesthesia.

PMID- 12402738
TI  - Hirudin and its reversal.

PMID- 12402739
TI  - Platelet function assessment in Glanzmann's thrombasthenia.

PMID- 12402740
TI  - Cerebrovascular carbon dioxide reactivity in children anaesthetized with
      sevoflurane.

PMID- 12402741
TI  - Ventilating in recovery--the way forward: intensive therapy or critical care?

PMID- 12402742
TI  - Anaphylactic reaction to isosulphan blue.

PMID- 12402743
TI  - Shortage of isoproterenol (isoprenaline) hydrochloride.

PMID- 12402744
TI  - The confidential enquiries into maternal deaths in the UK (CEMD)--a 'sub
      standard' report?

PMID- 12402745
TI  - World pharmaceutical developments.

PMID- 12402746
TI  - Using the Internet to empower patients and to develop partnerships with
      clinicians.
AB  - In combination with computerized and networked information systems, the Internet
      is poised to significantly alter many aspects of the clinician-patient
      relationship. In this paper, the clinician-patient relationships of cybermedicine
      are conceptualized as an elaboration of the democratizing power of the
      information age. This paper identifies common applications of what is known as
      cybermedicine and e-health and examines the implications of the Internet for the
      clinician-patient relationship, addressing concerns about standards of care,
      clinician duties, and interpersonal communication. It also looks at both the role
      of HIPAA legislation in shaping the clinician-patient relationships of
      cybermedicine and the economic issues involved with health websites. Further, the
      argument that an informational model for the clinician-patient relationships of
      cybermedicine would be appropriate as a normative framework is put forth. The
      article concludes that even though we should cautious and judicious in our
      adoption of various forms of cybermedicine, the Internet has the potential to
      create the conditions necessary for a real partnership between patients and
      clinicians and to improve patient care and health outcomes.

PMID- 12402747
TI  - Circumcision in boys: time for doctors to reconsider.
AB  - The Convention of the Rights of the Child from 1989 states in Article 19 that
      States "shall take all appropriate legislative, administrative, social and
      educational measures to protect the child from all forms of physical or mental
      violation, injury or abuse..." Article 24.3 urges all States "to take all
      effective and appropriate measures with a view to abolishing traditional
      practices prejudical to the health of children". Article 37 states that "no child
      shall be subjected to torture or other cruel, inhuman or degrading treatment...".
      In the UNICEF Implementation Handbook for the Convention (1998) it is stated in
      relation to Article 24.3 that a review is to be undertaken regarding "all forms
      of genital mutilation and circumcision". Other traditional practices which are to
      be reviewed include "binding, scarring, burning, branding, forced holding under
      water..." and similar cruel treatment of children. No doubt it is time to act!
      Apparently no such action has been taken and the Convention is not applied in any
      country as regards circumcision of boys--let alone regarding mutilation of girls
      (which is done by the hundreds of thousands every year).

PMID- 12402748
TI  - [The accreditation procedure: An external recognition of quality in public and
      private health centres in France. ].
AB  - Since early 1990, the structures and financing of various health systems have
      been reformed. For the first time, some western Europe countries have admitted
      that quality insurance within the health system can become a governmental
      responsibility and, as in the past, simply the responsibility of the
      professionals and/or the health service administrators. During the last decade of
      the XXth century, pressure has gradually been increased for governments to become
      more involved in health system quality. This focus on quality was linked to human
      safety. In this historical perspective, the emergence of AIDS and the difficulty
      to control this epidemic, and the consequences of contamination by injection
      needles have probably played a part in this collective awareness. In this
      context, quality has become a major concern in Europe.

PMID- 12402749
TI  - Health sector decentralization in developing countries: unique or universal!
AB  - Experiments with decentralization began in the late 1970s and continued
      throughout the 1980s. decentralization was regarded as a key element of the
      primary health care approach. It was seen initially as having important political
      value that can be used as a means to enhance health service policy. However, in
      many instances, western donors who believe that because one form of
      decentralization works in developed countries, it will also work in the
      developing world often pursue decentralization. This paper identifies key
      political, managerial, technical and structural issues underpinning each
      individual country which vary enormously from one country to another. The
      relevance of experience of transfer will need to be considered with these
      variations in mind. The paper draws lessons from the experiences of various
      countries and highlights the need to approach formulation and implementation
      strategies for health sector reforms systematically, rather than importing,
      uncritically, structural models developed abroad. Political considerations are
      inherent in any decision made, and a political environment limits the extent of
      decentralization. Without doubt, the most serious mistake any reformer can make
      is to assume decentralization to be a managerial exercise devoid of political
      cause and consequences.

PMID- 12402750
TI  - Trends in international health development.
AB  - "... Good population health is a crucial input into poverty reduction, economic
      growth and long-term economic development... This point is widely recognised by
      analysts and policy makers, but is greatly underestimated in its qualitative and
      quantitative significance, and in the investment allocations of many developing
      country and donor governments."--Commission on Macroeconomics and Health PURPOSE
      OF ARTICLE: The international health development scene has changed rapidly during
      the past 5 years. From being a merely bilateral effort together with a few
      multilateral organisations and many NGOs new global partnerships have entered the
      scene and become major funding agencies. The provision of aid has also changed
      from small-scale project basis to financial support of large programmes. The
      purpose of this article is to describe some of the major transformations taken
      place in the organising, delivery and objective of international health
      development. But before presenting the new international health development
      agenda, a short introduction to the challenges inducing the need for renewed
      thinking about international aid is shortly presented.

PMID- 12402751
TI  - Biotechnology's foreign policy.
AB  - From its inception, biotechnology has been a uniquely international enterprise.
      An American and an Englishman working together elucidated the structure of DNA
      almost 50 years ago; more recently, the Human Genome Project linked researchers
      around the world, from the Baylor College of Medicine in Houston to the Beijing
      Human Genome Center. Today our industry's researchers hail from African villages
      and Manhattan high rises; from Munich and Melbourne; from London, Ontario, and
      London, England; from Scotland and Nova Scotia--New Scotland; from Calcutta and
      Calgary. But in the beginning, the infrastructure that supported these efforts-
      intellectual property, venture capital, streamlined technology transfer--was less
      widely dispersed and the world's brightest biotech researchers clustered in only
      half a dozen scientific Meccas. Previous technological revolutions have spread
      around the world. Following in their footsteps, biotechnology's global diaspora
      seems inevitable, especially since governments are promoting it. But as our
      science and business emigrate from early strongholds in the United States, Canada
      and Europe across oceans and borders and into new cultures, international
      tensions over biotechnology continue to grow. In just the last few years,
      controversies have rolled over R&D spending priorities, genetic patents,
      bioprospecting, transgenic agriculture and drug pricing. My premise today is that
      our industry needs to formulate its first foreign policy, one which is cognizant
      of the miserable judgments and mistakes of other industries--and avoids them.

PMID- 12402752
TI  - [Drawbacks and problems of infectiology today].

PMID- 12402753
TI  - [An obesity gene].

PMID- 12402754
TI  - [Short or long course antibiotics. Is there a debate on the duration of
      treatment?].
AB  - FROM EMPIRIC DATA: The duration of antibiotic treatments in most cases is
      comprised between 7 and 14 days. However, although a duration is indicated on
      prescribing an antibiotic, the true duration, for a precise patient, can vary
      depending on the organ infected, the causal agent, the time passed since the
      first symptoms and the onset of treatment, eventual complications and notably the
      presence of suppuration or deep bacterial centers, not necessarily accessible to
      the antibiotic, its localization, the progress during treatment and the quality
      of the treatment selected. NORMAL, SHORT OR LONG TREATMENT CYCLES: For common
      infections, the normal treatment cycles indicated are extracted from the
      literature. Short (or shortened) cycles have been and are the subject of studies
      predominantly on upper respiratory and lower urinary tracts infections. When
      indisputable studies, with wide experience, have validated short treatment
      cycles, explicit marketing authorizations have been issued. An exhaustive list
      exists. There are also situations in which long or even very long treatment
      cycles are required. DAY ZERO: The debate on the shortening of treatment cycles
      must not serve as an alibi to the consensus that is required in France, which is
      that the prescription of antibiotics in affections that do not require them must
      cease: 10 to 20 million treatments are prescribed every year for no good reason.
      The list of infections targeted is clearly established by the official guidelines
      of the AFSSAPS (French Medicines Agency). For such infections, the aim is not to
      shorten the duration of the antibiotic, but not to prescribe one.

PMID- 12402755
TI  - [A new cause of false positives when analyzing expired air carbon monoxide].
AB  - INTRODUCTION: Measurement of expired air carbon monoxide expired is an essential
      examination to be conducted in smokers during consultation. However, this can be
      the source of errors, such as that identified in the case report we present here.
      OBSERVATION: A 65 year-old man, wishing to stop smoking, consumed a large
      quantity of polyol-rich sweets and exhibited increased expired air carbon
      monoxide levels, intestinal gases and increased volume of his liver. All these
      signs regressed when he stopped taking the sweets. COMMENTS: The production of
      intestinal gases related to polyol and isomalt contained in some products may be
      the cause of error in the measurement of expired air carbon monoxide.

PMID- 12402756
TI  - [Effects of diving on ventilation function of patients with Duchenne myopathy.
      Preliminary results].

PMID- 12402757
TI  - [The importance of infections in the elderly finally acknowledged].

PMID- 12402758
TI  - [Nosocomial infections in geriatric facilities].
AB  - EPIDEMIOLOGY: In long term geriatric facilities, the prevalence of nosocomial
      infections (to the order of 10% in the surveys) is greater than that observed in
      short-term medical care centers. An endemia of methicillin-resistant
      Staphylococcus aureus, of between 24 and 57% of hospitalized patients, is noted
      in many geriatric facilities. In decreasing order, the infections that
      predominate are: urinary (1/3), lower respiratory tract (1/4) and cutaneous
      tissue infections (1/5). However, these are often manifested by misleading
      semiology, and orient towards an organ other that which is infected. TRANSMISSION
      AND PREVENTION: Nosocomial infections are frequently related to the general
      health of the patient and/or to transmission during handling. Invasive treatments
      are rarely the cause in geriatry. Preventive measures are identical to those used
      in short-term care centers (handwashing, source isolation and appropriate use of
      antibiotics). PROBLEMS: Encountered However, their application raises many
      problems. The living conditions (few facilities with single beds), the state of
      health of these elderly patients, often exhibiting multiple diseases and
      requiring assistance for their daily gestures, and the reduced number of staff at
      the bedside, require that these measures be adapted to each particularity.

PMID- 12402759
TI  - [The risk of contagious epidemics in geriatric facilities].
AB  - THE RISKS OF EPIDEMICS IN INSTITUTIONAL SETTINGS: An epidemic must be suspected
      when an increase in the number of cases of a same type of infection is observed.
      Numerous microorganisms are responsible for epidemics in geriatric facilities:
      viruses, bacteria and parasites. In the case of an epidemic, a certain number of
      specific measures must be taken in order to prevent the transmission of infection
      and eradicate the epidemic. IN THE CASE OF INFLUENZA: Other than the vaccination
      of elderly institutional residents, that of the nursing staff appears essential.
      If a severe epidemic occurs, specific antivirals can be used, three of which are
      already available. IN THE CASE OF PNEUMOCOCCI: Examples of epidemics of
      pneumococcal infections in elderly institutional residents in the United States
      underlines the interest of pneumococcal vaccines, particularly since the strain
      responsible corresponded to a serotype contained in the 23 valence vaccine. WITH
      REGARD TO SCABIES: All the patients and all the staff must be treated on the same
      day and at the same time their clothing and bed linen. All persons in contact
      with the patient, the families and friends of the staff, their clothes and the
      environement must be treated.

PMID- 12402760
TI  - [Characteristics of infectious diseases in the elderly].
AB  - IN GENERAL: Infectious diseases represent the third cause of mortality in
      patients aged over 65. Age-related immune deficiency and underlying diseases
      frequently favour infections. The symptoms are often fickle and misleading, delay
      diagnosis and worsen the prognosis. THE PRINCIPLE INFECTIONS: Broncho-pulmonary
      and urinary infections predominate in this context. More rare but severe
      complications specifically related to age are also possible, notably meningitis,
      tuberculosis, herpes zoster and septicemia in the elderly. PREVENTIVE MEASURES:
      Influenza and anti-pneumococcal vaccines have demonstrated their efficacy in
      limiting the broncho-pulmonary infections in these patients.

PMID- 12402761
TI  - [Ocular infections of the elderly].
AB  - A CLINICAL ASPECT DEPENDING ON THE PHYSIOPATHOGENESIS: Ocular infections are a
      frequent motive for ophthalmological consultations in geriatric settings because
      of the mechanical factors related to age (modifications in palpebral dynamics and
      lacrymal function) and in local and general immune factors leading to the rapid
      and/or more severe development of infections. The mechanism of microbial
      contamination of the eye also determines the clinical damage: predominantly local
      (dirty hands, traumas) with involvement of the surface tissues (conjunctive and
      cornea) or general, hematogenic or neurogenic, frequently at the origin of more
      internal infections (iris, choroid, retina, optical nerve). CONJUNCTIVITIS AND
      KERATITIS: These provoke reddening of the eyes, tears and above all pain when the
      corneal epithelium is involved. Microbiological samples are useful in cases of
      severe, presumably infectious keratitis or conjunctivitis. Two emergency
      situations must be distinguished: any suspicion of herpes for which local
      corticosteroids are contraindicated and keratitis or conjunctivitis with the use
      of lenses, often due to Gram negative bacilli, amoeba or fungus, the treatment of
      which is intensive and the prognosis often severe. OPHTHALMOLOGICAL HERPES
      ZOSTER: The rapid diagnosis and introduction of efficient doses of antivirals
      reduces the initial pain, the ocular complications of herpes zoster and post
      zoster pain. The latter, when it exists, requires specialized management. ACUTE
      UVEITIS: A context of intra-ocular inflammation in an elderly patient must always
      evoke a pseudo-uveitis syndrome, the principle cause of which is lymphoma.
      Conversely, an uveitis occurring in the days or weeks following ocular surgery,
      including cataract, must be considered as suggestive of a post-surgical infection
      and rapidly referred to a specialist. ACUTE DACRYOCYSTITIS: Is manifested by a
      hard and painful tumefaction below the internal angle of the eye. Following
      collection, it requires draining through an in incision in the skin, washing and
      packing of the sac, and systemic antibiotherapy. The preventive treatment of
      recurrences requires open dacryocystorhinostomy or via endonasal endoscopy.

PMID- 12402762
TI  - [Risks related to cytostatic exposure for nursing staff].

PMID- 12402763
TI  - [Comments on the fatal recurrence of pseudomembranous colitis].

PMID- 12402764
TI  - [Prospects for preoperative low-intensity laser therapy in preventing
      postoperative thrombohemorrhagic complications in adenomectomy].
AB  - The authors analyse the results of preoperative preoperation of 143 patients with
      benign prostatic hyperplasia (BPH). Conventional preoperative preparation
      (antibiotics, uroantiseptics and phytotherapy) was used in combination with
      intravascular laser irradiation of blood (group 1, 30 patients), local laser
      therapy (transurethral and transrectal) (group 2, 27 patients), variation of
      laser methods (group 3, 28 patients) and alone (61 patients, group 4). Such
      preoperative preparation was aimed at prophylaxis of thrombohemorrhagic
      complications after adenomectomy. The efficiency of the treatment was assessed by
      hemostasis parameters. It was found that conventional antiinflammatory therapy
      had a weak effect on hemostasis, the greatest positive effects being achieved
      with combined laser preoperative preparation. Hyperfibrinogenemia, thrombinemia
      and activation of XII + a-dependent finrinolysis were stopped in patients of
      group 3. Because of less number of postoperative hemorrhages, hemotransfusions
      and transfusions of blood preparations were used less frequently, red cell
      parameters improved, exacerbations of chronic pyelonephritis occurred less often.

PMID- 12402765
TI  - [Use of avelox in treating urogenital infections in men].
AB  - We used the drug avelox, a new fluoroquinolone of the fourth generation, in
      therapy of urogenital infections (caused by chlamydia, mycoplasma, ureaplasma) in
      men. The test group consisted of 45 men with urethritis, urethroprostatitis given
      avelox in a single dose of 400 mg/day for 10 days. 18 control patients with
      urethritis took ofloxacin in a dose of 200 mg twice a day for 10 days.
      Examination for infection eradication was made 2 weeks and 2 months after the end
      of the treatment. Eradication of chlamydial infection was achieved in 18 (94.73%)
      patients, mycoplasma (ones in 23 (80%), ureaplasma--in 29 (86%) patients. Thus,
      clinical efficiency of avelox may be characterized as very good in chlamydial
      infection, good in ureaplasma and mycoplasma infections. Side effects occurred
      only in 5 patients who had short-term transient gastrointestinal disorder.
      Compared to ofloxacin, avelox is more effective and less toxic.

PMID- 12402766
TI  - [Functional changes and structural features of the testis in patients after acute
      parotid orchitis].
AB  - Structural changes and functional features of the testes were studied in 20
      patients who had had parotid orchitis (PO) 6 months to 1.5 years before the
      study. The examination including ultrasonography of the testes, investigation of
      ejaculate, radioimmunoassay for serum testosterone, FSH, LH brought out a
      significant reduction of the mean volume and echogenicity of the affected
      testicles by 44.7 and 50%, respectively, in 15 patients; a 58.2% decrease in the
      number of spermatozoa in ml; a 71.2% rise in FSH level in 6 patients. Morphometry
      of biopsy specimen of the testicles on the affected side has shown that mean
      sectional area of the tubules has diminished by 40%, the spermatogenesis index-
      by 77.1% while the volume of the intertubular connective tissue increased by
      47.7%. Thus, after acute PO, the patients develop atrophic changes in the testes
      and a decline in spermatogenic function up to secretory infertility.

PMID- 12402767
TI  - [Experience in long term use of tamsulosin (Omnik) in patients with chronic
      prostatitis].
AB  - Tamsulosin (omnik), a selective adrenoreceptor blocker-alpha 1A/D, was used in a
      long-term regimen of chronic prostatitis (CP) treatment conducted in 39 patients.
      Tamsulosin was given in a standard dose of 0.4 mg once a day for 1 year. The IPSS
      total scores, quality of life (Qol, Q max) and size of the prostate were
      assessed. Tamsulosin proved highly effective in symptoms of the lower urinary
      tracts (SLUT) and CP. In patients with exacerbation of CP and with SLUT
      combination of tamsulosin with antibacterial, antiinflammatory, immunomodulating
      and symptomatic therapy raises the treatment efficiency. Tamsulosin monotherapy
      can be recommended for treatment of micturition disorders in patients with
      nonaggravated CP.

PMID- 12402768
TI  - [Fractionated low-intensity thermotherapy of benign prostatic hyperplasia].
AB  - 120 patients with benign prostatic hyperplasia (BPH) (mean age 65.8 +/- 7.7
      years) received fractional low-intensity transurethral microwave thermotherapy
      (FLITMT). Each patient was exposed to 4 FLITMT procedures with 3-4 day interval
      (duration--60 min at 48.5-49.9 degrees C, ProsTek 3000 unit, USA). Subjective and
      objective effects of FLITMT were observed in 87 (82.9%) and 75 (71.4%) patients,
      respectively. A stable effect on IPSS persisted for 3 years, on acceleration of
      maximal urination rate--within a year. Moreover, FLITMT was associated with a low
      frequency of complications. This makes the above thermotherapy usable in all BPH
      patients without absolute indications for surgical treatment.

PMID- 12402769
TI  - [Use of proscar in preoperative preparation of patients with benign prostatic
      hyperplasia before transureteral resection].
AB  - Effects of proskar-MSD used before transurethral resection (TUR) of the prostate
      in patients with benign prostatic hyperplasia (BPH) were studied with
      specification of the drug action on hematuria during and after operation.
      Patients with histologically verified BPH received proskar for 3 and 6 months in
      a dose of 5 mg/day. Control patients did not receive preoperative proskar. Of
      patients who received proskar for 3 months, TUR with estimation of the
      intraoperative blood loss and changes in microcirculation and structure of
      prostatic tissue induced by proskar was made in 20 patients (mean age 68 years).
      A 3-month course of proskar reduced prostatic volume and its hyperplasia by 18-20
      cm3, on the average. Mean blood loss was about 111 ml vs control 223 ml.
      Dopplerography revealed consolidation of adenomatous tissue and decline of
      volumic blood flow in the prostate after 3-month proskar course. Thus,
      preoperative proskar administration before TUR of prostatic adenoma results in
      sclerosing of prostatic tissue, decrease of microcirculation manifesting
      intraoperatively with diminished hematuria and less number of subsequent
      complications; promotes a favourable outcome of the operation; improves life
      quality.

PMID- 12402770
TI  - [Dynamic magnetic resonance prostatovesiculography in diagnosing prostatic
      cancer].
AB  - Dynamic MR prostatovesiculography (DMRP) is a new method of prostatic cancer
      diagnosis based on the ability of cancer tissue to accumulate contrast substance
      (omniscan) than benign tissue. Urologists from the I.M. Sechenov Moscow Medical
      Academy have examined 23 patients (5 patients with prostatic cancer and 18
      suspects) who have undergone standard investigations (test for PSA, finger rectal
      examination, transrectal ultrasound investigation) and DMRP. DMRP detected
      prostatic areas suspected of malignancy. Taking biopsy from such areas verified
      diagnosis of prostatic cancer in 2 patients.

PMID- 12402771
TI  - [Monotherapy with casodex at a dose of 150 mg--a new method of hormonal treatment
      of disseminated prostatic cancer].

PMID- 12402772
TI  - [Anemia syndrome in patients with chronic renal insufficiency on peritoneal
      dialysis treated with recombinant erythropoietin].
AB  - The paper presents the results of the studies of erythrocytic and iron metabolism
      parameters in the course of treatment with recombinant erythropoietin (RE) and
      iron preparations in 60 patients with chronic renal failure (CRF) on peritoneal
      dialysis (PD) aged 20 to 75 years. Pretreatment iron deficiency in CRF patients
      on PD persisted to the end of the third observation period. Hyperferritinemia
      registered in CRF patients on PD with frequent peritonitis may be considered as a
      result of active ferritin synthesis by the cells of the system of mononuclear
      phagocytes in response to inflammation. The only parameter indicating the
      presence of iron deficiency seems to be the percentage of hypochrome erythrocytes
      indirectly evidencing for insufficient supply and iron utilization in bone
      marrow. Pathogenetic mechanisms of anemia development in CRF patients on PD may
      be both low EP and high levels of proinflammatory cytokines as well as
      oversecretion of ferritin by activated by monocytes/macrophages ferrin, promoting
      apoptosis of late erythropoiesis precursors, development of ineffective
      erythropoiesis and having a suppressive effect on erythropoiesis cell precursors.

PMID- 12402773
TI  - [Use of a three-component scheme of immunosuppression on morphologic and
      immunohistochemical changes of transplants in the early postoperative period].
AB  - Three-component (cyclosporin A, corticosteroids and azathioprine)
      immunosuppression has been widely introduced in the treatment of recipients of
      renal transplants because it allows a significant reduction of the components'
      doses in greater effectiveness. The analysis of the results of 83 puncture
      biopsies obtained in the immediate postoperative period after kidney
      transplantation has shown that administration of an imidazole derivative allows
      raising therapeutic concentration of cyclosporin up to 200-300 ng/ml, thus
      preventing rejection crises. However, increased blood concentration of
      cyclosporin does not increase its toxicity as a result of a significant fall in
      the overall level of the metabolites.

PMID- 12402774
TI  - [Ovestin in preparation for transvaginal surgeries].
AB  - The trial of the efficiency of the drug estriol-ovestin in preoperative
      preparation of patients to transvaginal operations included 118 patients (mean
      age 48.6 years). 82 patients received ovestin as a vaginal suppository and creams
      in a daily dose of 500 mu for 2-3 weeks before the operation. 36 control patients
      did not receive ovestin in their preoperative preparation. Effectiveness of
      ovestin was assessed by duration of pain symptom in the postoperative period,
      duration of the vaginal postoperative discharge, duration of dysuria after
      removal of a urethral catheter, the time of renewal of sexual intercourses. The
      results of the study proved effectiveness of ovestin in preoperative preparation
      of patients for vaginal surgery.

PMID- 12402775
TI  - [Afferent stimulation of the tibial nerve in patients with hyperactive bladder].
AB  - 36 patients with overactive bladder (24 with idiopathic detrusor instability; 12
      with detrusor hyperreflexia due to multiple sclerosis) underwent percutaneous
      afferent neuromodulation. The treatment consisted of percutaneous insertion of a
      34-gauge solid stainless steel needle at a point of 5 cm cephald from the medial
      malleolus. The patients were treated weekly for 12 weeks for 30 minutes. A
      subjective effect was assessed using a dairy. An objective effect was analysed by
      urodynamic studies. We noticed a decrease in the average voiding frequency,
      number of leakage episodes and pad use per 24 hours after 12 sessions of the
      stimulation. Symptomatic improvement of more than 50% was achieved in 28 of 36
      patients. No significant adverse events related to the treatment were observed.
      Thus, stimulation of the posterior tibial nerve is effective in patients with
      overactive bladder.

PMID- 12402776
TI  - [Endotomy in treating strictures of the upper urinary tract].
AB  - The analysis of outcomes of 102 operations of transurethral and percutaneous
      endotomy in 100 patients is provided. Primary strictures of the upper urinary
      tract (UUT) were detected in 26 cases. Postoperative strictures existed up to 3
      months in 19 cases, 3 to 12 months in 21 cases and at least 12 months in 36
      cases. The causes of the strictures lie in previous surgical interventions on the
      UUT. Of the 102 endoscopic operations, 49 ones were conducted via percutaneous
      approach, nephrostomic fistula was used in 11 cases. In 42 endotomies the
      approach to UUT strictures was transurethral, a "cold knife" was applied in 78
      operations, electric current in 24 cases. Follow-up for 12 months to 9 years
      documented good and satisfactory results in 90 (90%) patients. Open operative
      intervention was necessary for elimination of the intraoperative complication in
      1 case, of the postoperative one also in 1 case. The remaining endotomy
      complications were treated conservatively. Reoperations due to endotomy failure
      were made in 8 cases of 10. Endotomy of UUT strictures is indicated in primary
      and early postoperative strictures 0-1 cm in size located at any site of normally
      developed UUT accessible for rigid endoscopic instruments from percutaneous or
      transurethral approaches.

PMID- 12402777
TI  - [Results of transcutaneous nephrolithotripsy using the combined lithotriptor "2
      in 1" "Swiss Lithoclast Master"].
AB  - The aim of the study was to determine frequency of infectious-inflammatory
      complications regarding the duration of transcutaneous nephrolithotripsy (TCNL).
      Two groups of nephrolithiasis patients were compared. Group 1 consisted of 37
      nephrolithiasis patients aged 20 to 78 years (15 males, 22 females). Size of the
      concrements ranged from 1.8 to 4.9 cm. They underwent contact lithotripsy
      performed by an ultrasound lithotriptor. Group 2 consisted of 22 patients aged 34
      to 74 years (11 males and 11 females). Nephroliths were 2.0 to 8.5 cm in size.
      Group 2 patients underwent combined contact pneumatic and ultrasound lithotripsy
      on a novel Swiss LithoClast Master unit. Elimination of the nephroliths was
      observed in 27 (72.9%) patients of group 2 and in 19 (86.3%) patients of group 2.
      Residual calculi were detected in 10 (27%) patients of group 1. Surgery lasted 66
      to 140 min (mean 81.2) and 40 to 120 min (mean 58.5 min) in groups 1 and 2,
      respectively. Pyelonephritis activity was registered in 24 (77.4%) and 3 (13.6%)
      patients, respectively. Thus, in percutaneous lithotripsy of large stones,
      frequency of inflammatory complications depends not only on technical faults and
      initial bacteriuria, but also on the duration of the operation. If surgical
      intervention took more than 60 min, frequency of the infectious-inflammatory
      complications increased 1.6-fold. Utilization of the lithotriptor Swiss
      LithoClast Master raises efficiency, accelerates destruction and evacuation of
      stones.

PMID- 12402778
TI  - [Use of biodegradable stents in treating complex urethral strictures].
AB  - Seven men with complex urethral strictures after examination using three
      dimentional and echocontrast sonourethrography were subjected to transurethral
      laser vaporation of the scar tissue in the region of the narrowing, implantation
      of the biodegradable urethral SR PLGA stents at contra cystourethroscopy.
      Internal drainage of the urinary bladder with the use of SR-PLGA stents provides
      protection against exogenous infection and complications of epicystostomic or
      urethral cathetarization. High informative value, low invasiveness and relative
      safety of sonourethrography allows one to revise the role of ultrasound
      investigation in the algorithm of diagnosis and choice of treatment for patients
      with strictures and obliterations of the urethra.

PMID- 12402779
TI  - [Long-term results of treating children with kidney and ureteral stones with
      extracorporeal lithotripsy].
AB  - Long-term outcomes of urolithiasis treatment with extracorporeal lithotripsy
      (ECLT) have been analysed for 132 children using, as the basic criterion, data of
      dynamic nephroscintigraphy. The results of ECLT were considered regarding
      characteristics of the concrement, inflammatory process, parameters of the shock
      wave. It was found that low-energy restruction regimens in minimal number of
      impulses per session and adequate intervals between them prevent irreversible
      changes in renal parenchyma in response to focused shock waves. Monitoring and
      adequate treatment late after ECLT lead to recovery of renal function if
      obstructive complications and stone formation are found early and if the course
      of the inflammation is controlled.

PMID- 12402780
TI  - [A method of one-stage correction of proximal hypospadia by deepithelialized
      foreskin graft].
AB  - The author proposes a modification of one-stage urethral plastic repair with
      cross-over graft from the foreskin according to Duckett for correction of
      proximal hypospadias with malformation or absence of the free trunkal part of the
      penis in well developed foreskin. From 1996 to 2001 one-stage operations were
      made in 82 boys at the age of 8 months to 15 years. Expanding of the cavernous
      bodies with loss of the urethral platform and plastic repair of a long urethral
      area were performed in 69 patients. These cases were most difficult for
      correction. Only plastic repair was made in the rest 13 children as their
      cavernous body deformation had been corrected previously. One-stage surgery of
      the urethra with dissection of the chorda was conducted by Hodgson-III in 13
      patients, by modified Hodgson-III technique in 29 and by Duckett in 5 patients.
      Plastic repair with diagonal deepithelized graft from the foreskin was tried in
      22 patients with underdeveloped volar surface of the penis. The modification
      consisted in cutting out the diagonal graft from the foreskin entoderm, forming a
      tube of it with uninterrupted suture, creation of the graft vascular pedicle by
      skeletization and deepithelization of the skin of the foreskin ectoderm and
      partially of the penis trunk, creation of a wide anastomosis of the formed tube
      with external opening of the urethra isolated by edge incision, mobilization of
      the glans penis wings by longitudinal incisions and creation of meatus on the top
      of the glans penis, mobilization of the foreskin and penis trunk tunica dartos
      with its placing from the dorsal surface on the ventral at both sides of the
      cavernous bodies. The treatment outcomes were followed up from 6 months to 3.5
      years. Complications (stenosis of the external urethral opening, urethral
      fistulas and stenosis of the anastomosis zone) were observed in 13 (18.84%)
      patients. The proposed modification reduced the number of complications up to
      13.63%, improved cosmetic and functional results.

PMID- 12402781
TI  - [Biological and psychosocial factors as a reason for enuresis in children].
AB  - Biological (pregnancy in neurotic mothers) and psychosocial (wrong attitude of
      the family to enuretic child) risk factors were studied in 68 children with
      enuresis aged 4 to 15 years. It is shown that the presence of biological and
      psychosocial factors in combination with enuresis in children necessitate
      antenatal consultations of obstetricians, pediatrists, psychologists and parents
      on prevention of enuresis in children, active screening-testing children with
      enuresis for dysfunction of the urinary bladder and psychoneurological disorders
      affecting harmonic development of personality in children.

PMID- 12402782
TI  - [Replacement of the pelvic portion of the right ureter with vermiform process].

PMID- 12402783
TI  - [A case of a giant pointed Buschke-Lowenstein condyloma of the proximal urethra].

PMID- 12402784
TI  - [Purulent pyelonephritis: diagnosis and clinical course].

PMID- 12402785
TI  - [A method of treating calculi in the renal calices].

PMID- 12402786
TI  - [Physiologic function of P-glycoprotein].
AB  - P-glykoprotein has been proposed to function as a membrane transport protein for
      a large variety of substrates, ranging from small lipophilic molecules, steroid
      hormones, lipophilic peptides, some drugs, biologically important molecules and
      xenobiotics. There is little doubt that P-glycoprotein transports a wide range of
      substrates out of cells, nevertheless it is difficult to explain its wide
      substrate specificity and mechanism of the transport. P-glycoprotein has been
      found to be a major cause of acquired multidrug resistance (MDR) of cancer cells
      to chemotherapeutic drugs. The identification and localization of P-glycoprotein
      expression in a variety of normal human tissues raised the question of the
      physiological functions of P-glykoprotein. Currently, there is considerable
      evidence that P-glycoprotein can protect the body and sensitive tissues against a
      range of different xenobiotics. In addition, P-glycoprotein might play a role in
      regulation of cell differentiation, proliferation, immune response and programmed
      cell death.

PMID- 12402787
TI  - [Catecholamine synthesis and expression of enzymes of the catecholamine pathway
      in the rat heart at rest and during stress].
AB  - Catecholamines participate in a variety of cell regulations and physiological
      mechanisms, but also in the development of neurological, psychiatrical, endocrine
      and cardiovascular diseases. Diseases of the cardiovascular system, such as
      hypertension, myocardial infarction, ischaemia, etc. represent a serious medical
      problem and a frequent cause of the human death. It is alarming that development
      of these diseases depends preferentially on the wrong life-style and affect lower
      age groups. One of the factors that participate on unwilling increase of the
      incidence of cardiovascular diseases is the stress. Under the stress, organism
      mobilizes its energetical sources, increases cardiac performance and activates
      other processes, which enable to handle this load. Catecholamines belong to the
      important mediators of the stress response. On the one side they are required to
      buffer the stress situation, but the pathological changes in the regulation of
      their synthesis, secretion and action significantly participate on the
      development of several diseases (e.g. also of the cardiovascular origin). The aim
      of this review is to show the role of catecholamines in the heart not only under
      the physiological, but also in pathophysiological conditions. Stress as a modern
      civilization factor participates on the development of several diseases.
      Understanding of the mechanism of development of these diseases is the first step
      to the development of an appropriate therapy. Changes in the catecholamine levels
      during stress, as well as enzymes, which participate on the synthesis of
      catecholamines, are undoubtedly the important part of this mechanism.

PMID- 12402788
TI  - [Molecular mechanisms of biological effects of lithium].
AB  - Lithium has the inhibitory effect on many enzymes and multiple effects on some
      physiological processes. Lithium is also highly effective in the treatment of
      bipolar disorder, however, the mechanism of lithium action in the treatment of
      this psychiatric disorder is still unknown. A number of lithium-sensitive enzymes
      and putative important biomolecules have been proposed as potential targets of
      lithium action and these mechanisms are discussed in this review.

PMID- 12402789
TI  - [Free radicals and antioxidants in cerebrospinal fluid in central nervous system
      diseases].
AB  - Free radicals and antioxidants may play a role in the etiology and pathogenesis
      of some central nervous diseases. The brain tissue is relatively insufficiently
      protected by antioxidants against the free radical induced damage. The brain
      situation may be reflected by the cerebrospinal fluid examination, which has not
      enough attention. It seems, that from this point of view subarachnoical
      hemorrhagy, meningitis, hydrocephalus, Alzheimer's, Parkinson's and Huntington's
      diseases, multiple sclerosis and probably schizophrenia should receive a special
      attention.

PMID- 12402790
TI  - A perspective on American health care: today's implications for managed care
      tomorrow.

PMID- 12402791
TI  - Innovations in incentivizing participation in disease management programs.

PMID- 12402792
TI  - Better use of ancillary health professionals in diabetes management.

PMID- 12402793
TI  - Medical errors, quality, and the corporate employer.

PMID- 12402794
TI  - Evidence-based medicine is not a branding device.

PMID- 12402795
TI  - Will HIPAA hamper disease management efforts?

PMID- 12402796
TI  - [Accumulation of abnormal psychosocial circumstances in juvenile delinquents with
      modified legal culpability].
AB  - The purpose of this study is to investigate specific influence on the exclupation
      according the medical-legal certificate approved by the courts decision. 34
      culpable young offenders have been compared with 40 young delinquents who have
      disorders of penal responsibility according to socio-demographic, anamnestic and
      diagnostic variables. A significant difference between the two compared groups
      was found in the associated, abnormal psychosocial situations. Those delinquents
      who were exculpated displayed more than three times higher scores in the abnormal
      psychosocial axis five of ICD-10 than among the non-exculpated group. The
      influence of actual abnormal psychosocial situations on a substantial general
      psychic vulnerability is discussed.

PMID- 12402797
TI  - [Social behavior disorders--therapeutic possibilities and limits in inpatient
      child and adolescent psychiatry].
AB  - The health system is engaged in conduct disorders by children and adolescents as
      they represent a psychiatric diagnosis. They come likewise under the
      responsibility of community services and in part even justice while they exhibit
      a broad spectrum of social and conduct problems. Where the activities of the
      institutions mentioned overlap, arise questions of competence and responsibility.
      According to available empirical data and clinical experiences issues of
      indication for inpatient treatment in child and adolescence psychiatry units,
      however, the difficulties how to deal with these patients will be described.
      Conclusions with regard to possibilities, limits and contraindications for
      inpatient treatment of children and adolescents with conduct disorders will be
      drawn.

PMID- 12402798
TI  - [Indications for inpatient child and adolescent treatment].
AB  - When the demand for inpatient treatment in acute psychiatric crisis of
      adolescents rises, it is not always recommended to admit a patient to the
      hospital. The limited number of hospital beds forces medical professionals to use
      their resources cautiously. This leads to the need to activate the intrapersonal
      and intrafamilial resources. The motivation for change emerging out of a crisis
      is to be used for clarification of the indication of inpatient treatment and of
      the order of treatment, a patient (and/or his legal representative) gives to the
      hospital representatives. A clarification of the aims of a hospitalisation prior
      to the admission to the ward rises the efficacy of the invested time.

PMID- 12402800
TI  - The changing face of AIDS.

PMID- 12402799
TI  - ["There is no room for more"--case report of a Kurdish adolescent with an eating
      disorder in relation to family background of political persecution].
AB  - Migrant families make up almost 10% of the population of the German state of
      Schleswig-Holstein and a significant number of patients in the clinics for
      paediatrics. A casuistry shall show the specific problems and needs in the
      psychosomatic treatment of foreign children and adolescents, especially the
      problems of children of political refugees. In the Clinic for Paediatrics at the
      University of Lubeck a task group for migration and health has been formed which
      deals with the special needs of these patients. A better and more specific
      treatment of these patients shall prevent unnecessary long stays at the clinics,
      false diagnoses, wrong treatments, and the chronification of illnesses in the
      future.

PMID- 12402801
TI  - Diarrhea in a patient with AIDS.

PMID- 12402803
TI  - Drug resistance. Navigating resistance pathways.
AB  - Treatment failure due to the rise of drug-resistant viral strains remains a
      serious problem confronting HIV treaters and patients alike. Among patients
      receiving antiretroviral therapy for HIV infection, new mutations associated with
      drug resistance continue to emerge, as do new patterns of cross-resistance and
      multidrug resistance. Drug-resistant HIV variants are now becoming so widespread
      that an increasing number of patients are experiencing "primary" resistance,
      having been infected with drug-resistant and sometimes multidrug-resistant
      strains. Drug-specific resistance mutations, in some cases, show resistance to a
      number of anti-retroviral drugs in the same class. Recent data have shown that
      there is more cross-resistance among the nucleoside reverse transcriptase
      inhibitors than initially thought. The growing complexity of the HIV-1 resistance
      spectrum calls for more sophisticated testing and clinical expertise, in addition
      to more effective drugs.

PMID- 12402802
TI  - Recent developments in HIV research.

PMID- 12402804
TI  - Diagnosis of diffuse CD8+ lymphocytosis syndrome in HIV-infected patients.
AB  - The diffuse infiltrative lymphocytosis syndrome (DILS) in HIV-infected persons is
      characterized by a persistent circulating CD8+ lymphocytosis. Certain HIV
      infected persons appear to respond to their infection by developing an
      oligoclonal expansion of CD8+ lymphocytes. These cells infiltrate multiple
      organs, but the salivary glands and the lung constitute the major sites involved
      in this process. This infiltrative process resembles in many aspects a Sjogren
      like syndrome, owing to the visceral lymphocytic infiltration. Unilateral parotid
      gland enlargement in a patient with HIV infection should prompt clinicians to
      suspect DILS. In addition, clinicians should be aware that the pulmonary process
      associated with DILS may mimic clinically and radiographically the pneumonic
      process caused by Pneumocystis carinii. Other manifestations of DILS to consider
      include a severe form of peripheral neuropathy; lymphocytic infiltration of the
      liver, evident as hepatitis; myositis; and lymphocytic interstitial nephritis.

PMID- 12402805
TI  - Editorial comment: CD8+ lymphocytosis and DILS--a tale of split personality.

PMID- 12402806
TI  - Slow epimerization of stereochemically rigid diastereomers of the equatorially
      substituted cluster [Os3H2(mu 3-S)(CO)8((S)-PhCHMeNH2)].
AB  - Turnstile rotation is suppressed in the equatorially substituted cluster [Os3(mu
      H)2(mu 3-S)(CO)8((S)-PhCHMeNH2)] which was separated by HPLC into two
      diastereomers which do not interconvert at room temperature and epimerize only
      slowly at 90 degrees C.

PMID- 12402807
TI  - Evaluation of studies of health economics.

PMID- 12402808
TI  - Review: continuous caregiver support during labour has beneficial maternal and
      infant outcomes.

PMID- 12402809
TI  - Review: group based parenting programmes improve short term mental health in
      infants and toddlers.

PMID- 12402810
TI  - An interactive monitoring device reduced asthma symptoms and functional
      limitations in inner city children with asthma.

PMID- 12402811
TI  - Review: oral antifungal drugs promote cure of fungal infections of the foot.

PMID- 12402812
TI  - A lifestyle intervention or metformin prevented or delayed the onset of type 2
      diabetes in people at risk.

PMID- 12402813
TI  - Review: pentoxifylline with standard compression treatment improves healing of
      venous leg ulcers.

PMID- 12402814
TI  - Mild hypothermia improved neurological outcome and reduced mortality after
      cardiac arrest because of ventricular fibrillation.

PMID- 12402815
TI  - Losartan reduced stroke and new onset diabetes more than atenolol in essential
      hypertension with signs of left ventricular hypertrophy.

PMID- 12402816
TI  - Review: psychoeducational interventions reduce depressive symptoms in cancer.

PMID- 12402817
TI  - Pharmacological and non-pharmacological interventions improve food intake in
      cancer related anorexia and cachexia.

PMID- 12402818
TI  - Review: NSAIDs and adjuvant treatments such as hypnosis can help to reduce cancer
      related pain.

PMID- 12402819
TI  - Review: intensive multidisciplinary biopsychosocial rehabilitation reduces pain
      and improves function in chronic low back pain.

PMID- 12402820
TI  - Review: early supported discharge may reduce length of hospital stay in patients
      with acute stroke, but does not reduce death.

PMID- 12402822
TI  - Review: specific combinations of symptoms effectively rule in the diagnosis of
      urinary tract infection based on history alone.

PMID- 12402821
TI  - Review: home visiting with multidimensional assessment and multiple visits
      reduces nursing home admissions in low risk elderly people.

PMID- 12402823
TI  - A height based graphic method was more accurate than estimation based on external
      landmarks for determining depth of paediatric gastric tube insertion.

PMID- 12402824
TI  - Review: nurse practitioner primary care improves patient satisfaction and quality
      of care with no difference in health outcomes.

PMID- 12402825
TI  - Parents found it difficult to obtain objective information and advice about the
      combined mumps, measles, and rubella vaccine.

PMID- 12402826
TI  - Younger and older children had different experiences of asthma and its
      management.

PMID- 12402827
TI  - Young homeless women encountered physical and individual barriers in obtaining
      health care.

PMID- 12402828
TI  - Adults experienced a long term indwelling urinary catheter as living with the
      forces of flowing water.

PMID- 12402829
TI  - A support group created a caring environment where women with heart disease felt
      understood, supported, and strengthened by peers and nurse facilitators.

PMID- 12402830
TI  - Scripting and performing a drama about living with metastatic breast cancer
      provided insight into women's experiences.

PMID- 12402831
TI  - 4 thematic patterns described the experience of placing a relative with
      Alzheimer's disease in a special care unit.

PMID- 12402832
TI  - [Docetaxel in the adjuvant treatment of operable breast carcinoma. News from ASCO
      2002].

PMID- 12402833
TI  - [Controversies in oncology. Venous thromboembolism and cancer: what is done and
      what should be done. Milan, May 18, 2002].

PMID- 12402834
TI  - [New prospects in the treatment of advanced colorectal tumors. Barcelona, June 20
      22, 2002].

PMID- 12402836
TI  - Prognostic value of p53 overexpression in T1G3 bladder tumours treated with
      bacillus Calmette-Guerin therapy.

PMID- 12402835
TI  - The rehabilitation of brain injured children: the case for including physical
      exercise and virtual reality: a clinical perspective.

PMID- 12402839
TI  - Plenary debate of randomized phase III trial of neoadjuvant MVAC plus cystectomy
      versus cystectomy alone in patients with locally advanced bladder cancer.

PMID- 12402837
TI  - Equivalent efficacy of mitomycin C plus doxorubicin instillation to bacillus
      Calmette-Guerin therapy for carcinoma in situ of the bladder.

PMID- 12402838
TI  - Integrated therapy for locally advanced bladder cancer: final report of a
      randomized trial of cystectomy plus adjuvant M-VAC versus cystectomy with both
      preoperative and postoperative M-VAC.

PMID- 12402841
TI  - Semenogelin, the main protein of semen coagulum, inhibits human sperm
      capacitation by interfering with the superoxide anion generated during this
      process.

PMID- 12402840
TI  - A sperm ion channel required for sperm motility and male fertility.

PMID- 12402842
TI  - ESHRE basic semen analysis courses 1995-1999: immediate beneficial effects of
      standardized training.

PMID- 12402844
TI  - This month in clinical urology.

PMID- 12402856
TI  - Bibliography. Current world literature. Hematopoietic stem cell transplantation.

PMID- 12402857
TI  - Bibliography. Current world literature. Transfusion medicine.

PMID- 12402870
TI  - Fat transplantation and breast augmentation.

PMID- 12402881
TI  - [Mirko Drazen Grmek, a memory].

PMID- 12402894
TI  - Clinical do's and don'ts: automated external defibrillator.

PMID- 12402895
TI  - IGIV: blood product linked to clotting problems.

PMID- 12402899
TI  - Preventing the progressive nature of type 2 diabetes.

PMID- 12402901
TI  - Chart smart: keeping tabs on arrhythmias.

PMID- 12402908
TI  - [Paracelsian thought, neo-platonism, and hermetic medicine: Joseph du Chesne].

PMID- 12402911
TI  - Myths & facts....about beta-blockers and hypertension.

PMID- 12402916
TI  - Legal questions. Patient safety: hallway hazard.

PMID- 12402918
TI  - [Beginnings of criminology and the concept of identification].

PMID- 12402919
TI  - [Logical bases of technological anthropology: the measurement of man and bio
      sociology (1860-1920)].

PMID- 12402920
TI  - [The question of realism in psychology].

PMID- 12402921
TI  - [Male sexuality and pathologies in the traditional medicine of Akan (Ghana): a
      discussion about kooko].
AB  - The paper discusses a pathology, known in Ghana with the name of kooko. According
      to Akan medicine, the disease is a symptom of a social and cosmic disorder, the
      consequence of a divine punishment. Kooko is a red protuberance, index of a very
      serious disease, appearing all over the body, in the brain, ears, uterus, anus or
      penis. In the last case, kooko causes increasing sexual weakness.

PMID- 12402922
TI  - [Medieval andrology and the pseudo-galenic De spermate].
AB  - The pseudo-Galenic De spermate, a theoretical treatise on reproduction that was
      probably translated into Latin in the early Salernitan period and remained
      influential throughout the Middle Ages, provides valuable information about
      medieval ideas concerning the male reproductive system. The emphasis is on
      reproductive physiology. The text describes semen as a fluid that is originally
      drawn from the four bodily humours, primarily blood, is turned into sperm by
      coction in specific veins and arteries, and passes through the man's body along
      spermatic vessels, first ascending to the head and from there desending through
      particular organs to the testicles, where it is finally made complete for
      emission. The text also contains a description of male reproductive anatomy,
      including the internal structure of the testicles. Male reproductive pathology is
      not explored in any detail in this theoretical account, but a few potential
      problems in reproductive funtioning are mentioned in the discussion of
      physiological processes.

PMID- 12402923
TI  - Experimental analysis of gravitational effects on amphibian gastrulation.
AB  - The effects of simulated microgravity on blastopore (Bp) formation were analysed
      in Xenopus laevis and Cynops pyrrhogaster embryos. Simulated microgravity
      produced by clinostat rotation shifted the Bp-forming region toward the vegetal
      pole, more markedly in Cynops embryos than in Xenopus embryos. The simulated
      microgravity induced aggregation of endoderm cells at the center of the embryo
      and separation between the endoderm and presumptive mesoderm (PM). These findings
      suggest that clinostat treatment disrupts cell-to-cell interaction between
      endoderm and PM by increasing the separation between them and, as a result, Bp
      formation may be shifted towards the vegetal pole.

PMID- 12402924
TI  - [An easy introduction to organismal and cellular mechanisms for graviperception].
AB  - In this review paper, organismal and also cellular mechanisms for perception of
      gravity are explained. A statolith and a number of hair cells which surround the
      statolith is a basic structure of statocysts for detecting the direction of
      gravity or tilting of the body in various animals. The vestibular system of
      vertebrate was explained, especially on the process from the body-tilting to
      impulse frequencies which travel to brain. For the cellular responses to gravity,
      contribution of various organella (??) and cytoskeleton are introduced. Such
      cellular responses may change when the gravity values become less or null.
      Gravity perception mechanisms of plants are also explained.

PMID- 12402925
TI  - Prevention and cure of type 2 diabetes. Let's move upstream to obesogenic
      environments, please.

PMID- 12402926
TI  - Discontinuation of thioridazine. What happened to thioridazine?

PMID- 12402927
TI  - The global response to mental illness. Focus on mental health means new
      opportunities for developing countries.

PMID- 12402928
TI  - Temple healing. Spiritual care is important.

PMID- 12402929
TI  - Glimepiride--well tolerated in daily practice.

PMID- 12402930
TI  - Reducing dementia and cognitive decline in stroke patients.

PMID- 12402931
TI  - EC approves irbesartan for the treatment of diabetic renal disease.

PMID- 12402932
TI  - Cardiovascular risk reduction with pioglitazone.

PMID- 12402933
TI  - Early lytic treatment of massive pulmonary embolism.

PMID- 12402934
TI  - Case made for aggressive, early treatment of severe sepsis and septic shock.

PMID- 12402935
TI  - Having more ICU nurses saves money, study finds.

PMID- 12402936
TI  - Tool may help nursing homes avoid risky pneumonia hospitalizations.

PMID- 12402937
TI  - Counseling about anti-inflammatory drugs plays role in peptic ulcer disease
      outcomes, study reveals.

PMID- 12402938
TI  - Use of problematic drugs is still common among the elderly.

PMID- 12402939
TI  - [Birth control and mild therapies in Medieval Islam].
AB  - Birth control in Medieval Islam is usually permitted by tradition (hadith), by
      the ijma c and by theologists' opinion. In fact, there is no possibility of
      restraining God's will. The most common means of contraception is coitus
      interruptus, but it can not be used without the consent of free women. Birth
      control is not allowed under particular conditions. The paper deals with the
      acquisition and reject of Islamic medicine in Western Latin texts from 12th
      century.

PMID- 12402940
TI  - Physician specialty and experience influences asthma outcomes, study finds.

PMID- 12402941
TI  - Adherence to national asthma guidelines is poor among high-risk children, study
      says.

PMID- 12402942
TI  - Revised heart failure guidelines use new classification scheme aimed at
      prevention.

PMID- 12402943
TI  - [Virility examined: andrology between gynaecology and sexual hygiene in a
      physician of the XVI century].
AB  - The paper examines ideas, representations and descriptions of male physiology and
      pathology in a text written by the physician Giovanni Marinello and published in
      Venice in 1536. Marinello's successful work, written in Italian and entirely
      devoted to gynaecological problems, is a short guide for women interested in
      their own health and in the sexual hygiene of their marriages. Tracing a short
      history of female diseases, the book offers also interesting issues of
      andrological interest.

PMID- 12402944
TI  - How safe is that burger?
AB  - We tested ground beef from across the U.S. for bacteria, spoilage, and fat
      content. Although most samples were OK, there are gaps in the safety net that
      could leave you vulnerable.

PMID- 12402945
TI  - [Succcus nerveus and succus seminalis in Borelli's living machine].
AB  - Analogy between testicles and brain is an ancient one, and it has often taken the
      form of an analogy between semen and 'succus nerveus' (a liquid substance
      produced by the brain and circulating in the nerves). The paper deals with an
      Early Modern version of the analogy, outlined by Giovanni Alfonso Borelli in his
      De motu animalium (1680-81). Elements from the medical tradition of Antiquity and
      Renaissance can be traced in Borelli's system, together with the effort towards
      the creation of a mechanico-chemical model of the machine of the living organism.
      Nervous and seminal fluids are supposed to animate and perfect the machine.

PMID- 12402946
TI  - Isolation and characterization of an infectious HIV type 1 molecular clone from a
      patient with primary infection.
AB  - We isolated a subtype B infectious DNA clone of human immunodeficiency virus type
      1 (HIV-1) from a seronegative patient with acute infection and determined the
      entire nucleotide sequence. All the reading frames encoding the structural
      proteins (Gag, Pol, and Env) and nonstructural proteins (Tat, Rev, Vpr, Vif, and
      Nef) were found. Although moat functional domains in these proteins were
      conserved, we identified a duplication of the T cell factor lei (TCF-1alpha)
      element in the long terminal repeat and many variations in the N-linked
      glycosylation sites in the V4-V5 region but not in the V1-V3 loop of Env,
      compared with prototype subtype B clones. Furthermore, phylogenetic analysis of
      the entire nucleotide sequence indicated that this HIV-1 was distinct from the
      prototype subtype B clones, suggesting that transmitted viruses can be variants.
      This HIV-1 DNA done will be a useful prototype for investigating the mechanism of
      HIV-1 transmission.

PMID- 12402947
TI  - [In venerem ignavus: medicine, impotence and law in modern age].
AB  - Surgical and forensic medical texts of modern age classifies male impotence
      according to two different patterns. If both psychological and functional causes
      can be admitted as responsible of male disfunctions, physical deficiencies only
      can be regarded as legal reason to obtain divorce.

PMID- 12402948
TI  - Precise mapping of recombination breakpoints suggests a common parent of two BC
      recombinant HIV type 1 strains circulating in China.
AB  - Two different BC recombinant HIV-1 strains have arisen and begun to circulate
      among intravenous drug users in China. The recombinants are mostly subtype C with
      a few small subtype B segments. Additional full-genome sequences of the two
      recombinants, termed CRF07_BC and CRFO&_BC, are now available for analysis. Four
      CRF07_BC strains, including c54, 97CNU01, 98CN009, and a new strain CNGL-179,
      described here, and four CRF08_BC strains, including 97CNGX-6, 97CNGX-7, 97CNGX
      9, and 98CN006, were compared for their recombination breakpoints by bootscanning
      and software for fine mapping of recombinants. The four CRF07_BC strains shared
      an identical recombination structure and the four CRF08_BC strains shared an
      identical, but different, recombination structure. The two CRFs share five
      precise subtype B/C boundaries, although although other segments differ between
      them, suggesting that they shared a common ancestor, itself a BC recombinant that
      separately "back-crossed" onto different subtype C strains. Both CRFs are broadly
      distributed from north to south in western China and have maintained low
      interpatient diversity.

PMID- 12402949
TI  - [The male sexual organs in the human bodies embalming].
AB  - The embalming of male sexual organs follows the development of anatomical and
      physiological discoveries and the consequent new systems of the art of embalming.

PMID- 12402950
TI  - A five-residue HIV envelope helper T cell determinant: does this peptide-MHC
      interaction leave the binding groove half empty?
AB  - High-resolution structures have revealed major pockets in the MHC class II
      peptide binding groove within a region designated Pl-P9. The region can
      accommodate 9-mer peptides, consistent with the observation that minimal core
      helper T (Th) cell determinants are usually eight or nine residues in size. Here
      we describe mouse Th cell hybridomas that are specific for a core peptide of only
      five residues (NPIIL) in the HIV envelope glycoprotein. Effective Th cell
      stimulation requires that these MHC class II Ia(b)-presented peptides contain
      amino acids flanking the minimal pentamer, but the flanking residues may be
      located on either the N or C terminus. To explain these findings, we suggest that
      mini-Th cell epitopes may effectively associate with MHC when only five (or
      possibly fewer) of the P1-P9 positions are filled. The remaining positions may be
      empty, or may be associated with a second, perhaps unrelated, peptide moiety.

PMID- 12402951
TI  - Transforming the testicle: science, medicine and masculinity, 1800-1950.
AB  - The article explores episodes the history of the discovery of function and
      actions of testicle - focusing first on their transformation from a quasi -
      mystical organ of virility to chemical factory secreting substances essential to
      physical and psychological attributes of masculinity; then showing how the powers
      of the testicular secretions were soon seen to extend for beyond the narrowly
      sexual sphere.

PMID- 12402952
TI  - First report of CRF03_AB recombinant HIV type 1 in injecting drug users in
      Ukraine.
AB  - It has been reported that subtypes A throughout H of HIV-1 are circulating in the
      former Soviet Union. In this sequence note, we analyzed the genetic prevalence of
      HIV-1 among injecting drug users (IDUs) in Ukraine. The subjects studied included
      two individuals from Kiev and six individuals from Simferopol', the latter
      located in the Crimean Peninsula. We found that one of eight IDUs was infected
      with a CRF03 gagA/envB recombinant HIV-1 and was from Simferopol', whereas the
      others were infected with HIV-1 subtype A. There combinant was closely related to
      other A/B recombinants reported previously, and had silent mutations Inthe V3
      region, the same as other envB strains of HIV-1 circulating among mDUs in the
      former Soviet Union. The data supported reports that the Russian AIB recombinant
      HIV-1 was probably from Ukraine. This is the first report of a CRF03 gagA/envB
      recombinant HIV-1 found in Ukraine.

PMID- 12402953
TI  - Characterization of pol, vif, vpr, and vpu genes of HIV type 1 in AIDS patients
      with high viral load and stable CD4+ T cell counts on combination therapy.
AB  - The success of combination therapy has also led to AIDS patients who exhibit
      elevated viral load without a corresponding decline in CD4+ T cells. In this
      study, we characterized changes in the pol gene and accessory genes vif, vpr, and
      vpu of HIV-1 isolated from the plasma of patients receiving highly active
      antiretroviral therapy. From each patient three sequences were obtained and
      compared with the sequence of HIV-1 from nontreated patients, revealing many
      substitutions that were similar in most cases. Protease and reverse transcriptase
      genes showed many mutations that were due to antiviral drugs. Premature
      termination was observed in the vif gene of one patient, leading to a protein
      truncated after 187 amino acids. In another patient the entire vpr open reading
      frame was missing, with no synthesis of Vpu protein because the 5' end of the
      gene was missing, including the start codon. In the same patient, the Vif protein
      was also truncated because of the deletion of 100 nucleotides at the 3' end of
      the vif gene.

PMID- 12402954
TI  - [Bioethics and andrology].
AB  - In the present article the Author examines the relationship between Andrology and
      Bioethics. He takes into consideration the historical context in which the two
      new disciplines were born. They are practically coeval, being both come to the
      light about at the 60th years of XXth Century. He analyses the clinical problems
      of the sexuality and some diagnostic and therapeutic potentialities of the
      Andrology in connection with the implications of moral order. After synthetically
      outlining the most diffuse Bioethics' theories, and later outlining a scheme of
      methodological approach, he reaches the conclusions inclining for a personalist
      vision of the moral problems and he is wishing a theoretical and practical
      attitude by Andrology specialist doctor in conformity with virtues' ethics.

PMID- 12402956
TI  - Opening speech of the 11th Stockholm Water Symposium.

PMID- 12402955
TI  - Molecular analysis in support of an investigation of a cluster of HIV-1-infected
      women.
AB  - An investigation of a possible single-source sexual transmission case was
      conducted in upstate New York in 1997-1998 (MMWR 1999;48:413-416). Of 42 primary
      female contacts with the putative male index case, 13 tested positive for HIV
      infection. Blood was available for DNA sequencing (C2V3C3 region of the env gene
      and the p17-coding region of gag) from 10 of the 13 women, 1 HIV-infected
      secondary contact, and 2 HIV-infected persons from the community, but not from
      the index cam. Phylogenetic and distance analyses were performed with the
      inclusion of reference HIV subtype strains for both the env and gag gene regions,
      as was the two regions combined. A high degree of relatedness was found among DNA
      sequences of the 10 primary contacts that excluded reference strains, the
      secondary contact, and the community HIV control subjects. In conclusion,
      phylogenetic analysis of HIV strains in an epidemiologic investigation is highly
      useful in support of cluster identification, even without sampling from the
      putative index patient.

PMID- 12402958
TI  - Opening address of the 11th Stockholm Water Symposium.

PMID- 12402957
TI  - HIV type 1 strains from East and West Africa are intermixed in Sudan.
AB  - The genetic subtypes of HIV-1 in the Sudan epidemic have not been characterized.
      Here we report the partial sequencing and analysis of 30 strains collected from
      HIV-1-positive patients and blood donors in Khartoum in 1998 and 1999. From
      analysis of partial pol and env sequences, it was determined that 50% were
      subtype D and 30% were subtype C. Of interest, some subtype D clustered with
      those from East Africa whereas others joined subtype D from West Africa. Subtype
      A, subtype B, and three unique recombinants were also found, some partially
      unclassifiable. One unclassified strain matched another reported previously from
      the Democratic Republic of Congo. Sudan borders nine other African countries, and
      has suffered more than 20 years of civil strife with large population
      displacements. The intermixing of HIV-1 subtypes previously separated in Africa
      may be occurring there, with the potential to generate novel new strains by
      recombination.

PMID- 12402959
TI  - Future water policy for the European Union.

PMID- 12402960
TI  - [ARS mingendi cum instrumentis, probes: candelette, minugie, catheters].
AB  - The Museum of History of Medicine of the University of Rome "La Sapienza" has a
      rich collection of probes and metal catheters, some of which in surgical kits.
      Tracing the history of catheters, the authors follow the technical evolution in
      the field of urology techniques, also highlighting the intelligent craft of
      artisans, surgeons, barbers - and the industrial effort to ameliorate techniques.
      The use and the crafting of these instruments are to be related to new knowledge
      in the fields of urethral, vesical and prostatic occlusion. Italian contribution
      of the field is stressed, highlighting the original experience of Michele Troja,
      who invented and diffused metal catheters covered in caouthouc.

PMID- 12402961
TI  - Global compact to leverage world development.

PMID- 12402962
TI  - An end to national science: the meaning and the extension of local knowledge.

PMID- 12402963
TI  - Experimental animal behaviour studies: the loss of initiative in Britain 100
      years ago.

PMID- 12402964
TI  - [Dextromethorphane intoxication under co-medication with cytochrome P450
      inhibitor fluoxetin: prolonged and accentuated signs of intoxication].

PMID- 12402965
TI  - [Development of a opioid dependence in a not diagnosed restless legs syndrome].

PMID- 12402966
TI  - Infant formula supplemented with probiotics or prebiotics: never, now, or
      someday?

PMID- 12402967
TI  - Improving the status of clinical trials in pediatric gastrointestinal diseases.

PMID- 12402968
TI  - My father and his teachers.

PMID- 12402969
TI  - Hashimoto's disease and Dr. Hakaru Hashimoto.

PMID- 12402970
TI  - The heritage of Dr. Hakaru Hashimoto (1881-1934).

PMID- 12402972
TI  - Differences in leptin production by regional fat mass in postmenopausal women.
AB  - To investigate the differences in leptin production by regional fat mass, 76
      postmenopausal Japanese women were enrolled in this study. Age, height, weight,
      and body mass index (BMI, wt/ht2) were recorded. Serum leptin levels were
      measured by RIA. Trunk fat mass, total body fat mass, and percentage of body fat
      were measured by dual-energy x-ray absorptiometry (DEXA). The ratio of trunk to
      leg fat mass (trunk-leg fat ratio), an index of body fat distribution, was also
      assessed by DEXA. Relationship of leptin levels with baseline characteristics and
      anthropometric variables were investigated by Pearson correlation test. Serum
      leptin levels were positively correlated with BMI (r = 0.683, p < 0.0001), total
      body fat mass (r = 0.680, p < 0.0001), trunk fat mass (r = 0.632, p < 0.0001),
      and percentage of body fat (r = 0.624, p < 0.0001). However, no significant
      correlation was observed between trunk-leg fat ratio and leptin levels (r =
      0.181). Age and height were not correlated with leptin levels. Based on these
      results, we concluded that body fat distribution does not serve as a predictor of
      leptin levels in postmenopausal women.

PMID- 12402971
TI  - Metyrapone-induced corticosterone deficiency impairs glucose oxidation and
      steroidogenesis in Leydig cells of adult albino rats.
AB  - The present study was designed to identify the effects of metyrapone-induced
      corticosterone deficiency on Leydig cell steroidogenesis in adult male rats.
      Adult Wistar rats (200-250 g body weight) were treated with metyrapone, an
      inhibitor of corticosterone synthesis (10 mg/100 g body weight, s.c., twice
      daily) for 10 days. Experimental animals were killed along with controls, blood
      was collected, and sera separated for testosterone and estradiol assays. Testes
      were removed and Leydig cells were isolated, purified and used for estimating the
      specific activity of 17beta-hydroxysteroid dehydrogenase (17beta-HSD) and 14C
      glucose oxidation. Serum testosterone (p < 0.05), Leydig cellular 14C-glucose
      oxidation (p < 0.001) and the specific activity of 17beta-HSD (p < 0.01) were
      significantly decreased in metyrapone treated rats. However, serum estradiol was
      not markedly altered compared to control. In addition to this, a set of in vitro
      experiments were also performed to identify the effects of metyrapone-induced
      corticosterone deficiency on hCG and prolactin-induced Leydig cell testosterone
      production. Metyrapone treatment significantly (p < 0.05) decreased the Leydig
      cellular basal as well as hCG and its combination with prolactin stimulated
      testosterone production in vitro. It is concluded from the present study that the
      inhibitory effects of metyrapone-induced corticosterone deficiency on Leydig cell
      steroidogenesis are mediated through impaired glucose oxidation and 17beta-HSD
      activity. In vitro studies showed that corticosterone deficiency impairs not only
      hCG action but also the potentiating effect of prolactin on Leydig cell
      steroidogenesis.

PMID- 12402973
TI  - Is leptin a key factor which develops obesity by ovariectomy?
AB  - Withdrawal of estrogen by ovariectomy increases adiposity, but decreases the
      circulating levels of the ob gene product, leptin, which inhibits food intake.
      The reduction of circulating leptin levels may thus play an important role in the
      induction of obesity by ovariectomy. To examine this hypothesis, body weight
      change by ovariectomy was investigated in leptin-deficient genetically obese
      (ob/ob) mice with leptin supplement. Prior to the operation, obese (ob/ob) female
      mice were treated with intraperitoneal administration of recombinant mouse leptin
      (1.0 microg/g body weight/day) for 8 days. Then, half of the leptin-treated mice
      and their lean littermates were bilaterally ovariectomized and their body weight
      changes were observed for 56 days. From 16 days after the operation, a
      significant increase in body weight by ovariectomy was observed only in lean mice
      without leptin treatment. From 44 days, a significant body weight gain by
      ovariectomy was observed in leptin-treated obese mice. Ovariectomy significantly
      increased retroperitoneal white adipose tissue weight in their lean littermates,
      but not in leptin-treated obese mice. It was suggested that the reduction of
      circulating leptin levels may play an important role in the increases of acute
      phase body weight gain by ovariectomy, but during static phase, the direct
      effects of estrogen withdrawal may appear independent of leptin-mediated effects.

PMID- 12402974
TI  - A kindred of familial acromegaly without evidence for linkage to MEN-1 locus.
AB  - Familial acromegaly (FA) is a rare inherited disease characterized by clustering
      of somatotrophic adenomas and acromegaly within a family without other
      manifestations of multiple endocrine neoplasia-type 1 (MEN-1). The genetic basis
      of this pituitary-specific phenotype is largely unknown, and its relationship to
      the MEN-1 locus on chromosome 11q13 also remains unclear. To test the hypothesis
      that FA results from a germline mutation of the MEN-1 locus, we performed a
      linkage analysis in a Japanese family with 2 members showing manifestations of
      acromegaly due to somatotroph adenomas. We also examined the adenoma of one
      patient for loss of heterozygosity (LOH) at 11q13 locus and for the presence of
      mutations of codon 201 and 227 in the gene for Gsalpha. Our results provided no
      evidence that either germline alterations of the MEN-1 locus, LOH at 11q13, or
      somatic mutation of Gsalpha plays a causative role in the development of
      somatotroph adenomas in our FA family. Together with the previous reports, these
      results suggest that there are at least two distinct subgroups of FA: one that
      results from a mutation in MEN-1 locus and the other whose causative gene is
      located outside the 11q13 locus.

PMID- 12402975
TI  - Association of vitamin D receptor gene polymorphism with renal cell carcinoma in
      Japanese.
AB  - Molecular epidemiologic studies have reported a relationship between 1alpha,25
      dihydroxyvitamin D3 (1,25(OH)2D3) and the development and progression of
      malignant tumors. (1,25(OH)2D3) exerts its biological activity by binding the
      vitamin D receptor (VDR), while recent studies have demonstrated that VDR gene
      polymorphisms affect serum levels of (1,25(OH)2D3). Serum levels of (1,25(OH)2D3)
      are reported to be significantly lower in patients with renal cell carcinoma
      (RCC) compared to non-cancer control patients. The purpose of this study was to
      investigate the TaqI VDR polymorphism in Japanese RCC patients and non-cancer
      controls in order to determine if an association exists between VDR genotype and
      the risk of developing RCC as well as clinical risk factors. A total of 102 RCC
      patients and 204 controls were genotyped for a previously described TaqI
      restriction fragment length polymorphism (RFLP) of the VDR gene. Products were
      digested into T allele or the t allele according to the absence or presence of a
      TaqI restriction site. Individuals were classified as TT, Tt or tt. The genotype
      TT was statistically more frequent among RCC patients (80.4%) compared to
      controls (61.8%) (OR = 2.54; 95% CI, 1.44-4.46; p = 0.0006). In addition, the
      occurrence of the genotype TT was significantly higher in patients with rapid
      growth-type group (92.1%) compared to slow-growth-type group (73.4%) (OR = 4.22;
      95% CI, 1.15-15.53; p = 0.0175). These data demonstrate that VDR genotype plays
      an important role in determining the risk of developing more aggressive RCC in
      Japanese.

PMID- 12402976
TI  - Clonal endothelial cells produce humoral factors that inhibit osteoclast-like
      cell formation in vitro.
AB  - Angiogenesis and bone remodeling are closely associated, and vascular endothelial
      cells may have potential roles for osteoclastic bone resorption. We examined
      whether clonal endothelial cells established from bone, aorta and brain of Balb/c
      mice influenced osteoclast-like cell formation in vitro. As low as 1% conditioned
      media of those endothelial cells inhibited osteoclast-like cell formation in bone
      marrow cultures induced by 1,25-dihydroxyvitamin D3, and did so in spleen cell
      cultures in the presence of soluble receptor activator of nuclear factor-kappaB
      ligand (RANKL), M-CSF and prostaglandin E2. The level of osteoprotegerin (OPG), a
      decoy receptor for RANKL, secreted by endothelial cells was not high enough to
      inhibit osteoclastogenesis. These observations suggest that endothelial cells
      derived from various tissues secrete factor(s) that inhibits precursors to
      differentiate into osteoclasts even in the presence of optimal stimulators for
      osteoclastogenesis. Hence, endothelial cells in bone may inhibit recruitment of
      fresh osteoclasts, and those in tissues other than bone may be involved in
      prohibiting ectopic osteoclastogenesis.

PMID- 12402977
TI  - New analytical method for pancreas and liver regeneration: normalization of
      streptozotocin-induced hyperglycemia by retrograde injection of insulin producing
      cells.
AB  - We established a new analytical system in which functioning cells were
      transplanted directly into the pancreas and liver. The retrograde transplantation
      of beta cell line, Min6 cells, into the streptozotocin-diabetic mice normalized
      plasma glucose and insulin levels. The injected cells were protected from
      pancreatic enzymes with enzyme inhibitor. Blood glucose decreased gradually over
      10 days and the diabetic mice recovered weight at the same time. Intraperitoneal
      glucose tolerance test showed that the peak of plasma glucose of the transplanted
      mice was less than half that of the control. The insulin secretion of the
      transplanted mice was recovered and stimulated 4.6 times from the basal
      secretion. Histological analyses showed that the pancreas and liver were
      characterized by Min6 cell clusters dispersed throughout the organs. Min6 cells
      were detected near the pancreatic or bile ducts. It is suggested that the
      injected cells obstructed the peripheral ducts where they settled. The weight of
      pancreas and liver did not differ significantly in either Min6 transplanted or
      the control mice. The metabolic effects on the weights of these organs appeared
      the same in both groups. This is the first report that cells transplanted via
      ducts into the pancreas and liver performed their biological function. Our
      transplantation model makes possible the in vivo analysis of the regeneration
      machinery of the pancreas and liver.

PMID- 12402978
TI  - Relationship between visceral fat accumulation and anti-lipolytic action of
      insulin in patients with type 2 diabetes mellitus.
AB  - Insulin resistance is closely related to developing type 2 diabetes mellitus.
      Visceral fat accumulation is associated with insulin resistance, which affects
      the free fatty acid (FFA) metabolism. We investigated the interactions among
      visceral fat accumulation, FFA metabolism and insulin resistance in 20 patients
      with type 2 diabetes mellitus, including 11 obese and 9 non-obese subjects. Body
      fat distribution was estimated by measuring the areas of both subcutaneous and
      visceral fat mass on abdominal computed tomography at the umbilical level.
      Glucose infusion rate (GIR) and plasma FFA responses to insulin were determined
      as an index of insulin resistance and anti-lipolytic action, respectively, in a
      euglycemic hyperinsulinemic clamp study. There was an inverse correlation between
      GIR and insulin-induced decrease in plasma FFA in all diabetic patients (r = 
      0.652, P < 0.01). Visceral fat mass area was well correlated with GIR (r = 
      0.583, P < 0.01) and insulin-induced decrease in plasma FFA (r = 0.724, P <
      0.001), whereas subcutaneous fat mass area was not correlated either with GIR or
      plasma FFA decrease. These findings suggest that visceral fat accumulation
      results in increasing the resistance against the anti-lipolytic action of
      insulin, and that FFA metabolism is closely related with glucose utilization in
      patients with type 2 diabetes mellitus.

PMID- 12402979
TI  - The activity of bisphenol A depends on both the estrogen receptor subtype and the
      cell type.
AB  - Bisphenol A (BPA), a monomer of plastic used in consumer products, is abundant in
      the environment and enters the body by ingestion or adsorption. In order to
      characterize the estrogenic effect of BPA, we performed luciferase assay on three
      independent cell lines derived from different tissues transfected with either
      human ERalpha cDNA or ERbeta cDNA. The estrogenic activities of BPA were
      detectable in all cell lines via both ERalpha and ERbeta. In 293T cells and Hec-1
      cells, the estrogenic activities were significantly decreased when cells
      expressing ERalpha were incubated with 10(-6) M BPA in the presence of 10(-8) M
      17beta-estradiol (E2) while the activities via ERbeta were essentially unchanged
      in the same conditions. Interestingly, no reduction of estrogenic activity was
      detected in HOS-TE85 cells via either ERalpha or ERbeta. Our results indicate
      that BPA only acts as an agonist of estrogen via ERbeta whereas it has dual
      actions as an agonist and antagonist in some types of cells via ERalpha. Thus,
      the activity of BPA may depend on the ER subtype and the tissue involved.

PMID- 12402980
TI  - Progesterone receptor mRNA variant containing novel exon insertions between exon
      4 and exon 5 in human uterine endometrium.
AB  - The presence of human progesterone receptor (PR) mRNA variants has been
      demonstrated in uterine endometrium and breast tissues as well as in cancer cells
      of these tissues. While exon deletions by the alternative splicing in these
      variants have been reported, there are few reports available on the PR mRNA
      variants with exon insertion. In the present study, we attempted to detect a PR
      mRNA variant containing the exon insertions in normal uterine endometrium.
      Endometrial tissues were subjected to reverse transcription-polymerase chain
      reaction (RT-PCR) with PCR primers which were located in exons 3 and 8. Analysis
      of the RT-PCR products revealed the presence of a novel PR mRNA variant which
      contained a 232 bp inserted nucleotide sequence between exons 4 and 5. We termed
      this transcript the "i45 PR mRNA variant". Genomic analysis indicated that the
      inserted sequence was derived from two novel independent exons of 123 bp and 109
      bp, termed "exon i45a" and "exon i45b", respectively, which are located between
      exons 4 and 5 of the human PR gene. The i45 PR mRNA variant was further detected
      in uterine endometrial cancer tissues as well as in the normal uterine
      endometrium. These results demonstrate the presence of a novel PR mRNA variant
      with exon insertions in the human tissue for the first time. The i45 PR variant
      protein, possibly transcribed from this i45 PR mRNA variant, may play
      physiological and/or pathological roles in the human uterine endometrium.

PMID- 12402981
TI  - Cell-to-Cell adhesion via intercellular adhesion molecule-1 and leukocyte
      function-associated antigen-1 pathway is involved in 1alpha,25(OH)2D3, PTH and IL
      1alpha-induced osteoclast differentiation and bone resorption.
AB  - Cell-to-cell interaction is required for the differentiation of osteoclast
      precursors as well as for osteoclast function. The present study was undertaken
      to determine whether 1,25 dihydroxyvitamin D3 (1,25D), PTH, IL-1alpha and PGE2
      depend on cell-to-cell interactions through the intercellular adhesion molecule
      (ICAM)-1/leukocyte function-associated antigen (LFA)-1 pathway in osteoclast
      formation and bone resorption. We found that mouse osteoblasts expressed ICAM-1
      and that the expression was increased by treatment with PTH, IL-1alpha or 1,25D,
      but not by PGE2. In resorption assays measuring either 45Ca release from bone
      organ cultures or pit formation in bone cell cultures, 1,25D-, PTH- and IL-1alpha
      stimulated resorption was inhibited by anti-ICAM-1 monoclonal antibody (mAb)
      and/or anti-LFA-1 mAb, while basal and PGE2-stimulated bone resorbing activities
      were not affected by these mAbs. Furthermore, in a mouse bone marrow culture
      system, stimulation of osteoclast-like (OCL) cell formation by 1,25D (10 nM), PTH
      (10 ng/ml) or IL-1alpha (10 ng/ml) was inhibited by the addition of anti-ICAM-1
      mAb and/or anti-LFA-1 mAb. In a coculture system of murine spleen cells and
      osteoblasts, the ICAM-1/LFA-1 interaction was also involved in 1,25D-, PTH- and
      IL-1alpha-stimulated TRAP-positive MNC formation. However, anti-ICAM-1 mAb and
      anti-LFA-1 mAb did not alter either 1,25D- or PTH-stimulated receptor activator
      of NF-kappaB ligand (RANKL) mRNA transcription in bone marrow cultures. Taken
      together, we here propose that ICAM-1-mediated cell-to-cell adhesion of
      osteoblasts and osteoclast precursors is involved in RANKL-dependent osteoclast
      maturation stimulated by 1,25D, PTH, and IL-1alpha.

PMID- 12402982
TI  - Monozygotic twins with discordant sexual phenotypes due to different ratios of
      mosaicism of 47,X,idic(Y),idic(Y)/46,X, idic(Y)/45,X.
AB  - We report monozygotic twins of different sexual phenotypes. One of the twins had
      complete female external genitalia except for a mild clitoromegaly. She had
      bilateral gonads consisting of the wavy stroma and scant dysgenetic seminiferous
      tubules. No androgen secretion was induced by gonadotrophin stimulation. The
      other twin had hypospadiac male genitalia. His gonads were located intrascrotally
      and he had good androgenic response to a stimulation test. Conventional and
      fluorescence in situ hybridization chromosome analysis disclosed that both twins
      had a 47,X,idic(Y),idic(Y)/46,X,idic(Y)/45,X and 47,X, + mar x 2.ish
      idic(Y)(q11.2)(DYZ3++ x 2)/46,X, + mar.ish idic(Y)(q11.2)(DZY3++)/45,X. These
      twins were clinically monochorionic and allelotype analysis in these twins and
      their parents with microsatellite markers showed the affirmative probability of
      0.999999994 for monozygosity. The ratio of mosaicism, gonadal histology, and
      testosterone productivity were reasonably correlated to the genital virilization
      in these monozygotic twins, showing discordant sexual phenotypes.

PMID- 12402983
TI  - Body fat distribution and cardiovascular disease risk factors in pre- and
      postmenopausal obese women with similar BMI.
AB  - The aim of this study is to determine the body fat distribution and
      cardiovascular disease risk factors in pre- and postmenopausal obese women
      matched for weight, height and body mass index (BMI). Study group consisted of
      405 premenopausal overweight/obese (BMI > 27 kg/m2, mean 37.83 +/- 6.91 kg/m2)
      and 405 postmenopausal overweight/obese (BMI > 27 kg/m2), BMI-matched (mean 37.77
      +/- 6.84 kg/m2) women. None of the women were on hormone replacement therapy.
      Insulin resistance was evaluated by "homeostasis model assessment" (HOMA)
      formula. Intraabdominal fat volume was calculated according to the following
      formula: IAF (L) = [(0.370 x abdominal sagittal diameter) - 4.85]. Age, waist
      circumference, waist to hip ratio (WHR) and intraabdominal fat volume were
      significantly higher in postmenopausals compared with BMI-matched premenopausal
      women (p < 0.001). Systolic and diastolic blood pressure, glucose, uric acid,
      cholesterol and triglyceride were significantly higher (p < 0.001) and HDL
      cholesterol was significantly lower (p < 0.05) in postmenopausals. No significant
      differences were observed with respect to insulin and HOMA. When age-matched pre-
      and postmenopausal women were compared, only total cholesterol was significantly
      higher in the postmenopausal group. However, older postmenopausal women (> 50
      years) had significantly higher systolic blood pressure, waist circumference,
      WHR, glucose and uric acid concentrations compared with younger (< or = 50 years)
      postmenopausals. It is concluded that an increase in abdominal fat accumulation
      and unfavorable alterations in risk factors disturb postmenopausal obese women
      even if total body weight and BMI do not change during menopause transition.
      Ageing, particularly throughout the postmenopausal years, has important effects
      on the detrimental changes associated with menopause.

PMID- 12402984
TI  - Quantitative analysis of osteonectin mRNA in thyroid carcinomas.
AB  - Our recent study of the gene expression profile in thyroid carcinoma showed an
      overexpression of osteonectin mRNA, an extracellular matrix protein, in an
      anaplastic carcinoma. To confirm this, we measured the expression levels of
      osteonectin mRNA in 84 thyroid normal and tumor tissues, including five
      anaplastic carcinomas by realtime quantitative reverse-transcription PCR.
      Increased expression of osteonectin mRNA was observed in anaplastic carcinoma
      tissue. However, in five anaplastic carcinoma cell lines, no increase was
      observed in the expression levels of osteonectin mRNA. These findings suggest the
      possibility that increased expression of osteonectin mRNA in anaplastic carcinoma
      tissue may be due to its overexpression in stromal cells, but not in anaplastic
      carcinoma cells.

PMID- 12402985
TI  - Contrast-enhanced endoscopic ultrasonography improves the preoperative
      localization of insulinomas.
AB  - We report a case in which endoscopic ultrasonography (EUS), intraductal
      ultrasonography (IDUS) and contrast-enhanced EUS using Levovist helped to
      localize insulinoma correctly. A 74-year-old woman complained of symptomatic
      fasting hypoglycemia with relatively high concentration of serum insulin level.
      Dynamic contrast-enhanced computed tomography revealed a small tumor of 8 mm
      diameter in the pancreatic head. Insulin secretion was strongly stimulated by
      calcium injection into the gastroduodenal artery. To clarify the precise
      localization, we performed EUS, IDUS and contrast-enhanced EUS. The tumor was
      enhanced clearly by Levovist, and the distance from the main pancreatic duct was
      more than 3 mm. Therefore, a preoperative decision could be made to use the
      enucleation method for resection of the tumor. The surgeon could enucleate the
      tumor in a brief operation according to the preoperative diagnosis, and serum
      glucose levels returned to normal range after the operation. Contrast-enhanced
      EUS using Levovist was shown to be a useful diagnostic method for precise
      localization of small insulinoma.

PMID- 12402986
TI  - Multiple endocrine disorders and Rathke's cleft cyst with Klinefelter's syndrome:
      a case report.
AB  - A 46-year-old Japanese male was admitted for the evaluation of severe
      hypertension. He was obese and had a eunuchoidal body habitus. Chromosomal
      analysis revealed a 46, XY/47, XXY karyotype. Serum LH, FSH and testosterone
      levels were low, indicating hypogonadotropic hypogonadism. Endocrinological
      dynamic tests disclosed presence of hypothalamic panhypopituitarism, partial
      diabetes insipidus, type 2 diabetes mellitus and low renin essential
      hypertension. Brain computed tomography and magnetic resonance imaging revealed
      intra- and extrasellar masses. Histological examination of the tissue obtained at
      transsphenoidal surgery showed a Rathke's cleft cyst (RCC). To the best of our
      knowledge, this is the first case report of mosaic Klinefelter's syndrome
      accompanied by symptomatic RCC, type 2 diabetes mellitus and low renin essential
      hypertension.

PMID- 12402987
TI  - Target organ damage: use of pulse wave analysis as a manifestation of aortic
      degeneration in the assessment of hypertension.

PMID- 12402988
TI  - Alterations in endothelial cell proliferation and apoptosis contribute to
      vascular remodeling following hind-limb ischemia in rabbits.
AB  - Hind-limb ischemia is a potent stimulus for angiogenesis. However, capillary
      density does not change in tibialis anterior muscle (TA) following hind-limb
      ischemia, despite increases in angiogenic growth factors. The objective of this
      study was to determine whether changes in proliferation and apoptosis occurred in
      the same muscle. In total, 19 New Zealand white rabbits underwent femoral artery
      ligation and excision and the ischemic and contra-lateral (control) TA muscles
      were harvested after 1 (n = 7), 5 (n = 7) and 21 (n= 5). Terminal
      deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) was used to
      detect apoptosis and double staining was used to identify the apoptotic cell
      types. Proliferation was assessed by immunohistochemistry for proliferating cell
      nuclear antigen (PCNA) and [3H]thymidine incorporation, in vitro. TUNEL positive
      nuclei were greater in ischemic than control muscle at 1 day (1.83 +/- 0.70% vs
      1.03 +/- 0.20%), 5 days (2.13 +/- 0.50% vs 1.21 +/- 0.42%) and at 21 days the
      difference was statistically significant (3.42 +/- 0.80% vs 0.96 +/- 0.40%, p <
      0.01). The majority of TUNEL positive nuclei were endothelial (Tie2 positive)
      cells. The number of PCNA positive cells in ischemic versus control muscle was
      similar at 1 day (0.71 +/- 0.20% vs 0.53 +/- 0.20%) and 5 days (1.28 +/- 0.30% vs
      0.77 +/- 0.30%), but was significantly (p < 0.05) reduced in ischemic muscle at
      21 days (0.18 +/- 0.20% vs 1.35 +/- 0.30%) with no difference in [3H]thymidine
      incorporation. Directionally opposite changes in endothelial cell proliferation
      and apoptosis occur in TA muscle following hind-limb ischemia. Modulating
      apoptosis in ischemic skeletal muscle may present a novel therapeutic target in
      peripheral arterial disease.

PMID- 12402989
TI  - Laboratory thrombophilias and venous thromboembolism.
AB  - Inherited abnormalities of coagulation are increasingly recognized in patients
      with venous thromboembolism. Common causes of hypercoagulability, also known as
      thrombophilia, include factor V Leiden, the prothrombin gene mutation,
      hyperhomocysteinemia, and antiphospholipid antibodies. Thrombophilia should be
      suspected in patients who develop idiopathic venous thromboembolism at a young
      age, recurrent thrombosis, thromboses at unusual sites, recurrent unexplained
      pregnancy loss, or if there is a family history of thrombotic disorders. The most
      cost-effective approach is to initially screen for factor V Leiden, the
      prothrombin gene mutation, hyperhomocysteinemia, and antiphospholipid antibodies
      because these are the most common defects causing thrombophilia. Long-term
      anticoagulation is controversial but should be considered if unprovoked venous
      thromboembolism recurs.

PMID- 12402990
TI  - Effect of cardiac cycle on ultrasound assessment of endothelial function.
AB  - To investigate the effects of non-ECG-triggered imaging during ultrasound studies
      of endothelial function, brachial artery diameters were measured throughout the
      cardiac cycle at rest, during reactive hyperemia, and after administration of
      nitroglycerin. R-wave-triggered imaging using a 7.5-MHz ultrasound transducer
      with acquisition every 41.7-66.7 ms was performed in 24 subjects. Cardiac cycle
      related variation was computed as the maximum per cent change from the end
      diastolic diameter. The range of possible errors in flow-mediated dilation (FMD)
      and nitroglycerin-mediated vasodilation that may result from ignoring cyclic
      variations in diameter was determined for each condition. True FMD, true
      nitroglycerin-mediated vasodilation, and the maximum and minimum values that
      could be erroneously calculated for FMD if timing was ignored all differed
      dramatically (p < 0.05). The range of apparent FMD values that could be measured
      was nearly three times the true FMD value. Ignoring temporal position within the
      cardiac cycle artifactually increased calculated FMD into the normal range,
      despite truly impaired FMD. Peak arterial dilation occurred before end-systole
      and greater baseline vessel compliance was associated with greater FMD. Brachial
      arterial diameters vary significantly throughout the cardiac cycle. The magnitude
      of this variation is similar to the arterial dilation induced by reactive
      hyperemia and nitroglycerin, making ECG-triggered imaging mandatory for accurate
      and reproducible clinical and research measurements of artery diameters and FMD.
      Measurement of diameters at end-diastole may be preferred to other time-points in
      the cardiac cycle.

PMID- 12402991
TI  - Physical training for intermittent claudication: a comparison of structured
      rehabilitation versus home-based training.
AB  - In a non-randomized, open-label study results after a structured institution
      based peripheral arterial occlusive disease (PAD) rehabilitation program were
      compared with the results of training at home. Three groups were compared: group
      1 (n = 19) PAD rehabilitation; group 2 (n = 19) PAD rehabilitation + clopidogrel
      75 mg once daily; group 3 (n = 21) home-based training. The training period was 3
      months for all groups, which was followed by a 3-month observation phase (without
      prescribed training). The rehabilitation program consisted of 3 training hours
      per week. Background variables, demographics, and baseline claudication distances
      were comparable between groups. After 3 months of training the absolute
      claudication distances (ACD) improved by 82.7%, 131.4%, and 5.4% for groups 1, 2
      and 3. The initial claudication distances (ICD) changed by 163.8%, 200.6%, and
      44.4%, respectively. All changes, except the ACD result for group 3, were
      statistically significant (p < or = 0.05). Structured training groups (1 and 2)
      performed significantly better than group 3 (p < or = 0.05). When results from
      groups 1 and 2 were pooled, ACDs changed from 493.3 +/- 218.1 to 1026.0 +/- 468.9
      m, delta 546.0 +/- 378.8 m [95% CI 417.8-674.2 ml; p < or = 0.05. ICDs improved
      from 175.3 +/- 110.8 m to 493.1 +/- 326.7 m, delta 320.8 +/- 315.9 m [95% CI
      213.9-427.7 m]; p < or = 0.05. The difference between the pooled mean results of
      the structured training groups and the results of group 3 amounted to 474.3 m
      [95% CI 270.2-678.4 m] and 242.4 m [95% CI 99.0-385.7 m], for ACD and ICD,
      respectively. Structured, supervised PAD rehabilitation is a highly efficacious
      treatment for intermittent claudication and may be regarded as the present gold
      standard among conservative treatment options.

PMID- 12402992
TI  - The role of matrix metalloproteinases in vascular disease.
AB  - There is growing interest in the role of matrix metalloproteinases in vascular
      diseases. These conditions are often characterized by excessive tissue
      remodelling, and increased matrix metalloproteinase activity has been
      demonstrated in aneurysms, intimal hyperplasia and atherosclerotic plaque
      disruption. These enzymes represent a potential target for therapeutic
      intervention to modify vascular pathology. The core of this review is derived
      from a MEDLINE database literature search. The review found that there is
      convincing evidence of increased matrix metalloproteinase activity in a spectrum
      of vascular disease. Evidence for an imbalance promoting increased matrix
      degradation is less well documented. However, studies of matrix metalloproteinase
      inhibition in vascular disease models suggest potential therapeutic benefit. In
      conclusion, in vivo studies of matrix metalloproteinase inhibition are required
      to further study the potential for reversal or deceleration of the excessive
      tissue remodelling that accompanies vascular disorders.

PMID- 12402993
TI  - Biointerventional cardiology: the future interface of interventional
      cardiovascular medicine and bioengineering.
AB  - Major advances in cardiovascular intervention for chronic disease are underway.
      These innovations lie at the interface of minimally invasive catheter-based
      technologies and biologic approaches for the management of complex cardiovascular
      diseases. This review highlights key areas where such 'biointerventional'
      cardiovascular therapies are envisioned to occur: cardiac cell transplantation,
      myocardial gene therapy, genetic and photodynamic endovascular interventions, and
      vascular tissue engineering.

PMID- 12402994
TI  - Intermittent pneumatic compression for the treatment of lower extremity arterial
      disease: a systematic review.
AB  - This study aimed to identify the role of intermittent pneumatic compression in
      treating peripheral arterial disease and to investigate the types of treatment
      programs that are most effective. Data was sourced from English-language articles
      which were identified by a computer search using MEDLINE from 1966 to 2001,
      followed by extensive bibliography review. Studies were included if they
      contained pertinent material involving a compression device and arterial flow
      dynamics in lower limbs. A total of 26 English-language studies were identified
      that met the inclusion criteria. The diverse patient criteria and methods used in
      the studies provided an opportunity to examine the effectiveness of each, but
      made it difficult to compare one study with another. To assist in focusing on
      overall trends in improvement, patient type and treatment type disparities must
      be identified. In conclusion, it is evident that an intermittent pneumatic
      compression program appears promising and may be used in patients with severe
      peripheral arterial disease who are not candidates for revascularization using
      surgery or percutaneous angioplasty. It is now the goal to establish randomized,
      prospective, controlled trials to clarify the most beneficial regimen for
      treating such disease.

PMID- 12402995
TI  - Presidential address. Vascular medicine and biology: an evolving infrastructure.

PMID- 12402996
TI  - Splenic artery aneurysm.

PMID- 12402998
TI  - Structural differences between desmosome-like contacts in afferent chemical and
      mixed synapses of Mauthner neurons in the goldfish.

PMID- 12402997
TI  - The histophysiology of neocortical basket cells.

PMID- 12402999
TI  - Dynamics of changes in operant reflexes in rats after transection of the
      corticospinal tract and removal of the sensorimotor region of the cerebral
      cortex.
AB  - Prior unilateral transection of the bulbar pyramid facilitated recovery of
      operant reflexes and compensatory processes occurring after removal of the
      ipsilateral sensorimotor cortex in rats. This increase in corticofugal plasticity
      was absent when only the sensorimotor cortex was removed. This phenomenon is
      explained by switching of descending influences to the corticorubrospinal system
      via the following loop: corticobulbar projection--red nucleus--lower olive-
      cerebellum--thalamus--cortex. A general property of this phenomenon is that prior
      lesioning of the peripheral part of the descending spinal projection acquires
      anticipatory signal value for mobilizing the compensatory abilities of the brain
      with the aim of recovering from the deficit of the central branch of the system.

PMID- 12403000
TI  - Assessment of disturbances in internal time counting and emotional behavior in
      rats with lesions to the striatum and hippocampus.
AB  - Bilateral electrolytic lesioning of the striatum led to a delay in the
      acquisition of a conditioned reflex to time, along with an anxiogenic effect and
      disturbances to the normal relationship between the level of anxiety and
      chronometric ability. These changes progressed with increases in the size of the
      destruction zone in the striatum. Combined surgery consisting of lesions to the
      striatum and hippocampus, like hippocampectomy alone, completely eliminated the
      ability to count time regardless of the size of brain lesions. The anxiogenic
      effect was greater in animaLs with combined procedures. Thus, the striatum and
      hippocampus are involved to different extents in the mechanism of internal time
      counting. The two structures function synergistically.

PMID- 12403001
TI  - Non-electrical functions of neurons.
AB  - Classical histological preparations of metasympathetic nervous system impregnated
      with silver salts were compared with the dynamics of the development of plexuses
      in cultures of isolated neurons and electron microscopic studies to investigate
      the non-electrical properties of neurons. Two modes of neurite contraction were
      demonstrated, along with a means of translocation of the neuron soma within
      neurites, and formation of tail processes and autotomy. It is hypothesized that
      nerve receptor endings have tissue trophic effects, with autoamputation of
      terminals with subsequent activation of their lysosomal proteases, which appear
      to be growth factors for surrounding tissues. The morphogenetic functions of
      neurocytes are analyzed and evidence is presented for the occurrence of constant
      reconstruction of previously formed plexuses in healthy adult animals.

PMID- 12403003
TI  - Stages of sleep after psychoemotional tension: the individual character of
      changes.
AB  - This report describes complex psychophysiological studies of nocturnal sleep in
      healthy humans in normal concentrations and after emotional tension. A series of
      contemporary methods was used: questionnaires, psychological tests, motor tests,
      and polysomnography with heart rate recording. These experiments showed that
      psychoemotional tension induced changes mainly in the structure of the first
      sleep cycle, decreasing the proportion of the second stage of slow sleep in total
      nocturnal sleep, led to a redistribution of delta sleep, increasing delta sleep
      in the second half of nocturnal sleep, and suppressed the mechanisms underlying
      the organization of the phases of rapid sleep. Psychoemotional tension affected
      human cerebrovisceral functions, for example inducing increases in the frequency
      and variability of the heart rhythm during nocturnal sleep. The nature of these
      changes in sleep structure and autonomic responses depended on the personality
      characteristics of the individual person. Thus, the individual approach to the
      question of psychoemotional stress in sleep disturbances is, we believe, the most
      appropriate.

PMID- 12403002
TI  - Peptidergic mechanisms of hyperthermia-evoked convulsions in rats in early
      postnatal ontogenesis.
AB  - This report addresses the verification of the hypothesis that arginine
      vasopressin affects the formation of hyperthermia-evoked convulsions in early
      ontogenesis in rats on days 3, 5, 7, and 9 of postnatal life. The modification of
      experimental febrile convulsions by PACAP (pituitary adenylate cyclase-activating
      peptide) was investigated; PACAP is a physiological regulator of the
      neurosecretion of arginine-vasopressin. Arginine-vasopressin (10 microg/rat) and
      PACAP (0.01 microg/rat) decreased the latency of generalized tonic-clonic
      convulsions and the time of truncal generalization of convulsive activity on days
      3 and 5 of rat development. Animals given arginine-vasopressin (0.1-10
      microg/rat) sowed significant increases in the duration of generalized
      convulsions to the level of status epilepticus on day 9 of life. Conversely,
      administration of higher doses of PACAP (0.1 microg/rat) increased the threshold
      of tonic-clonic convulsions on days 3 and 5 and decreased it on days 7 and 9 of
      postnatal development. The indirect involvement of PACAP in the mechanisms of
      experimental febrile convulsions is suggested to act via changes in arginine
      vasopressin neurosecretion.

PMID- 12403004
TI  - Histochemical and morphological changes in various regions of the rat hippocampus
      in swimming-induced stress.
AB  - Swimming stress increased the functional activity of hippocampal pyramidal
      neurons in rats, as indicated by decreases in their glycogen contents and
      increases in their nucleic acid contents and the nucleus:cytoplasm ratio. These
      changes were most marked in hippocampal field CA1, while changes in other regions
      of the hippocampus were minimal.

PMID- 12403005
TI  - Antigen-induced activation of hypothalamic cells (assessed by expression of the c
      fos gene).
AB  - The aim of the present work was to study the activation of the expression of the
      c-fos gene (by in situ hybridization) in cells from rat (Sprague Dawley)
      hypothalamic structures 0.5, 2, 6, and 16 h after i.v. injections of tetanus
      toxoid (200 microg/kg). Tetanus toxoid was selected as the antigen because it
      does not induce any general non-specific body reactions. Control animals received
      i.v. doses of apyrogenic physiological saline. The number of c-fos mRNA-positive
      cells in all the hypothalamic structures studied was insignificant 30 min after
      injections of tetanus toxoid. c-fos mRNA-positive cells were seen in the
      posterior, lateral, and anterior hypothalamic fields and in the dorsomedial and
      ventromedial hypothalamic nuclei 2 h after injections of tetanus toxoid. The
      intensity of c-fos mRNA expression decreased in the posterior, lateral, and
      anterior hypothalamic fields 6 h after injections of tetanus toxoid. The maximum
      number of c-fos mRNA-positive cells in the anterior field and the paraventricular
      nucleus of the hypothalamic induced by tetanus toxoid, as compared with reactions
      to administration of physiological saline, were seen at 6 h. Administration of
      tetanus toxoid and physiological saline did not active the synthesis of c-fos
      mRNA in the arcuate or supraoptic nuclei at any time point. The number of c-fos
      mRNA-positive cells returned to baseline by 16 h after tetanus toxoid injections.
      Thus, this study revealed the temporospatial pattern of activation of
      hypothalamic structures in response to exposure to an antigen.

PMID- 12403006
TI  - Involvement of the nucleus accumbens in stimulation of the immune response in
      rats after activation of opioid mu receptors with DAGO.
AB  - The involvement of the nucleus accumbens in neuroimmunostimulation was
      demonstrated during activation of opioid mu receptors with the selective agonist
      DAGO (100 microg/kg); single doses of this agent to sham-operated (control)
      Wistar rats induced significant increases in the numbers of direct IgM antibody
      forming and total rosette-forming cells after immunization with sheep
      erythrocytes. Bilateral electrolytic lesioning of the nucleus accumbens in rats
      led to sharp decreases in the intensity of immune responses; there was no
      immunostimulation after administration of DAGO to these animals. These data
      provide evidence for the involvement of the nucleus accumbens in the process of
      immunomodulation and for the importance of opioid mu receptors in the nucleus
      accumbens in the stimulation of immunogenesis.

PMID- 12403007
TI  - Long-term potentiation of the AMPA and NMDA components of minimal postsynaptic
      currents in rat hippocampal field Ca1.
AB  - The aim of the present work was to study the potentiation of the AMPA and NMDA
      components of minimal excitatory postsynaptic currents (EPSC) evoked by
      activation of restricted numbers of synapses. EPSC of neurons in field CA1 in
      hippocampal slices were recorded in whole-call patch-clamp conditions selected
      such that both (AMPA and NMDA) components were present, and these were measured
      in parallel using computational methods in combination with pharmacological
      receptor blockade. There was a quite strong correlation between the amplitudes of
      the AMPA and NMDA components and this was regarded as evidence that they were
      generated by the same synapses. In cases producing this correlation, both
      components showed essentially equal long-term potentiation lasting from 5 min to
      2 h after afferent tetanization. The data did not support the postsynaptic
      hypothesis and were in better agreement with the concept that the major mechanism
      for the persistence of the initial phase of long-term potentiation (up to 1-2 h)
      is based on increases in the quantity of transmitter released presynaptically.

PMID- 12403008
TI  - The leading role of mitochondrial depolarization in the mechanism of glutamate
      induced disruptions in Ca2+ homeostasis.
AB  - Data obtained in studies of the nature of the correlation which we have
      previously observed [10,17] between mitochondrial depolarization and the level of
      disruption of Ca2+ homeostasis in cultivated brain neuronsare summarized.
      Experiments were performed on cultured cerebellar granule cells loaded with Fura
      2-AM or rhodamine 123 to measure changes in cytoplasmic Ca2+ and mitochondrial
      potential during pathogenic treatments of the cells. Prolonged exposure to 100
      microM glutamate induced a reversible increase in [Ca2+]i, which was accompanied
      by only a small degree of mitochondrial depolarization. A sharp increase in this
      mitochondrial depolarization, induced by addition of 3 mM NaCN or 300 microM
      dinitrophenol (DNP) to the glutamate-containing solution, resulted in further
      increase in [Ca2+]i, due to blockade of electrophoretic mitochondrial Ca2+
      uptake. Prolonged exposure to CN- or DNP in the post-glutamate period maintained
      [Ca2+]i at a high level until the metabolic inhibitors were removed. In most
      cells, this plateau was characterized by low sensitivity to removal of external
      Ca2+, demonstrating that the mechanisms of Ca2+ release from neurons were
      disrupted. Addition of oligomycin, a blocker of mitochondrial ATP
      synthase/ATPase, to the solution containing glutamate and CN- or DNP eliminated
      the post-glutamate plateau. Parallel experiments with direct measurements of
      intracellular ATP levels ([ATP]) showed that profound mitochondrial
      depolarization induced by CN- or DNP sharply enhanced the drop in ATP due to
      glutamate, while oligomycin significantly weakened this effect of the metabolic
      inhibitors. Analysis of these data led to the conclusion that blockade of
      mitochondrial Ca2+ uptake and inhibition of ATP synthesis resulted from
      mitochondrial depolarization and plays a key role in the mechanism disrupting
      [Ca2+]i homeostasis after toxic exposure to glutamate.

PMID- 12403009
TI  - The effects of noradrenaline on the amplitude-time characteristics of
      multiquantum endplate currents and the kinetics of induced secretion of
      transmitter quanta.
AB  - Experiments on frog neuromuscular junctions using a two-electrode membrane
      potential clamping method were used to study the effects of noradrenaline on the
      amplitude-time characteristics of multiquantum endplate current (EPC) parameters
      and the time course of secretion of transmitter quanta during the process of EPC
      generation. Noradrenaline (10 microM) induced significant increases in EPC
      amplitude (by 16%), with a decrease in the ratio of the duration of the leading
      front of the EPC to the duration of the leading front of the miniature endplate
      current (mEPC). Analysis of the time course of induced secretion, based on
      sequential subtraction of signals with displacement on the time scale, showed
      that noradrenaline induced synchronization of the process of secretion of quanta
      involved in generating multiquantum EPC, resulting in a 25% decrease in parameter
      P90, which characterizes the extent of synchronization of quantum release. The
      quantum composition of EPC, measured by dividing the area of induced and
      spontaneous signals and by analysis of the time course of the secretion of
      quanta, showed no changes in response to noradrenaline. Thus, in conditions in
      which responses to single stimuli applied to the motor nerve results in the
      release of several tens of quanta, noradrenaline can lead to increases in the
      amplitude of multiquantum EPC by increasing the level of synchronization of
      secretion of the transmitter quanta forming this signal.

PMID- 12403010
TI  - Biodegradation of diesel fuel by an Azolla-derived bacterial consortium.
AB  - The widely distributed water fern Azolla was investigated for use as an amendment
      in the bioremediation of fuel-contaminated environments. In a field experiment
      Azolla pinnata as well as Pistia stratiotes and Salvinia molesta were applied to
      plots containing soil that had been surface-contaminated with diesel fuel (2.4 L
      m(-2)) and flooded with water. The plants quickly died and bacterial flocs
      developed around the dead A. pinnata fronds. After 16 weeks, diesel
      concentrations (as determined by levels of gas chromatography-detectable
      hydrocarbons) in the plant-added plots were less than half that of the control
      plot, and concentrations of xylenes and ethylbenzene were 50-100 times lower. In
      laboratory experiments, a consortium composed of A. pinnata-derived bacteria
      displayed dense growth in a 4% diesel-containing mineral salts medium and was
      found to lower the fluorescence from aromatic compounds by approximately 50%
      after 19d. It is concluded that the observed enhancement of diesel degradation in
      the plant-added plots was due to the release of bacteria (bioaugmentation) and
      physiochemical improvement of the plot conditions (biostimulation).

PMID- 12403012
TI  - Studies on fixed-bed biosorption and elution of copper using polyvinyl alcohol
      immobilized seaweed biomass.
AB  - Biosorption of copper by inactivated biomass of the brown marine alga Sargassum
      baccularia immobilized in polyvinyl alcohol (PVA) beads was investigated. PVA
      immobilized biomass beads were packed in a laboratory-scale fixed-bed column and
      subjected to three consecutive cycles of copper loading and elution. Bound copper
      was eluted with solutions containing a range of ethylenediaminetetraacetic acid
      (EDTA) concentrations. Up to 100% of the bound copper was consistently recovered
      from immobilized biomass using an aqueous solution containing 4mM EDTA in
      repeated loading/elution cycles. The PVA-immobilized biomass beads were shown to
      be robust and stable with little decrease in the copper uptake capacity under
      dynamic flow conditions. The excellent reusability of the new biosorbent could
      lead to the development of a viable metal removal technology.

PMID- 12403011
TI  - Nitrogen removal in leachate using carrousel activated sludge treatment process.
AB  - This paper presents the application of Carrousel Activated Sludge Treatment
      Process (CASTP) for ammonium nitrogen removal. High concentrations of ammonium
      nitrogen were found in landfill leachate. When leachate is treated in a local
      wastewater treatment plant, it has the potential to disturb the operations in the
      wastewater treatment plant. Because of the advantages of Carrousel Activated
      Sludge Treatment Process, several pilot studies and kinetic reactions of ammonium
      nitrogen removal in the CASTP were studied. High circulation and low dissolved
      oxygen in the CASTP enhances nitrification and denitrification processes. The
      results indicated that approximately 50-85% ammonium nitrogen and nitrate
      nitrogen were removed by using a conventional CASTP process. Two key parameters
      in the CASTP were further studied. The system detention time (SDT) appeared more
      important than the sludge retention time (SRT) in the CASTP. According to the
      experimental data, 24 h of the system detention time and 25 days of the sludge
      retention time achieved 85% or more ammonium nitrogen removal.

PMID- 12403013
TI  - Baseline concentrations of ten metals in the freshwater sediments of a watershed
      in Taiwan.
AB  - Freshwater sediments and water samples were quarterly collected at different
      sampling stations from August 1996 to April 1998 in the Fei-Tsui reservoir
      watershed (FTRW) of northern Taiwan. The sediment and soil samples were digested
      using mixture of inorganic acids to analyze the total concentration of ten
      metals. The baseline concentrations of ten metals in the sediments of FTRW were
      calculated from the geometric mean (GM) values and the geometric standard
      deviation (GSD). The baseline concentrations of 10 metals in the 239 sediments of
      this watershed are listed as followings (mg/kg, only % for Fe): As 1.80-51.5, Cd
      0.04-7.54, Cr 5.25-273, Cu 2.65-91.7, Hg 0.03-0.26, Mn 18.6-2310, Ni 3.95-167, Pb
      1.10-75.4, Zn 6.46-327, and Fe 0.47-9.63%. However, the GMs of 10 metal
      concentrations in the sediments were lower than the regulated threshold
      concentrations in Taiwan rural soils. Highly correlations among different metals
      in the sediments of FTRW indicate that very similar sediments of formation
      process control the metal content associated with the parent materials.
      Inadequate land use results in As, Cr, Mn, and Ni accumulated in the sediment to
      show potentially contamination risk in the study area associated with accelerated
      erosion and runoff.

PMID- 12403014
TI  - The kinetics of catalytic incineration of (CH3)2S2 over the CuO-MoO3/gamma-Al2O3
      catalyst.
AB  - In this study, by varying reaction conditions including particle size, space
      velocity, reactant concentration and reaction temperature, the kinetics of
      catalytic incineration of (CH3)2S2 catalyzed by the CuO-MoO3/gamma-Al2O3 catalyst
      was investigated. Three kinetic models, i.e., the power-rate law model, Langmuir
      Hinshelwood model and Mars-Van Krevelen model, were applied to best fit the
      experimental results. It was shown that the Mars-Van Krevelen model was more
      appropriate than the other two models for describing the mechanism of catalytic
      incineration of (CH3)2S2 on the CuO-MoO3/gamma-Al2O3 catalyst. The reaction
      expression of the Mars-Van Krevelen model was as follows: -r=k(R)k(O)C(R)C(O)
      divided by alpha(k)(R)C(R) + k(O)C(O) where alpha is 5.5 and C(R) and C(O)
      represent concentrations of (CH3)2S2 and O2, respectively. The enlarged
      difference between experimental and predicted data was observed at higher
      operating temperatures. This might be due to the dominating mechanism at this
      temperature region was different.

PMID- 12403015
TI  - Photocatalytic destruction of methyl tert-butyl ether in the gas phase using
      titanium dioxide.
AB  - The efficiency of the photocatalytic destruction of methyl tert-butyl ether
      (MTBE) in the gas-phase using UV light and titanium dioxide was studied. TiO2 was
      coated on the inner side of the photoreactor. Specifically, the effect of
      residence time (0.17-2.22 min), MTBE concentration (500-5000 ppm), oxygen
      concentration (0-20,000 ppm) and water vapor on MTBE conversion was examined.
      Acetone and tert-butyl formate were detected in the photoreactor effluent. The
      formation of by-products from MTBE decomposition was determined with gas
      chromatography-mass spectrometry. The residence time affected dramatically the
      MTBE photo-oxidation as well as by-products existence and configuration. The
      increase in MTBE concentration at the reactor inlet and the addition of water
      vapor to the reactants resulted in decreased MTBE conversions. Increasing oxygen
      concentration up to 10,000 ppm enhanced the photocatalytic process but a further
      increase to 20,000 ppm had an adverse impact on MTBE decomposition. In all cases,
      the by-product formation profiles were extremely dependent on photocatalysis
      parameters studied.

PMID- 12403016
TI  - Effect of oxygenates on exhaust emissions from two-stroke motorcycles.
AB  - The advantages of adding oxygenates to gasoline include their raising of the
      octane rating and their ability to reduce toxic compounds in the gasoline. A
      study of impacts of various oxygenates used in 50cc two-stroke motorcycle fuel
      was conducted, using the two most popular motorcycles in Taiwan, to determine the
      effect of oxygenates on exhaust emissions. Oxygenates used in the study were
      methanol, ethanol, benzene, methyl tert-butyl ether (MTBE) and isopropyl ether
      (IPE). Addition of oxygenates effectively reduced exhaust emissions. Of the
      oxygenates tested, with oxygenate content 7% by volume, MTBE was found to be the
      most suitable for reducing exhaust emissions. Results showed that total
      hydrocarbon (THC), CO, and NO(x) emissions decreased by 50%, 70%, and 60%,
      respectively, compared with emissions without any oxygenate added.

PMID- 12403017
TI  - The effectiveness of street sweepers in removing pollutants from road surfaces in
      Florida.
AB  - To test the effectiveness of street sweepers in the sandy-surfaced, subtropical
      Florida Peninsula, a controlled experiment was set up to compare the
      effectiveness of two different sweeper types in removing sediments, heavy metals,
      and organic constituents from a paved surface. Both a rotary brush and a
      regenerative air sweeper were tested on an asphalt roadway. The results indicate
      that rotary brush sweepers are more effective in removing total sediment loads
      from roads in this type of environment. However, the chemical analyses proved
      somewhat inconclusive. Each sweeper was effective in removing particular
      chemicals off streets, but neither sweeper proved better in all categories.
      Nevertheless, the rotary brush sweeper was most effective in removing the total
      sediment load off streets and is therefore recommended for use in areas covered
      with coarse sediments in the local drainage basin.

PMID- 12403018
TI  - Adsorption behavior of zinc and cadmium ion on granular activated carbon in
      singular and binary systems and the influence of nitrilotricetic acid as a
      complexing agent.
AB  - Adsorption characteristics of zinc and cadmium ion on granular activated carbon
      have been studied in dynamic and equilibrium aspects and singular and binary
      adsorption behavior were compared. Based on the van't Hoff equation, reaction
      orders and rate constants were observed to increase as initial concentration of
      adsorbate was raised for both metal ions. Adsorption of Zn and Cd ion was found
      to increase with temperature, and this endothermic nature of adsorption reaction
      was further verified by thermodynamic calculation. Taking nitrilotriacetic acid
      (NTA) as a ligand, the influence of complexing agent was examined and the
      variation of adsorption percentage was found to closely relate with the change in
      ionic form of NTA depending upon pH conditions and amount of complexing agent
      used. Features of binary adsorption are discussed for several influential
      parameters and experimental observations for both ions were correlated with a
      predicted adsorption isotherm based on a Langmuir multi-component model.

PMID- 12403019
TI  - Arsenic removal from household drinking water by adsorption.
AB  - Geogenic inorganic arsenic contamination in drinking water has been raising
      public health concern especially in developing countries. Cost-effective and
      stopgap arsenic removal method for household use (cooking and drinking) is very
      urgent. Several iron treated natural materials such as Fe-treated activated
      carbon (FeAC), Fe-treated gel beads (FeGB) and iron oxide-coated sand (IOCS),
      were investigated in this study for arsenic removal from dispersed household
      drinking water supply (scattered wells in the endemic arsenic poisoning areas).
      IOCS showed consistently good performance in terms of As(III) and As(V) removal
      in batch tests, column tests and field experiment. As(V) adsorption decreased
      slightly but As(III) adsorption maintained relatively stable when the pH value
      was increased from 5 to 9. In strong hardness water (612.5 mg/L CaCO3), As(III)
      adsorption efficiency was noted to decrease. The adsorption data obtained in
      column test fitted well to the Langmuir isotherm model. The adsorbent recovery
      efficiency was above 94% when using 0.2N NaOH regenerated the columns. In
      addition, 200 L of product water was produced by the household device (containing
      3.0 kg IOCS produced) when the influent arsenic concentration ranging from 0.202
      to 1.733 mg/L was encountered during the field experimental study conducted in
      Shanyin County, China. Neither the iron leaching nor other water quality
      deterioration was observed. It was noted in this study that IOCS is a promising
      medium for arsenic removal from household drinking water supplies.

PMID- 12403020
TI  - Kinetics of an anaerobic moving bed reactor system treating synthetic milk
      wastewater.
AB  - In the present study, anaerobic moving bed reactor called anaerobic rotating
      biological contactor treating synthetic milk wastewater operated at different
      organic loading rates and different hydraulic retention times, were evaluated to
      determine kinetic parameters for the substrate, biomass and biogas based on
      various models. The maximum substrate loading rate and half velocity constant
      were evaluated as 5.71 kgCOD/m3 x d and 1178 mg/L respectively by using
      Lineweaver-Burke plot. Maximum substrate removal efficiency and critical
      hydraulic retention time were compared with modified Young and McCarty model and
      the model is best fitted for the study. The complete removal of substrate cannot
      be expected due to presence of metabolic refractory material produced within the
      reactor system from influent system. Kinetic constants for maximum specific
      growth rate and decay coefficient were compared with the modified Monod model.
      Kornegay and Andrews model were used to evaluate the area capacity constant and
      half velocity constant. Kinetic constants for maximum specific gas production
      rate and proportionality constant were evaluated using Stover model. The gas
      production and quality are dependent on the substrate removal and substrate
      loading rate. The kinetic relationships derived from lab-scale experiment
      provided good estimates of the performance of pilot- and full-scale anaerobic
      rotating biological contactor packed with fibrous nylon pads and treating
      synthetic milk wastewater in terms of the effluent chemical oxygen demand
      concentrations and specific biogas production rates.

PMID- 12403021
TI  - Feasibility study on the operation of UASB reactor treating acidified food waste.
      Upflow anaerobic sludge blanket.
AB  - A mesophilic upflow anaerobic sludge blanket (UASB) reactor seeded with granules
      adapted to VFA wastewater was operated as the methanogenic phase of a two-phase
      anaerobic batch process for food waste digestion. A semi-liquid recycle reactor
      filled with food waste was used as the acidification reactor and first
      recirculated for 8 days in the pre-acidification stage, resulting in 14,500 mg/L
      of total VFA and 15,800 mg/L of COD in the leachate. During the subsequent 8 days
      of two-phase operation, the leachate was circulated to the UASB reactor. In
      methanogenic phase, biogas with methane content of 68% on average was generated,
      and COD and total VFA removals were 74-93% and 77-99%, respectively. At the end
      of two-phase process, 65% of volatile solids removal and 0.30 L/gVS of methane
      yield were obtained. The results of this laboratory-scale study show that an UASB
      system can be used as the methanogenic phase in a two-phase anaerobic batch
      process, and is effective for conversion of the acidified food waste.

PMID- 12403022
TI  - Microbial contamination in Lake Pontchartrain Basin and best management practices
      on microbial contamination reduction.
AB  - The Lake Pontchartrain Basin is a complex system of physical and biological
      elements. Due to the actions of man, the Basin's ecosystem has changed
      significantly over the past half century. These changes have impaired water
      quality and habitats throughout the Pontchartrain Basin. Recreational activities
      including swimming have been banned in areas of the lake. This paper discusses
      sources of microbial contamination impacting designated use criteria and the need
      of disinfection for water quality enhancement. Quantification of microbial
      loadings and identification of organisms of particular concern are made.
      Alternative Best Management Practices (BMPs) are suggested with emphasis on
      disinfection and engineered microbial reduction technologies.

PMID- 12403024
TI  - Low back pain in a rural community in South West Nigeria.
AB  - A cross sectional in South West Nigeria to determined the prevalence and risk
      factors for low back pain within the community. Nine hundred adults were selected
      using a multistage sampling technique. A questionnaire was administered which
      sought information on demographic characteristics, smoking status, presence of
      low back pain in the last 12 months and at the time of the survey and the
      duration and severity of the low back pain. Three hundred and sixty one (40% of
      the population) had low back pain in the last 12 months while (303) 33% had low
      back pain at the time of the study. The prevalence among males was higher than
      among females; 44.7% and 35.6% respectively. The prevalence of low back pain was
      highest mong farmers (mostly men) and lowest among petty traders (mostly women).
      The severity and mean duration of low back pain was also highest among farmers.
      Risk factors highlighted on bivariate analysis were male sex and farming as an
      occupational category but neither of these were sustained in multivariate
      analysis, an indication that male preponderance in this study is related to
      occupational factors. This study concludes that low back pain is prevalent in
      rural income communities and may occur at levels similar to those reported in
      high income countries.

PMID- 12403023
TI  - A multicentre study to determine the efficacy and tolerability of a combination
      of nelfinavir (VIRACEPT), zalcitabine (HIVID) and zidovudine in the treatment of
      HIV infected Nigerian patients.
AB  - Summary Forty (40) HIV positive patients with CD4 cell counts between 100 - 500
      cellh/mm3 were recruited from 8 different centres in Nigeria including a research
      centre and specialist and teaching hospitaLs They were enrolled into an open, non
      comparative study of a triple combination regimen containing the Protease
      Inhibitor (PI), Nelfinavir and two Reverse Transcriptase Inhibitors (RTIs),
      Zakitabine (Hivid) and Zidovudine for a period of 24 weeks. Thirty-one (31)
      patients completed the study. Nine (9) patients withdrew from the study. Two of
      these because of Adverse Events (AE), 2 others because they developed
      tuberculosis and had to withdraw because of rifampicin therapy. The remaining
      five (5), withdrew voluntarily. Efficacy of the PI containing triple regimen was
      evaluated using viral load and absolute CD4 changes, weight gain and clinical
      response during the course of the triaL Twenty-two (22) patients had plasma viral
      loads measured at the beginning and at the end of the trial (24 weeks). Seventeen
      (17) out of the 22 patients (77%), experienced a significant reduction in their
      plasma viral loads (p<0.05 There was 1 log reduction in plasma viral load in 6
      patients (25%), 2 log in 4 patients (17%). In 2 patients (8%), plasma viral load
      was reduced below the level of detection. The viral load increased over the
      treatment period in five patients (21%). Similarly 22 out of the 26 patients
      (85%) experienced increase in the level of their CD4 lymphocyte counts at the end
      of the study. The average CD4 counts of all 26 patients rose from 272.94 +/-
      137.71/dl to 414 +/- 243.71/ul over 24 weeks (p<0.05). There was monthly rise of
      27 CD4 cells/microl. Four (4) patients (15%) had a fall in their CD4 lymphocyte
      counts. Twenty (20) out of the 26 patients (77%), who completed the study were
      observed to have weight gains ranging from 1.5 to 31 kilograms over the 24 week
      study period. In 4 patients, there was no weight gain during the study period.
      Two patients (5%) were withdrawn due to adverse events from the viracept
      combination. One of these was because of life threatening diarrhoea while the
      other patient had severe peripheral neuropathy and severe weakness in the lower
      limbs. Eight (8) other patients had diarrhoea but not severe enough to stop them
      from continuing with the triaL Other adverse events seen include anaemia (1
      patient), pancytopenia (1 patient), and transient elevation of serum urea and
      creatinine (1 patient). None of these adverse events was severe enough to warrant
      withdrawal from therapy. The study has therefore demonstrated the significant
      efficacy and tolerability of (Nelfinavir/Zalcitabine/ Zidovudine combination in
      suppressing viral replication, increasing the CD4 cell counts and improving the
      quality of life in Nigeria patients with HIV.

PMID- 12403025
TI  - Serial haemorheological changes in malnourished African children.
AB  - Malnutrition is a major cause of mortality and morbidity in the developing
      nations, and it is a problem which concerns about half of the worlds children. A
      total of 50 malnourished children were monitored along with 50 apparently healthy
      controls, aged 4-9 years for a period of four weeks after admission using
      haemorheological parameters as monitoring indices for recovery. The malnourished
      children had significant lower body weight, upper arm circumference and triceps
      skin fold thickness (P < 0.001). Plasma fibrinogen (PF), plasma viscosity (PV)
      and packed cell volume (PCV), were estimated. The PF (p < 0.001), PCV (P < 0.001)
      and PV (p < 0.001) values were significantly lower in the malnourished patients
      compared with controls. These parameters rose significantly throughout the four
      weeks of treatment. There was significant positive linear correlation between PCV
      vs fibrinogen (r = 0.665, P < 0.00137), PCV vs plasma viscosity (r = 0.575,
      P<0.00797), and fibrinogen vs plasma viscosity, (r = 0.581, P < 0.00718) in the
      malnourished patients. We suggest that rheological parameters could be a useful
      indices for monitoring response in African malnourished patients to treatment.

PMID- 12403026
TI  - Comparative analysis of parents' and teachers' view points on contraceptive
      practice among adolescents in Port Harcourt, Nigeria.
AB  - The study compares the viewpoint of parents and teachers on contraceptive
      practice by sexually active adolescents in the study environment The instrument
      for the study was a structured and pre-tested questionnaire. Data was analysed
      using frequency counts and chi-square statistical test of significance (P = .05).
      Findings showed that there was significant difference in opinion (P < 0.05)
      between parents and teachers on the use of contraceptives by adolescent girls.
      Most (79.1%) parents will not encourage girls to use contraceptives. However, a
      substantial number (45.8%) of teachers would similarly not encourage adolescents
      to use contraceptives. Various reasons are given by both repondents for
      discouraging adolescents from using contraceptives although there was significant
      difference (P < 0.05) in the reasons given. Based on the findings, it was
      concluded that for family planning programme directed towards adolescents to
      succeed parents' and teachers' view point must be put into consideration. In
      addition, teachers and parents need training in reproductive health.

PMID- 12403027
TI  - A five year analysis of death in accident and emergency room of a semi-urban
      hospital.
AB  - A 5 year retrospective survey of deaths at the Accident and Emergency Unit was
      carried out to determine the demographic pattern, causes and time spent before
      demise. There were 475 deaths, annual rate of 95 cases. Males in 279 (58.8%) and
      186 females (41.2%), age ranged from 15-90 years, mean 44 SD +/- 21 years.
      Medical diseases in 354 (74.5%), trauma in 72 (15.2%) and surgical conditions 49
      (10.3%) patients There were 135 (38%) cases of cardiovascular diseases and
      pulmonary diseases 115 (32.6%) patients. Tuberculosis and pneumonia were the most
      common of pulmonary conditions. Central nervous diseases and gastro-intestinal
      diseases in 46 (13%) and 40 (11.2) respectively, mainly infectious conditions.
      Road Traffic Accident caused death in 51 (70.5%), assaults in 8 (11.4%) cases,
      gunshot and poison 5 (6.8%) each, and snake bites in only 3 (4.5%) cases of
      trauma. Surgical acute abdomen with peritonitis occurred in 18 (36%) cases,
      pyomyositis with septicaemia in 7(133%), gastrointestinal bleeding 5 (10%) and
      burns in only 3 (6.7%) cases In conclusion, over two-thirds of deaths in accident
      and emergency unit were due to medical problems. The means of the age were in
      late thirties- mid forties, there was no significant difference in the mean age
      of those who died of medical, trauma and surgical problems. Trauma victims spent
      the shortest mean time in accident and emergency before death, the longest
      staying were the victims of medical diseases.

PMID- 12403028
TI  - Deficiencies in tetanus prophylaxis in wound management in Ibadan, Nigeria.
AB  - In a review of 94 paediatric patients treated for post-neonatal tetanus over a
      period of 11 years at the University College Hospital, Ibadan, Nigeria, reliable
      data regarding the care received for wounds that eventually resulted in tetanus
      was available in 58 patients. Seventeen of these patients had orthodox medical
      care for their wounds before developing tetanus. While some of the patients had
      received antibiotics and/or tetanus toxoid, no patient received antitetanus serum
      despite the fact that most of them had no previous immunization against tetanus.
      All the 3 victims of road traffic accidents were given tetanus toxoid but none of
      the 6 patients with chronic suppurative otitis media had any form of tetanus
      prophylaxis. The findings highlight the adverse consequences of failure to adhere
      to basic guidelines for management of the tetanus-prone wound.

PMID- 12403029
TI  - Chronic back pain successfully treated with supportive psychotherapy.
AB  - BACKGROUND: The primary purpose of this article is to report 4 cases of lower
      back pain successfully treated with psychoeducation. METHODS: Case studies of 4
      patients with chronic back pain. Medline data search of articles relating to
      chronic back pain. The patients were treated on an outpatient basis for a period
      of up to one year. RESULT: A structured program of psychoeducation was effective
      in reducing pain and disability in all four cases. CONCLUSION: There is
      increasing evidence of the role of psychological factors In the etiology and
      treatment of chronic back pain. A program of psychoeducation may be effective in
      treating certain patients with lower back pain.

PMID- 12403030
TI  - Contraceptive usage among abortion seekers in Nigeria.
AB  - A study on contraceptive usage among abortion seekers in 150 randomly selected
      health institutions in the most and the least urbanized states of the health zone
      B representing the South Western states of Nigeria was conducted over a period of
      2 months. There were 1839 abortion seekers during the period. About 30.4% (559)
      of the respondents admitted to ever used any form of contraceptive methods. Most
      of the respondents who admitted to ever used any form of contraceptives i.e.
      81.2% (454/559) were not using the contraceptive methods regularly and this cut
      across all the methods. Oral contraceptive pill was the commonest method used,
      though not on regular basis. The most frequent reason for not ever used
      contraceptive methods was ignorance. There is a need for intensification of
      strategies for promotion of use of family planning methods, which can be achieved
      through good counselling, sexuality education, and availability of cheap, and
      affordable contraceptive methods and services.

PMID- 12403031
TI  - The morbidity and mortality of laparotomy for uncomplicated intussusception in
      children.
AB  - Non-operative management by pressure reduction is now the preferred treatment for
      uncomplicated intussusception in children. However, in many developing countries,
      laparotomy is routinely performed for such cases. This is a retrospective
      anlaysis of 24 children who had operative reduction of intussusception. The age
      range was 3 months--10 years (median 7 months) and duration of symptoms 12 hours-
      7 days (median 2 days). The main features were abdominal pain, vomiting and
      rectal bleeding. Ten (42%) patients had varying degrees of dehydration, which
      were corrected. At laparotomy, the intussusceptions were reduced without
      difficulty. Thirteen (54%) patients developed 15 procedure related complications
      including wound infection 6(25%), ileus 2(8%), stitch sinus 2(8%), incisional
      hernia 2(8%), intestinal obstruction from adhesions resulting in intestinal
      gangrene 2(8%) and aspiration pneumonia 1 (4%). Mortality was 2( 8%) from
      aspiration pneumonia and overwhelming infection due to intestinal gangrene from
      adhesive intestinal obstruction respectively. Laparotomy for uncomplicated
      intussusception in children is attended by significant morbidity and mortality.
      Many of such intususceptions, may be successfully managed by pressure reduction
      and children should not be denied the benefits of this form of treatment.

PMID- 12403032
TI  - A blind parallel comparative study of the efficacy and safety of rovamycin versus
      augmentin in the treatment of acute otitis media.
AB  - A single blind randontised controlled parallel clinical trial of Rovamycin was
      conducted in which (Rovamycin Rhone-Poulenc Rorer) was compared with Augmentin in
      patients with acute otitis media. Forty patients were randomised to treatment
      with either Rovamycin or Augmentin and the drugs were evaluated for efficacy and
      safety. The efficacy parameters used were fever clearance, symptom clearance and
      cure rate after 8 days of treatment Our study showed that fever regressed in 19
      (95%) of the 20 patients in both groups; otalgia in 19 (95) patients for the
      Augmentin and 18 (90%) for Rovamycin after 8 days of application of the trial
      drugs in these parameters. There was also no significant difference between them
      in their safety and tolerability profiles. These results showed that Rovamycin is
      a useful addition to our armamentarium in the fight against bacterial otitis
      media. Operationally, Rovamycin has an advantage over Augmentin for the reason
      that is given only twice a day as against thrice-daily dosage f orAugmentin.
      Compliance and consequently effectiveness in practices should therefore be better
      for Rovamycin.

PMID- 12403033
TI  - Computed tomographic patterns of intracranial infarcts in Ghanaians.
AB  - Computed tomography has given a boost to intracranial imaging in general, and the
      diagnosis of the subtypes of Cerebrovascular Accident (CVA) in particular. In
      this study of 1,172 cases of CVA examined by Computed Tomography (CT), 552
      (47.10%) showed features of cerebral infarction. There was a male prevalence in
      the study and the mean age was 59.8 years. As in all infarcts the diagnostic
      appearance was a wedge shaped hypodensity within the brain parenchyma. This was
      most often found in the parietal lobe (73.6%) and was always without a mass
      effect. Even though solitary infarcts were frequent, multiple lesions were
      reported in 9.3% of cases and these group of respondents presented mostly with
      seizures. Diabetes mellitus was an important predisposing factor and was found in
      163% of cases, while hypertension was found in only 9.1% of cases studied. Other
      CT findings were cerebral and cerebrellar atrophy. Calcification of the falx and
      the basal ganglia were also noted.

PMID- 12403034
TI  - Antibiogram and beta-lactamase production of Staphylococcus aureus isolates from
      different human clinical specimens in Edo State, Nigeria.
AB  - The antibiogram and Beta-lactamase of 73 isolates of Staphylococcus aureus from
      235 different human clinical specimens were determined using standard procedures.
      These various clinical specimens were got from teaching hospitals and some
      private hospitals in Edo State. The results of the antibiogram showed 100%
      susceptibiity to Vancomycin, 78.1% to Gentamicin, 71.3% to Chloramphenicol, 69.8%
      to Erythromycin and 61.6% to Cloxacillin. The results of the beta-lactamase
      detection showed that 84.1% of the isolates were penicillinase positive, which
      probably accounted for the 100% resistance obtained for both Ampicillin and
      Penicillin. This thus suggests that clinicians should enlighten patients on the
      consequences of indiscriminate use of Penicillin and other antimicrobial agents.

PMID- 12403035
TI  - Cholelithiasis in Ibadan: an update.
AB  - This study is to ascertain the present status of cholelithiasis in our
      environment. Six hundred and seventy (670) consecutive abdominal, ultrasounds
      done for various abdominal complaints at the University College HospitaL Ibadan
      from January 1977 to December 1998 were studied for gall stones in addition to
      other studies of the abdomen. Only twelve (12) gallstones were found, giving a
      prevalence of 1.79%. Only 25% were silent stones. The male:female ratio was 1:3.
      The mean age was 30 years (S.D = 2.8) and peak age was between 30 and 40 years.
      The average body mass index (B.M.I) was 23.49 kg/m2 (S.D = 3.9). The average
      parity among the women was four (4). Only one ultrasound was false (false
      negative). This study shows an increase. In prevalence over previous figures
      (1.79%) as against 0.007% in the sixties). The peak age is a decade lower and the
      anthropometric measurements in our patients do not support the typical caucassian
      model.

PMID- 12403036
TI  - Eye health of industrial workers in Southeastern Nigeria.
AB  - A cross-sectional ophthalmological survey to determine the ocular health in
      Nigerian industries was undertaken in four randomly selected industrial
      establishments in Enugu State of Nigeria. The industrial establishments studied
      were the cement factory, coal mine, saw mill and iron/steel works where motor
      spare parts are fabricated. Of the 646 workers, 184 (28.5%) had a history of
      industrial accidents, 81 (12.5%) of which affected the eye. Eye injury was most
      commonly caused by metal chips, cement dust, fragments of wood, pieces of coal
      stone and welders' arc rays all of which could be prevented by wearing
      appropriate protective eye coverings. Contusion injury was the most common type
      of injury reported. Eye accident rate varied from factory to factory as also did
      the wearing of protective eye devices. overall, the percentage of workers using
      protective eye cover was 16.7% but there was a significant difference between the
      factories in this respect, protective eye wear being more often used in factories
      with higher eye accident rates. A total of 646 technical workers had detailed
      ophthalmological examination. The types and frequencies ofvisual disorders seen
      as well as the nature and causes of eye injuries were determined. Five hundred
      and twenty-eight workers (81.7%) had eye disorders. Presbyopla was responsible
      for 203 (31.4%) of these disorders while 169 (26.2%) were refractive errors. Of
      the others, pterygium and pingueculum together numbered 179 (27.7%) while
      cataract was found in 79 (12.2%) subjects. The results showed a high frequency of
      eye injuries among industrial workers and a low level of use of protective eye
      cover while at work. It is recommended that legislation requiring the use of
      protective devices in high-risk industries should be vigorously enforced to
      improve the eye health of Nigerian industrial workers.

PMID- 12403037
TI  - Helicobacter pylori infection in South Nigerians: a serological study of
      dyspeptic patients and healthy individuals.
AB  - Helicobacter pylori has now been well recognised to play a significant role in
      the pathogenesis of gastroduodenal disease. So far serology has been the most
      useful technique for rapid access to accurate information about H. pylori status
      of dyspeptic patients. This study reports on the seroprevalence of Hpylori
      infection in both dyspeptic and healthy adult Nigerian subjects in a community
      located in the South Western part of Nigeria. Two groups of subjects were
      studied, consisting of 25 adult Nigerian patients with dyspepsia who presented at
      the Gastroenterology Clinic, and 25 healthy adult Nigerian volunteers. Serum
      samples were prepared from five milliliters of blood collected from each of the
      subjects. The quantity of IgG antibodies to Hpylori was determined in each of
      these 50 samples, using the immunocomb II. Helicobacter pylori IgG kit, with each
      test result being validated by an internal controL Twenty-two (88%) of the 25
      dyspeptic patients and 20 (80%) of the normal individuals were seropositive for
      IgG antibody to H. pylori. The difference in infection rate between both sexes
      was not statistically significant These results indicate a high rate of Hpylori
      infection in this locality as reported in previous serological studies in this
      country and some other developing countries. The similarly high seroprevalence of
      H. pylori infection in both our healthy individuals and dyspeptic patients also
      supports the assertion, earlier made in the literature, that H. pylori exerts its
      influence in concert with other environmental factors as well as social and
      genetic factors.

PMID- 12403038
TI  - Alcohol, smoking and oral cancer. A 10-year retrospective study at Base Hospital,
      Yaba.
AB  - This paper is an attempt to document alcohol and smoking habits as risk factors
      in the aetiology of oral cancer. A retrospective survey of patients who presented
      with oral cancer at Base Hospital, Yaba (BHY) for 10 years (1987 - 1996) was
      carried out. Fifty eight patients were surveyed excluding those with incomplete
      data. There were 40 male (66%) and 18 female (33 1/3%) giving a M:F ratio of 2:1.
      There were 50% of the patients who were referred by hospitals and clinics, while
      the remaining 50% were self-referred. The maximum number of male patients with
      oral cancer occurred at 65-70 year age range while the corresponding figures for
      female was 50-60 years. A significant number of our patients, 40%, lived in rural
      areas and most of them presented with poor oral hygiene, oral sepsis, decayed
      and( missing teeth. It was noted that most of these were relations of military
      personnel. In the biopsy report, the most frequently diagnosed was squamos cell
      carcinoma, 84.6% of the total, however 7.1% of lymphoma, and 3.5% each of
      adenocystic carcinoma and odontogenic carcinoma were made. A case of melanoma was
      also recorded. From the study, alcohol consumption is a more implicated factor in
      the aetiology of oral cancer than tobacco, especially in patients with highest
      cancer incidence in floor of mouth, tongue and buccal mucosa (52.5% of cases).
      This perhaps shows that alcohol and tobacco has site specificity in the aetiology
      of oral cancer.

PMID- 12403039
TI  - Electrocardiographic changes among Nigerian Norplant users.
AB  - OBJECTIVE: To determine any cardiovascular morbidity in the short term with
      Norplant use by electrocardiography. DESIGN: Prospective observational study of
      consecutive volunteers. SELLING: Jos Univesity Teaching Hospital, Nigeria.
      METHODS: Twenty-one Nigerian women seeking long-term reversible contraception
      were recruited for this study during a Norplant training programme in our centre
      in August 1997. The clients had baseline (Pre-insertion) blood pressure checks
      and electrocardiographic (ECG) tracings. These were repeated at the 3,6 and 12
      months follow-up visits and the results were analysed. MAIN OUTCOME MEASURES:
      Heart rate, mean QRS electrical axis, PR and QRS intervals, rhthm assessment,
      chamber enlargement/hypertrophy. RESULTS: The mean age of subjects was 32.4 +/-
      3.98 years (range 25-38 years). The mean weight at pre-insertion and at the 3, 6
      and 12 months follow-up visits were 63.63 +/- 10.43, 60.59 +/- 10.07, 64.08 +/-
      12.15 and 62.29 +/- 12.25 kilograms respectively. The differences were not
      significant. The systolic and diastolic blood pressures did not show any
      significant changes throughout the period of study. The heart rate and cardiac
      axis measurements did not show any significant changes during the study period.
      There was no chamber enlargement or hypertrophy. Rhythm remained generally
      normal. The PR and QRS intervals remained within normal limits throughout the
      study period. However, they seemed to be significantly prolonged--mean PR
      interval (seconds) pre-insertion 0.153 +/- 0.003, and at 12 months 0.173 +/-
      0.006 (P = 0.019), mean QRS interval (seconds) pre-insertion 0.056 +/- 0.003 and
      at 12 months 0.74 +/- 0.002 (P = 0.005) CONCLUSION: There is a tendency to
      significant prolongation of ECG intervals in Norplant users. This requires longer
      observation.

PMID- 12403040
TI  - Deep vein thrombosis in non-anticoagulated head injury patients.
AB  - The aim of this study was to evaluate the risk of DVT in a group of head-injury
      patients admitted to the intensive care unit (ICU) at Asir Central Hospital
      (ACH), Abha, Saudi Arabia, without mechanical or anticoagulant prophylaxis
      against DVT. During the period from January 1998 to March 1999, we evaluated 103
      lower limbs in 54 such patients. 37(69%) patients presented with isolated head
      injury, while 17(31%) had other associated injuries. The mean age for the whole
      group was 29.9 years (range 8-70), with only one female patient. All patients
      underwent both clinical and continuous wave Doppler (CWD) examination on or after
      the 7th day post-trauma. 42(78%) patients had also D-dimer (latex) assay done at
      the same time. Although all the limbs were soft on clinical examination, 4(4%)
      were swollen and 7 (7%) were edematous. CWD examination was normal for all the
      limbs. 35 out of the 42 patients who had D-dimer testing (83%), showed high
      positive D-dimer concentration (500 - 1000 ng/ml), indicating the presence of
      thrombosis. We, therefore, recommend closer monitoring of these patients and
      application of prophylactic measures against DVT especially in the presence of
      associated injuries.

PMID- 12403041
TI  - HIV association with conventional STDS (sexual transmitted diseases) in Lagos
      State, Nigeria.
AB  - The study examined a possible association between HIV infection and conventional
      sexually transmitted diseases (STDS) in a population of 700 patients seen in some
      hospitals and clinics in Lagos State between November 1997 and December 1999. The
      patients were drawn mainly from LUTH and Jolad hospitals in Lagos State. In these
      hospitals, patients who presented with symptoms of STDS were screened clinically
      and microbiologically for agents of STDS and HIV antibodies. Screening was
      carried out using conventional methods. A total of 150 (21.5%) were found
      positive for various STDS while 550 (78.5%) were negative Also, 109 (15.8%) were
      sero-positive for HIV while 591 (84.4%) were sero-negative. The frequency of STDS
      diagnosed were, Treponema pallidum, 38(25.3%), Neisseria gonorrhoea 3(2.0%),
      Chlamydia trachomatis 26(17.3), Hepatitis B virus 60(40.0%) Staphylococcus
      aureaus, 20 (13.3%) and Candida albicans 3(2.0%). Data showed that Syphillis was
      the most prevalent STDS diagnosed while Calbicans and N. gonorrhoea are the
      least. Amongst the 150 (21.5%) patients positive with STDS, 82(54.65%) were found
      to be positive for HIV antibodies. The remaining 68(45.3%) patients were negative
      for HIV. The difference in sero-prevalence on the true group of patients rates
      was significant. The higher rate in the STDS patients strongly suggest some
      association between HIV infections andSTDS amongst the patients studied p = 0.05.
      It was also recorded that HIV-1 infection is four times more prevalent than HIV-2
      in these patients.

PMID- 12403042
TI  - Small intestinal leiomyoma in childhood: a case report.
AB  - A 6-year old girl presented with a painless, progressive abdominal mass for 4
      weeks without alteration in bowel habits. Physical examination showed a non
      tender, irregular and mobile abdominal mass. Abdominal ultrasonography was unable
      to define the exact origin of the mass. An ileal tumour was found at laparotomy
      necessitating resection and anastomosis. Histology confirmed an intestinal
      leiomyoma. The patient has remained well at 3.5 years of follow up. Leiomyomas of
      the small intestine are rare in childhood. This report discusses the
      presentation, diagnosis and management of this condition by briefly reviewing the
      literature.

PMID- 12403043
TI  - Cyanoacrylate (superglue) presenting as an otic foreign body.
AB  - This is a case report of a 55 years-old Nigerian woman who presented an unusual
      left ear foreign body consisting of cyanoacrylate (super glue) which was
      successfully removed after application of acetone.

PMID- 12403044
TI  - Occult metastatic follicular thyroid carcinoma masquerading as a soft tissue
      sarcoma of the gluteal region.
AB  - This is a case of an occult follicular thyroid carcinoma in a 61 year old civil
      servant presenting with bony metastasis to the left iliac bone twenty years after
      an initial subtotal thyroidectomy. There was a soft tissue mass with associated
      cup shaped Iytic detruction of the iliac bone and on ultrasound scan the mass was
      found to be of mixed echogenicity and areas of sonolucencies which were due to
      necroses. At autopsy, the thyroid gland appeared macroscopically within normal
      limits but histology confirmed Follicular Thyroid Carcinoma.

PMID- 12403045
TI  - Heart valve replacement; anticoagulation and pregnancy.
AB  - Three patients who had heart valve replacement surgery and were on
      anticoagulation therapy with warfarin presented with pregnancy, one patient in
      the first trimester and the other two patients in the second trimester All three
      patients were in good and stable haemodynamic condition and went through
      pregnancy without any Complications. Delivery in all three patients were by
      caesarian section. The management of these patient during pregnancy and delivery
      form the basis of this report. A scheme for anticoagulation therapy during
      pregnancy, delivery and the post-delivery period of such patients has also been
      presented.

PMID- 12403046
TI  - Gastric volvulus and gastroduodeno-jejunal intussusception (an unusual cause of
      acute abdomen).
AB  - An elderly man who presented with colicky abdominal pain had gastric volvulus
      which was reduced after barium meaL More than a year later the symptoms recurred
      and at laparotomy a gastroduodenojejunal intussusception was found and its apex
      was formed by a polypoidal gastric tumour (leiomyoma). The patient did very well
      without any recurrence after the resection of the tumour.

PMID- 12403047
TI  - Renal papillary necrosis as first presentation of a Nigerian sickle cell patient.
AB  - The clinical features of the sickle syndromes do not appear until after the sixth
      month of life, at which time most of the HbF has been replaced by HbS. Thrombo
      embolic complications, retinopathy and renal papillary necrosis are more frequent
      in HbSC disease than in other sickle cell syndromes. First presentation of HbSC
      disease after the second decade is considered late in this environment. A 25 year
      old Nigerian female patient is hereby presented with renal papillary necrosis as
      first presentation of HbSC disease. The patient presented with a sudden onset of
      total haematuria without history suggestive of urinary tract infection, trauma,
      instrumentation and significant analgesic consumption. No history of usage of
      herbal remedies, diabetes mellitus, sore throat, abdominal pains, skin rashes or
      joint pains. Physical examination did not show any characteristic habitus or
      findings. Findings on intravenous urography suggested renal papillary necrosis.

PMID- 12403048
TI  - Chylous ascites, tuberculosis and HIV/AIDS: a case report.
AB  - The case is reported of a 53 year old long distance bus driver who had complained
      of fever, weight loss, abdominal and leg swelling and had a past history of
      inadequately treated pulmonary tuberculosis. Physical findings included
      generalised lymphadenopathy, finger clubbing, pedal oedem and chylous ascites. He
      tested positive for HIV type 1 and the histology of a lymph node biopsy was
      compatible with tuberculosis which responded favourably to antituberculous
      chemotherapy.

PMID- 12403049
TI  - Transport of peptidomimetic drugs by the intestinal Di/tri-peptide transporter,
      PepT1.
AB  - The apical membrane of small intestinal enterocytes possess an uptake system for
      di- and tripeptides. The physiological function of the system is to transport
      small peptides resulting from digestion of dietary protein. Moreover, due to the
      broad substrate specificity of the system, it is also capable of transporting a
      number of orally administered peptidomimetic drugs. Absorbed peptides may be
      hydrolysed in the cells due to the high peptidase activity present in the
      cytosol. Peptidomimetic drugs may, if resistant to the cellular enzyme activity,
      pass the basolateral membrane via a basolateral peptide transport mechanism and
      enter the systemic circulation. As the number of new peptide and peptidomimetic
      drugs are rapidly increasing, the peptide transport system has gained increasing
      attention as a possible drug delivery system for small peptides and peptide-like
      compounds. In this paper we give an updated introduction to the transport system
      and discuss the substrate characteristics of the di/tri-peptide transporter
      system with special emphasis on chemically modified substrates and prodrugs.

PMID- 12403050
TI  - Validation of microdialysis sampling for oral availability studies by means of a
      new ganciclovir prodrug.
AB  - Microdialysis sampling was validated for oral availability studies using
      ganciclovir (9-(1, 3-dihydroxy-2-propoxymethyl) guanine) and a ganciclovir
      prodrug (9-(1-L-valyloxy-3-octadecanoyloxy-prop-2-oxymethyl) guanine). Three
      different techniques were used in the study; microdialysis, blood and
      urinesampling. The oral uptake (11+/-2%) and the urinary recovery (106+/-5%) were
      determined. Animals given ganciclovir subcutaneously were subject either to
      microdialysis and blood sampling or to microdialysis alone. There was no
      significant difference between microdialysis and blood sampling in terms of blood
      concentration data, CL, Vd, half-life or AUC by means of Student's t-test. The
      oral bioavailability of the prodrug was 40+/-7% estimated from microdialysis
      sampling data and 48+/-4% estimated from urine sampling data. It is concluded
      that microdialysis is a valid method to use in pharmacokinetic studies of oral
      availability as well as for basic pharmacokinetic parameter estimation.

PMID- 12403051
TI  - Effects of chronic citalopram treatment on central and peripheral spontaneous
      open-field behaviours in rats.
AB  - The spontaneous open-field behavioural effects of 10 days of chronic treatment
      with two clinical doses (10 and 20 mg/kg daily) and one high/toxic dose (100
      mg/kg daily) of the selective serotonin reuptake inhibitor citalopram (delivered
      subcutaneously by implanted osmotic pumps) were examined in rats. Central and
      peripheral arena locomotor and rearing activities were recorded simultaneously,
      and the data were assessed during the first hour as well as during the following
      24 hr (the latter for effects on the diurnal rhythm). Rats treated with 100 mg/kg
      daily exhibited lower peripheral locomotor and rearing activities than the other
      groups during the first test hour. The ratio between central and peripheral
      activity increased in a dose-dependent non-proportional manner during the first
      test hour, indicating a general increase in the central arena activity exerted by
      the rats when treated with citalopram. No major differences were observed between
      any of the four groups in overall behavioural activities over the 24-hr period.
      This study indicated that the open-field locomotor and rearing behaviours in
      normal rats were affected by increasing doses of racemic citalopram, particularly
      during the first hour of adaptation.

PMID- 12403052
TI  - Possible role of vasopressin in the thermoregulatory response to chlorpyrifos in
      the rat.
AB  - Arginine vasopressin is a naturally occurring antipyretic which is released into
      the CNS to prevent excessive elevations in body temperature during fever.
      Circulating levels of arginine vasopressin may also have a role in the tonic
      control of body temperature. We have found that the organophosphate insecticide
      chlorpyrifos will raise blood pressure and lower body temperature in the rat.
      Because arginine vasopressin is a potent hypertensive agent and is capable of
      lowering core temperature, we suspected that arginine vasopressin may be involved
      in the thermoregulatory response to chlorpyrifos. To this end, core temperature
      and motor activity of male and female Sprague-Dawely rats were monitored before
      and after treatment with the corn oil vehicle or chlorpyrifos (15 mg/kg in
      females; 30 mg/kg in males; oral) concomitant with injection of a saline vehicle
      or a type 1 arginine vasopressin antagonist (20 microg/kg in females; 30
      microg/kg in males; intraperitoneally). Rats dosed with chlorpyrifos and saline
      underwent a 2-3 degrees reduction in core temperature >50% decrease in motor
      activity. The V1 antagonist attenuated the hypothermic effect of chlorpyrifos in
      both sexes. Chlorpyrifos-induced inhibition in motor activity was unaffected by
      the V1 antagonist. In another experiment, the V1 antagonist (30 microg/kg) was co
      administered with saline or 0.2 mg/kg oxotremorine, a muscarinic agonist that
      stimulates a heat loss response and partially mimics the effects of chlorpyrifos.
      The V1 antagonist attenuated the hypothermic effect of oxotremorine in both
      sexes. Plasma arginine vasopressin levels were determined in male rats 3 hr after
      corn oil or 30 mg/kg chlorpyrifos. There was no significant effect of
      chlorpyrifos on plasma levels of arginine vasopressin. That the V1 antagonist
      blocked the hypothermic effect of chlorpyrifos suggests that the thermoregulatory
      response to chlorpyrifos is mediated by central and/or systemic vasopressin
      release. The lack of a significant increase in plasma vasopressin after
      chlorpyrifos suggests that localized release of vasopressin may be involved in
      the thermoregulatory response to chlorpyrifos.

PMID- 12403053
TI  - Generation of hydroxyl radicals mediated by streptozotocin in pancreatic islets
      of mice in vitro.
AB  - Type I diabetes is considered a multifactorial autoimmune process initiated by an
      environmental factor. There is evidence that reactive oxygen species are involved
      in destructing insulin-producing beta-cells. In mice, reactive oxygen species and
      nitric monoxide contribute to beta-cell damage in the non-obese diabetic strain
      developing spontaneously diabetes and in diabetes induced with multiple low doses
      of streptozotocin. Previously, we found that zinc sulfate induced metallothionein
      in pancreatic islets, protected beta-cells against streptozotocin toxicity in
      vitro, and prevented diabetes induced with multiple low doses of streptozotocin.
      Since metallothionein is known to scavenge hydroxyl radicals in cell-free
      systems, we hypothesize that the protective effect of zinc sulfate results from
      metallothionein induction scavenging hydroxyl radicals generated by multiple low
      doses of streptozotocin. Therefore, we studied whether levels of hydroxyl
      radicals are increased by streptozotocin in isolated islets in vitro. Here, we
      demonstrate basal and streptozotocin-stimulated hydroxyl radicals by electron
      spin resonance spectroscopy in combination with hydroxyl radical-specific spin
      trapping in islet homogenates. Furthermore, in islet cultures, streptozotocin
      augmented generation of reactive oxygen species as determined by fluorescence. Of
      the group of reactive oxygen species, the streptozotocin-augmented generation of
      hydrogen peroxide was also specifically determined. We conclude that
      streptozotocin-mediated hydroxyl radicals and generation of reactive oxygen
      species may be crucial effectors in beta-cell damage.

PMID- 12403054
TI  - Pharmacodynamic response of entacapone in rats after administration of entacapone
      formulations and prodrugs with varying bioavailabilities.
AB  - The aim of this in vivo study was to assess the effect of improved oral
      bioavailability of entacapone on its actual pharmacodynamic response, COMT
      inhibition in erythrocytes. Rats were administered entacapone orally as a
      suspension, as a plain solution, an entacapone/HP-beta-CD solution, two N-alkyl
      carbamate ester prodrugs and intravenously as a solution. Also the relationship
      between pharmacodynamic and pharmacokinetic responses of entacapone was
      investigated. The administration of entacapone as a solution (plain solution pH
      7.4; F=34.8% or entacapone/HP-beta-CD solution pH 3.0; F = 18.5%) resulted in
      significantly higher degree of COMT inhibition in erythrocytes than could be
      achieved by administering entacapone as a suspension (pH 3.0; F=8.9%). The
      inhibitory Emax model did not reveal any significant differences in EC50
      estimates of entacapone suspension, entacapone/HP-beta-CD solution or entacapone
      solution. The overall pharmacodynamic response of entacapone (AUE; area under
      effect-time curve) was dependent on the pharmacokinetic response (AUC; area under
      concentration-time curve) irrespective of the entacapone formulation and dosage
      form. However, this dependency did not extend to formulations producing very high
      peak concentrations of entacapone in plasma; high plasma concentrations reached
      transiently after administration of entacapone solution had only a minor effect
      on the overall pharmacodynamic response (AUE). The inhibitory Emax model revealed
      that a plateau of COMT inhibition near to Emax is attained by plasma
      concentrations under 2000 ng/ml, irrespective of the formulation. This supports
      the results concerning the dependence of AUE on AUC.

PMID- 12403055
TI  - Eumelanin is a major determinant for 2-amino-1-methyl-6-phenylimidazo[4,5
      b]pyridine (PhIP) incorporation into hair of mice.
AB  - Mice with different hair pigmentation were studied to evaluate the role of
      melanin in the incorporation of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine
      (PhIP) into hair. Mice C57BL/6J-c2j/+ (white), C57BL/6J-Ay (yellow), C57L/J
      (grey), C57BR/cdJ (brown) and C57BL/6J (black) were dosed with PhIP: 7-9 days old
      (total amount: 0.006 or 0.58 mg/kg b.wt., for 4 days) and adults (total amount 50
      mg/kg b.wt. during 8 weeks). Hair was collected either 30 days after the last
      PhIP administration (new-born mice) or 8 weeks after the first administration
      (adult mice). PhIP was incorporated into black hair to a greater extent than into
      brown, grey, yellow and non-pigmented hair. The concentration of PhIP in the hair
      of new-born mice exposed to 0.58 mg PhIP/kg b.wt. were (mean+/-S.D.): 328+/-135
      (black), 134+/-41 (brown), 9.1+/-1.2 (yellow) and 5.2+/-1.4 (white) ng/g hair.
      The PhIP concentrations in the hair of adult mice exposed to 50 mg/kg b.wt. were:
      4750+/-1449 (black), 810+/-235 (brown), 541+/-119 (grey), 35.5+/-4.6 (yellow) and
      21.6+/-8.8 (white) ng/g, and the eumelanin hair concentration in the same animals
      decreased in a similar pattern. A linear relationship (r2= 1.00, P<0.0001)
      between the relative PhIP incorporation and the eumelanin concentration in hair
      was found.

PMID- 12403056
TI  - Opposite effects of nicotinic acid and pyridoxine on systemic prostacyclin,
      thromboxane and leukotriene production in man.
AB  - The effects of nicotinic acid (2500 mg orally during 12 hr) and pyridoxine (300
      mg orally twice daily for seven days) on the excretion of urinary 2,3-dinor-6
      ketoprostaglandin F1alpha, 11-dehydrothromboxane B2 and leukotriene E4, the
      markers of systemic prostacyclin, thromboxane A2 and cysteinyl leukotriene
      production, respectively, were investigated in healthy male volunteers (n=6-8).
      Nicotinic acid increased 11-dehydrothromboxane B2 and leukotriene E4 excretions
      to 2.6- and 2.0 times the initial values (P<0.05), respectively. In the
      volunteers treated with pyridoxine, 11-dehydrothromboxane B2 and leukotriene E4
      excretions were decreased to 70% (P<0.05) and 65% (P<0.01) of the initial values,
      respectively, but the excretion of 2,3-dinor-6-ketoprostaglandin F1alpha was
      increased 1.7 times (P<0.01). The results suggest that nicotinic acid increases
      thromboxane and leukotriene synthesis which may not be beneficial for patients
      with cardiovascular diseases or asthma. In contrast, the increase in prostacyclin
      production and the inhibition in thromboxane and leukotriene synthesis by
      pyridoxine might be beneficial in disorders where the production of prostacyclin
      is decreased and the formation of thromboxane and cysteinyl leukotrienes is
      enhanced.

PMID- 12403057
TI  - Lovastatin induces cell death in cardiomyocytes that is not reversible by
      coenzyme Q 10.

PMID- 12403058
TI  - Immunosuppression in xenotransplantation with Wf10.

PMID- 12403060
TI  - Neotame anhydrate polymorphs. II: Quantitation and relative physical stability.
AB  - PURPOSE: To study the relative thermodynamic and kinetic stabilities of neotame
      anhydrate polymorphs A, D, F, and G, and to develop a quantitative method for
      analyzing polymorphic mixtures of A and G by powder X-ray diffractometry (PXRD).
      METHODS: Based on the melting points, heats of fusion, and densities of the four
      polymorphs, thermodynamic rules were applied to study their thermodynamic
      relationships. The phase transition temperature of Forms A and G was estimated
      from their heats of solution and intrinsic dissolution rates (J) in 2-propanol.
      Using PXRD, a method for the quantitative analysis of polymorphic mixtures of
      Forms A and G was developed. Binary polymorphic mixtures of Forms A, D, F, or G
      were stored under zero relative humidity at 23 or 70 degrees C, and their
      compositions were monitored by PXRD. RESULTS: The endothermic enthalpy of
      solution of A, D, F, and G follows the rank order: G (29.71 +/- 0.82 kJ/mol, n =
      4) > A (28.48 +/- 0.51 kJ/mol, n = 4) > D (20.43 +/- 0.45 kJ/mol, n = 4) > F
      (18.77 +/- 0.31 kJ/mol, n = 4). The van't Hoff plots of ln(J) against 1/T for A
      and G show good linearity between 25 degrees C and 32 degrees C. At 23 degrees C
      polymorphic mixtures remain unchanged for 4 months. However, at 70 degrees C the
      phase transition is fast and the relative stability of the four polymorphs
      follows the rank order: G > D > F and G > A. CONCLUSIONS: PXRD provides a
      reliable and accurate technique for the quantitative analysis of polymorphic
      mixtures of Forms A and G. Among the four polymorphs, A-G and A-D are
      enantiotropic pairs, whereas D-F, D-G, F-G are monotropic pairs. The phase
      transition temperature between A and G lies within the range 35-70 degrees C.

PMID- 12403059
TI  - Tumor vasculature directed drug targeting: applying new technologies and
      knowledge to the development of clinically relevant therapies.
AB  - Recognition of the dependence of solid tumor growth on the formation of new blood
      vessels has ignited an enormous research effort aimed at the development of new
      therapeutic strategies for cancer. Besides direct application of drugs inhibiting
      endothelial cell function during angiogenesis, tumor vasculature directed drug
      targeting strategies have been investigated for this purpose. In animal models of
      disease, proof of principle regarding the potential of selective interference
      with tumor blood flow as a powerful tumor therapy has been generated to its full
      extent. The challenge for the coming years will be to develop these strategies
      into clinically applicable ones. New insights into the molecular mechanisms
      prevailing in the endothelium during angiogenesis and into the mechanism(s) of
      action of drugs with anti-angiogenic activities, as well as new techniques to
      identify useful tumor endothelium specific target epitopes have in recent years
      been exploited to meet this challenge. This review summarizes vasculature
      directed therapeutic strategies proven to be successful in pre-clinical models
      and new (drug targeting) technologies enabling the development of more effective
      therapeutics for the treatment of cancer.

PMID- 12403061
TI  - Investigation of solid-state reactions using variable temperature X-ray powder
      diffractometry. II. Aminophylline monohydrate.
AB  - PURPOSE: The object of this investigation was to demonstrate the utility of X-ray
      powder diffractometry (XRD) to study the kinetics of a complex pharmaceutical
      solid-state reaction wherein the reactant, product and intermediate phases were
      all simultaneously quantified. METHODS: Aminophylline monohydrate (I) decomposed
      to anhydrous theophylline (III) either directly or through an intermediate
      (anhydrous aminophylline, II). The reaction kinetics were studied isothermally at
      several temperatures ranging from 65 to 100 degrees C. By measuring the
      intensities of the XRD peaks unique to I, II and III, it was possible to
      simultaneously quantify the 3 phases during the entire reaction. RESULTS:
      Assuming that all the reaction steps follow first-order kinetics. the three
      equations describing the concentrations of I, II and III as a function of time,
      were derived. By fitting the experimental data to these equations, it was
      possible to obtain the rate constants for the three reaction steps. The rate
      constants were obtained at different temperatures and were used to draw Arrhenius
      type plots from which the activation energies were determined. At lower
      temperatures (< 80 degrees C). the concentration of the intermediate phase, i.e.,
      II, was low throughout the reaction while at higher temperatures (> 90 degrees
      C), there was rapid formation and accumulation of II during the early stages of
      the reaction. These differences could be attributed to the fact that k1 (I -->
      II) had a more pronounced temperature dependence than k2 (I --> III) and k3 (II -
      > II). The XRD results were confirmed with isothermal thermogravimetry.
      CONCLUSIONS: Variable temperature XRD is a powerful tool to probe reaction
      kinetics in crystalline pharmaceuticals since it permits simultaneous
      quantification of multiple solid phases.

PMID- 12403062
TI  - Predicting the quality of powders for inhalation from surface energy and area.
AB  - PURPOSE: To correlate the surface energy of active and carrier components in an
      aerosol powder to in vitro performance of a passive dry powder inhaler. METHODS:
      Inverse gas chromatography (IGC) was used to assess the surface energy of active
      (albuterol and ipratropium bromide) and carrier (lactose monohydrate, trehalose
      dihydrate and mannitol) components of a dry powder inhaler formulation. Blends
      (1%w/w) of drug and carrier were prepared and evaluated for dry powder inhaler
      performance by cascade impaction. The formulations were tested with either of two
      passive dry powder inhalers, Rotahaler (GlaxoSmithKline) or Handihaler
      (Boehringer Ingelheim). RESULTS: In vitro performance of the powder blends was
      strongly correlated to surface energy interaction between active and carrier
      components. Plotting fine particle fraction vs. surface energy interaction
      yielded an R2 value of 0.9283. Increasing surface energy interaction between drug
      and carrier resulted in greater fine particle fraction of drug. CONCLUSIONS: A
      convincing relationship, potentially useful for rapid formulation design and
      screening, was found between the surface energy and area parameters derived from
      IGC and dry powder inhaler performance.

PMID- 12403063
TI  - Improvement of dissolution rates of poorly water soluble APIs using novel spray
      freezing into liquid technology.
AB  - PURPOSE: To develop and demonstrate a novel particle engineering technology,
      spray freezing into liquid (SFL), to enhance the dissolution rates of poorly
      water-soluble active pharmaceutical ingredients (APIs). METHODS: Model APIs,
      danazol or carbamazepine with or without excipients, were dissolved in a
      tetrahydrofuran/water cosolvent system and atomized through a nozzle beneath the
      surface of liquid nitrogen to produce small frozen droplets, which were
      subsequently lyophilized. The physicochemical properties of the SFL powders and
      controls were characterized by X-ray diffraction, scanning electron microscopy
      (SEM), particle size distribution, surface area analysis, contact angle
      measurement, and dissolution. RESULTS: The X-ray diffraction pattern indicated
      that SFL powders containing either danazol or carbamazepine were amorphous. SEM
      micrographs indicated that SFL particles were highly porous. The mean particle
      diameter of SFL carbamazepine/SLS powder was about 7 microm. The surface area of
      SFL danazol/poloxamer 407 powder was 11.04 m2/g. The dissolution of SFL
      danazol/poloxamer 407 powder at 10 min was about 99%. The SFL powders were free
      flowing and had good physical and chemical stability after being stored at 25
      degrees C/60%RH for 2 months. CONCLUSIONS: The novel SFL technology was
      demonstrated to produce nanostructured amorphous highly porous particles of
      poorly water soluble APIs with significantly enhanced wetting and dissolution
      rates.

PMID- 12403064
TI  - Hydrate formation during wet granulation studied by spectroscopic methods and
      multivariate analysis.
AB  - PURPOSE: The aim was to follow hydrate formation of two structurally related
      drugs, theophylline and caffeine, during wet granulation using fast and
      nondestructive spectroscopic methods. METHODS: Anhydrous theophylline and
      caffeine were granulated with purified water. Charge-coupled device (CCD) Raman
      spectroscopy was compared with near-infrared spectroscopy (NIR) in following
      hydrate formation of drugs during wet granulation (off-line). To perform an at
      line process analysis, the effect of water addition was monitored by NIR
      spectroscopy and principal components analysis (PCA). The changes in the crystal
      arrangements were verified by using X-ray powder diffraction (XRPD). RESULTS:
      Hydrate formation of theophylline and caffeine could be followed by CCD Raman
      spectroscopy. The NIR and Raman spectroscopic results were consistent with each
      other. NIR revealed the state of water, and Raman spectroscopy gave information
      related to the drug molecule itself. The XRPD confirmed the spectroscopic
      results. PCA with three principal components explained 99.9 of the spectral
      variation in the second derivative NIR spectra. CONCLUSIONS: Both CCD Raman and
      NIR spectroscopic methods can be applied to monitoring of hydrate formation
      processes. However, NIR is more suitable for monitoring solid-water interactions.

PMID- 12403065
TI  - Formation of plasmid-based transfection complexes with an acid-labile cationic
      lipid: characterization of in vitro and in vivo gene transfer.
AB  - PURPOSE: This study tests the hypothesis that gene transfer efficiency may be
      improved through the use of transiently stable transfection complexes that
      degrade within endosomal compartments and promote plasmid escape into the
      cytosol. METHOD: An acid labile cationic lipid, O-(2R-1,2-di-O-(1'Z, 9'Z
      octadecadienyl)-glycerol)-3-N-(bis-2-aminoethyl)-carbamate (BCAT), was designed,
      synthesized, and tested for enhanced gene transfer activity relative to non
      labile controls. RESULTS: The O-alkenyl chains of BCAT were completely hydrolyzed
      after 4 h incubation in pH 4.5 buffer at 25 degrees C. Addition of BCAT to
      plasmid DNA in 40% ethanol followed by ethanol evaporation yielded transfection
      complexes that transfected several cell types in the presence of fetal calf serum
      and without the need of a helper lipid. Transfection complexes prepared from BCAT
      displayed higher luciferase expression than the corresponding DCAT complexes (an
      acid-insensitive derivative of BCAT) for all cell types tested. Uptake studies
      showed that this increase was not due to a difference in the amount of DNA being
      delivered. FAGS analysis for GFP expression showed that BCAT transfection
      complexes yielded 1.6 more transfected cells and 20% higher log mean fluorescence
      than DCAT transfection complexes. In vivo gene transfer was demonstrated in
      subcutaneous tumor-bearing mice by systemic administration of a 60 microg plasmid
      dose. Expression was observed in the lungs and in the tumor, with the highest
      activity being observed in the lungs. CONCLUSIONS: Our results show that
      increased transfection can be obtained by coupling the cationic headgroup to the
      hydrophobic amphiphilic tails via acid-labile bonds. Acid-catalyzed release of
      the alkyl chains should facilitate dissociation of the cationic lipid headgroup
      from the plasmid, thus accelerating one of the rate-limiting steps in cationic
      lipid mediated transfection.

PMID- 12403066
TI  - Evaluation of strategies for the intracellular delivery of proteins.
AB  - PURPOSE: The intracellular delivery of functionally active protein represents an
      important emerging strategy for laboratory investigation and therapeutic
      applications. Although a number of promising approaches for protein delivery have
      been developed, thus far there has been no attempt to compare the merits of the
      various deliver technologies. This issue is addressed in the current study.
      METHODS: In this study we utilize a sensitive luciferase reporter gene assay to
      provide unambiguous and quantitative evaluation of several strategies for the
      intracellular delivery of a biologically active protein comprised of the Gal4 DNA
      binding domain and the VP16 transactivating domain. RESULTS: Both a cationic
      lipid supramolecular complex and a poly meric complex were able to effectively
      deliver the chimeric transcription factor to cultured cells. In addition, protein
      chimeras containing the Tat cell penetrating peptide, but not those containing
      the VP22 peptide, were somewhat effective in delivery. CONCLUSIONS: Both
      supramolecular protein-carrier complexes and protein chimeras with certain cell
      penetrating peptides can support intracellular delivery of proteins. In the cell
      culture setting the supramolecular complexes are more effective, but their large
      size may present problems for in vivo applications.

PMID- 12403067
TI  - Design and function of a dendrimer-based therapeutic nanodevice targeted to tumor
      cells through the folate receptor.
AB  - PURPOSE: We sought to develop nanoscale drug delivery material that would allow
      targeted intracellular delivery while having an imaging capability for tracking
      uptake of the material. A complex nanodevice was designed and synthesized that
      targets tumor cell through the folate receptor. METHODS: The device is based on
      an ethylenediamine core polyamidoamine dendrimer of generation 5. Folic acid,
      fluorescein, and methotrexate were covalently attached to the surface to provide
      targeting, imaging, and intracellular drug delivery capabilities. Molecular
      modeling determined the optimal dendrimer surface modification for the function
      of the device and suggested a surface modification that improved targeting.
      RESULTS: Three nanodevices were synthesized. Experimental targeting data in KB
      cells confirmed the modeling predictions of specific and highly selective
      binding. Targeted delivery improved the cytotoxic response of the cells to
      methotrexate 100-fold over free drug. CONCLUSIONS: These results demonstrate the
      ability to design and produce polymer-based nanodevices for the intracellular
      targeting of drugs, imaging agents, and other materials.

PMID- 12403068
TI  - Targeting microparticles to select tissue via radiation-induced upregulation of
      endothelial cell adhesion molecules.
AB  - PURPOSE: Certain endothelial cell adhesion molecules are up regulated in tissue
      that has been irradiated for therapeutic purposes. This up-regulation of adhesion
      molecules provides a potential avenue for targeting drugs to select tissues.
      METHODS: Microspheres were coated with a mAb to ICAM-1 and the level of adhesion
      of the anti-ICAM-1 microspheres to irradiated tissue in vitro and in vivo was
      quantified. RESULTS: Under in vitro flow conditions, the number of adherent
      microspheres on irradiated HUVEC was 4.8 +/- 0.9 times that of control; the
      adhesion of anti-ICAM-1 microspheres on irradiated HUVEC could be enhanced by
      more than 170% in the presence of RBC (20% hematocrit) in the medium. In vivo in
      a rat cranial window model, the number of adherent anti-ICAM-1 microspheres in
      locally irradiated cerebral tissue was 8 and 13 times that of IgG microspheres at
      24 h and 48 h post-irradiation, respectively and returned to baseline 7 days post
      irradiation. In locally irradiated animals, the number of adhering microspheres
      in unirradiated tissue remained at the basal level. CONCLUSIONS: Radiation
      induced up-regulation of endothelial cell adhesion molecules may be exploited to
      target drugs and/or genes to select segments of the endothelium.

PMID- 12403069
TI  - MDR1 up-regulated by apoptotic stimuli suppresses apoptotic signaling.
AB  - PURPOSE: Recently, MDR1 (P-glycoprotein) and related transporters have been
      suggested to play a fundamental role in regulating apoptosis, but little
      information is available concerning the role of MDR1. Here, the effect of
      apoptotic stimuli on the MDR1 mRNA and apoptotic signaling was examined in MDR1
      overexpressing cells. METHODS: The expression levels of mRNA for MDR1, MRP1,
      MRP2, p53, p21, Bax, and Bcl-2 were measured by real time quantitative polymerase
      chain reaction in HeLa and its MDR1-overexpressing sublines. The effects of
      apoptotic stimuli by cisplatin (CDDP) on their levels were also assessed as well
      as on caspase 3, 8, and 9 activities. RESULTS: MDR1 was rapidly upregulated when
      the cells were exposed to apoptotic stimuli by CDDP. The increase in Bax mRNA to
      Bcl-2 mRNA ratio after treatment with CDDP was suppressed in MDR1-overexpressing
      cells. The increases in caspase 3 and 9 activities after treatment with CDDP were
      suppressed in MDR1-overexpression cells. CONCLUSION: MDR1 is upregulated by
      apoptotic stimuli suppressed apoptotic signaling presumably via the mitochondrial
      pathway.

PMID- 12403070
TI  - On technological and immunological benefits of multivalent single-injection
      microsphere vaccines.
AB  - PURPOSE: With the aim of developing multivalent vaccines for single-injection, we
      examined the feasibility of combining antigens in biodegradable microspheres.
      Such vaccines are expected to improve vaccination coverage by reducing the number
      of vaccination sessions required to generate immunity. METHODS: Mono- and
      multivalent vaccines of Haemophilus influenzae type b (Hib) conjugate, diphtheria
      toxoid (DT), tetanus toxoid (TT), and pertussis toxin (PT) in poly (lactic acid)
      and poly(lactic-coglycolic acid) microspheres were prepared by spray drying, and
      the influence of coencapsulated antigens and excipients on antigen loading,
      release, and stability was examined. Two tetravalent formulations were tested in
      guinea pigs. RESULTS: Monovalent Hib and PT vaccines showed loading efficiencies
      of 10% (Hib) and 30% (PT) in both polymers. The loading efficiencies increased
      upon addition of trehalose and, even more, when the antigens were coencapsulated
      in di- and trivalent combinations. Highest loading efficiencies (> 80%) were
      achieved with trivalent formulations (DT + PT + Hib) that also contained
      coencapsulated albumin. The percentage of antigen released during 24 h of
      incubation was typically 10-40% and decreased as loading efficiency increased.
      Enzyme-linked immunosorbent assay (ELISA) data revealed that TT, DT, and PT
      remained antigenic throughout the encapsulation and subsequent release processes.
      Finally, all antigens maintained their immunogenicity, since strong and sustained
      antibody responses were elicited after a single injection of tetravalent
      microsphere vaccines (DT + TT + PT + Hib) in guinea pigs. CONCLUSIONS: This study
      reveals technologic benefit as well as an immunological potential of multivalent
      single-injection microsphere vaccines. The results support our hypothesis that
      coencapsulation of several antigens may intrinsically improve entrapment of
      antigenic and immunogenic antigen probably by virtue of increased protein
      concentration during microencapsulation leading to mutual stabilization of the
      components.

PMID- 12403072
TI  - Reduced gastrointestinal toxicity following inhibition of the biliary excretion
      of irinotecan and its metabolites by probenecid in rats.
AB  - PURPOSE: To ameliorate the late-onset of severe gastrointestinal toxicity
      provoked by irinotecan (CPT-11), which may be related to the biliary excretion of
      CPT-11 and/or its metabolites. METHODS: Effects of probenecid, an inhibitor of
      MRP2/ABCC2, on the biliary excretion and mucosal intestinal tissue concentration
      of CPT-11 and its metabolites were examined in rats. CPT-11-induced late-onset
      gastrointestinal toxicity was also evaluated. RESULTS: Coadministration of
      probenecid reduced the biliary excretion of CPT-11, an active metabolite (SN-38)
      and its glucuronide by half with a concomitant increase in their plasma
      concentration. When the dose of CPT-11, in the presence of probenecid, was set at
      half that in its absence, the plasma SN-38 concentration was maintained at the
      same level as the control, whereas the mucosal intestinal tissue concentration of
      SN-38 was reduced. Under this condition, CPT-11-induced watery diarrhea, changes
      in intestinal marker enzymes and body weight reduction were much less in the
      probenecid-treated group, although the degree of bone marrow suppression was
      almost the same as that in the control. CONCLUSIONS: Coadministration of
      probenecid with a reduced dose of CPT-11 potently reduces both SN-38 exposure and
      CPT-11-induced late-onset toxicity in gastrointestinal tissues, possibly by
      inhibiting the biliary excretion of CPT-11 and/or its metabolites.

PMID- 12403071
TI  - Transport characteristics of L-carnosine and the anticancer derivative 4
      toluenesulfonylureido-carnosine in a human epithelial cell line.
AB  - PURPOSE: The aim of the present study was to evaluate whether the transepithelial
      transport of the anticancer compound 4-toluenesulfonylureido-carnosine (Ts
      carnosine) and the dipeptide moiety L-carnosine was due to a hPepT1 carrier
      mediated flux. METHODS: Transport experiments were conducted using Caco-2 cell
      monolayers and either reversed-phase HPLC-UV or liquid scintillation counting
      methods for quantification. pKa, LogD, and LogP were determined using the Sirius
      GlpKa meter. RESULTS: L-carnosine was transported across the apical membrane with
      a Km,app of 2.48 +/- 1.16 mM and a Vmax of 2.08 +/- 0.34 nmol x cm(-2) x min(-1)
      and across the basolateral membrane with a Km,app of 7.21 +/- 3.17 mM and a Vmax
      of 0.54 +/- 0.10 nmol x cm(-2) x min(-1), and transepithelially with a Papp of
      4.46 x 10(-2) +/- 6.4 x 10(-6) cm x min(-10). Ts-carnosine had an affinity (Ki)
      for hPepT1 of 2.33 +/- 0.54 mM; however, the transepithelial transport was low as
      compared to that of L-carnosine. CONCLUSIONS: L-carnosine was transported across
      both the apical and basolateral membrane of Caco-2 cell monolayers in a carrier
      mediated manner however, the transepithelial transport followed apparent simple
      non-saturable kinetics. Ts-carnosine had an affinity for hPepT1 but a relatively
      low transepithelial transport. This indicates that the transepithelial transport
      of L-carnosine and Ts-carnosine is not hPepT1 carrier-mediated and that L
      carnosine is not a suitable dipeptide moiety for hPepT1-mediated absorption of
      sulfonamide-type anticancer compounds.

PMID- 12403073
TI  - Structured triglyceride vehicles for oral delivery of halofantrine: examination
      of intestinal lymphatic transport and bioavailability in conscious rats.
AB  - PURPOSE: To compare the influence of triglyceride vehicle intramolecular
      structure on the intestinal lymphatic transport and systemic absorption of
      halofantrine in conscious rats. METHODS: Conscious, lymph cannulated and nonlymph
      cannulated rats were dosed orally with three structurally different
      triglycerides; sunflower oil, and two structured triglycerides containing
      different proportion and position of medium-(M) and long-chain (L) fatty acids on
      the glycerol backbone. The two structured triglycerides were abbreviated MLM and
      LML to reflect the structural position on the glycerol. The concentration of
      halofantrine in blood and lymph samples was analyzed by HPLC. RESULTS: Both the
      lymphatic transport and the total absorption of halofantrine were enhanced by the
      use the MLM triglyceride. The estimated total absorption of halofantrine in the
      lymph cannulated animals was higher than in the nonlymph cannulated animals, and
      this was most pronounced for the animals dosed with the structured triglycerides.
      CONCLUSIONS: Using MLM as vehicle increases the portal absorption of halofantrine
      and results in similar lymphatic transport levels when compared to sunflower oil.
      Total absorption when assessed as absorption in the blood plus lymphatic
      transport for halofantrine after administration in the MLM triglyceride was
      higher than after administration in sunflower oil.

PMID- 12403074
TI  - Evaluation of pharmacokinetic interaction between cyclosporin A and probucol in
      rats.
AB  - PURPOSE: The purpose of this study was to clarify the mechanism of
      pharmacokinetic interaction between cyclosporin A and probucol in clinical cases.
      METHODS: The whole blood concentration of cyclosporin A was measured after oral
      administration of cyclosporin A with or without probucol in rats. Cyclosporin A
      was administered as three types of solutions: the contents of the conventional
      formulation (Sandimmun capsule) diluted with corn oil and the contents of the new
      microemulsion preconcentrate formulation (Neoral capsule) diluted with saline or
      corn oil. The solubility of cyclosporin A and another lipophilic agent tacrolimus
      in water with or without probucol was also measured. RESULTS: The area under the
      blood concentration-time curve (AUC) after the administration of Sandimmun (corn
      oil) and Neoral (corn oil) was significantly decreased to 26% and 41% of the
      control by coadministration of probucol. However in the case of Neoral (saline),
      it was unchanged. The terminal elimination rate constant was not affected by
      probucol in any type of cyclosporin A solution. The solubility of cyclosporin A
      or tacrolimus in water dropped to 49% or 16% of the respective control in the
      presence of probucol. CONCLUSION: The interaction between cyclosporin A and
      probucol is caused by the decreased absorption of cyclosporin A partly based on
      the lowered solubility in the presence of probucol.

PMID- 12403075
TI  - Influence of polyethylene glycol 400 on the gastrointestinal absorption of
      ranitidine.
AB  - PURPOSE: To investigate the effect of co-administered polyethylene glycol 400
      (PEG 400), a pharmaceutical excipient previously shown to accelerate small
      intestinal transit, on the absorption characteristics of ranitidine from the
      gastrointestinal tract. METHODS: Ten healthy male volunteers each received, on
      two separate occasions, an immediate-release pellet formulation of ranitidine
      (150 mg) encapsulated within a hard gelatin capsule and a liquid preparation
      consisting of 150 ml orange juice (control) or 150 ml orange juice containing 10
      g PEG 400 (test). The liquid preparations were also radiolabelled with indium-III
      to allow their transit through the gastrointestinal tract to be followed using a
      gamma camera. On a further occasion an intravenous injection of ranitidine (50
      mg) was administered. Blood samples were taken over a 12 h period on each study
      day to allow a ranitidine plasma and subsequent absorption rate profile to be
      generated for each oral formulation. Urine was collected for 24 h and assessed
      for PEG 400 concentration. RESULTS: The absolute bioavailability of ranitidine
      from the pellet formulation was significantly reduced by 31% (from 51% to 35%)
      and small intestinal liquid transit time was significantly shortened by 37% (from
      226 min to 143 min) as a consequence of PEG 400 in the test preparation. PEG 400
      also affected the rate of ranitidine absorption, with major differences noted in
      the mean absorption time and Cmax parameters. The appearance of double peaks were
      less evident in the ranitidine pharmacokinetic profiles in the presence of PEG
      400, and little or no correlation was observed between the absorption of
      ranitidine and PEG 400. CONCLUSIONS: These results clearly demonstrate that PEG
      400 adversely influences the gastrointestinal absorption of ranitidine. This in
      turn has ramifications for the use of PEG 400 as a pharmaceutical excipient in
      oral formulations.

PMID- 12403076
TI  - Enhanced percutaneous absoption of piroxicam via salt formation with
      ethanolamines.
AB  - PURPOSE: The aim of this work was to prepare piroxicam-ethanolamine salts (PX
      EAs) with improved physicochemical properties for transdermal application.
      METHODS: The physicochemical properties of prepared salts were investigated by
      DSC and FT-IR. Their percutaneous absorption characteristics across hairless
      mouse skin and the effect of various enhancers were studied using a flow-through
      diffusion cell system. RESULTS: Three piroxicam-ethanolamine salts were prepared.
      Piroxicam monoethanolamine salt (PX-MEA) and piroxicam diethanolamine salt (PX
      DEA) had higher solubility than piroxicam in most of vehicles tested and a higher
      permeation rate across the skin. The solubility and permeation rate of piroxicam
      triethanolamine salt (PX-TEA) was lower than those of piroxicam in most of
      vehicles tested. However, there was no significant change in octanol/water
      partition coefficient by salt formation. Salt formation lowered the melting point
      of piroxicam and, of the systems examined, PX-DEA showed the lowest melting
      point. When the effect of various enhancers were evaluated, nonionic surfactants
      having medium HLB, an alkyl chain length of C18 and an ethylene oxide chain were
      better able to modify the permeability of the stratum corneum and to promote the
      effective penetration of piroxicam and PX-EAs. CONCLUSIONS: Piroxicam salt
      formation with MEA and DEA improved the physicochemical properties and enhanced
      the skin permeability of piroxicam.

PMID- 12403077
TI  - Effects of calcium modulation on percutaneous absorption of a model drug.
AB  - PURPOSE: To investigate the effect of modulation of the calcium gradient in the
      skin on the percutaneous absorption of nicotinic acid (NA). METHODS: A skin model
      with an altered calcium gradient was produced by pretreatment with A23187 (25
      microg/ml). The immunohistochemistry was used to evaluate the change in
      phosphoprotein Elk-1. ATR-FTIR spectroscopy was employed to investigate the
      changes in lipid conformation in the skin. The permeation profiles of the model
      drug were studied and the distribution profile of the model drug in the skin
      layer was evaluated using the cryostat micro-sectioning method. RESULTS: The
      immunohistochemistry demonstrated that modulation of the calcium gradient
      increased phosphorylated Elk-1 in the dermis. The FTIR study showed a shift of
      the asymmetric stretch peak, implying an increase in lipid fluidity in the
      epidermis. The amount of NA permeated through the A23187-pretreated skin was
      significantly lower than that of the control (2.2714 +/- 0.6040 vs. 3.1895 +/-
      0.2456 microg/cm2/h). The Cryostat micro-sectioning study showed that there are
      concentration gradients of the model drug across the skin layers with a higher
      gradient in the control than in the A23187-pretreated skin. CONCLUSIONS: The
      alteration in the calcium gradient significantly decreased the permeation rate of
      a hydrophilic drug, such as nicotinic acid.

PMID- 12403078
TI  - The function of leptin in nutrition, weight, and physiology.
AB  - Recent advances indicate that a robust physiologic system acts to maintain
      relative constancy of weight in mammals. A key component of this system is
      leptin. Leptin is an adipocyte hormone that functions as the afferent signal in a
      negative feedback loop regulating body weight. In addition, leptin functions as a
      key link between nutrition and the function of most, if not all other physiologic
      systems. When at their set point, individuals produce a given amount of leptin
      and in turn maintain a state of energy balance. Weight gain results in an
      increased plasma leptin level, which elicits a biologic response characterized in
      part by a state of negative energy balance. Weight loss among both lean and obese
      subjects results in decreased plasma levels of leptin, which lead to a state of
      positive energy balance and a number of other physiologic responses. In humans,
      both the intrinsic sensitivity to leptin and its rate of production vary and both
      appear to contribute to differences in weight. Further studies of leptin, its
      receptor, and the molecular components of this system are likely to have a major
      impact on our understanding of obesity and the interplay between nutrition and
      physiology.

PMID- 12403079
TI  - The role of leptin in the control of body weight.
AB  - Physiologic responses to high and low leptin concentrations are strikingly
      asymmetrical. High concentrations often produce minimal effects, whereas low
      concentrations provoke strong counterregulatory responses. A model and rationale
      for the physiology is presented.

PMID- 12403080
TI  - Leptin and insulin action in the central nervous system.
AB  - Body adiposity is known to be carefully regulated and to remain relatively stable
      for long periods of time in most mammalian species. This review summarizes old
      and recent data implicating insulin and leptin as key circulating signals to the
      central nervous system, particularly the ventral hypothalamus, in communicating
      the size and the distribution of body fat stores. This input ultimately alters
      food intake and energy expenditure to maintain constancy of the adipose depot.
      The key primary neurons in the arcuate nucleus containing NPY/AgRP and POMC/CART
      appear be critical constituents of the CNS regulating system, and are shown to
      contribute to anabolic and catabolic signaling systems to complete the feedback
      loop. New data to indicate shared intracellular signaling from leptin and insulin
      is provided. The satiety system for meals, consisting of neural afferents to the
      hindbrain from the gastrointestinal tract, is described and its effectiveness is
      shown to vary with the strength of the insulin and leptin signals. This provides
      an efferent mechanism that plays a key role in a complex feedback system that
      allows intermittent meals to vary from day to day, but provides appropriate long
      term adjustment to need. Recently described contributions of this system to
      obesity are described and potential therapeutic implications are discussed.

PMID- 12403081
TI  - Leptin: defining its role in humans by the clinical study of genetic disorders.
AB  - Extremely unusual genetic conditions can reveal normal processes governing
      physiologic regulation and metabolism. Children with rare homozygous mutations in
      the leptin gene and complete leptin deficiency develop extreme hyperphagia and
      obesity soon after birth but respond with normal eating and a selective loss of
      excess body fat upon being given small amounts of leptin. Heterozygote relatives
      have 30% more fat than predicted and relatively low leptin levels. This
      demonstrates leptin's fundamental involvement in maintaining energy balance.
      Leptin also seems to act as a metabolic gate allowing children to enter puberty.

PMID- 12403082
TI  - Role of leptin in immunology.
AB  - Leptin seems to play an important role in the generation and maintenance of
      immune responses. Leptin is a cytokine similar in structure to interleukin 2, an
      important T-cell growth factor. Energy balance and supply is increasingly being
      realised as an important factor in the survival and function of immune cells.
      Immune responses are intrinsically energy expensive and come at a cost to the
      responding organism. A fall in leptin concentration, as occurs in starvation,
      causes impaired cellular immune responses with proinflammatory and Th1 immune
      responses being particularly affected. Animal models of leptin deficiency show
      impaired cognate immune responses and are resistant to a variety of autoimmune
      diseases, mainly those dependent on intact T-cell immunity. The next step is to
      determine whether modulation of the leptin axis is therapeutically beneficial in
      a variety of autoimmune or infectious diseases.

PMID- 12403083
TI  - Leptin and reproduction.
AB  - Leptin, a hormone secreted from adipose tissue, plays an important role in
      reproductive physiology. It has been shown to stimulate the reproductive system
      by rescuing the sterility of leptin-deficient mice and advancing the onset of
      puberty in normal mice. Although leptin is not critical for the biology of
      pregnancy in mice, its ability to reduce food intake is blunted in mid-gestation
      suggesting that late pregnancy may be a leptin-resistant state. Modifier genes
      originating from the Balb/cJ genetic background profoundly alter the sterile
      obese phenotype of ob/ob mice by reducing their obesity and stimulating their
      reproductive system despite the absence of leptin. The mechanism of leptin's
      action on the reproductive system remains to be determined but is likely to be
      mediated by multiple factors.

PMID- 12403084
TI  - Peripheral actions of leptin and its involvement in disease.
AB  - The discovery of leptin is broadening our understanding of the mechanisms
      underlying neuroendocrine function. To date, most investigations have focused on
      the effects of leptin on food intake control and body weight homeostasis with
      attention primarily focused on the central effects of leptin. However, the almost
      ubiquitous distribution of leptin receptors in peripheral tissues provides a
      fertile area for investigation and a more dynamic view of leptin is starting to
      unfold. Thus, leptin has generated enormous interest in the interaction as well
      as integration between brain targets and peripheral signals. The scientific
      evidence supporting the direct peripheral effects of leptin on angiogenesis,
      wound healing, lipolysis, blood pressure homeostasis, and satiety control is
      reviewed.

PMID- 12403085
TI  - Leptin and undernutrition.

PMID- 12403086
TI  - The International Museum of Surgical Science: past, present, and future.

PMID- 12403087
TI  - True giant common hepatic artery aneurysm associated with obstructive jaundice: a
      case report.
AB  - The appropriate treatment for extrahepatic hepatic artery aneurysms remains
      controversial, with arguments for and against embolization. We describe a case of
      a giant true aneurysm of the common hepatic artery associated with obstructive
      jaundice of nonhemobilia origin. The patient, a 49-year-old previously healthy
      man, presented with upper midepigastric pain, jaundice, and low-grade fever. The
      diagnosis of the aneurysm was mainly based on computed tomography scan findings.
      The aneurysm was successfully embolized using wire coils, and the patient was
      operated on for acute abdomen. Necrotizing acalculus cholecystitis was found, and
      cholecystectomy followed by aneurysmectomy without hepatic artery reconstruction
      was performed. The jaundice subsided spontaneously, and the patient was
      discharged in good condition. Giant common hepatic artery aneurysms can be
      managed by either surgery or embolization. In the absence of liver ischemia there
      is no need for common hepatic artery reconstruction unless a bilioenteric bypass
      has to be performed to resolve the issue of jaundice. If the latter is required,
      reconstruction of the hepatic artery might be justifiable to maximize the blood
      supply to the bile duct.

PMID- 12403088
TI  - Congenital pyloric atresia: the spectrum.
AB  - Congenital pyloric atresia (CPA) is a very rare malformation. It can occur as an
      isolated lesion or in association with other genetically determined conditions
      such as epidermolysis bullosa or aplasia cutis congenital, or form part of the
      hereditary multiple intestinal atresias syndrome. Five newborns with CPA
      representing the spectrum are presented. The clinical features, diagnosis, and
      outcome are also discussed.

PMID- 12403089
TI  - Posttraumatic cyst of the spleen: a case report and review of the literature.
AB  - Splenic cysts are rare lesions. They are mainly divided into primary or genuine
      cysts and secondary or false cysts according to their etiology and
      pathophysiology. Primary cysts have a cellular lining that can be caused by
      either congenital events or parasitic infestations (Echinococcus). Secondary
      cysts have no cellular lining and may be of hemorrhagic, serous, inflammatory, or
      degenerative origin. It is important for surgeons to assess each individual case
      and decide on the most suitable treatment, taking into account the features of
      the cyst, the time of onset, and the age of the patient, to avoid possible
      complications. We report a case of posttraumatic pseudocyst treated successfully
      by splenectomy and we review the literature.

PMID- 12403090
TI  - Intestinal obstruction caused by infarcted splenic hemangioma with renal vein
      thrombosis in a newborn: a case report.
AB  - The spleen in newborns, infants, and children is rarely involved in a variety of
      pathological processes. These processes may involve an isolated splenic disease
      or may be a part of a systemic illness. Renal vein thrombosis in infants of
      diabetic mothers has been reported. We report a case of a newborn with intestinal
      obstruction caused by an infarcted splenic hemangioma and renal vein thrombosis.
      To the best of our knowledge, this is the youngest case with both above-mentioned
      diagnoses and causes of intestinal obstruction in the English medical literature.

PMID- 12403091
TI  - Case report: complete lymphatic staging in breast cancer by lymphoscintigraphy
      and sentinel node biopsy.
AB  - The status of the lymph nodes in the axilla and in the internal mammary chain are
      the most significant prognostic factors for survival in breast cancer.
      Lymphoscintigraphy shows lymphatic drainage outside the axilla, most often to the
      internal mammary nodes, usually in 20% to 30% of breast cancer patients, when
      intraparenchymal techniques of the radioactive tracer injection are used.
      Lymphoscintigraphy and sentinel node biopsy are potential tools for more accurate
      staging in breast cancer, because they provide additional information compared to
      axillary staging alone. We report a breast cancer case with 10 hot spots in five
      different lymphatic basins (axilla, internal mammary chain, intramammary,
      infraclavicular, and high interpectoral) in the lymphoscintigraphy.

PMID- 12403092
TI  - Liposarcoma of the breast: a case report and review of the literature.
AB  - Sarcoma of the breast constitutes <1% of all malignant breast tumors, and
      liposarcoma of the breast represents 3-24% of the primary breast sarcomas. We
      report a case of a 74-year-old woman presenting with liposarcoma of the left
      breast. The patient presented with a fibrous and hard mass measuring
      approximately 10 x 5 cm in diameter in the upper part of the left breast.
      Aspiration breast cytology showed inflammatory changes and had no malignant
      element. Differential diagnosis with sonography, computed tomography, and
      magnetic resonance imaging was not successful. A wide excision was performed with
      a 2-cm margin of healthy tissue. The tumor was diagnosed histologically as a well
      differentiated liposarcoma (sclerosing type). The patient was discharged and her
      recovery was uneventful. We report a case of liposarcoma of the breast and
      discuss this rare malignant tumor and other types of sarcoma of the breast in
      light of the previously published literature.

PMID- 12403093
TI  - Cystic tumors of the pancreas: preoperative imaging, diagnosis, and treatment.
AB  - The objective of this retrospective study was to explore the accuracy of
      preoperative diagnostic methods and the efficacy of treatment for cystic
      pancreatic tumors. From 1989 to 1999, 18 patients underwent surgery for cystic
      tumor of the pancreas, classified as follows: one serous cystadenoma, eight
      mucinous cystadenomas, six mucinous cystadenocarcinomas, and three nonfunctioning
      islet cell tumors. Computed tomography (CT), endoscopic retrograde
      cholangiopancreatography (ERCP), and fine needle aspiration were performed and
      subsequently reviewed retrospectively by two radiologists. Three patients
      underwent the Whipple procedure and 14 and 1 patients underwent distal and
      central pancreatectomy, respectively. CT showed cystic pancreatic tumors in all
      cases. One case was misdiagnosed as a pseudocyst. The diagnosis was accurate in
      82%, 53%, 37%, and 60% of cases on CT, ERCP, and angiography, and in the
      cytologic analysis of the aspirated fluid, respectively. All operative procedures
      were performed without significant morbidity and there were no postoperative
      deaths. Preoperative diagnosis of cystic pancreatic tumours is imprecise. CT is
      the most reliable preoperative imaging method. Resection should be the treatment
      of choice for these lesions, except in cases of serous cystadenoma.

PMID- 12403094
TI  - Abdominal wall endometrioma after cesarean section: a preventable complication.
AB  - The occurrence of abdominal wall scar endometrioma after cesarean section has
      been reported previously in the literature. However, steps to prevent this
      complication have not been delineated. A study was undertaken of six patients
      seen at our general surgical clinic, each of whom had presented with a painful
      mass at a previous cesarean section site. Ages ranged from 20 to 34 years. The
      duration of their symptoms ranged from 6 to 84 months. All patients underwent
      surgical exploration and excision of the mass, which was revealed by histology to
      be endometrioma. It is strongly recommended that, at the conclusion of the
      procedure of cesarean section, the abdominal wall wound be cleaned thoroughly and
      irrigated vigorously with high-jet saline solution before closure.

PMID- 12403095
TI  - Comparison of hepatic abscess after operative and nonoperative management of
      isolated blunt liver trauma.
AB  - Hepatic abscess has been well recognized as a complication after blunt hepatic
      injuries. The clinical presentation of hepatic abscess after the operative and
      nonoperative management of isolated blunt liver injury is compared in this study.
      From 1995 to 2000, 674 patients with blunt liver injury were admitted and were
      managed either operatively or nonoperatively. Hepatic abscess occurred in 21 of
      these patients. Six of the 21 patients had their liver injuries managed
      nonoperatively (group 1) and the remaining 15 had their liver injuries managed
      operatively (group 2). The severity of injury of both groups of patients was
      similar, but group 2 patients required more blood transfusion and had a higher
      incidence of abscess formation. The formation of abscess occurred within 12 days
      after admission in the group 1 patients but ranged from 5 days to 6 years in the
      group 2 patients. One of the group 1 and eight of the group 2 patients had
      recurrent abscesses and required repeated admission. The nonoperative management
      of blunt hepatic trauma had a better outcome than the operative approach in terms
      of a significant decrease in abdominal infections and tended to result in
      complete recovery without the need of repeated admission and drainage.

PMID- 12403096
TI  - Clinical assessment of neoadjuvant chemotherapy and interval cytoreductive
      surgery for unresectable advanced ovarian cancer.
AB  - Sixty-five patients with unresectable advanced epithelial ovarian cancer who
      underwent exploratory laparotomy or unilateral oophorectomy were reviewed. Forty
      five of 65 patients received 3.8 cycles of neoadjuvant chemotherapy (NAC) and
      were successfully debulked at interval cytoreductive surgery (IRS); 31 of 45
      showed no evidence of disease. Patients with residuals <1 cm at IRS had a high
      possibility of achieving clinical remission. Patients who failed to receive IRS
      showed poor prognosis. Also, 63 patients who underwent conventional primary
      debulking surgery with residuals >1 cm were investigated as a contrast. No
      significant difference was observed in patient survival between the NAC group and
      the conventional treatment group. NAC and IRS offered patients with unresectable
      tumors survival similar to that of those with suboptimally resectable tumors at
      primary debulking. We conclude that this strategy has potential benefits for the
      patients with clinically aggressive ovarian cancer who are unable to receive
      standard treatment.

PMID- 12403097
TI  - Alpha blockade in preoperative preparation of patients with pheochromocytomas.
AB  - Preoperative preparation in pheochromocytoma is usually performed by alpha
      adrenergic blockers. We retrospectively reviewed the efficiency of
      phenoxybenzamine, prazosin, and doxazosin in preoperative preparation.
      Phenoxybenzamine was used for preoperative preparation of 21 pheochromocytoma
      patients, prazosin was used in 11 patients, and doxazosin was used in 17
      patients. Intraoperative and early postoperative blood pressure records and
      postoperative volume replacement records were reviewed. Intraoperative
      hypertension occurred in 17 patients in the phenoxybenzamine group (81%), eight
      patients in the prazosin group (73%), and 14 patients in the doxazosin group
      (82%). There was no statistical difference among the groups (P > 0.05). There was
      also no significant difference between postoperative blood pressure measurements
      and the operative and postoperative volume replacements. We have found that there
      were no significant difference in the operative and postoperative blood pressure
      and plasma volume control among the three groups. We conclude that
      pheochromocytoma surgery is safe with any of these preoperative medications.

PMID- 12403098
TI  - Prevention of intraperitoneal adhesions by intraperitoneal lavage and
      intraperitoneal 5-fluorouracil: experimental studies.
AB  - Postoperative adhesions remain the leading cause of small bowel obstruction.
      Peritoneal adhesions were induced in 180 rats by scraping the cecum and burning
      the adjacent parietal peritoneum by electrocoagulation. The adhesions were scored
      14 days later in a blinded manner. All four types of intraperitoneal
      instillations significantly reduced the extension and the severity of the
      adhesions, at both schedules, when compared to the control group. The use of 5
      fluorouracil at 20 mg/kg in peritoneal dialysis solution during 5 days
      significantly decreased the global score (P = 0.04), the extension (P = 0.04),
      and the severity (P = 0.04) of adhesions when compared to the 5-day instillation
      of peritoneal dialysis alone. Lavage of the abdomen with peritoneal dialysis
      solution or hetastarch decreased the formation of adhesions. Instillation of 5
      fluorouracil in a large volume of peritoneal dialysis solution could be novel and
      promising treatments for prevention of postoperative adhesions.

PMID- 12403099
TI  - Shifting serotypes, plasmid profile analysis and antimicrobial resistance pattern
      of shigellae strains isolated from Kolkata, India during 1995-2000.
AB  - One hundred and sixty-six shigellae strains, isolated from stool samples of
      paediatric patients (< 5 years old) at a Childrens' Hospital in Kolkata, India
      during the period of 1995-2000 were examined for serotyping, drug resistance
      pattern and plasmid profiles. Sh. flexneri (58 %) was found to be commonest
      isolate of total shigellae, followed by Sh. sonnei (28 %), Sh. boydii (9%) and
      Sh. dysenteriae (5%). This profile of species was in sharp contrast to the
      picture obtained before 1995, when Sh. dysenteriae 1 predominated over Sh.
      flexneri. In Sh. flexneri strains, Sh. flexneri 2a (35%) was the most prevalent
      serotype, following Sh. flexneri 3a (31%), Sh. flexneri 6 (14%), Sh. flexneri 2b
      (11%) and Sh. flexneri 4 (9%). Resistance patterns of the strains to 12 commonly
      used antimicrobial agents and minimum inhibitory concentrations (MICs) of the
      antibiotics were also tested. All strains were found uniformly susceptible to
      norfloxacin, but more than 90% strains were resistant to tetracycline, co
      trimoxazole and 67% strains were resistant to ampicillin. Resistance to
      amoxicillin, chloramphenicol and nalidixic acid was found in 55% (range 45-74%),
      46% (range 40-60%) and 29% (range 15-40%) strains respectively. Overall,
      shigellae strains showed statistically significant increase in resistance against
      tetracycline, nalidixic acid and furazolidone (P < 0.05) over the years of this
      study. This indicates decreased efficacy of furazolidone, cotrimoxazole and
      nalidixic acid for the empirical treatment of shigellosis in Kolkata. Although a
      few strains showed intermediate susceptibility to ciprofloxacin (4%) and
      cefotaxime (10%) by disk diffusion test, but the MICs of those antibiotics were
      within the normal limits. Almost 57% of the strains were resistant to four or
      more drugs with high MICs of the antibiotics. Plasmid profile analysis revealed
      presence of large plasmid of 220 kb in majority of the strains except in Sh.
      sonnei and a correlation between presence of smaller plasmids and shigellae
      serotypes. Hence this study reports epidemiological change of shigellae species
      in Kolkata, India with regard to serotypes and antibiotic resistance patterns.

PMID- 12403100
TI  - Preferential association of the heat-stable enterotoxin gene (stn) with
      environmental strains of Vibrio cholerae belonging to the O14 serogroup.
AB  - Toxigenic Vibrio cholerae O1 and O139 serogroups have the capacity of causing
      epidemic and pandemic cholera but are infrequently found in the environment. The
      other serogroups are abundant in aquatic environments but do not possess the
      virulence genes necessary for causing the disease. Of the 559 environmental
      strains of V. cholerae, collected during different periods from environmental
      samples in Calcutta, 9 (1.6%) harboured the heat-stable enterotoxin gene (stn).
      Six of the 9 strains belonged to the O14 serogroup. Thus, V. cholerae strains
      carrying the stn gene revealed preferential association with the O14 serogroup.
      Three of the six strains harboured the tcpA gene of the E1 Tor type, which is an
      unusual feature among environmental V. cholerae strains. A strain that possessed
      the E1 Tor type tcpA also had the CTX prophage. Pulsed field gel electrophoresis
      (PFGE) revealed that the stn gene positive O14 strains of V. cholerae were not
      clonal.

PMID- 12403101
TI  - Routes for salmonella contamination of poultry meat: epidemiological study from
      hatchery to slaughterhouse.
AB  - Data were collected on the prevalence of salmonella at different stages during
      the life cycle of 18 broiler flocks on different farms as well as during
      slaughter in different poultry slaughterhouses. For the isolation of salmonella,
      the highest sensitivity (93.9%) was obtained by enrichment in the semi-solid agar
      Diasalm. The 'overshoe method' utilizing several pairs of overshoes provided the
      highest sensitivity for determining the salmonella status of the broilers during
      rearing. A clear decrease of the relative importance of the first production
      stages was demonstrated for the salmonella contamination of the end product,
      whereas horizontal transmission of salmonella to broilers during rearing and to
      broiler carcasses in the slaughterhouse was shown to be the main determinative
      factor. Ten of the 18 flocks received a salmonella positive status with the
      highest shedding occurring during the first 2 weeks of rearing. The shedding of
      the animals was significantly negatively influenced by the use of subtherapeutic
      or therapeutic doses of antibiotics. The intake of portable material in the
      broiler house was identified as the most important risk factor for horizontal
      transmission. Significant associations were found between the contamination level
      of a flock and hygiene of the broiler house, feed and water in the broiler house
      and both animal and non-animal material sampled in the environment. No
      correlation was found between contamination during the rearing period and
      contamination found after slaughtering. The presence of faecal material in the
      transport crates and predominantly the identity of the slaughterhouse seemed to
      be the determining factors for carcass quality. Improved hygiene management
      during transport of broilers and in some slaughterhouses could significantly
      reduce the risk of salmonella contamination of poultry meat.

PMID- 12403102
TI  - Relationship between home food-handling practices and sporadic salmonellosis in
      adults in Louisiana, United States.
AB  - Salmonellosis is the leading cause of death caused by foodborne bacterial
      pathogens in the United States. Approximately 90% of salmonella infections are
      sporadic, but most of what is known about salmonellosis has come from outbreak
      investigations. We studied the risk for sporadic salmonellosis among 115 persons
      aged > or = 15 years reported to the Louisiana Office of Public Health during May
      1998-April 1999, compared with 115 age-matched controls. Significantly more case
      patients than controls had chronic underlying medical conditions [adjusted odds
      ratio (aOR) = 4.3; 95% confidence interval (CI) = 2.2-8.7]. Although reported
      consumption of specific food items likely to contain salmonella was not
      associated with illness, inconsistent handwashing between preparation of meat and
      non-meat items was associated with illness (aOR = 8.3; CI = 1.1-61.8). Enhanced
      measures to provide a consistently safe food supply and promote safer food
      preparation in households will depend on prevention of sporadic salmonellosis.

PMID- 12403103
TI  - Risk factors for salmonella food poisoning in the domestic kitchen--a case
      control study.
AB  - Domestic kitchen food handling risk factors for sporadic salmonella food
      poisoning are largely unknown. We compared food consumption and food handling
      practices, opportunities for cross contamination and refrigerator temperature
      control, in 99 households in South East Wales in 1997/8 with a case of salmonella
      food poisoning, and control households matched for electoral ward. On univariate
      analyses, cases were significantly more likely than control respondents to have
      purchased free-range eggs in the preceding week, and more likely than control
      households to have handled frozen whole chicken in the previous week, and to
      handle raw chicken portions at least weekly. In multivariate analysis, only
      consumption of raw eggs and handling free-range eggs were significant risk
      factors, independent of the age structure of the family and of the season.

PMID- 12403104
TI  - The use of sequential studies in a salmonellosis outbreak linked to continental
      custard cakes.
AB  - We investigated an outbreak of 54 cases of Salmonella Typhimurium phage type 9
      (STM9) with a specific antibiotic resistance pattern. We used sequential analytic
      studies: two retrospective cohort studies, a case-control study, and a modified
      case-control study. An outbreak of salmonellosis due to Salmonella Typhimurium
      PT9 SSu (resistant to streptomycin and sulphafurazole) was identified. Fifty-four
      cases had illness onset from November 1998 to March 1999. Notifications commenced
      following a restaurant birthday party in December 1998. An initial cohort and
      case control study found no association with consumption of custard cake.
      However, case follow-up identified another cohort of people who had attended a
      birthday party in February at which 8/27 people who consumed a continental
      custard cake were ill compared to 0/10 who did not (P = 0.07). A revised case
      control study found illness was strongly associated with consumption of a
      particular continental custard cake (Mantel-Haenszel matched OR infinity, P =
      0.00004). This report highlights the epidemiological value of using sequential
      study types, and persisting with the investigation of apparently sporadic food
      borne outbreaks.

PMID- 12403105
TI  - Escherichia coli O157 infection associated with a petting zoo.
AB  - A young child was admitted to hospital with haemolytic-uraemic syndrome caused by
      infection with a Shiga toxin 2-producing strain of Escherichia coli (STEC) O157.
      Five days before he became ill, the child had visited a small petting zoo. STEC
      O157 strains were isolated from faecal samples from goats and sheep housed on the
      farm. The human and the animal isolates were indistinguishable by molecular
      subtyping. The petting zoo voluntarily closed temporarily to prevent further
      cases of infection. Two out of 11 other, randomly selected petting zoos
      (including one deer park) visited subsequently, tested positive. Furthermore,
      during the study period there was one more notification of STEC O157 infection
      possibly linked with a farm visit. Although STEC O157 was indeed found in the
      petting zoo associated with this patient, transmission through animal contact
      could not be confirmed because the human isolate was not available for subtyping.
      The case study and the results of the other on-farm investigations highlight the
      risk of acquiring severe zoonotic infections during visits to petting zoos.

PMID- 12403106
TI  - Intra-familial transmission of life-threatening group A streptococcal infection.
AB  - Invasive group A streptococcal (GAS) infections have been of increasing concern
      worldwide during the past 15 years. Spread of group A streptococci to contacts
      with resulting invasive infection has been reported in families, in residential
      nursing homes, and even from patients to health care workers. We report an
      instance of temporally related life-threatening group A streptococcal infection
      in a husband and 2 weeks later in his wife. This example further emphasizes the
      need for careful observation among family members and other close contacts of
      patients with invasive group A streptococcal infection. Although at present there
      are no universal recommendations for monitoring or for antibiotic prophylaxis of
      close contacts of persons with invasive GAS infection, when added to existing
      literature, this report suggests additional consideration is required.

PMID- 12403107
TI  - The prevalence of TT virus and GB virus C/hepatitis G virus infection in
      individuals with raised liver enzymes but without HBV or HCV infection in Taiwan.
AB  - The prevalence of TT virus (TTV) and GB virus-C/hepatitis G virus (GBV-C/HGV)
      infection and the association with raised liver function tests in 546 Taiwanese
      with negative HBsAg, anti-HCV and HCV RNA was elucidated. They were tested for
      serum alanine aminotransferase (ALT), GBV-C/HGV RNA, anti-envelope protein 2
      antibody (anti-E2) and TTV DNA. Direct sequencing and phylogenetic analyses were
      performed on 58 isolates for TTV genotype determination. The prevalence of TTV
      DNA, GBV-C/HGV RNA, anti-E2 and over all GBV-C/HGV exposure was 24.9, 3.4, 8.2
      and 11.1%, respectively. Using uni- and multi-variate analyses, male gender and
      TTV viremia were associated significantly with raised ALT values. Sixty-nine
      percent of TTV isolates were deduced to be TTV genotype 1 and they had
      significantly lower mean age than genotype non-1 isolates. In the population,
      raised ALT may be related to male gender and be attributable to TTV infection but
      not to GBV-C/HGV among individuals with no evidence of current HBV and HCV
      infection. TTV genotype 1 is the most prevalent genotype and associated with
      younger age.

PMID- 12403108
TI  - Initiation, changes in use and effectiveness of highly active anti-retroviral
      therapy in a cohort of injecting drug users.
AB  - The prevalence of anti-retroviral therapy (ART) use over time and the incidence
      of AIDS in a cohort of HIV-seroconverting injecting drug users (IDUs) were
      assessed by means of a hospital-based study of IDUs with a well documented date
      of HIV infection. Use of ART and clinical endpoints were assessed by hospital
      records. Three calendar periods (before 1992, 1992-6 and 1997-2000) were defined
      as corresponding to modalities of ART available. Prevalence of ART usage in each
      calendar period, changes in medication and, hazard of AIDS in patients reaching
      the same duration of HIV infection at different calendar periods were analysed.
      In total, 132 IDUs with a median age of 23 years at seroconversion were followed
      up for 6.8 years (median) (range 0.2-15.7). At the end of the study, 58 patients
      (44%) had developed AIDS. Before the introduction of highly active anti
      retroviral therapy (HAART) 12% of patients were on ART. Starting in 1997, an
      increasing proportion were receiving HAART with a prevalence of 39.5% by January
      2000. Taking 1992-6 as the reference category the relative hazard of AIDS during
      1997-2000 was 0.42 (95% CI, 0.1-1.1) (P = 0.09). A 40% penetration of HAART in a
      cohort of IDUs with known dates of seroconversion resulted in a 58 % reduction of
      the hazard of AIDS.

PMID- 12403109
TI  - Epidemiology of Sindbis virus infections in Finland 1981-96: possible factors
      explaining a peculiar disease pattern.
AB  - Pogosta disease (PD), an epidemic rash-arthritis occurring in late summer is
      caused by Sindbis virus (SINV) and is transmitted to humans by mosquitoes.
      Altogether 2183 PD cases were serologically confirmed 1981-96 in Finland, with an
      annual incidence of 2.7/100000 (18 in the most endemic area of Northern Karelia).
      The annual average was 136 (varying from 1 to 1282) with epidemics occurring in
      August-September with a 7-year interval. Studies on 6320 patients with suspected
      rubella (1973-89) revealed 107 PD cases. The depth of snow cover and the
      temperature in May-July seemed to predict the number of cases. The morbidity was
      highest in 45- to 65-year-old females and lowest in children. Subclinical SINV
      infections were 17 times more common than the clinical ones. The SINV-antibody
      prevalence in fertile-age females was 0.6% in 1992; the estimated seroprevalence
      in Finland is about 2%. Among game animals the tetraonids (black grouse and
      capercaillie) had the highest seroprevalence (65%) in the epidemic year of 1981.

PMID- 12403110
TI  - Phylogenetic and antigenic analysis of influenza A(H3N2) viruses isolated from
      conscripts receiving influenza vaccine prior to the epidemic season of 1998/9.
AB  - Roughly half (54%) of the 910 young conscripts at a garrison in Finland were
      vaccinated with commercial influenza vaccines in autumn 1998. During the
      influenza outbreak in February 1999, 12 H3N2-subtype virus strains were isolated
      from vaccinated patients, and 11 such strains were isolated from unvaccinated
      patients. The isolates were related to the vaccine strain A/Sydney/5/97 and could
      be classified into three subgroups based on sequence variation in the HA1 gene
      coding for the variable domain of viral haemagglutinin (HA). A total of 6-10
      amino-acid substitutions in HA1, three of these in the receptor-binding site,
      differentiated the field strains from the vaccine virus. In haemagglutination
      inhibition (HI) tests, eight strains from the study population exhibited reduced
      reactivity with a variety of antisera including human post-vaccination sera. Six
      of these strains were isolated from vaccinated and two from unvaccinated
      patients. The reduced reactivity did not correlate with particular amino-acid
      changes in HA1. We suggest that low-reactivity viruses may have an advantage over
      other co-circulating variants under some circumstances characterized by enhanced
      immunity-mediated selection and high infection pressure. Whether the frequency of
      these viruses increased in our vaccinated study population cannot be determined,
      nor can their effect on vaccine efficacy.

PMID- 12403111
TI  - An outbreak of viral gastroenteritis following environmental contamination at a
      concert hall.
AB  - In January 1999, an outbreak of viral gastroenteritis affected more than 300
      people who attended a metropolitan concert hall over a 5-day period. Norwalk-like
      virus (NLV) was confirmed in faecal samples by reverse transcription polymerase
      chain reaction assay. The index case was a concert attendee who vomited in the
      auditorium and adjacent male toilet. Gastrointestinal illness occurred among
      members of 8/15 school parties who attended the following day. Children who sat
      on the same level of the auditorium as the index case were much more likely to be
      ill than those seated elsewhere (relative risk 7.1, 95% confidence interval 5.4
      9.2. P < 0.001). The majority of other reported cases had not been present on the
      evening of the vomiting incident. Disinfection procedure was poor and the
      disinfectant used contained no sodium hypochlorite. Transmission most likely
      occurred through direct contact with contaminated fomites. The outbreak has
      implications for disinfection procedures following vomiting incidents at public
      venues.

PMID- 12403112
TI  - Epidemiology of measles in Blantyre, Malawi: analyses of passive surveillance
      data from 1996 to 1998.
AB  - Measles surveillance data in Blantyre, Malawi were reviewed for 1996-8 to
      describe the epidemiology of infection and to estimate vaccine efficacy (VE) by
      the screening method. A total of 674 measles cases were reported to the Blantyre
      District Health Office during this period. Age distribution showed that 108
      (16.1%) of the cases were aged less than 1 year. The median age was 5 years.
      Eighty percent of the cases between 1 and 19 years had been previously
      vaccinated. VE was 68.6% (95% CI, 527-792) for children 12-23 months of age and
      67.3% (95% CI, 48.3-79.3) for infants 9-11 months of age. Reasons for this low
      vaccine efficacy are discussed. Previous vaccination history was negatively
      associated with the risk for developing cough during measles infection (odds
      ratio (OR), 0.30; 95% CI, 0.09-0.91), diarrhoea (OR, 0.64; CI, 0.44-0.95) and
      pneumonia (OR, 0.40; CI, 0.25-0.62). Logistic regression analysis showed that
      pneumonia in adults was negatively associated with vaccination history. The
      passive surveillance system for measles in Malawi was useful to describe the
      epidemiology of measles.

PMID- 12403113
TI  - Underreporting of malaria incidence in The Netherlands: results from a capture
      recapture study.
AB  - The aim of this study was to estimate the completeness of notification of malaria
      by physicians and laboratories in the Netherlands in 1996. We used a capture
      recapture (CRC) analysis of three incomplete, partially overlapping registers of
      malaria cases: a laboratory survey, the Notification Office and the hospital
      admission registration. The response of the laboratories was 83.2%. In 1996 the
      laboratories microscopically identified 535 cases of malaria, 330 patients with
      malaria were admitted to hospital and physicians notified 311 malaria cases. 667
      malaria cases were recorded in at least one register. CRC analysis estimated the
      total number of malaria cases at 774 (95 % CI of 740-821). This implies a
      completeness of notification of 40.2% for physicians and 69.1% for the
      laboratories. It can be concluded that laboratory-based notification can
      considerably increase the number of officially reported malaria cases as compared
      to notification by physicians. However, possibly one-third of the cases may still
      go unreported.

PMID- 12403114
TI  - Investigation of an outbreak of cercarial dermatitis.
AB  - We present the investigation of an outbreak of cercarial dermatitis that occurred
      in a recreational-tourist lake in the Quebec City region (Canada) in the summer
      of 1999. A case-reporting form was sent to 450 families likely to have activities
      that would bring them in contact with the lake's water. The snails were
      characterized and the prevalence of their infestation by schistosomes was
      investigated. In total, 63 episodes consistent with cercarial dermatitis were
      reported. Sixty-nine percent of the cases occurred from swimming at the same
      beach. This location was the one where the only population of snails in the lake
      was identified. Shoreline residents were informed that they should not feed
      waterfowl, and a clean-up of the snail population was done at the start of the
      following summer. There were no cases of cercarial dermatitis at this site the
      following summer.

PMID- 12403115
TI  - Use of pulsed-field gel electrophoresis for detecting differences in
      Staphylococcus aureus strain populations between dairy herds with different
      cattle importation practices.
AB  - The hypothesis tested was that dairy herds which import cattle for replacement or
      expansion have a higher prevalence of Staphylococcus aureus mastitis and a
      greater number of new Staphylococcus aureus strains enter their herds than closed
      herds. Fifteen commercial dairy herds were divided into four groups based on
      cattle importation practices. Composite foremilk samples were collected at 4
      monthly intervals for 1 year from all lactating cattle. Additionally, foremilk
      samples were collected from cattle at parturition and skin swabs were taken from
      the udder of primiparous heifers. All samples were cultured for Staphylococcus
      aureus and isolates were strain-typed using pulsed-field gel electrophoresis.
      Herds that purchased replacement heifers had a higher prevalence of
      Staphylococcus aureus mastitis than herds that purchased lactating cattle for
      expansion (P = 0.02). Herds that purchased replacement heifers had more total
      strains of Staphylococcus aureus (P = 0.01) and more new strains (P = 0.04) enter
      the herd than closed herds.

PMID- 12403116
TI  - A mathematical model of Staphylococcus aureus control in dairy herds.
AB  - An ordinary differential equation model was developed to simulate dynamics of
      Staphylococcus aureus mastitis. Data to estimate model parameters were obtained
      from an 18-month observational study in three commercial dairy herds. A
      deterministic simulation model was constructed to estimate values of the basic
      (R0) and effective (Rt) reproductive number in each herd, and to examine the
      effect of management on mastitis control. In all herds R0 was below the threshold
      value 1, indicating control of contagious transmission. Rt was higher than R0
      because recovered individuals were more susceptible to infection than individuals
      without prior infection history. Disease dynamics in two herds were well
      described by the model. Treatment of subclinical mastitis and prevention of
      influx of infected individuals contributed to decrease of S. aureus prevalence.
      For one herd, the model failed to mimic field observations. Explanations for the
      discrepancy are given in a discussion of current knowledge and model assumptions.

PMID- 12403117
TI  - Staphylococcus aureus nasal carriage in the community: a survey from central
      Italy.
AB  - Recently, concern has increased regarding the spread of methicillin-resistant
      Staphylococcus aureus (MRSA) in the community. We studied 812 subjects from
      central Italy to establish the rates of nasal carriage of S. aureus, and
      antibiotic susceptibility patterns, in the community. The prevalence of S. aureus
      nasal carriage was 30.5%. Only one subject, with predisposing risk factors for
      acquisition, was identified as carrier of MRSA (prevalence of 0.12%). The
      presence of MRSA in the community of our area still appears to be a rare event.
      Among methicillin-susceptible S. aureus (MSSA) isolates, a surprisingly high rate
      (18%) of resistance to rifampin was observed.

PMID- 12403118
TI  - Nucleotide substitutions in vanC-2 gene of Enterococcus casseliflavus isolates
      obtained from chickens.
AB  - DNA sequencing of the vanC-2 gene was partially carried out on 10 isolates of
      Enterococcus casseliflavus obtained from 8 samples of imported chickens in Japan
      between July 1999 and June 2001 to evaluate the variation in the gene. Forty
      nucleotide substitutions in 36 codons were identified within 345 base pairs when
      compared with the vanC-2 sequence of the reference strain E. casseliflavus
      ATCC25788. Identical nucleotide substitutions were commonly found in the isolates
      recovered from chickens imported from both Brazil and China. Pulsed-field gel
      electrophoresis (PFGE) patterns of NotI-digested chromosomal DNA of these strains
      were distinguished by two, or more than six, band differences. These observations
      suggest that sequencing of the vanC-2 gene may be helpful for epidemiological
      investigation in combination with the PFGE analyses of the isolates, although
      particular genotypes are unlikely to be restricted to each of the countries that
      exported chickens.

PMID- 12403119
TI  - Anthrax: what should the otolaryngologist know?

PMID- 12403120
TI  - Topical treatment with growth factors for tympanic membrane perforations:
      progress towards clinical application.
AB  - Basic scientific research has demonstrated that epidermal growth factor (EGF),
      basic fibroblast growth factor (bFGF), platelet-derived growth factor-AA (PDGF
      AA) and transforming growth factor-alpha (TGF-alpha) are induced by acute
      tympanic membrane (TM) perforation. The expression of these growth factors peaks
      during the inflammatory phase and then declines, suggesting their involvement in
      the healing process of the TM. Expression of EGF receptor, bFGF receptor, PDGF
      receptor and keratinocyte growth factor (KGF) receptor in the TM has also been
      reported. Identification of these receptors indicates that the target cells in
      the TM may be stimulated during the process of healing by the corresponding
      exogenous growth factor in vivo. Some reports from animal studies showed
      encouraging effects of EGF, bFGF and PDGF-AA in terms of accelerated or enhanced
      healing of acute and chronic TM perforations without significant adverse effects.
      Two reports of clinical trials of topical application of EGF or bFGF for TM
      perforations revealed mixed results. In this article special considerations for
      future directions of research into growth factors are discussed and related
      articles on healing of skin wounds and other lesions are reviewed. Further
      experimental and clinical studies on the mechanism of action of growth factors,
      timing of application, selection (either singly or in combination), delivery
      mode, dose and safety aspects, as well as more clinical trials, are warranted,
      and will pave the way for clinical application.

PMID- 12403121
TI  - Effects of intratympanic injection of steroids on changes in rat inner ear
      aquaporin expression.
AB  - Although steroid treatment is generally administered for patients with inner ear
      disorders, including Meniere's disease, the mechanism via which steroids exert
      their effects remains to be clarified. The aquaporins (AQPs) are a family of
      small transmembrane water transporters, and it has recently been revealed that
      they play a role in regulating homeostasis in the inner ear fluids. In order to
      elucidate the action points of steroids in the inner ear, we firstly identified
      AQPI, 2, 3, 4, 5 and 6 mRNAs in the rat cochlea and AQP1, 3, 4, 5 and 6 in the
      rat endolymphatic sac by means of reverse transcription-polymerase chain
      reaction. Subsequently, we found that intratympanic injections of steroids
      upregulated AQPI mRNA of the rat cochlea in a dose-dependent manner. These
      results suggest that steroids may affect water homeostasis in the rat inner ear
      mainly via AQP1.

PMID- 12403122
TI  - Cervical reflex induced by click stimuli in cats.
AB  - We studied click-evoked potentials in the anterior horn of the spinal cord in 17
      cats. A concentric needle electrode was inserted into the anterior horn of the
      spinal cord at levels C3-C6. Potentials evoked with 105 dB SPL clicks were
      recorded with a peak latency of 4.89-5.10 ms only at the C3 level. These
      responses were observed 45-60 dB SPL above the auditory brainstem response (ABR)
      threshold, and no potentials were evoked by stimulation of the contralateral ear.
      Average was performed 100 times with changes in stimulation frequency of 1-20 Hz.
      The amplitude of the potentials decreased with increasing stimulus frequency, but
      there were no changes in ABRs. The responses disappeared after destruction of the
      medial vestibulospinal tract at the obex level, but ABRs were still recorded. The
      spinal nucleus of the accessory nerves was located in the anterior horn of the
      spinal cord at levels C1-C6, and the sternocleidomastoid muscle motoneurons were
      found at levels C1-C3. The click-evoked potentials recorded in this study reflect
      responses of the spinal nucleus of accessory nerves through the vestibulospinal
      tract to click stimulation. The responses have the same characteristics as
      vestibular-evoked myogenic potentials that can be recorded using surface
      electrodes over the sternoclei-domastoid muscles of humans.

PMID- 12403123
TI  - Influence of contralateral stimulation by two-tone complexes, narrow-band and
      broad-band noise signals on the 2f1-f2 distortion product otoacoustic emission
      levels in humans.
AB  - In order to test the frequency specificity of the efferent suppressive effect on
      otoacoustic emissions, changes in the 2f1-f2 distortion product otoacoustic
      emission (DPOAE) levels induced by contralateral stimuli of different spectra
      were measured in 10 normally hearing adults. Three types of contralateral stimuli
      were used: (i) a set of 6 pairs of pure tones with the same frequencies as used
      for DPOAE stimulation; (ii) 6 narrow-band noise signals with cut-off frequencies
      equal to the frequencies of the primary tones used for DPOAE stimulation; and
      (iii) broad-band noise with a bandwidth of 840-6,000 Hz. A small suppressive
      effect was observed mainly in the mid-frequency region. Broad-band noise was more
      effective at suppressing DPOAEs than narrow-band noises and two-tone complexes.
      Occasionally, small enhancements in DPOAE amplitudes were observed. Based on the
      results of this study, it is concluded that DPOAE changes induced by
      contralateral stimuli are not frequency-specific, and are too small to have
      routine clinical value.

PMID- 12403124
TI  - Changes in fos expression in the rat brainstem after bilateral labyrinthectomy.
AB  - In order to elucidate the role of the vestibulocerebellar neural circuits during
      two-stage bilateral labyrinthectomy (BL) we examined Fos-like immunoreactive (
      LIR) neurons as a marker of neural activation in the rat brainstem after BL and
      the projections of these neurons into the vestibulocerebellum using retrograde
      tracing and immunohistochemical techniques. Simultaneous BL did not show any Fos
      expression in the medial vestibular nucleus (MVe). However, with an interval of >
      6 h between the two stages of BL, Fos-LIR neurons were induced in the ipsilateral
      (ipsi-) MVe of the side operated on second, partially projecting into the ipsi
      vestibulocerebellum. A previous study demonstrated that some of the unilateral
      labyrinthectomy-induced Fos-LIR neurons in the ipsi-MVe projected into the ipsi
      vestibulocerebellum and inhibited the contra-MVe neurons, resulting in the
      restoration of the right-left balance. Taken together with our present data, it
      is suggested that some of the labyrinthectomy-induced Fos expression in the ipsi
      MVe is representative of a switch-on signal for the vestibulo-cerebello
      vestibular inhibitory neural circuits, which remain turned off after symmetrical
      lesions such as simultaneous BL but are turned on after severe asymmetrical
      lesions in order to restore the balance.

PMID- 12403125
TI  - In vivo expression of adenovirus-mediated lacZ gene in murine nasal mucosa.
AB  - Adenovirus is a good tool for transferring exogenous genes into various organs
      because the virus has a wide spectrum of infection. In this report, we
      demonstrate that a recombinant adenovirus, Ax1CAlacZ, can transfer an exogenous
      lacZ gene into murine nasal mucosa in vivo. The efficiency of the exogenous gene
      expression varied for different cell types and was improved by optimizing the
      method of administration. In the olfactory region, the olfactory epithelia,
      sustentacular cells and olfactory nerve efficiently expressed lacZ gene
      transferred by Ax1CAlacZ using either of two administration methods, dripping or
      injecting. In contrast, in the respiratory region, the respiratory epithelia but
      not the subepithelial tissues expressed lacZ gene transferred by Ax1CAlacZ, and
      the efficiency of the gene transfer, which was low when the virus was
      administered by nasal drops, was improved when the virus was administered by
      injection. Our study demonstrated that gene transfer mediated by adenovirus is
      more efficient in the olfactory epithelia than in the respiratory epithelia, and
      may be applicable to nasal or paranasal diseases such as olfactory epithelial
      disturbances.

PMID- 12403126
TI  - Heme oxygenase and nitric oxide synthase in human middle ear epithelium indicates
      local carbon monoxide and nitric oxide production.
AB  - The gas mixture of the middle ear differs from that of the atmosphere, a fact
      that has been attributed to gas exchange across the middle ear mucosa. Several
      diseases of the middle ear seem to be related to impaired ventilation together
      with conjunctional changes in pressure and gas composition. Carbon monoxide (CO)
      and nitric oxide (NO) have recently been shown to be endogenously produced in the
      human lung as well as in the nasal airways. The production of CO and NO is
      enzymatically regulated by heme oxygenase (HO) and NO synthase (NOS),
      respectively. These enzymes display isoforms that are both constitutively
      expressed [HO-2, endothelial NOS (eNOS), neuronal NOS (nNOS)] and inducible [HO
      1, inducible NOS (iNOS)] following different types of stimulation. The present
      study was designed to investigate the presence of HO-1, HO-2 and eNOS in the
      middle ear epithelium, using immunocytochemistry. Specimens from human middle ear
      mucosa obtained at autopsy and during surgery revealed HO-1-, HO-2- and eNOS-like
      immunoreactivity, indicating the possibility of local CO and NO production in the
      middle ear. If this assumption is true, it may affect our understanding of middle
      ear physiology and give new insights into the mechanisms behind middle ear
      pathology.

PMID- 12403127
TI  - IL-13 suppresses MUC5AC gene expression and mucin secretion in nasal epithelial
      cells.
AB  - Recently, it was found that IL-13 is involved in allergic inflammation and mucus
      hypersecretion in in vivo animal models. However, the role of IL-13 in in vitro
      cellular models has yet to be determined. This study aimed to investigate the
      direct effect of IL-13 on mucin gene expression and mucin secretion in cultured
      normal human nasal epithelial cells. After treatment with IL-13, total mucin and
      MUC5AC mucin levels were measured using an immunoblotting assay. MUC2, MUC5AC and
      MUC8 mRNA expression were determined using reverse transcription-polymerase chain
      reaction. Also, immunostaining was performed using a MUC5AC antibody on
      histologic and cytospin slides. After treatment with > or = 5 ng/ml IL-13, the
      level of total mucin and MUC5AC mucin secretion decreased substantially. The
      expression of MUC2 and MUC8 mRNA increased with higher concentrations of IL-13,
      but the expression of MUC5AC mRNA decreased. On the 7th day after IL-13
      treatment, a significant decrease in the number of MUC5AC-positive cells was
      confirmed by immunostaining. These findings indicate that IL-13 suppresses MUC5AC
      mucin gene expression and mucin secretion in cultured normal human nasal
      epithelial cells in vitro.

PMID- 12403128
TI  - Correction of the glosso-larynx and resultant positional changes of the hyoid
      bone and cranium.
AB  - In ankyloglossia with deviation of the epiglottis and larynx (ADEL) the tongue is
      located forward and as a result the epiglottis is elevated and leans towards the
      mouth. The larynx is also raised and curves ventrally. Various symptoms have been
      observed as a result of this condition. Correction of the glosso-larynx (CGL) is
      the operation performed to treat ADEL. The CGL procedure and the results obtained
      with it are reported in this paper. In addition, we studied the following six
      parameters using head and neck X-rays before and after CGL (the changes in these
      parameters as a result of CGL are shown in parentheses): (i) the shortest
      vertical length between the hyoid bone and mandible (+ 10.3 mm); (ii) the
      vertical length between the hyoid bone and the tangent line of C2-4 (+ 4.6 mm);
      (iii) the shortest length between the hyoid bone and the chin (+ 2.9 mm); (iv)
      the angle between the hyoid bone and the tangent line of C2-4 (+ 3.3 degrees);
      (v) the length of H-M, where H is the intersection of a tangent line of C2-4 and
      a vertical line from the hyoid bone and M is the intersection of a tangent line
      of C2-4 and the mandible (+ 7.4 mm); and (vi) the width of the narrowest part of
      the hypopharynx (+ 3.0 mm). The changes in all the measured parameters after CGL
      were significantly different (p <0.05).

PMID- 12403129
TI  - Oral breathing in patients with sleep-related breathing disorders.
AB  - Mouth breathing may contribute to increased collapsibility of the upper airways
      because of decreased contractile efficiency of the upper airway muscles as a
      result of mouth opening. Nasal airflow is also hypothesized to have a stimulating
      effect on the respiratory drive via receptors in the nose. Accordingly, patients
      with sleep-related breathing disorders (SRBD) are believed to breathe more
      through their mouth than healthy persons. In our department, polysomnography is
      routinely performed with a nasopharyngeal/oesophageal catheter for continuous
      pressure and flow measurements. We have shown previously that these sensors are
      able to differentiate between oral and nasal breathing. The aim of this study was
      to use these sensors to estimate the degree of oral breathing during sleep in
      patients with SRBD. The proportions of mouth breathing during sleep were 9.8% (SD
      19.1%) for patients without SRBD, 16.4% (17.8%) for patients with mild SRBD,
      11.9% (13.4%) for patients with moderate SRBD and 4.5% (7.4%) for patients with
      severe SRBD. There were no significant differences in the amount of mouth
      breathing between these groups. The proportion of patients who breathed through
      the mouth was smaller than that described previously for healthy subjects. The
      more severe the disease, the less patients tended to breathe through their mouth
      alone, and this finding was the opposite of what we expected.

PMID- 12403130
TI  - Effect of meteorological parameters on acute laryngitis in adults.
AB  - The aim of this study was to investigate the influence of weather conditions on
      the frequency of acute laryngitis in adults. The medical records of 825 patients
      with a diagnosis of acute laryngitis obtained over a 5-year period were reviewed.
      Meteorological data reviewed included the daily values of 13 parameters. The
      monthly distribution of the disease was assessed. In addition, a detailed 2-part
      statistical analysis was performed as follows: (i) the relationship between each
      meteorological parameter and the frequency of the disease was investigated, using
      contingency tables; and (ii) the 1825-day period was divided into 8 groups
      characterized by similar weather, using factor and cluster analysis, and the
      disease frequency in each group was assessed. Our observations were as follows:
      1. Meteorological parameters, such as low temperature, low diurnal temperature
      range, low atmospheric pressure and low mean water vapor pressure, were
      associated with an increased occurrence of acute laryngitis. 2. Significant
      changes in maximum temperature or a significant drop in atmospheric pressure, as
      compared to the previous day's conditions, favored new cases of the disease. 3.
      The cold period of the year was associated with an almost two-fold increase in
      the frequency of disease cases, which peaked in March and reaching a minimum
      during August. 4. The peak frequency of cases was associated with winter weather
      conditions, which were characterized by high humidity readings. In conclusion,
      meteorological parameters, and their variation and covariation, are strongly
      associated with acute laryngitis in adults.

PMID- 12403131
TI  - Secondary shunt procedure for alaryngeal patients in an outpatient clinic.
AB  - The shunt procedure used for laryngectomized patients undergoing secondary
      tracheo-esophageal (T-E) puncture is inconvenient and causes stress to the
      patient. In order to overcome these problems we developed a novel surgical T-E
      shunt technique using the Groningen voice prosthesis that does not require
      esophagoscopy or general anesthesia and can be performed in an outpatient clinic.
      In this procedure, a shunt is created using a pair of nasal forceps with the
      patient seated. An endoscope with biopsy forceps is used to insert the Groningen
      voice prosthesis. The procedure is usually completed within 20 min after inducing
      local anesthesia. Neither the technique itself nor the time taken to complete the
      procedure differed for T-E and tracheo-neoesophageal (reconstructed with flap)
      shunting. We believe that this procedure is suitable for patients who are afraid
      of esophagoscopy and/or are not considered suitable candidates for esophagoscopy
      and repeated general anesthesia. The procedure is also beneficial for both
      patients and surgeons with regard to its duration and the cost-effectiveness of
      treatment.

PMID- 12403132
TI  - Evolution of laryngeal cancer surgery.

PMID- 12403133
TI  - Management of the neck in cancer of the major salivary glands, thyroid and
      parathyroid glands.

PMID- 12403134
TI  - Complication rates after operations for benign thyroid disease.
AB  - Controversy persists concerning the use of total thyroidectomy in benign thyroid
      disease and varying complication rates have been reported. We evaluated the
      safety of total thyroidectomy or lobectomy in benign thyroid disease. During a 5
      year period, 102 patients were operated on for benign thyroid disease, including
      multinodular goiter (n = 55), solitary nodule (n = 18), toxic nodular goiter (n =
      22) and Hashimoto's thyroiditis (n = 7). Recurrent laryngeal nerves were
      routinely investigated during dissection. Total thyroidectomy was performed in 27
      cases, unilateral total lobectomy with isthmectomy in 38 and unilateral total,
      contralateral subtotal lobectomy in 37. One (0.9%) temporary superior laryngeal
      nerve palsy, 1 (0.9%) temporary recurrent nerve palsy and 1 (0.9%) temporary
      hypoparathyroidism occurred. Wound seroma developed in 2 patients (1.9%). There
      were no deaths or permanent complications. This study shows that total
      thyroidectomy or lobectomy can be done with minimal morbidity in cases of benign
      thyroid disease affecting the whole gland.

PMID- 12403135
TI  - Autoimmune sensorineural hearing loss improved by tumor necrosis factor-alpha
      blockade: a case report.
AB  - Autoimmune inner ear disease is a treatable cause of sensorineural hearing loss
      and it is important for physicians and hearing health professionals to recognize
      that early diagnosis and proper management strategies may result in stabilization
      and improvement in hearing. The pathogenesis of autoimmune sensorineural hearing
      loss remains unclear but antibodies directed against the inner ear and/or
      cellular effectors have been proposed. Therefore, immunosuppressive drugs such as
      steroids and methotrexate are administered to interfere with the progression of
      hearing loss and in some cases have been found to improve hearing. We report
      herein the history of a patient who was treated by systemic administration of
      anti-tumor necrosis factor-alpha antibodies for Crohn's disease and who also had
      associated sensorineural hearing loss. Audiometric follow-up revealed not only
      the efficacy of tumor necrosis factor-alpha blockade in arresting the hearing
      loss but also an improvement in hearing of 15 dB on average across all
      frequencies. Hearing remained stable afterwards.

PMID- 12403136
TI  - Cryogenic dual-mode resonator for a fly-wheel oscillator for a caesium frequency
      standard.
AB  - A dual-mode, sapphire-loaded cavity (SLC) resonator has been designed and
      optimized with the aid of finite element software. The resonance frequency was
      designed to be near the frequency of a Cs atomic frequency standard. Experimental
      tests are shown to agree very well with calculations. The difference frequency of
      two differently polarized modes is shown to be a highly sensitive temperature
      sensor in the 50 to 80 K temperature range. We show that an oscillator based on
      this resonator has the potential to operate with fractional frequency instability
      below 10(-14) for measurement times of 1 to 100 seconds. This is sufficient to
      operate an atomic clock at the quantum projection noise limit.

PMID- 12403137
TI  - Novel method for driving the ultrasonic motor.
AB  - This paper reports a novel driving method for an annular plate-type ultrasonic
      motor. Instead of the direct current/alternating current (DC/AC) converter type
      driver using conventional electromagnetic transformer, a compact disc-type
      piezoelectric transformer is used to obtain high voltage output for driving the
      ultrasonic motor. The piezoelectric transformer is operated in the radial
      vibration mode at resonance frequency close to the resonance frequency of the
      ultrasonic motor. Later, it was found that the piezoelectric transformer could
      drive the ultrasonic motor, even if their resonance frequencies are not exactly
      the same by incorporating the matching network in the circuit. The maximum speed
      of the ultrasonic motor obtained by using this driving method is over 300 rpm. It
      is believed that the results of this study will have impact on the integration
      and miniaturization of the ultrasonic motor and its driving circuit.

PMID- 12403138
TI  - Ultrafast compound imaging for 2-D motion vector estimation: application to
      transient elastography.
AB  - This paper describes a new technique for two-dimensional (2-D) imaging of the
      motion vector at a very high frame rate with ultrasound. Its potential is
      experimentally demonstrated for transient elastography. But, beyond this
      application, it also could be promising for color flow and reflectivity imaging.
      To date, only axial displacements induced in human tissues by low-frequency
      vibrators were measured during transient elastography. The proposed technique
      allows us to follow both axial and lateral displacements during the shear wave
      propagation and thus should improve Young's modulus image reconstruction. The
      process is a combination of several ideas well-known in ultrasonic imaging: ultra
      fast imaging, multisynthetic aperture beamforming, 1-D speckle tracking, and
      compound imaging. Classical beamforming in the transmit mode is replaced here by
      a single plane wave insonification increasing the frame rate by at least a factor
      of 128. The beamforming is achieved only in the receive mode on two independent
      subapertures. Comparison of successive frames by a classical 1-D speckle tracking
      algorithm allows estimation of displacements along two different directions
      linked to the subapertures beams. The variance of the estimates is finally
      improved by tilting the emitting plane wave at each insonification, thus allowing
      reception of successive decorrelated speckle patterns.

PMID- 12403139
TI  - Velocity bias and fluctuation in the standard dual beam Doppler reconstruction
      algorithm.
AB  - Bias and fluctuation of the standard velocity reconstruction algorithm for dual
      beam vector Doppler velocity estimation systems are analyzed; both magnitude and
      angle properties are considered. Bias can arise from any of the error sources
      known to affect single beam systems in addition to both translation and angle
      misregistration between the two sample volumes; standard deviation is the result
      of random temporal fluctuations in Doppler frequency estimates in each beam.
      Approximate closed-form expressions for both biases and standard deviations of
      the velocity estimates are derived, and the performance of a typical practical
      dual beam system is discussed as an illustration of the theory.

PMID- 12403140
TI  - A new high resolution color flow system using an eigendecomposition-based
      adaptive filter for clutter rejection.
AB  - We present a new signal processing strategy for high frequency color flow mapping
      in moving tissue environments. A new application of an eigendecomposition-based
      clutter rejection filter is presented with modifications to deal with high blood
      to-clutter ratios (BCR). Additionally, a new method for correcting blood velocity
      estimates with an estimated tissue motion profile is detailed. The performance of
      the clutter filter and velocity estimation strategies is quantified using a new
      swept-scan signal model. In vivo color flow images are presented to illustrate
      the potential of the system for mapping blood flow in the microcirculation with
      external tissue motion.

PMID- 12403141
TI  - Dynamics and fragmentation of thick-shelled microbubbles.
AB  - Localized delivery could decrease the systemic side effects of toxic chemotherapy
      drugs. The unique delivery agents we examine consist of microbubbles with an
      outer lipid coating, an oil layer, and a perfluorobutane gas core. These
      structures are 0.5-12 microm in radius at rest. Oil layers of these acoustically
      active lipospheres (AALs) range from 0.3-1.5 microm in thickness and thus the
      agents can carry a large payload compared to nano-scale drug delivery systems. We
      show that triacetin-based drug-delivery vehicles can be fragmented using
      ultrasound. Compared with a lipid-shelled contrast agent, the expansion of the
      drug-delivery vehicle within the first cycle is similar, and a subharmonic
      component is demonstrated at an equivalent radius, frequency, and driving
      pressure. For the experimental conditions explored here, the pulse length
      required for destruction of the drug-delivery vehicle is significantly greater,
      with at least five cycles required, compared with one cycle for the contrast
      agent. For the drug-delivery vehicle, the observed destruction mechanism varies
      with the initial radius, with microbubbles smaller than resonance size undergoing
      a symmetric collapse and producing a set of small, equal-sized fragments. Between
      resonance size and twice resonance size, surface waves become visible, and the
      oscillations become asymmetrical. For agents larger than twice the resonance
      radius, the destruction mechanism changes to a pinch-off, with one fragment
      containing a large fraction of the original volume.

PMID- 12403142
TI  - Attenuation coefficient and propagation speed estimates of rat and pig
      intercostal tissue as a function of temperature.
AB  - Attenuation coefficient and propagation speed of intercostal tissues were
      estimated as functions of temperature (22, 30, and 37 degrees C) from fresh chest
      walls from eight 10- to 11-week-old female Sprague-Dawley (SD) rats, eight 21- to
      24-week-old female Long-Evans (LE) rats, and ten 6- to 10-week-old mixed sex
      Yorkshire (York) pigs. The primary purpose of the study was to estimate the
      temperature dependence of the intercostal tissue's attenuation coefficient so
      that accurate estimates of the in situ (at the pleural surface) acoustic pressure
      levels could be made for our ultrasound-induced lung hemorrhage studies. The
      attenuation coefficient of intercostal tissue for both species was independent of
      the temperature at the discrete frequencies of 3.1 MHz (-0.0076, 0.0065, and
      0.016 dB/cm/degrees C for SD rats, LE rats, and York pigs, respectively) and 6.2
      MHz (-0.015, 0.014, and 0.014 dB/cm/degrees C for SD rats, LE rats, and York
      pigs, respectively). However, the temperature-dependent regressions yielded a
      significant temperature dependency of the intercostal tissue attenuation
      coefficients in SD and LE rats (over the 3.1 to 9.6 MHz frequency range); there
      was no temperature dependency in York pigs (over the 3.1 to 8.6 MHz frequency
      range). There was no significant temperature dependency of the intercostal tissue
      propagation speed in SD rats; there was a temperature dependency in LE rats and
      York pigs (-0.59, -1.6, and -2.9 m/s/degrees C for SD rats, LE rats, and York
      pigs, respectively). Even though the attenuation coefficient's temperature
      dependency was significant from the linear regression functions, the differences
      were not very great (-0.040 to -0.13, 0.011 to 0.18, and 0.055 to 0.10
      dB/cm/degrees C for SD rats, LE rats, and York pigs, respectively, over the data
      frequency range). These findings suggest that it is not necessary to determine
      the attenuation coefficient of intercostal tissue at body temperature (37 degrees
      C), but rather it is sufficient to determine the attenuation coefficient at room
      temperature (22 degrees C), a much easier experimental procedure.

PMID- 12403143
TI  - Attenuation coefficient and propagation speed estimates of intercostal tissue as
      a function of pig age.
AB  - Attention coefficient and propagation speed of intercostal tissues were estimated
      from chest walls removed postmortem (pm) from 15 5.3+/-2.3-day-old, 19 31+/-6-day
      old, and 15 61+/-3-day-old crossbred pigs. These ultrasonic propagation
      properties were determined from measurements through the intercostal tissues,
      from the surface of the skin to the parietal pleura. The chest walls were placed
      in a 0.9% sodium chloride solution, sealed in freezer bags, and stored at -15
      degrees C prior to measurements. When evaluated, chest-wall storage time ranged
      between 1 and 477 days pm. All chest walls were allowed to equilibrate to 22
      degrees C in a water bath prior to evaluation. There was an age dependency of the
      intercostal tissue propagation speed, with the speed increasing with increasing
      age. The attenuation coefficient of intercostal tissue was shown to be
      independent of the age of the pig at the discrete frequencies of 3.1 and 6.2 MHz.
      For pig intercostal tissues, the estimated attenuation coefficient over the 3.1
      9.2 MHz frequency range was A = 1.94f(0.90) where A is in decibels per centimeter
      (dB/cm) and f is the ultrasonic frequency in megahertz. In order to determine if
      there was an effect of storage time pm on estimates of attenuation coefficient, a
      second experiment was conducted. Five of the youngest pig chest walls measured on
      day 1 pm in the first experiment were stored at 4 degrees C prior to the first
      evaluation then stored at -15 degrees C before being measured again at 108 days
      pm. There was no difference in the estimated intercostal tissue attenuation
      coefficient as a function of storage time pm.

PMID- 12403144
TI  - Transducer design for a portable ultrasound enhanced transdermal drug-delivery
      system.
AB  - For application in a portable transdermal drug-delivery system, novel transducers
      have been designed to enhance insulin transmission across skin using ultrasound.
      Previous research has shown transdermal delivery of insulin across skin using
      commercial sonicators operating at 20 kHz with intensities ranging from 12.5 to
      225 mW/cm2. The goal of this research was to design and construct a small,
      lightweight transducer or array that could operate with a similar frequency and
      intensity range as a commercial sonicator used in previous transdermal ultrasound
      insulin experiments, but without the weight and mass of a sonicator probe. To
      obtain this intensity range, a cymbal transducer design was chosen because of its
      light, compact structure and low resonance frequency in water. To increase the
      spatial ultrasound field for drug delivery across skin, two arrays, each
      comprising of four cymbal transducers, were constructed. The first array,
      designated the standard array, used four cymbals transducer elements in parallel.
      A second array (named the stack array) used four cymbal transducers that used
      stacked piezoelectric discs to drive the titanium flextensional caps. Under
      similar driving conditions, the standard array produced intensities comparable to
      those achieved using a commercial sonicator.

PMID- 12403145
TI  - Experimental evaluation of human teeth using noninvasive ultrasound:
      echodentography.
AB  - Anomalies present in the hard tissue of teeth are manifested in several ways such
      as cavities, decay, and caries. The most extensively and commonly used diagnostic
      modality for the assessment of these abnormalities are x-rays. Unfortunately,
      these rays are harmful to the human body and may be a source of health risk. This
      work describes the development of a new testing technique that uses ultrasound
      designed to complement, or even replace, existing tools used in dentistry
      applications. Previous studies have shown several models of acoustic field
      simulation, propagation, and interaction of ultrasound with the layers of several
      tooth structures. In this paper, experimental data is gathered for the purpose of
      assessing the viability of this technique in an attempt to detect cavities and
      fractures in extracted human teeth. A low-intensity, high-frequency ultrasonic
      set-up is used in all in vitro tests. Four cases have been examined: an intact
      tooth, a tooth containing an amalgam restoration and a natural surface fissure, a
      tooth containing a machine side-drilled hole that mimics a cavity, and a
      calcified tooth--a rare naturally occurring condition. Upon analysis of the
      obtained A-scans and B-scans, it is verified that these experimental measurements
      confirm predictions reported in earlier finite element and transmission line
      studies and suggest that ultrasound is a valuable tool which has the potential to
      be an addition to, or even an improvement upon, current dental imaging systems.

PMID- 12403146
TI  - Hardware and software platform for real-time processing and visualization of
      echographic radiofrequency signals.
AB  - In this paper the architecture of a hardware and software platform, for
      ultrasonic investigation is presented. The platform, used in conjunction with an
      analog front-end hardware for driving the ultrasonic transducers of any
      commercial echograph, having the radiofrequency echo signal access, make it
      possible to dispose of a powerful echographic system for experimenting any
      processing technique, also in a clinical environment in which real-time operation
      mode is an essential prerequisite. The platform transforms any echograph into a
      test-system for evaluating the diagnostic effectiveness of new investigation
      techniques. A particular user interface was designed in order to allow a real
      time and simultaneous visualization of the results produced in the different
      stages of the chosen processing procedure. This is aimed at obtaining a better
      optimization of the processing algorithm. The most important platform aspect,
      which also constitutes the basic differentiation with respect to similar systems,
      is the direct processing of the radiofrequency echo signal, which is essential
      for a complete analysis of the particular ultrasound-media interaction
      phenomenon. The platform completely integrates the architecture of a personal
      computer (PC) giving rise to several benefits, such as the quick technological
      evolution in the PC field and an extreme degree of programmability for different
      applications. The PC also constitutes the user interface, as a flexible and
      intuitive visualization support, and performs some software signal processing, by
      custom algorithms and commercial libraries. The realized close synergy between
      hardware and software allows the acquisition and real-time processing of the
      echographic radiofrequency (RF) signal with fast data representation.

PMID- 12403147
TI  - Damping, amplitude, aging tests of stacked transducers for shock wave generation.
AB  - New clinical concepts in lithotripsy demand small shock heads. Reducing the size
      of piezoelectric shock heads will be possible only if the pressure generated at
      the surface of each transducer can be increased so that the total pressure at the
      focus remains the same. To solve this problem, different solutions were proposed.
      For example, it has been demonstrated that piezocomposite material, as opposed to
      piezoceramic material, allows the generation of a higher surface pressure before
      breaking, mainly because radial modes are dramatically reduced. In addition, in a
      previous paper, we showed the feasibility of generating high-pressure pulse waves
      without increasing the transducer voltage by using sandwiched transducers, which
      are a stack of two or more transducers. Some discrepancies appeared, however,
      between the pressure measured at the surface of the front transducer and the
      arithmetic sum of the pressures generated by each transducer constituting the
      stack. In fact, development of such stacked transducers capable of generating
      surface pressures in the range of 2 to 5 MPa is very complex, which may explain
      why no aging tests have been reported in the literature thus far. In the first
      part of this paper, we theoretically determine the importance of the
      electroacoustical coupling between the two transducers on the generated surface
      pressure. We show that pressure losses due to these electroacoustical couplings
      are less than 5%. Experimental measurements done on a stacked transducer
      assembled and tightened in a castor oil-filled tank are in excellent accordance
      with the theoretical measurements. Using this assembly technique, it was possible
      to obtain, on average, out of four elements, a pressure of 7.5 MPa for the
      duration of 4 million shocks, which would allow the treatment of approximately
      1000 patients.

PMID- 12403148
TI  - Process, mechanism, and explanation related to externalizing behavior in
      developmental psychopathology.
AB  - Advances in conceptualization and statistical modeling, on the one hand, and
      enhanced appreciation of transactional pathways, gene-environment correlations
      and interactions, and moderator and mediator variables, on the other, have
      heightened awareness of the need to consider factors and processes that explain
      the development and maintenance of psychopathology. With a focus on attentional
      problems, impulsivity, and disruptive behavior patterns, I address the kinds of
      conceptual approaches most likely to lead to advances regarding explanatory
      models in the field. Findings from my own research program on processes and
      mechanisms reveal both promise and limitations. Progress will emanate from use of
      genetically informative designs, blends of variable and person-centered research,
      explicit testing of developmental processes, systematic approaches to moderation
      and mediation, exploitation of "natural experiments," and the conduct of
      prevention and intervention trials designed to accentuate explanation as well as
      outcome. In all, breakthroughs will occur only with advances in translational
      research-linking basic and applied science-and with the further development of
      transactional, systemic approaches to explanation.

PMID- 12403149
TI  - ADHD outside the laboratory: boys' executive function performance on tasks in
      videogame play and on a visit to the zoo.
AB  - One current theory of attention-deficit/hyperactivity disorder (ADHD) proposes
      that a primary deficit in behavioral inhibition gives rise to secondary deficits
      in 4 executive functions and motor control. To date, empirical support for this
      model is based primarily on laboratory-based cognitive methods. This study
      assessed behavioral inhibition and executive functioning in children with ADHD in
      2 real-life contexts: videogames (motor-skill target game, cognitively demanding
      adventure game) and an outing at the zoo (route tasks). Participants were a
      community sample of 57 boys diagnosed with ADHD (20 inattentive, 37 combined
      type) and 57 normally developing control boys, matched individually for age and
      nonverbal IQ. Operationally defined measures of behavioral inhibition and
      specific executive functions were derived from these activities and assessed
      under contrasting conditions of low or high working memory and distractor loads.
      There were no group differences in basic motor skills on the target game, nor in
      terms of the ability to inhibit a prepotent or ongoing response in the adventure
      videogame. However, boys with ADHD exhibited more self-talk, more effortful
      response preparation, and completed fewer challenges in the latter videogame.
      Also, they manifested inhibition deficits in terms of interference control during
      the route task at the zoo and took longer to complete the tasks. Typically, these
      differences were greatest under conditions of high working memory and distractor
      loads. Findings from this study suggest that cognitive difficulties in ADHD may
      be context dependent and that ADHD is associated with deficits in some but not
      all aspects of behavioral inhibition.

PMID- 12403150
TI  - Young adult follow-up of hyperactive children: self-reported psychiatric
      disorders, comorbidity, and the role of childhood conduct problems and teen CD.
AB  - We report on the psychiatric disorders present at young adult follow-up (Mean age
      20-21 years; 13+ year follow-up) and the comorbidity among them for a large
      sample of hyperactive (H; N = 147) and community control (CC; N = 71) children.
      The H group had a significantly higher risk for any nondrug psychiatric disorders
      than the CC group (59% vs. 36%). More of the H group met criteria for ADHD (5%);
      major depressive disorder (26%); and histrionic (12%), antisocial (21%), passive
      aggressive (18%), and borderline personality disorders (14%) at follow-up than
      the CC group. Severity of childhood conduct problems contributed to the risk for
      passive-aggressive, borderline, and antisocial personality disorders. But it only
      affected risk for antisocial personality after controlling for severity of teen
      conduct disorder (CD), which also contributed to the risk for these same 3
      disorders. Examination for comorbidity among these disorders indicated that
      presence of either borderline or antisocial personality disorder significantly
      increased the risk for major depression and the other significant personality
      disorders. More of the hyperactive group had received various forms of mental
      health treatment during and since leaving high school than the control group.
      Results suggest that hyperactive children are at significant risk for at least 1
      nondrug disorder in young adulthood, principally major depression and several
      personality disorders, and that this risk is largely mediated by severity of CD
      at adolescence.

PMID- 12403151
TI  - Serious delinquent behavior, sensation seeking, and electrodermal arousal.
AB  - Low tonic skin conductance level (SCL) has been related, inconsistently, to both
      delinquency and sensation-seeking. This study tests the hypothesis that there is
      an interaction such that high sensation seeking delinquents, in particular, have
      low SCLs. Participants consisted of 335 boys from the Pittsburgh Youth Study
      classified as serious delinquents or controls based upon 10 years of
      prospectively collected self-report delinquency data. Participants' skin
      conductance was evaluated at age 16 along with several personality and
      neuropsychological measures. Both delinquency and sensation seeking were
      characterized by low SCL. However, there was no evidence to suggest that the
      presence of both of these factors together lead to especially low skin
      conductance levels. This finding is not explained by differences between the
      groups on measures of negative emotionality, IQ, socioeconomic status, or
      impulsivity.

PMID- 12403152
TI  - Relations among children's perceptions of maternal behavior, attributional
      styles, and behavioral symptomatology in maltreated children.
AB  - This investigation examined relations among perceptions of mothers, attributional
      style, and counselor-rated behavior problems in 187 school age children (88
      maltreated, 99 nonmaltreated). Hypotheses regarding the presence of higher levels
      of internalizing and externalizing behavior problems in maltreated children were
      confirmed. Attributional style was found to function as a moderator of
      externalizing behavior problems, suggesting that attributional style exerts a
      protective role against the harmful effect of child maltreatment. Perceptions of
      mothers were found to operate as a mediator of both internalizing and
      externalizing symptomatology, with maltreated children with less positive
      perceptions of their mothers exhibiting greater internalizing and externalizing
      behavior problems. These findings advance knowledge of how cognitive processes
      contribute to behavior problems in maltreated children and possess implications
      for prevention and intervention efforts.

PMID- 12403153
TI  - Effortful control: factor structure and relation to externalizing and
      internalizing behaviors.
AB  - Effortful control, a temperamentally based ability to inhibit a dominant response
      and activate a subdominant response, was assessed on 3 occasions using a
      comprehensive, age-appropriate behavioral battery in this 4-year longitudinal
      study of children (N = 103) from toddlerhood to early school age. The focus was
      twofold: to explore the structure of effortful control in a normally developing
      sample and to examine the relations between effortful control and adaptive
      functioning. Exploratory factor analyses supported the contention that effortful
      control is a complex, multidimensional construct with longitudinally stable
      factors. Effortful control was also significantly associated with mother-reported
      total behavior problems in a nonlinear fashion, with lower and higher levels of
      effortful control contributing to higher total problem scores. These findings
      have implications for the assessment of temperament in children and, most
      importantly, for the study of nonlinear contributions of temperament to early
      childhood behaviors.

PMID- 12403154
TI  - An examination of the response styles theory of depression in third- and seventh
      grade children: a short-term longitudinal study.
AB  - The goal of this study was to test the response styles theory of depression in a
      sample of 3rd- and 7th-grade children. In addition, we examined whether the
      relationship between rumination and increases in depressive symptoms is mediated
      by hopelessness and low self-esteem. The procedure involved an initial assessment
      in which depressive symptoms, response styles, hopelessness, and self-esteem were
      assessed. The procedure also involved a follow-up assessment, 6 weeks later, in
      which depressive symptoms, hopelessness, and self-esteem were reassessed.
      Children with a ruminative response style exhibited increases in depressive
      symptoms over the 6-week period. In addition, the relationship between rumination
      and increases in depressive symptoms was mediated by both hopelessness and low
      self-esteem. Last, contrary to our hypotheses, neither distraction nor problem
      solving response styles predicted decreases in depressive symptoms over the
      course of the study.

PMID- 12403155
TI  - Exposure to violence and suicide risk in adolescents: a community study.
AB  - The prevalence of violence exposure is relatively unexplored in adolescents in
      European communities, and reports on the association between exposure to
      community violence and suicidal behavior are rare. The aim of this study was to
      investigate (1) the prevalence of community violence in a European urban
      adolescent sample, (2) the relationship between exposure to community violence
      and suicidal ideation/deliberate self-harm, and (3) the influence of depressive
      symptoms and aggressive behavior on this relationship. Self-report surveys were
      administered to a representative school-based sample of 1509 adolescents in
      Antwerp (Belgium). The prevalence rate of violence exposure was still high but
      lower than that reported in U.S. communities. Suicidal ideation and deliberate
      self-harm were both related to violence exposure. The gender-specific influence
      of depressive symptomatology and aggressive behavior on the association between
      exposure to violence and suicidal behavior suggests the need for further
      research.

PMID- 12403156
TI  - Apigenin--strong cytostatic and anti-angiogenic action in vitro contrasted by
      lack of efficacy in vivo.
AB  - The cancer chemopreventive agent apigenin also has strong cytostatic and anti
      angiogenic effects in vitro. We now investigated its efficacy against
      experimental Lewis lung carcinomas (LLC), C-6 gliomas and DHDK 12 colonic cancers
      in vivo. Tumour bearing mice received 50 mg/kg/day apigenin in three different
      galenical formulations during 12 days in 8-hourly intervals. Only weak effects of
      apigenin on the size and the number of new tumour blood vessels of both
      established and newly transplanted tumours were recorded although the
      intratumoural necrosis was elevated (45 +/- 15% vs. 20 +/- 7% (control), p <
      0.05%). These results contrast sharply with the high in vitro sensitivity of LLC,
      C-6, DHDK 12 and endothelial cells to apigenin where complete growth suppression
      occurs at concentrations beyond 30 g/ml. Possible causes are discussed.

PMID- 12403157
TI  - St. John's wort (Hypericum perforatum L.) and kindling epilepsy in rabbit.
AB  - Effects of different extracts of Hypericum perforatum L. on the kindling
      epileptic discharges were analyzed. The experiment was carried out on Chinchilla
      rabbits with chronically implanted electrodes in cortical structures and
      hippocampus. In our study we used water, n-butanol and ether fractions (mass
      concentrations 0.1 g/ml) of crude ethanol extract of Hypericum perforatum. The
      particular extracts were given intramuscularly in single dose of 1 ml/kg BW. The
      bioelectric activity was registered before and after applications of each
      extracts. The obtained results show that the effect depends on the constituents
      present in particular fractions. The repression of epileptic activity was in
      correlation with the polarity of plant constituents. Most polar constituents that
      remained in water fraction exerted highest antiepileptic activity in all (100%)
      animals tested. Substances present in butanol fraction repressed the epileptic
      manifestations in 40% of animals with kindling epilepsy, whereas lipid-soluble
      constituents in ether fraction potentated the epileptic activity.

PMID- 12403158
TI  - Central nervous system activity of Leucas inflata Benth. in mice.
AB  - The analgesic activity of the methanol and acetone extracts of Leucas inflata L.
      (family Labiatae) was evaluated in mice using different experimental models. The
      effect of the two extracts on pentobarbitone-sleeping time, motor activity,
      sensorimotor coordination, carrageen induced inflammation, and brewer's yeast
      induced pyrexia has also been investigated. The two crude extracts have been
      phytochemically analyzed and some constituents isolated and characterized. These
      included stigmasterols, a chromone and coumarins. Extracts of L. inflata L.,
      given at single oral doses of 0.25, 0.5, 1.0 or 2.0 g/kg, significantly and dose
      dependently, reduced formalin-induced pain, acetic acid induced abdominal
      constrictions and increased the reaction time in the hot-plate test. Both
      extracts caused significant and dose-related impairment in the sensorimotor
      control and ambulatory and total motor activity of treated mice. Both extracts
      exhibited anti-inflammatory action by reducing paw edema of treated mice. The
      extracts did not significantly affect the rectal temperature of normothermic
      mice. However, they were effective in preventing Brewers yeast induced pyrexia.
      It is concluded that the crude methanol and acetone extract of L. inflata has CNS
      depressant properties, manifested as antinociception and sedation. Both extracts
      have anti-inflammatory and antipyretic actions.

PMID- 12403159
TI  - Solanum paniculatum L. (Jurubeba): potent inhibitor of gastric acid secretion in
      mice.
AB  - Solanum paniculatum L. is used commonly in Brazilian folk medicine for the
      treatment of liver and gastrointestinal disorders. The freeze-dried aqueous
      extracts (WEs) obtained from distinct parts of the plant (flowers, fruits,
      leaves, stems and roots) were tested to determine their antiulcer and
      antisecretory gastric acid activities using mice. The aqueous extracts of roots,
      stems and flowers inhibited gastric acid secretion in pylorus-ligated mice with
      ED50 values of 418, 777 and 820 mg/kg body wt. (i.d.), respectively. Extracts of
      leaves (0.5-2 g/kg body wt., i.d.) did not affect gastric secretion, whereas
      fruit extracts (0.5-2 g/kg body wt., i.d.) stimulated gastric acid secretion. The
      stimulatory effect of the fruit extract was inhibited by pretreatment with
      atropine (5 mg/kg body wt., i.m.) but not with ranitidine (80 mg/kg body wt.,
      i.p.) suggesting that the fruit extract activates the muscarinic pathway of
      gastric acid secretion. In contrast, administration of the root extract into the
      duodenal lumen inhibited histamine- and bethanechol-induced gastric secretion in
      pylorus-ligated mice. In addition, the aqueous extract of roots (ED50 value, 1.2
      g/kg body wt., p.o.) protected the animals against production of gastric lesions
      subsequent to the hypersecretion induced in mice by stress following cold
      restraint. This effect was not reproduced when the lesions were induced by
      blockade of prostaglandins synthesis via subcutaneous injection of indomethacin.
      Thus, antiulcer activity of the plant extracts appears to be related directly to
      a potent anti-secretory activity. No toxic signs were observed following
      administration of different extracts up to 2 g/kg body wt., p.o. Collectively,
      the results validate folk use of Solanum paniculatum L. plant to treat gastric
      disorders.

PMID- 12403160
TI  - Gastroprotective effects of 'Amla' Emblica officinalis on in vivo test models in
      rats.
AB  - An ethanol extract of 'Amla' Emblica officinalis Gaertn. was examined for its
      antisecretory and antiulcer activities employing different experimental models in
      rats, including pylorus ligation Shay rats, indomethacin, hypothermic restraint
      stress-induced gastric ulcer and necrotizing agents (80% ethanol, 0.2 M NaOH and
      25% NaCl). Oral administration of Amla extract at doses 250 mg/kg and 500 mg/kg
      significantly inhibited the development of gastric lesions in all test models
      used. It also caused significant decrease of the pyloric-ligation induced basal
      gastric secretion, titratable acidity and gastric mucosal injury. Besides, Amla
      extract offered protection against ethanol-induced depletion of stomach wall
      mucus and reduction in nonprotein sulfhydryl concentration. Histopathological
      analyses are in good agreement with pharmacological and biochemical findings. The
      results indicate that Amla extract possesses antisecretory, antiulcer, and
      cytoprotective properties.

PMID- 12403161
TI  - Effect of essential oil obtained from Croton cajucara Benth. on gastric ulcer
      healing and protective factors of the gastric mucosa.
AB  - The bark of Croton cajucara Benth. (Euphorbiaceae) is used widely in Amazonian
      folk medicine for the treatment of a wide range of gastrointestinal symptoms.
      Infusions of C. cajucara bark contain dehydrocrotonin (DHC), the furan diterpene,
      and an essential oil, a rich mixture of sesquiterpenes. Although the
      antiulcerogenic activity of the essential oil has been studied in different
      gastric ulcer models in mice and rats, its mechanism remains unclear. In this
      work, we examined the ability of this essential oil to increase PGE2 release from
      mucus cells, as well as its effects on the amount of gastric mucus and on the
      healing of acetic acid-induced gastric ulcers. The essential oil (100 mg/kg body
      wt., p.o), significantly increased PGE2 production by glandular cells (by 102% as
      compared to control) and the amount of Alcian blue binding to the gastric mucus.
      In chronic gastric ulcers, a single daily oral dose of essential oil (100 mg/kg
      body wt.) for 14 consecutive days accelerated ulcer healing to an extent similar
      to that seen with an equal dose of cimetidine. Thus, the protective and healing
      actions of the essential oil from C. cajucara bark on gastric lesions resulted
      mainly from an increase in PGE2 release and gastric mucus formation which would
      protect the gastric mucosa.

PMID- 12403162
TI  - The inhibitory effect of propolis and caffeic acid phenethyl ester on
      cyclooxygenase activity in J774 macrophages.
AB  - The effect of an ethanolic extract of propolis, with and without CAPE, and some
      of its components on cyclooxygenase (COX-1 and COX-2) activity in J774
      macrophages has been investigated. COX-1 and COX-2 activity, measaured as
      prostaglandin E2 (PGE2) production, were concentration-dependently inhibited by
      propolis (3 x 10(-3) - 3 x 10(2) microgml(-1)) with an IC50 of 2.7 microgml(-1)
      and 4.8 x 10(-2) microgml(-1), respectively. Among the compounds tested
      pinocembrin and caffeic, ferulic, cinnamic and chlorogenic acids did not affect
      the activity of COX isoforms. Conversely, CAPE (2.8 x 10(-4) - 28 microgml(-1);
      10(-9) - 10(-4) M) and galangin (2.7 x 10(-4) - 27 microgml(-1); 10(-9) - 10(-4)
      M) were effective, the last being about ten-twenty times less potent. In fact the
      IC50 of CAPE for COX-1 and COX-2 were 4.4 x 10(-1) microgml(-1) (1.5 x 10(-6) M)
      and 2 x 10(-3) microgml(-1) (6.3 x 10(-9) M), respectively. The IC50 of galangin
      were 3.7 microgml(-1) (15 x 10(-6) M) and 3 x 10(-2) microgml(-1) (120 x 10(-9)
      M), for COX-1 and COX-2 respectively. To better investigate the role of CAPE, we
      tested the action of the ethanolic extract of propolis deprived of CAPE, which
      resulted about ten times less potent than the extract with CAPE in the inhibition
      of both COX-1 and COX-2, with an IC50 of 30 microgml(-1) and 5.3 x 10(-1)
      microgml(-1), respectively. Moreover the comparison of the inhibition curves
      showed a significant difference (p < 0.001). These results suggest that both CAPE
      and galangin contribute to the overall activity of propolis, CAPE being more
      effective.

PMID- 12403163
TI  - Activation of the alternative complement pathway by Agaricus blazei Murill.
AB  - Components of Agaricus blazei Murill have been demonstrated to have a wide range
      of immunopotentiating activities. The present study was designed to evaluate the
      effect of A. blazei Murill upon activation of the complement system in human
      serum in vitro. Additional studies were performed to determine the cytotoxic
      effect of complement-opsonized particles of A. blazei Murill against human tumor
      cells in culture. A fine particle of A. blazei Murill (ABP), prepared by
      mechanical disruption, was used throughout the experiments. ABP activated the
      human complement system via the alternative pathway in human serum. Activation of
      the alternative pathway was both time- and dose-dependent. When the particles
      from fruiting bodies of A. blazei Murill (ABP-F) were reacted with human serum,
      the formation of complement-opsonized ABP, iC3b-ABP-F complexes, and binding of
      the complexes to human peripheral blood monocytes, were demonstrated in vitro by
      immunofluorescence. Further, the resident human peripheral nucleated cells
      incubated in the presence of iC3b-ABP-F complexes inhibited the proliferation of
      human tumor cell line TPC-1 in vitro.

PMID- 12403164
TI  - Immunomodulating properties of Argentine plants with ethnomedicinal use.
AB  - Five Argentine medicinal plants selected according to folk traditional or
      ethnomedical use, references and primary pharmacological screening; were chosen
      to elucidate their immunomodulating properties. Dichloromethane, methanolic and
      aqueous extracts of the aerial parts of Achyrocline flaccida (A. flaccida),
      Eupatorium arnottianum (E. arnottianum) and Eupatorioum buniifolium (E.
      buniifolium), leaves of Lithraea molleoides (L. molleoides) and leaves and stems
      of Phyllanthus sellowianus (P. sellowianus) were analyzed to disclose their
      effects on murine normal and tumor cell growth as well as on complement hemolytic
      activity. Modulation of cell growth was evaluated by tritiated thymidine
      incorporation while inhibition of complement activity was measured on both
      classical and alternative complement pathways (CP and AP respectively). The
      results obtained show that most of the extracts exerted inhibitory effect on
      tumor as well as on mitogen activated normal spleen cell growth. On tumor cells,
      IC50 ranged between 1-75 microg/ml for most of the extracts with the exception of
      dichloromethane of L. molleoides and P. sellowianus which required concentrations
      higher than 100 microg/ml to produce the effect. On mitogenic activated
      splenocytes, IC50 ranged between < 1 to 85 microg/ml with the exception of
      methanolic extract of E. buniifolium or P. sellowianus which were not effective
      on ConA or LPS stimulated splenocytes respectively. Only E. buniifolium was
      active on murine normal splenocytes proliferation (IC50 0.5-1.5 microg/ml).
      Finally, one (7%) of 15 extracts showed inhibition of complement activity on CP
      and 6 extracts (40%) presented moderate activity on CP. The dichloromethane
      extract of E. arnottianum was the most active (IC50 5 microg/ml), although
      remarkable effect was also obtained with dichloromethane and methanolic extracts
      of P. sellowianus (IC50 11.2 and 17.3 microg/ml respectively). Besides, 2
      extracts (13%), dichloromethane extract of E. arnottianum and aqueous extract of
      P. sellowianus, showed moderate inhibition on AP.

PMID- 12403165
TI  - Hypoglycemic and hypolipidemic effects of aqueous extract of Arachis hypogaea in
      normal and alloxan-induced diabetic rats.
AB  - The hypoglycemic and hypolipidemic effect of aqueous extract of Arachis hypogaea
      was investigated in normal and alloxan-induced diabetic rats. The extract caused
      a significant (P < 0.05) decrease of fasting blood glucose of both normal and
      alloxan-induced diabetic rats from 102.60 +/- 1.65 mg/dl to 88.79 +/- 0.94 mg/dl
      for normal and 189.0 +/- 30.79 mg/dl to 107.55 +/- 1.54 mg/dl for alloxan-induced
      diabetic rats. The extract also caused a significant (P < 0.05) decrease in serum
      triglyceride, total cholesterol, HDL-cholesterol and LDL-cholesterol in both
      normal and alloxan-induced diabetic rats.

PMID- 12403166
TI  - The hypoglycemic effect of Phyllanthus sellowianus fractions in streptozotocin
      induced diabetic mice.
AB  - Phyllanthus sellowianus Muller Arg. (Euphorbiaceae) is a plant used in folk
      medicine as a hypoglycemic and diuretic agent. The present study describes the
      hypoglycemic effect of fractions obtained from the stem barks of P. sellowianus
      using a bioassay-guided fractionation protocol and streptozotocin-induced
      hyperglycemic mice. The aqueous extract was partitioned between dichloromethane
      and butanol to yield the dichloromethane (D), butanol (B) and the remaining
      aqueous (A) fractions. Fractions B and A, administered at the dose of 200 mg/kg
      p.o., caused a significant reduction in blood glucose concentration at 6 and 9 h,
      while the same dose of fraction D was ineffective. The reduction in blood glucose
      levels obtained with the B and A fractions was similar to that observed with
      glibenclamide (10 mg/kg) which was used as a reference for the hypoglycemic
      activity. Phytochemical analysis of fractions B and A revealed the presence of
      flavonoid compounds, of which rutin and isoquercitrin were the major
      constituents, respectively. The possible involvement of these flavonoids in the
      hypoglycemic effect of the active fractions is discussed.

PMID- 12403167
TI  - The cytotoxicity of protoneodioscin (NSC-698789), a furostanol saponin from the
      rhizomes of Dioscorea collettii var. hypoglauca, against human cancer cells in
      vitro.
AB  - Protoneodioscin (NSC-698789) is a furostanol saponin isolated from the rhizomes
      of Dioscorea collettii var. hypoglauca (Dioscoreaceae), a Chinese herbal remedy
      for cancer treatment. Our studies showed that protoneodioscin is cytotoxic
      against most cell lines from leukemia and solid tumors in the NCI's (National
      Cancer Institute, USA) anticancer drug screen. Leukemia, CNS cancer, and prostate
      cancer are the most sensitive subpanels to protoneodioscin, while melanoma,
      ovarian cancer, and renal cancer are less sensitive. The preliminary animal
      studies showed that the maximum tolerant dose of protoneodioscin was 600 mg/kg to
      mice. Based on an analysis of the COMPARE software with protoneodioscin as a seed
      compound, no compounds in the NCI's database have similar cytotoxicity patterns
      to those of protoneodioscin, indicating a potentially novel mechanism of
      anticancer action involved.

PMID- 12403168
TI  - Bioactivity of crude extracts and some constituents of Blutaparon portulacoides
      (Amaranthaceae).
AB  - Crude extracts (aerial parts and roots, both dried), methylenedioxyflavonol, and
      a mixture of acyl steryl glycosides isolated from Blutaparon portulacoides, were
      assayed for their toxicity against Trypanosoma cruzi trypomastigotes and
      Leishmania amazonensis amastigotes from axenic cultures. The antimicrobial
      activity was also investigated, in a screening conducted using fifteen strains of
      Gram-positive and Gram-negative bacteria, along with the yeasts, Candida albicans
      and Candida tropicalis. To assess the antibacterial activity of the isolated
      compounds, the minimum inhibitory concentrations (MICs) were determined. There
      are no reports of acyl steryl glycosides in the genus Blutaparon and their
      biological activities are being evaluated for the first time.

PMID- 12403169
TI  - Genome of Azotobacter vinelandii: counting of chromosomes by utilizing copy
      number of a selectable genetic marker.
AB  - Studies utilizing several physical, biochemical and spectroscopic methods have
      suggested that Azotobacter vinelandii contains multiple copies (40-80) of its
      chromosome per cell, whereas genetic analysis indicated that these cells function
      like haploid cells. To further verify if A. vinelandii indeed contains 40-80
      copies of its chromosome per cell, we have developed an 'in vivo chromosome
      counting' technique. The basic principle of this technique is to introduce the
      same genetic marker on the chromosome and on an extrachromosomal element of known
      copy number into the bacterium. The copy number of the chromosome can be
      determined by comparing the intensity of the hybridization signal generated by
      the DNA fragment carrying the chromosomal marker with that of the
      extrachromosomal marker when the total DNA isolated from this strain is
      hybridized with a probe made of the same genetic marker DNA. To do this we used
      an A. vinelandii BG102 strain which carries a kanamycin resistance marker gene
      integrated into the nifY locus on its chromosome(s). The plasmids pRK293 and
      pKT230, which can replicate in A. vinelandii and carry the kanamycin resistance
      gene (similar to the one present on the chromosome of A. vinelandii BG102),
      served as the extrachromosomal elements with known copy number. Southern blotting
      and hybridization analysis of the total DNA, isolated from A. vinelandii BG102
      containing these plasmids, with a probe made of the kanamycin resistance gene
      clearly indicated that the copy number of A. vinelandii chromosome is slightly
      lower than the copy number of the low-copy plasmid pRK293 and about 21-fold lower
      than the copy number of the high copy plasmid pKT230. We believe that this 'in
      vivo chromosome counting' technique can be used for determination of the copy
      number of the chromosome in other cells with appropriate modifications in the
      nature of the extrachromosomal element and the genetic marker.

PMID- 12403170
TI  - Nucleotide and repeat length variation at the nonA gene of the Drosophila virilis
      group species and its effects on male courtship song.
AB  - Genes found to affect male courtship song characters in Drosophila melanogaster
      are good candidates when tracing genes responsible for species-specific songs in
      other Drosophila species. It has previously been shown that Thr-Gly repeat length
      variation at the period gene affects song traits in D. melanogaster, which gives
      the repetitive regions a special interest. In this work, we have characterised
      the patterns of nucleotide variation for gene regions containing two Gly and one
      Gln-Ala repeat in another D. melanogaster song gene, no-on-transient A, in D.
      virilis group species. The levels of nucleotide variability in D. virilis nonA
      were similar to those found for other genes of the species, and the gene
      sequences showed no signs of deviation from neutrality. The Gly 2 repeat
      preceding the central domain of the gene exhibited length variation, which did
      not, however, correlate with song variation either within D. virilis or between
      the species of D. virilis group. The Gly 3 repeat located on the other side of
      the central domain showed amino acid divergence parallel to the consensus
      phylogeny of the D. virilis group species. The species of the virilis subgroup
      having Asn after the first three glycines in this repeat have simple songs with
      no species-specificity, while the species of the montana subgroup having two Gly
      or Asn-Ser in this site have unique courtship songs. Amino acid differences
      between the species in this repeat may, however, reflect species phylogeny rather
      than have an effect on song divergence per se.

PMID- 12403171
TI  - Karyotype evolution in Tilapia: mitotic and meiotic chromosome analysis of
      Oreochromis karongae and O. niloticus x O. karongae hybrids.
AB  - The karyotype of Oreochromis species is considered to be highly conserved, with a
      diploid chromosome complement of 2n = 44. Here we show, by analysis of mitotic
      and meiotic chromosomes, that the karyotype of O. karongae, one of the Lake
      Malawi 'chambo' species, is 2n = 38. This difference in chromosome number does
      not prevent the production of inter-specific hybrids between O. niloticus (2n =
      44) and O. karongae (2n = 38). Analysis of the meiotic chromosomes of the O.
      niloticus x O. karongae hybrids indicates that three separate chromosome fusion
      events have occurred in O. karongae. Comparison of the O. karongae and O.
      niloticus karyotypes suggests that these consist of one Robertsonian fusion and
      two fusions of a more complex nature.

PMID- 12403172
TI  - Repeated losses of TTAGG telomere repeats in evolution of beetles (Coleoptera).
AB  - We studied the occurrence of (TTAGG)n telomere repeats in 12 species of beetles,
      representing main lineages of the Coleoptera phylogenetic tree, by Southern
      hybridization and fluorescence in situ hybridization (FISH). In contrast to other
      insect orders, beetles were heterogeneous with respect to the occurrence of TTAGG
      repeats. In addition, the presence or absence of (TTAGG)n motif was irrespective
      of phylogenetic relationships. In the suborder Polyphaga, six species displayed
      positive hybridization signals. These were Silpha obscura, Agrilus viridis,
      Ampedus sanguineus, Stegobium paniceum, Oryzaephilus surinamensis, and
      Leptinotarsa decemlineata. Whereas negative signals were obtained in three
      polyphagan species, Geotrupes stercorarius, Thanasimusformicarius, and Sitophilus
      granarius. In the suborder Adephaga, the TTAGG sequence was present in one
      species, Graphoderus cinereus, and absent in two species, Orectochilus villosus
      and Pterostichus oblongopunctatus. We concluded that the telomerase-dependent
      (TTAGG)n motif had been repeatedly lost in different phylogenetic branches of
      Coleoptera and probably replaced with another mechanism of telomere elongation.
      This had to happen at least 5-6 times. The results suggest a predisposition or a
      backup mechanism of telomere maintenance in the genome of beetles that enabled
      them to make frequent evolutionary changes in the telomere composition.

PMID- 12403173
TI  - Chromosome analysis and FISH mapping of ribosomal DNA (rDNA), telomeric (TTAGGG)n
      and (GATA)n repeats in the leech Haemopis sanguisuga (L.) (Annelida: Hirudinea).
AB  - In the present paper the chromosome complement (n = 13; 2n = 26) of the common
      leech Haemopis sanguisuga (L.) (Annelida: Hirudinea: Hirudinidae) was analyzed
      using banding techniques and fluorescent in situ hybridization (FISH) with three
      repetitive DNA probes [ribosomal DNA (rDNA), (TTAGGG)n and (GATA)n]. FISH with
      the rDNA probe consistently mapped major ribosomal clusters (18S-28S rDNA) in the
      pericentromeric region of one large metacentric chromosome pair; this region,
      which consisted of heterochromatin rich in GC base pairs, was preferentially
      stained by silver nitrate (Ag-NOR). The (TTAGGG)n telomeric probe was hybridized
      with the termini of nearly all chromosomes, whereas the (GATA)n probe did not
      label any chromosome areas.

PMID- 12403174
TI  - Evidence of natural selection for disease resistance in Composite Cross Five
      (CCV) of barley.
AB  - Cambridge Composite Cross Five (CCV) of barley was studied utilising hordeins,
      restriction fragment length polymorphisms (RFLPs) and reaction to powdery mildew
      with a view to understanding the genetic changes occurring in the population.
      Changes in the frequency of individual hordein patterns as well as pattern
      combinations showed directional trends in successive generations in three
      parallel populations maintained as discrete populations since 1977 in Cambridge.
      Certain hordein pattern combinations were more common in the resistance classes
      and there was a strong association between hordein patterns and mildew reaction.
      RFLP analysis revealed that 80% of a random sample taken from generation F24 of
      Population I had the same restriction pattern as that of the cultivar Algerian,
      which was one of the original 30 parental lines of CCV. This cultivar is the
      source of the Mla1 allele in barley improvement programmes in Europe. We argue,
      based on supporting evidence from hordein analysis and tests of reaction to
      selected mildew isolates of known virulence isolates together with UK virulence
      surveys, that selection for Mla1 in Cambridge has been the predominant
      evolutionary force in CCV in Cambridge.

PMID- 12403175
TI  - Chromosomal location of 46 new RAPD markers in rye (Secale cereale L.).
AB  - The polymerase chain reaction (PCR) was used to locate RAPD markers using disomic
      wheat-rye addition lines in order to develop a set of molecular markers
      distributed on the seven rye chromosomes. We carried out RAPD amplifications on
      genomic DNA of wheat 'Chinese Spring' (CS), rye 'Imperial' (I), the amphiploid
      wheat-rye and the seven disomic wheat-rye addition lines (1R-7R) using 140
      different 10-mer oligonucleotides. Forty six new RAPD markers were located on the
      seven rye chromosomes and all the disomic wheat-rye addition lines were
      identified on the basis of their amplification patterns. The number of RAPD bands
      located on 1R, 2R, 3R, 4R, 5R, 6R and 7R chromosomes were 5, 8, 11, 8, 8, 10 and
      6, respectively. The seven wheat-rye addition lines can be distinguished using
      only the following three 10-mer oligonucleotides: OPA16, OPF19 and GEN3-605, the
      other RAPD primers being useful for this purpose. The use of these RAPDs as a
      source of molecular markers that could be linked to interesting genes or other
      important agronomic traits is discussed.

PMID- 12403176
TI  - Organization and phylogenetic analysis of kappa-bungarotoxin genes from Bungarus
      multicinctus (Taiwan banded krait).
AB  - Two genomic DNAs were isolated from the liver of Bungarus multicinctus (Taiwan
      banded krait) encoded kappa1-bungarotoxin and kappa3-bungarotoxin precursors,
      respectively. They shared virtually identical overall organization with three
      exons separated by two introns and a high degree of nucleotide-sequence identity
      with alpha-neurotoxin genes, including similar intron insertions. This suggests
      that kappa-neurotoxins and alpha-neurotoxins might have originated from a common
      ancestor. The consensus transcriptional factor binding sites within the promoter
      regions of these genes indicate that their transcriptions are, at least in part,
      regulated under the same mechanism. Comparative analyses on kappa-bungarotoxin
      and alpha-neurotoxin genes revealed that the protein-coding regions of exons were
      much more diversified than introns except for the signal peptide domain.
      Phylogenetic analyses on the exon and intron regions of kappa-bungarotoxin and
      alpha-neurotoxin genes showed that the evolution of exon regions were not in
      consensus with that of intron regions. The ratio of nonsynonymous to synonymous
      substitution is higher than 1, reflecting the occurrence of an adaptive selection
      during the evolution of kappa-bungarotoxins. In contrast to a conserved size of
      the second intron, segmental insertions and/or deletions within the first intron
      accelerate the evolutionary divergence of kappa- and alpha-neurotoxin genes.

PMID- 12403177
TI  - Karyotypic diversity in polyploid gibel carp, Carassius auratus gibelio Bloch.
AB  - Polyploid gibel carp, Carassius auratus gibelio, is an excellent model system for
      evolutionary genetics owing to its specific genetic background and reproductive
      modes. Comparative karyotype studies were performed in three cultured clones, one
      artificially manipulated group, and one mated group between two clones. Both the
      clones A and P had 156 chromosomes in their karyotypes, with 36 metacentric, 54
      submetacentric, 36 subtelocentric, 24 acrocentric, and six small chromosomes. The
      karyotype of clone D contained 162 chromosomes, with 42 metacentric, 54
      submetacentric, 36 subtelocentric, 24 acrocentric, and six small chromosomes. All
      the three clones had six small chromosomes in common. Group G, being originated
      from the clone D by artificial manipulation, showed supernumerary
      microchromosomes or chromosomal fragments, in addition to the normal chromosome
      complement that was identical to the clone D. The offspring from mating between
      clones D and A had 159 chromosomes. Comparing with the clone A, the DA offspring
      showed three extra metacentric chromosomes. In addition, variable RAPD
      fingerprint patterns and unusual SCAR marker inheritance were, respectively,
      detected among individuals of artificial group G and in the mated DA offspring.
      Both the chromosome and molecular findings suggest that genome reshuffling might
      have occurred by manipulation or mating of the clones.

PMID- 12403178
TI  - Tn5044-conferred mercury resistance depends on temperature: the complexity of the
      character of thermosensitivity.
AB  - Escherichia coli K12 containing the transposon Tn5044 mer operon (merR, T, P, C,
      and A genes) is resistant to mercuric chloride at 30 degrees C but sensitive to
      this compound at 37-41.5 degrees C. We have studied the mechanism underlying the
      temperature-sensitive nature of this mercury resistance phenotype, and found that
      the expression of the Tn5044 merA gene coding for mercuric reductase (MerA) is
      severely inhibited at non-permissive temperatures. Additionally, MerA showed a
      considerably reduced functional activity in vivo at non-permissive temperatures.
      However, the temperature-sensitive character of the functioning of this enzyme in
      cell extracts, where it interacted with one of the low-molecular weight SH
      compounds rather than with the transport protein MerT (as is the case in vivo),
      was not apparent. These data suggest that the temperature-sensitive mercury
      resistance phenotype should stay under control at two stages: when the merA gene
      is expressed and when its product interacts with MerT to accept the mercuric ion.

PMID- 12403179
TI  - Preserving the dentist-patient relationship.

PMID- 12403180
TI  - How long AMA, how long? ... An open letter to the American Medical Association.

PMID- 12403181
TI  - Mr. von Piekartz questions Dr. Stiesch-Sholtz, et al.'s conclusions in their
      April 2002 article in Cranio.

PMID- 12403182
TI  - Temporomandibular disorder treatment outcomes: second report of a large-scale
      prospective clinical study.
AB  - Longitudinal studies of outcomes for temporomandibular disorder (TMD) treatment
      are rarely done and even when conducted often suffer methodological weaknesses.
      These may include the lack of valid outcome measures for symptom changes. This
      second report of a long-term multi-site study of 2104 treated, 250 untreated, and
      44 long-term treated TMD patients is part of a continuing effort to study TMD
      treatment efficacy in a very large patient population. A validated symptom
      measurement system, the TMJ Scale, assured a valid and uniform assessment of
      treatment outcomes across a large number of practices. Data indicate that
      untreated TMD patients do not improve spontaneously over time and that patients
      treated with a variety of active modalities achieve clinically and statistically
      significant levels of improvement with no evidence of symptom relapse after
      treatment completion. The use of anterior repositioning appliance therapy
      produced better results than flat plane splint therapy.

PMID- 12403183
TI  - Diagnostic image analyses of activator treated temporomandibular joint in growth
      and maturing stages.
AB  - This study evaluates the condylar response to activator in growth and in maturing
      patients using radiographs and magnetic resonance images (MRI). Seven patients
      (four in growth and three in maturing stages) treated for mandibular distal
      occlusion were studied. In all seven patients, lateral roentgen cephalograms,
      panoramic radiograms, and MRIs were made before and following functional
      treatment. All patients' mandibles advanced during treatment. Downward and
      forward mandibular growth was observed by superimposition of lateral
      cephalograms. On the condylar posterosuperior regions for both groups, double
      contours were sometimes observed on the panoramic radiograms following therapy.
      These double contours coincided with an area of high intensity in the MRIs for
      both groups. In the mature adult group, the double contours were more clearly
      observed when compared with those in the growth group. There were differences in
      the condylar adaptation types between the growth and mature development stages.
      Condylar adaptation to the newly created mandibular position was nevertheless
      found even in adult patients.

PMID- 12403184
TI  - The effect of stepwise increases in vertical dimension of occlusion on isometric
      strength of cervical flexors and deltoid muscles in nonsymptomatic females.
AB  - This mixed, single-double blind study examined the effect of a stepwise increase
      in vertical dimension of occlusion (VDO) on the isometric strength of cervical
      flexor and deltoid muscles in 20 asymptomatic females with deep bite (age range
      20-40 years). Vertical dimension of occlusion was increased by mandibular acrylic
      bite plates, 2, 4, 6 and 12 mm. Subjects were instructed to bite while resisting:
      1. an increasing horizontal force was applied to the forehead; and 2. an
      increasing vertical downward force to the wrist of each extended arm. Forces were
      applied by a hand-held strain gauge until resistance yielded. The force applied
      at the point of yielding was recorded as isometric peak strength of that trial.
      The peak strength for each muscle group was measured twice and averaged to
      produce a mean peak strength measure. This procedure was repeated in the
      subject's habitual occlusion and for the four increased VDOs. Mean strength of
      cervical flexors with increased VDO (12.0 kg) was significantly greater than that
      for existing vertical dimension occlusion (9.6 kg). With the exception of pre
      experimental existing VD of occlusion, strength for right and left deltoids did
      not differ, but mean deltoid strength in the increased condition (8.6 kg) was
      significantly greater than biting in without a bite plate (6.6 kg). In the peak
      condition, cervical flexor strength increased 24% and deltoid strength increased
      an average of 29% from that of biting without an increase. As VDO increased
      further, strength in all sites was found to diminish. Repeating the strength test
      without a bite plate, after all trials were administered, did not show
      differences from pre-experimental levels, indicating that fatigue was not an
      important factor. The findings demonstrate that isometric strength of the
      cervical flexors and deltoids increases significantly from habitual occlusion as
      the VDO is increased, then diminishes as VDO is increased further. The strength
      of both cervical flexors and deltoids varied in concert with changes of VDO.

PMID- 12403185
TI  - Study of the signs and symptoms of temporomandibular dysfunction in individuals
      with normal occlusion and malocclusion.
AB  - The signs and symptoms of temporomandibular dysfunctions were studied in a well
      defined sample, divided into one group with normal occlusion and a second group
      with malocclusion, where the primary characteristic was Angle Class II a
      malocclusion with moderate to deep overbite. Each group comprised 30 individuals
      with a mean overall age of 22.6 years. The following were evaluated in both
      groups: tenderness to palpation of the muscles involved in the joint; presence of
      articular noises; subjective symptoms obtained via a questionnaire; and
      mandibular movements. The data gathered was subjected to statistical analysis and
      no significant differences were detected between the groups in the majority of
      variables studied. However, it was found that those individuals with malocclusion
      had a wider range of lateral movement and also complained of greater discomfort
      in the TMJ when compared to individuals in the normal occlusion group. The lack
      of uniformity between the results of this work and those of other authors may be
      attributed in particular to variations in age of the sample populations studied.

PMID- 12403186
TI  - Hostility in TMD/bruxism patients and controls: a clinical comparison study and
      preliminary results.
AB  - This study involved a group of 110 TMD/bruxing behavior patients (30 mild, 40
      moderate, and 40 severe bruxers) which was compared to a group of 40
      nonTMD/nonbruxer controls, with the objective to test the alternative hypothesis
      that, regarding hostility, there were significant differences between these
      groups. The mean age in the group of TMD/bruxers was 31.81 years (SD: 11.2, range
      14-61) and in the control group was 30.03 (SD: 10.96, range 16-66). Patients were
      initially classified as presenting TMD and bruxing behavior according to previous
      criteria. The Cook-Medley Inventory and the Beck Depression Inventory were used
      to assess levels of hostility and depression, respectively, in bruxers and
      controls. There were no statistically significant differences in the levels of
      depression between the three groups of bruxers. However, the difference between
      the groups of bruxers and controls reached significance (unpaired t test
      P<0.001). Our results indicated that there was not statistically and significant
      difference in the levels of hostility between the three groups of bruxers and
      between the mild group of bruxers and control group. However, there were
      statistically and significant differences in the level of hostility between the
      moderate group of bruxers and the control group (P<0.01), and between the severe
      group of bruxers and the control group (P<0.05). When bruxers were classified
      into two groups: one presenting minimal to mild depression (N:31) and the other
      presenting moderate to severe depression (N:19), the group presenting moderate to
      severe depression demonstrated a level of hostility of about 23.36. The group
      presenting minimal to mild depression demonstrated a level of hostility of about
      17.32, and this difference was statistically significant (unpaired t test,
      P<0.0004). These results suggest that in these subgroups of TMD/bruxers,
      increased depression corresponds to increased hostility and provides support for
      previous investigations indicating that there is a relationship between hostility
      and bruxism (but only in the groups with moderate and severe bruxism).

PMID- 12403187
TI  - Interexaminer agreement for muscle palpation procedures: the efficacy of a
      calibration program.
AB  - The purpose of this study is to assess the muscle palpation interexaminer
      agreement after a calibration program and to determine differences between time,
      groups of muscles, or side examined. A sample of 32 individuals, matched for sex,
      was divided into two groups: symptomatic (16 patients presenting with myogenic
      TMD) and asymptomatic (16 subjects with no TMD symptoms). Palpation procedures
      were performed three different times by four calibrated examiners, in masticatory
      and cervical muscles. The presence or severity of tenderness was judged by an
      ordinal scale (from "0" to "3"). Kendall's concordance test measured agreement
      between examiners. The sternocleidomastoid muscle showed the highest agreement
      (0.84), while the worst result was detected for the origin of the masseter
      (0.56). Levels of agreement for all muscles were considered fair and excellent,
      regardless of the time of examination or the side analyzed.

PMID- 12403188
TI  - Medullary and odontogenic disease in the painful jaw: clinicopathologic review of
      500 consecutive lesions.
AB  - Ischemic jawbone lesions were first discussed in the dental literature more than
      a century ago, but then seemingly forgotten. In recent years, there has been
      considerable resurgence in interest in this unique pathological condition.
      Controversy surrounds the subject. Some proclaim these lesions to be mere
      fabrications of the imaginations of non-traditional or alternative dental
      surgeons. Others attribute all human maladies to these maxillofacial lesions.
      Aside from these philosophical and metaphysical arguments, are there common
      diagnoses of jawbone pathologies that produce pain? This present investigation
      reviews the clinicopathologic features of 500 consecutive jawbone surgeries with
      pathological confirmation in patients with idiopathic facial pain. Four hundred
      seventy-six (476) of the 500 lesions (95.2%) were directly attributed to impaired
      blood flow in the jawbone, tooth, or both, according to histopathological
      analysis and confirming Cavitat (bone ultrasound) examination. Statistical data
      concerning the location, frequency, and pathological diagnoses of these bony
      lesions are presented, as are brief methods of diagnosis, and treatment is also
      discussed.

PMID- 12403189
TI  - Arthroscopic removal of nodules of synovial chondromatosis of the
      temporomandibular joint.
AB  - In this report we describe a new method for removing nodules of TMJ synovial
      chondromatosis using arthroscopic surgery instead of open surgery. We used two
      steps during arthroscopy. In the first, we lavaged the cavity with sterile
      saline. In the next step, the second cannula was replaced with ethmoid forceps.
      Under arthroscopic guidance through the first cannula, all loose bodies were
      removed using the forceps. Since the loose bodies are not fragmented during this
      procedure, the time needed for removal is shortened. Based on this experience, we
      suggest the use of ethmoid forceps should be considered as an alternative
      procedure when nodules are unable to pass through the cannula by lavage with
      sterile saline.

PMID- 12403190
TI  - Myofascial pain syndrome misdiagnosed as odontogenic pain: a case report.
AB  - The aim of this report is to illustrate the case of a patient whose myofascial
      pain syndrome was misdiagnosed as odontogenic pain, and who was treated using
      irreversible dental procedures. Even if dental pain commonly has an odontogenic
      etiology, it is also possible that pain arising from different orofacial sites
      such as jaw muscles, maxillary sinus, or nervous structures can be referred to
      the teeth. When the etiology of a dental pain condition cannot be clearly
      identified, it is necessary to consider all possible causes of dental pain, which
      may also be nonodontogenic. The need for comprehensive examination and careful
      diagnosis before irreversible dental treatment is emphasized.

PMID- 12403191
TI  - Impact of particulate air pollutants on allergic diseases, allergic skin
      reactivity and lung function.
AB  - Elevated levels of particulate matter can exacerbate existing asthma and atopy,
      while evidence that it can promote the induction of atopy and asthma is limited.
      A cross sectional study was taken to compare the prevalence of eye, nose, ear and
      airway allergic symptoms, allergic skin sensitivity and lung function in 290 high
      school students with a history of high 24 hour average exposure to particulate
      matter less than 10 microm in diameter (PM10) = 170 microg/m3 versus low PM10 of
      36 microg/m3 in central Bangkok. Multivariate analysis revealed an increased risk
      of eye and airway symptoms in groups exposed to higher PM10 levels (p = 0.003,
      and 0.05, respectively). Positive skin prick tests and a history of having a lawn
      at home were associated with nasal symptoms (p = 0.008 and 0.04, respectively).
      Mean FEF(25-75%) (forced expiratory flow that occurs during the middle 50% of the
      forced expiratory effort) was significantly lower in those who were exposed to
      higher PM10 levels (3.89 +/- 1 vs 4.42 +/- 0.9 l/sec, p < 0.001). A significant
      increase in days of school absence and medical expenses was associated with high
      PM10 exposure. It is concluded that chronic exposure to high PM 10 levels was
      significantly associated with increased prevalence of eye and airway symptoms and
      a decrement of FEF(25-75%) resulting in increase of school absence and medical
      expense.

PMID- 12403192
TI  - Causes of death and prognostic factors in Thai patients with systemic lupus
      erythematosus.
AB  - From a cohort study of 349 Thai patients (337 females [F] and 12 males [M]) with
      systemic lupus erythematosus (SLE), 52 patients (51 F, 1 M) died. Their 5- and 10
      year survival rates were 84.0% and 74.9%, respectively. Seventy-nine percent of
      deaths occurred within the first year of diagnosis. Infection contributed to 27
      deaths (51.9%). The lung and the urinary system were the 2 most common sites of
      infection. There were 18 SLE-related deaths (34.6%), and 7 non-SLE related deaths
      (13.5%). In a multivariate analysis of all causes of death, serositis,
      hematologic abnormality, central nervous system (CNS) and renal involvement were
      significantly associated with poor survival, while photosensitivity and arthritis
      were significantly associated with longer survival. Among SLE-related death,
      serositis and CNS involvement were significantly associated with poor survival,
      and arthritis was associated with longer survival. In conclusion, infection was
      the most common cause of death in Thai SLE patients. CNS and visceral involvement
      were associated with a poor outcome.

PMID- 12403193
TI  - Characteristic of HIV-1 in V3 loop region based on seroreactivity and amino acid
      sequences in Thailand.
AB  - The third variable (V3) domain of the envelop (env) protein has been used for
      determining genetic subtype and phenotypic characteristics of human
      immunodeficiency virus type 1 (HIV-1) isolates. Based on the seroreactivity of
      the HIV-1 subtype by V3 peptide binding enzyme immunoassay (EIA) of 351 samples
      obtained in 1998 from HIV-1 infected individuals and AIDS patients, we found that
      283 (80.6%) were subtype E, 20 (5.7%) were subtype B, 28 (8.0%) were cross
      reactive between both types and 20 (5.7%) were non-typeable. The degree of
      seroreactivity of HIV-1 subtype E decreased significantly when the amino acid at
      the crown of the V3 loop was substituted from a GPGQ motif to GPGR motif.
      Interestingly, AIDS patients who had V3 sequences of subtype E as GPGR motif had
      a stronger immunoreactivity to GPGQ motif peptides than to GPGR motif peptides,
      in contradiction for their proviral sequences. The results suggested that
      mutations in the V3 loop may lead to a changed immunoreactivity that makes HIV-1
      mutants unrecognizable or allow escape from the primary immune response by means
      of neutralizing sensitivity. In connection with vaccine development, it should be
      pointed out that the combination of V3 sequencing and peptide EIA could provide a
      novel approach to obtain a primarily infected virus sequence as a target for a
      preventive AIDS vaccine.

PMID- 12403194
TI  - Patterns of anti-HIV IgG3, IgA and p24Ag in perinatally HIV-1 infected infants.
AB  - The antibody patterns of HIV-1 IgG3, IgG and IgA and of HIV-1 p24 antigen were
      investigated in Thai infants born to mothers infected with HIV-1. In the 17 HIV-1
      infected infants, anti-HIV antibodies were detected continuously over a period of
      15-18 months and a high level of specific IgG3 subclass was observed. Anti-HIV
      IgA could be detected at 6 months of age whereas p24Ag was detected at 2 months.
      In 79 uninfected infants, maternal anti-HIV IgG gradually decreased over 9 months
      whilst specific IgG3 decayed rapidly during the first 6 months. Both p24Ag and
      anti-HIV IgA were not found in these uninfected infants. Thus, the disappearance
      of anti-IgG3 subclass antibodies within 6 months can predict whether infants are
      uninfected whereas the persistence of anti-HIV IgG and IgG3 subclass antibodies,
      the production of anti-HIV IgA antibody and the presence of p24Ag appear as an
      adjunct to the diagnosis of HIV vertical transmission. The necessary assays are
      relatively simple and could be performed individually.

PMID- 12403195
TI  - Significant differences between plasma HIV-1 RNA assays in HIV-1 subtype E
      infected patients treated with antiretroviral therapy.
AB  - A total of 72 HIV-1 infected Thai patients treated with didanosine (ddI) or
      stavudine (d4T) plus ddI at the time of interim analysis were analyzed. Sixty
      patients (83%) carried subtype E documented by HIV-1 V3 serotyping. HIV-1 RNA
      levels were measured using three commercial viral load assays. At baseline (n =
      57), Quantiplex 2.0 and NucliSens 2.0 showed mean log10 HIV-1 RNA of 0.7 log10 or
      5 fold lower than Amplicor 1.5 (mean 4.29 versus 5.0 log10, respectively, p <
      0.001). At week 20 of treatment (n = 29), HIV-1 RNA levels were detected in
      55.2%, 31%, and 33.5% of subjects tested by Amplicor 1.5, Quantiplex 2.0, and
      NucliSens 2.0, respectively. IN CONCLUSION: plasma HIV-1 RNA analyses showed
      comparable values with Quantiplex 2.0 and NucliSens 2.0 assays. In contrast,
      Amplicor 1.5 resulted in approximately 5 folds higher HIV-1 RNA levels and a 25%
      higher rate of detection of plasma HIV-1 RNA as compared to the other two assays.
      As the current goal of therapy is to suppress plasma viral load below the
      detection limit of the assays, the significant differences between the assays may
      influence antiretroviral efficacy evaluation and management.

PMID- 12403196
TI  - Concomitant administration of varicella vaccine with combined measles, mumps, and
      rubella vaccine in healthy children aged 12 to 24 months of age.
AB  - The reactogenicity and immunogenicity of three combined measles, mumps and
      rubella (MMR) vaccines and one administered with a varicella vaccine was studied
      in infants. The vaccines were Priorix (designated MeMuRu, Group 1), M-M-R II
      (Group 2), Triviraten (Group 3) and Priorix + a varicella vaccine, Varilrix
      (Group 4). Fever was greater in Group 2 (61.3%) compared to Group 1 (48.5%; p =
      0.033) or Group 3 (37.1%; p = 0.009). Rash with fever was reported in Group 2
      (4.8%) and Group 4 (3.3%), but not for Group 1. Anti-measles, -mumps and -rubella
      seroconversion was similar for Group 1 (96.1%, 96.1% and 100%, respectively),
      Group 4 (98% for all three), and Group 2 (91.5%, 93.6% and 97.9%) 60 days post
      vaccination. GMTs for measles (3,053.7-3,412.2 mIU/ml), mumps (1,001.5-1,158.8
      U/ml) and rubella (68.7-89.1 IU/ml) were similar for Groups 1, 2 and 4 at Day 60.
      Antibody persistence was noted 2 years post-vaccination. The MeMuRu + varicella
      combination showed no clinically relevant increase in reactogenicity and should
      facilitate introduction of a varicella vaccine into national immunization
      schedules.

PMID- 12403197
TI  - Childhood idiopathic hypereosinophilic syndrome: report of a case.
AB  - We described a 15-year-old girl who presented with persistent fever, bilateral
      flank pain, and worsening dyspnea. The peripheral blood cell count showed
      remarkable eosinophilia at the time of admission. Severe pleural effusion with
      eosinophilic Infiltrations as well as pericardial effusion were noted thereafter.
      Bone marrow examination disclosed markedly increased eosinophils. Bilateral
      ectasia of the renal pelvis was found in an ultrasonographic study of the
      kidneys. Spiking fever and progressive shortness of breath persisted despite
      treatment with empiric antibiotics for infection. Based on the clinical course
      and histological findings, a tentative diagnosis of idiopathic HES was made.
      After treatment with oral prednisolone daily (1 mg/kg/day) for one week, there
      was a rapid improvement in her clinical condition. She was discharged a few days
      later and the steroids were withdrawn gradually when she was asymptomatic. The
      absolute eosinophil count (AEC) was monitored during follow-up. At 3 weeks, the
      AEC had fallen from 8,060/mm3 to 4,792/mm3 and it further fell to 1,591/mm3 at 5
      months, and to 855/mm3 at 8 months during follow-up. There is no evidence of any
      other organ involvement until now. The clinical manifestations, diagnosis and
      management of idiopathic HES in children are also reviewed.

PMID- 12403198
TI  - Multicentric Castleman's disease, non-Hodgkin's lymphoma, and Kaposi's sarcoma: a
      rare simultaneous occurrence.
AB  - A rare simultaneous occurrence of multicentric Castleman's disease, non-Hodgkin's
      lymphoma, and Kaposi's sarcoma was diagnosed in a 70-year-old man who presented
      with fever, polyarthralgia, weight loss, vascular purpura, anemia, generalized
      lymphadenopathy, and hepatosplenomegaly. He had no risk of HIV infection and
      serological tests for HIV were negative twice, but a low number of T-cells and a
      reversed CD4/CD8 ratio were observed. During hospitalization, he developed
      Kaposi's sarcoma at the right sole. Lymph node biopsies revealed multicentric
      Castleman's disease together with a large B-cell lymphoma, which showed monotypic
      IgM-lambda lymphocytes. To our knowledge, this is the first report in which
      systemic manifestations of all three diseases occurred simultaneously prior to
      any specific treatment. The altered immune status and human herpesvirus-8
      infection might have played a role in the pathogenesis of this occurrence.

PMID- 12403199
TI  - Reversed passive hemagglutination test fails to detect HBsAg in a number of HBeAg
      positive sera.
AB  - In endemic areas of hepatitis B virus (HBV) infection, perinatal transmission
      from asymptomatic HBsAg carrier mothers to infants plays a major role in the
      transmission of HBV. HBeAg indicates a high level of viral replication and
      infectivity. Most of the infants born to HBeAg positive mothers become carriers.
      Prenatal screening of HBsAg would identify infected mothers and thus allow
      preventive administration of immunoglobulin and immunization to the newborns.
      Reversed passive hemagglutination assay (RPHA) is commonly used in Thailand for
      HBsAg screening. However this method has low sensitivity and gives false negative
      results. Therefore, infants born to HBsAg false negative mothers would not
      receive proper immunization. This study reveals the rate of false negative
      results for HBsAg by RPHA in high infectivity sera. Of 985 sera which were HBsAg
      positive by ELISA, 70 (7.1%) were negative for HBsAg by RPHA. Of these 70 false
      negative sera, 7 (10%) were HBeAg positive. Our results indicate that RPHA is a
      less sensitive method for detection of HBsAg than ELISA. RPHA can give false
      negative results even in sera with high HBV infectivity. Therefore, RPHA should
      be replaced by EIA for prenatal HBsAg screening or any other screening for HBV
      infection whenever possible.

PMID- 12403200
TI  - Actions of the scalene muscles for rotation of the cervical spine in macaque and
      human.
AB  - STUDY DESIGN: Multiple single-subject design in 2 parts: 1 in anesthetized
      monkeys and a follow-up in human cadavers. OBJECTIVES: To determine whether
      anterior, middle, and posterior scalene muscles rotate the cervical spine to the
      same (ipsilateral to the muscle) or opposite (contralateral to the muscle) side.
      BACKGROUND: Some physical therapy and anatomy textbooks indicate that all 3
      scalenes rotate the cervical spine to the same side, some indicate that all
      rotate to the opposite side, and the rest ascribe different functions to the
      different scalenes. METHODS AND MEASURES: While under anesthesia, macaques (n =
      3) already scheduled for euthanasia were implanted with stimulating electrodes in
      each scalene muscle on one side, and then a neuromuscular junction blocker was
      administered to prevent confounding movement from brachial plexus stimulation.
      Three observers independently rated the direction of rotation produced by
      electrical stimulation. Postmortem dissection of the macaques was used to
      determine which direction of passive rotation stretched each scalene. Postmortem
      analyses in 2 human cadavers were also conducted to determine which direction of
      rotation stretched the human scalenes. RESULTS: Electrical stimulation in the
      macaque produced rotation to the same side for each of the 3 scalenes. Passive
      rotation to the opposite side put each scalene muscle of the macaque on stretch.
      In the human, rotation to the opposite side also stretched each scalene.
      CONCLUSIONS: All 3 scalene muscles produce rotation of the cervical spine to the
      same side. Maximum stretching of the scalenes should include rotation to the
      opposite side.

PMID- 12403201
TI  - Shoulder instability: management and rehabilitation.
AB  - Shoulder dislocation and subluxation occurs frequently in athletes with peaks in
      the second and sixth decades. The majority (98%) of traumatic dislocations are in
      the anterior direction. The most frequent complication of shoulder dislocation is
      recurrence, a complication that occurs much more frequently in the adolescent
      population. The static (predominantly capsuloligamentous and labral) and dynamic
      (neuromuscular) restraints to shoulder instability are now well defined.
      Rehabilitation aims to enhance the dynamic muscular and proprioceptive restraints
      to shoulder instability. This paper reviews the nonoperative treatment and the
      postoperative management of patients with various classifications of shoulder
      instability.

PMID- 12403202
TI  - Risk factors for anti-inflammatory-drug- or aspirin-induced gastrointestinal
      complications in individuals receiving outpatient physical therapy services.
AB  - STUDY DESIGN: Prospective, multicenter, observational research study. BACKGROUND:
      Minimal research exists that describes the potential for serious gastrointestinal
      complications in individuals receiving outpatient physical therapy care.
      OBJECTIVE: To identify the prevalence of risk factors for gastrointestinal
      complications induced by anti-inflammatory drugs or aspirin in individuals
      receiving outpatient physical therapy services. METHODS AND MEASURES: A self
      administered questionnaire was used at 65 ambulatory physical therapy clinics to
      document past medical history, history of present illness, and medication use.
      Risk factors for anti-inflammatory-drug- or aspirin-induced gastrointestinal
      complications were identified and the proportion of patients reporting each
      factor was determined. RESULTS: A total of 2433 patients completed the survey. Of
      the 2311 evaluable patients included in the study, 78.6% reported over-the
      counter or prescribed use of an anti-inflammatory drug or aspirin during the week
      prior to the survey. Forty-nine percent of the patients reported at least 1 risk
      factor for drug-induced gastrointestinal complications, while 12.9% reported 2 or
      more risk factors. The most frequently reported established risk factors among
      anti-inflammatory drug or aspirin users were (1) combination (dual) therapy
      (22.3% reported concomitant use of anti-inflammatory and aspirin therapy), (2)
      advanced age (15.7% were over the age of 61 years), (3) history of peptic ulcer
      disease (7.8% had a history of peptic ulcer disease), and (4) significant
      systemic illness (6.8% reported having rheumatoid arthritis or heart disease). A
      frequently encountered risk factor combination was advanced age with a history of
      peptic ulcer disease (12.7%). CONCLUSIONS: Patients seen at physical therapy
      ambulatory clinics present with multiple risk factors for anti-inflammatory-drug-
      or aspirin-induced gastrointestinal complications and provide a potential
      opportunity for risk reduction by clinicians working in this environment.

PMID- 12403203
TI  - Comparison of static and placebo magnets on resting forearm blood flow in young,
      healthy men.
AB  - STUDY DESIGN: Prospective, randomized, double-blind, placebo-controlled crossover
      design. OBJECTIVES: To examine the effects of static magnets on resting forearm
      blood flow and vascular resistance. BACKGROUND: Despite little scientific
      evidence indicating benefits of wearing static magnets, recent reports have
      indicated a dramatic increase in the usage of magnets to treat a variety of
      medical conditions. Magnet manufacturers have proposed that one mechanism for
      pain reduction involves magnet-related blood flow alterations to the affected
      area. METHODS AND MEASURES: Twenty young, healthy men (mean age +/- SD = 25 +/- 2
      years) wore commercially available static magnets and placebos for 30 minutes on
      2 separate occasions. Resting forearm blood flow was assessed in triplicate at
      minutes 10, 20, and 30, using venous occlusion plethysmography. Forearm vascular
      resistance was estimated by dividing mean arterial pressure by blood flow.
      RESULTS: The average blood flow over the 30-minute measurement period was not
      significantly different between the magnet and placebo sessions (mean +/- SD for
      magnet session = 1.40 +/- 0.63 ml blood x 100 ml tissue(-1) x min(-1); mean +/-
      SD for placebo session = 1.36 +/- 0.46 ml blood x 100 ml tissue(-1) x min(-1); P
      = 0.66). Blood flow measurements at minutes 10, 20, and 30 were also not
      significantly different between the magnet and placebo sessions, and forearm
      vascular resistance was not different between the magnet and placebo sessions at
      any time (P > 0.05). CONCLUSION: Exposure to static magnets for up to 30 minutes
      had the same effect on resting forearm blood flow and vascular resistance as
      placebo magnets. These data suggest that static magnets do not result in
      significant alterations in resting blood flow.

PMID- 12403204
TI  - Effects of standing and sitting on finger-tapping speed in healthy adults.
AB  - STUDY DESIGN: A repeated-measures design was used to compare finger-tapping
      performance (hand functional control) across 4 standing and sitting conditions of
      limb body support postures. OBJECTIVES: The intent was to examine the
      hypothesized hemispheric control interference effects of lower limb body support
      postures on finger-tapping performance. A secondary objective was to gain a
      better understanding of the relationship between lower limb posture and
      concurrent finger-tapping activity. BACKGROUND: In a task such as kicking a ball
      with the right foot, foot control theory suggests that the left hemisphere
      contralaterally controls right-foot kicking action. However, it can also be
      interpreted that the postural support (with the left foot in this example)
      involving the action of antigravity muscles (leg extensors) is driven
      ipsilaterally. Based on this explanation, we would expect a hemispheric effect to
      occur during standing on the left limb while performing a finger-tapping task
      with the right hand. This study has theoretical and clinical significance for
      understanding hemispheric and functional control of limbs, which may underlie the
      assessment of movement control and the development and use of therapeutic
      interventions that can potentially improve functional movement control. METHODS
      AND MEASURES: Ninety-eight (98) adult participants (ages 19 to 32 years)
      performed a finger-tapping task in 4 postural conditions: seated, standing on
      both feet, standing on the right foot only (RF), and standing on the left foot
      only (LF). RESULTS: As predicted, manual performance was significantly slower in
      the LF condition as compared to the standing and sitting positions. However, when
      comparing performance between the LF and RF conditions, the difference was
      minimal. CONCLUSIONS: Although support for the ipsilateral effect was not found,
      postural position did influence manual performance.

PMID- 12403205
TI  - Ocular diseases in patients with rheumatic diseases.
AB  - To study the distribution of ocular involvement among persons with rheumatic
      disease, a cross-sectional survey was performed in 224 patients attending the
      Division of Rheumatology, Department of Medicine, Maharaj Nakorn Chiang Mai
      Hospital. Of these patients, 102 presented with rheumatoid arthritis, 74 systemic
      lupus erythematosus, 39 systemic sclerosis, 6 mixed connective tissue disease, 2
      polymyositis and 1 juvenile rheumatoid arthritis. It was found that the ocular
      involvement probably related to diseases including dry eye (19.9%) and uveitis
      (0.4%). The ocular involvement was presumably related to treatment including
      retinopathy (7.6%), cataract (6.3%), and glaucoma (0.9%). Rapid recognition of
      these complications would lead to early and appropriate management, which would
      prevent their sequelae.

PMID- 12403206
TI  - A longitudinal causal relationship among cardiovascular risk factors in the
      employees of the government savings bank.
AB  - A longitudinal structural causal model was generated to examine the causal
      relationship among determinants which were composed of four personal factors,
      stress, four health behaviors, and BMI on five physiological risks for
      cardiovascular disease: SBP, DBP, FBS, TC and HDL-C in 1,019 bank employees,
      within a five-year interval. A fourteen-item food frequency questionnaire for
      assessing eating habits and the Health Opinion Survey for the stress test were
      included in the self-administered questionnaires. Weight, height and blood
      pressure were measured and blood samples were collected for blood chemical
      analysis. Data analysis by LISREL showed that the determinants in the proposed
      model explained as much as 96 per cent variation in physiological risks for CVD
      (R2 = 0.96, relative chi-square = 1.92, RMSEA = 0.03, GFI = 0.96 and AGFI =
      0.95). The findings also indicated that current physiological status was affected
      by their status of age, education, health behaviors, BMI and physiological status
      5 years ago.

PMID- 12403207
TI  - Violence against children by parents.
AB  - The study aimed to identify the characteristics and frequency of physical and
      emotional violence against children by their biological parents and the
      relationship between children's characteristics, family factors and the extent of
      violent acts against children. The sample consisted of 212 grade six students in
      Muang District, Amnatcharoen Province. The data were collected from February 8 to
      20, 1999. The results showed that 95.3 per cent of respondents perceived being
      treated violently by their biological parents, as 76.7 per cent were physical
      violence and 95.0 per cent were emotional violence. The most common physical and
      emotional acts of violence were beating by a cane or belt and scolding with rude
      language respectively. However, the violent acts occurred only occasionally. Only
      the factors of self-esteem and child's gender could predict the violent acts by
      fathers for 10.5 per cent; whereas family crises, family relations and self
      esteem could predict the violent acts by mothers for 13.0 per cent. Therefore,
      building self-esteem, encouraging a healthy home environment, and creating proper
      coping skills against family crises are necessary for reducing violent acts.

PMID- 12403208
TI  - Psychosocial problems in children with thalassemia and their siblings.
AB  - Beta-thalassemia is a chronic illness causing serious symptoms to children and a
      burden to families. The purpose of this study was to evaluate psychosocial
      problems in children with thalassemia and their siblings by using a semi
      structured interview and the Pediatric Symptom Checklist (PSC). The study sample
      included 82 children with thalassemia, 20 siblings, and 50 control children
      without a chronic illness. With children and families demographically controlled,
      psychosocial problems were significantly more common in children with thalassemia
      than in those without chronic illness, 28.05 per cent vs 4 per cent (p=0.001),
      but there was no difference between siblings and the controls, 5 per cent vs 4
      per cent (p=0.64). The mean PSC score in children with thalassemia was higher
      than that in the sibling and control group (18.34 vs 10.95 and 10.28,
      respectively; p<0.001). These findings suggest an increased risk of psychosocial
      problems in children with thalassemia that psychosocial intervention may be
      required to prevent major psychiatric disorders.

PMID- 12403209
TI  - Infection due to nontuberculous Mycobacterium other than MAC in AIDS patients at
      Siriraj hospital during 1998-2000: saprophyte vs pathogen.
AB  - HIV is a major health problem in Thailand. These patients are vulnerable to
      opportunistic infections, especially Mycobacterium tuberculosis and MAC
      infection. However, NTM was considered a rare disease in Thailand before the AIDS
      era. In this study, there were 38 HIV seropositive patients with NTM (other than
      MAC) identified from clinical specimens during the 3 year period 1998-2000 at
      Siriraj Hospital, which has a higher prevalence than the previous report. Among
      these patients, 29 cases were likely to have had definite infection from NTM, 5
      cases possibly had NTM as a pathogen, and 4 cases had NTM as colonization. The
      most common site of infection was the lung (87%) and most common symptoms were
      cough (62.2%), fever (34.2%), weight loss (42.1%), and lymphadenopathy (5.3%).
      The outcome was poor because many NTM are not susceptible to standard medication
      for tuberculosis which is the empirical treatment for the majority of HIV
      seropositive patients with a clinical finding suspected of mycobacterial
      infection. The fatality rate was as high as 58.6 per cent. Awareness of NTM as a
      potential pathogen in HIV seropositive patientsand adjustment of medications even
      before the availability of culture results may improve the outcome of treatment
      of NTM infection in HIV seropositive patients.

PMID- 12403210
TI  - Efficacy of brimonidine 0.2 per cent as adjunctive therapy to beta-blockers: a
      comparative study between POAG and CACG in Asian eyes.
AB  - OBJECTIVE: To compare the efficacy and safety profile of brimonidine as
      adjunctive therapy to beta-blockers between primary open angle glaucoma (POAG)
      and chronic angle closure glaucoma (CACG) in Asian eyes. DESIGN: Three-months,
      open-label, prospective study. PARTICIPANTS: Twenty-three patients (35 eyes) with
      POAG and 25 patients (39 eyes) with CACG were enrolled in the study.
      INTERVENTION: Patients with POAG or CACG post iridectomy whose IOP was
      inadequately controlled with topical beta-blocker monotherapy were included.
      Then, brimonidine 0.2 per cent was added twice daily in both groups. Study visit
      occurred at weeks 2, 4, 8, and 12. Complete ophthalmic examinations were
      performed in all visits. MAIN OUTCOME MEASURES: Efficacy was determined by
      reduction in IOP from baseline and tolerability was assessed by reports of
      adverse events. RESULTS: After 3 months of brimonidine adjunctive treatment, the
      mean (+/- SEM) IOP reduction were 4.37+/-0.34 mmHg (19.4%) in POAG and 4.54+/
      0.37 mmHg (20.1%) in CACG (p= 0.741). No serious ocular or systemic adverse event
      was reported. CONCLUSION: Brimonidine was well tolerated, efficacious and
      provided additive IOP reduction in POAG and CACG.

PMID- 12403211
TI  - Prevalence of thyroid antibodies in Thai patients with chronic idiopathic
      urticaria.
AB  - One hundred Thai patients with chronic idiopathic urticaria (CIU) were studied to
      determine the prevalence of thyroid antibodies in comparison to 100 age- and sex
      matched healthy volunteers. It was found that 21 patients (21%) with CIU were
      positive for thyroid antibodies. Among normal volunteers, only nine cases (9%)
      had elevated titers of thyroid antibodies. The frequency of thyroid antibodies in
      the chronic urticaria group was significantly more common than the control group
      (chi-square = 4.75, p=0.03). Among 21 patients with CIU who were positive for
      thyroid antibodies, 9 cases were negative for thyroid antibodies when repeating
      the tests after 3 months. Only 12 patients still had persistent elevation of
      antibodies after 3 months and thyroid function test was performed in these 12
      patients. It was found that 9 cases had autoimmune thyroiditis with euthyroidism.
      One case had subclinical hyperthyroidism. One case had autoimmune
      hyperthyroidism, One case had subclinical hypothyroidism.

PMID- 12403212
TI  - The effect of growth hormone on the development of in vitro matured unstimulated
      human oocytes.
AB  - OBJECTIVE: To investigate the effect of growth hormone on the development of in
      vitro matured unstimulated human oocytes. DESIGN: Randomized controlled study.
      SETTING: Division of Reproductive Medicine, Department of Obstetrics and
      Gynecology, Faculty of Medicine, Chulalongkorn university. MATERIAL AND METHOD:
      108 germinal vesicle-stage oocytes were retrieved from 47 patients undergoing
      gynecologic surgery. They were aspirated either during gynecologic surgery or
      from excised ovaries. The oocytes were then cultured in vitro with or without
      growth hormone (1,000 ng/ml) in medium199 supplemented with sodium pyruvate, FSH,
      LH, antibiotic and synthetic serum. Incubation was done at 37 degree C with 5 per
      cent CO2 in air and nuclear stage was assessed after 18, 42, 66 and 90 h of
      incubation. MAIN OUTCOME MEASURE: Attainment of metaphase II and GVBD RESULTS:
      After in vitro culture, there were no significant differences in maturation and
      GVBD rate. 27 of 52 (51.9%) oocytes (GV) in growth hormone group matured to
      metaphase II compared with 25 of 53 (47.2%) GV in control group. GVBD rate for
      germinal vesicle-stage in growth hormone group was 76.9 per cent compared with
      79.2 per cent in control group. CONCLUSION: Culture of immature oocytes in vitro
      with growth hormone results in similar maturation rate as that without GH.

PMID- 12403213
TI  - Influence of normal ageing on mechanism of bone loss in women and men in Bangkok.
AB  - Age and sex related changes in bone metabolism are of interest in the
      pathogenesis of osteoporosis. However, most data in the literature were studied
      in Western countries. In a tropical country, such as Thailand, little is known of
      vitamin D status and bone remodeling. Thus, the aim of this study was to
      determine the changes of vitamin D levels and biochemical markers of bone
      turnover in healthy women and men of various age groups between 20-80 years who
      were living in Bangkok. From the results, vitamin D levels of various age groups
      did not alter significantly between men and women except in the sixth decade of
      women. However, men had higher levels of vitamin D than women. In women, all
      biochemical markers of bone turnover increased with age, with a sharp increase at
      the onset of menopause. In contrast, biochemical markers of bone turnover in men
      gradually declined with advancing age. CONCLUSION: There was no evidence of
      vitamin D deficiency in the Bangkok population. Women and men showed different
      age-related changes in bone metabolism.

PMID- 12403214
TI  - Reagent strip testing is not sensitive for the screening of asymptomatic
      bacteriuria in pregnant women.
AB  - The objective of the study was to assess the diagnostic performance of the
      reagent strip in screening for asymptomatic bacteriuria in pregnant women using
      urine culture as a gold standard. This study comprised 204 asymptomatic pregnant
      women who attended their first antenatal care at Srinagarind Hospital, Khon Kaen
      University from April 1, 1999 to June 30, 1999. Women with symptoms of urinary
      tract infection, antibiotic treatment within the previous 7 days, pregnancy
      induced hypertension, bleeding per vagina and history of urinary tract diseases
      were excluded. Urine specimens were collected by clean catched midstream urine
      technique for urinalysis, reagent strip test and urine culture. Diagnostic
      performance of reagent strip in terms of sensitivity, specificity, positive and
      negative predictive value was analyzed. Urine reagent strip test had a
      sensitivity of 13.9 per cent, a specificity of 95.6 per cent, a positive
      predictive value of 46.1 per cent, a negative predictive value of 80.6 per cent
      in detecting asymptomatic bacteriuria in pregnant women.

PMID- 12403215
TI  - Serum aluminium in alumina exposed workers.
AB  - This study was performed after skepticism occurred in 1994 when alumina, or
      aluminium oxide, was thought to be the cause of sickness and death for certain
      workers at the Northern Industrial Park, Lumphun province, Thailand. Zeeman
      graphite furnace atomic absorption spectrometric method has been developed to
      quantify the aluminium (Al) levels in the serum of 399 workers and 500 blood
      donors. The results showed that Al levels in the directly (n = 62) exposed
      workers was significantly different from the indirectly exposed (n = 130) and non
      exposed (n = 207) workers and donors. However, symptoms found in the directly
      exposed workers were not significantly different from those in the indirectly
      exposed workers. In addition, a high percentage of headache and fatigue found in
      both directly and indirectly exposed workers suggested that more than one hazard
      could be involved in the incidence of alumina.

PMID- 12403216
TI  - The perceived handicap questionnaire: a self perceived handicap measurement in
      patients with spinal cord injury.
AB  - Handicap exists when individuals with impairment or disability are unable to
      fulfill one or more of the roles that are considered normal for their age,
      gender, and culture. In fact, handicap is one of the most poorly measured of all
      rehabilitation outcomes. This study was performed to measure the subjective
      experience of handicap in spinal cord injury (SCI) patients who had permanent
      disabilities and were often faced with environmental barriers. Eighty-three new
      traumatic SCI patients with a mean age of 33 years were interviewed during follow
      up outpatient clinic visits using the Perceived Handicap Questionnaire (PHQ).
      This test provides a global measurement of the extent of self-perceived handicap
      across five dimensions based on the WHO's classification of handicap. When
      compared with normal persons, SCI subjects perceived themselves as more
      handicapped in all dimensions especially mobility and physical independence. In
      contrast, the majority of SCI subjects perceived themselves as less handicapped
      than others with SCI in physical independence, and equally handicapped in social
      integration and in economic self-sufficiency. In addition, the Barthel Index
      Score of self-care activities was negatively correlated with the PHQ score, but
      the depression score and hospitalization period were positively correlated with
      the PHQ score. Rehabilitation professionals should pay attention to the
      measurement of societal functioning or handicap in addition to disability.

PMID- 12403217
TI  - Repeated spontaneous quadriceps tendon rupture in hemodialysis patient: a case
      report and review of the literature.
AB  - A 43-year-old man experienced repeated spontaneous quadriceps tendon rupture
      after he had been on regular hemodialysis for 10 years. He had undergone a long
      period of secondary hyperparathyroidism as demonstrated by high serum parathyroid
      hormone and alkaline phosphatase level. He was successfully treated both times
      using the conservative method. The causes or risk factors, clinical character and
      appropriate management of this rare morbidity in hemodialysis patients are
      discussed with a literature review.

PMID- 12403218
TI  - Neurotoxic envenoming following bites by the Malayan krait (Bungarus candidus).
AB  - The author reports three cases of patient bitten by the Malayan krait (Bungarus
      candidus). Within two to six hours after bites, patients developed ptosis,
      ophthalmoplegia, dysarthria, dysphagia and generalized paralysis requiring
      assisted ventilation. After ventilatory support and other supportive treatments,
      all patients gradually recovered to normal activity.

PMID- 12403219
TI  - Ethics and the drafting of the "National Health Insurance Bill".

PMID- 12403220
TI  - Airway complications in neonates who received mechanical ventilation.
AB  - OBJECTIVE: To determine the incidence, type and severity of airway complications
      in high risk neonates who received conventional mechanical ventilation. METHOD:
      Forty-five infants who had received conventional mechanical ventilation in the
      Neonatal Intensive Care Unit, Department of Pediatrics, Faculty of Medicine
      Siriraj Hospital for at least 4 days were enrolled. Orotracheal intubation with
      blue line, non-cuffed, non-shouldered polyvinylchloride tube was used
      exclusively. The average number of intubations was 2 (range 1-7), and the average
      duration for intubation was 25 days. The details of the intubation, and the
      presence of respiratory distress after extubation were recorded. All of the
      infants had endoscopic examination of the airway within 5 days of extubation.
      RESULTS: Following extubation, 14 (31.1%) infants developed signs of upper airway
      obstruction, of which inspiratory dyspnea was the most common manifestation. Only
      4 infants developed inspiratory stridor, three of them had a birth weight greater
      than 2,500 g. Abnormal bronchoscopic findings were found in 42 infants, 68.8 per
      cent had multiple sites of injury. Supraglottic lesions were found in 55.7 per
      cent of cases. Laryngomalacia was an associated finding in 8 and gastroesophageal
      reflux (GER) in 1 occasion. CONCLUSIONS: From the result of this study, the
      authors found that airway complications related to endotracheal intubation are
      common among survivors from the Neonatal Intensive Care Unit. When the diagnosis
      of airway complications only depends on symptoms and signs of upper airway
      obstruction, the incidence and extent of injuries may be under-estimated. When
      attempted extubation fails or when VLBW infants develop increasing respiratory
      distress that is not clearly explained by an apparent disorder involving the
      pulmonary parenchyma, flexible bronchoscopic examination should be performed at
      the bedside with minimal risk.

PMID- 12403222
TI  - Inhaled nitric oxide therapy in premature infants with mild to moderate
      respiratory distress syndrome.
AB  - Inhaled nitric oxide (iNO) therapy has been demonstrated to acutely improve
      oxygenation in preterm infants with severe pulmonary disease. Administration of
      iNO to the premature infants with less severe pulmonary illness has not yet been
      studied extensively. Therefore, the authors performed a pilot study enrolling
      thirty-four premature infants with respiratory distress syndrome (RDS) within 72
      hours of age, birth weight between 500-2,000 g, whose oxygenation indexes
      exceeded our birthweight-specific criteria. Infants were randomly assigned to
      either treatment with (iNO group; n = 16) or without (control group; n = 18) iNO.
      Inhaled NO was started at 20 ppm and weaned to 5 ppm over 24-48 hours. Routine
      cranial ultrasonography was performed and the occurrence of intraventricular
      hemorrhage (IVH) was interpreted by an attending pediatric radiologist unaware of
      the treatment group assignment. The study showed that the two groups were of
      similar birth weight (mean+/-SEM): control 901+/-73 g vs iNO 874+/-70 g; and
      gestational age: control 27.2+/-0.5 wk vs iNO 26.8+/-0.5 wk. Other baseline
      parameters between the two groups were also similar. The mean ages of the infants
      at the time of entry were 11.7+/-2.2 and 8.3+/-0.9 hours in the controls and iNO
      group. The entry oxygenation index (OI) did not differ between the two groups:
      control 11.9+/-2.2 vs iNO 10.8+/-1.50. After 30 minutes of iNO therapy, there was
      a 50 per cent increase in partial pressure of oxygen tension (PaO2) and 15 per
      cent reduction in OI, (p = 0.02 and p = 0.04 vs baseline, respectively). No
      statistical difference in the incidence of significant IVH (Grade III and IV) was
      detected: control 27.8 per cent; iNO 25.0 per cent. The incidence of other acute
      complications as well as early neonatal death, were comparable between the
      groups. The mean methemoglobin concentration was 1.2+/-0.5 per cent. In
      conclusion, these preliminary data suggest that iNO, as used in this protocol,
      acutely improves oxygenation without increasing significant IVH in premature
      infants with mild to moderate RDS. These important findings serve to justify
      further study of the efficacy of iNO on long term pulmonary outcome and mortality
      in this group of infants.

PMID- 12403221
TI  - Pulmonary function in infants exposed to pethidine.
AB  - OBJECTIVE: To investigate the effects of maternal pethidine administration on
      pulmonary function tests in newborn infants. PATIENTS AND METHOD: The study was
      carried out in the Department of Obstetrics and Gynecology, Faculty of Medicine
      Siriraj Hospital. The study group consisted of 20 infants exposed to pethidine
      within 4 hours prior to delivery. Twenty infants whose mothers received no
      analgesic drug or regional anesthesia were randomly selected as the controls.
      Narcotic related respiratory depression was determined by Apgar scores, the need
      for ventilatory support in the delivery room and abnormal pulmonary function
      measurements. RESULTS: There was no difference in birth weight and gestational
      age between the two groups of infants. Pethidine was given to mothers at a dose
      of 72.5 +/- 7.6 mg/kg with a mean drug-delivery interval of 152 +/- 61 minutes.
      One infant in each group had a 1-minute Apgar score less than 7, but there was no
      statistical difference in the mean Apgar score between the two groups. None of
      the infants whose mothers received pethidine required ventilatory support, but
      oxygen was provided to eight infants who were apparently cyanosed at birth.
      Pulmonary function measurements were performed at the age of 7.4 +/- 2.3 hours in
      the controls and 6.0 +/- 2.5 hours in the study group. There was no significant
      difference in respiratory rate, tidal volume, inspiratory time, functional
      residual capacity, compliance and resistance between the two groups of infants.
      CONCLUSION: Severe narcotic related respiratory depression was uncommon in this
      study. In the first 12 hours of life, there was no significant difference in
      pulmonary function of the infants exposed to pethidine. It is quite safe to allow
      the baby to room-in with the mother if respiratory depression is not presented at
      birth.

PMID- 12403223
TI  - Neonatal group B streptococcal infection: incidence and clinical manifestation in
      Siriraj Hospital.
AB  - From 1996 to 2001, nineteen episodes of bacteremia due to group B Streptococci
      (GBS) were diagnosed in Siriraj Hospital, Mahidol University. The incidence of
      early onset group B streptococcal disease (EOD) was 0.27 cases/1,000 live births
      in 1996, and decreased to 0.10 cases/1,000 live births in 2001. The incidence of
      the late onset disease (LOD) was 0.05 cases/1,000 in 1996, and there has been
      none since 1998. All of the infants were inborn. Low birth weight was found in 53
      per cent of the infants. Fifty-eight per cent of infants were male. Forty-seven
      per cent of the infants were born prematurely. None of the mothers had antenatal
      GBS screening. Only one mother received one dose of intrapartum antibiotic
      prophylaxis. No risk factor could be identified in 72 per cent of the mothers.
      EOD accounted for 79 per cent of all infants with GBS infections, with a
      mortality rate of 40 per cent. All of them died within the first 72 hours of
      life. Most EOD infants developed disease manifestations within 12 hours of life.
      Most common clinical manifestations were respiratory distress (74%), temperature
      instability (68%), cyanosis (63%), hypotension (42%) and lethargy (42%). Only one
      infant with EOD had meningitis. There were two infants in the LOD group; one of
      whom had cellulitis, and the other had meningitis. Neutropenia was noted in 42
      per cent of all infants. Radiographic studies suggested a diffuse
      reticulogranular pattern or ground glass appearance in 38 per cent. The chest X
      ray was interpreted as normal in 25 per cent of the infants. In conclusion, the
      incidence of GBS infection in newborn infants in Thailand is still very low but
      with a very high mortality. Prematurity accounts for almost half of the cases.
      Even though antepartum screening with intrapartum antibiotic chemoprophylaxis has
      been recommended in developed counties, its benefit and cost needs to be further
      investigated in Thailand.

PMID- 12403224
TI  - Intensive diabetes education program and multidisciplinary team approach in
      management of newly diagnosed type 1 diabetes mellitus: a greater patient
      benefit, experience at Siriraj Hospital.
AB  - It is accepted worldwide that an effective multidisciplinary management team is
      essential for providing comprehensive self-management training to type I
      diabetics and their families. Therefore, the authors developed an intensive
      multidisciplinary education team that included pediatric endocrinologists, a
      dietitian, a psychologist, nurses, scientists and volunteers in the Department of
      Pediatrics, Siriraj Hospital in August 1996. This study aimed to analyze twenty
      four newly diagnosed diabetics who underwent this specified program and
      multidisciplinary team approach in comparison to twenty-eight diabetic patients
      who were diagnosed before the program and team were established in order to see
      whether the length of hospitalization had been reduced and to compare the
      readmission rates of recurrent DKA with previous patients. The results
      demonstrated that by using the intensive program and multidisciplinary team the
      average length of admission was reduced from 36.04 days to 17.63 days (p value =
      0.03). The readmission rate in the first year after diagnosis was also reduced
      from 17.8 per cent to 4 per cent. Concerning diabetes control, the average HbA1c
      level showed significantly better control. Therefore, this study demonstrated a
      successful team and program for newly diagnosed Thai childhood and adolescent
      diabetics and also emphasized that a multidisciplinary team approach with an
      effectively intensive education program is important in helping diabetics and
      families cope with their emerging problems and receive the long-term benefits of
      effective self-care.

PMID- 12403225
TI  - Ambiguous genitalia: an overview of 22 years experience and the diagnostic
      approach in the Pediatric Department, Siriraj Hospital.
AB  - The newborn with abnormal genital development presents a difficult diagnostic and
      treatment challenge for the pediatrician providing care. It is important that a
      definitive diagnosis be determined as quickly as possible so that the appropriate
      treatment plan can be established to minimize medical, psychological and social
      complications. The purpose of this study was to provide an extensive review of
      the clinical characteristics of a patient cohort with ambiguous genitalia, from
      22 years' experience in the Division of Endocrinology and Metabolism, Department
      of Pediatrics, Siriraj Hospital, and to classify them into diagnostic categories.
      Moreover, a cascade of diagnostic tools in approaching sexual ambiguity in the
      authors' institution, starting with history and physical examination and leading
      to further radiographic and laboratory investigations is demonstrated and can be
      adopted as a guideline for the clinical management of these disorders. From 1979
      to 2001, care was provided to a total of 109 patients with ambiguous genitalia,
      of whom 104 patients were reviewed. Among these individuals, 52 patients (50.0%)
      belonged to the diagnosis of female pseudohermaphroditism, 5 patients (4.8%) were
      in the true hermaphroditism group and the remaining 47 patients (45.2%) were in
      the male pseudohermaphroditism group. All female pseudohermaphrodites carried a
      diagnosis of congenital adrenal hyperplasia (CAH) and were reared as girls. 21
      hydroxylase deficiency CAH accounted for all except one (98%) in this group.
      Among the 47 male pseudohermaphrodites, 9 (19.1%) had dysgenetic male
      pseudohermaphroditism, 7 (14.9%) had either testosterone biosynthetic defects or
      hCG unresponsiveness, 22 (46.8%) had either androgen insensitivity syndrome or 5
      alpha-reductase deficiency, 4 (8.5%) had ambiguous genitalia in a 46,XY male
      associated with multiple anomalies and 5 (10.6%) had an unidentifiable cause. Sex
      reassignment occurred, not uncommonly, in 4 cases of female pseudohermaphrodites
      (7.7%) and at least 2 cases (3.9%) in the combined group of male
      pseudohermaphrodites and true hermaphrodites. The scope of the ambiguous
      genitalia problem is definitely not minor. An inappropriate approach to this
      problem poses an undue risk to the integrity of the physical and psychosexual
      health in the future for these children.

PMID- 12403226
TI  - Persistent hyperinsulinemic hypoglycemia of infancy: experience at Siriraj
      Hospital.
AB  - BACKGROUND: Persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is the
      most common cause of recurrent or persistent hypoglycemia in early childhood.
      Conventionally, pancreatectomy (Px) has often been recommended to control
      hypoglycemia. However, PHHI can be managed successfully by intensive medical
      treatment to avoid pancreatectomy. METHOD: Data from 10 infants (8M, 2F) with
      PHHI were retrospectively analyzed. RESULTS: Eight patients (80%) developed
      symptoms within 72 hours after birth (early-onset). Six patients (60%) underwent
      85 per cent-95 per cent Px due to failure of medical treatment. Two patients who
      underwent less than 95 per cent Px required second Px (97% and 99%). One patient
      developed permanent diabetes mellitus and malabsorption. Hypoglycemia could be
      successfully managed by medication alone in four patients (40%). Of these, three
      patients had early-onset neonatal hypoglycemia. Medication could be discontinued
      in three patients (75%). Three of ten patients (30%) had delayed development.
      Pancreatectomies and/or the diagnosis of PHHI were made late for these patients.
      One of these three children also developed epilepsy. CONCLUSIONS: Patients with
      PHHI frequently require pancreatectomy which commonly results in long-term
      complications especially diabetes mellitus and malabsorption. Our data suggest
      that PHHI can be managed successfully with an intensive medical regimen even in
      patients with early-onset hypoglycemia. Although medical management is very
      laborious for the family and physician, it should be applied until euglycemia is
      accomplished. Moreover, the early diagnosis of PHHI and the successful
      hypoglycemic control are very necessary to prevent permanent neurologic sequelae.

PMID- 12403227
TI  - Carrier detection by DNA linkage analysis in eighty Thai hemophilia A families.
AB  - DNA linkage analysis was performed in Thai hemophilia A families to evaluate its
      value for carrier detection. Both intragenic and extragenic polymorphic DNA
      regions of the factor VIII gene, including Bcl I-RFLP in intron 18,
      microsatellites (CA repeats) in introns 13 and 22, and extragenic Stl4 (DXS 52)
      VNTR, were amplified by polymerase chain reaction (PCR) before analyses by
      appropriate electrophoretic procedures. A total of 80 Thai hemophilia A families
      (48 with a family history and 32 with a sporadic case), containing 349 DNA
      samples from 90 hemophilia A patients, 143 parents, and 116 relatives, were
      analyzed. Heterozygosities in the patients' mothers from both families with a
      family history and with a sporadic case were observed in 71 out of 80 families
      (88.75%) for all polymorphic DNA markers analyzed. The carrier status could be
      identified in 36 females and excluded in 44 females. This result indicates that
      the DNA linkage analysis can be used for carrier detection or exclusion in the
      majority of Thai hemophilia A families. It should also be useful for prenatal
      diagnosis in families at risk of hemophilia A, which is part of the prevention
      and control of this disease.

PMID- 12403228
TI  - Effect of red blood cell glucose-6-phosphate dehydrogenase deficiency on patients
      with dengue hemorrhagic fever.
AB  - Eighty nine males aged 1-13 years diagnosed with dengue haemorrhagic fever (DHF)
      and admitted to the Department of Pediatrics Siriraj Hospital from March 1998 to
      April 2000 were included in this study. 17 cases (19.1%) had red blood cell
      glucose-6-phosphate dehydrogenase (G-6-PD) deficiency and 72 cases (80.9%) had
      normal G-6-PD enzyme activities. Most of the patients were classified as DHF
      grade II in severity. 3 of 17 G-6-PD deficient cases had serious complications
      and all of them had acute intravascular hemolysis requiring blood transfusions.
      One of these also had hematemesis, one had azothemia and the other one had renal
      failure and severe liver failure with hepatic encephalopathy. In the cases
      without obvious hemolytic or hepatic complications, G-6-PD deficient cases had
      mildly but significantly higher total birirubin and indirect bilirubin, as well
      as a lower hematocrit than those who had normal G-6-PD. Reticulocyte count was
      low during the acute phase, however, during recovery, the levels were
      significantly increased in both groups. In the non G-6-PD deficient group, G-6-PD
      enzyme levels were significantly decreased during the acute phase compared to the
      normal controls but rose significantly to normal levels during the recovery
      phase. There were no statistically significant differences in other laboratory
      data. All patients recovered fully from DHF. The prevalence of G-6-PD deficiency
      in male patients who had DHF in this study was 19.1 per cent which was higher
      than the prevalence in a previous study of 12 per cent in Bangkok. This may imply
      that G-6-PD deficient males suffer more from DHF compared to normal G-6-PD
      subjects.

PMID- 12403229
TI  - Secondary hemophagocytic lymphohistiocytosis in children: an analysis of etiology
      and outcome.
AB  - Fifty-two pediatric patients were diagnosed with secondary hemophagocytic
      lymphohistiocytosis (HLH) at the Department of Pediatrics, Siriraj Hospital
      between 1989 and 1998. Of these, 15 were infection-associated (IAHS), 25 were
      malignancy-associated (MAHS) and 12 were idiopathic HLH. Causative organisms for
      IAHS were Salmonella (3), Staphylococcus (2), enterobactor (2), dengue virus (3),
      malaria (2) and one each of Ebstein Barr virus (EBV), Serratia marcesens and
      Penicillium maneffei. Unlike those reported in adults and in the Western
      literature, 47 of 52 children in the present series were immunocompetent hosts.
      In addition, the proportion of MAHS was higher than expected (48.1%). Twenty-two
      of 25 MAHS presented with hemophagocytic syndrome and were subsequently found to
      have malignant diseases. Sixty per cent of MAHS (15 cases) were associated with
      non-Hodgkin's lymphoma (NHL), mainly T-cell. Other malignancies included acute
      leukemias (7) MDS (1), Langerhans cell histiocytosis (1) and histiocytic sarcoma
      (1). Treatment approaches were specific therapy for individuals with known
      causes. Supportive treatment with blood components transfusions, steroid,
      intravenous immunoglobulins (IVIG), and chemotherapeutic agents, mainly
      vinblastine and etoposides, were used in indicated cases. Of the 52 cases, 15
      (28.8%) had a fatal outcome during the acute phase, and other 4 died of their
      subsequent malignant diseases. There was a statistically significant association
      between poorer prognosis and patients' age < 3 years (p= 0.004) or MAHS
      (p=0.005). CONCLUSION: Secondary HLH is not uncommon in Thai children who are
      immunocompetent. Malignancies, particulary NHL, are highly suspicious especially
      for cases not responsive to conventional therapy. Poor prognostic factors are age
      less than 3 years and MAHS.

PMID- 12403230
TI  - Malignancies in HIV-infected children at Siriraj Hospital.
AB  - BACKGROUND: Some malignancies such as Kaposi's sarcoma, non-Hodgkin's lymphoma
      (NHL) are one of the acquired immunodeficiency syndrome (AIDS)-defining
      illnesses. With the improving survival of patients with AIDS due to better
      prevention and treatment of infectious complications, there may well be an
      increase in AIDS-related malignancies. OBJECTIVE: To study malignancies in human
      immunodeficiency virus (HIV)-infected children in view of demographic data, HIV
      disease status, characters of malignancies, and treatment outcome. METHOD:
      Retrospective study was performed in HIV-infected children with malignancies at
      Siriraj Hospital from January 1995 to October 2001. RESULTS: During the 6 year
      and 10 month period, there were 7 HIV-infected children (2 boys, 5 girls) with
      malignancies. Mean age at diagnosis of malignancies was 3 years 7 months (2 years
      6 months-5 years). Hepatomegaly and lymphadenopathy were the most common
      presenting symptoms. All patients had NHL stage III or IV. Burkitt's lymphoma was
      the predominant type. Six patients were treated with appropriate chemotherapy and
      one patient also received antiretroviral therapy. Only one patient with large
      cell lymphoma stage IV who received both antiretroviral and chemotherapy has
      survived to date. Five patients died during chemotherapy treatment and one
      patient died before receiving chemotherapy. Causes of death of these patients
      were infections. One of them with Burkitt's lymphoma stage III also had central
      nervous system (CNS) relapse at the time of death. Mean survival time after
      diagnosis with malignancies was 11 months (15 days-3 years 1 month). CONCLUSION:
      NHL is the most common malignancy in HIV-infected children at Siriraj Hospital.
      Age at presentation of NHL in these children is younger than their non-HIV
      counterpart. Outcome of treatment is poor. Adjustment protocol for treatment of
      malignancy in HIV-infected children combined with antiretroviral therapy for
      controlling HIV infection should be studied further.

PMID- 12403231
TI  - Thrombotic complications during induction chemotherapy of acute childhood
      lymphoblastic leukemia.
AB  - The incidence of thrombosis during induction chemotherapy of acute childhood
      lymphoblastic leukemia (ALL) patients was 6 found to be in 105 (5.7%). There were
      4 cerebral infarctions, 1 superior vena cava (SVC) obstruction and 1 deep vein
      thrombosis. Among these, 2 of them died. A prospective study was further
      conducted of the change in coagulation and anticoagulation factors during 6 weeks
      of induction chemotherapy. It was found that the activated partial thromboplastin
      time (aPTT) was within normal range in all cases throughout 6 weeks, while
      prothrombin time (PT) and thrombin time (TT) were slightly prolonged, especially
      during the first 3 weeks of this phase. The natural anticoagulant panels which
      included protein C (PC), protein S (PS) and antithrombin III (AT III) and also
      fibrinogen level, were lower during the first 3 weeks and reached its nadir
      during the second and third week. The lower level of natural anticoagulants might
      be an important predisposing factor for the occurrence of thrombosis in these
      patients.

PMID- 12403232
TI  - Allele related mutation specific-polymerase chain reaction for rapid diagnosis of
      Hb New York (beta 113 (G15) Val-->Glu, beta(CD113 GTG-->GAG)).
AB  - Hemoglobin New York (beta 113 (G15) Val-->Glu), a beta-globin variant, was first
      reported in a Chinese family living in New York. Subsequently, this abnormal
      hemoglobin was reported in many Chinese descendants from several groups and it
      was also known as Hb Kaohsiung. The subtle change in alpha1beta1 contact region
      apart from the heme group connecting area by Val-->Glu substitution has minor
      changes in both the electrophoretic mobility and stability making this hemoglobin
      variant difficult to distinguish from Hb A using routine hemoglobin analysis. The
      authors described a case of heterozygosity of Hb New York diagnosed by a
      molecular technique and revealed a mutation in beta(CD113 GTG-->GAG). A novel
      Allele Related Mutation Specific-Polymerase Chain Reaction (ARMS-PCR) for rapid
      diagnosis of this mutation has been proposed.

PMID- 12403233
TI  - Outcome of pediatric oncologic patients in the respiratory intensive care unit:
      Siriraj Hospital.
AB  - OBJECTIVES: To review the characteristics and outcome of patients with childhood
      malignancy requiring respiratory intensive care treatment and to assess the
      outcome of these patients. DESIGN: Retrospective review of 22 oncological
      patients admitted to the pediatric respiratory intensive care unit between
      January 1, 1996 and December 31, 1998 (total 3 years.) RESULTS: The overall
      survival at discharge from the intensive care unit was 10 out of 22 (45%). The
      mean age of the patients was 4 years 5 months old (range 1 month to 14 years).
      Male:Female ratio was 1.2:1.21 patients had fever. All patients with a systemic
      or respiratory infective illness were neutropenic with a positive hemoculture in
      17 out of 21 (81%) and 10 out of 20 (50%), respectively. The most common
      organisms detected were coagulase negative Staphylococcal aureus and Escherichia
      Coli. Sputum culture in the respiratory failure group was positive in 3 out of 7
      patients, all of them grew Pseudomonas aeruginosa. Antibiotics were given to all
      oncological patients presenting with fever. The most common antibiotics
      administered were Ceftazidime, Amikacin and Imipenem. Fourteen patients needed
      mechanical ventilation. 11 of these 14 patients had respiratory tract infections,
      1 patient had acute respiratory distress syndrome and the remainder were in a
      coma as a result of brain metastasis. Only 2 of them survived. The mean duration
      of stay in the respiratory intensive care unit was 10.9 days. CONCLUSIONS: There
      has been an improvement in the survival of oncology patients admitted to the
      intensive care unit especially for those with either a systemic or respiratory
      infection. Early and full intensive care treatment should be provided for these
      patients in order to improve the outcome.

PMID- 12403234
TI  - Pediatric allergy and immunology at Siriraj Hospital.
AB  - Like other parts of the world, prevalence of childhood allergic diseases in
      Thailand, particularly of asthma and allergic rhinitis, has risen sharply over
      the past decade. Epidemiologic studies in this country indicated that allergic
      sensitization (mainly to house dust mites, cockroaches and cat dander) is the
      major important risk factor for the development of asthma. House dust mites are
      the most important source of allergens causing sensitization among allergic Thai
      children. A nationwide survey indicated that house dust mites are ubiquitous in
      Thai homes. Despite the authors' earlier finding that mite allergen levels in
      Thailand (mean group-I allergen level of 11 mcg/g dust), exceeded the recommended
      international threshold level to induce asthmatic symptoms (10 mcg/g dust), mite
      allergen levels in homes within the Bangkok area are in the modest range (5 mcg/g
      dust). With mattresses in Thailand being commonly laid on hardwood surfaces, the
      authors demonstrated that only top-covering of these mattresses with locally
      produced mite-impermeable membrane, mite allergens could be substantially
      reduced. Other active research in pediatric allergy in Thailand include complete
      surveys of outdoor aeroallergens and research in pharmacologic managements of
      allergic diseases. The Thailand Registry of Primary Immune Deficiency has
      recently been established to collect data on patients with these disorders and to
      improve means for diagnosis and treatment for these unfortunate patients.
      Finally, with a recent approval for board certification in pediatric allergy and
      immunology, it is expected that the number of specialists in this field will
      increase to a sufficient level to provide adequate care for allergic/immunologic
      children in Thailand.

PMID- 12403235
TI  - Exercise-induced asthma among Thai asthmatic children.
AB  - BACKGROUND: Approximately seventy per cent of asthmatic children from temperate
      climates, with normal lung function, have exercise-induced asthma (EIA). There is
      certain evidence to suggest that EIA may be less frequently encountered among
      children who live in tropical climates. Prevalence of EIA in Asian asthmatic
      children has never been thoroughly studied. OBJECTIVE: To study the prevalence of
      EIA among Thai asthmatic children. METHOD: A prospective study was performed to
      determine the prevalence of EIA in 44 Thai asthmatic children who were able to
      perform the spirometric maneuver. Subjects were randomly selected asthmatic
      children from the Pediatric Allergy Clinic, Department of Pediatrics, Siriraj
      Hospital. They were subjected to exercise testing on a steady state, motor-driven
      treadmill for 6 minutes (mean speed +/- SD = 3.7 +/- 0.4 km/h, mean level of
      inclination + SD = 15.0 +/- 5.2 degrees). The testing was conducted in a
      temperature-controlled (mean temperature +/- SD = 24.4 +/- 0.8 degrees C) and
      humidity-controlled environment (mean relative humidity +/- SD = 41.7 +/- 2.1%).
      Lung function tests were performed before exercise, immediately after and at 3,
      5, 10, 15, 20 and 30 minutes after exercise. Results of the lung function test
      were calculated as per cent falls of forced expiratory volume in 1 sec (FEV1),
      peak expiratory flow rate (PEFR), and forced expiratory flow at 25 per cent-75
      per cent (FEF50) from baselines. EIAs were diagnosed when drops of FEV1, PEFR and
      FEF50 were greater than 20 per cent, 25 per cent and 25 per cent from baseline
      values, respectively. RESULTS: Of the 44 patients studied (31 boys and 13 girls;
      mean age 11.9 years), 34 per cent had mild asthma. Fifty-nine per cent had
      moderate asthma and 7 per cent had severe asthma. Eleven patients (25%) had EIA
      diagnosed by significant falls of FEV1's (26 +/- 12.6%), whereas, 13 patients
      (30%) and 20 patients (45%) had EIA defined by significant drops of PEFR's and
      FEF50's, respectively. A total of 23 patients (52%) had EIA by one or more
      diagnostic criteria. Peak times for EIA as diagnosed by FEV1, PEFR and FEF50
      occurred at 3, 10, and 10 minutes respectively, after exercise. Most EIA episodes
      observed were of mild degree. CONCLUSIONS: The prevalence of EIA in Thai children
      is much lower than figures reported in studies from Western countries. By using a
      significant fall of FEV1's as the diagnostic criteria, only 25 per cent were
      diagnosed as having EIA. By PEFR and FEF50 criteria, percentages of EIA increased
      to 30 per cent and 45 per cent respectively. Screening for EIA, therefore, may
      not be an appropriate diagnostic tool for the diagnosis of childhood asthma in
      tropical climates.

PMID- 12403236
TI  - Vacuum cleaning does not sufficiently reduce mite allergens from beddings.
AB  - INTRODUCTION: Conflicting results exist with regard to the efficacy of vacuum
      cleaners on the removal of mite allergens from bedding. OBJECTIVES: The authors
      prospectively compared a short term efficacy of two types of regular vacuum
      cleaners (National-N and Hoover-H) with a specialized cleaner (Vorwerk-V) in the
      removal of mite allergens from mattresses. MATERIAL AND METHOD: Thirty-five
      dormitory beds with high mite allergen concentrations at the baseline period
      (month 0) were selected. They were matched into three groups according to group I
      mite allergen concentrations (N 11 beds, H 12 beds, V 12 beds). Vacuuming was
      performed on months 1 and 4 by the assigned vacuum cleaner in each group.
      Immediately after, mattresses were vacuumed by a reference cleaner (another
      National vacuum cleaner) at both months. Vacuuming was performed over the entire
      bed for 2 minutes/square meter. Group I mite allergens (sums of Der p 1 and Der f
      1) were measured; concentrations and total mite allergens removed by the tested
      cleaners as well as by the reference cleaner, at various time points, were
      compared. RESULTS: Ability to remove mite allergens by vacuum cleaners depends on
      weight of dust removed and also on mite concentrations in the dust samples.
      Despite the fact that H and V appeared to remove higher mite allergens than N,
      such differences were not statistically significant (p > 0.05), both at month 1,
      and 4. Surprisingly, mattress mite concentrations removed by both high capacity
      cleaner groups (V & H) increased at month 4, whereas, it remained unchanged in
      the third group (N). This increase led to a concomitant increase in total
      allergen removed by V and H. Nevertheless, remaining total allergens in the
      mattresses in V and H, as judged from the amount of allergens obtained by the
      reference cleaner, increased at month 1 and 4 compared to baseline values (p <
      0.05), whereas, no change was observed in N. CONCLUSION: Although high capacity
      vacuum cleaners removed a large amount of mite allergens from mattresses, they
      did not sufficiently reduce mattress mite allergen burden as determined by the
      reference cleaner during this short term study.

PMID- 12403238
TI  - Linear growth of prepubertal asthmatic Thai children receiving long-term inhaled
      corticosteroids.
AB  - BACKGROUND: Long-term inhaled corticosteroids are recommended in persistent
      asthma in children. The aim of this study was to determine the growth rate of
      asthmatic Thai children who received long-term inhaled corticosteroids. METHOD:
      This controlled clinical trial was carried out on 145 prepubertal asthmatic Thai
      children, 81 in the study group (the group who received long-term inhaled
      corticosteroids) and 64 in the control group. RESULTS: The mean age of the
      patients when the study began was 5.9 years in the study group and 4.7 years in
      the control group. The average dose of inhaled corticosteroids used was 300
      microg/day. The average duration overtime of inhaled corticosteroid usage was 2
      years (9 months-5 years). The study showed that inhaled corticosteroids (300
      microg/day for 9-60 months) have no significant effects on growth rate. From
      linear regression analysis, the factors that influenced the growth rate of
      asthmatic patients were the severity of the asthma and the age of the patients
      when nasal corticosteroids were started. Insulin-like Growth Factor 1 (IGF 1) and
      Insulin-like Growth Factor Binding Protein 3 (IGFBP 3), were measured in 7
      patients in the study group and 5 in the control group. All were normal, the
      height standard deviation score (Ht.SDS) was below average. CONCLUSIONS: The
      average dose of inhaled corticosteroids (300 microg/day for 9 months) has no
      significant effects on the growth rate of prepubertal asthmatic Thai children.

PMID- 12403237
TI  - Evaluation of consistency between local and imported seafood allergen extracts.
AB  - BACKGROUND: Seafood is a common cause of food allergy in Thai adults and
      children. Skin prick test is a safe and convenient way to screen seafood allergy.
      To date, the Allergy Unit, Department of Pediatrics, Faculty of Medicine Siriraj
      Hospital, Mahidol University uses imported extracts for seafood skin prick test.
      The extracts are expensive and may not be the same species as seafood in
      Thailand. OBJECTIVES: To compare the consistency between local seafood allergen
      extracts prepared by the Department of Pharmacology, Faculty of Medicine Siriraj
      Hospital, Mahidol University and imported seafood allergen extracts. METHODS: The
      study was a prospective comparative trial performed in children who attended the
      Pediatric Allergy Clinic, Siriraj Hospital from March 1999 to October 2000. The
      skin prick test was performed with the local seafood allergen extracts prepared
      by a pharmacist from the Department of Pharmacology and the imported seafood
      allergen extracts included shrimp, fish and crab. Histamine and normal saline
      were used as positive and negative control respectively. The positive result was
      recorded when wheal reaction was > or = 3 mm larger than negative control.
      RESULTS: Eighty eight patients (57 boys and 31 girls) were included in this
      study. The average age was 7.7 years (1-15 years). Half of the patients had a
      history of seafood allergy. The study showed probable consistency between
      imported and local skin prick test of shrimp and crab extracts (kappa = 5-7) but
      no consistency between imported and local skin prick test of fish extracts (kappa
      < 5). The study also showed no consistency between history of seafood and skin
      prick test result. CONCLUSION: Local seafood allergen extracts from the
      Department of Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol
      University are safe but they cannot replace the imported seafood allergen
      extracts. Further investigations about sensitivity and specificity of both kinds
      of allergen extracts are necessary.

PMID- 12403239
TI  - Serum sickness and hepatitis B vaccine including review of the literature.
AB  - HB vaccine is one of the most widely administered vaccines in the world. Its
      efficacy approaches 95 per cent. The majority of adverse reactions are generally
      mild, although there have been individual case reports of serious reactions since
      the vaccine has become commercially available. Here, a patient with a serum
      sickness-like reaction after her second HB immunization is reported. Review of
      the literature for reports of serious adverse reactions to the vaccine was also
      carried out.

PMID- 12403240
TI  - Pediatric cardiology at Siriraj Hospital: past, present and future.
AB  - The incidence of congenital heart disease (CHD) at Siriraj Hospital for the year
      2000 was 4.36 patients per 1,000 livebirths. Types of congenital heart diseases
      seen by the authors were VSD (18.3%), PDA (16.3%), ASD (16.3%), combined simple
      left to right shunt lesion (24.7%), tetralogy of Fallot (TF; 6%), D-TGA 2 per
      cent, other complex congenital heart 8 per cent. Overall 3 out of 1,000
      livebirths will have congenital heart disease that will require immediate
      intervention including cardiac catheterization and surgical intervention. At the
      same period of time an average of 750 new cases of children were referred
      annually for evaluation and treatment of cardiac related problems. Reports of
      acquired heart disease such as acute rheumatic fever, myocarditis, Kawasaki's
      disease and arrhythmia problem were summarized here. The Division of Pediatric
      Cardiology performs both diagnostic and intervention cardiac catheterization in
      almost 310 children and adults with congenital heart disease yearly. Out of this
      35 per cent had interventional procedures including balloon valvuloplasty,
      balloon angioplasty and stenting, device closure of atrial septal defect and
      patent ductus arteriosus and radiofrequecy ablation of abnormal conduction
      pathway. Major progress has been made in pediatric cardiac imaging over the past
      two decades. At Her Majesty's Cardiac Center, cardiac MRI has been used to
      evaluate patients with congenital heart disease since June 2000. There were 146
      congenital heart disease patients who had cardiac MRI performed for the
      evaluation of anatomy, function, left to right shunt, and flow regurgitation
      quantification. CONCLUSION: Pediatric Cardiology practice has evolved over the
      past decade and expanded from clinical practice to therapeutic intervention
      procedures.

PMID- 12403241
TI  - Transcatheter coil occlusion of small patent ductus arteriosus: experience at
      Siriraj Hospital.
AB  - Transcatheter coil occlusion of small-to-moderate-size patent ductus arteriosus
      (PDA, < 3.5 mm) is well established as a procedure of first choice in many
      institutions. Its much lower cost compared with surgical ligation or other
      devices makes it an attractive option, especially in Thailand. PATIENTS AND
      METHOD: Between September 1995 and June 2000, all patients diagnosed with PDA
      with audible murmur and echo-Doppler confirmation of diameter less than 3.5 mm
      were scheduled for transcatheter coil occlusion at the Department of Pediatrics,
      Faculty of Medicine Siriraj Hospital. The hemodynamic studies were obtained both
      pre and post occlusion. The immediate and late outcome, including complication
      were assessed. RESULTS: A total of 77 cases, 78 procedures of transcatheter PDA
      coil occlusion were performed. Seventy cases (90.9%), comprised of 19 males
      (27.1%) and 51 females (72.9%) were successfully deployed with coils. The
      remainder were unsuccessfully deployed and later referred to surgery. The median
      age of the successful group was 6 years and 6 months and median weight was 16.5
      kg. Twenty cases (28.6%) had other associated intra and extracardiac anomalies.
      All patients were asymptomatic, except one case having bronchopulmonary dysplasia
      (BPD) from prolonged ventilation. Single-coil occlusions were performed in 74.3
      per cent and double-coil occlusions in 25.7 per cent. Conventional 0.038-inch
      Gianturco coils were deployed in 86.5 per cent. The mean procedure time was 78.1
      +/- 35.1 minutes. The mean fluoroscopic time was 20.2 +/- 15.6 minutes. The total
      complete occlusion rate was 87.7 per cent. Tiny residual flow of PDA was
      demonstrated by follow-up echocardiogram in 12.3 per cent. Seven per cent of the
      patients were lost to follow-up. There was no significant difference in PDA size
      and hemodynamics between the groups of patients with complete occlusion and
      having residual shunt. Minor complications occurred in 12.9 per cent, including
      mild left pulmonary artery stenosis (10%), coil embolization to distal pulmonary
      artery (8.6%), slippage of catheter with coil (2.9%) and decreased dorsalis pedis
      pulse (1.4%). One late death was found in a BPD patient from pneumonia 2 months
      after the procedure. CONCLUSION: Transcatheter coil occlusion of PDA is as
      effective, feasible, safe and less costly than surgical ligation. With
      improvement in technique and device selection and appropriate case selection,
      there should be an increase rate of complete occlusion and a decrease in
      complications.

PMID- 12403242
TI  - Prenatal diagnosis of cardiovascular diseases.
AB  - Fetal echocardiography is a safe means to obtain reliable anatomical and
      hemodynamic data of the fetal heart. The procedure is essential for prenatal
      diagnosis of cardiovascular abnormalities. In addition, fetal echocardiography is
      useful to follow-up the progression, monitoring during treatment and making a
      plan of treatment especially in life-threatening cardiac conditions. The
      objective of this study was to find the distribution of indications for fetal
      echocardiography, fetal cardiac anomalies detected, outcome of the fetuses and to
      assess the accuracy of the procedure. A retrospective study was done at Siriraj
      Hospital, Mahidol University, Bangkok, Thailand. Pregnant women whose fetuses had
      prenatal echocardiographic data and gave birth from January 1999 to December 2001
      were included. The total number of pregnant women was 54 cases. The indications
      for fetal echocardiography were suspicion of fetal cardiovascular disease by the
      obstetrician 42.6 per cent, family history of congenital heart diseases 14.8 per
      cent, multiple organ system anomalies 14.8 per cent, chromosomal anomalies 11.1
      per cent, hydrops fetalis 9.3 per cent, maternal systemic diseases 5.6 per cent
      and previous pregnancy with a dead fetus in utero 1.9 per cent. The gestational
      age at the time of the first fetal echocardiography ranged from 17 to 39 weeks
      (median 28 weeks). The number of fetal echocardiography done in each case ranged
      from 1 to 10 (median 1.4). Prenatal diagnosis of the abnormal cardiovascular
      system in fetuses was found in 19 cases (35.2%). There were abnormal cardiac
      anatomies in 42 per cent, cardiac tumors or abnormal masses in 37 per cent and
      rhythm disturbances in 21 per cent. When compared with postnatal echocardiography
      and/or autopsy finding, fetal echocardiography had a sensitivity of 100 per cent,
      specificity of 96.3 per cent and accuracy of 97.8 per cent. CONCLUSION: Fetal
      echocardiography has good accuracy in the diagnosis of cardiovascular diseases.
      Obstetrician's suspicion is important in the prenatal diagnosis of heart disease
      that would have affected the short and long-term outcome of the fetus.

PMID- 12403243
TI  - Myocardial diseases in Thai children.
AB  - Myocardial diseases are among the important causes of mortality and morbidity in
      children. This drew the authors attention to the study of myocardial diseases in
      children to find out the outcome, factors affecting the outcome, and management
      strategies. The authors retrospectively studied children who had been diagnosed
      with primary myocardial diseases at six university hospitals in Thailand from
      January 1996 to December 2000. The total number of cases was 209 which accounted
      for 1.2 per cent of cardiovascular diseases in children. The patients' ages
      ranged from 0.1-15 years. These myocardial diseases included dilated
      cardiomyopathy (DCM) 45 per cent, acute myocarditis 27.3 per cent, hypertrophic
      cardiomyopathy (HCM) 18.2 per cent, hypertrophic obstructive cardiomyopathy
      (HOCM) 8.1 per cent and restrictive cardiomyopathy (RCM) 1.4 per cent. Fifty-six
      per cent of the patients were female. Congestive heart failure was the most
      common presenting symptom (75%). Median ejection fraction (EF) of acute
      myocarditis was 42 per cent (15-79%) which was significantly higher than DCM
      (33.5%, 10-57%). Serum cardiac troponin T (cTnT) was also significantly higher in
      acute myocarditis than in DCM (0.08 ng/ml, 0.01-0.16 vs 0.01 ng/ml, 0.01-0.10).
      Within the follow-up period of 1 year (0.1-5.5 years), the mortality rates were
      18.8 per cent, 17.0 per cent, 5.4 per cent and 33.3 per cent in DCM, acute
      myocarditis, HCM and RCM respectively. Factors associated with the mortality rate
      in acute myocarditis were admission to ICU and low left ventricular EF at
      presentation while IVIG administration and cTnT level did not. CONCLUSION:
      Primary myocardial diseases are uncommon. Most of the patients had compromised
      cardiovascular reserve. Admission to ICU and low EF were factors that affected
      the mortality in acute myocarditis while intravenous immunoglobulin
      administration did not. Mortality rate in the subacute follow-up period was high
      in all groups.

PMID- 12403244
TI  - Cardiac magnetic resonance imaging of atrial septal defect for transcatheter
      closure.
AB  - BACKGROUND: The location, size of the defect and age of the patient are the major
      determining factors for transcatheter closure of an atrial septal defect (ASD).
      The precise shape and anatomy surrounding the defect cannot always be understood
      by the traditional transesophageal (TEE) echocardiographic technique. OBJECTIVES:
      The authors compared the measurement of ASD size and atrial septal rim using
      cardiac Magnetic Resonance Imaging (MRI) and TEE to the balloon sizing technique
      and device size. PATIENTS AND METHOD: Patients having an ASD which met
      established criteria were selected for evaluation with cardiac MRI and TEE for a
      closure procedure. Comparison of the ASD imaging and sizing between the different
      methods was made. RESULTS: There were 22 patients who had complete transcatheter
      closure. The mean age and standard deviation of the patients was 33.2+/-15.1 (8
      67) years old. The mean weight of the patients was 51.6+/-13.1 (20-99) kg. The
      average cardiac MRI measurement of the ASD was 24.9+/-6.4 mm compared to the TEE
      measurement of 20.8+/-5.5 mm. The transcatheter balloon measurement of the ASD
      was 25.2+/-6.9 (11-36) mm and the device closure size was 24.8+/-6.6 (11-36) mm.
      The correlation coefficient of cardiac MRI to device closure size was r = 0.784
      (p < 0.001) when compared to TEE measurement to device closure size; r = 0.761 (p
      = 0.001). CONCLUSION: The authors demonstrated the capability of the cardiac MRI
      in assessment of the ASD morphology and anatomy for transcatheter closure of the
      ASD with an Amplatzer Septal Occluder. Cardiac MRI can provide information about
      the type, location, size of the defect and direct visualization of the atrial
      septum anatomy. This detailed information enabled us to provide a safer, more
      effective application of the ASD occluder.

PMID- 12403245
TI  - Early detection of cardiac involvement in beta-thalassemia children.
AB  - BACKGROUND: Beta-thalassemia major and beta-thalassemia/HbE are the important
      causes of chronic hemolytic anemia in Thailand. The objectives of the study were
      to determine variables associated with cardiac involvement in asymptomatic beta
      thalassemia patients. PATIENTS AND METHOD: The authors studied beta-thalassemia
      major and beta-thalassemia/HbE patients who came to the clinic between July 1st
      1999 and July 31st 2000. There were 211 asymptomatic patients included in study.
      Their ages ranged from 2.6 to 18.2 years. Previous clinical history including
      blood transfusion and iron chelation were recorded. All patients received a
      thorough physical examination, chest X-ray, electrocardiogram and echocardiogram.
      Patients who had abnormal systolic or diastolic function detected by
      echocardiogram were identified as having cardiac involvement. RESULTS: Cardiac
      involvement was found in 26 patients (12.3%). There was no difference in physical
      examination between patients who had and did not have cardiac involvement.
      Abnormal chest X-Ray defined as cardiothoracic (CT) ratio>0.55 and
      electrocardiogram (ECG) findings of left or right ventricular hypertrophy were
      associated with cardiac involvement. Other associated findings were older age and
      lower average pretransfusion hematocrit (23 +/- 6.6%). CONCLUSIONS: In
      asymptomatic beta-thalassemia children, chest X-ray and ECG should be used for
      screening patients for the detection of cardiac involvement.

PMID- 12403246
TI  - The outbreak of Serratia marcescens bacteremia in a pediatric ward, Siriraj
      Hospital 1997.
AB  - Between October 20 and November 11, 1997, Serratia marcescens bacteremia was
      identified in 8 patients in a pediatric ward at Siriraj Hospital. The organism
      was isolated from 17 blood and 3 bone marrow specimens. The only common
      associated factor in these patients was that they all had received an intravenous
      fluid infusion. In the attempt to investigate the source of S. marcescens
      implicated in the outbreak, 108 specimens of intravenous fluid, 3 intravenous
      fluid bottle caps, 4 specimens from intravenous fluid tubing sets, 21 specimens
      of antiseptics used on the ward, 28 specimens of rectal swabs from patients on
      the ward, 1 sample of blood culture media prepared by the hospital for routine
      use, and 62 environmental specimens including hand swabs of the medical
      personnel, refrigerator, air conditioning, milk samples, room air, water sink,
      wooden splint and adhesive tape used to immobilize the intravenous access. Of 227
      specimens sent for culture, S. marcescens was isolated from only one specimen
      collected from the in-use intravenous fluid given to a patient with Serratia
      bacteremia. S. marcescens was not found in any other surveillance culture. The 8
      patients were placed under quarantine in the same room with an exclusive nursing
      team. With the investigation and intervention including monitoring for meticulous
      hand washing of the ward staff, the outbreak was stopped within 7 days. Although
      the investigation failed to discover the environmental reservoir of S. marcescens
      in this outbreak, the data suggested that intravenous fluid was probably the
      route of transmission and the medical personnel played an important role in
      spreading the infection.

PMID- 12403247
TI  - Mycobacterium avium complex in HIV-infected Thai children.
AB  - Of the 169 human immunodeficiency virus (HIV)-infected children being cared for
      at Siriraj Hospital from January 1998 to September 2000, 10 had Mycobacterium
      avium complex (MAC) infection; seven had disseminated disease and three had MAC
      pneumonia. Nine children were in the advanced stage of HIV disease at the time of
      diagnosis with the median CD4 count of 7 cells/mm3 and 127 cells/mm3 and the
      median age of 65 months and 63 months in disseminated MAC and MAC pneumonia
      respectively. None of these children had received prior chemoprophylaxis. Common
      clinical findings included prolonged fever, weight loss, lymphadenopathy,
      hepatosplenomegaly, diarrhea, anemia and leukopenia. The outcome of MAC infection
      was poor, with a mortality rate of 60 per cent. In in vitro susceptibility
      testing, clarithromycin was the least resistant drug. With the incidence rate of
      2.15 per 100 person-years, the high rate of antimicrobial resistance, and the
      poor outcome, primary chemoprophylaxis for MAC infection in conjunction with
      effective antiretroviral therapy should be considered for Thai children in the
      advanced stage of HIV infection.

PMID- 12403248
TI  - High CD4+ T-cells percentage and/or low viral load are predictors of 1-5 years
      survival in HIV-1 vertically infected Thai children.
AB  - OBJECTIVE: Enrolling pediatric HIV children into the clinical trial of when to
      initiate antiretroviral therapy is a crucial ethical issue. CD4+ T-cells
      percentage and/or viral load were able to identify potential cases of survival
      through 5 years of age. METHOD: HIV infected cohort from 1992 to 1994 from
      Children's and Siriraj Hospitals were followed from 1 through 5 years of age. The
      outcome was survival or death. The predictors were CD4 percentage and viral load
      (without age and clinical status adjustment). RESULT: 16 of 35 (45.71%) of the
      cohort survived through 5 years of age. The probability of survival increased to
      almost 100 per cent either with CD4+ T-cells percentage of over 22 or viral load
      of less than 500,000.

PMID- 12403249
TI  - Combination vaccines.
AB  - Recently multiple individual vaccines were put together into one syringe. This is
      ideal to simplify the administration of vaccines and reduce emotional distress
      from multiple injections. However, combination of many vaccines may interfere
      with the properties of each individual antigen and complicate the schedule. From
      earlier studies, most of the combinations of diphtheria-tetanus-pertussis (whole
      cell) vaccine (DTPw), Haemophilus influenzae type b vaccine (Hib), hepatitis B
      vaccine (HBV), and inactivated polio vaccine (IPV) were safe and adequately
      immunogenic. On the other hand, there was a notable reduction in anti-PRP when
      Hib was combined with acellular pertussis vaccine (DTPa). Combination of
      hepatitis A vaccine and HBV was safe and effective. Those coming soon in the
      pipeline are DTPa-Hib-HBV, MMR-varicella, pneumococcal-meningococcal. With the
      increase in demand, health-care providers need to be acquainted to these
      combination vaccines. The bottom line is to make sure that the children get
      vaccination appropriately.

PMID- 12403250
TI  - Inherited metabolic disorders in Thailand.
AB  - The study of inborn errors of metabolism (IEM) in Thailand is in its infancy. The
      majority are clinically diagnosed since there are only a handful of clinicians
      and scientists with expertise in inherited metabolic disorders, shortage of well
      equipped laboratory facilities and lack of governmental financial support.
      Genetic metabolic disorders are usually not considered a priority due to
      prevalence of infectious diseases and congenital infections. From a retrospective
      study at the Medical Genetics Unit, Department of Pediatrics, Siriraj Hospital;
      estimated pediatrics patients with suspected IEM were approximately 2-3 per cent
      of the total pediatric admissions of over 5,000 annually. After more than 10
      years of research and accumulated clinical experiences, a genetic metabolic
      center is being established in collaboration with expert laboratories both in
      Bangkok (Chulabhorn Research Institute) and abroad (Japan and the United States).
      Numerous inherited metabolic disorders were identified--carbohydrate, amino
      acids, organic acids, mitochondrial fatty acid oxidation, peroxisomal,
      mucopolysaccharidoses etc. This report includes the establishment of genetic
      metabolic center in Thailand, research and pilot studies in newborn screening in
      Thailand and a multicenter study from 5 institutions (Children's National Center,
      King Chulalongkorn Memorial Hospital, Pramongkutklao Hospital, Ramathibodi and
      Siriraj Hospitals). Inherited metabolic disorders reported are fructose-1,6
      bisphosphatase deficiency, phenylketonuria, homocystinuria, nonketotic
      hyperglycinemia, urea cycle defect (arginino succinate lyase deficiency,
      argininosuccinate synthetase deficiency), Menkes disease, propionic acidemia and
      mucopolysaccharidoses (Hurler, Hurler-Scheie).

PMID- 12403251
TI  - Mitochondrial fatty acid oxidation disorders in Thai infants: a report of 3
      cases.
AB  - Three infants with documented mitochondrial fatty acid oxidation disorders are
      described in this report. Case 1. Carnitine/acylcarnitine translocase deficiency.
      (CACT) (OMIM 212138) A two-day-old male developed sudden cardiac arrest 48 hours
      postpartum, with a previous history of early death (day 2) in siblings with a
      history of parental consanguinity; somnolence, inactivity, refusal to suck within
      24 h, hepatomegaly, persistent hypoglycemia, hypocalcemia, hyperkalemia and
      severe metabolic acidosis prior to cardiac arrest. Dried blood spots by tandem
      mass spectrometry demonstrated 10 x elevation of palmitoylcarnitine, moderate
      elevation of oleylcarnitine, steroylcarnitine and myristoylcarnitine. Case 2.
      Medium chain acyl CoA dehydrogenase (MCAD) deficiency. (OMIM 212139) A six-week
      old male infant, developed sudden cardiac arrest after contacting a viral
      illness, resuscitated successfully in the first episode, only to succumb during
      the second episode, 2 weeks apart. Plasma acylcarnitine via tandem mass
      spectrometry was reported normal; however, urine organic acids via gas liquid
      chromatography and mass spectrometry demonstrated characteristic metabolites
      consistent with MCADD. Case 3. Carnitine deficiency, systemic primary. (CDSP)
      (OMIM 212140) A one-year-old girl with progressive dyspnea since birth and a
      history of parental consanguinity. Severe dilated cardiomyopathy with episodes of
      cardiac decompensations, hepatomegaly, anemia, generalized hypotonia, but no
      hypoglycemia were demonstrated prior to cardiac arrest. Extremely low carnitine
      level noted in dried blood spots via tandem mass spectrometry.

PMID- 12403252
TI  - Urea cycle disorders in Thai infants: a report of 5 cases.
AB  - Urea Cycle Disorders (UCD) is an inborn error of urea synthesis in which ammonium
      and other nitrogenous precursors of urea accumulate leading to episodic coma and
      a high mortality rate. Therapy with peritoneal dialysis, essential amino acids or
      their nitrogen-free analogues has increased survival. The authors report 5 cases
      of urea cycle disorders, all of whom developed and were rescued from
      hyperammonemic coma. However, the eventual outcome was quite variable.
      Argininosuccinate lyase deficiency (ALD) Case 1. A 2 month old male infant, a
      product of a consanguineous marriage (Suphanburi province); developed poor
      feeding on day 7, lethargy, convulsion, hepatomegaly and respiratory alkalosis
      leading to respiratory failure and coma. Hyperammonemia, elevation of glutamic
      acid and argininosuccinic acid and its anhydrides confirmed the diagnosis of ALD.
      He is now 9 years old and severely retarded. Case 2. A male infant with history
      of lethargy, poor feeding on day 3, treated as sepsis and required respiratory
      support for 6 days; subsequently readmitted at age 2 weeks with vomitting,
      lethargy, seizure activity and hyperammonemia, and was treated by a local
      pediatrician in Songkhla province. There was a history of parental consanguinity
      and he was referred to Siriraj Hospital on day 64 with severe essential amino
      acid deficiency and acrodermatitis enteropathica with markedly elevated plasma
      citrulline level. In spite of aggressive treatment; the patient developed sepsis
      and he expired on day 78. Ornithine transcarbamylase deficiency (OTC) Case 3. An
      eleven-month-old male infant, the product of a non-consanguineous marriage,
      developed neonatal onset of hyperammonemia on day 5 after poor feeding, lethargy,
      hypothermia, seizure, apnea and coma. He was rescued from neonatal hyperammonemic
      coma on day 9 after aggressive treatment, but expired at eleven months of age
      after overwhelming sepsis. Case 4. A male infant, sibling of case 3 was referred
      to Siriraj Hospital on day 8 with hyperammonemia and coma. In spite of intensive
      genetic counseling given after the birth of their first child with OTC, the
      couple chose to have another baby without informing any physician. The baby
      developed vomiting and lethargy on day 2; subsequently hyperammonemia was noted.
      In spite of aggressive treatment given; hepatic dysfunction, renal failure and
      disseminated intravascular coagulation defects occurred on day 15. He expired on
      day 18 after parental permission for discontinuation of all treatment.
      Argininosuccinate synthetase deficiency (ASS) or Citrullinemia. Case 5. A seven
      week old female infant, the product of a consanguineous marriage and of Pakistani
      ethnic origin; developed intermittent vomiting from day 6. Initial diagnoses
      included ruminations, sepsis and pyloric stenosis for which she was operated on
      (day 30); however, vomiting continued; subsequently seizures, hyperammonemic coma
      developed and she was rescued from hyperammonemic coma within 30 hours.
      Significant elevations of citrulline and L-glutamine were demonstrated. She was
      discharged in excellent condition to her home in Dubai, the United Arab Emirates.

PMID- 12403253
TI  - Comparison of the nutrient content of fresh fruit juices vs commercial fruit
      juices.
AB  - OBJECTIVE: To compare the types and quantities of carbohydrate, electrolytes, pH
      and osmolarity of fresh fruit juices and commercial fruit juices. MATERIAL AND
      METHOD: Forty kinds of fresh fruits available in Thai markets were analyzed for
      types and quantities of carbohydrate, electrolyte, pH and osmolarity and compared
      with previously obtained data for commercial fruit juices. RESULTS: Most fresh
      fruit juices did not contain sucrose, whereas, commercial fruit juices mostly
      have sucrose in the range of 3-112 g/L. Although both fruit juices were acidic
      (pH varied from 3.6-6.7 and 3.2-5.8 of fresh juice and commercial juice), fresh
      fruit juices had a more neutral pH than commercial fruit juices. Apple, guava,
      orange, pear, and pineapple juices from commercial fruit juices had a high
      osmolarity compared with fresh fruit juices. All types of fresh fruit juices
      contained less sodium than commercial ones, whereas, most fresh fruit juices
      contained more potassium, phosphorus, and magnesium than commercial fluids.
      CONCLUSION: The nutrient content of fresh fruit juices and commercial fruit
      juices from the same kinds of fruits are not the same, possibly due to the
      manufacturing process. Therefore, physicians should know the composition of fruit
      juices in order to advise patients properly.

PMID- 12403254
TI  - Prevention of antibiotic-associated diarrhea in infants by probiotics.
AB  - Probiotics administration has been claimed to prevent antibiotic-associated
      diarrhea. The investigators thus conducted a double blind, placebo controlled
      study of providing probiotics to infants and children with severe bacterial
      infections and receiving broad spechum antibiotics. The results of the study
      showed that the group receiving probiotics had fewer diarrheal episodes (37.5%)
      than the control group (80%), although the numbers were too small for statistical
      analysis. In conclusion, probiotics administration to patients receiving high
      doses of broad spectrum antibiotics may prevent the occurrence of antibiotic
      associated diarrhea. A further study with a larger number is required.

PMID- 12403255
TI  - Cyclic vomiting syndrome in Thai children.
AB  - Cyclic vomiting syndrome (CVS) is a severe childhood vomiting disorder of unknown
      etiology and pathogenesis. Clinical manifestations and prophylactic therapy of
      vomiting have been described in the literature. The data were limited in Asian
      children. The aim of this study was to study the clinical manifestation, to
      evaluate using antimigraine prophylactic drugs and response in Thai children with
      CVS. The medical records of children with a diagnosis of CVS in the Department of
      Pediatrics, Siriraj Hospital, Mahidol University from 1994 to 2001 were
      retrospectively reviewed. Demographic data, clinical manifestations,
      investigations, treatment and outcome were collected and analyzed. Twenty five
      patients were enrolled in this study including 13 females and 12 males. Their
      ages ranged from 2.3 years to 14 years (7.8 +/- 3.4 years). The age of onset was
      5.2 +/- 3.2 years. They had 14.7 +/- 6.5 episodes per year with a duration of
      each attack 4 +/- 1.8 days. There were 8 mild, 10 moderate and 7 severe cases.
      There were only 6 patients (24%) who had headache and 50 per cent of these had a
      family history of migraine. Eight patients received pizotifen which had 3 good, 1
      fair, and 4 poor responses. Of this group, in 3 patients pizotifen was changed to
      amitriptyline. Eighteen patients received amitriptyline and the result of
      treatments were 11 good, 4 fair, and 3 poor. The other 2 patients were on
      propranolol with one good and one poor responses. The efficacy of amitriptyline
      and pizotifen were compared (83.3% vs 50%) which revealed no statistical
      significance (p = 0.14). There was no side effect from any of the medication in
      this study. In conclusion, the present report showed similar data of clinical
      features, prophylactic treatment and outcome as previous reports, except for
      fewer migraine headaches in patients and their families. Amitriptyline and
      pizotifen were effective in prophylactic therapy of vomiting episodes.

PMID- 12403256
TI  - Management of severe atopic dermatitis with thymostimulin.
AB  - Two patients with severe atopic dermatitis unresponsive to conventional therapy
      were enrolled in a clinical trial on thymostimulin (TP-1). TP-1 was administered
      by subcutaneous injection 1 mg/kg/day for 14 days and then 1 mg/kg/day on
      alternate days for 2 months. Clinical and immunological status were evaluated at
      baseline and at regular intervals during the treatment. Clinical severity scores
      included eight skin conditions (erythema, edema, vesicle, crust, excoriation,
      scaling, lichenification, pigmentation), two subjective components (itchiness and
      loss of sleep), and extent of area affected. There was a statistically
      significant improvement in the overall assessment of the severity scores. There
      were no definite changes in immunological parameters including CD4, CD8 T-cell
      subpopulations and serum IgE, but eosinophil count showed a mark decrease in one
      case. No serious side effects were observed.

PMID- 12403257
TI  - Percutaneous renal biopsy in children.
AB  - The authors studied the percutaneous renal biopsies performed in the Department
      of Pediatrics, Siriraj Hospital from January 2000 to March 2001 in order to
      evaluate the safety and benefit of the procedure. Eighty-five patients (90
      episodes) were included in the study, aged 7.8+/-3.7 year (range 16 months to 16
      years), with a male to female ratio of 1.2:1. Nephrotic syndrome (42.3%) and
      systemic lupus erythematosus (23.5%) were the two most common indications for
      biopsy. The kidney was localized by ultrasound prior to the procedure in nearly
      all cases (97.7%). Premedication with Ketamine was adequate in most patients
      (91.1%). A modified 13 G Vim-Silverman needle was used to obtain 1-4 biopsy
      cores. The mean number of glomeruli obtained was 44.0+/-29.9, with failure to
      obtain renal tissue in 6 episodes (6.6%). Percutaneous biopsy was performed twice
      in one patient without success and the patient eventually underwent an open
      biopsy. The most common complication was hematuria (74.4%), of these, gross
      hematuria was found in 23.3 per cent. Blood transfusion was needed in 2 patients,
      one of them also needed embolization to control bleeding. Transient hypotension
      occurred in 1 patient. Transient hypertension occurred in 6 episodes (6.6%).
      Muscle twitching occurred in 2 episodes and was treated with diazepam
      intravenously. Hypertension and muscle twitching only occurred in those who
      received ketamine. The Clinical Benefit Score was 2 (information yielding a
      definite diagnosis and/or prognosis, alternatively allowing a change in, or
      support of, therapy) in 89.4 per cent. It was concluded that the present practice
      of renal biopsy is safe, with high clinical benefit score. It remains to be
      studied whether an ultrasound guidance biopsy with a newer biopsy device will
      lower the incidence of complications even further.

PMID- 12403258
TI  - The management of environmental lead exposure in the pediatric population:
      lessons from Clitty Creek, Thailand.
AB  - During the month of September-October 1997, a depression storm caused massive
      flooding in the area of western Kanchanaburi province, Thailand, causing lead
      contaminated water from a nearby lead refinery plant to spill into the
      surrounding areas of Clitty Creek; exposing the village downstream to large
      amounts of lead. The Ministry of Public Health, together with the Ministry of
      Science, the Ministry of Industry, and officials from the Kanchanaburi Office of
      Public Health, began measures for environmental deleading and assessment of
      exposure and health risks of the population. METHOD: This was a retrospective
      cohort study of the effects that environmental remediation and chelation therapy
      had on the blood lead levels of children residing in Lower Clitty Creek Village
      during the period between 1997-2001. Sixty-eight children were followed yearly
      for their blood lead levels and hematocrit, beginning in early 1998.
      Simultaneously, programs for environmental remediation had begun. The blood lead
      levels (BLLs) of children were followed over a 3-year period. The BLLs during the
      2 year period of environmental remediation alone were compared. Subsequently,
      when chelation therapy was instituted, levels pre and post chelation therapy, as
      well as the efficacy of the two different chelation methods were compared using
      standard 2-tailed t-test. RESULTS: The initial average BLL was 27.75 +/- 5.4
      mg/dl (1998). After environmental remediation began, BLL at one year (1999) was
      30.64 +/- 4.49 mg/dl (p = 0.072), and at two years (2000) was 30.30 +/- 5.1 mg/dl
      (p = 0.537). There were 18 children with BLLs > 25 who were elected to receive
      chelation therapy with CaNa2EDTA (11) and DMSA (7). Post chelation average BLL
      was 18.73 +/- 7.50 mg/dl. The difference between pre and post chelation BLL was
      statistically significant (p < 0.001: paired t-test). The differences in average
      BLLs between pre and post chelation for the EDTA group was 15.37 mg/dl and for
      the DMSA group it was 8.91 mg/dl. Children treated with EDTA appeared, on
      average, to have 6.47 mg/dl (p < 0.05: 95% CI (0.821-12.12)) lower BLL than those
      treated with DMSA. CONCLUSION: The incident at Clitty Creek serves to illustrate
      the importance of environmental remediation as a priority to treating lead
      poisoning in children. Only when effective environmental deleading has taken
      place can medical intervention in the form of chelation therapy begin.

PMID- 12403259
TI  - Childhood onset myasthenia gravis.
AB  - The authors share experiences in taking care of 27 cases of childhood onset
      myasthenia gravis (MGS). In all cases, the diagnosis was confirmed by a
      combination of clinical examination and Neostigmine test. The majority (92%) had
      localized ocular myasthenia with median onset of symptoms at 33 months of age.
      About 24 per cent of them progressed to generalized MGS. A few (8%) presented
      with respiratory failure that required ventilatory support with onset of symptoms
      at about 22 months. Thymectomy was performed in 10 cases. Complete and partial
      remissions were achieved in about 70 per cent and 26 per cent of cases
      respectively with the combination of an immunosuppressant (azathioprine) and a
      Cholinesterase inhibitor (pyridostigmine). None experienced a myasthenic crisis
      with proper management and good follow-up using the above combinations.

PMID- 12403260
TI  - Vigabatrin therapy in infantile spasms.
AB  - RATIONALE: To determine the clinical outcome and side effects of vigabatrin (VGB)
      in the treatment of infantile spasms (IS) and its long-term outcome. METHOD: All
      children with IS treated with vigabatrin were studied. Clinical data regarding
      age of onset, duration of IS before therapy started, recurrence of IS, types of
      seizures that relapse, clinical outcome and side effects were monitored. RESULTS:
      36 children (17 girls, 19 boys) with IS participated in the study. The mean age
      of onset of IS was 115.55 +/- 67.3 days old (range, 15 to 300 days). Six were
      cryptogenic IS and 30 were symptomatic IS. The etiologies of symptomatic IS in
      this study were tuberous sclerosis, hypoxic ischemic encephalopathy
      (HIE)/periventricular leukomalacia, porencephaly, partial agenesis of corpus
      callosum, hemimegalencephaly, cortical dysplasia, and microcephaly. 66.67 per
      cent (24 of 36) of patients responded to VGB within a mean 2.95 +/- 2.25 days
      (range, 1 to 7 days). In those who responded to VGB, 3 patients developed
      recurrent IS within 69.3 +/- 46.7 days (range, 30 to 121 days). Five patients
      developed epilepsy with different types of seizure during long-term follow-up.
      The mean duration of subsequent epilepsy after cessation of IS was 16.4 months
      (range, 5 months to 3 years 10 months). The mean duration of follow-up was 2.74
      years (range, 1.09 years to 5.76 years). 10 patients were successfully weaned off
      VGB after a mean IS free period of 22.5 +/- 5.5 months (range, 12 to 27 months).
      Transient drowsiness was seen in 4 patients. Three patients had transient
      abnormal sleep patterns and irritability. Visual field abnormalities were not
      found but difficult to assess fully in this study. CONCLUSION: VGB therapy has a
      high response rate for the control of IS and is well tolerated in most children.
      All patients who responded to VGB and were spasm free for more than one year were
      successfully weaned off VGB therapy. Because serious side effects such as visual
      field abnormalities are difficult to monitor, the authors propose that VGB could
      be withdrawn or switched to another AED after a spasm-free period of more than
      one year.

PMID- 12403261
TI  - Risperidone in the treatment of autistic Thai children under 4 years of age.
AB  - The authors report five cases of very young children with autistic disorder, aged
      2.1-3.7 years, treated with risperidone, as part of the comprehensive
      intervention. Treatment with risperidone 0.25-0.5 mg per day was associated with
      clinically meaningful decreases in problem behaviors including hyperactivity,
      irritability, and aggressiveness. There were also improvements in social
      relatedness and cooperation with developmental treatment. All of the children
      tolerated the medication well and experienced no untoward effects. The efficacy
      of risperidone in the treatment of very young children with autistic disorder
      reported here is consistent with findings in the limited number of cases
      previously reported in the literature. Controlled studies are needed to confirm
      the efficacy and safety of risperidone in the treatment of these children.

PMID- 12403262
TI  - The use of a meditation programme for institutionalized juvenile delinquents.
AB  - The study applied intensive-seven consecutive days meditation programme in 101
      late adolescent male delinquents in Upekkha Detention Centre. All of the boys
      completed the programme and answered the questionnaires. All of them felt that
      the meditation practice had been beneficial. 70 per cent of the subjects
      described feelings of contentment and calm, 53 per cent requested the programme
      to be repeated, 52 per cent of the subjects declared a clearer undestanding in
      the doctrine of Karma, 44 per cent referred to improved concentration and
      awareness, 36 per cent felt less impulsive, 22 per cent had flashbacks of their
      criminal behavior and their victims. In conclusion, the boys in Upekkha Detention
      Centre had the willing to join and complete the intensive meditation programme.
      Their self assessment reports showed a positive attitude to the programme. It is
      possible to develop a meditation programme as an adjunctive therapy for
      institutionalized juvenile delinquents.

PMID- 12403263
TI  - Rapid enzyme immunoassays for the detection of carbaryl and methoprene in grains.
AB  - In order for grain handlers and traders to reliably estimate residues of grain
      protectants in the field, antibody-based rapid tests were developed for carbaryl
      (1-naphthyl methylcarbamate) and methoprene [isopropyl (E,E)-(RS)-11-methoxy
      3,7,11-trimethyldodeca-2,4-dienoate]. To complement the rapid analysis, a simple
      and rapid extraction technique was developed. In these tests, a pesticide
      containing methanol extract of the grain sample and an enzyme-labeled component
      are added to precoated strips. After a brief incubation, the strips are washed
      and a substrate/chromogen for the enzyme is added. The color developed is stopped
      by acidification and the results are read either by eye or in a portable field
      photometer. The overall test time is under 20 minutes. For carbaryl, the test had
      a limit of detection of 4.5 ppb (1.1 ppm in grain), while the methoprene test had
      a limit of detection of 4 ppb (1 ppm in grain) based on the lower datum point,
      which is 15% inhibition, in the standard curves. Both assays can be used as a
      screening test for carbaryl and methoprene in animal feed grains.

PMID- 12403264
TI  - Spectrophotometric determination of the fungicide captan.
AB  - A spectrophotometric method for the determination of the fungicide captan has
      been developed based on its reaction with thiosemicarbazide. The absorbance was
      measured at 315 nm. The effects of the proportion of water, thiosemicarbazide
      concentration, pH and temperature on this reaction was studied to select the best
      chemical conditions. The calibration graph was obtained between 1.2 and 30 ppm
      and the detection limit is 0.5 ppm. The RSD (n = 10) was 1.34%. Possible
      interference of various pesticides was examined. The method was applied to the
      determination of captan in agrochemical formulations. Results agree well with the
      labelled values and also with results that were obtained by a polarographic
      method.

PMID- 12403265
TI  - Effect of different inorganic and organic compounds on sorption of 2,4-D and
      atrazine.
AB  - In this study, the effects of size of adsorbent, temperature, pH of solution,
      ionic strength, presence of inorganic substances such as calcium ion, magnesium
      ions, chloride ions, fertilizers and presence of organic substances such as
      dissolved organic matter, surfactant, other herbicides on sorption of 2,4-D and
      atrazine onto rubber granules were investigated. The removal efficiency was more
      for fine adsorbent particles. Temperature played an important role in sorption
      process. Temperature effect was endothermic for 2,4-D and exothermic for
      atrazine, respectively. The removals were maximum at pH 4 for 2,4-D and at pH 6
      for atrazine. The presence of other herbicide (butachlor) reduced sorption
      capacity of rubber granules by approximately 10% for both 2,4-D and atrazine. All
      other factors had insignificant effect on sorption capacity. The mathematical
      expressions were developed for predicting the overall percentage removal of 2,4-D
      and atrazine on the basis of major four controlling factors viz. adsorbent size,
      temperature, pH and presence of other herbicide.

PMID- 12403266
TI  - Effect of soil sterilization by mercuric chloride on herbicide sorption by soil.
AB  - Microbial inhibitors such as mercuric chloride are frequently used to sterilize
      soil or soil-water slurries in experimental studies on the fate of xenobiotics in
      the environment. This study examined the influence of mercuric chloride additions
      to soil-water slurries on the sorptive behaviour of a phenoxy herbicide (2,4-D)
      in soil. The results demonstrated that mercuric chloride strongly decreased the
      capacity of the soil to retain herbicides, and that the interference of mercuric
      chloride with herbicide sorption increased with increasing soil organic carbon
      contents. Because of the competitive sorption between mercuric chloride and the
      phenoxy herbicide, we conclude that mercuric chloride may not be a good soil
      sterilization procedure for use in xenobiotic fate studies.

PMID- 12403267
TI  - Adsorption-desorption, persistence, and leaching behavior of dithiopyr in an
      alluvial soil of India.
AB  - Investigations were undertaken to determine the adsorption-desorption,
      persistence and leaching of dithiopyr (S,S'-dimethyl 2-difluoromethyl-4-isobutyl
      6-trifluoromethyl pyridine-3,5-dicarbothioate) in an alluvial soil under
      laboratory condition. The adsorption-desorption studies were carried out using
      batch equilibration technique. The mass balance studies showed that 83-97% of the
      pesticide was recovered during adsorption-desorption studies. The results
      revealed strong adsorption of dithiopyr in alluvial soil with Kd values ranging
      from 3.97-5.78 and Freundlich capacity factor (KF) value of 2.41. The strong
      adsorption was evident from the hysteresis effect observed during desorption. The
      hysteresis coefficients ranged from 0.17-0.40. The persistence studies were
      carried out at two concentrations (1.0 and 10.0 microg g(-1) level) under field
      capacity moisture and submerged condition by incubating the treated soil at 25 +/
      1 degrees C. In general, dithiopyr persisted beyond 90 days with half-life
      varying from 11.5-12.9 days under different conditions. The rate of application
      and moisture regimes had no overall effect on the persistence. The leaching
      studies carried out in packed column under saturated flow condition revealed that
      dithiopyr was highly immobile in alluvial soil. Only small amounts (0.02-0.04%)
      were recovered from leachate whereas major portion (99.9%) remained in top layer
      of the soil column. The data suggest that strong adsorption of dithiopyr will
      cause a greater persistence problem in the soil. However, the chances of its
      movement to ground water will be negligible due to its immobility.

PMID- 12403268
TI  - Retention of nitrogen and phosphorous from liquid swine and poultry manures using
      highly characterized peats.
AB  - This paper reports on research designed to test the hypothesis that differences
      in peat composition will cause differences in amounts of N and P retained during
      contact with liquid swine manure (LSM) and liquid poultry manure (LPM). Peat
      types representing a wide range of properties were tested in order to establish
      which chemical and physical properties might be most indicative of their
      capacities to retain N and P from LSM and LPM. Eight-percent slurries (peat/LSM
      and peat/LPM) were measured for total nitrogen (TKN) and total phosphorous (TP)
      after 6, 24 and 96 hours. Tests were done to determine the TKN and TP contents of
      these peats, the LSM, and the LPM, both before and after they were mixed
      together. The N and P retention results revealed that most peats worked
      reasonably well at retaining N and P from either LSM or LPM. However, some peats
      were more effective than others. These peats also decreased the N and P levels in
      the liquid portion of the LSM. Peats with higher N retention capacities tended to
      have lower ash contents, but higher macroporosities and total cellulose contents.
      Peats with higher P retention capacities tended to have lower bulk densities, ash
      contents, total guaiacyl lignins contents, fulvic acids contents, but higher
      microporosities, macroporosities, H contents, and total cellulose contents. Peats
      with higher N and P retention capacities also had humic acid contents between 5
      7%. The results of this study suggest that if these peats are used to reduce
      odors and N and P contamination, possible byproducts could be the production of
      odorless fertilizers.

PMID- 12403269
TI  - Precipitation of swine and cattle manure phosphorous using limestone dust.
AB  - The effectiveness of SPS and PULPRO, fine limestone dusts, in precipitating swine
      and dairy manure phosphorous (P) was determined in the laboratory. Both manures
      were sieved before being treated with limestone, to reproduce the treatment of
      mechanically separated manure and to observe the precipitation effect of
      limestone without that of the large manure solid particles. P precipitation was
      optimized by varying precipitation conditions (propeller blade speeds, mixing
      time and limestone levels) and limestone particle size. P precipitation was
      optimized using a propeller blade mixing speed of 0.3 m s(-1) for at least 5
      minutes, using 3% limestone (dry limestone mass over wet manure mass). In terms
      of particle size, PULPRO 20 (limestone with a particle size of 0.02 mm) produced
      the most P precipitation and the smallest volume and mass of sludge, as compared
      to PULPRO 10, PULPRO 3 and SPS (limestone with a particle size of 0.01, 0.003 and
      0.3 to 0.003 mm, respectively). For both 9.5% TS (total solids) dairy and 8.8% TS
      swine manure, mechanical separation followed by limestone precipitation
      concentrated 90% of manure TS and TP in a sludge volume representing 45% of the
      initial raw manure mass.

PMID- 12403270
TI  - Assessing copper thresholds for phytotoxicity and potential dietary toxicity in
      selected vegetable crops.
AB  - Copper pollution in soils is widespread, and its accumulation in crop products
      could pose a risk on human health. In this paper, bioavailability of added copper
      (Cu) and critical Cu concentrations in a vegetable garden soil was evaluated for
      Chinese cabbage (Brassica chinensis L.), pakchoi (Brassica chinensis L.), and
      celery (Apiumg graveolens L. var. dulce DC) based on human dietary toxicity. The
      availability of added Cu in the soil decreased with incubation time, and had
      minimal change after 10-12 weeks. After incubated for 12 weeks, about 60% of
      added Cu was not extractable by DTPA. The same crops were also grown in sand
      culture to determine their responses to solution Cu. Shoot growth was
      significantly inhibited at Cu concentrations above 10 mg kg(-1) in the solution
      or above 150 mg kg(-1) (DTPA-Cu) in the soil. The sensitivity of the crops to Cu
      toxicity differed among the three vegetable crops. Copper concentration in shoots
      and edible parts varied with Cu supply levels and type of the vegetables.
      Negative correlations (r=-0.90-0.99**) were noted between Cu concentration in
      shoots and fresh matter yields, but Cu concentrations in the edible parts were
      positively correlated with available and total Cu in the soil (r=0.91-0.99**).
      The critical tissue Cu concentrations at 10% shoot DM reduction were 19.4, 5.5,
      30.9 mg kg(-1) for Chinese cabbage, pakchoi, and celery, respectively. Based on
      the threshold of human dietary toxicity for Cu (10 mg kg(-1)), the critical
      concentrations of total and available Cu in the soil were 430 and 269 mg kg(-1)
      for pakchoi, 608 and 313 mg kg(-1) for celery, and 835 and 339 mg kg(-1) for
      Chinese cabbage, respectively.

PMID- 12403271
TI  - Bioavailability of calcium from sweetpotato and soy flour supplemented diets in
      hamsters.
AB  - The bioavailability of calcium from two varieties of sweetpotatoes and
      supplementation of sweetpotatoes with soy flour was investigated in hamsters
      using plasma calcium concentration and femur calcium content as indicators. Five
      different diets were fed to five groups of animals for 28 days. There was no
      significant difference in plasma calcium concentrations of hamsters in all the
      diet groups. However, the femur calcium content of hamsters with transgenic
      sweetpotato flour (TSPF) and parent nontransgenic (from which transgenic was
      produced) sweetpotato flour (NTSPF) diets was significantly higher than that of
      the transgenic sweetotato flour supplemented with soy flour (TSPF + SF) and
      parent nontransgenic sweetpotato flour supplemented with soy flour (NTSPF + SF)
      diets. The relative bioavailability of calcium from the control (100%), TSPF+SF
      (30%), NTSPF+SF (23%), TSPF (57%) and NTSPF (46%) indicated that sweetpotatoes
      could be the better source of calcium, however, supplementation with soy flour
      might reduce the bioavailability of calcium.

PMID- 12403272
TI  - Mevastatin, an inhibitor of HMG-CoA reductase, induces apoptosis, differentiation
      and Rap1 expression in HL-60 cells.
AB  - It has been reported that inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A
      (HMG-CoA) reductase suppress cell proliferation and induce apoptosis. One
      inhibitor which induces apoptosis is mevastatin. However, the molecular mechanism
      of apoptosis induction is not well understood so the effects of mevastatin on
      various functions of HL-60 cells were investigated. We confirmed that mevastatin
      activated caspase-3 by release of cytochrome c (Cyt. c) from mitochondria through
      a membrane permeability transition mechanism and also induced typical
      fragmentation and ladder formation of DNA in HL-60 cells. These effects were
      inhibited by mevalonate, a metabolic intermediate of cholesterol biosynthesis.
      Mevalonate and geranylgeraniol (GGOH) inhibited DNA fragmentation whereas
      farnesol (FOH) did not. Mevastatin also induced cell differentiation to monocytic
      cells via a mevalonate inhibitable mechanism. Furthermore, mevastatin decreased
      the amount of an isoprenylated membrane bound Rap1 small GTPase concomitant with
      an increase in cytosolic Rap1 which occurred before apoptosis and
      differentiation. On the contrary, both mevastatin and geranylgeranylacetone
      (GGA), which competes with geranylgeranyl pyrophosphate, induced membrane
      depolarization of isolated mitochondria without swelling and Cyt. c release.
      These results suggest that mevastatin-induced apoptosis of HL-60 cells might be
      caused indirectly by activation of the caspase cascade through the modulation of
      mitochondrial functions and that some relationship between a certain small GTPase
      molecule, such as Rap1, and mevastatin-induced apoptosis may exist.

PMID- 12403273
TI  - Hemoglobin/O2 systems: mechanistic discrimination based on Ackers' model.
AB  - The kinetics of the reaction of hemoglobin with molecular oxygen, in which rapid
      mixing is followed by a fast temperature jump, is numerically simulated. We use
      the system of Ackers (1998) which distinguishes four forms of bi-ligated
      hemoglobin. The data suggest the involvement of isomerization steps for bi- and
      triliganded hemoglobin. Our first model assumes a linear addition of oxygen with
      one path to and from each bi-ligated species. Our second model allows cross-overs
      between paths, as described by Ackers (1998). Our third model exploits the
      observation (Perrella et al., 1990) that two of the four bi-ligated forms are at
      low concentration. We explore whether these models can be distinguished
      experimentally. We find a narrow oxygen concentration range where Models 1 and 2
      can be distinguished by rapid flow experiments. The distinction between Models 2
      and 3 is larger in stopped flow experiments within a limited oxygen concentration
      range but not easily detectable in chemical relaxation following rapid flow. The
      detection of two special states of free hemoglobin may be possible at low oxygen
      concentration. However, the step reaction free enthalpy (or Gibbs free energy)
      values make it more likely that two special states are present in fully ligated
      hemoglobin.

PMID- 12403274
TI  - Fluorescence quenching of dimeric and monomeric forms of yeast hexokinase (PII):
      effect of substrate binding steady-state and time-resolved fluorescence studies.
AB  - Fluorescence quenching studies on the PII isoenzyme of yeast hexokinase have been
      performed using charged as well as polar uncharged quenchers. In both 'open'
      (i.e. in the absence of glucose) and 'closed' (i.e. in the presence of glucose)
      forms of the enzyme, bimolecular quenching rate constant (kq) for acrylamide is
      significantly larger than that of KI, indicating that all the tryptophans are not
      fully exposed to the solvent. Overall accessibility of tryptophans towards KI was
      greater in the presence of glucose than in the absence of glucose. At high ionic
      strength, the value of bimolecular quenching rate constant (kq) for KI did not
      change suggesting that the average environment of the accessible tryptophan
      residue(s) is almost neutral. Quenching by KI is dynamic in nature. Accessibility
      of tryptophans towards acrylamide at concentration > or = 0.2 M was more in the
      'open' form of the enzyme than that observed in the 'closed' form whereas at
      concentration < or = 0.2 M no significant difference in the extent of quenching
      was observed. It is reasonable to conclude that glucose induced conformational
      change leads some tryptophan residue(s) to be more exposed and at the same time
      some tryptophan residue(s) in the hydrophobic region become more buried. Dimeric
      and monomeric forms of the enzyme behave similarly towards the quenching by
      acrylamide. In the unfolded state, the accessibility of tryptophans was
      considerably higher for both the quenchers. Temperature dependent study and the
      fluorescence lifetime data indicate that the mechanism of quenching by acrylamide
      is primarily dynamic in nature.

PMID- 12403275
TI  - AFM study of microstructures on the cornea of the compound eye and ocelli of the
      hornet Vespa orientalis (Insecta, Hymenoptera).
AB  - The present study describes a novel structure occurring on the cornea in the
      compound eye and the ocellus of the Oriental hornet. This description is based on
      observations carried out via scanning electron microscopy (SEM) and primarily via
      atomic force microscopy (AFM). We report herein that the vespan cornea is densely
      covered with cupola-shaped protrusions, which in the compound eye have bases
      about 0.2 microm in diameter and an average height of 0.03 microm while upon the
      ocelli their diameter is rather variable, with some measuring 0.2-0.3 microm, and
      a length of submicrons to microns. Interspersed among the brief, cupola-shaped
      structures there are winding, longer structures whose height appears uniform at
      around 0.03 microm. It appears that the structures are formed from the
      epicuticular layer of the cornea and we conjecture that in both the compound eye
      and in the ocelli they serve to enhance the absorption of light, as well as to
      reduce light reflection.

PMID- 12403276
TI  - Synthesis and analysis of a methyl ether derivative of tetracycline which
      inhibits growth of Escherichia coli.
AB  - Tetracycline is a widely used broad spectrum antibiotic. A derivative of
      tetracycline was synthesized by methylation (-CH3) of the phenolic hydroxyl
      group, with the use of diazomethane (CH2N2). A methyl ether group is then formed
      from the reaction with diazomethane, which replaces the hydroxyl group. The newly
      formed derivative has reduced hydrogen bonding capability relative to the
      unmodified tetracycline. An infrared spectra shows the appearance of the ether
      group on the derivative and the Log P calculations indicate that the derivative
      has increased lipophilic tendency. The Lipophilic Substituent Constant calculated
      for the tetracycline derivative is 0.46, indicating a lipophilic substituent. The
      tetracycline derivative was soluble in aqueous solvents and was stable for more
      than five weeks when stored at < or = 0 degrees C. The derivative was placed in
      tissue culture utilizing Luria-Bertani (LB) media, at a concentration of 12.0
      microg/mL and inhibited the growth of E. coli (XL-1 blue) from 15% to 20% within
      the initial sixteen hours.

PMID- 12403277
TI  - Extracorporeal excretion of the mercury from organs by sulfur-bridged complex.
AB  - The extracorporeal excretion of mercury from the organs by [Mo3S4(Hnta)3]2-
      (referred to as the NTA complex) solution was investigated using mice exposed to
      metallic mercury vapor. A decrease in mercury levels was seen in the organs of
      mice that were administered NTA complex solution when compared to organs in mice
      receiving L-cysteine or water. Moreover, in mice that were administered NTA
      complex solution, mercury level in the kidneys decreased at the third and fifth
      days following mercury exposure. These results suggest that NTA complex solution
      has the effect of releasing mercury in the living-body as seen when mercury
      levels are compared with those in the organs of mice that were administered L
      cysteine or water.

PMID- 12403278
TI  - Human parvovirus B19 infection in pregnancy: should screening be offered to the
      low-risk population?
AB  - Human parvovirus B19 infection during pregnancy can result in fetal hydrops and
      death. Intra-uterine transfusion in hydropic fetuses affected by the virus can
      reduce perinatal deaths. Up to 33% of women with this infection are asymptomatic.
      In view of the significant adverse outcomes, the role of routine screening among
      low-risk pregnant women is discussed.

PMID- 12403280
TI  - The changes of circulating lymphocyte sub-populations in women with preterm
      labour: a case-controlled study.
AB  - OBJECTIVE: The aim of this study was to determine the changes in circulating T
      cell subpopulations, B cells and natural killer cells in patients with imminent
      preterm labour. METHODS: Thirty-five pregnant patients with imminent preterm
      labour and 35 women with uncomplicated pregnancies were included in the study.
      The gestational ages of the patients ranged from 28 to 36 weeks in both groups.
      The specific lymphocyte antigens were detected using direct staining with
      monoclonal antibodies, and analysed by flow cytometry. RESULTS: We observed no
      significant difference in the mean percentage of T cell subpopulations, natural
      killer cells and active T cells in the group of patients with preterm labor when
      compared to controls. The mean percentage of T CD3+ lymphocytes was significantly
      lower and that of B CD19+ cells higher in the study group when compared to
      controls. CONCLUSION: The alterations in maternal circulating lymphocyte
      subpopulations could be associated with the mechanisms mediating preterm labour.

PMID- 12403279
TI  - Who remains undelivered more than seven days after a single course of prenatal
      corticosteroids and gives birth at less than 34 weeks?
AB  - Minimal information exists as to how women who give birth more than seven days
      after initial corticosteroid treatment, who may benefit from repeat prenatal
      corticosteroids, differ from women who give birth within seven days, at < 34
      weeks gestation. OBJECTIVES: To examine the differences, if any, between women
      who received a single course of prenatal corticosteroids and remained undelivered
      more than seven days later and women who gave birth within seven days of
      treatment, at < 34 weeks gestation. DESIGN: Retrospective cohort. SETTING:
      Women's and Children's Hospital, Adelaide. POPULATION: Women who gave birth at <
      34 weeks gestation from 1 January 1994 to 31 December 1996. METHODS: Data were
      extracted from medical records and retrieved from the hospital's database. MAIN
      POTENTIAL PREDICTORS COLLECTED: Prenatal corticosteroid exposure, reason for risk
      of preterm birth, maternal demographics and previous and current obstetric
      history. RESULTS: Of the 506 women, 122 (24%) remained undelivered more than
      seven days following prenatal corticosteroid therapy Initial corticosteroid
      treatment was given on average 1.6 weeks earlier to women who remained
      undelivered more than seven days after treatment. Women who were given prenatal
      corticosteroids for placenta praevia (RR 6.03, 95% CI 2.67-13.61, p < 0.01) or
      cervical incompetence (RR 3.40, 95% CI 1.06-10.95, p = 0.04) were more likely to
      give birth more than seven days after corticosteroid treatment. CONCLUSIONS:
      Women who give birth very preterm, who remain undelivered more than seven days
      after prenatal corticosteroids, differ in the reasons for and timing of their
      first course from women who give birth within seven days.

PMID- 12403281
TI  - Early-onset group B streptococcus prevention protocols in New Zealand public
      hospitals.
AB  - OBJECTIVE: Determine group B streptococcus (GBS) prevention protocols. METHODS:
      Questionnaire survey of 19 hospitals accounting for 73% of New Zealand births.
      RESULTS: Prevention policies were reported by 16 (84%) hospitals (bacteriological
      screening n = 4, risk-factor determination n = 8, both strategies n = 4). Only
      five out of 12 (42%) centres using risk-assessment administered antibiotics for
      all high-risk criteria. Inadequate specimen collection and culture methods meant
      no hospital maximised culture-based strategies. Nevertheless, hospitals with
      prevention policies had lower early-onset GBS disease rates (0.46 versus 1.44 per
      1,000 births; OR 0.32; (95% CI 0.12, 0.98)). CONCLUSIONS: Prevention strategies
      can be further improved by hospitals fully implementing nationally agreed
      guidelines.

PMID- 12403282
TI  - Postpartum urinary retention: assessment of contributing factors and long-term
      clinical impact.
AB  - OBJECTIVES: To investigate the relationships between various obstetric parameters
      and postpartum urinary retention, and to offer some clinical guidance for
      resolution of urinary retention problems. DESIGN: An observational prospective
      study. SETTING: A private teaching hospital medical centre. POPULATION: A total
      of 2,866 vaginally delivered women were recruited with 114 women classified as
      urinary retention group and the remaining 2752 women categorised as control
      group. MAIN OUTCOME MEASURES AND RESULTS: Women in the urinary retention and
      control groups did not differ significantly in terms of age, fetal head
      circumference and fetal birth weight. Women suffering from postpartum urinary
      retention demonstrated significantly longer labour duration, more nulliparity and
      epidural analgesia and higher percentages of instrument-assisted delivery and
      vaginal or perineal damage. CONCLUSION: Nulliparity, longer labour course,
      instrumental delivery, extensive vaginal and perineal laceration and use of
      epidural analgesia were contributing obstetric factors to postpartum urinary
      retention. Long-term follow-up showed that the problems of all but three of the
      114 women, who complained of persistent minor urinary symptoms, were eventually
      resolved.

PMID- 12403283
TI  - Hypertension in pregnancy: do consensus statements make a difference?
AB  - OBJECTIVES: (i) To document variation in management of hypertension in pregnancy;
      (ii) to determine whether this variation falls within current management
      guidelines; and (iii) to make recommendations for developing future guidelines.
      DESIGN: Questionnaire-based survey. SETTING: Australia and New Zealand.
      POPULATION: All specialist obstetricians. METHODS: Questionnaires were sent to
      1198 obstetricians in Australia and New Zealand. Those returned by respondents
      currently in obstetric practice were analysed. Information was obtained on their
      current clinical practices relating to the diagnosis and management of
      hypertension in pregnancy. RESULTS: Of 1198 obstetricians surveyed, 973 (81%)
      replied. Of these, 686 (71%) were responsible for obstetric care. Considerable
      variation in practice was found, particularly in relation to the measurement of
      blood pressure, the determination of hypertension and significant proteinuria,
      and the decision to institute antihypertensive drug treatment. The
      recommendations of the Australasian 1993 Consensus Statement appeared to have had
      little influence on practice. There has been a striking increase in the use of
      magnesium sulphate for the prevention of convulsions in preeclampsia.
      CONCLUSIONS: There is significant variation in management of hypertensive
      pregnancies that differs from current guidelines. It is not known whether this
      diversity adversely affects clinical outcomes. Until further outcome evidence is
      available, consensus statements may be better confined to basic aspects of
      management for which there is high level evidence.

PMID- 12403284
TI  - A survey of practice preferences and attitudes to the New Zealand Guidelines for
      the Management of Heavy Menstrual Bleeding.
AB  - OBJECTIVE: To survey the practice preferences and the attitudes of New Zealand
      gynaecologists, general practitioners and family planning doctors to Guidelines
      for the Management of Heavy Menstrual Bleeding. STUDY DESIGN: A postal survey
      collected information on the following: demographics, practice preferences,
      knowledge of, usage of and attitudes toward the Guidelines for the Management of
      Heavy Menstrual Bleeding. The survey was sent to randomly selected practising
      general practitioners (n = 531), all specialist gynaecologists (n = 194) and all
      Family Planning Association doctors (n = 69) in New Zealand. Replies were
      received from 441 (56%). RESULTS: The preferred first choice for the management
      of heavy menstrual bleeding by general practitioners and family planning doctors
      was nonsteroidal anti-inflammatory medications (23%). Tranexamic acid was the
      preferred first choice medication for the management of heavy menstrual bleeding
      by specialists (57%), and preferred second choice (as well as levonorgestrel
      intrauterine system) by general practitioners and family planning doctors (34%).
      Barriers identified by general practitioners and family planning doctors to
      implementing the guideline included inability to access ultrasound scanning and
      specialist services, and a lack of subsidy for tranexamic acid and the
      levonorgestrel intrauterine system. CONCLUSIONS: There has been a change in
      prescribing patterns since 1995 among specialist and general practitioners and
      family planning doctors in New Zealand in accordance with the Guidelines for the
      Management of Heavy Menstrual Bleeding. Further attention to reducing barriers
      should focus on increasing access to ultrasound scanning, specialist services and
      subsidising the levonorgestrel intrauterine system.

PMID- 12403285
TI  - Evaluation of restaging in clinical stage 1A low malignant potential ovarian
      tumours.
AB  - OBJECTIVE: This study was undertaken to evaluate whether restaging clinical stage
      1A low malignant potential (LMP) tumours previously incompletely staged in a non
      gynaecology oncology centre yields useful information for management and
      prognosis. METHODS: A retrospective chart review was undertaken of all patients
      with LMP tumours treated at the Queensland Centre for Gynaecological Cancer
      (QCGC) from 1982-2000. RESULTS: Fifty-six (69%) of the 81 patients referred with
      a provisional stage 1A diagnosis underwent a second operation for staging
      purposes. Four (7%) out of the 56 patients who underwent restaging had their
      tumours upstaged. A single patient out of the 25 patients who did not undergo
      restaging had disease recurrence and died as a result. The mean follow-up for all
      patients in the study was 60 months. CONCLUSION: It is hard to justify routine
      surgical restaging for patients with a LMP ovarian tumour apparently confined to
      a single ovary At the very least, hundreds of patients with clinical stage 1A
      tumours will need to be restaged before a single patient will have data that will
      change management. Consequently the morbidity of routine restaging is difficult
      to justify for such a small clinical gain.

PMID- 12403286
TI  - Clinical relevance of urokinase-type plasminogen activator and its inhibitor type
      1 (PAI-1) in squamous cell carcinoma of the uterine cervix.
AB  - OBJECTIVE: The expression of uPA and PAI-1 as parameters of tumour-associated
      proteolysis has been implicated in the process of tumour cell invasion and the
      metastatic process. However, there is limited information on the impact of these
      parameters in cervical carcinoma. METHODS: Quantitative levels for uPA (n = 114)
      and PAI-1 (n = 103) were researched in operatively treated, surgically staged
      squamous cell cancer of the uterine cervix, using an ELISA-technique. Results
      were assessed regarding their impact in predicting pelvic lymph nodes metastases,
      tumour recurrence rate and recurrence free survival (RFS) using uni- and
      multivariate analysis. RESULTS: Median levels of both parameters were
      significantly higher in tumour tissue than in normal cervical tissue (p < 0.001).
      Detection of uPA gave no useful prognostic information. PAI-1 concentration
      showed a positive correlation with advanced tumour stage (p = 0.008), but no
      significant correlation with nodal status (pN0: 2.6 vs. pN1: 4.0 ng/mg protein; p
      = 0.092). Using a cut-off level of 2.4 ng/mg protein, patients with elevated PAI
      1 levels demonstrated reduced RFS (45.9 versus 52.9 months; p = 0.1).
      Multivariate analysis, including nodal status, tumour stage, lymphovascular space
      involvement and grading failed to demonstrate any prognostic impact of uPA and
      PAI-1. CONCLUSIONS: The results indicate, that PAI-1 expression is of some
      prognostic impact in cervical cancer, indicating an association of elevated PAI
      levels with local tumour progression and reduced recurrence-free survival.

PMID- 12403287
TI  - The pre-operative identification of low-risk endometrialcancer: an audit of women
      treated in the South Island of New Zealand 1998-2000.
AB  - OBJECTIVE: To determine whether pre-operative investigations identify a group of
      patients with low-risk endometrial cancer, who do not require tertiary referral
      for surgical staging or pelvic radiotherapy. DESIGN: Retrospective chart review.
      SETTING: South Island of New Zealand gynaecological oncology services. SAMPLE:
      One hundred and forty consecutive patients with newly diagnosed endometrial
      cancer from 1988 to 2000. METHODS: The results of preoperative investigations
      were compared with the final pathology. MAIN OUTCOME MEASURES: Correlation of
      preoperative investigations with low risk disease. For the purpose of the study,
      women with grade 1 or 2 endometrioid tumours confined to the uterine body and
      less than 50% myometrial invasion were considered to have low risk disease.
      RESULTS: In total, 50 women had low risk disease. Only 53% of patients with grade
      1 tumours on initial biopsy had low risk disease. Women who had a grade 1 tumour
      at biopsy and, an ultrasound report with an endometrial thickness of less than 20
      mm, and no evidence of myometrial invasion, cervical involvement or adnexal
      metastasis had a 76% chance of having low risk disease. CONCLUSION: We were
      unable to accurately define the low risk group from pre-operative assessment.

PMID- 12403288
TI  - High grade abnormalities following an 'inconclusive' smear.
AB  - OBJECTIVE: The National Health and Medical Research Council (NHMRC) recommends a
      report of 'inconclusive possible high grade epithelial abnormality', but many
      laboratories only report 'inconclusive' with reference to any possible high grade
      disease elsewhere in the report. This study was performed to determine possible
      reasons for cytological difficulties resulting in this category of report and to
      determine the rate of significant disease within this category. DESIGN:
      Retrospective record review. Clinical details were extracted without patient
      identifying data. SETTING: Gynaecological Oncology Department, King George
      V/Royal Prince Alfred Hospital. POPULATION: Two hundred patients referred with
      the cytological abnormality. MATERIALS AND METHODS: An adequate colposcopic
      diagram documenting size, distribution and grade of lesion was required. All
      patients had colposcopy with management according to colposcopic and histological
      results as appropriate to their disease. OUTCOME MEASURES: Colposcopic features,
      topography and size of any lesion, histological results, treatments performed and
      subsequent review of untreated patients. RESULTS: Colposcopy found high-grade
      lesions in 43% and carcinoma in 1%. Histopathology found 49% and 4% respectively.
      Treatment was performed in 124 patients. Inflammation was found in 27%, a small
      lesion in 43% and endocervical disease in 21%. CONCLUSIONS: The high rate of
      endocervical disease, inflammation and small lesions may explain the cytological
      difficulties leading to an 'inconclusive' result. The authors believe that the
      term 'inconclusive' alone does not adequately convey the high level of risk faced
      by these patients.

PMID- 12403289
TI  - Randomised trial of an integrated educational strategy to reduce investigation
      rates in young women with dysfunctional uterine bleeding.
AB  - OBJECTIVES: To assess the effectiveness of an integrated educational strategy to
      change clinician behaviour and reduce the number of hysteroscopies and/or
      dilatation and curettages for women 40 years or less with dysfunctional uterine
      bleeding (DUB). DESIGN: Randomised controlled trial with six-month follow-up.
      SETTING: Public teaching hospital gynaecology units with 12,000-13,000 relevant
      procedures per year. PARTICIPANTS: Six public gynaecology units made up of 62
      gynaecologists or trainees allocated at random to intervention group - three, or
      control group - 3. Intervention An educational strategy that included
      dissemination of evidence-based guidelines via a problem-based interactive
      workshop facilitated by an opinion leader and a laminated algorithm and
      guidelines. MAIN OUTCOME MEASURES: The number of hysteroscopies and/or dilatation
      and curettages performed for DUB on women 40 years or less, clinician behaviour
      change and perceived booking rates of the procedure. RESULTS: At six months,
      there was no significant effect on the number of hysteroscopies and/or dilatation
      and curettages performed but there was an increase in evidence-based behaviour.
      CONCLUSIONS: While the evidence-based educational strategy for the appropriate
      investigation of young women with DUB resulted in clinician behaviour change when
      applied to theoretical cases, it did not result in a reduction in
      hysteroscopy/D&C rates at six months.

PMID- 12403291
TI  - Small bowel perforation associated with microwave endometrial ablation.

PMID- 12403290
TI  - Medical and midwifery students: how do they view their respective roles on the
      labour ward?
AB  - BACKGROUND: It has been suggested that much of the medical and midwifery student
      curricula on normal pregnancy and birth could be taught as a co-operative effort
      between obstetric and midwifery staff. One important element of a successful
      combined teaching strategy would involve a determination of the extent to which
      the students themselves identify common learning objectives. AIM: The aim of the
      present study was to survey medical and midwifery students about how they
      perceived their respective learning roles on the delivery suite. METHODS: A
      descriptive cross-sectional survey study was undertaken. The study venue was an
      Australian teaching and tertiary referral hospital in obstetrics and gynaecology
      Survey participants were medical students who had just completed a 10 week
      clinical attachment in obstetrics and gynaecology during the 5th year of a six
      year undergraduate medical curriculum and midwifery students undertaking a one
      year full-time (or two year part-time) postgraduate diploma in midwifery.
      RESULTS: Of 130 and 52 questionnaires distributed to medical and midwifery
      students, response rates of 72% and 52% were achieved respectively The key
      finding was that students reported a lesser role for their professional
      colleagues than they identified for themselves. Some medical students lacked an
      understanding of the role of midwives as 8%, 10%, and 23% did not feel that
      student midwives should observe or perform a normal birth or neonatal assessment
      respectively. Of equal concern, 7%, 22%, 26% and 85% of student midwives did not
      identify a role for medical students to observe or perform a normal birth,
      neonatal assessment or provide advice on breastfeeding respectively. SUMMARY:
      Medical and midwifery students are placed in a competitive framework and some
      students may not understand the complementary role of their future colleagues.
      Interdisciplinary teaching may facilitate co-operation between the professions
      and improve working relationships.

PMID- 12403292
TI  - Triplet pregnancy complicated by feto-feto-fetal transfusion with very rapid
      deterioration and fetal demise in all three triplets.

PMID- 12403293
TI  - Bilateral retinal detachment in pregnancy.

PMID- 12403294
TI  - A still birth and uterine rupture during induction of labour with oral
      misoprostol.

PMID- 12403295
TI  - Cord prolapse though the urethra.

PMID- 12403296
TI  - Analytical studies on two amino acid derivatives of anticonvulsant activity.
AB  - Qualitative and quantitative methods of analysis of two new amino acid
      derivatives, potential anticonvulsants of low neurotoxicity: N-acetyl-gamma
      aminobutyric acid benzylamide (1) and N-melhyl-gamma-aminobutyric acid
      benzylamide (2) were developed. Qualitative analysis includes characteristic
      colour reactions, chromatographic (TLC) investigations, IR and UV spectra
      interpretation and quantitative analysis involves spectrophotometric,
      chromatographic (HPLC). acidimetric and argentomeric methods.

PMID- 12403297
TI  - Stability of cefepime dihydrochloride monohydrate in solid state.
AB  - The pseudo first-order rate constants and thermodynamic parameters for the
      decomposition of cefepime in solid state in absence of humidity and at a relative
      humidity of 76.4% were calculated. The effect of humidity on the stability of
      cefepime dihydrochloride monohydrate in the humidity range 25.0%-76.4% at 358 K
      is described by the equation ln ki = (0.031 +/- 0.0043) x RH% - 10.08 +/- 0.22.

PMID- 12403298
TI  - Studies on the influence of auxiliary substances on the physico-chemical
      characteristics of ophthalmic drugs. Part I. Studies on the influence of
      auxiliary substances on the critical micellar concentration of surfactants
      solutions in eye drops containing sulphacetamidum natricum.
AB  - Interactions between Tweens, surfactants used in eye drops and the remaining
      compounds of the preparations were investigated. The interactions were assessed
      by means of the surface tension measurement method. Obtained results demonstrate
      that the substances used in the facture of the preparation affect the critical
      micellar concentrations of Tweens. Only hydroxyethylcellulose was found to exert
      a stabilizing effect on the critical micellar concentration of these substances.
      The amount of used surfactant should be taken into consideration in the
      manufacture of eye preparations.

PMID- 12403299
TI  - Effect of various vehicles on diclofenac sodium and indomethacin pharmaceutical
      availability.
AB  - The aim of the study was to determine the pharmaceutical availability of various
      ointment systems containing antirheumatic substances and to establish an optimal
      system for cutaneous application. Topical application permits elimination or at
      least reduction of side effects connected with oral administration. Three systems
      were evaluated: emulsion W/O (ointment), emulsion O/W (cream) and gel, all of
      them containing diclofenac sodium or indomethacin. The investigated systems are
      characterized by proper rheological parameters and long physicochemical
      stability. Studies on diclofenac and indomethacin pharmaceutical availability
      show a good release of the substances from cream and hydrogel bases, but a very
      poor release from the ointment base.

PMID- 12403300
TI  - Quantitative determination of coumarins, flavonoids and chlorogenic acid in the
      leaves and underground parts of some species of genus Scopolia Jacq.
AB  - The quantitative determination of coumarins, flavonoids and chlorogenic acid in
      the leaves and underground parts of Scopolia carniolica Jacq., S. lurida Dun. and
      S. sinensis Hemsl. using the RP-HPLC method has been described.

PMID- 12403302
TI  - Flavonoids from some species of genus Scopolia Jacq.
AB  - Kaempferol 3-O-(2-glucosyl)-galactoside-7-O-glucoside was isolated from the
      leaves of Scopolia carniolica Jacq. and S. sinensis Hemsl. From the latter taxon
      as well as kaempferol 3-O-galactoside and 3-O-(2-glucosyl)-galactoside,
      kaempferol and quercetin 3-O-robinobiosides and quercetin 3-O-sophoroside have
      been obtained. Moreover, from the leaves of S lurida Dun. kaempferol and
      quercetin 3-O-glucosides and 3-O-rutinosides were isolated. The structures of
      compounds have been determined by means of chemical and spectral methods (UV, LSI
      MS, 1H and 13C NMR, 1H-1H COSY NMR).

PMID- 12403301
TI  - Investigations of the thymomimetic activity of a selected phytopharmaceutical
      preparation--Reumaherb tablets by flow cytometry.
AB  - The aim of the present study was to investigate the influence of Reumaherb
      tablets, a plant preparation, on the maturation of mice thymocytes in the
      presence of glycocorticosteroid by the method of cytotoxicity test performed in
      vitro in two versions differing in methodology. The cell source for incubation
      was thymus of female Balb/c mice, four weeks old. Reumaherb tablets were added to
      the culture of thymocytes diluted by a factor of 10-400. The searched
      thymomimetic activity of the investigated Reumaherb preparation was found in both
      versions of the test, this being demonstrated by a 17% increase in the number of
      surviving cells in the presence of glycocorticosteroid added to the culture. This
      effect strongly depends on the applied doses. By a microscopic evaluation of the
      results a maximum stimulation was found at a 200-fold dilution of the examined
      preparation, while in the cytometric analysis a similar maximum effect was
      observed at a 20-fold dilution.

PMID- 12403303
TI  - Synthesis and some pharmacological properties of 3-(4-phenyl-5-oxo-1,2,4
      triazolin-1-ylmethyl)-1,2,4-triazolin-5-thione derivatives.
AB  - In the reaction of (4-phenyl- or 3,4-diphenyl-5-oxo-1,2,4-triazeolin-1-ylmethyl)
      carbohydrazide (IIa, IIb) with isothiocyanates the thiosemicarbazide derivatives
      [IIIa, b - IXa, b] were obtained. Cyclization of those compounds in the presence
      of 2% or 10% NaOH led to formation of derivatives with the 1,2,4-triazolin-5
      thione system [Xa, b - XV[a, b]. Molecular structure proposed for this group of
      compounds was confirmed by X-ray structure analysis of Xa and XIVa. Compounds Xa,
      XIIa and XIVa were investigated pharmacologically for their central properties in
      mice. It was shown that only compound XIIa produced antinociceptive effects in
      mice.

PMID- 12403304
TI  - Synthesis, structural characterization and antimicrobial studies of hydrazone
      derivatives of 3-hydroxyimino-5-methyl-2-hexanone.
AB  - The derivatives of 3-hydroxyimino-5-methyl-2-hexanone oxime have been obtained in
      good yield by its reactions either with hydrazine hydrate or phenyl hydrazine,
      respectively. IR and 1H NMR spectral data of these compounds have been discussed.
      All the newly synthesised compounds have been tested for their biological
      activity against S. auerus, S. typhi, C. albicans, A. niger, S. cerevisiae and M.
      tuberculosis H47RV.

PMID- 12403305
TI  - Quantitative structure-activity relationships study of a series of imidazole
      derivatives as potential new antifungal drugs.
AB  - The Quantitative Structure-Activity Relationships (QSAR) has been developed to
      relate antifungal activity against Candida albicans and Rhodotorula glutinis of
      new imidazole derivatives with their physico-chemical and structural properties.
      For 265 imidazole derivatives the most significant statistically equations has
      been obtained with correlation coefficients R=0.800 and R=0.820 in case of
      activity against Ca. and Rh.g., respectively. The overall antifungal activity has
      been described by means of size and bulkiness related parameters as well as polar
      and lipophilic interactions. The significance of lipophilicity in terms of n
      octanol/water partition coefficient, ClogP, on antifungal potency against both
      fungi has been investigated. QSAR equations for different classes of antifungal
      activity have been obtained. With a very high probability level (92% and 96%) the
      weak or very weak antifungal potency against C.a. can be determined and thus the
      number of required experiments can be reduced.

PMID- 12403306
TI  - Effect of chronic hyperglycemia and vanadate treatment on erythrocyte Na/K-ATpase
      and Mg-ATpase in streptozotocin diabetic rats.
AB  - We have studied Na/K-ATPase and Mg-ATPase activities in red blood cells of
      diabetic rats treated in vivo with sodium vanadate. To our knowledge the effect
      of in vivo vanadate treatment on these two enzymes has not been studied. Red
      blood cell Na/K-ATPase plays a central role in the regulation of intra- and extra
      cellular cation homeostasis. Alteration of this transport enzymes is thought to
      be linked to several complications of diabetes mellitus: hypertension,
      nephropathy, peripherical neuropathy and microangiopathy. An Mg2+-dependent
      ATPase activity located in the erythrocyte membrane appears to be responsible for
      controlling the smoothing of echinocytic erythrocytes to discocytes and
      stomatocytes. Our results show that in alloxan diabetes activities of both
      ATPases are reduced (especially the activity of Na/K-ATPase). Vanadate treatment
      of normal animals reduced the activities of both enzymes: with 33.08% for Na/K
      ATPase and 22.76% for Mg-ATPase. Vanadate treatment of diabetic animals did not
      affect significantly the inhibition process for Na/K-ATPase. For Mg-ATPase we
      have obtained a significant cumulative inhibition. These results stand out the
      different functions and physiologic control mechanism of these two ionic pump in
      red blood cells.

PMID- 12403307
TI  - Synthesis of a new antischistosomally active and toxicologically tolerant C-12
      monothione surrogate of the universal antihelmintic praziquantel.
AB  - A new C-12 monothione mimic (III) of the universal antihelmintic Praziquantel (I)
      namely, 2-cyclohexylthiocarbonyl( 1,2.3,6,7,11b)-hexahydro-4H-pyrazino[2-1a]
      isoquinoline-4-one was chemically synthesized and structurally elucidated
      (Elemental analysis. El-Mass, 13C-NMR and IR spectroscopy). Antischistosomal
      potency in the order of -76% comparable to that for our newly reported C-12 and C
      4 dithion mimic II (-70%) and Praziquantel. Praziquantel (100%, mice infected
      with S. mansoni cercariae), was realized. Toxicological evaluation (mice liver
      and kidney functions) and biochemical parameters (cholesterol, triglycerides,
      albumin, total serum proteins and amino acid profile of liver protein homogenate)
      were also assayed. Comparable to the parent drug, general insignificant
      toxicological diferences could be attributed for III. Interestingly, III
      exhibited intermediate biological figures between I and II. An order of II<III<I
      with respect to the antischistosomal potency and II>III>I, for the other tested
      biochemical parameters was observed. A consideration of obtained results could
      indicate that, structurally, an intact glycine amide segment of the pyrazine
      moiety, as it is the case in both I and III, and not in II (glycine thioamide)
      seemed now more crucial for exhibiting an optimum antihelmintic potency as well
      as a more tolerant toxicity characteristics. Additionally, the obtained
      comparable amino acid profile of mice liver protein homogenate after the
      treatment by III, could suggest similar biochemical, lethal mechanistic and
      metabolic routes for II, III and I. The new lipophilic candidatee III seems to
      merit more profound chemical, biological, and pharmaceutical investigations.

PMID- 12403309
TI  - HELP for herpes.

PMID- 12403308
TI  - Lidocaine elimination in patients with liver cirrhosis.
AB  - The aim of the study was to evaluate lidocaine elimination in patients with liver
      cirrhosis. The study was carried out in 30 cirrhotic patients classified
      according to the Child-Pugh's score to subgroups A (n=11). B (n=12) and C (n=7),
      and 14 healthy volunteers. Lidocaine was administered intravenously, at a dose of
      I mg/kg, and blood samples for lidocaine and monoethylglycinexylidide (MEGX)
      assays were collected for up to 6 h. Decreased elimination half-live for
      lidocaine as well as reduced formation rate of MEGX was found in cirrhotic
      patients. Lidocaine metabolising capacity of the liver was irrespective of
      etiology of cirrhosis. It was also found that evaluation of elimination half-life
      of lidocaine is more closely related to the Child-Pugh's staging of liver
      dysfunction than 15-minute MEGX concentration.

PMID- 12403310
TI  - Pimecrolimus: a new treatment for seborrheic dermatitis.
AB  - Seborrheic dermatitis is a chronic recurrent inflammatory skin condition that
      mainly affects areas containing sebaceous glands. I present a case of a novel
      effective topical nonsteroidal treatment (pimecrolimus 1.0% cream) for facial
      seborrheic dermatitis. Pimecrolimus is a member of a new class of nonsteroidal
      agents- macrolactam immunomodulators.

PMID- 12403311
TI  - Trichosporon beigelii infection presenting as white piedra and onychomycosis in
      the same patient.
AB  - Trichosporon beigelii is a fungal organism that causes white piedra and has
      occasionally been implicated as a nail pathogen. We describe a patient with both
      hair and nail changes associated with T. beigelii.

PMID- 12403312
TI  - Anterolateral leg alopecia revisited.
AB  - Alopecia of the leg-an extremely common yet ill-defined condition-is described in
      few contemporary dermatology textbooks. In this article, we describe 3 patients
      with anterolateral alopecia of the legs and further characterize this condition
      through a review of the literature.

PMID- 12403313
TI  - Palmar petechiae in dermatitis herpetiformis: a case report and clinical review.
AB  - Palmar petechiae or purpura is an unusual finding in dermatitis herpetiformis
      (DH) that occurs in children but is only rarely reported in adults. We describe a
      46-year-old man with DH who presented with the classic pruritic papulovesicular
      eruption and associated volar finger and palmar petechiae. We discuss recent
      advances in the pathogenesis and treatment of DH.

PMID- 12403314
TI  - Pruritic linear papules on a 75-year-old woman: a case of localized Darier-White
      disease.
AB  - Darier-White disease (DWD), commonly called Darier disease or keratosis
      follicularis, is a genodermatosis seen in clinical practice. It exists more
      commonly in the generalized form but can present as a localized condition.
      Localized DWD is a rare entity characterized by epidermal changes that are like
      those seen in the generalized form but that are confined to a small area of skin.
      This entity is postulated to result from a postzygotic mutation and has the
      potential to be transmitted to offspring, which may result in the severe
      generalized form. We report a case of localized DWD diagnosed after biopsy of a
      recalcitrant linear dermatitis and discuss the salient features of this
      condition.

PMID- 12403315
TI  - Painful cutaneous metastases from esophageal carcinoma.
AB  - Cutaneous metastases, which are not included among the painful dermal tumors, are
      primarily asymptomatic and of variable clinical appearance. Although, to our
      knowledge, this case report of painful cutaneous metastases is only the fifth in
      the literature, physicians who discover a painful tumor perhaps now should
      consider cutaneous metastasis. In this report, we describe painful nodular scalp
      lesions related to esophageal adenocarcinoma, which rarely metastasizes to the
      skin.

PMID- 12403316
TI  - A double-blind study of the efficacy and safety of the ICP10deltaPK vaccine
      against recurrent genital HSV-2 infections.
AB  - A randomized double-blind trial to evaluate the safety of a novel recombinant
      virus, ICP10deltaPK, for reduction or prevention of recurrent herpes simplex
      virus type 2 (HSV-2) infection was carried out in public hospitals in Mexico
      City. Persons having a minimum of 5 documented herpetic recurrences in the
      previous year were randomized for vaccination. Patients were examined within 72
      hours of lesion occurrence. If accepted into the study, the patient was
      inoculated subcutaneously in the upper deltoid muscle area at days 7, 17, and 28
      after initiation of lesion occurrence. Recurrences were recorded by patient diary
      and physician examination. During the observation period (extending from 10 to
      180 days after the last booster dose), recurrences in the vaccine (V) group were
      prevented completely in 37.5% of the patients, whereas in the placebo (P) group,
      100% of the patients had at least one recurrence (P = .068). Vaccinated patients
      had fewer recurrences (V, 1.58; P, 3.13 [P = .028]). The mean number of illness
      days was 10 for the vaccine group and 18 for the placebo group (P = .028).
      Further studies to evaluate this vaccine and its dosimetry for the treatment of
      genital herpes infections appear warranted.

PMID- 12403317
TI  - Efficacy and cutaneous safety of adapalene in black patients versus white
      patients with acne vulgaris.
AB  - Acne vulgaris is the most common dermatologic disorder seen in American black
      patients (ie, African Americans and African Caribbeans, Fitzgerald skin types IV
      through VI). Despite its prevalence, there is a lack of data on the effects of
      treatments, such as the use of topical retinoids and retinoid analogs, in this
      patient population. Adapalene is a topical retinoid analog that has demonstrated
      efficacy in the reduction of noninflammatory and inflammatory lesions, along with
      excellent cutaneous tolerability. Most clinical studies of this agent have
      involved predominantly white patient populations. This meta-analysis of 5
      randomized US and European studies was designed to evaluate the efficacy and
      safety of adapalene in black versus white patients. The percentage reduction in
      the number of inflammatory lesions was significantly greater among black patients
      compared with white patients (P=.012). The percentage reductions in total
      inflammatory and noninflammatory lesion counts were similar in the 2 groups
      (P>.3). There were significantly less erythema and scaling in black patients
      compared with white patients (P<.001 and P=.026 for worst scores for erythema and
      scaling, respectively). Although the incidence of dryness was similar in both
      groups, a smaller percentage of black than white patients had moderate or severe
      scores for dryness (7% vs 18%, respectively). In summary, adapalene appears to be
      a viable treatment for black patients with acne vulgaris.

PMID- 12403318
TI  - Babesia divergens: cloning and biochemical characterization of Bd37.
AB  - The immunoprotective potential of Babesia divergens antigens released in
      supernatants of in vitro cultures of the parasite is generally known. Among a
      number of parasite molecules, a 37 kDa protein has been found in the supernatants
      of Babesia divergens cultures. In this report the cloning and biochemical
      characterization of this protein, called Bd37, are described. In addition, the
      processing of the protein was studied in vitro. Results suggest that Bd37 is
      encoded by a single copy gene. Bd37 appears to be a merozoite-associated molecule
      attached to the surface by a glycosylphosphatidylinositol moiety containing a
      palmitate residue attached to the inositol ring. In addition, it is demonstrated
      that both extremities of the protein are linked by a disulphide bond. Results
      further indicate that a soluble, hydrophilic form of Bd37 can be released from
      the merozoite surface by GPI-specific phospholipase D. The potential role the
      Bd37 protein and the GPI anchor are discussed.

PMID- 12403319
TI  - Chromosome number, genome size and polymorphism of European and South African
      isolates of large Babesia parasites that infect dogs.
AB  - Pulsed-field gel electrophoresis of intact chromosomes from 2 isolates of each of
      the 2 most pathogenic species of large Babesia parasites that infect dogs, i.e.
      Babesia canis (European species) and B. rossi (South African species), revealed 5
      chromosomes in their haploid genome. The size of chromosomes 1-5 was found to be
      different in the 2 species, ranging from 0.8 to 6.0 Mbp. The genome size was
      estimated to be approximately 14.5 Mbp for B. canis and 16 Mbp for B. rossi,
      respectively. Within each species, the size of chromosomes 1-3 of B. canis and 1
      2 of B. rossi was conserved between the 2 isolates, whereas the size of
      chromosomes 4-5 of B. canis and 3-5 of B. rossi was variable. Chromosomes 1-5
      hybridized with a 28-mer telomeric oligonucleotide probe derived from Plasmodium
      berghei. When NotI-digested chromosomes of the 4 isolates were hybridized with
      the telomeric probe a maximum of 10 fragments was revealed. Moreover,
      hybridization of this telomeric probe to a Southern blot of genomic DNA from the
      4 isolates, digested with a series of restriction enzymes, revealed a species
      specific restriction map. Hybridization of intact or NotI-digested chromosomes of
      both species with 2 sets of 3 cDNA-antigen probes derived from each species,
      revealed no cross-hybridization between these B. canis and B. rossi genes.

PMID- 12403320
TI  - Protease inhibitors and haemagglutinins associated with resistance to the
      protozoan parasite, Perkinsus marinus, in the Pacific oyster, Crassostrea gigas.
AB  - Perkinsus marinus is a protozoan responsible for dramatic mortality in the
      Eastern oyster, Crassostrea virginica, but not in the Pacific oyster, C. gigas.
      To understand the host-parasite relationship, we inoculated P. marinus
      trophozoites into the shell cavity of C. gigas and measured, over 2 months, (i)
      intensity of infection, (ii) protease inhibitory activities against P. marinus
      proteases and against bovine z-chymotrypsin, (iii) plasma haemagglutinin titre,
      (iv) plasma protein concentration, (v) plasma lysozyme activity and (vi) total
      haemocyte count. We observed that the highest protease inhibitory activities and
      haemagglutinin titres (3-10 days post-challenge) preceded parasite elimination
      (initiated 7 days post-challenge). In contrast, plasma protein concentration,
      lysozyme activity and total haemocyte count showed no significant modification
      following the challenge. It is hypothesized that the capacity of C. gigas to
      increase its protease inhibitors represents the key event in resistance to
      parasite infection by neutralizing the proteases secreted by P. marinus, thus
      preserving the oyster haemagglutinins from degradation. Such haemagglutinins will
      be ready to act as opsonins stimulating phagocytosis of parasites.

PMID- 12403321
TI  - Molecular characterization of Danish Cryptosporidium parvum isolates.
AB  - The genetic polymorphism among 271 Danish Cryptosporidium isolates of human and
      animal origin was studied by partial amplification and sequencing of the
      Cryptosporidium oocyst wall protein (COWP) gene, the 1 8S rDNA, and a
      microsatellite locus. Furthermore, the microsatellite locus was studied directly
      using fragment analysis. A comparative analysis of DNA sequences showed the
      presence of 3 different subgenotypes (Cl, C2 and C3) in C. parvum isolates from
      Danish cattle, with prevalences of 16.7, 17.2 and 73.1% including 13 (7.0%) mixed
      infections. Subgenotype Cl was significantly more prevalent (P < 0.001) in the
      southern part of Denmark. In Cryptosporidium isolates of human origin the
      anthroponotic subgenotype H1 was identified, in addition to the zoonotic
      subgenotypes C1, C2, and C3. Of 44 human samples, 56.8% were anthroponotic,
      whereas 40.9% were zoonotic genotypes. One human isolate was characterized as C.
      meleagridis. The porcine Cryptosporidium isolates (N = 4) revealed a pattern
      which was genetically distinct from human and bovine isolates. Cryptosporidium in
      a hedgehog (Erinaceus europaeus L.) was identified for the first time. By
      microsatellite sequencing the hedgehog isolate showed a subgenotype distinct from
      the previously detected types. The assignment to subgenotype by microsatellite
      sequencing and fragment typing was 100% identical in samples where results were
      achieved by both methods. In addition, the fragment analysis proved more
      sensitive, easier, faster, and less expensive compared to sequencing.

PMID- 12403322
TI  - Linkage between susceptibility of Phlebotomus papatasi to Leishmania major and
      hunger tolerance.
AB  - Phlebotomus papatasi sand flies, the vectors of Leishmania major, differ
      genetically in their susceptibility to the pathogens. The costs of infection
      appear to be so great that selection against Leishmania-susceptible flies could
      presumably occur, unless susceptibility is compensated for by some advantage.
      Foci of P. papatasi-transmitted L. major are mainly found in arid habitats where
      seasonal stress of dehydration and heat reduces the quantity of sugar in plant
      leaves. The sand flies feed on these leaves and with the lack of essential sugar
      only a few survive long enough to deposit eggs and transmit Leishmania. This
      association suggested that susceptibility to L. major infection may be linked
      with advantageous tolerance of sugar deprivation. Here we show that desert sand
      flies, provided with excess sugar, became progressively resistant to infection.
      Selection for survival under sugar-poor conditions increased the susceptibility
      of parent and first-generation offspring by more than 2-fold. The leaves of
      plants, on which flies naturally feed, contain more sugar in irrigated than in
      arid habitats. About 85% of first-generation flies colonized from a desert
      habitat retain experimental Leishmania infection compared to 25 % of offspring of
      flies from irrigated sites.

PMID- 12403323
TI  - Population genetics and dynamics at short spatial scale in Bulinus truncatus, the
      intermediate host of Schistosoma haematobium, in Morocco.
AB  - The population biology of the schistosome-vector snail Bulinus truncatus was
      studied in an irrigation system near Marrakech, Morocco using both genetic and
      demographic approaches. The population genetic survey was conducted in 4 sites, 2
      sites being sampled on 2 separate occasions. Individuals were genotyped at 6
      microsatellite loci. No variability was found at 4 loci, and the 2 other loci had
      less than 4 alleles. The differentiation, both spatial and temporal, among
      populations was extremely weak. The demographic survey was conducted using 2
      capture-mark-recapture analyses in 2 separate sites, the first in 1999 and the
      second in 2000. The second analysis permitted the estimation of parameters based
      on recent methodological developments (multisite models). Although these studies
      provided information on several traits, we report here on dispersal only. Both
      analyses showed that individual dispersal is of the order of a few hundreds of
      metres per reproductive life, that is the scale of the whole irrigation area.
      Both the genetic and demographic studies indicated that this area harbours a
      single--or no more than a few--populations of B. truncatus. This has implications
      for our understanding of the coevolutionary process between snails and flukes.

PMID- 12403324
TI  - Humoral immune response of Simulium damnosum s.l. following filarial and
      bacterial infections.
AB  - The time-course of the humoral immune response of female blackflies after a
      challenge with bacteria, different Onchocerca microfilariae species, bacterial
      endotoxin and microfilarial extract was investigated. Strong bacteriolytic and
      growth inhibition activities against the Gram-positive bacterium Micrococcus
      luteus were induced by all agents. Specific differences were found in activity
      levels and time-course. Notably the endotoxin lipopolysaccharide (LPS) induced a
      very early, profound bacteriolytic and antibacterial response, which declined
      within a day after injection. In contrast, the bacteriolytic activities after
      Escherichia coli D31 and Onchocerca microfilariae infections were lower, but
      remained elevated over the observation period of 4 days. The bacteriolytic
      activity was correlated to a haemolymph protein with a molecular weight of around
      14 kDa. Anti-Gram-positive activity in the E. coli infected group appeared within
      the first 6 h. However, it took 4 days in the microfilarial infected blackflies
      to reach significant levels. The active agent was identified to be a peptide with
      a molecular weight of around 4-4.5 kDa. Activity against the Gram-negative
      bacteria E. coli was detected in blackflies injected with E. coli D31, O. dukei
      microfilariae and microfilarial extract on days 1 and 4 after injection. The
      immune response in S. damnosum s.l. naturally infected via a bloodmeal on cattle
      supported the findings of the experimental infections. Similarities of the immune
      response kinetics between bacterial and filarial infections suggested that
      intracellular Wolbachia bacteria, released from microfilariae, could be
      responsible for the antibacterial response. This is supported by the observation
      that the induction of an immune response in the Drosophila melanogaster mbn-2
      cell line by the filarial extract is blocked by polymyxin B, which forms inactive
      complexes with bacterial LPS.

PMID- 12403325
TI  - Molecular and morphological characterization of Echinococcus granulosus of human
      and animal origin in Iran.
AB  - Iran is an important endemic focus of cystic hydatid disease (CHD) where several
      species of intermediate host are commonly infected with Echinococcus granulosus.
      Isolates of E. granulosus were collected from humans and other animals from
      different geographical areas of Iran and characterized using both DNA (PCR-RFLP
      of ITS1) and morphological criteria (metacestode rostellar hook dimensions). The
      sheep and camel strains/genotypes were shown to occur in Iran. The sheep strain
      was shown to be the most common genotype of E. granulosus affecting sheep,
      cattle, goats and occasionally camels. The majority of camels were infected with
      the camel genotype as were 3 of 33 human cases. This is the first time that cases
      of CHD in humans have been identified in an area where a transmission cycle for
      the camel genotype exists. In addition, the camel genotype was found to cause
      infection in both sheep and cattle. Results also demonstrated that both sheep and
      camel strains can be readily differentiated on the basis of hook morphology
      alone.

PMID- 12403326
TI  - Increased burdens of drug-resistant nematodes due to anthelmintic treatment.
AB  - Nine groups of lambs were challenged with 500 drug-resistant (R) Ostertagia
      circumcincta infective-stage larvae (L3) twice-weekly for 6 weeks; 3 of the
      groups were also given 500 susceptible (S) L3 and another 3 given 3000 L3 twice
      weekly. One week prior to parasite challenge, 1 group of each dose rate was
      administered ivermectin-capsules (IVM-CRCs). Following challenge, a second group
      from each dose rate was administered oxfendazole to remove susceptible parasites.
      The remaining groups received no drug treatment throughout the trial. No
      significant difference in faecal egg count was observed between the groups. The
      groups left untreated did not differ significantly in resulting worm burden.
      However, the percentage of the total L3 challenge recovered as 4th-stage larvae
      or adult worms demonstrated a density-dependent relationship and declined with
      increasing challenge. Those groups treated with anthelmintic to remove S worms
      prior to necropsy also showed density dependency as worm burdens were lower at
      the highest dose rate. In the groups administered IVM-CRCs, no dose-dependent
      effect on worm burden was observed. These differences resulted in more worms
      being present at the highest dose rate in the IVM-CRC-treated animals than in
      those animals treated orally with anthelmintic. Adult female worms from the IVM
      CRC high challenge group were significantly longer and contained more eggs in
      utero than those in the other high challenge groups. These results demonstrate
      that where resistance is present, IVM-CRCs can modify the density-dependent
      regulation of the parasite population, resulting in the acquisition of larger
      resistant worm burdens than might otherwise be expected. This could accelerate
      the build-up of resistant worm populations and decrease the time until treatment
      failure.

PMID- 12403327
TI  - Identification of potential protective antigens of Ostertagia ostertagi with
      local antibody probes.
AB  - The identification of protective helminth antigens remains the most important
      challenge in the development of parasitic vaccines. To identify protective
      antigens of Ostertagia ostertagi, an important abomasal parasite of cattle,
      parasite-specific local antibodies from the abomasal mucus and from the draining
      lymph nodes were collected from calves immunized with multiple infections and
      from 'primary infected' animals. With these probes, Western blots of extracts and
      excretion/ secretion (E/S) material from L3, L4 and adult life-stages as well as
      cDNA expression libraries were screened to identify antigens that were
      exclusively recognized by antibodies from 'immunized' calves. In the adult stage,
      a protein of 32 kDa was specifically detected on Western blot by mucus antibodies
      from 'immunized' animals. In the L3 and L4 larval stages, proteins situated in
      the regions of 28-29 kDa were recognized by mucus antibodies and a 59 kDa antigen
      was specifically recognized by lymph node antibodies from 'immunized' animals.
      Screening E/S material revealed no specific difference in recognition pattern
      between 'immunized' and 'primary infected' animals. Screening of the cDNA
      libraries revealed 26 relevant clones, coding for 15 proteins, among these
      several with potential protective capacity, immunodominant properties or
      functional and physiological importance e.g. metalloproteases, an aspartyl
      protease inhibitor and collagen.

PMID- 12403328
TI  - Temporal and geographical distribution of cases of foot-and-mouth disease during
      the early weeks of the 2001 epidemic in Great Britain.
AB  - Estimates of the likely dates of infection of the early cases of the 2001 foot
      and-mouth disease (FMD) epidemic indicate that at least 57 premises in 16
      counties in Great Britain were infected before the first case was disclosed.
      Nationwide animal movement controls were imposed within three days of the first
      case being confirmed on February 20, when FMD was only known to be in two
      counties, and these controls limited its geographical spread. After the first few
      cases were confirmed, new cases were rapidly discovered, and the epidemic curve
      for the daily number of confirmed cases peaked five weeks later, 11 days later
      than the peak of the curve based on the estimated dates of infection. In the peak
      week, both curves showed an average daily number of 43 new cases. The estimated
      dates of infection are believed to be relatively unbiased for the early cases,
      for which they were derived from a known contact with infection. However, for the
      later cases they were estimated mainly from the age of the clinical signs of the
      disease, and were biased by species and other factors, a bias which would
      probably have made the estimated dates later than was in fact the case.

PMID- 12403329
TI  - Relationship between milk urea concentration and the fertility of dairy cows.
AB  - The relationship between milk urea concentration and the fertility of dairy cows
      was examined in two studies. The first examined the relationship between bulk
      milk urea concentration and overall herd fertility, using data collected from 250
      herds in the UK. There was no relationship either between bulk milk urea
      concentration and fertility, or between changes in bulk milk urea concentration
      and fertility. The second study compared the relationship between the milk urea
      concentration five days after service, and the fertility of individual cows on 11
      UK dairy farms. There was no significant difference between the milk urea
      concentration of the cows that became pregnant and those that did not.

PMID- 12403330
TI  - Chronic nodular panniculitis in a three-year-old mare.
AB  - The clinical signs of chronic nodular panniculitis in a three-year-old mare were
      consistent with a diagnosis of sterile nodular panniculitis, but the mare had
      histopathological signs of both generalised steatitis and sterile nodular
      panniculitis. The mare was deficient in vitamin E and selenium.

PMID- 12403331
TI  - Capillaria hepatica (Calodium hepaticum) infection in a British dog.

PMID- 12403332
TI  - Outbreak of Pasteurella multocida septicaemia in neonatal lambs.

PMID- 12403333
TI  - Isolation of birnavirus and reovirus-like agents from penguins in the United
      Kingdom.

PMID- 12403335
TI  - RCVS Library and Information Service charges.

PMID- 12403334
TI  - Chorioptic mange of sheep.

PMID- 12403336
TI  - Veterinary cover and farm animal welfare.

PMID- 12403339
TI  - Primary immunodeficiency studies at University of Alabama at Birmingham:
      continuing the search for genetic causes.
AB  - Over the past two decades the genetic bases for virtually all the well
      characterized primary immunodeficiency syndromes have been identified. The
      investigation of rare, poorly differentiated immunodeficiencies is being hampered
      by a preoccupation of funding agencies with hypothesis-driven proposals that
      apply poorly in the case of individual patients. Recent studies at our
      institution in collaboration with groups at NIH have resulted in the
      identification of two separate kindreds bearing unique mutations in molecules
      affecting immune function and a chromosomal linkage in a third family. Thus, a
      potential solution to the funding problem for studies in primary immunodeficiency
      could lie in the centralization of investigative expertise and support, perhaps
      within the walls of the National Institutes of Health, as has been done with
      great success in Europe.

PMID- 12403340
TI  - Complement in central nervous system inflammation.
AB  - The complement system is well represented in the central nervous system. Glial
      cells and neurons produce or express all of the activation and regulatory
      proteins and the C3a/C5a receptors. Inhibition of complement activation is
      protective in experimental allergic encephalomyelitis, the animal model for
      multiple sclerosis, suggesting possible therapeutic approaches for human disease.
      New findings indicate that the C3a/C5a receptors are widely expressed in neurons
      and may modulate neuronal function.

PMID- 12403342
TI  - Adhesion molecules in inflammatory diseases: insights from knockout mice.
AB  - Leukocyte/endothelial cell adhesion molecules are essential mediators of both
      immune and inflammatory responses. However, their specific roles in the
      initiation and progression of inflammatory diseases remain largely undefined. The
      focus of our laboratory is the identification of the adhesion molecule
      interactions that mediate leukocyte recruitment and tissue damage during the
      development of rheumatoid arthritis, systemic lupus erythematosus, and psoriasis.
      For these studies, we use a basic genetic approach in mice, analyzing different
      gene-targeted adhesion molecule mutants, or "knockouts," in murine disease
      models. Our findings suggest that loss of intercellular adhesion molecule-1
      significantly inhibits the development of arthritis and glomerulonephritis, while
      selectin deficiency results in accelerated development of joint and kidney
      inflammation. Our results also indicate that the beta2 integrins may play a key
      role in regulating the initiation of psoriasiform skin diseases.

PMID- 12403341
TI  - Genetic influences on rheumatoid arthritis in African Americans.
AB  - Rheumatoid arthritis is a common autoimmune disease characterized by inflammation
      of the synovial membrane of diarthrodial joints, which often leads to joint
      damage and disability. There are known associations between major
      histocompatibility complex class II alleles and susceptibility to rheumatoid
      arthritis and its severity in Caucasians. African Americans, an admixed
      population in the United States, has been underrepresented in genetic studies of
      the susceptibility and severity of rheumatoid arthritis. With the advent of
      biologic agents, which target specific molecules of the immune system (e.g.,
      tumor necrosis factor, interleukin-1), biologic markers of treatment response in
      Caucasians and in African Americans would be clinically useful.

PMID- 12403343
TI  - B cell-restricted human mb-1 gene: expression, function, and lineage infidelity.
AB  - The antigen receptor on B cells (B cell receptor [BCR]) consists of two
      noncovalently associated modules. Immunoglobulin genes created somatically during
      B cell development encode the antigen-specific component of the receptor. The
      Igalpha/beta heterodimer, encoded by the mb-1 and B29 genes, is necessary to
      escort the receptor complex to the plasma membrane. Following antigen engagement
      of the BCR, Igalpha/beta nucleates signal transduction and promotes endocytosis
      of bound antigen for intracellular degradation and presentation to helper T
      cells. In this review, we outline the discovery of the mb-1 gene; summarize
      results from other laboratories on the function of Igalpha/beta in B cells; and
      conclude with our recent studies, which indicate that mb-1 is not a B-lineage
      restricted gene as originally proposed.

PMID- 12403344
TI  - Role of CD19 signal transduction in B cell biology.
AB  - Knockout studies have established an important role for the B lymphocyte surface
      protein CD19 in physiology. Previous studies by us and others have examined how
      CD19 might function at the biochemical level, with focus on the cytoplasmic
      tyrosines. We have mapped multiple different molecular associations with these
      tyrosines. However, the major question in CD19 signaling is, how do these
      tyrosines relate to what happens in vivo? To address this issue, we created mice
      expressing only mutant forms of CD19. Our initial studies have found that most
      CD19 function in vivo is dependent on two of these cytoplasmic tyrosines, Y482
      and Y513. However, the signaling defects in cells expressing this mutation are
      subtle. They demonstrate that how CD19 signals depends on how it is ligated, and
      that CD19 signals by more than one mechanism. These observations in primary cells
      give insights into how CD19 functions at the molecular level and likely explain
      some of the differences in CD19 function that have been reported in vivo.

PMID- 12403345
TI  - Cell cooperation in development of eosinophil-predominant inflammation in
      airways.
AB  - A large body of research supports a pathogenic role of Th2 cells in allergic
      diseases such as asthma. These disorders are characterized by recruitment to
      selected peripheral tissues of a mixed leukocyte inflammatory infiltrate
      including a predominant eosinophil component. The development of this
      inflammatory response is dependenton accumulation of Th2 cells in the affected
      tissues. Our studies aim to define the mechanisms that control the development of
      this tissue inflammatory response, focusing particularly on the mechanisms that
      recruit Th2 cells to the lung and airway. We have found that Th2 cells are on
      their own poorly competent for antigen-induced recruitment to the lung. By
      contrast, Th1 cells are avidly recruited to the lungs in response to airway
      antigen challenge. More important, recruitment of Th1 cells to the lung resulted
      in enhanced recruitment of Th2 cells to this tissue. The increased Th1 cell
      induced recruitment of Th2 cells was associated with upregulation of endothelial
      vascular cell adhesion molecule-1 (VCAM-1) expression in airway-associated
      endothelial cells and could be largely blocked by systemic treatment with a
      monoclonal anti-VCAM-1 antibody. Systemic blocking of tumor necrosis factor (TNF)
      also blunted the airway inflammatory response. The prominent roles of TNF and
      VCAM-1 in recruitment of Th2 cells suggested that an inflammatory
      microenvironment was essential for the recruitment of Th2 cells. In fact,
      recruitment of Th2 cells to the airway could be induced in an antigen-independent
      fashion by proinflammatory stimuli such as intranasal instillation of endotoxin.
      This antigen nonspecificity of the Th2 cell recruitment suggested a model in
      which Th2 cell recruitment is in response to general inflammatory signals rather
      than to antigen itself. This model provides an explanation for the clinical
      observation that bacterial or viral respiratory tract infections are associated
      with disease exacerbations in allergic asthmatics. More generally, these data
      imply that Th2 cells, like other leukocytes, are recruited efficiently to sites
      of tissue inflammation, and that these nonspecifically recruited Th2 cells have
      substantial potential to modulate local inflammatory processes.

PMID- 12403346
TI  - Gender dimorphism in immune responses following trauma and hemorrhage.
AB  - Previous studies have shown marked immunosuppression in males after trauma and
      hemorrhage. By contrast, immunosuppression was not evident in proestrous female
      animals. Further support for these findings came from studies demonstrating the
      immunosuppressive effects of male sex hormones and immunoenhancing effects of
      female sex hormones. In this regard, administration of 17beta-estradiol or
      prolactin to male animals after trauma and hemorrhage significantly improved
      immune function. Furthermore, castration or androgen receptor blockade with
      flutamide after trauma and hemorrhage in male mice showed similar beneficial
      effects. Thus, regulation of sex hormone synthesis or their receptor activity
      appears to be a useful therapeutic approach for patients to cope with the
      deleterious sequelae of severe trauma and hemorrhage.

PMID- 12403347
TI  - Inhibition of T cell responses by transferrin-coupled competitor peptides.
AB  - Activation of helperT cell has been implicated in a number of autoimmune diseases
      including rheumatoid arthritis. The underlying mechanism that initiates and
      promotes disease progression remains unclear, but it is apparent that helper T
      cells and autoantigens play prominent roles. Identification of the autoantigens
      has proven to be extremely difficult, and therefore strategies for promoting
      tolerance induction remain limited. Since autoimmune diseases are closely
      associated with specific major histocompatibility complex class II molecules such
      as HLA-DR4, the use of competitor peptides is an alternative strategy. A
      limitation of competitor peptides, however, is that they are ineffective in vivo.
      In the studies presented here, we demonstrate that coupling competitor peptides
      to a cell-surface receptor ligand, transferrin, enhances their ability to block
      helper T cell responses using the DO11.10 transgenic mouse as our model system.

PMID- 12403348
TI  - Understanding immune-microbial homeostasis in intestine.
AB  - The mechanisms concerning how the immune system is able to deal with the massive
      antigen challenge represented by the commensal bacterial flora have been a
      mystery. Recently a number of animal models with impairment of these mechanisms
      have been identified. One of these is the C3H/HeJBir mouse, which, under certain
      environmental conditions, can spontaneously develop colitis, which later remits.
      These mice show increased B cell and T cell reactivity to antigens of the enteric
      bacterial flora. CD4+ T cells from this strain cause colitis, when activated by
      enteric bacterial antigens and transferred to histocompatible severe combined
      immunodeficiency recipients. This colitis is mediated by CD4+ Th1 cells and
      requires a sustained mucosal production of interleukin-12, which, in turn, is
      dependent on CD40L-CD40 interactions in the gut. Regulatory T cells that appear
      to limit the colitis have been identified and have the properties of the T
      regulatory-1 subset. Functional Tr1 activity for bacterial antigens is present in
      the lamina propria CD4+ T cells. These Tr1 cells may exert their effects by
      inhibition of dendritic cell function in the mucosa, rather than by direct
      effects on Th 1 cells. Manyquestions remain to be answered, including, How do the
      enteric bacterial-host interactions shape the immune system for abnormal
      responses such as inflammatory bowel disease, autoimmunity, and allergy?

PMID- 12403349
TI  - Macrophage signaling and respiratory burst.
AB  - Macrophages are key defenders of the lung and play an essential role in mediating
      the inflammatory response. Critical to this is the activation of the NADPH
      oxidase. Through receptor-mediated interactions, extracellular stimuli activate
      pathways that signal for the phosphorylation and assembly of the NADPH oxidase.
      Once the NADPH oxidase is activated, it produces superoxide and H2O2 in a process
      known as the respiratory burst. The involvement of O2.- and H2O2 in the
      antimicrobicidal function of macrophages has been assumed for many years, but it
      is now clear that the H2O2 produced by the respiratory burst functions as a
      second messenger and activates major signaling pathways in the alveolar
      macrophage. Both the nuclear factor-kappaB and activator protein-1 transcription
      factors are activated by H2O2 produced by the respiratory burst, and, since these
      control the inducible expression of genes whose products are part of the
      inflammatory response, this may be a critical link between the respiratory burst
      and other inflammatory responses. The c-Jun N-terminal kinase (JNK) and
      extracellular-regulated kinase (ERK) pathways, two members of the mitogen
      activated protein kinase family, are also activated by the respiratory burst. JNK
      is activated by both exogenous and endogenously produced H2O2. Studies with ERK
      have shown that specific agonists of the respiratory burst, but not bolus H2O2,
      can activate this pathway. The ERK pathway also modulates the expression of genes
      via phosphorylation of the transcription factor Elk-1 that controls the
      production of the c-Fos transcription factor. Although an understanding of the
      mechanism of redox signaling is in its infancy, it is becoming clear that the
      reactive oxygen species produced by the respiratory burst have a profound effect
      on intracellular signaling pathways and ultimately in modulating gene expression.

PMID- 12403350
TI  - Oxidases and oxygenases in regulation of vascular nitric oxide signaling and
      inflammatory responses.
AB  - Nitric oxide (.NO) is a freely diffusible inter- and intracellular messenger
      produced by a variety of mammalian cells including vascular endothelium, neurons,
      smooth muscle cells, macrophages, neutrophils, platelets, and pulmonary
      epithelium. In smooth muscle cells, platelets, and neutrophils, .NO raises
      intracellular cyclic guanasine 5'-monophosphate levels by reacting with the
      catalytic heme domain of guanylate cylase, to activate it, thus leading to
      vasorelaxation, inhibition of platelet aggregation and inhibition of platelet and
      inflammatory cell adhesion to endothelium. The physiologic actions of .NO are
      highly dependent on changes in steady-state concentrations of reactive species
      and tissue-oxidant defense mechanisms. Vessel wall oxidases and oxygenases, in
      particular, are critical sources of oxygen radical production and can lead to an
      overall impairment of vascular .NO signaling, via the metalloprotein and free
      radical-mediated consumption of this vasoactive molecule. Vascular oxidase and
      oxygenase activities can thus account for the functional inactivation of .NO,
      leading to a prooxidative milieu and chronic inflammation.

PMID- 12403351
TI  - Molecular and cellular mechanisms of donor cell-induced tolerance.
AB  - The induction of immunologic tolerance to solid organ allografts is a subject of
      intense investigation because of the morbidity and mortality associated with
      standard immunosuppressive therapy. One method that is currently in clinical and
      preclinical testing involves the transient ablation of recipient T cells using
      polyclonal antithymocyte sera or monoclonal anti-CD4/CD8 antibody treatment,
      followed by the posttransplant administration of donor bone marrow cells or of
      donor peripheral lymphoid populations. Recent studies in our laboratory have
      shown that the molecular and cellular basis of the prolongation of graft survival
      by donor cell administration depends on the cellular compartment from which the
      donor cells were derived. We provide here a brief review of these data followed
      by new data suggesting that the mode of peripheral and central selection is also
      dependent on the source from which the donor cells were derived.

PMID- 12403352
TI  - Gene delivery into primary T cells: overview and characterization of a transgenic
      model for efficient adenoviral transduction.
AB  - Technologies for transfer of exogenous genes into primary T cells have been
      limited until recently. The introduction of new approaches for gene transfer via
      different viral vectors has expanded the options for genetic manipulation of
      primary T cells and has provided powerful tools for studies of T cell activation
      and differentiation. We provide a brief overview of the systems currently
      available and contrast the advantages and disadvantages of each. We also describe
      a new transgenic model that enables highly efficient gene delivery into primary T
      cells by nonreplicating adenoviral vectors.

PMID- 12403353
TI  - STEALTH in transplantation tolerance.
AB  - Although contemporary immunosuppressive regimens are responsible for major
      improvements in allograft acceptance, there are indications that long-term
      survival may be compromised through drug toxicity and/or chronic immune
      deficiency. The ultimate goal for transplantation is tolerance, defined as
      durable, donor-specific allograft acceptance in the absence of long-term
      immunosuppression. This article reviews the nonhuman primate STEALTH model of
      tolerance recently developed by the transplant immunobiology group at University
      of Alabama at Birmingham. The STEALTH model was designed for future application
      to human transplantation and comprises a concise peritransplant treatment
      strategy of only 2 wk. Tolerance is induced by depletion of T cells, with
      concomitant inhibition of nuclear factor-kappaB/RelB-dependent proinflammatory
      signaling. This treatment has resulted in an unprecedented frequency of kidney
      allograft survival (62.5% at 3 yr), with some primate recipients remaining in
      good health more than 6 yr posttransplant, in the complete absence of chronic
      pharmacologic immunosuppression.

PMID- 12403354
TI  - Evaluating function of transmembrane protein tyrosine phosphatase CD148 in
      lymphocyte biology.
AB  - The transmembrane protein tyrosine phosphatase CD148 is expressed on numerous
      cell types, including most cells of the hematopoietic lineage. CD148 has been
      shown to regulate density-dependent inhibition of cell growth as well as cellular
      differentiation in nonhematopoietic cells and has been shown to regulate signal
      transduction processes in several nonlymphoid hematopoietic cell types. Analysis
      of CD148 expression on lymphoid cells has demonstrated that CD148 is expressed at
      low levels on T cells and that it is upregulated in response to activation.
      Several groups have observed that CD148 negatively regulates T cell activation in
      response to crosslinking of the T cell antigen receptor, suggesting that it may
      play a role in feedback inhibition of the T cell immune response. In the B cell
      compartment, CD 148 expression appears to be restricted to the memory
      subpopulation, raising the possibility that it serves a unique function in these
      cells, which has yet to be determined. Recent studies have shown that CD148
      interacts with the PDZ domain-containing protein syntenin, raising the
      possibility that its function or its localization with substrates in T and B
      cells may be controlled through this or a related interaction with another PDZ
      domain protein.

PMID- 12403355
TI  - C-C chemokine receptor 2 and C-C chemokine receptor 5 genotypes in patients
      treated for chronic hepatitis C virus infection.
AB  - We explored the influence of the major CCR5 promoter or coding region variants as
      haplotypes and genotypes in a cohort of 250 chronically infected HCV patients
      receiving combined interferon/ ribavirin therapy. No haplotype, including the D32
      bearing haplotype (G*2) reportedly associated in homozygotes with high HCV viral
      load (VL), showed a similar effect. Patients with genotype C/G*2 showed slightly
      lower median VL (p = 0.05). Neither the G*2 haplotype nor the C/G*2 genotype
      influenced viral dynamics during the initial 12 wk of treatment (p = 0.53). The
      genotype E/E was more frequent among sustained responders (15.5%) than non
      responders (7.8%), and VL declined further among E/E homozygotes during the
      initial 12 wk of treatment, particularly those with HCV genotype 1 (p = 0.016).
      Differential receptor expression due to E/E homozygosity in HCV infection remains
      to be confirmed.

PMID- 12403357
TI  - Mast cell regulation via paired immunoglobulin-like receptor PIR-B.
AB  - Activating (PIR-A) and inhibitory (PIR-B) isoforms of the paired immunoglobulin
      (Ig)-like receptor family have been evaluated for their modulating potential in
      mast cell responses to IgE antibody and mast/stem cell growth factor (SCF). Mast
      cells produce PIR-A and PIR-B, but PIR-B was found to be predominantly expressed
      on the cell surface, where it was constitutively tyrosine phosphorylated and
      associated with SHP-1 tyrosine phosphatase. Efficient coligation of PIR-B with
      FcepsilonRI inhibited IgE-induced mast cell activation and serotonin release. PIR
      B and c-kit (or mast/SCF receptor) coligation also inhibited SCF-induced mast
      cell responses. The PIR-B inhibitory activity was unimpaired in SHP-1-deficient
      mast cells, perhaps because of non-SHP-1-binding tyrosine-based inhibitory motif
      in the cytoplasmic tail of PIR-B. This analysis suggests that PIR-B may serve to
      control mast cell activity.

PMID- 12403356
TI  - Diversity and duplicity: human FCgamma receptors in host defense and
      autoimmunity.

PMID- 12403358
TI  - Rearrangement of integrins in avidity regulation by leukocytes.
AB  - Leukocyte adhesion must be tightly controlled in order for leukocytes to patrol
      the body as nonadherent cells, yet stop and emigrate from the blood into tissues
      at sites of infection or inflammation. A key element in this process is
      activation of beta2 integrins. While beta2 integrin activation involves
      conformational changes that increase affinity for ligand, evidence is
      accumulating that rearrangement of integrins, resulting in increases in avidity,
      is at least as important in regulating binding capacity. Recent work has
      established the importance of diffusion and rearrangement of integrins to
      activation of leukocyte adhesion, and has begun to unravel the molecular basis of
      its regulation.

PMID- 12403359
TI  - Human gammadelta-T cells in adoptive immunotherapy of malignant and infectious
      diseases.
AB  - Human gammadelta-T cells are capable of mediating both innate antitumor and
      antiviral activity, functions that theoretically might be exploitable in the
      treatment of a variety of malignant or infectious diseases. Nonetheless,
      experimental therapies incorporating the adoptive transter of human gammadelta-T
      cells have remained unfeasible to date owing largely to the difficulty of
      isolating or expanding sufficient numbers of gammadelta-T cells. It is in this
      context that recent discoveries from our laboratory are presented. By identifying
      specific signaling pathways that selectively inhibit activation-induced apoptosis
      in apoptosis-prone gammadelta-T cells, we have been able to expand large numbers
      of viable and functional human gammadelta-T cells, an undertaking until now
      notpossible. As important, these apoptosis-resistant gammadelta-Tcells appear to
      retain major histocompatibility complex-unrestricted (innate) antitumor activity
      against a wide variety of human tumor cells both in vitro and in vivo. Moreover,
      apoptosis-resistant gammadelta-T cells also display potent innate antiviral
      activity in vitro against human immunodeficiency virus-1. Both the biologic and
      practical implications of these findings are considered and discussed
      particularly as they relate to the development of future adoptive immunotherapy
      strategies.

PMID- 12403360
TI  - Microbial/host interactions: mechanisms involved in host responses to microbial
      antigens.
AB  - The indigenous oral microflora and the host are normally in a state of
      equilibrium; however, the introduction of a pathogen can result in innate and
      adaptive immune responses that either contribute to the development of the
      disease or lead to host immunity. The interactions between the microorganisms and
      the host are very dynamic, thus allowing the complex interplay between host
      molecules and bacterial antigens. In this article, we focus on the mechanisms
      involved in the pathogenesis of and host responses to two oral pathogens: the
      Gram-negative bacterium Porphyromonas gingivalis, implicated in the etiology of
      periodontal disease, and the Gram-positive Streptococcus mutans, a primary agent
      involved in dental caries formation. Furthermore, we address mechanisms involved
      in the ability of select adjuvants and delivery systems to potentiate mucosal and
      systemic immune responses to microbial vaccine antigens.

PMID- 12403361
TI  - Specific deletion of autoreactive T cells by adenovirus-transfected, Fas ligand
      producing antigen-presenting cells.
AB  - Immune privilege is a unique strategy developed in several internal organs that
      can prevent the development of immune attack against these vital organs. One
      critical mechanism of immune privilege is utilization of Fas/FasL-mediated
      apoptosis to delete the invading T cells at the immune privilege sites. In this
      article, we describe the development and application of a unique cell-gene
      therapy to correct defective FasL-mediated apoptosis and autoimmune disease in
      autoimmune mice. This cell-gene therapy strategy using antigen-presenting cells
      (APCs) to express FasL is not only a therapeutic tool, but also has allowed us to
      understand the complexity of T cell regulation and the concept of eliminating T
      cells in the spleen, lymph node, or elsewhere in vivo to regulate the homeostasis
      of the peripheral T cell response. In this regard, the FasL-expressing APCs can
      be considered as circulating and regulatable immune privilege sites. Our studies
      provide substantial evidence that FasL-expressing APCs can be introduced
      exogenously without liver toxicity to eliminate infiltrating T cells and prevent
      the development of immune attack in lung, liver, kidney, joint, and salivary
      gland. Therefore, given the hazardous potential of persistent T cell invasion at
      the local inflammatory site, it is tempting to speculate that such an endogenous
      control mechanism occurs normally in vivo to limit a chronic T cell inflammatory
      response.

PMID- 12403362
TI  - Adenoassociated virus vectors for genetic immunization.
AB  - Genetic immunization has initiated a new era of vaccine research, which provides
      a stable and long-lived source of the protein antigen. Such a vaccine is a
      simple, robust, and effective means of eliciting both antibody- and cell-mediated
      immune responses compared with protein or peptide vaccines. Although naked DNA
      vaccines are relatively simple to produce and handle without significant toxicity
      or host immunity, those using viral vectors have shown greater efficacy in gene
      transfer and in inducing both protective and therapeutic immunity in preclinical
      models. However, clinical translation of results obtained in animal studies with
      viral vectors has not met with anticipated success so far because of inherent
      limitations of the vector-associated immunity and antigen specificity. Thus,
      understanding the requirements for the elicitation of target-specific immunity in
      host requires that a major cellular arm be unraveled, and modifications of the
      existing viral vectors and testing of newer ones encompass the technological arm
      of vaccine research. In this article, I give a comprehensive account of the
      potential of adenoassociated virus, a nonpathogenic human parvovirus in vaccine
      development.

PMID- 12403363
TI  - CD5, an important regulator of lymphocyte selection and immune tolerance.
AB  - The CD5 coreceptor is a cysteine-rich scavenger receptor family glycoprotein that
      is expressed constitutively on all T cells and a subset of B cells (B I a B
      cells). It is now generally accepted that the biologic role of CD5 is to regulate
      intracellular strength induced by antigen receptors in both T and B cells.
      However, at present it is unclear if this coreceptor's effect on antigen receptor
      signaling is primarily costimulatory or inhibitory since support for both exists.
      Our studies focus on understanding the physiologic role of CD5 in the context of
      regulation of antigen receptor activation, B and T cell selection, and
      generation/maintenance of immune tolerance. In this overview, I discuss studies
      using experimental models of lymphocyte selection and tolerance showing that CD5
      plays a key role in B and T cell selection as well as generation and maintenance
      of tolerance. I and others, reviewed here, now provide clear evidence that CD5 is
      a key regulator of immune tolerance and that alterations of its activity can
      promote development of autoreactivity.

PMID- 12403364
TI  - Regulation and chance in the ontogeny of B and T cell antigen receptor
      repertoires.
AB  - The adaptive immune system has to economically generate a large array of T and B
      cell antigen receptors (T cell receptors [TCRs], B cell receptors [BCRs]) that
      eliminate both longstanding and novel antigens from the host while preventing the
      production of deleterious (e.g., autoreactive) antigen receptors. Our studies
      focus on the mechanisms that shape the development of these antigen receptor
      repertoires during human ontogeny. The key to BCR and TCR diversity is the third
      complementarity determining region (CDR3) of the variable domain, which in the
      immunoglobulin heavy chain and TCR beta chain, is created by the junction between
      the variable, diversity, and joining gene segments. The CDR3 diversity is
      constrained by overrepresentation of gene segments and lack of N regions during
      the first trimester of gestation and then increases exponentially during ontogeny
      until it reaches adult levels months after birth. This process parallels, and may
      contribute to, the stepwise acquisition of the ability to respond to specific
      antigens. Recent studies indicate that maturation of the CDR3 repertoire is not
      accelerated by premature exposition to extrauterine antigen and thus appears to
      follow a strictly developmentally regulated program whose pacemaker(s) is still
      unknown.

PMID- 12403365
TI  - Varied biologic functions of C-reactive protein: lessons learned from transgenic
      mice.
AB  - Our investigations of human C-reactive protein (CRP) and CRP transgenic mice have
      produced novel data that firmly establish this protein as an important host
      defense molecule. For example, we have learned that depending on the disease
      model, the beneficial effect of CRP can be direct, depend on the protein's
      ability to engage complement and Fcy receptors, or rely on its ability to bridge
      innate and adaptive immunity. In addition, the degree of protection correlates
      with acute phase expression, but more important, also with the amount of CRP
      expressed constitutively. Furthermore, differences in baseline levels of CRP
      among healthy individuals and among patients can be attributed to a CRP gene
      polymorphism. In this article, we discuss these and other observations we have
      made during the last 5 yr and summarize our ongoing studies and future plans
      related to CRP biology.

PMID- 12403366
TI  - Islet transplantation in the twenty-first century.
AB  - Isolated islet transplantation is poised for clinical application to treat
      insulin-dependent diabetes. Unlike exogenous insulin therapy, islet
      transplantation has promise for preventing and/or reversing the dismal secondary
      complications of diabetes. Islet transplants are arguably the most unique type of
      allografts, and we discuss their properties, limitations, and potential in this
      overview. The induction of immunologic tolerance to allow islet grafts to endure
      and prevail, without the hardship of chronic immunosuppressive therapy, is a
      major goal in this field. In this context, we discuss our successful results in
      preclinical models of primate allogeneic and xenogeneic islet graft tolerance.

PMID- 12403367
TI  - Converting nonhuman primate dendritic cells into potent antigen-specific cellular
      immunosuppressants by genetic modification.
AB  - T cell depletion plus donor bone marrow cell (BMC) infusion induces long-term
      kidney allograft survival in a limited number of rhesus macaque recipients.
      Therefore, there is a need to enhance the tolerogenic activity of donor BMCs. The
      tolerogenic effect of donor BMCs is ascribed to a veto activity, mediated by a
      CD8+ subset that upregulates immunoregulatory effector molecules, transforming
      growth factor-beta1 (TGF-beta), and FasL, after interaction with donor-reactive
      cytotoxic T lymphocyte precursors (CTLp), leading to clonal inactivation/deletion
      of donor-reactive CTLp. Of note, the receptors for TGF-beta1- and FasL-induced
      signal transduction are upregulated in activated T cells. Since mature dendritic
      cells (DCs) are exceptionally efficient activators of T cells, we postulated that
      mature DCs modified to overexpress TGF-beta1 and FasL might exert potent veto
      (i.e., inactivating/deleting) activity independent of CD8 expression. A fusion
      protein comprising antihuman CD40 single-chain antibody and soluble coxsackie
      adenovirus receptor enabled high-efficiency transduction of rhesus monocyte
      derived DCs (Rh MDDCs) by recombinant adenovirus (Ad). Mature Rh MDDCs transduced
      with Ad encoding active TGF-beta1 retained a mature phenotype yet exhibited
      potent alloantigen-specific cellular immunosuppression. Such modified MDDCs have
      the potential to promote tolerance induction to allografts in vivo.

PMID- 12403368
TI  - Structure of interleukin-10/interleukin-10R1 complex: a paradigm for class 2
      cytokine activation.
AB  - The class II alpha-helical cytokine family consists of eleven members including
      the interferons, interleukin-10 (IL-10) and several newly discovered IL-10
      homologs. The molecules display a vast array of biologic activities including the
      ability to induce an antiviral state, modulate inflammatory responses, and
      inhibit cell growth. Biologic activity is dependent on cytokine-dependent
      aggregation of two different cell-surface receptors. The detailed protein-protein
      interactions that initiate these biologic responses are amenable to study using X
      ray crystallographic methods. In this article, I summarize my laboratory's
      contributions to understanding these recognition processes using IL-10 as the
      prototypic class II cytokine.

PMID- 12403369
TI  - T cell responses to viral infections: lessons from lymphocytic choriomeningitis
      virus.
AB  - The elaboration of a successful immune response is critical for the clearance of
      viral infections. CD8 T cells can directly kill virus-infected cells and also
      produce cytokines that modulate virus replication. Thus, the failure to induce or
      sustain these responses can profoundly impact the outcome of infections.
      Lymphocytic choriomeningitis virus (LCMV) infection of mice has proven to be one
      of the most informative experimental systems for examining antiviral T cell
      responses. In recent years, the application of newly developed approaches to
      analyze these responses has revealed that acute infections induce remarkably high
      levels of antiviral T cells. By contrast, protracted or chronic infections are
      associated with both the functional impairment and deletion of virus-specific CD8
      T cells. This article discusses some of our findings using LCMV infection of mice
      as well as their relevance to other infections of animals and humans.

PMID- 12403371
TI  - Ambulatory blood pressure monitoring in children and adolescents.
AB  - With recent technological advances, 24-hour ambulatory blood pressure (BP)
      monitoring (ABPM) has become a useful tool for the evaluation, diagnosis, and
      management of hypertensive children. It provides a more accurate representation
      of an individual's BP rather than intermittent casual or office BP measurements.
      Hence, ABPM is being used more often to assess the BP of children. In this
      comprehensive review, we provide the reader with the available literature on
      ABPM, discuss the advantages and limitations of ABPM, and the interpretation of
      ABPM data. The role of ABPM in various clinical conditions and hypertension
      research in children is presented.

PMID- 12403372
TI  - Differentiating between seizures and attention deficit hyperactivity disorder
      (ADHD) in a pediatric population.

PMID- 12403370
TI  - Immunobiology of tumor necrosis factor receptor superfamily.
AB  - The proteins of the tumor necrosis factor (TNF) receptor superfamily are a group
      of cell-surface receptors critically involved in the maintenance of homeostasis
      of the immune system. By interacting with their corresponding ligands, these
      receptors either induce cell death or promote cell survival of immune cells. The
      number of recognized members of the TNF receptor and ligand superfamily has
      expanded substantially in the last several years. More important, the biologic
      function of this group of proteins has been closely associated with the
      regulation of the immune response and the pathogenesis of autoimmune disease.
      Thus, the direct targeting of these receptors by either inducing apoptosis or
      blocking survival of autoimmune T and B cells may be an important therapeutic
      strategy in the treatment of autoimmune disease. This review summarizes the
      recent progress in immunobiology of the TNF receptor superfamily and focuses on
      our studies of three critical family members-FasL/Fas, TNF-related apoptosis
      inducing ligand (TRAIL)/TRAIL-Rs, and B lymphocyte stimulator(BLyS)/BLyS-Rs--to
      demonstrate the therapeutic potential of targeting these receptors for the
      treatment of autoimmune disease.

PMID- 12403373
TI  - Determinants of infant sleep position in an urban population.
AB  - The incidence of SIDS has decreased by 40% since the Back to Sleep campaign was
      initiated. However, the rate of SIDS in the District of Columbia continues to be
      approximately double the national rate. The purpose of this study was to
      determine the prevalence and determinants of prone sleeping among infants in the
      District of Columbia and to ascertain what information is being provided to
      parents by health care professionals by a cross-sectional survey of parents of
      infants 0-6 months of age presenting for well child care at Children's Health
      Center, Children's National Medical Center, in Washington, DC. We recruited a
      consecutive sample of 126 parent-infant pairs, of which 92.9% were African
      American. The average infant was 73 days old, was 3,003 grams at birth, and was
      full term. When asked how the infants were placed for sleep the night before the
      interview, 34.1 % of parents had placed the infant supine, 50.8% side, and 15.1%
      prone. Nearly half (48%) of infants slept in an adult bed with the mother. More
      than one third of the infants had been placed prone for sleep at least once since
      hospital discharge. Most common reasons for sleeping supine included SIDS risk
      reduction or health care professional advice. Side sleepers did so primarily
      because of concern about vomiting, health care provider advice, or SIDS. Infants
      were placed prone primarily because the infant slept better. When asked about
      information received from a health care provider, 70.6% of parents stated that
      they had received information about sleep position and 64.3% about the hazards of
      passive smoking. Eight parents observed nursery personnel placing their infants
      prone. Only 16.7% of the total study population had received a Back to Sleep
      brochure, read it, and recalled that it recommended back sleeping. Infants were
      more likely to sleep prone if there was a grandparent in the home (OR 2.9,
      p<0.05) or if they were the firstborn (OR 2.17, p<0.05). Infants were more likely
      to sleep supine if parents had heard a back recommendation from a health care
      professional (OR 5.7, p<0.001). Infants were least likely to sleep supine if the
      parents had heard a side or a side/back recommendation (OR 0.26, p=0.001). Infant
      sleep position was not ter, reading the Back to Sleep brochure. In conclusion,
      more than one third (35.7%) of infants in this predominantly African-American
      population have been placed prone for sleep at least once; 15% slept prone the
      night before the interview. Almost one third of parents received no information
      about sleep position, but parents receiving a verbal supine recommendation were
      most likely to place their infant supine. Receiving written information did not
      affect sleep position. Improved educational efforts for parents of African
      American newborns should continue to focus on encouraging supine positioning,
      smoke cessation, and other safe sleep practices.

PMID- 12403374
TI  - Physician weight counseling for adolescents.
AB  - Adolescent obesity prevalence is increasing, with minimal study of physician
      weight counseling with youth. This study examines adolescents' (n=110)
      perceptions of physicians' weight counseling. Overweight adolescents (> or =85th
      percentile for body mass index, BMI) report receiving counseling more than
      nonoverweight adolescents. Physicians more often have counseled obese (> or =95th
      BMI percentile) than overweight but not obese adolescents (85th-94th BMI
      percentile). Prior counseling and adolescents' ethnicity were related to greater
      perceived physician concern and adolescent receptivity to future counseling.
      Overweight adolescents report attempting weight loss strategies at rates similar
      to recommendations, but recommendations for specific weight control behaviors do
      not increase the likelihood of adolescent attempts. Clin Pediatr. 2002;41:575-585

PMID- 12403375
TI  - Intensive care management of the term neonate: are there regional differences in
      outcome?
AB  - The objective of this study was to evaluate the patterns of hospitalization of
      term infants in 3 major metropolitan areas. We hypothesized that regional
      practice variation occurred in the care of term infants and that these
      differences would be reflected in the hospitalization patterns of infants. All
      infants cared for in an Intensive Care Nursery (ICN) after maternal discharge in
      1 of 3 major metropolitan areas followed up by the same neonatal management
      company were compared (n=4,487). Term infants were grouped into 1 of 2 categories
      based on illness severity: Group 1 (G1) infants-those who required supplemental
      oxygen or ventilation for 24 hours or more (n=611); and Group 2 (G2) infants
      those infants without an oxygen or ventilation requirement (n=1,549). Excluded
      were infants in the following categories: birth weight <2,500 grams, major
      congenital anomalies, surgical patients, extracorporeal membrane oxygenation
      (ECMO) support, or babies who died before discharge. The number of infants in
      each of these categories was compared as a percentage of the total number of
      infants cared for in that region. The average length of stay (ALOS) and
      percentage of patient days attributed to infants in each category were compared
      across regions using multiple comparison tests (Tukey). The total ALOS was
      greatest in City A, as was the ALOS for sick term infants. Patient days for sick
      term infants were lowest in City C, and healthier term infants comprised the
      lowest percentage of patient days in City A. This difference resulted in the
      lowest percentage of patient days for all term admissions in City A. These data
      demonstrated that significant variation existed in the delivery of care to term
      neonates among major metropolitan regions. Cities that admitted fewer term
      infants for observation periods (G2) tended to have sicker term neonates with
      higher acuity hospitalizations (GI) and longer lengths of stay (LOS). These
      findings suggested that a conservative admission policy for this population can
      decrease overall LOS.

PMID- 12403376
TI  - Parental involvement in pediatric cardiology outpatient visits.
AB  - There is a lack of information regarding parental involvement in subspecialty
      care of their offspring. We evaluated trends in 3,118 parental visits,
      accompanied by their children to a pediatric cardiology office during a 5-year
      period. Offspring accompanied both parents 29%, mothers alone 64%, and fathers
      alone 5% of the total visits. The rates were similar for first-time visits and
      this trend was similar across all 5 years. Children were significantly younger
      when accompanied by both parents than by individual parents. Mothers play a major
      role in a child's subspecialty care. Our findings have important educational,
      social, research, and marketing implications.

PMID- 12403377
TI  - Comparison of high-dose and low-dose aspirin plus intravenous immunoglobulin in
      the treatment of Kawasaki syndrome.
AB  - The efficacy of intravenous immunoglobulin (IVIG) in the treatment of Kawasaki
      syndrome (KS) has been unequivocally established, but questions remain concerning
      the proper dose of adjunctive aspirin therapy in the treatment of KS. The medical
      records of 72 children with KS were reviewed. All patients were treated with
      IVIG; 21 received 400 mg/kg/dose on 4 consecutive days and 51 received 2 g/kg as
      a single infusion. Seventy patients also received aspirin. Twenty-four of the 70
      patients were started on high-dose aspirin (80-100 mg/kg/day) at the time of
      diagnosis. High-dose aspirin was given for a mean (+/- SE) duration of 6.1+/-0.9
      days, then switched to low-dose aspirin (3-5 mg/kg/day). Forty-six of the 70
      patients were started on low-dose aspirin at the time of diagnosis and remained
      on low-dose aspirin for the duration of treatment. Coronary artery abnormalities
      were present at the time of diagnosis in 12 of 72 patients (17%), including 6 of
      6 of patients (100%) with atypical KS and 6 of 66 patients (9%) with typical KS.
      None of the remaining 60 patients developed coronary artery abnormalities after
      treatment with IVIG and aspirin. The mean duration of fever after initiation of
      therapy was 44+/-6 hours in patients treated with IVIG 400 mg/kg/dose on 4
      consecutive days and 35+/-5 hours in patients treated with 2 g/kg as a single
      infusion (p=0.3). The mean duration of fever after the initiation of therapy was
      47+/-8 hours in patients treated with high-dose aspirin compared to 34+/-5 hours
      in patients treated with low-dose aspirin (p=0.13). These preliminary results
      indicate there is no benefit to high-dose aspirin compared to low-dose aspirin in
      the treatment of children with KS.

PMID- 12403378
TI  - Prolonged bottle use and its association with iron deficiency anemia and
      overweight: a preliminary study.
AB  - To determine the prevalence of prolonged bottle feeding practices in young
      children, and its association with body mass index (BMI) and iron deficiency
      anemia (IDA), we conducted a cross-sectional survey study at 3 Bronx, NY, WIC
      sites. Caregivers of 95 predominantly Hispanic and African-American WIC-enrolled
      children aged 18-56 months presenting for recertification completed
      questionnaires. Half were overweight (>85th% BMI) and 36% were obese (>95th%
      BMI); 21% met CDC criteria for anemia. Two thirds (63%) received daily bottles of
      milk or sweet liquids. Daily bottle use ranged from 3 to 10 (mean=3.3, median=3).
      Bottle use was significantly associated with obesity (>95th% BMI, p<0.0005), not
      significant with overweight (>85th% BMI, p<0.06) and statistically significant
      with IDA.

PMID- 12403379
TI  - Infancy onset of symptoms of narcolepsy in a child.

PMID- 12403380
TI  - Synthetic factor VIIa concentrate to treat coagulopathy and gastrointestinal
      bleeding in an infant with end-stage liver disease.

PMID- 12403381
TI  - False aneurysm of the modified Blalock-Taussig shunt mimicking pulmonary disease
      in an infant.

PMID- 12403382
TI  - Neonatal endocarditis: a unique encounter.

PMID- 12403383
TI  - An infant with meningitis and unexplained coagulopathy.

PMID- 12403385
TI  - Efficacy of eye patching for traumatic corneal abrasions: a controlled clinical
      trial.

PMID- 12403384
TI  - Emergency department evaluation of acute stress disorder symptoms in violently
      injured youths.

PMID- 12403386
TI  - Hospital preparedness for weapons of mass destruction incidents: an initial
      assessment.

PMID- 12403387
TI  - MRI in the assessment of pregnancy related intrauterine bleeding: a valuable
      adjunct to ultrasound?
AB  - MR imaging using ultrafast MR sequences is a useful method in assessing
      pregnancies at risk. This is especially the case for fetal imaging. However,
      reports of imaging of the placenta or the uterus are rare. We report the MR
      findings in 8 pregnant patients with vaginal blood loss in whom the obstetrical
      ultrasound was equivocal. MR imaging was performed with a 1.5 T magnet and
      consisted of T2- (HASTE), fat-suppressed gradient echo T1- and gradient echo T2
      weighted images. Adequate anatomical visualisation of the uterus, the placentary
      tissue and the intrauterine bleeding irrespective of size and location of the
      latter, were obtained in all cases.

PMID- 12403388
TI  - Omphalocele: prenatal MR findings.
AB  - We present the MR-findings in two cases of omphalocele in two second trimester
      pregnancies. Fast MR sequences were performed on a 1.5 T magnet. Both patients
      underwent previous evaluation with sonography. The findings were confirmed with
      MR and additional information about the severity and location of the anomaly were
      demonstrated. The MR images provided adequate anatomical detail of the major
      abdominal viscera to evaluate the content and extent of the disease.

PMID- 12403389
TI  - Renal macronodular tuberculoma: CT and MR findings in an asymptomatic patient.
AB  - We present the case of a 50-year-old man with a solitary mass lesion in the right
      kidney. Characteristics on ultrasound were a thick irregular hypoechoic wall and
      a slightly hyperechoic center. Computed tomography depicted the lesion as
      spontaneously hyperdense at its base. After administration of intravenous
      iodinated contrast only partial enhancement in the peripheral wall was seen. On
      MR imaging the lesion was hypointense on T1-weighted images, and T2-weighted
      images demonstrated a thick irregular hypointense peripheral wall and an
      intralesional fluid debris level. Gadolinium-chelates were not administered.

PMID- 12403390
TI  - Extramedullary paraspinal hematopoiesis in hereditary spherocytosis.
AB  - Extramedullary hematopoiesis is a rare condition, characterized by the appearance
      of hematopoietic elements outside the bone marrow. It occurs primarily in
      patients with chronic myeloproliferative disorder or congenital hemolytic anemia.
      We report on a 60-year-old man with hereditary spherocytosis who presented with
      an extramedullary paraspinal hematopoietic mass, splenomegaly, and bone marrow
      expansion in the right distal femur and proximal tibia metaphysis. The diagnosis
      was established after biopsy of the paravertebral mass. The patient underwent a
      splenectomy.

PMID- 12403391
TI  - Inflammatory pseudotumor of the lung.
AB  - Inflammatory pseudotumor is the most frequent primary lung tumor in children
      under the age of 16. Clinical history and radiological diagnosis are often non
      specific, making diagnosis uneasy. In some instances, only surgery can provide a
      definite diagnosis. However, when dealing with a solitary mass of the lung in an
      infant the radiologists should always include inflammatory pseudotumor among the
      entities of the differential diagnosis. This case report discusses the
      radiological features of inflammatory pseudotumors.

PMID- 12403392
TI  - Trauma of the pediatric ankle and foot.
AB  - This article presents a brief overview of the injuries to the ankle and foot
      encountered in children and adolescents. Trauma to the ankle or foot may result
      from acute, chronic, or repetitive forces. The role of the different imaging
      modalities in the assessment of ankle and foot trauma in the growing patient is
      discussed. Plain radiographs remain the mainstay in the diagnosis of most acute
      traumas, whereas CT may be helpful to unravel the complex anatomy of certain
      fractures like the triplane or juvenile Tillaux fracture. In the evaluation of
      chronic injuries, including osteochondrosis dissecans and osteonecrosis, MRI is
      evolving as the modality of choice.

PMID- 12403393
TI  - MRI of painful bipartite patella.

PMID- 12403395
TI  - Honoring living legends.

PMID- 12403394
TI  - Thumbprinting due to ischemic colitis in a patient on oral anticoagulation.

PMID- 12403396
TI  - Modification of dialysis regimens for pregnancy.

PMID- 12403397
TI  - Adequacy of peritoneal dialysis after the ADEMEX study. Back to the basics.

PMID- 12403398
TI  - Is steam sterilization really making any difference in dialysis-induced cytokine
      release?
AB  - Ethylene oxide (ETO) is presently the most commonly used sterilization method for
      medical devices. Although alternative sterilization modes such as steam
      sterilization have been suggested, the effect of steam on dialysis-induced
      cytokine release is unknown. We enrolled 9 patients on chronic hemodialysis and
      evaluated at different intervals IL-1beta production while treated with ETO (NC
      1785-Bellco) and steam sterilized NC 1785S-Bellco) Synthetically Modified
      Cellulose (SMC). A basal test during treatment with NC 1785 was performed (A);
      the same test was set up 4 weeks after treatment with NC 1785S (B) and, lastly, 4
      weeks after returning to NC 1785 (C). Peripheral blood mononuclear cells (PBMC)
      were purified before and after the dialysis session, were isolated on a
      Ficoll/Hypaque gradient and incubated for 24 h. Spontaneous IL-1beta release was
      evaluated in the supernatant and in the lysate. In A, IL-1beta levels were (in
      pg/ml/10(6) cells, in supematant and lysate, respectively): 5.8 +/- 4.8 and 7.6+/
      5.2 in pre-HD and 4.68 +/- 3.6 and 9.7 +/- 6.65 in post-HD. These levels showed a
      clear reduction in B: 2.5 +/- 2.2 and 4.4 +/- 3.1 in pre-HD, and 4.35+/- 6.6 and
      7.52 +/- 7.22 in post-HD. In the C test, 4 weeks after the return to the ETO
      membrane, IL-1beta levels remained unchanged: 2.9 +/- 1.8 and 4.5 +/- 3.1 in pre
      HD; and 2.6 +/- 3 and 5.7 +/- 6.6 in post-HD. Statistical analysis showed
      significant changes in the pre-HD levels both in supematant (p < 0.04) and in
      lysate (p < 0.04). Steam sterilization of SMC induced a lower spontaneous IL
      1beta release, but this effect was not statistically significant due to the large
      inter-individual variation. Hence, contrary to claims of better biocompatibility,
      steam sterilization does not result in a reduced production of pro-inflammatory
      IL-1beta.

PMID- 12403399
TI  - Hemodialysis (HD) versus peritoneal dialysis (PD): latent overhydration in PD
      patients?
AB  - Data on the difference in fluid status between hemodialysis (HD) and peritoneal
      dialysis (PD) patients are scarce. Bio-electrical impedance analysis (BIA) is
      able to detect total body water (TBW) and its distribution in intracellular (ICW)
      and extracellular water (ECW). Echographic determination of the diameter of the
      inferior caval vein (VCD) provides information about the intravascular space
      (IVS). Nineteen PD-patients and 20 HD-patients in stable clinical condition were
      studied. In HD-patients a significant decrease in VCD, mean arterial pressure
      (MAP), TBW and ECW was noted due to ultrafiltration. Both ratios of VCD to
      ICW/ECW and of VCD to ECW/TBW decreased. No significant differences were found in
      these variables between PD-patients and HD-patients before HD. In both patient
      groups the measured variables pointed towards overhydration and the increased
      ratios both of VCD to ICW/ECW and VCD to ECW/TBW towards the storage of surplus
      of fluid in the intravascular space. It can be concluded that both PD-patients
      and HD-patients before HD have a surplus of fluid in the extracellular
      compartment, predominantly stored in the intravascular space.

PMID- 12403400
TI  - Is decreased treatment time in hemodialysis patients harmful if solute clearance
      is maintained?
AB  - An association between decreased duration of hemodialysis and increased morbidity
      and mortality in patients has been suggested. Whether this is due only to
      decreased solute clearance is unclear. In this prospective randomised study the
      effect of reducing treatment time whilst maintaining constant solute clearance
      was examined in fourteen patients. The study lasted for a period of 36 weeks
      (3x12 week study periods) and used a crossover design. The patients dialysis
      prescription (KW) was not changed on entering the study and was maintained during
      short (150 minutes) and long dialysis (240 minutes) by varying blood flow,
      dialysate flow and dialyzer surface area. The delivered KW was kinetically
      assessed. Fractional urea clearance was also measured during each treatment
      period by measurement of urea concentration in spent dialysate and total body
      water using 3H2O. At the end of each treatment period a full biochemical and
      hematological profile, nutritional intake and status, 24 h ambulatory blood
      pressure, nerve conduction studies, and quality of life questionnaire were
      performed. Within patients the delivered single pool KW was uniform throughout
      the 3 treatment periods and fractional urea clearance did not vary. However, Kt/W
      assessed using equilibrated models (Daugardis and Smye) was significantly lower
      in the short dialysis period. No differences between short and long dialysis
      sessions were noted in any of the measured variables. Thus, over a 36 week period
      there is no evidence to suggest that hemodialysis patients are adversely affected
      by decreased duration of treatment provided that solute clearance is maintained.

PMID- 12403401
TI  - Epidemiology of end-stage renal disease and current status of hemodialysis in
      Yugoslavia.
AB  - Maintenance hemodialysis (HD) in Yugoslavia started in the sixties and followed
      the dialysis trends in the Western Europe. However, in the last decade the
      development of renal replacement therapy (RRT) slowed down. In this report the
      epidemiology of ESRD from 1997-1999 and the survey of the status of HD treatment
      in Yugoslavia in 1999 are presented. Epidemiological data are obtained by the
      annual center questionnaires (response rate: 92.6 -94.2%). The survey of HD
      status is based on a specific questionnaire and covered 2108 patients (65%). At
      the end of 1999 there were 56 RRT centers in Yugoslavia treating 3939 patients:
      3232 (82%) patients by HD, 248 (6.3%) by peritoneal dialysis, and 459 (11.7%)
      living with transplanted kidney. In a three year period, incidence of ESRD ranged
      from 108-128 pmp, point prevalence from 435-463 pmp and mortality rate from 20.7
      17.9. Numerous refugee patients were treated over the last 10 years. Main causes
      of ESRD were glomerulonephritis (30%); Balkan nephropathy represented 11% and
      diabetic nephropathy 7% of all primary renal diseases. Cardiovascular and
      cerebrovascular diseases were the most common causes of death of RRT patients.
      Most centers are overcrowded and HD machines are worn out. Mean Kt/V was 1.19+/
      0.08, mean URR% 58.8+/-7.4. The shortage of drugs prevented adequate management:
      83% of HD patients had hemoglobin level less than 100 g/L but only 10.3 -17.8%
      were treated with rHuEpo; 64.5% of patients had phosphate levels higher than 1.7
      mmol/L but only 33.5% used phosphate binders; 47% of patients had hypertension
      despite the antihypertensive therapy. The prevalence of hepatitis B remained
      unchanged (about 14%) in HD population during the last three years, but the
      prevalence of anti-HCV positive patients decreased (31-23%). In conclusion, there
      is a well developed dialysis service in Yugoslavia but insufficient conditions
      for adequate treatment.

PMID- 12403402
TI  - Teaching technology with technology: computer assisted lessons in the medical
      school the first Italian experience in nephrology and dialysis.
AB  - BACKGROUND: Dialysis is often neglected in academic teaching. At the University
      of Torino, Italy, teaching Nephrology (4th year of Medical School) consists of 21
      hours of formal lessons, 10 hours/student of interactive lessons (4/10 dedicated
      to dialysis) and 10 optional lessons (3 regarding dialysis). Interactive and
      optional lessons widely employ computer assisted teaching. Aim of the study was
      to evaluate student satisfaction on this approach. METHODS: Student satisfaction
      was assessed on 4 sample lessons (166 students), by two short dedicated
      questionnaires (0-10 scale, open questions). RESULTS: High scores were given to
      the dialysis lessons (median 8/10). Computer assisted interface (median 8/10,
      range 6-10) was of help in check of knowledge in real time (86%), enhancing
      participation (61%); 62% suggest extending this experience to selected courses,
      38% to all. CONCLUSIONS: Medical students consider dialysis an important part of
      the academic teaching of Nephrology; new interfaces may help to enhance student
      satisfaction.

PMID- 12403403
TI  - Hemodynamic comparison of two different pediatric aortic cannulas.
AB  - Any extracorporeal blood treatment requires an adequate and safe connection to
      the circulation. For cardiopulmonary bypass procedures, aortic and venous
      cannulas are utilized. However, the performance of these cannulas is not only
      dependent on their size (diameter), but also on their complete geometric design.
      In this paper two aortic cannula designs are evaluated hemodynamically for two
      different sizes (8, 10 Fr) both with aqueous fluids and with blood. Using the
      novel concept of equivalent diameter, a new performance parameter, and the theory
      of dynamic similarity the results obtained with different fluids can be compared.
      Data points of one cannula can be fitted to a parabolic equation. There is a
      significant performance difference between the two 8 Fr cannulas. The 10 Fr
      cannulas differ non-significantly except when water is used. Equivalent diameters
      obtained with water in the turbulent region are significantly higher than those
      obtained with fluids that have a higher viscosity (blood and aqueous glycerine
      mixture). The latter fluids have comparable viscosities and render an equal
      equivalent diameter. The coefficients of their proper parabolic fit lines can
      easily be recalculated into each other. This provides a simple method to quickly
      determine pressure drops in cannulas in the operating room.

PMID- 12403404
TI  - Closed, phosphorylcholine-coated circuit and reduction of systemic heparinization
      for cardiopulmonary bypass: the intraoperative ECMO concept.
AB  - Cardiopulmonary bypass with heparin-bonded circuits reduces systemic
      heparinization which is associated to a better clinical outcome in cardiac
      operations. In the present study, a novel biocompatible treatment, based on a
      phosphorylcholine coating without heparin, has been used to reduce systemic
      heparinization during cardiopulmonary bypass. Sixty patients underwent coronary
      revascularization with a fully phosphorylcholine-coated circuit. The circuit was
      entirely closed; suctions from the field were separated during the
      cardiopulmonary bypass time. A low systemic heparinization protocol based on half
      the loading dose of heparin (150 IU/kg) and a target activated clotting time of
      320 seconds was applied. No thrombus formation inside the extracorporeal
      circulation circuit occurred; in-hospital mortality was absent. One patient
      (1.6%) had a postoperative myocardial infarction and 2 (3.3%) were surgically
      revised due to bleeding. Homologous blood transfusion rate was 11.6%,
      postoperative bleeding was 310 +/- 136 ml. If compared to patients treated with
      heparin-coated circuits and low systemic heparinization, these patients have
      better platelet count preservation and lower postoperative bleeding. The low
      thrombogenicity of phosphorylcholine-treated surfaces, despite the absence of
      surface-immobilized heparin, allows a safe reduction of systemic heparinization
      in the setting of an ECMO-like intraoperative cardiopulmonary - bypass. This
      intraoperative ECMO approach offers promising results in terms of clinical
      outcome after coronary revascularization operations.

PMID- 12403405
TI  - Potential mechanical blood trauma in vascular access devices: a comparison of
      case studies.
AB  - Since vascular access devices may cause disturbances in blood flow, possibly
      damaging red blood cells (RBCs), the correlated risk of lysis must be assessed.
      The monodimensional approach for the evaluation of cannulae hydrodynamic
      behaviour (in vitro measured flow curves) does not furnish information on the
      local flow field occurring in specific clinical conditions. Researchers consider
      the prediction of blood trauma, induced by mechanical loading, to optimize the
      design phase, and to furnish indications on their optimal clinical use. In this
      study, a model of cannula inserted in a non compliant wall vessel was used as a
      test bench in a Computational Fluid Dynamics (CFD) problem. By means of CFD the
      flow field was 3D analysed to achieve information on velocity and shear stress
      local values, when cannula is used for inflow and outflow cannulation. A
      prediction of potential blood corpuscle damage, based on a power law, quantified
      the potential blood damage. Several numerical simulations, with different
      cannula/vessel flow rate ratios were provided, to investigate the incidence of
      local sites in the design on blood damaging potential during cannulation. Several
      regions appeared to be sensitive to the flow rate not only inside the cannula but
      also in the space between cannula and vessel, suggesting new indications for the
      assessment of a quality factor based on the evaluation of induced blood cells
      injury.

PMID- 12403406
TI  - Fabricated hyalS micropatterns and surface guidance of NCTC 2544 continuous cell
      line: an in vitro study.
AB  - Surface topography is important in establishing tissue organisation adjacent to
      implants, smooth surfaces generally being associated with fibrous encapsulation.
      By virtue of its large hydrated molecular volume and its capacity to form
      molecular matrix, hyaluronic acid can expand the interfibrillar collagen spaces
      to allow the movement of cells, although it can also hamper their locomotion. Low
      molecular-weight hyaluronan can also stimulate cell proliferation, especially at
      low concentrations. The aim of the present work was to evaluate in vitro the
      growth and migratory behaviour of NCTC 2544 keratinocytes cultured on different
      materials microstructured with hyaluronic acid or sulfated hyaluronic acid to
      assess the possibility of using these devices in the repair process of soft
      tissues. Ultrastructural morphological analyses, morphometric evaluations and
      detection of cytoskeletal elements were performed. Our observations provide
      evidence that micrometer-size parallel grooves of hyaluronic acid can influence
      cell growth behaviour since cells seeded onto the microstructured substrate
      arranged themselves according to a shape and an orientation that clearly
      reflected the chemotropism exerted on them by the two forms of acid. These data
      also highlight the importance of accurate microtexture fabrication. We intend to
      follow up these in vitro studies with in vivo experimental applications using PET
      and gelatin substrates structured with HyalS to evaluate wound healing responses,
      and to extend our investigations of the cytoskeletal modifications induced by
      different microstructures.

PMID- 12403407
TI  - Local transmission of Plasmodium vivax malaria--Virginia, 2002.
AB  - Malaria transmission in the United States was largely eliminated during the mid
      20th century; however, sporadic cases of locally acquired mosquito-transmitted
      malaria continue to occur. Since 1997, four separate probable mosquito
      transmitted malaria outbreaks have been reported to CDC, including one from
      Virginia. This report describes the investigation of two cases of Plasmodium
      vivax malaria that occurred in northern Virginia in August 2002, and underscores
      the need for clinicians to consider the possibility of malaria in patients with
      fever of unknown origin.

PMID- 12403408
TI  - Q fever--California, Georgia, Pennsylvania, and Tennessee, 2000-2001.
AB  - Q fever is a zoonotic disease caused by the bacterium Coxiella burnetii. The most
      common reservoirs are domesticated ruminants, primarily cattle, sheep, and goats.
      Humans acquire Q fever typically by inhaling aerosols or contaminated dusts
      derived from infected animals or animal products. Its highly infectious nature
      and aerosol route of transmission make C. burnetii a possible agent of
      bioterrorism. Although up to 60% of initial infections are asymptomatic, acute
      disease can manifest as a relatively mild, self-limited febrile illness, or more
      moderately severe disease characterized by hepatitis or pneumonia. It manifests
      less commonly as myocarditis, pericarditis, and meningoencephalitis. Chronic Q
      fever occurs in <1% of infected patients, months or years after initial
      infection. Chronic disease manifests most commonly as a culture-negative
      endocarditis in patients with valvular heart disease. During 2000-2001, a total
      of 48 patients who met the case definition of Q fever were reported to CDC. This
      report describes the case investigations for six of these patients, which
      indicate that these persons acquired Q fever probably through direct or indirect
      contact with livestock. To enhance surveillance efforts, health-care providers
      should report cases of Q fever to state health departments.

PMID- 12403409
TI  - Probable variant Creutzfeldt-Jakob disease in a U.S. resident--Florida, 2002.
AB  - On April 18, 2002, the Florida Department of Health and CDC announced the
      occurrence of a likely case of variant Creutzfeldt-Jakob disease (vCJD) in a
      Florida resident aged 22 years. This report documents the investigation of this
      case and underscores the importance of physicians increasing their suspicion for
      vCJD in patients presenting with clinical features described in this report who
      have spent time in areas in which bovine spongiform encephalopathy (BSE) is
      endemic.

PMID- 12403410
TI  - West Nile virus activity--United States, October 10-16, 2002, and update on West
      Nile virus infections in recipients of blood transfusions.
AB  - This report summarizes West Nile virus (WNV) surveillance data reported to CDC
      through ArboNET and by states and other jurisdictions as of 8 a.m. Mountain
      Daylight Time, October 16, 2002.

PMID- 12403411
TI  - Genetic basis of cross-resistance to three organophosphate insecticides in
      Drosophila melanogaster (Diptera: Drosophilidae).
AB  - To investigate the genetic basis of cross-resistance to insecticides, we
      conducted genetic analyses of resistance to three organophosphate insecticides,
      malathion, prothiophos, and fenitrothion. After isofemale lines resistant and
      susceptible to all of the three organophosphates had been screened from natural
      populations of Drosophila melanogaster (Meigen), chromosomal analyses were
      performed by using chromosome-substituted lines between the resistant and the
      susceptible lines. The chromosomal analyses revealed that both the second and the
      third chromosomes contributed to resistance to the organophosphates, suggesting
      that this resistant line possessed at least two factors for organophosphate
      resistance. However, the relative contribution of each chromosome was different
      in resistance to different organophosphates. We further carried out genetic
      mapping of a resistance factor for each organophosphate on each of the two
      chromosomes. Each resistance factor was mapped to the position of each
      chromosome, about II-62 and III-50. Results of the chromosomal analyses and the
      genetic mapping revealed that at least two resistance factors exhibiting
      different patterns of cross-resistance to the organophosphates existed within a
      natural population of D. melanogaster. Based on this research, genetic variation
      in insecticide resistance within natural populations and complex as well as
      simple aspects of the mechanism of cross-resistance are discussed.

PMID- 12403412
TI  - Biotechnology and the European corn borer: measuring historical farmer
      perceptions and adoption of transgenic Bt corn as a pest management strategy.
AB  - A 3-yr, multi-state survey of farmers who had planted transgenic Bacillus
      thuringiensis (Bt) corn was conducted to evaluate perceptions of Bt corn
      performance and its utility as a management option for European corn borer,
      Ostrinia nubilalis (Hubner). A questionnaire was sent to farmers in Illinois,
      Iowa, Kansas, Minnesota, Nebraska, and Pennsylvania who had grown Bt corn during
      the growing seasons of 1996, 1997, or 1998. There were 7,427 usable
      questionnaires returned with the following response percentages: 1996 (42.1%),
      1997 (35.0%), and 1998 (22.6%). Adoption rates, based on percentage of acreage
      planted to Bt corn, increased dramatically from 1996 (10.5%) to 1998 (40.7%). The
      states growing the highest percentage of Bt corn were Minnesota, Iowa, and then
      Nebraska However, Illinois, was adopting Bt corn at the fastest rate. Historical
      use of insecticides did not influence the adoption of Bt corn. In addition, of
      those farmers who used insecticides to control European corn borer, the
      percentage that decreased their use of insecticides nearly doubled from 13.2%
      (1996) to 26.0% (1998) over this 3-yr period. The primary reason farmers planted
      Bt corn was to eliminate the yield loss caused by European corn borer. Scouting
      for European corn borers decreased from 91% (scouting 2.2 times a year) in 1996
      to 75% (scouting 1.8 times a year) in 1998. The percentage of farmers not
      scouting for European corn borers increased from 9.6% (1996) to 25% (1998). Most
      farmers believed yields of Bt hybrids were either similar to or greater than the
      yields of non-Bt hybrids. Minnesota farmers perceived the greatest yield
      advantages. Farmers are becoming more aware of insect resistance management
      guidelines; however, they also clearly show preferences for having the
      flexibility to use different spatial plantings of Bt and non-Bt corn. Finally,
      after having planted Bt corn and obtained excellent control of European corn
      borer, most farmers believed that this insect had been causing more yield loss
      than they previously had suspected in their non-Bt corn. The data represented
      here provide an historical foundation for how transgenic Bt corn was used by
      farmers during the first 3 yr of commercial availability, their initial
      perceptions on the performance of this technology, and their attitudes regarding
      management of the European corn borer.

PMID- 12403413
TI  - Generic ionizing radiation quarantine treatments against fruit flies (Diptera:
      Tephritidae) proposed.
AB  - Tephritid fruit flies comprise the most important group of quarantined pests of
      fresh produce. Most quarantine treatments of fresh agricultural commodities are
      directed against these pests, and considerable effort in detection, trapping, and
      population control is expended worldwide to prevent these pests from invading new
      territories. Ionizing radiation has been studied for 70 yr for its possible use
      as a quarantine treatment against fruit flies, but has only been applied
      commercially on a limited basis since 1995. The treatment has great potential and
      will probably be used extensively in the future as it is tolerated by more
      species of fruits than any other major treatment. The U.S. Department
      Agriculture, Animal and Plant Health Inspection Service only recently proposed
      allowing irradiation for fresh agricultural imports from other countries, and
      other countries are studying proposals to do likewise. In 1991, the International
      Consultative Group on Food Irradiation recommended a generic dose against all
      tephritid fruit flies of 150 Gy. This article examines the literature dealing
      with irradiation quarantine treatments against fruit flies and recommends minimum
      absorbed doses of 70 Gy for Anastrepha spp., 101 Gy for Bactrocera jarvisi and B.
      tryoni, and 150 Gy for all Tephritidae except when fruits have been stored in
      hypoxic atmospheres.

PMID- 12403414
TI  - Longevity and reproductive success of Aethina tumida (Coleoptera: Nitidulidae)
      fed different natural diets.
AB  - The longevity and reproductive success of newly emerged, unfed adult Aethina
      tumida Murray assigned different diets (control = unfed; honey-pollen; honey;
      pollen; empty brood comb; bee brood; fresh Kei apples; and rotten Kei apples)
      were determined. Longevity in honey-fed small hive beetle adults (average
      maximum: 167 d) was significantly higher than on other diets. Small hive beetles
      fed empty brood comb lived significantly longer (average maximum: 49.8 d) than
      unfed beetles (average maximum: 9.6 d). Small hive beetle offspring were produced
      on honey-pollen, pollen, bee brood, fresh Kei apples, and rotten Kei apples but
      not on honey alone, empty brood comb, or in control treatments. The highest
      reproductive success occurred in pollen fed adults (1773.8 +/- 294.4 larvae per
      three mating pairs of adults). The data also show that A. tumida can reproduce on
      fruits alone, indicating that they are facultative parasites. The pupation
      success and sex ratio of small hive beetle offspring were also analyzed. Larvae
      fed pollen, honey-pollen, or brood had significantly higher pupation success
      rates of 0.64, 0.73, and 0.65 respectively than on the other diets. Sex ratios of
      emerging adults fed diets of pollen or brood as larvae were significantly skewed
      toward females. Because small hive beetle longevity and overall reproductive
      success was highest on foodstuffs located in honey bee colonies, A. tumida are
      efficient at causing large-scale damage to colonies of honey bees resulting in
      economic injury for the beekeeper. Practical considerations for the control of A.
      tumida are briefly discussed.

PMID- 12403415
TI  - Parasitization by pteromalid wasps (Hymenoptera) of freeze-killed house fly
      (Diptera: Muscidae) puparia at varying depths in media.
AB  - Three laboratory experiments were performed to assess parasitization of freeze
      killed house fly puparia, buried 0 to 6 cm in media, by Muscidifurax raptor
      Girault & Saunders, Muscidifurax raptorellus Kogan & Legner, Muscidifurax
      zaraptor Kogan & Legner, Trichomalopsis sarcophagae (Gahan) and Urolepis rufipes
      (Ashmead) (Hymenoptera: Pteromalidae). Virtually no parasitization occurred at
      depths greater than 1 cm in large arenas (988 cm2) with densities of 0.3 puparia
      and 0.008 female parasitoids per cm2. Parasitization was observed at depths as
      great as 4 cm for three of five species in small arenas (3 cm2) with densities of
      6.4 puparia and 1.0 female per cm2. Combined across experiments, M. raptor
      achieved the highest level of parasitization, followed by M. zaraptor, M.
      raptorellus, U. rufipes, and T. sarcophagae. The greatest number of F1 females
      was produced by the gregarious species T. sarcophagae (834 female female) and M.
      raptorellus (708 female female), and then by the solitary species M. raptor (530
      female female), M. zaraptor (365 female female) and U. rufipes (163 female
      female). High parasitization by M. raptor and high production of offspring by T.
      sarcophagae identify these species as being particularly attractive as biological
      control agents.

PMID- 12403416
TI  - Laboratory fecundity as predictor of field success in Trichogramma carverae
      (Hymenoptera: Trichogrammatidae).
AB  - Laboratory fecundity assessments are routinely used to determine the quality of
      commercially reared Trichogramma egg parasitoids before release for pest control,
      but there is little information on the relevance of this trait to the field
      success of Trichogramma. Herein, we characterize the parasitism success of
      strains of Trichogramma carverae Oatman & Pinto in the laboratory on a factitious
      (Sitotroga cerealella Olivier) and a natural (Epiphyas postvittana Walker) host.
      Differences in fecundity of the strains in the laboratory were consistent with a
      heritability of approximately 10%, allowing ranking of the strains from highest
      to lowest fecundity. The strains with particularly high and low fecundities were
      tested for successful parasitism in the field. Results of the field releases show
      that strain differences in laboratory fecundity did not influence field
      performance. The implications of this result for fecundity as a quality indicator
      for commercial stocks are discussed.

PMID- 12403417
TI  - Laboratory and field evaluation of Korean entomopathogenic nematode isolates
      against the oriental beetle Exomala orientalis (Coleoptera: Scarabaeidae).
AB  - The oriental beetle Exomala (Anomala) orientalis (Waterhouse) is an important
      pest of turfgrass in Korean golf courses, and although a few chemical
      insecticides are registered for insect pest control, they are not very effective
      against scarab larvae. There is also a growing concern in Korea about the run-off
      of insecticides into sensitive habitats and the potential for groundwater
      contamination. A safe and environmentally sound alternative is needed to
      conventional insecticides. We therefore evaluated six Korean entomopathogenic
      nematode isolates: S. carpocapsae Pocheon, S. glaseri Dongrae, S. glaseri
      Mungyeong, S. longicaudum Gongju, S. longicaudum Nonsan, and Heterorhabditis sp.
      Gyeongsan for their potential as bioinsecticides for control of E. orientalis. In
      addition, we evaluated a reduced chemical insecticide approach that combined
      chlorpyrifos-methyl with nematodes. In laboratory tests Heterorhabditis sp.
      Gyeongsan was the most efficacious, causing 100% mortality of the second and 38%
      of the third instars. All other nematode isolates caused 50-80% mortality of the
      second and 15-30% of the third instars. E. orientalis pupae were highly
      susceptible to all the Korean entomopathogenic nematode isolates except S.
      carpocapsae. In artificially infested field plots, all Korean nematode isolates
      cause 50-70% mortality of the third instar. A combination of a one-half rate of
      Heterorhabditis sp. and a one-half rate chlorpyrifos-methyl was synergistic,
      causing 91% mortality compared with 69% for the full rate of Heterorhabditis sp.
      or 22% for the full rate of chlorpyrifos-methyl. In a second field trial, a
      natural infestation of preoverwintering third instar was treated. In this trial a
      one-half rate of S. longicaudum Nonsan plus a one-half rate of chlorpyrifos
      methyl caused 96.8% mortality, much more than a full rate of S. longicaudum
      Nonsan (45.9% mortality) or a full rate of chlorpyrifos-methyl (28.7% mortality).
      The interactions of Heterorhabditis sp. and S. longicaudum Nonsan with
      chlorpyrifos-methyl in our field trials appear to be synergistic.

PMID- 12403418
TI  - Yolk protein immunoassays (YP-ELISA) to assess diet and reproductive quality of
      mass-reared Orius insidiosus (Heteroptera: Anthocoridae).
AB  - A yolk protein enzyme-linked immunosorbent assay (YP-ELISA) was developed for the
      predator Orius insidiosus (Say). The YP-ELISA is intended to assess reproductive
      response to dietary and other rearing conditions, and to assist in quality
      control and diet development for mass rearing. Hybridomas and monoclonal
      antibodies were produced against homogenates of eggs dissected from females.
      Hybridomas were selected for secretion of IgG that reacted with extracts of both
      females and their eggs, and that did not react with male extracts. Each cloned
      hybridoma produced a monoclonal antibody that specifically reacted on western
      blots against one of the two major yolk polypeptides, apoVn-I (180,000 molecular
      weight) or apoVn-II (40,000). Yolk protein ELISAs were developed with these
      antibodies to assess yolk protein content of female O. insidiosus as a measure of
      reproductive fitness and as a potential predictor of fecundity. Protocols for an
      indirect antigen ELISA and double antibody sandwich ELISA were developed to
      assess yolk protein contents of eggs and total contents in whole body
      homogenates. ELISA standards consisted of homogenates of eggs collected 0-24 h
      following oviposition. As determined with the sandwich ELISA, yolk protein
      contents of eggs declined with age before hatch, with a half-life of 32-34 h.
      Results were similar whether the detecting antibody-enzyme conjugate was anti
      apoVn-I or anti-apoVn-II. Optimal conditions and sampling parameters were
      developed for the sandwich ELISA, which demonstrated minimal nonspecific
      interference in whole-insect extracts. In an initial application of the YP-ELISA,
      oviposition rates over a 10-d period were compared with yolk protein contents at
      the end of that period, dependent on diets of differing nutritional composition
      and quality. High and low yolk protein contents correlated with oviposition rates
      on respective diets, though oviposition showed more graded response to diets than
      did yolk protein. Improvements in sampling methods are discussed.

PMID- 12403419
TI  - Comparison of two sterile Mediterranean fruit fly (Diptera: Tephritidae) strains
      released in California's Preventative Release Program.
AB  - At Mediterranean fruit fly rearing centers, genetic sexing strains such as the
      male-only temperature sensitive lethal (tsl) strains, are replacing many of the
      older bisexual strains, such as Maui-93. Three tests were performed to compare
      the performance of the Vienna-4 (which carries tsl) and Maui-93 strains. Using
      standard laboratory quality control tests, the Maui-93 strain had higher percent
      fliers and a lower percentage deformed and partially eclosed flies. Analyses of
      data from field mark-recapture tests with Jackson traps failed to find
      significant differences in recapture numbers between the two strains. In field
      cage survivorship tests, the Vienna-4 strain showed significantly lower mortality
      in comparison to the Maui-93 strain. These results suggest that although the
      quality of Vienna-4 flies is lower than Maui-93 at the time of adult emergence,
      it is comparable with or better than Maui-93 several days later, because weaker
      flies have been eliminated from the cohort. The benefits of releasing only
      sterile males, instead of both males and females, was not factored into the
      quality assessment in this study, but would be an additional benefit in using a
      strain that carries a tsl mutation.

PMID- 12403420
TI  - Relationship between leaf area index and yield in double-crop and full-season
      soybean systems.
AB  - Previous research indicates a correlation between leaf area index (LAI) and yield
      of full-season soybean [Glycine max (L.) Merrill], which is a single crop planted
      early in the season. Leaf area index values of at least 3.5-4.0 in the
      reproductive stages are required for maximum potential yield. It is unknown how
      yields of double-crop soybean, which is planted late into harvested small grain
      fields, respond to changes in leaf area index. We hypothesized that double-crop
      soybean would be more sensitive to defoliation than full-season soybean. This
      study used linear and linear plateau models to describe the yield response of
      full-season and double-crop soybean to reductions in leaf area index through
      manual defoliation, and evaluated the yield response of double-crop soybean to
      reductions in leaf area index through natural insect defoliation. From 15 manual
      defoliation experiments over 3 yr, significant linear decreases in yield occurred
      in both full-season and double-crop soybean when leaf area index values were
      below 3.5-4.0 by developmental stages R4 to R5, whereas yields usually reached a
      plateau at higher leaf area index levels. Average yield loss was 769 +/- 319 kg
      ha(-1) for each unit decrease in leaf area index below the plateau; average
      maximum yield was 3,484 +/- 735 kg ha(-1). From eight field experiments over 2
      yr, insect defoliators had no effect on double-crop soybean yield; leaf area
      index levels were above 4.0 by the developmental stage when leaf area index
      estimates were taken (R3 to R6). Therefore, double-crop soybean that maintains
      leaf area index values above the 3.5-4.0 critical level by mid-reproductive
      developmental stages can tolerate defoliating pests.

PMID- 12403421
TI  - Leaf cell and tissue damage of cucumber caused by twospotted spider mite (Acari:
      Tetranychidae).
AB  - To quantify the damage caused by twospotted spider mite, Tetranychus urticae
      Koch, feeding on cucumber, Cucumis sativus L., leaf-cell and -tissue damage was
      assessed. On the abaxial leaf surface, adult T. urticae could feed through the
      spongy parenchyma and part of the palisade parenchyma of the leaf, while immature
      T. urticae could feed only through the sponge parenchyma. T. urticae punctured
      individual epidermal cells and consumed the contents of the mesophyll cells.
      Injured leaves had more empty space in the spongy parenchyma and fewer
      chloroplasts per cell. Damage also occurred even in the adjacent uninjured
      parenchyma cells without additional T. urticae feeding injury. Net photosynthetic
      rate, total chlorophyll content, and greenness of the leaf were significantly
      affected by feeding as quantified by mite-days. The percent loss of these
      parameters increased linearly or nonlinearly as mite-days increased, regardless
      of mite developmental stages. At 1,000 mite-days per 6 cm2, net photosynthetic
      rate was reduced by approximately 50 and 95%, total chlorophyll content was
      reduced by approximately 55 and 80%, and greenness was reduced by approximately
      50 and 80% by feeding by immature and adult T. urticae, respectively.

PMID- 12403422
TI  - Integrated pest management of Rhagoletis mendax (Diptera: Tephritidae) in lowbush
      blueberry using vegetative field management.
AB  - Economic control of Rhagoletis mendax was achieved by applying insecticidal
      sprays to commercial lowbush blueberry vegetative fields, in a biennial
      production system, rather than to the fruiting fields, when the threshold was
      exceeded. The viability of this integrated pest management of R. mendax for
      lowbush blueberries was demonstrated over a 9-yr interval in New Brunswick where
      three sites were monitored for 2 yr, eight sites for 4 yr, and one site for 9 yr.
      Control of R. mendax in lowbush blueberry fields was achieved in 2 yr when the
      fields were isolated, and in 3 yr when there were adjacent lowbush blueberry
      fields.

PMID- 12403423
TI  - Impact of Phyllocnistis citrella (Lepidoptera: Gracillariidae) on leaf area
      development and yield of mature citrus trees in the Mediterranean area.
AB  - Seasonal population trends and damage to citrus trees by the leafminer
      Phyllocnistis citrella Stainton were studied in the Valencia area of eastern
      Spain from 1996 to 1999. The area-wide seasonal flushing pattern of citrus trees
      and leafminer population trends were determined in 10 mature citrus orchards. In
      the 10 orchards, the annual percentage of new shoots that developed in the spring
      ranged from 51 to 96% for individual orchards (mean of 80%). Phyllocnistis
      citrella populations damaged new leaves from July to November. During this
      period, approximately 45% of the new leaf area was lost due to leafminer mining.
      In addition, at three mature citrus orchards, two 'Navelina' sweet oranges from
      1996 to 1999 and one 'Clementine' mandarin (variety 'Clemenules') in 1998 and
      1999, the leaf area damage, spring flushing pattern, and crop yield were
      determined in trees sprayed one to three times a year with abamectin (Epimeck,
      0.02%) to control P. citrella and compared with nonsprayed control trees. In
      these three orchards, damaged leaf area in summer-fall flushes was on average 52%
      in nonsprayed and 8% in sprayed trees. No significant differences were found
      between sprayed and nonsprayed trees in the spring flushing and flowering
      pattern, number of fruits or fruit diameter. In Mediterranean areas, P. citrella
      damaged only 5-15% of the annual new leaf area of mature trees and yield was
      usually not affected by the pest.

PMID- 12403424
TI  - Dimensionally stable sensors for a continuous monitoring program to detect
      subterranean termite (Isoptera: Rhinotermitidae) activity.
AB  - A dimensionally stable sensor composed of a closed-cell polyethylene sheet on
      which a silver particle circuit was painted and sandwiched between two spruce
      stakes was tested for use in a monitoring program to detect subterranean
      termites. Sensors were connected to a datalogger for continuous monitoring of
      sensor circuit breakages over 12 mo, and were manually inspected monthly to
      assess sensor performance. The mean monthly sensor accuracy for three field test
      sites was 98.7%, with most false responses caused by early timing of the monthly
      inspection when termites entered the station before damaging the sensor circuits.
      Mean sensor longevity (the time for a sensor circuit to break in the absence of
      termites) of the dimensionally stable sensors was 11.7 mo; a substantial
      improvement over the 4.4-mo longevity recorded previously for wooden sensors.

PMID- 12403425
TI  - Acoustic detection of termite infestations in urban trees.
AB  - A portable, low-frequency acoustic system was used to detect termite infestations
      in urban trees. The likelihood of infestation was rated independently by a
      computer program and an experienced listener that distinguished insect sounds
      from background noises. Because soil is a good insulator, termite sounds could be
      detected easily underneath infested trees, despite the presence of high urban
      background noise. Termite sounds could be detected also in trunks, but background
      noise often made it difficult to identify termite signals unambiguously. High
      likelihoods of termite infestation were predicted at four live oak (Quercus
      virginiana Mill, Fagacae), two loblolly pine (Pinus taeda L., Pinacae), and two
      baldcypress (Taxodium distichum Rich. Pinacae) trees that wood-baited traps had
      identified as infested with Coptotermes formosanus Shiraki. Infestations also
      were predicted at two pine trees with confirmed recoveries of Reticulitermes
      flavipes (Kollar). Low likelihoods of infestation were predicted in four oak
      trees where no termites were found. Additional tests were conducted in anechoic
      environments to determine the range of acoustic detectability and the feasibility
      of acoustically estimating termite population levels. There was a significant
      regression between the activity rate and the number of termites present in a wood
      trap block, with a minimum detectable number of approximately 50 workers per
      liter of wood. The success of these field tests suggests that currently available
      acoustic systems have considerable potential to detect and monitor hidden
      infestations of termites in urban trees and around building perimeters in
      addition to their present uses to detect and monitor termite infestations in
      buildings.

PMID- 12403426
TI  - Effect of tolerance to insecticides on substrate penetration by Formosan
      subterranean termites (Isoptera: Rhinotermitidae).
AB  - Seven selected insecticides were applied to three substrates and bioassayed for
      barrier efficacy and toxicity against the Formosan subterranean termite,
      Coptotermes formosanus Shiraki, originating from colonies that differed in their
      tolerance to the insecticides. A profound substrate effect was seen with all
      insecticides tested. Sand was the most difficult substrate to penetrate and
      caused faster and greater mortality of C. formosanus. Increased tolerance in C.
      formosanus was accompanied by a decrease in penetration of treated substrata with
      chlordane, methoxychlor, chlorpyrifos, and deltamethrin. The opposite was true in
      the case of permethrin and bendiocarb. More tolerance C. formosanus displayed
      decreased mortality in the presence of chlorpyrifos, deltamethrin, bendiocarb,
      and fipronil. The opposite was true for permethrin.

PMID- 12403427
TI  - Isolation and identification of an esterase from a Mexican strain of Boophilus
      microplus (Acari: Ixodidae).
AB  - A strain of Mexican Boophilus microplus (Cz) collected near Coatzacoalcos,
      Veracruz, Mexico, exhibits a moderate, but significant, level of permethrin
      resistance. Unlike other highly permethrin resistant strains, the Cz strain does
      not have a mutation within the sodium channel gene that results in target-site
      insensitivity. However, the Cz strain possesses a substantial increase in general
      and permethrin esterase activity relative to highly permethrin resistant and
      control strains suggesting the involvement of a metabolic esterase(s) in the
      expression of permethrin resistance. We report the isolation of a 62.8 kDa
      protein from Cz strain larvae that we think is the esterase previously reported
      as Cz EST9. In addition, internal amino acid sequence data obtained from the 62.8
      kDa protein suggest that it is the gene product of a previously reported B.
      microplus carboxylesterase cDNA. We propose that the 62.8 kDa protein (Cz EST9)
      has permethrin hydrolytic activity and as a result plays an important role in Cz
      strain resistance to permethrin.

PMID- 12403428
TI  - Use of mathematical models to estimate characteristics of pyrethroid resistance
      in tobacco budworm and bollworm (Lepidoptera: Noctuidae) field populations.
AB  - Genetic models have been used to examine the evolution of insecticide resistance
      in pest species subject to data and assumptions regarding genetic, biological,
      and operational parameters. We used time-series data on pyrethroid tolerance and
      simple genetic models to estimate underlying genetic and biological parameters
      associated with resistance evolution in tobacco budworm, Heliothis virescens
      (F.), and bollworm, Helicoverpa zea (Boddie), Louisiana field populations.
      Assuming pyrethroid resistance is conferred by one gene at one locus in both
      species, inheritance of pyrethroid resistance was partially dominant in the
      tobacco budworm and partially recessive in the bollworm. Relative fitness
      estimates indicated that fitness costs associated with resistance selected
      against resistance alleles in the absence of selection pressure in the tobacco
      budworm, but not in the bollworm. In addition, relative fitness estimates
      obtained using the indirect method outlined in this study were similar in
      magnitude to estimates obtained using traditional direct approaches.

PMID- 12403429
TI  - Inheritance of resistance to Bt toxin crylac in a field-derived strain of pink
      bollworm (Lepidoptera: Gelechiidae).
AB  - Laboratory selection with Cry1Ac, the Bacillus thuringiensis (Bt) toxin in
      transgenic cotton, initially produced 300-fold resistance in a field-derived
      strain of pink bollworm, Pectinophora gossypiella (Saunders), a major cotton
      pest. After additional selection increased resistance to 3,100-fold, we tested
      the offspring of various crosses to determine the mode of inheritance of
      resistance to Cry1Ac. The progeny of reciprocal F1 crosses (resistant male x
      susceptible female and vice versa) responded alike in bioassays, indicating
      autosomal inheritance. Consistent with earlier findings, resistance was recessive
      at a high concentration of Cry1Ac. However, the dominance of resistance increased
      as the concentration of Cry1Ac decreased. Analysis of survival and growth of
      progeny from backcrosses (F1 x resistant strain) suggest that resistance was
      controlled primarily by one or a few major loci. The progression of resistance
      from 300- to 3,100-fold rules out the simplest model with one locus and two
      alleles. Overall the patterns observed can be explained by either a single
      resistance gene with three or more alleles or by more than one resistance gene.
      The pink bollworm resistance to Cry1Ac described here fits "mode 1" resistance,
      the most common type of resistance to Cry1A toxins in Lepidoptera.

PMID- 12403430
TI  - Carbaryl resistance in populations of grape berry moth (Lepidoptera: Tortricidae)
      in New York and Pennsylvania.
AB  - We collected grape berry moth, Endopiza viteana (Clemens) (from cultivated and
      wild Vitis along Lake Erie in Pennsylvania and New York), and measured carbaryl
      susceptibility in first instars. A model of susceptibility was based on the
      concentration-mortality curve of laboratory-maintained colonies originating from
      wild Vitis with no prior history of carbaryl exposure, and a noncommercial
      vineyard with modest previous exposure to carbaryl. We estimated LC50 and LC90
      for susceptible grape berry moth larvae at 45.4 and 2319 microg/ml, respectively.
      Bioassays on field-collected larvae from commercial vineyards in both states,
      where grape growers were abiding by current pest management guidelines for
      carbaryl use, revealed carbaryl resistance ratios from 7 to 71 at the LC50 level.
      With the loss or restriction of alternative chemical control tactics in the Food
      Quality Protection Act era, resistance management programs for grape berry moth
      should be immediately developed and implemented to regain the efficacy of this
      once effective insecticide and other related chemical compounds.

PMID- 12403431
TI  - Modeling the development of resistance by stalk-boring lepidopteran insects
      (Crambidae) in areas with transgenic corn and frequent insecticide use.
AB  - We simulated the population dynamics and population genetics of two bivoltine
      species of corn borers, the European corn borer, Ostrinia nubilalis (Hubner), and
      the southwestern corn borer, Diatraea grandiosella Dyar, in a hypothetical region
      of irrigated transgenic and nontransgenic corn where insecticide was applied only
      to the nontransgenic refuge crop. Over the 100-yr time horizon, resistance
      developed quickly in both species and to both transgenic corn and the insecticide
      when the allele for resistance to the respective toxin was dominant. When the
      allele for transgenic resistance was not dominant and the refuge location was
      constant over the time horizon, spraying the refuge to control southwestern corn
      borer had no effect on how quickly resistance to the transgenic corn developed.
      In contrast, the European corn borer developed resistance to transgenic corn much
      sooner when the refuge was sprayed once per year, and the time to 3% resistance
      allele frequency decreased as efficacy of the insecticide increased. Only when
      the refuge was treated less than once every 5 yr (10 generations) did the
      frequency of application decline enough to permit resistance management for the
      European corn borer to approximate the effectiveness of an unsprayed refuge. A
      consistently sprayed refuge <40% of the corn acreage was an inadequate resistance
      management strategy for the European corn borer even when a low efficacy
      insecticide (70% mortality) was used. When assumptions about European corn borer
      adult behavior were changed and the adults behaved similarly to adult
      southwestern corn borer, the development of resistance to the transgenic crop was
      slowed significantly.

PMID- 12403432
TI  - Antibiosis of the pith maize to Sesamia nonagrioides (Lepidoptera: Noctuidae).
AB  - Thirteen inbred lines of maize (Zea mays L.) with different levels of stem
      resistance to the stem borer Sesamia nonagrioides Lefevbre were evaluated in the
      field and the laboratory to determine the antibiotic resistance to this pest.
      Inbreds CM151, CO125, and EP39 had antibiotic pith as well as stem resistance, so
      the pith could play a role in stem resistance. Inbreds A509, F473, and PB130 did
      not have antibiotic pith but had stem resistance; therefore, other mechanisms
      could confer stem resistance. Finally, the inbred MS1334 had antibiotic pith and
      did not show stem resistance; thus, other factors could compensate the effect of
      the pith. Therefore, although pith antibiotic compound seems to play a role in
      the defense against S. nonagrioides attack, it is not the only possible mechanism
      of defense.

PMID- 12403433
TI  - Southwestern corn borer (Lepidoptera: Crambidae) damage and aflatoxin
      accumulation in maize.
AB  - Aflatoxin, a potent carcinogen, is produced by the fungus Aspergillus flavus
      Link: Fr. Drought, high temperatures, and insect damage contribute to increased
      levels of aflatoxin contamination in corn, Zea mays L. Plant resistance is widely
      considered a desirable method of reducing aflatoxin contamination. Germplasm
      lines with aflatoxin resistance have been developed. This investigation was
      undertaken to determine whether crosses among these lines exhibited resistance to
      southwestern corn borer, Diatraea grandiosella Dyar, and to assess the effects of
      southwestern corn borer feeding on aflatoxin accumulation. Differences in ear
      damage among southwestern corn borer infested hybrids were significant. Estimates
      of general combining ability effects indicated that the lines Mp80:04, Mp420, and
      Mp488 contributed to reduced ear damage, and SC213 and T165 contributed to
      greater damage when used in hybrids. Mean aflatoxin levels were 254 ng/g for
      hybrids infested with southwestern corn borer larvae and 164 ng/g for noninfested
      hybrids in 2000 when environmental conditions were conducive to aflatoxin
      production. In contrast, the overall mean aflatoxin level for southwestern corn
      borer infested hybrids was only 5 ng/g in 1999 when environmental conditions did
      not favor aflatoxin accumulation. Crosses that included lines selected for
      aflatoxin resistance as parents (Mp80:04 and Mp313E) exhibited lower levels of
      aflatoxin contamination both with and without southwestern corn borer infestation
      in 2000. Only the experimental line Mp80:04 contributed significantly to both
      reduced southwestern corn borer damage and reduced aflatoxin contamination.

PMID- 12403434
TI  - Evaluation of buffalograss germplasm for resistance to Blissus occiduus
      (Hemiptera: Lygaeidae).
AB  - Blissus occiduus Barber has emerged as an important insect pest of buffalograss,
      Buchloe dactyloides (Nuttall) Engelmann, in Nebraska. This research evaluated
      selected buffalograss germplasm for resistance to B. occiduus. Eleven
      buffalograss selections were screened for chinch bug resistance in three
      greenhouse studies and two field evaluations. Based on chinch bug damage, NE91
      118, 'Tatanka', 'Bonnie Brae', and 'Cody' were rated highly to moderately
      resistant. These four buffalograsses exhibited minimal damage, even though all
      were heavily infested with chinch bugs. NE84-45-3 and '378' were highly
      susceptible to B. occiduus. Field evaluations confirmed chinch bug resistance
      ratings under field conditions. NE91-118 displayed high levels of resistance in
      the field screening evaluations, whereas Cody and Tatanka showed moderate levels
      of resistance, and 378 was highly susceptible.

PMID- 12403435
TI  - Is there meaningful plant resistance to diaprepes abbreviatus (Coleoptera:
      Curculionidae) in citrus rootstock germplasm?
AB  - Host plant resistance to the Diaprepes root weevil, Diaprepes abbreviatus (L.)
      was assessed for seedlings of 54 Poncirus trifoliata (L.) Raf. selections and two
      families of progeny from crosses between Citrus and P. trifoliata. Weight gain
      was consistently lower when larvae were reared in pots containing the progeny of
      Citrus reticulata Blanco 'Sunki' x P. trifoliata 'Flying Dragon' compared with
      larvae reared on progeny of 'Pearl' (C. reticulata x C. paradisi Macf.) x 'Flying
      Dragon'. This is the first evidence of genetic control of resistance to the
      Diaprepes root weevil within sexually compatible citrus rootstock germplasm.
      There was a significant positive correlation between percentage root loss and
      larval weight gain within the resistant progeny, indicating a possible
      antixenotic effect. Two varieties of P. trifoliata were identified as more
      resistant than 'Flying Dragon' based on larval weight gain.

PMID- 12403436
TI  - Resistance to Thrips palmi (Thysanoptera: Thripidae) in beans.
AB  - Resistance in beans, Phaseolus vulgaris L., to the melon thrips Thrips palmi
      Karny was studied under field conditions at two sites in Colombia. Genotypes were
      rated for resistance on the basis of visual damage scores, bean production
      ratings (a visual estimate of pod and seed set), and grain yields. Of 1,138
      genotypes tested, only 60 (5.3%) were rated as resistant. Repeated testing
      allowed us to identify potential sources of resistance in five germplasm
      accessions (G 02402, G 02852, G 03177, G 03569, and G 04055), one commercial
      variety ('Brunca'), six elite breeding lines (A 216, DOR 714, EMP 486, FEB 115,
      FEB 161, and FEB 162), 41 recombinant inbred lines derived from the BAT 881 x G
      21212 cross, and seven recombinant inbred lines derived from a cross between DOR
      364 and BAT 477. Resistance was not associated with maturity, growth habit,
      pubescence, and seed color or seed size. In general, correlations between visual
      damage scores and bean production ratings and between damage scores and yield
      were high and significant meaning that selection on damage rating is useful to
      identify genotypes that may have tolerance as a mechanism of resistance. The
      continuous distribution of damage scores of 139 recombinant inbred lines
      suggested that the inheritance of resistance to the melon thrips might be
      quantitative. Overall, resistance levels in beans can be considered as moderate,
      because none of the genotypes tested received damage scores of <3 on a 1-9 scale
      and none was ever rated as highly resistant in terms of bean production ratings.

PMID- 12403437
TI  - High-temperature controlled atmosphere for post-harvest control of Indian meal
      moth (Lepidoptera: Pyralidae) on preserved flowers.
AB  - High carbon dioxide atmospheres combined with high temperature were effective for
      controlling Indian meal moth, Plodia interpunctella (Hubner) pupae. Pupae were
      exposed to atmospheres of 60, 80, or 98% carbon dioxide (CO2) in nitrogen (N2),
      or 60 or 80% CO2 in air at temperatures of 26.7 degrees C or 32.2 degrees C and
      60% RH. Controlled atmosphere treatments at 32.2 degrees C controlled pupae
      faster than the same treatments at the lower temperature. At both temperatures
      high CO2 concentration treatments combined with nitrogen killed pupae faster than
      high CO2 concentration treatments combined with air. Exposure to 80% carbon
      dioxide mixed with nitrogen was the most effective treatment causing 100%
      mortality in 12 h at 32.2 degrees C and 93.3% mortality in 18 h at 26.6 degrees
      C. High-temperature controlled atmosphere treatments had no adverse effects on
      quality of two preserved floral products, Limonium sinuatum (L.) and Gypsophila
      elegans (Bieb.), tested for 12, 18, and 24 h according to industry standards.

PMID- 12403438
TI  - Pest management in traditional maize stores in West Africa: a farmer's
      perspective.
AB  - Farmers in the Republic of Benin have few resources to invest in protection of
      stored maize, and prophylactic pesticide application is often recommended by
      extension and development agencies. Neither the efficacy nor profitability of
      such an application in traditional maize storage facilities has been addressed
      quantitatively. In this study, existing management options for stored maize were
      evaluated monthly over 6 mo in central and southern Benin with respect to their
      effects on grain injury and on densities of Prostephanus truncatus (Horn) and
      Sitophilus zeamais Motschulsky. P. truncatus infested 54% of the experimental
      stores in the study even though Teretrius nigrescens (Lewis), a natural enemy
      introduced against P. truncatus, was well established in the region. S. zeamais
      was the most common pest, found in 85% of the experimental storage facilities.
      Prophylactically treated maize was, on average, worth more than untreated maize
      for month 1 through 5 in southern Benin, after taking into account market price,
      pesticide costs, percentage grain damage and weight loss, but maize storage was
      not profitable overall. No difference was observed between treatments in central
      Benin. After 6 mo treated storage facilities were not significantly different
      from untreated storage facilities in terms of either percentage damage or profit
      in either region. A rapid scouting plan intended to provide farmers with a means
      for identifying storage facilities at greatest risk of severe P. truncatus
      infestation was field validated. Given that unsafe pesticide use is prevalent in
      Benin, research and extension services should clearly state the limitations to
      prophylactic treatment and increase the effort to educate farmers on appropriate
      pesticide use, store monitoring and marketing.

PMID- 12403439
TI  - Monitoring stored-product pests in food processing plants with pheromone
      trapping, contour mapping, and mark-recapture.
AB  - Distribution and movement patterns of several species of stored-product pests in
      a food processing plant were investigated. The objectives of this study were to
      determine the temporal and spatial variation in abundance of stored-product pests
      using pheromone traps; assess the effectiveness of trap type, location, and
      number on monitoring insect populations; and to evaluate the nature of pheromone
      trap capture hot spots by measuring patterns of insect movement. We determined
      that the distributions of Trogoderma variabile Ballion, Lasioderina serricorne
      (F.), Tribolium castaneum (Herbst), and Plodia interpunctella (Hubner) within the
      facility were typically clumped and that foci of high trap captures, based on
      visual observation of contour maps, varied among species and over time. Trap type
      and location influenced the number of T. variabile captured: traps on the floor
      and along walls captured more individuals than hanging traps and traps next to
      support pillars. T. variabile was the predominant insect pest at this facility
      and from mark-recapture studies, we found that individual beetles moved across
      multiple floors in the facility and from 7 to 216 m though the warehouse.

PMID- 12403440
TI  - Persistence and efficacy of spinosad residues in farm stored wheat.
AB  - Degradation and insecticidal effectiveness of spinosad residues were evaluated in
      Kansas during November 2000 to November 2001 in farm bins holding wheat (34
      metric ton capacity). About 50 kg of hard red winter wheat from each of three
      bins were brought to the laboratory and treated separately with 1-ml aqueous
      suspensions of spinosad to provide rates of 0.1, 0.5,1, 3, 6 mg (AI)/kg of wheat.
      Wheat treated with distilled water served as the control treatment. Untreated and
      spinosad-treated wheat samples (250 g each) were placed in three plastic pouches
      of two different mesh sizes, and buried 2.5 cm below the grain surface. Pouches
      with large mesh openings were used to monitor insect infestations and kernel
      damage in untreated and spinosad-treated samples. Pouches with small mesh were
      used for extracting spinosad residues and for conducting laboratory bioassays
      with adults of the lesser grain borer, Rhyzopertha dominica (F.) and red flour
      beetle, Tribolium castaneum (Herbst) at 28 degrees C and 65% RH. Wheat
      temperature and relative humidity near the pouches during the 1 yr of storage
      ranged from -10 to 32 degrees C and 50 to 70%, respectively. Moisture of wheat
      samples varied from 12.4 to 13%. Observed spinosad residues on wheat samples were
      25% less than the calculated rates of 0.1 to 6 mg/kg. However, these residues
      were stable during the 1 yr of storage, and killed all R. dominica adults exposed
      for 14 d in the laboratory. Mortality of T. castaneum adults increased with an
      increase in spinosad rate. The linear regression slope of LD50s (0.3-2.7 mg/kg)
      against storage time was not significantly different from zero, indicating no
      loss in spinosad toxicity to T. castaneum adults. Insect species, insect numbers,
      and kernel damage over time in wheat samples inside pouches with large mesh
      openings were highly inconsistent, and failed to accurately characterize spinosad
      performance. Laboratory bioassays with R. dominica and T castaneum adults using
      grain from pouches with small mesh openings accurately gauged spinosad
      persistence and insecticidal activity under the field conditions.

PMID- 12403441
TI  - Development of granular boric acid sugar baits for house flies (Diptera:
      Muscidae).
AB  - Freeze-dried, granular sugar baits containing boric acid as the toxicant were
      evaluated against house flies, Musca domestica L., in two bioassays with toxicant
      dose ranges of 3, 5, 7, 8, and 12%, and 3, 5, 9, 17, and 33% boric acid,
      respectively, calculated and expressed on a dry weight basis. Flies in bioassay 1
      were mixed sex and unstarved and flies in bioassay 2 were females only and
      starved 4 h before testing began. LC50s were 8.97 and 14.33%, and LT50s were
      59.75 and 53.34 h in bioassays 1 and 2, respectively. Baits were tested at
      concentrations as high as 33%, however there was no indication of repellency as
      seen previously with liquid baits. Reasons for lack of repellency and potential
      uses for baits are discussed. Development of efficacious granular baits would
      allow the presentation of higher levels of boric acid in volumes much smaller
      than required for liquid baits.

PMID- 12403442
TI  - Managing the horn fly (Diptera: Muscidae) using an electric walk-through fly
      trap.
AB  - An electric walk-through fly trap was evaluated for the management of the horn
      fly, Hematobia irritans (L.), on dairy cattle in North Carolina over 2 yr. The
      trap relies on black lights and electrocution grids to attract and kill flies
      that are brushed from the cattle passing through. During the first season, horn
      fly densities were reduced from >1,400 to <200 flies per animal. Horn fly density
      averaged 269.2 +/- 25.8 on cattle using the walk-through fly trap twice daily,
      and 400.2 +/- 43.5 on the control group during the first year. The second year,
      seasonal mean horn fly density was 177.3 +/- 10.8 on cattle using the walk
      through fly trap compared with 321.1 +/- 15.8 on the control group. No
      insecticides were used to control horn flies during this 2-yr study.

PMID- 12403443
TI  - Dynamic study of excited state hydrogen-bonded complexes of harmane in
      cyclohexane-toluene mixtures.
AB  - Photoinduced proton transfer reactions of harmane or 1-methyl-9H-pyrido[3,4
      b]indole (HN) in the presence of the proton donor hexafluoroisopropanol (HFIP) in
      cyclohexane-toluene mixtures (CY-TL; 10% vol/vol of TL) have been studied. Three
      excited state species have been identified: a 1:2 hydrogen-bonded proton transfer
      complex (PTC), between the pyridinic nitrogen of the substrate and the proton
      donor, a hydrogen-bonded cation-like exciplex (CL*) with a stoichiometry of at
      least 1:3 and a zwitterionic exciplex (Z*). Time-resolved fluorescence
      measurements evidence that upon excitation of ground state PTC, an excited state
      equilibrium is established between PTC* and the cationlike exciplex, CL*,
      lambdaem approximately/= 390 nm. This excited state reaction is assisted by
      another proton donor molecule. Further reaction of CL* with an additional HFIP
      molecule produces the zwitterionic species, Z*, lambda(em) approximately/= 500
      nm. From the analysis of the multiexponential decays, measured at different
      emission wavelengths and as a function of HFIP concentration, the mechanism of
      these excited state reactions has been established. Thus, three rate constants
      and three reciprocal lifetimes have been determined. The simultaneous study of
      1,9-dimethyl-9H-pyrido[3,4-b]indole (MHN) under the same experimental conditions
      has helped to understand the excited state kinetics of these processes.

PMID- 12403444
TI  - Observation of a fluorescent dimer of a sulfonated phthalocyanine.
AB  - With very few exceptions, phthalocyanine dimers are found to be nonfluorescent.
      We report here the observation of a fluorescent dimer of a tetrasulfonated copper
      phthalocyanine in ethanol and water. Fluorescence excitation and emission spectra
      at room temperature and at 77 K are presented. These are consistent with the
      conventional model of exciton coupling in a cofacial dimer.

PMID- 12403445
TI  - Photoinduced N-demethylation of rufloxacin and its methyl ester under aerobic
      conditions.
AB  - Irradiation of rufloxacin (RF) under aerobic conditions gives rise to N
      demethylation of the piperazinyl ring, which is enhanced in aerated D2O. Two
      primary processes seem to be involved in RF N-demethylation: photoionization from
      1RF and singlet oxygen generation from 3RF. Both processes may lead to the same
      key intermediates, namely, RF*+ and superoxide radical anion; coupling of these
      intermediates explains N-demethylation of RF via an iminium cation. Formation of
      the hydrated electron by a monophotonic process (with a quantum yield of 0.09) is
      detected along with 3RF (with a intersystem-crossing quantum yield phiISC = 0.36)
      by laser flash photolysis. Studies performed on RF methyl ester give
      qualitatively similar results.

PMID- 12403446
TI  - Photoionization of DNA and RNA bases, nucleosides and nucleotides through a
      combination of one- and two-photon pathways upon 266 nm nanosecond laser
      excitation.
AB  - The 266 nm nanosecond laser photolysis of various purine and pyrimidine
      derivatives results in their photoionization (PI) as one of the primary
      photochemical pathways. Electron photoejection occurs through a combination of
      one- and two-photon mechanisms. The PI values depend on the substituents attached
      to the chromophore of the base. The net PI of the purine bases at 266 nm are of
      the same order of magnitude (10(-2)) as those of the pyrimidine bases under
      similar experimental conditions. The monophotonic component is approximately one
      third of the net PI yield of the bases. A nonrelaxed singlet excited state
      intermediate is tentatively proposed for this pathway. It is proposed that this
      state is significantly stabilized by water solvation, transforming it into a
      charge transfer to solvent state from which the hydrated electron evolves.

PMID- 12403447
TI  - Estimation of biologically damaging UV levels in marine surface waters with DNA
      and viral dosimeters.
AB  - We have surveyed the biologically harmful radiation penetrating the water column
      along a transect in the western Gulf of Mexico using dosimeters consisting of
      intact viruses or naked calf-thymus DNA (ctDNA). The indigenous marine
      bacteriophage PWH3a-P1, which lytically infects the heterotrophic bacterium
      Vibrio natriegens (strain PWH3a), displayed decay rates for infectivity
      approaching 1.0 h(-1) in surface waters when deployed in a seawater-based
      dosimeter. The accumulation of pyrimidine dimers in ctDNA dosimeters provided a
      strong correlation to these results, with pyrimidine dimers representing more
      than 0.3% (up to ca 3800 dimers Mb(-1) DNA) of the total DNA in dosimeters
      exposed to sea surface levels of solar radiation. The results demonstrate a
      strong correlation between the dimer formation in the DNA dosimeters, the decay
      rates of viral infectivity and the penetration of UVB radiation into the water
      column. The decay of viral infectivity attenuated with depth in a manner similar
      to the decay of solar radiation and was still significant at 10 m in offshore
      oligotrophic water and at dimer frequencies less than 0.1% (ca 200-300 dimers Mb(
      1) DNA).

PMID- 12403448
TI  - Evaluation of DNA dosimetry to assess ozone-mediated variability of biologically
      harmful radiation in Antarctica.
AB  - In this study we investigated the use of a DNA dosimeter to accurately measure
      changes in ultraviolet B radiation (UVBR; 280-315 nm) under Antarctic ozone hole
      conditions. Naked DNA solution in quartz tubes was exposed to ambient solar
      radiation at Rothera Research Station, Antarctica, between October and December
      1998 for 3 h during UVBR peak hours (1200-1500 h). Trends in UVBR-mediated DNA
      damage (formation of cyclobutane pyrimidine dimers [CPD]) were related to cloud
      cover, ozone-column depth and spectroradiometric measurements of ambient
      radiation. Ozone-column depths ranged from 130 to 375 DU during the study period,
      resulting in highly variable UVBR doses, from 1.6 to 137 kJ m(-2) over the 3 h
      exposure, as measured by spectroradiometry. There was a strong positive
      correlation (86%) between dosimeter CPD concentrations and DNA-weighted UVBR
      doses. Ozone depth was a strong predictor of DNA damage (63%), and there was no
      significant relationship between CPD formation and cloud cover. Subtle changes in
      spectral characteristics caused by ozone depletion were detected by the
      biodosimeter; the highest CPD concentrations were observed in October when ozone
      mediated shifts favored shorter wavelengths of UVBR. We conclude that the DNA
      biodosimeter is an accurate indicator of biologically effective UVBR, even under
      highly variable ozone conditions.

PMID- 12403449
TI  - Parameterization of daily solar global ultraviolet irradiation.
AB  - Daily values of solar global ultraviolet (UV) B and UVA irradiation as well as
      erythemal irradiation have been parameterized to be estimated from pyranometer
      measurements of daily global and diffuse irradiation as well as from atmospheric
      column ozone. Data recorded at the Meteorological Observatory Potsdam (52 degrees
      N, 107 m asl) in Germany over the time period 1997-2000 have been used to derive
      sets of regression coefficients. The validation of the method against independent
      data sets of measured UV irradiation shows that the parameterization provides a
      gain of information for UVB, UVA and erythemal irradiation referring to their
      averages. A comparison between parameterized daily UV irradiation and independent
      values of UV irradiation measured at a mountain station in southern Germany
      (Meteorological Observatory Hohenpeissenberg at 48 degrees N, 977 m asl)
      indicates that the parameterization also holds even under completely different
      climatic conditions. On a long-term average (1953-2000), parameterized annual UV
      irradiation values are 15% and 21% higher for UVA and UVB, respectively, at
      Hohenpeissenberg than they are at Potsdam. Daily global and diffuse irradiation
      measured at 28 weather stations of the Deutscher Wetterdienst German Radiation
      Network and grid values of column ozone from the EPTOMS satellite experiment
      served as inputs to calculate the estimates of the spatial distribution of daily
      and annual values of UV irradiation across Germany. Using daily values of global
      and diffuse irradiation recorded at Potsdam since 1937 as well as atmospheric
      column ozone measured since 1964 at the same site, estimates of daily and annual
      UV irradiation have been derived for this site over the period from 1937 through
      2000, which include the effects of changes in cloudiness, in aerosols and, at
      least for the period of ozone measurements from 1964 to 2000, in atmospheric
      ozone. It is shown that the extremely low ozone values observed mainly after the
      eruption of Mt. Pinatubo in 1991 have substantially enhanced UVB irradiation in
      the first half of the 1990s. According to the measurements and calculations, the
      nonlinear long-term changes observed between 1968 and 2000 amount to +4%, ...,
      +5% for annual global irradiation and UVA irradiation mainly because of changing
      cloudiness and + 14%, ..., +15% for UVB and erythemal irradiation because of both
      changing cloudiness and decreasing column ozone. At the mountain site,
      Hohenpeissenberg, measured global irradiation and parameterized UVA irradiation
      decreased during the same time period by -3%, ..., -4%, probably because of the
      enhanced occurrence and increasing optical thickness of clouds, whereas UVB and
      erythemal irradiation derived by the parameterization have increased by +3%, ...,
      +4% because of the combined effect of clouds and decreasing ozone. The
      parameterizations described here should be applicable to other regions with
      similar atmospheric and geographic conditions, whereas for regions with
      significantly different climatic conditions, such as high mountainous areas and
      arctic or tropical regions, the representativeness of the regression coefficients
      would have to be approved. It is emphasized here that parameterizations, as the
      one described in this article, cannot replace measurements of solar UV radiation,
      but they can use existing measurements of solar global and diffuse radiation as
      well as data on atmospheric ozone to provide estimates of UV irradiation in
      regions and over time periods for which UV measurements are not available.

PMID- 12403450
TI  - Solar UVB and plant damage irradiances for different Argentinean regions.
AB  - We calculated the integrated UVB and plant damage irradiances for Argentina, a
      country in the Southern Hemisphere spread over a large latitudinal range. The
      irradiances were calculated for clear sky days using the Madronich code for the
      average conditions of the months corresponding to the summer and winter solstices
      and the fall and spring equinoxes. Ozone, aerosol and ground albedo typical for
      each region and for each period of the year have been considered. A comparison
      was made of the behavior of these irradiances at the different locations. A more
      pronounced time dependence of the plant damage irradiance was obtained because of
      the fact that the corresponding spectrum is largely concentrated at a small
      wavelength of the UVB interval. We established a correlation between both
      irradiances, which can be approximated by a quadratic function. Because the plant
      damage irradiance is a quantity that is not directly measured by instruments, we
      showed the utility of the correlation by determining this biological
      effectiveness from the integrated UVB irradiance measured at the Astronomical
      Observatory of Rosario, Argentina, on clear sky days of the year 2001, as a
      characteristic example of the midlatitude near-sea level location of a highly
      productive agricultural region, which can be extended to other regions of the
      world. The plant damage results are relative ones (as is the case for the
      erythemal irradiance). So, they can be used to determine the maximum/minimum and
      asymmetry ratios, to study the influence of atmospheric variables and to make
      comparisons with other geographical locations.

PMID- 12403451
TI  - UVB irradiation of normal human skin favors the development of type-2 T-cells in
      vivo and in primary dermal cell cultures.
AB  - To determine the effect of UVB exposure on the balance of type-1 or type-2 T
      cells in skin, we examined the expression of key markers interferon (IFN)-gamma
      and interleukin (IL)-4 in cryostat sections. IFN-gamma mRNA was clearly
      detectable in nonirradiated control skin, and IFN-gamma protein was found in 2%
      of the dermal CD3pos T-cells, whereas IL-4 mRNA was hardly detectable, and no IL
      4 protein was found. In contrast, IL-4 mRNA expression increased upon
      irradiation, and IL-4 was found in 2% of the T-cells at day 2 after UVB-exposure.
      Concomitantly, IFN-gamma mRNA expression decreased, and IFN-gamma protein became
      absent. We also analyzed T-cells present in primary dermal cell cultures, which
      were used as an in vitro equivalent of the in vivo situation. As compared with T
      cells from control skin, T-cells in dermal cell cultures from UVB-exposed skin
      displayed an increased IL-4 and decreased IFN-gamma expression. No such skewing
      occurred when the T-cells from irradiated skin were cloned in the absence of a
      dermal microenvironment. Except for an occasional positive T-cell, type-1
      associated cell-surface markers (CCR5, CXCR3) or type-2 markers (CCR3, CD30,
      CRTH2) were undetectable in situ. But these markers were expressed on cultured
      dermal T-cells from UVB-exposed and control skin at a comparable level, but did
      not correlate with the IFN-gamma and IL-4 production. Altogether, UVB-induced
      changes of the dermal microenvironment favor the development of type-2 T-cells.

PMID- 12403452
TI  - Fluorescence emission and absorption spectra of single Anabaena sp. strain
      PCC7120 cells.
AB  - The fluorescence emission and absorption spectra of single Anabaena sp. strain
      PCC7120 cells including vegetative cells and heterocysts have been studied in
      intact filaments in vivo with confocal microscopy and grating spectrography. The
      diameters of the excitation and detection areas in the cells are less than 1.0
      microm. Heterogeneities within the same cell and among different cells are
      observed. The evident spectral heterogeneities in heterocysts, not reported
      previously, are attributed to the different stages of the evolution of
      phycobilisomes in heterocysts. The photosystem II in heterocysts were found to be
      not metabolized completely.

PMID- 12403453
TI  - Apoptotic response to photodynamic therapy versus the Bcl-2 antagonist HA14-1.
AB  - In this study, murine leukemia L1210 cells were used to compare the effects of
      photodynamic therapy (PDT) with those of the apoptotic nonpeptidic Bcl-2 ligand
      ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate
      (HA14-1). The photosensitizing agent capronyloxy-tetrakis methyloxyethyl
      porphycene (CPO) was selected from a group of sensitizers previously shown to
      target the antiapoptotic protein Bcl-2 for photodamage. Like PDT with CPO, HA14-1
      caused the rapid activation of procaspase-3, followed by the appearance of an
      apoptotic morphology within 60 min. Caspase activation after a sublethal dose of
      either PDT or HA14-1 was enhanced by staurosporine or the bile acid
      ursodeoxycholic acid. Moreover, PDT promoted procaspase activation and lethality
      of HA14-1 and vice versa. Effects of PDT versus HA14-1 could not be distinguished
      on the basis of the reactive oxygen species formation. Both caused the rapid
      oxidation of 2',7'-dichlorofluorescein. These results are consistent with the
      hypothesis that Bcl-2 photodamage is a target for some photosensitizing agents.

PMID- 12403454
TI  - Photobleaching of hypericin bound to human serum albumin, cultured adenocarcinoma
      cells and nude mice skin.
AB  - Hypericin is a promising photosensitizer for photodynamic therapy (PDT)
      characterized by a high yield of singlet oxygen. Photobleaching of hypericin has
      been studied by means of absorption and fluorescence spectroscopy in different
      biological systems: in human serum albumin solution, in cultured human
      adenocarcinoma WiDr cells and in the skin of nude mice. Prolonged exposure to
      light (up to 95 min, 100 mW/cm2) of wavelength around 596 nm induced fluence
      dependent photobleaching of hypericin in all studied systems. The photobleaching
      was not oxygen dependent, and singlet oxygen probably played no significant role.
      Emission bands in the spectral regions 420-560 nm and above 600 nm characterize
      the photoproducts formed. An emission band at 615-635 nm was observed after
      irradiation of cells incubated with hypericin or of mouse skin in vivo but not in
      albumin solution. The excitation spectrum of these products resembled that of
      hypericin. Hypericin appears to be more photostable than most sensitizers used in
      PDT, including mTHPC and Photofrin.

PMID- 12403455
TI  - Topical application of 5-aminolevulinic acid and its methylester, hexylester and
      octylester derivatives: considerations for dosimetry in mouse skin model.
AB  - Ester derivatives of 5-aminolevulinic acid (ALA-esters) have been proposed as
      alternative drugs for ALA in photodynamic therapy. After topical application of
      creams containing ALA, ALA methylester (ALA-Me), ALA hexylester (ALA-Hex) and ALA
      octylester (ALA-Oct) on mouse skin, typical fluorescence excitation and emission
      spectra of protoporphyrin IX (PpIX) were recorded, exhibiting a similar spectral
      shape for all the drugs in the range of concentrations (0.5-20%) studied. The
      accumulation kinetics of PpIX followed nearly a similar profile for all the drug
      formulations. The fluorescence of PpIX peaked at around 6-12 h of continuous
      cream application. Nevertheless, some differences in pharmacokinetics were
      noticed. For ALA cream, the highest PpIX fluorescence was achieved using 20% of
      ALA in an ointment. Conversely, 10% of ALA-Me and ALA-Hex, but not of ALA-Oct, in
      the cream was more efficient (P < 0.05) than was 20%. The cream becomes rather
      fluid when 20% of any of these ALA-esters is used in ointment, whereas 10% and
      lower concentrations of ALA-esters do not significantly increase fluidity of the
      cream. The dependence of PpIX accumulation on the concentration of ALA and ALA
      ester in the applied cream followed (P < 0.002) kinetics as described by a
      mathematical model based on the Michaelis-Menten equation for enzymatic
      processes. Under the present conditions, the PpIX amount in the skin increased by
      around 50% by the application of ALA-Me, ALA-Hex or ALA-Oct for 4-12 h as
      compared with ALA for the same period. Observations of the mice under exposure to
      blue light showed that after 8-24 h of continuous application of ALA, the whole
      mouse was fluorescent, whereas in the case of ALA-Me, ALA-Hex and ALA-Oct the
      fluorescence of PpIX was located only at the area of initial cream application.
      The amount of the active compound in the applied cream necessary to induce 90% of
      the maximal amount of PpIX was determined for normal mouse skin. Optimal PpIX
      fluorescence can be attained using around 5% ALA, 10% ALA-Me and 5% ALA-Hex
      creams during short application times (2-4 h). Topical application of ALA-Oct may
      not gain optimal PpIX accumulation for short applications (<5 h). For long
      application times (8-12 h), it seems that around 1% ALA, 4% ALA-Me, 6% ALA-Hex
      and 16% ALA-Oct can give optimal PpIX fluorescence. But for long application
      times and high concentrations, systemic effect of ALA applied topically on
      relatively large areas should be considered.

PMID- 12403456
TI  - Wavelength-dependent properties of photodynamic therapy using hypericin in vitro
      and in an animal model.
AB  - Wavelength effects in photodynamic therapy (PDT) with hypericin (HY) were
      examined in a C26 colon carcinoma model both in vitro and in vivo. Irradiation of
      HY-sensitized cells in vitro with either 550 or 590 nm caused the loss of cell
      viability in a drug- and light-dose-dependent manner. The calculated ratio of HY
      based PDT (HY-PDT) efficiencies at these two wavelengths was found to correlate
      with the numerical ratio of absorbed photons at each wavelength. In vivo
      irradiation of C26-derived tumors, 6 h after intraperitoneal administration of HY
      (5 mg/kg), caused extensive vascular damage and tumor necrosis. The depth of
      tumor necrosis (d) was more pronounced at 590 than at 550 nm and increased when
      the light dose was raised from 60 to 120 J/cm2. The maximal depths of tumor
      necrosis (at 120 J/cm2) were 7.5+/-1.5 mm at 550 nm and 9.9+/-0.8 mm at 590 nm.
      Both values are rather high in view of the limited penetration of green-yellow
      light into the tissue. Moreover, the depth ratio, d590/d550 = 1.3 (P < 0.001), is
      smaller than expected considering the 2.2-fold lower HY absorbance and the 1.7
      fold lower tissue penetration of radiation at 550 than at 590 nm. This finding
      indicates that in vivo the depth at which HY-PDT elicits tumor necrosis is not
      only determined by photophysical considerations (light penetration, number of
      absorbed photons) but is also influenced significantly by other mechanisms such
      as vascular effects. Therefore, despite the relatively short-wavelength peaks of
      absorption, our observations suggest that HY is an effective photodynamic agent
      that can be useful in the treatment of tumors with depths in the range of 1 cm.

PMID- 12403457
TI  - A Fourier transform infrared study of Neurospora rhodopsin: similarities with
      archaeal rhodopsins.
AB  - The NOP-1 gene from the eukaryote Neurospora crassa, a filamentous fungus, has
      recently been shown to encode an archaeal rhodopsin-like protein NOP-1. To
      explore the functional mechanism of NOP-1 and its possible similarities to
      archaeal and visual rhodopsins, static and time-resolved Fourier transform
      infrared difference spectra were measured from wild-type NOP-1 and from a mutant
      containing an Asp-->Glu substitution in the Schiff base (SB) counterion, Asp131
      (D131E). Several conclusions could be drawn about the molecular mechanism of NOP
      1: (1) the NOP-1 retinylidene chromophore undergoes an all-trans to 13-cis
      isomerization, which is typical of archaeal rhodopsins, and closely resembles
      structural changes of the chromophore in sensory rhodopsin II; (2) the NOP-1 SB
      counterion, Asp131, has a very similar environment and behavior compared with the
      SB counterions in bacteriorhodopsin (BR) and sensory rhodopsin II; (3) the O-H
      stretching of a structurally active water molecule(s) in NOP-1 is similar to
      water detected in BR and is most likely located near the SB and SB counterion in
      these proteins; and (4) one or more cysteine residues undergo structural changes
      during the NOP-1 photocycle. Overall, these results indicate that many features
      of the active sites of the archaeal rhodopsins are conserved in NOP-1, despite
      its eukaryotic origin.

PMID- 12403458
TI  - Flavonoid distribution in tissues of Phillyrea latifolia L. leaves as estimated
      by microspectrofluorometry and multispectral fluorescence microimaging.
AB  - A new method for detecting the tissue-specific distribution of flavonoids has
      been developed by coupling microspectrofluorometry and multispectral fluorescence
      microimaging techniques. Fluorescence responses of cross sections taken from 1
      year old Phillyrea latifolia leaves exposed to full (sun leaves) or 15% (shade
      leaves) solar radiation in a coastal area of Southern Tuscany were analyzed.
      Fluorescence spectra of different tissue layers, each normalized at its
      fluorescence maximum, that were stained or not stained with Naturstoff reagent A
      (in ethanol), under excitation with UV light (lambdaexc = 365 nm) or blue light
      (lambdaexc = 436 nm) were recorded. The shape of the fluorescence spectra of
      tissue layers from shade and sun leaves differed only under UV excitation. The
      fluorescence of stained cross sections from sun and shade leaves as well as from
      different layers of sun leaves received a markedly different contribution from
      the blue (470 nm) and the yellow-red (580 nm) wavebands. Such changes in tissue
      fluorescence signatures were related to light-induced changes of extractable
      caffeic acid derivatives and flavonoid glycosides, namely quercetin 3-O
      rutinoside and luteolin 7-O-glucoside. Wall-bound phenolics, i.e. hydroxycinnamic
      acids (p-coumaric, ferulic and caffeic acid) and flavonoids (apigenin and
      luteolin derivatives), did not substantially differ between sun and shade leaves.
      A Gaussian deconvolution analysis of fluorescence spectra was subsequently
      performed to estimate the contribution of flavonoids (emitting at 600 nm, F600
      [red fluorescence contribution = signal integrated over a Gaussian band centered
      at about 600 nm]) relative to the tissue fluorescence (Ftot [total fluorescence =
      signal integrated over the whole fluorescence spectrum]). The F600/ Ftot ratios
      sharply differed between analogous tissues of sun and shade leaves, as well as
      among tissue layers within each leaf type. A highly resolved picture of the
      tissue flavonoid distribution was finally provided through a fluorescence
      microimaging technique by acquiring fluorescence images at the blue (fluorescence
      at about 470 nm [F470]) and yellow-red (fluorescence at about 580 nm [F580])
      wavelengths and correcting the F580 image for the contribution of nonflavonoids
      to the fluorescence at 580 nm. Monochrome images were elaborated by adequate
      computing functions to visualize the exclusive accumulation of flavonoids in
      different layers of P. latifolia leaves. Our data show that in shade leaves
      flavonoids almost exclusively occurred in the adaxial epidermal layer. In sun
      leaves flavonoids largely accumulated in the adaxial epidermal and subepidermal
      cells and followed a steep gradient passing from the adaxial epidermis to the
      inner spongy layers. Flavonoids also largely occurred in the abaxial epidermal
      cells and constituted the exclusive class of phenylpropanoids synthesized by the
      cells of glandular trichomes. The proposed method also allowed for the
      discrimination of the relative abundance of hydroxycinnamic derivatives and
      flavonoids in different layers of the P. latifolia leaves.

PMID- 12403459
TI  - Impairment of eye lens cell physiology and optics by broadband ultraviolet A
      ultraviolet B radiation.
AB  - The phototoxicity of ultraviolet A (UVA) alone and UVA plus ultraviolet B (UVB)
      combined on cultured porcine lenses was investigated by analyzing cellular
      function as measured with a fluorescence bioassay approach and optical integrity,
      in terms of sharpness of the lens focus as measured with a scanning laser system.
      The bioassay consisted of carboxyfluorescein diacetate-acetoxymethyl ester and
      alamarBlue fluorescent dyes. Aseptically dissected porcine lenses were maintained
      in modified medium 199 without phenol red supplemented with 1% penicillin
      streptomycin and 4% porcine serum. At 1 week of preincubation, baseline
      measurements were obtained. Then the lenses were treated with single exposures of
      different UVA and UVB energy levels. The lenses treated with 86 J/cm2 UVA alone
      showed a significant (P < 0.05) decrease in cellular and optical integrity at 48
      h after exposure, whereas those treated with 43 J/cm2 UVA alone did not show
      significant phototoxic effect. Lenses treated with 15.63 J/cm2 UVA plus 0.019
      J/cm2 UVB combined showed significant adverse effects beginning from 48 h after
      exposure. Also, there was no recovery. These findings show that a high UVA dose
      alone and relatively low UVA in combination with low UVB radiant exposure can
      impair lens cellular and optical functions, respectively.

PMID- 12403460
TI  - Role of xanthurenic acid 8-O-beta-D-glucoside, a novel fluorophore that
      accumulates in the brunescent human eye lens.
AB  - We have been able to identify a blue fluorophore from the low-molecular weight
      soluble fraction of human adult nondiabetic brunescent cataract lenses as
      xanthurenic acid 8-O-beta-D-glucoside (XA8OG) (excitation = 338 nm and emission =
      440 nm). To determine the role of this fluorophore in the lens, we have examined
      its photophysical and photodynamic properties. We found XA8OG to have a
      fluorescence quantum yield (phi) of 0.22 and a major emission lifetime of 12 ns.
      We found it to be a UVA-region sensitizer, capable of efficiently generating
      singlet oxygen species but little of superoxide. We also demonstrated that XA8OG
      oxidizes proteins when irradiated with UVA light, causing photodynamic covalent
      chemical damage to proteins. Its accumulation in the aging human lens (and the
      attendant decrease of its precursor O-beta-D-glucoside of 3-hydroxykynurenine)
      can, thus, add to the oxidative burden on the system. XA8OG, thus, appears to be
      an endogenous chromophore in the lens, which can act as a cataractogenic agent.

PMID- 12403462
TI  - A general role for splicing enhancers in exon definition.
AB  - Exonic splicing enhancers (ESEs) facilitate exon definition by assisting in the
      recruitment of splicing factors to the adjacent intron. Here we demonstrate that
      suboptimal 5' and 3' splice sites are activated independently by ESEs when they
      are located on different exons. However, when they are situated within a single
      exon, the same weak 5' and 3' splice sites are activated simultaneously by a
      single ESE. These findings demonstrate that a single ESE promotes the recognition
      of both exon/intron junctions within the same step during exon definition. Our
      results suggest that ESEs recruit a multicomponent complex that minimally
      contains components of the splicing machinery required for 5' and 3' splice site
      selection.

PMID- 12403461
TI  - tRNomics: analysis of tRNA genes from 50 genomes of Eukarya, Archaea, and
      Bacteria reveals anticodon-sparing strategies and domain-specific features.
AB  - From 50 genomes of the three domains of life (7 eukarya, 13 archaea, and 30
      bacteria), we extracted, analyzed, and compared over 4,000 sequences
      corresponding to cytoplasmic, nonorganellar tRNAs. For each genome, the complete
      set of tRNAs required to read the 61 sense codons was identified, which permitted
      revelation of three major anticodon-sparing strategies. Other features and
      sequence peculiarities analyzed are the following: (1) fit to the standard
      cloverleaf structure, (2) characteristic consensus sequences for elongator and
      initiator tDNAs, (3) frequencies of bases at each sequence position, (4) type and
      frequencies of conserved 2D and 3D base pairs, (5) anticodon/tDNA usages and
      anticodon-sparing strategies, (6) identification of the tRNA-Ile with anticodon
      CAU reading AUA, (7) size of variable arm, (8) occurrence and location of
      introns, (9) occurrence of 3'-CCA and 5'-extra G encoded at the tDNA level, and
      (10) distribution of the tRNA genes in genomes and their mode of transcription.
      Among all tRNA isoacceptors, we found that initiator tDNA-iMet is the most
      conserved across the three domains, yet domain-specific signatures exist. Also,
      according to which tRNA feature is considered (5'-extra G encoded in tDNAs-His,
      AUA codon read by tRNA-Ile with anticodon CAU, presence of intron, absence of
      "two-out-of-three" reading mode and short V-arm in tDNA-Tyr) Archaea sequester
      either with Bacteria or Eukarya. No common features between Eukarya and Bacteria
      not shared with Archaea could be unveiled. Thus, from the tRNomic point of view,
      Archaea appears as an "intermediate domain" between Eukarya and Bacteria.

PMID- 12403463
TI  - A biosensor for theophylline based on fluorescence detection of ligand-induced
      hammerhead ribozyme cleavage.
AB  - Recently, Breaker and coworkers engineered hammerhead ribozymes that rearrange
      from a catalytically inactive to an active conformation upon allosteric binding
      of a specific ligand. To monitor cleavage activity in real time, we have coupled
      a donor-acceptor fluorophore pair to the termini of the substrate RNA of such a
      hammerhead ribozyme, modified to cleave in trans in the presence of the
      bronchodilator theophylline. In the intact substrate, the fluorophores interact
      by fluorescence resonance energy transfer (FRET). The specific FRET signal breaks
      down as the effector ligand binds, the substrate is cleaved, and the products
      dissociate, with a rate constant dependent on the concentration of the ligand.
      Our biosensor cleaves substrate at 0.46 min(-1) in 1 mM theophylline and 0.04
      min(-1) without effector, and discriminates against caffeine, a structural
      relative of theophylline. We have measured the theophylline-dependence profile of
      this biosensor, showing that concentrations as low as 1 microM can be
      distinguished from background. To probe the mechanism of allosteric regulation, a
      single nucleotide in the communication domain between the catalytic and ligand
      binding domains was mutated to destabilize the inactive conformation of the
      ribozyme. As predicted, this mutant shows the same activity (0.3 min(-1)) in the
      presence and absence of theophylline. Additionally, time-resolved FRET
      measurements on the biosensor ribozyme in complex with a noncleavable substrate
      analog reveal no significant changes in fluorophore distance distribution upon
      binding of effector.

PMID- 12403465
TI  - Inhibition of protein synthesis by aminoglycoside-arginine conjugates.
AB  - Inhibition of translation by small molecule ligands has proven to be a useful
      tool for understanding this complex cellular mechanism, as well as providing
      drugs of significant medical importance. Many small molecule ligands inhibit
      translation by binding to RNA or RNA/protein components of the ribosomal subunits
      and usurping their function. A class of peptidomimetics [aminoglycoside-arginine
      conjugates (AAC)] has recently been designed to inhibit HIV TAR/tat interaction
      and in experiments aimed at assessing the inhibitory effects of AACs on TAR
      containing transcripts, we found that AACs are general inhibitors of translation.
      Experiments reported herein aim at characterizing these novel properties of AACs.
      We find that AACs are inhibitors of eukaryotic and prokaryotic translation and
      exert their effects by blocking peptide chain elongation. Structure/activity
      relationship studies suggest that inhibition of translation by AACs is directly
      related to the number of arginine groups present on the aminoglycoside backbone
      and to the nature of the core aminoglycoside. AACs are therefore attractive tools
      for understanding and probing ribosome function.

PMID- 12403464
TI  - Two proteins that form a complex are required for 7-methylguanosine modification
      of yeast tRNA.
AB  - 7-methylguanosine (m7G) modification of tRNA occurs widely in eukaryotes and
      bacteria, is nearly always found at position 46, and is one of the few
      modifications that confers a positive charge to the base. Screening of a
      Saccharomyces cerevisiae genomic library of purified GST-ORF fusion proteins
      reveals two previously uncharacterized proteins that copurify with m7G
      methyltransferase activity on pre-tRNA(Phe). ORF YDL201w encodes Trm8, a protein
      that is highly conserved in prokaryotes and eukaryotes and that contains an S
      adenosylmethionine binding domain. ORF YDR165w encodes Trm82, a less highly
      conserved protein containing putative WD40 repeats, which are often implicated in
      macromolecular interactions. Neither protein has significant sequence similarity
      to yeast Abd1, which catalyzes m7G modification of the 5' cap of mRNA, other than
      the methyltransferase motif shared by Trm8 and Abd1. Several lines of evidence
      indicate that both Trm8 and Trm82 proteins are required for tRNA m7G
      methyltransferase activity: Extracts derived from strains lacking either gene
      have undetectable m7G methyltransferase activity, RNA from strains lacking either
      gene have much reduced m7G, and coexpression of both proteins is required to
      overproduce activity. Aniline cleavage mapping shows that Trm8/Trm82 proteins
      modify pre-tRNAPhe at G46, the site that is modified in vivo. Trm8 and Trm82
      proteins form a complex, as affinity purification of Trm8 protein causes
      copurification of Trm82 protein in approximate equimolar yield. This functional
      two-protein family appears to be retained in eukaryotes, as expression of both
      corresponding human proteins, METTL1 and WDR4, is required for m7G
      methyltransferase activity.

PMID- 12403466
TI  - Mutational analysis identifies two separable roles of the Saccharomyces
      cerevisiae splicing factor Prp18.
AB  - Prp18 functions in the second step of pre-mRNA splicing, joining the spliceosome
      just prior to the transesterification reaction that creates the mature mRNA.
      Prp18 interacts with Slu7, and the functions of the two proteins are intertwined.
      Using the X-ray structure of Prp18, we have designed mutants in Prp18 that imply
      that Prp18 has two distinct roles in splicing. Deletion mutations were used to
      delineate the surface of Prp18 that interacts with Slu7, and point mutations in
      Prp18 were used to define amino acids that contact Slu7. Experiments in which
      Slu7 and mutant Prp18 proteins were expressed at different levels support a model
      in which interaction between the proteins is needed for stable binding of both
      proteins to the spliceosome. Mutations in an evolutionarily conserved region show
      that it is critical for Prp18 function but is not involved in binding Slu7.
      Alleles with mutations in the conserved region are dominant negative, suggesting
      that the resulting mutant prp18 proteins make proper contacts with the
      spliceosome, but fail to carry out a Prp18-specific function. Prp18 thus appears
      to have two separable roles in splicing, one in stabilizing interaction of Slu7
      with the spliceosome, and a second that requires the conserved loop.

PMID- 12403467
TI  - The dispersal of five group II introns among natural populations of Escherichia
      coli.
AB  - Group II introns are self-splicing RNAs that also act as retroelements in
      bacteria, mitochondria, and chloroplasts. Group II introns were identified in
      Escherichia coli in 1994, but have not been characterized since, and, instead,
      other bacterial group II introns have been studied for splicing and mobility
      properties. Despite their apparent intractability, at least five distinct group
      II introns exist naturally in E. coli strains. To illuminate their function and
      learn how the introns have dispersed in their natural host, we have investigated
      their distribution in the ECOR reference collection. Two introns were cloned and
      sequenced to complete their partial sequences. Unexpectedly, southern blots
      showed all ECOR strains to contain fragments and/or full-length copies of group
      II introns, with some strains containing up to 15 intron copies. One intron,
      E.c.14, has two natural homing sites in IS629 and IS911 elements, and the intron
      can be present in one, both, or neither homing site in a given strain. Nearly all
      strains that contain full-length introns also contain unfilled homing sites,
      suggesting either that mobility is highly inefficient or that most full-length
      copies are nonfunctional. The data indicate independent mobility of the introns,
      as well as mobility via the host DNA elements, and overall, the pattern of intron
      distribution resembles that of IS elements.

PMID- 12403468
TI  - The SBP2 and 15.5 kD/Snu13p proteins share the same RNA binding domain:
      identification of SBP2 amino acids important to SECIS RNA binding.
AB  - Selenoprotein synthesis in eukaryotes requires the selenocysteine insertion
      sequence (SECIS) RNA, a hairpin in the 3' untranslated region of selenoprotein
      mRNAs. The SECIS RNA is recognized by the SECIS-binding protein 2 (SBP2), which
      is a key player in this specialized translation machinery. The objective of this
      work was to obtain structural insight into the SBP2-SECIS RNA complex. Multiple
      sequence alignment revealed that SBP2 and the U4 snRNA-binding protein 15.5
      kD/Snu13p share the same RNA binding domain of the L7A/L30 family, also found in
      the box H/ACA snoRNP protein Nhp2p and several ribosomal proteins. In corollary,
      we have detected a similar secondary structure motif in the SECIS and U4 RNAs.
      Combining the data of the crystal structure of the 15.5 kD-U4 snRNA complex, and
      the SBP2/15.5 kD sequence similarities, we designed a structure-guided strategy
      predicting 12 SBP2 amino acids that should be critical for SECIS RNA binding.
      Alanine substitution of these amino acids followed by gel shift assays of the
      SBP2 mutant proteins identified four residues whose mutation severely diminished
      or abolished SECIS RNA binding, the other eight provoking intermediate down
      effects. In addition to identifying key amino acids for SECIS recognition by
      SBP2, our findings led to the proposal that some of the recognition principles
      governing the 15.5 kD-U4 snRNA interaction must be similar in the SBP2-SECIS RNA
      complex.

PMID- 12403469
TI  - The KH domains of Xenopus Vg1RBP mediate RNA binding and self-association.
AB  - Xenopus Vg1 mRNA is localized to the vegetal cortex during oogenesis in a process
      involving microtubules and microfilaments and proteins that specifically
      recognize the vegetal localization element (VLE) within the 3' untranslated
      region. One of the best characterized VLE-binding proteins is Vg1RBP or Vera.
      Primary sequence analysis of Vg1RBP and its homologs suggests that most of its
      open reading frame is occupied by RNA-binding modules, including two RRMs and
      four KH domains, arranged as three pairs of didomains. In the first detailed
      domain analysis of Vg1RBP, we show that the interaction of Vg1RBP with the VLE
      requires both KH didomains, but not the RRM didomain, and moreover that the KH
      didomains contribute cooperatively to RNA binding. In the full-length protein,
      individual KH domains display significant redundancy, and their relative
      importance appears to vary with the RNA target. We also demonstrate that the KH34
      didomain mediates Vg1RBP self-association, which is stabilized by RNA, and occurs
      in vivo as well as in vitro. Altogether, our findings highlight the importance of
      multiple KH domains in mediating RNA-protein and protein-protein interactions in
      the formation of a stable complex of Vg1RBP and Vg1 mRNA.

PMID- 12403472
TI  - Nourishing our roots.

PMID- 12403470
TI  - PSF and p54nrb bind a conserved stem in U5 snRNA.
AB  - PTB-associated splicing factor (PSF) has been implicated in both early and late
      steps of pre-mRNA splicing, but its exact role in this process remains unclear.
      Here we show that PSF interacts with p54nrb, a highly related protein first
      identified based on cross-reactivity to antibodies against the yeast second-step
      splicing factor Prpl8. We performed RNA-binding experiments to determine the
      preferred RNA-binding sequences for PSF and p54nrb, both individually and in
      combination. In all cases, iterative selection assays identified a purine-rich
      sequence located on the 3' side of U5 snRNA stem 1b. Filter-binding assays and
      RNA affinity selection experiments demonstrated that PSF and p54nrb bind U5 snRNA
      with both the sequence and structure of stem 1b contributing to binding
      specificity. Sedimentation analyses show that both proteins associate with
      spliceosomes and with U4/U6.U5 tri-snPNP.

PMID- 12403471
TI  - An active precursor in assembly of yeast nuclear ribonuclease P.
AB  - The RNA-protein subunit assembly of nuclear RNase P was investigated by specific
      isolation and characterization of the precursor and mature forms of RNase P using
      an RNA affinity ligand. Pre-RNase P was as active in pre-tRNA cleavage as mature
      RNase P, although it contained only seven of the nine proteins found in mature
      RNase P. Pop3p and Rpr2p were not required for maturation of the RPR1 RNA subunit
      and virtually absent from pre-RNase P, implying that they are dispensable for pre
      tRNA substrate recognition and cleavage. The RNase P subunit assembly is likely
      to occur in the nucleolus, where both precursor and mature forms of RNase P RNA
      are primarily localized. The results provide insight into assembly of nuclear
      RNase P, and suggest pre-tRNA substrate recognition is largely determined by the
      RNA subunit.

PMID- 12403474
TI  - Dentistry for people with special needs.

PMID- 12403473
TI  - Discussion on laser curettage continues.

PMID- 12403475
TI  - Loma Linda University School of Dentistry--from dream to reality.

PMID- 12403476
TI  - Reducing bacterial counts in dental unit waterlines: distilled water vs.
      antimicrobial agents.
AB  - BACKGROUND: This study evaluated five chemical disinfectants to compare their
      abilities to improve dental unit waterline quality and assess their effects, if
      any, on the biofilm layer. METHODS: Sixty new dental units, with a closed-circuit
      water system, were used to compare microbial levels in DUWLs treated with five
      antimicrobials: Listerine, Bio 2000, Rembrandt, Dentosept, and sodium fluoride to
      a control group of sterile distilled water alone over a six-week period. For all
      units, the waterlines were filled with solution, left overnight, and then flushed
      for 30 seconds with sterile distilled water the following morning prior to
      patient treatment. Waterlines were examined for biofilm buildup using scanning
      electron microscopy and colony-forming-unit counts. RESULTS: The sodium fluoride
      and the four chemical antimicrobials reduced the microbial count to 200 cfu/ml or
      less. Only samples taken from dental units receiving the control treatment
      (distilled water with no added antimicrobial) failed to meet ADA's stated goal.
      Examination of the SEMs revealed an apparent decrease in the biofilm mass but not
      elimination, despite repeated treatment with the four antimicrobial materials.
      CONCLUSIONS: Even in a closed-circuit water system, distilled water alone cannot
      reduce microbial contamination of dental treatment water from dental unit
      waterlines to the 200 cfu/ml ADA stated goal. However, water treated with
      Listerine mouthrinse, Rembrandt mouthrinse, Bio 2000, 0.5 percent sodium fluoride
      and Dentosept, did meet the microbial reduction goal. The biofilm apparently was
      reduced in volume, but not entirely eliminated. CLINICAL SIGNIFICANCE: The ADA
      goal of a maximum of 200 cfu/ml was achieved using any of five chemical
      antimicrobials and distilled water in a closed-water system. Despite the
      successful reduction in microbial contamination of the dental treatment water,
      the biofilm was not completely eliminated. Biofilm elimination and prevention
      would be needed through some other means.

PMID- 12403477
TI  - UCLA School of Dentistry: successes, challenges, and opportunities.

PMID- 12403478
TI  - The School of Dentistry at the University of California, San Francisco: service
      to humanity.

PMID- 12403479
TI  - Implementing an infant oral care program.
AB  - The American Academy of Pediatric Dentistry, American Dental Association,
      American Public Health Association, Association of State and Territorial Dental
      Directors, California Dental Association, and California Society of Pediatric
      Dentists currently recommend that children receive their first dental evaluation
      within the first year of life. Providing early care to children from ages 6
      months to 5 years offers an opportunity to educate and inform parents about their
      children's oral health. Anticipatory guidance - counseling of parents by health
      providers about developmental changes that will occur in their children between
      health visits - for children's dental health is an important part of preventive
      care. It may be the most effective way to prevent problems that traditional
      infectious disease models have failed to address, such as early childhood caries.
      The model of anticipatory guidance is valuable for dental professionals because
      it emphasizes prevention of dental problems rather than restorative care. A
      comprehensive infant oral care program utilizes (1) oral health assessment at
      regularly scheduled dental visits, (2) risk assessments, (3) counseling sessions
      with parents during either regular dental visits or additional visits scheduled
      if a child is deemed at risk, (4) preventive treatment such as the application of
      fluoride varnish or sealants, and (5) outreach and incentives to reinforce
      attendance. Facilitating access to early and regular dental care is a crucial
      part of any effective intervention strategy, and intervention techniques should
      be tailored to the community being served.

PMID- 12403480
TI  - University of the Pacific School of Dentistry: a dental school that serves the
      practicing profession.

PMID- 12403481
TI  - Clinical evolution of the Invisalign appliance.
AB  - The Invisalign System of tooth movement has been available to orthodontists since
      1999 and has now become available to the entire dental profession. This paper
      explores the role of this system within the dental armamentarium and describes
      the clinical evolution of the appliance, based on a feasibility study initiated
      at the University of the Pacific in 1997.

PMID- 12403482
TI  - University of Southern California School of Dentistry: dental education for the
      21st century.

PMID- 12403483
TI  - Saliva: a fountain of opportunity.
AB  - Saliva continues to demonstrate that it is more complex than generally perceived
      and has more diagnostic value than is generally appreciated. This article will
      review some of the components and functions of saliva; discuss its promise as a
      diagnostic aid; review some of the problems associated with inadequate salivary
      function; and, it is hoped, enhance oral health care providers' appreciation of
      the importance of saliva in everyday clinical practice.

PMID- 12403484
TI  - Oral gratification out of control.

PMID- 12403485
TI  - Decreased morbidity in homozygous sickle cell disease detected at birth.
AB  - In metropolitan France, newborn screening for sickle cell disease has been
      performed at the Hjpital Henri Mondor, Creteil, since 1985. After confirmation of
      the diagnosis, children are enrolled in a comprehensive medical-care program. Our
      aim was to evaluate the effectiveness of this program in France where most
      families are first generation immigrants with cultural and social differences
      that can interfere with medical follow-up. We compared the complications of
      sickle cell disease in two populations of homozygous SS children aged more than
      two years at their last medical visit, and recruited from an initial register of
      134 SS children: (1) 38 diagnosed by neonatal screening; (2) 69 controls,
      diagnosed at a mean age of 24 months. Mean age at the last medical visit is 58
      months in both groups. Splenic sequestrations and painful crises were
      significantly reduced in the screened group. Two screened children, belonging to
      the initial register from which the 38 other screened children were collected,
      died from overwhelming infection at 15 and 23 months, respectively. Neonatal
      diagnosis of sickle cell disease, coupled with specific preventive measures may
      lead, in the initial six years of life, to reduced painful events and splenic
      sequestration episodes. Education of parents is one of the hallmarks of
      preventive measures and may be difficult in first generation immigrants. Because
      of the bias of this type of study, a large prospective follow-up since birth is
      necessary to have a better understanding of the clinical course.

PMID- 12403486
TI  - Beta-thalassemia intermedia and non-Hodgkin's lymphoma.
AB  - The presenting symptoms of malignancies like anemia and splenomegaly in
      thalassemic patients can be overlooked and considered as complications of
      thalassemia. Our paper deals with a case of large B cell lymphoma with bone
      marrow involvement in an old lady with thalassemia intermedia. The patient showed
      complete response after the second cycle of chemotherapy that consists of
      cyclophosphamide, vincristine, and prednisone (CVP protocol). However, the
      patient relapsed with bone marrow involvement shortly after (2 weeks) completion
      of the sixth cycle of chemotherapy, and she was started on monoclonal antibodies
      Rituximab. On reviewing the literature, only four cases of thalassemia and
      lymphoma have been reported worldwide, thus making our case the fifth report of
      this rare combination of diseases.

PMID- 12403487
TI  - Hb Pakse [(alpha2) codon 142 (TAA-->TAT or Term-->Tyr)J in Thai patients with
      EAbart's disease and Hb H Disease.
AB  - Hb Pakse is caused by an alpha2-globin gene termination codon mutation, TAA-->TAT
      or Term-->Tyr, initially described in a Laotian family. We now report for the
      first time that the same mutation has been found in 14 Thai patients, seven with
      EABart's disease, four with Hb H disease, and three with alpha-thalassemia trait
      who were initially diagnosed as having Hb Constant Spring (Hb CS; alpha2-globin
      gene termination codon mutation TAA-->CAA or Term-->Gln). Co-inheritance of this
      mutation with alpha-thalassemia-1 (SEA type) leads to Hb H disease (hereafter
      designated as Hb H-Pakse disease) and to a complex thalassemia syndrome, namely
      EABart's-Pakse disease. Hematological data of these patients were compared with
      those of classical Hb H-CS and the EABart's patients. To facilitate
      epidemiological and diagnostic screening of Hb Pakse, a simple assay procedure
      based on allele specific polymerase chain reaction (PCR) amplifications was
      developed and validated. Using this allele specific PCR as a screening method,
      five additional individuals with Hb Pakse were found among 71 Thai subjects
      previously thought to have Hb CS.

PMID- 12403488
TI  - Coexistence of a novel beta-globin gene deletion (codons 81-87) with the codon 30
      (G-->C) mutation in an Indian patient with beta0-thalassemia.
AB  - We identified and characterized a novel beta0-thalassemia mutation due to the
      deletion of 22 bases from codons 81 through 87, found in a compound heterozygous
      state with codon 30 (G-->C) in a patient originating from West Bengal State,
      India. The deletion causes a shift in the reading frame of the coding sequence
      and creates a stop codon at position 81. Direct and inverted repeat sequences
      present in the deleted region might be involved in the origin of this mutation.
      The patient had moderate anemia and did not require blood transfusions
      (thalassemia intermedia).

PMID- 12403489
TI  - Hb G-Makassar [beta6(A3)Glu-->Ala; codon 6 (GAG-->GCG)]: molecular
      characterization, clinical, and hematological effects.
AB  - We report a Thai family in which five members are Hb G-Makassar heterozygotes and
      one member is, in addition, a heterozygote for beta0-thalassemia (IVS-I-1, G-
      >T). We confirm that the previously presumed mutation at codon 6 of the beta
      globin gene is GAG-->GCG. Hb G-Makassar heterozygotes are asymptomatic and
      hematologically normal. The Hb G-Makassar/beta0-thalassemia compound heterozygote
      has features of thalassemia minor. A simple and rapid polymerase chain reaction
      restriction fragment length polymorphism for the detection of Hb G-Makassar is
      described.

PMID- 12403490
TI  - Hb Groene Hart: a new Pro-->Ser amino acid substitution at position 119 of the
      alpha1-globin chain is associated with a mild alpha-thalassemia phenotype.
AB  - Alpha-Thalassemia (thal) is generally considered to be an expression defect
      caused mostly by deletions silencing one or more alpha-globin genes. Although
      nondeletional alpha-thalassemia is considered rare, in our laboratory we
      frequently observe alpha-thal phenotypes induced by point mutations. We report a
      new point mutation generating an abnormal hemoglobin (Hb) associated with a mild
      alpha-thal phenotype in two members of a Moroccan family, who presented with mild
      but persistent microcytic hypochromic parameters and a balanced beta/alpha
      synthetic ratio. All attempts to separate an abnormal native or denatured
      fraction were unsuccessful using electrophoresis, isoelectrofocusing (IEE), ion
      exchange and reversed phase high performance liquid chromatography (HPLC),
      denaturing polyacrylamide gel electrophoresis (PAGE), and electrospray mass
      spectrometry (ES/MS). The anomalous protein was only predictable by DNA analysis.
      The mutated gene product, not separable with any of the techniques used, could be
      a monomer unsuitable for tetramer formation, which is proteolyzed at an early
      stage. Alternatively, this mutation could perhaps lead to an abnormal splicing.
      The CCTCT sequence generated by the mutant, not found in the translated region of
      the gene, but normally present at the end of the IVS-II, could induce a possible
      exon skipping. This mutant could generate a mild or a critical Hb H disease in
      combination with one of the common alpha0-thal deletion defects.

PMID- 12403491
TI  - Molecular characterization of Hb D-Punjab [beta121(GH4)Glu-->Gln] in Thailand.
AB  - We describe the hematological and DNA characterization of Hb D-Punjab
      [beta121(GH4)Glu-->Gln] in Thailand. Nine patients from five unrelated families
      were studied; four patients were simple carriers of Hb D-Punjab, two were
      compound heterozygotes for Hb D-Punjab/beta+-thalassemia; another two patients
      were double heterozygotes for Hb D-Punjab and alpha-thalassemia-2, and one
      patient was a compound heterozygote for Hb D-Punjab and Hb E [beta26(B8)Glu-
      >Lys]. Typical thalassemic indices with hypochromic microcytosis were observed in
      compound Hb D-Punjab/ beta+-thalassemia and Hb D-Punjab/Hb E but normal
      hematological profiles were observed in the remaining cases. DNA sequencing of
      the beta-globin gene identified the GAA-->CAA substitution at codon 121 causing
      Hb D-Punjab in all cases, and the -28 (A-->G) mutation for the beta+-thalassemia
      alleles. beta-Globin gene haplotype analysis demonstrated, for the first time,
      that all these Asian beta(D-Punjab) globin genes were associated with haplotype [
      ++-+++], previously undescribed in other populations. The finding of Hb D-Punjab
      in Thailand is compatible either with an independent origin of this abnormal
      hemoglobin or a spread of the Hb D-Punjab gene with a single origin among Asians.

PMID- 12403492
TI  - Globin chain analysis by reversed phase high performance liquid chromatography:
      recent developments.
AB  - Reversed phase high performance liquid chromatography of globin chains is an
      important additional tool in the study of hemoglobin abnormalities. Using a
      technique modified from that of Leone et al.,[1] we report here the relative
      chromatographic behavior of about 200 different hemoglobin variants. This method
      provides an additional dimension in the presumptive characterization of
      hemoglobin variants. It was also found to be of special value for measuring the
      expression of neutral variants, such as thalassemic or unstable hemoglobins, and
      to identify neutral mutations associated with another variant, resulting in
      unusual hematological presentations.

PMID- 12403493
TI  - Thrombotic events in compound heterozygotes for a high affinity hemoglobin
      variant: Hb Milledgeville [alpha44(CE2)Pro-->Leu (alpha2)] and factor V Leiden.

PMID- 12403494
TI  - Three new variants of the alpha1-globin gene without clinical or hematologic
      effects: Hb Hagerstown [alpha44(CE2)Pro-->Ala (alpha1)]; Hb Buffalo
      [alpha89(FG1)His-->Gln (alpha1)], a hemoglobin variant from Somalia and Yemen; Hb
      Wichita [alpha95(G2)Pro-->Gln (alpha1)]; and a second, unrelated, case of Hb
      Roubaix [alpha55(E4)Val-->Leu (alpha1)].

PMID- 12403495
TI  - Four new beta chain hemoglobin variants without clinical or hematological
      effects: Hb San Bruno [beta39(C5)Gln-->His]; Hb Fort Dodge [beta93(F9)Cys-Tyr];
      Hb Rhode Island [beta116(G18)His-->Tyr]; and Hb Inglewood [beta142(H20)Ala-
      >Thr].

PMID- 12403496
TI  - Alpha-thalassemia does not significantly contribute to the low MCV level of Hb C
      trait.

PMID- 12403497
TI  - Detection of a small novel deletion in the alpha-globin gene and type II
      alpha(3.7) deletion by heteroduplex formation.

PMID- 12403498
TI  - Identification of a compound beta-thalassemia homozygosity [codon 10 (GCC-->GCA)
      and codon 16 (-C)] in an Afghan family.

PMID- 12403499
TI  - Thalassemia intermedia: heterozygous beta-thalassemia and co-inheritance of an a
      gene triplication.

PMID- 12403500
TI  - Hb G-Honolulu [alpha30(B11)Glu-->Gln (alpha2)], Hb J-Meinung [beta56(D7)Gly-
      >Asp], and beta-thalassemia [codons 41/42 (-TCTT)] in a Taiwanese family.

PMID- 12403501
TI  - Recent guidance on resuscitation: patients' choices and doctors' duties.

PMID- 12403502
TI  - How many inpatients at an acute hospital have palliative care needs? Comparing
      the perspectives of medical and nursing staff.
AB  - The primary aim of this prospective face-to-face interview survey was to identify
      the proportion of inpatients at an acute hospital (Royal Hallamshire Hospital,
      Sheffield, UK) considered to have palliative care needs by medical and nursing
      staff directly responsible for their care. During the 1-week period of the survey
      (6-10 September 1999), 452 inpatients were present in the hospital. Nursing staff
      were interviewed for 99% of patients; medical staff for 81%. Staff interview data
      were supplemented by case note review. Overall, 23% of the total inpatient
      population were identified as having palliative care needs and/or being
      terminally ill by staff and 11% were considered suitable for referral to a
      specialist palliative care bed. However, there was a low level of concurrence
      between medical and nursing staff as to which individual patients had palliative
      care needs (although this increased with perceived increased proximity to death),
      including which would be suitable for referral to a specialist palliative care
      bed. A need for further palliative care education for medical and nursing staff
      working within acute hospital settings was identified to ensure that the best use
      is made of hospital-based specialist palliative care services.

PMID- 12403503
TI  - Provider perspectives on palliative care needs at a major teaching hospital.
AB  - Jericho Metropolitan Hospital (JMH) is a major Australian teaching hospital which
      lacked a designated palliative care service at the time this study was conducted.
      A questionnaire addressing palliative care service needs, and educational and
      support needs of staff, was sent to 267 multi-disciplinary oncology staff at JMH.
      A response rate of 83% was achieved. Staff identified a number of palliative care
      needs that were being particularly poorly addressed by existing services. These
      included: spiritual support, cultural needs, grief and bereavement support,
      pleasant surroundings, adequate privacy and facilities for families. The majority
      of respondents identified the following issues as critical problems in palliative
      care provision: lack of a designated palliative care service, lack of palliative
      care education of staff, unmanageable caseloads and inadequate physical
      facilities for the provision of care. Only 24% of respondents reported having had
      any palliative care education, and 92% of respondents expressed a need for
      further education. The majority of respondents (79%) expressed a need for
      improved staff support. There was a significant association between perceived
      need for improved support and professional discipline (chi2 = 31.33, P < 0.002),
      with medical staff being significantly less likely than other staff groups to
      report a need for improved support. Overall, the health providers surveyed
      identified major deficiencies in the provision of palliative care to cancer
      patients at JMH and in the palliative care education and support for staff caring
      for terminally ill cancer patients. The findings support the need for a
      designated palliative care service at JMH to improve the standard of care of
      dying cancer patients, and the need for improved palliative care education and
      support for staff.

PMID- 12403504
TI  - The emergence of Medicare hospice care in US nursing homes.
AB  - Although Medicare-financed hospice care has been provided in nursing homes in the
      USA for over 10 years, very little is known regarding the use of this government
      health care benefit in nursing homes. Using resident assessment data and hospice
      and inpatient Medicare claim data from five US states, we were able to identify
      and describe nursing home residents receiving hospice care between 1992 and 1996,
      and their hospice utilization patterns. Six per cent of all dying nursing home
      residents received hospice care at some point in time and, in 1996, an estimated
      24% of all Medicare hospice patients in the five study states received hospice
      while in a nursing home. Of those residents beginning hospice care after nursing
      home admission, 48% were 85 years or older, 70% were female, 94% were white, 76%
      were unmarried and 62% had a non-cancer principal diagnosis. The average length
      of stay in the hospice programme for residents receiving hospice care while in
      the nursing home was 90.6 days, the median 35 and the mode 2. Hospice care in US
      nursing homes is a prevalent model of care that appears further to extend the
      Medicare hospice benefit to older adults who are female and to those with non
      cancer diagnoses. Lengths of stay in the programme are similar to those observed
      in the community and the average length of stay is substantially shorter than
      previously estimated by an influential government study.

PMID- 12403505
TI  - The concept of palliative care in The Netherlands.
AB  - Palliative care in The Netherlands is growing and the climate for further
      development is favourable. Although there is a great deal of consensus on the
      current debates within palliative care, important disagreements persist. These
      disagreements relate to the history of palliative care within the country, the
      scope of palliative care, its values, the appropriate institutional context, and
      the moral acceptability of euthanasia in palliative care. In this paper, the
      consensus and the disagreements are described and discussed. It is concluded that
      many disagreements emerge from so-called external goals of palliative care. It is
      recommended that the debate should refocus on the internal goal of palliative
      care, which is the quality of life of the patient and his or her loved ones.

PMID- 12403506
TI  - Palliative care: a suitable setting for undergraduate interprofessional
      education.
AB  - Effective delivery of high-quality palliative care requires effective
      interprofessional teamworking by skilled health and social care professionals.
      Palliative care is therefore highly suitable for sowing the seeds of
      interprofessional teamworking in early professional education. This paper
      describes experiences of running undergraduate interprofessional workshops in
      palliative care for medical, nursing, social work, physiotherapy and occupational
      therapy students. These workshops are unusual in three respects: first, the
      involvement of family carers mean that these learning experiences are rooted in
      clinical reality; secondly, there is no attempt to 'tidy up' the story for the
      students; thirdly, unlike many undergraduate interprofessional programmes, these
      workshops have been sustained over several years. Evaluation of these workshops
      demonstrate that students value and enjoy the opportunity to work together; they
      find the experience moving, informative and interesting. Feedback from carers
      showed that they appreciated the opportunity to present their real-life
      experiences to students. Our evidence suggests that palliative care is a suitable
      subject for undergraduate interprofessional education.

PMID- 12403507
TI  - Inpatient palliative medicine is evidence based.
AB  - Specialist palliative care services have previously been studied to see whether
      their intervention is of benefit. However, there is a lack of data on whether
      interventions in individual palliative care units are evidence based. This study
      looked at 32 problems and 114 interventions over 1 month in January 2000 in an
      inpatient palliative care unit. These interventions were then researched to see
      if there had been trials showing their benefit. The results were then classified:
      81% were evidence based (randomized controlled trials 48%, evidence from other
      trials 27%, convincing non-experimental evidence 6%). This compares favourably
      with studies performed in other areas of medicine.

PMID- 12403508
TI  - Patients' perceptions of visiting: a phenomenological study in a specialist
      palliative care unit.
AB  - It is assumed that visiting increases peace of mind and patient's well-being, but
      this assumption has not yet been formally studied from the patient's viewpoint.
      The family and close friends are seen as an integral part of the care team for
      patients receiving palliative care, yet the perception of their contribution in
      the experiences of the patients has been rarely recorded. This study uses
      qualitative methods to investigate patients' perceptions of visiting, by using a
      phenomenological approach. Six patients took part in semi-structured interviews;
      these were thematically analysed for common experiences, and highlighted two
      themes: coping and control. Whilst being different themes, they are inextricably
      linked, as an element of control will usually help coping. Methods of increasing
      patient control over visiting may, therefore, enhance coping mechanisms.

PMID- 12403509
TI  - Euthanasia: moral paradoxes.
AB  - Over the past 30 years, euthanasia has been under continuous debate in The
      Netherlands. This contribution aims to provide a moral assessment of this debate.
      It is argued that euthanasia should be understood within a historical context, as
      a protest against medical power and as a way to bring about good death. Within
      the euthanasia debate, two paradoxes are identified which make the issue
      inherently complex and hard to regulate. The first paradox results from the
      dialectical relation between individual autonomy and relief of suffering as the
      major justifications of euthanasia. Although euthanasia represents an ultimate
      effort to give the individual patient control over his dying, the result of the
      debate is an increase of medical power. The second paradox is that although
      euthanasia emerged from a commitment to good death, it is resulting in a reduced
      range of options to bring about good death.

PMID- 12403510
TI  - Palliative care involvement in patients stopping haemodialysis.

PMID- 12403511
TI  - Breaking good news.

PMID- 12403512
TI  - Using computers in the analysis of qualitative data.

PMID- 12403513
TI  - Corticosteroids and oral candidosis.

PMID- 12403514
TI  - The prescription of steroids in the terminal phase.

PMID- 12403515
TI  - Antibiotic resistance--an evolving problem.
AB  - In 1998, an influential report on antimicrobial resistance from the House of
      Lords Select Committee on Science and Technology highlighted the threat posed to
      public health by resistance, and called for products to be used more prudently in
      both human and veterinary medicine. Here, Lord Soulsby, who chaired the Lords'
      committee on antimicrobials, and Richard Wise, who advised the committee and is
      now chairman of the Government's Specialist Advisory Committee on Antimicrobial
      Resistance, consider what has been achieved since then, along with the challenges
      that remain.

PMID- 12403516
TI  - Treatment of urethral sphincter mechanism incompetence in 11 bitches with a
      sustained-release formulation of phenylpropanolamine hydrochloride.
AB  - Between 1995 and 1999, urethral sphincter mechanism incompetence was diagnosed in
      11 bitches. They had been treated with phenylpropanolamine hydrochloride at the
      recommended dose rate, but had shown no response or had become refractory to
      treatment. They were treated with phenylpropanolamine hydrochloride in a
      sustained-release formulation combined with diphenylpyraline hydrochloride. The
      urinary incontinence resolved fully in six of the bitches, two of which remained
      continent after the treatment was withdrawn; two showed a marked improvement on
      daily treatment, but the other three bitches failed to respond and underwent
      colposuspension.

PMID- 12403517
TI  - Effect of a treatment with eprinomectin or trichlorfon on the yield and quality
      of milk produced by multiparous dairy cows.
AB  - The effects of a strategic antiparasitic treatment against Hypoderma species and
      other parasites on the milk yield, composition, and somatic cell counts of 742
      multiparous dairy cattle were investigated on 79 farms in a Hypoderma species
      endemic area in western Switzerland; 357 of the cows were treated with
      eprinomectin, 252 with trichlorfon, and 133 were left untreated. The treatments
      were given between October and early December 1998, on average 53 days before
      calving. Milk yield, fat, protein and somatic cell counts were measured once a
      month until the end of lactation. Eprinomectin and trichlorfon significantly
      increased milk yield during the first month after treatment compared with the
      control cows by 2.14 (P < 0.001) and 2.50 kg per day (P < 0.001), respectively.
      Initially, the difference between the eprinomectin- and trichlorfon-treated
      animals was not significant, but the effect of eprinomectin on milk yield was
      persistent, whereas the effect of trichlorfon decreased significantly by 0.12 kg
      per day per month (P < 0.05). The somatic cell counts increased significantly
      slower in the treated cows than in the control cows (P < 0.05). Milk composition
      was not affected by the treatments.

PMID- 12403518
TI  - Evaluation of three ancillary treatments in the management of equine grass
      sickness.
AB  - Brotizolam, acetylcysteine and aloe vera gel were evaluated as ancillary
      treatments for 29 cases of equine grass sickness. None of the treatments had any
      significant beneficial effect on the survival of the horses. However, 11 of 13
      horses with mild chronic grass sickness survived solely with intensive nursing
      care.

PMID- 12403520
TI  - Influence of back fat thickness on the reproductive performance of dairy cows.

PMID- 12403519
TI  - Renal reabsorption of magnesium and calcium by cattle with renal tubular
      dysplasia.
AB  - The concentrations of magnesium and calcium in the serum and urine and their
      rates of clearance were determined in cattle with renal tubular dysplasia, an
      autosomal recessive hereditary disease associated with a deletion of the
      paracellin-1 gene in Japanese Black cattle. There were no significant differences
      in the serum or urine magnesium concentrations between normal cattle and cattle
      which were heterozygous or homozygous for the condition. Serum calcium
      concentrations tended to be lower in the homozygous cattle, and the serum
      creatinine and urea nitrogen concentrations were significantly higher in the
      homozygous cattle. The ratio of magnesium:creatinine and the fractional excretion
      of magnesium were higher in cattle with the disease than in normal cattle. There
      were no significant differences in urine calcium concentration, the
      calcium:creatinine ratio, and fractional excretion of calcium between normal
      cattle and cattle which were homozygous or heterozygous for the condition. The
      creatinine clearance was significantly lower in the homozygous cattle than in
      normal cattle. The clearance, excretion rate, reabsorption rate and reabsorption
      rate:clearance ratio of magnesium in cattle with renal tubular dysplasia were
      significantly lower than in normal cattle. The clearance rate and reabsorption
      rate of calcium were also significantly lower in the affected cattle, but the
      excretion rate and reabsorption rate:clearance of calcium were not different
      between the normal cattle and the cattle homozygous for the condition. In cattle
      with the condition the rate of reabsorption of magnesium by the kidneys was low,
      but the rate of reabsorption of calcium was normal.

PMID- 12403521
TI  - Testing the performance of electrical stunning equipment for poultry.

PMID- 12403522
TI  - Reactivity of immunoglobulins eluted from the isolated renal glomeruli of
      nephritic pigs with Actinobacillus pleuropneumoniae antigen.

PMID- 12403523
TI  - Bergeyella (Weeksella) zoohelcum associated with respiratory disease in a cat.

PMID- 12403524
TI  - Modelling and FMD.

PMID- 12403525
TI  - What is veterinary science?

PMID- 12403526
TI  - Equine faecal egg counts and comparison of fenbendazole and moxidectin.

PMID- 12403527
TI  - BVA governance.

PMID- 12403528
TI  - Murine pathogens in wild grey squirrels.

PMID- 12403530
TI  - Risks, fears and choices: unexpected lessons from the women's health initiative.

PMID- 12403531
TI  - Nitrous oxide and alcohol.

PMID- 12403532
TI  - JADA Industry Advisory Board.

PMID- 12403533
TI  - TENS revisited.

PMID- 12403534
TI  - Curing lights.

PMID- 12403535
TI  - In your view, is the influence of 'junk science' on public knowledge and public
      policy a growing problem?

PMID- 12403536
TI  - Do regular dental visits affect the oral health care provided to people with HIV?
AB  - BACKGROUND: Financial factors related to income and insurance coverage have been
      found to limit access to, and influence use of, oral health care services by
      people with human immunodeficiency virus, or HIV. METHODS: The authors determined
      if visiting a dentist regularly affected the oral health services provided to
      people with HIV when financial barriers were eliminated as an impediment to
      access. They analyzed dental claims data for services submitted for payment to
      the Minnesota Access to Dental Care Program. The analyses focused on comparisons
      of dental utilization patterns among 273 people classified as regular patients,
      or RPs, and 222 people classified as nonregular patients, or NRPs. RESULTS: RPs
      were found to have been provided more diagnostic and preventive care, and less
      restorative, endodontic, periodontic, removable prosthodontic and oral surgical
      treatment than were NRPs. Although the mean submitted cost per patient visit was
      much higher for NRPs, total mean submitted costs per patient for RPs and NRPs
      were not significantly different. Even though NRPs underwent fewer procedures and
      had fewer clinic visits than did RPs, the procedures provided to NRPs were more
      complex and costly. As indicated by differences in the mix of dental care
      services provided to RPs vs. NRPs, continuity of primary oral health care for RPs
      led to a better oral health result at no increase in cost over that for NRPs.
      CONCLUSIONS: The study findings provide substantial evidence regarding the value
      of regular oral health care for people with HIV. CLINICAL IMPLICATIONS: This
      study reinforces the need for dentists to educate and encourage people with HIV
      to integrate regular oral health care into the ongoing maintenance of their
      overall health and well-being.

PMID- 12403537
TI  - Management of patients with trigeminal nerve injuries after mandibular implant
      placement.
AB  - BACKGROUND: Placement of mandibular endosseous implants can result in damage to
      the lingual nerve, the inferior alveolar nerve or both nerves. All dentists who
      place mandibular implants should be aware of the appropriate early management of
      these injuries, as well as the appropriate time to refer patients with these
      injuries to a microneurosurgeon. OVERVIEW: The lingual nerve is less likely to
      undergo spontaneous regeneration than is the inferior alveolar nerve, which is
      protected within the inferior alveolar canal. Since the inferior alveolar canal
      can be seen on most panoramic radiographs and on all high-quality computed
      tomographic scans, it is easier to avoid damage to the inferior nerve than to the
      lingual nerve, which is not visualized on radiographs and whose relationship to
      the posterior portion of the mandible varies from person to person. RESULTS: The
      authors reviewed one study that showed that lingual nerve repair helped 90
      percent of patients. A second study found that patients who underwent lingual
      nerve repair reported a mean score of 7 on a scale from 0 to 10 in regard to the
      postoperative return of nerve function. Several other studies reported favorable
      patient responses to inferior alveolar nerve repair. CONCLUSIONS AND CLINICAL
      IMPLICATIONS: These results reinforce the need for early referral and
      intervention when inferior alveolar nerve injuries occur. Failure to refer
      patients with trigeminal nerve injury before distal nerve degeneration develops
      prevents minimization of the injury through microneurosurgical repair.

PMID- 12403538
TI  - Cross-reactivity between gutta-percha and natural rubber latex: assumptions vs.
      reality.
AB  - BACKGROUND: Immunological cross-reactivity between gutta-percha and natural
      rubber latex, or NRL, has not been demonstrated clearly despite recent concerns
      and several suspected cases reported in the literature. METHODS: The authors
      analyzed aqueous extracts of commercial gutta-percha points and raw gutta-percha
      samples for cross-reactivity to NRL by radioallergosorbent test, or RAST,
      inhibition; immunoblot inhibition; direct enzyme-linked immunosorbent assay, or
      ELISA; and ELISA inhibition using sera from NRL-allergic people as the source of
      anti-NRL immunoglobulin E, or IgE, antibodies. To confirm in vitro results, the
      authors conducted skin prick testing, or SPT, on a patient with type I NRL
      allergy using aqueous extracts from raw gutta-percha, ammoniated gutta-percha and
      gutta-percha points. RESULTS: Aqueous extracts from commercial gutta-percha
      points did not cross-react to NRL in RAST inhibition or immunoblot inhibition,
      ELISA or ELISA inhibition assays. However, three of 13 sera from subjects with
      type I NRL allergy exhibited IgE binding to raw gutta-percha extracts in direct
      ELISA. Moreover, in ELISA inhibition, the binding of IgE to raw gutta-percha
      extracts was inhibited in a dose-dependent manner by raw NRL and vice versa. SPT
      results from a subject with type I NRL allergy were positive for NRL and raw
      gutta-percha extracts but negative for gutta-percha point extracts. CONCLUSIONS:
      The authors found no detectable cross-reactivity between NRL and commercial gutta
      percha points. However, their ELISA and SPT results demonstrated that some
      allergenic cross-reactivity exists between raw gutta-percha and raw NRL. CLINICAL
      IMPLICATIONS: Gutta-percha alone is not likely to induce symptoms in patients
      with type I NRL allergy. However, other materials used in obturating root canals
      may be irritating and potentially allergenic in patients with pre-existing
      allergies.

PMID- 12403540
TI  - A safe and convenient technique for the cementation of fixed partial dentures.

PMID- 12403539
TI  - Oral health, nutrient intake and dietary quality in the very old.
AB  - BACKGROUND: Limited food choices and inadequate nutrient intake are linked to
      poor oral health. The authors describe relationships between dietary variety,
      nutrient intake and oral health measures in community-dwelling, rural Iowans aged
      79 years and older. METHODS: Dental examinations were conducted by trained and
      calibrated examiners, and trained interviewers completed standardized interviews
      in subjects' homes. Subjects (n = 220) then completed three-day dietary records.
      Adequate nutrient intakes were defined using the Dietary Reference Intakes of the
      Food and Nutrition Board of the National Academy of Sciences. RESULTS: Mean daily
      nutrient intakes were significantly lower in subjects who had fewer natural or
      functional teeth and ill-fitting mandibular dentures than in subjects who had
      more teeth or did not have these problems. Adequacy of intakes was lower in
      subjects who had fewer natural or functional teeth and ill-fitting mandibular
      dentures. Mean daily nutrient intakes did not differ between subjects with well
      fitting dentures (either complete or partial) and subjects with natural teeth.
      Neither mean daily intake nor adequacy of intake was associated with subjects'
      perceptions of oral health problems, chewing difficulties or temperature
      sensitivity. CONCLUSIONS: The presence of natural teeth and well-fitting dentures
      were associated with higher and more varied nutrient intakes and greater dietary
      quality in the oldest old Iowans sampled. Clinical Implications. Maintenance of
      natural dentition or provision and maintenance of adequate mandibular prostheses
      are important for nutrient intakes to support systemic health.

PMID- 12403541
TI  - Platelet-rich plasma: clinical applications in dentistry.
AB  - BACKGROUND: Platelet-rich plasma, or PRP, has become a valuable adjunct in wound
      healing in dentistry. Postsurgically, blood clots initiate the healing and
      regeneration of hard and soft tissues. Clinicians and scientists are
      investigating the use of PRP in dentistry as a way to enhance the body's natural
      wound-healing mechanisms. TYPES OF ARTICLES REVIEWED: The authors reviewed
      scientific articles that discuss the basic knowledge of wound healing mechanisms
      and that directly studied the growth factors shown to be concentrated in PRP.
      They also reviewed articles written by clinicians and researchers in dentistry
      fields, including oral and maxillofacial surgery and periodontics to determine
      applications of PRP in the field of dentistry. RESULTS: All of the reviewed
      articles expressed promise in PRP use and in the growth factors expressed by the
      platelets concentrated in PRP-namely platelet-derived growth factor, or PDGF, and
      transforming growth factor-beta, or TGF-beta--as an adjunct to postsurgical wound
      healing. Both PDGF and TGF-beta have been shown in vivo to accelerate wound
      healing through different mechanisms. The development of an autologous PRP has
      been shown to be relatively easy, to be effective as a surgical adjunct, to
      retain high levels of the desired growth factors after preparation and to be
      clinically effective in accelerating postsurgical healing in both periodontal and
      oral surgery applications. CLINICAL IMPLICATIONS: PRP has proven to be effective
      at improving surgical results in a variety of procedures in the field of oral and
      maxillofacial surgery. PRP also shows promise in periodontal regenerative therapy
      and should continue to be studied by scientists and clinicians alike.

PMID- 12403542
TI  - An alternative method to reduce polymerization shrinkage in direct posterior
      composite restorations.
AB  - BACKGROUND: Polymerization shrinkage is one of dental clinicians' main concerns
      when placing direct, posterior, resin-based composite restorations. Evolving
      improvements associated with resin-based composite materials, dental adhesives,
      filling techniques and light curing have improved their predictability, but
      shrinkage problems remain. METHODS: The authors propose restoring enamel and
      dentin as two different substrates and describe new techniques for placing
      direct, posterior, resin-based composite restorations. These techniques use
      flowable and microhybrid resin-based composites that are polymerized with a
      progressive curing technique to restore dentin, as well as a microhybrid
      composite polymerized with a pulse-curing technique to restore enamel. Combined
      with an oblique, successive cusp buildup method, these techniques can minimize
      polymerization shrinkage greatly. CONCLUSIONS: Selection and appropriate use of
      materials, better placement techniques and control polymerization shrinkage may
      result in more predictable and esthetic Class II resin-based composite
      restorations. CLINICAL IMPLICATIONS: By using the techniques discussed by the
      authors, clinicians can reduce enamel microcracks and substantially improve the
      adaptation of resin-based composite to deep dentin. As a consequence, marginal
      discoloration, recurrent caries and postoperative sensitivity can be reduced, and
      longevity of these restorations potentially can be improved.

PMID- 12403543
TI  - The importance of productivity in estimating need for dentists.
AB  - BACKGROUND: Although the number of dentists is an important determinant of
      supply, other factors also contribute. Technological advancements and well
      trained and managed auxiliary personnel affect supply by allowing dentists to
      produce more dental services per unit of time. METHODS: This article examines
      trends in dental output, productivity, number of dentists and dental care
      utilization from 1960 through 1998. The authors estimated growth rates for the
      entire period and selected subperiods using regression analysis. Growth rates for
      dentist productivity and per capita utilization are important to estimate the
      number of active dentists needed in the year 2020. RESULTS: Based on ADA practice
      survey data, the annual growth rate in dentists' productivity was 1.41 percent
      from 1960 through 1998. However, productivity grew at different rates during this
      period. It increased 3.95 percent per year from 1960 to 1974. There was a decline
      in productivity of 0.13 percent annually from 1974 to 1991. From 1991 to 1998,
      productivity grew 1.05 percent annually. CONCLUSIONS: Accurate estimates of
      changes in dentist productivity are important in evaluating the adequacy of the
      number of dentists to meet the demand for dental services. PRACTICE IMPLICATIONS.
      Since productivity generally increases over time, failure to account for changes
      in productivity can lead to an overestimation of the number of dentists required
      for any given level of demand for dental services.

PMID- 12403544
TI  - Fluorosis: is it really a problem?
AB  - BACKGROUND: Scientists have noted an association between mottled enamel and
      fluoride exposure since the early 1900s. By the mid-1900s, they also recognized
      that fluoride intake was related to lower caries incidence. To harness the
      protective effect of fluoride while limiting the occurrence of fluorosis, dental
      researchers have recommended that the fluoride level in chinking water be 1 part
      per million or less. OVERVIEW: Despite the recognition that fluoride levels in
      water can be controlled to offer caries protection with minimal risk of
      fluorosis, the cosmetic defect continues to appear. However, although the word
      "fluorosis" conjures up images of brown stained and pitted enamel, such severe
      cases rarely are seen in the United States. Children in this country are exposed
      to fluoride from numerous sources and the appearance of mild fluorosis is not
      unusual. CONCLUSIONS AND PRACTICE IMPLICATIONS: In most cases, fluorosis is a
      minor cosmetic defect that should not be cause for alarm. Dentists should educate
      their patients about the optimal range of fluoride intake for caries protection,
      sources of fluoride and the possibility of fluorosis.

PMID- 12403545
TI  - Future of dentistry: access to care. Today's vision: tomorrow's reality.

PMID- 12403547
TI  - Visible light curing.

PMID- 12403546
TI  - Visible light-curing unit.
AB  - Ortholux XT is a high-intensity light source emitting filtered visible blue light
      in the 400- to 500-nanometer range for polymerization of visible-light-cured
      resins. The Ortholux handpiece comes with a portable power supply, a light
      intensity check in the power supply, a spare lamp, an eyeshield and a mounting
      kit. The handpiece consists of a pistol grip with a thermoplastic housing that
      contains the light source, cooling fan, light guide receptacle (8- or 13
      millimeter-diameter fused quartz lightguide), optical filter, light switch and
      timer switch. The timer is operator-selectable with options of five, 10, 15 and
      20 seconds and an XT option of up to 600 seconds. The push-button switch allows
      for timer disruption and reactivation. 3M Unitek reported (3M Unitek, unpublished
      data submitted to the ADA, date not known) that the cooling fan generates noise
      below 43 decibels when the internal handpiece temperature is below 100 C. At 120
      C, the fan speed increases, generating 52 dBA. The U.S. Air Force Dental
      Investigative Service reported that the cooling fan is extremely quiet. The light
      shuts off when it reaches 140 C. The light source is a 75-watt tungsten/halogen
      lamp. The handpiece weighs less than one pound. The power supply contains the
      built-in intensity meter that illuminates a green light-emitting diode when the
      tested light exceeds 400 milliwatts per square centimeter. The power cord is six
      feet in length. A built-in voltage regulator ensures a steady voltage supply to
      the unit.

PMID- 12403548
TI  - Are electric handpieces an improvement?

PMID- 12403549
TI  - Employment discrimination: federal law may apply to small dental offices that
      accept federal funding.

PMID- 12403550
TI  - For the dental patient. Do you have dry mouth?

PMID- 12403551
TI  - Neurobiology of disease in children: neurofibromatosis 1.

PMID- 12403552
TI  - Neurofibromatosis 1: clinical manifestations and diagnostic criteria.
AB  - Neurofibromatosis 1 occurs in 2 to 3 people per 10,000. The most frequent
      clinical features are cafe-au-lait macules, neurofibromas, intertriginous
      freckling, Lisch nodules, and learning disabilities, but optic and other gliomas,
      malignant peripheral nerve sheath tumors, and characteristic osseous lesions also
      can be present. Two striking aspects of neurofibromatosis 1 are its progressive
      nature and its extreme variability. This article reviews the natural history and
      some important clinical manifestations of neurofibromatosis 1, with emphasis on
      features that constitute the standard diagnostic criteria. The pathogenic
      implications of these clinical manifestations are also considered.

PMID- 12403553
TI  - NF1 mutations and molecular testing.
AB  - Neurofibromatosis 1 is a progressive autosomal dominant condition caused by
      mutations in the NF1 gene on chromosome 17. The condition shows clinical variable
      expressivity, with varying features even between family members who share the
      same mutation. Furthermore, it is impossible to precisely predict the severity
      and course of the condition, a source of frustration for families and physicians.
      Neurofibromatosis 1 is also heterogeneous at the mutation level, with more than
      300 independent mutations having been reported in this gene. The mutation data
      have accumulated slowly owing to the variability of the mutation types and the
      size and complexity of the gene. This is also reflected in the lack of a simple,
      inexpensive, highly accurate DNA-based test for neurofibromatosis 1 at present.
      This article reviews current NF1 mutation spectrum and testing, discussing and
      illustrating mutation mechanisms and pathogenetic effects, as well as factors
      affecting DNA testing and interpretation/diagnosis.

PMID- 12403554
TI  - Genetics of neurofibromatosis 1 and the NF1 gene.
AB  - Neurofibromatosis 1 serves as a paradigm for understanding the principles of
      human genetics. The concepts of gene mutation, penetrance of the condition,
      variable clinical expressivity, mosaicism, age-dependent expression of clinical
      manifestations, and pleiotropy are evident in this autosomal dominant condition.
      The lack of genotype-phenotype correlation, except the whole-gene deletion
      phenotype, leads to speculation on modifiers of the haploinsufficient state of
      the NF1 gene product neurofibromin. The variant form of neurofibromatosis,
      neurofibromatosis Noonan's syndrome, suggests potential interaction of
      independent biochemical pathways. Identification of the NF1 gene led to the
      discovery of its role in ras signal transduction. Neurofibromin is a negative
      regulator of intracellular ras signaling. This observation now provides the
      framework for the development of rational medical therapies. In addition,
      knowledge of the molecular basis of the variable expression of clinical
      manifestations could provide better anticipatory guidance and more effective
      management of the medical complications that are associated with this condition.

PMID- 12403555
TI  - Clinical features and pathobiology of neurofibromatosis 1.
AB  - Neurofibromatosis 1 is a progressive multisystem disorder. The hallmark feature
      is the occurrence of nerve sheath tumors, neurofibromas. Other features include
      tumors such as optic gliomas and malignant peripheral nerve sheath tumors. There
      are also nontumor manifestations, such as skeletal dysplasia and learning
      disabilities. Since the NF1 gene was identified, much has been learned about the
      molecular genetics of the disorder; recently, this has led to insights about
      pathogenesis. Ultimately, it is hoped that this will be translated into specific
      means of treatment. This review describes the various clinical features of
      neurofibromatosis 1 and considers them in the context of the pathophysiology of
      the disorder.

PMID- 12403556
TI  - Antiangiogenesis in neurofibromatosis 1.
AB  - Antiangiogenesis therapy has become a potentially promising tool to inhibit tumor
      growth by targeting an essential yet untransformed tissue component. Identifying
      the factors involved and understanding the mechanisms required for tumor
      angiogenesis will facilitate efficient and specific targeting. In neurofibromas,
      tumor growth is facilitated by a genetically and cytologically diverse mixture of
      cell types, including Schwann cells, fibroblast, mast cells, and neurons where nf
      /- Schwann cells are most likely the tumorigenic cell type. The matrix forming
      nf+/- cells may provide a permissive environment, facilitating tumor development,
      perhaps by providing landscaping factors such as the angiogenic molecules
      fibroblast growth factor-2, platelet-derived growth factor, endothelial growth
      factor, vascular endothelial growth factor, and midkine, which have been detected
      in neurofibromas. Systemic overexpression of specific factors such as midkine
      owing to loss of one nf allele might further lower the overall threshold for
      tumorigenesis and development of a tumor vasculature. Targeting these heparin
      binding growth factors might inhibit not only angiogenesis but also proliferation
      of tumor cells because most of these factors also stimulate proliferation of
      neurofibroma-derived Schwann cells. We discuss the role of specific secreted
      molecules for angiogenesis in tumors of neurofibromatosis 1 and possible
      Approaches for their targeting. Furthermore, results are discussed that
      demonstrate the efficacy of antiangiogenesis targeting to inhibit growth of
      neurofibrosarcomas in experimental animal models.

PMID- 12403557
TI  - Neurofibromas in children with neurofibromatosis 1.
AB  - Neurofibromatosis 1 is a common autosomal dominant disease reported in
      approximately 1 in 3000 individuals. Although some features of neurofibromatosis
      1, such as cafe-au-lait spots and Lisch nodules, are clinically silent,
      neurofibromas cause a significant degree of morbidity, mortality, and cosmetic
      disfigurement. Childhood through early adulthood is a vulnerable period for the
      growth of these lesions. Neurofibromas are a heterogeneous group of benign tumors
      that grow from intraneural and extraneural tissues. These tumors take on
      different morphology, grow at variable rates, and occur in multiple locations.
      Symptoms arise as neurofibromas enlarge, compressing and distorting local
      structures. The unpredictable nature of neurofibromas has a serious impact on the
      quality of life of patients with neurofibromatosis 1, and their management is
      challenging for physicians. Surgical removal remains the mainstay of treatment.
      However, advances in the understanding of the genetics and pathogenesis of
      neurofibromatosis 1 have led to the development of promising new biologically
      directed therapies. The purpose of this review is to summarize the defining
      characteristics, incidence, clinical course, management options, and outcome of
      neurofibromas in children with neurofibromatosis 1.

PMID- 12403558
TI  - Neurofibromin in the brain.
AB  - Neurofibromatosis 1 is one of the most common autosomal dominant disorders
      affecting the nervous system. Individuals with neurofibromatosis 1 present with
      abnormalities of both astrocytes and neurons that result from reduced or absent
      expression of the NF1 gene product neurofibromin. Impaired neurofibromin function
      in these nervous system cells contributes to the development of astrocytomas,
      learning disabilities, and radiographic abnormalities of the brain. With the
      identification of NF1, significant advances have begun to unlock some of the
      mysteries that surround the molecular pathogenesis of neurofibromatosis 1
      associated brain abnormalities. With continued advances in our basic
      understanding of NF1 function, future targeted therapies for neurofibromatosis 1
      associated central nervous system abnormalities can be developed.

PMID- 12403559
TI  - Cognitive deficits in neurofibromatosis 1.
AB  - Cognitive deficits and academic learning difficulties are the most common
      neurologic "complication" of neurofibromatosis 1 in childhood and can be
      responsible for significant lifetime morbidity. There is a slight increase in the
      frequency of mental retardation (Wechsler Full-Scale IQ < 70) in children with
      neurofibromatosis 1, but the mean Full-Scale IQ for the patient group is within 1
      SD of the population mean. Academic difficulties are common, as are specific
      deficits in visuospatial ability, executive function, expressive and receptive
      language, and attentional skills. Behavioral and psychosocial problems have a
      major impact on quality of life, although there are few objective studies in this
      area Current research is focusing on the pathogenesis of the disorder. Clinical
      studies have identified possible radiologic and pathologic markers for cognitive
      deficits in neurofibromatosis 1, which can now be explored in animal models.

PMID- 12403560
TI  - Neurofibromatosis 1: clinical review and exceptions to the rules.
AB  - Neurofibromatosis 1 is an autosomal dominant, multisystem disorder with myriad
      clinical manifestations. Between 1991 and 1998, 495 adults and children were
      diagnosed with neurofibromatosis 1 at a specialized neurogenetics clinic in
      Sydney, Australia. This review establishes the prevalence of the clinical
      manifestations of neurofibromatosis 1 in these patients and provides guidelines
      for assessment and management. In addition, we review in detail patients who had
      unusual presentations and who represent important "exceptions to the rules" of
      clinical practice.

PMID- 12403561
TI  - Molecular and cellular mechanisms underlying the cognitive deficits associated
      with neurofibromatosis 1.
AB  - Neurofibromatosis 1 is one of the most common single-gene disorders affecting
      neurologic function in humans. Mutations in the NF1 gene cause abnormalities in
      cell growth and differentiation and lead to a variety of learning disabilities.
      Neurofibromin has several biochemical functions, such as Ras-guanosine
      triphosphatase activity, adenylate cyclase modulation, and microtubule binding,
      all of which could be critical for brain function. We review how studies in mouse
      models are helping to unravel the molecular and cellular mechanisms underlying
      cognitive deficits in neurofibromatosis 1. These studies suggest that the
      learning disabilities associated with neurofibromatosis 1 are caused by excessive
      Ras activity that leads to increased gamma-aminobutyric acid (GABA(A)) inhibition
      and to decreased long-term potentiation. These findings have brought us closer
      than ever to the development of possible treatments for the learning disabilities
      associated with neurofibromatosis 1.

PMID- 12403562
TI  - Intracranial neoplasms in children with neurofibromatosis 1.
AB  - Neurofibromatosis 1 is associated with an increased risk for the development of
      benign and malignant tumors involving neural and non-neural tissues. Children as
      well as adults with neurofibromatosis 1 are affected. Central nervous system
      neoplasms represent a significant portion of these malignancies and appear
      primarily in children less than 10 years of age. Optic pathway gliomas and
      brainstem gliomas are the most common intracranial neoplasms found in
      neurofibromatosis 1, although there also is an increased incidence of other brain
      tumors in this population. The majority of these intracranial neoplasms are
      benign pilocytic astrocytomas, which may behave in a less aggressive manner than
      histologically identical tumors in non-neurofibromatosis 1 patients. Owing to the
      indolent nature of these tumors, conservative management with close follow-up is
      recommended. When intervention is required, conventional treatment with surgery,
      radiation, or chemotherapy has been used with variable results. The current
      challenge lies in understanding the pathogenesis of gliomas in neurofibromatosis
      1, which may lead to the development of biologically directed therapies with less
      associated morbidity and mortality for neurofibromatosis 1 as well as non
      neurofibromatosis 1 children.

PMID- 12403563
TI  - Therapy for plexiform neurofibromas in children with neurofibromatosis 1: an
      overview.
AB  - Plexiform neurofibromas are one of the most common and disabling features of
      neurofibromatosis 1. Treatment options for patients with plexiform neurofibromas
      have been limited, with surgery being the primary option for patients with
      progressive lesions causing significant morbidity. Trials have evaluated other
      treatment approaches, including the use of antihistamines, maturation agents, and
      antiangiogenic agents. The design of such trials and entry criteria have been
      quite variable, and results have been difficult to interpret. As more is
      understood concerning the molecular genetic underpinnings of plexiform
      neurofibromas, new avenues of treatment are being explored. Evaluation of
      clinical trials is challenging because of the unpredictable nature of plexiform
      neurofibromas and difficulties in measuring objective responses. The use of
      innovative neuroimaging techniques and other outcome measures may greatly improve
      the design of trials and evaluation of potential effective agents.

PMID- 12403564
TI  - Determination of end points for treatment of neurofibromatosis 1.
AB  - Neurofibromatosis 1 is a progressive disorder that affects multiple systems of
      the body. Management is currently focused on anticipatory guidance, genetic
      counseling, and symptomatic treatment of specific lesions, usually through
      surgery. Insights into pathogenesis of the disorder are beginning to suggest
      possible mechanisms of treatment, and clinical trials have begun for some types
      of lesions. The unpredictable natural history and variable phenotype present
      challenges for clinical trials in neurofibromatosis 1, which will need to be
      addressed to develop a system for reliable testing of potential therapies.

PMID- 12403565
TI  - Future research directions: follow-up to the Neurofibromatosis Workshop, October
      17, 2001.

PMID- 12403566
TI  - Characterization and optimization of peptide arrays for the study of epitope
      antibody interactions using surface plasmon resonance imaging.
AB  - The characterization of peptide arrays on gold surfaces designed for the study of
      peptide-antibody interactions using surface plasmon resonance (SPR) imaging is
      described. A two-step process was used to prepare the peptide arrays: (i) a set
      of parallel microchannels was used to deliver chemical reagents to covalently
      attach peptide probes to the surface by a thiol-disulfide exchange reaction; (ii)
      a second microchannel with a wraparound design was used as a small-volume flow
      cell (5 microL) to introduce antibody solutions to the peptide surface. As a
      demonstration, the interactions of the FLAG epitope tag and monoclonal anti-FLAG
      M2 were monitored by SPR imaging using a peptide array. This peptide-antibody
      pair was studied because of its importance as a means to purify fusion proteins.
      The surface coverage of the FLAG peptide was precisely controlled by creating the
      peptide arrays on mixed monolayers of alkanethiols containing an amine-terminated
      surface and an inert alkanethiol. The mole fraction of peptide epitopes was also
      controlled by reacting solutions containing FLAG peptide and the non-interacting
      peptide HA or cysteine. By studying variants based on the FLAG binding motif, it
      was possible to distinguish peptides differing by a single amino acid
      substitution using SPR imaging. In addition, quantitative analysis of the signal
      was accomplished using the peptide array to simultaneously determine the binding
      constants of the antibody-peptide interactions for four peptides. The binding
      constant, K(ads), for the FLAG peptide was measured and found to be 1.5 x 10(8)
      M(-1) while variants made by the substitution of alanine for residues based on
      the binding motif had binding constants of 2.8 x 10(7), 5.0 x 10(6), and 2.0 x
      10(6) M(-1).

PMID- 12403567
TI  - Entropic recoil separation of long DNA molecules.
AB  - A novel technique that can rapidly separate long-strand polymers according to
      length is presented. The separation mechanism is mediated by a confinement
      induced entropic force at the abrupt interface between regions of vastly
      different configuration entropy. To demonstrate this technique, DNA molecules
      were partially inserted into a dense array of nanopillars (an entropically
      unfavorable region) using a pulsed electric field and allowed to relax to their
      natural state by removal of the field. Molecules of dissimilar lengths (T2 and T7
      coliphage DNA) were inserted into this region in such a way that shorter
      molecules were fully inserted in this region, while longer molecules remained
      partially across the interface. The longer T2 molecules were observed to recoil
      entirely out of the pillar array, leaving the shorter T7 molecules inserted, and
      effecting separation of the two species in a single step. To show how this method
      can be used for separation of unknown samples, the inserting electric field was
      pulsed for progressively longer times, allowing passage of progressively longer
      molecules and producing the equivalent of a conventional electropherogram. The
      effects limiting resolution in this device are discussed, and the expected
      separating power of a multistage device is reported. The extracted resolution and
      running separation time compare favorably with current conventional separation
      techniques.

PMID- 12403568
TI  - Selective ion extraction: a separation method for microfluidic devices.
AB  - A separation concept, selective ion extraction (SIE), is proposed on the basis of
      the combination of hydrodynamic and electrokinetic flow controls in microfluidic
      devices. Using a control system with multiple pressure and voltage sources, the
      hydrodynamic flow and electric field in any section of the microfluidic network
      can be set to desired values. Mixtures of compounds sent into a T-junction on a
      chip can be completely separated into different channels on the basis of their
      electrophoretic mobilities. A simple velocity balance model proved useful for
      predicting the voltage and pressure settings needed for separation. SIE provides
      a highly efficient separation with minimal additional dispersion. It is an ideal
      technique for high-throughput screening systems and demonstrates the power of lab
      on-a-chip systems.

PMID- 12403569
TI  - Separation of neutral saccharide mixtures with capillary electrochromatography
      using hydrophilic monolithic columns.
AB  - While developing a combination of capillary electrochromatography (CEC) with
      tandem mass spectrometry (MS) for the benefit of characterizing complex
      oligosaccharide mixtures, we needed highly efficient CEC columns operating in an
      "MS-friendly" mode. We demonstrate here novel types of polar, monolithic CEC
      columns that separate effectively complex mixtures of saccharides with the use of
      mobile phases containing acetonitrile/dilute ammonium formate buffers. Using the
      positive-ion mode of detection for neutral saccharides, the detection conditions
      were optimized down to the low-femtomole sensitivities with the use of an ion
      trap mass spectrometer. This column technology provides a nearly universal system
      that can separate a wide range of carbohydrates: mono- and oligosaccharides with
      the intact reducing end, as well as saccharide alditols. Even the anomers formed
      due to mutarotation could be resolved with a high content of organic phase.

PMID- 12403570
TI  - Qualitative and quantitative analysis of tocopherols in toothpastes and gingival
      tissue employing HPLC NMR and HPLC MS coupling.
AB  - Gingival samples treated with toothpastes containing tocopherols (vitamin E) were
      investigated employing HPLC chromatography. The aim was to verify that vitamin E
      is actually enriched in the tissue, which could have beneficial effects on oral
      health. After determination of the tocopherols available in the toothpastes,
      control samples from healthy test persons and subjects suffering from gingivitis
      were analyzed. Subsequently, gingival tissues from diseased test persons who
      treated their teeth with the toothpastes containing tocopherols using various
      kinds of concentrations or applications were investigated. The first step of the
      analysis was a fast and careful extraction employing matrix solid-phase
      dispersion (MSPD). Afterward, the separation of the different tocopherol
      homologues existing was performed by HPLC chromatography on highly selective C30
      RP phases. The identification of the tocopherol homologues was performed using
      the on-line coupling of HPLC with NMR spectroscopy and mass spectrometry.

PMID- 12403571
TI  - Solid-phase microextraction in combination with GC/MS for quantification of the
      major volatile free fatty acids in ewe cheese.
AB  - This work describes a method for quantification of the major free fatty acids of
      ewe cheese that contribute to its distinct and strongly marked flavor. A
      headspace SPME method in combination with GC/MS was used for the extraction,
      identification, and quantification of butanoic, hexanoic, octanoic and decanoic
      acids in ewe cheeses. The method used for sample preparation was simple. A fiber
      coated with 85-microm polyacrylate film was chosen to extract the free fatty
      acids. To perform a reliable quantification, several factors were taken into
      consideration for reliable quantification, namely, (i) the influence of addition
      of water, of an electrolyte or of a hygroscopic salt, on the release of free
      fatty acids from the matrix; (ii) the linear relationship between the amount of
      analyte adsorbed by the SPME polymer film and the initial concentration of the
      analyte in the cheese sample; and (iii) the competition for adsorption by fiber.
      Water removal with sodium sulfate promoted a more efficient extraction of
      volatile free fatty acids; biases due to competition or linear range excesses
      were controlled by choosing the appropriate amount of sample for each ewe cheese.
      The method of standard additions was used with success for the quantification of
      free fatty acids. Calibration curves that were constructed for the major short
      chain free fatty acids (butanoic, hexanoic, octanoic, and decanoic acids) spiked
      into cheese followed linear relationships with highly significant (p < 0.001)
      correlation coefficients (r > 0.999). Coefficients of variation of <7.9%
      indicated that the technique was reproducible. A marked increase in concentration
      of short-chain free fatty acids was observed during cheese ripening, ranging from
      0.35 to 9.33 mg/100 g for butanoic acid, 0.363 to 4.34 mg/100 g for hexanoic
      acid, 0.343 to 2.0 mg/100 g for octanoic acid, and 1.291 to 3.85 mg/100 g for
      decanoic acid. The limits of quantification were registered at levels of parts
      per million. The absolute quantification of butanoic acid was also carried out by
      using isotope dilution assays (IDA). The levels of acid obtained with this method
      were similar to those obtained by the standard additions method.

PMID- 12403572
TI  - Vancomycin dimerization and chiral recognition studied by high-performance liquid
      chromatography.
AB  - The retention and separation of D,L-dansylvaline enantiomers (used as test
      solutes) were investigated using silica gel as stationary phase and vancomycin as
      chiral mobile-phase additive. A retention model was developed to describe the
      mechanistic aspects of the interaction between solute and vancomycin in the
      chromatographic system. It considered the formation of vancomycin dimers both
      "free" in the mobile phase and adsorbed on silica. By fitting the model equation
      to experimental data, it appeared clearly that the approach taking into account
      the vancomycin dimerization described accurately the retention behavior of the
      compounds. The examination of the model equation parameters showed that the
      glycopeptide dimerization increased the enantioselectivity by a factor of
      approximately 3.7. This study demonstrated the preponderant role of the
      vancomycin dimerization on the chiral recognition process of D,L-dansylvaline.
      Also, an additional analysis on a vancomycin chiral stationary phase indicated
      that the addition of vancomycin in the mobile phase promoted a greater
      enantioselectivity mediated by the formation of dimers in the stationary phase.

PMID- 12403573
TI  - Resolution of tert-butyl-1-(2-methyinaphthyl)phosphine oxide using selectors
      identified from a chemical combinatorial library.
AB  - Resolution of racemic tert-butyl-1-(2-methylnaphthyl)-phosphine oxide 1, a chiral
      phosphorus compound, was achieved using selectors developed from a small peptide
      library. Separation factors as high as 3.2 were observed. The library consists of
      81 peptide-based potential chiral selectors on polymeric synthesis resins. The
      linker needed to immobilize the identified chiral selectors onto silica gel
      proved important in the chiral separation; a longer linker provided a
      significantly higher separation factor in this study.

PMID- 12403574
TI  - Characterization of fluorescein isothiocyanate-dextrans used in vesicle
      permeability studies.
AB  - Fluorescein Isothiocyanate-dextrans of various weight average molecular masses
      (4,400-487,000) were analyzed in buffer solution for pH, osmolarity, fluorescence
      intensity as a function of the polymer concentration, average molecular masses,
      and radii of gyration. Labeling of polymers and conformation of the polymers were
      characterized by high-performance gel exclusion chromatography (HPLC-GEC) and
      small-angle X-ray scattering. The fluorescence measurements evidence the absence
      of fluorescence quenching of the FITC chromophores but the existence of an inner
      filter effect at high polymer concentration. The conformation of the polymers in
      buffer is very likely of random coil type, as shown by the relationship between
      the radii of gyration and the weight-average molecular masses of the dextrans
      (Mw). The medium used to analyze the FITC-dextrans by HPLC-GEC strongly
      influences their elution behavior. In buffer medium, they are sieved over the TSK
      G4000 PW column through a single population according to their Mw. whereas in
      pure water, they are separated into several species by an exclusion mechanism
      that depends on the number of labeled sites per dextran molecule. A Monte Carlo
      simulation was used to analyze the distribution of the fluorescent labels. HPLC
      GEC in water could interestingly be applied to yield labeled polymers bearing a
      known number of functionalized groups.

PMID- 12403575
TI  - The influence of correlated calibration samples on the prediction performance of
      multivariate models based on mid-infrared spectra of animal cell cultures.
AB  - The effect of the presence of metabolism-induced concentration correlations in
      the calibration samples on the prediction performance of partial least-squares
      regression (PLSR) models and mid-infrared spectra from Chinese hamster ovary cell
      cultures was investigated. Samples collected from batch cultures contained highly
      correlated metabolite concentrations as a result of metabolic relations.
      Calibrations based on such samples could only be used to predict concentrations
      in new samples if a similar correlation structure was present and failed when the
      new samples were randomly spiked with the analytes. On the other hand, such
      models were able to predict glucose correctly even if they were based on a
      spectral range in which glucose does not absorb, provided that the correlations
      in the calibration and in the new samples were similar. If however, samples from
      a calibration culture were randomly spiked with the main analytes, much more
      robust PLSR models resulted. It was possible to predict analyte concentrations in
      new samples irrespective of whether the correlation structure was maintained or
      not. Validity of all established models for any given use could be predicted a
      priori by computing the space inclusion and observer conditions. Predictions from
      these computations agreed in all cases with the experimental test of model
      validity.

PMID- 12403576
TI  - Evaluation of accelerated solvent extraction for butyltin speciation in PACS-2
      CRM using double-spike isotope dilution-GC/ICPMS.
AB  - Pressurized liquid extraction using the accelerated solvent extractor (Dionex ASE
      200) has been evaluated for the determination of mono-, di- and tributyltin (MBT,
      DBT, and TBT, respectively) in PACS-2 certified reference material. A double
      enriched spike containing 119Sn-enriched MBT and TBT and 118Sn-enriched DBT
      allowed for the simultaneous determination of the three butyltin species and the
      factors governing species interconversion. The stability of the spike was
      evaluated by reverse isotope dilution experiments covering more than one year
      with satisfactory results. Quantitative recoveries using ASE for TBT and DBT were
      obtained at temperatures above 110 degrees C. The effect of the extraction time
      and number of static cycles was evaluated. Results suggest that extraction
      efficiency was quantitative with extraction times as low as 10 min for all
      butyltin species at 110 degrees C. Decomposition reactions were only detected at
      the higher temperatures assayed (140 and 175 degrees C) and that was only for the
      degradation of DBT to MBT (approximately 4%). The results found for MBT were
      approximately 25% higher than the certified value for the PACS-2 sediment
      reference material in agreement with previous results obtained by ultrasonic and
      microwave assisted extraction.

PMID- 12403577
TI  - Three-dimensional microfluidic confinement for efficient sample delivery to
      biosensor surfaces. application to immunoassays on planar optical waveguides.
AB  - A microchip-based flow confinement method for rapid delivery of small sample
      volumes to sensor surfaces is described. For flow confinement, a sample flow is
      joined with a perpendicular makeup flow of water or sample medium. Under laminar
      flow conditions, the makeup flow confines the sample into a thin layer above the
      sensing area and increases its velocity. This can benefit mass transport limited
      processes such as DNA hybridization or heterogeneous immunoassays. For proof of
      concept, this method was applied to a high-affinity immunoassay with excess
      capture antibody. Rabbit IgG was immobilized onto a silicon nitride waveguide.
      Cy5-labeled anti-rabbit IgG was hydrodynamically pumped over the immobilized zone
      through an attached 3D-PDMS flow cell with 20-microm-deep microchannels. The
      degree of confinement was adjusted through the volume flow rate of the confining
      flow. Evanescent field-based fluorescence detection enabled monitoring of the
      binding event. Assays were allowed to reach equilibrium to enable sensorgram
      normalization for inter-run comparison. The corresponding assay completion times
      could be reduced from 55 min for static drop conditions to 13 min for 25:1 flow
      confinement (ratio of confining to sample flow). For typical analytical
      applications, where equilibrium formation is not required, the faster response
      should translate to very short analysis times. Concurrently with the faster
      binding, sample consumption was reduced by 96% compared to conventional whole
      channel sample delivery. Diffusional loss of analyte into the confining layer was
      identified as the main limitation of flow confinement, particularly for long
      sensing pads.

PMID- 12403578
TI  - Mass-produced lonophore-based fluorescent microspheres for trace level
      determination of lead ions.
AB  - The development and characterization of small, uniform, and mass-produced
      plasticized PVC-based sensing microspheres in view of rapid trace level analysis
      of lead ions is reported. Micrometer-sized particles obtained via an automated
      casting process were rendered selective for lead ions by doping them with highly
      selective components in a manner analogous to traditional optode sensing films.
      Single particles that contained the lipophilic ionophore N,N,N',N'-tetradodecyl-3
      6-dioxaoctane-1-thio-8-oxodiamide (ETH 5493), the chromoionophore ETH 5418
      together with a lipophilized indocarbocyanine derivative as internal reference
      dye (DiIC18), and lipophilic ion-exchanger sites sodium tetrakis[3,5
      bistrifluoromethylphenyl]borate, yielded measurable lead responses at the low
      nanomolar level in pH buffered solutions. The detection limit for single
      particles was 3 x 10(-9) M at pH 5.7. The microspheres were fabricated via a
      reproducible formation of polymer droplets within a flowing aqueous phase
      followed by collection of spherical particles of approximately 13 microm in size.
      The particles were immobilized and assayed individually in a microflow cell via
      fluorescence microscopy. Selectivity patterns found were in agreement with those
      reported earlier for the lead-selective ligand ETH 5493, and all response
      functions were fully described by theory. In contrast to optode films that
      necessitated very long equilibration times and large sample volumes in diluted
      samples of analyte, particles exhibited extremely enhanced equilibrium response
      times. Thus, for lead sample concentrations at and above 5 x 10(-8) M, response
      times were approximately 3 min, whereas at the detection limit, complete
      equilibrium was recorded after just 15 min, with required sample volumes on the
      order of 1 mL This new class of microspheres appears to be suitable for rapid and
      sensitive ion detection at trace levels in environmental and biological
      applications.

PMID- 12403579
TI  - Separate detection of BTX mixture gas by a microfluidic device using a function
      of nanosized pores of mesoporous silica adsorbent.
AB  - We achieved separate detection of the components of 10 ppm of a benzene, toluene,
      and o-xylene mixture gas by using mesoporous silica powder incorporated in our
      microfluidic device. The device consists of concentration and detection cells
      formed of 3 cm x 1 cm Pyrex plates. We first introduced the mixture gas into the
      concentration cell where it was adsorbed on an adsorbent in a channel formed in
      the cell. We then raised the temperature using a thin-film heater and introduced
      the desorbed gas into the detection cell. Here, we measured the changes in the
      absorption spectra of the mixture gas in the detection cell. We found that the
      mixture ratio of the compounds in the desorbed gas varies with time because the
      thermal desorption property of each compound is different from that of the
      adsorbent. We analyzed the thermal desorption mechanism by comparing two types of
      silica adsorbents with different pore structures. We found that an adsorbent that
      has pores with a periodic and uniform nanosized column shape provides better
      component separation. We concluded that the uniform pore structure might cause
      the adsorbate molecules to exhibit a homogeneous adsorption state thus revealing
      the desorption properties of the gas more clearly.

PMID- 12403580
TI  - Chromatographic and ionization properties of polybrominated diphenyl ethers using
      GC/high-resolution MS with metastable atom bombardment and electron impact
      ionization.
AB  - The chromatographic and ionization properties of 35 polybrominated diphenyl ether
      (PBDE) congeners were investigated using GC/HRMS with metastable atom bombardment
      (MAB) and electron impact (EI) ionization. A multiple linear regression model
      based on bromine substitution patterns and MOPAC calculated physical properties
      was developed to predict relative GC retention times of individual PBDE
      congeners. Although five different sources of metastable rare gas atoms (He, N2,
      Ar, Xe, and Kr) were investigated with MAB ionization, only MAB-N2 provided
      adequate ionization efficiency and predictability. Because of reduced background
      noise to the MS detector, MAB-N2 had a lower limit of detection for tetra- and
      penta-BDEs than EI, despite having a lower sensitivity. Using MAB-N2, the
      molecular ion was always the base peak, with little fragmentation taking place.
      Conversely, using EI ionization, the [M - nBr]+ peak (where n = 1-4, depending on
      the number of Br substituents) was the dominant ion for all PBDE congeners.
      Multiple linear regression models representing the molecular ion response of PBDE
      congeners analyzed by GC/ HRMS with MAB-N2 and EI ionization were also developed
      using the number and type of Br substituents and ionization potentials. A
      significantly higher level of predictability was obtained for the MAB-N2 response
      model than for EI.

PMID- 12403581
TI  - Simultaneous LC-MS/MS determination of reference pharmaceuticals as a method for
      the characterization of the Caco-2 cell monolayer absorption properties.
AB  - Since its introduction a decade ago, the Caco-2 in vitro model for testing
      intestinal permeability has found wide application, in particular for screening
      new molecules in the pharmaceutical industry. An important issue for the
      validation of the model is to verify integrity and proper functionality of the
      Caco-2 cells monolayer, to ensure reproducibility and consistency of results.
      Several of these methods are based on measuring the apparent permeability
      coefficients (Papp) of well-characterized reference compounds, having known
      absorption characteristics, and comparing the observed values to those expected.
      Most of them use fluorescent or radioactive chemicals to test different
      parameters. The main limitation of such approaches is that each parameter to be
      tested is associated with a single specific method, so that multiple procedures
      are needed to adequately characterize the cell monolayer. This work describes the
      use of a unique LC-MS/MS method to simultaneously determine the Papp of a set of
      reference substances having well-characterized absorption behavior, i.e.,
      phenylalanine, atenolol, and propranolol. The method is routinely used in our
      laboratory to check on model reproducibility and proved useful in verifying the
      consistency of the results derived from the experiments.

PMID- 12403582
TI  - Accurate mass measurements for peptide and protein mixtures by using matrix
      assisted laser desorption/ionization Fourier transform mass spectrometry.
AB  - A new analytical scheme based on a combination of scanning FTMS, multiple-ion
      filling, and potential ramping methods has been developed for accurate molecular
      mass measurement of peptide and protein mixtures using broadband MALDI-FTMS. The
      scanning FTMS method alleviates the problems of time-of-flight effect for FTMS
      with an external MALDI ion source and provides a systematic means of sampling
      ions of different mass-to-charge ratios. The multiple-ion filling method is an
      effective way of trapping and retaining ions from successive ion
      generation/accumulation events. The potential ramping method allows the use of
      high trapping potentials for effective trapping of ions of high kinetic energies
      and the use of low trapping potentials for high-resolution detection of the
      trapped ions. With this analytical scheme, high-resolution broadband MALDI mass
      spectra covering a wide mass range of 1000-5700 Da were obtained. For peptide
      mixtures of mass range 1000-3500 Da, calibration errors of low part-per-millions
      were demonstrated using a parabolic calibration equation f2 = ML1/m2 + ML2/m +
      ML3, where f is the measured cyclotron frequency and ML1, ML2, and ML3 are
      calibration constants.

PMID- 12403583
TI  - Determination of 4-hydroxy-3-methoxyphenylethylene glycol 4-sulfate in human
      urine using liquid chromatography-tandem mass spectrometry.
AB  - A major metabolite of norepinephrine (NE) in brain is 4-hydroxy-3
      methoxyphenylethylene glycol (MHPG). In many species, a large fraction of MHPG
      formed in brain is converted to the sulfate conjugate. Consequently, MHPG sulfate
      has been proposed as a biomarker for NE metabolism in the central nervous system.
      As part of the clinical trials of the monoamine oxidase inhibitor selegiline for
      treating cocaine addiction, we required a method for measuring urine
      concentrations of MHPG sulfate. Using a deuterium-labeled analogue as an internal
      standard, we developed a liquid chromatography-electrospray ionization tandem
      mass spectrometry (LC-MS/ MS) method for determination of MHPG sulfate in human
      urine. Sample preparation involves simply diluting 50 microL of urine with 1 mL
      of ammonium formate buffer and adding the internal standard. The sample is
      centrifuged, the supernate is transferred to an autosampler vial, and 10 microL
      is injected into the LC-MS/MS system. Standard curves from 50 to 10,000 ng/mL are
      generated. Only one sample of 277 clinical samples analyzed had a concentration
      outside of this range. Precision (coefficient of variation) ranged from 1.9 to
      9.7%, and accuracy ranged from 97 to 103% of expected values for controls
      prepared by spiking sulfatase-treated urine with MHPG sulfate.

PMID- 12403584
TI  - Increased sensitivity of surface plasmon resonance of gold nanoshells compared to
      that of gold solid colloids in response to environmental changes.
AB  - Gold nanoshells have been synthesized by reacting aqueous HAuCl4 solutions with
      solid templates such as silver nanoparticles. The morphology, void space, and
      wall thickness of these hollow nanostructures were all determined by the
      templates, which were completely converted into soluble species during the
      replacement reaction. The surface plasmon peaks of these gold nanoshells were
      considerably red-shifted as compared to gold solid colloids having approximately
      the same dimensions. In addition, the surface plasmon resonance of gold
      nanoshells exhibited a much more sensitive response toward environmental changes
      even when compared with solid colloids with a mean size much smaller than that of
      gold nanoshells. For example, the sensitivity factor (i.e., the shift in peak
      position per unit change in the refractive index of the surrounding medium) was
      408.8, 60.0, and 70.9 nm per refractive index unit for gold nanoshells with a
      mean diameter of 50 nm and wall thickness of 4.5 nm, gold solid colloids of 50 nm
      in diameter, and gold solid colloids of 30 nm in diameter, respectively. The
      formation of alkanethiolate self-assembled monolayers on their surfaces caused
      the plasmon peaks to red-shift by 3.0 nm per methylene unit for gold nanoshells
      and 0.2 nm per methylene unit for solid colloids with a mean size of 50 nm. Such
      enhanced sensitivities should make gold nanoshells particularly useful as optical
      probes for chemical or biological binding events at solid-liquid interfaces.

PMID- 12403585
TI  - Patterning flows using grooved surfaces.
AB  - Through a simple analytical description we quantify how pressure-driven flows
      over grooved surfaces develop transverse components, which, for shallow grooves,
      can be modeled with simple anisotropic effective boundary conditions. Helical
      recirculation results in channels or capillaries with grooved walls. An
      experimental validation of our model is presented. Our analysis provides a
      workable guide for the design of 3D flows with simple patterns of grooved
      regions, e.g., to control the position of streams in the cross section of a
      channel or to promote mixing. Potential applications in microfluidics are
      outlined.

PMID- 12403586
TI  - RNA-peptide binding and the effect of inhibitor and RNA mutation studied by on
      line acoustic wave sensor.
AB  - Acoustic wave devices of the transverse shear-wave type are becoming increasingly
      important in the study of biochemical binding events at the solid-liquid
      interface in real time. The operation of the sensor is based on the principle
      that perturbations occurring at the solid-liquid interface result in changes in
      the propagating characteristics of the acoustic wave. The binding of the human
      immunodeficiency virus-type 1 Tat protein to the transactivation-responsive RNA
      element has been studied using this sensor. Variable acoustic signals in terms of
      frequency and motional resistance changes are obtained when surface-immobilized
      RNA is challenged by different peptide fragments derived from Tat protein. The
      effect of peptide concentration and mutation in addition to the inhibition of RNA
      peptide binding by neomycin has been investigated. The results of this study
      suggest that acoustic physics offers considerable potential for the screening of
      small-molecule interactions with nucleic acids.

PMID- 12403587
TI  - Enhanced measurement stability and selectivity for choline and acetylcholine by
      capillary electrophoresis with electrochemical detection at a covalently linked
      enzyme-modified electrode.
AB  - Enzyme-modified microelectrodes were developed for the indirect amperometric
      detection of acetylcholine and choline following separation by capillary
      electrophoresis. Electrodes were prepared by first sequentially electrodepositing
      polypyrrole and polytyramine from the monomers on a 200-microm platinum
      electrode. The polymer bilayer provides enhanced selectivity and pendant amino
      groups for covalent coupling of acetylcholinesterase (AChE) and choline oxidase
      (ChO) by their reaction with glutaraldehyde. The AChE/ChO-modified electrode was
      then employed as an end-column detector to determine acetylcholine and choline
      with and without the internal standard butyrylcholine. Excellent operational
      stability during 2 days of continuous use was observed, with detection limits of
      2 microM or 50 fmol for both acetylcholine and choline. The response from
      potential interferences, such as dopamine, catechol, and norepinephrine, were
      significantly reduced in comparison to a bare platinum electrode. The utility of
      this approach was demonstrated by monitoring the uptake of choline into
      synaptosomes.

PMID- 12403588
TI  - Characterization of a focal plane camera fitted to a Mattauch-Herzog geometry
      mass spectrograph. 1. Use with a glow-discharge source.
AB  - A Mattauch-Herzog geometry mass spectrograph (MHMS) has been equipped with a
      novel array detector, the focal plane camera (FPC). The FPC consists of an array
      of gold Faraday cups, each coupled to its own integrator, with interrogation of
      the integrators performed by a multiplexer. The initial coupling of this
      instrument with a pin-type glow discharge source has provided limits of detection
      in the single to hundreds of nanograms per gram regime; isotope ratio accuracy
      and precision better than 5% error and 0.2% RSD, respectively; and a linear
      dynamic range of at least 6 orders of magnitude. A current weakness of the FPC is
      its pixel size, which limits both sensitivity and baseline resolution (to R =
      130). The minimum data acquisition time for multiple images at present is 1
      ms/image, with a dead time of 3.2 ms between images, which will limit the ability
      of the FPC to monitor extremely short transient signals.

PMID- 12403589
TI  - Deuterium nuclear magnetic resonance spin-lattice relaxation of analytically
      relevant solvent systems.
AB  - We previously reported that the nuclear magnetic resonance (NMR) 14N spin-lattice
      relaxation times (T1) of CH3CN in CH3CN-H2O mixtures directly correlate with the
      solution viscosity when scaled for temperature (eta/T) in this common
      chromatographic mobile phase system.' Here, we demonstrate that the 2HT1
      relaxation times also correlate with viscosity, contrary to a previous report.
      (2) This establishes 2HT1 relaxation times as a useful means of measuring changes
      in solution viscosity in CH3CN-H2O mixtures. We show thermal convection to result
      in grossly decreased, apparent T1's, by as much as approximately 40%, in
      nonspinning samples. This effect can be eliminated by moderate sample rotation or
      confinement of the sample to within the rf-irradiated region. The problem of
      thermal convection is revealed in systems having long Ti's and has implications
      in T1 experiments employing nonspinning samples at elevated temperatures,
      including inherently nonspinning systems, such as those used in high-pressure
      studies.

PMID- 12403590
TI  - Determination of binding constants of cyclodextrins in room-temperature ionic
      liquids by near-infrared spectrometry.
AB  - Near-infrared spectrometry has been successfully used to determine association
      binding constants between phenol and alpha-, beta- and gamma-cyclodextrin (CD) in
      [butylmethylimidazolium][chloride] room-temperature ionic liquid (RTIL). It was
      found that adding CD into the RTIL solution of phenol resulted in an enhancement
      in the absorption coefficient of the stretching overtone of the aromatic C-H
      groups. However, the enhancement induced by CDs in RTIL is much lower (order of
      magnitude) than those corresponding in D20. The binding constants in RTIL are
      also much lower than those in D2O ((11 +/- 2), (16 +/- 2), and (40 +/- 6) M(-1)
      for phenol and alpha-, beta- and gamma-CD, respectively, as compared to 87 and
      214 M(-1) for a- and beta-CD in D2O). The results obtained seem to suggest that
      in ionic liquid, the main interaction between phenol and CDs may not be inclusion
      complex formation but rather external adsorption. A variety of reasons may be
      responsible for relatively weaker interactions and lower binding constants in the
      ionic liquid, including differences in the polarity and viscosity of RTIL and
      D20. However, the main reason may be due to the possibility that the 1-butyl-3
      methylimidazolium cation of the ionic liquid may form inclusion complexes with
      CDs either through its imidazolium moiety or its butyl group. Such complex
      formation would prevent phenol from being included in the cavity of the CDs.

PMID- 12403591
TI  - Measuring the number of independent emitters in single-molecule fluorescence
      images and trajectories using coincident photons.
AB  - A simple new approach is described and demonstrated for measuring the number of
      independent emitters along with the fluorescence intensity, lifetime, and
      emission wavelength for trajectories and images of single molecules and
      multichromophoric systems using a single PC plug-in card for time-correlated
      single-photon counting. The number of independent emitters present in the
      detection volume can be determined using the interphoton times in a manner
      similar to classical antibunching experiments. In contrast to traditional
      coincidence analysis based on pulsed laser excitation and direct measurement of
      coincident photon pairs using a time-to-amplitude converter, the interphoton
      distances are retrieved afterward by recording the absolute arrival time of each
      photon with nanosecond time resolution on two spectrally separated detectors.
      Intensity changes that result from fluctuations of a photophysical parameter can
      be distinguished from fluctuations due to changes in the number of emitters
      (e.g., photobleaching) in single chromophore and multichromophore intensity
      trajectories. This is the first report to demonstrate imaging with contrast based
      on the number of independently emitting species within the detection volume.

PMID- 12403592
TI  - Detection of flowing fluorescent particles in a microcapillary using fluorescence
      correlation spectroscopy.
AB  - Capillary flow experiments are described with fluorescent molecules, bacteria,
      and microspheres using fluorescence correlation spectroscopy as an analytical
      tool. The flow velocity in the microcapillary is determined by fitting
      autocorrelation traces with a model containing parameters related to diffusion
      and flow. The flow profile of pressure-driven flow inside a microcapillary is
      determined by using the fluorescence fluctuations of a small dye molecule. It was
      found that bacteria and microspheres are retarded in their flow by optical forces
      produced by the laser beam.

PMID- 12403593
TI  - Determination of boron-containing compounds in urine and blood plasma from boron
      neutron capture therapy patients. The importance of using coupled techniques.
AB  - The necessity of using coupled techniques to analyze samples from boron neutron
      capture therapy (BNCT) patients prior to element-specific detection has been
      demonstrated. BNCT patients were infused with p-boronophenylalanine (BPA)
      fructose complex before the therapy started. Urine and blood plasma samples were
      collected at different times after the start of the BPA administration and were
      run on a porous graphitic carbon column coupled on-line to an inductively coupled
      plasma-atomic emission spectrometer (ICP-AES) and an ICP time-of-flight mass
      spectrometer (TOF-MS). In addition to BPA, a possible metabolite to BPA and some
      minor boron-containing compounds, eluting close to the front, were also found in
      the urine and plasma samples. Because only the total concentration of boron has
      been measured so far in earlier studies, the suspected metabolite could not be
      detected, and this is the first report indicating its presence in urine and
      plasma of BNCT patients. The abundance of 10B in urine was about the same for BPA
      and its possible metabolite (98-99%). The ratio between the possible metabolite
      and BPA was found to differ in the urine from different patients. Most of the
      patients had a metabolite concentration of approximately 10 mol % of the BPA
      content in their urine 5-11 h after the start of the BPA administration. This
      ratio increased to between 30 and 80% when 24 h had passed. The ratio of
      metabolite to BPA was found to be lower in the plasma than in the urine samples
      at comparable time after the start of BPA infusion. Preliminary results from
      micro-LC-electrospray ionization (ESI)-MS/MS measurements on four urine samples
      indicate that the metabolite has a higher mass than BPA.

PMID- 12403594
TI  - Miniaturized flow fractionation device assisted by a pulsed electric field for
      nanoparticle separation.
AB  - Electric field flow fractionation (EFFF) is a powerful separation technique based
      on an electrical field perpendicular to a pressure-driven flow. Previous studies
      of microelectric field flow fractionation (micro-EFFF) indicate that separation
      performance was limited due to a weak effective electric field caused by
      polarization layers on the electrode surfaces. In this work, we report on a micro
      EFFF device that uses a pulsed voltage scheme to overcome these limitations. The
      device was fabricated in indium tin oxide (ITO)-coated glass with ITO as
      electrodes. The effective electric field for pulsed voltage operation was found
      to be 50-fold stronger when compared with constant voltage operation. A strong
      influence of pulsed voltage frequency on nanoparticle retention times was
      observed. Using pulsed voltage, improved separation of polystyrene particles of
      different surface charge and particle size is demonstrated. Pulsed voltage also
      offers more parameters compared to the constant voltage mode, e.g., pulse
      frequency, duty cycle, and waveform to optimize the retention behavior of
      analytes.

PMID- 12403595
TI  - Dopamine transport into a single cell in a picoliter vial.
AB  - The analysis of chemical events in small volumes requires careful manipulation of
      samples and sensitive detection methods. Here, we describe the measurement of the
      neurotransmitter dopamine in a picoliter vial with electrochemical techniques.
      The vials were fabricated from fused-silica capillaries that provided a
      transparent container suitable for the observation and manipulation of a
      biological cell, sample solutions, and electrodes. Evaporation of the sample was
      prevented with a mineral oil layer, allowing for experiments lasting for several
      minutes. The small volume of these vials (100-200 pL) allows rapid mixing of all
      of the solution reagents. Similarly, the small volume allows exhaustive
      electrolysis of the vial contents with a 3-microm radius, disk-shaped carbon
      fiber microelectrode within 60 s. Fast-scan cyclic voltammetry at carbon fiber
      microelectrodes was used to monitor the concentration of analyte in the vial
      without depleting its contents. The concentration of dopamine introduced by
      pneumatic injection remained stable when sampled by cyclic voltammetry, and no
      evidence for adsorption to the walls was observed. However, when the vial
      contained a single HEK-293 cell transfected to express the dopamine transporter,
      the dopamine concentration decreased with time at a rate consistent with the
      uptake kinetics mediated by the transporter located on the cell membrane.

PMID- 12403596
TI  - Quantitative determination of N7-methyldeoxyguanosine and O6-methyldeoxyguanosine
      in DNA by LC-UV-MS-MS.
AB  - The N-7 and O-6 positions of 2'-deoxyguanosine are the predominant sites of
      methylation by N-methyl-N-nitrosourea (MNU), which is used to produce a variety
      of experimental cancers in animal models. Here we report the development of a
      highly sensitive quantitative assay based on high-performance liquid
      chromatography-UV-tandem mass spectrometry (LC-UV-MS-MS) to measure N7-methyl-2'
      deoxyguanosine (N7-MedG) and O6-methyl-2'-deoxyguanosine (O6-MedG) in DNA
      hydrolysates. Since this assay was selective for deoxyribonucleosides, potential
      interference from methylated RNA was eliminated. Isotopically labeled analogues,
      [2H3]N7-MedG and [2H3]O6-MedG, were synthesized and added to the DNA hydrolysates
      as internal standards. In-line UV absorbance detection was used for the
      quantitative analysis of the native deoxyribonucleoside dG, and MS-MS was used
      for the determination of N7-MedG and O6-MedG. The limits of detection for N7-MedG
      and O6-MedG were determined to be 64 and 43 fmol, respectively. The limits of
      quantification were 0.13 pmol for N7-MedG and 0.085 pmol for O6-MedG. The
      stabilities of N7-MedG and O6-MedG were also investigated. Although O6-MedG was
      stable at room temperature for at least 11 days, the half-life of N7-MedG at room
      temperature was 2 days. Both adducts were stable at -20 degrees C. Calf thymus
      DNA and DNA from the livers of MNU-treated Sprague-Dawley rats were assayed using
      LC-UV-MS-MS, which was optimized for speed as well as for sensitivity. The levels
      of N7-MedG and 06-MedG in calf thymus DNA increased with MNU concentration and
      incubation time. The levels of N7-MedG and O6-MedG in the rat livers 2 h after
      treatment with a single dose of 50 mg/kg MNU were 95.2 N7-MedG/105 dG and 14.8 O6
      MedG/105 dG. This LC-UV-MS-MS assay provides the sensitivity and speed required
      to evaluate the extent of methylated DNA lesions in animal models of cancer
      induced by the methylating agent MNU.

PMID- 12403597
TI  - Empirical statistical model to estimate the accuracy of peptide identifications
      made by MS/MS and database search.
AB  - We present a statistical model to estimate the accuracy of peptide assignments to
      tandem mass (MS/MS) spectra made by database search applications such as SEQUEST.
      Employing the expectation maximization algorithm, the analysis learns to
      distinguish correct from incorrect database search results, computing
      probabilities that peptide assignments to spectra are correct based upon database
      search scores and the number of tryptic termini of peptides. Using SEQUEST search
      results for spectra generated from a sample of known protein components, we
      demonstrate that the computed probabilities are accurate and have high power to
      discriminate between correctly and incorrectly assigned peptides. This analysis
      makes it possible to filter large volumes of MS/MS database search results with
      predictable false identification error rates and can serve as a common standard
      by which the results of different research groups are compared.

PMID- 12403598
TI  - Analyzing the physiological signature of anabolic steroids in cattle urine using
      pyrolysis/metastable atom bombardment mass spectrometry and pattern recognition.
AB  - Pyrolysis coupled to metastable atom bombardment (MAB) and time-of-flight mass
      spectrometry (TOFMS) is used for generating mass spectra from bovine urine
      samples obtained from cattle treated with anabolic steroids. These spectra
      constitute fingerprints, which can be discriminated by multivariate statistical
      analysis. Four main conclusions can be drawn from this work: (i) The use of
      different metastable gases, such as Xe*, Kr*, or N2*, as an energy-tunable
      ionization beamline allows control of the internal energy and the dissociation
      processes of the produced odd electron molecular ions, thus giving rise to
      complementary mass spectra fingerprints. (ii) A variable transformation depending
      on the biofluid matrix suitably contracts the frequency distribution of the
      generated data for low m/z ratios holding information related to endogenous
      metabolites encountered in urine. (iii) Coupling variable selection to
      statistical pattern recognition methods results in low error rates (< 1%) for
      predicting MAB mass fingerprints, especially using lineardiscriminant analysis
      (LDA). (iv) LDA discriminates controls from treated animals and also correlates
      to quantitative physiological responses induced by anabolic steroids. This work
      shows that Py-MAB-TOFMS could be a suitable method for complementary monitoring
      anabolic use in sports, medicine, and cattle breeding, as well as monitoring many
      other long-lasting although weak physiological disruptions.

PMID- 12403599
TI  - A colloidal graphite-coated emitter for sheathless capillary
      electrophoresis/nanoelectrospray ionization mass spectrometry.
AB  - A colloidal graphite-coated emitter is introduced for sheathless capillary
      electrophoresis/nanoelectrospray ionization time-of-flight mass spectrometry
      (CE/ESI-TOFMS). The conductive coating can be produced by brushing the capillary
      tip to construct a fine layer of 2-propanol-based colloidal graphite. The
      fabrication involves a single step and requires less than 2 min. Full cure
      properties develop in approximately 2 h at room temperature and then the tip is
      ready for use. The coated capillary tip is applied as a sheathless electrospray
      emitter. The emitter has proven to bear stable electrospray and excellent
      performance for 50 microm i.d. x 360 microm o.d. and 20 microm i.d. x 360 microm
      o.d. capillaries within the flow rate of 80-500 nL/min; continuous electrospray
      can last for over 200 h in positive mode. Baseline separation and structure
      elucidation of two clinically interesting basic drugs, risperidone and 9
      hydroxyrisperidone, are achieved by coupling pressure-assisted CE to ESI-TOFMS
      using the described sheathless electrospray emitter with a bare fused-silica
      capillary at pH 6.7. It is found that the signal intensity of m/z in sheathless
      CE/ESI-TOFMS at pH 6.7 is approximately 50 times higher than that at pH 9.0 for
      the two analytes, although the electroosmotic flow (EOF) at pH 9.0 provides
      sufficient flow rate (approximately 150 nL/min) to maintain electrospray.

PMID- 12403600
TI  - Comparison of delta18O measurements in nitrate by different combustion
      techniques.
AB  - Three different KNO3 salts with delta18O values ranging from about -31 to +54 per
      thousand relative to VSMOW were used to compare three off-line, sealed glass tube
      combustion methods (widely used for isotope studies) with a more recently
      developed on-line carbon combustion technique. All methods yielded roughly
      similar isotope ratios for KNO3 samples with delta18O values in the midpoint of
      the delta18O scale near that of the nitrate reference material IAEA-NO-3 (around
      +21 to +25 per thousand). This reference material has been used previously for
      one-point interlaboratory and intertechnique calibrations. However, the isotope
      ratio scale factors by all of the off-line combustion techniques are compressed
      such that they are between 0.3 and 0.7 times that of the on-line combustion
      technique. The contraction of the 6180 scale in the off-line preparations
      apparently is caused by O isotope exchange between the sample and the glass
      combustion tubes. These results reinforce the need for nitrate reference
      materials with delta18O values far from that of atmospheric O2, to improve
      interlaboratory comparability.

PMID- 12403601
TI  - Chemical imaging of surface reactions by multiplexed capillary electrophoresis.
AB  - A new technique for in situ imaging of surface reactions and screening
      heterogeneous catalysts by using multiplexed capillary electrophoresis was
      developed. By bundling together the inlets of a large number of capillaries, an
      aligned imaging probe can be created that can be used to sample directly products
      formed at a surface with spatial resolution determined by the outer diameter of
      the capillaries. In this work, we used surfaces made of platinum, iron, or gold
      wires to generate electrochemical products for imaging. Various shapes were
      recorded including crosses, squares, and triangles. A model multifunctional
      catalytic surface consisting of both iron and platinum electrodes in the shape of
      a cross was also imaged successfully. Each of the two wires produced a different
      electrochemical product that could be subjected to capillary electrophoresis to
      provide chemical selectivity. On the basis of the collected data, we were able to
      distinguish the products from each wire in the reconstructed image.

PMID- 12403602
TI  - Flow cytometric ion detection with plasticized poly(vinyl chloride) microspheres
      containing selective lonophores.
AB  - The use of flow cytometry as a rapid, high-throughput diagnostic tool for the
      analysis of ions is described. Monodisperse, uniform microspheres, which obey
      bulk optode theory and are governed by bulk extraction processes rather than
      surface phenomena, were prepared under mild, nonreactive conditions using a sonic
      stream particle casting apparatus. As an initial example demonstrating the
      utility of this approach, microspheres that contained a H+-selective fluorescent
      chromoionophore (ETH 5294), a cation-exchanger (NaTFPB), and either a highly
      sodium-selective (sodium ionophore X) or a potassium-selective ionophore (BME-44)
      were prepared. Separate solution analysis of sodium- and potassium-selective
      microspheres resulted in the generation of functional response curves using peak
      channel fluorescence intensities. The selectivity observed for both types of
      particles is sufficient for the clinical determination of Na+ and K+.
      Furthermore, sodium- and potassium-selective microspheres were analyzed in
      parallel using sodium sample solutions, resulting in the successful determination
      of sodium ion concentrations and providing important information about the
      selectivity of the potassium-selective sensors over sodium. This work
      demonstrates the potential applicability of flow cytometry as a means for
      developing multiplexed, rapid, high-throughput analyses for clinically relevant
      ions.

PMID- 12403603
TI  - Comprehensive two-dimensional gas chromatography with fast enantioseparation.
AB  - The development of fast chiral analysis for use in comprehensive two-dimensional
      gas chromatography in which a short second dimension enantioselective capillary
      column provides a route to precise measurement of chiral ratios of enantiomers is
      described. Retention times as short as 8 s are reported for (+/-)-limonene, with
      adequate enantioseparation maintained (Rs approximately 1.0) on a 1-m
      cyclodextrin derivative-coated capillary column. Sufficiently fast elution on the
      second column was achieved by using GC/ MS in which the subambient pressure
      (vacuum outlet) conditions promote increased diffusion coefficients and higher
      component volatility; a 4-fold reduction of second-dimension retention time was
      observed, as compared with ambient pressure outlet conditions. The enantiomeric
      distribution of several monoterpene compounds in bergamot essential oil is
      reported as a demonstration of the method. Total analysis time of the target
      components was approximately 8.5 min.

PMID- 12403604
TI  - Independent control of ion transmission in a jet disrupter dual-channel ion
      funnel electrospray ionization MS interface.
AB  - A new atmospheric pressure ionization mass spectrometer (API-MS) interface has
      been developed to allow the control of ion transmission through the first vacuum
      stage of the mass spectrometer. The described interface uses a dual-heated
      capillary and a dual-inlet ion funnel design. Two electrosprays, aligned with the
      dual-capillary inlet, are used to introduce ions from different solutions
      independently into the MS. The initial design was specifically aimed at
      developing a method for the controlled introduction of calibrant ions in highly
      accurate mass measurements using Fourier transform ion cyclotron resonance mass
      spectrometer (FTICR). The dual-channel ion funnel has different inlet diameters
      that are aligned with the dual capillaries. The large diameter main channel of
      the ion funnel is used for analyte introduction to provide optimum ion
      transmission. The second, smaller diameter channel inlet includes a jet disrupter
      in the ion funnel to modulate the ion transmission through the channel. The two
      inlet channels converge into a single-channel ion funnel where ions from both
      channels are mixed, focused, and transmitted to the mass analyzer. Both
      theoretical simulations and experimental results show that the transmission of
      different m/z species in the small diameter channel of the ion funnel can be
      effectively modulated by varying the bias voltage on the jet disrupter. Both
      static and dynamic modulations of ion transmission are demonstrated
      experimentally by applying either a constant DC or a square waveform voltage to
      the jet disrupter. High ion transmission efficiency, similar to the standard
      single-channel ion funnel, is maintained in the main analyte channel inlet of the
      ion funnel over a broad m/z range with negligible "cross talk" between the two
      ion funnel inlet channels. Several possible applications of the new interface
      (e.g., for high-accuracy MS analysis of complex biological samples) are
      described.

PMID- 12403605
TI  - Breaking the 10(-7) barrier for RI measurements in nanoliter volumes.
AB  - Refractive index (RI) detection is a common technique used in chemical and
      biochemical analysis. It can be employed to perform universal solute detection in
      microHPLC and CE, as well as temperature measurements. However, accurate RI
      measurements in nanoliter volumes still present a significant challenge. Here we
      present an alternative method to extract RI information encoded in spatial
      distribution of the backscattered fringes produced by a microinterferometric
      backscatter detector (MIBD) based on spatial Fourier analysis. By monitoring the
      phase in the Fourier domain, we were able to obtain detection limits of 7 x 10(
      8) RIU. It was also shown that such calculations could be performed in real time,
      thus making MIBD with Fourier analysis compatible with microHPLC, CE, and FIA.

PMID- 12403606
TI  - Effects of high-frequency emphasis and compression time constants on speech
      intelligibility in noise.
AB  - The objectives of the study were to evaluate the effect of different settings
      with regard to speech intelligibility in noise both objectively and subjectively
      and thus determine a favoured setting of compression time parameters, pre-set
      program (high-frequency emphasis) or combination for each individual user in a
      prospective study. Another objective was to evaluate the relationship between
      patient characteristics (e.g. slope of hearing loss) and favoured settings. In
      total, 38 subjects divided over five audiological centres were fitted with the
      Philips Spaceline D71-40 BTE digital hearing aid. Subjects were asked to compare
      three predefined compression algorithms with different time constants, slow
      (indicated by the manufacturer as AVC), intermediate (NORMAL) and fast (SYLLABIC)
      over two 4-week periods using the intermediate setting in both comparisons and
      randomizing over the fast and slow conditions. A randomization determined whether
      a subject started with the comfort-oriented pre-set program (AUTO) or the speech
      intelligibility-oriented setting with high-frequency emphasis (SPIN). In a third
      4-week period, the pre-sets AUTO and SPIN were compared using the setting of the
      compression time constants that gave the best results during the first two
      periods. Comparisons were made using a standard speech-in-noise test with three
      types of noise: continuous speaker noise, modulated ICRA-4 noise, and car noise.
      The patients were also asked to fill in a Dutch translation and adaptation of the
      APHAB questionnaire to indicate their impression of performance. The results
      indicate that no compression algorithm, pre-set or combination is favoured
      overall. The largest improvement in speech-in-noise scores was found with
      syllabic compression. The advantageous effect of high-frequency emphasis after
      optimization of compression timing is small. The APHAB showed that users tend to
      prefer the SPIN setting. We found no relationship between favoured compression or
      pre-set and the degree or steepness of the hearing loss User preference and best
      performance in noise do not always coincide. Acclimatization may play a role. It
      could be advisable to let a user listen to a subjectively less favoured condition
      for at least some time if an optimal setting for speech intelligibility in noise
      is preferred over comfort.

PMID- 12403607
TI  - Horizontal localization and speech intelligibility with bilateral and unilateral
      hearing aid amplification.
AB  - Speech intelligibility and horizontal localization of 19 subjects with mild-to
      moderate hearing loss were studied in order to evaluate the advantages and
      disadvantages of bilateral and unilateral hearing aid (HA) fittings. Eight
      loudspeakers were arranged in a circular array covering the horizontal plane
      around the subjects. Speech signals of a sentence test were delivered by one,
      randomly chosen, loudspeaker. At the same time, the other seven loudspeakers
      emitted noise with the same long-term average spectrum as the speech signals. The
      subjects were asked to repeat the speech signal and to point out the
      corresponding loudspeaker. Speech intelligibility was significantly improved by
      HAs, bilateral amplification being superior to unilateral. Horizontal
      localization could not be improved by HA amplification. However, bilateral HAs
      preserved the subjects' horizontal localization, whereas unilateral amplification
      decreased their horizontal localization abilities. Front-back confusions were
      common in the horizontal localization test. The results indicate that bilateral
      HA amplification has advantages compared with unilateral amplification.

PMID- 12403608
TI  - Adaptive noise suppression for a dual-microphone hearing aid.
AB  - An adaptive beamformer for behind-the-ear dual-microphone hearing aids has been
      optimized for speech intelligibility enhancement in the presence of disturbing
      sounds or noise. The noise reduction approach is based on the scheme presented by
      Vanden Berghe and Wouters (1998). A real-time implementation of the signal
      processing is realized in Audallion, a wearable, small digital signal processing
      (DSP) platform. After physical evaluation, speech-in-noise intelligibility tests
      have been carried out on three normally-hearing and two hearing-impaired
      subjects. A significant speech reception threshold improvement of 11.3 dB was
      obtained in a moderately reverberant environment for one jammer sound source
      (steady speech-weighted noise or multi-talker babble) in a direction of 90
      degrees relative to the direction of the speech.

PMID- 12403609
TI  - Is the real-ear to coupler difference independent of the measurement earphone?
AB  - Direct measurement of real-ear hearing aid performance can be obtained using a
      probe tube microphone system. Alternatively, it can be derived by adding the real
      ear to coupler difference (RECD) to the electroacoustic performance of the
      hearing instrument measured in a 2-cc coupler. Inherent in this derivation is the
      assumption that the RECD measured with one transducer can be applied to a coupler
      measurement performed with a different transducer. For the RECD procedure to be
      valid, it should be independent of the measurement transducer. The Audioscan
      RM500 is an example of a commercially available real-ear measurement system that
      incorporates a clinical protocol for the measurement of the RECD. The RECD can be
      measured on the Audioscan RM500 using a standard EAR-Tone ER-3A insert earphone
      or the Audioscan's own RE770 insert earphone. The aim of this study was to
      compare the RECDs obtained with these two earphones. The Audioscan RM500 was used
      to measure the RECD from the right ears of 18 adult subjects ranging in age from
      22 to 36 years (mean 25 years). Measurements were made with the EAR-Tone ER-3A
      and RE770 insert earphone and three earmould configurations: (1) the EARLINK foam
      ear-tip; (2) a hard acrylic shell earmould with the same length of acoustical
      tubing as the foam ear-tip (25 mm); and (3) the shell ear mould with the
      appropriate length of tubing for a behind-the-ear (BTE) hearing aid fitting
      (approximately 35-45 mm). The results show that the mean RECD was around 3 dB
      higher at 1.5 kHz with the foam ear-tip when measured with the RE770 earphone
      than when measured with the ER-3A earphone. The same magnitude of difference was
      obtained with the shell earmould and 25-mm tubing; however, this increased to 9
      dB when the tubing was increased to around 40 mm for a BTE fitting. The
      difference in mean RECD with the two earphones was statistically significant on a
      repeated-measures ANOVA for every earmould configuration (p<0.001). The results
      of this study demonstrate that the RECD procedure that uses an HA2 coupler and
      earmould is not independent of the measurement earphone. This has important
      implications for clinical practice.

PMID- 12403610
TI  - The effects of phonemic compression and anti-upward-spread-of-masking (anti-USOM)
      on the perception of articulatory features in hearing-impaired listeners.
AB  - The effect of speech processing on articulatory-feature recognition was studied
      in a group of hearing-impaired listeners with high-frequency sensorineural
      losses. Individual difference scaling (INDSCAL) and sequential information
      analysis (SINFA) were applied to a set of consonant-vowel-consonant responses
      measured under various conditions of speech processing. The processing consisted
      of high-frequency phonemic compression combined with compensation for anti-upward
      spread-of-masking (i.e. anti-USOM). In quiet, we found an improved recognition of
      frication with compression, whereas additional anti-USOM improved the recognition
      of the second and third vowel-formants. In background noise, we found remarkably
      negative effects of anti-USOM on the recognition of features containing low
      frequency cues, such as voicing and nasality. We conclude that the combined
      results of SINFA and INDSCAL provide important insights into the possibilities
      and limitations of phonemic compression and anti-USOM.

PMID- 12403611
TI  - Evaluation of cochlear implant benefit with auditory cortical evoked potentials.
AB  - Endogenous P300 and exogenous slow vertex potentials were obtained with tone and
      speech stimuli in a group of five children using a cochlear implant (CI) with
      poor speech recognition (group A) and compared with those from another group of
      five children using a CI with good speech recognition (group B). The responses
      were also compared to those of children with normal hearing (n= 14) and a group
      of adult CI users (n=9). N1 and P2 latencies of CI group A and group B were
      prolonged compared to those of normally-hearing children. In group A, P300 was
      present when contrasts with tone stimuli were used. When speech stimuli were
      used, P300 potentials were absent or delayed. P300 potentials obtained in group B
      were no different from those obtained in normally-hearing children. It is
      suggested that the poor results evoked with speech stimuli in contrast to those
      evoked with pure-tone stimuli in group A are due to the immaturity of (sub)
      cortical generators associated with acoustical and phonetic processing. In
      contrast to the children in group B, all children in group A suffered from
      congenital deafness.

PMID- 12403612
TI  - Carbohydrate sulfotransferases of the GalNAc/Gal/GlcNAc6ST family.

PMID- 12403613
TI  - The place of inactivated actin and its kinetic predecessor in actin folding
      unfolding.
AB  - The kinetics of actin unfolding induced by guanidine hydrochloride of different
      concentrations was studied. The parametric representation of the kinetic
      dependencies of tryptophan fluorescence intensity changes recorded at two
      wavelengths allowed us to detect and characterize a new essentially unfolded
      kinetic intermediate. Its characteristics suggested that this intermediate state
      is a premolten globule. It was shown that the equilibrium transition between
      inactivated and completely unfolded states is also a two-step process and
      proceeds via an essentially unfolded kinetic intermediate. The new kinetic
      pathway of actin unfolding--refolding was proposed. According to it, the founded
      essentially unfolded kinetic state is the on-pathway intermediate, while
      inactivated actin is the off-pathway misfolded state stabilized by aggregation of
      partially folded macromolecules of protein.

PMID- 12403614
TI  - Reconstitution and characterization of the human DNA polymerase delta four
      subunit holoenzyme.
AB  - Mammalian DNA polymerase delta was originally characterized as a tightly
      associated heterodimer consisting of the catalytic subunit, p125, and the p50
      subunit. Recently, two additional subunits, the third (p68) and fourth subunits
      (p12), have been identified. The heterotetrameric human pol delta complex was
      reconstituted by overexpression of the four subunits in Sf9 cells, followed by
      purification to near-homogeneity using FPLC chromatography. The properties of the
      four-subunit enzyme were shown to be functionally indistinguishable from those of
      pol delta isolated from calf thymus. The physicochemical properties of both the
      reconstituted heterotetramer and the heterodimer of the p125 and p50 subunits
      were examined by gel filtration and glycerol gradient ultracentrifugation. These
      studies show quite clearly that the heterodimer and heterotetramer complexes do
      not behave in solution as dimeric structures. This issue is of significance
      because several studies of the yeast pol delta complexes have indicated that the
      third subunit is able to bring about the dimerization of the pol delta complex.
      The heterodimer is only weakly stimulated by PCNA, whereas the heterotetramer is
      strongly stimulated to a level with a specific activity comparable to that of the
      calf thymus enzyme. These results resolve earlier, conflicting reports on the
      response of the heterodimer to PCNA. Nevertheless, the heterodimer does have some
      ability to interact functionally with PCNA, consistent with evidence that the
      p125 subunit itself has an ability to interact with PCNA. The functional
      interaction of PCNA with the pol delta complex may likely involve multiple
      contacts.

PMID- 12403615
TI  - Disulfide-bond formation in the transthyretin mutant Y114C prevents amyloid
      fibril formation in vivo and in vitro.
AB  - The Y114C mutation in human transthyretin (TTR) is associated with a particular
      form of familial amyloidotic polyneuropathy. We show that vitreous aggregates ex
      vivo consist of either regular amyloid fibrils or disordered disulfide-linked
      precipitates that maintain the ability to bind Congo red. Furthermore, we
      demonstrate in vitro that the ATTR Y114C mutant exists in three forms: one
      unstable but nativelike tetrameric form, one highly aggregated form in which a
      network of disulfide bonds is formed, and one fibrillar form. The disulfide
      linked aggregates and the fibrillar form of the mutant can be induced by heat
      induction under nonreduced and reduced conditions, respectively. Both forms are
      recognized by the amyloid specific antibody MAB(39-44). In a previous study, we
      have linked exposure of this epitope in TTR to a three-residue shift in beta
      strand D. The X-ray crystallographic structure of reduced tetrameric ATTR Y114C
      shows a structure similar to that of the wild type but with a more buried
      position of Cys10 and with beta-mercaptoethanol associated with Cys114, verifying
      the strong tendency for this residue to form disulfide bonds. Combined with the
      ex vivo data, our in vitro findings suggest that ATTR Y114C can lead to disease
      either by forming regular unbranched amyloid fibrils or by forming disulfide
      linked aggregates that maintain amyloid-like properties but are unable to form
      regular amyloid fibrils.

PMID- 12403616
TI  - 2-Aminopurine electronic structure and fluorescence properties in DNA.
AB  - 2-Aminopurine (2AP) fluorescence intensity and decay lifetimes have been used as
      indicators of nucleic acid geometry and dynamics. To characterize 2AP
      photophysics in the context of a DNA strand, time-dependent density functional
      theory is applied to 2AP stacked with two flanking nucleobases. Calculations show
      that 2AP in the trimers suffers a reduction in the oscillator strength of its low
      lying pi-pi* 2AP-like allowed transition, manifested in a reduction of its
      radiative rate. Trimers also exhibit two or three lower-energy excited states
      (charge transfer states) that are predicted to facilitate nonradiative
      transitions from the fluorescent excited state.

PMID- 12403617
TI  - Degradation pathway of the phosphonate ciliatine: crystal structure of 2
      aminoethylphosphonate transaminase.
AB  - Phosphonates allow certain organisms to thrive in otherwise hostile environments,
      and 2-aminoethylphosphonate (AEP) is a precursor of many cellular phosphonates.
      AEP transaminase (AEPT) is an enzyme essential to phosphonate synthesis and
      degradation pathways. The crystal structure of AEP transaminase was determined by
      multiwavelength anomalous diffraction of 66 selenium atoms. The refined structure
      at 2.2 A resolution revealed an overall fold and active site location similar to
      those of the dimeric, two-domain structure of type I aminotransferases. The
      active site contains a cofactor, pyridoxal 5'-phosphate (PLP), and the product
      phosphonoacetaldehyde. Comparison with other type I aminotransferase structures
      shows that the PLP-protein interactions are conserved. Modeling of bound
      substrates and products reveals the structural basis for AEP recognition and the
      stereospecificity of proton elimination at the alpha-carbon and indicates
      conformational changes along the reaction pathway.

PMID- 12403618
TI  - The closed state of a H+ channel helical bundle combining precise orientational
      and distance restraints from solid state NMR.
AB  - An interhelical distance has been precisely measured by REDOR solid-state NMR
      spectroscopy in the transmembrane tetrameric bundle of M2-TMP, from the M2 proton
      channel of the influenza A viral coat. The high-resolution structure of the
      helical backbone has been determined using orientational restraints from
      uniformly aligned peptide preparations in hydrated dimyristoylphosphatidylcholine
      bilayers. Here, the distance between (15)N(pi) labeled His37 and (13)C(gamma)
      labeled Trp41 is determined to be less than 3.9 A. Such a short distance, in
      combination with the known tilt and rotational orientation of the individual
      helices, permits not only a determination of which specific side chain pairings
      give rise to the interaction, but also the side chain torsion angles and
      restraints for the tetrameric bundle can also be characterized. The resulting
      proton channel structure is validated in a variety of ways. Both histidine and
      tryptophan side chains are oriented in toward the pore where they can play a
      significant functional role. The channel appears to be closed by the proximity of
      the four indoles consistent with electrophysiology and mutagenesis studies of the
      intact protein at pH 7.0 and above. The pore maintains its integrity to the N
      terminal side of the membrane, and at the same time, a cavity is generated that
      appears adequate for binding amantadine. Finally, the observation of a 2 kHz
      coupling in the PISEMA spectrum of (15)N(pi)His37 validates the orientation of
      the His37 side chain based on the observed REDOR distance.

PMID- 12403619
TI  - Structure of the Plasmodium falciparum triosephosphate isomerase-phosphoglycolate
      complex in two crystal forms: characterization of catalytic loop open and closed
      conformations in the ligand-bound state.
AB  - Triosephosphate isomerase (TIM) has been the subject of many structural and
      mechanistic studies. At position 96, there is a highly conserved Ser residue,
      which is proximal to the catalytic site. Thus far, no specific role has been
      ascribed to this residue. Plasmodium falciparum TIM (PfTIM), a fully
      catalytically active enzyme, is unique in possessing a Phe residue at position
      96. The structure of PfTIM complexed to phosphoglycolate (PG), a transition state
      analogue, has been determined in an effort to probe the effects of the mutation
      at residue 96 on the nature of inhibitor-enzyme interactions and the orientation
      of the critical catalytic loop (loop 6, residues 166-176) in TIM. Crystal
      structures of PfTIM complexed to phosphoglycolate in orthorhombic (P2(1)2(1)2(1))
      and monoclinic (C2) forms were determined and refined at resolutions of 2.8 and
      1.9 A, respectively. The P2(1)2(1)2(1) form contains two dimers in the asymmetric
      unit. In the C2 form, the molecular and crystal 2-fold axes are coincident,
      leading to a monomer in the asymmetric unit. The catalytic loop adopts the open
      state in the P2(1)2(1)2(1) form and the closed conformation in the C2 crystal.
      The open conformation of the loop in the P2(1)2(1)2(1) form appears to be a
      consequence of the Ser to Phe mutation at residue 96. The steric clash between
      Phe96 and Ile172 probably impedes loop closure in PfTIM-ligand complexes. The
      PfTIM-PG complex is the first example of a TIM-ligand complex being observed in
      both loop open and closed forms. In the C2 form (loop closed), Phe96 and Leu167
      adopt alternative conformations that are different from the ones observed in the
      open form, permitting loop closure. These structures provide strong support for
      the view that loop closure is not essential for ligand binding and that dynamic
      loop movement may occur in both free and ligand-bound forms of the enzyme.

PMID- 12403620
TI  - Detergent-free domain isolated from Xenopus egg plasma membrane with properties
      similar to those of detergent-resistant membranes.
AB  - Microdomains known as "rafts" have been isolated from many cell types as
      detergent-resistant membranes (DRMs) and are enriched in sphingolipids and
      cholesterol. However, there has been considerable controversy over whether such
      domains are found in native membranes or are artificially generated by the
      purification procedure. This controversy is based at least in part on the fact
      that raft membranes were first detected following detergent extraction in the
      cold. We isolated two plasma membrane fractions, without detergent treatment,
      using a discontinuous sucrose density gradient. One fraction was designated
      "light" and the other "heavy." These fractions were compared with DRMs, which
      were isolated in the presence of 1% Triton X-100. We found that Xenopus DRMs are
      enriched with sphingomyelin and cholesterol and exhibit a phase state similar to
      the liquid-ordered phase. Comparison of DRM complexes with the light and heavy
      plasma membrane fractions revealed some physical and biochemical similarities
      between the light fraction of the plasma membrane and the DRM complexes, based on
      (1) the phosphatidylcholine/sphingomyelin ratio and (2) the protein composition
      visualized on a two-dimensional gel. These two fractions are also quite similar
      in their thermotropic phase behavior, and their high levels of ganglioside GM1.
      We conclude that the light membrane fraction isolated in a detergent-free
      environment has many of the characteristics normally associated with DRMs.

PMID- 12403621
TI  - Site-specific labeling of supercoiled DNA at the A+T rich sequences.
AB  - Progress in structural biology studies of supercoiled DNA and its complexes with
      regulatory proteins depends on the availability of reliable and routine
      procedures for site-specific labeling of circular molecules. For this, we made
      use of oligonucleotide uptake by plasmid DNA under negative superhelical tension.
      Subsequent circularization of the oligonucleotide label facilitated by an
      oligonucleotide scaffold results in its threading between the two strands of
      duplex DNA. Several lines of evidence, including direct AFM mapping of the label,
      show that the circular oligonucleotide is stably localized at its target, an A+T
      rich region. The specific binding mode when the oligonucleotide threads the
      double helix results in a DNA kink that tends to occupy an apical position in a
      plectonemically wound supercoiled DNA, similar to the positioning of an A-tract
      bend. Site-specific labels may allow visualization techniques, such as electron
      and atomic force microscopies, to reliably map protein binding sites, identify
      local alternative structures in supercoiled DNA, and monitor structural dynamics
      of DNA molecules in real time. Site-specific oligonucleotide reactions with DNA
      may also have application in biotechnology and gene therapy.

PMID- 12403622
TI  - Putrescine activation of Trypanosoma cruzi S-adenosylmethionine decarboxylase.
AB  - S-Adenosylmethionine decarboxylase (AdoMetDC) is a pyruvoyl-dependent enzyme that
      is processed from a single polypeptide into two subunits creating the cofactor.
      In the human enzyme, both the proenzyme processing reaction and enzyme activity
      are stimulated by the polyamine putrescine. The processing reaction of
      Trypanosoma cruzi AdoMetDC was studied in an in vitro translation system. The
      enzyme was fully processed in the absence of putrescine, and the rate of this
      reaction was not stimulated by addition of the polyamine. Residues in the
      putrescine binding site of the human enzyme were evaluated for their role in
      processing of the T. cruzi enzyme. The E15A, I80K/S178E, D174A, and E256A mutant
      T. cruzi enzymes were fully processed. In contrast, mutation of R13 to Leu (the
      equivalent residue in the human enzyme) abolished processing of the T. cruzi
      enzyme, demonstrating that Arg at position 13 is a major determinant for
      proenzyme processing in the parasite enzyme. This amino acid change is a key
      structural difference that is likely to be a factor in the finding that
      putrescine has no role in processing of the T. cruzi enzyme. In contrast, the
      activity of T. cruzi AdoMetDC is stimulated by putrescine. Equilibrium
      sedimentation experiments demonstrated that putrescine does not alter the
      oligomeric state of the enzyme. The putrescine binding constant for binding to
      the T. cruzi enzyme (K(d) = 150 microM) was measured by a fluorescence assay and
      by ultrafiltration with a radiolabeled ligand. The mutant T. cruzi enzyme D174V
      no longer binds putrescine, and is not activated by the diamine. In contrast,
      mutation of E15, S178, E256, and I80 had no effect on putrescine binding. The
      k(cat)/K(m) values for E15A and E256A mutants were stimulated by putrescine to a
      smaller extent than the wild-type enzyme (2- and 4-fold vs 11-fold,
      respectively). These data suggest that the putrescine binding site on the T.
      cruzi enzyme contains only limited elements (D174) in common with the human
      enzyme and that the diamine plays different roles in the function of the
      mammalian and parasite enzymes.

PMID- 12403623
TI  - Residue 19 of the parathyroid hormone: structural consequences.
AB  - Residue 19 of the parathyroid hormone (PTH) has been shown to play an important
      role in both binding to and activation of the PTH receptor; specifically, Arg(19)
      containing analogues have improved biological function over similar Glu(19)
      peptides [Shimizu et al. (2002) Biochemistry 41, 13224-13233]. Additionally the
      juxtamembrane portion of the receptor is involved in the different biological
      responses. Here, we determine the conformational preferences of PTH analogues to
      provide a structural basis for their biological actions. On the basis of circular
      dichroism results, the Arg(19) --> Glu(19) mutations within the context of both
      PTH(1-20) and PTH(1-34) analogues lead to increases in helix content, ranging
      from a 8-15% increase. High-resolution structures as determined by (1)H NMR and
      NOE-restrained molecular dynamics simulations clearly illustrate the difference
      between Arg(19) and Glu(19)-PTH(1-20), particularly with the extent and stability
      of the C-terminal helix. The Arg(19)-containing analogue has a well defined,
      stable alpha-helix from Ser(4)-Arg(19), while the Glu(19) analogue is less
      ordered at the C-terminus. On the basis of these observations, we propose that
      position 19 of PTH(1-20) must be alpha-helical for optimal interaction with the
      juxtamembrane portion of the receptor. This mode of binding extends the current
      view of PTH binding (indeed ligand binding for all class B GPCRs), which invokes
      a bihelical ligand with the C-terminus of the ligand interacting with the N
      terminus of the receptor (responsible for binding) and the N-terminus of the
      ligand interacting with the seven-helical bundle (leading to receptor
      activation).

PMID- 12403624
TI  - Residue 19 of the parathyroid hormone (PTH) modulates ligand interaction with the
      juxtamembrane region of the PTH-1 receptor.
AB  - Recent data suggest that the binding of parathyroid hormone (PTH)-(1-34) to the
      PTH-1 receptor (P1R) involves a high-affinity interaction between the C-terminal
      (15-34) domain of the ligand and the amino-terminal extracellular (N) domain of
      the receptor and a low-affinity interaction between the N-terminal (1-14) portion
      of PTH and the juxtamembrane (J) region of the receptor, with the latter
      interaction giving rise to signal transduction. We investigated whether residues
      C-terminal of position 14 in PTH(1-34) contribute to the J component of the
      interaction mechanism by comparing the capacity of PTH analogues N-terminally
      modified to improve J domain affinity and C-terminally truncated at position 14,
      20, or 34 to stimulate cAMP formation in COS-7 cells transiently transfected with
      P1R-delNt, a P1R construct that lacks most of the N domain. In these cells, the
      potency of [M]PTH(1-34) (M = Ala(1,3,12),Gln(10),Har(11),Trp(14),Arg(19)) was 120
      fold greater than that of [M]PTH(1-14) (EC(50)s = 3.0 +/- 0.8 and 360 +/- 90 nM,
      respectively) but was equal to that of [M]PTH(1-20) (EC(50) = 2.3 +/- 0.3 nM).
      Reverting the Arg(19) substitution of [M]PTH(1-20) to the native Glu reduced cAMP
      signaling potency on P1R-delNt by 12-fold (EC(50) of [M]PTH(1-20)-Glu(19) = 27 +/
      4 nM), and it decreased the analog's capacity to inhibit the binding of the J
      domain-selective radioligand, (125)I-[Aib(1,3),Nle(8),M,Tyr(21)]ratPTH(1-21), to
      the full-length P1R stably expressed in LLC-PK1 cells by 40-fold. The Glu(19) -->
      Arg modification, however, did not affect the capacity of PTH(15-31) to inhibit
      the binding of the N domain-selective radioligand (125)I-bPTH(3-34) to the full
      length receptor. The overall data suggest that residues (15-20) of PTH, and
      particularly residue 19, contribute to the capacity of the N-terminal portion of
      the ligand to interact with the juxtamembrane region of the receptor. The NMR
      data presented in the accompanying manuscript suggests that this role could
      involve intramolecular effects on secondary structure in the N-terminal portion
      of the ligand.

PMID- 12403625
TI  - Solvent interactions of halophilic malate dehydrogenase.
AB  - Malate dehydrogenase from the extreme halophilic Haloarcula marismortui (Hm
      MalDH) is an acidic protein that is unstable below molar salt concentrations. The
      solvated folded protein was studied by small-angle neutron scattering in solvents
      containing salt: NaCl, NaCH(3)CO(2), KF, NH(4)Cl, NH(4)CH(3)CO(2),
      (NH(4))(2)SO(4), MgCl(2), and MgSO(4). It was found that the global solvent
      interactions depend mainly on the nature of the cation. Complementary mass
      density measurements in MgCl(2), NaCl, NaCH(3)CO(2), and (NH(4))(2)SO(4) allowed
      determining the partial molal volumes of the protein, which were found to
      increase slightly with the salt, and the preferential salt binding parameters for
      each solvent condition. These are strongly dependent on the cation type and salt
      concentration. Hm MalDH can be modeled as an invariant particle binding 4100
      water molecules in MgCl(2) and 2000 +/- 200 in NaCl, NaCH(3)CO(2), or
      (NH(4))(2)SO(4). The number of salt molecules associated to the particle
      decreases from about 85 to 0 in the order MgCl(2) > NaCl = NaCH(3)CO(2) >
      (NH(4))(2)SO(4). Alternatively, we considered exchangeable sites for water and
      salt with the effects of solvent nonideality. It does not change the description
      of the solvent interactions. Solvent anions act on Hm MalDH stability through a
      limited number of strong binding sites, as those seen at the interfaces of Hm
      MalDH by crystallography. Cations would act through some strong and numerous weak
      binding sites defined on the folded protein, in possible addition to nonspecific
      hydration effects.

PMID- 12403626
TI  - Link between protein-solvent and weak protein-protein interactions gives insight
      into halophilic adaptation.
AB  - Malate dehydrogenase (Hm MalDH) from the extreme halophile Haloarcula marismortui
      is a very acidic protein with extensive ion binding properties. It is a good
      model for the study of solvation-solubility relationships. We measured the small
      angle neutron or X-ray scattering profiles of folded and stable Hm MalDH at
      various protein concentrations and derived the second virial coefficients A(2).
      In NaCl, CsCl, KF, KCl, and NaCH(3)CO(2), A(2) values are positive, indicating
      globally repulsive protein-protein interactions. Below 1 M MgCl(2) and MgSO(4) or
      above 2 M (NH(4))(2)SO(4), A(2) rapidly decreases. From structure factor modeling
      with DLVO (Derjaguin, Landau, Verwey, and Overbeek)-like potentials, an effective
      diameter of 80-82 A is found for the protein particle in solution, compatible
      with its structural dimensions; the effective charge of the particle is undefined
      because of the high salt concentration. The strong variations of the protein
      protein interaction are correlated to an attractive potential whose depth evolves
      with the salinity but in an opposite way in Mg salts and (NH(4))(2)SO(4). A
      repulsive Donnan term, corresponding to counterion dissociation, and an
      attractive term related to previously measured preferential salt binding
      parameters are discussed from well-established thermodynamics considerations and
      qualitatively account for the behavior of the protein-protein interactions in the
      various solutions. Because a solvation shell with a composition different from
      bulk induces protein-protein attraction, molecular adaptation to high salt would
      be directed to allow protein-salt interactions in order to avoid water or salt
      enrichment at the surface of the protein and thus preserve its solubility.

PMID- 12403627
TI  - Multiple inequivalent metal-nucleotide coordination environments in the presence
      of the VO2+-inhibited nitrogenase iron protein: pH-dependent structural
      rearrangements at the nucleotide binding site.
AB  - Nitrogenase naturally requires adenosine nucleoside triphosphates and divalent
      metal cations for catalytic activity. Their energy of hydrolysis controls several
      mechanistic functions, most probably via separate structural conformers of the
      nitrogenase Fe protein. To characterize the ligand environment of the divalent
      metal in the ternary complex, with ADP or ATP and the Fe protein from Klebsiella
      pneumoniae, the hyperfine structures have been investigated by electron
      paramagnetic resonance (EPR) spectroscopy by substituting naturally occurring
      diamagnetic Mg(2+) by paramagnetic oxovanadium. This metal replacement leads to
      inhibition of nitrogenase activity. Moreover, depending on pH, two distinctly
      different VO(2+) EPR spectra are detected. At pH 7.4 each of the vanadyl EPR
      hyperfine lines is further split into two. This indicates that several
      spectroscopically distinguishable metal coordination environments coexist for
      VO(2+)-nucleotide chelate complexes in the presence of the reduced Fe protein.
      Overall, a total of at least three distinct local metal coordination environments
      have been identified. We report the EPR parameters for each of the disparate
      metal coordinations measured at different pH values with ADP and ATP bound. EPR
      spectra have also been recorded for the oxidized Fe protein showing essentially
      similar spectra to that of the reduced protein. The EPR parameters of VO
      nucleotides in the presence of the Fe protein are consistent, for all metal
      coordination environments, with direct metal ligation by nucleotide phosphate
      groups and the formation of mononucleotide complexes. The nucleotide binding
      environment with the highest ligand field strength is compatible with a metal
      coordination structure that is also found in various G-proteins with GTP bound.
      No significant EPR line width change is detected after exchange into D(2)O buffer
      solution for any of the pH forms although differences exist between the pH forms.
      The missing difference between the EPR parameters in the presence of ADP or ATP
      suggests that there is little or no conformational rearrangement between these
      two forms; this contrasts with behavior of G-proteins that undergo substantial
      conformational changes upon hydrolysis. This could be related to the inhibition
      of nitrogenase by VO(2+).

PMID- 12403628
TI  - Fine-tuning of the binding and dissociation of CO by the amino acids of the heme
      pocket of Coprinus cinereus peroxidase.
AB  - Resonance Raman and infrared spectra and the CO dissociation rates (k(off)) were
      measured in Coprinus cinereus peroxidase (CIP) and several mutants in the heme
      binding pocket. These mutants included the Asp245Asn, Arg51Leu, Arg51Gln,
      Arg51Asn, Arg51Lys, Phe54Trp, and Phe54Val mutants. Binding of CO to CIP produced
      different CO adducts at pH 6 and 10. At pH 6, the bound CO is H-bonded to the
      protonated distal His55 residue, whereas at alkaline pH, the vibrational
      signatures and the rate of CO dissociation indicate a distal side which is more
      open or flexible than in other plant peroxidases. The distal Arg51 residue is
      important in determining the rate of dissociation in the acid form, increasing by
      8-17-fold in the Arg51 mutants compared to that for the wild-type protein.
      Replacement of the distal Phe with Trp created a new acid form characterized by
      vibrational frequencies and k(off) values very similar to those of cytochrome c
      peroxidase.

PMID- 12403629
TI  - The catalytic role of the copper ligand H172 of peptidylglycine alpha
      hydroxylating monooxygenase (PHM): a spectroscopic study of the H172A mutant.
AB  - The spectroscopic characterization of the H172A mutant of peptidylglycine alpha
      hydroxylating monooxygenase (PHM) was undertaken to determine the importance of
      this Cu(H) ligand in the catalytic mechanism of PHM. Mutation of this histidine
      reduced the activity of the enzyme over 300-fold with little effect on the
      structure of the oxidized form. However, the reduced enzyme showed a decrease in
      the average Cu-N(His) distances from 1.96 A in wild-type PHM to 1.89 A in H172A
      associated with a change in the structure of Cu(H) from distorted T-shaped planar
      in the wild type to 2-coordinate in the mutant. Binding of CO was retained at the
      Cu(M) site (similar to wild type), and peptide substrate binding continued to
      activate a second site for CO binding. Confirmation of this substrate-induced CO
      binding site at Cu(H) was obtained through the observation that loss of the H172
      Cu(H) ligand caused a 3 cm(-)(1) blue shift in the nu(CO) for this copper
      carbonyl. Possible mechanistic roles for the H172 ligand are discussed.

PMID- 12403630
TI  - Kinetic analysis of NodST sulfotransferase using an electrospray ionization mass
      spectrometry assay.
AB  - A novel and efficient enzyme kinetics assay using electrospray ionization mass
      spectrometry was developed and applied to the bacterial carbohydrate
      sulfotransferase (NodST). NodST catalyzes the sulfuryl group transfer from 3'
      phosphoadenosine 5'-phosphosulfate (PAPS) to chitobiose, generating 3'
      phosphoadenosine 5'-phosphate (PAP) and chitobiose-6-OSO(3)(-) as products.
      Traditional spectrophotometric assays are not applicable to the NodST system
      since no shift in absorption accompanies sulfuryl group transfer. Alternative
      assays have employed thin-layer chromatography, but this procedure is time
      consuming and requires radioactive materials. The ESI-MS assay presented herein
      requires no chromophoric substrate or product, and the analysis time is very
      short. The ESI-MS assay is used to determine NodST kinetic parameters, including
      K(M), V(max), and K(i) (for PAP). In addition, the mode of inhibition for PAP was
      rapidly determined. The results were in excellent agreement with those obtained
      from previous assays, verifying the accuracy and reliability of the ESI-MS assay.
      This unique technique is currently being used to investigate the enzymatic
      mechanism of NodST and to identify sulfotransferase inhibitors.

PMID- 12403631
TI  - Comparable levels of Ca-ATPase inhibition by phospholamban in slow-twitch
      skeletal and cardiac sarcoplasmic reticulum.
AB  - Alterations in expression levels of phospholamban (PLB) relative to the
      sarcoplasmic reticulum (SR) Ca-ATPase have been suggested to underlie defects of
      calcium regulation in the failing heart and other cardiac pathologies. To
      understand how variation in PLB expression relative to that of the Ca-ATPase can
      modulate calcium transport, we have investigated the inhibition of the Ca-ATPase
      by PLB in native SR membranes from slow-twitch skeletal and cardiac muscle and in
      reconstituted proteoliposomes. Quantitative immunoblotting in combination with
      affinity-purified protein standards was used to measure protein concentrations of
      PLB and of the Ca-ATPase. Functional inhibition of the Ca-ATPase was determined
      from both the calcium concentrations for half-maximal activation (Ca(1/2)) and
      the shift in the calcium concentrations following release of PLB inhibition
      (i.e., (Delta)Ca(1/2)) by incubation with monoclonal antibodies against PLB,
      which are equivalent to phosphorylation of PLB by cAMP-dependent protein kinase.
      We report that equivalent levels of PLB inhibition and antibody-induced
      activation ((Delta)Ca(1/2) = 0.25 +/- 0.02 microM) are observed in SR membranes
      from slow-twitch skeletal and cardiac muscle, where molar stoichiometries of PLB
      expressed per Ca-ATPase vary, respectively, from 0.9 +/- 0.1 to 4.1 +/- 0.8.
      Similar levels of inhibition to those observed in isolated SR vesicles were
      observed using reconstituted proteoliposomes following co-reconstitution of
      affinity-purified Ca-ATPase with PLB. These results indicate that total
      expression levels of one PLB per Ca-ATPase result in full inhibition of the Ca
      ATPase and, based on the measured K(D) (140 +/- 30 microM), suggests one PLB
      complexed with two Ca-ATPase molecules is sufficient for full inhibition of
      activity. Therefore, the excess PLB expressed in the heart over that required for
      inhibition suggests a capability for graded responses of the Ca-ATPase activity
      to endogenous kinases and phosphatases that modulate the level of phosphorylation
      necessary to relieve inhibition of the Ca-ATPase by PLB.

PMID- 12403632
TI  - Evidence that phosphate release is the rate-limiting step on the overall ATPase
      of psoas myofibrils prevented from shortening by chemical cross-linking.
AB  - It has been suggested that the mechanical condition determines the rate-limiting
      step of the ATPase of the myosin heads in fibers: when fibers are isometrically
      contracting, the ADP release kinetics are rate-limiting, but as the strain is
      reduced and the fibers are allowed to shorten, the ADP release kinetics
      accelerate and P(i) release becomes rate-limiting. We have put this idea to the
      test with myofibrils as a model because with these both mechanical and chemical
      kinetic measurements are possible. With relaxed or rapidly shortening myofibrils,
      P(i) release is rate-limiting and (A)M.ADP.P(i) states accumulate in the steady
      state [Lionne, C., et al. (1995) FEBS Lett. 364, 59]. We have now studied the
      kinetics of P(i) release with chemically cross-linked myofibrils that, when
      adequately cross-linked, appear to be a good model for isometric contraction. By
      using a method that is specific for free P(i) and rapid quench flow that measures
      the amount of (A)M.ADP.P(i) states and free P(i), we show that (A)M.ADP.P(i)
      states predominate which suggests that the overall ATPase is limited by P(i)
      release kinetics. Therefore, under our experimental conditions with myofibrils
      prevented from shortening, the concentration of (A)M.ADP states is low, as with
      rapidly shortening and relaxed myofibrils. This result is difficult to reconcile
      with the sensitivity of force development in fibers and myofibrils to P(i) which
      implies interaction of P(i) with an (A)M.ADP state. We discuss two models for
      accommodating the mechanical and chemical kinetics with reference to the duty
      cycle in skeletal muscle.

PMID- 12403633
TI  - Crystal structure of a ternary complex of Tritrichomonas foetus inosine 5'
      monophosphate dehydrogenase: NAD+ orients the active site loop for catalysis.
AB  - Inosine 5'-monophosphate dehydrogenase (IMPDH) catalyzes the conversion of IMP to
      XMP with the reduction of NAD(+), which is the rate-limiting step in the
      biosynthesis of guanine nucleotides. IMPDH is a promising target for
      chemotherapy. Microbial IMPDHs differ from mammalian enzymes in their lower
      affinity for inhibitors such as mycophenolic acid (MPA) and thiazole-4
      carboxamide adenine dinucleotide (TAD). Part of this resistance is determined by
      the coupling between nicotinamide and adenosine subsites in the NAD(+) binding
      site that is postulated to involve an active site flap. To understand the
      structural basis of the drug selectivity, we solved the X-ray crystal structure
      of the catalytic core domain of Tritrichomonas foetus IMPDH in complex with IMP
      and beta-methylene-TAD at 2.2 A resolution. Unlike previous structures of this
      enzyme, the active site loop is ordered in this complex, and the catalytic Cys319
      is 3.6 A from IMP, in the same plane as the hypoxanthine ring. The active site
      loop forms hydrogen bonds to the carboxamide of beta-Me-TAD which suggests that
      NAD(+) promotes the nucleophillic attack of Cys319 on IMP. The interactions of
      the adenosine end of TAD are very different from those in the human enzyme,
      suggesting the NAD(+) site may be an exploitable target for the design of
      antimicrobial drugs. In addition, a new K(+) site is observed at the subunit
      interface. This site is adjacent to beta-Me-TAD, consistent with the link between
      the K(+) activation and NAD(+). However, contrary to the coupling model, the flap
      does not cover the adenosine subsite and remains largely disordered.

PMID- 12403634
TI  - A circularly permuted myoglobin possesses a folded structure and ligand binding
      similar to those of the wild-type protein but with a reduced thermodynamic
      stability.
AB  - A circular permutein of sperm whale myoglobin in which the G helix is C-terminal,
      the H helix is N-terminal, and 16 amino acids link the H helix to the A helix has
      been expressed in Escherichia coli. The permutein sequence begins with Gly121
      (using the numbering scheme for the wild-type protein) and terminates with
      Pro120. The ligand binding function of the permutein was assayed using stopped
      flow methods and shown to be essentially identical to that of the wild-type
      protein. In addition, one- and two-dimensional NMR studies of the cyanomet
      isoform of the permutein show a nativelike structure with a heme binding pocket
      very similar to that of the wild-type myoglobin. Although the structure and
      function of the permutein resemble those of the wild-type myoglobin, the
      permutein is less stable to chemical denaturation by 5.2 kcal/mol.

PMID- 12403635
TI  - The two substrate-water molecules are already bound to the oxygen-evolving
      complex in the S2 state of photosystem II.
AB  - The first direct evidence which shows that both substrate-water molecules are
      bound to the O(2)-evolving catalytic site in the S(2) state of photosystem II
      (PSII) is presented. Rapid (18)O isotope exchange measurements between H(2)(18)O
      incubated in the S(2) state of PSII-enriched membrane samples and the
      photogenerated O(2) reveal a fast and a slow phase of exchange at m/e 34 (which
      measures the level of the (16)O(18)O product). The rate constant for the slow
      phase of exchange ((34)k(1)) equals 1.9 +/- 0.3 s(-1) at 10 degrees C, while the
      fast phase of exchange is unresolved by our current experimental setup ((34)k(2)
      >or= 175 s(-1)). The unresolvable fast phase has left open the possibility that
      the second substrate-water molecule binds to the catalytic site only after the
      formation of the S(3) state [Hillier, W., and Wydrzynski, T. (2000) Biochemistry
      39, 4399-4405]. However, for PSII samples depleted of the 17 and 23 kDa extrinsic
      proteins (Ex-depleted PSII), two completely resolvable phases of (18)O exchange
      are observed in the S(2) state of the residual activity, with the following rate
      constants: (34)k(1) = 2.6 +/- 0.3 s(-1) and (34)k(2) = 120 +/- 14 s(-1) at 10
      degrees C. Upon addition of 15 mM CaCl(2) to Ex-depleted PSII, the O(2) evolution
      activity increases to approximately 80% of the control level, while the two
      resolvable phases of exchange remain the same. In measurements of Ex-depleted
      PSII at m/e 36 (which measures the level of the (18)O(18)O product), only a
      single phase of exchange is observed in the S(2) state, with a rate constant
      ((36)k(1) = 2.5 +/- 0.2 s(-1)) that is identical to the slow rate of exchange in
      the m/e 34 data. Taken together, these results show that the fast phase of (18)O
      exchange is specifically slowed by the removal of the 17 and 23 kDa extrinsic
      proteins and that the two substrate-water molecules must be bound to independent
      sites already in the S(2) state. In contrast, the (18)O exchange behavior in the
      S(1) state of Ex-depleted PSII is no different from what is observed for the
      control, with or without the addition of CaCl(2). Since the fast phase of
      exchange in the S(1) state is unresolved (i.e., (34)k(2) > 100 s(-1)), the
      possibility remains that the second substrate-water molecule binds to the
      catalytic site only after the formation of the S(2) state. The role of the 17 and
      23 kDa extrinsic proteins in establishing an asymmetric dielectric environment
      around the substrate binding sites is discussed.

PMID- 12403636
TI  - Theoretical arguments for the discounting of health consequences: where do we go
      from here?
AB  - Despite the theoretical arguments presented in the literature regarding
      discounting over the last 25 years, no satisfactory reply has yet been offered to
      the question of whether health consequences have to be discounted at the same
      rate as monetary consequences in the economic evaluation of health programmes or
      interventions designed to improve health. Against this background, the main
      objective of this paper was to review and systemise these theoretical arguments,
      with the aim of determining whether any of the positions identified can be
      accepted without reservation. Having determined that this is not possible, we
      investigated the rationality of discounting in the literature and, on this basis,
      propose a potential way to resolve the problem. Thus, we argue that the
      relationship between the discount of monetary and health consequences has to be
      determined in an indirect manner, by reference to the relationship maintained by
      the individual time preference rates for health and money in the context of
      private and social choice. Although this proposal moves the debate into the
      empirical field, its advantages must be weighed against the difficulties
      associated with the estimation of the time preferences.

PMID- 12403637
TI  - Pharmacoeconomic considerations in assessing and selecting congestive heart
      failure therapies.
AB  - Over the last two decades the incidence of congestive heart failure (CHF) has
      increased with aging of the population and in spite of the decline in age
      adjusted mortality rates due to coronary heart disease. Its management has seen
      substantial progress, embodied in the introduction of ACE inhibitors, initially
      as part of triple therapy in which they complemented diuretics and digoxin, and
      latterly as first-line therapy. The current consensus on treatment of CHF has
      been based on the multiple clinical studies performed with ACE inhibitors in
      which these agents have been shown to prevent a new cardiovascular accident
      and/or progression to more severe CHF in an increasingly wide range of patients
      with symptomatic CHF or post-infarction left ventricular dysfunction (ejection
      fraction </= 40% in some trials or </= 35% in others). Not only have the results
      shown a marked decrease in all-cause (and especially cardiovascular) mortality,
      but also a great number of cost-effectiveness analyses have shown the advantages
      of ACE inhibitors in terms of resource allocation: they are either cost saving or
      convincingly cost effective compared with standard treatment with digoxin and
      diuretics. Other drugs require similar cost and clinical analyses before they can
      earn their place in an add-on strategy. To date, cost savings have been
      documented only for beta-blockers; implantable devices are still undergoing
      assessment. Two trends are now competing: one is to downplay add-on strategies
      and to recommend first-line therapy with ACE inhibitors and beta-blockers at
      effective doses, supplemented by a raft of non-pharmaceutical measures
      (specialist nurses, patient education, dietary advice, exercise) in a
      multidisciplinary approach to CHF; the second is, on the contrary, to prescribe
      up to five drugs for patients with advanced CHF. The evidence that this decreases
      hospital admission rates and patient cost is more than anecdotal, but conclusive
      proof of cost effectiveness is still lacking and the approach presupposes
      dedicated structures. This review argues that despite technical limitations, a
      combined approach of CHF therapy based on clinical trials and cost-effectiveness
      analyses is essential. However, improvements can be made. The absence of
      sufficient comparative data still makes it difficult to choose between drugs
      within the same class; institutional purchasers need to conduct such analyses to
      identify the drugs best suited to their patients' profiles and budgetary
      constraints.

PMID- 12403638
TI  - Cost-effectiveness analysis of enoxaparin versus unfractionated heparin in the
      secondary prevention of acute coronary syndrome.
AB  - BACKGROUND: The Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave
      Coronary Events (ESSENCE) and Thrombolysis in Myocardial Infarction (TIMI) 11B
      studies revealed that enoxaparin reduced the incidence of death, myocardial
      reinfarction and recurrent angina in patients with acute coronary syndrome (ACS)
      compared with unfractionated heparin (UFH). OBJECTIVE: To perform a
      pharmacoeconomic analysis to evaluate the cost effectiveness of treatment with
      enoxaparin compared with UFH in Spanish patients with ACS. DESIGN AND SETTING:
      Retrospective cost-effectiveness analysis using data and costs from Spanish
      sources, conducted from the perspective of the National Health System. PATIENTS,
      INTERVENTIONS AND OUTCOMES MEASURES: The study was based on the results of the
      ESSENCE and TIMI 11B clinical trials, which included more than 7,000 patients
      with ACS treated with enoxaparin or UFH. The main variables studied were the
      success rate, expressed as patients with no complications (reinfarction, unstable
      angina or death), and the decrease in the utilisation of healthcare resources
      (revascularisation procedures and hospitalisation). RESULTS: The base-case
      results of the analysis showed superior efficacy and lower total treatment and
      follow-up costs with enoxaparin compared with UFH. The total savings in direct
      health costs per patient with enoxaparin ranged between 448 and 659 euros (time
      horizons of 1 month and 1 year, respectively) [2001 values]. The sensitivity
      analysis results confirmed the advantage of enoxaparin in all cases, except in
      one scenario: when simultaneously using all the minimum values of the confidence
      interval for absolute risk reduction (ARR) in the utilisation of health
      resources. CONCLUSIONS: This study suggests that enoxaparin is a more effective
      and less expensive treatment option than UFH in secondary prevention of patients
      with ACS in Spain, confirming the results obtained in other pharmacoeconomic
      analyses performed in the UK, USA, France and Canada.

PMID- 12403640
TI  - Do drug metabolism and pharmacokinetic departments make any contribution to drug
      discovery?
AB  - The alignment of drug metabolism and pharmacokinetic departments with drug
      discovery has not produced a radical improvement in the pharmacokinetic
      properties of new chemical entities. The reason for this is complex, reflecting
      in part the difficulty of combining potency, selectivity, water solubility,
      metabolic stability and membrane permeability into a single molecule. This
      combination becomes increasingly problematic as the drug targets become more
      distant from aminergic seven-transmembrane-spanning receptors (7-TMs). The leads
      available for aminergic 7-TMs, like the natural agonists, are invariably small
      molecular weight, water soluble and potent. Even moving to 7-TMs for which the
      agonist is a peptide invariably produces lead matter that is less drug-like
      (higher molecular weight and lipophilic). The role of drug metabolism
      departments, therefore, has been to guide chemistry to obtaining adequate, rather
      than optimal, pharmacokinetic properties for these 'difficult' drug targets. A
      consistent belief of many researchers is that a high value is placed on optimal,
      rather than adequate, pharmacokinetic properties. One measure of value is market
      sales, and when these are examined no clear pattern emerges. Part of the success
      of amlodipine in the calcium channel antagonist sector must be due to its
      excellent pharmacokinetic profile, but the best-selling drugs among the
      angiotensin antagonists and beta-blockers have a much greater market share than
      other agents with better pharmacokinetic properties. Clearly, many other factors
      are important in the successful launch of a medicine, some reflected in the
      manner the compound is developed and the subsequent structure of the labelling.
      Overall, therefore the presence of drug metabolism in drug discovery has probably
      contributed most by allowing 'difficult' drug targets to be prosecuted, rather
      than by guiding medicinal chemists to optimal pharmacokinetics. These 'difficult'
      target candidates become successful drugs when skilfully developed. There is no
      doubt that skilful development relies heavily on drug metabolism and
      pharmacokinetic departments, in this case those with a clinical rather than a
      preclinical orientation.

PMID- 12403639
TI  - Insulin lispro: a pharmacoeconomic review of its use in diabetes mellitus.
AB  - Insulin lispro is a recombinant insulin analogue with transposed amino acids
      (proline and lysine) at positions 28 and 29 near the C-terminus of the B-chain.
      The most prominent practical advantage of insulin lispro over human soluble
      insulin lies in its very rapid onset of action. This property allows it to be
      injected immediately before meals and minimises the demands made on patients with
      type 1 diabetes mellitus, and those with type 2 disease who require insulin, by
      the ongoing need for careful meal planning and timing. Numerous clinical studies
      have shown significant improvements in postprandial glycaemic control, with some
      evidence of reduced rates of severe or nocturnal hypoglycaemia, relative to
      conventional human insulin in patients receiving lispro-based insulins. Quality
      of-life studies show consistent preferences by patients for and increased
      treatment satisfaction with insulin lispro over human soluble insulin,
      particularly with variations of the Diabetes Treatment Satisfaction
      Questionnaire. Willingness of patients and taxpayers to pay additional costs for
      insulin lispro or a premixed lispro-based formulation over conventional human
      insulins, and cost benefits favouring formulary inclusion, have been shown in
      well designed studies carried out in Australia and Canada. Spanish data suggest
      cost effectiveness in terms of episodes of severe hypoglycaemia avoided, and
      preliminary German resource utilisation data indicate cost savings related to
      reduced hospitalisation and general practice costs, with insulin lispro relative
      to human soluble insulin. CONCLUSIONS: Insulin lispro and premixed formulations
      of lispro-based insulins offer quality-of-life improvements relative to
      conventional human insulins in patients with diabetes mellitus. Participants in
      well designed studies have expressed a preference for lispro-based insulins and
      have been shown to be willing to pay for the advantages they offer, and current
      cost-benefit data favour the inclusion of these insulins in formularies and their
      reimbursement by third party payers. Further research into the pharmacoeconomic
      implications of insulin lispro use in the long term is needed, particularly with
      respect to effects on indirect costs and those associated with complications of
      diabetes mellitus.

PMID- 12403641
TI  - Clinical pharmacokinetics of tegaserod, a serotonin 5-HT(4) receptor partial
      agonist with promotile activity.
AB  - Tegaserod, a selective serotonin (5-hydroxytryptamine; 5-HT) 5-HT(4) receptor
      partial agonist, is indicated in patients with irritable bowel syndrome (IBS) who
      identify abdominal pain or discomfort and constipation as their predominant
      symptoms. Tegaserod at dosages of 1 to 12 mg/day exerts pharmacodynamic actions
      in the upper and the lower gastrointestinal tract, accelerating small bowel and
      colonic transit in patients with IBS. Tegaserod is rapidly absorbed following
      oral administration; peak plasma concentrations (C(max)) are reached after
      approximately 1 hour. Absolute bioavailability is about 10% under fasted
      conditions. Food reduces the bioavailability of tegaserod by 40 to 65% and the
      C(max) by 20 to 40%. Systemic exposure to tegaserod is not significantly altered
      at neutral gastric pH compared with the fasted state (pH 2). Tegaserod is
      approximately 98% bound to plasma proteins, primarily to alpha(1)-acid
      glycoprotein, and has a volume of distribution at steady-state of 368 +/- 223L.
      Tegaserod is metabolised mainly via two pathways. The first is a presystemic acid
      catalysed hydrolysis in the stomach followed by oxidation and conjugation which
      produces the main metabolite of tegaserod, 5-methoxyindole-3-carboxylic acid
      glucuronide (M 29.0). This metabolite has negligible affinity for 5-HT(4)
      receptors and is devoid of promotile activity. The second is direct
      glucuronidation which leads to generation of three isomeric N-glucuronides. The
      plasma clearance of tegaserod is 77 +/- 15 L/h, with an estimated terminal half
      life of 11 +/- 5 hours following intravenous administration. Approximately two
      thirds of the orally administered dose of tegaserod is excreted unchanged in
      faeces, with the remainder excreted in urine, primarily as M 29.0. The
      pharmacokinetics of tegaserod are dose-proportional over the range 2 to 12mg
      given twice daily for 5 days, with no relevant accumulation. The pharmacokinetics
      of tegaserod in patients with IBS are comparable to those in healthy individuals,
      and similar between men and women. No dosage adjustment is required in elderly
      patients or those with mild to moderate hepatic or renal impairment. Tegaserod
      should not be used in patients with severe hepatic or renal impairment. No
      clinically relevant drug-drug interactions with tegaserod have been identified.
      In vivo drug-drug interaction studies with theophylline [a cytochrome P450 (CYP)
      1A2 prototype substrate], dextromethorphan (a CYP2D6 prototype substrate),
      digoxin, warfarin and oral contraceptives have indicated no clinically relevant
      interactions and no requirement for dosage adjustment.

PMID- 12403642
TI  - Clinical pharmacokinetics and pharmacodynamics of insulin lispro mixtures.
AB  - Rapid-acting insulin analogues such as insulin lispro and insulin aspart produce
      a more physiological profile of insulin activity than does conventional regular
      human insulin because of their unique pharmacokinetics. These insulin analogues
      are absorbed rapidly from the subcutaneous injection site, resulting in a better
      matching of the appearance of insulin in the circulation with nutrient absorption
      from the intestine. In addition, they are shorter-acting than regular human
      insulin, thus decreasing the risk of late postprandial hypoglycaemia due to
      inappropriate hyperinsulinaemia. Because self-prepared mixtures of these rapid
      acting insulin analogues with longer-acting insulins such as neutral protamine
      Hagedorn (NPH) insulin have been shown to be clinically useful, and because
      manufactured fixed-ratio mixtures of regular human insulin and NPH already
      represent a large proportion of insulin use, manufactured fixed-ratio mixtures of
      insulin lispro and a sustained-release insulin known as NPL have been developed
      (insulin lispro mixtures). NPL is a protamine-based insulin lispro formulation
      with pharmacokinetics and glucodynamics comparable to those of human NPH insulin.
      NPL was developed for use within insulin lispro mixtures because an exchange
      between soluble insulin lispro and protamine-bound human insulin within human NPH
      precludes prolonged storage of mixtures of these insulins. An insulin lispro
      mixture consisting of 25% insulin lispro and 75% NPL is now commercially
      available. This preparation is intended primarily as an alternative to human
      insulin 30/70, which is commonly used within a twice-daily injection regimen. A
      mixture containing 50% insulin lispro and 50% NPL is also available. The rapid
      activity of insulin lispro is maintained within insulin lispro mixtures, allowing
      injection just prior to a meal, a convenience that is not available with
      commercial mixtures of regular human insulin and human NPH insulin, which should
      be injected 30 to 45 minutes prior to meals. As with insulin lispro itself, the
      rapid action of insulin lispro within the insulin lispro mixtures also results in
      a smaller increase in blood glucose levels after meals than with comparable human
      insulin mixtures. In addition, data from two studies have shown that when Mix25
      is injected prior to the evening meal the incidence of nocturnal hypoglycaemia is
      decreased in comparison with the same dose of human insulin 30/70. The combined
      rapid and prolonged insulin activity provided by insulin lispro mixtures has been
      defined both in healthy subjects without diabetes and in patients with diabetes.

PMID- 12403643
TI  - Pharmacokinetics and pharmacodynamics of rapacuronium bromide.
AB  - Rapacuronium is an aminosteroidal nondepolarising neuromuscular blocking agent
      (NMBA). Its neuromuscular blocking effects have a different time course to those
      of most currently available agents. It also has lower potency than many of the
      other NMBAs. In doses consistent with short to medium duration of action,
      rapacuronium has rapid and complete onset. In some doses it gives tracheal
      intubating conditions that compare favourably with those produced by
      suxamethonium (succinylcholine) during rapid sequence induction of anaesthesia.
      Tracheal intubating conditions improve as dose increases, but adverse effects
      (including potentially severe bronchospasm) become more prominent. Rapacuronium
      has an active metabolite that is at least as potent as the parent compound and is
      eliminated much less efficiently. Consequently, the time course of action of
      rapacuronium is prolonged after multiple doses or an infusion. Its potency is
      similar across age ranges and its time course after single doses is little
      altered in patients with hepatic or renal insufficiency. At least in part because
      of its active metabolite, rapacuronium is highly cumulative in renal failure. In
      keeping with its rapid onset and short to medium duration of action, rapacuronium
      has a more rapid clearance than most other NMBAs. Values for clearance are in the
      range 0.26-0.67 L/h/kg, with most studies giving a value of approximately 0.45
      L/h/kg. There is some evidence that clearance declines marginally with advanced
      age, and it is also reduced in children. A typical value for steady-state volume
      of distribution is 0.3 L/kg. This is similar to that of many other NMBAs, but is
      small compared with many other drugs, as expected with a highly polar compound.
      Pharmacokinetic parameters do not appear to differ markedly in hepatic
      insufficiency, but clearance is reduced by approximately 30% in renal failure.
      Rapacuronium equilibrates very rapidly between the plasma and the site of effect.
      This is the principal explanation behind its unusually rapid onset. It also
      appears to have a similar potency at the larynx compared with the adductor
      pollicis; most other NMBAs are less effective at the larynx. Because it gives
      rapid onset in a dose consistent with brief duration of action, it was hoped that
      rapacuronium might be a suitable alternative to suxamethonium. It does not have
      the problems associated with suxamethonium, but its use is associated with
      bronchospasm, the incidence of which is dose-related. Rapacuronium has been
      withdrawn from sale because of this adverse effect, and its future availability
      is uncertain.

PMID- 12403644
TI  - Ontogeny of hepatic and renal systemic clearance pathways in infants: part II.
AB  - Maturation of drug systemic clearance mechanisms during the postnatal period
      produces dramatic and rapid changes in an infant's capacity to eliminate drugs. A
      tentative general mathematical model describing the ontogeny of hepatic
      cytochrome P450 (CYP) enzyme-mediated clearance and renal clearance due to
      glomerular filtration in the first 6 months of life was elaborated from age
      specific in vitro hepatic microsomal activity data (normalised to amount of
      hepatic microsomal protein) for enzyme-specific probe substrates and in vivo
      probe substrate data for glomerular filtration (normalised to bodyweight),
      respectively. The model predicts an age- and clearance pathway-specific Infant
      Scaling Factor (ISF) for the first 6 months of life. The ISF reflects functional
      maturation of a specific clearance pathway (normalised to bodyweight) relative to
      adult values. Therefore, the ISF directly correlates adult clearance values with
      an infant's capacity to eliminate drugs. Substitution of appropriate model
      parameter estimates and the age of the infant into the model provides an
      estimated ISF value, which may then be used to predict the contribution of a
      particular clearance pathway to total systemic clearance in the infant when adult
      systemic clearance values are known. The model was tested for its ability to
      predict infant systemic clearance of drugs whose elimination is principally
      mediated by a single CYP enzyme or by glomerular filtration. The model performed
      reasonably well for CYP1A2 and CYP3A4, but poorer predictions were obtained for
      CYP2D6 and CYP2C because of lack of model complexity and/or inadequate hepatic
      microsomal activity data to fully describe the maturational process of functional
      enzyme. For renal clearance due to glomerular filtration, data normalised to
      bodyweight (kg) showed a limited maturational trend, suggesting that adult renal
      clearances normalised to bodyweight might reasonably predict infant renal
      clearances in the first 6 months of life. The model provided reasonable
      predictions of renal clearance due to glomerular filtration in the infant.

PMID- 12403645
TI  - Bayesian estimation of methotrexate pharmacokinetic parameters and area under the
      curve in children and young adults with localised osteosarcoma.
AB  - BACKGROUND: Methotrexate is the most efficient anticancer drug in osteosarcoma.
      It requires individual exposure monitoring because of the high doses used, its
      wide interpatient pharmacokinetic variability and the existence of demonstrated
      relationships between efficacy, toxicity and serum drug concentrations.
      OBJECTIVE: To develop a maximum a posteriori (MAP) Bayesian estimator able to
      predict individual pharmacokinetic parameters and exposure indices such as area
      under the curve (AUC) for methotrexate from a few blood samples, in order to
      prevent toxicity and facilitate further studies of the relationships between
      efficacy and exposure. METHODS: Methotrexate population pharmacokinetics were
      estimated by a retrospective analysis of concentration data from 40 children and
      young adults by using the nonparametric expectation maximisation method NPEM. A
      linear two-compartment model with elimination from the central compartment was
      assumed. Individual pharmacokinetic parameters and AUC were subsequently
      estimated in 30 other young patients, using MAP Bayesian estimation as
      implemented in two programs, ADAPT II and an inhouse program Winphar((R)).
      RESULTS: The pharmacokinetic parameters used in the model were the volume of the
      central compartment (V(1)) and the transfer constants (k(10), k(12) and k(21)).
      The mean values (with percentage coefficient of variation) obtained were: 18.24L
      (54.1%) and 0.41 (42.3%), 0.0168 (68.7%), and 0.1069 (61.3%) h(-1), respectively.
      Bayesian forecasting enabled nonbiased estimation of AUC and systemic clearance
      using a schedule with two sampling times (6 and 24 hours after the beginning of
      the infusion) and either program. Collection of a third sample at 4 hours
      improved the precision. CONCLUSION: The Bayesian adaptive method developed herein
      allows accurate estimation of individual exposure to methotrexate and can easily
      be used in clinical practice.

PMID- 12403646
TI  - Pharmacokinetic-pharmacodynamic modelling of magnesium plasma concentration and
      blood pressure in preeclamptic women.
AB  - OBJECTIVE: To describe the relationship between plasma magnesium (Mg(2+))
      concentration and blood pressure response in pregnant women with preeclampsia.
      METHODS: Fifty-one preeclamptic women were studied after receiving two
      consecutive magnesium sulfate infusions (120 mg/kg for 1 hour and 24 mg/kg for 5
      hours). Mg(2+) concentration and systolic/diastolic blood pressure were measured
      at 0, 0.5, 1, 2, 4, 6, 7, 9, 11, 13 and 15 hours after the beginning of the first
      infusion. A population pharmacokinetic-pharmacodynamic model was fitted to the
      data with the computer program NONMEM. RESULTS: Pharmacokinetics were described
      by a two-compartment model. Population parameter estimates were 5.0 L/h for body
      clearance (CL), 24L for central volume (V(c), 25L for peripheral volume ((V)(p))
      and 5.6 L/h for intercompartment clearance (Q). The interindividual variability
      in CL, V(c), V(p) and Q was 39, 26, 38, and 59%, respectively. The mean
      population estimates for systolic (diastolic) blood pressure were 36.8 (27.8) mm
      Hg for the maximum decrease (E(max)), 0.75 (0.88) mmol/L for the Mg2+
      concentration (above baseline) eliciting half-maximum effect (EC(50)) and 0.76
      (0.5) h(-1) for the equilibrium rate (k(eo)) of the effect compartment model.
      CONCLUSION: Mg(2+ )concentrations within the range (2-4 mmol/L) proposed for
      treatment of preeclampsia produce greater than half-maximal lowering of systolic
      and diastolic blood pressure.

PMID- 12403647
TI  - CD38-dependent ADP-ribosyl cyclase activity in developing and adult mouse brain.
AB  - CD38 is a transmembrane glycoprotein that is expressed in many tissues throughout
      the body. In addition to its major NAD+-glycohydrolase activity, CD38 is also
      able to synthesize cyclic ADP-ribose, an endogenous calcium-regulating molecule,
      from NAD+. In the present study, we have compared ADP-ribosyl cyclase and NAD+
      glycohydrolase activities in protein extracts of brains from developing and adult
      wild-type and Cd38 -/- mice. In extracts from wild-type brain, cyclase activity
      was detected spectrofluorimetrically, using nicotinamide-guanine dinucleotide as
      a substrate (GDP-ribosyl cyclase activity), as early as embryonic day 15. The
      level of cyclase activity was similar in the neonate brain (postnatal day 1) and
      then increased greatly in the adult brain. Using [14C]NAD+ as a substrate and
      HPLC analysis, we found that ADP-ribose is the major product formed in the brain
      at all developmental stages. Under the same experimental conditions, neither NAD+
      glycohydrolase nor GDP-ribosyl cyclase activity could be detected in extracts of
      brains from developing or adult Cd38 -/- mice, demonstrating that CD38 is the
      predominant constitutive enzyme endowed with these activities in brain at all
      developmental stages. The activity measurements correlated with the level of CD38
      transcripts present in the brains of developing and adult wild-type mice. Using
      confocal microscopy we showed, in primary cultures of hippocampal cells, that
      CD38 is expressed by both neurons and glial cells, and is enriched in neuronal
      perikarya. Intracellular NAD+-glycohydrolase activity was measured in hippocampal
      cell cultures, and CD38-dependent cyclase activity was higher in brain fractions
      enriched in intracellular membranes. Taken together, these results lead us to
      speculate that CD38 might have an intracellular location in neural cells in
      addition to its plasma membrane location, and may play an important role in
      intracellular cyclic ADP-ribose-mediated calcium signalling in brain tissue.

PMID- 12403648
TI  - Cytotoxic activity of Bacillus thuringiensis Cry proteins on mammalian cells
      transfected with cadherin-like Cry receptor gene of Bombyx mori (silkworm).
AB  - Cry1Aa, an insecticidal protein produced by Bacillus thuringiensis, has been
      shown to bind to cadherin-like protein, BtR175, in Bombyx mori (silkworm) midgut.
      We previously reported three variant alleles of BtR175 (BtR175a, b and c). When
      transiently expressed in COS7 cells, all the three BtR175 variants bound to
      Cry1Aa. We stably expressed BtR175b in HEK293 cells. These BtR175b-expressing
      cells swelled and died in the presence of activated Cry1Aa in a dose- and time
      dependent manner, showing that BtR175b itself can impart Cry1Aa-susceptibility to
      mammalian cells. These cells were more susceptible to Cry1Aa than to Cry1Ab and
      Cry1Ac. Since dispersed B. mori midgut cells were reported to be highly
      susceptible to Cry1Ac, this result suggested that other Cry1Ac-specific
      receptor(s) were simultaneously working with BtR175 in the midgut cells.
      Advantages are also discussed of applying these transfected mammalian cells to
      toxicity assays of mutant Cry proteins.

PMID- 12403649
TI  - Upstream stimulatory factor activates the vasopressin promoter via multiple
      motifs, including a non-canonical E-box.
AB  - We have described previously a complex E-box enhancer (-147) of the vasopressin
      promoter in small-cell lung cancer (SCLC) extracts [Coulson, Fiskerstrand, Woll
      and Quinn, (1999) Biochem. J. 344, 961-970]. Upstream stimulatory factor (USF)
      heterodimers were one of the complexes binding to this site in vitro. We now
      report that USF overexpression in non-SCLC (NSCLC) cells can functionally
      activate vasopressin promoter-driven reporters that are otherwise inactive in
      this type of lung cancer cell. Site-directed mutagenesis and electrophoretic
      mobility-shift analysis demonstrate that although the -147 E-box contributes,
      none of the previously predicted E-boxes (-147, -135, -34) wholly account for
      this USF-mediated activation in NSCLC. 5' Deletion showed the key promoter region
      as -52 to +42; however, USF-2 binding was not reliant on the -34 E-box, but on a
      novel adjacent CACGGG non-canonical E-box at -42 (motif E). This mediated USF
      binding in both SCLC and USF-2-transfected NSCLC cells. Mutation of motif E or
      the non-canonical TATA box abolished activity, implying both are required for
      transcriptional initiation on overexpression of USF-2. Co-transfected dominant
      negative USF confirmed that binding was required through motif E for function,
      but that the classical activation domain of USF was not essential. USF-2 bound
      motif E with 10-fold lower affinity than the -147 E-box. In NSCLC, endogenous USF
      2 expression is low, and this basal level appears to be insufficient to activate
      transcription of arginine vasopressin (AVP). In summary, we have demonstrated a
      novel mechanism for USF activation, which contributes to differential vasopressin
      expression in lung cancer.

PMID- 12403650
TI  - Group D prothrombin activators from snake venom are structural homologues of
      mammalian blood coagulation factor Xa.
AB  - Procoagulant venoms of several Australian elapids contain proteinases that
      specifically activate prothrombin; among these, Group D activators are
      functionally similar to coagulation factor Xa (FXa). Structural information on
      this class of prothrombin activators will contribute significantly towards
      understanding the mechanism of FXa-mediated prothrombin activation. Here we
      present the purification of Group D prothrombin activators from three Australian
      snake venoms (Hoplocephalus stephensi, Notechis scutatus scutatus and Notechis
      ater niger) using a single-step method, and their N-terminal sequences. The N
      terminal sequence of the heavy chain of hopsarin D (H. stephensi) revealed that a
      fully conserved Cys-7 was substituted with a Ser residue. We therefore determined
      the complete amino acid sequence of hopsarin D. Hopsarin D shows approximately
      70% similarity with FXa and approximately 98% similarity with trocarin D, a Group
      D prothrombin activator from Tropidechis carinatus. It possesses the
      characteristic Gla domain, two epidermal growth factor-like domains and a serine
      proteinase domain. All residues important for catalysis are conserved, as are
      most regions involved in interactions with factor Va and prothrombin. However,
      there are some structural differences. Unlike FXa, hopsarin D is glycosylated in
      both its chains: in light-chain residue 52 and heavy-chain residue 45. The
      glycosylation on the heavy chain is a large carbohydrate moiety adjacent to the
      active-site pocket. Overall, hopsarin D is structurally and functionally similar
      to mammalian coagulation FXa.

PMID- 12403651
TI  - Sorting of carboxypeptidase E to the regulated secretory pathway requires
      interaction of its transmembrane domain with lipid rafts.
AB  - Carboxypeptidase E (CPE) functions as a regulated secretory pathway sorting
      receptor for several prohormones, including pro-opiomelanocortin (POMC),
      proenkephalin and proinsulin. The association of CPE with lipid rafts in the
      trans -Golgi network and secretory granule membranes is necessary for its sorting
      receptor function. We now provide evidence that a domain within the C-terminal 25
      residues of CPE functions as a signal for both raft association and the sorting
      of CPE to the regulated secretory pathway. A fusion protein containing the
      extracellular domain of the human interleukin-2 receptor Tac (N-Tac) and the C
      terminal 25 amino acids of CPE was transfected into Neuro2A cells. This fusion
      protein floated in sucrose density gradients, indicating raft association, and co
      localized with chromogranin A (CGA), a secretory granule marker. To define
      further a minimum sequence required for raft association and sorting, deletion
      mutants of CPE that lacked the C-terminal four or 15 residues (CPE-Delta4 and CPE
      Delta15 respectively) were transfected into a clone of CPE-deficient Neuro2A
      cells. In contrast with full-length CPE, neither CPE-Delta4 nor CPE-Delta15
      floated in sucrose density gradients. The sorting of both CPE-Delta4 and CPE
      Delta15 to the regulated secretory pathway was impaired, as indicated by
      significantly increased basal secretion and a lack of response to stimulation.
      Additionally, there was a significant decrease in the co-localization of mutant
      CPE immunofluorescence with CGA when compared with full-length CPE. Finally, the
      sorting of the prohormone POMC to the regulated pathway was impaired in cells
      transfected with either CPE-Delta4 or CPE-Delta15. We conclude that the sorting
      of CPE to the regulated secretory pathway in endocrine cells is mediated by lipid
      rafts, and that the C-terminal four residues of CPE, i.e. Thr(431)-Leu-Asn
      Phe(434), are required for raft association and sorting.

PMID- 12403653
TI  - Prediction scores after myocardial infarction: value, limitations, and future
      directions.

PMID- 12403654
TI  - Patterns of left ventricular dilatation with an opened artery after acute
      myocardial infarction: missing links to long-term prognosis.

PMID- 12403655
TI  - Systemic drug therapy for restenosis: "deja vu all over again".

PMID- 12403656
TI  - Cardiology patient page. Online program aids heart patients and their doctors.

PMID- 12403657
TI  - First model of spontaneous vagal hyperreactivity and its mode of genetic
      transmission.
AB  - BACKGROUND: The main purpose of our study was to define an animal model of vagal
      hyperreactivity and its genetic transmission. METHODS AND RESULTS: We first
      investigated the vagal reactivity with phenylephrine in conscious rabbits.
      Barosensitivity and the maximal bradycardic response were measured at the upper
      mean blood pressure plateau. Hyperreactive (H) animals were selected and
      crossbred with normal (N) ones. Results showed no significant difference between
      calculated barosensitivity values after the different doses of phenylephrine. In
      contrast, an increase of the values and a great dispersion appeared 1 to 5 beats
      after the end of the ramp. Marked pauses (6000 to 20 000 ms) were obtained with
      some rabbits, which were blocked by atropine. A significant excess of
      hyperreactive offspring was observed in HxH crossings compared with NxN ones
      (39.4% male and 42.3% female offspring versus 14.4% and 4.4%, respectively). Few
      female offspring were hyperreactive compared with males in NxH and NxN crossings
      (4.1% versus 23.4% and 4.4% versus 14.4%, respectively). CONCLUSIONS: This study
      describes the first model of spontaneous vagal pauses. The inheritance could be
      polygenic with a partial sex-limited character.

PMID- 12403658
TI  - Endothelin-A receptor blockade prevents left ventricular hypertrophy and
      dysfunction in salt-sensitive experimental hypertension.
AB  - BACKGROUND: Salt-sensitive hypertension represents a major cause of left
      ventricular (LV) dysfunction. We therefore explored the potential effects of the
      selective endothelin-A (ETA) receptor antagonist darusentan on the development of
      hypertension, LV hypertrophy (LVH), and dysfunction in a genetic rat model of
      salt-sensitive hypertension. METHODS AND RESULTS: Animals from the salt-sensitive
      Sabra rat strain (SBH/y) and the salt-resistant strain (SBN/y) were treated with
      either normal diet (SBH/y and SBN/y) or with deoxycorticosterone-acetate (DOCA)
      and salt (SBN/y-DOCA and SBH/y-DOCA). Additional groups were treated with 50 mg x
      kg(-1) x d(-1) of darusentan (SBH/y-DOCA-DA and SBN/y-DOCA-DA). Systolic blood
      pressure and LV weight increased in response to DOCA only in the SBH/y strain
      (+75 mm Hg and +30%; P<0.05). LV end-diastolic pressure increased and -dP/dtmax
      decreased in SBH/y-DOCA compared with SBH/y (P<0.05). This was paralleled by a 5
      fold upregulation of LV mRNA expression of atrial natriuretic factor (ANF) and a
      significant reduction of sarcoplasmic reticulum (SR) Ca2+-reuptake and the SR
      Ca2+-ATPase to phospholamban protein ratio (-30%). Whereas treatment with
      darusentan in SBH/y-DOCA-DA reduced the SBP increase by 50%, LVH elevation of ANF
      mRNA and LV dysfunction were completely prevented (P<0.05); this was associated
      with a normalization of SR Ca2+-reuptake and SR Ca2+-ATPase to phospholamban
      ratio by darusentan (P<0.05). A moderate elevation of interstitial fibrosis in
      SBH/y-DOCA (P<0.05) remained unaffected by darusentan treatment. CONCLUSION: In
      the Sabra model of salt-sensitive hypertension, ETA-receptor blockade
      demonstrated striking effects on the prevention of LVH and LV dysfunction beyond
      its considerable antihypertensive effect.

PMID- 12403659
TI  - Scores for post-myocardial infarction risk stratification in the community.
AB  - BACKGROUND: Several scores, most of which were derived from clinical trials, have
      been proposed for stratifying risk after myocardial infarctions (MIs). Little is
      known about their generalizability to the community, their respective advantages,
      and whether the ejection fraction (EF) adds prognostic information to the scores.
      The purpose of this study is to evaluate the Thrombolysis in Myocardial
      Infarction (TIMI) and Predicting Risk of Death in Cardiac Disease Tool (PREDICT)
      scores in a geographically defined MI cohort and determine the incremental value
      of EF for risk stratification. METHODS AND RESULTS: MIs occurring in Olmsted
      County were validated with the use of standardized criteria and stratified with
      the ECG into ST-segment elevation (STEMI) and non-ST-segment elevation (NSTEMI)
      MI. Logistic regression examined the discriminant accuracy of the TIMI and
      PREDICT scores to predict death and recurrent MI and assessed the incremental
      value of the EF. After 6.3+/-4.7 years, survival was similar for the 562 STEMIs
      and 717 NSTEMIs. The discriminant accuracy of the TIMI score was good in STEMI
      but only fair in NSTEMI. Across time and end points, irrespective of reperfusion
      therapy, the discriminant accuracy of the PREDICT score was consistently superior
      to that of the TIMI scores, largely because PREDICT includes comorbidity; EF
      provided incremental information over that provided by the scores and
      comorbidity. CONCLUSION: In the community, comorbidity and EF convey important
      prognostic information and should be included in approaches for stratifying risk
      after MI.

PMID- 12403660
TI  - Dietary fat intake determines the effect of a common polymorphism in the hepatic
      lipase gene promoter on high-density lipoprotein metabolism: evidence of a strong
      dose effect in this gene-nutrient interaction in the Framingham Study.
AB  - BACKGROUND: Gene-nutrient interactions affecting high-density lipoprotein
      cholesterol (HDL-C) concentrations may contribute to the interindividual
      variability of the cardiovascular disease risk associated with dietary fat
      intake. Hepatic lipase (HL) is a key determinant of HDL metabolism. Four
      polymorphisms in linkage disequilibrium have been identified in the HL gene
      (LIPC), defining what is known as the -514T allele. This allele has been
      associated with decreased HL activity and increased HDL-C concentrations.
      However, the effect is variable among populations. METHODS AND RESULTS: We have
      examined interaction effects between the -514(C/T) LIPC polymorphism, dietary
      fat, and HDL-related measures in 1020 men and 1110 women participating in the
      Framingham Study. We found a consistent and highly significant gene-nutrient
      interaction showing a strong dose-response effect. Thus, the T allele was
      associated with significantly greater HDL-C concentrations only in subjects
      consuming <30% of energy from fat (P<0.001). When total fat intake was > or =30%
      of energy, mean HDL-C concentrations were lowest among those with the TT
      genotype, and no differences were observed between CC and CT individuals. We
      found similar gene-nutrient interactions when the outcome variables were HDL2-C
      (P<0.001), large HDL subfraction (P<0.001), or HDL size (P=0.001). These
      interactions were seen for saturated and monounsaturated fat intakes (highly
      correlated with animal fat in this population), but not for polyunsaturated fat.
      CONCLUSIONS: Dietary fat intake modifies the effect of the -514(C/T) polymorphism
      on HDL-C concentrations and subclasses. Specifically, in the Framingham Study, TT
      subjects may have an impaired adaptation to higher animal fat diets that could
      result in higher cardiovascular risk.

PMID- 12403661
TI  - Reproducibility of chronic infarct size measurement by contrast-enhanced magnetic
      resonance imaging.
AB  - BACKGROUND: The reproducibility of contrast-enhanced MRI has not been
      established. We compared MRI reproducibility for infarct size determination with
      that of (99m)Tc-sestamibi (MIBI) single photon emission computed tomography
      (SPECT). METHODS AND RESULTS: Patients with chronic myocardial infarction defined
      by enzymes (peak creatine kinase-MB 173+/-119 U/L) were scanned twice by MRI (MRI
      I and MRI II, n=20) and twice by SPECT (SPECT I and SPECT II, n=15) on the same
      day. The MRI contrast agent was injected during MRI I but not MRI II to test the
      effect of imaging time after contrast. Resting Tc-MIBI SPECT images were acquired
      and infarct size was determined with commercial software. Infarct size in
      patients scanned by MRI and SPECT was 14+/-6% of left ventricular mass (%LV) by
      MRI (range 4%LV to 27%LV) and 14+/-7%LV by SPECT (range 4%LV to 26%LV). MRI I and
      II scans were performed 10+/-2 and 27+/-3 minutes after contrast, respectively.
      For MRI, the difference in infarct size between scans I and II (bias) was 
      0.1%LV, and the coefficient of repeatability was +/-2.4%LV. For SPECT, bias was 
      1.3%LV, and the coefficient of repeatability was +/-4.0%LV. Within individual
      patients, no systematic differences in infarct size were detected when the 2 MRI
      scans were compared, the 2 SPECT scans were compared, or MRI was compared to
      SPECT. CONCLUSION: The size of healed infarcts measured by contrast-enhanced MRI
      does not change between 10 and 30 minutes after contrast. The clinical
      reproducibility of contrast-enhanced MRI for infarct size determination compares
      favorably with that of routine clinical SPECT.

PMID- 12403662
TI  - Magnetic resonance imaging determination of cardiac prognosis.
AB  - BACKGROUND: Regional assessments of left ventricular (LV) wall motion obtained
      during MRI cardiac stress tests can be used to identify myocardial injury and
      ischemia, but the utility of MRI stress test results for the assessment of
      cardiac prognosis is not known. METHODS AND RESULTS: Two hundred seventy-nine
      patients referred (because of poor LV endocardial visualization with
      echocardiography) for dobutamine/atropine MRI for the detection of inducible
      ischemia were followed for an average of 20 months. After MRI stress testing, the
      occurrence of myocardial infarction, cardiac death, death attributable to any
      cause, coronary arterial revascularization, and unstable angina or congestive
      heart failure requiring hospitalization was determined. In a multivariate
      analysis, the presence of inducible ischemia (hazard ratio 3.3, CI 1.1 to 9.7) or
      an LV ejection fraction <40% (hazard ratio 4.2, CI 1.3 to 13.9) was associated
      with future MI or cardiac death independent of the presence of risk factors for
      coronary arteriosclerosis. CONCLUSIONS: In patients with poor echocardiograms,
      the results of cardiac MRI stress tests can be used to forecast myocardial
      infarction or cardiac death.

PMID- 12403663
TI  - Delivered dose and vascular response after beta-radiation for in-stent
      restenosis: retrospective dosimetry and volumetric intravascular ultrasound
      analysis.
AB  - BACKGROUND: Observations from previous intracoronary radiation therapy trials
      noted a considerable discrepancy between the prescribed radiation dose and the
      dose actually delivered. The aims of this study were to investigate the effect of
      actual delivered dose on vascular changes and to test the appropriateness of the
      current dose prescription. METHODS AND RESULTS: Serial volumetric intravascular
      ultrasound (IVUS) analysis was performed in 30 in-stent restenosis cases treated
      with a 40-mm (90)Sr/Y source train. The fixed dose was prescribed at 2 mm from
      the centerline of the source train (18.4 Gy at 2 mm for reference diameter < or
      =3.35 mm and 23 Gy for diameter > or =3.36 mm). Only stent segments with full
      radiation coverage and device injury were enrolled and divided into 2-mm-long
      subsegments (n=202). D(S90)EEM (the minimum dose absorbed by 90% of the external
      elastic membrane surface) was calculated as the delivered dose corresponding to
      each segment, assuming that the radiation catheter occupied the same position in
      the vessel as the IVUS catheter. Mean D(S90)EEM of 23.5+/-5.82 Gy (range 12.3 to
      41.7 Gy) was delivered to these subsegments. Overall, intimal hyperplasia volume
      remained constant from postintervention to follow-up (2.23+/-1.10 to 2.32+/-1.09
      mm3/m; P=NS). Regression analysis revealed there was no correlation between
      delivered dose intensity and changes in intimal hyperplasia volume. No particular
      dose-dependent complications were appreciated in this delivered dose range.
      CONCLUSIONS: The current dose-prescription protocol of (90)Sr/Y radiation to
      native in-stent restenosis lesions may provide substantial inhibition of
      neointimal reproliferation regardless of the actual delivered dose intensity.

PMID- 12403664
TI  - Long-term outcome of patients treated with repeat percutaneous coronary
      intervention after failure of gamma-brachytherapy for the treatment of in-stent
      restenosis.
AB  - BACKGROUND: Although (192)Ir intracoronary brachytherapy has been demonstrated to
      dramatically reduce the recurrence of in-stent restenosis, up to 24% of these
      patients will still require repeat target-vessel revascularization. The short-
      and long-term outcomes of repeat percutaneous intervention in this population
      have not been characterized. METHODS AND RESULTS: Analysis was performed of all
      patients enrolled in the GAMMA-I and GAMMA-II brachytherapy trials who underwent
      repeat percutaneous target lesion revascularization (TLR) because of restenosis.
      Subjects were divided into 2 cohorts: those who had received (192)Ir
      brachytherapy and those randomized to placebo. Forty-five (17.6%) of a total of
      256 patients whose index treatment was intracoronary radiation therapy and 36
      (29.8%) of 121 patients whose index treatment was placebo required repeat
      percutaneous TLR. The mean time to this first TLR was 295+/-206 days in the
      irradiated group and 202+/-167 days in the placebo group (P=0.03). Acute
      procedural success occurred in 100% of irradiated patients and 94% of placebo
      controls (P=0.19). After the first TLR, a subsequent TLR was required in 15
      (33.3%) of 45 brachytherapy patients versus 17 (47.2%) of 36 placebo failure
      patients (P=0.26). There was no significant difference in time to second TLR
      between the 2 groups. Other long-term major adverse event rates in both groups
      were comparable to those of other contemporary angioplasty/stenting series.
      CONCLUSIONS: In those patients who "fail" (192)Ir intracoronary brachytherapy for
      in-stent restenosis, treatment with (192)Ir delays the time to first TLR.
      Additionally, repeat percutaneous intervention in these patients is safe and
      efficacious in the short term, with acceptable long-term results.

PMID- 12403665
TI  - Emergency coronary artery bypass surgery in the contemporary percutaneous
      coronary intervention era.
AB  - BACKGROUND: Since the advent of percutaneous coronary interventions (PCIs),
      technological advances, adjunctive pharmacotherapy, and increasing operator
      experience have contributed to lowering the occurrence of major complications.
      However, emergency coronary artery bypass surgery (CABG) for failed PCI is still
      associated with important morbidity and mortality, even in the era of coronary
      stenting. We sought to determine the prevalence, indications, predictors, and
      complications of emergency CABG after PCI in the past decade. METHODS AND
      RESULTS: We reviewed 18 593 PCIs performed from 1992 through 2000. There was a
      need for emergency CABG in 113 (0.61%) cases. The major indications were
      extensive dissection (n=61, 54%), perforation/tamponade (n=23, 20%), and
      recurrent acute closure (n=23, 20%). Prevalence of emergency CABG decreased from
      1.5% of PCIs in 1992 to 0.14% in 2000 (P<0.001). Independent predictors of the
      need for emergency CABG included the worst ACC/AHA scoring of the intervened
      lesion (P<0.001) and female sex (P= 0.028), whereas history of prior bypass
      surgery and use of stents resulted in a decreased need for emergency CABG
      (P<0.001 for both). In patients undergoing emergency CABG, there were 17 (15%) in
      hospital deaths, 14 (12%) perioperative Q-wave myocardial infarctions, and 6 (5%)
      cerebrovascular accidents. CONCLUSIONS: The need for emergency CABG has
      considerably decreased over time. Risk factors include female sex and a higher
      ACC/AHA score of the intervened lesion. However, morbidity and mortality of
      emergency CABG remain high even in the new millennium.

PMID- 12403666
TI  - Left ventricular remodeling after primary coronary angioplasty: patterns of left
      ventricular dilation and long-term prognostic implications.
AB  - BACKGROUND: We prospectively evaluated the prevalence, pattern, and prognostic
      impact of left ventricular (LV) remodeling after acute myocardial infarction
      (AMI) successfully treated with primary PTCA. The prevalence, course, and
      prognostic value of LV remodeling after primary PTCA are still to be clarified.
      METHODS AND RESULTS: In 284 consecutive patients with AMI treated with primary
      PTCA, serial echocardiographic and angiographic studies, within 24 hours (T1), at
      1 (T2) and 6 months (T3) after AMI were performed. Long-term (61+/-14 months)
      clinical follow-up data were collected for 98.6% patients enrolled in the study.
      Overall, 85 (30%) patients showed LV dilation (>20% end-diastolic volume
      increase) at T3 as compared with T1. Early (from T1 to T2), late (from T2 to T3),
      and progressive dilation patterns (from T1 to T2 to T3) were detected in 42
      (15%), 41 (14%), and 36 (13%) patients, respectively. Cardiac death and combined
      events rate was significantly higher among patients with than among those without
      LV dilation (P=0.005 and P=0.025, respectively). The pattern of LV dilation
      during 6 months did not significantly affect survival. Cox survival analysis
      identified end-systolic volume at T1 and age as baseline predictors and end
      systolic volume at T3 and age as 6-month predictors of cardiac death,
      respectively. CONCLUSIONS: LV remodeling after successful PTCA occurs despite
      sustained patency of the infarct-related artery and preservation of regional and
      global LV function. LV dilation at 6 months after AMI but not the specific
      pattern of LV dilation is clearly associated with worse long-term clinical
      outcome.

PMID- 12403667
TI  - Cardiac sympathetic dysautonomia in chronic orthostatic intolerance syndromes.
AB  - BACKGROUND: In postural tachycardia syndrome (POTS) and repeated neurocardiogenic
      presyncope (NCS), orthostatic intolerance occurs without persistent sympathetic
      neurocirculatory failure. Whether these conditions involve abnormal cardiac
      sympathetic innervation or function has been unclear. METHODS AND RESULTS:
      Patients with POTS or NCS underwent measurements of neurochemical indices of
      cardiac release, reuptake, and synthesis of the sympathetic neurotransmitter
      norepinephrine based on entry of norepinephrine into the cardiac venous drainage
      (cardiac norepinephrine spillover), cardiac extraction of circulating (3)H
      norepinephrine, and cardiac production of dihydroxyphenylalanine and measurement
      of left ventricular myocardial innervation density using 6-[(18)F]fluorodopamine
      positron emission tomographic scanning. Mean cardiac norepinephrine spillover in
      POTS (171+/-30 pmol/min, N=16) was higher and in NCS (62+/-9 pmol/min, N=20) was
      lower than in a large group of healthy volunteers (102+/-9 pmol/min, N=52) and in
      a subgroup of age-matched healthy women (106+/-18 pmol/min, N=11). Both patient
      groups had normal cardiac extraction of (3)H-norepinephrine, normal cardiac
      production of dihydroxyphenylalanine, and normal myocardial 6
      [(18)F]fluorodopamine-derived radioactivity. CONCLUSIONS: POTS and NCS differ in
      tonic cardiac sympathetic function, with increased cardiac norepinephrine release
      in the former and decreased release in the latter. Both groups had normal values
      for indices of function of the cell membrane norepinephrine transporter,
      norepinephrine synthesis, and density of myocardial sympathetic innervation.
      Because POTS and NCS both include specific abnormalities of cardiac sympathetic
      function, both can be considered forms of dysautonomia.

PMID- 12403668
TI  - Cardiac troponin I predicts short-term mortality in vascular surgery patients.
AB  - BACKGROUND: Cardiac troponin I (cTnI) is a highly sensitive and specific marker
      for myocardial injury that predicts outcomes in patients with acute coronary
      syndromes. Cardiovascular complications are the leading cause of morbidity and
      mortality in patients who have undergone vascular surgery. However, postoperative
      surveillance with cardiac enzymes is not routinely performed in these patients.
      We evaluated the association between postoperative cTnI levels and 6-month
      mortality and perioperative myocardial infarction (MI) after vascular surgery.
      METHODS AND RESULTS: Two hundred twenty-nine patients having aortic or
      infrainguinal vascular surgery or lower extremity amputation were included in
      this study. Blood samples were analyzed for cTnI immediately after surgery and
      the mornings of postoperative days 1, 2, and 3. An elevated cTnI was defined as
      serum concentrations >1.5 ng/mL in any of the 4 samples. Twenty-eight patients
      (12%) had postoperative cTnI >1.5 ng/mL, which was associated with a 6-fold
      increased risk of 6-month mortality (adjusted OR, 5.9; 95% CI, 1.6 to 22.4) and a
      27-fold increased risk of MI (OR, 27.1; 95% CI, 5.2 to 142.7). Furthermore, we
      observed a dose-response relation between cTnI concentration and mortality.
      Patients with cTnI >3.0 ng/mL had a significantly greater risk of death compared
      with patients with levels < or =0.35 ng/mL (OR, 4.9; 95% CI, 1.3 to 19.0).
      CONCLUSIONS: Routine postoperative surveillance for cTnI is useful for
      identifying patients who have undergone vascular surgery who have an increased
      risk for short-term mortality and perioperative MI. Further research is needed to
      determine whether intervention in these patients can improve outcome.

PMID- 12403669
TI  - Plasminogen activator inhibitor-1 promotes formation of endothelial
      microparticles with procoagulant potential.
AB  - BACKGROUND: Endothelial dysfunction is emerging as a common denominator for
      diverse and highly prevalent cardiovascular diseases. Increased level of
      plasminogen activator inhibitor-1 (PAI-1) and procoagulant activity have been
      recognized as hallmarks of endothelial dysfunction. This study was aimed at
      investigating cellular actions of PAI-1 and a potential link between PAI-1 and
      procoagulant state. METHODS AND RESULTS: Human umbilical vein endothelial cells
      treated with PAI-1 were subjected to laser confocal fluorescence microscopy,
      immunoprecipitation and Western blotting, and FACS analysis for isolation and
      identification of endothelial microparticles. PAI-1 treatment resulted in a
      reduced expression of uPAR, its colocalization with caveolin, and the concomitant
      increase of uPAR abundance in the culture medium. FACS analysis revealed that PAI
      1 rapidly and dose-dependently increased the number of endothelial microparticles
      expressing uPAR and alpha(V)beta3 integrin. This process was attenuated by
      pretreatment with neutralizing anti-uPAR antibodies. PAI-1 knockout mice showed a
      significantly decreased number of circulating endothelial microparticles than
      wild-type mice; however, PAI-1-deficient animals responded to infusion of PAI-1
      with a more pronounced rise in the number of microparticles. PAI-1 treatment
      increased the number of microparticles stained with Annexin V, evidence for the
      expression of anionic phospholipids. This was accompanied by the accelerated
      generation of thrombin. CONCLUSIONS: The data disclose a novel effect of PAI-1 to
      dose-dependently promote formation of endothelial microparticles with the reduced
      transmembrane asymmetry of phospholipids. This phenomenon may be responsible for
      the observed increase in in vitro thrombin generation. These findings could
      potentially link these hallmarks of endothelial dysfunction-elevated levels of
      PAI-1 and propensity toward thrombosis.

PMID- 12403670
TI  - Oral everolimus inhibits in-stent neointimal growth.
AB  - BACKGROUND: Rapamycin (sirolimus)-eluting stents are associated with reduced
      restenosis rates in animal studies and initial human trials. The present study
      evaluated whether orally administered everolimus (a macrolide of the same family
      as sirolimus) inhibits in-stent neointimal growth in rabbit iliac arteries.
      METHODS AND RESULTS: New Zealand white rabbits were randomized to everolimus 1.5
      mg/kg per day starting 3 days before stenting and reduced to 1 mg/kg per day from
      days 14 to 28 (group 1), everolimus 1.5 mg/kg given 1 day before stenting
      followed by 0.75 mg/kg per day for 28 days (group 2), or matching placebo for
      each group. Drugs were administered by oral gavage. Stents were deployed in both
      iliac arteries, and arteries were harvested 28 days after stenting. Group 1
      everolimus-treated rabbits experienced weight loss and anorexia, which resolved
      after the everolimus dose was lowered on day 14. Group 2 animals were healthy for
      the duration of everolimus dosing. Both everolimus treatment groups significantly
      reduced in-stent neointimal growth (46% reduction and 42% reduction in intimal
      thickness in groups 1 and 2, respectively). In group 2 everolimus-treated
      animals, the neointima was healed or healing, characterized by stent struts
      covered by a thin neointima, overlying endothelial cells, and only small foci of
      fibrin. Scanning electron microscopy showed >80% stent surface endothelialization
      in group 2 everolimus-treated rabbits. CONCLUSIONS: Oral everolimus suppresses in
      stent neointimal growth in the rabbit iliac artery. At a dose of 1.5 mg/kg given
      1 day before stenting followed by 0.75 mg/kg per day for 28 days, everolimus was
      well tolerated and was associated with significant neointimal healing.

PMID- 12403671
TI  - Prevention of hypertrophy by overexpression of Kv4.2 in cultured neonatal
      cardiomyocytes.
AB  - BACKGROUND: Prolonged action potentials (APs) and decreased transient outward K+
      currents (I(to)) are consistent findings in hypertrophic myocardium. However, the
      connection of these changes with cardiac hypertrophy is unknown. The present
      study investigated the effects of changes in I(to) and the associated alterations
      in AP on myocyte hypertrophy induced by phenylephrine. METHODS AND RESULTS:
      Chronic incubation of cultured neonatal ventricular rat myocytes (NVRMs) with
      phenylephrine (PE) reduced I(to) density and prolonged AP duration, leading to a
      2-fold increase in the net Ca2+ influx per beat and a 1.4-fold increase in Ca2+
      transient amplitude. PE treatment of chronically paced (2-Hz) NVRM also induced
      increases in cell size, protein/DNA ratio, atrial natriuretic factor mRNA
      expression, as well as beta/alpha myosin mRNA ratio. These hypertrophic changes
      were associated with a 2.4-fold increase in activation of nuclear factor of
      activated T-cells (NFAT), indicating increased activity of the Ca2+-dependent
      phosphatase calcineurin. Overexpression of Kv4.2 channels using adenovirus
      prevented the AP duration prolongation as well as the increases in Ca2+ influx
      and Ca2+-transient amplitude induced by PE. Kv4.2 overexpression also prohibited
      the PE-induced increases in cell size, protein/DNA ratio, atrial natriuretic
      factor expression, beta/alpha myosin mRNA ratio, and NFAT activation.
      CONCLUSIONS: Our results demonstrate that PE-mediated hypertrophy in NRVMs seems
      to require I(to) reductions and AP prolongation associated with increased Ca2+
      influx and Ca2+ transients as well as calcineurin activation. The clinical
      implications of these studies and the possible involvement of other signaling
      pathways are discussed.

PMID- 12403672
TI  - Effects of selective inhibitors of nitric oxide synthase-2 dimerization on acute
      cardiac allograft rejection.
AB  - BACKGROUND: Nitric oxide synthase-2 (NOS2) is expressed during acute cardiac
      allograft rejection in association with myocardial inflammation, contractile
      dysfunction, and death of cardiomyocytes by necrosis and apoptosis. Recently,
      allosteric inhibitors of NOS2 monomer dimerization that block NOS2 activity have
      been developed. METHODS AND RESULTS: To investigate effects of selective NOS2
      blockade, 15 mg/kg of BBS-1 or BBS-2 was administered twice daily subcutaneously
      to rats starting the day of heterotopic heart transplantation. Cardiac allograft
      survival was increased significantly, from 6.8 days in controls to 13.3 and to
      14.2 days in NOS2-inhibited allografts. At day 5 after heart transplantation,
      synthesis of NOx was reduced by 53%. There were significantly fewer T lymphocytes
      and macrophages in the inflammatory infiltrate, as well as less edema and
      cardiomyocyte damage, and the International Society of Heart and Lung
      Transplantation score fell from 5 to 4 and 3.5. NOS2 and nitrotyrosine
      immunostaining and the mean numbers of apoptotic cells and of apoptotic
      cardiomyocytes were significantly diminished in the treated allografts.
      CONCLUSIONS: The data indicate that selective inhibition of NOS2 dimerization
      prolongs survival and reduces myocardial inflammation and cardiomyocyte damage in
      acute cardiac allograft rejection.

PMID- 12403673
TI  - Prostacyclin-deficient mice develop ischemic renal disorders, including
      nephrosclerosis and renal infarction.
AB  - BACKGROUND: Prostacyclin (PGI2) is a short-lived endogenous inhibitor of platelet
      aggregation and a potent vasodilator and regulator of the growth of vascular
      smooth muscle cells. To study the role of PGI2 in the vascular system in vivo,
      PGI2-deficient (PGID) mice were established by genetic disruption of the PGI2
      synthase gene. METHODS AND RESULTS: PGI2 synthase-null mice were generated by
      replacing the exons of PGI2 synthase gene that encodes for the catalytic site of
      the enzyme with a neomycin resistance gene. In these mice, PGI2 levels in the
      plasma, kidneys, and lungs were reduced, whereas thromboxane and prostaglandin E2
      levels became elevated. Blood pressure and the amounts of urea nitrogen and
      creatinine in plasma of the PGID mice were significantly higher than those of
      wild-type mice (P<0.05). They developed progressive morphological abnormalities
      in the kidneys, accompanied by atrophy, surface irregularity, fibrosis, cyst,
      arterial sclerosis, and hypertrophy of vessel walls. Thickening of the thoracic
      aortic media and adventitia were observed in aged PGID mice. Importantly, these
      phenotypes have not been reported in PGI2 receptor-deficient mice. CONCLUSIONS:
      PGI2 deficiency resulted in the development of vascular disorders with the
      thickening of vascular walls and interstitial fibrosis, especially in mouse
      kidneys. The findings demonstrated in vivo that PGI2 is important in the
      homeostasis of blood vessels. Our established PGID mice are useful for studies on
      the initiation and development of vascular diseases, such as ischemic renal
      disorders with arterial sclerosis and infarction, and also for studies on the
      novel signaling pathway of PGI2.

PMID- 12403674
TI  - The puzzle of nitrate tolerance: pieces smaller than we thought?

PMID- 12403675
TI  - Images in cardiovascular medicine. Intracoronary imaging with optical coherence
      tomography: a new high-resolution technology providing striking visualization in
      the coronary artery.

PMID- 12403676
TI  - Cardiac chimerism: methods matter.

PMID- 12403677
TI  - Safety of C1-inhibitor for clinical use.

PMID- 12403678
TI  - Importance of diet in vascular prevention: vastly underestimated.

PMID- 12403679
TI  - Every acronym should be defined when it first appears in a publication.

PMID- 12403680
TI  - Atherosclerosis: lipid infiltration or Chlamydia pneumoniae infection?

PMID- 12403681
TI  - Need for emergency CABG decreases, but morbidity and mortality remain high.

PMID- 12403683
TI  - Does blocking cytokines in sepsis work?

PMID- 12403684
TI  - Rare lung diseases: orphans no more?

PMID- 12403685
TI  - Investigating invasive aspergillosis.

PMID- 12403686
TI  - Rheumatology.

PMID- 12403687
TI  - Lung cancer--where are we today? Current advances in staging and nonsurgical
      treatment.
AB  - Lung cancer remains the commonest cause of cancer death in both men and women in
      the developed world, although mortality rates for men are dropping. Spiral
      computed tomography (CT) of the chest in middle-aged, smoking subjects may
      identify two to four times more lung cancers than a chest X-ray, with more than
      70% of tumors being Stage I. The incidence of benign nodules is high, making
      interpretation difficult. Randomized controlled trials are required to determine
      whether spiral CT detects lung cancer early enough to improve mortality.
      Preoperative staging has relied on CT scans, but positron emission tomography
      scanning has greater sensitivity, specificity, and accuracy than CT and is
      recommended as the final confirmatory investigation when the CT shows resectable
      disease. In locally advanced non-small cell lung cancer, there is a small
      advantage for the addition of chemotherapy to radiotherapy, but no advantage for
      postoperative radiotherapy. Chemotherapy gives no benefit when given as
      neoadjuvant or adjuvant treatment around surgery. In advanced disease, newer
      cytotoxic agents confer a small survival advantage over older combinations, but
      the advantage in median survival over best supportive care remains a few months
      with modest improvements in quality of life. Survival with small cell lung cancer
      has shown little increase over the last 15 years despite multiple attempts to
      manipulate the timing, dose intensity of chemotherapy, and the potential of
      radiotherapy. Novel therapies are urgently needed for all cell types of lung
      cancer.

PMID- 12403688
TI  - Risk and the efficacy of antiinflammatory agents: retrospective and confirmatory
      studies of sepsis.
AB  - We investigated whether a relationship between risk of death and treatment effect
      could explain the disparate results between the preclinical and clinical sepsis
      trials of antiinflammatory agents over the last decade. A metaregression analysis
      of cited preclinical studies showed that the treatment effects of these agents
      were highly dependent on risk of death (p = 0.0001) and that animals were studied
      at significantly higher control mortality rates than humans (median [25th-75th
      quartile], 88% [79-96%] versus 39% [32-42%], p = 0.0001). An analysis of the
      clinical trials showed that antiinflammatory agents were also significantly more
      efficacious in septic patients with higher risk of death (p = 0.002) and were
      harmful in those with low risk. To test this relationship prospectively, we
      studied antiinflammatory agents in models employing differing doses of bacterial
      challenge to produce the full range of risk of death. We found that the efficacy
      of these agents, although very beneficial at high control mortality rates, was
      much reduced (p = 0.0001) and similar to those in human trials at moderate
      control mortality rates (i.e., 30 to 40%). The efficacy of antiinflammatory
      agents during sepsis is dependent on the risk of death, an observation that
      explains the apparent contradiction between preclinical and clinical trial
      results. Accounting for this relationship may be necessary for the safe and
      effective development of antiinflammatory therapies for sepsis.

PMID- 12403689
TI  - Effects of bronchial obstruction on lower esophageal sphincter motility and
      gastroesophageal reflux in patients with asthma.
AB  - The relationship between gastroesophageal reflux and asthma remains unclear. The
      aim of this study was to analyze the effect of bronchial obstruction on lower
      esophageal sphincter (LES) motility and reflux in patients with asthma. LES
      motility and esophageal pH were assessed in eight subjects with intermittent
      asthma and eight healthy volunteers during three consecutive 30-minute periods:
      baseline, methacholine-induced bronchospasm, and after inhalation of the beta2
      agonist salbutamol. Healthy subjects inhaled 2 mg of methacholine, whereas
      subjects with asthma inhaled the dose of methacholine causing a 15% fall in
      FEV(1), as determined by a previous methacholine challenge. LES motility,
      esophageal pH, and FEV(1) were not significantly different between the three
      periods in healthy subjects. In patients with asthma, methacholine induced a 21.9
      +/- 2.6% decrease in FEV(1) and a concomitant increase in the rate of transient
      LES relaxation (TLESR) and reflux episodes. Inhalation of salbutamol decreased
      the rate of TLESRs but not the number of reflux episodes. We conclude that in
      patients with asthma, methacholine-induced bronchospasm increases the rate of
      TLESR and the number of reflux episodes. These results support the belief that,
      in asthma, bronchial obstruction may be responsible for reflux or may aggravate
      reflux through a mechanism that remains to be further clarified.

PMID- 12403690
TI  - Effects of montelukast and budesonide on airway responses and airway inflammation
      in asthma.
AB  - Inhaled corticosteroids are effective antiinflammatory therapy for asthma;
      however, they do not completely abolish allergen-induced airway inflammation.
      Leukotriene modifiers attenuate both early and late allergen responses and have
      antiinflammatory properties. We reasoned that treatment with budesonide and
      montelukast in combination might provide greater antiinflammatory effects than
      either drug alone, and the purpose of this study was to compare the effects of
      treatment with budesonide and montelukast, alone or in combination, on outcome
      variables after allergen inhalation. Ten subjects with asthma with dual responses
      after allergen inhalation were included in this randomized, double-blind,
      crossover study. Outcomes included early and late asthmatic responses, and
      changes in airway responsiveness and sputum eosinophilia, measured before and
      after challenge. Treatment with montelukast attenuated the maximal early
      asthmatic response compared with placebo (p < 0.001) and budesonide (p = 0.002).
      Both budesonide and montelukast, alone and in combination, attenuated the maximal
      late asthmatic response compared with placebo (p < 0.01). Budesonide and
      montelukast, alone and in combination, afforded protection against allergen
      induced airway hyperresponsiveness (p < 0.05), although the treatment effect of
      budesonide was greater than that of montelukast (p < 0.05). Treatment with
      budesonide and montelukast, alone and in combination, also attenuated allergen
      induced sputum eosinophilia. Thus, montelukast and budesonide attenuated allergen
      induced asthmatic responses, airway hyperresponsiveness, and sputum eosinophilia,
      although combination treatment did not provide greater antiinflammatory effects
      than either drug alone.

PMID- 12403691
TI  - Local and systemic inflammation in patients with chronic obstructive pulmonary
      disease: soluble tumor necrosis factor receptors are increased in sputum.
AB  - Chronic obstructive pulmonary disease (COPD) is characterized by significant
      chronic inflammation in the pulmonary compartment as well as in the circulation.
      This study aimed to elucidate the relationship between local and systemic
      inflammation in smoking-induced COPD by assessing levels of soluble (s) tumor
      necrosis factor (TNF) receptors, TNF-alpha, and interleukin-8 (IL-8) in induced
      sputum and in plasma. Sputum induction was performed in 18 subjects with COPD
      (FEV(1) 56% predicted) and 17 healthy smokers (FEV(1) 99% predicted). Patients
      with COPD showed significantly higher percentages of neutrophils and levels of
      sTNF-R55 and IL-8 in sputum as compared with control subjects, whereas sputum
      sTNF-R75 levels tended to be higher in COPD. Sputum TNF-alpha levels were similar
      in both groups. When comparing sTNF receptors in sputum and plasma, no direct
      correlations were found despite elevation of circulating sTNF-R75 levels in
      patients with COPD. In addition, sputum sTNF receptors were inversely related to
      the FEV(1) in patients with COPD, whereas circulating sTNF receptors were not,
      suggesting different regulation of inflammation in the pulmonary and systemic
      compartment. When subjects were divided according to their current smoking
      status, levels of sTNF-R55, sTNF-R75, and IL-8 in sputum were significantly
      elevated in ex-smoking versus currently smoking patients with COPD, suggesting
      ongoing inflammation in airways and circulation of patients with COPD after
      smoking cessation.

PMID- 12403692
TI  - Evidence of a sleep-specific blunted cortical response to inspiratory occlusions
      in mild obstructive sleep apnea syndrome.
AB  - Obstructive sleep apnea syndrome (OSAS) patients have elevated non-rapid eye
      movement (REM) sleep arousal thresholds to inspiratory loading. To test the
      hypothesis that this is due to sleep-specific dampening of cortical responses to
      inspiratory effort, respiratory-related evoked potentials (RREPs) were evaluated
      in six mild OSAS patients and six age- and body mass index-matched controls
      during wakefulness and Stage 2 non-REM sleep. Electroencephalogram was recorded
      from six scalp sites (Fz, FCz, Cz, CPz, Pz, and O(2)). Electrooculogram,
      electromyogram, and mask pressure signals were also recorded. During sleep,
      pharyngeal pressure was recorded using a Millar pressure catheter placed 2 cm
      below the glottis. The RREP waveform was broadly similar in the two groups during
      wakefulness, but was markedly different during Stage 2 non-REM sleep. During
      wakefulness, only the N1 component showed reduced amplitude in the OSAS group.
      During sleep, the occlusion stimulus elicited fewer K-complexes in the OSAS
      patients. In addition, the N550 component in the average of K-complex responses
      was smaller in amplitude in the OSAS group. The data suggest that patients with
      mild OSAS have a "blunted" response to the respiratory occlusion stimulus. This
      appears not to be related to compromised mechanoreceptor function, as the RREP
      was normal in the patients when they were awake.

PMID- 12403693
TI  - Idiopathic acute eosinophilic pneumonia: a study of 22 patients.
AB  - Idiopathic acute eosinophilic pneumonia (IAEP) is characterized by acute febrile
      respiratory failure associated with diffuse radiographic infiltrates and
      pulmonary eosinophilia. We conducted a multicenter retrospective study to
      characterize this rare clinical entity further and to improve its diagnostic
      criteria. A total of 13 male and 9 female patients (mean age: 29 +/- 15.8 years)
      presented with severe hypoxemia (Pa(O2)/fraction of inspired oxygen ratio = 156
      +/- 74.1) requiring mechanical ventilation in 14 cases. Bronchoalveolar lavage
      was performed on all patients and showed 54.4 +/- 19.2% eosinophils on
      differential cell count, but no open-lung biopsies were done. No clinical
      differences were found between patients seen at less than 7 days (n = 15) or at 7
      to 31 days (n = 7) from the onset of IAEP. A total of 12 patients met the
      clinical criteria of acute lung injury, and eight of these patients met the
      criteria for acute respiratory distress syndrome. All patients recovered, either
      spontaneously (6) or on corticosteroid treatment (16). No relapses occurred. We
      conclude that: (1) diagnostic criteria of IAEP are compatible with a duration of
      symptoms for up to 1 month, but the response to corticosteroid treatment is not
      diagnostic because of possible spontaneous recovery; (2) IAEP should be
      considered as differential diagnosis of acute lung injury or acute respiratory
      distress syndrome; (3) bronchoalveolar lavage eosinophilia obviates the need for
      lung biopsy in IAEP.

PMID- 12403694
TI  - Ultrafine particle deposition and clearance in the healthy and obstructed lung.
AB  - Numerous epidemiologic studies have shown associations between exposure to
      particulate air pollution and acute increases in morbidity and mortality,
      particularly in persons with chronic obstructive pulmonary disease. The dosimetry
      of ultrafine particles in the human lung is poorly characterized. We studied the
      deposition and clearance of an ultrafine technetium-99m-labeled aerosol in 10
      patients with chronic obstructive pulmonary disease and in 9 healthy subjects.
      Particle retention was followed for 2 hours after inhalation and again at 24
      hours by gamma scintigraphy. Central-to-peripheral ratios indexed airway
      deposition. Particle accumulation in the liver was examined by quantifying
      activity below the right lung. The dose rate for an aerosol exposure of 10 micro
      g/m(3) was calculated. Patients had a significantly greater dose rate than
      healthy subjects (2.9 +/- 1.0 versus 1.9 +/- 0.4 micro g/h, p = 0.02). Central-to
      peripheral ratios were slightly greater in patients than in healthy subjects
      (1.11 +/- 0.10 versus 1.01 +/- 0.11, p = 0.05). Clearance did not statistically
      differ between health and disease. On average, 24-hour retention was 85 +/- 8%
      (corrected for isotope dissolution). No accumulation in the liver's vicinity was
      observed. Data suggest that relative to healthy subjects, patients with moderate
      to-severe airways obstruction receive an increased dose from ultrafine particle
      exposure.

PMID- 12403695
TI  - Inflammatory response in airway epithelial cells isolated from patients with
      cystic fibrosis.
AB  - The concept that inflammatory gene expression is dysregulated in airway
      epithelial cells from patients with cystic fibrosis (CF) is controversial. To
      examine this possibility systematically, responses to inflammatory stimuli were
      compared in CF airway epithelial cell lines without versus with wild-type CF
      transmembrane conductance regulator (CFTR) complementation and in
      tracheobronchial epithelial cells from patients with versus without CF.
      Epithelial cell expression of the leukocyte adhesion glycoprotein intercellular
      adhesion molecule-1 (ICAM-1) and release of the neutrophil chemoattractant
      interleukin (IL)-8 were determined under basal conditions or after exposure to
      stimuli important in CF airway inflammatory responses. We found that uncorrected
      CF airway epithelial cell lines inconsistently expressed higher ICAM-1 and IL-8
      levels. Human CF tracheobronchial epithelial cells in primary culture released
      moderately increased IL-8 only after exposure to Pseudomonas aeruginosa. In CF
      cells with higher IL-8 release, transient expression of wild-type CFTR using an
      adenoviral vector did not specifically affect cytokine levels. The results
      indicate that there is considerable variability in airway epithelial cell
      responses to inflammatory stimuli among different individuals and cell models
      systems. Although increased ICAM-1 and IL-8 expression are observed in some CF
      airway epithelial cell models, many CF cells do not exhibit significant
      dysregulation of these important inflammatory genes.

PMID- 12403696
TI  - Computer-assisted analysis helps detect inner dynein arm abnormalities.
AB  - The diagnosis of primary ciliary dyskinesia is based on demonstration of ciliary
      defects, mainly concerning dynein arms. Whereas the absence of outer dynein arms
      can be easily distinguished, the absence of inner dynein arms is difficult to
      confirm because of their low contrast on electron microscopy. Ciliary
      ultrastructure was studied in 40 patients suffering from respiratory tract
      infections. Conventional transmission electron microscopy showed normal cilia in
      6 patients, confirmed a diagnosis of primary ciliary dyskinesia in 26 patients,
      and was inconclusive in 8 patients. All doubtful cases were related to inner
      dynein arm determination. Conventional electron microscopic analysis was able to
      define the ultrastructural phenotype of inner dynein arms in 40.5% of cases (6
      presence of inner dynein arms, 13 absence of inner dynein arms). We developed
      computer-assisted analysis of electron microscopic micrographs to improve inner
      dynein arm visualization. Computer-assisted analysis consisted of image
      transformations designed to enhance the signal/noise ratio, based on the symmetry
      of ciliary axonemes. The sensitivity and specificity of computer-assisted
      analysis were 100 and 98%, respectively. The efficiency of computer-assisted
      analysis to visualize inner dynein arms, evaluated in the patients with
      undetermined phenotype after electron microscopy, was 86% (three normal cilia,
      seven primary ciliary dyskinesia with absence of outer dynein arms, three primary
      ciliary dyskinesia with absence of inner dynein arms, five partial absence of
      inner dynein arms). Computer-assisted analysis of ciliary micrographs improves
      the characterization of inherited axonemal defects.

PMID- 12403697
TI  - Transient lung-specific expression of the chemokine KC improves outcome in
      invasive aspergillosis.
AB  - Invasive aspergillosis is a common and devastating pneumonia in immunocompromised
      hosts. Neutrophils are critical for defense against this infection, and ELR+ CXC
      chemokines are potent neutrophil chemoattractants. We hypothesized that transient
      lung-specific overexpression of one such ligand, KC, in mice with invasive
      aspergillosis improves the outcome of disease. We generated mice in which
      transgenic expression of KC was limited to the lungs and occurred only upon
      exposure to tetracycline analogues, and we exposed them to doxycycline after the
      onset of invasive aspergillosis. Transgenic mice had a threefold greater
      survival, a 74% lower lung fungal burden, a greater magnitude of lung KC
      induction, and an earlier and higher peak of lung neutrophil influx compared with
      wild-type mice. In addition to a higher number of neutrophils, we found a 1.8
      fold higher number of monocytes-macrophages in the lungs of transgenic mice as
      compared with wild-type mice. Furthermore, transgenic mice had greater lung
      expression of interferon-gamma and interleukin-12 in response to infection,
      suggesting that transgenic expression of KC indirectly regulated the expression
      of other cytokines associated with improved host defense against this pathogen.
      Taken together, these data suggest that overexpression of KC in the lung in the
      setting of established invasive aspergillosis results in improved host defense
      and outcome of disease.

PMID- 12403698
TI  - Three-dimensional mapping of sensory innervation with substance p in porcine
      bronchial mucosa: comparison with human airways.
AB  - In asthma, neurogenic inflammation in bronchial airways may occur though the
      release of neuropeptides from C fibers via an axon reflex. Structural evidence
      for this neural pathway was sought in the pig and in humans by three-dimensional
      mapping of substance P-immunoreactive (SP-IR) nerves in whole mounts of mucosa
      using immunofluorescent staining and confocal microscopy. To show continuity,
      nerves were traced with 1,1'-didodecyl-3,3,3',3'-tetramethyl indocarbocyanine
      perchlorate from their epithelial endings through the mucosa. The pan-neuronal
      marker protein gene product 9.5 revealed an extensive apical and basal plexus of
      nerves in the epithelium; 94% of these were varicose SP-IR fibers. Apical SP-IR
      fibers had a length density of 88 mm/mm(2). Varicose apical processes followed
      closely around the circumference of goblet cells. Calcitonin gene-related peptide
      was colocalized with SP-IR in varicosites. The epithelial fibers converged into
      bundles as they entered the lamina propria where lateral branches ran along
      arterioles, often contiguous with the vascular smooth muscle. 1,1'-didodecyl
      3,3,3',3'-tetramethyl indocarbocyanine perchlorate tracing showed that they
      projected to the epithelium. SP-IR fibers were rare near postcapillary venules.
      In human bronchial epithelium, protein gene product 9.5 revealed a similar apical
      and basal plexus of varicose fibers that weakly stained for SP-IR. Thus, a
      continuous sensory nerve pathway from the epithelium to arterioles provides
      structural support for a local axon reflex.

PMID- 12403699
TI  - Role of deformation-induced lipid trafficking in the prevention of plasma
      membrane stress failure.
AB  - Cells experience plasma membrane stress failure when the matrix to which they
      adhere undergoes large deformations. In the lung, such a mechanism might explain
      mechanical ventilation-associated cell injury. We have previously shown that in
      alveolar epithelial cells, deformation induces lipid trafficking to the plasma
      membrane, thereby accommodating the required increase in the cell surface area.
      We now show that cell wounding is strain amplitude and rate dependent and that
      under conditions of impaired exocytosis strain-induced cell wounding is
      significantly increased. In addition, the susceptibility of cells to mechanical
      injury was not correlated with changes in cell stiffness. Using a dual-labeling
      technique, we differentiated between cell populations that were reversibly and
      irreversibly injured and showed that interventions that impair deformation
      induced lipid trafficking also reduce the likelihood of plasma membrane
      resealing. Our findings suggest that cell plasticity and remodeling responses
      such as deformation-induced lipid trafficking are more important for
      cytoprotection from strain injury than are the innate mechanical properties of
      the cell. We also conclude that in deformation experiments, tests of cell
      membrane integrity cannot be interpreted as tests of cell viability because an
      intact plasma membrane after deformation does not mean that no injury had
      occurred.

PMID- 12403700
TI  - Corticosteroid-induced epithelial shedding in asthma.

PMID- 12403701
TI  - Should sodium bicarbonate be administered in diabetic ketoacidosis?

PMID- 12403702
TI  - Factor viia for alveolar hemorrhage in microscopic polyangiitis.

PMID- 12403703
TI  - Surfactant lavage demonstrates protein fibrils in a neonate with congenital
      surfactant protein b deficiency.

PMID- 12403704
TI  - Control of Drosophila eye specification by Wingless signalling.
AB  - Organ formation requires early specification of the groups of cells that will
      give rise to specific structures. The Wingless protein plays an important part in
      this regional specification of imaginal structures in Drosophila, including
      defining the region of the eye-antennal disc that will become retina. We show
      that Wingless signalling establishes the border between the retina and adjacent
      head structures by inhibiting the expression of the eye specification genes eyes
      absent, sine oculis and dachshund. Ectopic Wingless signalling leads to the
      repression of these genes and the loss of eyes, whereas loss of Wingless
      signalling has the opposite effects. Wingless expression in the anterior of wild
      type discs is complementary to that of these eye specification genes. Contrary to
      previous reports, we find that under conditions of excess Wingless signalling,
      eye tissue is transformed not only into head cuticle but also into a variety of
      inappropriate structures.

PMID- 12403705
TI  - Shh signaling within the dental epithelium is necessary for cell proliferation,
      growth and polarization.
AB  - Sonic hedgehog (Shh), a member of the mammalian Hedgehog (Hh) family, plays a key
      role during embryogenesis and organogenesis. Tooth development, odontogenesis, is
      governed by sequential and reciprocal epithelial-mesenchymal interactions.
      Genetic removal of Shh activity from the dental epithelium, the sole source of
      Shh during tooth development, alters tooth growth and cytological organization
      within both the dental epithelium and mesenchyme of the tooth. In this model it
      is not clear which aspects of the phenotype are the result of the direct action
      of Shh on a target tissue and which are indirect effects due to deficiencies in
      reciprocal signalings between the epithelial and mesenchymal components. To
      distinguish between these two alternatives and extend our understanding of Shh's
      actions in odontogenesis, we have used the Cre-loxP system to remove Smoothened
      (Smo) activity in the dental epithelium. Smo, a seven-pass membrane protein is
      essential for the transduction of all Hh signals. Hence, removal of Smo activity
      from the dental epithelium should block Shh signaling within dental epithelial
      derivatives while preserving normal mesenchymal signaling. Here we show that Shh
      dependent interactions occur within the dental epithelium itself. The dental
      mesenchyme develops normally up until birth. In contrast, dental epithelial
      derivatives show altered proliferation, growth, differentiation and polarization.
      Our approach uncovers roles for Shh in controlling epithelial cell size,
      organelle development and polarization. Furthermore, we provide evidence that Shh
      signaling between ameloblasts and the overlying stratum intermedium may involve
      subcellular localization of Patched 2 and Gli1 mRNAs, both of which are targets
      of Shh signaling in these cells.

PMID- 12403706
TI  - Recruitment of cell groups through Delta/Notch signalling during spider
      neurogenesis.
AB  - Early neurogenesis in the spider is characterised by a stereotyped pattern of
      sequential recruitment of neural cells from the neuroectoderm, comparable with
      neuroblast formation in Drosophila: However, in contrast to Drosophila, where
      single cells delaminate from the neuroectoderm, groups of cells adopt the neural
      fate and invaginate into the spider embryo. This raises the question of whether
      Delta/Notch signalling is involved in this process, as this system normally leads
      to a singling out of individual cells through lateral inhibition. I have
      therefore cloned homologues of Delta and Notch from the spider Cupiennius salei
      and studied their expression and function. The genes are indeed expressed during
      the formation of neural cells in the ventral neuroectoderm. Loss of function of
      either gene leads to an upregulation of the proneural genes and an altered
      morphology of the neuroectoderm that is comparable with Delta and Notch mutant
      phenotypes in Drosophila: Thus, although Delta/Notch signalling appears to be
      used in the same way as in Drosophila, the lateral inhibition process produces
      clusters of invaginating cells, rather than single cells. Intriguingly,
      neuroectodermal cells that are not invaginating seem to become neural cells at a
      later stage, while the epidermal cells are derived from lateral regions that
      overgrow the neuroectoderm. In this respect, the neuroectodermal region of the
      spider is more similar to the neural plate of vertebrates, than to the
      neuroectoderm of Drosophila:

PMID- 12403707
TI  - early in short days 4, a mutation in Arabidopsis that causes early flowering and
      reduces the mRNA abundance of the floral repressor FLC.
AB  - The plant shoot is derived from the apical meristem, a group of stem cells formed
      during embryogenesis. Lateral organs form on the shoot of an adult plant from
      primordia that arise on the flanks of the shoot apical meristem. Environmental
      stimuli such as light, temperature and nutrient availability often influence the
      shape and identity of the organs that develop from these primordia. In
      particular, the transition from forming vegetative lateral organs to producing
      flowers often occurs in response to environmental cues. This transition requires
      increased expression in primordia of genes that confer floral identity, such as
      the Arabidopsis gene LEAFY. We describe a novel mutant, early in short days 4
      (esd4), that dramatically accelerates the transition from vegetative growth to
      flowering in Arabidopsis: The effect of the mutation is strongest under short
      photoperiods, which delay flowering of Arabidopsis: The mutant has additional
      phenotypes, including premature termination of the shoot and an alteration of
      phyllotaxy along the stem, suggesting that ESD4 has a broader role in plant
      development. Genetic analysis indicates that ESD4 is most closely associated with
      the autonomous floral promotion pathway, one of the well-characterized pathways
      proposed to promote flowering of Arabidopsis: Furthermore, mRNA levels of a
      floral repressor (FLC), which acts within this pathway, are reduced by esd4, and
      the expression of flowering-time genes repressed by FLC is increased in the
      presence of the esd4 mutation. Although the reduction in FLC mRNA abundance is
      likely to contribute to the esd4 phenotype, our data suggest that esd4 also
      promotes flowering independently of FLC. The role of ESD4 in the regulation of
      flowering is discussed with reference to current models on the regulation of
      flowering in Arabidopsis.

PMID- 12403708
TI  - The chicken RaxL gene plays a role in the initiation of photoreceptor
      differentiation.
AB  - The paired type homeodomain gene, Rax, was previously identified as a key
      molecule in early eye formation in mice and humans. We report the expression
      patterns of two Rax family members from chicken, Rax and RaxL, and on the
      function of RaxL in photoreceptor development. Both Rax and RaxL are expressed in
      early retinal progenitor cells, with Rax being expressed at a significantly
      higher level than RaxL. At the time that photoreceptors begin to form, RaxL
      appears at a relatively high level in a subset of cells within the zone of
      proliferating progenitor cells. Subsequently, it is expressed in cells migrating
      to the photoreceptor layer, where it is highly expressed during the initial, but
      not late, stages of photoreceptor differentiation. To test the function of RaxL,
      a putative dominant-negative allele of RaxL comprising a fusion of the engrailed
      repressor domain and a region of RaxL (EnRaxLDeltaC) was introduced in vivo into
      the early chick eye using a retroviral vector. EnRaxLDeltaC, but not the dominant
      negative Rax (EnRaxDeltaC), caused a significant reduction in expression of early
      markers of photoreceptor cells. Examination of the transactivation activity of
      RaxL on a reporter construct bearing a canonical photoreceptor-specific enhancer
      element showed that RaxL exhibited significant activation activity, and that this
      activity was severely diminished in the presence of EnRaxLDeltaC. The effect on
      photoreceptor gene expression in vivo was specific in that other cell types were
      unaffected, as was general proliferation in the retina. The reduction in numbers
      of cells expressing photoreceptor markers was probably due to decreased survival
      of developing photoreceptor cells, as there was increased apoptosis among cells
      of the retina expressing dominant-negative RaxL. We propose that RaxL plays a
      role in the initiation of differentiation, and also possibly commitment, of
      photoreceptor cells in the chicken retina.

PMID- 12403709
TI  - Eyes absent, a key repressor of polar cell fate during Drosophila oogenesis.
AB  - Throughout Drosophila oogenesis, specialized somatic follicle cells perform
      crucial functions in egg chamber formation and in signaling between somatic and
      germline cells. In the ovary, at least three types of somatic follicle cells,
      polar cells, stalk cells and main body epithelial follicle cells, can be
      distinguished when egg chambers bud from the germarium. Although specification of
      these three somatic cell types is important for normal oogenesis and subsequent
      embryogenesis, the molecular basis for establishment of their cell fates is not
      completely understood. Our studies reveal the gene eyes absent (eya) to be a key
      repressor of polar cell fate. EYA is a nuclear protein that is normally excluded
      from polar and stalk cells, and the absence of EYA is sufficient to cause
      epithelial follicle cells to develop as polar cells. Furthermore, ectopic
      expression of EYA is capable of suppressing normal polar cell fate and
      compromising the normal functions of polar cells, such as promotion of border
      cell migration. Finally, we show that ectopic Hedgehog signaling, which is known
      to cause ectopic polar cell formation, does so by repressing eya expression in
      epithelial follicle cells.

PMID- 12403710
TI  - Establishing the trochlear motor axon trajectory: role of the isthmic organiser
      and Fgf8.
AB  - Formation of the trochlear nerve within the anterior hindbrain provides a model
      system to study a simple axonal projection within the vertebrate central nervous
      system. We show that trochlear motor neurons are born within the isthmic
      organiser and also immediately posterior to it in anterior rhombomere 1. Axons of
      the most anterior cells follow a dorsal projection, which circumnavigates the
      isthmus, while those of more posterior trochlear neurons project anterodorsally
      to enter the isthmus. Once within the isthmus, axons form large fascicles that
      extend to a dorsal exit point. We investigated the possibility that the
      projection of trochlear axons towards the isthmus and their subsequent growth
      within that tissue might depend upon chemoattraction. We demonstrate that both
      isthmic tissue and Fgf8 protein are attractants for trochlear axons in vitro,
      while ectopic Fgf8 causes turning of these axons away from their normal routes in
      vivo. Both inhibition of FGF receptor activation and inhibition of Fgf8 function
      in vitro affect formation of the trochlear projection within explants in a manner
      consistent with a guidance function of Fgf8 during trochlear axon navigation.

PMID- 12403711
TI  - Influence of cell fate mechanisms upon retinal mosaic formation: a modelling
      study.
AB  - Many types of retinal neurone are arranged in a spatially regular manner so that
      the visual scene is uniformly sampled. Several mechanisms are thought to be
      involved in the development of regular cellular positioning. One early-acting
      mechanism is the lateral inhibition of neighbouring cells from acquiring the same
      fate, mediated by Delta-Notch signalling. We have used computer modelling to test
      whether lateral inhibition might transform an initial population of
      undifferentiated cells into more regular populations of two types of
      differentiated cells. Initial undifferentiated cells were positioned randomly,
      subject only to a minimal distance constraint. Each undifferentiated cell then
      acquired either primary or secondary fate using one of several lateral inhibition
      mechanisms. Mosaic regularity was assessed using the regularity index and the
      packing factor. We found that for irregular undifferentiated mosaics, the
      arrangement of resulting primary (but not secondary) fate cells was more regular
      than in the initial undifferentiated population. However, for regular
      undifferentiated mosaics, no further increases in the regularity of the primary
      fate mosaics were observed. We have used this model to test the specific
      hypothesis that on- and off-centre retinal ganglion cells emerge from an initial,
      irregular undifferentiated population of ganglion cells. Lateral inhibition can
      subdivide an initially irregular population into two types of cell that are
      mildly regular. However, lateral inhibition alone is insufficient to produce
      mosaics of the same regularity as observed experimentally. Likewise, and in
      contrast to earlier reports, cell death alone is insufficient to match the
      regularity of experimental mosaics. We conclude that lateral inhibition can
      transform irregular distributions into regular mosaics, upon which subsequent
      processes (such as lateral cell movement or cell death) can further refine mosaic
      regularity.

PMID- 12403712
TI  - Role of a positive regulator of root hair development, CAPRICE, in Arabidopsis
      root epidermal cell differentiation.
AB  - In Arabidopsis, root hairs are formed only from a set of epidermal cells named
      trichoblasts or hair-forming cells. Previous studies showed CAPRICE (CPC)
      promotes differentiation of hair-forming cells by controlling a negative
      regulator, GLABRA2 (GL2), which is preferentially expressed in hairless cells.
      Here, we show that CPC is also predominantly expressed in the hairless cells, but
      not in the neighboring hair-forming cells, and that CPC protein moves to the hair
      forming cells and represses the GL2 expression. We also show that the N terminus
      of bHLH protein interacts with CPC and is responsible for the GL2 expression. We
      propose a model in which CPC plays a key role in the fate-determination of hair
      forming cells.

PMID- 12403713
TI  - Induction and patterning of the telencephalon in Xenopus laevis.
AB  - We report an analysis of the tissue and molecular interplay involved in the early
      specification of the forebrain, and in particular telencephalic, regions of the
      Xenopus embryo. In dissection/recombination experiments, different parts of the
      organizer region were explanted at gastrula stage and tested for their
      inducing/patterning activities on either naive ectoderm or on midgastrula stage
      dorsal ectoderm. We show that the anterior dorsal mesendoderm of the organizer
      region has a weak neural inducing activity compared with the presumptive anterior
      notochord, but is able to pattern either neuralized stage 10.5 dorsal ectoderm or
      animal caps injected with BMP inhibitors to a dorsal telencephalic fate.
      Furthermore, we found that a subset of this tissue, the anterior dorsal endoderm,
      still retains this patterning activity. At least part of the dorsal telencephalic
      inducing activities may be reproduced by the anterior endoderm secreted molecule
      cerberus, but not by simple BMP inhibition, and requires the N-terminal region of
      cerberus that includes its Wnt-binding domain. Furthermore, we show that FGF
      action is both necessary and sufficient for ventral forebrain marker expression
      in neuralized animal caps, and possibly also required for dorsal telencephalic
      specification. Therefore, integration of organizer secreted molecules and of FGF,
      may account for patterning of the more rostral part of Xenopus CNS.

PMID- 12403714
TI  - The Drosophila cytokine receptor Domeless controls border cell migration and
      epithelial polarization during oogenesis.
AB  - In mammals, the JAK/STAT (Janus Kinase/Signal Transducer and Activator of
      Transcription) signaling pathway is activated in response to cytokines and growth
      factors to control blood cell development, proliferation and cell determination.
      In Drosophila, a conserved JAK/STAT signaling pathway controls segmentation in
      embryos, as well as blood cell development and other processes in larvae and
      adults. During embryogenesis, transduction of the Unpaired [Upd; also known as
      Outstretched (Os)] ligand through the JAK/STAT pathway requires Domeless, a
      putative membrane protein with distant homology to vertebrate type I cytokine
      receptors. We have isolated domeless (dome) in a screen to identify genes
      essential in epithelial morphogenesis during oogenesis. The level of dome
      activity is critical for proper border cell migration and is controlled in part
      through a negative feedback loop. In addition to its essential role in border
      cells, we show that dome is required in the germarium for the polarization of
      follicle cells during encapsulation of germline cells. In this process, dome
      controls the expression of the apical determinant Crumbs. In contrast to the
      ligand Upd, whose expression is limited to a pair of polar cells at both ends of
      the egg chamber, dome is expressed in all germline and follicle cells. However,
      the Dome protein is specifically localized at apicolateral membranes and
      undergoes ligand-dependent internalization in the follicle cells. dome mutations
      interact genetically with JAK/STAT pathway genes in border cell migration and
      abolish the nuclear translocation of Stat92E in vivo. We also show that dome
      functions downstream of upd and that both the extracellular and intracellular
      domains of Dome are required for JAK/STAT signaling. Altogether, our data
      indicate that Dome is an essential receptor molecule for Upd and JAK/STAT
      signaling during oogenesis.

PMID- 12403715
TI  - Restoration of synapse formation in Musk mutant mice expressing a Musk/Trk
      chimeric receptor.
AB  - Mice lacking Musk, a muscle-specific receptor tyrosine kinase that is activated
      by agrin, fail to form neuromuscular synapses and consequently die at birth
      because of their failure to move or breathe. We produced mice that express a
      chimeric receptor, containing the juxtamembrane region of Musk and the kinase
      domain of TrkA, selectively in muscle, and we crossed this transgene into Musk
      mutant mice. Expression of this chimeric receptor restores presynaptic and
      postsynaptic differentiation, including the formation of nerve terminal arbors,
      synapse-specific transcription, and clustering of postsynaptic proteins, allowing
      Musk mutant mice to move, breathe and survive as adults. These results show that
      the juxtamembrane region of Musk, including a single phosphotyrosine docking
      site, even in the context of a different kinase domain, is sufficient to activate
      the multiple pathways leading to presynaptic and postsynaptic differentiation in
      vivo. In addition, we find that Musk protein can be clustered at synaptic sites,
      even if Musk mRNA is expressed uniformly in muscle. Moreover, acetylcholine
      receptor clustering and motor terminal branching are restored in parallel,
      indicating that the extent of presynaptic differentiation is matched to the
      extent of postsynaptic differentiation.

PMID- 12403716
TI  - Expression of pair-rule gene homologues in a chelicerate: early patterning of the
      two-spotted spider mite Tetranychus urticae.
AB  - Embryo segmentation has been studied extensively in the fruit fly, Drosophila.
      These studies have demonstrated that a mechanism acting with dual segment
      periodicity is required for correct patterning of the body plan in this insect,
      but the evolutionary origin of the mechanism, the pair-rule system, is unclear.
      We have examined the expression of the homologues of two Drosophila pair-rule
      genes, runt and paired (Pax Group III), in segmenting embryos of the two-spotted
      spider mite (Tetranychus urticae Koch). Spider mites are chelicerates, a group of
      arthropods that diverged from the lineage leading to Drosophila at least 520
      million years ago. In T. urticae, the Pax Group III gene Tu-pax3/7 was expressed
      during patterning of the prosoma, but not the opisthosoma, in a series of stripes
      which appear first in even numbered segments, and then in odd numbered segments.
      The mite runt homologue (Tu-run) in contrast was expressed early in a circular
      domains that resolved into a segmental pattern. The expression patterns of both
      of these genes also indicated they are regulated very differently from their
      Drosophila homologues. The expression pattern of Tu-pax3/7 lends support to the
      possibility that a pair-rule patterning mechanism is active in the segmentation
      pathways of chelicerates.

PMID- 12403717
TI  - Kinesin light chain-independent function of the Kinesin heavy chain in
      cytoplasmic streaming and posterior localisation in the Drosophila oocyte.
AB  - Microtubules and the Kinesin heavy chain, the force-generating component of the
      plus end-directed microtubule motor Kinesin I are required for the localisation
      of oskar mRNA to the posterior pole of the Drosophila oocyte, an essential step
      in the determination of the anteroposterior axis. We show that the Kinesin heavy
      chain is also required for the posterior localisation of Dynein, and for all
      cytoplasmic movements within the oocyte. Furthermore, the KHC localises
      transiently to the posterior pole in an oskar mRNA-independent manner.
      Surprisingly, cytoplasmic streaming still occurs in kinesin light chain null
      mutants, and both oskar mRNA and Dynein localise to the posterior pole. Thus, the
      Kinesin heavy chain can function independently of the light chain in the oocyte,
      indicating that it associates with its cargoes by a novel mechanism.

PMID- 12403718
TI  - Drosophila regulatory factor X is necessary for ciliated sensory neuron
      differentiation.
AB  - Ciliated neurons play an important role in sensory perception in many animals.
      Modified cilia at dendrite endings serve as sites of sensory signal capture and
      transduction. We describe Drosophila mutations that affect the transcription
      factor RFX and genetic rescue experiments that demonstrate its central role in
      sensory cilium differentiation. Rfx mutant flies show defects in chemosensory and
      mechanosensory behaviors but have normal phototaxis, consistent with Rfx
      expression in ciliated sensory neurons and neuronal precursors but not in
      photoreceptors. The mutant behavioral phenotypes are correlated with abnormal
      function and structure of neuronal cilia, as shown by the loss of sensory
      transduction and by defects in ciliary morphology and ultrastructure. These
      results identify Rfx as an essential regulator of ciliated sensory neuron
      differentiation in Drosophila.

PMID- 12403719
TI  - The divergent C. elegans ephrin EFN-4 functions inembryonic morphogenesis in a
      pathway independent of the VAB-1 Eph receptor.
AB  - The C. elegans genome encodes a single Eph receptor tyrosine kinase, VAB-1, which
      functions in neurons to control epidermal morphogenesis. Four members of the
      ephrin family of ligands for Eph receptors have been identified in C. elegans.
      Three ephrins (EFN-1/VAB-2, EFN-2 and EFN-3) have been previously shown to
      function in VAB-1 signaling. We show that mutations in the gene mab-26 affect the
      fourth C. elegans ephrin, EFN-4. We show that efn-4 also functions in embryonic
      morphogenesis, and that it is expressed in the developing nervous system.
      Interestingly, efn-4 mutations display synergistic interactions with mutations in
      the VAB-1 receptor and in the EFN-1 ephrin, indicating that EFN-4 may function
      independently of the VAB-1 Eph receptor in morphogenesis. Mutations in the LAR
      like receptor tyrosine phosphatase PTP-3 and in the Semaphorin-2A homolog MAB-20
      disrupt embryonic neural morphogenesis. efn-4 mutations synergize with ptp-3
      mutations, but not with mab-20 mutations, suggesting that EFN-4 and Semaphorin
      signaling could function in a common pathway or in opposing pathways in C.
      elegans embryogenesis.

PMID- 12403720
TI  - Lineage analysis of the hemangioblast as defined by FLK1 and SCL expression.
AB  - Accumulating studies support the idea that a common progenitor, termed the
      hemangioblast, generates both hematopoietic and endothelial cell lineages. To
      better define the relationship between these cell lineages, we have generated
      knock-in embryonic stem (ES) cells carrying a non-functional human CD4 at the Scl
      locus. By using in vitro differentiated Scl(+/CD4) ES cells, we demonstrate that
      FLK1 and SCL are molecular determinants of the hemangioblast. Furthermore, our
      studies demonstrate that hematopoietic and endothelial cells develop via
      distinct, sequential generation of FLK1 and SCL-expressing cells. FLK1(+)CD4(-)
      cells first arise in developing embryoid bodies. The Scl gene is turned on within
      FLK1(+)CD4(-) cells to give rise to FLK1(+)CD4(+) cells. Alternatively, a
      subpopulation of the initial FLK1(+)CD4(-) cells remains as SCL negative. Within
      the FLK1(+)CD4(+) cells, FLK1 is down regulated to generate FILK1(-)CD4(+) cells.
      Replating studies demonstrate that hematopoietic progenitors are enriched within
      FLK1(+)CD4(+) and FLK1(-)CD4(+) cells, while endothelial cells develop from
      FLK1(+)CD4(+) and FLK1(+)CD4(-) cell populations.

PMID- 12403721
TI  - Evolutionary conserved sequences are required for the insulation of the
      vertebrate Hoxd complex in neural cells.
AB  - Transcriptional regulation of vertebrate Hox genes involves enhancer sequences
      located either inside or outside the gene clusters. In the mouse Hoxd complex,
      for example, series of contiguous genes are coordinately controlled by regulatory
      sequences located at remote distances. However, in different cellular contexts,
      Hox genes may have to be insulated from undesirable external regulatory
      influences to prevent ectopic gene activation, a situation that would likely be
      detrimental to the developing embryo. We show the presence of an insulator
      activity, at one extremity of the Hoxd complex, that is composed of at least two
      distinct DNA elements, one of which is conserved throughout vertebrate species.
      However, deletion of this element on its own did not detectably affect Hoxd gene
      expression, unless another DNA fragment located nearby was removed in cis. These
      results suggest that insulation of this important gene cluster relies, at least
      in part, upon a sequence-specific mechanism that displays some redundancy.

PMID- 12403722
TI  - Gene profiling during neural induction in Xenopus laevis: regulation of BMP
      signaling by post-transcriptional mechanisms and TAB3, a novel TAK1-binding
      protein.
AB  - The earliest decision in vertebrate neural development is the acquisition of a
      neural identity by embryonic ectodermal cells. The default model for neural
      induction postulates that neural fate specification in the vertebrate embryo
      occurs by inhibition of epidermal inducing signals in the gastrula ectoderm. Bone
      morphogenetic proteins (BMPs) act as epidermal inducers, and all identified
      direct neural inducers block BMP signaling either intra- or extracellularly.
      Although the mechanism of action of the secreted neural inducers has been
      elucidated, the relevance of intracellular BMP inhibitors in neural induction is
      not clear. In order to address this issue and to identify downstream targets
      after BMP inhibition, we have monitored the transcriptional changes in ectodermal
      explants neuralized by Smad7 using a Xenopus laevis 5000-clone gastrula-stage
      cDNA microarray. We report the identification and initial characterization of 142
      genes whose transcriptional profiles change in the neuralized explants. In order
      to address the potential involvement during neural induction of genes identified
      in the array, we performed gain-of-function studies in ectodermal explants. This
      approach lead to the identification of four genes that can function as neural
      inducers in Xenopus and three others that can synergize with known neural
      inducers in promoting neural fates. Based on these studies, we propose a role for
      post-transcriptional control of gene expression during neural induction in
      vertebrates and present a model whereby sustained BMP inhibition is promoted
      partly through the regulation of TGFbeta activated kinase (TAK1) activity by a
      novel TAK1-binding protein (TAB3).

PMID- 12403723
TI  - Regulation of the chondrocyte phenotype by beta-catenin.
AB  - beta-Catenin regulates important biological processes, including embryonic
      development and tumorigenesis. We have investigated the role of beta-catenin in
      the regulation of the chondrocyte phenotype. Expression of beta-catenin was high
      in prechondrogenic mesenchymal cells, but significantly decreased in
      differentiated chondrocytes both in vivo and in vitro. Accumulation of beta
      catenin by the inhibition of glycogen synthase kinase-3beta with LiCl inhibited
      chondrogenesis by stabilizing cell-cell adhesion. Conversely, the low level of
      beta-catenin in differentiated articular chondrocytes was increased by post
      translational stabilization during phenotypic loss caused by a serial monolayer
      culture or exposure to retinoic acid or interleukin-1beta. Ectopic expression of
      beta-catenin or inhibition of beta-catenin degradation with LiCl or proteasome
      inhibitor caused de-differentiation of chondrocytes. Transcriptional activation
      of beta-catenin by its nuclear translocation was sufficient to cause phenotypic
      loss of differentiated chondrocytes. Expression pattern of Jun, a known target
      gene of beta-catenin, is essentially the same as that of beta-catenin both in
      vivo and in vitro suggesting that Jun and possibly activator protein 1 is
      involved in the beta-catenin regulation of the chondrocyte phenotype.

PMID- 12403724
TI  - Drug marketing: unsafe at any dose?

PMID- 12403727
TI  - Questions of trust.

PMID- 12403728
TI  - Questions of trust.

PMID- 12403731
TI  - Medical newsletters: can they be trusted?

PMID- 12403732
TI  - The lockout of '62.

PMID- 12403735
TI  - Putting West Nile virus into perspective.

PMID- 12403736
TI  - Risks: absolute or relative?

PMID- 12403737
TI  - Salty broth for salicylate poisoning? Adequacy of overdose management advice in
      the 2001 Compendium of Pharmaceuticals and Specialties.
AB  - BACKGROUND: The Compendium of Pharmaceuticals and Specialties (CPS) is a
      collection of monographs written by pharmaceutical companies and published by the
      Canadian Pharmacists Association. The CPS is widely available and is consulted
      frequently by Canadian physicians. We examined overdose management advice
      contained in the CPS to see whether it reflects current standards. METHODS: We
      restricted our review to 10 classes of medication for which an overdose is
      frequently fatal: acetaminophen, beta-blockers, calcium-channel blockers,
      digoxin, lithium, opioids, salicylates, tricyclic antidepressants, theophylline
      and valproic acid. A panel of 3 toxicologists arrived at a consensus on
      indicated, contraindicated and futile interventions for each of these classes of
      drug. Monographs were then rated for their inclusion of essential interventions
      as excellent (listed all interventions and unique supportive care issues and gave
      correct and complete indications), good (listed the key interventions and gave
      correct and complete indications), fair (listed the key indications but failed to
      give proper indications) or poor (failed to list the key interventions).
      Monographs were also rated on how well they warned against contraindicated
      interventions as excellent (did not advocate any futile or contraindicated
      treatments and warned against contraindicated treatments), good (did not advocate
      any futile or contraindicated treatments), fair (did not advocate any
      contraindicated treatments but did list some simple futile treatments) or poor
      (advocated contraindicated or complicated futile treatments, such as unnecessary
      hemodialysis). We also considered whether the monograph would allow a clinician
      to manage an overdose, whether it served to refresh one's memory and whether it
      was simply misleading or dangerous. RESULTS: We reviewed 119 monographs, of which
      25 (21%) were adequate to allow a clinician to manage an overdose. Another 25
      monographs were not adequate to allow a clinician to manage an overdose but would
      serve to refresh the memory regarding key management points. Sixty monographs
      (50%) contained misleading or dangerous advice. Nine monographs (8%) did not fall
      into any of these categories. In terms of listing essential interventions, 61
      monographs (51%) were poor, 35 (29%) were fair, 22 (18%) were good, and 1 (1%)
      was excellent. For warning against contraindicated interventions, 57 monographs
      (48%) were poor, 9 (8%) were fair, 51 (43%) were good, and 2 (2%) were excellent.
      INTERPRETATION: Overdose management advice in the CPS is inadequate in most cases
      and is misleading or dangerous in half of the monographs examined. These sections
      should be omitted or rewritten to reflect current standards of care. Physicians
      should refer to authoritative sources (e.g., current toxicology texts,
      computerized databases or local poison control centres) for poisoning management
      advice.

PMID- 12403738
TI  - Community-based exercise program reduces risk factors for falls in 65- to 75-year
      old women with osteoporosis: randomized controlled trial.
AB  - BACKGROUND: Exercise programs improve balance, strength and agility in elderly
      people and thus may prevent falls. However, specific exercise programs that might
      be widely used in the community and that might be "prescribed" by physicians,
      especially for patients with osteoporosis, have not been evaluated. We conducted
      a randomized controlled trial of such a program designed specifically for women
      with osteoporosis. METHODS: We identified women 65 to 75 years of age in whom
      osteoporosis had been diagnosed by dual-energy X-ray absorptiometry in our
      hospital between 1996 and 2000 and who were not engaged in regular weekly
      programs of moderate or hard exercise. Women who agreed to participate were
      randomly assigned to participate in a twice-weekly exercise class or to not
      participate in the class. We measured baseline data and, 20 weeks later, changes
      in static balance (by dynamic posturography), dynamic balance (by a timed figure
      eight run) and knee extension strength (by dynamometry). RESULTS: Of 93 women who
      began the trial, 80 completed it. Before adjustment for covariates, the
      intervention group tended to have greater, although nonsignificant, improvements
      in static balance (mean difference 4.8%, 95% confidence interval [CI] -1.3% to
      11.0%), dynamic balance (mean difference 3.3%, 95% CI -1.7% to 8.4%) and knee
      extension strength (mean difference 7.8%, 95% CI -5.4% to 21.0%). Mean crude
      changes in the static balance score were -0.85 (95% CI -2.91 to 1.21) for the
      control group and 1.40 (95% CI -0.66 to 3.46) for the intervention group. Mean
      crude changes in figure-eight velocity (dynamic balance) were 0.08 (95% CI 0.02
      to 0.14) m/s for the control group and 0.14 (95% CI 0.08 to 0.20) m/s for the
      intervention group. For knee extension strength, mean changes were -0.58 (95% CI 
      3.02 to 1.81) kg/m for the control group and 1.03 (95% CI -1.31 to 3.34) kg/m for
      the intervention group. After adjustment for age, physical activity and years of
      estrogen use, the improvement in dynamic balance was 4.9% greater for the
      intervention group than for the control group (p = 0.044). After adjustment for
      physical activity, cognitive status and number of fractures ever, the improvement
      in knee extension strength was 12.8% greater for the intervention group than for
      the control group (p = 0.047). The intervention group also had a 6.3% greater
      improvement in static balance after adjustment for rheumatoid arthritis and
      osteoarthritis, but this difference was not significant (p = 0.06).
      INTERPRETATION: Relative to controls, participants in the exercise program
      experienced improvements in dynamic balance and strength, both important
      determinants of risk for falls, particularly in older women with osteoporosis.

PMID- 12403739
TI  - Preventing fractures by preventing falls in older women.

PMID- 12403740
TI  - An editorial on editorials.

PMID- 12403741
TI  - Should combination therapy with inhaled corticosteroids and long-acting beta2
      agonists be prescribed as initial maintenance treatment for asthma?

PMID- 12403742
TI  - New insights into the mechanisms and management of atrial fibrillation.
AB  - Atrial fibrillation (AF) is a common contributor to cardiovascular morbidity and
      mortality. Two generally acceptable strategies exist for long-term AF management,
      with ongoing studies comparing the overall mortality associated with each. One
      strategy aims to maintain sinus rhythm, with antiarrhythmic agents if necessary,
      thereby preserving physiological cardiac electrical function but exposing the
      patient to the potential side effects of potent drugs. The second approach is to
      control the ventricular rate and prevent thromboembolic complications with
      anticoagulants, leaving the patient with AF. Both beta-blocking agents and
      calcium antagonists are more effective than digoxin in achieving rate control.
      Several nonpharmacological therapies including catheter ablation, implantable
      devices and surgical interventions show promise for rate control and maintenance
      of sinus rhythm. This paper provides an overview of new developments in
      pharmacological and nonpharmacological therapy. Key features of recently
      published clinical guidelines, including a unified classification scheme for AF
      and issues relating to rate control and maintenance of sinus rhythm, are
      considered. In addition, preliminary results from the recently presented AFFIRM
      study, the largest AF trial to date, are summarized. Finally, we discuss recent
      insights into the basic mechanisms underlying AF that have potentially
      significant clinical implications.

PMID- 12403743
TI  - Medical genetics: 3. An approach to the adult with a genetic disorder.
AB  - Many genetic disorders do not manifest themselves until the adult years. Such
      disorders often involve multiple genetic factors interacting with multiple
      environmental factors, over time, to produce a phenotype. This paper reviews the
      modes of inheritance of genetic disorders and describes the types of genetic
      testing that are currently available. It offers clues that should lead physicians
      to suspect that an adult patient might have a genetic disorder and raises issues
      that should be considered in counselling the patient about genetic testing.
      Resources for patients and their family physicians are also discussed.

PMID- 12403744
TI  - Genetics 101: polymerase chain reaction.

PMID- 12403745
TI  - Brief safety updates: acetaminophen, ASA and kava.

PMID- 12403748
TI  - Warfarin, acetylsalicylic acid or both?

PMID- 12403746
TI  - Dental caries: a nation divided.

PMID- 12403749
TI  - Symmetrical peripheral gangrene: a rare but dreadful complication of sepsis.

PMID- 12403753
TI  - Large numbers of would-be Canadian MDs migrating down under.

PMID- 12403755
TI  - Forget US politicians' promises--Canada still cheap-drug mecca.

PMID- 12403759
TI  - Canada must bolster its GM food regulations, not add labels: report.

PMID- 12403765
TI  - The pentose phosphate pathway.

PMID- 12403766
TI  - The early influence of the Institut Pasteur on the emergence of molecular
      biology.

PMID- 12403767
TI  - A gold mine of fascinating enzymes: those remarkable, strictly anaerobic
      bacteria, Methanococcus vannielii and Clostridium sticklandii.

PMID- 12403768
TI  - SHP2 and SOCS3 contribute to Tyr-759-dependent attenuation of interleukin-6
      signaling through gp130.
AB  - Interleukin-6 (IL-6) activates the Jak/STAT pathway as well as the mitogen
      activated protein kinase cascade. Tyrosine 759 of the IL-6 signal-transducing
      receptor subunit gp130 has been identified as being involved in negative
      regulation of IL-6-induced gene induction and activation of the Jak/STAT pathway.
      Because this site is known to be a recruitment motif for the protein-tyrosine
      phosphatase SHP2, it has been suggested that SHP2 is the mediator of tyrosine 759
      dependent signal attenuation. We recently observed that the suppressor of
      cytokine-signaling SOCS3 also acts through the tyrosine motif 759 of gp130.
      However, the relative contributions of SHP2 and SOCS3 to the repression of IL-6
      signaling are not understood. Therefore, we designed experiments allowing the
      independent recruitment of each of these proteins to the IL-6-receptor complex.
      We show that receptor- and membrane-targeted SHP2 counteracts IL-6 signaling
      independent of SOCS3 binding to gp130. On the other hand, SOCS3 inhibits
      signaling in cells expressing a truncated SHP2 protein, which is not recruited to
      gp130. These data suggest, that there are two, largely distinct modes of negative
      regulation of gp130 activity, despite the fact that both SOCS3 and SHP2 are
      recruited to the same site within gp130.

PMID- 12403769
TI  - Translational regulation of human neuronal nitric-oxide synthase by an
      alternatively spliced 5'-untranslated region leader exon.
AB  - Expression of the neuronal nitric-oxide synthase (nNOS) mRNA is subject to
      complex cell-specific transcriptional regulation, which is mediated by
      alternative promoters. Unexpectedly, we identified a 89-nucleotide alternatively
      spliced exon located in the 5'-untranslated region between exon 1 variants and a
      common exon 2 that contains the translational initiation codon. Alternative
      splicing events that do not affect the open reading frame are distinctly uncommon
      in mammals; therefore, we assessed its functional relevance. Transient
      transfection of reporter RNAs performed in a variety of cell types revealed that
      this alternatively spliced exon acts as a potent translational repressor. Stably
      transfected cell lines confirmed that the alternatively spliced exon inhibited
      translation of the native nNOS open reading frame. Reverse transcription-PCR and
      RNase protection assays indicated that nNOS mRNAs containing this exon are common
      and expressed in both a promoter-specific and tissue-restricted fashion.
      Mutational analysis identified the functional cis-element within this novel exon,
      and a secondary structure prediction revealed that it forms a putative stem-loop.
      RNA electrophoretic mobility shift assay techniques revealed that a specific
      cytoplasmic RNA-binding complex interacts with this motif. Hence, a unique
      splicing event within a 5'-untranslated region is demonstrated to introduce a
      translational control element. This represents a newer model for the
      translational control of a mammalian mRNA.

PMID- 12403770
TI  - Analysis of ligand-stimulated CC chemokine receptor 5 (CCR5) phosphorylation in
      intact cells using phosphosite-specific antibodies.
AB  - Human CC chemokine receptor 5 (CCR5), a member of the superfamily of G protein
      coupled receptors, regulates the activation and directed migration of leukocytes
      and serves as the main coreceptor for the entry of R5 tropic strains of human
      immunodeficiency viruses. We have previously shown that RANTES/CCL5 binding to
      CCR5 induces GPCR kinase (GRK)- and protein kinase C (PKC)-mediated
      phosphorylation of four distinct C-terminal serine residues. To study these
      phosphorylation events in vivo, we have generated monoclonal antibodies, which
      specifically react only with either phosphorylated or nonphosphorylated CCR5.
      These phosphosite-specific antibodies reveal that following ligand stimulation of
      the receptor serine 337 is exclusively phosphorylated by a PKC-mediated
      mechanism, while GRKs phosphorylate serine 349. GRK-mediated receptor
      phosphorylation proceeds in a regular time-dependent manner (t(12) approximately
      2 min) with an apparent EC(50) of 5 nm. In contrast, PKC phosphorylates serine
      337 at 50-fold lower concentrations and in a very rapid, albeit transient manner.
      Protein phosphatases that are active at neutral pH and are inhibited by okadaic
      acid rapidly dephosphorylate phosphoserine 337, but less efficiently
      phosphoserine 349, in intact cells and in an in vitro assay. Immunofluorescence
      microscopy demonstrates that phosphorylated receptors accumulate in a perinuclear
      compartment, which resembles recycling endosomes. This study is the first to
      analyze in detail the spatial and temporal dynamics of GRK- versus PKC-mediated
      phosphorylation of a G protein-coupled receptor and its subsequent
      dephosphorylation on the level of individual phosphorylation sites.

PMID- 12403771
TI  - Orientation-dependent influence of an intergenic enhancer on the promoter
      activity of the divergently transcribed mouse Shsp/alpha B-crystallin and
      Mkbp/HspB2 genes.
AB  - The mouse Shsp/alphaB-crystallin and Mkbp/HspB2 genes are closely linked and
      divergently transcribed. In this study, we have analyzed the contribution of the
      intergenic enhancer to Shsp/alphaB-crystallin and Mkbp/HspB2 promoter activity
      using dual-reporter vectors in transient transfection and transgenic mouse
      experiments. Deletion of the enhancer reduced Shsp/alphaB-crystallin promoter
      activity by 30- and 93-fold and Mkbp/HspB2 promoter activity by 6- and 10-fold in
      transiently transfected mouse lens alpha-TN4 and myoblast C2C12 cells,
      respectively. Surprisingly, inversion of the enhancer reduced Shsp/alphaB
      crystallin promoter activity by 17-fold, but did not affect Mkbp/HspB2 promoter
      activity in the transfected cells. In contrast, enhancer activity was orientation
      independent in combination with a heterologous promoter in transfected cells.
      Transgenic mouse experiments established the orientation dependence and
      Shsp/alphaB-crystallin promoter preference of the intergenic enhancer in its
      native context. The orientation dependence and preferential effect of the
      Shsp/alphaB-crystallin enhancer on the Shsp/alphaB-crystallin promoter provide an
      example of adaptive changes in gene regulation accompanying the functional
      diversification of duplicated genes during evolution.

PMID- 12403772
TI  - BMS-345541 is a highly selective inhibitor of I kappa B kinase that binds at an
      allosteric site of the enzyme and blocks NF-kappa B-dependent transcription in
      mice.
AB  - The signal-inducible phosphorylation of serines 32 and 36 of I kappa B alpha is
      critical in regulating the subsequent ubiquitination and proteolysis of I kappa B
      alpha, which then releases NF-kappa B to promote gene transcription. The
      multisubunit I kappa B kinase responsible for this phosphorylation contains two
      catalytic subunits, termed I kappa B kinase (IKK)-1 and IKK-2. BMS-345541 (4(2'
      aminoethyl)amino-1,8-dimethylimidazo(1,2-a)quinoxaline) was identified as a
      selective inhibitor of the catalytic subunits of IKK (IKK-2 IC(50) = 0.3 microm,
      IKK-1 IC(50) = 4 microm). The compound failed to inhibit a panel of 15 other
      kinases and selectively inhibited the stimulated phosphorylation of I kappa B
      alpha in cells (IC(50) = 4 microm) while failing to affect c-Jun and STAT3
      phosphorylation, as well as mitogen-activated protein kinase-activated protein
      kinase 2 activation in cells. Consistent with the role of IKK/NF-kappa B in the
      regulation of cytokine transcription, BMS-345541 inhibited lipopolysaccharide
      stimulated tumor necrosis factor alpha, interleukin-1 beta, interleukin-8, and
      interleukin-6 in THP-1 cells with IC(50) values in the 1- to 5-microm range.
      Although a Dixon plot of the inhibition of IKK-2 by BMS-345541 showed a non
      linear relationship indicating non-Michaelis-Menten kinetic binding, the use of
      multiple inhibition analyses indicated that BMS-345541 binds in a mutually
      exclusive manner with respect to a peptide inhibitor corresponding to amino acids
      26-42 of I kappa B alpha with Ser-32 and Ser-36 changed to aspartates and in a
      non-mutually exclusive manner with respect to ADP. The opposite results were
      obtained when studying the binding to IKK-1. A binding model is proposed in which
      BMS-345541 binds to similar allosteric sites on IKK-1 and IKK-2, which then
      affects the active sites of the subunits differently. BMS-345541 was also shown
      to have excellent pharmacokinetics in mice, and peroral administration showed the
      compound to dose-dependently inhibit the production of serum tumor necrosis
      factor alpha following intraperitoneal challenge with lipopolysaccharide. Thus,
      the compound is effective against NF-kappa B activation in mice and represents an
      important tool for investigating the role of IKK in disease models.

PMID- 12403773
TI  - Hydrogen peroxide-coupled cis-diol formation catalyzed by naphthalene 1,2
      dioxygenase.
AB  - Naphthalene 1,2-dioxygenase (NDOS) catalyzes the NAD(P)H and O(2)-dependent
      oxidation of naphthalene to (+)-cis-(1R,2S)-dihydroxy-1,2-dihydronaphthalene.
      NDOS consists of three protein components: a flavo-[2Fe-2S] reductase (NDR), a
      ferredoxin electron transfer protein (NDF), and an (alphabeta)(3) oxygenase (NDO)
      containing a mononuclear iron site and a Rieske-type [2Fe-2S] cluster in each
      alpha-subunit. The active site is built across a subunit-subunit boundary, and
      each subunit contributes one type of metal center. Our previous studies have
      shown that NDO with both metal centers reduced is capable of an O(2)-coupled
      single turnover to yield the correct cis-diol product in the absence of the NDR
      and NDF components (Wolfe, M. D., Parales, J. V., Gibson, D. T., and Lipscomb, J.
      D. (2001) J. Biol. Chem. 276, 1945-1953). It is shown here that addition of
      H(2)O(2) to NDO allows reaction with naphthalene to rapidly yield the correct
      product in a "peroxide shunt" reaction that does not require a reduced Rieske
      cluster. The mononuclear Fe(2+) center is oxidized during turnover, while the
      Rieske cluster remains in the oxidized state. Peroxide shunt turnover in the
      presence of (18)O-labeled H(2)O(2), H(2)O, or O(2) shows that both oxygen atoms
      in the product derive primarily from H(2)O(2). The peroxide shunt halts after one
      turnover despite the presence of excess H(2)O(2) and naphthalene, but this is not
      the result of enzyme inactivation. Rather, it appears that the product cannot be
      released when the mononuclear iron is in the Fe(3+) state, blocking a second
      turnover. This work supports the hypotheses that the cis-dihydroxylation activity
      of NDOS requires only the NDO component, that a peroxo intermediate is formed
      during normal catalysis, and that product release requires an additional reducing
      equivalent beyond those necessary for the first turnover.

PMID- 12403774
TI  - Mitochondrial outer membrane permeability change and hypersensitivity to
      digitonin early in staurosporine-induced apoptosis.
AB  - We have shown here that the apoptosis inducer staurosporine causes an early
      decrease in the endogenous respiration rate in intact 143B.TK(-) cells. On the
      other hand, the activity of cytochrome c oxidase is unchanged for the first 8 h
      after staurosporine treatment, as determined by oxygen consumption measurements
      in intact cells. The decrease in the endogenous respiration rate precedes the
      release of cytochrome c from mitochondria. Moreover, we have ruled out caspases,
      permeability transition, and protein kinase C inhibition as being responsible for
      the decrease in respiration rate. Furthermore, overexpression of the gene for Bcl
      2 does not prevent the decrease in respiration rate. The last finding suggests
      that Bcl-2 acts downstream of the perturbation in respiration. The evidence of
      normal enzymatic activities of complex I and complex III in staurosporine-treated
      143B.TK(-) osteosarcoma cells indicates that the cause of the respiration
      decrease is probably an alteration in the permeability of the outer mitochondrial
      membrane. Presumably, the voltage-dependent anion channel closes, thereby
      preventing ADP and oxidizable substrates from being taken up into mitochondria.
      This interpretation was confirmed by another surprising finding, namely that, in
      staurosporine-treated 143B.TK(-) cells permeabilized with digitonin at a
      concentration not affecting the mitochondrial membranes in naive cells, the outer
      mitochondrial membrane loses its integrity; this leads to a reversal of its
      impermeability to exogenous substrates. The loss of outer membrane integrity
      leads also to a massive premature release of cytochrome c from mitochondria. Most
      significantly, Bcl-2 overexpression prevents the staurosporine-induced
      hypersensitivity of the outer membrane to digitonin. Our experiments have thus
      revealed early changes in the outer mitochondrial membrane, which take place long
      before cytochrome c is released from mitochondria in intact cells.

PMID- 12403775
TI  - Deficient in DNA methylation 1 (DDM1) defines a novel family of chromatin
      remodeling factors.
AB  - Deficient in DNA Methylation 1 (DDM1) protein is required to maintain the DNA
      methylation status of Arabidopsis thaliana. DDM1 is a member of the broad
      SWI2/SNF2 protein family. Because of its phylogenetic position, DDM1 has been
      speculated to act as a chromatin-remodeling factor. Here we used a purified
      recombinant DDM1 protein to investigate whether it can remodel chromatin in
      vitro. We show that DDM1 is an ATPase stimulated by both naked and nucleosomal
      DNA. DDM1 binds to the nucleosome and promotes chromatin remodeling in an ATP
      dependent manner. Specifically, it induces nucleosome repositioning on a short
      DNA fragment. The enzymatic activity of DDM1 is not affected by DNA methylation.
      The relevance of these findings to the in vivo role of DDM1 is discussed.

PMID- 12403776
TI  - DnaK promotes the selective export of outer membrane protein precursors in SecA
      deficient Escherichia coli.
AB  - Consistent with many other results indicating that SecA plays an essential role
      in the translocation of presecretory proteins across the Escherichia coli inner
      membrane, we previously found that a approximately 95% depletion of SecA
      completely blocks the export of periplasmic proteins in vivo. Surprisingly, we
      found that about 25% of the outer membrane protein (OMP) OmpA synthesized after
      SecA depletion was gradually translocated across the inner membrane. In this
      study we analyzed the export of several other OMPs after SecA depletion. We found
      that 25-50% of each OMP as well as an OmpA-alkaline phosphatase fusion protein
      was exported from SecA-deficient cells. This partial export was completely
      abolished by the SecA inhibitor sodium azide and therefore still required the
      participation of SecA. Examination of a variety of OmpA derivatives, however,
      ruled out the possibility that OMPs are selectively translocated in SecA
      deficient cells because SecA binds to their N termini with unusually high
      affinity. Export after SecA depletion was observed in cells that lack SecB, the
      primary targeting factor for OMPs, but was abolished by partial inactivation of
      DnaK. Furthermore, OmpA could be isolated in a stable complex with DnaK. The data
      strongly suggest that OMPs require only a relatively low level of translocase
      activity to cross the inner membrane because they can be preserved in a prolonged
      export-competent state by DnaK.

PMID- 12403777
TI  - TcUBP-1, an mRNA destabilizing factor from trypanosomes, homodimerizes and
      interacts with novel AU-rich element- and Poly(A)-binding proteins forming a
      ribonucleoprotein complex.
AB  - Trypanosomes, protozoan parasites causing worldwide infections in human and
      animals, mostly regulate protein expression through post-transcriptional
      mechanisms and not at the transcription initiation level. We have previously
      identified a Trypanosoma cruzi RNA-binding protein named TcUBP-1. This protein is
      involved in mRNA destabilization in vivo through binding to AU-rich elements in
      the 3'-untranslated region of SMUG mucin mRNAs (D'Orso, I., and Frasch, A. C.
      (2001) J. Biol. Chem. 276, 34801-34809). In this work we show that TcUBP-1 is
      part of an approximately 450-kDa ribonucleoprotein complex with a poly(A)-binding
      protein and a novel 18-kDa RNA-binding protein, named TcUBP-2. Recombinant TcUBP
      1 and TcUBP-2 proteins recognize U-rich RNAs with similar specificity and
      affinity through the approximately 92-amino acid RNA recognition motif. TcUBPs
      can homo- and heterodimerize in vitro through the glycine-rich C-terminal region.
      This interaction was also detected in vivo by co-immunoprecipitation of the
      ribonucleoprotein complex and using yeast two-hybrid assay. The poly(A)-binding
      protein identified was shown to disrupt the formation of TcUBP-1, but not TcUBP
      2, homodimers in vitro. The possible role of TcUBP-1 ligands in the pathways that
      govern mRNA-stability and stage-specific expression in trypanosomes is discussed.

PMID- 12403778
TI  - Endotoxin contamination in recombinant human heat shock protein 70 (Hsp70)
      preparation is responsible for the induction of tumor necrosis factor alpha
      release by murine macrophages.
AB  - Using commercially available recombinant human heat shock protein 70 (rhHsp70),
      recent studies have shown that rhHsp70 could induce the production of tumor
      necrosis factor alpha (TNFalpha) by macrophages and monocytes in a manner similar
      to lipopolysaccharide (LPS) e.g. via CD14 and Toll-like receptor 4-mediated
      signal transduction pathway. In the current study, we demonstrated that a highly
      purified rhHsp70 preparation (designated as rhHsp70-1) with a LPS content of 1.4
      pg/microg was unable to induce TNFalpha release by RAW264.7 murine macrophages at
      concentrations up to 5 microg/ml. In contrast, a less purified rhHsp70
      preparation (designated as rhHsp70-2) at 1 microg/ml with a LPS content of 0.2
      ng/microg was able to induce TNFalpha release to the same extent as that induced
      by 0.2 ng/ml LPS. Failure of rhHsp70-1 to induce TNFalpha release was not because
      of defective physical properties since rhHsp70-1 and rhHsp70-2 contained
      identical hsp70 content as determined by SDS gels stained with Coomassie Blue and
      Western blots probed with an anti-rhHsp70 antibody. Both rhHsp70 preparations
      also had similar enzymatic activities as judged by their ability to remove
      clathrin from clathrin-coated vesicles. Removal of LPS from rhHsp70-2 by
      polymyxin B-agarose column or direct addition of polymyxin B to the incubation
      medium essentially eliminated the TNFalpha-inducing activity of rhHsp70-2. The
      addition of LPS at the concentration found in rhHsp70-2 to rhHsp70-1 resulted in
      the same TNFalpha-inducing activity as observed with rhHsp70-2. The TNFalpha
      inducing activities of rhHsp-2, LPS alone, and LPS plus rhHsp70-1 were all
      equally sensitive to heat inactivation. These results suggest that rhHsp-70 does
      not induce TNFalpha release from murine macrophages and that the observed
      TNFalpha-inducing activity in the rhHsp70-2 preparation is entirely due to the
      contaminating LPS.

PMID- 12403779
TI  - The cystic fibrosis transmembrane conductance regulator interacts with and
      regulates the activity of the HCO3- salvage transporter human Na+-HCO3-
      cotransport isoform 3.
AB  - Cystic fibrosis transmembrane conductance regulator (CFTR) regulates both HCO(3)(
      ) secretion and HCO(3)(-) salvage in secretory epithelia. At least two luminal
      transporters mediate HCO(3)(-) salvage, the Na(+)/H(+) exchanger (NHE3) and the
      Na(+)-HCO(3)(-) cotransport (NBC3). In a previous work, we show that CFTR
      interacts with NHE3 to regulate its activity (Ahn, W., Kim, K. W., Lee, J. A.,
      Kim, J. Y., Choi, J. Y., Moe, O. M., Milgram, S. L., Muallem, S., and Lee, M. G.
      (2001) J. Biol. Chem. 276, 17236-17243). In this work, we report that transient
      or stable expression of human NBC3 (hNBC3) in HEK cells resulted in a Na(+)
      dependent, DIDS (4,4'-diisothiocyanostilbene-2,2'-disulfonic acid)- and 5
      ethylisopropylamiloride-insensitive HCO(3)(-) transport. Stimulation of CFTR with
      forskolin markedly inhibited NBC3 activity. This inhibition was prevented by the
      inhibition of protein kinase A. NBC3 and CFTR could be reciprocally
      coimmunoprecipitated from transfected HEK cells and from the native pancreas and
      submandibular and parotid glands. Precipitation of NBC3 or CFTR from transfected
      HEK293 cells and from the pancreas and submandibular gland also
      coimmunoprecipitated EBP50. Glutathione S-transferase-EBP50 pulled down CFTR and
      hNBC3 from cell lysates when expressed individually and as a complex when
      expressed together. Notably, the deletion of the C-terminal PDZ binding motifs of
      CFTR or hNBC3 prevented coimmunoprecipitation of the proteins and inhibition of
      hNBC3 activity by CFTR. We conclude that CFTR and NBC3 reside in the same HCO(3)(
      )-transporting complex with the aid of PDZ domain-containing scaffolds, and this
      interaction is essential for regulation of NBC3 activity by CFTR. Furthermore,
      these findings add additional evidence for the suggestion that CFTR regulates the
      overall trans-cellular HCO(3)(-) transport by regulating the activity of all
      luminal HCO(3)(-) secretion and salvage mechanisms of secretory epithelial cells.

PMID- 12403780
TI  - The protein kinase C pathway plays a central role in the fibroblast growth factor
      stimulated expression and transactivation activity of Runx2.
AB  - Fibroblast growth factor (FGF)/FGF receptor (FGFR) signaling induces the
      expression of Runx2, a key transcription factor in osteoblast differentiation,
      but little is known about the molecular signaling mechanisms that mediate this.
      Here we examined the role of the protein kinase C (PKC) pathway in regulating
      Runx2 gene expression and its transactivation function. Treatment with FGF2 or
      FGF4, or transfection with a vector expressing a mutant FGFR2 that is
      constitutively activated in the absence of ligand, strongly stimulates Runx2
      expression. Electrophoretic mobility shift assays also showed that FGF2 treatment
      increases the specific binding of Runx2 to the cognate response element in the
      osteocalcin gene promoter. Blocking PKC completely inhibited FGF2-induced Runx2
      expression, whereas mitogen-activate protein kinase inhibitors had no effect. The
      FGF/FGFR-stimulated 6xOSE2 promoter activity was also blocked by inhibiting PKC,
      as was the FGF2 stimulation of the DNA-binding activity of Runx2. Experiments
      with PKC isoform-specific inhibitors and dominant negative isoforms of PKC
      indicate that PKCdelta is one of key isoforms involved in the FGF2-stimulated
      Runx2 expression. In addition, experiments with Runx2-knockout cells showed that,
      although the PKC pathway largely regulates FGF2-stimulated Runx2 activity by up
      regulating Runx2 expression, it also modifies Runx2 protein post-translationally
      and thereby increases its transcriptional activity. Thus, we show for the first
      time that FGF/FGFR signaling stimulates the DNA-binding and transcriptional
      activities of Runx2 as well as its expression, and these are largely regulated by
      the PKC pathway.

PMID- 12403781
TI  - DNA damage-induced inhibition of securin expression is mediated by p53.
AB  - Tumor suppressor p53 induces the cellular response to DNA damage mainly by
      regulating expression of its downstream target genes. The human securin is an
      anaphase inhibitor, preventing premature chromosome separation through inhibition
      of separase activity. It is also known as the product of the human pituitary
      tumor-transforming gene, pttg, a proto-oncogene. Here we report that the
      expression of human securin is suppressed in cells treated with the DNA-damaging
      drugs doxorubicin and bleomycin. This suppression requires functional p53.
      Analysis of the human securin promoter reveals that DNA-binding sites for Sp1 and
      NF-Y are both required for activation of securin expression; however, only the NF
      Y site is essential for the suppression by p53. Our study indicates that securin
      is a p53 target gene and may play a role in p53-mediated cellular response to DNA
      damage.

PMID- 12403782
TI  - Molecular basis of leukocyte rolling on PSGL-1. Predominant role of core-2 O
      glycans and of tyrosine sulfate residue 51.
AB  - Interactions between the leukocyte adhesion receptor L-selectin and P-selectin
      glycoprotein ligand-1 play an important role in regulating the inflammatory
      response by mediating leukocyte tethering and rolling on adherent leukocytes. In
      this study, we have examined the effect of post-translational modifications of
      PSGL-1 including Tyr sulfation and presentation of sialylated and fucosylated O
      glycans for L-selectin binding. The functional importance of these modifications
      was determined by analyzing soluble L-selectin binding and leukocyte rolling on
      CHO cells expressing various glycoforms of PSGL-1 or mutant PSGL-1 targeted at N
      terminal Thr or Tyr residues. Simultaneous expression of core-2 beta1,6-N
      acetylglucosaminyltransferase and fucosyltransferase VII was required for optimal
      L-selectin binding to PSGL-1. Substitution of Thr-57 by Ala but not of Thr-44,
      strongly decreased L-selectin binding and leukocyte rolling on PSGL-1.
      Substitution of Tyr by Phe revealed that PSGL-1 Tyr-51 plays a predominant role
      in mediating L-selectin binding and leukocyte rolling whereas Tyr-48 has a minor
      role, an observation that contrasts with the pattern seen for the interactions
      between PSGL-1 and P-selectin where Tyr-48 plays a key role. Molecular modeling
      analysis of L-selectin and P-selectin interactions with PSGL-1 further supported
      these observations. Additional experiments showed that core-2 O-glycans attached
      to Thr-57 were also of critical importance in regulating the velocity and
      stability of leukocyte rolling. These observations pinpoint the structural
      characteristics of PSGL-1 that are required for optimal interactions with L
      selectin and may be responsible for the specific kinetic and mechanical bond
      properties of the L-selectin-PSGL-1 adhesion receptor-counterreceptor pair.

PMID- 12403783
TI  - The transcriptional coactivator CREB-binding protein cooperates with STAT1 and NF
      kappa B for synergistic transcriptional activation of the CXC ligand 9/monokine
      induced by interferon-gamma gene.
AB  - Signal transducers and activators of transcription 1 (STAT1) and NF-kappaB
      cooperatively regulate the expression of many inflammatory genes. In the present
      study, we demonstrate that the transcriptional coactivator CREB-binding protein
      (CBP) mediated the STAT1/NF-kappaB synergy for transcription of the gene for CXC
      ligand 9 (CXCL9), an interferon-gamma (IFN-gamma)-inducible chemokine. Reporter
      gene analysis showed that expression of CBP potentiated IFN-gamma and tumor
      necrosis factor (TNFalpha)-induced promoter activity and that the CBP-mediated
      synergy depended upon STAT1- and NF-kappaB-binding sites in the promoter.
      Experiments with CBP mutants indicated that the N-terminal and C-terminal regions
      were necessary for the transcriptional synergy, although the histone
      acetyltransferase activity of CBP was dispensable. A co-immunoprecipitation assay
      demonstrated that STAT1 and NF-kappaB RelA (p65) simultaneously associated with
      CBP in vivo. Furthermore, chromatin immunoprecipitation revealed that, although
      costimulation with IFN-gamma and TNFalpha did not cooperatively enhance the
      levels of acetylated histones, it did result in increased recruitment of STAT1,
      CBP, and RNA polymerase II at the promoter region of the CXCL 9 gene. Together,
      these results demonstrate that the STAT1/NF-kappaB-dependent transcriptional
      synergy could result from the enhanced recruitment of RNA polymerase II complex
      to the promoter via simultaneous interaction of CBP with STAT1 and NF-kappaB.

PMID- 12403784
TI  - Regulation of the inward rectifying properties of G-protein-activated inwardly
      rectifying K+ (GIRK) channels by Gbeta gamma subunits.
AB  - Gbetagamma subunits are known to bind to and activate G-protein-activated
      inwardly rectifying K(+) channels (GIRK) by regulating their open probability and
      bursting behavior. Studying G-protein regulation of either native GIRK (I(KACh))
      channels in feline atrial myocytes or heterologously expressed GIRK1/4 channels
      in Chinese hamster ovary cells and HEK 293 cells uncovered a novel Gbetagamma
      subunit mediated regulation of the inwardly rectifying properties of these
      channels. I(KACh) activated by submaximal concentrations of acetylcholine
      exhibited a approximately 2.5-fold stronger inward rectification than I(KACh)
      activated by saturating concentrations of acetylcholine. Similarly, the inward
      rectification of currents through GIRK1/4 channels expressed in HEK cells was
      substantially weakened upon maximal stimulation with co-expressed Gbetagamma
      subunits. Analysis of the outward current block underlying inward rectification
      demonstrated that the fraction of instantaneously blocked channels was reduced
      when Gbetagamma was over-expressed. The Gbetagamma induced weakening of inward
      rectification was associated with reduced potencies for Ba(2+) and Cs(+) to block
      channels from the extracellular side. Based on these results we propose that
      saturation of the channel with Gbetagamma leads to a conformational change within
      the pore of the channel that reduced the potency of extracellular cations to
      block the pore and increased the fraction of channels inert to a pore block in
      outward direction.

PMID- 12403785
TI  - Phospholipid-induced monomerization and signal-peptide-induced oligomerization of
      SecA.
AB  - The SecA ATPase drives the processive translocation of the N terminus of secreted
      proteins through the cytoplasmic membrane in eubacteria via cycles of binding and
      release from the SecYEG translocon coupled to ATP turnover. SecA forms a
      physiological dimer with a dissociation constant that has previously been shown
      to vary with temperature and ionic strength. We now present data showing that the
      oligomeric state of SecA in solution is altered by ligands that it interacts with
      during protein translocation. Analytical ultracentrifugation, chemical cross
      linking, and fluorescence anisotropy measurements show that the physiological
      dimer of SecA is monomerized by long-chain phospholipid analogues. Addition of
      wild-type but not mutant signal sequence peptide to these SecA monomers
      redimerizes the protein. Physiological dimers of SecA do not change their
      oligomeric state when they bind signal sequence peptide in the compact, low
      temperature conformational state but polymerize when they bind the peptide in the
      domain-dissociated, high-temperature conformational state that interacts with
      SecYEG. This last result shows that, at least under some conditions, signal
      peptide interactions drive formation of new intermolecular contacts distinct from
      those stabilizing the physiological dimer. The observations that signal peptides
      promote conformationally specific oligomerization of SecA while phospholipids
      promote subunit dissociation suggest that the oligomeric state of SecA could
      change dynamically during the protein translocation reaction. Cycles of SecA
      subunit recruitment and dissociation could potentially be employed to achieve
      processivity in polypeptide transport.

PMID- 12403786
TI  - The tight junction protein ZO-2 localizes to the nucleus and interacts with the
      heterogeneous nuclear ribonucleoprotein scaffold attachment factor-B.
AB  - Zonula occludens proteins (ZOPs), currently comprising ZO-1, ZO-2, and ZO-3,
      belong to the family of membrane-associated guanylate kinase homologue (MAGUK)
      proteins that are involved in the organization of epithelial and endothelial
      intercellular junctions. ZOPs bind to the cytoplasmic C termini of junctional
      transmembrane proteins linking them to the actin cytoskeleton. They are
      characterized by several conserved modules, including three PDZ domains, one SH3
      domain, and a guanylate kinase-like domain, elements indicating that ZOPs may
      serve multiple purposes. Interestingly, ZOPs contain some unique motifs not
      shared by other MAGUK family members, including nuclear localization and nuclear
      export signals and a leucine zipper-like sequence. Their potential involvement in
      cell growth and proliferation has been suggested earlier based on the observation
      that the N-terminal half of ZOPs displays significant similarity to the product
      of the Drosophila tumor suppressor gene lethal(1)discs-large (dlg). The nuclear
      targeting of ZOPs in subconfluent epithelial cell cultures is well documented,
      although the action of the junctional MAGUKs in the nucleus has remained elusive.
      Here we show for the first time that nuclear ZO-2 directly interacts with the DNA
      binding protein scaffold attachment factor-B (SAF-B). Our results from two-hybrid
      assays and in vivo co-immunoprecipitation studies provide evidence to suggest
      that ZO-2 associates with the C-terminal portion of SAF-B via its PDZ-1 domain.
      We further demonstrate that enhanced green fluorescent protein (EGFP)- and DsRed
      tagged ZO-2 and SAF-B fusion proteins partially co-localize in nuclei of
      transfected epithelial cells. As shown by laser confocal microscopy and
      epifluorescent analysis, nuclear ZO-2 is present in epithelial and endothelial
      cells, particularly in response to environmental stress conditions.
      Interestingly, no association of SAF-B with ZO-1 was found, which supports the
      notion that junctional MAGUKs serve nonredundant functions.

PMID- 12403787
TI  - Adenovirus-mediated hepatocyte growth factor expression in mouse islets improves
      pancreatic islet transplant performance and reduces beta cell death.
AB  - Hepatocyte growth factor (HGF) increases beta cell proliferation and function in
      rat insulin promoter (RIP)-targeted transgenic mice. RIP-HGF mouse islets also
      function superiorly to normal islets in a transplant setting. Here, we aimed to
      determine whether viral gene transfer of the HGF gene into mouse islets ex vivo
      could enhance the performance of normal islets in a streptozotocin-diabetic
      severe combined immunodeficient mouse marginal islet mass model in which 300
      uninfected or adenovirus (Adv) LacZ-transduced islet equivalents were
      insufficient to correct hyperglycemia. In dramatic contrast, 300 AdvHGF
      transduced islet equivalents promptly (day 1) and significantly (p < 0.01)
      decreased random non-fasting blood glucose levels, from 351 +/- 20 mg/dl to an
      average of 191 +/- 7 mg/dl over 8 weeks. At day 1 post-transplant, beta cell
      death was significantly (p < 0.05) decreased, and the total insulin content was
      significantly (p < 0.05) increased in AdvHGF-transduced islets containing grafts.
      This anti-beta cell death action of HGF was independently confirmed in RIP-HGF
      mice and in INS-1 cells, both treated with streptozotocin. Activation of the
      phosphatidylinositol 3-kinase/Akt intracellular-signaling pathway appeared to be
      involved in this beta cell protective effect of HGF in vitro. In summary,
      adenoviral delivery of HGF to murine islets ex vivo improves islet transplant
      survival and blood glucose control in a subcapsular renal graft model in immuno
      incompetent diabetic mice.

PMID- 12403788
TI  - Role of p38 MAPK in CYP2E1-dependent arachidonic acid toxicity.
AB  - Polyunsaturated fatty acids such as arachidonic acid (AA) play an important role
      in alcohol-induced liver injury. AA promotes toxicity in rat hepatocytes with
      high levels of cytochrome P4502E1 (CYP2E1) and in HepG2 E47 cells, which express
      CYP2E1. The possible role of mitogen-activated protein kinase (MAPK) members in
      this process was evaluated. SB203580, a p38 MAPK inhibitor, and PD98059, an ERK
      inhibitor, but not wortmannin a phosphatidylinositol 3-kinase (PI3K) inhibitor,
      prevented AA toxicity in pyrazole hepatocytes and E47 cells. SB203580 prevented
      the enhancement of AA toxicity by salicylate. SB203580 neither lowered the levels
      of CYP2E1 nor affected CYP2E1-dependent oxidative stress. The decrease in
      mitochondrial membrane potential produced by AA was prevented by SB203580.
      Treating CYP2E1-induced cells with AA activated p38 MAPK but not ERK or AKT. This
      activation was blocked by antioxidants. AA increased the translocation of NF
      kappaB to the nucleus. Salicylate blocked this translocation, which may
      contribute to the enhancement of AA toxicity by salicylate. SB203580 restored AA
      induced NF-kappaB translocation, which may contribute to protection against
      toxicity. In conclusion, AA toxicity was related to lipid peroxidation and
      oxidative stress, and to the activation of p38 MAPK, as a consequence of CYP2E1
      dependent production of reactive oxygen species. Activation of p38 MAPK by AA
      coupled to AA-induced oxidative stress may synergize to cause cell toxicity by
      affecting mitochondrial membrane potential and by modulation of NF-kappaB
      activation.

PMID- 12403789
TI  - A phage display technique identifies a novel regulator of cell differentiation.
AB  - The formation of new bone during the process of bone remodeling occurs almost
      exclusively at sites of prior bone resorption. In an attempt to discover what
      regulatory pathways are utilized by osteoblasts to effect this site-specific
      formation event we probed components of an active bone resorption surface with an
      osteoblast phage expression library. In these experiments primary cultures of rat
      osteoblasts were used to construct a phage display library in T7 phage. Tartrate
      resistant acid phosphatase (type V) (TRAP) was used as the bait in a biopanning
      procedure. 40 phage clones with very high affinity for TRAP were sequenced, and
      of the clones with multiple consensus sequences we identified a regulatory
      protein that modulates osteoblast differentiation. This protein is the TGFbeta
      receptor-interacting protein (TRIP-1). Our data demonstrate that TRAP activation
      of TRIP-1 evokes a TGFbeta-like differentiation process. Specifically, TRIP-1
      activation increases the activity and expression of osteoblast alkaline
      phosphatase, osteoprotegerin, collagen, and Runx2. Moreover, we show that TRAP
      interacts with TRIP intracellularly, that activation of the TGFbeta type II
      receptor by TRIP-1 occurs in the presence of TRAP and that the differentiation
      process is mediated through the Smad2/3 pathway. A final experiment demonstrates
      that osteoblasts, when cultured in osteoclast lacunae containing TRAP, rapidly
      and specifically differentiate into a mature bone-forming phenotype. We
      hypothesize that binding to TRAP may be one mechanism by which the full
      osteoblast phenotype is expressed during the process of bone remodeling.

PMID- 12403790
TI  - Crystal structure of interleukin-19 defines a new subfamily of helical cytokines.
AB  - Interleukin-19 (IL-19) is a novel cytokine that was initially identified during a
      sequence data base search aimed at finding potential IL-10 homologs. IL-19 shares
      a receptor complex with IL-20, indicating that the biological activities of these
      two cytokines overlap and that both may play an important role in regulating
      development and proper functioning of the skin. We determined the crystal
      structure of human recombinant IL-19 and refined it at 1.95-A resolution to an R
      factor of 0.157. Unlike IL-10, which forms an intercalated dimer, the molecule of
      IL-19 is a monomer made of seven amphipathic helices, A-G, creating a unique
      helical bundle. On the basis of the observed structure, we propose that IL-19, IL
      20, and other putative members of the proposed IL-10 family together form a
      distinct subfamily of helical cytokines.

PMID- 12403791
TI  - A novel nuclear export signal and a REF interaction domain both promote mRNA
      export by the Epstein-Barr virus EB2 protein.
AB  - A striking characteristic of mRNA export factors is that they shuttle
      continuously between the cytoplasm and the nucleus. This shuttling is mediated by
      specific factors interacting with peptide motifs called nuclear export signals
      (NES) and nuclear localization signals. We have identified a novel CRM-1
      independent transferable NES and two nuclear localization signals in the Epstein
      Barr virus mRNA export factor EB2 (also called BMLF1, Mta, or SM) localized at
      the N terminus of the protein between amino acids 61 and 146. We have also found
      that a previously described double NES (amino acids 213-236) does not mediate the
      nuclear shuttling of EB2, but is an interaction domain with the cellular export
      factor REF in vitro. This newly characterized REF interaction domain is essential
      for EB2-mediated mRNA export. Accordingly, in vivo, EB2 is found in complexes
      containing REF as well as the cellular factor TAP. However, these interactions
      are RNase-sensitive, suggesting that the RNA is an essential component of these
      complexes.

PMID- 12403793
TI  - Survival characteristics and age-adjusted disease incidences in C57BL/6 mice fed
      a commonly used cereal-based diet modulated by dietary restriction.
AB  - Studies of C57BL/6 mice are often restricted to one sex, with limited
      characterization of pathology as a function of age. As part of the National
      Institute on Aging/National Center for Toxicological Research Collaboration on
      Biomarkers, over 3000 males and 1500 females of this strain were raised,
      maintained, and used to evaluate longevity under specific pathogen-free
      conditions. A diet commonly used in testing the impact of agents was fed ad
      libitum or was restricted to 60% of normal consumption, starting when the mice
      were 14-16 weeks of age. Cardiac, renal, and central nervous system pathologies
      were significantly inhibited by dietary restriction (DR), as were bone
      degeneration, inflammation, hyperplasia, amyloid induction, and atrophy of
      secretory organs. Hematological disorders and tumors were among the most common
      problem in this strain, and they were ameliorated by DR. In males, for other
      neoplasms, adrenal adenomas, liver tumors, and hemangiomas combined with
      hemangiosarcomas were decreased by DR, variably in onset and progression. In
      females, DR decreased pituitary tumors, mammary tumors, and alveolar carcinomas,
      again variably in onset and progression.

PMID- 12403792
TI  - Metalloprotease-mediated GH receptor proteolysis and GHBP shedding. Determination
      of extracellular domain stem region cleavage site.
AB  - Growth hormone-binding protein (GHBP) is complexed to a substantial fraction of
      circulating GH. In humans, rabbits, and other species, GHBP derives from
      proteolytic shedding of the GH receptor (GHR) extracellular domain. In cell
      culture studies, stimuli such as phorbol ester, platelet-derived growth factor,
      or serum induce GHR proteolysis, which concomitantly yields shed GHBP in cell
      supernatants and a cell-associated cytoplasmic domain-containing GHR remnant.
      This process is sensitive to metalloprotease inhibition, and genetic
      reconstitution studies identify tumor necrosis factor-alpha converting enzyme
      (TACE/ADAM-17), a transmembrane metalloprotease, as a GHR sheddase. Stimuli that
      induce GHR proteolysis render cells less responsive to GH, but the mechanism(s)
      of this desensitization is not yet understood. In this study, we mapped the
      rabbit (rb) GHR cleavage site. We adenovirally expressed a C-terminal epitope
      tagged rbGHR lacking most of its cytoplasmic domain, purified the remnant protein
      induced by the phorbol ester, PMA, and derived the cleavage site by N-terminal
      sequencing of the purified remnant. The N-terminal sequence, (239)FTCEEDFR(246),
      matched perfectly the rbGHR and suggests that cleavage occurs eight residues from
      the membrane in the proximal extracellular domain stem region. Deletion and
      alanine substitution mutagenesis indicated that, similar to other TACE
      substrates, the spacing of residues in this region, more than their identity,
      influences GHR cleavage susceptibility. Further, we determined that PMA
      pretreatment desensitized a cleavage-sensitive GHR mutant, but not a cleavage
      insensitive mutant, to GH-induced JAK2 activation. These results suggest that
      inducible GHR proteolysis can regulate GH signaling.

PMID- 12403794
TI  - Different age-specific demographic profiles are generated in the same normal
      lived Drosophila strain by different longevity stimuli.
AB  - We review the empirical data obtained with our normal-lived Ra control strain of
      Drosophila and show that this one genome is capable of invoking at least three
      different responses to external stimuli that induce the animal to express one of
      three different extended longevity phenotypes, each of which arises from one of
      three different antagonistic molecular mechanisms of stress resistance. The
      phenotypes are distinguished by different age-specific mortality patterns.
      Depending on the selected mechanism, the genome may respond by expressing a
      delayed onset of senescence (type 1), an increased early survival (type 2), or an
      increased late survival (type 3) phenotype, suggesting their different
      demographic effects. We suggest that the different demographic effects stem in
      part from the differential ability of each selection regime to reallocate the
      organism's energy from reproduction to somatic maintenance. These data document
      the complexity of the aging process and argue for a relationship between
      molecular mechanisms and longevity phenotypes.

PMID- 12403795
TI  - Designer microarrays: from soup to nuts.
AB  - The recognition that multigene mechanisms control the pathways determining the
      aging process renders gene screening a necessary skill for biogerontologists. In
      the past few years, this task has become much more accessible, with the advent of
      DNA chip technology. Most commercially available microarrays are designed with
      prefixed templates of genes of general interest, allowing investigators little
      freedom of choice in attempting to focus gene screening on a particular thematic
      pathway of interest. This report describes our "designer microarray" approach as
      a next generation of DNA chips, allowing individual investigators to engage in
      gene screening with a user friendly, do-it-yourself approach, from designing the
      probe templates to data mining. The end result is the ability to use microarrays
      as a platform for versatile gene discovery.

PMID- 12403796
TI  - Editorial: Something about frailty.

PMID- 12403797
TI  - Social and political influences on services for older people in the United
      Kingdom in the late 20th century.

PMID- 12403798
TI  - Plasma HDL levels highly correlate with cognitive function in exceptional
      longevity.
AB  - BACKGROUND: Families of centenarians have high levels of plasma high-density
      lipoprotein (HDL) cholesterol, which may have neurological as well as
      cardiovascular protective effects during aging. Because plasma HDL level declines
      progressively with aging, we examined whether centenarians with higher plasma HDL
      levels have better cognitive function. METHODS: Total plasma cholesterol, low
      density lipoprotein (LDL) cholesterol, HDL, triglycerides, and apolipoprotein
      levels were measured in a group of centenarians (N = 139; older than 95 years)
      and were correlated with their cognitive function (measured by Mini-Mental State
      Examination [MMSE]). RESULTS: Plasma HDL levels correlated significantly with
      MMSE (r =.32; p <.0001). Each decrease in plasma HDL tertile (74.9 +/- 2.1, 50.6
      +/- 0.5, and 36.8 +/- 1.0 mg/dl) was associated with a significant decrease in
      MMSE (23.4 +/- 1.5, 17.7 +/- 1.8, and 12.4 +/- 1.8; p <.04 for each plasma HDL
      tertile). As expected, increased plasma apolipoprotein A-I and decreased plasma
      triglyceride levels were also correlated with a significantly superior cognitive
      function. Biological markers of hydration and nutritional status did not differ
      between the groups with the higher or lower plasma HDL or MMSE. CONCLUSIONS:
      These data demonstrate that cognitive dysfunction in centenarians is associated
      with a progressive decline in plasma HDL concentrations. This underscores the
      protective effects of increased plasma HDL and its role in maintaining superior
      cognition in longevity.

PMID- 12403799
TI  - Chronic disease, functional status, and self-ascribed causes of disabilities
      among noninstitutionalized older people in Spain.
AB  - BACKGROUND: A major component of disability is related to chronic disease, but
      the study of self-reported causes of disability could add new aspects in
      understanding this process. The main objective of this work was to determine the
      associations between chronic diseases and disability and to describe the pattern
      of self-reported causes of the disabilities present in older persons. METHODS: We
      carried out a survey in a probabilistic sample of people aged 65 and older of the
      city of Madrid. The initial sample size was 1001. Subjects were interviewed in
      their homes. We asked about the presence of 14 chronic conditions. Self-reported
      difficulty and dependence in 9 noninstrumental activities of daily living (ADLs)
      were ascertained. Subjects were asked to report the main cause responsible for
      the disability. Multivariate logistic regression models were constructed to
      estimate the association of each chronic condition with the probability of having
      disability. RESULTS: Final sample size was 772 people (overall response rate
      77.0%). Interviews answered by proxies were 7.5%. Only 4.5% declared no chronic
      condition. Osteoarthitis/rheumatism was the most prevalent condition (56.8%). In
      addition, 63.2% were independent, 21.3% were independent with difficulty (in at
      least one ADL), and 15.5% were dependent (in at least one ADL). Subjects
      attributed to osteoarthitis and to aging 41.8% and 17.1% of all disabilities,
      respectively. Chronic conditions strongly associated with disability were
      cerebrovascular disease (adjusted odds ratio [OR]: 3.51 [95% confidence interval:
      1.44-8.60]), depression/anxiety disorders (OR: 2.72 [1.83-4.05]), and diabetes
      (OR: 2.18 [1.24-3.83]). CONCLUSIONS: Cerebrovascular diseases, depression/anxiety
      disorders, and diabetes were the conditions more clearly related to disability.
      On the other hand, a large proportion of subjects attribute their disabilities to
      osteoarthritis and old age.

PMID- 12403800
TI  - Prevalence and risk factors for falls in an older community-dwelling population.
AB  - BACKGROUND: Falls are responsible for considerable morbidity, immobility, and
      mortality among elderly people. The aim of this study was to determine the
      prevalence of falls and related intrinsic and extrinsic risk factors in a
      community-dwelling older population. METHODS: An observational study was
      performed on all patients (N = 5570) admitted from 1997 to 2001 to home care
      programs in 19 home health agencies that participated in the National Silver
      Network project in Italy. Patient evaluation was performed through the Minimum
      Data Set-Home Care (MDS-HC) instrument. RESULTS: A 35.9% falls prevalence was
      found within 90 days of the patient assessment through the MDS-HC instrument.
      After adjusting for all potential confounding factors, the logistic regression
      showed a high increase in risk of falling for those patients who wandered (odds
      ratio [OR] 2.38; 95% confidence interval [CI] 1.81-3.12) or suffered with gait
      problems (OR 2.13; 95% CI 1.81-2.51). Patients affected by depression were more
      likely to fall (OR 1.53; 95% CI 1.36-1.73). Those who lived in an unsafe place
      with environmental hazards had an increase in the risk of falling (OR 1.51; 95%
      CI 1.34-1.69). The associations of main risk factors for falls were also
      evaluated. CONCLUSIONS: Rate of falls among frail elderly people living in the
      community is very high and frequently correlates with potentially reversible
      factors. To identify those with higher falling risk, home care staff and general
      practitioners could use the MDS-HC assessment tool.

PMID- 12403801
TI  - Pain-related disability among older male veterans receiving primary care.
AB  - BACKGROUND: Pain is common among older persons and is associated with substantial
      disability, but factors that increase the risk for pain-related disability remain
      poorly defined. We sought to identify factors associated with disability due to
      pain in a sample of older veterans receiving primary care. METHODS: Participants
      (N = 494) in this cross-sectional study included male veterans aged 65 years and
      older who were enrolled in a Veterans Affairs primary care clinic and who
      reported pain within the prior 12 months. Candidate factors included demographic,
      psychological, medical, and pain (e.g., intensity, site, duration)
      characteristics and were ascertained during face-to-face interviews. We assessed
      participants' level of pain-related disability by asking them to rate on a 0 to
      10 scale the extent to which pain interfered with their ability to do daily
      activities (0 = no interference at all and 10 = no longer doing daily activities
      due to pain). Patients with scores of 0, 1-6, and 7-10 (approximate upper
      quartile) were classified as having no, low/moderate, and high pain-related
      disability. RESULTS: The distribution of pain-related disability was none = 149
      (30%), low/moderate = 210 (43%), and high = 135 (27%). Factors associated with
      high (vs no) pain-related disability included the presence of depressive
      symptoms, defined as a score of 16 or greater on the Center for Epidemiologic
      Studies-Depression scale (adjusted odds ratio [AOR] = 3.12, 95% confidence
      interval [CI] = 1.42-6.85), and pain intensity, defined as a one-unit increase on
      a 0-10 numeric rating scale (AOR = 1.84, 95% CI = 1.61-2.12). Other factors
      associated with high pain-related disability included the presence of pain on
      most days of every month (AOR = 3.59, 95% CI = 1.82-7.08) and low back pain (AOR
      = 2.36, 95% CI = 1.13-4.94). Depressive symptoms, pain intensity, and the
      presence of pain on most days of every month were also significantly and
      independently associated with low/moderate (vs no) pain-related disability.
      CONCLUSIONS: Pain-related disability is common among older male veterans
      receiving primary care. As modifiable factors, depressive symptoms and pain
      intensity are associated with pain-related disability and represent appropriate
      targets for intervention efforts among older persons with pain.

PMID- 12403802
TI  - Effects of nurse counseling on walking for exercise in elderly primary care
      patients.
AB  - Background. Counseling sedentary primary care patients can increase physical
      activity, but whether this approach will increase exercise and fitness in elderly
      adults with chronic diseases remains to be determined. Methods. After receiving
      individualized nurse counseling to begin a program of walking for health, 60- to
      80-year-old primary care patients were randomized to one of three levels of
      telephone contacts over 10 months: (i) 20 nurse-initiated calls, (ii) 10 nurse
      initiated calls plus 10 motivational calls programmed through an automated phone
      calling system, or (iii) no program-initiated phone contacts. Self-reported
      (diary) walking adherence was the primary outcome; other activity, social
      support, health quality of life, and measured walking performance, mobility, and
      body mass index and girths were also assessed during the initiation (months 1-6)
      and maintenance (months 7-10) phases of the trial. Results. Average adherence for
      the 181 participants to the goal of walking at least 20 minutes on 3 or more days
      per week was 44% for initiation and 42% for maintenance. Participants receiving
      the combination of nurse-initiated personal and automated phone calls walked
      significantly more frequently than those with no phone contacts. Fitness improved
      in all three groups; changes were generally correlated with self-reported
      walking. Having a companion was associated with more frequent walking. Perceived
      quality of physical and mental health did not change. Conclusions. Simple and
      relatively inexpensive nurse contacts can motivate elderly primary care patients
      to walk for exercise, and this activity is associated with measurable health
      benefits.

PMID- 12403803
TI  - Undernutrition and risk of mortality in elderly patients within 1 year of
      hospital discharge.
AB  - BACKGROUND: The importance of undernutrition as a determinant of postdischarge
      mortality among hospitalized elderly people remains controversial. The purpose of
      this study was to investigate this issue. METHODS: The study included 660 elderly
      patients (85% white, 98% men, average age 73 +/- 6 years) discharged from a
      university-affiliated Department of Veterans Affairs Hospital, who were followed
      for 1 year. Associations between patient characteristics at hospital discharge
      and mortality were identified utilizing Cox Proportional Hazards Regression
      analysis. RESULTS: In the year following hospital discharge, 85 subjects (13%)
      died. After adjusting for illness severity (Acute Physiology and Chronic Health
      Evaluation II score) and functional status (Katz Index of Activities of Daily
      Living score), a body mass index (BMI) </=20 kg/m(2) was strongly associated with
      mortality (adjusted relative risk, [95% confidence interval] 1.83 [1.17-2.85]),
      as was more than 10% weight loss in the prior year (2.31 [1.35-3.94]), and weight
      as percent of usual weight (WPU) </=85% (1.78 [1.14-2.77]). Albumin </=30 g/l was
      only weakly associated with mortality (1.10 [0.67-1.81]). When all of the
      putative nutrition variables were included in a multivariable analysis with the
      two control variables, only BMI followed by WPU </=85% entered the model.
      Utilizing this model, the predicted probabilities of death at 1 year were
      calculated for the study subjects and for a hypothetical group of patients who
      were identical to the study subjects except they were assigned a BMI of 28
      kg/m(2) and their WPU was 100%. Compared to 24% of the actual subjects, only 7%
      of the hypothetical well-nourished patients would have been classified as being
      at high risk for mortality (a 71% relative reduction). CONCLUSIONS: Older
      patients who have evidence of chronic body mass depletion are at significantly
      increased risk of mortality within the year following hospital discharge.

PMID- 12403804
TI  - Reduction of new coronary events and new atherothrombotic brain infarction in
      older persons with diabetes mellitus, prior myocardial infarction, and serum low
      density lipoprotein cholesterol >/=125 mg/dl treated with statins.
AB  - BACKGROUND: We report the incidence of new coronary events and new
      atherothrombotic brain infarction (ABI) in older men and women with diabetes
      mellitus, prior myocardial infarction, and a serum low-density lipoprotein (LDL)
      cholesterol of >/=125 mg/dl treated with statins and with no lipid-lowering drug.
      METHODS: The incidence of new coronary events and of new ABI was investigated in
      an observational prospective study of 529 diabetics, mean age 79 +/- 9 years,
      with prior myocardial infarction and a serum LDL cholesterol of >/=125 mg/dl
      treated with statins (279 persons or 53%) and no lipid-lowering drug (250 persons
      or 47%). Follow-up was 29 +/- 18 months. RESULTS: At follow-up, the stepwise Cox
      regression model showed that after controlling for other risk factors, the use of
      statins was associated with a 37% significant independent reduction in the
      incidence of new coronary events and with a 47% significant independent reduction
      in the incidence of new ABI. CONCLUSIONS: Use of statins was associated with a
      37% significant, independent reduction in new coronary events and a 47%
      significant, independent reduction in new ABI in older men and women with
      diabetes mellitus, prior myocardial infarction, and a serum LDL cholesterol of
      >/=125 mg/dl. Elderly diabetics with prior myocardial infarction and increased
      serum LDL cholesterol should especially be treated with statins.

PMID- 12403805
TI  - The 6-minute walk test in mobility-limited elders: what is being measured?
AB  - BACKGROUND: The 6-minute walk (6mw) is a well-established measure of aerobic
      capacity in elders with cardiorespiratory and peripheral vascular disease and may
      be an accurate measure of functional performance in healthy elders. In mobility
      limited elders, a population at risk for disability, impairments in strength and
      power are predictive of performance-based measures of function. Though commonly
      utilized as an outcome measure among otherwise healthy mobility-limited elders,
      it is not clear whether the 6mw best represents a measure of functional
      limitation, aerobic capacity, or both. METHODS: We hypothesized that the 6mw
      would be strongly representative of performance-based measures of function being
      determined by impairments in muscle strength and power. We performed a cross
      sectional analysis of 45 community-dwelling elders with mild to moderate mobility
      limitations. RESULTS: The 6mw was strongly associated with established functional
      measures (r =.61-.83; p <.001), but was poorly associated with indirect measures
      of aerobic capacity (r <.25; p >.05). Multivariate linear regression models
      demonstrated that impairments in leg strength and power, especially those at the
      knee and ankle, were predictive of 6mw performance. CONCLUSIONS: These findings
      emphasize the 6mw as a measure of functional limitation among mobility-limited
      elders without cardiorespiratory or peripheral vascular disease.

PMID- 12403806
TI  - A cross-sectional study of lipids and ApoC levels in Alzheimer's patients with
      and without cardiovascular disease.
AB  - BACKGROUND: There is increasing evidence supporting the role of atherogenic
      phenomena in Alzheimer's disease (AD). The possible significance of specific
      plasma lipid levels in the pathogenesis of AD remains controversial. While lipids
      such as cholesterol or chaperons such as apolipoprotein (Apo) E2 to ApoE4 have
      been assessed in AD, ApoC2 and ApoC3 have not been studied before. The present
      study investigated possible differences in levels of these lipids in AD patients,
      with or without cardiovascular diseases or risk factors. METHODS: This is a cross
      sectional study. The medical charts of patients diagnosed with probable AD were
      screened for the presence of cardiovascular disease and cardiovascular risk
      factors. Included in the study were 105 AD patients: 53 with cardiovascular risk
      factors (AD(+CVD)) and 52 without risk factors (AD(-CVD)). Blood samples were
      analyzed for lipoproteins, ApoC2, and ApoC3. We used t tests, chi-square tests,
      and regression analyses to identify significant differences and to compare the
      relationships of variables among the groups. RESULTS: ApoC2 levels (3.5 +/- 0.3
      and 3.4 +/- 0.4 mg/dl, respectively), ApoC3 (13.7 +/- 0.9 and 14.7 +/- 1.1 mg/dl,
      respectively), and high-density lipoprotein (HDL)/non-HDL ApoC3 ratios (1.6 +/-
      0.2 and 1.3 +/- 0.2, respectively) were similar for the AD patients with and
      without cardiovascular risk factors. Levels of total cholesterol, triglycerides,
      low-density lipoproteins (LDL), very LDLs, and HDLs were similar in the two
      groups. A substantial proportion of both AD(+CVD) and AD(-CVD) patients showed
      high levels of total cholesterol and LDL, as well as low levels of HDL, ApoC2,
      and ApoC3, compared to normative values. Surprisingly, patients treated by
      cognitive enhancers showed significantly higher cholesterol ( p =.002) and
      triglyceride ( p =.015) levels, independent of age, gender, and cognitive level.
      CONCLUSIONS: There was no difference between AD patients, either with or without
      cardiovascular diseases or risk factors, with respect to plasma lipid profile,
      including ApoC2 and ApoC3. This could indicate that lipid metabolism may play a
      role in AD, whether with or without cardiovascular risk factors. The higher
      levels of some lipids, observed in a subset of patients treated by cognitive
      enhancers, deserves further investigation.

PMID- 12403807
TI  - The face of TSR revealed: an extracellular signaling domain is exposed.
AB  - In this issue, Tan et al. (2002) report the first high resolution (1.9 A)
      structural data for thrombospondin (TSP)-1, a large multifunctional protein that
      regulates cell adhesion, angiogenesis, cell proliferation and survival, TGFbeta
      activation, and protease function (for review see Chen et al., 2000). Because TSP
      1 has multiple binding partners and many functions, precise structural
      information is crucial to understanding its biology. The structure now reported,
      derived from crystals of the second and third type I repeats of TSP-1 is of
      particular interest because of the specific functions attributed to these repeats
      and because domains homologous to the repeats appear in many other proteins in
      nature. The novel layered fold motif described brings great insight into how the
      complicated functions of TSP-1 and related molecules are affected.

PMID- 12403808
TI  - Unfolded cholera toxin is transferred to the ER membrane and released from
      protein disulfide isomerase upon oxidation by Ero1.
AB  - The toxic effect of cholera toxin (CT) on target cells is caused by its A1 chain.
      This polypeptide is released from the holotoxin and unfolded in the lumen of the
      ER by the action of protein disulfide isomerase (PDI), before being
      retrotranslocated into the cytosol. The polypeptide is initially unfolded by
      binding to the reduced form of PDI. We show that upon oxidation of the COOH
      terminal disulfide bond in PDI by the enzyme Ero1, the A1 chain is released. Both
      yeast Ero1 and the mammalian Ero1alpha isoform are active in this reaction. Ero1
      has a preference for the PDI-toxin complex. We further show that the complex is
      transferred to a protein at the lumenal side of the ER membrane, where the
      unfolded toxin is released from PDI by the action of Ero1. Taken together, our
      results identify Ero1 as the enzyme mediating the release of unfolded CT from PDI
      and characterize an additional step in retrotranslocation of the toxin.

PMID- 12403809
TI  - Tuberous sclerosis complex tumor suppressor-mediated S6 kinase inhibition by
      phosphatidylinositide-3-OH kinase is mTOR independent.
AB  - The evolution of mitogenic pathways has led to the parallel requirement for
      negative control mechanisms, which prevent aberrant growth and the development of
      cancer. Principally, such negative control mechanisms are represented by tumor
      suppressor genes, which normally act to constrain cell proliferation (Macleod, K.
      2000. Curr. Opin. Genet. Dev. 10:81-93). Tuberous sclerosis complex (TSC) is an
      autosomal-dominant genetic disorder, characterized by mutations in either TSC1 or
      TSC2, whose gene products hamartin (TSC1) and tuberin (TSC2) constitute a
      putative tumor suppressor complex (TSC1-2; van Slegtenhorst, M., M. Nellist, B.
      Nagelkerken, J. Cheadle, R. Snell, A. van den Ouweland, A. Reuser, J. Sampson, D.
      Halley, and P. van der Sluijs. 1998. Hum. Mol. Genet. 7:1053-1057). Little is
      known with regard to the oncogenic target of TSC1-2, however recent genetic
      studies in Drosophila have shown that S6 kinase (S6K) is epistatically dominant
      to TSC1-2 (Tapon, N., N. Ito, B.J. Dickson, J.E. Treisman, and I.K. Hariharan.
      2001. Cell. 105:345-355; Potter, C.J., H. Huang, and T. Xu. 2001. Cell. 105:357
      368). Here we show that loss of TSC2 function in mammalian cells leads to
      constitutive S6K1 activation, whereas ectopic expression of TSC1-2 blocks this
      response. Although activation of wild-type S6K1 and cell proliferation in TSC2
      deficient cells is dependent on the mammalian target of rapamycin (mTOR), by
      using an S6K1 variant (GST-DeltaC-S6K1), which is uncoupled from mTOR signaling,
      we demonstrate that TSC1-2 does not inhibit S6K1 via mTOR. Instead, we show by
      using wortmannin and dominant interfering alleles of phosphatidylinositide-3-OH
      kinase (PI3K) that increased S6K1 activation is contingent upon the suppression
      of TSC2 function by PI3K in normal cells and is PI3K independent in TSC2
      deficient cells.

PMID- 12403810
TI  - Visualization of replication initiation and elongation in Drosophila.
AB  - Chorion gene amplification in the ovaries of Drosophila melanogaster is a
      powerful system for the study of metazoan DNA replication in vivo. Using a
      combination of high-resolution confocal and deconvolution microscopy and
      quantitative realtime PCR, we found that initiation and elongation occur during
      separate developmental stages, thus permitting analysis of these two phases of
      replication in vivo. Bromodeoxyuridine, origin recognition complex, and the
      elongation factors minichromosome maintenance proteins (MCM)2-7 and proliferating
      cell nuclear antigen were precisely localized, and the DNA copy number along the
      third chromosome chorion amplicon was quantified during multiple developmental
      stages. These studies revealed that initiation takes place during stages 10B and
      11 of egg chamber development, whereas only elongation of existing replication
      forks occurs during egg chamber stages 12 and 13. The ability to distinguish
      initiation from elongation makes this an outstanding model to decipher the roles
      of various replication factors during metazoan DNA replication. We utilized this
      system to demonstrate that the pre-replication complex component, double-parked
      protein/cell division cycle 10-dependent transcript 1, is not only necessary for
      proper MCM2-7 localization, but, unexpectedly, is present during elongation.

PMID- 12403811
TI  - Chromosomes are predominantly located randomly with respect to each other in
      interphase human cells.
AB  - To test quantitatively whether there are systematic chromosome-chromosome
      associations within human interphase nuclei, interchanges between all possible
      heterologous pairs of chromosomes were measured with 24-color whole-chromosome
      painting (multiplex FISH), after damage to interphase lymphocytes by sparsely
      ionizing radiation in vitro. An excess of interchanges for a specific chromosome
      pair would indicate spatial proximity between the chromosomes comprising that
      pair. The experimental design was such that quite small deviations from
      randomness (extra pairwise interchanges within a group of chromosomes) would be
      detectable. The only statistically significant chromosome cluster was a group of
      five chromosomes previously observed to be preferentially located near the center
      of the nucleus. However, quantitatively, the overall deviation from randomness
      within the whole genome was small. Thus, whereas some chromosome-chromosome
      associations are clearly present, at the whole-chromosomal level, the predominant
      overall pattern appears to be spatially random.

PMID- 12403813
TI  - Karyopherins in nuclear pore biogenesis: a role for Kap121p in the assembly of
      Nup53p into nuclear pore complexes.
AB  - The mechanisms that govern the assembly of nuclear pore complexes (NPCs) remain
      largely unknown. Here, we have established a role for karyopherins in this
      process. We show that the yeast karyopherin Kap121p functions in the targeting
      and assembly of the nucleoporin Nup53p into NPCs by recognizing a nuclear
      localization signal (NLS) in Nup53p. This karyopherin-mediated function can also
      be performed by the Kap95p-Kap60p complex if the Kap121p-binding domain of Nup53p
      is replaced by a classical NLS, suggesting a more general role for karyopherins
      in NPC assembly. At the NPC, neighboring nucleoporins bind to two regions in
      Nup53p. One nucleoporin, Nup170p, associates with a region of Nup53p that
      overlaps with the Kap121p binding site and we show that they compete for binding
      to Nup53p. We propose that once targeted to the NPC, dissociation of the Kap121p
      Nup53p complex is driven by the interaction of Nup53p with Nup170p. At the NPC,
      Nup53p exists in two separate complexes, one of which is capable of interacting
      with Kap121p and another that is bound to Nup170p. We propose that fluctuations
      between these two states drive the binding and release of Kap121p from Nup53p,
      thus facilitating Kap121p's movement through the NPC.

PMID- 12403812
TI  - Assembly of centrosomal proteins and microtubule organization depends on PCM-1.
AB  - The protein PCM-1 localizes to cytoplasmic granules known as "centriolar
      satellites" that are partly enriched around the centrosome. We inhibited PCM-1
      function using a variety of approaches: microinjection of antibodies into
      cultured cells, overexpression of a PCM-1 deletion mutant, and specific depletion
      of PCM-1 by siRNA. All approaches led to reduced targeting of centrin,
      pericentrin, and ninein to the centrosome. Similar effects were seen upon
      inhibition of dynactin by dynamitin, and after prolonged treatment of cells with
      the microtubule inhibitor nocodazole. Inhibition or depletion of PCM-1 function
      further disrupted the radial organization of microtubules without affecting
      microtubule nucleation. Loss of microtubule organization was also observed after
      centrin or ninein depletion. Our data suggest that PCM-1-containing centriolar
      satellites are involved in the microtubule- and dynactin-dependent recruitment of
      proteins to the centrosome, of which centrin and ninein are required for
      interphase microtubule organization.

PMID- 12403815
TI  - Recapitulation of embryonic neuroendocrine differentiation in adult human
      pancreatic duct cells expressing neurogenin 3.
AB  - Regulatory proteins have been identified in embryonic development of the
      endocrine pancreas. It is unknown whether these factors can also play a role in
      the formation of pancreatic endocrine cells from postnatal nonendocrine cells.
      The present study demonstrates that adult human pancreatic duct cells can be
      converted into insulin-expressing cells after ectopic, adenovirus-mediated
      expression of the class B basic helix-loop-helix factor neurogenin 3 (ngn3),
      which is a critical factor in embryogenesis of the mouse endocrine pancreas.
      Infection with adenovirus ngn3 (Adngn3) induced gene and/or protein expression of
      NeuroD/beta2, Pax4, Nkx2.2, Pax6, and Nkx6.1, all known to be essential for beta
      cell differentiation in mouse embryos. Expression of ngn3 in adult human duct
      cells induced Notch ligands Dll1 and Dll4 and neuroendocrine- and beta-cell
      specific markers: it increased the percentage of synaptophysin- and insulin
      positive cells 15-fold in ngn3-infected versus control cells. Infection with
      NeuroD/beta2 (a downstream target of ngn3) induced similar effects. These data
      indicate that the Delta-Notch pathway, which controls embryonic development of
      the mouse endocrine pancreas, can also operate in adult human duct cells driving
      them to a neuroendocrine phenotype with the formation of insulin-expressing
      cells.

PMID- 12403814
TI  - Myosin Va binding to neurofilaments is essential for correct myosin Va
      distribution and transport and neurofilament density.
AB  - The identification of molecular motors that modulate the neuronal cytoskeleton
      has been elusive. Here, we show that a molecular motor protein, myosin Va, is
      present in high proportions in the cytoskeleton of mouse CNS and peripheral
      nerves. Immunoelectron microscopy, coimmunoprecipitation, and blot overlay
      analyses demonstrate that myosin Va in axons associates with neurofilaments, and
      that the NF-L subunit is its major ligand. A physiological association is
      indicated by observations that the level of myosin Va is reduced in axons of NF-L
      null mice lacking neurofilaments and increased in mice overexpressing NF-L, but
      unchanged in NF-H-null mice. In vivo pulse-labeled myosin Va advances along axons
      at slow transport rates overlapping with those of neurofilament proteins and
      actin, both of which coimmunoprecipitate with myosin Va. Eliminating
      neurofilaments from mice selectively accelerates myosin Va translocation and
      redistributes myosin Va to the actin-rich subaxolemma and membranous organelles.
      Finally, peripheral axons of dilute-lethal mice, lacking functional myosin Va,
      display selectively increased neurofilament number and levels of neurofilament
      proteins without altering axon caliber. These results identify myosin Va as a
      neurofilament-associated protein, and show that this association is essential to
      establish the normal distribution, axonal transport, and content of myosin Va,
      and the proper numbers of neurofilaments in axons.

PMID- 12403816
TI  - Down-regulation of Delta by proteolytic processing.
AB  - Notch signaling regulates cell fate decisions during development through local
      cell interactions. Signaling is triggered by the interaction of the Notch
      receptor with its transmembrane ligands expressed on adjacent cells. Recent
      studies suggest that Delta is cleaved to release an extracellular fragment, DlEC,
      by a mechanism that involves the activity of the metalloprotease Kuzbanian;
      however, the functional significance of that cleavage remains controversial.
      Using independent functional assays in vitro and in vivo, we examined the
      biological activity of purified soluble Delta forms and conclude that Delta
      cleavage is an important down-regulating event in Notch signaling. The data
      support a model whereby Delta inactivation is essential for providing the
      critical ligand/receptor expression differential between neighboring cells in
      order to distinguish the signaling versus the receiving partner.

PMID- 12403817
TI  - Identification of amino acid residues lining the pore of a gap junction channel.
AB  - Gap junctions represent a ubiquitous and integral part of multicellular
      organisms, providing the only conduit for direct exchange of nutrients,
      messengers and ions between neighboring cells. However, at the molecular level we
      have limited knowledge of their endogenous permeants and selectivity features. By
      probing the accessibility of systematically substituted cysteine residues to
      thiol blockers (a technique called SCAM), we have identified the pore-lining
      residues of a gap junction channel composed of Cx32. Analysis of 45 sites in
      perfused Xenopus oocyte pairs defined M3 as the major pore-lining helix, with M2
      (open state) or M1 (closed state) also contributing to the wider cytoplasmic
      opening of the channel. Additional mapping of a close association between M3 and
      M4 allowed the helices of the low resolution map (Unger et al., 1999. Science.
      283:1176-1180) to be tentatively assigned to the connexin transmembrane domains.
      Contrary to previous conceptions of the gap junction channel, the residues lining
      the pore are largely hydrophobic. This indicates that the selective
      permeabilities of this unique channel class may result from novel mechanisms,
      including complex van der Waals interactions of permeants with the pore wall,
      rather than mechanisms involving fixed charges or chelation chemistry as reported
      for other ion channels.

PMID- 12403818
TI  - Distinct claudins and associated PDZ proteins form different autotypic tight
      junctions in myelinating Schwann cells.
AB  - The apposed membranes of myelinating Schwann cells are joined by several types of
      junctional specializations known as autotypic or reflexive junctions. These
      include tight, gap, and adherens junctions, all of which are found in regions of
      noncompact myelin: the paranodal loops, incisures of Schmidt-Lanterman, and
      mesaxons. The molecular components of autotypic tight junctions have not been
      established. Here we report that two homologues of Discs Lost-multi PDZ domain
      protein (MUPP)1, and Pals-associated tight junction protein (PATJ), are
      differentially localized in myelinating Schwann cells and associated with
      different claudins. PATJ is mainly found at the paranodal loops, where it
      colocalized with claudin-1. MUPP1 and claudin-5 colocalized in the incisures, and
      the COOH-terminal region of claudin-5 interacts with MUPP1 in a PSD-95/Disc
      Large/zona occludens (ZO)-1 (PDZ)-dependent manner. In developing nerves, claudin
      5 and MUPP1 appear together in incisures during the first postnatal week,
      suggesting that they coassemble during myelination. Finally, we show that the
      incisures also contain four other PDZ proteins that are found in epithelial tight
      junctions, including three membrane-associated guanylate-kinase proteins
      (membrane-associated guanylate-kinase inverted-2, ZO-1, and ZO-2) and the adaptor
      protein Par-3. The presence of these different tight junction proteins in regions
      of noncompact myelin may be required to maintain the intricate cytoarchitecture
      of myelinating Schwann cells.

PMID- 12403819
TI  - Coordinate regulation of energy transduction modules in Halobacterium sp.
      analyzed by a global systems approach.
AB  - The extremely halophilic archaeon Halobacterium NRC-1 can switch from aerobic
      energy production (energy from organic compounds) to anaerobic phototrophy
      (energy from light) by induction of purple membrane biogenesis. The purple
      membrane is made up of multiple copies of a 1:1 complex of bacterioopsin (Bop)
      and retinal called bacteriorhodopsin that functions as a light-driven proton
      pump. A light- and redox-sensing transcription regulator, Bat, regulates critical
      genes encoding the biogenesis of the purple membrane. To better understand the
      regulatory network underlying this physiological state, we report a systems
      approach using global mRNA and protein analyses of four strains of Halobacterium
      sp.: the wild-type, NRC-1; and three genetically perturbed strains: S9 (bat+), a
      purple membrane overproducer, and two purple membrane deficient strains, SD23 (a
      bop knockout) and SD20 (a bat knockout). The integrated DNA microarray and
      proteomic data reveal the coordinated coregulation of several interconnected
      biochemical pathways for phototrophy: isoprenoid synthesis, carotenoid synthesis,
      and bacteriorhodopsin assembly. In phototrophy, the second major biomodule for
      ATP production, arginine fermentation, is repressed. The primary systems level
      insight provided by this study is that two major energy production pathways in
      Halobacterium sp., phototrophy and arginine fermentation, are inversely
      regulated, presumably to achieve a balance in ATP production under anaerobic
      conditions.

PMID- 12403820
TI  - Catalysis of amide synthesis by RNA phosphodiester and hydroxyl groups.
AB  - The functional groups found among the RNA bases and in the phosphoribose backbone
      represent a limited repertoire from which to construct a ribozyme active site.
      This work investigates the possibility that simple RNA phosphodiester and
      hydroxyl functional groups could catalyze amide bond synthesis. Reaction of amine
      groups with activated esters would be catalyzed by a group that stabilizes the
      partial positive charge on the amine nucleophile in the transition state. 2'
      Amine substitutions adjacent to 3'-phosphodiester or 3'-hydroxyl groups react
      efficiently with activated esters to form 2'-amide and peptide products. In
      contrast, analogs in which the 3'-phosphodiester is replaced by an uncharged
      phosphotriester or is constrained in a distal conformation react at least 100
      fold more slowly. Similarly, a nucleoside in which the 3'-hydroxyl group is
      constrained trans to the 2'-amine is also unreactive. Catalysis of synthetic
      reactions by RNA phosphodiester and ribose hydroxyl groups is likely to be even
      greater in the context of a preorganized and solvent-excluding catalytic center.
      One such group is the 2'-hydroxyl of the ribosome-bound P-site adenosine
      substrate, which is close to the amine nucleophile in the peptidyl synthesis
      reaction. Given ubiquitous 2'-OH groups in RNA, there exists a decisive advantage
      for RNA over DNA in catalyzing reactions of biological significance.

PMID- 12403822
TI  - Non-Lipschitz minimizers of smooth uniformly convex functionals.
AB  - We construct non-Lipschitz minimizers of smooth, uniformly convex functionals of
      type I(u) = integral (Omega) f(Du(x))dx. Our method is based on the use of null
      Lagrangians.

PMID- 12403821
TI  - Synthetic small inhibiting RNAs: efficient tools to inactivate oncogenic
      mutations and restore p53 pathways.
AB  - Single base pair mutations that alter the function of tumor suppressor genes and
      oncogenes occur frequently during oncogenesis. The guardian of the genome, p53,
      is inactivated by point mutation in more than 50% of human cancers. Synthetic
      small inhibiting RNAs (siRNAs) can suppress gene expression in mammalian cells,
      although their degree of selectivity might be compromised by an amplification
      mechanism. Here, we demonstrate that a single base difference in siRNAs
      discriminates between mutant and WT p53 in cells expressing both forms, resulting
      in the restoration of WT protein function. Therefore, siRNAs may be used to
      suppress expression of point-mutated genes and provide the basis for selective
      and personalized antitumor therapy.

PMID- 12403823
TI  - A previously undescribed chemical link between smoking and metabolic disease.
AB  - Over the past 20 years, protein glycation has been implicated in a variety of
      pathological states. Although smoking also can contribute to many of these
      diseases, the precise mechanism by which this occurs is not known. Previously, we
      have demonstrated that nornicotine, a constituent of tobacco and metabolite of
      nicotine, can catalyze aldol reactions under aqueous conditions. This finding has
      caused us to question whether this reaction has physiological consequences. We
      now report that nornicotine causes aberrant protein glycation and catalyzes the
      covalent modification of certain prescription drugs such as the commonly used
      steroid, prednisone. Furthermore, we show that the plasma of smokers as compared
      with nonsmokers contains higher concentrations of nornicotine-modified proteins,
      suggesting an unrecognized pathway for the development of the pathology of
      tobacco abuse.

PMID- 12403824
TI  - Dobzhansky-Muller incompatibilities in protein evolution.
AB  - We study fitness landscape in the space of protein sequences by relating sets of
      human pathogenic missense mutations in 32 proteins to amino acid substitutions
      that occurred in the course of evolution of these proteins. On average,
      approximately 10% of deviations of a nonhuman protein from its human ortholog are
      compensated pathogenic deviations (CPDs), i.e., are caused by an amino acid
      substitution that, at this site, would be pathogenic to humans. Normal
      functioning of a CPD-containing protein must be caused by other, compensatory
      deviations of the nonhuman species from humans. Together, a CPD and the
      corresponding compensatory deviation form a Dobzhansky-Muller incompatibility
      that can be visualized as the corner on a fitness ridge. Thus, proteins evolve
      along fitness ridges which contain only approximately 10 steps between successive
      corners. The fraction of CPDs among all deviations of a protein from its human
      ortholog does not increase with the evolutionary distance between the proteins,
      indicating that substitutions that carry evolving proteins around these corners
      occur in rapid succession, driven by positive selection. Data on fitness of
      interspecies hybrids suggest that the compensatory change that makes a CPD fit
      usually occurs within the same protein. Data on protein structures and on
      cooccurrence of amino acids at different sites of multiple orthologous proteins
      often make it possible to provisionally identify the substitution that
      compensates a particular CPD.

PMID- 12403825
TI  - Missense models [Gustm(E536A)Sly, Gustm(E536Q)Sly, and Gustm(L175F)Sly] of murine
      mucopolysaccharidosis type VII produced by targeted mutagenesis.
AB  - Human mucopolysaccharidosis VII (MPS VII, Sly syndrome) results from a deficiency
      of beta-glucuronidase (GUS) and has been associated with a wide range in severity
      of clinical manifestations. To study missense mutant models of murine MPS VII
      with phenotypes of varying severity, we used targeted mutagenesis to produce
      E536A and E536Q, corresponding to active-site nucleophile replacements E540A and
      E540Q in human GUS, and L175F, corresponding to the most common human mutation,
      L176F. The E536A mouse had no GUS activity in any tissue and displayed a severe
      phenotype like that of the originally described MPS VII mice carrying a deletion
      mutation (gus(mps/mps)). E536Q and L175F mice had low levels of residual activity
      and milder phenotypes. All three mutant MPS models showed progressive lysosomal
      storage in many tissues but had different rates of accumulation. The amount of
      urinary glycosaminoglycan excretion paralleled the clinical severity, with
      urinary glycosaminoglycans remarkably higher in E536A mice than in E536Q or L175F
      mice. Molecular analysis showed that the Gus mRNA levels were quantitatively
      similar in the three mutant mouse strains and normal mice. These mouse models,
      which mimic different clinical phenotypes of human MPS VII, should be useful in
      studying pathogenesis and also provide useful models for studying enzyme
      replacement therapy and targeted correction of missense mutations.

PMID- 12403826
TI  - Enhancing polyethylenimine's delivery of plasmid DNA into mammalian cells.
AB  - The effect of various chemical modifications of nitrogen atoms on the efficiency
      of polyethylenimines (PEIs) as synthetic vectors for the delivery of plasmid DNA
      into monkey kidney cells in vitro has been systematically investigated. The
      resultant structure-activity relationship has both provided mechanistic insights
      and led to PEI derivatives with markedly enhanced performance. For example, N
      acylation of PEI with the molecular mass of 25 kDa (PEI25, one of the most potent
      polycationic gene delivery vectors) with alanine nearly doubles its transfection
      efficiency in the presence of serum and also lowers its toxicity. Furthermore,
      dodecylation of primary amino groups of 2-kDa PEI yields a nontoxic polycation
      whose transfection efficiency in the presence of serum is 400 times higher than
      the parent's and which exceeds 5-fold even that of PEI25.

PMID- 12403827
TI  - Mutations in Mcoln3 associated with deafness and pigmentation defects in varitint
      waddler (Va) mice.
AB  - Deafness in spontaneously occurring mouse mutants is often associated with
      defects in cochlea sensory hair cells, opening an avenue to systematically
      identify genes critical for hair cell structure and function. The classical
      semidominant mouse mutant varitint-waddler (Va) exhibits early-onset hearing
      loss, vestibular defects, pigmentation abnormalities, and perinatal lethality. A
      second allele, Va(J), which arose in a cross segregating for Va, shows a less
      severe phenotype. By using a positional cloning strategy, we identify two
      additional members of the mucolipin gene family (Mcoln2 and Mcoln3) in the 350-kb
      Va(J) minimal interval and provide evidence for Mcoln3 as the gene mutated in
      varitint-waddler. Mcoln3 encodes a putative six-transmembrane-domain protein with
      sequence and motif similarities to the family of nonselective transient-receptor
      potential (TRP) ion channels. In the Va allele an Ala419Pro substitution occurs
      in the fifth transmembrane domain of Mcoln3, and in Va(J), a second sequence
      alteration (Ile362Thr) occurring in cis partially rescues the Va allele. Mcoln3
      localizes to cytoplasmic compartments of hair cells and plasma membrane of
      stereocilia. Hair cell defects are apparent by embryonic day 17.5, assigning
      Mcoln3 an essential role during early hair cell maturation. Our data suggest that
      Mcoln3 is involved in ion homeostasis and acts cell-autonomously. Hence, we
      identify a molecular link between hair cell physiology and melanocyte function.
      Last, MCOLN2 and MCOLN3 are candidate genes for hereditary and/or sporadic forms
      of neurosensory disorders in humans.

PMID- 12403828
TI  - Spectral mixing of rhythmic neuronal signals in sensory cortex.
AB  - The ability to compute the difference between two frequencies depends on a
      nonlinear operation that mixes two periodic signals. Behavioral and
      psychophysical evidence suggest that such mixing is likely to occur in the
      mammalian nervous system as a means to compare two rhythmic sensory signals, such
      as occurs in human audition, and as a means to lock an intrinsic rhythm to a
      sensory input. However, a neurological substrate for mixing has not been
      identified. Here we address the issue of nonlinear mixing of neuronal activity in
      the vibrissa primary sensory cortex of rat, a region that receives intrinsic as
      well as sensory-driven rhythmic input during natural whisking. In our
      preparation, the intrinsic signal originates from cortical oscillations that were
      induced by anesthetics, and the extrinsic input is introduced by periodic
      stimulation of vibrissae. We observed that the local extracellular current in
      vibrissa primary sensory cortex contained oscillatory components at the sum and
      difference of the intrinsic and extrinsic frequencies. In complementary
      experiments, we observed that the simultaneous stimulation of contralateral and
      ipsilateral vibrissae at different frequencies also led to current flow at the
      sum and difference frequencies. We show theoretically that the relative
      amplitudes of the observed mixture terms can be accounted for by a threshold
      nonlinearity in the input-output relation of the underlying neurons. In general,
      our results provide a neurological substrate for the modulation and demodulation
      of rhythmic neuronal signals for sensory coding and feedback stabilization of
      motor output.

PMID- 12403829
TI  - A viral suppressor of RNA silencing differentially regulates the accumulation of
      short interfering RNAs and micro-RNAs in tobacco.
AB  - Two major classes of small noncoding RNAs have emerged as important regulators of
      gene expression in eukaryotes, the short interfering RNAs (siRNAs) associated
      with RNA silencing and endogenous micro-RNAs (miRNAs) implicated in regulation of
      gene expression. Helper component-proteinase (HC-Pro) is a viral protein that
      blocks RNA silencing in plants. Here we examine the effect of HC-Pro on the
      accumulation of siRNAs and endogenous miRNAs. siRNAs were analyzed in transgenic
      tobacco plants silenced in response to three different classes of transgenes:
      sense-transgenes, inverted-repeat transgenes, and amplicon-transgenes. HC-Pro
      suppressed silencing in each line, blocking accumulation of the associated siRNAs
      and allowing accumulation of transcripts from the previously silenced loci. HC
      Pro-suppression of silencing in the inverted-repeat- and amplicon-transgenic
      lines was accompanied by the apparent accumulation of long double-stranded RNAs
      and proportional amounts of small RNAs that are larger than the siRNAs that
      accumulate during silencing. Analysis of these results suggests that HC-Pro
      interferes with silencing either by inhibiting siRNA processing from double
      stranded RNA precursors or by destabilizing siRNAs. In contrast to siRNAs, the
      accumulation of endogenous miRNAs was greatly enhanced in all of the HC-Pro
      expressing lines. Thus, our results demonstrate that accumulation of siRNAs and
      miRNAs in plants can be differentially regulated by a viral protein. The fact
      that HC-Pro affects the miRNA pathway raises the possibility that this pathway is
      targeted by plant viruses as a means to control gene expression in the host.

PMID- 12403830
TI  - Expression of the antiapoptotic baculovirus p35 gene in tomato blocks programmed
      cell death and provides broad-spectrum resistance to disease.
AB  - The sphinganine analog mycotoxin, AAL-toxin, induces a death process in plant and
      animal cells that shows apoptotic morphology. In nature, the AAL-toxin is the
      primary determinant of the Alternaria stem canker disease of tomato, thus linking
      apoptosis to this disease caused by Alternaria alternata f. sp. lycopersici. The
      product of the baculovirus p35 gene is a specific inhibitor of a class of
      cysteine proteases termed caspases, and naturally functions in infected insects.
      Transgenic tomato plants bearing the p35 gene were protected against AAL-toxin
      induced death and pathogen infection. Resistance to the toxin and pathogen co
      segregated with the expression of the p35 gene through the T3 generation, as did
      resistance to A. alternata, Colletotrichum coccodes, and Pseudomonas syringae pv.
      tomato. The p35 gene, stably transformed into tomato roots by Agrobacterium
      rhizogenes, protected roots against a 30-fold greater concentration of AAL-toxin
      than control roots tolerated. Transgenic expression of a p35 binding site mutant
      (DQMD to DRIL), inactive against animal caspases-3, did not protect against AAL
      toxin. These results indicate that plants possess a protease with substrate-site
      specificity that is functionally equivalent to certain animal caspases. A
      biological conclusion is that diverse plant pathogens co-opt apoptosis during
      infection, and that transgenic modification of pathways regulating programmed
      cell death in plants is a potential strategy for engineering broad-spectrum
      disease resistance in plants.

PMID- 12403831
TI  - Neuron-restricted expression of the rat gonadotropin-releasing hormone gene is
      conferred by a cell-specific protein complex that binds repeated CAATT elements.
AB  - GnRH gene expression is restricted to a tiny population of neurons scattered
      throughout the mediobasal hypothalamus. The combination of a 300-bp enhancer and
      the 173-bp promoter from the rat GnRH gene can confer this narrow specificity in
      transgenic mice and in transfections of hypothalamic GT1-7 cells. In the present
      study, we identify repeated CAATT elements in the 3' region of the rat GnRH
      enhancer that bind a tissue-restricted protein complex and play a significant
      role in cell-restricted expression of the GnRH gene. Deletions of multiple
      repeats demonstrate their importance in transcriptional activity. In fact, even
      mutation of a single repeat reduces expression. This reduction can be compensated
      by the conserved GnRH promoter, which also contains such elements and binds this
      protein complex. In Southwestern analysis, three proteins from GT1-7 nuclear
      extract bind to the CAATT element, and these proteins are not found in NIH3T3
      cells. This cell-specific protein complex has properties of the Q50 homeodomain
      family of transcription factors and binds to as many as seven binding sites in
      the enhancer and promoter to play a key role in GnRH gene expression in the
      hypothalamus.

PMID- 12403832
TI  - Exonic splicing enhancer-dependent splicing of the gonadotropin-releasing hormone
      premessenger ribonucleic acid is mediated by tra2alpha, a 40-kilodalton
      serine/arginine-rich protein.
AB  - In an earlier study, we found that excision of the first intron (intron A) from
      the rat GnRH primary transcript is attenuated in non-GnRH-producing cells. This
      attenuation can be partially relieved by exonic splicing enhancers (ESEs) located
      in GnRH exons 3 and 4. In the present study, we confirmed that intron A of the
      mouse GnRH pre-mRNA was not excised in a HeLa nuclear extract (NE) in vitro or in
      COS-7 cells in vivo. Intron A could, however, be partially removed when exon 3
      and/or 4 were linked to exon 2. In the presence of an ESE in exon 4 (ESE4), an
      addition of GT1 NE further increased the excision rate of intron A, whereas the
      addition of KK1 (a non-GnRH-producing cell) NE decreased it. To define the GnRH
      neuron-specific splicing activity, GT1 NE was fractionated by ultracentrifugation
      and ammonium sulfate precipitation. A 50-90% ammonium sulfate pellet (ASP50-90)
      fraction was further precipitated with 20 mM MgCl(2) to isolate a serine/arginine
      rich (SR) protein fraction. Among the ASP fractions, ASP40-50 significantly
      increased the excision rate of intron A in the presence of HeLa NE or SR protein
      rich fraction. However, the ASP40-50 fraction alone could not remove intron A.
      This result suggests the presence of a cofactor protein(s) in the ASP40-50
      fraction that may mediate the interaction between a 3' spliceosome complex and
      the ESE4-SR protein complex. UV cross-linking and gel mobility shift analysis
      revealed that Tra2alpha but not other SR proteins tested, specifically binds to
      ESE4. Moreover, Tra2alpha stimulated intron A excision in a dose-dependent
      manner. These results imply that Tra2alpha and a cofactor protein in the ASP40-50
      fraction are involved in mediating the GnRH neuron-specific excision of intron A
      from the GnRH primary transcript.

PMID- 12403833
TI  - A complex deoxyribonucleic acid response element in the rat Ca(2+)/calmodulin
      dependent protein kinase IV gene 5'-flanking region mediates thyroid hormone
      induction and chicken ovalbumin upstream promoter transcription factor 1
      repression.
AB  - Ca(2+)/calmodulin-dependent protein kinase IV (CaMKIV) is regulated by T(3) in a
      time- and concentration-dependent manner in the developing rat brain and plays an
      important role in neuronal-specific gene regulation. T(3) treatment, but not
      retinoic acid (RA), stimulated endogenous CaMKIV mRNA 5-fold in mouse embryonic
      stem (ES) cells differentiated into neurons. We localized a region -750 to -700
      in the CaMKIV gene 5'-flanking region that conferred T(3) responsiveness and
      bound thyroid hormone receptor (TR), retinoic acid receptor (RAR), and chicken
      ovalbumin upstream promoter-transcription factor 1 (COUP-TF1). T(3) and RA
      treatment stimulated the CaMKIV hormone response element. Cotransfection of a
      COUP-TF1 expression vector repressed the T(3) response and augmented the RA
      response. Mutational analysis identified three half-sites arranged in a direct
      repeat (AB) and overlapping inverted repeat (BC), required for functional
      induction and receptor binding. TR and RAR bound predominantly to the BC portion
      of the element and COUP-TF1 to the AB region, with a close correlation of binding
      and functional studies. COUP-TF1 binding did not influence TR/retinoid X receptor
      binding but modestly augmented RAR/retinoid X receptor binding. A single element
      confers T(3) and COUP-TF1 regulation of CaMKIV expression.

PMID- 12403834
TI  - Synaptosome-associated protein of 25 kilodaltons modulates Kv2.1 voltage
      dependent K(+) channels in neuroendocrine islet beta-cells through an interaction
      with the channel N terminus.
AB  - Insulin secretion is initiated by ionic events involving membrane depolarization
      and Ca(2+) entry, whereas exocytic SNARE (soluble N-ethylmaleimide-sensitive
      factor attachment protein receptor) proteins mediate exocytosis itself. In the
      present study, we characterize the interaction of the SNARE protein SNAP-25
      (synaptosome-associated protein of 25 kDa) with the beta-cell voltage-dependent
      K(+) channel Kv2.1. Expression of Kv2.1, SNAP-25, and syntaxin 1A was detected in
      human islet lysates by Western blot, and coimmunoprecipitation studies showed
      that heterologously expressed SNAP-25 and syntaxin 1A associate with Kv2.1. SNAP
      25 reduced currents from recombinant Kv2.1 channels by approximately 70% without
      affecting channel localization. This inhibitory effect could be partially
      alleviated by codialysis of a Kv2.1N-terminal peptide that can bind in vitro SNAP
      25, but not the Kv2.1C-terminal peptide. Similarly, SNAP-25 blocked voltage
      dependent outward K(+) currents from rat beta-cells by approximately 40%, an
      effect that was completely reversed by codialysis of the Kv2.1N fragment.
      Finally, SNAP-25 had no effect on outward K(+) currents in beta-cells where Kv2.1
      channels had been functionally knocked out using a dominant-negative approach,
      indicating that the interaction is specific to Kv2.1 channels as compared with
      other beta-cell Kv channels. This study demonstrates that SNAP-25 can regulate
      Kv2.1 through an interaction at the channel N terminus and supports the
      hypothesis that SNARE proteins modulate secretion through their involvement in
      regulation of membrane ion channels in addition to exocytic membrane fusion.

PMID- 12403836
TI  - Calnuc, an EF-hand Ca(2+)-binding protein, is stored and processed in the Golgi
      and secreted by the constitutive-like pathway in AtT20 cells.
AB  - Calnuc is an ubiquitous, EF-hand Ca(2+) binding protein found in the cytoplasm
      where it binds to Galphai3, in the Golgi lumen where it constitutes a Ca(2+)
      storage pool, and secreted outside the cell. Here we investigated the pathway of
      secretion of calnuc in AtT20 cells. We found by pulse-chase experiments that
      calnuc is synthesized in the endoplasmic reticulum, transported to the Golgi
      where it remains greater than 12 h and undergoes posttranslational modification
      (O-glycosylation and sulfation) followed by secretion into the culture medium. We
      examined if calnuc is secreted by the constitutive or regulated secretory pathway
      in AtT20 cells. By immunofluorescence and immunogold labeling, endogenous calnuc
      is found in immature secretion granules (ISG) but not mature regulated secretory
      granules (RSG), whereas overexpressed calnuc-green fluorescent protein (GFP) is
      found in both ISG and RSG, where it colocalizes with ACTH. Neither calnuc nor
      calnuc-GFP are released by the regulated secretory pathway, suggesting that
      endogenous calnuc and calnuc-GFP are progressively removed from ISG and RSG
      during granule maturation. We conclude that calnuc is secreted via the
      constitutive-like pathway and represents a useful endogenous marker for this
      pathway in AtT20 cells. Together, these observations indicate that calnuc has a
      unique itinerary as it is retained in the Golgi and is then constitutively
      secreted extracellularly where it may influence cell behavior via its Ca(2+)
      binding properties.

PMID- 12403837
TI  - A novel LacZ reporter mouse reveals complex regulation of the progesterone
      receptor promoter during mammary gland development.
AB  - To further our understanding of progesterone (P) as an endocrine mammogen, a
      PR(lacz) knockin mouse was generated in which the endogenous progesterone
      receptor (PR) promoter directly regulated lacZ reporter expression. The PR(lacz)
      mouse revealed PR promoter activity was restricted to the epithelial compartment
      during the prenatal and postnatal stages of mammary gland development. At
      puberty, PR promoter activity was unexpectedly robust and restricted to the body
      cells within the terminal end buds and to the luminal epithelial cells in the
      subtending ducts. In the adult, the preferential localization of PR(lacz)
      positive cells to the distal regions of ductal side branches provided a cellular
      context to the recognized mandatory role of P in ductal side-branching, and
      segregation of these cells from cells that undergo proliferation supported an
      intraepithelial paracrine mode of action for P in branching morphogenesis. Toward
      the end of pregnancy, the PR(lacz) mouse disclosed a progressive attenuation in
      PR promoter activity, supporting the postulate that the preparturient removal of
      the proliferative signal of P is a prerequisite for the emergence of a functional
      lactating mammary gland. The data suggest that PR expression before pregnancy is
      to ensure the specification and spatial organization of ductal and alveolar
      progenitor cell lineages, whereas abrogation of PR expression before lactation is
      required to enable terminal differentiation of the mammary gland.

PMID- 12403838
TI  - Interaction among four residues distributed through the secretin pharmacophore
      and a focused region of the secretin receptor amino terminus.
AB  - The amino terminus of the secretin receptor (SecR) is known to be critical for
      natural agonist action, although the role it plays is still unclear. We have
      demonstrated that photolabile residues within both the amino-terminal (position
      6) and carboxyl-terminal (positions 22 and 26) halves of secretin each covalently
      label receptor amino-terminal tail residues [Dong et al., J Biol Chem, 274:19161
      19167 (1999), 274:903-909 (1999), and 275:26032-26039 (2000)]. Here, we extend
      this series of studies with an additional probe having its site of covalent
      attachment in a distinct region of the peptide, between amino- and carboxyl
      terminal helical domains. This probe incorporated a photolabile (epsilon-p
      benzoylbenzoyl)lysine in position 18 and a site for oxidative radioiodination
      [(tyrosine(10),(benzoyl-benzoyl)lysine(18))rat secretin-27]. This analog
      represented a full agonist, stimulating cAMP accumulation in Chinese hamster
      ovary-SecR cells in a concentration-dependent manner. It bound to the SecR
      specifically and saturably, and was able to efficiently label that molecule
      within its amino terminus. Sequential specific cleavage, purification, and
      sequencing demonstrated that this probe labeled receptor residue arginine(14), in
      the same subdomain as that labeled by previous probes. Consistent with the
      importance of this residue, alanine replacement mutagenesis (R14A) resulted in
      substantial reductions in the potency (127-fold) and binding affinity (400-fold)
      of secretin relative to its action at the wild-type receptor. We have been able
      to accommodate all four extant pairs of residue-residue approximations between
      divergent regions of the secretin pharmacophore and the first forty residues of
      the SecR into a credible molecular model of this interaction. Additional
      experimentally derived constraints will be necessary to determine the spatial
      positioning of this complex with the remainder of the SecR.

PMID- 12403839
TI  - Homologous and heterologous regulation of somatostatin receptor 2.
AB  - We previously demonstrated that phosphorylation of somatostatin receptor 2A
      (sst2A) is rapidly increased in transfected cells both by agonist and by the
      protein kinase C (PKC) activator phorbol myristate acetate (PMA). Here, we
      investigate whether PKC-mediated receptor phosphorylation is involved in the
      homologous or heterologous regulation of endogenous sst2 receptors in AR42J
      pancreatic acinar cells upon stimulation by agonist or by cholecystokinin (CCK)
      or bombesin (BBS). Somatostatin, PMA, CCK, and BBS all increased sst2A receptor
      phosphorylation 5- to 10-fold within minutes. Somatostatin binding also caused
      rapid internalization of the ligand-receptor complex, and PMA, CCK, and BBS all
      stimulated this internalization further. Additionally, sst2 receptor-mediated
      inhibition of adenylyl cyclase was desensitized by all treatments. Somatostatin,
      as well as peptidic (SMS201-995) and nonpeptidic (L-779,976) sst2 receptor
      agonists increased the EC(50) for somatostatin inhibition 20-fold. In contrast,
      pretreatment with BBS, CCK, or PMA caused a modest 2-fold increase in the EC(50)
      for cyclase inhibition. Whereas the PKC inhibitor GF109203X abolished sst2A
      receptor phosphorylation by CCK, BBS, and PMA, it did not alter the effect of
      somatostatin, demonstrating that these reactions were catalyzed by different
      kinases. Consistent with a functional role for PKC-mediated receptor
      phosphorylation, GF109203X prevented PMA stimulation of sst2 receptor
      internalization. Surprisingly, however, GF109203X did not inhibit BBS and CCK
      stimulation of sst2A receptor endocytosis. These results demonstrate that
      homologous and heterologous hormones induce sst2A receptor phosphorylation by PKC
      independent and -dependent mechanisms, respectively, and produce distinct effects
      on receptor signaling and internalization. In addition, the heterologous hormones
      also modulate sst2 receptor internalization by a novel mechanism that is
      independent of receptor phosphorylation.

PMID- 12403840
TI  - Multiple internalization motifs differentially used by prolactin receptor
      isoforms mediate similar endocytic pathways.
AB  - Prolactin (PRL) regulates a variety of physiological processes, including mammary
      gland growth and differentiation, modulation of behavior, and immune function. A
      long PRL receptor (lPRLR) and short (sPRLR) isoform were identified in ruminants
      and rodents, which differ in their distal cytoplasmic domains and possess
      markedly distinct signaling capacities. Here we compared endocytosis of the
      bovine isoforms and found that the lPRLR internalized faster than the sPRLR,
      which would contribute to short-term down-regulation of lPRLR signaling at
      targets expressing both isoforms. Multiple motifs were required to mediate
      internalization of the lPRLR, including a phenylalanine (F290) plus a nearby
      dileucine, and three dileucines proximal to amino acid 272. This is different
      from the closely related GH receptor that requires only the phenyl-alanine
      containing motif for endocytosis. Truncated lPRLR (cT272), which is the same
      length as the sPRLR and contained the proximal three dileucines, internalized at
      the same rate as the full-length lPRLR. Finally, the two dileucines shared by the
      sPRLR were able to mediate similar endocytic pathways as the lPRLR, as revealed
      by overexpression of mutant dynamin and clathrin hub, despite the slower rate.
      These studies define the basis of cellular trafficking of PRLR isoforms and
      increase our understanding of control of target cell responsiveness by PRL.

PMID- 12403842
TI  - Real-time analysis of molecular interaction of retinoid receptors and receptor
      interacting protein 140 (RIP140).
AB  - Receptor interacting protein 140 (RIP140) is a coregulator for a large number of
      transcription factors. RIP140 interacts with retinoic acid receptor (RAR) and
      retinoid X receptor (RXR) with or without ligands. The C-terminal domain of
      RIP140 (RIP-C') contains a novel sequence (1063-1076, LTKTNPILYYMLQK) and has
      been shown to interact with RAR and RXR ligand dependently in two-hybrid
      interaction and pull-down assays. To examine the kinetic characteristics of
      molecular interaction of RIP-C' with RAR and RXR, a surface plasmon resonance
      technology (BIAcore) was applied for real-time analyses of this molecular
      interaction with highly purified proteins. A modified pull-down assay using
      purified proteins was also conducted to obtain supporting data. The effect of
      retinoid ligands on this type of interaction was addressed. By using receptor
      mutants, it was demonstrated that the activation function-2 domain and the
      ability to form dimers of the receptors are required for an efficient interaction
      of receptor with RIP140. Finally, with a mutagenesis approach, we determined the
      effects of specific point mutations on the kinetics of RIP-C' interaction with
      RAR/RXR.

PMID- 12403843
TI  - A novel mutation in helix 12 of the vitamin D receptor impairs coactivator
      interaction and causes hereditary 1,25-dihydroxyvitamin D-resistant rickets
      without alopecia.
AB  - Hereditary vitamin D-resistant rickets (HVDRR) is a genetic disorder most often
      caused by mutations in the vitamin D receptor (VDR). The patient in this study
      exhibited the typical clinical features of HVDRR with early onset rickets,
      hypocalcemia, secondary hyperparathyroidism, and elevated serum concentrations of
      alkaline phosphatase and 1,25-dihydroxyvitamin D [1,25-(OH)(2)D(3)]. The patient
      did not have alopecia. Assays of the VDR showed a normal high affinity low
      capacity binding site for [(3)H]1,25-(OH)(2)D(3) in extracts from the patient's
      fibroblasts. However, the cells were resistant to 1,25-dihydroxyvitamin D action
      as demonstrated by the failure of the patient's cultured fibroblasts to induce
      the 24-hydroxylase gene when treated with either high doses of 1,25-(OH)(2)D(3)
      or vitamin D analogs. A novel point mutation was identified in helix H12 in the
      ligand-binding domain of the VDR that changed a highly conserved glutamic acid at
      amino acid 420 to lysine (E420K). The patient was homozygous for the mutation.
      The E420K mutant receptor recreated by site-directed mutagenesis exhibited many
      normal properties including ligand binding, heterodimerization with the retinoid
      X receptor, and binding to vitamin D response elements. However, the mutant VDR
      was unable to elicit 1,25-(OH)(2)D(3)-dependent transactivation. Subsequent
      studies demonstrated that the mutant VDR had a marked impairment in binding
      steroid receptor coactivator 1 (SRC-1) and DRIP205, a subunit of the vitamin D
      receptor-interacting protein (DRIP) coactivator complex. Taken together, our data
      indicate that the mutation in helix H12 alters the coactivator binding site
      preventing coactivator binding and transactivation. In conclusion, we have
      identified the first case of a naturally occurring mutation in the VDR (E420K)
      that disrupts coactivator binding to the VDR and causes HVDRR.

PMID- 12403844
TI  - The thyroid hormone-regulated corepressor hairless associates with histone
      deacetylases in neonatal rat brain.
AB  - Thyroid hormone (TH) influences multiple aspects of neural development,
      presumably by controlling the transcriptional activity of TH receptors to
      modulate gene expression. The mammalian hairless (hr) gene is likely an important
      component of TH action as 1) hr expression is directly regulated by TH in brain,
      and 2) the protein encoded by hr (Hr) acts as a corepressor, facilitating
      transcriptional repression by unliganded TH receptors. Here we examine the
      properties of endogenous Hr in developing rat brain. Using coimmunoprecipitation,
      we show that Hr interacts with TH receptor and histone deacetylases (HDACs) in
      brain extracts. We find that inhibition of HDAC activity impairs Hr-mediated
      transcriptional repression, indicating that Hr-HDAC interaction is functionally
      significant. To identify potential sites of Hr action in developing brain, we
      assessed hr transcript and protein expression. We show that hr is broadly
      expressed in brain and overlaps with the expression of multiple HDACs in multiple
      regions including cortex, hippocampus, and cerebellum. Additionally, Hr
      expression is TH sensitive and developmentally regulated. The striking
      correlation of Hr expression with brain regions, cell types, and developmental
      stages influenced by TH, together with its function as a corepressor, suggests Hr
      is a key mediator of TH action in developing brain.

PMID- 12403845
TI  - Regulation of nuclear factor-kappaB by corticotropin-releasing hormone in mouse
      thymocytes.
AB  - CRH, a major mediator of the stress response, has been shown to exert potent
      immunomodulatory effects in vivo, through mechanisms that have not been
      elucidated yet. To determine the molecular pathways mediating the proinflammatory
      effects of peripheral CRH, we studied its role in the activation of nuclear
      factor-kappaB (NF-kappaB), a transcription factor crucial for the regulation of a
      variety of inflammatory mediator genes. Our studies demonstrate that, in mouse
      thymocytes, CRH induces the NF-kappaB DNA-binding activity in a time- and dose
      dependent manner, with parallel degradation of its inhibitor protein inhibitor of
      NF-kappaB. The effect of CRH is not inhibited by dexamethasone and is mediated by
      the protein kinase A and protein kinase C signaling pathways. In vivo, we show
      that CRH-deficient mice respond to lipopolysaccharide administration by reduced
      activation of thymus NF-kappaB, despite their significantly elevated
      proinflammatory cytokine and their low corticosterone levels. These findings
      suggest a putative molecular pathway mediating the proinflammatory effects of
      peripheral CRH through induction of the NF-kappaB DNA binding activity.

PMID- 12403846
TI  - Transcriptional synergism on the pS2 gene promoter between a p160 coactivator and
      estrogen receptor-alpha depends on the coactivator subtype, the type of estrogen
      response element, and the promoter context.
AB  - The pS2 gene is estrogen responsive in hepatocarcinoma cells (HepG2) in the
      presence of estrogen receptor alpha (ERalpha). The estrogenic activity is
      mediated through an estrogen response element (ERE) in the 5'-flanking region of
      the pS2 gene; however, an activator protein 1 (AP1) response element located
      close to the ERE in the pS2 promoter has also proven essential for a maximum
      response to estrogen. In the present study, we show estrogen-induced synergistic
      activity by the p160 coactivator steroid receptor coactivator-1 (SRC-1), mediated
      via the ERE and the AP1 response element in the pS2 promoter. In addition, we
      present data that support an interaction between the ERE and the AP1 motif via
      SRC-1. The related but distinct p160 coactivator, transcriptional intermediary
      factor-2, was a more potent activator of pS2 gene expression. In addition,
      transcriptional intermediary factor-2 was less dependent on an intact AP1
      response element in the pS2 promoter than SRC-1. Furthermore, the type of ERE in
      the pS2 promoter influenced the potentiation by SRC-1, supported by less
      dependence on the AP1 motif when the natural ERE was substituted for by a
      consensus ERE. These results highlight several mechanisms whereby fine-tuning of
      estrogen responsiveness of an individual gene may be achieved.

PMID- 12403847
TI  - An activated human follicle-stimulating hormone (FSH) receptor stimulates FSH
      like activity in gonadotropin-deficient transgenic mice.
AB  - FSH mediates its testicular actions via a specific Sertoli cell G protein-coupled
      receptor. We created a novel transgenic model to investigate a mutant human FSH
      receptor (FSHR(+)) containing a single amino acid substitution (Asp567Gly)
      equivalent to activating mutations in related glycoprotein hormone receptors. To
      examine the ligand-independent gonadal actions of FSHR(+), the rat androgen
      binding protein gene promoter was used to direct FSHR(+) transgene expression to
      Sertoli cells of gonadotropin-deficient hypogonadal (hpg) mice. Both normal and
      hpg mouse testes expressed FSHR(+) mRNA. Testis weights of transgenic FSHR(+) hpg
      mice were increased approximately 2-fold relative to hpg controls (P < 0.02) and
      contained mature Sertoli cells and postmeiotic germ cells absent in controls,
      revealing FSHR(+)-initiated autonomous FSH-like testicular activity. Isolated
      transgenic Sertoli cells had significantly higher basal ( approximately 2-fold)
      and FSH-stimulated ( approximately 50%) cAMP levels compared with controls,
      demonstrating constitutive signaling and cell-surface expression of FSHR(+),
      respectively. Transgenic FSHR(+) also elevated testosterone production in hpg
      testes, in the absence of circulating LH (or FSH), and it was not expressed
      functionally on steroidogenic cells, suggesting a paracrine effect mediated by
      Sertoli cells. The FSHR(+) response was additive with a maximal testosterone dose
      on hpg testicular development, demonstrating FSHR(+) activity independent of
      androgen-specific actions. The FSHR(+) response was male specific as ovarian
      expression of FSHR(+) had no effect on hpg ovary size. These findings reveal
      transgenic FSHR(+) stimulated a constitutive FSH-like Sertoli cell response in
      gonadotropin-deficient testes, and pathways that induced LH-independent
      testicular steroidogenesis. This novel transgenic paradigm provides a unique
      approach to investigate the in vivo actions of mutated activating gonadotropin
      receptors.

PMID- 12403848
TI  - Differential regulation of gonadotropin-releasing hormone secretion and gene
      expression by androgen: membrane versus nuclear receptor activation.
AB  - Steroid hormones induce rapid membrane receptor-mediated effects that appear to
      be separate from long-term genomic events. The membrane receptor-mediated effects
      of androgens on GT1-7 GnRH-secreting neurons were examined. We observed androgen
      binding activity with a cell-impermeable BSA-conjugated testosterone
      [testosterone 3-(O-carboxymethyl)oxime (T-3-BSA)] and were able to detect a 110
      kDa protein recognized by the androgen receptor (AR) monoclonal MA1-150 antibody
      in the plasma membrane fraction of the GT1-7 cells by Western analysis. Further,
      a transfected green fluorescent protein-tagged AR translocates and colocalizes to
      the plasma membrane of the GT1-7 neuron. Treatment with 10 nM 5alpha
      dihydrotestosterone (DHT) inhibits forskolin-stimulated accumulation of cAMP,
      through a pertussis toxin-sensitive G protein, but has no effect on basal cAMP
      levels. The inhibition of forskolin-stimulated cAMP accumulation by DHT was
      blocked by hydroxyflutamide, a specific inhibitor of the nuclear AR. DHT,
      testosterone (T), and T-3-BSA, all caused significant elevations in intracellular
      calcium concentrations ([Ca(2+)](i)). T-3-BSA stimulates GnRH secretion 2-fold in
      the GT1-7 neuron, as did DHT or T. Interestingly GnRH mRNA levels were down
      regulated by DHT and T as has been reported, but not by treatment with T-3-BSA or
      testosterone 17beta-hemisuccinate BSA. These studies indicate that androgen can
      differentially regulate GnRH secretion and gene expression through specific
      membrane-mediated or nuclear mechanisms.

PMID- 12403849
TI  - Epididymal dysfunction initiated by the expression of simian virus 40 T-antigen
      leads to angulated sperm flagella and infertility in transgenic mice.
AB  - We have generated two transgenic mouse lines (GPX5-Tag1 and GPX5-Tag2) by
      expressing the Simian virus 40 large and small T-antigens under a 5-kb promoter
      of the murine glutathione peroxidase 5 (GPX5) gene. In GPX5-Tag1 mice, with a
      high level of T-antigen expression, severe dysplasia was found in the epididymis
      and seminal vesicles. These mice also developed adrenal and prostate tumors, and
      spermatogenesis was disrupted. In GPX5-Tag2 mice, with a lower level of T-antigen
      expression, the only histological change was the slightly hyperplastic epithelium
      in the initial segment of the epididymidis and in the seminal vesicles. Despite
      normal mating behavior, these mice were infertile. The most conspicuous feature
      of the sperm was angulation of the flagellum, which appeared during epididymal
      transit, probably due to the observed reduction in the osmotic pressure of cauda
      epididymidal fluid. The angulation did not affect the motility or kinematic
      parameters of the sperm, but the sperm were also incapable of fertilization in
      vitro. The lack of expression of several genes specific for the initial segment
      suggests that in the GPX5-Tag2 mice the transgene expression brings about a
      differentiation arrest in this part of epididymis. This novel mouse line provides
      a model for epididymal dysfunction leading to defects in posttesticular sperm
      maturation and infertility.

PMID- 12403850
TI  - Unexpected deposition of brown fat in mammary gland during postnatal development.
AB  - Mammary fat tissue is crucial for mammary ductal morphogenesis in both fetal and
      adult mice. There are two kinds of adipocytes, the energy-storing white and the
      energy-dissipating brown adipocyte. The precise identity of the types of
      adipocyte in the mammary gland has never been investigated but was always assumed
      to be only white fat. In this study, we show that both white and brown adipocytes
      are present in the postnatal mammary gland. The amount of brown adipose tissue
      (BAT) examined by histology and electron microscopy correlates with the
      transcript levels of uncoupling protein 1, which is a mitochondrial carrier
      expressed exclusively in BAT. Uncoupling protein 1 mRNAs are the highest during
      prepuberty, decrease upon puberty, and are finally undetectable in the adult
      mammary gland. The analysis of a BAT-depleted mouse model showed that depletion
      of mammary BAT in early postnatal development induces epithelial differentiation.
      Alveolar structures were formed along all ducts and were functional since they
      produced beta-casein. However, mammary transplantation experiments indicated that
      a systemic effect was responsible for epithelium differentiation. Our data
      suggest that BAT negatively regulates the differentiation of mammary epithelial
      cells in a systemic manner during prepubertal ductal outgrowth.

PMID- 12403851
TI  - A new selective peroxisome proliferator-activated receptor gamma antagonist with
      antiobesity and antidiabetic activity.
AB  - Peroxisome proliferator-activated receptor gamma (PPAR-gamma) plays a key role in
      adipocyte differentiation and insulin sensitivity. Its synthetic ligands, the
      thiazolidinediones (TZD), are used as insulin sensitizers in the treatment of
      type 2 diabetes. These compounds induce both adipocyte differentiation in cell
      culture models and promote weight gain in rodents and humans. Here, we report on
      the identification of a new synthetic PPARgamma antagonist, the
      phosphonophosphate SR-202, which inhibits both TZD-stimulated recruitment of the
      coactivator steroid receptor coactivator-1 and TZD-induced transcriptional
      activity of the receptor. In cell culture, SR-202 efficiently antagonizes hormone
      and TZD-induced adipocyte differentiation. In vivo, decreasing PPARgamma
      activity, either by treatment with SR-202 or by invalidation of one allele of the
      PPARgamma gene, leads to a reduction of both high fat diet-induced adipocyte
      hypertrophy and insulin resistance. These effects are accompanied by a smaller
      size of the adipocytes and a reduction of TNFalpha and leptin secretion.
      Treatment with SR-202 also dramatically improves insulin sensitivity in the
      diabetic ob/ob mice. Thus, although we cannot exclude that its actions involve
      additional signaling mechanisms, SR-202 represents a new selective PPARgamma
      antagonist that is effective both in vitro and in vivo. Because it yields both
      antiobesity and antidiabetic effects, SR-202 may be a lead for new compounds to
      be used in the treatment of obesity and type 2 diabetes.

PMID- 12403852
TI  - Fetal brain progenitor cells transdifferentiate to fates outside the nervous
      system.
AB  - Central nervous system stem cells give rise to neurons and glia when exposed to
      specific trophic factors. In our studies with rat fetal brain-derived stem cells
      (RSCs), we showed that they could be induced to express the developmentally
      regulated transcription factors and cell markers characteristic of cells derived
      from another germ layer, e.g. pituitary cells. Therefore, rat fetal brain-derived
      stem cells do not seem to be restricted to a defined developmental fate. They may
      retain pluripotentiality and can be redirected to develop into other cell types
      not found in the brain provided the correct set of stimuli is present. This
      multipotent developmental behavior also suggests that instructive signals are
      operative.

PMID- 12403853
TI  - Gene expression patterns in calorically restricted mice: partial overlap with
      long-lived mutant mice.
AB  - To gain insight into the pathways by which caloric restriction (CR) slows aging,
      gene expression levels were assessed for each of 2,352 genes in the livers of 9
      month-old CR and control mice. A total of 352 genes were found to be
      significantly increased or decreased by CR. The distribution of affected genes
      among functional classes was similar to the distribution of genes within the test
      set. Surprisingly, a disruption or knockout of the gene for the GH receptor (GHR
      KO), which also produces life extension, had a much smaller effect on gene
      expression, with no more than 10 genes meeting the selection criterion. There
      was, however, an interaction between the GHR-KO mutation and the CR diet: the
      effects of CR on gene expression were significantly lower in GHR-KO mice than in
      control mice. Of the 352 genes altered significantly by CR, 29 had shown a
      significant and parallel alteration in expression in a previous study of liver
      gene expression that compared mice of the long-lived Snell dwarf stock (dw/dw) to
      controls. These 29 genes, altered both by CR and in dwarf mice, provide a list of
      biochemical features common to both models of delayed aging, and thus merit
      confirmation and more detailed study.

PMID- 12403854
TI  - Endocrine-related resources from the national institutes of health.

PMID- 12403856
TI  - Journal of Pediatric Psychology (JPP), 1998-2002: editor's vale dictum.

PMID- 12403857
TI  - The diabetes social support questionnaire-family version: evaluating adolescents'
      diabetes-specific support from family members.
AB  - OBJECTIVE: To develop and evaluate the Diabetes Social Support Questionnaire
      Family Version (DSSQ-Family) for adolescents with type 1 diabetes. METHODS:
      Normative and individualized approaches to scoring were examined. Also examined
      were associations between diabetes-specific family support and adolescents' age,
      disease duration, gender, emotional support from family and friends, and
      treatment adherence. The most supportive family behaviors were identified as
      well. Adolescents (n = 74) rated 58 DSSQ-Family behaviors on their supportiveness
      and frequency and completed measures of emotional support from family and friends
      and treatment adherence. After eliminating nonsupportive items, the Total DSSQ
      Family and five areas of diabetes care (insulin, blood testing, meals, exercise,
      emotions) were scored for frequency (normative approach) and frequency x support
      (individualized approach). The upper quartile of the DSSQ-Family items was
      identified as most supportive. RESULTS: Scores from the DSSQ-Family had high
      internal consistency. Higher frequency and individualized ratings were related to
      younger adolescent age and to more family emotional support and cohesion, but not
      to friend support or family conflict (in general). The individualized ratings
      were significant predictors of adolescents' adherence, even when controlling for
      age and general levels of family support. The most supportive family behaviors
      reflected emotional support for diabetes. CONCLUSIONS: The DSSQ-Family is a
      useful clinical and research tool for measuring adolescents' perceptions of
      diabetes-specific family support. Future interventions should stress family
      support for management tasks, taking into account the adolescent's perceptions of
      supportive behaviors. Additional research is needed with culturally diverse
      adolescents and with other chronic pediatric conditions.

PMID- 12403858
TI  - Home-based asthma education of young low-income children and their families.
AB  - OBJECTIVE: To conduct a controlled trial of a home-based education program for
      low-income caregivers of young children with asthma. METHODS: Participants were
      randomized to treatment-eight weekly asthma education sessions adapted from the
      Wee Wheezers program (n = 49)-or usual care (n = 46). Baseline and 3- and 12
      month follow-up data were gathered from caregivers and from children's medical
      records. RESULTS: Treatment was associated with less bother from asthma symptoms,
      more symptom-free days, and better caregiver quality of life at follow-up for
      children 1-3, but not those 4-6, years of age. Treatment and control groups did
      not differ in caregiver asthma management behavior or children's acute care
      utilization. CONCLUSIONS: This home-based asthma education program was most
      effective with younger children; perhaps their caregivers were more motivated to
      learn about asthma management. Targeting psychosocial factors associated with
      asthma morbidity might also enhance the efficacy of asthma education for these
      families.

PMID- 12403859
TI  - Social consequences of children's pain: when do they encourage symptom
      maintenance?
AB  - OBJECTIVE: To examine the influence of social factors (e.g., attention, relief
      from responsibility) and children's perceived competence on pediatric symptom
      maintenance. METHODS: Participants were 151 pediatric patients (ages 8-18) with
      recurrent abdominal pain. They were interviewed at a clinic visit and again 2
      weeks later. The Social Consequences of Pain questionnaire assessed four types of
      social consequences: positive attention, negative attention, activity
      restriction, and privileges. RESULTS: Two types of social consequences (positive
      attention and activity restriction) predicted greater symptom maintenance, but
      this effect was moderated by children's perceived self-worth and academic
      competence. To the extent that children rated their self-worth and academic
      competence as low, the impact of social factors on symptom maintenance was
      stronger. CONCLUSIONS: Children's success in their normal social roles may affect
      the extent to which they identify with the sick role and find it a rewarding
      alternative to other social roles.

PMID- 12403860
TI  - Siblings of children with a chronic illness: a meta-analysis.
AB  - OBJECTIVE: To review the literature pertaining to the siblings of children with a
      chronic illness. METHODS: Fifty-one published studies and 103 effect sizes were
      identified and examined through meta-analysis. RESULTS: We found (1) a modest,
      negative effect size statistic existed for siblings of children with a chronic
      illness relative to comparison participants or normative data; (2) heterogeneity
      existed for those effect sizes; (3) parent reports were more negative than child
      self-reports; (4) psychological functioning (i.e., depression, anxiety), peer
      activities, and cognitive development scores were lower for siblings of children
      with a chronic illness compared to controls; and (5) a cluster of chronic
      illnesses with daily treatment regimes was associated with negative effect
      statistics compared to chronic illnesses that did not affect daily functioning.
      CONCLUSIONS: More methodologically sound studies investigating the psychological
      functioning of siblings of children with a chronic illness are needed. Clinicians
      need to know that siblings of children with a chronic illness are at risk for
      negative psychological effects. Intervention programs for the siblings and
      families of children with a chronic illness should be developed.

PMID- 12403861
TI  - Integrated sibling-parent group intervention to improve sibling knowledge and
      adjustment to chronic illness and disability.
AB  - OBJECTIVE: To evaluate an integrated group intervention for siblings and parents
      designed to increase sibling understanding of and adjustment to chronic illness
      and developmental disability (CI/DD). METHODS: Fifty-four well siblings (ages 8
      13 years) and their parents were recruited through hospital-based and community
      agencies serving children with CI/DD. Measures of sibling knowledge, sibling
      adjustment to the disorder, sibling connectedness, and sibling global behavioral
      functioning were collected before and after the intervention. A subsample of 20
      families completed a 3-month follow-up to assess maintenance of results. RESULTS:
      Sibling knowledge of the child's disorder and sibling connectedness increased,
      while sibling reports of negative adjustment to the disorder and parent reports
      of sibling global behavioral functioning decreased significantly from pre- to
      posttreatment for both boys and girls, regardless of the type of diagnostic
      condition. Improvements in sibling knowledge, connectedness, and behavioral
      problems maintained at 3-month follow-up. Parent satisfaction with the program
      was high. CONCLUSIONS: Results support the future conduct of more controlled
      evaluation of the integrated sibling and parent group intervention model to
      improve sibling knowledge of and adjustment to CI/DD.

PMID- 12403862
TI  - Health risks in American Indian adolescents: a descriptive study of a rural, non
      reservation sample.
AB  - OBJECTIVE: To identify health risks among a rural, non-reservation group of
      American Indian adolescents. METHODS: A non-reservation sample of 243 American
      Indian students from a total sample of 1,815 students in a southwestern state
      completed health-risk screenings in the public schools. The students were between
      14 and 18 years of age and in grades 9 through 12. Archival survey data were
      analyzed by age, gender, and race. RESULTS: Student reports of health-risk
      behaviors in the areas of physical health, substance use, emotional health, risk
      of injury, perceived grades, and academic expectations were examined. The
      majority of study participants reported average or below levels of health risks.
      CONCLUSIONS: Non-reservation American Indian students have average or better
      health habits and expect to continue their educations beyond high school. There
      are some differences by gender and age.

PMID- 12403863
TI  - Unintentional injury in preschool boys with and without early onset of disruptive
      behavior.
AB  - OBJECTIVE: To determine subsequent risk of unintentional injury among preschool
      boys diagnosed with ODD, boys with comorbid ODD and ADHD, and boys matched
      demographically to the clinical sample; to test predictive validity of a measure
      of injury proneness; and to examine factors that might predict injury beyond
      clinic status. METHODS: Seventy-nine consecutive clinic-referred preschool-age
      boys and 76 demographically matched boys without disruptive behavior participated
      in a 2-year prospective longitudinal design. Time 1 assessment included clinical
      diagnosis, parent-reported injury proneness, attachment, and verbal abilities.
      Injury history was measured 1 and 2 years later. RESULTS: Clinic-referred
      children had more injuries than the comparison group. Children with comorbid ODD
      and ADHD had approximately the same injury rate as those with ODD but not ADHD.
      Parent-reported injury proneness was unrelated to subsequent injuries. Neither
      attachment nor verbal ability predicted injury significantly beyond clinic
      status. CONCLUSIONS: Children with early disruptive behavior are at increased
      risk of unintentional injury and therefore should be considered prime candidates
      for injury prevention campaigns.

PMID- 12403864
TI  - Cognitive functioning in children with sickle cell disease: a meta-analysis.
AB  - OBJECTIVE: To establish whether sickle cell disease (SCD) affects cognitive
      functioning in children with no evidence of cerebral infarction. METHODS: We
      conducted a meta-analysis of studies of cognition in SCD to determine the size of
      any statistical difference between children with SCD and controls. Methodological
      factors were evaluated according to the size and frequency of group differences.
      RESULTS: There were small but reliable decrements in cognitive functioning on IQ
      measures (4.3-point difference overall). The most methodologically rigorous
      studies showed a highly similar pattern. Sampling issues associated with the
      effect size for IQ were identified. Measures of specific abilities appear more
      sensitive than IQ scores to cognitive decrements in SCD. CONCLUSIONS: SCD is
      associated with cognitive effects even in the absence of cerebral infarction. The
      causes of this cognitive decrement may include direct effects of SCD on brain
      function or indirect effects of chronic illness.

PMID- 12403865
TI  - A child-focused intervention for coping with procedural pain: are parent and
      nurse coaches necessary?
AB  - OBJECTIVE: To examine the efficacy of training children to cope with immunization
      pain without the assistance of trained coaches and determine whether untrained
      parents or nurses are more effective at decreasing children's distress. METHODS:
      We compared the procedural coping and distress behavior of 31 3- to 7-year-old
      children trained in coping skills to 30 who did not receive training. The
      behavior of the untrained parents and nurses was evaluated as it related to child
      coping and distress. RESULTS: Children demonstrated understanding of the
      training, but they did not use the coping skills during the procedure. In
      general, the nurses' behavior was associated with child coping and parents'
      behavior with child distress. CONCLUSIONS: More extensive child training or the
      involvement of coaches for procedural distress might be necessary. Nurses'
      behavior appears to center on encouraging child coping, and parents tend to
      comfort child distress.

PMID- 12403866
TI  - Brief report: self-care behaviors of children with type 1 diabetes living in
      Puerto Rico.
AB  - OBJECTIVE: To examine self-care behaviors among children and adolescents with
      type 1 diabetes living in Puerto Rico, to determine the relationship between self
      care and demographic variables, and to investigate the utility of the 24-hour
      recall interview within a Hispanic population. METHOD: Forty-one children (M age
      = 12.6 years) with type 1 diabetes, and their mothers, were administered the 24
      hour recall interview on three separate occasions to assess diabetes-related self
      care behaviors. RESULTS: Children reported self-care behaviors that included
      daily administration of an average of two insulin injections and two blood
      glucose tests, and consumption of 5.5 meals a day comprised of 52% carbohydrates
      and 29% fat. Younger age, female gender, longer illness duration, and better
      metabolic control were associated with higher rates of several self-care
      behaviors. CONCLUSIONS: Data provide a first look at self-care behaviors of
      children with type 1 diabetes living in Puerto Rico and suggest the utility of
      the 24-hour recall interview within this population.

PMID- 12403867
TI  - The legacy of Lizette Peterson-Homer in pediatric psychology (1951-2002).

PMID- 12403869
TI  - Cross infection of cystic fibrosis patients with Pseudomonas aeruginosa.

PMID- 12403870
TI  - Opioids for dyspnoea.

PMID- 12403871
TI  - Increased treatment requirements of patients with cystic fibrosis who harbour a
      highly transmissible strain of Pseudomonas aeruginosa.
AB  - BACKGROUND: A group of patients who harbour the same highly transmissible strain
      of Pseudomonas aeruginosa were identified at a cystic fibrosis (CF) centre.
      Isolates of this strain display a number of unusual phenotypic features including
      resistance to most typical antipseudomonal antibiotics. A study was undertaken to
      see if there was a difference in treatment requirements between CF patients with
      chronic infection with their own unique P aeruginosa strains (group 1) and those
      who harbour a highly transmissible strain (group 2). METHODS: Data on treatment
      requirements for the year 2000 were collected from the case records of CF
      patients with chronic P aeruginosa infection who had received inpatient
      treatment. Patients co-infected with Burkholderia cepacia or other highly
      transmissible strains of P aeruginosa were excluded. RESULTS: There were 2/56 and
      3/22 deaths in groups 1 and 2, respectively; these patients were excluded from
      the analysis. No difference was found between the two groups for mean age, %
      predicted forced expiratory volume in 1 second (FEV(1)), % predicted forced vital
      capacity (FVC), and body mass index. Patients in group 2 had a greater median
      (range) number of intravenous antibiotic days (60 (17-216) v 33 (4-237) days;
      p=0.01), inpatient days (39 (7-183) v 16 (1-172) days; p<0.01), and inpatient
      episodes (3 (1-9) v 2 (1-6); p<0.01), and more respiratory exacerbations (mean
      (SD) 8.2 (3.4) v 6.1 (3.2); p=0.01). CONCLUSIONS: Patients who harbour the highly
      transmissible P aeruginosa strain have a greater treatment burden than patients
      with CF who harbour their own unique strains. These findings support the need for
      microbiological surveillance for highly transmissible P aeruginosa and the
      implementation of infection control measures to prevent cross infection.

PMID- 12403872
TI  - Airways in cystic fibrosis are acidified: detection by exhaled breath condensate.
AB  - BACKGROUND: The loss of cystic fibrosis transmembrane conductance regulator
      (CFTR) mediated chloride conductance does not fully explain the diverse
      pathologies evident in patients with cystic fibrosis (CF). Bicarbonate (HCO(3)(
      )) secretion is also impaired in CFTR expressing tissues and CFTR is thought to
      regulate HCO(3)(-) secretion at the apical membrane of epithelial cells. We
      hypothesised that the epithelial lining fluid (ELF) of patients with CF would be
      acidified and that this may be worsened during an infective exacerbation due to
      the increased inflammatory burden. METHODS: pH and nitrite levels in exhaled
      breath condensate (EBC) from 12 healthy non-smoking controls and 30 patients with
      CF (11 of whom were in an infective exacerbation) were measured. A further nine
      patients were studied before and after intravenous antibiotic treatment for an
      exacerbation of CF. RESULTS: The pH of EBC was significantly lower in patients
      with stable CF than in controls (5.88 (0.32) v 6.15 (0.16), p=0.017), and was
      further reduced in CF patients with an exacerbation (5.32 (0.38), p=0.001)
      compared with stable CF patients. EBC pH increased significantly following
      antibiotic treatment from 5.27 (0.42) to 5.71 (0.42), p=0.049). Nitrite levels in
      EBC were increased in CF patients with an exacerbation compared with control
      subjects (4.4 (4.0) micro m v 1.6 (1.6) micro m p=0.047). No correlation was
      found between EBC pH and nitrite levels. CONCLUSIONS: These findings support the
      hypothesis that airway acidification occurs in CF. This acidity is in part a
      function of inflammation as the pH of the EBC of patients increased significantly
      with treatment of an exacerbation, although not to control levels. Acidic pH of
      the ELF may play a role in the pathophysiology of CF lung disease and requires
      further investigation.

PMID- 12403873
TI  - Matrix metalloproteases in BAL fluid of patients with cystic fibrosis and their
      modulation by treatment with dornase alpha.
AB  - BACKGROUND: Matrix metalloproteinases (MMPs) are involved in the remodelling and
      degradation of extracellular matrix and may play a role in pulmonary tissue
      destruction in cystic fibrosis (CF). METHODS: Bronchoalveolar lavage (BAL) fluid
      levels of MMP-8, MMP-9, and their natural inhibitor TIMP-1 were measured on two
      occasions within 18 months in 23 children with mild CF, 13 of whom were treated
      with DNase. RESULTS: MMP-8 (39.3 (6.8) v 0.12 (0.01) ng/ml), MMP-9 (58.0 (11.4) v
      0.5 (0.02) ng/ml), and the molar ratio of MMP-9/TIMP-1 (0.36 (0.05) v 0.048
      (0.01)) were significantly higher in patients with CF than in control children
      without lung disease. Gelatine zymography showed the typical banding pattern of
      neutrophil derived MMP-9, including 130 kDa NGAL-MMP-9 complex and 92 kDa latent
      MMP-9 bands; 85 kDa bands (corresponding to active MMP-9) were seen in all
      patients. There was a close correlation between BAL fluid concentrations of MMPs
      and alpha(2)-macroglobulin, a marker of alveolocapillary leakage. After 18 months
      MMP levels were increased in untreated patients and decreased in patients treated
      with DNase. CONCLUSIONS: Uninhibited MMPs may contribute to pulmonary tissue
      destruction even in CF patients with mild lung disease that may be positively
      affected by treatment with DNase.

PMID- 12403874
TI  - Bronchoscopic findings in children with non-cystic fibrosis chronic suppurative
      lung disease.
AB  - BACKGROUND: Published data on the frequency and types of flexible bronchoscopic
      airway appearances in children with non-cystic fibrosis bronchiectasis and
      chronic suppurative lung disease are unavailable. The aims of this study were to
      describe airway appearances and frequency of airway abnormalities and to relate
      these airway abnormalities to chest high resolution computed tomography (cHRCT)
      findings in a cohort of children with non-cystic fibrosis chronic suppurative
      lung disease (CSLD). METHODS: Indigenous children with non-cystic fibrosis CSLD
      (>4 months moist and/or productive cough) were prospectively identified and
      collected over a 2.5 year period at two paediatric centres. Their medical charts
      and bronchoscopic notes were retrospectively reviewed. RESULTS: In all but one
      child the aetiology of the bronchiectasis was presumed to be following a
      respiratory infection. Thirty three of the 65 children with CSLD underwent
      bronchoscopy and five major types of airway findings were identified (mucosal
      abnormality/inflammation only, bronchomalacia, obliterative-like lesion,
      malacia/obliterative-like combination, and no macroscopic abnormality). The
      obliterative-like lesion, previously undescribed, was present in 16.7% of
      bronchiectatic lobes. Structural airway lesions (bronchomalacia and/or
      obliterative-like lesion) were present in 39.7% of children. These lesions, when
      present, corresponded to the site of abnormality on the cHRCT scan. CONCLUSIONS:
      Structural airway abnormality is commonly found in children with post-infectious
      bronchiectasis and a new bronchoscopic finding has been described. Airway
      abnormalities, when present, related to the same lobe abnormality on the cHRCT
      scan. How these airway abnormalities relate to aetiology, management strategy,
      and prognosis is unknown.

PMID- 12403875
TI  - A systematic review of the use of opioids in the management of dyspnoea.
AB  - BACKGROUND: Opioids are commonly used to treat dyspnoea in palliative medicine
      but there has been no formal evaluation of the evidence for their effectiveness
      in the treatment of dyspnoea. A systematic review was therefore carried out to
      examine this. METHODS: The criteria for inclusion required that studies were
      double blind, randomised, placebo controlled trials of opioids for the treatment
      of dyspnoea secondary to any cause. The methods used to identify suitable studies
      included electronic searching of the literature, hand searching of the
      literature, and personal contact with relevant individuals and organisations.
      Random effects meta-analyses were performed on all included studies and on
      various subgroups (studies involving nebulised opioids or patients with chronic
      obstructive pulmonary disease (COPD)). Subgroups were compared using meta
      regression. Some studies included in the systematic review could not be included
      in the meta-analysis because insufficient data were presented. RESULTS: Eighteen
      studies fulfilled the criteria for the review. The meta-analysis showed a
      statistically significant positive effect of opioids on the sensation of
      breathlessness (p=0.0008). Meta-regression indicated a greater effect for studies
      using oral or parenteral opioids than for studies using nebulised opioids
      (p=0.02). The subgroup analysis failed to show a positive effect of nebulised
      opioids on the sensation of breathlessness. The results of the subgroup analysis
      of the COPD studies were essentially similar to the results of the main analysis.
      CONCLUSION: This review supports the continued use of oral and parenteral opioids
      to treat dyspnoea in patients with advanced disease. There are insufficient data
      from the meta-analysis to conclude whether nebulised opioids are effective, but
      the results from included studies that did not contribute to the meta-analysis
      suggest that they are no better than nebulised normal saline.

PMID- 12403876
TI  - Early exposure to children in family and day care as related to adult asthma and
      hay fever: results from the European Community Respiratory Health Survey.
AB  - BACKGROUND: The literature indicates that early exposure to children in the
      family and to day care permanently influences the development of allergic
      disease. A study was undertaken to examine the associations of family size and
      day care with adult asthma and hay fever and to determine whether these
      associations are mediated through specific IgE production and whether they vary
      with allergic predisposition. METHODS: 18,530 subjects aged 20-44 years from 36
      areas predominantly in the market economies participated in the European
      Community Respiratory Health Survey and provided information through interviewer
      led questionnaires. 13,932 subjects gave blood samples for measurement of
      specific IgE. RESULTS: Hay fever was less common in subjects with many siblings
      (OR=0.92; 95% CI 0.90 to 0.95 per sib). There was a U-shaped relationship between
      asthma and number of siblings (quadratic effect of siblings, pwheeze=0.014,
      pFEV(1)=0.016). In subjects without siblings but exposed to children in day care,
      hay fever was less common (OR=0.76; 95% CI 0.60 to 0.98) and asthma symptoms were
      more common (ORwheeze=1.48; 95% CI 1.12 to 1.95). Adjustment for specific IgEs
      did not alter these associations. The inverse association of hay fever with
      siblings was found in sensitised subjects (OR=0.89; 95% CI 0.84 to 0.94) and in
      those with parental allergy (OR=0.91; 95% CI 0.85 to 0.97), but not in subjects
      without such a predisposition (OR=1.02; 95% CI 0.97 to 1.09). CONCLUSION:
      Subjects exposed to many children at home or in day care experienced less hay
      fever and more asthma in adulthood. Microbial challenge through children may
      contribute to a non-allergic immunological development giving less hay fever but
      more airways infections predisposing to asthma. These effects were not mediated
      through production of specific IgE. The protective effect of siblings on hay
      fever was particularly strong in those with an allergic predisposition.

PMID- 12403877
TI  - Comparative epidemiology of atopic and non-atopic wheeze and diagnosed asthma in
      a national sample of English adults.
AB  - BACKGROUND: There is debate as to whether asthma has distinct atopic and non
      atopic forms and whether in epidemiological studies asthma cases should be
      defined by a physician diagnosis or by self-reported asthma symptoms. METHODS: A
      total of 24,952 people aged 11 and over were surveyed as part of the 1995-6
      health surveys for England. Participants were asked if they had experienced
      wheezing in the past year and if they had ever been given a diagnosis of asthma
      by a doctor. Serum total IgE and house dust mite (HDM) specific IgE were
      measured. RESULTS: Wheeze in the past year without an asthma diagnosis was more
      common in men and older age groups, whereas wheeze with an asthma diagnosis was
      more common in women and younger people. Both types of wheeze were more common in
      the lower social classes, among ex-smokers and current smokers, and in urban
      areas. Thirty two percent of people reporting wheezing and 22% of those with
      diagnosed asthma had neither raised total IgE nor HDM IgE. Among the non-atopic
      subjects the prevalence of wheeze rose with age and lower social class, largely
      due to an increase in wheeze without diagnosed asthma. In contrast, among atopic
      subjects there was no overall trend with age or social class, but wheeze with
      diagnosed asthma decreased with age. CONCLUSIONS: Clear epidemiological
      differences are evident between adult wheeze with and without an asthma diagnosis
      and between atopic and non-atopic wheeze. Subjects with diagnosed asthma are more
      likely to be atopic, but the results challenge the premise that adult asthma is
      almost always associated with some IgE mediated reaction.

PMID- 12403879
TI  - Tobacco smoking and pulmonary tuberculosis.
AB  - BACKGROUND: The prevalence of tuberculosis in adult men in India is 2-4 times
      higher than in women. Tobacco smoking is prevalent almost exclusively among men,
      so it is possible that tobacco smoking may be a risk factor for developing
      pulmonary tuberculosis. A nested case control study was carried out to study the
      association between tobacco smoking and pulmonary tuberculosis. METHODS: A
      tuberculosis disease survey was carried out in two Panchayat unions in the
      Tiruvallur district of Tamil Nadu in India. Eighty five men aged 20-50 years with
      bacteriological tuberculosis (smear and/or culture positive) were selected as
      cases and 459 age matched men without tuberculosis were selected randomly as
      controls. Information on smoking status, type of tobacco smoked, quantity of
      tobacco smoked, and duration of tobacco smoking was collected from cases and
      controls using a questionnaire. RESULTS: The estimated crude odds ratio (OR) of
      the association between tobacco smoking and bacillary tuberculosis was 2.48 (95%
      confidence interval (CI) 1.42 to 4.37), p<0.001. The age adjusted OR (Mantel
      Hanszel estimate) was 2.24.(95% CI 1.27 to 3.94), p<0.05. The ORs for mild (1-10
      cigarettes/day), moderate (11-20/day), and heavy (>20/day) smokers were 1.75,
      3.17, and 3.68, respectively (p<0.0001 test for linear trend). The ORs for
      smokers with <10 years, 11-20 years, and >20 years of smoking were 1.72, 2.45,
      and 3.23, respectively (p<0.0001 test for linear trend). CONCLUSION: There is a
      positive association between tobacco smoking and pulmonary (bacillary)
      tuberculosis (OR 2.5). The association also shows a strong dose-response
      relationship.

PMID- 12403878
TI  - Paracetamol use in pregnancy and wheezing in early childhood.
AB  - BACKGROUND: We recently reported links between frequent paracetamol
      (acetaminophen) use and wheezing and asthma in adults and children, but data are
      lacking on possible effects of prenatal exposure on wheezing in early childhood.
      METHODS: In the population based Avon Longitudinal Study of Parents and Children
      (ALSPAC) women were asked twice during pregnancy (at 18-20 weeks and 32 weeks)
      about their usage of paracetamol and aspirin. Six months after birth, and at
      yearly intervals thereafter, mothers were asked about wheezing and eczema
      symptoms in their child. The effects of paracetamol and aspirin use in pregnancy
      on the risk in the offspring of wheezing at 30-42 months (n=9,400) and eczema at
      18-30 months (n=10,216) and on their risk of different wheezing patterns (defined
      by presence or absence of wheezing at <6 months and at 30-42 months) were
      examined. RESULTS: Paracetamol was taken frequently (most days/daily) by only 1%
      of women. After controlling for potential confounders, frequent paracetamol use
      in late pregnancy (20-32 weeks), but not in early pregnancy (<18-20 weeks), was
      associated with an increased risk of wheezing in the offspring at 30-42 months
      (adjusted odds ratio (OR) compared with no use 2.10 (95% CI 1.30 to 3.41);
      p=0.003), particularly if wheezing started before 6 months (OR 2.34 (95% CI 1.24
      to 4.40); p=0.008). Assuming a causal relation, only about 1% of wheezing at 30
      42 months was attributable to this exposure. Frequent paracetamol use in
      pregnancy was not associated with an increased risk of eczema. Frequent aspirin
      use in pregnancy was associated with an increased risk of wheezing only at <6
      months. CONCLUSIONS: Frequent use of paracetamol in late pregnancy may increase
      the risk of wheezing in the offspring, although such an effect could explain only
      about 1% of the population prevalence of wheezing in early childhood.

PMID- 12403880
TI  - Risk of hospital admission for COPD following smoking cessation and reduction: a
      Danish population study.
AB  - BACKGROUND: Little is known about the effects of changes in smoking habits on the
      subsequent risk of chronic obstructive pulmonary disease (COPD). The aim of this
      study was to investigate the relationship between smoking cessation and reduction
      and admission to hospital for COPD in a general population sample. METHODS: A
      total of 19,709 participants from three prospective population studies in
      Copenhagen were followed with record linkage for date of first hospital admission
      for COPD until 1998 (mean follow up 14 years). Heavy smokers (>/=15
      cigarettes/day) who reduced their tobacco consumption by at least 50% between the
      two initial examinations without quitting and smokers who stopped smoking during
      this time were compared with continuous heavy smokers using a Cox proportional
      hazards model. RESULTS: During the follow up period 1,260 subjects (741 men and
      519 women) were admitted to hospital for COPD. After multivariate adjustment,
      quitting smoking was associated with a significant reduction in the risk of
      hospital admission. The relative hazard (HR) was 0.57 (95% confidence interval
      (CI) 0.33 to 0.99). Those who reduced smoking did not show a significantly lower
      risk of hospitalisation than continuing heavy smokers (HR 0.93 (95% CI 0.73 to
      1.18)). Exclusion of events during the first 5 study years, detailed adjustment
      for lung function, or restriction of analyses to participants with impaired
      pulmonary function did not reverse the observed trend. CONCLUSIONS: Self-reported
      smoking cessation is associated with a reduction in the risk of COPD morbidity of
      approximately 40%; the benefit of smoking reduction is questionable.

PMID- 12403881
TI  - Exposure to indoor combustion and adult asthma outcomes: environmental tobacco
      smoke, gas stoves, and woodsmoke.
AB  - BACKGROUND: Because they have chronic airway inflammation, adults with asthma may
      be particularly susceptible to indoor air pollution. Despite widespread exposure
      to environmental tobacco smoke (ETS), gas stoves, and woodsmoke, the impact of
      these exposures on adult asthma has not been well characterised. METHODS: Data
      were used from a prospective cohort study of 349 adults with asthma who underwent
      structured telephone interviews at baseline and 18 month follow up. The
      prospective impact of ETS, gas stove, and woodsmoke exposure on health outcomes
      was examined. RESULTS: ETS exposure at baseline interview was associated with
      impaired health status at longitudinal follow up. Compared with respondents with
      no baseline self-reported exposure to ETS, higher level exposure (>/=7
      hours/week) was associated with worse severity of asthma scores at follow up,
      controlling for baseline asthma severity, age, sex, race, income, and educational
      attainment (mean score increment 1.5 points; 95% CI 0.4 to 2.6). Higher level
      baseline exposure to ETS was also related to poorer physical health status (mean
      decrement -4.9 points; 95% CI -8.4 to -1.3) and asthma specific quality of life
      (mean increase 4.4 points; 95% CI -0.2 to 9.0) at longitudinal follow up. Higher
      level baseline ETS exposure was associated with a greater risk of emergency
      department visits (OR 3.4; 95% CI 1.1 to 10.3) and hospital admissions for asthma
      at prospective follow up (OR 12.2; 95% CI 1.5 to 102). There was no clear
      relationship between gas stove use or woodstove exposure and asthma health
      outcomes. CONCLUSION: Although gas stove and woodstove exposure do not appear
      negatively to affect adults with asthma, ETS is associated with a clear
      impairment in health status.

PMID- 12403882
TI  - Comparison of proportional assist ventilation and pressure support ventilation in
      chronic respiratory failure due to neuromuscular and chest wall deformity.
AB  - BACKGROUND: The physiological and symptomatic effects of proportional assist
      ventilation (PAV) and pressure support ventilation (PSV) were compared in stable
      awake patients with neuromuscular and chest wall deformity (NMCWD). METHODS:
      Oxygen saturation (SaO(2)), transcutaneous carbon dioxide (TcCO(2)), minute
      ventilation (VE), tidal volume (VT), respiratory rate (RR), and diaphragm
      electromyography (EMGdi) were measured in 15 patients during both modes.
      Subjective effort of breathing and synchrony with the ventilator were assessed
      using visual analogue scales. RESULTS: Three of 15 patients failed to trigger the
      ventilator in either mode and were excluded. In the 12 remaining patients there
      were similar improvements in SaO(2), TcCO(2), VE, VT, and RR during both modes.
      The mean (SD) percentage fall in EMGdi was greater during PSV (-80.5 (10.7)%)
      than during PAV (-41.3 (35.2)%; p= 0.01). Effort of breathing (p=0.004) and
      synchrony with the ventilator (p=0.004) were enhanced more with PSV than with
      PAV. CONCLUSION: Both PSV and PAV produced similar improvements in physiological
      parameters. However, greater diaphragm unloading was observed with PSV than with
      PAV, associated with greater symptomatic benefit. These findings suggest that
      tolerance to PAV may be compromised in patients with NMCWD.

PMID- 12403883
TI  - Chronic obstructive pulmonary disease. 4: imaging the lungs in patients with
      chronic obstructive pulmonary disease.
AB  - The role of chest radiography and computed tomography in the evaluation of
      pulmonary emphysema and chronic bronchitis is reviewed.

PMID- 12403884
TI  - The pulmonary physician in critical care. 10: difficult weaning.
AB  - The study of patients being weaned from mechanical ventilation has offered new
      insights into the physiology of respiratory failure. Assessment of the balance
      between respiratory muscle strength, work and central drive is essential if
      difficulty in weaning occurs, and optimisation of these elements may improve the
      success of weaning. Psychological support of patients and the creation of units
      specialising in weaning have also resulted in a higher success rate.

PMID- 12403885
TI  - Lung cancer. Introduction.
AB  - A series of review articles on lung cancer beginning in this issue of Thorax aims
      to increase the awareness of up to date evidence based knowledge and to generate
      further interest and optimism in its diagnosis and management.

PMID- 12403888
TI  - NIV guidelines.

PMID- 12403887
TI  - Pneumonitis induced by rifampicin.
AB  - An 81-year-old man was admitted to hospital with pulmonary Mycobacterium
      tuberculosis infection and was treated with rifampicin (RFP), isoniazid (INH),
      and ethambutol (EB). On day 9 he developed fever and dyspnoea. Chest radiographs
      showed new infiltration shadows in the right lung. Bronchoalveolar lavage (BAL)
      was performed and increased numbers of lymphocytes were recovered. Drug induced
      pneumonitis was suspected so the antituberculous regimen was discontinued and
      methylprednisolone was administered. The symptoms and infiltration shadows
      improved. INH and EB were reintroduced without any recurrence of the abnormal
      shadows. T cell subsets in the BAL fluid and a positive lymphocyte stimulation
      test for RFP suggest that RFP induced pneumonitis may be related to a complex
      immunological response.

PMID- 12403886
TI  - Lung cancer. 1: prevention of lung cancer.
AB  - Cancer of the lung causes more deaths from cancer worldwide than at any other
      site. The environmental, genetic, and dietary risk factors are discussed and
      progress in chemoprevention is reviewed. A better understanding of the molecular
      events that occur during carcinogenesis has opened up new areas of research in
      cancer prevention and a number of biochemical markers of high risk individuals
      have been identified. It is predicted that greater success in chemoprevention
      will be achieved in the next decade than in the last.

PMID- 12403890
TI  - Should interventional cardiologists treat ischemic strokes? A global perspective.
AB  - Stroke is the third leading cause of death and the leading cause of severe
      neurological disability in our nation. The stroke death rate has the potential to
      reach epidemic proportions as the elderly segment of the population continues to
      rise. There is an insufficient number of trained physicians to supply the care
      for this patient population. The logical source for qualified physicians to care
      for these patients is the interventional cardiologist. We review the recent
      intraarterial therapy trials and detail the training necessary to allow
      interventional cardiologists to treat ischemic strokes.

PMID- 12403891
TI  - Percutaneous femoral arteriotomy repair -- initial experience with a novel staple
      closure device.
AB  - The Vascular Closure System (EVS ) is the first device to utilize a staple
      mechanism to close percutaneous femoral arteriotomies following catheter-based
      procedures. To assess safety and efficacy, the EVS  was used to close 89
      consecutive femoral arteriotomies. Closure success was defined as complete
      cessation of bleeding within five minutes of staple delivery. The overall closure
      success rate was 92.1% (n = 82). Mean time to complete hemostasis was 2.47   1.42
      minutes. No complication (re-bleeding, pseudoaneurysm, transfusion, arteriovenous
      fistula, infection or decrease in distal pulses) occurred at 24-hour and 7-day
      follow-up. We conclude that staple-based technology provides a safe and useful
      method for mechanical closure of percutaneous femoral arteriotomies.

PMID- 12403892
TI  - Usefulness of fractional flow reserve guidance for PCI in acute myocardial
      infarction.
AB  - Objectives. After conventional balloon angioplasty (PTCA) for acute myocardial
      infarction in 77 patients (77 lesions), we used myocardial fractional flow
      reserve (FFR(myo)) to assess the endpoint of percutaneous coronary intervention
      (PCI) and to determine whether adjunctive stenting was required. Of these, a
      total of 37 lesions with FFR > or = 0.94 after PTCA received no further treatment
      (FFR-PTCA group), while the remaining 40 lesions (FFR < 0.94) underwent
      adjunctive stenting (FFR-stent group). A further 78 patients (78 lesions)
      comprised the control group; these patients underwent direct stenting without FFR
      measurement (stent-only group). The restenosis rate at 14-day discharge (mean
      time to discharge) was 5.1% in the two groups treated with FFR guidance (FFR-PTCA
      and FFR-stent), but was 0% in the control group (p = ns). There were no
      significant differences in reocclusion rates between the FFR-guided patients
      (1.7%) and the controls (0%). There was no incidence of in-hospital mortality or
      reinfarction in any of the groups. The number of balloons used (mean, 1.3 0.6
      balloons for FFR patients versus 1.8 0.5 balloons for control patients) and the
      total cost of hospitalization and treatment ($16,213 versus $19,730 in U.S.
      currency; 1,945,571 998,726 yen versus 2,367,656 538,444 yen in Japanese
      currency) were both higher in the control group. Long-term survival rates were
      comparable in the two groups. These findings indicate that FFR guidance for PCI
      of acute myocardial infarction is a useful, low-cost technique that results in
      similar clinical outcomes as primary stenting.

PMID- 12403893
TI  - Stenting for acute myocardial infarction -- can we do better?

PMID- 12403894
TI  - Long-term cardiac function and outcome in patients receiving primary angioplasty
      for AMI at a community hospital without on-site surgical back-up.
AB  - BACKGROUND: Short- and long-term comparative follow-up studies of patients
      receiving primary angioplasty or thrombolytic therapy for acute myocardial
      infarction show higher 30-day survival, and sustained benefits in mortality,
      reinfarction and ejection fraction in patients treated with primary angioplasty.
      Long-term benefits of primary angioplasty on cardiac function performed in
      community hospitals without surgical back-up have not been fully assessed.
      METHODS: Sixty-one patients who underwent primary angioplasty were compared with
      patients receiving thrombolytic therapy who were matched for age, gender and
      location of acute myocardial infarction. Clinical information, reviewed through
      August 2000, was provided by retrospective analysis of healthcare databases and
      office and hospital charts. Mortality data were confirmed by the social security
      death index. RESULTS: Of the original 61 primary angioplasty patients, two died
      during initial hospitalization. Of the 59 surviving patients, fifty-four (92%)
      had complete follow-up averaging 57 months. Of the original 61 thrombolytic
      therapy patients, three died during initial hospitalization. Of the 58 surviving
      patients, fifty-two (90%) had complete follow-up averaging 46 months. At follow
      up, averaging 57 months, ejection fraction was significantly higher in the
      primary angioplasty group, as compared with the thrombolytic therapy group (51.4%
      versus 45.8%, respectively; p = 0.038). There was no statistical difference
      between the two groups regarding reinfarction, revascularization at > or = 6
      months after the initial presentation or cardiac death. CONCLUSIONS: Primary
      angioplasty performed in a community hospital without surgical back-up results in
      improved cardiac function when compared to thrombolytic therapy. These results
      are similar to those reported from large tertiary centers with on-site surgical
      back-up, and provide an explanation for the improved long-term outcome that is
      observed in patients with acute myocardial infarction treated with primary
      angioplasty.

PMID- 12403895
TI  - Five French versus 6 French PCI: a case control study of efficacy, safety and
      outcome.
AB  - We report our experience of percutaneous coronary intervention (PCI) with 5
      French (Fr) guiding catheters in a retrospective analysis of consecutive cases
      undergoing ad hoc PCI. Results were compared with a cohort of 6 Fr PCI cases
      matched for age, sex and operator over the same study period. A total of 210
      patients (311 lesions) underwent PCI using 5 Fr guiding catheters and 174 matched
      patients (300 lesions) underwent PCI with 6 Fr guiding catheters. Multivessel PCI
      was performed in 18% of patients in the 5 Fr group and in 26% of the 6 Fr group
      (p = 0.046). There was no difference in clinical, angiographic or procedural
      characteristics between groups. Technical success rate was superior in the 5 Fr
      group compared with the 6 Fr (99% versus 95%; p = 0.03). The rate of stent
      implantation did not differ and the 5 Fr guiding catheter did not prohibit the
      use of large or long stents/balloons. Failure of 5 Fr PCI in 3 cases was not due
      to inadequate guiding catheter support. In-hospital major adverse cardiac events
      (MACE) and serious femoral complications were rare and at 6-month follow-up did
      not differ between groups. However, compared with 6 Fr PCI, procedure time and
      contrast medium usage was significantly less in the 5 Fr group (contrast: 274 +/-
      101 ml versus 313 +/- 124 ml; p = 0.0008; fluoroscopy time: 16 +/- 9 minutes
      versus 19 +/- 12 minutes; p = 0.006). We conclude that the use of 5 Fr guiding
      catheters is effective and safe in unselected patients undergoing PCI and may
      even confer certain advantages. The 5 Fr approach can be recommended for routine
      interventional practice.

PMID- 12403896
TI  - Spontaneous multivessel coronary artery dissection in a long-distance runner
      successfully treated with oral antiplatelet therapy.
AB  - Spontaneous coronary artery dissection is an unusual yet clinically important
      cause of acute coronary syndromes. We present the case of a 37-year-old woman,
      actively training for a marathon, who presented with a non-Q wave myocardial
      infarction due to multivessel spontaneous coronary artery dissection, along with
      a review of the literature on spontaneous coronary artery dissections manifesting
      as acute myocardial infarctions.

PMID- 12403897
TI  - Spontaneous coronary artery dissection following low-intensity blunt chest
      trauma: a case report and review of current treatment options.

PMID- 12403898
TI  - Successful rotational atherectomy and stenting in a situs inversus patient.
AB  - We describe a case of successful high-speed rotational atherectomy and stenting
      of a long calcified lesion in a patient with dextrocardia and situs inversus.

PMID- 12403899
TI  - Recurrent myocardial infarction due to obstruction of the RCA ostium by an aortic
      papillary fibroelastoma.
AB  - A 69-year-old healthy woman was hospitalized twice within a few weeks for
      management of acute inferior myocardial infarction with thrombolysis and stenting
      of the right coronary artery (RCA) ostium. After the second myocardial
      infarction, follow-up angiography showed subocclusion of the proximal RCA, and
      transesophageal echocardiography and chest computed tomography revealed the
      presence of a mobile, 2-cm diameter spherical mass partially adherent to the RCA
      ostium and penetrating the stent. A benign papillary fibroelastoma was surgically
      excised, the stent was removed, and vein bypass grafting of the RCA was
      performed. The literature relevant to this case report is reviewed.

PMID- 12403900
TI  - Late clinical presentation of femoral artery occlusion after deployment of the
      angio-seal closure device.
AB  - We report a case of late femoral artery thrombosis after deployment of the Angio
      Seal closure device. The unusual late clinical presentation, aggressive
      anticoagulation which likely delayed clinical symptoms and the challenging
      surgical findings are discussed. Physicians need to be alert for possible
      complications arising late after deployment of closure devices and vascular
      surgeons must be familiar with the design of these devices since they may be
      required to repair a variety of arterial injuries associated with their use.

PMID- 12403901
TI  - Late spontaneous epigastric arterial bleeding associated with abciximab:
      successful percutaneous treatment with coil gel-foam embolization.
AB  - We describe a case of spontaneous hemorrhage from a branch of the right inferior
      epigastric artery, unrelated to the access site. This complication occurred in
      association with the administration of abciximab. Prompt identification of this
      unusual complication resulted in successful bleeding control using coil and gel
      foam embolization. Our purpose is to draw attention to yet another potentially
      catastrophic adverse side effect of abciximab infusion. To our knowledge,
      spontaneous rupture of an inferior epigastric artery during abciximab therapy has
      not been previously reported. In addition, the treatment of such an artery with
      coil and gel-foam has not been previously described. As with the other described
      complications, due diligence is required so that spontaneous arterial bleeding
      can be identified and swift intervention be taken.

PMID- 12403902
TI  - Spontaneous dissection of coronary artery treated by primary stenting as the
      first presentation of systemic lupus erythematosus.
AB  - A 39-year-old woman was admitted to the Intensive Care Unit; she was diagnosed
      with acute anterior myocardial infarction, treated with thrombolytics, and
      referred for elective coronary angiography on the basis of her age. At
      angiography, the operator referred the patient for angioplasty with the diagnosis
      of a long atherosclerotic lesion in the left anterior descending coronary artery
      (LAD). On reviewing the angiogram, the interventionalist revised the initial
      diagnosis of an atherosclerotic lesion to a typical long spiral dissection of the
      LAD (spontaneous dissection). Successful treatment of the lesion by primary
      stenting ensued. Retrospective analysis of the laboratory findings revealed the
      presence of some collagen fiber disease. The final diagnosis, confirmed by renal
      biopsy, was systemic lupus erythematosus with secondary spontaneous dissection of
      the LAD.

PMID- 12403903
TI  - Cutting Balloon angioplasty for underexpanded stent deployed through struts of
      previously implanted stent.
AB  - We describe a case in which stenting through the struts of a previously deployed
      stent resulted in stent underexpansion despite 25 atm inflation pressure. Four
      months later, follow-up angiography demonstrated in-stent restenosis. It was
      successfully expanded with a Cutting Balloon.

PMID- 12403904
TI  - Drug-eluting stents: current outcomes and potential impact on coronary disease
      management.

PMID- 12403905
TI  - Acute myocardial infarction in a young male while playing paintball.

PMID- 12403906
TI  - Development of vaccination policy in Japan: current issues and policy directions.
AB  - Until November 2001, eight vaccinations had been offered to Japanese children on
      a routine basis; namely, diphtheria-tetanus-pertussis, polio, measles, rubella,
      Japanese encephalitis, and BCG. The 2001 amendment of the Immunization Law
      introduced an influenza vaccine for the elderly population. This paper reviews
      the progress of the immunization program in the broader context of infectious
      disease control in Japan. There are two recent major policy changes in the field
      of infectious disease control in Japan. One is the strengthening and
      revitalization of the infectious disease control program, particularly
      surveillance, by the enactment of new 1999 legislation entitled "Law concerning
      the Prevention of Infectious Diseases and Patients with Infectious Diseases". The
      other major policy change is a review of existing immunization programs and the
      amendment of the Immunization Law in 2001. In this article, the present routine
      vaccination program, as well as the recent amendments to the law, are described.
      Current policy issues are then discussed, including polio vaccination after the
      WHO "Zero Polio" announcement in the Western Pacific Region in 2000; strategies
      for changes in measles, rubella, tuberculosis, and influenza control; as well as
      adverse reaction monitoring/surveillance and feedback for improving vaccine
      safety. Finally, the future prospects of intended/planned changes in the
      vaccination policy are considered.

PMID- 12403907
TI  - Duration of immunity after smallpox vaccination: a study on vaccination policy
      against smallpox bioterrorism in Japan.
AB  - The success of global smallpox eradication in 1980 led all the nations of the
      world to discontinue smallpox vaccination. To date, however, the threat of
      deliberate release of smallpox virus has led health authorities to reconsider
      smallpox vaccination and at the same time, to urge to evaluate duration of the
      immunity of the population vaccinated before 1980. Although available data is
      scarce and incomplete, the study suggests that protective immunity lasts longer
      in a good percentage of vaccinees, although the real percentage and duration are
      not known. Accordingly, how to establish a national vaccination policy for
      preparedness in Japan and elsewhere was discussed. The study is intended to cause
      interest and debate among the medical and public health community.

PMID- 12403908
TI  - Effect of ethanol on antigenicity of hepatitis B virus envelope proteins.
AB  - Hepatitis B e antigen-positive human serum was treated with 50-90% ethanol at
      room temperature for 1-60 min, then the antigenicity of S antigen (hepatitis B
      surface antigen, in a narrow sense) was determined by radioimmunoassay and the
      antigenicities of pre-S1 and pre-S2 antigens were measured by enzyme immunoassay.
      In addition, hepatitis B virus (HBV) DNA in the treated serum was detected by
      polymerase chain reaction. All antigenicities markedly decreased within 60 min at
      an ethanol concentration of 70-80%, and the decrease was faster in pre-S1 and pre
      S2 antigens than in S antigen. Although HBV DNA remained in all ethanol-treated
      serum samples, no HBV DNA was detected after treatment with 1% sodium
      hypochlorite for 1 min. Based on the results, we speculate that one mechanism of
      loss of HBV infectivity by ethanol is the inhibition of virus binding to
      hepatocytes.

PMID- 12403909
TI  - Comparison of different methods for extraction of mitochondrial DNA from human
      pathogenic yeasts.
AB  - Methods of rapidly extracting chromosomal DNA from human pathogenic yeasts were
      used in mitochondrial DNA (mtDNA) studies. This paper is concerned with rapid and
      reliable methods of extracting mtDNA for sequence analysis for species or strain
      identification, and epidemiological study of medically important fungi and fungal
      infections. To determine the optimal method of mtDNA extraction without isolating
      mitochondria, we examined three commonly used methods: 1). boiling, 2). glass
      bead disruption, and 3). a commercially available kit. We assessed the amount and
      quality of DNAs using a spectrophotometer and specific polymerase chain reaction
      (PCR). The DNA yield depended on the extraction method used and the yeast
      species. An adequate amount of mtDNA was obtained with both glass beads and a
      commercially available kit to amplify the mitochondrial gene using PCR without
      isolating the mitochondria. These techniques are convenient for extracting DNA
      from a variety of small-scale samples.

PMID- 12403910
TI  - Fungal Infection in Neutropenic Patients in a Hospital during Construction.

PMID- 12403911
TI  - Genotyping of Encephalitozoon cuniculi isolates found in Hokkaido.

PMID- 12403912
TI  - Polymorphisms and haplotypes of the CD209L gene and their association with the
      clinical courses of HIV-positive Japanese patients.

PMID- 12403913
TI  - Rapid serological diagnosis of enterovirus 71 infection by IgM ELISA.

PMID- 12403914
TI  - Identification and characterization of transferable integron-mediated antibiotic
      resistance among Salmonella serovar Typhimurium and Salmonella serovar Infantis
      isolates from 1991 to 2002.

PMID- 12403915
TI  - Japan's contribution to research on infectious disease.
AB  - We explored the degree of Japan's contribution to research in the field of
      infectious disease in the last decade. Articles published from 1991-2000 in
      highly reputed journals on infectious disease were accessed through the MEDLINE
      database. The number of articles having an affiliation with a Japanese
      institution was counted in total and for the respective journals. The proportions
      of randomized controlled trials (RCTs), case-control/cohort studies, and case
      reports among the articles affiliated with Japan were also calculated, and were
      compared with the overall proportions of these types of articles for all articles
      published in these journals. Japan's contribution to research on infectious
      disease was 3.4% of the total articles and ranked sixth among all countries. The
      recent trend in contribution was negative, although not statistically significant
      (P = 0.19). RCTs in total articles published in these journals were 3.9%, which
      proportion has been increasing significantly over time. On the other hand, only
      one RCT (0.2%) was reported from Japan in the last decade. In addition, the
      proportion of case-control/cohort studies (2.2%) was smaller for articles from
      Japan than those from other countries. Compared with those of other developed
      countries, Japan's contribution to research on infectious disease has been
      unsatisfactory in the last decade. An explanation for this phenomenon should be
      determined and remedial measures should be taken forthwith.

PMID- 12403916
TI  - Temperature-sensitive viral infection: inhibition of hemagglutinating virus of
      Japan (Sendai virus) infection at 41 degrees.
AB  - While investigating myoblast fusion using enveloped viruses, we unexpectedly
      found that the production of hemagglutinating virus of Japan (HVJ; Sendai virus)
      was suppressed temperature dependently in quail myoblasts transformed with a
      temperature-sensitive Rous sarcoma virus, which proliferate at 35.5 degrees but
      differentiate at 41 degrees; viral production was normal at 35.5 degrees but
      suppressed at 41 degrees irrespective of the species of host cells. The
      production of some viruses, i.e. measles virus, influenza virus, herpes simplex
      virus type 1 and poliovirus, was also markedly suppressed at 41 degrees,
      suggesting that a temperature of 41 degrees affects viral infection generally. To
      clarify the mechanism of the suppression, the infectious pattern of HVJ was
      examined both at 37 degrees and at 41 degrees in LLC-MK2 cells. The synthesis of
      HVJ-specific proteins was inhibited at the transcriptional level at 41 degrees,
      although viral penetration by envelope fusion was not affected. The
      transcriptional inhibition was also seen in quail fibroblasts, which do not
      express a 70-kD heat shock protein (HSP70), suggesting that HSP70 is dispensable
      for the inhibition of viral gene transcription at 41 degrees. Further, when the
      infected cells were incubated at 41 degrees after the viral proteins had been
      synthesized at 37 degrees, viral production was also inhibited. Immunofluorescent
      staining of the cells exposed to 41 degrees showed that HVJ envelope proteins
      formed large aggregates on the cell surface, into which both M and NP proteins
      were assembled. Under the electron microscope, HVJ virions appeared normal even
      at 41 degrees, but were detected in clusters on the cell surface, unlike at 37
      degrees. These observations suggested that the release of HVJ virions from the
      cell surface was inhibited for some reason at 41 degrees. Consequently, it was
      indicated that two steps, viral gene transcription and the release of virions,
      were inhibited at 41 degrees.

PMID- 12403917
TI  - Human rhinovirus 87 identified as human enterovirus 68 by VP4-based molecular
      diagnosis.
AB  - Human rhinoviruses (HRVs) are the major cause of respiratory infections. We
      developed a diagnostic method for HRVs based on the reverse-transcription
      polymerase chain reaction (RT-PCR) and VP4-based phylogenetic analysis. A set of
      primers used in the RT-PCR of human enteroviruses (EVs) appeared to be capable of
      amplifying all prototype strains of HRVs, each of which generated a 530-bp
      fragment. The single exception was HRV-87, which generated a 650-bp fragment, as
      observed in human EVs. The VP4 nucleotide sequence of HRV-87 showed more than 97%
      nucleotide identity with human EV-68, and formed a monophyletic cluster along
      with the prototype strain of EV-68 in the human EV-D cluster. HRV-87 showed the
      second highest homology (76.8%) with EV-70, another member of the human EV-D, in
      a sample of 66 human EVs and 12 HRVs. Therefore, HRV-87 should be reclassified
      into the cluster containing human EV-68.

PMID- 12403918
TI  - Large hepatitis delta antigen is phosphorylated at multiple sites and
      phosphorylation is associated with protein conformational change.
AB  - Hepatitis delta antigen (HDAg) consists of two species, small HDAg (SHDAg) and
      large HDAg (LHDAg), which are identical in sequence with the exception that the
      large form contains an additional 19 amino acids at the C-terminus. Both HDAgs
      are nuclear phosphoproteins. However, LHDAg is hyperphosphorylated, i.e. it is at
      least 10 times more phosphorylated than SHDAg. To determine the phosphorylation
      site(s) of the LHDAg, we mutated all the conserved serine residues and expressed
      these mutant proteins using a recombinant baculovirus expression system. By
      labeling insect cells in vivo with (32)P-orthophosphate and immunoprecipitation,
      we showed that LHDAg is phosphorylated at multiple serine residues. Although
      LHDAg contains two additional serines at its 19-amino acid extension, mutations
      of these two amino acids did not affect the overall phosphorylation level. Most
      importantly, the phosphorylation level of middle domain-deleted LHDAg (M75del)
      was significantly higher than that of wild-type LHDAg. We conclude that
      phosphorylation of the LHDAg occurs at multiple sites and that
      hyperphosphorylation is associated with alteration of protein conformation.

PMID- 12403919
TI  - Experimental infection of lacertids with lizard erythrocytic viruses.
AB  - OBJECTIVE: Lizard erythrocytic viruses (LEVs) produce inclusions in the cytoplasm
      of erythrocytes, but their impact on the infected host is poorly understood. This
      work reports on an experimental study of the infection process in Lacerta
      monticola and Lacerta schreiberi from Serra da Estrela Mountain, Portugal.
      METHODS: A time sequence light microscope and transmission electron microscope
      (TEM) study of the infection process was performed in peripheral blood
      erythrocytes of experimentally infected lizards. Virions were searched for by TEM
      in visceral organs and bone marrow of the animals. RESULTS: Infection was usually
      restricted to erythrocytes, but occasionally became systemic and induced disease.
      In the first case, a prevalence of infected erythrocytes of up to 98% followed by
      recovery was observed. In the latter, infection spread to leukocytes, leading to
      the death of the infected animals. CONCLUSIONS: The potential of LEVs to induce
      systemic infections was demonstrated. Sequential TEM examination of LEV-infected
      cells is described for the first time, demonstrating features such as dense
      inclusions related to virus nucleoid formation, intranuclear virions,
      intermediate structures in virion capsid morphogenesis and virus release by
      budding.

PMID- 12403920
TI  - The genome organization of pea stem necrosis virus and its assignment to the
      genus Carmovirus.
AB  - The complete sequence of the single-stranded, positive-sense RNA genome of pea
      stem necrosis virus (PSNV) has been determined. The 4,048-nucleotide genome
      contains five open reading frames (ORFs). The 5'-proximal ORF encodes a 25-kD
      protein (p25). If the amber termination codon is read through, the ORF produces a
      read-through protein of 84 kD (p84). Two small, centrally located ORFs encoded a
      7-kD protein (p7) and a 6-kD protein (p6), respectively. The 38-proximal ORF
      encodes a 38-kD (p38) capsid protein. Comparison of the genome organization with
      that of other viruses justifies the assignment of PSNV to the genus Carmovirus.

PMID- 12403921
TI  - Detection of human T-lymphotropic virus type I (HTLV-I) infection during
      coculture of HTLV-I infected and uninfected cells using inverse long PCR.
AB  - OBJECTIVE: Identifying the new integration of human T-lymphotropic virus type I
      (HTLV-I) proviral genome into initially uninfected cells after cocultivation with
      HTLV-I infected cells is important for clarifying the process of infection. We
      examined the usefulness of inverse long polymerase chain reaction (IL-PCR) for
      this purpose. METHODS: An experimental system using IL-PCR was applied to detect
      the transmission of HTLV-I between irradiated HTLV-I infected cells (HUT102) and
      uninfected targed cells (MOLT4, K562) after short-term and long-term coculturing.
      RESULTS: In every coculture experiment with irradiated HTLV-I infected cells and
      uninfected cells, the new integration of HTLV-I was easily identified by IL-PCR.
      Oligoclonal proliferation of HTLV-I-positive cells was shown among MOLT4 cells
      even 4 months after the cocultivation; however, no evidence of viral replication
      was observed by indirect immunofluorescence assay or reverse transcription-PCR.
      We also used IL-PCR to assess the inhibitory effects of azidothymidine, anti
      gp46, anti-vascular cell adhesion molecule-1 and anti-heat shock cognate protein
      70 (HSC70) monoclonal antibody. Integration of HTLV-I provirus was inhibited in
      all of these cases except for anti-HSC70. CONCLUSION: This experimental method
      enabled the detection of cell-to-cell transmission of HTLV-I directly and was
      useful for studying the mechanisms of cell-associated HTLV-I infection.

PMID- 12403922
TI  - Efficient haemodialysis improves the response to hepatitis B virus vaccination.
AB  - BACKGROUND: As patients on chronic haemodialysis (PCHD) elicit a weaker response
      to vaccination with recombinant hepatitis B virus surface antigen (HBsAg), we
      conducted this study to see how dialysis efficacy affects response to hepatitis B
      virus (HBV) vaccination. METHODS: Study subjects consisted of 30 PCHD. All
      subjects were vaccinated with 4 x 40 microg HBsAg i.m. at 0, 1, 2, and 6 months.
      If a subject had an HBsAg antibody (HBsAb) level <10 IU/l after vaccination, he
      or she received a booster dose. Subjects were divided into groups according to
      the level of HBsAb: non-responders (<10 IU/l), weak responders (10-100 IU/l), and
      good responders (>100 IU/l). RESULTS: The group of responders had a significantly
      more efficient dialysis (Kt/V) than the group of non-responders (p = 0.027). This
      difference was not observed between groups of non-responders and weak responders.
      The group of good responders had a significantly better Kt/V than the group of
      non-responders (p = 0.012). Good responders had a significantly better Kt/V than
      weak responders (p = 0.019). Kt/V values showed a significantly positive
      correlation with the HBsAb level (r = 0.47; p = 0.006). CONCLUSIONS: The HBV
      vaccination reaction was weaker in PCHD with inefficient dialysis. Efficient
      haemodialysis significantly improves the response to vaccination with recombinant
      HBsAg.

PMID- 12403923
TI  - Production of monospecific antibody to immunodominant epitopes of the caprine
      arthritis encephalitis virus transmembrane glycoprotein and analysis of their
      activity in vitro.
AB  - Caprine arthritis encephalitis virus (CAEV)-infected goats develop high titers of
      nonneutralizing antibody to several immunodominant epitopes of the viral envelope
      glycoprotein. Antibodies directed to these structures, and especially the
      principal immunodominant domain (PID) of the transmembrane portion of the
      envelope glycoprotein, have been implicated in the immunopathological mechanisms
      leading to the development of arthritis. We previously mapped the PID and
      additional epitopes of CAEV gp38 and showed an association between the
      development of clinical arthritis in infected animals and the antibody response
      to these epitopes. The development of clinical arthritis is associated with a
      higher rate of viral expression, especially in the affected tissue, indicating
      that antibody may favorably modulate virus replication. To test this hypothesis,
      we immunized goats with synthetic peptides corresponding to the mapped epitopes.
      The immunized animals developed high titers of nonneutralizing antibody to the
      immunizing peptides. In radioimmunoprecipitation experiments these antibodies
      were shown to react to the envelope glycoproteins in extracts obtained under
      nondenaturing conditions. Finally, these sera were tested in cultures of primary
      macrophages infected at low multiplicity without showing any (either positive or
      negative) modulatory activity.

PMID- 12403924
TI  - Upregulation of Ku expression in human neuroectodermal tumor cells after
      retroviral DNA integration.
AB  - OBJECTIVE: To examine the expression of DNA-dependent protein kinase (DNA-PK);
      including DNA-PKcs, Ku70 and Ku80 in human neuroectodermal tumor cells with or
      without retroviral DNA integration. METHODS: RT-PCR assay was used to examine the
      transcript of DNA-PK. Western blot and immunocytochemistry assays were used to
      examine the protein level of DNA-PK. RESULTS: The expression of DNA-PKcs was
      similar in the cells with or without retroviral DNA integration, but the
      expression of Ku (both mRNA and protein for Ku70 and only protein for Ku80) was
      higher in cells with retroviral DNA integration than in cells without retroviral
      DNA integration. CONCLUSION: The expression of Ku but not the expression of DNA
      PKcs is induced by retroviral DNA integration. Ku70 may play an important role in
      the regulation of Ku function in response to retroviral DNA integration.

PMID- 12403925
TI  - A 72-bp internal deletion in the left inverted terminal repeat of the bovine
      adenovirus type 3 genome does not affect virus replication.
AB  - The genome of bovine adenovirus type 3 (BAV3) is flanked by 195-base pair (bp)
      inverted terminal repeats (ITR). We isolated a BAV3 mutant (BAV3c29) having an
      internal deletion within the left ITR. The deletion eliminated 72 bp between
      nucleotides (nt) 89 and 162, including most of the GC-rich sequences located
      close to the end of the ITR sequences. This deletion did not seem to have any
      affect on the virus plaque size or morphology and the kinetics of viral
      replication compared to wild-type (wt) BAV3. The nt sequence of the right ITR of
      BAV3c29 remained identical to the right or left ITR of wt BAV3. These results
      indicate that the cis-acting sequences present within the 72 bp between nt 89 and
      162 of the left ITR are not essential for BAV3 DNA replication in cultured cells.

PMID- 12403926
TI  - Atopic and nonatopic IgE-mediated allergy: a new interpretation of old facts?
AB  - Coined 80 years ago, the term 'atopy' to designate a group of diseases associated
      with IgE and a hereditary background has raised many discussions. In particular,
      it is difficult to consider as part of an atopic syndrome cases of IgE-mediated
      allergies to isolated allergens without evidence of a familial inheritance. The
      postulate expressed in this essay is that in humans we are essentially dealing
      with an atopic IgE-mediated allergy, which is the equivalent of a genetically
      determined high IgE response, and with a nonatopic IgE-mediated allergy, which is
      the equivalent of a low IgE response in mammals and rodents.

PMID- 12403927
TI  - Petasins in the treatment of allergic diseases: results of preclinical and
      clinical studies.
AB  - Plant extracts are causing an increased interest in the treatment of many chronic
      diseases, including asthma and other allergic diseases. Several laboratories
      characterized petasins (petasin, isopetasin, and neopetasin) isolated from
      extracts of butterbur (Petasites hybridus) as pharmacologically active
      components, which inhibit leukotriene synthesis in leukocytes. The molecular
      mechanisms by which petasins abrogate inflammatory effector cell functions have,
      at least partially, been identified. In vitro studies revealed that petasins may
      have several intracellular targets and this may depend on the stereoisomer used.
      In an open clinical trial in patients suffering from allergic rhinitis, a
      reduction of leukotriene and histamine levels in nasal fluids was associated with
      the butterbur extract administration. To better evaluate the clinical value in
      this particular allergic disease, the clinical efficacy of the drug was compared
      with an established antihistamine treatment scheme in a double-blind study; no
      significant difference was observed between the two treatment groups. In this
      article, we critically review recently published work and summarize the current
      stage in the pharmacological characterization of butterbur extracts.

PMID- 12403928
TI  - Role of CD83 in the immunomodulation of dendritic cells.
AB  - Glycoprotein CD83 is one of the best-known maturation markers for human dendritic
      cells (DCs). The fact that CD83 is strongly upregulated together with co
      stimulatory molecules such as CD80 and CD86 during DC maturation suggests it
      plays an important role in the induction of immune responses. Infection studies
      with herpes simplex virus type 1 (HSV-1) and the inhibition of the CD83 mRNA
      specific transport from the nucleus to the cytoplasm suggested a possible
      functional role for CD83. The first clear proof that CD83 is indeed important for
      DC biology came from recently performed studies using a soluble form of the
      extracellular CD83 domain. DC-mediated T cell proliferation could be completely
      inhibited using this recombinant molecule. Additional studies elucidated
      immunostimulatory as well as regulatory effects of the CD83 molecule.
      Furthermore, CD83-/- knockout mice revealed a block in CD4+ T cell generation, a
      new possible immunomodulatory function of CD83.

PMID- 12403929
TI  - Modification of acute and late-phase allergic responses to ovalbumin with
      lipopolysaccharide.
AB  - BACKGROUND: We have previously shown that lipopolysaccharide (LPS) exposure in
      sensitised animals 18 h after ovalbumin (OVA) challenge inhibits OVA-induced
      airway hyper-responsiveness (AHR). In the present study, we investigated the
      effect of LPS on OVA-induced acute and late-phase allergic responses in
      sensitised rats when challenged with OVA. METHODS: Rats were sensitised with OVA
      and 11 days later challenged with 1% OVA in the presence or absence of LPS (0.5
      50 microg/ml) given in the same nebulizer. Acute responses to OVA were measured
      each minute for 30 min after challenge. In a separate group of animals, late
      phase responses to OVA were determined at 24 h. At the end of each study, Evans
      blue dye was injected and animals sacrificed 30 min later. Bronchoalveolar lavage
      was obtained to monitor inflammatory cell migration and microvascular leakage.
      RESULTS: OVA challenge in sensitised animals produced an acute response with
      changes in lung mechanics peaking 10.0 +/- 0.9 min after OVA and returning to
      baseline within 30 min. This was followed 24 h later by increased responses to
      methacholine chloride (MCh), inflammatory cell influx and increased Evans blue
      leakage into the lungs. Presence of 5 or 50 microg/ml LPS in the nebulizer during
      OVA challenge altered the kinetics of the acute-phase response, with an immediate
      decrease in lung function (time to peak decreased from 10.3 +/- 1.2 to 1.8 +/-
      0.2 and 2.2 +/- 0.3 min, respectively: p < 0.001, n = 6) and a dose-dependent
      attenuation of late-phase AHR, cellular influx (n = 5, p < 0.001) and Evans blue
      leakage (n = 5, p < 0.001) at 24 h. CONCLUSIONS: In summary, co-administration of
      OVA with LPS modifies both the acute and late-phase responses to the allergen,
      inducing an earlier acute change in lung function and a dose-dependent inhibition
      of late-phase responses to the allergen.

PMID- 12403930
TI  - Alkaline serine proteinase from Aspergillus fumigatus has synergistic effects on
      Asp-f-2-induced immune response in mice.
AB  - BACKGROUND: Exposure to Aspergillus fumigatus allergens results in the
      sensitization and the development of allergic bronchopulmonary aspergillosis in
      susceptible individuals. Aspergillus antigen consists of a number of chemically
      diverse components and their cumulative or synergistic effect may result in
      disease. When mice were challenged with individual recombinant allergens, there
      was only reduced inflammation and immunological responses compared to the whole
      antigen. Various enzymes identified from A. fumigatus have been thought to cause
      airway damage. In the present study, we evaluated the effect of exposure to Asp f
      13, an alkaline serine proteinase, and Asp f 2 in mice. METHODS: BALB/c mice were
      challenged intranasally with Asp f 2 and Asp f 13 alone and in combination. The
      antibody response, pulmonary inflammation, and airway hyperreactivity were
      studied. RESULTS: Results demonstrated no major difference in antibody response
      and airway responses among the different groups. The inflammatory responses in
      the lungs, however, showed marked differences in the various groups. CONCLUSION:
      In spite of the similar immunological responses in the different groups of mice
      studied, the results demonstrate enhanced inflammation in the lungs of mice
      exposed to a combination of both allergens. Allergens with proteinase activity
      have been found to be involved in airway inflammation and remodeling, which may
      also apply for Aspergillus-induced allergy.

PMID- 12403931
TI  - Inhibition of eotaxin expression in human corneal fibroblasts by interferon
      gamma.
AB  - BACKGROUND: The chemokine eotaxin is a potent and selective chemoattractant for
      eosinophils. The production of eotaxin by corneal fibroblasts likely contributes
      to eosinophil infiltration into the corneal stroma. The regulation of eotaxin
      synthesis in these cells was investigated by examining the effect of interferon
      gamma (IFN-gamma), a T helper cell 1-derived cytokine, on eotaxin expression in
      cultured human corneal fibroblasts. METHODS: The release of eotaxin from cultured
      corneal fibroblasts was measured by enzyme-linked immunosorbent assay, and the
      abundance of eotaxin mRNA in these cells was determined by reverse transcription
      combined with real-time polymerase chain reaction analysis. RESULTS: IFN-gamma
      inhibited in a dose-dependent manner the release of eotaxin induced by each of
      the proinflammatory cytokines tumor necrosis factor-alpha (TNF-alpha),
      interleukin-1 alpha (IL-1 alpha) and IL-1 beta in corneal fibroblasts. IFN-gamma
      also inhibited the increase in the abundance of eotaxin mRNA induced by each of
      these cytokines. The synergistic increases in eotaxin release and in eotaxin mRNA
      abundance induced by the combination of TNF-alpha and the T helper cell 2-derived
      cytokine IL-4 were also both markedly inhibited by the treatment of cells with
      IFN-gamma. CONCLUSIONS: IFN-gamma inhibited eotaxin expression at both the
      protein and mRNA levels in cultured human corneal fibroblasts. This effect of IFN
      gamma may contribute to the inhibition of eosinophil infiltration into the
      cornea. Exogenous IFN-gamma thus represents a potential new therapeutic agent for
      the treatment of corneal disorders associated with inflammatory ocular diseases
      such as vernal keratoconjunctivitis.

PMID- 12403932
TI  - Ozone-induced release of neuropeptides from human nasal mucosa cells.
AB  - Studies examining the effect of pharmacological agents on respiratory responses
      to ozone support the concept that the effects are mediated, at least in part, by
      neural mechanisms, including neuropeptide release. Using a special tissue culture
      system the influence of ozone (0.1 ppm/24 h) on nasal mucosa from allergic and
      nonallergic patients undergoing surgery for chronic nasal obstruction was
      examined. Substance P (SP)-immunoreactive nerves were found in air-exposed as
      well as in ozone-exposed tissue samples. The content of neurokinin A (NKA) and SP
      in the culture supernatants was significantly increased following ozone exposure
      compared to controls. Tissue of allergic patients showed an ozone-induced
      increase in the release of NKA and SP compared to tissue of nonallergic patients.
      These results suggest that the mode of action of ozone results in an increased
      activity of sensory nerves in the upper airways with a subsequent increased
      release of neuropeptides. In addition to the known ozone-induced release of
      proinflammatory mediators, these mechanisms may explain the increased
      responsiveness of patients with hypersensitive airways.

PMID- 12403933
TI  - Effects of triamcinolone acetonide on adult human lung fibroblasts: decrease in
      proliferation, surface molecule expression and mediator release.
AB  - BACKGROUND: Lung fibroblasts may have a pivotal role in airway inflammation as
      they are involved in continuous cycles of mediator secretion, proliferation,
      activation and cross-talk with recruited inflammatory cells. The role of
      fibroblasts as intermediate participants in the inflammatory network suggests
      that they could represent an important target for drugs commonly used in asthma;
      thus, we investigated the effects of triamcinolone acetonide (TAA) on primary
      human lung fibroblasts. METHODS: The in vitro activity of increasing
      concentrations (10(-9) to 10(-7) M) of TAA in fibroblast cultures was evaluated
      as regards the following parameters: proliferation, extracellular matrix (ECM)
      release, cytokine/chemokine secretion and surface antigen expression. RESULTS:
      All concentrations of TAA decreased fetal calf serum (FCS)-induced fibroblast
      proliferation, whereas in the presence of FCS plus basic fibroblast growth factor
      TAA was only effective at 10(-8) and 10(-7) M. TAA failed to decrease ECM,
      whereas at 10(-8) and 10(-7) M it decreased IL-6 and IL-8 secretion to different
      extents. In the presence of IFN-gamma the drug was able to reduce VCAM-1
      expression at all of the tested concentrations; on the other hand, in TGF-beta 1
      driven cultures a decrease in CD54 expression was detected with TAA at 10(-8) and
      10(-7) M. CONCLUSIONS: TAA acts on some functional properties of human lung
      fibroblasts that make these cells active participants in the inflammatory
      network. The ability of TAA to inhibit lung fibroblast proliferation may prevent
      or even reverse some of the histological changes that characterize airway
      remodeling in chronic inflammatory diseases; moreover, IL-6, IL-8 and surface
      molecule decreases by TAA may suggest a direct anti-inflammatory effect of the
      drug by suppression of resident lung cell function.

PMID- 12403934
TI  - Individual hymenoptera venom compounds induce upregulation of the basophil
      activation marker ectonucleotide pyrophosphatase/phosphodiesterase 3 (CD203c) in
      sensitized patients.
AB  - BACKGROUND: Bee and wasp venom extracts contain potent allergens capable of
      inducing severe clinical reactions. To analyze immediate-type hypersensitivity to
      defined hymenoptera venom components, a recently developed in vitro test was
      applied that is based on the upregulation of CD203c expression on basophils.
      METHODS: CD203c expression on blood basophils of 9 healthy donors and 39 patients
      allergic to bee and/or wasp venom was analyzed by flow cytometry before and after
      activation with the purified bee venom allergens phospholipase A2 (Api m 1),
      hyaluronidase (Api m 2) and melittin (Api m 4), or the purified wasp venom
      allergens phospholipase A1 (Ves v 1), hyaluronidase (Ves v 2) and the recombinant
      antigen 5 (Ves v 5). Venom-induced CD203c upregulation on basophils was compared
      with skin tests and assessment of specific IgE. Basophils of nonresponders were
      preincubated with 10 ng/ml interleukin-3 (IL-3) prior to allergen stimulation.
      RESULTS: CD203c upregulation on basophils was induced by defined hymenoptera
      venom components in 35/39 patients with a diagnosed allergy to wasp and/or bee
      venom. Twenty-seven of the 34 tested patients with wasp allergy showed CD203c
      upregulation in response to Ves v 5, 26 of these patients also reacted with Ves v
      2 and 17 with Ves v 1. Nine of 13 patients with bee allergy reacted with Api m 1,
      13 individuals with Api m 2 and none of these patients with the minor allergen
      Api m 4. A diagnosed wasp allergy could also be confirmed in the prestimulated
      basophils (IL-3) of 2 nonresponder individuals who failed to upregulate CD203c in
      response to IgE receptor cross-linking prior to culture with IL-3. CONCLUSIONS:
      Flow-cytometric determination of CD203c upregulation on basophils activated by
      molecularly defined allergens is a powerful method to identify the precise
      allergen reactivity in sensitized individuals.

PMID- 12403935
TI  - Diagnosing nonimmediate reactions to penicillins by in vivo tests.
AB  - BACKGROUND: Maculopapular and urticarial rashes are nonimmediate manifestations
      common during penicillin treatment; the former often represent cell-mediated
      hypersensitivity. Our objectives were to assess the incidence of allergy in
      adults reporting nonimmediate manifestations during penicillin therapy and to
      evaluate the diagnostic potential of patch tests, delayed-reading skin tests and
      challenges in such cases. METHODS: We used prick and intradermal tests as well as
      patch tests with penicillin determinants, ampicillin, amoxicillin and any other
      suspect penicillins. We also performed challenges with the suspect antibiotics.
      RESULTS: Such antibiotics were aminopenicillins in 93.1% of 259 patients, most of
      whom had suffered from maculopapular rashes followed by piperacillin (4.2%).
      Three subjects displayed immediate skin test positivity. Ninety-four subjects
      showed patch test and delayed intradermal test positivity to the culprit
      penicillin (90 to aminopenicillins and 4 to piperacillin) and were considered as
      having had delayed hypersensitivity reactions. Five of the 8 subjects who
      displayed delayed intradermal test positivity and patch test negativity to the
      suspect penicillin underwent challenges, 2 reacted positively to the responsible
      aminopenicillin. Among the remaining 154 with negative results in allergologic
      tests, 125 agreed to undergo challenges; only 3 reacted. In all, 98 patients --
      93 of whom had experienced maculopapular rashes -- displayed delayed
      hypersensitivity (94 to aminopenicillins and 4 to piperacillin). CONCLUSIONS:
      Both patch and intradermal tests are useful in evaluating nonimmediate reactions
      to penicillins, particularly maculopapular rashes. Patch test and delayed
      intradermal positivity together indicate delayed hypersensitivity. Intradermal
      testing appears to be slightly more sensitive than patch testing.

PMID- 12403936
TI  - Aberrant Fas ligand expression in lymphocytes in patients with Behcet's disease.
AB  - BACKGROUND: Defects in immune responses have been reported in patients with
      Behcet's disease (BD). To further characterize the immune dysfunction and its
      contribution to the pathogenesis, we have studied Fas ligand (FasL) expression in
      peripheral blood lymphocytes (PBL) and mononuclear cells in the skin lesions in
      patients with BD. METHODS: FasL expression in PBL was studied with RT-PCR and
      immunoblotting with rabbit anti-human FasL antibody. We studied the expression of
      FasL in cryostat sections of biopsy specimens of erythema nodosum lesions from 4
      patients with BD and of a genital ulcer lesion in another patient using
      immunohistochemical staining. Apoptotic cell death was detected with the terminal
      deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) method.
      RESULTS: We found that FasL mRNA and FasL protein expression was detected
      marginally in the unstimulated PBL, and was induced upon activation in normal
      individuals. PBL from patients with BD exhibited an enhanced expression of FasL
      mRNA and FasL protein without in vitro stimulation. Moreover, mitogen stimulation
      failed to augment FasL expression of their lymphocytes, suggesting a
      dysregulation of FasL expression of PBL in patients with BD. The skin biopsy
      specimens revealed that cells infiltrating into skin lesions expressed FasL and
      there were several TUNEL staining-positive cells in the lesions, suggesting that
      Fas/FasL-mediated apoptosis is involved in the development of the skin lesion and
      thus may be associated with the pathogenesis. CONCLUSIONS: We found an excessive
      expression of FasL in circulating as well as skin-infiltrating lymphocytes and
      the presence of apoptotic cells in the skin lesions, suggesting that lymphocytes
      expressing FasL aberrantly may play a role in the development and pathogenesis of
      BD.

PMID- 12403937
TI  - Prognostic significance of p21 and p27 protein, apoptosis, clinical and
      histologic factors in rectal cancer without lymph node metastases.
AB  - The aim of this study was to evaluate the prognostic role of clinical and
      histopathologic factors, cell-cycle regulator proteins (p21(Waf1/Cip1),
      p27(Kip1)), and apoptotic index in lymph node-negative rectal cancer. Formalin
      fixed, paraffin-embedded tissue samples of 97 rectal carcinomas (UICC stages I
      and II) resected curatively within five years were used. Immunohistochemical
      analysis of protein expression was performed by monoclonal antibodies: p21 (clone
      SX118), p27 (clone SX53G8). Apoptosis was assessed by the TUNEL method. Clinical,
      surgical, histopathologic, and follow-up data were prospectively recorded in a
      computerized registry. To assess prognostic significance (end points:
      metachronous distant metastases, 5-year disease-free and overall survival),
      statistics included univariate and multivariate analysis (p < 0.05 statistically
      significant). Of the 97 rectal carcinomas without lymph node metastases, 46.4%
      (45/97) were p21-positive, 49.5% were p27-positive (48/97), whereas 27.8% (27/97)
      showed a high apoptotic index. Within a median follow-up of 54 months, 4 patients
      developed local recurrence (4.1%). Distant metastases occurred in 12 patients
      (12.4%). Univariate analysis showed that gender, UICC stage, p21 and p27 were
      significantly associated with the incidence of distant metastases (p < 0.05).
      UICC stage and p21 were the only factors to be significantly related to 5-year
      disease-free survival by univariate analysis (p < 0.05). Only UICC stage was
      significantly related to 5-year overall survival (p < 0.05). The apoptotic index
      was correlated neither to recurrence nor to survival (p > 0.05). Multivariate
      analysis demonstrated that gender, UICC stage and p21 were independently related
      to the incidence of distant metastases; however, UICC stage was the only
      independent factor predictive of 5-year disease-free survival and overall
      survival (p < 0.05).

PMID- 12403938
TI  - Reperfusion but not acute ischemia in pig small intestine induces
      transcriptionally mediated heat shock response in situ.
AB  - BACKGROUND: Although there is data on the cytoprotective role of heat shock
      proteins in intestinal ischemia-reperfusion, the effects of ischemia and
      reperfusion per se on the small intestinal heat shock response have been poorly
      characterized. METHODS: Four female pigs were subjected to 60-min ischemia by
      superior mesenteric artery occlusion followed by 360-min reperfusion. Systemic
      and local hemodynamics were monitored. Samples from the jejunal mucosa and
      muscularis were obtained for histology and for time series molecular biologic
      analyses of heat shock transcription factor 1 (HSF1), hsp70 mRNA and Hsp70
      protein. RESULTS: A 30-min reperfusion of jejunum after a preceding 1-hour
      ischemia results in a significantly increased DNA-binding activity of HSF1, in a
      10-fold increase of hsp70 mRNA in the mucosal and in a 7-fold increase in the
      muscular layers. Translational activation and accumulation of Hsp70 protein
      occurs after 60 min of reperfusion in the intestine. Nevertheless, a 60-min
      ischemia inducing mucosal detachment does not induce the heat shock response at
      any level analyzed. CONCLUSIONS: Ischemia alone is insufficient to induce the
      heat shock response, whereas subsequent reperfusion induces the response via
      transcriptionally mediated induction of Hsp70 synthesis both in the mucosal and
      muscular layers.

PMID- 12403939
TI  - Esophageal, tracheal and pulmonary parenchymal alterations in experimental
      esophageal atresia and tracheoesophageal fistula. A histological and morphometric
      study.
AB  - Pulmonary complications are among the most important causes of morbidity and
      mortality in neonates with esophageal atresia and tracheofistula. We aimed to
      investigate the possible causes of respiratory complications encountered in
      esophageal atresia (EA) and tracheoesophageal fistula (TEF) in an experimental
      model. Sprague-Dawley fetal rats treated with adriamycin were used for the
      experiment. Time mated pregnant rats were given 1.75 mg/kg of adriamicyn
      intraperitoneally on days 6-9 of gestation. The fetuses were sacrificed on day
      21, weighed, and dissected under the surgical microscope. The animals were
      divided into four groups: (1) control group; (2) saline-injected group; (3)
      adriamycin-induced EA group, and (4) adriamycin administered but without
      development of EA. The lungs, esophagus, and trachea were excised and underwent
      histological examination. The mucosa of distal esophagus was thickened (p <
      0.05); the submucosa was thinner (p < 0.05); and the muscular layer was thickened
      (p < 0.05) in fetuses with EA and TEF. In adriamycin-treated rats, in which EA
      and TEF developed, tracheal cartilage was loosened and formed into a D or C
      shape. The cartilage was fragmented into several segments on transverse sections
      in most fetuses. Alveolar septa were thin in lungs of fetus with EA and TEF (p <
      0.05), without any fibrosis or evidence of parenchymal abnormality
      microscopically. Our findings suggest that respiratory complications may
      contribute to structural lesions in the trachea and particularly in the distal
      esophagus but not in the pulmonary parenchyma itself.

PMID- 12403940
TI  - Microcirculatory changes associated with gastric tube formation in the pig.
AB  - The standard reconstruction after esophagectomy is the formation of a gastric
      tube with partial devascularization of the lesser curvature. The purpose of this
      experimental study was to establish an animal model in order to analyze
      microcirculation associated with the formation of a gastric tube. In 17 pigs
      tissue perfusion was measured with a laser Doppler imager (LDI) and partial
      tissue oxygen pressure (ptO(2)) with a Clark-type polarographic oxygen electrode
      before and after formation of a gastric tube in well-defined regions of the
      stomach. The operative procedure included the dissection of the left gastric and
      short gastric arteries; the left gastroepiploic artery along the greater
      curvature was preserved. LDI and ptO(2) baseline measurement were significantly
      lower in the fundus compared to the antrum and corpus. After formation of a
      gastric tube LDI and ptO(2) baseline values calculated from the mean measurements
      of the antrum, corpus and fundus decreased significantly (LDI: 1,099 PU +/- 228
      SD to 601 PU +/- 125 SD, p < 0.0001; ptO(2): 50.8 mm Hg +/- 5.9 SD to 40.7 mm Hg
      +/- 9.3 SD, p = 0.0003). Microcirculatory changes did not correlate with changes
      of cardiac output and systemic vascular resistance. This study suggests that the
      pig is an appropriate model to investigate microcirculation associated with
      gastric tube formation. Its use for esophageal reconstruction by pull-up of the
      gastric interponate is limited.

PMID- 12403941
TI  - Extracorporeal circulation induced microvascular perfusion injury of the small
      bowel.
AB  - Gastrointestinal complications following cardiopulmonary bypass (CPB) are
      relatively uncommon, but are associated with a high mortality rate. Impairment of
      bowel perfusion during and following CPB may serve as a trigger for the
      development of multiorgan failure. The aim of our study was the development of a
      new animal model allowing quantitative analysis of small bowel microcirculation
      during and after CPB. Twelve Landrace pigs served as laboratory animals. A 15-cm
      loop of the terminal ileum was exteriorized for microscopic observation. In 6
      animals, a normothermic, partial left heart bypass (pLHB) was established for 2 h
      with a flow rate of 2,000 ml/min. Arterioles, collecting venules and the
      capillaries of the small bowel were recorded for the analysis of the
      microcirculation. All parameters were recorded prior to, during pLHB and up to 2
      h after weaning off the bypass. Six sham operated animals served as controls.
      Despite unchanged hemodynamics, pLHB leads to microvascular perfusion
      disturbances of the small bowel. In pLHB animals, blood cell velocity in
      postcapillary venules (30-70 microm) was significantly decreased during and
      following bypass. Capillary density was also reduced during bypass and decreased
      even further after pLHB to only 30% of the control values. With this new large
      animal model for quantitative assessment of microvascular perfusion of the small
      bowel during CPB, it could be clearly demonstrated that partial normothermic left
      heart bypass leads to a significant disturbance of the small bowel
      microcirculation even under stable hemodynamic conditions.

PMID- 12403942
TI  - Participation of the intestinal layers in supplying of the mechanical strength of
      the intact and sutured gut.
AB  - The tensile properties of the intact and sutured human intestine were examined
      using Instron 1122 tensimeter on 471 cadaveric and 98 surgically removed
      specimens. By a constant strain rate method two maxima curves were received,
      which permit examination of the intestinal wall as a multi-layered structure.
      Repeatable results were generated for cadaveric and surgically removed
      intestines, whose mechanical properties were similar under certain storage
      conditions. The mechanical properties of intact intestine in axial and
      transversal directions were different. The mechanical strength of the intact
      intestinal wall was conditioned by the submucosa and muscularis, while the serosa
      and mucosa showed no significant strength. Comparison of axial specimens'
      mechanical properties of the intact intestinal wall and intestinal wall with all
      layers sutured through determined that only the submucosa supplies mechanical
      strength to anastomosis. Other layers contribute no significant force to
      anastomotic strength. The strength applied to thread during knot tying does not
      change the participation of the intestinal layers in supplying suture-holding
      capacity for 8 and 12 mm stitch depth. It was shown graphically why sutures that
      don't stitch onto the submucosa are unreliable.

PMID- 12403943
TI  - Attenuated gastric mucosal blood flow predicts non-healing of benign gastric
      ulcers.
AB  - BACKGROUND: A subset of benign gastric ulcers do not respond to therapy and may
      require surgery. A predictor of non-healing may allow modification of therapy.
      Gastric mucosal blood flow plays an important role in gastric ulcer pathogenesis
      and healing. AIMS: Mucosal blood flow was measured with Laser Doppler flowmetry
      at initiation of and during therapy to assess the variability of mucosal blood
      flow in healing and non-healing ulcers as a possible predictor of healing.
      METHODS AND SUBJECTS: Mucosal blood flow was measured at the mid-antrum in 105
      normal human stomachs and on the circumference of 26 benign gastric ulcers. The
      gastric ulcers were followed up with repeat endoscopy and repeat measurements
      were made. RESULTS: The ulcers that healed had significantly higher mucosal blood
      flow than normal stomachs at both initial and follow-up measurement (59.8 +/-
      26.1 vs. 75.7 +/- 17.5 and 69.8 +/- 13.7). The refractory ulcers persistently had
      significantly lower mucosal blood flow than normal stomachs and healing ulcers
      (59.8 +/- 26.1 vs. 45.2 +/- 21.9 and 39.2 +/- 6.7). CONCLUSIONS: Gastric mucosal
      blood flow seems to increase in response to mucosal injury and healing.
      Attenuation of this response is associated with delayed healing. Attenuated peri
      ulcer mucosal blood flow may predict non-healing of a benign gastric ulcer.

PMID- 12403944
TI  - Partial pancreatic head resection for intraductal papillary mucinous carcinoma
      originating in a branch of the duct of santorini.
AB  - We report partial pancreatic head resection of intraductal papillary mucinous
      carcinoma originating in a branch of the duct of Santorini. The tumor was located
      in the ventral part of pancreatic head at a distance from the Wirsung duct.
      Magnetic resonance cholangiopancreatography accurately showed the communication
      between the duct of Santorini and the cystic tumor, and was useful for
      determining the part of the pancreas to be resected. Both the duct of Wirsung and
      the duct of Santorini were preserved. Partial pancreatic head resection would
      play an important role in surgical management of low-grade malignant neoplasm.

PMID- 12403945
TI  - Hemodynamic flow patterns evaluated by transcranial color-coded duplex sonography
      after STA-MCA bypass for internal carotid artery occlusion.
AB  - Extracranial-intracranial (EC-IC) bypass surgery had been widely performed for
      the treatment of internal carotid artery occlusion. However, it is presently
      difficult to predict how the bypass flow will contribute to intracranial
      circulation. We examined intracranial hemodynamics by transcranial color-coded
      duplex sonography (TCCD) after superficial temporal artery (STA)-middle cerebral
      artery (MCA) bypass and retrospectively studied the relationship between the
      postoperative contribution of the bypass flow and the preoperative collateral
      circulation and cerebrovascular perfusion status in 10 patients. Hemodynamics in
      the MCA detected by TCCD were classified into three patterns. In pattern A,
      perfusion of the whole MCA area is completely dependent on the bypass flow. In
      pattern B, perfusion of the M2 segment is dependent on the bypass flow, but
      perfusion of the M1 segment is independent of the bypass flow. In pattern C,
      perfusion of the whole MCA area is supplied by collateral flow and the bypass
      does not function efficiently. Preoperative absence of collateral flow via
      anterior communicating artery and cerebral perfusion status type 3 (reduced
      regional cerebral blood flow and regional cerebral vasoreactivity) seems to
      predict hemodynamic usefulness of the bypass flow after surgery. TCCD is an easy
      and noninvasive method for evaluating intracranial cerebral circulation after EC
      IC bypass surgery.

PMID- 12403946
TI  - Overshoot and undershoot: control system analysis of haemodynamics in a
      functional transcranial Doppler test.
AB  - BACKGROUND: Local cerebral blood flow is adjusted to cortical activity in a rapid
      and fine-tuned manner. The responsible mechanism, called neurovascular coupling,
      is suggested to be governed by a complex biological control system. The main
      characteristics of the regulative process can be modelled in terms of a control
      system of low order. We aimed to test the hypothesis that the overshoot and
      undershoot in haemodynamics are part of the regulative processes of the
      neurovascular coupling mechanism. METHODS: Using a visual stimulation paradigm,
      the evoked blood flow velocity in the posterior cerebral artery was measured in
      20 healthy volunteers (aged 24.7 +/- 0.4 years, 12 males) with transcranial
      Doppler. The dynamic flow velocity response was evaluated according to a 5
      parameter control system model. RESULTS: The parameter time delay (1.2 +/- 1; 2.2
      +/- 1.3; p < 0.05) and natural frequency (0.23 +/- 0.06; 0.47 +/- 0.18; p <
      0.001) were significantly smaller, the parameter rate time (4.9 +/- 2.3; 2.2 +/-
      1.6; p < 0.01) greater in conditions of stimulation. CONCLUSIONS: The finding of
      an identical control system model for both regulative conditions supports the
      hypothesis that the mechanism is mainly functionally governed and that the
      underlying biological elements do not appear to be limiting factors. The
      difference in parameters is suggested to reduce the time span of an initial
      hypoperfusion in conditions of cortical activation.

PMID- 12403947
TI  - Atherothrombotic risk factors in subjects with a family history of stroke.
AB  - BACKGROUND: Subjects with stroke in a first-degree relative are at increased risk
      of atherothrombotic vascular disease. We aimed to examine atherothrombotic risk
      factors in such a population. METHODS: 145 subjects with a first-degree relative
      with stroke and 143 controls were recruited. Measurements were made of features
      of the insulin resistance syndrome, haemostatic and fibrinolytic risk factors,
      and glucose tolerance tests. RESULTS: The relatives had higher systolic blood
      pressure, HDL, 2-hour glucose, factor VII:C, fibrinogen, vWF and more had smoked.
      Differences remained in factor VII:C, systolic BP and 2-hour glucose after
      adjustment. CONCLUSIONS: This population demonstrates adverse thrombotic risk
      factors and increased FVII:C activity may contribute to increased cardiovascular
      risk.

PMID- 12403948
TI  - High incidence rates of stroke in Orebro, Sweden: Further support for regional
      incidence differences within Scandinavia.
AB  - BACKGROUND AND PURPOSE: As a basis for comparison of differences in stroke
      incidence in Scandinavian countries, a community-based stroke register was
      established in Orebro in the centre of Sweden. METHODS: All first-ever cases of
      stroke were registered during a 12-month period 1999-2000. The study population
      was 123,503. The WHO definition of stroke was used. Cases were searched inside as
      well as outside hospital. Multiple overlapping sources and 'hot pursuit'
      technique were used in the process of case ascertainment. RESULTS: 388 cases of
      first-ever stroke were found, corresponding to a crude incidence rate of 314 (95%
      CI, 283-348) per 100,000 per year, 337 (95% CI, 294-386) for females, and 289
      (95% CI, 248-336) for males. Adjusted to the European population, the
      corresponding rates were 254 (95% CI, 227-284) per 100,000 per year, 273 (95% CI,
      238-311) for females and 232 (95% CI, 206-261) for males. The overall 28-day case
      fatality rate was 19% (95% CI, 15-23). The case-fatality rates for the different
      subtypes of stroke were as follows: brain infarction, 10%; intracerebral
      haemorrhage, 20%; subarachnoidal haemorrhage 45%, and undetermined pathological
      type 56%. CONCLUSIONS: The present study as well as other studies in northern and
      middle Scandinavia show significantly higher incidence rates than studies from
      other regions. The crude incidence rate, reflecting the age distribution of the
      population, is even higher, indicating a burden to the community that is rather
      increasing than decreasing.

PMID- 12403949
TI  - Characteristics of elderly people readmitted to the hospital during the first
      year after stroke. The Goteborg 70+ stroke study.
AB  - BACKGROUND AND PURPOSE: Readmissions after acute stroke vary over time and with
      age and comorbidity. Knowledge of the reasons for readmissions and
      characteristics of readmitted patients is sparse. This 1-year prospective study
      examined whether readmissions were related to severity of the index stroke or to
      comorbidity and explored outcomes in readmitted patients with respect to daily
      life activities and health-related quality of life. METHODS: The study included
      216 elderly patients (aged >/=70 years) discharged to their homes or a nursing
      home after index stroke. The main outcomes were readmission rates and reported
      diagnoses, performance of daily life activities and health-related quality of
      life. RESULTS: Nearly half (45%) of the patients were readmitted to the hospital
      after being discharged to their homes. One readmission was most common, and
      stroke-related diagnoses were most frequently reported as the reason for
      readmission. Different forms of heart disease were the next most common reason.
      The readmitted patients were significantly more dependent in daily life
      activities, and health-related quality of life was significantly lower among this
      group. CONCLUSIONS: Recurrent stroke and sequelae after stroke were major factors
      behind readmissions, followed by heart disease in elderly stroke patients. The
      readmitted patients were more dependent in daily life activities and reported a
      lower health-related quality of life compared with not readmitted patients.

PMID- 12403950
TI  - 'Footprints' of transient ischemic attacks: a diffusion-weighted MRI study.
AB  - OBJECTIVE: Diffusion-weighted imaging (DWI) conveys temporal as well as anatomic
      information about brain infarction, and is therefore well suited to identify
      ischemic injury that has occurred simultaneously, or closely linked in time, with
      a transient ischemic attack (TIA). We aimed to determine the proportion and
      clinical characteristics of patients with TIA who harbor infarction(s) on DWI.
      METHODS: Using T(2)-weighted imaging (T(2)-WI), fast fluid attenuated inversion
      recovery (FLAIR), and DWI, we studied 57 consecutive patients presenting with
      acute focal neurologic symptoms lasting less than 24 h. RESULTS: A hyperintense
      DWI lesion was identified in a vascular territory appropriate to the symptoms in
      27 patients (47%). Lesions judged to be clinically appropriate on T(2)-WI and
      FLAIR overlapped with a DWI lesion in 41 and 48% of patients, respectively.
      Independent predictors of infarction on DWI were previous nonstereotypic TIAs,
      presentation with motor symptoms, and identified stroke mechanism. CONCLUSION:
      DWI establishes that recent infarction occurs in almost half of patients with the
      clinical syndrome of TIA and this subgroup is more likely to harbor an underlying
      cardiac or cerebrovascular abnormality.

PMID- 12403951
TI  - Diffusion-weighted imaging in acute stroke--a tool of uncertain value?
AB  - The concept of a mismatch between the lesion volume in diffusion- and perfusion
      weighted magnetic resonance imaging (MRI) indicating 'tissue at risk of
      infarction' is based on the assumption that tissue with diffusion slowing in
      diffusion-weighted MRI (DWI) or decreased values of the apparent diffusion
      coefficient represents irreversibly damaged tissue. Recent experimental as well
      as clinical studies, however, have shown that tissue with diffusion slowing may
      well normalize if the hypoperfusion is moderate or transient. We will interpret
      these findings in the light of experimental data and suggest a way for the
      interpretation of different time courses of lesion development in DWI within a
      clinical MRI protocol. MR stroke imaging delivers important information in acute
      stroke, particularly in defining the 'tissue at risk of infarction'.

PMID- 12403952
TI  - Antithrombotic therapy in patients with any form of intracranial haemorrhage: a
      systematic review of the available controlled studies.
AB  - Patients with intracranial haemorrhage may sometimes require antithrombotic drugs
      or be inadvertently given antithrombotic therapy. We systematically reviewed all
      published trials comparing any antithrombotic agent with control among patients
      with any form of intracranial haemorrhage. We extracted data on deaths, recurrent
      intracranial haemorrhage and functional outcome. There were 9 randomised trials
      of 5 different antithrombotic agents versus control in patients with subarachnoid
      haemorrhage (6 trials, n = 1,224) or with acute intracerebral haemorrhage (3
      trials, n = 819). The overall odds ratio (OR) for death among patients with any
      intracranial haemorrhage given an antiplatelet agent (8 trials, 1,997 patients)
      was 0.85 (95% confidence interval, CI, 0.63-1.15), and for recurrent intracranial
      haemorrhage it was 1.00 (95% CI 0.73-1.37). The corresponding ORs for patients
      with intraparenchymal cerebral haemorrhage were 0.96 (0.62-1.5) and 1.02 (0.5
      1.8), respectively, but 65% of these patients received only a few doses of
      antithrombotic treatment. The overall OR for death in patients with any
      intraparenchymal cerebral haemorrhage given heparin compared with control (3
      trials, 819 patients, subcutaneous heparin) was 0.96 (95% CI 0.38-2.40), and for
      recurrent intracranial haemorrhage it was 2.00 (95% CI 0.86-4.70). There were no
      reliable data on the effects of antithrombotic agents on functional outcome.
      These scant data do not support reliable conclusions about the safety or
      otherwise of antithrombotic agents in patients with acute intracranial
      haemorrhage. Antithrombotic agents should be avoided where possible in patients
      with acute intracerebral haemorrhage.

PMID- 12403953
TI  - Management and outcome of non-traumatic cerebellar haemorrhage.
AB  - Thirty-seven patients with non-traumatic cerebellar haemorrhage were treated in
      our department between 1984 and 1999. The outcome was retrospectively analysed
      according to the neurological status, CT findings and the selected treatment
      modality (conservative therapy vs. surgery). Our data indicate that in that
      sample size, the size of the haematoma was the only significant predictor of the
      outcome (p = 0.04). The prediction of the outcome by a logistic regression model
      includes both the size of the haematoma and the treatment modality (surgery or
      conservative) as variables. The data suggest that patients in a good neurological
      status on admission (Glasgow Coma Scale 13-15) with a small haematoma (<3 cm)
      should be treated conservatively. In all patients with large haematomas (>3 cm),
      including those in a good neurological status, and in all comatose patients,
      surgical evacuation is indicated. A different haematoma size as a cut-off point
      for choosing surgery as the preferred therapeutic modality, as well as the
      indication for ventriculostomy as a temporizing measure or a substitute for
      surgery are yet undetermined and need further investigation in a randomized
      trial.

PMID- 12403954
TI  - Dynamic single-section CT demonstrates reduced cerebral blood flow in acute
      intracerebral hemorrhage.
AB  - Optimum blood pressure (BP) management in acute intracerebral hemorrhage (ICH)
      remains controversial. BP reduction may limit hematoma expansion, but may also
      exacerbate ischemia. Reduced regional cerebral blood flow (rCBF) has been
      reported in ICH. Its extent and precise pattern, however, remain uncertain.
      Dynamic single-section CT perfusion (CTP) is rapid, easily performed and offers
      superior spatial resolution to PET, SPECT and MRI. It may be the most applicable
      method for assessing the effects of BP management on rCBF in ICH. We sought to
      assess whether CTP can identify rCBF abnormalities in acute ICH in 5 patients
      with ICH who underwent CTP within 24 h of symptom onset. rCBF was measured in
      serially expanded 2-mm rings around the hematoma and compared with rCBF in the
      uninvolved hemisphere. Mean time to CTP was 9 h (range 3-23). Mean ICH volume was
      25 ml (range 9-64). Perihematoma perfusion was reduced in all patients compared
      with contralateral hemisphere rCBF. rCBF reduction was most pronounced
      immediately adjacent to the hematoma (p < 0.05 at 2 mm, p = 0.084 at 4 mm, p >
      0.2 at 6 and 8 mm). Perihematoma rCBF increased as a function of the distance
      from hematoma perimeter. Rate of rCBF increase over distance correlated with time
      from onset (p = 0.006). We conclude that CTP identifies a rim of reduced rCBF in
      ICH. A gradient of hypoperfusion appears to extend at least 4 mm beyond the
      hematoma edge and may be time dependent. Whether reduced CBF is associated with
      perihematoma ischemia requires additional study.

PMID- 12403955
TI  - CT patterns and long-term outcome in patients with an aneurysmal type of
      subarachnoid hemorrhage and repeatedly negative angiograms.
AB  - The fate of patients with subarachnoid haemorrhage, an aneurysmal pattern of
      haemorrhage on CT and two or more negative angiographies is unknown. We studied
      the long-term outcome of patients with three negative angiograms (n = 15) and
      compared the pattern of hemorrhage of these patients with that of patients with
      perimesencephalic hemorrhage (n = 73). We reviewed the CT scans of all patients
      and we followed up the patients with three negative angiograms. The mean period
      of follow up was 65 months; the number of patient years was 81. In five of the 15
      patients with an aneurysmal pattern of hemorrhage the CT scan showed a hemorrhage
      resembling an anterior circulation aneurysm; in the other 10 patients the center
      of hemorrhage was behind the chiasm but extended too far in anterior or lateral
      cisterns to meet the criteria of a true perimesencephalic hemorrhage ('extended
      perimesencephalic pattern'). During follow up no episodes of proven aneurysmal
      rupture had occurred. Three patients subsequently had serious vascular events;
      one patient (with an extended perimesencephalic pattern) died suddenly; two
      patients with a pattern of hemorrhage suggestive of an anterior circulation
      aneurysm were left disabled, one from two episodes of cerebral ischemia and
      another from a spontaneous intracerbral hemorrhage. In contrast to patients with
      perimesencephalic hemorrhage who have an uneventful clinical course and an
      excellent outcome, patients with three negative angiograms and an aneurysmal
      pattern of hemorrhage are still at some risk of vascular complications and poor
      outcome. Subdivisions according to the center of hemorrhage once the anterior
      cisterns are involved is not helpful in identifying patients with good or poor
      outcome.

PMID- 12403956
TI  - Cognitive functions and depression as predictors of poor outcome 15 months after
      stroke.
AB  - The prognostic predictors of poor outcome, as defined by death between 3 and 15
      months and dependent living at 15 months, were examined in the Helsinki Stroke
      Aging Memory (SAM) study cohort. Death between 3 and 15 months was registered
      from the whole study group of 486 consecutive patients aged 55-85 years.
      Altogether 286 of the 486 patients went through a detailed follow-up examination
      both 3 and 15 months after stroke, including structured measures of emotion
      (Beck's Depression Inventory, BDI), cognition (Mini-Mental State Examination,
      MMSE), dementia assessment according to the Diagnostic and Statistical Manual of
      Mental Disorders (DSM-III), and handicap (Rankin scale, RS). The only independent
      correlate of death between 3 and 15 months was dependent living at 3 months (OR
      2.6, 95% CI 1.2-5.8), which also had the most powerful association with dependent
      living at 15 months (OR 5.8, 95% CI 2.6-13.1). Also, both worsening in cognition
      (change in MMSE, OR for each point of worsening 1.2, 95% CI 1.1-1.3) and
      worsening of depression (change in BDI, OR for each point of worsening 1.1, 95%
      CI 1.02-1.12), between 3 and 15 months follow-up, had an independent effect on
      dependent living 15 months after ischemic stroke. This challenges the care and
      rehabilitation of these items even at the stable period after stroke.

PMID- 12403957
TI  - Effects of dipyridamole and aspirin on shear-induced platelet aggregation in
      whole blood and platelet-rich plasma.
AB  - BACKGROUND: Shear-induced platelet aggregation (SIPA) is an important mechanism
      of thrombosis at arterial bifurcations or stenotic lesions. METHODS: We
      investigated the in vitro effects of dipyridamole (DP) and acetylsalicyclic acid
      (ASA) on SIPA in whole blood and platelet-rich plasma (PRP). RESULTS: In whole
      blood, DP 20 microM significantly inhibited SIPA, while DP 5 microM or ASA 5 or
      20 microM did not. SIPA in whole blood was, however, significantly inhibited by
      the combination of 5 or 20 microM of DP and ASA. SIPA in PRP was not inhibited by
      any concentration of DP or ASA, alone or in combination. CONCLUSIONS: These
      results suggest that DP has an effect on red blood cells and that ASA enhances
      the inhibitory effect of DP on SIPA in whole blood. These effects may be related
      to the additive effect of combination therapy with DP and ASA on stroke
      prevention.

PMID- 12403959
TI  - Effect of increasing doses of aspirin on platelet aggregation among stroke
      patients.
AB  - BACKGROUND AND PURPOSE: Aspirin has been shown to reduce the risk of myocardial
      infarction and stroke. Some investigators believe that low-dose aspirin inhibits
      platelet aggregation to the same degree as high-dose aspirin. Our study aimed to
      assess the effect of increasing doses of aspirin on the degree of platelet
      aggregation induced by collagen and adenosine diphosphate (ADP) among stroke
      patients. METHODS: Sixteen poststroke patients were prescribed aspirin at daily
      doses of 40, 80, 160, 325, 650, and 1,300 mg, each dose to be taken for 14 days
      (total duration 12 weeks). Platelet aggregation studies using 2 microgram/ml
      collagen and 2 microM ADP were performed on platelet-rich plasma at baseline and
      on the 14th day of each dose. RESULTS: Platelet aggregation studies using 2
      microgram/ml collagen at the start of treatment and at the 14th day of each dose
      revealed dose-dependent inhibition by aspirin starting at 40 mg/day, but was
      optimal at 80- 160 mg/day. ADP-induced platelet aggregation inhibition appears to
      be dose dependent up to 1,300 mg/day. CONCLUSION: Inhibition of collagen-induced
      platelet aggregation by aspirin appears to be optimal at 80-160 mg/day, while ADP
      induced platelet aggregation inhibition by aspirin appears to be dose dependent
      up to 1,300 mg/day in our poststroke patients, albeit to a less remarkable degree
      at higher doses.

PMID- 12403958
TI  - Fiblast (trafermin) in acute stroke: results of the European-Australian phase
      II/III safety and efficacy trial.
AB  - BACKGROUND: Trafermin (basic fibroblast growth factor) has been shown to reduce
      infarct volume in acute ischemic stroke models, and to promote functional
      recovery and new synapse formation when given to animals with completed cerebral
      infarction. A previous study in acute stroke patients suggested that trafermin
      was safe and well tolerated when given over a 3-hour period over a wide dose
      range. METHODS AND RESULTS: Double-blind, parallel group, placebo-controlled
      trial of a single 24-hour intravenous infusion of trafermin. Patients having
      onset of stroke symptoms within 6 h and a baseline score of >/=7 on the NIH
      Stroke Scale (>/=2 motor) were randomized to receive 5 or 10 mg of trafermin or
      placebo intravenously infused over 24 h. The primary efficacy outcome was a
      categorized combination of the Barthel and Rankin scales assessed at 90 days. A
      total of 286 patients had been enrolled at 55 sites in 11 countries when the
      sponsor directed that enrollment be stopped because an interim analysis of
      efficacy data predicted too small a chance of demonstrating a statistically
      significant benefit after recruitment of the planned 900 patients. The 5-mg group
      showed a slight but nonsignificant advantage over placebo (OR 1.2, 95% CI 0.72
      2.00, p = 0.48); the 10-mg group showed a nonsignificant disadvantage (OR 0.74,
      95% CI 0.44-1.22, p = 0.24). Mortality rates at 90 days were 17% in the 5-mg
      group, 24% in the 10-mg group and 18% in the placebo group. Treatment with
      trafermin was associated with an increased leukocytosis and a decrease in blood
      pressure: mean decrease in systolic blood pressure from baseline was 19 mm Hg in
      the 5-mg group, 22 mm Hg in the 10-mg group and 8 mm Hg in the placebo group. In
      a post hoc subgroup analysis, patients in the 5-mg group treated more than 5 h
      after the onset of symptoms showed an apparent advantage over placebo (OR 2.1,
      95% CI 1.00-4.41, p = 0.044; after age adjustment: OR 1.9, 95% CI 0.91-4.13, p =
      0.08). CONCLUSIONS: With the proper treatment regimen, trafermin can likely be
      given safely to stroke patients. The 5-mg dose showed a trend toward a treatment
      advantage. The ideal time window for this agent may exceed 5 h. This may open new
      avenues for acute stroke therapy, aiming at enhancing recovery mechanisms rather
      than immediate neuroprotection.

PMID- 12403960
TI  - Cardiac papillary fibroelastoma as a cause of recurrent ischemic strokes: the
      diagnostic value of serial transesophageal echocardiography.

PMID- 12403961
TI  - No evidence for microembolism in clustering transient ischemic attacks.

PMID- 12403962
TI  - Central poststroke pain in a consecutive cohort of stroke patients.

PMID- 12403963
TI  - Isolated ischemic third-nerve palsy as a warning sign of severe internal carotid
      artery stenosis.

PMID- 12403964
TI  - Chronobiology of cerebral vein and dural sinus thrombosis.

PMID- 12403965
TI  - Recurrent thromboembolism, adenocarcinoma and antiphospholipid syndrome.

PMID- 12403966
TI  - Disclosure of paradoxical brain embolism in two stroke patients with ultrasound
      test for right-to-left shunt and diffusion-weighted MRI.

PMID- 12403967
TI  - Imaging of stroke pathology without predefined gold standard.

PMID- 12403969
TI  - Pituitary haemorrhage after leuprolide therapy for prostatic cancer, clinically
      imitating acute subarachnoidal haemorrhage.

PMID- 12403972
TI  - Drugs past their expiration date.

PMID- 12403971
TI  - Acetaminophen safety.

PMID- 12403974
TI  - A new era in neuroscience.

PMID- 12403975
TI  - Exploratory clinical testing of neuroscience drugs.

PMID- 12403976
TI  - Patenting basic research: myths and realities.

PMID- 12403977
TI  - From chemical to drug: neurodegeneration drug screening and the ethics of
      clinical trials.

PMID- 12403978
TI  - The challenge of translational research--a perspective from the NINDS.

PMID- 12403979
TI  - Avoiding the pediatrician's error: how neuroscientists can help educators (and
      themselves).

PMID- 12403980
TI  - Memory enhancement: the search for mechanism-based drugs.
AB  - Rapid progress has been made in understanding the synaptic changes required for
      memory encoding. Several companies are now attempting to use information about
      the induction and consolidation phases of this process to build memory-enhancing
      drugs. These efforts have produced novel compounds that improve retention scores
      across a broad range of tests and species. Initial clinical results are
      encouraging. Issues now arise about appropriate applications of candidate drugs
      and optimal cellular targets for future development.

PMID- 12403981
TI  - NMDA receptor pathways as drug targets.
AB  - Since the mid 1980s, there has been a great deal of enthusiasm within both
      academia and industry about the therapeutic potential of drugs targeting the NMDA
      subtype of glutamate receptors. That early promise is just beginning to translate
      into approvable drugs. Here we review the reasons for this slow progress and
      critically assess the future prospects for drugs that act on NMDA receptor
      pathways, including potential treatments for some major disorders such as stroke
      and Alzheimer's disease, for which effective therapies are still lacking.

PMID- 12403982
TI  - Dollars and scents: commercial opportunities in olfaction and taste.
AB  - Research successes over the past decade have provided a broad outline of the
      neuroscience of olfaction and taste. Our understanding of these systems now spans
      the molecular to the psychological. It will soon reach critical mass and begin to
      generate a variety of practical applications with commercial potential. Given the
      ubiquity of smell and taste and their importance to health, nutrition and quality
      of life, these applications could have a major impact on consumer product markets
      and create entirely new ones. Sensory biotechnology could be the first post
      genomic application to break through to the consumer market. We describe odor
      modulation technologies with implications for food intake, health care and other
      arenas. Our deeper understanding of olfaction and taste in animal behavior and
      reproduction provides opportunities in pest control and animal husbandry, where
      environmentally neutral interventions are much in demand.

PMID- 12403983
TI  - Neurotrophins: from enthusiastic expectations through sobering experiences to
      rational therapeutic approaches.
AB  - Despite high enthusiasm, early attempts to develop clinical treatments based on
      animal research with neurotrophins were not successful. Here we survey clinical
      trials with neurotrophins, compared with neurotrophic factors of other gene
      families, and delineate the most likely reasons for their failure. We then
      suggest improved methods for regulated local supply of NTs to specific
      populations of neurons and discuss future therapeutic procedures evolving from
      the more detailed knowledge of the signal transduction pathways activated by
      neurotrophins via their receptors.

PMID- 12403984
TI  - Miracles and molecules--progress in spinal cord repair.
AB  - Severe spinal cord injury (SCI) leads to devastating loss of neurological
      function below the level of injury and adversely affects multiple body systems.
      Most basic research on SCI is designed to find ways to improve the unsatisfactory
      cellular and molecular responses of spinal cord to injury, which include an array
      of early processes of autodestruction and a subsequent lack of functional tissue
      repair. This research has brought us to the threshold of practical application
      along three lines of approach, derived from animal model studies: acute
      neuroprotection, enhanced axonal regeneration or plasticity, and treatment of
      demyelination. There is a growing commercial interest in this previously
      neglected therapeutic area.

PMID- 12403985
TI  - Alzheimer's disease: treatments in discovery and development.
AB  - Alzheimer's disease is the single biggest unmet medical need in neurology.
      Current drugs are safe, but of limited benefit to most patients. This review
      discusses the scientific basis and current status of promising disease-modifying
      therapies in the discovery and development stages. I describe the major targets
      of anti-amyloid therapy and the main focus of disease modification approaches. In
      addition, two new potential treatment approaches supported by retrospective
      epidemiology are outlined.

PMID- 12403986
TI  - Neuroprotective and neurorestorative strategies for Parkinson's disease.
AB  - Advances in understanding the molecular mechanisms of cell death and the
      pathogenesis of sporadic and familial Parkinson's disease are creating new
      opportunities for the development of neuroprotective and/or neurorestorative
      therapies. Here we review many of these advances, highlighting areas and
      strategies that might be particularly suited to the development of innovative
      approaches that prevent degeneration and/or restore function in Parkinson's
      disease.

PMID- 12403987
TI  - Can we conquer pain?
AB  - Pain can be an adaptive sensation, an early warning to protect the body from
      tissue injury. By the introduction of hypersensitivity to normally innocuous
      stimuli, pain may also aid in repair after tissue damage. Pain can also be
      maladaptive, reflecting pathological function of the nervous system. Multiple
      molecular and cellular mechanisms operate alone and in combination within the
      peripheral and central nervous systems to produce the different forms of pain.
      Elucidation of these mechanisms is key to the development of treatments that
      specifically target underlying causes rather than just symptoms. This new
      approach promises to revolutionize pain diagnosis and management.

PMID- 12403988
TI  - Treatment of mood disorders.
AB  - Depression is a leading cause of morbidity and mortality, and its treatment
      includes a high percentage of the medications prescribed by physicians. Available
      antidepressant drugs are safe and effective, but less than half of all patients
      attain complete remission after therapy with a single antidepressant. Others
      exhibit partial, refractory or intolerant responses to treatment, emphasizing the
      need to discover new antidepressants. The mechanisms of action of available
      medications are directing the field toward new research avenues. This review
      highlights those areas we believe will influence the field and soon lead to
      better treatment.

PMID- 12403989
TI  - Sleeping with the hypothalamus: emerging therapeutic targets for sleep disorders.
AB  - Delineating the basic mechanisms that regulate sleep will likely result in the
      development of better treatments for sleep disorders. The hypothalamus is now
      recognized as a key center for sleep regulation, with hypothalamic
      neurotransmitter systems providing the framework for therapeutic advances. An
      increased awareness of the close interaction between sleep and homeostatic
      systems is also emerging. Progress has occurred in the understanding of
      narcolepsy--molecular techniques have identified the lateral hypothalamic
      hypocretin (orexin) neuropeptide system as key to the disorder. Other sleep
      disorders are now being tackled in the same way and are likely to yield to
      efforts combining basic and clinical research. Here we highlight the role of the
      hypothalamus in sleep physiology and discuss neurotransmitter systems, such as
      adenosine, dopamine, GABA, histamine and hypocretin, that may have therapeutic
      applications for sleep disorders.

PMID- 12403990
TI  - From neurobiology to treatment: progress against addiction.
AB  - Most advances in addiction treatment to date have addressed the physical
      dependence and withdrawal that accompany addiction to some drugs of abuse. In
      contrast, it has proven more difficult to develop medications that effectively
      treat drug craving and relapse, the core features of addictive disorders. Current
      efforts focus on developing medications that prevent a drug from getting to its
      protein target, that mimic drug action and thereby partially alleviate drug
      craving, or that affect the addiction process per se. The latter approach is the
      most speculative, but also the most promising in terms of translating basic
      knowledge of addiction into clinical progress.

PMID- 12403991
TI  - The role of neuroscience in the remediation of students with dyslexia.
AB  - Dyslexia is a specific learning disability that is neurobiological in origin. It
      is characterized by difficulties with accurate and/or fluent word recognition,
      spelling and decoding abilities. Research findings agree that these and other
      observed behavioral manifestations largely result from a deficit in the
      phonological component of language. However, conflicting theories on the exact
      nature of the phonological deficit have given rise to divergent treatment
      approaches. Recent advances in functional brain imaging and genetics have allowed
      these theories to be examined more closely. If implemented appropriately,
      commercial programs can be effective in identifying dyslexia. Treatment of
      dyslexia has been advanced through neuroscience, yet further study is needed to
      provide rigorous, reproducible findings that will sustain commercial approaches.

PMID- 12403992
TI  - Connecting cortex to machines: recent advances in brain interfaces.
AB  - Recent technological and scientific advances have generated wide interest in the
      possibility of creating a brain-machine interface (BMI), particularly as a means
      to aid paralyzed humans in communication. Advances have been made in detecting
      neural signals and translating them into command signals that can control
      devices. We now have systems that use externally derived neural signals as a
      command source, and faster and potentially more flexible systems that directly
      use intracortical recording are being tested. Studies in behaving monkeys show
      that neural output from the motor cortex can be used to control computer cursors
      almost as effectively as a natural hand would carry out the task. Additional
      research findings explore the possibility of using computers to return
      behaviorally useful feedback information to the cortex. Although significant
      scientific and technological challenges remain, progress in creating useful human
      BMIs is accelerating.

PMID- 12403993
TI  - Virtual reality in behavioral neuroscience and beyond.
AB  - Virtual reality (VR) has finally come of age for serious applications in the
      behavioral neurosciences. After capturing the public imagination a decade ago,
      enthusiasm for VR flagged due to hardware limitations, an absent commercial
      market and manufacturers who dropped the mass-market products that normally drive
      technological development. Recently, however, improvements in computer speed,
      quality of head-mounted displays and wide-area tracking systems have made VR
      attractive for both research and real-world applications in neuroscience,
      cognitive science and psychology. New and exciting applications for VR have
      emerged in research, training, rehabilitation, teleoperation, virtual archeology
      and tele-immersion.

PMID- 12403994
TI  - Recognizing complex patterns.
AB  - How the brain recognizes complex patterns in the environment is a central, but
      little understood question in neuroscience. The problem is of great significance
      for a host of applications such as biometric-based access control, autonomous
      robots and content-based information management. Although some headway in these
      directions has been made, the current artificial systems do not match the
      robustness and versatility of their biological counterparts. Here I examine
      recognition tasks drawn from two different sensory modalities--face recognition
      and speaker/speech recognition. The goal is to characterize the present state of
      artificial recognition technologies for these tasks, the influence of
      neuroscience on the design of these systems and the key challenges they face.

PMID- 12403995
TI  - In search of self.

PMID- 12403996
TI  - Influences of laboratory environment on behavior.

PMID- 12403997
TI  - Do somatic markers mediate decisions on the gambling task?

PMID- 12403999
TI  - Representing whole objects: temporal neurons learn to play their parts.

PMID- 12404000
TI  - Specifying axon identity with Syd-1.

PMID- 12404001
TI  - AMPA autoreceptors fill the gap in olfactory temporal coding.

PMID- 12404002
TI  - Optimal strategies for movement: success with variability.

PMID- 12404003
TI  - Chickens, eggs and hippocampal atrophy.

PMID- 12404004
TI  - How ephrins sculpt dendritic spines.

PMID- 12404006
TI  - Emerging ethical issues in neuroscience.

PMID- 12404007
TI  - The neurotrophin receptor p75(NTR): novel functions and implications for diseases
      of the nervous system.
AB  - Neurotrophins have long been known to promote the survival and differentiation of
      vertebrate neurons. However, these growth factors can also induce cell death
      through the p75 neurotrophin receptor (p75(NTR)), a member of the tumor necrosis
      factor receptor superfamily. Consistent with a function in controlling the
      survival and process formation of neurons, p75(NTR) is mainly expressed during
      early neuronal development. In the adult, p75(NTR) is re-expressed in various
      pathological conditions, including epilepsy, axotomy and neurodegeneration.
      Potentially toxic peptides, including the amyloid beta- (Abeta-) peptide that
      accumulates in Alzheimer's disease, are ligands for p75(NTR). Recent work also
      implicates p75(NTR) in the regulation of both synaptic transmission and axonal
      elongation. It associates with the Nogo receptor, a binding protein for axonal
      growth inhibitors, and appears to be the transducing subunit of this receptor
      complex.

PMID- 12404008
TI  - Optimal feedback control as a theory of motor coordination.
AB  - A central problem in motor control is understanding how the many biomechanical
      degrees of freedom are coordinated to achieve a common goal. An especially
      puzzling aspect of coordination is that behavioral goals are achieved reliably
      and repeatedly with movements rarely reproducible in their detail. Existing
      theoretical frameworks emphasize either goal achievement or the richness of motor
      variability, but fail to reconcile the two. Here we propose an alternative theory
      based on stochastic optimal feedback control. We show that the optimal strategy
      in the face of uncertainty is to allow variability in redundant (task-irrelevant)
      dimensions. This strategy does not enforce a desired trajectory, but uses
      feedback more intelligently, correcting only those deviations that interfere with
      task goals. From this framework, task-constrained variability, goal-directed
      corrections, motor synergies, controlled parameters, simplifying rules and
      discrete coordination modes emerge naturally. We present experimental results
      from a range of motor tasks to support this theory.

PMID- 12404010
TI  - NIH changes rules governing timing of protocol reviews; Funds chimpanzee
      sanctuary.

PMID- 12404011
TI  - Animal breeding and research protocols--the missing link.

PMID- 12404012
TI  - What's your diagnosis?

PMID- 12404013
TI  - Chocolate, an effective means of oral drug delivery in rats.
AB  - Oral gavage is an important procedure for drug discovery and efficacy studies
      using rodents. However, there are welfare issues related to the use of the method
      by inexperienced persons or for long-term studies. The authors describe an
      effective method of administering drugs to rats by mixing the drug with chocolate
      to provide a consistent and reliable method of oral drug delivery to large groups
      of rats for a long period of time.

PMID- 12404014
TI  - Incorporation of an enrichment program into a study protocol involving long-term
      restraint in macaques.
AB  - Nonhuman primates might experience stress during periods of restraint associated
      with research procedures. In an attempt to minimize such stress, the authors
      describe an enrichment program they designed for use with restrained adult male
      rhesus macaques.

PMID- 12404015
TI  - Email lists in laboratory animal science.
AB  - Email lists can be invaluable for acquiring information that may not be easily
      accessible in the published literature. The author discusses the general format
      and functioning of email lists and describes six lists that can be valuable tools
      for education, training, and information exchange in the field of laboratory
      animal science.

PMID- 12404016
TI  - Comparison of two oxygen delivery systems for safe sedation and spinal anesthesia
      in sheep.
AB  - Proper oxygenation is critical to prevent hypoxia and myocardial ischemia in
      animals during pharmacological sedation. The authors compared the efficacy of two
      oxygen delivery masks during sedation and spinal anesthesia for knee surgery in
      sheep.

PMID- 12404017
TI  - [Mental Health Residents 2000. Their opinion about their training six years after
      a previous survey].
AB  - OBJECTIVE: To assess the subjective perception of Clinical Psychology and
      Psychiatry Residents from Buenos Aires regarding their training in the year 2000.
      METHODOLOGY: During the Seventh Annual Meeting of Mental Health Residents from
      the metropolitan area of Buenos Aires, an anonymous and self completed survey was
      carried out by Clinical Psychology and Psychiatry Residents. These quantitative
      results were combined with a qualitative analysis of Residents' papers published
      in a previous article. RESULTS: 62% of the sample answered the survey. 90% of
      Clinical Psychology Residents and 77% of Psychiatry Residents are satisfied with
      their clinical training. Regarding their theoretical training, Psychology and
      Psychiatry Residents are pleased in 52% and 43% of cases respectively. Both think
      clinical presentations are more important to share than clinical practice itself.
      Only 6% see themselves as being prepared for conducting any kind of research.
      Mental Health Residents desire and believe that it is possible to work in private
      practice at the end of their training and only 36% of cases see the hospital as
      part of their future work. CONCLUSIONS: Psychiatry Residents are increasingly
      separating themselves from the Psychologists with an increased satisfaction with
      their training. This transformation has taken place simultaneously with a greater
      compromise of Mental Health Residents with the activities that gather all
      Metropolitan Area Residents and an updated psychiatric curricula

PMID- 12404018
TI  - [A pilot community study of subjective memory in over and under 65 years old].
AB  - Elderly adults are appropriate targets for objective memory assessment and
      cognitive testing in the promotion of earlier recognition of people with symptoms
      of a dementing process. The major change in memory with age is the decline in
      ability to recall things explicitly. There is a need for education of the general
      public and health professionals about memory impairment and its relationship with
      stress, depression, anxiety and dementia.

PMID- 12404019
TI  - [Dementia and cognitive impairment in Parkinson disease].
AB  - Changes in cognitive function and disturbances in behavior are commonly seen in
      parkinsonian patients and they are inherent features of the disease. Estimates on
      the prevalence of dementia in this disorder are quite variable, ranging from 15
      to 25%. Advanced age, depression, severity of akinesia, and the presence of
      dopaminomimetic psychosis, are considered as risk factors in the development of
      cognitive deterioration within this patient population. Cognitive dysfunction may
      manifest as relatively circumscribed deficits or overt dementia. The finding of
      mild cognitive deficits is common in Parkinson's disease, such as reduced
      flexibility, psychomotor slowing, reduction in learning capacity and information
      retrieval, and disturbances in visuospatial tasks. The most prevalent cognitive
      disturbance is an impairment in visuospatial tasks, not necessarily related to
      the degree of motor disability. Dementia, when present early on in the course of
      the disease may suggest alternative diagnoses (Diffuse Lewy body dementia,
      Alzheimer's disease with extrapyramidal features, Fronto-temporal dementia,
      etc.), while in those cases in whom the dementing disorder develops at a later
      stage, it is assumed to be an integral part of the disease, albeit corresponding
      to variable pathogenetic mechanisms.

PMID- 12404020
TI  - [Neurodevelopment and schizophrenia].
AB  - The evidence of neuroleptics' antipsychotic action due to their antagonism of
      dopamine receptors led to the hyperdopaminergic theory of schizophrenia. But the
      functional disturbance of the dopamine neurons should explain the increase and
      the reduction of some symptoms at the same time through the D2 receptors
      blockade. The prodromical manifestations of schizophrenia include abnormal
      movements which precede and predict the beginning of the disease. They also
      suggest a dopamine deficit. An injury in the mesocortical dopamine projection
      during the neural development could result in a functional impairment of the
      prefrontal cortex which causes the cognitive deficit symptoms. It would result
      also in an excessive compensatory subcortical dopamine activity which would cause
      the psychotic symptoms. The evidence in behalf of this physiopathology is
      complex. The mechanism of the subcortical compensation of the prefrontal dopamine
      deficit remains unknown. It is necessary to find out which is the exact mechanism
      of the injury that causes the mesocortical projection loss in the schizophrenia.
      We have suggested that the injury would depend on the excitotoxicity induced by
      the perinatal hypoxia which would provoke the selective death of a dopamine
      neurons subset which are very sensitive during the critical period of the
      mesencephalic development.

PMID- 12404021
TI  - [QEEG and brain mapping. Historial develoment, clinical practices and
      epistemological issues].
AB  - Although it has been more than two decades since brain mapping was introduced in
      medicine, its scientific value and clinical practice have not been proved. This
      paper makes an overview about the historical development of brain mapping, its
      usefulness in psychiatry and lays epistemological issues concerning the role of
      technology in medical settings. Both historical and technological development of
      qEEG gives us the opportunity to think about complexity between ethics, science,
      technology and medicine.

PMID- 12404022
TI  - [Psychiatric aspects of Epilepsy].
AB  - The classification of epileptic seizures is reviewed, emphasizing the clinical
      features of partial seizures with psychic symptoms. Psychiatric issues in
      epilepsy are also assessed, particularly affective disorders and psychosis.
      Although there currently is no internationally accepted syndromic classification
      for them, we expose recently proposed definitions. The concept of "epileptic
      personality" is reviewed, and the matter of aggression as well. Finally we
      include a case report that illustrates what we understand as the complexity for
      the clinical diagnosis.

PMID- 12404023
TI  - [Neurobiologia y psicoanalisis].
AB  - There would be a conceptual bridge between Psychoanalysis and the Neurosciences
      that would allow the translation of psychoanalytic concepts into neural
      mechanisms and vice-versa. Different Freudian postulates, such as that different
      types of anxiety would emerge from various cerebral interactions, the
      motivational regulatory functions of the impulse, the conscious emotion as the
      perception of something basically unconscious, the mechanism of repression in the
      traumatic memory, the existence of a system associated with the unconscious
      affective processes and regulated by the principle of pleasure - displeasure, the
      emotional representation as a basis of the more primitive cerebral structures,
      and the Oedipo complex, among others, are finding their biological ratification
      in different laboratory studies. This conceptual bridge would not only be a
      "Psychoanalysis-Neurobiological mechanisms" translator, but would also, through
      the integrated conceptualization of the psychoanalytical neurobiological aspects
      of emotion, generate relevant therapeutic models.

PMID- 12404024
TI  - [Neuropsychiatric and cognitive aspectos of multiple sclerosis].
AB  - Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease that can
      affect cognitive and emotional functioning. About 50% of MS patients present some
      degree of neuropsychological impairment. Due to its onset in young adulthood (a
      period of life in which the individual is professionally and socially very
      active) the presence of cognitive impairment may greatly alter the patient's
      daily living activities and future life plans. Memory, attention, executive
      function and information processing speed are the most commonly reported impaired
      aspects of cognition. Depression, euphoria, and pathological laughing and crying
      are frequent psychiatric findings. In this paper we describe the distinctive
      features of cognitive and psychopathological impairments and their relationship
      to certain disease variables such as illness duration, lesion sites, physical
      impairment and clinical course. We also deal with aspects of the
      neuropsychological and psychiatric assessment, emphasizing its importance when
      psychological counseling or an eventual cognitive training are needed.

PMID- 12404025
TI  - [John Hughling Jackson (1834-1911). In the origins of concepts of positive and
      negative symptoms in psychology and psychiatry].

PMID- 12404026
TI  - [Psychoanalysis in inherited medicine. Psychoanalysis or psychotherapy of limited
      time, a perverse option].

PMID- 12404027
TI  - ["Reumatismo" in Index Medicus/Med-Line and Online].

PMID- 12404028
TI  - [Italian rheumatology for the Bone and Joint Decade 2000-2010; balance of the
      first two years and future prospects].

PMID- 12404029
TI  - [Leptin: regulatory role in bone metabolism and in inflammation].
AB  - Leptin is a peptidic molecule synthesized almost exclusively by adipocytes, that
      regulates appetite and energy expenditure at the hypothalamic level. In the last
      few years, further actions have been attributed to this molecule, as modulating
      the immune response and affecting the bone metabolism. We have reviewed if leptin
      contributes to the metabolic changes leading to cachexia and to the regulation of
      inflammation, paying attention to the pathogenetic mechanisms of chronic
      arthritis. Besides, considering the relationship between body mass index (BMI) e
      bone mineral density (BMD) and the protective role of the obesity towards
      osteoporosis, we have analysed the role of leptin on the bone metabolism

PMID- 12404030
TI  - [Early electroretinografic changes in elderly RA patients treated with
      hydroxychloroquine].
AB  - OBJECTIVE: To evaluate the effectiveness of fundoscopy, electrooculography,
      electroretinogram and visually evoked potentials in early detection of
      hydroxychloroquine retinal toxicity in RA patients and to evaluate the influence
      of patients' age, drug dosage, concomitant therapy (prednisone and methotrexate)
      and serum creatinine levels in the development of this side effect. METHODS: From
      september to december 1999, we have enrolled 32 RA patients (13 males, 19
      females) starting hydroxychloroquine treatment. The patients underwent regular
      ophthalmological examination (fundoscopy, electro-oculography, electroretinogram
      and visually evoked potentials) every 4 months. Disease activity was evaluated
      every two months by clinical and routine serological examination. RESULTS: No
      patients developed retinopathy during 1 year's follow-up; fundoscopy,
      electrooculography, and visually evoked potentials did not vary from the
      baseline. On the other hand, electroretinogram showed early alterations of
      scotopic and photopic response; moreover a significant statistical correlation
      between patients' age (more than 65 years) and b1 photopic wave increase (p <
      0,05) was observed. No correlation was found between the development of electro
      retinographic alterations and hydroxychloroquine dosage, concomitant therapy and
      serum creatinine levels CONCLUSION: Our data show the inefficacy of fundoscopy,
      electrooculography and visually evoked potentials in early detection of
      hydroxychloroquine retinopathy. On the other hand electroretinogram allows early
      detection of retinal alterations during hydroxychloroquine treatment, in patients
      older than 65 years.

PMID- 12404032
TI  - [Analgesic dose range finding of lornoxicam compared to diclofenac. Crossover
      double blind study in rheumatoid arthritis].
AB  - OBJECTIVE: To evaluate the therapeutic action and safety of lornoxicam, a new non
      steroidal anti-inflammatory drug, in 2 oral daily dose regimens of 8 and 16 mg in
      comparison with oral diclofenac 150 mg/day in patients with rheumatoid arthritis.
      METHODS: Double blind double-dummy cross-over, controlled trial. The two
      treatments were given for ten-day periods, separated by a three-day wash-out
      interval. Patients of both sexes with classical or definite rheumatoid arthritis
      according to the A.R.A. criteria were enrolled in the study. RESULTS: Fourteen
      patients (12F, 2M) were admitted, mean age 61.6 years +/- 6.7 (+/-SD), duration
      of illness 12.7 years +/- 11.9. Lornoxicam 8 and 16 mg/day showed a good
      therapeutic activity, comparable with diclofenac 150 mg/day. Two patients
      complained adverse events with diclofenac. CONCLUSIONS: Lornoxicam 16 mg/day was
      associated with a more sharp action and a better tolerability than diclofenac in
      rheumatoid arthritis. The twice a day dosage of lornoxicam revealed to be
      appropriate.

PMID- 12404031
TI  - [Clinical significance of fluoroscopic patterns specific for the mitotic spindle
      in patients with rheumatic diseases].
AB  - OBJECTIVE: To determine the clinical significance of anti-NuMA and anti-HsEg5
      antibodies in a group of patients affected with rheumatic diseases. MATERIALS AND
      METHODS: Indirect immunofluorescence on HEp-2000 cells at serum dilution of 1:40
      was used to examine 26 sera which had previously showed a "mitotic spindle"
      fluoroscopic pattern type during laboratory routine. RESULTS: 21 sera (80,7%)
      were identified with NuMA and 5 (19,3%) with HsEg5 patterns alone or associated
      with other ANA patterns. However only patients with isolated positivity and that
      is 15 with NuMA and 4 with HsEg5 stainings were included in this study. Of the
      NuMA positive patients 5 were affected with arthropathies associated to different
      forms of thyroiditis, 2 with seronegative arthritis, 2 with antiphospholipid
      syndrome, 1 with systemic lupus erythematosus (SLE), 1 with rheumatoid arthritis,
      1 with sicca syndrome, 1 with undifferentiated connective tissue disease, 1 with
      Mycoplasma pneumoniae infection and 1 with retinal thrombosis. Of the HsEg5
      positive patients 3 were affected with SLE and 1 with seronegative arthritis.
      CONCLUSIONS: NuMA does not prevail in any defined rheumatic disease, while HsEg5
      staining were more frequent (75%) in patients affected with SLE all of whom
      showing high antibody titres.

PMID- 12404033
TI  - [Role of anti-prothrombin in antiphospholipid syndrome].
AB  - We studied 99 patients with systemic autoimmune disease (5 males, 94 women; mean
      age 37 year, range 16-72): 28 Primary Antiphospholipid Syndrome, 67 Systemic
      lupus Erythematosus, 1 Mixed Connective Tissue Disease, 2 Undifferentiated
      Connective Tissue Disease and 1 Discoid Lupus. Based on the observation that
      native PT shows conformational changes in presence of Ca++ ions and discloses new
      epitopes available for binding with phospholipids, we performed 3 different
      methods for the detection of aPT in presence and absence of Ca++, finding a
      different incidence of specific autoantibodies, associated with clinical features
      of APS (aPT in presence of Ca++) or non associated (aPT in absence of Ca++). The
      presence of aPT was significantly associated also with the presence of Lupus
      Anticoagulant (LAC). The detection of aPT (in presence of Ca++) significantly
      enhances diagnostic sensibility of APS allowing the identification of a subset of
      patients (6/99) with clinical features of APS, but with negative LAC, aCL and a
      beta2-GPI; in fact (limited to thrombotic episodes) the sensibility rises from
      56.2% with one test (LAC) to 81.1% with the application of LAC, aCL, a(beta)2GPI
      and aPT.

PMID- 12404034
TI  - [Sodium gold thiosulfate therapy: an open, viewed, multicenter trial in
      rheumatoid arthritis patients followed for two years].
AB  - OBJECTIVE: To evaluate if parenteral gold-therapy with Sodium gold thiosulfate is
      effective and safe for the treatment of rheumatoid arthritis we began an open,
      multicenter trial. METHODS: 126 rheumatoid arthritis patients were treated with
      Sodium gold thiosulfate for two years. Efficacy, quality of life, progression of
      joint damage, inflammatory parameters and side effects were evaluated. RESULTS:
      Gold salts reduced joint inflammation and improved subjective and objective
      symptoms, quality of life and activity of illness within 6 months. Side effects
      appeared in 13,8% of all cases and regressed, promptly, when gold therapy
      stopped. The poor efficacy caused the interruption and the change from the gold
      therapy to others disease-modifying anti-rheumatic drugs (DMRDs) in 17,8 % of the
      patients. CONCLUSIONS: The follow-up showed Sodium gold thiosulfate was effective
      in Rheumatoid Arthritis and the survival in therapy was of 77,8% to one year and
      of 68,4% to two years.

PMID- 12404035
TI  - [Cardiac tamponade preceding skin involvement in progressive systemic sclerosis].
AB  - The frequency of pericardial involvement in Systemic Sclerosis (SSc) is high on
      autoptic or echocardiographic studies, but the clinical recognition of
      pericarditis with or without effusion is rare. We describe a case of a 71-year
      old female with no previous history of heart disease, who presented with a large
      pericardial effusion and tamponade that required pericardial drain. She had
      suffered from Raynaud's phenomenon since 25 years. Six weeks after hospital
      discharge she complained of skin hardening on left leg. Pericardial tamponade is
      a very rare manifestation of SSc and occurs both early or late in the course of
      the disease, but in our case it preceded the recognition of scleroderma. We have
      only identified two other cases of pericardial effusion preceding cutaneous
      involvement in scleroderma.

PMID- 12404036
TI  - [Sonographic findings for synovial fluid].
AB  - OBJECTIVE: The aim of this pictorial essay was to evaluate the sonographic
      features of synovial fluid in patients with arthritis. METHODS: Sixty-nine
      patients with active synovitis (rheumatoid arthritis, psoriatic arthritis,
      osteoarthritis, septic arthritis, crystal arthropathies, post-traumatic
      arthritis) were studied. Sonographic evaluation was performed with a AU-5
      Harmonic, Esaote Biomedica (Genoa, Italy) equipped with a 10-14 MHz broadband
      linear transducer and a Diasus Dynamic Imaging Ltd.(Livingston, Scotland UK)
      equipped with a 8-16 MHz broadband linear transducer. RESULTS: Six main different
      sonographic patterns were detected: 1) Anechoic: increased amount of homogeneous
      anechoic synovial fluid (exudative synovitis). 2) Cloudy: echogenic structures
      (proteinaceous material). 3) Mixed: anechoic synovial fluid and proteinaceous
      material. 4) "Snow-storm" aspect: multiple mildly and heterogeneous echoic spots
      (9 out of 10 patients with acute gouty synovitis). 5) Dotted: multiple sparkling
      hyperechoic dots without posterior acoustic shadow (10 out of 12 patient with
      chondrocalcinosis). 6) Granular: irregular turbid aspect of the synovial fluid.
      It was present in 3 patient with septic arthritis. CONCLUSIONS: The results of
      this study indicate that high resolution ultrasonography is able to detect
      different features of synovial fluid. Further studies are needed to assess both
      sensitivity and specificity of ultrasonography in "in vivo" synovial fluid
      examination.

PMID- 12404037
TI  - [The role of HLA-B27 molecules in the pathogenesis of ankylosing spondylitis].
AB  - Ankylosing Spondylitis (AS) is characterised by the strongest association with an
      HLA antigen ever described for any disease. It represents therefore the ideal
      model for the understanding of the link between immune-mediated diseases and the
      HLA system. The role of HLA-B27 in the pathogenesis of AS will be discussed
      focusing on the recently described higher expression of these molecules in
      patients with AS compared with healthy controls.

PMID- 12404038
TI  - Contributions of paleorheumatology to understanding contemporary disease.
AB  - As paleopathology has evolved from observational speculation to analysis of
      testable hypotheses, so too has recognition of its contribution to vertebrate
      paleontology. In the presence of significant structural and density variation
      (between matrix and osseous structures), x-rays provide an additional perspective
      of osseous response to stress and disease. As film techniques are time and cost
      expensive, fluoroscopy has proven a valuable alternative. Radiologic techniques
      also allow non-invasive "sectioning" of specimens, illustrating significant
      internal detail. The object can be "split" on a plane and the two portions
      rotated to "open" the image. This three-dimensional approach now can be applied
      to other forms of sequential data to their facilitate 3-dimensional
      representation graphically or with solid representations. Antigen and
      microstructure may be well preserved in fossils. Molecular preservation with
      retention of helical structure and sensitivity to collagenase has been
      demonstrated in 10,000 year old collagen. Antigen has been extracted from 100
      million year old bone and documented, in situ, in 11,000 year old bone. If the
      appropriate site in the tissue is assessed, if antigen is still present, and if
      the appropriate antisera is utilized, fixation of the antibody to the specimen
      can be detected. Minute amounts of DNA can be amplified and analyzed. Recovery of
      DNA from a 40,000 year old mammoth, 17,000 year old bison and from 25 million
      year old insects provides opportunity for cloning and independent assessment of
      relationships. Implications of available technology focuses direction for
      development of collaborative approaches.

PMID- 12404039
TI  - Progression of cutaneous B-cell pseudolymphoma to cutaneous B-cell lymphoma.
AB  - BACKGROUND: Debates regarding nosology and clonality surround the entity known as
      cutaneous pseudolymphoma and its questionable transformation to frank cutaneous
      lymphoma. The relevance of these arguments is important, not only from a
      diagnostic standpoint, but also for making inferences based upon behavior,
      prognosis, and treatment. OBJECTIVE: Our goal was to demonstrate further evidence
      of progression from cutaneous pseudolymphoma to malignant lymphoma while at the
      same time advocating a comprehensive plan for evaluation, treatment, and followup
      of these patients. METHODS: A retrospective review was conducted of four patients
      initially considered to have cutaneous B-cell pseudolymphoma (CBPL) and who were
      later treated for primary cutaneous B-cell lymphoma (CBCL). A review of the
      literature of cases suggesting progression to malignant lymphoma from precursor
      lesions was also performed. RESULTS: Four patients initially diagnosed with CBPL
      by a combination of histologic, immunophenotypic, and gene rearrangement criteria
      had a progressive clinical course that, over a range of 17-51 months, evolved
      into CBCL. All patients had a comprehensive systemic workup to rule out the
      possibility of extracutaneous disease and were treated with local radiation
      therapy and close followup. There has been no evidence of extracutaneous disease
      with an average followup of 14 months. CONCLUSION: The potential for certain
      cutaneous pseudolymphomas to progress to CBCL is real. The combination of
      histologic and immunophenotypic criteria, along with the clinical picture,
      remains the best way to judge the aggressiveness of the lesion. Gene
      rearrangement studies, whether performed by Southern blot or polymerase chain
      reaction (PCR), are of limited value and should be used to support the overall
      clinicopathologic picture. Radiation therapy of these patients should be thought
      of early in the management plan and is a very successful form of treatment when
      combined with close followup.

PMID- 12404042
TI  - Aortic reconstruction in patients with functioning renal allografts.
AB  - Patients with functioning renal allografts requiring aortic reconstruction pose a
      considerable challenge to the vascular surgeon. A variety of strategies for renal
      allograft preservation during intervention have been described including
      hypothermia, indwelling shunts, cold renal perfusion, axillofemoral bypass, and
      endovascular stent-grafting. Reported here are two cases of successful aortic
      reconstruction utilizing standard open surgical techniques designed simply to
      minimize warm renal ischemia. The first case was that of a 55 year-old patient
      with a functional renal allograft originating from the right external iliac
      artery, who presented acutely with large symptomatic aortic and bilateral iliac
      artery aneurysms. He was treated with aorto-right femoral/left iliac bypass
      grafting. The right femoral anastomosis was performed first so that warm renal
      ischemia was limited to the 34 min required to perform the proximal end-to-end
      aortic anastomosis. The second case was that of a 44-year-old patient also with a
      transplanted kidney originating from the right external iliac artery. He
      presented with worsening hypertension, decreasing renal function, claudication,
      and severe aortoiliac occlusive disease. He was treated with aorto-left femoral
      bypass grafting via a retroperitoneal approach, followed by femorofemoral
      crossover bypass for retrograde perfusion of the kidney (total warm ischemia time
      20 min). Both patients recovered uneventfully without a decrement in renal
      function and remain well on follow-up. It is concluded that standard open surgery
      without adjunctive shunts or bypasses remains a viable treatment option for these
      patients, provided warm renal ischemia can be minimized.

PMID- 12404040
TI  - Use of transcutaneous nerve stimulation wristband to treat methotrexate-induced
      nausea.
AB  - BACKGROUND: Although methotrexate is a highly effective treatment for psoriasis,
      nausea and vomiting may be dose-limiting side effects. Various approaches have
      been used to improve the tolerability of methotrexate therapy, including changing
      the dose or form of administration of the methotrexate or concomitant
      administration of folic acid or an antiemetic. OBJECTIVE: The objective of this
      case report is to present the use of a novel, nonpharmacologic approach for
      controlling the nausea associated with methotrexate therapy. RESULTS: A 47-year
      old patient with long-standing psoriasis was treated with methotrexate. She
      developed nausea refractory to standard antiemetic measures. She noted almost
      immediate relief of her nausea when using a transcutaneous nerve stimulation
      wristband. CONCLUSIONS: Nerve stimulation may be a valid alternative to other
      first-line antiemetic therapies.

PMID- 12404043
TI  - The benefit of exercise in intermittent claudication: effects on collateral
      development, circulatory dynamics and metabolic adaptations.

PMID- 12404044
TI  - Patency of superficial femoral vein employed as a crossover femoral artery bypass
      conduit.
AB  - This study assesses the patency of superficial femoral vein used as a crossover
      femoral artery bypass conduit in patients presenting either with localized groin
      sepsis, generalized sepsis or in patients with occluded or heavily diseased
      superficial femoral artery outflow. Twenty patients were followed prospectively
      with femoral crossover grafts constructed of superficial femoral vein. Twelve
      patients presented with sepsis and 8 with chronic ischemia from iliac artery
      occlusion and severely diseased superficial femoral artery outflow. Graft patency
      was assessed with regular duplex ultrasound examination. There was one
      perioperative death. Six patients died during the follow-up period. Mean follow
      up time was 24.3 months. No graft occluded or required revision. There was no
      limb loss, graft infection, or graft hemorrhage. Superficial femoral vein offers
      an effective femoral crossover bypass graft in patients with either
      localized/generalized sepsis or disadvantaged outflow tracts.

PMID- 12404045
TI  - Coronary and carotid artery disease in patients with degenerative aneurysm of the
      descending thoracic or thoracoabdominal aorta: prevalence and impact on operative
      mortality.
AB  - From January 1, 1995 to July 31, 2000, a total of 133 patients underwent elective
      surgical treatment for degenerative aneurysm of the descending thoracic (n = 45)
      or thoracoabdominal (n = 88) aorta. There were 116 men (87%) and 17 women (13%)
      with a mean age of 66.4 +/- 8.7 years (range, 39 to 84 years). Sixteen patients
      (12%) died in the immediate postoperative period. Thirteen patients (10%) had
      already undergone myocardial revascularizaton. Thirty-five patients (26%)
      presented clinical symptoms of coronary artery disease. Preoperative coronary
      arteriography was performed in 84 (63%) patients, demonstrating normal findings
      or clinically insignificant lesions in 48 patients (57%), single-vessel lesions
      (>70% reduction in diameter) in 19 patients, two-vessel lesions in 12 patients,
      and three-vessel lesions in 5 patients. On the basis of these findings,
      myocardial revascularization was performed before aortic repair in 11 patients.
      The total number of myocardial revascularization procedures in this series was 24
      (18%). Four patients had previously undergone a total of 6 carotid endarterectomy
      procedures. Routine duplex ultrasound demonstrated significant carotid artery
      lesions in 12 patients (9%). Ten of these patients (8%) underwent carotid
      endarterectomy. The total number of carotid endarterectomy procedures in this
      series was 16 in 14 patients. The prevalence of coronary and carotid lesions in
      patients indicated for elective treatment for degenerative aneurysm of the
      descending thoracic or thoracoabdominal aorta was similar to that observed in
      patients presenting degenerative aneurysm of the infrarenal abdominal aorta.
      Univariate analysis demonstrated that coronary and carotid lesions with or
      without treatment are a significant risk factor for mortality following surgical
      repair of degenerative aneurysm of the descending thoracic or thoracoabdominal
      aorta. This finding suggests that routine preoperative coronary arteriography and
      duplex ultrasound are warranted.

PMID- 12404046
TI  - Extraanatomical revascularization of the artery of Adamkiewicz: anatomical study.
AB  - Spinal cord ischemia is a major cause of complications after operative and
      endovascular treatment of descending thoracic or thoracoabdominal aortic
      aneurysms. Prior revascularization of the intercostal artery (IA) giving rise to
      the artery of Adamkiewicz (AA) using an artery of the thoracic wall would
      preserve circulation in the AA and allow obstruction of the IA at its origin. The
      purpose of this study was to determine the feasibility of revascularization of
      the IA giving rise to the AA using three thoracic wall arteries, i.e., lateral
      thoracic artery, thoracodorsal artery, and descending scapular artery. A total of
      16 specimens from 8 cadavers (6 men and 2 women) were prepared. The length and
      diameter of the thoracic wall arteries were measured to ascertain the feasibility
      of revascularization of the IA giving rise to the AA. In addition, 12
      preoperative spinal cord arteriograms were studied. We found that
      revascularization of the IA giving rise to the AA using thoracic wall arteries is
      feasible. This technique could be used to prevent spinal cord complications after
      treatment of descending thoracic or thoracoabdominal aortic aneurysms.

PMID- 12404047
TI  - Laparoscope-assisted distal gastrectomy for early gastric cancer in a 76-year-old
      man with situs inversus totalis.
AB  - We report a case of a 76-year-old man with situs inversus totalis (SIT) who
      developed early gastric cancer. He was successfully treated by laparoscope
      assisted distal gastrectomy for the gastric cancer. This case suggests that
      patients with SIT with malignancy could also undergo laparoscopic surgery. To the
      best of our knowledge, no case of laparoscopic surgery for malignant neoplasms
      associated with SIT has been reported in the English literature. We therefore
      believe this is the first case report.

PMID- 12404048
TI  - Transgastric endoluminal laparoscopic resection of a villous adenoma of the
      duodenum.
AB  - Laparoscopic transgastric techniques have been introduced in the recent
      literature for the management of gastroduodenal lesions. The case study in this
      article describes a novel approach to a duodenal adenoma using endoscopically
      assisted laparoscopic transgastric resection.

PMID- 12404049
TI  - Laparoscopic relief of reduction en masse of incarcerated inguinal hernia.
AB  - Reduction en masse of a hernia is defined as the displacement of a hernia mass
      without relief of incarceration or strangulation. This entity is an extremely
      rare occurrence. This diagnosis should be considered in all cases of intestinal
      obstruction after apparent reduction of an incarcerated hernia. Because of the
      extremely rare occurrence of this condition, however, the definitive diagnosis of
      reduction en masse may be difficult. We report the first case of laparoscopic
      relief of reduction en masse of incarcerated inguinal hernia. Laparoscopic
      surgery can be considered a better approach than open surgery because, while it
      is just as effective as the latter in making a definitive diagnosis and relieving
      incarceration, it is much less invasive and allows the patient to make a more
      rapid recovery.

PMID- 12404050
TI  - Totally laparoscopic management of gallstone ileus.
AB  - Gallstone ileus is an uncommon disease of elderly patients who present with bowel
      obstruction. Mortality and severe complications are common, even in modern
      series, due to the comorbidities in the affected patient population. A number of
      less invasive ways to treat this disease are described. We report on a case where
      enterolithotomy was performed laparoscopically. The patient is a 60-year-old
      diabetic woman who presented with a bowel obstruction and pneumobilia on
      abdominal radiographs. She underwent exploratory laparoscopy using three reusable
      ports, an enterolithotomy, and her remaining bowel was examined. The benefits to
      a minimal access approach to this rare disorder are discussed. The ability to
      suture laparoscopically is emphasized.

PMID- 12404051
TI  - Role of self-expandable metal stents in the palliation of malignant duodenal
      obstruction.
AB  - BACKGROUND: Palliative surgical intervention for malignant duodenal obstruction
      is often associated with a significant morbidity. Endoscopic enteral stenting
      offers a suitable alternative, that is safe, effective, and less invasive. This
      study reports our experience with the use of self-expanding metal stents in the
      palliation of malignant gastric duodenal obstruction. METHODS: A retrospective
      review of all patients who underwent duodenal stenting from November 1998 to
      February 2001 was performed. All the patients had symptomatic gastric outlet and
      duodenal obstruction with nausea, vomiting, and decreased oral intake. All of
      them underwent enteral stenting with self-expandable metal Wallstents 20 or 22 mm
      in diameter and 6 or 9 cm long. RESULTS: For this study, 33 patients (19 men and
      14 women) with a mean age of 62 years (range, 37-81 years) were identified, 32 of
      whom had successful duodenal stent placement (6 were performed as outpatient
      surgery). The malignancies were pancreatic 18 (54%), gastric 4 (12%), duodenal 3
      (9%), metastatic 6 (18%), and cholangiocarcinoma 2 (6%) disorders. The site of
      obstruction was pyloric (n = 5; 15%), pyloroduodenal (n = 3; 9%), duodenal bulb
      (n = 11; 33%), second portion of duodenum (n = 9; 27%), second and third portion
      of duodenum (n = 3; 9%), C-loop (n = 1; 3%), and anastomotic (n = 1; 3%). A total
      of 29 patients (91%) had good clinical outcomes, with relief of obstructive
      symptoms, Two of three patients with no symptomatic relief underwent
      gastrojejunostomy. One patient refused further treatment. No immediate stent
      related complications were noted. During the follow-up period, 20 patients died
      (none as a result stent-related causes) due to progression of cancer. Median
      survival was 102 days. Four patients had recurrent obstruction (2 tumor
      ingrowths, 1 overgrowth, and 1 distally migrated stent) at a mean interval of 82
      days. All four had successful restenting without complications. CONCLUSION: Self
      expandable metal stents placed endoscopically provide a safe, less invasive
      palliative treatment option with good clinical outcome in the management of
      malignant gastric outlet-duodenal obstruction.

PMID- 12404052
TI  - Use of a new energy-based vessel ligation device during laparoscopic gynecologic
      oncologic surgery.
AB  - BACKGROUND: Achieving hemostasis may sometimes be challenging, especially in
      minimal access surgery. The objective of this study was to evaluate the safety
      and effectiveness of a new ligation device. METHODS: The LigaSure vessel sealing
      system, consisting of a bipolar radio frequency generator and a 5-mm laparoscopic
      Maryland-style grasper-dissector (LigaSure Lap), was used in 15 patients
      undergoing advanced laparoscopic gynecologic procedures. RESULTS: Reliable vessel
      sealing was achieved in all the patients, with minimal sticking, charring, and
      lateral thermal spread. A decrease in blood loss and operating time was noted.
      CONCLUSIONS: This new energy-based vessel ligation device appears to be effective
      in advanced laparoscopic gynecologic procedures. Larger studies are needed to
      evaluate the complication rate and the cost effectiveness of this new technology.

PMID- 12404053
TI  - Clinical outcome of simultaneous self-expandable metal stents for palliation of
      malignant biliary and duodenal obstruction.
AB  - BACKGROUND: Previous studies have shown that self-expanding metal stents are an
      effective method for palliation of malignant biliary or duodenal obstruction. We
      present our experience with the use of simultaneous self-expandable metal stents
      for palliation of malignant biliary and duodenal obstruction. METHODS: We
      performed a retrospective review of all patients undergoing simultaneous biliary
      and duodenal self-expandable metal stent placement between November 98 and May
      2001. All the patients had documented evidence of biliary obstruction and
      symptomatic duodenal obstruction. The patients received endoscopic biliary
      stenting with biliary Ultraflex or Wallstents, and endoscopic duodenal stenting
      using enteral Wallstents. They were followed until their death. RESULTS: We
      identified 18 patients (11 men and 7 women) whose mean age was 65 years, (range,
      46-85 years). Malignancies included pancreatic 14 (78%), biliary 2 (11%),
      lymphoma 1 (5%), and metastatic 1 (5%) disorders. Ten patients previously had
      plastic biliary stents placed for past malignant biliary obstruction (4 patients
      had recurrent biliary obstruction). All the patients had evidence of duodenal
      obstruction. Combined metal stenting was successful in 17 patients. One procedure
      failed due to a tortuous duodenal stricture. All the patients had effective
      palliation of biliary obstruction, as evidenced by a decrease in the level of
      total bilirubin and alkaline phosphatase. Of the 17 patients with successful
      duodenal stenting, 16 had a good clinical outcome, with relief of obstructive
      symptoms. No immediate stent-related complications were noted. During the follow
      up period, 12 patients died of progression of the underlying malignancy. None of
      the deaths were stent related. Median survival time was 78 days. Two patients had
      recurrent biliary obstruction from tumor ingrowth at 45 and 68 days,
      respectively. Both underwent restenting: one by endoscopic retrograde
      cholangiopancreatography (ERCP) and the other by percutaneous transhepatic
      cholangiography (PTC). Two other patients had recurrent duodenal obstruction,
      respectively, 36 and 45 days after the initial stenting. One obstruction was
      secondary to tumor ingrowth, and the other was caused by distal stent migration.
      Both patients had successful duodenal restenting. CONCLUSION: Combined self
      expandable metal stenting for simultaneous palliation of malignant biliary and
      duodenal obstruction may provide a safe and less invasive alternative to surgical
      palliation with an acceptable clinical outcome. Simultaneous self-expandable
      metal stents should be considered as a treatment option for patients who are poor
      candidates for surgery.

PMID- 12404054
TI  - Is gastroscopy still a valid diagnostic tool in detecting gastric MALT lymphomas?
      A dilemma beyond the eye. Mucosa-associated lymphoid tissue.
AB  - BACKGROUND: Primary gastric lymphomas are distinct entities with an indolent
      clinical course and biologic behavior. They account for 2-8% of all gastric
      malignancies. We conducted this study to evaluate the role of gastroscopy as the
      principal diagnostic method in detecting gastric MALT lymphomas. METHODS: Sixty
      three consecutive patients with gastric MALT lymphomas, who were evaluated and
      treated at our institution between January 1978 and December 1997, are
      retrospectively reviewed. There were 36 males and 27 females, with a mean age of
      53 years (range 20-80 years). All patients underwent the standard diagnostic
      evaluation, including gastroscopy and biopsy. Patients were staged according to
      revised Musshof modification of the Ann Arbor classification system, whereas
      histological evaluation was made according to the Isaacson classification system
      for gastric MALT lymphomas. RESULTS: According to endoscopic findings, the antrum
      harbored the neoplasm in 31 patients (49%), the body in 38% (24 patients), and
      the fundus in 4% (3 patients), whereas in 5 patients (8%) the neoplasm occupied
      the entire stomach. The macroscopic appearance was not in most cases
      pathognomonic of the disease. Three macroscopic patterns were recognized at
      endoscopy: (a) the ulcerative in 51% (32 patients), (b) the polypoid in 33% (21
      patients) and (c) the diffuse infiltrative in 16% (10 patients). The neoplasm was
      characterized as a benign disease in 24 patients (38%), with malignancy being
      suspected in 62% (39 patients). Endoscopy displayed a sensitivity of 61% in
      detecting malignancy; however, the sensitivity dropped to 27% when endoscopic
      diagnosis of non-Hodgkin's lymphoma was hypothesized. CONCLUSIONS: Although the
      impact of gastroscopy as a diagnostic tool in the patients of our study was of
      limited value, due to the nonspecific gross pattern of gastric MALT lymphomas, it
      should be maintained in the diagnostic intervention of the upper GI tract
      pathologies.

PMID- 12404056
TI  - Genetic progression of renal cell carcinoma.
AB  - Initiation, progression, and metastasis of cancer are due to genetic alterations.
      The major challenges of cancer research include the identification of genes
      involved in metastasis and the evaluation of emerging candidate genes for a
      potential clinical significance. Renal cancer with its unpredictable metastatic
      behavior is particularly challenging. The combination of several new molecular
      technologies, including comparative genomic hybridization, fluorescence in situ
      hybridization, and cDNA and tissue microarrays have advanced our understanding of
      renal cancer. However, one usually obtains a limited view of the dynamic process
      of renal tumor development in a particular cancer patient because renal cell
      carcinoma is characterized by an accumulation of complex molecular alterations
      during tumor progression. Some early chromosomal alterations in the
      carcinogenesis of renal tumors are known, but the nature of subsequent events,
      their interrelationships, and sequence is poorly understood. To analyze and model
      cancer development processes, including the presence of multiple pathways, a
      mathematical method for comparative genomic hybridization data was developed to
      search for tree models of the oncogenesis process. Tree modeling of comparative
      genomic hybridization data has provided new information on the interrelationships
      of genetic changes in renal cancer, their possible order, and a clustering of
      these events. This review concentrates on the application of comparative genomic
      hybridization in the area of renal cancer research

PMID- 12404057
TI  - Quality assurance for detection of estrogen and progesterone receptors by
      immunohistochemistry in Austrian pathology laboratories.
AB  - Steroid hormone receptors are important prognostic and predictive factors in
      breast carcinomas. Thus their determination is of essential importance. The aims
      of this study were to assess the quality of the immunohistochemical assays, and
      to assess the interlaboratory and interobserver variability performed by
      different laboratories in Austria. Ten unstained slides for interlaboratory
      variability evaluation and ten immunohistochemically prestained slides for
      interobserver variability evaluation from breast carcinomas known to show
      different degrees of steroid hormone receptor expressions were sent to 32
      surgical pathology laboratories in Austria (participation rate 97%). The
      participants were requested to perform their in-house immunohistochemistry (IHC)
      technique for estrogen receptors (ERs) and progesterone receptors (PRs) on the
      unstained slides. All slides were evaluated by estimating percentage and
      intensity of stained nuclei semiquantitatively. From these data the Reiner,
      Remmele and the Allred scores were calculated. A less than 10% cut-off level was
      chosen as threshold for positive cases. Regarding the series of prestained
      slides, both sensitivity and specificity were very high (>96.88%); false-positive
      and -negative rates were low (<3.31%). Interobserver variability showed moderate
      multirater kappa values concerning the ER (Reiner score: kappa=0.57) and PR
      scores (Reiner score: kappa=0.53). The agreement among observers was better for
      negative cases than positive cases. In-house slides representing interlaboratory
      variability showed fair to moderate kappa values concerning the ER and PR scores
      (kappa for ER Reiner score=0.41; PR=0.32). In this slide series, sensitivity and
      specificity were high (>82.2%) and false-positive or -negative rates were low in
      ER cases (<3.03) and moderately low in PR cases (17.46%). These results
      demonstrate that variability is higher when participants use their own staining
      method. In more detailed analysis, the automated IHC techniques showed an
      advantage over manual techniques concerning interlaboratory variability. There
      exists no difference in reproducibility with respect to scoring systems for
      steroid hormone receptor estimation.

PMID- 12404058
TI  - Bone marrow biopsy in hemophagocytic syndrome.
AB  - AIMS: Hemophagocytic syndrome (HPS) is a severe and acute clinical event
      occurring with fever, hepatosplenomegaly, and pancytopenia due to uncontrolled
      phagocytosis of blood cells and precursors. Although HPS represents a secondary
      phenomenon, it can mask the underlying condition, generally a neoplastic or
      infective disease, thus making the patient management rather difficult. The aims
      of this study were to point out the main pathological features useful to
      highlight the primary disease and show the eventual discrepancies among the
      different cases. METHODS AND RESULTS: Bone-marrow biopsies (BMBs) of 26 patients
      with HPS were morphologically and immunophenotypically evaluated; the patients
      were 12 females and 14 males with mean age of 45.8 years (range 18-80 years).
      Fifteen patients had a hematological neoplasia either at onset (13 cases) or
      relapse (2 cases); 5 patients had evidence of active infection immediately prior
      to HPS development, whereas in 6 patients no definite etiology was established.
      Cases were therefore divided into neoplasia related, infection related, and
      "idiopathic". In all cases BMB showed marked histiocyte hyperplasia with
      hemophagocytosis. In cases of bone-marrow lymphoma or leukemia involvement,
      immunohistochemistry allowed diagnosis of the underlying disease to be made;
      infection-related cases showed a reactive marrow with mature interstitial T
      lymphoid infiltration, whereas in idiopathic cases T-cells were mainly aggregated
      in small clusters. In no cases were significant percentages of natural-killer
      (NK) cells detected. INTERPRETATION AND CONCLUSIONS: Although no strict
      morphological or immunophenotypical criteria able to allow an immediate diagnosis
      of underlying disease were pointed out, in most cases BMB proved to be an
      essential and reliable diagnostic tool. According to our experience, when HPS
      occurs, the first diagnosis to investigate is a neoplastic disease which
      sometimes can be latent or hidden.

PMID- 12404059
TI  - Expression of osteopontin and vascular endothelial growth factor in benign and
      malignant bone tumors.
AB  - Osteopontin (OPN), one of the major non-collagenous proteins of bone matrix, is
      together with vascular endothelial growth factor (VEGF) a potent angiogenic
      protein. In this study we determined the expression of OPN in benign and
      malignant bone tumors and investigated the prognostic influence of OPN expression
      on the outcome of osteosarcoma patients. Fifty-seven osteosarcomas and 11
      osteoblastomas as well as 5 bone specimens with remodeling sites were
      immunohistochemically analyzed for expression of OPN and VEGF. OPN was not
      detected in osteoblasts of remodeling sites. Osteoblastoma osteoblasts as well as
      osteoclastlike giant cells and osteosarcoma mononuclear cells showed variable
      staining. In osteosarcomas OPN and VEGF expression correlated with each other
      (r=0.390, P=0.003, Spearman's test). Although osteosarcoma patients with high
      VEGF expression showed a trend towards shorter overall survival ( P=0.0841, log
      rank test), OPN expression had no influence on patients overall or on disease
      free survival. Our data indicate that expression of this protein might be
      upregulated in bone neoplasia. Although OPN expression correlates with VEGF
      expression in osteosarcomas, OPN expression does not provide predictive
      information about the outcome of osteosarcoma patients.

PMID- 12404060
TI  - Vertical and horizontal growth features of superficial esophageal squamous cell
      carcinomas: histopathological evaluation of endoscopically resected specimens.
AB  - Endoscopic mucosal resection (EMR) has been performed for intramucosal carcinomas
      with excellent results. To evaluate invasion depth of superficial esophageal
      squamous cell carcinomas (SESCCs) accurately, it is important to elucidate
      vertical and horizontal growth features. Using 179 specimens of SESCC taken by
      EMR, various factors associated with vertical and horizontal growth were examined
      pathologically to determine which were correlated with invasion depth, classified
      for this purpose into four levels, m1, m2, m3, and sm. Maximum tumor diameter,
      including high-grade intraepithelial neoplasia, differed between m1 and m2 cases
      and for invasive lesions between m2 and m3. Maximum tumor thickness varied
      between m1 and m2, m2 and m3, and m3 and sm. Multivariate analysis showed tumor
      thickness and diameter of invasion to be correlated with submucosal invasion.
      Tumor thickness and depth of the depressed lesions were correlated in
      depressed/flat type cases. In elevated type cases the thickness of the tumor did
      not differentiate between m3 and sm. Shape of the elevated lesion also influenced
      the invasion depth. Frequency of infiltrating type tumors, composed of irregular
      and small invading nests, was higher with sm than m3. To differentiate m3 and sm
      tumor the classification of gross type, thickness, depth of depressed lesions,
      shape of elevated lesions, and invasion patterns should all be evaluated.

PMID- 12404061
TI  - Amyloid cored plaques in Tg2576 transgenic mice are characterized by giant
      plaques, slightly activated microglia, and the lack of paired helical filament
      typed, dystrophic neurites.
AB  - We examined the brains of Tg2576 transgenic mice carrying human amyloid precursor
      protein with the Swedish mutation and Alzheimer's disease (AD) by means of
      immunohistochemistry and electron microscopy to clarify the characteristics of
      amyloid-associated pathology in the transgenic mice. In 12- to 29-month-old
      Tg2576 mice, congophilic cored plaques in the neocortex and hippocampus were
      labeled by all of the Abeta1-, Abeta40- and 42-specific antibodies, as seen in
      the classical plaques in AD. However, large-sized (>50 micro m in core diameter)
      plaques were seen more frequently in the older mice (18-29 months) than in those
      with AD (approximately 20% vs 2% in total cored plaques), and Tg2576 mice
      contained giant plaques (>75 micro m in core diameter), which were almost never
      seen in the brain of those with AD. Neither thread-like structures nor peripheral
      coronas were observed in the cored plaques of the transgenic mice in the silver
      impregnations. Immunohistochemically, plaque-accompanied microglia showed a
      slight enlargement of the cytoplasm with consistent labeling of Mac-1 and
      macrosialin (murine CD68), and with partial labeling of Ia antigen and macrophage
      colony stimulating factor receptor. Ultrastructurally, the microglia surrounding
      the extracellular amyloid fibrils in the large, cored plaques showed some
      organella with phagocytic activity, such as secondary lysosomal, dense bodies,
      but intracellular amyloid fibrils were not evident. Dystrophic neurites in the
      plaques of the transgenic mice contained many dense multilaminar bodies, but no
      paired helical filaments. Our results suggest that giant cored plaques without
      coronas or paired helical filament-typed, dystrophic neurites are characteristic
      in Tg2576 mice, and that plaque-associated microglia in transgenic mice are
      activated to be in phagocytic function but not sufficient enough to digest
      extracellularly deposited amyloid fibrils.

PMID- 12404062
TI  - Effects of pregnancy-associated Listeria monocytogenes infection: necrotizing
      hepatitis due to impaired maternal immune response and significantly increased
      abortion rate.
AB  - The impact of L. monocytogenes infection on maternal immune responses as well as
      on the outcome of pregnancy was studied in a murine model of pregnancy-associated
      listeriosis. Mice infected i.v. with L. monocytogenes at day 15 of pregnancy
      showed a significantly impaired bacterial elimination, which resulted in a severe
      necrotizing hemorrhagic hepatitis. The aggravated course of the infection could
      be attributed to a suppressed transcription and production of anti-listerial, pro
      inflammatory cytokines and chemokines, namely interferon-gamma, tumor necrosis
      factor, interleukin-12p40, inducible nitric oxide synthase, murine monokine
      induced by interferon-gamma, and interferon-gamma-inducible protein-10. In
      addition, listeriosis significantly increased the abortion rate. Infection of the
      placenta and fetuses was characterized by placental and fetal necrosis with
      unrestricted bacterial multiplication. A weak transcription of anti-listerial
      cytokines in the placenta in the absence of a cellular immune response could not
      prevent the fatal outcome of pregnancy-associated listeriosis.

PMID- 12404063
TI  - Fibroblast growth factor 8 expression in breast carcinoma: associations with
      androgen receptor and prostate-specific antigen expressions.
AB  - Recent experimental data have clearly demonstrated that fibroblast growth factor
      (FGF)8 plays a key role in the development of human prostate and breast cancers.
      However, little is known about the FGF8 expression profile in human breast cancer
      specimens. In this study, we analyzed FGF8 expression in 78 surgically resected
      specimens of breast cancer using an immunohistochemical method. In total, FGF8
      expression was found in 40 (51.3%) of the breast carcinomas. FGF8 expression was
      not associated with any of the general clinicopathological parameters, including
      age, tumor size, histological grade, and histological type. In addition, there
      was no correlation between FGF8 expression and either c-erbB-2 overexpression or
      the status of the axillary lymph-node metastasis, both of which have been
      established as important prognostic factors in breast carcinomas. While no
      significant association was found between FGF8 expression and estrogen- or
      progesterone-receptor status, it is of interest that FGF8 expression was
      significantly associated with androgen-receptor status and the expression of
      prostate-specific antigen (PSA), one of the androgen-regulated proteins, in human
      breast carcinomas. These associations support the reported in vitro data
      demonstrating the regulation of FGF8 by androgens, and also suggest that PSA may
      be a useful marker for patients with FGF8-expressing breast carcinomas.

PMID- 12404064
TI  - ErbB2 oncogene expression supports the acute pancreatitis-chronic pancreatitis
      sequence.
AB  - The pathogenesis of chronic pancreatitis remains controversial. According to the
      general opinion, chronic pancreatitis is a de novo disease with a silent but
      progressive restructure of the pancreas in response to environmental, nutritional
      or genetic factors. The necrosis-fibrosis sequence hypothesis, on the other hand,
      postulates that relapsing attacks of acute pancreatitis with subsequent
      development of fibrosis leads to chronic pancreatitis. Since in our previous
      studies the expression of two anti-ErbB2 growth factor receptor (ErbB2)
      antibodies was shown to discriminate between primary chronic pancreatitis, normal
      tissue, and secondary chronic pancreatitis caused by pancreatic cancer, we
      studied the ErbB2 expression in tissues obtained from acute, recurrent acute, and
      chronic pancreatitis to investigate a possible evolution of the ErbB2 expression
      pattern during the course of the disease. We subjected 14 normal pancreas, 15
      chronic pancreatitis, and 12 acute pancreatitis (three with recurrent acute
      pancreatitis) specimens to immunohistochemical studies using polyclonal anti
      ErbB2 antibodies from Santa Cruz and Dako. The immunoreactivity of islet cells in
      acute pancreatitis cases with the Santa Cruz antibody was less than that in
      normal pancreas in relation to the degree of tissue damage and fibrosis, and was
      negative in recurrent acute and chronic pancreatitis tissues. The Dako antibody,
      on the other hand, revealed a membrane staining of ductal and ductular cells only
      in chronic pancreatitis specimens and in some areas of recurrent acute
      pancreatitis. In conclusion, the similarities in the immunoreactivity of anti
      ErbB2 antibodies in recurrent acute pancreatitis and chronic pancreatitis support
      the hypothesis that acute pancreatitis can be a forerunner of chronic
      pancreatitis.

PMID- 12404065
TI  - Differential expression of collagen IV alpha1 to alpha6 chains in basement
      membranes of benign and malignant odontogenic tumors.
AB  - Type IV collagen, the major component of basement membrane (BM), demonstrates a
      stage- and position-specific distribution of its isoforms during tooth
      development. To determine its localization in BM of odontogenic neoplasms,
      immunohistochemistry using six anti-alpha(IV) chain-specific monoclonal
      antibodies was performed. Results disclosed that BM demonstrated an irregular
      alpha(IV) chain profile in malignant odontogenic tumors as compared to benign
      odontogenic neoplasms. No alpha3(IV) chains were detected. Expression of
      alpha1(IV)/alpha2(IV) and alpha5(IV)/alpha6(IV) chains was stronger in
      desmoplastic ( n=3) than in ordinary (n=5) ameloblastomas. The adenomatoid
      odontogenic tumor ( n=2) distinctly expressed these chains in BM of cribriform
      areas and hyaline materials (which was also alpha4(IV)-positive), but weakly
      around epithelial whorls/rosettes/nests and mineralized foci. These five chains
      also stained BM and tumor cells of ameloblastic fibroma ( n=3) and ameloblastic
      fibro-odontosarcoma (n=1), but not the inductive hard tissues. Ameloblastic
      carcinoma ( n=2) showed specific alpha1(IV)/alpha2(IV) chain loss, while primary
      intraosseous carcinoma ( n=1) demonstrated a discontinuous alpha1(IV)/alpha2(IV)
      and alpha5(IV)/alpha6(IV) staining pattern. The present results suggest that
      modification and remodeling of BM collagen IValpha chains occur during
      odontogenic neoplasms' progression.

PMID- 12404066
TI  - Angiomyoid proliferative lesion: an unusual stroma-rich variant of Castleman's
      disease of hyaline-vascular type.
AB  - The stroma-rich variant of Castleman's disease of hyaline-vascular type (CDHV) is
      a newly identified entity that shows overgrowth of a variety of stromal cells.
      Six CDHV patients showed proliferation of vasculature and actin-positive myoid
      cells in the expanded interfollicular (IF) area. There were three women and three
      men, and the median age was 29.5 years. Of the six lesions, four were located in
      the retroperitoneum, one in the neck, and one in the mediastinum. All patients
      were asymptomatic. Microscopically, the degree of widening of the IF area varied
      from slight overgrowth of the IF area (approximately 55% of the lymph node area)
      to vague nodularity and finally to the formation of prominent nodules. In the
      nodular lesions, lymph follicles were compressed and attenuated. In the IF area,
      there were numerous vessels and proliferation of spindle cells that possessed
      blunt nuclei. The long, slender, dendritic cytoplasms of the spindle cells were
      stained by alpha smooth muscle actin. The spindle cells were negative for desmin,
      CD34, factor VIII-related antigen, S-100, CD21, and CD68. No patient has had
      recurrence after simple excision. We maintain that these angiomyoid proliferative
      lesions in CDHV are of a hyperplastic nature. This condition encompasses
      proliferation of small vessels and myoid cells. Its characteristics include an
      asymptomatic, solitary nodule that predominantly develops in the retroperitoneum.

PMID- 12404071
TI  - Effects of cannabinoid receptor ligands on psychosis-relevant behavior models in
      the rat.
AB  - RATIONALE: Marijuana is known to have psychotropic effects in humans. In this
      study, we used rat models of sensorimotor gating, hyperactivity and stereotypy to
      explore whether CB(1) receptor stimulation or blockade induces behavioral changes
      consistent with psychotomimetic or antipsychotic agents, respectively.
      OBJECTIVES: We determined whether (a) the cannabinoid agonist CP 55940 decreased
      pre-pulse inhibition (PPI) as might be expected from a psychotomimetic agent, and
      (b) the selective CB(1) receptor antagonist, SR 141716A, had any effect on PPI on
      its own or following disruptions by psychotomimetic agents. In addition, we
      investigated the effects of SR 141716A on elevated levels of hyperactivity and
      stereotypy elicited by d-amphetamine. METHODS: These studies were conducted in
      rats using standard methodologies for determination of PPI following acoustic
      stimuli, and d-amphetamine-induced hyperactivity and stereotypies. RESULTS:
      Decreased startle responses to 120 dB stimuli were observed in rats treated with
      CP 55940 (0.1 mg/kg IP) in the absence and presence of a 73 dB pre-pulse. These
      effects were reversed by SR 141716A (5 and 10 mg/kg, respectively). SR 141716A
      (0.1, 5, 10 mg/kg) had no effect on PPI on its own or following disruptions by
      apomorphine, d-amphetamine or MK-801. Conversely, in separate experiments
      different antipsychotic agents reversed disruptions in PPI induced by d
      amphetamine (haloperidol), apomorphine (haloperidol or clozapine) or MK-801
      (clozapine or olanzapine). In addition, unlike haloperidol, SR 141716A (5 mg/kg)
      did not reverse d-amphetamine-mediated increases in hyperactivity or stereotypy.
      CONCLUSIONS: The CP 55940-mediated decreases in startle amplitude confound
      assessment of the effects of CB(1) receptor activation on PPI. The failure of SR
      141716A to reverse disruptions in PPI, hyperactivity or stereotypy induced by non
      cannabinoid psychotomimetic agents suggests that blockade of the CB(1) receptor
      on its own is not sufficient for antipsychotic therapy.

PMID- 12404072
TI  - Characterizing the subjective, psychomotor, and physiological effects of a
      hydrocodone combination product (Hycodan) in non-drug-abusing volunteers.
AB  - RATIONALE: The subjective, psychomotor, and physiological effects of prescription
      compounds containing the opioid hydrocodone have not been studied in a population
      of non-drug-abusing people who might be prescribed these compounds for cough or
      pain relief. OBJECTIVES: To characterize the effects of a hydrocodone combination
      product, Hycodan, which contains hydrocodone and a peripherally-acting
      anticholinergic, homatropine, in non-drug-abusing volunteers. METHODS: Eighteen
      volunteers participated in a crossover, double-blind study in which they received
      placebo; 5 mg hydrocodone/1.5 mg homatropine, 10 mg hydrocodone/3 mg homatropine,
      20 mg hydrocodone/6 mg homatropine (all PO); 40 mg morphine (PO); and 2 mg
      lorazepam (PO). Measures were assessed before and for 300 min after drug
      administration. End-of-session and 24-h measures were taken to assess residual
      drug effects and overall subjects' assessment of the drug effects. RESULTS.
      Subjective effects of the hydrocodone/homatropine combination were dose-related,
      although the majority of statistically significant effects were limited to the
      highest dose combination tested. A combination of 20 mg hydrocodone/6 mg
      homatropine and morphine had a similar profile of subjective effects, which
      included both pleasant and unpleasant effects. Peak liking ratings were increased
      by 20 mg hydrocodone/6 mg homatropine and morphine, and trough ratings of liking
      (dislike) were lower in the 20 mg hydrocodone/6 mg homatropine condition,
      relative to the placebo condition. Post-session ratings of overall liking were
      not significant, either at the end of the session or 24 h later. Cognitive and
      psychomotor impairment were more marked with lorazepam than with
      hydrocodone/homatropine and morphine. Miosis and exophoria were increased in a
      dose-related manner by hydrocodone/homatropine. CONCLUSIONS: Hycodan at the
      highest dose tested had effects similar to that of a prototypic mu agonist,
      morphine. Both drugs produced pleasant (including drug liking) as well as
      unpleasant subjective effects. Post-session ratings of overall liking and "want
      to take drug again" were not significant.

PMID- 12404073
TI  - Time series modeling of heroin and morphine drug action.
AB  - RATIONALE: Clinical observations and recent findings suggested different
      acceptance of morphine and heroin by intravenous drug users in opiate maintenance
      programs. We postulated that this is caused by differences in the perceived
      effects of these drugs, especially how desired and adverse effects of both drugs
      interacted. OBJECTIVES: We measured the desired and adverse effects of high doses
      of injected morphine and heroin in patients to determine the causal interactions
      between both types of effects and test the hypothesis of a differential mechanism
      of action. METHODS: Thirty-three patients (five females, 28 males; mean duration
      of previous street heroin use 10.7 years, mean age 30.1 years) were randomly
      allocated double-blind to the substance groups. The average daily dose per
      participant in the heroin condition (n=17) was 491 mg, in the morphine condition
      (n=16) 597 mg. The observation period lasted 3 weeks; an average of 70 injections
      was received. After each injection of either substance, various aspects of drug
      effects were recorded systematically. Ratings were summarized into the factors
      "euphoria" and "adverse effects". Time series models were computed for each
      participant on the basis of the factor scores, using vector autoregression (VAR).
      RESULTS: A highly significant difference between the substances was found in the
      interaction between "euphoria" and "adverse effects". Adverse effects of heroin
      preceded higher euphoria, whereas adverse effects of morphine preceded subsequent
      lower euphoria. Additionally, the finding of a higher level of adverse effects in
      morphine was replicated. CONCLUSIONS: Results point to different mechanisms of
      action of the two opioids when the perceived drug effects are evaluated in a
      field setting. This may explain the better acceptance of heroin in opiate
      assisted treatment of intravenous drug patients. The method used can be a
      valuable tool for the comparison of substance groups other than opioids.

PMID- 12404074
TI  - Biological basis of sex differences in drug abuse: preclinical and clinical
      studies.
AB  - The recent focus on drug abuse in women has brought attention to numerous
      differences between women and men. In this review, we discuss both preclinical
      and clinical findings of sex differences in drug abuse as well as mechanisms that
      may underlie these differences. Recent evidence suggests that the progression to
      dependence and abuse may differ between women and men; thus, different prevention
      and treatment strategies may be required. Similar sex differences in drug
      sensitivity and self-administration have been reported in laboratory animal
      studies. Females appear to be more vulnerable than males to the reinforcing
      effects of psychostimulants, opiates, and nicotine during many phases of the
      addiction process (e.g. acquisition, maintenance, dysregulation-escalation,
      relapse). Male and female animals differ in their behavioral, neurological, and
      pharmacological responses to drugs. Although the role of sex in the mechanisms of
      drug action remains unclear, preclinical and clinical studies indicate that
      ovarian hormones, particularly estrogen, play a role in producing sex differences
      in drug abuse. Future research is necessary to provide information on how to
      design more effective drug abuse treatment programs and resources that are sex
      specific.

PMID- 12404075
TI  - Genotype- and experience-dependent susceptibility to depressive-like responses in
      the forced-swimming test.
AB  - RATIONALE: The forced-swimming test (FST) is utilized to reproduce passive coping
      responses to stress that may model a relevant aspect of human depression in
      rodent species. Animals showing high levels of passive responses to the FST are
      assumed to model pathologically depressed individuals. OBJECTIVES: We evaluated
      sensitivity of FST-induced behavioral responses to the interaction between
      genetic and environmental influences. METHODS: Behavioral responses to FST were
      evaluated in naive mice of the C57BL/6 and DBA/2 strains, in mice of both strains
      pre-exposed to FST 14 days before test, and in FST-experienced animals
      subsequently exposed to 12 days of stress experience (food restriction). RESULTS:
      C57BL/6 mice are characterized by high propensity to adopt passive coping
      responses in the FST. Moreover, stress enhances FST-induced immobility in mice of
      the C57BL/6 strain but reduces this response in DBA/2 mice. Finally, FST-induced
      immobility in C57BL/6 mice is reduced by chronic treatment with clinically
      effective antidepressants. CONCLUSIONS: These results support the view that
      behavioral and neural responses to FST exhibited by C57BL/6 mice can be usefully
      exploited by pre-clinical research on depression.

PMID- 12404076
TI  - Blockade of ionotropic glutamatergic transmission in the ventral tegmental area
      reduces heroin reinforcement in rat.
AB  - RATIONALE: While the role of the mesocorticolimbic (MCL) dopamine (DA) system in
      mediating the reinforcing properties of drugs of abuse has been well established,
      how and where other neurotransmitter systems interact to modify this system is
      less well understood. OBJECTIVES: The present study sought to assess whether
      blockade of ionotropic glutamate receptors in the ventral tegmental area (VTA)
      would modulate heroin self-administration (SA) behavior in rats. METHODS: The
      effects of systemic or regional administration of ionotropic glutamate receptor
      antagonists into the VTA on the maintenance of heroin SA were assessed. Rats were
      reinforced each time they responded on a lever with a single injection of
      intravenous heroin. To determine the specificity of their effects on heroin SA,
      the ability of these antagonists to modify locomotion and food-reinforced
      behavior was also examined. RESULTS: Systemic or regional administration of the
      non-competitive NMDA antagonist dizocilpine into the VTA significantly increased
      the rate of heroin SA and shifted the heroin dose-response curve to the right.
      Similarly, when systemically administered, ketamine, another non-competitive NMDA
      antagonist, also increased the rate of heroin SA. However, when administered
      directly into the VTA, ketamine or AP5 [ D-(-)-2-amino-5-phosphonopentanoic acid,
      a competitive NMDA antagonist], dose-dependently blocked heroin SA. In contrast,
      6,7-dinitroquinoxaline-2,3-dione (DNQX), an AMPA/kainate receptor antagonist,
      significantly increased heroin SA. CONCLUSION: These data suggest that ionotropic
      glutamate receptors in the VTA, presumably by modulating MCL DA efferents and/or
      tegmental interneurons, modulate opiate reinforcement.

PMID- 12404077
TI  - Selective antagonism of the ataxic effects of zolpidem and triazolam by the
      GABAA/alpha1-preferring antagonist beta-CCt in squirrel monkeys.
AB  - RATIONALE: Delineation of the receptor mechanisms underlying the behavioral
      effects of benzodiazepines should allow for the development of drugs with
      improved clinical utility and reduced side effects. OBJECTIVES. The purpose of
      the present study was to investigate the role of GABAA/alpha1 receptors in the
      sedative and motor-impairing effects of benzodiazepines. METHODS: Squirrel
      monkeys were tested with the GABAA/alpha1-preferring agonist zolpidem and the
      nonselective benzodiazepine agonist triazolam alone and in combination with the
      GABAA/alpha1-preferring antagonist beta-CCt and the nonselective benzodiazepine
      antagonist flumazenil. During 30-min experimental sessions, all occurrences of
      normal behaviors like locomotion, environment- and self-directed behaviors, as
      well as side effects such as ataxia, rest and procumbent postures were scored.
      RESULTS: Zolpidem and triazolam produced dose-dependent reductions in locomotion
      and environment-directed behavior and increased ataxia and procumbent posture.
      Triazolam, but not zolpidem, also engendered species-typical rest posture at some
      doses. Flumazenil antagonized all of the behavioral effects of zolpidem and
      triazolam, whereas beta-CCt antagonized only zolpidem- and triazolam-induced
      ataxia. CONCLUSIONS: GABAA/alpha1 receptor mechanisms appear to play a key role
      in the ataxic effects of benzodiazepine agonists in squirrel monkeys, similar to
      recent results with transgenic mice. In contrast to the findings of these recent
      studies, GABAA mechanisms other than or in addition to those mediated at the
      alpha1 subunit may play a more important role in the sedative/hypnotic effects of
      benzodiazepines in squirrel monkeys.

PMID- 12404078
TI  - Acute effects of baclofen, a gamma-aminobutyric acid-B agonist, on laboratory
      measures of aggressive and escape responses of adult male parolees with and
      without a history of conduct disorder.
AB  - RATIONALE: The possible role of gamma-aminobutyric acid (GABA) in human
      aggression was evaluated by administering baclofen, a GABA-B agonist and
      comparing the effects on laboratory measures of aggression and escape among
      subjects with and without a history of conduct disorder. METHODS: Twenty male
      subjects with a history of criminal behavior participated in experimental
      sessions, which measured aggressive and escape responses. Ten subjects had a
      history of childhood conduct disorder (CD+) and ten control subjects had no
      history of CD. Aggression was measured using the point subtraction aggression
      paradigm (PSAP), which provides subjects with aggressive, escape, and monetary
      reinforced response options. RESULTS: Acute doses (0.07, 0.14 and 0.28 mg/kg) of
      baclofen had remarkably different effects on aggressive responses among CD+
      subjects relative to control subjects. Aggressive responses of CD+ subjects
      decreased, while aggressive responses of control subjects increased following
      baclofen administration. Baclofen decreased escape responses for both CD+ and
      control subjects. No changes in monetary-reinforced responses were observed,
      indicative of no central nervous system stimulation or sedation. CONCLUSIONS: The
      GABA-B agonist baclofen suppressed aggressive responses in subjects with a
      history of childhood CD, while producing the opposite effect in control subjects.
      These suggest a possible unique role for GABA in the regulation of aggression in
      CD+ population.

PMID- 12404079
TI  - Orphanin FQ/nociceptin blocks cocaine-induced behavioral sensitization in rats.
AB  - RATIONALE: Orphanin FQ/nociceptin (OFQ/N), the endogenous ligand of the opioid
      receptor-like (ORL-1) receptor, shows similarities to dynorphin A (1-17) in
      structure and functions. Dynorphin and other kappa opioid receptor agonists have
      been shown to block cocaine sensitization. OBJECTIVE: The present study was
      designed to examine the ability of OFQ/N to block cocaine-induced behavioral
      sensitization. METHODS: Rats were habituated to testing chambers for 1 h,
      injected with artificial cerebrospinal fluid (aCSF) or OFQ/N (15 nmol) followed
      by saline or cocaine (20 mg/kg) and locomotor activity was measured for a further
      1 h. Rats were treated similarly for the next 2 days except the dose of OFQ/N was
      doubled on each subsequent day. Rats were then challenged with cocaine (7.5
      mg/kg) in the absence of OFQ/N on day 8. The specificity of OFQ/N's action was
      examined in the presence of J-113397 (30 nmol), an ORL-1 receptor antagonist. The
      ability of OFQ/N to block the context-independent component of cocaine
      sensitization was also tested wherein rats were treated in their home cages on
      days 1-3. Finally, the effect of intra-VTA OFQ/N administration on cocaine
      sensitization was examined. RESULTS: Sensitization did not develop in rats
      repeatedly treated with OFQ/N, via either route of administration, prior to
      cocaine administration on days 1-3. The inhibitory effect of OFQ/N was not
      dependent on context and was blocked by pretreatment with J-113397. CONCLUSION:
      Our results indicate that OFQ/N blocks cocaine-induced behavioral sensitization
      through activation of the ORL-1 receptor and that the VTA may be one of the
      substrates for this action of OFQ/N.

PMID- 12404080
TI  - Smokers deprived of cigarettes for 72 h: effect of nicotine patches on craving
      and withdrawal.
AB  - RATIONALE: Research on the effects of nicotine abstinence and nicotine
      replacement has not provided consistent information about the impact of
      replacement therapies on tobacco withdrawal and craving. OBJECTIVE: . This study
      investigated craving and withdrawal symptoms over a 72-h period of abstinence
      from cigarettes. METHODS: . Twenty-four healthy volunteers, not intending to quit
      smoking, were housed in an experimental unit during three 72-h conditions,
      consisting of either free smoking, enforced smoking cessation with nicotine
      replacement therapy (NRT) patches, or enforced smoking cessation with placebo
      patches. The conditions were adhered to using a randomized crossover design, each
      separated by at least 10 days of washout. Patches, administered in a double-blind
      fashion, were given as nicotine (21 mg/24 h) and placebo every 24 h. Self
      reported cigarette craving and withdrawal were assessed using multi-item scales
      at fixed intervals over each condition period. Urinary and plasma cortisol levels
      were also assayed at fixed intervals over each period. RESULTS: Craving intensity
      was significantly lower with free smoke than with placebo and with NRT patches
      than with placebo. No difference in craving levels was found between those who
      smoked or those who had NRT patches. Withdrawal symptoms were significantly lower
      with free smoke than with either placebo or NRT patches, but there was no
      difference in levels of withdrawal between those on NRT patches and those on
      placebo. During the placebo and NRT patch periods, craving intensity displayed a
      circadian rhythm, with craving levels lowest in the morning and peaking in the
      evening. Nicotine delivered via the patch had no impact on these circadian
      variations in craving. There was no evidence of systematic temporal variations in
      craving levels during the free smoking period. CONCLUSIONS: The data suggested
      that craving and withdrawal symptoms may be sustained by different physiological
      pathways, and that only selected components of cigarette craving are influenced
      by NRT.

PMID- 12404081
TI  - Effects of caffeine on mood and performance: a study of realistic consumption.
AB  - RATIONALE: There is a vast literature on the behavioural effects of caffeine.
      Many of the studies have involved single administration of a large dose of
      caffeine that is not representative of the way in which caffeine is usually
      ingested. Further information is required, therefore, on the behavioural effects
      of realistic patterns of consumption. OBJECTIVES: The present study aimed to
      determine whether a realistic drinking regime (multiple small doses - 4 x 65 mg
      over a 5-h period) produced the same effects as a single large dose (200 mg). The
      smaller doses were selected so that the amount of caffeine present in the body
      after 5 h would be equivalent to that found with the single dose. METHODS: A
      double-blind, placebo-controlled, within-subjects experiment was, therefore,
      carried out. The participants ( n=24) attended for four sessions. Each session
      started with a baseline measurement of mood and performance at 0930 hours. On two
      of the sessions, coffee was then consumed at 1000, 1100, 1200 and 1300 hours. In
      one of these sessions 65 mg caffeine was added to the de-caffeinated coffee. In
      the other two sessions, the participants consumed coffee at 1300 hours and 200 mg
      caffeine was added in one of the sessions. The volunteers completed the battery
      of tests again at 1500 hours. RESULTS: The results showed that in both
      consumption regimes caffeine led to increased alertness and anxiety and improved
      performance on simple and choice reactive tasks, a cognitive vigilance task, a
      task requiring sustained response and a dual task involving tracking and target
      detection. CONCLUSIONS: These results suggest that previous findings from studies
      using a large single dose may be applicable to normal patterns of caffeine
      consumption.

PMID- 12404082
TI  - Decreased CCK(B) receptor binding in rat amygdala in animals demonstrating
      greater anxiety-like behavior.
AB  - RATIONALE: The potentiation of the acoustic startle response (ASR) by stimuli
      associated with aversive events is mediated via the amygdala and is used as an
      index of "anxiety" and "fear". In laboratory animals, cholecystokinin(B) (CCK(B))
      agonists increase anxiety and fear and activation of amygdala CCK(B) receptors
      potentiates ASR. Additionally, antagonism of CCK(B) receptors attenuates fear
      potentiated ASR. OBJECTIVES: To investigate the putative role of CCK(B) receptors
      in individual differences in fear and anxiety, we examined individual differences
      in amygdala CCK(B) receptor binding for animals demonstrating low versus high
      baseline and fear-potentiated ASR. Additionally, we examined individual
      differences in CCK(B) binding for animals demonstrating low versus high anxiety
      like behavior on the elevated plus-maze (EPM). METHODS: Male Wistar rats were
      tested in the ASR, fear-potentiated ASR, and EPM paradigms. Following testing,
      brain slices were mounted and incubated with 50 pM (125)I-CCK8 (non-sulfated), a
      selective CCK(B) receptor ligand, in the presence or absence of 1 micro M non
      radioactively labeled CCK and then exposed on tritium-sensitive film for 2-3
      days. RESULTS: Animals with high fear-potentiated ASR showed decreased CCK(B)
      receptor binding in both the basolateral and central amygdaloid nuclei. Animals
      with high anxiety-like responses on the EPM showed decreased CCK(B) binding in
      the basolateral, but not central, amygdala. There were no differences in amygdala
      CCK(B) binding in animals demonstrating low versus high baseline ASR. None of the
      groups showed differences in CCK(B) receptor binding in the nucleus accumbens.
      CONCLUSIONS: These results show that there is a down-regulation of amygdala
      CCK(B) receptor binding in animals demonstrating greater anxiety-like responding
      in the fear-potentiated ASR and EPM models of anxiety, possibly as a compensation
      for increased CCK activity.

PMID- 12404083
TI  - Effects of buprenorphine on candy and sweetened fluid self-administration by
      rhesus monkeys.
AB  - RATIONALE: . Previous studies have shown that buprenorphine differentially
      suppresses the reinforcing effects of different drugs (cocaine, alfentanil), drug
      versus nondrug reinforcers (food, drug), and the same reinforcer (food)
      maintained under different schedules of reinforcement. OBJECTIVES: The purpose of
      the present study was to determine whether buprenorphine (0.03, 0.1, 0.3 mg/kg)
      differentially affects candy versus sweetened fluid self-administration. The
      hypotheses were that (1) candy would maintain higher rates of responding and
      would be chosen on more occasions than sweetened fluid, and (2) buprenorphine
      would produce smaller disruptions in responding for the more-preferred
      reinforcer. METHODS: During separate sessions, rhesus monkeys self-administered
      candy alone, sweetened fluid alone, or had the opportunity to choose between
      candy and sweetened fluid. Monkeys responded under a second order, two-chain
      schedule of reinforcement. RESULTS: Candy was a more-preferred reinforcer than
      sweetened fluid. Buprenorphine significantly decreased rates of responding for
      fluid, but increased rates of responding for candy. Although buprenorphine
      significantly decreased both candy and fluid intake, it produced a more robust,
      and longer-lasting suppression of sweetened-fluid intake than candy. Choice to
      self-administer candy or fluid was not affected by buprenorphine. CONCLUSIONS:
      These results demonstrate that behavior maintained by a less-preferred reinforcer
      is more easily disrupted by buprenorphine than is behavior maintained by a more
      preferred reinforcer.

PMID- 12404084
TI  - The discrimination of drug mixtures using a four-choice procedure in pigeons.
AB  - RATIONALE: The purpose of these experiments was to study drug combinations as
      discriminative stimuli using a new four-choice procedure. OBJECTIVES: To
      determine whether pigeons could discriminate among a mixture of two drugs, each
      of the component drugs and saline, and to study other drug combinations in these
      birds. METHODS: Pigeons were trained to discriminate among saline, 5 mg/kg
      morphine, 5 mg/kg pentobarbital, and a mixture of these two doses using a four
      choice procedure. RESULTS: When responding stabilized, the birds responded on the
      correct key more than 90% of the time. Low doses of all drugs given alone
      produced responding on the saline key. Higher doses of pentobarbital and
      chlordiazepoxide produced responding on the pentobarbital key, and higher doses
      of morphine produced responses on the morphine key. Methamphetamine produced
      responding on the saline key. None of the drugs given alone produced responding
      on the mixture key. When pentobarbital was combined with morphine, doses both
      below and above the combined training doses of these drugs usually produced
      responding on the mixture key. The combination of chlordiazepoxide with morphine
      produced similar results. Combinations of methamphetamine with pentobarbital or
      with morphine produced effects similar to those of pentobarbital or morphine
      given alone. CONCLUSIONS: A wide range of combinations of pentobarbital and
      morphine, or chlordiazepoxide and morphine produce responding on the mixture key,
      even though the pigeons were not exposed to these dose combinations during
      training. The four-choice procedure provides the opportunity to study drug
      mixtures in a detail not possible with more limited response choices.

PMID- 12404085
TI  - 5-HT2C receptor mediation of unconditioned escape behaviour in the unstable
      elevated exposed plus maze.
AB  - RATIONALE AND OBJECTIVES: m-Chlorophenylpiperazine (mCPP) induces panic in humans
      and dose dependently increases unconditioned escape behaviour in a novel pre
      clinical model of extreme anxiety in rats, the unstable elevated exposed plus
      maze (UEEPM). Numerous studies indicate that the anxiogenic effects of mCPP may
      be mediated by its action at the 5-HT2C receptor. This study aimed to examine the
      involvement of the 5-HT2C receptor in the unconditioned fear responses observed
      in the UEEPM (after an acute dose of mCPP) by pre-treatment with the selective 5
      HT2C receptor antagonist SB-242084. METHODS: Male Hooded Lister rats received a
      single dose of SB-242084 (0.1-1.0 mg/kg IP) or vehicle 40 min pre-test followed
      by a single dose of mCPP (1.0 mg/kg IP) or saline 30 min before being exposed to
      the UEEPM for a period of 5 min. Subjects' behaviour was analysed to determine
      the effects of SB-242084 on mCPP-induced increases in escape behaviour. RESULTS:
      mCPP alone increased animals' propensity to escape from the UEEPM despite
      producing marked decreases in locomotor/exploratory behaviour. SB-242084 dose
      dependently inhibited the increases in escape and hypolocomotor effects induced
      by mCPP. CONCLUSIONS: These results suggest that the escape-related behaviours
      exhibited by animals in the UEEPM are mediated, at least in part, by activation
      of the 5-HT2C receptor subtype.

PMID- 12404086
TI  - Acute tryptophan depletion decreases intensity dependence of auditory evoked
      magnetic N1/P2 dipole source activity.
AB  - RATIONALE: Intensity dependence of the N1/P2 components may be regulated by
      serotonergic neurons in the primary auditory cortex, where low activity leads to
      a high intensity dependence and vice versa. Depletion of tryptophan (TRP), a
      precursor for serotonin has been described to reduce serotonin content in brain
      of animals and humans. OBJECTIVE: We investigated the intensity dependence of
      magnetic and electric N1/P2 components in ten subjects in a double-blind,
      controlled, cross-over design study after oral mixture of amino-acids leading to
      acute tryptophan depletion (ATD) and control. METHODS: Auditory evoked magnetic
      fields (AEF) and potentials (AEP) were recorded with 122-channel
      magnetoencephalography simultaneously with 64-channel EEG 5 h after ingestion of
      mixtures. The AEF sources and strength were estimated by a least-squares fit of a
      single equivalent current dipole. The amplitudes and latencies of N1 and P2
      recorded with EEG were analyzed at frontal electrode site. RESULTS: TRP depletion
      decreased the total and free TRP levels by 76 and 45% and control mixture
      increased it by 48 and 28%. ANOVA showed that ATD had a significant main effect
      on the N1m/P2m dipole moments at the contralateral ( P=0.02), but failed
      significantly to influence the ipsilateral responses. A significant mixture
      ingestion-by-stimulus intensity interaction was observed on the N1m/P2m dipole
      moments at the contralateral hemisphere ( P=0.01). The N1/P2 slope for intensity
      dependence function was decreased following ATD compared with the control
      experiment ( P=0.01) at the contralateral hemisphere. For EEG, a significant
      mixture ingestion-by-stimulus intensity interaction on the N1 latencies at the Fz
      electrode position was observed ( P=0.01). CONCLUSION: ATD decreased the
      intensity dependence of N1m/P2m source dipole moments in the primary auditory
      cortex at the hemisphere contralateral to the ear stimulated. These results
      suggest that serotonin participates in the regulation of intensity of auditory
      stimulation.

PMID- 12404087
TI  - Intracortical excitability is modulated by a norepinephrine-reuptake inhibitor as
      measured with paired-pulse transcranial magnetic stimulation.
AB  - OBJECTIVE: Paired-pulse transcranial magnetic stimulation (ppTMS) of the motor
      cortex can be used to measure intracortical inhibition and facilitation of evoked
      motor potentials dependent on different interstimulus intervals (ISI). The
      reuptake-inhibition of norepinephrine, known as an excitatory neuromodulator and
      neurotransmitter, was postulated to enhance cortical excitability through
      increased facilitation and reduced inhibition as measured with ppTMS. METHODS:
      Eight healthy subjects were examined with ppTMS at ISIs of 2, 3, 4, 5, 6, 7, 8,
      10, 15 and 20 ms before and approximately 1.5 h after ingestion of 8 mg
      reboxetine. The group effects at the different ISIs pre/post reboxetine intake
      were analysed. RESULTS: Post-reboxetine ppTMS showed an enhanced intracortical
      facilitation effect at ISIs of 8, 10, 15 and 20 ms. A decreased inhibition was
      found at an ISI of 3 ms. CONCLUSIONS: Reboxetine-induced higher postsynaptic
      norepinephrine level enhances intracortical excitability as measured with ppTMS.
      This finding provides new perspectives for evaluating neurophysiological
      properties of antidepressive medication and for investigating the pathophysiology
      of depression.

PMID- 12404088
TI  - Rosmarinic acid and caffeic acid reduce the defensive freezing behavior of mice
      exposed to conditioned fear stress.
AB  - RATIONALE: We previously showed that rosmarinic acid from the leaves of Perilla
      frutescens Britton var. acuta Kudo (Perillae Herba) and its major metabolite
      caffeic acid have antidepressive-like activity in the forced swimming test.
      OBJECTIVE: The present study was designed to examine whether rosmarinic acid and
      caffeic acid might also be effective in other types of stress model. METHODS: The
      conditioned fear stress paradigm was used as a stress model for assessing the
      effects of rosmarinic acid and caffeic acid. RESULTS: Rosmarinic acid (0.25-4
      mg/kg, IP) induced a dose-dependent, U-shaped reduction in the duration of the
      defensive freezing behavior of mice exposed to conditioned fear stress. Caffeic
      acid (1-8 mg/kg, IP) also dose-dependently reduced this freezing behavior.
      However, neither substance, at doses that produced a significant reduction in the
      freezing behavior, affected spontaneous motor activity. CONCLUSIONS: These
      results confirm that rosmarinic acid and caffeic acid may inhibit the emotional
      abnormality produced by stress.

PMID- 12404090
TI  - NovoSeven: mode of action and use in acquired haemophilia.
AB  - Recombinant activated factor VII (rFVIIa, 'NovoSeven') is indicated for the
      treatment of spontaneous and surgical bleeding in patients with haemophilia A or
      B with antibodies to factors VIII or IX (FVIII or FIX) worldwide, and in patients
      with acquired haemophilia in Europe. In vitro cell models have demonstrated that
      rFVIIa can bind to activated platelets and generate small amounts of Fxa,
      independent of the presence of tissue factor. The amount of platelet-surface Fxa
      formed increases with rising concentrations of FVIIa and, at levels of rFVII a
      that are effective in patients, sufficient platelet surface Fxa is generated
      partially to restore platelet surface thrombin generation. Acquired haemophilia
      is a rare but potentially life-threatening condition, caused by the autoimmune
      reduction of clotting factor levels as a result of the spontaneous development of
      auto-antibodies directed against the deficient factor. Bleeding into the skin or
      muscles is common in acquired haemophilia and the associated mortality rate is
      approximately 20%. rFVIIa has reported efficacy in the treatment of major
      bleeding episodes in patients with acquired haemophilia, which may be explained
      by its distinct mechanism of action that induces haemostasis at the site of
      injury, independent of the presence of FVIII or FIX. Also, the localisation of
      the action of rFVIIa at the site of injury may explain why it is well tolerated
      in these patients.

PMID- 12404089
TI  - Alcohol self-administration, craving and HPA-axis activity: an intriguing
      relationship.

PMID- 12404091
TI  - Haemorrhagic complications of thrombocytopenia and oral anticoagulation: is there
      a role for recombinant activated factor VII?
AB  - Recombinant activated factor VII (rFVIIa, 'NovoSeven') is indicated for the
      treatment of bleeding in patients with haemophilia and inhibitors to factors VIII
      or IX. However, by virtue of its ability to promote thrombin generation on the
      platelet surface rFVIIa may also be effective in non-haemophilic bleeding, for
      example, in patients with thrombocytopenic or oral anticoagulant-induced
      haemorrhage. Studies in thrombocytopenia indicate that rFVIIa increases the
      generation of thrombin at the site of injury, leading to the control of bleeding
      episodes in these conditions. Additionally, preclinical and early clinical
      evidence has demonstrated the ability of rFVIIa to normalise prothrombin times
      and international normalised ratios in situations of over-anticoagulation.
      Although initial observations indicate that rFVIIa may be fast, efficacious, and
      safe in reversing oral anticoagulant-induced bleeds and those associated with
      thrombocytopenia, randomised, double-blind, placebo-controlled trials must be
      conducted to confirm its utility in these and other investigational uses.

PMID- 12404092
TI  - Intracerebral hemorrhage: natural history and rationale of ultra-early hemostatic
      therapy.
AB  - Stroke is a major health problem worldwide, causing high morbidity and mortality.
      Intracerebral hemorrhage (ICH) accounts for 15% of stroke cases in the US and
      Europe and up to 30% in Asian populations. It is less treatable than other forms
      of stroke and causes higher morbidity and disability. Data suggest that early
      hematomy growth is the principal cause of early neurological deterioration after
      ICH. Prospective and retrospective studies indicate that early hematoma growth
      occurs in 18-38% of patients scanned within 3 h of ICH onset, and that hematoma
      volume is an important predictor of 30-day mortality. As hematoma growth in acute
      ICH is a dynamic process, intervention with ultra-early hemostatic therapy could
      lead to minimization and even prevention of early hematomy growth. Recombinant
      activated factor VII (rFVIIa, 'NovoSeven'), a powerful initiator of hemostasis,
      is approved for the treatment of bleeding in patients with hemophilia and
      inhibitors and may also promote hemostasis in patients with normal coagulation.
      rFVa acts locally at the bleeding site without activating systemic coagulation
      and may be a valuable therapy during the hyperacute stage of ICH. A randomized,
      double-blind, placebo-controlled, dose-ranging trial is currently in progress to
      investigate the potential of rFVIIa as an ultra-early hemostatic therapy to
      prevent or minimize hematoma growth in ICH patients without coagulopathy.

PMID- 12404093
TI  - Updates in the management of severe coagulopathy in trauma patients.
AB  - Coagulopathy is the major cause of bleeding-related mortality in patients who
      survive the operating room. Its association with hypothermia and metabolic
      acidosis is common and constitutes a vicious cycle. Usually, post-traumatic
      coagulopathy is an early event and may be present during surgery. The
      pathogenesis of severe post-traumatic coagulopathy is complex and multifactorial.
      Virtually every aspect of the normal coagulation cascade is affected in the cold,
      acidotic, exsanguinating trauma patient. In the last decade many surgeons have
      emphasized the role of prevention or early treatment of this vicious cycle.
      Damage control surgery with planned re-operations has demonstrated superiority
      over the traditional approach in cases where the patients' condition is
      deteriorating. Early control of surgical bleeding and significant contamination,
      together with vigorous correction of hypothermia and continuous resuscitation,
      has improved the survival of these patients. Recently, a new adjunct to the
      treatment of coagulopathy in trauma patients has been reported and is undergoing
      controlled animal trials. Recombinant activated factor VII (rFVIIa) was
      originally developed as a pro-hemostatic agent for the treatment of bleeding
      episodes in hemophilia patients. rFVIIa has been successfully used in moribund
      trauma patients in whom standard procedures had failed to correct bleeding.
      Preliminary preclinical and clinical studies are under way.

PMID- 12404094
TI  - Ongoing NovoSeven trials.
AB  - Recombinant activated factor VII (rFVIIa, 'NovoSeven' was initially developed for
      the treatment of bleeding in patients with haemophilia and inhibitors, and is
      currently licensed in most countries worldwide. The mechanism of action suggests
      that its enhancing effects in haemostasis are limited to the site of injury and
      that systemic activation of the coagulation cascade does not occur. These
      properties, together with anecdotal reports of its beneficial effects in
      different patient populations with severe bleeds, suggest that rFVIIa may be
      valuable as a general haemostatic agent. In case reports, rFVIIa has been
      reported to reduce bleeding in patients with liver disease, thrombocytopenia or
      thrombocytopathia, trauma those undergoing radical prostatectomy or receiving
      oral anticoagulant therapy. A number of clinical trials have recently been
      initiated to collect data on the safety and efficacy of rFVIIa in these patient
      groups. The beneficial effects of rFVIIa occurring in these studies will support
      the potential use of rFVIIa as a universal haemostatic agent.

PMID- 12404095
TI  - Time to take epigenetic inheritance seriously.

PMID- 12404096
TI  - Diagnosis of Hb-pathies.

PMID- 12404097
TI  - Marfan syndrome in the third Millennium.
AB  - The Marfan syndrome (MFS) is a prominent member of heritable disorders of
      connective tissue with manifestations involving primarily the skeletal, ocular
      and cardiovascular systems but also and less systematically investigated the
      lung, skin and integument, and dura. Over the last two decades, a considerable
      amount of clinical, molecular and protein data had accumulated. In combination
      with the study of natural and transgenic animal models, this new information
      provides greater insight into the pathogenic mechanisms underlying not only the
      pleiotropic manifestations of MFS but also the important degree of clinical
      variability (age of onset and severity) observed between patients. The following
      aspects will be described in this review: the structure and function of fibrillin
      1; the fibrillin proteins; mutations in the FBN1 gene and pathogenic mechanisms;
      animal models. Finally, the currently available laboratory diagnostic tests and
      their limits will be discussed.

PMID- 12404098
TI  - Cardiovascular and diabetes mortality determined by nutrition during parents' and
      grandparents' slow growth period.
AB  - Overfeeding and overeating in families are traditions that are often transferred
      from generation to generation. Irrespective of these family traditions, food
      availability might lead to overfeeding, in its turn leading to metabolic
      adaptations. Apart from selection, could these adaptations to the social
      environment have transgenerational effects? This study will attempt to answer the
      following question: Can overeating during a child's slow growth period (SGP),
      before their prepubertal peak in growth velocity influence descendants' risk of
      death from cardiovascular disease and diabetes? Data were collected by following
      three cohorts born in 1890, 1905 and 1920 in Overkalix parish in northern Sweden
      up until death or 1995. The parents' or grandparents' access to food during their
      SGP was determined by referring to historical data on harvests and food prices,
      records of local community meetings and general historical facts. If food was not
      readily available during the father's slow growth period, then cardiovascular
      disease mortality of the proband was low. Diabetes mortality increased if the
      paternal grandfather was exposed to a surfeit of food during his slow growth
      period. (Odds Ratio 4.1, 95% confidence interval 1.33-12.93, P=0.01). Selection
      bias seemed to be unlikely. A nutrition-linked mechanism through the male line
      seems to have influenced the risk for cardiovascular and diabetes mellitus
      mortality.

PMID- 12404099
TI  - Prenatal testing for Huntington's disease: a European collaborative study.
AB  - This European study involving seven genetic centres from six countries -
      Aberdeen, Cardiff (UK), Leiden (Netherlands), Leuven (Belgium), Paris (France),
      Rome (Italy), Athens (Greece) has gathered information on prenatal testing by
      direct mutation analysis and exclusion testing for Huntington's disease (HD) from
      the six European countries during the period 1993-1998. Data describing the
      parent belonging to the HD family was collected; this included their sex and age
      as well as their risk of developing HD. Information about previous pregnancies,
      the rank of the pregnancy being tested and its outcome was also gathered. In
      addition the number of previous prenatal tests for HD was recorded. Three hundred
      and five results were recorded by the participating countries between 1993 and
      1998. The largest groups came from the UK (157) and the Netherlands (90). The
      mean age for the parent from the HD family was 30.8 years. In half of the tests
      the prospective parent was an asymptomatic gene carrier, 42% remained at risk,
      and 6% of the prospective parents were already showing clinical features of HD.
      65% of tests performed used mutation analysis.

PMID- 12404100
TI  - Maternal uniparental isodisomy 20 in a foetus with trisomy 20 mosaicism:
      clinical, cytogenetic and molecular analysis.
AB  - The clinical significance of trisomy 20 mosaicism detected prenatally remains
      uncertain due to the rarity of liveborn cases with inconsistent clinical
      findings, and lack of long-term follow-up and outcome. We describe a case of true
      trisomy 20 mosaicism in a liveborn girl with maternal uniparental isodisomy of
      chromosome 20 in the diploid blood cells. Trisomy 20 mosaicism was originally
      detected in amniotic fluid (98%) and was confirmed in the term placenta (100%),
      as well as in the blood (10%) and urine sediment (100%) of the neonate. There was
      intrauterine and postnatal growth retardation, but otherwise the newborn
      manifested no gross abnormalities. At 9 months of age moderate psychomotor
      retardation, central hypotonia with peripheral hypertonia, numerous minor
      morphogenetic variants, marked kyphosis, and extensive Mongolian spot were
      observed. To our knowledge this represents the first case of trisomy 20 mosaicism
      detected prenatally and confirmed in different tissues of the newborn, where
      uniparental disomy was demonstrated in the diploid cell line. The clinical and
      laboratory findings in our patient are compared with those of five previously
      reported cases of UPD20, suggesting that maternal UPD20 might be associated with
      a characteristic phenotype.

PMID- 12404101
TI  - Overgrowth and trisomy 15q26.1-qter including the IGF1 receptor gene: report of
      two families and review of the literature.
AB  - Overgrowth is rarely associated with chromosomal imbalances. Here we report on
      four children from two unrelated families presenting with overgrowth and a
      terminal duplication of the long arm of chromosome 15 diagnosed using cytogenetic
      and FISH studies. In both cases, chromosome analysis of the parents showed a
      balanced translocation involving 15q26.1-qter. Molecular and cytogenetic studies
      showed three copies of the insulin-like growth factor 1 receptor (IGF1R) gene.
      This finding suggests that overgrowth observed in our patients might be causally
      related to a dosage effect of the IGF1R gene, in contrast to severe growth
      retardation observed in patients with terminal deletion of 15q. The present
      observation emphasises the importance of chromosome analysis in patients with
      overgrowth and mental retardation. Moreover, it further delineates a specific
      phenotype related to trisomy 15q26.1-qter with macrosomia at birth, overgrowth,
      macrocephaly and mild developmental delay being the major clinical features.

PMID- 12404102
TI  - An 11p;17p telomeric translocation in two families associated with recurrent
      miscarriages and Miller-Dieker syndrome.
AB  - Translocations occur in a proportion of couples affected by recurrent
      miscarriages. We describe two such families in which the underlying cause was a
      cryptic subtelomeric 11p;17p translocation detected only after the birth of an
      affected child carrying an unbalanced form of the rearrangement. Unbalanced
      subtelomeric rearrangements are now recognised as a significant cause of mental
      impairment and we believe that these rearrangements may also be an important
      cause of recurrent miscarriages. In these two families the translocation is most
      likely to have arisen from a single ancestral event because all translocation
      carriers shared almost identical haplotypes around the breakpoints on both
      chromosomes.

PMID- 12404103
TI  - Detection of putative functional angiotensinogen (AGT) gene variants controlling
      plasma AGT levels by combined segregation-linkage analysis.
AB  - Previous studies have suggested that angiotensinogen (AGT) gene variants are
      associated with increased plasma AGT levels, and may also contribute towards the
      inherited component of predisposition to essential hypertension in humans. To
      explore the potential functionality of several AGT polymorphisms and estimate
      their effects, together with other sources of familial correlations, on plasma
      AGT, we undertook a large study involving 545 healthy French volunteers in 130
      nuclear families that include 285 offspring. Plasma AGT levels were measured in
      all participants, and bi-allelic AGT variants were analysed as candidate
      functional variants at three sites in the 5'-flanking region (C-532T, A-20C, G
      6A), two sites in exon 2 (M235T, T174M) and two newly identified variant sites in
      the untranslated sequence of exon 5 and the 3'-flanking region (C+2054A, C+2127T)
      of the gene. Analysis with the class D regressive model showed significant
      effects influencing plasma AGT levels of all AGT polymorphisms tested, with the
      exception of T174M. The most significant result was found at C-532T (P=0.000001),
      which accounts for 4.3% of total plasma AGT variability in parents and 5.5% in
      offspring, with substantial residual familial correlations. Maximum likelihood
      estimates of haplotype frequencies and tests of linkage disequilibrium between
      each AGT polymorphism and a putative QTL are in agreement with a complete
      confounding of C-532T with the QTL, when taking into account sex and generation
      specific effects of the QTL. However, further combined segregation-linkage
      analyses showed significant evidence for additional effects of G-6A, M235T and
      C+2054A polymorphisms after accounting for C-532T, which supports a complex model
      with at least two functional variants within the AGT gene controlling AGT levels.

PMID- 12404104
TI  - Androgen receptor CAG repeat length in Jewish Israeli women who are BRCA1/2
      mutation carriers: association with breast/ovarian cancer phenotype.
AB  - BRCA1/2 mutation carriers are at an increased risk for developing breast and/or
      ovarian cancer. Yet, the genetic and environmental factors that govern the
      phenotypic expression of mutant BRCA1/2 alleles remain elusive. The CAG repeat
      within exon 1 of the androgen receptor (AR) gene is reportedly associated with
      breast cancer phenotype in BRCA1 mutation carriers. Two hundred and twenty seven
      BRCA1/2 mutation carriers were genotyped for the polymorphic AR CAG repeat, and
      allele size was correlated with breast/ovarian cancer morbidity parameters. Of
      227 BRCA1/2 carriers, 169 were BRCA1 mutation carriers and 58 carried a BRCA2
      mutation, 149 had breast and/or ovarian cancer and 78 were asymptomatic mutation
      carriers. The mean age at diagnosis in women with either or both neoplasms was
      46.7+/-11.2 years, and that of the asymptomatic group - 45.8+/-9.4 years, a
      statistically insignificant difference. The AR CAG repeat ranged from eight to 28
      in all tested women, and the mean number of the repeats were not statistically
      different between affected (18.3+/-2.4) and asymptomatic mutation carriers
      (18.6+/-2.1). The AR CAG repeat among patients with early onset (<42 years)
      breast cancer was significantly shorter (17.5+/-2.3) compared with asymptomatic
      individuals (18.6+/-2.1) (P<0.01), and the shorter allele - the younger the age
      at diagnosis. There is no conclusive evidence of association between AR CAG
      repeat size and breast or ovarian cancer risk in Jewish BRCA1/2 mutation
      carriers. A small effect of a short AR CAG allele size on breast cancer at early
      age (<42 years) cannot be excluded.

PMID- 12404105
TI  - CFTR gene mutations in sarcoidosis.
AB  - Sarcoidosis is a complex disease of multiorgan granulomatous inflammation.
      Genetic susceptibility is involved in the pathogenesis of the disorder. Two
      successive studies from Italy have shown a high frequency of mutations of the
      cystic fibrosis transmembrane conductance regulator (CFTR) gene in patients
      suffering from sarcoidosis. We have genotyped a panel of 63 families with two or
      more affected siblings for the CFTR gene mutation R75Q, which was found to be
      present in three of 26 cases of the Italian study. Although R75Q was present in
      seven families, it was neither associated with the sarcoidosis phenotype in the
      German population (P=0.5), nor was it linked to sarcoidosis (P=0.54). In
      addition, a screening for 34 functional CFTR mutations was performed in a subset
      of 54 patients from 25 families. These patients were known to be concordant for
      at least one parental copy of the CFTR gene. With the exception of the mayor CF
      mutation deltaF508, which was present in three patients and absent in one patient
      from two families, we did not find any other CF mutation in these 54 patients.
      Our results do not support the hypothesis that CFTR mutations have a major
      influence on the pathogenesis of sarcoidosis.

PMID- 12404106
TI  - Spectrum and expression analysis of KRIT1 mutations in 121 consecutive and
      unrelated patients with Cerebral Cavernous Malformations.
AB  - Cerebral Cavernous Malformations (CCM/MIM 604214) are vascular malformations
      characterised by abnormally enlarged capillary cavities without intervening brain
      parenchyma. Clinical manifestations include seizures, cerebral haemorrhages and
      focal neurological deficits. They occur as a sporadic or autosomal dominant
      condition. Most often, sporadic cases have only one lesion and familial cases are
      characterised by a high frequency of multiple lesions. Three CCM loci were
      previously mapped on 7q (CCM1), 7p (CCM2) and 3q (CCM3) and CCM1 gene was
      identified as coding Krit1, a protein of unknown function, which was shown
      initially to interact in yeast two hybrid assays with Rap1A, a small ras GTPase
      and more recently to Icap1alpha, a modulator of beta1 integrin signal
      transduction. Herein, we screened KRIT1 gene in 121 unrelated, consecutively
      recruited, CCM probands having at least one affected relative and/or showing
      multiple lesions on cerebral MRI. Fifty-two of these probands (43%) were shown to
      carry a KRIT1 mutation. Forty-two distinct mutations were identified including
      six recurrent ones. Three-quarters of these mutations were located in the C
      terminal half of the gene, mostly within exons 13, 15 and 17. All of them are
      predicted to lead to a premature stop codon. No missense mutation was identified.
      The only two nucleotide substitutions predicted to be missense mutations led in
      fact to an abnormal splicing and a premature stop codon. Altogether these data
      suggest that KRIT1 mRNA decay due to the presence of premature stop codons and
      Krit1 haploinsufficiency may be the underlying mechanism of CCM.

PMID- 12404107
TI  - Systematic analysis of the regulatory and essential myosin light chain genes:
      genetic variants and mutations in hypertrophic cardiomyopathy.
AB  - Hypertrophic cardiomyopathy (HCM) can be caused by mutations in genes encoding
      for the ventricular myosin essential and regulatory light chains. In contrast to
      other HCM disease genes, only a few studies describing disease-associated
      mutations in the myosin light chain genes have been published. Therefore, we
      aimed to conduct a systematic screening for mutations in the ventricular myosin
      light chain genes in a group of clinically well-characterised HCM patients.
      Further, we assessed whether the detected mutations are associated with malignant
      or benign phenotype in the respective families. We analysed 186 unrelated
      individuals with HCM for the human ventricular myosin regulatory (MYL2) and
      essential light chain genes (MYL3) using polymerase chain reaction, single strand
      conformation polymorphism analysis and automated sequencing. We found eight
      single nucleotide polymorphisms in exonic and adjacent intronic regions of MYL2
      and MYL3. Two MYL2 missense mutations were identified in two Caucasian families
      while no mutation was found in MYL3. The mutation Glu22Lys was associated with
      moderate septal hypertrophy, a late onset of clinical manifestation, and benign
      disease course and prognosis. The mutation Arg58Gln showed also moderate septal
      hypertrophy, but, in contrast, it was associated with an early onset of clinical
      manifestation and premature sudden cardiac death. In conclusion, myosin light
      chain mutations are a very rare cause of HCM responsible for about 1% of cases.
      Mutations in MYL2 could be associated with both benign and malignant HCM
      phenotype.

PMID- 12404108
TI  - Null mutation in human ciliary neurotrophic factor gene confers higher body mass
      index in males.
AB  - Ciliary neurotrophic factor (CNTF) administration reduces weight in leptin
      resistant mice via the signalling pathway normally activated by leptin. A G>A
      null mutation in the CNTF gene results in complete absence of protein. We
      hypothesised that absence of CNTF could lead to diminished initiation of
      anorectic pathways, with consequent increase in body mass. In 575 Caucasian men
      aged 59-73 years, the A/A genotype (frequency 1.9%) was associated with a 10 kg
      increase in weight (P=0.03, 2 df) and 3 kg/m(2) greater BMI (P=0.02, 2 df). There
      was no effect in women. The CNTF G>A null mutation therefore confers a moderate
      effect on obesity in males of A/A genotype, who represent 1% of the general
      population.

PMID- 12404109
TI  - Evaluation of BMP4 and its specific inhibitor NOG as candidates in human neural
      tube defects (NTDs).
AB  - Neural tube defects (NTD) are among the most common congenital malformations in
      humans. The current view is that there are no major genes causing NTDs, but
      combinations of sequence variants in different genes have additive effects on
      determining the malformation. Therefore it is important to identify such sequence
      variants to get a better understanding of NTD pathogenesis. Studies on animal
      models have shown that BMP4 and NOG are involved in the patterning of the neural
      tube. We therefore performed a single-strand conformation analysis (SSCA)
      mutation screen for both genes in 179 spina bifida aperta (SBA) patients. Our
      SSCA screen revealed four missense mutations in BMP4 and one in NOG. It is likely
      that these mutations have acted together with other gene variants in
      independently segregating loci as susceptibility factors in these SBA cases. In
      addition, a case-control association study provides evidence for a genotype
      disequilibrium of BMP4 polymorphism 455T-->C (V152A) in exon 5. The frequency of
      the heterozygous 455TC genotype is lower in cases than in controls (nominal
      P=0.017), although allele frequencies are similar in both groups. A possible
      explanation for this finding might be that BMP4 455TC heterozygosity at this site
      is a protective factor in the normal population, although this hypothesis cannot
      be proven to date.

PMID- 12404110
TI  - Genomic rearrangements of EYA1 account for a large fraction of families with BOR
      syndrome.
AB  - Branchio-Oto-Renal (BOR) syndrome is transmitted as an autosomal dominant
      disorder, affects an estimated 2% of profoundly deaf children, and is caused by
      mutations in the human EYA1 gene. However, in up to half of the reported cases,
      EYA1 mutation screening is negative. This finding has been taken as evidence of
      genetic heterogeneity. Mutation screening of the coding region of EYA1 in a panel
      of families linked to chromosome 8 was conducted using SSCP and direct
      sequencing. Only one point mutation in five probands was detected. However,
      complex rearrangements, such as inversions or large deletions, were discovered in
      the other four patients using Southern blot analysis. These data suggest that
      more complex rearrangements may remain undetected in EYA1 since SSCP and
      sequencing were commonly used to detect mutations in this gene.

PMID- 12404111
TI  - A novel gene, FAM11A, associated with the FRAXF CpG island is transcriptionally
      silent in FRAXF full mutation.
AB  - The cytogenetic expression of the FRAXF fragile site is due to an expanded,
      hypermethylated and unstable CGG repeat in Xq28. Normal individuals have 6-38
      triplet repeats while individuals expressing the fragile site have expansions of
      greater than 300 triplets. Through analysis of the region adjacent to the fragile
      site, we have identified a approximately 2.6 kb cDNA originating from the FRAXF
      fragile site associated CpG island, and containing the unstable FRAXF CGG repeat
      in its 5' UTR region. This gene, FAM11A, comprises at least seven exons, shows
      alternative splicing, and extends over 35 kb of genomic DNA distal to the FRAXF
      fragile site. Analysis of the FAM11A cDNA sequence has identified a 1050 bp open
      reading frame encoding a 350 amino acid protein. We have also identified FAM11B a
      highly conserved (88% at the protein level) transcribed chromosome 2
      retropseudogene. We show that the novel FRAXF fragile site associated gene FAM11A
      is transcriptionally silenced in a normal individual with a cytogenetically and
      molecularly detectable FRAXF CGG full mutation (fragile site). Finally, we were
      able to reactivate FAM11A transcription by treatment of a FRAXF lymphoblastoid
      cell line with the demethylating agent 5-azadeoxycytidine, thus demonstrating the
      critical role of FRAXF methylation in FAM11A silencing.

PMID- 12404114
TI  - Pro-apoptotic BH3-only Bcl-2 family members in vertebrate model organisms
      suitable for genetic experimentation.

PMID- 12404112
TI  - Mutational spectrum of the CHAC gene in patients with chorea-acanthocytosis.
AB  - Chorea-acanthocytosis (ChAc) is an autosomal recessive neurological disorder
      whose characteristic features include hyperkinetic movements and abnormal red
      blood cell morphology. Mutations in the CHAC gene on 9q21 were recently found to
      cause chorea-acanthocytosis. CHAC encodes a large, novel protein with a yeast
      homologue implicated in protein sorting. In this study, all 73 exons plus
      flanking intronic sequence in CHAC were screened for mutations by denaturing high
      performance liquid chromatography in 43 probands with ChAc. We identified 57
      different mutations, 54 of which have not previously been reported, in 39
      probands. The novel mutations comprise 15 nonsense, 22 insertion/deletion, 15
      splice-site and two missense mutations and are distributed throughout the CHAC
      gene. Three mutations were found in multiple families within this or our previous
      study. The preponderance of mutations that are predicted to cause absence of gene
      product is consistent with the recessive inheritance of this disease. The high
      proportion of splice-site mutations found is probably a reflection of the large
      number of exons that comprise the CHAC gene. The CHAC protein product, chorein,
      appears to have a certain tolerance to amino-acid substitutions since only two
      out of nine substitutions described here appear to be pathogenic.

PMID- 12404115
TI  - Retinoid-related orphan receptors (RORs): roles in cell survival, differentiation
      and disease.

PMID- 12404116
TI  - HIV-1 protease processes procaspase 8 to cause mitochondrial release of
      cytochrome c, caspase cleavage and nuclear fragmentation.
AB  - Infection of T cells with HIV-1 induces apoptosis and modulates apoptosis
      regulatory molecules. Similar effects occur following treatment of cells with
      individual HIV-1 encoded proteins. While HIV-1 protease is known to be cytotoxic,
      little is known of its effect on apoptosis and apoptosis regulatory molecules.
      The ability of HIV-1 protease to kill cells, coupled with the degenerate
      substrate specificity of HIV-1 protease, suggests that HIV-1 protease may
      activate cellular factor(s) which, in turn, induce apoptosis. We demonstrate that
      HIV-1 protease directly cleaves and activates procaspase 8 in T cells which is
      associated with cleavage of BID, mitochondrial release of cytochrome c,
      activation of the downstream caspases 9 and 3, cleavage of DFF and PARP and,
      eventually, to nuclear condensation and DNA fragmentation that are characteristic
      of apoptosis. The effect of HIV-1 protease is not seen in T cell extracts which
      have undetectable levels of procaspase 8, indicating a specificity and
      requirement for procaspase 8.

PMID- 12404117
TI  - Gene expression profile of Vitamin D3 treated HL60 cells shows an incomplete
      molecular phenotypic conversion to monocytes.
AB  - By high density oligonucleotide microarrays we have studied the expression
      profile of proliferating and VD treated HL60 cells and the molecular phenotype of
      VD monocytes and that of CD14+ peripheral monocytes has been compared. The
      results indicate that important changes in functional categories of the
      differentially expressed genes underlie the differentiation transition from
      myeloblasts to monocytes. This differential gene expression pattern leads to an
      increased expression of mRNAs involved in surface and external activities since
      many of the VD induced genes belong to ligand binding, receptors, cell surface
      antigens, defense/immunity and adhesion molecules functional categories. The
      results also indicate that the molecular phenotypes of monocytes and VD induced
      cells diverge for a small but significant set of defense related genes.
      Particularly, class II MHC genes are not expressed in these cells. Furthermore,
      the high levels of expression of these genes induced by serum treatment of
      monocytes are decreased by VD.

PMID- 12404118
TI  - Ex vivo whole-embryo culture of caspase-8-deficient embryos normalize their
      aberrant phenotypes in the developing neural tube and heart.
AB  - Caspase-8 plays the role of initiator in the caspase cascade and is a key
      molecule in death receptor-induced apoptotic pathways. To investigate the
      physiological roles of caspase-8 in vivo, we have generated caspase-8-deficient
      mice by gene targeting. The first signs of abnormality in homozygous mutant
      embryos were observed in extraembryonic tissue, the yolk sac. By embryonic day
      (E) 10.5, the yolk sac vasculature had begun to form inappropriately, and
      subsequently the mutant embryos displayed a variety of defects in the developing
      heart and neural tube. As a result, all mutant embryos died at E11.5.
      Importantly, homozygous mutant neural and heart defects were rescued by ex vivo
      whole-embryo culture during E10.5-E11.5, suggesting that these defects are most
      likely secondary to a lack of physiological caspase-8 activity. Taken together,
      these results suggest that caspase-8 is indispensable for embryonic development.

PMID- 12404119
TI  - Caspases are not localized in mitochondria during life or death.
AB  - Caspases are crucial for the initiation, propagation and execution of apoptosis.
      They normally exist as proenzymes, which can be activated through recruitment
      into activating complexes and by proteolytic cleavage by other caspases or
      proteases. Perturbation of organelles such as nuclei, endoplasmatic reticulum and
      mitochondria results in the activation of caspases. A number of caspases (-2, -3,
      -8 and -9) were published as being localized in the intermembrane space of
      mitochondria. However, in three different models of apoptosis (anti-Fas-induced
      cell death in murine hepatocytes, Fas ligand-induced apoptosis in Jurkat cells
      and apoptosis induced by growth factor withdrawal in Ba/F3 cells) we could not
      identify a mitochondrial location of caspases, neither under control nor under
      apoptotic conditions. In all three apoptotic models caspases were found in the
      cytosolic (caspases-2, -3, -6, -7, -8, -9) and nuclear subcellular fractions
      (caspases-2, -3). In another approach we treated isolated liver mitochondria with
      truncated Bid. Although tBid-dependent release of Cytochrome c, AIF, adenylate
      kinase, Smac/DIABLO and Omi/HtrA2 could be demonstrated, none of the caspases
      were detectable both in the supernatant and the mitochondrial fraction after
      treatment. Our results demonstrate that, in contrast to previous studies, no
      caspases-2, -3, -8 and -9 are associated with the mitochondrial fraction. These
      findings support the concept of a separate compartmentalization between
      proapoptotic cofactors in the mitochondria and silent precursor caspases in the
      cytosol.

PMID- 12404120
TI  - The C-terminal moiety of HIV-1 Vpr induces cell death via a caspase-independent
      mitochondrial pathway.
AB  - Previous biochemical studies suggested that HIV-1-encoded Vpr may kill cells
      through an effect on the adenine nucleotide translocase (ANT), thereby causing
      mitochondrial membrane permeabilization (MMP). Here, we show that Vpr fails to
      activate caspases in conditions in which it induces cell killing. The knock-out
      of essential caspase-activators (Apaf-1 or caspase-9) or the knock-out of a
      mitochondrial caspase-independent death effector (AIF) does not abolish Vpr
      mediated killing. In contrast, the cytotoxic effects of Vpr are reduced by
      transfection-enforced overexpression of two MMP-inhibitors, namely the endogenous
      protein Bcl-2 or the cytomegalovirus-encoded ANT-targeted protein vMIA. Vpr,
      which can elicit MMP through a direct effect on mitochondria, and HIV-1-Env,
      which causes MMP through an indirect pathway, exhibit additive (but not synergic)
      cytotoxic effects. In conclusion, it appears that Vpr induces apoptosis through a
      caspase-independent mitochondrial pathway.

PMID- 12404121
TI  - Caspase-independent photoreceptor apoptosis in vivo and differential expression
      of apoptotic protease activating factor-1 and caspase-3 during retinal
      development.
AB  - Apoptosis is the mode of photoreceptor cell death in many retinal dystrophies.
      Exposure of Balb/c mice to excessive levels of light induces photoreceptor
      apoptosis and represents an animal model for the study of retinal degenerations.
      Caspases have emerged as central regulators of apoptosis, executing this tightly
      controlled death pathway in many cells. Previously we have reported that light
      induced photoreceptor apoptosis occurs independently of one the key executioners
      of apoptosis, caspase-3. This present study extends these results reporting on
      the lack of activation of other caspases in this model including caspases-8, -9, 
      7, and -1. Furthermore, photoreceptor apoptosis cannot be inhibited with the
      broad range caspase inhibitor zVAD-fmk indicating that light-induced retinal
      degeneration is caspase-independent. We demonstrate that cytochrome c does not
      translocate from mitochondria to the cytosol during photoreceptor apoptosis. We
      also show that during retinal development apoptotic protease activating factor
      (Apaf-1) protein levels are markedly decreased and this is associated with the
      inability to activate the mitochondrial caspase cascade in the mature retina. In
      addition, there is also a significant reduction in expression of caspases-3 and 
      9 during retinal maturation and these levels do not increase following light
      exposure. Finally, we show that the calcium-dependent proteases calpains are
      active during light-induced retinal degeneration and establish that the calcium
      channel blocker D-cis-diltiazem completely inhibits photoreceptor apoptosis.

PMID- 12404122
TI  - Cyclin D1-dependent regulation of B-myb activity in early stages of neuroblastoma
      differentiation.
AB  - Levels of the transcription factor B-myb must be down-regulated to allow terminal
      differentiation of neuroectodermal cells and yet its constitutive expression
      induces early markers of neural differentiation. Thus, we investigated potential
      mechanisms of enhanced B-myb activity in early stages of neural differentiation.
      We report here that B-myb expression does not decrease, cyclin A and Sp1 levels
      remain constant while p21 levels increase continuously upon retinoic acid-induced
      differentiation of the LAN-5 neuroblastoma cell line. In contrast, cyclin D1
      expression is down-regulated at the onset of the differentiative process by
      protein destabilization. Luciferase assays of promoter activity indicate that B
      myb-dependent transactivation is enhanced in LAN-5 cells treated with retinoic
      acid (RA) for 24 h. The enhancement is independent from cyclin A but is
      suppressed by a degradation-resistant mutant form of cyclin D1. The importance of
      cyclin D1 in controlling B-myb activity is further suggested by co
      immunoprecipitation experiments, showing that the amount of cyclin D1 co
      immunoprecipitated with B-myb decreased after RA treatment. Thus, B-myb may play
      an active role in the early stages of differentiation when its transactivation
      activity is enhanced as a consequence of cyclin D1 down-modulation.

PMID- 12404123
TI  - The proapoptotic BH3-only protein BAD transduces cell death signals independently
      of its interaction with Bcl-2.
AB  - The BH3-only protein BAD binds to Bcl-2 family proteins through its BH3 domain.
      Recent studies suggest that BAD binds to both Bcl-2 and Bcl-X(L), however
      mediates its pro-apoptotic functions through inhibition of Bcl-X(L), but not Bcl
      2. In this paper we addressed this issue using a BAD mutant within the BH3
      domain, by substitution of Asp 119 with Gly (BAD(D119G)), which selectively
      abrogates an ability to interact with Bcl-2. Confocal microscopy revealed that
      mutation of BAD at D119 does not affect BAD targeting to the mitochondrial
      membrane in serum-starved COS-7 cells. However, co-precipitation assays indicated
      that, whereas wild-type BAD (BADwt) directly interacts with Bcl-2 and Bcl-X(L),
      BAD(D119G) interacts only with Bcl-X(L). Nevertheless both BADwt and BAD(D119G)
      could introduce apoptosis and diminish the anti-apoptotic effect of Bcl-2 and Bcl
      X(L) in a similar manner in a co-transfection assay. These data thus suggest that
      Asp119 is a crucial site within the BH3 domain of BAD for interaction of BAD with
      Bcl-2, but is dispensable for the interaction of BAD with Bcl-X(L), for its
      targeting to mitochondria, and most importantly, for its pro-apoptotic functions.
      Thus, we confirm that neutralization of Bcl-2 function is marginal for BAD
      mediated apoptosis.

PMID- 12404124
TI  - Cyclic GMP-dependent inhibition of acid sphingomyelinase by nitric oxide: an
      early step in protection against apoptosis.
AB  - Activation of acid and neutral sphingomyelinases, and the ensuing generation of
      ceramide, contributes to the biological effects of tumour necrosis factor-alpha
      (TNF-alpha), one of which is apoptosis. While the mechanisms of activation of
      sphingomyelinases by the cytokine are being unravelled, less is known about
      regulation of their activity. Nitric oxide has previously been shown to exert a
      cyclic GMP-dependent inhibition of early apoptotic events triggered by TNF-alpha
      in the U937 monocytic cell line. We therefore investigated whether inhibition of
      sphingomyelinases by nitric oxide plays a role in regulating such early events.
      We found that activation of both acid and neutral sphingomyelinases, triggered in
      the first minutes after U937 cell stimulation with TNF-alpha, is regulated in an
      inhibitory fashion by nitric oxide, working through generation of cyclic GMP and
      activation of protein kinase G. Using a range of inhibitors selective for either
      sphingomyelinase we found that the acid sphingomyelinase contributes to
      activation of the initiator caspase-8 and early DNA fragmentation and that
      inhibition of the acid enzyme by nitric oxide accounts for cyclic GMP-dependent
      early protection from apoptosis. We also found that the protective effect by both
      cGMP and acid sphingomyelinase inhibitors progressively disappeared at later
      stages of the apoptotic process. Inhibition of sphingomyelinases represents a
      novel action of nitric oxide, which might be of physiological relevance in
      regulating initial phases of apoptosis as well as other biological actions of
      ceramide.

PMID- 12404125
TI  - The anti-inflammatory sesquiterpene lactone parthenolide suppresses CD95-mediated
      activation-induced-cell-death in T-cells.
AB  - Apoptosis is a morphologically distinct form of cell death involved in many
      physiological and pathological processes. The death receptor CD95 (APO-1/Fas) and
      its ligand (L) CD95L are critically involved in activation-induced-cell-death
      (AICD) of activated T-cells. Here we show that the anti-inflammatory
      sesquiterpene lactone parthenolide derived from the European traditional herb
      medicine feverfew and many Mexican India medicinal plants suppresses expression
      of the CD95L and CD95 at the mRNA levels, thus, preventing T-cells from AICD. We
      demonstrate that parthenolide blocks NF-kappaB binding to the two NF-kappa
      binding sites of the CD95L promoter and suppresses promoter activity upon T-cell
      activation. Aberrant expression of CD95 and, particularly CD95L is dangerous and
      may lead to severe diseases. Our study indicates that parthenolide supports T
      cell survival by down-regulating the CD95 system, at least in part, and,
      therefore, may have therapeutic potential as a new anti-apoptotic substance
      against AICD in T-cells.

PMID- 12404126
TI  - P-glycoprotein inhibits caspase-8 activation but not formation of the death
      inducing signal complex (disc) following Fas ligation.
AB  - Previous studies by our laboratory have shown that the drug transporter protein P
      glycoprotein, P-gp, can specifically inhibit Fas-induced caspase-3 activation and
      apoptosis. Importantly, inhibition of both caspase-3 activation and cell death
      could be reversed by pharmacological and antibody inhibitors of P-gp function.
      However, the molecular mechanisms underpinning P-gp-mediated resistance to Fas
      induced cell death and caspase activation remained unknown. We therefore sought
      to identify the point(s) within the death receptor pathway at which P-gp exerted
      its inhibitory effect and to determine whether the ATPase activity of P-gp was
      required. Structure-function analysis determined that ATP hydrolysis was
      necessary for P-gp to confer resistance to Fas-induced caspase activation and
      cell death. Importantly, although both FADD and caspase-8 were recruited to the
      Death Inducing Signal Complex (DISC) in wild-type P-gp expressing cells following
      Fas ligation, subsequent activation of caspase-8 at the DISC was inhibited. The
      ability of P-gp to inhibit caspase-8 activation was also ATP dependent. These
      studies demonstrate that P-gp inhibits Fas-induced caspase-8 activation but not
      formation of the DISC and that this activity of P-gp is dependent on ATP
      hydrolysis.

PMID- 12404127
TI  - Differential requirement for Apaf1 and Bcl-X(L) in the regulation of programmed
      cell death during development.

PMID- 12404128
TI  - Arterialized venous free flaps for soft-tissue reconstruction of digits: a 40
      case series.
AB  - When there is not sufficient local tissue available for reconstruction of one or
      multiple digital defects, distant flap reconstructions are required. Available
      thin flaps with defined arterial inflow and venous outflow are limited and
      require the sacrifice of an arterial pedicle. In addition, a functional
      limitation can occur at the donor site. During the last decades, experimental and
      clinical attempts have been made in using venous flaps, based just on the venous
      network for in- and outflow. A 40-case series of arterialized venous free flaps
      in soft-tissue reconstruction of the digits and hand is presented. Neovessel
      formation induced by an intact venous plexus within the flap proved clinically to
      be the survival mechanism. Postoperative congestion was present in all flaps and
      subsided within 14 days; 92 percent of all flaps eventually survived. In 57.5
      percent of cases, total flap survival was observed; in 17.5 percent of flaps, a
      superficial epidermolysis occurred, not requiring further surgery; in 17.5
      percent of flaps, a full-thickness skin necrosis developed, requiring grafting
      (minor complication); in 7.5 percent of reconstructions, total flap necrosis was
      observed. Thus, in the authors' experience, when conventional local flaps are not
      available, arterialized venous free flaps proved to be a successful solution for
      soft-tissue reconstruction in digits and hands. The authors present the main
      indications and advantages of arterialized venous free flaps, emphasizing the
      essential technical steps and the most frequent pitfalls in treatment.

PMID- 12404130
TI  - Effects of late loss of arterial inflow on free flap survival.
AB  - Greater than 80 percent of free flap thromboses have been shown to occur within
      the first three postoperative days, warranting immediate re-exploration and
      restoration of adequate vessel patency. The infrequency of thromboses beyond this
      period is reflected in the lack of reported cases in the literature and the
      absence of accepted guidelines for the treatment of such delayed complications. A
      single study reported free flap survival in vessel thromboses only when
      encountered after postoperative day (POD) 7 in a pig model. Since 1990, over 800
      free tissue transfers have been done at the University of Rochester. A total of
      ten cases of late (defined as after POD 7) arterial inflow loss were identified
      and examined. A retrospective chart review recorded patient demographics, site of
      tissue defect, free tissue transferred, major co-morbidities, preoperative XRT,
      timing of arterial inflow loss, nature of inflow loss, and flap survival. The
      mean POD of arterial inflow loss was 53 days (range: 8 to 166). The mean age of
      patients was 58 years. No major co-morbidities correlated with late arterial
      inflow loss. Loss of inflow occurred as anastomotic rupture (5), occlusion of
      recipient bypass graft in lower extremity cases (3), primary donor arterial
      thrombosis (1), and pedicle avulsion during re-exploration for seroma (1). Five
      flaps survived, one sustained partial necrosis, and four were completely lost. Of
      the five surviving flaps, three were inset into healthy recipient sites. One was
      utilized on a dysvascular lower extremity, and another was used in an irradiated
      neck defect. Of the four failed flaps, all were placed in recipient beds
      compromised by radiation, ischemia, or scarring. Two exemplary case reports are
      presented. The timing of late loss of arterial inflow does not appear to be the
      primary determinant of free tissue survival. The condition and quality of the
      recipient site plays a large role in survival of these flaps. Ischemic,
      irradiated, and scarred beds are inadequate in providing late flap
      neovascularization, compared to healthy recipient sites. When encountering late
      loss of arterial inflow in flaps placed on such compromised beds, the
      microsurgeon should not anticipate survival based on surrounding vessel ingrowth.
      More aggressive salvage attempts may be warranted.

PMID- 12404131
TI  - Free radial forearm osteocutaneous perforator flap for reconstruction of total
      nasal defects.
AB  - A case in which a radial forearm osteocutaneous perforator flap was successfully
      transferred for one-stage reconstruction of total nasal loss is described. This
      thin flap consists of vascularized radial bone, superficial adiposal tissue, and
      no deep fascia. It is nourished by a single perforator of the radial artery and a
      cutaneous vein. The advantages of this flap are minimal donor-site morbidity,
      easy reconstruction for preservation of the radial arterial system, and no need
      for longer dissection through the radial artery. The donor defect can be repaired
      with a flow-through flap, such as an anterolateral thigh flap or a latissimus
      dorsi perforator flap.

PMID- 12404133
TI  - A new flap design for monitoring the circulation of a buried free radial forearm
      flap in pharyngoesophageal reconstruction.
AB  - The viability of a free radial forearm flap which is used in pharyngoesophageal
      reconstruction is difficult to monitor because it is hidden by skin. As the most
      reliable method for monitoring, exteriorization of a small island flap has been
      reported. The authors used a skin paddle which is placed ulnar to the radial
      forearm reconstruction flap at the ulnar side of the distal part of the forearm
      as a monitor flap in one patient. Flap viability was assessed by observing tissue
      color, turgor, capillary refill, and bleeding of the monitor flap. This monitor
      flap is easy to elevate. The perfusion of the flap is good because it has a wide
      pedicle. It permits a long vascular pedicle for the radial forearm reconstruction
      flap and does not reduce available forearm skin for pharyngoesophageal
      reconstruction.

PMID- 12404134
TI  - Easy venous superdrainage in DIEP flap breast reconstruction through the
      intercostal branch.
AB  - The deep inferior epigastric perforator (DIEP) flap has been shown to be a valid
      option for breast reconstruction, as it has certain advantages over the free TRAM
      flap, including lower morbidity in the donor area, conservation of abdominal wall
      function, and reduced postoperative pain. However, some cases of venous
      congestion in using the DIEP flap have been described. The authors present a case
      in which the venous return in a DIEP flap objectively (by measurement with a flux
      meter) presented a marked improvement (from 4 ml/min to 13.9 ml/min) after venous
      drainage was increased by means of the supplementary anastomosis of a comitant
      vein from the deep inferior epigastric pedicle to the intercostal branch of the
      internal mammary vein. The preservation of this branch is a simple and effective
      technique to improve the venous drainage of DIEP flaps, whether signs of
      congestion are present or not.

PMID- 12404135
TI  - Effect of blood loss on vascular responsiveness in pedicled groin flaps in a rat
      model.
AB  - Using the clamping method (closing and opening the flap feeding artery) and
      continuous laser Doppler flowmetry, the effects of blood withdrawals on flap
      blood flow and on active and passive mechanisms regulating it were investigated
      in 12 Sprague-Dawley rats. Measurements were made during stable normovolemic
      conditions, during hypovolemia (after 3 ml/kg and after 6 ml/kg blood
      withdrawal), and after retransfusion of the shed blood. The continuous blood flow
      responses during and after the clamping procedure were analyzed. After clamp
      release, the increase in blood flow, duration of overshoot, and peak flow of
      overshoot were significantly greater (the level of significance was set equal to
      0.05) in the registrations performed after blood withdrawals than before them.
      The post-ischemic response curves indicating significantly increased flap
      hyperemia during reperfusion in the registrations after blood withdrawals may be
      associated with decreased vascular resistance in the flap. Thus, the authors
      conclude that a short-term decrease in blood pressure caused by blood loss may
      prepare the flap microcirculation for tolerating more ischemia.

PMID- 12404136
TI  - Nitric oxide levels in peripheral blood as an indicator of microvascular
      anastomotic patency.
AB  - Nitric oxide (NO) was first recognized as the endothelial-derived relaxing factor
      in 1987, and since then has been extensively studied. It was found to be involved
      in almost every physiologic or pathophysiologic process in human biology. This
      study examined the correlation between peripheral blood levels of NO and the
      microvascular anastomotic patency of an infrarenal aortic anastomosis in a rat
      model. Four groups of six Sprague-Dawley rats each were studied. Three groups
      underwent microsurgical manipulation which included: anastomosis followed by
      ligation of the aorta in one group; anastomosis of the aorta in another; and
      dissection of the infrarenal aorta in the third group. A fourth group served as
      controls. Peripheral blood samples for NO levels were taken at different times
      before and during the first 24 hr after surgery. Results demonstrated a transient
      rise of NO levels in all operated groups. The ligated group exhibited the most
      prominent rise in NO blood levels. This rise was statistically significant,
      compared to the rise in other groups during the first 6 hr postoperatively. The
      anastomosed group levels were only mildly higher than the dissected group,
      showing no statistically significant difference postoperatively. NO blood levels
      in all of the groups returned to baseline at 24 hr postoperatively. The study
      shows that changes in NO levels in peripheral blood are detectable after
      microsurgical manipulation of the infrarenal aorta in a rat model. Furthermore,
      in rats undergoing ligation of the anastomosed aorta, mimicking anastomotic
      occlusion, NO peripheral blood levels are significantly higher than when the
      anastomosis remains patent.

PMID- 12404137
TI  - Effects of methylprednisolone on the viability of experimental flow-through
      venous flaps.
AB  - In this study, the effects of a corticosteroid, methylprednisolone, on the
      survival of flow-through venous flaps were investigated in rabbits. Flow-through
      venous flaps, sized 3.0 x 4.5 cm, were raised in the rabbit-ear model. Animals
      were randomly distributed into three groups, and 30 flaps were raised as follows:
      Group 1 (n=10): control flow-through venous flaps (intramuscular saline injection
      2 ml/d); Group 2 (n=10): flow-through venous flaps with daily intramuscular
      methylprednisolone injection (30 mg/kg/d); and Group 3 (n=10): negative control
      composite grafts with the flow-through vein ligated at both edges of the flap.
      All injections were done 24 hr and 1 hr preoperatively, and for 5 days
      postoperatively. Observations included gross and histologic examination, and
      percentage of survival of the flaps on the tenth day. Venous flaps of the animals
      receiving daily methylprednisolone injections (Group 2) were noted to have
      statistically significantly improved flap survival ( p<0.05), compared to the
      control group (Group 1). Flaps in Groups 1 and 2 demonstrated significantly
      higher survival rates, compared to the composite grafts ( p<0.01). Histologic
      examination of methylprednisolone-treated animals showed normal stratified
      squamous epithelium, while complete necrosis was noted in the composite grafts.
      Untreated flow-through venous flaps demonstrated patchy epidermal sloughing,
      crusting, and partial necrosis. These results suggest that the survival of
      potentially ischemic flow-through venous flaps can be enhanced in rabbits by
      daily methylprednisolone treatment in the perioperative period. Increased
      tolerance to ischemia and modulation of venous flap microcirculation might be
      possible mechanisms for this salutary effect.

PMID- 12404140
TI  - [One-sided spinal anaesthesia--does it really work?].

PMID- 12404141
TI  - [Phylogeny and evolution of hormone systems].
AB  - Classically hormones are defined as molecules that are secreted by endocrine
      glandular or neurosecretory cells into the blood stream and transported to their
      target tissue where they induce physiological processes at very low
      concentrations. Studies on the potential origin and the evolution of cell-to-cell
      communication systems suggest that exocrine pheromones (food signals and toxins)
      might have been the primitive bioregulatory molecules of unicellular organisms
      for chemical communication with each other and with the biosphere. The broad
      distribution and the structural diversity of pheromones suggests that these
      molecules and their receptors were predecessor modules of cell communication
      systems in metazoa. Neurosecretory cells, as we find them in Cnidarians, possibly
      served as basic modules for the evolution of neurohormonal systems of higher
      animals. Studies on genetic model organisms, such as Drosophila or the mouse,
      have demonstrated that chemical communication between neighbouring or more
      distant cells does not just involve endocrine and neurosecretory cells, but also
      unexpectedly tissues and organs such as the heart or the adipose tissue (e. g.
      the leptin signalling pathway). Comparative endocrinology could show that
      molecular components of hormonal systems represent signalling networks that are
      generally used during cellular communication processes and the differentiation of
      cell types during ontogenesis. Some of their functions are evolutionarily
      conserved, others not, as disscussion on steroid hormones and the prolactin
      signalling pathway will demonstrate.

PMID- 12404142
TI  - [Influence of positioning on the quality of unilateral spinal anesthesia].
AB  - OBJECTIVE: Unilateral spinal anaesthesia ("hemi-spinal") is theoretically
      associated with the advantages of fewer cardiovascular effects and longer
      duration of action while offering high density motor block of the extremity
      affected. METHODS: In a prospective, randomised study 60 patients received 2 mls
      of 4 % hyperbaric mepivacaine intrathecally. Group I (n = 30) was returned into
      the supine position after 5 minutes in the lateral position, Group II (n = 30)
      was kept in the lateral position for 15 minutes. Spread and subsequently offset
      of sensory and motor block were assessed separately for each side at
      predetermined time intervals pre-, intra-, and postoperatively. RESULTS: Both
      groups were identical regarding their morphometric parameters. In Group I (5
      minutes), the mean cephalad spread of sensory block of the initially dependent
      side was T6 after 15 mins and T4 after 25 mins. On the initially non-dependent
      side, the sensory block reached to T5 after 25 mins. In Group II (15 mins), the
      initial mean difference was equivalent to two segments (T7/T9). After 25 minutes
      there was no difference to the results in Group I. CONCLUSIONS: Unilateral spinal
      anaesthesia ("hemi-spinal") is an attractive concept, supposed to be associated
      with the above mentioned advantages and the additional benefit of a partially
      maintained sensation of one limb. The results demonstrated in this study
      seriously question this theoretical concept. The most likely reason for the lack
      of inter-lateral differences in sensory block is the high concentration of
      hyperbaric local anaesthetic in the cerebrospinal fluid on the dependent side,
      which, on turning the patient to the supine position, will transit to the
      previously non-dependent side subsequently leading to a significant block.

PMID- 12404143
TI  - [Mechanical interaction between patient and ventilator in biphasic positive
      airway pressure (BIPAP)--digital and mechanical simulations].
AB  - OBJECTIVE: Biphasic Positive Airway Pressure (BIPAP) and the closely related
      Airway Pressure Release Ventilation (APRV) are characterised by asynchronous
      actions of ventilator and patient. Clinical observation and physiological
      reasoning suggest, that in BIPAP patient and ventilator can interact in various
      ways. This study was to elucidate the mechanical interaction. METHODS:
      Ventilation and interaction between patient and ventilator were analysed in
      digital and mechanical simulations of BIPAP with a variety of patient effort
      magnitudes and durations, machine pressures and phase durations, and passive
      respiratory system (RS) mechanics. RESULTS AND CONCLUSIONS: Patient efforts were
      most likely to effect a breath if they were strong relative to the machine
      pressure swing, and if they occurred late in a ventilator phase. Conversely,
      efforts occurring with or shortly after a machine pressure swing or relatively
      weak efforts were more or less ineffective. The postulated permanently
      unrestricted spontaneous breathing in BlPAP mode, although indeed assured in the
      technical sense, has to be qualified: Every change in machine pressure defines a
      new balance of the forces driving the RS, and the lung volume will approach a new
      elastic equilibrium volume ( = relaxation volume); the speed of this approach is
      determined by the time constant (tau = R x C) of the RS. Patient efforts are most
      effective when the RS is at or close to an equilibrium. An increase in the
      assisting machine pressure swing can unload the patient and assure a minimum
      ventilation, but it reduces the patient"s influence on ventilation and thus
      potentially patient comfort. In contrast, Automatic Tube Compensation (ATC), an
      assist component accelerating the RS by reducing resistances, combines unloading
      with more patient influence; this has to be weighed against the potential
      disadvantage of higher peak flows.

PMID- 12404144
TI  - Autologous transfusion--from euphoria to reason: clinical practice based on
      scientific knowledge-part I.

PMID- 12404146
TI  - [Autologous transfusion--pros and cons from the public health politics point of
      view].

PMID- 12404147
TI  - [Mechanisms of immunomodulation after transfusion of allogeneic and autologous
      red cell concentrate].

PMID- 12404148
TI  - [Clinical relevance of immunomodulation after blood transfusion in non-oncologic
      patients].

PMID- 12404149
TI  - [Establishment of the leucocyte - depleted autologous whole blood pack].

PMID- 12404150
TI  - [Physical principles of autotransfusion systems].

PMID- 12404151
TI  - [Epiglottic abscess as a rare reason for airway obstruction in adults].
AB  - Acute epiglottitis in adults is a potentially life-threatening disease of
      increasing incidence. Although pharyngitis is the most common cause of sore
      throat in the adult, acute epiglottitis must be considered in the differential
      diagnosis when there is unrelenting throat pain and minimal objective signs of
      pharyngitis. We report the case of a 45-year old man with acute epiglottitis and
      occlusion of the upper airways due to an epiglottic abscess. A brief discussion
      of the diagnosis and treatment of adult epiglottitis is presented. Patients with
      acute painful dysphagia should be considered to have epiglottitis until the
      diagnosis is proven. Early diagnosis and aggressive airway management can be life
      saving.

PMID- 12404152
TI  - Seroprevalence and correlates of herpes simplex virus type 2 infection in five
      sexually transmitted-disease clinics.
AB  - The seroprevalence of herpes simplex virus type 2 (HSV-2) infection was studied
      among 4128 patients from sexually transmitted disease (STD) clinics who were
      enrolled in a randomized controlled trial of human immunodeficiency virus and STD
      counseling efficacy. HSV-2 seroprevalence was 40.8% and was higher in women than
      in men (52.0% vs. 32.4%; P<.0001) and higher in blacks than in nonblacks (48.1%
      vs. 29.6%; P<.0001). Among 14-19-year-old patients, 36.8% of black women and
      25.8% of nonblack women were infected with HSV-2. Independent predictors of HSV-2
      seropositivity included female sex, black race, older age, less education, more
      lifetime sex partners, prior diagnosis of syphilis or gonorrhea, and lack of HSV
      1 antibody. The majority of HSV-2-seropositive persons (84.7%) had never received
      a diagnosis of genital herpes. HSV-2 infection is common in STD clinic attendees
      in the United States, even among young age groups, especially among women.
      Efforts to prevent genital herpes should begin at an early age. The high rate of
      undiagnosed HSV-2 infection likely contributes to ongoing transmission.

PMID- 12404153
TI  - Maporal viral infection in the Syrian golden hamster: a model of hantavirus
      pulmonary syndrome.
AB  - Hantavirus pulmonary syndrome (HPS) is a severe and often fatal rodent-borne
      zoonosis. Maporal (MAP) virus is a newly discovered hantavirus that originally
      was isolated from an arboreal rice rat captured in central Venezuela. The results
      of this study indicate that MAP virus in the Syrian golden hamster (Mesocricetus
      auratus) can cause a disease that is clinically and pathologically remarkably
      similar to HPS. The similarities include the time course of clinical disease,
      presence of virus-specific IgG at the onset of clinical disease, subacute
      pneumonitis, rapid onset of diffuse alveolar edema in the absence of necrosis,
      hepatic-portal triaditis, mononuclear-cellular infiltrate in lung and liver,
      widespread distribution of hantaviral antigen in endothelial cells of the
      microvasculature of lung and other tissues, and variable lethality. These
      similarities suggest that the MAP virus-hamster system is a useful model for
      studies of the pathogenesis of HPS and for the evaluation of potential
      therapeutic agents.

PMID- 12404154
TI  - Seroprevalence of human papillomavirus type 16 infection in the United States.
AB  - Infection with human papillomavirus (HPV) type 16 accounts for about half of
      cervical cancers worldwide. This study investigated the seroepidemiology of HPV
      16 infection in the United States by using a population-based survey. Serum
      samples and questionnaire data were collected from 1991 to 1994 for the National
      Health and Nutrition Examination Surveys. HPV-16-specific IgG antibody was
      detected by use of an HPV-16 virus-like particle ELISA. HPV-16 seropositivity in
      the US population aged 12-59 years was 13.0% (95% confidence interval, 11.5%
      14.7%). Seroprevalence was higher in women (17.9%) than in men (7.9%). Age,
      race/ethnicity, and number of lifetime sex partners were associated with HPV
      seropositivity in women. Race/ethnicity, age at first intercourse, urban/nonurban
      residence, years of sexual activity, and having had sex with a man were
      associated with HPV seropositivity in men. Information on HPV-16 seroepidemiology
      will be important for designing prevention efforts including vaccine programs.

PMID- 12404155
TI  - Intensification and stimulation therapy for human immunodeficiency virus type 1
      reservoirs in infected persons receiving virally suppressive highly active
      antiretroviral therapy.
AB  - Highly active antiretroviral therapy (HAART) has led to significant changes in
      mortality and morbidity in the human immunodeficiency virus type 1 (HIV-1)
      epidemic. Nevertheless, because of molecular mechanisms of viral persistence,
      HAART does not eradicate HIV-1. Didanosine and hydroxyurea were added to the
      antiretroviral regimens of 3 HIV-1-infected men who were receiving stable HAART
      and who had HIV-1 RNA levels <50 copies/mL at the initiation of the study
      protocol, as a novel intensification to attack cryptic viral replication; low
      dose OKT3 was then administered, followed by a course of interleukin-2, to
      stimulate latent provirus. Replication-competent virus was undetectable after
      treatment, and plasma viral RNA was either undetectable or <5 copies/mL. In trial
      periods during which no antiretroviral therapy was administered, the patients
      developed plasma viral rebound. This translational approach combines novel
      intensification and stimulation therapy to deplete residual HIV-1 reservoirs.
      Additional experimental approaches must be developed if HIV-1 eradication is to
      become possible in patients receiving virally suppressive HAART.

PMID- 12404156
TI  - Development of a novel transgenic mouse/SCID-hu mouse system to characterize the
      in vivo behavior of reservoirs of human immunodeficiency virus type 1-infected
      cells.
AB  - To develop a system in which transgenic and knockout technologies are used to
      study the in vivo behavior of human immunodeficiency virus type 1 (HIV-1)
      reservoirs, 2 different mouse models were combined: transgenic mice carrying full
      length provirus encoding the monocyte-tropic HIV-1(JR-CSF) isolate (JR-CSF mice)
      and severe combined immunodeficient mice implanted with human fetal thymus and
      liver tissues (thy/liv-SCID-hu mice). Extensive HIV-1 infection of human thymic
      implants occurred after injection of JR-CSF mouse leukocytes into thy/liv-SCID-hu
      mice, indicating that these cells provide an in vivo source of replication
      competent HIV-1. In vivo persistence of transferred JR-CSF mouse leukocytes
      carrying replication-competent HIV-1 in thy/liv-SCID-hu mice was indicated by the
      emergence of HIV-1 infection in mice that had no detectable HIV-1 infection until
      after highly active antiretroviral therapy. Thus, thy/liv-SCID-hu mice populated
      with JR-CSF mouse leukocytes, a persistent cellular reservoir harboring
      replication-competent HIV-1, present a new in vivo system for characterizing
      reservoirs of HIV-1 and evaluating therapeutic strategies designed to eliminate
      them.

PMID- 12404157
TI  - Induction of functional secretory IgA responses in breast milk, by pneumococcal
      capsular polysaccharides.
AB  - Capsule-specific secretory IgA (s-IgA) in breast milk may enhance protection
      against pneumococcal disease in infants. After immunization of 3 lactating
      mothers with 23-valent polysaccharide vaccine, specific s-IgA, but not IgG,
      increased by >2-fold in milk of at least 1 subject for 6 of 7 serotypes. The s
      IgA was predominantly IgA1, in secretory form, and highly specific with avidity
      distinct from serum IgA and IgG. Milk whey from 2 immunized women supported dose-
      and complement-dependent killing of Streptococcus pneumoniae serotypes 19F and 14
      by human neutrophils, as did purified s-IgA to serotype 19F. These data reveal
      that capsule-specific human s-IgA in breast milk can initiate killing of S.
      pneumoniae, providing proof of concept that vaccine-induced human mucosal s-IgA
      can support functional bactericidal activity. Determining the biologic role for s
      IgA in killing and inhibiting adherence of S. pneumoniae in vivo will contribute
      to the development of mucosal vaccines against S. pneumoniae.

PMID- 12404158
TI  - Detection of attenuated, noninfectious spirochetes in Borrelia burgdorferi
      infected mice after antibiotic treatment.
AB  - Xenodiagnosis by ticks was used to determine whether spirochetes persist in mice
      after 1 month of antibiotic therapy for vectorborne Borrelia burgdorferi
      infection. Immunofluorescence and polymerase chain reaction (PCR) were used to
      show that spirochetes could be found in Ixodes scapularis ticks feeding on 4 of
      10 antibiotic-treated mice up to 3 months after therapy. These spirochetes could
      not be transmitted to naive mice, and some lacked genes on plasmids correlating
      with infectivity. By 6 months, antibiotic-treated mice no longer tested positive
      by xenodiagnosis, and cortisone immunosuppression did not alter this result. Nine
      months after treatment, low levels of spirochete DNA could be detected by real
      time PCR in a subset of antibiotic-treated mice. In contrast to sham-treated
      mice, antibiotic-treated mice did not have culture or histopathologic evidence of
      persistent infection. These results provide evidence that noninfectious
      spirochetes can persist for a limited duration after antibiotics but are not
      associated with disease in mice.

PMID- 12404159
TI  - Mechanism of Clostridium difficile toxin A-induced apoptosis in T84 cells.
AB  - This study is an investigation into the mechanism of Clostridium difficile toxin
      A-induced apoptosis in human intestinal epithelial cells. Toxin A induced
      apoptosis of T84 cells in a dose- and time-dependent fashion. Toxin A-induced
      apoptosis was completely inhibited by blocking toxin enzymatic activity on Rho
      GTPases with uridine 5'-diphosphate-2',3'-dialdehyde by a nonspecific caspase
      inhibitor and was partially inhibited by caspase-1, -3, -6, -8, and -9
      inhibitors. Caspases 3, 6, 8, and 9 and Bid activation were detected. Toxin A
      also induced changes in mitochondrial membrane potential and cytochrome c release
      at 18-24 h, a time course similar to caspase-9 activation. In conclusion, toxin A
      induces apoptosis by a mechanism dependent on inactivation of Rho, activation of
      caspases 3, 6, 8, and 9 and Bid, and mitochondrial damage followed by cytochrome
      c release. Toxin A proapoptotic activity may contribute to the mucosal disruption
      seen in toxin A-induced enteritis.

PMID- 12404160
TI  - Investigation of the relationships between immune-mediated inhibition of
      mycobacterial growth and other potential surrogate markers of protective
      Mycobacterium tuberculosis immunity.
AB  - Tuberculosis (TB) vaccine development is hindered by the lack of clear surrogate
      markers of protective human immunity to Mycobacterium tuberculosis. This study
      evaluated the hypothesis that immune-mediated inhibition of mycobacterial growth
      would more directly correlate with protective TB immunity than other immunologic
      responses. Bacille Calmette-Guerin (BCG) vaccination, known to induce partial
      protection against TB, was used as a model system to investigate mechanistic
      relationships among different parameters of antigen-specific immunity. Effects of
      primary and booster intradermal BCG vaccinations were assessed in 3 distinct
      assays of mycobacterial inhibition. Correlations between vaccine-induced growth
      inhibition and other immune responses were analyzed. BCG significantly enhanced
      all antigen-specific responses. Peak responses occurred at 2 months after
      boosting. Statistical analyses suggested that each assay measured unique aspects
      of mycobacterial immunity. Despite previous evidence that type 1 immune responses
      are essential for TB immunity, interferon-gamma production did not correlate with
      mycobacterial inhibition. These results have important implications for TB
      vaccine development.

PMID- 12404161
TI  - Association of a polymorphism in the P2X7 gene with tuberculosis in a Gambian
      population.
AB  - Adenosine triphosphate (ATP) ligation of P2X(7) receptors expressed on human
      macrophages that are infected with mycobacteria induces cell death and subsequent
      loss of intracellular bacterial viability. Marked heterogeneity observed in cell
      donor ATP responsiveness suggests that this antimycobacterial mechanism may be
      genetically regulated. Five single-nucleotide polymorphisms (SNPs) previously
      identified in a putative 1.8-kb promoter region upstream of P2RX7 exon 1 were
      screened for associations with clinical tuberculosis. The frequencies of these
      promoter SNPs and a polymorphism in P2RX7 exon 13 at position 1513 were compared
      among >300 Gambian patients with tuberculosis and >160 ethnically matched control
      subjects by sequence-specific oligonucleotide hybridization and ligation
      detection reaction analysis. A significant protective association against
      tuberculosis was found for 1 promoter SNP, at nucleotide position -762 (odds
      ratio [OR] for variant C allele, 0.70; 95% confidence interval [CI], 0.54-0.89;
      P=.003; OR for CC genotype, 0.545; 95% CI, 0.318-0.934; P=.027). This association
      supports a role for ATP/P2X(7)-mediated host regulation of Mycobacterium
      tuberculosis infection.

PMID- 12404162
TI  - Ethnic-specific genetic associations with pulmonary tuberculosis.
AB  - Several susceptibility-associated genetic polymorphisms have been proposed to
      explain differential susceptibility to tuberculosis (TB) disease progression in
      different populations. Here, polymorphisms in the natural resistance-associated
      macrophage protein 1 (NRAMP1), vitamin D receptor, tumor necrosis factor-alpha,
      interleukin (IL)-1, and IL-10 genes were evaluated in 358 Cambodian patients with
      pulmonary TB and 106 tuberculin-positive control subjects. Heterozygosity for the
      -1082 polymorphism of the IL-10 promoter and heterozygosity for 2 linked
      polymorphic NRAMP1 variants, D543N and 3' untranslated region, were associated
      with TB susceptibility and resistance, respectively. Other polymorphisms
      associated with differential susceptibility to TB were not associated with
      susceptibility or resistance to TB in Cambodians. The novel pattern of genetic
      associations with susceptibility and resistance to TB detected in Cambodia is
      consistent with the conclusion that unique environmental and natural selective
      factors have resulted in the development of ethnic-specific host genetic factors
      associated with TB susceptibility and resistance worldwide.

PMID- 12404163
TI  - Chlamydial heat-shock protein-60 antibody and correlation with Chlamydia
      pneumoniae in atherosclerotic plaques.
AB  - A study was performed to determine whether serum antibody to Chlamydial heat
      shock protein-60 (CHSP-60) and C-reactive protein (CRP) were associated with the
      presence of Chlamydia pneumoniae in atheromatous plaques in 75 patients. The mean
      (+/-SD) ELISA optical density (OD) of anti-CHSP-60 was 0.19+/-0.15 in 54 patients
      with detectable C. pneumoniae antigen, versus an OD of 0.11+/-0.08 in 21 patients
      without detectable C. pneumoniae I antigen (P=.008). Higher anti-CHSP-60 at an OD
      > or =0.12 was present in 38 (70.4%) of patients with detectable C. pneumoniae in
      atheromas, compared with 5 (23.8%) of patients without C. pneumoniae antigen
      (P<.001; 2-tailed test). The mean CRP concentration was 7.4+/-10.3 mg/L in
      patients with detectable C. pneumoniae antigen, versus 5.7+/-6.1 mg/L in those
      without (P=.556). Immune response to CHSP-60 may play a role in atherogenesis,
      but CRP serum levels does not appear to be related to C. pneumoniae infection.

PMID- 12404164
TI  - Immune responses induced by repeated treatment do not result in protective
      immunity to Schistosoma haematobium: interleukin (IL)-5 and IL-10 responses.
AB  - The hypothesis that repeated treatments enhance acquired immunity against
      schistosomes by stimulating strong T helper 2 responses was tested. Schistosoma
      haematobium-infected schoolchildren were monitored for 3 years. During the first
      2 years, children who did not receive chemotherapy were compared with those
      treated once or repeatedly. After specific immune responses were measured at 24
      months, praziquantel was given to all children to clear any schistosome
      infections. Twelve months later, the infection status of the children was
      determined and compared with cytokine profiles at month 24, to gain insight into
      which immunologic profiles can predict resistance or susceptibility to
      schistosome infections. Repeated treatment led to high specific levels of
      interleukin (IL)-5 and low interferon-gamma production but did not protect
      against reinfection. After adjusting for variables, such as sex, age, and
      infection status at study onset, high levels of parasite-specific IL-10 were a
      risk factor for reinfection, and high levels of IL-5 were associated with
      hematuria development.

PMID- 12404165
TI  - Measles epidemic in the Netherlands, 1999-2000.
AB  - In 1999-2000, a measles epidemic occurred in The Netherlands, with 3292 reported
      cases; 94% of the affected patients had not been vaccinated. Only 1 patient had
      received 2 doses of vaccine. Three patients died, and 16% had complications. For
      the unvaccinated population, the incidence per 1000 inhabitants 15 months to 14
      years old increased from 83 (95% confidence interval [CI], 53-113), in
      municipalities with vaccine coverage rates < or =90%, to 200 (95% CI, 153-247),
      in municipalities with coverage rates >95%; for the vaccinated population, the
      incidence increased from 0.2 (95% CI, 0.1-0.4) to 1.4 (95% CI, 0.9-1.9).
      Unvaccinated individuals were 224 times (95% CI, 148-460 times) more likely to
      acquire measles than were vaccinated individuals; the relative risk increased
      with decreasing vaccine coverage. Herd immunity outside unvaccinated clusters was
      high enough to prevent further transmission. More case patients came from the
      vaccine-accepting population living among unvaccinated clusters than from
      individuals who declined vaccination and who lived among the vaccine-accepting
      population.

PMID- 12404166
TI  - Second-year follow-up evaluation of live, attenuated human rotavirus vaccine 89
      12 in healthy infants.
AB  - Rotavirus vaccine development is a high priority. The association between the
      tetravalent rhesus-human reassortant rotavirus vaccine and intussusception has
      increased the need to develop new vaccines. In a small efficacy trial, the human
      rotavirus vaccine 89-12 recently has been shown to be safe and effective; 184 of
      the 215 healthy infants initially enrolled in this trial were followed for a
      second year. Vaccine efficacy during the second year was 59% (P=.047). For the 2
      years of observation, vaccine efficacy was 76% against rotavirus gastroenteritis,
      83% against severe rotavirus gastroenteritis, and 100% against rotavirus
      illnesses requiring medical intervention (P<.001 for each). These encouraging
      results have led to continued evaluation, in several countries, of a vaccine
      candidate derived from strain 89-12.

PMID- 12404167
TI  - Intercontinental circulation of human influenza A(H1N2) reassortant viruses
      during the 2001-2002 influenza season.
AB  - Reassortant influenza A viruses bearing the H1 subtype of hemagglutinin (HA) and
      the N2 subtype of neuraminidase (NA) were isolated from humans in the United
      States, Canada, Singapore, Malaysia, India, Oman, Egypt, and several countries in
      Europe during the 2001-2002 influenza season. The HAs of these H1N2 viruses were
      similar to that of the A/New Caledonia/20/99(H1N1) vaccine strain both
      antigenically and genetically, and the NAs were antigenically and genetically
      related to those of recent human H3N2 reference strains, such as
      A/Moscow/10/99(H3N2). All 6 internal genes of the H1N2 reassortants examined
      originated from an H3N2 virus. This article documents the first widespread
      circulation of H1N2 reassortants on 4 continents. The current influenza vaccine
      is expected to provide good protection against H1N2 viruses, because it contains
      the A/New Caledonia/20/99(H1N1) and A/Moscow/10/99(H3N2)-like viruses, which have
      H1 and N2 antigens that are similar to those of recent H1N2 viruses.

PMID- 12404168
TI  - Human parvovirus Bb19 detection in asymptomatic blood donors: association with
      increased neopterin concentrations.
AB  - Serum neopterin concentrations were determined in 20,000 blood donations. For the
      400 donations with neopterin concentrations above the 98 th percentile and
      another 1200 donations with neopterin concentrations in the lower range, results
      of human parvovirus (HPV) B19 tests were compared. Infectious specimens were
      identified by dot blot hybridization assay and polymerase chain reaction (PCR)
      that used the outer primers and detected 1 pg of HPV B19 DNA, corresponding to
      approximately 10(5) copies of the genome, in the specimens and by a nested PCR
      that detected 1-10 fg of DNA, corresponding to 10(2)-10(3) copies of the genome.
      Of 400 specimens with neopterin concentrations > or =12 nmol/L (98th percentile,
      current cutoff), 10 tested positive by dot blot hybridization assay (9 of these
      were confirmed by nested PCR). Among 1200 specimens with low neopterin
      concentrations (<12 nmol/L), no specimen containing HPV B19 DNA was detected.
      These findings suggest an association between elevated neopterin concentrations
      and HPV B19 infectivity.

PMID- 12404169
TI  - Association of increased hepatitis C virus (HCV)-specific IgG and soluble CD26
      dipeptidyl peptidase IV enzyme activity with hepatotoxicity after highly active
      antiretroviral therapy in human immunodeficiency virus-HCV-coinfected patients.
AB  - Hepatotoxicity was investigated, using plasma collected before and during
      treatment, in 16 human immunodeficiency virus (HIV)-hepatitis C virus (HCV)
      coinfected patients who responded to highly active antiretroviral therapy
      (HAART), during a retrospective longitudinal study. Eleven patients experienced
      hepatotoxicity (i.e., a >3-fold increase in alanine aminotransferase level) while
      receiving HAART, including 4 patients with clinical hepatitis. Control subjects
      were 5 patients without hepatotoxicity. Markers of HCV-specific immune responses
      (HCV core-specific immunoglobulin G [IgG] antibody), T cell activation (soluble
      [s] CD26 dipeptidyl peptidase IV [DPP IV] enzyme activity), and inflammation
      (nitrate/nitrite and soluble tumor necrosis factor receptor I [sTNFRI] levels)
      were correlated with liver damage and immune reconstitution. All patients with
      hepatotoxicity had increased HCV core-specific IgG antibody and sCD26 (DPP IV)
      activity but did not have increased nitrate/nitrite or sTNFRI levels.
      Hepatotoxicity without clinical hepatitis was associated with increased CD8 T
      cell counts. Thus, hepatotoxicity in HIV-HCV-coinfected patients who respond to
      HAART is associated with increased HCV-specific immune responses and T cell
      activation.

PMID- 12404170
TI  - Mechanisms of early virologic failure in antiretroviral-naive patients starting
      protease inhibitor-containing regimens: the APROVIR Study.
AB  - The virologic and pharmacologic mechanisms of virologic failure (VF) were studied
      in 243 antiretroviral-naive patients starting first-line protease inhibitor (PI)
      containing therapy (nelfinavir in 66% and indinavir in 19%). Among the 220
      patients with follow-up data, VF occurred in 35 (16%) during the first year of
      follow-up. A higher baseline virus load and poorer adherence to therapy were
      associated with VF. At the time of VF, key PI-resistance mutations were detected
      in 11 (48%) of 23 patients who started on nelfinavir but were absent in 6
      patients with indinavir treatment failure. PI plasma levels were more often below
      the range of active concentrations in VF with wild-type viruses (74%) than in VF
      with PI-resistant viruses (25%; P=.02). The mechanisms of early VF and of
      selection of PI-resistant viruses differed by type of PI and were dependent on PI
      plasma levels.

PMID- 12404171
TI  - Topical administration of low-dose tenofovir disoproxil fumarate to protect
      infant macaques against multiple oral exposures of low doses of simian
      immunodeficiency virus.
AB  - Simian immunodeficiency virus (SIV) infection of infant macaques is a useful
      animal model to determine whether topical (oral) administration of antiviral
      compounds to the nursing infant could reduce human immunodeficiency virus
      transmission through breast-feeding. The reverse-transcriptase inhibitor
      tenofovir was selected because of previous demonstrations that systemic drug
      levels are effective in preventing SIV infection. To mimic the multiple exposures
      to virus during breast-feeding, 14 infant macaques were fed 15 low doses of
      SIVmac251 without chemical restraint. Six animals were treated with placebo, and
      2 groups of 4 animals received oral topical doses of tenofovir disoproxil
      fumarate (DF; equivalent to 0.037 mg of tenofovir/day). About half the animals of
      each group became infected. In a subsequent study, 2 oral inoculations of 4
      juvenile macaques with a mixture of tenofovir DF and SIVmac251 induced persistent
      infection. Topical administration of low doses of tenofovir DF did not protect
      against oral SIV infection.

PMID- 12404172
TI  - Cross-reactivity between immunodominant human T lymphotropic virus type I tax and
      neurons: implications for molecular mimicry.
AB  - Human T lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic
      paraparesis (HAM/TSP) is associated with immunoreactivity to HTLV-I tax.
      Antibodies isolated from patients with HAM/TSP and monoclonal antibodies (MAbs)
      to HTLV-I tax stained neurons. In neuronal extracts, HAM/TSP immunoglobulin G
      identified heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) as the
      autoantigen. Importantly, tax MAbs reacted with hnRNP A1. To identify the epitope
      recognized by the tax MAbs, the fine epitope specificity of the antibodies was
      determined using overlapping peptides. This analysis identified an epitope at the
      C-terminus (tax(346-353)), which overlaps a human immunodominant domain.
      Preincubation of this peptide with tax MAbs inhibited antibody binding to tax,
      hnRNP A1, and neurons. This indicates that a cross-reactive immune response
      between HTLV-I tax and neuronal hnRNP A1 is contained within the human
      immunodominant epitope of tax and suggests that molecular mimicry plays a role in
      the pathogenesis of HAM/TSP.

PMID- 12404173
TI  - Synergistic action of nitric oxide release from murine macrophages caused by
      group B streptococcal cell wall and beta-hemolysin/cytolysin.
AB  - Group B streptococcus (GBS) is the leading cause of sepsis in neonates. Nitric
      oxide (NO) release plays a role in the hypotension that characterizes septic
      shock. It has been shown that GBS beta-hemolysin/cytolysin (beta-h/c) stimulates
      the transcription of inducible NO synthase (iNOS) in murine macrophages via
      intracellular pathways similar to those that mediate lipopolysaccharide-induced
      iNOS activation. Here, it is demonstrated that the GBS cell wall and beta-h/c act
      synergistically to induce iNOS in interferon (IFN)-gamma-primed [corrected] RAW
      264.7 murine macrophages. In nonprimed macrophages, combined activation by the
      GBS cell wall plus beta-h/c is necessary to induce an NO response, which
      indicates that both virulence factors cooperate to substitute for the priming
      signal typically provided by IFN-gamma [corrected].

PMID- 12404174
TI  - Human toll-like receptor 4 mutations but not CD14 polymorphisms are associated
      with an increased risk of gram-negative infections.
AB  - Human toll-like receptor 4 (hTLR4) and CD14 are known to be components of the
      lipopolysaccharide receptor complex. Our study investigated the association
      between TLR4 mutations (Asp299Gly and Thr399Ile) and CD14 polymorphism(s) with
      outcome in an intensive care unit (ICU) population at risk for sepsis. By use of
      a polymerase chain reaction-based restriction fragment-length polymorphism
      analysis technique, the hTLR4 gene was altered in 14 (18%) of 77 ICU patients
      (all positive for systemic inflammatory response syndrome) and in 5 (13%) of 39
      volunteers. There was a significantly higher incidence of gram-negative infection
      among patients with the mutations (11 [79%] of 14), compared with that in the
      wild-type population (11 [17%] of 63; P=.004). No association between CD14
      polymorphism(s) and the incidence of infection or outcome was observed. These
      findings indicate that hTLR4 mutations are associated with an increased incidence
      of gram-negative infections in critically ill patients in a surgical setting.

PMID- 12404175
TI  - Viable but nonculturable Salmonella species recovery and systemic infection in
      morphine-treated mice.
AB  - In vivo recovery and pathogenicity of Salmonella enterica serovar Oranienburg
      that became viable but nonculturable (VNC) in food were examined. VNC cells were
      completely eliminated in normal mice but caused systemic bacteremia and were
      subsequently lethal to morphine-treated mice. Therefore, morphine-treated mice
      might be a useful bioassay for VNC Salmonella species in implicated food items.

PMID- 12404176
TI  - Seroconversion against Lutzomyia longipalpis saliva concurrent with the
      development of anti-Leishmania chagasi delayed-type hypersensitivity.
AB  - Antibody responses to salivary gland sonicate (SGS) from Lutzomyia longipalpis
      were investigated using serum samples from individuals living in an area where
      visceral leishmaniasis is endemic. Individuals were classified into 2 groups,
      according to the alteration of their responses to Leishmania chagasi antigen over
      the course of 6 months. Group 1 included children who experienced anti-L. chagasi
      seroconversion from negative to positive; group 2 included children who
      experienced delayed-type hypersensitivity (DTH) response to L. chagasi antigen
      conversion from negative to positive. Individuals who experienced seroconversion
      against L. chagasi antigens did not have increased anti-saliva antibody response,
      whereas those who developed a positive anti-L. chagasi DTH response had increased
      immunoglobulin (Ig) G, IgG1 and IgE anti-SGS antibody levels. Despite wide
      variation, serum samples from individuals in group 2 recognized more bands in SGS
      than did those from individuals in group 1. This simultaneous appearance of anti
      saliva humoral response and anti-L. chagasi cell-mediated immunity supports the
      hypothesis that induction of immune response against SGS can facilitate induction
      of a protective response against leishmaniasis.

PMID- 12404177
TI  - Identification of indigenous hepatitis E virus from a Japanese patient who
      contracted sporadic acute hepatitis in 1982.

PMID- 12404179
TI  - The changing age and seasonal profile of pertussis in British Columbia, not
      Canada.

PMID- 12404181
TI  - Structural analysis of insulin minisatellite alleles reveals unusually large
      differences in diversity between Africans and non-Africans.
AB  - The insulin minisatellite (INS VNTR) associates with susceptibility to a variety
      of diseases. We have developed a high-resolution system for analyzing variant
      repeat distributions applicable to all known minisatellite alleles, irrespective
      of size, which allows lineages of related alleles to be identified. This system
      has previously revealed extremely low structural diversity in the minisatellite
      among northern Europeans from the United Kingdom, with all alleles belonging to
      one of only three highly diverged lineages called "I," "IIIA," and "IIIB." To
      explore the origins of this remarkably limited lineage diversity, we have
      characterized an additional 780 alleles from three non-African and three African
      populations. In total, 22 highly diverged lineages were identified, with
      structural intermediates absent from extant populations, suggesting a bottleneck
      within the ancestry of all humans. The difference between levels of diversity in
      Africans and non-Africans is unusually large, with all 22 lineages identified in
      Africa compared with only three lineages seen not only in the United Kingdom but
      also in the other non-African populations. We also find evidence for
      overrepresentation of lineage I chromosomes in non-Africans. These data are
      consistent with a common out-of-Africa origin and an unusually tight bottleneck
      within the ancestry of all non-African populations, possibly combined with
      differential and positive selection for lineage I alleles in non-Africans. The
      important implications of these data for future disease-association studies are
      discussed.

PMID- 12404182
TI  - Bone growth oscillation: longitudinal metabolic process of bone growth in
      congenital adrenal hyperplasia and nonendocrine short stature.
AB  - To clarify the longitudinal metabolic process of bone growth in children, we
      observed the relationship between the level of serum osteocalcin (OC), a marker
      of bone metabolism, and growth velocity in 10 prepubertal patients with
      congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency and 9
      prepubertal patients with nonendocrine short stature (NESS), but no major
      hormonal abnormalities influencing bone metabolism. Observations were made every
      6 months over a 7-year period. In patients with CAH who exhibited a wide
      variation in growth velocity during the course of the investigation, the levels
      of OC fluctuated over a wide range, suggesting metabolically variable bone
      growth. In contrast, in patients with NESS who exhibited a relatively stable
      growth velocity, the OC level remained within a narrow range, suggesting
      metabolically stable bone growth. The meaning of such divergent metabolic
      processes of bone growth observed in CAH and NESS and its relationship to actual
      bone structure or bone intensity should be further investigated.

PMID- 12404183
TI  - Triiodothyronine supplementation for hypothalamic obesity.
AB  - Patients with suprasellar lesions develop profound hypothalamic obesity and
      listlessness with no effective treatment. We added triiodothyronine (T(3))
      supplementation in 3 such patients and present their response. All had previous
      nutritional counseling without benefit. All were treated for diabetes insipidus
      (DI) and hypopituitarism; serum free thyroxine (T(4)) level was normal. A 24-year
      old woman (pineal tumor and astrocytoma) had weight gain (4.7 kg/yr for 3 years),
      cold intolerance, fatigue, dry skin, and constipation; after T(3), she lost 14 kg
      over 27 months and reported overall improvement. Her bone mineral density also
      improved. A 10.6-year-old boy (optic glioma) was gaining 6 kg/yr for 4 years;
      after T(3) supplement, he lost 4.3 kg over 11 months. A 12-year-old girl (mixed
      germ cell tumor) had weight gain (8.3 kg/yr for 3 years) and listlessness; after
      T(3), she lost 8.1 kg over 16 months and had improved alertness. All patients
      were asymptomatic despite supraphysiologic T(3) levels. We suggest that T(3) may
      serve as a simple and effective supplement, which can promote weight loss and
      improve the well being of these patients with hypothalamic obesity.

PMID- 12404184
TI  - Apoptosis in human aortic endothelial cells induced by hyperglycemic condition
      involves mitochondrial depolarization and is prevented by N-acetyl-L-cysteine.
AB  - We investigated whether the dissipation of mitochondrial transmembrane potential
      (Delta(Psi)(m)) was involved in apoptosis of cultured human aortic endothelial
      cells (HAECs) exposed to hyperglycemic conditions (30 mmol/L glucose). In
      parallel experiments, N-acetyl-L-cysteine (NAC) was added to the culture medium
      to verify whether this antioxidant may prevent apoptosis in these cells. The
      binding of annexin V and DNA fragmentation were measured, in addition to the
      production of reactive oxygen species (ROS), the number of cells with depolarized
      mitochondria, and the intracellular glutathione (GSH) content. As compared to the
      control (5 mmol/L glucose), high-glucose treatment increases both ROS generation
      and the number of cells binding annexin V. Moreover, a simultaneous decrease of
      intracellular GSH content was observed, which was accompanied by an increased
      number of cells showing both depolarized mitochondria and fragmented DNA.
      Incubation of HAECs with high glucose in the presence of 10 mmol/L NAC prevented
      the drop of intracellular GSH content, and decreased both ROS generation and the
      number of cells committed to apoptosis. These results suggest that high glucose
      triggers the same cascade of molecular events as do other apoptosis inducers in
      other cells. Among these events, the disruption of mitochondrial membrane barrier
      function might be decisive because it causes the release of soluble proteins from
      intermembrane space, which then induce nuclear apoptotic changes.

PMID- 12404185
TI  - Effects of oral L-carnitine supplementation on in vivo long-chain fatty acid
      oxidation in healthy adults.
AB  - Despite an abundance of literature describing the basic mechanisms of action of L
      carnitine metabolism, there remains some uncertainty regarding the effects of
      oral L-carnitine supplementation on in vivo fatty acid oxidation in normal
      subjects under normal conditions. It is well known that L-carnitine normalizes
      the metabolism of long-chain fatty acids in cases of carnitine deficiency.
      However, it has not yet been shown that L-carnitine influences the metabolism of
      long-chain fatty acids in subjects without disturbances in fatty acid metabolism.
      Therefore, we investigated the effects of oral L-carnitine supplementation on in
      vivo long-chain fatty acid oxidation by measuring 1-[(13)C] palmitic acid
      oxidation in healthy subjects before and after L-carnitine supplementation (3 x 1
      g/d for 10 days). We observed a significant increase in (13)CO(2) exhalation.
      This is the first investigation to conclusively demonstrate that oral L-carnitine
      supplementation results in an increase in long-chain fatty acid oxidation in vivo
      in subjects without L-carnitine deficiency or without prolonged fatty acid
      metabolism.

PMID- 12404186
TI  - Zn metabolism affects apoptosis rate and proliferative responsiveness of PBMC
      from patients on chronic hemodialysis.
AB  - Patients with end-stage renal failure suffer from severe plasma trace metal
      deficiency that is not corrected by dialysis. Trace metals, including Zn(2+), are
      critical for cell differentiation and replication. Zn(2+)also plays important
      role in cell apoptosis. Both processes are known to be impaired in uremia. The
      present study was undertaken to evaluate the effect of Zn(2+) supplementation on
      apoptosis of cultured peripheral blood mononuclear cells (PBMC) from patients on
      chronic hemodialysis versus those from healthy control subjects, concomitantly
      with assessment of mitogen-induced cell proliferation. The results showed that
      (1) basal total cell-associated Zn(2+) was elevated in uremic PBMC, compared to
      normal controls (23.9 +/- 5.64 v 10.5 +/- 2.64 micromol/L/mg protein). The gap
      persisted following incubation in Zn(2+)-enriched medium (63.3 +/- 26.12 v 81.6
      +/- 13.4 micromol/L/mg protein, P <.005). (2) Basal proliferative response to
      phytohemagglutinin (PHA) was significantly decreased in uremic PBMC compared to
      normal controls (12,000 +/- 1,560 cpm v 16,600 +/- 1,460 cpm, P <.01). Incubation
      of uremic PBMC in Zn(2+)-enriched medium improved their proliferative response to
      PHA, yielding counts per minute significantly higher compared to their normal
      counterparts (37,000 +/- 7,500 cpm v 22,000 +/- 3,000 cpm, P <.001). (3) Basal
      apoptosis rate in uremic PBMC was significantly elevated compared to normal
      control cells (7.6% v 2.6%, P <.05). Following incubation in Zn(2+)-enriched
      medium, apoptosis was increased both in normal and uremic PBMC. Percent apoptosis
      of uremic PBMC remained significantly elevated compared to control cells (11.7% v
      5.7%). We conclude that uremic PBMC are more responsive to exogenous Zn(2+) in
      culture than their normal counterparts. This, among other abnormalities, might
      reflect an abnormal regulation of Zn(2+) transport by uremic mononuclear cell
      membranes. The resultant increase in total cell-associated Zn(2+) content
      improves poor proliferative responsiveness of uremic PBMC. On the other hand,
      increased total cell-associated Zn(2+) stimulates enhanced apoptosis in uremic
      PBMC, which, probably by eliminating defective cells, contributes to the
      functional capability of the population as a whole. The net effect of the 2
      processes is still augmentation of cell proliferation.

PMID- 12404187
TI  - Effect of ovariectomy and estradiol replacement on skeletal muscle enzyme
      activity in female rats.
AB  - In female rats, ovariectomy (OVX) is associated with increased body fat and
      insulin resistance, and estradiol replacement prevents these alterations. These
      metabolic changes related to the estrogen-deficient state might be due, in part,
      to alterations in skeletal muscle substrate metabolism. We tested the hypothesis
      that estradiol affects the regulation of enzymes involved in substrate oxidation
      and storage within skeletal muscle. Specifically, we examined enzymes involved in
      the regulation of glycogen synthesis (glycogen synthase [GS]), glycolysis
      (phosphofructokinase [PFK]), tricarboxylic acid cycle activity (citrate synthase
      [CS]), and beta-oxidation (beta-hydroxyacyl-CoA dehydrogenase [beta-HADH]).
      Twenty-two, female Sprague-Dawley rats (7 to 8 weeks old) were separated into 3
      groups: OVX + placebo (P; n = 8), OVX + estradiol (E(2); n = 8), and sham
      operated (S; n = 6). Rats from E(2) and P groups were pair-fed to the S group to
      control for OVX-induced changes in food intake. After 16 days, activities of GS,
      PFK, CS, and beta-HADH were measured in vastus medialis muscle. GS fractional
      velocity was significantly lower (P <.05) in P (mean +/- SE; 39.7% +/- 6.2%)
      compared with both S (61.9% +/- 8.8%) and E(2) (65.8% +/- 8.4%) rats. In
      addition, E(2) rats (41.4 +/- 2.0) had significantly higher (P <.05) CS activity
      than P (34.9 +/- 2.0) and S (33.9 +/- 1.4 micromol/min/g) groups. There was no
      effect of OVX or estradiol replacement on beta-HADH or PFK. Our results suggest
      that, independent of alterations in food intake, estradiol availability affects
      the regulation of enzymes involved in nonoxidative glucose disposal (GS) and
      oxidative metabolism (CS) in skeletal muscle.

PMID- 12404188
TI  - Aerobic exercise training improves insulin sensitivity independent of plasma
      tumor necrosis factor-alpha levels in older female hypertensives.
AB  - The purpose of the present study was to determine if the improvement in insulin
      sensitivity following aerobic exercise training (AEX) is associated with a
      decline in plasma tumor necrosis factor-alpha (TNF-alpha) levels. Fourteen older
      hypertensive females (age, 62 +/- 2 years) participated in a 6-month AEX program.
      Following AEX there was a significant increase in maximal aerobic capacity
      (VO(2)max) (P =.0001), and a significant decline in systolic (P =.01) and
      diastolic (P =.006) blood pressure. In addition, following AEX there was a
      significant decline in total body fat mass (P =.005), abdominal fat mass (P
      =.048), and percent body fat (P =.006). Insulin sensitivity, as assessed by the
      insulin-assisted frequently sampled intravenous glucose tolerance test (FSIVGTT),
      increased significantly following AEX (P =.007). Despite the increase in insulin
      sensitivity and the decline in body fat, plasma TNF-alpha levels were not altered
      by AEX (P =.223). No significant relationship existed among the changes in TNF
      alpha levels and the changes insulin sensitivity or any measure of body
      composition following AEX. In conclusion, in this population of older
      hypertensive females, AEX improved insulin sensitivity and lowered blood pressure
      without a reduction in plasma TNF-alpha levels.

PMID- 12404189
TI  - PPAR(gamma)2 gene Pro12Ala polymorphism may influence serum level of an adipocyte
      derived protein, adiponectin, in the Japanese population.
AB  - Adiponectin is an adipocyte-derived protein, which possesses an anti
      atherosclerotic action and improves insulin sensitivity. Peroxisome proliferator
      activated receptor gamma (PPAR(gamma)) regulates the transcription of many
      adipocyte-specific genes. A Pro12Ala polymorphism has been detected in the
      PPAR(gamma)2 gene, and this substitution has been reported to reduce
      transactivation activity in vitro. We hypothesized that individuals possessing
      this Ala12 allele may have a lower serum adiponectin level, because of the
      observation that PPAR(gamma) agonists increase the plasma adiponectin level in
      humans. To test this hypothesis, we investigated the effects of the PPAR(gamma)2
      Pro12Ala polymorphism on anthropometric and metabolic parameters, including serum
      adiponectin level, in 478 Japanese men and 117 women aged 30 to 65 years. There
      were no homozygous subjects for the Ala12 allele of the PPAR(gamma)2 gene in this
      study. Plasma adiponectin levels were significantly lower in subjects with the
      Ala12 allele in the Japanese population of both sexes, although body mass index
      (BMI), plasma glucose, serum lipids, and insulin resistance index were not
      significantly different between subjects with and without this polymorphism. It
      is suggested that the Pro12Ala polymorphism of the PPAR(gamma)2 gene may reduce
      serum adiponectin level in the Japanese population.

PMID- 12404190
TI  - Sequential estrogen-progestin replacement therapy in healthy postmenopausal
      women: effects on cholesterol efflux capacity and key proteins regulating high
      density lipoprotein levels.
AB  - Thirty healthy postmenopausal women were randomized into 2 groups that received a
      sequential combined hormone-replacement therapy (HRT) (n = 18; conjugated equine
      estrogen 0.625 mg/d for 28 days and 5 mg of medroxyprogesterone acetate during
      the last 14 days) or placebo (n = 12). Plasma samples were collected before and
      during treatment (days 0, 15, 43, 71). High-density lipoprotein (HDL) lipid
      content, lipoprotein (Lp)A-I and LpA-I:LpA-II concentration, lecithin:cholesterol
      acyl transferase activity (LCAT), phospholipid transfer protein (PLTP) activity,
      and the plasma capacity to carry out cholesterol efflux from Fu5AH cells were
      measured. Most significant changes were found within the first 15 days after HRT.
      After 71 days of HRT, we found an increase in LpA-I lipoparticles (27%) and the
      following HDL lipids: phospholipids (21%), triglycerides (45%), and free
      cholesterol (43%), as well as an increase in cholesterol efflux (12.5%). PLTP
      activity, on the other hand, decreased 21% after 71 days of treatment. No
      significant changes in LCAT activity, HDL-cholesterol ester or LpA-I:LpA-II
      particles were found. Positive correlation between cholesterol efflux and the
      variables LpA-I and HDL-phospholipids were observed. PLTP was negatively
      correlated with apolipoprotein (apo) A-I, LpA-I, and LpA-I:LpA-II. In summary,
      our study, performed during 3 hormonal cycles, shows that HRT not only modifies
      HDL-cholesterol level, but also its lipid composition and HDL lipoparticle
      distribution. HRT enhances the plasma capacity to carry out cholesterol efflux
      from the Fu5AH system and decreases the activity of PLTP, a key protein
      regulating HDL levels. Considering the protocol sampling, these results represent
      mainly the estrogenic effect of HRT.

PMID- 12404191
TI  - Urea production and leucine oxidation in malnourished children with and without
      acute infection.
AB  - We compared the kinetics of urea production and leucine oxidation in severely
      malnourished Malawian children. We tested the hypotheses that the rate of urea
      production was directly proportional to the rate of leucine oxidation and that
      the relationship between the two is altered by acute infection. Thirty-six
      marasmic children, aged 12 to 60 months, were enrolled; 26 had acute infection
      and 10 did not. The rates of urea and CO(2) production were estimated using
      primed, constant, intravenous stable isotope-labeled tracer infusions followed by
      intermittent sampling of breath and blood. The rate of urea production was
      greater in infected children when compared to uninfected children (169 +/- 85 v
      105 +/- 44 micromol urea x kg(-1) x h(-1), P <.02). For children with and without
      infection, the rates of leucine oxidation and urea production were directly
      correlated (r = 0.49 and r = 0.74, respectively; P <.01), but the slopes of the
      regression lines were different. In uninfected children the degree of wasting was
      correlated with the rates of urea production and leucine oxidation (r = 0.67 and
      r = 0.48, respectively; P <.05). These data suggest that the rates of leucine
      oxidation and urea production are both measures of nitrogen catabolism, that
      acute infection alters the relationship between the two, and that less nitrogen
      is lost as urea in children with more wasting.

PMID- 12404192
TI  - Circulating brain natriuretic peptide values in healthy men before and after
      exercise.
AB  - Circulating brain natriuretic peptide (BNP) has recently served as a marker of
      left ventricular dysfunction, while treadmill exercise has been used clinically
      for assessing cardiac problems. The current study was undertaken to investigate
      the possible effect of exercise on circulating BNP concentrations. A total of 138
      blood samples from 23 healthy men aged 23 to 27 years (mean, 25) was analyzed.
      All subjects maintained a similar diet and physical activity a week before the
      test. Plasma samples were drawn at baseline and immediately, 1 hour, 4 hours, 24
      hours, and 48 hours after exercise. Every subject completed exercise according to
      the Bruce protocol with normal electrocardiogram (EKG) results. Specimens were
      simultaneously analyzed for concentrations of plasma BNP and other biochemical
      parameters including aldosterone (Aldo), adrenocorticotropic hormone (ACTH),
      cortisol, creatine phosphokinase (CPK), triiodothyronine (T(3)), and thyroxine
      (T(4)). Hematocrit (Hct), red blood cell count (RBC), and hemoglobin (Hgb) were
      analyzed immediately after each sampling. A transient increase in plasma BNP was
      found immediately after exercise (8.21 v baseline value, 3.38 pg/mL, P <.01).
      Twenty-two percent (5/23 subjects) had values above the normal limit (18.2
      pg/mL). The Hct-corrected concentrations of plasma BNP were also significantly
      increased immediately after exercise compared with the baseline values (0.17 +/-
      0.04 v baseline, 0.07 +/- 0.01, P <.01), but returned rapidly to baseline. Weak,
      but significantly positive, relationships were found between plasma BNP and T(3)
      and T(4). Our study demonstrates that circulating BNP values increase immediately
      after treadmill exercise in young adults. The elevation did not result from
      exercise-induced hemoconcentration. BNP concentration, however, returned to
      normal levels within 1 hour after exercise. Thus, we suggest that plasma samples
      should not be taken immediately after exercise to avoid possible artifacts.

PMID- 12404193
TI  - The relationship between waist circumference and metabolic risk factors: cohorts
      of European and Chinese descent.
AB  - Waist circumference (WC) may be the best anthropometric index for identifying
      individuals at risk for cardiovascular disease (CVD) and diabetes mellitus (DM).
      The objectives of this study were to determine if the relationship between WC and
      metabolic risk factors is similar in men and women of Chinese and European
      descent, and to assess the effect of ethnicity on these relationships. Apparently
      healthy men and women of Chinese (n = 92) and European (n = 99) descent were
      recruited from hospital staff and assessed for anthropometric variables and blood
      pressure (BP), lipids, insulin, and glucose. The study cohort was stratified by
      sex, and regression analyses were performed with the various metabolic risk
      factors as the outcome and WC and ethnicity as predictors. Chinese men and women
      had significantly lower WC than European men and women. Age and metabolic risk
      factors were similar between the 2 ethnic groups except for BP. Metabolic risk
      factors significantly correlated with WC within each gender and ethnic cohort. In
      men, ethnicity was an independent predictor for total cholesterol (TC), low
      density lipoprotein cholesterol (LDL-C), triglycerides (TG), and the ratio of TC
      to high-density lipoprotein cholesterol (HDL-C) after controlling for WC. In
      women, ethnicity significantly interacted with WC as an independent predictor of
      TG, TC:HDL-C ratio, insulin, and glucose. As ethnic descent modifies the
      relationship between WC and metabolic risk factors, current WC targets derived
      from relationships in European populations are not applicable to Chinese men and
      women. Therefore, ethnic background should be considered when using WC as a
      marker of cardiovascular risk.

PMID- 12404194
TI  - Plasma homocysteine and malondialdehyde are correlated in an age- and gender
      specific manner.
AB  - Homocysteine is an independent risk factor for peripheral vascular and coronary
      artery disease. The exact mechanism by which homocysteine promotes vascular
      dysfunction is unclear, but it is speculated to involve oxidative stress. Several
      studies have investigated the role of homocysteine in promoting oxidative stress
      and have obtained conflicting results. The age and gender of the subject
      populations in these studies may have influenced the outcome. Therefore, we
      investigated whether plasma homocysteine concentrations were correlated with
      plasma malondialdehyde (MDA, a marker of oxidative stress), and if the subject's
      age and gender affected this correlation. Plasma homocysteine and MDA were
      measured in 35 premenopausal women, 14 young men, 38 postmenopausal women, and 18
      older men. Homocysteine was significantly higher in men than women (P <.01) and
      in older subjects versus younger. However, MDA was significantly greater only in
      the young men (P <.01). Furthermore, there was a significant correlation between
      homocysteine and MDA only in these young men (R(2) = 0.50, P <.01). Lastly,
      subjects undergoing a methionine load did not exhibit increased MDA despite
      significant increases in homocysteine. Since oxidative stress correlates with
      basal homocysteine only in young men and does not increase with acutely increased
      homocysteine, it is unlikely to be the result of a direct effect of homocysteine.

PMID- 12404196
TI  - Uptake of alpha-tocopherol by the mammary gland but not by white adipose tissue
      is dependent on lipoprotein lipase activity around parturition and during
      lactation in the rat.
AB  - This study was undertaken to test the potential role of changes in lipoprotein
      lipase (LPL) activity in the mammary gland and adipose tissue around parturition
      and lactation on the uptake of alpha-tocopherol in the rat. Plasma levels of
      alpha-tocopherol and triglycerides were higher in 20-day pregnant rats than in
      virgin rats, whereas its concentration was higher in the mammary gland of the
      former, and no differences were detected in adipose tissue between the groups.
      After an oral alpha-tocopherol and triglyceride load, both appeared in plasma
      faster in pregnant rats than in virgin rats, the change being even faster for
      alpha-tocopherol than for triglycerides. After 24 hours, both alpha-tocopherol
      and triglycerides in d < 1.006 lipoproteins were higher in pregnant rats than in
      virgin rats, LPL activity was higher in the mammary gland, and lower in adipose
      tissue in the former, whereas alpha-tocopherol concentration also appeared higher
      in the mammary gland of pregnant rats, and no differences were detected between
      the groups in adipose tissue. At day 13 of lactation, an oral load of alpha
      tocopherol and triglycerides caused a higher increase of plasma alpha-tocopherol
      levels than triglycerides, and this effect decreased when rats had their litter
      removed 48 hours before analysis. In these litter-removed rats, the appearance of
      alpha-tocopherol and triglycerides in plasma was higher in d < 1.006 lipoproteins
      than in lactating rats. Also, both LPL activity and alpha-tocopherol
      concentration in the mammary gland plus milk was lower in litter-removed rats
      than in the lactating rats, whereas LPL in adipose tissue was higher in the
      former, although no difference in alpha-tocopherol was found. Thus, data are
      consistent with the role of LPL activity in the mammary gland modulating the
      uptake of alpha-tocopherol during pregnancy and lactation, although this is not
      true in adipose tissue.

PMID- 12404195
TI  - Effects of berberine on glucose metabolism in vitro.
AB  - The action of berberine was compared with metformin and troglitazone (TZD) with
      regard to the glucose-lowering action in vitro. HepG2 cell line, phenotypically
      similar to human hepatocytes, was used for glucose consumption (GC) studies. Cell
      proliferation was measured by methylthiotetrazole (MTT) assay. In moderate high
      glucose concentration (11.1 mmol/L), GC of HepG2 cells was increased by 32% to
      60% (P <.001 to P <.0001) with 5 x 10(-6) mol/L to 1 x 10(-4) mol/L berberine,
      which was comparable to that with 1 x 10(-3) mol/L metformin. The glucose
      lowering effect of berberine decreased as the glucose concentration increased.
      The maximal potency was reached in the presence of 5.5 mmol/L glucose, and it was
      abolished when the glucose concentration increased to 22.2 mmol/L. The effect was
      not dependent on insulin concentration, which was similar to that of metformin
      and was different from that of TZD, whose glucose-lowering effect is insulin
      dependent. TZD had a better antihyperglycemic potency than metformin when insulin
      was added (P <.001). In the meantime, a significant toxicity of the drug to HepG2
      cells was also observed. The betaTC3 cell line was used for insulin release
      testing, and no secretogogue effect of berberine was observed. These observations
      suggest that berberine is able to exert a glucose-lowering effect in hepatocytes,
      which is insulin independent and similar to that of metformin, but has no effect
      on insulin secretion.

PMID- 12404197
TI  - Decreased blood glucose excursion by nateglinide ameliorated neuropathic changes
      in Goto-Kakizaki rats, an animal model of non-obese type 2 diabetes.
AB  - In the present study, we examined the effect of long-term suppression of
      postprandial hyperglycemia and glycemic fluctuation in Goto-Kakizaki (GK) rats, a
      type 2 diabetic animal model, by nateglinide (NG), a fast-acting hypoglycemic
      agent, on some measures of neuropathy and compared the outcome with the slow
      acting effect of glibenclamide (GC). GK rats fed twice daily were given NG (50
      mg/kg) or GC (1 mg/kg) orally before each meal for 24 weeks. The dose of NG and
      GC was determined by the data of their comparable suppressive effects on
      hyperglycemia as a total sum of glucose values after glucose load. At the end,
      there was no significant influence of treatment with NG or GC on body weight,
      fasting blood glucose, and glycated hemoglobin in GK rats. However, NG treatment
      suppressed postprandial hyperglycemia by 50% throughout the observation period,
      whereas this effect was not apparent in GC-treated rats. Delayed motor nerve
      conduction velocity was normalized by NG treatment, while GC had a partial (50%)
      effect. GK rats showed elevated contents of sorbitol and 3-deoxyglucosone in the
      sciatic nerve, and these changes were inhibited by NG treatment. Reduced
      Na(+)/K(+)-adenosine triphosphatase (ATPase) activity in GK rats was not affected
      by either NG or GC treatment. These results suggest that meticulous control of
      postprandial hyperglycemia is essential to inhibit the development of neuropathy
      in type 2 diabetes.

PMID- 12404198
TI  - Low circulating estradiol and adrenal androgens concentrations in men on
      glucocorticoids: a potential contributory factor in steroid-induced osteoporosis.
AB  - Reductions in circulating estradiol concentrations could be implicated in the
      pathogenesis of steroid-induced osteoporosis (SIOP) in men. We assessed serum
      estradiol and adrenal androgens (dehydroepiandrosterone sulfate [DHEAS] and
      androstenedione) in 77 men (group A: idiopathic osteoporosis [IOP], n = 38, aged
      [mean +/- SD] 57.7 +/- 12.1 years; group B: SIOP, n = 39, aged 55.3 +/- 13.1
      years). We also studied the relationship between bone mineral density (BMD) and
      serum estradiol in the group of men with SIOP. In group B, we observed a higher
      prevalence of low serum testosterone concentrations (<9.0 nmol/L) (P =.0052),
      which was significantly correlated with steroid dosage (r = -0.42, P =.0089) and
      estradiol concentrations (r = 0.42, P =.012). There was a significant positive
      association between BMD at the lumbar spine and serum estradiol (P =.004) in the
      men with SIOP (group B). A high proportion of subjects had low serum estradiol
      concentrations (<48 pmol/L) in both groups (group A: 44.7 %, group B: 36 %).
      Serum adrenal androgens concentrations were also significantly suppressed in
      group B (serum androstenedione-group A: 4.99 +/- 1.8; Group B: 2.1 +/- 1.6
      nmol/L; P =.0001). Serum DHEAS was undetectable in 59% of patients in group B
      versus 6% in group A (P =.001). Reductions in androstenedione also correlated
      with steroid dosage (r = -0.35, P =.01). In conclusion, the data show that
      adrenal androgens synthesis is markedly suppressed in men with SIOP. The clinical
      relevance of this finding remains to be determined. This study also shows a
      positive association between serum estradiol and BMD and a high prevalence of low
      serum estradiol in men with SIOP. Low serum estradiol may contribute to bone loss
      in men with SIOP.

PMID- 12404199
TI  - Simvastatin, transdermal patch, and oral estrogen-progestogen preparation in
      early-postmenopausal hypercholesterolemic women: a randomized, placebo-controlled
      clinical trial.
AB  - Hormone replacement therapy (HRT) seems to have a favorable influence on the
      plasma lipid profile. Only a few investigations have examined the effects of HRT
      versus hepatic hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors.
      We compared the relative effects of different hypolipidemic strategies on
      lipoproteins and coagulative parameters in women with recent-onset spontaneous
      menopause. In this 24-week, placebo-controlled trial, 60 consecutive healthy
      women aged >/= 45 years, with amenorrhea from 6 to 60 months (mean, 1.9 +/- 1.4
      years), serum follicle stimulating hormone (FSH) greater than 40 U/L, and slight
      to moderate hypercholesterolemia (low-density lipoprotein-cholesterol [LDL-C] 160
      to 250 mg/dL, high-density lipoprotein-cholesterol [HDL-C] < 75 mg/dL, and
      triglycerides < 200 mg/dL) were enrolled and randomized to dietetic advice
      (placebo group), simvastatin 10 mg, 0.625 mg of conjugated equine estrogen (CEE),
      or 50 microg estrogen transdermal patch (ETP). In the latter 2 cases, the
      progestative nomegestrol was added to estrogens (days 17 to 28 of the cicle).
      Lipoprotein parameters were evaluated after separating very-low-density
      lipoproteins (VLDLs) by ultracentrifugation, while fasting glucose and insulin,
      homocysteine, and hemocoagulative parameters were determined in plasma. Fifty
      four patients completed the trial. Total cholesterol (TC) and LDL-C significantly
      decrased in the simvastatin (-62 mg/dL [-20%] and -72 mg/dL [-30%],
      respectively), CEE (-42 mg/dL [-13%] and -45 mg/dL [-18%]), and ETP (-30 mg/dL [
      10%] and -26 mg/dL [-11%]) groups compared to baseline, but only simvastatin
      showed an effect significantly superior to diet alone. Apolipoprotein (Apo) B was
      decreased by simvastatin (-25%, P <.001) and by CEE (-10%, P <.05); again,
      simvastatin was more effective than either diet or ETP. Triglyceride
      concentration and VLDL-C were unmodified by treatments. HDL-C and Apo A-I
      significantly increased in the simvastatin group (+18% and +8%, respectively),
      while HDL-C was unmodified by both HRT regimens and Apo A-I was reduced by ETP
      treatment (-17%); lipoprotein[a] (Lp[a]) was decreased by both HRTs (-38%, P
      <.05, and -22%, P =.07, for CEE and ETP, respectively). Among coagulative
      parameters, plasminogen activator inhibitor-1 (PAI-1) was significantly reduced
      by CEE (-29%, P <.05) but not ETP treatment (+16%, P = not significant), while
      fibrinogen, antithrombin, and homocysteine were unaffected by therapy. Thus, HRT,
      particularly CEE, seems well tolerated and moderately effective in improving the
      lipid pattern and, perhaps, the coagulative/fibrinolytic balance in
      postmenopausal hypercholesterolemic women; it may represent a therapeutic option
      in slightly dyslipidemic subjects. Statins are preferred in case of more severe
      disease.

PMID- 12404200
TI  - The role of plasma fatty acid composition in endogenous glucose production in
      patients with type 2 diabetes mellitus.
AB  - Hepatic insulin resistance and increased endogenous glucose production (EGP) are
      associated with increased plasma free fatty acids (FFA). However, the
      contribution of FFA composition to the regulation of EGP is not known. Six obese
      nondiabetic subjects and 6 patients with type 2 diabetes mellitus (DM2) were
      studied after an overnight and a 3-day fast. Plasma insulin concentrations after
      an overnight fast were similar in the DM2 and nondiabetic patients (88.8 +/- 26.4
      v 57.6 +/- 12.6 pmol/L, not significant [NS]) despite increased plasma glucose
      (9.9 +/- 1.8 v 5.1 +/- 0.1 mmol/L, P <.01) and EGP (510.3 +/- 77.7 v 298.3 +/-
      18.3 micromol x m(-2) x min(-1), P <.05) in the patients with DM2. Absolute rates
      of gluconeogenesis using the heavy water method were also increased in the
      patients with DM2 (346.8 +/- 74.9 v 198.8 +/- 16.4 micromol x m(-2). min(-1), P
      <.05). No differences were observed in plasma polyunsaturated fatty acids (PUFA)
      between the diabetic and nondiabetic subjects. However, total saturated fatty
      acid (SFA) concentrations (350 +/- 37.4 v 230.9 +/- 33.3 micromol/L, P <.02) were
      significantly increased in the diabetic subjects. Rates of EGP were correlated
      with total plasma FFA concentration (r =.71, P <.01) and the concentration of SFA
      (r =.71, P <.01), but not monounsaturated fatty acids or PUFA. Rates of
      gluconeogenesis were also correlated with plasma FFA (r =.64, P <.05) and SFA (r
      =.67, P <.05). We observed no relationship between EGP and either total FFA or
      fatty acid composition after a 3-day fast. We conclude that increases in EGP are
      associated with concentrations of plasma SFA after an overnight fast.

PMID- 12404201
TI  - Whole-body insulin sensitivity, low-density lipoprotein (LDL) particle size, and
      oxidized LDL in overweight, nondiabetic men.
AB  - Insulin resistance is often accompanied by elevated plasma triglycerides (TG) and
      a preponderance of small, dense low-density lipoprotein (LDL) particles. However,
      it remains unclear whether or not insulin resistance is related to LDL particle
      size, independent of plasma TG. We sought to determine the strength of the
      relationships among these variables in a group of overweight, nondiabetic men (N
      = 34; body mass index [BMI], 25 to 35 kg/m(2); age, 50 to 75 years), as well as
      to examine the possible relation between insulin sensitivity and oxidized LDL
      (oxLDL). We also examined the strength of the relationships between these lipid
      variables and estimates of insulin sensitivity using calculated indices based on
      fasting insulin and glucose concentrations. Insulin sensitivity (Si) was
      significantly associated with total TG (r = -0.61, P <.001), very-low-density
      lipoprotein (VLDL)-TG (r = -0.60, P <.001), and LDL size (r =.414, P <.05). LDL
      size was also significantly associated with TG (r = -0.73, P <.001), VLDL-TG (r =
      -0.73, P <.001), high-density lipoprotein-cholesterol (HDL-C) (r = 0.65, P
      <.001), the quantitative insulin sensitivity check index (QUICKI) (rho = 0.46, P
      <.01), and the homeostatic model for the assessment of insulin resistance (HOMA
      IR) (rho = -0.45, P <.01). Si was a significant predictor of LDL size, with age
      and BMI also independent contributors to the variance in LDL size (R(2) = 0.172).
      However, when TG and HDL-C were added to the model, Si was no longer a
      significant predictor of LDL size. The correlation between Si and oxLDL was weak,
      but stastically significant (rho = -0.40, P =.02). These data suggest that the
      relation between Si and LDL size is largely mediated by plasma TG, and that Si is
      only weakly related to oxLDL in overweight, nondiabetic men.

PMID- 12404202
TI  - A three-day insulin-induced normoglycemia improves carbohydrate oxidation in type
      2 diabetic subjects.
AB  - Two months of a better glycemic control improve carbohydrate oxidation in type 2
      diabetes. However, this benefit is uncertain for a shorter duration. We tested
      the effect of 3 days of normoglycemia induced by an insulin infusion. Ten type 2
      diabetic subjects (body mass index [BMI], 30.0 +/- 1.1; glycosylated hemoglobin
      [HbA(1C)], 10.1 +/- 0.5) were studied twice, before and after normal glucose
      levels were maintained by a 72-hour intravenous insulin infusion. Indirect
      calorimetry was performed 1 hour before (basal) and during the 3 hours after
      (postprandial) the ingestion of a standard meal (carbohydrates, 72 g; fat, 21 g;
      protein, 32 g), at noon. Carbohydrate storage was calculated as ingested
      carbohydrate - (postprandial glycosuria + suprabasal postprandial carbohydrate
      oxidation). After normoglycemia, glucose and triglyceride levels were decreased
      (basal glucose, 13.8 +/- 1.1 mmol/L to 8.8 +/- 0.5; postprandial, 14.9 +/- 0.9 to
      11.0 +/- 0.5; basal triglycerides, 2.2 +/- 0.1 mmol/L to 1.6 +/- 0.2;
      postprandial, 2.7 +/- 0.2 to 1.9 +/- 0.2; all P <.01), C peptides were unchanged.
      Glycosuria (before, 0.30 mg/kg/min) was abolished after normoglycemia. Basal
      carbohydrate, lipid, protein oxidation, and energy production rates were
      unchanged. Postprandial carbohydrate oxidation was increased after normoglycemia
      (before, 1.33 +/- 0.38 mg/kg/min; after, 1.77 +/- 0.42; P <.05). Lipid oxidation
      and plasma free fatty acids (FFA) tended to be more suppressed by the meal after
      normoglycemia (not significant [NS]). Carbohydrate storage (before, 67,5 +/- 4.6
      g; after, 65.7 +/- 3.6; NS) and diet-induced thermogenesis did not change after
      normoglycemia. Short-term insulin-induced normoglycemia improves the postprandial
      oxidation of carbohydrates, but not their storage.

PMID- 12404203
TI  - Serum monocyte chemoattractant protein-1 is increased in chronic autoimmune
      thyroiditis.
AB  - Chemokines are a large family of cytokines, which may be involved in the
      pathogenesis of a wide variety of inflammatory or autoimmune conditions. The role
      of chemokines in chronic autoimmune thyroiditis is unknown. We sought to examine
      the role of CC chemokines in chronic autoimmune thyroiditis. We measured serum
      levels of CC chemokines, including monocyte chemoattractant protein-1 (MCP-1) and
      macrophage inflammatory protein 1a and 1b (MIP-1a and MIP-1b) in 32 women with
      chronic autoimmune thyroiditis in comparison with 2 control groups (33 apparently
      healthy women and 43 women with benign cold thyroid nodules) by enzyme-linked
      immunosorbent assay (ELISA). We found a 45% increase in serum MCP-1 levels in
      women with chronic autoimmune thyroiditis compared with either of the 2 control
      groups (P =.01). There was no difference in either serum MIP-1a (P =.69) or MIP
      1b (P =.81) levels between women with chronic autoimmune thyroiditis and
      controls. Among women with chronic autoimmune thyroiditis, women with a family
      history of hypothyroidism had a 59% increase in serum MCP-1 levels compared with
      women with no family history of hypothyroidism (P =.02). Serum MCP-1 levels were
      associated with serum levels of antithyroid peroxidase (r =.2, P =.03) (anti-TPO
      Ab) and antithyroglobulin (r =.2, P =.04) antibodies (anti-TG Ab). There was no
      association between serum MCP-1 levels and serum free thyroxine index (P =.57),
      triiodothyronine (T(3)) (P =.47) or thyroid-stimulating hormone (TSH) (P =.47)
      levels. Serum MCP-1 is increased in women with chronic autoimmune thyroiditis,
      especially in the presence of a family history of hypothyroidism, indicating a
      possible pathogenetic role for MCP-1 in this condition.

PMID- 12404204
TI  - Exogenous insulin replacement in type 2 diabetes reverses excessive hepatic
      glucose release, but not excessive renal glucose release and impaired free fatty
      acid clearance.
AB  - In type 2 diabetes renal and hepatic glucose release are increased and free fatty
      acids (FFA) clearance is reduced. Restoration of normoglycemia by exogenous
      insulin replacement normalizes overall glucose release and plasma FFA
      concentrations. However, it is unclear to what extent normalization of overall
      glucose release is due to suppression of hepatic (HGR) and renal glucose release
      (RGR) and whether the abnormal FFA clearance is improved. We therefore determined
      overall, renal, and hepatic glucose release, as well as systemic FFA release and
      clearance by tracer techniques in type 2 diabetic subjects with (DM(+)) and
      without (DM(-)) physiologic overnight insulin infusion and in nondiabetic
      volunteers (NV). Insulin infusion normalized plasma glucose (5.3 +/- 0.1 v 5.2 +/
      0.1 mmol/L in NV) and overall glucose release (10.1 +/- 0.7 v 10.6 +/- 0.4
      micromol x kg(-1) x min(-1) in NV), (both P >.9). Values in DM(-) were 9.1 +/-
      0.6 mmol/L and 14.6 +/- 0.8 micromol x kg(-1) x min(-1), respectively (both P
      <.001 v DM(+) and NV). The correction of overall glucose release in DM(+) was due
      to suppression of HGR to rates below normal (6.11 +/- 0.53 v 8.67 +/- 0.44
      micromol x kg(-1) x min(-1) in NV, P <.03). RGR remained increased (3.91 +/- 0.38
      v 1.90 +/- 0.28 micromol x kg(-1) x min(-1) in NV, P <.002) and was similar to
      DM(-) (3.97 +/- 0.33 micromol x kg(-1) x min(-1), P >.9). Insulin infusion also
      normalized plasma FFA levels (450 +/- 45 v 476 +/- 42 in NV, P >.9 and v613 +/-
      33 micromol/L in DM(-), P <.04). This was due to suppression of FFA release to
      below normal (4.04 +/- 0.45 v 5.25 +/- 0.25 micromol x kg(-1) x min(-1) in NV, P
      <.04). Plasma FFA clearance remained reduced (7.2 +/- 1.0 v 11.4 +/- 1.2 mL x kg(
      1) x min(-1) in NV, P <.04) and was similar to DM(-) (7.3 +/- 0.5 mL x kg(-1) x
      min(-1), P >.9). We conclude that in contrast to the excessive HGR, excessive RGR
      and impaired FFA clearance are not corrected by acute exogenous insulin
      replacement.

PMID- 12404205
TI  - Glucose uptake, glucose transporter GLUT4, and glycolytic enzymes in brown
      adipose tissue from rats adapted to a high-protein diet.
AB  - In vivo rates of glucose uptake, insulin-responsive glucose transporter (GLUT4)
      content, and activities of glycolytic enzymes were determined in brown adipose
      tissue (BAT) from rats adapted to a high-protein, carbohydrate-free (HP) diet.
      Adaptation to the HP diet resulted in marked decreases in BAT glucose uptake and
      in GLUT4 content. Replacement of the HP diet by a balanced control diet for 24
      hours restored BAT glucose uptake to levels above those in rats fed the control
      diet, with no changes in GLUT4 levels in 4 of 5 animals examined. BAT denervation
      of rats fed the control diet induced a 50% reduction in glucose uptake, but did
      not significantly affect the already markedly reduced BAT hexose uptake in HP
      diet-fed rats. It is suggested that the pronounced decrease in BAT glucose uptake
      in these animals is due to the combined effects of the HP diet-induced reductions
      in plasma insulin levels and in BAT sympathetic activity. Adaptation to the HP
      diet was accompanied by decreased activities of hexokinase, phosphofructo-1
      kinase, and pyruvate kinase (PK). The activity of BAT PK in HP diet-fed rats was
      reduced to about 50% of controls, and approached normal levels 24 hours after
      diet reversion. BAT denervation induced a small (15%) decrease in BAT PK activity
      in control rats, but did not affect the activity of the enzyme in HP diet-adapted
      rats. Also, denervation did not interfere with the restoration of PK activity
      induced by diet substitution. Treatment with anti-insulin serum resulted in an
      almost 50% reduction in PK activity in both innervated and denervated BAT from
      rats fed the control diet, but caused a much smaller ( thick approximate 20%)
      decrease in BAT from HP diet-fed rats. Furthermore, anti-insulin serum
      administration completely suppressed the restoration of BAT PK activity induced
      by diet reversion. These data suggest that, differently from glucose uptake, BAT
      PK activity is predominantly controlled by hormonal/metabolic factors.

PMID- 12404207
TI  - Differences in the lipolytic function of adipose tissue preparations from Black
      American and Caucasian women.
AB  - The purpose of this study was to determine the potential causes of the lower
      lipolytic rates in obese Black American women compared to obese Caucasian women.
      Subcutaneous and omental adipose tissue were obtained from subjects during
      abdominal surgery, and hormone-sensitive lipase (HSL) mass, mRNA, and activity
      were determined. HSL mRNA levels did not differ between the Black American and
      Caucasian women in either subcutaneous or omental adipose tissue. However, HSL
      mass was approximately 35% lower (P <.05) in both subcutaneous and omental
      adipose tissue of the Black Americans. Because of these differences, we measured
      HSL activity in frozen subcutaneous and omental adipose tissue, and also measured
      basal and isoproterenol-stimulated lipolytic rates in tissue fragments. No racial
      differences were found in the activity of HSL in either subcutaneous or omental
      adipose tissue. However, basal lipolytic rates in the Black Americans were 53%
      and 44% lower (P <.05) in the subcutaneous and omental fat, respectively,
      compared to the Caucasian women, despite a lack of difference in cell size
      between the 2 groups. Interestingly, the degree of stimulation by isoproterenol
      was higher in both the subcutaneous and omental adipose tissue of the Black
      American than those of the Caucasian women, resulting in equal stimulation by
      isoproterenol in the 2 groups. These results indicate that despite the lower mass
      and lower basal HSL activity in the obese Black American women, stimulation of
      HSL results in equal activity of the enzyme in the 2 races. This suggests that
      the signaling pathway of HSL stimulation is more efficient in the Black American
      women.

PMID- 12404206
TI  - Lack of effect of alpha- and beta-adrenergic inhibition on forearm glucose uptake
      despite differences in forearm blood flow in healthy humans.
AB  - Insulin has both sympathoexcitatory and vasodilatory actions. It is unclear how
      these interact to affect muscular glucose uptake. The current study was designed
      to determine the systemic and local contributions of alpha- and beta-adrenergic
      activity to muscle glucose uptake. Forearm blood flow (FBF, plethysmography),
      arterial-venous glucose difference (AV-diff), and forearm glucose uptake (FGU)
      were measured during a 40-mU/m(2)/min insulin infusion with 120 minutes of
      euglycemia in 6 normal subjects (age, 28.8 +/- 4.9 years, mean +/- SD). Each
      subject was studied 5 times, once each with intravenous propranolol (IV PROP, 80
      microg/min), intravenous phentolamine (IV PHEN, 500 microg/min), intra-arterial
      propranolol (IA PROP, 25 microg/min), intra-arterial phentolamine (IA PHEN, 12
      microg/min/100 mL forearm tissue), and saline (SAL). FBF did not change during
      insulin with SAL, IA PROP, or IV PROP, but increased during insulin with IA PHEN
      and IV PHEN (P <.05). Despite the increased glucose delivery during insulin plus
      IA PHEN and IV PHEN, FGU did not differ between study sessions at any time during
      the insulin infusion. This was due to the lower AV-diff during insulin with IA
      PHEN and IV PHEN compared to the other studies (P <.05). AV-diff negatively
      correlated with FBF at the end of the insulin infusion (P <.001) for all studies.
      In normal humans, inhibition of basal sympathetic activity does not alter
      muscular glucose uptake. The increased insulin-induced vasodilation during alpha
      adrenergic inhibition suggests that insulin-induced sympathetic activation
      prevents excess vasodilation. This inhibition does not alter glucose uptake
      because changes in flow are counterbalanced by changes in glucose extraction.

PMID- 12404209
TI  - Future research directions from HCV and alcohol workshop.

PMID- 12404214
TI  - Image of the month. Splenic artery aneurysms (SAA).

PMID- 12404215
TI  - Cancer incidence in a population-based cohort of individuals hospitalized with
      celiac disease or dermatitis herpetiformis.
AB  - BACKGROUND & AIMS: Studies of cancer risk in celiac disease (CD) or dermatitis
      herpetiformis (DH) indicate increased risks for malignant lymphoma and
      occasionally other neoplasms, but are characterized by small numbers, lack of
      systematic cancer assessment, and subjects identified from referral institutions.
      METHODS: By using Swedish population-based inpatient and cancer registry data, we
      followed-up 12,000 subjects with CD or DH, and evaluated cancer incidence by
      using standardized incidence ratios (SIR). RESULTS: Adults (but not children and
      adolescents) with CD had an elevated overall risk for cancer (SIR = 1.3) that
      declined with time and eventually reached unity. Elevated risks were found for
      malignant lymphomas, small-intestinal, oropharyngeal, esophageal, large
      intestinal, hepatobiliary, and pancreatic carcinomas. The excess occurrence of
      malignant lymphomas was confined to adults, decreased with time of follow-up
      evaluation, and decreased over successive calendar periods. Decreased risks were
      found for breast cancer. Subjects with DH had a slightly increased overall cancer
      risk (SIR = 1.2) owing to excesses of malignant lymphoma and leukemia, but no
      increases of gastrointestinal carcinomas. CONCLUSIONS: Albeit increased, the
      relative risks for lymphomas and gastrointestinal cancers in this study are lower
      (and declining) than in most previous reports. The overall cancer risk is only
      moderately increased, and nonelevated during childhood and adolescence.

PMID- 12404216
TI  - Primary chronic interstitial nephritis in Crohn's disease.
AB  - BACKGROUND & AIMS: In Crohn's disease, cases of interstitial nephritis with renal
      failure have been reported in connection with the use of mesalamine. METHODS: We
      observed 4 patients with severe interstitial nephritis proven by examination of
      kidney biopsy specimens. Renal failure was discovered before or simultaneously
      with the diagnosis of Crohn's disease, and patients were not treated with
      mesalamine. Impairment of renal function progressed to end-stage renal failure in
      3 of the 4 patients. RESULTS: Our results show that the kidney can be an
      extraintestinal target of Crohn's disease. CONCLUSIONS: Several unanswered
      questions remain concerning the frequency of interstitial nephritis in patients
      with Crohn's disease, as well as the exact role of mesalamine in the development
      of chronic interstitial nephritis.

PMID- 12404217
TI  - Calot of the triangle of Calot.

PMID- 12404218
TI  - Significance of pelvic floor muscles in anal incontinence.
AB  - BACKGROUND & AIMS: The pathophysiology of anal incontinence may be elusive using
      current parameters. Our aim was to establish the role of the levator ani in anal
      continence. METHODS: In 53 patients with anal incontinence, 30 with constipation
      as disease controls, and 15 healthy controls, we evaluated incontinence severity
      by a 0-12 scale, anorectal function by standard manometric tests, and levator ani
      contraction by a perineal dynamometer. RESULTS: Patients with incontinence
      exhibited various physiologic abnormalities (3.2 +/- 0.3 per patient), but
      multiple regression analysis showed that levator ani contraction was the
      independent variable with strongest relation to the severity of incontinence (R =
      -0.84; P < 0.0001), as well as a predictive factor of the response to treatment
      (R = 0.53; P < 0.01). Furthermore, in contrast to other physiologic parameters,
      clinical improvement in response to treatment (4.4 +/- 0.5 score vs. 7.9 +/- 0.5
      score pre; P < 0.001) was associated with a marked and significant strengthening
      of levator ani contraction (448 +/- 47 g vs. 351 +/- 35 g pre; P < 0.05).
      CONCLUSIONS: We have shown the importance of levator ani failure in understanding
      the etiology of anal incontinence and in predicting response to treatment.

PMID- 12404219
TI  - Do changes in visceral sensory function determine the development of dyspepsia
      during treatment with aspirin?
AB  - BACKGROUND & AIMS: We hypothesized that the development of dyspeptic symptoms
      during treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) would be
      linked to alterations in gastric mechanosensory function and gastric emptying.
      METHODS: In the first study, gastric mechanosensory thresholds (barostat
      technique) and gastric emptying ((13)C-octanoic breath test) were measured and
      endoscopy was performed at entry and after 5 days of treatment with aspirin (500
      mg 3 times daily) in 8 patients with functional dyspepsia (initially without
      symptoms) and 8 healthy controls. In a second, double-blind, placebo-controlled,
      cross-over study, 6 new patients with functional dyspepsia and 6 controls were
      started with either placebo or aspirin for 5 days. Sensory thresholds were tested
      after the fifth day of aspirin or placebo treatment. Abdominal symptoms were
      assessed daily. RESULTS: In the first study, 6 of 8 patients and 3 of 8 controls,
      and in the second trial 6 of 6 patients and 1 of 6 healthy subjects, developed
      dyspepsia on aspirin (P < 0.005 patients vs. healthy subjects). No symptoms
      occurred during placebo treatment. Lanza scores were not associated with
      symptoms. After aspirin, sensory thresholds increased in both studies in subjects
      without development of symptoms (by 25.9% +/- 7.9%, and 31.0% +/- 4.1%,
      respectively, all P < 0.05), whereas there was no significant increase in
      subjects who developed symptoms (-11.2% +/- 5.3% and -3.4% +/- 13.4%, all P >
      0.4). Neither thresholds nor symptoms were linked with the severity of mucosal
      damage, baseline gastric emptying (t1/2), or changes of gastric emptying (all P >
      0.4). CONCLUSIONS: Failure to increase sensory thresholds during treatment with
      aspirin is associated with the development of dyspepsia.

PMID- 12404220
TI  - Enteric nerves and interstitial cells of Cajal are altered in patients with slow
      transit constipation and megacolon.
AB  - BACKGROUND & AIMS: A variety of gastrointestinal motility disorders have been
      attributed to alterations of interstitial cells of Cajal and malformations of the
      enteric nervous system. This study evaluates both the distribution of
      interstitial cells of Cajal and the pathohistology of the enteric nervous system
      in 2 severe human colorectal motility disorders. METHODS: Colonic specimens
      obtained from patients with slow-transit constipation (n = 11), patients with
      megacolon (n = 6), and a control group (n = 13, nonobstructing neoplasia) were
      stained with antibodies against c-kit (marker for interstitial cells of Cajal)
      and protein gene product 9.5 (neuronal marker). The morphometric analysis of
      interstitial cells of Cajal included the separate registration of the number and
      process length within the different regions of the muscularis propria. The
      structural architecture of the enteric nervous system was assessed on
      microdissected whole-mount preparations. RESULTS: In patients with slow-transit
      constipation, the number of interstitial cells of Cajal was significantly
      decreased in all layers except the outer longitudinal muscle layer. The myenteric
      plexus showed a reduced ganglionic density and size (moderate hypoganglionosis)
      compared with the control group. Patients with megacolon were characterized by a
      substantial decrease in both the number and the process length of interstitial
      cells of Cajal. The myenteric plexus exhibited either complete aganglionosis or
      severe hypoganglionosis. CONCLUSIONS: The enteric nervous system and interstitial
      cells of Cajal are altered concomitantly in slow-transit constipation and
      megacolon and may play a crucial role in the pathophysiology of colorectal
      motility disorders.

PMID- 12404221
TI  - Dysregulated peripheral and mucosal Th1/Th2 response in Whipple's disease.
AB  - BACKGROUND & AIMS: An impaired monocyte function and impaired interferon (IFN)
      gamma production has been suggested as a possible pathogenetic factor in
      Whipple's disease (WD) and as a cause for the delayed elimination of Tropheryma
      whipplei in some patients. METHODS: We studied, in a series of 20 WD patients
      with various degrees of disease activity, cellular immune functions. RESULTS: We
      found an increased in vitro production of interleukin (IL)-4 by peripheral
      mononuclear blood cells as determined by enzyme-linked immunosorbent assay, but
      reduced secretion of IFN-gamma and IL-2 as compared with age- and sex-matched
      controls. In addition, we observed a significantly reduced monocyte IL-12
      production in response to various stimuli in WD patients whereas other cytokines
      were comparable with controls; these immunologic alterations were not
      significantly different in patients with various disease activities. At the
      mucosal level, we found decreased CD4 T-cell percentage and a significantly
      impaired IFN-gamma secretion. CONCLUSIONS: Our data define a defective cellular
      immune response in a large series of WD patients and point to an important
      pathogenetic role of impaired Th1 responses. The decreased monocyte IL-12 levels
      may result in reduced peripheral and mucosal IFN-gamma production and lead to an
      increased susceptibility to T. whipplei infection in certain hosts.

PMID- 12404222
TI  - Prognostic significance of calcium-binding protein S100A4 in colorectal cancer.
AB  - BACKGROUND & AIMS: Prognostication in colon cancer almost exclusively still rests
      on the tumor stage. Furthermore, tumor-derived markers to improve discrimination
      of low- and high-risk subtypes generally are not in use. S100A4 has been reported
      to be associated with invasion and metastasis; however, no data are available on
      its prognostic value in colorectal carcinoma. Therefore, we investigated the
      prognostic significance of immunohistochemical S100A4 expression in colorectal
      carcinoma compared with clinicopathologic parameters and expression of cell-cycle
      markers p16, p21, p27, p53, Ki-67, and RB. METHODS: Archival tissue from 709
      patients with colorectal cancer were retrieved, applied in tissue array
      technology, and investigated immunohistochemically. Univariate and multivariate
      survival analyses were carried out on all investigated parameters. RESULTS:
      Sixteen percent of cases showed high; 31%, low; and 53%, no S100A4 expression. In
      Kaplan-Meier analysis, S100A4 positively stained cases showed a significantly
      decreased survival time compared with negatively stained cases (P < 0.0001). In
      multivariate regression analysis, S100A4 expression emerged as a highly
      significant independent parameter (P < 0.001) with the highest relative-risk
      factor among other covariates. Nodal status (pN) lost its prognostic value if
      S100A4 was added to the model. High S100A4 expression was associated with tumor
      stage pT3/4, secondary metastasis, women, p16, and RB expression. CONCLUSIONS:
      S100A4 expression represents a highly significant prognostic marker in colorectal
      carcinoma, which is able to identify a subset of patients at high risk. In this
      respect, it is superior to established prognostic markers such as nodal status,
      pT stage, and p53 expression.

PMID- 12404223
TI  - Evolution of hepatitis C viral quasispecies after liver transplantation.
AB  - BACKGROUND & AIMS: To determine whether HCV quasispecies diversity correlated
      positively with liver disease progression after orthotopic liver transplantation
      (OLT). METHODS: We studied 11 patients undergoing OLT for HCV-related cirrhosis
      with recurrent hepatitis C in 2 groups according to the stage of hepatic fibrosis
      on follow-up. The mild group had stage 1 or 2 fibrosis; the severe group, stage 3
      or 4 fibrosis. HCV quasispecies diversity was assessed by cloning and sequencing
      in pretransplantation and posttransplantation serum samples. RESULTS: In the mild
      fibrosis group, intrasample hypervariable region 1 (HVR1) genetic distance and
      nonsynonymous substitutions increased after OLT, whereas in the severe fibrosis
      group, these parameters decreased in follow-up. In contrast, intrasample
      diversity progressed similarly in both groups in the adjacent sequences flanking
      HVR1. There was an inverse correlation between the stage of hepatic fibrosis and
      amino acid complexity after OLT. Among all patients, the estimated rate of amino
      acid change was greater initially and became more constant after 36 months.
      CONCLUSIONS: After OLT, a more complex HCV HVR1 quasispecies population was
      associated with mild disease recurrence. Among those patients with severe
      recurrent hepatitis C, HCV appeared to be under greater immune pressure. The
      greatest change in viral amino acid sequences occurred in the first 36 months
      after OLT.

PMID- 12404224
TI  - Long-term impact of renal transplantation on liver fibrosis during hepatitis C
      virus infection.
AB  - BACKGROUND & AIMS: During hepatitis C virus (HCV) infection, liver fibrosis
      progression after renal transplantation remains controversial. The aim of this
      cohort study with controls was to compare liver histopathologic features during
      HCV infection between renal transplant recipients and matched groups of
      hemodialyzed patients or controls without renal disease and untreated for HCV.
      METHODS: Each renal transplant recipient (group 1, n = 30) was matched at first
      liver biopsy (LB) using the main factors known to influence progression of
      fibrosis with one HCV hemodialyzed patient (group 2, n = 30) and one HCV-infected
      patient (nonhemodialyzed, nontransplanted; group 3, n = 30). Patients from group
      1 were also matched with those of group 3 on the time between 2 consecutive LBs
      performed 37 months apart. LBs were evaluated according to the Knodell index,
      METAVIR score, and rate of fibrosis progression per year (fibrosis unit).
      RESULTS: The rate of fibrosis progression per year between the first and second
      LBs was significantly lower (P = 0.03) in group 1 (0.067; 95% confidence
      interval: -0.05, 0.18) than group 3 (0.20; 95% confidence interval: 0.13, 0.26).
      At the second LB, the Knodell index and activity or fibrosis in METAVIR were
      lower in group 1 than group 3 (4.2 +/- 0.4 vs. 7.5 +/- 0.6, 0.5 +/- 0.1 vs. 1.3
      +/- 0.2, and 1.4 +/- 0.2 vs. 2.3 +/- 0.2 respectively, P < 0.01). CONCLUSIONS:
      Our study suggests that liver fibrosis progression is low in most HCV-infected
      renal transplant recipients with moderate liver disease at baseline.

PMID- 12404225
TI  - Study of recurrence after surgical resection of intraductal papillary mucinous
      neoplasm of the pancreas.
AB  - BACKGROUND & AIMS: The aim of this study was to determine recurrence and long
      term survival after resection of pancreatic intraductal papillary mucinous
      neoplasm and to correlate recurrence and survival with histology, extent of
      resection, and duration of follow-up. METHODS: A single pathologist, without
      knowledge of previous interpretations of histology or clinical data,
      retrospectively reviewed and classified 113 resected intraductal papillary
      mucinous neoplasms as invasive carcinoma (n = 40) or as noninvasive neoplasms
      (adenoma, borderline, or carcinoma in situ; n = 73). Data on recurrence
      (locoregional or metastatic), follow-up, and cause of death were obtained from
      patient records and/or by contacting patients and their physicians. RESULTS: In
      invasive intraductal papillary mucinous neoplasm, recurrence was similar after
      partial pancreatectomy (18/27; 67%) and total pancreatectomy (8/13; 62%) and
      occurred within 3 years of resection in 91%. Among noninvasive neoplasms, 5 of 60
      (8%) recurred after partial pancreatectomy (median follow-up, 37 months); none
      recurred after total pancreatectomy (n = 13; median follow-up, 32 months).
      Recurrence after resection in noninvasive neoplasms was diagnosed after a median
      of 40 months (range, 23-75 months); recurrence was noninvasive in 3 and invasive
      cancer in 2. Five-year survival was better for noninvasive compared with invasive
      intraductal papillary mucinous neoplasm (84.5% vs. 36%; P < 0.001). CONCLUSIONS:
      Invasive intraductal papillary mucinous neoplasm recurs frequently even after a
      complete "curative" resection and portends poor survival. In contrast,
      noninvasive intraductal papillary mucinous neoplasm recurs infrequently after
      resection, and survival is excellent regardless of the degree of epithelial
      dysplasia in the tumor.

PMID- 12404226
TI  - Beta3 adrenergic stimulation inhibits the opossum lower esophageal sphincter.
AB  - BACKGROUND & AIMS: Previous studies have identified adrenergic receptor sites in
      the lower esophageal sphincter (LES) of animals and humans. A beta3 adrenoceptor
      has been identified and cloned. The binding site for this receptor has been found
      in the rat LES in vitro. The aim of the study was to assess the role of a
      specific beta3 agonist (CL316243) on LES pressure (LESP) in vivo. METHODS:
      Anesthetized adult opossums were given CL316243 and isoproterenol intravenously
      as boluses before and after continuous infusion of L748337 (a specific beta3
      antagonist), propranolol, and bethanechol. Blood pressure, heart rate, and LESP
      were continuously recorded. RESULTS: CL316243 caused a dose-dependent maximal
      inhibition of LESP of 88.5% +/- 4.8%. The mean duration of inhibition was 62.2 +/
      9.2 minutes with minimal change in cardiovascular parameters. Isoproterenol
      caused dose-dependent maximal inhibition of 89.4% +/- 4.7% with mean duration of
      action of 5.1 +/- 0.9 minutes but was associated with significant hypotension and
      tachycardia. L748337 and propranolol significantly blocked the effects of
      CL316243 and isoproterenol, respectively. CL316243 and isoproterenol inhibited
      the bethanechol-mediated hypertensive LES. CONCLUSIONS: (1) A selective beta3
      agonist, CL316243, caused significant, prolonged, and dose-dependent inhibition
      of LESP and, unlike isoproterenol, had minimal effect on heart rate and mean
      arterial pressure. (2) The beta3 antagonist, L748337, selectively inhibited
      CL316243 without altering the isoproterenol response. (3) CL316243 and
      isoproterenol both caused inhibition of cholinergic-mediated hypertensive LESP.

PMID- 12404227
TI  - Expansion of CD8+ T cells with regulatory function after interaction with
      intestinal epithelial cells.
AB  - BACKGROUND & AIMS: Regulatory T cells play a role in the control of immune
      responses in the intestinal mucosa and their absence may predispose to
      inflammatory bowel disease (IBD). We have previously shown that T cells activated
      by intestinal epithelial cells (IECs) are suppressive in function. Our goal was
      to characterize the phenotype and function of T cells proliferating after
      interaction with IECs. METHODS: Irradiated human IECs, isolated from normal
      resection specimens, were cultured with carboxy fluorescein succinimidyl ester
      (CFSE) labeled T cells. Flow cytometric analysis of T cells was performed at days
      5-10. CD8+ T cells proliferating in culture with IECs were sorted and added to
      suppressive assays. RESULTS: The precursor frequency of T cells proliferating in
      response to IECs ranged from 0.3%-0.9%. Several subpopulations were shown to
      proliferate (CD8+CD28-/CD8+CD28+/CD4+CD25+), but one population (CD8+CD28
      CD101+CD103+) appeared to be dependent on contact with the CD8 ligand gp180.
      After sorting, culture in the presence of interleukin (IL)-7 and IL-15 allowed
      for the generation of cell lines. IEC-activated CD8+ T cells, but not
      nonactivated CD8+ T cells, were suppressive in function. Suppression belonged to
      the CD101+CD103+ subset of IEC-activated CD8+ T cells and appeared to require
      cell contact. CD8+ lamina propria T cells also showed suppressive function,
      suggesting the presence of CD8+ regulatory T cells in the mucosa. CONCLUSIONS:
      IECs are able to induce the proliferation of a small fraction of CD8+ peripheral
      T cells. The CD8+CD28- subset of IEC-activated CD8+ T cells, which express CD101
      and CD103, interacts with IECs through gp180 and has regulatory function.

PMID- 12404229
TI  - The role of dietary microparticles and calcium in apoptosis and interleukin-1beta
      release of intestinal macrophages.
AB  - BACKGROUND & AIMS: The intestinal mucosa is exposed to micron-sized, man-made
      exogenous particles (e.g., titanium dioxide) and freshly formed endogenous
      particles (calcium phosphate). A role for such microparticles in inflammation has
      been proposed, and here we examined their effects on lamina propria mononuclear
      cells. METHODS: Lamina propria mononuclear cells were isolated from patients with
      and without inflammatory bowel disease and incubated with lipopolysaccharide,
      titanium dioxide, and calcium +/- citrate, as well as a conjugate of
      lipopolysaccharide, calcium, and titanium dioxide. Interleukin-1beta and
      interleukin-1 receptor antagonist were measured by enzyme-linked immunosorbent
      assay in culture supernatants and macrophage apoptosis by flow cytometry.
      Mechanistic studies were undertaken in normal peripheral blood mononuclear cells.
      RESULTS: Baseline levels of interleukin-1beta and macrophage apoptosis were
      greater in inflammatory bowel disease than in normal lamina propria mononuclear
      cells. Lipopolysaccharide and titanium dioxide had no additional effect, but
      calcium, and more so the conjugate, induced interleukin-1beta release in
      proportion to the degree of inflammation. Citrate, used to prevent in situ
      calcium phosphate formation, negated lamina propria mononuclear cell stimulation.
      Macrophage apoptosis was also increased by calcium and the conjugate. In
      peripheral blood mononuclear cells, inhibition of caspase 1 reduced interleukin
      1beta secretion, whereas blockade of phagocytosis inhibited calcium-induced
      apoptosis and interleukin-1beta release. CONCLUSIONS: The endogenous luminal
      microparticle calcium phosphate Promotes apoptosis of intestinal macrophages.
      Concomitantly, interleukin-1beta is released, which is enhanced in the presence
      of inflamed cells and/or exogenous dietary microparticles. Endogenous or
      exogenous microparticles could aggravate the ongoing inflammation of inflammatory
      bowel disease.

PMID- 12404228
TI  - Rapid development of colitis in NSAID-treated IL-10-deficient mice.
AB  - BACKGROUND & AIMS: Interleukin (IL)-10 is an anti-inflammatory and immune
      regulatory cytokine. IL-10-deficient mice (IL-10(-/-)) develop chronic
      inflammatory bowel disease (IBD), indicating that endogenous IL-10 is a central
      regulator of the mucosal immune response. Prostaglandins are lipid mediators that
      may be important mediators of intestinal inflammation. In this study we assessed
      the role of prostaglandins in the regulation of mucosal inflammation in the IL
      10(-/-) mouse model of IBD. METHODS: Prostaglandin (PG) synthesis was inhibited
      with nonselective or cyclooxygenase (COX)-isoform selective inhibitors. Severity
      of inflammation was assessed histologically. Cytokine production was assessed by
      ribonuclease protection analysis and enzyme-linked immunosorbent assay. PGE(2)
      levels were assessed by enzyme immunoassay. COX-1 and COX-2 expression was
      assessed by Western blot analysis. RESULTS: Nonsteroidal anti-inflammatory drug
      (NSAID) treatment of wild-type mice had minimal effect on the colon. In contrast,
      NSAID treatment of 4-week-old IL-10(-/-) mice resulted in rapid development of
      colitis characterized by infiltration of the lamina propria with macrophages and
      interferon gamma-producing CD4(+) T cells. Colitis persisted after withdrawal of
      the NSAID. NSAID treatment decreased colonic PGE(2) levels by 75%. Treatment of
      IL-10(-/-) mice with sulindac sulfone (which does not inhibit PG production) did
      not induce colitis whereas the NSAID sulindac induced severe colitis. COX-1- or
      COX-2-selective inhibitors used alone did not induce IBD in IL-10(-/-) mice.
      However, the combination of COX-1- and COX-2-selective inhibitors did induce
      colitis. CONCLUSIONS: NSAID treatment of IL-10(-/-) mice results in the rapid
      development of severe, chronic IBD. Endogenous PGs are important inhibitors of
      the development of intestinal inflammation in IL-10(-/-) mice.

PMID- 12404230
TI  - Serine proteases excite myenteric neurons through protease-activated receptors in
      guinea pig small intestine.
AB  - BACKGROUND & AIMS: Serine proteases are postulated to influence gastrointestinal
      function by stimulating protease-activated receptors (PARs). This study
      identified the effects on myenteric neurons of activating PARs and investigated
      underlying mechanisms of action. METHODS: Intracellular electrophysiologic
      methods were used to study the effects of proteases on electrical and synaptic
      behavior of morphologically identified neurons in the guinea pig enteric nervous
      system. Fluorescent immunohistochemistry was used to study the chemical coding of
      neurons that responded to PARs stimulation. RESULTS: Application of thrombin,
      trypsin, or mast cell tryptase evoked slowly activating excitatory responses
      reminiscent of slow synaptic excitation in enteric neurons. Synthetic activating
      peptides for PAR-1, -2, and -4 receptors mimicked the actions of the proteases.
      The depolarizing responses evoked by PARs were insensitive to cyclooxygenase
      inhibitors and were suppressed by agents that inhibit phospholipase C (PLC) or
      block intraneuronal receptors for inositol triphosphate. A majority of PAR
      sensitive uniaxonal neurons expressed immunoreactivity for nitric oxide synthase.
      Most of the PAR-sensitive AH Dogiel morphologic type II neurons were
      immunoreactive for calbindin. CONCLUSIONS: Excitatory responses to the serine
      proteases are mediated by PAR-1, -2, and -4 receptors. The mechanism of signal
      transduction involves stimulation of PLC and intraneuronal calcium mobilization
      and is independent of prostanoid formation.

PMID- 12404231
TI  - CDX2 regulates liver intestine-cadherin expression in normal and malignant colon
      epithelium and intestinal metaplasia.
AB  - BACKGROUND & AIMS: The intestine-specific caudal-related homeobox transcription
      factor CDX2 seems to play a key role in intestinal development and
      differentiation. Inactivation of one Cdx2 allele predisposes mice to develop
      colon polyps, and loss of CDX2 expression is a feature of some poorly
      differentiated colon carcinomas in humans. Conversely, aberrant CDX2 expression
      is often seen in intestinal metaplasias in the stomach and esophagus and in some
      gastric carcinomas. To better understand CDX2 function, we sought to define CDX2
      regulated genes. METHODS: HT-29 colon cancer cells with minimal endogenous CDX2
      expression were engineered to express exogenous CDX2, and gene expression changes
      relative to control cells were assessed using high-density oligonucleotide
      arrays. RESULTS: The gene for liver intestine (LI)-cadherin (cadherin 17) was
      strongly induced by CDX2 in HT-29. In other colorectal cancer lines, endogenous
      CDX2 and LI-cadherin expression were well correlated. Activation of a ligand
      regulated form of CDX2 rapidly induced LI-cadherin gene expression, even in the
      presence of protein synthesis inhibitor. Analysis of the 5'-flanking region of
      the LI-cadherin gene defined 2 CDX2 responsive elements, and chromatin
      immunoprecipitation assays indicate CDX2 binds to the elements. In primary
      colorectal cancers and intestinal metaplasias in the stomach, CDX2 and LI
      cadherin expression were tightly correlated. CONCLUSIONS: CDX2 regulates LI
      cadherin gene expression in normal, metaplastic, and neoplastic tissues of the
      gastrointestinal tract via binding to elements in the 5'-flanking region of the
      gene. Given the well-established roles of cadherins in morphogenesis and
      differentiation, LI-cadherin may be a key factor mediating CDX2 function in
      intestinal cell fate determination.

PMID- 12404232
TI  - Motilin regulates interdigestive gastric blood flow in dogs.
AB  - BACKGROUND & AIMS: Gastric blood flow exhibits cyclical increases in phase with
      the interdigestive contractions and secretion of the stomach in dogs. The aim of
      this study is to clarify the regulatory role of motilin in interdigestive gastric
      blood flow in dogs. METHODS: Blood flow of the left gastric (LGA) and superior
      mesenteric (SMA) arteries were measured by ultrasound transit-time blood-flow
      meters in 5 conscious dogs. Motilin was infused intravenously with or without Phe
      cyclo[Lys-Tyr(3-tBu)-betaAla-]. trifluoroacetate (GM-109; motilin antagonist),
      granisetron (5-HT3 antagonist), atropine, hexamethonium (C6), phenoxybenzamine,
      propranolol, or cimetidine. RESULTS: Motilin (12.5, 25, 50, and 100 pmol x kg(-1)
      x h(-1)) induced LGA blood-flow responses, consisting of a sustained increase and
      a rapid phasic change coupled with a contraction, without affecting the blood
      pressure, heart rate, and SMA blood flow. GM-109 completely abolished the LGA,
      motility, and secretory responses to motilin (100 pmol x kg(-1) x h(-1)).
      Atropine abolished motilin-induced gastric contractions, secretion, and phasic
      changes of LGA blood flow but failed to affect the sustained flow increase.
      However, atropine partially inhibited the LGA responses to lower doses of
      motilin. The LGA flow responses to motilin were not inhibited by granisetron, C6,
      alpha-adrenergic, beta-adrenergic, or H2 blockers. Motilin induced significantly
      larger gastric vasodilatation than the equivalent doses of VIP. CONCLUSIONS:
      Motilin has a potent and selective gastric vasodilator effect, which appears to
      be mediated by both cholinergic and noncholinergic mechanisms. Motilin plays an
      important role in the regulation of interdigestive gastric blood flow in dogs.

PMID- 12404233
TI  - Restoration of acid secretion following treatment with proton pump inhibitors.
AB  - BACKGROUND & AIMS: Proton pump inhibitors (PPIs) are covalent inhibitors of the
      gastric H+,K+-adenosine triphosphatase (ATPase) forming disulfide bonds. Recovery
      of acid secretion after PPI inhibition may be due to de novo synthesis of pump
      protein and/or disulfide reduction and reactivation of inhibited pump. The half
      time of recovery of acid secretion in rats following omeprazole treatment is
      approximately 15 hours, whereas pump protein half-life is 54 hours. In humans,
      the half-life of the inhibitory effect on acid secretion is approximately 28
      hours for omeprazole and approximately 46 hours for pantoprazole. Whereas all
      PPIs bind to cysteine 813, pantoprazole additionally binds to cysteine 822,
      deeper in the membrane domain of TM6. Their different durations of action may
      reflect different rates of pump reactivation due to differing accessibility of
      the disulfides to glutathione. METHODS: Rats were stimulated and treated with 30
      mg/kg of each PPI. Gastric ATPase was prepared and reversal of inhibition of the
      H+,K+-ATPase was measured as the time-dependent restoration of activity by
      incubation with dithiothreitol or glutathione. RESULTS: One hundred percent
      reactivation of ATPase following inhibition in vivo by omeprazole or its
      enantiomers was seen with dithiothreitol and 89% with glutathione. Similar data
      were found for lansoprazole or rabeprazole. No reactivation by either reducing
      agent was seen following inhibition by pantoprazole. CONCLUSIONS: Recovery of
      acid secretion following inhibition by all PPIs, other than pantoprazole, may
      depend on both protein turnover and reversal of the inhibitory disulfide bond. In
      contrast, recovery of acid secretion after pantoprazole may depend entirely on
      new protein synthesis.

PMID- 12404234
TI  - Cyclooxygenase-2-derived lipoxin A4 increases gastric resistance to aspirin
      induced damage.
AB  - BACKGROUND & AIMS: Cyclooxygenase-2 (COX-2) has been implicated as contributing
      to mucosal defense. Acetylation of COX-2 by aspirin can result in production of
      an antiinflammatory substance, 15(R)-epi-LXA4. We determined whether aspirin
      triggered lipoxin (LX) production via COX-2 diminishes aspirin-induced damage in
      the rat stomach. METHODS: Rats were treated with aspirin plus or minus celecoxib
      or rofecoxib. Gastric generation of LXA4 was measured. Effect of exogenous LXA4
      or an LXA4 receptor antagonist on gastric resistance to aspirin-induced damage
      was examined. Aspirin-induced leukocyte adherence in mesenteric venules, and the
      effects of LXA4, were examined by intravital microscopy. RESULTS: Celecoxib and
      rofecoxib significantly increased the severity of aspirin-induced gastric damage.
      Aspirin rapidly up-regulated COX-2 expression in the stomach and caused a
      significant increase in gastric 15(R)-epi-LXA4 production, which was abolished by
      celecoxib. LXA4 dose dependently (0.25-2.5 microg/kg, intraperitoneally) reduced
      the severity of aspirin-induced gastric damage and suppressed aspirin-induced
      leukocyte adherence, whereas an LXA4 antagonist had the opposite effects.
      CONCLUSIONS: Aspirin administration results in elevated production of 15(R)-epi
      LXA4 via COX-2. LXA4 exerts very potent protective actions on the gastric mucosa.
      Co-administration of aspirin and a selective COX-2 inhibitor results in
      substantially more severe gastric injury than is produced with either agent
      alone.

PMID- 12404235
TI  - Host-dependent zonulin secretion causes the impairment of the small intestine
      barrier function after bacterial exposure.
AB  - BACKGROUND & AIMS: Enteric infections have been implicated in the pathogenesis of
      both food intolerance and autoimmune diseases secondary to the impairment of the
      intestinal barrier. On the basis of our recent discovery of zonulin, a modulator
      of small-intestinal tight junctions, we asked whether microorganisms might induce
      zonulin secretion and increased small-intestinal permeability. METHODS: Both ex
      vivo mammalian small intestines and intestinal cell monolayers were exposed to
      either pathogenic or nonpathogenic enterobacteria. Zonulin production and changes
      in paracellular permeability were monitored in Ussing chambers and micro
      snapwells. Zonula occludens 1 protein redistribution after bacteria colonization
      was evaluated on cell monolayers. RESULTS: Small intestines exposed to enteric
      bacteria secreted zonulin. This secretion was independent of either the species
      of the small intestines or the virulence of the microorganisms tested, occurred
      only on the luminal aspect of the bacteria-exposed small-intestinal mucosa, and
      was followed by a decrease in small-intestinal tissue resistance (transepithelial
      electrical resistance). The transepithelial electrical resistance decrement was
      secondary to the zonulin-induced tight junction disassembly, as also shown by the
      disengagement of the protein zonula occludens 1 protein from the tight junctional
      complex. CONCLUSIONS: This zonulin-driven opening of the paracellular pathway may
      represent a defensive mechanism, which flushes out microorganisms and contributes
      to the host response against bacterial colonization of the small intestine.

PMID- 12404236
TI  - Xenin-immunoreactive cells and extractable xenin in neuroendocrine tumors of
      duodenal origin.
AB  - BACKGROUND & AIMS: Xenin is a 25-amino acid peptide produced by specific
      endocrine cells of the duodenal mucosa. We investigated whether xenin is
      expressed in neuroendocrine tumors. METHODS: Seventy-two foregut and midgut
      neuroendocrine tumors were examined by means of immunohistochemistry, confocal
      laser microscopy with an antibody against the C-terminus of xenin, and high
      pressure liquid chromatography after acidic extraction, assessed by
      radioimmunoassay. RESULTS: We found xenin-immunoreactive cells in 23 of 26
      duodenal neuroendocrine tumors, including gastrinomas, somatostatinomas, and
      nonfunctioning and enterochromaffin cell tumors. In these tumors, up to 20% of
      the endocrine cells were xenin immunoreactive, and xenin immunoreactivity was
      concentrated in secretory granules. Xenin was coexpressed with chromogranin A. We
      found no xenin expression in gastrin-, somatostatin-, and serotonin
      immunoreactive cells. High-pressure liquid chromatography after acidic extraction
      revealed 497 +/- 285 pmol of xenin per gram of tissue in 5 duodenal gastrinomas.
      The other neuroendocrine tumors, such as bronchial carcinoids, gastric
      enterochromaffin-like cell carcinoids, gastric and ileal enterochromaffin cell
      carcinoids, insulinomas, and gastrinomas of pancreatic origin, did not contain
      immunoreactive xenin. CONCLUSIONS: Xenin is a peptide marker specific to
      neuroendocrine tumors of the duodenum. This finding may be useful in tumor
      classification and in the differential diagnosis of neuroendocrine tumors of the
      upper gut.

PMID- 12404237
TI  - High-conductance chloride channels generate pacemaker currents in interstitial
      cells of Cajal.
AB  - BACKGROUND & AIMS: Interstitial cells of Cajal (ICCs) are responsible for slow,
      wave-driven, rhythmic, peristaltic motor patterns in the gastrointestinal tract.
      The aim was to identify and characterize the ion channels that generate the
      underlying pacemaker activity. METHODS: Single ion channel recordings were
      obtained from nonenzymatically isolated ICCs and studied by using the cell
      attached and inside-out configurations of the patch clamp technique. RESULTS: A
      high-conductance chloride channel was observed in ICCs that was spontaneously and
      rhythmically active at the same frequency as the rhythmic inward currents
      defining ICC pacemaker activity, 20-30 cycles/min at room temperature. Main
      conductance levels occurred between 122-144 pS and between 185-216 pS.
      Periodicity in the channel opening coincided with periodicity in membrane
      potential change, hence, at the single channel level, chloride channels were seen
      to be associated with the generation of rhythmic changes in membrane potential.
      CONCLUSIONS: ICCs harbor high-conductance chloride channels that participate in
      the generation of pacemaker activity and may become a target for pharmacologic
      treatment of gut motor disorders.

PMID- 12404238
TI  - Global analysis of Helicobacter pylori gene expression in human gastric mucosa.
AB  - BACKGROUND & AIMS: Helicobacter pylori inhabits a highly restricted ecological
      niche in the human gastric mucosa. Microbial gene expression in the context of
      persistent infection remains largely uncharacterized. METHODS: An RNA analysis
      method, selective capture of transcribed sequences, was used in conjunction with
      genomic array hybridization to characterize H. pylori complementary DNAs (cDNAs)
      obtained from both human and experimentally infected gerbil gastric tissue
      specimens. RESULTS: Bacterial cDNAs obtained by selective capture of transcribed
      sequences from tissues hybridized to arrayed DNA fragments representing
      approximately 70% of open reading frames in the H. pylori genome. RNAs for most
      of these open reading frames were also detected by array hybridization analyses
      of total RNA prepared from the isolated H. pylori strains cultured in vitro.
      However, a subset of H. pylori RNAs detected in gastric tissue specimens was
      consistently undetectable in bacteria grown in vitro. The majority of these RNAs
      encode factors unique to H. pylori that are potentially produced in response to
      interactions with mammalian gastric mucosa. CONCLUSIONS: The combination of
      selective capture of transcribed sequences with array hybridization has allowed a
      global analysis of bacterial gene expression occurring in human tissues during a
      natural infection.

PMID- 12404239
TI  - The human bile salt export pump: characterization of substrate specificity and
      identification of inhibitors.
AB  - BACKGROUND & AIMS: The bile salt export pump (BSEP) is the major bile salt
      transporter in the liver canalicular membrane. Our aim was to determine the
      affinity of the human BSEP for bile salts and identify inhibitors. METHODS: Human
      BSEP was expressed in insect cells. Adenosine triphosphatase (ATPase) assays were
      performed, and bile salt transport studies were undertaken. RESULTS: The BSEP
      gene, ABCB11, was cloned and a recombinant baculovirus was generated. Infected
      insect cells expressed a 140-kilodalton protein that was absent in uninfected and
      in mock-infected cells. An ATPase assay showed BSEP to have a high basal ATPase
      activity. Transport assays were used to determine the Michaelis constant for
      taurocholate as 4.25 micromol/L, with a maximum velocity of 200 pmol x min(-1) x
      mg(-1) protein. Inhibition constant values for other bile salts were 11
      micromol/L for glycocholate, 7 micromol/L for glycochenodeoxycholate, and 28
      micromol/L for taurochenodeoxycholate. Cyclosporin A, rifampicin, and
      glibenclamide were proved to be competitive inhibitors of BSEP taurocholate
      transport, with inhibition constant values of 9.5 micromol/L, 31 micromol/L, and
      27.5 micromol/L, respectively. Progesterone and tamoxifen did not inhibit BSEP.
      CONCLUSIONS: The human BSEP is a high-affinity bile salt transporter. The
      relative affinities for the major bile salts differ from those seen in rodents
      and reflect the different bile salt pools. BSEP is competitively inhibited by
      therapeutic drugs. This is a potentially significant mechanism for drug-induced
      cholestasis.

PMID- 12404240
TI  - Functional expression of the canalicular bile salt export pump of human liver.
AB  - BACKGROUND & AIMS: Hepatic bile salt secretion is an essential function of
      vertebrate liver. Rat and mouse bile salt export pump (Bsep) are adenosine
      triphosphate (ATP)-dependent bile salt transporters. Mutations in human BSEP were
      identified as the cause of progressive familial intrahepatic cholestasis type 2.
      BSEP protein is highly identical with its rat and mouse orthologs and has not yet
      been functionally characterized; the effect of BSEP mutations on its function has
      also not been studied. Therefore, the aim of this study was to functionally
      characterize human BSEP. METHODS: Complementary DNA for BSEP was isolated from
      human liver and expressed with the baculovirus system in Sf9 cells. ATP-dependent
      bile salt transport assays were performed with Sf9 cell vesicles expressing BSEP
      and a rapid filtration assay. RESULTS: Cloning of human BSEP required the
      inactivation of a bacterial cryptic promoter motif within its coding region. BSEP
      expressed in Sf9 cells transports different bile salts in an ATP-dependent manner
      with Michaelis constant values as follows: taurocholate, 7.9 +/- 2.1 micromol/L;
      glycocholate, 11.1 +/- 3.3 micromol/L; taurochenodeoxycholate, 4.8 +/- 1.7
      micromol/L; tauroursodeoxycholate, 11.9 +/- 1.8 micromol/L. The rank order of the
      intrinsic clearance of bile salts was taurochenodeoxycholate > taurocholate >
      tauroursodeoxycholate > glycocholate. CONCLUSIONS: This study characterizes human
      BSEP as an ATP-dependent bile salt export pump with transport properties similar
      to its rat and mouse orthologs. Expression of BSEP in Sf9 cells will enable
      functional characterization of the consequences of mutations in the human BSEP
      gene.

PMID- 12404241
TI  - Up-regulation of components of the renin-angiotensin system in the bile duct
      ligated rat liver.
AB  - BACKGROUND & AIMS: Angiotensin II (ANG II) has profibrotic actions in the heart
      and kidney, whereas blockade of the renin angiotensin system (RAS) attenuates
      injury. This study examines whether the RAS is present in the liver and examines
      its regulation in the bile duct-ligation model of hepatic fibrogenesis. METHODS:
      Sham-operated and bile duct-ligated (BDL) Sprague-Dawley rats were studied. Gene
      and protein expression of hepatic renin, angiotensinogen, angiotensin-converting
      enzyme (ACE), and the angiotensin receptors AT1 and AT2 were assessed using real
      time reverse-transcription polymerase chain reaction, in vitro autoradiography,
      and immunohistochemistry. RESULTS: Angiotensinogen and renin messenger RNA were
      detected in sham liver but were not increased following BDL. Angiotensinogen
      protein was widely distributed in hepatocytes in both normal and injured livers,
      but in BDL livers, it was also expressed within areas of active fibrogenesis.
      Both ACE and AT1 receptor genes were up-regulated following BDL. The low level of
      ACE activity in sham animals was significantly increased in areas of active
      fibrogenesis in BDL livers. The AT1 receptor was present in both normal and
      diseased liver parenchyma, with increased AT1 receptor binding seen in fibrotic
      areas in the diseased liver. The AT2 receptor gene was not detected in normal or
      diseased liver. CONCLUSIONS: Key elements of the RAS are present in normal liver
      tissue, and there is major up-regulation of the system in the bile duct-ligated
      liver. These findings are in keeping with recent experimental studies that have
      demonstrated antifibrotic effects of RAS blockade in the bile duct-ligated liver.

PMID- 12404242
TI  - Kupffer cells participate in early clearance of syngeneic hepatocytes
      transplanted in the rat liver.
AB  - BACKGROUND & AIMS: Kupffer cells are activated shortly after deposition of
      hepatocytes in liver sinusoids, with clearance of a significant fraction of
      transplanted cells, especially when cells are entrapped in portal spaces. We
      determined whether perturbation of Kupffer cells would improve transplanted cell
      engraftment. METHODS: Dipeptidyl peptidase IV-deficient rats were used as
      recipients of syngeneic Fischer 344 rat hepatocytes. Kupffer cell function was
      analyzed by measuring phagocytic activity with carbon particle or (99m)Tc-sulfur
      colloid incorporation. Transplanted cell survival and integration in the liver
      parenchyma was determined by histochemical analysis of tissues. Transplanted cell
      proliferation was analyzed in rats conditioned with retrorsine and partial
      hepatectomy. RESULTS: Gadolinium chloride significantly impaired Kupffer cell
      function, especially in periportal areas, where transplanted cells were
      localized. Transplanted cell survival increased by approximately 2-fold in
      animals treated with gadolinium chloride 24 hours before cell transplantation. In
      gadolinium-treated rats, more transplanted cells were observed in portal vein
      radicles, as well as in liver sinusoids, albeit integration of cells in the liver
      parenchyma was slower in gadolinium-treated rats and cells separated from other
      hepatocytes in portal vein radicles that failed to exhibit bile canalicular
      reconstitution. Finally, hepatocyte transplantation in rats primed with
      retrorsine and partial hepatectomy showed accelerated kinetics of liver
      repopulation in animals pretreated with gadolinium chloride. CONCLUSIONS:
      Perturbation of Kupffer cell activity will benefit liver repopulation with cells
      and further analysis of clinically suitable approaches to exploit this mechanism
      will be appropriate.

PMID- 12404243
TI  - Gender differences in irritable bowel syndrome.
AB  - In the United States and other Western cultures, a greater number of women seek
      health care services for symptoms of functional pain disorders, including
      irritable bowel syndrome, than men. Recent clinical trials indicate that gender
      differences in responsiveness to drug therapy also occur. Several lines of
      inquiry have focused on explaining this gender-related difference due to the
      higher prevalence of these disorders in women. Evidence of a physiologic
      component is based on gender differences in gastrointestinal transit time,
      visceral sensitivity, central nervous system pain processing, and specific
      effects of estrogen and progesterone on gut function. Additional factors may play
      a role, including gender-related differences in neuroendocrine, autonomic nervous
      system, and stress reactivity, which are related to bowel function and pain.
      However, the link between these measures and gut motility or sensitivity remains
      to be clarified. Psychological characteristics, including somatization,
      depression, and anxiety as well as a history of sexual abuse, may also contribute
      to gender-related differences in the prevalence of irritable bowel syndrome.
      Although gender differences in the therapeutic benefit of serotonergic agents
      have been observed, less is known about potential differences in responsiveness
      to nondrug therapies for irritable bowel syndrome.

PMID- 12404244
TI  - American Gastroenterological Association medical position statement: nonalcoholic
      fatty liver disease.

PMID- 12404245
TI  - AGA technical review on nonalcoholic fatty liver disease.

PMID- 12404246
TI  - Cancer risk in celiac disease.

PMID- 12404247
TI  - Hepatitis C virus in solid organ transplantation: not always a bad thing?

PMID- 12404248
TI  - A biliary milestone: functional expression of the human bile salt export pump.

PMID- 12404249
TI  - Baclofen effects on esophageal function: a possible therapy for GERD?

PMID- 12404250
TI  - Methotrexate in IBD--move over 6-MP? Not so fast...

PMID- 12404251
TI  - New insights into microbially initiated gastric malignancies: beyond the usual
      suspects.

PMID- 12404253
TI  - All kidding aside with the use of lamivudine in children with chronic hepatitis
      B.

PMID- 12404258
TI  - Discussion on 3-hydroxy-3-methylglutaryl-coenzyme a reductase inhibitors reduce
      human pancreatic cancer cell invasion and metastasis.

PMID- 12404260
TI  - Controversies about the histological features of chronic HCV patients with
      persistently normal alanine transaminase levels: what can be done about the
      present definition?

PMID- 12404262
TI  - Improvement of masseter spasticity by botulinum toxin facilitates PEG placement
      in amyotrophic lateral sclerosis.

PMID- 12404263
TI  - Markov models in primary biliary cirrhosis.

PMID- 12404264
TI  - Leptin and gastric neuroendocrine system.

PMID- 12404267
TI  - Origins of the cognitive (r)evolution.
AB  - The well documented cognitive "revolution" was, to a large extent, an evolving
      return to attitudes and trends that were present prior to the advent of
      behaviorism and that were alive and well outside of the United States, where
      behaviorism had not developed any coherent support. The behaviorism of the 1920
      to 1950 period was replaced because it was unable to address central issues in
      human psychology, a failure that was inherent in part in J. B. Watson's founding
      manifesto with its insistence on the seamless continuity of human and nonhuman
      animal behavior. The "revolution" was often slow and piecemeal, as illustrated by
      four conferences held between 1955 and 1966 in the field of memory. With the
      realization that different approaches and concepts were needed to address a
      psychology of the human, developments in German, British, and Francophone
      psychology provided some of the fuel of the "revolution."

PMID- 12404268
TI  - Moral education for the elite of democracy: the classe de philosophie between
      sociology and philosophy.
AB  - In this article, I address the issues at stake in the relationship between
      sociology and philosophy in the second half of the nineteenth century by focusing
      on a debate between two parties: Emile Durkheim, who was attempting to found an
      independent scientific sociology, and the editors and collaborators of the Revue
      de metaphysique et de morale (RMM), one of the central philosophical journals of
      the period. This debate focused on the role of philosophy in secondary school
      education, but at its heart, this was a struggle between two disciplines over
      which ought to direct the formation of good citizens for Third Republic France.

PMID- 12404269
TI  - Psychology's public image in "Topics of the Times": commentary from the editorial
      page of the New York Times between 1904 and 1947.
AB  - Between 1904 and 1947, the New York Times published in a section of its editorial
      page, "Topics of the Times," 196 commentaries on psychology. Prior to World War
      I, the majority of editorials centered on Hugo Munsterberg; psychological topics
      most frequently examined after the war were the mental test, child rearing
      advice, and psychoanalysis. Although the Times was enthusiastic in its support
      for psychology in the years immediately before and after World War I, editorial
      opinion soon turned negative. Critical of psychology for promising more than it
      could deliver, being inconsistent in its assertions over time, and not rising
      above the level of common sense, Times editorials weighed heavily on the side of
      undermining, rather than promoting, psychology's credibility from the late 1920s
      to 1940s.

PMID- 12404270
TI  - When scientific knowledge becomes scientific discovery: the disappearance of
      classical conditioning before Pavlov.
AB  - In the nineteenth century, scientific materials in experimental physiology
      changed dramatically. In this context, phenomena that had been widely accepted
      were lost, sometimes to be reintroduced later as "discoveries." I describe the
      loss of the phenomenon of classical conditioning, later rediscovered by Ivan
      Pavlov. In 1896, Austrian physiologist Alois Kreidl demonstrated experimentally
      that animals anticipate the occurrence of food that is cued by a variety of
      stimuli. Kreidl stated, moreover, that the fact that animals can be called to
      food had been widely known to science since the 1830s. I describe Kreidl's work
      and discuss several factors that may have led to the disappearance of
      conditioning prior to its rediscovery by Pavlov.

PMID- 12404273
TI  - Estrogen replacement therapy for menopausal women with a history of breast
      carcinoma: results of a 5-year, prospective study.
AB  - BACKGROUND: Women with a history of breast carcinoma generally have been advised
      to avoid estrogen replacement therapy (ERT). The validity of this approach has
      been scrutinized and debated in recent years, and reassessment through
      appropriate clinical trials has been suggested. METHODS: The authors conducted a
      prospective clinical trial to assess the safety and efficacy of prolonged ERT in
      a group of menopausal women with localized (Stage I or Stage II) breast carcinoma
      and a minimum disease free interval of 2 years if estrogen receptor (ER) was
      negative or 10 years if ER status was unknown. For 5 years, the authors followed
      77 trial participants and 222 other women with clinical and prognostic
      characteristics comparable to those of the trial participants. Overall, 56 women
      were on ERT, and 243 women were not on ERT. The association of ERT with skeletal
      and lipid changes was assessed in the randomized trial participants. The effect
      of ERT on the development of recurrent or new breast carcinoma and other
      carcinomas was analyzed both in the trial participants and in the overall group.
      RESULTS: Patient and disease characteristics, such as tumor size, number of lymph
      nodes involved, ER status, menopausal status, and disease free interval were
      comparable for women who were on ERT and women who were not on ERT. These same
      parameters also were comparable for women who joined the trial and women who did
      not. ERT use was associated with modest lipid and skeletal benefits. The
      introduction of ERT did not compromise disease free survival. Two of 56 women on
      ERT (3.6%) developed a contralateral, new breast carcinoma. In the group that was
      not on ERT, 33 of 243 women (13.5%) developed new or recurrent breast carcinoma.
      There were no differences in the development of other carcinomas with respect to
      ERT. CONCLUSIONS: ERT did not compromise disease free survival in select patients
      who were treated previously for localized breast carcinoma. Larger scale
      randomized trials are needed to confirm these findings.

PMID- 12404274
TI  - Tumor necrosis factor alpha induces three-dimensional cytomorphologic
      differentiation of human anaplastic thyroid carcinoma cells through activation of
      nuclear factor kappaB.
AB  - BACKGROUND: Anaplastic thyroid carcinoma is almost uniformly fatal. Microvilli
      are an important three-dimensional (3-D) cytomorphologic feature of thyrocyte
      differentiation, because fewer microvilli are seen in less differentiated tumors.
      Differentiation therapies, such as retinoic acid and somatostatin, have been
      tested previously in experimental models of differentiated thyroid carcinoma but
      not in anaplastic thyroid carcinoma. The objective of this study was to determine
      whether tumor necrosis factor alpha (TNF-alpha) is capable of inducing 3-D
      cytomorphologic differentiation of anaplastic thyroid carcinoma cells, and, if
      so, to investigate the mechanism involved. METHODS: Anaplastic thyroid carcinoma
      cells were treated with TNF-alpha and examined for evidence of cytomorphologic
      differentiation using electron microscopy. To study the mechanism of
      differentiation, immunoblotting was used to analyze inhibitory kappaB (I-kappaB)
      proteins and electrophoretic mobility shift assays to analyze nuclear factor
      kappaB (NF-kappaB) activation. The effect of NF-kappaB SN50, a NF-kappaB
      translocation inhibitor, on cytomorphologic changes induced in anaplastic thyroid
      carcinoma cells by TNF-alpha also was studied. In addition, levels of
      thyroglobulin and vascular endothelial growth factor (VEGF) secreted into the
      culture medium were measured. RESULTS: The results showed that TNF-alpha can
      induce activation of NF-kappaB and that the activation and translocation of NF
      kappaB into the nucleus is responsible for promoting the 3-D cytomorphologic
      differentiation of anaplastic thyroid carcinoma cells, which was inhibited by the
      NF-kappaB translocation inhibitor, NF-kappaB SN50. TNF-alpha also induced
      increased thyroglobulin secretion and reduced VEGF secretion by anaplastic tumor
      cells. CONCLUSIONS: The current data suggest that TNF-alpha can induce thyrocyte
      differentiation in anaplastic thyroid carcinoma cells through NF-kappaB and that
      it merits investigation as differentiation therapy for the treatment of patients
      with anaplastic thyroid carcinoma. The authors also found that microvilli were
      useful markers for studying thyrocyte differentiation in anaplastic thyroid
      carcinoma cells.

PMID- 12404275
TI  - Telomerase activity in stage II colorectal carcinoma.
AB  - BACKGROUND: Telomerase is a ribonucleoprotein polymerase that adds telomeric
      repeats to chromosome ends. This enzyme is deficient in the majority of normal
      somatic cells, but often is reactivated during tumorigenesis. In the current
      study, the authors examined telomerase activity in human American Joint Committee
      on Cancer Stage II colorectal carcinomas and correlated it with traditional
      prognostic indicators and disease outcome. METHODS: The telomerase repeat
      amplification protocol (TRAP) was employed to determine telomerase activity in
      122 surgical specimens (from 77 male and 45 female patients) of human Stage II
      colorectal carcinoma. The primary site of the tumor was the colon in 52 cases and
      the rectum in 70 cases. Telomerase activity was correlated with traditional
      prognostic indicators such as gender, age, T classification, tumor size, tumor
      grade, and disease outcome (overall survival and disease-free survival). The
      Median follow-up for patients who still were alive was 5.8 years. RESULTS:
      Telomerase activity was detected in 80% of the tumors (98 of 122 tumors).
      Telomerase-positive patients differed from telomerase-negative patients in that
      they tended to be female (41% vs. 21%; P = 0.1), presented with primary tumors of
      the colon more frequently (49% vs. 17%; P = 0.01), and had a higher T
      classification (T(4)) (62% vs. 38%; P = 0.04). Univariate and multivariate
      analyses demonstrated a correlation between telomerase activity and disease-free
      survival (P = 0.05). CONCLUSIONS: Although a large percentage of Stage II
      colorectal carcinoma samples were positive for telomerase activity, the prognosis
      for patients with telomerase-negative tumors was found to be worse than that for
      patients with telomerase-positive tumors.

PMID- 12404276
TI  - Association of proline-directed protein kinase FA with tumorigenesis, invasion,
      and poor prognosis of human colon carcinoma.
AB  - BACKGROUND: Initial studies revealed that the multisubstrate proline-directed
      protein kinase F(A) (PDPK F(A)) is overexpressed in various types of human
      carcinomas relative to normal controls. Suppression of overexpressed PDPK F(A)
      inhibits the growth of cancer cells, suggesting a role of this PDPK in human
      malignancy. In this study, we combine immunohistologic, molecular, cellular,
      animal, and clinicopathologic studies to demonstrate an essential and critical
      role of PDPK F(A) in progression and poor prognosis of human colon carcinoma.
      METHODS: The stable antisense clones of human colon carcinoma cells with specific
      suppression of PDPK F(A) were established for tumorigenesis and invasion studies.
      In immunohistologic and clinicopathologic studies, the expression and
      localization of PDPK F(A) were analyzed by immunohistochemical staining of the
      specimens obtained from human colon carcinoma patients with Dukes Stage B/C.
      RESULTS: Initial molecular and cellular studies revealed that the antisense clone
      of colon carcinoma cells (COLO-205) with specific suppression of PDPK F(A)
      dramatically lost capabilities of adhesion, chemotaxis, and invasion when
      compared with the parental or control-transfected colon carcinoma cells. This is
      the first indication of an association of overexpressed PDPK F(A) with colon
      carcinoma progression. In agreement with this notion, the in vivo study also
      revealed that the mice injected with the antisense clone with low-level PDPK F(A)
      only developed very small tumors (< 0.5 cm(3)) even after a 6-week observation.
      This is in contrast to the parental or control-transfected cells that developed
      large tumors (> 5 cm(3)) under identical conditions. Pathologic evaluation
      revealed invasion to the muscle layer in all tumors formed by the parental cells.
      In contrast, there was no sign of invasion in mice injected with the antisense
      clone, confirming an essential role of PDPK F(A) in colon carcinoma progression.
      Clinicopathologic study also revealed that PDPK F(A) is preferentially
      overexpressed in the invasive area of colon carcinomatous tissues and
      overexpression of PDPK F(A) is statistically and closely correlated with
      venous/lymphatic infiltration, lymph node metastasis, and poor prognosis of colon
      carcinoma patients with Dukes Stage B/C. CONCLUSIONS: The results demonstrate an
      essential and critical role of overexpressed PDPK F(A) in progression and poor
      prognosis of colon carcinoma patients. Suppression of overexpressed PDPK F(A) may
      provide a new powerful adjuvant approach to prevent human colon carcinoma
      progression and poor prognosis after surgery and chemotherapy.

PMID- 12404277
TI  - Comparison of selection strategies for genetic testing of patients with
      hereditary nonpolyposis colorectal carcinoma: effectiveness and cost
      effectiveness.
AB  - BACKGROUND: Molecular testing for hereditary nonpolyposis colorectal carcinoma
      (HNPCC) is becoming standard care and it is cost-effective compared with no
      genetic testing. However, the best strategy for detection of HNPCC gene carriers
      is unknown. METHODS: We use a decision analytic model to evaluate the
      effectiveness and incremental cost-effectiveness of four commonly used testing
      strategies to detect HNPCC gene carriers. The model starts with a population of
      colorectal carcinoma (CRC) patients and measures costs, the number of gene
      carriers detected, and incremental costs per gene carrier detected. RESULTS: We
      found that germline testing on only those CRC probands who meet the Amsterdam
      criteria detects the fewest gene carriers and has the lowest cost whereas tumor
      microsatellite instability (MSI) testing of all CRC patients and families has the
      highest cost and detects the most gene carriers. When cost-effectiveness is
      considered, the mixed strategy (MSH2 and MLH1 testing on those who meet the
      Amsterdam criteria and germline testing for the remainder who meet less stringent
      modified criteria and are MSI-High) seems superior. The mixed strategy detects
      59.6 mutation carriers per 1000 CRC cases and costs much less than the test all
      strategy, which has an incremental cost-effectiveness of $51,151. The mixed
      strategy often other strategies and when compared to the Amsterdam strategy, has
      a cost-effectiveness of only $6441 per gene carrier detected. CONCLUSIONS: It is
      not very effective to limit genetic testing to only individuals who meet the
      Amsterdam criteria, as many gene carriers are missed. However, testing all CRC
      patients for tumor MSI-H, although effective, may be prohibitively expensive. A
      mixed strategy is the more cost-effective approach.

PMID- 12404278
TI  - Testicular carcinoma and HLA Class II genes.
AB  - BACKGROUND: The association with histocompatibility antigens (HLA), in particular
      Class II genes (DQB1, DRB1), has recently been suggested to be one of the genetic
      factors involved in testicular germ cell tumor (TGCT) development. The current
      study, which uses genotyping of microsatellite markers, was designed to replicate
      previous associations. METHODS: In 151 patients, along with controls comprising
      parents or spouses, the HLA region (particularly Class II) on chromosome 6p21 was
      genotyped for a set of 15 closely linked microsatellite markers. RESULTS: In both
      patients and controls, strong linkage disequilibrium was observed in the
      genotyped region, indicating that similar haplotypes are likely to be identical
      by descent. However, association analysis and the transmission disequilibrium
      test did not show significant results. Haplotype sharing statistics, a haplotype
      method that derives extra information from phase and single marker tests, did not
      show differences in haplotype sharing between patients and controls. CONCLUSION:
      The current genotyping study did not confirm the previously reported association
      between HLA Class II genes and TGCT. As the HLA alleles for which associations
      were reported are also prevalent in the Dutch populations, these associations are
      likely to be nonexistent or much weaker than previously reported.

PMID- 12404279
TI  - Selective aromatase inhibition for patients with androgen-independent prostate
      carcinoma.
AB  - BACKGROUND: First and second-generation aromatase inhibitors have shown activity
      in patients with androgen-independent prostate carcinoma. These early-generation
      aromatase inhibitors are nonselective, however, and inhibition of other
      steroidogenic enzymes may contribute to their reported clinical activity. The
      authors conducted a Phase II clinical study of letrozole to determine the safety
      and efficacy of a potent and selective third-generation aromatase inhibitor in
      men with androgen-independent prostate carcinoma. METHODS: Forty-three men with
      androgen-independent prostate carcinoma were treated with oral letrozole (2.5 mg
      daily). Treatment was continued until progressive disease or Grade 3 toxicity
      developed. Response and progressive disease were defined according to
      recommendations of the Prostate Specific Antigen Working Group. RESULTS: In
      total, 380 weeks of treatment were administered to the 43 study patients. The
      median duration of treatment was 8 weeks. Forty men discontinued treatment due to
      progressive disease. Only one patient responded to treatment with a sustained
      decrease > 50% in serum prostate specific antigen (PSA) levels. Three other
      patients experienced transient minor decreases (< 50%) in serum PSA levels. There
      were no serious treatment-related adverse events. CONCLUSIONS: Selective
      aromatase inhibition with letrozole is not active in men with androgen
      independent prostate carcinoma.

PMID- 12404280
TI  - Metastatic renal cell carcinoma to the thyroid gland: a clinicopathologic study
      of 36 cases.
AB  - BACKGROUND: Clear cell tumors of the thyroid gland in general are uncommon.
      Metastatic renal cell carcinoma (RCC) to the thyroid gland is a rare occurrence
      but must be considered in the differential diagnosis of a thyroid gland clear
      cell neoplasm to prevent misclassification, potentially resulting in
      inappropriate clinical management. METHODS: Thirty-six cases of metastatic RCC to
      the thyroid were retrospectively retrieved from the files of the Endocrine
      Registry of the Armed Forces Institute of Pathology. RESULTS: The tumors occurred
      in 22 women and 14 men, ages 53-80 years (mean, 64.9 years). Symptoms were
      present for a mean of 13.0 months. The tumors generally affected a single lobe of
      the thyroid gland as a solitary mass (n = 30; 83%), measuring 1.0-15.0 cm in
      diameter (mean, 3.8 cm). Histologically, the tumors were composed of polygonal
      cells with clear cytoplasm, distinct cell membranes, and small compact eccentric
      nuclei within a rich vascular network. Diastase-sensitive, periodic acid-Schiff
      positive material (n = 22; 61%) and/or Oil Red O-positive material (n = 5; 14%)
      were noted. Thyroglobulin immunohistochemistry was negative in the foci of
      metastatic RCC. Although the majority of the patients had documented previous
      evidence of an RCC (n = 23; 64%) as remotely as 21.8 years before the thyroid
      metastases (mean, 9.4 years), the metastatic tumor to the thyroid gland was the
      initial manifestation of RCC in 13 patients. The majority of patients (n = 23;
      64%) died with disseminated disease (mean, 4.9 years), but 13 patients (36%) were
      alive or had died without evidence of disease (mean, 9.1 years). CONCLUSIONS: In
      the presence of a clear cell tumor of the thyroid gland, the diagnostic
      considerations must include metastatic RCC. The light microscopic features may
      suggest this possibility and the diagnosis can be established by supplemental
      histochemical and immunohistochemical studies. Surgical treatment of the
      metastatic disease is suggested, as this may result in prolonged patient
      survival.

PMID- 12404281
TI  - Irinotecan plus cisplatin has substantial antitumor effect as salvage
      chemotherapy against germ cell tumors.
AB  - BACKGROUND: Only 20-30% of patients with refractory or recurrent germ cell tumors
      (GCT) are cured by salvage chemotherapy. Irinotecan, a new derivative of
      camptothecin, is a potent anticancer agent against a variety of solid cancers.
      The current pilot study investigated the efficacy of salvage chemotherapy with
      irinotecan in combination with cisplatin (CDDP) or nedaplatin (NDP), a derivative
      of cisplatin, for GCT. METHODS: The combination chemotherapy consisted of 100-150
      mg/m(2) irinotecan on Days 1 and 15 or 200-300 mg/m(2) on Day 1 in combination
      with 20 mg/m(2) CDDP on Days 1-5 or 100 mg/m(2) NDP on Day 1 every 4 weeks.
      Patients with refractory GCT, ranging in age from 17 to 43 years, received 2-11
      cycles of the combination chemotherapy. The median duration of follow-up is 28
      months (8-140 months). RESULTS: Twenty patients entered this study, 18 of whom
      were assessed for response and toxicity. The response rate was 50 % (two complete
      responses and seven partial responses). Nine patients remain alive without
      disease. However, six patients died of the disease and one patient died of a
      brain glioma. The 5-year survival rate was approximately 53%. Myelosuppression
      was the major toxicity, but was manageable. CONCLUSIONS: This pilot study
      demonstrates that the chemotherapy with irinotecan in combination with CDDP or
      NDP showed significant anticancer activity for patients with refractory GCT,
      without serious side effects. Although this study comprised only a few patients,
      these findings suggest that the combination chemotherapy may be one of the
      options of salvage chemotherapy for patients with refractory GCT.

PMID- 12404282
TI  - Comparative analysis of CA125, tissue polypeptide specific antigen, and soluble
      interleukin-2 receptor alpha levels in sera, cyst, and ascitic fluids from
      patients with ovarian carcinoma.
AB  - BACKGROUND: The serum markers CA125, tissue polypeptide specific antigen (TPS),
      and soluble interleukin-2 receptor alpha (sIL-2Ralpha) concentrations were
      determined in sera, cyst, and ascitic fluids from patients with malignant and
      benign ovarian neoplasms. METHODS: CA125, TPS, and sIL-2Ralpha concentrations
      were measured in sera, cyst, and ascitic fluids by immunoassays in 67 patients
      with carcinoma and in 32 patients with benign ovarian neoplasms. RESULTS: CA125,
      TPS, and sIL-2Ralpha levels were elevated significantly in sera from patients who
      had ovarian carcinoma compared with patients who had benign neoplasms (P <
      0.001). Patients who had International Federation of Gynecology and Obstetrics
      (FIGO) Stage III-IV disease had significantly higher serum levels for the markers
      studied compared with patients who had FIGO Stage I-II disease (P < 0.001 for
      CA125; P = 0.02 for TPS and sIL-2Ralpha). Concurrent measurement of CA125 and sIL
      2Ralpha in sera identified 100% of ovarian carcinomas in FIGO Stage I-II. All
      patients with carcinoma demonstrated markedly higher levels of CA125 and TPS for
      both cyst and ascites compared with corresponding sera (P < 0.001). The level of
      sIL-2Ralpha was higher statistically in ascitic fluid compared with the level in
      serum (P < 0.001); however, its values in sera and cyst fluids were comparable.
      In ascitic fluid, the CA125 level was significantly higher in patients who had
      FIGO Stage III-IV disease compared with patients who had FIGO Stage I-II disease
      (P = 0.002), whereas such correlations were not found for TPS or sIL-2Ralpha. In
      cyst fluids, the levels of all studied markers were independent of the FIGO
      stage. In cyst fluids from patients with benign ovarian neoplasms, TPS and sIL
      2Ralpha levels were significantly lower compared with the levels in patients with
      ovarian carcinoma (P < 0.001), whereas the values of CA125 were overlapping.
      CA125 and TPS concentrations were higher in cyst fluids compared with
      corresponding sera, whereas sIL-2Ralpha levels were comparable and low in cyst
      fluids and in the circulation of patients with benign neoplasms. CONCLUSIONS: In
      patients with ovarian carcinoma, TPS and CA125 concentrations were significantly
      higher in the place of their generation compared with the concentrations in blood
      circulation. sIL-2Ralpha values were higher in ascites compared with the values
      in corresponding sera, and its concentrations in sera and cyst fluids were
      comparable. The assessment of serum sIL-2Ralpha levels showed potential
      complementary value to CA125 for the detection of ovarian carcinoma in early FIGO
      stages; however, a 9% false positive rate limited the significance of cumulative
      value for a combination of these circulating markers.

PMID- 12404283
TI  - Analysis of survival after laparoscopy in women with endometrial carcinoma.
AB  - BACKGROUND: The effect of the laparoscopic surgical approach on the survival of
      women with endometrial carcinoma remains unclear. The objectives of the current
      study were to assess the effect of laparoscopic surgery on the survival of women
      with early-stage endometrial carcinoma and to analyze the factors that affect
      such survival. METHODS: A retrospective review of women presenting with clinical
      stage I endometrial carcinoma (according to the 1988 International Federation of
      Gynecology and Obstetrics Staging System) was performed. Women treated with
      laparoscopy were compared with those treated with laparotomy with regard to their
      characteristics, surgical procedure, treatment, surgical stage, histology, tumor
      grade, and recurrence-free and overall survival. Factors affecting survival
      (surgical approach, histology, grade, and surgical stage) were evaluated using
      multivariate analysis and survival curves were constructed using Kaplan-Meier
      analyses. RESULTS: One hundred women underwent laparoscopy and 86 underwent
      laparotomy. Both groups were similar with regard to age, parity, menopausal
      status, lymphadenectomy, surgical stage, tumor grade, histology, and
      postoperative radiation therapy. Women who underwent laparoscopy and those who
      underwent laparotomy had similar 2-year and 5-year estimated recurrence-free
      survival rates (93% vs. 94% and 90% vs. 92%, respectively), as well as similar 2
      year and 5-year overall survival rates (98% vs. 96% and 92% vs. 92%,
      respectively). There was no apparent difference with regard to the sites of
      recurrence between both groups. In univariate and multivariate analyses, surgical
      stage, tumor grade, and histology (but not the surgical approach) were found to
      have a significant effect on survival. CONCLUSIONS: Although longer follow-up is
      needed, the survival of women with early-stage endometrial carcinoma does not
      appear to be worsened by laparoscopy. Surgical stage, tumor histology, and tumor
      grade were found to significantly affect survival regardless of the surgical
      approach used.

PMID- 12404284
TI  - Expression of matrix metalloproteinase 1, matrix metalloproteinase 2, and matrix
      metalloproteinase 9 in carcinoma of the head and neck.
AB  - BACKGROUND: Numerous reports have documented a direct involvement of matrix
      metalloproteinase (MMP) overexpression in the development and progression of head
      and neck squamous cell carcinoma (HNSCC). In this study, the authors examined
      whether the expression of MMPs in HNSCC is correlated with other steps involved
      in tumor growth and metastasis, like angiogenesis, activation the nitric oxide
      (NO) pathway, and alteration of the p53 tumor suppressor gene. METHODS: MMP-1,
      MMP-2, and MMP-9 expression levels were examined immunohistochemically in samples
      from 43 patients with HNSCC. Microvessel density (MVD) was determined by
      immunostaining of endothelial cells with anti-CD31 monoclonal antibody. Inducible
      nitric oxide synthase (iNOS) activity and cyclic guanosine monophosphatate (cGMP)
      levels were assessed in fresh tumor samples, whereas exons 5-9 of the p53 gene
      were analyzed by reverse transcriptase-polymerase chain reaction, single-strand
      conformation polymorphism analysis and were sequenced. RESULTS: MMP-1
      overexpression (>10% of tumor cells) was identified in 32 tumors (74.5%), whereas
      elevated levels of MMP-2 and MMP-9 were detected in 17 tumors (39.5%) each.
      Tumors with MMP-9 overexpression were characterized by significantly higher MVD
      (P = 0.05) and significantly higher iNOS activity and cGMP levels (P = 0.005 and
      P = 0.02, respectively). Moreover, p53 mutation was associated strongly with MMP
      9 overexpression (P = 0.004). Conversely, no correlation was found between MMP-1
      and MMP-2 expression, angiogenesis, iNOS activity, cGMP levels, and p53 mutation
      in this series. CONCLUSIONS: This study documents the existence of a correlation
      between MMP-9 expression, activity of the iNOS pathway, p53 status, and
      angiogenesis in patients with HNSCC. This raises the possibility that p53
      mutation, which frequently is present in HNSCC, may result in increased
      angiogenesis and invasiveness related to increased nitric oxide and MMP
      production by tumor cells, ultimately contributing to tumor progression.

PMID- 12404285
TI  - Effects of cyclosporine on hematopoietic and immune functions in patients with
      hypoplastic myelodysplasia: in vitro and in vivo studies.
AB  - BACKGROUND: Immunosuppression may benefit some patients with hypoplastic
      myelodysplasia (HMDS) and refractory anemia (RA), but its mechanism of action is
      still obscure. METHODS: Using flow cytometry, we studied Fas-receptor (Fas-R),
      Fas-ligand (Fas-L), and interferon-gamma (IFN-gamma) expression in CD34(+) cells
      and lymphocytes obtained from 11 HMDS and 20 RA patients. In colony assays and
      long-term cultures, the effects of Fas triggering, IFN-gamma blockade, or
      cyclosporine(CsA) on the growth of hematopoietic progenitors (colony-forming
      cells [CFC]) were determined. The effects of CsA at daily doses of 1-3 mg/kg for
      at least 3 months in HMDS patients were also studied. RESULTS: In basal
      conditions, committed and immature progenitor cells were found decreased in
      myelodysplastic (MDS) patients. No significant differences between HMDS and RA
      patients were detected. IFN-gamma-expressing CD4(+) cells were significantly
      increased in HMDS patients, whereas intracytoplasmic Fas-L expression was only
      borderline elevated in CD3(+) MDS cells. Increased numbers of CD34(+) cells
      expressing Fas-R were found in HMDS and RA patients. CFC and secondary CFC showed
      higher susceptibility to Fas-L-mediated inhibition and the blockade of IFN-gamma
      improved marrow primary, but not secondary, CFC growth. CsA added in vitro to
      patient's lymphocytes significantly decreased the number of IFN-gamma-expressing
      CD4(+) cells, but not Fas-L production. These effects were associated with
      increased colony formation. Similar to IFN-gammablockade, production of secondary
      CFC was not enhanced by CsA. Administration of CsA to patients resulted in
      prolonged partial hematologic improvement in 8 of 11 HMDS patients. CONCLUSIONS:
      Increased frequency of IFN-gamma producing CD4(+) cells supports the involvement
      of lymphocyte-mediated suppression of hematopoiesis in the development of
      cytopenia in MDS patients. The ability of CsA to decrease in vitro IFN-gamma
      production may improve hematopoietic function, explaining the beneficial effect
      of this agent in HMDS patients.

PMID- 12404286
TI  - Plasma vascular endothelial growth factor levels have prognostic significance in
      patients with acute myeloid leukemia but not in patients with myelodysplastic
      syndromes.
AB  - BACKGROUND: Vascular endothelial growth factor (VEGF) and basic fibroblast growth
      factor (bFGF) are positive regulators of angiogenesis. Increased levels in urine,
      serum, plasma, or malignant tissue have been associated with an adverse prognosis
      in patients with solid tumors. METHODS: The authors used an enzyme-linked
      immunosorbent assay to measure VEGF and bFGF levels in plasma samples from 99
      patients with previously untreated myelodysplastic syndromes (MDS) (n = 41
      patients; 42%) or acute myeloid leukemia (AML) (n = 58 patients; 58%) and
      compared the results with the results from a group of normal control
      participants. RESULTS: Increased expression levels of VEGF and bFGF were found in
      the plasma from patients with AML and MDS (P < 0.01) compared with the levels
      found in the control group. Plasma levels of VEGF in patients with AML or MDS
      were similar (median, 30.63 pg/mL and 34.41 pg/mL, respectively). There was no
      significant difference in bFGF levels between patients with AML and patients with
      MDS (median, 6.38 pg/mL and 6.98 pg/mL, respectively). Elevated levels of VEGF
      were associated with reduced survival (P = 0.02) in patients with AML as well as
      lower complete remission (CR) rates (P = 0.004). Elevated VEGF levels were not
      associated with reduced remission duration (CRD) in patients with AML. There was
      no correlation between VEGF levels and survival, CRD, or CR rates in patients
      with MDS. There was no correlation between bFGF levels and CR rates or survival
      in patients with either AML or MDS. CONCLUSIONS: Plasma VEGF levels have
      prognostic significance in patients with AML. The lack of clinical relevance of
      VEGF levels in patients with MDS suggests some biologic difference between AML
      and MDS.

PMID- 12404287
TI  - Satellite lesions in patients with small hepatocellular carcinoma with reference
      to clinicopathologic features.
AB  - BACKGROUND: It is not rare to find satellite lesions in patients with small
      hepatocellular carcinoma (HCC). The purpose of this study was to elucidate the
      factors associated with satellite lesions in these patients. METHODS: We
      investigated the prevalence of satellite lesions, the relationship of
      clinicopathologic factors to satellite lesions, and the distance from the main
      tumor to the satellite lesion in 149 patients. Patients, who had a solitary HCC
      of 3.0 cm or less in diameter but no satellite lesions on preoperative imaging
      procedures, underwent potentially curative resection. The main tumors were
      macroscopically classified into four groups: early HCC, a vaguely nodular type
      showing preservation of the preexisting liver structure; single nodular type;
      single nodular type with extranodular growth; and confluent multinodular type.
      RESULTS: Of 149 resected specimens, 28 (19%) showed satellite lesions. Of the
      clinicopathologic factors investigated, the macroscopic type and tumor
      differentiation were significantly associated with the prevalence of satellite
      lesions. Both the single nodular type with extranodular growth and the confluent
      multinodular type showed satellite lesions more frequently than the early HCC and
      the single nodular type. A significantly higher prevalence of satellite lesions
      was observed in poorly differentiated HCC than in well and moderately
      differentiated HCC. The satellite lesions were located 0.5 cm or less from the
      main tumor in 8 (33%) specimens, 0.6-1.0 cm in 12 (50%), and 1.1-2.0 cm in 4
      (17%). No identifiable factors were significantly related to the distance from
      the main tumor to the satellite lesion. However, all satellite lesions located
      more than 1.0 cm from the main tumor coexisted with poorly differentiated HCC,
      which were the single nodular type with extranodular growth or the confluent
      multinodular type. CONCLUSION: In the single nodular type with extranodular
      growth, confluent multinodular type, and poorly differentiated HCC, extensive
      treatment achieving a large safety margin and/or frequent posttreatment follow-up
      examinations may be needed because of the high prevalence of satellite lesions.

PMID- 12404288
TI  - Quantitative analysis of apoptosis-related gene expression in hepatocellular
      carcinoma.
AB  - BACKGROUND: The suppression of apoptosis is an important factor in tumor
      progression in hepatocellular carcinoma (HCC). However, to the authors knowledge
      the clinicopathologic importance of the expression of apoptosis-related genes
      (bcl-2, bax, and survivin) in HCC remains unclear. In the current study, the
      authors investigated the correlation between expression of apoptosis-related
      genes and the occurrence of spontaneous apoptosis in HCC. In addition, the
      prognostic significance of the expression of apoptosis-related genes in patients
      with HCC was analyzed. METHODS: Tissue samples were obtained through surgical
      resection of the liver in 53 patients with HCC and 5 patients without HCC. The
      expression levels of bcl-2, bax, survivin, and glyceraldehyde-3-phosphate
      dehydrogenase (GAPDH) mRNA were analyzed using real-time reverse transcriptase
      polymerase chain reaction (RT-PCR). The bcl-2/bax ratio and survivin/GAPDH ratio
      of the tumors were compared with clinicopathologic findings. In addition,
      apoptotic tumor cells and the proliferative activity of tumor cells were detected
      using immunohistochemistry. RESULTS: The bcl-2/bax ratios of the tumors were not
      different from those of noncancerous liver tissue samples obtained from regions
      distant from the tumors and were not found to correlate with apoptosis or with
      clinical importance in HCC. In contrast, the survivin/GAPDH ratios of the tumors
      were significantly higher than those of noncancerous liver tissue and
      demonstrated a negative correlation with apoptosis and a positive correlation
      with the proliferative activity of tumor cells. Moreover, patients who had tumors
      with a high survivin/GAPDH ratio were found to have a high incidence of disease
      recurrence. CONCLUSIONS: The real-time RT-PCR method appears to be a useful
      technique with which to detect reliable gene expression in tissues, and the
      detection of survivin mRNA expression by this method may be a useful marker for
      identifying patients with HCC who have a high risk of disease recurrence.

PMID- 12404289
TI  - Helicobacter pylori and the risk of benign and malignant biliary tract disease.
AB  - BACKGROUND: The etiology of tumors arising in the biliary tract remains unclear.
      Several previous studies have detected Helicobacter pylori organisms in bile from
      patients with gallstones or cholecystitis. The objective of this study was to
      determine whether there is an association between H. pylori in bile and biliary
      tract carcinoma. METHODS: The authors used polymerase chain reaction (PCR) assays
      to detect the presence of H. pylori in the stomach and bile from 89 patients:
      Sixty-three disease free patients had biliary calculi, 15 patients had carcinoma
      of the biliary tract, and 11 patients had neither gallstones nor carcinoma. Bile
      was considered to contain H. pylori only if the results of PCR determinations
      were positive in two or more samples assayed independently in two separate
      laboratories. RESULTS: There was a strong association between the presence of H.
      pylori in the stomach and in the bile (P < or = 0.01). Biliary H. pylori was
      associated with age but not with gender, and it was associated strongly with the
      clinical diagnosis. Patients with gallstones were 3.5 times as likely to have H.
      pylori in the bile compared with patients in a control group (95% confidence
      interval [95%CI], 0.8-15.8; P = 0.100), and H. pylori was 9.9 times more frequent
      in patients with biliary tract carcinoma compared with patients in the control
      group (95%CI, 1.4-70.5; P = 0.022). CONCLUSIONS: There is a strong association
      between biliary tract carcinoma and H. pylori in bile. If these results are
      confirmed by prospective studies, H. pylori may be responsible for a significant
      proportion of malignant biliary tract disease.

PMID- 12404290
TI  - Expression and immunogenicity of a tumor-associated antigen, 90K/Mac-2 binding
      protein, in lung carcinoma.
AB  - BACKGROUND: The authors attempted to obtain shared proteins among lung carcinoma
      cells by column chromatographies. A glycoprotein with approximately 500 kDa
      isolated from QG56 cells showed an identical amino acid sequence to 90K/Mac-2
      binding protein (M2BP). This protein has been reported to be highly expressed and
      to modulate the expression of surface molecules involved in immune responses on
      cultured cancer cells. Therefore, it would be beneficial for M2BP to be targeted
      in cancer immunotherapy. METHODS: The authors analyzed the expression of M2BP in
      lung carcinoma cells and M2BP's immunogenicity as a tumor antigen. Eight cultured
      lung carcinoma cell lines and 28 tumor tissues from patients with lung carcinoma
      were examined for the expression of M2BP mRNA and protein. Sera from cancer
      patients (n = 23) and healthy donors (n = 19) were studied for their reactivity
      to M2BP peptides by enzyme-linked immunosorbent assay. RESULTS: Seven of the 8
      (87.5%) lung carcinoma cell lines and 17 of the 28 (60.7%) tumor tissues
      expressed high levels of M2BP mRNA. Most of the M2BP mRNA-positive cancer cell
      lines and tumors also showed M2BP protein expression. The serum levels of
      antibodies to M2BP were elevated in 30.4% of the patients. In addition, M2BP
      specific immunoglobulin G was observed in all patients with anti-M2BP antibodies.
      CONCLUSIONS: M2BP is highly expressed in lung carcinoma cells and is sufficiently
      immunogenic to elicit specific immunity to this molecule in patients with lung
      carcinoma. M2BP is expected to be useful as a tumor marker and a target antigen
      in cancer immunotherapy.

PMID- 12404291
TI  - Immunohistochemical expression of vascular endothelial growth factor, matrix
      metalloproteinase 2, and matrix metalloproteinase 9 in cutaneous melanocytic
      lesions.
AB  - BACKGROUND: Vascular endothelial growth factor (VEGF), an endothelial cell
      mitogen, plays a hierarchical role in regulating physiologic and pathologic
      angiogenesis. Moreover, the transformation from noninvasive to invasive
      carcinomas is accompanied by focal disruption and discontinuity of the basement
      membrane. Several groups of proteases have been implicated in tumor cell
      invasion, including the 72-kDa gelatinase A/Type IV collagenase (matrix
      metalloproteinase 2 [MMP-2]) and the 92-kDa gelatinase B/Type IV collagenase (MMP
      9). METHODS: The authors assessed the immunohistochemical expression of VEGF and
      metalloproteinases MMP-2 and MMP-9 in paraffin embedded biopsy specimens of
      malignant melanomas (18 invasive melanomas and 10 in situ melanomas); dysplastic
      nevi with architectural disorder and cytologic atypia of melanocytes; Spitz nevi;
      and compound or predominantly intradermal, ordinary, benign melanocytic nevi.
      RESULTS: Strong cytoplasmic staining for VEGF was observed in melanoma cells in
      as many as 77% of primary invasive melanomas, whereas only 25% of the in situ
      melanomas exhibited a detectable immunoreactivity for VEGF. It is interesting to
      note that no immunoreactivity was shown by any nevi; Spitz nevi, in particular,
      showed negative immunoreactivity to VEGF. Invasive melanomas and in situ
      melanomas displayed coexpression of MMP-2 and MMP-9, although to a variable
      extent. In particular, high MMP-2 staining was observed in 14 of 18 invasive
      melanomas; moreover, strong MMP-2 expression also was observed in 60% of in situ
      melanomas, whereas the residual 40% of those melanomas showed a moderate level of
      positivity. CONCLUSIONS: On the basis of the current data showing that malignant
      melanocytic tumors displayed strong VEGF expression, whereas benign melanocytic
      proliferations showed no immunoreactivity for VEGF, VEGF also may be used as a
      discriminating factor to distinguish malignant melanoma from lesions of uncertain
      histology.

PMID- 12404292
TI  - Delirium in patients undergoing hematopoietic stem cell transplantation.
AB  - BACKGROUND: Delirium is common in patients with malignant disease and is
      associated with significant morbidity. Studies have not examined the epidemiology
      of delirium in patients undergoing hematopoietic stem cell transplantation
      (HSCT). The objectives of this study were to determine the prevalence, incidence,
      severity, and duration of delirium in the acute phase of HSCT and to determine
      the pretransplantation risk factors for the occurrence and severity of delirium
      during this period. METHODS: Ninety adult patients with malignancies who were
      admitted to the Fred Hutchinson Cancer Research Center for their first HSCT were
      assessed prospectively from 1 week pretransplantation to 30 days
      posttransplantation. Delirium occurrence using the Delirium Rating Scale (DRS)
      and severity using the Memorial Delirium Assessment Scale (MDAS) were assessed
      three times per week. Pretransplantation risk factors were assessed by patient
      self-report, charts, and computerized records. RESULTS: The cumulative
      posttransplantation incidence of delirium events (DRS score > 12) was 66 (73%),
      and the incidence of delirium episodes (DRS score > 12 for 2 of 3 consecutive
      assessments) was 45 (50%). The mean +/- standard deviation duration of delirium
      episodes was 4.8 +/- 2.8 assessments (approximately 10 days). Pretransplantation
      risk factors for having a delirium episode were lower cognitive functioning
      (Trailmaking B test [a standardized test of visual conceptual and visuomotor
      tracking and cognitive flexibility]; P = 0.0008), higher blood urea nitrogen (P =
      0.002), higher alkaline phosphatase (P = 0.008), lower physical functioning (SF
      12 [self report questionnaire that is a general measure of functioning]; P =
      0.03), and higher magnesium (P = 0.03). Pretransplantation risk factors for
      higher delirium severity scores were higher creatinine (P < 0.0001), the presence
      of total body irradiation (P = 0.0001), higher magnesium (P = 0.0003), lower Mini
      Mental State Examination score (P = 0.002), malignancy diagnosis category (P =
      0.002), female gender (P = 0.008), higher alkaline phosphatase (P = 0.02), older
      age (P = 0.03), and prior alcohol or drug abuse (P = 0.046). CONCLUSIONS: Half of
      patients who undergo HSCT experience a delirium episode during the 4 weeks
      posttransplantation. Pretransplantation risk factors can assist in identifying
      patients who are more likely to develop delirium posttransplantation.

PMID- 12404293
TI  - Classical Kaposi sarcoma: prognostic factor analysis of 248 patients.
AB  - BACKGROUND: Classical Kaposi sarcoma (CKS) is a rare indolent neoplasm that is
      particularly prevalent among Jews of Ashkenazi and Mediterranean origin. Data
      regarding prognostic factors for CKS are scarce. The aim of the current
      retrospective analysis was to better define prognostic subgroups among patients
      with CKS. METHODS: Between 1960 and 1995, 248 consecutive patients with CKS were
      treated at the Rambam and Rabin Medical Centers in Israel. Although treatment
      options included local excision, radiotherapy, and chemotherapy, observation
      alone was used for 31% of patients. For prognostic factor analysis, disease
      progression was classified as any progression and dissemination, and progression
      free survival was calculated for each. RESULTS: At a median follow-up of 20
      months, four patients (1.6%) died of CKS. Of the patients eligible for analysis,
      94 of 220 (39%) had any progression and 23 of 120 (18%) had dissemination. Only 8
      of 202 (4%) had visceral spread. On univariate analysis, age was a statistically
      significant prognostic factor for any progression (P = 0.04), whereas
      immunosuppression and visceral involvement at presentation had only borderline
      significance. Immunosuppression was the only prognostic factor for dissemination
      (P = 0.003). On multivariate analysis, both age and immunosuppression were
      significant prognostic factors for any progression (P = 0.001 and 0.01,
      respectively). Immunosuppression was also predictive of dissemination (P =
      0.006). CONCLUSIONS: Immunosuppression and older age (50 years and older) are
      strongly associated with poorer outcome among CKS patients. The two end points
      used in this study may be used for future prognostic factor analyses.

PMID- 12404294
TI  - Race, socioeconomic status, and breast carcinoma in the U.S: what have we learned
      from clinical studies.
AB  - BACKGROUND: Whether African-American women have biologically more aggressive
      breast carcinoma compared with white women and whether race acts as a significant
      independent prognostic factor for survival have not been determined.
      Alternatively, race merely may be a surrogate for socioeconomic status (SES).
      METHODS: A literature review was performed of clinical trials and retrospective
      studies in the U.S. that compared survival between white women and black women
      with breast carcinoma after adjustment for known prognostic factors (patient age,
      disease stage, lymph node status, and estrogen receptor status) to assess the
      impact of race and SES. RESULTS: Single institutional and clinical studies
      suggest that, when black patients are treated appropriately and other prognostic
      variables are controlled, their survival is similar to the survival of white
      patients. Twelve retrospective studies and 1 analysis of a clinical trial
      included SES and race as variables for survival. Only three of those studies
      revealed race as a significant prognostic factor for survival after adjusting for
      SES. CONCLUSIONS: SES replaces race as a predictor of worse outcome after women
      are diagnosed with breast carcinoma in many studies. However, black women present
      with more advanced disease that appear more aggressive biologically, and they
      present at a younger age compared with white women. Further research should be
      conducted concerning the precise elements of SES that account for the incidence
      of breast carcinoma, age at diagnosis, hormone receptor status, and survival to
      devise better strategies to improve outcome.

PMID- 12404295
TI  - A phase I study of a weekly schedule of paclitaxel and carboplatin in patients
      with advanced carcinoma.
AB  - BACKGROUND: We conducted a Phase I study of weekly paclitaxel (P) and carboplatin
      (C) in patients with advanced malignancies to determine the maximum tolerated
      dose (MTD) of this combination. METHODS: Dose levels were escalated independently
      for patients with and without previous chemotherapy exposure and advanced
      malignancies. Both agents were administered weekly for 6 weeks followed by a 2
      week break per cycle. P, escalated to tolerance starting at 135 mg/m(2) per week,
      and C, fixed dose at area under the curve (AUC) = 2 mg/mL/min, were administered
      to groups of three or six patients. Doses were modified for granulocyte counts
      less than 1800/microL or for neurotoxicity greater than Grade 1. MTD was defined
      as the highest dose level at which less than 50% of patients developed
      unacceptable toxicity and received more than 80% of the intended dose during the
      first cycle. Dose levels were escalated until these conditions were exceeded.
      RESULTS: Twenty-seven patients (12 patients with previous chemotherapy exposure
      and 15 chemotherapy-naive patients) were examined for toxicity. Dose escalation
      was halted due to neutropenia and/or Grade 2/3 neuropathy in both arms. The MTD
      was P = 135/C = 2 for patients with previous chemotherapy exposure and P = 150/C
      = 2 for chemotherapy-naive patients. CONCLUSIONS: The combination of P and C
      administered on a weekly schedule permits a two to threefold enhancement of P
      dose intensity with full doses of C. Phase II trials of this regimen in patients
      with various malignancies are being evaluated to determine efficacy and
      tolerance.

PMID- 12404296
TI  - An overview of the pharmacology and pharmacokinetics of the newer generation
      aromatase inhibitors anastrozole, letrozole, and exemestane.
AB  - BACKGROUND: The newer generation, nonsteroidal aromatase inhibitors (AIs)
      anastrozole and letrozole have shown superior efficacy compared with tamoxifen as
      first-line treatments and compared with megestrol acetate as second-line therapy
      in postmenopausal women with advanced breast carcinoma. In an open-label, Phase
      II trial, it was reported that exemestane showed numerical superiority compared
      with tamoxifen for objective response and clinical benefit. Because these agents
      ultimately may be administered for periods of up to 5 years in the adjuvant
      setting, it is of increasing importance to assess their tolerability and
      pharmacologic profiles. METHODS: In the absence of data from direct clinical
      comparisons, the published literature was reviewed for the clinical pharmacology,
      pharmacokinetic characteristics, and selectivity profiles of anastrozole,
      letrozole, and exemestane. RESULTS: At clinically administered doses, the plasma
      half-lives of anastrozole (1 mg once daily), letrozole (2.5 mg once daily), and
      exemestane (25 mg once daily) were 41-48 hours, 2-4 days, and 27 hours,
      respectively. The time to steady-state plasma levels was 7 days for both
      anastrozole and exemestane and 60 days for letrozole. Androgenic side effects
      have been reported only with exemestane. Anastrozole treatment had no impact on
      plasma lipid levels, whereas both letrozole and exemestane had an unfavorable
      effect on plasma lipid levels. In indirect comparisons, anastrozole showed the
      highest degree of selectivity compared with letrozole and exemestane in terms of
      a lack of effect on adrenosteroidogenesis. CONCLUSIONS: All three AIs
      demonstrated clinical efficacy over preexisting treatments. However, there were
      differences in terms of pharmacokinetics and effects on lipid levels and
      adrenosteroidogenesis. The long-term clinical significance of these differences
      remains to be elucidated.

PMID- 12404297
TI  - Relations between fatigue, neuropsychological functioning, and physical activity
      after treatment for breast carcinoma: daily self-report and objective behavior.
AB  - BACKGROUND: Previous research indicates that disease free breast carcinoma
      survivors who experienced severe fatigue also had many problems with regard to
      neuropsychological functioning and physical activity, measured with general self
      report questionnaires. Both neuropsychological functioning and physical activity
      can be measured with daily self-report measures in addition to measures of
      objective behavior. The main objective of this study was to examine the relations
      between 1) fatigue and 2) daily self-reported and objective measures of
      neuropsychological functioning and physical activity. METHODS: Disease free
      breast carcinoma survivors and age-matched women with no history of breast
      carcinoma filled out a daily self-observation list and wore an actometer during a
      period of 12 days. Furthermore, they performed two standardized tests to assess
      neuropsychological functioning. RESULTS: No differences were found between
      severely fatigued disease free breast carcinoma survivors, nonseverely fatigued
      disease free breast carcinoma survivors, and women in a control group with regard
      to daily self-reported and objective physical activity. The severely fatigued
      disease free patients reported more impairment in neuropsychological functioning
      on daily questionnaires compared with nonseverely fatigued disease free patients
      and women in the control group. However, no differences were found between these
      three groups on a standardized concentration task. On a standardized reaction
      time task, no significant differences were found between the two groups of
      disease free breast carcinoma survivors: However, women in the severely fatigued
      group had a significantly longer reaction time compared with women in the control
      group. CONCLUSIONS: Fatigue is correlated strongly with daily self-reported
      neuropsychological functioning, but not with objective neuropsychological
      functioning, in a laboratory setting. In the current study, fatigue was not
      correlated with daily self-reported and objective physical activity.

PMID- 12404298
TI  - Gliomatosis cerebri: treatment results with radiotherapy alone.
AB  - BACKGROUND: Gliomatosis cerebri (GC) is a rare primary brain tumor characterized
      by proliferation of neoplastic glial cells that typically involve multiple brain
      areas, with preservation of brain structures and sparing of neurons. The optimal
      therapeutic strategy is not well established. The impact of radiotherapy on
      survival in patients with GC remains undefined. METHODS: Between 1980 and 2001,
      12 patients with GC were identified, representing less than 1% of all patients
      with primary brain neoplasms treated at the Cleveland Clinic. RESULTS: All 12
      patients had brain biopsies between March 1986 and July 2001 (seven males, five
      females, with a median age of 53 years [range, 13-85 years]). Median Karnofsky
      performance status at the time of presentation was 70 (range, 40-90). Eight
      patients had low-grade gliomas and four patients had anaplastic astrocytomas.
      Eight patients received radiation treatment to the brain as the only treatment,
      and four received neither radiation nor chemotherapy. The median dose of
      megavoltage radiation was 55.4 Gy (range, 45-61.2 Gy). Of the eight patients who
      received brain radiotherapy, the clinical and radiologic follow-up findings
      improved in three patients, stabilized in three patients, and worsened in two
      patients. Median follow-up was 10.3 months (range, 1-55 months). The median
      survival for the eight patients who received brain radiotherapy was 11.4 months.
      The one- and two-year survival rates were 45% and 30%, respectively. Two of the
      eight patients who received radiotherapy were alive at the time of writing. The
      four patients who did not receive radiotherapy died of the disease at 0.6, 1.0,
      1.9, and 2.4 months after diagnosis. CONCLUSIONS: Gliomatosis cerebri is
      associated with poor survival. Although brain radiotherapy controlled or
      stabilized disease progression in most patients, the overall survival after brain
      radiotherapy alone was not satisfactory. More aggressive therapy may be needed.

PMID- 12404299
TI  - Intravenous gamma globulin inhibits the production of matrix metalloproteinase-9
      in macrophages.
AB  - BACKGROUND: Degradation of the extracellular matrix (ECM) is essential for
      progression and metastasis of cancer cells. The ECM-degrading enzymes, matrix
      metalloproteinases (MMPs), are produced mainly by intratumor
      monocytes/macrophages. MMPs, particularly MMP-9, are reported to be of crucial
      significance for both growth and tumor invasiveness. Inhibition of the expression
      of MMP-9 may prevent tumor development. High-dose intravenous gamma globulins
      (IVIG) effectively inhibit metastatic spread of tumors in mice and humans and a
      variety of mechanisms have been suggested to explain this effect. METHODS: We
      studied the effect of purified IVIG on MMP-9 secretion and mRNA expression by in
      vitro differentiated human monocytic cells (cell lines and peripheral blood
      monocytes). Zymography was employed to measure gelatinase secretion and Northern
      blot analysis was used to detect mRNA expression. Involvement of F(ab)(2) and Fc
      components in IVIG activity was also evaluated. RESULTS: IVIG dose dependently
      and significantly reduced the amount of secreted MMP-9 and its mRNA expression.
      F(ab)(2), but not Fc fragments, led to suppressed MMP-9 activity. However,
      competitive experiments demonstrated that Fc, but not F(ab)(2) fragments,
      reversed the IVIG-induced inhibitory effects. CONCLUSIONS: These results suggest
      that the whole IgG molecule may be needed for pertinent IVIG-induced MMP-9 down
      regulation. This study points to an additional new mechanism whereby IVIG may
      play a beneficial role in the prevention of tumor spread in humans.

PMID- 12404300
TI  - Factors predicting response and survival in 149 patients with unresectable
      hepatocellular carcinoma treated by combination cisplatin, interferon-alpha,
      doxorubicin and 5-fluorouracil chemotherapy.

PMID- 12404302
TI  - A review of the role of serotonin receptors in psychiatric disorders.
AB  - Serotonin (5-hydroxytryptamine, 5-HT) mediates a wide variety of physiological
      functions by activating multiple receptors, and abnormalities of these receptor
      systems has been implicated in many psychiatric disorders including anxiety,
      depression, psychosis, migraine, disorders of sexual functioning, sleep,
      cognition, and feeding. Many of the currently used treatments for these disorders
      act by affecting the serotonergic system. Observation of serotonin receptor
      alterations, before and following effective treatments, may yield important
      insights into the aetiology of these psychiatric disorders and may ultimately
      lead to more selective and effective therapies. Copyright 2000 John Wiley & Sons,
      Ltd.

PMID- 12404303
TI  - Estimation of plasma serotonin using isopycnic centrifugation.
AB  - The valid measurement of the concentration of serotonin (5-HT) in blood plasma is
      important when using the platelet as a model for the serotonergic neuron. The
      assay is hampered by the release of 5-HT by (residual) platelets during the
      preparation for assay. We developed an isopycnic method that separates cells
      gently and completely from plasma by centrifuging a diluted Percoll density
      gradient to which whole blood was added. In this study this method was compared
      with the usual differential centrifugation method. The isopycnic method on
      average resulted in nine times lower levels of plasma 5-HT. This difference was
      linearly related to the number of residual platelets in plasma after differential
      centrifuging. The proportion of intra-individual variation decreased three-fold.
      Therefore, the use of a Percoll density-gradient may lead to a more precise and
      more accurate estimate of the level of plasma 5-HT. Copyright 2000 John Wiley &
      Sons, Ltd.

PMID- 12404304
TI  - The effect of the serotonergic system on opioid withdrawal-like syndrome in a
      mouse model of cholestasis.
AB  - There is a marked elevation of endogenous opioid levels in plasma of human
      subjects with biliary cirrhosis as well as animal model of cholestasis. In
      addition, development of morphine tolerance and dependence has been shown to be
      inhibited by drugs which reduce brain serotonin levels. However,
      intracerebroventricular injection of serotonin increases the morphine analgesia.
      In the present study we have investigated the role of the serotonergic pathway in
      determining the withdrawal syndrome in a mouse model of cholestasis. There were
      three experimental groups: unoperated mice, sham operated mice and mice in which
      the main bile duct was ligated. Physical dependency was assessed by precipitating
      a withdrawal syndrome (writing, climbing, rearing, grooming and jumping) by
      naloxone (2 mg/kg) 5 days after induction of cholestasis. In separate
      experimental same groups, the antinociception was evaluated by the tail flick
      latency (TFL) test. Administration of serotonin receptors antagonists,
      cyproheptadine (10 mg/kg), methysergide (6 mg/kg) and ondansetron (10 mg/kg)
      attenuated withdrawal signs and decreased the antinociception. However, treatment
      by fluoxetine (15 mg/kg), an inhibitor of serotonin reuptake, increased the
      withdrawal signs and antinociception. These experiments lead us to conclude that
      the naloxone-precipitated withdrawal signs which occur in the mouse model of
      cholestasis are potentially dependent on the serotonergic pathway. Copyright 2000
      John Wiley & Sons, Ltd.

PMID- 12404305
TI  - Clinical impacts of single transcranial magnetic stimulation (sTMS) as an add-on
      therapy in severely depressed patients under SSRI treatment.
AB  - Research on single and rapid transcranial magnetic stimulation (sTMS/rTMS)
      indicates an antidepressive efficacy of these methods. In our 4 week study of
      sTMS, 12 patients affected by severe non-psychotic major depression (DSM-III-R)
      were enrolled and put on standardized combined antidepressant medication with the
      serotonin re-uptake inhibitor citalopram, and the serotonin modulating drug,
      trazodone. They underwent sTMS in a specific method as an add-on therapy. Age,
      gender, illness and episode duration, episode number, Hamilton Rating Depression
      Scale-24 (HRDS), Mini-Mental State (MMS), drug levels assessed by HPLC, magnesium
      and thyroid stimulating hormone (TSH) were recorded. For each patient functional
      brain imaging was performed by (18)FDG and (99m)Tc HMPAO SPECT at the beginning
      of the study, as were EEG tracings which also were recorded at the end. Lorazepam
      was allowed as co-medication. Of the patients, 66.7 per cent (N=8) could be
      identified as sTMS responders. Possible predictors for sTMS response as add-on
      therapy may be duration, pattern of improvement in global and in specific single
      items of the HRDS, lorazepam dosage, functional involvement of basal ganglia and
      cortical temporal lobe and the initially lower mean frequency and lability of the
      alpha-activity of EEG. These variables possibly predict the clinical outcome of
      depressed patients treated by sTMS as an add-on therapy. Copyright 2000 John
      Wiley & Sons, Ltd.

PMID- 12404306
TI  - Citalopram.
AB  - Citalopram is a selective serotonin (5-HT) reuptake inhibitor (SSRI) developed by
      H. Lundbeck A/S in Denmark. It is the most selective serotonin antidepressant
      with proven efficacy, a favourable pharmacokinetic profile and a low potential
      for interactions with other concomitant medication. The drug has a low incidence
      of side effects, even when compared to the other SSRIs and good patient
      compliance and satisfaction is a feature of this drug. These factors make the
      drug a good choice for depressed patients who require continuation and long-term
      treatment, as well as for elderly patients. Copyright 2000 John Wiley & Sons,
      Ltd.

PMID- 12404307
TI  - Relationship between clinical effects, serum drug concentration, and concurrent
      drug interactions in depressed patients treated with citalopram, fluoxetine,
      clomipramine, paroxetine or venlafaxine.
AB  - The relationship between clinical effects and plasma concentrations of
      citalopram, fluoxetine, clomipramine, paroxetine and venlafaxine was studied in
      119 cases of major depression. Clinical effects were evaluated using the Clinical
      Global Impression (CGI) improvement scale. Antidepressants were quantified by a
      separative chromatographic methodology. Plasma concentrations in responder
      patients were compared with the plasma concentrations proposed in literature as
      effective values. We found that the usual therapeutic window is convenient for
      citalopram and clomipramine, but could be reduced for fluoxetine and increased
      for venlafaxine and paroxetine. Concurrent drug interactions were also evaluated
      and clomipramine or citalopram plasma levels were found to be influenced by the
      presence of associated drugs. A larger study is needed, taking into account not
      only plasma concentrations and clinical effects, but also some pharmacokinetic
      data, especially the metabolic activity characterising the patient, and the
      presence or not of associated drugs. Copyright 2000 John Wiley & Sons, Ltd.

PMID- 12404308
TI  - A double-blind, placebo-controlled trial of sertraline in depressed adolescent
      alcoholics: a pilot study.
AB  - In order to preliminarily evaluate the efficacy, safety and tolerability of the
      serotonin reuptake inhibitor, sertraline, in the treatment of adolescents with a
      primary depressive disorder and a comorbid alcohol use disorder, a 12-week double
      blind, placebo-controlled trial of sertraline plus cognitive behavior group
      therapy was conducted. Subjects were 10 outpatient treatment-seeking adolescents.
      Baseline assessment included the K-SADS, HAM-D, SCID, and the Time-Line Follow
      Back. The HAM-D and the Time-Line Follow-Back were performed weekly thereafter.
      Both groups showed a significant reduction in depression scores with an average
      reduction between baseline and endpoint HAM-D score of -9.8 (F(1,8)=26.14,
      p</=0.001), although there were no significant group differences. There was an
      overall reduction in Percent Days Drinking (PDD); (F(1,8)=8.90, p<0.02) and in
      Drinks Per Drinking Day (DDD); (F(1,8)=20.48, p<0.002), however, there were no
      group differences. Depression responders tended to have higher baseline PDD than
      non-responders (F(1,8)=3.9, p=0.08) and change in HAM-D scores tended to
      correlate with change in PDD (r=0.57, p=0.09). Our data support that sertraline
      is safe and well tolerated in the treatment of adolescents with depression and
      alcohol dependence. Small sample size and cognitive behavior group therapy given
      to all subjects may limit the lack of group differences. Copyright 2000 John
      Wiley & Sons, Ltd.

PMID- 12404309
TI  - Antidepressants and violence: cause for concern or media hype?
AB  - No Abstract

PMID- 12404310
TI  - Serotonergic drugs in the treatment of depressive and anxiety disorders.
AB  - Serotonergic dysfunction has been implicated in the aetiology of several
      psychiatric conditions, including depressive and anxiety disorders. Much of the
      evidence for the role of serotonin (5-HT) in these disorders comes from treatment
      studies with serotonergic drugs, including selective serotonin reuptake
      inhibitors (SSRIs), 5-HT(1A) agonists and 5-HT antagonists. This review considers
      the place of these drugs in the treatment of panic disorder, obsessive-compulsive
      disorder (OCD), social phobia, and generalized anxiety disorder (GAD). Among
      these agents, the SSRIs stand out with proven efficacy in the treatment of a
      spectrum of disorders, such as depression, panic disorder, OCD and social phobia.
      They may also be a suitable treatment for GAD. 5-HT(1A) agonists have been used
      extensively for the treatment of depression and GAD but evidence of their
      efficacy in other anxiety disorders is equivocal. 5-HT antagonists are the least
      well studied of these agents: while they may have activity in depression, their
      efficacy has not been fully investigated in anxiety disorders. However,
      preliminary reports suggest that they may be useful as adjuvants to SSRIs in
      treatment-refractory OCD. The high incidence of comorbidity amongst psychiatric
      disorders means that pharmacotherapy that is effective against a range of
      disorders, such as the SSRIs, is of considerable use to clinicians. Future
      research into the biological mechanisms underlying such disorders is likely to
      further enhance pharmacotherapy. Copyright 2000 John Wiley & Sons, Ltd.

PMID- 12404311
TI  - Sexual dysfunction in depression.
AB  - Sexual dysfunction is a well-known symptom of depression. However, it has
      received little, if any, attention from clinicians and researchers. A review of
      published literature suggests that sexual dysfunction occurs in the majority of
      depressed patients. It has a major impact on the quality of life of the patients.
      The pathophysiology of sexual dysfunction in depression involves a complex
      interplay of various neurotransmitters and hormones. Clinicians need to be more
      proactive in enquiring about sexual dysfunction in depressed patients. More
      information is needed about the nature, prevalence and pathophysiology of sexual
      dysfunction in depression. Copyright 2000 John Wiley & Sons, Ltd.

PMID- 12404312
TI  - Exhibitionism and low-dose trazodone treatment.
AB  - We describe the case of a 37-year-old man who had suffered from exhibitionism for
      10 years. The strength of the patient's urges to act out decreased gradually with
      the commencement of low-dose trazodone treatment. During the 2 years of trazodone
      treatment, there was no acting out. The medicine was gradually decreased and
      eventually discontinued. The patient's impulse manifested only once, but is
      responded well to trazodone resumption. Thereafter, the patient has neither acted
      out nor had impulses, even without trazodone, for the following 2 years. This
      case suggests that trazodone can be useful in the treatment of exhibitionism and
      it can enhance the remitting process of exhibitionism in some patients. Copyright
      2000 John Wiley & Sons, Ltd.

PMID- 12404313
TI  - Hypothalamic-pituitary-adrenal axis early-feedback responses are preserved in
      melancholic depression: a study of sertraline treatment.
AB  - Major depression with melancholia is associated with hypercortisolaemia. Loss of
      the early-phase of negative feedback - acute suppression of ACTH in response to
      rising cortisol levels - is the subject of conflicting reports in patients with
      major depression. Using a within-subjects design, six patients with DSM-IIIR
      melancholic depression received a 60 min infusion of hydrocortisone at 0900 with
      measurement of ACTH and cortisol before and after 4 weeks of antidepressant
      treatment. All patients responded clinically. ACTH responses (early feedback) did
      not differ between test conditions. Baseline cortisol fell significantly
      following treatment response. This provides further evidence for the preservation
      of the acute phase of negative feedback, even in the presence of
      hypercortisolism. Copyright 2000 John Wiley & Sons, Ltd.

PMID- 12404314
TI  - Changes in plasma monoamine metabolites during acute lithium intoxication.
AB  - A case of acute lithium intoxication is presented in which plasma levels of 3
      methyoxy-4-hydroxyphenylglycol (MHPG), 5-hydroxyindoleacetic acid (5-HIAA), and
      homovanillic acid (HVA) were longitudinally measured during the intoxication
      period. Plasma levels of MHPH and 5-HIAA, but not HVA were increased during the
      intoxication period. These results suggest that toxic levels of lithium
      concentration occurred due to transient enhancement of serotonin and
      noradrenaline function. Dopamine function was not affected. Copyright 2000 John
      Wiley & Sons, Ltd.

PMID- 12404315
TI  - Clinical pharmacology of psychotropic drugs.
AB  - No Abstract

PMID- 12404316
TI  - Sertraline in paired blood plasma and breast-milk samples from nursing mothers.
AB  - Paired blood and breast-milk samples were collected from 10 nursing mothers
      receiving sertraline. Samples were collected at steady state when the patients
      had been taking stable doses of 50-150 mg/day over several weeks. Sertraline
      concentrations in both fluids were determined using a specific, validated HPLC
      method. Plasma and milk concentrations showed a wide inter-individual variability
      for the same dose. Mean plasma concentrations were linearly related to dose, but
      this was not the case for breast-milk concentrations. An overall milk to plasma
      ratio of 1.76+/-1.72 was recorded. The average dose to the infants ranged from
      1.1 to 31.1 &mgr;g/kg, which is less than 2 per cent of the maternal dose per
      day. Further studies are necessary to determine if these doses are detrimental to
      the development of the infant. Copyright 2000 John Wiley & Sons, Ltd.

PMID- 12404317
TI  - The effects of Ginkgo biloba extract (LI 1370) supplementation on activities of
      daily living in free living older volunteers: a questionnaire survey.
AB  - This survey assessed the impact of four months supplementation with 120 mg/day of
      the standardized Ginkgo biloba special extract (LI 1370) on activities of daily
      living and various aspects of mood and sleep in a population of free living older
      volunteers using both observer- and self-rated scales. 5028 Participants (mean
      age 68.9 years) were recruited through a magazine editorial. One thousand
      received Ginkgo biloba extract (GBE) and the remainder were allocated to the
      Control group. The B-ADL (activities of daily living) Scale was completed at
      baseline and at the end of month 4 by an informant familiar with the participant,
      a Self-rating ADL scale and Line Analogue Ratings Scales of mood and sleep were
      completed by the participants at the end of months 1, 2, 3, and 4. There were
      significant differences between the GBE and Control groups on all scales at each
      time point. The GBE group felt better able to cope with their daily activities
      and showed positive changes in mood and sleep compared to the Control group.
      These results suggest that GBE supplementation has beneficial effects on areas of
      functioning that have implications for quality of life in an older population.
      Copyright 2000 John Wiley & Sons, Ltd.

PMID- 12404318
TI  - Possible relationships between plasma carbamazepine-10,11-epoxide levels and
      antimanic efficacy and side effects in patients with schizoaffective disorde.
AB  - We examined the relationships of plasma levels of carbamazepine (CBZ) and its two
      major metabolites, carbamazepine-10,11-epoxide (CBZ-E) and carbamazepine-10,11
      diol (CBZ-D), with antimanic efficacy and side effects in patients with
      schizoaffective disorder. Positive relationships were found among plasma
      concentrations of CBZ-E and the degree of clinical improvement and side effects,
      whereas neither plasma CBZ nor CBZ-D levels were correlated with the degree of
      clinical improvement or side effects. Copyright 2000 John Wiley & Sons, Ltd.

PMID- 12404319
TI  - Nonorganic insomnia in panic Disorder: comparative sleep laboratory studies with
      normal controls and placebo-controlled trials with alprazolam.
AB  - Objective and subjective sleep and awakening quality was investigated in 11 drug
      free patients (4 females, 7 males) aged 30-55 (mean: 44+/-9) years with
      nonorganic insomnia (F 51.0) related to panic disorder (F 41.0) as compared with
      11 age- and sex-matched normal controls aged 30-58 (mean: 44+/-9) years,
      utilising polysomnography (PSG) and psychometry. PSG demonstrated decreased sleep
      efficiency (primary target variable), total sleep time (TST) and S2 as well as
      increased middle and late insomnia, S1, S3+S4, snoring and PLM in patients. There
      were no intergroup differences in REM variables. Subjective sleep quality
      deteriorated, as did drive and fine motor activity in the morning, while
      concentration increased. Blood pressure in the evening and morning and pulse rate
      in the evening were elevated. These differences as compared with normals were
      distinct from those observed in other sleep disorders. In a subsequent acute,
      placebo-controlled cross-over design study, patients received alprazolam 0.5 mg
      (Xanor((R));) and placebo. As compared with placebo, alprazolam induced an
      increase in sleep efficiency (primary target variable), TST and S2, a decrease in
      wakefulness during the total sleep period, S3+S4 and the oxygen desaturation and
      PLM indices, and improved subjective sleep quality, somatic complaints, drive,
      affectivity and drowsiness in the morning. There were no changes in REM
      variables. Thus, alprazolam induced changes that were opposite to the differences
      observed between patients and controls before treatment, thereby normalizing
      sleep and awakening quality. As observed in insomnia related to GAD and
      subsequent benzodiazepine therapy, the present study also points to a key-lock
      principle in the treatment of insomnia caused by anxiety disorders and
      neurophysiologically visualizes processes at the receptor level (e.g.
      benzodiazepine agonists versus inverse agonists). Copyright 2000 John Wiley &
      Sons, Ltd.

PMID- 12404320
TI  - Milnacipran: an antidepressant with dual selectivity of action on noradrenaline
      and serotonin uptake.
AB  - Milnacipran is a new antidepressant which possesses potent and doubly selective
      action in that it inhibits both the re-uptake of serotonin and noradrenaline
      without any effect on other neurotransmitter systems. The almost equipotent
      inhibition of serotonin and noradrenaline by milnacipran is functionally
      reflected in the several-fold and long-lasting increase of the levels of these
      monoamines in the brain and in antidepressant-like effects in animals. In man,
      milnacipran distinguishes itself from many other antidepressants by its simple
      pharmacokinetics. It shows linear dose-concentration relationship over a dose
      range of 25-200 mg/day. It is rapidly and extensively absorbed and almost
      completely eliminated after 12 h (t1/2 approx. 8 h). Steady-state plasma levels
      are reached within 32-48 h after twice daily oral administration. Milnacipran is
      highly bioavailable (>85 per cent) and its metabolism does not involve the
      cytochrome P450 enzyme system. In clinical studies, milnacipran showed
      antidepressant efficacy similar to that of TCAs and SSRIs and superior to that of
      placebo. At the optimum dose of 100 mg/day, after 4-8 weeks of treatment, 60-64
      per cent of in- or out-patients with major depression improve (>/=50 per cent
      reduction of HAMD and MADRS score) and about 32-39 per cent of them achieve full
      remission (HAMD score</=7). Milnacipran has proved to be a very safe drug with a
      benign adverse event profile clearly superior to that of TCAs and, to a certain
      extent, that of SSRIs. Only about 10 per cent of patients experience side-effects
      and only dysuria occurred more frequently (2 per cent) with milnacipran than with
      TCAs or SSRIs. Milnacipran appears therefore to be an antidepressant with a very
      favourable benefit/risk ratio. Copyright 2000 John Wiley & Sons, Ltd.

PMID- 12404321
TI  - Plasma noradrenaline response to a cognitive stressor in subtypes of depressive
      illness.
AB  - Noradrenergic function has been shown to be disrupted in depressive illness. The
      plasma noradrenaline response to a cognitive stressor (the Stroop test) was used
      to investigate noradenergic activity in subtypes of depressive illness. A Stroop
      test was carried out, under standardised conditions, on patients with melancholic
      or psychotic depression, non-melancholic depression, general anxiety disorder and
      normal controls. Blood samples were taken during testing for measurement of
      plasma noradrenaline. Although there was a trend for the plasma noradrenergic
      response to be reduced in the melancholic/psychotic depressed patients compared
      to all other groups, this did not reach statistical significance. No other inter
      group comparisons were statistically significant. The plasma noradrenaline
      response to a cognitive stressor does not discriminate subtypes of depressive
      illness from normal controls. Copyright 2000 John Wiley & Sons, Ltd.

PMID- 12404322
TI  - A second trial of clozapine in a case of granulocytopenia.
AB  - It is generally believed that agranulocytosis, a major problem with clozapine
      treatment, will tend to occur dose-dependently once it develops in an individual.
      Therefore, despite clinical progress obtained, the drug has to be discontinued
      and treatment shifts to another drug. We report on the case of a 29-year-old
      woman with DSM-IV undifferentiated schizophrenia who developed agranulocytosis
      after 5 years of 300 mg/day clozapine treatment. The drug was withdrawn and two
      trials with thioridazine and olanzapine were unsuccessful. Four months after
      clozapine suspension, we decided to make a further trial, reintroducing clozapine
      titrated up to 500 mg/day. The patient's symptoms improved and blood leukocytes
      remained within the normal range after eight months. Copyright 2000 John Wiley &
      Sons, Ltd.

PMID- 12404323
TI  - GABAAbenzodiazepine receptor (GBzR) sensitivity: test-retest reliability in
      normal volunteers.
AB  - Rationale: Alcohol, benzodiazepines and barbiturates act through the GABA(A)
      benzodiazepine receptor (GBzR). Patients with some forms of anxiety disorder have
      reduced GBzR sensivity, although it is not clear whether this is a state or a
      trait phenomenon. We have developed a paradigm for assessing GBzR sensitivity
      using slowing of saccadic eye movements in response to intravenous
      midazolam.Objectives: To obtain reliability data for GBzR sensitivity in normal
      volunteers and to look at factors that might influence sensitivity.Methods: Five
      male volunteers received an intravenous infusion of midazolam (50 &mgr;m/kg)
      given over 10 min. Saccadic eye movement velocity (SEMV) was recorded at baseline
      and at 15 min intervals up to 120 min post infusion. Blood was taken at these
      times for mixazolam assay. The study was repeated at 4 weeks. Pharmacodynamic
      (PD) effect was calculated by measuring area under the curve (AUC) of SEMV plot
      versus time for each individual on both study days. Pharmacokinetic (PK) effect
      was calculated by measuring AUC from t = 0 to t = 120 min. Ratio of PD/PK effect
      was then calculated to give a measure of GBzR sensitivity.Results: There was a
      very strong correlation between individual GBzR sensitivity on both study days (r
      = 0.99; p = 0.008).Conclusion: The results suggest that GBzR sensitivity is
      relatively stable over time in normal volunteers and that the paradigm described
      has good reliability. Copyright 2000 John Wiley & Sons, Ltd.

PMID- 12404324
TI  - Effects of smoking on diurnal variations of subjective activation and mood.
AB  - This study assessed the influence of smoking on diurnal variations in subjective
      activation and mood, with no restrictions placed on subjects' usual smoking
      habits after the first cigarette of the day. Forty-two students (21 smokers and
      21 non-smokers) responded to questions on unipolar visual analogue scales every
      hour from 08:00 to 21:00 hours. At 08:00 h, the smokers were in a situation of
      nicotine deprivation. Each visual analogue scale was analyzed independently to
      determine whether they differ in sensitivity to time of day. We confirmed that
      subjective activation and mood improved after subjects smoked their first morning
      cigarette, with vigour, sleepiness and sadness being the most sensitive scales.
      Smokers' diurnal functions on negative scales of activation varied within a wider
      range than did non-smokers' and optimal moments were delayed 3 h as a result of
      worse morning ratings and greater post-lunch interference. The only mood scale
      sensitive to smoking was happiness, with smokers having a lower mean score than
      non-smokers, and a delay of 6 h in peak ratings. These results support reports of
      differences in the circadian rhythmicity of smokers and non-smokers, even when
      the former smoke at will. Smokers' presentation of suboptimal levels of
      activation and mood at critical diurnal periods is consistent with models of
      deprivation-reversal and acute nicotine depletion over the course of the day.
      Copyright 2000 John Wiley & Sons, Ltd.

PMID- 12404325
TI  - The use of stimulants in the treatment of post traumatic stress disorder: case
      report.
AB  - Post Traumatic Stress disorder (PTSD) is a condition where the individual suffers
      re-experiencing phenomena, avoidance behaviour or emotional numbing and
      hyperarousal following a major traumatic event. Psychological treatments,
      primarily behavioural, and psychopharmacological interventions have been shown to
      be of considerable benefit. This case report describes an individual suffering
      from PTSD who experienced almost complete remission of her symptoms following the
      prescription of a centrally acting stimulant for unrelated reasons. The actions
      of centrally acting stimulants and the current knowledge about the
      neurophysiology of PTSD may help to explain the patient's recovery. Further
      investigation of amphetamine-like substances and related compounds in PTSD is
      required. Copyright 2000 John Wiley & Sons, Ltd.

PMID- 12404326
TI  - Risperidone as an antidote to hallucinogenics -should it be prescribed?
AB  - A novel clinical and ethical problem is discussed. There are patients who want to
      use atypical neuroleptics as a self-administered antidote to illicit drugs.
      Copyright 2000 John Wiley & Sons, Ltd.

PMID- 12404327
TI  - Effects of psychopharmacotherapy on phenotypic expression of cytochrome P450 2D6
      in patients genotyped for CYP2D6 mutations.
AB  - No Abstract

PMID- 12404328
TI  - Serotonin and information processing: a pharmacodynamic study on the effects of
      citalopram on cognitive and psychomotor function.
AB  - No Abstract

PMID- 12404329
TI  - Effects of a new slow release formulation of caffeine on EEG, psychomotor and
      cognitive functions in sleep-deprived subjects.
AB  - Caffeine is a widely-consumed psychoactive substance whose stimulant effects on
      mood, attention and performance are largely recognised. The central nervous
      system pharmacodynamic profile of a single oral dose of a new slow release (SR)
      caffeine formulation (600 mg) was assessed in a randomised, double-blind,
      crossover, placebo-controlled study. Twelve young, health, male, sleep-deprived
      (for 36 h) subjects were studied using EEG and various measures of psychomotor
      and cognitive functions, including critical flicker fusion (CFF), choice reaction
      task (CRT), tracking, continuous performance task (CPT), Stroop test, body sway
      and subjective evaluation (Stanford Sleepiness Scale). Caffeine significantly ( <
      0/05) antagonised the detrimental effects of sleep-deprivation on EEG (i.e.
      produced a significant decrease in delta and theta relative power and a
      significant increase in alpha and beta (12-40 Hz) relative power) and psychomotor
      performance (significant increase in speed of reaction on the CRT and Stroop
      tests, significant decrease in body sway, significant increase in accuracy of the
      CPT and significant reduction in subjective sedation) compared to placebo. The
      effect peaked 4 h after dosing and was maintained until the end of sleep
      deprivation (i.e. 24 h after dosing). In conclusion, the present results
      demonstrate that a single dose of caffeine SR possesses alerting effects which
      are able to reverse the deleterious effect of 36 h sleep deprivation for at least
      24 h. Copyright 2000 John Wiley & Sons, Ltd.

PMID- 12404330
TI  - The effect of sleep deprivation on memory and psychomotor function in healthy
      volunteers.
AB  - Benzodiazepines and other psychotropic drugs have been implicated in the
      production of memory deficits. The mechanism is unclear, but both a distinct
      pharmacological action and a non-specific sedative effect have been suggested as
      being causal or contributory. These two postulated mechanisms of action may be
      examined separately by using sleep deprivation as a method of non-pharmacological
      sedation. We measured psychomotor and memory functions in eight sleep-deprived
      healthy volunteers and eight controls. There was both subjective and objective
      evidence of sedation, but memory function was not affected. These findings
      support the view that the effect on memory of psychotropic drugs is principally
      caused by a direct amnestic effect rather than by drug-induced sedation.
      Copyright 2000 John Wiley & Sons, Ltd.

PMID- 12404331
TI  - Ritanserin as add-on medication to neuroleptic therapy for patients with chronic
      or subchronic schizophrenia.
AB  - The effect of ritanserin, a potent 5HT 2A/2C receptor antagonist, used as an add
      on medication to neuroleptic treatment in patients with schizophrenia, was
      compared with that of placebo, in an international, double-blind, parallel-group
      study. Previously established neuroleptic therapy was maintained, and ritanserin
      10 mg or placebo was given once daily for 8 weeks. Psychopathology was assessed
      with the Positive and Negative Syndrome Scale (PANSS) and the Clinical Global
      Impression (CGI) cale. Safety assessments included the Extrapyramidal Symptom
      Rating Scale (ESRS), and the requirement for antiparkinsonian medication was
      monitored. About 70 per cent of patients completed the treatment. There was no
      difference between the two groups in the numbers of patients with clinical
      improvement at endpoint on the PANSS negative subscale and total PANSS. The CGIs
      of overall severity of schizophrenia were better under placebo. The overall
      prevalence of side effects and the requirements for antiparkinsonism medication
      were comparable in the two groups. Copyright 2000 John Wiley & Sons, Ltd.

PMID- 12404333
TI  - The interaction between cytokines and neurotransmitters in depression and stress:
      possible mechanism of antidepressant treatments.
AB  - No Abstract

PMID- 12404332
TI  - Decreased expression of Galphas mRNA and protein levels in lithium-treated
      bipolar affective disorder.
AB  - The present work was aimed at assessing the GTP-binding (Galphas subunit) protein
      expression in lithium-treated bipolar patients (BP). Mononuclear leukocyte
      Galphas protein and mRNA were measured both in patients and in a comparison
      group. The patient group consisted of 15 lithium-treated patients with bipolar
      affective disorder, all diagnosed as euthymic bipolars, and a comparison group of
      15 drug-free healthy subjects. The method of competitive Reverse Transcriptase
      coupled to Polymerase Chain Reaction (RT-PCR) was used to estimate the relative
      abundance of Galphas mRNA, whereas the Western-immunoblot method was used to
      estimate Galphas levels. Results of both Galphas proteins and Galphas mRNA levels
      from patients were compared to those of non-treated control subjects. By using
      the competitive RT-PCR method, the Galphas mRNA displayed a significant decrease
      in the lithium-treated bipolar patients compared to non-treated controls: the
      ratio / was 1?81+/-0?05 versus 2?51+/-0?6 for BP and controls, respectively (Mann
      Whitney test, < 0%sol;001). Studying the same groups with respect to their
      protein levels, it was shown that Galphas levels were also significantly
      decreased in the group of bipolar patients (normalized values to a standard
      yielded 81?2+/-21 per cent versus 122?5+/-25 per cent for BP and controls,
      respectively; Mann-Whitney test, < 0?001). Data indicated that lithium induces a
      decrease both in Galphas protein levels and in Galphas mRNA synthesis in BP with
      respect to drug-free healthy subjects. Copyright 2000 John Wiley & Sons, Ltd.

PMID- 12404334
TI  - Effect of NMDA receptor antagonist on naloxone-precipitated withdrawal signs in
      cholestatic mice.
AB  - The ability of NMDA antagonist MK-801 to block the expression of opioid-like
      withdrawal signs was examined in bile duct-ligated mice and the signs were
      compared with sham operated and unoperated animals. Administration of MK-801 (0/1
      mg/kg), 10 min prior to naloxone challenge, significantly reduced the
      investigated withdrawal signs (jumping, diarrhoea, grooming and climbing) in bile
      duct-ligated animals. Chronic administration (five consecutive days) of MK-801
      (0/1 mg/kg) also decreased all the withdrawal signs in the experimental animals.
      In an independent series of experiments, the effect of acute and chronic
      administration of MK-801 on tail-flick latency was investigated in bile duct
      ligated animals. Pretreatment with the drug significantly decreased the
      antinociception induced by bile duct ligation in the mice. The results of this
      study support evidence for the involvement of the NMDA receptor in yopioidergic
      dependent manifestations in a model of obstructive cholestasis. Copyright 2000
      John Wiley & Sons, Ltd.

PMID- 12404335
TI  - Olanzapine treatment of clozapine-induced NMS.
AB  - No Abstract

PMID- 12404336
TI  - Extrapyramidal symptoms and residual psychopathology with low-dose neuroleptics.
AB  - Residual psychopathology associated with EPS has been mainly assessed in
      experimental studies where neuroleptics were administered at standard, fixed
      dosages. The present study evaluates residual psychopathology in 69 schizophrenic
      patients treated with moderate, flexible doses of neuroleptics (430 mg eq. CPZ)
      at the out-patient Community Mental Health Services (CMHSs) in Bologna. Akathisia
      was present in 27.5 per cent of patients and parkinsonism in 27.5 per cent. A
      more severe psychopathological state was associated with both side-effects, as
      seen by significantly higher BPRS global scores. This severity was due to tension
      and anxiety-depression symptoms in patients with akathisia and to negative
      symptomatology in patients with parkinsonism, as shown by significant
      associations with BPRS subscales ANS-DEP and NEG, respectively. In conclusion,
      the present study underlines that EPS are frequent even in an out-patient setting
      where moderate neuroleptic doses are employed, and more importantly shows that in
      these conditions, the residual psychopathology resulting from EPS is clinically
      very significant. Copyright 2000 John Wiley & Sons, Ltd.

PMID- 12404337
TI  - Comparison of simultaneous administration of lithium with L-NAME or L-arginine on
      morphine withdrawal syndrome in mice.
AB  - Due to the claim that chronic administration of lithium or L-N(G)-nitroarginine
      methyl ester (L-NAME), a nitric oxide synthase (NOS) inhibitor reduces morphine
      withdrawal syndrome, the effects of chronic administration of lithium, L-NAME, or
      L-arginine (L-Arg), a precursor of NO, alone or co-administration of lithium with
      L-Arg or L-NAME, on naloxone-precipitated withdrawal syndrome and physical
      dependence development to morphine in mice chronically treated with morphine,
      were evaluated. Morphine dependency was induced by the intraperitoneal injection
      (i.p.) of morphine (10 mg/kg), once daily for 7 days. Physical dependence to
      morphine was observed by precipitating an abstinence syndrome with naloxone (2
      mg/kg, i.p.). Chronic administration of L-NAME (10 mg/kg, i.p., once daily, for 7
      days after 10 days of receiving only tap water and food prior to naloxone),
      decreased all withdrawal signs significantly, while L-Arg (200 mg/kg, as above)
      increased only some withdrawal signs significantly in morphine-dependent mice.
      Chronic administration of lithium (600 mg/kg, in drinking water) alone or co
      administration of lithium (as above) with L-NAME (10 mg/kg) or L-Arg (200 mg/kg,
      i.p., once daily) for 7 days after 10 days of receiving only lithium (as above)
      and food, decreased all withdrawal signs and physical dependence significantly in
      morphine-dependent mice. The results obtained indicate that co-administration of
      L-NAME with lithium increases the effect of lithium or L-NAME alone, on
      withdrawal signs, but this increase is not significantly different as compared to
      chronic lithium or L-NAME administration alone; while co-administration of L-Arg
      with lithium decreases the effects of lithium on withdrawal signs and this
      decrease is not significant as compared to chronic lithium administration alone.
      These findings indicate that nitric oxide may be involved in modulation of
      naloxone-induced withdrawal syndrome, and treatment with lithium could have some
      effect on this system. Copyright 2000 John Wiley & Sons, Ltd.

PMID- 12404338
TI  - Comparison of the effect of levodopa and bromocriptine on naloxone-precipitated
      morphine withdrawal symptoms in mice.
AB  - In this study, the effect of l-dopa and bromocriptine on morphine withdrawal
      syndrome was compared. Both l-dopa (125, 250 mg/kg, i.p.) and low doses of
      bromocriptine (0.04, 0.08 mg/kg, i.p.) potentiated naloxone-induced morphine
      withdrawal symptoms such as jumping, climbing and rearing in mice. Higher doses
      of bromocriptine (0.16, 0.32 mg/kg, i.p.) attenuated these naloxone-induced
      symptoms. SKF 83566, D(1) dopamine antagonist (0.4, 0.8 mg/kg, i.p.) and
      sulpiride, D(2) dopamine antagonist (5, 10 mg/kg, i.p.) when used alone, also
      produced inhibitory effects on naloxone-induced morphine withdrawal symptoms.
      Pretreatment with sulpiride (5, 10 mg/kg, i.p.) and SKF 83566 (0.4, 0.8 mg/kg,
      i.p.) attenuated the potentiating effects of l-dopa on withdrawal symptoms
      significantly. Pretreatment with sulpiride also decreased the potentiating effect
      of bromocriptine and reinforced the inhibitory action of it, but SKF 83566
      pretreatment just reinforced the effect of higher doses of bromocriptine.
      Concurrent pretreatment of animals with sulpiride (10 mg/kg, i.p.) and SKF 83566
      (0.8 mg/kg, i.p.) markedly decreased the potentiating effects of l-dopa and
      bromocriptine and reinforced the inhibitory action of bromocriptine on the
      naloxone-induced morphine withdrawal syndrome. Prazosin, alpha(1) antagonist (1,
      2 mg/kg, i.p.) decreased the naloxone-induced morphine withdrawal syndrome
      significantly. Pretreatment with yohimbine, alpha(2)-antagonist (5 mg/kg, i.p.)
      reversed the inhibitory effects of bromocriptine (0.16, 0.32 mg/kg, i.p.) on
      naloxone-induced morphine withdrawal syndrome significantly. In conclusion, our
      results show that bromocriptine at lower doses (0.04, 0.08 mg/kg, i.p.) acts
      similar to l-dopa, but at higher doses (0.16, 0.32 mg/kg, i.p.) shows different
      effects on naloxone-induced morphine withdrawal syndrome which may be due to the
      interaction of bromocriptine with alpha-adrenoceptors. Copyright 2000 John Wiley
      & Sons, Ltd.

PMID- 12404339
TI  - Critical flicker fusion threshold: a potentially useful measure for the early
      detection of Alzheimer's disease.
AB  - Critical Flicker Fusion Threshold (CFFT) is a psychophysical threshold and, in
      psychological terms, it is regarded as a measure of information processing
      capacity. CFFT has previously been shown to be a valid and reliable measure in
      young healthy volunteers and it also has a long history of use as a
      psychopharmacological measure in this group. Furthermore, the test satisfies many
      of the requirements of an 'ideal' measure for monitoring change, especially in a
      psychopharmacological context. Despite this, CFFT has been neglected as a
      research tool in elderly and Alzheimer's disease (AD) populations and was
      therefore investigated further in this regard. CFFT in community-based healthy
      elderly subjects was normally distributed, but CFFT and ascending and descending
      thresholds were not significantly correlated with age. The difference between
      ascending and descending thresholds was, however, significantly correlated with
      age and this relationship appeared to be due almost entirely to a change in the
      descending threshold. In addition, descending thresholds were found to be
      significantly greater than ascending thresholds in healthy elderly subjects. In
      contrast, patients with AD were found to have significantly lower CFFT and
      descending scores compared with healthy elderly subjects. Interestingly,
      descending thresholds were significantly lower than ascending thresholds in the
      patient group, a feature that may be a characteristic of AD. Mean CFFT and
      ascending and descending thresholds were found to have a high test-retest, split
      half and inter-rater reliability, in addition to being significantly correlated
      with a number of psychometric measures, clinical scales and neuropsychological
      instruments commonly used to assess patients with AD. CFFT is a quick and simple
      measure to administer and patients had no difficulty completing the test. Because
      the measure is a psychophysical threshold, it is free from educational and
      cultural bias and there are no floor or ceiling effects. From the results of this
      work, CFFT appears to be a useful research tool in AD. It may be a suitable
      measure for monitoring cognitive change over time, either in community studies of
      AD or a clinical trial context, but further work is required. The technique might
      also contribute to the early detection of AD. This application would be
      particularly important because it would enable effective pharmacotherapies to be
      started early during the course of the illness before neuronal damage is too
      advanced and this would have significant benefits for patients. Copyright 2000
      John Wiley & Sons, Ltd.

PMID- 12404340
TI  - 5-HT1A and beyond: the role of serotonin and its receptors in depression and the
      antidepressant response.
AB  - Since its discovery 50 years ago, the role of the indoleamine 5-HT (5
      hydroxytryptamine; serotonin) in the pathogenesis of depression and in the
      mechanism of action of antidepressant drugs has been the subject of considerable
      research. Advances in molecular biology and radioligand techniques have led to
      the functional characterisation of at least 14 serotonin receptor subtypes. This
      classification has led to the development of selective compounds that have aided
      in the efforts of dissecting the complex role of 5-HT in depression and in
      mediating the antidepressant response. This review focuses largely on novel
      strategies of targeting specific 5-HT receptors subtypes, especially the
      presynaptic 5-HT(1A) and 5-HT(1B/1D) receptors. These subtypes are of primary
      importance in that they control the firing of the 5-HT neuron and the release of
      5-HT. In addition, a number of postsynaptic 5-HT receptors have been shown to be
      dysfunctional in depression and are also potential targets for a number of
      antidepressants. We conclude that selective targeting of 5-HT receptors may lead
      to a faster acting and more efficient antidepressant response. Copyright 2000
      John Wiley & Sons, Ltd.

PMID- 12404341
TI  - Evaluation of cognitive and psychomotor effects of nisoldipine or placebo in
      healthy volunteers.
AB  - The purpose of this study was to compare the cognitive and psychomotor effects of
      the calcium antagonist nisoldipine with placebo in healthy volunteers over the
      three-week period of this randomised, double-blind, parallel group trial. Thirty
      volunteers received either a twice-daily dose of 10 mg nisoldipine or placebo.
      Psychometric testing and measurement of blood pressure and heart rate were
      carried out on days 0, 7, 14 and 21. Psychometric testing included: Critical
      Flicker Fusion (CFF), Choice Reaction Time (CRT), Digit Span (DS), Digit Symbol
      Substitution Test (DSST), and Letter Cancellation (LC). No significant treatment
      effects were found. CFF performance improved for both groups during the first
      week. In the CRT task, significant improvements were observed on days 14 and 21,
      relative to baseline, for total and motor reaction time. Similar improvements
      over time were found on the LC and DSST tasks. There were no significant
      differences between the active treatment and placebo for heart rate and
      systolic/diastolic blood pressure and nisoldipine was well tolerated. The results
      of this study indicate that nisoldipine does not have any cognition enhancing
      properties but, unlike some calcium antagonists, it does not markedly impair CNS
      activity. Copyright 2000 John Wiley & Sons, Ltd.

PMID- 12404342
TI  - Effect of reboxetine augmentation in SSRI resistant patients.
AB  - No Abstract

PMID- 12404343
TI  - A unifying hypothesis of Alzheimer's disease. III. Risk factors.
AB  - Normal ageing and Alzheimer's disease (AD) have many features in common and, in
      many respects, both conditions only differ by quantitative criteria. A variety of
      genetic, medical and environmental factors modulate the ageing-related processes
      leading the brain into the devastation of AD. In accordance with the concept that
      AD is a metabolic disease, these risk factors deteriorate the homeostasis of the
      Ca(2+)-energy-redox triangle and disrupt the cerebral reserve capacity under
      metabolic stress. The major genetic risk factors (APP and presenilin mutations,
      Down's syndrome, apolipoprotein E4) are associated with a compromise of the
      homeostatic triangle. The pathophysiological processes leading to this
      vulnerability remain elusive at present, while mitochondrial mutations can be
      plausibly integrated into the metabolic scenario. The metabolic leitmotif is
      particularly evident with medical risk factors which are associated with an
      impaired cerebral perfusion, such as cerebrovascular diseases including stroke,
      cardiovascular diseases, hypo- and hypertension. Traumatic brain injury
      represents another example due to the persistent metabolic stress following the
      acute event. Thyroid diseases have detrimental sequela for cerebral metabolism as
      well. Furthermore, major depression and presumably chronic stress endanger
      susceptible brain areas mediated by a host of hormonal imbalances, particularly
      the HPA-axis dysregulation. Sociocultural and lifestyle factors like education,
      physical activity, diet and smoking may also modulate the individual risk
      affecting both reserve capacity and vulnerability. The pathophysiological
      relevance of trace metals, including aluminum and iron, is highly controversial;
      at any rate, they may adversely affect cellular defences, antioxidant competence
      in particular. The relative contribution of these factors, however, is as
      individual as the pattern of the factors. In familial AD, the genetic factors
      clearly drive the sequence of events. A strong interaction of fat metabolism and
      apoE polymorphism is suggested by intercultural epidemiological findings. In
      cultures, less plagued by the 'blessings' of the 'cafeteria diet-sedentary'
      Western lifestyle, apoE4 appears to be not a risk factor for AD. This intriguing
      evidence suggests that, analogous to cardiovascular diseases, apoE4 requires a
      hyperlipidaemic lifestyle to manifest as AD risk factor. Overall, the etiology of
      AD is a key paradigm for a gene-environment interaction. Copyright 2000 John
      Wiley & Sons, Ltd.

PMID- 12404345
TI  - Monitoring free flaps using laser-induced fluorescence of indocyanine green: a
      preliminary experience.
AB  - In a prospective, clinical study, the clinical utility of indocyanine green for
      intraoperative monitoring of free tissue transfer was evaluated. The study
      comprised 20 surgical patients undergoing elective microsurgical procedures.
      Indocyanine green angiography was performed intraoperatively, immediately after
      flap inset, and the operating team was blind to the fluoremetric findings.
      Thereafter, postoperative monitoring was done exclusively by clinical examination
      (color, temperature, time for recapillarization, and bleeding after puncture).
      Final outcome was compared with results of perioperative indocyanine (ICG)
      imaging, and classified either as total flap loss, partial flap loss, or
      successful tissue transplantation. A total of 2 (10%) complications was recorded,
      and included one partial and one total flap loss. Both complications were
      detected by intraoperative ICG imaging. Another case of intraoperative
      subclinical arterial spasm at the place of microvascular anastomosis was revealed
      by dynamic ICG-videography. This flap did not develop postoperative
      complications. In conclusion, evaluation of perfusion by ICG imaging is feasible
      in all kinds of microsurgical flaps, irrespective of the type of tissue. Even
      though not meeting all the criteria of an ideal monitoring device, significant
      additional information can be obtained. In this study, cases with arterial spasm,
      venous congestion, and regional hypoperfusion were revealed by intraoperative ICG
      videography. There was a strong correlation between intraoperative findings and
      clinical outcome.

PMID- 12404346
TI  - Effect of long-term application of epinephrine on rat skin vasculature:
      experimental study.
AB  - As a potent vasoconstrictor, epinephrine is used ubiquitously in plastic surgery.
      It is typically delivered subcutaneously in very low concentrations over a brief
      time interval. We are aware of no reports describing the long-term release of
      epinephrine as an independent agent to the soft tissues for the purpose of
      causing prolonged local vasoconstriction. This study was designed to address two
      goals: first, to investigate the effect of long-term local release of epinephrine
      from a drug delivery system on rat abdominal skin vasculature; secondly, to
      evaluate the pharmacological properties of this drug delivery system (DDS).
      Thirty male Sprague-Dawley rats, weighing 300-400 g, were included in the study.
      Animals were subdivided into two groups of 15 each. Group A (control group) and
      Group B (experimental group) were treated with saline and epinephrine-loaded
      microspheres (msps), respectively. The manufacturing process and formulation
      studies of the DDS are described. In vivo assays revealed a 7-day sustained
      release of epinephrine. After 7 days, neither residual nor supraphysiologic
      release of epinephrine was shown with high-performance liquid chromatography
      (HPLC). Histological studies with hematoxylin-eosin and periodic acid Schiff
      revealed a statistically significant increase in number of vessels as well as
      their diameter and wall thickness (P <0.05). Epinephrine release via this msp/DDS
      predictably induces local vasoconstriction over a time sequence known to be
      optimally associated with hypoxia and promotion of vascular augmentation. This
      model can be valuable in sustaining hemostasis during long-lasting (more than a
      few hours) surgical procedures by its long-acting vasoconstructive effect. The
      system's ability to intentionally cause vascular augmentation also bodes great
      potential in flap and graft surgery.

PMID- 12404347
TI  - Replantation of a crush amputation of distal tibia followed by lengthening with
      Ilizarov circular external fixator: two-year follow-up.
AB  - A 20-year-old male sustained a severe crush injury to his left leg, resulting in
      amputation of the foot at the level of the distal tibia. Despite 12-h warm
      ischemia, replantation was attempted after radical debridement, bone shortening,
      and proximal fasciotomies. The replanted part survived totally. Four months
      later, a 13-cm shortness of the extremity was managed by 10-cm lengthening with
      distraction osteogenesis, using Ilizarov's circular external fixator and by means
      of a special shoe. Two-year follow-up of the patient revealed acceptable
      functional and sensorial recovery. Success of replantation despite the excessive
      warm-ischemia time was attributed to the sparse muscle content of the distal
      tibia and foot. Fasciotomies performed on the proximal segment of the leg ensured
      the patency of anastomoses by maintaining adequate blood flow distally despite
      increasing edema after the crush injury. Debridement and bone shortening at the
      proximal stump eliminated the vein and nerve grafts to bridge the gap. In
      conclusion, considering the functional outcome of our case, replantation of
      distal parts of a lower extremity should be attempted first, even if the nature
      of the injury is unfavorable and the ischemia time is longer than the documented
      ischemia-tolerance.

PMID- 12404348
TI  - Neurotrophins and their receptors in early axonal regeneration along muscle-vein
      combined grafts.
AB  - Experimental and clinical studies have shown that a vein segment filled with
      skeletal muscle used to bridge a peripheral nerve defect (muscle-vein-combined
      graft) leads to good nerve repair. However, the molecular basis of the nerve
      fiber regeneration process along this type of graft still remains to be
      elucidated. The aim of this study was to verify the expression of two
      neurotrophins, nerve growth factor (NGF) and brain-derived neurotrophic factor
      (BDNF), as well as their receptors, trkA and p75, in an early stage of axonal
      regeneration in muscle-vein-combined grafts. Severed rat sciatic nerves were
      repaired by means of 1-cm-long muscle-vein-combined grafts and withdrawn
      immediately after surgery (control grafts) and 5 days after surgery. Longitudinal
      sections of grafts were immunostained by means of the following antibodies: anti
      NGF, anti-BDNF, anti-trkA, and anti-p75. An anti-glial fibrillar acid protein
      (anti-GFAP) antibody was used to recognize Schwann cells. Results showed the
      presence of a number of GFAP-positive Schwann cells inside the muscle-vein
      grafts. Many of these cells reacted for NGF, BDNF, and p75, but not trkA. In
      control grafts, i.e., immediately after surgery, no immunostaining was detected
      for any of the antibodies used in this study. These observations suggest that,
      very early after surgery, the muscle-vein-combined graft offers to growing axons
      an environment particularly favorable for regeneration, providing us with a
      possible explanation for the efficacy of this grafting technique for peripheral
      nerve repair.

PMID- 12404349
TI  - In vivo model for visualizing flap microcirculation of ischemia-reperfusion.
AB  - Since ischemia-reperfusion injury continues to be a major problem in
      reconstructive microsurgery, improvement of experimental models is still
      desirable. We developed a model that allows direct visualization of flap
      microcirculation in mice by intravital microscopic techniques. A newly designed
      skinfold chamber was installed on the dorsum of mice, and microcirculation was
      inspected with an intravital microscope. An island flap, nourished by the deep
      circumflex iliac arteries, was elevated after implantation of the chamber,
      allowing visualization of the microcirculation in the island flap. The island
      flap was exposed to global ischemia by clamping the pedicles, and the clamps were
      then released to allow reperfusion. Various microcirculatory responses induced by
      ischemia-reperfusion were visualized. This model accurately simulated the
      clinical situation in reconstructive surgery and successfully realized chronic
      visualization of the flap microcirculation in vivo.

PMID- 12404350
TI  - Reconstruction of peripheral nerves using acellular nerve grafts with implanted
      cultured Schwann cells.
AB  - The bridging of nerve gaps is still one of the major problems in peripheral nerve
      surgery. The present experiment describes our attempt to engineer different
      biologic nerve grafts in a rat sciatic nerve model: cultured isogenic Schwann
      cells were implanted into 2-cm autologous acellular nerve grafts or autologous
      predegenerated nerve grafts. Autologous nerve grafts and predegenerated or
      acellular nerve grafts without implanted Schwann cells served as controls. The
      regenerated nerves were assessed histologically and morphometrically after 6
      weeks. Predegenerated grafts showed results superior in regard to axon count and
      histologic appearance in comparison to standard grafts and acellular grafts. The
      acellular nerve grafts showed the worst histologic picture, but axon counts were
      in the range of standard grafts. The implantation of Schwann cells did not yield
      significant improvements in any group. In conclusion, the status of activation of
      Schwann cells and the stadium of Wallerian degeneration in a nerve graft might be
      key factors for regeneration, rather than total number of Schwann cells.
      Predegenerated nerve grafts are therefore superior to standard grafts in the rat
      model. Acellular grafts are able to bridge nerve gaps of up to 2 cm in the rat
      model, but even the addition of cultivated Schwann cells did not lead to results
      as good as in the group with autologous nerve grafts.

PMID- 12404351
TI  - Absorptive properties of synovium harvested from the carpal tunnel.
AB  - Ischemia-induced reperfusion injury seems to play an important role in the
      pathophysiology of "idiopathic" carpal tunnel syndrome (CTS). The common final
      pathway in this developmental sequence is thought to be an intermittent increase
      in interstitial pressure, leading to degenerative changes in the flexor
      tenosynovium and fibrotic changes in the perineural tissue. We hypothesize that
      this concurrently leads to alteration in the physical properties of the synovium,
      leading to its rapid and persistent swelling. A prospective study was conducted
      on synovial tissue obtained from 27 CTS patients. The in vitro synovial
      absorption rate of CTS patients was significantly higher in the first hour
      compared to controls (n = 7). This difference was maintained up to 5-6 h, albeit
      at a slower rate. Rapid absorption and retention of fluid by the synovium led to
      increased interstitial pressure and nerve compression, resulting in early and
      persistent manifestation of symptoms in sensitized patients.

PMID- 12404356
TI  - On the Beneficial Effect of ortho-Methoxy Groups in the Asymmetric Ring Opening
      of meso Epoxides with Silicon Tetrachloride Catalyzed by Chiral ortho
      Methoxyphenyldiazaphosphonamide Lewis Bases A Response to the correspondence by
      Professor Scott E. Denmark et al.3.

PMID- 12404355
TI  - Graphical Abstract.

PMID- 12404357
TI  - A Lewis Acid Catalyst Anchored on Silica Grafted with Quaternary Alkylammonium
      Chloride Moieties T.M.J. is grateful to the Blechner fund for a postdoctoral
      fellowship. 

PMID- 12404358
TI  - The B-Alkyl Suzuki-Miyaura Cross-Coupling Reaction: Development, Mechanistic
      Study, and Applications in Natural Product Synthesis A list of abbreviations can
      be found at the end of the article. 
AB  - The development of new reactions that facilitate the creative and efficient
      synthesis of molecular structures with desirable properties continues to
      fascinate chemists. The test of a significant contribution is its acceptance over
      time by the scientific community. The B-alkyl Suzuki-Miyaura cross-coupling
      reaction appears to be one such reaction. Since its disclosure by Suzuki and
      Miyaura in 1986, this reaction has been an attractive solution to challenging
      synthetic problems.

PMID- 12404359
TI  - Oxygen Binding, Activation, and Reduction to Water by Copper Proteins.
AB  - Copper active sites play a major role in biological and abiological dioxygen
      activation. Oxygen intermediates have been studied in detail for the proteins and
      enzymes involved in reversible O(2) binding (hemocyanin), activation
      (tyrosinase), and four-electron reduction to water (multicopper oxidases). These
      oxygen intermediates exhibit unique spectroscopic features indicative of new
      geometric and electronic structures involved in oxygen activation. The
      spectroscopic and quantum-mechanical study of these intermediates has defined
      geometric- and electronic-structure/function correlations, and developed detailed
      reaction coordinates for the reversible binding of O(2), hydroxylation, and H
      atom abstraction from different substrates, and the reductive cleavage of the O-O
      bond in the formation water.

PMID- 12404360
TI  - Enantioselective Construction of Quaternary Stereocenters.
AB  - The stereoselective formation of C-C bonds is of great importance for the
      synthesis of enantiomerically pure natural products and pharmaceuticals. A broad
      repertoire of chiral auxiliaries, reagents, and catalysts can be utilized for the
      reliable generation of tertiary stereocenters. In contrast, the synthesis of
      organic compounds with quaternary stereocenters is a much more demanding and
      challenging task. Every enantioselective synthetic method can demonstrate its
      value through the generation of a fully substituted carbon center. In this
      Minireview examples of newer stoichiometric and catalytic methods are summarized
      which have proved their suitability for the enantioselective construction of
      quaternary stereocenters.

PMID- 12404361
TI  - Coping with Fritz Haber's Somber Literary Shadow We are grateful to the reviewers
      of this paper for their provocative comments. 

PMID- 12404362
TI  - The "Rocky" Road to Literary Fame: Marcel Proust and the Diamond Synthesis of
      Professor Moissan.

PMID- 12404363
TI  - Ru- and Rh-Catalyzed Asymmetric Hydrogenations: Recent Surprises from an Old
      Reaction.

PMID- 12404364
TI  - Comment on the Communication "The Key to Solving the Protein-Folding Problem Lies
      in an Accurate Description of the Denatured State" by van Gunsteren et al. We
      thank Eugene Shakhnovich (Harvard University) for pointing out the references on
      lattice polymer simulations and very helpful discussions. We also thank Wilfred
      van Gunsteren for comments on the manuscript. A.R.D. is a Burroughs Wellcome Fund
      Hitchings-Elion Postdoctoral Fellow. The work done at Harvard was supported in
      part by the National Institutes of Health. 

PMID- 12404365
TI  - Reply.

PMID- 12404366
TI  - A Trifunctional Catalyst for the Synthesis of Chiral Diols N.S.C. and S.M. thank
      the Council of Scientific and Industrial Research, India, for providing research
      fellowships. We also thank Prof. I. E. Marko for his helpful comments. 

PMID- 12404367
TI  - TlF and PbO under High Pressure: Unexpected Persistence of the Stereochemically
      Active Electron Pair This work was supported by the Swedish National Science
      Research Council (NFR) and the Goran Gustafsson Foundation. 

PMID- 12404368
TI  - Solid-Phase Synthesis of Transition Metal Linked, Branched Oligonucleotides This
      work was supported by NSERC (Canada), CFI (Canada) and FCAR (Quebec). The authors
      gratefully acknowledge Prof. M. J. Damha and his laboratory, McGill University,
      for helpful discussion. 

PMID- 12404369
TI  - The mechanism of hydroamination of allenes, alkynes, and alkenes catalyzed by
      cyclopentadienyltitanium-imido complexes: a density functional study.

PMID- 12404370
TI  - Self-Assembly of Cyclic Peptides into Nanotubes and Then into Highly Anisotropic
      Crystalline Materials This work was supported by FCAR Quebec. 

PMID- 12404371
TI  - Single-Step, Highly Active, and Highly Selective Nanoparticle Catalysts for the
      Hydrogenation of Key Organic Compounds We gratefully acknowledge the support (by
      a rolling grant to J.M.T. and an award to B.F.G.J.) of EPSRC (UK), of the
      Cambridge Overseas Trust (Schlumberger research), and ICI (for T.K.), and the
      award of a research fellowship (for S.H.) from Newnham College, Cambridge. 

PMID- 12404372
TI  - Influence of Structural and Rotational Isomerism on the Triplet Blinking of
      Individual Dendrimer Molecules J.H. thanks the FWO for a post-doctoral
      fellowship. T.V. wishes to thank the I.W.T. for a doctoral fellowship. Financial
      support by the FWO, the DWTC (through IUAP-4-11), and the Flemish Ministry of
      Education (through GOA/1/2001) is gratefully acknowledged. The EC (through TMR
      Sisitomas), ESF (through Smarton), and the Volkswagen-Stiftung are also thanked
      for financial support. Dr. L. Latterini is thanked for the triplet absorption
      measurements. 

PMID- 12404373
TI  - Hydrophobic Groups Stabilize the Hydration Shell of 2'-O-Methylated RNA Duplexes.

PMID- 12404374
TI  - Formation and Stabilization of a Decanuclear Cu(II) Wheel Linked by Chloride and
      O.H-N Hydrogen Bonds We thank the National Science Council of Taiwan, R.O.C.
      (Grant No. NSC 90-2113-M-007-007) as well as the National Research Council,
      Canada for providing the financial support. 

PMID- 12404375
TI  - Structure, Immunogenicity, and Protectivity Relationship for the 1585 Malarial
      Peptide and Its Substitution Analogues.

PMID- 12404376
TI  - beta-Fibrillogenesis from Rigid-Rod beta-Barrels: Hierarchical Preorganization
      Beyond Microns We thank J. Buffle and J. Dubochet for their fruitful discussions
      and the Swiss NSF (21-57059.99 (S.M.), 2000-050629.97 (K.J.W.), and the National
      Research Program "Supramolecular Functional Materials" 4047-057496 (S.M.)) for
      their financial support. 

PMID- 12404377
TI  - Construction of Carbon Nanotube "Stars" with Dendrimers.

PMID- 12404378
TI  - Direct Microscopic Observation of the Time Course of Single-Molecule DNA
      Restriction Reactions We thank Dr. Werner Wolf for helpful discussions and the VW
      foundation, Grant No. I/75099 for supporting this work. 

PMID- 12404379
TI  - Extremely Long Dendronized Polymers: Synthesis, Quantification of Structure
      Perfection, Individualization, and SFM Manipulation This work was supported by
      the Deutsche Forschungsgemeinschaft (Sfb 448, TPs 1 and 5) and the Fonds der
      Chemischen Industrie; SFM=scanning force microscopy. 

PMID- 12404380
TI  - Homoaromaticity in Tris(ethylene)nickel(0) and Tris(ethyne)nickel(0).

PMID- 12404381
TI  - On the Stability of Electrochemically Generated Nanoclusters-A Computer
      Simulation This work was supported by Consejo Nacional de Investigaciones
      Cientificas y Tecnicas (CONICET), by Consejo de Investigaciones Cientificas y
      Tecnologicas de la Provincia de Cordoba (CONICOR), by the Secretaria de Ciencia y
      Tecnica de la Universidad Nacional de Cordoba (SeCyT-UNC; program BID 802/OC-AR
      PICT Nr. 06-04505) and by the Fundacion Antorchas (E.P.M.L and M.G.D.) as well as
      by the Deutsche Forschungsgemeinschaft under the program "Grundlagen der
      elektrochemischen Nanotechnologie" (W.S.). Some of the calculations were
      performed on a Digital workstation financed by the Alexander von Humboldt
      Stiftung. 

PMID- 12404382
TI  - Single-Compound Libraries of Organic Materials: Parallel Synthesis and Screening
      of Fluorescent Dyes This work was made possible with funds from Fonds der
      Chemischen Industrie. We also thank Prof. V. Austel and Dr. E. Mena-Osteritz,
      University of Ulm, for valuable discussions and general input; Dr. G. Gotz,
      University of Ulm, for photography and also Boehringer Ingelheim, Biberach, for
      apparatus support. 

PMID- 12404383
TI  - Single-Compound Libraries of Organic Materials: From the Combinatorial Synthesis
      of Conjugated Oligomers to Structure-Property Relationships This work was made
      possible with funds donated from Fonds der Chemischen Industrie, the BMBF (Kekule
      grant to C.A.B) and the DFG (Schu 929/5-1). We thank Prof. V. Austel, the
      University of Ulm, for valuable discussions and also Boehringer Ingelheim
      Pharmaceuticals Inc., Ridgefield (USA), for apparatus support. 

PMID- 12404384
TI  - Temperature and Viscosity Dependence of the Spin-Directed Stereoselectivity of
      the Carbonyl-Alkene Photocycloaddition This work was funded by the Deutsche
      Forschungsgemeinschaft and the Fonds der Chemischen Industrie. S.B. thanks the
      Egyptian government for a Ph.D. grant. 

PMID- 12404386
TI  - Dimerization of Molecular Phosphorus Oxides.

PMID- 12404385
TI  - The Biosynthesis of Vancomycin-Type Glycopeptide Antibiotics-The Order of the
      Cyclization Steps This work was supported by the Deutsche Forschungsgemeinschaft
      (SFB 323) and by a grant of the EU (MEGATOP, QLK3-1999-00650). R. D. S.
      gratefully acknowledges the support of a Feodor-Lynen Fellowship granted by the
      Alexander-von-Humboldt Stiftung. We thank Corina Bihlmaier and Volker Pfeifer for
      help with transformation and Southern hybridization, J. A. Moss (La Jolla (USA))
      for critical comments on the manuscript and Prof. Dr. M. E. Maier and Prof. Dr.
      H.-P. Fiedler (Tubingen) for generous support. 

PMID- 12404387
TI  - Dehydrocoupling of Phosphanes Catalyzed by a Rhodium(I) Complex We thank the
      National Institutes of Health (NIH) for financial support and O. Daugulis for
      samples of dimesitylphosphane and 2,4,6-tri-tert-butylphenylphosphane. V.P.W.B.
      acknowledges a Feodor Lynen fellowship of the Alexander-von-Humboldt-Stiftung
      (Germany). 

PMID- 12404388
TI  - The First Dectection of Peroxo and Bis-superoxo Complexes of Aluminum: FAlO(2)
      and FAlO(4) We thank Professor R. Ahlrichs for fruitful discussions and the
      Deutsche Forschungsgemeinschaft for the award of an Habilitation grant to H.-J.H.

PMID- 12404389
TI  - The Catalytic Enantioselective Claisen Rearrangement of an Allyl Vinyl Ether This
      work was financially supported by the Deutsche Forschungsgemeinschaft, the Fonds
      der Chemischen Industrie, and the Dr. Otto Rohm Gedachtnisstiftung. M.H. thanks
      Prof. P. Metz and Prof. H.-U. Reissig for their support. 

PMID- 12404390
TI  - Construction of the Complete Aromatic Core of Diazonamide A by a Novel Hetero
      Pinacol Macrocyclization Cascade Reaction We thank Drs. D. H. Huang and G.
      Suizdak for NMR spectroscopic and mass spectrometric assistance, respectively.
      Financial support for this work was provided by The Skaggs Institute for Chemical
      Biology, the National Institutes of Health (USA), American Biosciences, a
      predoctoral fellowship from the National Science Foundation (S.A.S.), a
      postdoctoral fellowship from the Association pour la Recherche sur le Cancer
      (N.G.), and grants from Abbott, Amgen, Array Biopharma, Boehringer-Ingelheim,
      Glaxo, Hoffmann-LaRoche, DuPont, Merck, Novartis, Pfizer, and Schering Plough. 

PMID- 12404391
TI  - Studies in the Total Synthesis of Heliquinomycinone: Proof of Concept and
      Assembly of a Fully Mature Spirocyclization Precursor This work was supported by
      the National Institutes of Health (Grant numbers: AI 16943 and HL25848). A
      Postdoctoral Fellowship is gratefully acknowledged by R.X.R. (NIH, Grant Number
      IF32EY06750-0181). The authors thank Dr. Daniel Chen for important initial
      experiments, Dr. Brian Bridgewater and Prof. Ged Parkin of Columbia University
      for X-ray crystal structure analysis of 11 a, and Yashuiro Itagaki for high
      resolution mass spectral analyses. 

PMID- 12404392
TI  - The Total Synthesis of Heliquinomycinone This work was supported by the National
      Institutes of Health (Grant numbers: AI 16943 and HL25848). The authors thank Dr.
      Makoto Chino of Nippon Kayaku Co., Ltd. for kindly providing a sample of
      heliquinomycin, and Yashuiro Itagaki of Columbia University for high-resolution
      mass spectral analyses. 

PMID- 12404393
TI  - Heat Capacity of the Mixed-Valence Complex {[(n
      C(3)H(7))(4)N][Fe(II)Fe(III)(dto)(3)]}( infinity ), Phase Transition because of
      Electron Transfer, and a Change in Spin-State of the Whole System Contribution
      No. 48 from the Research Center for Molecular Thermodynamics. This work was
      partially supported by a Grant-in-Aid for Scientific Research on the Priority
      Areas of "Metal-Assembled Complexes" (Area No. 401/12023229) from the Ministry of
      Education, Science, Sports and Culture, Japan; dto=dithiooxalato. 

PMID- 12404394
TI  - Olefin Polymerization with [{bis(imino)pyridyl}Co(II)Cl(2)]: Generation of the
      Active Species Involves Co(I) This research was sponsored by CW/STW and Basell
      Technology Company. 

PMID- 12404395
TI  - Design and Synthesis of a Peptide That Binds Specific DNA Sequences through
      Simultaneous Interaction in the Major and in the Minor Groove This work was
      supported by the Spanish M.E.C. (PB97-0524) and the Xunta de Galicia
      (PGIDT00PXI20912PR). M.E.V. and A.M.C. thank the Xunta de Galicia and the
      University of Santiago for their predoctoral fellowships. We are very grateful to
      Prof. G. L. Verdine for his input and support in the early phases of this work.
      We also thank Prof. J. Benavente for allowing us to use the radioactivity
      facilities and Prof. C. Abell for critical reading of the manuscript. 

PMID- 12404396
TI  - Solid-Phase Capture-Release Strategy Applied to Oligosaccharide Synthesis on a
      Soluble Polymer Support This work was supported in part by the Mizutani
      Foundation for Glycoscience (grant to Y.I.), the RIKEN Presidential Fund (grant
      to S.M.), and the Ministry of Education, Culture, Sports, Science and Technology
      (Grant-in-Aid for Scientific Research to S.M.). We thank Dr. Teiji Chihara and
      his staff for the elemental analyses, Ms. Yasuko Tanaka for her contribution at
      the exploratory stage of this work, and Ms. Akemi Takahashi for her technical
      assistance. 

PMID- 12404397
TI  - From Solutions to Surfaces: A Novel Molecular Imprinting Method Based on the
      Conformational Changes of Boronic-Acid-Appended Poly(L-lysine).

PMID- 12404398
TI  - Protein-Polymer Hybrid Amphiphiles This research was supported by the Netherlands
      Foundation for Chemical Research (CW-NWO), the EC TMR Sisitomas and ESF Smarton
      programs, and the Ministerio de Educacion y Cultura (Spain). The authors thank H.
      P. M. Geurts, P. J. H. M. Adams, and J. L. J. van Dongen for experimental
      assistance. 

PMID- 12404399
TI  - A Tetrameric Nickel(II) "Chair" with both Antiferromagnetic Internal Coupling and
      Ferromagnetic Spin Alignment A.W.A. and M.J.P. thank Drexel University for
      support. 

PMID- 12404400
TI  - A Calix[4]arene Gd(III) Complex Endowed with High Stability, Relaxivity, and
      Binding Affinity to Serum Albumin This work was supported by CNR (Programma
      M.U.R.S.T. - Chimica Legge 95/95) "Agenti di contrasto, di shift e sonde
      luminescenti". We thank C.I.M. (Centro Interdipartimentale Misure)
      dell'Universita di Parma for the NMR and mass spectroscopy facilities. 

PMID- 12404401
TI  - Li(10)Mg(6)Zn(31)Al(3): A New Intermetallic Phase Containing Building Blocks for
      Decagonal Quasicrystals The Ames Laboratory is operated for the U.S. Department
      of Energy (US DOE) by Iowa State University under contract No. W-7405-ENG-82.
      This work was supported by the Office of Basic Energy Sciences, Materials
      Chemistry Division of the US DOE. The Bruker CCD-1000 diffractometer was
      purchased by a grant from the U.S. National Science Foundation, NSF 97-11121. 

PMID- 12404402
TI  - Novel Coordination in the First Tellurium Porphyrin Complex: Synthesis and
      Crystal Structure of [Te(ttp)Cl(2)] This work was supported in part by the
      Research Corporation. ttp=meso-tetra-p-tolylporphyrin. 

PMID- 12404403
TI  - An Efficient Total Synthesis of (+/-)-Galanthamine We are grateful to the CNRS
      for financial support, and the French Ministry of Education and Research for Ph.D
      grants to J.L.B. and E.G. Professor P. Potier is gratefully acknowledged for his
      interest in our work. 

PMID- 12404404
TI  - Trimerization of a Steroid Ketone To Form a Chiral Molecular Cleft This work was
      supported by a National Science Foundation Grant (CHE-0077990).

PMID- 12404405
TI  - Recognition and Stabilization of Quadruplex DNA by a Potent New Telomerase
      Inhibitor: NMR Studies of the 2:1 Complex of a Pentacyclic Methylacridinium
      Cation with d(TTAGGGT)(4) We thank the EPSRC of the UK and AstraZeneca for
      financial support to E.G. M.F.G.S. and R.A.H. are supported by the Cancer
      Research Campaign of the UK. 

PMID- 12404406
TI  - Heterolytic Cleavage of the C-C Bond of Acetonitrile with Simple Monomeric Cu(II)
      Complexes: Melding Old Copper Chemistry with New Reactivity This work was
      supported by a grant from the National Science Foundation (CHE-9818492). 

PMID- 12404407
TI  - Pt(II)-Catalyzed Intramolecular Reaction of Furans with Alkynes This work was
      supported by the DGICYT (project PB97-0002) and the MCyT (predoctoral fellowship
      to B.M.-M.). We also acknowledge Johnson Matthey PLC for a generous loan of
      PtCl(2). 

PMID- 12404408
TI  - Catalytic Enantioselective Isomerization of Silacyclopentene Oxides: New Strategy
      for Stereocontrolled Assembly of Acyclic Polyols Initial funding of this work was
      provided by the University of Chicago. We are grateful to the donors of the
      Petroleum Research Fund for further financial support. 

PMID- 12404409
TI  - The First Catalytic, Diastereoselective, and Enantioselective Crossed-Aldol
      Reactions of Aldehydes We are grateful to the National Science Foundation for
      generous financial support (NSF CHE 9803124). 

PMID- 12404410
TI  - Consecutive Three- and Four-Component Coupling Reactions with Anions Generated
      from a Butane Diacetal Desymmetrized Glycolic Acid Derivative We gratefully
      acknowledge financial support from the EPSRC (to D.J.D.), the EU (Marie Curie
      Fellowship to F.R.), and the Novartis Research Fellowship (to S.V.L.). We are
      also indebted to Dr. John E. Davis for the X-ray crystal structure
      determinations. 

PMID- 12404411
TI  - Total Synthesis of Nominal Diazonamides-Part 1: Convergent Preparation of the
      Structure Proposed for (-)-Diazonamide A Funding provided by the NIH (RO1
      GM60591), the NSF (CAREER 9984282), the Howard Hughes Medical Institute (junior
      faculty support), the Robert A. Welch Foundation, and the Advanced Research
      Program of the Texas Higher Education Coordinating Board. 

PMID- 12404412
TI  - Total Synthesis of Nominal Diazonamides-Part 2: On the True Structure and Origin
      of Natural Isolates Funding provided by the NIH (RO1-GM60591), the NSF (CAREER
      9984282), the Howard Hughes Medical Institute (junior faculty support), the
      Robert A. Welch Foundation, and the Advanced Research Program of the Texas Higher
      Education Coordinating Board. We are grateful to Professor Michael Roth for his
      time, insight, and advice. 

PMID- 12404413
TI  - Preview.

PMID- 12404415
TI  - Graphical Abstract.

PMID- 12404416
TI  - Combined Effects of Metal and Ligand Capable of Accepting a Proton or Hydrogen
      Bond Catalyze Anti-Markovnikov Hydration of Terminal Alkynes The support of San
      Diego State University is acknowledged. 

PMID- 12404417
TI  - Organic Nanoparticles in the Aqueous Phase-Theory, Experiment, and Use.
AB  - Many active organic compounds and organic effect materials are poorly soluble in
      water, or even insoluble. Aqueous forms of application thus require special
      formulation techniques to utilize or optimize the physiological (pharmaceuticals,
      cosmetics, plant protection, nutrition) or technical (varnishes, printing inks,
      toners) action. The most interesting properties of nanodispersions of active
      organic compounds and effect materials include the impressive increase in
      solubility, the improvement in biological resorption, and the modification of
      optical, electrooptical, and other physical properties which are achievable only
      with particle sizes in the middle or lower nanometer range (50-500 nm). Hence in
      addition to economic and ecological constraints there are also technical demands
      which appear to urgently require the development of new processes for the
      production of organic nanoparticles as alternatives to the established mechanical
      milling processes. In this context attention is drawn to the recent increase in
      research activities which have as their objective the continuous, automatic
      preparation of nanodispersed systems by precipitation from molecular solution. In
      this review the current state of knowledge of the fundamentals of particle
      formation from homogeneous solution and the effect of solvent and polymer
      additives on the morphology and supramolecular structure of the nanoparticle will
      be discussed. The practical implementation of this new formulation technology
      will be explored in detail for the carotenoids, a class of compounds of both
      physiological and technical interest.

PMID- 12404418
TI  - Self-Complementary Quadruple Hydrogen-Bonding Motifs as a Functional Principle:
      From Dimeric Supramolecules to Supramolecular Polymers.
AB  - The self-association of individual molecules can lead to the formation of highly
      complex and fascinating supramolecular aggregates. However, for binding motifs
      which rely only on hydrogen bonds, a combination of several such weak
      interactions is necessary to observe self-association in solution. Systems based
      on four hydrogen bonds in a linear array can be obtained which efficiently
      aggregate at least in chloroform. Besides the physical-organic characterization
      of these aggregates and the factors influencing their stability, such quadruple
      hydrogen-bonding motifs can also be used in the field of materials science to
      synthesize, for the first time, supramolecular polymers through the self
      association of self-complementary monomers. As the formation of noncovalent
      interactions is reversible and their strength depends significantly on the
      chemical environment (for example, solvent, temperature), the macroscopic
      properties of such polymers can be controlled by variation of these parameters;
      hence a first step towards intelligent materials with tailor-made properties is
      made.

PMID- 12404419
TI  - Chemistry at the Uncertainty Limit This contribution is an extended version of a
      recent commentary published in Nature, in the new section Concepts.([1]) The
      invitation by the Editor of Angewandte Chemie made me steer the piece towards
      chemistry questions and provide the experimental-theoretical bridge relevant to
      molecular dynamics. 

PMID- 12404420
TI  - Recent Progress in the Enantioselective Synthesis of beta-Lactams: Development of
      the First Catalytic Approaches.

PMID- 12404421
TI  - Towards the Understanding of Solid-State Structures: From Cubic to Chainlike
      Arrangements in Group 11 Halides This work was supported by the Alexander von
      Humboldt Foundation, the Marsden Fund managed by the Royal Society of New Zealand
      (contract number 96-UOA-PSE-0081), and the Auckland University Research
      Committee. 

PMID- 12404422
TI  - A Metallosupramolecular Capsule with the Topology of the Tetrahedron, 3(3),
      Assembled from Four Guanidine-Based Ligands and Twelve Cadmium Centers This work
      was supported by the "Deutsche Forschungsgemeinschaft" DFG and the Australian
      Research Council. The authors thank Dr. B. F. Abrahams for help with the X-ray
      crystallography. 

PMID- 12404423
TI  - Polarizabilities Inside Molecular Containers This work was supported by the Swiss
      National Science Foundation (projects 620-58000.99 and 4047-057552) within the
      program NFP 47 "Supramolecular Functional Materials". 

PMID- 12404424
TI  - The Highly Flexible Bis(hydroxylamine) Ligand [ON(Me)](2)CH(2)(2-) and Its
      Different Behavior in the Chemistry of Aluminum and Gallium This work was
      supported by the Deutsche Forschungsgemeinschaft, the Fonds der Chemischen
      Industrie, and the Leonhard-Lorenz-Stiftung. We are grateful to Professor Hubert
      Schmidbaur (Technische Universitat Munchen) for generous support. 

PMID- 12404425
TI  - The Synthesis and Oxidative Properties of Polymer-Supported IBX.

PMID- 12404426
TI  - Oxidizing Polymers: A Polymer-Supported, Recyclable Hypervalent Iodine(V) Reagent
      for the Efficient Conversion of Alcohols, Carbonyl Compounds, and Unsaturated
      Carbamates in Solution J.R. gratefully acknowledges generous support from Prof.
      M. E. Maier, Tubingen, the Strukturfonds of the University of Tubingen, the Fonds
      der Chemischen Industrie, and the DFG. We thank Graeme Nicholson, Dietmar Schmid,
      and Daniel Bischoff for analytical support. 

PMID- 12404427
TI  - Alkali Metal Tetrelide-Tetrelates: "Double Salts" With [E(4)](4-) Zintl Anions
      (E=Si, Ge) and the First Dimeric Cyclotrisilicate Ions [Si(6)O(17)](10- ) This
      work was supported by the Deutsche Forschungsgemeinschaft, the Verband der
      Chemischen Industrie, the Eidgenossische Technische Hochschule Zurich, the
      Bundesministerium fur Forschung und Technik, and the Adolf-Messer-Stiftung. T.F.
      and S.H. thank Prof. Dr. D. Gunther for the LA-ICP-MS and Dr. V. Shklover (both
      of the ETH Zurich) for the EDX measurements, C.H. and C.R. thank Mr. M. Idilbi
      for assistance in the preparative work. 

PMID- 12404428
TI  - The First Biscarbene Complex of a Group 4 Metal: [Zr{C(Me(2)P=NSiMe(3))(2)}(2)]
      We thank the Natural Sciences and Engineering Research Council of Canada, NOVA
      Chemicals Corp., and the University of Alberta for financial support. 

PMID- 12404429
TI  - Syntheses and Structures of Niobium Copper Chalcogenido Clusters:
      [Cu(4)Nb(6)Se(12)O(PMe(3))(10)][Cu(4)NbSe(4)Cl(2)(PMe(3))(4)]. 1.5 DMF,
      [Cu(4)Nb(2)Se(6)(PMe(3))(8)], (NEt(4))[Cu(6)Nb(2)S(6)Cl(5)(PEt(3))(6)], and
      [Cu(6)NbTe(3)(Te(2))(2)(PEt(3))(6)][CuCl(2)] This work was supported by the
      Deutsche Forschungsgemeinschaft and the Fonds der Chemischen Industrie. 

PMID- 12404430
TI  - P(5)X(2)(+) (X=Br, I), a Phosphorus-Rich Binary P-X Cation with a C(2v)-Symmetric
      P(5) Cage This work was supported by the Deutsche Forschungsgemeinschaft and the
      Fonds der Chemischen Industrie. We thank Prof. H. Schnockel for valuable
      discussions. 

PMID- 12404431
TI  - Lewis Acid/Base Stabilized Phosphanylalane and -gallane This work was supported
      by the Deutsche Forschungsgemeinschaft and the Fonds der Chemischen Industrie.
      A.Y.T. is grateful to the Alexander von Humboldt Foundation for a research
      fellowship. 

PMID- 12404432
TI  - Norbornadiene-Quadricyclane Valence Isomerism for a Tetraphosphorus Derivative
      The Netherlands Organization for Scientific Research (NOW/CW) is acknowledged for
      partial support (A.L.S., M.L., K.L.), as are the NSERC of Canada for a
      scholarship (S.B.C.), and EPSRC for funding phosphaorganometallic chemistry at
      Sussex University (J.F.N.). Dr. H. Zappey is thanked for the HR-MS spectra and J.
      C. Slootweg for his initiative. 

PMID- 12404433
TI  - From Cyclodextrin Assemblies to Porous Materials by Silica Templating We thank
      the Max-Planck society for funding. 

PMID- 12404434
TI  - Enantioseparation of Racemic Organic Molecules by a Zeolite Analogue This work
      was supported by The Major State Basic Research Development Program (Grant No.
      G2000077500), the National Natural Science Foundation of China, the Camille
      Dreyfus Teacher-Scholar Program, the National Science Foundation of the USA (CHE
      9904338), and the University of Tennessee SARIF EPPE Fund. 

PMID- 12404435
TI  - Control of Liquid Crystallinity of Diazadibenzoperylene Dyes by Covalent and
      Hydrogen-Bonded Attachment of Mesogens We thank P. Zell for his assistance in the
      practical work, Frau G. Dorfner and Prof. U. Thewalt (Sektion Rontgenbeugung,
      Universitat Ulm) and Dr. B. Heise (Abteilung Experimentelle Physik, Universitat
      Ulm) for X-ray diffraction studies. Financial support from the Deutsche
      Forschungsgemeinschaft (Habilitandenstipendium for F.W.), the Fonds der
      Chemischen Industrie (Liebig-Stipendium for F.W.), and the Dr. Otto Rohm
      Gedachtnisstiftung is gratefully acknowledged. 

PMID- 12404436
TI  - Origin of Ferromagnetism in Cyano-Bridged Compounds Containing d(1)
      Octacyanometallates Financial support by the Belgian National Science Foundation
      and Flemish Government under the Concerted Action Scheme, the ESF programme on
      molecular magnets, the Russian Foundation for Basic Research (Grant No. 01-02
      32210), and the INTAS Grant 00-00565 are gratefully acknowledged. The authors
      thank Professor Silvio Decurtins and the members of his group for stimulating
      discussions and for sending us the structural data on the niobium compound prior
      the publication, and Dr. Hogni Weihe for useful discussions. We also thank Ken
      Somers for the help with the Figures. 

PMID- 12404437
TI  - "Cap-Tag"-Novel Methods for the Rapid Purification of Oligosaccharides Prepared
      by Automated Solid-Phase Synthesis Financial support from the donors of the
      Petroleum Research Fund, administered by the ACS (ACS-PRF 34649-G1), Merck
      (Predoctoral Fellowship for E.R.P.), Boehringer-Ingelheim (Predoctoral Fellowship
      for E.R.P.), and the NIH (Biotechnology Training Grant for M.C.H.) is gratefully
      acknowledged. Funding for the MIT-DCIF Inova 501 was provided by the NSF (Award
      CHE-9808061). Funding for the MIT-DCIF Avance (DPX) 400 was provided by the NIH
      (Award 1S10RR13886-01). We thank Silicycle (Quebec City, Canada) for the generous
      gift of fluorous silica gel and isocyanate silica gel scavenger resin. We thank
      Dr. O. Plante for helpful discussions and help with the automated oligosaccharide
      synthesizer. 

PMID- 12404438
TI  - From CO(2) to Methanol by Hybrid QM/MM Embedding This work was supported by EU
      Esprit IV project 25047. S.A.F. is grateful to ICI and Synetix for funding. K.
      Waugh, L. Whitmore, S. Cristol, and P. Sushko are thanked for their helpful
      insights. QM/MM=quantum mechanics/molecular mechanics. 

PMID- 12404439
TI  - cis-3,4-Dichlorocyclobutene as a Versatile Synthon in Organic Synthesis. Rapid
      Entry into Complex Polycyclic Systems with Remarkably Stereospecific Reactions We
      thank Drs. D. H. Huang and G. Siuzdak for their assistance with NMR spectroscopy
      and mass spectrometry, respectively. This work was financially supported by the
      National Institutes of Health (USA) and The Skaggs Institute for Chemical
      Biology, a postdoctoral fellowship from the Skaggs Institute for Research (to
      V.G.), and grants from Abbott, Amgen, ArrayBiopharma, Boehringer-Ingelheim,
      Glaxo, Hoffmann-La Roche, DuPont, Merck, Novartis, Pfizer, and Schering Plough. 

PMID- 12404440
TI  - A New Class of Modular Phosphinite-Oxazoline Ligands: Ir-Catalyzed
      Enantioselective Hydrogenation of Alkenes We thank Dr. Martin Studer and Dr.
      Benoit Pugin (Solvias AG, Basel) for fruitful discussions, and Prof. Kevin
      Burgess (Texas A&M University) for preprints of related unpublished work.
      Financial support by the Swiss National Science Foundation is gratefully
      acknowledged. 

PMID- 12404441
TI  - Synthesis of Highly Magnetic, Air-Stable Iron-Iron Carbide Nanocrystalline
      Particles by Using Power Ultrasound A. Gedanken is grateful for the support of
      the German Ministry of Science through the Deutsche-Israeli DIP program. I.
      Felner and A. Gedanken thank also the Israeli Ministery of Science, Culture and
      Sport for an infrastructure grant. S. I. Nikitenko thanks the Bar-Ilan Research
      Authority for his fellowship. The authors also thank Dr. Shifra Hochberg for
      editorial assistance. 

PMID- 12404442
TI  - Concise Stereoselective Routes to Advanced Intermediates Related to Natural and
      Unnatural Pinnaic Acid This work was supported by the National Institutes of
      Health (Grant Numbers: CA28824). Postdoctoral Fellowship support is gratefully
      acknowledged by M.W.C. (U.S. Army BCRP, DAMD17-98-1-8154), M.F.H. (5T32 CA62948
      05), and D.T. (Schering Research Foundation, Berlin). We thank Dr. George
      Sukenick of the MSKCC NMR Core Facility for NMR and mass spectral analyses. 

PMID- 12404443
TI  - Total Synthesis and Proof of Stereochemistry of Natural and Unnatural Pinnaic
      Acids: A Remarkable Long-Range Stereochemical Effect in the Reduction of 17-Oxo
      Precursors of the Pinnaic Acids This work was supported by the National
      Institutes of Health (Grant Numbers: CA28824). Postdoctoral Fellowship support is
      gratefully acknowledged by M.W.C. (U.S. Army BCRP, DAMD17-98-1-8154). We thank
      Dr. George Sukenick of the MSKCC NMR Core Facility for NMR and mass spectral
      analyses. We would like to thank professor Nakanishi for his supportive interest
      in the project. 

PMID- 12404444
TI  - Enzyme Fingerprints by Fluorogenic and Chromogenic Substrate Arrays We would like
      to thank Prof. R. Furstoss and Dr. A. Archelas at the Faculte des Sciences de
      Luminy, Marseille, France, for providing a sample of Aspergillus niger EH, and
      Dr. C. Weijers at the Department of Food Technology and Nutrition Sciences,
      Wageningen University, the Netherlands, for providing a sample of Rhodotorula
      glutinis EH. This work was supported by the University of Bern, the European COST
      program (Action D12), the Swiss Office Federal de l'Education et de la Science,
      Proteus SA (Nimes, France), the Ministero della Universita e della Ricerca
      Scientifica e Tecnologica (MURST), and Consiglio Nazionale delle Ricerche (CNR)
      (Roma). P.C. gratefully acknowledges Merck for generous financial support from a
      2000 ADP Chemistry Award. 

PMID- 12404445
TI  - Synthesis of Fluorogypsetin and Fluorobrevianamide E by a Novel Fluorination
      Cyclization of cyclo-L-Trp-L-AAs This work was supported by a Grant-in-Aid for
      Scientific Research from the Ministry of Education, Science, Sports and Culture,
      Japan. N.S. wishes to thank the Novartis Foundation (Japan) for the Promotion of
      Science for support. We thank Prof. Yoshio Takeuchi very much for generously
      sharing his facilities, for very kind encouragement and for giving us the
      opportunity to study in the field of fluorine chemistry. We also thank F-TECH
      INC. for a gift of FP-T300. 

PMID- 12404446
TI  - The First Alkaline Earth Metal Complex Containing a &mgr;-eta(1):eta(1) Allyl
      Ligand: Structure of [{HC[C(tBu)NC(6)H(3)(CHMe(2))(2)](2)Mg(C(3)H(5))}(6)] The
      financial support of the UK EPSRC (S.T.L., S.P.) and The Royal Society (C.A.M.)
      is gratefully acknowledged. 

PMID- 12404447
TI  - An Unorthodox Conformation of [18]porphyrin-(1.1.1.1) Heteroanalogue-21,23
      Ditelluraporphyrin with a Flipped Tellurophene Ring Financial support from the
      State Committee for Scientific Research KBN of Poland (Grant: 3 T09A 155 15) and
      the Foundation for Polish Science is gratefully acknowledged. 

PMID- 12404448
TI  - Remarkable Rate Enhancement of Ligand Substitution Promoted by Geometrical
      Arrangement of Tridentate "Spectator" Ligands K.J.T. acknowledges Arco Chemical
      and the National Science Foundation for support of this research. M.H.V.H.
      gratefully acknowledges postdoctoral fellowship support from the Director's
      Office of Los Alamos National Laboratory. Los Alamos National Laboratory is
      operated by the University of California for the U.S. Department of Energy under
      Contract W-7405-ENG-36. M.H.V.H. also thanks Dr. Beverly K. Hartline (Deputy
      Laboratory Director, Argonne National Laboratory), Dr. Donald G. Lee (Chemistry
      Professor, University of Regina, Saskatchewan, Canada, S4S0A2), Dr. R. Thomas
      Baker (Los Alamos National Laboratory), and Dr. David E. Morris (Los Alamos
      National Laboratory) for their suggestions and discussions. 

PMID- 12404449
TI  - Homogeneous Reactions in Supercritical Carbon Dioxide Using a Catalyst
      Immobilized by a Microporous Silica Membrane.

PMID- 12404450
TI  - Catalytic Electronic Activation: Indirect Addition of Nucleophiles to an Allylic
      Alcohol This work was supported by the University of Bath and Roche Discovery
      (P.J.B.). 

PMID- 12404451
TI  - The tmbp Dianion in the Contact Ion Pair [(tmbp)Na(2)(dme)(1.5)](n) and in the
      Solvent-Separated Ion Pair [tmbp][(2.2.1)Li](2) This work was supported by the
      CNRS and the Ecole Polytechnique; tmbp=4,4',5,5'-tetramethyl-2,2'-biphosphinine,
      DME=1,2-dimethoxyethane. 

PMID- 12404452
TI  - Identification of a PLP-Dependent Threonine Transaldolase: A Novel Enzyme
      Involved in 4-Fluorothreonine Biosynthesis in Streptomyces cattleya This work was
      supported by the Biotechnological and Biological Sciences Research Council and
      the University of St Andrews. 

PMID- 12404453
TI  - [(Indenyl)Ru(biphop-F)](+): A Lewis Acid Catalyst That Controls both the Diene
      and the Dienophile Facial Selectivity in Diels-Alder Reactions This work was
      supported by the Swiss National Science Foundation (FNS grant 20-59374.99) and
      The Ministere des Affaires Etrangeres from France (Lavoisier grant to V.A.).
      biphop-F=1,2-bis[bis(pentafluorophenyl)phosphanyloxy]-1,2-diphenylethane. 

PMID- 12404454
TI  - CH.O Hydrogen Bonding Influences pi-Facial Stereoselective Epoxidations We are
      grateful to the National Institute of General Medical Sciences, National
      Institutes of Health (GM-36700) for financial support of this research and the
      National Computational Science Alliance (Illinois) for computer time and support.

PMID- 12404455
TI  - Use of a Perfluoroalkylsulfonyl (PFS) Linker in a "Traceless" Synthesis of
      Biaryls through Suzuki Cleavage.

PMID- 12404456
TI  - Asymmetric Allylsilane Additions to Enantiopure N-Acylhydrazones with Dual
      Activation by Fluoride and In(OTf)(3) We thank the National Science Foundation
      (Vermont EPSCoR) and the University of Vermont for generous support. 

PMID- 12404457
TI  - Molecular Insight Into Surface Organometallic Chemistry Through the Combined Use
      of 2D HETCOR Solid-State NMR Spectroscopy and Silsesquioxane Analogues We are
      also indebted to the CNRS, ENS Lyon, and ESCPE Lyon for financial support. M.C.
      is grateful to the French ministry of education, research, and technology (MENRT)
      for a pre-doctoral fellowship. E.A.Q. gratefully acknowledges Universita di Pisa
      and S.N.A.M. for financial support. 2D HETCOR=two-dimensional heteronuclear
      correlation. 

PMID- 12404458
TI  - Asymmetric Permanganate-Promoted Oxidative Cyclization of 1,5-Dienes by Using
      Chiral Phase-Transfer Catalysis This work was supported by the EPSRC (J.F.K.) and
      the Royal Society (R.C.D.B.). We thank Dr. Barry Lygo (University of Nottingham)
      for helpful discussions, and Syngenta and Merck Sharp and Dohme for unrestricted
      grants. 

PMID- 12404459
TI  - Reactivity of Dimetallapentaboranes-nido-[Cp$?rm{^{{?ast}}_{2}}$M(2)B(3)H(7)]
      with Alkynes: Insertion to Form a Ruthenacarborane (M=RuH) versus Catalytic
      Cyclotrimerization to Form Arenes (M=Rh) This work was supported by the National
      Science Foundation. Cp*=eta-C(5)Me(5). 

PMID- 12404460
TI  - (eta(3)-Allyl)palladium Complexes Bearing Diphosphinidenecyclobutene Ligands:
      Highly Active Catalysts for the Hydroamination of 1,3-Dienes This work was
      supported by a Grant-in-Aid for Scientific Research from the Ministry of
      Education, Science, Sports and Culture, Japan. 

PMID- 12404461
TI  - Web Site: Thermochemistry Standards.

PMID- 12404462
TI  - Preview.

PMID- 12404464
TI  - Graphical Abstract.

PMID- 12404465
TI  - Directed Evolution and Biocatalysis.
AB  - This review describes the current state of biocatalysis in the chemical industry.
      Although we recognize the advantages of chemical approaches, we suggest that the
      use of biological catalysis is about to expand dramatically because of the recent
      developments in the artificial evolution of genes that code for enzymes. For the
      first time it is possible to consider the rapid development of an enzyme that is
      designed for a specific chemical reaction. This technology offers the opportunity
      to adapt the enzyme to the needs of the process. We describe herein the
      development of enzyme evolution technology and particularly DNA shuffling. We
      also consider several classes of enzymes, their current applications, and the
      limitations that should be addressed. In a review of this length it is impossible
      to describe all the enzymes with potential for industrial exploitation; there are
      other classes, which given appropriate activity, selectivity, and robustness,
      could become useful tools for the industrial chemist. This is an exciting era for
      biocatalysis and we expect great progress in the future.

PMID- 12404466
TI  - Imido Analogues of Common Oxo Anions: A New Episode in the Chemistry of Cluster
      Compounds.
AB  - Oxo anions of p- and d-block elements, for example, SiO(4)(4-), PO(4)(3-),
      SO(4)(2-), and CrO(4)(2-), are commonly encountered species. The full or partial
      replacement of the oxo ligands by isoelectronic imido (NR) groups generates
      homoleptic polyimido anions of the type [E(NR)(x)](z-) or heteroleptic imidooxo
      anions with the general formula [O(y)E(NR)(x-y)](z-) (where E=main group element
      or transition metal). The alkali metal derivatives of this new class of anions
      form ternary or quaternary cluster systems, respectively. The structures of these
      clusters can be rationalized in terms of the self-assembly of fundamental
      building blocks. An understanding of the factors that control this process may
      allow the design of functional materials with specific properties. In addition,
      these anions are attracting attention as multidentate ligands with unique
      electronic and stereochemical properties that may engender novel metal-centered
      chemistry.

PMID- 12404467
TI  - About the Antiaromaticity of Planar Cyclooctatetraene I thank Jens Panitzky for
      the additional DFT calculations, and Professor Jay Siegel, La Jolla, CA, and
      Professor Otto Ermer, Cologne, for helpful comments. 

PMID- 12404468
TI  - Recent Developments in Transition Metal Catalyzed Intermolecular Hydroamination
      Reactions-A Breakthrough?

PMID- 12404469
TI  - Carbon Dioxide Fixation by Binuclear Complexes with Hydrophobic Binding Pockets
      This work was supported by the Deutsche Forschungsgemeinschaft (Project No. KE
      585/3-1). The author thanks Prof. Dr. H. Vahrenkamp for his support of this work.

PMID- 12404470
TI  - Functionalized DNA: A New Replicable Biopolymer We thank Dr. Andreas Marx,
      University of Bonn, for helpful advice and discussions. This work was supported
      by the Fonds der Chemischen Industrie, the Karl-Ziegler Stiftung, and the
      Deutsche Forschungsgemeinschaft. 

PMID- 12404471
TI  - Nitrogen Photofixation at Nanostructured Iron Titanate Films This work was
      supported by the Deutsche Forschungsgemeinschaft and Fonds der Chemischen
      Industrie. Experimental help by Dipl.-Chem. Harald Weiss is gratefully
      acknowledged. 

PMID- 12404472
TI  - PASSflow Syntheses Using Functionalized Monolithic Polymer/Glass Composites in
      Flow-Through Microreactors Part of these studies were supported by the Fonds der
      Chemischen Industrie and the European Community (EC project number HPRI-CT-1999
      00085) for which we are grateful. PASSflow=Polymer Assisted Solution-Phase
      Synthesis technique in flow-through mode. 

PMID- 12404473
TI  - An Analytical Approach for a Comprehensive Study of Organic Aerosols The
      financial support by the Bundesministerium fur Bildung und Forschung and the
      Senatsverwaltung fur Wissenschaft, Forschung und Kultur des Landes Berlin (ISAS
      Berlin), and the Ministerium fur Schule, Wissenschaft und Forschung NRW (ISAS
      Dortmund) is gratefully acknowledged. The authors want to thank U. Marggraff and
      W. Nigge (Dortmund) for assistence during MS measurements and Dr. R. Koppe (Univ.
      Karlsruhe) and Dr. H. Sievers (GSG Karlsruhe) for assistance in FT-ICR-MS
      measurements. 

PMID- 12404474
TI  - Sidewall Functionalization of Carbon Nanotubes This work was supported by the
      European Union under the 5th Framework Research Training Network 1999, HPRNT 1999
      00011 FUNCARS. 

PMID- 12404475
TI  - No Polymerization with Metallocenes in Water?-A Prejudice is Refuted We thank Dr.
      A. Haunschild and Dr. M. Geprags for valuable discussions and Dr. W. Heckmann
      (SEM), Dr. I. Hennig (DSC), and Dr. S. Lehmann (NMR) for polymer analysis. 

PMID- 12404476
TI  - alpha(1-3)-Galactosyltransferase Inhibition Based on a New Type of Disubstrate
      Analogue This work was supported financially by the Deutschen
      Forschungsgemeinschaft and the Fonds der Chemischen Industrie. 

PMID- 12404477
TI  - Polyphenylene Dendrimers as Sensitive and Selective Sensor Layers This work has
      been supported by the TMR European Research Program, through the SISITOMAS
      Project, by the Volkswagen Foundation, the German Science Foundation (DFG), the
      German Federal Ministry for Science and Technology (BMBF), and the Fonds of the
      German Chemical Industry, Frankfurt (Main); U.M.W. thanks the latter for a
      graduate fellowship, we all thank C. Beer and S. Spang for valuable support
      during the syntheses. 

PMID- 12404478
TI  - Gold Nanoparticles with Covalently Attached Polymer Chains This work was
      supported by the Deutsche Forschungsgemeinschaft and by the Fonds der Chemischen
      Industrie. We are grateful to Prof. Dr. H. Weller, Institut fur Physikalische
      Chemie der Universitat Hamburg, for the transmission electron microscopy pictures
      and to Prof. Dr. M. Moller and Dipl.-Chem. Bernd Tartsch, Abteilung Organische
      Chemie III der Universitat Ulm, for the scanning forcce microscopy
      investigations. 

PMID- 12404479
TI  - Solvothermal Synthesis of a 24-Nuclear, Cube-Shaped Squarato-oxovanadium(IV)
      Framework: [N(nBu)(4)](8)[V(24)O(24)(C(4)O(4))(12)(OCH(3))(32)].

PMID- 12404480
TI  - 1,6-Methano[10]annulene has a Delocalized Structure in S(0) and S(1): High
      Resolution Spectroscopy in a Supersonic Jet This work was supported by the Fonds
      der Chemischen Industrie. 

PMID- 12404481
TI  - Silynes (RC identical with SiR') and Disilynes (RSi identical with SiR'): Why Are
      Less Bonds Worth Energetically More? The research is supported by an Israel
      Science Foundation (ISF) and a Niedersachsen grant (to S.S.), by a U.S.-Israel
      Binational Science Foundation (BSF) grant (to Y.A.) and by the Minerva
      Foundation. S.S. and F.O. thank the European Union for a Marie Curie Fellowship
      (Contract number: MCFI-1999-00145). S.S. and D.D. thank P. C. Hiberty for the
      helpful advice. 

PMID- 12404482
TI  - Intrinsic Bond Strengths of Multiple C-C, Si-Si, and C-Si Bonds Thanks are given
      to Prof. Y. Apeloig and Dr. M. Karni for the discussions. I would also like to
      thank Prof. H. Hopf and Prof. R. Herges for providing me with computing time. 

PMID- 12404483
TI  - A New Type of Heteropolyoxometalates formed from Lacunary Polyoxotungstate Ions
      and Europium or Yttrium Cations We gratefully acknowledge Dr. Gerard Parkin and
      Dr. Brian Bridgewater for the use of the diffractometer at Columbia University
      and helpful discussions. Supported by NSF-CHE9502213, NIH-GM60654-01 (LCF), NIH
      MARC (FGP), NSF-CHE-9705788 (W.D.H), and NSF Grant PCM8111745 for the purchase of
      the 400 MHz Spectrometer. Infrastructure at Hunter College is supported in part
      by NIH-Research Centers in Minority Institutions Grant RR03037-08S2.

PMID- 12404484
TI  - "Nanoobjects" by Self-Assembly Concomitant with Modifications under Alterable
      Boundary Conditions: Incorporation of Paramagnetic Metal Centers (Cu(2+)) in Ring
      Shaped Molybdenum-Oxide Based Clusters The authors thank Prof. D. Gatteschi,
      University of Florence (Italy), for helping with the interpretation of the ESR
      spectrum, and Dipl.-Chem. A. Berkle and Dr. J. Hockemeyer, University of
      Bielefeld (Germany), for their collaboration. C. R. thanks the Alexander von
      Humboldt Foundation for her fellowship. Financial support by the Deutsche
      Forschungsgemeinschaft and the Fonds der Chemischen Industrie is gratefully
      acknowledged. 

PMID- 12404485
TI  - Structure of Ca(13)Cd(76): A Novel Approximant to the MCd(5.7) Quasicrystals
      (M=Ca, Yb) This study was financially supported by the Swedish Natural Science
      Research Council. 

PMID- 12404486
TI  - X-ray Crystal Structure of a Bisubstrate Inhibitor Bound to the Enzyme Catechol-O
      methyltransferase: A Dramatic Effect of Inhibitor Preorganization on Binding
      Affinity We thank F. Hoffmann-La Roche for generous support of this work. We are
      grateful to P. Malherbe for the cloning of COMT, P. Caspers for the expression of
      COMT, A. Cesura for enzyme purification, B. Wipf for fermentation, and H. W. Lahm
      for sequencing. 

PMID- 12404487
TI  - A Blue Luminescent Star-Shaped Zn(II) Complex that Can Detect Benzene This work
      was supported by the Natural Sciences and Engineering Research Council of Canada
      and the Xerox Research Foundation. 

PMID- 12404488
TI  - Lamellae-Nanotube Isomerism in Hydrogen-Bonded Host Frameworks This work was
      supported by the National Science Foundation (DMR-9908627), in part by the MRSEC
      Program of the National Science Foundation (DMR-9809364), and the Natural
      Sciences and Engineering Research Council of Canada (postdoctoral fellowship for
      K.T.H.). 

PMID- 12404489
TI  - Isolation and Characterization of the Osmium(V)-Imido Complex
      [Os(V)(Tp)(Cl)(2)(NH)] We are grateful to the National Science Foundation under
      Grant number CHE-9503738, the Los Alamos National Laboratory (DOE) under Grant
      Number 10730-001-00-2C, and the Laboratory Directed Research and Development
      Program for support of this research. M. H. V. Huynh gratefully acknowledges
      postdoctoral fellowship support from the Directorapos;s Office of Los Alamos
      National Laboratory. Los Alamos National Laboratory is operated by the University
      of California for the U.S. Department of Energy under Contract W-7405-ENG-36. We
      also thank Dr. Paul R. Sharp (Professor of Chemistry, University of Missouri,
      Columbia, MO, 65211) for the information on transition metal parent imido
      complexes. 

PMID- 12404490
TI  - Chiral Recognition of O-Phosphoserine by Mass Spectrometry This work was
      supported by the Ministero della Universita e della Ricerca Scientifica e
      Tecnologica (MURST) and the Consiglio Nazionale delle Ricerche (CNR). The authors
      express their gratitude to F. Angelelli for technical assistance. 

PMID- 12404491
TI  - Stereocontrolled Total Synthesis of (+)-Altohyrtin A/Spongistatin 1 Financial
      support was provided by the EPSRC (GR/L41646), Cambridge Commonwealth Trust
      (Scholarship to M.J.C.), EC (Marie Curie Postdoctoral Fellowship to J.L.A.), DFG
      (Postdoctoral Fellowship to T.T.), NSERC-Canada (Postdoctoral Fellowship to
      R.M.O.), Churchill College (Research Fellowship to D.J.W.), Kingapos;s College
      and Sims Fund, Cambridge (Scholarship to D.Y.K.C.). We also thank Merck and
      AstraZeneca Pharmaceuticals for generous support, and Dr. Anne Butlin (AZ) and
      Dr. Nick Bampos (Cambridge) for valuable assistance. 

PMID- 12404492
TI  - Synthesis of a 10-Membered Carbocycle By Olefin Metathesis Financial support has
      been provided by the Academy of Finland and HUT. 

PMID- 12404493
TI  - Experimental Detection of Tetraoxygen This work was supported by the University
      of Rome, the Italian National Research Council (CNR), and the Ministero
      dellapos;Universita e della Ricerca Scientifica e Tecnologica (MURST). 

PMID- 12404494
TI  - Fundamental Zeolite Crystal Growth Rates from Simulation of Atomic Force
      Micrographs J.R.A. gratefully acknowledges the EPSRC for Advanced Fellowship no
      AF/990985 and N.H. acknowledges financial support from the EPSRC. 

PMID- 12404495
TI  - Synthesis of the ABCD Ring System of Azaspiracid We thank Drs. D. H. Huang and G.
      Siuzdak for NMR spectroscopic and mass spectrometric assistance, respectively.
      This work was financially supported by the National Institutes of Health (USA),
      The Skaggs Institute for Chemical Biology, a predoctoral fellowship from Bristol
      Myers Squibb (to F.B.), postdoctoral fellowships from The Skaggs Institute for
      Research (to W.Q.), the Academy of Finland, the Ella and Georg Ehrnrooth
      Foundation and the Tauno Tonning Foundation (all to P.M.P.), and Bayer AG (to
      J.H.), as well as grants from Abbott, Amgen, ArrayBiopharma, Boehringer
      Ingelheim, Glaxo, Hoffmann-La Roche, DuPont, Merck, Novartis, Pfizer, and
      Schering Plough. 

PMID- 12404496
TI  - [12.12]Paracyclophanedodecaynes C(36)H(8) and C(36)Cl(8): The Smallest
      Paracyclophynes and Their Transformation into the Carbon Cluster Ion C(36)(-)
      This work was supported in part by Grants-in-Aid for Scientific Research from the
      Ministry of Education,Science,Sports and Culture of Japan. Y.T. is grateful to
      Shin-Etsu Chemical Co. for the generous gift of an organosilicon reagent. 

PMID- 12404498
TI  - Polystyrene-Bound Tetrafluorophenylbis(triflyl)methane as an Organic-Solvent
      Swellable and Strong Bronsted Acid Catalyst The authors thank Mr. Shoichi Kondo
      for the single-crystal X-ray analysis. Sodium triflate was generously donated by
      Central Glass Co., Ltd., Japan. The authors also acknowledge Dr. Yuko Wasada and
      Dr. Manabu Kubota for their helpful discussions on the theoretical calculations. 

PMID- 12404497
TI  - The Zipper-Mode Domino Intramolecular Diels-Alder Reaction: A New 0-->ABCD
      Strategy for Steroids and Related Compounds We thank Dr. Simon Fielder
      (HortResearch New Zealand) and Mr. Leon Wong (University of Sydney) for
      preliminary experiments, Dr. Kelvin Picker (University of Sydney) for assistance
      with HPLC and GC analyses, and Dr. Ian Luck (University of Sydney) for 2D NMR
      experiments. This work was supported by The Australian Research Council and The
      University of Sydney. 

PMID- 12404499
TI  - Steric Turnoff of Vibrationally Mediated Negative Differential Resistance in a
      Single Molecule This work was supported by the National Science Foundation (DMR
      9417866) and by the Cornell Center for Materials Research (CCMR), a Materials
      Research and Engineering Center of the National Science Foundation (DMR-9632275).
      Particular acknowledgement is made of the use of the Computing and Materials
      Facilities of the CCMR. 

PMID- 12404500
TI  - First Desymmetrization of a Centrosymmetric Molecule in Natural Product
      Synthesis: Preparation of a Key Fragment in the Synthesis of Hemibrevetoxin B
      This work was supported by the University of Leeds (through a Brotherton
      Scholarship to J.M.H.) and Pfizer. We are extremely grateful to Professor T.
      Nakata of the Institute of Physical and Chemical Research (RIKEN), Saitama,
      Japan, for providing us with the NMR spectra of the epoxide 2, the Royal Society
      for a grant, and AstraZeneca for strategic research funding. 

PMID- 12404501
TI  - Discrete Mixed-Valence Metal Chains: Iridium Pyridonate Blues The generous
      financial support from DGES and MCyT-PNI (Projects PB98-641 and BQU2000-1170) is
      gratefully acknowledged. 

PMID- 12404502
TI  - Enantiomeric Discrimination in a Reiterative Domino Coupling Process: Cu(I)
      mediated Syn Cyclotrimerization of Racemic Polycyclic Trimethylstannyl
      Bromonorbornadienes This work was funded by MURST (Rome) within the national
      project "Stereoselezione in Sintesi Organica. Metodologie e Applicazioni". 

PMID- 12404503
TI  - Yttrate Metathesis: Ligand Design for the Controlled Synthesis of f-Block
      Heterobimetallic Compounds We thank the Royal Society for the provision of a
      University Research Fellowship (M.S.H.) and Dr. A. G. Avent for assistance with
      NMR spectra. 

PMID- 12404504
TI  - Helical Chiral Polyisocyanides Possessing Porphyrin Pendants: Determination of
      Helicity by Exciton-Coupled Circular Dichroism This work was supported by a Grant
      in-Aid for COE Research and Scientific Research from the Ministry of Education,
      Science, Sports, and Culture. F.T. gratefully acknowledges partial support of
      this work by the Hayashi Memorial Foundation for Female Natural Scientists. 

PMID- 12404505
TI  - Redox Activation of a Polyaniline-Coated Cantilever: An Electro-Driven
      Microdevice Parts of this research are supported by The Israel Ministry of
      Science and the Israel Science Foundation. M. Lahav gratefully acknowledges the
      support of The Clore Israel Foundation Scholars Programme. 

PMID- 12404506
TI  - Web Site: Looking for Alternatives.

PMID- 12404507
TI  - Expression of the green fluorescent protein in the oligodendrocyte lineage: a
      transgenic mouse for developmental and physiological studies.
AB  - We generated a transgenic mouse expressing the enhanced green fluorescent protein
      (EGFP) under the control of the 2'-3'-cyclic nucleotide 3'-phosphodiesterase
      (CNP) promoter. EGFP(+) cells were visualized in live tissue throughout embryonic
      and postnatal development. Immunohistochemical analysis in brain tissue and in
      sciatic nerve demonstrated that EGFP expression was restricted to cells of the
      oligodendrocyte and Schwann cell lineages. EGFP was also strongly expressed in
      "adult" oligodendrocyte progenitors (OPs) and in gray matter oligodendrocytes.
      Fluorescence-activated cell sorting allowed high-yield purification of EGFP(+)
      oligodendrocyte-lineage cells from transgenic brains. Electrophysiological patch
      clamp recordings of EGFP(+) cells in situ demonstrated that OP cells displayed
      large outward tetraethylammonium (TEA)-sensitive K(+) currents and very small
      inward currents, whereas mature oligodendrocytes were characterized by expression
      of large inward currents and small outward K(+) currents. The proliferation rate
      of EGFP(+) cells in developing white matter decreased with the age of the animals
      and was strongly inhibited by TEA. Oligodendrocyte development and physiology can
      be studied in live tissue of CNP-EGFP transgenic mice, which represent a source
      of pure EGFP(+) oligodendrocyte-lineage cells throughout development.

PMID- 12404508
TI  - Primary motor neurons fail to up-regulate voltage-gated sodium channel
      Na(v)1.3/brain type III following axotomy resulting from spinal cord injury.
AB  - Epilepsy occurs in a small proportion of patients with spinal cord injury (SCI),
      but whether it is due to concomitant traumatic head injury or to changes in
      cortical motor neurons secondary to axotomy within the spinal cord is not known.
      Na(v)1.3/brain type III sodium channel expression is up-regulated following
      peripheral axotomy of dorsal root ganglion (DRG) and facial motor neurons, but,
      to date, Na(v)1.3 expression has not been examined in upper (cortical) motor
      neurons following axotomy associated with SCI. In the present study, we examine
      Na(v)1.3 expression in upper motor neurons within rat primary motor cortex
      following midthoracic (T9) dorsal column transection, which severs the axons of
      those cells. Axotomized pyramidal cells were identified by retrograde transport
      of fluorogold. Immunolabeled cells were confined to layer V of the primary motor
      cortex and exhibited low levels of Na(v)1.3 staining. After axotomy, no
      significant changes were detected in Na(v)1.3 density or distribution in injured
      or uninjured cells, compared with control brains, in contrast to up-regulation of
      Na(v)1.3 in ipsilateral DRG neurons after sciatic nerve transection. These
      results do not preclude a role for voltage-gated sodium channels in post-SCI
      epilepsy but suggest that up-regulated expression of Na(v)1.3 channel is not
      involved.

PMID- 12404509
TI  - Expression of glutamate receptor subtypes in the spinal cord of control and mnd
      mice, a model of motor neuron disorder.
AB  - We studied the expression and distribution of glutamate receptor subtypes in the
      spinal cord of mnd mice, a model of motor neuron disorders and neuronal ceroid
      lipofuscinosis, and control mice using immunocytochemistry and in situ
      hybridization. The constitutive subunit of the NMDA ionotropic glutamate
      receptor, NMDAR1, was expressed in all neurons of the grey matter and was not
      modified in the spinal cord of mnd mice in either its normal or phosphorylated
      form. The immunoreactivity of GluR2, but not its mRNA, was increased mainly in
      the substantia gelatinosa both in presymptomatic and in 8-month-old symptomatic
      mice, suggesting compensatory changes aimed at reducing the Ca2+ permeability of
      the receptor channel. In spinal cord of mnd mice, mRNA, and protein levels of
      GluR3 were low only at the symptomatic stage, possibly as a consequence of motor
      neuron dysfunction. This was not due to motoneuron degeneration, because the
      number of choline acetyltransferase (ChAT) immunopositive lumbar motor neurons
      and the ChAT activity in the spinal cord and hind leg muscles of symptomatic mnd
      mice were no different from control mice. GluR4 mRNA was increased throughout the
      grey matter, presumably in relation to the marked microglia activation reported
      in the grey matter of the lumbar spinal cord in mnd mice. These changes in
      ionotropic glutamate receptors may alter glutamatergic neurotransmission and play
      some role in the pathology of mnd mice.

PMID- 12404510
TI  - Calpain and calpastatin expression in primary oligodendrocyte culture:
      preferential localization of membrane calpain in cell processes.
AB  - The cellular localization of calpain is important in understanding the roles that
      calpain may play in physiological function. We, therefore, examined calpain
      expression, activity, and immunofluorescent localization in primary cultures of
      rat oligodendrocytes. The mRNA expression of m-calpain was 64.8% (P = 0.0033) and
      50.5% (P = 0.0254) higher than that of mu-calpain and calpastatin, respectively,
      in primary culture oligodendrocytes. The levels of mRNA expression of mu-calpain
      and calpastatin were not significantly different. As revealed by Western
      blotting, cultured oligodendrocytes contained a 70 kD major band identified by
      membrane m-calpain antibody, a 80 kD band recognized by cytosolic m-calpain
      antibody, and calpastatin bands ranging from 45 to 100 kD detected by a
      calpastatin antibody. Calpain activity in oligodendrocytes was determined by
      Ca(2+)-dependent 71.2% degradation of endogenous myelin basic protein compared
      with control; this activity was inhibited significantly (P = 0.0111) by EGTA and
      also substantially by calpeptin. Localization of calpain in cultured
      oligodendrocytes revealed strong membrane m-calpain immunofluorescence in the
      oligodendrocyte cell body and its processes. In contrast, the cytosolic antibody
      stained primarily the oligodendrocyte cell body, whereas the processes were
      stained very weakly or not at all. These results indicate that the major form of
      calpain in glial cells is myelin (membrane) m-calpain. The dissimilar
      localization of cytosolic and membrane m-calpain may indicate that each isoform
      has a unique role in oligodendrocyte function.

PMID- 12404511
TI  - Effects of intrauterine inflammation on developing rat brain.
AB  - Damage to the white matter in the brain during development can lead to cerebral
      palsy (CP), a heterogeneous group of clinical syndromes that results in life-long
      disorders of movement and posture. Periventricular leukomalacia (PVL) is a
      pathological process within the white matter characterized by oligodendrocyte
      loss and is associated with the development of CP. Clinically, CP and PVL are
      associated with intrauterine infection and inflammation, but mechanisms involved
      are not well understood. We developed a model of intrauterine inflammation in
      Lewis and Fischer 344 rats to study the effects of intrauterine inflammation on
      developing glia. Pregnant rats were intracervically injected with
      lipopolysaccharide (LPS) at 15 days of gestation (E15) and a dose of LPS that
      caused low fetal mortality was determined. At E20, treated fetuses had increased
      TUNEL(+) nuclei and tumor necrosis factor (TNF)-alpha-immunoreactive areas within
      the brains. In a second series of animals allowed to survive until postnatal day
      21 (PND 21), immunostaining was performed against several glial markers. Staining
      for the oligodendrocyte-specific proteins 2', 3'-cyclic nucleotide
      phosphodiesterase (CNP) and myelin proteolipid protein (PLP) was decreased in
      treated pups compared to shams within the corpus callosum, a white matter
      structure used as a representative area of developing white matter. Treated pups
      had activated astrocytes lining cerebral blood vessels, as observed by glial
      fibrillary acidic protein (GFAP) staining, while sham pups did not. Activated
      microglia were not detected using OX42 as a cell marker. Our model of
      intrauterine inflammation causes increased TUNEL and TNF-alpha staining early
      after injury, suggesting increased apoptotic cell death, possibly by cytokine
      related mechanisms.

PMID- 12404512
TI  - Nitric oxide synthase is present in the cerebrospinal fluid of patients with
      active multiple sclerosis and is associated with increases in cerebrospinal fluid
      protein nitrotyrosine and S-nitrosothiols and with changes in glutathione levels.
AB  - Nitric oxide (NO) is hypothesized to play a role in the immunopathogenesis of
      multiple sclerosis (MS). Increased levels of NO metabolites have been found in
      patients with MS. Peroxynitrite, generated by the reaction of NO with superoxide
      at sites of inflammation, is a strong oxidant capable of damaging tissues and
      cells. Inducible NO synthase (iNOS) is up-regulated in the CNS of animals with
      experimental allergic encephalomyelitis (EAE) and in patients with MS. In this
      study, Western blots of cerebrospinal fluid (CSF) from patients with MS
      demonstrated the presence of iNOS, which was absent in CSF from control subjects.
      There was also NOS activity present in both MS and control CSF. Total NOS
      activity was increased (by 24%) in the CSF from MS patients compared with matched
      controls. The addition of 0.1 mM ITU (a specific iNOS inhibitor) to the samples
      did not change the activity of the control samples but decreased the NOS activity
      in the MS samples to almost control levels. The addition of 1 mM L-NMMA (a
      nonisoform specific NOS inhibitor), completely inhibited NOS activity in CSF from
      control and MS subjects. Nitrotyrosine immunostaining of CSF proteins was
      detectable in controls but was greatly increased in MS samples. There were also
      significant increases in CSF nitrate + nitrite and oxidant-enhanced luminescence
      in MS samples compared with controls. Additionally, a significant decrease in
      reduced glutathione and significant increases in oxidized glutathione and S
      nitrosothiols were found in MS samples compared with controls. Parallel changes
      in NO metabolites were observed in the plasma of MS patients, compared with
      controls, and accompanied a significant increase of reduced glutathione. These
      data strongly support a role for nitrosative stress in the pathogenesis of MS and
      indicate that therapeutic strategies focussed on decreasing production of NO by
      iNOS and/or scavenging peroxynitrite may be useful in alleviating the
      neurological impairments that occur during MS relapse.

PMID- 12404513
TI  - Type-2 astrocyte-like cells are more resistant than oligodendrocyte-like cells
      against non-N-methyl-D-aspartate glutamate receptor-mediated excitotoxicity.
AB  - Glutamate causes excitotoxicity via non-N-methyl-D-aspartate (NMDA) glutamate
      receptors (GluR) in oligodendrocytes. Because both oligodendrocytes and type 2
      astrocytes are differentiated from oligodendrocyte-type 2 astrocyte (O-2A)
      progenitor cells, we investigated whether astrocytes are also vulnerable to non
      NMDA GluR-mediated excitotoxicity. For these studies, oligodendrocyte-like cells
      (OLC) and type 2 astrocyte-like cells (2ALC) were derived from CG-4 cells, an
      immortalized rat O-2A progenitor cell line. About 50% of 2ALC were positive for
      glial fibrillary acidic protein and 90% were positive for A2B5, verifying that
      these cells have an type 2 astrocytic phenotype. A 24-hr exposure of OLC to 2 mM
      kainate, an activator of non-NMDA GluR, caused cell damage as shown by the
      release of lactate dehydrogenase. The extent of kainate-induced OLC damage was
      increased by cyclothiazide. In contrast, exposure of 2ALC to 2 mM kainate alone
      did not induce injury, though mild 2ALC injury was elicited by exposure to 2 mM
      kainate plus 100 microM cyclothiazide. Furthermore, we found that the kainate
      induced Ca(2+) uptake by 2ALC was 27.5% of that induced by kainate in OLC.
      Finally, both OLC and 2ALC expressed non-NMDA GluR subunit mRNAs, including
      GluR2, GluR3, GluR4, GluR6, GluR7, KA1, and KA2, but quantitative Western blot
      analysis revealed higher immunodetectable GluR2 and lower immunodetectable GluR3
      and GluR4 in 2ALC than in OLC. Together, these results suggest that astrocytes
      are relatively resistant to non-NMDA GluR-mediated excitotoxicity because they
      have a higher expression of GluR2 and lower expression of GluR3 and GluR4.

PMID- 12404514
TI  - Modeling Alzheimer's disease immune therapy mechanisms: interactions of human
      postmortem microglia with antibody-opsonized amyloid beta peptide.
AB  - The induction of an antibody response to amyloid beta (Abeta) peptide has become
      a strategy for the treatment of Alzheimer's disease (AD). This has proven
      effective in reducing the plaque burden in transgenic mice that develop Abeta
      plaques similar to human AD patients. The mechanism for enhanced clearance of
      Abeta is partly due to the interaction of immunoglobulin Fcgamma receptor
      expressing microglia and specific antibody-opsonized Abeta deposits. This
      interaction can stimulate Fcgamma receptor-mediated phagocytosis, but also
      results in inflammatory activation of these cells. Consequently, interaction of
      microglia with antibody-antigen complexes could exacerbate the existing
      inflammation in the brains of AD patients. In this study, we used substrate-bound
      Abeta and cultured human microglia from AD and non-demented cases to model
      interaction of microglia and antibody-opsonized plaques in AD brains. Enhanced
      production of tumor necrosis factor-alpha, macrophage colony stimulating factor,
      interleukin-10, and superoxide ions was detected. We also demonstrated enhanced
      uptake of opsonized Abeta by microglia, which was reduced significantly in the
      presence of excess IgG, indicative of the involvement of Fcgamma receptor
      mediated mechanisms. Human microglia were shown in this study to express mRNA for
      Fcgamma receptors I, IIa, IIb, and III. The expression of Fcgamma receptor II was
      augmented by proinflammatory stimulation. These results suggest that initial
      interactions of human microglia with antibody-opsonized amyloid could result in
      increased inflammation. The consequence of this on inflammatory pathology in AD
      brains needs to be considered before immunization is used as a strategy for
      treating AD.

PMID- 12404516
TI  - Comparison of two-dimensional and three-dimensional sonography in evaluating
      fetal malformations.
AB  - PURPOSE: We assessed the differences between 2-dimensional (2D) and 3-dimensional
      (3D) sonography (US) in evaluating fetal malformations. METHODS: Both 2D US and
      3D US were used to examine pregnant women whose fetuses had malformations. The
      diagnostic information provided by the modalities was evaluated and compared.
      RESULTS: A total of 62 malformations were confirmed by postnatal or postmortem
      follow-up in 41 fetuses of 40 pregnant women. 2D US made a definite and correct
      diagnosis of 49 malformations (79%), whereas 3D US definitely diagnosed 58
      malformations (94%) (p < 0.01). 3D US definitely diagnosed all the abnormalities
      in 38 fetuses (93%), whereas 2D US did so in only 32 fetuses (78%) (p < 0.05). In
      35 (60%) of the 58 malformations revealed by both 3D US and 2D US, the former
      provided more diagnostic information than the latter. 3D US was particularly
      superior to 2D US in evaluating fetal malformations of the cranium and face,
      spine and extremities, and body surface. CONCLUSIONS: In comparison with 2D US,
      3D US improves the diagnostic capability by offering more diagnostic information
      in evaluating fetal malformations, particularly in displaying fetal malformations
      of the cranium and face, spine and extremities, and body surface. 3D US is a
      valuable adjunct to 2D US in prenatal diagnosis.

PMID- 12404515
TI  - Single cell activity patterns of pedunculopontine tegmentum neurons across the
      sleep-wake cycle in the freely moving rats.
AB  - Microinjections of the excitatory amino acid, L-glutamate into the cholinergic
      cell compartment of the pedunculopontine tegmentum (PPT) of the rat induces both
      wakefulness and/or rapid eye movement (REM) sleep depending on the glutamate
      dosage. However, no studies have systematically recorded the electrical activity
      of these cells in the freely moving rat across the sleep-wake cycle. In this
      study, we have recorded the spontaneous activity patterns of single PPT cells (n
      = 70) in the freely moving rat across the sleep-wake cycle. PPT neurons were
      classified into three groups based on patterns in their spontaneous activity. The
      first group of cells (12.86%) was more active during REM sleep than they were
      during wakefulness or slow-wave sleep (SWS). The second group of cells (60.0%)
      was more active during REM and wakefulness than during SWS. The firing rate of
      the third group of cells (27.14%) did not change as a function of behavioral
      state. This study also demonstrated that the level of activity within the
      cholinergic cell compartment of the PPT during SWS drops to 7.4% of that observed
      during wakefulness and that during REM sleep it changes to 65.5% of wakefulness
      levels. These findings indicate that in the freely moving rat, the discharging of
      PPT neurons correlates with wakefulness and REM sleep. Additionally, these
      neurons may be an integral part of the brainstem wakefulness and REM sleep
      generating mechanisms in the rat.

PMID- 12404517
TI  - Does gestational sac volume predict the outcome of missed miscarriage managed
      expectantly?
AB  - PURPOSE: The aim of this study was to investigate whether gestational sac volume
      (GSV) can predict the outcome of missed miscarriages that are managed
      expectantly. METHODS: This was a prospective observational study. Between
      February 1, 2000, and January 31, 2001, all patients with a confirmed first
      trimester missed miscarriage who chose to undergo expectant management were
      recruited to participate. A single investigator performed all sonographic
      examinations and measurements. The main outcome measure was a complete
      spontaneous abortion within 4 weeks of the initial diagnosis. A complete
      miscarriage was defined as a maximum anteroposterior diameter of the endometrium
      of less than 15 mm on transvaginal sonography and no persistent heavy vaginal
      bleeding. The patients could opt to undergo surgery at any time, but those who
      had not expelled the products of conception within 4 weeks of the diagnosis were
      advised to have surgical uterine evacuation. RESULTS: In total, 90 patients were
      enrolled, and 86 patients completed the study. The mean GSV, as measured by 3
      dimensional sonography, was 9.7 +/- 8.9 ml, and the mean sac diameter was 24.5 +/
      8.0 mm. A significant exponential correlation was found between the mean sac
      diameter and the GSV (r = 0.86; p < 0.0001). Forty-six (53.5%) of the 86 patients
      experienced a complete miscarriage within 4 weeks of the diagnosis (ie, expectant
      management was successful), but expectant management was unsuccessful in the
      remaining 40 (46.5%) patients (5 had an incomplete miscarriage, and 35 did not
      expel the products of conception). The GSV did not differ significantly between
      the "successful" and "unsuccessful" groups (p = 0.82). A logistic regression
      analysis showed no significant correlation between GSV and the outcome of missed
      miscarriages managed expectantly (p = 0.59). CONCLUSIONS: The GSV does not
      predict the outcome of expectant management of missed miscarriage within 4 weeks
      of the diagnosis.

PMID- 12404518
TI  - Accuracy of sonography with a hydration test in differentiating between excretory
      renal obstruction and renal sinus cysts.
AB  - PURPOSE: The aim of this prospective study was to determine whether sonography
      with a hydration test to induce diuresis can be used to reliably differentiate
      between excretory renal obstruction and renal sinus cysts. METHODS: We performed
      sonographic examination of all patients diagnosed with minimal or moderate
      obstruction of the intrarenal collecting system or renal sinus cysts on the basis
      of excretory urography, CT, or both between September 1, 1998, and October 31,
      1999. The largest fluid-filled structures in the renal sinus were sonographically
      measured before and after each patient ingested 1.5 l of water. Cases in which
      the maximum diameters of the largest anechoic structures increased by at least
      10% after hydration were diagnosed with excretory renal obstruction. The
      sonographic diagnoses were compared with the final diagnoses on excretory
      urography, CT, or both. RESULTS: Both kidneys were affected in 16 of the 36
      patients examined, for a total of 52 kidneys. The sonographic diagnosis was
      consistent with the results of urography or CT in 48 (92%) of the 52 kidneys. The
      sonographic approach had a specificity of 92% and a sensitivity of 93% for the
      diagnosis of excretory renal obstruction, with only 1 false-negative and 3 false
      positive results. CONCLUSIONS: When used with the stimulated diuresis test,
      sonography can reliably distinguish between excretory renal obstruction and renal
      sinus cysts and can be used as an alternative to other imaging techniques such as
      urography.

PMID- 12404519
TI  - Quantitative Doppler evaluation of the splenoportal venous system in various
      stages of cirrhosis: differences between right and left portal veins.
AB  - PURPOSE: The purpose of our study was to evaluate the relationship between the
      splenoportal hemodynamics in patients with cirrhosis and the stage of the
      disease. METHODS: Patients with cirrhosis were grouped according to modified
      Child-Pugh scoring into stages A, B, and C of cirrhosis. A control group of
      healthy volunteers was included. After gastroenterologic clinical and laboratory
      examinations, all participants underwent a splenoportal Doppler sonographic
      evaluation in which the vessels' diameter, area, and blood flow velocity were
      measured and blood flow rate and the congestion index in the splenoportal venous
      system were calculated. RESULTS: Seventy-five patients with cirrhosis (25 women
      and 50 men) were enrolled; the control group consisted of 30 healthy volunteers
      (15 women and 15 men) with no liver disease. The mean age (+/- standard
      deviation) of the patients was 54.4 +/- 14.8 years (range, 13-80 years) and of
      the control subjects was 47.3 +/- 14.5 years (range, 18-72 years). No significant
      differences in vessel diameter, blood flow velocity, and blood flow rate were
      found in the main and left portal veins between the study group and the control
      group. In the right portal vein, we found decreases in the vessel diameter, blood
      flow velocity, and blood flow rate, and in the splenic vein, we found increases
      in vessel diameter and blood flow rate. The congestion index was increased in the
      main portal and splenic veins but was unchanged in the left portal vein.
      CONCLUSIONS: Although our data indicate that there is no difference in Doppler
      sonographic parameters of the main portal vein according to Child-Pugh scores,
      the hemodynamic differences between the left and right branches of the portal
      vein may be clinically useful in patients with cirrhosis.

PMID- 12404520
TI  - Thyrotoxic periodic paralysis: sonographic appearances of the thyroid.
AB  - PURPOSE: The aim of the study was to describe the sonographic appearances of the
      thyroid in patients with thyrotoxic periodic paralysis (TPP). METHODS: Of the 25
      patients diagnosed with TPP between January 1, 1998, and December 31, 2001, as
      identified by a search of our patient database, 13 had undergone sonography of
      the thyroid. We retrospectively reviewed the clinical records and thyroid
      sonograms of these 13 patients. The sonograms were assessed subjectively for
      thyroid size, echogenicity, vascularity, and the presence of solid nodules and
      cysts. RESULTS: Sonography showed abnormality of the thyroid in all 13 patients.
      In 11 patients (85%), sonography showed widespread hypoechogenicity (compared
      with the muscle) whose distribution was diffuse (6 patients) or patchy (5
      patients) and diffusely distributed areas of hypervascularity (type 1 pattern).
      All 11 of these patients had a clinical diagnosis of Graves' disease. One patient
      (8%) had multinodular goiter and enlargement of the thyroid with multiple
      heterogeneous solid nodules and cysts (type 2 pattern); the clinical diagnosis
      was toxic multinodal goiter. One patient (8%) had a combination of type 1 and
      type 2 patterns and a clinical diagnosis of Graves' disease. CONCLUSIONS: The
      sonographic abnormalities of the thyroid in patients with TPP reflect the common
      underlying causes of thyrotoxicosis in the general population. The sonographic
      appearances associated with Graves' disease (type 1 pattern) were the most common
      abnormality detected. No sonographic features specific to TPP were identified.

PMID- 12404521
TI  - Sonographic features with histologic correlation in two cases of palpable breast
      cancer after breast augmentation by liquid silicone injection.
AB  - Sonography is rarely used to evaluate the breasts in patients who have undergone
      liquid silicone injections for breast augmentation because strong acoustic
      shadowing from the resulting silicone granulomas hampers the examination. We
      report on 2 patients who underwent silicone injection 18 and 20 years earlier and
      in whom breast cancers (1 invasive ductal carcinoma and 1 carcinosarcoma) were
      diagnosed by sonographically guided core-needle biopsy. On sonograms, both
      cancers had a peripheral hypoechoic rim surrounding an echogenic center. The
      echogenic center corresponded histologically to a silicone granuloma in 1 patient
      and to a large area of necrosis in the other; the hypoechoic rims corresponded to
      areas of cancer in both patients.

PMID- 12404522
TI  - Acute lymphoblastic leukemia relapse in the breast diagnosed with gray-scale and
      color Doppler sonography.
AB  - Extramedullary relapses of acute lymphoblastic leukemia (ALL) in children and
      young adults are rare and in most cases are localized in the central nervous
      system, testes, or both. We describe a rare case of extramedullary relapse of ALL
      in the breast of a 17-year-old girl. The patient, who had been diagnosed with ALL
      1 year before and had been in complete remission for 5 months, was admitted to
      the hospital for investigation of a mass in her left breast. On clinical
      examination, she had a large, palpable, nontender mass in her left breast.
      Mammography revealed a very dense mass. On gray-scale and power Doppler
      sonography, the appearance of the mass was consistent with malignancy.
      Histopathologic examination of a surgical biopsy specimen permitted accurate
      diagnosis of ALL.

PMID- 12404523
TI  - Unusual sonographic finding in a patient with late recurrence of a perianal
      fistula.
AB  - We describe a case of late recurrence of a perianal fistula in a 51-year-old man
      with a 4.5-year history of recurrent perianal fistulas and abscesses. This was
      the fourth recurrence he had experienced; at each occurrence, he had undergone
      various examinations, including sigmoidoscopy, anoscopy, barium enema,
      fistulography, probe exploration, instillation of hydrogen peroxide, and/or
      sonography, and he had also undergone surgery. At our examination, transperineal
      sonography with a portable ultrasound scanner revealed an echogenic linear
      structure within the fistulous tract. Under endoanal sonographic guidance,
      surgery was performed, and a tan solid cylindrical structure longer than 2 cm was
      removed. Histopathologic examination revealed stratified squamous epithelium and
      soft tissue with substantial fibrosis and mild chronic inflammation, findings
      consistent with the characteristics of a remnant cast from a previous fistulous
      tract. Our findings suggest that some patients may benefit from relatively
      inexpensive sonographic examination with appropriate transducers.

PMID- 12404524
TI  - Lower-extremity deep venous thrombosis after upper-extremity port catheter
      placement: an unusual complication.
AB  - We describe the case of a woman with breast carcinoma who experienced deep venous
      thrombosis of the right lower extremity after placement of a double-lumen central
      venous chemotherapy port catheter in the left upper extremity. Color Doppler
      sonography revealed a linear tubular structure within the right common femoral
      vein and sonographic features of thrombosis, suggesting deep venous thrombosis
      secondary to displacement of the port catheter.

PMID- 12404525
TI  - Sonographic findings in a duodenal duplication cyst.
AB  - We report the sonographic features of a duodenal duplication cyst containing
      ectopic pancreatic tissue in a 5-month-old boy who presented with symptoms of
      partial gastric outlet obstruction. Sonography revealed an anechoic, double
      walled, bilobed cystic lesion containing debris in the pyloroduodenal region.
      There was sound through-transmission but no air or communication with the
      gastrointestinal tract. Surgical resection and histopathologic examination
      confirmed a duodenal duplication cyst containing pancreatic tissue.

PMID- 12404526
TI  - Acoustic streaming versus venous pseudoaneurysm in a scrotal mass.

PMID- 12404529
TI  - Preface.

PMID- 12404527
TI  - Value of transvaginal sonography in the evaluation of live monochorionic
      diamniotic twin ectopic pregnancy.

PMID- 12404530
TI  - Concepts of depression: sporadic revolutions of continuous evolution.
AB  - The classification of depressive disorders has been changing ever since the first
      descriptions of mood disorders were produced some 2500 years ago. The interest in
      their classification has recently been revived as a result of the introduction of
      new types of medicaments for the treatment of the disorders belonging to the
      spectrum of mood disorders and of the emphasis that has been given to the
      diagnosis and treatment of mental disorders, and in particular depression in
      primary health care services. The currently used systems of classification
      contain a relatively large number of categories reserved for depressive disorders
      and it is to be hoped that the experience and information obtained by the use of
      these classifications, as well as the results of research into the
      psychopathology and the effects of treatment of mood disorders, will make it
      possible to arrive at a simplified and better classification of these conditions.
      It is likely that this improvement will be incremental, that the development of
      significantly better classifications will take time and the result of this
      developmental process will be a classification that will reflect consensus of the
      mental health professions based on the best available evidence. Copyright 2001
      John Wiley & Sons, Ltd.

PMID- 12404531
TI  - Stress and hippocampal plasticity: implications for the pathophysiology of
      affective disorders.
AB  - The hippocampal formation, a structure involved in declarative, spatial and
      contextual memory, is a particularly sensitive and vulnerable brain region to
      stress and stress hormones. The hippocampus shows a considerable degree of
      structural plasticity in the adult brain. Stress suppresses neurogenesis of
      dentate gyrus granule neurons, and repeated stress causes atrophy of dendrites in
      the CA3 region. In addition, ovarian steroids regulate synapse formation during
      the estrous cycle of female rats. All three forms of structural remodeling of the
      hippocampus are mediated by hormones working in concert with excitatory amino
      acids (EAA) and N-methyl-D-aspartate (NMDA) receptors. EAA and NMDA receptors are
      also involved in neuronal death that is caused in pyramidal neurons by seizures
      and by ischemia and prolonged psychosocial stress. In the human hippocampus,
      magnetic resonance imaging studies have shown that there is a selective atrophy
      in recurrent depressive illness, accompanied by deficits in memory performance.
      Hippocampal atrophy may be a feature of affective disorders that is not treated
      by all medications. From a therapeutic standpoint, it is essential to distinguish
      between permanent damage and reversible atrophy in order to develop treatment
      strategies to either prevent or reverse deficits. In addition, remodeling of
      brain cells may occur in other brain regions. Possible treatments are discussed.
      Copyright 2001 John Wiley & Sons, Ltd.

PMID- 12404532
TI  - Comorbidity and mixed anxiety-depressive disorder: clinical curiosity or
      pathophysiological need?
AB  - The paper reviews available epidemiological evidence for the existence of and the
      implications of comorbidity of anxiety and depressive disorders and mixed anxiety
      depressive (MAD) disorders. Using epidemiolological evidence of prevalence and
      incidence and data relating to time-course of illness, risk factor and outcome,
      it is concluded: (1) that anxiety-depression comorbidity is quite frequent in
      epidemiological and clinical settings throughout the world; (2) this comorbidity
      is diagnosis-specific and is associated with increased vulnerabilities and risks
      as well as poorer outcome and marked disabilities; and (3) no such evidence was
      found for MAD disorders. Contrary to what was predicted, the prevalence of MAD
      disorders was quite low even when using the more recent criteria of the
      Diagnostic and Statistical Manual of Mental Disorders, 4th edition. (4)
      Furthermore, there was quite a heterogeneous pattern in terms of risk, severity
      and outcome making it questionable whether this disorder, as currently defined,
      is a clinical entity. These findings are discussed in terms of two perspectives,
      the 'lumpers' with their dimensional view and the 'splitters' with their
      categorical view. It is concluded that although comorbidity of threshold anxiety
      and depressive disorders seems to be an important phenomenon, no such evidence is
      provided for MAD disorders. Copyright 2001 John Wiley & Sons, Ltd.

PMID- 12404533
TI  - Efficacy and safety of tianeptine in the treatment of depressive disorders in
      comparison with fluoxetine*
AB  - Depression is treated by a great variety of antidepressant treatments. SSRIs
      (such as fluoxetine) are well known: it is, however, sure that further progress
      is needed and the search for antidepressants with other mechanisms of action
      (such as tianeptine) or different efficacy is still of interest. A multinational
      study compared tianeptine with fluoxetine in 387 patients with Depressive
      Episode, or Recurrent Depressive Disorder, or Bipolar Affective Disorder (ICD
      10), in a double-blind parallel group design. They were treated for six weeks. At
      inclusion, no significant difference between groups was shown. Final MADRS scores
      were 15.7 and 15.8 with tianeptine and fluoxetine, respectively (ITT population)
      (p = 0.944). MADRS responders were 58% and 56% with tianeptine and fluoxetine,
      respectively (p = 0.710). No statistical difference was observed for the other
      efficacy parameters. Thirty-six withdrawals occurred in each group, without any
      difference for the reasons of discontinuation. There was no major difference
      between groups for the other safety parameters. In this study, both tianeptine
      and fluoxetine exhibited a good efficacy and safety. Copyright 1999 Elsevier
      Science B. V. All rights reserved.

PMID- 12404534
TI  - Efficacy of tianeptine vs placebo in the long-term treatment (16.5 months) of
      unipolar major recurrent depression*
AB  - To compare the efficacy and acceptability of tianeptine vs placebo in the long
      term treatment of unipolar major recurrent depression, 268 hospitalized and
      ambulatory patients meeting DSM III-R criteria for major depression with a 21
      item Hamilton depression rating scale (HDRS) score >/= 17 and at least one
      episode in the previous 5 years received tianeptine in a 6-week multicenter open
      study. At D42, 185 responders (intention-to-treat population) were randomized for
      ethical reasons into two unbalanced groups to receive tianeptine 37.5 mg/day (n=
      111) or placebo (n= 74) for 16.5 months; 173 of the 185 responders were defined
      as strict responders (per-protocol population) by an HDRS score which was both <
      15 and at least halved vs D1, combined with clinical confirmation by the
      investigator. The groups were similar at baseline except in the severity of the
      depressive episode (greater in the tianeptine group: 33 vs 18%, p= 0.018).
      Relapse (before 6 months) and recurrence (after 6 months) were defined by an HDRS
      score >/= 15 and/or clinical global impression score >/= 4, and clinical
      confirmation by the investigator. Visits were at D63 and M3, M6, M9, M12, M15,
      and M18. Efficacy was measured by the number of relapses and recurrences and
      their time of onset (Kaplan-Meier survival curve analysis). Between D42 and M18
      (intention-to-treat population), relapse and recurrence were less frequent on
      tianeptine vs placebo (16 vs 36%, p= 0.002). Comparison over time also showed a
      higher proportion of patients without relapse or recurrence on tianeptine (p<
      0.001); the intergroup difference increased with follow-up duration. Secondary
      analysis of relapse in the intention-to-treat group showed a higher proportion on
      placebo (p= 0.002); secondary analysis of recurrence over time showed that the
      difference in the percentages of recurrence-free patients was nonsignificant in
      the intention-to-treat population (p= 0.067) but significant in the per-protocol
      population (p= 0.036) in favor of tianeptine. Acceptability did not differ
      between the groups. Treatment-induced adverse events were rare and mild in both
      groups. These data support the use of tianeptine in the long-term treatment of
      unipolar major recurrent depression. Relapse and recurrence were decreased two-
      to threefold on tianeptine vs placebo with no difference in acceptability between
      the two groups. Copyright 1997 Doin Editeurs

PMID- 12404535
TI  - The psychobiology and psychopharmacology of PTSD.
AB  - This paper reviews the currently available knowledge about the psychobiology and
      psychopharmacology of post-traumatic stress disorder (PTSD). It also reviews the
      various studies that have elucidated changes in brain function and structure in
      PTSD populations, including position emission tomography (PET), single photon
      emission computed tomography (SPECT), and event-related potential (ERP) studies.
      It then reviews the literature on catecholamine and hypothalamic-pituitary
      adrenal (HPA) axis abnormalities in PTSD, and finally reviews the literature
      available on the psychopharmacology of PTSD. It discusses how the pathophysiology
      of PTSD determines the nature of psychopharmacological interventions.
      Psychopharmacological interventions in PTSD are largely limited to good studies
      on the effects of the selective serotonin reuptake inhibitors (SSRIs). In order
      to effectively intervene in PTSD, studies of other psychopharmacological agents
      are necessary, specifically of agents which affect limbic activation, decreased
      frontal lobe functioning, altered HPA activity, and other biological features of
      PTSD. Copyright 2001 John Wiley & Sons, Ltd.

PMID- 12404536
TI  - Human psychopharmacology of Ecstasy (MDMA): a review of 15 years of empirical
      research.
AB  - MDMA (3,4-methylenedioxymethamphetamine) or 'Ecstasy' was scheduled as an illegal
      drug in 1986, but since then its recreational use has increased dramatically.
      This review covers 15 years of research into patterns of use, its acute
      psychological and physiological effects, and the long-term consequences of
      repeated use. MDMA is an indirect monoaminergic agonist, stimulating the release
      and inhibiting the reuptake of serotonin (5-HT) and, to a lesser extent, other
      neurotransmitters. Single doses of MDMA have been administered to human
      volunteers in double-blind placebo-controlled trials, although most findings are
      based upon recreational MDMA users. The 'massive' boost in neurotransmitter
      activity can generate intense feelings of elation and pleasure, also
      hyperactivity and hyperthermia. This psychophysiological arousal may be
      exacerbated by high ambient temperatures, overcrowding, prolonged dancing and
      other stimulant drugs. Occasionally the 'serotonin syndrome' reactions may prove
      fatal. In the days after Ecstasy use, around 80% of users report rebound
      depression and lethargy, due probably to monoaminergic depletion. Dosage
      escalation and chronic pharmacodynamic tolerance typically occur in regular
      users. Repeated doses of MDMA cause serotonergic neurotoxicity in laboratory
      animals, and there is extensive evidence for long-term neuropsychopharmacological
      damage in humans. Abstinent regular Ecstasy users often display reduced levels of
      5-HT, 5-HIAA, tryptophan hydroxylase and serotonin transporter density;
      functional deficits in learning/memory, higher cognitive processing, sleep,
      appetite and psychiatric well-being, and, most paradoxically, 'loss of sexual
      interest/pleasure'. These psychobiological deficits are greatest in heavy Ecstasy
      users and may reflect serotonergic axonal loss in the higher brain regions,
      especially the frontal lobes, temporal lobes and hippocampus. These problems seem
      to remain long after the recreational use of Ecstasy has ceased, suggesting that
      the neuropharmacological damage may be permament. Copyright 2001 John Wiley &
      Sons, Ltd.

PMID- 12404537
TI  - Investigating the potential neurotoxicity of Ecstasy (MDMA): an imaging approach.
AB  - Human users of 3,4-methylenedioxymethamphetamine (MDMA, 'Ecstasy') users may be
      at risk of developing MDMA-induced neuronal injury. Previously, no methods were
      available for directly evaluating the neurotoxic effects of MDMA in the living
      human brain. However, development of in vivo neuroimaging tools has begun to
      provide insights into the effects of MDMA in the human brain. In this review,
      contributions of brain imaging studies on the potential neurotoxic effects of
      MDMA and functional consequences are highlighted. An overview is given of PET,
      SPECT and MR spectroscopy studies, most of which show evidence of neuronal injury
      in MDMA users. Different neuroimaging tools are discussed that have investigated
      potential functional consequences of MDMA-induced 5-HT neurotoxic lesions.
      Finally, the contribution of brain imaging in future studies is discussed,
      emphasising the crucial role it will play in our understanding of MDMA's short-
      and long-term effects in the human brain. Copyright 2001 John Wiley & Sons, Ltd.

PMID- 12404538
TI  - Which neuroreceptors mediate the subjective effects of MDMA in humans? A summary
      of mechanistic studies.
AB  - In preclinical studies, 3,4-methylenedioxymethamphetamine (MDMA, 'Ecstasy') has
      been shown to release serotonin (5-HT), dopamine and norepinephrine. However, the
      role of these neurotransmitters and their corresponding receptor sites in
      mediating the subjective effects of MDMA has not yet been studied in humans.
      Therefore, we investigated the effects of three different neuroreceptor
      pretreatments on the subjective, cardiovascular and adverse effects of MDMA (1.5
      mg/kg orally) in 44 healthy human volunteers. Pretreatments were: the selective
      serotonin reuptake inhibitor citalopram (40 mg intravenously) in 16 subjects, the
      5-HT(2) antagonist ketanserin (50 mg orally) in 14 subjects, and the D(2)
      antagonist haloperidol (1.4 mg intravenously) in 14 subjects. Each of these
      studies used a double-blind placebo-controlled within-subject design and all
      subjects were examined under placebo, pretreatment, MDMA and pretreatment plus
      MDMA conditions. Citalopram markedly reduced most of the subjective effects of
      MDMA, including positive mood, increased extraversion and self-confidence.
      Cardiovascular and adverse effects of MDMA were also attenuated by citalopram.
      Haloperidol selectively reduced MDMA-induced positive mood but had no effect on
      other subjective effects of MDMA or the cardiovascular or adverse responses to
      MDMA. Ketanserin selectively reduced MDMA-induced perceptual changes and
      emotional excitation. These results indicate that the overall psychological
      effects of MDMA largely depend on carrier-mediated 5-HT release, while the more
      stimulant-like euphoric mood effects of MDMA appear to relate, at least in part,
      to dopamine D(2) receptor stimulation. The mild hallucinogen-like perceptual
      effects of MDMA appear to be due to serotonergic 5-HT(2) receptor stimulation.
      Copyright 2001 John Wiley & Sons, Ltd.

PMID- 12404539
TI  - Ecstasy abuse and dependence among adolescents and young adults: applicability
      and reliability of DSM-IV criteria.
AB  - As part of an ongoing National Institute on Drug Abuse study on the reliability
      of DSM substance use disorders, 173 adolescents and young adults have been
      interviewed to date with the CIDI-Substance Abuse Module (SAM) to determine use
      and abuse of and dependence on 'club drugs' and other substances. Respondents are
      recruited from a substance abuse program, high school ads, college dorm flyers,
      the internet and chain referral. Retest interviews after 5 days determined the
      reliability of responses. Ecstasy use was reported by 52 respondents (30%); of
      these users 52% were female and 23% were non-white. Nearly all users (94%)
      reported recent Ecstasy use. Among Ecstasy users, 'continuing to use despite
      knowledge of physical or psychological harm' was the most prevalent dependence
      criterion (63%), with excellent retest agreement (kappa = 0.66). Withdrawal (59%)
      and tolerance (35%) were also commonly reported dependence criteria. Hazardous
      use was the most commonly reported abuse symptom. Most surprising were the rates
      of Ecstasy use disorders: 43% met DSM-IV criteria for dependence; 34% met
      criteria for abuse; only 23% met neither. This is the first effort to assess the
      reliability of Ecstasy abuse and dependence, and the first to determine abuse and
      dependence using criteria specific to Ecstasy. The importance of additional
      studies and the relevance of such work to DSM-V are discussed. Copyright 2001
      John Wiley & Sons, Ltd.

PMID- 12404540
TI  - Prospective memory, everyday cognitive failure and central executive function in
      recreational users of Ecstasy.
AB  - Chronic use of MDMA (3,4-methylenedioxymethamphetamine), or Ecstasy, is believed
      to lead to impaired psychological performance, including well-documented
      decrements in laboratory and field tests of retrospective memory. Less is known
      about the impact of Ecstasy on aspects of 'everyday' memory, despite obvious
      concerns about such effects. The three studies reported here focused on the
      impact of chronic Ecstasy use on prospective memory (PM), associated central
      executive function and other aspects of day-to-day cognition. In study 1 46
      regular Ecstasy users were compared with 46 Ecstasy-free controls using the
      Prospective Memory Questionnaire (PMQ). Ecstasy users reported significantly more
      errors in PM (remembering to do something in the future); these findings
      persisted after controlling for other drug use and the number of strategies used
      to aid memory. No difference was found between representative subgroups on the
      Lies Scale of the Eysenck Personality Questionnaire. In study 2 a different group
      of 30 regular Ecstasy users and 37 Ecstasy-free controls was assessed on the PMQ
      and on a central executive task comprising verbal fluency measures. The results
      confirmed the significant impairments in long- and short-term PM and revealed
      corresponding impairments in verbal fluency. In study 3 15 Ecstasy users, 15
      cannabis users and 15 non-drug users were assessed using the Cognitive Failures
      Questionnaire, which requires participants to provide ratings of the frequency of
      various day-to-day cognitive slips. The results indicate that the Ecstasy users
      did not perceive their general cognitive performance to be worse than that of
      controls. Taken together, these results suggest that Ecstasy users have impaired
      PM that cannot be explained by an increased propensity to exaggerate cognitive
      failures. These may be attributable, in part, to central executive deficits that
      are due to frontal lobe damage associated with Ecstasy use. Copyright 2001 John
      Wiley & Sons, Ltd.

PMID- 12404541
TI  - Auditory verbal learning in drug-free Ecstasy polydrug users.
AB  - Drug-free Ecstasy polydrug users have shown impairment on tasks of verbal working
      memory and memory span. Current research aims to investigate how these deficits
      may affect the learning of verbal material by administration of the Auditory
      Verbal Learning Task (AVLT) (Rey, 1964). The task provides a learning curve by
      assessing immediate memory span over multiple trials. Learning strategies are
      further analysed by tendencies to confabulate as well as demonstrate either
      proactive or retroactive interference elicited by a novel 'distractor' list.
      Three groups completed the task: two groups of 14 Ecstasy users (short- and long
      term) and one group of 14 polydrug controls. Compared with controls both Ecstasy
      groups recalled significantly fewer words and made more confabulation errors on
      the initial three recall trials as well as a delayed recall trial. Long-term
      users demonstrated increased confabulation on the initial trials and the novel
      'distractor7' trial, compared with short-term users. Only following repeated
      presentations were both short- and long-term users shown to perform at control
      levels. As such, deficits in verbal learning may be more related to storage
      and/or retrieval problems than problems associated with capacity per se. No
      interference errors were demonstrated by either of the Ecstasy groups. However, a
      high level of intrusion errors may indicate selective working memory problems
      associated with longer-term use of the drug. Copyright 2001 John Wiley & Sons,
      Ltd.

PMID- 12404542
TI  - Differential effects of Ecstasy and cannabis on self-reports of memory ability: a
      web-based study.
AB  - Given the legal status of MDMA (3,4-methylenedioxymethamphetamine), or Ecstasy,
      face-to-face access to participants is sometimes difficult. The number of
      participants in studies of cognitive performance amongst Ecstasy users is
      variable, with the average being around 30. Access to a larger number of
      participants is clearly desirable. The present investigation accessed a larger
      sample size using a web-based design. A website was developed and used for data
      collection. Prospective memory ability was assessed using the Prospective Memory
      Questionnaire. Self-report of day-to-day memory performance was investigated
      using the Everyday Memory Questionnaire. The Drug Questionnaire assessed the use
      of other substances as well as Ecstasy, allowing a regression design to isolate
      the contribution of each substance to any variance on the cognitive measures.
      Preliminary findings (N = 488) indicate that there is a clear double dissociation
      between the impact of Ecstasy and cannabis. We found that cannabis was associated
      with reports of 'here-and-now' cognitive problems in short-term and internally
      cued prospective memory. In contrast, Ecstasy was associated with reports of long
      term memory problems, which were more related to storage and retrieval
      difficulties. Copyright 2001 John Wiley & Sons, Ltd.

PMID- 12404543
TI  - Psychological profile of abstinent recreational Ecstasy (MDMA) users and
      significance of concomitant cannabis use.
AB  - The popular recreational drug Ecstasy (3,4-methylenedioxymethamphetamine, or
      MDMA, and related congeners) is neurotoxic upon central serotonergic systems in
      animal studies. So far, the most convincing evidence for neurotoxicity-related
      functional deficits in humans derives from neurocognitive studies demonstrating
      dose-related memory problems in Ecstasy users. The aim of the current
      investigation was to study the relationship between the psychological profile of
      recreational Ecstasy users and the patterns of their drug use. Twenty-eight
      abstinent recreational Ecstasy users with concomitant use of cannabis only and
      two equally sized, matched groups of cannabis users and non-users were
      administered standardized self-rating scales for the assessment of psychological
      problems which are thought to be related to central serotonergic function.
      Ecstasy users had elevated scores on subscales measuring impulsiveness, anxiety,
      sensation seeking, somatic complaints, obsessive-compulsive behavior and
      psychoticism. Higher scores were associated with both heavier Ecstasy and heavier
      cannabis use. After controlling for cannabis use, most group differences in
      psychometric scores no longer achieved statistical significance. The present data
      are in line with other reports demonstrating a broad range of psychological
      problems in Ecstasy users. However, the concomitant use of other drugs,
      specifically cannabis, seems to be crucial in this respect. Therefore, compared
      with cognitive deficits, psychological problems appear to be less suitable
      functional indices of Ecstasy-related neurotoxic damage of central serotonergic
      systems in humans. Copyright 2001 John Wiley & Sons, Ltd.

PMID- 12404544
TI  - Personality dimensions and psychopathological profiles of Ecstasy users.
AB  - Only limited information is available with respect to personality traits and the
      psychopathological characteristics of Ecstasy users. To shed some light on the
      issue, we compared a group of 43 Ecstasy consumers (made up of both
      'experimenters', those who took </= 27.5 tablets in their lifetime, and
      'abusers', those who took larger amounts of the drug) with a composite control
      group of 77 subjects (made up of drug-free people, cannabis users and users of
      illicit drugs other than Ecstasy). Three instruments were used: the Questionnaire
      for the Assessment of the Use of Entactogenic Drugs (to assess modalities and
      characteristics of Ecstasy use); the Cloninger Tridimensional Personality
      Questionnaire (which measures harm avoidance, reward dependence and novelty
      seeking) and the SCL-90 (which measures 10 different psychiatric variables). The
      Ecstasy consumer group subjects showed higher novelty seeking scores than the
      controls (p < 0.001), and Ecstasy experimenters showed lower harm avoidance
      scores than the abusers (p = 0.029), but values of both reward dependence and
      harm avoidance dimensions were associated with sex. On the SCL-90, Ecstasy users
      showed higher scores than the controls on the obsession-compulsion (p = 0.004),
      phobic anxiety (p = 0.037), psychoticism (p = 0.005) and sleep disturbances (p =
      0.046) subscales. However, many of the SCL-90 subscale results were associated
      with sex, and only the psychoticism values seemed to suggest a clinical
      condition. The main finding of this study is that high novelty seeking scores are
      characteristic of Ecstasy consumers: The propensity to look selectively for
      novelties could possibly act as a predisposing factor for Ecstasy abuse itself.
      Copyright 2001 John Wiley & Sons, Ltd.

PMID- 12404545
TI  - Psychiatric disorders in Ecstasy (MDMA) users: a literature review focusing on
      personal predisposition and drug history.
AB  - 3,4-methylenedioxymethamphetamine (MDMA or Ecstasy) has been implicated in the
      onset of a number of psychological disorders and associated with a number of
      psychiatric symptoms that have persisted after cessation of the drug. This paper
      is a review of the published psychiatric case studies from the last 10 years
      involving MDMA. Only 24% of patients had a previous psychiatric history and 34%
      had a psychiatric illness amongst first degree relatives. The percentage of
      patients not having had a personal or family history of psychiatric illness and
      the temporal relationship between MDMA ingestion and the experience of recurring
      symptoms strongly suggest a causal relationship between the drug and
      neuropsychiatric manifestations. Further supporting evidence comes from several
      studies using non-clinical samples. Ecstasy users that don't present themselves
      in healthcare settings as having clinical symptoms have significantly higher
      scores on certain subscales of the SCL-90 compared with Ecstasy-naive controls,
      with higher pathology scores in heavier Ecstasy users. The full-blown psychiatric
      cases may represent the broad end of this problematic spectrum. Copyright 2001
      John Wiley & Sons, Ltd.

PMID- 12404546
TI  - A critical review of akathisia, and its possible association with suicidal
      behaviour.
AB  - The purpose of this paper was to make a critical review of akathisia, based on
      the principles of evidence-based medicine, and to explore a possible link between
      akathisia and suicidal behaviour (suicidal thinking, parasuicide and completed
      suicide). An extensive systematic search was carried out on three major
      databases, Embase, ClinPsych and Medline. Fifty-seven relevant references were
      found, and a further 26 references were reviewed after careful selection from the
      references of the original references. The Cochrane Library did not contain any
      systematic reviews on the subject. Akathisia can be caused by several different
      groups of drugs, but most frequently by antipsychotics and to a lesser extent
      antidepressants. Research into akathisia is made considerably more difficult by
      the lack of a universally agreed definition of the condition. The underlying
      pathophysiology is still far from clear, but the literature offers guidelines on
      less hazardous management regimes for patients. On the basis of the existing
      literature, akathisia cannot at this stage unequivocally be linked to suicidal
      behaviour. It is certain, however, that the condition of akathisia does cause
      considerable distress in an already vulnerable group of patients. Because it is
      largely avoidable, new, more rigorous strategies must be put in place to prevent
      it. Copyright 2001 John Wiley & Sons, Ltd.

PMID- 12404547
TI  - Caffeine levels in saliva: associations with psychosocial factors and behavioural
      effects.
AB  - The present study had two main aims. The first was to examine associations
      between psychosocial factors, health-related behaviours, regular level of
      caffeine consumption, time of day and levels of caffeine in saliva following
      acute caffeine challenges. The second aim was to determine whether individual
      differences in changes in performance following ingestion of caffeine were
      related to levels of caffeine in saliva. One hundred and forty-four young adults
      participated in the study. Questionnaires were administered prior to the study to
      measure psychosocial characteristics, health-related behaviours and habitual
      levels of caffeine consumption. Two double-blind acute caffeine challenges were
      then carried out 1 week apart. Volunteers were given either placebo or 1.5 or 3
      mg/kg of caffeine on each occasion. The challenges were carried out at 8 : 00, 11
      : 00, 14 : 00 or 18 : 00 h so that the impact of time of day could be assessed.
      In the week between the two challenges the volunteers consumed either caffeinated
      or decaffeinated products. This allowed investigation of the effects of caffeine
      withdrawal on caffeine metabolism. Prior to each caffeine challenge volunteers
      performed a range of tasks, and a baseline saliva sample was taken. The tasks
      were repeated 1 h after ingestion of the caffeine, with saliva samples being
      taken at the start and end of the 1 h test battery. The results showed that the
      level of caffeine in the saliva was a good indicator of the dose of caffeine
      consumed and of compliance with the withdrawal manipulation. Caffeine levels were
      not influenced by time of day, habitual caffeine consumption, psychosocial
      factors or health-related behaviours. Individual differences in caffeine levels
      in saliva were not related to the individual variation in the effects of caffeine
      on performance. Copyright 2001 John Wiley & Sons, Ltd.

PMID- 12404548
TI  - The effects of caffeine on simulated driving, subjective alertness and sustained
      attention.
AB  - There is evidence that caffeine increases alertness and reduces fatigue. This may
      be especially so in low arousal situations (e.g. working at night or for
      prolonged hours). Caffeine has also been found to improve performance on
      vigilance tasks and simple tasks requiring sustained response. Again, these
      effects are often clearest when alertness is reduced, although there is evidence
      that benefits may still occur when the individual is unimpaired. Most studies to
      date have investigated the behavioural effects of caffeine in laboratory
      experiments using artificial tasks. In the current study 3 mg/kg caffeine was
      found to improve steering accuracy in a 1 h simulated drive. Measures of mood and
      performance on a sustained attention task also showed the benefits of caffeine.
      These findings suggest that laboratory results reflect a general benefit of
      caffeine that may also be observed in real-life situations. Other evidence
      examining the effects of caffeine on performance efficiency over the working day
      has shown the benefits of caffeine consumption on measures of sustained attention
      and alertness. This study also provided evidence suggesting that caffeine is
      often consumed when alertness is low to maximise alertness and performance
      efficiency. The implications of these findings for road safety are also
      considered. Copyright 2001 John Wiley & Sons, Ltd.

PMID- 12404549
TI  - Sex differences in estimation of time intervals and in reaction time are removed
      by moderate but not high doses of caffeine in coffee.
AB  - Estimation of the passage of time in the seconds-to-minutes range and reaction
      time are strongly dependent on a hypothetical internal clock. Dopamine is the
      neurotransmitter most closely related to the rate of this clock. Caffeine,
      probably the most consumed drug in the world, leads to an augmentation of
      dopamine neurotransmission. In this study coffee, which reproduces the conditions
      under which caffeine is normally ingested, containing 3, 75, 150 or 300 mg of
      caffeine, was given to healthy male and female volunteers. A computerized time
      estimation and reaction time test was carried out 50 min after ingestion. Sex
      differences in placebo control subjects (who took decaffeinated coffee with 3 mg
      of caffeine), with females making more accurate estimates of time intervals than
      males and males showing shorter reaction times than females, were removed in
      subject taking doses of 75 and 150 mg of caffeine in the case of time estimation
      and 150 mg in the case of reaction time. The 300 mg dose induced overestimation
      of time in females and shortened the reaction time in males. There were no sex
      differences in the pharmacokinetics of caffeine, as measured in salivary
      concentration of caffeine using high-performance liquid chromatography. Results
      indicating sex differences in time estimation or reaction time should not be
      generalized from the laboratory to real life without considering the fact that
      everyday coffee consumption may eliminate these differences. Copyright 2001 John
      Wiley & Sons, Ltd.

PMID- 12404550
TI  - In vitro metabolism of mirtazapine enantiomers by human cytochrome P450 enzymes.
AB  - The metabolism of mirtazapine enantiomers was investigated in vitro using human
      lymphoblast microsomes transfected with human cDNA to overexpress either CYP1A2,
      CYP2C9, CYP2C19, CYP2D6 or CYP3A4 and assayed for mirtazapine enantiomers using a
      validated chiral method of high-performance liquid chromatography. (+)
      Mirtazapine was extensively metabolised by CYP2D6 (K(m) = 9.3 +/- 3.3 &mgr;mol/l,
      V(max) = 40.9 +/- 7.9 &mgr;mol/h/mg, intrinsic clearance = 4.41 l/h/mg). CYP1A2
      and CYP3A4 showed low metabolic activity towards (+)-mirtazapine and (-)
      mirtazapine respectively. Neither CYP2C9 nor CYP2C19 appeared to be involved in
      the metabolism of the enantiomers of mirtazapine. Copyright 2001 John Wiley &
      Sons, Ltd.

PMID- 12404551
TI  - The Pharmacokinetics of the THC in fat and brain: Resulting functional responses
      to marihuana smoking: G. Nahas, Volume 16 Issue 3, April 2001, pages 247-255.
AB  - The original article to which this Erratum refers was published in Human
      Psychopharmacology: Clinical and Experimental 16 (3) 2001, 247-255.

PMID- 12404552
TI  - Differential efficacy of risperidone versus haloperidol in psychopathological
      subtypes of subchronic schizophrenia.
AB  - The aim of this study was to evaluate the efficacy and tolerability of
      risperidone versus haloperidol in subchronic schizophrenia, using
      psychopathological subgroups of patients with negative or positive and mixed
      symptoms to analyse the possible differential efficacy of the drugs. A total of
      33 patients diagnosed using DSM-IV criteria entered the 6 week double-blind study
      with either risperidone or haloperidol 5 mg/day. Twenty-nine patients completed
      at least 2 weeks of treatment and entered the last observation carried-forward
      analysis. Both treatments were effective in reducing total scores and positive
      and negative subscale scores on the Positive and Negative Scale for Schizophrenia
      (PANSS), with a significantly better extrapyramidal profile in the risperidone
      treated group. When analysis was repeated in each treatment group by
      psychopathological subtype (negative vs positive-mixed subgroups based on the
      PANSS composite index), risperidone was significantly superior to haloperidol in
      the intention to treat analysis in the negative subgroup. Repeated measures
      multivariate analysis of variance showed a significantly greater improvement in
      the PANSS negative subscale scores of risperidone-treated patients in the
      negative subgroup and a significant improvement in the PANSS positive subscale
      scores in both psychopathological subtypes. Haloperidol was significantly
      effective only in reducing positive symptoms in the positive subtype. Our results
      indicate that risperidone may be proposed for first-line treatment of subchronic
      schizophrenia, in particular the negative subtype. Copyright 2001 John Wiley &
      Sons, Ltd.

PMID- 12404553
TI  - Mirtazapine and paroxetine: a drug-drug interaction study in healthy subjects.
AB  - Paroxetine inhibits cytochrome P(450) 2D6, which is involved in the metabolism of
      mirtazapine. The possible drug-drug interaction between two pharmacologically
      distinct antidepressants, mirtazapine and paroxetine, has been investigated in a
      randomized, three-way crossover study in 24 healthy male and female subjects.
      After a titration phase of 3 days, each subject received single daily doses of 30
      mg mirtazapine, 40 mg paroxetine or the combination for 6 days. Assessments
      included serial blood sampling for pharmacokinetics at steady state, cognitive
      testing using the test battery of CDR Ltd, a visual analogue mood rating scale
      (Bond and Lader) and the Leeds Sleep Evaluation Questionnaire. Paroxetine
      inhibits the metabolism of mirtazapine, as shown by increases of approximately
      17% and 25% of the 24 h AUC's of mirtazapine and its demethyl metabolite,
      respectively. Mirtazapine did not alter the pharmacokinetics of paroxetine. The
      combined administration of mirtazapine and paroxetine probably does not alter
      cognitive functioning or result in major changes on the visual analogue mood
      rating scale and Sleep Evaluation Questionnaire, compared with the administration
      of either drug alone. The incidence of adverse events was lower during combined
      administration of mirtazapine and paroxetine than during administration of either
      drug alone. Fatigue, dizziness, headache, nausea, anxiety and somnolence were the
      most common adverse events during combined administration. These data suggest
      that the combination of mirtazapine and paroxetine is unlikely to lead to
      clinically relevant drug-drug interactions and can be used without dose
      adjustment of either drug. The combination may even be better tolerated than
      either drug alone. Copyright 2001 John Wiley & Sons, Ltd.

PMID- 12404554
TI  - Fluvoxamine in obsessive-compulsive disorder: similar efficacy but superior
      tolerability in comparison with clomipramine.
AB  - Some meta-analyses have suggested that the selective serotonin reuptake
      inhibitors (SSRIs) are less effective than clomipramine in the treatment of
      obsessive-compulsive disorder (OCD). The aim of this double-blind, randomised,
      multicentre study was to directly compare the efficacy and safety of fluvoxamine
      and clomipramine in patients with OCD. A total of 227 patients were randomised to
      flexible doses of fluvoxamine or clomipramine (both 150-300 mg/day) for 10 weeks.
      Fluvoxamine and clomipramine were both clinically effective and there were no
      statistically significant differences between the two treatment groups, at any
      visit, on the National Institute of Mental Health Obsessive-Compulsive global
      rating scale, the Yale-Brown Obsessive-Compulsive scale (total score and
      obsession and compulsion subscores), the Clinical Global Impression severity of
      illness and global improvement subscales, the Clinical Anxiety Scale and the 17
      item Hamilton Depression Rating Scale. However, there were differences in safety
      between the two treatments. Compared with fluvoxamine-treated patients, those
      treated with clomipramine had more anticholinergic side effects (dry mouth,
      constipation and tremor) and premature withdrawals due to adverse events (18
      versus 9). The results from this controlled study indicate that fluvoxamine is as
      effective as clomipramine in the treatment of OCD but has a better tolerability
      profile. Copyright 2001 John Wiley & Sons, Ltd.

PMID- 12404555
TI  - Comparative study of short-term anxiolytic potency of alprazolam and tandospirone
      in psychiatric outpatients with anxiety disorders.
AB  - Anxiolytic potency of 1 week of treatment with alprazolam or tandospirone in
      psychiatric outpatients with anxiety disorders was evaluated by changes in the
      scores on the Hamilton Anxiety Scale and the State and Trait Anxiety Inventory
      and in the saliva level of free-3-methoxy-4-hydroxyphenylglycol (free-MHPG).
      Saliva level of free-MHPG was significantly reduced by 1 week of treatment with
      alprazolam but not with tandospirone. Reductions in the HAS score after 1 week of
      drug treatment were greater in patients treated with alprazolam than in those
      treated with tandospirone. These results indicate that the short-term anxiolytic
      potency of alprazolam is greater than that of tandospirone and that the saliva
      level of MHPG would be a useful marker for the evaluation of the therapeutic
      potency of anxiolytic agents. Copyright 2001 John Wiley & Sons, Ltd.

PMID- 12404556
TI  - Effects of temazepam on memory and psychomotor performance: a dose-response
      study.
AB  - In a randomised, three-period crossover study, psychomotor performance and memory
      were tested and mood assessed for 3 h after single doses of placebo (PL), 20 mg
      temazepam (T20) or 30 mg temazepam (T30) were given to six healthy females aged
      21-23. A composite measure of psychomotor speed showed a dose-dependent slowing
      (Page's L trend test: p < 0.001; sign test PL vs T20 and T30 vs T20: p < 0.05).
      The number of errors in the performance of tasks was increased, significantly in
      the case of some measures. Explicit memory (Buschke Selective Reminding Task)
      showed significant impairment of long-term but not short-term memory (Page's L
      trend test: p < 0.05). The form of the dose-response curve was positively
      accelerating, with the difference in performance between T20 and T30 at least as
      great as that between PL and T20. Visual Analogue Scales showed a decrease in a
      factor representing functional integrity (Page's L trend test: p < 0.05;) sign
      test (PL vs T20: p < 0.05), but no changes in mood. These results show that 30 mg
      is a useful extension of the dose range of temazepam, being well tolerated and
      that it produces a substantially greater impairment of performance than 20 mg.
      Copyright 2001 John Wiley & Sons, Ltd.

PMID- 12404557
TI  - Cholinergic modulation of cognitive function in healthy subjects: acute effects
      of donepezil, a cholinesterase inhibitor.

PMID- 12404558
TI  - Pharmacodynamic profile of Zaleplon, a new non-benzodiazepine hypnotic agent.
AB  - The challenge in developing hypnotic agents for the treatment of insomnia is to
      balance the sedative effect needed at bedtime with the residual sedation on
      awakening. Zaleplon is a novel pyrazolopyrimidine hypnotic agent that acts as a
      selective agonist to the brain omega(1) receptor situated on the alpha(1) subunit
      of the GABA(A) receptor complex. Zaleplon was proven to be an effective hypnotic
      drug as it consistently and significantly reduced latency to persistent sleep in
      insomniac patients for doses of 10 mg and above in polysomnography studies. The
      pharmacodynamic profile of zaleplon on psychomotor performance, actual driving
      and cognitive function, including memory, was assessed in several randomized,
      double-blind, placebo-controlled studies in healthy young subjects as well as
      insomniac patients by using various positive controls (zolpidem, zopiclone,
      triazolam and flurazepam). The recommended hypnotic dose of zaleplon in young
      adults (10 mg) produced minimal or no impairment of psychomotor and memory
      performance even when administered during the night as little as 1 h before
      waking. No impairment of actual driving was observed when zaleplon 10 mg was
      administered either at bedtime or in the middle of the night as little as 4 h
      before waking. Zaleplon 20 mg, twice the recommended dose, generally produced
      significant impairment of performance and cognitive functions when these
      functions were measured at the time of peak plasma concentration, i.e. 1 h after
      dose administration, and no impairment of driving abilities was observed 4 h
      after a middle-of-the-night administration. In contrast, consistent detrimental
      residual effects on various aspects of psychomotor and cognitive functions were
      observed with the therapeutic doses of the various commonly prescribed hypnotic
      agents used as comparators, e.g. zolpidem 10 mg up to 5 h after dose
      administration, zopiclone 7.5 mg up to 10 h after, flurazepam 30 mg up to 14 h
      after and triazolam 0.25 mg up to 6 h after. Also, zolpidem 10 mg and zopiclone
      7.5 mg were also shown to significantly impair driving ability the next morning
      when this was measured 4 h and up to 10 h after dose administration,
      respectively. The present review shows that zaleplon 10 mg has little or no
      residual effect when administered in the middle of the night, as late as 1 h
      before waking, and is devoid of impairment of driving abilities as assessed by
      actual driving 4 h after dose administration. The lack of clinically significant
      or minimally statistically significant residual effects of zaleplon even at its
      peak concentration may be explained by its unique pharmacokinetic (rapid
      elimination half-life) and pharmacodynamic (low affinity, and specific binding
      profile to various subunits of the GABA(A)receptor) profiles. These properties
      allow zaleplon to be used for treatment of symptoms only when they occur, either
      at bedtime or later in the night, without incurring significant risk of
      developing next-day impairment of psychomotor and cognitive functioning.
      Copyright 2001 John Wiley & Sons, Ltd.

PMID- 12404559
TI  - Visual search and urban driving under the influence of marijuana and alcohol.
AB  - The purpose of the present study was to assess the effects of low doses of
      marijuana and alcohol, and their combination, on visual search at intersections
      and on general driving proficiency in the City Driving Test. Sixteen recreational
      users of alcohol and marijuana (eight males and eight females) were treated with
      these substances or placebo according to a balanced, 4-way, cross-over, observer-
      and subject-blind design. On separate evenings, subjects received weight
      calibrated doses of THC, alcohol or placebo in each of the following treatment
      conditions: alcohol placebo + THC placebo, alcohol + THC placebo, THC 100
      &mgr;g/kg + alcohol placebo, THC 100 &mgr;g/kg + alcohol. Alcohol doses
      administered were sufficient for achieving a blood alcohol concentration (BAC) of
      about 0.05 g/dl. Initial drinking preceded smoking by one hour. The City Driving
      Test commenced 15 minutes after smoking and lasted 45 minutes. The test was
      conducted over a fixed route within the city limits of Maastricht. An eye
      movement recording system was mounted on each subject's head for providing
      relative frequency measures of appropriate visual search at intersections.
      General driving quality was rated by a licensed driving instructor on a shortened
      version of the Royal Dutch Tourist Association's Driving Proficiency Test. After
      placebo treatment subjects searched for traffic approaching from side streets on
      the right in 84% of all cases. Visual search frequency in these subjects did not
      change when they were treated with alcohol or marijuana alone. However, when
      treated with the combination of alcohol and marijuana, the frequency of visual
      search dropped by 3%. Performance as rated on the Driving Proficiency Scale did
      not differ between treatments. It was concluded that the effects of low doses of
      THC (100 &mgr;g/kg) and alcohol (BAC < 0.05 g/dl) on higher-level driving skills
      as measured in the present study are minimal. Copyright 2001 John Wiley & Sons,
      Ltd.

PMID- 12404560
TI  - Plasma serotonin response to carbohydrate-rich food in chronic schizophrenic
      patients: clozapine versus classic antipsychotic agents.
AB  - Researchers have reported a stimulatory effect of carbohydrate-rich intake on
      platelet-poor plasma (PPP) serotonin (5-HT) levels in healthy human subjects.
      Dietary manipulation may serve as a safer and less invasive means than
      pharmacologic challenge to provoke serotonergic responsivity in studies of
      schizophrenia. In the present study, we used the carbohydrate-rich meal test as
      an indicator of 5-HT activity in 12 patients with chronic schizophrenia
      maintained for at least 6 months on clozapine. PPP 5-HT levels were measured at
      baseline and at 1, 2 and 3 h after administration of the test. Findings were
      compared with those in schizophrenic patients treated with classic antipsychotic
      agents for the same duration. The maximal PPP 5-HT response was reached 120 min
      after meal administration in the clozapine-treated group and 60 min after in the
      classic antipsychotic-treated group (P<0.05 vs baseline for both). The 5-HT level
      (as percentage of baseline) at 60 min was significantly lower in the clozapine
      treated group (P<0.02), as were individual PPP 5-HT peak values (P<0.05). The
      individual time to reach the peak response was similar in the two groups. Our
      results indicate that in patients with chronic schizophrenia 5-HT responsivity to
      the natural challenge of carbohydrate-rich meals is lower in those treated with
      clozapine than in those given classic antipsychotic agents. Values in both groups
      were lower than those in an appropriate historical comparative group of healthy
      subjects. We suggest that both clozapine and classic antipsychotic agents
      suppress serotonergic system sensitivity, but to a different degree. Copyright
      2001 John Wiley & Sons, Ltd.

PMID- 12404561
TI  - Cognitive effects of a Ginkgo biloba/vinpocetine compound in normal adults:
      systematic assessment of perception, attention and memory.
AB  - A computerized test battery was used in a double-blind design to assess the
      cognitive effects of a nutrient compound containing Ginkgo biloba in 24 normal
      adults. Ten tasks (perceptual, attention and short-term memory) were presented in
      a standardized manner designed to maximize performance, with substantial pre-test
      practice employed to minimize response variability. Subjects were given either
      placebo or Ginkgo biloba extract capsules to consume for 14 days, after which
      they performed all tasks twice. They then received the other condition, and after
      14 days completed the final test session. Response time and error rate stabilized
      after pre-test practice. A 'working memory capacity' paradigm demonstrated a
      reliable 50 ms response time decrease between the placebo and Ginkgo biloba
      testing, suggesting that Ginkgo biloba speeds short-term working memory
      processing in normal adults. Copyright 2001 John Wiley & Sons, Ltd.

PMID- 12404562
TI  - Evaluation of tiapride in agitated elderly outpatients: an open study.
AB  - The aim of this study was the evaluation of the efficacy and safety of tiapride
      50-100 mg administered 3 times a day to elderly patients with aggressive
      behavior. Data from 425 questionnaires concerning aggressive behavior in Greek
      elderly patients were evaluated before and after treatment. The Brief Agitation
      Rating Scale (BARS), which has 10 items, was used to evaluate the effectiveness
      of tiapride. To test the overall effectiveness of the drug during the trial, the
      statistical method of repeated measures ANOVA was applied to the total score and
      the very small F-value (p < 0.0005) led us to accept the hypothesis that tiapride
      significantly improves the condition of elderly patients with aggressive
      behavior. Only 6.2% of patients developed an adverse event during the trial. With
      95% probability one may state that the probability of an adverse event occurring
      during the administration of tiapride is between 5% and 7.4%. We conclude that
      tiapride, apart from being very efficient in ameliorating aggressive behavior in
      elderly patients, is also very safe to administer. Copyright 2001 John Wiley &
      Sons, Ltd.

PMID- 12404563
TI  - A comparative study of venlafaxine with a focused education and psychotherapy
      program versus venlafaxine alone in the treatment of depression in general
      practice.
AB  - The efficacy of a focused education and psychotherapy program (FEPP) plus
      antidepressant was compared with that of usual psychosocial treatment and
      antidepressant in a general practice setting. The FEPP comprised interpersonal
      counselling (IPC) delivered in a modified way to suit the general practice
      setting, together with patient education and selected cognitive behavioural
      techniques. All patients were treated with venlafaxine-XR. Thirty-one patients
      entered the study, three withdrawing before completion of the 12 week trial. Both
      treatments produced a statistically significant reduction in BDI and POMS scores
      from baseline, with greater improvement evident in the FEPP plus antidepressant
      group. Copyright 2001 John Wiley & Sons, Ltd.

PMID- 12404564
TI  - Glucocorticoids and cognitive function: from physiology to pathophysiology.
AB  - This paper reviews the literature on the relationship between glucocorticoids and
      cognitive functioning, including memory and selective attention. The main body of
      evidence suggests that hypothalamic-pituitary-adrenal (HPA) axis dysfunction or a
      state of hypercortisolaemia can be correlated with cognitive deficits specific to
      the medial temporal lobe declarative memory system. These impairments are
      discussed in relation to patients with HPA abnormalities, as seen in a
      significant number of patients with major depression or Cushing's syndrome, and
      also in relation to healthy volunteers after administration of glucocorticoids.
      It remains to be seen whether there are differential effects on acquisition,
      consolidation or retrieval processes. However, it would seem that glucocorticoids
      have a preferential effect on recall of information as opposed to recognition,
      possibly because recognition is more automatic.Type 2 glucocorticoid receptors
      (GRs), which are occupied by cortisol in humans in times of stress, are thought
      to be responsible for the glucocorticoid-induced memory impairment. GRs alter the
      feedback of the HPA axis, which in turn disrupts hippocampal functioning. While
      this can be reversible, animal studies suggest that chronic elevation of
      glucocorticoid levels can lead to the loss of hippocampal neurons and
      irreversible decline in declarative memory. Copyright 2001 John Wiley & Sons,
      Ltd.

PMID- 12404565
TI  - Personality pathology, depression and HPA axis functioning.
AB  - Hypothalamic pituitary adrenal (HPA) axis functioning, as measured by the
      dexamethasone suppression test (DST), has been extensively investigated in major
      depressive disorder (MDD). Evaluating DST response in MDD patients while
      simultaneously considering clinically relevant personality disorders may further
      clarify the contribution of both personality pathology and HPA axis function to
      depressive symptoms. The present study measured personality pathology by
      administering the revised version of the Millon Clinical Multiaxial Inventory
      (MCMI-II) in a sample of 25 patients diagnosed with MDD. Analyses revealed that
      suppressors (n = 19) scored significantly higher than non-suppressors (n = 6) on
      six of the 13 MCMI-II personality disorder scales: Avoidant, Schizoid, Self
      Defeating, Passive-Aggressive, Schizotypal and Borderline. Increased personality
      pathology was associated with normal suppression of cortisol following the DST.
      This suggests that suppression of the DST may be associated with depressive
      states linked with personality pathology while the more biologically based
      depression is associated with abnormal HPA pathophysiology. Copyright 2001 John
      Wiley & Sons, Ltd.

PMID- 12404566
TI  - Caffeine (4 mg/kg) influences sustained attention and delayed free recall but not
      memory predictions.
AB  - This experiment was conducted to examine the influence of a moderate dose of
      caffeine (4 mg/kg) on delayed memory, metamemory, and sustained attention. One
      hundred and forty-two volunteers ingested either caffeine or placebo during a
      study session which included three different memory tasks (free recall, cued
      recall, and recognition), and they made predictions of future memory performance.
      On day 2, participants again ingested either caffeine or placebo and completed
      memory tests. Sustained attention performance was measured on both days, and
      caffeine reliably improved hit rates and response latencies. A reliable drug
      state interaction was detected only in the free recall test of memory. Caffeine
      did not affect the magnitude or accuracy of memory predictions, but there was
      some evidence that expectancies about caffeine were related to cognitive
      performance. Overall, caffeine's impact on memory and metamemory was not robust
      in this study. Copyright 2001 John Wiley & Sons, Ltd.

PMID- 12404567
TI  - Influence of cigarette smoking on prepulse inhibition of the acoustic startle
      response in schizophrenia.
AB  - The prevalence of tobacco smoking is known to be higher in patients with
      schizophrenia than other psychiatric disorders and general population. These
      patients also show reduced prepulse inhibition (PPI) of the startle response. PPI
      refers to a reduction in response to a strong startling stimulus if preceded
      shortly by a stimulus of sub-threshold intensity. PPI is thought of as an
      objective index of sensorimotor gating. Nicotine administered subcutaneously or
      via cigarette smoking enhances PPI in healthy human beings. It also enhances PPI
      at low, but not high, doses in the rat. We examined the influence of smoking on
      PPI of the acoustic startle response in 46 male patients with chronic
      schizophrenia. In a naturalistic design, patients (n = 9) who smoked a cigarette
      less than 10 min prior to being tested on PPI were compared with other smoking (n
      = 23) and non-smoking patients (n = 14). We found that the group of patients who
      smoked a cigarette prior to being tested had significantly greater PPI than other
      two groups. These observations suggest a PPI-enhancing effect of cigarette
      smoking on PPI in patents with schizophrenia. Higher prevalence of cigarette
      smoking in schizophrenic patients may reflect an attempt to improve sensorimotor
      gating deficits. Copyright 2001 John Wiley & Sons, Ltd.

PMID- 12404568
TI  - Fluvoxamine is ineffective in the treatment of enuresis in children and
      adolescents: an open-label pilot study.
AB  - Tricyclic antidepressants possess established antienuretic properties. The
      selective serotonin reuptake inhibitors (SSRIs) have similar antidepressant
      properties to the tricyclic antidepressants and a safer side effect profile. The
      aim of the present study was to evaluate the antienuretic efficacy of one SSRI,
      fluvoxamine. Nine children aged 9 to 14 years with primary enuresis which was
      resistant to behavioral therapy participated in the study. All received
      fluvoxamine, 75-100 mg per day. In four, the enuresis was the only focus of
      clinical attention, and five received fluvoxamine for other primary indications.
      Enuresis was monitored daily, and mean voiding frequency was compared between
      three phases: baseline, on treatment and off treatment. Fluvoxamine had no
      statistically significant effect on enuresis. Fluvoxamine does not seem to
      possess significant antienuretic properties. We suggest that the combination of
      serotonergic with anticholinergic activity is a major factor in the antienuretic
      activity. In the treatment of children or adolescents with obsessive-compulsive
      disorder and comorbid enuresis, clomipramine may be preferred over SSRIs.
      Copyright 2001 John Wiley & Sons, Ltd.

PMID- 12404569
TI  - The influence of three months of methylphenidate treatment on platelet-poor
      plasma biogenic amine levels in boys with attention deficit hyperactivity
      disorder.
AB  - Attention deficit hyperactivity disorder (ADHD) is related to dysregulation in
      the activity of brain monoamines. The aim of the present study was to assess the
      impact of three months' methylphenidate (MPH) treatment on platelet-poor plasma
      (PPP) norepinephrine (NE), dopa and serotonin (5-HT) levels as well as on ADHD
      symptomatology. Three months of MPH treatment in 16 ADHD boys, aged 11.4 +/- 1.6
      years, resulted in a significant reduction in PPP NE levels (p < 0.05). A
      tendency towards a reduction of PPP 5-HT and dopa levels was detected (p < 0.1
      for both). The decrease in PPP biogenic amine levels after three months of MPH
      treatment was accompanied by a significant reduction in all psychometric
      characteristics of ADHD. This result indicates the possible role of overactivity
      of the noradrenergic system in the pathophysiology of ADHD and suggests that the
      MPH therapeutic action may be related to stimulant-induced inhibitory effect on
      the noradrenergic system. Copyright 2001 John Wiley & Sons, Ltd.

PMID- 12404570
TI  - Subjective ratings of prospective memory deficits in MDMA ('ecstasy') users.
AB  - Chronic use of MDMA (3,4-methylenedioxymethamphetamine), or 'ecstasy', is
      associated with significant cognitive impairments, particularly in laboratory and
      field tests of memory for previously encoded material. Less is known about the
      effects of a history of MDMA use on aspects of everyday cognitive functioning-of
      which prospective memory (typically characterised as 'remembering to do something
      at some future point') is an important aspect. Self-ratings of prospective memory
      among 30 regular ecstasy users (taking the drug 10 or more times per month) and
      31 ecstasy-free controls were compared. Each participant completed the
      Prospective Memory Questionnaire, which measures self-rated error frequencies
      relating to three aspects of prospective memory (short-term habitual, long-term
      episodic and internally cued); the scale also records the use of strategies to
      aid remembering. Compared with non-users, ecstasy users reported significantly
      more self-rated errors in prospective memory, an effect which was evident after
      co-varying levels of other drug use. There were no significant differences in the
      use of strategies to aid memory. These findings provide new insights into
      prospective memory dysfunction in recreational drug users. Prospective memory
      deficits may be related to the reported serotonergic and frontal lobe deficits in
      chronic MDMA users. It is necessary to use more objective tasks to assess
      putative prospective memory deficits in ecstasy users. Copyright 2001 John Wiley
      & Sons, Ltd.

PMID- 12404571
TI  - The acute effects of an extract of Bacopa monniera (Brahmi) on cognitive function
      in healthy normal subjects.
AB  - The Ayurvedic medicine Bacopa monniera (Brahmi) has been shown to exert cognitive
      enhancing effects in animals. The current study examined the acute effects of an
      extract of Bacopa monniera on cognitive function in normal healthy human
      subjects. The study was a double-blind, placebo-controlled independent group
      design in which subjects were randomly allocated to one of two treatment
      conditions, Bacopa monniera (300 mg) (n = 18) or placebo (n = 20).
      Neuropsychological testing was conducted before and 2 h after drug
      administration. No significant changes were found on any of the tests. The
      findings suggest that Bacopa monniera, at least for the dose administered, has no
      acute effects on cognitive functioning in normal healthy subjects. Copyright 2001
      John Wiley & Sons, Ltd.

PMID- 12404572
TI  - Stress-induced insomnia treated with kava and valerian: singly and in
      combination.
AB  - Kava and valerian are herbal remedies that are claimed to have anxiolytic and
      sedative properties respectively, without dependence potential or any appreciable
      side effects. In this pilot study, 24 patients suffering from stress-induced
      insomnia were treated for 6 weeks with kava (LI-150), 120 mg daily. This was
      followed by a 2-week 'wash-out' period off treatment, and then, five patients
      having dropped out, 19 received valerian (LI-156), 600 mg daily, for another 6
      weeks. Then there was a further 2-week period off treatment, and a final 6 weeks
      of treatment of these 19 patients with the two compounds combined (kava +
      valerian). Stress was measured in three areas: social, personal and life events;
      insomnia in three areas also: time to fall asleep, hours slept and waking mood.
      Total stress severity was significantly relieved by both compounds individually
      (p < 0.01), with no significant differences between them; and there was also
      improvement with the combination, significant in the case of insomnia (p < 0.05).
      On direct questioning, 16 patients (67%) reported no side effects on kava, 10
      (53%) on valerian and 10 (53%) on the combination. The 'commonest' effect was
      vivid dreams with kava + valerian (4 cases (21%)) and with valerian alone (3
      cases (16%)), followed by gastric discomfort and dizziness with kava (3 cases
      each (3 %)). These results are considered to be extremely promising but further
      studies may be required to determine the relative roles of the two compounds for
      such indications. Copyright 2001 John Wiley & Sons, Ltd.

PMID- 12404573
TI  - Expanding the horizons of depression: beyond the monoamine hypothesis.
AB  - The monoamine hypothesis has dominated our understanding of depression and of
      pharmacological approaches to its management and it has produced several
      generations of antidepressant agents, ranging from the monoamine oxidase
      inhibitors (MAOIs), through tricyclics (TCAs) and selective serotonin reuptake
      inhibitors (SSRIs), to the recently introduced selective noradrenaline reuptake
      inhibitor (NARI), reboxetine. Greater receptor selectivity has improved
      tolerability, but not efficacy, when newer compounds are compared with the
      original tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors.
      Essentially, the newer antidepressants have the same distinguishing feature as
      older ones, i.e. acute enhancement of monoaminergic neurotransmission. The
      monoamine hypothesis cannot conclusively link the acute biochemical action of
      antidepressants on monoamine levels with their delayed clinical effect of 10-14
      days, nor can it explain the mode of action of antidepressants that are effective
      despite being very weak inhibitors of monoaminergic transmission (e.g. iprindole)
      or, incongruously, enhancing monoamine uptake (e.g. tianeptine). Compared with
      other fields of medicine, there has been a lack of progress in understanding the
      pathophysiology of depression and producing truly novel antidepressant agents.
      Other biological approaches to depression, such as overactivity of the
      hypothalamic-pituitary-adrenal axis, hippocampal neural plasticity in response to
      stress, and the link between the inflammatory response and depression, offer new
      approaches to finding pharmacological agents, aided by improved techniques for
      visualising the human brain, better animal models, and increased knowledge of
      human markers of depression. Copyright 2001 John Wiley & Sons, Ltd.

PMID- 12404574
TI  - Tianeptine and paroxetine in major depressive disorder, with a special focus on
      the anxious component in depression: an international, 6-week double-blind study
      dagger.
AB  - Tianeptine (37.5 mg/day) and paroxetine (20 mg/day) were compared in a population
      of depressive patients without past or current history of co-morbid anxiety
      and/or important anxiolytic treatment. In a 6-week, double blind trial, the
      special focus was on anxious symptoms.Both drugs showed good efficacy on
      depressive symptomatology, assessed with MADRS and HDRS, but no difference was
      detected between tianeptine and paroxetine, for any assessment criterion. Despite
      the choice of selected depressive patients, without any co-morbid anxious
      disorder, anxiety scale scores at inclusion (HAMA and BAS) were appreciable but
      correlated poorly with depressive scores. Both tianeptine and paroxetine improved
      the apparent anxious component in depression. Tolerability of both drugs was
      good, although significantly better with tianeptine.Thus tianeptine and
      paroxetine are effective and safe treatments for major depression and may also
      act directly on the anxious component of the psychopathology. Copyright 2001 John
      Wiley & Sons, Ltd.

PMID- 12404575
TI  - The platelet as a peripheral marker in psychiatric illness.
AB  - The identification of peripheral markers of psychiatric illness is important if
      an improvement in the diagnosis and treatment of various diseases with
      overlapping symptomatology is desired. There are many disorders that not only
      have overlapping symptomatology, but also have similar biological disturbances.
      The functional capability of the neurons involved in the disease processes may be
      at the crux of the underlying pathology. The platelet intracellular calcium
      response to neurotransmitter stimulation has previously been used as a peripheral
      marker of psychiatric illness. This review discusses evidence in support of the
      extended use of the platelet as a peripheral marker. The use of the platelet
      intracellular calcium response to neurotransmitter stimulation as a state or
      trait marker in major depression, the specificity and selectivity of this
      response, and the possible use of the platelet as a peripheral marker in
      psychotic disorders such as schizophrenia, mania and psychotic depression are
      shown. Finally, a proposed mechanism for the association between certain
      psychiatric disorders and cardiovascular disease is discussed. Copyright 2001
      John Wiley & Sons, Ltd.

PMID- 12404576
TI  - Influence of the serotonin antagonist, metergoline, on the anxiogenic effects of
      carbon dioxide, and on heart rate and neuroendocrine measures, in healthy
      volunteers.
AB  - The mechanism of action of carbon dioxide (CO(2)) angiogenesis is unknown; only
      recently have possible serotonergic (5-HT) influences begun to be studied. In
      separate double-blind challenges 1 week apart, 14 healthy volunteers received two
      vital capacity inhalations each of 35% CO(2) and of air, once after a single
      capsule of placebo and once after a single capsule containing 4 mg of the 5-HT
      antagonist metergoline in a randomized crossover design. The inhalations were
      repeated 1 and 2 days after the ingestion of capsules, to investigate possible
      delayed effects of metergoline, and possible tolerance to repeated CO(2) after
      placebo. We observed increased anxiety, and a trend for increased plasma
      noradrenaline (NA), after CO(2). CO(2) anxiogenesis was significantly enhanced by
      metergoline. Heart rate increased after both gas mixtures following metergoline
      administration. Plasma prolactin levels were lower after metergoline. Responses
      to CO(2) did not differ between the day of placebo administration and the two
      subsequent days; on the days following metergoline administration there were
      almost no delayed effects. We hypothesize that 5-HT may function as an inhibitor
      of CO(2) anxiogenesis, and that this is opposed by the 5-HT antagonist,
      metergoline. Absence of tolerance after repeated CO(2) argues against
      psychological explanations of tolerance after other panicogens. Copyright 2001
      John Wiley & Sons, Ltd.

PMID- 12404577
TI  - The pharmacokinetics of THC in fat and brain: resulting functional responses to
      marihuana smoking.
AB  - A pleasant sensory perception (PSP), the high of THC or of marihuana consumption,
      is a consistent functional response to this drug only manifested by man, and
      which occurs concurrently with an increased heart rate. However, it has not been
      possible to relate consistently magnitude and duration of these functional
      markers to THC plasma concentration, whatever the route of administration. A re
      analysis of all the available clinical and experimental data reporting the
      pharmacokinetics and storage of THC in tissues in function of time, have
      indicated that the discrepancies between functional responses and plasma
      molecular THC concentration may be accounted for by the pharmacokinetics of THC.
      The instant uptake and unlimited storage of THC by neutral fat limits the
      molecular concentration of the drug present in the plasma to a level which does
      not exceed 6 x 10(14) molecules/ml. The physicochemical nature of the membrane
      lipid bilayer (of the blood-brain barrier) will restrict the access of THC into
      the bilayer receptors and its: reactive enzymes. The PSP and increased heart rate
      of marihuana is correlated with the molecular concentration of THC in the bilayer
      (blood-brain barrier) of the order of 10(12)-10(14) molecules/ml. This number in
      turn would be related to the number of functional THC receptor sites in the lipid
      bilayer. THC would exert its functional properties on PSP and heart rate through
      a molecular transmission to specific receptor site and bilipid layer
      physicochemical interations. Rapid uptake and slow release of THC in fat
      associated with a rate-limited uptake into brain may be a general philogenetic
      mechanism which would protect brain function from prolonged exposure to
      xenobiotics like THC and other fat soluble drugs. Copyright 2001 John Wiley &
      Sons, Ltd.

PMID- 12404578
TI  - A pilot, open clinical study of depakote in the treatment of cocaine abuse.
AB  - The effectiveness of increasing levels of valproic acid on cocaine abstinence was
      evaluated in an open-label trial of 55 subjects. Significantly lower percentages
      of individuals with valproate serum levels above 50 mcg/ml reported cocaine use
      and had less positive urinalyses as compared to those with serum levels less than
      50 mcg/ml. The total number of days of cocaine use decreased significantly (p <
      0.001) and improved levels of subject functioning were found with increasing
      serum levels of valproic acid. This pilot study offers confirmation that the
      divalproex sodium form of valproic acid, when used in sufficient serum levels,
      may provide an effective pharmacologic adjunct in the management and treatment of
      cocaine dependency. Copyright 2001 John Wiley & Sons, Ltd.

PMID- 12404579
TI  - The effect of clozapine on blood glucose metabolism.
AB  - The aim of this prospective study was to examine the effect of clozapine on blood
      glucose metabolism compared with haloperidol. Oral glucose tolerance tests were
      taken every week for 8 weeks to assess the prevalence of diabetes mellitus,
      impaired glucose tolerance and glycemic peak delay in 19 patients of the
      clozapine group compared with 15 patients of the haloperidol group. There were
      two dropouts in the clozapine group and five in the haloperidol group. Finally 17
      patients in the clozapine group and 10 patients in the haloperidol group
      participated in this study. In the clozapine group, six patients (35%) had
      impaired glucose tolerance, and seven patients (41%) had glycemic peak delay. In
      the haloperidol group, no patient (0%) had impaired glucose tolerance, and one
      patient (10%) had glycemic peak delay. None of either group developed diabetes
      mellitus. In conclusion, the clozapine group had more impaired glucose tolerance
      and glycemic peak delay than the haloperidol group. However, this difference did
      not achieve statistical significance (p = 0.056, p = 0.189). Copyright 2001 John
      Wiley & Sons, Ltd.

PMID- 12404580
TI  - The association between risk factors for tardive dyskinesia and phenylalanine
      induced abnormal movements in schizophrenia.
AB  - We examined whether an oral challenge dose of the amino acid phenylalanine (a
      dopamine precursor) exacerbates the abnormal movements of tardive dyskinesia
      (TD). We also examined age, gender, treatment duration, and baseline movement
      severity in relation to phenylalanine-induced changes in movements. Lastly, we
      assessed the influence of fasting amino acid levels on phenylalanine-induced
      movements. In a placebo-controlled fashion, the abnormal involuntary movement
      scale (AIMS) was obtained on 25 patients before and after a phenylalanine
      challenge drink. A general linear model determined the relative effects of age,
      gender, treatment duration, and fasting amino acid levels on the magnitude of
      induced movements. Age and treatment duration did not affect phenylalanine
      induced movements. Lower fasting levels of phenylalanine were associated with
      greater movements after controlling for age, F = 11.89, p < 0.003. The severity
      of abnormal movements at baseline also predicted response to phenylalanine, F =
      8.62, p = 0.0079. Brain amino acid and neurotransmitter pools are influenced by
      changes in dietary protein, which may have implications in the development and
      prevention of movement disorders. This study suggests that fasting amino acid
      levels may predict differences in vulnerability to movements during an influx of
      neurotransmitter precursors, perhaps due to long-term compensatory changes in
      receptor sensitivity. Copyright 2001 John Wiley & Sons, Ltd.

PMID- 12404581
TI  - Neuroleptic malignant syndrome with olanzapine associated with severe
      hypernatremia.
AB  - A 30-year-old white man with schizophrenia developed anorexia and nausea, and was
      admitted to hospital for confusion and delirium. He was on olanzapine, 10 days
      prior to admission. On admission, typical neuroleptic malignant syndrome (NMS)
      developed with elevated body temperature (39.7 degrees C), obtundation, tremor,
      rigidity, diaphoresis, fluctuating pupillary diameter, tachycardia, labile
      hypertension, elevated serum creatine kinase and severe hypernatremia (190
      meq/l). Olanzepine was stopped few days after admission to the hospital and the
      NMS manifestations resolved by hospital day 12. The patient had all of the major
      manifestations of NMS. There was no other likely explanation for his illness.
      This is the first case reported in which NMS was associated with olanzapine and
      extremely elevated levels of serum sodium. Copyright 2001 John Wiley & Sons, Ltd.

PMID- 12404582
TI  - Strategies for the rapid treatment of depression.
AB  - The purpose of this article is to review current literature relating to the
      determination of the time course of antidepressant effects. Further, this work
      explores studies examining the safety and effectiveness of pharmacological
      techniques for accelerating the therapeutic effects of antidepressant medication.
      A review of the literature pertaining to strategies for accelerating
      antidepressant medication effects was accomplished using the MEDLINE database,
      employing the key title words, antidepressant, rapid, and accelerating. A
      preponderance of evidence suggests that there is a multiple week latency for the
      onset of action of antidepressant medications. This latency appears to apply to
      virtually all standard antidepressants and may reflect slow adaptive changes to
      the inciting event of increased monoamine levels. Several strategies have
      received attention as potential strategies with which to accelerate the
      therapeutic effects of antidepressant medications. These include the use of high
      initial doses of some agents and also the use of initial augmentation strategies.
      Specifically, studies exist suggesting the acceleration of antidepressant effects
      using high initial doses of tricyclic antidepressants or venlafaxine, as well as
      the potential for acceleration by using initial augmentation with
      psychostimulants, lithium, or pindolol. Considering the morbidity and mortality
      associated with severe depression, a critical need exist for the exploration of
      ways in which to achieve antidepressant effects more quickly. A number of
      preliminary studies suggest strategies for the rapid treatment of depression,
      each with an apparent high degree of safety. Further investigations in more
      carefully defined patient populations and utilizing advances in the techniques
      for assessing antidepressant onset are needed. Copyright 2001 John Wiley & Sons,
      Ltd.

PMID- 12404583
TI  - Treatment-emergent behavioural side effects with selective serotonin re-uptake
      inhibitors in adults with learning disabilities.
AB  - Selective serotonin re-uptake inhibitors are widely used for the treatment of
      depression suffered by adults with learning disabilities. However, the
      presentation, time of onset and prevalence of treatment emergent symptoms, have
      not been extensively studied in adults with learning disabilities. The aim of
      this study was to determine these aspects of treatment. The study design involved
      retrospective analysis of case notes of all adults with learning disabilities
      treated with either fluoxetine or paroxetine for depression. During 31% of
      treatment episodes, patients suffered treatment emergent symptoms during
      treatment with either selective serotonin re-uptake inhibitor (SSRI). These
      symptoms subsided on discontinuation of the SSRI. The common emergent symptoms in
      this group were elevated mood (39%), decreased sleep (35%), hyperactivity (30%),
      overtalkativeness (26%), agitation (24%) and aggression (37%). In 20% symptoms
      developed within 1 month and in 67% within 7 months of starting treatment with a
      SSRI. There were no significant differences noted in the frequency and nature of
      treatment emergent symptoms between fluoxetine and paroxetine. Few guidelines, if
      any, exist for initiating and continuing antidepressant treatment for therapeutic
      or prophylactic use in this patient population. Close monitoring of efficacy and
      tolerability, including treatment emergent psychiatric symptoms is warranted.
      Copyright 2001 John Wiley & Sons, Ltd.

PMID- 12404584
TI  - Glutamate and its role in psychiatric illness.
AB  - Glutamate, a dicarboxylic amino acid, is the most abundantly active
      neurotransmitter in the mammalian brain; it is also the principal excitatory
      neurotransmitter in the cerebral cortex. As our knowledge of this
      neurotransmitter deepens, it is increasingly being implicated in the
      pathophysiology of mental illness. This review begins by examining the physiology
      of glutamate and its receptors. Its role in memory, movement, perception and
      neuronal development is discussed. The development of the glutamate hypothesis of
      schizophrenia is traced, and the emerging lines of evidence for attenuated
      function of the N-methyl-D-aspartate receptor in schizophrenia are examined. For
      ease of discussion, these are divided into pharmacological, post-mortem, imaging,
      platelet and genetic studies. Interactions between glutamate and other
      neurotransmitters are discussed, as are possible mechanisms by which such altered
      receptor activity might result in the clinical expression of schizophrenia. The
      possible role of glutamate in major depression and bipolar disorder is explored.
      The review concludes by highlighting the importance of avoiding a reductionist
      approach to the pathophysiology of any mental illness. Copyright 2001 John Wiley
      & Sons, Ltd.

PMID- 12404585
TI  - Zolpidem and triazolam interact differentially with a delay interval on a digit
      enter-and-recall task.
AB  - Zolpidem (AMBIEN((R))), an imidazopyridine, is now the most commonly prescribed
      hypnotic in the United States. Zolpidem is neuropharmacologically distinct from
      benzodiazepine hypnotics in that it binds with low affinity to alpha(5)
      containing GABA(A)-receptor subtypes. Despite its unique benzodiazepine-receptor
      binding profile, the results of most of the published studies conducted with
      humans suggest that the absolute magnitude of impairment produced by zolpidem is
      comparable to that observed with benzodiazepine hypnotics like triazolam. The
      present study compared the acute effects of zolpidem (0, 7.5, 15 and 22.5 mg) and
      triazolam (0, 0.1875, 0.375 and 0.5625 mg) in 10 non-drug-abusing humans using a
      Digit-Enter-and-Recall task with varying delay intervals (0, 10 and 20 s). To
      more fully characterize the behavioral effects of zolpidem and triazolam, several
      other performance tasks and subject-rated drug-effect questionnaires were
      included. Zolpidem and triazolam impaired performance on the Digit-Enter-and
      Recall task as a function of dose under all delay intervals. However, the dose
      related effects of the drugs interacted differentially with the delay interval
      such that zolpidem produced significantly less impairment than triazolam
      following the longest delay (i.e., 20 s). Zolpidem and triazolam produced
      comparable dose-related impairment on the digit symbol substitution test (DSST),
      circular lights task, and picture recall/recognition task. Zolpidem and triazolam
      generally produced qualitatively and quantitatively similar subject-rated drug
      effects, although some between-drug differences were observed. Consistent with
      the pharmacokinetics of these drugs, the effects of zolpidem peaked sooner and
      were shorter in duration than those observed with triazolam. The results of this
      experiment suggest that zolpidem may have less potential than triazolam to impair
      recall, which may be due to differences between these compounds in terms of their
      benzodiazepine-receptor binding profile. The results of the present study are
      also concordant with previous studies that found that drugs that act at the
      GABA(A)-receptor complex can be differentiated based on their interaction with
      the delay interval on a Digit-Enter-and-Recall task. Copyright 2001 John Wiley &
      Sons, Ltd.

PMID- 12404586
TI  - Residual effects of zaleplon and zolpidem following middle of the night
      administration five hours to one hour before awakening.
AB  - The objective was to assess residual effects of zaleplon and zolpidem after a
      middle of the night administration. This was a randomized, double-blind, placebo
      controlled, crossover study, conducted in 40 healthy young male and female
      subjects. Subjects were awakened in the middle of the night and administered
      either placebo or zaleplon 10 or 20 mg or zolpidem 10 mg. A battery of objective
      tests exploring psychomotor and cognitive functions such as critical flicker
      fusion (CFF), choice reaction time (CRT), digit symbol substitution test (DSST),
      and memory tests (Sternberg memory scanning and a word list) were administered
      immediately after morning waking. Zaleplon 10 mg was devoid of residual effects
      whatever - the time of dosing - except a minimal but significant decrease in DSST
      scores when administered 1 h before awakening. Zaleplon 20 mg produced
      significant residual effects on performance (increase in CRT, and decrease in CFF
      threshold and in DSST scores) and memory (decrease in immediate and delayed free
      recall of words) only when administered 1 h before awakening. In contrast,
      zolpidem 10 mg produced significant detrimental residual effects on CRT and
      delayed free recall of words, when administered up to 5 h before waking, on DSST
      and Sternberg when administered up to 3 h before awakening and on CFF when
      administered 1 h before awakening. The residual effects of zolpidem 10 mg were
      more marked than those observed after zaleplon 20 mg. The present results
      demonstrate that zaleplon 10 mg has no or minimal residual effects when
      administered in the middle of the night as little as 1 h before waking. The lack
      of clinically significant residual effects with zaleplon may be explained by its
      unique pharmacokinetic (rapid elimination half-life) and pharmacodynamic
      (selective binding for GABA(A) receptors with the alpha(1) subunit, dissociation
      between sleep inducing properties and impairment of cognitive functions)
      profiles. Copyright 2001 John Wiley & Sons, Ltd.

PMID- 12404587
TI  - Comparative efficacy of zolpidem and temazepam in transient insomnia.
AB  - This study compared hypnotic effects of zolpidem 10 mg, temazepam 15 mg and
      placebo in healthy adults. Two factors expected to promote insomnia, the 'first
      night effect' and a 2-hour phase advance, were combined in a single night
      laboratory-based double-blinded protocol. This was a multi-center study, with
      data collected in 13 sleep laboratories. Subjects with normal sleep histories and
      without prior sleep laboratory experience were randomly assigned to treatment
      groups. Medications were administered 15 min before lights out, with
      polysomnographic monitoring for 7.5 h. Subjective questionnaires and performance
      tests, digit symbol substitution test (DSST) and symbol copying test (SCT), were
      administered at study entry and after arising. 630 subjects completed the study
      and provided data analyzed using repeated measures ANOVAs. Neither agent
      significantly reduced objective sleep latency relative to placebo. Zolpidem
      reduced awakenings and wake after sleep onset (WASO); temazepam did not. Both
      agents improved sleep efficiency and most subjective sleep measures relative to
      placebo, with zolpidem superior for five of six subjective outcome measures
      compared to temazepam. SCT, morning sleepiness and morning concentration were not
      altered by any treatment. Zolpidem significantly reduced morning DSST
      performance; temazepam did not. Zolpidem 10 mg provided greater subjective
      hypnotic efficacy than temazepam 15 mg in this model of transient insomnia, with
      reduced polysomnographic awakenings and WASO. Impairment of DSST was seen with
      zolpidem but not temazepam. Copyright 2001 John Wiley & Sons, Ltd.

PMID- 12404588
TI  - Sleep laboratory studies in periodic limb movement disorder (PLMD) patients as
      compared with normals and acute effects of ropinirole.
AB  - Periodic limb movement disorder (PLMD) occurs in a variety of sleep disorders and
      can cause insomnia as well as hypersomnia with daytime somnolence. The aim of
      this study was to investigate 12 untreated PLMD patients as compared with 12
      normal controls and to measure the acute effects of 0.5 mg ropinirole
      (Requip((R))) - a non-ergoline dopamine agonist - as compared with placebo. In
      three nights (adaptation, placebo, ropinirole night) objective and subjective
      sleep and awakening quality were evaluated. In the target variable 'periodic leg
      movements per hour of sleep' (PLM/(hTST)) PLMD patients showed an increased value
      of 42/h (normal 0-5/h) with a greater number of arousals due to periodic leg
      movements (PLM) in sleep. They further demonstrated an increased number of
      awakenings, sleep stage S1, S4, stage shifts and decreased S2, but there were no
      significant differences concerning total sleep time, sleep efficiency (SE),
      subjective sleep quality and morning measures of mood, drive and drowsiness.
      However, measures of attention variability, numerical memory, fine motor activity
      and reaction time performance were impaired. Ropinirole 0.5 mg was shown to
      significantly improve the index PLM/(hTST) by 64% and arousals due to PLM,
      increase spontaneous arousals, REM-latency, stage 2 and stage shifts and decrease
      SREM. In the morning attention variability was attenuated and numerical memory
      augmented. Thus, ropinirole improved some sleep architecture and early morning
      measures of performance but specifically all PLM variables, which suggests a
      dopaminergic pathogenesis in PLMD. Copyright 2001 John Wiley & Sons, Ltd.

PMID- 12404589
TI  - Lack of association between joint hyperlaxity and, I: panic disorder, and II:
      reactivity to carbon dioxide in healthy volunteers.
AB  - This study attempted to replicate previous reports of associations between panic
      disorder and joint hyperlaxity. The authors also examined possible associations
      between reacitivity to carbon dioxide (CO(2)), a model for panic vulnerability,
      and hyperlaxity in healthy volunteers. One hundred and one patients with DSM-IV
      panic disorder and 39 healthy volunteers were assessed for hyperlaxity by
      Beighton's criteria. Healthy volunteers also received two vital capacity
      inhalations of CO(2). Thirteen (13%) patients had five or more hyperlax joints.
      This rate did not differ from that in the healthy volunteers. Anxiety in healthy
      volunteers, as measured by the NIMH self-rating scale, DSM-IV panic symptom
      scores, and 100 mm visual analog scales of anxiety, increased after CO(2) from a
      mean of 1.8 to 2.8 (not significant); from 0.5 to 4 ( p < 0.001) and from 8.7 to
      11.6 mm ( p < 0.1), respectively. There were no associations between responses to
      CO(2) and hyperlaxity. Copyright 2001 John Wiley & Sons, Ltd.

PMID- 12404590
TI  - Neuroprotective effects of low-doses of aspirin.
AB  - Aspirin appears to have a neuroprotective role against glutamate excitotoxicity.
      In fact, recent animal studies have demonstrated the neuroprotective role of
      acetylsalicylic acid (ASA) against glutamatergic excitants. It has been pointed
      out that ASA is neuroprotective against hypoxic hypoxia, chemical hypoxia and
      also delays the decline of intracellular ATP. Prostaglandins may cause
      convulsions and high-doses of aspirin appear to protect neurons from
      excitotoxicity. A case is reported of a woman whose electroencephalogram (EEG)
      abnormalities reversed and whose psychological symptomatology regressed after
      treatment with low-doses of aspirin. This appears to be the first description of
      a disappearance of EEG abnormalities with low-doses of aspirin. The
      neuroprotective effect of ASA could be of extreme importance in metabolic
      neuronal disfunction, reversing both clinical symptoms and EEG genetic anomalies:
      it is probably due to transient neurotransmitter concentration disequilibrium
      caused by subclinical hypoxic cortical suffering. Copyright 2001 John Wiley &
      Sons, Ltd.

PMID- 12404591
TI  - Editorial.
AB  - No Abstract

PMID- 12404592
TI  - Past expectations, present disappointments, future hopes or psychopathology as
      the rate-limiting step of progress in psychopharmacology.
AB  - In 1974 I published a paper in which we predicted that biological depression
      research would lead to new, innovative antidepressants, to more sophisticated
      prescription of antidepressants and ultimately to 'functional
      psychopharmacology'. These expectations have not materialized. The reasons why
      are discussed and the conclusion is reached that there are reasons to believe
      that, belated, they will come true. I consider it no bold venture to uphold them.
      Copyright 2001 John Wiley & sons, Ltd.

PMID- 12404593
TI  - How valuable are animal models in defining antidepressant activity?
AB  - Animal models of depression have been utilised to screen novel compounds with
      antidepressant potential although uncertainty lingers concerning their clinical
      relevance. In order for a model to be considered of any value, it must possess
      predictive validity (does drug action in the model correspond to that in the
      clinic?), face validity (are there phenomenological similarities between the
      model and the clinic?) and construct validity (does the model possess a strong
      theoretical rationale?). On the one hand, there are models based on stress such
      as the learned helplessness model, the forced swimming test and the chronic mild
      stress model and, on the other hand, models based on neuronal deficits such as
      the olfactory bulbectomy model. To date, among models more frequently used in
      depression, none of them meet all these criteria. Moreover, improvements to tests
      are often poorly validated and estimating time of onset of action of
      antidepressants remains a major challenge in animal model research. Finally,
      reproducing the tests outside the laboratory of origin continues to be
      problematic and leads to variability in results. Although animal models of
      depression fail to be unequivocally valid, they represent the best tool to define
      potential antidepressant activity of drugs, to investigate their mechanism of
      action and, to a greater extent, explore this complex heterogeneous illness.
      Copyright 2001 John Wiley & Sons, Ltd.

PMID- 12404594
TI  - Enhancement of serotoninergic function - a sometimes insufficient cause of
      antidepressant action.
AB  - No Abstract

PMID- 12404595
TI  - Limitations to enhancing the speed of onset of antidepressants - are rapid action
      antidepressants possible?
AB  - Existing antidepressant treatments suffer from a limited efficacy and a slow
      onset of action. Some first-generation antidepressant drugs are still among the
      most effective treatments. Several neurobiological adaptive mechanisms are
      involved in the delayed action of antidepressants. Among these, a negative feed
      back involving somatodendritic autoreceptors plays an important role in such
      delay. In the case of the SSRIs, the prevention of this effect with 5-HT(1A)
      autoreceptor antagonists enhances their effects at experimental level. Open-label
      and placebo-controlled trials with the mixed beta-adrenoceptor/5-HT(1A)
      antagonist pindolol support that this agent reduces the latency to achieve a
      clinical improvement when used in combination with SSRIs. Displacement studies
      support that this action is mediated by its interaction with 5-HT(1A) receptors.
      The design of clinical trials for the evaluation of fast-acting antidepressants
      is critical. The use of loose criteria of response may result in a poor
      discriminating power. Conversely, stringent clinical criteria may be more helpful
      in revealing the differences between treatments. The data of a double-blind,
      placebo-controlled trial comparing fluoxetine plus placebo and fluoxetine plus
      pindolol suggests that the use of sustained response (i.e., one maintained until
      the end of the trial) is critical for the establishment of differences between
      treatments. Other factors, such as a placebo lead-in phase or the frequency of
      visits, appear to play a minor role. Overall, these data indicate that faster
      antidepressant drugs can be obtained through a better knowledge of their actions
      in CNS. Copyright 2001 John Wiley & Sons, Ltd.

PMID- 12404596
TI  - Combination of antidepressant drugs: the case of inositol.
AB  - Inositol is a second messenger precursor that is effective in depression and
      obsessive-compulsive disorder via a mechanism different from serotonin reuptake
      inhibitors. However, controlled trials of inositol combined with serotonin
      reuptake inhibitors in depression or in reuptake inhibitor resistant depressed
      patients, or in partially responsive obsessive-compulsive patients, did not
      reveal added benefit. This is comparable to results with combinations of other
      antidepressant treatments, such as tricyclics plus monoamine oxidase inhibitors.
      Copyright 2001 John Wiley & Sons, Ltd.

PMID- 12404597
TI  - Phospholipid metabolism and depression: the possible roles of phospholipase A2
      and coenzyme A-independent transacylase.
AB  - Phospholipids make up 60 per cent of the dry weight of the brain. They are
      essential for neuronal and especially for synaptic structure and play key roles
      in the signal transduction responses to dopamine, serotonin, glutamate and acetyl
      choline. The unsaturated fatty acid components of phospholipids are abnormal in
      depression, with deficits of eicosapentaenoic acid and other omega-3 fatty acids
      and excesses of the omega-6 fatty acid arachidonic acid. Correction of this
      abnormality by treatment with eicosapentaenoic acid improves depression. The
      fatty acid abnormalities provide a rational explanation for the associations of
      depression with cardiovascular disease, immunological activation, cancer,
      diabetic complications and osteoporosis. The abnormalities cannot be explained by
      diet, although diet may attenuate or exacerbate their consequences. A number of
      enzyme abnormalities could explain the phenomena: phospholipase A(2), and
      coenzyme A-independent transacylase are strong candidates. Copyright 2001 John
      Wiley & Sons, Ltd.

PMID- 12404598
TI  - On the feasibility of designing new antidepressants.
AB  - Modern antidepressants lack many of the side-effects and much of the toxicity of
      the first generation tricyclics and monoamine oxidase inhibitors. Knowledge of
      the receptor interactions that are responsible for poor tolerability and
      potential lethality in overdosage has enabled the design of agents that have low
      or no affinity for such receptors. Nevertheless, even the second generation
      selective serotonin reuptake inhibitors (SSRIs), the serotonin noradrenaline
      reuptake inhibitors (SNRIs) and the noradrenaline and serotonin specific
      antidepressants (NaSSAs) have not substantially improved upon the efficacy of the
      older agents. They still take some time to be effective, although venlafaxine and
      mirtazapine may be faster in onset than SSRIs, and they leave a substantial
      minority of patients unaffected.Innovative new antidepressants may be based upon
      a variety of mechanisms, including receptors, G-proteins, second messengers, gene
      transcription factors and the hypothalamic - pituitary - adrenal axis, but their
      availability may be hindered by recent advances in pharmaceutical research
      technology. Thus, the creation of large chemical libraries containing millions of
      new entities has increased structural diversity, but pharmacological evaluation
      has narrowed down to simple assays in high-throughput screening systems. Such
      assays depend to a major extent on how well they reflect the biological aetiology
      of the disease under study. While new antidepressant moieties will undoubtedly
      emerge, optimal use of the new research tools will necessitate a more
      sophisticated level of knowledge about the true causes of depression. Copyright
      2001 John Wiley & Sons, Ltd.

PMID- 12404599
TI  - Neurotrophins: possible role in affective disorders.
AB  - Various monoamine hypotheses of affective disorders have been unable to provide a
      complete explanation for the observed clinical findings. Recently Duman et al.
      (1997) have produced a molecular and cellular theory of depression which seems to
      be a worthy successor to these hypotheses. Whereas the earlier theories were
      unable to explain the time lag between antidepressant drug administration and
      lightening of affect, Duman's group pinpoints intracellular mechanisms, in the
      right time frame, which decrease or increase the generation of neurotrophic
      factors necessary for the survival of certain neurons, particularly in the
      hippocampus. This new concept may lead to novel therapeutic approaches. Copyright
      2001 John Wiley & Sons, Ltd.

PMID- 12404600
TI  - Imidazoline receptors: possible involvement in the pathophysiology and treatment
      of depression.
AB  - Imidazoline receptors (IR), a novel family of non-adrenergic receptors, are
      present in brain, especially the limbic system, and platelets among other organs.
      Their functions include central mediation of blood pressure control and possibly
      modulation of affective symptomatology. Studies of unipolar depressed patients
      have revealed consistent up-regulation of the I(1) subtype on the platelet.
      Treatment with cyclic antidepressants is accompanied by down-regulation in
      responders. Treatment with the non-cyclic bupropion produced similar findings.
      Studies of human post-mortem brain show changes in depressed subjects but the
      protein fragments assessed are of different molecular weights than in the
      platelet. Plasma agmatine is believed to be a putative endogenous ligand for I
      receptors. Thus, IR may be useful state markers of affective disorders. Copyright
      2001 John Wiley & Sons, Ltd.

PMID- 12404601
TI  - Antidepressant activity and calcium signaling cascades.
AB  - Although antidepressant treatments produce clear effects on monoaminergic
      neuronal function, the link between these effects and therapeutic response to
      treatment is controversial. Previous studies have demonstrated that antagonists
      of the NMDA receptor-gated calcium ionophore result in antidepressant-like
      responses in rodents and humans. Likewise, antidepressant treatments produce
      regionally selective adaptation of the NMDA receptor suggestive of diminished
      capacity to gate calcium into receptive neurons. Similarly, voltage-dependent
      calcium channel antagonists have been reported to produce antidepressant-like
      effects in rodents. A major target of increases in subcellular calcium
      concentration is nitric oxide synthase (NOS) which liberates NO in response to
      stimulation. Recently, we have demonstrated that nitric oxide synthase
      antagonists produced antidepressant-like response in both in vivo preclinical
      screening procedures and in post-mortem in vitro studies of beta-adrenoceptor
      density. We propose: 1) that interruption of the Ca(2+)-calmodulin-NOS-guanylyl
      cyclase subcellular signaling pathway at any point will produce antidepressant
      like effects; 2) that the acute actions of antidepressants in preclinical
      screening procedures are a consequence of their ability to disrupt Ca(2+)
      calmodulin-NOS-guanylyl cyclase signaling; 3) that chronic but, not acute
      treatment with antidepressants results in adaptation of the Ca(2+)-calmodulin-NOS
      guanylyl cyclase signaling pathway; 4) that this adaptation is necessary for the
      achievement of the therapeutic actions of antidepressants and; 5) that major
      depression is accompanied by an alteration (hyperactivity?) of subcellular Ca(2+)
      signaling. Copyright 2001 John Wiley & Sons, Ltd.

PMID- 12404602
TI  - Are CRF receptor antagonists potential antidepressants?
AB  - Corticotropin-releasing factor (CRF) is the major regulator of the hypothalamic
      pituitary-adrenal (HPA) axis, and plays a key role in coordinating the endocrine,
      as well as autonomic and behavioral responses of an organism to stress. Direct
      CNS administration of CRF to laboratory animals produces an aggregate of effects
      that mimic the mammalian stress response. Impeding CRF function with CNS
      administration of a peptidergic CRF antagonist can block these manifestations of
      the stress response whether produced by exogenous CRF or occurring naturally in
      response to a stressor. A role for hypersecretion of CRF in the pathophysiology
      of depression is suggested by the finding that CNS administration of CRF mirrors
      many of the signs and symptoms utilized as diagnostic criteria for major
      depression. In addition, a large body of clinical evidence points to excess
      hypothalamic secretion of CRF and an accompanying HPA axis hyperactivity in
      patients with major depression. The recent development of selective, small
      molecule CRF(1) receptor antagonists, which block the effects of CRF both in
      vitro and in vivo, suggest that these compounds may be effective in the treatment
      of affective and anxiety disorders. Early evidence indicates that these agents
      possess anxiolytic and antidepressant activity in animal behavioral models.
      Copyright 2001 John Wiley & Sons, Ltd.

PMID- 12404603
TI  - Novel approaches to the treatment of depression by modulating the hypothalamic -
      pituitary - adrenal axis.
AB  - Many patients with major depression show evidence of over-activation of the
      hypothalamic - pituitary - adrenal axis (HPA), as evidenced by hypercortisolism
      and adrenal hyperplasia. Such over-activity is associated with increased
      corticotropin releasing factor (CRF) reactivity in the CSF and blunted release of
      ACTH in response to CRF infusion. Recent evidence suggests a switch from CRF to
      AVP regulation of the axis during depression, with depressed patients showing
      enhanced response to ddAVP infusion. The HPA provides multiple potential sites
      for antidepressant development. The use of glucocorticoid antagonists, cortisol
      synthesis inhibitors, CRF and AVP antagonists have been suggested. Copyright 2001
      John Wiley & Sons, Ltd.

PMID- 12404604
TI  - The immunoregulatory effects of antidepressants.
AB  - There is some evidence that major depression is accompanied by activation of the
      inflammatory-response system (IRS). It has been hypothesized that increased
      production of proinflammatory cytokines may play a role in the etiology of major
      depression. If increased production of proinflammatory cytokines is at all
      involved in the etiology of depression, one would expect antidepressive
      treatments to have negative immunoregulatory effects. This paper reviews the
      effects of antidepressants, such as tricyclic antidepressants (TCAs), selective
      serotonin reuptake inhibitors (SSRIs), heterocyclic antidepressants (HCAs),
      serotonin-noradrenaline reuptake inhibitors (SNRIs), lithium, l-5
      hydroxytroptophan (L-5-HTP), reversible inhibitors of MAO-A (RIMA) on the
      production of proinflammatory cytokines, e.g. interferon-gamma (IFNgamma), and
      negative immunoregulatory cytokines and agents, e.g. interleukin-10 (IL-10). In
      depressed patients, prolonged treatment with antidepressants and mood stabilizers
      normalizes signs of activation of the IRS, such as increased serum IL-6 and acute
      phase protein concentrations. In vitro, it has been shown that various types of
      antidepressive drugs, including TCAs (imipramine; clomipramine); SSRIs
      (citalopram, fluoxetine, sertraline); lithium; SNRIs (venlafaxine); HCAs
      (trazodone); RIMAs (moclobemide) and L-5-HTP significantly suppress the ratio of
      IFNgamma/IL-10 production by peripheral blood immunocytes. These antidepressant
      drugs appear to have a common effect on the IRS, i.e. in vitro they increase the
      production of IL-10 by peripheral blood leukocytes. Thus, the results suggest
      that antidepressants have negative immunoregulatory effects. It may be speculated
      that antidepressants exert some of their antidepressant effects through their
      negative immunoregulatory capacities. Copyright 2001 John Wiley & Sons, Ltd.

PMID- 12404605
TI  - Antidepressants in clinical practice: limitations of assessment methods and drug
      response.
AB  - There is a recognized gap between knowledge derived from 'efficacy' data - based
      on usually brief randomized controlled trials and findings in natural practice
      'effectiveness' studies. In considering the limitations of current
      antidepressants in clinical practice, we have selected three clinically important
      issues to examine in a natural practice data base that has been in existence for
      several years. These relate to: (1) Diagnostic heterogeneity and potential
      advances using functional brain imaging; (2) Variability of outcome measures
      during treatment and (3) Time to response and prediction of outcome. Copyright
      2001 John Wiley & Sons, Ltd.

PMID- 12404606
TI  - Depression and practice guidelines.
AB  - Over the past two decades there have been great advances in the understanding of
      depression and in the development of pharmacological agents and psychosocial
      treatments that have demonstrated efficacy in the treatment of this common and
      disabling illness. Unfortunately, this knowledge and evidence is not consistently
      translated into actual treatment, and depression remains undiagnosed in a large
      percentage of patients, and when it is accurately diagnosed, it often is
      suboptimally treated.The frequent failure to properly diagnose depression may be
      due to the continuing stigma of mental illness, the persistence of the
      biomedical, rather than the biopsychosocial, paradigm of illness and treatment,
      educational issues and the time constraints in the typical medical practice. The
      suboptimal treatment may be due to all of these issues plus the difficulty in
      changing physician behaviours even when there exists much evidence that would
      seem to dictate such a change. The development of a criteria-based nomenclature
      and the subsequent development and dissemination of evidence-based practice
      guidelines addresses some of these issues. Copyright 2001 John Wiley & Sons, Ltd.

PMID- 12404607
TI  - Preface.
AB  - No Abstract

PMID- 12404608
TI  - Sedation and antihistamines: a review of inter-drug differences using
      proportional impairment ratios.
AB  - The use of antihistamines (AHs) has until recently been associated with a number
      of undesirable side effects, the most troublesome of which is sedation. There are
      two aspects to sedation. The first, an objectively determined measure based on
      the results of psychometric tests from controlled trials, and the second, the
      subject's response to the administration of a drug. Since AHs are largely used in
      ambulant patients, a complete evaluation of sedation should be performed through
      standardised objective and subjective tests, shown to be sensitive to the central
      effects of AHs.An extensive review of the literature identified 76 studies of
      H(1) receptor antagonists in healthy volunteers, in which assessment of sedation
      was the primary objective. Results from studies published in peer-reviewed
      journals which employed a placebo condition as well as a positive internal
      control using a crossover design were analysed to determine the extent to which a
      particular antihistamine produced impairments on a battery of psychometric tests.
      The impairment index for each antihistamine was calculated and subsequently
      compared with the impairment index obtained for all other AHs.The calculation of
      this proportional impairment ratio enabled the sedative potential of an
      individual antihistamine to be identified relative to all other AHs and thus
      allowed the ranking of AHs with respect to their ability to cause impairments of
      cognitive and psychomotor function.Findings from this review clearly demonstrate
      that there are distinct classes of AHs with respect to their ability to impair
      cognitive function and psychomotor performance. Copyright 2000 John Wiley & Sons,
      Ltd.

PMID- 12404609
TI  - Habitual caffeine consumption and its relation to memory, attention, planning
      capacity and psychomotor performance across multiple age groups.
AB  - The present study evaluated the association between habitual caffeine intake via
      coffee and tea and cognitive performance. This was done as part of a larger
      research programme into the determinants of cognitive ageing (the Maastricht
      Aging Study: MAAS). Possible withdrawal effects that may have explained in part
      the positive association between performance and intake in an earlier study were
      controlled for. In addition, all cognitive tests in this study were administered
      under strict laboratory conditions. A group of 1875 healthy adults, stratified
      for age (range 24 - 81 years), sex, and general ability, were screened for
      habitual intake of coffee and tea and took part in extensive cognitive testing.
      Multiple regression analysis with control for age, sex, socio-demographic
      variables, and substance use showed that habitual caffeine consumption was
      significantly related to better long-term memory performance and faster locomotor
      speed. No relationships were found between habitual caffeine consumption and
      short-term memory, information processing, planning, and attention as measured
      with the Stroop Test. Moreover, no difference in sensitivity to caffeine intake
      between different age groups was found, suggesting that caffeine intake did not
      counteract age-related cognitive decline. Several recommendations are made to
      improve the design of future studies in this field. Copyright 2000 John Wiley &
      Sons, Ltd.

PMID- 12404610
TI  - Self-report of memory and affective dysfunction in association with medication
      use in a sample of individuals with chronic sleep disturbance.
AB  - Benzodiazepines produce memory disturbance after acute administration. It is not
      clear whether chronic use of benzodiazepines is hazardous to memory processes.
      Epidemiological data indicate that a large proportion (10-30 per cent) of
      individuals with sleep dysfunction take hypnotic aids for a year or longer. The
      purpose of the present study was to evaluate self-reported memory dysfunction in
      a sample of individuals who considered their sleep disturbance sufficiently
      severe to seek investigation in sleep clinics. It was hypothesized that
      individuals taking benzodiazepines for sleep would report greater perceived
      everyday memory failures than individuals taking other sleep aids or no
      medication. Questionnaires were given to 368 individuals referred into the study
      by investigators in six sleep disorders clinics. All respondents completed a
      lengthy (700-item) questionnaire, which included scales assessing memory
      difficulties, affective status and sleep disturbance. Respondents also reported
      any medication use for sleep problems and duration of use of the current drug.
      Information on medication use was reported by 289 participants. Fifty-six per
      cent of respondents reported using some form of psychoactive medication
      (antidepressants, benzodiazepines, Zopiclone). Twenty-two per cent reported using
      no medication. Analysis of covariance showed that these medications had no
      detectable effect on subjective memory difficulties during chronic use,
      F(4,226)=1.34, p=0.25. Copyright 2000 John Wiley & Sons, Ltd.

PMID- 12404611
TI  - Ontogenetic effects of MAO-A inhibition on rat pineal n-acetylserotonin and
      melatonin during the first month of neonatal life.
AB  - Inhibitors of monoamine oxidase A (MAO-A) but not MAO-B stimulate the activity of
      pineal serotonin N-acetyltransferase (AANAT) in the adult rat pineal leading to
      increased formation of N-acetyl serotonin (NAS) and melatonin (MEL). The pineal
      gland of the neonatal rat has AANAT activity, but the second enzyme in melatonin
      biosynthesis, HIOMT (hydroxyindole-O-methyltransferase) converting NAS to MEL, is
      absent during the first week of neonatal life. In this study we examined the
      effects of acute clorgyline treatment in vitro and in vivo, on pineal indoles
      over the first month of neonatal life. The results show that clorgyline
      stimulates NAS production by pineal both in vitro and in vivo from day five on
      with a marked increase between day 14 and day 21. In contrast, MEL is not
      increased until day 21, with a sharp rise thereafter. Copyright 2000 John Wiley &
      Sons, Ltd.

PMID- 12404612
TI  - Dose-response effects of zaleplon as compared with triazolam (0.25 mg) and
      placebo in chronic primary insomnia.
AB  - The effects of two nights of treatment with the short-acting benzodiazepine
      receptor agonist zaleplon, triazolam, or placebo was assessed in chronic primary
      insomniacs using two concurrent, multi-center, randomized, double-blind, Latin
      Square crossover studies. Study 1 (n = 47) compared zaleplon (10 and 40 mg) to
      triazolam (0.25 mg) and placebo. Study 2 (n = 36) compared zaleplon (20 and 60
      mg) to triazolam (0.25 mg) and placebo. For each study, polysomnographically
      recorded sleep parameters and patient reports of sleep quality were collected
      during baseline and two consecutive nights during the four treatment phases in
      each study. All doses of zaleplon produced significant decreases in latency to
      persistent sleep. Although no minimally effective dose could be determined, dose
      response effects were apparent. Triazolam 0.25 mg produced a decrease in latency
      to persistent sleep that was comparable to that of zaleplon 10 mg. Only the
      triazolam dose and the 60 mg dose of zaleplon produced significant increases in
      total sleep time over placebo. Zaleplon 40 and 60 mg and triazolam produced
      decreases in the percentage of REM sleep compared to placebo. Patient reports of
      efficacy were consistent with objective findings. In addition, all doses of
      zaleplon tended to increase while triazolam decreased the percentage of stage 3/4
      sleep. There was no evidence of residual daytime impairment for any of the
      zaleplon doses, however, triazolam administration produced significant impairment
      in performance on a digit copying test. A higher number of adverse events were
      seen with the 40 and 60 mg doses of zaleplon compared to triazolam (0.25) and
      placebo. At higher doses, zaleplon is more effective than triazolam at reducing
      latency to persistent sleep in chronic insomnia and is not associated with the
      decrease in slow-wave sleep or residual impairment observed with triazolam.
      However, increases in total sleep time were apparent only at doses which produced
      concomitant increases in the number of adverse events. In contrast, triazolam
      (0.25 mg) produced increases in total sleep time (;25 min) and decreases in
      latency to persistent sleep at a dose of 0.25 mg. Copyright 2000 John Wiley &
      Sons, Ltd.

PMID- 12404613
TI  - Moxonidine versus placebo as an aid in smoking cessation.
AB  - This study assessed the effects of moxonidine as an aid in smoking cessation in
      166 heavily addicted smokers who were motivated to quit smoking completely.
      Recruitment was via advertisement. Patients were randomly allocated to receive
      double-blind placebo or moxonidine (0.1 mg once or twice daily) for 6 weeks.
      Brief counseling was provided. An encouragement letter was sent prior to the quit
      date. Success was defined as not smoking any cigarettes during weeks 3 - 6, an
      expired carbon monoxide level of < 10 ppm, and a plasma cotinine level of < 25
      ng/ml. The study failed to demonstrate a statistically significant effect for
      moxonidine on either nicotine withdrawal symptoms or smoking cessation. Reported
      side effects were not different with moxonidine than with placebo, however.
      Copyright 2000 John Wiley & Sons, Ltd.

PMID- 12404614
TI  - Functional magnetic resonance imaging reflects changes in brain functioning with
      sedation.
AB  - Functional magnetic resonance imaging (fMRI) studies have demonstrated localized
      brain activation during cognitive tasks. Brain activation increases with task
      complexity and decreases with familiarity. This study investigates how sleepiness
      alters the relationship between brain activation and task familiarity. We
      hypothesize that sleepiness prevents the reduction in activation associated with
      practice. Twenty-nine individuals rated their sleepiness using the Stanford
      Sleepiness Scale before fMRI. During imaging, subjects performed the Paced
      Auditory Serial Addition Test, a continuous mental arithmetic task. A positive
      correlation was observed between self-rated sleepiness and frontal brain
      activation. Fourteen subjects participated in phase 2. Sleepiness was induced by
      evening dosing with chlorpheniramine (CP) (8 mg or 12 mg) and terfenadine (60 mg)
      in the morning for 3 days before the second fMRI scan. The Multiple Sleep Latency
      Test (MSLT) was also performed. Results revealed a significant increase in fMRI
      activation in proportion to the dose of CP. In contrast, for all subjects
      receiving placebo there was a reduction in brain activation. MSLT revealed
      significant daytime sleepiness for subjects receiving CP. These findings suggest
      that sleepiness interferes with efficiency of brain functioning. The sleepy or
      sedated brain shows increased oxygen utilization during performance of a familiar
      cognitive task. Thus, the beneficial effect of prior task exposure is lost under
      conditions of sedation. Copyright 2000 John Wiley & Sons, Ltd.

PMID- 12404615
TI  - Fenfluramine challenge in anxious children.
AB  - The study objective was to determine if serotonergic challenge with oral racemic
      fenfluramine would differentiate between childhood anxiety disorders in
      comparison to normal controls. Subjects were 24 children with anxiety diagnoses
      (DSM-IIIR) by structured interview, and 14 normal controls (ages 7 - 14 years)
      matched for age and sex. All subjects were given a standard challenge dose of d,1
      fenfluramine (1 mg/kg) followed by serial assessments of cardiovascular,
      neurohormonal, and mood parameters over a five hour period. In response to
      fenfluramine, controls demonstrated increases in subjective anxiety and systolic
      blood pressure relative to anxious subjects. Fenfluramine was safely tolerated
      and did not induce panic symptoms in any subject. Exaggerated prolactin response
      to fenfluramine differentiated an obsessive - compulsive disorder (OCD) subset
      from both controls and other anxiety disorders. Fenfluramine challenge
      differentiates anxious children from healthy controls by elevated anxiety ratings
      and systolic blood pressure in controls. Increased prolactin response to
      fenfluramine discriminates children with obsessive - compulsive disorder from
      both healthy children and children with other anxiety diagnoses. As adults with
      OCD appear to demonstrate a blunted prolactin response to fenfluramine challenge,
      the serotonin pathways involved may differ between 'early' and 'late' onset
      disorder, or the serotonin substrates tapped by this challenge may change over
      time. Copyright 2000 John Wiley & Sons, Ltd.

PMID- 12404616
TI  - Serum trace elements in animal models and human depression: Part III. Magnesium.
      Relationship with copper.
AB  - In the present study we report the results of investigations into the serum
      magnesium levels in a clinical study of 19 patients with unipolar depression; 16
      normal controls and in three animal models of depression: chronic severe stress
      (CSS), chronic mild stress (CMS) and olfactory bulbectomy (OB) in rats. There was
      no alteration in the values found in the rat models of depression. Unipolar
      depressed patients exhibit significantly lower serum magnesium levels than the
      appropriate controls (depression 19.1+/-2.2 mg/l; control 21.0 mg/l). There is no
      correlation between serum magnesium levels and the severity of depression. A
      significant positive correlation between serum magnesium/copper ratio and the
      severity of depression indicates a clear relationship between alterations of the
      homeostasis of these two ions in human depression. Copyright 2000 John Wiley &
      Sons, Ltd.

PMID- 12404617
TI  - Erratum: sedation and antihistamines.
AB  - No Abstract

PMID- 12404618
TI  - Quantitative EEG methods and measures in human psychopharmacological research.
AB  - The quantitative analysis of electroencephalographic (EEG) signals is an
      established methodology for objectively describing the central impact of drugs
      administered to human subjects. This paper outlays the essential objectives and
      findings of this electrophysiologic measurement model of drug action and
      addresses the subject, recording, analytical and statistical standards which are
      required to ensure valid pharmaco-EEG profiling. Copyright 2000 John Wiley &
      Sons, Ltd.

PMID- 12404619
TI  - Efficacy and safety of novel antipsychotics: a critical review.
AB  - Efficacy and safety of novel antipsychotic (AP) drugs (amisulpride, olanzapine,
      quetiapine, ziprasidone and zotepine) have been reviewed. Data on their
      antipsychotic efficacy and side effects profile have been evaluated only on the
      basis of controlled trials so far published. Overall, all these drugs have shown
      an antipsychotic efficacy on positive symptoms of schizophrenia similar to that
      of the conventional AP drugs. On negative symptoms, all novel AP drugs, except
      quetiapine and ziprasidone, demonstrated a better efficacy than haloperidol. Long
      term efficacy of these AP drugs in the maintenance treatment of schizophrenia
      needs to be explored by further, better-designed, epidemiological studies. The
      safety profile shows that the novel AP drugs are generally well-tolerated and
      induce significantly less acute extrapyramidal side effects in comparison with
      haloperidol. Some methodological flaws in the experimental design of the clinical
      trials analysed are discussed. Although these novel AP drugs have potential
      clinical advantages, a number of relevant questions still remain to be addressed,
      in order to establish the impact of these drugs in the overall treatment of
      schizophrenia. Copyright 2000 John Wiley & Sons, Ltd.

PMID- 12404620
TI  - A preliminary study of the comparative effects of olanzapine and fluphenazine on
      cognition in schizophrenic patients.
AB  - The aim of the study was to compare the effect of olanzapine versus fluphenazine
      treatment on cognitive functioning. Eighteen schizophrenic outpatients, aged 25 -
      61 (average 37 years), all meeting DSM-IV diagnostic criteria for schizophrenia,
      were included in the study. They were randomly assigned to 22 weeks of either
      olanzapine or fluphenazine treatment. Certain subscales of the Wechsler Adult
      Intelligence Scale, the Stroop Neuropsychological Screening Test and the
      Wisconsin Card Sorting Test were performed. Olanzapine treatment proved to have a
      beneficial effect on digit-symbol performance and some aspects of executive
      function. In comparison to the fluphenazine treatment, the olanzapine treatment
      only showed a beneficial effect in increased percentage of conceptual level
      responses. Although the results are preliminary, they could implicate that the
      benefit of olanzapine treatment is primarily related to certain aspects of
      executive function, i.e. frontal lobe functioning. Copyright 2000 John Wiley &
      Sons, Ltd.

PMID- 12404621
TI  - A pilot study of intramuscular ziprasidone in the short-term treatment of
      patients with acute exacerbation of schizophrenia.
AB  - Ziprasidone is a novel antipsychotic which, in oral formulation, has been shown
      to be effective and well tolerated in the treatment of acute psychosis. This
      pilot study examined the efficacy and tolerability of the intramuscular (IM)
      formulation and the transition from IM to oral ziprasidone in patients with acute
      schizophrenia. The study design was an open, prospective, 5-day treatment trial
      of IM ziprasidone followed by oral dosing in 12 patients with acute exacerbation
      of schizophrenia. Various doses (2.5, 5, 10, or 20 mg) up to 60 mg/day total were
      administered over 3 days, followed by transition to oral ziprasidone on Days 4-5.
      All patients completed the study. Mean improvements between baseline and Day 3
      were observed in Brief Psychiatric Rating Scale (47.8 to 28.9) and Clinical
      Global Impression of Severity (6.1 to 5.3), and improvements were maintained on
      Days 4 and 5. No extrapyramidal syndrome, acute dystonia, or serious adverse
      events were reported. In these patients, IM ziprasidone 20-60 mg/day reduced
      psychomotor agitation and other symptoms of psychosis. The transition from IM to
      oral ziprasidone was well tolerated. Copyright 2000 John Wiley & Sons, Ltd.

PMID- 12404622
TI  - Dream features in psychiatric patients on multiple psychoactive drugs.
AB  - An investigation into dreams was conducted in 100 subjects involving 50
      psychiatric in-patients and fifty normal volunteers with the help of a
      questionnaire. The dream patterns of the two groups were compared. Results
      revealed that dreams of the patients were different from normal individuals even
      before the onset of psychiatric illness. The dreams in normal subjects were
      mostly related to present life situations whereas, the dreams of the patients
      were less frequent in this respect. On the other hand, frightening dreams,
      repetitive dreams and vision of snakes in the dreams were more frequent in
      patients. These differences became more conspicuous with the onset of illness.
      The dreams were suppressed in 78% patients after the institution of drug therapy.
      Most of the patients were getting three to four psychoactive drugs which alter
      the sleep pattern and may therefore affect the dreaming process. Thus, the
      qualitative changes in dreams of a person may serve as an early warning for an
      impending future illness. The suppressant effect of psychoactive drugs on dreams
      demands further investigations.

PMID- 12404623
TI  - The impact of antidepressants on sleep and anxiety: a comparative study of
      fluoxetine and dothiepin using the Leeds Sleep Evaluation Questionnaire.
AB  - Fluoxetine (20 mg) was compared to dothiepin (150 mg) in a multicentre,
      prospective, double blind, randomised clinical trial involving 125 patients with
      major depression treated for an initial phase of 6 weeks and then followed up for
      a further 6 months. There was no difference in the efficacy of the two drugs
      based on the results of established rating scales (MADRS, HAM-D, BPRS). The
      impact of both drugs on sleep measured using the Leeds Sleep Evaluation
      Questionnaire showed no significant differences between treatments, however
      drowsiness and disturbed sleep were reported more frequently as side effects with
      dothiepin. Symptoms of anxiety responded equally well to both treatments. The
      short term and long term tolerability of dothiepin was inferior to that of
      fluoxetine. The place of dothiepin in treatment should be reassessed in the light
      of its anticholinergic adverse event profile, particularly in the elderly.
      Copyright 2000 John Wiley & Sons, Ltd.

PMID- 12404624
TI  - Psychoactive cannabinoids and membrane signaling.
AB  - THC-like psychoactive cannabinoids permeate the lipid bilayer of the membrane,
      altering its physicochemical properties and activating phospholipases. As a
      result, an increased production of arachidonic acid occurs with its cascade of
      eicosanoids, including prostaglandins. In addition, THC and its psychoactive
      derivatives bind within the membrane in a stereospecific fashion, to a
      transmembrane G protein coupled receptor (GPCR) for which THC has a much higher
      affinity than the natural ligands, arachidonylethanolamide (AEA) and 2
      arachidonyglycerol (2-AG). These natural lipid ligands may be considered
      signaling molecules which are generated in the membrane lipid bilayer. THC alters
      the physicochemical disposition of the lipid bilayer and interacts with the
      integral membrane protein receptors through alteration of the boundary lipid.
      This effect is distinct from the mechanism resulting from its persistent binding
      to a G protein coupled transmembrane receptor. THC does not interact directly
      with neurotransmitter receptors but alters their pharmacological response in an
      allosteric fashion. It is proposed that the binding of AEA and 2-AG to the G
      protein coupled transmembrane receptor possesses a physiological function which
      is to regulate the signaling between boundary lipids and membrane receptors in
      response to extracellular signals. AEA and 2-AG are eicosanoid signaling
      molecules which modulate the activity of G protein coupled transmembrane
      receptors. AEA and 2-AG should not be identified with synthetic ligand molecules
      dubbed 'endogenous cannabinoids' which are 'xenobiotics' with no physiological
      regulating function. THC deregulates persistently a basic signaling mechanism of
      the membrane lipid bilayer and of its integrated receptors with resulting
      impairment of cellular function of brain, heart and male gonads. Copyright 2000
      John Wiley & Sons, Ltd.

PMID- 12404625
TI  - Marijuana, alcohol and actual driving performance.
AB  - The objective of the current study was to assess the separate and combined
      effects of marijuana and alcohol on actual driving performance. Eighteen subjects
      were treated with drugs and placebo according to a balanced, 6-way, crossover
      design. On separate evenings they were given weight calibrated Delta(9)
      tetrahydrocannabinol (THC) doses of 0, 100 and 200 &mgr;g/kg with and without an
      alcohol dose sufficient for achieving blood alcohol concentrations (BAC) of 0.04
      g/dl while performing a Road Tracking and Car Following Test in normal traffic.
      Main outcome measures were standard deviation of lateral position (SDLP), time
      driven out of lane (TOL), reaction time (RT) and standard deviation of headway
      (SDH). Both THC doses alone, and alcohol alone, significantly impaired the
      subjects performances in both driving tests. Performance deficits were minor
      after alcohol and moderate after both THC doses. Combining THC with alcohol
      dramatically impaired driving performance. Alcohol combined with THC 100 and 200
      &mgr;g/kg produced a rise in SDLP the equivalent of that associated with BAC=0.09
      and 0.14 g/dl, respectively. Mean TOL rose exponentially with SDLP. Relative to
      placebo mean RT lengthened by 1.6 s under the combined influence of alcohol and
      THC 200 &mgr;g/kg. Changes in SDH ranged between 0.9 and 3.8 m. Low doses of THC
      moderately impair driving performance when given alone but severely impair
      driving performance in combination with a low dose of alcohol. Copyright 2000
      John Wiley & Sons, Ltd.

PMID- 12404626
TI  - Hallucinogenic drugs attenuate the subjective response to alcohol in humans.
AB  - This study investigated possible interactions between alcohol and hallucinogens
      in 22 lysergic acid diethylamide (LSD) and/or psilocybin users through
      retrospective structured interviews. Of those who had used LSD with alcohol, 86;7
      per cent reported a complete blockade of subjective alcohol effects, while the
      remaining cases reported a diminished response. In addition, 60 per cent of
      respondents who had used alcohol and psilocybin together reported a partial
      antagonism of subjective alcohol effects.T-test analyses revealed that LSD's
      antagonism of alcohol effects were significantly greater than those associated
      with psilocybin. It is proposed that LSD's effect on alcohol intoxication may
      involve interactions with various serotonergic and/or dopaminergic receptor
      systems. Copyright 2000 John Wiley & Sons, Ltd.

PMID- 12404628
TI  - The inhibitory glycine receptor-simple views of a complicated channel.
AB  - The strychnine-sensitive glycine receptor is the principal mediator of fast
      inhibitory synaptic transmission in the mammalian spinal cord and brain stem. As
      a member of the ligand-gated ion-channel family, it shares structural homology
      with the nicotinic acetylcholine, GABA(A/C) and serotonin 5-HT(3) receptors. Ion
      channel activation and desensitisation are controlled by a variety of factors
      such as subunit composition, posttranslational modification, absence or presence
      of modulatory ions or other agents and possibly protein-protein interactions.
      Glycine-receptor mutations, either associated with the human motor disorder
      hyperekplexia or artificially introduced, have helped to define the regulatory
      domains of the receptor protein. In addition to their effects on glycine-receptor
      function, allelic variants of glycine-receptor genes may also affect biogenesis,
      assembly and degradation of the receptor.

PMID- 12404629
TI  - Cleavable substrate containing molecular beacons for the quantification of DNA
      photolyase activity.
AB  - In order to gain deeper insight into the function and interplay of proteins in
      cells it is essential to develop methods that allow the profiling of protein
      function in real time, in solution, in cells, and in cell organelles. Here we
      report the development of a U-type oligonucleotide (molecular beacon) that
      contains a fluorophore and a quencher at the tips, and in addition a substrate
      analogue in the loop structure. This substrate analogue induces a hairpin
      cleavage in response to enzyme action, which is translated into a fluorescence
      signal. The molecular beacon developed here was used to characterize DNA
      photolyase activity. These enzymes represent a challenge for analytical methods
      because of their low abundance in cells. The molecular beacon made it possible to
      measure the activity of purified class I and class II photolyases. Photolyase
      activity was even detectable in crude cell extracts.

PMID- 12404630
TI  - An organometallic route to oligonucleotides containing phosphoroselenoate.
AB  - Unlike the widespread use of phosphorothioates in nucleic acid chemistry,
      complementary research on phosphoroselenoates has been severely limited. Previous
      routes to DNA and RNA that contain phosphoroselenoates employ elemental Se and
      KSeCN as Se transfer agents, although these reagents suffer from low or
      unselective reactivity. The metastability of the Pbond;Se bond demands soluble,
      selective Se transfer reagents. The organometallic reagent
      (iPrC(5)H(4))(2)TiSe(5) satisfies these criteria, as we demonstrate by the
      synthesis of phosphoroselenoate derivatives of mono- and oligonucleotides of DNA
      and a dinucleotide of RNA. The new general method is compatible with high
      throughput phosphoramidate oligonucleotide synthesis, which allows for the
      preparation of site-specifically labeled oligonucleotides. A (31)P NMR
      spectroscopy study shows that the phosphoroselenoate of (5')-d(GGAATGTC(Se)TGTCG)
      (3') selectively binds to soft Cd(2+) ions but not Mg(2+) ions.

PMID- 12404631
TI  - Selection of hammerhead ribozyme variants with low Mg2+ requirement: importance
      of stem-loop II.
AB  - Variants of the hammerhead ribozyme with high in trans (intermolecular) cleavage
      activity at low Mg(2+) concentrations were in vitro selected from a library with
      18 nucleotides randomised in the core and in helix II. The most active hammerhead
      ribozyme selected had the same sequence as the consensus ribozyme in the core but
      only two base pairs in stem II, G(10.1)-C(11.1) and U(10.2)-A(11.2), and a
      tetrauridine loop II. This ribozyme (clone 34) was found to be very active in
      single-turnover reactions at 1 mM Mg(2+) concentration in the context of several
      substrates with differences in the lengths of stem I and III, including the well
      characterised HH16 substrate and a derivative thereof with a GUA triplet at the
      cleavage site, as well as a substrate used previously in a related study. For the
      HH16 substrate, a change of base pair 10.2-11.2 to C-G in stem II further
      improved activity by about 2.5-fold to 0.8 min(-1) (at 1 mM Mg(2+) concentration,
      25 degrees C, pH 7.5). Interestingly, this very active variant was not identified
      by the selection procedure. Changing loop II from UUUU to GCAA or extension of
      stem II to three or four base pairs reduced the cleavage rate by 2.0-2.5-fold.
      Thus, small hammerhead ribozymes carrying a tetrauridine loop with two base pairs
      in stem II represent the most active versions known so far at low Mg(2+)
      concentrations; single-turnover rates of approximately 1 min(-1) are reached at
      25 degrees C and pH 7.5 in monophasic reactions, with endpoints between 75 and 90
      %. Such constructs promise to be advantageous for the inhibition of gene
      expression in vivo.

PMID- 12404632
TI  - Binding of sucrose octasulphate to the C-type lectin-like domain of the
      recombinant natural killer cell receptor NKR-P1A observed by NMR spectroscopy.
AB  - NKR-P1A is a C-type lectin-like receptor on natural killer cells believed to be
      involved in the cytotoxicity of these cells. Ligands for this protein are not
      known. Here, we describe the binding of a fully sulphated disaccharide, sucrose
      octasulphate, by the recombinant C-type lectin-like domain of NKR-P1A. The
      binding was observed by NMR spectroscopy methods that have recently been
      described for the screening of compound libraries for bioaffinities, namely the
      2D NOESY and saturation transfer difference NMR experiments. (1)H titration
      studies indicate that the binding is specific. These findings raise the
      possibility that NKR-P1A recognises sulphated natural ligands in common with
      certain other members of the C-type lectin family.

PMID- 12404633
TI  - Synthesis and biological investigation of novel tricyclic benzodiazepinedione
      based RGD analogues.
AB  - Integrins, a widely expressed family of heterodimeric cell surface adhesion
      proteins, are expressed in a variety of cell types. They play a decisive role in
      cell-cell adhesion or cell to extracellular matrix adhesion events. Antagonists
      of alpha(v)beta(3) or alpha(IIb)beta(3) integrin may have a potential use in
      suppression of pathological processes. We present the synthesis of novel
      tricyclic benzodiazepinedione-based RGD analogues, which were subsequently tested
      in a solid-phase receptor assay in order to investigate their binding affinities
      towards alpha(v)beta(3) and alpha(IIb)beta(3) integrin.

PMID- 12404634
TI  - Binding of organic anions by synthetic supramolecular metallopores with internal
      Mg2+-aspartate complexes.
AB  - We report that cation-selective transmembrane pores formed by synthetic p
      octiphenyl beta barrels with internal aspartate residues can be transformed into
      anion-permeable metallopores with internal Mg(2+)-aspartate complexes. These
      metallopores are shown to be useful for fluorimetric sensing of a broad variety
      of organic anions of biological relevance such as phytate, heparin, thiamine
      phosphates, and adenosine triphosphate. The negligible flippase activity
      measurable for Mg(2+)-free pores indicates that transmembrane p-octiphenyl beta
      barrels do not disturb the lipid bilayer suprastructure, in other words, they
      form barrel-stave rather than toroidal pores.

PMID- 12404635
TI  - Examining reactivity and specificity of cytochrome c peroxidase by using
      combinatorial mutagenesis.
AB  - Combinatorial mutagenesis was used to investigate the role of three key residues
      in cytochrome c peroxidase (CCP) from Saccharomyces cerevisiae, Arg48, Trp51, and
      Trp191, in control of the reactivity and selectivity of the heme-containing
      enzyme. Libraries were prepared by randomization of these residues and were
      subsequently screened for activity against the phenolic substrate guaiacol.
      Screening conditions were employed that favor either mutants with high activity
      or those with both high activity and stability of the reactive enzyme
      intermediates. The results obtained suggest a dual role for Arg48 of CCP: in
      addition to stabilizing reactive enzyme intermediates, the distal arginine
      residue plays a major role in restriction of access to the ferryl oxygen atom by
      small molecules and thereby controls reactivity and substrate specificity of the
      peroxidase. At position 51 of CCP, either a phenylalanine or a tryptophan residue
      is required both for catalytic and structural reasons. In contrast, either polar
      or positively charged residues are accepted at the position of Trp191, which is
      located inside the core of the protein. The variability at position 191 can be
      interpreted as a reflection of the mechanism of cytochrome c peroxidase, which
      transforms the nonpolar Trp191 into a transient cation radical.

PMID- 12404636
TI  - A non-antibacterial oxazolidinone derivative that inhibits epithelial cell sheet
      migration.
AB  - We have developed a high-throughput assay for screening chemical libraries for
      compounds that affect cell sheet migration during wound closure in epithelial
      cell monolayers. By using this assay, we have discovered a new inhibitor of cell
      sheet migration. This compound (UIC-1005) is a 3,4-disubstituted oxazolidinone
      that bears an electrophilic alpha,beta-unsaturated N-acyl group required for
      activity. UIC-1005 also inhibits growth in an epithelial cell proliferation
      assay. The molecule does not display general toxicity at concentrations at which
      it potently inhibits cell sheet migration and growth. Unlike certain 3,5
      disubstituted oxazolidinones, it exhibits no antibacterial activity. UIC-1005
      therefore represents a new class of bioactive oxazolidinone derivative that may
      prove useful as a probe for signaling pathways leading to cell motility.

PMID- 12404637
TI  - Reversible acetonitrile-induced inactivation/activation of thermolysin.
AB  - Thermolysin is catalytically inactive in mixtures of 10-15 % acetonitrile in
      aqueous buffer. Unexpectedly, dilution of the inactive enzyme with acetonitrile
      leads to complete recovery of the catalytic activity in a similar way to dilution
      with aqueous buffer. Circular dichroism and fluorescence studies of thermolysin
      in the same solvent mixtures reveal discontinuous changes in the overall
      secondary and tertiary protein structure that correlate well with the reversible
      differences in catalytic activity. The spectra on either side of the minimum
      activity point are different from each other, a fact indicating that the enzyme
      may be able to access two active conformations which are thermodynamically stable
      in different solvent environments.

PMID- 12404638
TI  - High-resolution capillary zone and gel electrophoresis of structurally similar
      amphipathic glutathione conjugates based on interaction with beta-cyclodextrins.
AB  - The tripeptide glutathione is a prominent intracellular constituent that provides
      protection against genotoxic and carcinogenic electrophiles and is also a
      component of several biological signal substances. Glutathione conjugates, free
      glutathione, and glutathione disulfide contain charged amino acid residues, which
      contribute to solubility in aqueous media. However, the amphipathic nature of
      glutathione conjugates and the small differences that may distinguish the S
      substituents, pose analytical problems in their resolution. The present study
      demonstrates how homologous S-alkyl and S-benzyl conjugates of high structural
      similarity can be efficiently resolved by capillary electrophoresis. Inclusion of
      beta-cyclodextrins in the buffer or in a polyacrylamide gel affords baseline
      separation of the analytes. The separation methods described are applicable to
      enzyme assays in vitro and to the identification and quantification of
      glutathione conjugates of importance in toxicology and physiology. The
      contribution of beta-cyclodextrin to the separation is primarily based on
      interactions between its hydrophobic cavity and the S-alkyl and S-benzyl groups
      of the analytes.

PMID- 12404639
TI  - Macrocyclic hairpin mimetics of the cationic antimicrobial peptide protegrin I: a
      new family of broad-spectrum antibiotics.
AB  - The problems associated with increasing antibiotic resistance have stimulated
      great interest in newly discovered families of naturally occurring cationic
      antimicrobial peptides. These include protegrin, tachyplesin, and RTD-1, which
      adopt beta-hairpin-like structures. We report here an approach to novel
      peptidomimetics based on these natural products. The mimetics were designed by
      transplanting the cationic and hydrophobic residues onto a beta-hairpin-inducing
      template, either a D-Pro-L-Pro dipeptide or a xanthene derivative. The mimetics
      have good antimicrobial activity against Gram-positive and Gram-negative bacteria
      (minimal inhibitory concentration approximately 6-25 microgram mL(-1)). Analogues
      with improved selectivity for microbial rather than red blood cells (1 %
      hemolysis at 100 microgram mL(-1)) were identified from a small library prepared
      by parallel synthesis. Thus, it is possible to separate the antimicrobial and
      hemolytic activities in this class of mimetics. NMR studies on one mimetic
      revealed a largely unordered structure in water, but a transition to a regular
      beta-hairpin backbone conformation in the presence of dodecylphosphocholine
      micelles. This family of mimetics may provide a starting point for the
      optimization of antimicrobial agents of potential clinical value in the fight
      against multiple-drug-resistant microorganisms.

PMID- 12404640
TI  - In vivo photocrosslinking with unnatural amino Acid mutagenesis.

PMID- 12404641
TI  - De Novo design, synthesis, and in vitro evaluation of a new class of nonpeptidic
      inhibitors of the malarial enzyme plasmepsin II.

PMID- 12404642
TI  - Protease inhibitors formed in situ from copper and tridentate chelates: a
      generalized approach towards metal-based pharmaceuticals.

PMID- 12404643
TI  - On the origin of deoxypentoses: evidence to support a glucose progenitor in the
      biosynthesis of calicheamicin.

PMID- 12404644
TI  - Alkylation of microperoxidase-11 by the antimalarial drug artemisinin.

PMID- 12404645
TI  - Natural products from Marine microorganisms.

PMID- 12404647
TI  - Process consultancy can help to improve the quality of mental health services for
      older people.

PMID- 12404648
TI  - Is late onset depression a prodrome to dementia?
AB  - BACKGROUND: Recent research suggests there are clinical and biological
      differences between late onset depression (LOD) and early-onset depression (EOD).
      OBJECTIVES: In this paper we review clinical, epidemiological, structural
      neuroimaging and genetic investigations of late life depression that have been
      performed over the past two decades and offer evidence that LOD is often a
      prodromal disorder for dementia. RESULTS: LOD patients are more likely to have
      cognitive impairment and to have more deep white matter lesions (DWMLs). Evidence
      concerning cortical and temporal lobe atrophy is conflicting, while the ApoE 4
      allele is not associated with LOD. CONCLUSIONS: It is likely that LOD is not a
      prodrome for a particular type of dementia, but the majority of patients who do
      develop dementia will acquire Alzheimer's disease (AD) or a vascular dementia, as
      these are by far the most common causes of dementia. This issue requires further
      clarification with follow-up of patients over the long term.

PMID- 12404649
TI  - Improving clinical descriptions to understand the effects of dementia treatment:
      consensus recommendations.
AB  - OBJECTIVES: To recommend how the description of clinically detectable treatment
      effects might be improved for antidementia drug trials. METHOD: Consensus
      conference, with review of available evidence. RESULTS: We suggest widespread,
      systematic, qualitative studies, based on prospective observations such as the
      clinicians' narrative descriptions of patient's changes used in the Clinician's
      Interview-Based Impressions of Change (CIBIC-Plus), plus caregiver input. The
      identification of patient and caregiver expectations, and an understanding of how
      these expectations are met, are proposed as priorities for future study.
      CONCLUSION: Better descriptions of treatment effects can enhance our
      understanding of both clinical meaningfulness and cholinergic function in the
      brain.

PMID- 12404650
TI  - The effect of age on the pharmacological management of ambulatory patients
      treated with depot neuroleptic medications for schizophrenia and related
      psychotic disorders.
AB  - BACKGROUND: Cross-sectional studies indicate that, in comparison to younger
      patients, older schizophrenic patients have a higher risk for neuroleptic-induced
      Parkinsonism and tardive dyskinesia (TD). It has been suggested, therefore, that
      older patients with schizophrenia could be maintained on reduced doses of
      conventional neuroleptics. METHOD: We examined the effect of age on
      psychopharmacological management in a naturalistic study of a group of 165
      patients with a clinical diagnosis of schizophrenia or a related psychotic
      disorder (age range = 21-84 years; subjects > or = 1;45 years n = 86) treated
      with either haloperidol decanoate or fluphenazine decanoate. RESULTS: Increasing
      age was not correlated with total daily dose of neuroleptics or anticholinergic
      medication. However, a modest negative correlation of age with daily neuroleptic
      dose was found in patients aged 45 years and older. CONCLUSION: The results of
      this study highlight the need for prospective assessments of depot neuroleptic
      dose requirements in older patients suffering from primary psychotic disorders.

PMID- 12404651
TI  - Policy, organisation and practice of specialist old age psychiatry in England.
AB  - OBJECTIVE: To describe and compare service arrangements in old age psychiatry
      across England according to three broad domains: (i) levels of professional
      autonomy; (ii) degree of community orientation (delivery of and links with
      community services) and (iii) degree of integration between health and social
      care provision. DESIGN: Cross sectional survey of consultants in old age
      psychiatry in England. Potential respondents were sourced from the Royal College
      of Psychiatrists and Regional Advisers in Old Age Psychiatry. MEASURES: A self
      administered postal questionnaire was piloted and refined. The questionnaire
      domains listed above reflect core policy issues for older people's services,
      covering the domains above. RESULTS: There is marked variation in the deployment
      and use of professional staff in old age psychiatry, ranging from open access to
      multidisciplinary assessment to services only accessible by clinician referral.
      Patterns of linkage with primary care are likewise variable with only half of
      services providing the types of support recommended by the Audit Commission
      (2000). Community orientation was evident to a considerable extent in support to
      care homes and assessment practices. Links between health and social care
      appeared strongest in terms of liaison and training. There was less evidence of
      more formal integration through shared management of staff or for links with
      intensive home support for those with dementia. CONCLUSIONS: The data provide a
      unique picture and benchmark of the configuration of old age psychiatry, a core
      element of mental health care in old age, after some 25 years of development in
      the UK. There appears to be substantial variation on all three domains of
      comparison.

PMID- 12404652
TI  - Screening for mild cognitive impairment (MCI) utilizing combined mini-mental
      cognitive capacity examinations for identifying dementia prodromes.
AB  - OBJECTIVE: To test correctness of results when combining Mini-Mental State
      Examination (MMSE) and Cognitive Capacity Screening Examination (CCSE) for
      identifying mild cognitive impairment (MCI) among non-demented elderly subjects
      at risk for developing dementia. METHODS: A retrospective study was conducted
      among consecutively referred volunteers with memory complaints to a research out
      patient clinic. Two cognitive screening tests (MMSE and CCSE) were performed
      according to established protocol. Resulting combined screening test (termed by
      acronym as CMC) combined the non-overlapping test items derived from both MMSE
      and CCSE. Conversion to dementia at follow-up served as the 'gold-standard' for
      evaluating correctness of CMC for identifying MCI. RESULTS: Of 351 subjects
      completing cognitive assessments and meeting requirements for study protocol, 84
      (23.9%) developed dementia of different types within 3-6 years (3.89 +/- 2.17) of
      follow-up. Among these, 47 met criteria for probable Alzheimer disease (AD), 22
      for probable vascular dementia (VaD), 12 for mixed AD/VaD and three for probable
      frontotemporal dementia. When final diagnosis of AD was used as the 'gold
      standard' for testing correctness of MCI identified by cognitive screening tests,
      sensitivities of MMSE, CCSE and CMC for identifying MCI were relatively 61.0%,
      74.3% and 83.1% with minimum specificity set at 80%. When diagnosis of all types
      of dementia was used as the standard for testing predictive correctness of MCI,
      CCSE emerged as an optimal MCI screening test. CONCLUSION: Combining the CCSE and
      MMSE screening tests resulted in higher sensitivity than was achieved by MMSE
      alone and maintained specificity at comparable levels for identifying MCI. The
      results confirmed that CMC has optimal correctness and utility as a brief
      cognitive test for screening MCI as a prodrome for dementia among non-demented
      elderly populations.

PMID- 12404653
TI  - Complaints of informal caregivers providing home care for dementia patients: the
      Pixel study.
AB  - CONTEXT: Prospective study of the complaints, problems and requirements of the
      main caregiver providing home care for dementia patients. OBJECTIVES: To
      determine the complaints of home caregivers, how they are interrelated and what
      causes them. RESOURCES: Self-administered questionnaire of 42 questions on the
      patient and caregiver, including a list of complaints, given to the main
      caregiver. Medical questionnaire on the patient filled in by the attending
      physician, usually a specialist, freelance or salaried doctor. RESULTS: 408 sets
      of records were compiled, concerning 236 demented women (77.1 +/- 0.47 years) and
      172 demented men (75.7 +/- 0.57 years). In two-thirds of cases, the main
      caregiver was a woman aged 60.6 +/- 0.79 years. Female caregivers were more
      vulnerable than male caregivers. The most frequent caregiver complaint,
      regardless of the stage of the disease, concerned loss of motivation and
      withdrawal. The patient's awareness of the disorder was accompanied by a
      reduction in motor dysfunction and aggressiveness, but associated with a higher
      frequency of the complaint regarding loss of motivation reported by the
      caregiver. The caregivers' problems concerned mainly the absence of relief and
      the impossibility of having any time to themselves. Caregivers' requests for
      information concerned medical information, care structures and day care
      facilities. DISCUSSION: The attending physician comes into close contact with the
      patient, but must take into account the patient's environment. The physician can
      provides a separate analysis to the caregiver and does not completely answer to
      certain family questions or needs. He or she is not the family's prime source of
      information. The caregivers' requirements relate to the areas that are the
      attending physician's responsibility: the development and characteristics of the
      disease. The caregiver is anxious about the patient's future and is trapped by
      his or her involvement in the care, suffering greatly from the lack of relief.
      CONCLUSIONS: It is necessary to change the focus of home care for dementia
      patients to fit the context in which they live and to allow for periods of relief
      for home caregivers.

PMID- 12404654
TI  - The clock drawing test and questionable dementia: reliability and validity.
AB  - OBJECTIVES: In order to evaluate the suitability of the clock drawing test (CDT)
      for the detection of questionable dementia (QD), we assessed the inter-rater
      reliabilities and intercorrelations of four common scoring methods of the CDT in
      a sample of non-demented subjects and determined the concurrent validity.
      METHODS: The study sample consisted of 253 discharged general hospital patients,
      aged between 65 and 85 years. Subjects were screened for cognitive impairment
      during their hospital stay. Four to six weeks after discharge each non-demented
      patient was visited at home and interviewed by a trained psychologist. The
      interview procedure included a cognitive test battery incorporating the CDT, the
      Mini-Mental State Examination (MMSE), the Syndrome Short Test (SKT), and a verbal
      fluency test (VF). The criteria of the Clinical Dementia Rating (CDR) were used
      to differentiate between cognitively normal subjects and those with QD. Clock
      drawings were scored independently and blindly by two raters according to four
      different methods. The agreement between raters was assessed, as well as the
      agreement between the different scoring methods. The association of gender,
      education, age, test performance and CDR-rating with CDT scores was examined.
      Accuracy of the CDT for the detection of QD was calculated. RESULTS: Inter-rater
      reliabilities were high for all four scoring methods. However, substantial
      differences among the scoring methods were observed, the proportion of abnormal
      test results varying between 9% and 50%. The CDT correlated significantly with
      MMSE, SKT and VF, but correlation coefficients were low (r = 0.13 to r = 0.32).
      Furthermore, CDT scores were influenced by age, gender, and education.
      Sensitivity of the CDT for QD was 66%, specificity was 65%; the negative
      predictive value was 73%, the positive predictive value 58%. CONCLUSION: In a
      sample of non-demented elderly, the reliability of the CDT was sufficiently high,
      but the different scoring methods were not equivalent. When established cut-off
      scores were used, the proportion of abnormal CDTs were significantly different.
      Concurrent validity with other common cognitive tests was unsatisfactory. The CDT
      lacks sufficient sensitivity and specificity for the identification of QD and
      should not be used alone to screen for possible prodromal stages of dementing
      illnesses. The association of age, gender and level of education with CDT scores
      should be taken into account by clinicians using the CDT.

PMID- 12404655
TI  - Which factors influence cognitive decline in older adults suffering from
      dementing disorders?
AB  - BACKGROUND: Although extensive research has been done on dementing disorders in
      recent decades, their natural course and prognosis are not yet well understood.
      The aim of our study was to assess cognitive decline in a representative sample
      of demented elderly and to analyse the predictive value of a broad spectrum of
      sociodemographic, neurological and clinical variables. METHODS: A random sample
      of elderly patients in primary care (n = 407) was drawn from a total of 3721
      patients. The sample has been stratified according to the degree of cognitive
      impairment as assessed by their GPs. The patients were examined by means of a
      standardized research interview, including comprehensive cognitive testing
      (Hierarchic Dementia Scale) and the assessment of neurologic and physical
      impairments as well as of mental state (CAMDEX criteria). After a mean interval
      of 28 months, a follow-up study was conducted using essentially the same
      instruments. RESULTS: At baseline, 117 of the 407 patients were identified as
      suffering from mild, moderate, or severe dementia. The two-year follow-up of
      those patients revealed high mortality rates (53/117). The surviving patients
      showed significant cognitive decline, although the rate varied considerably
      between individuals. The rate of progression was strongly related to the initial
      degree of severity, but also to the use of psychotropic medication, which was
      associated with a more rapid deterioration. CONCLUSIONS: There are some
      prognostic indicators that can help to establish the prognosis for dementia
      patients. The best indicator for both--the rate of cognitive decline and the
      probability of survival--is the severity of dementia.

PMID- 12404656
TI  - Dementia Care Mapping as a research tool for measuring quality of life in care
      settings: psychometric properties.
AB  - BACKGROUND: There are a paucity of validated measures focusing on quality of life
      for people with dementia in care facilities. METHOD: The current study evaluated
      the internal consistency of Dementia Care Mapping (DCM) in a group of 123 people
      with dementia residing in care facilities and further evaluated the test retest
      reliability and concurrent validity of key DCM constructs in an additional group
      of 54 residents. RESULTS: The results show good internal consistency. Well-ill
      being score was significantly correlated with an informant rated quality of life
      measure (r = 0.73, p < 0.0001) and showed good test retest reliability (r = 0.55,
      p < 0.0001). An abbreviated assessment period focusing on the hour before lunch
      showed significant correlation with the total assessment period (well-ill being
      score r = 0.5, p = 0.02). CONCLUSION: The current study indicates that DCM is a
      valid tool for the longitudinal evaluation of quality of life in people with
      dementia in care settings and that some abbreviation of the method may facilitate
      its use more widely.

PMID- 12404657
TI  - Paranoid delusions and hallucinations and bright light therapy in Alzheimer's
      disease.
AB  - INTRODUCTION: Bright light therapy (BLT) is becoming increasingly popular as an
      adjunct in the treatment of non-SAD depression and circadian rhythm disturbances
      in demented patients. Although the rate of side-effects is low, special attention
      should be paid when treating new groups of patients. We present the case of an 80
      year-old woman suffering from dementia of Alzheimer's type (DAT). METHOD: Bright
      light (2.500 lux) was administered two hours daily between 10 and 12 a.m. for 14
      days. Changes in delusion or agitation were recorded using the confusion rating
      scale (CRS). RESULTS: Out of five patients, three already had delusional symptoms
      which slightly improved during the course of BLT, one patient never showed
      delusions before or during BLT, and one patient, which we present here, showed an
      increase in agitation and developed delusional symptoms. After eight days of
      treatment, the patient developed conjunctival irritation with marked red eyes and
      complained about blurred vision. After 12 days of treatment, the patient was
      disorientated in time and place and after 14 days the patient started to
      hallucinate and BLT had to be discontinued. The paranoid delusions and
      hallucinations stopped one day after treatment discontinuation. CONCLUSION:
      Looking at all the presented evidence, BLT seems to be a useful treatment
      supplement in DAT patients, when suffering from delusions or agitation. On the
      other hand, caution should be used when using BLT in demented patients if
      agitation develops or increases during BLT.

PMID- 12404658
TI  - Physical complaints do not decrease linearly with increasing cognitive
      impairment.

PMID- 12404659
TI  - Re: Chan et al. A double-blind randomised comparison of risperidone and
      haloperidol in the treatment of behavioural and psychological symptoms in Chinese
      dementia patients. Int J Geriatr Psychiatry 16: 1156 - 1162.

PMID- 12404661
TI  - Re: Keene et al. Death and dementia. Int J Geriatr Psychiatry 16: 969-974.

PMID- 12404662
TI  - Evaluating a hearing voices group for older people: preliminary findings.

PMID- 12404663
TI  - Prevalence, recognition and management of depression in primary care in Germany:
      the Depression 2000 study.
AB  - 'Depression 2000' is a major epidemiological study conducted in a representative
      sample of 412 primary care settings (which examined a total of 15,081 unselected
      patients) in Germany in order to address the current lack of information on the
      prevalence, recognition and treatment of depression in primary care. The study
      revealed that depression is a key challenge in primary care because of its
      prevalence (point prevalence according to ICD-10: 10.9%), type of presenting
      complaints and the time constraints of the doctors. Participating doctors had a
      very high workload (average of 62 patients per day) and perceived the management
      of depressed patients as a major burden. The majority of cases of depression
      identified met criteria for moderate or severe depression, and 51% had a chronic
      and/or recurrent course. A total of 55% of patients were correctly diagnosed as
      having a clinically significant depressive disorder, although only 21% received a
      diagnosis of 'definite' depression. In conclusion, these findings confirm the
      high prevalence of depressive disorders in primary care settings and underline
      the particular challenges posed by these patients. Although recognition rates
      among more severe major depressive patients, as well as treatments prescribed,
      appear to be more favourable than in previous studies, the high proportion of
      unrecognised patients with definite depression still raises significant concerns.
      It remains of continued prime importance to educate primary care doctors to
      better recognise depression in order to increase the patients' chances of
      receiving appropriate treatment.

PMID- 12404664
TI  - New directions in the development of antidepressants: the interface of
      neurobiology and psychiatry.
AB  - There have been considerable advances in neurobiology in recent years that are
      providing new directions for the development of novel classes of antidepressants.
      For example, the finding that corticotropin-releasing factor (CRF) is
      hypersecreted in depressed patients and mediates certain symptoms of depression
      has led to the development of specific antagonists of the CRF(1) receptor. These
      are expected to prove highly effective for the treatment of mood and anxiety
      disorders. Another related avenue of research is based on evidence that cortisol
      is integral to the pathophysiology of major depression with psychotic features.
      One alternative for treating this subtype of affective disorder is, therefore, to
      block the action of glucocorticoids using a receptor antagonist such as
      mifepristone. These are just two of the many new directions that will likely lead
      to the development of antidepressants in the near future.

PMID- 12404665
TI  - Pharmacological principles of antidepressant efficacy.
AB  - Both noradrenaline (NA) and serotonin (5-HT) appear to be involved in depression.
      Evidence suggests that dual-acting antidepressants, i.e. those that affect both
      monoamine systems, such as tricyclic antidepressants and the noradrenergic and
      specific serotonergic antidepressant mirtazapine, may have greater efficacy and a
      faster onset of action than drugs that act on a single monoamine system only,
      such as the selective serotonin reuptake inhibitors (SSRIs). Cell firing is
      reduced by SSRIs in the short-term, but is increased by mirtazapine, probably due
      to its actions on both NA (via alpha(2) antagonism) and 5-HT (via alpha(1)
      stimulation by NA). This may help to explain clinical evidence suggesting that
      mirtazapine has a faster onset of action than the more selective antidepressants.

PMID- 12404666
TI  - An overview of the clinical efficacy of mirtazapine.
AB  - Mirtazapine is at least as effective as the tricyclic antidepressants and
      trazodone in a wide range of patient subgroups including in- and out-patients
      with moderate to severe depression. It also appears to be at least as effective
      as the serotonin and noradrenaline reuptake inhibitor venlafaxine in the
      treatment of severely depressed melancholic patients. When compared with the
      selective serotonin reuptake inhibitors (SSRIs), mirtazapine shows a
      significantly earlier onset of action. Further analysis of a study comparing
      mirtazapine with the SSRI paroxetine indicated that early improvement was a
      highly sensitive predictor of later stable response for both drugs. The positive
      predictive value of an early improvement was significantly higher during
      mirtazapine treatment compared with paroxetine. The negative predictive value
      approached maximum values as early as week 2 with mirtazapine and week 3 with
      paroxetine. This suggests that the predictability of the response to treatment is
      better with mirtazapine than with paroxetine.

PMID- 12404667
TI  - Onset of action of antidepressants: results of different analyses.
AB  - Because the value of antidepressants is hampered by their delay in onset of
      action, considerable attention has been focused on developing a drug that acts
      more rapidly. However, although specific studies are now ongoing, there have been
      no peer-reviewed prospective onset of action trials published in the literature
      to date. Some data are currently available from post-hoc pooled analyses and
      numerous methods have been developed for evaluating the onset of action; these
      include the time to response, the time to onset of therapeutic effect, pattern
      analysis and survival analyses. Such an analysis of four large-scale, double
      blind studies has provided evidence for an earlier onset of action with
      mirtazapine than with the SSRIs (fluoxetine, paroxetine and citalopram).
      Significant differences were seen between mirtazapine and the SSRIs after 1 week
      of treatment. This effect was consistent across the four different methodologies
      and appears to be due to a specific antidepressant effect rather than an early
      effect on, for example, sleep. These findings await confirmation from
      specifically designed prospective onset of action studies.

PMID- 12404668
TI  - The use of mirtazapine in difficult-to-treat patient populations.
AB  - Patients who have failed previous antidepressant treatment present substantial
      clinical management challenges. Similarly, elderly patients require special
      attention. Three recent studies have shown that mirtazapine has a role to play in
      the management of these patients. Mirtazapine has proved effective in the
      treatment of patients who were resistant or intolerant to selective serotonin
      reuptake inhibitors (SSRIs) and the switch to mirtazapine could be made
      immediately without the necessity for a taper period. In a double-blind study in
      patients who were resistant to SSRI treatment, mirtazapine had a more rapid onset
      of action than sertraline. Mirtazapine has also proved effective in elderly
      depressed patients and again showed a faster onset of action than another of the
      SSRIs, paroxetine.

PMID- 12404669
TI  - Tolerability and safety aspects of mirtazapine.
AB  - The tolerability and safety profile of the noradrenergic and specific
      serotonergic antidepressant (NaSSA) mirtazapine reflects its unique
      pharmacological profile. The 5-HT(2) blocking effect contributes towards its
      anxiolytic effects and benefits on sleep, as well as preventing the sexual
      dysfunction that may occur with non-specific stimulation of the serotonin system
      by drugs such as the selective serotonin reuptake inhibitors (SSRIs). In
      addition, 5-HT(3) blockade by mirtazapine helps to prevent nausea and vomiting.
      Weight gain is the most commonly reported side-effect of mirtazapine, although
      there is evidence to suggest that this is not a significant problem during long
      term treatment. In conclusion, mirtazapine has a good tolerability and safety
      profile that demonstrates several benefits over other antidepressants.

PMID- 12404670
TI  - Rationale and options for the long-term treatment of depression.
AB  - Depression is a chronic and disabling illness that frequently requires long-term
      maintenance treatment. The probability of recurrence after recovery is extremely
      high, especially amongst patients who have experienced previous episodes of
      depression. Indeed, once a patient has suffered from three episodes of
      depression, the likelihood that they will have another episode within the next 2
      years is more than 95%. Despite this, depression remains an under-recognized and
      under-treated disease. Mirtazapine has shown sustained efficacy in the long-term
      treatment of depression, being more effective than amitriptyline and at least as
      effective as the selective serotonin reuptake inhibitors paroxetine and
      citalopram. It is also well tolerated over prolonged periods. It should therefore
      prove suitable for use as maintenance treatment in depressed patients.

PMID- 12404671
TI  - A double-blind, placebo-controlled, randomized trial of Ginkgo biloba extract EGb
      761 in a sample of cognitively intact older adults: neuropsychological findings.
AB  - There appears to be an absence of large-scaled clinical trials that have examined
      the efficacy of Ginkgo biloba extract on the neuropsychological functioning of
      cognitively intact older adults. The importance of such clinical research appears
      paramount in light of the plethora of products containing Ginkgo biloba that are
      currently being widely marketed to predominantly cognitively intact adults with
      claims of enhanced cognitive performances. The purpose of this research was to
      conduct the first known, large-scaled clinical trial of the efficacy of Ginkgo
      biloba extract (EGb 761) on the neuropsychological functioning of cognitively
      intact older adults. Two hundred and sixty-two community-dwelling volunteers
      (both male and female) 60 years of age and older, who reported no history of
      dementia or significant neurocognitive impairments and obtained Mini-Mental State
      Examination total scores of at least 26, were examined via a 6-week, randomized,
      double-blind, fixed-dose, placebo-controlled, parallel-group, clinical trial.
      Participants were randomly assigned to receive either Ginkgo biloba extract EGb
      761(n = 131; 180 mg/day) or placebo (n = 131) for 6 weeks. Efficacy measures
      consisted of participants' raw change in performance scores from pretreatment
      baseline to those obtained just prior to termination of treatment on the
      following standardized neuropsychological measures: Selective Reminding Test
      (SRT), Wechsler Adult Intelligence Scale-III Block Design (WAIS-III BD) and Digit
      Symbol-Coding (WAIS-III DS) subtests, and the Wechsler Memory Scale-III Faces I
      (WMS-III FI) and Faces II (WMS-III FII) subtests. A subjective Follow-up Self
      report Questionnaire was also administered to participants just prior to
      termination of the treatment phase. Analyses of covariance indicated that
      cognitively intact participants who received 180 mg of EGb 761 daily for 6 weeks
      exhibited significantly more improvement on SRT tasks involving delayed (30 min)
      free recall (p < 0.04) and recognition (p < 0.01) of noncontextual, auditory
      verbal material, compared with the placebo controls. The EGb 761 group also
      demonstrated significantly greater improvement on the WMS-III FII subtest
      assessing delayed (30 min) recognition (p < 0.025) of visual material (i.e. human
      faces), compared with the placebo group. However, based on the significant
      difference (p < 0.03) found between the two groups' pretreatment baseline scores
      on the WMS-III FII, this result should be interpreted with caution. An
      examination of the participants' subjective ratings of their overall abilities to
      remember by treatment end on the Follow-up Self-report Questionnaire also
      revealed that significantly more (p = 0.05) older adults in the EGb 761 group
      rated their overall abilities to remember by treatment end as 'improved' compared
      with the placebo controls. Overall, the results from both objective,
      standardized, neuropsychological tests and a subjective, follow-up self-report
      questionnaire provided complementary evidence of the potential efficacy of Ginkgo
      biloba EGb 761 in enhancing certain neuropsychological/memory processes of
      cognitively intact older adults, 60 years of age and over.

PMID- 12404672
TI  - A placebo-controlled, double-blind trial of Ginkgo biloba for antidepressant
      induced sexual dysfunction.
AB  - The aim of this study was to examine the effect of Ginkgo biloba on
      antidepressant-induced sexual dysfunction. The Ginkgo biloba (n=19) and the
      placebo groups (n=18) were divided; each to be administered with Ginkgo biloba
      and placebo respectively for 2 months by means of a randomized placebo
      controlled, double-blind study. The results of this 2 month trial were: (1) there
      was no statistical significant difference from the placebo at weeks 2, 4 and 8
      after medication; (2) in comparison with baseline, both the Ginkgo biloba group
      and the placebo group showed improvement in some part of the sexual function,
      which is suggestive of the importance of the placebo effect in assessing sexual
      function. This study did not replicate a prior positive finding supporting the
      use of Ginkgo biloba for antidepressant, especially SSRI, induced sexual
      dysfunction.

PMID- 12404673
TI  - Acute cholecystokinin effects on event-related potentials in healthy volunteers.
AB  - This study investigated the effects of a continuous slow infusion of
      cholecystokinin tetrapeptide (CCK-4), a neuropeptide with panicogenic properties,
      on brain event-related potentials (ERPs) in healthy adults. Twenty-four
      volunteers, 15 females and 9 males, were assigned to infusion with either placebo
      or CCK-4 in a randomized, double-blind, parallel group design. ERPs, elicited
      within a standard auditory odd-ball paradigm requiring the counting of rare (20%)
      occurring 'deviant' tones interspersed among more frequent (80%) occurring
      'standard' tones, were assessed once before infusion, and at 10 min and 40 min
      after the onset of infusion. Compared with the placebo, CCK-4 delayed the
      latencies of N100 and P200 components elicited by 'deviant' stimuli. No
      significant treatment differences were observed with respect to N200, P300b, mood
      or adverse symptoms. These preliminary findings suggest that CCK-4 may interfere
      with information processing relating to the selection of significant stimuli and
      as such, may be of relevance to mechanisms underlying panic disorder.

PMID- 12404674
TI  - Effects of serotonin and catecholamine depletion on interleukin-6 activation and
      mood in human volunteers.
AB  - There is increasing evidence that depression and related neurotic illnesses are
      associated with alterations in immune function that may contribute to their
      pathogenesis. For example, clinical and experimental studies have shown that
      abnormal HPA-axis activation and monoamine neurotransmission may be related to an
      increased release of proinflammatory cytokines from stimulated lymphocytes in the
      periphery and brain. In the present investigation, the effects of tryptophan
      depletion (TD) on unstimulated plasma interleukin-6 (IL-6) concentrations were
      investigated in order to determine whether acute changes in serotonin (5-HT)
      neurotransmission would induce a proinflammatory response in healthy individuals.
      The effects of TD were compared with the analogous procedure of tyrosine
      depletion (TPD), which reduces catecholamine metabolism in humans. Thirteen
      female participants completed three experimental sessions: TD, TPD and a balanced
      control condition (B). Mood-ratings and blood sampling were performed at baseline
      and 5 h after the administration of the mixtures. Analyses revealed that TD and
      TPD markedly reduced tryptophan and tyrosine/phenylalanine levels, respectively.
      No changes in plasma IL-6 production or ratings of lowered mood were observed,
      however, subjects did report feeling more fatigued after TD. These findings
      indicate that a transient disruption in global monoamine function does not
      stimulate a proinflammatory response of IL-6 in normal volunteers.

PMID- 12404675
TI  - Tianeptine and fluoxetine in major depression: a 6-week randomised double-blind
      study.
AB  - In a 6-week, multicentre, randomised, double-blind controlled study, tianeptine
      (37.5 mg/day) and fluoxetine (20 mg/day) were compared for efficacy and safety in
      178 patients with major depression. No significant difference was shown between
      the two drugs, either in terms of efficacy (MADRS, CGI, COVI) or in terms of
      safety, except for the CGI 'severity of illness' which was lower at the end point
      with tianeptine than with fluoxetine. The percentages of responders (as defined
      by a 50% decrease of the MADRS score from baseline to end point) were 75% with
      tianeptine and 67% with fluoxetine, showing the efficacy of both drugs. In
      conclusion, both tianeptine and fluoxetine are effective and well-tolerated
      treatments for major depression.

PMID- 12404676
TI  - Tardive dyskinesia and impaired glucose tolerance.
AB  - The authors examined the role of impaired glucose metabolism in the
      pathophysiology of tardive dyskinesia in schizophrenic patients with and without
      persistent TD. Glucose tolerance and insulin levels were determined in 86
      patients with persistent tardive dyskinesia and in 108 patients without tardive
      dyskinesia. Dyskinesias were assessed by the abnormal involuntary movement scale
      (AIMS) and extrapyramidal symptoms by the Simpson--Angus rating scale (SARS).
      Fasting blood glucose levels were significantly lower while the first and second
      hour glucose levels did not reveal any differences in patients with tardive
      dyskinesia compared with those without tardive dyskinesia. Insulin levels did not
      differ in these two groups. Our cross-sectional epidemiological study does not
      suggest hyperglycemia to be a risk factor for tardive dyskinesia. However,
      prospective long-term studies with multiple assessment points are needed to
      clarify the role of glucose metabolism in the development of tardive dyskinesia.

PMID- 12404677
TI  - Ecstasy/MDMA attributed problems reported by novice, moderate and heavy
      recreational users.
AB  - RATIONALE: The recreational use of MDMA/Ecstasy (3,4
      methylenedioxymethamphetamine) is associated with many psychobiological problems,
      but there is a paucity of data on how these relate to the level of past use.
      OBJECTIVES: to assess the incidence of Ecstasy-attributed problems as reported by
      novice, moderate and heavy users. METHODS: 763 unpaid volunteers took part in a
      WWW study of recreational drug use. This report is based on the 282 Ecstasy users
      from that sample, who comprised 109 novice users (1-9 occasions), 136 moderate
      users (10-99 occasions), and 36 heavy users (+100 occasions). Yes/no responses
      were automatically recorded to a series of questions covering psychobiological
      problems experienced when drug-free, which were attributed by the respondents to
      their Ecstasy use. RESULTS: Depression, memory problems, anxiety, mood
      fluctuation, poor concentration, infections, tremors/twitches and weight loss,
      were all significantly associated with the extent of Ecstasy use. Thus memory
      problems attributed to Ecstasy were reported by 19% of novice users, 52% of heavy
      users and 73% of heavy users (chi-square 42.74, df=2, p<0.001); many of the other
      variables showed similar trends. CONCLUSIONS: The incidence of problems
      attributed to Ecstasy use, is directly related to the number of occasions it has
      been used.

PMID- 12404678
TI  - The role of cortisol suppression on craving for and satisfaction from nicotine in
      high and low impulsive subjects.
AB  - The rewarding properties of drug self-administration have been shown to depend on
      mesolimbic dopamine release but also on the availability of corticosterone, as
      shown in rats. Since this became particularly evident when tested in rat strains
      bred for high (HR) and low (LR) reactivity to novel stimuli, the role of cortisol
      and personality in drug craving was investigated in 60 male nicotine-deprived
      smokers divided according to questionnaire scores into high and low impulsives, a
      dimension considered to represent HR/LR rats. They either received the peripheral
      cortisol blocker metyrapone (MET) or the centrally blocking substance
      dexamethasone (DEX) or placebo (n=20 each) and were then allowed to smoke. MET
      more than DEX reduced craving for cigarettes during deprivation. This was only
      observed in low impulsives while high impulsives developed low craving unmodified
      by blockade of cortisol. Satisfaction from smoking was less achieved with DEX
      than with MET and not modified by impulsivity. Differences between MET and DEX in
      influencing craving during deprivation and satisfaction from smoking were
      discussed on the basis of different glucocorticoid receptors. The
      mineralocorticoid receptor (MR) seems to be the 'turn on switch' and the
      glucocorticoid receptor (GR) the 'turn off switch' in mediating the rewarding
      properties of dopamine in drug self-administration.

PMID- 12404679
TI  - Rates of adherence to pharmacological treatment among children and adolescents
      with attention deficit hyperactivity disorder.
AB  - Pharmacological intervention, mainly with psychostimulants, alone or with
      psychotherapy or behavioural modification, was found to be effective in
      increasing sustained attention span, improving concentration, reducing
      hyperactive behaviour and improving areas of academic deficits in children and
      adolescents with the diagnosis of attention deficit-hyperactivity disorder
      (ADHD). Despite their proven efficacy, noncompliance of the children and
      adolescents to the prescribed medication presents serious problems to patients
      and health care providers alike. OBJECTIVE: To investigate the rate of adherence
      to prescribed medication in a clinically referred sample of children and
      adolescents diagnosed as having ADHD. In addition, the stability of reports of
      adherence over a 3 month period was explored. METHOD: Fifty-one children and
      adolescents (males: n = 42; females: n = 9) between the age of 7 years and 16.6
      years diagnosed with ADHD and their parents were administered a children
      behaviour checklist, a teacher report form scale and a compliance with treatment
      opinion and attitude scale. RESULTS: There were very high reports of adherence by
      children to prescribed medications for ADHD with rates of compliance greater than
      70%. Correlation between the children and adolescents' reports and the parents'
      reports revealed high agreement both at the end of week 1 and at the end of the
      study (week 12). There were also findings of stability of adherence reports over
      a 3 month period. CONCLUSION: The results of this study documented high rates of
      adherence to medication prescribed for symptoms of attention deficit
      hyperactivity disorder in a sample of children and adolescents. Their reports of
      adherence were well correlated with parents' reports. Several factors were found
      to be related to the high level of adherence.

PMID- 12404680
TI  - Glucuronidation of olanzapine by cDNA-expressed human UDP
      glucuronosyltransferases and human liver microsomes.
AB  - Olanzapine is a widely used, newer antipsychotic agent, which is metabolized by
      various pathways: hydroxylation and N-demethylation by cytochrome P450, N
      oxidation by flavin monooxygenase and direct glucuronidation. In vivo studies
      have pointed towards the latter pathway as being of major importance.
      Accordingly, the glucuronidation reaction was studied in vitro using cDNA
      expressed human UDP-glucuronosyltransferase (UGT) enzymes and a pooled human
      liver microsomal preparation (HLM). Glucuronidated olanzapine was determined by
      HPLC after acid or enzymatic hydrolysis. The following UGT-isoenzymes were
      screened for their ability to glucuronidate olanzapine: 1A1, 1A3, 1A4, 1A6, 1A9,
      2B7 and 2B15. Only UGT1A4 was able to glucuronidate olanzapine obeying saturation
      kinetics. The K(m) value was 227 micromol/l (SE 43), i.e. of the same order of
      magnitude as for other psychotropic drugs, and the V(max) value was 2370
      pmol/(min mg) (SE 170). Glucuronidation was also mediated by the HLM preparation,
      but a saturation level was not reached. The olanzapine glucuronidation reaction
      was inhibited by several drugs known as substrates for UGT1A4, e.g.
      amitriptyline, trifluoperazine and lamotrigine. Thus, competition for
      glucuronidation by UGT1A4 represents a possibility for drug-drug interactions in
      subjects receiving several of these psychotropic drugs at the same time. Whether
      such possible interactions are of any clinical importance may await further
      studies in patients.

PMID- 12404681
TI  - Relationship between cerebral pharmacokinetics and anxiolytic activity of
      diazepam and its active metabolites after a single intra-peritoneal
      administration of diazepam in mice.
AB  - The relationship between the cerebral pharmacokinetics of diazepam and its active
      metabolites (desmethyldiazepam, oxazepam) and the anxiolytic effect evaluated by
      the four-plates test and the light/dark test were investigated after a single
      intra-peritoneal injection of diazepam (1 mg/kg or 1.5 mg/kg). For up to 30 min
      after administration, the sedative effect interfered with the anxiolytic effect,
      thus the results of the anxiolytic effect were not interpretable. From 30 min to
      60 min after administration, this interference disappeared, the cerebral level of
      benzodiazepines was stable (the brain elimination of diazepam was compensated for
      by the appearance of desmethyldiazepam followed by oxazepam) but the anxiolytic
      effect decreased dramatically in all the tests with diazepam 1 mg/kg or 1.5
      mg/kg. The acute tolerance to benzodiazepines and the difference of affinity for
      subtypes of GABA(A) receptors between diazepam, desmethyldiazepam, oxazepam could
      explain this result.

PMID- 12404682
TI  - Olanzapine improves social dysfunction in cluster B personality disorder.
AB  - Treatment with antipsychotics is a common approach for personality disorder.
      Conventional antipsychotics may be efficacious particularly against psychoticism,
      but less against other symptoms in these patients. They are, furthermore,
      associated with adverse drug reactions poorly tolerated by patients with
      personality disorder. Atypical antipsychotics have a more convenient
      pharmacological profile with a lower risk for extrapyramidal symptoms and a
      broader therapeutic profile, showing some efficacy against impulsivity,
      aggressivity and affective symptoms. The medical records of ten patients with a
      DSM-IV diagnosis of a cluster B personality disorder who had received olanzapine
      treatment were reviewed. A mirror-image design anchored to the start date of
      olanzapine treatment and extending 8 weeks in either direction was used. The
      assessment consisted of a qualitative chart review and a retrospective completion
      of the GCI-C and an adapted French version of the SDAS, using the observer-rated
      items. The olanzapine dose range was 2.5-20 mg during the 8 weeks of observation.
      The mean SDAS score (items 1-15) was 28.8+/-8.4 for the 8 weeks preceding
      olanzapine prescription and was improved to 13.6+/-5.8 after 8 weeks of
      treatment.

PMID- 12404683
TI  - Efficacy of clozapine in a non-schizophrenic patient with psychogenic polydipsia
      and central pontine myelinolysis.
AB  - Clozapine is an atypical antipsychotic drug that has been demonstrated to be a
      highly effective treatment for polydipsia in schizophrenic patients. The authors
      report the first case of a non-schizophrenic patient affected by polydipsia and
      central pontine myelinolysis who was successfully treated with clozapine.

PMID- 12404684
TI  - Serological observations in patients suffering from acute manic episodes.
AB  - Although abnormalities of the immune system have been described in depression,
      information on serological alteration in acutely manic patients has been scarce.
      The present study undertook to investigate the levels of C-reactive proteins,
      circulating immune complexes, total immunoglobulins and immunoglobulin
      subclasses, complement proteins C3, C4, C6 and Factor B in the sera of 45
      patients suffering from an acute manic episode. The findings were compared with
      assessments on the sera of 45 controls. The results demonstrate a number of
      significant differences between patients and controls. Whilst levels of
      immunoglobulin D were significantly lower, the levels of total immunoglobulin and
      immunoglobulin G1, complement proteins C3, C6 and Factor B were raised in the
      patient group when compared with the controls. Our results suggest a relationship
      between acute mania and immunological parameters associated with acute phase
      responses.

PMID- 12404685
TI  - Short-term treatment of post-traumatic stress disorder with naltrexone: an open
      label preliminary study.
AB  - Eight patients (6 men and 2 women) with chronic post-traumatic stress disorder
      (PTSD) were treated with naltrexone 100-200 mg/day. Seven patients completed 2
      weeks of treatment. A subtle and clinically insignificant improvement was noted
      in intrusive and hyperarousal symptoms (p < 0.05 for both), but not in avoidance
      symptoms. All patients demonstrated side effects which limited the targeted dose.
      It is suggested that the subtle positive effect of naltrexone and the
      hypersensitivity of these patients to its side effects do not encourage the use
      of naltrexone in the treatment of PTSD patients.

PMID- 12404686
TI  - Cytochrome P450 2D6 genotype does not predict SSRI (fluoxetine or paroxetine)
      induced hyponatraemia.
AB  - AIMS: The aims of this study were to determine if patients with SSRI-related
      hyponatraemia were (1) genetically poor metabolizers of CYP2D6, and/or (2) had
      excessive plasma concentrations of the SSRI antidepressant. METHODS: Plasma DNA
      from 20 people with hyponatraemia attributable to fluoxetine or paroxetine was
      analysed for the CYP2D6 alleles *1-*16. Trough plasma concentrations of
      fluoxetine and norfluoxetine, or paroxetine were assayed in nine people who
      remained on the antidepressant. RESULTS: Genotype results were compared with
      those published in a large population study. The poor metabolizer PM/PM genotype
      was present in one subject only, or 5% of the study population, compared with
      7.2% of a general population. The 95% Cl of this result was 0-21%, suggesting
      that it is most unlikely that hyponatremia is related to the PM/PM genotype. The
      intermediate IM/PM genotype was present in 5% compared with 19.7% of a general
      population. All differences were not statistically significant. Antidepressant
      concentrations of fluoxetine (n = 5, all EM) and paroxetine (n = 1 IM/PM and n =
      3 EM) were all within the lower half of the reference range. CONCLUSIONS: These
      results do not support the hypothesis that SSRI-related hyponatraemia is linked
      to genetically poor metabolizers, or excessive drug concentrations.

PMID- 12404687
TI  - Effect of serotonin 1A agonist tandospirone on depression symptoms in senile
      patients with dementia.
AB  - The treatment of depression in senile patients with dementia is difficult with
      the drugs used formerly. The effects of a new anxiolytic drug, tandospirone, were
      investigated on depression symptoms in nine senile patients with dementia using
      Hamilton Depression Rating Scale (HAM-D) items. Tandospirone improved the
      symptoms, especially the depressive mood, agitation and anxiety, although a
      slight gastrointestinal symptom was found in one patient. The findings in the
      present study may suggest that tandospirone is a useful and comparatively safe
      drug for depression symptoms in senile patients with dementia.

PMID- 12404688
TI  - Remarkable effect of milnacipran in the treatment of Japanese major depressive
      patients.

PMID- 12404689
TI  - A case of Meige dystonia induced by short-term quetiapine treatment.

PMID- 12404690
TI  - Evidence-based analysis of the worldwide abuse of licit and illicit drugs.
AB  - In order to place the issues of drug abuse in a proper perspective and to allow
      rational, evidence-based decision-making, an analysis of the international data
      on the use of illicit drugs and the misuse of legally prescribed psychotropic
      drugs was undertaken. The data show that by far the most widely abused drug is
      cannabis, followed, according to region, by amphetamine-type stimulants or
      cocaine. While opiate abuse is far less widespread, it accounts for a
      disproportionately large proportion of medical and social problems. The illicit
      use of licit medicines is a very small, and declining, problem. The implications
      of these data for physicians, politicians, regulators and administrators are
      discussed.

PMID- 12404691
TI  - Effects of alcohol on risk-taking during simulated driving.
AB  - The effect of alcohol on judgement or conscious risk-taking may increase the
      likelihood of an automobile accident. This study examined the direct effects of
      penalty severity and alcohol on risk-taking in a novel simulated-driving lane
      choice task. Thirteen male social drinkers received alcohol (0.3 g/kg, 0.5 g/kg,
      0.8 g/kg) or placebo during each of four test sessions in a randomized, within
      subject design. In repeated trials, subjects selected, then drove through a cone
      defined lane. Contingent upon performance, points were added (+ 5 for the
      narrower lane, + 3 for the wider lane) and taken away (- 1, - 3, or - 5 points
      per hit cone) after each trial. Risk-taking was defined as a selection of the
      narrower-width lane. The frequency of risk-taking decreased as the penalty
      increased. The 0.5 g/kg dose, compared to other alcohol doses or placebo,
      significantly increased risk-taking in the high-risk (5-point penalty) condition.
      This finding suggests that breath alcohol concentrations within current legal
      standards can alter a driver's decision-making such that the willingness to enter
      a high-risk situation is increased.

PMID- 12404692
TI  - Interactions between alcohol and caffeine in relation to psychomotor speed and
      accuracy.
AB  - Unlike other CNS depressants, alcohol intoxication can be associated with
      increased error rates, coupled with unaffected (or speeded) response rates during
      psychomotor and cognitive processing. The present study examined whether
      concurrent consumption of caffeine may differentially affect these aspects of
      alcohol and performance.A randomised, double-blind, placebo-controlled design was
      utilised in which 64 healthy young volunteers received either 0.66 g/kg alcohol,
      caffeine (110-120 mg), both or neither. Performance was assessed using a four
      choice reaction time task (FCRT) with elements of repetitive (predictable) and
      random stimuli sequences and the digit symbol substitution task (DSST).
      Individuals on alcohol made significantly more errors during both fixed and
      random FCRT sequences, and there was evidence of weak antagonism of these effects
      by caffeine on the latter measure. On the DSST test of psychomotor speed, alcohol
      was associated with a significant slowing, the caffeine group were significantly
      faster and there was clear antagonism of the effects of alcohol by caffeine.
      These findings confirm that alcohol consumption is associated a greater number of
      errors and provide some evidence for task-specific antagonism of alcohol's
      cognitive effects by caffeine.

PMID- 12404693
TI  - The effects of transdermal nicotine on inspection time.
AB  - RATIONALE: The acute administration of nicotine via a cigarette has been
      demonstrated to enhance inspection time (IT), a measure of rapid visual
      information processing, while the nicotinic antagonist mecamylamine impairs IT.
      However, as transdermal nicotine patches provide a slow delivery of nicotine, it
      is unclear if they produce similar effects to nicotine administered by more rapid
      methods. OBJECTIVES: To examine the effects of transdermal nicotine on inspection
      time. METHODS: Ten moderate smokers were administered nicotine (21 mg/day) or
      placebo via a transdermal patch in a randomized, double-blind, repeated measures
      design. Subjects were administered the IT task at baseline, then 1, 3, and 6 h
      subsequent to patch application. RESULTS: The change in IT from baseline was
      significantly different in the nicotine condition, relative to placebo, at 3 h
      but not 1 or 6 h. CONCLUSIONS: The findings suggest that nicotine administered
      via transdermal patches improves IT, but this improvement may be subject to
      tolerance. Data from previous studies on tolerance to the cognitive effects of
      nicotine have been inconclusive. However, the slow delivery of nicotine from
      patches may be more likely to produce such effects.

PMID- 12404694
TI  - The acute effects of combined administration of Ginkgo biloba and Bacopa monniera
      on cognitive function in humans.

PMID- 12404695
TI  - Antipsychotics in clinical practice: guidelines for safe and effective use.
AB  - Antipsychotic drugs have made a significant contribution to the treatment of
      schizophrenia but the older drugs in particular have significant side-effects.
      The newer atypical drugs are effective for the treatment of both positive and
      negative symptoms and they also have significantly fewer serious side-effects.
      However, these drugs are considerably more expensive that the older drugs and
      this has generated intense debate about their cost effectiveness. There is now
      good evidence that when all factors are taken into consideration the atypical
      drugs are both cost effective and improve the quality of life of patients with
      schizophrenia. Despite the importance of these drugs there is widespread
      variation in their use and a national consensus on this important issue is long
      overdue.

PMID- 12404697
TI  - Psychomotor performance of psychiatric inpatients under therapy: assessment by
      paper and pencil tests.
AB  - Fifty psychiatric inpatients included in the study were diagnosed as having
      substance related disorder, schozophrenia, bipolar disorder, depressive disorder
      or anxiety disorder based on DSM-IV and ICD-10. All the patients were on multiple
      drug therapy for a minimum of 7 days in the hospital. The psychomotor performance
      score assessed with the help of the six letter cancellation test and the digit
      letter substitution test was compared with a matched group of 50 normal
      volunteers. The significantly low scores for patients may be considered
      indicative of the fact that prolonged therapy would be required to attain normal
      psychomotor status. Thus, simple paper and pencil tests may provide valuable
      information in assessment of psychomotor and cognitive functions of psychiatric
      patients during recovery.

PMID- 12404696
TI  - Saccadic peak velocity and EEG as end-points for a serotonergic challenge test.
AB  - We previously reported that a single dose of the serotonin receptor agonist meta
      chlorophenylpiperazine increased the peak velocity of saccadic eye movements and
      decreased low-frequency electroencephalographic activity. METHODS: We
      administered a single dose of the serotonin releaser dexfenfluramine in a double
      blind, placebo controlled randomised cross-over design and measured saccadic eye
      movements and EEG every hour up to 6 h. Subjects were 62 males (18-30 years) with
      a history of no, moderate or heavy use of ecstasy tablets. RESULTS:
      Dexfenfluramine increased saccadic peak velocity and decreased alpha, delta and
      theta electroencephalographic activity, the latter predominantly in heavy users
      of ecstasy. CONCLUSIONS: This study supports the idea that saccadic peak velocity
      and EEG can be useful endpoints of a serotonergic challenge. This could be an
      important anatomical extension of these end-points, which until now were limited
      to the effect on hypothalamic serotonergic projections.

PMID- 12404698
TI  - Fluvoxamine augmentation in risperidone-resistant schizophrenia: an open trial.
AB  - We investigated the efficacy and safety of augmenting risperidone with
      fluvoxamine for the treatment of residual positive and negative symptoms in
      patients with chronic schizophrenia who had shown an incomplete response to
      risperidone. A total of 30 patients completed the open trial over a 12-week
      period during which fluvoxamine was added to risperidone. The result from the
      positive and negative syndrome scale (PANSS) and Simpson-Angus extrapyramidal
      effects (S-A) scale were examined at baseline, 1, 2, 4, 8 and 12 weeks of
      treatment. There were no significant differences in PANSS positive, negative and
      general psychopathology scores, or in S-A scale scores at any point during the
      treatment. These results suggest that fluvoxamine appears to be ineffective in
      augmenting the risperidone treatment response in chronic schizophrenic patients.
      Further controlled trials will be needed to confirm this observation.

PMID- 12404699
TI  - Clinical risk factors for neuroleptic malignant syndrome.
AB  - Pharmacological risk factors for neuroleptic malignant syndrome (NMS) are better
      defined than clinical risk factors. We examined the psychopathological status
      preceding the onset of NMS in 20 patients. We evaluated four key psychiatric
      symptoms (psychomotor agitation, catatonia, disorganization and confusion) and
      grouped them into definite clinical syndromes. Six patients presented with an
      acute and severe catatonic syndrome, with all the four key psychiatric symptoms.
      Twelve patients presented with an acute and severe disorganized psychotic
      episode, with two or three key psychiatric symptoms, but not catatonia. Our study
      suggests that a clinical syndrome of acute disorganization, in addition to acute
      catatonia, is a potential clinical risk factor for NMS. The two syndromes, which
      can occur in the context of different mental disorders, are related to each other
      as both implicate alteration in behavioural monitoring, and were, in our
      experience, unresponsive to neuroleptics. In conclusion, we hypothesize that the
      recognition of these two syndromes should reduce NMS occurrence. We recommend a
      judicious use of neuroleptics not only in patients with acute catatonia, but also
      in patients with acute disorganization.

PMID- 12404700
TI  - Pharmacokinetics of THC in brain and testis, male gametotoxicity and premature
      apoptosis of spermatozoa.
AB  - An earlier report described the pharmacokinetics of delta-9 THC and the resulting
      brain function responses. In the present studies the pharmacokinetics of THC in
      plasma, brain and testis were related to impairment of spermatogenesis. THC-
      containing preparations, whatever their route of administration, were associated
      with the induction of gametotoxicity in all species studied including man. The
      pharmacokinetics and molecular binding of THC is similar in all experimental
      models. Concentrations of THC in plasma, fat, testis, brain and spleen were
      measured following administration of tracer amounts of C(14) delta-8 THC labelled
      at the C(11) position. Rats were administered 2 microCi of the tracer by i.m.
      injection, and killed at regular intervals after a single or multiple dose of the
      label. After a single dose, the maximal radioactivity was reached in brain after
      2 and 4 h and amounted to 0.06% of the administered dose. In the testis, the
      concentration did not exceed 0.023% of the administered dose. In epididymal fat,
      the total radioactivity after 4 h was five times higher than in the brain and
      after 24 h it was eight times greater. After multiple injections of C(14) THC,
      concentrations of the drug remained low in the plasma, brain and testis not
      exceeding 2-7 ng/g, but the epididymal fat tracer concentration was 40-80 times
      higher. Plasma concentrations of C(14) THC were of the same magnitude as those
      measured by GCMS in the plasma of men exposed to marihuana smoke or THC, and in
      whom alterations of spermatogenesis were observed. In these studies, plasma THC
      ranged from 9.5x10(12) M to 2.4x10(14) M. These data illustrate the efficiency of
      the blood-brain barrier and blood-testicular barrier in limiting the storage of
      THC into brain and testis. During chronic exposure to THC the pharmacokinetic
      molecular mechanisms which limit the storage of THC in the brain and testis are
      not sufficient to prevent a persistent deregulation of membrane signalling and
      the induction of functional and morphological changes which reflect a premature
      apoptosis of spermatogenic cells. Long term, longitudinal epidemiological studies
      have reported decreased spermatogenesis in healthy, fertile adult males. But no
      study has been initiated to relate the oligospermia of this population to the
      consumption of widely used psychoactive drugs.

PMID- 12404701
TI  - Epilepsy, psychosis and clozapine.
AB  - Six patients with epilepsy and severe psychosis were treated with the atypical
      antipsychotic clozapine. The use of clozapine might be complicated in epileptic
      patients because of an increased risk of seizures. However, none of the reported
      patients had an increase of their seizure frequency, in contrast, three patients
      had a substantial reduction of seizures. One patient had a reduction of non
      epileptic seizures as well. In the second part of this paper, combinations of
      clozapine with newer and older anticonvulsants as well as their interactions and
      associated risks are discussed.

PMID- 12404702
TI  - A review of the pharmacokinetics, tolerability and pharmacodynamics of
      amisulpride in healthy volunteers.
AB  - Amisulpride binds selectively to dopamine D(2) and D(3) receptors in the limbic
      system. Low doses of amisulpride preferentially block presynaptic D(2)/D(3)
      dopamine autoreceptors, thereby enhancing dopaminergic transmission, whereas
      higher doses block postsynaptic receptors, thus inhibiting dopaminergic
      hyperactivity. Amisulpride is clinically effective on the negative symptoms of
      acute schizophrenia exacerbations at low dosages (50-300 mg/day), and also on the
      positive symptoms of the disease at high dosages (400-800 mg/day). Nineteen
      clinical studies involving 358 volunteers have investigated the pharmacokinetics,
      pharmacodynamics and tolerability of amisulpride. Amisulpride shows linear
      pharmacokinetics, a bioavailability of 48%, low protein binding (17%) and an
      elimination half-life of approximately 12 h. It is predominantly eliminated in
      the urine as the parent compound. It exhibits no significant detrimental effects
      in psychometric or memory tests up to the dose of 400 mg/day, inducing only mild
      impairment at high doses, whereas EEG data suggest an alertness-enhancing effect
      at low doses (<or= 50 mg). Moreover, amisulpride does not potentiate the
      depressant effects on the central nervous system of alcohol and lorazepam. This
      tolerability profile is clearly better than that of haloperidol 4 mg/day and is
      consistent with a weak blocking effect on striatal D(2) receptors. In summary,
      studies in humans have shown that amisulpride is free of behavioural toxicity at
      doses exerting clear antipsychotic efficacy and confirm that its CNS effects may
      vary with the dose administered.

PMID- 12404703
TI  - Relations of clinical features, subgroups and medication to serum monoamines in
      schizophrenia.
AB  - BACKGROUND: Plasma and serum indices of monoaminergic activity reflect partly the
      illness of schizophrenia (e.g. HVA/deficit syndrome) and sometimes the symptoms
      (e.g. HVA/anhedonia). But, such studies have rarely taken both metabolites and
      parent amines or inter-amine activity ratios into account. We hypothesized that
      comparing the major symptom dimensions to measures of transmitter activity (with
      and without control for antipsychotic drug treatment) would show differential
      patterns of activity useful for the design of pharmacological treatments.
      METHODS: Dopamine (DA), noradrenaline (NA), serotonin (5-HT), their three major
      metabolites and prolactin were measured in the serum of 108 patients with
      schizophrenia and 63 matched controls: DA D2-receptor blocking-activity was
      estimated from a regression of butyrophenone displacement in striatum in vitro on
      to PET reports of drug-binding in vivo. Symptoms were factored into four
      dimensions (disorganized/thought disorder, nonparanoid/negative, ideas-of
      reference and paranoid/positive symptoms). RESULTS: (1). Patients' DA activity
      did not differ from controls: but their 5-HT and NA turnovers
      increased/decreased, respectively, and the DA/5HT-metabolite ratio was lower.
      Increased DA-D2-receptor occupancy was predicted by decreased DA-metabolism and
      its ratio to 5-HT-metabolism. (2). Patients had higher levels of NA, DA
      metabolites and DA-/5-HT-metabolite ratios on atypical vs typical drugs. (3).
      Increased D2-occupancy was associated with lower DA metabolism in paranoid
      patients but was unrelated to relative increases of DA/5-HT- and NA-metabolism in
      nonparanoid patients. (4). Low DA-/5-HT-metabolite ratios, high prolactin and low
      DA-metabolism characterized thought-disordered patients. (5). High DA-/5-HT
      metabolite ratios paralleled many ideas-of-reference. The metabolites were
      sensitive, respectively, to control for D2-occupancy and prolactin. CONCLUSIONS:
      The role of DA in paranoid, and 5-HT in thought-disordered and ideas-of-reference
      dimensions point both to the mechanisms underlying the features typical of these
      subgroups and the type of medication appropriate.

PMID- 12404704
TI  - Detection of endogenous lithium in neuropsychiatric disorders--a model for
      biological transmutation.
AB  - The human hypothalamus produces an endogenous membrane Na(+)-K(+) ATPase
      inhibitor, digoxin. A digoxin induced model of cellular/neuronal quantal state
      and perception has been described by the authors. Biological transmutation has
      been described in microbial systems in the quantal state. The study focuses on
      the plasma levels of digoxin, RBC membrane Na(+)-K(+) ATPase activity, plasma
      levels of magnesium and lithium in neuropsychiatric and systemic disorders.
      Inhibition of RBC membrane Na(+)-K(+) ATPase activity was observed in most cases
      along with an increase in the levels of serum digoxin and lithium and a decrease
      in the level of serum Mg(++). The generation of endogenous lithium would
      obviously occur due to biological transmutation from magnesium. Digoxin and
      lithium together can produce added membrane Na(+)-K(+) ATPase inhibition. The
      role of membrane Na(+)-K(+) ATPase inhibition in the pathogenesis of
      neuropsychiatric and systemic disorders is discussed. The inhibition of membrane
      Na(+)-K(+) ATPase can contribute to an increase in intracellular calcium and a
      decrease in magnesium, which can result in a defective neurotransmitter transport
      mechanism, mitochondrial dysfunction and apoptosis, defective golgi body function
      and protein processing dysfunction, immune dysfunction and oncogenesis.

PMID- 12404705
TI  - Acute, dose-dependent cognitive effects of Ginkgo biloba, Panax ginseng and their
      combination in healthy young volunteers: differential interactions with cognitive
      demand.
AB  - The present paper describes three studies examining the acute effects of single
      doses of Ginkgo biloba (GK501), Ginseng (G115) and their combination (Ginkoba
      M/E, Pharmaton SA) on the performance of healthy young adults (mean age 21 years)
      during serial arithmetic tasks with differing cognitive load. In each double
      blind, placebo-controlled study three different treatment doses and a placebo
      were administered, according to a balanced crossover design, with a 7-day washout
      period between each dose. Participants' scores on two computerised serial
      subtraction tasks (Serial Threes and Serial Sevens) were assessed pre-dosing and
      at 1, 2.5, 4 and 6 h thereafter. A number of significant time, dose and task
      specific effects were associated with each treatment. There was a dose-dependent
      improvement in speed of responding during Serial Threes following Ginkgo biloba.
      Different doses of Ginseng improved accuracy and slowed responses during Serial
      Sevens. The most striking result, however, was a highly significant and sustained
      increase in the number of Serial Sevens responses following 320 mg of the Ginkgo
      Ginseng combination at all post-treatment testing times. This was accompanied by
      improved accuracy during Serial Sevens and Serial Threes following the 640 mg and
      the 960 mg dose, respectively. The paper concludes with speculation into the
      possible mechanisms underlying these effects.

PMID- 12404706
TI  - The acute nootropic effects of Ginkgo biloba in healthy older human subjects: a
      preliminary investigation.
AB  - Ginkgo biloba has been shown to have chronic memory enhancing effects in healthy
      subjects and patients with dementia. There is limited research on the acute
      nootropic effects of Ginkgo biloba in humans. The current study aimed to examine
      the acute effects of Ginkgo biloba (120 mg) on memory functioning in healthy
      older volunteers using the cognitive drug research (CDR) battery of memory tests
      and the Rey auditory verbal learning task (AVLT). The study was a double-blind
      placebo-controlled design, with each participant tested under both placebo and
      Ginkgo biloba treatment conditions. Testing was conducted pre- and 90 min post
      drug administration for each treatment condition. Treatment conditions were
      separated by a 7 day wash out period. No acute effects of Ginkgo biloba were
      found for any of the memory tests examined. The findings suggest that 120 mg of
      Ginkgo biloba has no acute nootropic effects in healthy older humans.

PMID- 12404707
TI  - Verbal fluency facilitated by the cholinergic blocker, scopolamine.
AB  - This study was designed to explore putative facilitatory effects of low doses of
      scopolamine (SP) on phonemic (letter) and semantic (category) verbal fluency. A
      double-blind, parallel-group design was used with 36 subjects who completed a
      test battery before and 2 h after 0.6 mg or 1.2 mg of SP or placebo. Fluency
      measures included total number of words generated, clustering (the production of
      words within semantic or phonemic subcategories) and switching (the ability to
      shift efficiently to new subcategories). Low doses of scopolamine increased
      phonemic fluency, as has been shown previously. Semantic fluency was not
      increased by SP, although subjects treated with 1.2 mg of SP generated higher
      frequency words. SP did not affect clustering or switching. It is suggested that
      phonemic and semantic fluency reflect distinct cognitive processes.

PMID- 12404708
TI  - Diabetes is not a risk factor for tardive dyskinesia: a retrospective
      observational study.
AB  - The aim of this observational study was to compare the prevalence of tardive
      dyskinesia (TD) in diabetic and non diabetic patients. We compared 34 diabetic
      patients with 34 non diabetic controls, matched by sex, age and time of
      admission, who had received a complete neuropsychiatric evaluation and who had
      been exposed to antidopaminergic treatment for at least 3 months. Among them, 8
      of 24 diabetic (33.3%) and 6 of 15 (40.0%) non diabetic patients presented TD.
      The prevalence of TD in the diabetic group is numerically lower than in the
      controls but the difference is not statistically significant (chi(2) = 0.006; fd
      = 1; p = 0.937). These results suggest that diabetes is unlikely to play a major
      role in the pathogenesis of TD.

PMID- 12404709
TI  - An introduction to the 'enantiomer debate'

PMID- 12404710
TI  - Do single enantiomers have something special to offer?
AB  - Single enantiomers have a significant role to play in enhancing drug discovery
      and development. Researchers are overcoming the technical limitations associated
      with developing single enantiomers, and the growth in targeted drug development
      already means that more single enantiomers are developed ab initio. Moreover, as
      pharmaceutical companies decide whether to progress a single enantiomer, rather
      than a racemate, early in development, increasingly fewer racemates will reach
      the market. Developing a single enantiomer as a line extension of a profitable
      drug is of growing importance and is reflected in the increasing number of
      speculative patents on chiral switches. The implications are that single
      enantiomers will eventually touch every area of clinical medicine. As the number
      of chiral drugs launched onto the market increases, so clinicians need to be
      aware of the key issues surrounding enantiomers. This review examines some of the
      issues arising from the growing importance of enantiomers in medicine. Copyright
      2001 John Wiley & Sons, Ltd.

PMID- 12404711
TI  - The therapeutic promise of single enantiomers: introduction.
AB  - This review uses several examples drawn from the literature to show how using
      active enantiomers as therapeutic agents may yield several benefits, including
      more predictable pharmacokinetics, more accurate drug monitoring and enhanced
      tolerability. As a result of these benefits, the therapeutic use of single
      enantiomers will become increasingly important not only in psychopharmacology,
      but in medicine generally. Indeed, over the early years of the new millennium,
      the therapeutic use of single active enantiomers is set to redefine the benefit
      risk ratio in the management of many common conditions. Copyright 2001 John Wiley
      & Sons, Ltd.

PMID- 12404712
TI  - An introduction to enantiomers in psychopharmacology.
AB  - There is growing scientific, clinical, commercial and regulatory recognition that
      enantiomers offer benefits over racemates in the management of psychiatric
      diseases as well as in clinical medicine generally. However, relatively few
      studies consider enantiomers' individual characteristics. This review considers
      some of the clinical benefits associated with using stereochemically pure drugs
      in psychiatric conditions other than depression.A review of the evidence shows
      that enantiomers offer four main benefits. Firstly, using a single enantiomer may
      allow a reduction in total dose, while maintaining or improving outcomes. For
      example, (+)-nefopam's antinociceptive activity is greater than that produced by
      both the racemate and (-)-nefopam, but with the same level of acute toxicity.
      Thus, a single enantiomer may offer greater efficacy, dose for dose, than the
      racemate. Secondly, assessing dose-response relationships is simpler. There is no
      reason to suppose that a racemate will necessarily contain the isomers' optimum
      therapeutic ratio, that one of the isomers will be inactive or that the
      enantiomers' dose-response curves will coincide. For example, the dose-response
      relationship for the induction of catalepsy in the rat by thioridazine suggested
      that the racemate was around 12 times more potent than (+)-thioridazine and three
      times more potent than (-)-thioridazine, when considering the actual
      concentrations in the striatum. Thirdly, using a single enantiomer may reduce
      pharmacokinetic and pharmacodynamic variability between patients. For example,
      the coefficients of variation for some of methadone's pharmacokinetic parameters
      may reach 70%, which might have clinical consequences. Finally, using a single
      enantiomer may reduce toxicity arising from the therapeutically inactive
      stereoisomer. For example, the single enantiomers of bupivacaine and ropivacaine
      are significantly less cardiotoxic than their respective racemates.This review
      illustrates why stereochemistry should be considered when assessing the
      toxicology, pharmacokinetics, metabolism and efficacy of a racemate. Indeed, the
      differences may be so marked that achiral analyses may be misleading, and
      clinicians should consider prescribing an enantiomer whenever possible. In many
      cases, prescribing a single enantiomer improves the benefit:risk ratio. Finally,
      there is no reason to suppose that a racemate's characteristics will apply to the
      constituent enantiomers. Copyright 2001 John Wiley & Sons, Ltd.

PMID- 12404713
TI  - Enantiomeric antidepressant drugs should be considered on individual merit.
AB  - Many antidepressants have been introduced as racemic drugs, the enantiomers of
      which may differ in some of their pharmacodynamic and pharmacokinetic properties.
      This review argues that each enantiomer of a chiral antidepressant should be
      evaluated according to its individual characteristics rather than by
      extrapolation from the racemate, or by assumptions based on the stereoselective
      characteristics of other enantiomeric drugs. For example, in some cases the
      enantiomers' pharmacodynamic and therapeutic properties can be complementary,
      which suggests that the racemate should be used clinically. In other cases where
      enantiomers show qualitatively similar but quantitatively different properties to
      the racemate, using a single enantiomer might be more appropriate. In yet further
      cases, a distomer may induce the metabolism of the eutomer, enantiomers may be
      metabolised by different enzymes, there may be a different profile of drug-drug
      interactions, and therapeutic drug monitoring may be simpler. Therefore, this
      review exemplifies the principle that each enantiomer of a chiral antidepressant
      should be evaluated according to its individual pharmacological, pharmacokinetic
      and pharmacogenetic characteristics. These factors are discussed in relation to
      five chiral antidepressants: trimipramine, mianserin, mirtazapine, fluoxetine and
      citalopram. It is hoped that an appreciation of the stereoselective differences
      between enantiomers will facilitate improvements in the benefit:risk ratio of
      drugs used in the management of depression. Copyright 2001 John Wiley & Sons,
      Ltd.

PMID- 12404714
TI  - Unmet needs in the pharmacological management of depression.
AB  - Newer antidepressants, such as the selective serotonin reuptake inhibitors
      (SSRIs), selective noradrenaline reuptake inhibitors (NRIs) and drugs acting on
      both serotonin and noradrenaline, represent a clinically significant advance over
      the tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors.
      Nevertheless, all current pharmacological treatments for depression fall somewhat
      short of the 'ideal', and unmet needs remain in the pharmacological management of
      depression. In general, current antidepressants differ little in terms of
      efficacy. However, in terms of tolerability, SSRIs appear to offer clear
      advantages over older therapies. For example, the proportion of patients who
      discontinue treatment because of adverse events and the risk of fatal toxicity
      both appear to be lower with SSRIs, compared with TCAs. Some adverse events,
      however, such as sexual dysfunction and nausea (typical serotonergic side
      effects), tend to be more frequent with SSRIs. Also, individual SSRIs appear to
      differ in the likelihood that they will be associated with these side effects.
      However, no clear advantage emerges for any one SSRI over another, and the
      current recommendation is that the anticipated side-effect profile should be
      tailored to the patient. Current pharmacoeconomic data do not appear to favour
      any antidepressant over another, with no cost benefits associated with
      prescribing TCAs instead of SSRIs.The refinement of current drugs arising from
      the introduction of their active enantiomers may translate into clinical benefit,
      bringing closer the 'ideal' antidepressant. Potential benefits of a single
      enantiomer versus the racemate in the management of depression include: a
      reduction in the total dose, while maintaining desired outcomes, as well as a
      possible greater efficacy, dose for dose,simpler assessment of dose-response
      relationships,a reduction in pharmacokinetic and pharmacodynamic variability
      between patients, anda reduction in any toxicity arising from the inactive
      stereoisomer. However, these benefits remain to be proved in clinical trials and
      naturalistic studies. Further refinement of the benefit:risk ratio of current
      'gold standard' drugs may go some way to addressing the shortfalls in existing
      antidepressant therapy. Copyright 2001 John Wiley & Sons, Ltd.

PMID- 12404715
TI  - The enantiomer debate: current status and future directions.
AB  - Psychopharmacology, and the treatment of depression in particular, is one area
      where there is currently an increasing awareness of chiral drug phenomena. It is
      now generally agreed that the pharmacological and pharmacokinetic properties of
      chiral drugs and their enantiomers should be assessed early on in the drug
      development process. However, issues surrounding the potential advantages and
      disadvantages of enantiomeric drugs, compared with racemates, continue to be
      debated. This article highlights some of the key issues raised during one such
      debate, the aim of which was to address the hypothesis that each enantiomeric
      drug should be considered on its own merit. The idea is considered both in
      general terms and specifically in the context of clinical psychiatry, with an
      emphasis on the treatment of depression. An update on recent developments in
      enantiomeric antidepressant therapy is also provided. Copyright 2001 John Wiley &
      Sons, Ltd.

PMID- 12404716
TI  - Stereochemistry: definitions and a note on nomenclature.
AB  - The impact of stereochemistry in medicine is increasingly being felt with the
      realisation of the therapeutic potential offered by single enantiomers.
      Consequently, a basic comprehension of the terminology and nomenclature used in
      stereochemistry is becoming a requirement for many researchers and clinicians.
      The first aim of this article is to familiarise readers with some of the well
      established terms used to define key principles in stereochemistry. The issue of
      nomenclature in stereochemistry can be confusing to the uninitiated. A search
      through the literature reveals a number of different designation systems, some of
      which may not be interchangeable or may be obsolete. The second aim of this
      article is, therefore, to clarify this issue. It is hoped that this article will
      assist the reader of this supplement, as well as facilitate the interpretation of
      both new and existing literature concerning enantiomeric drugs. Copyright 2001
      John Wiley & Sons, Ltd.

PMID- 12404717
TI  - Aseptic processing, elephants, blind men, and sterility.

PMID- 12404718
TI  - Consideration of media fill tests for evaluation and control of aseptic
      processes: a statistical approach to quality criteria.
AB  - The concept of upper and lower statistical confidence limits has been introduced
      to the current media fill tests used for the assurance of aseptic operation.
      Results of media fill tests can be evaluated with rationale and interpreted more
      clearly by introducing the upper and lower limits for the number of observed
      positive units. Quality criteria derived by the misuse of statistics should be
      reconsidered. Media fill tests are one of the most useful methods for the
      evaluation of aseptic filling processes, and acceptance criteria have been issued
      in various official compendia. In some official compendia, various combinations
      of the number of media fills and the number of detected allowable contaminated
      units have been indicated based on the misuse of statistics. This study has
      statistically revealed that the larger number of fills allows for the worse
      average accepted quality. This study has shown that media fill tests can be used
      for the evaluation of aseptic operation with fully scientific and statistical
      rationale by evaluating the statistical lower limit for the number of positive
      units observed. This study proposed that the new criteria should be simply
      expressed as the process should be in a controlled state and can manufacture
      product whose sterility can be statistically assured with 95% confidence level.

PMID- 12404719
TI  - Study of sterilizing effectivity of different ethylene oxide gaseous mixtures
      using CFCs and HCFCs (Oxyfume 12R and 2002R).
AB  - The use of ethylene oxide as a sterilizing agent has been frequently practiced,
      especially taking into account the huge variety of medical devices produced with
      heat sensitive materials. Mixtures of ethylene oxide and inert gases have been
      widely adopted in order to decrease the undesirable flammable and explosive
      properties of ethylene oxide. This article provides a study regarding the
      sterilizing effectiveness of two ethylene oxide blends: Oxyfume 2002R (using
      HCFCs 22 and 124) and Oxyfume 12R (using CFC 12), at different temperatures (45,
      55, and 65 degrees C). To accomplish this procedure, sub-lethal challenges were
      performed (0, 3, 6, 9, 12, and 15 minutes) using biological indicators (obtained
      in the laboratory) made of Bacillus subtilis var. niger ATCC 9372. The
      sterilizing efficacy of both mixtures was equivalent at the gas concentration of
      600 mg/L. The influence of higher temperatures was thus proved.

PMID- 12404720
TI  - Microbial retention characteristics of sterilizing-grade membrane filters with
      alginate substituted for oil-based products.
AB  - For oil-based products, FDA recommends substitution of the oil with a compound
      which has similar viscosity and physical characteristics. In this study, a
      substitute for oil-based products was screened by measuring the viscosity and
      filterability, and examined for the presence of cell clumps in the various test
      fluids using an optical microscopy. The viscosity of the test fluids measured in
      the range of about 60-75 cP. Brevundimonas diminuta (formerly Pseudomonas
      diminuta), a standard challenge test organism for validation of 0.2 micron rated
      membrane filters, formed clumps in oils (corn, olive, sesame, and soybean) and
      polyethylene glycol (PEG, Molecular Weight (MW) = 400 and 1,000). During the
      viability test, cells suspended in 80% glycerol showed a ten-fold mortality rate
      after an exposure for 6 hours, but there was no significant change in viability
      in alginate (low, medium, and high viscosity) for 24 hours. These results
      suggested that alginate is better suited as a substitute for oil-based products
      than 80% glycerol. Since high viscosity fluids take longer to filter, the
      glycerol mortality rate would influence the challenge test negatively. A scaled
      down filtration system has been developed for the described trials, and the
      bacterial challenge and bubble point tests have been performed in 1.6% alginate
      (66.7 cP), which was the choice of carrier fluid.

PMID- 12404721
TI  - Validation of microbial recovery from disinfectants.
AB  - We evaluated the efficacy of different neutralizing solutions for use in
      disinfectant efficacy assays. Our approach used comparisons between the
      recoveries of low inocula in different treatment populations. The challenge
      organisms employed were those described by the AOAC for use in determining
      germicidal, tuberculocidal, sporicidal, and fungicidal activity of disinfectants.
      Neutralizer efficacy (NE) ratios were determined by comparing the recovery of
      identical inocula from the neutralizing solution in the presence, or the absence,
      of a 1:10 dilution of the biocide. Neutralizer toxicity (NT) ratios were
      determined between recovery of viable microorganisms incubated for a short period
      in peptone, and in the neutralizing medium without the biocide. An effective and
      non-toxic neutralizer was initially identified by NE and NT ratios of > or =
      0.75. Statistical evaluation of the data was performed by ANOVA, with Dunnett's
      test for multiple comparisons used to confirm failures. By this analysis, 239/244
      identified failures were confirmed by ANOVA of 588 NT and NE comparisons (5
      presumptive failures were not confirmed by statistical analysis). We therefore
      conclude that recovery of 75% is a suitable criterion (2% false negative rate)
      for neutralizer evaluations. There was a wide degree of variability seen among
      the responses of different test organisms to the different recovery broths.
      Pseudomonas aeruginosa and Salmonella choleraesuis were particularly sensitive to
      commercial neutralizer broths. Interestingly, no commercially available
      neutralizer proved adequate for all index organisms against all biocides tested.
      This finding underscores the need to evaluate potential neutralizers against all
      microorganisms and biocides employed.

PMID- 12404722
TI  - Air Sampling System for use in monitoring viable and non-viable particulate air
      quality under dynamic operating conditions of blow/fill/seal processing.
AB  - An Air Sampling Link (ASL), employed in conjunction with an Air Sampling Device
      (ASD) or a laser particle counter, has been developed for sampling flowing air
      for viable and non-viable particulate analyses. Typically, the ASL could be used
      to sample filtered air supplied to an air shower of a Blow/Fill/Seal machine
      operating in the dynamic state. The ASL allows sample volumes of air to be taken
      from flowing air without significant loss from the sample flow of airborne
      particles possessing aerodynamic sizes relevant to those found in practice. The
      link has no moving parts, is steam sterilizable in-situ, and allows for the
      taking of continuous samples of air without the need for intervention into the
      'critical zone' of the filling machine. This article describes (i) the design
      criteria for the ASL and the ASD, (ii) the rationale underlying the concept of
      the ASL design, (iii) the collection performance of the ASL against that of a
      conventional sampling arrangement, and (iv) a functionality assessment of the ASL
      based sampling system installed on a Rommelag style 305 B/F/S machine over a
      seven week period.

PMID- 12404723
TI  - [Nosocomial infections at a neurologic hospital, analysis of 10 years].
AB  - OBJECTIVE: To describe the results of 10 years of nosocomial infection (NI)
      surveillance at a neurological center and evaluate the impact of control
      measures. PATIENTS AND METHODS: A descriptive and retrospective study was
      performed at a reference center for adult neurologic and neurosurgical patients
      located in Mexico City. Between 1990 and 2000, the number, site and type of NI
      were registered. Chi Square test was employed for statistical analysis of
      numerical data. RESULTS: Mean NI rate observed was 21 episodes per 100
      discharges, with a 40% reduction during the period. Predominant NI were urinary
      tract infections (36%), lower respiratory tract infections (31%), phlebitis (9%),
      primary bacteremia (7%), surgical wound infections (7%), and pneumonia (4%).
      Control measures with a definite impact were organization of intravenous therapy
      teams with reduction in bacteremia (p = 0.009). Changes in preoperative care,
      hair clipping instead of shaving, clorhexidine shampoo, and technique of long
      tunneled ventriculostomy with a 57% reduction (p = 0.00006) in infections related
      with neurosurgical procedures. The increase in staff and equipment renewal of the
      respiratory therapy service decreased respiratory infections. CONCLUSIONS: The
      measures that reduced our NI rate may be useful in other centers for neurologic
      patients.

PMID- 12404724
TI  - [Evaluation of the clinical diagnostic reasoning. Use of dynamic attractors as an
      alternative].
AB  - The purpose of this study was to apply diagnostic clinical reasoning, based upon
      cognitive teaching, to help the student develop their own mental structure of an
      ailment or disease. Such a structure is built as mathematical chaotic
      deterministic type that can be evaluated through identification of dynamic
      attractors. To achieve our purpose, clinical diagnostic reasoning skills of two
      groups of students was compared against those of an expert through revision of 17
      clinical cases. Such revision, selection of relevant data, allows for
      construction of conceptual maps in which several dynamic attractors can be
      identified, based on the largest number of connections that stem from some
      concepts. In the majority of cases, statistical analysis showed similarity among
      types of connections established by the expert; several similar dynamic
      attractors could be identified, leading us to conclude that cognitive-based
      teaching of diagnostic clinical reasoning is useful in developing this type of
      skill, and that it can be evaluated through identification of dynamic attractors.

PMID- 12404725
TI  - [Chromophobe cell renal carcinoma. Clinico-pathologic study of 36 cases].
AB  - INTRODUCTION: Chromophobe renal cell carcinoma (CCRC) comprises 5% of neoplasms
      of renal tubular epithelium. CCRC may have a slightly better prognosis than clear
      cell carcinoma, but outcome data are limited. OBJECTIVE: In this study, we
      analyzed 250 renal cell carcinomas to a) determine frequency of CCRC at our
      Hospital and b) analyze clinical and pathologic features of CCRCs. METHODS: A
      total of 250 renal carcinomas were analyzed between March 1990 and March 1999.
      Tumors were classified according to well-established histologic criteria to
      determine stage of disease; the system proposed by Robson was used. RESULTS: Of
      250 renal cell carcinomas analyzed, 36 were classified as chromophobe renal cell
      carcinoma, representing 14% of the group studied. The tumors had an average
      diameter of 14 cm. Robson staging was possible in all cases, and 10 patients were
      stage 1) 11 stage II; 10 stage III, and five stage IV. The average follow-up
      period was 4 years and 18 (53%) patients were alive without disease. CONCLUSION:
      The highly favorable pathologic stage (RI-RII, 58%) and the fact that the
      majority of patients were alive and disease-free suggested a more favorable
      prognosis for this type of renal cell carcinoma.

PMID- 12404726
TI  - [Multidisciplinary treatment of airway obstruction].
AB  - The airway obstruction may be for many diseases. In some cases is for malignant
      pathology and other cases for benign pathology. The etiology of malignant
      pathology may be for bronchogenic carcinoma, metastatic tumours, trachea primary
      tumours and larynx. The benign pathology may be for late obstruction post
      tracheostomy and granulomas at many infections diseases. In this cases the most
      important etiology is Mycobacterium tuberculosis. The early diagnosis and the
      intervention of multidisciplinary group, with the participation at
      otorrinolaringologies, bronchoscopist, neck surgeons, chest surgeons, and
      radioterapeuts, can result in a best life quality and resolve the airway
      obstruction.

PMID- 12404727
TI  - [The scavenger receptor and its importance in amyloid processes].
AB  - The scavenger receptor (SRA or RPA) belongs to a wide family of receptor
      proteins. The classification is based on sequence homologies and structural
      similarities; nevertheless, it has been useful to group them on the basis of
      ligand specificity. The SRA was first identified as a receptor for modified low
      density lipoproteins, where such modification permits to regulate the uptake of
      modified LDL by macrophages leading to a massive cholesterol accumulation.
      Moreover, SRA facilitates the clearance by phagocytic cells of microbial
      pathogens and senescent cells. SRA is a transmembrane glycoprotein that exists as
      a trimer comprised of a cystein-linker dimer and a non-covalently bound monomer.
      SRA has an a-helical coiled coil domain, which is essential for both trimer
      formation and acid-dependent ligand dissociation. It also contains a collagenous
      domain, essential for ligand binding. The majority of these ligands are
      polyanionic molecules, such as the A beta-peptide, important in the development
      of Alzheimer's disease. Present findings including our own consider that binding
      of these peptides to SRA activates an inflammatory response with the production
      of oxidative stress.

PMID- 12404728
TI  - [Cellular and biochemical mechanisms involved in physiopathogenesis of autoimmune
      thrombocytopenic purpura].
AB  - Autoimmune thrombocytopenic purpura (ATP) is a bleeding disorder caused by
      excessive destruction of antibody-coated platelets. It is known that platelet
      destruction takes place in macrophages of reticulo-endothelial system, but
      immunological mechanisms involved in such destruction are unknown. The objective
      of this article is to review the literature concerning pathogenesis of ATP: to
      have controlled experimental conditions some animal laboratory models have been
      used. The (NZW X BXSB) F1 mice have been studied as autoimmune disease model and
      Harrington mouse as an immune purpura model. Studies in humans suggest that there
      are some differences in pathogenesis of acute or chronic ATP, particularly in
      reactive T cells. For example, in chronic form there are high levels of The
      (CD4+) activity concomitant with low levels of T suppressor (CD8+) activity,
      while in acute form there is no dominance of any particular T cell activity or
      CD4+ is even decreased. Mitogen lymphocyte proliferation is increased in chronic
      ATP but decreased in acute form.

PMID- 12404729
TI  - [Young patient with recurrent myocardial infarction without coronary
      atherosclerosis].

PMID- 12404730
TI  - [Unusual causes of chronic meningitis, report of 5 cases].
AB  - Chronic meningitis is a frequent disease; it constitutes a real diagnostic
      challenge because of different etiologic possibilities, the most important being
      infectious, chemical, inflammatory, tumoral, autoimmune and of unknown origin.
      Chronic meningitis, as a rule, needs the use of a wide and expensive battery of
      studies, but frequently despite all this, it is not possible to make a diagnosis.
      Biopsies of meninges and brain play a key role in the study of this type of
      patients. We present five cases of chronic meningitis; some important
      considerations are made in relation to diagnosis and therapeutic management.

PMID- 12404731
TI  - [Erasmian influences among renaissance physicians].
AB  - The fundamental aspects of Erasmus's ethic humanism consisted of ideals of
      universal peace and tolerance. These ideals are exposed in the great works of his
      maturity Colloquia and Adagia read and meditated on by renaissance physicians in
      England, Spain, Germany, Italy, and also in the New Spain. Erasmus's readers were
      learned and numerous. Among his pupils and supporters in Spain were humanist
      physicians of Madrid such as Doctors Suarez and Juan de Jarava. Other supporters
      were in the group of the Sevillian physicians and naturalists. Among the Erasmist
      physicians, residing in other regions was doctor Andres Laguna, who translated
      into Spanish the Dioscorides treatise on medical botany. Many physicians living
      in New Spain owned copies of Erasmian works, such as Doctors Pedro Lopez (the
      second) and Juan de la Fuente, who was in charge of the first medical chair at
      the University of Mexico. The protophysician Francisco Hernandez, in response to
      a petition of Archbishop Pedro Moya de Contreras, wrote a Christian catechism of
      Erasmian influence, destined for humanists in NewSpain. As asserted by Johan
      Huizinga, Erasmus was the sole humanist who really wrote for everyone, i.e. for
      all cultured people.

PMID- 12404732
TI  - [Gaucher's disease: ultrasonography findings in the spleen].

PMID- 12404733
TI  - [New therapeutic strategies in Alzheimer's disease].

PMID- 12404734
TI  - [Concepts and clarifications on oral bioavailability of cyclosporin].

PMID- 12404735
TI  - [Health provisions for medical care facilities].

PMID- 12404736
TI  - [Critical medicine in obstetrics: a reality in Mexico].

PMID- 12404737
TI  - [Relevance of nifedipine].

PMID- 12404738
TI  - [Cost-effectiveness of hip fracture in Japan].

PMID- 12404739
TI  - [Prion disease and its therapeutic approaches: bovine spongiform encephalopathy
      (BSE) and variant CJD].

PMID- 12404740
TI  - [Relationship between aging and vitamin E].
AB  - We investigated the pathophysiological significance in biomembranes of the redox
      dynamics of Vitamin E (alpha-tocopherol) which is lipophilic radical scavenger
      related to aging or pathologic status such as non-insulin-dependent diabetes
      mellitus or primary hyperlipidemia. Vitamin E eliminates lipid peroxyl radicals
      by the peroxidation chain reaction of the membrane lipid, and it becomes Vitamin
      E radical. Furthermore, the Vitamin E radical becomes Vitamin E quinone which is
      an oxidic metabolite of Vitamin E. Therefore, it was needed to determine the
      alpha-tocopherol and alpha-tocopherolquinone simultaneously to evaluate the
      antioxidative status of alpha-tocopherol in biomembranes exactly. For this
      purpose, we developed the assay method for the simultaneous determination of the
      two substances using HPLC system. Then we applied this method to basic and
      clinical research. 1) For the simultaneous determination of alpha-tocopherol and
      alpha-tocopherolquinone, highly-sensitive measurement system by HPLC-multiple
      coulometric ECD was developed. This system is useful to estimate the redox
      dynamics of alpha-tocopherol in biomembranes. 2) The utilization rate of alpha
      tocopherol in the erythrocyte membrane of 10- to 120-week-old rats was
      significantly increased, whereas alpha-tocopherol uptake in the erythrocyte
      membrane decreased age-dependently. Furthermore, a significant increase in lipid
      hydroperoxide content and a marked decrease in the fluidity of the erythrocyte
      membrane were seen with age. 3) There was a strongly significant positive
      correlation between age and the utilization rate of alpha-tocopherol in the
      erythrocyte membrane of healthy volunteers aged between 23 and 103. 4) The alpha
      tocopherol uptake in erythrocyte membrane was significantly lower in elderly non
      insulin-dependent diabetes mellitus patients (average 68.1 years old) than in
      healthy subjects (average 71.8 years old). 5) The utilization rate of alpha
      tocopherol in erythrocyte membrane and the alpha-tocopherol uptake in erythrocyte
      membrane were significant lower in elderly patients with primary hyperlipidemia
      (average 74.1 years old) compared to healthy subjects (average 71.2 years old).
      These findings suggest that the redox dynamics of alpha-tocopherol in
      biomembranes should be investigated with special regard to the onset, aggravation
      and complications of several diseases or aging as a result of oxidative stress.
      In addition redox dynamics were suggested to be useful to evaluate the grade of
      aging.

PMID- 12404741
TI  - [Gastrointestinal diseases in the elderly].

PMID- 12404742
TI  - [Treatment and management of heart failure in the eldery].

PMID- 12404743
TI  - [Geriatric rehabilitation].

PMID- 12404744
TI  - [Vertigo of the elderly in otolaryngological practice].

PMID- 12404745
TI  - [Skin diseases in the elderly].

PMID- 12404746
TI  - [Bone and joint diseases in the elderly].
AB  - As a current attention of the medical treatment has been paid to improve guality
      of the life rather than to save the life of the patient, so the treatment of bone
      and joint diseases, which are not ordinarily fatal and deteriorate quality of the
      life of the patient, would become important in the aged society of 21 century. In
      a strategy to improve the quality of life in the patient with osteoarthritis,
      disease modifying anti-osteothritis drugs are investigated for primary prevention
      and complete recovery of osteoarthritis. In osteoporosis, a characteristic bone
      disease of the aged, aims of the treatment have been changed from freeing of pain
      in the nineteen sixties, increase of bone mass in the nineteen eighties and
      reduction of the fracture rate in the nineteen nineties to improve of quality of
      the life through decrease of pain and fracture in 21 century. In conclusion,
      current management for bone and joint diseases in the elderly is finally designed
      to enjoy a healthy life of long span by medical intervention.

PMID- 12404747
TI  - [Clinical significance of carotid artery lesions].

PMID- 12404748
TI  - [Heart rate variability analysis and neurobehavioral function in community
      dwelling older people aged 75 or older].
AB  - BACKGROUND: Although heart rate variability (HRV) has been found to be associated
      with increased mortality in the elderly, the association of HRV and cognitive
      function and activity of daily living (ADL) capacity in the very elderly are not
      clear. METHODS: A sample of very elderly people (N = 138), aged 75 years and
      older, living in Urausu, Hokkaido, participated in this study. Participants were
      classified into three groups: normal, borderline, and dementia. Time and
      frequency domain measures of HRV were compared with behavioral and cognitive
      functions. RESULTS: HRV components, except for the LF/HF ratio, did not correlate
      with age in the very elderly. The LF component showed a statistically significant
      correlation with all the variables of behavioral functions. Most HRV components
      showed statistically significant and positive correlations with the flexibility
      of the back. The LF and LF/HF ratio were significantly lower in the dementia
      group than in the normal group. CONCLUSION: Although the meaning of the LF
      component is still controversial, we foundadefinite relationship between the LF
      component and behavioral functions. A positive relationship between most HRV
      components and the flexibility of the back may suggest that reduced flexibility
      leads to deteriorated cardiopulmonary function and reduced HRV. A further
      prospective study is needed to examine whether HRV and neurobehavioral functions
      are independent predictors of morbidity and mortality in very elderly people.

PMID- 12404749
TI  - [Development of a new method for simple dietary education in elderly individuals
      with diabetes mellitus].
AB  - Some elderly diabetic patients find it difficult to understand conventional
      dietary and nutritional education using a Japanese food exchange list. We
      developed a new method for simple dietary education including several dietary
      instructions. We compared the effects of simple dietary education on food intake,
      nutritional components, and glycemic control with conventional dietary education,
      using a randomized control trial. We randomly allocated 30 new elderly diabetic
      outpatients and 38 outpatients who had been visiting our clinic for a long time
      to the simple education group and the conventional education group. Before, and 2
      or 3 months after simple or conventional education, we assessed food intake and
      nutritional components for a week using Yoshimura's food frequency questionnaire.
      In the new diabetic patients, simple and conventional nutritional education
      similarly reduced HbA1c levels as well as intakes of total energy, sweets, and
      fruits after the education. However, patients who had been visiting for a long
      time had no significant differences in total energy intake and HbA1c levels
      between before and after education in both the simple and conventional groups.
      Our results suggest that simple dietary education is useful and effective for
      elderly diabetic patients on their first visit.

PMID- 12404750
TI  - [Association between carotid artery diameter and aortic aneurysm].
AB  - Although it has been suggested that an increase in arterial diameter is related
      to atherosclerotic risk factors, there are only a few reports about the
      relationship between the diameter of the common carotid artery(CCA) and the
      presence of aortic aneurysm (AA). We measured CCA diameters by carotid
      ultrasonography in 132 consecutive AA patients over 40 years of age (aneurysm
      group), and in 414 consecutive subjects over 40 years of age without AA (control
      group). We also studied the size of AA based on CT, MRA or surgical findings. We
      compared CCA diameters with atherosclerotic risk factors between the two groups,
      and studied the relationship between the CCA diameters and AA size by types of
      aneurysm. In the aneurysm group, men (85% vs 69%, p < 0.001), hypertension (88%
      vs 67%, p < 0.001) and smoking (63% vs 46%, p < 0.001) were more frequent, and
      the diameter of the CCA (right, 7.0 +/- 1.1 mm vs 6.3 +/- 1.0 mm, p < 0.001;
      left, 6.7 +/- 1.1 mm vs 6.1 +/- 1.0 mm, p < 0.001) was significantly larger than
      those in the control group. Multiple logistic regression analysis indicated that
      dilatation of CCA on either side was a significant risk factor for AA (right,
      odds ratio 1.69, p < 0.001, left, odds ratio 1.48, p < 0.001) as well as
      hypertension and smoking. There were no differences in size of the CCA according
      to the site of aneurysm. However the CCA diameter was significantly related to
      the size of the thoracic AA (r = 0.350, p < 0.05 for the right CCA) and
      dissecting AA (r = 0.506, p < 0.05 for the left CCA). In conclusion, the increase
      in CCA diameter may suggest the presence of AA, and CCA diameter appears to be
      related to AA size.

PMID- 12404751
TI  - [Development of a tree model that allows simple estimation of the required care
      level using the items of the basic investigation of long-term care insurance].
AB  - In long-term care insurance, the required care level of the disabled elderly is
      calculated from the results of the basic investigation. However, this calculation
      involves complex mathematical processes, and the estimation of the required care
      level at small facilities is difficult. We, therefore, developed a tree model
      that allows simple estimation of the required care level from the state of
      noticeable disabilities in daily activities. The model was prepared separately
      for dementia and physical disabilities. From the patients being cared for at
      Higashiyama Geriatric Hospital for the Elderly who had undergone primary rating,
      a total of 240 individuals consisting of 20 each in each of the 6 required care
      levels for both dementia and physical disabilities were selected, and the results
      of their primary rating were reviewed. "Putting on and taking off a jacket" and
      "care after urination", in which the required care levels increase relatively
      consistently as the investigation items progressed from those for "independent"
      to those for "totally assisted", were selected as the first selection items in
      dementia and physical disability models respectively. In a dementia model, the
      state of "putting on and taking off a jacket" and "care after urination" were
      matched for various required care levels as follows: "Independent"-->assistance
      needed, "observation needed" and "independent" in "standing up"-->required care
      level 1, "observation needed" and "not independent" in "standing up"-->required
      care level 2, "partly assisted"-->required care level 3, "totally assisted" and
      "not totally assisted" in "eating"-->required care level 4, and "totally
      assisted" and "totally assisted" in "eating"-->required care level 5. In a
      physical disability model, the state of "care after urination" was matched for
      various required care levels as follows: "Independent" and "independent" in
      "walking"-->assistance needed, "independent" and "not independent" in "walking"-
      >required care level 1, "direct or indirect assistance"-->required care level 2,
      "totally assisted" and "independent" or "observation needed" in "eating"-
      >required care level 3, "totally assisted" and "partly assisted" in "eating"-
      >required care level 4, "totally assisted" and "totally assisted" in "eating"-
      >required care level 5. The accuracy rate, i.e. the frequency of complete
      matching between the estimation of the required care level using this tree and
      that of the primary rating, was 71.1% in those with dementia and 66.7% in those
      with physical disabilities. The near accuracy rate, i.e. the frequency of
      matching between the two estimations within one rank higher or lower was 98.3% in
      those with dementia and 99.2% in those with physical disabilities. From these
      results, this tree model is considered to be useful for clinical rating.

PMID- 12404752
TI  - [A case of Parkinson's disease associated with pyogenic spondylitis in the
      cervical vertebrae].
AB  - A 68-year-old woman with Parkinson's disease (PD) was admitted due to aspiration
      pneumonia. The symptoms improved partly by administration of antimicrobial agents
      and a steroid-pulse treatment, but she suffered repeated MRSA pneumonia, which
      caused a long-term bed confinement. Shoulder pain that appeared after she started
      rehabilitation did not improve on administration of NSAIDs. We suspected pyogenic
      spondylitis in the cervical vertebraes based on the cervical X-rays and the
      cervical MRI. Patients of PD often have a shoulder pain due to various causes.
      When a patient with PD has a severe shoulder pain, we should suspect pyogenic
      spondylitis in the cervical vertebraes as one of the differential diagnoses. It
      is necessary to do immediately thorough imaging examinations.

PMID- 12404753
TI  - [Endocrine cell carcinoma (atypical carcinoid) of the ileocecal region adjacent
      to an adenocarcinoma].
AB  - An 86-year-old woman was admitted because of right lower abdominal pain. A 7 by 6
      cm tumor palpable in the right lower quadrant was poorly mobile. Abdominal CT
      scan showed a huge tumor with a strong enhancement effect. Barium enema and
      colonoscopic examination revealed a submucosal tumor located from the cecum to
      the ascending colon on the oral side. An undifferentiated adenocarcinoma was
      suspected after examination of the biopsy specimen, right hemicolectomy was
      performed. The tumor invaded the retroperitoneal membrane. Histological
      examination showed a very atypical carcinoid tumor with central necrosis invading
      the veins. Pathohistologically, the huge tumor was diagnosed as endocrine cell
      carcinoma or atypical carcinoid. Furthermore, an elevated lesion, 2.5 cm in size,
      was revealed in the cecum closed to the huge tumor. Histological examination
      showed that the polypoid lesion was early moderately differentiated
      adenocarcinoma. There was no transition between the two tumors. The patient was
      discharged, but died of local recurrence 9 months after the surgery. Endocrine
      cell carcinoma of the large bowel is rare, in particular of the ileocecal region.
      Endocrine cell carcinoma of the ileocecal region adjacent to an adenocarcinoma
      without transition had not been reported previously in Japan.

PMID- 12404754
TI  - [An elderly case of advanced gastric cancer with gynecomastia and high serum
      levels of hCG].
AB  - A 74-year-old man was admitted because of appetite loss in November 1999. A
      gastric ulcer was diagnosed, and a H2 blocker was given. He had had appetite loss
      since July 1997 and had experienced epigastric discomfort since October of 1997.
      On admission, hepatic and pancreatic lymph node swelling was detected by
      ultrasonography of the abdomen. Physical examination revealed a palpable mass in
      the middle region of the upper abdomen as well as gynecomastia. Laboratory
      findings showed high serum levels of hCG (11,700 mIU/ml) and high urinary levels
      of hCG (1,600 mIU/ml). Upper gastrointestinal endoscopy showed a gastric cancer
      of Borrmann type 3 in the posterior wall of the middle body. A biopsy revealed a
      moderately differentiated adenocarcinoma. hCG immunoreactivity was not seen in
      the cancer tissue. A contrast-enhanced CT scan of the abdomen revealed multiple
      lymph node swelling in the hepatic and pancreatic lymph nodes. There was a low
      density area suggesting liver metastases. No other primary carcinomas were not
      detected. We believe that the gynecomastia was due to the hCG-producing tumor.
      The patient died 2 months after diagnosis.

PMID- 12404755
TI  - [Monoclonal antiprothrombin antibodies from patients with antiphospholipid
      syndrome].

PMID- 12404756
TI  - [Effects of antidepressants on the expression of rat brain dopamine receptors].

PMID- 12404757
TI  - [Effects of temocapril on the prevention of early diabetic nephropathy in OLETF
      rat, an animal model for type 2 diabetes].

PMID- 12404758
TI  - [Inhibitory effect of elastase on diabetic nephropathy in experimental diabetic
      mice].

PMID- 12404759
TI  - [Analysis of mechanisms for decrease or loss of E-cadherin expression in human
      melanoma cells].

PMID- 12404760
TI  - [Clinico-pathological investigation of radiation therapy for brain tumors].

PMID- 12404761
TI  - [Involvement of the mediodorsal thalamic nucleus in contextual fear conditioning
      in rats].

PMID- 12404762
TI  - [Studies on phenotype-genotype association and X-monosomy mosaicism in the human
      sex differentiation abnormality].

PMID- 12404763
TI  - [Clinical significance of measurement of cerebral circulation: update].

PMID- 12404764
TI  - [Analysis using positron emission topography (PET) in hemiparetic patients with
      chronic subdural hematoma].
AB  - Chronic subdural hematoma (CSH) is a disease caused by minor head trauma and can
      be cured by surgical treatment. It remains unclear why CSH can cause neurologic
      dysfunction such as hemiparesis, although some reports describe the contribution
      of impaired cerebral blood flow (CBF) and oxygen metabolism of patients with CSH.
      We studied five hemiparetic patients with unilateral CSH using positron emission
      tomography (PET). Before the operation, both the regional CBF (rCBF) and regional
      cerebral metabolic rate of oxygen (rCMRO2) were observed to have decreased
      slightly in the motor cortex and the lentiform nucleus on the bilateral side.
      However, regional oxygen extraction fraction (rOEF), regional cerebral blood
      volume (rCBV) and cerebral vascular response (CVR) in the same regions were
      normal. In the thalamus, no significant findings were observed. Although rCBF and
      rCMRO2 recovered to within normal range in the motor cortex and lentiform nucleus
      on the bilateral side by four weeks after the the operation, hemiparesis improved
      in all the patients within 3 days after the operation. In conclusion, this study
      suggests that a circulatory disturbance in the motor cortex under the hematoma
      was not indicated as a definite cause that induced hemiparesis with CSH.

PMID- 12404765
TI  - [A review of dural arteriovenous fistulas with hemorrhagic onset].
AB  - The majority of dural arteriovenous fistulas are considered to have a benign
      clinical course, but some behave more aggressively, causing progressive
      neurological symptoms and/or intracranial hemorrhage. Several classifications of
      angiographic findings have been reported to predict what findings might result in
      catastrophic presentation. Cortical venous drainage has been described as one of
      the major risk factors of hemorrhage. We reviewed the records of 50 patients with
      dural arteriovenous fistulas admitted to our institution from 1991 to 2001 and
      analyzed their venous drainage patterns with reference to Cognard's
      classification. Six patients had hemorrhagic episodes caused by dural
      arteriovenous fistula and all of them had retrograde drainage through cerebral
      veins. The frequency of hemorrhage in Type I and IIa was 0%, in Type IIb it was
      33.3%, in Type IIa + b it was 9.1%, in Type III and Type IV it was 50%, and in
      Type V it was 100%. These results agreed with those of Cognard reported in 1994,
      and we reconfirmed the usefulness of Cognard's classification. In order to adapt
      a firm strategy and treat them promptly and aggressively, it is important to be
      able to recognize what type of dural arteriovenous fistulas are perilous.

PMID- 12404766
TI  - [Delineation of the cisternal architecture with three-dimensional CT
      cisternography and its transparent imaging].
AB  - We used three-dimensional imaging of the cisternal architecture with perspective
      volume rendering of CT cisternography in patients with unruptured cerebral
      aneurysms. Selective changes in the opacity chart of computed tomographic values,
      based on the use of a function of downward slope, represented the contour of the
      structures located in the cisternal space. In addition to this, using a spiked
      peak curve, it was possible to show the contour of the outer wall of the
      cisternal structures as a series of rings, which provided a transparent view
      inside and/or outside the cistern through the spaces between the rings.
      Transparent imaging technique allowed direct visualization of the underlying
      objects and offered an extensive perspective view of the anatomical architecture
      of the cisternal structure, including an aneurysm, major basal arteries and optic
      pathway, in a single view. Three-dimensional CT cisternography may be a useful
      adjunct for the diagnosis of the cisternal architecture in relation to the
      surrounding cerebrospinal fluid, and for simulation of the surgical procedures
      considered for lesions occupying intra-cisternal space, including cerebral
      aneurysms.

PMID- 12404767
TI  - [The efficacy of prophylactic administration of SBT/ABPC for postoperative
      infection in neurosurgical operations].
AB  - We investigated prospectively the efficacy of sulbactam sodium/ampicillin sodium
      (SBT/ABPC), which is a combination drug of ampicillin and beta-lactamase
      inhibitor, as a preventive drug against postoperative infection in the field of
      neurological surgery. One hundred and six patients were given SBT/ABPC as
      follows: Before anesthetic induction at surgery, 1.5 g of SBT/ABPC was
      administrated by intravenous drip infusion, and further doses were continued at
      12-hour intervals for 5 to 7 days. We assessed postoperative infection, type of
      surgery, duration of operation, and amount of hemorrhage. Search for related side
      effects and bacteriological examinations of the nasal cavity and throat before
      and after treatment were performed. The result was that postoperative infection
      was found in none of the patients. Adverse reactions due to SBT/ABPC such as
      apparent skin symptoms or gastrointestinal symptoms were not observed.
      Considering infections highly resistant to MRSA, SBT/ABPC would be effective to
      prevent postoperative infection in neurosurgical operations and could be used
      safely.

PMID- 12404768
TI  - [Hydrocephalus after subarachnoid hemorrhage regressing spontaneously through the
      subgaleal layer: case report].
AB  - Spontaneous regression was recognized in a case of hydrocephalus after
      subarachnoid hemorrhage. The regression resulted after the absorption of
      cerebrospinal fluid through the subgaleal layer. The absorption of cerebrospinal
      fluid through this layer takes a long time but is one of nature's physiological
      pathways. The spontaneous regression of hydrocephalus through the subgaleal layer
      may be temporarily useful until a more effective physiological pathway is
      provided by a shunt operation to deal with hydrocephalus.

PMID- 12404769
TI  - [A case presenting brain abscess with multiple infectious aneurysms].
AB  - We report a case presenting a brain abscess with multiple infectious aneurysms. A
      59-year-old man was transferred to our hospital suffering from left hemiparesis.
      MRI demonstrated a huge mass in the right frontal lobe with marked brain edema in
      the surrounding area. Diffusion-weighted image revealed heterogenous intensity,
      which is not typical in cases of brain abscess. Surgical removal was planned, and
      preoperative angiography was performed. Angiography demonstrated aneurysms at the
      distal branch of both the right middle cerebral artery and the anterior cerebral
      artery. These aneurysms were surgically resected, and the abscess was totally
      removed. Postoperative course was uneventful. Left hemiparasis was resolved, and
      there was no ischemic lesion seen on postoperative MRI. In the treatment of brain
      abscess, stereotactic aspiration has recently been preferred to removal by
      craniotomy. We conclude that cerebral angiography might be necessary to evaluate
      cerebrovascular complications including infectious aneurysms, in cases presenting
      atypical findings in neuroimaging study.

PMID- 12404770
TI  - [Three cases of successful stenting for radiation-induced carotid arterial
      stenosis].
AB  - We report three cases of radiation-induced carotid arterial stenosis that
      underwent successful angioplasty with stenting. The patients had received
      radiation therapy for tongue or laryngeal cancers and developed minor completed
      strokes 6 to 14 years after irradiation. All patients had multiple and bilateral
      stenosis, measuring more than 50%, of the carotid arteries. The stenosis was
      located in the internal, external, and common carotid arteries. We performed
      percutaneous transluminal angioplasty with stenting. All interventions were
      successful and carotid stenosis decreased to less than 28%. No permanent
      complications occurred. During follow-up periods of up to 26 months, all of these
      cases were free from ischemic symptoms. Neither carotid angiography nor
      ultrasound sonography showed evidence of restenosis. The present results suggest
      the usefulness of angioplasty with stenting for radiation-induced carotid
      arterial stenosis.

PMID- 12404771
TI  - [Staged bilateral VA embolization for SAH due to bilateral VA dissection: case
      report].
AB  - Vertebral artery (VA) dissections are uncommon, but are increasingly recognized
      as a cause of posterior circulation stroke in young adults. We describe a patient
      with bilateral VA dissection who presented SAH. The patient was successfully
      treated by proximal coil occlusion of the bilateral vertebral arteries in two
      stages. In the treatment of SAH due to bilateral VA dissection, it is important
      to estimate the status of the treated vessels or contralateral vessels by follow
      up angiography. Staged bilateral proximal VA occlusions should be considered in
      the case of recurrent VA dissection or progressive aneurysm enlargement.

PMID- 12404772
TI  - [A case of post-traumatic pseudoaneurysm on the posterio meningeal artery].
AB  - A case is reported of post-traumatic delayed appearance of a pseudoaneurysm on
      the posterior meningeal artery. In the immediate post-traumatic stage, the
      patient had mild disturbance of consciousness, mild subarachnoid hemorrhage, and
      mid-line skull fracture of the posterior cranial fossa. At 15 hours after the
      trauma, the patient suddenly developed deep coma and respiratory arrest. CT
      scanning showed further spreading of the subarachnoid hemorrhage and newly
      detected subdural hemorrhage. After the patient regained spontaneous respiration,
      cerebral angiography was performed 24 hours after admission. This initial
      angiography showed no aneurysm, but at 17 days after the trauma, follow-up
      angiography demonstrated the delayed appearance of an aneurysmal dilatation on
      the posterior meningeal artery. The aneurysm was resected surgically and proved
      to be a pseudoaneurysm. Having developed normal pressure hydrocephalus
      afterwards, the patient received a V-P shunt, and was discharged 150 days after
      the trauma with no major neurological deficit. We discussed the indication for
      and timing of angiography for detecting pseudoaneurysms. Posterior meningeal
      artery pseudoaneurysms should be resected surgically, because intravascular
      surgery through the vertebral artery involves considerable risk of embolic
      complications.

PMID- 12404773
TI  - [Cerebrovascular disease (2): infarction, No. 4 in series of articles: basic
      knowledge of neuropathology for neurosurgeons].

PMID- 12404774
TI  - [Problems and proposals from neurosurgical practice, no. 7 in series of articles:
      controversy and reform proposals concerning insured medical care in
      neurosurgery].

PMID- 12404775
TI  - [Does MSA lead the Japanese Health Insurance Reform to success? No. 8 in series
      of articles: controversy and reform proposals concerning insured medical care in
      neurosurgery].

PMID- 12404776
TI  - Lithium and conduct disorder.
AB  - Lithium administration has been effective in treating severe aggression in
      children and adolescents with Conduct Disorder. An overview of the pertinent
      literature is presented. Side effects associated with lithium administration are
      discussed. Guidelines for lithium administration are given, including dosage
      regulation, monitoring of serum lithium, as well as of side effects and
      laboratory measures. When prescribed judiciously, under careful monitoring,
      lithium can be an important part of the comprehensive treatment program.

PMID- 12404778
TI  - [Depressive symptomatology and sleep apnea syndrome].
AB  - The sleep apnea syndrome (SAS), which is defined by more than 5 apneas or
      hypopneas per hour of sleep (9), is quite a frequent affection which concerns 1.4
      to 10% of general population (1.7). The major daytime complaints of the SAS are
      daytime sleepiness, memory and attention disorders, headaches and asthenia
      especially in the morning, and sexual impotence (9). The nocturnal manifestations
      are dominated by sonorous and generally long standing snoring, increased by
      dorsal decubitus and intake of alcohol, with repeated interruptions by
      respiratory arrests. These manifestations are always noted but rarely
      spontaneously reported. The sleep, non refreshing, is agitated and perturbed by
      numerous awakenings. The findings of the clinical examination are poor: obesity
      is found in 2/3 of the cases and arterial hypertension in 1/2 of the cases (20).
      Polygraphic recording during sleep only permits an absolute diagnosis. This
      frequent affection is a real problem of public health because of its numerous
      complications (3, 10, 12, 13, 18, 21). Symptoms of depression are often found
      when a patient with a SAS is examined and conversely, symptoms which evoke a SAS
      can be found in the clinical examination of depressed patients. We decided so to
      study the thymic and anxious status of 24 patients investigated for a SAS and
      submitted to a polygraphic recording during sleep. Four clinical parameters were
      studied: DSM III-R diagnosis criteria, Montgomery and Asberg Depression Rating
      Scale (MADRS), Hamilton Anxiety Rating Scale (HARS) and thymasthenia rating scale
      of Lecrubier, Payan and Puech. We also reported Total Sleep Time (TST = 6.5 +/-
      1.5), Apnea Hypopnea Index (AHI = 26.7 +/- 21.6), number (2.1 +/- 2.8/h) and
      duration (174.2 +/- 150.8 s/h) of hypoxic events. Results showed that among 24
      patients, 8 were depressed according to DSM III-R diagnosis criteria and had
      MADRS > 25, 22 were anxious, 11 had a major anxiety (HARS > 15) and 15 presented
      thymasthenia (SET > 15). Significative correlations existed between anxiety and
      depression (r = 0.82; p < 0.0001), depression and thymasthenia (r = 0.77; p <
      0.0001) and thymasthenia and anxiety (r = 0.75; p < 0.0001). Among the 8
      depressed patients a correlation existed between AHI and depression (r = 0.72; p
      = 0.04), but no correlation was found between depression and hypoxic events.
      These results were comparable to those of Guilleminault (10), Reynolds (21),
      Kales (12), Bliwise (3), Klonoff (13) and Millman (18) who studied relations
      between SAS and depression. The evaluation of thymasthenia gave a more precise
      typology of the depressive state associated to SAS: the type of the mood disorder
      is more "blunted" and "anhedonic" than "sorrowful", particularly characterised by
      asthenia, lack of energy, reduction of interests (leisures, libido, work), loss
      of initiative, difficulties to organise tasks, fall of performances and reduction
      of pleasure usually felt in pleasant events (15). The physic symptomatology
      dominated the psychic one. The sleep disorganization, more than metabolic
      consequences of apneas, could be involved in this associated depressive state.
      Other neuropsychiatric troubles can be associated to the SAS. In fact, cognitive
      troubles (2, 8, 14, 16, 19, 22, 24) and personality disorders (12, 18) have been
      described. Our data confirm previous observations suggesting a frequent
      association between SAS, depression, fatigue and anxiety. Clinicians should
      consequently be aware that a depression with severe complaints of fatigue should
      deserve an investigation oriented towards SAS. Conversely, when a SAS is
      diagnosed, it is necessary to look for a possible depression in order to set up
      the most appropriate treatment. The frequency of SAS, like depression's one,
      increases with age. Prescription and consummation of sedative psychotropic drugs
      increase too with age. Since respiratory depressant effects of these drugs have
      been clearly demonstrated, it is important to evoke SAS when depressive and/or
      anxious states are diagnosed and not to aggravate it. An efficacious treatment of
      SAS can also cure the associated depressive state, but this one can persist. It
      is necessary, in this case, to select a non sedative antidepressant.

PMID- 12404777
TI  - [Open trial of carbamazepine in the prevention of recurrence of bipolar disorder
      in adolescents].
AB  - While the existence of bipolar disorder in children and adolescents is now
      recognized, the prevalence of the disorder is still unknown, although it is clear
      that its' incidence increases markedly at puberty. The risks inherent in the
      course of the disorder, including recurrence and suicidal gestures, highlight the
      importance of its early recognition; however, diagnosis and identification of
      predictive factors in childhood bipolar disorder is problematic. Given the
      development of new mood-regulating psychopharmacological treatments for adults,
      early diagnosis in children is even more important. For children and adolescents,
      previous studies have shown the efficacy of lithium in the prevention of
      recurrence of bipolar disorder, but only over short periods of time. There are
      very few published studies on the use of carbamazepine in bipolar disorder; those
      that exist are most often single case studies. The authors present the results of
      an uncontrolled study of 11 patients, aged 10 to 17 years, diagnosed with bipolar
      according to DSM III-R criteria. These patients were treated with carbamazepine
      for a period of over 1 year. Two cases, especially noteworthy for their
      improvement, are presented in greater detail. A positive response was considered
      to have been obtained if a period greater than 1 year of normal affect was
      obtained. According to this criterion, seven patients were positive responders,
      two were moderate responders and two did not respond to treatment. Tolerance to
      the medication was good; in no cases it was necessary to interrupt treatment.
      Principle adverse side effects were biological, involving an increase in a single
      liver enzyme. Comparison among positive, moderate and non responders did not
      reveal any criteria predictive of therapeutic effectiveness. Despite
      methodological difficulties, these data point the importance of developing
      controlled studies with carbamazepine in the prevention of recurrence of bipolar
      disorder.

PMID- 12404779
TI  - [Adrenoleukomyeloneuropathy presenting as a mental disorder].
AB  - Troubles of cognitive functions are generally observed in the X-linked
      adrenoleucodystrophy. This disease can be revealed at late onset
      (adrenomyeloneuropathy) or contemporary of the demyelinisation in central nervous
      system (adrenoleucodystrophy). Cerebral variants with only psychic involvement
      remain uncommon, the lesions are located in the temporo-parieto-occipital areas.
      The diagnosis occurs by biological investigations and/or the familial history
      before any defect of neurological signs. Therapeutics hopes in this storage
      disorder lay by the earlier diagnosis. In this way, we found interest to
      investigate the adult forms.

PMID- 12404780
TI  - [Life events and military service].
AB  - OBJECTIVE: Life events preceding the year of enrollment in the military service
      were researched in 175 patients invalid out of army because of psychiatric
      disorders. METHOD: We assessed the diagnostic according to the DSM III-R
      criteria, using a semi-structured interview. We completed the evaluation with
      socio-demographic data. The scale for the assessment of life events was the
      Paykel's scale. RESULTS: 58% of patients fulfilled the diagnostic of adaptation
      disorders. The anxiety disorders (14.28%) and depressive disorders (9.71%) come
      after. Compared with an age and socio-demographic data matched conscript group
      without psychiatric disorders, it seems that the patients experienced twice as
      much events during the year preceding the enrollment than the control-group
      (respectively 6.92 and 3.65). In term of quality, the results show more events
      related to interpersonal conflict (inadaptation in family, affective relation or
      professional field). Whereas the events related to recent separation, the major
      events life; decrease, serious illness and the maternal loss were similar in both
      groups. CONCLUSION: Those data suggest that there is a relationship between
      excess of life events and personality disorders, which may explain the
      inadaptation in the military service. Some recent factors of stress could
      represent a risk of psychiatric disorders occurring during the military service.

PMID- 12404781
TI  - [Suicide attempts in Brittany (France). Distribution at the regional level].
AB  - A prospective study on para-suicide has been conducted in all 4 "departements" of
      a french region, Brittany. This paper analyses the distribution of the
      sociodemographic data collected in one of the "departement" of the region, Ille
      et-Vilaine. The comparison between urban and rural areas is presented. METHODS: 
      INCLUSION CRITERIA: Parasuicide was defined as any autoaggressive act which
      required to be taken in charge either medically or surgically, independently of
      the nature and seriousness of the somatic consequences. Patients included in the
      study were over ten years of age. ANALYSIS: Three types of ratios have been
      calculated: the crude incidence ratios obtained by dividing the total number of
      events of parasuicide (including repeated admissions for the same individual) by
      the number of individuals in the catchment area; the age-specific ratios, for
      which the denominator consists of all the persons of particular age-group in the
      area and the standardized ratios, for which the total number of parasuicide
      events in each "departement" has been reported to the french population (general
      population census 1990) taken as a reference, in order to eliminate the influence
      of the age structure. Comparisons between the general population and the one of
      parasuicidal patients in the area, were done using a chi-square test.
      GEOGRAPHICAL COMPARISON: Crude incidence rates of parasuicides calculated for
      each "departement" in Brittany are compared with recent figures published for
      other parts of France. RESULTS: 2,040 persons domiciled in the "departement" were
      admitted in one of the emergency wards of Ille-et-Vilaine during the year 1990.
      The crude incidence rates of parasuicides in Ille-et-Villaine was of 2.4/1,000
      for men and 3.8/1,000 for women, 3.7/1,000 for men and 5.4/1,000 for women
      residing in the town of Rennes. The sex ratio is 1.8 female/male in the
      "departement" and 1.7 in town. DEMOGRAPHIC DATA: In the male group, the incidence
      ratio was maximum for the 25-34 years old (4.2/1,000). In the female group, there
      was no significant difference between the ratio for the 15-24 and the 25-34 years
      old (5.9/1,000). For each age group, the ratios are higher for the women. The
      specific rates of parasuicide calculated in the breton towns of more than 50,000
      inhabitants are twice as high as those calculated for the whole region. MARITAL
      STATUS: The marital status is correlated to the incidence rates of parasuicide
      events for both sexes (p < 0.001). The incidence of parasuicide is higher for
      married, single and/or divorced women than for men. One notes the high impact of
      divorce on parasuicide events for men (10.1/1/1,000) and women (11.8/1,000). The
      correlation is significative (p < 0.001). In contrast, rates of parasuicides are
      higher for widows than for widowers. OCCUPATION: The incidence rate of
      parasuicide is 8 times higher for unemployed men and twice as high for unemployed
      women than for those having an occupation (regular or temporary). Unemployment is
      significatively linked with the occurrence of parasuicides (p < 0.001). PLACE OF
      ABODE: Comparative rates in towns (calculated for both sexes together) and twice
      as high as those observed in rural districts. GEOGRAPHICAL COMPARISON: The crude
      incidence rates in various french "departement" vary from 0.8 to 2.4/1,000 for
      men and from 1.7 to 3.8/1,000 for women. The highest rates are observed for both
      sexes in Ille-et-Vilaine. In Rennes, the standardized ratios of parasuicide among
      men are maximum for the 35-44 years old (7.68/1,000) and decrease drastically
      after the age of 45. Among the women, the ratios are nearly identical for the 25
      34 and the 35-44 years old (9.90 and 9.87/1,000). CONCLUSION: The survey
      conducted in 1990 confirms the overall conclusions drawn in previous surveys on
      parasuicide in France or in other countries. The distribution of the incidence
      rates of parasuicide among single and unemployed and the percentages of single or
      unemployed persons is weak but not at random. An increase of the incidence rates
      among single women and unemployed men is concomitant with higher percentages of
      single women and unemployed men in the general population. One cannot infer the
      existence of a cause effect relationship, and these indicators may only be
      confounding factors.

PMID- 12404782
TI  - [New anxiolytic drugs: methodological issues].
AB  - Compared to benzodiazepinic anxiolytics, new anxiolytic drugs are supposed to
      have a comparable efficacy, but a better profile of safety (abuse liability,
      rebound effects, cognitive impairment, sedative effects for example).
      Methodological issues concerning the development of new anxiolytic drugs are
      numerous: The diagnostic definition and classification of "Anxiety Disorders"
      (DSM, ICD) remain discussed and regularly revised. Anxiety disorders, while being
      heterogeneous, often occur in combination with each other or with depression and
      anxiety appears to be an ubiquitous component of most psychiatric disorders.
      Studies of new anxiolytic drugs use to assess their efficacy and safety. In most
      cases, those studies are double-blind, randomized, parallel-group studies versus
      placebo and reference drug. Usually, the reference drugs remain benzodiazepinic
      anxiolytics. It would be interesting to develop trials comparing new anxiolytics
      with each other and with non-pharmacological therapeutics, to improve therapeutic
      strategies in anxiety disorders. But, in this topic, a lot of methodological
      difficulties remain unsolved. The choice of dosages may be difficult because dose
      ranging studies are not always available for the drugs and the anxiety disorders
      studied: it actually the lowest effective dose is not well known. Moreover, it
      could be more useful to study the therapeutic index of the drug. The duration of
      short and medium term studies, which are the most performed with anxiolytics, is
      about 4 to 12 weeks. The duration of long term studies is about 4 to 6 months.
      Those durations are empirically determined and might not always be appropriate.
      For clinical efficacy assessment, the choice of evaluation criteria is difficult
      because no tool is perfect. Then, a main criterion and several different criteria
      have to be chosen among anxiety rating scales, self rating scales and global
      ratings of psychopathology. Safety assessment of a new anxiolytic specifically
      use to focus on sedative effects, cognitive impairment, rebound effects and abuse
      liability. Several methods are interesting to assess abuse liability: for
      example, looking for a withdrawal syndrome (the most common), determining the
      profile of subjective effects of the drug using questionnaires and auto
      administration or discrimination studies. Sedative effects and cognitive
      impairment assessment use various batteries of tests. Concerning general
      assessment of side effects, both check-lists and open reporting have got
      advantages and drawbacks. Assessment intervals depend on the aim and the duration
      of the study: weekly in short-term studies and two-weekly or monthly in long-term
      studies. Those empirically determined intervals, which take into account the
      practical achievement of the studies, might not detect some drug effects. The
      number of subjects entering the study has to be determined before its beginning:
      about 30 to 40 subjects in each group in trials versus placebo and about 120 to
      150 subjects in each group in studies versus reference drug. Ethical and legal
      issues are important in clinical trials of new anxiolytics. The french law (Loi
      Huriet 1988) has introduced the necessity for investigators to obtain from
      subjects their informed and written consent for their participation in the study.
      Also, the representatively of subjects participating in new anxiolytics trials is
      a matter of concern. However, those difficulties and the requirements of french
      health department have not yet obstructed clinical research of new anxiolytic
      drugs, as shown by the number of new beginning studies.

PMID- 12404783
TI  - [Adaptation and French validation of physical anhedonia scale: PAS (Chapman and
      Chapman, 1978)].
AB  - This work presents the validation of the French version of the Physical Anhedonia
      Scale (PAS). The scale's validity, fidelity and reliability were studied in two
      groups: 61 normal subjects, 61 subjects who met RDC criteria for major depressive
      disorder. The internal consistency and reliability were determined by the Kuder
      Richardson coefficient (KR 20) which values were 0.7 in the control group and
      0.83 in the depressed group. The internal consistency was also studied by the
      correlation between each item and the PAS total score using the point biserial
      coefficient. 54 items on 61 showed a significant correlation coefficient which
      ranged from 0.18 to 0.59. For the concurrent validity we studied the correlation
      (Pearson correlation coefficient) between the PAS and the French version of the
      Fawcett-Clark Pleasure Capacity Scale (FCPCS). The values were -0.31 (p = 0.014)
      in the control group and -0.53 (p = 0.00001) in the depressed group. These values
      show the degree of correlation between the two measures of anhedonia. The French
      version of the PAS is reliable and allow us to study the physical anhedonia in
      psychopathology.

PMID- 12404784
TI  - [Short-term sequelae of lithium discontinuation].
AB  - It has long been considered that lithium therapy could be abruptly stopped
      because it was guessed that lithium salts did not induce withdrawal symptoms.
      However, several open and controlled studies have shown that lithium
      discontinuation was associated with a possible withdrawal syndromee and with an
      incontestable rebound effect. Lithium withdrawal symptoms have been described in
      some patients, but it is not easy to distinguish them from depressive or manic
      symptoms, because no specific somatic withdrawal symptoms have been observed. The
      most important risk related to lithium discontinuation is the early recurrence of
      bipolar illness. Especially, it has been shown that the risk of manic recurrences
      is increased in the first weeks after discontinuation of lithium therapy, and
      that this risk is higher than the one predicted by the natural history of the
      manic-depressive illness. Relapses can occur even when lithium is stopped only
      for a few days. Abrupt discontinuation of lithium seems to be associated with an
      increased risk of recurrence. The pathophysiology of this rebound effect is still
      unknown. In clinical practice, lithium discontinuation has to be gradual when
      possible. Further studies are needed to precise at what time the risk of lithium
      withdrawal syndromee develops after starting lithium therapy. It is also
      necessary to establish more precise clinical guidelines for lithium
      discontinuation.

PMID- 12404785
TI  - [Carbamazepine and aggressive behavior: a review].
AB  - Carbamazepine which has been used as an anticonvulsivant for many years, has more
      recently been advocated for the control of aggressive behavior in epileptic and
      non epileptic populations. Carbamazepine is the drug of choice for patients whose
      aggressive outbursts are related to epilepsy. It appears that carbamazepine may
      also be affective in aggressive individuals with varying diagnoses (especially
      schizophrenic patients) but additional double-blind studies are needed. Patients
      experienced good control of aggressive behavior on carbamazepine in doses of 600
      to 1,200 mg per day but the relationship of carbamazepine responsiveness to
      carbamazepine blood levels and concurrent medication (neuroleptic treatment)
      requires further studies. No significant problem has been encountered in the
      majority of patients receiving carbamazepine. However, it can rarely cause bone
      marrow suppression and hepatotoxicity so that blood counts and liver functions
      require monitoring.

PMID- 12404786
TI  - [Neuroleptic-induced movement disorders: historical perspectives].
AB  - Soon after the discovery of neuroleptics, neurological side effects of the
      extrapyramidal type were reported. The first description of neuroleptic-induced
      parkinsonism dates back to the "Swiss Symposium on Chloropromazine" held in 1953.
      Steck in 1954 vividly described the symptoms in a convincing manner. In 1955,
      Delay and Denicker, observing the therapeutic efficacy and extrapyramidal
      activity of two seemingly different compounds as chloropromazine and reserpine,
      used the term "neuroleptic" to characterize this common property. Two years later
      they proposed a definition of neuroleptics taking into account therapeutic
      efficacy as well as side effects. Such a definition was not accepted by American
      authors who preferred term like "major tranquilizers" and finally
      "antipsychotics". The meaning of neuroleptic parkinsonism (whether it was a side
      effect or part of the therapeutic action) had been discussed for a long time. The
      analogy with the clinical manifestations of Von Economo's encephalitis lethargica
      was also mentioned. Tardive dyskinesia appeared in the literature in the late
      1950's. The first report was made by Schoenecker in 1957 who described bucco-oral
      movements persisting after the neuroleptics were diminished or discontinued. He
      concluded that these manifestations were different from the acute extrapyramidal
      side effects. Two years later Sigwald et al. reported involuntary movements of
      the tongue, lips and facial muscles which appeared after several years of
      phenothiazine treatment. In 1960 Uhrbrand and Faurbye described bucco-linguo
      masticatory movements sometimes associated with trunk and foot movements. Half of
      these cases persisted (and a few aggravated) after neuroleptic withdrawal. In
      others the condition was unmasked by the neuroleptic discontinuation. In 1964
      Faurbye et al. proposed the term "tardive dyskinesia" for this extrapyramidal
      side effect. After an initial description by Druckman et al. in 1962, the term of
      "tardive dystonia" was first used in 1973 by Keegan and Rajput. The patients
      described in the early literature were mainly of an advanced age with organic
      involvement. The first serious epidemiological studies were undertaken in the
      late 1960's, showing prevalences varying between 0.5 to 65%! Most of the
      predisposing factors suspected in early studies (cerebral lesions, lobotomy, ECT)
      were not confirmed in more recent studies that emphasized the role of an older
      age and a female gender. The interest in tardive dyskinesia varies from one
      country to another. Perhaps, dyskinesia was more severe and problematic in the
      USA because of more liberal indications for neuroleptic use, higher doses and
      smaller choice of neuroleptic medications. Medicolegal aspects have also
      increased the apprehension of american physicians. Tardive dyskinesia remains an
      enigmatic phenomenon and a therapeutic challenge. In the future, the possible
      discovery of antipsychotic molecules devoid of extrapyramidal side effects may
      discourage the research on these unresolved issues.

PMID- 12404787
TI  - [Tolerance to monoamine oxidase inhibitors. A case report of tolerance of
      nialamide and moclobemide].

PMID- 12404788
TI  - [Neuropsychiatric manifestation of lupus: etiopathological complexities and
      difficulties of costs].

PMID- 12404789
TI  - [Do neuroleptics take part in the treatment of AIDS? The role of the association
      of sultopride-AZT in the proliferation of CD4 lymphocytes among patients treated
      for AIDS: a report of two cases].

PMID- 12404790
TI  - GHA raises curtain on statewide media campaign.

PMID- 12404791
TI  - And now it's time for the rest of the story.

PMID- 12404792
TI  - Sonochemical synthesis of mesoporous transition metal and rare earth oxides.
AB  - Straight-extended layered mesostructures based on transItion metal (Fe, Cr) and
      rare earth (Y, Ce, La, Sm, Er) oxides are synthesized by sonication for 3 h.
      After a longer period of sonication (6 h), hexagonal mesostructures based on Y-
      and Er-oxides are obtained. The surface areas of the Y-based hexagonal mesophases
      before and after extraction are 46.5, 256 m2/g, respectively. For Er-based
      hexagonal mesophases, the surface areas before and after extraction are 157 and
      225 m2/g. The pore sizes after extraction are 5.0 and 2.2 nm for Y- and Er-based
      mesophases, respectively. Hexagonal mesostructures are also obtained for Zr-based
      material after sonication for 3 h and the hexagonal structure is still maintained
      after calcinations at 400 degrees C for 4 h, although the surface area is only 35
      m2/g.

PMID- 12404793
TI  - Sonolysis of chlorobenzene in Fenton-type aqueous systems.
AB  - The influence of ultrasounds (200 kHz frequency) on the decomposition of
      chlorobenzene (CB) in a water solution (around 100 ppm concentration) containing
      iron or palladium sulfates was investigated. The intermediates of the sonolysis
      were identified, thus allowing a deeper insight into the degradation mechanism.
      It was established that CB degradation starts by pyrolysis inside the cavitation
      bubbles. The initial sonolysis product is benzene, formed in a reaction occurring
      outside the cavitation from phenyl radicals and the hydrogen atoms sonolytically
      generated from the water. Polyphenols as products of the CB sonochemical
      degradation are reported for the first time. The palladium salt was found to be a
      useful and sensitive indicator for differentiating the sites and mechanisms of
      the product formation. An alternative mechanism for the CB sonolysis is advanced,
      explaining the formation of phenols, polyphenols, chlorophenols and benzene.

PMID- 12404794
TI  - Surface acoustic cavitation understood via nanosecond electrochemistry. Part III:
      Shear stress in ultrasonic cleaning.
AB  - Acoustic cavitation is extensively used for cleaning purposes. However, little is
      known about the fundamental aspects of the cleaning process. Our previous
      electrochemical data suggested that acoustic bubbles were oscillating at a
      distance of only a few tens of nanometers above the surface [J. Phys. Chem. B 105
      (2001) 12,087; E. Maisonhaute, B.A. Brookes, R.G. Compton, J. Phys. Chem. B 106
      (2002) 3166-3172]. The flow velocities resulting from the bubble collapse lead to
      important drag and shear forces on the surface, responsible for cleaning and/or
      eroding the latter. We review here the forces acting on an adsorbed particle
      located on the surface, and develop arguments to explain why small adsorbates are
      harder to remove by sonication. Then, experimental results on particle desorption
      and surface effects brought about by ultrasound are presented and shown to agree
      with our theoretical predictions.

PMID- 12404795
TI  - Ultrasonic power measurements in the milliwatt region by the radiation force
      float method.
AB  - The radiation force float technique is extended in the present investigation, for
      the determination of the total radiated low ultrasonic power in the milliwatt
      region. It is elucidated, experimentally, using floats having a conical
      reflecting target comprising of new material (teflon insulated copper wire) stems
      with smaller diameters (0.55 and 1 mm). The sensitivity is improved with these
      two stems and the ultrasonic power levels are measured in the range from 1.4 to
      140 mW and 4.6 to 460 mW respectively and the results are reproducible within +/-
      5%. Limitations of float technique and factors influencing the uncertainties
      involved for the high quality ultrasonic power measurements are discussed. The
      proposed method is simple, versatile and inexpensive and can be used as an
      interim standard.

PMID- 12404796
TI  - Formation of vesicle-templated CdSe hollow spheres in an ultrasound-induced
      anionic surfactant solution.
AB  - Hollow sphere of CdSe with size of approximately 100-200 nm can be templated from
      anionic surfactant sodium dodecyl sulfate (SDS) vesicles induced by the
      ultrasonic irradiation. The successful vesicle templating indicated that the
      outer leaflet of the bilayer is the receptive surface in the controlled growth of
      CdSe nanoparticles, which provide the unique reactor for the nucleation and
      mineralization growth of CdSe nanoparticles. The products were characterized by
      XRD, TEM, and HRTEM techniques. UV-vis spectrum recorded the optical properties
      of CdSe hollow spheres (2.01 eV), which showed an obvious blue shift relative to
      the bulk cubic CdSe (1.73 eV). Surfactant molecules (SDS) passivated in the CdSe
      hollow spheres were completely extracted, as determined by thermal gravimetric
      analysis (TGA). Systematic studies found that the ultrasound irradiation and
      concentration of surfactant (SDS) in the system were important factors on the
      controlled synthesis desired hollow sphere morphologies, and also the temperance
      have an importance influence on the mineralization and crystallization of the
      CdSe hollow spheres. Based on the observation on morphological difference of CdSe
      in different systems, the possible mechanism for the formation of CdSe hollow
      spheres was discussed.

PMID- 12404797
TI  - Kinetics and mechanisms of ultrasonic degradation of volatile chlorinated
      aromatics in aqueous solutions.
AB  - Ultrasonic decompositions of chlorobenzene (ClBz), 1,4-dichlorobenzene and 1
      chloronaphthalene were investigated at 500 kHz in order to gain insight into the
      kinetics and mechanisms of the decomposition process. The disappearance of ClBz
      on sonication is almost simultaneously accompanied by the release of chloride
      ions as a result of the rapid cleavage of carbon-chlorine bonds with a
      concomitant release of CO, C2H2, CH4 and CO2. The intermediates resulting from
      attack of HO. radicals were detected but in a quite low yield (less than 2
      microM). The generation of H2O2 on sonolysis is not significantly affected by the
      presence of aqueous ClBz while the generation of NO2- and NO3- is inhibited
      initially due to the presence of ClBz which diffuses into the gas-bubble
      interfaces and inhibits the interactions between free radicals and nitrogen.
      Moreover, brown carbonaceous particles are present throughout the ultrasonic
      irradiation process, which are consistent with soot formation under pyrolytic
      conditions. These important features suggest that, at the relatively high initial
      substrate concentrations used in this study, ultrasonic degradation of ClBz takes
      place predominantly both within the bubbles and within the liquid-gas interfaces
      of bubbles where it undergoes high-temperature combustion. Under these
      conditions, the oxidation of ClBz by free radical HO. outside of bubbles is a
      minor factor (though results of recent studies suggest that attack by HO. is more
      important at lower initial substrate concentrations). The sonochemical
      decomposition of volatiles follows pseudo-first-order reaction kinetics but the
      degradation rates are affected by operating conditions, particularly initial
      substrate concentration and ultrasonic intensity.

PMID- 12404798
TI  - Time-evolving statistics of cavitation damage on metallic surfaces.
AB  - The statistics of surface damage on polycrystalline aluminium plates caused by
      acoustic cavitation is studied experimentally as a function of time. Cavitation
      is shown to produce a uniform distribution of crater-like holes with different
      depth, area and eccentricity. Most notably, the size distribution of such craters
      evolves with time from a gamma function into a power law. By contrast, on the
      surface of a martensitic Cu-Ni-Al crystal cavitation damage generates ramified
      patterns, reminiscent of a fractal object.

PMID- 12404799
TI  - [Ettore Biocca, an unattainable example of life].

PMID- 12404800
TI  - [The publications of Ettore Biocca].

PMID- 12404801
TI  - [The Emile Brumpt Prize].

PMID- 12404802
TI  - [Remembrance of Ettore Biocca].

PMID- 12404803
TI  - [Ettore Biocca as anthropologist].

PMID- 12404804
TI  - [Professor Ettore Biocca and the University of Turin].

PMID- 12404805
TI  - Remembrances. Ettore Biocca: his activities in the "Consiglio Superiore di
      Sanita".

PMID- 12404806
TI  - [The political passion of Ettore Biocca].

PMID- 12404807
TI  - Historical outline of the World Federation of Parasitologists from 1961 to 1986.

PMID- 12404808
TI  - Novel and challenging infections of man. A brief overview.
AB  - The greatest challenge to human health of recent times is the pandemic caused by
      the retroviruses known as HIV1 and HIV2. These have unleashed a plethora of
      opportunistic infections with organisms ranging from other viruses to helminths,
      some of which are newly recognised taxa or organisms never before identified as
      serious pathogens of man. Animal and bird migration as well as human travel and
      international trade have extended, to an alarming degree, the dissemination of
      other viral infections. Malaria is an increasing global challenge to human
      health, a reversal of the downward trend that was achieved in the latter half of
      the 20th century. Moreover, evidence is currently accumulating for the existence
      of a fifth species of Plasmodium in man. In the bacterial and protozoal fields,
      other novel organisms are being described. Powerful new tools of molecular
      biology are being deployed to probe parasite genetics, for example to reveal the
      genome of Plasmodium falciparum. These and molecular immunological techniques are
      also helping to resolve puzzling taxonomic questions, as well as aiding
      epidemiological studies that are revealing the unforeseen scale of human
      infection with a number of parasitic helminths in both tropic and temperate
      climatic areas. This paper presents a brief review of the major, as well as some
      of the relatively minor changes and advances of recent decades.

PMID- 12404809
TI  - Cystic echinococcosis and the Mediterranean Region: a long-lasting association.
AB  - Cystic echinococcosis (CE) is an important zoonosis in Italy and in the whole
      Mediterranean Region, as confirmed by the work by Ettore Biocca, whose
      contributions to the subject are reported in a summarised annex to the
      bibliography. The contribution to the understanding and control of CE are
      presented, with special emphasis on the socio-economic impact, on factors
      affecting the maintenance of CE in the Mediterranean Region, on the
      epidemiological situation and control measures, on the present status of
      epidemiological surveillance, on the control problems in normal and emergency
      situations, on health education and training. Also, the justifications of
      combined control programmes are discussed, which may be applied only in
      situations of peace and well-being.

PMID- 12404810
TI  - Allintoshius bioccai n. sp. (Nematoda), a parasite of the bat Eptesicus furinalis
      from Paraguay, and new data on A. parallintoshius (Araujo, 1940).
AB  - A new species of parasitic nematode (Nematoda: Trichostrongylina,
      Heligmosomoidea) Allintoshius bioccai n. sp., found in the small intestine of the
      vespertilionid bat Eptesicus furinalis from Paraguay, is described. The new
      species can be differentiated from A. urumiac (Freitas and Mendonca, 1960) by the
      absence of vulvar spines in females, and from A. nudicaudus (Freitas and
      Mendonca, 1963) by the shape of the spicules and the dorsal ray of the copulatory
      bursa. New data on the morphology and distribution of Allintoshius
      parallintoshius (Araujo, 1940) are also reported. E. furinalis, Myotis albescens
      and M. riparius are recorded as new hosts for this species. A key for the
      identification of the species belonging to the genus Allintoshius is also given.

PMID- 12404811
TI  - Mark-release-recapture of sand flies fed on leishmanial dogs: the natural life
      cycle of Leishmania infantum in Phlebotomus ariasi.
AB  - Wild-caught Phlebotomus ariasi Tonnoir permitted to feed on dogs infected with
      Leishmania infantum Nicolle were marked with fluorescent powder and released into
      their natural habitat in an uninhabited area of the Cevennes in southern France.
      Over a period of 29 days after release, 253 females were recaptured with CDC
      miniature light traps or by active search at night with portable UV lamps. The
      ovaries and infections in the alimentary tract were then examined. The females
      oviposited 6 nights after in infecting blood meal. Second blood meals were never
      taken during the maturation of eggs. During the first ovarian cycle, midgut
      infections with promastigotes were only moderately heavy. The intensity of
      infection increased markedly during the second ovarian cycle and, in the third
      ovarian cycle, the first pharynx infected with paramastigotes was seen (on day
      19). From day 19 to day 29, 76% of the flies had pharyngeal infections. Three out
      of 19 sand flies with pharyngeal infections recaptured during this period had
      metacyclic promastigotes in their mouthparts. The long time required for
      parasites to reach the proboscis in completely natural conditions suggests that
      their presence in the mouthparts is not a prerequisite for transmission by bite.
      It is more likely that transmission is most commonly by the regurgitation of
      metacyclic promastigotes from the thoracic midgut following damage to the
      stomodaeal valve by chitinase produced by the parasite during its development in
      the gut of the fly. Nevertheless, it is reasonable to assume that the bite of a
      fly with metacyclic promastigotes in the proboscis (or salivary glands) would
      also be infective.

PMID- 12404812
TI  - Distribution, density and migration dynamics of Ixodes ricinus in an area of the
      Jurassic mountains of Switzerland.
AB  - In an area of the Jurassic mountains of Switzerland ecological aspects of the
      tick species Ixodes ricinus were studied. In particular, the influence of
      temperature, humidity and vegetation parameters on tick density and distribution
      were investigated several times in six different habitat types. This was carried
      out on two scales; on a small scale, within a habitat type and on a larger scale,
      where all six habitat types were included. By a marking experiment, aspects of
      the migration dynamics of the ticks were studied. The densities of the six
      habitat types differed significantly in most of the cases. An analysis of the
      distribution pattern within a habitat type showed a contagious distribution
      mostly for the forests and the forest edge, whereas a random distribution was
      found as well, mainly for the meadows. But these distribution patterns tend
      towards randomness with time. On a small scale none of the factors showed an
      influence on tick distribution, therefore the most important factor on this scale
      might be the hosts of Ixodes ricinus. On a larger scale, temperature and humidity
      do in some cases influence tick densities. The marking experiment suggests an
      extremely high turnover of the ticks in an area with an average host density,
      probably due to passive transportation by hosts and to activation of resting
      individuals.

PMID- 12404813
TI  - Australian hookworms (Ancylostomatoidea): a review of the species present, their
      distributions and biogeographical origins.
AB  - Ancylostomatoidea or hookworms recorded in Australia are reviewed and the attempt
      is made to provide the biogeographical background to their occurrence. The poor
      representation of this nematode superfamily is probably a reflection of the fact
      that they are primarily parasites of Carnivora, Artiodactyla, Insectivora,
      Rodentia, Edentata, Proboscoidea and primates, eutherian mammals which are either
      absent from the Australian fauna or which have only recently reached the
      continent. The principal genera of hookworms recorded to date from Australia are
      Ancylostoma, Bunostomum, Necator and Uncinaria. The majority of the
      ancylostomatoid fauna is represented by introduced species of man and domestic
      animals. Native or endemic species of hookworms are restricted to members of the
      genus Uncinaria with two species occurring in rodents and pinnipeds. Only a
      single endemic species of hookworm is known, U. hydromyidis, which is found in
      the small intestine of a rat. Significant problems remain in understanding the
      systematics, epidemiology and evolutionary relationships of the Australian
      ancylostomatoid fauna.

PMID- 12404814
TI  - First account on the larval biology of a Litomosoides filaria, from a bat.
AB  - Litomosoides filariae are parasites of unrelated groups of hosts, including bats,
      marsupials, ancient and modern rodents. The four life cycles to-date elucidated,
      develop in terrestrial mammals and, at least experimentally, in the mite
      Ornithonyssus bacoti. A batch of mites was fed on an infected bat, Artibeus
      jamaicensis captured in Costa Rica, and 18 days later one infective larva was
      recovered. Its morphology was similar to that of other Litomosoides species, with
      the characteristic long buccal capsule. These first accounts on the larval
      biology of Litomosoides from Microchiroptera confirm the unity of the genus which
      supports the view that it has passed from one group of hosts to another by means
      of captures.

PMID- 12404815
TI  - Human dirofilariasis in Italy: a new case in the spermatic cord.
AB  - A new case of human dirofilariasis associated with Dirofilaria (Nochtiella)
      repens (Nematoda, Filarioidea, Onchocercidae) located in the spermatic cord is
      reported in a 71-year-old man from the province of Campobasso (Central Italy).
      When clinical signs pointed to a testicular tumor, a monolateral
      orchifuniculectomy was performed. According to the scientific literature, this
      case appears to be exceptional in its location, being only the eighth such case
      recorded in the world until now. The nematode, as well as the presence of vectors
      suitable for its transmission, had already been observed both in dogs and in
      humans (3 subcutaneous cases) in the same geographical area.

PMID- 12404816
TI  - Two new species of Nippostrongylinae (Nematoda, Trichostrongylina) parasites of
      Cricetomys gambianus and Arvicanthis niloticus (Muridae) from Senegal.
AB  - Two new Nippostrongylinae (Heligmosomoidea, Heligmonellidae) originating from
      Senegal are described. Heligmonina bioccai n. sp., a parasite of Cricetomys
      gambianus (Cricetomyinae) found in the surroundings of Dakar and Neoheligmonella
      bai n. sp., a parasite of Arvicanthis niloticus (Murinae) from the Province of
      Richard Toll. H. bioccai n. sp. is related to H. hybomysi (Durette-Desset, 1966)
      a parasite of Hybomys univittatus from the Central African Republic by some
      characteristics of the caudal bursa and of the synlophe. They are the only two
      species with the same pattern of caudal bursa: type 1-3-1 for the right lobe, 2-3
      for the left lobe, and with the same number and disposition of the cuticular
      ridges at mid-body in the female. The two species are differentiated by the size
      (three times smaller in H. hybomysi), the ratio of spicule length on body length
      (7.6% versus 17% in H. hybomysi) and by a different synlophe in male and
      posterior part of female. N. bai n. sp. is differentiated from the closely
      related species N. dielmensis Diouf, Ba and Durette-Desset, 1997, also a parasite
      of Arvicanthis niloticus from Senegal by rays 8 arising asymmetrically on the
      dorsal ray and by the deirids situated at the same level as the excretory pore.

PMID- 12404817
TI  - Recent findings of Phlebotomus neglectus Tonnoir, 1921 in Italy and its western
      limit of distribution.
AB  - During the sand fly season of 2001, sand flies were collected in two different
      regions of Italy to investigate the northern distribution of Phlebotomus
      neglectus. The study areas were two provinces of northern Italy, Ivrea and
      Verona, in Piedmont and Veneto regions respectively. Sticky traps and CDC
      miniature light traps were used both inside and outside domestic and peri
      domestic environments. Sand flies were also collected in domestic resting sites
      with mouth and electric aspirators. Of 1,295 sand fly specimens collected, 855
      were from the Veneto region and 440 were from the Piedmont region. Five species
      of the genera Phlebotomus and Sergentomyia were identified. S. minuta (66.3%) was
      the most abundant sand fly followed by P. perniciosus (22.2%), P. neglectus
      (10.3%) and P. papatasi (1.2%). Only one specimen of P. mascittii was caught in
      Piedmont region. P. neglectus was found in 9 out of 15 (60%) of the sites where
      sand flies were found with a prevalence of 1.5% to 45.8%; the highest value was
      recorded in Piedmont region. P. neglectus was mostly associated with peridomestic
      and domestic sites. The results confirm previous observations on the presence of
      P. neglectus in northern Italy and suggest that this species is probably
      widespread in the area. From a review of all previous published and unpublished
      records of P. neglectus, it appears that this species is present in only two
      areas of the country, namely in the regions of Friuli Venezia Giulia, Veneto and
      Piedmont in northern Italy and the regions of Calabria, Apulia and Sicily in
      southern Italy. The apparent absence of P. neglectus in Central Italy is
      discussed and the resulting settlement through two probable migration routes from
      the East is analysed.

PMID- 12404818
TI  - Parasitic pattern of rodent Plasmodium in blood from mouse tail and from
      Anopheles blood meal.
AB  - During the course of the infection of mice by rodent malaria parasites (P. yoelii
      yoelii, P. vinckei petteri, and P. chabaudi chabaudi) the parasitic pattern in
      the blood smears differed according to the site of sampling: mosquito blood meal
      (usually actively sucked from capillaries) or mouse tail (issued from larger
      vessels). There were fewer old trophozoites and mature schizonts, and more
      immature schizonts, in the mosquito blood meal than in the tail blood of mice. It
      is suggested that the erythrocyte containing a schizont becomes less rigid when
      merozoites formation begins. The greater abundance in the mosquito blood meal of
      the gametocytes infective stage (0-I for P. yoelii, II for P. vinckei),
      previously shown, could be due to a particular flexibility of this stage, a
      character progressively selected.

PMID- 12404819
TI  - Loose ends: axenic culture, parasitophorous vacuoles, bird malaria.
AB  - The successful extracellular cultivation of the erythrocytic stages of Plasmodium
      falciparum is briefly summarized, with a discussion of its implications. This
      leads to consideration of the roles of the parasitophorous vacuole and its
      membrane and of the tubulo vesicular network. It is concluded that these
      structures are mainly concerned with modification of the host erythrocyte for the
      benefit of the parasite. Requirements for additional nutritional factors under
      axenic culture conditions are also considered with special reference to
      erythrocyte membrane protein and to pantothenate. Finally, attention is given to
      speculations on the origin of P. falciparum.

PMID- 12404821
TI  - Contraception. We've come a long way.

PMID- 12404820
TI  - The bloodsucking arthropod bite as possible cofactor in the transmission of human
      herpesvirus-8 infection and in the expression of Kaposi's sarcoma disease.
AB  - Based on a review of the literature on human herpesvirus-8 (HHV8) and Kaposi's
      sarcoma (KS) and on the distribution of KS in Italy (Veneto region particularly),
      we hypothesize that the bite of bloodsucking arthropods is a cofactor in the
      seroconversion to HHV8 positivity and probably in the pathogenesis of KS. The
      bloodsucking arthropod releases with saliva powerful antihaemostatics and
      immunomodulators which may favour the replication and the establishment of the
      pathogen. Transmission would depend on the close contact of the child with a
      seropositive mother (or relatives) whose infective saliva is used to relieve
      itching and scratching at the arthropod bite's sites. During any deregulation of
      the immune system (e.g. ageing), local immune responses to new insect bites may
      induce virus activation which could prelude KS insurgence. The pathogen is not
      directly transmitted by the arthropod which merely prepares the cutaneous
      microenvironment for the virus. We have therefore introduced a new category of
      medically important arthropods, "promoter arthropods", besides those already
      defined as biological or mechanical vectors. Promoter arthropods are species able
      to induce in the host long-lasting, immediate or delayed-type hypersensitivity
      responses as well as local immunosuppression due to substances injected with
      their saliva. The striking variability of ORF-K1 gene of HHV8 could be due to the
      adaptation of the virus to the specific microenvironments resulting from the
      immune response to the salivary antigens characteristic of the bloodsucking
      arthropod species prevalent in each geographical area. It is worth noting that
      other viruses (especially Hepatitis B Virus) may exploit the same non-sexual
      transmission route.

PMID- 12404822
TI  - Antiherpes zoster treatment.

PMID- 12404823
TI  - Antiherpes zoster treatment.

PMID- 12404824
TI  - History of medicine series--the development of the RACGP.

PMID- 12404825
TI  - Oral contraceptives.
AB  - BACKGROUND: There are a plethora of different combined oral contraceptive (COC)
      formulations marketed in Australia, containing variable doses of
      ethinyloestrodiol and different progestogens, which clinically may have different
      effects. The number available will be further increased as new preparations are
      marketed. OBJECTIVE: This article aims to provide guidelines to assist general
      practitioners in prescribing COCs for women with different clinical conditions
      and needs. DISCUSSION: Although for the majority of healthy women who take COCs,
      any low dose combined pill will be appropriate, women with risk factors or
      certain conditions such as epilepsy need to be given careful consideration when
      prescribing. Venous thromboembolism, although rare, is the commonest serious side
      effect associated with COC use. The risk increases with age, obesity, smoking,
      and a variety of medical conditions. These women need to be advised of the risk
      associated with different progestogens and be involved in the decision about
      which pill to take.

PMID- 12404826
TI  - Implanon. The new alternative.
AB  - BACKGROUND: It is a long time since Australian women have had any new
      contraceptive choices available to them. In May 2001, the new progestagen only
      hormone implant Implanon (containing etonogestrel) was introduced, providing an
      effective, long term contraceptive option which has few serious adverse effects.
      OBJECTIVE: By attending training, doctors can become familiar with the clinical
      profile of etonogestrel and the techniques involved with its insertion and
      removal. Only then can they counsel women on its use, select appropriate users,
      plan the correct timing of insertion and become skilled in the techniques
      involved. DISCUSSION: Etonogestrel is a well tolerated, third generation
      progestagen. The implant provides reversible contraception to women across the
      reproductive age range. There have been few problems with its use and those
      problems seen have been related to intolerance of progestogenic side effects,
      poor patient selection and counselling, inappropriate timing of insertion or
      incorrect insertion techniques.

PMID- 12404827
TI  - Take a fresh look at IUDs. Things have changed.
AB  - BACKGROUND: Over the past few years, the intrauterine contraceptive device (IUD)
      has overcome many of the problems that had initially made it unpopular. Today it
      is probably the most cost effective reversible form of contraception available.
      OBJECTIVE: To examine the reasons for poor utilisation of IUDs in Australia and
      to describe recent developments in the field of intrauterine devices/systems.
      DISCUSSION: Myths concerning mechanisms of action and the potential for pelvic
      inflammatory disease, lack of familiarity, training and high insurance costs
      continue to limit the ability of general practitioners to fully utilise the
      potential of IUDs. The introduction of the levonorgestrel releasing intrauterine
      system has however, broadened the indication for IUDs from just being
      contraceptive to being therapeutic for several gynaecological conditions.

PMID- 12404828
TI  - Emergency contraception.
AB  - BACKGROUND: Humans have long sought an effective method of contraception that
      could be utilised after unprotected sex. OBJECTIVE: This article aims to examine
      the range of available emergency contraceptive options, with particular emphasis
      on the advantages of progestogen only emergency contraception over the combined
      regimens advocated in the past. DISCUSSION: The recent release of the first
      commercially packaged emergency contraceptive regimen on the Australian market
      has refocussed attention on this important public health issue. The widespread
      adoption of effective emergency contraceptive regimens has the potential to
      reduce the rate of unplanned pregnancy and termination of pregnancy in Australia.
      This article aims to discuss available regimens, their mode of action and
      existing barriers to use, and controversies such as over-the-counter supply of
      emergency contraception.

PMID- 12404829
TI  - Emergency contraceptive pill. Managing risk associated with unprotected sexual
      intercourse.
AB  - This document is an independent statement about emergency contraception developed
      by the RACGP in collaboration with the Drug and Therapeutics Information Service
      (DATIS).

PMID- 12404830
TI  - Guidelines for the treatment of postmenopausal osteoporosis for general
      practitioners.
AB  - BACKGROUND: Osteoporosis Australia has been committed to the education of general
      practitioners and the community with a series of updated guidelines on the
      management of osteoporosis. Since the last series was published in Australian
      Family Physician (August 2000), there have been further advances in our
      understanding of the treatments involved in both prevention of bone loss and the
      management of established osteoporosis. OBJECTIVE: This article represents
      updated guidelines for the treatment of postmenopausal osteoporosis to assist GPs
      identify those women at risk and to review current treatment strategies.
      DISCUSSION: Osteoporosis and its associated problems are major health concerns in
      Australia, especially with an aging population. While important principles of
      management are still considered to be maximising peak bone mass and preventing
      postmenopausal bone loss, new clinical trial data about drugs such as the
      bisphosphonates, raloxifene and oestrogen have recently become available and the
      relative role of various agents is gradually becoming clearer. The use of long
      term hormone replacement therapy has mixed risks and benefits that requires
      individual patient counselling.

PMID- 12404831
TI  - A growing dilemma--breast cancer and pregnancy.
AB  - BACKGROUND: Breast cancer and pregnancy are events that have an enormous impact
      on the lives of women. When these events are associated they become a highly
      emotive issue with possible devastating consequences. OBJECTIVE: While
      information on breast cancer is widely available, much less is reported on the
      association between breast cancer and pregnancy. This article reviews the
      available evidence on which general practitioners can base their management of
      women with gestational breast cancer or breast cancer survivors who may want to
      conceive. DISCUSSION: Breast cancer can be diagnosed during pregnancy or in the
      12 months postpartum (including lactation), known as gestational breast cancer or
      pregnancy associated breast cancer. Previous treatment for breast cancer may have
      detrimental effects for women who subsequently conceive or wish to conceive.
      General practitioners, as the primary care giver, have an integral role in the
      successful education, management and support of these women.

PMID- 12404832
TI  - Contraception failure and wrongful birth claims.
AB  - Case histories are based on actual medical negligence claims, however, certain
      facts have been omitted or changed by the author to ensure the anonymity of the
      parties involved. Medical negligence claims involving an allegation or 'wrongful
      birth' can arise from a negligent failure of contraception. In these wrongful
      birth claims, the patient sues the medical practitioner who failed to prevent her
      conception and subsequent pregnancy. This article outlines some risk management
      strategies for general practitioners to minimise the possibility of a claim
      arising from a failure of contraception involving the use of the long acting
      contraceptive implant, Implanon.

PMID- 12404834
TI  - Test your knowledge: breathlessness with cough and fever.

PMID- 12404833
TI  - The immunisation cold chain. Why is it so hard to get right?
AB  - BACKGROUND: Although the standards for vaccine storage required for accreditation
      of general practices, and the Guidelines for Australian Immunisation are widely
      available, all research to date suggests that in Australia compliance with these
      standards has not been readily achieved. OBJECTIVE: The New South Wales Central
      West Division of General Practice (NSWCWDGP) and the Public Health Unit of the
      New South Wales Mid Western Area Health Service (NSW MWAHS) worked together from
      1999 to 2001 to produce an intervention that would gather information about
      current vaccine storage, and provide practical help to storage sites which were
      not complying with accepted standards. DISCUSSION: Cooperation between a general
      practice division and the public health unit can deliver coverage of 100% of
      vaccinators in a large geographic region. We have demonstrated that the lack of a
      designated person to take on ultimate responsibility for vaccines at a site is
      associated with less chance of achieving safe storage. Persistent difficulty in
      'getting it right' has been documented. One new measure we have suggested and
      trialled is the installation of affordable commercial thermostats in the domestic
      refrigerators that are now widely used. Another is the piloting of a general
      practice division administered mailout program of temperature dataloggers to
      document the ongoing compliance of vaccine storage sites with accepted standards.

PMID- 12404837
TI  - The Professional Development Program of the Australian College of Rural and
      Remote Medicine.
AB  - BACKGROUND: The case for doctors' performance and maintenance of competence are
      issues of increasing importance for the profession, governments and communities.
      There is also increasing public expectation that the profession will be pro
      active in protecting patients from under performing doctors. The Australian
      College of Rural and Remote Medicine (ACRRM) positions itself as the arbiter of
      standards for rural and remote medical practice and has assumed responsibility
      for providing a mandatory Professional Development Program (PDP) for its Fellows.
      OBJECTIVE: This paper outlines the steps taken by the ACRRM to design and develop
      a PDP. DISCUSSION: The PDP aims to enable doctors to participate in a range of
      continuing education activities that enhance their clinical, management and
      professional skills. Participation is mandatory but the program is designed to be
      flexible and responsive to the range of practice characteristics in rural
      Australia as well as to individual needs. The PDP includes categories on
      continuing medical education, quality assurance and clinical assessment (with
      minimum compulsory requirements), practice assessment, educator activities and
      educational development activities. The PDP will evolve over time to meet the
      needs of doctors and communities in rural and remote Australia.

PMID- 12404838
TI  - The Royal Australian College of General Practitioners. The development--Part 3.

PMID- 12404839
TI  - Health and social circumstances of women admitted to a private mother baby unit.
      A descriptive cohort study.
AB  - BACKGROUND: The health and social circumstances of economically advantaged
      mothers who are caring for infants with unsettled behaviour or feeding
      difficulties has been under investigated. METHODOLOGY: An observational survey of
      consecutive admissions to one private hospital's mother baby unit in Melbourne
      admitted with infant feeding or sleeping problems. RESULTS: Of 146 eligible
      participants, 109 (75%) completed the questionnaire. All had partners and
      previous employment in the professional/managerial sector. There were low rates
      of previous psychiatric illness, family history of psychiatric illness, childhood
      sexual abuse or current domestic violence, despite which most felt currently
      unwell. They had experienced high rates of reproductive difficulties, (6.5% IVF
      conception, 25% invasive prenatal testing, 26% antenatal admission, and 53%
      operative delivery). Many (52%) perceived their postnatal obstetric care as
      unsatisfactory. Breastfeeding problems were common (29% had experienced
      mastitis). Severe sleep deprivation associated with frequent infant night time
      waking was universal. Partner's working hours greatly exceeded the community
      average and many women felt under supported and unable to confide in their
      partners. More than half reported serious, coincidental life events. CONCLUSION:
      Some economically advantaged mothers experience such significant postpartum ill
      health they seek hospital admission.

PMID- 12404840
TI  - Duration of cough in acute upper respiratory tract infections.
AB  - OBJECTIVE: To determine the duration of cough in patients without pre-existing
      respiratory problems presenting to general practitioners with acute upper
      respiratory tract infections (URTIs). METHOD: Patients without chronic chest
      problems who presented to two general practices with an URTI during the winter of
      1999 were surveyed to assess the duration of cough. RESULTS: One hundred and
      seventy-nine patients were recruited, of whom 131 could be followed until their
      cough ceased. Of these, 93% developed a cough, 78% coughed for at least one week,
      58% for at least two weeks, 35% for three weeks, and one continued into the tenth
      week. CONCLUSION: The acute cough associated with an URTI often continues for
      several weeks. There may be benefits from educating the community and medical
      profession about this natural history.

PMID- 12404841
TI  - Do people prefer general practitioners of the same sex?
AB  - OBJECTIVE: To explore people's preferences for their general practitioners' sex,
      testing the hypothesis that more women than men prefer a GP of the same sex.
      METHOD: A random sample of 1220 people in Victoria surveyed about visits to,
      satisfaction with, and preferences for their GP. A set of 14 characteristics of
      GPs and their practices revealed the preferences of consumers, and which were
      related to each other. RESULTS: Twenty-four percent of women and 19% of men
      preferred to see a GP of the same sex. The most important characteristic was
      being 'a good doctor', associated with clinical and communication ability.
      CONCLUSION: General practitioners' communication skills, experience and quality
      of care are more important to consumers than the age or sex of the GP.

PMID- 12404842
TI  - [The intern in surgery].

PMID- 12404843
TI  - [Surgeons and low volume operation centers: is this reasonable?].

PMID- 12404844
TI  - [Relation between activity volume and surgeon's results: myth or reality?].
AB  - The relationship between volume and surgical outcome seems logical, but needs to
      be demonstrated in the real world. A qualitative systematic review has been
      conducted to verify this hypothesis. Five systematic reviews and hundred original
      papers have been retrieved and analysed. Most of the studies were retrospective
      and used administrative data instead of medical charts. Moreover few studies
      involved a good case mix adjustment when comparing surgical units or individual
      surgeons. These methodological flaws do not allow any evidence based conclusions.
      Even though a positive relationship is suggested for surgical units, the
      relationship between volume and outcome was however less obvious for an
      individual surgeon. There is some evidence that the relationship varied greatly
      according to the specialty or the procedure evaluated. A new approach based on
      predictive scores comparing expected versus observed outcomes is mandatory and
      seems to be the best way to assess objectively the relationship between surgical
      volume and outcomes.

PMID- 12404845
TI  - [Lessons learned from 274 laparoscopic adrenalectomies].
AB  - AIMS: To define the role of minimally invasive video-assisted surgery in the
      surgical management of adrenal disease and discuss the respective indications of
      the trans and retroperitoneal video assisted approaches. MATERIALS AND METHODS:
      During the last 8 years (1994-2001), 330 adrenalectomies were performed in 305
      patients: 274 (83%) laparoscopic approaches and 56 (17%) open approach. Open
      surgery was reserved for patients presenting with large or malignant tumours (29
      cases), multiple and/or extraadrenal phaeochromocytomas (13 cases), previous
      intraabdominal intestinal surgery (10 cases), and in those requiring concomitant
      intraabdominal surgery (4 cases). Laparoscopic adrenalectomy was performed using
      the lateral transperitoneal approach for 89 Conn's syndrome, 67 Cushing's
      syndrome, 2 virilizing tumours, 51 phaeochromocytomas and 65 non secretory
      tumours greater than 4 cm in diameter. Nineteen patients underwent bilateral
      adrenalectomy. RESULTS: There were no deaths. Twenty patients (7.3%) had a
      complication. Eleven cases required open conversion (4%) because of difficulties
      with dissection (8 cases), preoperative suspicion of malignancy (2 cases), and
      one pneumothorax. The average size of tumours was 34 mm (7-110 mm). There were 18
      malignant tumours (6.5%): 8 adrenocortical carcinomas, 1 leiomyosarcoma, and 9
      metastases. All patients with hormonally secreting tumours were cured of their
      endocrinopathy. There was 1 death secondary to hepatic metastases in a patient
      with an adrenocortical carcinoma. CONCLUSION: Most adrenal tumours are suitable
      for video assisted excision. The only absolute contraindication is an invasive
      carcinoma requiring an extended excision. The lateral, transperitoneal approach
      is the most suitable for tumours greater than 5-6 cm in diameter. Both the
      transperitoneal or retroperitoneal approaches are suitable for smaller tumours
      depending on operator choice and experience. However in the presence of a large
      right lobe of liver or previous intraabdominal surgery the retroperitoneal
      approach may be preferable.

PMID- 12404846
TI  - [Dynamic graciloplasty in the treatment of severe fecal incontinence. French
      multicentric retrospective study].
AB  - The aim of this study was to retrospectively assess the safety and efficacy of
      dynamic graciloplasty performed in 5 French surgical centers involved in the
      treatment of fecal incontinence. PATIENTS AND METHODS: Between March 1994 and
      March 2000, a total of 24 patients were treated with dynamic graciloplasty for
      fecal incontinence excluding case of anal reconstruction for cancer.
      Intramuscular leads and neurostimulators were implanted to stimulate the
      transposed gracilis. Continence and safety were evaluated using patients' records
      during hospitalisation and during the out-patient visit or further
      hospitalisation. RESULTS: No death occurred. A successful functional outcome was
      reported for 19 patients (79%) during the follow up period. Twenty-two
      complications occurred including wound. Wound infection in 6 patients and tendon
      detachment in 4. One patient presented with an infected anal erosion leading to
      material explantation. CONCLUSION: Dynamic graciloplasty is an effective
      procedure for patients with refractory fecal incontinence. However, the procedure
      has significant morbidity which seems to be correlated with the surgeons'
      experience. Moreover, this procedure should now be compared to the artificial
      anal sphincter.

PMID- 12404847
TI  - [Surgical treatment of pancreatic metastases from renal carcinoma].
AB  - OBJECTIVES: Pancreatic metastases from renal carcinoma are poorly known. The aim
      of this study was to report clinical and radiological manifestations, the
      treatment performed, and the observed survival in 7 patients with this rare
      entity. RESULTS: All patients were operated on. One patient had nonresectable
      tumor. Six patients underwent curative resection. There was one postoperative
      death. Follow-up after pancreatectomy ranged from 6 months to 3 years. Two
      patients developed extra-pancreatic metastases one year and 3 years after
      pancreatectomy respectively. CONCLUSIONS: Pancreatic metastases from renal
      carcinoma are rare and often occur several years after nephrectomy. However their
      resection is often possible and allows a good long-term survival. PATIENTS AND
      METHODS: From 1988 to 2000, 7 patients (5 men and 2 women, mean age = 66 years)
      with pancreatic metastases from a renal cell carcinoma were observed in the same
      center. One patient had synchronous metastasis; in the 6 others, metastases were
      diagnosed 4 to 16 years after nephrectomy, and were revealed by pain (n = 2),
      gastrointestinal bleeding (n = 1), faintness (n = 1) or routine follow-up (n =
      2). The diagnosis of metastases was made by contrast-enhanced abdominal CT-scan.

PMID- 12404848
TI  - [Intrathyroid metastases from kidney cancers: two case reports].
AB  - The thyroid metastasis are under estimated in clinical practice because they are
      in the vast majority of cases "silent". Over than 50% of clinically apparent
      metastatic lesions are due to kidney carcinomas. We report two cases of thyroid
      metastasis from clear-cell renal carcinoma occurred 3 years and 8 years after
      nephrectomies. The previous history of any type of carcinoma should suggest a
      possibility of metastasis for every thyroid nodules. Fine-needle aspiration
      cytology is recommended by some authors. Finally, clear-cell carcinoma metastases
      seem to have a propensity to occur in abnormal thyroid tissue and further study
      could be interesting.

PMID- 12404849
TI  - [Bilateral compartment syndrome after colorectal surgery in the lithotomy
      position].
AB  - Lower limb compartment syndrome is an unusual but severe complication of
      prolonged surgery more than four hours in lithotomy position. It is usually a
      consequence of hypoperfusion of the lower extremities and muscle necrosis may
      occur. Several risk factors are pointed out: trendelenburg, the hardness of
      operating table, hypothermia, control hypotension, occlusion of arterial blood
      flow of the lower extremity, arteritis (and smoking), diabetes, obesity, arterial
      hypertension, myopathy and an important muscle mass. The symptoms are
      postoperative pain with neurological signs. A rapid diagnosis and aggressive
      management (i.e. resuscitation and aponevrotomy) is recommended. Neurological
      sequelae are sometimes invalidating. Reporting a case of bilateral syndrome, we
      reviewed the literature and describe the present diagnosis and therapeutic
      management as well as prevention modalities of this iatrogenic complication.

PMID- 12404850
TI  - [Compensation for damage caused by medical hazards: new legislative aspects].

PMID- 12404851
TI  - [Renal transplantation, a centenary epic].
AB  - The year 2002 marks the centenary of the first attempts of renal
      transplantations. The steps of this great human enterprise are reminded, from the
      first animal experiments at the dawn of the century, the attempts of renal grafts
      in humans with animal and then human kidneys, to the present era during which
      renal transplantation has become the treatment of choice of chronic end-stage
      renal insufficiency.

PMID- 12404852
TI  - Scorpions and snakes, such as cobras, mambas and vipers made the African
      continent famous for venomous animals.

PMID- 12404853
TI  - [Action of venoms on blood coagulation: diagnosis of hemorrhagic syndromes].
AB  - Venoms from Viperidae, Crotalidae, some Australian Elapidae and few Colubridae
      are a mixture of enzymes which impact on blood coagulation in several ways. These
      proteins can be classified as haemorragins which induce disorders of the
      capillary permeability, disintegrins and related proteins which disturb the
      clotting time while acting on plate adhesion, and proteases which cleave
      peptides. Venoms contain molecules directed against several targets of the
      coagulation system. The same molecule may present different activities.
      Components of snake venoms are used in diagnostic coagulation tests, fundamental
      research and as drugs against infectious agents, cancer or haematological
      disorders. The structural differences between proteins from snake venoms and
      natural coagulation factors and the target diversity of the venom components
      explain why it remains illusory to treat bleedings when acting just at symptom
      level. Conversely, antivenom, whose components are directed against the venom
      proteins, is the only aetiological therapy effective against snake envenomations.

PMID- 12404854
TI  - [Clinical and biological surveillance of envenomed patients].
AB  - Faced with an envenomation, the problem is to take sufficiently rapidly the
      decision to administer the only effective treatment--immunotherapy--, to know
      which antivenom to choose and how long to administrate it. If the snake is not
      identified, symptoms and initial development give information on the type of
      venom. It is convenient to classify the symptoms according to four clinical
      types: i) the cobra syndrome with a potentially fatal evolution within two to ten
      hours and which resembles an Elapid bite, ii) the viper syndrome associating
      bleeding and inflammation, which can be due either to a viper, pit viper or, in
      Australia, to Elapids, iii) disturbance of blood circulating functions and iv)
      disturbance of other live functions. Between the third to the half of snakebite
      victims present no envenomation. Severe envenomations must be monitored in an
      intensive care unit, with experience in emergency management and monitoring of
      patients with major life-threatening conditions. Throughout the world, snakebites
      induce more than 100,000 deaths every year. Schematically, the emergency may be
      considered in terms of seconds for blood circulation disorders, minutes for
      respiratory paralysis, and hours for the coagulopathy.

PMID- 12404855
TI  - [Comparative titration of three antivenin serums used against sub-Saharan African
      snakes].
AB  - The standardisation of serotherapy is necessary in Africa mainly because of the
      frequency of envenomations and the lack of alternative treatments. Comparative
      titrations of FAV-Afrique (Aventis Pasteur), Polyvalent serum (Serum Institute of
      India = SII) and Polyvalent antivenin (South African Vaccine Fabricants Ltd =
      SAIMR) were carried out on venoms of Echis ocellatus from Cameroun, E. ocellatus
      from Mali, E. leucogaster and Naja melanoleuca. The 50% protective doses (ED50)
      of the antivenoms were given according either to i) the in vitro method which
      consists of inoculating 5 batches of 5 mice with a mixture containing 3 DL50 of
      venom and increasing volumes of antivenom incubated for 30 mn at 37 degrees C and
      ii) the in vivo method which consists of successive administration of venom and
      then antivenom after a 30 to 60 mn interval. The three antivenoms showed a
      similar efficacy against all the Echis venoms. Interestingly, the SAIMR proved to
      be effective against the venom of E. leucogaster and E. ocellatus although no
      venom of Echis was used to immunise horses during the preparation of antivenom.
      Conversely, this paraspecificity did not exist with the Naja melanoleuca venom
      against which FAV Afrique showed a higher efficacy. The electrophoresis pattern
      of FAV-Afrique performed on acetate gel strips showed only one protein fraction
      (76 g.l-1), whereas both the SII and SAIMR antivenoms showed four fractions whose
      protein concentrations was respectively 64 g.l-1 and 145 g.l-1.

PMID- 12404856
TI  - [The snakes of Senegal: an annotated species list].
AB  - Between 1990 and 2001, the laboratory of Paludologie of IRD at Dakar collected
      over 5,500 snakes from all over Senegal. By studying this collection, an entirely
      new species was discovered for science and eight new species for Senegal. The
      presence of many specimens of rare species and the great number of localities
      from which snakes were collected also allowed us to solve several delicate
      taxonomic problems and better to specify the biogeography of Senegalese snakes.
      Currently, the presence in Senegal of at least 55 different species has been
      established with certainty. The data collected simultaneously on the burden of
      snakebites for public health shows considerable differences according to
      geographic area, with populations from south-eastern Senegal being more exposed
      to the risk of death by snakebite.

PMID- 12404857
TI  - [Evaluation of snake bite incidence in the Sahelian zone of Senegal, example of
      Niakhar].
AB  - An exhaustive household survey was carried out in the study zone of Niakhar, a
      rural sahelian area in Senegal 150 km east of Dakar. Results were compared with
      those of the data base updated quarterly since 1983 and to the notifications of
      snakebites in the 7 health centres of the zone (130 inhabitants per km2). The
      questionnaire related to the snakebites (identification of victims, circumstances
      of bite, symptoms and treatment). The annual incidence was low (23 bites per
      100,000 inhabitants) as the morbidity (by 20 envenomations per 100,000). The case
      fatality rate was relatively high (7%) and there were 1.5 deaths per 100,000
      inhabitants per year. Males were more often bitten than females (1.8:1). Field
      work (agriculture and breeding) induced about half of the accidents. Traditional
      practitioners were systematically consulted by over 93% of victims. This explains
      why collecting data from health centre registers is not sufficient to estimate
      the importance of envenomations in this area.

PMID- 12404858
TI  - [Mortality from snake bites, wild and domestic animal bites and arthropod stings
      in the savannah zone of eastern Senegal].
AB  - From 1976 to 1999, we conducted a prospective study of overall and cause-specific
      mortality among the population of 42 villages of south-eastern Senegal. Of 4,228
      deaths registered during this period, 26 were brought on by snakebites, 4 by
      invertebrate stings and 8 by other wild or domestic animals. The average annual
      mortality rate from snakebite was 14 deaths per 100,000 population. Among persons
      aged 1 year or more, 0.9% (26/2,880) of deaths were caused by snakebite and this
      cause represented 28% (26/94) of the total number of deaths by accident. We also
      investigated the snake fauna of the area. Of 1,280 snakes belonging to 34 species
      that were collected, one-third were dangerous and the proportion of Viperidae,
      Elapidae and Atractaspididae was 23%, 11% and 0.6%, respectively. The saw-scaled
      viper Echis ocellatus was the most abundant species (13.6%). Other venomous
      species were Causus maculatus (6.5%), Naja katiensis (5.5%), Bitis arietans
      (2.7%), Elapsoidea trapei (2.4%), Naja nigricollis (1.2%), Naja melanoleuca
      (1.1%), Atractaspis aterrima (0.4%), Dendroaspis polylepis (0.3%) and Naja haje
      (0.1%).

PMID- 12404859
TI  - [Problems with envenomations in Guinea].
AB  - Only a few years after its creation, the Kindia Pasteur Institute (currently
      Institut de Recherche de Biologie Appliquee de Guinee, IRBAG), owing to its
      geographical situation, began regularly supplying the Paris Pasteur Institute
      with snake venom for manufacturing antivenom. The diversity of the biotopes in
      Guinea due mainly to the diversity of vegetation (savannah, forest, mangrove) and
      altitudes (coastal zone, mountains of Fouta-Djalon and mountain of High Guinea),
      induces a wide variety of the herpetological fauna. Envenomations are
      consequently a significant cause of morbidity and mortality in a country where
      agriculture is an important economic activity. Unfortunately, precise statistics
      for envenomations are unavailable. A retrospective study was performed based on
      IRBAG registers (1980-1990). A total of 584 snakebites were reported with a 2.2%
      case fatality rate. Between 1997 and 1999, 379 cases of snakebites were reported
      with 18.2% death, mainly due to the lack of antivenom, and 2.1% amputations. By
      combining the fang marks and victim or relative assessments, we were able to
      identify most of the snakes involved in the envenomations: Naja (21.3%), Bitis
      (15%), Dendroaspis (12.4%) and Causus (12.9%). In 38.2% of the cases, the snake
      was not identified. This survey confirmed that envenomations are a problem in
      Guinea. However, more studies are necessary to appreciate the real importance of
      the herpetological Guinean fauna and its consequences on morbidity and mortality
      in order to improve the management of envenomations.

PMID- 12404860
TI  - [Evaluation and treatment of snake bites in Bancoumana village in Mali].
AB  - A retrospective study was conducted on the epidemiological patterns and treatment
      of snakebites in the village of Bancoumana, 60 km south-west from Bamako. We
      analysed a total of 17 cases (8 males and 9 females). The distribution of
      snakebite cases by gender and by age showed that among subjects aged 5 to 20
      years, boys were more exposed than girls (6 vs. 2), whereas, in those of 21 years
      and above, females were more frequently bitten than males (7 vs. 2) (p = 0.04).
      The treatment was mainly based on the use of anti-inflammatories and antibiotics,
      and sometimes of saline, glucose or anti-tetanic serum. Vitamin K was used in 7
      cases and no patient was treated specifically. The success of therapy mostly
      depended on the shortness of delay between the snakebite occurring and patient
      referral to the health centre, and the low rate of envenomation. All the patients
      referred the same day they were bitten were cured, whereas three persons referred
      to the health centre at D3, D7 and D43 after bite died. The surveillance
      parameters were oedema, bleeding and vomiting.

PMID- 12404862
TI  - [Epidemiology of snake bites in the Republic of Ivory Coast].
AB  - A national survey was carried out in Cote d'Ivoire in 1979 in order to evaluate
      the incidence, morbidity and mortality of snakebites. This unpublished survey has
      not been renewed to our knowledge. Although 20 odd years have passed since, the
      survey is not obsolete and can be usefully presented at this congress. We
      associated a retrospective survey using health centre registers and a prospective
      survey performed in 7 health centres between 1972 and 1979. The incidence,
      estimated prospectively for rural areas, exceeded 200 bites for 100,000
      inhabitants. This evaluation could be an underestimation because many victims
      consulted traditional practitioners. Annual morbidity was higher in forest areas
      (195 envenomations per 100,000 inhabitants) than in the savannah (130
      envenomations per 100,000 inhabitants). Conversely, the case fatality rate was
      higher in the savannah (3.1%) than in forest areas (2%). More than half of the
      bites involved men aged 15 to 50 years. The risks were significantly higher for
      farmers, particularly in industrial plantations, where 27% of the total of number
      of bites involved 1.5% of the population. At the beginning of the 1980s,
      envenomations could be estimated at over 13,000 per 8 million inhabitants and the
      number of deaths 200 per annum.

PMID- 12404861
TI  - [Epidemiology and management of snake envenomations in the Dano health district,
      Ioba province (Burkina Faso) from 1981 to 2000].
AB  - A series of investigations concerning snakebites and management of envenomations
      was carried out from 1981 to 2000 in the medical District of Dano, Province of
      loba in Burkina Faso. Viper bites were more frequent than Elapid ones. The
      seasonal distribution of the envenomations reflected the cycle of field work and
      other specific activities. Care seeking within the Traditional System of Health
      Care (STSS) was more frequent than within the Conventional System of Health Care
      (SCSS). Lethality was higher at STSS level in cases of viper bites and,
      conversely, higher in SCSS in the cases of Elapid envenomations. This highlighted
      the interest in medicinal plants for treating snakebites particularly in case of
      neurotoxic envenomation. We classified several dozens medicinal plants within an
      inventory. Some of them have been studied and deemed worthy of interest. Others
      are used for the treatment of other types of poisoning (pesticides, plants toxic)
      and/or used in traditional rites. We hope to follow the Cote d'Ivoire experience
      such that African snake venom, neutralised by modern antivenom, might also be
      neutralised by the African natural resources.

PMID- 12404863
TI  - [Snake bite epidemiology in Benin].
AB  - The incidence and the severity of envenomations in the savannah area of Central
      and Northern Benin were evaluated between 1985 and 1997 following 3 methods. i)
      Retrospective surveys were carried out in 9 hospitals, including a sugar-cane
      infirmary, covering a 3 to 10 year period according to locality. The average
      annual incidence was approximately 200 envenomations per 100,000 inhabitants
      (range 20-450) and the lethality was 3.1% (range 0-9.7%). In the plantation, the
      annual incidence was 1,300 bites per 100,000 workmen with a lethality below 1.5%.
      ii) Household surveys were conducted in 13 villages inhabited by 2,500 people.
      The average annual incidence was 430 bites, including dry-bites i. e. without
      envenomation, per 100,000 inhabitants (range 215-650). Lethality was 3.3%, iii)
      Finally, a prospective investigation was performed over 3 years in 7 villages
      involving 1,300 residents. The average annual incidence was 440 bites, including
      dry-bites, per 100,000 inhabitants and the lethality was 5.9%. The majority of
      the bites occurred during the rainy season. During this period, envenomations
      represented up to 20% of hospitalised patients. However, the village surveys
      showed that 80% of the patients first consulted traditional practitioners,
      reducing the proportion of patients consulting in hospitals to less than a third
      of snakebite victims. The population at risk was made up primarily of active
      males. The sex ratio was 2.3 men to 1 woman and more than 60% of snakebite
      patients were aged 21 to 50 years. The evaluation of the frequency of clinical
      syndromes was as follows: oedema (66%), haemorrhage (12%) and necrosis (5%).
      Neurological disorders seemed to be rare.

PMID- 12404864
TI  - [Geoclimatology and severity of snake bite envenomations in Benin].
AB  - Envenomations following snakebite are common in Benin where they constitute,
      particularly in certain areas, a significant problem for the local populations
      and health workers. The present epidemiological study describes the snakebite
      envenomations which occurred in 18 medical centres of the country (6 departmental
      hospitals and 12 provincial hospitals). The studied variables were: prevalence,
      length of hospitalisation, major complications, quality of therapeutic management
      and development of the disease according to area. The study covered a period from
      April 2000 to March 2001. 486 cases of snakebite necessitating hospitalisation
      were notified including 413 (85%) in the two northern departments: Atacora and
      Borgou. Males were largely predominant (90%) and patients under 40 years were the
      most numerous (82%). The dry season seemed a period of higher risk (75% of the
      cases). The delay between the bite and admission to hospital, studied for 120
      patients in the area of Atacora (North-West Benin), was relatively long: the
      average was 4 days, with extremes ranging from 10 hours to 21 days. This delay
      explained the severity of the complications diagnosed. They can be listed
      according to decreasing frequency: shock, coagulopathy, acute renal failure,
      respiratory distress. Less than 20% of the patients could benefit from antivenom.
      Management in emergency care units was impossible in most cases, none of the
      medical centres (except in Porto-Novo, the capital) having an intensive care unit
      with artificial ventilation available. Average mortality was 22%. Poisonous
      snakebites remain serious in Benin, mainly in the northern part of the Country.
      Access to health care and the quality of the management must be improved. This
      will require significant efforts from health workers, medical authorities as well
      as the local population. It is urgent to plan a national therapeutic consensus to
      reduce the high mortality due to snakebites.

PMID- 12404865
TI  - [Epidemiological data on snake bite cases reported in Benin from 1994 to 2000].
AB  - Snake bites constitute a frequent occupational injury, mainly occuRring during
      agricultural activities in Benin as in the majority of tropical countries. The
      present study was performed within the scope of a periodic epidemiological
      analysis of occupational injuries over the past 15 years. It is a retrospective
      study based on the snake bites reported by the Ministry of Public Health from
      1994 to 2000. The data collected through the medical centre registers showed
      that, with a total of 30,273 cases declared during these 7 years, snakebites
      represent less than 1% of the whole causes of admission. Although the prevalence
      was weak, the lethality was very high (15%). Envenomations involved more deaths
      than malaria and acute respiratory infections together. One third of cases
      occurred in adults and teenagers. Lethality in infants was not negligible. The
      two departments of northern Benin accounted for 314 of the envenomations.
      Lethality does not appear to be decreasing. The routine management of cases
      should be improved by appropriate training for health care workers and the
      introduction of a therapeutic strategy at every level of the medical system.

PMID- 12404866
TI  - [Snake bites and antivenom availability in the urban community of Niamey, Niger].
AB  - In order to appreciate certain aspects of the epidemiology of snake bites and the
      availability of antivenom in Niamey (the capital of Niger), we performed a series
      of retrospective and prospective studies. The retrospective study involved 175
      snake bite patients hospitalised from 1 January 1997 to 31 December 1999 in the
      internal medicine and surgery wards of the two national hospitals of Niamey. The
      average age of patients was 29 years, with 3 years and 80 years as limits. The
      average number of snake bites was 58 cases per year with an annual incidence of
      approximately 10 cases for 100,000 inhabitants. Males were mainly concerned with
      a sex-ratio of 2.4 (124 males versus 51 females). Snake bites involved mostly
      teenagers (29.1%). 84.6% of bites occurred in persons aged 15 to 60 years.
      Incidence was higher during the farming period: 65% of cases occurred between
      June and October. Lethality reached 6.9%. However, 25.7% of the patients left
      hospital without staff permission before the end of the treatment. Complications
      represented 4.6% of the cases and consisted in necrosis, gangrene and
      coagulopathy. The treatment protocol was inconsistent, such that both therapeutic
      algorithm and formation are necessary. The prospective survey involved 41
      pharmacies or drug middlemen and hospital drug stocks, prospected from 1 January
      to 31 May 2000. Antivenom was available in 1 hospital and 1 pharmacy and stocks
      could be considered sufficient for 1 year. However, it appeared that the supply
      policy had not been clearly defined.

PMID- 12404867
TI  - [Epidemiology of snake envenomations in northern Cameroon].
AB  - Epidemiological surveys concerning snakebites were carried out in the savannah
      area of North Cameroon according to two methods. A retrospective survey carried
      out in 5 hospitals or dispensaries covering a 3- to 8-year period according to
      locality was followed by a prospective survey in 4 of these health centres
      lasting 1 or 2 years according to location. These studies involved respectively
      1,710 and 359 patients. The annual incidence varied between 50 and 250
      envenomations per 100,000 inhabitants according to year and locality. The average
      annual incidence was close to 200 cases. Echis ocellatus corresponded to 85% of
      the identified snakebites. Lethality ranged from 0 to 23.9% of the envenomations.
      It significantly decreased during the prospective study due to the systematic use
      of antivenoms administered through the venous route (IPSER Africa then FAV
      Afrique). During the prospective study, we observed that 25% of snakebite victims
      did not present any symptoms: 71% presented an oedema, 63% a coagulopathy and
      less than 5% a necrosis. The population at risk involved people aged 15 to 44
      years, especially males. Most of the bites had occurred during agricultural
      activity. In the cotton zone, more than 40% of the envenomations took place
      during the 3 months of the field preparation and cotton sowing. Elsewhere, the
      snakebites were spread out over time with a clear increase during the rain
      season.

PMID- 12404868
TI  - [Analysis of snake bite envenomations in Gabon].
AB  - In tropical zones, snakebites are considered serious. Exotic snakes are
      characterised by the poisonousness of their venom and its abundance. Death is
      rapid in some cases and in others the sequelae are serious. Worldwide, there are
      more than 5 million victims per year, with 50,000 deaths registered and 400,000
      amputations. The frequency and severity of snakebites in Gabon remain unknown. It
      is estimated that there is an average of one snakebite every 4 days, thus some 91
      snakebites per year. Through a study carried out at the Libreville Hospital, we
      evaluated the frequency, severity, and fatality of this circumstantial pathology.
      A retrospective study conducted on 157 patients admitted for snakebite at the
      Intensive Care Unit of the Libreville Hospital was carried out between 1998 and
      2001. 1.32% of all admissions were for snakebites. Signs of venom poisoning were
      observed in 27 patients (17%), versus 130 cases without envenomation. The
      majority of cases were in adults (78%) and children affected (22%) were aged
      mainly 6-14 years. The snakebite season usually coincided with the rainy season.
      During this period, 19 cases were registered. Snakebites occurred during the
      daytime (93%), in the fields in 20 cases (75%) or in the home courtyard (25%).
      The victims lived in town in 25 cases (93%). Antivenom was used in all
      envenomation cases, and the result was favourable in 23 cases (18%) but
      unfavourable in 4 (15%).

PMID- 12404869
TI  - [Scorpion stings in sub-Saharan Africa].
AB  - Scorpionism in Sub-Saharan Africa is a poorly known problem but regarded as a
      public health preoccupation in several countries, especially Niger. The lack of
      knowledge of this question is due to non-existent information concerning mainly
      the composition of the scorpion fauna in Sub-Saharan areas, the distribution and
      density of dangerous species and the frequency and severity of scorpion stings in
      the Sub-Saharan areas. Until now, only the presence of Leiurus quinquestriatus
      and its involvement in fatal accidents have been attested to. In many areas, the
      presence of other classically dangerous species has not been confirmed, nor the
      dangerous potential of certain species belonging for example to the genera
      Androctonus. Buthus or Hottentota. The efficacy of prevention, treatment and
      scorpion control depend necessarily on further study of the fauna and medical
      investigations. Such studies are entirely feasible.

PMID- 12404870
TI  - [Rapid immunotitration of individual toxins from Androctonus australis venom].
AB  - Passive immunotherapy against scorpion envenomations is facilitated by the
      preliminary titration of circulating toxins in envenomed patients. Currently,
      routinely used ELISA tests allow only the titration of the whole venom, without
      reference to the toxins which compose the venom and spread variably within the
      tissue. Taking as a model one of the three toxins responsible for the lethal
      effects of Androctonus australis hector (Aahl) venom, we developed an ELISA
      sandwich test based on a fragment of recombining antibody (scFv) consisting of
      the variable chains of the monoclonal IgG 9C2 coupled to a decapeptide showing
      high affinity for streptavidine. Conjugate scFvlStrep-tag was prepared by genetic
      engineering. It was produced in the periplasm of recombining bacteria, in a
      reproducible way, in a soluble form, at low cost and with an output, after
      purification, of 0.8 mg/L of bacterial culture. The recombinant protein, of small
      size (28 kDa), is bifunctional. It preserves a very high affinity for the toxin
      Aah I (Kd of 2.3 10(-10) M, very close to that of IgG 9C2), yet recognises
      streptavidine and its conjugate (streptavidine-peroxidase). The titration of the
      Aahl toxin used an ELISA sandwich test in which the toxin was captured in a
      specific way by a monoclonal antibody; the immunocomplexes were then detected by
      recombinant immunoconjugate, thus conferring a high specificity on titration. The
      test is quick (90 mn), reproducible and sensitive, with a limit of detection of
      0.6 toxin (ng.ml-1). This method could be extended to two other lethal toxins of
      the venom of the scorpion Androctonus australis hector and to those of other
      species. New perspectives are thus possible for the diagnosis of the
      envenomations.

PMID- 12404871
TI  - [Theoretical and experimental bases for treatment of scorpion envenomations].
AB  - Improving the efficacy of envenomation treatment depends on what is known about
      active molecules present in venoms. Regarding scorpions, studies carried out
      mainly on the most poisonous species have shown that the toxicity and mortality
      were due to small proteins-toxins--able to interfere with the normal process of
      the ionic channels. In certain cases, using the mouse model, it has been shown
      that over 90% of mortality was due to toxins operating on the sodium channels
      implicated in the action potential of the excitable cells. Pharmacokinetic
      studies have shown the diversity of their mode of action implying an adaptation
      of the means and tools intended to neutralise them. The toxins active on the
      sodium channels represent a family of proteins from 60 to 65 amino acids linked
      by 4 disulphide bridges with a very strong antigenic polymorphism; this has
      certain implications in terms of paraspecificity of antivenoms. The problem is
      even more complicated when one considers the variation of toxin quantity from one
      animal to another of the same species. Another approach is to identify the most
      active and represented toxins in venoms for each antigenic group and to develop a
      means of neutralizing them. It would also be possible to define toxoids for use
      either in the production of the antivenoms or as immunological protection for
      individuals at risk. Lastly, where symptomatic treatment is concerned, certain
      drugs such as aspirin, quinine or dandrolene have been shown definitely to
      increase the value of the LD50 in the mouse.

PMID- 12404872
TI  - [Clinical evolution and circulating venom levels in scorpion envenomations in
      Morocco].
AB  - We conducted a clinical and biological study in Morocco in order to assess the
      efficacy of antivenom therapy against scorpion stings. Epidemiological and
      clinical data were collected in 275 patients envenomed by Androctonus
      mauretanicus mauretanicus and Buthus occitanus scorpions. Patients received
      antivenom or symptomatic drugs. Blood samples were collected upon hospital
      admission, at 1 hr and 3 hrs after the treatment. An enzyme linked immunosorbent
      assay (ELISA) was set up to quantify the venom levels in serum of envenomed
      patients. Mean serum venom concentrations showed an association between clinical
      signs and the venom level. The venom concentration at admission, in patients who
      received 10 ml of antivenom, was significantly reduced after antivenom therapy.
      The decrease was less important in patients who received only 2 to 5 ml of
      antivenom. No difference was shown in the venom concentration of patients not
      treated with antivenom. The clinical signs decreased significantly after
      antivenom treatment. The absence of antivenom administration increased the risk
      to develop clinical signs at the end of hospitalisation. This risk was much
      higher when the delay between scorpion sting and hospital admission increased.
      The results of our study have demonstrated the efficacy of antivenom in reducing
      circulating venom and symptoms. Antivenom therapy is more efficient when
      administered as soon as possible after envenomation and with appropriate
      quantities of antivenom. This study is favourable to the use of SAS but a
      prospective study would be useful to confirm these data.

PMID- 12404873
TI  - [Fifteen years' experience in scorpion envenomation control in Algeria].
AB  - In Algeria, scorpion envenomation is real public health problem. Since the
      creation of the National Committee of Control of Scorpion envenomations (CNLES),
      several steps have been taken to deal with this problem. After a brief historical
      introduction, we present the main elements of the action carried out both in
      terms of treatment and of prevention of scorpion proliferation. The
      epidemiological situation is presented by stressing the difficulties involved in
      collecting reliable data. We also address the question of citizen and stakeholder
      awareness since public participation is crucial in all prevention programmes.
      Training for healthcare providers is also one of the principal axes of the
      Committee's programme which includes national, regional, and even local seminars.
      We describe the improvement of production and research on venoms carried out by
      the Institute Pasteur of Algeria. We conclude by discussing the action plan for
      2001 and prospects for an enhanced strategy in the fight against the scorpion
      envenomation.

PMID- 12404874
TI  - [Epidemiology of scorpion envenomations in the pediatric service of the Agadez
      hospital center (Niger) in 1999].
AB  - In Agadez, northern Niger, envenomations due to scorpion sting is a major public
      health problem, ranking first among reasons for emergency admission to hospital
      and inducing significant mortality. In order to provide best medical care,
      improved knowledge of scorpion sting envenomation was required. From April to
      September 1999, we carried out a prospective, descriptive survey on the
      paediatric ward of the departmental hospital of Algadez. All children admitted to
      the ward for scorpion stings were included. Data was collected by questionnaire.
      Requested items were age, sex, type of scorpion, sting location, and clinical
      development. Over the 6 months of the survey, a total of 44 cases of scorpion
      sting were recorded on the ward. The majority of the cases (52%) were recorded in
      July. The main types of scorpion identified according to colour were black (18%),
      yellow (18%), and brown (5%). In 59% of the cases, the type of scorpion was not
      identified. 6-15 year-old children represented 50% of the cases. The lower limb
      was the main site of stings (66%). A majority of cases (52%) were admitted fewer
      than 30 minutes after the sting, and 30% between 30 minutes and 1 hour after the
      sting. The overall lethality rate was 23% (10/44). All the deaths occurred within
      2 hours following the sting. Of all the deaths, 60% (6/10) occurred with 30
      minutes after the sting. Our study has shown that scorpion stings remain a
      significant health problem in the area. As a consequence of our findings, we have
      introduced a new therapeutic protocol for the early case management.

PMID- 12404875
TI  - [New mass spectrometry techniques applied to the study of venoms].
AB  - Mass spectrometry is a technique for the analysis and very sensitive
      identification of molecules. It allows one to determine the mass of the studied
      product, whether pure or in a mixture, and provides some information on its
      molecular structure. In the particular case of peptides, this method can, under
      certain conditions, also provide information on the amino acid sequence. There
      are two complementary methods in mass spectrometry for the study of the
      biological molecules: i) ionisation by laser desorption assisted by matrix
      (MALDI) coupled to a mass analyser of the time of flight type (TOF), which is
      very effective for the direct study of a mixture of products and ii) ionisation
      by electronebulisation (ESI) coupled to mass analysers of the quadripolar type
      and time of flight (Qq-TOF), which allows the interfacing between high phase
      liquid chromatography and mass spectrometry. These two complementary techniques
      were already used to draw up toxin charts of snake and spider venoms. The purpose
      is to be able to characterise species based on an actual peptide print of
      poisonous gland secretions.

PMID- 12404876
TI  - [Installation of a toxicology information center at the National University
      Hospital Center of Cotonou (Benin)].
AB  - The need for toxicology information centres in West Africa in order to improve
      the management of poisoning, diagnosis and prevention is now largely recognised.
      African Governments have been encouraged to support the establishment of such
      centres equipped with appropriate means for prevention and management. Burden of
      toxic morbidity and mortality in Benin incited the Public Health Ministry to
      pursue this policy. The project has been integrated as part of the process
      seeking to reinforce emergency services in Benin. It consists of providing the
      emergency services with the means of prevention and management of poisonings. The
      principal functions of such a centre will be providing information on toxicology
      as well as recommendations for poisoning management, toxicovigilance, research,
      education and training in prevention and treatment of poisoning. This project
      will involve health workers, national authorities and the entire population of
      Benin. The estimated cost cost is 572,000 euros over 3 years.

PMID- 12404877
TI  - Round table and synthesis of the meeting.
AB  - Our knowledge of the epidemiology of scorpion stings and snakebites remains
      fragmentary but sufficient, nevertheless, to be able to confirm that
      envenomations constitute a real public health problem throughout Africa. In order
      for the health authorities to be able to improve management of this problem, data
      collection must be enhanced. The objective should be to determine what kinds of
      intervention are necessary (quantity of antivenom serum and drugs, in particular)
      and where they should be applied. Specialists must come to a rapid consensus for
      a simple therapeutic protocol to be used in peripheral health centres where means
      are often scarce. Training for health personnel is also insufficient. Appropriate
      courses must be organised for medical doctors and nurses within both their basic
      and on-going training. These courses must necessarily involve health personnel
      from rural zones must affected by envenomations. The availability of antivenom
      serum--the only specific, efficacious drug--must be improved as soon as possible.
      If quantitative and geographic needs can be determined by epidemiological
      studies, then distribution must be developed by original means (grouping orders
      at national level, direct orders) and diversified financial support (purchase on
      the open market, local authority grants, community participation). The symposium
      attendees agreed to meet again within two years' time to evaluate progress in the
      area.

PMID- 12404878
TI  - Principles of a topical chemosensory receptor intervention. The basis for a
      chemosensory CNS medicine.
AB  - A topical chemosensory receptor intervention on the level of olfactory receptors
      is based on a local effect of a chemical molecule (inducer) which triggers a
      biophysical CNS signaling. The action of the inducer is limited to a temporary
      contact (receptor imprint) and the molecule is hereafter eliminated (revolving
      door effect). The CNS bioresponse is triggered by afferent neuronal signal
      patterns which effect secondary reactions of endogenous substances and is
      dissociated from a physical presence of the inducer. The pharmacological
      mechanism of topical chemosensory receptor intervention is principally different
      to a systemic administration since it excludes pharmacokinetic components. A
      descriptive differentiation between a topical chemosensory effect and a systemic
      drug effect can be determined by application of the relation Teff << TCmax. A
      chemosensory medicine represents the therapeutic use of a topical chemosensory
      receptor intervention. It employs chemosensory delivery systems (CDS) and
      provides for various CNS indications a possibility of more selective, faster and
      safer effects than a systemic drug administration.

PMID- 12404879
TI  - Synthesis and beta 1-, beta 2-adrenergic receptor binding studies of 4-acylamino
      substituted phenoxypropanolamine and 5-acylamino-substituted
      naphthyloxypropanolamine derivatives.
AB  - The object of this study was to investigate the beta-adrenergic receptor binding
      affinity of 4-acylaminophenoxypropanolamine (10-15) and 5
      acylaminonaphthyloxypropanolamine (21-24) derivatives, which were prepared from 4
      aminophenol (5) and 5-amino-1-naphthol (16), respectively. The in vitro beta 1-
      and beta 2-adrenergic receptor binding affinities of the newly synthesized
      compounds were assessed in turkey erythrocyte membrane (beta 1) and lung
      homogenates of rats (beta 2). The binding affinities were compared with that of
      propranolol (3) (propranolol hydrochloride, CAS 318-98-9). The compound N-[5-(3
      tert-butylamino-2-hydroxy-propoxy)-naphthalen-1-yl]-acetamide (22) has beta
      adrenergic receptor affinity comparable with that of propranolol and shows
      selectivity to beta 1-adrenergic receptors.

PMID- 12404880
TI  - Pharmacokinetic interaction between TAK-044, a new endothelin antagonist, and
      ciclosporin in rats.
AB  - The pharmacokinetic interaction between TAK-044 (cyclo[D-alpha-aspartyl-3-[(4
      phenylpiperazin-1-yl)carbonyl]-L-alanyl-L- alpha-aspartyl-D-2-(2-thienyl) glycyl
      L-leucyl-D-tryptophyl] disodium, CAS 157380-72-8) and ciclosporin (CAS 59865-13
      3) was investigated after concomitant intravenous (i.v.) administration in rats.
      After i.v. administration of 14C-labeled TAK-044 ([14C]TAK-044 alone at a dose of
      3 mg/kg, the radioactivity concentration in the plasma was 1.65 micrograms/ml at
      5 min and decreased biphasically with half-lives of 0.09 h and 0.39 h. AUC0-1 h
      was 0.38 microgram.h/ml. The pharmacokinetics of [14C]TAK-044 were affected dose
      dependently by coadministration with ciclosporin. The AUC value for [14C]TAK-044
      was increased 5- and 14-fold by the coadministration with cyclosporin at doses of
      3 and 10 mg/kg, respectively. On the other hand, TAK-044 (3 and 10 mg/kg) did not
      change the pharmacokinetic parameters for ciclosporin (3 mg/kg). Biliary
      excretion is the major elimination route for both TAK-044 and cyclosporin.
      Ciclosporin delayed biliary excretion of [14C]TAK-044 in a dose-dependent manner,
      which might be due to inhibition of process(es) of hepato-biliary excretion of
      TAK-044. In conclusion, the AUC values for TAK-044 in rats are increased dose
      dependently by coadministration with ciclosporin. Therefore, it may be necessary
      to adjust the dosage of the TAK-044 in combination with ciclosporin in the course
      of the first clinical trials.

PMID- 12404881
TI  - Human neutrophil oxidative bursts and their in vitro modulation by different N
      acetylcysteine concentrations.
AB  - Reactive oxygen species released by activated polymorphonuclear leukocytes as an
      expression of their defensive function are considered to be a major source of the
      cytotoxic oxidant stress, that triggers a self-sustaining phlogogenic loop in the
      respiratory system. N-Acetylcysteine (CAS 616-91-1, NAC), a known mucolytic drug,
      possesses also antioxidant properties, but it undergoes a rapid and extensive
      first-pass metabolism resulting in low tissue availability. Thus to further
      improve the NAC bioavailability a single oral administration of 1200 mg NAC has
      been recently proposed. This study has been performed to investigate in vitro by
      means of luminol amplified chemiluminescence the ability of the concentration of
      35 mumol/l NAC available after single oral administration of 1200 NAC to
      interfere with human neutrophil oxidative burst evoked by both corpuscolate and
      soluble stimulants, in comparison with 16 mumol/l NAC, the serum concentration
      obtainable after single oral administration of 600 mg NAC. At concentrations of
      16 and 35 mumol/l, NAC significantly reduced in a concentration-dependent manner
      the activation of polymorphonuclear neutrophils (PMNs) oxidative bursts induced
      by all of the stimulants (C. albicans, formyl-methionyl-leucyl-phenylalanine
      (fMLP), phorbol myristate acetate (PMA)). This effect was also present in cell
      free systems, thus confirming the scavenger activity of these two concentrations
      of NAC. The fact that no effects were seen on PMN phagocytosis and bacterial
      killing indicates that NAC has no negative influence on other PMN functions such
      as antimicrobial activity.

PMID- 12404882
TI  - Volume independent stimulation of renin secretion by a single dose of amiloride
      in man.
AB  - The regulation of renin secretion is not understood in detail. There is evidence
      that amiloride (CAS 17440-83-4) has a stimulatory effect on the renin secretion
      but it is still in question whether this is volume and/or sodium independent. The
      purpose of this study was to investigate whether a single dose of amiloride has a
      direct stimulatory effect on the renin secretion in humans independent of its
      diuretic effect. Blood pressure, plasma renin activities and plasma aldosterone
      concentrations as well as serum electrolytes and serum creatinine were assessed
      in 11 healthy male humans over a period of 6 hours after a single dose of 20 mg
      of amiloride (Midamor), or placebo. Furthermore every hour urine was collected
      for analysis of urinary creatinine and electrolytes. To avoid a possible effect
      on the renin secretion via augmented diuresis induced by amiloride the urinary
      volume loss was replaced by 0.9% NaCl solution. There was a decrease in plasma
      renin activities and plasma aldosterone concentrations after amiloride and
      placebo administration, but the plasma renin activity after amiloride was
      significantly higher compared with placebo. Also the plasma aldosterone
      concentration was higher after amiloride compared with placebo, but the
      difference did not reach statistical significance. Serum and urinary
      concentrations of sodium and potassium clearly confirmed the known potassium
      saving and natriuretic effect of amiloride. Serum creatinine concentrations
      decreased and urinary sodium chloride concentrations increased due to the
      administered volume load using physiologic sodium chloride solution. The present
      study provides evidence that amiloride induces renin secretion by direct
      mechanisms in man, which might go along with augmented aldosterone secretion.

PMID- 12404883
TI  - Improvement of the bioavailability of colchicine in rats by co-administration of
      D-alpha-tocopherol polyethylene glycol 1000 succinate and a polyethoxylated
      derivative of 12-hydroxy-stearic acid.
AB  - Two surface-active formulation ingredients, a water-soluble derivative of vitamin
      E (D-alpha-tocopherol polyethylene glycol 1000 succinate, vitamin E-TPGS) as well
      as a polyethoxylated derivative of 12-hydroxy-stearic acid (Solutol HS 15) were
      investigated in rats for their potential to increase the oral bioavailability of
      the p-glycoprotein (p-gp) and cytochrome P450 substrate colchicine. D-alpha
      Tocopherol polyethylene glycol 1000 succinate and the polyethoxylated derivative
      of 12-hydroxy-stearic acid will be referred to as "surfactant 1" and "surfactant
      2" in the following. Colchicine was administered to the animals at a dose level
      of 5 mg/kg in each 10% surfactant containing formulation. A solution of
      colchicine in isotonic saline was selected as a reference formulation. It was
      found that the administration of colchicine in the surfactant containing
      formulations resulted in significantly higher systemic exposures as compared to
      the aqueous reference vehicle (2-fold increase in AUC in the presence of
      surfactant 1 and 4-fold increase in AUC in the presence of surfactant 2). The
      aqueous solubility of colchicine was about 16.7 mg/ml, and the increase in
      solubility in the presence of 1% surfactant 1 or surfactant 2 to about 20.5 and
      18.5 mg/ml was not considered to significantly affect the oral bioavailability.
      In summary, it was demonstrated that both surfactants are suitable formulation
      ingredients to improve the systemic exposure of colchicine in the rat. Due to the
      high aqueous solubility of colchicine the most likely reasons for these findings
      are inhibition of p-gp and/or metabolism as well as permeability enhancement by
      interactions of the surfactants with the intestinal membrane.

PMID- 12404884
TI  - Effects of lerisetron, a new 5-HT3 receptor antagonist, on ipecacuanha-induced
      emesis in healthy volunteers.
AB  - The purpose of these studies was to evaluate the effect of lerisetron (1-phenyl
      methyl-2-piperazinyl-1H-benzimidazole hydrochloride, CAS 143257-98-1, F-0930
      RS2), a new 5-HT3 receptor antagonist, on ipecacuanha-induced nausea and
      vomiting. The ipecacuanha model of emesis has been used to test the anti-emetic
      activity of several different 5-HT3 antagonists and the anti-emetic doses that
      were effective in the ipecacuanha model have been found to correlate well with
      the clinically effective doses. Study 1 investigated oral doses of lerisetron
      from 4 mg to 40 mg. Study 2 evaluated the duration of effect of a single dose of
      20 mg oral lerisetron. Study 3 evaluated intravenous doses of 18 mg and 12 mg
      lerisetron. In Study 1, the 40 mg dose of oral lerisetron inhibited emesis in all
      test subjects. The percentage of subjects who experienced an emetic episode
      increased as the dose of lerisetron decreased. At the lowest dose level tested
      five of six subjects had an emetic episode compared with four out of five in the
      placebo group. In Study 2, 20 mg oral lerisetron was effective up to 12 h after
      administration. When ipecacuanha was administered at 18 h post-dose three of
      seven subjects had an emetic episode and at 24 h post-dose the incidence of
      emesis was similar to the placebo treatment groups in the previous study. Study 3
      demonstrated the effectiveness of intravenous doses of lerisetron. The 18 mg
      intravenous dose reduced the number of patients experiencing emetic episodes by
      75% compared with placebo, doses below 12 mg i.v. were not evaluated because of
      the reduced efficacy of the compound at this dose level. In conclusion,
      lerisetron has been shown to be effective in the treatment of ipecacuanha-induced
      nausea and vomiting at intravenous doses of 18 mg and at oral doses of 20 mg for
      up to 12 hours.

PMID- 12404885
TI  - Total synthesis and anti-leishmanial activity of some curcumin analogues.
AB  - Curcumin (1) an important yellow dye isolated from Curcuma longa rhizomes,
      exhibits a variety of pharmacological effects such as anti-inflammatory,
      antioxidant and antiviral activity. Ten curcuminoids (2-11) were synthesized by
      the condensation of 2,4-pentanedione with differently substituted benzaldehydes,
      using the boron complex approach, which avoided Knoevenagel condensation at C-3
      of the diketone. The curcuminoids were assayed in vitro against Leishmania
      amazonensis promastigotes using pentamidine isethionate (CAS 140-64-7) as the
      reference drug. Compound (5) 1,7-bis-(2-hydroxy-4-methoxyphenyl)-1,6-heptadiene
      3,5-dione) was the most effective.

PMID- 12404886
TI  - Antimicrobial activity of dequalinium chloride against leading germs of vaginal
      infections.
AB  - Dequalinium chloride (CAS 522-51-0) and povidone iodine (CAS 25655-41-8) are
      known as antiseptic agents and used in the local treatment of vaginal infections.
      Clotrimazole (CAS 23593-75-1) is an anti-fungal drug and applied primarily in the
      therapy of vulvo-vaginal candidiasis and to a lesser extent in bacterial
      vaginosis and trichomoniasis. However, antimicrobial activities of those three
      agents in comparison to each other have not been reported so far. To address this
      issue the antimicrobial activities of these agents against 18 germs relevant to
      vaginal infections were determined. The tested species are representatives of the
      genera Staphylococcus, Streptococcus, Enterococcus, Listeria, Escherichia,
      Proteus, Gardnerella, Bacteroides, Prevotella, Porphyromonas, Candida, and
      Trichomonas. All micro-organisms were susceptible to dequalinium chloride with
      the exception of Proteus mirabilis. At a given dose, the activity of dequalinium
      chloride was higher as compared to the other substances. In view of its wide
      antimicrobial spectrum dequalinium chloride is an efficient alternative in the
      local therapy of vaginal infections such as fluor vaginalis, bacterial vaginosis,
      aerobic vaginitis, vulvo-vaginal candidiasis and trichomoniasis.

PMID- 12404887
TI  - Local treatment of vaginal infections of varying etiology with dequalinium
      chloride or povidone iodine. A randomised, double-blind, active-controlled,
      multicentric clinical study.
AB  - This randomised, double-blind, multicentric clinical study compared the efficacy
      and tolerability of the two vaginal antiseptics, 10 mg dequalinium chloride (CAS
      522-51-0, Fluomycin N) and 200 mg povidone iodine (CAS 25655-41-8), in a parallel
      group design. A total of 180 patients with vaginal infections of varying etiology
      participated in this study (bacterial vaginosis, fluor vaginalis, vulvo-vaginal
      candidiasis, trichomoniasis). Patients were randomly allocated to one of the two
      treatment groups and were treated once per day for 6 days. Control examinations
      took place 5 to 7 days after the end of treatment, and 3 to 4 weeks after the
      first control examination. The total symptoms score, a summary score for the
      clinical symptoms, discharge, burning, pruritus, redness of vulva/vagina, was
      defined as primary efficacy parameter. The treatments at the first control
      examination were compared in the full analysis set using the Wilcoxon-Mann
      Whitney U-test, 2-sided, thereby proving equivalence of both treatments at the 5%
      level. Both treatments strongly improved the symptoms of vaginal infections both
      on short-term and long-term follow-up. Descriptive analysis of the secondary
      parameters, vaginal pH, degree of purity of the vaginal flora, and number of
      lactobacilli in the wet mounts, supported the comparable efficacy of both
      therapies to restore the vaginal milieu. Analysis of the diagnostic subgroups
      indicated that irrespective of the diagnosis, both treatments improved the
      efficacy criteria as observed for the entire population. The global assessment of
      the therapeutic efficacy by investigators and patients supported the results of
      the efficacy analysis with good to very good ratings in 70-90% of the cases. A
      good tolerability of both preparations was observed in this study with a low
      number of adverse events in the test group (5.8%).

PMID- 12404888
TI  - Studies of interferences of apomorphine and its metabolites or decomposition
      products with immunochemical screening tests for legal and illicit drugs after
      therapeutic doses of apomorphine.
AB  - This study deals with the question of whether apomorphine (CAS 314-19-2; e.g. in
      Ixense) and its metabolites or decomposition products interfere with the
      specificity of immunochemical screening tests (immunoassays) for legal and
      illicit drugs. It was the result of the investigations that after the therapeutic
      use of apomorphine no relevant false-positive screening findings were observed
      with the CEDIA (cloned enzyme donor immuno assay) and FPIA (fluorescence
      polarisation immuno assay) tests, which are commonly encountered in drug
      screening programs, when using recommended cut-off values for urine.

PMID- 12404889
TI  - [Proposing a teaching program for the first of the 3 "I's" (english, informatics,
      internet) in medicine and surgery in Italy].
AB  - BACKGROUND: Since the beginning of the 90s, medical students in Italian Faculties
      have been required to pass a compulsory English exam. In the light of the growing
      importance of reasonably fluent spoken and written English at the start of the
      new millennium, the authors present an English teaching program spanning the 6
      years of medical studies leading to a degree in Medicine and Surgery. THE
      PROGRAM: Features an initial test of basic English proficiency; the specific
      terminology: macroscopic anatomy, physiology, etc., to be learnt in the 3rd year;
      the true course in the 4th year, focusing on fluent spoken English, tips for
      formal correspondence and a knowledge of the typical format and language used in
      scientific papers; update courses in the form of medical seminars in the 5th and
      6th years. CONCLUSION: No graduate in any field can be considered equipped for
      his/her chosen career unless he/she possesses an adequate knowledge of spoken and
      written English. The course presented aims to provide Italian medical students
      with the necessary skills.

PMID- 12404890
TI  - [Traumatic lesions of the hand extensor system: epidemiology and surgical
      considerations].
AB  - AIMS: To investigate demographics, modalities and type of injuries among a
      population of isolated traumatic injuries of extensor tendons in order to
      evaluate the consequences on health service and on prevention. METHODS:
      Retrospective study of injuries treated at the divisions of Plastic Surgery and
      Orthopedics in a third level referral center among the years 1993-1999. MAIN
      RESULTS: Data from 173 patients were analyzed, a prevalence of males (81%) and
      injuries at home (55%) has been observed. Especially young adults (46.88%) have
      been involved, the thumb has been most interested finger and the middle finger
      the least, with two peaks of incidence in spring and autumn. The lesions, exposed
      through an extension of the existing wound, have been usually sutured according
      to Kessler, adding an early protected motion protocol. CONCLUSIONS: We discuss
      the possible causes and consequences of data observed, with special reference to
      the possibility of treating isolated extensor tendon injuries at district
      hospitals by non-hand surgeons, and primary actions of prevention.

PMID- 12404891
TI  - [Histochemical assessment of immunoreactivity of thyroid peroxidase and its
      correlation with biochemical activity].
AB  - BACKGROUND: Peroxidase content has been recently evaluated in normal thyroid and
      in different thyroid disorders by biochemical, histochemical, ultrastructural and
      immunocytochemical methods Nevertheless immunocytochemical detection of thyroid
      peroxidase in thyroid samples conventionally processed for histology hes never
      been done using a commercially available antibody, neither its correlation with
      the biochemical activity on adjacent samples. METHODS: In this study we have
      analyzed normal thyroid tissue (3 patients), follicular adenoma (2 patients) and
      multinodular goiter (2 patients) conventionally processed for histology and
      stiined by immunocytochemistry (Avidin Biotin System) using a polyclonal (rabbit)
      antibody for horseradish peroxidase (Serotec). Biochemical assay was performed on
      adjacent samples according to Hosoya method. RESULTS: Normal thyroid showed
      peroxidase immunoresectivity in the majority of follicular celis; neoplastic
      cells of adenomas were variably stained. Biochemical assay showed positive
      correlation with ICC ranging from 20.4 mg/mg/prot a in multinodular goiter to
      42.12 in normal thyroid, up to 122 of follicular adenoma. CONCLUSIONS: Peroxidase
      content in the thyroid gland may be of clinical interest in several thyroid
      diseases, and in this study we have demonstrated that thyroid peroxidase can be
      detected by ICC in routinely processed thyroid samples using a commercially
      available antibody.

PMID- 12404892
TI  - Study of the antireflux function of the Roux-en-y jejunal loop in reconstruction
      following gastrectomy.
AB  - Persistence of global orthograde peristaltic propulsion in the Y jejunal loop
      according to Roux makes this latter adequate for reconstruction of digestive
      transit after gastric resection or total gastrectomy, simultaneously avoiding
      reflux. Ectopic pacemakers can set in its proximal tract and favor intestinal and
      bile juice reflux in the gastric stump or esophagus, especially if the loop is
      too short and the new pacemaker is far from its superior margin. Moreover, the
      slower peristaltic waves can favor a relative stasis and, thus, a containing
      function, which could represent an element of morbidity over a certain limit. If
      the Y loop is not too long, but long enough to include the higher frequency
      ectopic pacemaker, which overcomes the lower frequency ones located distally, the
      positive aspects of both these characteristics can be exploited for satisfying
      and free of morbidity results. We believe that the best length is 35-40 cm, with
      positive clinical results. 99Tc-HIDA sequential scintigraphy clearly shows the
      absence of bile material reflux in the digestive tract proximal to the
      anastomosis.

PMID- 12404893
TI  - [Surgical treatment of bleeding peptic lesions: our experience].
AB  - The authors report their experience on surgical treatment of peptic bleeding
      lesions. From January 1994 till April 1999 they observed and surgically treated
      35 patients (mean age 65) suffering from bleeding gastroduodenal ulcer.
      Complications linked to surgical treatment had an incidence of 17.5%, while those
      ones linked to the patient's general conditions of 21%; mortality was 20%.
      Surgery has been gradually substituted by endoscopy which represent the principal
      examination for diagnosis of bleeding gastroduodenal ulcer with the aid of
      different hemostatic techniques, so that surgery has been relegated to the last
      place in uncontrollable bleeding treatment. Observed results, following those
      ones of other authors, show the unfavourable prognosis linked to patient's
      different conditions when surgeon operates.

PMID- 12404894
TI  - [Intrahepatic biliary lithiasis: experience in 20 years].
AB  - In confirming that intrahepatic gallstones don't represent a frequent disease in
      western countries, Authors specify how this incidence is going to grow up slowly,
      but in a progressive way. In reporting their experience since 1980 to nowadays
      they point out how different diagnostic procedures and therapy way of acting were
      in the first and in the second deca. After having explained actual therapeutic
      direction that is described in literature, they finish by stating how this is
      often conditioned by complex anatomicopathological picture and by seriousness of
      hepatic damage that often comes with intrahepatic lithiasis.

PMID- 12404895
TI  - [Integration of operative endoscopy and laparoscopic surgery in the treatment of
      cholecysto-choledocholithiasis].
AB  - Laparoscopic cholecystectomy has become first choice for symptomatic gallstones,
      but there are not agreement about therapy of supposed synchronous
      choledocholithiasis. We report our experience about the sequential treatment
      (endoscopic-laparoscopic) of the gallstone and the associated common bile duct
      stones. METHODS: During the period Jan. 1992 Dec. 1997 we have evaluated 128
      patients that were submitted to ERCP for suspicion CBDS and gallstone. All
      patients undertook a systematic assessment: Patient age, sex, history of
      jaundice, history of pancreatitis, levels of serum alanine aminotransferase,
      alkaline phosphatase, amylase, total and direct bilirubin and CBD diameter on
      ultrasonography. RESULTS: In the 96 (75%) cases of choledocholithiasis endoscopic
      sphincterotomy has been performed and combined with laparoscopic cholecystectomy.
      Thirty-two patients (25%) submitted to ERCP have been negative for stones. Only 4
      patients have needed surgery because of big stones inside the CBD after ESWL
      failure. The incidence of complications of ERCP-ES has been, in our experience,
      7.1% and mortality 0.8%. All the complications have been treated conservatively
      and did not need surgery. CONCLUSIONS: The sequential treatment (endoscopic
      laparoscopic) of synchronous CBDS and gallstone, in hands of expertise, is
      efficient with high rate of success and low rate of complications in order to
      morbidity and mortality. Finally we believe that it is very important to discover
      CBDS preoperatively with the non invasive methods as the MRI-Colangiography and
      to assay the liver tests in order to avoid negative ERCP for choledocholithiasis.

PMID- 12404896
TI  - [Clinical and functional results after restorative proctocolectomy with ileal J
      reservoir in the treatment of ulcerative colitis].
AB  - PURPOSE: Restorative proctocolectomy is the procedure of choice in the treatment
      of ulcerative colitis. The operation is successful in removing all diseased
      mucosa while preserving a normal bowel function and a good quality of life for
      the patient. In this article are presented the clinical and functional results
      obtained in 28 patients, 19 males (68%) and 9 females (32%) after stapled
      restorative proctocolectomy with ileal J pouch-anal anastomosis. RESULTS: There
      were no perioperative deaths. The overall morbidity rate was 31%. Six patients
      (21%) presented pelvic abscess; 2 (7%) pelvic hematoma, 4 patients (14%) ileo
      anal anastomotic stricture, 1 patient (3.6%) pouch-vagina fistula, three patients
      (11%) intestinal obstruction and 7 (25%) pouchitis. All patients were able to
      evacuate their pouches spontaneously. The mean bowel movements were 6-9/24 hours
      at the first postoperative month and 3-5/24 hours at the sixth month. Infrequent
      nocturnal seepage occurred in 6 patients (21%). Stool consistency returned to
      normal within 3-6 months. The mean pouch capacity was 210 cc. The mean resting
      pressure was diminished in 11 patients (39%), the men and maximal squeeze
      pressures were improved in 9 (32%); the ileo-rectal-anal inhibitory reflex was
      normal in 5 patients (18%), not defined in 12 (43%). Impotence or impaired
      bladder function was not present. CONCLUSION: The use of staplers in the surgical
      technique of restorative proctocolectomy with J shaped ileo-anal pouch is
      associated with low morbidity and better long-term results. The procedure
      requires a good selection of patients, a correct surgical timing, a very
      carefully technique and a low pre and postoperative treatment with steroids.

PMID- 12404897
TI  - [Tension-free prosthetic repair in the surgical treatment of epigastric hernia].
AB  - From November 1994 to June 2001, the authors have performed 16 operations for
      epigastric hernia. Local anaesthesia was used in 8 patients with small hernias,
      in the remaining 8 general anaesthesia was preferred. In defects smaller than 4
      cm, the repair was achieved by insertion of a polypropylene dart plug sutured to
      the margins of the hernial defect. In larger defects a double layer mesh placed
      in the pre-peritoneum was used. All patients were discharged within 24 hours of
      surgery. Postoperative pain was mild and required hospital analgesia in 25% of
      cases and domiciliary analgesia in 1 patient only. During a follow-up ranging 3
      to 79 months (mean 31.2), no recurrence has been recorded. The proposed technique
      is simple, safe and absolutely effective, allows immediate rehabilitation with a
      low risk of complications.

PMID- 12404898
TI  - [Skin metastasis from renal carcinoma: epidemiologic and clinical features].
AB  - The Authors present an additional case of a 70-years old male patient with skin
      metastasis from renal cell carcinoma, 15 months after nephrectomy. The patient
      died ten months later for advanced neoplastic disease. Skin metastasis affect 3
      6% of patients with renal cell carcinoma. The surgical treatment is mandatory for
      single nodule. Chemotherapy is often ineffectual. The prognosis is poor, with a 0
      8% 5-years survival for patients with multiple nodules.

PMID- 12404899
TI  - [Complication of acute diverticulitis: colo-vesical fistula (a clinical case)].
AB  - BACKGROUND: A patient presenting a colo-vescical fistula together with a number
      of other pathologies, and the absolute absence of a set scheme for the treatment
      of septic diverticular complications has prompted us to publish this case.
      PATIENT AND METHODS: The patient aged 80 was admitted urgently, diagnosed with
      intestinal occlusion. Generally poor conditions: renal insufficiency, abdomen
      globose and hypertympanic, systaltic mass in the epigastric site. The patient had
      experienced abdominal pains for about 4 months; severe tenesmo during evacuation:
      fever temperature as high as 38.5 degrees C; dysuria; aero-hydro levels; stenosis
      of the sigmoid. A decision was taken to operate. SURGERY: The presence of a large
      mass at the level of the sigmoid, which subsumed the ileal ansae, the vescical
      and the sigmoid itself. While isolating the pelvic anatomical structures, a
      purulent sac in the Douglas was uncovered, which united the bladder and the
      sigmoid. It was thought appropriate only to fit a colostomy, thus excluding the
      descendents. DISCUSSION: Surgery must resolve the peritonitis and the
      fenestration itself. Due to the existing septic conditions, it was not believed
      advisable to perform a primary anastomosis; a Hartmann's or a simple colostomy
      was thought preferable. CONCLUSIONS: This case underlines the difficulty in
      standardising operational conduct when this in turn will depend on the experience
      of the operator and the circumstances met at the time.

PMID- 12404900
TI  - [Breast carcinoma in pregnancy: a clinical case].
AB  - Breast cancer is a rare, but frequently hidden pathology. A woman, 36 years old,
      during the early months of pregnancy found a little tumor in her right breast. A
      fine needle biopsy was negative for cancer. Despite this, the tumor rose and two
      months after delivery (the patient breast-fed her daughter for a month), she had
      pain in the right axillary region and the tumors involved all superior dials of
      the right breast. A Madden mastectomy was performed. The histopathological report
      was: ductal invasive breast cancer 3 of 19 lymph nodes involved, stage IIIA, TNM
      pT3N2M0, ER -, PgR +--. Chemotherapeutic regimens were: at first ADM 75 mg/m2 for
      5 cycles, and after CMF 1-8 for 6 cycles. After six months the woman had a
      cutaneous recurrence in the scar of mastectomy, treated with surgery and RT.
      Thirteen months after, she had lung MTS and then brain MTS. The patient died
      thirty months after the mastectomy. The surgeons have to discover the women high
      risk for the breast cancer before and during the pregnancy. Excisional biopsy is
      the diagnostic procedure of choice for breast lump during pregnancy. When a
      breast cancer develops during a pregnancy, the surgeon has to operate immediately
      the tumors. Chemotherapeutic regimens should be delayed until the second o third
      trimester or after delivery.

PMID- 12404901
TI  - [Intestinal endometriosis. Three new cases and review of the literature].
AB  - OBJECTIVE: The study was undertaken to identify some features of the intestinal
      endometriosis such as symptoms, helpful investigations, pattern of distribution
      and surgical management. PATIENTS: Three consecutive cases, observed during a
      sixteen month period, are reported. The most frequent symptoms were chronic
      pelvic and abdominal pain, dysmenorrhea, alterated bowel habit and menorrhagia.
      The diagnosis of intestinal endometriosis was incidental in all but one case
      admitted for an intestinal subocclusive syndrome in patient with a past history
      of pelvic endometriosis previously documented by laparoscopy. RESULTS: All
      patients presented a sigmoid localization of endometriosis with different degree
      of stenosis and underwent sigmoid resection, followed by a resolution of
      abdominal symptoms. DISCUSSION: Although the exact frequency of intestinal
      endometriosis is difficult to know because of the lack of specific symptoms and
      reliable investigations, it has been estimated that implants to the bowel may
      occur in 3%-37% of women affected by endometriosis. The sigmoid colon is the most
      common site of localization. The main symptoms are pelvic pain, dysmenorrhea,
      infertility and diarrhoea or constipation; rarely patients present bowel
      occlusion due to stenosis (less than 15% of the cases) or cyclic rectal bleeding.
      CONCLUSION: Generally, intestinal endometriosis is not suspected preoperatively
      in those patients without a past history of this condition; however an accurate
      diagnosis can be provided throughout laparoscopy, before open surgery. The
      hormonal therapy is not successful in alleviating moderate to severe obstructive
      symptoms. Thus surgery still remains the most effective treatment for advanced
      intestinal endometriosis.

PMID- 12404902
TI  - [Pseudomyxoma peritonei associated with mucinous cystadenoma of the appendix].
AB  - The authors report a case of a male 86 years old patient with peritoneal
      pseudomyxoma associated to cystoadenoma of the appendix. Preoperative CT scan
      showed the presence of a mass in the appendiceal site containing a gelatinous
      fluid collection and calcifications. Notwithstanding, diagnosis of pseudomyxoma
      was preoperatively considered less probable due to the rarity of the affection
      and the advanced age. At laparatomy was revealed the presence of the large mass
      observed at CT scan, involving the caecum and occupying the retroperitoneal space
      along the ascending colon. Mucinous ascites was present without invasive mucinous
      implants in the peritoneum. Operation consisted in a right hemicolectomy with
      total removal of the retroperitoneal mass and evacuation of the mucinous ascites.
      Histology confirmed the clinical diagnosis of pseudomyxoma peritonei associated
      to cystoadenoma of the appendix. The case is of paradigmatic interest as being
      quite correspondent to the classical Ronnett's definition of pseudomyxoma: a
      clinicopathological entity characterized by mucinous ascites and non-invasive
      mucinous implants with a characteristic distribution and containing
      histologically benign mucinous epithelium derived from an appendiceal mucinous
      adenoma and having a benign course. According to such definition, the authors
      stress the importance of an appropriate classification of the observed cases of
      pseudomyxoma, under whose term is often collected a heterogeneous group of
      pathological lesions, in order to better evaluate the prognosis and treatment.

PMID- 12404903
TI  - Hernia of the posterior lamina of the rectus abdominis muscle sheath: report of a
      case.
AB  - A case of hernia of the posterior lamina of the rectus abdominis muscle sheath in
      a 30 years old female, six months pregnant, is reported. The symptomatology was
      almost exclusively characterized by a persistent abdominal pain, located in the
      right costal margin at the intersection with the right adsternal line and
      aggravated by changes in position and by increases of intra-abdominal pressure.
      No bulge or specific hernial defect was clinically appreciable. The key to
      diagnosis, in this case, was an echography of soft tissues performed in the area
      where the pain was greater: with the patient in orthostatic position, it was
      possible to demonstrate a defect in the posterior sheath of the rectus abdominis
      muscle, that, increasing the intra-abdominal pressure, let pass preperitoneal fat
      between sheath and muscle. Both the predisposing (anatomic and clinical) factors
      and the provocateurs ones, probably involved in the genesis of this peculiar
      case, are discussed.

PMID- 12404904
TI  - [Serious invasive pneumococcal disease in young children: the importance of
      vaccination].
AB  - In three children with fever, two girls aged 8 and almost 10 months and one boy
      aged 5 months, invasive pneumococcal disease was present. The youngest girl
      presented with pneumococcal sepsis which was complicated by haemolytic uraemic
      syndrome--she recovered--and the boy developed fulminant fatal pneumococcal
      sepsis/meningitis. The oldest girl was admitted for pneumococcal cellulitis and
      recovered. More than 80% of the cases of childhood invasive pneumococcal disease
      occur in children less than 2 years of age. However, the long available 23-valent
      pneumococcal polysaccharide vaccine is not effective in this age group. Recently,
      a 7-valent pneumococcal conjugate vaccine was registered in the Netherlands. This
      conjugate vaccine is effective in protecting infants and children from invasive
      pneumococcal disease. The Health Council of the Netherlands has recommended
      inclusion of the conjugate vaccine in the standard vaccine schedule. In the
      absence of a universal vaccination, the 7-valent pneumococcal conjugate vaccine
      is recommended for children at high risk of invasive disease.

PMID- 12404905
TI  - [Broader indication for treatment with statins; the 'heart protection study'].
AB  - The introduction of statins has been a breakthrough in the treatment of
      hypercholesterolaemia. Statins are safe and effective in reducing the risk of
      coronary heart disease in the general population. The 'Heart protection study'
      has provided evidence for the benefit of statin treatment in much broader
      populations than is presently indicated in the Dutch national guidelines, i.e.
      also in high-risk persons with diabetes mellitus, and irrespective of age or
      cholesterol level. The use and cost of statins, which have been referred to as
      'lifestyle-drugs' in the lay press, have risen enormously. Recently, the Dutch
      College of Healthcare Insurers issued a report in which recommendations
      concerning the reimbursement of the costs for cholesterol-lowering drugs are
      based on 'generally accepted insights into the appropriate use of these drugs'.
      Lifestyle and/or age are not exclusion criteria for treatment with statins. The
      expiration of patents of some statins and modifications to the reimbursement
      system in 2003 could lead to cost reductions.

PMID- 12404906
TI  - [Photo dermatology].
AB  - Photodermatology has become an important part of the dermatologist's area of
      focus. This subspeciality is not only involved with studying basic biological
      processes such as the effects of ultraviolet (UV) irradiation on the skin's
      immune system (photo-immunology), melanocytes or DNA (carcinogenesis), but also
      with clinical issues such as photoprotection, photosensitive skin diseases
      (photodermatoses) and phototherapy. Increasing knowledge about the effects of UV
      irradiation on the skin, with or without photosensitising agents, has led to the
      development of new forms of photo(chemo)therapy. These allow good therapeutic
      results to be achieved in the treatment of not only psoriasis, but also other
      chronic inflammatory skin diseases, with minimal side effects. DNA can absorb UV
      irradiation. This can lead to irreversible DNA damage and mutations in genes
      responsible for cell cycle control. These events can lead to skin cancer. The
      presence of pheomelanin, which is an inferior type of UV light-absorbing melanin,
      can add to this process of DNA damage. The three most important types of skin
      cancer are basal cell carcinoma (more than 30,000 new patients per year in the
      Netherlands), squamous cell carcinoma and melanoma.

PMID- 12404907
TI  - [Ghrelin, an important hormone produced by the stomach].
AB  - Ghrelin is a hormone produced by endocrine cells in the stomach. Ghrelin
      stimulates the secretion of growth hormone by the anterior pituitary. This effect
      is mediated by hypothalamic growth-hormone secretagogue receptors. Binding to
      these receptors not only stimulates growth hormone secretion, but also has
      vascular effects (positive inotropic effects), modifies (decreases) insulin
      sensitivity, affects glucose metabolism (hyperglycaemia) and stimulates gastric
      acid production. Antiproliferative effects of ghrelin have been described on
      experimental tumour models. Ghrelin seems to play a role in stimulating the
      appetite as well as promoting a more effective storage of food components.
      Whether or not ghrelin could play any role in the induction of weight gain has
      yet to be established. This is also true for the role of potential ghrelin
      antagonists in the induction of weight loss in case of obesity.

PMID- 12404908
TI  - [From gene to disease; a defect in the regulation of protein production leading
      to vanishing white matter].
AB  - Leukoencephalopathy with vanishing white matter (VWM) is a newly defined
      autosomal recessive disorder. The clinical course is chronically progressive with
      additional episodes of rapid deterioration, provoked by fever and minor head
      trauma. We recently identified the five genes associated with VWM: EIF2B1-5. They
      encode the five subunits of eIF2B, which is a eukaryotic translation initiation
      factor expressed in all human tissues and highly conserved during evolution.
      eIF2B has a key role in the regulation of protein synthesis. It is the most
      important factor to down-regulate protein synthesis during mild temperature
      stress, when a decrease in protein synthesis is necessary to prevent proteins,
      not protected by heat shock proteins, from coagulating. Most mutations found in
      the eIF2B genes are 'mild' and lead to the substitution of a single amino acid.
      Major rearrangements are only found in the heterozygous state with an amino acid
      substitution as second mutation. It is likely that the presence of two mutations,
      which lead to a total loss of one subunit, is not viable. Two founder effects
      were observed in the Dutch population. One concerned EIF2B5 and was observed in
      the region of Zwolle; the second was observed in the region of Weert and
      concerned EIF2B2. The diagnosis of VWM is based on typical MRI findings. DNA
      analysis is possible and will be limited to cases in which MRI findings are
      suggestive of VWM. Prenatal diagnosis is an option in the families in which the
      responsible mutations have been identified.

PMID- 12404909
TI  - [Diagnostic image (109). A man with furuncles. Cutaneous myiasis].
AB  - A 27-year-old man had 'furuncles' after a one-month stay in Gambia, which proved
      to be cutaneous myiasis due to Cordylobia anthropophaga.

PMID- 12404910
TI  - [Characterisation of families with hereditary prostate cancer in the
      Netherlands].
AB  - OBJECTIVE: To inventory the characteristics of Dutch families with hereditary
      prostate carcinoma (HPC). DESIGN: Descriptive. METHOD: From a national registry
      of families that meet the criteria of HPC, information was collected about
      patients with HPC and their first-degree relatives from 1995 through to 30 June
      2001. The ages of the HPC patients at diagnosis were compared with those of all
      patients with prostate cancer in the Dutch population during the period 1990 to
      1996. The cumulative risk of prostate cancer for HPC families was calculated on
      the basis of the ages of the patients with prostate cancer and their first-degree
      male relatives. RESULTS: A total of 70 families fulfilled the criteria. The
      families included 273 patients with prostate cancer. The diagnosis had been
      confirmed in 208 (76%) of these patients. Two cases of prostate cancer were
      observed in 3 families, 3 cases were found in 31 families, and in the remaining
      families 4-8 cases of prostate cancer were observed. The mean age at diagnosis of
      prostate cancer was 65.5 years (range: 46-89). Of the 273 HPC patients, 128 (47%)
      were younger than 65 years at the time of diagnosis, whereas in unselected cases
      of prostate cancer this figure was 16%. The risk of developing prostate cancer
      before the age of 70 years for members of HPC families was 39%. The mean age of
      death due to prostate cancer was 71 years (54-84). The mean value of prostate
      specific antigen (PSA), known for 47 (17%) of the HPC patients, was 36.8 ng/ml
      (2.1-280).

PMID- 12404911
TI  - [Deterioration of schizoaffective disorder due to an interaction between
      haloperidol and carbamazepine].
AB  - A 40-year-old woman with a schizoaffective disorder was initially treated with
      lithium carbonate and haloperidol decanoate, but after three years the lithium
      was replaced with carbamazepine. Following this, her performance deteriorated
      over several years despite increasing dosages of haloperidol. After withdrawal of
      the carbamazepine a remarkable recovery occurred. A pharmacokinetic interaction
      between haloperidol and carbamazepine, which results in decreased haloperidol
      blood levels, provides a good explanation of this clinical picture. This
      clinically relevant interaction should be incorporated into pharmacovigilance
      systems.

PMID- 12404912
TI  - [Centenary of the Health Council of the Netherlands. IV. Infectious diseases].
AB  - Many advisory reports of the Health Council of the Netherlands in the past
      century have dealt, directly or indirectly, with infectious diseases. One example
      is vaccination against smallpox. At the start of the last century, advice on this
      subject was important: initially, vaccination was compulsory by law, but people
      became increasingly aware of the associated side effects. A second example is
      immunisation against acute anterior poliomyelitis, which became a reality during
      the fifties. The advice also contained a discussion of which vaccine should be
      chosen: the inactivated 'dead' (Salk) form or the attenuated 'live' form (Sabin).
      Due to sound national organisation and associated logistics, a high level of
      vaccination was (and still is) achieved and the clinical disease known as polio
      disappeared from the Netherlands. Food-borne infections form the third example.
      The effect of the advice published by the Council on this subject (from 1960
      onwards) has been limited, for a large part due to the significant economic
      consequences of the proposals for beef farming. The developments in the field of
      infectious diseases, immunology and vaccinology, together with social
      developments make it likely that in the coming years the Council will also
      frequently be asked for advice in the field of infectious diseases and the fight
      against them.

PMID- 12404913
TI  - [Centenary of the Health Council of the Netherlands. V. Ethical-social issues].
AB  - Since its inception, the Health Council of the Netherlands has included normative
      aspects in its reports. Over the past decades, ethics and rights have received
      increasing attention, particularly since the establishment of the Standing
      Committee on Medical Ethics and Health Law in 1977. In particular, the ethical
      implications of bio-molecular life sciences (genetic counselling, genetic
      screening, research with human embryos) have been discussed in the Council's
      publications. The Council has also been involved from an early stage in the
      euthanasia discussion. It is accepted that policy advice concerning scientific
      developments implies normative considerations. However, the extent to which the
      Council's role is simply to highlight these considerations or to present
      conclusions remains a recurring question. In the latter case, priority is often
      given to the principle of respect for autonomy, while underestimating the
      significance of solidarity.

PMID- 12404914
TI  - [Posttraumatic dystrophy: question marks on the advantages of early treatment].

PMID- 12404915
TI  - [Posttraumatic dystrophy: question marks on the advantages of early treatment].

PMID- 12404916
TI  - [Concealed local recurrence after breast-conserving treatment].

PMID- 12404917
TI  - [Concealed local recurrence after breast-conserving treatment].

PMID- 12404918
TI  - [Contacts outside of office hours: complaints presented to the general
      practitioner and to the emergency department].

PMID- 12404919
TI  - [A comparative study of the expenditures on health research in 7 western
      countries in 1997 places the Netherlands at the bottom of the list].

PMID- 12404920
TI  - [A comparative study of the expenditures on health research in 7 western
      countries in 1997 places the Netherlands at the bottom of the list].

PMID- 12404922
TI  - [Education, science, and technology].

PMID- 12404921
TI  - [The practice guideline 'Refraction errors' from the Dutch College of General
      Practitioners: response from the perspective of ophthalmology].

PMID- 12404923
TI  - [Amyloidosis in infected Didelphis marsupialis].
AB  - A male opossum, Didelphis marsupialis, captured in Teruel (Huila), Colombia, was
      inoculated intraperitoneally with 1 x 10(6) promastigotes of Leishmania chagasi
      (MHOM/CO/84/CL044B). The animal died 5 weeks after inoculation. Autopsy revealed
      signs of visceral leishmaniasis along with amastigote parasite form in Kupffer
      cells and spleen macrophages. Amyloid deposits in liver and spleen were
      demonstrated by histological staining and electron microscopy. The rapid death
      was considered a consequence of a secondary, reactive amyloidosis.

PMID- 12404924
TI  - [Preparation of DNA libraries of Plasmodium falciparum for searching calmodulin
      binding protein genes, GOGAT and Pfmyo A].
AB  - A cDNA library of Plasmodium falciparum (Colombian strain FCB2) asexual stage was
      constructed in the lambda ZipLox vector. The lambda ZipLox library and a lambda
      ZAPII (Dd2 strain) were screened for genes coding for proteins that bind with or
      are related to calmodulin (CaM). Screening was accomplished with Hot start PCR
      assays and hybridization with radiolabeled probes. Actin I, CaM, glutamate
      synthase (GOGAT) and the three myosin clones--Pfmyo A, Pfmyo B and Pfmyo C--were
      identified. The clones coding for actin I, CaM and GOGAT were retrieved from the
      lambda ZipLox library, and the GOGAT and Pfmyo A clones from the lambda ZAP II
      library. The GOGAT clone contained an insert of 2,413 base pairs corresponding to
      24.8% of the reported sequence. The Pfmyo A insert was 2,457 base pairs long, and
      represented the complete mRNA coding for this gene. Finally, the first report of
      a complete cDNA clone containing the P. falciparum myosin A is presented.

PMID- 12404925
TI  - [In vitro encystation of Giardia lamblia: analysis with two-dimensional
      electrophoresis of differentially expressed proteins].
AB  - The reconstruction of Giardia lamblia life cycle in vitro is an excellent tool
      for the study of the parasite's molecular biology. The present work describes
      techniques developed that better define parasite differentiation. An encystation
      protocol is presented along with a method for isolation and purification of the
      produced cysts. The cyst morphology at the light microscopy level is identical to
      that of in vivo cysts. A two-dimension protein map obtained by high-resolution
      electrophoresis indicated that most of the parasite's proteins are acid. Based on
      this result, the two dimension gel electrophoresis used a pH 4-7 gradient in the
      first, isoelectric focusing dimension. Differences in protein expression during
      the stages of encystation were clearly discerned, as well as images of the
      parasite obtained by light and by transmission electron microscopy that describe
      the morphological and the ultrastructural changes that occur as the cysts are
      produced in vitro.

PMID- 12404926
TI  - [Variability of 6 Colombian strains of Trypanosoma cruzi with restriction
      fragment length polymorphisms (RFLP) and random amplification of polymorphic DNA
      (RAPD)].
AB  - Chagas disease, caused by the hemoflagellate Trypanosoma cruzi, is a public
      health problem in Colombia. Previous reports have indicated the presence of
      heterogeneity among parasite populations. Six Colombian T. cruzi strains were
      obtained that differed by host, geographical region and transmission cycle. The
      genetic variability of each was compared by random amplified polymorphic DNA
      (RAPD), and isoenzymes. A restriction fragment length polymorphism (RFLP) was
      extracted using the 1.2 kb unit encoding the parasite's H2A histone as a probe.
      Genetic distances between the isolates varied greatly, from 0.611 to 0.99 as
      determined by RAPD profiles (M13F and M13R primers), between 0 and 0.81 by RFLP
      profiles (5 endonucleases), and between 0.10 and 0.55 by isoenzymes (13 enzymatic
      systems). Genetic distance matrixes derived from each of the three methods showed
      that Colombian strains exhibit a high degree of genetic differentiation. This may
      account for the broad clinical spectrum of Chagas disease in Colombia.

PMID- 12404927
TI  - [Acute diarrhea outbreak caused by Shigella flexneri at a school in Madrid,
      Cundinamarca: phenotypic and genotypic characterization of the isolates].
AB  - Shigellosis is an acute diarrhoeal disease that is the main cause of morbidity
      and mortality in developing countries. In 1997, the Colombian Instituto Nacional
      de Salud Microbiology Group organized a network surveillance program with the
      country's Public Health Laboratories (PHLs) to monitor the principal etiological
      agents responsible for acute diarrhoeal disease. In May, 2001, the PHL of the
      state of Cundinamarca reported a food poisoning outbreak involving an elementary
      school community. The main goal of the Microbiology Group involvement was to
      establish the molecular relationships among the isolates from the outbreak by
      phenotypic and genotypic methods of characterization. Stool cultures were
      obtained from 22 of 195 affected individuals. The Microbiology Group confirmed
      the identification of the isolates by biochemical and serological probes. The
      antimicrobial susceptibilities were tested against the following battery of
      antibiotics: chloramphenicol, trimehoprim-sulfamethozazole, cefotaxime,
      gentamicin, ampicillin and ciprofloxacin. The isolates were subjected to pulsed
      field gel electrophoresis (PFGE) using the following CDC (U.S. Centers for
      Disease Control) protocols: Xbal restriction enzyme, Shigella sonnei CDC F2353 as
      the reference standard, and lambda phage as a molecular weight marker. In 15 of
      22 (68%) stool cultures Shigella was recovered, all isolates were identified as
      Shigella flexneri serotype 6 biotype Newcastle with the same antimicrobial
      susceptibility profile. PFGE showed that 3 (20%) isolates were identical (100%
      genetic similarity) and the other 12 (80%) were very closely related (genetic
      similarity between 86-98%). The network system permitted the INS ready access to
      the isolates and the implementation of the PFGE permitted a quantitative
      characterization of the clonal relationship among the isolates from the outbreak.

PMID- 12404928
TI  - [Adrenal gland insufficiency secondary to paracoccidioidomycosis].
AB  - Paracoccidioidomycosis is regularly associated with adrenal insufficiency in 10
      15% of symptomatic cases, and in some instances, diagnosis of the mycosis
      precedes the adrenal manifestation. To establish the frequency of this
      association, records were reviewed of 207 cases diagnosed with mycosis at the
      Mycology Service of the Corporacion para Investigaciones Biologicas. Six cases
      (2.9%) were found to have adrenal insufficiency. Patients were all males with a
      mean age of 67.2 years (range 48-75) and most worked in agriculture. The duration
      of the symptoms of adrenal damage was 4.1 months (range 2-6). All patients
      experienced weight loss and malaise; all had abnormal lung X-rays. Major clinical
      improvement was recorded after initiation of the specific treatments consisting
      of itraconazole, prednisolone and fluorcortisone. Diminished antibody titers
      against Paracoccidioides brasiliensis were also recorded after treatment. Prompt
      treatment re-established adrenal function and effected recovery of normal gland
      morphology. Consequently, early detection of hypoadrenalism in patients living in
      the endemic areas is necessary to avoid further adrenal damage and permits a
      shorter hormonal treatment period in patients afflicted by the mycosis.

PMID- 12404929
TI  - Viral hemorrhagic fevers of South America.
AB  - This paper reviews the epidemiology and distinguishing features of three viral
      hemorrhagic fevers (dengue hemorrhagic fever, yellow fever and arenaviral
      hemorrhagic fever) that have emerged as important public health problems in South
      America. Although the etiology, natural history and control of the three diseases
      are different, their clinical manifestations and histopathology findings are
      similar and can be difficult to differentiate. Consequently, early recognition
      and correct diagnosis are essential for effective control measures to be
      initiated.

PMID- 12404930
TI  - [Definition of appropriate temperature and storage conditions in the detection of
      Leishmania DNA with PCR in phlebotomine flies].
AB  - For epidemiological studies and control programs of leishmaniasis, taxonomic
      identification of the etiologic agent of the disease in the insect vector is of
      critical importance. The implementation of molecular techniques such as the
      polymerase chain reaction (PCR) has permitted great advances in the efficacy and
      sensitivity of parasite identification. Previously, these investigations involved
      labor-intensive dissections and required expert personnel. The present work
      evaluates the effects of storage methods of phlebotomine samples in the
      optimization of PCR identification of Leishmania. Females of Lutzomyia
      longipalpis, from the colony of the Instituto Nacional de Salud, were
      experimentally infected with Leishmania chagasi (= L. infantum), from the upper
      Magdalena Valley (Quipile, Cundinamarca, Colombia). The infected insects were
      preserved in three solutions: 100% ethanol, 70% ethanol, and TE; subsamples of
      each class were stored at -80 degrees C, -20 degrees C and room temperature. To
      determine infection rates, samples were dissected and screened microscopically.
      Chelex 100 was used for extraction of total Leishmania DNA. For PCR
      amplification, the kinetoplastic minicircle DNA primers OL1 and OL2 of Leishmania
      were used, and the products were visualized by electrophoresis in 1% agarose
      gels. For each of the 3 storage conditions, amplifications were successful,
      producing a approximately 120 base pair product unique to Leishmania. The results
      demonstrated the advantage of PCR as a routine screening method for detecting
      infected flies in endemic foci of visceral leishmaniasis. Since storage method
      did not affect PCR amplification success, the most cost effective method -70%
      ethanol at room temperature--is the option recommended for storing entomological
      samples in vector incrimination studies.

PMID- 12404931
TI  - [AIDS mortality and its economic impact in Cartagena de Indias, Colombia, 1995
      2000].

PMID- 12404932
TI  - The prevalence and management of trauma in the public domain: an agency and
      clinician perspective.
AB  - This descriptive study surveyed the ways in which trauma survivor needs have been
      addressed within the public mental health system in one sector of Connecticut.
      Information was obtained about the prevalence of traumatic history among
      consumers, the existence of policy related to trauma, trauma screening and cross
      referral mechanisms, and trauma-related supervision and education. The study maps
      current service system functioning related to the provision of trauma-specific
      services at both the agency and the clinician level. The study data indicate a
      need for service enhancement and increased service system collaboration and
      integration to permit access to a full range of trauma interventions. The data
      also indicate a need for increased clinician education and supervision specific
      to trauma both across agencies and among individual clinicians.

PMID- 12404933
TI  - The integration of psychiatric rehabilitation services in behavioral health care
      structures: a state example.
AB  - This article describes a model for integrating psychiatric rehabilitation
      services in a managed behavioral health care structure. Psychiatric
      rehabilitation and managed care are two distinct developments in the provision of
      mental health services that have proceeded independently though they can have
      compatible methods and outcomes. Descriptive detail is provided about a state
      initiative in Iowa to provide psychiatric rehabilitation services to those with
      serious mental illness through the state-contracted managed behavioral health
      care corporation. The article describes factors leading to the program's
      implementation, service delivery structures, reimbursements, personnel
      requirements, and performance indicators. Evidence for supporting this innovation
      is provided through a case-controlled outcomes study of mental health service
      units used and their costs for participants and matched controls.

PMID- 12404934
TI  - Evaluating mental health outcomes in an inpatient setting: convergent and
      divergent validity of the OQ-45 and BASIS-32.
AB  - The evolution of managed behavioral health care has led to an increased emphasis
      on reliable and valid assessment of outcomes in clinical practice. The present
      study evaluated the convergent, divergent, and concurrent validity and
      sensitivity to change of two widely used measures: Behavior and Symptom
      Identification Scale (BASIS-32) and Outcome Questionnaire (OQ-45). Comparisons of
      the two measures revealed that both were sensitive to change over a relatively
      short inpatient stay. Both measures also showed evidence of convergent and
      divergent validity of specific subscales, although the total scores of each
      measure also were highly correlated. Evidence of concurrent validity was
      suggested by differences between diagnostic groups on specific subscale scores.
      Together with previous research, these results suggest that the BASIS-32 and OQ
      45 can be useful measures for tracking patient functioning over a range of
      treatment contexts.

PMID- 12404935
TI  - Cohesion of the primary social network and sustained service use before the first
      psychiatric hospitalization.
AB  - This study analyzed the relationship between social network dynamics and initial
      help-seeking behaviors. The primary social network was reconstructed for the
      period beginning with initial observation of unusual behavior and ending with
      first psychiatric hospitalization. The social network's influence was analyzed
      based on the concept of social network cohesion, considering both structure and
      content of social ties. The results demonstrate that networks succeed in
      referring the family member to services and in maintaining a clinical follow-up
      to the degree that they are cohesive. When a network lacks cohesiveness, the
      onset and development of problem behaviors are less easily recognized. These
      findings confirm the importance of social and interactional contexts in decision
      making processes leading to use of psychiatric services and specify the roles
      they play.

PMID- 12404937
TI  - Linking mental health and addiction services: a continuity-of-care team model.
AB  - Reorganization of mental health care delivery services at a Department of
      Veterans Affairs medical center addressed problems with the coordination of
      addiction treatment and mental health programming for patients with significant
      psychiatric and addiction comorbidity. Clinical services were organized into
      interdisciplinary continuity-of-care teams that follow patients across different
      levels of care. The teams provide addiction treatment through "universally
      available" resources such as a partial hospital addiction rehabilitation module.
      Continuity of care remains within the team structure as clinicians follow
      patients throughout their rehabilitation course. Patient and staff satisfaction
      focus on improved accessibility of addiction services and continuity of care
      providers across time and levels of care. Overall inpatient utilization and
      recidivism decreased after model implementation.

PMID- 12404936
TI  - The Resident Assessment Instrument-Mental Health (RAI-MH): inter-rater
      reliability and convergent validity.
AB  - An important challenge facing behavioral health services is the lack of good
      quality, clinically relevant data at the individual level. The article describes
      a multinational research effort to develop a comprehensive, multidisciplinary
      mental health assessment system for use with adults in facilities providing
      acute, long-stay, forensic, and geriatric services. The Resident Assessment
      Instrument-Mental Health (RAI-MH) comprehensively assesses psychiatric, social,
      environmental, and medical issues at intake, emphasizing patient functioning.
      Data from the RAI-MH are intended to support care planning, quality improvement,
      outcome measurement, and case mix-based payment systems. The article provides the
      first set of evidence on the reliability and validity of the RAI-MH.

PMID- 12404938
TI  - Improving access to primary health care for chronic drug users: an innovative
      systemic intervention for providers.
AB  - An intervention was designed to improve access to primary care for chronic drug
      users (CDUs) by enhancing health care providers' knowledge and skills. Using a
      case study method, three study sites were systematically selected for
      intervention implementation: a primary care clinic (PC), an emergency department
      (ED), and a drug treatment (DT) facility. Participants completed pre- and
      postintervention tests of knowledge, skills, and intentions to practice. Compared
      with pretest scores, participants had significantly higher posttest scores
      concerning knowledge of CDUs' health care needs. Postintervention evaluations
      indicated intentions to practice skills learned in the intervention. As
      hypothesized, the PC and ED subsequently instituted formal screening mechanisms
      to identify CDUs. This intervention revealed potential to build bridges between
      health care providers and CDUs. By overcoming provider resistance, primary care
      access can be realized for this and other disadvantaged populations.

PMID- 12404939
TI  - Self-reported lifetime psychiatric hospitalization histories of jail detainees
      with mental disorders: comparison with a non-incarcerated national sample.
AB  - Lack of access to hospitalization is an often-cited risk factor for incarceration
      among persons with severe mental illness. This proposition is examined by
      comparing self-reports of lifetime psychiatric hospitalization histories of
      mentally ill jail inmates with data from a national sample of non-incarcerated
      mentally ill. Roughly 52% of mentally ill jail detainees reported at least one
      psychiatric hospitalization, a rate nearly three times that of the comparison
      group. The data call into question the notion that mentally ill jail inmates have
      reduced access to psychiatric inpatient treatment, without addressing the
      adequacy of the treatment received. Longitudinal studies are needed to explore
      temporal relationships to better understand the relationship between mental
      health treatment and criminal justice involvement.

PMID- 12404940
TI  - Home-based treatment, rates of ambulatory follow-up, and psychiatric
      rehospitalization in a Medicaid managed care population.
AB  - This study reports on the effect of home-based mental health treatment following
      psychiatric hospitalization on ambulatory follow-up rates and readmission rates
      in a Medicaid managed care population. Logistic regression models were used to
      predict the odds of ambulatory treatment after hospitalization and to predict
      rehospitalization. A consumer who received in-home treatment was 22 times more
      likely to follow-through with aftercare treatment of more than one visit than
      were those who did not receive in-home treatment. However, in-home treatment,
      age, gender, and previous hospitalization did not significantly predict the odds
      of rehospitalization. While home-based services did not reduce the incidence of
      rehospitalization, providing services within the home has the potential to
      increase attendance in aftercare services by Medicaid managed care recipients.

PMID- 12404941
TI  - Current evaluation and future needs of a mental health data linkage system in a
      remote region: a Canadian experience.
AB  - Linking client data across care sectors and agencies is becoming essential to
      ensure continuity of care, evaluation, and planning of mental health services
      delivery. The Data Linkage System (DLS), a record-linked, client-based, mental
      health database in northwestern Ontario, was established in response to this
      need. It is a voluntary system currently used by 30 of 40 mental health programs.
      The study surveyed program administrators to determine the system's utilization,
      perceived value, and future needs regarding data collection. The survey results
      delineated the perceived usefulness of the DLS in a remote region. The findings
      will provide direction for continued development of the DLS.

PMID- 12404942
TI  - The influence of patient characteristics on ratings of managed behavioral health
      care.
AB  - Despite current emphasis on consumer-based performance measures, little is known
      about factors that influence consumer ratings of behavioral health care. This
      study examines the influence of patient characteristics, health care use, and
      insurance coverage on patients' ratings of their managed behavioral health care
      in both commercial and public plans. Older and healthier patients rated their
      behavioral health care and health plan more highly than did other patients.
      Patients with less education and those whose insurance paid all costs of care
      gave consistently higher plan ratings. Women and frequent users enrolled in
      commercial plans gave more positive care ratings. After adjusting for enrollee
      characteristics and coverage, there were no differences between ratings of
      patients in commercial and public plans. These results are consistent with other
      research that illustrates the importance of adjusting health care ratings for
      patient characteristics when comparing plans.

PMID- 12404944
TI  - [Rethinking required].

PMID- 12404943
TI  - Frequent visitors to psychiatric emergency services: staff attitudes and temporal
      patterns.
AB  - Providing quality psychiatric emergency services is becoming more difficult as
      utilization rates soar, especially by individuals who are frequent visitors. To
      address this issue, a staff survey and analysis of admission patterns were
      conducted. Staff were more likely to believe that frequent visitors sought care
      because they had difficulty accessing alternative services, had basic needs
      unmet, were substance abusers, wanted inpatient admission, and were noncompliant
      with treatment plans. The 1999 temporal admission pattern documented that
      frequent visitors' admissions were higher during the first week of the month and
      inclement weather. Surprisingly, the infrequent visitors' admissions also were
      higher during the first week of the month. Together, these findings suggest that,
      in this urban location, frequent visitors are disadvantaged individuals lacking
      support and alternative treatment settings who use psychiatric emergency services
      to meet basic needs.

PMID- 12404945
TI  - [In the midpoint of the cancer patient].

PMID- 12404946
TI  - [Hormone replacement therapy and breast cancer].

PMID- 12404947
TI  - [The basis and development of homeopathy. Holistic oriented diagnosis and therapy
      forms].

PMID- 12404948
TI  - [Toward high cholesterol values?].

PMID- 12404949
TI  - [Syndromes and diseases caused by mutations of trinucleotide expansions].
AB  - A novel type of mutation--due to expansion of DNA trinucleotide repeats--has been
      discovered about 10 years ago. Nowadays 15 genetic syndromes and diseases caused
      by these mutations are known such as FRA X A syndrome, FRA X E syndrome, Kennedy
      syndrome spinobulbare muscle atrophy, Curschmann-Steinert syndrome of myotonic
      dystrophia, Huntington disease, Friedreich ataxia, spinocerebellare ataxias types
      I., II., III., VI., VII., VIII., XII. and Taylor's oculopharyngeal muscle
      dystrophy. The mutations of instable trinucleotids represent some exceptions from
      the regular monogenic transmission such as premutation, genomic imprinting,
      generation anticipation (acceleration, accentuation), somatic mosaicism. A good
      understanding of their special properties is necessary for efficient
      interdisciplinar collaboration of medical teams taking care for these patients
      and their families.

PMID- 12404950
TI  - [Biological activity in colorectal carcinoma].
AB  - The trend of current research is not only to obtain a complete characterisation
      of the cause of inception of tumor proliferation, but in particular to
      characterize in detail multi-degree cascades of the metastatic process. Precise
      description of the effector genes and their protein products which influence
      individual processes of the metastatic cascade, is of great significance not only
      for the early diagnosis of the possible tumor invasion into its immediate
      environment and the creation of distant metastases, but particularly for the
      development of new therapeutic procedures which will help to change from
      empirical to causal treatment. In practice this means a shift from those
      therapeutic procedures which lead only to simple blocking of cell division or
      cell growth, to addressing the individual stages of tumor development (correction
      of genetic defects in tumor cells, inhibition of the metastatic cascade,
      inhibition of angiogenesis and apoptosis, etc.). The article characterizes the
      biological activity of tumors in connection with the metastatic process in
      colorectal carcinoma.

PMID- 12404951
TI  - [Protection of reproductive functions in patients with tumors].
AB  - BACKGROUND: Survival from cancer continues to improve. Antimitotic therapy can
      induce failure of spermatogenesis and oogenesis, gonadal disturbances and
      infertility. Recent advances in reproductive medicine have opened opportunities
      for the preservation of reproductive potential of patients with cancer. The aim
      of our study was to analyse by a multidisciplinary team the contemporary state of
      art and proposal of the Czech model of fertility preservation starting in
      childhood and continuing through the whole reproductive period. METHODS: This
      paper highlights the problems associated with gonadal failure as a consequence of
      therapy for malignancy in childhood, adolescence and adulthood. Analysis of these
      problems served as a principle for the management strategy for fertility
      preservation. CONCLUSIONS: Patients undergoing treatment for malignancy are at
      the high risk of gonadal damage and infertility. Therefore, alternative
      treatments with less gonadal toxicity and different treatment protocols were
      evaluated. Fertility can be preserved with the freezing and banking of
      spermatozoa, embryos, and oocytes obtained prior to the cancer treatment. In
      female patients (starting in puberty) pharmacological preservation of gonads with
      gonadoliberin analogues is also possible. Chance for the future fertility
      preservation for children offers freezing and thawing of primordial follicles and
      spermatozoa obtained during the gonadal biopsies. Long-term follow-up study by a
      multidisciplinary medical team is necessary.

PMID- 12404952
TI  - [HLA-DRB1/DQA1/DQB1 alleles and haplotypes in Czech children with celiac sprue].
AB  - BACKGROUND: The celiac disease (CD) is a multifactor disease resulting from a
      life time abnormal immune response to gluten accompanied by autoimmune
      characteristics, which can in sensitive individuals evoke small bowel mucosa
      morphologic changes. The genetically sensitive individual to CD has not been
      defined yet, it is obvious, however, that this illness is closely linked to the
      HLA class II genes. The objective of our study was to detect associations of HLA
      class II alleles and haplotypes DRB1/DQA1/DQB1 in Czech CD children. METHODS AND
      RESULTS: A group of Czech CD children diagnosed according to ESPGHAN criteria was
      genotyped HLA for alleles of DRB1/DQA1/DQB1 loci. Genotyping of the HLA-DRB1/DQB1
      haplotypes proved statistically significant association CD with haplotypes and
      alleles of this genetic system. 92.9% of patients have in their HLA phenotype
      allele DQA1*0501 in either cis or trans configuration with the DQB1 allele
      *0201/*0202. The extended HLA haplotype DRB*0301/DQA1*0501/DRB1*0201 as well as
      the haplotype DRB1*0701/DQA1*0201/DQB1*0202, are presented in 63.6% or in 61.0%
      CD patients respectively. The individual HLA class II alleles DRB*0301, *0701,
      DQA1*0201, *0501, DQB1*0201, *0202 and the above mentioned HLA haplotypes
      inclusively provide genotypic frequencies significantly different from healthy
      Czech individuals (P < or = 0.06 +/- 0.001). These results support the opinion
      that the HLA molecule expressed on the cellular surface as a alpha beta
      heterodimer encoded by the DQA1*0501 and DQB1*0201/02 alleles in either cis or
      trans configuration is responsible for the primary sensitivity to this disease.
      We were, however, not able to find an association of various clinical forms of
      the CD with a certain HLA haplotype in the followed group. CONCLUSION: The CD
      patients have in comparison with healthy population significantly different
      frequency of HLA class II haplotypes. Though the finding of these alleles is not
      sufficient for an explicit confirmation of this diagnosis, the proof of this
      risky haplotype/s may notably contribute to it, namely in case of potential or
      latent forms of this disease.

PMID- 12404953
TI  - [Acute diarrhea in adults. Recommended procedures].

PMID- 12404954
TI  - [Radiology at the Institute for Clinical and Experimental Medicine (IKEM)-
      history and present status].

PMID- 12404955
TI  - [Comments on problems with Czech scientific publications].

PMID- 12404956
TI  - [Mechanisms of arterial hypertension, transplantation and renal therapies].
AB  - Considerable evidence exists indicating that pressure-volume regulation, based on
      the pressure-natriuresis/diuresis phenomena, is of fundamental importance in
      maintaining long-term arterial pressure--a theory evolved by A. C. Guyton and his
      co-workers during the four last decades. In all forms of hypertension studied so
      far, the pressure natriuresis is abnormal. The present article focuses on
      selected, well-documented examples illustrating how experimental and clinical
      impairment of renal structure and its blood supply contributed to our
      understanding of the aetiology and pathogenesis of hypertension. Partial
      nephrectomy, transplantation, renal hypoperfusion and hypersecretion of natrium
      retaining hormones represent the major topics discussed in the article.

PMID- 12404957
TI  - [Fluid resuscitation in conditions with disorders of capillary permeability].
AB  - Fluid resuscitation remains a cornerstone in the treatment of various types of
      circulatory failure. Alterations in microvascular permeability are a hallmark of
      a number of inflammatory conditions including sepsis, septic shock, burns and the
      acute respiratory distress syndrome. As a result, the loss of plasma fluid into
      the interstitial space leads to hypovolaemia and tissue hypoperfusion.
      Administration of large volumes of fluids in often necessary to restore the
      nutritional blood flow to tissues. This strategy, however, involves the risk of
      interstitial edema formation, which in turn may further impair tissue oxygen
      distribution. The presented paper briefly reviews the principles of transvascular
      fluid exchange and the pathophysiology of capillary permeability. It discusses
      the ongoing controversy on the optimal way and the end points of volume
      replacement as well as the choice of fluid in conditions associated with
      capillary leakage.

PMID- 12404958
TI  - [Minimal residual disease in breast carcinoma].
AB  - The incidence of breast cancer continuously increases in developed countries. The
      introduction of screening methods such as mammography or ultrasound lead to
      higher proportion of early diagnosed tumors. However, even in early stage tumors
      occult neoplastic cells can spread to the organism. Such tumor cells are very
      likely precursors of distant metastases. Using several monoclonal antibodies
      against epithelial mucins or cytokeratins on the cell surface could be detected
      one tumor cell among 10(5) or 10(6) of normal bone marrow cells. These cells are
      not detectable by routine histopathologic exam. More sensitive but also more
      costly and technically demanding are PCR assays. The sensitivity might reach
      almost 1:10(7). Prospective clinical trials using immunocytochemistry have shown
      that the presence of stained cells in bone marrow is clearly associated with
      shorter disease free survival and overall survival. In the near future we may use
      the bone marrow examination for the presence of occult tumor cells in order to
      improve current staging system or as a surrogate marker in the decision-making in
      regard to adjuvant systemic therapy or in the assessment of efficacy of adjuvant
      treatment. The review summarizes contemporary knowledge assembled in preclinical
      and clinical studies.

PMID- 12404959
TI  - [Variation in manifestations of heteroplasmic mtDNA mutation 8993 T>G in two
      families].
AB  - BACKGROUND: The most frequent manifestations of heteroplasmic mitochondrial DNA
      (mtDNA) mutation 8993 T > G are Leigh syndrome or NARP syndrome (Neurogenic
      Muscle Weakness, Ataxia, and Retinitis Pigmentosa). The authors describe
      heterogeneity of clinical symptoms and results of biochemical and molecular
      analyses in seven severely clinically affected children from two unrelated
      families with heteroplasmic mtDNA mutation 8993 T > G. METHODS AND RESULTS: Seven
      clinically affected children from two unrelated families were born in term after
      an uneventful pregnancy. The failure to thrive, psychomotor retardation,
      hypotonic or spastic quadruparesis, hypertrophic cardiomyopathy, hepatopathy and
      hyperlactacidaemia developed after birth. Five children died in the first year of
      life during acute respiratory infection, one girl died at the age of 3 months
      with sudden death syndrome, only one boy with spastic quadruparesis and severe
      psychomotor retardation survived to the age of 8 years. Molecular analyses in all
      investigated children and their clinically non-affected mothers revealed the
      presence of heteroplasmic mtDNA mutation 8993 T > G. Mutated copies of mtDNA
      molecules in maternal tissues were in the range of 15-22%. The mutation load in
      all analysed children's tissues was higher than 90%. CONCLUSIONS: A broad
      spectrum of clinical symptoms may be observed in families with heteroplasmic
      mtDNA mutations 8993 T > G. Affected children with a mutation load higher than
      90% usually do not survive after infancy. In both investigated families, a
      profound increase in the levels of heteroplasmy of mtDNA mutation 8993 T > G was
      observed in two subsequent generations.

PMID- 12404960
TI  - [Relation between cytokines, adhesive immunoglobulins and matrix
      metalloproteinases in osteoarthritic joints].
AB  - BACKGROUND: The dysbalance of proteinase production and their inhibitors leads to
      destruction of tissues in many pathological processes. Recently it was shown that
      the expression of proteinases is regulated also by interactions of cells which is
      mediated by adhesive molecules. We wanted to find out whether this mechanism is
      involved also in the destruction of joints in osteoarthritis. METHODS AND
      RESULTS: Cartilage, synovial and subchondral bone tissues, and synovial fluids
      were obtained from 23 joints after total endoprosthesis surgery. The solid
      tissues were extracted by TRIS buffer. The investigated protein concentrations
      were assessed immunochemicaly. In all specimens gelatinase A, gelatinase B,
      stromelysin-1, TIMP-1, soluble adhesive molecules sICAM-1 and sVCAM-1 and
      cytokines TNF-alpha and IL-8 were found. In cartilage and synovial fluid the
      proteolytic potential of metalloproteinases was balanced with high concentrations
      of their inhibitor TIMP-1 (259.4 +/- 105.2 pmol/g protein vs 2343.8 +/- 637.5
      pmol/g protein in synovial fluid, p < 0.00001, and 178.9 +/- 175.7 pmol/g dry
      weight vs 647.2 +/- 561.3 pmol/g dry weight in cartilage, p < 0.001) but in
      synovial tissues and pathological subchondral bones was not (257.4 +/- 617.2
      pmol/g dry weight vs 171.3 +/- 170.8 pmol/g dry weight in synovium, p = 0.61716,
      and 17.4 +/- 15.4 pmol/g dry weight 33.6 +/- 33.3 pmol/g dry tissue in
      pathological subchondral bone, p = 0.16705). CONCLUSION: From correlation
      analysis ensues that the bond of ICAM-1 and VCAM-1 on chondrocytes with
      appropriate integrin ligands probably leads to up-regulation of gelatinase A and
      B and to down-regulation of TIMP-1. Moreover it is apparent that TNF-alpha up
      regulates both investigated adhesive molecules followed and stromelysin-1 and
      TIMP-1.

PMID- 12404962
TI  - Combining quantitative and qualitative research to engage stakeholders in
      developing quality indicators in general practice.
AB  - In 2000, the Newcastle Institute of Public Health (NIPH) undertook a project that
      aimed to review, identify and where necessary, develop a range of indicators of
      quality service provision in general practice. We describe the way in which
      quantitative and qualitative research methods (including a Delphi style survey)
      were combined to investigate consensus amongst stakeholders in defining quality
      indicators. Over 500 general practice stakeholders were consulted. They included
      general practitioners (GPs) and their representative groups, academics, policy
      makers, and consumers. Several important lessons were learnt from the process,
      including the importance of involving a broad representative group of
      stakeholders, informing workshop participants in advance, providing adequate
      response times for the Delphi surveys and using videoconferencing technologies.

PMID- 12404961
TI  - Uptake of health assessments, care plans and case conferences by general
      practitioners through the Enhanced Primary Care program between November 1999 and
      October 2001.
AB  - We aimed to describe the uptake of the Enhanced Primary Care (EPC) item numbers
      listed on the Medicare Benefits Schedule for health assessment (HA), care plan
      (CP) and case conference (CC) between November 1999 (when these items first
      became available) and October 2001. We used data provided by the Commonwealth
      Department of Health and Ageing. General practitioners rendered 371,409 EPC
      services in all. Most services were HA (225,353; 61%), most of the remainder were
      CP (134,688; 36%), and CC comprised the rest (11,368; 3%). The number of HA done
      increased steadily and has stabilised at around 13,000 HA per month. Most CP done
      (80%) were in the community and with the GP preparing the plan. From a slow
      start, the number of CP done increased rapidly in 2001 to about 15,000 per month.
      There has been a slow and steady increase in the number of CC done each month,
      reaching 8-900 per month. Uptake of the EPC item numbers in the first two years
      of their availability has been rapid and has reached substantial levels,
      especially for HA and CP. The uptake of CC has been slower.

PMID- 12404963
TI  - Privatised family group practices in Mongolia: an initial assessment of service
      access.
AB  - Mongolia is changing the way that primary care is delivered, by replacing
      salaried government staff with private family group practices (FGPs) paid by risk
      adjusted capitation. As part of a mid-project evaluation, we surveyed a sample of
      FGPs in order to assess the patterns of access to care. We found that generally
      satisfactory services are being provided in an equitable way, and therefore that
      the main goals of the new model are being achieved. However, there are some
      concerns. Inter alia, we argue that more should be done to establish better
      standards of clinical practice through the distribution of protocols and
      illustrative pathways, and to increase the extent to which services are organised
      in a manner that is sensitive to informed consumers' needs. A design limitation
      meant that few baseline data were available, and the survey will need to be
      repeated if valid conclusions are to be drawn.

PMID- 12404964
TI  - Experiencing "change" from within: situating the transition to primary health
      care in a remote Australian context.
AB  - The transition to primary health care (PHC) is often described in an idealized
      manner, which either ignores or obscures the experiences associated with its
      implementation at the local level. By adopting an anthropological perspective,
      this article highlights some of these experiences and the context within which
      they occur for one health care organisation in remote Western Australia. It
      specifically focuses on problems associated with economic rationalism,
      managerialism, and the inherently fragmented character of health service
      organisations. Such issues must be allowed to inform idealized PHC models in
      order to make them more applicable and attuned to local needs and realities.

PMID- 12404965
TI  - Waiting time information services: what are the implications of waiting list
      behaviour for their design?
AB  - In some countries, patients requiring elective surgery can access comparative
      waiting time information for various surgical units. What someone can deduce from
      this information will depend upon how the statistics are derived, and how waiting
      lists behave. However, empirical analyses of waiting list behaviour are scarce.
      This study analysed three years of waiting list data collected at one hospital in
      Sydney, Australia. The results highlight various issues that raise questions
      about using particular waiting time statistics to make inferences about patient
      waiting times. In particular, the results highlight the considerable variation in
      behaviour that can exist between surgeons in the same specialty, and that can
      occur over time.

PMID- 12404966
TI  - Standardised assessment of older patients by a nurse in an emergency department.
AB  - The primary aim of this study was to evaluate the ability of a nurse practitioner
      in geriatrics, working in the emergency department of a tertiary referral
      hospital, to assess high-risk elderly patients comprehensively. A secondary aim
      was to explore patient characteristics associated with referral to community aged
      care services. Of 469 patients assessed by the nurse, 327 (70%) were admitted to
      the hospital. A comprehensive set of data was obtained for 334 (71%) patients.
      For 142 patients not admitted, 163 new referrals were made, mostly to the Aged
      Care Assessment Team. Those referred were more likely to be living alone and non
      English speaking. They were also less satisfied with the support they received
      from family and friends. A single nurse working in a busy emergency department
      can successfully identify patients with increased care needs, and direct high
      risk patients to existing services.

PMID- 12404967
TI  - Managing access block.
AB  - There is pessimism regarding the ability of the Acute Health Sector to manage
      access block for emergency and elective patients. Melbourne Health suffered an
      acute bed crisis in 2001 resulting in record ambulance diversions and emergency
      department (ED) delays. We conducted an observational study to reduce access
      block for emergency patients whilst maintaining elective throughput at Melbourne
      Health. This involved a clinician-led taskforce using previously proven
      principles for organisational change to implement 51 actions to improve patient
      access over a three-month period. The primary outcome measures were ambulance
      diversion, emergency patients waiting more than 12 hours for an inpatient bed,
      elective throughput and theatre cancellations. Despite a reduction in multi-day
      bed numbers all primary objectives were met, ambulance diversion decreased to
      minimal levels, 12-hour waits decreased by 40% and elective throughput was
      maintained. Theatre cancellations were also minimised. We conclude that access
      block can be improved by clinician-led implementation of proven process
      improvements over a short time frame. The ability to sustain change over the
      longer term requires further study.

PMID- 12404968
TI  - Interpretation of hospital-specific outcome measures based on routine data.
AB  - Hospital-specific outcome measures based on routine data are useful for
      stimulating interest in quality of care and for suggesting avenues for more in
      depth analyses. They might also identify serious, once-in-a-lifetime failures of
      health care. However, such analyses are not definitive. They are a way of
      screening large amounts of routine data and, like all screening tools, they can
      generate false positives and false negatives. This is because differences in
      outcome measures across hospitals can be due to differences in types of patients
      seen (casemix), differences in data quality, and the play of chance; rather than
      differences in the quality of care. End-users of such analyses should be aware of
      these technical difficulties, otherwise skilled health workers in high-quality
      hospitals might be subjected to unwarranted criticism.

PMID- 12404969
TI  - Coding errors and the trauma patient--is nursing case management the solution?
AB  - The aim was to investigate the accuracy of clinical information coding and the
      financial consequence for trauma patients at a tertiary trauma centre using the
      resources of trauma nursing case managers. Clinical data for admitted trauma
      patients in August and September 2000 were compared with data routinely obtained
      by trauma case managers on their daily rounds. We audited patient injuries, in
      hospital complications, investigations, and procedures. Clinical information
      records requiring alteration were returned to the clinical information manager
      with additional information and re-entered into the clinical information
      database. 100 trauma patient records (15% of admissions for 2000) were audited.
      28% of recoded records had to have their diagnosis related group (DRG) changed,
      which resulted in the identification of additional funding of over $39,000. We
      conclude that the implementation of episode funding for acute episodes, such as
      the complex trauma patient, is placing increased importance on accuracy of
      coding. The validity of coding is dependent on legible, comprehensive and
      complete documentation and is improved dramatically by using nursing case manager
      patient progress summaries.

PMID- 12404970
TI  - Audit of long-term mortality and morbidity outcomes for carotid endarterectomy.
AB  - There have been no Australian studies of long-term mortality status and cause of
      death after carotid endarterectomy (CEA) or, for survivors, quality-of-life. We
      first determined rate and cause of death for a cohort of patients four years
      after CEA. Surviving patients were surveyed to ascertain health status, using MOS
      SF-36. Of 238 patients who underwent CEA in our health service in 1995, 44
      (18.5%) had died within four years. The majority of deaths (61.4%) were
      attributable to vascular causes. Of the surviving 162 patients (survey response
      fraction 90%), 10 (6.2%) subsequently had suffered a non-fatal stroke in the four
      years following their CEA. With respect to health status, Physical Functioning
      scores differed significantly by age (t = 2.65, df = 149, P = 0.01) as did Role
      Physical scores (t = 2.10, df = 142, P = 0.04). We conclude that patients
      undergoing CEA are at high risk of dying from vascular causes, inviting concerted
      efforts in discharge planning to co-ordinate optimal vascular risk factor
      management.

PMID- 12404971
TI  - Managing the healthcare workforce: cost reduction or innovation.
AB  - Labour costs are the largest proportion of total costs in the health industry in
      developed countries and are a target in health sectory reform. The Kennett
      government in Victoria introduced policies based on competition and cost
      reduction and the decentralisation of industrial relations through enterprise
      bargaining. These policies directly impacted on the health workforce leading to
      work intensification, labour shortages and poor morale. The Bracks government has
      since returned to centralisation. This paper argues that it is time for a more
      innovative approach to health workforce management based on recognising staff as
      an asset rather than a cost.

PMID- 12404972
TI  - Workplace change and the internal labour market: evidence from the NSW hospital
      industry.
AB  - After a decade of labour market reform and workplace change, increasing attention
      has focussed on public sector industries. In this paper, domestic and maintenance
      occupations in the hospital industry are examined, as previous work has focussed
      on nursing, with other occupations being largely ignored. Grimshaw and Rubery's
      (1998) model of internal labour markets is adopted as the preferred theoretical
      approach. This model, in acknowledging external factors, the role of workers, and
      custom and norms within the firm, provides a basis from which to examine labour
      use practices within the hospital industry.

PMID- 12404974
TI  - Report of the mid-term review of Victoria's Maternity Services Program.
AB  - Substantial State Government funding has been committed in Victoria for the
      enhancement of maternity services. The funding is intended to improve the quality
      of care for women and meet consumer expectations for choice and continuity of
      care in maternity services. This paper reports on a mid-term review (the
      'Review') of the Victorian Maternity Services Program, which was conducted by the
      authors on behalf of the Victorian Department of Human Services. Documentary
      analysis was conducted for the review, and workshops and key informant interviews
      were held throughout Victoria with midwives, medical staff and Department of
      Human Services staff. The Review found that there had been many gains as a result
      of the Maternity Services Program and identified directions for further
      development. Issues of change and facilitators of change processes in maternity
      services are highlighted in this article.

PMID- 12404973
TI  - Patterns and characteristics of ethnic Australian women utilising ethno-specific
      maternal and child health services.
AB  - Few studies have explored the socio-economic profile, service utilisation,
      obstetric history and pregnancy outcomes of ethnic women who utilise ethno
      specific obstetric services in Australia. The purpose of this study was to form a
      profile of women who accessed the Ethnic Obstetric Liaison Services (EOLO) in
      South Western Sydney Area Health Service (SWSAHS), New South Wales and explore
      their beliefs about using maternal and infant health services. We found that the
      prevalence of risks and special needs varied significantly by language groups in
      this study sample. Our results suggest that equity of access to quality care for
      this group of mothers and infants can be assured if models similar to the EOLO in
      SWSAHS are thoroughly planned and developed, and take account of cultural
      appropriateness for the population served.

PMID- 12404975
TI  - A case study in strategic change: developing a strategic research program to
      address cardiovascular disease and related disorders in aboriginal and Torres
      Strait Islander peoples and rural and remote settings.
AB  - This paper presents an analysis of a strategic change process. It identifies and
      reviews the critical factors that impact on, and need to be considered in order
      to successfully initiate and implement change. The problem was the narrow focus
      and priorities of a well-established research program. We undertook a stringent
      process to refocus the program to the areas of greatest need. The paper provides
      information on the process undertaken to achieve the change and other factors
      that impacted. The outcome has been considered successful in the first instance.
      However the long-term picture may not be as positive. Reviewing and presenting
      the process and influential factors provides the reader with the opportunity to
      compare this scenario with their own experience and thereby develop their own
      change strategies.

PMID- 12404976
TI  - Self-reported health beliefs of government housing tenants.
AB  - Our aim was to provide a description of the self-reported health beliefs of a
      sample of Victorian public housing tenants, and to identify how gender, age and
      geographic location relate to these beliefs. Telephone interviews were conducted
      with a stratified random sample of 360 tenants, asking questions such as what
      they believe are the major health problems for men and women, what they do to
      keep healthy, and what makes it difficult to keep healthy. There were many
      differences in the beliefs held by older participants compared with those of
      younger participants. By asking about health in general, rather than specific
      aspects of health, this research identified the views about health which are most
      salient to participants, rather than those prompted by a survey on a particular
      disease or health behaviour. The health promotion implications of these findings
      are discussed.

PMID- 12404977
TI  - Democratising health care governance? New Zealand's inaugural district health
      board elections, 2001.
AB  - New Zealand's 'district health board' (DHB) system has been under implementation
      since the 1999 general election. A key factor motivating the change to DHBs is
      the democratisation of health care governance. A majority of the new DHB members
      are popularly elected. Previously, hospital board members were government
      appointees. Inaugural DHB elections were held in October 2001. This article
      reports on the election results and the wider operating context for DHBs. It
      notes organisational issues to be considered for the next DHB elections in 2004,
      and questions the extent to which the elections and DHB governance structure will
      enhance health care democratisation in New Zealand.

PMID- 12404978
TI  - Sex in prisons--a management guide.
AB  - Prisons are invariably unisex institutions where, besides many deprivations,
      heterosexual expression in its normal sense is absent. It is this characteristic
      that make prisons settings potentially fertile grounds for sexual aberrations.
      Since definite and accurate data concerning sexual activities among prison
      inmates are difficult to obtain, the phenomenon of sexual practices in prisons
      has traditionally been a topic of much speculation. However, the descriptions and
      explanations of most authors on the subject are often contradictory, and some of
      the best information are from unpublished sources. This article is an attempt to
      subsume many fragmented explanations about seven main types of sexual issues in
      prisons (i.e. consensual homosexuality, masturbation, transsexualism,
      prostitution, conjugal visits, sex between prisoners and prison staff, and rape
      among prison inmates) under more general criminological and management concepts.
      Suggestions for prison administrators on how to manage these complex issues in
      the best interests of security and inmates' health are also provided.

PMID- 12404979
TI  - Health service capacity modelling.
AB  - This paper aims to describe a modelling tool that gives a framework for the
      estimation of future bed demand for hospital services. It also outlines some
      issues regarding the application of the model. A quantitative mathematical model
      was constructed that was based on two years of seasonally adjusted inpatient
      data. To calculate the number of beds required five years into the future, ten
      factors were applied to the number of bed-days used for each service. In the
      example given (Figure 1), 7,924 bed-days used in 1998-99 translated into a
      requirement for twenty-six beds in 2004. The value of this approach lies in the
      ability to describe and delineate each of the varying factors, and thus allowing
      clinicians, healthcare managers, the purchasers of health services and other
      stakeholders to be involved in a clear and explicit decision-making process.

PMID- 12404980
TI  - Assistive devices: self-reported use by older people in Victoria.
AB  - A qualitative study was conducted in Victoria to explore factors affecting the
      acceptability and use of assistive devices by older people. Four focus groups and
      fifteen home-based interviews were conducted with older people (mean age 77
      years) who had been issued with 2 or more assistive devices. Analysis of the data
      indicated that almost all participants were content to be advised by
      professionals on suitable equipment. Most considered the equipment and home
      modifications safe and easy to use, and appreciated the benefits for mobility,
      confidence and independence. Reasons for non-use were commonly related to changes
      in functional ability. Cost was a major deterrent for a small number who opted to
      'make do'. Recommendations are made for improvements to the existing system of
      equipment provision and use, including review and development of consistency of
      provision and payment policy among service providers; flexibility of payment
      options; adequate education and follow-up support for clients.

PMID- 12404982
TI  - The impact of the variation in death certification and coding practices on trends
      in mortality from ischaemic heart disease.
AB  - This review examines the literature relating to the effect of death certification
      practices, coding and the terminology used by certifiers on trends in mortality
      from ischaemic heart disease (IHD). The review identifies factors that affect
      mortality trends in a number of countries and discusses methods for assessing the
      impact of these issues on trends in mortality from IHD. The review found that
      although the magnitude of the effects of the issues on trends in mortality from
      ischaemic heart disease varied among countries and sub-populations,
      miscertification and the resultant assignment of misleading ICD codes,
      particularly for ill-defined cardiovascular conditions, were important factors
      affecting the IHD mortality trends. In light of these findings, it is essential
      to monitor regularly the accuracy of death certificates for IHD and consider
      necessary adjustments in analysing mortality trends from IHD.

PMID- 12404981
TI  - Evidence-based practice for young people who self harm: can it be sustained and
      does it improve outcomes?
AB  - In 1998-1999, two Area Health Services in NSW conducted a project to implement
      evidence-based service enhancements for the clinical management of young people
      who present with Deliberate Self Harm (DSH) behaviour. The present study examined
      what structures and procedures were required to implement and sustain evidence
      based practice in different health care settings for patients with DSH behaviour.
      Service provision was assessed at three points during the initial project to
      assess the degree of change that occurred, and 9 months after the completion of
      the project to allow an assessment of sustainability of the service provision. We
      examined staff perceptions of the importance of education, management directives,
      policy and procedure changes, and cultural/attitudinal changes, in implementing
      clinical best practice. Results indicated that support from both service
      management and clinical staff is necessary for successful implementation of
      service enhancements. High levels of staff education and policy development were
      also associated with high levels of service performance. The best sustained
      enhancements were those that were developed by the services themselves.

PMID- 12404983
TI  - Midwifery regulation in the Northern Territory.

PMID- 12404984
TI  - Hospital bed utilization management team tackles 'bed crunch' problem.

PMID- 12404985
TI  - Resource Center aids discharge decisions.

PMID- 12404986
TI  - Community CM program targets prison population.

PMID- 12404987
TI  - ED diversions reduced by tight monitoring.

PMID- 12404988
TI  - Don't give up: ED copays are 'built into contracts'.

PMID- 12404989
TI  - 2002 salary survey results. How do your salary and benefits stack up when
      compared to those of your hospital case management peers?

PMID- 12404990
TI  - Documenting in the medical record.

PMID- 12404991
TI  - Nutrition and hospice.

PMID- 12404992
TI  - Guidelines for interviewing new residents.

PMID- 12404993
TI  - Sorting out the facts: the importance of controlling your impulses while making
      decisions.

PMID- 12404994
TI  - Awareness of zero tolerance laws in three states.
AB  - PROBLEM: A prior study indicated that zero tolerance laws differ in their
      enforceability and likelihood of enforcement, with California's law being easier
      to enforce than New York's, and New Mexico's being the hardest of all. The
      question is, do these differences in enforcement affect teenagers' knowledge and
      perception of these laws? METHOD: A telephone survey was conducted to investigate
      awareness of the laws among 17-20 year olds in these three states and perceptions
      of enforcement. RESULTS: Estimated percentages of teenagers who knew of the laws
      were much higher in New York and California (71% and 65%, respectively) than in
      New Mexico (34%). Perceptions that police were enforcing the law, that licenses
      could be suspended, and that penalties were often applied were also lowest in New
      Mexico. IMPACT ON INDUSTRY: The potential of zero tolerance laws will not be
      realized without better awareness among young people. Full enforcement of the
      laws accompanied by publicity about the enforcement is recommended. Changes to
      the laws and their application may encourage enforcement efforts.

PMID- 12404995
TI  - Using an injury diary to describe the ecology of children's daily injuries.
AB  - PROBLEM: Two problems were addressed in this study. First, are daily injury
      diaries an effective means to gather information about children's unintentional
      injuries? Second, what are the circumstances of children's injuries as recorded
      through the diary method? METHOD: Two studies were conducted with a total of 172
      children to describe the ecology of children's daily unintentional injuries.
      Families completed a daily diary for 14 days, describing the circumstances
      surrounding the injuries children experienced each day. RESULTS: Descriptive data
      is provided on the locations, causes, and types of injuries children incurred, as
      well as who was present when they were injured. Daily injury rate was modestly
      related to the number of major injuries children had incurred in their lifetimes.
      DISCUSSION: The diary methodology was an effective means to study the ecology of
      children's daily injuries. Children's injuries occur in a wide range of
      circumstances that can be quantified through diary techniques. IMPACT ON
      INDUSTRY: Data obtained from daily injury diaries may be useful in a variety of
      areas, including study of the etiology of childhood injury, design of
      interventions to prevent injury, and engineering of toys and playground equipment
      for children.

PMID- 12404996
TI  - Turning gap acceptance decision-making: the impact of driver distraction.
AB  - PROBLEM: A number of studies have found that use of in-car phones by drivers can
      interfere with the cognitive processing necessary for making appropriate and
      timely vehicle control decisions. However, the specific linkage between
      communication-based distraction and unsafe decision-making has not been
      sufficiently explored. METHOD: In a closed-course driving experiment, 39 subjects
      were exposed to approximately 100 gaps each in a circulating traffic stream of
      eight vehicles on an instrumented test track that was wet about half the time.
      The subjects were at the controls of an instrumented car, which was oriented in a
      typical left-turn configuration (traffic-crossing situation in North America) and
      with parking brake on and the transmission in neutral. The subjects were
      instructed to press on the accelerator pedal when they felt that a gap was safe
      to accept. Their performances were monitored and incentives were provided for
      balancing safe decision-making with expeditious completion of the task. For half
      of the gap exposures (randomly assigned), each subject was required to listen and
      respond to a complex verbal message. RESULTS: When not distracted, the subjects'
      gap acceptance judgment was found to be significantly influenced by their age,
      the gap size, the speed of the trailing vehicle, the level of "indecision," and
      the condition of the track surface. However, when distracted, the subjects did
      not factor pavement surface condition into the decision process. On wet pavement,
      the subjects were judged to have initiated twice the level of potential
      collisions when distracted by the messages that they did when not distracted.
      DISCUSSION: Listening/responding to verbal messages may reduce the capacity of
      drivers to process adequately all the important information necessary for safe
      decision-making. The effects of the messages in our study seemed to cause the
      subjects to misjudge gap size and speed information when operating under the
      additional disadvantage of adverse pavement condition. SUMMARY: Attention to
      complex messages while making decisions about turning through gaps in an on
      coming vehicle stream was associated with significantly increased unsafe decision
      making by subjects in our experiment when the additional complexity of wet
      surface condition was introduced. IMPACT ON INDUSTRY: While the results reflected
      a somewhat artificial situation where the measure was signaled intention to act
      rather than the act itself, nevertheless, they do strongly suggest a scenario in
      which mental distraction could contribute to crash risk. With the rapid
      proliferation of telematics in the vehicle market, even with the laudable
      objectives represented by the Intelligent Transportation Systems initiative,
      there is a danger of the primary task of the driver being subordinated to a
      perceived need to enhance information flow to/from the external "world." Industry
      and governments need to work together to ensure that apparently desirable in
      vehicle communication improvements do not compromise safety.

PMID- 12404997
TI  - Comparison of two fatal occupational injury surveillance systems in the United
      States.
AB  - INTRODUCTION: Using different methods, two national systems compile fatal
      occupational injury data in the United States: the National Institute for
      Occupational Safety and Health (NIOSH) National Traumatic Occupational Fatalities
      (NTOF) surveillance system, and the Bureau of Labor Statistics (BLS) Census of
      Fatal Occupational Injuries (CFOI). The NTOF uses only death certificates, while
      CFOI uses multiple sources for case ascertainment. METHODS: Through overall and
      case-by-case comparisons, this study compares these systems and evaluates counts
      for the nation and by state for worker and case characteristics. RESULTS: From
      1992 through 1994, NTOF reported an average of 84% of the number of traumatic
      occupational fatalities reported in CFOI. This percentage changed somewhat when a
      case-by-case comparison was conducted--88% of the NTOF cases were matched
      directly to the CFOI cases. Although CFOI captured a larger number of fatalities
      annually, the additional fatalities did not follow a discernable pattern. IMPACT
      ON INDUSTRY: By understanding the distribution of fatalities, targeted efforts to
      reduce them will benefit all industries.

PMID- 12404998
TI  - A study of stopping propensity at matured red light camera T-intersections.
AB  - PROBLEM: This paper evaluates the stopping propensity of drivers at matured in
      service red light camera (RLC) signalized T-intersections after a number of years
      of camera operation. METHOD: A special-purpose data logger working in conjunction
      with loop sensors was used to gather traffic parameters, vehicle
      stopping/crossing movements, and signal phases at camera (treatment) and
      noncamera (comparison) approaches. Logistic modeling was employed to determine
      the stopping/crossing decisions of civilian vehicle drivers in response to the
      onset of yellow (amber) with traffic and the associated situational and
      behavioral variables, including their interactions. SUMMARY: The propensity to
      stop at camera approaches was about 17 times more than at noncamera approaches.
      This finding strongly affirmed the positive effect of RLC in encouraging drivers
      to stop. The likelihood to stop was about 6.5 times higher for an approach that
      faces an opposing right-turn conflict immediately after the onset of red. Higher
      stopping propensity was also more prevalent during weekdays and in periods of low
      traffic volumes. IMPACT ON INDUSTRY: The findings provided an objective measure
      on the effectiveness of RLC that would be useful to evaluate intersections for
      camera installation as well as on the implementation and operational aspects of
      RLC program.

PMID- 12404999
TI  - Reconstructing human contributions to accidents: the new view on error and
      performance.
AB  - PROBLEM: How can human contributions to accidents be reconstructed? Investigators
      can easily take the position a of retrospective outsider, looking back on a
      sequence of events that seems to lead to an inevitable outcome, and pointing out
      where people went wrong. This does not explain much, however, and may not help
      prevent recurrence. METHOD AND RESULTS: This paper examines how investigators can
      reconstruct the role that people contribute to accidents in light of what has
      recently become known as the new view of human error. The commitment of the new
      view is to move controversial human assessments and actions back into the flow of
      events of which they were part and which helped bring them forth, to see why
      assessments and actions made sense to people at the time. The second half of the
      paper addresses one way in which investigators can begin to reconstruct people's
      unfolding mindsets. IMPACT ON INDUSTRY: In an era where a large portion of
      accidents are attributed to human error, it is critical to understand why people
      did what they did, rather than judging them for not doing what we now know they
      should have done. This paper helps investigators avoid the traps of hindsight by
      presenting a method with which investigators can begin to see how people's
      actions and assessments actually made sense at the time.

PMID- 12405000
TI  - An algorithm for assessing the risk of traffic accident.
AB  - INTRODUCTION: This study is aimed at developing an algorithm to estimate the
      number of traffic accidents and assess the risk of traffic accidents in a study
      area. METHOD: The algorithm involves a combination of mapping technique
      (Geographical Information System (GIS) techniques) and statistical methods
      (cluster analysis and regression analysis). Geographical Information System is
      used to locate accidents on a digital map and realize their distribution. Cluster
      analysis is used to group the homogeneous data together. Regression analysis is
      performed to realize the relation between the number of accident events and the
      potential causal factors. Negative binomial regression model is found to be an
      appropriate mathematical form to mimic this relation. Accident risk of the area,
      derived from historical accident records and causal factors, is also determined
      in the algorithm. The risk is computed using the Empirical Bayes (EB) approach. A
      case study of Hong Kong is presented to illustrate the effectiveness of the
      proposed algorithm. RESULTS: The results show that the algorithm improves
      accident risk estimation when comparing to the estimated risk based on only the
      historical accident records. The algorithm is found to be more efficient,
      especially in the case of fatality and pedestrian-related accident analysis.
      IMPACT ON INDUSTRY: The output of the proposed algorithm can help authorities
      effectively identify areas with high accident risk. In addition, it can serve as
      a reference for town planners considering road safety.

PMID- 12405001
TI  - Distractions and the risk of car crash injury: the effect of drivers' age.
AB  - PROBLEM: Motor-vehicle accidents are one of the major causes of injury in most
      motorized countries. Driver distractions have been suggested as a contributor to
      traffic accidents. Moreover, age of the driver seems to have a role in the
      relationship between distractions and car crashes. But very few studies have
      investigated the effect of driver's age on this relationship. This exploratory
      study investigated the association between distractions, both inside and outside
      the vehicle, and the increased risk of car crash injury among drivers across
      different ages. METHOD: This study used a case series design to analyze data
      routinely collected by the NSW police in Australia. A special focus of this study
      was on how drivers' age affects the risk of car crash injury, which was
      determined by using a well-documented risk estimation methodology. RESULTS: The
      results obtained indicated that drivers of all ages, on the whole, are more
      susceptible to distractions inside the vehicle than distractions coming from
      outside. Age was shown to affect the relationship between in-vehicle distraction
      and the risk of car crash injury. A separate analysis was also conducted on hand
      held phone usage while driving with results supplementing previous findings
      reported in the literature. IMPACT TO INDUSTRY: Safety strategies to
      countermeasure in-vehicle distractions have been suggested and discussed.

PMID- 12405002
TI  - Writing about nursing research: a storytelling approach.
AB  - In this article Gavin Fairbairn and Alex Carson argue that much of what is
      written by nurses is needlessly difficult, especially when it concerns research
      they have carried out. The authors make a positive contribution to the ways in
      which nurses think about what they write and how they write it, suggesting that
      one way in which things might become better would be for nurses to view their
      writing as a form of storytelling.

PMID- 12405003
TI  - The whole story: towards an ethical research methodology.
AB  - In this paper Alex Carson and Gavin Fairbairn argue that closer links between
      nursing education, research and practice may be developed through the use of a
      narrative methodology. The debate is cited in the wider practical and political
      context of a more democratic model of healthcare delivery. The authors provide a
      rationale for the use of stories in both nursing research and nursing practice by
      suggesting that each rests upon an ethic of helping whole people, rather than
      simply amounting to a technical undertaking. They suggest that the relationship
      between the ethical and the technical should be a more explicit feature in
      discussions of methodological issues in nursing research. They locate ideas about
      narrative research outside both qualitative and quantitative paradigms. Finally,
      they offer a philosophical and methodological argument for the use of narratives
      as an approach to research in which respect for people is central.

PMID- 12405004
TI  - An overview of three different approaches to the interpretation of qualitative
      data. Part 1: Theoretical issues.
AB  - In this paper, the first of two, Helena Priest, Paula Roberts and Leslie Woods
      discuss the essential features and methods inherent within three approaches to
      the interpretation of qualitative data. An overview of three methodologies
      commonly used in nursing and healthcare research is presented: grounded theory,
      qualitative content analysis and narrative analysis. The paper considers the
      philosophical bases of the three methods and the principles inherent within each
      analytical approach. Key stages and steps are presented and described.

PMID- 12405005
TI  - An overview of three different approaches to the interpretation of qualitative
      data. Part 2: Practical illustrations.
AB  - This paper continues the discussion of the essential features and methods
      inherent within three approaches to the interpretation of qualitative data
      presented in Part 1 (Priest et al 2002). Leslie Woods, Helena Priest and Paula
      Roberts explore the use of grounded theory, qualitative content analysis and
      narrative analysis through the use of an illustrative example.

PMID- 12405006
TI  - Eliciting nursing knowledge from practice: the dualism of nursing.
AB  - Nursing knowledge has traditionally been examined and developed through the main
      research approaches based on the positivist, interpretive or phenomenological
      philosophies. These approaches are used either from a single and individual
      stance or combined to address particular research questions. They all, however,
      retain a focus that deals primarily or exclusively with what can be measured,
      observed or expressed as a fundamental unit of analysis to reconstruct, interpret
      and explain nursing practice. In this paper, Vince Ramprogus challenges the
      traditional approach to how nursing knowledge is defined and the common
      understanding of the purpose of nursing research. It is argued that adhering to
      empirical rigour while investigating or measuring nursing practice interferes
      with the very act and experience of nursing. Indeed, it becomes an either/or
      situation. It is also argued that nursing is not an empirical subject, and,
      therefore, the purpose of researching nursing is not about seeking the truth but
      about improving practice to achieve better patient care. The arguments are
      intended to provoke discussion and debate rather than to present a set position.

PMID- 12405007
TI  - Effective dissemination strategies.
AB  - Dissemination of research findings or other key messages is increasingly
      acknowledged as a vital yet complex process. In this paper, Philip Scullion sets
      out to explore and disentangle some of these complexities, examine examples of
      successful dissemination strategies and provide valuable insights. It is argued
      that the process of dissemination needs to be afforded greater emphasis by
      project-funding bodies, research supervisors, researchers, and those responsible
      for implementing changes in clinical practice. Important initiatives are
      acknowledged before the concept of dissemination is explored. The source,
      message, medium and target groups, all key elements in the dissemination process,
      are then examined. It is argued that dissemination needs to be carefully
      considered at the design stage of research projects in relation to each of these
      elements. This paper concludes that the current commitment to research and
      evidence-based practice will have limited impact on patient care until a similar
      commitment to dissemination is evident at both corporate and individual levels.

PMID- 12405008
TI  - Thoughts on teaching physiology to medical students in 2002.

PMID- 12405009
TI  - [Acute coronary syndrome without ST-segment elevation. Current guidelines].
AB  - Coronary-artery disease is the leading cause of death in western countries.
      Unstable angina and myocardial infarction without ST-segment elevation are now
      recognized as among the most frequent and important clinical manifestations of
      coronary-artery disease. The European and American professional societies have
      released guidelines on diagnosis, risk stratification and treatment of these
      disorders. These guidelines summarise current evidences and translate them in
      clinical practice. Most important changes relate to the inclusion of troponins
      into the risk stratification algorithm. In addition, some guidelines released by
      scientific committees of the laboratory area further define the quality
      specifications for cardiac troponin assays. Powerful tests, such as cardiac
      troponins, on which critical decisions will rest need highly reliable methods,
      quality control and external quality assurance schemes.

PMID- 12405010
TI  - [Vasopeptidases and their inhibitors].
AB  - The term vasopeptidase means any peptidase able to generate or to inactivate a
      vasoactive peptide. This term got a more definitive meaning when a new class of
      drugs, the vasopeptidase inhibitors, was introduced. These drugs are especially
      represented by the inhibitors of angiotensin-converting enzyme (ACE) and neutral
      endopeptidase (NEP). ACE is now primarily considered a kininase rather than an
      angiotensinase and ACE-inhibitors have been used successfully in the treatment of
      many cardiovascular diseases, including hypertension and heart failure.
      Preliminary results suggest that the use of NEP inhibitors could also contribute
      to improve prognosis of cardiovascular diseases. Vasopeptidase inhibitors
      simultaneously inhibiting both NEP and ACE have shown to be more effective than
      currently available ACE inhibitors. (Omapatrilat is at present the most
      clinically advanced in these drugs). However, many side-effects of vasopeptidase
      inhibitors have been reported, but the most dangerous is angioedema which is
      potentially life threatening. Since this complication is mediated by bradykinin,
      and both inhibition of ACE and NEP can produce bradykinin increasing, it has been
      suggested that the incidence of angioedema due to vasopeptidase inhibitors could
      be higher compared with that related to ACE-inhibitors. The FDA raised concern
      about this adverse effect, and the manufacturer decided to withdraw the
      application temporarily. In order to identify patients at risk of angioedema we
      have recently shown that low plasma levels of aminopeptidase P, another enzyme
      which cabolises bradykinin, could indicate a predisposition for development of
      angioedema in some patients treated with vasoinhibitor drugs.

PMID- 12405011
TI  - [First-aid treatment for acute myocardial infarction. Experience at the San
      Camillo Hospital of Rome].
AB  - STUDY OBJECTIVE: The aim of the study is to verify: 1) the trustworthiness level
      of the diagnosis of AMI defined in Emergency Department (ER); 2) the frequency
      and the effectiveness (length of staying in hospital, mortality rate) of the
      invasive or not invasive treatment which are implemented in the ER area. METHODS:
      We have studied the crowding of the patients suffering from chest pain (CP) who
      asked the ER for assistance during the year 2000 and that of the patients with
      AMI diagnosed in ER (diagnosis at the admittance and at the discharge from the
      hospital, therapeutic procedures, staying in hospital, mortality rate). RESULTS:
      The patients suffering from CP have been the 5.4% of all the patients who reached
      the ER and were admitted to the hospital more than the patients who reached the
      ER for all the other causes (41.5% versus 22.1%). In 61.7% of the patients
      affected by AMI the disease was identified by the physicians of the ER; the
      invasive treatment has been developed in 67.7% of those patients and the not
      invasive in 32.3% of the same patients. The mean length of the staying in
      hospital for the patients who have been treated with PTCA was 10.3 days; on the
      contrary, the same value for the patients treated with thrombolysis was 13.8 days
      and the difference was significant at the 0.001 level. The mortality rate during
      the staying in Hospital was 5.9% in the patients treated with PTCA and 13% in the
      patients treated with thrombolysis but the difference was not significant because
      of the little number of the dead patients. CONCLUSION: The sensitivity (62%) and
      the specificity (100%) of the diagnosis of AMI defined in the ER demonstrate the
      utility of a Cardiologic Service in ER.

PMID- 12405012
TI  - [Recent onset atrial fibrillation at a unit of internal medicine].
AB  - The study is including 239 patients (145 males, 94 females, mean age 68.2 years),
      with recent-onset atrial fibrillation, hospitalised in a Unit of Internal
      Medicine. Valvular disease and systemic hypertension were the predominant
      diseases. Management of patients: clinical observation, electrical shock,
      antiarrhythmic drug therapy, reduction of heart frequency. Sinus rhythm was
      restored in 176 patients (74%). Antiarrhythmic drug therapy included propafenone,
      quinidine and amiodarone. Sinus rhythm was restored by antiarrhythmic drug
      therapy in 115 of 161 patients (71%); there was no difference of efficacy in
      antiarrhythmic drugs. Electrical shock restored sinus rhythm in 33 of 38 patients
      (87%). The following characteristics predicted the restoration of sinus rhythm:
      absence of valvular disease versus presence of systemic hypertension (p = 0.01),
      duration of atrial fibrillation < 12 hours (p = 0.02), age > 70 years (p =
      0.00001). There were 2 serious complications: 1 stroke, 1 torsade de pointes.

PMID- 12405013
TI  - [Measurement of carotid intima-media thickness and of pressure variability in
      arterial hypertension in menopause].
AB  - Forty women, with hypertension developed during menopause, were divided into two
      groups, depending on whether from the time of its beginning there were
      occurrences of clinic episodes expressing a more or less acute "organ damage" or
      not. In all patients a 24 hrs ambulatory blood pressure monitoring and a carotid
      ultrasound were carried out to evaluate the carotid intima-media thickness (IMT).
      The IMT resulted significantly superior in those patients presenting a vascular
      episode and as much significantly correlated to the pressure values, especially
      systolic; in particular, in "non dippers" patients there is evidence of
      correlations between percentages of "at risk" systolic pressure peaks, prevalence
      of plaques in carotidal vessels and higher IMT compared to those patients with
      night-time blood pressure decrease. The authors think that the presence of blood
      pressure values which are persistently, or nearly, high in 24 hrs, especially
      with wide variations, favours the development of plaques and, in any case, of a
      higher IMT, all "at risk" elements for acute events. The IMT carotid represents a
      further easily measurable index with non-invasive method, which can supply a
      useful evidence of structural alterations in menopause, especially when it is
      associated with hypertension, and also it represents a predictive evolutive
      marker for acute cerebro-cardiovascular lesions.

PMID- 12405014
TI  - [The renin-angiotensin-aldosterone system, angiotensin I converting enzyme, and
      the ACE-inhibitors. Historical perspective and recent findings].
AB  - The renin-angiotensin-aldosterone system (RAAS) is committed to the regulation of
      circulatory homeostasis. This system, present in the majority of animal species,
      is constituted by several elements which behave as effectors able to increase
      their levels in response to the reduction of the intravascular volume and to the
      decrease of the renal perfusion. In turn, RAAS is regulated by a number of
      mechanisms. In our review a historical view precedes the description of the major
      functions of RAAS, i.e. the regulation of arterial pressure and the control of
      the hydroelectrolytic homeostasis. The evolution of the achievements about the
      angiotensin I converting enzyme is reviewed and the currently investigated
      relationship between RAAS and hemostatic system is assessed. The historical
      perspective of this review is useful to follow the key passages leading from
      clinical research to evidence-based therapeutic applications, in particular to
      the development of ACE-inhibitors. The evaluation of the rationale of ACE
      inhibitors therapy in the treatment of arterial hypertension, acute myocardial
      infarction, heart failure, and diabetic nephropathy, and a discussion of the
      angiotensin receptor blockers, close the review.

PMID- 12405015
TI  - [Coronary calcification. Physiopathology, clinical significance, and new
      diagnostic-therapeutic prospects].
AB  - Coronary acute syndromes (CAD) are the result of atherosclerosis, a vascular
      disorder characterized by abnormalities in endothelial function, ultimately
      resulting to partial or complete vessel occlusion. Although recognized risk
      factors for CAD are helpful to predict the development of atherosclerosis, their
      ability to identify individual patients at risk of hard events is limited. In
      addition research has showed that excessive emphasis on the severity of coronary
      luminal stenosis may be misleading, and the majority of acute events occurs in
      patients with pre-existing noncritical arterial stenoses. Coronary calcium is
      intimately associated with coronary atherosclerotic plaque development, and may
      be used as surrogate marker to assessment the risk for an hard event in an
      individual subject. Coronary calcification is not a passive process of mineral
      precipitation but a biologically regulated phenomenon that has many similarities
      to bone formation. New imaging noninvasive methods, as electron beam computed
      tomography (EBCT), are able to identify, in asymptomatic patients, unstable
      coronary plaques that underline the clinical acute coronary syndromes. After a
      detailed description of the abovementioned context, clinical implications,
      diagnostic approaches and prospects for therapy of coronary calcifications are
      reviewed and discussed.

PMID- 12405016
TI  - [Hibernating and stunned myocardium. Pathogenetic mechanisms during and after
      myocardial ischemia].
AB  - In this paper the Authors consider the concept of stunning/hibernating
      myocardium, analizing the most recent articles and reviews in literature, until
      April 2002 (database PubMed). Dysfunctional segments with normal perfusion and
      normal glucose utilization are considered to be "stunned", and dysfunctional
      segments with reduced perfusion and preserved glucose utilization are considered
      to be "hibernated". Together with the two major hypothesis (generation of oxygen
      derived free radicals and transient calcium overload) in developing of
      dysfunctional myocardium after ischaemia, recent studies have demonstrated an
      important role in down-regulation of beta-adrenergic receptors both in the
      stunned and in the hibernated segments. Moreover, the increase of negatively
      inotropic cytokines TNF-alpha and NOS2 has been observed in dysfunctional
      segments. The number of copies of mRNA has been quantified by reverse
      transcription-polymerase chain reaction (reverse-PCR).

PMID- 12405017
TI  - [Hospital discharge report of patients treated with resuscitation for heart
      arrest].
AB  - Recent studies have demonstrated the importance of the etiology, risk
      stratification and long-term follow-up in post cardiac arrest resuscitated
      patients. Nowadays improved prognosis and a better quality of life could be
      assured by new diagnostic tools and, lost of all, a great variety of therapeutic
      options.

PMID- 12405018
TI  - [Image of the month. False aneurysm of the left ventricle].

PMID- 12405019
TI  - [How I treat...rheumatoid arthritis. The arrival of a new therapeutic era: anti
      tumor necrosis factor alpha antibodies].
AB  - Rheumatoid arthritis (RA) is the most frequent autoimmune inflammatory
      arthropathy. Chronic synovial inflammation usually results in cartilage
      destruction, bone erosion and subsequent joint deformities with impaired physical
      function. These consequences are more or less delayed by standard disease
      modifying antirheumatic drugs (DMARDs). A better knowledge of the basic
      mechanisms of the disease and new biomolecular tools led to the development of
      novel biological agents including TNF alpha blockers. TNF alpha is a key
      inflammatory cytokine that plays a critically important role in the pathogenesis
      of RA. TNF alpha blockers brought dramatic improvements in efficacy of RA
      treatment. Here we will review the pathophysiological elements of RA wich explain
      the therapeutic efficacy of these TNF alpha blockers and we will describe in
      details the molecules, Remicade (Infliximab) and Enbrel (Etanercept), wich will
      be very soon used in daily practice in Belgium.

PMID- 12405020
TI  - [Clinical case of the month. A recurrent chylothorax in Bourneville tuberous
      sclerosis].
AB  - Bourneville's disease, first described in 1862, is a phacomatosis that is either
      autosomal dominant or sporadic. Its typical clinical signs include mental
      retardation, epilepsy and cutaneous adenomas. The pulmonary form is rare, less
      than 1%, and is secondary to occlusion of the bronchus, vascular and lymphatics
      by immature smooth muscle cells. Chylothorax may appear in more than 50% of all
      cases. No guidelines currently exist for treatment of recurrent chylothorax.
      However, several possibilities are described in the literature.

PMID- 12405021
TI  - [Arterial hypertension and tachycardia: monitoring the patient's personal drug
      therapy].
AB  - The case report of a young patient with an increase in blood pressure and heart
      rate offers the opportunity to discuss the clinical guidelines to explore and
      treat high blood pressure. The value of the 24 h blood pressure monitoring and
      the need for precise information on all drugs taken are stressed.

PMID- 12405022
TI  - [Skin necrosis after prophylactic treatment with heparin].
AB  - The authors present a case of cutaneous necrosis following local injection of
      heparin. The physiopathology and the clinical aspect are discussed.

PMID- 12405023
TI  - [Prevention of skin cancers with sunscreening agents].
AB  - How do sunscreens protect against skin cancers? The answer to this question is a
      matter of controversy among scientist for several years. The doubt persists
      because the wise use of such products is only one of the factors involved in sun
      behavior together with avoiding excessive sunlight exposure and wearing
      protective clothes.

PMID- 12405024
TI  - [Pathological implications in the neuroendocrine gastrointestinal system].
AB  - The neuroendocrine system is made of endocrine cells disseminated in various
      organs. In this article, we will focus on the implication of the neuroendocrine
      system in digestive pathology. First of all, we will review the neuroendocrine
      tumors in every location and then describe their classification, epidemiology,
      symptomatology, diagnosis and treatment. Finally, we will consider the
      implications of the neuroendocrine system in the inflammatory and functional
      pathology of the digestive tract.

PMID- 12405025
TI  - [Narcolepsy-cataplexy].
AB  - The diagnosis of narcolepsy-cataplexy is based on three axes: 1) the medical
      history is strongly suggestive when diurnal sleep attacks (narcolepsy) and drop
      attacks (cataplexy) are reported or observed; 2) the polysomnography is mandatory
      and shows nocturnal and diurnal (multiple sleep latency test) REM sleep onsets;
      3) HLA typing, practically helps to exclude the diagnosis when HLA DR15-DQB1*0602
      is not present. New pathogenetic hypotheses have been proposed, mostly based the
      absence of hypocretin in narcoleptic cerebrospinal fluid. This neurotransmitter
      was previously known exclusively by its involvement in alimentary behaviours. The
      new therapies remain symptomatic, but they are powerful to prevent somnolence,
      daytime sleepiness, cataplexy and insomnia associated with this syndrome.

PMID- 12405026
TI  - [Between dermatoses and enteropathies].
AB  - A series of gastro-intestinal diseases exhibits some connection with various
      cutaneous lesions. Some skin manifestations are clinically or histologically
      evocative, while others lack specificity. These manifestations can occur in overt
      digestive disease or be the clue for a silent one. A careful skin examination can
      thus reveal some inflammatory or neoplastic diseases of the gastro-intestinal
      tract, a malabsorption syndrome or food intolerance.

PMID- 12405028
TI  - [Management of HIV infected patients. Experience of the Liege University Hospital
      Center].
AB  - We present data from 112 patients followed in the Infectious Diseases Unit of the
      Liege University Hospital (CHU Sart-Tilman). The primary goal of this study was
      to evaluate the efficiency of highly active antiretroviral therapy (HAART) on
      surrogate immunological and virological parameters. The study also aimed at
      determining the prevalence of opportunistic infections and iatrogenic metabolical
      abnormalities in the era of HAART. Data from HIV infected patients under combined
      treatment were collected from March 1996 till July 1999. The follow-up focused on
      the variation of the CD4 cell counts and viral load, and the occurrence of
      opportunistic infections. The average age was 39 +/- 10 years and the sex ratio
      (M/F) was 2.3. At baseline, the CD4 count was 352 +/- 244/mm3 and the viral load
      was 4.1 +/- 1.2 log. After 12 months, the CD4 cells were at 540 +/- 374 and the
      viral load at 2.5 +/- 1.5 log. This favourable outcome was observed in 70% of
      patients (naive and experienced). Clinically, patients in therapeutic success
      presented few opportunistic infections, but many drugs related toxicity. Our data
      demonstrate the efficiency of combined treatment in the management of HIV
      infected patients. However, the apparition of toxicity problems could limit the
      benefit brought by these drugs.

PMID- 12405029
TI  - [Drug of month. Topical tacrolimus (Protopic)].
AB  - Tacrolimus is a potent inhibitor of immune mechanisms. It belongs to the
      macrolactam group. It inhibits the release of both Th1 and Th2 cytokines. It
      proves to be efficacious after topical application in the treatment of atopic
      dermatitis. In this indication, tacrolimus challenges topical corticosteroids.
      Irritation risks are present. The local immuno-depression can boost disseminated
      infections including herpes. The risk to promote photocarcinogenesis on the long
      term, and that bound to chronic resorption remain theoretical concerns that have
      not been assessed so far.

PMID- 12405031
TI  - [Ultrasound diagnosis? Intramuscular joint ganglion of the hip in the right
      iliopsoas muscle].

PMID- 12405027
TI  - [Barrett's esophagus: overview].
AB  - Barrett's oesophagus (BE) is a segment of columnar lined epithelium in the distal
      oesophagus, above the gastrooesophageal junction. So it is important to localize
      this junction endoscopically; the proximal margin of the gastric folds is the
      anatomic landmark. Another important feature of BE is the specialized intestinal
      metaplasia. In the aetiology of this condition, acid reflux is a primary event
      but there is evidence that other factors are causal. As BE is a well known
      premalignant condition, detection of dysplastic epithelium and its severity is
      the crucial element. Practical guidelines are presented for endoscopic
      surveillance program. The purpose is the early detection of high grade dysplasia
      and carcinoma to advise oesophagectomy or endoscopic ablation therapy for
      patients unfit to undergo surgery.

PMID- 12405032
TI  - [Cerebral ischemia tolerance].
AB  - Ischemic tolerance means a rapid adaptative cerebral reaction to one or more
      cycles of short ischemia and reperfusion, improving the tolerance to a subsequent
      longer ischemia. The basic molecular mechanisms of ischemic tolerance are largely
      unknown. The pathophysiological course can be divided in induction, transduction
      and tolerance. During induction NMDA- and adenosin receptors, free radicals and
      conservation of energy metabolism are required. Protein kinases, transcription
      factors, and immediate early genes play a role in transduction. Tolerance can be
      observed in different time windows. The early phase lasts for several hours after
      the preconditioning stimulus and can be related to adenosine receptors and ATP
      dependent potassium channels. A delayed phase, after 1-7 days, is explained by
      genetic remodeling. Clinically, there is evidence for a protective effect of
      transient ischemic attacks occurring before stroke.

PMID- 12405030
TI  - [Clinical study of the month. Benefit/risk balance of postmenopausal estrogen
      progestin treatment in peril in the Women's Health Initiative study: practical
      attitude of the clinician].
AB  - The Women's Health Initiative (WHI) is sponsored by the NIH. The study focuses on
      risk and benefits of strategies that could potentially reduce the incidence of
      heart disease, breast and colon cancer, and fractures in postmenopausal women.
      One arm of the study, a double-blind, placebo-controlled trial, looking at the
      effects of continuous combined estrogen-progestin regimen was stopped prematurely
      based on health risks which exceeded health benefits. The main reason for this
      decision was the increase in risk of invasive breast cancer, as well as a slight
      increase in the rate of myocardial infarction and stroke. In this paper, we
      inform our colleagues of the detailed results of the study. We comment on its
      limitation and discuss the new original observations. Finally, we integrate the
      others to previous world literature data that are confirmed by the WHI study. It
      is important for the individual prescribing practitioner to issue practical
      conclusions and therapeutic recommendations. The department of Obstetrics and
      Gynaecologic of the University of Liege, in agreement with the European Menopause
      Society and the International Menopause Society, is convinced that there is no
      alternative to the hormone replacement therapy for menopausal symptoms. We should
      stick to the traditional indications for hormones, namely vasomotor symptoms and
      osteoporosis. We should continue to recommend hormones for symptomatic women. One
      should realize that the risk for breast cancer appears only after several years
      of use, and the risk for cardiovascular events below age 60 is very small (the
      age of the patients was 63 at inclusion in the WHI study). We should encourage
      women to take the necessary measures for routine, periodic breast examinations
      (both manual, echographic and radiographic). Women who use HRT for more than 5
      years should discuss the latest data of the WHI study with their physician, in
      order to consider their individual benefit-risk equation. Those who feel good on
      hormones and are fully satisfied with this treatment should learn of possible
      harm after long-term use. It is important to take into account the importance of
      quality of life. We should leave to the patient the final decision whether or not
      to continue the treatment. It is presently impossible to decide whether other
      estroprogestin associations, other administration routes and other molecules such
      as estradiol, natural progesterone or other progestins, SERMS and Tibolone could
      have an impact very different from that of the estroprogestin combination used in
      the WHI study. It is the duty of every physician to decide, from the complex
      epidemiological data obtained in the aged women (63-68 years) with a high
      cardiovascular risk in the WHI study, if it is possible or not in each individual
      case to recommend the initiation or pursue of an hormone replacement therapy.

PMID- 12405033
TI  - [EndNote 5 reference manager--functions--improvements--personal experiences].
AB  - Bibliography database managers are used to manage information recourses:
      specifically, to maintain a database to references and create bibliographies and
      reference lists for written works. A good reference management program should
      make it easy to read and to record the elements that a reference comprises, e.g.
      authors name, year of publication, title of article etc. It should offer tools
      that let you find and retrieve references quickly, and it should be able to
      produce the bibliography in the format required for a particular publication. You
      can create your database reference by reference or you can download batches of
      references from one of the popular searching services (e.g. MEDLINE) and you can
      search in the Internet. When you want to cite a reference you simply paste the
      reference wherever you want your intext citation to appear. There are many
      computer programs, but very few stands out as truly useful, time saving, and work
      enhancing. One of them is EndNote. The reference manager EndNote 5.0 was recently
      released in Germany. As long-time fans of this excellent program, we upgraded
      from the previous version. The use of the software package EndNote 5.0 for
      Windows is described. The main reason for getting EndNote 5.0 is its clearly
      improved functions and features: especially the co-operation with Microsoft Word
      (cite while you write) and the spelling examination. Altogether EndNote 5.0
      provides also an excellent combination of features and ease of use.

PMID- 12405034
TI  - [Rapid induction of withdrawal with opiate antagonists under anesthesia: an
      alternative to treatment of opiate dependence?].
AB  - Rapid induction of withdrawal by opiate antagonists under anesthesia is an opiate
      detoxification technique. This technique is useful to reduce intensity and
      duration of withdrawal. Therefore, this technique represents an alternative
      strategy in the treatment of opiate addicted patients. This paper attempts to
      present a brief history of this technique, and a critical review of related
      issues.

PMID- 12405035
TI  - [Is snoring a health risk?].
AB  - Snoring is a marker for sleep apnea. Additionally, snoring per se is a cause of
      excessive vascular morbidity and an excessive risk for accidents. These health
      risks of snoring could be lowered by using CPAP (continuous positive airway
      pressure). Despite this evidence, CPAP-therapy is still limited to patients with
      hypersomnolence (excessive daytime sleepiness), due to conflicting results in the
      literature and the well-known lack of compliance in patients without
      hypersomnolence.

PMID- 12405037
TI  - [Recurrent painful cyanosis of fingers and palm. Recurrent paroxysmal finger
      hematoma (Achenbach syndrome)].

PMID- 12405036
TI  - [Retired patient with vertigo. Benign paroxysmal positional vertigo].

PMID- 12405038
TI  - Executive coaching: optimizing the potential of healthcare leaders.

PMID- 12405039
TI  - American Sign Language and end-of-life care: research in the deaf community.

PMID- 12405040
TI  - Homelessness and clinical ethics.

PMID- 12405041
TI  - The voice of home care workers in clinical ethics.

PMID- 12405043
TI  - Assessing capacity for clinical decisions and research for persons with low
      English proficiency: ethical and practical challenges.

PMID- 12405042
TI  - Concealing accidental nursing home deaths.

PMID- 12405044
TI  - What the Navajo culture teaches about informed consent.

PMID- 12405045
TI  - The board and care facility's resident forum has formed a bank!

PMID- 12405046
TI  - Who decides? A look at ethics committee membership.

PMID- 12405047
TI  - Hospital policy on terminal sedation and euthanasia.

PMID- 12405048
TI  - Rejuvenating the Minnesota Network of Healthcare Ethics Committees.

PMID- 12405049
TI  - Shamans and conventional care: are we prepared?

PMID- 12405050
TI  - An ethics committee in Turkey: physician sexual misconduct.

PMID- 12405051
TI  - [Excesses, deficiencies and errors in functional diagnosis and therapy. Part II].

PMID- 12405052
TI  - Preparing for the new face(s) of terrorism.

PMID- 12405053
TI  - Product reimbursement and APCs: why all the fuss?

PMID- 12405054
TI  - Combating bioterrorism with bioengineering.

PMID- 12405055
TI  - Homeland security: the possible, probable, and perils of information technology.
      Information technology is a key component in both defending against and aiding
      terrorism threats.

PMID- 12405056
TI  - Key participants in combating terrorism. The role of American citizens and their
      communities in homeland security.

PMID- 12405057
TI  - An anthrax "smoke" detector. Online monitoring of aerosolized bacterial spores.

PMID- 12405058
TI  - High-speed advanced sensors for bioterror weapons. What we have done, what more
      needs to be done now, and what needs to be done in the future.

PMID- 12405059
TI  - Information technology in the age of emergency public health response. The
      framework for an integrated disease surveillance system for rapid detection,
      tracking, and managing of public health threats.

PMID- 12405060
TI  - The future of command and control for disaster response. Utilizing information
      and virtual reality technology, the Cybercare system can link resources
      throughout the country for distributed yet coordinated command and control.

PMID- 12405061
TI  - Information infrastructure tools for bioterrorism preparedness. Building dual- or
      multiple-use infrastructures is the task at hand for state and local health
      departments.

PMID- 12405062
TI  - A system for electronic disease reporting and management. Determining the
      extent/spread of problems and minimizing consequences through rapid reporting and
      dissemination of critical information.

PMID- 12405063
TI  - Terrorism risks in rural and frontier America. Their importance to the successful
      functioning of urban America makes rural and frontier areas ripe targets for
      terrorism.

PMID- 12405064
TI  - The far-reaching impact of bioterrorism. What the European Union is doing
      regarding deliberate releases of biological/chemical agents based on the events
      in the United States.

PMID- 12405065
TI  - International mechanisms for threat reduction of chemical and biological weapons.
      Steps the United States needs to take to strengthen current global initiatives.

PMID- 12405066
TI  - Cortical architecture and self-referential control for brain-like computation. A
      new approach to understanding how the brain organizes computation.

PMID- 12405067
TI  - New methods in fMRI analysis. Hierarchical cluster analysis for improved signal
      to-noise ratio compared to standard techniques.

PMID- 12405068
TI  - Hidden Markov model classification of myoelectric signals in speech.

PMID- 12405070
TI  - Implementation of a data acquisition system for contactless conductivity imaging.

PMID- 12405069
TI  - Classification of sleep stages in infants: a neuro fuzzy approach.

PMID- 12405071
TI  - Confidence-based anisotropic filtering of magnetic resonance images.

PMID- 12405072
TI  - A digital signal processor for Doppler radar sensing of vital signs.

PMID- 12405073
TI  - The fantastic pacemaker system.

PMID- 12405074
TI  - System theory as a means of increasing innovation in the medical instrumentation
      industry.

PMID- 12405075
TI  - Controversy over the dicrotic notch and wave in the blood pressure record.

PMID- 12405076
TI  - Electromagnetic hypersensitivity--a COMAR Technical Information Statement. June
      27, 2002.

PMID- 12405077
TI  - Relationships between God and people in the Bible: a core conflictual
      relationship theme study of the Pentateuch/Torah.
AB  - The most widely known images of God are from the Bible. An important
      characteristic of these images is their portrayal of God's interactions with
      people. Although there have been many religious and literary discussions of God's
      relationships with people in the Bible, no systematic psychological assessment
      has been reported. Therefore, the aim of this study was an innovation: to
      identify patterns of relationship between God and people portrayed in the first
      five books of the Bible, the Pentateuch or Torah, by using the core conflictual
      relationship theme (CCRT) method, a widely used scoring system for the assessment
      of interpersonal relationships. Reliability for the application of the CCRT
      method to relationship episode narratives in the Pentateuch/Torah was assessed
      and found to be very good. Results show that the most frequent theme in
      relationship episode narratives about God and people is that God is helpful. Two
      less frequent but also highly repetitive themes are that God controls or hurts
      the other person. Many differences were found between relationship themes defined
      by the type of person with whom God interacted: patriarch, Moses, woman, non
      Israelite, or not a non-Israelite. Thus, the CCRT results identify several
      different patterns of relationship between God and people.

PMID- 12405078
TI  - Insight and personal narratives of illness in schizophrenia.
AB  - Insight in schizophrenia tends to be assessed as the degree to which one
      possesses specific knowledge. It therefore often fails to account for the fact
      that awareness of illness is an inextricable part of a personal narrative and may
      be incoherent or incomplete for many different narrative reasons. Accordingly, we
      have developed a means of eliciting narratives of illness: the Indiana
      Psychiatric Illness Interview, and a method for rating the coherence of those
      narratives: the Narrative Coherence Rating Scale. In this article we describe
      these methods and present data on their reliability and validity in a study of
      the illness narratives of 33 outpatients with schizophrenia or schizoaffective
      disorder. Results suggest our measures possess sufficient internal consistency
      and good to excellent interrater reliability. Additionally, as predicted, our
      measures of narrative coherence were significantly correlated with traditional
      measures of insight and with measures of cognitive impairment and hopelessness
      gathered earlier.

PMID- 12405080
TI  - 60,000 disaster victims speak: Part II. Summary and implications of the disaster
      mental health research.
AB  - On the basis of the literature reviewed in Part I of this two-part series
      (Norris, Friedman, Watson, Byrne, Diaz, and Kaniasty, this volume), the authors
      recommend early intervention following disasters, especially when the disaster is
      associated with extreme and widespread damage to property, ongoing financial
      problems for the stricken community, violence that resulted from human intent,
      and a high prevalence of trauma in the form of injuries, threat to life, and loss
      of life. Meeting the mental health needs of children, women, and survivors in
      developing countries is particularly critical. The family context is central to
      understanding and meeting those needs. Because of the complexity of disasters and
      responses to them, inter-agency cooperation and coordination are extremely
      important elements of the mental health response. Altogether, the research
      demands that we think ecologically and design and test societal- and community
      level interventions for the population at large and conserve scarce clinical
      resources for those most in need.

PMID- 12405079
TI  - 60,000 disaster victims speak: Part I. An empirical review of the empirical
      literature, 1981-2001.
AB  - Results for 160 samples of disaster victims were coded as to sample type,
      disaster type, disaster location, outcomes and risk factors observed, and overall
      severity of impairment. In order of frequency, outcomes included specific
      psychological problems, nonspecific distress, health problems, chronic problems
      in living, resource loss, and problems specific to youth. Regression analyses
      showed that samples were more likely to be impaired if they were composed of
      youth rather than adults, were from developing rather than developed countries,
      or experienced mass violence (e.g., terrorism, shooting sprees) rather than
      natural or technological disasters. Most samples of rescue and recovery workers
      showed remarkable resilience. Within adult samples, more severe exposure, female
      gender, middle age, ethnic minority status, secondary stressors, prior
      psychiatric problems, and weak or deteriorating psychosocial resources most
      consistently increased the likelihood of adverse outcomes. Among youth, family
      factors were primary. Implications of the research for clinical practice and
      community intervention are discussed in a companion article (Norris, Friedman,
      and Watson, this volume).

PMID- 12405081
TI  - An overview of trichotillomania and its response to treatment with quetiapine.
AB  - There is a lack of consensus about the pharmacological agent of choice to treat
      trichotillomania and which rating scales are best suited to measure the clinical
      severity and improvement of this condition. This overview summarizes the
      historical background, etiology, diagnostic criteria, epidemiology, course,
      prognosis, and various pharmacological treatments of trichotillomania. The case
      report describes a favorable clinical response of a 33-year-old female veteran
      with trichotillomania to the atypical antipsychotic quetiapine. It also provides
      data from the Massachusetts General Hospital (MGH) Hair Pulling Scale, a 7-item
      self-report scale that monitors symptom severity and treatment progress.

PMID- 12405082
TI  - A tribute to Prof. Dr. med. Hans-Joachim Denecke. Heidelberg, Germany October 2,
      1911-April 28, 1990.

PMID- 12405083
TI  - Chondroma in the bony external ear canal.

PMID- 12405085
TI  - Posthemorrhagic vascular mass on the left true vocal fold.

PMID- 12405084
TI  - Isolated polyp of the ethmoid sinus.

PMID- 12405086
TI  - Electronystagmography in a patient with a peripheral vestibular disorder.

PMID- 12405087
TI  - Eagle's syndrome.

PMID- 12405088
TI  - Distal esophageal meat impaction.

PMID- 12405089
TI  - Measuring staff productivity with technology.

PMID- 12405090
TI  - Relapsing polychondritis.

PMID- 12405091
TI  - Delay in maturation of the auditory pathway and its relationship to language
      acquisition disorders.
AB  - We studied 81 children, mostly boys, who experienced language acquisition delay
      but whose audiometric thresholds were normal. We assessed the evolution of
      children with delayed maturation of auditory pathways by brainstem evoked
      response audiometry (BERA). We also used a questionnaire administered during
      diagnostic procedures to determine if there was a probable etiology in each
      patient. In addition, we further studied language evolution in 29 patients by
      means of a second questionnaire that was administered approximately 2 years
      later. Finally, we studied the evolution of the I-V interwave interval and the
      I/V amplitude ratio in 16 patients by performing a second BERA after a mean
      interval of 3 years. We observed improvement in both brainstem transmission time
      and language acquisition in all 81 patients. However, only a few patients
      achieved normal range results. Morphologic alterations, which were most common in
      patients who had had perinatal jaundice, remained unchanged. The most common
      possible risk factors for the delayed maturation pattern observed on BERA were
      parental consanguinity, prematurity, perinatal anoxia and jaundice, and postnatal
      seizure and infection. Some patients had more than one of these possible risk
      factors. We conclude that high-risk newborns and 2-year-old children who have no
      primitive verbal language skills should undergo BERA as well as investigation of
      hearing thresholds, interwave intervals, and I/V amplitude ratios. The alteration
      of the parameters points out the need for early intervention if there is no
      favorable prognosis.

PMID- 12405092
TI  - Comparison of bipolar scissors and bipolar forceps in tonsillectomy.
AB  - Bipolar diathermy scissors tonsillectomy is a relatively new surgical technique.
      We conducted a prospective study of 90 patients to compare this technique with
      bipolar forceps tonsillectomy. We found that the use of the bipolar scissors
      required significantly less operating time (mean: 3.03 min less) and allowed
      patients to resume eating solid food more rapidly (mean: 40.35 min earlier).
      Bipolar scissors tonsillectomy was safe, and there were no intraoperative
      complications or primary hemorrhages. A postoperative follow-up telephone survey
      revealed that patients who underwent scissors tonsillectomy experienced no more
      morbidity than did the forceps group during the first 2 weeks after surgery. We
      conclude that bipolar scissors tonsillectomy is a safe and rapid technique that
      can be used successfully as an outpatient procedure.

PMID- 12405093
TI  - Revision tympanomastoid surgery.
AB  - We conducted a retrospective study of 50 ears in 48 patients in whom we performed
      revision tympanomastoid surgery for chronic otitis media. We found that the most
      common probable causes for the failure of previous surgery were incomplete
      lowering of the facial ridge (94% of cases), persistent sinodural-angle air-cell
      disease (92%), persistent tegmental air-cell disease (88%), recurrent or
      persistent cholesteatoma (66%), persistent mastoid-tip air-cell disease (62%), a
      small meatus (60%), and persistent hypotympanic air-cell disease (56%). After a
      mean postoperative follow-up of 26 months, we found no appreciable difference in
      success rates between patients who had undergone only one previous surgery (93%)
      and those who had undergone more than one previous surgery (95%) prior to
      referral to our center. Follow-up hearing data revealed a statistically
      significant improvement in air and bone conduction and a nonsignificant reduction
      in the air-bone gap. We conclude that revision mastoid surgery following multiple
      earlier surgical failures does not carry an appreciably higher risk of failure
      than does initial revision surgery. Moreover, there appears to have been no
      change in the causes of failure following mastoid surgery over the past 3
      decades.

PMID- 12405094
TI  - A rare case of a foreign body migration from the upper digestive tract to the
      subcutaneous neck.
AB  - Ingested foreign bodies are not unusual in Singapore. The most common of these
      objects are fish bones, which typically become lodged in the tonsils or in the
      base of the tongue. We report a rare case of an ingested fish bone that migrated
      from the upper digestive tract and into the soft tissues of the neck just below
      the skin.

PMID- 12405095
TI  - A simple and reliable method of patient evaluation in the surgical treatment of
      nasal obstruction.
AB  - We have developed a simple method of evaluating nasal obstruction both before and
      after corrective surgery. With our system, patients self-rate their nasal patency
      on a 10-point visual analog scale under different conditions. After a baseline
      self-assessment, patients rate their breathing while the examiner lifts the lower
      lateral nasal cartilage with an ear curette and again during lifting of the upper
      lateral cartilage. Separate assessments during cartilage support are made before
      and after the patient has received nasal decongestion therapy. The results of
      these manipulations help identify the specific structural abnormality and its
      anatomic site, thereby serving as a reliable aid to planning surgery (i.e., open
      septorhinoplasty, turbinoplasty, external valve surgery with alar batten grafts,
      and/or internal valve surgery with spreader grafts with or without composite
      skin/cartilage grafts). We tested our method in preoperative evaluation and
      surgical planning on 19 patients with nasal obstructions. Our method was just as
      useful in making postoperative assessments, and it allowed us to judge the
      effectiveness of specific procedures in restoring nasal patency. Of the 19
      patients, 18 (94.7%) reported that their nasal breathing had improved following
      surgery.

PMID- 12405097
TI  - Immune restoration and HAART: new clinical and in vitro data.

PMID- 12405096
TI  - Tracheal necrosis and surgical emphysema: a rare complication of thyroidectomy.
AB  - We describe the first reported case of tracheal necrosis following a
      thyroidectomy. This complication resulted in massive subcutaneous emphysema and
      pneumomediastinum, which required emergency exploration of the neck to decompress
      the trapped air. We also discuss the suggested etiology and management of this
      rare condition.

PMID- 12405098
TI  - Policy watch. It still doesn't add up...

PMID- 12405100
TI  - Associations between water-treatment methods and diarrhoea in HIV-positive
      individuals.
AB  - This manuscript extends our previously published work (based on data from one
      clinic) on the association between three drinking water-treatment modalities
      (boiling, filtering, and bottling) and diarrhoeal disease in HIV-positive persons
      by incorporating data from two additional clinics collected in the following
      year. We conducted a cross-sectional survey of drinking water patterns,
      medication usage, and episodes of diarrhoea among HIV-positive persons attending
      clinics associated with the San Francisco Community Consortium. We present
      combined results from our previously published work in one clinic (n = 226) with
      data from these two additional clinics (n = 458). In this combined analysis we
      employed logistic regression and marginal structural modelling of the data. The
      relative risk of diarrhoea for 'always' vs. 'never' drinking boiled water was
      0.68 (95% CI 0.45-1.04) and for 'always' vs. 'never' drinking bottled water was
      1.22 (95 % CI 0.82-1.82). Drinking filtered water was unrelated to diarrhoea
      (1.03 (95% CI 0.78, 1.35) for 'always' vs. 'never' drinking filtered water].
      Adjustment for confounding did not have any notable effect on the point estimates
      (0.61, 1.35 and 0.98 for boiled, bottled, and filtered water respectively, as
      defined above). The risk of diarrhoea was lower among those consuming boiled
      water but this finding was not statistically significant. Because of these
      findings, the importance of diarrhoea in immunocompromised individuals, and the
      limitations of cross-sectional data further prospective investigations of water
      consumption and diarrhoea among HIV-positive individuals are needed.

PMID- 12405099
TI  - Hypertension-related disease in African Americans. Factors underlying disparities
      in illness and its outcome.
AB  - African Americans have a higher prevalence of hypertension, diabetes,
      cardiovascular disease (CVD), stroke, and renal disease than white Americans. The
      high rates of diabetes and hypertension in children and of type 2 diabetes,
      stroke, and CVD in women are particularly striking. In this article, Drs Sowers,
      Ferdinand, Bakris, and Douglas examine the biologic, social, and genetic factors
      that contribute to these health disparities, the risk for which appears in early
      childhood.

PMID- 12405102
TI  - Cellular Signalling in Neuroprotection and Plasticity. Abstracts of an
      international conference. 26-28 September 2002, Magdeburg, Germany.

PMID- 12405101
TI  - [Pictorial essay. Infarction of the greater omentum: can US and CT findings help
      to avoid surgery?].
AB  - Infarction with or without torsion of the greater omentum is an uncommon but well
      recognised acute abdominal condition which was seldom diagnosed preoperatively
      before the widespread clinical use of US and CT. The aetiology is unknown and
      speculative. In most cases the pathology is right sided and clinical presentation
      consists of an acute or subacute flank pain with mild peritonism usually evoking
      appendicitis or cholecystitis. Recently, US and CT have proved to provide
      sufficiently typical, consistent and well-recognizable features to avoid
      unnecessary surgery. We report on six typical -five right sided and one left
      sided- cases investigated with CT and US. Two patients underwent surgical
      treatment, one because the usually spontaneous regression of the entity was
      ignored and the other because of extremely severe clinical symptoms. In the other
      four patients, conservative medical management was preferred and successful. Even
      though US may be efficient if performed by a well-trained echographist, CT
      appears to be the procedure of choice as it is operator independent and reliable
      for excluding mimicking surgical conditions or associated pathology.

PMID- 12405103
TI  - Biobehavioral Mechanisms of Work-Related Upper Extremity Disorders. Proceedings
      of a symposium. 6-7 November 2000, Washington, DC, USA.

PMID- 12405104
TI  - [Abstracts of the 13th Workshop of Experimental and Clinical Liver
      Transplantation and Hepatology. Wilsede, 20-22 June 2002].

PMID- 12405105
TI  - Abstracts of the 17th Annual Meeting of the Society for Urology and Engineering,
      Inc. 25 May 2002, Orlando, Florida, USA.

PMID- 12405106
TI  - Abstracts of the Research on Calculus Kinetics (ROCK) Society Meeting. 9-10
      February 2002, San Antonio, Texas, USA.

PMID- 12405108
TI  - Abstracts of the 11th International Congress of Biorheology and the 4th
      International Conference of Clinical Hemorheology. Antalya, Turkey, 22-26
      September 2002.

PMID- 12405107
TI  - Bioavailability 2001: Bioavailability of Micronutrients in Relation to Human
      Health. Proceedings of the 4th International Bioavailability Symposium.
      Interlaken, Switzerland, May 30-June 1, 2001.

PMID- 12405109
TI  - Pennsylvania Medical Society 2002-2003 membership directory.

PMID- 12405110
TI  - Abstracts of the British Pharmaceutical Conference. Manchester. September 23-25,
      2002.

PMID- 12405111
TI  - Abstracts of the 7th International Congress of Behavioural Medicine. 28-31 August
      2002, Helsinki, Finland.

PMID- 12405113
TI  - CME rules changes.

PMID- 12405114
TI  - [2002 German Pain Conference. 25-29 September 2002, Aachen].

PMID- 12405112
TI  - What's happening at HIPAA? The privacy rules are final...but don't panic.

PMID- 12405115
TI  - In-Stent Restenosis: Treatment Controversies. May 14-16, 2002.

PMID- 12405117
TI  - [Names-Lab, a nomenclature from another age].

PMID- 12405119
TI  - [Historical study on spectrometry innovation for the structural analysis of
      organic compounds (part 1)].
AB  - Structural determination methods of organic compounds have long been accomplished
      by a comparison of the physical properties (e.g., melting point) of the known
      compounds. After World War II, these methods were converted to methods comparing
      the spectra of the compounds. Some spectrometries such as ultraviolet (UV),
      infrared (IR), mass (MS), and nuclear magnetic resonance (NMR) were used to
      determine the structures. The first spectrometry innovations (1950s). In the
      1950s, some functional groups of organic compounds were confirmed by UV
      spectrometry, especially for enones and holoketones. Several groups, such as
      carbonyl, hydroxyl, and cyano groups, were confirmed by IR spectrometry. Second
      spectrometry innovations (1960s). In the 1960s, the organic MS spectrometer (a
      single-focus instrument) was presented. The determination of the organic formula
      and molecular weight in the organic compounds are effective by MS spectrometry.
      The NMR spectrometer (a 60 MHz instrument) was presented, in which the chemical
      shift values and the H-H coupling constant were very effective in the structural
      confirmation of many organic compounds.

PMID- 12405118
TI  - [Paracetamol interference with vanilmandelic and homovanillic acid quantification
      by the Bio-Rad HPLC kit].

PMID- 12405120
TI  - Abstracts of the 10th Annual Meeting of the Canadian Society for Exercise
      Physiology. St John's, Newfoundland, Canada. 16-19 October 2002.

PMID- 12405121
TI  - Frontiers in Cancer Prevention Research. 14-18 October 2002, Boston,
      Massachusetts, USA. Abstracts.

PMID- 12405122
TI  - Abstracts of the 13th Mediterranean Congress of Chemotherapy.

PMID- 12405124
TI  - Abstracts of the 9th Annual Conference of the International Society for Quality
      of Life Research. October 30-November 2, 2002, Orlando, Florida, USA.

PMID- 12405123
TI  - The management of nausea and vomiting of pregnancy.
AB  - OBJECTIVES: To review the evidence-based management of nausea and vomiting of
      pregnancy (NVP) and hyperemesis gravidarum. EVIDENCE: MEDLINE and Cochrane
      database searches were performed using the medical subject headings (MeSH) of
      treatment, nausea, vomiting, pregnancy, and hyperemesis gravidarum. The quality
      of evidence reported in these guidelines has been described using the Evaluation
      of Evidence criteria outlined in the Report of the Canadian Task Force on the
      Periodic Health Exam. BENEFITS: NVP has a profound effect on women's health and
      quality of life during pregnancy, as well as a financial impact on the health
      care system, and its early recognition and management are recommended. (III-B)
      COST: Costs, including hospitalizations, additional office visits, and time lost
      from work, may be reduced if NVP is treated early.

PMID- 12405125
TI  - [Therapy education for the adult and adolescent asthma patient].

PMID- 12405126
TI  - Kathy Giusti. Fundraising for her life.

PMID- 12405127
TI  - Cardiac scoring.

PMID- 12405128
TI  - Clinical cardiac electrophysiology.

PMID- 12405130
TI  - Healthcare costs rising feverishly.

PMID- 12405129
TI  - Night of two town meetings.

PMID- 12405131
TI  - Defrosting the past. Ancient human and animal remains are melting out of
      glaciers, a bounty of a warming world.

PMID- 12405132
TI  - [Historical study on spectrometry innovation for the structural analysis of
      organic compounds (part 2)].
AB  - Third spectrometry innovation (1970s) Pulse Fourier transformation NMR
      spectrometry (PFT-NMR) (at 100 MHz) was presented. Therefore the H-1 and C-13 NMR
      spectra of organic compounds can be measured with a small amount of the samples.
      Proton-proton spin decoupling methods in NMR spectrometry are helpful for the
      structural analysis of organic compounds. The Stereostructures of organic
      compounds were elucidated by new techniques, the nuclear Overhauser effect (NOE),
      and the application of NMR chift reagents. Double-focus MS spectrometers were
      introduced in the 1970s. The MS instruments related to computer-aided data
      processor systems were also introduced. The molecular weight and the formula were
      directly obtained by the use of the on-line MS system. Several ionizing
      techniques of mass spectrometry were also introduced, such as electron ionization
      (EI), chemical ionization (CI), and in-Beam methods. Fourth spectrometry
      innovation (1980s). In the 1980s, NMR spectrometers had super conductivity
      magnets (200-500 MHz) introduced. Some new NMR spectral techniques, such as 2D (H
      H, H,-C) and 3D (H-H,H,C-H) NMR spectral methods, were introduced. The structures
      of complex organic compounds could then be elucidated by the above methods.
      Gaschromatography (GC) and liquid chromatography (LC) were connected to MS
      spectrometers. Several instruments were introduced, including GC-MS and LC-MS,
      which were applied to organic medicines and their metabolites. Many new ionizing
      techniques (such as FD, API, PD, SIMS, TSP, FAB, and ESP) were then applied. Bio
      organic mass-spectrometry (BMS) was developed in a new research field. The
      structural determination method by the X-ray single-crystal analysis method is
      also described.

PMID- 12405133
TI  - Granuloma faciale with extrafacial lesions.

PMID- 12405134
TI  - Generic Drugs.

PMID- 12405135
TI  - Women, sex, and HIV: social and contextual factors, meta-analysis of published
      interventions, and implications for practice and research.
AB  - This article is focused on examining social and contextual factors related to HIV
      risk behavior for women. Specifically, this article has three main purposes: to
      review the literature on selected social and contextual factors that contribute
      to the risk for the heterosexual transmission of HIV and AIDS, to review and
      conduct a meta-analysis of HIV-prevention interventions targeting adult
      heterosexual populations, and to suggest future directions for HIV-prevention
      intervention research and practice. Results suggest that the HIV-prevention
      interventions reviewed for this article had little impact on sexual risk
      behavior, that social and contextual factors are often minimally addressed, and
      that there was a large gap between research and the practice of HIV-prevention
      intervention.

PMID- 12405136
TI  - Acute stress disorder: a synthesis and critique.
AB  - The diagnosis of acute stress disorder (ASD) was introduced to describe initial
      trauma reactions that predict chronic posttraumatic stress disorder (PTSD). This
      review outlines and critiques the rationales underpinning the ASD diagnosis and
      highlights conceptual and empirical problems inherent in this diagnosis. The
      authors conclude that there is little justification for the ASD diagnosis in its
      present form. The evidence for and against the current emphasis on peritraumatic
      dissociation is discussed, and the range of biological and cognitive mechanisms
      that potentially mediate acute trauma response are reviewed. The available
      evidence indicates that alternative means of conceptualizing acute trauma
      reactions and identifying acutely traumatized people who are at risk of
      developing PTSD need to be considered.

PMID- 12405137
TI  - Cognitive theories of early gender development.
AB  - The contribution of cognitive perspectives (cognitive-developmental theory and
      gender schema theory) to a contemporary understanding of gender development is
      evaluated. Recent critiques of cognitive approaches are discussed and empirical
      evidence is presented to counter these critiques. Because of the centrality of
      early gender development to the cognitive perspective, the latest research is
      reviewed on how infants and toddlers discriminate the sexes and learn the
      attributes correlated with sex. The essence of cognitive approaches--emphasis on
      motivational consequences of gender concepts; the active, self-initiated view of
      development; and focus on developmental patterns-is highlighted and contrasted
      with social-cognitive views. The value of cognitive theories to the field is
      illustrated, and recommendations are made concerning how to construct
      comprehensive, integrative perspectives of gender development.

PMID- 12405138
TI  - Belief and feeling: evidence for an accessibility model of emotional self-report.
AB  - This review organizes a variety of phenomena related to emotional self-report. In
      doing so, the authors offer an accessibility model that specifies the types of
      factors that contribute to emotional self-reports under different reporting
      conditions. One important distinction is between emotion, which is episodic,
      experiential, and contextual, and beliefs about emotion, which are semantic,
      conceptual, and decontextualized. This distinction is important in understanding
      the discrepancies that often occur when people are asked to report on feelings
      they are currently experiencing versus those that they are not currently
      experiencing. The accessibility model provides an organizing framework for
      understanding self-reports of emotion and suggests some new directions for
      research.

PMID- 12405139
TI  - Ultrasonic vocalizations as indices of affective states in rats.
AB  - Adult rats spontaneously vocalize in ultrasonic frequencies. Although these
      ultrasonic vocalizations (USVs) have been described as by-products of locomotor
      activity or social signals, accumulating evidence suggests that they may also
      index anticipatory affective states. Converging ethological, pharmacological, and
      brain stimulation research indicates that whereas long low-frequency (> 0.3-s,
      approximately 22-kHz) USVs occur during anticipation of punishment or avoidance
      behavior, short, high-frequency (< 0.3-s, approximately 50-kHz) USVs typically
      occur during anticipation of reward or approach behavior. Thus, long 22-kHz USVs
      may index a state of negative activation, whereas short, 50-kHz USVs may instead
      index a state of positive activation. This hypothesis has theoretical
      implications for understanding the brain circuitry underlying mammalian affective
      states and clinical applicability for modeling hedonic properties of different
      psychotropic compounds.

PMID- 12405140
TI  - Logic and human reasoning: an assessment of the deduction paradigm.
AB  - The study of deductive reasoning has been a major paradigm in psychology for
      approximately the past 40 years. Research has shown that people make many logical
      errors on such tasks and are strongly influenced by problem content and context.
      It is argued that this paradigm was developed in a context of logicist thinking
      that is now outmoded. Few reasoning researchers still believe that logic is an
      appropriate normative system for most human reasoning, let alone a model for
      describing the process of human reasoning, and many use the paradigm principally
      to study pragmatic and probabilistic processes. It is suggested that the methods
      used for studying reasoning be reviewed, especially the instructional context,
      which necessarily defines pragmatic influences as biases.

PMID- 12405141
TI  - "Getting in" revisited: an analysis of manuscript characteristics, reviewers'
      ratings, and acceptance of manuscripts in Psychological Bulletin.

PMID- 12405142
TI  - Bacteriochlorophyll e monomers, but not aggregates, sensitize singlet oxygen:
      implications for a self-photoprotection mechanism in chlorosomes.
AB  - Sensitization of singlet delta oxygen (O2(1delta(g))) by bacteriochlorophyll e
      (BChle) has been investigated to gain a better understanding of the
      photoprotection mechanism(s) operating in chlorosomes of green photosynthetic
      bacteria. The sensitization process has been studied in media where BChle forms
      monomers (acetone and aqueous solutions containing 0.5% Triton X-100 [TX]) and in
      systems where BChle aggregates, namely, aqueous solutions containing 0.003%
      monogalactosyl diglyceride (MGDG) and chlorosomes(control as well as hexanol
      perturbed) from Chlorobium phaeobacteroides strain CL1401. In Ar-purged acetone,
      BChle triplets (BChle triplets) have a lifetime of a few tens of microseconds;
      however, in air-saturated acetone, quenching of BChle triplets by ground-state
      oxygen (O2(3sigma(-)g)) and formation of O2(1delta(g)) take place. The
      O2(1delta(g)) so formed is susceptible to quenching by BChle0, a ground-state
      BChle molecule. A Stern-Volmer analysis reveals a linear fit between the decay
      rate of O2(1delta(g)) and the BChle concentration. The rate constants for the
      quenching of O2(1delta(g)) by BChle0 and for the deactivation of O2(1delta(g)) by
      the solvent come out to be kq = (1.4 +/- 0.1) x 10(9) M(-1) s(-1) and k0 = (18.5
      +/- 0.7) x 10(3) s(-1), respectively. The absolute quantum yield of O2(1delta(g))
      sensitization by BChle monomers is 0.65 +/- 0.15 in air-saturated acetone. In
      aqueous phase, the triplet lifetime of BChle aggregates in native or hexanol
      perturbed chlorosomes shortens by more than two orders of magnitude when compared
      with the triplet lifetime of BChle monomers in 0.5% TX solution (a few hundreds
      of microseconds). Quenching by carotenoids (Car) makes only a minor contribution
      to the decay of BChle triplets in aggregates. Because O2(1delta(g)) sensitization
      by BChle triplets could be detected neither in MGDG aggregates nor in chlorosomes
      (control as well as hexanol perturbed), it is concluded that (1) this process is
      highly likely when BChle is present as a monomer but not when it is tightly
      packed in artificial aggregates or in chlorosomes; and (2) Car, though vital for
      the baseplate BChla, are dispensable for BChle.

PMID- 12405143
TI  - Resolution of tryptophan-ANS fluorescence energy transfer in apomyoglobin by site
      directed mutagenesis.
AB  - Resonance energy transfer between tryptophanyl residues and the apolar
      fluorescent dye 1-anilino-8-naphthalene sulfonate (ANS) occurs when the
      fluorophore is bound to native folded sperm whale apomyoglobin. The individual
      transfer contribution of the two tryptophanyl residues (W7 and W14, both located
      on the A-helix of the protein) was resolved by measuring the tryptophan-ANS
      transfer efficiency for the ANS-apomyoglobin complexes formed by wild-type
      protein and protein mutants containing one or no tryptophanyl residues, i.e. W7F,
      W14F and W7YW14F. The transfer efficiency of W14 residue was found to be higher
      than that of W7, thus indicating that W14 acts as the main energy donor in the
      ANS-apomyoglobin complex. This suggests that the plane containing the
      anilinonaphthalene ring of the extrinsic fluorophore has a spatial orientation
      similar to that of W14 and, hence, to the heme group in the holoprotein.

PMID- 12405144
TI  - The excited-state interaction of resazurin and resorufin with amines in aqueous
      solutions. Photophysics and photochemical reactions.
AB  - The photophysics and photochemical behavior of the phenoxazin-3-one dyes,
      resazurin and resorufin, have been studied in aqueous solutions. The irradiation
      of resazurin in the presence of amines leads to deoxygenation of the N-oxide
      group, giving resorufin. This photoreaction is highly dependent on the amine
      structure and is efficient only in the presence of tertiary aliphatic amines. The
      absorption and fluorescence properties of these dyes are dependent on pH. At pH
      above 7.5 both dyes are in their anionic form. For resorufin this form is highly
      fluorescent (phiF = 0.75). At lower pH the fluorescence is strongly reduced. The
      N-oxide dye presents a very weak fluorescence quantum yield (0.11), which also is
      reduced at low pH. Flash photolysis experiments allowed characterization of the
      triplet state and the transients formed after irradiation of these dyes in the
      absence and presence of amines. The triplet quantum yields are 0.08 for resazurin
      and 0.04 for resorufin. The photodeoxygenation of N-oxide in the presence of
      amines occurs from the triplet state.

PMID- 12405145
TI  - Biological UV dosimeters in quality control of tanning tubes.
AB  - Although according to the International Radiological Protection Association
      International Non-Ionizing Radiation Committee recommendation (1991) the use of
      sunbeds for cosmetic purposes is not recommended, tanning devices are used
      widely. Ten different types of commercially available sunbed tubes have been
      studied using a uracil biological UV dosimeter, and three of them were analyzed
      in detail. Dimerization effectiveness of the tubes was measured directly, whereas
      efficiency of erythema induction was calculated weighting the emission spectra by
      the Commission Internationale de l'Eclairage erythema action spectrum. The data
      obtained demonstrate that quality control of sunbed tubes has to include not only
      the determination of the UV doses administered but also the assessment of the
      health risk due to the UVB and UVA components of the lamp. A method of quality
      control using the uracil biological dosimeter was elaborated, and the estimation
      of the "acceptable" exposure time was checked/controlled on 15 volunteers by
      assessing individually the erythema induction threshold. A correct classification
      of the sunbed tubes is proposed by characterizing the erythema induction versus
      DNA-damaging effectiveness of tubes.

PMID- 12405146
TI  - Formation of cyclobutane pyrimidine dimers and 8-oxo-7,8-dihydro-2'
      deoxyguanosine in mouse and organ-cultured human skin by irradiation with
      broadband or with narrowband UVB.
AB  - Narrowband UVB (NB-UVB) is a newly developed UVB source that, in addition to the
      previously used broadband UVB (BB-UVB), has been effectively used in phototherapy
      of various skin diseases. Besides its therapeutic effectiveness, NB-UVB also has
      some adverse effects that should be evaluated. As with all phototherapies, the
      photocarcinogenic potential of NB-UVB is the major concern. To assess the
      carcinogenic potential we measured the DNA damage induced by the two UVB sources
      because exposure of cells to UVB directly or indirectly induces DNA damage such
      as cyclobutane pyrimidine dimers (CPD) or 8-oxo-7,8-dihydro-2'-deoxyguanosine (8
      oxodGuo), respectively. These types of DNA damage cause mutations of oncogenes
      and tumor suppressor genes, which can lead to photocarcinogenesis. In the present
      study we measured the yield of CPD and the oxidative DNA damage marker, 8
      oxodGuo, in organ-cultured human skin and in mouse skin after exposure to NB-UVB
      or BB-UVB at therapeutically equivalent doses. We show that a 10-fold higher dose
      of NB-UVB yields a similar amount of CPD compared with BB-UVB in two types of
      samples examined. In contrast to CPD, the formation of 8-oxodGuo after
      irradiation with NB-UVB at a 10-fold higher dose is 1.5-3 times higher than that
      caused by BB-UVB. These results suggest that although NB-UVB at equivalent
      erythema-edema doses is not more potent in inducing CPD formation than is BB-UVB,
      NB-UVB may generate a higher yield of oxidized DNA damage.

PMID- 12405147
TI  - Refractoriness of UVA-induced protection from photoimmunosuppression correlates
      with heme oxygenase response to repeated UVA exposure.
AB  - Single suberythemal exposures of UVA radiation have been shown to block the
      immunosuppressive effects of UVB radiation in the mouse. The immunoprotection is
      dependent both on the presence of the cytokine, IFN-gamma, and on the induction
      of the antioxidant stress enzyme, heme oxygenase (HO), in the skin. Recently, the
      transcriptional response of the HO-1 gene to UVA radiation in cultured human skin
      fibroblasts was reported to be refractory to a second UVA irradiation. In this
      study on the hairless mouse, we demonstrate that the inducibility of HO enzyme
      activity in the skin similarly became refractory to a second UVA irradiation at
      24 h but, like the fibroblast response, was restored when the interval between
      the UVA exposures was increased to 96 h. Under the conditions of refractory HO
      enzyme induction, the protective effect of UVA radiation against the suppression
      of contact hypersensitivity induced by UVB radiation or cis-urocanic acid was
      strongly attenuated but was restored when the interval between UVA exposures was
      increased to 96 h. The results thus confirm the strong relationship between HO
      induction and photoimmunoprotection by UVA radiation, and describe a new
      phenomenon of immunological refractoriness that develops with rapidly repeated
      UVA exposures.

PMID- 12405148
TI  - Ultraviolet inactivation of feline calicivirus, human enteric viruses and
      coliphages.
AB  - Norwalk and Norwalk-like viruses (NLV) are major causes of food- and water
      related disease in the United States. There is no host cell line in which the NLV
      can be tested for infectivity. Feline calicivirus (FCV) and NLV both belong to
      the family Caliciviridae. FCV can be assayed for infectivity in the Crandell
      Reese feline kidney cell line, so FCV serves as a surrogate for NLV. This study
      is the first report of UV inactivation of FCV and also of using the plaque
      technique, in contrast to the 50% tissue culture infectious dose end point
      technique, to determine the FCV infectivity titer. The infectivity titers (log10
      plaque-forming units/mL) of UV-inactivated FCV, hepatitis A virus (HAV),
      poliovirus type 1 (PV1) and two small, round coliphages were plotted as a
      function of UV dose and analyzed by regression analysis and analysis of variance.
      These fitted straight-line curves represent exponential inactivation, so UV
      inactivation can be said to show "one-hit kinetics." The decimal inactivation
      doses of UV for FCV, HAV, PV1, MS2 and phiX174 were 47.85, 36.50, 24.10, 23.04
      and 15.48 mW s/cm2, respectively. FCV appears to be the most UV resistant among
      the tested viruses.

PMID- 12405149
TI  - Effects of combined photodynamic therapy and ionizing radiation on human glioma
      spheroids.
AB  - The effects of combined photodynamic therapy (PDT) and ionizing radiation are
      studied in a human glioma spheroid model. The degree of interaction between the
      two modalities depends in a complex manner on factors such as PDT irradiation
      fluence, fluence rate and dose of ionizing radiation. It is shown that gamma
      radiation and PDT interact in a synergistic manner only if both light fluence and
      gamma radiation dose exceed approximately 25 J cm(-2) and 8 Gy, respectively.
      Synergistic interactions are observed only for the lower fluence rate (25 mW cm(
      2)) investigated. The degree of interaction appears to be independent of both
      sequence and the PDT or ionizing radiation time intervals investigated (1 and 24
      h). Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick
      end labeling assays show that low-fluence rate PDT is very efficient at inducing
      apoptotic cell death, whereas neither high-fluence rate PDT nor ionizing
      radiation produces significant apoptosis. Although the mechanisms remain to be
      elucidated, the data imply that the observed synergism is likely not due to gamma
      induced cell cycle arrest or to PDT-induced inhibition of DNA repair.

PMID- 12405150
TI  - H-NMR studies of duplex DNA decamer containing a uracil cyclobutane dimer:
      implications regarding the high UV mutagenecity of CC photolesions.
AB  - To determine the origin of the UV-specific CC to TT tandem mutation at the CC
      site, we made a duplex DNA decamer containing a uracil cis-syn cyclobutane dimer
      (CBD) as the deaminated model of a cytosine dimer. Two-dimensional 1H-NMR
      spectroscopy studies were performed on this sequence where two adenines (Ade)
      were opposite to the uracil dimer. Two imino protons of the uracil dimer were
      found to retain Watson-Crick hydrogen bonding with the opposite Ade, although the
      5'-U(NH) of the dimer site showed unusual upfield shift like that of the 5'-T(NH)
      of the TT dimer, which seemed to be associated with deshielding by the flanking
      base rather than with reduced hydrogen bonding. (McAteer et al. 1998, J. Mol.
      Biol. 282:1013-1032). Hydrogen bondings at the dimer site were also supported by
      detecting typical strong nuclear Overhauser effects (NOE) between two imino
      protons and the opposite Ade H2 or NH2. But sequential NOE interactions of base
      protons with sugar protons were absent at the two flanking nucleotides of the 5'
      side of the uracil dimer and at the intradimer site, contrasting with its thymine
      analog where sequential NOE was absent only at the A4-T5 step. In addition, NOE
      cross peak for U5(NH) <--> A4(H2) was detected, although the NOE interactions of
      U6(NH) with A7(H2) and A17(H2) were not observed in contrast to the thymine dimer
      duplex. This different local structural alteration may be affected by the induced
      right-hand twisted puckering mode of cis-syn cyclobutane ring of the uracil dimer
      in the B-DNA duplex, even though the isolated uracil dimer had left-hand twisted
      puckering rigidly. In parallel, these observations may be correlated with
      observed differences in mutagenic properties between cis-syn UU dimer and cis-syn
      TT dimer.

PMID- 12405151
TI  - Nitric oxide modulates tumor cell death induced by photodynamic therapy through a
      cGMP-dependent mechanism.
AB  - Photodynamic therapy (PDT) of cancer is a very promising technique based on the
      formation of singlet oxygen induced by a sensitizer after irradiation with
      visible light. The stimulation of tumor growth by nitric oxide (NO) was reported
      recently, and NO was shown to have a protective effect against PDT-induced tumor
      death. We investigated a putative direct effect of NO on tumor cell death induced
      by PDT, using the human lymphoblastoid CCRF-CEM cells and bisulfonated aluminum
      phthalocyanine (AlPcS2) as a sensitizer. Cells were incubated with AlPcS2 in the
      presence or absence of NO donors ((Z)-1-[(2-aminoethyl)-N-(2
      ammonioethyl)amino]diazen-1-ium-1,2-diolate, hydroxylamine and S-nitroso-N
      acetylpenicillamine) or L-arginine. Under these conditions, in the absence of NO
      donors or L-arginine the cells died rapidly by apoptosis upon photosensitization.
      In the presence of NO donors or L-arginine, apoptotic cell death after
      photosensitization was significantly decreased. Modulation of cell death by NO
      was not due to S-nitrosylation of caspases and occurred at the level or upstream
      of caspase-9 processing. The protective effect of NO was reversed by incubating
      the cells with 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, an inhibitor of
      guanylyl cyclase, or with KT5823, an inhibitor of protein kinase G (PKG).
      Incubation with 8-bromo-cyclic guanosine monophosphate, a membrane permeable
      cyclic guanosine monophosphate analog, also decreased cell death induced by PDT.
      Although the protective effect of NO against apoptotic cell death in several
      models has been attributed to an increase in the expression of heme oxygenase-1,
      heat shock protein 70 or Bcl-2, this was not the case under our experimental
      conditions. These results show that NO decreases the extent of apoptotic cell
      death after PDT treatment through a PKG-dependent mechanism, upstream or at the
      level of caspase activation.

PMID- 12405152
TI  - Photodynamic inactivation of isolated crayfish mechanoreceptor neuron: different
      death modes under different photosensitizer concentrations.
AB  - To study the mechanism of photodynamic nerve cell killing, isolated crayfish
      mechanoreceptor neurons were photosensitized by the sulfonated aluminum
      ophthalocyanine Photosens. Neuron activity was continuously recorded until
      irreversible abolition. Intense (10(-5) M Photosens) or weak (10(-7) M Photosens)
      photosensitization induced different bioelectric neuron responses: firing
      activation followed by irreversible depolarization block or gradual inhibition
      until firing abolition, respectively. These bioelectric responses were
      accompanied by different biochemical and morphological changes. In the case of
      intense photosensitization, neuron nuclei swelled and then shrank. Succinate
      dehydrogenase (SDH) was inhibited, and the plasma membrane was compromised just
      after firing cessation. Weak photosensitization did not induce these changes but
      caused swelling of the endoplasmic reticulum and destruction of the matrix,
      cristae and membranes in some of the mitochondria. Other mitochondria, however,
      retained the normal structure. Plasma membrane damage, SDH inhibition, nucleus
      shrinkage and impairment of the nuclear border occurred after 2-4 h. It is
      concluded that intense photosensitization induced necrotic processes during
      irradiation, whereas weaker impact caused delayed necrosis 2-4 h later. The
      observed electrophysiological neuron responses to photodynamic therapy may be
      considered as early hallmarks of different modes of forthcoming cell death.

PMID- 12405153
TI  - Preclinical studies in normal canine prostate of a novel palladium
      bacteriopheophorbide (WST09) photosensitizer for photodynamic therapy of prostate
      cancers.
AB  - Photodynamic therapy (PDT) uses light to activate a photosensitizer to achieve
      localized tumor control. In this study, PDT mediated by a second-generation
      photosensitizer, palladium-bacteriopheophorbide WST09 (Tookad) was investigated
      as an alternative therapy for prostate cancer. Normal canine prostate was used as
      the animal model. PDT was performed by irradiating the surgically exposed
      prostate superficially or interstitially at 763 nm to different total fluences
      (100 or 200 J/cm2; 50, 100 or 200 J/cm) at 5 or 15 min after intravenous
      administration of the drug (2 mg/kg). Areas on the bladder and colon were also
      irradiated. The local light fluence rate and temperature were monitored by
      interstitial probes in the prostate. All animals recovered well, without urethral
      complications. During the 1 week to 3 month post-treatment period, the prostates
      were harvested for histopathological examination. The PDT-induced lesions showed
      uniform hemorrhagic necrosis and atrophy, were well delineated from the adjacent
      normal tissue and increased linearly in diameter with the logarithm of the
      delivered light fluence. A maximum PDT-induced lesion size of over 3 cm diameter
      could be achieved with a single interstitial treatment. There was no damage to
      the bladder or rectum caused by scattered light from the prostate. The bladder
      and rectum were also directly irradiated with PDT. At 80 J/cm2, a full-depth
      necrosis was observed but resulted in no perforation. At 40 J/cm2, PDT produced
      minimal damage to the bladder or rectum. On the basis of optical dosimetry, we
      have estimated that 20 J/cm2 is the fluence required to produce prostatic
      necrosis. Thus, the normal structure adjacent to the prostate can be safely
      preserved with careful dosimetry. At therapeutic PDT levels, there was no
      structural or functional urethral damage even when the urethra was within the
      treated region. Hence, Tookad-PDT appears to be a promising candidate for
      prostate ablation in patients with recurrent, or possibly even primary, prostate
      cancer.

PMID- 12405154
TI  - Spectroscopic characterization of human and mouse primary cells, cell lines and
      malignant cells.
AB  - Fourier transform infrared (FTIR) spectroscopy is currently being developed as a
      new optical approach to the diagnosis and characterization of cell or tissue
      pathology. The advantage of FTIR microspectroscopy over conventional FTIR
      spectroscopy in the diagnosis of malignancies is that it facilitates inspection
      of restricted regions of the cell culture or tissue. In this study, we set out to
      evaluate FTIR microspectroscopy as a diagnostic tool for identifying retrovirus
      induced malignancies. Our study showed significant and consistent differences
      between cultures of different types of cells of both mouse and human origin, i.e.
      primary fibroblast cells (one to two passages in cell culture), fibroblast cell
      lines and malignant cells transformed by murine sarcoma virus. An impressive
      decrease in the levels of phosphate and other metabolites was seen in malignant
      cells compared with primary cells. The levels of these metabolites in the cell
      lines were significantly lower than in the primary cells but higher than in the
      malignant cells. In addition, the peak attributed to the PO2- symmetric
      stretching mode at 1082 cm(-1) in primary cells shifted significantly to 1085 cm(
      1) for the cell line and to 1087 cm(-1) for the malignant cells. These
      differences taken together with differences in the shapes of various bands
      throughout the spectrum strongly support the possibility of developing FTIR
      microspectroscopy for the detection and study of malignant--and possibly
      premalignant--cells.

PMID- 12405155
TI  - Temperature effect on accumulation of protoporphyrin IX after topical application
      of 5-aminolevulinic acid and its methylester and hexylester derivatives in normal
      mouse skin.
AB  - Significant amounts of protoporphyrin IX (PpIX) are formed after 6 min of topical
      application of 5-aminolevulinic acid (ALA) and its hexylester derivative, whereas
      PpIX is formed after 10 min of topical application of ALA-methylester derivative
      in normal mouse skin at 37 degrees C. Lowering the skin temperature to 28-32
      degrees C by the administration of the anesthetic Hypnorm-Dormicum reduces the
      PpIX fluorescence by a factor of 2-3. Practically no PpIX was formed as long as
      the skin temperature was kept at 12-18 degrees C. At around 30 degrees C PpIX
      fluorescence appears later after application of ALA-ester derivatives (14-20 min)
      than after application of ALA (8 min), indicating differences in their
      bioavailability (delayed penetration through the stratum corneum, cellular
      uptake, conversion to ALA, PpIX production) in mouse skin in vivo. The difference
      in lag time in the PpIX formation after application of ALA and ALA-esters may be
      partly related to deesterification of the ALA-ester molecules. The temperature
      dependence of PpIX production may be used for improvement of photodynamic therapy
      with ALA and ALA-ester derivatives, where accumulation of PpIX can be selectively
      enhanced by increasing the temperature of the target tissue.

PMID- 12405156
TI  - Heterologous expression and characterization of recombinant phytochrome from the
      green alga Mougeotia scalaris.
AB  - The full-length apoprotein (124 kDa) and the chromophore-binding N-terminal half
      (66 kDa) of the phytochrome of the unicellular green alga Mougeotia scalaris have
      been heterologously expressed in the methylotrophic yeast Pichia pastoris.
      Assembly with the tetrapyrrole phycocyanobilin (PCB) yielded absorption maxima
      (for the full-length protein) at 646 and 720 nm for red- and far-red absorbing
      forms of phytochrome (Pr and Pfr), respectively, whereas the maxima of the N
      terminal 66 kDa domain are slightly blueshifted (639 and 714 nm, Pr and Pfr,
      respectively). Comparison with an action spectrum reported earlier gives evidence
      that in Mougeotia, as formerly reported for the green alga Mesotaenium
      caldariorum, PCB constitutes the genuine chromophore. The full-length protein,
      when converted into its Pfr form and kept in the dark, reverted rapidly into the
      Pr form (lifetimes of 1 and 24 min, ambient temperature), whereas the truncated
      chromopeptide (66 kDa construct) was more stable and converted into Pr with time
      constants of 18 and 250 min. Also, time-resolved analysis of the light-induced
      Pfr formation revealed clear differences between both recombinant chromoproteins
      in the various steps involved. The full-length phytochrome showed slower kinetics
      in the long milliseconds-to-seconds time domain (with dominant Pfr formation
      processes of ca 130 and 800 ms), whereas for the truncated phytochrome the major
      component of Pfr formation had a lifetime of 32 ms.

PMID- 12405157
TI  - Illumination accelerates the decay of the O-intermediate of pharaonis
      phoborhodopsin (sensory rhodopsin II).
AB  - pharaonis phoborhodopsin (ppR, also called pharaonis sensory rhodopsin II
      [psRII]) is a member of the archaeal rhodopsin family and acts as a repellent
      phototaxis receptor of Natronobacterium pharaonis. Upon illumination, ppR is
      excited and undergoes a linear cyclic photoreaction, namely, a photocycle that
      constitutes photointermediates such as M- and O-intermediates (ppRM and ppRO,
      respectively). Under a constant background illumination (>600 nm) that irradiates
      ppRO, the decay rate of the flash-induced ppRO increased with an increase in the
      background light intensity, indicating the photoreactivity of ppRO. Azide did not
      influence the light-accelerated ppRO decay, but the time required for the cycle
      to be completed became shortened in an azide concentration-dependent manner
      because of acceleration of ppRM decay. Hence, the turnover rate of photocycling
      increased appreciably in the presence of both the background illumination and the
      azide. The observation reported previously (Schmies, G. et al. 2000, Biophys. J.
      78:967-976) is discussed in connection with the present observations.

PMID- 12405158
TI  - Cytotoxic HIV-1 p55gag-specific CD4+ T cells produce HIV-inhibitory cytokines and
      chemokines.
AB  - CD4+ T-helper cells appear to be essential in sustaining immune responses in
      chronic viral infections, as the maintenance of CD8+ cytotoxic T-lymphocyte
      responses and the control of viremia were demonstrated to depend on CD4+ T cell
      help. In order to investigate the function of HIV-specific CD4+ T cells in
      chronic HIV-1-infection, 49 chronically HIV-infected patients were analyzed
      before and 3 and 6 months after initiation of antiviral treatment. Ten patients
      showed a substantial, although weak, proliferative response to HIV-1-p55gag
      protein for which no improvement was observed upon initiation of HAART. From one
      individual, HIV-1-p55gag-specific CD4-positive T-cell clones were generated that
      were heterogeneous in their TCR Vbeta gene usage and HLA-DRB1*13 and DRB1*03
      restricted, respectively. In addition, some CD4+ TCC produced substantial amounts
      of IFN-gamma and MIP-1alpha/beta were perforin-positive, and showed cytotoxic
      activity. These diverse functional features of HIV-specific CD4+ T cells suggest
      that they may exert direct antiviral activity.

PMID- 12405159
TI  - Immunomodulatory effects of estrogen and progesterone replacement in a nonhuman
      primate model.
AB  - A novel postmenopausal nonhuman primate model consisting of healthy young and old
      ovariectomized rhesus macaques was used to assess the short-term immunomodulatory
      effects of transdermally administered estrogen and progesterone. Specifically, we
      determined estrogen- and progesterone-induced changes in absolute numbers of
      circulating lymphocytes (B lymphocytes, CD4+ lymphocytes, and CD8+ lymphocytes)
      as well as lymphocytes expressing the activation markers CD25 and CD69. In
      addition, we assessed B and T lymphocyte activity, i.e, immunoglobulin (Ig) and
      interferon-gamma (IFN-gamma) production by peripheral blood mononuclear cells
      (PBMCs). In general, treatment with estrogen or progesterone resulted in
      decreased lymphocyte numbers and in down-modulation of activation markers. In
      addition, hormone replacement resulted in a decreasing trend for PBMC IFN-gamma
      production, whereas PBMC Ig production was minimally affected. Hormone treatment
      seemed to influence young and old animals differently, with the young animals
      appearing more susceptible to its immune system-related effects. These results
      indicate that, in our animal model exogenously administered hormones may
      dynamically interact with the immune system, resulting in in vivo modulation of
      lymphocyte numbers and activity.

PMID- 12405160
TI  - NK 1.1+ T cell: a two-faced lymphocyte in immune modulation of the IL-4/IFN-gamma
      paradigm.
AB  - T lymphocytes expressing NK1.1 marker (NK1.1+) have been suggested as being
      important in peripheral immune modulation. Alteration of the balance between Th1
      proinflammatory and Th2 anti-inflammatory cytokine-producing cells can ameliorate
      immune-mediated disorders. The aim of the study was to determine the role of
      NK1.1+ lymphocytes in the pathogenesis of tolerance and proinflammatory states
      and to determine their role in altering the Th1/Th2 balance in experimental
      colitis. Colitis was induced in C57/B6 mice by intracolonic instillation of
      trinitrobenzenesulfonic acid (TNBS). Mice received five oral doses of colonic
      proteins extracted from TNBS colitis colonic wall. Standard clinical,
      macroscopic, and microscopic scores were used for colitis assessment. Liver
      associated lymphocytes and splenocytes were harvested 14 days following tolerance
      induction. Depletion of NK 1.1+ lymphocytes was performed 36 hr before lymphocyte
      harvesting. Lymphocytes were cultured for 12 hr with Con A and colitis extracted
      proteins. To evaluate the role of NK1.1+ lymphocytes in keeping a balance between
      immunogenic and tolerogenic subsets of cells, intracellular staining and flow
      cytometry assays were performed in tolerized and nontolerized mice. IL-4, IL-12,
      and IFN-gamma levels were measured by ELISA. Administration of mouse-derived
      colitis-extracted proteins ameliorated experimental colitis. Tolerized mice
      exhibited significant improvement in all macroscopic and microscopic parameters
      for colitis. Depletion of NK1.1 following tolerance induction significantly
      decreased the CD4(+)IL-4(+)/CD4(+)IFN-gamma(+) ratio in tolerized mice. However,
      depletion of NK1.1 lymphocytes in nontolerized mice increased the CD4(+)IL
      4(+)/CD4(+)IFN-gamma(+) ratio, compared with nondepleted nontolerized mice.
      Induction of tolerance led to an increase in IL4 and a decrease in IFN-gamma
      levels. In the experimental colitis model NK1.1+ lymphocytes play a dual role: In
      the presence of peripheral tolerance they may be accountable for keeping the high
      CD4(+)IL-4(+)/CD4(+)IFN-gamma(+) ratio and disease alleviation. However, in
      nontolerized conditions they may induce a proinflammatory shift.

PMID- 12405161
TI  - Diagnostic value of anti-Saccharomyces cerevisiae and antineutrophil cytoplasmic
      antibodies for inflammatory bowel disease: high prevalence in patients with
      celiac disease.
AB  - Both celiac disease and inflammatory bowel disease (IBD) are characterized by
      chronic diarrhea and the presence of distinct (auto)antibodies. In the present
      study we wanted to determine the prevalence of serological markers for
      inflammatory bowel disease, i.e., perinuclear antineutrophil cytoplasmic
      antibodies (pANCA) and/or anti-Saccharomyces cerevisiae antibodies (ASCA), in 37
      patients with biopsy-confirmed celiac disease (Marsh IIIb/c). The majority of the
      patients was positive for IgA (auto)antibodies typically associated with celiac
      disease, i.e., antiendomysium antibodies (EMA) (86.5%), antigliadin antibodies
      (AGA) (73%), and antirecombinant human tissue transglutaminase antibodies (rh
      tTGA) (86.5%). Four patients with selective IgA deficiency could be identified by
      analyzing EMA, AGA, and rh-tTGA for the IgG isotype. The prevalence of pANCA and
      ASCA, markers that are used for IBD, was unexpectedly high in our cohort of
      patients with celiac disease: 8 patients were positive for pANCA (IgG) and 16
      patients were positive for ASCA (IgG and/or IgA). These results indicate that the
      presence of pANCA or ASCA in the serum of patients with chronic diarrhea does not
      exclude celiac disease. A prospective study is required to determine whether
      pANCA and/or ASCA identify patients at risk for developing secondary autoimmune
      disease.

PMID- 12405162
TI  - The soluble tumor necrosis factor receptor I is an early predictor of local
      infective complications after colorectal surgery.
AB  - The clinical implications of increased cytokine levels after major surgery remain
      unclear. In this study, systemic concentration of a spectrum of cytokines,
      including interleukins IL-6, IL-8, IL-10, IL-1ra, and soluble tumor necrosis
      factor receptor-I (sTNF-RI) was examined in patients with and without
      postoperative septic complications following colorectal surgery. Although there
      were no significant changes in IL-1beta, TNF-alpha, and IL-8 serum levels during
      the observation period, there was a significant rise in IL-6, IL-1ra, and sTNF-RI
      concentrations in the entire group of patients between postoperative day 1 and
      14. There were no differences between the group without and with local
      complications when IL-6, IL-1ra, and IL-10 were examined. The serum levels of
      sTNF-RI, IL-1ra, and IL-6 were found to be sensitive indicators of the pro- and
      anti-inflammatory response to the surgical trauma, but only sTNF-RI turned out to
      be a sensitive early marker of local septic postoperative complications in
      patients with colorectal carcinoma.

PMID- 12405163
TI  - A primary immunodeficiency disorder associated with absence of lymphoid germinal
      centers.
AB  - In this article we describe three infants who suffered from a disorder
      characterized by splenomegaly, anemia, and severe infections beginning during the
      first months of life. Immunologic studies revealed agammaglobulinemia. However,
      normal numbers of lymphocytes and lymphocyte subsets were present in peripheral
      blood, and lymphocyte proliferation in responses to mitogenic stimulation in
      vitro was normal. Histologic and immunohistologic studies performed in one of the
      patients revealed lack of secondary follicles and follicular dendritic cells in
      lymphoid tissues and absence of plasma cells in the intestinal lamina propria.
      Similar findings have been observed in the hyper-IgM syndrome. However, these
      patients can be distinguished from currently recognized genetic variants of hyper
      IgM syndrome on the basis of their clinical and histologic features, together
      with information obtained from DNA sequence analysis. Thus, their condition is
      likely to represent a novel form of primary immune deficiency with features of
      hyper-IgM syndrome.

PMID- 12405164
TI  - XLA patients with BTK splice-site mutations produce low levels of wild-type BTK
      transcripts.
AB  - X-linked agammaglobulinemia is caused by mutations in the BTK gene, which result
      in a precursor B-cell differentiation arrest in the bone marrow and the absence
      of or strongly reduced B lymphocytes in blood. We identified a patient with a
      mild clinical phenotype, low numbers of B lymphocytes, and a splice-site mutation
      in the BTK gene. The precursor B-cell compartment in the bone marrow of this
      patient was almost identical to that in healthy children. Using real-time
      quantitative polymerase chain reaction, we were able to detect low levels of wild
      type BTK transcripts in his granulocytes. Therefore, we speculated that wild-type
      BTK transcripts might be responsible for a milder clinical and immunological
      phenotype, as has been shown in several other diseases. Consequently, we
      quantified the expression of wild-type BTK transcripts in granulocytes of eight
      additional patients with splice-site mutations and compared their phenotypes with
      17 patients with other types of BTK mutations. In these eight patients, the
      presence of low levels of wild-type BTK transcripts did not show a clear
      correlation with the percentage, absolute number, or immunophenotype of B
      lymphocytes nor with age or serum immunoglobulin levels at diagnosis.
      Nevertheless, we postulate that the presence of wild-type BTK transcripts can be
      one of the many factors that influence the clinical and immunological phenotype
      in X-linked agammaglobulinemia.

PMID- 12405165
TI  - Hepatitis B immunization.

PMID- 12405166
TI  - Children at risk of developing dehydration from diarrhoea: a case-control study.
AB  - To identify the factors related to dehydration from diarrhoea, a hospital-based
      case-control study was carried out among under-2-year-old Bangladeshi children.
      The study compared 80 cases who had 'some' or severe dehydration with 160 age
      matched controls who had 'no signs' of dehydration. All the cases and controls
      were examined and the mothers were interviewed in the hospital and followed at
      home on the 14th day of illness. Thirty-eight factors were studied for their
      probable influence on the development of dehydration. In bivariate analysis, 17
      factors were found to be associated significantly with the development of
      dehydration and were treated with stepwise logistic regression analysis. A
      combination of vomiting, oral rehydration therapy at home, mother's dirty finger
      nails, and residing more than 3 km away from the hospital provided the maximum
      sensitivity (77.5 per cent) and specificity (91.2 per cent) for predicting
      development of dehydration. These prognostic factors would be helpful for
      community health workers to identify children at risk of developing diarrhoea
      associated dehydration, and preventive strategies could be designed to alter the
      prognostic factors.

PMID- 12405167
TI  - Adoption and hospital admission in Port Moresby, Papua New Guinea.
AB  - We report a study of adopted children admitted to the children's wards of Port
      Moresby General Hospital, Papua New Guinea over a 5-month period in 2000. The
      proportion of hospitalized children known to be adopted was almost three times
      that in the children's outpatients department. Gastroenteritis and neonatal
      sepsis were more common causes of admission in adopted children than in the
      general paediatric hospital population. Admitted adopted children were lighter
      and shorter than the controls with no difference in weight-for-height, suggesting
      that stunting is the predominant nutritional problem among adopted children.
      These differences were even more marked in children with diagnoses other than
      gastroenteritis. Thirty-three (82.5 per cent) of the adopted children had ever
      been bottle fed compared with 11 (13.75 per cent) of the controls (p = 0.029).
      Twelve (30 per cent) children had been adopted because of neglect or abandonment.
      The biological mothers of seven of these children had died, and two children had
      been bought for cash. Biological mothers were more likely than the adoptive or
      control mothers to be single and less than 20 years of age. Knowledge of formal
      adoption procedures was very poor. The present study therefore shows that
      adoption in Papua New Guinea is not without risk and it is important that
      adoption should be recognized as having the potential for serious adverse effects
      on the child's well-being, especially since adoption is likely to become even
      more prevalent as the HIV epidemic continues. Consideration needs to be given to
      protection of the rights of children at high risk of adoption.

PMID- 12405168
TI  - How accurate is the postnatal estimation of gestational age?
AB  - The aim of the present study was to determine the accuracy of postnatal
      gestational age assessment of babies using three different methods. Two hundred
      women attending the university obstetric unit of North Colombo Teaching Hospital,
      Ragama, Sri Lanka whose expected date of delivery (EDD) by early ultrasonography
      fell within a week of EDD by dates were included in the study. Postnatal
      assessment was performed within 24 h of birth. Two co-researchers performed
      Dubowitz and Parkin methods separately without prior knowledge of menstrual
      gestation. Data was analysed using EpiInfo 6 and SPSS packages. The mean
      difference between menstrual gestation and Dubowitz physical criteria was -0.45
      weeks; between menstrual gestation and classical Dubowitz method, +2.18 weeks;
      and between menstrual gestation and Parkin's method, +0.34 weeks. It was
      concluded that postnatal assessment of gestational age by the Parkin's method is
      much closer to menstrual gestation than the classical Dubowitz method and is also
      easier and quicker to perform.

PMID- 12405169
TI  - Seven days vs. 10 days ceftriaxone therapy in bacterial meningitis.
AB  - Ceftriaxone is recommended in children with acute bacterial meningitis (ABM) for
      10 days. However, the drug is expensive, and shorter duration of therapy, if
      equally effective, would cut costs of therapy and hospitalization. The aim of
      this study was to compare the outcome of 7 days vs. 10 days' ceftriaxone therapy
      in children with ABM. Seventy-three children aged 3 months to 12 years with ABM,
      consecutively admitted to hospital were enrolled. Ceftriaxone was given for 7
      days to all. Randomization to group I (7 days) and group II (10 days) therapy was
      done on the seventh day. At the end of 7 days' therapy in group I and 10 days in
      group II, children were evaluated using a clinical scoring system. Children with
      a score of more than 10 were labelled as 'treatment failures' and were continued
      on ceftriaxone. If a score was less than 10, the antibiotic was stopped.
      Complications were appropriately evaluated and managed. All children were
      followed-up 1 month after discharge: neurodevelopmental assessment, Denver
      Development Screening Tests, IQ and hearing assessment were done. After excluding
      four patients, there were 35 children in group I and 34 in group II. The two
      groups were comparable with respect to age, sex, nutritional status, presenting
      clinical features, and CSF parameters. Organism identification was possible in 38
      per cent of children: (Streptococcus pneumoniae, 21 per cent; Haemophilus
      influenzae, 13 per cent; meningococcus, 4 per cent). Treatment failure rate was
      comparable in both groups (9 in group I and 8 in group II) as was the sequelae at
      discharge and at 1 month (9 in group I, 15 in group II,p > 0.1). Status
      epilepticus and focal deficits at presentation were significantly associated with
      treatment failures and sequelae in both the groups (p < 0.05). Length of hospital
      stay was shorter in group I (10.8 +/- 6.0 days) as compared with group II (14.4
      +/- 7.2 days,p < 0.05) and frequency of nosocomial infection was significantly
      more in group II (p < 0.05). It was concluded that clinical outcome of patients
      treated with 7 days' ceftriaxone therapy is similar to that of 10 days' therapy,
      and is associated with lesser nosocomial infection and earlier hospital
      discharge. Seven days ceftriaxone therapy may be recommended for uncomplicated
      ABM in children in developing countries.

PMID- 12405170
TI  - Effects of three different iron supplementations in term healthy infants after 5
      months of life.
AB  - The aim of this study was to investigate the effects of different doses of iron
      on haematological status of breastfed infants. One hundred and thirteen infants
      were randomized into four groups at 5 months of age. Iron supplementation was
      given at doses of 1 mg/kg/day, 2 mg/kg/day, and 2 mg/kg/every other day in the
      first three study groups, respectively, and the last group received placebo. The
      hematological values, except hemoglobin, were higher in the group supplemented
      with iron at a dose of 2 mg/kg/day, and ferritin values were statistically higher
      in the group supplemented with iron at a dose of 2 mg/kg/every other day than in
      the group supplemented with iron at a dose of 1 mg/kg/day. We suggest that
      intermittent iron supplementation is more effective than a daily regimen in equal
      dosages.

PMID- 12405171
TI  - Identification of clinical criteria for group A-beta hemolytic streptococcal
      pharyngitis in children living in a rheumatic fever endemic area.
AB  - A cross-sectional study was conducted over a 1-year period (1 January-31 December
      2000) during which cases suffering from uncomplicated tonsillopharyngitis were
      recruited from the private and public health services in Alexandria. The
      objective was to determine the prevalence of group A-beta haemolytic streptococci
      (GABHS) among children suffering from tonsillopharyngitis and to identify the
      clinical criteria predicting GABHS pharyngitis in children. A total of 578
      children aged between 1 and 15 years with a mean of 6.3 +/- 3.7 years, presenting
      with sore throat were enrolled in the study. Demographic data and presenting
      signs and symptoms for each patient were recorded on a standardized form and a
      throat swab was taken using the filter paper technique. The overall prevalence of
      GABHS was 17 per cent and the highest isolation rate was reported in children
      aged 10-15 years. Non-GABHS comprised 11.9 per cent of the total isolates. The
      most prevalent of them were group C and G streptococci. The highest frequency of
      both GABHS and non-GABHS was in early spring. Significant predictors of GABHS
      pharyngitis were: age 10-15 years, the presence of dysphagia, vomiting,
      pharyngeal exudate, and scarlatiniform rash. Watery eyes and/or rhinitis had a
      protective value against the diagnosis of GABHS pharyngitis, while fever was
      considered to be a non-specific finding in cases with GABHS pharyngitis.
      Antibiotic sensitivity test showed higher sensitivity to both penicillin and
      erythromycin. Only 1 per cent of the GABHS isolates showed resistance to
      cephadroxil. We concluded that a syndrome of signs and symptoms could be used as
      a clinical predictor for the diagnosis of GABHS pharyngitis.

PMID- 12405172
TI  - Tuberculosis meningitis and attention deficit hyperactivity disorder in children.
AB  - The purpose of this study was to investigate the prevalence of attention deficit
      hyperactivity disorder (ADHD) in children who recovered from tuberculous
      meningitis (TBM) as part of an ongoing TBM research project. During this study,
      each TBM group subject underwent a thorough clinical-neurological examination,
      and a test battery which included the child behaviour check list (CBCL) Teacher's
      Report Form and Conners Rating Scale. The parents and teachers of each of the 21
      TBM group and 21 control group subjects completed the above-mentioned
      questionnaires. All 21 TBM group subjects displayed symptoms of ADHD. The TBM
      group was significantly more hyperactive and unable to sustain attention than the
      control group. Furthermore, TBM group subjects were perceived as being
      significantly more unpopular, obsessive, compulsive and aggressive than the
      control group subjects. With regard to the frequency of externalizing behaviour,
      the TBM group subjects displayed significantly more externalizing behaviours as
      well as symptoms of attention deficit and hyperactivity. No significant
      differences between parents' and teachers' ratings were found. We conclude that
      ADHD is a common long-term complication of TBM.

PMID- 12405173
TI  - Tetravalent rhesus-human rotavirus vaccine (RRV-TV) in Belem, Brazil: efficacy
      against prevailing P and G genotypes.
AB  - To determine the efficacy of a reassortant rhesus-human tetravalent rotavirus
      vaccine (RRV-TV) (4 x 10(4) pfu/dose) against P and G rotavirus genotypes, 90
      positive samples were tested using reverse transcription-polymerase chain
      reaction. The efficacy of the RRV-TV vaccine against P[8] and G1 individually or
      in binary combination P[8], G1 was 72 per cent (p < 0.005) 61 per cent (p <
      0.013), and 70 per cent (p < 0.009), respectively, only for the first year of
      follow-up. In the second year, as well as after 2 years of follow-up, no efficacy
      was observed to these genotypes. These data indicate that further studies with
      rotavirus vaccines should focus on the molecular characterization of rotaviruses
      genotypes, in order to see whether or not cross-protection among different G and
      P genotypes may occur as a result of common bearing of VP4 specificities.

PMID- 12405174
TI  - Pyridoxine-dependent seizures: long-term follow-up of two cases with clinical and
      MRI findings, and pyridoxine treatment.
AB  - Pyridoxine-dependency is a rare autosomal recessive disorder causing a severe
      seizure disorder of neonatal onset. There are a few reports including
      neuroimaging studies, such as cranial CT and MRI, and one report with
      longitudinal MRI findings in two cases with pyridoxine-dependent seizures (PDS).
      We report long-term follow-up of two siblngs with PDS in the light of clinical,
      EEG, CT and MRI findings, and pyridoxine treatment. The first patient, an 8-year
      old female who had neonatal seizures, has sequential cranial CT and MRIs which
      are normal except for mega cistema magna thus far. She still has mild mental
      retardation, although the accurate diagnosis was made when she was 6 years old
      and pyridoxine treatment was initiated. The second patient, a 1-year-old female,
      who is the younger sibling of the first patient, presented with neonatal seizures
      and PDS was diagnosed immediately, with resulting pyridoxine treatment (10
      mg/kg/day). She is now neurologically normal, seizure-free, and has sequential
      normal CT and MRIs. These patients show rather benign clinical courses.

PMID- 12405175
TI  - Internal jugular phlebectasia: usefulness of color Doppler ultrasonography in the
      diagnosis.
AB  - Jugular phlebectasia (JP) is an entity that has been increasingly recognized in
      recent years. It is a rare entity. This paper reports three new cases presenting
      with swelling on the right side of the neck, and reviews all cases of internal JP
      published in English literature up to 2001. This article also discusses the
      usefulness of color Doppler ultrasonography for the diagnosis of internal jugular
      venous ectasia.

PMID- 12405176
TI  - Antenatal hydronephrosis, a clinical dilemma.

PMID- 12405177
TI  - Clinical profile of late hemorrhagic disease of the newborn in Punjab, India.

PMID- 12405178
TI  - Cardiopulmonary resuscitation in the delivery room; experience from Istanbul,
      Turkey.

PMID- 12405180
TI  - Sexually transmitted diseases in children, a cause for concern.

PMID- 12405179
TI  - Gall bladder wall edema is not pathogenic of dengue infection.

PMID- 12405181
TI  - Lymphocyte development in neonatal and adult c-Kit-deficient (c-KitW/W) mice.
AB  - Hematopoietic stem cells and lymphocyte progenitors express the receptor tyrosine
      kinase c-Kit. In fetal and neonatal life, c-Kit plays a redundant role in T, and
      no apparant role in B cell development. In neonatal mice deficient for both c-Kit
      and the common gamma chain (gammac), a component of the interleukin-7 (IL-7)
      receptor, the thymus is alymphoid, and therefore lacks T cell receptor (TCR)
      beta, gamma, and delta rearrangements. Thus, a critical role for c-Kit in T cell
      development around birth is well established. More recently, it has become
      possible to examine the impact of c-Kit deficiency under conditions of steady
      state lymphopoiesis in adult life. Such analysis has been made possible by the
      identification of a viable adult c-Kit-deficient (c-KitW/W) variant, termed the
      Vickid mouse. The Vickid mouse arose by outcrossing c-KitW-bearing mice of the WB
      strain, in which lack of c-Kit is lethal, to a mixed genetic background. In adult
      Vickid mice, mainstream alphabeta TCR+ thymocyte development, and B cell
      development in the bone marrow are severely c-Kit-dependent with progressive age.
      Analysis of other pathways of developing T cells, i.e. CD4-CD8- (double neagative
      [DN]) alphabeta TCR+ and DN gammadelta TCR+ thymocytes revealed that the
      development of both lineages is also severely affected by lack of c-Kit. However,
      numbers of gammadelta TCR+ T cells decline before numbers of alphabeta TCR+ T
      cells in the thymus. In contrast to T and B cell development, generation of NK
      cells is not affected in adult c-KitW/W mice.

PMID- 12405182
TI  - Development of antigen-specific helper T cell responses in vivo: antigen-specific
      Th cell subsets.

PMID- 12405183
TI  - Bcl-6 uncouples B lymphocyte proliferation from differentiation.

PMID- 12405184
TI  - The role of Vav proteins in B cell responses.

PMID- 12405185
TI  - Traffic patterns of B cells and plasma cells.

PMID- 12405186
TI  - Lymphocyte traffic in lymphoid organ neogenesis: differential roles of Ltalpha
      and LTalphabeta.
AB  - In these studies the differential roles of LTalpha and LTalphabeta complex have
      been discussed with regard to development of lymphoid organs in ontogeny and in
      inflammation, LTalpha is necessary for PLNand MLN, most likely as both LTalpha
      and LTalphabeta complex, whereas only LTalphabeta is required for MLN. Both are
      involved in the cellularity of the NALT. When expressed as a transgene, LTa alone
      can induce cellular accumulation and MAdCAM, but not PNAd, an epitope associated
      with PLN HEV. These data suggest that LTalphabeta complex plays a crucial role in
      PNAd. One hypothesis is that LTalphabeta induces PNAd through modification via an
      HEV sulfotransferase. RIPLTalpha.RIPLTbeta mice will provide an important tool to
      investigate this question.

PMID- 12405187
TI  - Regulation of spleen white pulp structure and function by lymphotoxin.

PMID- 12405188
TI  - Enzymatic control of leukocyte trafficking: role of VAP-1.

PMID- 12405189
TI  - Factors regulating naive T cell homeostasis.

PMID- 12405190
TI  - IL-7, the thymus, and naive T cells.

PMID- 12405191
TI  - Neonates support "homeostatic" proliferation.

PMID- 12405192
TI  - Self-recognition and the regulation of CD4+ T cell survival.
AB  - CD4+ T cells differentiate in the thymus from committed precursors to mature
      naive cells ready for peripheral circulation. Successful maturation depends on
      adequate but not excessive signaling upon T cell receptor (TCR) engagement of
      self-peptide/MHC class II molecule ligands present in the thymic environment.
      Persistent TCR signaling throughout development from the CD4+CD8+ to the CD4+
      state is required for completion of the developmental process. Recent work has
      suggested that a continuation of this signaling is essential for sustained
      survival of CD4+ T cells once they leave the thymus but our studies suggest
      otherwise. Although we found clear evidence for active TCR signaling involving
      recognition of self-ligands in peripheral lymphoid tissues, we did not see a
      substantial effect of loss of such signaling on the life-time of naive CD4+ T
      cells. Based on a careful review of the literature, we conclude that essentially
      all previous claims that MHC class II recognition plays a significant role in the
      survival of CD4+ T cells can be reinterpreted as an effect of self-recognition on
      proliferation in lymphopenic environments, maintaining population numbers without
      a marked effect on individual cell viability. We propose a possible explanation
      for why, in contrast, the viability of naive CD8+ T cells appears to show such
      self-MHC dependence and suggest that a primary function of self-recognition by T
      cells may be to enhance responses to foreign antigen.

PMID- 12405193
TI  - TCR-independent proliferation and differentiation of human CD4+ T cell subsets
      induced by cytokines.
AB  - Naive and memory T cells can divide in an antigen-independent manner in vivo
      maintaining independently a constant pool size. While naive T cells require TCR
      tickling by self-MHC for homeostatic proliferation in lymphopenic mice, memory
      cells do not but respond to cytokines. Human naive and memory CD4+ T cell subsets
      can be selectively expanded in vitro with different cytokine combinations.
      Responsiveness of T cells to homeostatic cytokines is associated with the
      differentiation state. Thus, while memory cells respond directly to IL-7 and IL
      15, naive T cells require costimulation by dendritic cell-derived cytokines, and
      selectively respond to IL-4. This differential cytokine responsiveness is
      associated with the expression and modulation of the relevant cytokine receptors.
      Cytokine-driven proliferation is independent of TCR-stimulation and shows
      distinct signal transduction requirements. While cytokine-expanded naive T cells
      maintain a naive phenotype, memory cells differentiate acquiring new effector
      functions and switching expression of chemokine receptors. Thus human naive and
      memory T cell pools can be maintained with homeostatic cytokines in the absence
      of TCR stimulation.

PMID- 12405194
TI  - Regulation of memory CD4 T cells: generation, localization and persistence.

PMID- 12405195
TI  - Some properties of T cells in animals.

PMID- 12405196
TI  - Generation and characterization of memory CD4 T cells.

PMID- 12405197
TI  - T cell proliferation, differentiation, and restoration in lymphopenic
      individuals: for contributed volumes.

PMID- 12405199
TI  - Cytokines and memory-phenotype CD8+ cells.

PMID- 12405198
TI  - Migration of primary and memory CD8 T cells.
AB  - Our results indicate that a substantial proportion of the antimicrobial CD8 and
      CD4 T cell response is focused in non-lymphoid tissues. This finding makes
      teleological sense since maximum protection against infection is better served by
      the widespread presence of effector and memory cells. In the case of CD8 T cells,
      it appears that irrespective of the site at which initial activation of naive
      cells occurs, the end result is production of effector cells with broad migratory
      capabilities. Memory T cells perhaps have more restricted migratory abilities as
      compared to effector cells, although this needs to be tested definitively. Our
      results suggest that memory CD8 T cells in the intestinal LP may not be part of
      the recirculating pool of memory cells, though our data does not preclude the
      possibility that migrants from outside the mucosa contribute to the LP memory
      pool. Our data also demonstrates that CD8 memory T cells in non-lymphoid tissue
      exhibit heightened effector function as compared to their splenic counterparts.
      Whether these findings indicate the existence of distinct lineages of memory
      cells remains to be seen. The functional abilities of migrating memory cells
      could be modulated by the migration process and/or by the environmental milieu of
      a particular tissue. Although the development of CD8 memory T cells is a complex
      process requiring multiple signalling pathways, we identified IL-7 as an
      important player in memory generation. Much further work is needed to decipher
      the cellular and molecular mechanisms of memory induction as well as to learn the
      in vivo functional significance of memory cell subsets.

PMID- 12405200
TI  - Antiviral memory T cell responses: correlation with protective immunity and
      implication for vaccine development.

PMID- 12405201
TI  - Homeostatic proliferation but not the generation of virus specific memory CD8 T
      cells is impaired in the absence of IL-15 or IL-15Ralpha.
AB  - The generation and efficient maintenance of antigen specific memory T cells is
      essential for long-lasting immunological protection. Antigen specific memory CD8
      T cells are known to be maintained via antigen-independent homeostatic
      proliferation. However, signals that drive memory T cell generation and/or
      influence the slow turnover of memory T cells are unknown. Recently, IL-15 has
      received attention for its potential effect on memory CD8 T cells. In this report
      we examine the role of IL-15 in the generation and maintenance of virus specific
      memory CD8 T cells using mice deficient in either IL-15 or the IL-15 receptor a
      chain. Both cytokine and receptor deficient mice mount a robust CD8 T cell
      response to infection with lymphocytic choriomeningitis virus (LCMV) that is
      initially only slightly lower than in control mice. Further, virus specific
      memory CD8 T cells are generated in both IL-15 -/- and IL-15Ralpha -/- mice.
      However, longitudinal analysis reveals a slow attrition of LCMV specific memory
      CD8 T cells in the absence of IL-15 signals. Indeed, direct examination of
      homeostatic proliferation reveals a severe defect in the turnover of antigen
      specific memory CD8 T cells in the absence of IL-15. Together these results
      suggest that IL-15 is not essential for the generation of memory CD8 T cells, but
      is required for homeostatic proliferation to maintain populations of memory cells
      over long periods of time.

PMID- 12405202
TI  - Irreversible marking of dendritic cells in vivo: for contributed volumes.

PMID- 12405203
TI  - Tracking arterial smooth muscle-specific T cells in the inflamed vasculature.

PMID- 12405204
TI  - Regulation of T cell migration through formation of immunological synapses: the
      stop signal hypothesis.

PMID- 12405205
TI  - Two-photon imaging in intact lymphoid tissue.

PMID- 12405206
TI  - Dong-Sha Atoll, South China Sea: ground zero!

PMID- 12405207
TI  - Galapagos Islands threatened by second oil spill in less than two years.

PMID- 12405208
TI  - The pollution of the marine environment by plastic debris: a review.
AB  - The deleterious effects of plastic debris on the marine environment were reviewed
      by bringing together most of the literature published so far on the topic. A
      large number of marine species is known to be harmed and/or killed by plastic
      debris, which could jeopardize their survival, especially since many are already
      endangered by other forms of anthropogenic activities. Marine animals are mostly
      affected through entanglement in and ingestion of plastic litter. Other less
      known threats include the use of plastic debris by "invader" species and the
      absorption of polychlorinated biphenyls from ingested plastics. Less conspicuous
      forms, such as plastic pellets and "scrubbers" are also hazardous. To address the
      problem of plastic debris in the oceans is a difficult task, and a variety of
      approaches are urgently required. Some of the ways to mitigate the problem are
      discussed.

PMID- 12405209
TI  - Offshore oil platforms and fouling communities in the southern Arabian Gulf (Abu
      Dhabi).
AB  - This study examined the fouling organisms on the legs of offshore oil platforms
      at two sites in the southern Arabian Gulf (offshore Abu Dhabi, United Arab
      Emirates). 100% of the metal structures was colonized by encrusting organisms.
      Both the number of individuals and the total biomass tended to decrease with
      depth. The total weight of dead shells always exceeded that of living organisms.
      Sessile filter feeders dominated the biomass, whereas small mobile forms had the
      largest number of individuals. The biomass at the deeper platform (22 m) was
      dominated by bivalves, barnacles and bryozoans, while polychaetes and amphipods
      had the greatest number of individuals. Biomass values here ranged from 1 g/0.1
      m2 at 20 m to 147 g/0.1 m2 at 5 m; the corresponding individual numbers were 266
      (20 m) and 11,814 indiv./0.1 m2 (5 m). The results at the shallower platform (11
      m) differed in several respects: barnacles clearly dominated over bivalves, and
      sponges exceeded byrozoans, while total individual numbers fell due to a decline
      in polychaete dominance. Biomass values here ranged from 84 g/0.1 m2 at 10 m to
      153 g/0.1 m2 at 0 m; the corresponding individual numbers were 695 (10 m) and
      3,125 indiv./0.1 m2 (0 m). The potential role of such fouling communities on
      artificial structures in the Gulf is discussed.

PMID- 12405210
TI  - Assessment of potential transport of pollutants into the Barents Sea via sea ice-
      an observational approach.
AB  - The present estimates of ice drift in the Arctic include utilization of satellite
      imagery data (special sensor microwave/imager) and a reconstruction of air
      pressure for the period 1899-1998. A significant part of the sea ice in the
      Arctic Ocean has its origin in the Kara Sea and melts in the Greenland and the
      Barents Sea (BS). Consequently there may be a particular risk of pollutants in
      the Kara Sea entering the food webs of the Greenland and BS. The ice export from
      the Kara Sea between 1988 and 1994 was about 208,000 km2 (154 km3) per year. The
      import of ice into the BS was during the same period 161,000 km2 (183 km3) per
      year while the ice drift through the Fram Strait into the Greenland Sea was
      583,000 km2 (1859 km3) per year. Ice which formed adjacent to the Ob and Yenisey
      rivers in early January, drifted into the BS within two years (with a probability
      of about 50%.

PMID- 12405211
TI  - The influence of diet on comparative trace metal cadmium, copper and zinc
      accumulation in Thais clavigera (Gastropoda: Muricidae) preying on intertidal
      barnacles or mussels.
AB  - The influence of diet on comparative metal accumulation was investigated using a
      predatory muricid gastropod Thais clavigera. Individuals were fed for up to 56
      days on either barnacles, i.e., Tetraclita squamosa, or mussels, i.e., Perna
      viridis, collected from metal-contaminated and clean sites. Barnacles and mussels
      have contrasting metal handling strategies and, therefore, different body
      concentrations, intracellular distributions and detoxification systems. Field
      collection of prey items that accumulated body metal concentrations over a
      lifetime of exposure allowed bioavailability to the predator, T. clavigera, to be
      assessed naturally, which may not be the case for prey exposed to metals for a
      short time in the laboratory. T. clavigera that was fed cadmium- and copper
      contaminated barnacles or mussels ingested significantly greater amounts compared
      to those fed conspecifics collected from clean locations. T. clavigera body
      cadmium and copper concentrations were not, however, significantly different
      between individuals fed either contaminated or clean prey. Amount of zinc
      ingested was similar in mussels collected from clean and contaminated
      environments but much less when compared to the barnacle prey. The body
      concentrations of zinc in T. clavigera fed mussels collected from both sites
      fell. In contrast, the amount of zinc ingested from barnacle prey was
      significantly greater from those collected from the metal-contaminated site as
      compared to the clean one. This was reflected as significantly greater body zinc
      concentrations in T. clavigera fed contaminated barnacles compared to those fed
      clean individuals. Copper and zinc accumulation from prey was, therefore,
      complex. It varied between metal and between prey type, but appeared to be
      related to the amount ingested and the metal handling strategy of the prey.

PMID- 12405212
TI  - Biomonitoring of coastal pollution status using protozoan communities with a
      modified PFU method.
AB  - Structural and functional parameters of protozoan communities were assessed as
      indicators of water quality in Korean coastal waters in the summer of 2000. A
      modified polyurethane foam unit (PFU) method, named the bottled PFU (BPFU)
      system, was used in order to carry out the bioassessment. Both parameters
      suggested that biomonitoring using the BPFU system was more effective than the
      conventional PFU method in offshore areas. The species number collected by the
      BPFU system generally decreased as pollution intensity increased at three main
      stations and was greater than that collected using the PFU method (paired t-test,
      t = 4.83, p < 0.0001). The Margalef diversity index coincided well with the water
      conditions. The diversity index values calculated from the BPFU system were also
      significantly higher than those from the PFU method (paired t-test, t = 5.37, p <
      0.0001). Furthermore, the functional parameters, i.e. S(eq),G and T90%,
      correlated with the pollution status and could thus clearly discriminate the
      different classes of water quality.

PMID- 12405213
TI  - A survey of imposex in muricids from 1996 to 2000 and identification of optimal
      indicators of tributyltin contamination along the east coast of Phuket Island,
      Thailand.
AB  - The present investigation is the most extensive survey of imposex in gastropods
      from the west coast of Thailand. Imposex in Thais distinguenda increased
      significantly (p < 0.001; Chi Square test for trend) from 1996 to 2000 at 21
      stations in Phangna Bay, Thailand. Females with imposex increased, extending from
      3.5 km in 1996 to 10 km from the harbour areas in 1999 and 2000. Increasing
      intensity of imposex was also observed for Thais bitubercularis from 1996 to
      2000. The less sensitive species: Morula musiva, Morula granulata, Morula
      margariticola and Thais rufotincta only developed imposex at the three main areas
      of intense shipping activities. T. bitubercularis and T. distinguenda are
      recommended as indicators of tributyltin (TBT) in Southeast Asia because of their
      sensitivity and wide distribution in the region. The results suggest that TBT
      contamination is worsening, against global trends, because regulations
      prohibiting the use of TBT-based paints, do not exist in Thailand.

PMID- 12405214
TI  - The dose-response relationship between No. 2 fuel oil and the growth of the salt
      marsh grass, Spartina alterniflora.
AB  - The effect of No. 2 fuel oil on the biomass production of the salt marsh plant,
      Spartina alterniflora, was studied in a greenhouse dose-response experiment. S.
      alterniflora were transplanted into soil with 10 dosage levels of No. 2 fuel oil
      ranging from 0 to 456 mg g(-1) dry soil. Three months after transplantation,
      values for plant biomass, stem density, and shoot height decreased significantly
      with increasing fuel oil level in a dose-response fashion. Evapo-transpiration
      rates were correlated with the total biomass response. Relative to the control, a
      significant decrease in total (above- plus below-ground) plant biomass was
      observed at concentrations above 57 mg g(-1) dry soil. Within the 3-month
      experimental period, detrimental effects on below-ground biomass accumulation and
      bioluminescence of the marine bacterium Viberio fisheri in the Microtox Solid
      Phase Test were observed at oil concentrations >29 mg g(-1) dry soil, suggesting
      that biological effects of oil within the sediment matrix may be more pronounced
      than on above-ground biomass, requiring a dosage 228 mg g(-1) dry soil to elicit
      a significant detrimental effect. Hence, measurements of oil effects with
      biological end-points based solely on above-ground responses may underestimate
      the potential impacts of petroleum hydrocarbon spills, especially when the oil
      has penetrated the soil. While S. alterniflora was proved to be relatively
      tolerant to the No. 2 fuel oil spills, its effectiveness in phytoremediation
      operations may be limited at fuel oil levels 228 mg g(-1) dry soil, as both plant
      growth and microbial activity may be constrained.

PMID- 12405215
TI  - Polycyclic aromatic hydrocarbons in sediments, mussels and crustacea around a
      former gasworks site in Shoreham-by-Sea, UK.
AB  - Concentrations of polycyclic aromatic hydrocarbons have been determined in
      sediments, mussels and crustacea in the vicinity of a former gasworks site by
      Shoreham Harbour, UK. Very high concentrations of PAH were found in the
      substrate, an ash-like material deposited on the former gasworks site, which
      exhibited a profile consistent with the major source of contamination being coal
      or coke tar produced during the period of gas production at the site. Elevated
      PAH concentrations were also found in mussels both from the beach below the
      former gasworks site, and from sites further to the east in Portslade and Hove.
      The significance of these concentrations were assessed using an approach which
      involved the calculation of benzo[a]pyrene equivalent conoentrations (BaPEs),
      summing concentrations of individual PAH on the basis of their comparative
      potency as carcinogens. BaPE ranged from values of, or close to, zero for
      crustacea, to 336 microg kg(-1) wet weight in mussels from Southwick Beach. The
      contaminated mussels are not exploited commercially but may be taken by casual
      gatherers, and notices have been posted to warn potential consumers.

PMID- 12405216
TI  - Application of biomarkers for assessing the biological impact of dredged
      materials in the Mediterranean: the relationship between antioxidant responses
      and susceptibility to oxidative stress in the red mullet (Mullus barbatus).
AB  - In the period 1997-2000, approximately 1,800,000 m3 of material dredged from the
      Port of Leghorn was discharged into a sea dumping site located 14 miles from the
      coast. The red mullet (Mullus barbatus) was used as a bioindicator species for
      monitoring the biological impact of these discharges on a geographical and
      temporal scale. Organisms were sampled over three years (1998-2000) at different
      stations and several biomarkers, both of exposure and effect, were analyzed.
      Bioavailability of specific classes of pollutants was evaluated by analyzing
      levels of metallothioneins, the activity of cytochrome P450 1A (CYPIA) and of
      glutathione S-transferases. Among biomarkers of effect, special attention was
      paid to the balance between prooxidant challenge and antioxidant defenses, and to
      the appearance of damage caused by oxidative stress. The analyses of the main
      components of the antioxidant system included superoxide dismutase, catalase,
      glutathione peroxidases, glutathione reductase, glyoxalase I and II, and total
      glutathione. These data were integrated with the measurement of total oxyradical
      scavenging capacity (TOSC) as an indication of the overall biological resistance
      to toxicity of different forms of oxyradicals (peroxyl radicals, hydroxyl
      radicals and peroxynitrite). Results indicated a biological impact in organisms
      sampled near the disposal site; the impact was particularly evident during 1999
      and mainly related to organic chemicals such as PAH. Exposure to these pollutants
      also caused variations in the levels and activity of several antioxidants. The
      analysis of TOSC, however, revealed that the overall capacity of specific tissues
      of organisms to absorb various oxidants was not seriously compromised when
      challenged with increased prooxidant pressures. Variations of single antioxidants
      were useful in revealing early warning "biological responses", while integration
      with TOSC analyses indicated if such changes also reflect a more integrated and
      functional "biological effect" with possible consequences at the organisms level.
      The red mullet appears to be a useful sentinel species for a biomarker approach
      to monitoring impact caused by dredged materials.

PMID- 12405217
TI  - Oxidative stress in the mussel Mytella guyanensis from polluted mangroves on
      Santa Catarina Island, Brazil.
AB  - Digestive glands of the mangrove mussel Mytella guyanensis, collected at one non
      polluted site (site 1) and two polluted sites (sites 2 and 3), were analysed for
      different antioxidant defenses, lipid peroxidation and DNA damage. Thiobarbituric
      acid-reactive substance (TBARS) and 8-oxo-7,8-dihydro-2'-deoxyguanosine levels
      were enhanced at the polluted sites. With the exception of superoxide dismutase,
      the activities of catalase and glutathione peroxidase were also higher at the
      polluted sites. Greater increases were observed in glutathione reductase,
      glutathione S-transferase and etoxyresorufine-O-deethylase activities at the
      polluted sites. Conversely, reduced glutathione content was higher at the control
      site. Trace metal contents in mussels collected at polluted sites were increased
      compared to the control site, and there were strong positive correlations between
      TBARS and Cu and Pb contents. M. guyanensis is routinely exposed to an oxidative
      stress condition at both polluted sites, and considering xenobiotic
      bioaccumulation in bivalve molluscs, the mangrove mussel represents an excellent
      bioindicator for environmental monitoring studies.

PMID- 12405218
TI  - Spatial variability of metals in the inter-tidal sediments of the Medway Estuary,
      Kent, UK.
AB  - Concentrations of major and trace metals were determined in eight sediment cores
      collected from the inter-tidal zone of the Medway Estuary, Kent, UK. Metal
      associations and potential sources have been investigated using principal
      component analysis. These data provide the first detailed geochemical survey of
      recent sediments in the Medway Estuary. Metal concentrations in surface sediments
      lie in the mid to lower range for UK estuarine sediments indicating that the
      Medway receives low but appreciable contaminant inputs. Vertical metal
      distributions reveal variable redox zonation across the estuary and historically
      elevated anthropogenic inputs. Peak concentrations of Cu, Pb and Zn can be traced
      laterally across the estuary and their positions indicate periods of past erosion
      and/or non-deposition. However, low rates of sediment accumulation do not allow
      these sub surface maxima to be used as accurate geochemical marker horizons. The
      salt marshes and inter-tidal mud flats in the Medway Estuary are experiencing
      erosion, however the erosion of historically contaminated sediments is unlikely
      to re-release significant amounts of heavy metals to the estuarine system.

PMID- 12405219
TI  - Long-term changes in the type, but not amount, of ingested plastic particles in
      short-tailed shearwaters in the southeastern Bering Sea.
AB  - We report the current (1997-1999, 2001) incidence and amount of ingested plastic
      in short-tailed shearwaters (Puffinus tenuirostris) in the southeastern Bering
      Sea and compare our results with plastic reported in shearwaters during 1970
      1978. We also examine correlations between plastic loads and shearwater body
      mass. We found that 84% (N = 330) of shearwaters sampled in 1997-1999 and 2001
      contained plastic. The incidence and amount of ingested plastic have not
      significantly changed since the 1970s. In contrast, the predominant type of
      plastic has changed over time, from industrial plastic to user plastic. S,asonal
      patterns in the incidence and amount of ingested plastic also changed from peak
      levels during early and late summer in the 1970s to mid summer in the late 1990s
      and 2001. We suggest that the availability of neuston plastic to seabirds in the
      Bering Sea has undergone a shift in composition since the 1970s. Shearwater body
      mass appears little if at all impaired by plastic, at least at present levels of
      consumption.

PMID- 12405220
TI  - Effective metal concentrations in porewater and seawater labile metal
      concentrations associated with copper mine tailings disposal into the coastal
      waters of the Atacama region of northern Chile.

PMID- 12405221
TI  - Physico-chemical characteristics and pollutants of the benthic environment in the
      Montevideo coastal zone, Uruguay.

PMID- 12405222
TI  - Antifoulant concentrations at the site of the Bunga Teratai Satu grounding, Great
      Barrier Reef, Australia.

PMID- 12405223
TI  - Heavy metals in molluscs from the Basque Coast (Northern Spain): results from an
      11-year monitoring programme.

PMID- 12405224
TI  - Stress, synaptic plasticity, and psychopathology.
AB  - It is now generally recognized that stressful events play a critical role in the
      genesis of psychopathology. The neurobiological mechanisms that mediate the
      contribution of stressful events to the manifestation of psychiatric disorders
      may include changes in synaptic efficacy in different brain areas. Numerous
      studies in animals have begun to identify some of these areas through experiments
      manipulating stressful components. This review focuses on alterations of synaptic
      efficacy in the hippocampus, the lateral septum, and the medial prefrontal cortex
      that mimic the pathophysiology of depression and post-traumatic stress disorder.

PMID- 12405225
TI  - Gene expression profiles--a new dynamic and functional dimension to the
      exploration of learning and memory.
AB  - Many experiments in the past have demonstrated the requirement of de novo gene
      expression during the long-term retention of learning and memory. Although
      previous studies implicated individual genes or genetic pathways in learning and
      memory they did not uncover the collective behaviors of the genes. In view of the
      broad variety of genes and the cross-talk of genetic pathways, gene expression
      profiles offer a new dynamic and functional dimension to the exploration of
      learning and memory. This review illustrates how DNA microarray-based gene
      expression profiling may help to dissect and analyze the complex mechanisms
      involved in gene regulation during the acquisition and storage of memory.

PMID- 12405226
TI  - Reciprocal interactions between microglia and neurons: from survival to
      neuropathology.
AB  - Microglia represent a major cellular component of the brain, where they
      constitute a widely distributed network of immunoprotective cells. During the
      last decades, it has become clear that the functions traditionally ascribed to
      microglia, i.e. to dispose of dead cells and debris and to mediate brain
      inflammatory states, are only a fraction of a much wider repertoire of functions
      spanning from brain development to aging and neuropathology. The aim of the
      present survey is to critically discuss some of these functions, focusing in
      particular on the reciprocal microglia-neuron interactions and on the complex
      signaling systems subserving them. We consider first some of the functional
      interactions dealing with invasion, proliferation and migration of microglia as
      well as with the establishment of the initial blueprint of neural circuits in the
      developing brain. The signals related to the suppression of immunological
      properties of microglia by neurons in the healthy brain, and the derangement from
      this physiological equilibrium in aging and diseases, are then examined. Finally,
      we make a closer examination of the reciprocal signaling between damaged neurons
      and microglia and, on these bases, we propose that microglial activation,
      consequent to neuronal injury, is primarily aimed at neuroprotection. The loss of
      specific communication between damaged neurons and microglia is viewed as
      responsible for the turning of microglia to a hyperactivated state, which allows
      them to escape neuronal control and to give rise to persistent inflammation,
      resulting in exacerbation of neuropathology. The data surveyed here point at
      microglial-neuron interactions as the basis of a complex network of signals
      conveying messages with high information content and regulating the most
      important aspects of brain function. This network shares similar features with
      some fundamental principles governing the activity of brain circuits: it is
      provided with memory and it continuously evolves in relation to the flow of time
      and information.

PMID- 12405227
TI  - A multiple target neural transplantation strategy for Parkinson's disease.
AB  - Intracerebral transplantation of embryonic ventral mesencephalic tissue is a
      potential treatment for patients with Parkinson's disease for whom medical
      management is unsatisfactory. Neural transplantation for parkinsonism has been
      studied experimentally in animal models of Parkinson's disease for more than two
      decades. These animal studies have shown significant graft survival, synapse
      formation, graft induced-dopamine release, and behavioural recovery in
      transplanted animals. Encouraged by these results, clinical programs have been
      initiated over the past 15 years; more than 250 patients worldwide have undergone
      neural transplantation. Both animal and clinical studies indicate that neural
      transplantation has the potential to become a valuable treatment option for
      Parkinson's disease. However, while many transplant recipients obtain clinically
      useful symptom relief, in all cases functional recovery is incomplete. Certain
      symptoms do not respond well to transplant therapy, and those symptoms that do
      typically do not resolve completely. This has spurred efforts to optimize the
      transplant procedure. One important approach is exploring novel methods such as
      multiple site transplantation. This transplantation strategy results in a more
      complete reinnervation of the dopaminergic circuitry that is affected in
      Parkinson's disease. In principle, multiple site transplantation should provide a
      more satisfactory resolution of symptoms. Here we review the progress made in
      multiple site neural transplantation for Parkinson's disease. The effects of
      intrastriatal, intranigral, intrasubthalamic nucleus, and intrapallidal grafts in
      animal models of Parkinson's disease are analysed. The current data suggest that
      intrastriatal grafts alone are inadequate to promote complete functional
      recovery. A multiple target strategy may restore dopaminergic input to affected
      basal ganglia nuclei and improve outcomes of neural transplantation in
      Parkinson's disease.

PMID- 12405228
TI  - Effects of transcutaneous electrical nerve stimulation (TENS) on non-pain related
      cognitive and behavioural functioning.
AB  - An extensive search through nine electronic bibliographic databases (PubMed,
      Cochrane Library, Web of Science, ERIC, PsychINFO, Psyndex, Cinahl, Biological
      Abstracts, Rehabdata) was performed in order to review the effects of
      Transcutaneous Electrical Nerve Stimulation (TENS) on non-pain related cognitive
      and behavioural functioning. Eight studies were identified on neglect due to
      stroke, six studies on Alzheimer's disease (AD), one study on aging, and two
      studies on coma due to traumatic brain injury. The results of the various studies
      revealed that TENS has a variety of effects. These consist of enhancement of
      somatosensory functioning, visuo-spatial abilities and postural control in
      neglect, improved memory, affective behaviour and rest-activity rhythm in AD and
      acceleration of awakening in coma. Effectiveness of TENS is discussed in relation
      to various stimulation parameters: duration, frequency, pulse width and
      intensity. It is argued that arousal may underlie the beneficial influence of
      TENS in various conditions. Finally, suggestions are offered for future research.

PMID- 12405229
TI  - Central nervous system control of heat acclimation adaptations: an emerging
      paradigm.
AB  - The role of the central nervous system (CNS) in the control of human heat
      acclimation (HA) and HA adaptations at the ultrastructural and biochemical level
      are not well described, although empirical evidence demonstrates that the
      hypothalamus adjusts thermoregulation subsequent to 8-14 days of exercise in a
      hot environment. Therefore, numerous investigations and concepts are presented in
      this paper that 1) describe plausible mechanisms for the development and CNS
      control of physiological adaptations and enhanced performance during heat
      acclimation, 2) include adaptations of neuron morphology and biochemical
      pathways, 3) account for situations in which homeostatic control during exercise
      in heat is inadequate, and 4) describe applications to other phenomena in
      physiology and medicine. The resulting paradigm incorporates information storage,
      temperature-sensitive neurons in the brain, and neural plasticity.

PMID- 12405230
TI  - Issue on maternal mortality.

PMID- 12405232
TI  - Women in medicine: a four-nation comparison.
AB  - OBJECTIVES: to determine the impact of increasing numbers of women in medicine on
      the physician work force in Australia, Canada, England, and the United States.
      METHODS: We collected data on physician work force issues from professional
      organizations and government agencies in each of the 4 nations. RESULTS: Women
      now make up nearly half of all medical students in all 4 countries and 20% to 30%
      of all practicing physicians. Most are concentrated in primary care specialties
      and obstetrics/gynecology and are underrepresented in surgical training programs.
      Women physicians practice largely in urban settings and work 7 to 11 fewer hours
      per week than men do, for lower pay. Twenty percent to 50% of women primary care
      physicians are in part-time practice. CONCLUSIONS: Work force planners should
      anticipate larger decreases in physician full-time equivalencies than previously
      expected because of the increased number of women in practice and their tendency
      to work fewer hours and to be in part-time practice, especially in primary care.
      Responses to these changes vary among the 4 countries. Canada has developed a
      detailed database of work/family issues; England has pioneered flexible training
      schemes and reentry training programs; and Australia has joined consumers,
      physicians, and educators in improving training opportunities and the work
      climate for women. Improved access to surgical and subspecialty fields, training
      and practice settings that provide balance for work/family issues, and improved
      recruitment and retention of women physicians in rural areas will increase the
      contributions of women physicians.

PMID- 12405231
TI  - Differences in income between male and female primary care physicians.
AB  - OBJECTIVES: to determine whether sex differences in income persist among primary
      care physicians in light of the increasing proportion of women entering the
      field. METHODS: We obtained sex- and age-specific self-reported data from the
      American Medical Association's annual survey of physicians to determine the
      annual income, annual income per hours worked, proportion of time in direct
      patient care, and outpatient productivity for family practice physicians, general
      internists, and pediatricians between 1989 and 1998. We compared female to male
      results for respondents in the 36- to 45-year-old age group as well as for the
      age-weighted gender aggregate. RESULTS: Female primary care physicians reported
      lower annual incomes (between 60% and 85% of those of their male counterparts)
      and lower incomes per hours worked (between 71% and 98% of those of their male
      counterparts). The income disparities decreased during the 10 years, at a rate of
      about 1% per year on average. Although the proportion of time female physicians
      spent in direct patient care activities was similar to that of their male
      counterparts, female physicians saw substantially more patients per office hour
      (about 17% more, on average, over time). CONCLUSIONS: Gender inequities persist
      in the incomes of primary care physicians. Although the disparities appear to be
      decreasing, female primary care physicians' increased productivity compared with
      men's suggests that these inequities are perpetuated in more subtle ways and
      warrant immediate examination and remediation.

PMID- 12405233
TI  - Sex differences in physician burnout in the United States and The Netherlands.
AB  - OBJECTIVE: to determine if there are sex differences in physician burnout in the
      Netherlands and, if not, to explore why they are present in the United States.
      METHODS: Separate physician surveys were conducted in the United States (n=2326)
      and the Netherlands (n=1426). Thirty-three percent of US respondents were female
      (adjusted response rate 52%); 18% of Dutch respondents were female (adjusted
      response rate 63%). Standardized mean sex differences (effect sizes) in burnout
      variables were calculated and compared crossnationally. RESULTS: US women
      experienced more burnout than US men did (28% v 21%, p<.01), but the sex
      difference in burnout among Dutch physicians was not significant. Women in both
      countries worked fewer hours than men did (48 v 56 US, 44 v 56 NL, difference in
      effect sizes of sex differences between US and NL, p<.001). Although women in
      both countries described less work control than men, the effect size of the sex
      difference in the United States was more than twice that in the Netherlands (.34
      US v .15 NL, p<.01). Children, home support, and work-home interference were
      comparable between sexes in the United States. CONCLUSIONS: Gender parity in
      physician burnout in the Netherlands may be due to fewer work hours and greater
      work control of women compared to those in the United States.

PMID- 12405235
TI  - Sex differences in career progression and satisfaction in an academic medical
      center.
AB  - Are differences in men's and women's career progression and satisfaction in
      academia related to their sex? This article discusses the variables that
      contribute to sex-based career differentials and the implications both for the
      individual and for society.

PMID- 12405234
TI  - Sex differences in career progress and satisfaction in an academic medical
      center.

PMID- 12405236
TI  - A randomized controlled educational intervention on emergency contraception among
      drugstore personnel in southern Thailand.
AB  - OBJECTIVE: to document the effectiveness of an educational intervention in
      improving knowledge of and practice in dispensing emergency contraception (EC)
      among drugstore personnel in Thailand. METHODS: Sixty of 120 drugstores in Hat
      Yai, a city in Southern Thailand, were randomly selected, and half of them were
      randomly assigned to participate in an educational program. Well-trained "secret"
      shoppers went into each store before the intervention and at 1 and 3 months after
      the program to assess the knowledge of and practice in dispensing EC among the
      drugstore personnel. RESULTS: Dispensing practices at baseline were poor to fair
      and knowledge was fair in both groups. Sellers in the intervention group improved
      significantly in choice of drug, advice provided, and knowledge of the time limit
      for initiating EC, but those in the control group did not. However, proper
      history taking on the time of intercourse and menstrual cycle was poor in both
      groups at all study periods. CONCLUSION: All drugstore personnel should be
      educated on the importance of history taking and on the time limit for initiating
      EC.

PMID- 12405237
TI  - Differences between emergency contraception users in the United States and the
      United Kingdom.
AB  - OBJECTIVES: to characterize emergency contraception (EC) users and clinical trial
      participants in the United States and the United Kingdom, comparing previous EC
      use and awareness, contraceptive history, and experience with EC. METHODS: We
      collected data from all EC seekers (n=5383) at 1 US and 2 UK clinics (9/97-8/98).
      We also collected detailed information from women (n=2157) enrolling in an EC
      trial at the first 3 clinics and 2 additional UK sites (9/97-2/00). RESULTS: More
      US (16%) than UK (4%) women reported additional acts (other than in the last 5
      days) of unprotected sex during the cycle in which they sought EC. Fifty-eight
      percent of UK trial participants had used EC previously compared to 18% in the
      United States. Most participants in both groups used contraception regularly and
      reported needing EC because of condom breaks (67% and 56%). More UK than US
      participants used an ongoing method of contraception (38% v 28%). US women
      reported more side effects at follow-up than UK women did (76% v 59%), although
      similar proportions would take EC again or recommend it. CONCLUSIONS: US and UK
      women in our trial experienced different side effects. Researchers should use
      caution when presenting aggregate results from international multicenter trials.
      In addition, readers should be aware that such aggregate results might mask
      important geographical differences. More research on experience with EC and
      barriers to contraceptive use in the United States is needed.

PMID- 12405238
TI  - Prophylaxis provided to sexual assault victims seen at US emergency departments.
AB  - OBJECTIVE: to report on prophylaxis provided to victims of sexual assault seen at
      hospital emergency departments in the United States. METHODS: Secondary analysis
      was performed on data from the National Hospital Ambulatory Medical Care Survey
      (NHAMCS) for 1994 to 1999. NHAMCS is a national probability sample of patient
      visits to US hospital emergency departments. Cases of sexual assault were
      identified using reason for visit, diagnostic, and injury codes. The medications
      provided for each case were examined. RESULTS: We identified 160 cases of sexual
      assault from 137 822 emergency department visits. None of these victims received
      the full regimen of antibiotics for sexually transmitted infections (STIs)
      recommended by the Centers for Disease Control and Prevention. Antibiotics for
      gonorrhea and chlamydia, 2 of the more frequently diagnosed STIs, were provided
      for only 24.8% of adults and adolescents. No antibiotics were ordered in 62.5% of
      all cases or in 51.3% of cases of patients 12 years and older. Twenty-one percent
      of those eligible received emergency contraception. Human immunodeficiency virus
      prophylaxis was amongthe medications ordered in one 1999 case. Roughly estimated,
      more than 60000 victims of sexual assault who visit US emergency departments
      annually may not be offered antibiotic treatment for the prevention of STIs.
      CONCLUSION: Even when data limitations are taken into account, our results
      suggest that emergency department staff may not be routinely providing antibiotic
      therapy for the prevention of STIs or emergency contraception to victims of
      sexual assault. A comprehensive national standard of care is needed for the
      medical treatment of victims of sexual assault along with more training for
      health care providers.

PMID- 12405239
TI  - Abuse during pregnancy and stress because of abuse during pregnancy and
      birthweight.
AB  - OBJECTIVE: to determine whether there is an independent association between
      physical abuse during pregnancy or stress because of emotional, sexual, or
      physical abuse during pregnancy and birthweight after adjusting for behavioral,
      psychosocial, demographic, and medical variables. METHODS: We conducted a cross
      sectional study of 808 low-income women, age 18 years or older, who delivered
      single infants from pregnancies of 20 weeks or longer. Abuse during the current
      pregnancy was measured as reported events of physical abuse and stress because of
      emotional, sexual, or physical abuse. Multiple regression models were developed
      to estimate the association of low birthweight (LBW) and mean birthweight with
      abuse during pregnancy, adjusting for behavioral, psychosocial, demographic, and
      medical variables. RESULTS: Physical abuse during pregnancy was not associated
      with LBW or with mean birthweight. Women who reported stress because of abuse had
      2.1 times higher odds of LBW (95% CI 1.2, 3.6) than those who did not, and the
      mean birthweight of their infants was 236 g lower (95% CI -371, -102) than those
      of women who reported no stress because of abuse in the adjusted regression
      models. Furthermore, the adjusted mean birthweight for LBW infants of women
      reporting stress because of abuse was significantly lower (-372, 95% CI 595, 
      149) than for LBW infants of women reporting no stress. CONCLUSIONS: Stress
      because of abuse during pregnancy was associated with both LBW and lower mean
      birthweight after adjusting for behavioral, psychosocial, demographic, and
      medical variables.

PMID- 12405240
TI  - Time trends in the HERS secondary prevention trial: much ado about nothing?
AB  - The Heart and Estrogen/progestin Replacement Study was the first randomized,
      double-blind, placebo-controlled study evaluating whether hormone replacement
      therapy (HRT) reduces the incidence of nonfatal myocardial infarction (MI) and
      coronary heart disease (CHD) death. The main conclusion was that HRT provided no
      benefit for secondary prevention. This paper examines the statistical evidence
      for a subsidiary analysis suggesting that the effects of HRT varied over time;
      that the HRT group had more cardiac events in year 1, but fewer by the last years
      of the study. An accurate reading of the HERS results indicates an increased
      incidence of MI and CHD death in the HRT group in year 1, but no evidence that
      the HRT group had fewer CHD events by the end of the study.

PMID- 12405241
TI  - Screening questions to identify women with von Willebrand disease.

PMID- 12405242
TI  - Adolescent menstrual symptoms in a diverse sample of girls.

PMID- 12405243
TI  - Epidemiology of infertility in the west of Tehran in 2000.

PMID- 12405244
TI  - Hepatocellular carcinoma--history, current status and perspectives.

PMID- 12405245
TI  - Infliximab for ulcerative colitis.

PMID- 12405246
TI  - Liver transplantation in Italy. Letter to Italian friends.

PMID- 12405247
TI  - Helicobacter pylori infection and expression of the angiogenic factor platelet
      derived endothelial cell growth factor by pre-neoplastic gastric mucosal lesions
      and gastric carcinoma.
AB  - BACKGROUND: Expression of the angiogenic factor platelet-derived endothelial cell
      growth factor is induced in some gastric carcinomas. Whether angiogenesis is
      induced early in the development of gastric pre-neoplastic lesions and whether
      Helicobacter pylori infection affects platelet-derived endothelial cell growth
      factor expression is not known. AIM: To assess whether chronic gastritis,
      intestinal metaplasia, gastric dysplasia and gastric carcinomas express platelet
      derived endothelial cell growth factor and whether Helicobacter pylori infection
      might affect the expression of platelet-derived endothelial cell growth factor in
      these lesions. PATIENTS AND METHODS: Patients with gastric carcinomas, atrophic
      gastritis with associated intestinal metaplasia, dysplasia and controls without
      infection or carcinoma were studied. RESULTS: Platelet-derived endothelial cell
      growth factor was detected by immunohistochemistry in 9 out 19 gastric carcinomas
      (45%). Only focal immunostaining was detected in intestinal metaplasia adjacent
      to dysplasia and in dysplastic cells. Of the tumours, 90% contained platelet
      derived endothelial cell growth factor-positive interstitial cells. A significant
      correlation was found between active Helicobacter pylori infection and a larger
      number of platelet-derived endothelial cell growth factor-positive interstitial
      cells in areas of intestinal metaplasia (p<0.05). CONCLUSION: Helicobacter pylori
      infection does not influence the expression of platelet-derived endothelial cell
      growth factor, once gastric cancer has developed. However, Helicobacter pylori
      infection may increase the extension of expression of platelet-derived
      endothelial cell growth factor by infiltrating interstitial cells in premalignant
      lesions, such as intestinal metaplasia, which may help create a favourable
      environment for tumour development. This may possibly be due to non-specific
      increase in recruitment of inflammatory cells caused by Helicobacter pylori
      infection. Further studies, with a larger number of samples, are now needed in
      order to confirm this finding.

PMID- 12405248
TI  - Anti-tumour necrosis factor alpha (infliximab) in the treatment of severe
      ulcerative colitis: result of an open study on 13 patients.
AB  - BACKGROUND: Conventional treatment options for patients with severe steroid
      refractory ulcerative colitis include intravenous cyclosporine, which is
      frequently burdened by toxicity, or colectomy. Preliminary data suggest a benefit
      from anti-tumour necrosis factor alpha (Infliximab) therapy in patients with
      steroid refractory ulcerative colitis. AIM: To evaluate the efficacy of
      Infliximab in the treatment of severe ulcerative colitis refractory to
      conventional therapy PATIENTS AND METHODS: A series of 13 patients with severe
      ulcerative colitis, refractory to therapy with methyl-prednisolone, 60 mg daily
      for seven or more days, were treated with a single intravenous infusion of
      Infliximab 5 mg/kg. RESULTS AND CONCLUSIONS: Of these 13 patients, 10 (77%) had a
      clinical response to therapy defined by a clinical activity index 10 on two
      consecutive days. In 2 patients (15%) total colectomy was necessary on account of
      clinical worsening whilst one patient refused surgery and was lost to follow-up.
      All patients who responded showed very rapid clinical improvement, within 2 to 3
      days of infusion. Infusion with Infliximab produced no significant adverse
      events. The mean time of follow-up was 10.1 months (range 5-12; during this time,
      9 out of 10 patients (90%) maintained clinical remission and were able to
      discontinue corticosteroid therapy. Infliximab appears to be an effective agent
      for inducing long-standing remission in refractory patients with severe
      ulcerative colitis.

PMID- 12405249
TI  - Infliximab for treatment of steroid-refractory ulcerative colitis.
AB  - BACKGROUND: Success achieved in two subtypes of Crohn's disease has persuaded a
      few investigators to experiment the monoclonal anti-tumour necrosis factor
      antibody infliximab in the treatment of ulcerative colitis. So far, however, the
      results (achieved in some 30 steroid-refractory patients included in two
      independent full-papers) indicate a rate of initial response of 50% and of
      remission of 25%. AIMS: To analyse data of an open trial conducted on consecutive
      steroid-refractory severely ill patients admitted to our referral Unit. PATIENTS
      AND METHODS: In 9 months, infliximab was given to 8 patients (4 male, 4 female
      aged 20-60 years) with uncontrolled ulcerative colitis of whom 6 were non
      responders to parenteral steroids. All received the first infliximab dose as an
      intravenous infusion of 5 mg/kg. RESULTS: Of the 8, 4 (50%) did not respond to
      the first injection and were submitted to urgent colectomy; the other four
      responded clinically. Two have maintained clinical remission for 7 months,
      without the need for steroids; both have received daily azathioprine at 2 mg/kg,
      and only one has received two further infliximab injections. Of the other two,
      one received a second injection at week 5, despite this relapsed, and underwent
      elective colectomy at that time; the other relapsed at 6 months and showed a
      partial response to a repeat infliximab infusion. Thus, the rate of sustained
      response is 2/8 (25%) in this study. CONCLUSION: These results, achieved in an
      open uncontrolled fashion, seem to reflect those of other independent studies. In
      our opinion, these findings warrant an in-depth reappraisal of the indication to
      use infliximab as rescue treatment for refractory ulcerative colitis.

PMID- 12405250
TI  - Diverticular disease as a risk factor for sigmoid colon adenomas.
AB  - BACKGROUND: Diverticular disease and colorectal neoplasia share similar
      epidemiological features and risk factors. AIM: To evaluate a possible
      association between diverticular disease and both adenomas and colorectal cancer
      in patients undergoing total colonoscopy. METHODS: Overall, 630 consecutive
      patients were recruited from the 3 Units. Inclusion criteria were age over 45
      years and the performance of total colonoscopy. Demographic and clinical data
      were recorded. Adenomas were defined as advanced when their size was >1 cm in
      diameter, and/or the percentage of the villous component was >30% and/or high
      grade dysplasia was present. RESULTS: At endoscopy, 291 (47%) out of 630 patients
      presented evidence of diverticular disease. Adenomas were found in 92 (31.9%)
      patients with diverticular disease and in 98 (28.9%) patients without [p=ns]. The
      prevalence of adenomas located in the sigmoid colon was significantly higher in
      patients with diverticula than in controls (64.1% vs 41.8%; p<0.05). Similarly,
      the detection of advanced adenomas located in the sigmoid colon was more likely
      in patients with diverticula than in controls (59.6% vs 37.5%; p<0.05).
      Colorectal cancer prevalence was similar in patients with and without diverticula
      (8.3% vs 7.1%; p=ns), and no difference was detected regarding site, between the
      two groups. CONCLUSIONS: Patients with diverticular disease have a higher risk of
      harbouring adenomas and advanced adenomas in the sigmoid colon. This observation
      should be taken into account in screening and surveillance programmes for
      colorectal neoplasia.

PMID- 12405251
TI  - Liver transplantation: the Italian experience.
AB  - BACKGROUND: Liver transplantation is the standard treatment for patients with end
      stage liver disease no longer responsive to conventional medical treatment AIMS:
      To report the long-term experience of liver transplantation in Italy. PATIENTS
      AND METHODS: Data were obtained retrospectively by means of a multiple-item form
      collected from 15 Italian liver transplant centres. The filing centre was
      centralized. RESULTS: A total of 3323 liver transplants were performed on 3026
      patients, with a cumulative proportional survival of 72.4%. Three, 5 and 10
      years' patient survival rates were 72.3%, 68.8% and 61.3%, respectively. The most
      common indication for liver transplantation were hepatitis B virus (+/- hepatitis
      D virus)- and hepatitis C virus-related cirrhosis (59.4%). Excellent survival
      rates were observed particularly in controversial indications, such as alcoholic
      cirrhosis, hepatitis B virus-related cirrhosis and hepatocellular carcinoma.
      Retransplantation was required in 8.9% of the cases. The overall prevalence of
      acute cellular rejection episodes was 43.5%. In our study population, primary non
      function and disease recurrence were the most common causes of graft failure
      (28.7% and 25.4%, respectively). Infections and/or sepsis were the most common
      causes of death after transplantation (42%). CONCLUSION: This study confirms that
      patients with controversial indications to liver transplantation such as
      alcoholic cirrhosis, HBV-related cirrhosis and hepatocellular carcinoma can
      achieve excellent survival when properly selected.

PMID- 12405252
TI  - The Italian experience on paediatric liver transplantation: 1988-1999 report.
AB  - BACKGROUND: Liver transplantation is the treatment of choice for end-stage liver
      disease in both adult and paediatric patients. The Italian experience in
      paediatric liver transplantation during the period 1988-1999 is reported herein.
      PATIENTS AND METHODS: This report concerns 228 liver transplantations performed
      in 207 patients (100 male, 107 female, mean age 5.1+/-4.4 years) in 11 Italian
      centres. The mean waiting time on the transplantation list was 6.1+/-8.9 months
      and the main indications for the procedure were biliary atresia, inborn metabolic
      disorders, liver cirrhosis, liver neoplasms, Alagille syndrome, and fulminant
      hepatic failure. RESULTS: The cumulative survival rate was 77%, 76%, 73%, and 71%
      at 1, 3, 5, and 7 years. The overall prevalence of acute rejection was 54%.
      Survival was significantly affected by re-transplantation (p=0.0002), by United
      Network for Organ Sharing 4 status at transplantation (p=0.016), and, among the
      indications for the procedure, by fulminant hepatic failure (p=0.004). Fifty
      patients (24%) died during the observation period. The main causes of death were
      primary non-function of the graft and sepsis CONCLUSIONS: This study shows that
      liver transplantation in paediatric age, in Italy, is an effective procedure
      providing a 5-year survival rate comparable to that attained in the largest
      published series.

PMID- 12405253
TI  - Anti-hepatitis A virus seroprevalence and seroconversion in a cohort of patients
      with chronic viral hepatitis.
AB  - BACKGROUND: Patients with chronic hepatitis C infected by hepatitis A virus have
      a substantial risk of fulminant hepatitis or death, while the course of hepatitis
      A virus is uncomplicated in most subjects with chronic hepatitis B. AIM: To
      evaluate the prevalence of anti-hepatitis A virus antibodies and the incidence of
      hepatitis A virus seroconversion in a nationwide sample of 530 patients with
      chronic hepatitis B and/or hepatitis C infection initially susceptible to this
      infection after a follow-up of some years. RESULTS: The overall anti-hepatitis A
      virus prevalence was 85.7%, with no difference between males and females. By the
      age of 50 years, almost all patients were found to have been exposed to hepatitis
      A virus. After a mean follow-up period of 76 months the overall anti-hepatitis A
      virus seroconversion rate in the 76 initially susceptible individuals was 1.2 per
      100 person/years. However, it was 0.3 per 100 person/years in those hepatitis B
      surface antigen positive but 3.36 per 100 person/years in those anti-hepatitis C
      virus positive. None of the seroconverters was affected by a clinically evident
      disease or showed deterioration of underlying chronic liver disease. CONCLUSIONS:
      The present study shows that Italian patients >50 years of age with chronic liver
      disease have already been exposed to hepatitis A virus suggesting that anti
      hepatitis A virus screening is not advisable in these subjects.

PMID- 12405254
TI  - Dysphagia in Crohn's disease: a diagnostic challenge.
AB  - Dysphagia is a rare manifestation in a patient with Crohn's disease. We report on
      the case of a patient with long-standing Crohn's disease who developed
      progressive dysphagia over 3 years. Endoscopy showed minimal distal oesophagitis
      with non-specific histological findings. Further investigation with
      cinematography, barium swallow and manometry established an achalasia-like
      motility disorder. Biopsies obtained from the oesophagus were non-specific.
      Balloon dilatation was performed. Initial success was followed by recurrent
      dysphagia. At repeat endoscopy, an oesophageal fistula was detected. An attempt
      at conservative medical management failed and oesophagectomy was successfully
      performed. Pathology results of the resected specimen confirmed the suspected
      diagnosis of oesophageal Crohn's disease. Even if achalasia is suspected in a
      Crohn's patient, it should be taken into consideration that the motility disorder
      could be the result of a transmural inflammation with or without fibrosis caused
      by Crohn's disease.

PMID- 12405255
TI  - Thrombocytopenic purpura: an unusual complication of eradication therapy for
      Helicobacter pylori.
AB  - A case of severe thrombocytopenic purpura is described in a 56-year-old female
      following Helicobacter pylori eradication therapy consisting of omeprazole,
      clarithromycin and amoxycillin. The pathogenesis of this patient's
      thrombocytopenia appears to be quite complex. Whilst it was clearly triggered by
      antibiotic treatment, a direct toxic mechanism does not provide an adequate
      explanation for the severity and lack of responsiveness to drug treatment. It is
      tempting to suggest that an immunological mechanism and splenomegaly were also
      involved.

PMID- 12405256
TI  - Molecular insights into gastrointestinal neuroendocrine tumours: importance and
      recent advances.
AB  - A subset of gastrointestinal neuroendocrine tumours (carcinoids and pancreatic
      endocrine tumours) show aggressive growth. Early identification of this subset is
      essential for management; however, clinical, laboratory and histologic features
      frequently fail to achieve this. Currently, there is an increased understanding
      of the molecular pathogenesis/changes in neuroendocrine tumours and this may
      identify important prognostic factors and possibly, new treatments. Recent
      findings and progress in this area are briefly reviewed in this article.

PMID- 12405257
TI  - Haemobilia and gallbladder carcinoma.

PMID- 12405258
TI  - What a coeliac patient must not eat.

PMID- 12405259
TI  - Development of a simple and sensitive technique for detection of point mutations
      in the K-ras oncogene.
AB  - We sought to develop a simple and sensitive method based on mutant allele
      specific amplification (MASA) for the detection of point mutations in the k-ras
      oncogene in blood samples. We used MASA and three nested MASA methods to detect a
      point mutation (GGT-->GAT) in rat DHD cells at codon 12 of exon 1 of the k-ras
      gene. MASA allowed us to detect one k-ras mutated cell on a background of 10(7)
      normal cells. The third nested-MASA (nested-MASA.c) method that we developed
      allowed us to detect one mutated cell among 10(10) normal cells. Our methods
      should allow the detection of small amounts of mutant k-ras DNA in tissue, serum,
      and plasma, combining speed with efficiency and specificity.

PMID- 12405260
TI  - Brn-3a, a neuronal transcription factor of the POU gene family: indications for
      its involvement in cancer and angiogenesis.
AB  - Brn-3a, a member of the POU gene family (so-called because of the similarity with
      the group of transcription factors Pit, Oct, and Unc), was found in neuronal
      cells engaged in the transcription activity of the p1 and p2 promoters of the
      most powerful antiapoptotic gene, namely, Bcl-2. The alternative splicing of Brn
      3a mRNA produces two molecular forms: a longer, Bcl-2 transactivating form, and a
      shorter inactive form, lacking 84 AA in the aminoterminus. In neuronal cells,
      following Brn-3a gene transfection and superexpression, an increase of 30 fold of
      the Bcl-2 protein occurs, leading to apoptosis protection. However, recent works
      demonstrate that Brn-3a expression is not restricted to neuronal cells, as its
      activity was detected also in cancer cells of non-neuronal nature. Looking for
      mechanisms linking Brn-3a to carcinogenesis, we discuss the role of this
      transcription factor in influencing Bcl-2/p53 antagonism and Bcl-2/VEGF induction
      of tumor angiogenesis, concluding this review with a proposal for the oncogenic
      nature of Brn-3a.

PMID- 12405261
TI  - The convergence of hormone regulation and cell cycle in prostate physiology and
      prostate tumorigenesis.
AB  - Despite the intense research focused on prostate cancer, it remains the most
      frequently diagnosed malignancy in men over 40-yr-of-age, and the second most
      frequent cause of cancer-related deaths in men in the United States (1). In 1990,
      the National Cancer Institute convened 50 experts and leaders from various
      disciplines in the prostate cancer field to discuss research directions that
      would help elucidate the molecular basis of this disease and reduce the incidence
      and mortality of prostate cancer (2). Critical issues identified at this meeting
      included the role of androgens and the regulation of cell cycle in prostate
      tumorigenesis and its progression to androgen-independence. Hormones and cell
      cycle clearly play important roles in normal and cancerous prostate physiology;
      however, little information has emerged that clearly delineates their function in
      the etiology of prostate cancer. Some of the mutational events that occur during
      prostate tumorigenesis and its progression to androgen-independence involve
      alterations to normal growth, developmental and apoptotic programs regulated by
      androgen, and the cell cycle. As such, the delineation of events by which
      prostate cancer cells circumvent these regulatory mechanisms will be central to
      our understanding of prostate tumorigenesis and to the development of new
      modalities to treat this disease. This article is then intended to summarize the
      functional convergence of androgen regulation and cell cycle in normal prostate
      physiology and prostate tumorigenesis.

PMID- 12405262
TI  - Current perspectives in cancer proteomics.
AB  - Proteome technology has been used widely in cancer research and is a useful tool
      for the identification of new cancer markers and treatment-related changes in
      cancer. This article details the use of proteome technology in cancer research,
      and laboratory-based and clinical cancer research studies are described. New
      developments in proteome technology that enable higher sample-throughput are
      evaluated and methods for enhancing conventional proteome analysis (based on two
      dimensional electrophoresis) discussed. The need to couple laboratory-based
      proteomics research with clinically relevant models of the disease is also
      considered, as this remains the next main challenge of cancer-related proteome
      research.

PMID- 12405263
TI  - Gene transfer to the vasculature: historical perspective and implication for
      future research objectives.
AB  - Cardiovascular diseases are a major cause of fatality, disability, and economic
      burden in Western civilization. Although the pharmaceutical industry has
      delivered a plethora of drugs for treatment of diverse cardiovascular complaints,
      there remain many conditions for which pharmacological regimens are either
      nonexistent or largely ineffective. In contrast, remarkable progress has been
      made in the field of vascular gene transfer in the last decade. The vast majority
      of studies are preclinical, although a number of high profile vascular gene
      therapy clinical trials are in progress. In principle, vascular gene therapy
      represents an unprecedented opportunity to treat a host of cardiovascular
      diseases in humans although many scientific, clinical, and ethical obstacles
      remain. Here we discuss the rapid progress in preclinical vascular gene therapy,
      highlight the most appropriate gene delivery vectors, and discuss the advances
      toward the ultimate goal of an efficient and safe gene therapy for diverse
      cardiovascular diseases.

PMID- 12405267
TI  - Sepsis recognition--a greater role for nursing?

PMID- 12405265
TI  - Airway inflammation and remodeling in asthma: current concepts.
AB  - Asthma is a chronic inflammatory disorder of the airways interacting with altered
      structure and function of the formed elements including smooth muscle. While
      atopy and polarization of the airway T-cell response toward a Th-2 phenotype are
      important factors in asthma pathogenesis, there is increasing realization that
      remodeling events are also important. Evidence is presented that inflammation and
      altered airway structure in asthma interact through the epithelium and underlying
      mesenchyme. As in other chronic inflammatory disorders, a dynamic interplay
      between mediators, cytokines, and growth factors provides a broader base on which
      to identify novel preventative and therapeutic strategies in asthma.

PMID- 12405266
TI  - Genetically engineered intracellular single-chain antibodies in gene therapy.
AB  - The delineation of the molecular basis of cancer allows for the possibility of
      specific intervention at the molecular level for therapeutic purposes. To a large
      extent, the genetic lesions associated with malignant transformation and
      progression are being identified. Thus, not only in the context of inherited
      genetic diseases, but also for many acquired disorders, characteristic
      aberrancies of patterns of gene expression may be precisely defined. It is
      therefore clear that elucidation of the genetic basis of inherited and acquired
      diseases has rendered gene therapy both a novel and rational approach for these
      disorders. To this end, three main strategies have been developed: mutation
      compensation, molecular chemotherapy, and genetic immunopotentiation. Mutation
      compensation relies on strategies to ablate activated oncogenes at the level of
      DNA (triplex), messenger RNA (antisense or ribozyme), or protein (intracellular
      single-chain antibodies), and augment tumor suppressor gene expression. This
      article will review in detail practical procedures to generate a single-chain
      intracellular antibody (scFv). We will emphasize in this article the different
      steps in our protocol that we have employed to develop scFvs to a variety of
      target proteins.

PMID- 12405264
TI  - Copper-dependent functions for the prion protein.
AB  - Prion diseases such as bovine spongiform encephalopathy and Creutzfeldt-Jakob
      disease are fatal neurodegenerative diseases. These diseases are characterized by
      the conversion of a normal cellular protein, the prion protein, to an abnormal
      isoform that is thought to be responsible for both pathogenesis in the disease
      and the infectious nature of the disease agent. Understanding the biology and
      metabolism of the normal prion protein is therefore important for understanding
      the nature of these diseases. This review presents evidence for the normal
      function of the cellular prion protein, which appears to depend on its ability to
      bind copper (Cu). There is now considerable evidence that the prion protein is an
      antioxidant. Once the prion protein binds Cu, it may have an activity like that
      of a superoxide dismutase. Conversion of the prion protein to an abnormal isoform
      might lead to a loss of antioxidant protection that could be responsible for
      neurodegeneration in the disease.

PMID- 12405269
TI  - Witnessed resuscitation in critical care: the case against.
AB  - The aim of this discussion is to raise awareness of the negative aspects of
      witnessed resuscitation. The historical precedents associated with the
      introduction of the concept are outlined. The disadvantages of introducing
      witnessed resuscitation are delineated. These include issues of human dignity,
      personal privacy and the provision of adequately trained staff to help relatives
      cope with the emotional trauma the experience of being a witness may invoke. The
      paper concludes by calling for more widespread debate and research into the
      efficacy of introducing such policies into practice.

PMID- 12405268
TI  - Will he get back to normal? Survival and functional status after intensive care
      therapy.
AB  - The study aim was to address healthcare workers' and patients' questions about
      the likely level of recovery at 6 months of patients admitted to an Australian
      intensive care unit (ICU). Ninety-three consecutive, eligible adults were
      identified and followed prospectively. Severity of illness on admission was
      assessed using Acute Physiological and Chronic Health Evaluation (APACHE II),
      while functional status at 6 months was evaluated using the Sickness Impact
      Profile (SIP). Cumulative mortality was 25%. Admission severity of illness was
      associated with survival at 6 months (P < or = 0.001). Fifty-one (78%) of the 70
      survivors were interviewed. Admission severity of illness scores correlated with
      functional status at 6 months (r = 0.34, P = 0.01), a finding reported in only
      one other study. More than half of those interviewed had returned to near pre
      admission functional status. Those with poor functional status included high
      proportions of people with chronic illness and head injury. Overall, physical
      recovery was more complete than psychosocial recovery. The findings provide
      useful information for addressing questions relating to physical and psychosocial
      recovery, appetite, sleep patterns and return to work post discharge.

PMID- 12405270
TI  - Admissions for critically ill children: where and why?
AB  - INTRODUCTION: Planning services for critically ill children requires
      identification of overall critical care activity as well as an assessment of
      population needs. METHOD AND OBJECTIVES: This prospective needs assessment took a
      census approach to estimating population-based admission rates for paediatric
      critical care irrespective of where care was provided. A survey form was
      completed for every child in the study population for all of their admissions.
      CRITERIA: The need for tracheal intubation was used as a proxy for defining need
      for intensive care in this study. Critical illness was defined by clinical
      criteria adapted from the Advanced Paediatric Life Support Guidelines. STUDY
      POPULATION: All children under 17 years resident in south-east England (Thames
      regions) who required care for a critical illness in any inpatient setting
      between 1 December 1996 and 30 November 1997. Critical illness was the presence
      of acute body-system or multi-system failure. RESULTS: A wide variation in the
      rates of critical care admission to different types of care settings was reported
      ranging from 1.2 admissions per 1000 resident children per year for PIC units
      (general and cardiothoracic units) to 0.02 admissions per 1000 children per year
      for children admitted from the community to neonatal units. The age of children
      and their rates of admission were directly related to the type of ward or unit
      where children received care. Tracheal intubation occurred in all care settings.
      The proportion of intubated children transferred to paediatric intensive care
      units (PICUs) or paediatric cardiothoracic intensive care units (PCICUs) varied
      according to the type of referring unit. The proportion of episodes involving
      tracheal intubation where the child was not transferred to a PICU or PCICU was
      52% for children in stand-alone neurosurgical units, 41% for those in adult
      intensive care units (AICUs), and 4% for those in children's wards. CONCLUSIONS:
      This baseline study shows a significant number of critically ill children who are
      never cared for in PIC units. With national changes in UK policy to regionalise
      care for these children, monitoring care in all locations by cause of admission
      remains important. While the data were collected in 1997, the findings from this
      study remain relevant and provide the basis for planning regional critical care
      services for children. Results are also relevant to other geographical areas in
      that measuring the use of services for critically ill children must go beyond
      documenting admission to ICUs for children and adults. All settings for critical
      care must be identified, the activity documented, and the use of services
      measured against existing resources. Clear clinical criteria are needed to
      identify children who can be cared for appropriately on high dependency units.

PMID- 12405271
TI  - From ward-based critical care to educational curriculum 1: a literature review.
AB  - There has been recent recognition in the literature, and a longer standing
      awareness amongst clinicians, that critically ill patients are to be found
      outside of intensive care units. These patients are not always well managed and
      some have concluded that their care is 'suboptimal' [Br. Med. J. 316 (1998) 1853]
      and that they die of preventable clinical problems [Extremes of Age: the 1999
      Report of the National Confidential Enquiry into Perioperative Deaths (1999)
      NCEPOD]. Whilst the cause of this situation in the NHS probably involves a
      complex interplay of factors including failures in management, policy and the
      evidence/information base for practice, education failures have also been blamed.
      In response the government has mandated formal critical care education for ward
      nurses [Comprehensive Critical Care: a Review of Adult Critical Care Services
      (2000) Department of Health]. In this two-part paper, the literature around
      education for ward-based critical care is examined (Part 1) prior to a report of
      the findings (Part 2) of a case study exploring the everyday practices, context
      and culture of an acute surgical ward where seriously ill patients were cared for
      prior to the introduction of a critical care outreach service (Part 2).
      Implications for practice, education and future research are discussed.

PMID- 12405273
TI  - A critical analysis of the philosophy, knowledge and theory underpinning mouth
      care practice for the intensive care unit patient.
AB  - In the provision of high quality mouth care practice for the intensive care unit
      (ICU) patient, the nurse draws on philosophy, knowledge and theory. The
      complexity of mouth care for the ICU patient is compounded by their medical or
      surgical condition and the psychological effects of mouth care problems.
      Effective mouth care practice includes proactive prediction and prevention of
      complications, and prompt and skilled intervention in the problems arising.
      Therefore, critical analysis of the philosophy, knowledge and theory relevant to
      mouth care practice is important. The philosophical approach to mouth care
      requires the nurse to view the practice from different perspectives. Nursing
      knowledge has inextricable links with nursing practice that challenges the nurse
      in her/his everyday work. This application of knowledge to practice is
      conceptualised as ways of thinking, which is also based on what the nurse might
      know. Therefore, the judicious use of theory and the necessary skills are
      essential to provide high quality and effective mouth care practice. The purpose
      of this paper is to illustrate the ways in which philosophy, knowledge and theory
      all have an impact on the practice of mouth care for the ICU patient.

PMID- 12405272
TI  - The perceived function of health care assistants in intensive care: nurses views.
AB  - The purpose of this study was to discover nurses' views on the function of Health
      Care Assistants (HCA) in Intensive Care (ICU). A questionnaire that utilised open
      ended questions was distributed to all registered nurses working on the
      researchers ICU. Questions were based on issues including; general views on the
      utilisation of HCA, the transfer of aspects of nursing workload, education and
      training. A response rate of 96% was achieved. The results indicated strong
      support for the introduction of HCA on the researchers ICU but conflicting
      opinion in regards to the function they should serve. In light of the results,
      this study seeks to open the debate concerning HCA' suitability for employment in
      the researchers ICU. Recommendations are also made for practice and further
      research.

PMID- 12405274
TI  - The glitazones: a new treatment for type 2 diabetes mellitus.
AB  - The glitazones are a new class of anti-diabetic drugs that act by improving
      sensitivity to insulin and are indicated in the treatment of type 2 diabetes. The
      glitazones have effects on carbohydrate and lipid metabolism and hold the promise
      of being able to influence the many components of the insulin resistance syndrome
      seen in type 2 diabetes. It is possible that the glitazones may be able to
      prevent or delay the cardiovascular disease which accompanies type 2 diabetes,
      long-term studies are required to determine if this is the case. In addition to
      drug treatment patients with type 2 diabetes should be strongly encouraged to
      make life style changes which will improve glycaemic control such as weight
      reduction and increase exercise.

PMID- 12405275
TI  - Chest x-ray quiz.

PMID- 12405276
TI  - Developing practice: individual and organisational responsibilities.

PMID- 12405277
TI  - Behaviour of older people admitted for residential respite care.
AB  - The aim of this pilot study was to determine whether residential respite care is
      used because of disruptive behaviour displayed by older people. The specific
      objectives were to 1) characterise older people being admitted for residential
      respite care, 2) obtain a preliminary estimate of the proportion of older people
      in residential respite care because of disruptive behaviour, and, 3) examine the
      relationship between residential respite care and disruptive behaviour. A
      quantitative approach using a cross-sectional survey was employed. The respite
      recipients were 35 older people with a mean age of 81.5 years (range 67-96
      years). The respite recipients had been admitted for residential respite care to
      aged care hostels and nursing homes in a provincial city and its surrounding
      rural area. Nurses rated disruptive behaviour using the Dementia Behavior
      Disturbance Scale (DBDS). Additional reliability data for the DBDS are provided.
      The study found that the largest specific group of residential respite care users
      were widows (31.4%) who lived alone in their own home. The reason for over half
      (51.4%) of the residential respite admissions was to give a carer a 'break' from
      the older person. Although a large proportion (80%) of respite recipients were
      rated as having disruptive behaviour, the proportion of admissions because of
      disruptive behaviour was much less (28.6%). People with dementia (37.1%) scored
      significantly higher than people without dementia on the DBDS [F (1,33)=15.57,
      p<0.001]. Older people with dementia were prescribed a greater number of
      psychotropic medications. It is concluded that despite residential respite care
      being offered primarily to assist with carer burden it is not being used mainly
      for older people whose behaviour is problematic for the carers.

PMID- 12405278
TI  - Health care workers' knowledge of hepatitis C and attitudes towards patients with
      hepatitis C: a pilot study.
AB  - A questionnaire was developed to determine health care workers' (HCWs) knowledge
      of, and attitudes towards, hepatitis C in order to inform an education strategy
      to prevent discrimination towards hepatitis C-positive patients. The study's aim
      was to determine the questionnaire's reliability and validity. Fifty-eight of 100
      questionnaires distributed to HCWs were returned. The internal consistency of the
      scale was 0.7 following the removal of one item. The face validity of the
      instrument was high. It was found that a number of demographic variables impacted
      on HCWs' level of knowledge regarding hepatitis C and their willingness to care
      for patients with hepatitis C. Further research with a larger sample size is
      needed to clarify these issues.

PMID- 12405279
TI  - Nursing and health care in Sweden.
AB  - Sweden, one of the Nordic countries, has a long history of social justice and
      equality of access to health care. Nursing plays an important role in this and
      nursing education is of a high standard. The aim of this paper is to describe
      Sweden's health system and nursing within it, thereby giving Australian nurses
      information which may generate an interest in, and provide background for,
      collaborative work. It is part of a series initiated by the first author who
      visited Sweden, Iceland and England in 2000 under the auspices of a Churchill
      Fellowship, and who has returned to Sweden and England to continue work begun
      during the Fellowship. Sweden's health service is characterised by an ethic of
      egalitarianism and high standards; primary health care plays a large role and
      tertiary health care is easily accessible. Nursing in Sweden is of a high
      standard, with devolvement of responsibility and decision-making to those working
      in the wards and units. Nursing education has been influenced by the historical
      development of nursing in Europe and today, Swedish nurses enjoy a high standard
      of university education with government support readily available to make
      specialist education accessible. Because of the similarities in both the
      cultures, and nursing, in Australia and Sweden, Australian nurses would find
      Sweden a wonderful country in which to implement cross-cultural, collaborative
      work. This paper provides

PMID- 12405280
TI  - Mentoring: improving transition to practice.
AB  - Nurse graduates indicate the transition from student of nursing to registered
      nurse (RN) is a difficult conversion. This impending change of role and
      accompanying higher expectations placed upon newly graduating RNs causes concern
      for students as their Bachelor of Nursing program nears completion. A career
      mentor scheme is suggested as a way to better prepare final year students for
      this transition. Evaluations indicate the positive impact the scheme has made on
      both mentors and mentees as it has enhanced their career development.

PMID- 12405281
TI  - The clinical environment: a source of stress for undergraduate nurses.
AB  - The clinical area is an important learning environment for undergraduate nursing
      students. Unfortunately, it can also be a source of significant stress and
      anxiety for students and there are a number of reasons for this. Much can be done
      to help alleviate this stress and create a positive learning environment for
      students. This paper explores the literature to ascertain the common sources of
      stress for undergraduate students in the clinical area. It also reviews
      strategies for improving the quality of the learning experience.

PMID- 12405282
TI  - The role of a psychiatric consultation liaison nurse in a general hospital: a
      case study approach.
AB  - Growing support for the role of the psychiatric consultation-liaison nurse in
      assisting general nurses in caring for patients experiencing mental health
      problems in the general hospital environment is evident from the relevant
      literature. However, there remains a paucity of research which examines the
      process of this nursing role or its impact on outcomes for nurses and patients.
      This paper seeks to contribute to the literature in articulating the role of the
      psychiatric consultation-liaison nurse using a case study approach to describe
      the role of the nurse in assessing the needs of, and, planning and providing care
      to two general hospital patients experiencing mental health problems, and the
      general nurses caring for them.

PMID- 12405283
TI  - Nucleoside diphosphate kinase (NDPK/NM23) and the waltz with multiple partners:
      possible consequences in tumor metastasis.
AB  - Tumor metastasis is responsible for a high degree of mortality in cancer
      patients. One of the genes involved in tumor metastasis is NM23. At present,
      eight human isoforms, transcribed from different NM23 genes, have been detected.
      The gene products have been identified as nucleoside diphosphate kinases (NDPKs),
      most of which catalyse the transfer of the gamma-phosphate of a (deoxy)nucleoside
      triphosphate to a (deoxy)nucleoside diphosphate. However, the function of NDPK
      isoforms involved in tumor metastasis cannot be explained on the basis of their
      phosphotransferase activity alone. At present, several other properties, like
      transcriptional regulation and protein kinase activity, have been assigned to
      these proteins. Moreover, it has also been shown that NDPKs interact with several
      other proteins, and binding partners of NDPKs are identified at an increasing
      rate. Accumulating evidence indicates that protein-protein interactions modulate
      the molecular action of NDPKs. In this review we provide a brief overview of how
      NDPKs are correlated with cancer, and discuss when and how the activities
      assigned to NDPKs may affect metastasis, with special emphasis on the role of
      protein-NDPK interactions in this process.

PMID- 12405284
TI  - Establishment of human osteosarcoma cell lines with high metastatic potential to
      lungs and their utilities for therapeutic studies on metastatic osteosarcoma.
AB  - Relevant animal models for metastasis of osteosarcoma is needed to understand the
      biology and to develop the treatment modality of metastasis of human
      osteosarcoma. Therefore, we screened six human osteosarcoma cell lines for
      metastatic ability in nude mice. The HuO9 cell line was identified as being
      metastatic to the lung after intravenous injection. We established two sublines,
      HuO9-M112 and HuO9-M132, with high metastatic potential to the lung from the
      parental HuO9 cells by in vivo selection. There were no differences between these
      two sublines and the parental cells in the growth rate in vitro and the
      tumorigenicity after subcutaneous injection in nude mice, however, mice injected
      with the metastatic sublines became moribund earlier than mice injected with the
      parental HuO9 cells did. Thus, adriamycin (ADR) and recombinant interleukin-12
      (IL-12) were administered to mice injected with the HuO9-M112 subline to suppress
      experimental lung metastases. Production of lung colonies was significantly
      suppressed and the prognoses of mice were significantly improved by both ADR and
      IL-12 treatments. These results indicate that both ADR and IL-12 are effective
      agents against pulmonary metastatic osteosarcoma, and that these sublines are
      useful for studies on the biological behavior and treatment of pulmonary
      metastatic osteosarcoma.

PMID- 12405285
TI  - Investigations into the potential role of aberrant N-acetylgalactosamine glycans
      in tumour cell interactions with basement membrane components.
AB  - The expression of the aberrant N-acetylgalactosamine (GalNAc) glycoconjugates,
      detected by binding of the lectin from Helix pomatia (HPA) is reported to be
      associated with metastatic competence and poor prognosis in a range of human
      adenocarcinomas, but the functional significance of the glycoconjugates in
      metastatic mechanisms is unknown. We have employed seven cell lines derived from
      normal breast epithelium, primary breast cancer and breast cancer metastases
      which stably express varying levels of HPA-binding glycoconjugates consistent
      with their derivation and phenotype. These cell lines have been thoroughly
      characterised and express identical profiles of HPA-binding glycoconjugates as
      tumour cells derived from clinical samples. Their ability to adhere to, and
      invade through, basement membrane components was investigated in a matrigel assay
      system, and the functional role of the aberrant GalNAc glycans assessed by
      competitive inhibition experiments using HPA. The behaviour of the cell lines in
      these assay systems was entirely consistent with their derivation and phenotype,
      but there was no evidence that the glycoconjugates of interest were functionally
      involved in adhesion or invasion mechanisms. Research in our laboratory is
      ongoing to seek a functional role for the HPA-binding glycoconjugates in other
      aspects of the metastatic cascade.

PMID- 12405286
TI  - Flow cytometry correlates with RT-PCR for detection of spiked but not circulating
      colorectal cancer cells.
AB  - The aim of this study was to determine whether flow cytometry (FACS) could detect
      spiked or circulating colorectal cancer cells. A flow cytometric assay was
      developed and its sensitivity compared with the reverse transcription polymerase
      chain reaction (RT-PCR), using carcinoembryonic antigen (CEA) and cytokeratin
      (CK) 20 mRNA as target markers. Sensitivity limits for RT-PCR and flow cytometry
      (FACS) were established using spiked blood, and pre-operative blood samples from
      20 colorectal cancer patients and 16 healthy no-cancer controls were analysed for
      circulating tumour cells (CTC) using both methods. Blood samples for FACS
      analysis were immuno-magnetically enriched using ferrofluid particles. CTC were
      defined as positive for pan-cytokeratin and negative for CD45 pan-leucocyte
      antigen (CK+/CD45- events). There was a significant (P < 0.0001) correlation
      between the number of spiked cancer cells and their recovery using FACS. The
      lowest detectable concentration was 20 spiked cancer cells in 14 ml blood for
      both RT-PCR and FACS. A positive FACS result significantly (P < 0.05) concurred
      with a positive RT-PCR result in spiked blood. The number of CK+/CD45- events
      detected in the blood of colorectal cancer patients was not significantly greater
      (P = 0.07) than in blood taken from 'no cancer' controls and furthermore there
      was no concordance (P = 1) between RT-PCR and FACS positivity in cancer patients'
      blood. FACS detection of tumour cells was feasible in vitro, and correlated with
      RT-PCR. However, its sensitivity in vivo was poor and did not correlate with RT
      PCR detection of CTC. Uncertainties about antigen expression on normal
      circulating cells and about CTC phenotype need to be resolved, before FACS can be
      developed for detection of tumour cells within the circulation.

PMID- 12405287
TI  - Transduction of HOXD3-antisense into human melanoma cells results in decreased
      invasive and motile activities.
AB  - Homeobox genes regulate sets of genes that determine cellular fates in embryonic
      morphogenesis and maintenance of adult tissue architecture by regulating cellular
      motility and cell-cell interactions. Our previous studies showed that a specific
      member, HOXD3, when overexpressed, enhanced cell motility and invasiveness of
      human lung cancer A549 cells (Hamada et al. Int. J. Cancer 2001; 93: 516-25
      [19]). In the present study, we investigated the roles of HOXD3 in motile and
      invasive behavior of human malignant melanoma cells. Of seven melanoma cell lines
      examined here, six cell lines expressed the HOXD3 gene, whereas normal
      melanocytes did not. We transduced the HOXD3-antisense gene expression vector
      into two cell lines (A375M and MMIV). The cell transduced with the HOXD3
      antisense gene showed reduced in vitro invasion of Matrigel. The transduction of
      the HOXD3-antisense gene also decreased cell spreading, haptotactic activity to
      vitronectin and laminin-1, and phagokinetic activity. To find the difference of
      gene expression between the HOXD3-antisense-transduced A375M cells and the
      control A375MNeo2 cells, we carried out cDNA microarray analysis. The results of
      the microarray analysis indicated that the increased expression of cdc42
      interacting protein 4, KIAA0554 and tropomyosin 1, which are all associated with
      the cytoskeletal system, may be involved in the reduction of motile and invasive
      activity by the HOXD3-antisense gene transduction.

PMID- 12405288
TI  - Inhibition of cervical lymph node metastasis by marimastat (BB-2516) in an
      orthotopic oral squamous cell carcinoma implantation model.
AB  - Activation of matrix metalloproteinase-2 (MMP-2) is a common event in head and
      neck squamous cell carcinoma. An OSC-19 cell line, derived from human oral
      squamous cell carcinoma and known to metastasize to cervical lymph nodes, was
      implanted into the lingual margin of mice. The effect of marimastat (BB-2516), a
      broad MMP inhibitor, on the suppression of regional cervical lymph node
      metastasis was evaluated with an orthotopic implantation nude mice model.
      Marimastat was given immediately after OSC-19 implantation and continuously
      administered by an osmotic pump. The mice were divided into three groups by
      marimastat dose; Group A; 0 mg/kg/day, Group B; 30 mg/kg/day, and Group C; 150
      mg/kg/day. Twenty-one days after implantation, primary oral tumors and cervical
      lymph nodes were resected. Cervical lymph node status was microscopically
      examined. Activation of MMP-2 in primary oral tumor was examined by gelatin
      zymography. Both cervical lymph node metastasis and activation of MMP-2 were
      significantly suppressed in Group C (P < 0.05). Moreover, the Group C mice had a
      significantly better survival than group A (P = 0.0026). There was a significant
      difference between Group A and Group C in terms of proliferation of tumor cells
      by proliferating cell nuclear antigen immunostaining (P = 0.0120). These results
      suggest a positive role for marimastat in the inhibition of MMP-2 activation and
      prevention of cervical lymph node metastasis in oral squamous cell carcinoma
      (OSCC). Improvement of survival in patients with OSCC could be expected using
      adjuvant therapy with marimastat.

PMID- 12405289
TI  - Augmented anti-metastatic efficacy of a selective matrix metalloproteinase
      inhibitor, MMI-166, in combination with CPT-11.
AB  - The anti-metastatic efficacy of MMI-166, which is a selective matrix
      metalloproteinase (MMP) inhibitor, in combination with CPT-11 was examined using
      two metastasis models of human gastrointestinal cancer cells. In the liver
      metastasis model, C-IH human colon cancer cells were injected into the spleen of
      athymic BALB/c nude mice. Daily oral (p.o.) dosing of MMI-166 at 200 mg/kg
      starting 1 day after tumor inoculation led to a significantly prolonged survival
      effect by inhibiting liver metastasis of C-1H tumor cells. CPT-11 (5 or 20 mg/kg)
      was administered intraperitoneally (i.p.) three times on day 3, day 7 and day 11
      and also improved the survival of tumor-inoculated mice compared with the vehicle
      control. When MMI-166 was combined with CPT-11, the anti-metastatic efficacy was
      significantly augmented. Moreover, long tumor-free survival was noted in two of
      eight mice that were given the combination therapy but not either MMI-166 or CPT
      11 monotherapy. In the peritoneal dissemination model, TMK-1 human gastric cancer
      cells were injected i.p. into nude mice. While both MMI-166, administered daily
      p.o. from day 1 at 200 mg/kg, and CPT-11, administered intravenously (i.v.) three
      times, inhibited the tumor dissemination and growth, the combination therapy of
      MMI-166 plus CPT-11 showed a greater inhibitory effect than each monotherapy. A
      hematotoxicity study demonstrated that CPT-11 alone significantly decreased the
      number of white blood cells (WBC) and bone marrow cells (BMC) in the mice during
      treatment, while the daily administration of MMI-166 alone had no such effect.
      More importantly, the combination therapy of MMI-166 with CPT-11 did not augment
      the hematotoxicity caused by CPT-11. An in vitro cytotoxicity study showed that
      MMI-166 itself neither has direct cytotoxicity in C-1H and TMK-1 tumor cells, nor
      does it augment the cytotoxicity of SN-38, an active form of CPT-11. The findings
      indicate that the augmented anti-metastatic efficacy in combination treatment was
      not simply due to the augmentation of direct cytotoxic activity, but was rather
      an additive or synergistic effect of anti-metastatic activities with different
      mechanisms. In conclusion, we demonstrated that the anti-metastatic efficacy
      against C-1H colon cancer and TMK-1 gastric cancer were augmented by the
      combination therapy of MMI-166, an orally active MMP inhibitor, with CPT-11.
      However, the hematotoxicity caused by CPT-11 was not augmented in the combination
      with MMI-166. Thus, the combination therapy of MMI-166 and CPT-11 exhibited
      potent anti-metastatic efficacy without increased hematotoxicity. These results
      point to the clinical advantage of using MMI-166 in combination with CPT-11.

PMID- 12405291
TI  - Dietary supplementation with isolated soy protein reduces metastasis of mammary
      carcinoma cells in mice.
AB  - The present study investigated the effect of dietary supplementation with
      isolated soy protein (ISP) on pulmonary metastasis of carcinoma cells from
      primary mammary tumors induced by orthotopic injection of 4526 murine mammary
      carcinoma cells in female BALB/c mice. Three diets were compared: a basal AIN-93G
      diet and the basal diet supplemented with 10% or 20% ISP. After three weeks on
      the experimental diets, each mouse was injected 4 x 10(5) carcinoma cells into
      the right inguinal mammary fat pad. The primary tumors were excised when they
      reached a size of 1.0 cm in diameter. After surgery, mice were maintained on
      their respective diets for another three weeks. At necropsy, the incidence of
      metastasis, the number and size of macroscopic tumors, and the number of
      microscopic tumors in the lungs were determined. The incidence of mice with
      macroscopically visible tumors was 93%, 76%, and 67%, and the median number of
      macroscopic tumor was 5, 2, and 1 for the control, 10%, and 20% ISP groups (P <
      or = 0.05, 20% ISP vs. control). The median cross-sectional area of the
      macroscopic tumors was 0.93 mm2, 0.80 mm2, and 0.31 mm2, and the median volume
      was 0.73 mm3, 0.56 mm3, and 0.14 mm3 for the control, 10%, and 20% ISP groups (P
      < or = 0.01, 20% ISP vs. control). Histological examination revealed fewer
      microscopically detectable tumors in the ISP groups compared with the control.
      These results demonstrated that dietary supplementation with ISP reduced
      pulmonary metastasis of carcinoma cells from primary mammary tumors in BALB/c
      mice.

PMID- 12405290
TI  - Cyclooxygenase-2 expression correlates with uPAR levels and is responsible for
      poor prognosis of colorectal cancer.
AB  - Considering recent findings that cyclooxygensase-2 (COX-2) is involved in the
      progression of colorectal carcinoma (CRC), the role of COX-2 in promoting
      invasion and angiogenesis was investigated by evaluating the relationship of COX
      2 expression to various clinicopathological variables, including plasminogen
      activating system (PA system) and vascular endothelial growth factor (VEGF).
      Tumor tissues from 71 patients with CRC were assayed to determine the antigen
      levels of urokinase-type plasminogen activator (uPA), uPA receptor (uPAR), and
      plasminogen activator inhibitor-1 and -2 (PAI-1 and PAI-2), as well as
      immunohistochemical expression of VEGF. COX-2 was assayed immunohistochemically
      in 56 patients. COX-2 expression was detected in cancer cells and it was also
      expressed by stromal cells in some patients. Fourteen patients (25%) were COX-2
      positive, whereas 42 were negative. COX-2 expression was significantly related to
      lymphatic invasion (P = 0.0317), but was not related to microvessel density or
      VEGF expression. In the PA system, uPAR antigen levels were significantly higher
      in tumors with COX-2 expression than in tumors without (P = 0.0233). Univariate
      analysis showed that significant prognostic variables for survival were tumor
      size, lymph node involvement, lymphatic invasion, vascular invasion, liver
      metastasis, high uPAR level, and COX-2 expression, but only liver metastasis was
      an independent prognostic factor (P = 0.0065) in multivariate analysis. COX-2
      expression was a more important prognostic indicator than any other factor except
      liver metastasis (P = 0.0526). The significant relationship between the presence
      of COX-2 protein and uPAR antigen levels contributed to the enhancement of tumor
      invasion and the poor outcome in patients with CRC.

PMID- 12405292
TI  - Expression profiling and interferon-beta regulation of liver metastases in
      colorectal cancer cells.
AB  - Liver metastasis is the major cause of death among colorectal cancer patients.
      Many gene products have been associated with the colon cancer cells' ability to
      metastasize to the liver, including carcinoembryonic antigen (CEA) and mucins. In
      this study we examined changes in expression of 384 genes in a model of human
      colorectal cancer metastasis in nude mice. Using DNA microarrays, we compared
      expression between MIP-101 cells, a poorly metastatic human colon cancer cell
      line, with an interferon-beta (IFN-beta) resistant subline of MIP-101 (beta-MIP)
      that is metastatic to the liver. Treatment of beta-MIP cells with increasing
      concentrations of IFN-beta caused a reversion to the non-metastatic phenotype.
      The array data showed down-regulation of genes involved in apoptosis in beta-MIP
      cells and their return to the MIP-101 pattern upon IFN-beta treatment. Cluster
      analysis also showed involvement of genes belonging to cell cycle, angiogenesis
      and invasion pathways. Selected genes were chosen to validate the microarray data
      by semi-quantitative RT-PCR. Association between gene expression pattern and
      metastatic phenotype was verified by intra-splenic injection in nude mice. The
      number of genes examined in this study was small, but carefully selected.
      Significant changes associated with cell growth and survival were observed, which
      gave the metastatic cells an advantage to grow in the liver. This information may
      help identifying new markers for colorectal cancer prognosis as well as aid the
      development of new therapeutic approaches.

PMID- 12405293
TI  - Lovastatin alters cytoskeleton organization and inhibits experimental metastasis
      of mammary carcinoma cells.
AB  - Lovastatin is a competitive inhibitor of 3-hydroxy 3-methylglutaryl coenzyme A
      reductase, the key regulatory enzyme of cholesterol biosynthesis. This enzyme
      catalyzes the formation of mevalonate, which is also the precursor of isoprenoid
      moieties, such as farnesol and geraniol, that are incorporated into several
      molecules essential for tumor cell signaling. Here, we describe that pretreatment
      with a non-cytotoxic concentration of lovastatin (10 microM) dramatically
      inhibited the metastatic ability of F311 mammary carcinoma cells in syngeneic
      BALB/c mice. Similarly, daily i.p. treatment of animals with a well-tolerated
      dose of lovastatin (10 mg/kg/day) significantly reduced the number of
      experimental lung metastases. In vitro, incubation of F3II monolayers in the
      presence of lovastatin caused a rounded-cell morphology. Immunofluorescence
      analysis revealed a lack of cortical actin organization, micrutubule disruption
      and inhibition of integrin-mediated focal contacts in lovastatin-treated cells.
      Exposure of F3II cells to lovastatin significantly inhibited tumor cell adhesion
      and migration, and coincubation with the cholesterol precursor mevalonate
      prevented these effects. Lovastatin reduced membrane localization of Rho protein,
      a signaling molecule involved in the regulation of actin-based cell motility that
      needs geranylation for membrane association and activation. In addition,
      lovastatin induced a dose-dependent inhibition in the secretion of urokinase, a
      key proteolytic enzyme during tumor invasion and metastasis, and a significant
      increase of tissue-type plasminogen activator, a marker of good prognosis in
      mammary cancer. These data suggest that antimetastatic properties of lovastatin
      are strongly associated with alterations in cytoskeleton organization and the
      consequent modulation of adhesion, motility and proteolysis.

PMID- 12405294
TI  - Hypertension and stroke in Africans.

PMID- 12405295
TI  - Diabetic neuropathy.

PMID- 12405297
TI  - Practical management of neuropathic feet.

PMID- 12405296
TI  - Haemorrhoids, fissures and anal fistulae.

PMID- 12405298
TI  - Treatment of malaria in Ethiopian folk medicine.
AB  - Key informant interviews of herbalists were conducted to document the traditional
      management of malaria in Ethiopia. The perceptions of the cause and symptoms of
      malaria, the use of plants, their preparation and administration were recorded.
      Interviews were performed in rural Butajira and Addis Ababa (the main city). The
      result showed that 33 (75%) of the interviewed healers treat malaria using herbal
      drugs. Sixteen plants were reported to have been used of which eight were used as
      a single remedy and the rest as composite remedies with other plants. The
      ethnopharmacological data generated in this study on antimalarial plants is
      useful for further evaluations of the traditional claims of antimalarial plants
      in Ethiopia.

PMID- 12405299
TI  - The profile of stroke in Nigeria's federal capital territory.
AB  - The pattern of stroke has been well characterized in many settings in Nigeria.
      The profile of stroke, has, however, not been previously reported from Nigeria's
      new federal capital. The aim of this study was to characterize the pattern of
      stroke in a specialist centre in Nigeria's federal capital territory over a 5
      year period.

PMID- 12405300
TI  - Diabetes self-care and educational needs in Tanzanian and Swedish diabetic
      patients: a cross-cultural study.
AB  - The aim was to compare self-care and perceived educational needs in adult
      Tanzanian and Swedish diabetic patients. One hundred and fifty Tanzanians were
      matched with Swedes (n=150). All 300 patients filled in questionnaires about
      their self-care and educational needs. The comparison indicated the Tanzanians
      were almost as satisfied with their self-care as the Swedes, but Tanzanians were
      dissatisfied with the lack of drugs and wanted more diabetes education while the
      Swedes were more dissatisfied with their own self-care behaviour. None of
      theTanzanians monitored their own blood glucose, whereas half the patients in the
      Swedish group did so weekly or monthly. The findings suggest that diabetes
      education in Tanzania should concentrate more on basic diabetes knowledge. In
      Sweden, however, the main points to be stressed should be life style and
      psychology.

PMID- 12405301
TI  - Surgical bypass is still relevant in the palliation of malignant obstructive
      jaundice.
AB  - Malignant tumours of the biliopancreatic system causing obstructive jaundice are
      not curable in most of the patients, and palliation plays a very important
      therapeutic role. The role of surgery in palliation of malignant obstructive
      jaundice has been questioned in the light of availability of endoscopic
      techniques. In developing countries, however, exploratory laparotomy and
      palliative surgery (when possible) is the only option available as sophisticated
      instruments and the expertise to use them is limited to a very few centres. This
      was a retrospective study of 83 consecutive cases with malignant obstructive
      jaundice admitted to the Department of Surgery, NSCB Government Medical College,
      Jabalpur, MP, India from January 1996 to December 2000.

PMID- 12405302
TI  - The maternal mortality review meeting: experiences from Kalabo District Hospital,
      Zambia.
AB  - We report on our experiences with a maternal mortality review meeting in Kalabo
      District Hospital between 1999 and 2001. Patient files and minutes of the
      maternal mortality review meetings of 15 cases of maternal death were reviewed.
      Causes of death, classification, substandard care factors, recommendations and
      implementation were analysed. In nine cases of maternal death 20 different
      substandard care factors were found; 12 caused by organizational weaknesses,
      eight by substandard clinical care. In nine cases, recommendations were
      formulated, which were completely implemented in five and partially implemented
      in two cases. A maternal mortality review meeting can be an important tool for
      improving essential obstetric services in a district hospital. It can easily and
      directly correct some substandard care factors, has a high educational value for
      staff and leads to a better understanding of maternal mortality for everyone
      involved.

PMID- 12405303
TI  - Palliation by coeliac plexus block for upper abdominal visceral cancer pain.
AB  - Palliation of cancer related pain is one of the major concerns of patients
      suffering from cancer of the upper abdominal organs. The non-availability of
      imaging techniques to guide needle placement prompted us to use a blind technique
      of neurolytic coeliac plexus block. Thirty consecutive patients with intractable
      pain, due to documented inoperable upper abdominal visceral cancers, underwent
      neurolytic coeliac plexus block by blind percutaneous retrocrural unilateral
      neurolysis. The severity of pain was documented on a 0-10 visual analogue scale
      (VAS) performed pre-block and post-block at 1 day, 1 week, 1 month and 3 months.
      Pain relief was graded as excellent if the score was 0-2, good when VAS was 3-5,
      satisfactory whenVAS was 6-7 and unsatisfactory if VAS was 8-10. Excellent pain
      relief was obtained in 26/30 patients (86.6%). Relief from pain diminished with
      time and after 3 months, 16/30 patients (53.35) graded their pain relief as
      excellent. Transient but severe hypotension complicated 73% of blocks. Despite
      the proximity of vital structures, blind unilateral retrocrural neurolytic
      coeliac plexus blockade is a safe and effective means to relieve the terminal
      pain associated with upper abdominal visceral cancer. It deserves more widespread
      use in patients with upper abdominal cancer. Results of the present study are
      encouraging and relevant for clinicians working in developing countries.

PMID- 12405304
TI  - The prevalence, presentation and outcome of diabetic foot lesions in a Nigerian
      teaching hospital.

PMID- 12405305
TI  - Measuring the burden of ocular morbidity.
AB  - This hospital-based study highlights the spectrum of eye ailments in 35,273
      patients who attended the Department of Ophthalmology at the B P Koirala
      Institute of Health Sciences, Eastern Nepal, during a 5-year period with varied
      clinical diagnosis. The attendance each year showed a progressive increase with a
      male preponderance. More than 13% of the patients were children. Cataract was the
      most common problem for which patients needed ophthalmic advice; diabetic and
      hypertensive retinopathy were frequent occurrences and infection was a common
      problem. Over 21% of the eyes examined had a refractive error: as high as 2.54%
      were amyblyopic caused by non-correction of refractive errors. Allergic
      conjunctivitis was frequently encountered. As shown by the magnitude of the
      problem, the existing eye care facilities must be enhanced and new strategies
      developed.

PMID- 12405306
TI  - Pancreatitis in Weil's disease.

PMID- 12405307
TI  - Sunlight and the Mantoux reaction.

PMID- 12405308
TI  - Medical record keeping and information retrieval in developing countries:
      surgeons' perspective.

PMID- 12405309
TI  - Outbreak of beri-beri in a prison in West Africa.
AB  - The International Committee of the Red Cross investigated an outbreak of beri
      beri in a prison in West Africa. Twenty-five prisoners out of a total of 1020
      died over a period of 11 weeks--exceeding the crude mortality rate of
      1/10,000/day, a threshold for serious concern. Two hundred and eleven prisoners
      had clinical signs of beri-beri. An immediate response to treatment with thiamine
      was seen and no further deaths occurred. The triad of a positive squatting test,
      oedema and a diet consisting exclusively of white rice should lead to the
      diagnosis of beri-beri. The disease is more common than generally assumed, also
      in Africa and especially in prisons.

PMID- 12405310
TI  - Laryngeal carcinoma: clinical features seen at University College Hospital,
      Ibadan.

PMID- 12405311
TI  - Traditional clay pots as storage containers for insulin in hot climates.

PMID- 12405312
TI  - Polio eradication at a crossroad: a brief survey on immunization coverage
      conducted in the centre of the 'Golden Triangle'.

PMID- 12405313
TI  - Facial dog bites in Southwestern Nigerian children: an analysis of eight cases.
AB  - This paper analyses the prevalence, pattern and treatment outcome of eight cases
      of facial dog bite in Nigerian children seen and managed at the Obafemi Awolowo
      University Teaching Hospital's Complex, a tertiary hospital located in
      Southwestern Nigeria. During the study period of 18 months (July 1996-December
      1997), a total of 174 cases of facial soft tissue injuries in children were
      managed, two of which resulted in rabies and death of the patients. Based on the
      findings of this analysis, we suggest that unprovoked facial dog bites inflicted
      by familiar domestic dogs may be complicated by rabies. Ignorance about the risk
      of uncompleted treatment, financial constraints and scarcity of the vaccine may
      be implicated in the outcome. The need to improve community knowledge of rabies
      and the availability and affordability of rabies vaccine are highlighted.

PMID- 12405314
TI  - Hand-made colostomy bag.

PMID- 12405315
TI  - A novel method of the use of a tubular polythene cover for arms and forearms as a
      part of universal precautions.

PMID- 12405316
TI  - Omental torsion with acute appendicitis: an interesting association.

PMID- 12405317
TI  - The use of a balloon catheter for breech extraction.

PMID- 12405318
TI  - Clinical thermometer--a rarely ingested foreign body.

PMID- 12405319
TI  - Splenic abscess.

PMID- 12405320
TI  - Anthrax peritonitis.

PMID- 12405321
TI  - Microfilaria in a thyroid nodule which resolved on treatment.

PMID- 12405322
TI  - Syphilis--an endemic disease in Kwazulu, Natal: a plea for generalized screening.

PMID- 12405323
TI  - Identification of Mansonella perstans microfilariae in ascitic fluid.

PMID- 12405324
TI  - When there is no plasticine.

PMID- 12405325
TI  - The Blantyre Septic Joint Score: a new scoring system for septic arthritis.

PMID- 12405326
TI  - Knowledge, attitude and practices of parents/guardians toward poliomyelitis
      infection and its immunization in Banki Community, Bama LGA, Borno State.

PMID- 12405328
TI  - Move for health.

PMID- 12405330
TI  - Paucibacillary tuberculosis--a retrospective study.
AB  - Paucibacillary tuberculosis poses difficulty in the treatment and control of
      tuberculosis. The present study aims at understanding the extent of such cases
      among the patients, with respiratory symptoms, attending the outpatient
      department of the VP Chest Institute, Delhi. The analysis is based on the smear
      and culture examination of the sputum specimens, submitted from such patients
      during 1992-1998. Present results demonstrate that 34.8% were paucibacillary
      (direct smear negative; culture positive cases). Sex has no influence on smear
      examination results. The frequency of smear negative cases varied in the
      different age groups; the largest number belonged to the > or = 45 years age
      group (p < 0.05). Culture examination elicited positive result in these cases.

PMID- 12405329
TI  - Hindu-Muslim differences in the prevalence of coronary heart disease and risk
      factors.
AB  - Differences in coronary risk factors and coronary heart disease (CHD) prevalence
      between the Hindus and the Muslims have not been adequately studied. This study
      aims to determine the prevalence of certain socio-economic and biological
      coronary risk factors in urban communities and to compare the findings found in
      the Hindus and the Muslims. The study employed a cross-sectional survey design
      and stratified random sampling technique consisting of 1,415 males and 797
      females. Among males there were 1,092 Hindus (77.2%) and 272 Muslims (19.2%)
      while in females there were 685 Hindus (85.9%) and 91 Muslims (11.4%). Prevalence
      of illiteracy and sedentary lifestyle were significantly more in Muslims
      (p<0.05). Smoking or tobacco use in males was similar but in females it was more
      in the Hindus. Self-reported diabetes was found in 1.4% Hindu males and in 1.2%
      Hindu females. No Muslim reported diabetes. Hindu males were significantly taller
      than Muslims (163.9 +/- 8.3 versus 160.9 +/- 8.9 cm; p < 0.001). In both males
      and females there was no significant difference in body mass index and obesity.
      In Hindu males the diastolic BP was significantly greater than in Muslims (81.2
      +/- 9.2 versus 79.0 +/- 8.6 mm Hg; p < 0.001); prevalence of hypertension (30.5%
      versus 25.7%) was also significantly more (p = 0.048). In Hindu females the mean
      systolic BP was significantly more and there was also difference in hypertension
      prevalence (35.2% versus 25.3%). CHD prevalence was significantly greater in
      Hindu males as compared to the Muslims when determined by the presence of either
      ECG changes alone (4.3% versus 0.7%; p = 0.008) or ECG changes combined with
      clinical history (7.1% versus 1.8%; p = 0.002). A similar, though not
      significant, trend was seen in females (ECG changes: 8.9% versus 6.6%, clinical
      and ECG changes: 10.4% versus 6.6%). The prevalence of CHD is significantly more
      in Hindu males as compared to the Muslims and is associated with a greater
      prevalence of diabetes and hypertension.

PMID- 12405331
TI  - Labour admission test--an effective risk screening tool.
AB  - Recording of foetal heart tracing on cardiotocogram for 30 minutes was done in
      500 women on admission in labour and contraction mediated responses were recorded
      as labour admission test (LAT). Subjects were also stratified into high or low
      risk groups based on antenatal factors. Seventy-seven out of 500 labour cases (36
      out of 433 cases with reactive, 16 out of 37 with suspicious and 25 out of 30
      cases with ominous LATs) manifested foetal distress. Eighty-two per cent of
      antenatal high risk and 89% of low risk pregnancies showed reactive LATs. The LAT
      was found to have high specificity (93%) and negative predictive value (91%).
      However, the sensitivity and positive predictive values were lower (53% and 61%
      respectively). Patients with pre-existing risk factors showed intrapartum foetal
      distress by 3 hours of reactive LAT, whereas the ones with no antenatal risk
      factors did not develop foetal distress till 6 hours after reactive LAT. Reactive
      LAT tracing is of some predictive value; at least for the first few hours after
      admission in labour.

PMID- 12405333
TI  - Haematocolpos--an uncommon cause of lower abdominal pain in adolescent girls.
AB  - Two cases of haematocolpos in adolescent girls due to imperforate hymen are
      reported. Both of them presented with lower abdominal pain and urinary retention.
      Hymenotomy was performed in both the cases. The condition is discussed with brief
      review of literature.

PMID- 12405332
TI  - Clinicopathological study of hysterectomies.
AB  - A randomised study of 100 cases undergoing hysterectomy in the age group of 20-70
      years was carried out and clinicopathological correlation was done. Maximum
      number of women who underwent hysterectomy were in the age group of 31-50 years.
      Abnormal menstrual flow was the most common complaint (66%). Clinically main
      indications for hysterectomy were fibroid (34%), dysfunctional uterine bleeding
      (DUB) (26%) and uterine prolapse (24%). Abdominal hysterectomy was the procedure
      of choice in conditions other than uterovaginal prolapse. Out of 34 cases,
      clinically diagnosed as fibroid uterus, leiomyoma was found on histopathology in
      25 cases and adenomyosis in 3 cases. In 3 cases, both leiomyoma and adenomyosis
      were present. Out of 26 cases, clinically diagnosed as DUB, histopathological
      examination revealed leiomyoma in 6 cases, adenomyosis in 9 cases, endometrial
      polyp in 3 cases. Hence, after exclusion of organic pathology, DUB was confirmed
      in 8 cases.

PMID- 12405334
TI  - Atypical hepatic pathology associated with diabetes mellitus--report of two
      cases.
AB  - Generalised oedema of short onset without evidences of cardiac or renal failure
      in two diabetic patients, irrespective of diabetes type with common features of
      non-hepatomegaly, without altered liver enzymes, absence of viral markers,
      absence of diabetic angiopathy, poor glycaemic control and improvement with
      glycaemic care are reported. Both the patients had certain biochemical and
      hepatic histologic features in common.

PMID- 12405335
TI  - A case of an absent diseased appendix in an incompletely rotated gut.
AB  - A case of an absent diseased appendix in an incompletely rotated gut in a 35-year
      old farmer along with its management and review of literature is presented here.

PMID- 12405336
TI  - Essential thrombocythaemia.
AB  - A case of essential thrombocythaemia which responded to aspirin and hydroxyurea
      is presented.

PMID- 12405337
TI  - Congenital erythropoietic porphyria.
AB  - A case of congenital erythropoietic porphyria born out of consanguineous marriage
      with features of red coloured urine, photosensitivity, hypertrichosis of face and
      extremities, erythrodontia and haemolytic anaemia is reported.

PMID- 12405339
TI  - Polycythaemia vera.
AB  - A rare case of polycythaemia vera occurring in a 60-year-old female has been
      reported here, along with a brief discussion.

PMID- 12405338
TI  - Virilising adrenocortical carcinoma.
AB  - A 16-year-old, Hindu, female presented with rapidly growing abdominal lump for 6
      months, primary amenorrhoea and non-development of secondary sex characters. Her
      BP was 180/120 mmHg. There was an excessive hirsutism involving face, neck,
      shoulders, abdomen and thighs. A lump was felt at left lumbar region extending on
      to left hypochondrium and part of umbilical region. Her serum testosterone level
      was 224 ng/dl and cortisol level was 15 microg/dl. Ultrasonography revealed a
      solid mass arising from the upper pole of left kidney. Exploratory laparotomy
      revealed a huge left adrenal tumour which was removed completely. Histopathology
      of the resected mass showed sheets of large round to polyhedral cells with
      hyperchromatic nuclei and eosinophilic granular cytoplasm with numerous giant
      cells. The case was diagnosed as virilising adrenocortical carcinoma.

PMID- 12405340
TI  - Primary intraventricular haemorrhage: a rare presenting feature of arteriovenous
      malformation in children.
AB  - Two cases of arteriovenous malformation (AVM) of the brain presented with primary
      intraventricular haemorrhage in eleven and thirteen years old children,
      respectively. The cases responded favourably to therapy with steroids, anti
      epileptic drugs and therapeutic embolisation in the former. Though such
      presentation accounts for 3% of the adult intracranial bleeds secondary to AVM
      rupture, the same has not been reported in children.

PMID- 12405341
TI  - An unusual foreign body in the vagina producing vesicovaginal fistula.
AB  - A case of vasicovaginal fistula occurring in an adolescent unmarried girl
      following insertion of a matalic glass deep inside the gagine is reported here
      along with a brief discussion and review of literature.

PMID- 12405342
TI  - Cholelithiasis in thalassaemia major.
AB  - The incidence of gall stones in thalassaemia is less than that in sickle cell
      anaemia or hereditary spherocytosis. With adequate blood transfusions, the
      incidence is as low as 2%. There are not many reports on cholelithiasis in
      thalassaemia. A case of 24-year-old female with thalassaemia major and gall stone
      is reported here.

PMID- 12405343
TI  - Primary health centres surpass medical colleges in newborn care in West Bengal.

PMID- 12405344
TI  - Harnessing malE for the study of antigen/antibody recognitions.
AB  - The construction of hybrids between the variable fragment (Fv) of antibodies and
      protein MalE of Escherichia coli at the genetic level makes possible their
      preparation in a functional state, independently of any interaction with the
      antigen. We used such hybrids and a mutagenesis approach to study the recognition
      between antibody D1.3 and its antigen lysozyme, and its maturation. We
      subsequently transformed D1.3 into a reagentless fluorescent biosensor by
      knowledge-based design.

PMID- 12405345
TI  - Folding and aggregation of export-defective mutants of the maltose-binding
      protein.
AB  - We previously characterized a defective-folding variant of the periplasmic
      maltose-binding protein, MalE31. To examine the alternative folding pathways open
      to the MalE31 precursor, we have analyzed the cellular fates of this aggregation
      prone protein carrying altered signal sequences. Our results are most easily
      interpreted by a kinetic competition between exportation, folding, and
      degradation.

PMID- 12405346
TI  - Phylogeny of phosphoryl transfer proteins of the phosphoenolpyruvate-dependent
      sugar-transporting phosphotransferase system.
AB  - Some bacteria lack sugar permeases of the bacterial phosphotransferase system
      (PTS) but encode within their genomes phosphoryl transfer proteins of the PTS
      that probably function in regulation. These proteins include homologues of HPr
      (PtsH), the ATP-dependent HPr(ser) kinase/phosphatase (PtsK) and the PEP
      dependent HPr(his) kinase known as Enzyme I (PtsI). We identify all currently
      sequenced homologues of these proteins, multiply align their sequences and
      construct phylogenetic trees in order to derive functional, structural and
      evolutionary conclusions. We show that no bacterium possesses more than one HPr
      kinase and that these proteins are probably all orthologous. alpha-Proteobacteria
      possess truncated HPr kinases which probably serve a unified regulatory function
      together with other PTS proteins. The Enzymes I are orthologous in all Gram
      positive bacteria and some Gram-negative bacteria, but other Gram-negative
      bacteria exhibit paralogues that fall into 5 functional types. No bacterium with
      a fully sequenced genome exhibits all of these types. With the exception of the
      classical Enzymes I, each of these functional types exhibits a distinctive set of
      accompanying domains, usually with a characteristic domain order. One functional
      type, the fructose-specific type, includes two phylogenetically different
      subgroups with different domain orders. The results establish that domain
      associations occurred early during evolutionary history of the PTS, and that
      subsequent domain rearrangements occurred rarely. Our findings define the
      evolutionary histories of these important bacterial proteins and provide guides
      for functional assignment of PTS-related proteins encoded by genes revealed by
      genome sequencing.

PMID- 12405347
TI  - Mechanism of maltodextrin transport through LamB.
AB  - The Gram-negative bacterial outer membrane contains several independent,
      biochemically distinct transport systems for the acquisition of solutes from the
      environment. Three or more different classes of membrane proteins exist within
      the porin superfamily, that facilitate the uptake of sugars, amino acids,
      nucleotides, vitamins and metals. In spite of crystallographic descriptions of
      these protein transporters over the past decade, the mechanisms by which porins
      catalyze solute internalization are controversial, and in some cases still
      obscure. For many years the research of Maurice Hofnung endeavored to explain the
      transport of maltose and maltodextrins by LamB, also known as maltoporin. In the
      shadow of recent crystal structures, his work helped outline a different picture
      of outer membrane transport physiology, that is a tribute to the powerful genetic
      approaches Maurice pioneered. These data suggest that the principal determinant
      of maltodextrin recognition by maltoporin derives from the configuration of
      aromatic amino acids in its surface loops.

PMID- 12405348
TI  - From maltose to cell division.
AB  - Seeing connections between apparently unrelated areas is the hallmark of a deep
      thinker. Maurice Hofnung showed that his interest in the maltose regulon and my
      own interest in the regulation of cell division in Escherichia coli could lead to
      fruitful collaboration. From the maltose regulon to the LamB receptor to phage A
      to the SOS response to the Mutatest to induction of expression of the SOS
      inducible division inhibitor SfiA to the SOS Chromotest based on sfiA::lacZ
      induction to the development of a commercial kit for measuring the genotoxicity
      of environmental substances...this was but one of the original trails that
      Maurice Hofnung blazed and exploited successfully.

PMID- 12405349
TI  - Genotoxicity of 2-nitro-7-methoxy-naphtho[2,1-b]furan (R7000): a case study with
      some considerations on nitrofurantoin and nifuroxazide.
AB  - Two nitrofurans present broad-spectrum antimicrobial properties and some of them
      are used in human and veterinary medicine. Most of these molecules are mutagens
      and some of them were reported as carcinogens. Due to its extreme mutagenic
      potency in bacteria, the nitronaphtho derivative 2-nitro-7-methoxy-naphtho[2,1
      b]furan (R7000) was used as a tool to analyze the mechanism of the genotoxic
      action of this family of chemicals. In the present paper, we review essential
      data on the genotoxicity of R7000 and briefly discuss the case of nitrofurantoin
      and nifuroxazide, two nitrofurans, still in use as urinary and gastrointestinal
      disinfectants.

PMID- 12405350
TI  - SOS Chromotest methodology for fundamental genetic research.
AB  - The present mini-review summarizes data in selected fields of basic genetics
      which were exclusively obtained in agreement with the principles of SOS
      Chromotest methodology and with Escherichia coli PQ37 sfiA::lacZ as a tester
      strain.

PMID- 12405351
TI  - Molecular mechanisms of UV-induced mutations as revealed by the study of DNA
      polymerase eta in human cells.
AB  - Replication of UV-induced photoproducts requires the activity of specific DNA
      polymerases. The DNA polymerase eta, the absence of which gives rise to the
      cancer-prone xeroderma pigmentosum variant syndrome, is one of these translesion
      DNA polymerases. Other error-prone DNA polymerases are present in human cells and
      may contribute to the UV-induced mutation spectrum.

PMID- 12405352
TI  - Repetitive DNA, genome system architecture and genome reorganization.
AB  - Repetitive DNA elements are major organizational components of the genome
      involved in replication, in transmission to daughter cells, and controlling
      expression of genomic coding sequences. Repetitive elements format the genome
      system architecture characteristic of each taxonomic group. Appreciating the
      functional significance of repetitive DNA provides new concepts of genome
      organization and genome reorganization in evolution.

PMID- 12405353
TI  - Host/pathogen interactions at mucosal surfaces: immune consequences.
AB  - The mucosal immune system has evolved to protect the host against the
      establishment of infections at or through the mucosal surfaces of the body.
      Protective immunity must be activated to specific pathogenic agents or their
      products but inappropriate immune responses to food/environmental antigens must
      be avoided. Thus, the mucosal immune system is under tight regulation. Pathogenic
      bacteria and their products can be exploited as specific probes of mucosal immune
      responses. Bacterial enterotoxins such as cholera toxin are potent mucosal
      immunogens and adjuvants that activate both mucosal and systemic immune
      responses. Infection models involving microorganisms such as Citrobacter
      rodentium can also be used to investigate the consequences of mucosal
      colonisation that lead to immune disfunction.

PMID- 12405354
TI  - Histone-like proteins and the Shigella invasivity regulon.
AB  - The contribution of histone-like proteins to the transcriptional regulation of
      virulence gene networks is a common feature among pathogenic bacteria. In this
      article we review current knowledge about the regulative role of major histone
      like proteins in the silencing/activation of the invasivity phenotype of
      Shigella, the etiological agent of bacillary dissentery.

PMID- 12405355
TI  - Expression and folding of an antibody fragment selected in vivo for high
      expression levels in Escherichia coli cytoplasm.
AB  - In this review, we summarize some of our results on folding and directed
      evolution of an antibody fragment in Escherichia coli cytoplasm. We will also
      discuss some attempts to construct other antibodies active in this cellular
      compartment.

PMID- 12405356
TI  - Posterior inferior cerebellar artery.

PMID- 12405357
TI  - Benign dural arteriovenous fistulas.

PMID- 12405358
TI  - Protection from rebleeding.

PMID- 12405359
TI  - Treatment of arteriovenous malformations: gamma knife surgery.

PMID- 12405360
TI  - Distal posterior inferior cerebellar artery aneurysms: clinical features and
      management.
AB  - OBJECT: Aneurysms located on the distal portion of the posterior inferior
      cerebellar artery (PICA) are uncommon, and their underlying pathology, natural
      history, and clinical management are poorly understood. To clarify these lesions
      more fully, the authors undertook a retrospective analysis of the clinical
      features and management results of 22 distal PICA aneurysms in 20 consecutive
      patients treated at one institution by the same surgeon during the past decade.
      METHODS: The series included 10 men and 10 women (mean age at presentation 51
      years). Nine patients presented with only subarachnoid and/or intraventricular
      hemorrhage (median Hunt and Hess Grade II). In seven patients intracerebellar
      hemorrhage was also found; two patients presented with pressure effects and two
      hemorrhages were incidentally discovered. Prominent comorbidities included
      cigarette smoking (50%) and hypertension (50%). The 13 saccular and nine fusiform
      distal PICA aneurysms were distributed on the following segments of the PICA:
      lateral medullary (seven lesions), tonsillomedullary (five lesions),
      telovelotonsillar (five lesions), and cortical (five lesions). Six oases were
      associated with cerebellar arteriovenous malformations. Skull-base and far
      lateral transcondylar surgical approaches were used to secure the aneurysms in
      86% of cases, either by direct clipping (13 lesions), vessel sacrifice (four
      lesions), or vessel sacrifice plus bypass (two lesions). Two aneurysms were
      treated using endovascular PICA ablation. Overall outcome at hospital discharge
      was excellent or good in 70% of cases. At long-term follow up (100% of patients,
      mean 123 days), an excellent or good outcome had been achieved in 85% of cases.
      CONCLUSIONS: Depending on the PICA segment that was affected, variations in
      clipping strategies and surgical exposures aimed at the PICA branch and main
      trunk preservation were major contributors to good long-term results.

PMID- 12405361
TI  - Benign cranial dural arteriovenous fistulas: outcome of conservative management
      based on the natural history of the lesion.
AB  - OBJECT: Cranial dural arteriovenous fistulas (DAVFs) can be classified into
      benign or aggressive, based on their patterns of venous drainage. A benign
      condition requires the absence of cortical venous drainage (CVD). The clinical
      and angiographic features of a consecutive single-center group of 117 patients
      harboring benign cranial DAVFs were evaluated over time to validate the behavior
      and appropriate management of these lesions. METHODS: At the initial assessment
      four patients were asymptomatic. Two infants presented with congestive heart
      failure. All other patients presented with other benign symptoms: chronic
      headache, bruit, or orbital phenomena. Observational management was instituted in
      73 patients (62%). Intolerable bruit or ophthalmological sequelae were deemed
      indications for palliative embolization in 43 patients and surgical treatment in
      one patient. A median follow-up period of 27.9 months (range 1 month-17.5 years)
      was available in 112 patients (95.7%), among whom repeated angiography was
      performed in 50. Overall, observational and palliative management resulted in a
      benign and tolerable level of disease in 110 (98.2%) of 112 cases. In two cases
      managed conservatively CVD developed. In both of these cases the conversion from
      benign to aggressive DAVF was associated with spontaneous progressive thrombosis
      of venous outlets. CONCLUSIONS: The disease course of a cranial DAVF without CVD
      is indeed benign, obviating the need for a cure of these lesions. Symptoms are
      well tolerated with either observation or palliative treatment. After a long-term
      follow-up review of 68 patients, this conservative management resulted in a
      benign and tolerable level of disease in 98.5% of cases. It is noteworthy,
      however, that a benign DAVF carries a 2% risk of developing CVD, mandating close
      clinical follow-up review in such cases and renewed radiological evaluation in
      response to any deterioration in the patient's condition.

PMID- 12405362
TI  - Immediate administration of tranexamic acid and reduced incidence of early
      rebleeding after aneurysmal subarachnoid hemorrhage: a prospective randomized
      study.
AB  - OBJECT: By pursuing a policy of very early aneurysm treatment in neurosurgical
      centers, in-hospital rebleeds can be virtually eliminated. Nonetheless, as many
      as 15% of patients with aneurysm rupture suffer ultraearly rebleeding with high
      mortality rates, and these individuals are beyond the reach of even the most
      ambitious protocol for diagnosis and referral. Only drugs given immediately after
      the diagnosis of subarachnoid hemorrhage (SAH) has been established at the local
      hospital level can, in theory, contribute to the minimization of such ultraearly
      rebleeding. The object of this randomized, prospective, multicenter study was to
      assess the efficacy of short-term antifibrinolytic treatment with tranexamic acid
      in preventing rebleeding. METHODS: Only patients suffering SAH verified on
      computerized tomography (CT) scans within 48 hours prior to the first hospital
      admission were included. A 1-g dose of tranexamic acid was given intravenously as
      soon as diagnosis of SAH had been verified in the local hospitals (before the
      patients were transported), followed by doses of 1 g every 6 hours until the
      aneurysm was occluded; this treatment did not exceed 72 hours. In this study, 254
      patients received tranexamic acid and 251 patients were randomized as controls.
      Age, sex, Hunt and Hess and Fisher grade distributions, as well as aneurysm
      locations, were congruent between the groups. Outcome was assessed at 6 months
      post-SAH by using the Glasgow Outcome Scale (GOS). Vasospasm and delayed ischemic
      neurological deficits were classified according to clinical findings as well as
      by transcranial Doppler (TCD) studies. All events classified as rebleeding were
      verified on CT scans or during surgery. CONCLUSIONS: More than 90% of patients
      reached the neurosurgical center within 12 hours of their first hospital
      admission after SAH; 70% of all aneurysms were clipped or coils were inserted
      within 24 hours of the first hospital admission. Given the protocol, only one
      rebleed occurred later than 24 hours after the first hospital admission. Despite
      this strong emphasis on early intervention, however, a cluster of 27 very early
      rebleeds still occurred in the control group within hours of randomization into
      the study, and 13 of these patients died. In the tranexamic acid group, six
      patients rebled and two died. A reduction in the rebleeding rate from 10.8 to
      2.4% and an 80% reduction in the mortality rate from early rebleeding with
      tranexamic acid treatment can therefore be inferred. Favorable outcome according
      to the GOS increased from 70.5 to 74.8%. According to TCD measurements and
      clinical findings, there were no indications of increased risk of either ischemic
      clinical manifestations or vasospasm that could be linked to tranexamic acid
      treatment. Neurosurgical guidelines for aneurysm rupture should extend also into
      the preneurosurgical phase to guarantee protection from ultraearly rebleeds.
      Currently available antifibrinolytic drugs can provide such protection, and at
      low cost. The number of potentially saved lives exceeds those lost to vasospasm.

PMID- 12405363
TI  - Retrospective analysis of a 10-year experience of stereotactic radio surgery for
      arteriovenous malformations in children and adolescents.
AB  - OBJECT: To obtain information essential to the decision to perform radiosurgery
      for arteriovenous malformations (AVMs) in children and adolescents, the authors
      retrospectively analyzed their experience with gamma knife surgery for AVMs in
      100 patients ranging in age from 4 to 19 years. METHODS: Follow-up periods ranged
      from 6 to 124 months (median 71 months), and the actuarial obliteration rates
      demonstrated by angiography were 84.1, 89.4, and 94.7% at 3, 4, and 5 years,
      respectively. Factors associated with better obliteration rates in univariate
      analysis included the following: a patient age of 12 years or younger; a mean
      nidus diameter of 2 cm or less; a nidus volume of 3.8 cm3 or less; a maximum
      diameter of the nidus less than 3 cm; and a Spetzler-Martin grade of III or less.
      Radiation-induced neuropathy was seen in four patients, and the risk factors were
      considered to be a nidus in the brainstem and a maximum radiation dose greater
      than 40 Gy. Hemorrhage developed during the latency interval in four patients,
      and one patient with a cerebellar AVM died of the hemorrhage. The annual bleeding
      rate was 1.5%. Feeding arteries located in the posterior cranial fossa and an AVM
      nidus located in the cerebellum were significantly associated with the risk of
      hemorrhage. After angiographically verified obliteration of the nidus, 51
      patients continued to be observed from 1 to 110 months (median 67 months);
      hemorrhage developed in one patient 38 months after nidus obliteration.
      CONCLUSIONS: Radiosurgery is an acceptable treatment for small AVMs in children
      and adolescents in whom a higher obliteration rate can be achieved with lower
      risks of interval hemorrhage compared with the reported results in the general
      population. Careful follow-up observation seems to be required, however, even
      after angiographically verified obliteration.

PMID- 12405364
TI  - Repeated gamma knife surgery for multiple brain metastases from renal cell
      carcinoma.
AB  - OBJECT: The aim of this study was to evaluate the therapeutic profile of repeated
      gamma knife surgery (GKS) for renal cell carcinoma that has metastasized to the
      brain on multiple occasions. METHODS: Data from this study were culled from a
      single institution and cover a 6-year period of outpatient radiosurgery. A
      standard protocol for indication, dose planning, and follow up was established.
      In cases of distant or local recurrences, radiosurgery was undertaken repeatedly
      (up to six times in one individual). Seventy-five patients harboring 350 cerebral
      metastases were treated. Relief from pretreatment neurological symptoms occurred
      in 72% of patients within a few days or a few weeks after the procedure. The
      actuarial local tumor control rate after the initial GKS was 95%. In patients
      free from relapse of intracranial metastases after repeated radiosurgery, long
      term survival was 91% after 4 years; median survival was 11.1+/-3.2 months after
      radiosurgery and 4.5+/-1.1 years after diagnosis of the primary kidney cancer.
      Survival following radiosurgery was independent of patient age and sex, side of
      the renal cell carcinoma, pretreatment of the cerebrum by using radiotherapy or
      surgery, number of brain metastases and their synchronization with the primary
      renal cell carcinoma, and the frequency of radiosurgical procedures. In contrast,
      survival was dependent on the patient's clinical performance score and the
      extracranial tumor status. Tumor bleeding was observed in seven patients (9%) and
      late radiation toxicity (LRT) in 15 patients (20%). Treatment-related morbidity
      was moderate and mostly transient. Late radiation toxicity was encountered
      predominantly in long-term survivors. CONCLUSIONS: Outpatient repeated
      radiosurgery is an effective and only minimally invasive treatment for multiple
      brain metastases from renal cell cancer and is recommended as being the method of
      choice to control intracranial disease, especially in selected patients with
      limited extracranial disease. Physicians dealing with such patients should be
      aware of the characteristic aspects of LRT.

PMID- 12405365
TI  - Histopathological validation of a three-dimensional magnetic resonance
      spectroscopy index as a predictor of tumor presence.
AB  - OBJECT: Data obtained preoperatively from three-dimensional (3D)/proton magnetic
      resonance (MR) spectroscopy were compared with the results of histopathological
      assays of tissue biopsies obtained during surgery to verify the sensitivity and
      specificity of a choline-containing compound-N-acetylaspartate index (CNI) used
      to distinguish tumor from nontumorous tissue within T2-hyperintense and contrast
      enhancing lesions of patients with untreated gliomas. The information gleaned
      from the biopsy correlation study was used to test the hypothesis that there is
      metabolically active tumor in nonenhancing regions of the T2-hyperintense lesion
      that can be detected using MR spectroscopy. METHODS: Patients suspected of
      harboring a glioma underwent 3D MR spectroscopy during their preoperative MR
      imaging examination. Surgical navigation techniques were used to record the
      location of tissue biopsies collected during open resection of the tumor. A
      receiver operating curve analysis of the CNI and histological characteristics of
      specimens at each biopsy location was performed to determine the optimal
      threshold of the CNI required to separate tumor from nontumorous tissue.
      Histograms of the CNIs within enhancing and nonenhancing regions of lesions
      appearing on MR images were generated to determine the spatial distribution of
      CNIs consistent with tumor. CONCLUSIONS: Biopsy samples containing tumor were
      distinguished from those containing a mixture of normal, edematous, gliotic, and
      necrotic tissue with 90% sensitivity and 86% specificity by using a CNI threshold
      of 2.5. The CNIs of nontumorous specimens were significantly different from those
      of biopsy specimens containing Grade II (p < 0.03), Grade III (p < 0.005), and
      Grade IV (p < 0.01) tumors. On average, one third to one half of the T2
      hyperintense lesion outside the contrast-enhancing lesion contained CNI greater
      than 2.5.

PMID- 12405366
TI  - Treatment of chronic pain by using intrathecal drug therapy compared with
      conventional pain therapies: a cost-effectiveness analysis.
AB  - OBJECT: The object of this study was to compare the cost-effectiveness of
      intrathecal drug therapy (IDT) with that of conventional pain therapy (CPT) in
      patients suffering from chronic low back pain caused by failed back syndrome. In
      this study, the authors tabulated actual costs, in Canadian dollars, in a
      consecutive series of patients undergoing IDT within the Canadian health care
      system and have compared them with costs in a control group in the same
      environment. The influence of these treatments on the quality of life (QOL) was
      also analyzed. METHODS: The authors report on a series of 67 patients suffering
      from failed back syndrome, 23 of whom underwent implantation of a programmable
      drug delivery pump and 44 of whom acted as controls. Patients were followed for a
      5-year period during which the investigators tabulated the actual costs incurred
      for diagnostic imaging, professional fees, implantation costs including hardware,
      nursing visits for maintenance of the pumps, alternative therapies, and
      hospitalization costs for breakthrough pain. From this data, cumulative costs for
      each group were calculated for a 5-year period. Patient responses on the Oswestry
      Pain Questionnaire were analyzed to assess the impact of treatment on QOL. The
      actual cumulative costs for IDT during a 5-year period were $29,410, as opposed
      to $38,000 for CPT. High initial costs of equipment required for IDT were
      recovered by 28 months. After this time point, managing patients with CPT became
      the more expensive treatment option for the remainder of the follow-up period.
      The Oswestry Disability Index showed a 27% improvement for patients in the IDT
      group, compared with a 12% improvement in the control group. CONCLUSIONS: In
      patients who respond to this treatment, IDT is cost effective in the long term
      despite high initial costs of implantable devices.

PMID- 12405367
TI  - Organ donation rates in a neurosurgical intensive care unit.
AB  - OBJECT: The number of patients waiting for organ transplantation continues to
      grow, while organs are donated by very few of the thousands of potential donors
      who die every year. The authors' neurosurgical intensive care unit (NICU) has
      worked closely with coordinators from the local organ procurement organization
      (OPO) for many years. In this study, the authors analyze donation rates in the
      NICU and discuss factors that may be important in maximizing these rates.
      METHODS: All referrals from the NICU to the OPO from 1996 to 1999 were analyzed.
      Of the 180 referrals, 98 patients were found to be medically suitable as
      potential donors. Another 15 patients died of hemodynamic collapse shortly after
      admission to the NICU. If one assumes that all 15 patients would have been
      suitable donors, the unsuccessful resuscitation rate becomes 15 (13.3%) of 113.
      Of the 98 eligible donors, consent was obtained and organs or tissue were
      recovered in 72, yielding a successful organ procurement rate of 73.5%.
      CONCLUSIONS: Close working relationships among physicians, nurses, and OPO
      coordinators can result in higher donation rates than have been reported
      previously. Aggressive resuscitation and stabilization of all patients, early
      identification of potential organ donors, prompt declaration of brain death, and
      attempts by the OPO coordinator to build rapport with families are all important
      factors that may increase donation rates. Because most organ donors have
      sustained catastrophic intracranial events, neurosurgeons are uniquely positioned
      to influence organ donation policies at their hospitals and thus to salvage some
      benefit from tragic cases of overwhelming brain injury.

PMID- 12405368
TI  - Thalamic deep brain stimulation for the treatment of tremor due to multiple
      sclerosis: a prospective study of tremor and quality of life.
AB  - OBJECT: In several studies a significant reduction in tremor after thalamic deep
      brain stimulation (DBS) has been reported among patients with multiple sclerosis
      (MS). It has not been determined if this results in an improved quality of life.
      In this study the authors prospectively evaluated the effects of thalamic DBS on
      tremor and quality of life. METHODS: Videotapes of the patients' tremor were made
      preoperatively and 2 and 12 months postoperatively, and tremor was scored by a
      neurologist blinded to the treatment. Patients were tested pre- and
      postoperatively to measure any changes in their reported ability to perform
      selected activities of daily living and in their health-related quality of life.
      Patients were asked to complete a questionnaire about their satisfaction with the
      surgery. Postoperative changes were examined using paired t-tests. There were
      significant reductions in postural, action, and overall tremor at 2 and 12 months
      postoperatively. The patients' reported ability to feed themselves was
      significantly improved 2 months after surgery (p = 0.01). There were short-term
      trends toward improvement in reported dressing ability, personal hygiene, and
      writing. There were no significant changes in the SF-36 subscales or total score.
      CONCLUSIONS: In this cohort of patients with MS who suffered from tremor,
      thalamic DBS significantly improved their tremor and ability to feed themselves.
      Patient satisfaction with the procedure, however, was variable. Preoperative
      patient education about what functions might (and might not) be improved is
      crucial to avoid unrealistic expectations. Our results indicate that younger
      patients with MS tremor who had a shorter disease duration and no superimposed
      ataxia benefited most from this surgery.

PMID- 12405369
TI  - Surgical procedures for posterior fossa tumors in children: does craniotomy lead
      to fewer complications than craniectomy?
AB  - OBJECT: Traditionally, access to the posterior fossa involved a suboccipital
      craniectomy. More recently, posterior fossa craniotomies have been described,
      although the long-term benefits of this procedure are not clear. The authors
      compared the postoperative complications of craniectomies and craniotomies in
      children with posterior fossa tumors. METHODS: From a total of 110 children
      undergoing surgery for posterior fossa tumors, 56 underwent craniectomy and 54
      had a craniotomy. The mean duration of the hospital stay was longer in the
      craniectomy group (17.5 compared with 14 days). At operation, similar numbers of
      patients in both groups had total macroscopic clearance of the tumor, complete
      dural closure, and duraplasty. Postoperatively, more patients in the craniectomy
      group were noted to have cerebrospinal fluid (CSF) leakage (27 compared with 4%;
      p < 0.01) and pseudomeningoceles (23 compared with 9%; p < 0.05). There was no
      significant difference between the two groups in the numbers of patients with CSF
      infections, wound infections, or hydrocephalus requiring permanent CSF drainage.
      Patients with CSF leaks had a longer duration of hospital stay (20.7 compared
      with 14.9 days; p < 0.01), and were more likely to have CSF infections (35
      compared with 12%; p < 0.01) and wound infections (24 compared with 1%; p < 0.01)
      than patients without CSF leaks. Postoperatively, wound exploration and
      reclosures for CSF leakage were more likely in the craniectomy group (11 compared
      with 0%; p < 0.01). Multivariate analysis revealed that the only predictor of CSF
      leakage postoperatively was the type of surgery (that is, craniotomy compared
      with craniectomy; odds ratio 10.8; p = 0.03). CONCLUSIONS: Craniectomy was
      associated with postoperative CSF leaks, pseudomeningocele, increased wound
      reclosures, and thus prolonged hospital stays. In turn, CSF leakage was
      associated with infections of the CSF and wound. The authors propose mechanisms
      that may explain why CSF leakage is less likely if the bone flap is replaced.

PMID- 12405370
TI  - Ependymoma in childhood: prognostic factors, extent of surgery, and adjuvant
      therapy.
AB  - OBJECT: The aim of this study was to investigate the effect of patient-related
      factors, extent of surgery, and adjuvant therapy on survival in children
      presenting with intracranial ependymoma. METHODS: Between 1980 and 1999, 83
      children (mean age 36 months) underwent surgery for intracranial ependymomas.
      Complete resection, verified on postoperative computerized tomography scans, was
      achieved in 73%. Adjuvant therapy modalities have changed over the years: before
      1990 all patients received radiotherapy, whereas after 1990 the children younger
      than 3 years of age and later those younger than 5 years of age were treated
      first with chemotherapy and received radiotherapy only after their first tumor
      recurrence. The follow-up period averaged 70 +/- 49 months. CONCLUSIONS: Overall
      survival, intraoperative deaths excluded, was 73 +/- 11% and 51 +/- 14% at 5 and
      10 years, respectively. The event-free survival rate at 5 and 10 years was 48 +/-
      12% and 46 +/- 12%, respectively. Most of the events were local recurrences.
      Despite multiple reinterventions, the overall survival rate in this group dropped
      to 14%. On univariate analysis, the only significant prognostic factors were
      complete resection and radiotherapy. Both of these factors combined increased the
      5- and 10-year survival rates to 93 and 75%, respectively. Age of the patients
      was not a statistically independent prognostic factor. The patients in the
      chemotherapy group did not fare as well as those in the radiotherapy group. A
      subgroup (36%) within the chemotherapy group, however, survived tumor free after
      a mean follow-up period of 67 months. It is not clear whether this subgroup
      either responded well to chemotherapy or needed no adjuvant therapy. Further
      research is warranted to answer this question.

PMID- 12405371
TI  - Temporary arterial occlusion in the repair of ruptured intracranial aneurysms: an
      analysis of risk factors for stroke.
AB  - OBJECT: This study was performed to further elucidate technical and patient
      specific risk factors for perioperative stroke in patients undergoing temporary
      arterial occlusion during the surgical repair of their aneurysms. METHODS: One
      hundred twelve consecutive patients in whom temporary arterial occlusion was
      performed during surgical repair of an aneurysm were retrospectively analyzed.
      Confounding factors (inadvertent permanent vessel occlusion and retraction
      injury) were identified in six cases (5%) and these were excluded from further
      analysis. The demographics for the remaining 106 patients were analyzed with
      respect to age, neurological status, aneurysm characteristics, intraoperative
      rupture, duration of temporary occlusion, and number of occlusive episodes; end
      points considered were outcome at 3-month follow up and symptomatic and
      radiological stroke. CONCLUSIONS: Overall 17% of patients experienced symptomatic
      stroke and 26% had radiological evidence of stroke attributable to temporary
      arterial occlusion. A longer duration of clip placement, older patient age, a
      poor clinical grade (Hunt and Hess Grades IV-V), early surgery, and the use of
      single prolonged clip placement rather than repeated shorter episodes were
      associated with a higher risk of stroke based on univariate analysis.
      Intraoperative aneurysm rupture did not affect stroke risk. On multivariate
      analysis, only poorer clinical grade (p = 0.001) and increasing age (p = 0.04)
      were significantly associated with symptomatic stroke risk.

PMID- 12405372
TI  - Complementary management of partially occluded aneurysms by using surgical or
      endovascular therapy.
AB  - OBJECT: The authors present a series of patients in whom partially occluded
      aneurysms were retreated using complementary surgical or endovascular therapy.
      METHODS: During a period of 18 months, 301 patients with intracranial aneurysms
      were treated using either clip application (171 patients) or endovascular
      embolization with Guglielmi Detachable Coils ([GDCs] 130 patients). Routine
      posttreatment angiography studies revealed residual aneurysms in 21 of these
      patients, nine of whom were retreated using an endovascular or surgical method,
      with a mean treatment latency of 1.2 months. Four patients underwent primary
      surgical clip application, whereas five patients experienced GDC packing first.
      Among patients in the surgical group, the residual aneurysm neck was small and
      total elimination of the aneurysm was achieved by packing in GDCs. In patients in
      the endovascular group the authors incompletely packed the aneurysm because of
      its wide neck or fusiform component in two patients, perforation of a very small
      aneurysm in one patient, and coil dislocation in another patient. Typical coil
      compaction occurred in one case. Complete clip application was achieved in all
      patients. There was no complication in any patient due to the second treatment
      modality. Final outcome was excellent or good in six and fair in three.
      CONCLUSIONS: Following clip application or endovascular embolization of
      intracranial aneurysms, the use of complementary surgical or endovascular
      management is successful and associated with low morbidity.

PMID- 12405373
TI  - Ophthalmological outcome after orbital entry during anterior and anterolateral
      skull base surgery.
AB  - OBJECT: Partial resection of the orbital bones is not uncommon during the
      excision of anterior and anterolateral skull base tumors. Controversy exists
      regarding the need for and extent of reconstruction after this procedure. The
      authors studied this factor in a series of patients. METHODS: The authors
      conducted a retrospective review of 56 patients in whom resection of 57 anterior
      or anterolateral skull base tumors and partial excision of the orbital bone were
      performed. Adverse ophthalmological outcomes were noted in 16 patients, in nine
      of whom adverse outcomes were believed to be directly related to resection of the
      orbital walls. Some degree of orbital reconstruction was performed during 23 of
      the 57 procedures. An adverse orbital outcome was strongly associated with
      resection of the orbital floor and resection of two thirds or more of two or more
      orbital walls, but not with the presence or absence of orbital reconstruction.
      The later finding, however, is likely a function of selection bias. CONCLUSIONS:
      In most patients elaborate orbital reconstruction is not necessary after partial
      excision of the orbital bones. Isolated medial and lateral orbital wall defects,
      or combined superior and lateral orbital wall defects, especially in cases in
      which the periorbita is intact, probably do not require primary reconstruction.
      In cases of orbital floor defects, whether isolated or part of a multiple-wall
      resection, primary reconstruction is recommended.

PMID- 12405374
TI  - Organization of language areas in bilingual patients: a cortical stimulation
      study.
AB  - OBJECT: In an attempt to gain a better understanding of how multiple languages
      are represented in the human brain, the authors studied bilingual patients who
      underwent surgery for brain tumors, during which the authors mapped cortical
      language sites by using electrostimulation. METHODS: Reading, counting, and word
      retrieval tasks were studied in 12 right-handed bilingual patients with no
      language deficit. All bilingual patients were native to France. One patient spoke
      four languages. The patients constituted a nonhomogeneous group in terms of
      language proficiency or age of acquisition. Languages were evaluated and
      classified into three major groups, depending on proficiency and date of
      acquisition. Strict conditions of language site validation were applied,
      separating typical anomia sites from speech arrest or other language sites (such
      as hesitation sites). A total of 30 speech arrest sites, 16 anomia sites, and
      three sites of language difficulties (not typically classified as speech arrest)
      were found throughout the 26 language studies performed. Strict overlapping of
      language areas (for all language tasks) was found in five patients, whereas the
      remaining seven had at least one area that was language-specific and sometimes
      task-specific. Specific areas for a particular language were found for word
      retrieval tasks (anomia) in eight sites (50%) but also in six (20%) of the
      reading or counting sites (speech arrest), either in frontal (three patients) or
      in temporoparietal (four patients) regions. Among the four early bilingual
      patients tested (languages acquired before the age of 7 years), three had
      language-specific cortical areas. Interestingly, six patients in this series who
      had a discrepancy between two languages did not have more cortical areas devoted
      to the less proficient language (with acknowledgment of the limit in cortical
      exposure available for testing by the craniotomy). CONCLUSIONS: In this series,
      the authors found that bilingual patients could have common but also different
      cortical areas for both languages in temporoparietal areas and in frontal areas.
      In some cases, the authors found that language tasks such as counting, reading,
      or word retrieval in different languages can be sustained by language- and task
      specific cortical areas. In bilingual patients, cortical mapping should ideally
      be performed using different language tasks in all languages in which the patient
      is fluent.

PMID- 12405375
TI  - Magnetoencephalography-directed surgery in patients with neocortical epilepsy.
AB  - OBJECT: Magnetoencephalography (MEG) and magnetic source (MS) imaging are
      techniques that have been increasingly used for preoperative localization of
      epileptic foci and areas of eloquent cortex. The use of MEG examinations must be
      carefully balanced against the high cost and technological investments required
      to perform these studies, particularly when less expensive alternative
      localization methods are available. To help elucidate the value of MEG, the
      authors have critically reviewed their experience with whole-head MEG in the case
      management of patients undergoing epilepsy surgery. METHODS: The authors
      identified 23 patients with suspected focal epilepsy who underwent whole-head MEG
      and MS imaging at Huntington Memorial Hospital and, subsequently, underwent
      invasive intracranial electrode monitoring and electrocorticography (ECoG) to
      localize the zone of seizure origin for surgical resection. The results of the MS
      imaging were retrospectively stratified into three groups by the number of
      interictal spikes recorded during a 4-hour recording session: Class I (no
      spikes), Class II (< or = five spikes), and Class III (> or = six spikes). Class
      III was further subdivided according to the clustering density of the interictal
      spikes: Class IIIA represents a mean distance between interictal spikes of 4 mm
      or greater (that is, diffusely clustered) and Class IIIB represents a mean
      distance between interictal spikes of less than 4 mm (that is, densely
      clustered). The authors analyzed these groups to determine to what extent the
      results of MS imaging correlated with the ECoG-determined zone of seizure origin.
      In addition, they assessed whether the MS imaging study provided critical
      localization data and correlated with surgical outcome following resection. A
      statistical analysis of these correlations was also performed. Of the 40 patients
      studied, 23 underwent invasive monitoring, including 13 with neocortical
      epilepsy, four with mesial temporal lobe epilepsy, and six with suspected
      neocortical epilepsy that could not be clearly localized by ECoG. Depth
      electrodes were used in nine cases, subdural grids in nine cases, depth
      electrodes followed by subdural grids and strips in four cases, and
      intraoperative ECoG in one case. Electrocorticography was able to localize the
      zone of seizure origin in 16 (70%) of 23 cases. In 11 (69%) of the 16 cases in
      which ECoG was able to localize the zone of seizure origin, the interictal spikes
      on the MS images were classified as Class IIIB (densely clustered) and regionally
      correlated to the MS imaging-determined localization in all cases (that is, the
      same lobe). In contrast, no Class IIIB cases were identified when ECoG was unable
      to localize the zone of seizure origin. This difference showed a trend toward,
      but did not achieve, statistical significance (p < 0.23), presumably because of
      the relatively small number of cases available for analysis. In three cases (all
      Class IIIB), MS imaging was used to guide invasive electrodes to locations that
      otherwise would not have been targeted and provided unique localization data, not
      evident from other imaging modalities, that strongly influenced the surgical
      management of the patient. The classification of findings on MS images into
      subgroups and subsequent statistical analysis generated a model that predicted
      that Class IIIB MS imaging data are likely to provide reliable information to
      guide surgical placement of electrodes, but all other data groups do not provide
      localization information that is reliable enough to guide surgical decision
      making. CONCLUSIONS: Magnetic source imaging can provide unique localization
      information that is not available when other noninvasive methods are used.
      Magnetic source imaging appears most useful for cases of neocortical epilepsy. In
      particular, when an MS imaging study revealed six or more interictal spikes that
      were densely clustered in a single anatomical location, the MS image was highly
      correlated with the zone of seizure origin identified by ECoG. In these cases the
      MS imaging data may be useful to guide placement of intracranial electrodes.

PMID- 12405376
TI  - Trigeminal neuralgia caused by microarteriovenous malformations of the trigeminal
      nerve root entry zone: symptomatic relief following complete excision of the
      lesion with nerve root preservation.
AB  - OBJECT: Within a series of 341 consecutive patients who underwent posterior fossa
      surgery for trigeminal neuralgia (TN), in five the cause was found to be a
      microarteriovenous malformation (micro-AVM) located in the region of the
      trigeminal nerve root entry zone (REZ). The surgical management and clinical
      outcomes of these cases are presented. METHODS: Patients were identified from a
      prospectively collected database of all cases of TN treated at one institution
      between 1980 and 2000. Presentation was clinically indistinguishable from TN
      caused by vascular compression. Preoperative imaging, including computerized
      tomography scanning (two cases) and magnetic resonance (MR) imaging and MR
      angiography (three cases), failed to demonstrate an AVM except for one case in
      which multiple abnormal vessels were identified in the trigeminal REZ on an MR
      image obtained using a 1.5-tesla magnet. All patients underwent a standard
      retromastoid craniotomy. In all cases a small AVM embedded in the trigeminal REZ
      was identified and completely excised, with preservation of the trigeminal nerve.
      All patients experienced immediate relief of pain following surgery.
      Postoperatively, in one patient a small pontine hematoma developed, resulting in
      permanent trigeminal nerve anesthesia in the V2 and V3 divisions. All patients
      were free from pain at a mean follow-up period of 30 months. CONCLUSIONS: These
      rare lesions are usually angiographically occult, but may sometimes be
      identifiable on high-resolution MR images. Total microsurgical resection with
      nerve preservation is possible, although operative complications are relatively
      common, reflecting the intimate association between these lesions and the pons.
      Complete resection is advised not only for symptom relief, but also to eliminate
      the theoretical risk of pontine hemorrhage.

PMID- 12405377
TI  - A mixture of ethylene vinyl alcohol copolymer and ethanol yielding a nonadhesive
      liquid embolic agent to treat cerebral arteriovenous malformations: initial
      clinical experience.
AB  - OBJECT: The authors report their clinical experience with their new nonadhesive
      liquid embolic agent, an ethylene vinyl alcohol copolymer (EVAL)/ethanol mixture,
      to treat arteriovenous malformations (AVMs). METHODS: Between June 1995 and April
      2001, 57 patients with confirmed AVMs underwent embolization of their lesions
      with the EVAL/ethanol mixture. In 87 procedures consisting of one to three
      stages, the authors embolized 185 feeding arteries to occlude as much of the AVM
      as possible. Repeated injections under fluoroscopic control could be performed
      smoothly without encountering cementing of the catheter to the vessel wall. Among
      the 87 embolizations undertaken in 57 patients, seven procedures (8%) in six
      patients produced new postembolization symptoms. Resolution of these symptoms
      occurred within hours or days after four of the seven procedures; permanent
      neurological deficits remained after the other three procedures (3.4%). Of the 57
      patients, three underwent postembolization radiosurgery, and 54 underwent radical
      treatment with microsurgical extirpation. Histopathological examination of the 54
      specimens disclosed mild inflammation within the embolized lumen without
      inflammatory reactions in the media or adventitia. Follow-up angiograms obtained
      3 years after radiosurgery was administered showed that in all three patients
      treated in this fashion the nidus had completely disappeared. CONCLUSIONS: The
      EVAL/ethanol mixture is handled easily and appears to be an effective and safe
      agent for preoperative embolization of AVMs.

PMID- 12405378
TI  - A nonadhesive liquid embolic agent composed of ethylene vinyl alcohol copolymer
      and ethanol mixture for the treatment of cerebral arteriovenous malformations:
      experimental study.
AB  - OBJECT: The authors have developed a mixture of ethylene vinyl alcohol copolymer
      (EVAL) and iopamidol, which is dissolved in ethanol, as an alternative solvent to
      provide a safe means of embolizing arteriovenous malformations (AVMs). METHODS: A
      two-stage delivery technique is required to prevent premature precipitation in
      the catheter when using this material: the catheter is first infused with 30%
      ethanol and this is followed by the delivery of the EVAL-ethanol mixture. Acute
      angiographic changes were analyzed after superselective delivery of dimethyl
      sulfoxide (DMSO) and 30% ethanol into the renal artery of rabbits. Histological
      changes following the embolization of the renal artery achieved using the EVAL
      ethanol mixture were recorded at 1 hour and at 2 and 16 weeks after the
      procedure. Although DMSO always produced severe, rapidly progressive vasospasm in
      the renal artery during a 1- to 60-minute postinfusion, 30% ethanol did not.
      Microscopically, the lumens of embolized vessels examined 1 hour after
      embolization with EVAL-ethanol appeared to be filled with EVAL sponges, leaving
      almost no open spaces. The space between the EVAL sponges and the inner surface
      of the vessels was filled with fresh thrombus. In the vessel walls of specimens
      examined 2 weeks after embolization there was no or a slight inflammatory
      reaction. Scattered in the EVAL sponges were almost equal numbers of neutrophilic
      granulocytes and mononuclear cells, indicative of a mild inflammatory response.
      In specimens examined 16 weeks postembolization, the changes noted at 2 weeks
      were intensified. There was no definite histopathological evidence of mural
      hemorrhage, perivascular extravasation of the mixture, or perivascular hemorrhage
      in any specimen that was examined. CONCLUSIONS: Although the degree of permanence
      of this embolization material is yet unknown, the mixture was easy to handle, and
      appeared safe and effective for AVM embolization. Its nonadhesive characteristic
      and its ability to be infused by repeated injections make it an attractive
      alternative to currently available materials. The good results obtained in this
      study led us to undertake a clinical trial, the results of which are contained in
      a companion article in this issue of the Journal of Neurosurgery.

PMID- 12405379
TI  - Evaluation of the microvasculature and cerebral ischemia after experimental
      subarachnoid hemorrhage in dogs.
AB  - OBJECT: Whether cerebral vasospasm occurs only in surface vessels or also in
      parenchymal arterioles is debatable. The present study was undertaken to evaluate
      comprehensively the microvasculature of the brainstem after experimental
      subarachnoid hemorrhage (SAH). METHODS: Nine mongrel dogs of either sex, each
      weighing between 18 and 24 kg, underwent double blood injections spaced 48 hours
      apart; the injections were infused into the cisterna magna immediately after
      angiography of the basilar arteries (BAs). Three additional dogs assigned to a
      control group received no blood injections. The dogs were killed on Day 7. Axial
      sections obtained from the midpontine region of both control dogs and animals
      subjected to SAH were evaluated with respect to the morphological characteristics
      of vessels and neurons, and for ultrastructural changes. Severe vasospasm
      occurred in the BAs of all dogs subjected to SAH. Nevertheless, in these animals,
      the luminal areas and vessel perimeter in parenchymal arterioles, but not in
      parenchymal venules, were observed to have increased when compared with those of
      control dogs (p < 0.01, t-test). No corrugation of the internal elastic lamina
      was observed and smooth-muscle and endothelial cells remained normal at the
      ultrastructural level in the dogs with SAH. CONCLUSIONS: In this model, vasospasm
      of the BAs did not extend into the region of the pons to affect the
      intraparenchymal arterioles. Dilation of the parenchymal arterioles might serve
      as compensation for reduced blood flow. Thus, no neuronal ischemia or infarction
      resulted in the pontine region of the brain.

PMID- 12405380
TI  - Successful and safe perfusion of the primate brainstem: in vivo magnetic
      resonance imaging of macromolecular distribution during infusion.
AB  - OBJECT: Intrinsic disease processes of the brainstem (gliomas, neurodegenerative
      disease, and others) have remained difficult or impossible to treat effectively
      because of limited drug penetration across the blood-brainstem barrier with
      conventional delivery methods. The authors used convection-enhanced delivery
      (CED) of a macromolecular tracer visible on magnetic resonance (MR) imaging to
      examine the utility of CED for safe perfusion of the brainstem. METHODS: Three
      primates (Macaca mulatta) underwent CED of various volumes of infusion ([Vis];
      85, 110, and 120 microl) of Gd-bound albumin (72 kD) in the pontine region of the
      brainstem during serial MR imaging. Infusate volume of distribution (Vd),
      homogeneity, and anatomical distribution were visualized and quantified using MR
      imaging. Neurological function was observed and recorded up to 35 days
      postinfusion. Histological analysis was performed in all animals. Large regions
      of the pons and midbrain were successfully and safely perfused with the
      macromolecular protein. The Vd was linearly proportional to the Vi (R2 = 0.94),
      with a Vd/Vi ratio of 8.7 +/- 1.2 (mean +/- standard deviation). Furthermore, the
      concentration across the perfused region was homogeneous. The Vd increased
      slightly at 24 hours after completion of the infusion, and remained larger until
      the intensity of infusion faded (by Day 7). No animal exhibited a neurological
      deficit after infusion. Histological analysis revealed normal tissue architecture
      and minimal gliosis that was limited to the region immediately surrounding the
      cannula track. CONCLUSIONS: First, CED can be used to perfuse the brainstem
      safely and effectively with macromolecules. Second, a large-molecular-weight
      imaging tracer can be used successfully to deliver, monitor in vivo, and control
      the distribution of small- and large-molecular-weight putative therapeutic agents
      for treatment of intrinsic brainstem processes.

PMID- 12405381
TI  - Effects of the nitric oxide donor 3-morpholinosydnonimine (SIN-1) in focal
      cerebral ischemia dependent on intracellular brain pH.
AB  - OBJECT: A nitric oxide (NO) donor that has been successfully used in the
      treatment of myocardial infarction, 3-morpholinosydnonimine (SIN-1), may be a
      potential neuroprotective agent. Production of NO in brain microsomes is
      dependent on the pH. The purpose of this study was to determine the efficacy of
      SIN-1 and its dependence on pH in vivo during periods of focal cerebral ischemia.
      METHODS: At 0.1 or 1 mg/kg, SIN-1 was administered to 54 Wistar rats 30 minutes
      before a 2-hour period of focal cerebral ischemia under moderate hypo-, normo-,
      and hyperglycemic conditions. Measurements of brain intracellular pH (pHi);
      regional cortical blood flow, and the redox state of nicotinamide adenine
      dinucleotide were obtained in three additional animals to confirm the effects of
      the serum glucose manipulations. The animals were killed at 72 hours after the
      ischemic period to obtain infarction volumes. Administration of SIN-1
      significantly reduced infarction in normoglycemic animals and, to a lesser
      extent, in hyperglycemic animals, indicating that SIN-1 was less effective under
      hyperglycemic conditions. At either dose SIN-1 had no significant effect on
      infarction volume in moderately hypoglycemic animals because moderate
      hypoglycemia in itself significantly (p < 0.005) reduced infarction volume.
      CONCLUSIONS: The NO donor SIN-1 may be a useful intraoperative cerebral
      protective agent. Furthermore, it is hypothesized that a mechanism that could
      explain the published discrepancies regarding the effects of NO donors in vivo
      may be affected by differences in ischemic brain acidosis.

PMID- 12405382
TI  - Comparison of different infratentorial-supracerebellar approaches to the
      posterior and middle incisural space: a cadaveric study.
AB  - OBJECT: The purpose of this investigation was to describe and compare through
      cadaveric dissection the microsurgical exposure afforded by the median,
      paramedian, and extreme-lateral infratentorial-supracerebellar approaches to the
      posterior and middle incisural space. METHODS: The median, paramedian, and
      extreme-lateral infratentorial-supracerebellar approaches were performed in 10
      embalmed cadaveric heads by using standard microneurosurgical methods; each
      approach was executed a minimum of five times. The dissections were performed in
      a stepwise fashion, comparing the exposure afforded by each surgical route and
      highlighting the relationships among the targeted neurovascular structures.
      Exposure of the dural sinuses and transection of the tentorium were also
      evaluated in relation to the degree of exposure achieved. The median
      infratentorial-supracerebellar route provides direct exposure of the posterior
      incisural space, although the culmen represents a relative obstacle to exposure
      of the lower quadrigeminal plate. The paramedian variant allows a more lateral
      perspective on the posterolateral brainstem surface at the level of the middle
      incisural space, in addition to exposing the homolateral collicular plate. The
      extreme-lateral corridor widens the exposure of the paramedian approach to
      include the anterolateral brainstem surface, offering a complete view of the
      cisternal space surrounding the middle incisural space. Complete, constant
      exposure and retraction of the dural sinuses facilitated the surgical exposure.
      CONCLUSIONS: The infratentorial-supracerebellar approaches allow safe
      circumferential exposure of the posterior and middle incisural space. Choosing
      among different variants allows the surgeon to reach selected areas, with the
      midline variant being best for exposure of the posterior incisural space, and the
      paramedian and extreme-lateral variants being best for reaching the posterior and
      the anterior part of the middle incisural space, respectively. The more lateral
      the approach, the more anterior and multiangled the exposure gained. Complete,
      constant exposure and retraction of the dural sinuses improves the exposure.
      Accurate knowledge of the regional anatomy is mandatory.

PMID- 12405383
TI  - Temporal pattern of cochlear nerve degeneration following compression injury: a
      quantitative experimental observation.
AB  - OBJECT: It has been empirically recognized that the cochlear nerve is highly
      vulnerable to traumatic stress resulting from surgical procedures; therefore,
      careful manipulation of the cochlear nerve is mandatory in preventing trauma
      induced hearing loss during cerebellopontine angle (CPA) surgery. There is,
      however, no precise knowledge about the temporal pattern of cochlear nerve
      degeneration following trauma. This study was performed to determine the temporal
      pattern of injury that occurs after cochlear nerve trauma, knowledge of which is
      indispensable not only to neurosurgeons but also to all those who manage lesions
      involving the cochlear nerve. METHODS: Right suboccipital craniectomies were
      performed in groups of rats with the aid of a surgical microscope, and the
      seventh and eighth cranial nerve trunks were identified at the internal auditory
      meatus. The cochlear nerve was quantifiably compressed while compound action
      potentials of the cochlear nerve were monitored and recorded. Following injury,
      one group of rats was killed for histological examination at the end of each week
      for 4 weeks. Data from this study disclosed that the degeneration of the
      compressed cochlear nerve progressed in a relatively rapid manner and was
      complete within 1 week after the insult. The main pathophysiological mechanisms
      responsible for cochlear neuronal death in this experimental setting appeared to
      be necrosis, and an apoptotic mechanism seemed to play a subsidiary role.
      CONCLUSIONS: Accurate knowledge about the temporal profile of trauma-induced
      cochlear nerve degeneration is closely linked with the problem of the therapeutic
      time window. The results of the present study indicated that any measures to
      ameliorate cochlear nerve degeneration following trauma should be started as
      early as possible (within 1 week) after an injury.

PMID- 12405384
TI  - Neural and marrow-derived stromal cell sphere transplantation in a rat model of
      traumatic brain injury.
AB  - OBJECT: This study was designed to investigate the effect of treatment with a
      novel composite material consisting of embryonic neurospheres and bone marrow
      derived stromal cell spheres (NMSCSs) in a rat model of traumatic brain injury
      (TBI). METHODS: The NMSCS composite was injected into the TBI contusion site 24
      hours after injury, and all rats were killed on Day 14 after the transplantation.
      The Rotarod test and the neurological severity score were used to evaluate
      neurological function. The transplanted NMSCS was analyzed in recipient rat
      brains by using histological staining and laser scanning confocal microscopy. The
      lesion volumes in the brains were also calculated using computer image analysis.
      CONCLUSIONS: Rats that received NMSCS transplants had reduced lesion volume and
      showed improved motor and neurological function when compared with control groups
      14 days after the treatment. These results suggest that transplantation of this
      novel biological material (NMSCS) may be useful in the treatment of TBI.

PMID- 12405385
TI  - Origins of surface potentials evoked by electrical stimulation of oculomotor
      nerves: are they related to electrooculographic or electromyographic events?
AB  - OBJECT: Evoked potentials elicited by electrical stimulation of the oculomotor
      nerve and recorded from surface electrodes placed on the skin around the eyeball
      reportedly originate in the eye and are represented on electrooculograms. Because
      evoked potentials recorded from surface electrodes are extremely similar to those
      of extraocular muscles, which are represented on electromyograms, the authors
      investigated the true origin of these potentials. METHODS: Evoked potentials
      elicited by electrical stimulation of the canine oculomotor nerve were recorded
      from surface electrodes placed on the skin around the eyeball. A thread sutured
      to the center of the cornea was pulled and the potentials that were evoked during
      the resultant eye movement were recorded. These potentials were confirmed to
      originate in the eye and to be represented on electrooculograms because their
      waveforms were unaffected by the administration of muscle relaxant. To eliminate
      the influence of this source, the retina, a main origin of standing potentials of
      the eyeball, was removed. This resulted in the disappearance of
      electrooculography (EOG) waves elicited by eye movement. Surface potentials
      elicited by oculomotor nerve stimulation were the same before and after removal
      of the retina. Again the oculomotor nerve was electrically stimulated and
      electromyography (EMG) response of the extraocular muscles was recorded at the
      same time that potentials were recorded from the surface electrodes. In their
      peak latencies, amplitudes, and waveforms, the evoked potentials obtained from
      surface electrodes were almost identical to EMG responses of extraocular muscles.
      CONCLUSIONS: Evoked potentials elicited by electrical stimulation of the
      oculomotor nerves and obtained from surface electrodes originated from EMG
      responses of extraocular muscles. These evoked potentials do not derive from the
      eye.

PMID- 12405386
TI  - The effect of brain temperature on hemoglobin extravasation after traumatic brain
      injury.
AB  - OBJECT: Although the benefits of posttraumatic hypothermia have been reported in
      experimental studies, the potential for therapeutic hypothermia to increase
      intracerebral hemorrhage remains a clinical concern. The purpose of this study
      was to quantify the amount of extravasated hemoglobin after traumatic brain
      injury (TBI) and to assess the changes in intracerebral hemoglobin concentrations
      under posttraumatic hypothermic and hyperthermic conditions. METHODS: Intubated
      and anesthetized rats were subjected to fluid-percussion injury (FPI). In the
      first experiment, rats were divided into moderate (1.8-2.2 atm) and severe (2.4
      2.7 atm) TBI groups. In the second experiment, the effects of 3 hours of
      posttraumatic hypothermia (33 or 30 degrees C), hyperthermia (39 degrees C), or
      normothermia (37 degrees C) on hemoglobin levels following moderate trauma were
      assessed. The rats were perfused with saline at 24 hours postinjury, and then the
      traumatized and contralateral hemispheres, including the cerebellum, were
      dissected from whole brain. The hemoglobin level in each brain was quantified
      using a spectrophotometric hemoglobin assay. The results of these assays indicate
      that moderate and severe FPI induce increased levels of hemoglobin in the
      ipsilateral hemisphere (p < 0.0001). After severe TBI, the hemoglobin
      concentration was also significantly increased in the contralateral hemisphere (p
      < 0.05) and cerebellum (p < 0.005). Posttraumatic hypothermia (30 degrees C)
      attenuated hemoglobin levels (p < 0.005) in the ipsilateral hemisphere, whereas
      hyperthermia had a marked adverse effect on the hemoglobin concentration in the
      contralateral hemisphere (p < 0.05) and cerebellum (p < 0.005). CONCLUSIONS:
      Injury severity is an important determinant of the degree of hemoglobin
      extravasation after TBI. Posttraumatic hypothermia reduced hemoglobin
      extravasation, whereas hyperthermia increased hemoglobin levels compared with
      normothermia. These findings are consistent with previous data reporting that
      posttraumatic temperature manipulations alter the cerebrovascular and
      inflammatory consequences of TBI.

PMID- 12405387
TI  - Fibrinolysis therapy achieved with tissue plasminogen activator and aspiration of
      the liquefied clot after experimental intracerebral hemorrhage: rapid reduction
      in hematoma volume but intensification of delayed edema formation.
AB  - OBJECT: Fibrinolysis therapy accomplished using tissue plasminogen activator
      (tPA) and aspiration is considered to be a viable alternative to microsurgery and
      medical therapy for the treatment of deep-seated spontaneous intracerebral
      hematomas (SICHs). Tissue plasminogen activator is a mediator of thrombin- and
      ischemia-related delayed edema. Because both thrombin release and ischemia occur
      after SICH, the authors planned to investigate the effect of fibrinolytic therapy
      on hematoma and delayed edema volume. METHODS: A spherical hematoma was created
      in the frontal white matter of 18 pigs. In the tPA-treated group (nine pigs), a
      mean of 1.55 ml tPA was injected into the clot and the resulting liquefied blood
      was aspirated. Magnetic resonance (MR) imaging was performed on Days 0 (after
      surgery), 4, and 10, and the volumes of hematoma and edema were determined. In
      the animals not treated with tPA (untreated group; nine pigs), the volume of
      hematoma dropped from 1.43+/-0.42 ml on Day 0 to 0.85+/-0.28 ml on Day 10. In the
      tPA-treated group, the volume of hematoma was reduced from 1.51 +/- 0.28 ml on
      Day 0 to 0.52 +/- 0.39 ml on Day 10. In comparison with the untreated group, the
      reduction in hematoma volume was significantly accelerated (p = 0.02). In the
      untreated group, perihematomal edema increased from 0.32 +/- 0.61 ml to 1.73 +/-
      0.73 ml on Day 4, before dropping to 1.17 +/- 0.92 ml on Day 10. In the tPA
      treated group, the volume of the edema increased from 0.09 +/- 0.21 ml on Day 0
      to 1.93 +/- 0.79 ml on Day 4, and further to 3.34 +/- 3.21 ml on Day 10. The
      increase in edema volume was significantly more pronounced in the tPA-treated
      group (p = 0.04). CONCLUSIONS: Despite a significantly accelerated reduction in
      hematoma volume, the development of delayed perifocal edema was intensified by
      fibrinolytic therapy, which is probably related to the function of tPA as a
      mediator of edema formation after thrombin release and ischemia. Further
      experimental and clinical investigations are required to establish the future
      role of fibrinolysis in the management of SICH.

PMID- 12405388
TI  - Reversal of attenuation of cerebrovascular reactivity to hypercapnia by a nitric
      oxide donor after controlled cortical impact in a rat model of traumatic brain
      injury.
AB  - OBJECT: Traumatic brain injury (TBI) attenuates the cerebral vasodilation to
      hypercapnia. Cortical spreading depression (CSD) also transiently reduces
      hypercapnic vasodilation. The authors sought to determine whether the CSD
      elicited by a controlled cortical impact (CCI) injury masks the true effect of
      TBI on hypercapnic vasodilation, and whether a nitric oxide (NO) donor can
      reverse the attenuation of hypercapnic vasodilation following CCI. METHODS:
      Anesthetized rats underwent moderate CCI. Cerebral blood flow was monitored with
      laser Doppler flowmetry and the response to hypercapnia was determined for
      injured and sham-injured animals. The effect of the NO donor, S-nitroso-N
      acetylpenicillamine (SNAP), on this response was also assessed. At an uninjured
      cortical site ipsilateral to the CCI, a single wave of CSD was recorded and the
      CO2 response at this location was significantly attenuated for up to 30 minutes
      (seven rats, p < 0.05). At the injured cortex, hypercapnic vasodilation continued
      to be attenuated for 7 hours. The cerebral vasodilation to CO2 was 37 +/- 5% in
      injured rats (six) compared with 84 +/- 10% in the sham-injured group (five rats,
      p < 0.05). After 30 minutes of topical superfusion with SNAP, hypercapnic
      vasodilation was restored to 74 +/- 7% (nine rats, p > 0.1 compared with that in
      the sham-injured group). In contrast, papaverine, an NO-independent vasodilator,
      failed to reverse the attenuation of the CO2 response to CCI. CONCLUSIONS: The
      authors conclude that CSD elicited by CCI can mask the true effect of TBI on
      hypercapnic vasodilation for at least 30 minutes. Exogenous NO, but not
      papaverine, can reverse the attenuation of cerebrovascular reactivity to CO2
      caused by TBI. This result supports the hypothesis that NO production is reduced
      after TBI and that the NO donor has a potential beneficial role in the clinical
      management of head injury.

PMID- 12405389
TI  - Photoirradiation therapy of experimental malignant glioma with 5-aminolevulinic
      acid.
AB  - OBJECT: Accumulation of protoporphyrin IX (PPIX) in malignant gliomas is induced
      by 5-aminolevulinic acid (5-ALA). Because PPIX is a potent photosensitizer, the
      authors sought to discover whether its accumulation might be exploited for use in
      photoirradiation therapy of experimental brain tumors, without injuring normal or
      edematous brain. METHODS: Thirty rats underwent craniotomy and were randomized to
      the following groups: 1) photoirradiation of cortex (200 J/cm2, 635-nm argon-dye
      laser); 2) photoirradiation of cortex (200 J/cm2) 6 hours after intravenous
      administration of 5-ALA (100 mg/kg body weight); 3) cortical cold injury for
      edema induction; 4) cortical cold injury with simultaneous administration of 5
      ALA (100 mg/kg body weight) and photoirradiation of cortex (200 J/cm2) 6 hours
      later; or 5) irradiation of cortex (200 J/cm2) 6 hours after intravenous
      administration of Photofrin II (5 mg/kg body weight). Tumors were induced by
      cortical inoculation of C6 cells and 9 days later, magnetic resonance (MR) images
      were obtained. On Day 10, animals were given 5-ALA (100 mg/kg body weight) and
      their brains were irradiated (100 J/cm2) 3 or 6 hours later. Seventy-two hours
      after irradiation, the brains were removed for histological examination.
      Irradiation of brains after administration of 5-ALA resulted in superficial
      cortical damage, the effects of which were not different from those of the
      irradiation alone. Induction of cold injury in combination with 5-ALA and
      irradiation slightly increased the depth of damage. In the group that received
      irradiation after intravenous administration of Photofrin II the depth of damage
      inflicted was significantly greater. The extent of damage in response to 5-ALA
      and irradiation in brains harboring C6 tumors corresponded to the extent of tumor
      determined from pretreatment MR images. CONCLUSIONS: Photoirradiation therapy in
      combination with 5-ALA appears to damage experimental brain tumors selectively,
      with negligible damage to normal or perifocal edematous tissue.

PMID- 12405391
TI  - Separation of craniopagus joined at the occiput. Case report.
AB  - Siamese or conjoined twins have intrigued both the physician and layperson for
      centuries. The craniopagus type (joined at the head) is exceedingly rare, with an
      incidence of one in 2.5 million births. Most clinicians never see a case of
      craniopagus, and those who do rarely see more than one. The authors present a
      case of the craniopagus type of conjoined twins born and recently separated in
      Brisbane, Australia. The prenatal diagnosis, subsequent investigations,
      separation, and outcome are presented.

PMID- 12405390
TI  - Analysis of von hippel-lindau mutations with comparative genomic hybridization in
      sporadic and hereditary hemangioblastomas: possible genetic heterogeneity.
AB  - OBJECT: Hemangioblastomas (HBs) occur sporadically or as a manifestation of von
      Hippel-Lindau (VHL) disease. In the majority of VHL-related HBs, inactivation of
      the VHL tumor suppressor gene (TSG), which is located on chromosome 3p25-26, is
      found. The VHL gene is assumed to be involved also in the development of sporadic
      HBs. In a previous study of chromosomal aberrations of sporadic HBs, multiple
      chromosomal imbalances were found in the majority of tumors. The aim of this
      study was to analyze further both sporadic HBs and VHL-related HBs to determine
      if these histopathologically identical tumors have a different genetic
      background. METHODS: Sixteen sporadic HBs and seven VHL-related HBs were
      identified by clinical criteria and analyzed. Comparative genomic hybridization
      was used to screen for chromosomal imbalances throughout the entire HB genome.
      Additionally, mutation analysis of the VHL gene was performed using direct
      sequencing. Loss of chromosome 3 and multiple other chromosomal imbalances were
      found in the sporadic HBs, although only one imbalance, a loss of chromosome 3,
      was detected in the seven VHL-related HBs. Somatic VHL gene mutations were found
      in one third of sporadic HBs, whereas a mutation of the VHL gene was detected in
      all VHL-related HBs. CONCLUSIONS: These results indicate that the molecular
      mechanisms underlying sporadic HBs and VHL-related HBs are different.
      Inactivation of the VHL gene is probably not the most important event in the
      tumorigenesis of sporadic HBs. Other mechanisms of inhibition of VHL protein
      function, or inactivation of other TSGs, on chromosome 3p or on other
      chromosomes, might be important in the development of sporadic HBs.

PMID- 12405392
TI  - Intracerebral Whipple disease: unusual location and bone destruction. Case
      report.
AB  - Whipple disease is a rare systemic bacterial infection characterized by migratory
      polyarthralgia and chronic diarrhea. In 5 to 20% of patients with Whipple
      disease, the infection may present initially with or eventually develop symptoms
      related to the central nervous system (CNS). Although CNS involvement is a known
      feature of systemic Whipple disease, intracerebral mass lesions are uncommon.
      Mass lesions in these cases are typically deep seated and multifocal.
      Corticosubcortical regions are unusual sites of CNS involvement in cases of
      Whipple disease. In the present paper, the authors describe the first case of
      Whipple disease to feature a single corticosubcortical solid frontoparietal mass
      lesion that displayed homogeneous contrast enhancement on neuroimaging and was
      associated with bone destruction of the calvaria. Although CNS involvement has
      been observed in the form of deep-seated mass lesions in cases of systemic
      Whipple disease, unusual manifestations should be kept in mind during diagnosis
      and follow-up review in these patients.

PMID- 12405393
TI  - Ventriculoperitoneal shunt failure as a secondary complication of ovarian
      hyperstimulation syndrome. Case report.
AB  - The authors report on a patient who presented with shunt failure due to ovarian
      hyperstimulation syndrome (OHSS) following in vitro fertilization treatment.
      Shunt dysfunction was attributed to intraabdominal hypertension as a consequence
      of ascites. At surgery, the shunt was found to be patent. The peritoneal catheter
      was externalized and subsequently revised to become a ventriculoatrial shunt
      system. This led to clinical improvement in the patient and restoration of
      ventricular size. Such a shunt complication has not previously been reported.
      Neurosurgeons should be alerted to this possibility in view of the increasing use
      of assisted conception in many developed countries.

PMID- 12405394
TI  - Large cerebral arteriovenous malformation presenting with venous ischemia in the
      contralateral hemisphere. Case report.
AB  - The authors report a rare case in which a large cerebral arteriovenous
      malformation (AVM) located in the left parietooccipital region presented with
      venous ischemia in the contralateral hemisphere. A 74-year-old man was admitted
      to the hospital because he was experiencing a loss of appetite, disorientation,
      and left hemiparesis. Computerized tomography scans revealed a low-density area
      in the right temporal lobe. Angiography demonstrated a large AVM in the left
      parietooccipital lobe and dilation, stagnation, and meanders of cortical veins in
      the contralateral hemisphere. The authors speculated that the elevated sinus
      pressure caused by a huge venous return of blood from the AVM produced venous
      ischemia in the contralateral hemisphere.

PMID- 12405395
TI  - Hyperventilation.

PMID- 12405396
TI  - Xanthomatosis.

PMID- 12405397
TI  - Sterically and electrosterically stabilized emulsion polymerization. Kinetics and
      preparation.
AB  - The principal subject discussed in the current paper is the radical
      polymerization in the aqueous emulsions of unsaturated monomers (styrene, alkyl
      (meth)acrylates, etc.) stabilized by non-ionic and ionic/non-ionic emulsifiers.
      The sterically and electrosterically stabilized emulsion polymerization is a
      classical method which allows to prepare polymer lattices with large particles
      and a narrow particle size distribution. In spite of the similarities between
      electrostatically and sterically stabilized emulsion polymerizations, there are
      large differences in the polymerization rate, particle size and nucleation mode
      due to varying solubility of emulsifiers in oil and water phases, micelle sizes
      and thickness of the interfacial layer at the particle surface. The well-known
      Smith-Ewart theory mostly applicable for ionic emulsifier, predicts that the
      number of particles nucleated is proportional to the concentration of emulsifier
      up to 0.6. The thin interfacial layer at the particle surface, the large surface
      area of relatively small polymer particles and high stability of small particles
      lead to rapid polymerization. In the sterically stabilized emulsion
      polymerization the reaction order is significantly above 0.6. This was ascribed
      to limited flocculation of polymer particles at low concentration of emulsifier,
      due to preferential location of emulsifier in the monomer phase. Polymerization
      in the large particles deviates from the zero-one approach but the pseudo-bulk
      kinetics can be operative. The thick interfacial layer can act as a barrier for
      entering radicals due to which the radical entry efficiency and also the rate of
      polymerization are depressed. The high oil-solubility of non-ionic emulsifier
      decreases the initial micellar amount of emulsifier available for particle
      nucleation, which induces non-stationary state polymerization. The continuous
      release of emulsifier from the monomer phase and dismantling of the non-micellar
      aggregates maintained a high level of free emulsifier for additional nucleation.
      In the mixed ionic/non-ionic emulsifiers, the released non-ionic emulsifier can
      displace the ionic emulsifier at the particle surface, which then takes part in
      additional nucleation. The non-stationary state polymerization can be induced by
      the addition of a small amount of ionic emulsifier or the incorporation of ionic
      groups onto the particle surface. Considering the ionic sites as no-adsorption
      sites, the equilibrium adsorption layer can be thought of as consisting of a
      uniform coverage with holes. The de-organization of the interfacial layer can be
      increased by interparticle interaction via extended PEO chains--a bridging
      flocculation mechanism. The low overall activation energy for the sterically
      stabilized emulsion polymerization resulted from a decreased barrier for entering
      radicals at high temperature and increased particle flocculation.

PMID- 12405398
TI  - Shape analysis based critical Eotvos numbers for buoyancy induced partial
      detachment of oil drops from hydrophilic surfaces.
AB  - Removal of oil drops from solid surfaces immersed in an aqueous medium is of
      interest in many applications. It has been shown that drop shape analysis can be
      used to predict conditions at which the stability limit of a lighter than water
      oil drop on a solid surface immersed in an aqueous bath is reached (Adv. Colloid
      Interface Sci. 98 (2002) 265). However the above analysis is restricted to cases
      where the contact angle made by the drop is below 90degrees and when the surface
      conditions result in a 'pinned' contact line. In this paper, it is shown that
      drop shape analysis can be used to predict the critical conditions at which drop
      stability limit is reached for drop contact angles of 90degrees and above, which
      is encountered with 'hydrophilic' surfaces. This critical condition can predict
      the occurrence of partial oil drop detachment, before complete removal due to
      'roll-up', which occurs when the hydrophilic surface is adequately smooth which
      prevents 'pinning' of the contact line. The critical conditions at which partial
      drop detachment occurs can also be approximately predicted from simple force
      balances. It has been shown (Adv. Colloid Interface Sci. 98 (2002) 265) that for
      contact angles less than 90degrees, the critical limit based on shape analysis
      appears to resolve the differences that arise due to alternate expressions for
      capillary retention force. This paper shows that even for contact angles above
      90degrees, the critical conditions predicted from the shape analysis resolves the
      differences in the predictions from the alternate force balances. Drop shape
      analysis used in this paper is based on the 'Arc-length' form of Young-Laplace or
      'drop shape' equation, which is different from the 'Y vs X' form of the above
      equation that is used in Adv. Colloid Interface Sci. 98 (2002) 265. The above
      drop shape equation is solved by a fourth order Runge-Kutta technique and it is
      shown that for angles less than 90degrees, the two forms of the drop shape
      equation, predict almost identical values of the critical Eotvos number. This
      paper highlights the competing effects of interfacial tension lowering induced
      drop instability and 'roll-up', a term that is used to describe the retraction of
      the contact line of an oil drop on a surface, in being the primary c ause for
      drop detachment.

PMID- 12405399
TI  - Theories and theoretical models for percolation and permeability in multiphase
      systems: comparative analysis.
AB  - The terminology and the physical sense of percolation and permeability were
      analyzed. Existing theories of percolation and permeability were analytically
      compared with respect to their applicability and effectiveness. It is concluded
      that the main tendency in the development of the concept of
      percolation/permeability consists in the fundamental investigation of the
      relationship between the preparation conditions of the solid, its structural
      characteristics and measured properties - not only percolation/permeability but
      also adsorption, Hg-intrusion, etc.

PMID- 12405400
TI  - Measuring forces with the AFM: polymeric surfaces in liquids.
AB  - This review links together for the first time both the practicalities of force
      measurement and the work carried out to date on force detection between polymeric
      surfaces in liquids using the atomic force microscope (AFM). Also included is
      some of the recent work that has been carried out between surfactant surfaces and
      biologically coated surfaces with the AFM. The emphasis in this review is on the
      practical issues involved with force measurement between these types of surfaces,
      and the similarities and irregularities between the observed types of forces
      measured. Comparison is made between AFM and surface force apparatus (SFA)
      measurements, as there is a much longer history of work with the latter. Results
      indicate that forces between the surfaces reviewed here are a complicated mixture
      of steric-type repulsion, conformational behaviour on separation and long-range
      attraction, which is often ascribed to 'hydrophobic' forces. The origin of this
      latter force remains uncertain, despite its almost ubiquitous appearance in force
      measurements with these types of surfaces.

PMID- 12405401
TI  - Struvite formation, control and recovery.
AB  - Recent legislation on the removal of nutrients from wastewater has led to a
      number of operation problems with struvite scaling. Struvite is MgNH4PO4 x 6H2O
      and this paper reviews the formation, control and recovery of struvite from
      primarily municipal wastewater and other waste streams. Treatment options for
      control and technologies for recovery are discussed.

PMID- 12405402
TI  - A tanks-in-series bioreactor to simulate macromolecule-laden wastewater
      pretreatment under sewer conditions by Aspergillus niger.
AB  - Sewers are typically a means of transporting wastewater to a treatment facility,
      with little biotransformation of the soluble polymeric organic matter by
      suspended biomass. In the interest of providing an effective pretreatment of
      wastewater in a sewer network, it is necessary to design an accurate tool
      simulating sewer conditions and introduce an appropriate biomass for
      macromolecular pollutant degradation. Such a model reactor was built using a
      tanks-in-series design and the degradation of a polysaccharide (starch) by
      Aspergillus niger MUCL 28817 was studied. Starch degradation and the accumulation
      of intermediates (hydrolysis fragments) in the individual reactors were
      quantified under transient conditions, at a mean hydraulic residence time of 17
      h. Starch was degraded by 90% in this reactor system and an accumulation of
      oligosaccharides with molecular weight lower than 1,000 Da was observed. These
      results may be helpful in the development of wastewater treatment in sewers and
      in the alleviation of the burden on undersized wastewater treatment systems.

PMID- 12405403
TI  - Temporal coherence in water temperature and chemistry under the ice of boreal
      lakes (Finland).
AB  - Temporal coherence was assessed for 11 limnological variables--water temperature,
      oxygen, conductivity, alkalinity, pH, colour, calcium (Ca), iron, aluminium,
      total phosphorus and total nitrogen--between 28 boreal lakes in southern Finland
      for the winter ice-covered period. The lakes were mainly small (<0.2 km2) and
      brown-coloured, and located within a circle of 10-km radius. A mean Pearson
      correlation coefficient for all lake pairs and variables averaged 0.37. Temporal
      coherence of variables across lake pairs was highest for conductivity, Ca, water
      temperature and alkalinity. The lake pairs with a direct surface water channel
      connection had a higher coherence than the lake pairs not connected by a stream.
      The size of the lake or catchment area had little effect on the coherence between
      the lakes. Temporal coherence was not strongly related to the difference in water
      colour (dystrophy) between the lakes. However, between polyhumic lakes (colour >
      100 g Pt m(-3)) the coherence was generally higher than between less coloured
      lakes. Year-to-year variation in limnological characteristics could be partly
      explained by the variation in local weather. In March, water temperature and
      chemistry were infrequently related to winter weather, rather they correlated
      with the weather conditions of the previous autumn, while the ambient late winter
      weather seemed to have a stronger influence on lake conditions in April. Temporal
      variation in some variables was related to the atmospheric pressure changes over
      the North Atlantic (the North Atlantic Oscillation, NAO). Our results suggest
      that the potential effects of climatic change on lakes can be generalised
      regionally for brown-coloured dystrophic lakes.

PMID- 12405404
TI  - Adsorption mechanism of cationic surfactants onto acid- and heat-activated
      sepiolites.
AB  - Systematic adsorption tests were carried out to determine the uptake of typical
      quaternary amines, dodecyltrimethylammonium bromide and
      hexadecyltrimethylammonium bromide and a primary amine, dodecylamine
      hydrochloride by sepiolite. Bottle adsorption tests conducted with untreated,
      acid- and heat-activated sepiolites exhibit two distinct regions. The first stage
      is characterized by low rate and governed through an ion exchange process between
      ammonium ions and magnesium ions in the octahedral sheet. The second stage is
      ascribed to a combination of chain-chain interactions through Van der Waals
      forces and ion exchange process. Despite several-fold increases in surface areas
      upon activation, surprisingly no improvement in adsorption is observed. The
      observed differences are explained on the basis of partial collapse of the
      sepiolite crystal structure, the removal of zeolitic and bound waters and
      modification of the pore size distribution of sepiolite upon treatments.

PMID- 12405405
TI  - Bacteria and fungi in aerosols generated by two different types of wastewater
      treatment plants.
AB  - Raw wastewater is a potential carrier of pathogenic microorganisms and may pose a
      health risk when pathogenic microorganisms become aerosolized during aeration.
      Two different types of wastewater treatment plants were investigated, and the
      amounts of cultivable bacteria and fungi were measured in the emitted aerosols.
      Average concentrations of 17,000 CFU m(-3) of mesophilic, 2,100 CFU m(-3) of TSA
      SB bacteria (bacteria associated with certain waterborne virulence factors), 1700
      CFU m(-3) of mesophilic and 45 CFU m(-3) of thermotolerant fungi, were found in
      the aerosol emitted by the aeration tank of the activated sludge plant. In the
      aerosol of the fixed-film reactor 3000 CFU m(-3) mesophilic and 730CFUm(-3) TSA
      SB bacteria, and 180 CFUm(-3) mesophilic and 14 CFU m(-3) thermotolerant fungi
      were measured. The specific emissions per population equivalent between the two
      types of treatment plants differed by two orders of magnitude. The microbial flux
      based on the open water surface area of the two treatment plants was similar. The
      aerosolization ratios of cultivable bacteria (expressed as CFU m(-3) aerosol/m(
      3) wastewater) ranged between 8.4 x 10(-11) and 4.9 x 10(-9). The aerosolization
      ratio of fungi was one to three orders of magnitude higher and a significant
      difference between the two types of treatment plants could be observed.

PMID- 12405406
TI  - Struvite formation and the fouling propensity of different materials.
AB  - Struvite (MgNH4PO4 x 6H2O) fouling was investigated to identify the impact
      supersaturation and material had on scaling rates. Tests were undertaken at three
      supersaturation ratios and with three different materials: stainless steel,
      teflon and acrylic. Impellers consisting of a clasp unit and two corrosion
      coupons that could be attached were used to mix centrate liquor and precipitation
      was initiated by the change in pH caused by degassing. Increasing the
      supersaturation ratio from 1.7 to 5.3 led to a doubling in the scaling rate of
      stainless-steel coupons. Experiments with acrylic and teflon coupons showed the
      influence of surface roughness upon scaling propensity. Coarsely roughened
      coupons following 40 h of mixing had a mass of 413 mg of struvite attached
      compared to smooth coupons that had a mass of 240 mg attached. Material did have
      an influence upon struvite fouling but this influence diminished with increasing
      surface roughness.

PMID- 12405407
TI  - Pilot scale treatment of textile wastewater by combined process (fluidized
      biofilm process-chemical coagulation-electrochemical oxidation).
AB  - The performance of pilot scale combined process of fluidized biofilm process,
      chemical coagulation and electrochemical oxidation for textile wastewater
      treatment was studied. In order to enhance biological treatment efficiency, two
      species of microbes, which can degrade textile wastewater pollutants efficiently,
      were isolated and applied to the system with supporting media. FeCl3 x 6H2O, pH 6
      and 3.25 x 10(-3) mol/l were determined as optimal chemical coagulation condition
      and 25 mM NaCl of electrolyte concentration, 2.1 mA/cm2 of current density and
      0.71/min of flow rate were chosen for the most efficient electrochemical
      oxidation at pilot scale treatment. The fluidized biofilm process showed 68.8% of
      chemical oxygen demand (COD) and 54.5% of color removal efficiency, even though
      using relatively low MLSS concentration and short sludge retention time. COD and
      color removals of 95.4% and 98.5% were achieved by overall combined process. The
      contribution of fluidized biofilm process to the overall combined process was
      increased over 25.7% of COD reduction and 20.5% of color reduction by adopting
      support media in biological treatment. It can be thought that the fluidized
      biofilm process was effective, and pollutant loading on post-treatment was pretty
      much decreased by this system. This combined process was highly competitive in
      comparison to the other similar combined systems. It was concluded that this
      combined process was successfully employed and much effectively decreased
      pollutant loading on post-treatment for textile wastewater treatment at pilot
      scale.

PMID- 12405408
TI  - Sulphur isotopes as tracers of the influence of potash mining in groundwater
      salinisation in the Llobregat Basin (NE Spain).
AB  - Conventional chemical data for spring and river waters are presented together
      with sulphur isotopic data for dissolved sulphate to elucidate the source of
      water salinisation in the middle section of the Llobregat River. As dilution
      processes do not affect sulphur isotopic composition, the analysis of delta34S of
      dissolved sulphate in waters provides an excellent tool for quantifying the
      environmental impact caused by the mining activity existing in the area. The
      delta34S of dissolved sulphate from mining effluents and saline springs unrelated
      to mining activity was analysed. The results obtained range from + 18 per
      thousand to + 20 per thousand (VCDT) for mining effluents and from + 10 per
      thousand to + 14 per thousand (VCDT) for natural saline springs. These values are
      in accordance with the pattern of sulphur isotopic composition of sulphates from
      the evaporite materials of this area. This distinctive isotopic composition has
      allowed us to determine the origin of salinity in those cases in which chemical
      features are not conclusive. In addition, two fertilisers widely used in the
      studied area are chemically and isotopically characterised and their contribution
      to groundwater salinisation is assessed.

PMID- 12405409
TI  - Use of granular slag columns for lead removal.
AB  - The use of granular blast furnace slag (GBFS)-packed columns to treat lead
      containing solutions has been investigated. The results obtained indicated that
      the slag usage rate decreased with increasing flow velocity, particle size,
      initial lead concentration and decreasing with bed height. Lead removed
      selectively in the presence of other heavy metal ions. High concentrations of
      sodium and especially calcium in the solutions impeded the uptake of lead. For 20
      mg l(-1) lead concentration an empty bed contact time greater of 4 min provided
      to efficient use of the slag bed. Column pH was an important parameter to lead
      removal under dynamic conditions and reflected the influence of the investigated
      factors. During all runs lead breakthrough coincided with an abrupt drop in
      effluent pH. The apparent mechanisms of lead removal in GBFS column are sorption
      (ion exchange and adsorption) on the slag surface and precipitation.

PMID- 12405410
TI  - Enhanced coagulation using a magnetic ion exchange resin.
AB  - The objective of this investigation was to examine the effectiveness of a
      magnetic ion exchange resin (MIEX) to enhance the coagulation of disinfection by
      product precursors in nine surface waters, each representing a different element
      of the USEPA's 3 x 3 enhanced coagulation matrix. The effect of MIEX-pretreatment
      on the requisite alum dose needed for subsequent coagulation of turbidity was
      also evaluated. Enhanced coagulation with MIEX was found to be very effective for
      removing trihalomethane (THM) and haloacetic acid (HAA) precursors from the nine
      waters examined. THM and HAA formation potential was reduced by more than 60% in
      all of the waters studied; reductions approaching 90% were seen in the waters
      with the highest specific ultraviolet absorbance values. The residual total
      organic carbon concentration, ultraviolet absorbance, and THM and HAA formation
      potential were all substantially lower as a result of MIEX and alum treatment
      compared to alum coagulation alone. MIEX pre-treatment also lowered the coagulant
      demand of each of the waters substantially.

PMID- 12405411
TI  - Characterization of humic substances present in landfill leachates with different
      landfill ages and its implications.
AB  - Humic and fulvic acids extracted from landfill leachates were characterized using
      elemental analysis and various spectroscopic methods. Molecular size distribution
      of the humic substances (HS) was also determined using batch ultrafiltration
      technique and permeation coefficient model. The element analysis and spectral
      features obtained from UV/visible, IR, and 1H and 13C NMR showed that the
      aromatic character in the leachate HS was relatively lower than that of
      commercial humic acid (Aldrich Co.), and higher in the HS of older landfill
      leachate. Fluorescence spectra indicated that humic acids had a relatively higher
      content of condensed aromatic compounds than the fulvic acids obtained from the
      same sources, and the spectrum of commercial humic acid showed that aromatic
      compounds may be present in a much more condensed and complex form. Molecular
      size distribution data revealed that the leachate humic acids contained a higher
      percentage of smaller molecules of < 10,000 D, compared with that of the
      commercial humic acid (45 approximately 49% vs. 33%), and molecular size of the
      leachate HS had a tendency to increase as landfill age increased. These results
      indicate that the HS from landfill leachates were in an early stage of
      humification, and the degree of humification increased as the landfilling age
      increased, which implies important information on various related researches,
      such as interactions of HA with pollutants in terrestrial environments, and
      optimization of leachate treatment processes with respect to landfill age.

PMID- 12405413
TI  - Detoxification of phenolic solutions with horseradish peroxidase and hydrogen
      peroxide.
AB  - Phenolic solutions were treated with hydrogen peroxide and horseradish peroxidase
      (HRP) resulting in more than 95% removal of phenols within 3 h. Toxic compounds
      were formed during the treatment of aqueous solutions of phenol, 2-chlorophenol,
      4-chlorophenol, 2,4-dichlorophenol and 2-methylphenol. However, the toxicities of
      HRP-treated solutions decreased within 21 h after the completion of the enzymatic
      reaction, except in the case of 2-methylphenol. The process of detoxification was
      significantly accelerated upon the addition of hydrogen peroxide to the
      dephenolized solutions. Solutions that were treated in the presence of chitosan
      exhibited lower toxicities than solutions treated in its absence if they were
      allowed to incubate for an extended period of time. Treatment in the presence of
      polyethylene glycol resulted in significantly higher toxicities. The toxicity of
      treated solutions was dependent on the addition mode of HRP and hydrogen
      peroxide. Treated solutions were also completely detoxified following
      illumination with UV light.

PMID- 12405412
TI  - In situ tests for water quality assessment: a case study in Pampean rivers.
AB  - Two invertebrate species (Hyalella curvispina and Palaemonetes argentinus) and
      one macrophyte (Egeria densa) from a naturally high nutrient content system
      (Pampean rivers of La Plata, Argentina) were evaluated for their potential use in
      situ assays aiming to assess changes in water quality. Invertebrates were
      individually placed in cylindrical chambers in polluted sections of rivers and in
      reference upstream sites. Mortality after 48 h was high in polluted and reduced
      in control sites. Mortality was also higher in situ assays than in laboratory
      static tests. Standard sections of the macrophyte were also deployed at the
      reference and control sites. Growth (7 days) in terms of mass increment (but not
      in length) was consistently reduced in polluted sites. Results of benthic
      invertebrate and periphitic algae surveys were consistent with the in situ tests:
      pollution resulted in a decrease in the number of taxa, taxa replacement and in
      changes in the value of the biotic indices Indice Biotico PAMPeano and Indice de
      Diatomeas Pampeano, indicating deterioration of water quality. In situ assays
      have a high potential as environmental tools in integrated approaches of
      bioassessment programs.

PMID- 12405414
TI  - Inactivation of Cryptosporidium parvum oocysts with ozone and free chlorine.
AB  - The objective of this study is to investigate the synergy involved in the
      sequential inactivation of C. parvum oocysts with ozone followed by free chlorine
      at 1-20 degrees C. Primary ozone and free chlorine inactivation curves are
      characterized by an initial lag-phase, followed by one or two post-lag-phase
      segments, the first segment at a faster rate than the second, of pseudo-first
      order inactivation. The kinetics of primary inactivation with ozone and free
      chlorine has a relatively strong temperature dependence, and vary both with
      oocyst lot and oocyst age. Synergy is observed for the sequential inactivation of
      C. parvum oocysts with ozone/free chlorine. Ozone pre-treatment results in the
      disappearance of the lag-phase and the occurrence of a secondary free chlorine
      inactivation curve with generally two pseudo-first-order segments, the first
      segment at a faster rate than the second. The kinetics of both secondary segments
      is significantly faster than the post-lag-phase rate of inactivation with free
      chlorine alone. The temperature dependence for both phases of the secondary free
      chlorine inactivation kinetics is weaker compared to that for primary
      inactivation with ozone or free chlorine. As a result, the level of synergy in
      sequential disinfection with ozone/free chlorine increases with decreasing
      temperature within the range relevant to drinking water utilities. Good agreement
      is found between the kinetics determined using the modified in-vitro excystation
      method of viability assessment and animal infectivity data recently reported in
      the literature for both primary inactivation with ozone, and sequential
      disinfection with ozone/free chlorine.

PMID- 12405415
TI  - Laboratory study of electro-coagulation-flotation for water treatment.
AB  - An electro-coagulation-flotation process has been developed for water treatment.
      This involved an electrolytic reactor with aluminium electrodes and a
      separation/flotation tank. The water to be treated passed through the reactor and
      was subjected to coagulation/flotation, by Al(III) ions dissolved from the
      electrodes, the resulting flocs floating after being captured by hydrogen gas
      bubbles generated at cathode surfaces. Apparent current efficiencies for Al
      dissolution as aqueous Al(III) species at pH 6.5 and 7.8 were greater than unity.
      This was due to additional reactions occurring in parallel with Al dissolution:
      oxygen reduction at anodes and cathodes, and hydrogen evolution at cathodes,
      resulting in net (i.e. oxidation + reduction) currents at both anodes and
      cathodes. The specific electrical energy consumption of the reactor for drinking
      water treatment was as low as 20 kWh (kg Al)(-1) for current densities of 10-20A
      m(-2). The water treatment performance of the electrocoagulation process was
      found to be superior to that of conventional coagulation with aluminium sulphate
      for treating a model-coloured water, with 20% more dissolved organic carbon (DOC)
      being removed for the same Al(III) dose. However, for a lowland surface water
      sample, the two processes achieved a similar performance for DOC and UV
      absorbance removal. In addition, an up-flow electrocoagulator configuration
      performed better than a horizontal flow configuration, with both bipolar and
      monopolar electrodes.

PMID- 12405416
TI  - Biological nitrogen removal from municipal landfill leachate: low-cost
      nitrification in biofilters and laboratory scale in-situ denitrification.
AB  - The slow leaching of nitrogen from solid waste in landfills, resulting in high
      concentrations of ammonia in the landfill leachate, may last for several decades.
      The removal of nitrogen from leachate is desirable as nitrogen can trigger
      eutrophication in lakes and rivers. In the present study, a low-cost
      nitrification-denitrification process was developed to reduce nitrogen load
      especially in leachates from small landfills. Nitrification was studied in
      laboratory and on-site pilot aerobic biofilters with waste materials as filter
      media (crushed brick in upflow filters and bulking agent of compost in a downflow
      filter) while denitrification was studied in a laboratory anoxic/anaerobic column
      filled with landfill waste. In the laboratory nitrification filters, start-up of
      nitrification took less than 3 weeks and over 90% nitrification of leachate (NH4
      N between 60 and 170mg N l(-1), COD between 230 and 1,300 mg l(-1)) was obtained
      with loading rates between 100 and 130 mgNH4-N l(-1) d at 25 degrees C. In an on
      site pilot study a level of nitrification of leachate (NH4-N between 160 and 270
      mg N l(-1), COD between 1,300 and 1,600 mg l(-1)) above 90% was achieved in a
      crushed brick biofilter with a loading rate of 50mg NH4-N l(-1) d even at
      temperatures as low as 5-10 degrees C. Ammonium concentrations in all biofilter
      effluents were usually below the detection limit. In the denitrification column.
      denitrification started within 2 weeks and total oxidised nitrogen in nitrified
      leachate (TON between 50 and 150mg N l(-1)) usually declined below the detection
      limit at 25 degrees C, whereas some ammonium, probably originating from the
      landfill waste used in the column, was detected in the effluent. No adverse
      effect was observed on the methanation of waste in the denitrification column
      with a loading rate of 3.8 g TON-N/t-TS(waste) d. In conclusion, nitrification in
      a low-cost biofilter followed by denitrification in a landfill body appears
      applicable for the removal of nitrogen in landfill leachate in colder climates.

PMID- 12405417
TI  - Microbial population in a hydrogen-dependent denitrification reactor.
AB  - The bacterial population in an H2-dependent denitrification system was studied.
      The laboratory set-up was designed for the treatment of potable water and
      consisted of an electrochemical cell, where the water to be treated was enriched
      with H2 prior to entering a bioreactor. Bioreactors (columns packed with
      granulated active carbon) were inoculated with denitrifying bacterial strains
      isolated from a previous reactor, then sampled immediately after inoculation, or
      after 1 or 3 months of continuous operation. Total number of the bacteria and
      numbers of each different strain were determined at various levels of the
      bioreactor. The strains present in the inoculum were identified as Ochrobactrum
      anthropi, Pseudomonas stutzeri, Paracoccus panthotrophus and Paracoccus
      denitrificans. Numbers of the latter declined markedly with time with the other
      three strains being responsible for nitrate removal. A correlation was found
      between the relative abundance of each strain and its specific denitrification
      activity.

PMID- 12405418
TI  - Multi-metallic modelling for biosorption of binary systems.
AB  - In this paper a specially propagated biomass of Sphaerotilus natans was tested as
      adsorbent for binary solutions of Cu-Cd, Cu-Pb and Cu--Zn at different
      equilibrium pH. The experimental results outline the buffering effect of H+ at
      low pH. which masks the competition among metals. In each binary system the
      biomass affinity follows the acidic properties of the heavy metals probably due
      to an ionic exchange mechanism operating among active sites and metals in
      solution. The experimental results were fitted according to an empirical approach
      with growing complexity that outlines the inadequacy of the predictive models and
      the non-ideal interactions among metals.

PMID- 12405419
TI  - Photocatalytic oxidative degradation of acridine orange in aqueous solution with
      polymeric metalloporphyrins.
AB  - In the presence of polymeric M [meso-tetra (4,4'-biphenybisulfony)
      phenylporphyrin] (PMTBPBSOPP, M = Co, Mn, Cu, Zn, Fe), the photocatalytic
      oxidative degradation of acridine orange (AO) was investigated under conditions
      of irradiation with high-pressure mercury lamp (HPML), iodine tungsten lamp (ITL)
      and natural sunlight (NSL), respectively. The results indicated that PCoTBPBSOPP
      had remarkable effects on photodegradation of AO under NSL irradiation. The
      experiments also proved that the photocatalytic degradation of AO in aqueous
      solutions could be enhanced when hydrogen peroxide 0.4 g/L was added. When the
      initial concentration of AO was 43.8 mg/L, the degradation and the decolorization
      rates of AO under HPML irradiation were up to 98% and 97%, respectively. A number
      of factors affecting photocatalytic degradation effects, such as the initial
      concentration of AO, light sources, pH etc., were studied in detail. The
      experimental results confirmed that polymeric metalloporphyrins could fully
      decompose AO by using artificial light source such as HPML and ITL, moreover
      could degrade AO rapidly under NSL in 3 h. Definitely, polymer of
      metalloporphyrins in the heterogeneous photocatalysis phase had a potential
      application

PMID- 12405420
TI  - Practical identifiability of ASM2d parameters--systematic selection and tuning of
      parameter subsets.
AB  - In many applications, some parameters of the Activated Sludge Model No. 2d
      (ASM2d) need calibration. Since ASM2d usually is overparameterized with respect
      to the available data, the subset of calibration parameters is not unique. In
      practice, calibration of ASM2d (and other ASMs) is often addressed by ad hoc
      selecting and tuning procedures. In this paper, a more systematic approach based
      on parameter identifiability analysis of parameter subsets is applied. The
      approach consists of a preliminary prior parameter analysis and a subsequent
      iterative parameter subset selection and tuning procedure. The former includes
      the choice of suitable prior parameter values and uncertainties and a pre
      selection of parameters which are reasonably estimated from the data available.
      The latter is based on three diagnostic measures which are simple to calculate
      and easy to interpret. It is demonstrated as to how these measures can be used to
      identify the most important model parameters and to analyze their
      interdependencies. In addition, it is shown how these measures facilitate the
      analysis of the influence of fixed parameter values on parameter estimates.

PMID- 12405422
TI  - Removal of organic matter from water by PAC/UF system.
AB  - The laboratory-scale ultrafiltration (UF) experiments were conducted to determine
      the effect of the presence of powdered activated carbon (PAC) on the UF process
      performance, in terms of flux decline and the possibilities of membranes cleaning
      during backwashing. Poly(vinylidene fluoride) membranes formed by the phase
      inversion technique were used in the UF experiments. A model solution was
      prepared as a mixture of humic acids (HA) and phenol in concentration of 10 and 1
      mg l(-1), respectively. Commercial powdered activated carbons CWZ 11 and CWZ 30
      (Gryfskand Sp. z o. o., Hajnowka, Poland) were used as the adsorbents. PAC dosage
      was in the range of 10-100 mg PAC l(-1). The process was carried out in the cross
      flow system. It was found that PAC addition to the distilled water leads to a
      small drop in the permeate flux, regardless of PAC dose and its type. Although
      PAC particles are too large to block the membrane pores inside, they deposit on
      the membrane surface and partially can plug the surface pores. The experimental
      results demonstrate that the backwashing process applied in combined PAC/UF
      system was especially effective when PAC dosages were <20mg PAC l(-1). However, a
      similar permeate flux was maintained for all carbon dosages used and reached the
      value of about 1 m3 m(-2) d(-1). Moreover, no further drop in the permeate flux
      for PAC addition to the solution containing foulants (HA) was observed.
      Effectiveness of the removal of HA and phenol from the model solutions was also
      investigated. In the PAC/UF system HA were removed in about 90%, whereas the
      complete removal of phenol was achieved for PAC dosage equal to 100 mg l(-1).

PMID- 12405421
TI  - Removal of free and complexed heavy-metal ions by sorbents produced from fly
      (Musca domestica) larva shells.
AB  - Fly larva shells (FLS) are formed as a side product in the biological treatment
      of organic wastes, and chitin and chitosan produced from the FLS have been used
      as sorbents for heavy-metal ions. Sorbents are characterised by FT-IR
      measurements and pH-potentiometric titration and by determination of their
      surface area, and the content of main elements (C, N, P, S) and ashes. Free metal
      ions are sorbed best (up to 0.5-0.8 mmol g(-1)) onto chitin and chitosan. The
      sorption ability for free metal ions of chitin decreases in the order Fe(III) >
      Cu(II) (Pb(II) > Zn(II). > Ni(II) > Mn(II) and that of chitosan decreases in the
      order Cu(II) > Mn(II) > Ni(II) > Zn(II) > Pb(II) > Fe(III). The complexed metal
      ions are sorbed by the FLS up to 0.2-0.4mmol g(-1). The sorption ability for
      metal ions and ligands depends on pH, concentration of complexed metal ions and
      the ligand species in the solution. Glycine has the retarding effect on the
      sorption of Ni(II) and Cu(II) ions, and EDTA enhances the Cu(II) ion sorption.
      Ni(II) and glycine sorption obeyed the Langmuir isotherm. The observed sorption
      data show the promising potentialities of the FLS for the heavy-metal removal
      from the solutions, containing strong complexing agents. Mechanisms for the
      removal of free and complexed metal ions by chitin, chitosan and the FLS have
      been discussed.

PMID- 12405423
TI  - Decomposition of 2-naphthalenesulfonate in aqueous solution by ozonation with UV
      radiation.
AB  - This study investigates the ozonation of 2-naphthalenesulfonate (2-NS) combined
      with ultraviolet (UV) radiation. Naphthalenesulfonic acids are of importance as
      dye intermediates for the dye and textile auxiliary industries. Its derivatives,
      such as 2-NS, have been found in rivers and tannery effluents causing pollution
      problems. Thus, the 2-NS is of concern for the aquatic pollution control
      especially in the surface and waste waters. Ozonation combined with UV radiation
      is employed for the removal of 2-NS in the aqueous solution. Semibatch ozonation
      experiments were proceeded under different reaction conditions to study the
      effects of ozone dosage and UV radiation on the oxidation of 2-NS. The
      concentrations of 2-NS and sulfate are analyzed at specified time intervals to
      elucidate the decomposition of 2-NS. In addition, values of pH and oxidation
      reduction potential are continuously measured in the course of experiments. Total
      organic carbon is chosen as a mineralization index of the ozonation of 2-NS. The
      mineralization of 2-NS via the ozonation is remarkably enhanced by the UV
      radiation. These results can provide useful information for the proper removal of
      2-NS in the aqueous solution by the ozonation with UV radiation.

PMID- 12405424
TI  - Decomposition of phorate in aqueous solution by photolytic ozonation.
AB  - The degradation of phorate, a highly toxic organic phosphate pesticide, in
      aqueous solution by photolytic ozonation was studied under various experimental
      conditions. The rate constants of phorate decomposition and formation of various
      anions by photolytic ozonation were roughly independent of the solution's pH
      value. The initial step of the photolytic decomposition of phorate is considered
      to be the breakage and subsequent oxidation of the P=S double bond on the phorate
      molecule, followed by isomerization and consequent oxidation of various organic
      intermediates.

PMID- 12405425
TI  - Degradation of the (R)- and (S)-enantiomers of the herbicides MCPP and
      dichlorprop in a continuous field-injection experiment.
AB  - An aerobic field-injection experiment was performed to study the degradation and
      migration of different herbicides at trace levels in an aerobic aquifer at Vejen,
      Denmark. Mecoprop (MCPP) and dichlorprop monitored in a dense network of
      multilevel samplers were both degraded within a distance of 1 m after a period of
      120 days. The study showed that no preferential degradation of the (R)- and (S)
      enantiomers of MCPP and of dichlorprop took place as the enantiomeric forms of
      the phenoxy acids were degraded simultaneously in the aquifer.

PMID- 12405426
TI  - Long-term storage of natural water samples for dissolved oxygen determination.
AB  - A method for preserving natural water samples for dissolved oxygen analysis is
      recommended. The conventional method of using greased glass stoppers have been
      found to cause an increase in oxygen concentration by 12% over 1-month period as
      a result of evaporation of water sample through micro-gaps and concurrent
      intrusion of air into the water sample bottles. Sealing the sample bottles with
      water has been found to be the optimal storage method. It permits a 100.2 +/-
      0.3% recovery of dissolved oxygen concentration from storage seawater samples
      over 4 months.

PMID- 12405427
TI  - Coupling of anodic and cathodic reactions for phenol electro-oxidation using
      three-dimensional electrodes.
AB  - We studied the electrochemical oxidation of phenol by the coupling of anodic and
      cathodic reactions. The experiments were done in an electrochemical filter press
      cell equipped with an Sb-doped SnO2-coated titanium foam and a RVC cathode. The
      oxidation occurs by a direct oxidation on the anodic side, while on the cathodic
      side oxidation occurs via an electro-Fenton mechanism. We studied the influence
      of the working parameters. The electrical yield increases when pH decreases and
      is strongly dependent on an optimum between current density, iron and dissolved
      oxygen concentration. This method may be applicable to refractory compounds.

PMID- 12405428
TI  - The molecular basis of hypertension.
AB  - Hypertension is a substantial public health problem affecting about 25% of the
      population in industrialized societies. The disorder is responsible for many
      common causes of morbidity and mortality. Despite the important role of
      hypertension as a cause of disease, its pathogenesis remains largely unknown. The
      application of genetic approaches to rare monogenic (Mendelian) forms of
      hypertension and hypotension has begun to delineate molecular pathways underlying
      human blood pressure variation, defining disease pathogenesis and identifying
      targets for therapeutic intervention. In all cases the pathophysiology is altered
      net renal salt reabsorption. Mutations are either affecting circulating
      mineralocorticoid hormones or renal ion channels and transporters. Examples are
      glucocorticoid-remediable aldosteronism (GRA), Liddle's syndrome, the syndrome of
      hypertension exacerbated in pregnancy, and apparent mineralocorticoid-excess
      (AME). Recently, alterations in genes of a novel serine-threonine kinase family
      (WNK1 and WNK4) were identified causing pseudohypoaldosteronism type II. The
      molecular pathway of this syndrome remains unclear. Additionally, there is the
      syndrome of hypertension associated with brachydactyly type E (Bilginturan's
      syndrome), for which the molecular mechanism has yet to be identified.

PMID- 12405429
TI  - Television viewing and its effect on physical health of schoolage children.
AB  - Obesity is an increasing health problem all over the world. In addition to
      genetic and many environmental factors, television is also thought to be a risk
      factor. This study examined the effects of television viewing on obesity and
      other physical complaints among Turkish children. From two different
      socioeconomic class primary schools, 886 second- and third-grade children were
      visited at their schools, and their weight, height and triceps skin fold
      thickness (TST) were measured and body mass index (BMI) calculated. Television
      viewing behavior of the children, parental weight and height, and physical
      complaints of children were investigated by a questionnaire sent to parents. A
      subgroup of children was also called to the hospital, and their blood lipid
      profile and visual acuity were measured. According to the questionnaires,
      children were found to watch television 2.1 +/- 1.2 hours/day (hr/d) during the
      weekdays, 3.4 +/- 2.1 hr/d at the weekend and 2.5 +/- 1.3 hr/d generally.
      Children were also grouped according to the amount of time they watch television.
      Group 1 (n = 298) children watched television less than 2 hr/d, Group 2 (n = 323)
      watched 2-4 hr/d, and Group 3 (n = 68) more than 4 hr/d. The prevalence of
      obesity was 10.9% according to BMI, 11.8% according to TST and 6.4% according to
      both criteria. Obese girls were found to watch television longer than their peers
      (2.9 +/- 1.2 hr/d vs 2.3 +/- 1.3 hr/d, respectively, p = 0.034), but no other
      relation was found between television viewing and obesity. Headache, back pain,
      eye symptoms and sleep problems were found to be more often among children who
      watched television longer (p < 0.05). It was concluded that television viewing is
      related to many physical complaints, which may have lifelong consequences
      (obesity). Thus, pediatricians should give appropriate guidance to families about
      television habits and health consequences.

PMID- 12405430
TI  - Hepatitis A seroprevalence in a random sample of the Turkish population by
      simultaneous EPI cluster and comparison with surveys in Turkey.
AB  - This study was conducted to determine the hepatitis A virus (HAV) seroprevalence
      in nine provinces representative of Turkey as a whole. These provinces are
      representative of the country's geographical location, and demographic, economic
      and social characteristics. In each province, sample sizes were determined using
      published data on HAV seroprevalence, and sample sizes for each province and for
      the cluster were calculated for each group of subjects under the age of 30 for
      seroprevalence estimates within a 95% confidence interval. The samples were
      selected by a cluster method, and the planned recruitment was a total of 4,800
      subjects, including 600 subjects each from five large provinces (Istanbul,
      Ankara, Izmir, Adana, Diyarbakir) and 450 subjects from each of the remaining
      four provinces (Samsun, Erzurum, Trabzon, Edirne). These numbers were distributed
      in accordance with the percentages for age groups in five-year increments
      starting from age five for the population under the age of 30 living in the rural
      and urban areas in each province. This study of 4,462 subjects under the age of
      30 in nine provinces of Turkey identified an overall HAV seroprevalence rate of
      71.3%. The distribution of HAV seroprevalences by age showed a steady increase
      from one year of age from 42.7% to 91.1% at 25-29 years of age. HAV
      seroprevalence was slightly higher in female subjects (73%) than in male subjects
      (69.3%). By educational status, seroprevalences were comparable except in young
      children under age six. Seroprevalence was notably higher in large families with
      six and more members (80.1%) than in small families with five or fewer members
      (66.7%). According to our study results, 50% of Turkish children are seropositive
      for HAV by the age of 10 years. We believe the date support the need for a
      routine primary immunization policy in Turkey and the development of effective
      prophylactic programs after possible exposure. Consequently, an immunization
      policy can be developed for each region according to its epidemiological
      conditions.

PMID- 12405431
TI  - Leptin levels in children with insulin dependent diabetes mellitus.
AB  - Leptin, a product of the ob gene, is a polypeptide hormone produced in adipose
      tissue that informs the brain about the amount of energy storage of body fat. It
      has very important effects on neuroendocrine functions and energy expenditure.
      The aim of our study was to determine leptin levels of children with insulin
      dependent diabetes mellitus (IDDM), which is known to affect body metabolism, and
      to investigate the relationship between duration of the disease, insulin dosage,
      HbA1c levels, body mass index (BMI), serum lipids and IGF-1 levels. Sixteen
      patients with IDDM (chronological age 13.8 +/- 2.6 years) whose HbAlc levels were
      10.2 +/- 1.9 %, BMI 21.2. +/- 2.7 kg/m2, insulin dosage 0.9 +/- 0.4 U/kg/day and
      duration of the disease 6.7 +/- 2.6 years, and 12 healthy controls (13.4 +/- 2.6
      years) were included in the study. Fasting plasma leptin levels were measured by
      radioimmunoassay method. The mean plasma leptin levels of the patient and the
      control groups were 19.1 +/- 7.6 ng/ml and 6.1 +/- 2.9 ng/ml, respectively, and
      significant difference was found between the two groups (p < 0.05). No
      correlation was found between leptin values and IGF-1, cholesterol, HDL
      cholesterol, LDL-cholesterol, triglyceride levels, atherogenic index, insulin
      dosage or HbA1c levels in the patient group. A weak statistical correlation was
      determined between BMI and leptin levels in the IDDM group (r = 0.28, p < 0.05).
      A positive correlation was also found between leptin levels and the duration of
      the disease (r = 49, p < 0.05). As a result, it seems that leptin levels of
      children with IDDM differed from the levels of the control group significantly,
      and that the duration of insulin therapy was responsible for this difference.

PMID- 12405432
TI  - Serum insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 levels in
      severe iodine deficiency.
AB  - Iodine deficiency is an important public health problem worldwide. It is well
      known that it has severe consequences such as brain damage, developmental delay,
      deficits in hearing and learning and lower intellectual attainment. It also has a
      negative impact on growth. In this study, we aimed to address this issue and we
      assessed height standard deviation scores of children living in an area of severe
      iodine deficiency in comparison to those living in a mild iodine deficiency area.
      Serum levels of insulin-like growth factor-I (IGF-I), IGF-binding protein-3
      (IGFBP-3), thyroxine (T4), and thyroid stimulating hormone (TSH) were also
      analyzed to investigate the mechanisms by which iodine depletion leads to growth
      failure. Pubertal children in a severe iodine deficient SID area had lower height
      standard deviation scores (HSDS), IGF-I and IGFBP-3 levels than those living in
      mild iodine deficient MID area. Similar findings could not be elucidated in the
      prepubertal age group. The major determinants of HSDS were age, IGF-I, IGFBP-3
      and TSH. IGF-I and IGFBP-3 were negatively correlated with T4. These findings
      suggest that iodine deficiency has a negative impact on growth, as well as IGF-I
      and IGFBP-3 levels. This effect seems to be due to the derangements in thyroid
      hormone economy arising from iodine depletion. The degree of this impact may be
      related to the duration of iodine depletion or may be dependent on the
      developmental stage of the organism at the time of iodine depletion.

PMID- 12405433
TI  - Incidence of dysrhythmias in congenitally corrected transposition of the great
      arteries.
AB  - We reviewed hospital records of 45 children with corrected transposition of the
      great arteries (c-TGA) to determine the incidence and outcome of congenital and
      postoperative dysrhythmias seen in this congenital anomaly. Our study comprised
      45 patients (12 girls, 33 boys). The mean age of the patients at initial
      evaluation was 3.4 +/- 3.7 years, and they were followed for a mean period of 3.5
      +/- 4 years. Forty-three patients (95%) with c-TGA had associated intracardiac
      defects. Two patients (5%) did not have any cardiac defects. In 31 (69%) of the
      45 patients, ventricular septal defect (VSD) was present, while the remaining 14
      patients (31%) had intact ventricular septum. VSD repair was done in 17 of 31
      patients. Different types of dysrhythmias were detected in 19 of 45 patients. Six
      patients (13%) presented initially with congenital complete atrioventricular
      block (AVB) and five patients with postoperative complete ve AVB. Pacemaker
      implantation was required for 11 patients with complete AVB. In eight patients,
      ventricular and supraventricular ectopic beats, left bundle-branch block (LBBB)
      and first-degree AVB were determined but therapy was not required. TWenty-five
      (58%) of 43 patients with intracardiac defects underwent different surgical
      procedures. Permanent pacemaker implantation was required for five patients (29%)
      after VSD repair (17 patients) due to postoperative complete AVB. The incidence
      of congenital AVB in 14 patients with intact ventricular septum was found to be
      high (29%) in comparison to the group with VSD (6%). Patients diagnosed as c-TGA
      with or without cardiac defects should be followed carefully during their
      clinical course to identify and treat different types of dysrhythmias that can
      appear at any time.

PMID- 12405434
TI  - Early physiotherapy intervention in premature infants.
AB  - Preterm infants are more likely to have disabling cerebral palsy (CP) than term
      infants. It has been reported that early therapeutic approaches may be
      appropriate for infants at risk of neuromotor dysfunction, to minimize the degree
      of future handicaps. Two hundred and twenty-nine infants born at less than 34
      weeks' gestation, with birth weight < or = 2,000 g, cared for in the neonatal
      intensive care unit of Hacettepe University Hospital between January 1997-June
      1999 were included in this study. Of the 229 infants initially included, 39 (17%)
      were dropped from the study within the first 12 months' assessment, due to lack
      of participation from the families. Thirty of the remaining 190 infants were
      found to have perinatal hypoxia or abnormal neurosonography, and were taken as
      the group at risk of development of CP, thus receiving early intervention
      therapy; these are listed as "premature at risk". The study group consisted of
      160 infants not considered at risk. These were randomly paired into two groups of
      80 infants, one that was given early interventional therapy, and the control
      group that received no program. Eleven of the 30 infants at risk, 2 of the 80
      infants from the intervention group, and 4 of the 80 from the control group were
      diagnosed as having CP within the first six months of life. There was no
      difference in the age of loss or acquisition of reflexes and general abilities
      between the intervention and control groups. There was no difference in the
      prevalence of CP between the intervention and control groups. In conclusion this
      study showed no effect of early intervention in premature babies without risk of
      CP other than prematurity.

PMID- 12405435
TI  - Risk factors of early childhood caries in Turkish children.
AB  - This study was performed to determine the relationship between infant feeding
      habits, oral hygiene patterns, parents' education level and early childhood
      caries (ECC) in nine-to 59-month-old Turkish children. Clinical examinations were
      carried out by a pediatric dentist using dmft indices, and the dmft was found to
      be 5.8. In the other part of the study, the mothers completed questionnaires for
      information related to risk factors. Father's education level and fluoride
      consumption showed statistical associations with caries. Breast - bottle-feeding
      together was more common, and these children had a higher prevalence of caries
      than the children who were only breast-fed. Also, children who were bottle-fed at
      night developed more caries lesions. Frequent consumption of sugar-containing
      beverages was a common habit among children. Brushing habit did not have any
      effect on carious development in this study. Based on these associations it is
      concluded that ECC is a risk factor for general health of children in Turkey.

PMID- 12405436
TI  - A hospital outbreak of aseptic meningitis due to echovirus type 30 in Antalya,
      Turkey.
AB  - We analyzed clinical and laboratory findings of 23 hospitalized patients with
      aseptic meningitis in the Department of Pediatrics, Akdeniz University Hospital.
      The patients presented with the classic symptoms and signs of aseptic meningitis.
      Protein levels of the cerebrospinal fluid (CSF) samples ranged from 18 to 99
      mg/dl, with a mean of 36.5 +/- 4.9 mg/dl. The mean ratio of CSF glucose compared
      to blood samples was 0.73. Echovirus type 30 was identified in CSF and/or stool
      samples of 19 patients. Four patients had negative virus culture. The outcome was
      favorable in all patients. We thought that this outbreak of aseptic meningitis in
      our department might denote a summer outbreak in the city. However, this remained
      unproven since field investigations could not be completed. Advances in virus
      culture or polymerase chain reaction techniques and satisfactory medical records
      may help patient care by promoting early diagnosis and by eliminating unnecessary
      antibiotic therapy, allowing epidemiological studies.

PMID- 12405437
TI  - Familial vesicoureteral reflux in asymptomatic siblings.
AB  - A prospective study was established to identify the incidence of vesicoureteral
      reflux in the asymptomatic siblings of patients with reflux in our region. Of 32
      patients with reflux, 37 siblings were screened with urine analysis, urine
      culture and contrast voiding cystourethrograms, and six (16.2%) were found to
      have reflux. Renal scan revealed scarring in five. We concluded that siblings of
      children with vesicoureteral reflux are at high risk, and must be screened so
      that renal damage and associated morbidity secondary to reflux might be
      minimized.

PMID- 12405438
TI  - Malignant pleural mesothelioma in a child: long-term survival with ICE-WAC
      chemotherapy regimen.
AB  - Malignant mesothelioma is a very rare tumor in childhood. Presently, treatment of
      this disease continues to be frustrating and prognosis remains poor. We here
      report a pediatric case of malignant pleural mesothelioma who gave a complete
      response to ICE-VAC chemotherapy regimen and achieved a long-term survival. An
      eight-year-old girl underwent exploratory thoracotomy and decortication because
      of a unilateral loculated and multicystic pleural effusion. Histopathological
      diagnosis was sarcomatoid pleural malignant mesothelioma. After decortication,
      chemotherapy with ICE (ifosfamide, carboplatin, etoposide) - VAC (vincristine,
      adriamycin, cyclophosphamide) combination was started. Six courses of
      chemotherapy resulted in complete clinical and radiological tumor response. She
      did not receive any further therapy and remains disease-free three years after
      the first remission. ICE-VAC chemotherapy combination resulted in a complete
      tumor response and a long-term disease-free survival for the presented case. The
      efficacy of this chemotherapy regimen in malignant mesothelioma needs to be
      documented in future trials.

PMID- 12405439
TI  - Hemolytic disease of the newborn due to isoimmunization with anti-E antibodies: a
      case report.
AB  - Minor blood group hemolytic disease is extremely rare, since the overall potency
      of minor blood groups in inducing antibodies is significantly lower when compared
      with that of Rh (D) antigen. We hereby report a very rare case of severe neonatal
      anti-E hemolytic disease due to E minor blood group incompatibility. A term
      newborn born to a 27-year-old, gravida 3, para 3 mother was referred due to a
      high and increasing serum bilirubin level despite phototherapy on the 4th day of
      life. On admission physical examination was normal except for the jaundice, and
      results of the laboratory investigation demonstrated a moderate-to-severe anemia
      (hemoglobin 7.8 g/dl) and a severe hemolytic hyperbilirubinemia (serum total and
      indirect bilirubin levels 36 mg/ dl and 32.8 mg/dl, respectively; reticulocyte
      count 15%; and a positive direct antiglobulin test). As there was no apparent
      cause of the hemolytic disease such as Rh or ABO incompatibilities, further
      investigation (a positive indirect antiglobulin test and a positive irregular
      anti-E antibody in both the patient and mother, and minor blood group antigen
      profiles in family members compatible with E minor blood group isoimmunization)
      revealed the presence of anti-E hemolytic disease due to E minor blood group
      incompatibility. Two exchange transfusions with a 12-hour-interval were performed
      with minor blood group compatible fresh whole blood, and the patient was
      discharged in a healthy condition on the 10th postnatal day. If the most common
      causes of severe neonatal hemolytic disease such as Rh and ABO incompatibilities
      cannot be demonstrated in a newborn with significant hemolytic
      hyperbilirubinemia, anti-E hemolytic disease should strongly be considered in
      differential diagnosis. It should be kept in mind that a very severe from of
      minor group antibody hemolytic disease characterized by anemia and severe
      hyperbilirubinemia many exchange transfusions may be encountered during the
      course of the disease.

PMID- 12405440
TI  - Utility of dobutamine stress echocardiography in Kawasaki disease: a case report
      and review of the literature.
AB  - Dobutamine stress echocardiography (DSE) has become widely accepted in the
      evaluation of adult patients with coronary heart disease. There are new
      challenges about the use of DSE in the pediatric age group to document ischemia.
      DSE can demonstrate ischemia noninvasively in Kawasaki disease (KD) patients who
      are candidates for coronary angiography. We wanted to assess the feasibility and
      the physiologic responses of DSE in a KD patient with coronary aneurysm. The
      patient had no ischemia in DSE, which was confirmed by coronary angiography
      showing no stenosis. The literature about DSE use in KD is reviewed.

PMID- 12405441
TI  - Dissection of aorta: a pediatric case report.
AB  - We present a 15-year-old boy who developed sudden walking disability and sensory
      loss. He could not stand up on his feet and had no feeling following a sudden
      fall while playing basketball. He had been referred to a local hospital with
      these symptoms. In his physical examination absence of deep tendon reflexes and
      sensory loss were noted. His arterial blood pressure was 210/160 mmHg. He was
      transferred to our hospital with these findings and diagnosis of Guillain-Barre
      syndrome and hypertensive encephalopathy. There was sudden onset of sensory loss,
      walking disability and history of trauma. In the following hours hematuria, back
      pain and lower extremity ischemia developed. We suspected spinal artery injury
      based on the findings. Dissection of descending aorta was established with the
      help of magnetic resonance imaging of spinal region and contrasted aortography.
      The patient went to surgery immediately. He was lost on the second day after
      operation because of malperfusion. We report this case because dissecting aorta
      is very rare in the pediatric age group. High index of suspicion and early
      aortography are needed to diagnose aorta dissection.

PMID- 12405442
TI  - Severe iron deficiency anemia in a child with idiopathic pulmonary hemosiderosis:
      a case report.
AB  - We report a case of idiopathic pulmonary hemosiderosis (IPH) in a three-year-old
      male patient who presented with severe iron deficiency anemia. The child had been
      diagnosed with iron deficiency anemia nine months earlier and had received
      multiple blood transfusions, but the cause of his anemia had not been
      established. The diagnosis of IPH was made after a biopsy of the left lung showed
      large numbers of hemosiderin-filled macrophages in the alveoli. He did not
      respond to standard dose corticosteroid (CS) treatment (2 mg/kg/d). However, high
      dose short-term CS treatment was successful in two episodes of acute respiratory
      hemorrhage in this patient. We conclude that IPH should always be considered when
      investigating the cause of iron deficiency anemia. A more rapid diagnosis in this
      case could have prevented unnecessary investigations and blood transfusions. We
      also suggest that high-dose short-term CS treatment should be kept in mind,
      especially in patients who do not respond to a standard dose.

PMID- 12405443
TI  - Complete heart block in thalassemia major: a case report.
AB  - Cardiac complications of iron overload are the most common cause of death in
      patients with thalassemia major. These complications include recurrent
      pericarditis, refractory congestive heart failure and rhythm disorders. The usual
      rhythm disturbances are supraventricular or ventricular premature contractions
      and first-or second-degree heart block. Complete heart block is a very rare
      complication of thalassemia major. Herein, we report a case of complete heart
      block with thalassemia major. The patient also had serious congestive heart
      failure. Management of the heart block with pacemaker brought no clinical
      improvement, and she died in the second month of hospitalization.

PMID- 12405444
TI  - Hypodipsia-hypernatremia syndrome associated with holoprosencephaly in a child: a
      case report.
AB  - We report a child with diabetes insipidus and hypodipsia associated with
      holoprosencephaly. A two-year-old girl with the history of several admittances to
      hospital during and after the newborn period with hypernatremic dehydration,
      acute renal failure and convulsions is presented. The patient had hypodipsia,
      hypernatremia, microcephaly, failure to thrive, and unilateral cleft lip and
      palate. Magnetic resonance imaging revealed lobar type holoprosencephaly.
      Increased plasma osmolality and decreased urinary osmolality were detected. Her
      urine ADH level was 10 ng/day. Plasma osmolality levels returned to normal after
      hydration and administration of a vasopressin analogue. These findings suggest
      that in children with hypernatremia-hypodipsia syndrome, the possibility of
      cerebral malformations should always be kept in mind.

PMID- 12405445
TI  - Presentation of a case with Salmonella glomerulonephritis.
AB  - Salmonella infection is frequently encountered in childhood, but it is rarely
      associated with glomerulonephritis. We present in this report a case with
      Salmonella glomerulonephritis, which is infrequent in children. His general
      condition was found moderate, and temperature and blood pressure were 38 degrees
      C and 150/90 mmHg, respectively. The whole blood counts were as follows: white
      blood cell count 3,800/mm3, hemoglobin 6.3 g/dl and platelet count 240,000/mm3.
      Serum urea was 140 mg/dl, albumin 2.5 g/dl and complement (C3) 23.6 mg/dl. Both
      Salmonella type O and Salmonella typhi H were detected positive (1/800 titer). In
      view of these findings, the case was considered as Salmonella glomerulonephritis;
      his clinical and laboratory recovery were achieved by supportive therapy.

PMID- 12405446
TI  - Cerebro-oculo-facio-skeletal syndrome: report of two cases from Turkey with
      postmortem findings.
AB  - We describe two cases of COFS (cerebro-oculo-facio-skeletal) syndrome in two
      newborn females of consanguineous parents. The clinical, radiological and
      pathological features of the patients are presented. One of the two cases had 11
      pairs of ribs (Case 1) and the other had three-lobed left lung (Case 2), neither
      of which has been described in COFS syndrome previously. To our knowledge, these
      are the first reported cases of COFS syndrome from Turkey.

PMID- 12405447
TI  - Megalocornea, macrocephaly, mental and motor retardation: MMMM syndrome
      (Neuhauser syndrome) in two sisters with hypoplastic corpus callosum.
AB  - We report two sisters with Neuhauser [megalocornea, macrocephaly, mental and
      motor retardation MMMM] syndrome. They also had hypotonia, incomplete cleft
      palate, bifid uvula, depressed nasal bridge, epicanthal folds, hypoplastic labia
      major, micrognathia and pectus excavatum. Their brain magnetic resonance imaging
      showed cortical atrophy, large fourth ventricle and hypoplasia of corpus
      callosum. These findings have not been reported before in MMMM syndrome. Prenatal
      sonography could have been helpful if the mother had asked for genetic counseling
      given the presence of hypoplasia of corpus callosum and Dandy-Walker variant.

PMID- 12405448
TI  - Effect of cooling and freezing, the two first steps of a freezing protocol, on
      the fertilizing ability of the rabbit sperm.
AB  - The effect of different phases of a freezing protocol on the fertilising ability
      of rabbit spermatozoa was evaluated. An extender containing 1.75 M DMSO and 0.05
      M sucrose (final concentration) was used to freeze rabbit sperm. In the first
      experiment, the results obtained with fresh and cooled (5 degrees C for 45 min)
      sperm were compared; no differences were observed between fresh and cooled semen
      for any of the parameters studied: fertility rate (78% vs. 91% for fresh and
      cooled sperm, respectively), and normal embryos two days after insemination (6.8
      vs. 8.5 normal embryos for fresh and cooled sperm). In the second experiment, the
      results obtained with fresh semen and sperm which had passed the first two steps
      of a freezing protocol (5 degrees C for 45 min and -30 degrees C for 30 min, and
      thawed at 50 degrees C for 15 s) were compared; the differences between them were
      obtained for fertility rate (94% vs. 61% for fresh and frozen sperm,
      respectively) and normal embryos two days after insemination (7.8 vs. 3.8 fresh
      and frozen sperm). These observations indicated that the differences in the
      results obtained with fresh and cryopreserved sperm were produced during the
      second step of the freezing protocol, and that apparently no toxic effect of DMSO
      was produced.

PMID- 12405449
TI  - Dexamethasone-mediated regulation of death and differentiation of muscle cells.
      Is hydrogen peroxide involved in the process?
AB  - The hypothetical involvement of H2O2 in dexamethasone-mediated regulation of
      muscle cell differentiation and elimination was studied. Rat L6 myoblasts and
      mouse C2C12 satellite cells were chosen for acute (24 h) and chronic (5 or 10
      day) experiments. Mitogenicity and anabolism were both affected by H2O2.
      Micromolar concentrations of H2O2 inhibited DNA while stimulating protein
      synthesis. At the millimolar level, H2O2 led to cell death by apoptosis.
      Synthetic glucocorticoi - dexamethasone (Dex) was shown to effect muscle cell
      fate similarly to H2O2. Chronic treatment with H2O2 or Dex dose-dependently
      accelerated either the formation of myotubes or cell elimination. Dex-induced
      cell death slightly differed from classical apoptosis and was featured by the
      symptoms of cell senescence such as extensive cytoplasm vacuolisation,
      accumulation of inclusion-bodies and lack of low molecular weight
      oligonucleosomal DNA fragmentation but chromatin condensation. Antioxidants
      (sodium ascorbate, N-acetyl-L-cysteine, catalase) abrogated Dex-dependent cell
      death. We conclude that H2O2 directly influences myogenesis and muscle cell
      elimination. Moreover, H2O2 can be considered as the potent mediator of
      glucocorticoid-dependent effects on muscle cells.

PMID- 12405451
TI  - Characterization of pregnancy-associated glycoproteins extracted from zebu (Bos
      indicus) placentas removed at different gestational periods.
AB  - In the present work, two biochemical approaches were used to characterize PAGs
      isolated from Bos indicus fetal cotyledons removed at different gestational ages.
      The first procedure included acidic and ammonium sulfate precipitations, anion
      and cation exchange chromatographies and the second included pepstatin-agarose
      affinity chromatography. A bovine PAG radioimmunoassay was used to monitor the
      immunoreactivity throughout the isolation procedures. The most immunoreactive
      fractions issued from cation exchange and affinity chromatographies were analyzed
      by SDS-PAGE and Western blotting, before transfer to a polyvinylidene difluoride
      (PVDF) membrane for NH2-microsequence determination. Use SDS-PAGE and Western
      blotting, different isoforms of PAG with apparent molecular masses of 51 to 69
      kDa and isoelectric points varying from 4.4 to 6.7 were identified in the
      placentas from different gestational ages. N-terminal microsequencing (10 to 25
      aa long) indicates the expression of one single terminal amino acid sequence in
      the Bos indicus placenta, which is 100% identical to the bovine PAG-1.

PMID- 12405450
TI  - Comparison between glycerol and ethylene glycol for the cryopreservation of
      equine spermatozoa: semen quality assessment with standard analyses and with the
      hypoosmotic swelling test.
AB  - The aims of this study were to compare glycerol (G) at customary concentrations
      and ethylene glycol (EG) as cryoprotectants for stallion semen in a skimmed milk
      (SM) extender, to test different EG concentrations and to compare the results of
      manual and computerized analysis with the hypoosmotic swelling (HOS) test.
      Ejaculates from two stallions were collected over 3 weeks (6 ejaculates per
      stallion), diluted in a SM based extender, divided into 4 fractions, centrifuged
      and diluted again to a concentration of 100 x 10(6) mL(-1) progressive motile
      spermatozoa (PMS) in addition with the cryoprotectant (3% G, 3% EG, 6% EG, 9%
      EG). Sperm motility was assessed both by microscopy (in raw and frozen-thawed
      semen immediately after thawing) and with an HTM-IVOS analyzer (Hamilton-Thorne
      Research, MA, USA), at 0, 1, 4, 6, and 12 h after thawing and storage at 21
      degrees C. Raw and frozen-thawed (0 h) semen samples for G and EG at 3% were also
      submitted to the HOS test with a 100 mOsm sucrose solution and were evaluated to
      detect the presence of swollen tails. The higher EG concentrations (i.e. 6% EG
      and 9% EG) significantly reduced the percentage of motile and PMS, immediately
      after thawing. At the same concentration, i.e. 3%, G resulted in a higher
      percentage of PMS than EG (36.2 vs. 30%, P < 0.05), but at 12 h after thawing and
      storage at 21 degrees C, no significant differences were detected between G and
      EG at 3%. The correlations between progressive motility (assessed by direct
      microscope observation or measured through the HTM analyzer) and the HOS test
      results for 3%G and EG were r = 0.61 and r = 0.35, respectively. The HOS test
      confirmed its suitability as a complementary method of analysis for stallion
      semen. We conclude that with the SM extender used, EG could substitute G as the
      cryoprotectant for stallion semen if used at the same or lower concentration.

PMID- 12405452
TI  - Copper deficiency in Creole goat kids.
AB  - Serum copper determination is important to confirm hypocupremia. Twenty healthy
      kids constituted the Control Group, and sixteen kids with symptoms of copper
      deficiency, the Problem Group. Animals from the Problem Group showed a low number
      of red blood cells (RBC) and variations in RBC size and shape. The values found
      for hemoglobin and mean corpuscular hemoglobin (MCH) in the Control Group were
      10.42 +/- 1.34 g.dL(-1) and 33.07 +/- 1.11 g.dL(-1) respectively, while the
      levels of the Problem Group were 7.95 +/- 1.21 g.dL(-1) and 29.45 +/- 0.78 g.dL(
      1), respectively. The kids from the Problem Group presented an important increase
      in monocytes, neutrophiles and leukocytes; precursor cells of the neutrophile
      were also observed. The anemia of these animals was hypochromic and macrocytic.
      Our results indicate that Creole kids with serum copper levels > 450 microg.L(-1)
      improved after treatment with copper glycinate. The six goats with cupremia < 450
      microg.mL(-1) were unable to improve their deficiency and died.

PMID- 12405453
TI  - Comparison of the effects of two GnRH antagonists on LH and FSH secretion,
      follicular growth and ovulation in the mare.
AB  - The effects of two GnRH antagonists were tested in order to delay and/or
      synchronise ovulation in mares. Five mares received Antarelix (0.01 mg.kg(-1)), 5
      mares received Cetrorelix (the same dose), 5 mares (control mares) received the
      vehicle intravenously, twice daily, for 8 days from the day the largest follicle
      reached 22 mm following prostaglandin administration. Ovulation was postponed in
      all mares injected with Antarelix (19.4 +/- 1.2 days after the beginning of the
      treatment) and in 2/5 mares injected with Cetrorelix (20 +/- 1 days) vs. 6.2 +/-
      0.4 days in control mares. During the treatment, LH concentrations were strongly
      depressed in Antarelix and in Cetrorelix mares (1.6 +/- 0.1 and 3.8 +/- 0.5
      ng.mL(-1) respectively vs. 21 +/- 2.5 ng.mL(-1) in control mares). In the 3
      Cetrorelix mares which ovulated during the treatment. 2 initiated their LH surge
      at this moment. FSH concentrations were not affected in Antarelix or in
      Cetrorelix mares during the treatment (11.4 +/- 1.3 and 7.9 +/- 0.8 ng.mL(-1)
      respectively vs. 10.5 +/- 0.8 ng.mL(-1) in control mares). In conclusion,
      Antarelix seems more efficient than Cetrorelix for postponing ovulation in mares.
      The role of LH in antral follicular development before the preovulatory stage is
      confirmed.

PMID- 12405454
TI  - Influence of co-culture with oviductal epithelial cells on in vitro maturation of
      canine oocytes.
AB  - The process of oocyte maturation in the canine species is unique among mammals:
      oocytes are immature at ovulation and the resumption and progression of meiotic
      maturation occur in the oviduct. This study was performed to investigate (i) the
      effect of co-culture with infundibulum and ampullar oviductal epithelial cells on
      the in vitro maturation of canine oocytes and (ii) the culture time necessary to
      reach full meiotic maturation. For this purpose the oocytes, collected from the
      ovaries of bitches undergoing ovariectomies, were divided into three groups and
      cultured for 48 and 72 h with the following systems: (A) TCM 199 + 10% oestrus
      bitch serum + FSH (0.1 IU.mL(-1)), LH (0.1 IU.mL(-1)) + progesterone (1
      microg.mL(-1)) + oestradiol (1 microg.mL(-1)) + cysteamine (100 microM); (B)
      medium A plus infundibulum cells; (C) medium A plus ampullar cells. Infundibulum
      and ampullar cells were recovered from the oviducts of bitches at the oestrus
      stage of their cycle. The results showed that after 48 h of incubation, a
      significantly higher meiotic resumption (P < 0.01) was observed in the oocytes
      cultured with infundibulum (59%) and ampullar cells (60.0%), than in the control
      group (40.0%). There was also a significantly (P < 0.01) higher meiotic
      progression to the MII in systems B and C (15.6% and 16.7%) than in system A
      (4.0%). After 72 h of culture, the percentages of meiotic resumption and
      progression were unchanged. These results showed that both the infundibulum and
      the ampullar oviductal epithelial cells positively influence the meiotic
      resumption and progression of canine oocytes and that 48 h are sufficient for the
      completion of nuclear maturation.

PMID- 12405455
TI  - In vitro maturation and fertilisation of bovine oocytes in relation to GH gene
      polymorphism (Leu/Val).
AB  - The present study describes the analysis of the associations between the growth
      hormone gene polymorphism (Leu/Val) and oocyte maturation and in vitro
      fertilisation in cattle. Two independent experiments were carried out. In the
      first one, oocytes were collected from 49 single ovaries, matured in vitro,
      measured and cytogenetically analysed. One ovary was considered as a donor. The
      procedure of the donor's genotyping at the GH locus was based on DNA extracted
      from the granulosa cells. The GH genotype did not influence the oocyte diameter
      nor the number of oocytes collected, which were selected for maturation and
      matured. An unreduced chromosome number was found in 8.8% of the cells at the
      second metaphase stage and 42.9% of the donors. This anomaly was observed in all
      genotype groups with a higher frequency in the VV cows (P < 0.01). In the second
      experiment, the oocytes collected from 72 single ovaries were matured and
      fertilised in vitro. The GH genotype of a donor did not influence the number of
      zygotes cleaved on day-2. It has to be mentioned, that due to the low frequency
      of the VV genotype (0.03), the results of the present study should be treated as
      preliminary and need further analysis.

PMID- 12405456
TI  - Dental awareness month and the three 'Rs' of dental care.

PMID- 12405457
TI  - A new era of dental education at the University of Sydney, Australia.
AB  - Dental education is currently under scrutiny in order to most appropriately
      address community needs for the new millennium. Educational outcomes need to
      include a commitment to life-long learning, and an emphasis on professional
      ethics and moral responsibility. These needs are supported by new forms of
      information delivery with a focus on the electronic media, by student centred and
      self-directed coursework, and by clinical stimulation. Additionally, at the
      University of Sydney, selection will follow a first degree. This will allow
      candidates time for an informed decision to be made for their future professional
      career and for a period of experience in the tertiary education system.

PMID- 12405458
TI  - Dentists, diabetes and periodontitis.
AB  - This review updates the relationship between diabetes mellitus and periodontitis.
      A checklist has been included to assist the general dental practitioner identify
      individuals with undiagnosed diabetes. The literature indicates a similar
      incidence of periodontitis exists between well-controlled diabetics and non
      diabetics. However, a greater incidence and severity of periodontitis is observed
      in both Type 1 and 2 long-term diabetics with poor metabolic control. There is an
      undeniable link between diabetes mellitus and periodontitis with complex
      interactions occurring between these diseases. A critical review of the
      literature fails to support the notion that periodontal therapy has a beneficial
      effect on the long-term control of diabetes. We have explored the associations
      between periodontitis and diabetes in the hope of providing the general dental
      practitioner with the knowledge to support the diabetic patient with the best
      possible dental care and advice.

PMID- 12405459
TI  - Arthritis and use of dental services: a population based study.
AB  - BACKGROUND: Rheumatoid arthritis (RA) and osteoarthritis (OA) are chronic
      systemic conditions that can have a profound effect on oral health as the result
      of physical disability, immunosuppressant and other medications and autoimmune
      disease. However, there is insufficient information available on the use of
      dental services by the people suffering from RA or OA. The purpose of this study
      was to investigate dental visits and factors associated with dental attendance in
      those with RA and OA in order to improve access to dental care in these groups.
      METHODS: The study used population based data from the 1995 National Health
      Survey (total n=53828). The main variables of interest were reported RA (n=1193)
      and OA (n=3091) and the main outcome variable was having visited a dental
      professional in the previous 12 months. Chi-square analysis was performed using
      SAS software. RESULTS: The proportion of people visiting a dental professional in
      previous 12 months was significantly less in both RA and OA respondents compared
      to non-arthritic respondents. Both males and females with RA and OA were found to
      be less likely to have visited a dental professional when compared to general
      population (p=0.001 in each case). Furthermore, the findings have revealed that
      RA and OA patients living in metropolitan centres were more likely to have a
      dental visit than those living in rural or remote areas (p=0.001 in each case).
      CONCLUSIONS: When compared to non-arthritic subjects, all patients with RA and OA
      were less likely to receive dental care, in particular preventive care. This is
      especially important in patients with Sjogren's Syndrome and those who are
      immunosuppressed.

PMID- 12405460
TI  - A study of titanium release into body organs following the insertion of single
      threaded screw implants into the mandibles of sheep.
AB  - BACKGROUND: Titanium is generally considered a safe metal to use in implantation
      but some studies have suggested that particulate titanium may cause health
      problems either at the site overlying the implant or in distant organs,
      particularly after frictional wear of a medical prosthesis. It was the purpose of
      this investigation to study the levels of dissemination of titanium from threaded
      screw type implants following placement of single implants in sheep mandibles.
      METHOD: Twelve sheep were implanted with a single 10x3.75mm self-tapping implant
      for time intervals of one, four and eight to 12 weeks. Four unoperated sheep
      served as controls. Regional lymph nodes, lungs, spleens and livers were
      dissected, frozen and subsequently analysed by Graphite Furnace Atomic Absorption
      Spectroscopy. RESULTS: Results associated with successful implants showed no
      statistically significant different levels of titanium in any organ compared to
      controls, although some minor elevations in titanium levels within the lungs and
      regional lymph nodes were noted. Two implants failed to integrate and these
      showed higher levels of titanium in the lungs (2.2-3.8 times the mean of the
      controls) and regional lymph nodes (7-9.4 times the levels in controls).
      CONCLUSIONS: Debris from a single implant insertion is at such a low level that
      it is unlikely to pose a health problem. Even though the number of failed
      implants was low, multiple failed implants may result in considerably more
      titanium release which can track through the regional lymph nodes. Results
      suggest that sheep would be an excellent model for following biological changes
      associated with successful and failed implants and the effect this may have on
      titanium release.

PMID- 12405462
TI  - Tooth development standards for South Australia.
AB  - BACKGROUND: Chronological age, as recorded by registration of birth date, is
      referred to throughout an individual's life. This information is relevant in
      medical and dental practice for evaluating developmental progress, for
      educational purposes, and in legal matters, particularly in the application of
      criminal law. The absence of birth date information raises particular concerns,
      and estimates of chronological age are often required. Standards of dental
      maturation may be used to estimate age, but they have been shown to be gender and
      population sensitive. METHODS: The revised Demirjian' system of dental age
      estimation was applied to a sample of 615 South Australian children in order to
      assess its accuracy. RESULTS: The results of our study have shown that the
      Demirjian system is of limited accuracy when used to estimate the age of South
      Australian children. CONCLUSIONS: Generation of new standard curves, specific to
      the Australian population, is indicated.

PMID- 12405461
TI  - Strains in the marginal ridge during occlusal loading.
AB  - BACKGROUND: The marginal ridge is considered fundamental to the ability of the
      tooth to resist functional and parafunctional occlusal loads without damage.
      Despite this role, very little is known of patterns of stress and strain in
      marginal ridges under load. This study investigated strains in proximal enamel of
      mandibular premolars using finite element analysis (FEA) and strain gauge
      measurements. METHODS: A three-dimensional FEA model of a human mandibular
      premolar was developed using commercial FEA software, and strains were computed
      in response to loads simulating clenching and chewing functions. Strains were
      measured in extracted premolars using strain gauges mounted on the proximal
      surfaces, under similar occlusal loading conditions. RESULTS: Strains in the
      vicinity of contact areas and marginal ridges were lower than near the cemento
      enamel junction and on buccal and lingual surfaces. The magnitude of proximal
      strains increased with oblique loading on cuspal inclines. Finite element
      analysis results correlated well with strain gauge measurements and can be used
      to predict strain directions and magnitudes. CONCLUSIONS: At least for mandibular
      premolars, the marginal ridges are not highly stressed areas during simulated
      occlusal loading.

PMID- 12405463
TI  - Acidic diet and dental erosion among athletes.
AB  - BACKGROUND: The consumption of acidic foods and drinks is increasing in
      popularity. The purposes of the present study were to investigate the consumption
      patterns of acidic foods and drinks among several sport groups and to examine any
      relationships between consumption patterns and dental erosion. METHODS: A
      questionnaire of oral health habits, diet and dental health was developed. Thirty
      two sports clubs (690 members) of the University of Melbourne participated in a
      survey. A total of 508 usable questionnaires were received (74.9 per cent
      response). Descriptive statistics were prepared and logistic regression was used
      to explore relationships between dental erosion (dependent variable) and the
      independent variables. RESULTS: Dental erosion was reported by 25.4 per cent of
      respondents, particularly among athletes of the Martial arts (affecting 37.4 per
      cent). The consumption of acidic foods and drinks was frequent among most
      athletes. No significant associations were identified between dental erosion and
      the frequency of drinking soft drinks or sports drinks. Statistically significant
      associations were found between dental erosion and age group (p=0.004), frequency
      of drinking juices (p=0.05), and tooth sensitivity (p=0.001). CONCLUSION:
      Athletes may be placing themselves unintentionally at risk of dental erosion and
      dentists could counsel athletes to control and reduce the effect of potentially
      erosive foods and drinks.

PMID- 12405464
TI  - Minimizing the risks of latex allergy: the effectiveness of written information.
AB  - BACKGROUND: Latex allergy has been identified as an occupational risk for the
      dental profession. This study assessed whether identified latex-allergic dental
      personnel changed their practices after receiving verbal and written information
      about the management of latex allergy. METHODS: A survey conducted at the 1998
      Australian Dental Association Congress identified 157 dental personnel with
      clinical latex allergy, or at high risk from latex exposure. The workplace
      implications were then explained to them by a consultant allergist. Four weeks
      later, follow up written information on latex allergy was mailed out. The
      information sheet outlined possible symptoms and cross-reactions, implications
      for the workplace, hand care advice and management strategies to reduce latex
      exposure in the workplace. After six weeks, a questionnaire, designed to assess
      whether appropriate steps to reduce latex exposure had been taken, was mailed
      out. RESULTS: Seventy per cent of the questionnaires were returned. All
      respondents felt the information was easy to understand and informative. While 50
      per cent of respondents indicated that they had changed to powder-free or non
      latex gloves, only five respondents were fully compliant with all instructions.
      CONCLUSION: Compliance with instructions regarding minimizing exposure to latex
      in a group of latex-allergic dental personnel was poor.

PMID- 12405465
TI  - Ethical dilemmas confronting dentists in Queensland, Australia.
AB  - BACKGROUND: This paper details contemporary ethical dilemmas encountered by
      Queensland dentists. METHODS: An age-stratified sample of 499 dentists resident
      in Queensland was surveyed. The questionnaire contained scenarios of five common
      ethical dilemmas. In addition, open-ended questions sought the respondent's most
      frequent, difficult and recent ethical dilemmas, and where they would seek
      guidance in dealing with ethical problems. RESULTS: Respondents acknowledged the
      patient's rights in treatment decisions and the dentist's right to refuse demands
      for inappropriate treatment. However, responses varied in the extent to which
      dentists may influence treatment decisions. Few respondents would ignore evidence
      of poor dental treatment but they are evenly divided in choosing to inform the
      patient, the dentist or both. Poor quality treatment is the most frequent and
      difficult dilemma, and half have experienced this problem recently. Requests by
      patients for fraudulent receipts occur in a third of responses. Dentists develop
      ethical values from multiple sources but for help with dental ethical problems,
      90 per cent of respondents would consult another dentist. CONCLUSIONS: Of the
      ethical dilemmas discussed in this survey, those relating to poor quality
      treatment confronted most respondents. Also the actions of dentists in dealing
      with these dilemmas were most varied.

PMID- 12405466
TI  - An investigation into the use of pilocarpine as a sialagogue in patients with
      radiation induced xerostomia.
AB  - BACKGROUND: Radiation therapy to the head and neck region can be an effective
      form of treatment for malignancies. Unfortunately damage to salivary glands may
      occur. Treatment of resultant dry mouth is at present very poor. The purpose of
      this pilot study was to investigate whether pilocarpine dissolved in artificial
      saliva and administered in a mouth spray would be effective in relieving such
      symptoms. METHODS: Twenty-three patients with radiation induced hyposalivation
      were recruited for this randomized, double-blind investigation. Subjects were
      randomly allocated to placebo or control medicaments used for eight weeks. All
      subjects were evaluated for the severity of their xerostomia associated symptoms
      prior to administration of the spray and again eight weeks later. RESULTS: The
      questionnaire and the visual analogue scale did not reveal any improvements in
      the dry mouth symptoms between cases and controls. Side-effects were reported
      among cases, mostly mild and tolerable. All patients taking pilocarpine (with
      base salivary flow rates > 0ml/min) demonstrated improvement in stimulated and
      unstimulated salivary flow rates. Candida counts decreased among the cases and
      controls although decrease among the cases was much greater. CONCLUSIONS: The
      results obtained indicate that provided residual functioning salivary tissue
      exists, pilocarpine used as formulated is effective and warrants further
      investigation.

PMID- 12405468
TI  - Chest pain in the dental surgery: a brief review and practical points in
      diagnosis and management.
AB  - If a dental patient develops chest pain it must always be managed promptly and
      properly, i.e., the practitioner immediately stops the procedure and, being aware
      of the patient's medical history, questions the patient regarding the nature of
      the pain to help determine the likely diagnosis. It will most likely be a
      manifestation of coronary artery disease (synonymous with ischaemic heart
      disease), i.e., angina pectoris or acute myocardial infarction, most usually the
      former. Angina will usually resolve with proper intervention whereas up to about
      one-half of myocardial infarction cases will develop cardiac arrest, mostly in
      the first few hours, and this will be fatal in up to two-thirds of cases. As
      health care professionals, dental practitioners have an inherent duty of care to
      be able to initiate appropriate care if such a medical emergency occurs.

PMID- 12405467
TI  - Undergraduate student experience in dental service delivery in rural South
      Australia: an analysis of costs and benefits.
AB  - BACKGROUND: Rural experience for dental students can provide valuable clinical
      education, change attitudes to rural practice, and make a valuable contribution
      to clinical service provision. The aim of this paper is to assess the costs and
      benefits of service delivery by students through rural training programmes.
      METHODS: Groups of two students worked in the public dental clinics in adjacent
      rural centres where there had been long-term difficulties in recruiting staff.
      The costs and benefits of the programme were assessed by the impact on waiting
      lists, the total cost per patient of a course of care and by the marginal cost of
      adding service provision by students to existing arrangements. RESULTS: The total
      costs of emergency and complete treatment provided by students were greater than
      the costs of treatment provided by public-sector dentists but less than the costs
      of private providers treating public patients. However, the value of services
      were greater when care was provided by students or private providers and the
      marginal cost of students providing services was 50-70 per cent of the cost of
      care provided by public dentists. CONCLUSION: This assessment suggests that the
      service benefits achieved compliment the primary objective of influencing the
      attitude of students to rural practice.

PMID- 12405469
TI  - Pericoronal radiolucencies and the significance of early detection.
AB  - Pericoronal radiolucencies are common radiographic findings encountered in
      general dental practice. They usually represent a normal or enlarged dental
      follicle that requires no intervention; alternatively they may represent a
      pathological entity that requires appropriate management and histopathological
      interpretation. A pericoronal space of greater than 2.5mm on an intraoral
      radiograph and greater than 3mm on a rotational panoramic radiograph should be
      regarded as suspicious. Although many pathological processes may present
      radiographically as pericoronal radiolucencies associated with unerupted teeth,
      the most common is the dentigerous cyst. These lesions may enlarge considerably
      if allowed to develop unchecked, and have the potential for pathological
      transformation. In this report we present four cases of large pericoronal
      radiolucencies associated with unerupted teeth, and highlight the importance of
      early detection and management of such lesions.

PMID- 12405470
TI  - A quick and simple method to obtain a radiographic evaluation of remaining
      alveolar bone height before implant placement.
AB  - This article describes a method for making a diagnostic radiographic evaluation
      of remaining alveolar bone height in the bounded-saddle patient without the
      previous fabrication of a study model and radiographic ball-bearing template. The
      method presented is simple, enabling the busy practitioner to perform immediate
      radiographic diagnosis and inform the patient at the first visit about the
      available alveolar bone height at the site of planned implant insertion. This
      method is therefore time saving for both the dentist and the patient.

PMID- 12405471
TI  - Cast post and core foundation for the badly broken down molar tooth.

PMID- 12405472
TI  - Dental research.

PMID- 12405473
TI  - Annotation: attachment disorganisation and psychopathology: new findings in
      attachment research and their potential implications for developmental
      psychopathology in childhood.
AB  - BACKGROUND: The past 10 years have seen a fruitful line of enquiry building on
      identification of previously unclassifiable patterns of infant-mother
      interaction. A critical review of these new findings in attachment theory,
      highlighting their potential relevance to child psychopathology, is presented.
      METHOD: Selective literature review relating to disorganised attachment in
      childhood. RESULTS: Disorganised patterns of attachment have only relatively
      recently been described. They show characteristic patterns of evolution in
      development. There is evidence that disorganised attachments are associated with
      specific forms of distorted parenting, which are distinct from general parental
      insensitivity and are associated with unresolved loss or trauma in the caregiver.
      There are also links with aspects of neurodevelopment vulnerability in the child.
      Attachment disorganisation is a powerful predictor of a range of later social and
      cognitive difficulties and psychopathology. CONCLUSIONS: The identification of
      disorganised attachment has greatly increased the potential relevance of
      attachment theory to general clinical work. However, the concept raises many
      methodological and theoretical issues. Among issues needing further exploration
      is the way in which attachment disorganisation relates to children's general
      mental states and may be affected by cognitive functioning and developmental
      impairment.

PMID- 12405474
TI  - The cost of understanding other people: social cognition predicts young
      children's sensitivity to criticism.
AB  - BACKGROUND: Individual differences in sensitivity to teacher criticism, and their
      links with individual differences in social cognition, were examined in 141 young
      children from diverse family backgrounds. METHODS: Children's sensitivity to
      teacher criticism was assessed in their first year of school (mean age 5.13
      years), using a puppet scenario in which a teacher criticises the child for
      making an error in school work. Understanding of false belief and mixed emotions
      was assessed at the same time. One hundred and thirteen of the children had been
      seen one year earlier in preschool, when comprehensive assessments were made of
      false belief and emotion understanding. RESULTS: Individual differences were
      apparent in children's sensitivity to teacher criticism, which were correlated
      with individual differences in both preschool and concurrent social cognition:
      children with more advanced social cognition were more sensitive to teacher
      criticism. Regression analyses showed that preschool social cognition was
      especially important, explaining unique variance in sensitivity to criticism over
      and above variance accounted for by concurrent sociocognitive ability.
      CONCLUSIONS: The results suggest that there are costs as well as benefits to
      understanding other people, at least for young children, and that individual
      differences in early social cognition may have distinct developmental
      trajectories. These issues, along with implications for research into children's
      responses to criticism and failure, are discussed.

PMID- 12405475
TI  - Maternal predictors of children's social cognition: an attachment perspective.
AB  - BACKGROUND: This paper assumes that the capacities to (1) openly acknowledge, and
      (2) elaborate a resourceful plan for coping with distress in the self and others
      are central features of social cognition. METHOD: These capacities were assessed
      in a sample (N = 51) of 11-year-old children whose mothers and fathers had
      previously provided Adult Attachment Interviews (AAIs) before their children were
      born. The children were shown six line-drawn sequences of child(ren), with
      peer(s) and/or family in diverse situations involving some moderate distress. The
      experimenter described the adversity shown in the sequence (e.g., bully pushing
      over another school-aged child in the presence of onlookers) and then invited the
      child to attribute thoughts and feelings to the characters, and comment upon what
      might happen next. RESULTS: Children whose responses scored highly for
      acknowledgement of the distress, and elaborating a resolution, were significantly
      more likely to have had mothers (but not fathers) whose AAIs were judged
      autonomous-secure as opposed to insecure (i.e., dismissing, preoccupied and/or
      unresolved). The significant influence of maternal representations of attachment
      upon the 11-year outcome remained even after taking account of concurrent
      parenting attitudes, children's verbal intelligence, as well as the previously
      assessed infant-parent attachment patterns. CONCLUSIONS: Discussion concerns the
      differential predictive power of maternal responses to the Adult Attachment
      Interview as related to the domain of children's social and emotional
      understanding.

PMID- 12405476
TI  - General and relationship-specific models of social cognition: explaining the
      overlap and discrepancies.
AB  - BACKGROUND: This study examined the degree of overlap and sources of
      discrepancies between two alternative models of social cognition in early
      adolescence, a general model based on 'theory of mind' and a relationship
      specific model rooted in attachment theory. METHODS: We administered newly
      developed, age-appropriate measures of advanced theory of mind or 'mentalising'
      and child-parent attachment, indexed by the coherence of children's narratives
      about attachment relationships, to a sample of 70 early adolescents (mean age
      12.6 years). RESULTS: The central findings were that, as expected, there was
      significant overlap between the mentalising and attachment indices of social
      cognition (r(70) = .35, p < .01). The overlap was not significantly mediated by
      verbal ability or general measures of parenting. There were also substantial
      discrepancies in children's performance on these measures that were conceptually
      interesting and statistically reliable. Specifically, adolescent reports of
      parenting discriminated between measures of mentalising and attachment coherence.
      In addition, those children who exhibited a less coherent model of attachment
      than was predicted from performance on a mentalising task were more likely to be
      rated as exhibiting a 'Dismissing/Avoidant' style in the attachment interview.
      CONCLUSIONS: Findings support a connection between mentalising and attachment in
      early adolescence, and further suggest that social cognitive processes may be
      context and relationship-specific.

PMID- 12405477
TI  - Theory of mind in children with 'lesser variants' of autism: a longitudinal
      study.
AB  - BACKGROUND: The study investigated the development of theory-of-mind (ToM)
      knowledge in children with lesser variants' of autism (PDD-NOS) over a period
      thought to be critical for ToM development (i.e., 3 to 5 years of age). METHOD:
      The sample included 11 children with PDD-NOS; 23 normally developing children
      were included for cross-sectional comparison and 13 normally developing children
      for longitudinal comparison. The groups were comparable in verbal and non-verbal
      mental age. Two storybooks were used for repeated assessment of various aspects
      of the children's theory of mind: emotion recognition, the distinction between
      physical and mental entities, prediction of behaviour and emotions on the basis
      of desires and prediction of behaviour and emotions on the basis of beliefs.
      RESULTS: The results showed that the children with PDD-NOS had specific
      difficulties in understanding and predicting other people's emotions on the basis
      of situational cues, desires and beliefs. However, their ability to predict
      actions from beliefs and desires were relatively intact. Compared to the normally
      developing children, these children achieved lower levels of theory-of-mind
      knowledge, both at time of initial assessment and approximately 6 months later.
      CONCLUSIONS: The data suggest that the theory-of-mind development of children
      with PDD-NOS is both delayed and deviant. The growth pattem of theory-of-mind
      skills in children with PDD-NOS seemed to be qualitatively different from the
      growth pattern found in the group of normally developing children.

PMID- 12405478
TI  - Preschool understanding of emotions: contributions to classroom anger and
      aggression.
AB  - BACKGROUND: We sought to identify patterns of social cognitive differences among
      preschoolers that were related to risk of stable aggressive behavior with peers.
      Following Lemerise and Arsenio (2000), we considered the emotional components of
      early social cognition, reasoning that young children's substrate of emotion
      knowledge serves them in decoding social encounters. METHOD: One hundred and
      twenty-seven children from a longitudinal study from age 3 to 4 though to their
      kindergarten year were interviewed on their emotional knowledge initially using a
      puppet procedure and later with stories about mixed emotions and display rule.
      Each year their anger and antisocial responses to others' emotions were observed.
      Teachers also provided information on each child's anger and aggression. RESULTS:
      Children's deficits in emotion knowledge assessed at age 3 and 4 predicted
      subsequent years' aggression. This effect was especially pronounced for boys.
      CONCLUSIONS: The pattern of findings suggests that the processes implicated in
      Dodge's work with older children may begin earlier than previously thought, with
      a focus on emotions.

PMID- 12405479
TI  - Exploring the borderlands of autistic disorder and specific language impairment:
      a study using standardised diagnostic instruments.
AB  - BACKGROUND: Two studies were conducted to test claims that pragmatic language
      impairment (PLI - previously referred to as semantic-pragmatic disorder) is
      simply another term for autistic disorder or pervasive developmental disorder not
      otherwise specified (PDDNOS). METHOD: In Study 1, 21 children aged from 6 to 9
      years with language impairments were subdivided on the basis of the Children's
      Communication Checklist into 13 cases of pragmatic language impairment (PLI) and
      eight cases of typical specific language impairment (SLI-T). Parents completed
      the Autism Diagnostic Interview - Revised (ADI-R) and the Social Communication
      Questionnaire (SCQ), and the children were given the Autism Diagnostic
      Observation Schedule - Generic (ADOS-G). In Study 2, a further 11 children with
      SLI-T and 18 with PLI were assessed using the SCQ and ADOS-G. In addition, six
      children diagnosed with high-functioning autism and 18 normally developing
      children were assessed. RESULTS: There was good agreement between ADI-R and SCQ
      diagnoses, but poor agreement between diagnoses based on these parental report
      measures and those based on ADOS-G. In many children, symptom profiles changed
      with age. Four PLI children from Study 1 and one from Study 2 met criteria for
      autistic disorder on both parental report (ADI-R or SCQ) and ADOS-G. Many of the
      others showed some autistic features, but there was a subset of children with
      pragmatic difficulties who were not diagnosed as having autism or PDDNOS by
      either instrument. These children tended to use stereotyped language with
      abnormal intonation/prosody, but they appeared sociable and communicative, had
      normal nonverbal communication, and showed few abnormalities outside the
      language/social communication domains. CONCLUSIONS: Presence of pragmatic
      difficulties in a child with communication problems should prompt the clinician
      to evaluate autistic symptomatology, but it is dangerous to assume that all
      children with pragmatic difficulties have autism or PDDNOS.

PMID- 12405480
TI  - Auditory processing in children with dyslexia.
AB  - BACKGROUND: It has been claimed that children with dyslexia show a general
      impairment in the processing of rapid auditory stimuli. However, most previous
      studies in this field have focused on children with language impairment or
      children who do not meet accepted criteria for dyslexia. METHODS: In the present
      study, the processing of rapid non-verbal auditory stimuli (complex tones) was
      examined in a population-based sample of 24 children with dyslexia, 10 to 12
      years of age, and a matched control group. RESULTS: The dyslexia group showed
      reduced tone processing relative to the control group, with significant main
      effects of tone duration, inter-stimulus interval and task complexity. The
      deficit was not specific for temporal order errors, and could not be explained by
      differences in short-term memory or verbal IQ. However, correlations between tone
      processing and reading ability were generally low or absent. CONCLUSION: Although
      a general processing deficit for rapid auditory stimuli in dyslexia was
      confirmed, its relevance for reading problems and hence for treatment programmes
      for dyslexia is questioned.

PMID- 12405481
TI  - Sociodynamic relationships between children who stutter and their non-stuttering
      classmates.
AB  - BACKGROUND: Previous research has indicated that children who stutter are more
      likely to be bullied and to hold a lower social position than their peers who do
      not stutter. However, the majority of this research has used data from
      respondents who were in the educational system more than 20 years ago. The
      current policy on integration of children with severe disabilities into
      mainstream education and the increased awareness of bullying in schools would
      indicate that attitudes toward children who stutter might have changed in the
      intervening period. METHOD: The study uses a sociometric scale (adapted from
      Coie, Dodge, & Coppotelli, 1982) to assess children who stutter in classroom
      groups with fluent peers. The peer relationships between 16 children who stutter
      and their classmates (403 children in total) were examined. RESULTS: Children who
      stutter were rejected significantly more often than were their peers and were
      significantly less likely to be popular. When compared to children who do not
      stutter, the children who stutter were less likely to be nominated as 'leaders'
      and were more likely to be nominated to the 'bullied' and 'seeks help'
      categories. CONCLUSIONS: The changes in integration policy and the implementation
      of anti-bullying policies in many schools appear to have made little impact on
      the social status of children who stutter. The incidence of bullying and
      rejection reported in this study has implications for schools and clinicians.

PMID- 12405482
TI  - Psychopathology and familial stress - comparison of boys with Fragile X syndrome
      and spinal muscular atrophy.
AB  - BACKGROUND: Chronic illness and mental retardation are both associated with an
      increased rate of behavioural problems in children and with considerable
      emotional strain in families. The aim of the study was to analyse and compare the
      specific effects of two exemplary conditions on familial stress and coping.
      METHODS: Forty-nine boys with Fragile X syndrome (FXS) were compared with 46 boys
      with Spinal Muscular Atrophy (SMA) and 32 male controls. Intelligence was
      measured with the RAVEN or K-ABC tests. Psychopathology was assessed with the
      CBCL questionnaire and a structured psychiatric interview (Kinder-DIPS), parental
      stress with the QRS, coping with the F-COPES and social support with the F-SOZU
      questionnaires. RESULTS: The mean age of the FXS boys was 8.6, of the SMA boys
      12.7 and of the controls 11.2 years. The mean IQ was 47 for the FXS, 112 for the
      SMA and 103 for the control groups. According to the CBCL, 89.8% of the FXS boys,
      21.7% of the SMA and 15.7% of the controls had a total score in the borderline or
      clinical range. The rates were 63.3%, 34.8% and 21.9% for internalising and
      67.3%, 10.9% and 18.8% for externalising behaviour, respectively. 81.6% of the
      FXS and 10.9% of the SMA patients had a DSM-IV or ICD-10 psychiatric diagnosis.
      The most common were ADHD (FXS: 36) and Separation Anxiety Disorder (SMA: 4). In
      total, parental stress was significantly higher in the FXS than in the SMA
      families (and in both compared to controls). There were no major inter-group
      differences regarding social support and familial coping. CONCLUSIONS: Children
      with FXS are severely mentally retarded and have a high rate of mainly
      externalising disorders. Despite good coping abilities and social support, this
      is associated with high familial stress. The SMA boys, with an intelligence in
      the upper normal range, are no more deviant than their healthy controls. Parental
      stress is lower in the SMA families with good coping abilities. In conclusion,
      families with mentally retarded children are in even greater need of help than
      those of children with severe chronic illness/physical handicap.

PMID- 12405483
TI  - Diagnostic efficiency of symptoms in the diagnosis of DSM-IV: generalized anxiety
      disorder in youth.
AB  - BACKGROUND: Evaluated five probability indices, including odds ratios, to
      determine relative contribution of Uncontrollable Excessive Worry (DSM-IV
      criterion A and criterion B) and Physiological Symptoms associated with
      uncontrollable excessive worry (DSM-IV criterion C) for diagnosing DSM-IV
      generalized anxiety disorder in youth. METHOD: One hundred eleven youths (6 to 17
      years old) and their parents who presented to a childhood anxiety disorders
      specialty clinic were administered a semi-structured diagnostic interview
      schedule. Separate evaluations were conducted for children and adolescents.
      RESULTS: Results showed that symptoms comprising DSM-IV's generalized anxiety
      disorder diagnosis vary relative to one another in the degree to which they
      contribute to the diagnosis, with certain symptoms having relatively higher
      diagnostic value than other symptoms. The relative value of symptoms also
      appeared to vary with children's and adolescents' reports, and parents' reports
      about their children and adolescents. CONCLUSIONS: Despite variations in
      symptoms' values, with only a few exceptions, almost all symptoms were still
      quite useful for diagnosis, whether reported by children, adolescents, or their
      parents.

PMID- 12405484
TI  - Can persistent tumor necrosis factor release lead to refractory sarcoidosis?

PMID- 12405485
TI  - Update of ocular manifestations in sarcoidosis.
AB  - Although the lung is the primary target of involvement, sarcoidosis can involve
      any organ in the body, including the eye. Ocular involvement may also be the
      initial manifestation of sarcoidosis in many patients. Since no characteristic
      clinical feature heralds the onset of ocular involvement in sarcoidosis, a
      systematic eye examination is advised. This review discusses ocular
      manifestations and changes based upon the anatomic site of the eye, ocular tissue
      biopsy, and treatment. Early recognition and intervention are essential for the
      reduction of ocular morbidity and the improvement of the patient's quality of
      life.

PMID- 12405486
TI  - Sarcoidosis in India: practical issues and difficulties in diagnosis and
      management.
AB  - Although sarcoidosis has emerged as an important lung disease in this country,
      clinicians continue to face difficulties in diagnosis and management of the
      illness. The relative rarity of sarcoidosis and the remarkable similarity of
      clinical, radiological and histopathological features with tuberculosis pose
      problems in the differential diagnosis. Although the pattern and sites of
      involvement do help, the prevalence of tuberculosis, including those of
      extrapulmonary sites, is so high that a confident exclusion of the illness is not
      easy. One important point of difference is the presence of tuberculin-anergy in
      sarcoidosis vis a vis tuberculosis. Bronchoscopic transbronchial lung biopsy is
      positive in over 80 percent of patients with sarcoidosis. Exclusion of
      tuberculosis to diagnose sarcoidosis is important in particular because
      corticosteroids form the mainstay of treatment for sarcoidosis. Asymptomatic
      patients with stage I pulmonary and other milder forms of cutaneous sarcoidosis
      do not need systemic steroid therapy. We have found favorable results with
      steroid sparing drugs such as methotrexate and azathioprine. Patients with
      refractory disease, relapse of illness and those with steroid induced
      complications or concomitant illnesses likely to be worsened by corticosteroids,
      are mostly treated with weekly, low-dose methotrexate.

PMID- 12405487
TI  - Exaggerated TNFalpha release of alveolar macrophages in corticosteroid resistant
      sarcoidosis.
AB  - BACKGROUND AND AIM OF WORK: The aim of the present study was to determine the
      TNFalpha release of cultured alveolar macrophages (AM) and the bronchoalveolar
      lavage (BAL) cellular profile in 35 patients suffering from long lasting
      sarcoidosis. METHODS: The AM TNFalpha release and the BAL cellular profile of 35
      patients with a mean duration of sarcoidosis of 10.4 +/- 1.3 years at the time of
      BAL was compared to 35 healthy controls. RESULTS: The BAL profile of 12 sarcoid
      patients with a stable disease was similar to that known from acute sarcoidosis.
      Sarcoid patients with progressive disease (n = 12) and sarcoid patients with
      corticosteroid resistant disease (n = 11) were characterised by a normal CD4/CD8
      ratio and a significant increase of BAL neutrophils (2.7 +/- 1.0% and 3.8 +/-
      1.1%, respectively). The AM TNFalpha release of sarcoid patients with stable
      disease did not differ significantly from controls (523 +/- 124 pg/ml vs. 410 +/-
      104 pg/ml). In contrast, we observed a significantly elevated TNFalpha release in
      sarcoid patients with progressive (2,124 +/- 550 pg/ml; p < 0.01) as well as in
      those with a corticosteroid resistant disease (1,585 +/- 520 pg/ml; p < 0.01)
      compared to controls. CONCLUSION: Chronic sarcoid patients in a progressive phase
      of the disease and those with a corticosteroid resistant disease are
      characterised by a significantly increased TNFalpha release of cultured AM. Our
      results support the usage of chimeric anti-TNFalpha antibodies as an alternative
      therapeutic regimen in chronic corticosteroid resistant sarcoidosis.

PMID- 12405488
TI  - CSF-ACE activity in probable CNS neurosarcoidosis.
AB  - OBJECTIVE: To redefine the utility of CSF-ACE as a selective indicator of
      probable CNS neurosarcoidosis. METHODS: The diagnosis of probable CNS
      neurosarcoidosis required: (a) biopsy evidence of systemic sarcoidosis, (b)
      cortical, brainstem, and/or spinal cord deficits, (c) enhancing lesions on brain
      and/or spinal cord MRI, and (d) exclusion of other etiologies which could account
      for the neurological deficits. Radioassay measurement of CSF-ACE activity was
      performed in 11 patients who met our criteria for probable CNS neurosarcoidosis
      and 207 control patients. RESULTS: The M +/- SD for CSF-ACE activity was
      significantly higher (p < 0.05) for the 11 probable CNS neurosarcoidosis patients
      (9.5 +/- 6.9 nmol/mL/min) than for the control patients (2.9 +/- 2.7
      nmol/mL/min). The optimal CSF-ACE activity discriminator value was 8 nmol/mL/min.
      At this value, the sensitivity and specificity of CSF-ACE activity was 55% and
      94%, respectively. CONCLUSIONS: CSF-ACE activity is a useful biochemical marker
      of probable CNS neurosarcoidosis when brain and/or spinal cord MRI show diffuse
      enhancing lesions.

PMID- 12405489
TI  - Use of fluticasone in acute symptomatic pulmonary sarcoidosis.
AB  - BACKGROUND: Inhaled corticosteroids have been used with variable success in
      sarcoidosis. The role of the inhaled corticosteroid fluticasone in symptomatic
      pulmonary patients was studied. METHODS: Twenty-two patients at five institutions
      who had been given an initial dose of oral corticosteroids within the prior four
      weeks were enrolled in a randomized double blind trial of inhaled fluticasone. An
      algorithm for the dosage of prednisone including rules for reducing dose was
      developed and applied at all centers. RESULTS: Of the 21 patients seen for more
      than one visit, 10 received fluticasone and 11 placebo. There was no significant
      difference in the improvement of vital capacity or average daily dose of
      prednisone for the fluticasone versus placebo. Eight of ten patients taking
      fluticasone had improvement in cough, while only 6 of 11 patients on placebo had
      improved cough despite taking oral corticosteroids (p = 0.36, N.S.). The
      algorithm for decreasing corticosteroid dosage was exactly applied in over 80% of
      patient visits and oral corticosteroids were used throughout most of the year of
      treatment. Patients registered higher complaints regarding increased appetite and
      polyuria when on ten mg or more prednisone a day. There was no clinical
      difference in the rate of toxicity for the fluticasone versus placebo group.
      CONCLUSION: A standard approach to tapering oral corticosteroids was followed in
      over 80% of patient visits. Oral corticosteroids were associated with significant
      complaints, while inhaled corticosteroids were well tolerated.

PMID- 12405490
TI  - Comparison of sputum induction with bronchoalveolar lavage cell differential
      counts in patients with sarcoidosis.
AB  - BACKGROUND AND AIM: Induced sputum (IS) has been proposed as a useful non
      invasive method mainly for the assessment of airway diseases. The aim of this
      study was to evaluate IS cellular composition and T-lymphocyte subpopulations and
      to compare them with those of bronchoalveolar lavage fluid (BALF) in patients
      with sarcoidosis. METHODS: We studied prospectively 20 patients (12 female, 8
      male) of median age 46 yr (range 25-65) with sarcoidosis and 10 normal subjects
      (5 female, 5 male) of median age 39 yr (range 26-60). IS was performed with
      hypertonic saline solution using an ultrasonic nebulizer (De Vilbis 2000). BALF
      was performed by conventional procedure using fiberoptic bronchoscopy. May-Giemsa
      Grunewald stained preps were differentially counted and T-lymphocyte subsets were
      analyzed by flow activated cell sorter (FACS). RESULTS: The percentage of
      macrophages was significantly lower in IS than in BALF (p < 0.0001), the
      percentage of neutrophils was significantly lower in BALF than in IS (p <
      0.0001), while there was no difference in the percentage of lymphocytes (p =
      0.693) and eosinophils (p = 0.25) in IS vs BALF in patients with sarcoidosis. A
      significant correlation was found between BALF and IS lymphocyte counts (r =
      0.61, p = 0.004), macrophages (r = 0.51, p = 0.02), and CD4+/CD8+ ratio (r =
      0.700, p = 0.001). CONCLUSIONS: These results suggest that the inflammation in
      sarcoidosis could be effectively and non-invasively determined by the analysis of
      cell differential counts and T-lymphocyte subsets in IS. Further studies are
      needed to explore the role of IS vs BALF in the follow-up of these patients.

PMID- 12405491
TI  - Chronic interstitial pneumonia with honeycombing in coal workers.
AB  - BACKGROUND: Coal worker's pneumoconiosis (CWP) results from coal mine dust
      inhalation. PATIENTS AND METHODS: We report here the presence of a chronic
      interstitial pneumonia (CIP) with honeycombing in 38 cases of coal miners, with
      or without CWP. The 38 patients were selected on the basis of clinical criteria
      which are unusual in CWP, i.e. fine inspiratory crackles and severe dyspnea.
      There were 37 men and one woman; mean age was 67.5 +/- 9.1 years. Thirty-two were
      smokers. Duration of exposure was 26.7 +/- 9.9 years. All the patients had
      clinical examination, chest radiography, computed tomography (CT), lung function,
      laboratory investigations, wedged fiberoptic bronchoscopy with bronchoalveolar
      lavage (BAL). In eight cases, lung specimens were obtained (lung biopsy n = 6,
      explanted lungs n = 2). RESULTS: Seventeen out of 38 had finger clubbing. 17 had
      radiological signs of CWP limited to the upper lobes (n = 11) or diffusely
      distributed (n = 6). CT showed honeycombing (36 cases), and/or ground glass
      opacities (30 cases) with traction bronchiectasis (8 cases) predominant in the
      lower lobes. BAL analysis demonstrated an increased percentage of neutrophils
      (9.4% +/- 6). Lung function showed a restrictive pattern (TLC = 75.1% +/- 16 and
      FVC = 79.7% +/- 17 of predicted values) associated with a decreased DLCO (50.4 %
      +/- 22.9 of predicted values) and hypoxemia (at rest = 65.9 mmHg +/- 13.5, upon
      effort = 56.5 mmHg +/- 13.4). Lung specimens demonstrated in 2 cases a homogenous
      interstitial fibrosis of intra-alveolar septum with an accumulation of immune and
      inflammatory cells without temporal variation and with obvious honeycombing. The
      6 other cases showed features of usual interstitial pneumonia. CONCLUSION: In
      presenting these cases, we would like to alert other clinicians to a possible
      association between CIP with honeycombing and coal dust exposure, with or without
      associated CWP.

PMID- 12405492
TI  - Sarcoidosis in northern Israel; clinical characteristics of 120 patients.
AB  - BACKGROUND: As the clinical features of sarcoidosis vary among patients from
      different ethnic groups and geographic areas, local reports are of great
      interest. PATIENTS AND METHODS: The files of 120 patients (72 females, 48 males),
      65% of Jewish and 35% of Arab origin, with a mean age at diagnosis of 49.7 +/-
      11.1 years, with biopsy-proven sarcoidosis, and residents of northern Israel were
      evaluated and disease parameters recorded. RESULTS: The mean annual incidence
      between 1980-1996 was 0.8/100,000. Most patients presented with pulmonary
      symptoms of at least one month's duration. Thoracic and extra-thoracic
      involvement was found in 90% and 47% of patients, respectively. Radiographic
      stage 0,1,2,3,4 disease was found in 9.2, 31.7, 18.3, 37.5 and 3.3% of the
      patients respectively. Sixty-two patients received medical therapy, mostly for
      pulmonary involvement. The majority of patients recovered without sequelae. Six
      patients died from sarcoidosis during the follow-up period (cardiac: 2,
      pulmonary: 4), providing a 5% mortality rate. CONCLUSIONS: Sarcoidosis in
      northern Israel is a fairly uncommon condition that occurs mainly in older
      patients with female predominance. Patients in this area have a higher incidence
      of clinically significant pulmonary involvement necessitating medical therapy as
      compared to other parts of the world.

PMID- 12405493
TI  - Sarcoidosis of the upper respiratory tract. Selected cases emphasizing diagnostic
      and therapeutic difficulties.
AB  - BACKGROUND: Sarcoidosis of the upper respiratory tract (SURT) is a frequently
      overlooked and inadequately treated complication of sarcoidosis. AIM: The aim of
      this descriptive study is to present selected cases of sarcoidosis of the upper
      respiratory tract depicting diagnostic and therapeutic challenges. METHODS AND
      RESULTS: Five selected patients who either had an unusual initial presentation or
      an unusual clinical course were included if they also had long follow up. The
      diagnosis of SURT was based on the conventional criteria including histological
      evidence and appropriate microbiological studies. CONCLUSION: These case studies
      underline problems that may arise when SURT is not recognized early and
      appropriate and adequate treatment is delayed.

PMID- 12405494
TI  - Bronchiolitis obliterans organizing pneumonia associated with lower respiratory
      tract infection by respiratory syncytial virus in an immunocompetent adult.

PMID- 12405495
TI  - Sarcoidosis and B-cell MALT lymphoma.

PMID- 12405496
TI  - The Shipman Inquiry.

PMID- 12405497
TI  - Pain in newborns.

PMID- 12405498
TI  - A prospective study of preferred versus actual place of death among patients
      referred to a palliative care home-care service.
AB  - In this first such study in an Irish setting, patients referred to a Hospice Home
      Care Team were asked where they would prefer to die, and were then followed until
      death to determine actual place of death, and factors that influenced same. Over
      80% expressed a preference to die at home. Almost 50% of those who expressed a
      preference for a home death actually died there. Of those admitted to hospital or
      hospice to die, uncontrolled symptoms and inability of family to cope were the
      main reasons precipitating admission. On closer assessment, it was felt that a
      significant minority of those admitted could have been cared for at home had
      additional resources been available in the community. Facilitating choice in
      place of care for the dying is acknowledged government policy and, as such,
      greater resources should be made available to community health and social
      services to support ongoing care at home.

PMID- 12405499
TI  - Changing trend in congenital abdominal wall defects in eastern region of Ireland.
AB  - In the past six years, there have been reports from abroad of an unexplained rise
      in the birth prevalence rate of the congenital abdominal wall defect
      gastroschisis, while rates for the macroscopically similar anomaly omphalocoele
      have remained stable. The Dublin EUROCAT Registry of congenital anomalies
      monitors trends in the birth prevalence of birth defects in the eastern region of
      Ireland. We analysed births of children with omphalocoele and gastroschisis born
      in the period 1981-2000, with comparisons of a number of demographic and
      obstetric variables. During the 20 year period the birth prevalence rate for
      omphalocoele remained stable at 2.5/10,000 births, whereas the rate for
      gastroschisis increased significantly during the 1990s from 1.0/10,000 in 1991 to
      4.9/10,000 in 2000. Most of the increase occurred among mothers under 25 years of
      age. Omphalocoele was associated with a relatively high proportion of other major
      congenital anomalies. This study showed that there has been an unexpected rise in
      the birth prevalence of gastroschisis in the region, similar to that experienced
      in other countries in the same time period and likely to have common aetiological
      features.

PMID- 12405500
TI  - Community and social interventions at a geriatric medical OPD.
AB  - Health and social services in Ireland tend to be relatively poorly coordinated.
      Surveys confirm the perceptions of older people with disability that access to
      and availability of both health and social services are limited. Multi
      disciplinary geriatric medical clinics may provide a focus for better utilization
      and coordination of these services. The purpose of this study was to measure not
      only the existing service use but also the potential for community and social
      care intervention with older people living in the community when using multi
      disciplinary geriatric medical clinics. A sample of 60 consecutive patients aged
      over 65, attending our geriatric medical OPD for the first time, were interviewed
      using a semistructured questionnaire on the current and potential use of
      community and social care services. Our service arranged for 229 interventions or
      referral to services, an average of 3.8 interventions per patient. Ninety-six
      services were already in place (an average of 1.6 per patient) and 455 services
      were not applicable, an average of 7.6 per patient. A combined health and social
      care response is critical to a successful strategy to disease and disability in
      later life. Although this study describes a relative utilitarian approach to
      increase community and social care support, it shows there is significant scope
      to improve uptake of basic community and social care services by a focussed
      approach to the care needs of older people.

PMID- 12405501
TI  - Perceived quality of life and mental health status of Irish female prisoners.
AB  - Mental health status and quality of life of female prisoners, the majority of
      whom are drug-users, was examined as part of a larger, cross-sectional, general
      healthcare study of the Irish prisoner population. Comparisons were made with
      drug using and non-drug using male prisoners and females from the general
      population. Instruments include the GHQ-12 and the WHOQOL-BREF. While their
      quality of life profile was closer to drug-using male prisoners than other
      comparison groups, female prisoners still had significantly poorer physical and
      psychological Quality of Life scores. While poorer quality of life scores may be
      associated with the more severe drug use patterns of female prisoners it is
      likely that other factors also contribute. Before resorting to drugs/crime women
      may have already experienced adversity. There may also be gender differences in
      response to the combined dimensions of environmental distress. If women are to be
      imprisoned appropriate comprehensive mental health promotion approaches must
      address their specific needs.

PMID- 12405502
TI  - Paget's disease of bone: presentation, extent and response to bisphosphonates.
AB  - According to a radiograph survey in 1982, Paget's disease of bone is common in
      Ireland but, to date, there have been no clinical reports. In a survey of 24
      patients with Paget's disease of bone, we found monostotic disease in 8 and
      polyostotic disease in 16. Complications were common including deformity (21%),
      fracture (17%) and deafness (8%). Bisphosphonate therapy induced a remission in
      22 patients.

PMID- 12405503
TI  - Endometriosis in caesarean section scars.
AB  - We report two cases of endometriosis in caesarean section scars. This is a
      condition, which, in our experience, follows approximately one caesarean section
      in every thousand. With increasing rates of caesarean section this potentially
      troublesome condition may be seen more frequently, and we propose a modification
      in practise to reduce its incidence.

PMID- 12405504
TI  - Osteoid osteoma of the distal humerus mimicking tennis elbow.
AB  - Osteoid osteoma is an uncommon bony neoplasm which rarely occurs in the elbow
      region. We present a case in a sixteen year old male whose symptoms were
      suggestive of lateral epicondylitis, or tennis elbow, and he had been treated as
      such for a period of eighteen months. CT scan and isotope bone scan showed
      typical features of osteoid osteoma and his symptoms resolved rapidly following
      excision of the lesion. Tennis elbow is rare in the adolescent age group, and
      other diagnoses should be excluded in cases where the clinical findings are
      suggestive of this condition.

PMID- 12405505
TI  - Primary care research: patient registration.

PMID- 12405506
TI  - Ectopic pregnancy associated with tubal schistosomiasis.

PMID- 12405507
TI  - Mental Health Act 2001.

PMID- 12405508
TI  - Putting language back in the body: speech and gesture on three time frames.
AB  - This article investigates the role that nonverbal actions play in language
      processing over 3 different time frames. First, we speculate that nonverbal
      actions played a role in how formal language systems emerged from our primate
      ancestors over evolutionary time. Next, we hypothesize that if nonverbal
      behaviors played a foundational role in the emergence of language over evolution,
      these actions should influence how children learn language in the present.
      Finally, we argue that nonverbal actions continue to play a role for adults in
      the moment-to-moment processing of language. Throughout, we take an embodied view
      of language and argue that the neural, cognitive, and social components of
      language processing are firmly grounded in bodily action.

PMID- 12405509
TI  - Impaired processing of brief, rapidly presented auditory cues in infants with a
      family history of autoimmune disorder.
AB  - Studies have shown that individuals with language disorders, such as
      developmental dyslexia and specific language impairment, exhibit impairments in
      the processing of brief, successive, or rapidly changing auditory information. It
      is also the case that a higher rate of autoimmune disorders have been identified
      in those with language-based learning disorders and, conversely, that individuals
      with autoimmune disorders show a higher incidence of language-related disorders.
      The rapid auditory processing (RAP) deficits described for older individuals with
      language impairments may also be used as a behavioral marker to identify infants
      at higher risk for language delays. Thus, we were interested in examining RAP
      abilities in a subset of infants with a positive family history of autoimmune
      disorders. Eleven infants from our ongoing prospective longitudinal studies were
      identified based on parental response to a question about the presence of a
      family history of autoimmune disease and compared to 11 matched controls. The RAP
      threshold of each infant was assessed at 6 and 9 months of age using a
      conditioned head-turn procedure (using tone pairs with brief interstimulus
      intervals) and an auditory-visual habituation-recognition memory task using
      computer-generated consonant-vowel syllables (/ba/ vs. /da/). A visual
      habituation-recognition memory task that did not require processing of brief
      temporal cues was also administered. Group differences emerged on the infant RAP
      tasks, and on language outcome measures at 12 and 16 months of age. Infants from
      families with a history of autoimmune disorder had significantly higher (i.e.,
      poorer) RAP thresholds and lower language scores than did control infants,
      whereas visual discrimination scores did not differ between family history
      infants and controls. Moreover, when brief auditory cues were necessary for the
      discrimination of /ba/ vs. /da/, infants with a family history of autoimmune
      disorder performed significantly more poorly than did controls. These findings
      lend support to the hypothesis that a similar mechanism, perhaps a neural-immune
      interaction, may underlie the observed co-occurrence of autoimmune disorders and
      learning impairments.

PMID- 12405510
TI  - Word and picture processing in children: an event-related potential study.
AB  - In an investigation of the N400 component, event-related potentials (ERPs)
      elicited by 4 types of word stimuli (real words, pseudowords, random letter
      strings, and false fonts) and 3 types of picture stimuli (real pictures,
      pseudopictures, and picture parts) presented in separate lists were recorded from
      10- and 11-year-old children. All types of word stimuli elicited an anteriorly
      distributed negativity peaking at about 400 msec (antN400). Words and pseudowords
      elicited similar ERPs, whereas ERPs to letter strings differed from those to both
      pseudowords and false fonts. All types of picture stimuli elicited dual anterior
      negativities (N350 and N430). Real pictures and pseudopictures elicited similar
      ERPs, whereas pseudopictures and picture parts elicited asymmetrical processing.
      The results are discussed in terms of increased sensitivity to and dependence on
      context in children.

PMID- 12405511
TI  - Brain responses to changes in speech sound durations differ between infants with
      and without familial risk for dyslexia.
AB  - A specific learning disability, developmental dyslexia, is a language-based
      disorder that is shown to be strongly familial. Therefore, infants born to
      families with a history of the disorder are at an elevated risk for the disorder.
      However, little is known of the potential early markers of dyslexia. Here we
      report differences between 6-month-old infants with and without high risk of
      familial dyslexia in brain electrical activation generated by changes in the
      temporal structure of speech sounds, a critical cueing feature in speech. We
      measured event-related brain responses to consonant duration changes embedded in
      ata pseudowords applying an oddball paradigm, in which pseudoword tokens with
      varying /t/ duration were presented as frequent standard (80%) or as rare deviant
      stimuli (each 10%) with an interval of 610 msec between the stimuli. The infants
      at risk differ from control infants in both their initial responsiveness to
      sounds per se and in their change-detection responses dependent on the stimulus
      context. These results show that infants at risk due to a familial background of
      reading problems process auditory temporal cues of speech sounds differently from
      infants without such a risk even before they learn to speak.

PMID- 12405512
TI  - The Maudsley Reactive and Nonreactive strains: a new perspective.
AB  - Research on the Maudsley Reactive and Maudsley Nonreactive strains conducted
      primarily between 1980 and 2001 is reviewed. One line of research, which has
      found consistent differences between the Harrington derivation of the Maudsley
      Reactive (MR/Har) and Maudsley Nonreactive (MNRA/Har) strains in conflict
      situations, appears to support the traditional view of the two strains as
      representing models of global differences in emotionality. In contrast,
      comparisons of the two strains in two commonly used tests that involve a
      component of fear either do not reveal differences between the strains (escape
      avoidance conditioning) or are inconsistent in expression (elevated plus maze).
      Emphasis is placed on the importance of recognizing that most of the phenotypic
      differences discovered among selected inbred strains, including the Maudsleys,
      will inevitably be unrelated to the original selection criterion, but that many
      of these phenotypic differences will have their own intrinsic interest. For
      example, the fact that, relative to MNRA/Har, two bottle ethanol preference is
      greater in MR/Har rats and that MR/Har rats exhibit greater exploration of novel
      stimuli when these are presented in a familiar environment may have little to do
      with the hypothesized differences in emotionality among the strains. It is
      suggested the MR/Har drinking pattern in alcohol preference tests, which is
      characterized by considerable variability, may complement other models of
      alcoholism, especially in the investigation of environmental influences which
      contribute to the variability. In the case of strain differences in response to
      novelty, this may help explain some of the inconsistencies in findings in the
      elevated plus maze, which, aside from provoking fear, also contains an important
      element of novelty. Finally, it has been found that alterations in the peripheral
      sympathetic nervous system (PSNS) are correlated with strain differences in open
      field defecation (OFD) in the Maudsley model, and it has been proposed that the
      lower OFD of MNRA/Har rats is a direct result of sympathetic inhibition of
      colonic motility. These strain differences in the PSNS are furthermore associated
      with important alterations in the response of the central noradrenergic system to
      acute and chronic stress. It is hypothesized that genes may have influenced PSNS
      tone by altering CNS structures with descending projections. If the link between
      low levels of OFD and higher peripheral sympathetic tone is supported by
      additional experiments, this will force reconsideration of OFD as an index of
      emotionality.

PMID- 12405513
TI  - High vs low anxiety-related behavior rats: an animal model of extremes in trait
      anxiety.
AB  - In addition to their robust difference in trait anxiety, as illustrated by a
      variety of behavioral tests, HAB and LAB rats differ in their stress coping
      strategies, the former being more susceptible and vulnerable to stressor exposure
      and preferring more passive strategies. HAB rats of either gender show signs of a
      hyper-reactive hypothalamic-pituitary-adrenocortical (HPA) axis, thus resembling
      psychiatric patients. As shown by in situ hybridization and microdialysis in
      freely behaving animals, both the expression and release of vasopressin in the
      hypothalamic paraventricular nucleus are higher in HAB than in LAB rats, thus
      contributing to the HPA axis hyperdrive. Accordingly, in HAB animals,
      administration of a V1 receptor antagonist normalized the pathological outcome of
      the dexamethasone/corticotropin-releasing hormone test and triggered behavioral
      changes toward reduced anxiety and active stress coping. Pharmacological
      validation has revealed signs of depressive-like behavior, as HAB but not LAB
      rats have shown more active stress coping behavior and a normalized HPA axis
      after treatment with paroxetine. Of interest, this antidepressant reduced the
      hypothalamic overexpression of vasopressin; this novel mechanism of action is
      likely to contribute to paroxetine effects on both behavioral and neuroendocrine
      parameters. Cross-mating and cross-fostering paradigms showed that the divergent
      emotionality in HAB vs. LAB rats is determined genetically, rather than
      postnatally through maternal behavior. As the behavioral and neuroendocrine
      phenotyping pointed to the vasopressin gene as a candidate gene critically
      involved in anxiety, preliminary genetic approaches have been focused on this
      gene, revealing single nucleotide polymorphisms (SNPs) in the promotor area of
      the vasopressin gene in HAB, but not LAB rats. HAB/LAB rats are thus proving to
      be a unique animal model to identify and characterize neurobiological,
      neuroendocrine, and genetic correlates of trait anxiety, and perhaps depression,
      in humans.

PMID- 12405514
TI  - The Naples High- and Low-Excitability rats: selective breeding, behavioral
      profile, morphometry, and molecular biology of the mesocortical dopamine system.
AB  - The Naples High- (NHE) and Low-Excitability (NLE) rat lines have been selected
      since 1976 on the basis of behavioral arousal to novelty (Lat-maze). Selective
      breeding has been conducted under continuous genetic pressure, with no brother
      sister mating. The behavioral analyses presented here deal with (1) activity in
      environments of different complexity, i.e., holeboard and Lat maze; (2) maze
      learning in hexagonal tunnel, Olton, and Morris water mazes and; (3) two-way
      active avoidance and conditioned taste aversion tests. Morphometric analyses deal
      with central dopaminergic systems at their origin and target sites, as well as
      the density of dopamine transporter immunoreactivity. Molecular biology analyses
      are also presented, dealing with recent experiments on the prefrontal cortex
      (PFc), cloning and identifying differentially expressed genes using subtractive
      libraries and RNAase protection. The divergence between NLE and NHE rats varies
      as a function of the complexity level of the environment, with an impaired
      working and reference memory in both lines compared to random bred (NRB)
      controls. Moreover, data from the PFc of NHE rats show a hyperdopaminergic
      innervation, with overexpression of mRNA species involved in basal metabolism,
      and down-regulation of dopamine D1 receptors. Altogether, the evidence gathered
      so far supports a hyperfunctioning mesocorticolimbic system that makes NHE rats a
      useful tool for the study of hyperactivity and attention deficit, learning and
      memory disabilities, and drug abuse.

PMID- 12405515
TI  - Behavioral characteristics of rat lines selected for differential hypothermic
      responses to cholinergic or serotonergic agonists.
AB  - The present review will describe the formation of two pharmacologically selected
      lines of rats, their behavioral phenotypes, their responses to select drugs,
      their possible neurochemical correlates, and their use to detect the therapeutic
      potential of antidepressant drugs. The Flinders Line rats were established at
      Flinders University in Australia by selectively breeding for differential
      responses to an anticholinesterase agent from outbred Sprague-Dawley (SD) rats;
      the Flinders Sensitive Line (FSL) rats were more sensitive to the hypothermic and
      behavioral suppressing effects of this agent than the Flinders Resistant Line
      (FRL) rats. The 8-OH-DPAT line rats were established at the University of North
      Carolina at Chapel Hill by selectively breeding for differential hypothermic
      responses to the 5-HT1A receptor agonist, 8-OH-DPAT; the high DPAT sensitive
      (HDS) line rats were more sensitive to the hypothermic effects of 8-OH-DPAT than
      the low DPAT sensitive (LDS) line rats. Studies of these two pairs of lines have
      indicated that the FSL and HDS rats are both more susceptible to stress-induced
      behavioral disturbances. Their usefulness in detecting potential antidepressant
      drugs and the relationship between mood disorders and drug abuse will be
      discussed.

PMID- 12405516
TI  - Apomorphine susceptibility and animal models for psychopathology: genes and
      environment.
AB  - Many years ago we found a bimodal distribution of a number of different behaviors
      in our regular outbred Wistar stock. This was observed in the response to
      novelty, the response in a resident-intruder test as well as in the stereotypy
      response to the dopamine agonist apomorphine. On the basis of that, we decided to
      selectively breed these animals, which resulted in the the APO-SUS and APO-UNSUS
      lines. The APO-SUS rats show a strong, stereotyped gnawing response, whereas APO
      UNSUS show only a weak gnawing response. Follow-up studies have shown that the
      phenotypical expression of these rats depend on genetic and early and late
      environmental factors. Because these rats were not selected on the basis of a
      specific behavioral trait, but rather on the basis of a difference in
      susceptibility for a specific neurotransmitter, it is not surprising that these
      animals show major differences in the neurochemical state of the central nervous
      system. In fact, in many respects they represent mirror images of each other.
      Moreover, these animals show clear differences in their endocrine and
      immunological systems. APO-SUS rats can be characterized as having a hyper
      reactive hypothalamus-pituitary-adrenal axis, and a dominance of the T(H2)
      system. Apart from discussing the main differences between APO-SUS and APO-UNSUS
      rats, the review specifically focuses on the former as a potential model for
      schizophrenia. We have been able to show that APO-SUS rats indeed share a large
      number of behavioral, neurochemical, endocrinological, and immunological
      similarities with patients suffering from schizophrenia. Because schizophrenia is
      also likely to result from an interaction between genetic and early stressful
      life events, the APO-SUS rat might represent a promising animal model for
      studying this severe mental disorder.

PMID- 12405517
TI  - Phenotypic and genotypic characterization of the Indiana University rat lines
      selectively bred for high and low alcohol preference.
AB  - The Indiana lines of selected rats, the HAD and LAD replicates and the P and NP
      lines, were bred for high and low alcohol preference. The P and HAD lines have
      met criteria for an animal model of alcoholism in that they voluntarily consume
      sufficient ethanol to achieve significant blood alcohol concentrations, and their
      alcohol-seeking behavior is reinforced by the pharmacological effects of ethanol
      rather than its taste, caloric content, or other properties. These lines have
      been characterized extensively for associated behavioral and physiological
      phenotypes. The P and HAD rats show an enhanced responsiveness to the stimulatory
      effects of ethanol and reduced sensitivity to the aversive sedative effects of
      ethanol. Consistent findings with the selected lines include differences in the
      mesolimbic dopamine reward system, as well as differences in serotonin, GABA,
      endogenous opioid, and neuropeptide Y systems. Genetic mapping studies have
      identified quantitative trait loci influencing alcohol preference on chromosomes
      3, 4, and 8 in the inbred P/NP rats and on chromosomes 5, 10, 12, and 16 in the
      noninbred HAD1/LAD1 rats. The elucidation of the genotypes and phenotypes that
      result in excessive alcohol intake may lead to a better understanding of alcohol
      abuse and alcoholism and could guide strategies for potential treatment and
      prevention.

PMID- 12405518
TI  - The assessment of contemporary fears in adolescents using a modified version of
      the Fear Survey Schedule for Children-Revised.
AB  - The FSSC-Hawaii (FSSC-HI; Journal of Anxiety Disorders, 12, 437-461) is a
      modified version of the Fear Survey Schedule for Children-Revised (FSSC-R;
      Behaviour Research and Therapy, 21, 685-692) that includes a number of
      contemporary fear stimuli and situations (e.g., "drugs", "being raped", "AIDS").
      The psychometric properties of the FSSC-HI were examined in a large sample of
      Belgium adolescents (n = 551) aged 12-19 years. Results showed that a five- and
      seven-factor model both provided satisfactory fits for the structure of the FSSC
      HI. Furthermore, the internal consistency of the scale was good and this appeared
      to be true for the five-factor as well as the seven-factor solution. Support was
      found for the convergent validity of the FSSC-HI. That is, FSSC-HI scores
      correlated in a meaningful way with scores on alternative measures of childhood
      anxiety. Finally, a considerable number of the "new" fear items were found to
      rank high in the top 10 of most common fears. The implications for the assessment
      of fears in children and adolescents are briefly discussed.

PMID- 12405519
TI  - Scrutinizing the relationship between shyness and social phobia.
AB  - The nature of the relationship between shyness and social phobia can be clarified
      by assessing rates of social phobia in highly shy and normative samples. In the
      present study, 2202 participants were screened and categorized on a shyness scale
      as highly shy (90th percentile) or "normatively" shy (40-60th percentile). The
      Composite International Diagnostic Interview and the Structured Clinical
      Interview for DSM-IV Axis II Personality Disorders (SCID-II; Avoidant Personality
      Disorder module) were used to assign clinical diagnoses. Approximately 49% of
      individuals in the highly shy group had a social phobia diagnosis compared to 18%
      in the normatively shy group. Significantly more generalized social phobia (36%
      vs. 4%) and avoidant personality disorder (14% vs. 4%) diagnoses were present in
      the highly shy group compared to the normatively shy group. Equal rates of
      nongeneralized social phobia (i.e., 14% vs. 14%) were present in the highly shy
      and the normatively shy comparison group. Findings suggest that shyness and
      social phobia (especially the generalized type) are related constructs but not
      completely synonymous; an individual can be extremely shy yet not have a social
      phobia diagnosis.

PMID- 12405520
TI  - Lifetime trauma history and panic disorder: findings from the National
      Comorbidity Survey.
AB  - OBJECTIVE: The purpose of this article is to examine prevalence of lifetime
      traumatic experiences in a community sample of panic disorder patients. METHOD:
      We examined trauma rates in a cohort of panic disorder patients. Also, we
      statistically disaggregated comorbid PTSD from individuals diagnosed with panic
      disorder in the National Comorbidity Survey. FINDINGS: Panic disorder patients
      suffer lifetime traumatic experiences at high rates. We found that 24.2% of
      females and 5% of males with panic disorder reported previous history of being
      sexually molested. CONCLUSIONS: These results suggest that trauma may act as a
      risk factor for panic disorder, as well as comorbid panic disorder and PTSD.

PMID- 12405521
TI  - Priming panic interpretations in children of patients with panic disorder.
AB  - Cognitive and psycho-physiological models of panic disorder stress the role of
      interpretation bias in the maintenance of the disorder. Several studies have
      reported results consistent with this hypothesis, but it is still unclear whether
      this bias precedes panic disorder or is a consequence of it. In the present
      study, we compared the interpretations of ambiguous scenarios of children of
      individuals with panic disorder, children of individuals with animal phobia, and
      children of healthy controls. Children were presented with three types of
      scenarios each including one of the following descriptions: panic-relevant
      physical sensations, animal-relevant stimuli, and panic-irrelevant physical
      sensations (i.e., cold symptoms). To test, if children's interpretation bias is
      affected by priming, we compared their responses to the scenarios before and
      after watching a panic, a spider phobic, and a cold model. The results revealed
      that (a) children of panic disordered parents but not of parents with animal
      phobia and of healthy controls showed a significant increase in anxious
      interpretations after priming; and (b) this significant increase emerged only
      after priming through presentation of a panic-relevant model and not after
      priming through presentation of a phobia-relevant or cold-relevant model. Because
      the children of panic disordered parents did not have panics themselves, their
      increase in panic interpretations can be viewed as a vulnerability factor.
      Longitudinal studies should clarify the role of interpretation style in the
      etiology of panic disorder.

PMID- 12405522
TI  - Classification of panic attack subtypes in patients and normal controls in
      response to biological challenge: implications for assessment and treatment.
AB  - Panic attacks are symptomatically heterogeneous but efforts to describe such
      heterogeneity are relatively new. With regard to symptom presentation, at least
      three types of panic attack have been proposed based on the coupling or
      decoupling of verbal-cognitive and physiological symptoms: prototypic, cognitive,
      and nonfearful panic. The central aim of the present study was to address whether
      patients with panic disorder (PD) and nonclinical controls (NC) could be
      classified and discriminated (within and between groups) in terms of subtypes of
      panic attacks based on convergence and divergence of physiological and subjective
      arousal. Two samples of patients with PD (n = 94) and NC (n = 70) were exposed to
      single-breath vital capacity (VC) inhalations of 35% CO2/65% O2. Subjective
      anxiety and cardiovascular (heart rate (HR), systolic blood pressure (SBP),
      diastolic blood pressure (DSP)) reactivity to the challenge were measured. For
      reactive participants, response patterns suggested the production of
      differentiated and stable panic attack subtypes described as: (1) prototypical
      (high subjective, high physiological), (2) cognitive (high subjective, low
      physiological), and (3) nonfearful (low subjective, high physiological). Subtype
      frequency differed between groups (prototypical: 33% PD, 8% NC; cognitive: 37%
      PD, 4% NC; nonfearful: 11% PD, 42% NC). A panic attack typology based on
      convergence and divergence of different response systems appears to reliably
      discriminate patients with panic disorder and may have relevance for predicting
      clinical characteristics, treatment modality, and prognosis.

PMID- 12405523
TI  - Worry and heart rate variables: autonomic rigidity under challenge.
AB  - [Borkovec, T. D. (1994). Worrying: perspectives on theory, assessment and
      treatment (pp. 5-34). West Sussex: Wiley] proposes that the cognitive activity of
      worry restricts autonomic nervous system activity, producing autonomic rigidity.
      Autonomic rigidity affects both sympathetic nervous system [Behav. Res. Ther. 28
      (1990) 69.] and parasympathetic nervous system activity [Behav. Ther. 26
      (1995)457.]. Three experiments investigated the relationship between worry and
      autonomic system activity as indexed by heart activity measures. In the first
      experiment, we measured average heart rate when worriers were required to perform
      a public speaking task. No difference was found in heart rate between worriers
      and controls. The second and third experiments measured average heart rate and
      heart period variability (HPV) in worriers and controls during relaxation, non
      stressful cognitive tasks, worried thinking, and aversive imagery conditions.
      There was no support for the autonomic rigidity view as worriers did not respond
      differently to non-worriers. These findings challenge the view that autonomic
      rigidity applies generally to worry.

PMID- 12405524
TI  - Screening for social anxiety disorder in the clinical setting: using the
      Liebowitz Social Anxiety Scale.
AB  - OBJECTIVE: We sought to determine optimal cutoff values for the Liebowitz Social
      Anxiety Scale (LSAS) total and subscale scores for the diagnosis of social
      anxiety disorder (SAD) and designation of the generalized subtype of SAD. METHOD:
      Three hundred and sixty-four patients from a multi-site sample who met criteria
      for SAD according to structured diagnostic interview, 262 of whom met criteria
      for the generalized subtype, and 34 control participants free of current Axis I
      disorders participated in this study. All participants were given the Liebowitz
      Social Anxiety Scale by an independent assessor. RESULTS: Receiver Operating
      Characteristics analysis revealed that the LSAS performed well in identifying
      individuals who met criteria for SAD and for the generalized subtype of SAD.
      Cutoffs of 30 for SAD and 60 for its generalized subtype on the LSAS total score
      represented the best balance of specificity and sensitivity. CONCLUSIONS: These
      findings provide support for the use of the Liebowitz Social Anxiety Scale for
      the identification of individuals with SAD and its generalized subtype in
      clinical settings. Identification of patients with SAD should increase the
      percentage of these patients who receive appropriate treatment for this impairing
      disorder.

PMID- 12405525
TI  - Attentional and memory bias for emotional information in crime victims with acute
      posttraumatic stress disorder (PTSD).
AB  - A combined emotional Stroop, implicit memory (tachistoscopic identification) and
      explicit memory (free recall) task with three types of words (trauma-related,
      positive, and neutral) and two exposure conditions (subliminal and supraliminal)
      was administered to 39 crime victims with acute posttraumatic stress disorder
      (PTSD) and 39 age- and sex-matched controls. PTSD subjects showed supraliminal
      Stroop interference for trauma-related words and a similar effect on positive
      words. A specific explicit memory bias was found for trauma-related words among
      the PTSD subjects, but no preattentive bias on the subliminally presented words,
      nor any implicit memory bias. Findings suggest that acute PTSD subjects have an
      attentional and memory bias for threat-related material. Methodological
      limitations of the study are reviewed, and it is proposed that further studies
      are needed in order to elucidate whether acute PTSD Ss display a preattentive and
      implicit memory bias for trauma-related material.

PMID- 12405527
TI  - Chemistry for an essential biological process: the reduction of ferric iron.
AB  - In biological systems, the predominant form of iron is the trivalent Fe(III)
      form, which is potentially not readily bioavailable because of its hydrolysis and
      polymerization to insoluble forms. It is also the easiest of the two predominant
      forms of iron to chelate selectively. In a short overview of iron chemistry, we
      point out some of the pitfalls using standard redox potentials, comment on the
      interaction of ferric complexes with hydrogen peroxide to give hydroxyl radicals
      and address the release of iron from ferrisiderophores. In biological systems
      there are two classes of ferric reductases, the soluble flavin reductases found
      in prokaryotes, and the membrane-bound cytochrome b-like reductases found in
      eukaryotes. Finally the role of dissimilatory ferric reduction in microbial
      respiration and biomineralization is discussed.

PMID- 12405526
TI  - Chemical aspects of siderophore mediated iron transport.
AB  - In this mini-review we describe selected aspects of the coordination chemistry
      relevant to siderophore mediated iron transport and bioavailability. Specific
      emphasis is placed on a discussion of in vitro kinetic and thermodynamic data
      that are relevant to elucidating possible in vivo mechanisms for environmental
      iron acquisition by microbial cells.

PMID- 12405528
TI  - Do some carriers of hemochromatosis gene mutations have higher than normal rates
      of disease and death?
AB  - Some heterozygote carriers of hemochromatosis HFE gene mutations become iron
      loaded with ensuing increased risk of disease and premature death. Contributing
      nutritional, behavioral and genetic factors are beginning to be identified.
      Carriers of HFE gene mutations should be advised to minimize contributing
      factors, if possible, and to have their iron values tested periodically. If
      values begin to rise, a schedule of phlebotomies should be considered.

PMID- 12405529
TI  - A kinetic study on the copper-albumin catalyzed oxidation of ascorbate.
AB  - Serum albumin can specifically bind one Cu(II)-ion, and is proposed to function
      as a copper transport protein in vivo. Cu(II)-albumin is rapidly reduced by
      ascorbate. A second order rate constant of 0.54 mM(-l) x min(-1) was estimated
      for the reaction. The oxidation process is catalytic, the Cu(I)-albumin molecule
      being reoxidized by molecular oxygen. The reaction was found to follow Michaelis
      Menten kinetics, characterized by an apparent Km-value of 0.89 mM, and a
      catalytic constant of 0.066 microM O2/min. An apparent inhibition of oxygen
      uptake was obtained with catalase (but not with superoxide dismutase), suggesting
      the formation of H2O2 in the system. Wilson's disease patients usually have
      increased amounts of non-ceruloplasmin copper in plasma. The low level of plasma
      ascorbate observed in such patients could possibly be due, at least in part, to
      an oxidation by Cu(II)-albumin.

PMID- 12405530
TI  - Oxidative cleavage of DNA by homo- and heteronuclear Cu(II)-Mn(II) complexes of
      an oxime-type ligand.
AB  - Novel homodinuclear Cu(II) (K1), heterodinuclear Cu(II)-Mn(II) (K2) and
      homotrinuclear Cu(II) (K3) complexes with a novel oxime-type ligand have been
      prepared and their nucleolytic activities on pCYTEXP were established by neutral
      agarose gel electrophoresis. The analyses of the cleavage products obtained
      electrophoretically indicate that although the examined complexes induces very
      similar conformational changes on supercoiled DNA by converting supercoiled form
      to nicked form than linear form in a sequential manner as the complex
      concentration or reaction period is increased, K3 is less effective than the two
      others. The oxime complexes were nucleolytically active at physiological pH
      values but the activities of Kl or K2 were diminished by increasing the pH of the
      reaction mixture. In contrast, K3 makes dominantly single strand nicking by
      producing nicked circles on DNA at almost all the applied pH values. Metal
      complex induced DNA cleavage was also tested for inhibition by various radical
      scavengers as superoxide dismutase (SOD), azide, thiourea and potassium iodide.
      The antioxidants inhibited the nucleolytic acitivities of the oxime complexes but
      SOD afforded no protection indicating that the nucleolytic mechanism involves of
      copper and/or manganese complex-mediated reactive oxygen species such as hydroxyl
      radicals being responsible for the oxidative DNA cleavage.

PMID- 12405531
TI  - High blood lead level among garage workers in Bangkok, public concern is
      necessary.
AB  - Lead is an important toxic metal agent found in many industrial processes in the
      present day. Lead exposure must be of particular concern because of ongoing
      exposure to thousands of workers in the industrial plants and recent research
      indicating that asymptomatic lead exposure can result in chronic toxicity
      manifestations. Therefore, determination and control lead exposure among the risk
      workers is very necessary. Like other developing countries, lead pollution
      becomes an important public health problem of Thailand, especially for the big
      cities as Bangkok but relatively few of these countries have introduced policies
      and regulations for significantly combating the problem. We set this pilot study
      to determine the blood lead levels by anodic stripping volammetry (ASV) method as
      a marker for lead exposure among the occupational exposed and control subjects.
      Totally 89 subjects, 20 control subjects and 69 garage workers (52 mechanics and
      17 dye sprayers), as the representatives of occupational exposed subjects, were
      included into this preliminary study. The mean blood lead level in the control
      group was 0.32 +/- 0.07 micromol/l. The mean blood lead level in the mechanics
      group was 0.42 +/- 0.13 micromol/l. The mean blood lead level in the dye sprayers
      was 0.58 +/- 0.07 micromol/l. Significant higher blood lead levels among the
      mechanics and dye sprayer groups were observed (P < 0.05). Based on this study,
      the considerations for prevention of possibly exposure to lead among the high
      risk workers as public health policies was recommended.

PMID- 12405532
TI  - Possible involvement of plasma histidine in differential brain permeability to
      zinc and cadmium.
AB  - Zinc gets into the brain parenchyma across the blood-brain and the blood
      cerebrospinal fluid barriers, while cadmium hardly gets into the brain
      parenchyma. Because histidine may be involved in zinc transport across the brain
      barrier systems, the binding to histidine was compared between zinc and cadmium
      to understand the difference in brain permeability to both metals. Sephadex G-10
      gel filtration indicated that 109Cd, unlike 65Zn, does not bind to histidine.
      When the plasma incubated with 65Zn or 109Cd was dialyzed in physiological saline
      containing histidine (0-10 mM), 65Zn concentration in the dialysate was increased
      with the increase of the histidine concentration, suggesting the transfer of zinc
      from plasma proteins to histidine. The low affinity of zinc to plasma proteins
      may be important for brain permeability to this metal. On the other hand, 109Cd
      was not detected in the dialysate in the presence of 0.1 mM histidine, which is
      equal to the concentration in the plasma, suggesting no transfer of cadmium from
      plasma proteins to histidine. These results suggest that the avid binding of
      cadmium to plasma proteins is related to brain impermeability to this metal.

PMID- 12405533
TI  - Biotechnological potential of immobilized algae for wastewater N, P and metal
      removal: a review.
AB  - This presentation comprises a review on the use of immobilized algae for
      wastewater nitrogen, phosphorus and metal removal purposes. Details of the use of
      immobilized algae, the techniques of immobilization and the effects of
      immobilization on cell function are included. Particularly relevant in their use
      for heavy metal removal from wastewaters; upon enriching the biomass in metal,
      can be recoverd, thereby providing economic advantages. The use of immobilized
      microalgae in these processes is very adequate and offers significant advantages
      in bioreactors. The future of this area of algal cell biotechnology is
      considered.

PMID- 12405534
TI  - Visible light induced hydrogen production with Mg chlorophyll-a from spirulina
      and colloidal platinum.
AB  - Photoinduced hydrogen production with Mg chlorophyll-a from spirulina as a
      visible light photosensitizer by use of three component system consisting of
      nicotineamide adenine dinucleotide phosphate, reduced form (NADPH) as an electron
      donor, methylviologen as electron relay reagent and colloidal platinum as
      hydrogen evolution catalyst was investigated. By the addition of NADPH, the
      photostability of Mg chlorophyll-a was increased. The effective visible-light
      induced hydrogen production system with colloidal platinum was established using
      Mg chlorophyll-a.

PMID- 12405535
TI  - Cadmium biomonitoring and renal dysfunction among a population environmentally
      exposed to cadmium from smelting in China (ChinaCad).
AB  - Cadmium, an environmental pollutant, can have adverse effects on the human body.
      The kidney is the critical organ. In order to improve the understanding of the
      dose-response relationship between cadmium exposure and health effects, and
      especially renal dysfunction, a study on a general population group in China was
      performed. This study was therefore concerned with cadmium exposure biomarkers,
      such as the concentrations in blood (BCd) and urine (UCd), and effect biomarkers
      of renal dysfunction, such as beta2-microglobulin (beta2m), retinol binding
      protein (RBP) and albumin (ALB). To improve the evaluation of exposure levels in
      relation to the adverse health effects of cadmium exposure in the general
      population, a quality control program was conducted to determine analytical
      quality in the determination of cadmium in blood and urine and for beta2m,
      creatinine, ALB and RBP. The measurements showed that analytical quality was
      adequate. The exposure and effect biomarkers were studied in the population
      groups living in three areas, namely a control area and two Cd polluted areas. In
      the highly exposed area, most of the BCd values were higher than 5 microg/l and
      most of the UCd values were higher than 5 microg/g creatinine. Beta2
      microglobulin, retinol binding protein, and albumin in urine were all
      significantly higher in the population living in the heavily polluted area than
      in that in the control area. Based on data from all three areas, a marked dose
      response relationship between UCd or BCd and the prevalence of renal dysfunction
      was demonstrated. The number of abnormalities in kidney was related to the level
      of cadmium exposure. Only one index of renal tubular dysfunction was affected in
      subjects exposed to low levels of cadmium, but more than two indices of renal
      function were affected in those exposed to high levels.

PMID- 12405536
TI  - Selenoprotein W gene regulation by selenium in L8 cells.
AB  - The effects of selenium on selenoprotein W gene expression were examined in
      cultured L8 rat skeletal muscle cells. Selenoprotein W contains selenium as
      selenocysteine in the primary protein structure and levels of this selenoprotein
      are affected by selenium. Northern blots indicated that there were no significant
      changes (P < 0.05) in selenoprotein W mRNA levels during cell proliferation and
      differentiation. Reduction of selenium concentration in the medium decreased the
      selenoprotein W mRNA levels. Nuclear run-on experiments with isolated L8 nuclei
      showed the same rate of selenoprotein W mRNA synthesis in cells cultured in
      either low selenium or selenium supplemented medium, suggesting that the
      transcription rate of the selenoprotein W gene is independent of selenium.
      Measurement of the selenoprotein W mRNA half-life in myoblasts treated with the
      transcription inhibitor, alpha-amanitin, showed that selenoprotein W mRNA levels
      decreased over time with an estimated half-life of 57 h for cells grown in low
      selenium medium. Selenium treatment increased the selenoprotein W mRNA half-life
      2-fold. These data suggest that selenium stabilizes selenoprotein W mRNA but has
      no effect on transcription.

PMID- 12405537
TI  - Isolation of GIF from porcine brain and studies of its zinc transfer kinetics
      with apo-carbonic anhydrase.
AB  - Neuronal growth inhibitory factor (GIF) of porcine brain, was isolated and
      purified by a similar procedure which was used on the isolation of human and
      bovine GIF. The native porcine protein with stoichiometry of 4Cu+, 3Zn2+ was
      obtained for the first time. The kinetics of zinc transfer from Cu4Zn3MT-3 to apo
      carbonic anhydrase were studied, and zinc transfer rate constants and
      thermodynamic parameters were obtained. It is found that like other MTs, porcine
      Cu4Zn3MT-3 can also transfer its zinc atom to apoCA, even much easier than other
      MTs. A possible association mechanism has been proposed, the formation of
      Cu4Zn3MT3-apoCA complex may be the rate-determining step. The obtained data
      indicate besides its neuronal growth inhibitory function, GIF might play a role
      in cellular Zn homeostasis in brain.

PMID- 12405538
TI  - Substance use and withdrawal: neuropsychological functioning over 8 years in
      youth.
AB  - This study prospectively examined neuropsychological (NP) functioning associated
      with adolescent substance use and withdrawal. Participants were youths with
      histories of substance use disorders (n = 47) and demographically comparable
      youths with no such lifetime histories (n = 26). They were followed with NP
      testing and substance involvement interviews at 7 time points spanning 8 years,
      from ages 16 to 24, on average. After controlling for recent use, age, education,
      practice effects, and baseline NP functioning, substance use over the 8-year
      follow-up period significantly predicted performances on tests of memory and
      attention at Year 8. Additionally, withdrawal symptoms during the follow-up
      predicted visuospatial and attention scores at Year 8. Findings suggest that use
      and withdrawal may differentially impact neurocognitive functioning during youth,
      with heavy use leading to learning, retention, and attentional difficulties, and
      withdrawal leading to problems with visuospatial functioning.

PMID- 12405539
TI  - Cross-modal semantic priming in schizophrenia.
AB  - Work on implicit memory in normal subjects has demonstrated the influence of
      stimulus modality on the retrieval of semantic information. The present study
      examined the effects of auditory and visual semantic priming on the recognition
      of visual words using a lexical decision task. Performance was studied in a group
      of 20 patients with DSM-IV schizophrenia and 26 normal volunteers of similar age
      and sex. There were two versions of the task: ipsimodal, in which the word or
      nonword visual target followed 400 ms after the onset of a visual word prime
      which may or may not be semantically related to the target; and cross-modal, in
      which the visual target followed 400 ms after the onset of an auditory word
      prime. Both groups showed significant priming in both modality conditions,
      although the schizophrenia patients exhibited significantly greater priming in
      the cross-modal condition. Priming effects in the ipsimodal condition did not
      differ substantially between patients and controls. The priming effects in the
      two conditions correlated with each other in the schizophrenia patients only. The
      results suggest that priming may occur through amodal semantic representations.
      In schizophrenia, there appears to be increased cross-modal connectivity (reduced
      modality modularity and informational encapsulation) between lexical
      representations that could result in impaired language, particularly speech,
      processing.

PMID- 12405540
TI  - Intraindividual variability in cognitive performance in three groups of older
      adults: cross-domain links to physical status and self-perceived affect and
      beliefs.
AB  - Intraindividual variability of physical status and affect/beliefs as well as
      their relations with cognition were examined in 3 groups of older adults: healthy
      elderly, individuals with a nonneurological health-related disturbance
      (arthritis) and people with neurological compromise (dementia). The findings
      showed that greater inconsistency in physical performance was observed in groups
      characterized by central nervous system dysfunction. By contrast, fluctuations in
      affect appeared to reflect other more transient sources, such as pain. In
      general, increased inconsistency in non-cognitive domains was associated with
      poorer cognitive function. There were cross-domain links between inconsistency in
      physical functioning and fluctuations in cognitive performance, although the
      nature of the links depended largely upon the neurological status of the
      individuals. Considered together, the result indicated that measures of cognitive
      as well as physical variability are important behavioral markers of neurological
      integrity.

PMID- 12405541
TI  - Dementia with Lewy bodies may present as dementia and REM sleep behavior disorder
      without parkinsonism or hallucinations.
AB  - Rapid eye movement (REM) sleep behavior disorder (RBD) is a sleep disturbance
      that commonly occurs in Dementia with Lewy bodies (DLB). Retrospective
      examination of DLB course has shown that RBD and cognitive decline may precede
      the onset of parkinsonism and visual hallucinations. Therefore, some patients
      with DLB may initially present with dementia and RBD, but would not meet current
      formal criteria for probable DLB at that time. The purpose of this study is to
      determine whether patients with dementia and RBD, who do not have parkinsonism or
      visual hallucinations, have cognitive profiles that can be distinguished from
      autopsy-confirmed definite AD, but not from clinically probable DLB. If so, this
      would support the hypothesis that the presence of RBD and dementia, as the only
      presenting symptoms, reflects the early manifestation of DLB. Results show that
      early dementia in probable DLB and dementia with RBD are neuropsychologically
      indistinguishable. Both groups differ from definite AD of a similar early stage
      with significantly worse visual perceptual organization, sequencing and letter
      fluency but significantly better confrontation naming and verbal memory. In
      addition, follow-up data from a subset of patients with dementia and RBD reveal
      the subsequent development of parkinsonism or hallucinations 1 to 6 years later.
      Results indicate that the presentation of dementia and RBD is suggestive of
      underlying Lewy body disease and not Alzheimer's disease. This provides further
      evidence in support of including RBD as one of the core diagnostic features of
      DLB.

PMID- 12405542
TI  - Genetic and brain imaging contributions to neuropsychological functioning in
      preclinical dementia.

PMID- 12405543
TI  - Neuropsychological manifestations of the genetic mutation for Huntington's
      disease in presymptomatic individuals.
AB  - A triplet repeat (CAG) expansion mutation in the huntingtin gene on chromosome 4
      is responsible for Huntington's disease (HD). Presymptomatic genetic testing for
      this mutation has identified clinically normal persons who are virtually certain
      to develop this dementing illness if they live a normal lifespan. The present
      study sought to determine whether these "mutation-positive" persons have
      impairments in cognitive functioning. Seventy-five mutation-positive persons did
      not differ from 128 mutation-negative persons on tests selected for their
      sensitivity to early-stage HD. Interestingly, however, those with the mutation
      viewed themselves as more likely to develop HD than did those without the
      mutation. Among mutation-positive subjects, having a longer CAG repeat mutation
      was likewise not associated with cognitive impairment. However, being closer to
      estimated disease onset (a product of repeat length and parent's age at onset)
      was associated with selected cognitive impairments. When viewed in light of
      previous studies showing atrophy of the caudate nucleus and putamen in mutation
      carriers who are close to onset but not those far from onset, these results
      suggest that subtle changes in brain and behavior may be detected shortly before
      subjects with the HD mutation develop sufficient signs and symptoms for
      diagnosis. Conceptual and methodological problems associated with the search for
      presymptomatic cognitive and behavioral indicators of dementing illness are
      discussed.

PMID- 12405544
TI  - Dementia, asymmetry of temporal lobe structures, and apolipoprotein E genotype:
      relationships to cerebral atrophy and neuropsychological impairment.
AB  - We examined asymmetry of hippocampal volume as well as other temporal lobe
      structures (temporal lobe, temporal horn of the lateral ventricular system,
      parahippocampal and fusiform gyri) in 194 subjects from the Cache County, Utah
      study, with varying disorders [85 with Alzheimer's disease (AD), 59 with some
      cognitive or neuropsychiatric disorder-referenced as a Mixed Neuropsychiatric
      group, 30 with mild ambiguous/mild cognitive impairment (MA/MCI) and 20 controls]
      and APOE genotypes. Asymmetry was determined by subtracting left-side volume from
      the right corrected by total intracranial volume. No significant asymmetry was
      observed to be associated with presence of the epsilon4 allele. Since the AD
      epsilon4 allele risk effect may be expressed early in the course of the disorder,
      we also examined asymmetry indices in AD, MA/MCI and Mixed Neuropsychiatric
      subjects early in the course of their disorder (2 years or less) to those with
      longer duration illness (greater than 2 years). We observed a leftward asymmetry
      (i.e., left side larger) regardless of APOE genotype in hippocampal volume where
      both AD and MCI subjects demonstrated a leftward shift in hippocampal size when
      length of disease (LOD) was less but not more than 2 years. Leftward asymmetry
      was not associated with LOD in the Mixed Neuropsychiatric group. These findings
      do not support an association between epsilon4 and hippocampal asymmetry in
      dementia. We also examined whether asymmetry influenced neuropsychological
      performance, but minimal effects were observed. Where significance or strong
      trends were observed, better neuropsychological performance was associated with
      larger parenchymal volume of temporal lobe structures. These findings were
      interpreted as representing cognitive reserve effects where larger volume was
      protective against impairment. The role of asymmetry research in understanding
      neuropsychological performance in dementia is discussed.

PMID- 12405545
TI  - 1H magnetic resonance spectroscopy, cognitive function, and apolipoprotein E
      genotype in normal aging, mild cognitive impairment and Alzheimer's disease.
AB  - The aim of this study was to examine the associations of apolipoprotein E (APOE)
      genotype, metabolic changes in the posterior cingulate detected by 1H magnetic
      resonance spectroscopy (MRS), and neuropsychologic measures of memory and
      cognition both in normally aging elderly, and in patients with mild cognitive
      impairment (MCI) and AD. We studied 67 controls, 18 MCI and 33 AD patients. We
      used the Dementia Rating Scale total score (DRSTOT) as a measure of general
      cognitive function and the total learning from the Auditory Verbal Learning Test
      (AVTOT) as a measure of memory performance. No differences were noted on 1H-MRS
      metabolite ratios or cognitive measures across APOE genotype within control and
      patient groups. In controls, age was a significant predictor of both cognitive
      test scores, and NAA/Cr was a univariate associate of DRSTOT. All 3 1H-MRS
      metabolite ratios, N-acetylaspartate (NAA)/creatine (Cr), myoinositol (MI)/Cr,
      and NAA/MI, were univariate associates of AVTOT and DRSTOT scores in the combined
      MCI and AD group. In stepwise regression analyses in the combined patient group
      only NAA/MI entered the models. These data suggest NAA/Cr could be a modest
      predictor of general cognitive function in both healthy elderly and impaired
      patients, while MI/Cr is a more specific marker for neuropsychologic dysfunction
      associated with neurodegenerative disease. Among 1H-MRS measurements, the NAA/MI
      ratio maybe the most efficient predictor of memory and cognitive function in
      patients with MCI and AD.

PMID- 12405547
TI  - A domain-specific deficit for foodstuffs in patients with Alzheimer's disease.

PMID- 12405546
TI  - Decline in verbal memory during preclinical Alzheimer's disease: examination of
      the effect of APOE genotype.
AB  - A subtle decline in episodic memory often occurs prior to the emergence of the
      full dementia syndrome in nondemented older adults who develop Alzheimer's
      disease (AD). The APOE-epsilon4 genotype may engender a more virulent form of AD
      that hastens this decline. To examine this possibility, we compared the rate of
      decline in episodic memory during the preclinical phase of AD in individuals with
      or without at least one APOE epsilon4 allele. Nondemented normal control (NC; n =
      84) participants, nondemented older adults who subsequently developed dementia
      within 1 or 2 years (i.e., preclinical AD; n = 20), and patients with mild AD (n
      = 53) were examined with 2 commonly employed tests of episodic memory, the
      Logical Memory subtest of the Wechsler Memory Scale-Revised and the California
      Verbal Learning Test. Results revealed a precipitous decline in verbal memory
      abilities 1 to 2 years prior to the onset of the dementia syndrome, but there was
      little effect of APOE genotype on the rate of this memory decline. The presence
      of an APOE-epsilon4 allele, however, did have a differential effect on the
      sensitivity of the 2 types of memory tests for tracking progression and made an
      independent contribution to the prediction of conversion to AD.

PMID- 12405548
TI  - Postural knowledge of transitive pantomimes and intransitive gestures.
AB  - Patients with apraxia are more impaired when performing transitive pantomimes
      than intransitive gestures. This dissociation might be related to the differences
      in movement complexity. Alternatively, the programs for intransitive gestures
      might be better defined, more widely distributed, or easier to activate than are
      those for transitive pantomimes. The purpose of this study was to test the
      complexity versus representational hypotheses. Twenty right-handed normal
      subjects both performed and discriminated correct from incorrect transitive
      pantomimes and intransitive gestures. The discrimination was performed by having
      subjects point at illustrations of hand postures. The subjects performed better
      when discriminating postures than when performing gestures or pantomimes. On both
      the production and discrimination tests, subjects performed better with
      intransitive gestures than transitive pantomimes. Although the finding that even
      normal subjects had more difficulty performing transitive pantomimes than
      intransitive gestures might appear to support the complexity hypothesis, that
      subjects also had more difficulty discriminating transitive than intransitive
      postures supports the representational activation hypothesis.

PMID- 12405549
TI  - Temperature effect on entrainment, phase shifting, and amplitude of circadian
      clocks and its molecular bases.
AB  - Effects of temperature and temperature changes on circadian clocks in
      cyanobacteria, unicellular algae, and plants, as well as fungi, arthropods, and
      vertebrates are reviewed. Periodic temperature with periods around 24 h even in
      the low range of 1-2 degrees C (strong Zeitgeber effect) can entrain all
      ectothermic (poikilothermic) organisms. This is also reflected by the phase
      shifts-recorded by phase response curves (PRCs)-that are elicited by step- or
      pulsewise changes in the temperature. The amount of phase shift (weak or strong
      type of PRC) depends on the amplitude of the temperature change and on its
      duration when applied as a pulse. Form and position of the PRC to temperature
      pulses are similar to those of the PRC to light pulses. A combined high/low
      temperature and light/dark cycle leads to a stabile phase and maximal amplitude
      of the circadian rhythm-when applied in phase (i.e., warm/light and cold/dark).
      When the two Zeitgeber cycles are phase-shifted against each other the phase of
      the circadian rhythm is determined by either Zeitgeber or by both, depending on
      the relative strength (amplitude) of both Zeitgeber signals and the sensitivity
      of the species/individual toward them. A phase jump of the circadian rhythm has
      been observed in several organisms at a certain phase relationship of the two
      Zeitgeber cycles. Ectothermic organisms show inter- and intraspecies plus
      seasonal variations in the temperature limits for the expression of the clock,
      either of the basic molecular mechanism, and/or the dependent variables. A step
      down from higher temperatures or a step-up from lower temperatures to moderate
      temperatures often results in initiation of oscillations from phase positions
      that are about 180 degrees different. This may be explained by holding the clock
      at different phase positions (maximum or minimum of a clock component) or by
      significantly different levels of clock components at the higher or lower
      temperatures. Different permissive temperatures result in different circadian
      amplitudes, that usually show a species-specific optimum. In endothermic
      (homeothermic) organisms periodic temperature changes of about 24 h often cause
      entrainment, although with considerable individual differences, only if they are
      of rather high amplitudes (weak Zeitgeber effects). The same applies to the phase
      shifting effects of temperature pulses. Isolated bird pineals and rat
      suprachiasmatic nuclei tissues on the other hand, respond to medium high
      temperature pulses and reveal PRCs similar to that of light signals. Therefore,
      one may speculate that the self-selected circadian rhythm of body temperature in
      reptiles or the endogenously controlled body temperature in homeotherms (some of
      which show temperature differences of more than 2 degrees C) may, in itself,
      serve as an internal entraining system. The so-called heterothermic mammals
      (undergoing low body temperature states in a daily or seasonal pattern) may be
      more sensitive to temperature changes. Effects of temperature elevation on the
      molecular clock mechanisms have been shown in Neurospora (induction of the
      frequency (FRQ) protein) and in Drosophila (degradation of the period (PER) and
      timeless (TIM) protein) and can explain observed phase shifts of rhythms in
      conidiation and locomotor activity, respectively. Temperature changes probably
      act directly on all processes of the clock mechanism some being more sensitive
      than the others. Temperature changes affect membrane properties, ion homeostasis,
      calcium influx, and other signal cascades (cAMP, cGMP, and the protein kinases A
      and C) (indirect effects) and may thus influence, in particular, protein
      phosphorylation processes of the clock mechanism. The temperature effects
      resemble to some degree those induced by light or by light-transducing neurons
      and their transmitters. In ectothermic vertebrates temperature changes
      significantly affect the melatonin rhythm, which in turn exerts entraining (phase
      shifting) functions.

PMID- 12405550
TI  - The photoperiodic entrainment and induction of the circadian clock regulating
      seasonal responses in the migratory blackheaded bunting (Emberiza melanocephala).
AB  - The properties of the circadian photoperiodic oscillator have been investigated
      in detail only in the Japanese quail. While the study of the quail is clearly
      very important, one cannot simply assume that other species, especially
      passerines that seem to have a different circadian organization than quail,
      function the same way. The current set of experiments was conducted to understand
      the entrainment and photoinduction of the circadian photoperiodic oscillator in a
      passerine species, the blackheaded bunting (Emberiza melanocephala). The
      experimental paradigm used skeleton photoperiods with two light periods, the
      first called the "entraining light pulse" (E-pulse) and the second called the
      "inducing light pulse" (I-pulse). Three experiments were performed on
      photosensitive male birds (N = 6-8/group). Experiment 1 investigated the effects
      of the temporal relationship between E- and I-pulses on photoperiodic induction.
      Buntings entrained to 8h: 16h L:D for 4 wk were released into constant dim light
      (LLdim, approximately 1 lux). Beginning on subjective day 8, they received for 8
      wk, E- and I-pulses only at alternate cycles. While I-pulse was 1h and always
      began at zt 11.5, E-pulse varied in duration and timing (the 1h E-pulse beginning
      either at zt 0, zt 5, or zt 9, the 4h one beginning at zt 0 or zt 6, and the 10 h
      one at zt 0; zeitgeber time 0 = time of lights-on under 8h: 16h L:D prior to
      release into LLdim). A photoperiodic response was induced only when the E-pulse
      began at zt 0, and thus the beginning of E- and 1-pulses were separated by 11.5h.
      Experiment 2 determined whether the duration of the E-pulse influences the
      position of the photoinducible phase (phii) of the circadian photoperiodic
      oscillator. Birds were entrained to 1h:23h L:D or 10h: 14h L:D for 2 wk, and then
      exposed to 1h I-pulse at zt 11.5, zt 15, or zt 18.5 for another 8 wk.
      Photoperiodic induction occurred at all 3 zts in birds entrained to 10h but only
      at zt 11.5 in birds entrained to 1h, which infers the circadian rhythm of
      photoinducibility (CRP) in buntings was re-entrained when I-pulse fell at zt 15
      and after. The last experiment examined the possibility of the re-entrainment of
      the CRP to light pulses falling at zt 15 and after. Birds received 1h I-pulse for
      8wk at zt 15 following 2wk of 2.5h:21.5h L:D or 3.5h:20.5h L:D, or at zt 21.5 or
      zt 22.5 following 2 wk of 10h: 14h LD. Photoperiodic induction was consistent
      with the hypothesis of the re-entrainment of the CRP under these light-dark
      cycles. The I-pulse appeared to be interpreted as a "new dawn", and so the
      photoperiodic induction was determined by the coincidence of phii with the E
      pulse. These results suggest a phase-dependent action of light on the circadian
      oscillator regulating photoperiodic responses in the blackheaded bunting. This
      could be a useful strategy for a photoperiodic species to regulate its seasonal
      responses in nature.

PMID- 12405551
TI  - Illumination of upper and middle visual fields produces equivalent suppression of
      melatonin in older volunteers.
AB  - Bright light treatment has become an important method of treating depression and
      circadian rhythm sleep disorders. The efficacy of bright light treatment may be
      dependent upon the position of the light-source, as it determines the relative
      illumination in each portion of the visual field. This study compared
      illumination of upper and middle visual fields to determine whether melatonin
      suppression is different or equivalent. Thirteen older volunteers received three
      illumination conditions in counterbalanced orders: 1000 lux in the upper visual
      field, 1000 lux in the middle visual field, or dim diffuse illumination < 5 lux.
      A four-choice reaction time task was performed during tests to ensure eye
      direction and illumination of the intended portion of the visual field.
      Illumination in the upper and middle visual fields significantly suppressed
      melatonin compared to < 5 lux (p < 0.001). Melatonin suppression was not
      significantly different with upper or middle field illumination. These results
      indicate that bright light treatments placed above the eye level might be as
      effective as those requiring patients to look directly at the light source.
      Clinical comparative testing would be valuable. In addition, this study
      demonstrates that significant suppression of melatonin may be achieved through
      the use of bright light in healthy older volunteers.

PMID- 12405552
TI  - Impact of night-float rotation on sleep, mood, and alertness: the resident's
      perception.
AB  - Night-float rotations were designed to alleviate the workload of residents on
      night call and thereby improve patient safety. However, the impact of the night
      float on residents is yet to be surveyed. We assessed the impact of the night
      float rotation on pediatric residents using an anonymous questionnaire that
      covered topics, based on recall, about sleep, mood, alertness, adjustment, and
      others. The study was conducted in a major tertiary pediatric teaching hospital
      in the United States. Participants were pediatric residents who had completed one
      or two night-float rotations and were in active training at our teaching hospital
      at the time of the study. Fifty-two of 60 eligible residents (87%) responded.
      Sleep duration during the night-float rotation was shorter than during day-shift
      work in 24 residents (46%), longer in 20 (38%), and unchanged in eight (15%). A
      higher proportion of residents took longer to fall asleep, had more difficulty
      falling asleep, had more sleep interruptions, and felt less rested upon
      awakening. Twenty-four residents (46%) felt that their bodies never adjusted to
      the night shift. Also, 22 residents (43%) felt moody or depressed in contrast to
      seven (14%) who felt depressed during the daytime rotation (p = 0.0001). Twenty
      one residents (41%) felt they were slower in their thinking during the night
      float than daytime rotations. The results suggest that disturbances of sleep and
      mood and decreased alertness, typical of night shift, are present in the night
      float rotation. Residency programs should monitor closely the impact of the night
      float rotation on resident well being and patient safety. The impact of night
      shift work should be considered in the design of night-float schedules, and
      teaching should be provided for residents to learn coping strategies for night
      shift work.

PMID- 12405553
TI  - Role of morning melatonin administration and attenuation of sunlight exposure in
      improving adaptation of night-shift workers.
AB  - The authors studied whether melatonin administration improves adaptation of
      workers to nightshift and if its beneficial effect is enhanced by attenuation of
      morning sunlight exposure. Twelve nightshift nurses received three treatments:
      Placebo (Pla), Melatonin (Mel), and Melatonin with Sunglasses (Mel-S). Each
      treatment procedure was administered for 2d of different 4d nightshifts in a
      repeated measures crossover design. In Pla, nurses were treated with placebo
      before daytime sleep and allowed exposure to morning sunlight. In Mel, 6mg of
      melatonin was similarly administered before daytime sleep with morning sunlight
      permitted. In Mel-S, 6 mg of melatonin was given as in Mel, with sunglasses worn
      in the morning to attenuate sunlight exposure. Placebo or melatonin was
      administered during days 2 and 3 when the first and second daytime sleep
      occurred. Nocturnal alertness and performance plus daytime sleep and mood states
      were assessed during all three treatments. The sleep period and total sleep times
      were significantly increased by melatonin treatments; yet, nocturnal alertness
      was only marginally improved. There were no differences between Mel and Mel-S.
      Performance tests revealed no difference between Pla and melatonin treatments.
      Melatonin exerted modest benefit in improving the adaptation of workers to
      nightshift, and its effect was not enhanced by attenuation of morning sunlight
      exposure.

PMID- 12405554
TI  - Chronobiotic effects of the melatonin agonist LY 156735 following a simulated 9h
      time shift: results of a placebo-controlled trial.
AB  - INTRODUCTION: The melatonin agonist LY 156735 (LY) is a new investigational drug
      under development to treat circadian rhythm disorders. The present study assessed
      the efficacy of LY to alleviate the symptoms of shift lag and to enhance
      readaptation of desynchronized circadian rhythms to a new time zone. SUBJECTS AND
      METHODS: Eight healthy male volunteers of age 25-35 yr participated in three
      identical trials of 13d duration in a temporal isolation unit separated by
      washout intervals. A high dose (HD) of 5 mg and a low dose (LD) of 0.5 mg of LY
      and placebo (PL) were administered double-blinded in a three-period cross-over
      design. Each trial consisted of an adaptation period, a pre-shift period for
      baseline measurements, a simulated 9h phase-advance shift, and a post-shift
      period for follow-up. The time shift was performed at 23:00h of day 6 by
      advancing the laboratory time to 08:00h of day 7. Double-blind study medication
      was administered at 14:30h on day 6, and at 22:30h on days 7-10. Subjective
      ratings of jet lag, alertness, tenseness, and daytime fatigue were assessed using
      visual analog scales (VAS) and standardized questionnaires. The objective markers
      of readaptation included core body temperature, wrist actigraphy, cortisol and
      electrolyte excretion, and a battery of computerized performance tests. RESULTS:
      HD but not LD enhanced the readaptation speed of all physiological rhythms
      investigated, as demonstrated by a significantly faster movement of acrophases
      towards the post-shift target time. HD (p = 0.05) significantly blunted the post
      shift deterioration of performance in those tests that were sensitive to shift
      lag. Parameters of subjective well-being were not significantly affected by
      either dose. CONCLUSION: This pilot study demonstrates the chronobiotic efficacy
      of LY when taken at a dose of 5 mg/d.

PMID- 12405555
TI  - Treatment-time-dependent difference of ketamine pharmacological response and
      toxicity in rats.
AB  - Circadian rhythms impact many physiological functions that may affect drug
      pharmacological response. Ketamine is a dissociative agent commonly used for
      surgical anesthesia in rats. The aim of the present study was to analyze the
      central nervous system (CNS) depression and lethality of ketamine injected
      intraperitoneally at different times during the 24 h. The study was conducted in
      October 2001, spring in the Southern hemisphere. Female prepuberal Sprague-Dawley
      rats synchronized to a 12h light: 12h dark cycle (light, 07:00h-19:00h) were
      studied. Ketamine (40 mg/kg) was administered to one of six different clock-time
      treatment groups (n = 6-7 rats each). Duration of latency period, ataxia, loss of
      righting reflex (LRR), post-LRR ataxia, and total pharmacological response were
      determined by visual assessment. To investigate acute toxicity, ketamine lethal
      dose 50 (148.0 mg/kg) was also administered as a single injection to six
      different treatment-time groups of rats. Significant temporal differences and
      circadian rhythms were detected in drug-induced post-LRR ataxia and total
      pharmacological response duration. The longest pharmacological response occurred
      in rats injected during the light (rest) phase and the shortest response in the
      dark (activity) phase. No circadian rhythm was detected in acute toxicity. The
      study findings indicate that the duration of CNS depression of ketamine in rats
      exhibits circadian rhythmic variation.

PMID- 12405556
TI  - Case study of circadian rhythm sleep disorder following haloperidol treatment:
      reversal by risperidone and melatonin.
AB  - A patient with Gilles de la Tourette syndrome treated with haloperidol, ingested
      once daily after awakening from sleep, exhibited an irregular sleep-wake pattern
      with a free-running component of approximately 48 h. Transfer to risperidone,
      ingested once daily after awakening from sleep, was beneficial resulting in a
      sleep-wake cycle more synchronized at the appropriate phase to the external
      zeitgebers, and fewer nocturnal disturbances. The circadian sleep-wake schedule
      was fully synchronized when the patient had been subsequently treated with
      melatonin at 21:00h, before intended nocturnal sleep, in addition to risperidone
      in the morning. Restoration of the sleep-wake circadian pattern was accompanied
      by the patient's subjective report of significant improvement in his quality of
      life, social interactions, and occupational status. This observation suggests
      that circadian rhythm sleep disorders can be related to the typical neuroleptic
      haloperidol and restored by the atypical neuroleptic risperidone. Similar
      findings reported in patients suffering from other disorders support the
      hypothesis that the described disruption of the sleep-wake schedule is medication
      rather than illness-related. Therefore, it is very important to realize that
      circadian rhythm sleep disorders may be a side effect of neuroleptics.

PMID- 12405557
TI  - Positive selection vectors.
AB  - This review describes information concerning positive selection vectors on their
      mechanism, classification, property, and limitation. A total of 72 positive
      selection vectors collected were discussed. Positive selection vectors can reduce
      background and directly screen transformants containing cloned DNA fragments. The
      mechanisms to perform positive selection include insertional inactivation and the
      replacement of functional genes of the vectors. In general, the former is much
      more convenient than the latter. The functional genes are controlled either by
      their promoters or by heterologous promoters introduced. On the basis of the
      structures, positive selection vectors could be classified into five groups. The
      positive selection vectors are commonly based on the mechanisms of lethal genes
      and the sensitivity of compounds. The vectors, with molecular weights ranging
      from 2.6 to 17.0 kb, have diverse genetic markers and wide host ranges, including
      Escherichia coli, Bacillus, Streptomyces, lactic acid bacteria, yeasts, and
      mammalian cells. Although some limitations exist for using some positive
      selection vectors, they are useful in recombinant DNA experiments.

PMID- 12405558
TI  - Botryococcus braunii: a renewable source of hydrocarbons and other chemicals.
AB  - Botryococcus braunii, a green colonial microalga, is an unusually rich renewable
      source of hydrocarbons and other chemicals. Hydrocarbons can constitute up to 75%
      of the dry mass of B. braunii. This review details the various facets of
      biotechnology of B. braunii, including its microbiology and physiology;
      production of hydrocarbons and other compounds by the alga; methods of culture;
      downstream recovery and processing of algal hydrocarbons; and cloning of the
      algal genes into other microorganisms. B. braunii converts simple inorganic
      compounds and sunlight to potential hydrocarbon fuels and feedstocks for the
      chemical industry. Microorganisms such as B. braunii can, in the long run, reduce
      our dependence on fossil fuels and because of this B. braunii continues to
      attract much attention.

PMID- 12405559
TI  - Promiscuity of hosting nitrogen fixation in rice: an overview from the legume
      perspective.
AB  - The subject area of this review provides extraordinary challenges and
      opportunities. The challenges relate to the fact that the integration of various
      fields such as microbiology, biochemistry, plant physiology, eukaryotic as well
      as bacterial genetics, and applied plant sciences are required to assess the
      disposition of rice, an alien host, for establishing such a unique phenomenon as
      biological nitrogen fixation. The opportunities signify that, if successful, the
      breakthrough will have a significant impact on the global economy and will help
      improve the environment. This review highlights the literature related to the
      area of legume-rhizobia interactions, particularly those aspects whose
      understanding is of particular interest in the perspective of rice. This review
      also discusses the progress achieved so far in this area of rice research and the
      possibility of built-in nitrogen fixation in rice in the future. However, it is
      to be borne in mind that such research does not ensure any success at this point.
      It provides a unique opportunity to broaden our knowledge and understanding about
      many aspects of plant growth regulation in general.

PMID- 12405560
TI  - On being a teacher.

PMID- 12405561
TI  - Orthopedic issues after cerebrovascular accident.
AB  - Patients who have had a cerebrovascular accident with resultant hemiplegia often
      present to the orthopedic surgeon with characteristic complaints and deformities.
      The most common of these include muscle spasticity and contracture, shoulder
      pain, hip fracture, and heterotopic ossification. Although some of these
      disorders are clinically evident, others may be easily overlooked. The purpose of
      this article is to summarize the most common orthopedic aspects of hemiplegic
      patients who have had a cerebrovascular accident.

PMID- 12405562
TI  - Grip strength after carpal tunnel release: role of the transverse caxpal
      ligament.
AB  - Weakness after carpal tunnel release is common. Potential factors are transverse
      carpal ligament (TCL) division, incision or pillar pain, swelling, and flexor
      tenosynovitis. In the study reported here, we examined the effect of TCL division
      on reactive grip-strength changes. A minimally invasive technique was used with
      local anesthesia and sedation for TCL release in 41 hands. Total grip strength
      and individual-digit grip strength were measured using a computerized
      dynamometer. These measurements were taken preoperatively; immediately after TCL
      division; and 1, 3, and 5 weeks postoperatively. There was no significant
      difference between total grip strength measured preoperatively and strength
      measured immediately after TCL division, but the difference between these values
      and strength measured 1 week postoperatively was significant. Preoperatively,
      index fingers contributed 25.3% of total grip strength; long fingers, 31.3%; ring
      fingers, 27.0%; and small fingers, 16.4%. These contributions were approximately
      the same after TCL division.

PMID- 12405563
TI  - Use of a fibular allograft strut in the treatment of benign lesions of the
      proximal femur.
AB  - Fifteen patients with a benign lesion of the proximal femur were surgically
      treated with augmented intralesional curettage and bone grafting using an
      allogenic fibular strut graft in conjunction with internal fixation with a
      sliding hip screw. Mean age was 26 years (range, 13-46 years). Patients were
      followed up for a mean of 30 months (range, 7-110 months). Clinical results were
      assessed using the functional-evaluation-of-reconstruction procedures described
      by the Musculoskeletal Tumor Society. Radiographic outcomes were assessed by
      comparing preoperative radiographs with radiographs taken at the most recent
      follow-up. Clinical results were excellent in all patients. Radiographic
      assessment of the patients showed no evidence of recurrent tumor, fracture, or
      graft resorption at the most recent follow-up. This method of treatment leads to
      excellent functional results and lessens the morbidity associated with autograft
      harvest.

PMID- 12405564
TI  - Spontaneous rupture of the gluteus medius and minimus tendons.
AB  - Tears and tendinopathy of the gluteus medius and minimus are potentially
      underrecognized clinical sources of hip pain. Magnetic resonance imaging is
      useful in diagnosing gluteal tears. This entity is frequently a result of
      predisposing conditions but may arise spontaneously. This clinical problem should
      be considered in the differential diagnosis of patients presenting with acute hip
      pain. In this article, we report a case of spontaneous rupture of the gluteus
      medius and minimus tendons in a previously healthy patient with no prior hip
      symptoms.

PMID- 12405565
TI  - Complete sciatic nerve palsy after open femur fracture: successful treatment with
      neurolysis 6 months after injury.
AB  - Although relatively uncommon, peripheral nerve can be injured secondary to
      fracture or dislocation. As therapeutic strategies may vary with the status of
      the nerve involved, accurate diagnosis is critical. The case described in this
      report involves a complete sciatic nerve palsy occurring after an open femur
      fracture treated 6 months earlier. The palsy was erroneously attributed to
      ischemic neuropathy from compartment syndrome, but late surgical exploration
      showed that the sciatic nerve was in continuity but enveloped by scar. Neurolysis
      resulted in full motor and sensory recovery below the knee. Accurate
      interpretation of physical findings and neurophysiologic tests in the management
      of fractures associated with nerve injury is emphasized.

PMID- 12405566
TI  - Low-energy anterior hip dislocation in a dancer.
AB  - In this article, we report the case of a healthy young woman who sustained an
      anterior hip dislocation while participating in a noncontact activity (ballet
      dancing). The patient's atraumatic dislocation failed closed reduction secondary
      to interposition of anterior capsule and rectus femoris muscle. Open reduction
      using a Smith-Petersen approach was concentric and stable. Postinjury femoral
      nerve neuropraxia resolved within 6 weeks. At 2-year follow-up, the patient was
      without complications of the injury-including avascular necrosis and
      posttraumatic arthritis. She returned to dancing and is now asymptomatic.

PMID- 12405567
TI  - Effect of Helicobacter pylori infection on fibrinogen level in elderly patients
      with ischaemic heart disease.
AB  - BACKGROUND: Fibrinogen is an important risk factor for ischaemic heart disease
      (IHD) (1) and an elevated fibrinogen level has been reported in younger patients
      infected with Helicobacter pylori (H pylori) infection (2, 3). However, the
      effect of Helicobacter pylori infection on fibrinogen level in elderly population
      with IHD is not known. Also in particular the effect on fibrinogen with
      eradication of Helicobacter pylori has not been previously reported. The aim of
      this study was to investigate the influence of H pylori on fibrinogen levels in
      elderly patients with IHD and to assess the effect of eradication therapy on
      fibrinogen levels. PATIENTS AND METHODS: Forty patients over the age of 65 years
      presenting with symptomatic IHD and an age-matched control group of 21 patients
      were studied. The 14-C urea breath test was used for detecting H pylori
      infection. Patients found to be H pylori positive were treated with omeprazole 40
      mg daily and amoxicillin 500 mg three times daily for 14 days. Fibrinogen
      concentration was measured at the beginning of treatment and repeated at 4 weeks
      after completion of treatment along with the urea breath test in those tested
      positive for H pylori and fibrinogen level was repeated at 6 weeks in the H
      pylori negative patients. RESULTS: The prevalence of H pylori infection was 19/40
      (47.5%) in the IHD group and 9/21 (42.8%) in the control group. The median serum
      fibrinogen level was 4.34 g/l (3.73-6.04 i.q. range) in H Pylori positive
      patients and 4.86 g/l (3.58-6.11 i.q. range) in H Pylori negative patients in
      both the IHD and age-matched control group, with no significant difference
      between the two groups, p = 0.78 (Mann-Whitney test). In the IHD group 27/40
      (67.5%) had a fibrinogen level >4.0 g/l compared to 11/21 (52.3%) in the control
      group. The median fibrinogen level decreased significantly from 5.75g/l (i.q.
      range 4.39-6.71) to 4.41 g/l (i.q. range 3.80-6.06) after eradication treatment
      of H pylori in patients with raised fibrinogen levels (p < 0.01). CONCLUSION: The
      presence of H Pylori infection did not correlate with the presence of IHD, and
      the fibrinogen level was not raised in the IHD group. However, in elderly
      patients with H pylori infection, eradication therapy lowered fibrinogen levels
      in those with elevated (>4.0 g/l) fibrinogen level.

PMID- 12405568
TI  - Left atrial mechanical function in patients with essential hypertension.
AB  - OBJECTIVE: This study was carried out to assess the left atrial (LA) mechanical
      function in patients with essential hypertension with two-dimensional
      echocardiography by means of left atrial volume measurements. METHODS: LA volumes
      were measured echocardiographically in 36 untreated hypertensive patients and 20
      age-sex-matched healthy controls according to biplane area-length method. LA
      volume measurements were done at the time of mitral valve opening (Vmax), at the
      onset of atrial systole (p wave at the electrocardiography = Vp) and at closure
      (Vmin). All volumes were indexed for body surface area, and the following left
      atrial emptying functions were calculated: LA passive emptying volume = Vmax -Vp,
      LA passive emptying fraction = LA passive emptying volume /Vmax, conduit volume =
      left ventricular stroke volume-(Vmax-Vmin), LA active emptying volume = Vp-Vmin,
      LA active emptying fraction = LA active emptying volume /Vp, LA total emptying
      volume = (Vmax-Vmin), LA total emptying fraction = LA total emptying volume
      /Vmax. RESULTS: Vmax (p < 0.01),Vmin (p < 0.005) and Vp (p < 0.001) were
      significantly greater in hypertensives than in controls. Although LA passive
      emptying volume (p < 0.001), LA passive emptying fraction (p < 0.001), conduit
      volume (p < 0.005) and LA total emptying fraction (p < 0.05) were found to be
      significantly lower in hypertensives than in controls, LA active emptying volume
      (p < 0.001) and LA active emptying fraction (p < 0.01) were found to be
      significantly greater in hypertensives than in controls. LA total emptying volume
      (p > 0.05) was similar in both groups. CONCLUSION: The results of the present
      study indicate that chronic hypertension is associated with an increased in left
      atrial volumes, a decrease in left atrial passive emptying function, and an
      increase systolic pump function. Increased left atrial pump function represents a
      compensatory mechanism in hypertensive patients with left ventricular
      hypertrophy.

PMID- 12405569
TI  - Transthoracic defibrillation of short-lasting ventricular fibrillation: a
      randomised trial for comparison of the efficacy of low-energy biphasic
      rectilinear and monophasic damped sine shocks.
AB  - BACKGROUND: Biphasic rectilinear shocks are more effective than monophasic shocks
      for transthoracic atrial defibrillation and for ventricular arrhythmias during
      electrophysiological testing. We undertook the present study to compare the
      efficacy of 100 J rectilinear biphasic waveform shocks with 150 J monophasic
      damped sine waveform shocks for transthoracic defibrillation of true ventricular
      fibrillation during defibrillation threshold testing (DFT). The second aim of the
      study was to analyse the influence of patch positions on the efficacy of
      defibrillation. METHODS: 50 episodes of 14 patients (age ranging from 37 to 82
      years) who underwent DFT testing were randomised for back-up shocks with either a
      sequence of 100 and 200 J biphasic waveform, or a sequence of 150 and 360 J
      conventional monophasic shocks. A binary search protocol was used at implantation
      and before hospital discharge. Patients were also randomised to an
      anteroposterior position versus a right-anterior-apical position. A crossover was
      performed between implantation and pre-hospital discharge for biphasic versus
      monophasic sequence as well as for the 2 different positions. RESULTS: After
      failed internal shocks, 27 episodes were treated with biphasic, and 23 with
      monophasic shocks. The first attempt by the external device did not terminate II
      episodes (2 biphasic, 9 monophasic). The first shock efficacy was significantly
      greater with biphasic than with monophasic shocks (p < 0.02). The overall success
      rate was 93% with biphasic shocks and 64% with monophasic shocks. In multivariate
      regression analysis including patch position, arrhythmia duration, type of
      waveform, testing order and session, only waveform was associated with successful
      defibrillation (p < 0.02). CONCLUSION: For transthoracic defibrillation of
      ventricular fibrillation, low-energy rectilinear biphasic shocks are more
      effective than monophasic shocks. The position of the defibrillation shock pads
      has no influence on the biphasic shock efficacy, but anteroposterior pad position
      is more effective using monophasic shocks.

PMID- 12405571
TI  - Sleep habits and their association with mortality during 5-year follow-up after
      coronary artery bypass surgery.
AB  - OBJECTIVE: To study various aspects of sleep quality and sleep patterns prior to
      and after coronary artery bypass surgery and their implications for 5-year
      survival. METHODS: All patients from western Sweden who underwent coronary artery
      bypass grafting (CABG) between 1988 and 1991 (n = 2,121) received a questionnaire
      addressing sleep habits prior to and I year after surgery. Various symptoms and
      habits related to sleep at the two evaluations were compared. Symptoms and habits
      related to sleep prior to CABG were then related to 5-year survival. RESULTS: In
      all, 1,224 patients took part in the evaluation. A highly significant improvement
      was observed with regard to the following symptoms and habits related to sleep:
      feeling refreshed upon awakening, feeling tired during daytime, waking up with
      headache, nightmares, sweating during night time, medication for pain relief at
      bedtime, involuntarily falling asleep during daytime, apnoea during sleep and
      mouth dryness during the night. Various symptoms and habits associated with sleep
      prior to CABG were generally not strongly related to prognosis. Exceptions were
      feeling refreshed upon awakening and infrequent consumption of pain relief
      medication at bedtime which both were associated with an improved long-term
      survival. CONCLUSIONS: A variety of symptoms associated with sleep improve highly
      significantly after CABG. The occurrence of these symptoms prior to CABG do not
      generally seem to influence the long-term prognosis.

PMID- 12405570
TI  - Medium-term follow-up of intermediate coronary stenoses left unrevascularized
      based on myocardial fractional flow reserve findings.
AB  - OBJECTIVE: Coronary stenoses of intermediate severity create difficulties in
      decision making when revascularization is concerned. Myocardial fractional flow
      reserve (mFFR), an accurate tool to identify physiological significance of
      individual coronary stenoses, may help solve this problem. METHODS AND RESULTS:
      Fifty-eight intermediate (30-70%) coronary stenoses in 51 patients (mean age 54.4
      +/- 8.9 years, 9 women) were left unrevascularized because of normal (> or =
      0.75) mFFR findings and the patients were prospectively followed with regard to
      the occurrence of death, myocardial infarction and target vessel
      revascularization. The mean reference vessel diameter, percent stenosis and mFFR
      of the intermediate lesions were 3.3 +/- 0.3 mm, 46.8 +/- 9.2% and 0.86 +/- 0.05,
      respectively. Of the 58 intermediate lesions, 20 (34%) were associated with
      perfusion defects on thallium scan. Significant (> 70%) disease in addition to
      the one with the intermediate stenosis was present in I coronary artery in 24
      (47%), and 2 coronary arteries in 6 (12%) patients and angioplasty of at least
      one significant stenosis was performed at the initial evaluation in 18 (35%)
      patients. Follow-up for a mean of 16.6 +/- 6.6 months disclosed no death or
      myocardial infarction. Target vessel revascularization was performed in 3 (6%)
      patients at a mean of 4 +/- 2.6 months. A control angiogram, which was performed
      in 12 of 18 patients who had undergone angioplasty at the initial evaluation
      revealed restenosis in 3 (25%) patients with no significant angiographic changes
      in the target intermediate stenoses. Anginal status was found to be significantly
      improved at follow-up. CONCLUSIONS: In this study, we found that intermediate
      coronary stenoses with an mFFR > or = 0.75 have a favourable medium-term clinical
      outcome with respect to major cardiac adverse events when left unrevascularized
      based on mFFR findings.

PMID- 12405572
TI  - Influence of the extent of vascular territory on fractional flow reserve
      measurements.
AB  - Although measurements of the fractional flow reserve (FFR) provide accurate
      information on functional stenosis severity in many conditions, it remains
      unknown whether the extent of the vascular territory distal to the target lesion
      influences FFR calculations. Across a total of 16 selected coronary lesions
      intracoronary pressure during maximal hyperaemia was measured using intracoronary
      pressure wire both in the target artery distal to the lesion (great territory,
      site A) and in a branch originating distal to this lesion (small territory, site
      B). Coronary segments between both measurement sites were free from significant
      atherosclerosis, allowing comparison of FFR for different sizes of vascular
      regions but with identical epicardial resistance. The extent of vascular
      territory was assessed by means of the vascular score used in the Bari trial. The
      vascular territory was twice as great for site A as for site B: a mean vascular
      score of 8.7 versus 3.6. The mean diameter of the stenosis at the target lesion
      was 49 +/- 17%. For an identical epicardial resistance, the FFR was 77.3% +/-
      14.6% for great vascular territories and 76.8% +/- 14.9% for small territories (p
      = 0.92, beta = 0.05). The mean difference between the FFR calculations was 0.5%
      +/- 3.4%. Thus, FFR measurements are not affected by the extent of the vascular
      territory underscoring the validity of the FFR concept. As a practical
      consequence, FFR measurements can be reliably carried out in cases of voluntary
      or obliged (eg. main stem lesions) access of the pressure wire into side
      branches.

PMID- 12405573
TI  - Acute myocardial infarction and sudden coronary death in young men.

PMID- 12405574
TI  - Intensive insulin treatment reduces transient ischaemic episodes during acute
      coronary events in diabetic patients.
AB  - OBJECTIVES: This study tested the impact of intensive metabolic treatment with
      insulin on transient myocardial ischaemia detected with continuous 12-lead ST
      segment monitoring during non-ST segment elevation acute coronary syndromes in
      type 2 diabetic patients. METHODS AND RESULTS: The study included 57 type 2
      diabetic patients with non-ST segment elevation acute coronary syndromes.Twenty
      eight patients randomized to conventional treatment plus intensive insulin
      therapy (group A) and twenty-nine to conventional therapy only (group B). Group A
      patients received insulin by infusion for 48 hours according to a predefined
      protocol aiming to maintain normoglycaemia. Group B patients received standard
      coronary care unit treatment. The ST-segment monitoring was performed for 48
      hours in the coronary care unit. The two groups were comparable in terms of
      medical history, clinical and biochemical data. Three patients from both groups
      were excluded from the analysis because there was objective evidence for
      evolution in persistent ST-segment elevation acute myocardial infarction. Six
      patients (24%) from group A vs. twelve from group B (46.2%) had evidence of
      transient ischaemia (p = 0.098). Group A patients showed significantly lower
      values in the mean number [group A vs. group B: 0.4 +/- 0.8 vs. 2 +/- 3.1, p <
      0.01] and total duration of ST-episodes [group A vs. group B: 2.4 +/- 5.1 vs.
      21.2 +/- 31 min, p < 0.01]. Multivariate analysis revealed that the mean plasma
      glucose during the study period was a powerful predictor of the presence
      (b:0.377,p < 0.01), the number (b:0.523,p < 0.001) and the total duration (b:
      0.686, p < 0.001) of ST-episodes, respectively. CONCLUSIONS; Intensive insulin
      treatment considerably decreases the number and the total duration of ST-episodes
      in type 2 diabetic patients suffering from non-ST segment elevation acute
      coronary syndromes.

PMID- 12405575
TI  - Images in cardiology: acute myocardial infarction as first manifestation of left
      atrial myxoma.

PMID- 12405576
TI  - QT length and heart function in primidone hypocalcaemia.

PMID- 12405577
TI  - A permanent junctional reciprocating tachycardia with atypical location, treated
      with radiofrequency catheter ablation.
AB  - Permanent junctional reciprocating tachycardia (PJRT) is an incessant or almost
      incessant supraventricular tachycardia with a long RP interval, usually occurring
      in children and young adults. The differential diagnosis of PJRT includes an
      atrial tachycardia and atypical atrioventricular nodal reentrant tachycardia
      (AVNRT). The accessory pathways in PJRT are typically located in the
      posteroseptal region. We report a case of successful radiofrequency catheter
      ablation in a 28-year-old male patient with PJRT due to a left posterolateral
      accessory pathway.

PMID- 12405578
TI  - A single coronary artery from the right sinus of valsalva associated with
      atherosclerosis.
AB  - Anomalous origin of the main coronary arteries from the aorta is rare. We report
      a case with a single coronary artery from the right sinus of Valsalva associated
      with atherosclerosis. The patient was treated with a coronary artery bypass
      procedure: left internal mammary artery (LIMA) to the left anterior descending
      artery (LAD), right internal mammary artery (RIMA) to the right coronary artery
      (RCA). The postoperative course was uneventful.

PMID- 12405579
TI  - A case of coronary spasm induced by 5-fluorouracil.
AB  - Cardiotoxicity is an uncommon adverse effect of 5-fluorouracil (5-FU). Coronary
      artery spasm has been postulated to be involved in the mechanism of this incident
      Patients may present with angina, myocardial infarction, arrhythmias and/or even
      sudden death. When the drug is readministered, there is a high risk of relapse.
      The underlying mechanisms of cardiotoxicity are not yet fully understood,
      although coronary vasospasm may be responsible. We report one woman receiving 5
      fluorouracil therapy with typical chest pain and electrocardiographic changes
      consistent with acute coronary syndrome. A resolving pain and normalisation of
      ECG changes with nitrate therapy and normal coronary arteries indicate that this
      incident was about a coronary spasm caused by 5-FU.

PMID- 12405580
TI  - Primary bacterial pericarditis.
AB  - Purulent pericarditis is rarely the primary site of bacterial infection. It is
      usually a complication of an infection originating elsewhere in the body, arising
      by contiguous spread or haematogenous dissemination.This paper, however,
      describes a previously healthy young man, who developed a purulent streptococcal
      pericarditis with no localizable primary focus. Although many possibilities were
      investigated, the entry site of the pericarditis remains unknown. The incidence
      of purulent pericarditis has decreased considerably since the antibiotic era. It
      is typically an acute and potentially lethal disease, necessitating rapid
      diagnosis and adequate therapy to improve prognosis. Standard treatment combines
      appropriate antibiotic therapy with surgical drainage. However, the exact timing
      and type of surgery is still under discussion. Our patient was treated with
      antibiotics, subxiphoidal tube drainage of the pericardial fluid and
      intrapericardial thrombolysis. After three weeks, he developed tamponade,
      requiring partial pericardiectomy. He recovered completely and resumed his normal
      activities after a two-month hospitalisation.

PMID- 12405581
TI  - Instant orthodontics: viable treatment option or "quick fix" cop-out?

PMID- 12405582
TI  - Ceramics.

PMID- 12405583
TI  - Esthetic restoration of the traumatized and surgically reconstructed anterior
      maxilla.
AB  - A car accident victim can lose not only anterior teeth but also the soft- and
      hard-tissue support for these teeth. This article describes a step-by-step
      approach to the treatment protocol for an accident victim in whom anterior teeth
      and the supporting tissues have been lost. The protocol is systematic and can be
      used for most accident cases, where the functional and esthetic demands are very
      high. CLINICAL SIGNIFICANCE: This article demonstrates how excellent teamwork
      among the dentist, implant surgeon, and laboratory technician can result in a
      well-conceived and successful restoration following traumatic injury of the
      dentition.

PMID- 12405584
TI  - Polymerization efficiency of LED curing lights.
AB  - PURPOSE: The purpose of this study was to compare the curing efficiency of three
      commercially available light-emitting diode (LED)-based curing lights with that
      of a quartz tungsten halogen (QTH) curing light by means of hardness testing. In
      addition, the power density (intensity) and spectral emission of each LED light
      was compared with the QTH curing light in both the 380- to 520-nm and the 450- to
      500-nm spectral ranges. MATERIALS AND METHODS: A polytetrafluoroethylene mold 2
      mm high and 8 mm in diameter was used to prepare five depth-of-cure test
      specimens for each combination of exposure duration, composite type (Silux Plus
      [microfill], Z-100 [hybrid]), and curing light (ZAP Dual Curing Light, LumaCure,
      VersaLux, Optilux 401). After 24 hours, Knoop hardness measurements were made for
      each side of the specimen, means were calculated, and a bottom/top Knoop hardness
      (B/T KH) percentage was determined. A value of at least 80% was used to indicate
      satisfactory polymerization. A linear regression of B/T KH percentage versus
      exposure duration was performed, and the resulting equation was used to predict
      the exposure duration required to produce a B/T KH percentage of 80% for the test
      conditions. The power densities (power/unit area) of the LED curing lights and
      the QTH curing light (Optilux 401) were measured 1 mm from the target using a
      laboratory-grade, laser power meter in both the full visible light spectrum range
      (380-780 nm) and the spectral range (between 450 and 500 nm), using a combination
      of long- and short-wave edge filters. RESULTS: The emission spectra of the LED
      lights more closely mirrored the absorption spectrum of the commonly used
      photoinitiator camphorquinone. Specifically, 95% of the emission spectrum of the
      VersaLux, 87% of the LumaCure, 84% of the ZAP LED, and 78% of the ZAP combination
      LED and QTH fell between 450 and 500 nm. In contrast, only 56% of the emission
      spectrum of the Optilux 401 halogen lamp fell within this range. However, the
      power density between 450 and 500 nm was at least four times greater for the
      halogen lamp than for the purely LED lights. As a result, the LED-based curing
      lights required from 39 to 61 seconds to cure a 2-mm thick hybrid resin composite
      and between 83 and 131 seconds to adequately cure a microfill resin composite. By
      comparison, the QTH light required only 21 and 42 seconds to cure the hybrid and
      microfill resin composites, respectively. CLINICAL SIGNIFICANCE: The first
      generation LED-based curing lights in this study required considerably longer
      exposure durations than the QTH curing light to adequately polymerize a hybrid
      and a microfill resin composite.

PMID- 12405585
TI  - Self-etching primer and resin-based restorative material: two-year clinical
      evaluation.
AB  - PURPOSE: This study was undertaken to evaluate the performance of posterior
      restorations placed using a self-etching primer (Fluorobond, Shofu Inc., Kyoto,
      Japan) and a universal resin-based restorative material (Beautifil, Shofu Inc.,
      Kyoto, Japan). MATERIALS AND METHODS: The 61 restorations evaluated were 26 Class
      I and 35 Class II that were placed by two clinicians in 31 patients. Two other
      calibrated clinicians evaluated the restorations using United States Public
      Health Service (USPHS)/Ryge criteria observing the following characteristics:
      color match, marginal adaptation, anatomy, roughness, marginal staining,
      interfacial staining, contact, secondary caries, and luster. Restorations were
      placed under rubber dam isolation. Chi-squared and Fisher's exact tests were used
      for statistical analysis (p = .05). RESULTS: All the restorations were assessed
      at baseline and alfa scores predominated for all criteria. At the 12-month recall
      examination, one patient dropped out of the study and two restorations were
      replaced by a clinician not involved in the project. At 24-month recall, 58
      restorations were examined (23 Class I and 35 Class II). From baseline to 24
      months, 19 of the 44 restorations changed from alfa to bravo and 13 from bravo to
      alfa for a variety of reasons. No significant differences were found for any of
      the clinical criteria (p > .05). The 2-year recall substantiated the 1-year
      results. CONCLUSION: Beautifil and the self-etching primer Fluorobond provided
      satisfactory restorations after a 2-year observation period. CLINICAL
      SIGNIFICANCE: Beautifil restorative material and Fluorobond bonding system
      provided satisfactory results when placed in Class I and Class II preparations
      for a period of 2 years.

PMID- 12405586
TI  - Posterior resin-based composite restorations: a second opinion.

PMID- 12405587
TI  - All-ceramic fixed partial dentures, Part III: clinical studies.

PMID- 12405588
TI  - Root caries.

PMID- 12405589
TI  - Identification of cross-sectional parameters of lateral meniscal allografts that
      predict tibial contact pressure in human cadaveric knees.
AB  - To guide the development of improved procedures for selecting meniscal
      allografts, the objective of this study was to identify which cross-sectional
      parameters of a lateral meniscal allograft predict the contact pressure of the
      articular surface of the tibia. To meet the objective, the contact pressure of
      the articular surface of the tibia was measured with a lateral meniscal autograft
      and a lateral meniscal allograft using pressure sensitive film in 15 fresh-frozen
      human cadaveric knees. Allografts were matched only in transverse dimensions to
      the autograft but not in cross-sectional dimensions. Knees were loaded to 1200 N
      in compression at flexion angles of 0, 15, 30 and 45 degrees using a load
      application system that allowed unconstrained motion in the remaining degrees of
      freedom. Five cross-sectional parameters for both of the grafts in each of the
      anterior, middle, and posterior regions were derived from measurements obtained
      using a laser-based non-contacting three-dimensional coordinate digitizing system
      (3-DCDS) (Haut et al., J. Orthop Res, 2000). Five contact variables (i.e. the
      maximum pressure, mean pressure, contact area, and anterior-posterior and medial
      lateral locations of the centroid of contact area) were determined from the
      pressure sensitive film. When each allograft was paired with the corresponding
      autograft, the root mean squared percent differences for the cross-sectional
      parameters ranged from a minimum of 28% for the width of the posterior region to
      572% for the height of the posterior region. The root mean squared percent
      differences between the contact variables for paired grafts were 29% for the
      maximum pressure, 19% for the mean pressure, and 24% for the contact area.
      Differences in the cross-sectional parameters between the grafts were related to
      differences in the contact variables using regression analysis. Difference in the
      width was most often a predictor variable in the regression models with R2 values
      > or = 0.45. Differences in all of the four remaining cross-sectional parameters
      were also important predictor variables. Because failure to match cross-sectional
      parameters causes substantial difference in contact variables between an
      allograft and autograft and because cross-sectional parameters predict the
      contact pressure on the tibial plateau, protocols used to prospectively select
      allografts should concentrate on matching cross-sectional parameters and
      particularly the width to those of the original meniscus.

PMID- 12405590
TI  - Deformation of angle profiles in forward kinematics for nullifying end-point
      offset while preserving movement properties.
AB  - This work describes a new approach that allows an angle-domain human movement
      model to generate, via forward kinematics, Cartesian-space human movement
      representation with otherwise inevitable end-point offset nullified but much of
      the kinematic authenticity retained. The approach incorporates a rectification
      procedure that determines the minimum postural angle change at the final frame to
      correct the end-point offset, and a deformation procedure that deforms the angle
      profile accordingly to preserve maximum original kinematic authenticity. Two
      alternative deformation schemes, named amplitude-proportional (AP) and time
      proportional (TP) schemes, are proposed and formulated. As an illustration and
      empirical evaluation, the proposed approach, along with two deformation schemes,
      was applied to a set of target-directed right-hand reaching movements that had
      been previously measured and modeled. The evaluation showed that both deformation
      schemes nullified the final frame end-point offset and significantly reduced time
      averaged position errors for the end-point as well as the most distal
      intermediate joint while causing essentially no change in the remaining joints. A
      comparison between the two schemes based on time-averaged joint and end-point
      position errors indicated that overall the TP scheme outperformed the AP scheme.
      In addition, no statistically significant difference in time-averaged angle error
      was identified between the raw prediction and either of the deformation schemes,
      nor between the two schemes themselves, suggesting minimal angle-domain
      distortion incurred by the deformation.

PMID- 12405591
TI  - Genetic algorithm-neural network estimation of cobb angle from torso asymmetry in
      scoliosis.
AB  - Scoliosis severity, measured by the Cobb angle, was estimated by artificial
      neural network from indices of torso surface asymmetry using a genetic algorithm
      to select the optimal set of input torso indices. Estimates of the Cobb angle
      were accurate within 5 degrees in two-thirds, and within 10 degrees in six
      sevenths, of a test set of 115 scans of 48 scoliosis patients, showing promise
      for future longitudinal studies to detect scoliosis progression without use of X
      rays.

PMID- 12405592
TI  - Importance of nonlinear and multivariable flexibility coefficients in the
      prediction of human cervical spine motion.
AB  - The flexibility matrix currently forms the basis for multibody dynamics models of
      cervical spine motion. While studies have aimed to determine cervical motion
      segment behavior, their accuracy and utility have been limited by both
      experimental and analytical assumptions. Flexibility terms have been primarily
      represented as constants despite the spine's nonlinear stiffening response. Also,
      nondiagonal terms, describing coupled motions, of the matrices are often omitted.
      Currently, no study validates the flexibility approach for predicting vertebral
      motions; nor have the effects of matrix approximations and simplifications been
      quantified. Therefore, the purpose of this study is to quantify flexibility
      relationships for cervical motion segments, examine the importance of nonlinear
      components of the flexibility matrix, and determine the extent to which
      multivariable relationships may alter motion prediction. To that end, using
      unembalmed human cervical spine motion segments, a full battery of flexibility
      tests were performed for a neutral orientation and also following an axial
      pretorque. Primary and coupled matrix components were described using linear and
      piecewise nonlinear incremental constants. A third matrix approach utilized
      multivariable incremental relationships. Measured motions were predicted using
      structural flexibility methods and evaluated using RMS error between predicted
      and measured responses. A full set of flexibility relationships describe primary
      and coupled motions for C3-C4 and C5-C6. A flexibility matrix using piecewise
      incremental responses offers improved predictions over one using linear methods
      (p<0.01). However, no significant improvement is obtained using nonlinear terms
      represented by a multivariable functional approach (p<0.2). Based on these
      findings, it is suggested that a multivariable approach for flexibility is more
      demanding experimentally and analytically while not offering improved motion
      prediction.

PMID- 12405594
TI  - Linear poroelastic cancellous bone anisotropy: trabecular solid elastic and fluid
      transport properties.
AB  - The mechanical performance of cancellous bone is characterized using experiments
      which apply linear poroelasticity theory. It is hypothesized that the anisotropic
      organization of the solid and pore volumes of cancellous bone can be physically
      characterized separately (no deformable boundary interactive effects) within the
      same bone sample. Due to its spongy construction, the in vivo mechanical function
      of cancellous or trabecular bone is dependent upon fluid and solid materials
      which may interact in a hydraulic, convective fashion during functional loading.
      This project provides insight into the organization of the tissue, ie., the
      trabecular connectivity, by defining the separate nature of this biphasic
      performance. Previous fluid flow experiments [Kohles et al., 2001, Journal of
      Biomechanics, 34(11), pp. 1197-1202] describe the pore space via orthotropic
      permeability. Ultrasonic wave propagation through the trabecular network is used
      to describe the solid component via orthotropic elastic moduli and material
      stiffness coefficients. The linear poroelastic nature of the tissue is further
      described by relating transport (fluid flow) and elasticity (trabecular load
      transmission) during regression analysis. In addition, an empirical relationship
      between permeability and porosity is applied to the collected data. Mean
      parameters in the superior-inferior (SI) orientation of cubic samples (n=20)
      harvested from a single bovine distal femur were the largest (p<0.05) in
      comparison to medial-lateral (ML) and anterior-posterior (AP) orientations:
      Apparent elastic modulus (2,139 MPa), permeability (4.65x10(-10) m2), and
      material stiffness coefficient (13.6 GPa). A negative correlation between
      permeability as a predictor of structural elastic modulus supported a parametric
      relationship in the ML (R2=0.4793), AP (R2=0.3018), and SI (R2=0.6445) directions
      (p<0.05).

PMID- 12405593
TI  - Analysis of crack growth in a 3D Voronoi structure: a model for fatigue in low
      density trabecular bone.
AB  - Both creep and crack growth contribute to the reduction in modulus associated
      with fatigue loading in bone. Here we simulate crack growth and subsequent strut
      failure in fatigue in an open-cell, three-dimensional Voronoi structure which is
      similar to that of low density, osteoporotic bone. The model indicates that
      sequential failure of struts leads to a precipitous drop in modulus: the failure
      of 1% of the struts leads to about a 10% decrease in modulus. A parametric study
      is performed to assess the influence of normalized stress range, relative
      density, initial crack size, crack shape and cell geometry on the fatigue life.
      The fatigue life is most sensitive to the relative density and the initial crack
      length. The results lead to a quantitative expression for the fatigue life
      associated with crack growth. Data for the fatigue life of trabecular bone are
      compared with the crack growth model described in this paper as well as with a
      previous model for creep of a three-dimensional Voronoi structure. In our models,
      creep dominates the fatigue behavior in low cycle fatigue while crack growth
      dominates in high cycle fatigue, consistent with previous observations on
      cortical bone. The large scatter in the trabecular bone fatigue data make it
      impossible to identify a transition between creep dominated fatigue and crack
      growth dominated fatigue. The parametric study of the crack growth model
      indicates that variations in relative density among specimens, initial crack size
      within trabeculae and crack shape could easily produce such variability in the
      test results.

PMID- 12405595
TI  - Non-linear characteristics in the dynamic responses of seated subjects exposed to
      vertical whole-body vibration.
AB  - The effect of the magnitude of vertical vibration on the dynamic response of the
      seated human body has been investigated. Eight male subjects were exposed to
      random vibration in the 0.5 to 20 Hz frequency range at five magnitudes: 0.125,
      0.25, 0.5, 1.0 and 2.0 ms(-2) r.m.s. The dynamic responses of the body were
      measured at eight locations: at the first, fifth, and tenth thoracic vertebrae
      (T1, T5, T10), at the first, third, and fifth lumbar vertebrae (L1, L3, L5) and
      at the pelvis (the posterior-superior iliac spine). At each location, the motions
      on the body surface were measured in the three orthogonal axes within the
      sagittal plane (i.e., the vertical, fore-and-aft, and pitch axes). The force at
      the seat surface was also measured. Frequency response functions (i.e.,
      transmissibilities and apparent mass) were used to represent the responses of the
      body. Non-linear characteristics were observed in the apparent mass and in the
      transmissibilities to most measurement locations. Resonance frequencies in the
      frequency response functions decreased with increases in the vibration magnitude
      (e.g. for the vertical transmissibility to L3, a reduction from 6.25 to 4.75 Hz
      when the vibration magnitude increased from 0.125 to 2.0 ms(-2) r.m.s.). The
      transmission of vibration within the spine also showed some evidence of a non
      linear characteristic. It can be concluded from this study that the dynamic
      responses of seated subjects are clearly non-linear with respect to vibration
      magnitude, whereas previous studies have reported inconsistent conclusions. More
      understanding of the dependence on vibration magnitude of both the dynamic
      responses of the soft tissues of the body and the muscle activity (voluntary and
      involuntary) is required to identify the causes of the non-linear characteristics
      observed in this study.

PMID- 12405596
TI  - Hydraulic resistance and permeability in human lumbar vertebral bodies.
AB  - Hydraulic resistance (HR) was measured for ten intact human lumbar vertebrae to
      further understand the mechanisms of fluid flow through porous bone. Oil was
      forced through the vertebral bodies under various volumetric flow rates and the
      resultant pressure was measured The pressure-flow relationship for each specimen
      was linear. Therefore, HR was constant with a mean of 2.22 +/- 1.45 kPa*sec/ml.
      The mean permeability of the intact vertebral bodies was 4.90x10(-10) +/-
      4.45x10(-10) m2. These results indicate that this methodology is valid for whole
      bone samples and enables the exploration of the effects of HR on the creation of
      high-speed fractures.

PMID- 12405597
TI  - An interface model for the periodontal ligament.
AB  - A nonlinear interface constitutive law is formulated for modeling the mechanical
      behavior of the periodontal ligament. This gives an accurate interpolation of the
      few available experimental results and provides a reasonably simple model for
      mechanical applications. The model is analyzed from the viewpoints of both
      mathematical consistency and effectiveness in numerical calculations. In order to
      demonstrate the latter, suitable two- and three-dimensional nonlinear interface
      finite elements have been implemented.

PMID- 12405598
TI  - A biomechanical model of sagittal tongue bending.
AB  - The human tongue is a structurally complex and extremely flexible organ. In order
      to better understand the mechanical basis for lingual deformations, we modeled a
      primitive movement of the tongue, sagittal tongue bending. We hypothesized that
      sagittal bending is a synergistic deformation derived from co-contraction of the
      longitudinalis and transversus muscles. Our model of tongue bending was based on
      classical bimetal strip theory, in which curvature is produced when one muscle
      layer contracts more so than another. Contraction was modulated via mismatched
      thermal expansion coefficients and temperature change (to simulate muscular
      contraction). Our results demonstrated that synergistic contraction produced
      curvature and strain results which were in better correspondence to empirical
      results derived from tagging MRI than were the results of contraction of the
      longitudinalis muscle alone. This fundamental reliance of tongue bending on the
      synergistic contraction of its intrinsic fibers supports the muscular hydrostat
      theory of tongue function.

PMID- 12405599
TI  - An automated approach for direct measurement of two-dimensional strain
      distributions within articular cartilage under unconfined compression.
AB  - An automated approachfor measuring in situ two-dimensional strain fields was
      developed and validated for its application to cartilage mechanics. This approach
      combines video microscopy, optimized digital image correlation (DIC), thin-plate
      spline smoothing (TPSS) and generalized cross-validation (GCV) techniques to
      achieve the desired efficiency and accuracy. Results demonstrate that sub-pixel
      accuracies can be achieved for measuring tissue displacements with this
      methodology with a measurement uncertainty ranging from 0.25 to 0.30 pixels. The
      deformational gradients (from which the strains are determined) can be evaluated
      directly using the optimized DIC, with a measurement uncertainty of 0.017 to
      approximately 0.032. In actual measurements of strain in cartilage, TPSS and
      differentiation can be used to achieve a more accurate measurement of the
      gradients from the displacement data. Using this automated approach, the two
      dimensional strain fields inside immature bovine carpometacarpal joint cartilage
      specimens under unconfined compression were characterized (n=21). The depth
      dependent apparent elastic modulus and Poisson's ratio were also determined and
      found to be smallest at the articular surface and increasing with depth. The
      apparent Poisson's ratio is found to decrease with increasing compressive strain,
      with values as low as 0.01 observed near the articular surface at 25%
      compression. The variation of the apparent Poisson's ratio with depth is found to
      be consistent with a theoretical model of cartilage which accounts for the
      disparity in its tensile and compressive moduli.

PMID- 12405600
TI  - Confined compression of a tissue-equivalent: collagen fibril and cell alignment
      in response to anisotropic strain.
AB  - A method to impose and measure a one dimensional strain field via confined
      compression of a tissue-equivalent and measure the resulting cell and collagen
      fibril alignment was developed Strain was determined locally by the displacement
      of polystyrene beads dispersed and entrapped within the network of collagen
      fibrils along with the cells, and it was correlated to the spatial variation of
      collagen network birefringence and concentration. Alignment of fibroblasts and
      smooth muscle cells was determined based on the long axis of elongated cells.
      Cell and collagen network alignment were observed normal to the direction of
      compression after a step strain and increased monotonically up to 50% strain.
      These results were independent of time after straining over 24 hr despite
      continued cell motility after responding instantly to the step strain with a
      change in alignment by deforming/convecting with the strained network. Since the
      time course of cell alignment followed that of strain and not stress which, due
      to the viscoelastic fluid-like nature of the network relaxes completely within
      the observation period, these results imply cell alignment in a compacting tissue
      equivalent is due to fibril alignment associated with anisotropic network strain.
      Estimation of a contact guidance sensitivity parameter indicates that both cell
      types align to a greater extent than the surrounding fibrils.

PMID- 12405601
TI  - Mechanics of tether formation in liposomes.
AB  - It is well-known that a "tether" may be drawn out from a pressurized liposome by
      means of a suitably applied radial-outward force applied locally to the lipid
      bilayer. The tether is a narrow, uniform cylindrical tube, which joins the main
      vesicle in a short "transition region." A first-order energy analysis establishes
      the broad relationship between the force F needed to draw the tether, the radius
      R0 of the tether, the bending-stiffness constant B for the lipid bilayer and the
      membrane tension T in the pressurized liposome. The aim of the present paper is
      to study in detail the "transition region" between the tether and the main
      vesicle, by means of a careful application of the engineering theory of
      axisymmetric shell structures. It turns out that the well-known textbook "thin
      shell" theory is inadequate for this purpose, because the tether is evidently an
      example of a thick-walled shell; and a novel ingredient of the present study is
      the introduction of elastic constitutive relations that are appropriate to the
      thick-shell situation. The governing equations are set up in dimensionless form,
      and are solved by means of a "shooting" technique, starting with a single
      disposable parameter at a point on the meridian in the tether, which can be
      adjusted until the boundary conditions at the far "equator" of the main vessel
      are satisfied. It turns out that the "transition region" between the tether and
      the main vessel is well characterized by only a few parameters, while the tether
      and main vessel themselves are described by very simple equations. Introduction
      of the thick-shell constitutive relation makes little difference to the
      conformation of and stress-resultants in, the main vessel; but it makes a great
      deal of difference in the tether itself Indeed, a kind of phase-change appears to
      take place in the "transition region" between these two zones of the liposome.

PMID- 12405602
TI  - An axisymmetric boundary integral model for assessing elastic cell properties in
      the micropipette aspiration contact problem.
AB  - The micropipette aspiration technique has been used extensively in recent years
      to measure the mechanical properties of living cells. In the present study, a
      boundary integral formulation with quadratic elements is used to predict the
      elastic equilibrium response in the micropipette aspiration contact problem for a
      three-dimensional incompressible spherical continuum cell model (Young's modulus
      E). In contrast to the halfspace model, the spherical cell model accounts for
      nonlinearities in the cell response which result from a consideration of
      geometric factors including the finite cell dimension (radius R), curvature of
      the cell boundary, evolution of the cell-micropipette contact region and
      curvature of the edges of the micropipette (inner radius a, edge curvature radius
      epsilon). The efficiency of the boundary element method facilitates the
      quantification of cell response as a function of the scaled pressure p/E, for the
      range of parameters a/R = 0.4-0.7, epsilon/a = 0.02-0.08, in terms of two
      measures that can be quantified using video microscopy. These are the aspiration
      length, which measures projection of the cell into the micropipette, and a
      characteristic strain, which measures stretching along the symmetry axis. For
      both measures of cell response, the resistance to aspiration is found to decrease
      with increasing values of the aspect ratio a/R and curvature parameter epsilon/a,
      and the nonlinearities in the cell response are most pronounced in the earlier
      portion of the aspiration test. The aspiration length is found to exhibit less
      sensitivity to the aspect ratio a/R than to the curvature parameter epsilon/a,
      whereas the characteristic strain, which provides a more realistic measure of
      overall cell stiffness, exhibits sensitivity to the aspect ratio a/R. The
      resistance to aspiration in the spherical cell model is initially less than that
      of the half space model but eventually exceeds the halfspace prediction and the
      deviation between the two models increases as the parameter epsilon/a decreases.
      Adjustment factors for the Young's modulus E, as predicted by the halfspace
      model, are presented and the deviation from the spherical cell model is found to
      be as large as 35%, when measured locally on the response curve. In practice, the
      deviation will be less than the maximum figure but its precise value will depend
      on the number of data points available in the experiment and the specific curve
      fitting procedure. The spherical cell model allows for efficient and more
      realistic simulations of the micropipette aspiration contact problem and
      quantifies two observable measures of cell response that, using video microscopy,
      can facilitate the determination of Young's modulus for various cell populations
      while, simultaneously, providing a means of evaluating the validity of continuum
      cell models. Furthermore, this numerical model may be readily extended to account
      for more complex geometries, inhomogeneities in cellular properties, or more
      complex constitutive descriptions of the cell.

PMID- 12405604
TI  - Three-dimensional, unsteady simulation of alveolar respiration.
AB  - A novel macroscopic gas transport model, derived from fundamental engineering
      principles, is used to simulate the three-dimensional, unsteady respiration
      process within the alveolar region of the lungs. The simulations, mimicking the
      single-breath technique for measuring the lung diffusing capacity for carbon
      monoxide (CO), allow the prediction of the red blood cell (RBC) distribution
      effects on the lung diffusing capacity. Results, obtained through numerical
      simulations, unveil a strong relationship between the type of distribution and
      the lung diffusing capacity. Several RBC distributions are considered, namely:
      normal (random), uniform, center-cluster, and corner-cluster red cell
      distributions. A nondimensional correlation is obtained in terms of a geometric
      parameter characterizing the RBC distribution, and presented as a useful tool for
      predicting the RBC distribution effect on the lung diffusing capacity. The effect
      of red cell movement is not considered in the present study because CO does not
      equilibrate with capillary blood within the time spent by blood in the capillary.
      Hence, blood flow effect on CO diffusion is expected to be only marginal.

PMID- 12405603
TI  - Mechanism of incomplete mitral leaflet coaptation--interaction of chordal
      restraint and changes in mitral leaflet coaptation geometry. Insight from in
      vitro validation of the premise of force equilibrium.
AB  - Clinically observed incomplete mitral leaflet coaptation was reproduced in vitro
      by altering the balance of the chordal tethering and chordal coapting force
      components. Mitral leaflet coaptation geometry was distorted by changes of the
      spatial relations between the papillary muscles and the mitral valve as well as
      hemodynamics. Mitral leaflet malalignment was accentuated by a redistribution of
      the chordal tethering and coapting force components. For the overall assessment
      of systolic mitral leaflet configuration in functional mitral regurgitation it is
      important to consider the interaction between chordal restraint and an altered
      mitral leaflet coaptation geometry.

PMID- 12405605
TI  - A dual-pressure boundary condition for use in simulations of bifurcating
      conduits.
AB  - A dual-pressure boundary condition has been developed for computational modelling
      of bifurcating conduits. The condition involves the imposition of a constant
      pressure on one branch while adjusting iteratively the pressure on the other
      branch until the desired flow division is obtained. The dual-pressure condition
      eliminates the need for specifying fully-developed flow conditions, which thereby
      enables significant reduction of the outlet branch lengths. The dual-pressure
      condition is suitable for both steady and time-periodic simulations of laminar or
      turbulent flows.

PMID- 12405606
TI  - Search for neuron-specific and nonneuron-specific antibodies in narcoleptic
      patients with and without HLA DQB1*0602.
AB  - STUDY OBJECTIVES: Narcolepsy is strongly associated with the presence of HLA
      DQB1*0602. This and other evidence suggests that human narcolepsy is an
      autoimmune disease. This is in distinction to that found in canine models where
      hypocretin receptor 2 mutations are etiologic. We decided to test for the
      presence of several neuron-specific and organ-specific autoantibodies to see if
      they were present in HLA DQB1*0602-associated or cataplexy-associated narcolepsy
      or could serve as a serologic marker of the illness. DESIGN: We tested for N-type
      and P/Q-type voltage-gated calcium-channel antibodies, neuronal nicotinic
      acetylcholine receptor alpha3 subunit, acetylcholine receptor-binding antibodies,
      striated muscle antibodies, Type 1 Purkinje cell cytoplasmic antibodies, types 1
      and 2 antineuronal nuclear antibodies and amphiphysin antibodies, GAD-65
      antibody, and thyroid microsomal and thyroglobulin antibodies in the serum of 43
      patients with or without cataplexy, 41 with known HLA status. SETTING:
      Narcoleptic subjects were recruited from the Mayo Sleep Disorders Center.
      PARTICIPANTS: N/A. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: No antibody test
      yielded significantly positive results for the group as a whole or for subgroups
      of patients with cataplexy or positive HLA DQB1*0602 status. CONCLUSIONS: These
      results do not support the hypothesis that narcolepsy is an autoimmune disease.
      However, it is possible that the autoimmune attack is very selective and does not
      involve the epitopes measured in this study. Recent findings that the hypocretin
      neurotransmission system is involved in animal models of narcolepsy should lead
      to research to look for antibodies directed against components of the hypocretin
      neurotransmission system in narcolepsy.

PMID- 12405607
TI  - Emotional experience during rapid-eye-movement sleep in narcolepsy.
AB  - STUDY OBJECTIVES: To describe emotional experience during sleep-onset rapid-eye
      movement [(REM) SOREM] sleep and nighttime REM in narcoleptic patients and to
      relate any differences in REM emotion to the more general abnormalities of this
      disorder. DESIGN: Awakenings were performed from SOREM (REM at the onset of
      daytime naps and nighttime sleep) and nighttime emergent (ascending) REM in 15
      patients with narcolepsy and from nighttime REM in 9 normal healthy participants.
      Subjects rated the occurrence and intensity of discrete emotion types for each
      line in their REM-mentation reports. Fragmentation of REM was measured and
      related to emoton. SETTING: Subjects were studied in their own homes over 2
      consecutive days and nights (3 nights for normals) and were monitored by
      ambulatory polysomnography. PARTICIPANTS: Fifteen patients with narcolepsy, aged
      17 to 70 years (mean = 45.3) and 9 normal healthy subjects, aged 31 to 60 years
      (mean = 43.0). RESULTS: Emotions were found more often and were more intense in
      narcoleptic SOREM than in nighttime REM of either narcoleptic or normal subjects,
      with anxiety/fear exhibiting the strongest increase, followed by joy/elation.
      Comparing nighttime REM in narcoleptic and normal subjects, narcoleptics were
      found to have more intense feelings of anxiety/fear and of joy/elation but to
      have a less frequent experience of surprise and anger. Positive and negative
      emotions occurred in a balanced fashion in SOREM and nighttime REM in narcoleptic
      subjects. In the SOREM of narcoleptic patients, high levels of positive emotions,
      in particular of joy/elation, were associated with a less fragmented (more
      stable) REM sleep. CONCLUSION: The REM sleep of patients with narcolepsy affords
      a unique opportunity to study emotion and to analyze its psychophysiology.
      Narcolepsy intensifies REM-dream emotion, especially anxiety/fear and
      joy/elation, and this is most clearly seen during SOREM sleep. The changes in REM
      emotion of narcoleptic patients could reflect the effect of the fundamental
      pathology of this disorder upon neurobiologic systems that support cognitive
      emotional functions.

PMID- 12405609
TI  - How well do school-aged children comply with imposed sleep schedules at home?
AB  - STUDY OBJECTIVES: To quantitatively assess compliance and experimental success
      with imposed sleep schedules among healthy children involved in an experimental
      comparison of optimized and restricted sleep. DESIGN: We asked children to follow
      assigned sleep schedules at home that created optimized (at least 10 hours time
      in-bed per night) and restricted (6.5 to 8 hours time-in-bed per night) sleep
      conditions across 2 weeks during the school year. Self-report or parent-report of
      bedtime and risetime was obtained daily and continuous actigraphy was recorded.
      SETTING: Home. PARTICIPANTS: 78 healthy children (41 boys, 37 girls; mean age,
      10.2 years; age range, 6.5 to 12.9 years) INTERVENTIONS: N/A. MEASUREMENTS AND
      RESULTS: We used reported time-in-bed to assess noncompliance with assigned
      schedules. Experimental failure was assessed with actigraphically based estimates
      of sleep period (time from sleep onset to sleep offset) and total sleep time
      (minutes of scored sleep during sleep period). Reported time-in-bed averaged 3.45
      hours less per night under restricted versus optimized conditions. Sleep period
      and total sleep time showed similar differences (2.97 and 2.32 hours less,
      respectively). Four children met a priori criteria for noncompliance (3 for
      optimized nights and 1 for restricted). Eight children met a priori criteria for
      experimental failure within conditions (7 for optimized nights and 1 for
      restricted), but most achieved a substantial difference in sleep behavior across
      optimized and restricted weeks. CONCLUSIONS: In general, healthy children as
      young as 6 years of age can maintain substantial changes in their usual schedules
      across several nights at home and should be considered for inclusion in
      experimental studies of sleep extension and restriction. This paper offers a
      methodologic "road-map" for scientists interested in pursuing this goal.

PMID- 12405608
TI  - Hypocretin (orexin) levels in cerebrospinal fluid of patients with narcolepsy:
      relationship to cataplexy and HLA DQB1*0602 status.
AB  - STUDY OBJECTIVES: Hypocretin (orexin) deficiency (< 40 pg/ml) is highly
      associated with narcolepsy with cataplexy (89.5%) and more specifically with
      patients with cataplexy who are HLA DQB1*0602 positive (95.7%). The relationship
      between hypocretin-1 levels and narcolepsy without cataplexy or the DQB1*0602
      allele is less clear. METHODS/DESIGN: This study compared cerebrospinal (CSF)
      hypocretin-1 in 13 patients with HLA DQB1*0602 allele and cataplexy to 4 HLA
      negative patients with cataplexy, 3 HLA positive patients without cataplexy, and
      6 HLA negative patients without cataplexy, plus 15 neurologic controls. SETTING:
      Data were collected at a sleep disorders center. PATIENTS/PARTICIPANTS: Twenty
      six patients with narcolepsy, with and without HLA DQB1*0602 and with and without
      cataplexy, as well as 15 neurologic controls. INTERVENTIONS: N/A. MEASUREMENT &
      RESULTS: Using analysis of variance techniques, statistically significant
      differences were found between the CSF hypocretin-1 levels in HLA positive
      patients and all other groups (P < 0.01). Although the sample size was small,
      subjects with the DQB1*0602 allele without cataplexy had lower hypocretin-1
      levels than did other groups (other than the HLA and cataplexy positive group).
      Hypocretin-1 levels were not associated with age at diagnosis, age at lumbar
      puncture, body mass index at time of diagnosis, or body mass index at time of
      lumbar puncture. CONCLUSION: This data confirms the previous finding that
      undetectable hypocretin-1 levels are highly specific for HLA positive narcolepsy
      with cataplexy. The data suggests that the pathophysiology and, by extension,
      etiology of this disorder are distinctly different from the other conditions
      studied. The relationship of the DQB1*0602 allele and reduced hypocretin-1 levels
      needs further study.

PMID- 12405610
TI  - Effects of age and sleeping position on arousal from sleep in preterm infants.
AB  - STUDY OBJECTIVES: Preterm infants are at increased risk of sudden infant death
      syndrome (SIDS). We investigated whether the prone sleeping position impaired
      arousal from sleep in healthy preterm infants and whether this impairment was
      related to cardiorespiratory variables, temperature or postnatal age. DESIGN:
      Longitudinal SETTING/PARTICIPANTS: 14 healthy preterm infants (mean 32 +/- 0.4
      weeks) were studied using daytime polysomnography on 4 occasions: 36-38 weeks
      postconception age, 2 to 3 weeks postterm, 2 to 3 months postterm, and 5 to 6
      months postterm. INTERVENTIONS: N/A. MEASUREMENTS: Multiple measurements of
      arousal threshold (cm H2O) in response to air-jet stimulation applied alternately
      to the nares were made in both active sleep and quiet sleep when infants slept
      both prone and supine. RESULTS: Arousal thresholds were significantly higher in
      both AS and QS when infants slept prone at 36 to 38 weeks postconception age and
      2 to 3 months postterm but not at 2 to 3 weeks or 5 to 6 months postterm. These
      increases were independent of any sleep position-related changes in either rectal
      or abdominal skin temperature, respiratory rate, oxygen saturation or heart rate.
      CONCLUSIONS: At the age when the risk of SIDS is highest, the prone position
      significantly impairs arousal from both active sleep and quiet sleep in healthy
      infants born prematurely. This impairment in arousability occurred with no
      clinically significant changes in cardiorespiratory parameters or body
      temperature. Decreased arousability from sleep in the prone position may explain
      its role as a risk factor for SIDS.

PMID- 12405611
TI  - Validation of a suprasternal pressure transducer for apnea classification during
      sleep.
AB  - STUDY OBJECTIVES: To validate a new method of evaluation of respiratory efforts
      during polysomnographic recordings. SETTING: NA PARTICIPANTS: 26 patients with
      sleep apnea syndrome, either during diagnostic assessment (n=16) or under nasal
      continuous positive airway pressure (n=10). METHODS: This method consists of
      measuring suprastemal pressure by a pressure transducer placed over the trachea
      above the sternal notch (Pst). It was compared to the reference method (ie,
      esophageal pressure) during the same polysomnogram. RESULTS: The analysis was
      based on 3,261 episodes of apnea, classified as obstructive in 2,556 cases, mixed
      in 347 cases, and central in 358 cases according to the esophageal pressure
      monitor. The concordance between the two methods was very good, with a
      sensitivity of Pst of 99.4% for the detection of apneas with respiratory efforts
      and a specificity of 93.6%. Twenty-three (6.4%) of the 358 central apneas were
      classified by Pst as apneas with respiratory efforts and 18 of the 353 central
      apneas classified by Pst were actually apneas with respiratory efforts on the
      esophageal pressure monitor. CONCLUSION: The suprasternal pressure transducer,
      which presents a good sensitivity and a good specificity for identification of
      respiratory efforts, can be used to classify apneas during polysomnographic
      recordings in clinical practice.

PMID- 12405612
TI  - Psychologic correlates of compliance with continuous positive airway pressure.
AB  - STUDY OBJECTIVES: To explore the relationship between psychologic variables
      measured prior to continuous positive airway pressure (CPAP) treatment and
      subsequent CPAP compliance. DESIGN: Participants were assigned to a CPAP
      treatment group. Psychologic questionnaires administered prior to the start of
      treatment assessed depression, anxiety, stress, anger or hostility, social
      support, social desirability, and coping. Polysomnography was performed on
      admission (prior to start of treatment) and at the end of 1 week of treatment.
      Compliance was measured nightly by an intemal clock counter in the CPAP unit and
      averaged over the 1-week treatment period. SETTING: N/A. PARTICIPANTS: Twenty
      three CPAP-naive patients with obstructive sleep apnea were enrolled in a study
      of the effects of CPAP on sympathetic nervous system functioning, quality of
      life, and psychologic functioning. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS:
      Objectively measured average daily compliance was significantly associated with a
      measure of coping strategies. Multiple regression analyses revealed that Active
      Ways of Coping accounted for a significant amount of variance in CPAP compliance,
      even after the respiratory disturbance index, daytime sleepiness, and Passive
      Ways of Coping were taken into account. No other psychologic variable assessed
      prior to CPAP treatment was associated with subsequent CPAP compliance.
      CONCLUSIONS: These results suggest that individuals who engage in active coping
      strategies with new and difficult situations used CPAP more. It may be that
      encouraging patients to use coping techniques, such as planful problem solving,
      will help to improve compliance with CPAP.

PMID- 12405613
TI  - Incorporation of pain in dreams of hospitalized burn victims.
AB  - It has been shown that realistic, localized painful sensations can be experienced
      in dreams either through direct incorporation or from past memories of pain.
      Nevertheless, the frequency of pain dreams in healthy subjects is low. This
      prospective study was designed to evaluate the occurrence and frequency of pain
      in the dreams of patients suffering from burn pain. Twenty-eight nonventilated
      burn victims were interviewed for 5 consecutive mornings during the first week of
      hospitalization. A structured-interview protocol was used to collect information
      on dream content, quality of sleep, and pain intensity and location. Patients
      were also administered the Impact of Event Scale to assess posttraumatic
      symptoms. Thirty-nine percent of patients reported 19 pain dreams on a total of
      63 dreams (30%). Patients with pain dreams showed evidence of worse sleep, more
      nightmares, higher intake of anxiolytic medication, and higher scores on the
      Impact of Event Scale than did patents reporting dreams with no pain content.
      Moreover, patients with pain dreams also had a tendency to report more intense
      pain during therapeutic procedures. Although more than half of our sample did not
      report pain dreams, these results suggest that pain dreams do occur at a greater
      frequency in suffering populations than in normal volunteers. More importantly,
      dreaming about pain may be an added stress for burn patents and may contribute to
      both poor sleep and higher pain intensity, which could evolve into a cycle of
      pain-anxiety-sleeplessness.

PMID- 12405614
TI  - Sleep in depressed and nondepressed participants with chronic low back pain:
      electroencephalographic and behaviour findings.
AB  - STUDY OBJECTIVES: To study the nature of sleep disturbance in depressed and
      nondepressed patients with chronic low back pain (CLBP). DESIGN: A controlled,
      consecutive 4-night polysomnographic study. PATIENTS: Participants were screened
      (psychologic, psychiatric, and physical) to determine their study group, and 21
      participants (CLBP: 4 depressed, 6 nondepressed and 11 controls) were studied.
      MEASUREMENTS AND RESULTS: On all nights, standard polysomnographic sleep measures
      as well as midline occipital and frontal electroencephalography and respiration
      were recorded on a Grass Model 7 polygraph. Pain, sleep quality, and depression
      were also measured. Participants with CLBP reported significant levels of pain
      and sleep disturbance as compared to controls, but all groups had equivalent
      amounts of sleep and comparable sleep architecture. The electroencephalographic
      power spectral analyses revealed significant differences, with controls having
      more sigma across sites, more low beta activity occipitally and frontally than
      nondepressed patients with CLBP, and more occipital sigma and less high beta
      activity than depressed participants. Between pain subgroups, the depressed
      participants showed more occipital delta, more occipital and central alpha, and
      more high beta activity across all sites than did the nondepressed participants.
      CONCLUSIONS: Lower sigma power in participants with CLBP suggests less-effective
      sensorimotor gating that may contribute to poor sleep quality. Pain subgroup
      differences underscore the need to consider the influence of depression in the
      evaluation of sleep in clinical populations. This study controlled for many
      factors other than pain that may contribute to the sleep complaints in this
      population. Consequently, the absence of signs of major sleep disturbance must
      not be interpreted as evidence of a lack of a true sleep problem in CLBP but more
      likely reflects control of these factors as well as the difficulty in measuring
      sleep quality.

PMID- 12405616
TI  - Noninvasive cardiovascular markers of acoustically induced arousal from non-rapid
      eye-movement sleep.
AB  - STUDY OBJECTIVES: Changes in cardiovascular measures such as heart rate (HR) and
      pulse transit time (PTT) have been advocated as sensitive markers of autonomic
      arousal from sleep. In animal studies, alerting stimuli produce particularly
      marked skin vascular responses. We hypothesized that changes in skin vascular
      conductance would provide more sensitive markers of autonomic arousal during
      sleep compared to central cardiovascular response measures such as HR and PTT.
      DESIGN: Cardiovascular responses to auditory-induced arousals were recorded
      during overnight sleep studies. SETTING: Sleep disorders unit in a 270-bed
      teaching hospital. PARTICIPANTS: Eleven young healthy male subjects.
      INTERVENTIONS: Throughout ovemight sleep studies, auditory tones (5-second
      duration, 54-90 decibels, 22-56 per subject) were presented during non-rapid-eye
      movement sleep. Beat-by-beat HR, PTT, laser-Doppler fingertip skin blood flow
      (SBF) and finger and ear photoplethysmogram pulse wave amplitudes (PWA) were
      measured in the 20 seconds preceding and 30 seconds following each tone and
      compared to control measurements obtained during 50-second periods of recording
      with no stimulus (no tone, 6-22 per subject). Electroencephalographic (EEG)
      arousals were scored according to standard criteria (American Sleep Disorders
      Association) into no discemible, 3- to 10-second duration, or 10- to 15-second
      duration arousals. Poststimulus cardiovascular measurements were expressed as a
      percentage of the prestimulus mean and response magnitudes quantified from peak
      responses and the area under the poststimulus response curve. The ability of each
      cardiovascular response measure to discriminate EEG arousals (EEG changes lasting
      more than 3 seconds) was assessed from the area under the receiver operating
      characteristic (ROC) curve. MEASUREMENTS AND RESULTS: There were no significant
      changes in any cardiovascular parameter during control recordings. In contrast to
      all other parameters, finger PWA and SBF decreased following tones that produced
      no discernible EEG arousal (P < 0.05). A significant HR rise and decreases in all
      cardiovascular measures occurred with greater than 3-second arousals, with longer
      duration arousals generally exhibiting larger responses. Conventional EEG
      arousals (greater than 3 seconds) were relatively poorly detected from HR
      responses (ROC area HR rise 0.80 +/- 0.04) compared to changes in SBF (0.85 +/-
      0.02), PTT (0.85 +/- 0.03) and finger PWA (0.90 +/- 0.01). CONCLUSIONS: Decreases
      in skin vascular conductance (finger PWA and SBF) provide sensitive markers of
      autonomic arousal during sleep. They are at least as sensitive as PTT for
      detecting conventionally scored EEG arousals and may be more sensitive in
      detecting "subcortical" arousals.

PMID- 12405617
TI  - Aspiration-related illnesses: definitions and diagnosis.
AB  - BACKGROUND: Aspiration is a leading cause of morbidity and mortality. It is the
      most common cause of pneumonia and one of the most serious adverse effects of
      enteral nutrition support. It is important to use standardized terminology to
      define and discuss aspiration-related illnesses. METHODS: Review of the medical
      literature and extraction of definitions and descriptions of aspiration-related
      illnesses. RESULTS: Definitions, clinical features, diagnosis, and treatment of
      common aspiration-related illnesses are discussed. CONCLUSIONS: Precisely defined
      terminology of aspiration-related illnesses adds consistency to this area of
      medicine and simplifies analysis and comparison of clinical studies.

PMID- 12405615
TI  - The impact of moderate sleep loss on neurophysiologic signals during working
      memory task performance.
AB  - STUDY OBJECTIVES: This study examined how sleep loss affects neurophysiologic
      signals related to attention and working memory. DESIGN: Subjective sleepiness,
      resting-state electroencephalogram, and behavior and electroencephalogram during
      performance of working-memory tasks were recorded in a within-subject, repeated
      measures design. SETTING: Data collection occurred in a computerized laboratory
      setting. PARTICIPANTS: Sixteen healthy adults (mean age, 26 years; 8 female)
      INTERVENTIONS: Data from alert daytime baseline tests were compared with data
      from tests during a late-night, extended-wakefulness session that spanned up to
      21 hours of sleep deprivation. MEASUREMENTS AND RESULTS: Alertness measured both
      subjectively and electrophysiologically decreased monotonically with increasing
      sleep deprivation. A lack of alertness-related changes in electroencephalographic
      measures of the overall mental effort exerted during task execution indicated
      that participants attempted to maintain high levels of performance throughout the
      late-night tests. Despite such continued effort, responses became slower, more
      variable, and more error prone within 1 hour after participants' normal time of
      sleep onset. This behavior failure was accompanied by significant degradation of
      event-related brain potentials related to the transient focusing of attention.
      CONCLUSIONS: Moderate sleep loss compromises the function of neural circuits
      critical to subsecond attention allocation during working-memory tasks, even when
      an effort is made to maintain wakefulness and performance. Multivariate analyses
      indicate that combinations of working-memory-related behavior and
      neurophysiologic measures can be sensitive enough to permit reliable detection of
      such effects of sleep loss in individuals. Similar methods might prove useful for
      assessment of functional alertness in patients with sleep disorders.

PMID- 12405618
TI  - Physiology of the aerodigestive system and aberrations in that system resulting
      in aspiration.
AB  - BACKGROUND: Aspiration pneumonia remains a significant and often devastating
      problem in critically ill patients. It is unclear whether aspiration pneumonia
      occurs because of problems in the handling of oropharyngeal secretions or if the
      reflux of gastric contents is the major etiological factor. Additionally, the
      obvious breakdown of upper aerodigestive protective mechanisms in the critically
      ill patient population is largely unstudied. Finally, the impact and contribution
      of tubes, both endotracheal and nasoenteral, on aspiration pneumonia is unclear.
      METHODS: A Medline literature search on scientific and review articles concerning
      the normal physiology of the aerodigestive tract and factors that compromised
      normal physiology was undertaken. Readings were supplemented by expert outside
      opinion from researchers in these fields and from the combined expertise from a
      multidisciplinary panel of experts assembled at a recent summit on aspiration
      pneumonia. RESULTS: Changes in the normal physiology of the aerodigestive tract
      are vast and varied and dependent on the response to injury, iatrogenic
      interventions, and the use of nasoenteral and endotracheal tubes. The effects on
      gastric and esophageal motility are likely dynamic and represent an ongoing but
      changing risk of reflux for the patient. Nasoenteral and endotracheal tubes
      likely compromise upper aerodigestive protective mechanisms. CONCLUSIONS: More
      research is needed on the functioning of the aerodigestive protective mechanisms
      in critically ill patients. Understanding of the dynamic changes in
      gastrointestinal motility will also be an important factor to decrease the
      incidence of aspiration pneumonia in this patient population.

PMID- 12405619
TI  - Aspiration pneumonia: incidence, mortality, and at-risk populations.
AB  - Pulmonary aspiration in the hospitalized patient can be devastating. Most
      aspiration events occur in patients with a swallowing disorder. Aspiration can be
      divided into 3 separate etiologies: oropharyngeal bacteria, particulate matter,
      and acidified gastric contents. Reported prevalence data are extremely variable,
      ranging from 10% to 70%. Mortality is related to the volume and content of the
      aspirate and is reported to be as high as 70%. Neurologic dysfunction, decreased
      consciousness, advancing age, gastroesophageal reflux, and tube feeding are all
      potential risk factors for the development of aspiration.

PMID- 12405620
TI  - Risk factors for aspiration.
AB  - BACKGROUND: There are numerous risk factors for aspiration in tube-fed critically
      ill patients. However, there is confusion about the extent to which these factors
      actually contribute to aspiration. The purpose of this literature review was to
      summarize findings from selected research studies. METHODS: A nonexhaustive
      literature search was conducted to identify risk factors for aspiration in tube
      fed, critically ill patients. The most commonly cited factors were decreased
      level of consciousness, supine position, presence of a nasogastric tube, tracheal
      intubation and mechanical ventilation, bolus or intermittent feeding delivery
      methods, high-risk disease and injury conditions, and advanced age. RESULTS: Many
      studies of aspiration risk factors have relatively small sample sizes and used
      equivocal definitions of aspiration. Although some addressed aspiration as an
      outcome, others considered gastroesophageal reflux or pneumonia as outcomes.
      Despite these variations, authors almost uniformly agree that a decreased level
      of consciousness and a sustained supine position are major risk factors for
      aspiration. There is less agreement regarding the effect of a nasogastric tube
      (or its size) on aspiration and on the effect of various formula delivery
      methods. CONCLUSIONS: A decreased level of consciousness is a major risk factor
      for aspiration, as is a sustained supine position. Although some authors favor
      using small-bore feeding tubes to prevent aspiration, there seems to be
      insufficient data to warrant this action. Although strong data are lacking
      regarding feeding delivery methods, there are more data to support continuous
      feedings than bolus/intermittent feedings in high-risk patients.

PMID- 12405621
TI  - Detection of aspiration in enterally fed patients: a requiem for bedside monitors
      of aspiration.
AB  - BACKGROUND: Pulmonary aspiration of gastric and oropharyngeal contents is common
      in enterally fed patients. Detection of early aspiration in these patients has
      relied on clinical impression, the coloring of enteral feedings with dyes, and
      less commonly the detection of elevated glucose in tracheal aspirates. The
      potential benefits, risks, and clinical use of bedside monitors of aspiration are
      under increasing scrutiny. METHODS: Literature review. Although this review
      reflects the opinions of the authors, recommendations of an expert consensus
      panel (North American Summit on Aspiration, which included one author, J. P.
      Maloney) were also used to guide recommendations. The specific recommendations of
      that panel are presented elsewhere. RESULTS: No large prospective clinical trials
      have been done to evaluate the use and safety of bedside monitors for aspiration.
      Clinical impression remains a poor "gold standard" of aspiration diagnosis in
      enterally fed patients. The coloring of enteral feedings with blue dyes (chiefly
      FD&C Blue No.1) is ubiquitous in hospitals despite evidence that it is not
      sensitive and potentially harmful. Cases of absorption of blue dye from enteral
      feedings in patients with critical illness have raised concern about the safety
      of the blue dye method, particularly in light of apparent toxic effects of these
      dyes on mitochondria. The glucose detection method has not been embraced; it too
      has little use and is labor intensive. CONCLUSIONS: Use of colored dyes in
      enteral feedings and glucose detection methods should be abandoned. Nonrecumbent
      positioning is an evidenced-based method for aspiration prevention that needs to
      be re-emphasized. Novel bedside methods of detecting early aspiration are needed
      to supplement preventative strategies.

PMID- 12405622
TI  - Clinical use of gastric residual volumes as a monitor for patients on enteral
      tube feeding.
AB  - BACKGROUND: The use of gastric residual volumes (GRVs) as a clinical monitor for
      patients receiving enteral tube feeding (ETF) is based on presumptions that are
      not physiologically sound and practice that is poorly standardized. METHODS: This
      systematic review of the medical literature summarizes results from studies that
      evaluate the practice, interpretation, and impact on patient outcome from use of
      GRV. RESULTS: Little data exist to support a correlation of GRV with gastric
      emptying, volume of gastric contents, or changes in the infusion of ETF. GRVs do
      not correlate to regurgitation or aspiration, and their use cannot be relied on
      to protect patients against aspiration pneumonia. Although recent reports suggest
      that elevated GRVs correlate to "intolerance" of ETF, use as a marker of
      impending clinical deterioration is limited by the fact that the timing of
      increases in GRV is unpredictable and high GRVs do not correlate independently to
      adverse outcome. The practice of GRV may in fact impede delivery of ETF by
      promoting inappropriate cessation and reducing potential infusion time.
      CONCLUSIONS: Modifying interpretation and the response by healthcare providers to
      GRV data are needed to preserve any clinical use for this practice.

PMID- 12405623
TI  - Optimizing the benefits and minimizing the risks of enteral nutrition in the
      critically ill: role of small bowel feeding.
AB  - BACKGROUND: Strategies that maximize the delivery of enteral nutrition while
      minimizing the associated risks have the potential to improve the outcomes of
      critically ill patients. By delivering enteral feeds in the small bowel, beyond
      the pylorus, the frequency of regurgitation and the risk of aspiration is thought
      to be decreased while at the same time, nutrient delivery is maximized. The
      purpose of this paper is to systematically review those studies that compare
      gastric with small bowel feeding. METHODS: We searched computerized bibliographic
      databases, personal files, and relevant reference lists to identify eligible
      studies. Only randomized, clinical trials of critically ill patients that
      compared small bowel and gastric feedings were included in this review. In an
      independent fashion, relevant data on the methodology and outcomes of primary
      studies were abstracted in duplicate. RESULTS: There were 10 studies that met the
      inclusion criteria for this review. In 1 study, small bowel feeding was
      associated with a reduction in gastroesophageal regurgitation and a trend toward
      reduced pulmonary aspiration. Several studies document that small bowel feeding
      was associated with an increase in protein and calories delivered and a shorter
      time to target dose of nutrition. Compared with gastric feeding, when the results
      of 7 randomized trials were aggregated statistically, small bowel feeding was
      associated with a reduction in pneumonia (relative risk, 0.76; 95% confidence
      intervals, 0.59, 0.99). There was no difference in mortality rates between the 2
      groups. CONCLUSIONS: Small bowel feeding may be associated with a reduction in
      gastroesophageal regurgitation, an increase in nutrient delivery, a shorter time
      to achieve desired target nutrition, and a lower rate of ventilator-associated
      pneumonia.

PMID- 12405624
TI  - Methods for decreasing risk of aspiration pneumonia in critically ill patients.
AB  - BACKGROUND: Pneumonia is a significant clinical concern in critically ill
      hospitalized patients, leading to increase in the use of antibiotics, length of
      hospital stay, and the risk of mortality. Pneumonia caused by aspiration of
      gastric contents is of particular concern in patients who need mechanical
      ventilation and feeding through a nasogastric tube. Therefore, methods for
      decreasing the risk of aspiration are very important. METHODS: This review
      article summarizes factors that might influence the development of aspiration
      pneumonia, such as the position of the patient's body or type of hospital bed,
      methods of feeding, medications administered, suctioning of subglottic
      secretions, and bacterial decontamination. RESULTS: Elevating the head of the bed
      (45 degrees), continuous subglottic suctioning, and oral decontamination seem to
      be effective in the prevention of aspiration pneumonia.

PMID- 12405625
TI  - When is the seriously ill patient ready to be fed?
AB  - BACKGROUND: After assessing the critically ill patient for risk of aspiration,
      the clinician still must decide if the patient is ready to be fed. The goal is to
      identify critically ill patients who are likely to tolerate enteral nutrition and
      attempt to minimize complications. METHODS: A synthesis of the both clinical and
      animal studies to identify factors related to patient readiness for enteral
      nutrition. RESULTS: The key issue to be resolved is adequacy of resuscitation and
      restoration of mesenteric perfusion. Currently, there is no reliable clinical
      tool to measure gut perfusion. The best indicators currently are stabilization of
      vital signs, decreasing fluid and blood requirements, normalization of the base
      deficit, and lactate and removal of inotropic or vasopressor support.
      CONCLUSIONS: Most critically ill patients should be ready for enteral nutrition
      within 24 to 48 hours of intensive care unit admission. Critically ill patients
      who need catecholamine support, heavy sedation, or therapeutic neuromuscular
      blockade should probably not receive enteral nutrition until they have been
      stabilized.

PMID- 12405626
TI  - Treatment of aspiration in intensive care unit patients.
AB  - BACKGROUND: Aspiration is a common event, but the clinical consequences are
      variable. The primary determinants are the nature of the aspirated material and
      the host response to it. The purpose of this paper is to present treatment
      algorithms that should be employed in critically ill patients who experience
      aspiration. METHODS: Expert review of the available literature was done to
      provide background information to support the logic of 3 treatment algorithms:
      (1) treatment of acute aspiration pneumonitis; (2) pulmonary care for acute
      aspiration; and (3) treatment of aspiration pneumonia. RESULTS: The discussion of
      aspirations is separated into 2 clinical scenarios: (1) aspiration pneumonitis
      (sterile inflammation) versus (2) aspiration pneumonia (an infectious process).
      Aspiration pneumonitis should be treated by aggressive pulmonary care to enhance
      lung volume and clear secretions. Intubation should be used selectively. Early
      corticosteroids and prophylactic antibiotics are not indicated. Treatment of
      aspiration pneumonia requires diligent surveillance for the clinical signs of
      pneumonia. Treatment decisions are based on 3 factors: (1) clinical diagnostic
      certainly (definite versus probable), (2) time of onset [early (< 5 days) versus
      late (> or = 5 days)], and (3) host factors (high risk versus low risk). There is
      no ideal antibiotic regimen. Unit-specific resistance patterns and known
      frequency pathogens should direct broad spectrum empiric therapy. Invasive
      diagnostic techniques (such as bronchoalveolar lavage) should be used when the
      diagnosis is not certain. Antibiotic coverage should be narrowed once sputum
      culture results become available. CONCLUSIONS: Aspiration is common in critically
      ill patients and should be aggressively treated by these treatment algorithms.

PMID- 12405627
TI  - Future considerations in aspiration pneumonia in the critically ill patient: what
      is not known, areas for future research, and experimental methods.
AB  - The medical literature supports the use of enteral feeding to provide nutrition
      and improve patient outcomes. A major complication of enteral feeding is
      aspiration and associated morbidity and mortality. Many knowledge gaps exist that
      inhibit our ability to define and diagnose aspiration, identify patients at risk,
      and develop prevention techniques. Several areas of inquiry should be explored to
      help us define and prevent the disorder--for instance, standardized criteria
      should be developed for diagnosing aspiration pneumonia and for differentiating
      it from other types of pneumonia, and accurate tests should be devised for
      detecting it. Research also is needed to evaluate the influence of (1) various
      enteral feeding sites on aspiration risk, (2) the effects of risk reduction
      techniques such as selective decontamination and use of promotility agents, and
      (3) potential benefits of immunonutrition. Current parameters used in decisions
      about when to initiate enteral feeding in critically ill patients are defined.

PMID- 12405628
TI  - North American Summit on Aspiration in the Critically Ill Patient: consensus
      statement.
AB  - Aspiration is the leading cause of pneumonia in the intensive care unit and the
      most serious complication of enteral tube feeding (ETF). Although aspiration is
      common, the clinical consequences are variable because of differences in nature
      of the aspirated material and individual host responses. A number of defense
      mechanisms normally present in the upper aerodigestive system that protect
      against aspiration become compromised by clinical events that occur frequently in
      the critical care setting, subjecting the patient to increased risk. The true
      incidence of aspiration has been difficult to determine in the past because of
      vague definitions, poor assessment monitors, and varying levels of clinical
      recognition. Standardization of terminology is an important step in helping to
      define the problem, design appropriate research studies, and develop strategies
      to reduce risk. Traditional clinical monitors of glucose oxidase strips and blue
      food coloring (BFC) should no longer be used. A modified approach to use of
      gastric residual volumes and identification of clinical factors that predispose
      to aspiration allow for risk stratification and an algorhythm approach to the
      management of the critically ill patient on ETF. Although the patient with
      confirmed aspiration should be monitored for clinical consequences and receive
      supportive pulmonary care, ETF may be continued when accompanied by appropriate
      steps to reduce risk of further aspiration. Management strategies for treating
      aspiration pneumonia are based on degree of diagnostic certainty, time of onset,
      and host factors.

PMID- 12405629
TI  - Q and A part 1.

PMID- 12405630
TI  - Citation etiquette in biomedical publications: false claim of "first reported
      case".

PMID- 12405631
TI  - Barrier facilities for transgenic rodents in academic centers--a two-edged sword.

PMID- 12405632
TI  - The mouse as a model for investigation of human granulocytic ehrlichiosis:
      current knowledge and future directions.
AB  - The use of laboratory mice to investigate correlates of infectious disease,
      including infection kinetics, cellular alterations, cytokine profiles, and immune
      response in the context of an intact host has expanded exponentially in the last
      decade. A marked increase in the availability of transgenic mice and research
      tools developed specifically for the mouse parallels and enhances this research.
      Human granulocytic ehrlichiosis (HGE) is an emerging, zoonotic disease caused by
      tick-borne bacteria. The HGE agent (Anaplasma phagocytophila) is one of two
      recognized pathogens to cause human granulocytic ehrlichiosis (HGE). The mouse
      model of HGE complements in vitro tissue culture studies, limited in vivo large
      animal studies, and ex vivo studies of human and ruminant neutrophils, and
      promises new avenues to approach mechanisms of disease. In the overview reported
      here, we focus principally on current research into HGE pathogenesis using the
      mouse model. Included is a discussion of current changes in ehrlichial
      classification and nomenclature, a review of ehrlichial biology and ecology, and
      highlights of clinical disease in animals and people.

PMID- 12405633
TI  - Assessment of genetic management at three specific-pathogen-free rhesus macaque
      (Macaca mulatta) colonies.
AB  - Genetic management is required to maintain genetic diversity by minimizing
      inbreeding and genetic subdivision in colonies of animals bred for biomedical
      research. Polymorphic short tandem repeat (STR) loci are useful for genetic
      management because they facilitate parentage assignments, genetic
      characterization of individuals, and estimates of baseline population genetic
      parameters. Using highly informative STR loci, we estimated gene diversity and F
      statistics to determine the level of genetic heterogeneity and genetic structure
      of three specific-pathogen-free (SPF) rhesus macaque (Macaca mulatta) colonies.
      Effective population sizes, variance in male reproductive success, and rate of
      decrease in genetic variability also were estimated for two of the three
      colonies. We documented the overall success of genetic management in maintaining
      genetic diversity in captive colonies. We report that even genetically managed
      SPF colonies, despite maintaining high and stable levels of gene diversity (over
      0.75), are prone to genetic subdivision due to different management strategies,
      founder effects, genetic isolation, and drift. These processes are accelerated by
      the high variances in male reproductive success and low adult sex ratios that are
      typical of captive rhesus macaque breeding groups, both of which reduce the
      effective population sizes of these groups.

PMID- 12405634
TI  - Relationship of canine bispectral index to multiples of sevoflurane minimal
      alveolar concentration, using patch or subdermal electrodes.
AB  - PURPOSE: The purpose of the study reported here was to determine the relationship
      of bispectral index (BIS) to multiples of sevoflurane minimal alveolar
      concentration (MAC), using proprietary patch or subdermal needle electrodes in
      dogs. METHODS: Eight English Pointers (4 males, 4 females; mean +/- SD age and
      body weight of 3.9+/-2.2 years and 20.7+/-4.1 kg, respectively) were studied.
      Sevoflurane MAC was determined in each dog, using the standard tail clamp
      technique. One week later, BIS was determined in each dog at 0.8, 1.0, 1.5, and
      2.0 MAC multiples of sevoflurane, using proprietary patch electrodes and 29-gauge
      platinum needle electrodes applied in randomized order. Ventilation was
      controlled, and atracurium (0.2 mg/kg of body weight, followed by 6
      microg/kg/min, i.v.) was administered to eliminate the electromyographic artifact
      from the electroencephalogram. The BIS was determined, using an A-2000 BIS
      monitor connected to a computer for data logging at five-second intervals. After
      a 15-min equilibration period at each sevoflurane MAC-multiple, BIS data were
      collected for five minutes, and median BIS values were calculated. Heart rate,
      direct mean arterial blood pressure, esophageal temperature, and arterial pH and
      blood gas tensions were measured immediately after each BIS collection period.
      End-tidal CO2 and sevoflurane concentrations were continuously monitored, using
      an infrared gas analyzer. Data were analyzed, using one-way repeated measures
      analysis of variance (P < 0.05). Agreement of BIS values from each electrode type
      was determined. RESULTS: Mean +/- SD sevoflurane MAC was 2.1 +/- 0.3%. Mean +/-
      SD BIS values at 0.8, 1.0, 1.5, and 2.0 MAC were 77 +/- 3, 73 +/- 5, 57 +/- 7,
      and 53 +/- 7, respectively, for patch electrodes and 80 +/- 6, 72 +/- 7, 56 +/-
      4, and 50 +/- 5, respectively, for subdermal needle electrodes. At 2 MAC, BIS
      could not be determined in six dogs due to presence of burst suppression in the
      EEG. The regression equation comparing electrodes was: BIS (subdermal) = -5.5 +
      (1.1 x BIS [patch]); R2= 0.846; bias = -0.192, with a 95% confidence interval of 
      9.96 to 9.56. Of the other measured variables, none were significantly different
      between electrode types. Within each group of electrode type, MAP was
      significantly different among MAC multiples. Within the patch electrode group,
      PaO2, bicarbonate concentration, and base excess were significantly different
      among MAC multiples. CONCLUSIONS: Bispectral index significantly decreased with
      increasing sevoflurane MAC multiples over the range of 0.8 to 2.0 MAC, using
      patch or subdermal electrodes in dogs. Use of subdermal needle electrodes is a
      reliable and practical alternative to use of patch electrodes for measurement of
      BIS in dogs.

PMID- 12405635
TI  - Influence of bedding type on mucosal immune responses.
AB  - The mucosal immune system interacts with the external environment. In the study
      reported here, we found that bedding materials can influence the intestinal
      immune responses of mice. We observed that mice housed on wood, compared with
      cotton bedding, had increased numbers of Peyer's patches (PP) visible under a
      dissecting microscope. In addition, culture of lymphoid organs revealed increased
      production of total and virus-specific IgA by PP and mesenteric lymph node (MLN)
      lymphocytes from mice housed on wood, compared with cotton bedding. However,
      bedding type did not influence serum virus-specific antibody responses. These
      observations indicate that bedding type influences the intestinal immune system
      and suggest that this issue should be considered by mucosal immunologists and
      personnel at animal care facilities.

PMID- 12405636
TI  - Magnetic resonance imaging assessment of a murine model of recessive polycystic
      kidney disease.
AB  - PURPOSE: The pathogenesis of polycystic kidney disease (PKD) has not been firmly
      established; however, our current knowledge of cystogenesis and human cystic
      disease has been greatly advanced by a variety of animal models of PKD. To study
      the onset and degree of cyst formation in PKD mouse models without requiring
      sacrifice of these animals, we have initiated magnetic resonance imaging (MRI)
      studies of the juvenile cystic kidney (jck) mouse model. METHODS: The MRI
      experiments were performed by use of a Bruker 8.5 T system, on seven-week-old
      mice that were homozygous for the recessive jck mutation and that manifested PKD.
      Kidney volume was measured, using three-dimensional segmentation postprocessing
      techniques. RESULTS: The MR images of the enlarged kidneys from affected mice had
      regions of high signal intensity, with a radial distribution, which reflected the
      dilated collecting ducts observed in the corresponding histologic slices. The
      volume of PKD-affected kidney was about 4 times greater than that of the normal
      kidney. CONCLUSIONS: Magnetic resonance imaging has the ability to non-invasively
      assess cystic disease in mouse models of PKD. Of considerable importance is the
      opportunity to characterize this disease without sacrificing the animal. The
      three-dimensional MRI segmentation method provides accurate calculation of renal
      volume.

PMID- 12405637
TI  - Comparison of an espB gene fecal polymerase chain reaction assay with
      bacteriologic isolation for detection of Citrobacter rodentium infection in mice.
AB  - PURPOSE: To develop a polymerase chain reaction (PCR) assay for specific
      detection of Citrobacter rodentium in fecal samples of mice and to compare this
      assay with bacterial isolation and identification methods. METHODS: The target
      sequence of the PCR assay was the espB gene encoding a secreted virulence factor.
      To facilitate visual identification during primary isolation on MacConkey agar
      containing ampicillin, C. rodentium ATCC type strain 51459 was transformed by use
      of a plasmid encoding the enhanced green fluorescent protein (EGFP) and
      ampicillin resistance. The EGFP-C. rodentium was inoculated into Swiss Webster
      (SW) mice to study the time course of detection of the organism by use of fecal
      PCR analysis, bacterial isolation, and development of colonic hyperplasia by
      light microscopy. Lactose-fermenting fluorescent bacterial colonies identified
      during primary isolation of fecal bacteria on MacConkey-ampicillin agar were
      identified by use of biochemical typing. RESULTS: Mice inoculated with EGFP
      transformed C. rodentium developed colonic mucosal hyperplasia, characterized by
      a three-fold increase in colonic crypt height that peaked at post-inoculation day
      (PID) 14. The espB PCR assay detected as little as 0.3 colony-forming units of C.
      rodentium. The PCR assay was specific in that it did not detect the espB gene of
      Escherichia coli 0157. Results of in vivo studies in SW mice indicated that EGFP
      C. rodentium could be detected by use of espB fecal PCR analysis in 100% of
      inoculated mice tested on PID 1, 3, 7, and 8, in 60% on PID 9, and in 20% on PID
      10 (n = 5). Bacterial isolation from the same fecal samples detected the organism
      in 100% of the inoculated mice on PID 7, in 50% on PID 8, and in none on
      subsequent PID 9-14. The ability of the PCR assay to detect C. rodentium in fresh
      feces of inoculated mice was significantly better than that of bacterial
      isolation methods (Fisher-Irwin exact test, P < 0.01). At the time of peak
      colonic hyperplasia, the organism could no longer be cultivated or detected in
      mice by use of fecal PCR analysis. CONCLUSIONS: The EGFP-C. rodentium was capable
      of inducing transmissible murine colonic hyperplasia similar to that previously
      reported in SW mice. The PCR assay for detection of the espB gene sequence of C.
      rodentium in total fecal DNA was a more sensitive diagnostic assay than was
      bacterial isolation.

PMID- 12405638
TI  - Safe and efficient methods of autologous hematopoietic stem cell transplantation
      for biomedical research in cynomolgus monkeys.
AB  - We have established safe and efficient methods for autologous hematopoietic stem
      cell (HSC) transplantation in cynomolgus monkeys (Macaca fascicularis) that
      include regimens of supportive care to ensure survival during hematopoietic
      reconstitution following otherwise lethal total body irradiation. Eleven young
      adult cynomolgus monkeys were studied. Bone marrow was aspirated from the ilium
      and/or tuber ischiae after administration of recombinant human stem cell factor
      (SCF) and granulocyte colony-stimulating factor (G-CSF). Using the immunomagnetic
      selection method, CD34+ cells were then isolated (90 to 95% pure) as a fraction
      containing HSCs. Just prior to transplantation, the animals received
      myeloablative total body irradiation-500 to 550 cGy daily for two days. The
      monkeys re-infused with CD34+ cells developed moderate to severe
      myelosuppression, with some animals requiring intravenous hyperalimentation,
      antibiotic administration, and blood transfusion. Hematopoiesis was restored in
      all animals after transplantation. It took 12 days, on average, until the
      peripheral white blood cell count reached more than 1,000 cells/microl. Up to two
      years after transplantation, signs of radiation-induced pneumonitis or other
      radiation-related disorders were not evident at the aforementioned dose of
      irradiation. This transplantation model will be useful for testing new approaches
      using HSCs for therapy of many diseases and will offer unique insights into the
      biology of these cells.

PMID- 12405639
TI  - Use of perphenazine to control cannibalism in DBA/1 mice.
AB  - Maternal administration of perphenazine decreased the incidence of cannibalism in
      colonies of interferon-gamma, interleukin (IL-4, IL-10, and IL-12) knockout mice
      of the DBA/1 and C57BL/6 background strains. This colony had high incidence of
      neonatal death due to cannibalism in approximately 50% of the pups. Perphenazine
      was administered to the dams in the drinking water, beginning on the day before
      or the morning of parturition. The medicated water was supplied at two dosages:
      0.5 mg/ml and 0.025 mg/ml, resulting in a dosage of 4 mg/kg of body weight and 2
      mg/kg, respectively, to the dams. Dams that were treated with perphenazine weaned
      76.4% of their pups, compared with nontreated dams that weaned only 59.4% of
      their pups. Timing of the administration of perphenazine did not have a
      significant impact on efficacy; also, both doses were equally effective at
      preventing cannibalism. These findings indicate that perphenazine can modify poor
      maternal behavior such as cannibalism, resulting in more efficient production of
      valuable knockout mice.

PMID- 12405640
TI  - Use of TaqMan reverse transcriptase-polymerase chain reaction analysis and
      serologic testing to eliminate an enzootic infection of mouse hepatitis virus.
AB  - Elimination of an enzootic infection of mouse hepatitis virus (MHV) from a large
      population of genetically engineered mice was accomplished by selecting
      seropositive, non-infective breeders for a newly restored MHV-free breeding
      colony. An ELISA was used to test for the presence of MHV-specific antibody, and
      TaqMan reverse transcriptase-polymerase chain reaction (RT-PCR) analysis was used
      to detect MHV in the feces. After 10 weeks of intentional exposure, approximately
      30% of mice with MHV antibodies continued to shed MHV in the feces. A natural
      transmission study was conducted to validate that positive fecal RT-PCR results
      indicated presence of infective virus. Sentinel results from the re-instituted
      breeding colony indicated that MHV was successfully eliminated by use of RT-PCR
      analysis for selection of non-infective mice.

PMID- 12405641
TI  - Early weaning and culling eradicated Helicobacter hepaticus from an
      acetylcholinesterase knockout 129S6/SvEvTac mouse colony.
AB  - The finding of Helicobacter hepaticus infection in our acetylcholinesterase
      (AChE) knockout mouse colony led to a search for a treatment. One-hundred percent
      of AChE +/+, 100% of AChE +/-, and 35% of AChE -/- mice tested positive. The
      lower infection rate in AChE -/- mice, who are routinely weaned on day 15,
      suggested that early weaning might be an effective eradication strategy. The AChE
      +/+ and +/- mice were weaned on days 13, 14, 15, or 16. Litters were placed in
      sterile, heated, isolator cages. Animals were fed liquid Ensure Fiber and 11% fat
      pelleted diet. Feces were tested for the presence of H. hepaticus by use of DNA
      amplification. Litters weaned on days 14, 15, or 16 had a high rate (68, 63, and
      100%, respectively), whereas litters weaned on day 13 had a lower (8%) rate of
      infection. Uninfected animals have remained free of H. hepaticus through day 120.
      Pups weaned on day 13 lost body weight, beginning on day 14, but recovered by day
      16. It is concluded that the non-coprophagic behavior of AChE -/- mice accounts
      for a low infection rate and that the combination of early weaning, routine
      testing, and culling provide an effective method for eradication of H. hepaticus.

PMID- 12405642
TI  - Comparative efficacy of a canine distemper-measles and a standard measles vaccine
      for immunization of rhesus macaques (Macaca mulatta).
AB  - Measles virus (MV), a highly infective paramyxovirus, has caused sporadic
      epizootics characterized by high morbidity and increased mortality in nonhuman
      primates. Measles vaccines for human use, although effective, are cost
      prohibitive for use in primate colonies. We compared the efficacy of one or two
      doses of Vanguard D-M, a canine distemper-measles (CD-M) vaccine, with a single
      dose of Attenuvax, a human measles vaccine. Compared with 81% of animals
      inoculated with Attenuvax, all animals inoculated with one or two doses of
      Vanguard developed detectable MV antibodies. One year after immunization, six
      juveniles from each vaccine group, along with three unvaccinated controls, were
      challenged with pathogenic MV and were monitored for clinical signs of disease,
      viremia, viral shedding, and immune response. All uninoculated controls developed
      clinical disease and viremia, and shed virus in nasopharangeal secretions.
      Subclinical viremia without viral shedding was identified in two Attenuvax- and
      two single-dose Vanguard-inoculated animals. Viremia was not detected in any two
      dose Vanguard-inoculated animals. Significantly higher neutralization antibody
      titers were observed in animals receiving Vanguard. Results of this study
      indicate that Vanguard is at least as efficacious as Attenuvax for protection of
      rhesus macaques. The considerably lower cost of Vanguard makes vaccination
      against measles in large breeding colonies economically feasible.

PMID- 12405643
TI  - Rhoads Lecture. Heat and life: the ongoing scientific odyssey.
AB  - The source of body heat has fascinated philosophers and scientists for millennia.
      Resting heat production is a major component of human energy requirements in
      health and disease. This review traces through mankind's attempts to understand
      the nature of resting heat production in humans and animals and its relationships
      to body mass and composition. Far from being fully understood, the study of heat
      production is an area of intense research interest bridging the gap between
      modern biology and physics.

PMID- 12405644
TI  - 2002 Harry M. Vars Research Award. Keratinocyte growth factor stimulates the
      recovery of epithelial structure and function in a mouse model of total
      parenteral nutrition.
AB  - BACKGROUND: Keratinocyte growth factor (KGF) increases intestinal growth and is
      expressed by intestinal intraepithelial lymphocytes (IEL). Because total
      parenteral nutrition (TPN) leads to villus atrophy and a loss of epithelial
      function, we hypothesized that KGF administration could reverse these changes.
      METHODS: Mice were randomized into three groups: oral feeding (Control); TPN; or
      TPN with recombinant human KGF. Mice were killed at 7 days, and the small bowel
      was harvested for histology, DNA, and protein content analysis. Epithelial cell
      proliferation was studied by 5-bromo-2-deoxyuridine (BrdU) incorporation, and
      apoptosis was detected by flow cytometry with Annexin V staining. Epithelial ion
      transport function was studied by Ussing chambers. Epithelial barrier function
      was assessed with transepithelial resistance and transmural passage of 3H
      mannitol. Epithelial KGF receptors expression was studied by using reverse
      transcriptase-polymerase chain reaction (RT-PCR) and Western blot. RESULTS: TPN
      decreased intestinal DNA, protein content, villus height, and crypt cell
      proliferation. TPN also resulted in an increase in epithelial cell apoptosis. KGF
      administration significantly stimulated the recovery of mucosal structures
      including intestinal protein and DNA content, villus height, and crypt cell
      proliferation, and decreased epithelial apoptosis. KGF also up-regulate the
      epithelial KGF receptor expression. Moreover, KGF attenuated the TPN-induced
      increase in ion transport and increased the epithelial barrier function.
      CONCLUSIONS: KGF administration reversed many of the adverse epithelial changes
      associated with TPN administration. Additionally, KGF up-regulated epithelial KGF
      receptor expression. It is possible that KGF may have a therapeutic efficacy in
      patients who are receiving TPN.

PMID- 12405645
TI  - Glutamine supplementation fails to affect muscle protein kinetics in critically
      ill patients.
AB  - BACKGROUND: In vitro work suggests that glutamine availability may be an
      important factor in controlling the rate of muscle protein synthesis. The
      objective of this study was to determine if enteral administration of glutamine
      affects muscle protein metabolism in critically ill patients. METHODS: Six
      postsurgical patients requiring prolonged mechanical ventilation for pneumonia
      (age, 51 +/- 12 years, Acute Physiology and Chronic Health Evaluation [APACHE] 22
      +/- 6, mean +/- SEM) and 6 normal healthy volunteers (age, 33 +/- 4 years)
      underwent evaluation of whole body and muscle protein metabolism using an 8-hour
      infusion of d5-phenylalanine, 5(15)N glutamine, and d3-alanine with serial blood
      sampling from the femoral artery and vein and biopsies from the vastus lateralis
      muscle. Metabolic measurements were obtained while subjects received Peptamen
      enterally (Basal Period) and with glutamine supplementation (24 g/3 h; Glutamine
      Period). RESULTS: Glutamine concentration in muscle was significantly less in the
      critically ill patients. Glutamine supplementation increased the arterial plasma
      concentration of glutamine, yet with no demonstratable effect on muscle glutamine
      concentration or on the rate of muscle protein synthesis in either volunteers or
      patients. Furthermore, muscle glutamine kinetics (incorporation into muscle,
      release from muscle, and rate of de novo glutamine synthesis in muscle) were not
      affected by glutamine supplementation in the critically ill patients. In
      contrast, there was a significant decrease in these kinetic parameters with
      glutamine supplementation within the muscle of healthy subjects. Metabolism of
      alanine was unaffected by administration of glutamine in either group.
      CONCLUSIONS: Enteral glutamine supplementation to critically ill patients fails
      to alter muscle glutamine metabolism or muscle protein synthesis. This suggests a
      possible restriction in transport of glutamine into muscle of critically ill
      patients.

PMID- 12405646
TI  - Omega-3 fatty acid supplementation increases anti-inflammatory cytokines and
      attenuates systemic disease sequelae in experimental pancreatitis.
AB  - BACKGROUND: The cytokines involved in the systemic inflammatory response in acute
      pancreatitis (AP) comprise lipid mediators (eg, prostanoids, thromboxanes,
      leukotrienes) generated from arachidonic acid (AA) and eicosapentaenoic acid
      (EPA). The AA-derived mediators are generated from omega-6-fatty acid (FA) and
      have strong proinflammatory effects and the EPA-derived mediators generated from
      omega-3-fatty acid are less active or even exhibit anti-inflammatory effects.
      Basic parenteral nutrition delivers omega-6-FA and omega-3-FA at a ratio of
      approximately 7:1. AIM: To investigate whether altering the FA composition by
      fish oil supplementation (omega-3-FA) affects cytokine production and the
      parameters reflecting systemic disease severity in experimental AP. METHODS:
      Severe AP was induced in 30 rats by standardized intraductal infusion of bile
      salt and IV cerulein. Six hours after AP induction, rats were randomized to TPN
      using commercial solutions with identical amounts of glucose, amino acids, and
      fat but different FA compositions: group 1 received a soybean-based fat solution
      without additional fish oil and group 2 was supplemented with 0.2 g/kg per day
      fish oil. TPN was continued for 2 days. Serum concentrations of IL-6 and IL-10
      were measured before and after AP induction and at 24 and 48 hours after starting
      TPN. Routine cardiorespiratory and renal parameters were monitored to assess the
      systemic response at the organ level. RESULTS: Animals treated with fish oil had
      significantly higher IL-10 values (at 24 hours, 63 +/- 7 versus 46 +/- 3 pg/mL),
      produced more urine (28 +/- 0.9 versus 21 +/- 1.6 mL), and had significantly
      fewer episodes of respiratory dysfunction (defined as a pO2 < 80 mm Hg or pCO2 >
      50 mm Hg for >15 minutes; 29% versus 67%) during the observation period.
      CONCLUSIONS: Altering eicosanoid mediator precursor availability by infusion of
      (omega-3 fatty acid increases anti-inflammatory cytokines in this model of AP.
      This together with improved renal and respiratory function suggests that the
      systemic response to pancreatic injury is attenuated.

PMID- 12405647
TI  - Body cell mass repletion and improved quality of life in HIV-infected individuals
      receiving oxandrolone.
AB  - BACKGROUND: The aim of this study was to measure changes in body cell mass (BCM)
      and quality of life in HIV-infected individuals undergoing oxandrolone therapy.
      Previous studies on oxandrolone have neither quantified changes in BCM using
      criterion methods nor quality of life using an HIV-specific instrument. METHODS:
      Twenty-five HIV-infected patients (15 with an AIDS diagnosis) on standard
      antiretroviral and nutrition management were studied before and an average of
      18.6 weeks after the initiation of oxandrolone therapy, as prescribed by their
      primary care physician for the treatment of weight loss. BCM was estimated from
      intracellular water measured by multiple dilution. Lean soft tissue mass (LTM)
      was measured by dual-energy X-ray absorptiometry. Quality of life was evaluated
      by the Functional Assessment of HIV Infection (FAHI) questionnaire. RESULTS:
      Significant gains in body weight (2.6 +/- 3.0 kg; p < .0001), BCM (3.6 +/- 3.0
      kg; p < .0001), and LTM (3.0 +/- 2.9 kg; p < .0001) occurred over an average
      course of 18.6 weeks of treatment. Overall quality of life improved (p = .056)
      and appetite improved (p = .032), both of which were positively associated with
      weight gain (p = .040 and p = .022, respectively). CONCLUSIONS: This is the first
      study involving oxandrolone therapy in HIV infection to document changes in
      quality of life and BCM, the metabolically active component of lean body mass
      that reflects nutritional status better than other more global body composition
      parameters. Nutritional status and quality of life can improve in HIV-infected
      individuals receiving a combined therapeutic approach that includes oxandrolone.

PMID- 12405648
TI  - Body composition changes in cachectic patients receiving home parenteral
      nutrition.
AB  - BACKGROUND: The purpose of this study was to evaluate the initial body
      compositional changes experienced by malnourished patients requiring home
      parenteral nutrition (HPN) for repletion. METHODS: Eight patients were
      prospectively studied for 3 months. Body composition was determined by dual
      energy X-ray absorptiometry (DXA), and a comprehensive nutrition assessment was
      performed including body weight, visceral proteins, triceps skinfold (TSF),
      midupper arm circumference (MUAC), midupper arm muscle circumference (MUAMC),
      body mass index (BMI), delayed hypersensitivity skin tests (DHST), and diet
      history. RESULTS: Body composition measured by DXA showed an increase in (mean +/
      SD) total fat from 5770 +/- 2805 to 10581 +/- 1980 g (p < .001) and bone mineral
      content from 2155 +/- 429 to 2190 +/- 443 g (p = .047). Lean soft tissue remained
      unchanged. Body weight and BMI increased from 47.7 +/- 6.6 to 53.6 +/- 8.2 kg (p
      = .006) and from 16.6 +/- 1.5 to 18.6 +/- 1.5 kg/m2 (p = .005), respectively. TSF
      increased from 6.3 +/- 3.1 to 10.4 +/- 4.0 mm (p < .001), and MUAMC remained
      stable. There was a significant improvement in transferrin from 191 +/- 82 to 326
      +/- 128 mg/dL (p = .043), and a trend toward improvement in albumin and DHST.
      Body weight was highly correlated with DXA weight at baseline (r = .997; 95%
      confidence interval [CI], 0.98 to 1.00; p < .001) and at 3 months (r = .988; 95%
      CI, 0.93 to 1.00; p <.001). TSF correlated with total fat as measured by DXA at
      baseline (r = .839; 95% CI, 0.33 to 0.97; p = .009) but not at 3 months (r =
      .693; 95% CI, -0.02 to 0.94; p = .057). MUAMC correlated with lean soft tissue
      measured by DXA both at baseline (r = .739; 95% CI 0.07 to 0.95; p = .036) and at
      3 months (r = .870; 95% CI, 0.43 to 0.98; p = .005). Physical activity, on a
      subjective scale of 1 (low activity) to 3 (high activity), improved over the 3
      month period from 1.3 +/- 0.5 to 2.2 +/- 0.8 (p = .031). CONCLUSIONS: Initial
      weight gain experienced by malnourished HPN patients is primarily fat. Bone
      mineral content increases, but lean soft tissue does not change. Overall
      nutritional status is improved as exhibited by significant improvements in body
      weight and serum transferrin and a trend toward improvement in albumin and
      delayed hypersensitivity skin tests.

PMID- 12405649
TI  - Effects of prebiotics on the immune response to vaccination in the elderly.
AB  - BACKGROUND: Prebiotics stimulate the growth of bifidogenic bacteria in the gut.
      The aim of this work was to assess the effects of a prebiotic mixture on the
      immune response in healthy elderly people. METHODS: Healthy free-living elderly
      people (age, > or = 70 years), receiving a nutritional supplement that provided
      1.6 MJ, 15 g of protein, and 50% of vitamin daily reference values per day, were
      randomly assigned to receive a prebiotic mixture (6 g/d of a 70% raftilose and
      30% raftiline mixture) or placebo (6 g of maltodextrin powder) for 28 weeks. At
      week 2 of the study, all subjects were vaccinated with influenza and pneumococcal
      vaccines. At weeks 0, 2, and 8 of the study, serum total proteins, albumin,
      immunoglobulins, saliva secretory immunoglobulin A (IgA), and serum titers of
      influenza A and B and pneumococcal antibodies were measured. At week 8, cultured
      peripheral monocyte cell secretion of interleukin-4, interferon-gamma, and
      lymphocyte proliferation, stimulated with phytohemagglutinin and influenza
      antigen, were measured. RESULTS: Sixty-six subjects were considered eligible for
      the study, and 43 (20 receiving prebiotics and 23 receiving placebo) were
      considered for final analyses on a per protocol basis. No changes in serum
      proteins, albumin, immunoglobulins, and secretory IgA were observed. Antibodies
      against influenza B and pneumococcus increased significantly from weeks 0 to 8,
      with no significant differences between groups. Antibodies against influenza A
      did not increase. No effects of prebiotics on interleukin-4 and interferon-gamma
      secretion by cultured monocytes were observed. CONCLUSIONS: No immunological
      effects of prebiotics were observed in this study.

PMID- 12405650
TI  - Effectiveness of a clinical practice guideline for parenteral nutrition: a 5-year
      follow-up study in a pediatric teaching hospital.
AB  - OBJECTIVE: To determine the effectiveness of a clinical practice guideline (CPG)
      on the use of parenteral nutrition (PN) at a tertiary care pediatric hospital.
      METHODS: Review of prospectively collected data on hospital-wide PN use 2 years
      before and 5 years after the establishment of the CPG. Effectiveness of the CPG
      was measured as the percentage of PN courses lasting fewer than 5 days and the
      number of PN starts per 1000 patient days. RESULTS: During the study period, 5745
      PN courses were administered. The mean (SD) number of PN starts per 1000
      inpatient days was 8.86 (0.78) before the CPG and 9.54 (2.49) afterwards (p =
      .28). The percentage courses of PN lasting for fewer than 5 days declined from
      26.3% before the CPG to 18.4% afterwards (p < .0001). A multivariate model
      confirmed that the rate of short-term PN starts declined after the CPG was
      issued. The mean (SD) number of PN courses shorter than 5 days in the 2 years
      before the CPG was 2.33 (0.42) per 1000 patient days versus 1.75 (0.45) in the 5
      years after the CPG was instituted (p = .005), which is a 25% decline. The
      services with the highest volume of PN use showed the most significant decreases
      in short-term PN use. A cost savings to the hospital of more than $50,000 may
      have been realized. CONCLUSIONS: In a large pediatric tertiary care hospital, a
      CPG was successfully deployed. CPGs can favorably affect the use rates and costs
      of parenteral nutrition.

PMID- 12405651
TI  - Contribution of the raw material to the aluminum contamination in parenterals.
AB  - BACKGROUND: The extent of aluminum contamination in parenteral nutrition
      solutions was measured in 35 different commercial products, including amino
      acids, electrolytes, glucose, lipids, vitamins trace elements, and albumin. The
      extent of aluminum contamination in substances used as raw material for
      preparation of parenterals was also measured. Chemicals from different
      manufacturers and of different quality grades were analyzed individually.
      METHODS: The measurements were done by atomic absorption spectrometry. RESULTS:
      The results showed that the same product might have different aluminum content
      depending on the manufacturer, either for commercial formulations or substances.
      The highest contaminated chemicals included cystine, NaOH, vitamin C, biotin,
      gluconate, and Fe and Cr salts. The lowest contaminated chemicals included
      lipids, apolar amino acids, glucose, HCI, acetic acid, KCl, NaCl, and heparin.
      Among commercial products, the major contamination rates appeared in calcium
      gluconate, followed by trace elements, some vitamins, bicarbonate, phosphates
      salts, and heparin. CONCLUSIONS: Comparing the aluminum in commercial products
      and substances, it can be concluded that the contamination may occur in
      parenterals because aluminum is present naturally in the chemicals. However, when
      the composition and concentration of the parenteral solution are considered, the
      contamination of calcium gluconate, trace elements, some vitamins, phosphates,
      bicarbonate, and heparin cannot be related only to the raw substances. The
      aluminum level present in these commercial formulations is too high to come only
      from the substances; therefore, it is possible that one of the steps of the
      manufacturing procedure is responsible for elevating the contamination of these
      products.

PMID- 12405652
TI  - Nutrition and metabolism.

PMID- 12405653
TI  - Effects on exercise metabolism of varying dietary starch and sugar proportions.
AB  - Studies of the effect of varying dietary carbohydrate compositions on exercise
      metabolism of horses are scarce. In the present study, the starch and sugar
      proportions were altered in the diet to 4 Standardbred horses. In a crossover
      experiment, the horses were offered a hay and oat diet, where the oats were
      substituted for barley syrup (BS) at 4 levels (BS 0, 0.5, 1.0 and 1.5 kg). Each
      diet was consumed for 21 days and both an incremental treadmill exercise test
      (IE) and a 40 min submaximal exercise test (SE) were performed. During the IE
      there was a significant (P<0.05) increase in mean VO2 on BS 1.5 and at the
      highest speed respiratory exchange ratio (RER) was significantly lower on BS 1.0
      and 1.5. During the SE, RER and HR were significantly higher on BS 1.0 and 1.5.
      There were no significant effects of diets on plasma levels of glucose, lactate
      and insulin. Following the SE there was a significant decrease in the muscle
      glycogen content on BS 0, which was not observed in the other diets. In addition,
      there was a numerical decrease in the glycogen utilisation with increasing
      proportions of sugar in the diet. In conclusion, this study indicates that horses
      on diets with a high sugar inclusion respond with an increased heart rate during
      exercise of lower intensities; and that the response in VO2 and RER may differ
      depending on the exercise intensity. In addition, glycogen utilisation during
      submaximal exercise was lowered when daily sugar intake was increased. However,
      further investigation is needed to evaluate whether this strategy of feeding
      could be beneficial for exercising horses competing over endurance distances.

PMID- 12405654
TI  - Training-induced alterations in glucose metabolism during moderate-intensity
      exercise.
AB  - In several species, physical conditioning (training) provokes a large shift in
      substrate utilisation during submaximal exercise. Few studies in horses have
      quantitatively examined these effects. Therefore, the effects of exercise
      training on plasma glucose kinetics during submaximal exercise were examined in 7
      horses (5 Thoroughbred, 2 Standardbred; age 3-9 years) that had been paddock
      rested for at least 6 months. Two days after determination of maximum aerobic
      capacity (VO2max), horses ran on a treadmill (4 degree incline) at 55% of VO2max
      (UT) for 60 min or until fatigue and then completed 6 weeks of moderate-intensity
      training on a treadmill (5 days/week). Following training and a second VO2max
      test, the horses completed exercise trials at the same absolute (ABS) and
      relative (REL) workload in random order, with at least 3 days between tests.
      After training, VO2max had increased (P<0.05) by 14.9% (mean +/- s.e. pretraining
      118.4 +/- 7.4 ml/kg bwt/min; post-training 136.1 +/- 7.8 ml/kg bwt/min). Mean
      exercise duration was longer (P<0.05) in the ABS trial (57 +/- 1.9 min) than in
      the UT (46 +/- 3.9 min) and REL (49 +/- 4.6 min) trials. Plasma glucose
      concentration increased during exercise, and was lower (P<0.05) in ABS than in UT
      and REL at the end of exercise. Mean glucose rate of appearance (Ra) and
      disappearance (Rd) were 22 and 21% lower (P<0.05), respectively, in ABS than in
      UT, but mean glucose Ra and Rd did not differ between the UT and REL trials.
      Exercise-induced changes in glucagon, epinephrine and norepinephrine were blunted
      (P<0.05) in ABS, but not REL, when compared to UT. It is concluded that 6 weeks
      of moderate-intensity training results in a decrease in glucose flux during
      submaximal exercise at the same absolute, but not relative, workload. The
      training-induced decrease in glucose flux may, in part, be due to altered plasma
      concentrations of the major glucoregulatory hormones.

PMID- 12405655
TI  - Exercise- and metabolism-associated blood variables in Standardbreds fed either a
      low- or a high-fat diet.
AB  - Feeding a high-fat diet increases fat utilisation and may decrease glycogen
      utilisation resulting in a lower lactate production during moderate exercise. The
      effects of fat feeding on exercise- and lipid metabolism-associated blood
      variables were evaluated in 6 Standardbred horses during submaximal exercise. The
      horses were fed a high- (11.8% fat in total dietary dry matter) or a low-fat diet
      (1.5% fat) in a cross-over experiment with feeding periods of 4 weeks. At the end
      of each feeding period, the horses were subjected to a submaximal standardised
      stepwise exercise test on a treadmill. Blood samples were obtained prior to the
      start, during the last 10 s of each exercise step, and after recovery (40 min
      walking in hand). Pre-exercise test values for plasma lactate, pH, pCO2, ionised
      sodium, ionised potassium, ionised calcium, ionised chloride, glucose,
      nonesterified fatty acids and glycerol did not differ for the 2 diets. The pre
      exercise concentration of triacylglycerols was significantly lower on the high-
      compared to the low-fat diet (mean +/- s.d. 0.17 +/- 0.06 and 0.23 +/- 0.08
      mmol/l, respectively), whereas the concentrations of cholesterol (3.00 +/- 0.47
      and 2.11 +/- 0.49 mmol/l, respectively), HDL cholesterol (1.80 +/- 0.18 and 1.35
      +/- 0.27 mmol/l, respectively) and phospholipids (2.30 +/- 0.11 and 1.72 +/- 0.20
      mmol/l, respectively) were significantly higher. There was significantly less
      plasma lactate accumulation during exercise when the horses were given the high
      fat diet (P = 0.011). Horses on a low-fat diet had significantly different plasma
      lipid values when compared to being on a high-fat diet. The alterations in these
      values during and after moderate exercise were comparable for both diets. These
      results indicate that fat metabolism is significantly adapted on a high-fat diet;
      feeding such a diet may enhance potential performance by delaying lactate
      accumulation and thereby delaying the onset of fatigue.

PMID- 12405656
TI  - Effects of fat adaptation on glucose kinetics and substrate oxidation during low
      intensity exercise.
AB  - This study was designed to determine the effects of fat adaptation on
      carbohydrate and fat oxidation in conditioned horses during low-intensity
      exercise. Five mature Arabians were studied. The study was conducted as a
      crossover design with 2 dietary periods, each of 10 week's duration: a) a control
      (CON) diet, and b) a fat-supplemented (FAT) diet. The total amount of digestible
      energy (DE) supplied by the fat in the CON and FAT diets was 7% and 29%,
      respectively. During each period, the horses completed exercise tests at the
      beginning of the period (Week 0) and after 5 and 10 weeks on the diet. Tests
      consisted of 90 min of exercise at a speed calculated to elicit 35% VO2max on a
      treadmill inclined to 3 degrees. Oxygen consumption (VO2), carbon dioxide
      production (VCO2), and respiratory exchange ratio (RER) were measured at 15-min
      intervals. For determination of glucose kinetics, a stable isotope ([6-6-d2]
      glucose) technique was used. Compared to the CON diet, FAT diet consumption for 5
      10 weeks was associated with an altered metabolic response to low-intensity
      exercise, as evidenced by a more than 30% reduction in the production and
      utilisation of glucose; a decrease in RER; a decrease in the estimated rate of
      whole-body carbohydrate utilisation; and an increase in the whole-body rate of
      lipid oxidation during exercise.

PMID- 12405657
TI  - Speed associated with plasma pH, oxygen content, total protein and urea in an 80
      km race.
AB  - To test the hypothesis that endurance performance may be related quantitatively
      to changes in blood, we measured selected blood variables then determined their
      reference ranges and associations with speed during an 80 km race. The plan had
      46 horses in a 2 x 2 factorial design testing a potassium-free electrolyte mix
      and a vitamin supplement. Blood samples were collected before the race, at 21,
      37, 56 and 80 km, and 20 min after finishing, for assay of haematocrit, plasma
      pH, pO2, pCO2, [Na+], [K+], [Ca++], [Mg++], [Cl-], lactate, glucose, urea,
      cortisol, alpha-tocopherol, ascorbate, creatine kinase, aspartate amino
      transferase, lipid hydroperoxides, total protein, albumin and creatinine, and
      erythrocyte glutathione and glutathione peroxidase. Data from 34 finishers were
      analysed statistically. Reference ranges for resting and running horses were wide
      and overlapping and, therefore, limiting with respect to evaluation of individual
      horses. Speed correlations were most repeatable, with variables reflecting blood
      oxygen transport (enabling exercise), acidity and electrolytes (limiting
      exercise) and total protein (enabling then, perhaps, limiting). Stepwise
      regressions also included plasma urea concentration (limiting). The association
      of speed with less plasma acidity and urea suggests the potential for fat
      adaptation and protein restriction in endurance horses, as found previously in
      Arabians performing repeated sprints. Conditioning horses fed fat-fortified and
      protein-restricted diets may not only improve performance but also avoid grain
      associated disorders.

PMID- 12405659
TI  - Effect of feeding exercised horses on high-starch or high-fat diets for 390 days.
AB  - Our hypothesis was that, because horses have not evolved as fat eaters, there may
      be negative metabolic long-term effects of feeding a high fat diet. The objective
      of the present study was to identify these long-term effects and compare them
      with the effects of isoenergetic long-term high starch feeding. This randomised
      block study with 20 exercised horses looked at the effect of feeding either a
      high starch (HS) or a high fat (HF) diet type in 3 periods during stabling
      (Stable 1), pasture, and stabling (Stable 2) over 390 days. The horses received a
      HS or HF concentrate, straw, hay and 6 h pasture/day in the pasture period. HF
      horses gained weight (2% of initial bwt) and, therefore, fat intake was reduced
      (from 1.43 to 0.88 g/kg bwt/day). Blood plasma glucose, total protein, albumins,
      gamma-globulins, free fatty acids, phospholipids and cholesterol concentrations
      were higher but urea concentration was lower with HF compared to HS feeding
      (P<0.05). Plasma concentrations of triglycerides, bilirubin and pre-beta
      lipoproteins were unaffected by the diet type. There were period effects (P<0.05)
      for all variables except triglycerides and pre-beta lipoproteins. In contrast to
      HS, in HF the quotient alpha/beta lipoproteins rose (P<0.05) throughout the
      stable periods and decreased (P<0.05) during 'pasture'. Glutamic acid
      dehydrogenase, gamma-glutamyl transferase, alkaline phosphatase, aspartate
      aminotransferase, creatine kinase and lactate dehydrogenase activity in sera were
      within the normal range. In conclusion, on the precondition that substantial
      bodyweight changes were prevented, no apparent adverse effects of long-term high
      fat feeding were identified and there were no apparent disadvantages of feeding
      on high fat compared with high starch diets.

PMID- 12405658
TI  - Effect of molassed sugar beet pulp on nutrient utilisation and metabolic
      parameters during exercise.
AB  - The aim of this study was to investigate the effect of partly replacing oats with
      molassed sugar beet pulp in a traditional hay/oat diet on nutrient utilisation
      and metabolic parameters in exercising horses. In a change-over experiment, 4
      Standardbred geldings were fed a hay and oat-based diet (Oat diet) and a hay and
      oat-based diet where oats was partially replaced with molassed sugar beet pulp
      (MSBP diet). Each experimental period was 21 days during which total collection
      of faeces and urine was made and an exercise test (ET) performed. The crude fat
      digestibility was lower on the MSBP diet (P<0.05), while there were no
      differences in digestibility of other nutrients and energy and in the urinary
      excretion of nitrogen and energy. At rest plasma insulin were lower (P<0.05) 60
      and 90 min postprandially on the MSBP diet, while no differences were found in
      plasma glucose and insulin between the diets during the ET. The peak plasma and
      muscle lactate values were lower (P<0.05) on the MSBP diet and the content of
      muscle glycogen was higher (P<0.05) after the ET on the MSBP diet. In conclusion,
      the metabolic response differed between diets giving a lower lactate response and
      a higher glycogen content in muscle after exercise on the MSBP diet. This
      suggests that the dietary carbohydrate composition may influence the rate of
      glycogenolysis with lactate production and support the hypothesis that MSBP can
      replace oats in a hay based diet without impairing nutrient utilisation and
      metabolic response in exercising horses.

PMID- 12405660
TI  - Antioxidant supplementation and pulmonary function at rest and exercise.
AB  - Antioxidants have been implicated in the reduction and prevention of oxidative
      stress during exercise. We hypothesised that a dietary supplement containing a
      mixture of natural antioxidants together with vitamins E, C and selenium, given
      for 4 weeks, would increase the systemic and pulmonary antioxidant capacity
      leading to a reduction in markers of oxidative damage and an improvement in
      pulmonary function during exercise. In 6 healthy horses studied, the antioxidant
      supplement significantly increased plasma concentrations of ascorbic acid (from
      mean +/- s.d. 16 +/- 7 to 23 +/- 4 micromol/l; P = 0.007) and alpha-tocopherol
      (from 10 +/- 3 to 14 +/- 3 micromol/l; P = 0.02) and increased the
      bronchoalveolar lavage pulmonary epithelial lining fluid (ELF) concentration of
      ascorbic acid compared to a placebo, but not significantly (2.0 +/- 0.9 mmol/l
      and 1.2 +/- 0.9 mmol/l, respectively; P>0.05). Alpha-tocopherol was not detected
      in ELF either before or after supplementation or exercise. The mean concentration
      of malondialdehyde (MDA) in ELF was lower following antioxidant supplementation
      compared to placebo and control periods, but not significantly. An intermittent
      exercise test consisting of 2 min at 70, 80 and 90% of the horses' individual
      maximum oxygen uptake, failed to induce significant systemic or pulmonary
      oxidative stress (based on the glutathione redox ratio (GRR) and the ascorbic
      acid redox ratio (ARR)) and lipid peroxidation (based on the concentration of
      thiobarbituric acid reactive substances in plasma and MDA in ELF) either for
      placebo or antioxidant treatments. There was a strong correlation between GRR and
      ARR in the pulmonary epithelial lining fluid (r = 0.89; P<0.0001). In healthy
      horses on a diet containing adequate levels of antioxidants, additional
      antioxidant supplementation has no apparent beneficial or detrimental effect on
      pulmonary function during moderate intensity exercise. The importance of
      antioxidant supplementation may only become apparent if the diet is deficient in
      antioxidants, if exercise intensity is higher or more prolonged, or if disease or
      additional stresses are present.

PMID- 12405661
TI  - Effect of forage intake on bodyweight and performance.
AB  - The horse evolved to survive on rations high in forage. Many performance horses
      are fed rations containing reduced levels of forage, with a corresponding
      increase in concentrate supply. Such reductions in forage intake are widely
      established to be associated with a corresponding number of physiological and
      psychological adaptations. Therefore, the influence of forage intake on
      bodyweight (bwt) and performance was investigated. Four Thoroughbred-type
      geldings in light to moderate work received 4 diets (100% forage [100H]; 80%
      forage:20% concentrate [80H]; 60% forage:40% concentrate [60H] and 50% forage:50%
      concentrate [50H]) in a 4 x 4 Latin-square design. A submaximal standardised
      exercise test (SET) was performed for each diet. Rate of passage, bwt and water
      intakes were measured throughout the trial and maximum, recovery heart rates and
      postexercise rectal temperatures recorded for each SET. Mean +/- s.e. bwt was
      significantly (P<0.001) higher for the 100H compared to the 50H ration (556.89
      and 546.28 kg, respectively). Rate of passage of digesta was significantly
      (P<0.01) slower for the 100H compared to the 50H ration. Water intakes and SET
      maximum and 1 min recovery heart rates were significantly (P<0.05) higher (mean
      +/- s.e. 44.72 and 39.07 l/day, 186 and 165 beats/min, and 105 and 96 beats/min,
      respectively) for 100H compared to the 50H diet. Post-SET rectal temperatures
      tended to increase with increasing forage intakes, although these effects were
      not significant (mean 39.85 and 38.65 degrees C for the 100H and 50H diets,
      respectively). In conclusion, forage intake has significant effects on equine bwt
      and submaximal performance and a compromise needs to be made between the
      potential detrimental effects of high forage intake on performance and the
      potential detrimental effects of low forage intake on equine welfare.

PMID- 12405662
TI  - Postprandial glucose and insulin responses to a postexercise grain meal.
AB  - Many studies have examined the effect of pre-exercise feeding on glucose and
      insulin responses of horses. The objective of this study was to determine whether
      exercise performed one hour prior to a meal would attenuate the glucose and
      insulin responses to a meal. Data collected from 8 mature geldings in a 2 period
      crossover design experiment were used to determine the postprandial glucose and
      insulin responses to a meal of oats offered 1 h postexercise. During each period,
      4 horses received a test meal following a 14 h fast (NoEx) or a 14 h fast and
      exercise bout (PostEx) that consisted of 48 min walking and trotting. Blood
      samples were collected before and at 30 min intervals for 5 h after the meal was
      offered. Glucose and insulin concentrations were similar between treatments at
      all time points (P>0.15). Postprandial glucose and insulin concentrations
      increased at similar rates in both groups from 0 to 90 min. Peak glucose and
      insulin concentrations and area under the response curves were similar between
      treatment groups. Glucose:insulin was not different between treatment groups at
      any time point before or after the meal (P>0.17). Overall, the 48 min of light
      work performed 1 h before a meal did not affect glucose or insulin responses to
      the meal. A one hour interval after mild exercise appears to be sufficient to
      allow normal glucose metabolism of a grain meal.

PMID- 12405663
TI  - Effect of dietary lipid on response to exercise: relationship to metabolic
      adaptation.
AB  - The aim of the present study was to relate changes in muscle oxidative capacity
      and free fatty acid flux in response to oil supplementation to fuel utilisation
      during subsequent exercise of varying intensities. Following 10 weeks of oil
      supplementation there was an increased capacity for fat utilisation during low
      and moderate intensity exercise as indicated by a lower respiratory exchange
      ratio (RER) (P<0.05). We suggest that this was contributed to by a parallel
      increase in the oxidative capacity of muscle as indicated by a significant
      increase in the activity of muscle citrate synthase (CS) (P<0.05) and trend
      towards an increase in beta-Hydroxy acyl CoA dehydrogenase (beta-HAD), (P>0.05).
      In addition, low and moderate intensity exercise was associated with an exercise
      induced increase in plasma free fatty acids (FFA) and there was an increased
      facility for uptake of FFA by working muscle from circulating triglycerides, as
      suggested by an increase in TL activity (P<0.01). The response to oil
      supplementation varied between individual horses and the magnitude of response,
      during the low intensity exercise test, in terms of difference in RER was
      correlated to the increase in CS activity (r2 = 0.95, P<0.05) following oil
      supplementation. There was no similar significant correlation with respect to
      FFA, TL or beta-HAD activity (P>0.05). The hypothesis in this study was that the
      metabolic adaptation to oil supplementation, in terms of exercise response, was
      related to individual increases in the activities of CS, beta-HAD or TL. However,
      the relationship between these parameters was unequivocal and requires further
      investigation, ideally with a larger group of horses.

PMID- 12405664
TI  - Effect of short-term exercise training on insulin sensitivity in obese and lean
      mares.
AB  - Twelve untrained aged mares were used to determine whether 7 days of light
      exercise improved peripheral tissue insulin sensitivity. Mares were divided into
      obese-exercised (n = 3), obese-sedentary (n = 3), lean-exercised (n = 3) and lean
      sedentary (n = 3) groups. The exercised groups were worked at a trot to a heart
      rate (HR) of not more than 140 beats/min for 30 min in a round pen. Each group
      was subjected to 3 euglycaemic hyperinsulinaemic clamps: prior to exercise (P),
      24 h following the seventh exercise training session (E) and 9 days postexercise
      training (PE). Prior to exercise training, the mares in the obese group were
      confirmed insulin-resistant compared to the mares in the lean group. There was no
      change in bodyweight or body condition in the obese or lean groups throughout the
      study. Glucose infusion rate (GIR) was higher (P<0.05) on E compared to P days in
      the obese-exercised and lean-exercised groups. Insulin sensitivity returned to
      pre-exercise values by 9 days postexercise in the obese-exercised and lean
      exercised groups. The results of this study suggest that improvement in insulin
      sensitivity occurs in obese mares without a long interval of exercise training
      and in the absence of a change in bodyweight.

PMID- 12405665
TI  - Effects of substituting starch with fat on the acid-base and mineral status of
      female horses.
AB  - Feeding a high-fat diet may have potential advantages by maintaining pH
      homeostasis during intense exercise; conversely, effects including elevated PCV
      and increased plasma concentration of total protein may indicate effects
      detrimental to performance by reducing perfusion of tissues and organs. Six
      horses were used to determine the effects of an replacement of starch (diet
      '0.00') with 0.33, 0.67, 1.00 and 1.33 g soybean oil/kg bwt/day (diets '033',
      '0.67', '1.00' and '1.33') on venous and renal acid-base status and fractional
      clearance (FC) of electrolytes in a postprandial state but prior to exercise.
      Venous blood and urine were sampled for 3 days at the end of the 28 day periods,
      in each case 3 h postprandially. Throughout the study, the horses put on weight
      by 35 kg (P<0.05). From diet '0.00' to '0.67', blood pH decreased (P<0.05) and
      carbon dioxide tension increased (P<0.05). Simultaneously, the base and net acid
      base concentration in the urine rose (P<0.05) but diuresis decreased (P<0.05)
      and, therefore, the daily excretion of bases and net acid-bases was only
      unsystematically affected. From diet '0.00' to '1.33', the FC of magnesium and
      chloride fell (P<0.05). These results suggested that the exchange of starch with
      up to moderate amounts of fat affects the venous and renal acid-base status of
      resting horses. The decrease in urine volume is most striking. Further research
      is needed to investigate the importance of these effects for sporting
      performance.

PMID- 12405666
TI  - Comparison of the metabolic responses of trained Arabians and Thoroughbreds
      during high- and low-intensity exercise.
AB  - In order to compare the metabolic responses to exercise in 2 similarly managed
      breeds of horses, 5 Arabian (AR) and 5 Thoroughbred (TB) horses, fed an identical
      diet with a similar diet and exercise training programme for the 2 preceding
      months, undertook 3 treadmill (3 degree incline) trials with a minimum of 7 days
      between tests: 1) an incremental test (MAX) for determination of aerobic
      capacity, V(LA4) and lactate threshold (LT; the percentage of VO2max when plasma
      lactate = 4 mmol/l); 2) a single high-speed exercise test (SPR) at 115% VO2max
      for estimation of maximal accumulated oxygen deficit (MAOD) and 3) a 90 min test
      at 35% VO2max (LO). VO2max (P<0.001) and running speed (P<0.05) at VO2max were
      higher in TB (mean +/- s.e. 154 +/- 3 ml/kg/min at 12.9 +/- 0.5 m/s) than in AR
      (129 +/- 2.5 ml/kg/min at 11.8 +/- 0.2 m/s). Total run time during MAX was
      greater (P<0.05) in TB (10.5 +/- 0.5 min) than in AR (93 +/- 0.3 min). However,
      V(LA4) and LT were not different between groups. Run time during SPR (TB 149 +/-
      16; AR 109 +/- 11 s) and MAOD (TB 88 +/- 4; AR 70 +/- 6 ml O2/kg) were higher
      (P<0.05) in the TB group. During LO, FFA were higher (P<0.05) and the respiratory
      exchange ratio (RER) lower (P<0.05) in AR than in TB between 60 and 90 min, of
      exercise, indicating a greater use of fat for energy. These metabolic differences
      may reflect breed variation in muscle fibre types. However, further studies are
      needed to determine the mechanisms underlying the apparent breed differences in
      energy metabolism during exercise.

PMID- 12405667
TI  - Effects of ageing and training on maximal heart rate and VO2max.
AB  - The purpose of this study was to test the hypotheses that ageing would result in
      a decline in maximal heart rate (HRmax) and maximal aerobic capacity (VO2max)
      and, secondarily, that those effects would be reversible with training. Eighteen,
      healthy, unfit Standardbred mares representing 3 age groups: young (Y = mean +/-
      s.e. 6.8 +/- 0.4 years, n = 6); middle-aged (MA = 15.2 +/- 0.4 years, n = 6); and
      old (O = 27.0 +/- 0.2 years, n = 6) were used. HRmax, VO2max and oxygen pulse at
      VO2max (OPmax) and the velocities producing HRmax (VHRmax) and VO2max (VVO2max)
      were measured during pretraining and post-training incremental exercise tests
      (GXT). During training, mares exercised 3 days/week (Weeks 1-8) and 4 days/week
      (Weeks 9-12) at a submaximal intensity (approximately 60% HRmax) for
      approximately 30 min/day. There were no differences (P>0.05) between Y and MA,
      before (218 +/- 2 vs. 213 +/- 3 beats/min; 116 +/- 3 vs. 109 +/- 3 ml/kg bwt/min;
      0.55 +/- 0.01 vs. 0.52 +/- 0.02 ml/kg/beat; 9.0 +/- 0.3 vs. 9.3 +/- 0.2 ms; 8.8
      +/- 0.2 vs. 8.8 +/- 0.2 m/s) or after training (224 +/- 2 vs. 218 +/- 2
      beats/min; 131 +/- 3 vs. 120 +/- 2 ml/kg bwt/min; 0.58 +/- 0.01 vs. 0.55 +/- 0.01
      ml/kg/beat; 10.5 +/- 0.2 vs. 9.5 +/- 0.1 ms; 10.6 +/- 0.2 vs. 9.5 +/- 0.1 m/s)
      for HRmax, VO2max, OPmax, VHRmax or VVO2max, respectively. Old horses had lower
      HRmax, VO2max and OPmax and reached them at lower velocities compared to Y and MA
      (P<0.05), both before (193 +/- 3 beats/min; 83.2 +/- 2.0 ml/kg bwt/min; 0.43 +/-
      0.01 ml/kg/beat; 7.8 +/- 0.1 m/s; 7.2 +/- 0.1 m/s) and after training (198 +/- 2
      beats/min; 95 +/- 2 ml/kg bwt/min; 0.48 +/- 0.01 ml/kg/beat; 8.2 +/- 0.2 m/s; 8.0
      +/-0.2 m/s). Training did not alter HRmax in any age group (P>0.05) but did cause
      increases in VO2max, OPmax and VVO2max for all groups (P<0.05). Interestingly,
      training increased VHRmax only in Y (P<0.05). These data demonstrate that there
      is a reduction in HRmax, VO2max, OPmax, VHRmax and VVO2max in old horses, and
      that training can partially reverse some effects of ageing.

PMID- 12405668
TI  - Use of the recovery check in long-distance endurance rides.
AB  - In an attempt to reduce morbidity, an additional veterinary examination is
      performed at the end of the hold time--the Recovery Check (RC)--of the last vet
      gate of all long distance endurance rides held in France. At the RC, a normal FEI
      type inspection is performed combined with a cardiac recovery index (CRI): the
      heart rate is taken before (HR0) and 1 min after (HR1) the horse trotted for 30 m
      out and back. Results from 12 (130 and 160 km long) rides and based on 489 horses
      were analysed. Of all RC performed, 10.4% lead to elimination of the horses and
      lameness was the most frequent reason (45%). Among horses allowed to continue in
      the ride, elimination rate was significantly higher in horses with HR0 > or =
      60/min compared to horses with HR0 < 60. High CRI (HR1-HR0 > or = 4) lead to
      greater disqualification rates only when HR0 was more than 60/min. RC appears to
      be useful in the assessment of a horse's fitness. However, standardisation of the
      examination is necessary in order to optimise its use.

PMID- 12405669
TI  - Metabolic responses to submaximal field exercise tests and relationships with
      racing performance in pacing Standardbreds.
AB  - This study was undertaken to invesigate the application of submaximal field tests
      in assessment of performance. A submaximal field exercise test consisting of 2
      bouts of pacing for 1600 m, with 5 min rest or walking between runs was performed
      on Standardbred racehorses at 2 training centres (A and B). Performance indices
      were compiled for each horse: number of race starts, number of race wins, number
      of race placings (1, 2 or 3), and lifetime earnings. Regression analysis was
      conducted to describe the relationship between plasma lactate concentrations and
      speed for tests one, 2 and pooled results. Using the regression equation,
      observed (measured) minus expected (predicted) (O-E) lactate concentrations for
      tests were calculated and plotted against performance indices to determine their
      relationship. For stables A and B the association between lactate and velocity
      for the 2 runs was best described by the exponential equations: y =
      0.0014(e07306x) (r2 = 0.54, P<0.001) and y = 0.002(e06812x) (r2 = 0.42, P<0.001),
      respectively, where y is lactate concentration (mmol/l) and x is speed (m/s). For
      the pooled results for heat 1 and heat 2 for stables A and B the relationship
      between lactate and velocity was best described by an exponential equation y =
      0.0016(e07117x) (r2 = 0.47, P<0.001). This study found no relationship between (O
      E) and performance indices (number of race wins, number of race placings,
      lifetime earnings and average $/start) at stables A or B for test run 1, 2 or
      pooled lactates. At stable A, there was a significant association between V(La4)
      and log lifetime earnings (r = 0.51, P = 0.053) and log average $/start (r =
      0.54, P = 0.036). There were no significant correlations at stable B. In
      conclusion a 2-step determination method of V(La4) is a possible means for
      studying limits to performance in pacing Standardbred racehorses.

PMID- 12405670
TI  - Antioxidant status and muscle cell leakage during endurance exercise.
AB  - Antioxidant status of 35 endurance horses was studied during an 80 (OD80) or 160
      km (OD160) race. Packed cell volume (PCV), total plasma protein (TPP), plasma
      ascorbic acid (VIT C), plasma alpha-tocopherol (VIT E) and erythrocyte
      glutathione (GSH) concentrations, erythrocyte glutathione peroxidase (GPX),
      plasma aspartate aminotransferase (AST) and plasma creatine kinase (CK)
      activities were measured at 0, 40, 80 km and 60 min of recovery (REC) at OD80,
      and 0, 64, 106, 142, 160 km and REC at OD160. In both races, no changes were
      found in plasma VIT E concentration, but VIT C and GSH concentrations decreased
      (P<0.05), and mean GPX, AST and CK activities increased from 0 km (P<0.05).
      Indices of muscle cell leakage (plasma AST and CK) were correlated (r = 0.36 to
      0.67; P<0.03) with indices of antioxidant status (VIT C, GSH and GPX).
      Associations between increased muscle leakage and decreased antioxidant status
      may, in part, reflect oxidative stress and suggest the testing of antioxidant
      supplements in endurance horses to improve performance and welfare.

PMID- 12405671
TI  - A lactate-guided conditioning programme to improve endurance performance.
AB  - Blood lactate measurements are used widely in horses to assess athletic
      performance, but there are few published data on using lactate as a guide for
      endurance improvement. The velocity at which blood lactate concentration ([LA])
      of 4 mmol/l is reached (v4) is widely used to determine fitness. In an earlier
      study of v4, exercise at low intensities for longer duration was more effective
      at improving endurance than shorter, higher intensities. However, the
      prescription was unchanged during the study (6 weeks). We hypothesised that, to
      produce greater improvement in v4 in the same time frame, it is necessary to
      adjust conditioning regimes more frequently. Six horses underwent an initial
      treadmill-based standard exercise test (SET). A regression analysis [LA]-speed
      relationship was used to calculate v2. Horses were then conditioned for 45 min at
      their calculated v2 3 times/week (6% incline). Every 2 weeks the horses performed
      an SET to evaluate the v2 conditioning protocol which ended with SET 4. Mean v4
      increased 17% from SET 1 to SET 4 (P = 0.003; 5.8 +/- 03 to 6.8 +/- 0.4 m/s).
      This study demonstrates that a lactate-guided conditioning programme can
      significantly enhance endurance performance over a 6-week time peroid when the
      conditioning protocol is adjusted every 2 weeks based on v4 improvement.

PMID- 12405672
TI  - The cost of transport in an extended trot.
AB  - We hypothesised that trotters during an extended trot have lower energetic costs
      of locomotion (CT) than horses not bred for this behaviour. VO2 was measured as a
      function of speed in 7 Arabian horses (3 trained to extend their trotting speeds)
      and in 2 horses, of similar mass, bred to trot (Hackney). Both oxygen consumption
      and CT increased with speed and there was, contrary to our hypothesis, no
      difference between breeds. In Arabians at 6.5 m/s, CT had increased 25% above the
      CT at 5.0 m/s (normal transition speed). For Hackneys at 6.8 m/s, the CT was
      almost 35% higher. Stride frequencies increased linearly in all horses up to 5.0
      m/s. At the canter at 5.0 m/s, the frequency increased 9% to 111 strides/min, but
      then increased minimally with speed. In the Hackneys and the Arabians that
      extended the trot, stride frequencies were approximately 102 and did not increase
      with speed. Stride length (SL) increased linearly with speed in both trotting and
      cantering horses, and cantering SL were lower than trotting (at 5.0 m/s, SL for
      trotting = 3.04 m and for cantering SL = 2.68 m). There were no differences
      between breeds in stride frequency or stride length. Extending the trot can have
      profound energetic requirements that could limit athletic performance and may
      lead to increased concussive impact on the limbs.

PMID- 12405673
TI  - Plasma lactate and uric acid responses to racing in pacing Standardbreds and
      relationships with performance.
AB  - Relationships between racing performance and plasma lactate and uric acid
      concentrations after racing were investigated in pacing Standardbred racehorses.
      The study was undertaken in order to better understand factors that limit racing
      performance. Twenty horses were tested after races of 1760 m and 28 horses after
      races over 2160 m. Blood samples were taken 30-60 min before and 8 and 30 min
      after a race. There were no significant differences between the race distances
      for prerace and 8 min postrace plasma lactates. Significant low correlations were
      obtained for plasma lactate concentration 8 min postrace and the number of race
      wins (r = 0.29, P = 0.04), number of race placings (1st, 2nd or 3rd; r = 0.34, P
      = 0.02) and lifetime earnings (r = 0.29, P = 0.04). Net lactate was correlated
      with the number of race placings (r = 0.31, P = 0.03). There were no significant
      correlations between performance indices and plasma uric acid concentrations in
      races of 1760 m. For races over 2160 m, correlations were found between plasma
      uric acid concentration at 8 min postrace and the number of race wins (r = 0.37,
      P = 0.06, 95% confidence limits 0-0.65). As well, there was a significant
      correlation between uric acid concentration at 8 min postrace and lifetime
      earnings (r = 0.35, P = 0.07, 95% confidence limits 0.06-0.64). Only 10-15% of
      the variability in retrospective career performance in pacing Standardbreds can
      be explained by these metabolic markers of the muscle anaerobic response to
      racing. Plasma lactate and uric acid responses to maximal exercise are unlikely
      to be useful for evaluating racing performance in pacing Standardbreds in
      univariate analysis.

PMID- 12405674
TI  - Heart rate and blood lactate responses during exercise in preparation for
      eventing competition.
AB  - The aim of this study was to investigate the heart rate and blood lactate
      responses to exercise in event horses in normal training, and to compare them to
      those encountered in eventing competition. It was hypothesised that the responses
      during exercise in the course of training for CCI*** events would be
      significantly different from those of the Cross-Country day. Heart rates and
      blood lactate concentrations were measured in 13 elite event horses after intense
      exercise sessions conducted during the late stages of preparation for CCI*** or
      CCI**** 3-day-event competition. Mean +/- s.d. heart rate during exercise was 138
      +/- 17 beats/min and mean blood lactate concentration after exercise was 1.0 +/-
      0.6 mmol/l. These values were compared to heart rates and blood lactate
      concentrations recorded during and after a CCI*** Cross Country course using
      unpaired t tests (unequal variances) and 99.9% confidence interval analysis. Mean
      heart rates during and blood lactate concentrations after the competition were
      195 +/- 8 beats/min and 10.2 +/- 4.2 mmol/l. The 99.9% confidence intervals were
      183-207 beats/min and 7.7-12.6 mmol/l. Heart rates and blood lactate
      concentrations recorded during exercise sessions were significantly lower than
      competition values (P<0.001) and lay outside 99.9% confidence intervals for most
      horses. Only one horse achieved heart rates and blood lactate concentrations
      during exercise sessions that were similar to those occurring in competition. The
      intensity of exercise during normal training sessions was much lower than during
      competition, suggesting that many event horses are not appropriately trained.

PMID- 12405675
TI  - Physiological responses of young Thoroughbreds during their first year of race
      training.
AB  - Yearling horses are typically trained for more than a year before they begin
      racing; therefore, we questioned how relevant analyses of the initial responses
      to training are compared to physiological responses that occur over a year of
      training, and whether young horses with no history of training would respond the
      same as older horses that had been trained previously. We hypothesised that
      changes in O2 transport over the last months of a year of training would be
      different than at the beginning. We trained 5 yearling Thoroughbreds and
      evaluated metabolism, O2 transport and echocardiograms. Measurements were made
      before breaking (T1), after 6 months of training (T2) and following an additional
      4 months of training (T3). We compared 5 trained horses (TR) with 5 untrained
      (UT) sex-, size- and age-matched yearlings kept at pasture and in boxes.
      Satellite telemetry indicated UT moved less total daily distance than TR during
      winter and more during summer, but UT walked for 80% of their distance, TR only
      25%. The UT increased body mass (Mb) after T1 by 13% and were significantly
      heavier and fatter than TR. Specific aerobic capacity (VO2max/Mb) increased by
      16% in both groups at T2, but by T3 was not different from T1 in UT, but was
      higher in TR (19%>T1, 15%>UT). In TR, specific cardiac output (Q/Mb) increased by
      13% at T2, and specific stroke volume (V(S)/Mb) were larger at T2 and T3 than T1
      and UT at the same times both by physiological (15-16%) and echocardiographical
      (22-23%) estimates. Increased Vs was a primary correlate of the sustained
      increase in VO2max/Mb in TR. The large increases in V(S) and VO2max had occurred
      by T2 and changed only slightly by T3.

PMID- 12405676
TI  - Effect of training on age-related changes in plasma insulin and glucose.
AB  - The purpose of the study was to determine whether 12 weeks of exercise training
      would affect plasma glucose and plasma insulin concentrations in young and older
      Standardbred mares. Eighteen healthy, unfit mares representing 3 age groups were
      used: young (Y = 6.8 +/- 0.4 years; n = 6), middle-aged (MA = 15.2 +/- 0.4; n =
      6), and old (O = 27.0 +/- 0.2; n = 6). Pre- and post-training incremental
      exercise tests (GXT) were performed to measure plasma glucose and insulin
      concentration from immediately after, until 120 min postexercise. Training
      consisted of exercise 3 days/week (weeks 1-8) and 4 days/week (weeks 9-12) at a
      submaximal intensity (approximately 60% of pretraining HRmax) for approximately
      30 min/day. Old mares had lower levels of glucose after the GXT when compared to
      Y and MA mares (P<0.05). There was also a time-by-age interaction (P = 0.003) in
      that, at 120 min post-GXT, glucose levels had not returned to pre-exercise
      values. Plasma glucose concentrations, in response to acute exercise, were not
      altered by training for any age group (P>0.05). Prior to exercise training, O
      mares had higher plasma insulin compared to Y and MA mares at 120 min
      postexercise (P<0.05), and insulin was also elevated in O mares compared to all
      other time points at 120 min post-GXT (P<0.05). Training resulted in increased
      plasma insulin concentrations at 120 min post-GXT in all age groups (P<0.05). In
      conclusion, age affected glucose and insulin responses to acute exercise prior to
      and after 12 weeks of exercise training. With regards to insulin, 12 weeks of
      exercise training resulted in a postexercise rebound hyperinsulinaemia, which may
      be related to an increased need for glycogen repletion in the muscle. These
      factors are important in considering the ability of an older horse to tolerate
      exercise.

PMID- 12405677
TI  - Does training affect mRNA transciption for cytokine production in circulating
      leucocytes?
AB  - Physical exertion is a stimulus for the upregulation of cytokine production
      including IL-1beta, IL-1ra, IL-2, IL-4, IL-6, IL-10 and TNF-alpha in horses. To
      investigate that hypothesis, we initiated training of 5 stall-rested
      Thoroughbreds. Blood samples were drawn before and weekly during training. The
      relative transcription of mRNA within the leucocytes was measured using real time
      TaqMan quantitative PCR. The training protocol was walking (3 min), trotting (3
      min) and cantering/galloping (6 min) increasing in intensity weekly (6 to 12 m/s)
      and culminating in an intense exercise period. Comparisons of mRNA concentrations
      were made using a repeated measures ANOVA on ranks and a Student-Newman-Keuls
      pair-wise multiple comparison (P<0.05). The training programme or intense
      exercise bout did not affect IL-2, IL-4, IL-6 and IL-10. IL1-beta and TNF-alpha
      transcription increased on Day 23. TNF-alpha peaked on Day 23 and IL1-beta on Day
      30. Neither demonstrated a response to intense exercise. IL-1ra decreased
      significantly on Day 9; rose significantly from Day 9 to Days 16 and 23; remained
      significantly elevated through Days 30 and 37 over Day 9, and rose very slightly
      after intense exercise on Day 56. Alterations in leukocyte cytokine responses may
      influence susceptibility to infectious disease, metabolic responses to exercise
      or exercised induced syndromes.

PMID- 12405678
TI  - Relationship between markers of blood oxidant status and physiological variables
      in healthy and heaves-affected horses after exercise.
AB  - Exercise-induced oxidative stress is investigated as a potential performance
      limiting factor in human sports medicine. Therefore, the present study aimed to
      assess whether physiological variables that change with exercise intensity were
      correlated with blood oxidant markers in healthy and heaves-affected horses.
      Seven healthy horses, 8 heaves-affected in remission and 7 heaves-affected in
      crisis performed a standardised exercise test (SET) of stepwise increasing
      intensity. Variables monitored during exercise were heart rate (HR), venous
      plasma lactate (LA), packed cell volume (PCV) and arterial oxygen tension (PaO2).
      Oxidant markers (uric acid [UA], 8-iso-PGF2alpha and reduced [GSH] and oxidised
      glutathione [GSSG]) were analysed in venous peripheral blood sampled at rest (R),
      at peak-exercise intensity (Emax), 15 (E15) and 60 (E60) min after SET. There was
      a significant effect of heaves on oxidant markers and, therefore, correlation
      analyses between physiological variables and oxidant markers were performed
      separately per horse group. In healthy horses, UA analysed at Emax was positively
      correlated with LA. Furthermore, GSH analysed at Emax and E15 was positively
      correlated with PaO2. In healthy and heaves-affected horses in remission, GSH and
      GSSG determined at Emax were negatively correlated with HR. There was no
      significant correlation between 8-iso-PGF2alpha and physiological variables. In
      conclusion, a correlation between the physiological response to exercise and some
      oxidant markers exists in healthy horses. However, in heaves-affected horses the
      blood oxidant status is probably more dependant on airway disease than on
      exercise. Future studies should be undertaken to assess whether antioxidant
      supplementation might positively influence the oxidant-antiodidant balance in
      exercising horses.

PMID- 12405679
TI  - Effect of frusemide on bodyweight loss and recovery in racing Standardbreds.
AB  - This study was conducted to compare bodyweight (bwt) loss and recovery in
      Standardbred horses receiving frusemide compared to controls. Thirty Standardbred
      horses from 7 training stables that were racing at the Red Mile in Lexington,
      Kentucky, during the spring 2001 pari-mutuel meeting were studied. Fourteen
      horses (FRU) received frusemide (250 mg/horse i.v.) 4 h prior to racing, while 16
      horses (NFRU) did not received frusemide. Horses were weighed on the morning of
      race day, prior to warm-up, after racing and the next day. Changes in bwt were
      calculated as percentage increase or decrease from initial bwt. Prior to warm-up,
      FRU horses had a mean bwt reduction of 1.30 +/- 0.63%, (P<0.01), compared to a
      0.19 +/- 0.63% increase for the NFRU horses. FRU horses had a greater (P<0.03)
      postrace bwt loss (3.55 +/- 0.55%) than the NFRU horses (2.71 +/- 0.66%). On the
      morning after racing, bwt was still below initial values by 0.90 +/- 0.55 and
      1.24 +/- 0.35% for the FRU and the NFRU horses, respectively. While frusemide
      administration increased the postrace weight loss in racing Standardbreds, it did
      not affect short-term bwt recovery. Further research is required into management
      strategies required to allow horses to replenish fluids and electrolytes safely
      following strenuous exercise.

PMID- 12405680
TI  - Equine endurance exercise alters serum branched-chain amino acid and alanine
      concentrations.
AB  - Six 2-year-old Arabian horses were used to determine whether 60 km prolonged
      endurance exercise (approximately 4 h) alters amino acid concentrations in serum
      and muscle, and the time required for serum amino acid concentrations to return
      to basal resting values. Blood and muscle samples were collected throughout
      exercise and during a 3 day recovery period. Isoleucine concentration in muscle
      tended to increase and leucine and valine did not change due to exercise. Serum
      alanine concentrations did not increase immediately after exercise, but increased
      at 24, 48 and 72 h postexercise. Serum isoleucine, leucine, and valine
      concentrations decreased after exercise and time required to reach pre-exercising
      concentrations was 48 h. In conclusion, endurance exercise in the horse decreases
      serum isoleucine, leucine, and valine concentrations, and increases serum alanine
      concentration. The decrease in serum branched-chain amino acid concentrations did
      not correspond to a measurable increase in total muscle branched-chain amino acid
      concentrations.

PMID- 12405681
TI  - Maintenance of bodyweight during a multiple-day chuckwagon race meet.
AB  - The gruelling race schedules maintained by horses competing in chuckwagon racing
      raises concern for the horses' ability to recover quickly and continue to perform
      at a high level. The amount of bodyweight lost and the time required for recovery
      of this weight loss have been used to assess the level of stress imposed on
      horses competing in various multiple-day events. In this study, bodyweights were
      obtained from 40 Thoroughbred geldings (mean +/- s.e.; bodyweight 521.5 +/- 4.4
      kg) before and after racing during a 5 day chuckwagon race meet. Body condition
      score (BCS) was determined on the first and last day of competition. Comparisons
      were based on the number of consecutive days the horse raced. Average bodyweight
      loss (P = 0.039) from each race was 3.5 +/- 0.3 kg (0.7% of initial bodyweight)
      and was not affected by the number of days the horse raced. The largest
      bodyweight deficit (P = 0.005) occurred within the 24 h period after their first
      race (5.3 +/- 0.5 kg; 1.0% of initial bodyweight). Horses racing on 2-5
      consecutive days retained a 4.8 +/- 0.3 kg deficit (P = 0.01), which was
      maintained throughout the remainder of the race meet. Horses began and ended the
      race meet with a BCS of 4.9 +/- 0.2 and 4.7 +/- 0.2, respectively (using the 1 to
      9 BCS system). Although chuckwagon horses compete in a strenuous event on several
      consecutive days, they appear to be managed well and have the ability to maintain
      their bodyweight despite the physical and psychological demands of frequent
      racing.

PMID- 12405682
TI  - Effects of weight carrying, exercise and a myo-anabolic supplement on growth and
      muscle.
AB  - Weight training is commonly used by human athletes to increase strength and
      fitness. This study was performed to examine the effect of weight-carrying and
      nutritional supplementation on muscle development and growth in young horses.
      This study examined the effect of weight-carrying and nutritional supplementation
      on muscle development and growth. Seventeen horses were divided into 3 groups:
      controls exercised in a free-flow exerciser, a weight group that performed the
      same exercise, carrying progressively increasing weight up to 45 kg, and a weight
      supplement group, that also received a myo-anabolic supplement. Horses were
      accustomed to handling for 30 days then baseline measurements of weight, body
      condition score, wither height, hip height, forearm and gaskin circumferences,
      and cross-sectional area of the longissimus dorsi were taken. Horses were stalled
      for 108 days then conditioned for 78 days. At the end of conditioning, all
      measurements were taken again. Supplemented weight-carrying horses increased
      their lean body tissue, as indicated by greater bodyweight (P<0.05) combined with
      decreased body condition score (P<0.01). Greater increases in wither height (P =
      0.09) and hip height (P<0.01) were seen in weight-carrying horses, probably the
      result of increased muscle tone. Supplemented weight-carrying horses increased
      forearm (P<0.01) and gaskin circumferences (P<0.05). It is believed that weight
      carrying, when combined with additional dietary protein, enabled greater muscle
      anabolism. Additional research into the potential additive effect of resistance
      training and diet are warrented.

PMID- 12405684
TI  - Effect of exercise on plasma ferritin concentrations: implications for the
      measurement of iron status.
AB  - Iron is of key importance for aerobic metabolism, and natural feeds of the horse
      are fairly rich sources of iron. Accordingly, the known incidence of iron
      deficiency anaemia is apparently rare in performance horses; despite this, iron
      deficiency in performance horses continues to be of concern to trainers and
      veterinarians. Effects of exercise on plasma ferritin concentrations were
      therefore studied in Standardbreds, Finnhorses and half-bred riding horses. Blood
      samples were taken after a moderate exercise test on a racetrack, a competition
      exercise test on a treadmill and a race. Even moderate exercise caused an
      increase in plasma ferritin concentration, with the increase being greater as the
      intensity and duration of exercise increased. Return to the basal level was
      slower after maximal-intensity exercise than after moderate exercise. In
      conclusion, although ferritin is a useful marker of low iron stores, samples
      should be taken only after at least 2 days rest following strenuous exercise.

PMID- 12405683
TI  - Benefits of moderate training to the nonspecific immune response of colts.
AB  - The aim of this work was to assess whether progressive training caused an
      improvement in the nonspecific immune response of colts because several unusual
      infections are due to defects inherent in the neutrophilic function among which
      respiratory diseases are a major defect in the performance of athletes taking
      part in professional sports activities. A group of 7 Anglo-Arabian colts
      belonging to the Army was selected. These animals carry out training programmes
      for their participation in National Jumping Competitions. During a submaximal
      exercise test (heart rate 150 beats/min and lactate levels maintained at aerobic
      anaerobic threshold of 3 mmol/l), they were compared with 5 colts of the same
      breed, just beginning training exercises. Immediately after the test, the
      nonspecific immune capacity of neutrophilic polymorphonuclear cells was valued by
      adherence, chemotaxis, ingestion and digestion of foreign substances tests. The
      results showed significant differences between trained and nontrained animals for
      the adherence and foreign particle digestion tests and, beginning with a greater
      adherence in untrained animals, a superior effectiveness was achieved in the
      immune function in trained colts, whose digestive capactiy was increased with
      respect to the untrained ones. It was, therefore, concluded that moderate
      training and exercise improves and reinforces the response of the nonspecific
      immune system against future infections in the organisms.

PMID- 12405685
TI  - Ribose supplementation in maximally exercising Thoroughbreds.
AB  - A diverse group of studies, which are equine exclusive, indicate that ribose
      administered to myocardial and skeletal muscle tissue stimulates ATP production
      and recovery. This study investigated the effects of ribose supplementation on
      blood and muscle metabolites and performance in Thoroughbred geldings performing
      a maximal treadmill standardised exercise test (SET). In Experiment 1, 6
      conditioned Thoroughbred geldings performed a baseline SET and horses were
      assigned to one of 2 experimental treatment groups, placebo or ribose, based on
      VO2max. The placebo treatment group received 0.07 g glucose/kg bodyweight (bwt)
      and ribose treatment group received 0.07 g ribose/kg bwt top dressed on the feed
      twice daily. Following a 2 week treatment period, a second SET was performed.
      After a one-week washout period, the horses switched treatment groups. Following
      another 2 week treatment period, a third SET was performed. Blood ammonia-N was
      lower in the ribose treatment group at 15 min (P = 0.06) and 30 min (P = 0.02)
      postexercise. Plasma lactic acid was lower in the ribose treatment group at 30
      min postexercise (P = 0.07). In Experiment 2, 1 h before a SET, 2 horses received
      3 l water (control) and 3 horses 250 g of ribose dissolved in 3 l water (single
      ribose dose) via a nasogastric tube. Following a 2 week washout period, the
      horses switched treatment groups and another SET was performed. There were no
      differences in blood ammonia-N, plasma lactic acid or glucose between treatment
      groups. No differences in performance were detected between treatment groups in
      either experiment. In conclusion, the results from Experiment 1 show a trend that
      daily ribose supplementation may be beneficial during recovery from exercise.
      However, a single dose of ribose 1 h before exercise revealed no effect on the
      variables measured. Because moderate to intense daily exercise can cause a
      decrease in total adenine nucleotide (TAN) pool with no meaningful recovery even
      after 72 h rest, future experiments should be designed to futher elucidate the
      effects of ribose supplementation on TAN metabolism in horses exercising at high
      intensity.

PMID- 12405686
TI  - Changes in skeletal muscle GLUT4 content and muscle membrane glucose transport
      following 6 weeks of exercise training.
AB  - This study examined changes in skeletal muscle GLUT4 content and glucose
      transport in isolated muscle membranes (GT) from horses before and 2 min after
      standardised submaximal exercise tests (SET) prior to and after completion of 6
      weeks of training. Seven horses, age 3-9 years, body mass mean +/- s.e. 530 +/-
      19 kg, and sedentary for at least 4 months, completed 6 weeks of training on a
      treadmill. An initial SET (UT) was performed on a 4 degree incline at a speed
      equivalent to 55% of pretraining VO2max and was repeated post-training at the
      same absolute workload (ABS). A third SET (REL) was performed at 55% of post
      training VO2max. There was no significant pre- to postexercise change in GLUT4
      content before or after training. Following training, total GLUT4 content was
      increased 2- or 3-fold in pre-exercise biopsies (pre UT: 0.30 +/- 0.05; pre ABS:
      1.05 +/- 0.32; pre REL: 1.34 +/- 0.28 arbitrary units) (P<0.05) with similar
      increases in postexercise GLUT4 content (P<0.05) (post UT: 033 +/- 0.06; post
      ABS: 1.19 +/- 0.44; post REL: 1.43 +/- 0.31). GT increased 2.5- to 6-fold in
      postexercise muscle membrane vesicles in UT over a range of glucose
      concentrations. After training (ABS and REL), there was a 25-50% attenuation
      (P<0.05) in membrane GT in response to exercise in ABS and REL. These finding
      indicate that moderate intensity exercise training increased middle gluteal
      muscle GLUT4 content, but this change was not reflected in an increase in muscle
      membrane glucose transport activity in postexercise muscle samples.

PMID- 12405687
TI  - Pro- and macroglycogenolysis in skeletal muscle during maximal treadmill
      exercise.
AB  - The purpose was to investigate the degradation of proglycogen and macroglycogen
      in skeletal muscle during intense exercise. Ten Standardbred trotters performed a
      maximal treadmill exercise test comprising a warm-up period, an exercise period,
      starting at 7 m/s with increments of 1 m/s every 60 s until the onset of fatigue
      (mean +/- s.d. 246 +/- 32 s) and a walking recovery period. Muscle biopsies were
      taken at rest, immediately after exercise and 15 min postexercise. The exercise
      caused a marked anaerobic metabolism as shown by the decrease in both muscle ATP
      and creatine phosphate and increase in muscle lactate. Free muscle glucose
      increased immediately postexercise and a further increase was noted 15 min later.
      There was a significant decrease (P<0.05) in proglycogen (57.1 +/- 22.2 mmol/kg
      dw) and macroglycogen (63.0 +/- 65.5 mmol/kg dw) during exercise. The proglycogen
      concentration tended to increase 15 min after exercise (19.9 +/- 27.3 mmol/kg dw;
      P = 0.06). The results from this study demonstrate that both proglycogen and
      macroglycogen contribute equally to glycogenolysis during intense exercise and
      suggest that glycogen resynthesis starts in the proglycogen pool.

PMID- 12405688
TI  - Effect of an endurance race on muscle amino acids, pro- and macroglycogen and
      triglycerides.
AB  - Glycogenolysis and lipolysis are essential for energy production in muscle during
      prolonged exercise but less is known about the role of amino acid metabolism. The
      aim was to study the effect of an endurance race on pro- and macroglycogen,
      triglycerides and amino acid concentrations in muscle and on selected blood
      parameters, especially the amino acid response in the blood during the recovery
      phase. Seven endurance-trained horses completed a race covering 100-120 km. Blood
      samples were collected one day before the race, after the finish and 1 and 8 days
      after the race. Needle biopsy specimens from the gluteus medius muscle were taken
      on completion of the race and 8 days postrace. The pro- and macroglycogen
      concentrations were lower and most amino acid concentrations were higher in the
      muscle after the finish of the race, than 8 days postrace, whereas the
      triglyceride concentrations did not differ. The concentrations of several amino
      acids in serum were higher during the recovery phase than before the race. The
      observed changes suggest that an endurance race influences amino acid metabolism
      and a net protein degradation may occur that persists during the recovery phase.
      Furthermore, the results suggest that macroglycogen is utilised to a greater
      extent than proglycogen during an endurance race. Further research is needed
      concerning amino acid metabolism during an endurance race as it seems to play an
      important role both for performance and recovery after exercise.

PMID- 12405689
TI  - Induction of heat shock protein 72 mRNA in skeletal muscle by exercise and
      training.
AB  - In response to stress, cells synthesise heat shock proteins (HSP) to maintain
      protein homeostasis. To study whether exercise and training induce expression of
      HSP72 in the middle gluteal muscle, 10 Finnhorses performed a submaximal 60 min
      exercise test on a treadmill. Test A was performed after 3 months of training,
      and the other two tests 2 (B) and 5 (C) weeks later. Blood samples were taken
      during and after the tests, and biopsy samples before, immediately after and 23 h
      after each test. HSP72 mRNA was analysed using a digoxigenin-labelled probe.
      Blood lactate concentration in the 3 tests varied between 7.2 and 10.2 mmol/l.
      Training increased HSP72 mRNA, as indicated by increases in samples taken at rest
      (A<B<C). Exercise also tended to increase HSP72 mRNA transiently but, 23 h later,
      values had returned to pre-exercise levels. HSP72 mRNA was expressed in all
      muscle fibres. After exercise, HSP72 mRNA correlated positively with the peak
      concentration of blood lactate, but not with indicators of energy status.
      Therefore, acidosis rather than energy depletion was the major inducer of HSP72
      expression after moderate intensity exercise. Because HSP72 may protect cells
      against stress, knowledge about their expression may help in planning optimal
      trainng regimes.

PMID- 12405690
TI  - Effect of glucosamine on interleukin-1-conditioned articular cartilage.
AB  - Glucosamine inhibits recombinant human interleukin-1 stimulated cartilage
      degradation in equine cartilage explants. Recently, recombinant equine
      interleukin-1 has been cloned and purified. Therefore, the objective of this
      study was to characterise the effects of glucosamine on indices of cartilage
      degradation in recombinant equine IL-1beta-stimulated equine articular cartilage
      explants. Cartilage discs were harvested from the weight-bearing region of the
      articular surface of the antebrachiocarpal and middle carpal joints of horses
      (age 2-8 years) and cultured under standard conditions. Explants were exposed to
      recombinant equine interleukin-1beta (reIL-1beta) on Days 1-4 in the presence or
      absence of glucosamine (0.25, 2.5 or 25 mg/ml), with appropriate controls. Nitric
      oxide, prostaglandin E2, sulphated proteoglycan, stromelysin and
      gelatinase/collagenase activity released into conditioned media and total tissue
      proteoglycan content were measured as indicators of cartilage catabolism.
      Glucosamine inhibited cartilage catabolic responses in a dose dependent manner
      that was statistically significant at a dose of 0.25 mg/ml for stromelysin
      activity and 2.5 mg/ml for collagenase/gelatinase activity. At 25 mg/ml
      glucosamine also prevented IL-1beta-induced increases in nitric oxide production,
      prostaglandin E2 and proteoglycan release to media. Glucosamine prevents equine
      articular cartilage degradation experimentally induced by reIL-1beta in vitro.
      These data provide further support for the use of glucosamine in treatment or
      prevention of cartilage loss in athletic horses.

PMID- 12405691
TI  - Inhibition of articular cartilage degradation by glucosamine-HCl and chondroitin
      sulphate.
AB  - Glucosamine and chondroitin sulphate in many animal and human trials has improved
      joint health. In vitro studies are beginning to clarify their mode of action. The
      objective of this research was to: 1) determine at what concentrations
      glucosamine-HCl (GLN) and/or chondroitin sulphate (CS) would inhibit the cytokine
      induced catabolic response in equine articular cartilage explants and 2) to
      determine if a combination of the 2 was more effective at inhibiting the
      catabolic response than the individual compounds. Articular cartilage was
      obtained from carpal joints of horses (age 1-4 years). Cartilage discs (3.5 mm)
      were biopsied and cultured. Explants were incubated with lipopolysaccharide (LPS)
      in the presence of varying concentrations of GLN, CS, or both. Control treatments
      included explants with no LPS and LPS without GLN or CS. Media were analysed for
      nitric oxide (NO), prostaglandin E2 (PGE2) and keratan sulphate. Cartilage was
      extracted for analysis of metalloproteinases (MMP). Four experiments were
      conducted. In all experiments, GLN at concentrations as low as 1 mg/ml decreased
      NO production relative to LPS stimulated cartilage without GLN over the 4 day
      period. In general, CS at either 0.25 or 0.5 mg/ml did not inhibit NO production.
      The addition of CS to GLN containing media did not further inhibit NO production.
      GLN at concentrations as low as 0.5 mg/ml decreased PGE2 production, whereas CS
      did not effect on PGE2. The combination of GLN/CS decreased MMP-9 gelatinolytic
      activity but had no effect on MMP-2 activity. The combination in 2 experiments
      tended to decrease MMP-13 protein concentrations and decreased keratan sulphate
      levels in media. Overall, the combination of GLN (1 mg/ml) and CS (0.25 mg/ml)
      inhibited the synthesis of several mediators of cartilage degradation. These
      results further support the effort to understand the role of GLN and CS in
      preserving articular cartilage in athletic horses.

PMID- 12405692
TI  - Forelimb skeletal scintigraphy responses in previously untrained Thoroughbreds
      undergoing initial treadmill training.
AB  - Scintigraphy has been used in numerous clinical settings to examine horses to
      determine the origin of lameness problems, but it has not been used previously to
      monitor prospectively the skeletal responses of a group of similarly-trained
      racehorses. Our hypothesis was that in naive Thoroughbred (TB) racehorses,
      initial treadmill training induces increased radiopharmaceutical uptake in high
      motion joints and in the dorsal third metacarpal bone (MC3). Eight previously
      untrained TB racehorses underwent sequential skeletal scintigraphic examinations
      as they exercised daily for 9 weeks on an inclined treadmill. At the end of Weeks
      0 (pre-training), 3 (trotting at 4.2 m/s and initial galloping), 6 (galloping at
      7.5 m/s), and 9 (sprinting 600 m at 12.5 m/s), horses received 140 mCi 99m
      Technetium-methylene diphosphonate i.v. followed by a standard skeletal
      scintigraphic forelimb examination 2 h later. Views were graded for increased
      radiopharmaceutical uptake by 3 co-investigators who were blinded to horse
      identification, breed, sex, date, and clinical findings. Results were compared
      before and after training for each skeletal location using the Mann-Whitney Rank
      Sum Test with the level of significance set at P<0.05. Initial treadmill training
      resulted in increased radiopharmaceutical uptake in the carpus (P = 0.031),
      metacarpophalangeal joint (P = 0.021), proximal phalanx (P = 0.035), and distal
      phalanx (P = 0.003). Training did not affect dorsal MC3 radiopharmaceutical
      uptake (P>0.05).

PMID- 12405693
TI  - Influence of trotting and supplemental weight on metacarpal bone development.
AB  - The use of weight-training to alter bone strength has not been investigated in
      horses. Recognising that bone responds to loading, we studied the effect of
      carrying weight on bone development during training. Seventeen horses were
      divided into 3 groups: controls exercised counterclockwise in a free-flow
      exerciser; the weight group performed the same exercise carrying progressively
      increasing weight up to 45 kg and the weight supplement group also received a myo
      anabolic supplement. Radiographic equivalence measure of bone mineral content of
      zones of the third metacarpi (MCIII) was determined on 4 occasions: baseline (Day
      108), pre-conditioning following 108 days stall confinement (Day 0), mid
      conditioning (Day 39) and end-conditioning (Day 78). Stall confinement resulted
      in loss of mineral in lateral and medial cortices of both MCIII. During
      conditioning, weight-carrying increased mineral deposition in lateral and medial
      cortices of MCIII of the left (inside) leg compared with controls. In the right
      leg, controls had lower mineral content of the lateral cortex at Day 39 than
      weight-carrying horses but no differences between treatments were recorded at Day
      78. Markers of bone metabolism did not change from baseline to pre-conditioning,
      but increased from Day 0 to 39 and 78 for all groups. This study demonstrates the
      benefits to bone mineral deposition in the third metacarpi of carrying weight
      when trained at low speeds and re-emphasises the potential for bone loss when not
      given sufficient exercise.

PMID- 12405694
TI  - Correlation of cartilage oligomeric matrix protein (COMP) levels in equine tendon
      with mechanical properties: a proposed role for COMP in determining function
      specific mechanical characteristics of locomotor tendons.
AB  - Over-strain injury of the superficial digital flexor tendon (SDFT) is a common
      injury in the horse. Tendon appears to adapt to loads placed on it during
      development, but fatigue damage accumulates after skeletal maturity, which is
      inadequately repaired and predisposes to clinical tendinitis. In any population
      of horses, there is a wide variation in SDFT mechanical properties. A
      noncollagenous protein, cartilage oligomeric matrix protein (COMP), is
      particularly abundant during growth in the equine SDFT and has been proposed to
      have an organisational role in the formation of collagenous matrices. This study
      aimed to determine whether COMP levels were correlated to mechanical properties
      at skeletal maturity. Tendons from 2 groups of 12 horses were analysed: Group 1
      horses with restricted age, 2 years +/- 2 months, showed a significant
      correlation between both ultimate tensile stress modulus of elasticity and
      stiffness and COMP, while Group 2 mature horses with varying age did not, because
      of age- and exercise-induced loss of COMP. These data supports the hypothesis
      that COMP is an important mediator in the growth of tendon. This data would
      suggest that the identification of low COMP levels in tendon during growth would
      indicate horses prone to tendon injury and methods of promoting COMP synthesis
      during growth would potentially improve tendon quality and reduce the risk of
      subsequent tendinitis.

PMID- 12405696
TI  - Effects of mild forelimb lameness on exercise performance.
AB  - Mild lameness is considered a performance-limiting problem that may escape
      detection until it worsens, and is considered the primary reason for reduced
      racing performance. The kinematics changes associated with a lame horse at the
      trot have been demonstrated previously, but the metabolic cost of these
      alterations in their gait have not been demonstrated. Six fit Thoroughbred horses
      with an established VO2max participated in 4 trials using a randomised cross-over
      design study, separated by 10-14 days. The horses were tested with one of 4 trial
      conditions: lead forelimb lameness (LL); off-lead forelimb lameness (OL);
      bilateral forelimb lameness (BL) or no lameness (NL). Lameness was induced by
      sole pressure from a modified shoe that resulted in a consistent slight head nod
      at a trot in a straight line while jogging in hand. Lameness was adjusted to
      provide a lameness that would be quantified as a 1-2/5 on the grading system
      recommended by the AAEP. Each trial consisted of 4 different levels of exercise
      intensity at speeds equivalent to 30, 60, 80 and 110% of an individual's speed
      required to elicit VO2max. Stride parameters, oxygen consumption (VO2), carbon
      dioxide production (VCO2), electrolytes, plasma lactate, glucose and PCV/TP were
      measured prior to exercise, at each exercise level and after exercise. A multiway
      ANOVA with repeated measures was utilised to examine possible effects of
      individual horse, lameness, and exercise intensity on measured parameters.
      Significance was set at alpha = 0.05. For horses exercising at the maximum
      intensity, VO2 was significantly lower for both of the single-leg lamenesses (LL
      or OL) when compared to NL or BL (mean +/- s.e. 165.6 +/- 2.5, 164.7 +/- 3.0,
      175.8 +/- 2.4 and 170.9 +/- 2.1 ml O2/min/kg bwt, respectively). Blood lactate
      concentrations were not significantly different among the treatment groups.
      However, lactate accumulation rates computed as the change with time in lactate
      concentration at the highest exercise intensity were significantly higher for LL
      and OL than for NL and BL (7.8 +/- 03, 83 +/- 0.2, 4.1 +/- 0.2 and 4.7 +/- 0.3
      mmol/min, respectively). Exercise intensity had significant effects on all of the
      measured parameters, but there were no other significant differences due to
      treatment. These results suggest that metabolic energy transduction is affected
      by even mild unilateral forelimb lamenesses.

PMID- 12405695
TI  - Effect of training duration and exercise on blood-borne substrates, plasma
      lactate and enzyme concentrations in Andalusian, Anglo-Arabian and Arabian
      breeds.
AB  - Metabolic responses to exercise differ between Andalusian horses and other
      breeds, although changes in plasma muscle enzymes have not been reported and most
      useful information is obtained from animals subjected to different training
      programmes. The objectives of this study were to 1) describe the changes in
      plasma enzymes during exercise in different horse breeds in relation to other
      biochemical parameters (Experiment A) and 2) assess the effect of training
      duration on these measures (Experiment B). Twenty stallions, 9 Andalusian (AN), 7
      Arabian (A) and 4 Anglo-Arabian (AA), age 5-10 years, were studied. They
      performed 3 exercise tests (ET), consisting of a warm-up of 800 m at 0.7 km/h and
      4 workloads at 15, 20, 25 and 30 km/h, at respective distances of 1250, 1670,
      2080 and 2500 m, with 5 min active recovery between each workload (Experiment A).
      Three ETs were performed at the beginning and after 2 and 6 months of training
      (Experiment B). Venous blood samples were collected during the ETs and plasma
      glucose (GLU), free fatty acids (FFA), lactate (LA), creatine kinase (CK),
      lactate dehydrogenase (LDH), alpha-hydroxybutyrate dehydrogenase (HBHD),
      aspartate aminotransferase (AST), Na+, K+ and Cl- were measured. AN horses
      responded to exercise with greater increases in GLU, HBHD, LDH, CK and AST
      compared to the other breeds. An unexpected result in Experiment A was the lack
      of interbreed differences in plasma peak LA concentrations, since it is commonly
      accepted that AA and A horses have greater athletic potential. Although the
      glycolytic response to exercise was reduced after 2 months of training in the AA
      and A horses, and after 6 months of training in the AN horses, at the end of
      Experiment B, AN horses produced more lactate than the other 2 breeds. Most of
      the adaptations linked to training were found in the AN breed. The more striking
      changes in plasma enzyme activities corresponded to CK in AN horses after 2
      months of training. The attenuation of CK response to exercise was related to
      lower extrafibrilar GLU utilisation with LA formation and greater fat metabolism.
      The results show that plasma muscle enzyme concentrations for the diagnosis of
      equine myopathies must be interpreted in relation to breed and training.

PMID- 12405697
TI  - Effects of prolonged training, overtraining and detraining on skeletal muscle
      metabolites and enzymes.
AB  - Thirteen Standardbred horses trained intensively for 34 weeks and detrained for
      12 weeks to investigate the effects of training, overtraining and detraining on
      muscle metabolites, buffering capacity and enzyme activities (CS, HAD and LDH).
      After a standardised exercise test to fatigue at 10 m/s (approximately 100%
      VO2max), there was significant depletion of [ATP], [PCr] and muscle [glycogen]
      and accumulation of muscle and plasma [lactate], [NH3] and elevated muscle
      temperature. After training, associated with increased run time to fatigue
      (148%), there was reduced depletion of muscle [glycogen] and increased [NH3] and
      muscle temperature at fatigue. Training resulted in increased muscle buffering
      capacity (19%) and activities of CS (29%) and HAD (32%) and reduced glycogen
      utilisation (1.32 mmol/s in week 1 to 0.58 mmol/s in week 32). Plasma [lactate]
      at fatigue increased with training as opposed to muscle [lactate] implying
      enhanced ability to remove lactate from muscle. Overtraining resulted in reduced
      run time and associated effects in overtrained horses. While muscle [glycogen]
      prior to exercise was lower in overtrained horses, glycogen utilisation/s was not
      reduced and it may not, therefore, have caused the reduced run time. Prolonged
      high intensity training caused primarily aerobic adaptations and poor performance
      associated with overtraining may not be due to metabolic disturbances.

PMID- 12405698
TI  - Exercise-induced tendon hypertrophy: cross-sectional area changes during growth
      are influenced by exercise.
AB  - Most skeletal tissues are thought to adapt to the mechanical environment they
      experience. While this has been demonstrated for muscle and bone, previous
      studies in the mature horse have failed to demonstrate adaptation in the
      superficial digital flexor tendon (SDFT), which suffers a high frequency of
      injury. This study tested the hypothesis that imposed exercise during growth
      would result in an increase in SDFT cross-sectional area (CSA). Fourteen
      Thoroughbred foals were divided into 2 sex-matched groups. A control group
      received 4 h pasture exercise and an exercise group had the same amount of
      pasture exercise with an additional short period of treadmill exercise daily from
      age 2-15 months. Activity at pasture was assessed objectively using a visual
      system. There was no significant difference in pasture activity between groups,
      although males were more active than females. The exercise programme resulted in
      a significantly larger tendon CSA in the exercise group at several, but not all,
      timepoints, which may be attributed to levels of variance. However, there was a
      significantly greater rate of increase in tendon CSA as a function of time in the
      exercised compared to the control group. This is the first evidence to suggest
      that tendon development can be modulated by exercise during growth in the horse,
      potentially increasing the ability of tendon to withstand the rigours of later
      athletic activity.

PMID- 12405699
TI  - Oral L-carnitine combined with training promotes changes in skeletal muscle.
AB  - The purpose of this study was to determine whether oral L-carnitine
      supplementation enhances the responses of skeletal muscle to training in seven 2
      year-old Standardbreds. Four horses were supplemented with 10 g/day L-carnitine
      for 10 weeks and 3 horses served as controls. All horses were exercised regularly
      every second day on a treadmill for 5 weeks (training period) and housed in
      individual boxes for 5 additional weeks (detraining period). The training period
      consisted of 8 high- and 8 low-speed exercises carried out in alternating
      sequence. Gluteus medius muscle biopsies were taken at Weeks 0 (pretraining), 5
      (post-training) and 10 (detraining). Muscular adaptations to training were
      observed mainly in the L-carnitine-supplemented horses and included an increase
      in the percentage of type IIA fibres (delta35%, P<0.05), atrophy of type I fibres
      (delta24%, P<0.01), a rise in the capillary-to-fibre ratio (delta40%, P<0.01) and
      an increase in the quantitative reaction of periodic acid Schiff stain (delta11%,
      P<0.05), used as an indicator of intrafibre glycogen content. After detraining,
      most of these adaptations reverted towards the pretraining situation. Therefore,
      exogenous carnitine has an additive effect on muscular responses to training and
      this should be favourable to improve athletic performance. Nevertheless, further
      studies are necessary to show whether muscle carnitine content is a limiting
      factor for fatty acid oxidation.

PMID- 12405700
TI  - Training-induced apoptosis in skeletal muscle.
AB  - Apoptosis or programmed cell death is a genetically controlled response of cells
      to commit suicide and is associated with DNA fragmentation or laddering. The
      common inducers of apoptosis include Ca2+i and oxygen free radicals/oxidative
      stress, which are also implicated in the pathogenesis of exercise-induced
      myopathies. To examine training-induced apoptosis, Thoroughbred horses were
      subjected to 3 months training programme on a treadmill. At the end of the
      training programme venous blood samples were taken for a creatine kinase (CK)
      assay. In addition, muscle biopsy samples were obtained for a membrane lipid
      peroxidation measurement by malondialdehyde (MDA) assay and for apoptosis
      detection. Apoptosis was studied by visualising the apoptotic myocytes on the
      paraffin sections by the modified TUNEL method. DNA laddering was evaluated by
      subjecting the DNA obtained from the biopsies to 1.5% agarose gel
      electrophoresis. There was a significant increase (P<0.05) of protein-bound MDA,
      and a nonsignificant trend (P = 0.14) for the control group to have higher levels
      of CK compared to the trained group. Under light microscopy, percentage of the
      TUNEL positive cells was higher (P<0.001) in the training group. This result was
      corroborated with the findings of DNA fragmentation by gel electrophoresis, which
      showed higher ladders of DNA band at the same group. In conclusion, these results
      clearly demonstrate that there is training-induced apoptosis in skeletal muscle.
      It is probable that apoptosis allows the work/recovery/rebound/supercompensation
      cycle, when unaccustomed muscle cells activate programmed cell death and are
      replaced by new and stronger cells, which is the mechanism for training-induced
      increases in fitness.

PMID- 12405701
TI  - Myosin heavy chain-based fibre types in red cell hyper- and normovolaemic
      Standardbred trotters.
AB  - An assumed link between red cell hypervolaemia, an excessive amount of training
      and impaired performance of hypervolaemic horses has led to a theory that the
      muscle fibres could be affected. Myosin heavy chain (MHC)-based fibre type
      composition in gluteus medius muscle of red blood cell normo- (NV) and
      hypervolaemic (HV) Standardbred trotters was evaluated using
      immunohistochemistry. Muscle biopsies were obtained from 13 NV and 16 HV horses.
      Serial transverse sections were cut and reacted with antibodies against different
      isoforms of the myosin heavy chains MHCI, MHCIIA and MHCIIX. Sections were also
      stained for myofibrillar ATPase pH 4,6 to identify types I, IIA and IIB, and NADH
      tetrazolium reductase to evaluate the oxidative capacity. The results show that
      types I and IIA fibres corresponded between staining methods, whereas IIB fibres
      in the ATPase stains were more numerous than pure MHCIIX fibres from
      immunohistochemistry. Many fibres identified histochemically as type IIB fibres
      contained both MHC isoforms IIA and IIX (MHCIIAX). Most fibres had a high
      oxidative capacity, but among the fibres within a section, the lowest was seen
      subjectively in pure MHCIIX fibres. Immunohistochemical stains make it possible
      to detect differences in fibre type composition that are not observed with myosin
      ATPase stainings, as it was found that HV horses had a lower percentage of MHCIIX
      fibres than NV horses. Immunohistochemical methods are, therefore, valuable for
      use in further research and clinical studies concerning muscle adaptations.

PMID- 12405702
TI  - Plasma carnosine concentration: diurnal variation and effects of age, exercise
      and muscle damage.
AB  - This study was undertaken as part of a larger investigation into carnosine
      metabolism and function in the Thoroughbred horse. More specifically, we wished
      to evaluate plasma carnosine concentration as a potential indicator of muscle
      carnosine status. In contrast to man, carnosine is present in equine plasma where
      its presence is consistent with the absence of plasma carnosinase. A significant
      effect of age on plasma carnosine concentration in resting Thoroughbred horses
      was observed. Values in horses age 3 years and older were 113-14.1 micromol/l,
      whereas concentrations in foals and yearlings were 3.9-8.7 micromol/l (P<0.001).
      Lower values in young horses may reflect lower skeletal muscle carnosine
      concentrations. There was no significant within-day variation in plasma carnosine
      concentration in fed and fasted horses (P>0.05). Intense exercise resulted in a
      small significant increase (P<0.05) in plasma carnosine concentration (pre
      exercise, 10.3 +/- 1.0 micromol/l; postexercise, 12.4 +/- 4.4 micromol/l).
      Greater increases were observed (57.6-702.3 micromol/l) following onset of
      exercise-induced rhadomyolysis (ERS). An apparent relationship was observed
      between elevated plasma carnosine and increased plasma creatine kinase (CK) and
      aspartate transaminase (AST) activities. Plasma carnosine concentrations did not
      reflect the severity of the condition as determined by clinical examination. In
      conclusion, elevated plasma carnosine levels are observed following exercise
      induced muscle damage, with the greatest elevations occurring during episodes of
      external rhabdomylosis syndrome. Plasma carnosine measurements could provide an
      alternative clinical indicator of muscle damage; and in conjunction with plasma
      taurine measurements may be indicative of selective type 1 or type 2 muscle fibre
      damage. However, given the complexity of the analytical technique, its
      applications would probably be confined to specialist referral or research
      centres.

PMID- 12405703
TI  - Do regional variations in flexor tendons predispose to site-specific injuries?
AB  - Partial rupture occurs most often to the superficial digital flexor tendon (SDFT)
      of the forelimb at the mid-metacarpal level. In this study, we tested the
      hypothesis that the mid-metacarpal region of the SDFT has the smallest cross
      sectional area (CSA) and a similar collagen content to other regions and,
      therefore, represents a weak point in the tendon. The SDFT was collected from the
      forelimbs of 9 horses. Each tendon was marked at 7 different levels from the
      origin of the accessory ligament to the phalangeal region. The CSA, water content
      and collagen content was measured at each level. The mid-metacarpal level had a
      significantly smaller CSA than the most proximal and distal levels measured and a
      significantly higher dry matter content than proximal levels. However, the total
      amount of collagen present in the mid-metacarpal section was not significantly
      less than other regions except for the most distal sections. The results of this
      study suggest that the mid-metacarpal region of the SDFT, although smaller in
      CSA, is not significantly weaker than the proximal end and manica flexoria region
      of the tendon. Therefore, other factors such as hypoxia and/or hyperthermia may
      be responsible for site-specific tendon lesions in the SDFT.

PMID- 12405704
TI  - Effects of trotting speed on muscle activity and kinematics in saddlehorses.
AB  - A thorough knowledge of the horse's back and limb movements at different speeds
      is important in the design of training programmes and the prevention of speed
      related injuries. The objective of this study was to investigate changes in
      muscle activity and kinematics of the trot with increased speed. To evaluate
      these effects, 4 Saddlehorses were recorded while trotting on a horizontal
      treadmill at speeds ranging from 3.5-6.0 m/s. The 3-D trajectories of skin
      markers on the left side of the horse and the dorsal midline of the trunk were
      established. Electrical activity was obtained simultaneously from 6 muscles using
      surface electrodes. Ten consecutive strides were analysed for each horse at each
      of the 5 velocity steps. The increase in speed resulted in a decrease in stride
      and stance phase duration, increased muscle activity and range of motion of the
      limbs, but a decrease in back movements. During the stance phase, the limbs
      appeared more loaded, which resulted in more flexion of the joints and higher
      excentric muscle activity. During the swing phase, the higher concentric activity
      of the muscles was responsible for an increased shortening of the limbs.
      Understanding the effects of speed on equine locomotion is a prerequisite for the
      development of training programmes.

PMID- 12405705
TI  - Jumping characteristics of naive foals: lead changes and description of temporal
      and linear parameters.
AB  - The selection of foals as future showjumpers remains a subjective process based
      on qualitative parameters; and hence, frequently suffers from disparity in the
      criteria used by experts in the field. A detailed biomechanical description of
      foals while jumping would be most helpful in providing a better basis for the
      accurate assessment of their future athletic ability. The Qualisys Pro Reflex
      system was used to capture 3-dimensional kinematics of 41 Dutch Warmblood foals
      age 6 months free jumping a vertical fence, preceded by a cross pole fence. The
      left lead was the most preferred lead for both the fore- and hindlimbs, from the
      landing following the cross poles to the first move-off stride after clearing the
      vertical fence. The foals displayed a high incidence of rotary gallop during both
      the jump stride (divided into take-off, jump suspension and landing) and the
      first move-off stride, while change of lead was frequently observed during jump
      suspension. At the take-off side of the fence, the trailing forelimb in the last
      approach stride was placed furthest from the fence, whereas the trailing hindlimb
      at take-off was placed closest (P<0.05). At the landing side, the trailing
      forelimb was the closest and the leading hindlimb of the move-off stride 1 was
      the furthest (P<0.05). The trailing forelimb in the approach stride 1 had a
      significantly longer stance phase duration than the leading forelimb. At landing,
      the leading forelimb stance phase lasted longer than that of the trailing
      forelimb (P<0.05). The hindlimbs did not differ in their stance phase duration at
      take-off. The height reached by the hooves above the fence top was significantly
      greater in the hind limbs (P<0.05). In addition, the hindlimbs (97.1 +/- 2.6%)
      shortened more than the forelimbs (92.6 +/- 5.7%) (P<0.05). It is concluded that
      the overall jumping technique of foals is similar to that reported in literature
      for mature horses. If the patterns are consistent throughout the rearing period,
      the quantitative analysis of the kinematics of free jumping foals may provide a
      valid quantitative basis for early selection.

PMID- 12405706
TI  - Three-dimensional kinematics of the tarsal joint at the trot.
AB  - The tarsal joint is a common site of injury for many sport horses. Understanding
      the biomechanics of this complex joint begins with developing a clear picture of
      the kinematics during normal locomotion. This study describes the 3D kinematics
      of the tarsal joint by measuring the motion of the tibia and third metatarsus in
      4 sound Quarter Horses with targets attached directly to the bones via steel
      pins. The objective was to determine if the tarsus had significant motion outside
      the tarsocrural joint. Two Steinmann pins were inserted into the lateral side of
      the right hindlimb and marker triads were fixed to the end of each pin. 3D motion
      of the bones was recorded as each subject trotted in hand. Three rotations were
      expressed using an attitude vector based on the finite helical angle method.
      Three translations were calculated as the motion of the tibia relative to the
      third metatarsus. Angular and translation data were mostly coupled with flexion
      angle. Internal/external rotation during stance and translations during swing
      showed evidence of noncoupled motion. Although the majority of tarsal motion
      occurs in the tarsocrural joint, there is evidence that translations and
      rotations occur in other locations within the tarsal joint and that some of these
      are related to the tarsal joint 'snapping' phenomenon. This research provides a
      set of reference 3D kinematics which will aid in the study of the aetiology and
      mechanical effects of tarsal joint lameness.

PMID- 12405707
TI  - Effect of conformational aspects on the movement of the equine back.
AB  - The relationship between structure and function is important in the judgement of
      the horse. Twenty sound riding horses walked and trotted on a treadmill. The
      movement of the backs of each of the horses was measured using a commercially
      available movement analysis system. Morphometric, spatiotemporal and kinematic
      information were correlated to investigate the effect of conformation on
      movement. Taller and heavier horses seem to have longer thoracic and lumbar
      backs, and are wider at the pelvis. Horses with longer strides extended and
      flexed their backs in the caudal saddle region to a greater extent at the walk,
      but not the trot. Horses with greater angle of L5 tend to extend and flex this
      region of the back more. At the walk and trot, a long thoracic back results in
      greater lumbar lateral bending. A negative relationship was found between the
      curvature of mid-thoracic back and the amount of lateral bending of L1 and L3 and
      axial rotation of the pelvis at the trot. There are clear relationships between
      back conformation and movement that may be important to the orthopaedic health of
      the horse. Further understanding of the relationships between conformation,
      movement and injury may provide an objective basis for the evaluation of future
      performance and soundness.

PMID- 12405708
TI  - Early evaluation of dressage ability in different breeds.
AB  - Dressage is one of the Olympic equestrian sports practiced in several countries
      using different horse breeds. Specific characteristics of the walk, trot and
      canter are required for dressage. It has been assumed that some of these traits
      could be selected for genetically and contribute to dressage performance. The
      purpose of this study was to compare the walk, trot and conformation
      characteristics in young horses of different breeds used for dressage. A total of
      142 horses age 3 years were classified into 3 groups of breeds (German, French
      and Spanish saddle horses) and tested using the same procedure. The skeletal
      conformation measurements were made by image analysis. Gait variables of the walk
      and trot were measured by the accelerometric gait analysis system Equimetrix.
      Discriminant analysis could explain the variability between the groups by taking
      into account the walk (P<0.0003), trot (P<0.0001) and conformation variables
      (P<0.0001). Many gait and conformation variables were significantly different
      between the breeds. In summary, the German horses had gait characteristics more
      adapted for dressage competition, and the results of this group could be used as
      a reference for early evaluation in dressage. Purebred Spanish horses could be
      considered as a reference for collected gaits used for farm work and old academic
      dressage. The gait and conformation tests could be applied in a breeding or
      crossing plan to detect more accurately young horses with good dressage ability.

PMID- 12405709
TI  - Effect of walking velocity on forelimb kinematics and kinetics.
AB  - A database of biomechanical variables obtained from normal horses walking at a
      range of velocities is needed for comparison with the variables obtained from
      lame horses in which velocity cannot be predetermined. The objective was to
      investigate velocity-dependent changes in selected kinematic variables, ground
      reaction forces (GRF) and net joint energies in the forelimb and to develop
      statistical equations to calculate expected values of these variables for horses
      walking at different velocities. Five sound horses walked at a range of
      velocities (0.82 to 1.91 m/s) over a force plate. Kinematic data were recorded
      simultaneously for 51 trials. Kinematic, GRF and energetic variables were
      determined using standard methods. Correlation and simple regression analyses
      between velocity and measured variables were performed. An increase in walking
      velocity was correlated with an increase in stride length and decreases in stride
      and stance duration. Vertical, braking and propulsive impulses decreased as a
      consequence of the large reduction in stance duration, even though peak vertical,
      braking and propulsive GRFs increased. There was no significant increase in
      energy generation at any of the forelimb joints, indicating that muscle activity
      was not the source of the increase in GRFs. Changes in the longitudinal GRFs
      appeared to be influenced by velocity-dependent increases in head and neck
      oscillations. The equations obtained in this study can be used to calculate the
      expected normal variables from a range of walking velocities and to detect
      deviations from normal values in lame horses.

PMID- 12405710
TI  - Effect of trotting speed, load and incline on hindlimb stance-phase kinematics.
AB  - The objective was to understand how the stance-phase kinematics of the hindlimb
      of trotting horses change with speed under 3 conditions (level, loaded and
      incline), to compare our results with the predictions of the spring-mass model
      and to help focus our future studies of muscle function. Video recordings were
      made of 5 Arabian horses trotting on a treadmill. Five consecutive strides were
      digitised and averaged for each trial. The angle-time diagrams were qualitatively
      similar to those reported previously. As speed increases, the range of motion of
      the hindlimb increases, as predicted by the spring-mass model. This is the result
      of increased range of motion in the coxofemoral and tarsal joints. The hindlimb
      does not 'land short-take off long'. When trotting up an incline, the hindlimb
      undergoes a greater range of motion because of increased retraction resulting
      from increased extension of the coxofemoral joint. At hoof contact on an incline,
      the 3 proximal joints are more flexed than on the level. Carrying a load had no
      effect on kinematics. These results suggest that there may be larger changes in
      strain with speed in muscles acting at the coxofemoral and tarsal joints than at
      the femorotibial joint, and that locomotion up an incline will change muscle
      strain more than carrying a load.

PMID- 12405711
TI  - Dorsal metacarpal cortex ultrasound speed and bone size and shape.
AB  - In Thoroughbred racehorses, the dorsal cortex (DC) of the third metacarpal bone
      (MC3) enlarges when horses are first exposed to fast exercise speeds. It is now
      possible to measure ultrasound speed through 3 to 5 mm depths of bone around the
      bone shaft using Sunlight Medical's 'Omnisense' machine. The aim of this
      experiment was to determine whether the ultrasound speed measured in the surface
      3-5 mm of the midshaft dorsal cortex of MC3 could be related directly to the
      midshaft shape and size of the MC3s of young Thoroughbred racehorses at the same
      stage of training. Sixteen 2-year-old and sixteen 3 to 6-year-old racehorses,
      exercising at racing speed at the same training stable, had their ultrasound
      speed measured and were radiographed to measure their MC3 midshaft size (width of
      DC) and shape ([DC/palmar cortex] x [[DC+palmar cortex]/medulla widths]). There
      were significant linear relationships between ultrasound speed and radiographic
      bone size and shape measurements. The faster ultrasound speeds were associated
      with bones that were both absolutely and proportionately thinner in the dorsal
      cortex in both groups of racehorses. The measurement of ultrasound speed with the
      Sunlight Omnisense machine should allow more detailed and accurate predictions to
      be made for responses of the bone to exercise in the midshaft of MC3 than is
      possible using radiographic size and shape measurements alone. This should make
      it possible to predict, for example, how soon after a change in bone shape a
      specific horse can race with minimal risk of damage to the newly-forming bone
      surface.

PMID- 12405712
TI  - Relationship between velocity and temporal variables of the flat shod running
      walk.
AB  - The running walk of the Tennessee Walking Horse is often described as a faster
      variation of the walk, indicating the importance of velocity on the mechanics of
      the gait. Variations in gait variables create difficulties in clearly identifying
      the normal and abnormal running walk in a clinical evaluation. The objectives of
      this study were, therefore, to describe the flat shod running walk and to
      determine the relationship between velocity and the running walk. From frame-by
      frame analysis of 60 Hz film, temporal variables were averaged for 6 strides from
      6 horses performing an 'easy' (slow) and 'strong' (fast) running walk during a
      flat shod, easy-rider Tennessee Walking Horse show class. The running walk at
      both velocities was a 4-beat, symmetrical stepping gait with a lateral footfall
      sequence and lateral couplets. The velocity ranged from mean +/- s.d. 2.66 +/-
      0.34 to 3.80 +/- 0.18 m/s. For both velocities (slow, fast), hind stance as a
      percentage of stride duration (58 +/- 3%, 56 +/- 2%) was significantly longer
      than fore (51 +/- 5%, 48 +/- 1%); diagonal advanced placement (29 +/- 2%, 37 +/-
      4%) and lift-off (35 +/- 5%, 39 +/- 2%) were significantly longer than lateral
      (advanced placement: 22 +/- 2%, 12 +/- 3%; lift-off: 18 +/- 4%, 10 +/- 2); and
      lateral bipedal support (50 +/- 9%, 67 +/- 7%) was significantly longer than
      diagonal (27 +/- 6%, 16 +/- 4%). Strong correlations were found between velocity
      and diagonal advanced placement (0.640), lateral lift-off (-0.924) and diagonal (
      0.648) and lateral (0.904) bipedal support. Understanding the running walk and
      the gait variations due to velocity may be important to both the performance and
      soundness of the Tennessee Walking Horse.

PMID- 12405713
TI  - Analysis of trotter gait on the track by accelerometry and image analysis.
AB  - The aim of this study was to describe the correlation between the phases of the
      limb cycle of trotters on the track and specific points on the acceleration
      curves obtained from a new gait analysis system. We compared kinematic data
      obtained by video image analysis and 3-dimensional acceleration recordings made
      on 3 French trotters in training. They trotted on a race track at speeds of 8.33,
      10 and 11.66 m/s, with a final stretch at maximum speed. Their locomotion was
      recorded with a synchronised video camera at a frame frequency of 200 Hz and with
      the Equimetrix gait analysis system. The gait variables were calculated using 3
      dimension acceleration data recorded at the sternum (dorso-ventral, longitudinal
      and lateral axes) at a sampling rate of 100 Hz. Three phases of the stride were
      clearly identified on the dorsoventral acceleration signal: hoof-landing,
      midstance phase and toe-off. Braking and propulsion phases were identified on the
      corresponding longitudinal acceleration signal. The weight-bearing diagonal was
      identified by observing the lateral signal. The stride temporal variables
      (stride, stance, braking and propulsion durations for both diagonals), measured
      by video analysis and by acceleration signal analysis, were not significantly
      different (P>0.05). The identification of specific points on the acceleration
      pattern allowed an accurate temporal analysis of the stride. Potential
      applications could be the determination of locomotor factors related to racing
      performance or assessment of locomotor disorders at high speed.

PMID- 12405714
TI  - Influence of draw reins on ground reaction forces at the trot.
AB  - According to riding texts, draw reins are supposed to support increased
      collection. This has not been measured objectively. Therefore, the objective of
      this study was to determine whether a horse ridden with draw reins would
      relatively increase weightbearing of the hindquarters while worked with the draw
      reins compared to a normal rein. Ground reaction forces were measured in 8 horses
      at the slow trot over a force plate in 3 different experimental set-ups: 1)
      riding with only a draw rein (DR); 2) riding with the combination of a normal and
      a draw rein (NR-DR) and 3) riding with a normal rein (NR). Horses ridden with NR
      DR showed significant higher vertical impulse in the hindlimb compared to riding
      both with only DR and only NR. Several significant differences were also seen in
      the horizontal force. It is concluded that draw reins, when used correctly,
      together with a normal rein, achieve the desired result of shifting the weight of
      the horse caudally. This was not the case when the draw rein was used alone. It
      is important that trainers, as well as veterinarians, recommending draw reins in
      a rehabilitation programme, know about these possible effects.

PMID- 12405715
TI  - Biomechanical implications of uphill training on the aetiology of tendinitis.
AB  - It has been reported that a small decrease in the strain in the superficial
      digital flexor tendon (SDFT) occurs if the toe is raised during walking. Although
      walking on a slope appears similar to raising the toe, it is unclear whether
      uphill exercise decreases the strain in the SDFT. Because the force or strain on
      tendons is one of the important factors leading to tendon stress injury, we
      hypothesised that reducing the force in the SDFT during exercise may prevent
      tendinitis. The purpose of this study was to determine the effects of treadmill
      inclination on the force in the SDFT in the walking horse. 'Arthroscopically
      implantable force probes' (AIFP) were implanted into the SDFT of the forelimb of
      4 horses. The AIFP output was recorded during walking on a treadmill inclined at
      0%, 3%, 8% and then 0% again. When the inclination increased from 0 to 8%, the
      first peak of force in the SDFT decreased significantly, the second increased
      significantly, but the maximal force and the area under the force-time curve did
      not change. In conclusion, uphill walking on an inclined treadmill did not
      decrease the maximal force in the SDFT or the area under the force-time curve,
      however, the patterns of force were altered. Future research should focus on the
      force distributions of tendons and ligaments at faster gaits, because the effects
      of a change in hoof angle and slope may be greater at faster gaits.

PMID- 12405716
TI  - The effect of reins on kinetic variables of locomotion.
AB  - The equestrian literature and reports of experienced riders indicated that
      attitude of a horse's head and neck is related to the equine locomotion
      characteristics. The purpose of this study was to quantify the effects of 3 types
      of reins on locomotion at walk and trot. Eight saddle horses were tested in an
      automatic walker without reins, with rubber bands, Chambons and Back lift, using
      the same procedure. The rubber bands closed the head-neck angle, whereas the
      Chambons and the Back lift opened it. The gait characteristics were measured with
      the Equimetrix gait analysis system. Two accelerometric devices were fixed on the
      sternum and sacrum to measure the kinetic characteristics of the fore- and
      hindlimbs at walk and trot. Analysis of variance was used to test the effects of
      reins on the fore- and hindlimbs. All 3 types of reins significantly (P<0.05)
      modified walk and trot, with increased forelimb propulsion at the trot (P<0.05).
      Chambons increased the dorsoventral activity of the hindlimbs at the trot and
      hindlimb propulsion at the walk (P<0.05). Back lift increased forelimb
      dorsoventral activity both at the trot and walk (P<0.05). It was concluded that
      the Chambons increased the activity of the hindlimbs while Back lift increased
      that of the forelimbs. The use of reins modified the head placement and the fore-
      and hindlimbs activity. The specific effect of each type of rein can be used for
      training, rehabilitation or management of locomotor's injury.

PMID- 12405717
TI  - Hindlimb net joint energies during swing phase as a function of trotting
      velocity.
AB  - Net joint powers and energies have been described in walking horses during the
      swing phase of the stride in the fore- and hindlimb (Clayton et al. 2001). During
      trotting, swing phase net joint powers have been described in the forelimb but
      not in the hindlimb. The effects of velocity on power profiles and energy
      patterns are important in relation to locomotor energetics. The objective of this
      study was to evaluate velocity-dependent changes in hindlimb net energy profiles
      of the swing phase during trotting. Inverse dynamic analysis was used to
      calculate net joint energies at the hindlimb joints of 6 horses trotting
      overground at velocities ranging from 2.27-5.17 m/s. At all velocities, there was
      net energy generation at the hip and tarsus and net energy absorption at the
      stifle, fetlock and coffin joints. Velocity-dependent bursts of energy generation
      at the hip actively protracted the limb in early swing and initiated retraction
      in late swing. Synchronous with the bursts of energy generation at the hip were
      velocity-dependent bursts of energy absorption across the stifle that acted to
      control flexion in early swing and extension in late swing. The distal limb was
      raised and lowered by velocity-dependent bursts of energy generation that flexed
      the tarsus in early swing and extended it in late swing. The energy bursts in
      early swing increased linearly with velocity, whereas the energy bursts in late
      swing increased as a function of the square or cube of velocity. The results
      contribute to understanding the mechanisms used to accelerate and decelerate the
      limbs more rapidly as velocity increases, which is an important consideration in
      racing and sporting performance.

PMID- 12405718
TI  - A radiographic technique to assess the longitudinal balance in front hooves.
AB  - The aim of this study was to validate a radiographic technique to measure
      objectively the longitudinal hoof balance in the horse. Ten left third phalanges
      (P3) obtained from front hooves and 19 left front hooves were used in order to
      assess the reliability of the radiographic technique and to identify any effect
      of rotation or alignment of specimens or distance between the X-ray machine and
      the radiographic cassette, in measuring P3s structures and balance related
      parameters. A rotational support was made to hold specimens in order to
      standardise some of the conditions of X-raying. The main axis of the frog was
      used as a marker for the sagittal plane of P3. Results showed that single
      radiographic measurements could have wide limits of agreement with actual
      measurements of the hoof (gold standard values). In order to limit errors we
      suggest the use of a combination instead of single parameters to assess balance.
      Rotation of the hoof is also to be controlled when a measurement of angles is
      needed. The radiographic technique used in this study can be used to objecticely
      measure balance parameters considered important in order to assess hoof balance.

PMID- 12405719
TI  - EIPH: postrace endoscopic evaluation of Standardbreds and Thoroughbreds.
AB  - The incidence and severity of exercise-induced pulmonary haemorrhage (EIPH) in
      the 2 most commonly raced horse breeds, Thoroughbreds (TB) and Standardbreds
      (STD), were studied, with particular interest in the possible influence of
      frusemide (F) and/or the breed (or running gait) on EIPH. The appearance of blood
      within the trachea was semi-quantified using a published 5-point system, with
      zero assigned when no blood was observed, and numbers 1-4 assigned with
      increasing amounts of blood. Considering each endoscopic examination as a
      separate event, approximately 75% of the postrace endoscopic examinations had
      blood-scores of 1, 2, 3, or 4, regardless of breed or F administration. For
      horses examined twice, the chances of finding blood-scores of 1 or greater in
      either of the examinations increased to approximately 95%. All horses examined 3
      or more times had endoscopic blood-scores of 1 or greater following one or more
      races, again, irrespective of the breed or F administration. Mean +/- s.e. 'blood
      scores' were 1.5 +/- 0.1 and 1.8 +/- 0.2 for TB, and 1.4 +/- 0.2 and 1.2 +/- 0.1
      for STD racing with and without prerace F, respectively. Therefore, there was no
      apparent effect of breed (or possibly racing gait) on EIPH, and no differences in
      the incidence or severity of EIPH were observed between horses with or without
      prerace frusemide administration.

PMID- 12405720
TI  - Effect of dorsal displacement of the soft palate on ventilation and airflow
      during high-intensity exercise.
AB  - Dorsal displacement of the soft palate (DDSP) is one of the most common
      obstructive conditions of the upper respiratory tract in the racehorse. The
      present study was conducted to determine the effects of intermittent dorsal
      displacement of the soft palate (DDSP) on ventilation and respiratory airflow
      during high intensity exercise. Videoendoscopic recordings were made of the
      nasopharynx and larynx simultaneously with measurements of airflow and
      respiratory gas exchange, during high-speed treadmill exercise in 9 horses with
      confirmed intermittent DDSP admitted for clinical investigation of poor racing
      performance. In all horses, DDSP resulted in a reduction in minute ventilation
      (VE) (P<0.001), associated with a decrease in tidal volume (VT) (P<0.01) with no
      change in breathing frequency (f) and a reduction in oxygen consumption (VO2)
      (P<0.01). Further, DDSP resulted in reduction of expiratory flow parameters,
      including peak expiratory flow (PEF), EF50, EF25 and EF125 (P<0.01), with no
      alteration of inspiratory flow. These results confirm that naturally-occurring
      intermittent DDSP creates a flow-limiting expiratory obstruction. The associated
      impairment of athletic performance is probably caused, at least in part, by the
      accompanying decrease of oxygen uptake.

PMID- 12405721
TI  - Movements of thoracic and abdominal compartments during ventilation at rest and
      during exercise.
AB  - The present investigation utilised simultaneous measurements of chest (Ch) and
      abdominal (Ab) circumferences and respiratory airflow to test the hypothesis that
      Ch circumferential expansion contributes proportionally little to tidal volume in
      the running Thoroughbred. During exercise, there were only small changes in Ch
      and Ab circumference and no increase with increasing tidal volume. At rest, walk
      and trot, the flow, Ch and Ab signals were in phase. However, during canter and
      gallop, the Ch and Ab changes were 180 degrees out of phase with each other and
      both were out of phase with airflow. In contrast to exercise, increase in
      ventilation at rest achieved by administration of lobeline resulted in a 4-6-fold
      increase in tidal volume; large excursions of the chest were always in phase with
      airflow. Furthermore, 3 horses showed an increase in chest circumference,
      demonstrating that chest stiffness per se does not preclude chest circumferential
      expansion. In conclusion, in the absence of significant increases in either Ch or
      Ab expansion during running, elongation of the thoracoabdominal segment may be
      the main determinant of tidal volume.

PMID- 12405722
TI  - Heterogeneity of intrapleural pressures during exercise.
AB  - We determined whether the caudodorsal region of the intrapleural space in
      exercising horses experiences larger pressure fluctuations than other regions and
      whether systematic phase-shifting of peak intrapleural pressures along the length
      of the thorax suggests the existence of locomotor-induced intrapleural pressure
      waves. We utilised percutaneous introducers and solid-state pressure-tip
      transducers implanted along the dorsal aspect of the thorax, mid-thorax or
      oesophagus to measure regional intrapleural pressures while 3 horses galloped on
      a flat treadmill at 13-14 m/s, then recorded pressures from the same catheters
      when horses exercised intensely (heart rate 170-190 beats/min) while swimming
      with no ground concussion. Pressure excursions in the caudodorsal region did not
      vary systematically from other regions during galloping or swimming, nor more
      than a few torr between different locations. During swimming, peak expiratory
      pressures were higher than during galloping (68-79 vs. 26-32 torr), and horses
      breathed explosively at frequencies 5 times slower than while galloping (28 vs.
      120/min). During galloping, individual catheter locations registered locomotor
      concussion; however, this was variable and did not indicate a systematic pressure
      wave passing through the lung or intrapleural space.

PMID- 12405723
TI  - Modelling the oxygen cost of transport in competitions over ground of variable
      slope.
AB  - This study provides an objective method for estimating the oxygen consumption of
      horses while running on variable slopes so that realistic comparisons may be made
      of the locomotory transport cost involved in 3-day events, particularly the Speed
      and Endurance Test, at sites of differing terrain. A knowledge of the work
      profile over a particular course would enable competitors to plan speed and
      interval times appropriately along its length. We have developed a semi
      empirical, but mechanistically based, model to calculate the oxygen cost of
      transport [COTpath in ml O2/kg/m path] for running on the flat, up or down a
      slope of given gradient (from -0.3 to +0.3). The model is then used to calculate
      the overall effort of running on a number of 3-day event courses of differing
      standard; the model does not assess the energetic cost of jumping. The cost of
      transport over the range of gradient of -0.3 to +0.3 was modelled using the
      following equations: On the flat or uphill: COTpath = 0.123 + 1.561(gradient);
      Downhill: COTpath = 0.123 + 1.591(gradient) + 9.762(gradient)2 + 14.0(gradient)3.

PMID- 12405724
TI  - Physiological measurements and upper and lower respiratory tract evaluation in
      French Standardbred Trotters during a standardised exercise test on the
      treadmill.
AB  - There are a variety of reasons for poor performance in racehorses. Exercise
      intolerance has often been associated with subclinical respiratory abnormalities,
      and diagnostic aids are therefore used to enhance clinical detection.
      Physiological variables can also be measured in order to evaluate the metabolic
      reponse to exercise. This study evaluated the relationship between physiological
      measurements and upper airway videoendoscopy during a standardised treadmill
      exercise test and bronchoalveolar lavage (BAL) cytology in control horses (good
      racing performance, n = 14) and poor performers (n = 27). The poor performers
      were divided into 2 groups: Group 1 = both upper and lower respiratory airway
      abnormal findings (n = 10); Group 2 = lower respiratory airway abnormal findings
      (n = 17). Horses in Group 2 were divided into 3 categories: Group 2A = exercise
      induced pulmonary haemorrhage (EIPH ; n = 5); Group 2B = small airway
      inflammation (SAI +/- EIPH; n = 7) and Group 2C = other (n = 5). During exercise,
      the poor performers had significantly lower arterial PaO2 and higher HR and blood
      lactate concentrations compared to controls. Total nucleated cell count of BAL
      fluid collected from poor racing performers was significantly higher than in
      controls; also, epithelial cells and haemosiderophage percentage collected from
      poor racing performers were significantly higher than in controls. Eight horses
      with dorsal displacement of the soft palate also had cytological evidence of
      lower respiratory airway disease. The results of this study suggest that there is
      a significantly different metabolic response (HR, blood lactate, PaO2) to
      exercise in poor compared to good performers. As both upper and/or lower
      respiratory problems can be associated with poor racing performance, a detailed
      examination of the upper and lower respiratory tracts at rest, during and after
      exercise is advised.

PMID- 12405725
TI  - Dynamic upper airway changes and arterial blood gas parameters during treadmill
      exercise.
AB  - The primary goal was to investigate the relationship between dynamic upper airway
      abnormalities and arterial blood gas tensions during exercise. Horses that
      completed a high-speed treadmill examination consisting of upper-airway
      videoendoscopy, blood gas evaluation and electrocardiogams and, postexercise,
      echocardiograms and tracheal washes, were included. An age-matched group of fit,
      healthy Thoroughbreds, trained to run on a high-speed treadmill, served as
      controls for blood gas values at specific exercise speeds. One hundred and
      nineteen horses completed the treadmill examination. Sixty (50%) were
      Thoroughbreds (TB), 51 (43%) Standardbreds (STD) and 8 (7%) other breeds. Mean +/
      s.d. age TB 3.8 +/- 2.2 years and STD 4.0 +/- 1.7 years, with no gender
      predilection. Fifty-four horses (45%) had abnormal upper respiratory tract (URT)
      abnormalities alone or in combination with abnormalities in another body system.
      Thirty-eight (70%) were TB, 14 (26%) were STD and 2 (4%) were other breeds. Of
      these, 24 (45%) had exercising PaO2 values significantly lower than those
      observed in healthy TB. Nineteen (35%) horses also had significantly elevated
      exercising PaCO2. Only 14 (12%) horses had abnormal clinical findings in the URT
      alone, and of these, only 3 (21%) had an abnormally low PaO2 and/or elevated
      PaCO2. Multiple URT abnormalities were more commonly associated with abnormal
      exercising blood gases than were single disorders, but pharyngeal collapse (PC)
      was much more commonly associated with abnormal values if only one disorder was
      detected. Fifty-five percent (n = 65) of all cases admitted had no evidence of
      URT disease. Twenty-two (35%) were TB and 37 (57%) were STD. Twenty (31%) of
      these had abnormally low PaO2 and 14 (22%) had elevated PaCO2 values. Seventy
      percent (14) of the horses with abnormal PaO2 were STD, while almost 80% (11) of
      the horses with elevated PaCO2 were STD. These data suggest that dynamic URT
      dysfunction can adversely affect gas exchange during exercise. While multiple
      abnormalities were more commonly associated with gas exchange problems than were
      single disorders, pharyngeal collapse, either alone or in combination with other
      URT problems, was the disorder most frequently associated with blood gas
      abnormalities. Additionally, URT disease was more commonly seen in TB, and the
      proportion of URT diagnoses in horses with abnormal blood gases reflected this
      percentage, while STD without URT disease had a much higher incidence of abnormal
      blood gases than did TB without URT abnormalities.

PMID- 12405726
TI  - Airway cooling and mucosal injury during cold weather exercise.
AB  - In human subjects that exercise strenuously in cold weather, there is evidence
      that hyperventilation with cold air leads to peripheral airway cooling,
      desiccation and mucosal injury. Our hypothesis was that hyperventilation with
      cold air can result in penetration of unconditioned air (air that is not
      completely warmed and humidified) into the peripheral airways of exercising
      horses, resulting in peripheral airway mucosal injury. To test this hypothesis, a
      thermister-tipped catheter was inserted through the midcervical trachea and
      advanced into a sublobar bronchus in three horses that cantered on a treadmill at
      6.6 m/s while breathing cold (5 degrees C) air. The mean (+/- s.e.) intra-airway
      temperature during cantering was 33.3 +/- 0.4 degrees C, a value comparable to
      the bronchial lumen temperatures measured in man during maximal exercise while
      breathing subfreezing dry air. In a second experiment, 6 fit Thoroughbred
      racehorses with satisfactory performance were used to determine whether strenuous
      exercise in cold conditions can produce airway injury. Horses were assigned to
      Exercise (E) or Control (C) groups in a random crossover design. Samples of
      bronchoalveolar lavage fluid (BALF) in the E treatment were recovered within 30
      min of galloping exercise in 4 degrees C, 100% relative humidity (E), while in C
      BALF samples were obtained when the horses had not performed any exercise for at
      least 48 h prior. Ciliated epithelial cells in BALF were higher in E than in the
      C treatment. Similar results have been found in human athletes and laboratory
      animal models of cold weather exercise. These results support the hypothesis
      that, similar to man, horses that exercise in cold weather experience peripheral
      airway mucosal injury due to the penetration of unconditioned air. Furthermore,
      these results suggest that airway cooling and desiccation may be a factor in
      airway inflammation commonly found in equine athletes.

PMID- 12405727
TI  - Evidence of an association between inflammatory airway disease and EIPH in young
      Thoroughbreds during training.
AB  - In an epidemiological study of risk factors for exercise-induced pulmonary
      haemorrhage (EIPH) in young Thoroughbreds in the UK, in which 148 horses
      contributed 1614 horse-months of data, there were 64 (4%) episodes of
      endoscopically visible tracheal bleeding and 824 (51%) episodes of increased
      quantities of haemosiderophages in tracheal washes. There were increases in
      prevalence and risk of EIPH by both definitions with age from < or = 2- > or = 4
      years, season of sampling from winter (Nov-Jan) to autumn (Aug-Oct) and several
      different measures of airway inflammation, including tracheal mucus, neutrophil
      proportion, inflammation score and fungal material in tracheal washes. There was
      considerable variability in the prevalence of EIPH between trainers. EIPH in the
      preceding month significantly increased the risk of the condition the following
      month. There was no evidence that EIPH was associated with infection of the
      airways with even large numbers of Streptococcus zooepidemicus or Pasteurella
      like spp., which are significantly associated with airway inflammation in younger
      racehorses. Multiple logistic regression modelling that took account of random
      variability between horses and the effects of each trainer and an episode the
      preceding month, confirmed that after controlling for the other risk factors,
      EIPH was still significantly associated with increasing age, different seasons,
      airway inflammation and evidence of airway fungal material.

PMID- 12405728
TI  - Hyperhydration prior to moderate-intensity exercise causes arterial hypoxaemia.
AB  - The second day of a 3-day event is the most physically demanding of the 3 days.
      If this is performed under hot and humid environmental conditions, detrimental
      effects on cardiovascular and thermoregulatory function and, therefore, on
      exercise capacity, may occur due to exercise-induced dehydration. We hypothesised
      that the administration of fluid equivalent to 6% of the horse's bodyweight prior
      to a simulated second day of a 3-day event would increase plasma volume and limit
      increases in core temperature. Seven Standardbred geldings underwent a training
      protocol prior to the study. A standardised exercise test was developed for each
      horse so that exercise intensity at each phase would be the same percentage of
      the maximal heart rate for all horses. The exercise test involved 4 phases: Phase
      A involved 30 min exercise at 3.7 m/s (approximately 25% VO2max); Phase B 4 min
      exercise at 8 m/s (approximately 60% VO2max); and Phase C 50 min at 3.7 m/s,
      after which there was a 10 min rest. Phase D involved 14 min at 7.3 m/s (55%
      VO2max). In a cross-over design, horses were grouped randomly and allocated to
      either exercise with no fluid (control) or approximately 26 l isotonic fluid by
      nasogastric tube, 120 min prior to exercise. Arterial and mixed venous blood
      samples were collected prior to exercise, towards the end of each of the phases
      and during the rest period. The administration of fluid prior to exercise
      resulted in a pre-exercise bodyweight gain of 21.3 +/- 1.2 kg. Hyperhydration
      resulted in a greater degree of arterial hypoxaemia than the control group in
      Phases B and D, but not in Phases A and C or at rest. During Phases B and D, mean
      PaO2 values in the horses that received fluid were about 15 torr lower than in
      the control group, but there were no differences in PaCO2 values between the 2
      groups. In both arterial and mixed venous blood, pH and HCO3- were significantly
      lower in the group that were hyperhydrated. We concluded that the most likely
      cause of the more severe arterial hypoxaemia in the hyperhydrated group during
      the intense exercise phase was some degree of pulmonary oedema, from the
      extravasation of the administered fluid. Hyperhydration prior to exercise may be
      detrimental to respiratory function and therefore care must be taken in
      administration of large volumes of fluid prior to exercise.

PMID- 12405729
TI  - The effect of a tongue-tie in horses with dorsal displacement of the soft palate.
AB  - Tongue-ties are frequently used in an attempt to prevent dorsal displacement of
      the soft palate (DDSP). The aim of this study was to determine the efficacy of a
      tongue-tie in horses clinically affected with the disorder. Videoendoscopic
      recordings and measurements of respiratory airflow were made simultaneously
      during high intensity treadmill exercise in 6 Thoroughbred racehorses with
      confirmed DDSP, with and without a tongue-tie. DDSP was confirmed in all 6 horses
      without the tongue-tie but occurred in only 4 horses with the tongue-tie in
      place. In one horse the palate displaced only on slowing down after intense
      exercise and in the other horse DDSP did not occur although palatal instability
      remained. The presence of the tongue-tie did not result in any significant
      alteration in run-time to fatigue or in any of the respiratory variables
      measured. The results suggest that the use of a tongue-tie may prevent DDSP in
      individual horses although it is not effective in the majority, consistent with
      the widely accepted anecdotal reports of success rates for its use. Where DDSP
      was not prevented, application of a tongue-tie did not improve ventilation.

PMID- 12405730
TI  - Gas exchange during intense exercise in Standardbreds with earlier Rhodococcus
      equi pneumonia.
AB  - It is not known if pulmonary function and gas exchange during exercise are
      altered after pyogranulomatous pneumonia caused by Rhodococcus equi infection in
      the foal. The aim was to evaluate whether pulmonary gas exchange during high
      intensity exercise was altered in mature Standardbreds with a history of R. equi
      pneumonia as foals. In 7 foals, R. equi pneumonia was confirmed and treated. At
      age 3 years, when these horses were subjected to professional training, an
      inclined treadmill exercise test including 4 speeds was performed. Samples were
      collected when a steady state in VO2 was obtained. Red cell volume, heart rate,
      respiratory rate, and systemic and pulmonary mean arterial pressures were
      measured and cardiac output calculated. Oxygen and carbon dioxide tensions in
      arterial and mixed venous blood were analysed. The alveolar ventilation and the
      alveolar-arterial oxygen tension difference were determined. Pulmonary gas
      exchange was assessed and the ventilation-perfusion distribution, VA/Q, was
      estimated by the multiple inert gas elimination technique. Ventilation-perfusion
      mismatch and shunt were determined and diffusion limitation calculated. The gas
      exchange in Standardbred trotters previously infected with R. equi and
      successfully treated was not compromised during intense treadmill exercise
      compared with reference values for healthy, fit Standardbreds. We conclude that
      adult Standardbreds trotters with diagnosed R. equi pneumonia as foals, can
      achieve an adequate gas exchange at a workload close to VO2peak.

PMID- 12405731
TI  - Effect of instillation into lung of autologous blood on pulmonary function and
      tracheobronchial wash cytology.
AB  - This study aimed at measuring the functional consequences and the pulmonary
      cytology changes following a simulation of pulmonary haemorrhage. Pulmonary
      function tests including lobeline-induced hyperventilation, cytology of tracheo
      bronchial wash (TBW) and thoracic radiographs were performed before, as well as
      1, 7, 14 and 28 days after, the instillation of 300 ml of blood into the lungs of
      4 horses deemed free of exercise-induced pulmonary haemorrhage (Group 1). Control
      data (Group 2) were obtained by instilling the same volume of saline into the
      lungs of the same horses in a crossover design (control). The instillation of
      blood or saline resulted in an increase in the number of neutrophils in the TBW.
      Thoracic radiographs showed increased opacity in the caudodorsal region of the
      lungs in 4/4 (Day 1) and 2/4 horses (Day 7), in Group 1, and in 2/4 (Day 1) and
      0/4 horses (Day 7) in the control group. These changes were attributed to the
      instillation procedure rather than the nature of the instilled material.
      Breathing mechanics and arterial blood gases at rest were not affected in either
      Groups 1 or 2. However, the maximal expiratory peak flow recorded during lobeline
      induced hyperventilation was significantly lower (P<0.05) and the total pulmonary
      resistance significantly higher (P<0.05) on Day 1 in Group 1, but not Group 2.
      These observations suggest that expiratory flows might be partly limited in
      bleeders when breathing at high airflow.

PMID- 12405732
TI  - Effects of different volumes of autologous blood instilled into the airways of
      horses on pulmonary function during treadmill exercise.
AB  - Exercise-induced pulmonary haemorrhage has been associated with reduced
      performance in racing horses. However, it is unclear what volume of blood loss
      into the lungs impairs performance. The purpose of the present study was to
      determine the minimal volume of autologous Horses blood instilled into the
      airways that significantly affects performance and pulmonary function in
      exercising horses. Six Thoroughbred horses performed 2 exercise bouts on each of
      4 treatment test days. Each exercise bout consisted of a 2 min warm-up at 4 m/s
      followed by running at a speed equivalent to 115% VO2max, until fatigued. For the
      first run of each testing day there was no treatment (baseline run). Prior to the
      second run either there was no treatment (control) or 100, 50 or 25 ml of
      autologous blood was instilled into the airways on the right hand side. During
      each test, arterial and mixed venous blood was sampled, and VO2, VCO2 and
      breathing mechanics measured. The results of this study indicate that unilateral
      instillation of 100 ml of blood or less into the airways of horses does not
      significantly affect pulmonary function, breathing mechanics or performance
      during supramaximal exercise. The results of this study may be helpful in
      determining the significance of exercise-induced pulmonary haemorrhage on racing
      performance.

PMID- 12405733
TI  - Alveolar fibrosis and changes in equine lung morphometry in response to
      intrapulmonary blood.
AB  - Necropsy studies of horses suffering exercise-induced pulmonary haemorrhage
      (EIPH) have identified mild inflammatory lesions with evidence of alveolar
      fibrosis and bronchiolitis. These lesions were thought to be the result of viral
      infections that predisposed the affected regions of the lung to EIPH. We have
      shown previously that during erythrophagocytosis in the alveolar space, there is
      a prolonged period of macrophage influx and activation. This present study used
      morphometric analysis to quantify the effects of macrophage activity during
      erythrophagocytosis, on the alveolar cell population and physical structure of
      the alveolar walls. Segments of the bronchial tree were inoculated with either
      autologous whole blood or serum, at 15, 8, 3 days, 24 h and 30 min prior to
      euthanasia. Blood inoculation produced many significant changes in the alveolar
      morphometry including, increased numbers of alveolar macrophages, increased
      septal thickness, and a markedly increased percentage of collagen in the alveolar
      walls. Signs of chronic inflammation including increased macrophage activity and
      erythrophagocytosis coincided with increased alveolar macrophage numbers (10,688
      +/- 1708 cells/mm3 to 30,957 +/- 6831 cells/mm3), septal thickness (4.1 +/- 0.4
      microm to 6.1 +/- 0.5 microm) and alveolar septal collagen content (6.6 +/- 0.5%
      to 27.5 +/- 3.3%). The results suggest that intrapulmonary blood induces a
      macrophage dominated inflammatory response, septal thickening and the development
      of alveolar fibrosis. These changes are the probable cause of the observed
      alveolar fibrosis and bronchiolitis that was once suspected to be the originating
      cause of EIPH.

PMID- 12405734
TI  - Structural and oxidative enzyme characteristics of the diaphragm.
AB  - During exercise, the horse can achieve oxygen uptakes and ventilations in excess
      of 200 ml/kg/min and 1800 l/min, respectively. Whether the diaphragm has the
      capacity to contribute substantially to inspiratory effort in the exercising
      horse is not known. To investigate the potential for the horse diaphragm to
      generate tension, lung displacement and sustain ventilatory function, we measured
      diaphragm thickness, muscle length and oxidative enzyme activity (citrate
      synthase) within the ventral, medial and dorsal costal and crural diaphragm. In
      the diaphragms of 6 mature horses (5 Thoroughbreds, one Quarter Horse; body mass
      (mean +/- s.e.) 475 +/- 14 kg, age 4 +/- 1 years), the mass of the freshly
      excised diaphragm was 4.54 +/- 0.19 kg of which 79% was the costal diaphragm, 17%
      the crural diaphragm and 4% the central tendon. The medial costal region (2.1 +/-
      0.1 cm) was significantly thicker (P<0.05) than either the ventral (1.4 +/- 0.1
      cm) or dorsal (1.2 +/- 0.2 cm) costal regions and the crural diaphragm was
      significantly thicker (>3.2 +/- 0.3 cm, P<0.05) than any costal diaphragm region.
      With respect to the costal diaphragm, excised muscle length was greatest (P<0.05)
      in the medial costal (17.2 +/- 1.0 cm) than either the ventral costal (<12.6 +/-
      1.5 cm) or dorsal costal (<13.9 +/- 1.8 cm) regions and therefore the medial
      region would be expected to exhibit the greatest absolute length change on
      inspiration. Citrate synthase activity was high throughout the diaphragm (40.8 +/
      113 to 55.3 +/- 9.7 micromol/g/min), but was not significantly different among
      regions. These structural characteristics and the oxidative potential of the
      horse diaphragm are consistent with the diaphragm providing a significant and
      substantial contribution to the inspiratory effort during exercise in the horse.
      Consequently, clinical and physiological investigations of exercise performance
      should not ignore the potentially crucial importance of the diaphragm.

PMID- 12405735
TI  - Heart size estimated by echocardiography correlates with maximal oxygen uptake.
AB  - Maximum oxygen uptake also appears to correlate to athletic performance in
      horses. In the Thoroughbred industry, there has long been an empirical theory
      that heart size is related to athletic performance, despite a lack of scientific
      evidence supporting this assertion. To investigate the relationship between peak
      oxygen consumption (VO2max) and cardiac size measured by echocardiography, guided
      M-mode and 2-dimensional echocardiography were performed in 17 conditioned
      Thoroughbreds with a range of VO2max from 126 to 217 ml/min/kg STPD (mean +/-
      s.d. 158 +/- 28 m/min/kg). Horses were age 2-10 years and weighed 430-510 kg.
      Echocardiography was performed using a Vingmed System V echocardiograph with a
      2.25 MHz phased array ultrasound transducer. All images were obtained from the
      right hemithorax using a short axis view of the left ventricle (LV) at the level
      of the chordae tendinae. All horses were free from significant regurgitation at
      the aortic or mitral valves. Maximal oxygen uptake was measured during a
      standardised incremental treadmill exercise test to fatigue. Maximal oxygen
      uptake was correlated significantly with LVIDd (r = 0.71; P = 0.001), MWT (r =
      0.72; P = 0.001), LV mass (r = 0.78; P = 0.0002) and LV short-axis area (r =
      0.69; P = 0.003). When indices of heart size were indexed to bodyweight, the
      correlation between VO2max and indices of heart size were LVIDd (r = 0.57; P =
      0.01), MWT (r = 0.44; P = 0.07), LV mass (r = 0.78; P = 0.0002) and LV short-axis
      area (r = 0.69; P = 0.003). The current study suggests there is a strong
      relationship between VO2max and measurements of left ventricular size in
      Thoroughbred horses when individuals with a range of VO2max are compared.

PMID- 12405736
TI  - Right ventricular pressure dynamics during exercise: relationship to stress
      echocardiography.
AB  - Thorough evaluation of myocardial function remains difficult to evaluate under
      exercising conditions. This study described right ventricular (RV) pressure
      dynamics during and immediately following exercise. Nine Thoroughbreds without
      evidence of cardiac disease completed treadmill exercise at 110% of the speed
      necessary to elicit VO2max while RV pressures were recorded. RV pressure dynamics
      were calculated at rest, maximal speed and at 10 s intervals for 2 min after
      exercise. Stress echocardiography was performed at rest and within 120 s after
      exercise. Mean dP/dtmax and dP/dtmin values were significantly greater at maximal
      speed and up to 30 s immediately postexercise than at rest and all time points
      from 60 to 120 s postexercise. Mean dP/dtmax and dP/dtmin were not significantly
      different from resting values after 60 s postexercise. Tau (the time constant for
      ventricular relaxation) decreased significantly with exercise, but was not
      significantly different from rest at time points from 60 to 120 s following
      exercise. Mean % fractional shortening (FS) increased postexercise; however, the
      coefficient of variability was large. Wall motion indices also showed large
      variability postexercise. These temporal changes in normal horses suggest that
      exercising RV pressure dynamics may provide a better estimation of cardiac
      function during exercise than postexercise stress echocardiography.

PMID- 12405737
TI  - Exercise-induced pulmonary perfusion redistribution in heaves.
AB  - This study aimed to compare exercise-induced pulmonary perfusion redistribution
      in healthy vs. 'heavey' horses using scintigraphy, a minimally invasive
      technique. Six healthy (A) and 5 'heavey' horses in remission (B(I)) and during
      clinical signs of disease (B(II)) were investigated. Dimensions of the exercising
      pulmonary perfusion (QE) images were expressed in percent of the resting
      perfusion (QR) images. Computed QE to QR ratios (QE/QR) images enabled the
      definition of the region more perfused at exercise than at rest (R1). In all
      groups, exercise induced a major enlargement of the Q image but a larger increase
      of the lung height was found in 'heavey' horses. Compared to A, 'heavey' horses
      showed a larger R1 region with a significantly higher QE/QR. Location of R1
      pointed out the dorsal lung region as a major site of pulmonary perfusion
      redistribution for all groups. This work demonstrated (1) the feasibility of
      using scintigraphy for studying exercise-induced pulmonary perfusion
      redistribution; (2) perfusion redistribution to the dorsal lung with exercise and
      (3) an intensified redistribution in 'heavey' horses, either clinically affected
      or not.

PMID- 12405738
TI  - Relationship between body composition, blood volume and maximal oxygen uptake.
AB  - It has long been known that body mass and, more specifically, lean body mass are
      strongly correlated with maximal oxygen uptake (VO2max) in man and animals.
      However, there are no data to date describing this phenomenon in the horse. The
      purpose of this paper is to examine the relationship between body composition and
      VO2max in the horse. Twenty-three healthy and unfit Standardbred mares performed
      an incremental exercise test (GXT) to measure VO2max. Rump fat thickness (RTH), a
      measure of fat covering, was measured using B-mode ultrasound. Plasma volume,
      total blood volume and red cell volume were determined, using the Evan's Blue dye
      dilution technique and packed cell volume. VO2max was correlated with body mass
      (r = 0.541; P<0.01) and exercise haematocrit (exHCT; r = 0.407; P<0.05) but not
      RTH or the other haematological variables. To eliminate the influence of body
      mass on the individual variables, a regression analysis was performed on the mass
      residuals of VO2max, RTH, plasma volume and exHCT. The residuals of VO2max were
      correlated negatively with the residuals of RTH (r = -0.687; P = 0.0003) and
      positively with the residuals of exHCT (r = 0.422; P = 0.045) but not plasma
      volume. VO2max could be predicted from a linear combination of the residuals of
      RTH and exHCT (r = 0.767; P<0.0001). These data indicate that VO2max in the horse
      is significantly related to fat-free mass (FFM), independent of body mass. Red
      blood cells from the splenic reserve constitute an important factor in the
      horse's ability to achieve a high VO2max. Therefore, lean body mass may be a more
      appropriate basis for assessing metabolic function in the athletic horse.

PMID- 12405739
TI  - Thermoregulatory-induced compromise of muscle blood flow in ponies during intense
      exercise in the heat: a contributor to the onset of fatigue?
AB  - Cardiac output (Q) and tissue blood flows (BF) were measured in four ponies at
      rest, after 30 min of moderate exercise (ME) (approximately 30% VO2max) and
      following moderately intense exercise (M-IE) (approximately 65%) until fatigue,
      in a mildly hot (MH) environment (dry bulb temperature = 41 degrees C, wet bulb
      temperature = 27.5 degrees C). Exercise at both intensities resulted in increases
      in Q (15.6 +/- 1.7 [rest] vs. 35.8 +/- 2.6 [ME] vs. 48.6 +/- 3.9 [M-IE] l/min)
      and VO2 (4.7 +/- 0.9 vs. 24.5 +/- 1.2 vs. 55.8 +/- 5.8 ml/kg/min). When compared
      to ME, M-IE resulted in decreases in BF to the skin (approximately 15%),
      nonworking muscle (46%), fat (93%), gut (56%), kidneys (57%), CNS (31-66%) and an
      increase in BF to respiratory (68%), limb (98.5%) and cardiac (50%) muscles. In
      contrast, BF to working muscle during ME in thermoneutral (TN) conditions
      (McConaghy et al. 2002) was higher than found during ME in MH. We calculated that
      limb BF was approximately 25% lower for ME in MH vs. ME in TN. Similarly, we
      estimated that limb BF during M-IE in MH was approximately 25% lower than for M
      IE in TN. Attenuation of the increases in muscle BF during exercise in the heat
      may be a determinant of the onset of fatigue.

PMID- 12405740
TI  - Effects of somatotropin and training on indices of exercise capacity in
      Standardbreds.
AB  - The recent availability of recombinant equine somatotropin (eST) has led to
      concern about its use as an ergogenic aid in racehorses. This study was
      undertaken to investigate the changes in exercise capacity in maturing horses in
      a training programme, and to assess whether eST is an ergogenic aid to this
      group. We tested the hypothesis that the combination of training and eST,
      compared to training alone, would further improve exercise capacity in maturing
      Standardbreds, by virtue of ST's anabolic effects and potential to enhance
      cardiac function, circulating fluid volume and red cell mass. Twelve, untrained
      Standardbreds (mean +/- s.d. 20.7 +/- 1.1 months) were paired according to
      similar bodyweight and then assigned randomly to treatment or control group. The
      horses underwent a 12 week treadmill training programme. Methionyl eST (10
      microg/kg for the first 7 days, then 20 microg/kg) was administered once daily,
      i.m., for 42 consecutive days (Weeks 4 to 9 inclusive) to 6 horses in the
      treatment group. All horses performed a standardised maximal exercise test to
      fatigue at Weeks 0, 3, 6, 9, and 12. During each exercise test VO2, VCO2, plasma
      lactate concentrations ([La]), heart rates, blood volume and total run time were
      measured. There was no significant effect of eST administration on VO2max, V200,
      V(LA4), LA9, red cell volume (RCV), plasma volume (PV), or run time to fatigue.
      Combining the data for all horses, training significantly altered the VO2max
      (mean +/- s.d. 98.2 +/- 11.1 ml/kg/min in Week 0 to 117.6 +/- 4.8 ml/kg/min in
      Week 12), V(LA4) (5.1 +/- 0.8 m/s to 7.4 +/- 1.0 m/s), LA9 (12.7 +/- 3.9 mmol/l
      to 7.1 +/- 1.9 mmol/l), RCV (46.3 +/- 4.7 ml/kg to 63.5 +/- 5.0 ml/kg), PV (46.0
      +/- 4.8 ml/kg to 57.0 +/- 6.3 ml/kg), and run time to fatigue (431.8 +/- 30.9 to
      490.2 +/- 30.5 s), but not V200 (5.0 +/- 0.5 m/s to 5.2 +/- 1.1 m/s). The
      administration of eST to young Standardbred horses in training did not
      significantly improve their exercise capacity or indices of fitness. However,
      these maturing horses demonstrated a rapid physiological response to training
      exercise. Further research is required to determine the relationship between
      exercise capacity and ST in the horse.

PMID- 12405741
TI  - Evaluation of binding of fibrinogen and annexin V to equine platelets in response
      to supramaximal treadmill exercise.
AB  - There is evidence that equine platelet reactivity is altered by strenuous
      exercise. Changes in platelet reactivity could impact haemostasis following
      exercise-induced injury and may play a role in the pathophysiology of exercise
      induced pulmonary haemorrhage. Interpretation of results of previous studies is
      hindered by potential in vitro-induced changes in platelet activity through the
      choice of anticoagulant and the use of platelet inhibitors. The present study was
      undertaken to re-evaluate the effect of exercise on equine platelets using
      methodologies that minimise in vitro-induced changes in platelet activation. The
      percentage of platelet-neutrophil aggregates increased significantly (P = 0.01)
      from mean +/- s.e. 3.5 +/- 0.6% at rest to 7.2 +/- 13% during exercise. There
      were no significant changes in binding of anti-fibrinogen antibody or annexin V
      to platelets in response to exercise. An inability to detect increased binding of
      fibrinogen or annexin V may be a result of poor test sensitivity or low
      statistical power. Alternatively, activated platelets may be quickly removed from
      the circulation and miss detection. The significance of increased numbers of
      platelet-neutrophil aggregates in association with exercise is currently unknown
      and warrants further investigation.

PMID- 12405742
TI  - Effect of body incline on cardiac performance.
AB  - Maximal cardiac performance is improved in man during upright compared to supine
      exercise. Whether cardiac performance in quadrupeds is dependent upon body
      position is unknown. Therefore, we undertook the present investigation to
      determine if peak cardiac output (Qpeak) would be influenced by body inclination
      in the Thoroughbred horse. To test the hypothesis, four Thoroughbred horses
      performed an incremental exercise protocol (speed increased by 1 m/s/min to
      fatigue) on both a level (L) and inclined (I: 6 degrees) treadmill. Specifically,
      we hypothesised that Qpeak would be increased on the incline, as this represents
      a progression towards upright exercise. Cardiac output was determined using the
      Fick relationship from continuous measurements of pulmonary VO2 and paired
      arterial (carotid artery or transverse facial) and mixed venous (pulmonary
      artery) samples. Qpeak was significantly increased on the incline (L: 279 +/- 20;
      I: 336 +/- 17 l/min; P<0.05), while CaO2 was not significantly different (L: 25.5
      +/- 1.1; I: 25.4 +/- 1.9 ml/100 ml), and therefore, whole body O2 delivery (QO2)
      was significantly increased (L: 70.7 +/- 4.9; I: 84.4 +/- 3.1 l/min; P<0.05). In
      conclusion, within the scope of this investigation, these data suggest that
      cardiac performance, as judged by increased Qpeak and QO2, is enhanced in the
      inclined body position. Furthermore, these findings provide preliminary
      information that level and incline treadmill exercise tests may yield
      significantly different results in the Thoroughbred horse and consequently this
      factor should be considered when interpreting exercise testing and performance
      data.

PMID- 12405743
TI  - Drinking salt water enhances rehydration in horses dehydrated by frusemide
      administration and endurance exercise.
AB  - Because the primary stimulus for thirst is an increase in plasma tonicity, we
      hypothesised that dehydrated horses would drink a greater total volume of fluid
      voluntarily during the first hour of recovery when they were initially offered
      salt water. To test this hypothesis, bodyweight (bwt), fluid intake (FI) and
      [Na+] were measured in 6 Arabian horses offered 3 rehydration solutions. After
      dehydration was induced by frusemide administration (1 mg/kg bwt, i.v.) followed
      by 45 km treadmill exercise, water (W), 0.45% NaCl and 0.9% NaCl were offered, in
      a randomised order, during the initial 5 min after completing exercise. Horses
      were subsequently placed in a stall and further intake of plain water during the
      first hour of recovery was measured. By the end of exercise, horses lost 5.2 +/-
      0.2, 5.6 +/- 0.3 and 5.7 +/- 0.2% (P>0.05) bwt and FI during the first 5 min of
      recovery was 10.5 +/- 0.7, 11.6 +/- 0.8 and 11.6 +/- 1.5 l (P>0.05) for W, 0.45%
      NaCl and 0.9% NaCl, respectively. After 20 min of recovery, [Na+] had decreased
      with W but remained unchanged from the end exercise values for both saline
      solutions. During the initial hour of recovery, further water intake was 0.9 +/-
      0.4, 5.0 +/- 0.5 and 6.9 +/- 0.7 l (P<0.05) for W, 0.45% NaCl and 0.9% NaCl,
      respectively. Therefore, total FI was 11.4 +/- 0.5, 16.6 +/- 0.7 and 18.5 +/- 1.7
      l (P<0.05) for W, 0.45% NaCl and 0.9% NaCl, respectively, and persisting bwt loss
      after 60 min of recovery was greater (P<0.05) for W (3.5%) than for the 2 saline
      solutions (24% for 0.45% NaCl and 1.9% for 0.9% NaCl). In conclusion, providing
      salt water as the initial rehydration fluid maintained an elevated [Na+] and
      resulted in greater total FI and recovery of bwt loss during the first hour of
      recovery, in comparison to offering only plain water.

PMID- 12405744
TI  - Effect of NaCl and NaHCO3 on serum ionised calcium and blood gas status during
      sprinting.
AB  - Sodium bicarbonate is often administered to horses before racing in an attempt to
      delay fatigue and improve performance. We examined the effect of acid-base status
      on serum ionised calcium concentration (iCa) during high intensity exercise in 8
      Standardbred mares. In a randomised, blinded, cross-over study, mares were
      administered each of 3 treatments, NaCl (0.7 g/kg bwt), NaHCO3 (1 g/kg bwt) in 3
      l water, or 3 l of water only, 4 h before performing a standardised exercise test
      to fatigue on a treadmill. Mixed venous blood samples were collected as the
      horses ran for 5 min at 3 m/s, to fatigue at a predetermined speed (approximately
      113% VO2max) and for 5 min at 3 m/s. There was no effect of treatment on time to
      fatigue (P = 0.744). NaHCO3 attenuated (P<0.05) the exercise-induced decrease in
      venous pH (mean +/- s.e. 6.97, 6.95 and 7.06 +/- 0.02 at end of sprint for water,
      NaCl and NaHCO3, respectively). Both serum total calcium concentration (tCa) and
      iCa increased (P<0.05) with running. NaHCO3 decreased iCa (P<0.05) compared to
      water; iCa of 1.58 and 1.44 +/- 0.04 mmol/l before exercise and 1.69 and 1.49 +/-
      0.05 end sprint, for water and NaHCO3 treatments, respectively. These results
      demonstrate an effect of NaHCO3 on iCa during exercise. Further study is
      necessary to determine the effect of alterations in iCa on exercise performance.

PMID- 12405745
TI  - Plasma aldosterone concentration and renal sodium excretion are altered during
      the first days of training.
AB  - The purpose of the present study was to determine whether the training-induced
      hypervolaemic response seen in the horse is associated with aldosterone-mediated
      renal mechanisms affecting sodium conservation during the first days of training.
      Five healthy, Standardbred mares (weight 450-500 kg, age 4-8 years) that were
      unfit, but accustomed to running on the treadmill, were used to test the
      hypothesis that repeated submaximal exercise would alter plasma aldosterone
      (ALDO) concentration and renal excretion of electrolytes in horses within the
      first 3 days of training. The experiment consisted of a 2 week housing
      equilibration period followed by a 1 week control period and a 3 day exercise
      training period (30 min/day at 60% VO2max). During control, ALDO and renal fluid
      and electrolyte losses were measured for 24 h on 3 separate days. Renal function
      (urine volume [UV], 24 h excretion of Na+, K+ and Cl- [UNA+ V, UK+ V, UCl- V],
      clearance of Na+ [CNa+], K+ [CK+] and Cl- [CCl-], creatinine [CCr], osmotic
      substances [Cosm], and solute-free water [FWC], and the fractional excretion of
      Na+, K+ and Cl-) and ALDO were measured for an additional 3 consecutive days
      during the training period. There were no differences (P>0.05) in any variable
      during the control period. Plasma volume increased (+18.7%, P<0.05) after 3 days
      of training. During training, there were no significant changes in plasma
      osmolality, electrolyte concentrations or CCr. Training caused decreases (P<0.05)
      in UV (-30%), UNA+ V (-73%), UK+ V, (-55%) and UCl- V (-70%). Training also
      caused decreases (P<0.05) in Cosm (-30%), through decreases in CNa+ (-60%), CK+ (
      60%), and CCl- (-66%). Interestingly, FWC increased (+30%, P<0.05), whereas,
      there were significant decreases in the fractional excretion of Na+ (-59%), K+ (
      48%) and Cl- (-60%). Training caused substantial elevations in both pre-exercise
      (967%, P<0.05) and postexercise (+3013%, P<0.05) plasma ALDO concentrations
      suggesting an increase in both basal levels and the responsiveness to acute
      exercise. Together, these observations suggest that mechanisms affecting tubular
      conservation of electrolytes contribute to the early response to training.
      However, it is also concluded that renal mechanisms appear to be only part of the
      mechanism for conserving sodium and water intake as well as training-induced
      changes in gastrointestinal mechanisms affecting electrolyte and water balance.

PMID- 12405746
TI  - Potassium and lactate uptake by noncontracting tissue during strenuous exercise.
AB  - Efflux of potassium (K+) and lactate (lac-) from active skeletal muscle during
      high intensity exercise leads to increased plasma [K+] and [lac-] in venous and
      arterial blood. The exercise-induced increases in these ions in human athletes is
      ameliorated, in part, by uptake by noncontracting tissue, reflected by an
      increase in the arteriovenous difference across these tissues from rest to
      exercise. To test the hypothesis that these ions are taken up by noncontracting
      tissue in strenuously exercising horses, plasma [K+] and [lac-] were measured in
      blood samples collected simultaneously from the carotid artery (CA), femoral vein
      (FV), and transverse facial vein (TFV) in 5 unconditioned Standardbred horses
      performing 4.5 min of strenuous treadmill exercise. Further, the arteriovenous
      differences ((a-v)diff) in [K+] and [lac-] were calculated across active tissue
      (CA-FV) and noncontracting tissue (CA-TFV). After 3 min of strenuous exercise,
      plasma [K+] in FV blood (mean +/- s.e. 7.1 +/- 0.2 mmol/l) was greater (P<0.05)
      than in CA blood (6.8 +/- 0.2 mmol/l) and both of these concentrations were
      greater (P<0.05) than a value of 5.7 +/- 0.1 mmol/l in TFV blood. Similarly,
      plasma [lac-] increased to 20.6 +/- 0.8 and 21.1 +/- 0.8 mmol/l in CA and FV
      blood, respectively, and these concentrations were greater (P<0.05) than a value
      of 19.1 +/- 0.8 mmol/l in TFV blood. The magnitude of the (a-v)diff for both [K+]
      and [lac-] increased (P<0.05) across active and noncontracting tissue during high
      speed exercise but the directions were opposite, supporting release by active
      tissue and uptake by noncontracting tissue. These results confirm that uptake of
      K+ and lac- by noncontracting tissue contributes to regulation of the plasma
      concentrations of these ions in strenuously exercising horses.

PMID- 12405747
TI  - Effect of sodium bicarbonate administration on metabolic responses to maximal
      exercise.
AB  - Administration of bicarbonate has been shown to cause metabolic alkalosis both in
      man and in horses and is, therefore, thought to increase the buffering capacity
      of the body and thereby delay the onset of fatigue. However, results regarding
      the influence of sodium bicarbonate loading on performance both in human athletes
      and in horses are conflicting. The aim of this study was, therefore, to
      investigate the metabolic response to a standardised treadmill exercise test to
      fatigue, in horses given bicarbonate (0.6 g/kg bwt), in comparison to horses
      given placebo (water). Five Standardbred trotters performed the test on 2
      occasions. Venous blood samples were collected before and after administration of
      test substance, during exercise and during recovery. Muscle biopsy specimens were
      taken at rest, postexercise and at 15 min of recovery. The increases in pH and
      concentration of bicarbonate in the blood and the shift seen in base excess
      showed that the administration of sodium bicarbonate caused metabolic alkalosis.
      Exercise caused similar decreases in muscle ATP, CP and glycogen and similar
      increases in muscle IMP, lactate and plasma lactate and uric acid concentrations
      both in the placebo- and bicarbonate-treated group. The effect upon postexercise
      muscle and plasma metabolites was similar with both test treatments. Duration of
      exercise did not change after sodium bicarbonate intake. In conclusion, sodium
      bicarbonate caused metabolic alkalosis, but did not affect the metabolic response
      or duration of exercise.

PMID- 12405748
TI  - Metabolic and osmoregulatory function at low and high (3800 m) altitude.
AB  - Altitude evokes physiological adjustments that include not only respiratory and
      cardiovascular properties, but also metabolic function, renal and endocrine
      responses. The purpose of the present study was designed to expand our
      understanding of the physiological process involved with acclimatisation to high
      altitude in equids. The study examined temporal effects on metabolic and
      osmoregulatory function in horses (n = 6) at rest and postexercise at 3800 m.
      Animals were studied at 225 m (Pb = 743 mmHg) and during a 10 day stay at
      altitude (Pb = 487 mmHg). Rest samples were taken 90 min postprandial at 0830 h
      and immediately after the gallop phase of a standard exercise test. Changes in
      glucose, insulin, cortisol, thyroxine, sodium, potassium, chloride and total
      protein were assessed at both altitudes. Exercise stimulated increases in
      cortisol, thyroxine, potassium, and chloride; while the concentrations of
      glucose, insulin, sodium and total protein (regardless of altitude) decreased.
      Acute (Day 2) altitude exposure (following transport stress) produced significant
      increases in glucose, cortisol, thyroxine, chloride and protein at rest and
      exercise. All variables (except cortisol) appeared to stabilise by Day 4 of
      altitude exposure. Observations from these data (coupled with haematological and
      blood gases data) indicate that equids acutely acclimate within 2-3 days to this
      altitude.

PMID- 12405749
TI  - Evaluation of the i-STAT hand-held chemical analyser during treadmill and
      endurance exercise.
AB  - This study examined the accuracy and precision of a hand-held, chemical analyser,
      i-STAT, in measuring selected blood constituents which may be of use in the
      diagnosis and management of metabolic disorders found in exercising horses.
      Venous blood samples were taken from 3 Thoroughbred geldings, fit and trained to
      exercise on a treadmill, both before and after exercise at a speed sufficient to
      elicit VO2max. The samples were analysed both with the i-STAT and with in-house
      analysers to compare the values of pH, partial pressure of oxygen (PO2), partial
      pressure of carbon dioxide (PCO2), bicarbonate (HCO3), lactate and base excess
      (BE). The i-STAT demonstrated acceptable accuracy and precision for determination
      of pH, PO2 and PCO2, and lactate. We concluded that these parameters could be
      reliably evaluated by the i-STAT. The i-STAT was further evaluated at veterinary
      checkpoints during a 60 and 100 mile endurance ride. Because a built-in
      thermostat prevents function when the temperature of the analyser is outside the
      optimum range (16-30 degrees C), it was necessary to insulate the i-STAT from
      extreme ambient temperatures. As this portion of the study was conducted in warm
      temperatures, the appropriate insulation was to maintain the i-STAT in an ice
      cooled container except during actual blood analyses. Further investigation into
      the feasibility of using hand-held chemical analysers at the veterinary
      checkpoints during endurance rides is recommended.

PMID- 12405750
TI  - Lactate transport in red blood cells by monocarboxylate transporters.
AB  - The lactate transport activity of red blood cells (RBC) varies widely among
      different species; in equine RBC, the activity of the main lactate carrier, H+
      monocarboxylate co-transporter (MCT), is distributed bimodally. The influence of
      lactate transport activity is measurable in vivo; after maximal exercise, the RBC
      lactate concentration in horses with high (HT) lactate transport activity is
      higher than in those with low (LT) activity. To study the expression of MCT in HT
      and LT horses, blood samples were taken from 10 horses at rest and after
      submaximal exercise. Blood and plasma lactate concentrations, lactate and
      pyruvate transport activities and the amounts of MCT1, MCT2 and MCT4 were
      measured. After exercise, RBC lactate concentration was higher in HT (n = 5) than
      in LT (n = 5) horses. At lactate concentrations of 0.25-30 mmol/l and at a
      pyruvate concentration of 1 mmol/l, transport activity was higher in HT horses.
      At a lactate concentration of 0.1 mmol/l, transport was similar. In Western
      blots, the signals for MCT1 and MCT2 were similar in both groups. The amount of
      CD147, a chaperone necessary for the activity of MCT1, was lower in LT horses. We
      suggest that MCT2 transports lactate at low concentrations, while MCT1 is needed
      at higher concentrations. MCT1 may be less active in LT horses and, therefore,
      during exercise their capacity to take up lactate is low. Further studies are
      needed to show whether the differences in lactate influx in RBC affect the
      function of erythrocytes or the performance capacity of horses.

PMID- 12405751
TI  - Carbonic anhydrase activity and sweat gland morphology in trained and untrained
      Standardbred trotters.
AB  - Sweat gland morphology and carbonic anhydrase (CA) distribution was studied after
      exercise in trained and untrained horses using a histochemical technique and
      light microscopic image analysis. Three trained and 3 untrained Standardbred
      trotters performed an exercise test (20 min trot at 6 m/s with 5 min walk at 1.8
      m/s in the beginning and end) on a high-speed treadmill at 35 degrees C. Skin
      biopsies were taken before exercise and after trot. The fluid loss after exercise
      was 10, 12 and 12 g/kg bwt in the untrained horses and 4, 6 and 11 g/kg in the
      trained. Trained horses had a larger cell area than untrained after exercise,
      which might be related to an increase in secretory capacity. The area of the cell
      occupied by CA was independent of training status, but increased with exercise in
      both groups. The CA activity was higher in untrained animals and increased after
      exercise in both groups. The change in CA during exercise might be a response to
      an increasing demand for HCO3- secretion during sweat formation. Therefore, the
      sweat gland undergoes morphological changes due to stimuli such as heat, exercise
      and training, but species differences are evident. To our knowledge, no one has
      previously studied the influence of training on the morphology of the equine
      sweat gland.

PMID- 12405752
TI  - The effect of coat clipping on thermoregulation during intense exercise in
      trotters.
AB  - The aim of this study was to study the physiological, especially
      thermoregulatory, responses during intense exercise in the clipped horse compared
      to the horse with winter coat. Six Standardbred trotters were studied before and
      after clipping. They performed an inclined incremental high intensity treadmill
      exercise test and were monitored during recovery. The clipped horse differed
      significantly (ANOVA) during exercise as compare to coated: less increase in
      central venous blood temperature, higher skin surface temperature, greater
      difference skin to ambient temperature and higher rate of nonevaporative heat
      loss. The clipped horse had significantly lower total cutaneous evaporative heat
      loss from walk to end of peak exercise and a shorter time for recovery for the
      respiratory rate using a paired t test. The clipped horse showed a tendency (P =
      0.059) to decreased oxygen uptake during the stepwise increase in workload. We
      concluded that the clipped horse experienced less strain on the thermoregulatory
      system due to an enhanced heat loss. Some clipped horses in the study showed a
      more efficient power output; future studies with emphasis on respiration and
      oxygen demand are needed to explain this.

PMID- 12405753
TI  - Age-related changes and inheritance of lactate transport activity in red blood
      cells.
AB  - In red blood cell membranes, the activity of the main lactate carrier, H+
      monocarboxylate co-transporter (MCT), varies interindividually and its
      distribution is bimodal. To show the repeatability of MCT activity, 2 to 5 blood
      samples were taken, at an interval of approximately 1 year, from 51 Standardbred
      horses, age 2 weeks-8 years, for a total of 128 observations. The horses could be
      divided into low (LT) and high (HT) lactate transport activity groups. Age
      significantly affected (P<0.05) MCT activity such that activity was highest in
      foals, reached a nadir at 2-3 years, and tended to increase again thereafter.
      Interindividual variation was not sufficiently high to allow a horse to switch
      from the LT-group to the HT-group, or vice versa. When MCT activity from 4 sires,
      15 dams and their 52 offspring was analysed, the data showed that MCT activity is
      heritable and supported the hypothesis that low MCT activity was caused by a
      recessive allele in a single autosomal locus. Because MCT activity affects RBC
      lactate concentrations, the phenomenon may be physiologically significant.

PMID- 12405754
TI  - Assay of riboflavin in sample wines by capillary zone electrophoresis and laser
      induced fluorescence detection.
AB  - To routinely assay the concentration of riboflavin (RF) in wines, a rapid and
      sensitive method was developed and evaluated. The method is based on a simple
      sample preparation, capillary zone electrophoretic separation and laser-induced
      fluorescence detection (CZE-LIF). Sample preparation required only dilution and
      filtration. Under optimized conditions, the limit of detection of riboflavin was
      0.5 micro g/L, using a hydrodynamic sample introduction of 10 s at 54 mbar. The
      method was fully validated: the recovery of RF in wines was >95%. The
      concentrations of RF within the three sample types of Italian wines investigated
      here ranged from 69 to 151 micro g/L with a mean value (+/-SD) of 112 +/- 25
      micro g/L, from 74 to 193 micro g/L with a mean value of 115 +/- 45 micro g/L,
      and from 156 to 292 micro g/L with a mean value of 226 +/- 40 micro g/L, for
      white, rose, and red wines, respectively. Such an accurate and highly sensitive
      CZE-LIF method represents a powerful improvement over previous methods in terms
      of sensitivity, simplicity, and efficiency. It is well suited to satisfy the
      demands for accurate and sensitive detection with minimal sample preparation and
      cleanup.

PMID- 12405755
TI  - Analysis of antioxidants from orange juice obtained by countercurrent
      supercritical fluid extraction, using micellar electrokinetic chromatography and
      reverse-phase liquid chromatography.
AB  - Antioxidants from orange juice were determined by the combined use of
      countercurrent supercritical fluid extraction (CC-SFE) prior to reverse-phase
      liquic chromatography (RP-LC) or micellar electrokinetic chromatography (MEKC).
      The separation of antioxidants found in the SFE fractions was achieved by using a
      new MEKC method and a published LC procedure, both using diode array detection.
      The characterization of the different antioxidants was further done by LC-mass
      spectrometry. Advantages and drawbacks of LC and MEKC for analyzing the
      antioxidants found in the different orange extracts are discussed. Although LC
      yields higher peak area and slightly better reproducibility than MEKC, the latter
      technique provides information about the CC-SFE extracts in analysis times 7
      times faster than by LC. This analysis advantage can be used for the quick
      adjustment of CC-SFE conditions, thus providing a fast way to obtain orange
      fractions of specific composition.

PMID- 12405756
TI  - Synthesis and stable isotope dilution assay of ethanethiol and diethyl disulfide
      in wine using solid phase microextraction. Effect of aging on their levels in
      wine.
AB  - Ethanethiol and diethyl disulfide (DEDS) most often occurred at levels above
      their olfactive threshold in wines with nauseous sulfur-linked smells. As
      ethanethiol is very oxidizable and chemically reactive, a stable isotopic
      dilution analysis of both ethanethiol and its disulfide in wines using solid
      phase microextraction and GC-MS was developed. The latter involved the
      determination of the proportion of DEDS formed by oxidation of the thiol during
      the analysis conditions, which was obtained by the use of two differently labeled
      disulfide standards. An original synthesis of labeled ethanethiol standards in
      conditions minimizing oxidation was developed, and the corresponding labeled
      diethyl disulfides were obtained from these thiols. This analytical method was
      used to follow the levels of these sulfur compounds during aging in a young red
      wine spiked with ethanethiol and added with enological tannins, with or without
      oxygen addition. The total levels of these two sulfur compounds were shown to
      decrease steadily after 60 days of aging, up to 83%. The effect of oxygen sped
      this decrease, but the effect of enological tannins was very slight. Residual
      ethanethiol was detected in its disulfide form from approximately 36% in the
      nonoxygenated wines to 69% in the oxygenated samples.

PMID- 12405757
TI  - Rapid time-resolved immunofluorometric assay for the measurement of creatine
      kinase in serum and whole blood samples.
AB  - A rapid and simple immunochemical method was developed for the assessment of the
      creatine kinase (MM) isoenzyme [CK(MM)], a protein marker linked with animal
      welfare and meat quality. The one-step time-resolved immunofluorometric assay
      produced quantitative results from serum or whole blood samples in 20 min. The
      analytical limit of detection (mean + 2s) for the immunoassay was 17 ng/mL (n =
      6), and the functional limit of detection for the analysis of porcine whole blood
      samples was 426 ng/mL (n = 24). The working range of the method was linear up to
      50 micro g/mL, and the within-assay precision varied between 2.1 and 10.9%. The
      analysis of porcine serum samples showed that the results from the immunoassay
      method and colorimetric CK enzyme activity determination were highly correlated
      (r(2) = 0.965, n = 17, p < 0.001). The practicability of the assay was
      demonstrated by the analysis of 300 porcine whole blood samples in a
      slaughterhouse environment.

PMID- 12405758
TI  - Spectrophotometric determination of yellow pigment content and evaluation of
      carotenoids by high-performance liquid chromatography in durum wheat grain.
AB  - The so-called "yellow pigment" content of durum wheat has been used for a long
      time as an indicator of the color quality of durum wheat and pasta products. For
      decades the chemical nature of these pigments has been assigned to carotenoids,
      mainly to the xanthophyll lutein and its fatty acid esters. The chemical
      composition of the yellow pigments of eight German durum wheat cultivars was
      studied. Grains were milled on a laboratory mill. Pigment extraction of
      millstream fractions was performed according to the optimized ICC standard method
      152 procedure, and the chemical composition of the extract was analyzed by
      isocratic reversed phase high-performance liquid chromatography. all-trans-Lutein
      ranged from 1.5 to 4 mg kg(-1), and zeaxanthin was found in traces. No lutein
      esters and carotenes were detected. Surprisingly, the fraction of carotenoids of
      the complete yellow pigment content amounted to only 30-50% of the yellow pigment
      quantities, so there are still compounds in durum wheat not yet identified that
      contribute considerably to the yellow color of the grain extracts. The isolation
      and chemical identification of those pigments are under investigation.

PMID- 12405759
TI  - Determination of naringin in rat blood, brain, liver, and bile using
      microdialysis and its interaction with cyclosporin a, a p-glycoprotein modulator.
AB  - To determine naringin levels in various biological fluids, we developed an in
      vivo microdialysis technique coupled with a microbore HPLC system to investigate
      the pharmacokinetics of naringin and its interaction with cyclosporin A in rat
      blood, brain, liver, and bile. After naringin administration, naringin was
      undetectable in the brain; the distribution ratios of area under the curve (AUC)
      of liver over that in blood (AUC(liver)/AUC(blood)) and of AUC of bile over that
      in blood (AUC(bile)/AUC(blood)) of naringin were 5.39 +/- 0.94 and 29.17 +/-
      3.58, respectively. When cyclosporin A (20 mg/kg) was concomitantly administered
      with naringin (30 mg/kg), the naringin was detected in brain dialysate, but the
      distribution ratios of liver and bile showed no statistical difference. These
      results suggest that naringin was concentrated in the liver and bile by the
      processes of active transport. The blood-brain barrier penetration of naringin
      may be enhanced by P-glycoprotein inhibitor; however, the pathway of
      hepatobiliary excretion of naringin may not be related to the P-glycoprotein.

PMID- 12405760
TI  - Development of an enzyme-linked immunosorbent assay for the organophosphorus
      insecticide bromophos-ethyl.
AB  - A competitive enzyme-linked immunosorbent assay (ELISA) was developed for the
      quantitative detection of the organophosphorus insecticide bromophos-ethyl. Four
      bromophos-ethyl derivatives (haptens) were synthesized and were coupled to
      carrier proteins through the pesticide thiophosphate group to use as an immunogen
      or as a coating antigen. Rabbits were immunized with either one of two haptens
      coupled to bovine serum albumin for production of polyclonal antibodies, and the
      sera were screened against one of the haptens coupled to ovalbumin. Using the
      serum with highest titer, an antigen-coated ELISA was developed, which showed an
      IC(50) of 3.9 ng/mL with a detection limit of 0.3 ng/mL (20% inhibition). An
      antibody-coated ELISA using an enzyme tracer was also developed, which showed an
      IC(50) of 6.5 ng/mL with a detection limit of 1.0 ng/mL (20% inhibition). The
      antibodies showed negligible cross-reactivity with other organophosphorus
      pesticides except with the insecticides bromophos-methyl and chlorpyrifos in the
      antibody-coated assay only. Recoveries of bromophos-ethyl from fortified crop and
      water samples ranged from 82 to 128% and from 95 to 127%, respectively.

PMID- 12405761
TI  - Survey on the presence of butyltin compounds in chinese alcoholic beverages,
      determined by using headspace solid-phase microextraction coupled with gas
      chromatography-flame photometric detection.
AB  - The use of butyltin compounds in some food packaging leads to the contamination
      of liquid food and may result in subsequent adverse effects on people's health
      through the food chain. A survey of butyltin compounds in Chinese alcoholic
      beverages purchased from retail markets was carried out by using solid-phase
      microextraction (SPME) followed by gas chromatography coupled with flame
      photometric detection. Forty-four samples including wine, liquor, and champagne
      were studied. The levels of monobutyltin and dibutyltin ranged from <0.016 to
      5.687 and from <0.0022 to 33.257 microg of Sn/L, respectively. Low levels of
      tributyltin were detected. The presence of dibutyltin in wine samples was further
      confirmed by GC-MS. The result indicated that dry wines generally contained more
      dibutyltin than sweet wines. The concentrations of butyltin compounds in liquor
      samples were lower than those in wine samples.

PMID- 12405762
TI  - Composition and antifungal activity on soil-borne pathogens of the essential oil
      of Salvia sclarea from Greece.
AB  - The hydrodistilled essential oils of the aerial parts of wild-growing Salvia
      sclarea originated from two localities in Greece were analyzed by GC-MS. Sixty
      six compounds, representing 93.26-98.19% of the oils, were identified. Linalyl
      acetate (19.75-31.05%), linalool (18.46-30.43%), geranyl acetate (4.45-12.1%),
      and alpha-terpineol (5.08-7.56%) were the main components. The antifungal
      activity of the oil of one locality and of the main components, linalyl acetate
      and linalool, was evaluated in vitro against three soil-borne pathogens.

PMID- 12405763
TI  - Anti-Salmonella activity of alkyl gallates.
AB  - A series of alkyl gallates (3,4,5-trihydroxybenzoates) was synthesized and tested
      for their antibacterial activity against Salmonella choleraesuis. Nonyl (C(9))
      and octyl (C(8)) gallates were noted to be the most effective against this food
      borne bacterium, each with a minimum bactericidal concentration (MBC) of 12.5
      microg/mL, followed by decyl (C(10)) gallate, with a MBC of 25 microg/mL. Dodecyl
      (C(12)) gallate exhibited activity against S. choleraesuis, with a MBC of 50
      microg/mL. Propyl (C(3)) gallate showed no activity against S. choleraesuis up to
      3200 microg/mL. The length of the alkyl group is not a major contributor but
      plays a role in eliciting the activity to a large extent. The same series of
      alkyl gallates, regardless of alkyl chain length, all showed nearly the same
      potent scavenging activity on the 1,1-diphenyl-2-picrylhydrazyl radical,
      indicating that the length of the alkyl group is not associated with the
      activity.

PMID- 12405764
TI  - Zoosporicidal activity of polyflavonoid tannin identified in Lannea coromandelica
      stem bark against phytopathogenic oomycete Aphanomyces cochlioides.
AB  - In a survey of nonhost plant secondary metabolites regulating motility and
      viability of zoospores of the Aphanomyces cochlioides, we found that stem bark
      extracts of Lannea coromandelica remarkably inhibited motility of zoospores
      followed by lysis. Bioassay-guided fractionation and chemical characterization of
      Lannea extracts by MALDI-TOF-MS revealed that the active constituents were
      angular type polyflavonoid tannins. Commercial polyflavonoid tannins, Quebracho
      and Mimosa, also showed identical zoosporicidal activity. Against zoospores, the
      motility-inhibiting and lytic activities were more pronounced in Lannea extracts
      (MIC 0.1 microg/mL) than in Quebracho (MIC 0.5 microg/mL) and Mimosa (MIC 0.5
      microg/mL). Scanning electron microscopic observation visualized that both Lannea
      and commercial tannins caused lysis of cell membrane followed by fragmentation of
      cellular materials. Naturally occurring polyflavonoid tannin merits further study
      as potential zoospore regulating agent or as lead compound. To the best of our
      knowledge, this is the first report of zoosporicidal activity of natural
      polyflavonoid tannins against an oomycete phytopathogen.

PMID- 12405765
TI  - Phase II enzyme-inducing and antioxidant activities of beetroot (Beta vulgaris
      L.) extracts from phenotypes of different pigmentation.
AB  - Free-radical scavenging, reducing, and phase II enzyme-inducing activities of
      aqueous and 5% aqueous ethanol extracts of freeze-dried root tissue of four beet
      (Beta vulgaris L.) strains (red, white, orange, and high-pigment (red)
      phenotypes) were determined. Aqueous and ethanolic tissue extracts of the regular
      and high-pigment red phenotypes were most capable of inhibiting
      metmyoglobin/H(2)O(2)-mediated oxidation of 2-2'-azino-bis(3-ethylbenzthiazoline
      6-sulfonic acid) (ABTS) and 2,2'-azobis-(2-amidinopropane) dihydrochloride (AAPH)
      mediated bleaching of beta-carotene. These same extracts were also most efficient
      at reducing ABTS radical cation and inducing quinone reductase in murine hepatoma
      (Hepa 1c1c7) cells in vitro.

PMID- 12405766
TI  - Inhibitory effects of cucurbitane glycosides and other triterpenoids from the
      fruit of Momordica grosvenori on epstein-barr virus early antigen induced by
      tumor promoter 12-O-tetradecanoylphorbol-13-acetate.
AB  - Two new triterpene benzoates, 5-dehydrokarounidiol dibenzoate (1) and karounidiol
      dibenzoate (2), and two new triterpene glycosides, 5alpha,6alpha-epoxymogroside
      IE(1) (8) and 11-oxomogroside A(1) (9), along with 15 known triterpenoids (one
      triterpene benzoate, 3; three triterpene mono-ols, 4-6; one triterpene aglycon,
      7; and 10 triterpene glycosides, 10-19), were isolated from the ethanol extract
      of the fruit of Momordica grosvenori. The structures of 1, 2, 8, and 9 were
      determined on the basis of spectroscopic and chemical methods. Among the known
      triterpene glycosides, mogroside I E(1) (12) was a new naturally occurring
      compound. Eighteen triterpenoids (2-19) and 11-oxomogrol (20), a hydrolysis
      product of 9, were evaluated with respect to their inhibitory effects on the
      induction of Epstein-Barr virus early antigen (EBV-EA) by 12-O
      tetradecanoylphorbol-13-acetate (TPA) in Raji cells, which is known to be a
      primary screening test for antitumor promoters. All of the compounds tested
      showed potent inhibitory effects on EBV-EA induction (70-100% inhibition at 1 x
      10(3) mol ratio/TPA).

PMID- 12405767
TI  - Identification of phenolic compounds in tissues of the novel olive cultivar
      hardy's mammoth.
AB  - A methodological approach to phenolic profiling making extensive use of LC-MS
      with extracted ion chromatograms was applied to extracts of five different olive
      tissues: pulp, seed, stone, new-season leaves, and old-season leaves. Tissue
      extracts of the cultivars Hardy's Mammoth, Corregiola, Verdale, and Manzanillo
      were analyzed by HPLC with UV and ESI MS detection. Chromatograms of samples of
      green Hardy's Mammoth drupes, a uniquely Australian olive cultivar, were
      dominated by a large, broad peak. This peak was not attributable to oleuropein,
      which is usually the dominant phenolic compound in green olive fruit, but the
      phenolic compound I. This compound was isolated by semipreparative HPLC and
      characterized by 1D- and 2D-NMR. Extraction studies showed that the compound was
      not likely to be an artifact of an enzymatic degradation process. Tritium
      labeling studies were used to establish a possible relationship between the
      biosynthesis of I and oleuropein.

PMID- 12405768
TI  - Kinetic modeling of reactions in heated monosaccharide-casein systems.
AB  - In the present study, a kinetic model of the Maillard reaction occurring in
      heated monosaccharide-casein systems was proposed. Its parameters, the reaction
      rate constants, were estimated via multiresponse modeling. The determinant
      criterion was used as the statistical fit criterion instead of the familiar least
      squares to avoid statistical problems. The kinetic model was extensively tested
      by varying the reaction conditions. Different sugars (glucose, fructose,
      galactose, and tagatose) were studied regarding their effect on the reaction
      kinetics. This study has shown the power of multiresponse modeling for the
      unraveling of complicated reaction routes as occur in the Maillard reaction. The
      iterative process of proposing a model, confronting it with experiments, and
      criticizing the model was passed through four times to arrive at a model that was
      largely consistent with all results obtained. A striking difference was found
      between aldose and ketose sugars as suggested by the modeling results: not the
      ketoses themselves but only their reaction products were found to be reactive in
      the Maillard reaction.

PMID- 12405769
TI  - Rheological characteristics of intermediate moisture blends of pregelatinized and
      raw wheat starch.
AB  - Rheological properties of intermediate moisture (35-45% wet basis) doughs from
      pregelatinized and raw wheat starch blends of various ratios were characterized
      using off-line capillary rheometry and online slit-die extrusion. In the case of
      capillary rheometer, viscosity of blends decreased by up to 50% as pregel starch
      concentration increased from 5 to 45%, whereas tests could not be conducted
      beyond 45% pregel starch concentration. For slit-die extrusion, viscosity was at
      a minimum at 60% pregel concentration, and it decreased by as much as 65% as
      pregel concentration increased from 0 to 60%. As pregel concentration increased
      (from 5 to 45% for the rheometer and from 0 to 60% for the extruder), the amount
      of water available in the system for gelatinization of existing raw starch
      granules decreased due to the stronger water-binding capacity of pregelatinized
      starch. This led to decreased additional conversion in the rheometer and
      extruder, which in turn caused a decrease in the volume fraction of starch and a
      reduction in viscosity.

PMID- 12405770
TI  - Pectins as possible source of the copper involved in the green staining
      alteration of cv. Gordal table olives.
AB  - The pectic and pigment compositions and Ca and Cu contents of the alcohol
      insoluble solid (AIS) residues were determined in cv. Gordal olives treated with
      NaOH solution and kept at different constant pH values (3.5-6.5). The same
      controls were made in table olives presenting green staining alteration. The
      ratio between the various pectin fractions of the more acid pH experiment samples
      remained similar in fruits not showing green staining. In altered fruits, the
      protopectin fraction was lower, and the calcium pectate or EDTA soluble pectins
      were higher. Regarding the presence of Ca and Cu in the AIS, it was observed
      that, whereas Ca levels fell at the most acid pH values, those of Cu increased.
      The concentration of Ca was higher in the AIS of altered olives than in
      nonaltered ones. The same trend was seen for the zone with or without green
      staining of an altered fruit. In the case of Cu, the relationship was the
      opposite: a decrease in the levels of AIS Cu in fruits and zones of fruits with
      green staining. This result was correlated with the highest concentration of Cu
      chlorophyll complexes found in such samples and suggested that pectins might act
      as a reservoir of Cu involved in the alteration.

PMID- 12405771
TI  - Volatile compounds in Hispanico cheese manufactured using a mesophilic starter, a
      thermophilic starter, and bacteriocin-producing Lactococcus lactis subsp. lactis
      INIA 415.
AB  - The effect of the addition of Lactococcus lactis subsp. lactis INIA 415, a strain
      harboring the structural genes of nisin Z and lacticin 481, on the formation of
      volatile compounds in Hispanico cheese manufactured with a mesophilic starter or
      with the mesophilic starter and a thermophilic starter was investigated. Addition
      of bacteriocin-producing L. lactis subsp. lactis INIA 415 to milk enhanced the
      formation of 2-methyl-propanal, 2-methylbutanal, 3-methylbutanal, 2-methyl-1
      propanol, 3-methyl-1-butanol, 1-octanol, 2-butanone, and 2,3-butanedione. On the
      other hand, addition of thermophilic starter enhanced the formation of
      acetaldehyde, ethanol, 3-methyl-2-buten-1-ol, ethyl butanoate, ethyl hexanoate, 2
      butanone, and 2,3-butanedione in Hispanico cheese. Stepwise discriminant analysis
      using the relative abundances of volatile compounds classified cheeses by type of
      starter, with function 1 related to thermophilic starter and function 2 to
      bacteriocin producer.

PMID- 12405772
TI  - Photoinduced degradation of carbaryl in a wetland surface water.
AB  - The photoinduced degradation of carbaryl (1-naphthyl-N-methyl carbamate) was
      studied in a wetland's surface water to examine the photochemical processes
      influencing its transformation. For this particular wetland water, at high pH, it
      was difficult to delineate the photolytic contribution to the overall degradation
      of carbaryl. At lower pH values, the extent of the degradation attributable to
      indirect pathways, that is, in the presence of naturally occurring
      photosensitizers, increased significantly. Moreover, the photoenhanced
      degradation at the lower pH values was found to be seasonally and spatially
      dependent. Analysis of water samples revealed two primary constituents
      responsible for the observed indirect photolytic processes: nitrate and dissolved
      natural organic matter (NOM). Nitrate in the wetland appears at high
      concentrations (> or =1 mM) seasonally after the application of fertilizers in
      the watershed and promotes contaminant destruction through the photochemical
      production of the hydroxyl radical (HO*). The extent of the observed indirect
      photolysis pathway appears to be dependent upon the concentration of nitrates and
      the presence of HO* scavengers such as dissolved NOM and carbonate alkalinity.
      Paradoxically, during low-nitrate events (<50 microM), NOM becomes the principal
      photosensitizer through either the production of HO*, direct energy transfer from
      the excited triplet state, and/or production of an unidentified transient
      species.

PMID- 12405773
TI  - Citrus limonoids and their semisynthetic derivatives as antifeedant agents
      against Spodoptera frugiperda larvae. A structure-activity relationship study.
AB  - The antifeedant activity of Citrus-derived limonoids limonin (1), nomilin (2),
      and obacunone (3) and their semisynthetic derivatives 4-26 was evaluated against
      a commercially important pest, Spodoptera frugiperda. Simple chemical conversions
      were carried out on the natural limonoids obtained from seeds of Citrus limon.
      These conversions focused on functional groups considered to be important for the
      biological activity, namely the C-7 carbonyl and the furan ring. In particular,
      reduction at C-7 afforded the related alcohols, and from these their acetates,
      oximes, and methoximes were prepared. Hydrogenation of the furan ring was also
      performed on limonin and obacunone. The known antifeedant properties of the
      Citrus limonoids are confirmed. Comparison with previously reported data shows
      that insect species vary in their behavioral responses to these structural
      modifications. Highly significant antifeedant activity (P < 0.01) for two natural
      (1 and 3) and three semisynthetic limonoids (4, 8, and 10) was observed against
      S. frugiperda.

PMID- 12405774
TI  - Efficiency of mannose-binding plant lectins in controlling a homopteran insect,
      the red cotton bug.
AB  - Yield losses of different crops due to the attack of various classes of insects
      are a worldwide problem. Sucking type homopteran pests causing damage to many
      crop species are not controlled by commonly known insecticidal proteins, namely,
      Bacillus thuringiensis delta-endotoxin (Bt). This study describes the
      purification of mannose-binding lectins from three different monocotyledonous
      plants (Allium sativum, Colocasia esculenta, and Diffenbachia sequina) and their
      effects on a homopteran insect, the red cotton bug. All of them had a detrimental
      effect on the growth and development of the insect, where A. sativum bulb lectin
      showed the highest mortality of all, in particular. The same bulb lectin not only
      affected the growth and fecundity of the insect but also imparted drastic changes
      in the color, weight, and size, even on the second generation of the insects
      which have been reared on artificial diet supplemented with a sublethal dose of
      the lectin. Thus, this finding opens up a possibility of using this lectin as an
      important component in crop management.

PMID- 12405775
TI  - Rapid loss of lampricide from catfish and rainbow trout following routine
      treatment.
AB  - Rainbow trout (Oncorhynchus mykiss) and channel catfish (Ictalurus punctatus)
      were exposed to 3-trifluoromethyl-4-nitrophenol (TFM) and Bayluscide
      (niclosamide) during a sea lamprey control treatment of the Ford River, located
      in the upper peninsula of Michigan. Caged fish were exposed to a nominal
      concentration of 0.02 mg/L of niclosamide for a period of approximately 12 h.
      Samples of fillet tissue were collected from each fish species before treatment
      and at 6, 12, 18, 24, 48, 96, and 192 h following the arrival of the block of
      chemical at the exposure site. The fish were dissected, homogenized, extracted,
      and analyzed by high-performance liquid chromatography. The major residues found
      in the fillet tissues were TFM and niclosamide. Niclosamide concentrations were
      highest 12 h after arrival of the chemical block for rainbow trout (0.0395 +/-
      0.0251 microg/g) and 18 h after arrival of the chemical block for channel catfish
      (0.0465 +/- 0.0212 microg/g). Residues decreased rapidly after the block of
      lampricide had passed and were below the detection limits in fillets of rainbow
      trout within 24 h and channel catfish within 96 h after the arrival of the
      lampricide.

PMID- 12405776
TI  - Relatively rapid loss of lampricide residues from fillet tissue of fish after
      routine treatment.
AB  - The selective sea lamprey (Petromyzon marinus) larvicide 3-trifluoromethyl-4
      nitrophenol (TFM) is currently used to control parasitic sea lampreys in
      tributaries to the Great Lakes basin. The concentration and persistence of TFM
      and its major metabolite, TFM glucuronide (TFM-glu), was determined in fillet
      tissue of fish after a typical stream application. Rainbow trout (Oncorhynchus
      mykiss) and channel catfish (Ictalurus punctatus) were exposed to a nominal
      concentration of 12.6 nmol/mL TFM for about 12 h during a sea lamprey control
      treatment of the Ford River in Michigan. Concentrations of TFM and TFM-glu were
      greatest in the fillet tissues during the exposure period, with greater residues
      in channel catfish (wet wt; mean, 6.95 nmol/g TFM; mean, 2.40 nmol/g TFM-glu)
      than in rainbow trout (wet wt; mean, 1.45 nmol/g TFM; mean, 0.93 nmol/g TFM-glu).
      After the exposure period, residues in both species decreased by 90-99% within 6
      12 h and were less than the quantitation limit (<0.03 nmol/g) within 36 h.

PMID- 12405777
TI  - Complexation of imazalil with beta-cyclodextrin, residue uptake, persistence, and
      activity against penicillium decay in citrus fruit following postharvest dip
      treatments.
AB  - A method for the inclusion of imazalil (IMZ) in the beta-cyclodextrin (betaCD),
      structural characterization of the inclusion complex and its antifungal activity
      against Penicillium digitatum and P. italicum assessed by in vitro and in vivo
      tests are reported. According to the starting stoichiometry of betaCD with
      respect to IMZ, an equimolar ratio beta-cyclodextrin-IMZ (betaCD-IMZ) was
      detected by (1)H NMR. In vitro assays showed that the freshly prepared betaCD-IMZ
      was as effective as IMZ, although 1- and 4-day-old betaCD-IMZ mixtures were more
      effective. Studies on Star Ruby grapefruit showed no significant differences in
      residue uptake between treatments with an IMZ commercially available fungicide
      (Deccozil) or betaCD-IMZ when equal active ingredient (a.i.) concentrations (250
      mg/L) and dip temperatures (20 or 50 degrees C) were used. By contrast,
      treatments of Tarocco oranges and Di Massa lemons with 250 mg/L betaCD-IMZ at 50
      degrees C produced significant differences in residue uptake in comparison with
      250 mg/L Deccozil treatments at 50 degrees C. The a.i. degradation rate in
      grapefruit during postquarantine and simulated marketing period (SMP) at 20
      degrees C was not affected by the type of formulation used, whether at 20 or 50
      degrees C. Conversely, IMZ in oranges and lemons had greater persistence when
      applied at 50 degrees C. All fungicide treatments showed a comparable efficacy
      against decay in grapefruit and oranges, whereas treatment in lemons at 250 mg/L
      a.i. of heated fungicides had higher suppressive effects against decay than
      unheated chemicals having equal a.i. concentrations and comparable activity at
      1200 mg/L IMZ at 20 degrees C.

PMID- 12405778
TI  - Plant-derived biomolecules in fermented cabbage.
AB  - The formation of plant-derived biomolecules during sauerkraut fermentation was
      studied. Cabbage was fermented with a starter culture, and the results were
      compared to the results of spontaneous fermentation. The concentration of
      flavonoids and glucosinolates was analyzed by HPLC, and that of the glucosinolate
      breakdown products, by GC-MS. Of the 20 different flavonoids tested, only
      kaempferol was found (0.9 mg/ kg FW, fresh weight). The content of kaempferol
      remained constant in the cabbage fiber matrix over the fermentation process. The
      nitrite concentration was below the detection limit in both fermentations. The
      total glucosinolate content in the raw material was 3.71 micro mol/g DW, dry
      weight. Glucosinolates were totally decomposed in both fermentations during two
      weeks, and different types of breakdown products were formed. Isothiocyanates,
      indole-3-carbinol, goitrin, allyl cyanide, and nitriles were determined in the
      fermented cabbage. Isothiocyanates and allyl cyanide were the predominant
      breakdown products in both fermentations. Sulforaphane nitrile and goitrin were
      found only in small quantities in the end products.

PMID- 12405779
TI  - Production in large quantities of highly purified hydroxytyrosol from liquid
      solid waste of two-phase olive oil processing or "Alperujo".
AB  - The effect of hydrothermal treatment of two-phase olive waste (alperujo) on the
      solubilization of hydroxytyrosol was studied. Different conditions of saturated
      steam were assayed. A high amount of hydroxytyrosol was solubilized and increased
      with increasing steaming temperature and time, reaching 1.4-1.7 g/100 g of dry
      alperujo. The effect of acidic (H(2)SO(4)) and basic (NaOH) catalysts was also
      evaluated. Acid-catalyzed treatment was more effective at milder conditions,
      whereas the alkali-catalyzed conditions were not very suitable. In the present
      study, the extracted hydroxytyrosol was purified by means of a new, simple, and
      inexpensive chromatographic system, under international patent application
      (PCT/ES02/00058). From 1000 kg of alperujo, with 70% humidity, can be obtained
      approximately 4.5-5 kg of hydroxytyrosol. After a purification process, at least
      3 kg of hydroxytyrosol, at 90-95% purity, would be obtained. The purified
      compound was identified by HPLC/UV and (1)H and (13)C NMR analyses, and its
      antioxidant activity was tested on refined olive oil without antioxidants by
      Rancimat method. The oxidative stability of refined olive oil was increased by a
      factor of 1.71 in the presence of 100 ppm of hydroxytyrosol.

PMID- 12405780
TI  - Phenolic compounds profile of cornicabra virgin olive oil.
AB  - This study presents the phenolic compounds profile of commercial Cornicabra
      virgin olive oils from five successive crop seasons (1995/1996 to 1999/2000; n =
      97), determined by solid phase extraction reversed phase high-performance liquid
      chromatography (SPE RP-HPLC), and its relationship with oxidative stability,
      processing conditions, and a preliminary study on variety classification. The
      median of total phenols content was 38 ppm (as syringic acid), although a wide
      range was observed, from 11 to 76 ppm. The main phenols found were the
      dialdehydic form of elenolic acid linked to tyrosol (p-HPEA-EDA; 9 +/- 7 ppm, as
      median and interquartile range), oleuropein aglycon (8 +/- 6 ppm), and the
      dialdehydic form of elenolic acid linked to hydroxytyrosol (3,4-DHPEA-EDA; 5 +/-
      8 ppm). In many cases the correlation with oxidative stability was higher when
      the sum of the dialdehydic form of elenolic acid linked to hydroxytyrosol (3,4
      DHPEA-EDA) and oleuropein aglycon (r (2) = 0.91-0.96) or the sum of these two and
      hydroxytyrosol (r (2) = 0.90-0.97) was considered than was observed with HPLC
      total phenols (r (2)= 0.91-0.95) and especially with colorimetric determination
      of total polyphenols and o-diphenols (r (2) = 0.77-0.95 and 0.78-0.92,
      respectively). 3,4-DHPEA-EDA, p-HPEA-EDA, the aglycons of oleuropein and
      ligstroside, and HPLC total phenols content presented highly significant
      differences (p = 0.001-0.010) with respect to the dual- and triple-phase
      extraction systems used, whereas colorimetric total polyphenols content did not
      (p = 0.348) and o-diphenols showed a much lower significant difference (p =
      0.031). The five variables that most satisfactorily classified the principal
      commercial Spanish virgin olive oil varieties were 1-acetoxypinoresinol, 4
      (acetoxyethyl)-1,2-dihydroxybenzene (3,4-DHPEA-AC), ligstroside aglycon, p-HPEA
      EDA, and RT 43.3 contents.

PMID- 12405781
TI  - Variation in the flavonol glycoside composition of almond seedcoats as determined
      by maldi-tof mass spectrometry.
AB  - Seedcoats of 16 almond varieties were screened for flavonol glycosides by using
      matrix-assisted laser desorption/ionization time-of-flight mass spectrometry
      (MALDI-TOF MS). Flavonol glycosides were extracted by a simple methanolic
      extraction followed by a quick cleanup procedure with a Sep-Pak C(18) cartridge.
      Each of the 16 seedcoat samples exhibited a unique composition. Four flavonol
      glycosides, isorhamnetin rutinoside, isorhamnetin glucoside, kaempferol
      rutinoside, and kaempferol glucoside, were detected and quantified with use of
      rutin as an internal standard. Individual peak ratios were very consistent across
      triplicate analyses of all samples; the average standard deviation was 9%. In all
      almond varieties, isorhamnetin rutinoside was the most abundant flavonol
      glycoside, and the total content ranged from 75 to 250 microg/g.

PMID- 12405782
TI  - Competitive sorption between imidacloprid and imidacloprid-urea on soil clay
      minerals and humic acids.
AB  - Soil organic matter and clay minerals are responsible for the adsorption of many
      pesticides. Adsorption and competitive sorption of imidacloprid on clay minerals
      and humic acids (HA) were determined using the batch equilibration method. The
      sorption coefficient of imidacloprid on humic acids was significantly higher than
      that on Ca-clay minerals, indicating that soil organic matter content was a more
      important property in influencing the adsorption of imidacloprid. Competitive
      sorption was investigated between imidacloprid and its main metabolite
      imidacloprid-urea on HA and Ca-clay minerals. The results showed that the
      sorption capacity of imidacloprid on clay minerals and HA was reduced in the
      presence of the metabolite, implying that imidacloprid-urea could occupy or block
      adsorption sites of imidacloprid on soil, potentially affecting the fate,
      transport, and bioavailability of imidacloprid in the environment. The
      interactions between a Ca-clay or HA-clay mixture and adsorption of imidacloprid
      and imidacloprid-urea were studied using IR differential spectra on thin films
      made of the adsorbent. The possible mechanisms were discussed from the shift of
      characteristic IR absorption bands of imidacloprid and imidacloprid-urea after
      sorption.

PMID- 12405783
TI  - Potentiation of the ionotropic GABA receptor response by whiskey fragrance.
AB  - It is well-known that the target of most mood-defining compounds is an ionotropic
      gamma-aminobutyric acid receptor (GABA(A) receptor). The potentiation of the
      response of these inhibitory neurotransmitter receptors induces anxiolytic,
      sedative, and anesthetic activity in the human brain. To study the effects of
      whiskey fragrance on the GABA(A) receptor-mediated response, GABA(A) receptors
      were expressed in Xenopus oocyte by injecting rat whole brain mRNA or cRNA
      prepared from the cloned cDNA for the alpha(1) and beta(1) subunits of the bovine
      receptors. Most whiskey components such as phenol, ethoxy, and lactone
      derivatives potentiated the electrical responses of GABA(A) receptors, especially
      ethyl phenylpropanoate (EPP), which strongly potentiated the response. When this
      compound was applied to mice through respiration, the convulsions induced by
      pentetrazole were delayed, suggesting that EPP was absorbed by the brain, where
      it could potentiate the GABA(A) receptor responses. The extract of other
      alcoholic drinks such as wine, sake, brandy, and shochu also potentiated the
      responses to varying degrees. Although these fragrant components are present in
      alcoholic drinks at low concentrations (extremely small quantities compared with
      ethanol), they may also modulate the mood or consciousness of the human through
      the potentiation of the GABA(A) receptor response after absorption into the
      brain, because these hydrophobic fragrant compounds are easily absorbed into the
      brain through the blood-brain barrier and are several thousands times as potent
      as ethanol in the potentiation of the GABA(A) receptor-mediated response.

PMID- 12405784
TI  - Important aroma compounds in freshly ground wholemeal and white wheat flour
      identification and quantitative changes during sourdough fermentation.
AB  - An investigation on the odor-active compounds of wholemeal (WWF) and white wheat
      flour (WF 550) by aroma extract dilution analysis (AEDA) and by quantitative
      studies using stable isotope dilution assays (SIDA) revealed a significant number
      of odor-active compounds, such as (E)-2-nonenal, (E,Z)- and (E,E)-2,4-decadienal,
      (E)-4,5-epoxy-(E)-2-decenal, 3-hydroxy-4,5-dimethyl-2(5H)-furanone, and vanillin,
      with high odor activities in both wheat flours. The amounts and, consequently,
      the aroma potencies of vanillin, (E,E)-2,4-decadienal, and 3-(methylthio)propanal
      were much higher in the WWF than in the WF 550 samples. Fermentation of
      suspensions of both flours with lactic acid bacteria did not generate new
      odorants; however, many compounds, such as acetic acid or 3-methylbutanal, were
      increased, whereas aldehydes (formed from the degradation of unsaturated fatty
      acids) were decreased. Comparing the odorant concentrations present before and
      after fermentation gave evidence that the main influence of the microorganisms on
      sourdough aroma is to either enhance or decrease specific volatiles already
      present in the flour. A comparison with literature data indicated that most of
      these odorants are also important for the bread crumb aroma present after baking
      of the dough.

PMID- 12405785
TI  - Discriminating significance of the free amino acid profile in almond seeds.
AB  - Known statistical techniques have been applied to the free amino acid composition
      of 107 samples from 10 different almond cultivars (Marcona, Desmayo-Largueta,
      Guara, Tuono, Ferragnes, Masbovera, Non Pareil, Titan, Texas, and Primorskyi)
      cultivated in seven different locations and growing conditions. It is concluded
      that free amino acid composition can constitute a basis for classifying and
      typifying these cultivars into five groups: (1) Marcona and Texas, (2) Ferragnes
      and Masbovera (and probably Primorskyi), (3) Tuono and Guara, (4) Non Pareil (and
      probably Titan), and (5) an isolated cultivar (Desmayo Largueta). As a result, an
      easy decision tree is proposed to discriminate the cultivar of an almond flour,
      as used in confectionery, if it consists of a single cultivar.

PMID- 12405786
TI  - Added triacylglycerols do not hasten hemoglobin-mediated lipid oxidation in
      washed minced cod muscle.
AB  - Hemoglobin-mediated lipid oxidation in washed, minced cod muscle was related to
      the triacylglycerol to membrane lipid ratio. The same rapid development of
      thiobarbituric acid reactive substances (TBARS) and painty odor occurred with and
      without the presence of up to 15% menhaden oil. Without hemoglobin, development
      of TBARS and painty odor was slow, despite a high amount of hydroperoxides in
      samples with oil added (1135 micromol/kg muscle). This suggested that hemoglobin
      reacted by cleaving preformed hydroperoxides into secondary oxidation products.
      Nearly doubling the hemoglobin concentration approximately doubled the extent of
      lipid oxidation with and without added oil. This indicated that hemoglobin was
      limiting for the oxidation reaction. The noneffect of added oil suggests that
      membrane lipids and/or preformed membrane lipid hydroperoxides provided
      sufficient substrate in hemoglobin-catalyzed oxidation of washed minced cod
      muscle. Fe(2+-)ADP did not induce any oxidation of washed minced cod with/without
      added oil. Results suggest that lipid oxidation in fatty fish may be more related
      to the quantity and type of the aqueous pro-oxidant and the membrane lipids than
      to variations in total fat contents.

PMID- 12405787
TI  - Preparation and characterization of papain-modified sesame (Sesamum indicum L.)
      protein isolates.
AB  - Defatted sesame meal ( approximately 40-50% protein content) is very important as
      a protein source for human consumption due to the presence of sulfur-containing
      amino acids, mainly methionine. Sesame protein isolate (SPI) is produced from
      dehulled, defatted sesame meal and used as a starting material to produce protein
      hydrolysate by papain. Protein solubility at different pH values, emulsifying
      properties in terms of emulsion activity index (EAI) and emulsion stability index
      (ESI), foaming properties in terms of foam capacity (FC) and foam stability (FS),
      and molecular weight distribution of the SPI hydrolysates were investigated.
      Within 10 min of hydrolysis, the maximum cleavage of peptide bonds occurred as
      observed from the degree of hydrolysis. Protein hydrolysates have better
      functional properties than the original SPI. Significant increase in protein
      solubility, EAI, and ESI were observed. The greatest increase in solubility was
      observed between pH 5.0 and 7.0. The molecular weight of the hydrolysates was
      also reduced significantly during hydrolysis. These improved functional
      properties of different protein hydrolysates would make them useful products,
      especially in the food, pharmaceutical, and related industries.

PMID- 12405788
TI  - Purification and characterization of three phytases from germinated lupine seeds
      (Lupinus albus var. amiga).
AB  - Three phytases were purified about 14200-fold (LP11), 16000-fold (LP12), and
      13100-fold (LP2) from germinated 4-day-old lupine seedlings to apparent
      homogeneity with recoveries of 13% (LP11), 8% (LP12), and 9% (LP2) referred to
      the phytase activity in the crude extract. They behave as monomeric proteins of a
      molecular mass of about 57 kDa (LP11 and LP12) and 64 kDa (LP2), respectively.
      The purified proteins belong to the acid phytases. They exhibit a single pH
      optimum at 5.0. Optimal temperature for the degradation of sodium phytate is 50
      degrees C. Kinetic parameters for the hydrolysis of sodium phytate are K(M) = 80
      microM (LP11), 300 microM (LP12), and 130 microM (LP2) and k(cat) = 523 s(-1)
      (LP11), 589 s(-1) (LP12), and 533 s(-1) (LP2) at pH 5.0 and 35 degrees C. The
      phytases from lupine seeds exhibit a broad affinity for various phosphorylated
      compounds and hydrolyze phytate in a stepwise manner.

PMID- 12405789
TI  - Pathway of dephosphorylation of myo-inositol hexakisphosphate by phytases of
      legume seeds.
AB  - Using a combination of high-performance ion chromatography analysis and kinetic
      studies, the pathway of dephosphorylation of myo-inositol hexakisphosphate by the
      phytases purified from faba bean and lupine seeds, respectively, was established.
      The data demonstrate that the legume seed phytases under investigation
      dephosphorylate myo-inositol hexakisphosphate in a stereospecific way. The
      phytase from faba bean seeds and the phytase LP2 from lupine seeds degrade
      phytate by sequential removal of phosphate groups via D-Ins(1,2,3,5,6)P(5), D
      Ins(1,2,5,6)P(4), D-Ins(1,2,6)P(3), and D-Ins(1,2)P(2) to finally Ins(2)P,
      whereas the phytases LP11 and LP12 from lupine seeds generate the final
      degradation product Ins(2)P via D-Ins(1,2,4,5,6)P(5), D-Ins(1,2,5,6)P(4), D
      Ins(1,2,6)P(3), and D-Ins(1,2)P(2).

PMID- 12405790
TI  - Hydrophilic carboxylic acids and iridoid glycosides in the juice of American and
      European cranberries (Vaccinium macrocarpon and V. oxycoccos), lingonberries (V.
      vitis-idaea), and blueberries (V. myrtillus).
AB  - Analysis of the hydrophilic fraction of cranberry juice by reversed-phase HPLC
      using an Aqua LUNA column with diode array or MS detection revealed the presence
      of quinic acid, malic acid, shikimic acid, and citric acid. For the first time,
      two iridoid glucosides were found in the juice. The two iridoid glucosides were
      shown to be monotropein and 6,7-dihydromonotropein by MS and NMR spectroscopy. A
      fast reversed-phase HPLC method for quantification of the hydrophilic carboxylic
      acids was developed and used for analyses of cranberry, lingonberry, and
      blueberry juices. The level of hydrophilic carboxylic acids in cranberries was
      2.67-3.57% (w/v), in lingonberries 2.27-3.05%, and in blueberries 0.35-0.75%. In
      lingonberries both iridoid glucosides were present, whereas only monotropein was
      present in blueberries.

PMID- 12405791
TI  - Effects of type of added salt and ionic strength on physicochemical and
      functional properties of casein isolates produced by electroacidification.
AB  - A procedure developed for soybean protein precipitation which was based on
      electrodialysis was tested for the production of acid casein from reconstituted
      skim milk. In a previous paper, the performance of bipolar membrane
      electroacidification (BMEA) was evaluated under different conditions of ionic
      strength (micro(added) = 0, 0.25, 0.5, or 1.0 M) and added salt (CaCl(2), NaCl,
      or KCl) (1). The aim of this study, which is the complement of the work on
      evaluation of BMEA performance, was to evaluate the functionality of the protein
      isolates produced by BMEA and to compare the BMEA isolates to commercial isolates
      and an isolate produced by chemical acidification. It was not possible to show
      differences between the functional properties of isolates produced by BMEA,
      except at 1 M CaCl(2) micro(added), due to the variability of the isolates.
      However, the results showed that it is possible to obtain isolates similar to
      commercial isolates and that the addition of salt during the process does not
      induce variations in functional properties. From results on mineral
      concentrations, it appeared that the addition of monovalent cations did not
      influence the retention of monovalent or divalent cations in the BMEA isolates,
      while addition of divalent cations (CaCl(2)) influenced the retention of
      magnesium. According to previous results on evaluation of BMEA performances under
      different conditions of ionic strength and added salt, the difference observed
      for the BMEA isolate produced at 1.0 M CaCl(2) was confirmed.

PMID- 12405792
TI  - Comparison between the radical scavenging activity and antioxidant activity of
      six distilled and nondistilled mediterranean herbs and aromatic plants.
AB  - Thirty-six different extracts of six herbs and aromatic plants (fennel, common
      melilot, milfoil, lavandin cv. Super, spike lavender, and tarragon) were
      evaluated for their radical scavenging activity by the DPPH*, NBT/hypoxanthine
      superoxide, and *OH/luminol chemiluminescence methods, and for their antioxidant
      activity by the beta-carotene blenching test. The total phenolic content was also
      determined by the Folin-Ciocalteu method. The plant material included cultivated
      plants and their wastes after being distilled for essential oils. Both remarkably
      high phenolic content and radical scavenging activities were found for the ethyl
      acetate and dichloromethane fractions among the different plant extracts. In
      general, the distilled plant material was found to exhibit a higher phenolic
      content as well as antioxidant and radical scavenging activities than the
      nondistilled material. Ethyl acetate and dichloromethane extracts, and even some
      crude extract, of both distilled and nondistilled plants exhibited activities
      comparable to those of commercial extracts/compounds, thus making it possible to
      consider some of them as a potential source of antioxidants of natural origin.

PMID- 12405793
TI  - Frequency of the high-molecular-weight glutenin allele in Asian hexaploid wheat
      (Triticum aestivum L.) and the transmission route through which the wheat may
      have reached Japan, the most geographically remote region of wheat production in
      the world.
AB  - The frequency of the Glu-D1f allele in Japanese, Chinese, and other Asian
      hexaploid wheat varieties was analyzed in order to investigate a possible
      transmission route for hexaploid wheat to the Far East, Japan. The 1380 published
      data sets were compared to the results for 1107 hexaploid Asian wheat varieties
      which were determined in this study. The frequency of the Glu-D1f allele was
      clearly different between areas; the allele was present from northern and
      southern Japan, from Xinjiang, Jiangsu, Zhejiang, and Beijing in China, and from
      Afghanistan. A high frequency of the high-molecular-weight glutenin Glu-D1f
      allele was found predominantly in southern Japan. This distribution of an
      adaptively neutral character suggests a specific route of transmission for
      hexaploid wheat to eastern China and the Far East, Japan. It was introduced from
      Afghanistan, carried to Xinjiang (in northwest China), Jiangsu, and Zhejiang (in
      southeast China), and then to southern Japan along the so-called Silk Road. It is
      believed that cultivated hexaploid wheat originated in the Middle East and the
      Near East and was carried along the Silk Road through China to the Far East,
      Japan. Japan is the most geographically remote region of wheat production in the
      world. During the course of its long journey and its adaptation to diverse local
      environments, Japanese hexaploid wheat has developed a unique composition of
      glutenin Glu-D1 alleles. The frequency of this allele in different wheat
      varieties allowed us to hypothesize a possible route for the transmission of
      hexaploid wheat into the Far East, Japan.

PMID- 12405794
TI  - Antioxidant activities of sicilian prickly pear (Opuntia ficus indica) fruit
      extracts and reducing properties of its betalains: betanin and indicaxanthin.
AB  - Sicilian cultivars of prickly pear (Opuntia ficus indica) produce yellow, red,
      and white fruits, due to the combination of two betalain pigments, the purple-red
      betanin and the yellow-orange indicaxanthin. The betalain distribution in the
      three cultivars and the antioxidant activities of methanolic extracts from edible
      pulp were investigated. In addition, the reducing capacity of purified betanin
      and indicaxanthin was measured. According to a spectrophotometric analysis, the
      yellow cultivar exhibited the highest amount of betalains, followed by the red
      and white ones. Indicaxanthin accounted for about 99% of betalains in the white
      fruit, while the ratio of betanin to indicaxanthin varied from 1:8 (w:w) in the
      yellow fruit to 2:1 (w:w) in the red one. Polyphenol pigments were negligible
      components only in the red fruit. When measured as 6-hydroxy-2,5,7,8
      tetramethylchroman-2-carboxylic acid (Trolox) equivalents per gram of pulp, the
      methanolic fruit extracts showed a marked antioxidant activity. Vitamin C did not
      account for more than 40% of the measured activity. In addition, the extracts
      dose-dependently inhibited the organic hydroperoxide-stimulated red cell membrane
      lipid oxidation, as well as the metal-dependent and -independent low-density
      lipoprotein oxidation. The extract from the white fruit showed the highest
      protection in all models of lipid oxidation. Purified betanin and indicaxanthin
      were more effective than Trolox at scavenging the [2,2'-azinobis(3
      ethylbenzothiazoline-6-sulfonic acid)] diammonium salt cation radical. Cyclic
      voltammetric measurements show two anodic waves for betanin and indicaxanthin,
      and differential pulse voltammetry shows three anodic waves for betanin, with
      calculated peak potentials of 404, 616, and 998 mV, and two anodic waves for
      indicaxanthin, with peak potentials of 611 and 895 mV. Betanin underwent complex
      formation through chelation with Cu(2+), whereas indicaxanthin was not modified.
      These findings suggest that the above betalains contribute to the antioxidant
      activity of prickly pear fruits.

PMID- 12405795
TI  - Determination of flavonol metabolites in plasma and tissues of rats by HPLC
      radiocounting and tandem mass spectrometry following oral ingestion of [2
      (14)C]quercetin-4'-glucoside.
AB  - Epidemiological studies suggest that consumption of flavonol-rich diets decreases
      the risk of developing heart disease and certain cancers. Recent studies have
      detected flavonol conjugates in blood and urine following various dietary
      interventions. To assess to what extent flavonols also accumulate in tissues,
      where they might be expected to exert anti-carcinogenic and anti-atherogenic
      effects, [2-(14)C]quercetin-4'-glucoside was synthesized and fed to rats. After
      60 min, 93.6% of the ingested radioactivity was recovered from the intestine,
      incorporated into 18 metabolites that had undergone deglycosylation followed by
      varying degrees of glucuronidation, methylation, and/or sulfation.
      [(14)C]Quercetin, the aglycon of the radiolabeled substrate, was present in the
      intestine and in trace amounts in the liver but was not detected in the plasma
      and kidneys. The original [2-(14)C]quercetin-4'-glucoside was detected
      exclusively in the intestine, where it accounted for only 26.2% of the
      radioactivity. The remainder of the recovered radioactivity was located mainly in
      the plasma, liver, and kidneys as (14)C-labeled metabolites. However, compared to
      the quantities in the gastrointestinal tract, the levels of metabolites in plasma
      and body tissues were very low, indicating only limited absorption into the blood
      stream. The data demonstrate that quercetin-4'-glucoside, which is a major
      flavonol in onions, undergoes rapid and extensive metabolism in the intestine,
      and this appears not to be associated to any extent with transport across the gut
      wall into the blood stream.

PMID- 12405797
TI  - Food-grade microemulsions based on nonionic emulsifiers: media to enhance
      lycopene solubilization.
AB  - Water-dilutable food-grade microemulsions consisting of ethoxylated sorbitan
      esters, and in some cases blended with other emulsifiers, water, (R)-(+)
      limonene, ethanol, and propylene glycol, have been prepared. These microemulsions
      are of growing interest to the food industry as vehicles for delivering and
      enhancing solubilization of natural food supplements with nutritional and health
      benefits. Lycopene, an active natural lipophilic antioxidant from tomato, has
      solubilized in water-in-oil, bicontinuous, and oil-in-water types of
      microemulsions up to 10 times the oil [(R)-(+)-limonene] dissolution capacity.
      The effects of aqueous-phase dilution, nature of surfactant (hydrophilic
      lypophilic balance), and mixed surfactant on solubilization capacity and
      solubilization efficiency were studied. Structural aspects studied by self
      diffusion NMR were correlated to the solubilization capacity, and
      transformational structural changes were identified.

PMID- 12405796
TI  - Antioxidant and antiproliferative activities of common vegetables.
AB  - Epidemiological studies have shown that consumption of fruits and vegetables is
      associated with reduced risk of chronic diseases. Increased consumption of fruits
      and vegetables containing high levels of phytochemicals has been recommended to
      prevent chronic diseases related to oxidative stress in the human body. In this
      study, 10 common vegetables were selected on the basis of consumption per capita
      data in the United States. A more complete profile of phenolic distributions,
      including both free and bound phenolics in these vegetables, is reported here
      using new and modified methods. Broccoli possessed the highest total phenolic
      content, followed by spinach, yellow onion, red pepper, carrot, cabbage, potato,
      lettuce, celery, and cucumber. Red pepper had the highest total antioxidant
      activity, followed by broccoli, carrot, spinach, cabbage, yellow onion, celery,
      potato, lettuce, and cucumber. The phenolics antioxidant index (PAI) was proposed
      to evaluate the quality/quantity of phenolic contents in these vegetables and was
      calculated from the corrected total antioxidant activities by eliminating vitamin
      C contributions. Antiproliferative activities were also studied in vitro using
      HepG(2) human liver cancer cells. Spinach showed the highest inhibitory effect,
      followed by cabbage, red pepper, onion, and broccoli. On the basis of these
      results, the bioactivity index (BI) for dietary cancer prevention is proposed to
      provide a simple reference for consumers to choose vegetables in accordance with
      their beneficial activities. The BI could be a new alternative biomarker for
      future epidemiological studies in dietary cancer prevention and health promotion.

PMID- 12405798
TI  - Antimutagenic effect of various honeys and sugars against Trp-p-1.
AB  - Honey has been used since ancient times as a flavorful sweetener and for its
      therapeutic and medicinal effects. Consumers' demand for natural, healthy
      products has driven renewed interest in honey's health benefits. The commonly
      encountered food mutagen, Trp-p-1, has been demonstrated to be mutagenic in
      bacteria and carcinogenic in animals. Chemically, honey is quite complex. Honey
      is comprised primarily of sugars; however, it contains many other potentially
      biologically active components, such as antioxidants. Sugars have been reported
      to display both mutagenic and antimutagenic effects in different systems;
      antioxidants often display antimutagenic activity. Little information exists
      about potential antimutagenic effects of honey. Antimutagenicity of honeys from
      seven different floral sources against Trp-p-1 was tested via the Ames assay and
      compared to that of a sugar analogue and to individually tested simple sugars.
      All honeys exhibited significant inhibition of Trp-p-1 mutagenicity; most
      demonstrated a linear correlation between percentage inhibition and log
      transformed honey concentration from 10 microg/mL to 20 mg/mL. Each displayed
      significant degrees of inhibition of mutagenicity above concentrations of 1
      mg/mL, with individual variations in degree of effectiveness. Buckwheat honey
      displayed the greatest inhibition at 1 mg/mL, with slightly less effectiveness at
      higher concentrations. A sugar analogue demonstrated a pattern of inhibition
      similar to that of the honeys, with enhanced antimutagenicity at concentrations
      greater than 1 mg/mL. Glucose and fructose were also similar to honeys and were
      more antimutagenic than maltose and sucrose.

PMID- 12405799
TI  - Antioxidative activities of oolong tea.
AB  - While the antioxidative properties of green and black tea have been extensively
      studied, less attention has been given to these properties in oolong tea. The
      reducing powers, the 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging activities,
      the amount of total phenolic compounds, the inhibitory effect on FeCl(2)/H(2)O(2)
      (Fenton reaction system)-induced DNA damage, and the inhibitory effect on
      erythrocyte hemolysis of an oolong tea water extract (OTE) were evaluated in the
      present study. The OTE was found to have strong antioxidative activities in all
      of the model systems tested. When the OTE was separated into different fractions
      according to molecular weight, it was found that the fractions with higher
      amounts of phenolic compounds (lower molecular weight) have stronger
      antioxidative activities. The present results support the concept that oolong tea
      contains several low molecular weight antioxidants that may have health promotion
      activities.

PMID- 12405800
TI  - Red grape juice inhibits iron availability: application of an in vitro
      digestion/caco-2 cell model.
AB  - Adequate bioavailable Fe intake is essential for optimal growth and intellectual
      development of infants and children. Fruit juices are nutritious and popular
      drinks for infants and children and are known to contain Fe uptake inhibitors
      (e.g., polyphenolic compounds) and a dominant promoter, ascorbic acid. Ascorbic
      acid is naturally present in fruit juices and is added during processing to
      almost all juices found in supermarkets. With these facts taken into account, an
      in vitro digestion/Caco-2 cell culture model was developed to compare the effects
      of apple, pear, white grape, red grape, prune, grapefruir, and orange juices on
      iron bioavailability. In two series of experiments, juices from a local
      supermarket were combined with FeCl(3) or commercial infant cereal fortified with
      elemental iron and subject to simulated gastric and intestinal digestion. Caco-2
      cell ferritin formation in response to exposure to the digests served as the
      measure of Fe uptake. The pear, apple, grapefruit, orange, and white grape juice
      significantly increased Fe bioavailability from FeCl(3). For the infant cereal
      studies, the apple, orange, pear, and white grape juices increased the Fe
      bioavailability of the infant cereal. In contrast, the red grape juice and prune
      juice had profound inhibitory effects on iron bioavailability. These inhibitory
      effects were likely due to high levels of polyphenolic compounds that bind and
      thereby prevent absorption of soluble Fe. These inhibitory compounds appeared to
      counteract the promotional effects of ascorbic acid as they were in considerable
      molar excess relative to ascorbic acid and Fe in the digest. From a nutritional
      standpoint, the results suggest that individuals in need of optimal Fe absorption
      should avoid red grape and prune juice or at least vary the types of juices
      consumed. Alternatively, individuals seeking to limit Fe uptake (e.g.,
      hemochromatitics and astronauts) may be able to utilize red grape or prune juice
      as effective inhibitors of Fe uptake. Consumers should be aware that the
      compounds that inhibit Fe availability are also linked to anticancer benefits;
      thus, a dietary balance of the above juices may be optimal.

PMID- 12405801
TI  - Solid-phase synthesis of bleomycin A(5) and three monosaccharide analogues:
      exploring the role of the carbohydrate moiety in RNA cleavage.
AB  - The solid-phase synthesis of bleomycin A5 (BLM A5) and three monosaccharide
      analogues is presented. The monosaccharide analogues incorporated alpha-d
      mannose, alpha-l-gulose, and alpha-l-rhamnose moieties in lieu of the
      disaccharide normally present in BLM A5. Also explored were the abilities of each
      of the monosaccharide congeners to cleave a 53-nt RNA. The elaboration of these
      carbohydrate-modified bleomycin analogues helps to define the role of the
      disaccharide moiety during the RNA cleavage event. The relatively facile solid
      phase synthesis of bleomycin A5 and each of the carbohydrate analogues
      constitutes an important advance in the continuing mechanistic studies of
      bleomycin.

PMID- 12405802
TI  - Gas-phase electrophilic attack of a double bond exhibits stereoselectivity.
AB  - Protonated acetaldehyde (ion 1) reacts with allyltrimethylsilane (allyl-TMS) in
      the gas phase to yield cis-piperylene (cis-1,3-pentadiene) as the major product.
      The cis isomer predominates over trans by a factor >/=15:1, a degree of
      stereoselectivity that is unprecedented in a reaction where the double bond
      geometry has not been specified in the reactant. The neutral products were
      assessed by creating tritiated 1 via decay of a tritium nucleus in gaseous
      ethanol molecules labeled with >1 tritium atom. The radioactive C5H8 products
      must result from addition of the electrophilic ion to the allyl group followed by
      an elimination. Deprotonation of C5H9+ cannot account for the product
      stereochemistry. One possible explanation is that addition of the electrophile to
      the double bond is followed by elimination of Me3SiOH2+ on a time scale faster
      than that by which the initially formed adduct ion can change its conformation.

PMID- 12405803
TI  - Membraneless vanadium redox fuel cell using laminar flow.
AB  - This paper describes the design and characterization of a small, membraneless
      redox fuel cell. The smallest channel dimensions of the cell were 2 mm x 50 mum
      or x 200 mum; the cell was fabricated in poly(dimethylsiloxane) using soft
      lithography. This all-vanadium fuel cell took advantage of laminar flow to
      obviate the need for a membrane to separate the solutions of oxidizing and
      reducing components.

PMID- 12405804
TI  - Supported ionic liquid catalysis--a new concept for homogeneous hydroformylation
      catalysis.
AB  - The new concept of supported ionic liquid catalysis involves the surface of a
      support material that is modified with a monolayer of covalently attached ionic
      liquid fragments. Treatment of this surface with additional ionic liquid results
      in the formation of a multiple layer of free ionic liquid on the support. These
      layers serve as the reaction phase in which a homogeneous hydroformylation
      catalyst was dissolved. Supported ionic liquid catalysis combines the advantages
      of ionic liquid media with solid support materials which enables the application
      of fixed-bed technology and the usage of significantly reduced amounts of the
      ionic liquid. The concept of supported ionic liquid catalysis has successfully
      been used for hydroformylation reactions and can be further expanded into other
      areas of catalysis.

PMID- 12405805
TI  - The tethered aminohydroxylation (TA) of cyclic allylic carbamates.
AB  - The tethered aminohydroxylation of cyclic allylic carbamates is described using
      catalytic amounts of potassium osmate. The mechanism of reaction involves
      formation of an imido-osmium complex which adds intramolecularly to alkenes with
      complete control of both regio- and stereoselectivity: the formation of syn
      aminodiol motifs is now straightforward using this chemistry. Proof of the
      mechanism was obtained with an X-ray crystal structure of an azaglycolate osmate
      ester intermediate.

PMID- 12405806
TI  - OCBBCO: a neutral molecule with some boron-boron triple bond character.
AB  - Molecules that contain boron-boron multiple bonds are extremely rare due to the
      electron-deficient nature of boron. Here we report experimental and theoretical
      evidence of a neutral OCBBCO molecule with some boron-boron triple bond
      character. The molecule was produced and unambiguously characterized by matrix
      isolation infrared spectroscopy. Quantum chemical calculations indicate that the
      molecule has a linear singlet ground state with a very short boron-boron bond
      length.

PMID- 12405807
TI  - Efficient pi-facial control in the ene reaction of nitrosoarene, triazolinedione,
      and singlet oxygen with tiglic amides of the bornane-derived sultam as chiral
      auxiliary: an economical synthesis of enantiomerically pure nitrogen- and oxygen
      functionalized acrylic acid derivatives.
AB  - The ene reaction of 4-nitronitrosobenzene (ArNO), N-phenyl-1,2,4-triazoline-3,5
      dione (PTAD), and singlet oxygen (1O2) with the optically active tiglic-acid
      derivatives of Oppolzer's bornane-derived sultam affords the respective ene
      products regioselectively in excellent diastereoselectivity (de up to 99%) and in
      good yield (55-90%). The enophiles ArNO and PTAD give with the methyl-substituted
      substrate exclusively the like-configured ene adduct, while 1O2 leads to an 83:17
      diastereomeric mixture. With the sterically more demanding isopropyl-substituted
      derivative even the smallest enophile 1O2 forms exclusively the like
      diastereomer. The high diastereoselectivity is rationalized in terms of the
      proper conformational alignment of the substrate and a preferred enophilic attack
      from the C(beta)-re face of the double bond. This concept offers an efficient
      synthetic route to enantiomerically pure nitrogen- and oxygen-functionalized
      acrylic acid derivatives.

PMID- 12405808
TI  - Paranemic cohesion of topologically-closed DNA molecules.
AB  - Specific cohesion of DNA molecules is key to the success of work in
      biotechnology, DNA nanotechnology and DNA-based computation. The most common form
      of intermolecular cohesion between double helices is by sticky ends, but sticky
      ends generated by naturally occurring restriction enzymes may often be too short
      to bind large constructs together. An alternative form of binding is available
      through the paranemic crossover (PX) motif. Each of the two components of a PX
      motif can be a DNA dumbbell or other topologically closed species. Alternate half
      turns of the dumbbell are paired intramolecularly. The intervening half-turns are
      paired with those of the opposite component. We demonstrate the efficacy of PX
      cohesion by showing that it can result in the 1:1 binding of two triangle motifs,
      each containing nearly 500 nucleotides. The cohesion goes to completion,
      demonstrating an alternative to binding nucleic acid molecules through sticky
      ends.

PMID- 12405809
TI  - The pyridyl-tag strategy applied to the hydrocarbon/perfluorocarbon phase
      switching of a porphyrin and a fullerene.
AB  - A new hydrocarbon/perfluorocarbon phase-switching strategy based on coordination
      of pyridyl-tagged molecules to a highly fluorinated dicopper-carboxylate complex
      possessing two accessible axial coordination sites is described. When a
      chloroform solution of the tetrapyridyl-substituted porphyrin 3 (0.1 mM, 2 mL) is
      layered on a perfluorodecalin solution of 2 (3.25 mM, 1.5 mL), complete
      extraction of the porphyrin into the fluorous phase is observed after 30 min of
      stirring. Quantitative release of both the porphyrin and 2 is achieved simply by
      adding excess THF to the biphasic system, the THF acting as a pyridine competing
      ligand. The recovered perfluorocarbon solution containing 2 can be reused for
      another complexation with the same efficiency. The scope of this approach is
      emphasized by the phase-switching of a dipyridyl-substituted fullerene, another
      example of a molecule for which solubilization in perfluorocarbons is very
      challenging.

PMID- 12405810
TI  - Crystal of semiconducting quantum dots built on covalently bonded t5
      [in(28)cd(6)s(54)](-12): the largest supertetrahedral cluster in solid state.
AB  - Periodic array of nanoparticles is essential for practical applications in
      optical devices. Periodic dot arrays often exhibit very interesting collective
      phenomenon. We report a periodic crystal of InCdS pseudo-T5 nanocluster, the
      largest supertetrahedral cluster found thus far in solid state. Each InCdS
      cluster behaves like a nanoparticle with the same size. Unlike the array of
      colloidal dots in which the dot-dot separation is large ( approximately 5 nm),
      the neighboring T5 clusters in [In28Cd6S54].[(CH3)4N]12[(HSCH2COOH)2]3.5 crystal
      form a natural point contact by sharing covalently bonded S atoms. Both
      experimental and theoretical studies show that this crystal is a semiconductor
      with a band gap of 3.0 eV.

PMID- 12405811
TI  - Phase-vanishing reactions that use fluorous media as a phase screen. Facile,
      controlled bromination of alkenes by dibromine and dealkylation of aromatic
      ethers by boron tribromide.
AB  - In fluorous triphasic reactions, such as bromination of alkenes by dibromine and
      dealkylation of aromatic ethers by boron tribromide, the middle fluorous phase
      acts as a liquid membrane permitting passive transport of the reagents at the
      bottom to the top layer involving the substrates, thereby regulating the
      reactions.

PMID- 12405812
TI  - The first chiral organometallic triangle for asymmetric catalysis.
AB  - A family of chiral organometallic triangles based on cis-Pt(PEt3)2 metallocorners
      and enantiopure atropisomeric bis(alkynyl) bridging ligands (L1-4) has been
      synthesized and characterized by 1H, 13C{1H}, and 31P{1H} NMR, UV-vis, and
      circular dichroism (CD) spectroscopies, FAB and MALDI-TOF mass spectrometry, and
      microanalysis. Metallocycle 4 which contains three 1,1'-bi-2-naphthol
      functionalities in combination with Ti(iOPr)4 has been shown to be an excellent
      catalyst for highly enantioselective additions of diethylzinc to aromatic
      aldehydes to afford chiral secondary alcohols. This research illustrates the
      potential of generating novel functional materials on the basis of supramolecular
      chemistry.

PMID- 12405813
TI  - Enantioselective synthesis of the bromopyrrole alkaloids manzacidin A and C by
      stereospecific C-h bond oxidation.
AB  - The manzacidins represent a small family of structurally unique secondary
      metabolites found only sparingly in nature. Efforts to probe the pharmacological
      profile of these intriguing bromopyrrole alkaloids have been precluded by a
      deficiency of available material. Access to substantive quantities of both
      manzacidins A and C is now made possible through a rapid, enantioselective, and
      highly efficient synthesis that is described herein. The path to these targets
      showcases for the first time the distinct power of our catalytic C-H bond
      amination methodology for simplifying problems in alkaloid total synthesis.
      Application of this chemistry enables the facile and enantiospecific installation
      of tetrasubstituted carbinolamine stereocenters, functionality common to all of
      the manzacidins. The requisite materials for implementing our plan are assembled
      using modern tools for catalytic asymmetric synthesis that include both carbonyl
      ene and directed hydrogenation reactions. In addition, a new protocol for
      tetrahydropyrimidine synthesis is established. The synthesis of each manzacidin
      comprises a 10-step sequence that proceeds in an overall yield of approximately
      30%.

PMID- 12405814
TI  - Smaller and faster: the 20-residue Trp-cage protein folds in 4 micros.
AB  - We have used laser temperature jump spectroscopy to measure the folding speed of
      the 20-residue Trp-cage, the smallest polypeptide known to exhibit truly
      cooperative folding behavior. The observed folding time (4 mus at room
      temperature) makes this not only the smallest foldable protein, but also the
      fastest, with a folding speed that exceeds contact-order predictions and
      approaches anticipated diffusional "speed limits" for protein folding.

PMID- 12405815
TI  - Biomimetic arrays of oriented helical ZnO nanorods and columns.
AB  - Extended helical or chiral nanostructures are usually associated with
      biomolecules but are mostly absent in synthetic materials. Here we report the
      first synthesis of unusual oriented and extended helical nanostructures in
      synthetic ceramics. Large arrays of oriented helical ZnO nanorods and columns are
      formed using simple citrate ions to control the growth habits of the ZnO crystal.
      This novel mechanism could lead to new approaches to control the orientation, the
      surface area, and the defect structure of synthetic materials that are critical
      for practical applications. The morphology generated in the helical ZnO
      nanostructure shows remarkable resemblance to the growth morphology of nacreous
      calcium carbonate and thus may shed new light on morphology and orientation
      control of biominerals.

PMID- 12405816
TI  - Structure of the decamethyl titanocene cation, a metallocene with two agostic C-h
      bonds, and its interaction with fluorocarbons.
AB  - The tetraphenylborate salt of the decamethyl titanocene cation, [Cp*2Ti][BPh4]
      (1, Cp* = C5Me5), was prepared by reaction of Cp*2TiH with [Cp2Fe][BPh4] and by
      reaction of Cp*2TiMe with [PhNMe2H][BPh4]. The crystal structure of 1 shows that
      the Cp*2Ti cation has a bent metallocene structure with agostic interactions with
      the metal center of two adjacent methyl groups on one of the Cp* ligands.
      Compound 1 reacts readily with THF to give the adduct [Cp*2Ti(THF)][BPh4] (2). In
      fluorobenzene, 1 forms the eta1-fluorobenzene adduct [Cp*2Ti(eta1-FC6H5)][BPh4]
      (3), which was structurally characterized. In contrast to the thermal stability
      of 3, addition of alpha,alpha,alpha-trifluorotoluene to either 1 or 2 results in
      C-F activation to give Cp*2TiF2 and PhCF2CF2Ph as the main products. This
      reactivity toward benzylic C-F bonds is also reflected in the reactivity toward
      the fluorinated borate anions [B(C6F5)4]- and {B(3,5-(CF3)2C6H3]4}-: reaction of
      Cp*2TiMe with their [PhNMe2H]+ salts results in a stable complex for the former
      anion, whereas rapid C-F activation is observed for the latter.

PMID- 12405817
TI  - Intrinsic lifetimes of the excited state of DNA and RNA bases.
AB  - The lifetimes of the excited state of free nucleobases were measured in the gas
      phase for the first time. They are, respectively, 1.0 and 0.8 ps for the purine
      bases adenine (shown above) and guanine and 3.2, 2.4, and 6.4 ps for the
      pyrimidine bases cytosine, uracil, and thymine at 267 nm. The longer lifetimes of
      the pyrimidine bases may be associated with their higher propensity toward
      photodegradation, especially in the case of thymine. The ultrashort lifetime of
      nucleobases conventionally known in solution was found to be an intrinsic
      molecular property due to extremely facile internal conversion, and therefore the
      lifetime should be largely independent of the medium at this energy, that is,
      whether in vacuo, in solution, or in vivo. The evolutionary selection of
      nucleobases as the durable carriers of genetic information is suggested to be due
      to their inherent immunity from photochemical reactions.

PMID- 12405818
TI  - Ruthenium-catalyzed s-propargylation of thiols enables the rapid synthesis of
      propargylic sulfides.
AB  - A new and highly efficient catalytic system based on CpRuClL2 is proposed for the
      S-propargylation of thiols by propargylic carbonates under neutral conditions, in
      which specific requirements inherent to the different reactivities of aliphatic
      and aromatic thiols are achieved by tuning both the nature of the ancillary
      ligand L and the experimental conditions.

PMID- 12405819
TI  - A miniature biofuel cell operating in a physiological buffer.
AB  - A glucose-O2 biofuel cell, consisting only of two electrocatalyst coated 7-mum
      diameter, 2-cm long carbon fibers is reported. The cell operated continuously at
      0.52 V at 37 degrees C in a physiological buffer solution for a week, producing
      1.9 muW during the first and 1.0 muW during the last day, generating in the
      period 0.9 J of electrical energy while passing a charge of 1.7 C. If a similar
      dimension zinc fiber were utilized in a battery at 100% current efficiency, only
      0.016 C would have been generated.

PMID- 12405820
TI  - Asymmetric catalytic Mannich reactions catalyzed by urea derivatives:
      enantioselective synthesis of beta-aryl-beta-amino acids.
AB  - Highly enantioselective addition reactions between silyl ketene acetals and N-Boc
      aldimines are catalyzed by the thiourea-based catalyst 1c. Extraordinary scope is
      observed in this methodology with regard to the imine substrate, with aryl and
      heteroaromatic derivatives generally affording nearly quantitative yields of beta
      amino ester product in up to 98% enantioselectivity.

PMID- 12405821
TI  - Oriented molecular sieve membranes by heteroepitaxial growth.
AB  - Heteroepitaxial growth of titanosilicates (ETS-10 and ETS-4) is reported. Using
      this heteroepitaxial growth, oriented ETS-10/-4 membranes have been fabricated,
      demonstrating a novel way to achieve preferred orientation of molecular sieve
      films.

PMID- 12405822
TI  - A solid-supported, enantioselective synthesis suitable for the rapid preparation
      of large numbers of diverse structural analogues of (-)-saframycin A.
AB  - A 10-step solid-supported, enantioselective synthesis suitable for the rapid
      preparation of large numbers of diverse structural analogues of saframycin A is
      described. The synthetic route, which bears analogy to solid-phase peptide
      synthesis, involves the directed condensation of N-protected alpha-amino aldehyde
      reactants. A novel dual linker was developed for attachment of intermediates to
      the solid support via a C-protective group, a substituted morpholino nitrile
      derivative. The route employs a novel diastereospecific cyclorelease mechanism,
      supports structural variation at multiple sites in the saframycin core, and
      obviates the need for chromatographic purification of the products or any
      intermediate. To demonstrate the feasibility of structural variation at multiple
      sites, a matrix of 16 saframycin A analogues was prepared by parallel synthesis
      with simultaneous variation of two sites. This work is notable not only as a
      preliminary step toward large-scale library construction but also as an example
      of the use of sequential stereoselective C-C bond-forming reactions on the solid
      phase for the preparation of natural product analogues.

PMID- 12405823
TI  - Can one derive the conformational preference of a beta-peptide from its CD
      spectrum?
AB  - CD spectroscopy is often used to elucidate the secondary structure of peptides
      built from non-natural amino acids such as beta-amino acids. The interpretation
      of such CD spectra is not always unambiguous. Here, we present a case where two
      beta-hexapeptides, a dimethyl-beta-hexapeptide indicated as DM-BHP (A) and its
      nonmethylated analogue indicated as BHP (B), exhibit similar CD spectra, whereas
      they are expected to differ in secondary structure. The structural properties of
      both peptides were studied by molecular dynamics simulation, and from the
      resulting trajectories, the corresponding CD spectra were calculated. Starting
      from a fully extended conformation, BHP is observed to form a 3(14)-helix, while
      DM-BHP remains unfolded. However, even though these two peptides hardly share any
      conformations, their calculated CD spectra are alike and show the same features
      as the experimentally measured ones. Our results imply that a particular CD
      pattern can be induced by spatially different structures, which makes it
      difficult to derive the conformational preference of a peptide from its CD
      spectrum alone. To gain more insight into the relationship between the preferred
      conformation of a peptide and its CD spectrum, more accurate methods to calculate
      the CD spectrum for a given conformation are required.

PMID- 12405824
TI  - Protein engineering of nitrile hydratase activity of papain: molecular dynamics
      study of a mutant and wild-type enzyme.
AB  - The mechanism of hydrolysis of the nitrile (N-acetyl-phenylalanyl-2-amino
      propionitrile, I) catalyzed by Gln19Glu mutant of papain has been studied by
      nanosecond molecular dynamics (MD) simulations. MD simulations of the complex of
      mutant enzyme with I and of mutant enzyme covalently attached to both neutral
      (II) and protonated (III) thioimidate intermediates were performed. An MD
      simulation with the wild-type enzyme.I complex was undertaken as a reference. The
      ion pair between protonated His159 and thiolate of Cys25 is coplanar, and the
      hydrogen bonding interaction S(-)(25).HD1-ND1(159) is observed throughout MD
      simulation of the mutant enzyme.I complex. Such a sustained hydrogen bond is
      absent in nitrile-bound wild-type papain due to the flexibility of the imidazole
      ring of His159. The nature of the residue at position 19 plays a critical role in
      the hydrolysis of the covalent thioimidate intermediate. When position 19
      represents Glu, the imidazolium ion of His159-ND1(+).Cys25-S(-) ion pair is
      distant, on average, from the nitrile nitrogen of substrate I. Near attack
      conformers (NACs) have been identified in which His159-ImH(+) is positioned to
      initiate a general acid-catalyzed addition of Cys-S(-) to nitrile. Though Glu19
      CO(2)H is distant from nitrile nitrogen in the mutant.I structure, MD simulations
      of the mutant.II covalent adduct finds Glu19-CO(2)H hydrogen bonded to the
      thioimide nitrogen of II. This hydrogen bonded species is much less stable than
      the hydrogen bonded Glu19-CO(2)(-) with mutant-bound protonated thioimidate
      (III). This observation supports Glu19-CO(2)H general acid catalysis of the
      formation of mutant.III. This is the commitment step in the Gln19Glu mutant
      catalysis of nitrile hydrolysis.

PMID- 12405825
TI  - Solution and crystallographic studies of branched multivalent ligands that
      inhibit the receptor-binding of cholera toxin.
AB  - The structure-based design of multivalent ligands offers an attractive strategy
      toward high affinity protein inhibitors. The spatial arrangement of the receptor
      binding sites of cholera toxin, the causative agent of the severe diarrheal
      disease cholera and a member of the AB(5) bacterial toxin family, provides the
      opportunity of designing branched multivalent ligands with 5-fold symmetry. Our
      modular synthesis enabled the construction of a family of complex ligands with
      five flexible arms each ending with a bivalent ligand. The largest of these
      ligands has a molecular weight of 10.6 kDa. These ligands are capable of
      simultaneously binding to two toxin B pentamer molecules with high affinity, thus
      blocking the receptor-binding process of cholera toxin. A more than million-fold
      improvement over the monovalent ligand in inhibitory power was achieved with the
      best branched decavalent ligand. This is better than the improvement observed
      earlier for the corresponding nonbranched pentavalent ligand. Dynamic light
      scattering studies demonstrate the formation of concentration-dependent unique
      1:1 and 1:2 ligand/toxin complexes in solution with no sign of nonspecific
      aggregation. This is in complete agreement with a crystal structure of the
      branched multivalent ligand/toxin B pentamer complex solved at 1.45 A resolution
      that shows the specific 1:2 ligand/toxin complex formation in the solid state.
      These results reiterate the power of the structure-based design of multivalent
      protein ligands as a general strategy for achieving high affinity and potent
      inhibition.

PMID- 12405826
TI  - NADH model systems functionalized with Zn(II)-cyclen as flavin binding site
      structure dependence of the redox reaction within reversible aggregates.
AB  - The relative positions and conformations of the prosthetic group FAD and the
      cofactor NADH have been remarkably conserved within the structurally diverse
      group of flavin enzymes. To provide a chemical rational for such an obviously
      optimal relative disposition of the redox partners for efficient reaction we have
      synthesized NADH models with Zn(II)-cyclen substituents for reversible flavin
      binding in water. Altogether, four of these model systems with systematically
      varying spacer length between the recognition site and the redox active
      dihydronicotinamide were prepared. The binding of these model systems to
      riboflavin tetraacetate was confirmed by potentiometric pH titration in water and
      their reaction with flavin was followed by UV-vis spectroscopy in aqueous media
      under physiological conditions. The measurements reveal a significant rate
      enhancement of up to 175 times that of an intermolecular reaction. Moreover, a
      strong dependence of the reaction rate on the spacer length was observed, which
      clearly shows that within the dynamic reversible assembly only the optimal
      relative disposition of the redox partners ensures an efficient redox reaction.

PMID- 12405827
TI  - Studies on the mechanism of action of azinomycin B: definition of
      regioselectivity and sequence selectivity of DNA cross-link formation and
      clarification of the role of the naphthoate.
AB  - Evaluation of the sequence selectivity, noncovalent association, and orientation
      of the DNA cross-linking agent azinomycin B on its duplex DNA receptor is
      described. A strong correlation between sequence nucleophilicity and cross
      linking yield was observed, and steric effects due to the thymine C5-methyl group
      were identified. Detailed studies on the role of the azinomycin naphthoate using
      viscometry, fluorescence contact energy transfer, and DNA unwinding assays point
      to a nonintercalative binding mode for this group. A kinetic assay for agent
      regioselectivity was used to determine the orientation of binding and covalent
      cross-link formation.

PMID- 12405828
TI  - Probing the exposure of tyrosine and tryptophan residues in partially folded
      proteins and folding intermediates by CIDNP pulse-labeling.
AB  - A nuclear magnetic resonance (NMR) technique has been devised to probe the
      structures of disordered, partially folded states of proteins at the level of
      individual amino acid residues. Chemically induced dynamic nuclear polarization
      (CIDNP) is first generated in exposed aromatic side-chains of the denatured state
      and then transferred to the high-resolution NMR spectrum of the native state by
      stimulating rapid refolding of the protein. Crucial improvements in sensitivity
      were achieved by carrying out the polarization-producing photochemistry in a
      deoxygenated sample of the disordered state of the protein in a magnetic field of
      4.0 T and recording the (1)H NMR spectrum of the refolded native state at 9.4 T
      (400 MHz). Application of this method to the low pH molten-globule state of alpha
      lactalbumin reveals remarkably nativelike environments for the aromatic residues
      in the primary hydrophobic core of the protein. This result provides compelling
      evidence that the detailed fold of a protein can be established prior to the
      formation of the cooperative close-packed native structure.

PMID- 12405830
TI  - High-avidity, low-affinity multivalent interactions and the block to polyspermy
      in Xenopus laevis.
AB  - The interaction of the lectin XL35 with the jelly coat protein (JCP) surrounding
      oocytes in Xenopus laevis is essential for the block to polyspermy. The molecular
      details of this event are poorly understood, and the present study has been
      undertaken with a view to delineating the mechanism of formation of the
      fertilization envelope. A range of JCP-derived oligosaccharides were synthesized,
      and all were installed with an artificial aminopropyl arm. This arm allowed the
      preparation of monovalent derivatives by acetylation of the amino group or the
      synthesis of polyvalent compounds by attachment to an activated polyacrylamide
      polymer. A number of analytical techniques, including enzyme-linked lectin assays
      and surface plasmon resonance, have been developed and utilized to study the
      interactions of the mono- and polyvalent compounds with XL35. The results reveal
      that the lectin XL35 has remarkably broad specificity for galactose-containing
      saccharides and the affinities are only slightly modulated by secondary features,
      such as anomeric configuration of the terminal sugar or the identity and linkage
      pattern of branching sugars. Broad specificity was also observed when the
      saccharides were presented in a polyvalent fashion. The glycopolymers displayed
      10-20-fold increases in valency-corrected affinities compared to the
      corresponding monovalent counterparts. Although the synthetic polymers are not as
      potent as the JCP, the kinetics of their interactions mirror closely those of the
      native ligand, and in each case extremely long-lived interactions were observed.
      The results of this study indicate that, in X. laevis, the true biological
      function of multivalency is not to create an extremely tightly binding complex
      between XL35 and its natural ligand but, instead, to create a very stable
      protective layer that will not dissociate and is yet flexible enough to
      encapsulate the developing embryo. It is postulated that, even if these partners
      are unable to attain true equilibrium on the time scale of the biological event,
      their mode of interaction would, nevertheless, be expected to guarantee an
      insurmountable physical block to polyspermy. This study has also highlighted that
      multivalent interactions require a very long time to achieve equilibrium, and
      this feature may well be the origin of several of the ambiguities reported in the
      literature when multivalent ligands have been evaluated.

PMID- 12405829
TI  - Structurally distinct active sites in the copper(II)-substituted aminopeptidases
      from Aeromonas proteolytica and Escherichia coli.
AB  - The aminopeptidase from Aeromonas proteolytica (AAP) was titrated with copper,
      which bound sequentially at two distinct sites. Both the mono- and disubstituted
      forms of AAP exhibited catalytic hyperactivity relative to the native dizinc
      enzyme. Monosubstituted AAP exhibited an axial Cu(II) EPR spectrum with slight pH
      dependence: at pH 6.0 g(parallel) = 2.249, g( perpendicular ) = 2.055, and
      A(parallel)((63/65)Cu) = 1.77 x 10(-)(2) cm(-)(1), whereas at pH 9.65 g(parallel)
      = 2.245, g( perpendicular ) = 2.056, and A(parallel)((63/65)Cu) = 1.77 x 10(-)(2)
      cm(-)(1). These data indicate oxygen and nitrogen ligation of Cu. AAP further
      substituted with copper exhibited a complex signal with features around g
      approximately 2 and 4. The features at g approximately 4 were relatively weak in
      the B(0) perpendicular B(1) (perpendicular) mode EPR spectrum but were intense in
      the B(0) parallel B(1) (parallel) mode spectrum. The g approximately 2 region of
      the perpendicular mode spectrum exhibited two components, one corresponding to
      mononuclear Cu(II) with g(parallel) = 2.218, g( perpendicular ) = 2.023, and
      A(parallel)((63/65)Cu) = 1.55 x 10(-)(2) cm(-)(1) and likely due to adventitious
      binding of Cu(II) to a site distant from the active site. Excellent simulations
      were obtained for the second component of the spectrum assuming that two Cu(II)
      ions experience dipolar coupling corresponding to an inter-copper distance of 5 A
      with the two Cu(II) g(z)() directions parallel to each other and at an angle of
      approximately 17 degrees to the inter-copper vector (H = betaB.g(CuA).S(CuA) +
      betaB.g(CuB).S(CuB) + [S.A.I](CuA) + [S.A.I](CuB) + [S(CuA).J.S(CuB)];
      g(parallel(CuA,CuB)) = 2.218, g( perpendicular )((CuA,CuB)) = 2.060;
      A(parallel(CuA,CuB))((63/65)Cu) = 1.59 x 10(-)(2) cm(-)(1), J(isotropic) = 50 cm(
      )(1), r(Cu)(-)(Cu) = 4.93 A, and chi = 17 degrees ). The exchange coupling
      between the two copper ions was found to be ferromagnetic as the signals
      exhibited Curie law temperature dependence. The Cu-Cu distance of approximately 5
      A indicated by EPR was significantly higher than the inter-zinc distance of 3.5 A
      in the native enzyme, and the dicopper species therefore represents a novel
      dinuclear site capable of catalysis of hydrolysis. In contrast to AAP, the
      related methionyl aminopeptidase from Escherichia coli (EcMetAP) was found to
      bind only one Cu(II) ion despite possessing a dinuclear binding site motif. A
      further difference was the marked pH dependence of the signal in EcMetAP,
      suggestive of a change in ligation. The structural motifs of these two Cu(II)
      substituted aminopeptidases provide important insight into the observed catalytic
      activity.

PMID- 12405831
TI  - Methylglyoxal synthetase, enol-pyruvaldehyde, glutathione and the glyoxalase
      system.
AB  - enol-Pyruvaldehyde (ePY or 2-hydroxypropenal, O=C(H)-C(OH)=CH(2)) a transient
      intermediate in the alkaline decomposition of the triosephosphates to
      methylglyoxal is now observed by UV and (1)H NMR spectroscopy as the immediate
      product of the methylglyoxal synthetase (MGS) reaction: dihydroxyacetone-P -->
      P(i) + ePY --> methylglyoxal (MG). Analysis of ePY formed from 1-(13)C- and (1R,
      3S) -[1,3-(2)H]-DHAP establishes the stereochemical course of its formation by
      MGS. Its rate of ketonization is much too slow to be in the sequence required for
      the assay of MGS by coupling of the MG produced to glyoxalase I (Glx I): MG +
      glutathione (GSH) --> (S)-lactylglutathione (D-LG). Instead, ketonization occurs
      by way of the hemithioacetal (HTA) formed between ePY and GSH, and could be
      either an enzymatic function of Glx I or occur nonenzymatically at an activated
      rate. Enzymatic ketonization was ruled out because the methyl group of D-LG
      formed from specifically labeled ePY is achiral. Chemical ketonization of ePY is
      activated by general bases, such as acetate, and by thiols such as GSH and 2
      mercaptoethanol, which disrupt its stabilizing double bond conjugation as
      hemithioacetal (HTA) adducts. 2-Mercaptoacetate combines both functions, acting
      as the HTA adduct of ePY with the appended carboxylate group presumably
      positioned to promote abstraction of the enol proton and protonation of the
      enolate carbon at an accelerated rate. In the MGS-Glx I system (dihydroxyacetone
      P --> ePY, ePY + GSH --> GS-ePY, GS-ePY --> GS-MG, GS-MG --> D-LG), the
      nonenzymatic 2nd and 3rd steps describe the catalytic role of GSH in the critical
      ketonization process and set the stage for its participation in the glyoxalase
      system.

PMID- 12405832
TI  - 2-Aminopurine: a probe of structural dynamics and charge transfer in DNA and
      DNA:RNA hybrids.
AB  - Spectroscopic techniques are employed to probe relationships between structural
      dynamics and charge transfer (CT) efficiency in DNA duplexes and DNA:RNA hybrids
      containing photoexcited 2-aminopurine (Ap). To better understand the variety of
      interactions and reactions, including CT, between Ap and DNA, the fluorescence
      behavior of Ap is investigated in a full series of redox-inactive as well as
      redox-active assemblies. Thus, Ap is developed as a dual reporter of structural
      dynamics and base-base CT reactions in nucleic acid duplexes. CD, NMR, and
      thermal denaturation profiles are consistent with the family of DNA duplexes
      adopting a distinct conformation versus the DNA:RNA hybrids. Fluorescence
      measurements establish that the d(A)-r(U) tract of the DNA:RNA hybrid exhibits
      enhanced structural flexibility relative to that of the d(A)-d(T) tract of the
      DNA duplexes. The yield of CT from either G or 7-deazaguanine (Z) to Ap in the
      assemblies was determined by comparing Ap emission in redox-active G- or Z
      containing duplexes to otherwise identical duplexes in which the G or Z is
      replaced by inosine (I), the redox-inactive nucleoside analogue. Investigations
      of CT not only demonstrate efficient intrastrand base-base CT in the DNA:RNA
      hybrids but also reveal a distance dependence of CT yield that is more shallow
      through the d(A)-r(U) bridge of the A-form DNA:RNA hybrids than through the d(A)
      d(T) bridge of the B-form DNA duplexes. The shallow distance dependence of
      intrastrand CT in DNA:RNA hybrids correlates with the increased conformational
      flexibility of bases within the hybrid duplexes. Measurements of interstrand base
      base CT provide another means to distinguish between the A- and B-form helices.
      Significantly, in the A-form DNA:RNA hybrids, a similar distance dependence is
      obtained for inter- and intrastrand reactions, while, in B-DNA, a more shallow
      distance dependence is evident with interstrand CT reactions. These observations
      are consistent with evaluations of intra- and interstrand base overlap in A-
      versus B-form duplexes. Overall, these data underscore the sensitivity of CT
      chemistry to nucleic acid structure and structural dynamics.

PMID- 12405833
TI  - Design of artificial transcriptional activators with rigid poly-L-proline
      linkers.
AB  - Typical eukaryotic transcriptional activators are composed of distinct functional
      domains, including a DNA binding domain and an activating domain. Artificial
      transcription factors have been designed wherein the DNA binding domain is a
      minor groove DNA binding hairpin polyamide linked by a flexible tether to short
      activating peptides, typically 16-20 residues in size. In this study, the linker
      between the polyamide and the peptide was altered in an incremental fashion using
      rigid oligoproline "molecular rulers" in the 18-45 A length range. We find that
      there is an optimal linker length which separates the DNA and the activation
      region for transcription activation.

PMID- 12405834
TI  - Vibrational spectrum of m-benzyne: a matrix isolation and computational study.
AB  - m-Benzyne (2) was generated in low-temperature matrices and IR spectroscopically
      characterized from four different precursors. To assign the IR absorptions, the
      perdeuterated derivative 2-d(4) was also investigated. By comparison with CCSD(T)
      calculations all vibrations between 200 and 2500 cm(-)(1) with a predicted
      relative intensity >2% could be assigned. All experimental and theoretical
      results are in accordance with a biradicaloid structure for 2, while there is no
      evidence for a bicyclic closed-shell structure. While benzyne 2 is stable under
      the conditions of matrix isolation at low temperature, flash vacuum pyrolysis at
      high temperatures or UV irradiation results in the rearrangement to cis-enediyne.
      A mechanism involving ring opening accompanied by hydrogen migration is proposed.

PMID- 12405835
TI  - Tandem 1,4-addition reactions with benzene and alkylated benzenes promoted by
      pentaammineosmium(II).
AB  - Electrophiles such as dimethoxymethane and 3-penten-2-one react with the complex
      [Os(NH(3))(5)(eta(2)-benzene)](2+) in the presence of triflic acid to form
      metastable benzenium intermediates. These benzenium intermediates further react
      with carbon nucleophiles including silyl ketene acetals, (silyloxy)alkenes, and
      phenyllithium in an overall tandem 1,4-addition sequence. The metal fragment
      controls the relative stereo- and regiochemistry for both electrophilic and
      nucleophilic addition steps. Upon oxidative demetalation with silver triflate,
      cis-1,4 cyclohexadienes are formed in yields ranging from 16 to 82%. This
      methodology can also be used to dearomatize toluene and ortho- and meta-xylene
      with unexpectedly high regio- and stereocontrol.

PMID- 12405836
TI  - Manifestation of stereoelectronic effects on the calculated carbon-hydrogen bond
      lengths and one bond (1)J(C-H) NMR coupling constants in cyclohexane, six
      membered heterocycles, and cyclohexanone derivatives.
AB  - Cyclohexane (1), oxygen-, sulfur-, and/or nitrogen-containing six-membered
      heterocycles 2-5, cyclohexanone (6), and cyclohexanone derivatives 7-16 were
      studied theoretically [B3LYP/6-31G(d,p) and PP/IGLO-III//B3LYP/6-31G(d,p)
      methods] to determine the structural (in particular C-H bond distances) and
      spectroscopic (specifically, one bond (1)J(C-H) NMR coupling constants)
      consequences of stereoelectronic hyperconjugative effects. The results confirm
      the importance of n(X) --> sigma*(C-H)(app) (where X = O, N), sigma(C-H)(ax) -->
      pi*(C=O), sigma(S-C) --> sigma*(C-H)(app), sigma(C-S)-->sigma*(C-H)(app), beta
      n(O) --> sigma*(C-H), and sigma(C-H) --> sigma*(C-H)(app) hyperconjugation, as
      advanced in previous theoretical models. Calculated r(C-H) bond lengths and
      (1)J(C-H) coupling constants for C-H bonds participating in more than one
      hyperconjugative interaction show additivity of the effects.

PMID- 12405837
TI  - Development of a catalytic enantioselective conjugate addition of 1,3-dicarbonyl
      compounds to nitroalkenes for the synthesis of endothelin-A antagonist ABT-546.
      Scope, mechanism, and further application to the synthesis of the antidepressant
      rolipram.
AB  - The enantioselective synthesis of endothelin-A antagonist ABT-546 has been
      accomplished via the discovery and development of a highly selective catalytic
      asymmetric conjugate addition of ketoesters to nitroolefins. Employing just 4 mol
      % bis(oxazoline)-Mg(OTf)(2) complex with an amine cocatalyst, we obtained the
      product nitroketone with 88% selectivity at the aryl-bearing stereocenter and in
      good yield on scales ranging to 13 mol. The effects of ligand structure, metal
      salt, and solvent on the reaction are described. Particularly important to the
      reaction is the water content. While water is necessary during the generation of
      the catalyst, the water must be then removed to maximize stereoselectivity and
      reactivity. The reaction has been extended to other dicarbonyl substrates, and a
      variety of substitution patterns are tolerated on the nitroolefin partner. The
      reaction has also been employed in the synthesis of the antidepressant rolipram.
      Investigations relating to the mechanism of the reaction are also described.

PMID- 12405838
TI  - Dehydration reaction of hydroxyl substituted alkenes and alkynes on the Ru(2)S(2)
      complex.
AB  - A variety of inter- and intramolecular dehydration was found in the reactions of
      [[Ru(P(OCH(3))(3))(2)(CH(3)CN)(3)](2)(mu-S(2))](CF(3)SO(3))(4) (1) with hydroxyl
      substituted alkenes and alkynes. Treatment of 1 with allyl alcohol gave a
      C(3)S(2) five-membered ring complex, [[Ru(P(OCH(3))(3))(2)(CH(3)CN)(3)](2)[mu
      SCH(2)CH(2)CH(OCH(2)CH=CH(2))S]](CF(3)SO(3))(4) (2), via C-S bond formation after
      C-H bond activation and intermolecular dehydration. On the other hand,
      intramolecular dehydration was observed in the reaction of 1 with 3-buten-1-ol
      giving a C(4)S(2) six-membered ring complex,
      [[Ru(P(OCH(3))(3))(2)(CH(3)CN)(3)](2) [mu-SCH(2)CH=CHCH(2)S]](CF(3)SO(3))(4) (3).
      Complex 1 reacts with 2-propyn-1-ol or 2-butyn-1-ol to give homocoupling
      products, [[Ru(P(OCH(3))(3))(2)(CH(3)CN)(3)](2)[mu-SCR=CHCH(OCH(2)C triple bond
      CR)S]](CF(3)SO(3))(4) (4: R = H, 5: R = CH(3)), via intermolecular dehydration.
      In the reaction with 2-propyn-1-ol, the intermediate complex having a hydroxyl
      group, [[Ru(P(OCH(3))(3))(2)(CH(3)CN)(3)](2)[mu-SCH=CHCH(OH)S]](CF(3)SO(3))(4)
      (6), was isolated, which further reacted with 2-propyn-1-ol and 2-butyn-1-ol to
      give 4 and a cross-coupling product, [[Ru(P(OCH(3))(3))(2)(CH(3)CN)(3)](2)[mu
      SCH=CHCH(OCH(2)C triple bond CCH(3))S]](CF(3)SO(3))(4) (7), respectively. The
      reaction of 1 with diols, (HO)CHRC triple bond CCHR(OH), gave furyl complexes,
      [[Ru(P(OCH(3))(3))(2)(CH(3)CN)(3)](2)[mu-SSC=CROCR=CH]](CF(3)SO(3))(3) (8: R = H,
      9: R = CH(3)) via intramolecular elimination of a H(2)O molecule and a H(+). Even
      though (HO)(H(3)C)(2)CC triple bond CC(CH(3))(2)(OH) does not have any
      propargylic C-H bond, it also reacts with 1 to give
      [[Ru(P(OCH(3))(3))(2)(CH(3)CN)(3)](2)[mu
      SCH(2)C(=CH(2))C(=C=C(CH(3))(2))]S](CF(3)SO(3))(4) (10). In addition, the
      reaction of 1 with (CH(3)O)(H(3)C)(2)CC triple bond CC(CH(3))(2)(OCH(3)) gives
      [[Ru(P(OCH(3))(3))(2)(CH(3)CN)(2)][mu
      S=C(C(CH(3))(2)OCH(3))C=CC(CH(3))CH(2)S][Ru(P(OCH(3))(3))(2)(CH(3)CN)(3)]](CF(3)S
      (3))(4) (11), in which one molecule of CH(3)OH is eliminated, and the S-S bond is
      cleaved.

PMID- 12405839
TI  - Structure and stereochemistry of a new cytotoxic polychlorinated sulfolipid from
      Adriatic shellfish.
AB  - A detailed analysis of the causative toxins contained in the hepatopancreas of
      toxic mussels from the northern Adriatic sea has been carried out. Along with
      some DSP (diarrhetic shellfish poisoning) type toxins, such as okadaic acid,
      yessotoxin, and their derivatives, which are involved in a number of human
      intoxications throughout the world, we have now isolated a new cytotoxin, a
      polychlorinated sulfolipid 1, whose gross structure has been elucidated by
      spectral analysis, including various 2D NMR techniques. The relative
      stereochemistry of 1 was elucidated by successful application of the J-based
      configuration analysis developed for acyclic compounds using carbon-proton spin
      coupling constants ((2,3)J(C,H)) and proton-proton spin-coupling constants
      ((3)J(H,H)); its absolute stereochemistry was established by the Mosher method.
      Compound 1 possesses in vitro cytotoxicity against WEHI 164 and RAW 264.7 cells.

PMID- 12405840
TI  - Synthesis of the eight enantiomerically pure diastereomers of the 12-F(2)
      isoprostanes.
AB  - Syntheses of the eight enantiomerically pure diastereomers of the 12-F(2)
      isoprostanes (4-11) are described. The key steps included rhodium-mediated
      intramolecular cyclopropanation and enzymatic resolution of the racemic diol 12.

PMID- 12405841
TI  - First total synthesis of a natural product containing a chiral, beta-diketone:
      synthesis and stereochemical reassignment of siphonarienedione and
      siphonarienolone.
AB  - The first total syntheses of siphonarienolone and siphonarienedione are
      described. The development of a stereoselective synthesis of beta-diketones
      facilitated the synthesis of the latter compound. The synthesis of the structures
      proposed for the natural products afforded compounds whose spectral data did not
      match those of the natural products. However, the synthesis of compounds isomeric
      to the proposed structures at C(4) and C(5) afforded compounds identical to the
      natural products, thereby reassigning the stereochemistry of the natural
      products.

PMID- 12405842
TI  - Pyrolysis in the mesophase: a chemist's approach toward preparing carbon nano-
      and microparticles.
AB  - A mild pyrolytic method is proposed for the generation of different carbon micro-
      and nanoparticles that are either unprecedented or have never been reported under
      the present experimental conditions. A hexa-alkyl-substituted hexa-peri
      hexabenzocoronene serves as a graphite-like starting compound that melts into a
      discotic liquid crystalline phase prior to heat-induced cross-linking and
      dehydrogenation. An essential feature of the process is that the liquid
      crystalline order persists even above 400 degrees C, i.e., during alkyl chain
      cleavage. The present approach bears a resemblance to carbomesophase formation
      during graphitization starting from pitch. The pyrolysis products are
      characterized by matrix-assisted laser desorption/ionization time-of-flight
      (MALDI-TOF) mass spectrometry, optical microscopy, selected area electron
      diffraction (SAED), scanning electron microscopy (SEM), and high-resolution
      transmission electron microscopy (HRTEM).

PMID- 12405843
TI  - Mechanism of preferential enrichment, an unusual enantiomeric resolution
      phenomenon caused by polymorphic transition during crystallization of mixed
      crystals composed of two enantiomers.
AB  - The mechanism of Preferential Enrichment, an unusual enantiomeric resolution
      phenomenon observed upon recrystallization of a series of racemic crystals which
      are classified as a racemic mixed crystal with fairly ordered arrangement of the
      two enantiomers, has been studied. On the basis of the existence of polymorphs
      and the occurrence of the resulting polymorphic transition during crystallization
      from solution, the mechanism has been accounted for in terms of (1) a
      preferential homochiral molecular association to form one-dimensional chain
      structures in the supersaturated solution of the racemate or nonracemic sample
      with a low ee value, (2) a kinetic formation of a metastable crystalline phase
      retaining the homochiral chain structures in a process of nucleation, (3) a
      polymorphic transition from the metastable phase to a stable one followed by
      enantioselective liberation of the excess R (or S) enantiomers from the
      transformed crystal into solution at the beginning of crystal growth to result in
      a slight enrichment (up to 10% ee) of the opposite S (or R) enantiomer in the
      deposited crystals, together with an enantiomeric enrichment of the R (or S)
      enantiomer in the mother liquor, and (4) a chiral discrimination by the once
      formed S (or R)-rich stable crystalline phase in a process of the subsequent
      crystal growth, leading to a considerable enantiomeric enrichment of the R (or S)
      enantiomer up to 100% ee in the mother liquor. The processes (3) and (4) are
      considered to be directly responsible for an enrichment of one enantiomer in the
      mother liquor. The association mode of the two enantiomers in solution has been
      investigated by means of (i) the solubility measurement and (ii) the number
      averaged molecular weight measurement in solution by vapor pressure osmometry,
      together with (iii) the molecular dynamics simulation of oligomer models. The
      polymorphic transition during crystallization has been observed visually and by
      means of the in situ FTIR technique and DSC measurement. Both metastable and
      stable crystals have been obtained, and their crystal structures have been
      elucidated by X-ray crystallographic analysis of their single crystals.

PMID- 12405844
TI  - Characteristic reactions and properties of C-apical O-equatorial (O-cis)
      spirophosphoranes: effect of the sigma(P)(-)(O) orbital in the equatorial plane
      and isolation of a hexacoordinate oxaphosphetane as an intermediate of the Wittig
      type reaction of 10-P-5 phosphoranes.
AB  - Novel spirophosphoranes (O-cis) that exhibit reversed apicophilicity having an
      apical carbon-equatorial oxygen array in a five-membered ring showed enhanced
      reactivity toward nucleophiles such as n-Bu(4)N(+)F(-) or MeLi in comparison with
      the corresponding stable isomeric spirophosphoranes (O-trans) having an apical
      oxygen-equatorial carbon configuration. The enhanced reactivity of the O-cis
      isomer could be explained by the presence of a lower-lying sigma(P)(
      )(O(equatorial)) orbital as the reacting orbital in the equatorial plane, whereas
      the corresponding orbital is a higher-lying sigma(P)(-)(C(equatorial)) in the O
      trans isomer. Density functional theory (DFT) calculation on the actual compounds
      provided theoretical support for this assumption. In addition, we found that the
      benzylic anion alpha to the phosphorus atom in O-cis benzyl phosphorane is much
      more stable than that generated from the corresponding O-trans compounds. The
      experimental results were considered to be due to the n(C) --> sigma(P)(-)(O)
      interaction in the O-cis anion, and this was confirmed by DFT calculations.
      Furthermore, the hexacoordinate anionic species derived from the reaction of the
      benzylic anion from O-cis benzylphosphorane with an aldehyde was also found to be
      stabilized as compared with analogous species from the corresponding O-trans
      isomer. The first X-ray structural characterization of a hexacoordinate phosphate
      intermediate in the Wittig type reaction using pentacoordinate phosphoranes is
      reported.

PMID- 12405845
TI  - Solid-phase synthesis of dysidiolide-derived protein phosphatase inhibitors.
AB  - Biologically active natural products can be regarded as evolutionary selected and
      biologically validated starting points in structural space for the development of
      compound libraries. For libraries designed and synthesized around a given natural
      product, a higher hit rate and the identification of biologically relevant hits
      can be expected, justifying a probably higher investment in the development of
      the corresponding syntheses. This approach requires the development of complex
      multistep reaction sequences on the solid phase. Employing the protein
      phosphatase Cdc25 inhibitor dysidiolide as an example, we demonstrate that this
      goal can be achieved successfully. The reaction sequences developed led to
      dysidiolide analogues in overall 8-12 linear steps with the longest sequence on
      the solid support amounting to up to 11 sequential transformations. The desired
      products were obtained in overall yields ranging from 6% to 27% and in
      multimilligram amounts starting from 100 mg of resin. The transformations applied
      include a variety of very different reaction types widely used in organic
      synthesis (i.e., an asymmetric cycloaddition employing a removable chiral
      auxiliary, different organometallic transformations, olefination reactions,
      different oxidation reactions, acidic hydrolyses, and a nucleophilic
      substitution). Biological investigation of the eight dysidiolide analogues
      synthesized showed that they inhibit Cdc25C in the low micromolar range with the
      IC(50) value varying by a factor of 20 and that they display considerable and
      differing biological activities in cytotoxicity assays employing different cancer
      cell lines.

PMID- 12405846
TI  - The first total synthesis of dragmacidin d.
AB  - The first total synthesis of the biologically significant bis-indole alkaloid
      dragmacidin D (5) has been achieved. Thermal and electronic modulation provides
      the key for a series of palladium-catalyzed Suzuki cross-coupling reactions that
      furnished the core structure of the complex guanidine- and aminoimidazole
      containing dragmacidins. Following this crucial sequence, a succession of
      meticulously controlled final events was developed leading to the completion of
      the natural product.

PMID- 12405847
TI  - Remarkably stable iron porphyrins bearing nonheteroatom-stabilized carbene or
      (alkoxycarbonyl)carbenes: isolation, X-ray crystal structures, and carbon atom
      transfer reactions with hydrocarbons.
AB  - Reactions of [Fe(TPFPP)] (TPFPP = meso-tetrakis(pentafluorophenyl)porphyrinato
      dianion) with diazo compounds N(2)C(Ph)R (R = Ph, CO(2)Et, CO(2)CH(2)CH=CH(2))
      afforded [Fe(TPFPP)(C(Ph)R)] (R = Ph (1), CO(2)Et (2), CO(2)CH(2)CH=CH(2) (3)) in
      65-70% yields. Treatment of 1 with N-methylimidazole (MeIm) gave the adduct
      [Fe(TPFPP)(CPh(2))(MeIm)] (4) in 65% yield. These new iron porphyrin carbene
      complexes were characterized by NMR and UV-vis spectroscopy, mass spectrometry,
      and elemental analyses. X-ray crystal structure determinations of
      1.0.5C(6)H(6).0.5CH(2)Cl(2) and 4 reveal Fe=CPh(2) bond lengths of 1.767(3) (1)
      and 1.827(5) A (4), together with large ruffling distortions of the TPFPP
      macrocycle. Complexes 2 and 4 are reactive toward styrene, affording the
      corresponding cyclopropanes in 82 and 53% yields, respectively. Complex 1 is an
      active catalyst for both intermolecular cyclopropanation of styrenes with ethyl
      diazoacetate and intramolecular cyclopropanation of allylic diazoacetates.
      Reactions of 2 and 4 with cyclohexene or cumene produced allylic or benzylic C-H
      insertion products in up to 83% yield.

PMID- 12405848
TI  - Synthesis, characterization, and catalytic performance of single-site iron(III)
      centers on the surface of SBA-15 silica.
AB  - A new molecular precursor strategy has been used to prepare a series of single
      site catalysts that possess isolated iron centers supported on mesoporous SBA-15
      silica. The iron centers were introduced via grafting reactions of the tris(tert
      butoxy)siloxy iron(III) complex Fe[OSi(O(t)Bu)(3)](3)(THF) with SBA-15 in dry
      hexane. This complex reacts cleanly with the hydroxyl groups of SBA-15 to
      eliminate HOSi(O(t)Bu)(3) (as monitored by (1)H NMR spectroscopy) with formation
      of isolated surface species of the type identical with SiO-Fe
      [OSi(O(t)Bu)(3)](2)(THF). In this way, up to 21% of the hydroxyl sites on SBA-15
      were derivatized (0.23 Fe nm(-)(2)), and iron loadings in the range of 0.0-1.90%
      were achieved. The structure of the surface-bound iron species, as determined by
      spectroscopic methods (electron paramagnetic resonance (EPR), nuclear magnetic
      resonance (NMR), UV-vis, and in situ infrared measurements) and by elemental
      analyses, contains a pseudotetrahedral iron(III) center. The THF ligand of this
      surface-bound complex was quantitatively displaced by acetonitrile (by (1)H NMR
      spectroscopy). Calcination of these materials at 300 degrees C for 2 h under
      oxygen resulted in removal of all organic matter and site-isolated iron surface
      species that are stable to condensation to iron oxide clusters. Spectroscopic
      data (UV-vis and EPR) suggest that the iron centers retain a mononuclear,
      pseudotetrahedral iron(III) structure after calcination. The calcinated, iron
      grafted SBA-15 materials exhibit high selectivities as catalysts for oxidations
      of alkanes, alkenes, and arenes, with hydrogen peroxide as the oxidant.

PMID- 12405849
TI  - Anisotropic NMR interaction tensors in the decamethylaluminocenium cation.
AB  - Solid-state NMR experiments, analytical and numerical simulations of solid NMR
      powder patterns, ab initio self-consistent field and hybrid density functional
      theory calculations, and single-crystal X-ray diffraction are used to
      characterize the molecular structure and anisotropic NMR interaction tensors in
      the bis(pentamethylcyclopentadienyl)aluminum cation, [Cp(2)Al](+). This highly
      symmetric main group metallocene has a structure analogous to that of ferrocene
      and the cobaltocenium cation. The single-crystal X-ray diffraction structure is
      reported for [Cp(2)Al][AlCl(4)]. Solid-state (27)Al[(1)H] magic-angle spinning
      and static NMR experiments are used to study the aluminum chemical shielding and
      electric field gradient tensors, revealing axial symmetry in both cases with a
      large chemical shielding span of Omega = 83(3) ppm and a small nuclear quadrupole
      coupling constant, C(Q)((27)Al) = 0.86(10) MHz. Carbon-13 CPMAS NMR experiments
      in combination with ab initio calculations and simulations of the effects of
      chemical exchange on (13)C static powder patterns reveal dynamic rotation of
      rings and suggest a low internal rotational barrier for this process. Theoretical
      computations of interaction tensors using the Gaussian 98 and Amsterdam Density
      Functional software packages are in good agreement with experiment and lend
      insight into the molecular origin of these NMR interactions. Orientations of the
      NMR tensors determined from theory, the large chemical shielding span, and the
      very small value of C(Q)((27)Al) can all be rationalized in terms of the high
      molecular symmetry.

PMID- 12405850
TI  - Structural isomers of aryl-substituted eta(3)-propargyl complexes: eta(2)-1
      Metalla(methylene)cyclopropene and eta(3)-benzyl complexes.
AB  - Hydride abstraction from C(5)Me(5)(CO)(2)Re(eta(2)-PhC triple bond CCH(2)Ph) (1)
      gave a 3:1 mixture of eta(3)-propargyl complex [C(5)Me(5)(CO)(2)Re(eta(3)-PhCH-C
      triple bond CPh)][BF(4)] (5) and eta(2)-1-metalla(methylene)cyclopropene complex
      [C(5)Me(5)(CO)(2)Re(eta(2)-PhC-C=CHPh)][BF(4)] (6). Observation of the eta(2)
      isomer requires 1,3-diaryl substitution and is favored by electron-donating
      substituents on the C(3)-aryl ring. Interconversion of eta(3)-propargyl and
      eta(2)-1-metalla(methylene)cyclopropene complexes is very rapid and results in
      coalescence of Cp (1)H NMR resonances at about -50 degrees C. Protonation of the
      alkynyl carbene complex C(5)Me(5)(CO)(2)Re=C(Ph)C triple bond CPh (22) gave a
      third isomer, the eta(3)-benzyl complex [C(5)Me(5)(CO)(2)Re[eta(3)(alpha,1,2)
      endo,syn-C(6)H(5)CH(C triple bond CC(6)H(5))]][BF(4)] (23) along with small
      amounts of the isomeric complexes 5 and 6. While 5 and 6 are in rapid
      equilibrium, there is no equilibration of the eta(3)-benzyl isomer 23 with 5 and
      6.

PMID- 12405851
TI  - New description of the disorder in zeolite ZSM-48.
AB  - A new description of the disorder in ZSM-48 is given. It is shown that ZSM-48 is
      not a code for one material but for a family of materials consisting of tubular
      pores. The pores are formed of rolled up honeycomb-like sheets of fused T6-rings
      (T= tetrahedral), and the pore aperture contains 10 T-atoms. Neighboring pores
      are related by a zero shift along the pore direction or by a shift of half the
      repeat distance along the pore direction ( approximately 0.5 x 8.40 A).
      Additional T-T dimers fill spaces between the tubes. Using different degrees of
      disorder, the X-ray diffraction patterns of a variety of samples of ZSM-48 can be
      simulated. The present description of the disorder yields calculated diffraction
      patterns that are in better agreement with experimental patterns than previous
      descriptions. Unlike previous reports on ZSM-48, it is found that some materials
      can be highly ordered, others present mostly planar faults, and others still are
      better described by a two-dimensional (disordered) stacking of tubular pores. The
      local pore topology is the same in all (disordered) models, and the disorder does
      not block the pores. Differences in catalytic properties are probably due to
      differences in crystal morphology and size and to differences in the distribution
      of aluminum in the framework.

PMID- 12405852
TI  - Donor/acceptor interactions in systematically modified Ru(II)-Os(II)
      oligonucleotides.
AB  - Donor/acceptor (D/A) interactions are studied in a series of doubly modified 19
      mer DNA duplexes. An ethynyl-linked Ru(II) donor nucleoside is maintained at the
      5' terminus of each duplex, while an ethynyl-linked Os(II) nucleoside, placed on
      the complementary strands, is systematically moved toward the other terminus in
      three base pair increments. The steady-state Ru(II)-based luminescence quenching
      decreases from 90% at the shortest separation of 16 A (3 base pairs) to
      approximately 11% at the largest separation of 61 A (18 base pairs). Time
      resolved experiments show a similar trend for the Ru(II) excited-state lifetime,
      and the decrease in the averaged excited-state lifetime for each duplex is
      linearly correlated with the fraction quenched obtained by steady-state
      measurements. Analysis according to the Forster dipole-dipole energy transfer
      mechanism shows a reasonable agreement. Deviation from idealized behavior is
      primarily attributed to uncertainty in the orientation factor, kappa(2).
      Analyzing D/A interactions in an analogous series of doubly modified
      oligonucleotides, where the ethynyl-linked Ru(II) center is replaced with a
      saturated two-carbon linked complex, yields an excellent correlation with the
      Forster mechanism. As this simple change partially relaxes the rigid geometry of
      the donor chromophore, these results suggest that the deviation from idealized
      Forster behavior observed for the duplexes containing the rigidly held Ru(II)
      center originates, at least partially, from ambiguities in the orientation
      factor. Surprisingly, analyzing both quenching data sets according to the Dexter
      mechanism also shows an excellent correlation. Although this can be interpreted
      as strong evidence for a Dexter triplet energy transfer mechanism, it does not
      imply that this electron exchange mechanism is operative in these D/A duplexes.
      Rather, it suggests that systems that transfer energy via the Forster mechanism
      can under certain circumstances exhibit Dexter-like "behavior", thus illustrating
      the danger of imposing a single physical model to describe D/A interactions in
      such complex systems. While we conclude that the Forster dipole-dipole energy
      transfer mechanism is the dominant pathway for D/A interactions in these modified
      oligonucleotides, a minor contribution from the Dexter electron exchange
      mechanism at short distances is likely. This complex behavior distinguishes DNA
      bridged Ru(II)/Os(II) dyads from their corresponding low molecular-weight and
      covalently attached counterparts.

PMID- 12405853
TI  - X-ray absorption and resonance Raman studies of methyl-coenzyme M reductase
      indicating that ligand exchange and macrocycle reduction accompany reductive
      activation.
AB  - Methyl-coenzyme M reductase (MCR) catalyzes methane formation from methyl
      coenzyme M (methyl-SCoM) and N-7-mercaptoheptanoylthreonine phosphate (CoBSH).
      MCR contains a nickel hydrocorphin cofactor at its active site, called cofactor
      F(430). Here we present evidence that the macrocyclic ligand participates in the
      redox chemistry involved in catalysis. The active form of MCR, the red1 state, is
      generated by reducing another spectroscopically distinct form called ox1 with
      titanium(III) citrate. Previous electron paramagnetic resonance (EPR) and (14)N
      electron nuclear double resonance (ENDOR) studies indicate that both the ox1 and
      red1 states are best described as formally Ni(I) species on the basis of the
      character of the orbital containing the spin in the two EPR-active species.
      Herein, X-ray absorption spectroscopic (XAS) and resonance Raman (RR) studies are
      reported for the inactive (EPR-silent) forms and the red1 and ox1 states of MCR.
      RR spectra are also reported for isolated cofactor F(430) in the reduced,
      resting, and oxidized states; selected RR data are reported for the (15)N and
      (64)Ni isotopomers of the cofactor, both in the intact enzyme and in solution.
      Small Ni K-edge energy shifts indicate that minimal electron density changes
      occur at the Ni center during redox cycling of the enzyme. Titrations with
      Ti(III) indicate a 3-electron reduction of free cofactor F(430) to generate a
      stable Ni(I) state and a 2-electron reduction of Ni(I)-ox1 to Ni(I)-red1.
      Analyses of the XANES and EXAFS data reveal that both the ox1 and red1 forms are
      best described as hexacoordinate and that the main difference between ox1 and
      red1 is the absence of an axial thiolate ligand in the red1 state. The RR data
      indicate that cofactor F(430) undergoes a significant conformational change when
      it binds to MCR. Furthermore, the vibrational characteristics of the ox1 state
      and red1 states are significantly different, especially in hydrocorphin ring
      modes with appreciable C=N stretching character. It is proposed that these
      differences arise from a 2-electron reduction of the hydrocorphin ring upon
      conversion to the red1 form. Presumably, the ring-reduction and ligand-exchange
      reactions reported herein underlie the enhanced activity of MCR(red1), the only
      form of MCR that can react productively with the methyl group of methyl-SCoM.

PMID- 12405854
TI  - Comparison of various types of hydrogen bonds involving aromatic amino acids.
AB  - Ab initio calculations are used to compare the abilities of the aromatic groups
      of the Phe, Tyr, Trp, and His amino acids (modeled respectively by benzene,
      phenol, indole, and imidazole) to form H-bonds of three different types.
      Strongest of all are the conventional H-bonds (e.g., OH..O and OH..N). His forms
      the strongest such H-bond, followed by Tyr, and then by Trp. Whereas OH..phi
      bonds formed by the approach of a proton donor to the pi electron cloud above the
      aromatic system are somewhat weaker, they nonetheless represent an important
      class of stabilizing interactions. The strengths of H-bonds in this category
      follow the trend Trp > His > Tyr approximately Phe. CH.O interactions are weaker
      still, and only those involving His and Trp are strong enough to make significant
      contributions to protein structure. A protonated residue such as HisH(+) makes
      for a very powerful proton donor, such that even its CH..O H-bonds are stronger
      than the conventional H-bonds formed by neutral groups.

PMID- 12405855
TI  - Electrochemical sensing in microfluidic systems using electrogenerated
      chemiluminescence as a photonic reporter of redox reactions.
AB  - This paper describes a microfluidics-based sensing system that relies on
      electrochemical detection and electrogenerated chemiluminescent (ECL) reporting.
      The important result is that the ECL reporting reaction is chemically decoupled
      from the electrochemical sensing reaction. That is, the electrochemical sensing
      reaction does not participate directly in the ECL process, but because
      electrochemical cells require charge balance, the sensing and ECL reactions are
      electrically coupled. This provides a convenient and sensitive means for direct
      photonic readout of electrochemical reactions that do not directly participate in
      an ECL reaction and thus broadens the spectrum of redox compounds that can be
      detected by ECL. The approach can be implemented in either a two-electrode or
      bipolar (single-electrode) configuration. By manipulating the placement and
      dimensions of the conductors, the photonic response can be enhanced. The system
      is used to electrochemically detect benzyl viologen present in solution and
      report its presence via Ru(bpy)(3)(2+) (bpy = 2,2'-bipyridine) luminescence.

PMID- 12405856
TI  - An electrostatic model for the frequency shifts in the carbonmonoxy stretching
      band of myoglobin: correlation of hydrogen bonding and the stark tuning rate.
AB  - The effect of internal and applied external electric fields on the vibrational
      stretching frequency for bound CO (nu(CO)) in myoglobin mutants was studied using
      density functional theory. Geometry optimization and frequency calculations were
      carried out for an imidazole-iron-porphine-carbonmonoxy adduct with various small
      molecule hydrogen-bonding groups. Over 70 vibrational frequency calculations of
      different model geometries and hydrogen-bonding groups were compared to derive
      overall trends in the C-O stretching frequency (nu(CO)) in terms of the C-O bond
      length and Mulliken charge. Simple linear functions were derived to predict the
      Stark tuning rate using an approach analogous to the vibronic theory of
      activation.(1) Potential energy calculations show that the strongest interaction
      occurs for C-H or N-H hydrogen bonding nearly perpendicular to the Fe-C-O bond
      axis. The calculated frequencies are compared to the structural data available
      from 18 myoglobin crystal structures, supporting the hypothesis that the vast
      majority of hydrogen-bonding interactions with CO occur from the side, rather
      than the end, of the bound CO ligand. The nu(CO) frequency shifts agree well with
      experimental frequency shifts for multiple bands, known as A states, and site
      directed mutations in the distal pocket of myoglobin. The model calculations
      quantitatively explain electrostatic effects in terms of specific hydrogen
      bonding interactions with bound CO in heme proteins.

PMID- 12405857
TI  - Lactone enols are stable in the gas phase but highly unstable in solution.
AB  - 2-Hydroxyoxol-2-ene (C(5)-1), the enol tautomer of gamma-butyrolactone, was
      generated in the gas phase as the first representative of the hitherto elusive
      class of lactone enols and shown by neutralization-reionization mass spectrometry
      to be remarkably stable as an isolated species. Ab initio calculations by
      QCISD(T)/6-311+G(3df,2p) provided the enthalpies of formation, proton affinities,
      and gas-phase basicities for gaseous lactone enols with four- (C(4)-1), five-
      (C(5)-1), and six-membered rings (C(6)-1). The acid-base properties of C(4)-C(6)
      lactones and enols and reference carboxylic acid enols CH(2)=C(OH)(2) (3) and
      CH(2)=C(OH)OCH(3) (4) were also calculated in aqueous solution. The C(4)-C(6)
      lactone enols show gas-phase proton affinities in the range of 933-944 kJ mol(
      )(1) and acidities in the range of 1401-1458 kJ mol(-)(1). In aqueous solution,
      the lactone enols are 15-20 orders of magnitude more acidic than the
      corresponding lactones, with enol pK(a) values increasing from 5.6 (C(4)-1) to
      14.5 (C(6)-1). Lactone enols are moderately weak bases in water with pK(BH) in
      the range of 3.9-8.1, whereas the lactones are extremely weak bases of pK(BH) in
      the range of -10.5 to -17.4. The acid-base properties of lactone enols point to
      their high reactivity in protic solvents and explain why no lactone enols have
      been detected thus far in solution studies.

PMID- 12405858
TI  - [Ni(0)L]-catalyzed cyclodimerization of 1,3-butadiene: a density functional
      investigation of the influence of electronic and steric factors on the regulation
      of the selectivity.
AB  - We present a comprehensive theoretical investigation of the influence of the
      ligand L on the regulation of the product selectivity for the [Ni(0)L]-catalyzed
      cyclodimerization of 1,3-butadiene. The investigation was based on density
      functional theory (DFT) and a combined DFT and molecular mechanics (QM/MM)
      approach for the real [bis(butadiene)Ni(0)L] catalysts with L = PMe(3), I;
      PPh(3), II; P((i)Pr)(3), III; and P(OPh)(3), IV. The role of electronic and
      steric effects has been elucidated for all crucial elementary steps of the entire
      catalytic cycle. Allylic isomerization, allylic enantioface conversion, as well
      as oxidative coupling are shown to be influenced to a minor extent by electronic
      and steric effects. In contrast, the ligand's properties have a distinct
      influence on the preestablished equilibrium between the eta(3),eta(1)(C(1)) and
      bis-eta(3) forms 2 and 4, respectively, of the [(octadienediyl)Ni(II)L] complex
      and on the rate-determining reductive elimination following competing routes for
      generation of either VCH, cis-1,2-DVCB, or cis,cis-COD. Electronic factors are
      shown to predominantly determine the position of the kinetically mobile 2 right
      harpoon over left harpoon 4 equilibrium. 4 is the prevailing species for ligands
      L that are pi-acceptors (L = P(OPh)(3)) or weak sigma-donors (L = PPh(3)), while
      stronger sigma-donors (L = PMe(3), P((i)Pr)(3)) displace the equilibrium to the
      left. Steric bulk on the ligand as well as its pi-acceptor ability act to
      facilitate the reductive elimination, while sigma-donor abilities serve to retard
      this process. Electronic and steric factors are found to not influence uniformly
      the reductive elimination routes with either 2 or 4 involved. The regulation of
      the product selectivity is elucidated on the basis of both thermodynamic and
      kinetic considerations.

PMID- 12405859
TI  - Molecular responses of proteins at different interfacial environments detected by
      sum frequency generation vibrational spectroscopy.
AB  - Sum frequency generation (SFG) vibrational spectroscopy has been applied to
      investigate molecular responses of bovine serum albumin (BSA) molecules adsorbed
      at different interfacial environments. Molecular level and in situ SFG studies
      demonstrate that albumin molecules have different adsorption behaviors when
      contact with fused silica, polystyrene, and poly(methyl methacrylate). Adsorbed
      albumin molecules exhibit different structural changes when exposed to different
      chemical environments, including air, water, and hydrophobic solvents. This paper
      provides direct molecular insight into protein responses to different interfacial
      environments.

PMID- 12405860
TI  - Mechanism of the addition of nonenolizable aldehydes and ketones to
      (Di)metallenes (R(2)X=YR(2), X = Si, Ge Y = C, Si, Ge): a density functional and
      multiconfigurational perturbation theory study.
AB  - The mechanism of the addition of nonenolizable aldehydes and ketones to group 14
      (di)metallenes has been examined through a theoretical study of the addition of
      formaldehyde to Si=C, Ge=C, Si=Si, Si=Ge, and Ge=Ge bonds at the B3LYP/6
      311++G(d,p) and CAS-MCQDPT2/6-31++G(d,p) levels of theory. The reaction pathways
      located can be grouped as either involving the formation of singlet diradical or
      zwitterionic intermediates or as concerted processes. Within each group of
      reaction pathways, several different mechanisms have been located, with not all
      mechanisms being available to all of the (di)metallenes. It was found that for
      reactions in which a Si-O bond results (i.e., addition to Si=C, Si=Si, and Si=Ge)
      both diradical and zwitterionic intermediates are possible; however, the
      formation of diradical intermediates was not found for reactions that result in
      the formation of a Ge-O bond (addition to Ge=C and Ge=Ge). The underlying cause
      of this pathway selectivity is examined, as well as the effect of solvent on the
      relative energies of the pathways. The results of the study shed light on the
      cause of experimentally obtained results regarding the mechanism of the reaction
      of (di)metallenes with nonenolizable ketones and aldehydes.

PMID- 12405861
TI  - Quantized double-layer charging of highly monodisperse metal nanoparticles.
AB  - We describe unprecedented resolution of electrochemically observed quantized
      double layer (QDL) charging, attained with use of reduced solution temperatures
      and with an annealing procedure that produces hexanethiolate monolayer protected
      gold clusters (C6 MPCs) with a high level of monodispersity in charging
      capacitance, C(CLU). The spacing DeltaV = e/C(CLU) on the electrochemical
      potential axis between one electron changes in the electronic charge of
      nanoscopic metal particles is determined by their effective capacitance C(CLU).
      The high monodispersity of the C6 MPCs with Au(140) cores facilitates (a)
      detailed rotated disk and cyclic voltammetric measurements, (b) simulation of QDL
      waveshapes based on assumed reversible, multivalent redox-like behavior, (c)
      determination of nanoparticle diffusion rates, and (d) observation of as many as
      13 changes in the MPC charge state, from MPC(6-) to MPC(7+). The single electron
      QDL charging peaks are quite evenly spaced (DeltaV constant) at potentials near
      the MPC potential of zero charge, but are irregularly spaced at more positive and
      negative potentials. The irregular spacing is difficult to rationalize with
      classical double layer capacitance ideas and is proposed to arise from a
      correspondingly structured (e.g., not smooth) density of electronic states of the
      nanoparticle core, resulting from its small HOMO/LUMO gap and incipiently
      molecule-like behavior.

PMID- 12405862
TI  - Fluorescence of cis-1-amino-2-(3-indolyl)cyclohexane-1-carboxylic acid: a single
      tryptophan chi(1) rotamer model.
AB  - A constrained derivative, cis-1-amino-2-(3-indolyl)cyclohexane-1-carboxylic acid,
      cis-W3, was designed to test the rotamer model of tryptophan photophysics. The
      conformational constraint enforces a single chi(1) conformation, analogous to the
      chi(1) = 60 degrees rotamer of tryptophan. The side-chain torsion angles in the X
      ray structure of cis-W3 were chi(1) = 58.5 degrees and chi(2) = -88.7 degrees.
      Molecular mechanics calculations suggested two chi(2) rotamers for cis-W3 in
      solution, -100 degrees and 80 degrees, analogous to the chi(2) = +/-90 degrees
      rotamers of tryptophan. The fluorescence decay of the cis-W3 zwitterion was
      biexponential with lifetimes of 3.1 and 0.3 ns at 25 degrees C. The relative
      amplitudes of the lifetime components match the chi(2) rotamer populations
      predicted by molecular mechanics. The longer lifetime represents the major chi(2)
      = -100 degrees rotamer. The shorter lifetime represents the minor chi(2) = 80
      degrees rotamer having the ammonium group closer to C4 of the indole ring
      (labeled C5 in the cis-W3 X-ray structure). Intramolecular excited-state proton
      transfer occurs at indole C4 in the tryptophan zwitterion (Saito, I.; Sugiyama,
      H.; Yamamoto, A.; Muramatsu, S.; Matsuura,T. J. Am. Chem. Soc. 1984, 106, 4286
      4287). Photochemical isotope exchange experiments showed that H-D exchange occurs
      exclusively at C5 in the cis-W3 zwitterion, consistent with the presence of the
      chi(2) = 80 degrees rotamer in solution. The rates of two nonradiative processes,
      excited-state proton and electron transfer, were measured for individual chi(2)
      rotamers. The excited-state proton-transfer rate was determined from H-D exchange
      and fluorescence lifetime data. The excited-state electron-transfer rate was
      determined from the temperature dependence of the fluorescence lifetime. The
      major quenching process in the -100 degrees rotamer is electron transfer from the
      excited indole to carboxylate. Electron transfer also occurs in the 80 degrees
      rotamer, but the major quenching process is intramolecular proton transfer. Both
      quenching processes are suppressed by deprotonation of the amino group. The
      results for cis-W3 provide compelling evidence that the complex fluorescence
      decay of the tryptophan zwitterion originates in ground-state heterogeneity with
      the different lifetimes primarily reflecting different intramolecular excited
      state proton- and electron-transfer rates in various rotamers.

PMID- 12405863
TI  - Antiretroviral pharmacokinetics in the paediatric population: a review.
AB  - Characteristics unique to paediatric pharmacotherapy should be considered when
      treating children infected with human immunodeficiency virus (HIV). Processes of
      growth and development in the paediatric patient can significantly affect drug
      absorption and disposition. Immature renal function, altered hepatic enzyme
      activity and differences in drug absorption lead to variations in systemic
      exposure of antiretrovirals among children. Paediatric patients are also subject
      to unique circumstances that may prevent adherence to antiretroviral regimens.
      The pharmacokinetics of nucleoside reverse transcriptase inhibitors differ
      significantly among preterm infants, full-term infants and older children.
      Decreased hepatic glucuronidation activity in neonates results in pharmacokinetic
      differences in zidovudine disposition when compared with older children.
      Didanosine, stavudine and lamivudine are renally eliminated, thus resulting in
      differences among young children with immature renal function. Pharmacokinetic
      data for non-nucleoside reverse transcriptase inhibitors in children are limited.
      Decreased elimination of nevirapine among neonates has been observed, primarily
      due to decreased enzymatic activity. Pharmacokinetic differences across age
      groups have been noted for efavirenz, but no formal assessments have been
      conducted in children weighing less than 10kg. Protease inhibitors are
      metabolised by the cytochrome P450 enzyme system, which is not fully developed in
      younger children. Decreased metabolism can result in elevated plasma
      concentrations, thereby increasing the chance of toxicity. Unfortunately, few
      studies exist evaluating the pharmacokinetics of antiretrovirals in children. As
      a result, dosage selection of antiretrovirals in children often occurs without
      adequate data. As the life expectancy of HIV-infected children increases, use of
      antiretrovirals to prevent disease progression also increases. If prevention of
      treatment failure continues to be the goal of antiretroviral therapy, the
      pharmacokinetics of antiretrovirals in children need to be assessed early in the
      drug development process.

PMID- 12405864
TI  - Pharmacokinetic and pharmacodynamic considerations when treating patients with
      sepsis and septic shock.
AB  - Sepsis and septic shock are accompanied by profound changes in the organism that
      may alter both the pharmacokinetics and the pharmacodynamics of drugs. This
      review elaborates on the mechanisms by which sepsis-induced pathophysiological
      changes may influence pharmacological processes. Drug absorption following
      intramuscular, subcutaneous, transdermal and oral administration may be reduced
      due to a decreased perfusion of muscles, skin and splanchnic organs. Compromised
      tissue perfusion may also affect drug distribution, resulting in a decrease of
      distribution volume. On the other hand, the increase in capillary permeability
      and interstitial oedema during sepsis and septic shock may enhance drug
      distribution. Changes in plasma protein binding, body water, tissue mass and pH
      may also affect drug distribution. For basic drugs that are bound to the acute
      phase reactant alpha(1)-acid glycoprotein, the increase in plasma concentration
      of this protein will result in a decreased distribution volume. The opposite may
      be observed for drugs that are extensively bound to albumin, as the latter
      protein decreases during septic conditions. For many drugs, the liver is the main
      organ for metabolism. The determinants of hepatic clearance of drugs are liver
      blood flow, drug binding in plasma and the activity of the metabolic enzymes;
      each of these may be influenced by sepsis and septic shock. For high extraction
      drugs, clearance is mainly flow-dependent, and sepsis-induced liver hypoperfusion
      may result in a decreased clearance. For low extraction drugs, clearance is
      determined by the degree of plasma binding and the activity of the metabolic
      enzymes. Oxidative metabolism via the cytochrome P450 enzyme system is an
      important clearance mechanism for many drugs, and has been shown to be markedly
      affected in septic conditions, resulting in decreased drug clearance. The kidneys
      are an important excretion pathway for many drugs. Renal failure, which often
      accompanies sepsis and septic shock, will result in accumulation of both parent
      drug and its metabolites. Changes in drug effect during septic conditions may
      theoretically result from changes in pharmacodynamics due to changes in the
      affinity of the receptor for the drug or alterations in the intrinsic activity at
      the receptor. The lack of valid pharmacological studies in patients with sepsis
      and septic shock makes drug administration in these patients a difficult
      challenge. The patient's underlying pathophysiological condition may guide
      individual dosage selection, which may be guided by measuring plasma
      concentration or drug effect.

PMID- 12405867
TI  - Pharmacokinetics of ciprofloxacin as a tool to optimise dosage schedules in
      community patients.
AB  - OBJECTIVE: To evaluate the dosage regimens of ciprofloxacin prescribed for
      outpatients by applying the principles of antibacterial therapy. DESIGN:
      Retrospective analysis of prescription and demographic data. SETTING: Community
      pharmacy in Valladolid, Spain. PATIENTS: Fifty male and female patients aged 18
      93 years and with bodyweight 41-95kg. METHODS: Prescribed dosage regimen, age,
      weight, height, type of infection, comorbidity and coadministered drugs were
      recorded for each patient. Plasma concentration curves were simulated from
      literature values of the pharmacokinetic parameters of the drug and the age and
      weight of the patients. Urine concentrations were estimated from simulated plasma
      concentrations, literature values of renal clearance and an average urinary flow
      rate of 2 L/day. The potential efficacy of the prescribed treatment was evaluated
      from the ratio of the simulated peak plasma concentration (C(max)) to the
      literature value of the minimum inhibitory concentration (MIC) for the bacterium
      most probably responsible for the infection (C(max) /MIC). The ratio of area
      under the plasma concentration-time curve over 24 hours to MIC (AUC24 /MIC) was
      also estimated for non-urinary infections. RESULTS: Demographic variables such as
      age or bodyweight do not seem to be taken in consideration when ciprofloxacin is
      prescribed, at least in the patients considered here, leading to wide
      interindividual variability in plasma concentrations. This may not be relevant
      for urinary infections, since ciprofloxacin concentrates in the urine, leading to
      high Cmax /MIC ratios in all patients. Simulated plasma concentration-time curves
      revealed consistent underdosing for systemic infections in young patients over
      60kg, for whom the plasma concentrations achieved led to Cmax /MIC and AUC24 /MIC
      ratios lower than those associated with clinical efficacy and minimal spread of
      bacterial resistance. CONCLUSIONS: The standard regimen of ciprofloxacin 250mg
      every 12 hours prescribed for urinary infections may not be the best choice,
      since a more convenient regimen of 500mg once daily leads to a higher Cmax /MIC
      ratio, which is associated with a more significant postantibiotic effect and
      higher efficacy of fluoroquinolones. For non-urinary infections, the age and
      weight of patients should be taken into account to achieve optimum plasma
      concentrations.

PMID- 12405866
TI  - Interactions between antiretroviral drugs and drugs used for the therapy of the
      metabolic complications encountered during HIV infection.
AB  - Treatment of HIV infection with potent combination antiretroviral therapy has
      resulted in major improvement in overall survival, immune function and the
      incidence of opportunistic infections. However, HIV infection and treatment has
      been associated with the development of metabolic complications, including
      hyperlipidaemia, diabetes mellitus, hypertension, lipodystrophy and osteopenia.
      Safe pharmacological treatment of these complications requires an understanding
      of the drug-drug interactions between antiretroviral drugs and the drugs used in
      the treatment of metabolic complications. Since formal studies of most of these
      interactions have not been performed, predictions must be based on our
      understanding of the metabolism of these agents. All HIV protease inhibitors are
      metabolised by and inhibit cytochrome P450 (CYP) 3A4. Ritonavir is the most
      potent inhibitor of CYP3A4. Ritonavir and nelfinavir also induce a host of CYP
      isoforms as well as some conjugating enzymes. The non-nucleoside reverse
      transcriptase inhibitor delavirdine potently inhibits CYP3A4, whereas nevirapine
      and efavirenz are inducers of CYP3A4. Drug interaction studies have been
      performed with HIV protease inhibitors and HMG-CoA reductase inhibitors.
      Coadministration of ritonavir plus saquinavir to HIV-seronegative volunteers
      resulted in increased exposure to simvastatin acid by 3059%. Atorvastatin
      exposure increased by 347%, but exposure to active atorvastatin increased by only
      79%. Conversely, pravastatin exposure decreased by 50%. Similar results have been
      obtained with combinations of simvastatin and atorvastatin with other HIV
      protease inhibitors. Thus, the lactone prodrugs simvastatin and lovastatin should
      not be used with HIV protease inhibitors. Atorvastatin may be used with caution.
      Although there are no formal studies available, calcium channel antagonists and
      repaglinide may have significant interactions and toxicity when used with HIV
      protease inhibitors because of their metabolism by CYP3A4. Sulfonylurea drugs
      utilise mainly CYP2C9 for metabolism, and this isoenzyme may be induced by
      ritonavir and nelfinavir with a resulting decrease in efficacy of the
      sulfonylurea. Losartan may have increased effect when coadministered with
      ritonavir and nelfinavir because of the induction of CYP2C9 and the expected
      increase in formation of the active metabolite, E-3174. Overall, well-designed
      drug-drug interaction studies at steady state are needed to determine whether
      antiretroviral drugs may be safely coadministered with many of the drugs used in
      the treatment of the metabolic complications of HIV infection.

PMID- 12405868
TI  - Ultrasound device calibration.

PMID- 12405869
TI  - Craniosacral therapy is not medicine.

PMID- 12405865
TI  - Interindividual variability of the clinical pharmacokinetics of methadone:
      implications for the treatment of opioid dependence.
AB  - Methadone is widely used for the treatment of opioid dependence. Although in most
      countries the drug is administered as a racemic mixture of (R)- and (S)-
      methadone, (R)-methadone accounts for most, if not all, of the opioid effects.
      Methadone can be detected in the blood 15-45 minutes after oral administration,
      with peak plasma concentration at 2.5-4 hours. Methadone has a mean
      bioavailability of around 75% (range 36-100%). Methadone is highly bound to
      plasma proteins, in particular to alpha(1)-acid glycoprotein. Its mean free
      fraction is around 13%, with a 4-fold interindividual variation. Its volume of
      distribution is about 4 L/kg (range 2-13 L/kg). The elimination of methadone is
      mediated by biotransformation, followed by renal and faecal excretion. Total body
      clearance is about 0.095 L/min, with wide interindividual variation (range 0.02-2
      L/min). Plasma concentrations of methadone decrease in a biexponential manner,
      with a mean value of around 22 hours (range 5-130 hours) for elimination half
      life. For the active (R)-enantiomer, mean values of around 40 hours have been
      determined. Cytochrome P450 (CYP) 3A4 and to a lesser extent 2D6 are probably the
      main isoforms involved in methadone metabolism. Rifampicin (rifampin),
      phenobarbital, phenytoin, carbamazepine, nevirapine, and efavirenz decrease
      methadone blood concentrations, probably by induction of CYP3A4 activity, which
      can result in severe withdrawal symptoms. Inhibitors of CYP3A4, such as
      fluconazole, and of CYP2D6, such as paroxetine, increase methadone blood
      concentrations. There is an up to 17-fold interindividual variation of methadone
      blood concentration for a given dosage, and interindividual variability of CYP
      enzymes accounts for a large part of this variation. Since methadone probably
      also displays large interindividual variability in its pharmacodynamics,
      methadone treatment must be individually adapted to each patient. Because of the
      high morbidity and mortality associated with opioid dependence, it is of major
      importance that methadone is used at an effective dosage in maintenance
      treatment: at least 60 mg/day, but typically 80-100 mg/day. Recent studies also
      show that a subset of patients might benefit from methadone dosages larger than
      100 mg/day, many of them because of high clearance. In clinical management,
      medical evaluation of objective signs and subjective symptoms is sufficient for
      dosage titration in most patients. However, therapeutic drug monitoring can be
      useful in particular situations. In the case of non-response trough plasma
      concentrations of 400 microg/L for (R,S)-methadone or 250 microg/L for (R)
      methadone might be used as target values.

PMID- 12405870
TI  - Case reports: still a priority.

PMID- 12405871
TI  - The effects of a contoured foam seat on postural alignment and upper-extremity
      function in infants with neuromotor impairments.
AB  - BACKGROUND AND PURPOSE: Physical therapists and occupational therapists
      frequently use adaptive seating devices to improve stability in sitting for
      children with neuromotor impairments. The purpose of this study was to examine
      the effects of a contoured foam seat (CFS) on postural alignment and on the
      ability of infants with neuromotor impairments to engage with toys. Parental
      perceptions regarding the use and effects of the CFS also were assessed via
      semistructured interviews. SUBJECTS: Subjects were 4 infants, ages 9 to 18
      months, who were unable to sit independently. METHOD: A time-series, alternating
      treatments design was used, with data collected under 3 conditions: (1) a regular
      highchair, (2) a regular highchair with a thin foam liner, and (3) a CFS used as
      an insert in a regular highchair. The primary dependent measures were postural
      alignment and engagement with toys. Engagement with toys was defined as
      percentage of intervals with 2 hands on a toy and percentage of intervals with no
      hands on a highchair tray and 1 or 2 hands on a toy. RESULTS: Results showed a
      sustained effect of the CFS on improving postural alignment for all subjects.
      Effects of the CFS on increasing the number of intervals of bimanual play were
      not demonstrated for any subjects, although some improvement in the infant's
      ability to free the arms from support was observed for 2 subjects. Mothers
      reported acceptability of the CFS for everyday use and described benefits for
      themselves and their infants. DISCUSSION AND CONCLUSION: The results support the
      use of a CFS for improving postural alignment. Future research on adaptive
      seating should focus on interventions and outcomes that help children participate
      in functional activities relevant to them and their families.

PMID- 12405872
TI  - Examination of and intervention for a patient with chronic lateral elbow pain
      with signs of nerve entrapment.
AB  - BACKGROUND AND PURPOSE: Lateral elbow pain has several causes, which can make
      diagnosis difficult. The purpose of this case report is to describe the
      examination of and the intervention for a patient with chronic lateral elbow pain
      who had signs of nerve entrapment. CASE DESCRIPTION: The patient was a 43-year
      old woman who had right lateral elbow pain for about 4 months, which she
      attributed to extensive keyboard work on a computer. She had a reduction in joint
      passive range of motion during "neural tension testing," an examination procedure
      to detect nerve entrapment. This sign, in combination with other findings,
      suggested that the patient had a mild entrapment of the deep radial nerve (radial
      tunnel syndrome). The patient was treated 14 times over a 10-week period with
      "neural mobilization techniques," which are designed to free nerves for movement;
      ultrasound; strengthening exercises; and stretching. OUTCOMES: The patient had
      minimal symptoms at discharge, was pain-free, and had resumed all activities at a
      4-month follow-up visit. DISCUSSION: Neural tension testing may be a useful
      examination procedure and mobilization may be useful for intervention for
      patients who have lateral elbow pain.

PMID- 12405873
TI  - Use of a static adjustable ankle-foot orthosis following tibial nerve block to
      reduce plantar-flexion contracture in an individual with brain injury.
AB  - BACKGROUND AND PURPOSE: Ankle plantar-flexion contractures are a common
      complication of brain injuries and can lead to secondary limitations in mobility.
      CASE DESCRIPTION: The patient was a 44-year-old woman with left hemiplegia
      following a right frontal arteriovenous malformation resection. She had a left
      ankle plantar-flexion contracture of -31 degrees from neutral. After a tibial
      nerve block, an adjustable ankle-foot orthosis was applied 23 hours a day for 27
      days. Adjustments of the orthosis were made as the contracture was reduced. The
      patient received physical therapy during the 27-day period for functional
      mobility activities and stretching the plantar flexors outside of the orthosis.
      OUTCOMES: The patient's dorsiflexion passive range of motion increased from -31
      degrees to +10 degrees. DISCUSSION: The application of an adjustable ankle-foot
      orthosis following a tibial nerve block, as an addition to a physical therapy
      regimen of stretching and mobility training, may reduce plantar-flexion
      contractures in patients with brain injury.

PMID- 12405874
TI  - Use of the ICF model as a clinical problem-solving tool in physical therapy and
      rehabilitation medicine.
AB  - The authors developed an instrument called the "Rehabilitation Problem-Solving
      Form" (RPS-Form), which allows health care professionals analyze patient
      problems, to focus on specific targets, and to relate the salient disabilities to
      relevant and modifiable variables. In particular, the RPS-Form was designed to
      address the patients' perspectives and enhance their participation in the
      decision-making process. Because the RPS-Form is based on the International
      Classification of Functioning, Disability, and Health (ICF) Model of Functioning
      and Disability, it could provide a common language for the description of human
      functioning and therefore facilitates multidisciplinary responsibility and
      coordination of interventions. The use of the RPS-Form in clinical practice is
      demonstrated by presenting an application case of a patient with a chronic pain
      syndrome.

PMID- 12405875
TI  - Thirty-third Mary McMillan Lecture: "Look forward, walk tall": Exploring our
      "What if" questions.

PMID- 12405876
TI  - 2002 APTA presidential address: What's all the fuss about direct access?

PMID- 12405877
TI  - Animal experiments: are there no limits?

PMID- 12405878
TI  - The prediction of human skin responses by using the combined in vitro fluorescein
      leakage/Alamar Blue (resazurin) assay.
AB  - A range of cosmetics formulations with human patch-test data were supplied in a
      coded form, for the examination of the use of a combined in vitro permeability
      barrier assay and cell viability assay to generate, and then test, a prediction
      model for assessing potential human skin patch-test results. The target cells
      employed were of the Madin Darby canine kidney cell line, which establish tight
      junctions and adherens junctions able to restrict the permeability of sodium
      fluorescein across the barrier of the confluent cell layer. The prediction model
      for interpretation of the in vitro assay results included initial effects and the
      recovery profile over 72 hours. A set of the hand-wash, surfactant-based
      formulations were tested to generate the prediction model, and then six others
      were evaluated. The model system was then also evaluated with powder laundry
      detergents and hand moisturisers: their effects were predicted by the in vitro
      test system. The model was under-predictive for two of the ten hand-wash
      products. It was over-predictive for the moisturisers, (two out of six) and eight
      out of ten laundry powders. However, the in vivo human patch test data were
      variable, and 19 of the 26 predictions were correct or within 0.5 on the 0-4.0
      scale used for the in vivo scores, i.e. within the same variable range reported
      for the repeat-test hand-wash in vivo data.

PMID- 12405879
TI  - Evaluation of a porcine lens and fluorescence assay approach for in vitro ocular
      toxicological investigations.
AB  - Cell biology, as monitored with the fluorescent indicator dyes Alamar Blue and 5
      carboxyfluorescein diacetate acetoxymethyl ester (CFDA-AM), and lens optical
      quality, as measured with an in vitro scanning laser system, have been used to
      evaluate in vitro the condition of porcine lenses after being placed in a culture
      medium. The measurements, beginning from week one of culture, were compared
      statistically. Optical quality and cellular viability, as measured with either
      dye, were unchanged in lenses that had been maintained for 6 weeks in modified
      M199 medium. Some lenses were treated with 0.152J/cm(2) UVB radiation, and a
      decline was observed after 48 hours in both optical and metabolic capabilities,
      as indicated by a decreased capacity of the lenses to reduce Alamar Blue. The
      measurements with CFDA-AM did not show complete concordance with the other
      indicators of lens health after UV treatment, making this dye less reliable as
      applied currently to lens cultures. Overall, the findings suggest that porcine
      lenses can be maintained for weeks in culture, and that their condition can be
      evaluated quantitatively by assays that probe cellular functions and optical
      properties. Such a system should prove valuable for in vitro ocular
      pharmacotoxicological research.

PMID- 12405880
TI  - Long-term in vitro toxicity models: comparisons between a flow-cell bioreactor, a
      static-cell bioreactor and static cell cultures.
AB  - In vitro long-term toxicity testing is becoming an important issue in the field
      of toxicology, and there is a need to develop new model systems that mimic human
      chronic exposure and its effects. The aim of this work was to test two long-term
      in vitro toxicity systems which are available, a flow-cell bioreactor
      (Tecnomouse, Integra, Wallisellen, Switzerland) and a static cell bioreactor
      system (CELLine CL 6-well, Integra), and to compare them with the use of
      conventional cell culture flasks. A human cell line, Int 407, was exposed to
      cadmium chloride (CdCl(2); 10-(7-)10-(8)M) for 4 weeks. Cell numbers and cell
      viabilities were determined by the trypan blue (TB) exclusion assay and from
      exclusion of propidium iodide (PI) as determined by flow cytometry; and cell
      viability and metabolic activity were determined by the MTT assay. In addition,
      total protein determination and cadmium uptake measurements were performed. The
      results obtained with TB and PI exclusion did not show clear differences in cell
      viability with increasing CdCl(2) concentration. However, in the static cell
      culture systems, an increase in MTT reduction was found at low concentrations of
      CdCl(2). Expression of heat-shock protein (Hsp27 and Hsp70) increased
      differently, depending on the CdCl(2) concentration applied and the system used.
      In summary, of the two bioreactors, the CELLine CL 6-well bioreactor was shown to
      be the more efficient system for performing long-term cytotoxicity studies. It is
      easy to handle, it permits the assessment of several endpoints, and sufficient
      replicates can be made available.

PMID- 12405882
TI  - Comments on the use of bootstrap resampling to assess the uncertainty of Cooper
      statistics.

PMID- 12405881
TI  - Three-dimensional co-culture of primary human liver cells in bioreactors for in
      vitro drug studies: effects of the initial cell quality on the long-term
      maintenance of hepatocyte-specific functions.
AB  - In vitro culture models that employ human liver cells could be potent tools for
      predictive studies on drug toxicity and metabolism in the pharmaceutical
      industry. A bioreactor culture model was developed that permits the three
      dimensional co-culture of liver cells under continuous medium perfusion with
      decentralised mass exchange and integral oxygenation. We tested the ability of
      the system to support the long-term maintenance and differentiation of primary
      human liver cells. The effects of the initial cell quality were investigated by
      comparing cultures from resected, non-preserved liver with cultures from liver
      graft tissue damaged by long-term preservation. In cultures originating from non
      preserved liver, protein and urea synthesis, glucose metabolism, and cytochrome
      (CYP450) activities were stable over the 2-week culture period, with maximal
      activities at the end of the first week in culture. Enzyme induction led to
      increased 7-ethoxyresorufin O-deethylase activities of up to 20 times the basal
      value. In cultures from preservation-damaged liver, recovery of metabolic
      activities was detected during bioreactor culture. After two weeks, most
      biochemical parameters approached those of cultures from non-preserved human
      liver. Light microscopy demonstrated the three-dimensional reorganisation of
      hepatocytes and non-parenchymal cells in co-culture. Long-term maintenance, and
      even the regeneration of specific functional activities of human liver cells, can
      be achieved in the bioreactor. This could facilitate the introduction into the
      pharmaceutical industry of in vitro drug testing with primary human liver cells.

PMID- 12405884
TI  - National guidelines for antenatal testing.

PMID- 12405885
TI  - The Australian coordinated care trials: success or failure? The second round of
      trials may provide more answers.

PMID- 12405886
TI  - The ethics of participating in research. Simple statements of risks and benefits
      may not reveal the complexity of human responses to research participation.

PMID- 12405887
TI  - Global cardiology comes to Australia: 14th World Congress of Cardiology, Sydney,
      5-9 May 2002.

PMID- 12405888
TI  - The clinical utility of routine urinalysis in pregnancy: a prospective study.
AB  - OBJECTIVES: To determine whether routine urinalysis in the antenatal period
      facilitates diagnosis of pre-eclampsia. Can routine urinalysis during pregnancy
      be discontinued in women with normal results of dipstick urinalysis and
      microscopy at the first antenatal visit? DESIGN: Prospective observational study.
      SETTING: A metropolitan public hospital and a private hospital in Sydney (NSW).
      PARTICIPANTS: One thousand women were enrolled at their first antenatal visit
      (March to November 1999), and 913 completed the study. OUTCOME MEASURES: The
      primary outcome was a diagnosis of de novo hypertension (gestational
      hypertension, pre-eclampsia, or pre-eclampsia superimposed on chronic
      hypertension). RESULTS: Thirty-five women had dipstick proteinuria at their first
      antenatal visit. In 25 (71%) of these women, further dipstick proteinuria was
      detected during pregnancy, and two (6%) were diagnosed with pre-eclampsia. Of the
      867 without dipstick proteinuria at the first visit, 338 (39%) had dipstick
      proteinuria (> 1+) at some time during pregnancy. There were no statistically
      significant differences in the proportion of women with and without dipstick
      proteinuria at their first visit who developed hypertension during pregnancy.
      Only six women developed proteinuria before the onset of hypertension. Women who
      had an abnormal result of a midstream urine test at their first visit, compared
      with women with a normal result, were more likely to have a urinary tract
      infection diagnosed during pregnancy; however, the numbers were small.
      CONCLUSION: In the absence of hypertension, routine urinalysis during pregnancy
      is a poor predictor of pre-eclampsia. Therefore, after an initial screening
      urinalysis, routine urinalysis could be eliminated from antenatal care without
      adverse outcomes for women.

PMID- 12405889
TI  - The effectiveness of coordinated care for people with chronic respiratory
      disease.
AB  - OBJECTIVES: To evaluate the effectiveness of coordinated care for chronic
      respiratory disease. DESIGN AND SETTING: Community-based geographical control
      study, in western (intervention) and northern (comparison) metropolitan Adelaide
      (SA). PARTICIPANTS: 377 adults (223 intervention; 154 comparison) with chronic
      obstructive pulmonary disease, asthma or other chronic respiratory condition,
      July 1997 to December 1999. INTERVENTION: Coordinated care (includes care
      coordinator, care guidelines, service coordinator and care mentor). MAIN OUTCOME
      MEASURES: Hospital admissions (any, unplanned and respiratory), functionality
      (activities of daily living) and quality of life (SF-36 and Dartmouth COOP).
      RESULTS: At entry to the study, intervention and comparison subjects were
      dissimilar. The intervention group was 10 years older (P < 0.001), less likely to
      smoke (P = 0.014), had higher rates of hospitalisation in the previous 12 months
      (P < 0.001) and had worse self-reported quality of life (SF-36 physical component
      summary score [P < 0.001] and four of nine COOP domains [P = 0.002-0.013]). After
      adjustment for relevant baseline characteristics, coordinated care was not
      associated with any difference in hospitalisation, but was associated with some
      improvements in quality of life (SF-36 mental component summary score [P = 0.023]
      and three of nine COOP domains [P = 0.008-0.031]) compared with the comparison
      group. CONCLUSIONS: Coordinated care given to patients with chronic respiratory
      disease did not affect hospitalisation, but it was associated with an improvement
      in some quality-of-life measures.

PMID- 12405890
TI  - Gestational diabetes in Victoria in 1996: incidence, risk factors and outcomes.
AB  - OBJECTIVES: To describe the epidemiology of gestational diabetes mellitus (GDM)
      in Victoria. STUDY DESIGN: Population study of all women having singleton births
      in Victoria in 1996. METHODS: Probabilistic record linkage of routinely collected
      data and capture-recapture techniques to provide an estimate of the incidence of
      GDM. MAIN OUTCOME MEASURES: Risk factors for and the adverse outcomes associated
      with GDM compared with the non-diabetic population by univariate and multivariate
      analysis. RESULTS: The estimated incidence of GDM was 3.6% (95% confidence
      interval [CI], 3.60%-3.64%). GDM is associated with women who are older,
      Aboriginal, non-Australian born, or who give birth in a larger hospital. The
      adverse outcomes associated with GDM pregnancies were hypertension/pre-eclampsia
      (adjusted odds ratio [OR], 1.6; 95% CI, 1.4-1.9), hyaline membrane disease (1.6;
      1.2-2.2), neonatal jaundice (1.4; 1.2-1.7) and macrosomia (2.0; 1.8-2.3).
      Interventions during childbirth were also associated with GDM - for example,
      induction of labour (3.0; 2.7-3.4) and caesarean section (1.7; 1.6-1.9).
      CONCLUSION: Women with GDM had increased rates of hypertension, pre-eclampsia,
      induced labour, and interventional delivery. Their offspring had a higher risk of
      macrosomia, neonatal jaundice and hyaline membrane disease.

PMID- 12405891
TI  - The access-block effect: relationship between delay to reaching an inpatient bed
      and inpatient length of stay.
AB  - OBJECTIVES: To investigate the relationship between access block in the emergency
      department (ED) (defined as total time from arrival to transfer from the ED over
      eight hours) and inpatient length of stay (LOS). DESIGN AND SETTING:
      Retrospective cohort study of all admissions through the ED to a tertiary
      hospital in Canberra, Australian Capital Territory, during 1999. MAIN OUTCOME
      MEASURES: Total time in the ED and LOS, calculated in days from ED departure to
      hospital discharge (non-overnight admissions were assigned LOS of one day, and
      all LOS were truncated at 10 days). RESULTS: 11 906 admissions were included, and
      919 experienced access block (7.7%). Mean LOS was 4.9 days in those who
      experienced access block (95% CI, 4.7-5.1), compared with 4.1 days in the no
      block group (95% CI, 4.0-4.2; P < 0.0001). Subgroup analysis showed that this
      "access block effect" occurred across different severities of illness and
      diagnoses. A strong relationship was found between longer LOS and arrival of
      access-block patients on the inpatient ward outside office hours (0800-1600
      weekdays). CONCLUSIONS: This is the first study to show an association between
      access block and a measure of outcome outside the ED. If the effect of access
      block on LOS is reproduced in other settings, there are major implications for
      hospital management.

PMID- 12405892
TI  - Professional monitoring and critical incident reporting using personal digital
      assistants.
AB  - OBJECTIVE: To assess the practicality of using personal digital assistants (PDAs)
      for the collection of logbook data, procedural performance data and critical
      incident reports in anaesthetic trainees. DESIGN: Pilot study. SETTING: Two
      tertiary referral centres (in Victoria and New Zealand) and a large district
      hospital in Queensland. PARTICIPANTS: Six accredited Australian and New Zealand
      College of Anaesthetists (ANZCA) registrars and their ANZCA training supervisors.
      INTERVENTIONS: Registrars and supervisors underwent initial training for one
      hour, and supervisors were provided with ongoing support. MAIN OUTCOME MEASURES:
      Reliable use of the program, average time for data entry and number of procedures
      logged. RESULTS: ANZCA trainees reliably enter data into PDAs. The data can be
      transferred to a central database, where they can be remotely analysed before
      results are fed back to trainees. CONCLUSIONS: This technology can be used to
      monitor professional performance in ANZCA trainees.

PMID- 12405893
TI  - Remission of lymphoma after drug withdrawal in rheumatoid arthritis.
AB  - A 63-year-old man with rheumatoid arthritis presented with pain and swelling of
      his right buttock. Imaging and tissue biopsy revealed a diffuse large B-cell, non
      Hodgkin's lymphoma. The disease-modifying drugs he was taking, cyclosporin and
      methotrexate, were stopped, and the lymphoma resolved spontaneously without the
      use of chemotherapy.

PMID- 12405894
TI  - Clinicians' attitudes to clinical practice guidelines: a systematic review.
AB  - OBJECTIVE: To systematically review surveys of clinicians' attitudes to clinical
      practice guidelines. DATA SOURCES: MEDLINE, HealthStar, Embase and CINAHL were
      searched electronically for English-only surveys published from 1990 to 2000.
      STUDY SELECTION: We included surveys with responses to one or more of seven
      propositions (see below). Studies were excluded if they had fewer than 100
      respondents or if the response rate was less than 60%. RESULTS: Thirty studies
      included responses to one or more of the seven items, giving a total of 11 611
      responses. The response rate for the included studies was 72% (95% confidence
      interval [CI], 69%-75%). Clinicians agreed that guidelines were helpful sources
      of advice (weighted mean, 75%; 66%-83%), good educational tools (71%; 63%-79%)
      and intended to improve quality (70%; 60%-80%). However, clinicians also
      considered guidelines impractical and too rigid to apply to individual patients
      (30%; 23%-36%), that they reduced physician autonomy and oversimplified medicine
      (34%; 22%-47%), would increase litigation (41%; 32%-49%) and were intended to cut
      healthcare costs (52.8%; 39%-66%). CONCLUSIONS: Surveys of healthcare providers
      consistently report high satisfaction with clinical practice guidelines and a
      belief that they will improve quality, but there are concerns about the
      practicality of guidelines, their role in cost-cutting and their potential for
      increasing litigation.

PMID- 12405895
TI  - Does research into sensitive areas do harm? Experiences of research participation
      after a child's diagnosis with Ewing's sarcoma.
AB  - OBJECTIVE: To investigate family members' experiences of involvement in a
      previous study (conducted August 1995 to June 1997) following their child's
      diagnosis with Ewing's sarcoma. DESIGN: Retrospective survey, conducted between 1
      November and 30 November 1997, using a postal questionnaire. PARTICIPANTS: Eighty
      one of 97 families who had previously completed an in-depth interview as part of
      a national case-control study of Ewing's sarcoma. MAIN OUTCOME MEASURES:
      Participants' views on how participation in the previous study had affected them
      and what motivated them to participate. RESULTS: Most study participants
      indicated that taking part in the previous study had been a positive experience.
      Most (n = 79 [97.5%]) believed their involvement would benefit others and were
      glad to have participated, despite expecting and finding some parts of the
      interview to be painful. Parents whose child was still alive at the time of the
      interview recalled participation as more painful than those whose child had died
      before the interview. Parents who had completed the interview less than a year
      before our study recalled it as being more painful than those who had completed
      it more than a year before. CONCLUSIONS: That people suffering bereavement are
      generally eager to participate in research and may indeed find it a positive
      experience is useful information for members of ethics review boards and other
      "gatekeepers", who frequently need to determine whether studies into sensitive
      areas should be approved. Such information may also help members of the community
      to make an informed decision regarding participation in such research.

PMID- 12405896
TI  - Treatment of sore throat in light of the Cochrane verdict: is the jury still out?
AB  - There are few good-quality studies of the effectiveness of antibiotic treatment
      of proven group A streptococcal (GAS) pharyngitis in children; available data
      suggest that antibiotics may reduce symptom duration. While there is limited
      justification for antibiotic treatment of GAS pharyngitis to prevent acute
      rheumatic fever in non-Indigenous Australians, there is no justification for
      routine antibiotic treatment of all patients with sore throat. Two strategies are
      open to clinicians: not to treat GAS pharyngitis with antibiotics, in which case
      no investigations should be done; or to treat cases of sore throat with clinical
      features that suggest GAS, in which case diagnosis should be confirmed with a
      throat swab, and penicillin started while awaiting the result. Penicillin should
      be discontinued if the swab is negative, or continued for 10 days if it is
      positive for GAS. Surveillance of GAS infections and acute rheumatic fever is
      needed in Australia, as are further studies of effectiveness (including cost
      effectiveness) of antibiotic treatment of proven GAS pharyngitis.

PMID- 12405897
TI  - Improving doctors' letters.
AB  - Information contained in letters of referral and reply often does not meet the
      information needs of letter recipients. Missing reports of previous
      investigations and insufficient detail in the referral letter to specialists are
      the most serious and common problems. General practitioners prefer structured,
      computer-generated letters to unstructured, dictated letters. Referring surgeons
      and GPs identify delay in receiving the reply letter and insufficient detail as
      relatively common problems after a new patient consultation. They want the reply
      letter to describe the proposed treatment, expected outcomes and any psychosocial
      concerns, yet these items are often omitted. A letter content and format prompt
      card has the potential to enhance the quality of correspondence between medical
      specialists and referring doctors. Specialist medical bodies should consider
      preparing prompt cards (setting out preferred information content and format for
      letters) to distribute to their members.

PMID- 12405898
TI  - Recurrent facial swelling following dental procedures.

PMID- 12405899
TI  - Privacy legislation and research.

PMID- 12405900
TI  - Opportunistic screening for type 2 diabetes mellitus in public hospitals.

PMID- 12405901
TI  - Is breastfeeding best practice?

PMID- 12405902
TI  - Chronic fatigue syndrome clinical practice guidelines: psychological factors.

PMID- 12405903
TI  - Colorectal cancer prevention.

PMID- 12405904
TI  - Should radiologists and pathologists talk to patients?

PMID- 12405906
TI  - Classification of idiopathic interstitial pneumonias: making sense of the
      alphabet soup.
AB  - Since Liebow and Carrington's original classification of idiopathic interstitial
      pneumonias, there have been controversies over which histological patterns should
      be included and how they relate to clinicopathological diseases such as
      cryptogenic fibrosing alveolitis/idiopathic pulmonary fibrosis (CFA/IPF). Because
      of these differences and the wealth of overlapping terminology, a consensus
      classification system has been proposed, devised by a group of clinicians,
      radiologists and pathologists. Seven histological patterns are recognized: usual
      interstitial pneumonia (UIP), non-specific interstitial pneumonia (NSIP), diffuse
      alveolar damage (DAD), organizing pneumonia (OP), desquamative interstitial
      pneumonia (DIP), respiratory bronchiolitis (RB) and lymphocytic interstitial
      pneumonia (LIP), each with a clinicopathological counterpart, the most well
      defined being UIP and CFA/IPF. The system is applicable both in terms of the
      pathologist identifying histological patterns in isolation and in terms of the
      pathologist's role in contributing to the final clinicopathological diagnosis. It
      will probably provide greater consistency in diagnosis, early studies suggesting
      that the system is reproducible, and also identify purer cohorts for studies
      investigating causation. It also highlights the fact that the 'gold standard for
      diagnosis' is no longer a surgical lung biopsy in isolation but more the
      clinicopathological conference, when clinical, imaging and histological data are
      jointly discussed to produce the final clinicopathological diagnosis.

PMID- 12405905
TI  - Mechanism of action of interleukin-2 (IL-2)-Bax, an apoptosis-inducing chimaeric
      protein targeted against cells expressing the IL-2 receptor.
AB  - The chimaeric protein interleukin-2 (IL-2)-Bax was designed to target and kill
      specific cell populations expressing the IL-2 receptor. However, it is not well
      understood how IL-2-Bax causes target cells to die. In the present study, we
      investigated the pathway of apoptosis evoked by IL-2-Bax and the possible
      involvement of endogenous Bax in this process. We report here that, upon
      internalization of IL-2-Bax into target cells, it is localized first mainly in
      the nucleus, and only later is it translocated to the mitochondria. Similarly,
      endogenous Bax is also partially localized in the nucleus, and accumulates mainly
      in this compartment soon after physiological triggering of apoptosis. Despite the
      fact that Bax has no nuclear localization sequence, our data suggest that Bax has
      one or more physiological roles and/or substrates within the nucleus. Indeed, a
      dramatic repression of nuclear Tax protein expression was induced following
      treatment of HUT-102 cells with IL-2-Bax, similar to what occurs following serum
      deprivation of these cells. Unexpectedly, induction of apoptosis using IL-2-Bax
      was preceded by enhanced expression of newly synthesized Bax protein and
      suppression of Bcl-2. This imbalance between the pro- and anti-apoptotic genes
      was associated with p53 induction, although IL-2-Bax activity was also evident in
      cells lacking p53 expression. By studying the mechanism of action of IL-2-Bax, we
      were able to follow the intrinsic events and their cascade that culminates in
      cell death. We have shown that the ability of IL-2-Bax to affect the
      intracellular apoptotic machinery within the target cells, and to cause the cells
      to die, uses a mechanism similar to that induced following a normal apoptotic
      signal.

PMID- 12405907
TI  - Can pulmonary sclerosing haemangioma be accurately diagnosed by intra-operative
      frozen section?
AB  - AIMS: Pulmonary sclerosing haemangioma is a rare benign tumour with a
      characteristic variegated histological pattern. In this retrospective study we
      aimed to identify features that can aid in making a correct diagnosis and
      avoiding potential pitfalls at the time of intra-operative frozen section.
      METHODS AND RESULTS: Twenty cases of pulmonary sclerosing haemangioma with intra
      operative frozen section were reviewed. The four major histological patterns
      (solid, sclerotic, papillary and haemorrhagic) were found in various combinations
      in the frozen sections. In 17 cases, three or more patterns were present. There
      could be focal areas mimicking epithelioid haemangioendothelioma or carcinoid
      tumour. Intra-operative imprint/scrape cytology served as a helpful adjunct in
      confirming the cytological blandness, although occasional atypical cells could be
      present. An intra-operative frozen section diagnosis of 'sclerosing haemangioma'
      or 'benign tumour' was given in 14 cases; the diagnosis was deferred in six
      cases. Retrospective analysis of the deferred cases showed that a definitive
      intra-operative diagnosis could have been made in three, because three or more
      major histological patterns were present. One case showed a pure papillary
      pattern at frozen section, mimicking the appearance of papillary adenocarcinoma
      (primary or secondary), bronchioloalveolar carcinoma, epithelioid mesothelioma or
      papillary adenoma; two tumours from a patient with multicentric disease showed
      widespread significant cytological atypia in the tumours raising a serious
      consideration of malignancy. CONCLUSION: A diagnosis of pulmonary sclerosing
      haemangioma can be made at intra-operative frozen sections in most cases based on
      the tumour circumscription and variegated histological patterns. When only a
      single histological pattern is identified or when there is significant
      cytological atypia, distinction from other tumours can be problematic, and the
      diagnosis is best deferred.

PMID- 12405908
TI  - Unusual sclerosing haemangiomas and sclerosing haemangioma-like lesions, and the
      value of TTF-1 in making the diagnosis.
AB  - AIMS: Sclerosing haemangiomas typically comprise a mixture of four architectural
      patterns (papillary, sclerotic, solid and haemorrhagic) and two cell types,
      eosinophilic cuboidal epithelial lining cells and sheets of rounded cells with
      either eosinophilic or clear cytoplasm. In most instances, recognition of these
      architectural and cytological features provides sufficient evidence for
      diagnosis. This study presents and discusses the histogenesis of four cases where
      difficulties in diagnosis were encountered, and reports the value of the antibody
      TTF-1 in making the diagnosis. METHODS AND RESULTS: Four cases with focal areas
      reminiscent of sclerosing haemangioma were reviewed and immunostained with an
      antibody panel including antibodies to TTF-1 and surfactant apoprotein A. Of
      these, one case was classified as sclerosing haemangioma combined with typical
      carcinoid, in which there was a mediastinal lymph node metastasis solely
      comprising the solid component of sclerosing haemangioma. The second was
      classified as an alveolar adenoma with sclerosing haemangioma-like areas. In the
      remaining two cases, diagnosis was confounded by presentation with predominantly
      cystic masses, the largest 70 mm in diameter. Immunohistochemically, TTF-1 was of
      greater value than surfactant apoprotein, in particular in identifying the solid
      component of sclerosing haemangioma when this was solely present. CONCLUSION:
      Sclerosing haemangiomas should be considered in the differential diagnosis of
      cystic pulmonary masses. They may also present histologically as combined tumours
      and metastasize to mediastinal nodes, indicating an, albeit low, malignant
      potential. TTF-1 is a valuable antibody in identifying the presence of a
      sclerosing haemangioma when typical features are absent.

PMID- 12405909
TI  - Immunohistochemical expression of CD10 and t(14;18) chromosomal translocation may
      be indicators of follicle centre cell origin in nodal diffuse large B-cell
      lymphoma.
AB  - AIMS: Although diffuse large B-cell lymphoma is categorized as a distinct entity
      in the REAL classification of lymphomas, it represents a heterogeneous group of
      neoplasms. A subgroup is probably of follicle centre cell origin and may evolve
      from a pre-existing follicular lymphoma. The t(14;18) chromosomal translocation
      can be demonstrated in the majority of follicular lymphomas and the aim of this
      study was to investigate the prevalence of t(14;18) translocation in a series of
      de novo nodal diffuse large B-cell lymphomas. We correlated this with the
      immunohistochemical expression of CD10, bcl2 and bcl6, markers which are usually
      expressed by the neoplastic cells in follicular lymphomas. We also correlated
      these parameters with the presence or absence of p53 protein expression by the
      neoplastic cells. METHODS AND RESULTS: Nodal diffuse large B-cell lymphomas
      (n=34) were stained immunohistochemically with monoclonal antibodies to CD10,
      bcl2, bcl6 and p53 (D07). Polymerase chain reaction (PCR) for the t(14;18)
      translocation was also performed. Fourteen, 24 and 29 (41%, 71%, 85%) cases
      exhibited positivity for CD10, bcl2 and bcl6, respectively. In 12 cases there was
      positivity with D07 (35%). By PCR, the t(14;18) translocation was identified in
      five cases (15%), four of which were positive for CD10 and bcl2 and all of which
      were positive for bcl6. One of five cases positive for the chromosomal
      translocation exhibited positivity with D07. CONCLUSIONS: In this study the
      t(14;18) translocation was identified in 15% of diffuse large B-cell lymphomas,
      all but one of which exhibited positivity for CD10, bcl2 and bcl6. These may
      represent cases of follicle centre cell origin which may or may not have evolved
      from a pre-existing follicular lymphoma. It is possible that positivity for CD10
      especially may identify cases which are of follicle centre cell origin and that
      the absence of t(14;18) translocation in some of these cases may reflect the fact
      that the translocation cannot normally be demonstrated in all follicular
      lymphomas. Whether the presence or absence of the translocation and the
      immunophenotype are prognostically important should be investigated further.

PMID- 12405910
TI  - Non-HTLV-1-associated primary gastric T-cell lymphomas show cytotoxic activity:
      clinicopathological, immunohistochemical characteristics and TIA-1 expression in
      31 cases.
AB  - AIMS: Most primary gastrointestinal lymphomas are of B-cell origin and T-cell
      origin is very rare. Recent studies have suggested that human T-cell
      lymphotrophic virus type 1 (HTLV-1) may be involved in the development of primary
      gastric T-cell lymphoma. We analysed 31 patients with primary gastric T-cell
      lymphoma in south-west Japan, an area endemic for HTLV-1, and determined their
      phenotypes, genotypes, and HTLV-1 status. METHODS AND RESULTS: Here we present 31
      cases of primary gastric T-cell lymphoma in a HTLV-1-endemic area in Japan and
      analyse the clinical status, histology, phenotype and virus status. The median
      age at onset of primary gastric T-cell lymphoma was 57 years with a gender ratio
      of M:F = 1.58:1. Six of the 31 primary gastric T-cell lymphoma cases had HTLV-1
      proviral DNA (five males, one female), nine of the 31 cases were positive for
      anti-adult T cell leukaemia antibody, without examination of HTLV-1 proviral DNA
      (five males, four females), eight were non-HTLV-1-associated primary gastric T
      cell lymphoma (four males, four females) and the other eight cases were unknown.
      Primary gastric T-cell lymphoma usually presented as a large ulcerated tumour at
      the corpus to the antrum and histologically consisted of anaplastic large cell
      type (n = 2), pleomorphic large cell type (n = 3), pleomorphic medium and large
      cell type (n = 14), pleomorphic medium cell type (n = 11), and angioimmunoblastic
      T-cell lymphoma type (n = 1). There were no clear macroscopic and microscopic
      differences between HTLV-1-associated and non-HTLV-1-associated primary gastric T
      cell lymphoma. Most patients died within 2 years of diagnosis, and both types of
      primary gastric T-cell lymphoma (with and without HTLV-1) were associated with
      poor prognosis. Cytotoxic marker analysis showed that HTLV-1-associated lymphomas
      were negative for TIA-1, while non-HTLV-1-associated lymphomas were positive for
      TIA-1. CONCLUSIONS: Our results suggest that in HTLV-1-endemic areas, patients
      with HTLV-1-associated primary gastric T-cell lymphoma should be managed
      carefully and that TIA-1 seems to be useful for identifying the aetiology of this
      lesion.

PMID- 12405911
TI  - Alteration of PTEN expression in endometrial carcinoma is associated with down
      regulation of cyclin-dependent kinase inhibitor, p27.
AB  - AIMS: PTEN is a recently identified tumour suppressor inactivated in a wide
      variety of human cancers, including endometrial cancers. Mutation of the PTEN
      tumour suppressor gene has been reported in approximately 50-83% of endometrial
      adenocarcinoma. Despite this fact, study of the expression of PTEN protein in
      human tumours is limited. PTEN protein functions as a tumour suppressor by
      regulating the cell cycle and survival through signal transduction pathway. PTEN
      protein was considered to have a dual-specificity phosphatase activity, but it is
      now known that its principal physiological activity is mainly derived from its
      lipid phosphatase activity. The cyclin-dependent kinase inhibitor, p27, has been
      suggested as a downstream target of cell cycle arrest of PTEN in various in vitro
      studies. In this study, we evaluated the alteration of PTEN protein expression in
      endometrial carcinoma and assessed its relationship to the expression of p27, the
      presumed downstream target of PTEN. METHODS AND RESULTS: Immunohistochemical
      staining was performed on 66 cases of endometrial carcinoma including 61
      endometrioid type and five serous type, using antibodies to PTEN and p27. Loss or
      decrease of PTEN expression was observed in 66% (40/61 cases) of uterine
      endometrioid carcinoma, whereas most uterine serous carcinoma (4/5 cases) showed
      intense PTEN expression. Four (30%) of 13 endometrial hyperplasia synchronous
      with endometrioid carcinoma demonstrated complete loss of PTEN expression. All
      endometrioid carcinoma synchronous with PTEN-negative endometrial hyperplasia
      showed loss of PTEN expression. Alteration of PTEN expression was not correlated
      with histological grade or stage. Decreased immunoreactivity of p27 was found in
      48 cases (79%) of 61 endometrioid carcinoma, and 76% (36 cases) of them also
      showed loss or decrease of PTEN expression. Four of five uterine serous carcinoma
      revealed strong p27 immunoreactivity, all of which showed intense PTEN
      expression. A positive correlation between PTEN and p27 expression was
      statistically significant (Mantel-Haenszel chi2 test, P=0.001). Immunoreactivity
      of p27 was not related to histological grade and clinical stage. CONCLUSION:
      These results show that PTEN and p27 are differentially expressed in endometrioid
      type carcinoma compared with those of the serous type, and suggest that the
      cyclin-dependent kinase inhibitor, p27, is a downstream target of PTEN-dependent
      cell cycle arrest in endometrial carcinoma.

PMID- 12405912
TI  - Extrauterine placental site trophoblastic tumour in association with a
      lithopedion.
AB  - AIM: We describe an unusual case of extrauterine placental site trophoblastic
      tumour located in pouch of Douglas in association with a lithopedion. METHODS AND
      RESULTS: A 35-year-old female presented with acute abdomen and peritonitis
      following rectal perforation. The patient gave a history of 5 months amenorrhoea
      followed by vaginal bleeding 5 years prior to admission. At laparotomy, a
      lithopedion was found in pouch of Douglas with rectal perforation and
      peritonitis. The lithopedion was removed, rectal perforation was sutured and a
      colostomy was performed. The colostomy was closed later and tumour was seen in
      the colostomy wound as well as attached to the lithopedion removed previously.
      The patient presented with a repeated episode of rectal perforation and the
      tumour had spread to colon, small intestine, omentum, mesentery and right ovary.
      CONCLUSION: A high-grade malignant placental site trophoblastic tumour with
      aggressive clinical course occurred at an extrauterine site. It complicated
      calcified abdominal pregnancy and resulted in repeated rectal perforation and
      peritonitis.

PMID- 12405913
TI  - Malignant myopericytoma: expanding the spectrum of tumours with myopericytic
      differentiation.
AB  - AIMS: The spectrum of tumours showing myopericytic differentiation is
      increasingly being defined and includes lesions such as myofibroma and infantile
      haemangiopericytoma. Here we seek to describe for the first time and
      clinicopathologically characterize examples of malignant myopericytoma. METHODS
      AND RESULTS: Five cases of malignant myopericytoma were identified in the
      authors' consultation files. Immunostains were performed and clinical information
      was obtained. Tumours arose in three females and two males (median age 67 years,
      range 19-81 years) on the neck, arm, thigh and foot. One patient presented with
      disseminated metastases. One patient had a prior history of multiple benign
      myopericytomas in the same location. Four patients developed metastases and three
      died within 1 year. Tumours were composed of highly mitotic myoid-appearing ovoid
      to-spindle cells showing at least focally striking perivascular orientation
      resembling that seen in benign myopericytoma; three cases were focally fascicular
      and three showed thin-walled branching vessels. All tumours showed at least
      focally prominent positivity for smooth muscle actin. One case showed dot-like
      desmin positivity. CONCLUSIONS: In reporting examples of malignant myopericytoma,
      we further characterize and broaden the morphological spectrum of myopericytic
      neoplasms. Available data indicate that malignant myopericytomas are associated
      with aggressive clinical behaviour.

PMID- 12405914
TI  - ALK protein expression in rhabdomyosarcomas.
AB  - AIMS: The ALK p80 chimeric protein is thought to be up-regulated as a result of
      the t(2;5) as classically seen in anaplastic large cell lymphoma. However,
      rhabdomyosarcomas (in particular, the alveolar subtype) have also been noted to
      show expression of this protein. This study set out to examine ALK expression in
      a large number of rhabdomyosarcomas. METHODS AND RESULTS: Eighty-three cases of
      rhabdomyosarcomas and 16 cases of malignant mixed mullerian tumours with a
      rhabdomyosarcomatous component were retrieved from the archives of the Department
      of Anatomical Pathology for the period 1983-2001. The sections were stained with
      polyclonal ALK antibody. There were 52 male and 30 female patients. In one case,
      the gender of the patient was not indicated. The ages ranged from 1 week to 77
      years. The most common site was the head and neck region, followed by the pelvis
      and extremities. Thirty-one cases were of the alveolar subtype while 40 cases
      were embryonal. There were four mixed embryonal/alveolar, six pleomorphic and two
      unclassifiable rhabdomyosarcomas. Fourteen of the 31 (45%) alveolar
      rhabdomyosarcomas stained positively for the ALK protein, while only six of the
      40 embryonal (15%) cases showed positivity. One case each of the mixed
      embryonal/alveolar, pleomorphic and unclassified cases was also immunopositive.
      The rhabdomyosarcomatous component in the malignant mixed mullerian tumours was
      positive in four of the 16 cases. CONCLUSION: We conclude that a proportion of
      alveolar rhabdomyosarcomas (in particular) exhibit ALK protein expression.
      However, ALK expression is not restricted to this subtype. An extension of this
      study is to determine if this over-expression is as a result of the t(2;5)
      translocation.

PMID- 12405915
TI  - Malignant plasmacytosis mimicking erythrophagocytosis.

PMID- 12405916
TI  - Placental site nodule of the ovary.

PMID- 12405917
TI  - Iron-induced bronchial injury.

PMID- 12405918
TI  - Small solitary littoral cell angioma associated with splenic marginal zone
      lymphoma and villous lymphocyte leukaemia in a patient with hepatitis C
      infection.

PMID- 12405919
TI  - Extramedullary haematopoiesis in a hyalinized mammary fibroadenoma.

PMID- 12405923
TI  - Carcinoma in situ of the testis: frequency and relationship to invasive germ cell
      tumours in infertile men.

PMID- 12405921
TI  - Carcinoma in situ of the testis: frequency and relationship to invasive germ cell
      tumours in infertile men. N. E. Skakkebaek. Histopathology 1978; 2; 157-170.

PMID- 12405924
TI  - Ultrastructure of airways in children with asthma. E. Cutz, H. Levison, D. M.
      Cooper. Histopathology 1978; 2; 407-421.

PMID- 12405926
TI  - Ultrastructure of airways in children with asthma.

PMID- 12405927
TI  - Regional pattern of degeneration in Alzheimer's disease: neuronal loss and
      histopathological grading. A. Brun & E. Englund. Histopathology 1981; 5; 549-564.

PMID- 12405929
TI  - Regional pattern of degeneration in Alzheimer's disease: neuronal loss and
      histopathological grading.

PMID- 12405930
TI  - The grading of rectal cancer: historical perspectives and a multivariate analysis
      of 447 cases. J. R. Jass, W. S. Atkin, J.Cuzick, H. J. R. Bussey, B. C. Morson,
      J. M. A. Northover, I.P. Todd. Histopathology 1986; 10; 437-459.

PMID- 12405932
TI  - The grading of rectal cancer: historical perspectives and a multivariate analysis
      of 447 cases.

PMID- 12405933
TI  - Cytokeratin expression in smooth muscle and smooth muscle tumours. D. C. Brown,
      J. M. Theaker, P. M. Banks, K. C. Gatter & Mason D. Y. Histopathology 1987; 11;
      477-486.

PMID- 12405935
TI  - Cytokeratin expression in smooth muscle and smooth muscle tumours.

PMID- 12405936
TI  - Evaluation of nucleolar organizer region-associated proteins in breast
      malignancy. R. Smith & J. Crocker. Histopathology 1988; 12; 113-25.

PMID- 12405938
TI  - Evaluation of nucleolar organizer region-associated proteins in breast
      malignancy.

PMID- 12405939
TI  - A comparison of Ki67 immunostaining and nucleolar organiser region staining in
      non-Hodgkin's lymphoma. P. A. Hall, J. Crocker, A. Watts, A. G. Stansfeld.
      Histopathology 1988; 12; 373-381 & Detection of the Ki67 antigen in fixed and wax
      embedded sections with the monoclonal antibody MIB1.D. McCormick, H. Chong, C.
      Hobbs, C. Datta &P. A. Hall. Histopathology 1993; 22; 355-360.

PMID- 12405941
TI  - A comparison of nucleolar organizer region staining and Ki-67 immunostaining in
      non-Hodgkin's lymphoma.

PMID- 12405942
TI  - Anaplastic large cell Ki-1 lymphoma. Delineation of two morphological types. J.
      K. C. Chan, C. S. Ng, P. K. Hui, T. W. Leung, E. S. F. Lo, W. H. Lau, L. J.
      McGuire. Histopathology 1989; 15; 11-34.

PMID- 12405944
TI  - Anaplastic large cell Ki-1 lymphoma. Delineation of two morphological types.

PMID- 12405945
TI  - Pathological prognostic factors in breast cancer. I. The value of histological
      grade in breast cancer: experience from a large study with long-term follow-up.
      C. W. Elston & I. O. Ellis. Histopathology 1991; 19; 403-410.

PMID- 12405947
TI  - Pathological prognostic factors in breast cancer. I. The value of histological
      grade in breast cancer: experience from a large study with long-term follow-up.

PMID- 12405948
TI  - The assessment of proliferating cell nuclear antigen (PCNA) immunostaining in
      primary gastrointestinal lymphomas and its relationship to histological grade, S
      + G2 + M phase fraction (flow cytometric analysis) and prognosis. A. L. Woods, P.
      A. Hall, N. A. Shepherd, A. M. Hanby, N. H. Waseem, D. P. Lane & D. A. Levison.
      Histopathology 1991; 19; 21-27.

PMID- 12405950
TI  - The assessment of proliferating cell nuclear antigen (PCNA)immunostaining in
      primary gastrointestinal lymphomas and its relationship to histological grade, S
      + G2 + M phase fraction (flow cytometric analysis) and prognosis.

PMID- 12405951
TI  - Detection of the Ki-67 antigen in fixed and wax-embedded sections with the
      monoclonal antibody MIB1. D. McCormick H. Chong, C. Hobbs, C. Datta & P. A. Hall.
      Histopathology 1993; 22; 355-360.

PMID- 12405952
TI  - Detection of the Ki-67 antigen in fixed and wax-embedded sections with the
      monoclonal antibody MIB1.

PMID- 12405953
TI  - Microarray analysis suggests the involvement of proteasomes, lysosomes, and
      matrix metalloproteinases in the response of motor neurons to root avulsion.
AB  - We used microarray analysis of RNA expression from punch samples from ventral
      horn of spinal cord to identify alterations in gene expression in motor neurons 3
      days after proximal spinal root avulsion, a traumatic injury that results in the
      death of 80% of the motor neurons. This analysis identified the anticipated
      increases in expression of genes coding for proteins involved in the apoptosis
      cascades and abortive cell cycle re-entry, as well as decreases in expression of
      genes coding for proteins related to neuronal functional activity, including
      groups of genes related to energy metabolism, transporter proteins, ion channels,
      and receptors. It was also found that cathepsins, metalloproteinases, and
      proteasome-related protein products were highly up-regulated in motor neurons
      following axotomy. Each of these products represent pathways that have been
      implicated in other models of neuronal damage, but which have not previously been
      described as a response to axotomy.

PMID- 12405954
TI  - Brain-derived neurotrophic factor induces long-lasting Ca2+-activated K+ currents
      in rat visual cortex neurons.
AB  - Brain-derived neurotrophic factor (BDNF) increases postsynaptic intracellular
      Ca2+ and modulates synaptic transmission in various types of neurons. Ca2+
      activated K+ currents, opened mainly by intracellular Ca2+ elevation, contribute
      to hyperpolarization following action potentials and modulate synaptic
      transmission. We asked whether BDNF induces Ca2+-activated K+ currents by
      postsynaptic elevation of intracellular Ca2+ in acutely dissociated visual cortex
      neurons of rats. Currents were analysed using the nystatin-perforated patch clamp
      technique and imaging of intracellular Ca2+ mobilization with fura-2. At a
      holding potential of -50 mV, BDNF application (20 ng/mL) for 1-2 min induced an
      outward current (IBDNF-OUT; 80.0 +/- 29.0 pA) lasting for more than 90 min
      without attenuation in every neuron tested. K252a (200 nm), an inhibitor of Trk
      receptor tyrosine kinase, and U73122 (3 microm), a specific phospholipase C (PLC)
      gamma inhibitor, suppressed IBDNF-OUT completely. IBDNF-OUT was both
      charybdotoxin- (600 nm) and apamin- (300 nm) sensitive, suggesting that this
      current was carried by Ca2+-activated K+ channels. BAPTA-AM (150 microm)
      gradually suppressed IBDNF-OUT. Fura-2 imaging revealed that a brief application
      of BDNF elicited a long-lasting elevation of intracellular Ca2+. These results
      show that BDNF induces long-lasting Ca2+-activated K+ currents by sustained
      intracellular Ca2+ elevation in rat visual cortex neurons. While BDNF, likely
      acting through the Trk B receptor, was necessary for the induction of long
      lasting Ca2+-activated K+ currents via intracellular Ca2+ elevation, BDNF was not
      necessary for the maintenance of this current.

PMID- 12405955
TI  - Changes in Fos expression in the rat brain after unilateral lesions of the
      anterior thalamic nuclei.
AB  - Activity of the immediate early gene c-fos was compared across hemispheres in
      rats with unilateral anterior thalamic lesions. Fos protein was quantified after
      rats performed a spatial working memory test in the radial-arm maze, a task that
      is sensitive to bilateral lesions of the anterior thalamic nuclei. Unilateral
      anterior thalamic lesions produced evidence of a widespread hippocampal
      hypoactivity, as there were significant reductions in Fos counts in a range of
      regions within the ipsilateral hippocampal formation (rostral CA1, rostral
      dentate gyrus, 'dorsal' hippocampus, presubiculum and postsubiculum). A decrease
      in Fos levels was also found in the rostral and caudal retrosplenial cortex but
      not in the parahippocampal cortices or anterior cingulate cortices. The Fos
      changes seem most closely linked to sites that are also required for successful
      task performance, supporting the notion that the anterior thalamus, retrosplenial
      cortex and hippocampus form key components of an interdependent neuronal network
      involved in spatial mnemonic processing.

PMID- 12405956
TI  - A novel stereocilia defect in sensory hair cells of the deaf mouse mutant
      Tasmanian devil.
AB  - Stereocilia are specialized actin-filled, finger-like processes arrayed in rows
      of graded heights to form a crescent or W-shape on the apical surface of sensory
      hair cells. The stereocilia are deflected by the vibration of sound, which opens
      transduction channels and allows an influx of ions to depolarize the hair cell,
      in turn triggering synaptic activity. The specialized morphology and organization
      of the stereocilia bundle is crucial in the process of sensory transduction in
      the inner ear. However, we know little about the development of stereocilia in
      the mouse and few molecules that are involved in stereocilia maturation are
      known. We describe here a new mouse mutant with abnormal stereocilia development.
      The Tasmanian devil (tde) mouse mutation arose by insertional mutagenesis and has
      been mapped to the middle of chromosome 5. Homozygotes show head-tossing and
      circling and have raised thresholds for cochlear nerve responses to sound. The
      gross morphology of the inner ear was normal, but the stereocilia of cochlear and
      vestibular hair cells are abnormally thin, and they become progressively
      disorganized with increasing age. Ultimately, the hair cells die. This is the
      first report of a mutant showing thin stereocilia. The association of thin
      stereocilia with cochlear dysfunction emphasizes the critical role of stereocilia
      in auditory transduction, and the discovery of the Tasmanian devil mutant
      provides a resource for the identification of an essential molecule in hair cell
      function.

PMID- 12405957
TI  - Calcium-dependent acetylcholine release from Xenopus oocytes: simultaneous ionic
      currents and acetylcholine release recordings.
AB  - The fusion of synaptic vesicles with presynaptic membranes is controlled by a
      complex network of protein-protein and protein-lipid interactions. SNAP-25,
      syntaxin and synaptobrevin (SNARE complex) are thought to participate in the
      formation of the core of the membrane fusion machine but the molecular basis of
      SNARE interactions is not completely understood. Thus, it would be interesting to
      design experiments to test those relationships in a new model. Xenopus laevis
      oocytes are valuable tools for studying the molecular structure and function of
      ionic channels and neurotransmitter receptors. Here we show that SNARE proteins
      are present in native Xenopus oocytes and that those oocytes injected with
      acetylcholine and presynaptic plasma membranes extracted from the electric organ
      of Torpedo marmorata assume some of the functions of a cholinergic nerve
      terminal. Neurotransmitter release and macroscopic currents were recorded and
      analysed simultaneously in a single oocyte electrically depolarized:
      acetylcholine release was detected using a chemiluminiscent method and calcium
      entry was measured by exploiting the endogenous Ca2+-activated chloride current
      of the oocyte with a two-electrode voltage-clamp system. Neurotransmitter release
      was calcium- and voltage-dependent and partially reduced in the presence of
      several calcium channel blockers. Clostridial neurotoxins, both holotoxin and
      injected light-chain forms, also inhibited acetylcholine release. We also studied
      the role of the SNARE complex in synaptic transmission and membrane currents by
      using monoclonal antibodies against SNAP-25, syntaxin or VAMP/synaptobrevin. The
      use of antibodies against VAMP/synaptobrevin, SNAP-25 and syntaxin inhibited
      acetylcholine release, as did clostridial toxins. However, macroscopic currents
      were only modified either by syntaxin antibody or by Botulinium-C1 neurotoxin.
      This model constitutes a new approach for understanding the vesicle exocytosis
      processes.

PMID- 12405958
TI  - Dynamic patterns of BDNF expression in injured sensory neurons: differential
      modulation by NGF and NT-3.
AB  - It has been suggested that altered retrograde neurotrophin support contributes to
      the phenotypic switch observed in BDNF expression in injured sensory neurons.
      Thus, modulatory influences of NGF and NT-3 on BDNF expression in injured adult
      rat DRG neurons were examined using in situ hybridization and immunohistochemical
      approaches. Quantitative analysis reveals a biphasic response to sciatic nerve
      injury, whereby in the first day following injury, BDNF expression is up
      regulated in approximately 83% of injured neurons including all small neurons,
      and a larger pool of trkB expressing neurons than in intact. By 1 week and up to
      3 weeks later expression is still seen in approximately 66% of injured neurons,
      but the characteristic phenotypic switch in the subpopulations expressing BDNF
      occurs, whereby expression in the trkA population is reduced and expression in
      trkB- and in trkC-positive neurons is elevated. NGF infusion results in elevated
      levels of BDNF expression in both intact and injured trkA-positive neurons,
      accompanied by reduced trkB expression. NT-3 acts in an opposite fashion
      effecting a down-regulation in BDNF expression in intact neurons and
      preventing/reducing the injury-associated increases in BDNF expression in both
      trkC- and nontrkC-expressing subpopulations of injured neurons. These effects
      suggest NGF can regulate BDNF expression in trkA-expressing neurons regardless of
      the axonal state and that elevated levels of BDNF may contribute to the down
      regulation in trkB expression associated with these states. Furthermore, the
      findings demonstrate that NT-3 can act in an antagonistic fashion to NGF in the
      regulation of BDNF expression in intact neurons, and mitigate BDNF's expression
      in injured neurons.

PMID- 12405959
TI  - Caspase-mediated death of newly formed neurons in the adult rat dentate gyrus
      following status epilepticus.
AB  - A large proportion of cells that proliferate in the adult dentate gyrus under
      normal conditions or in response to brain insults exhibit only short-term
      survival. Here, we sought to determine which cell death pathways are involved in
      the degeneration of newly formed neurons in the rat dentate gyrus following 2 h
      of electrically induced status epilepticus. We investigated the role of three
      families of cysteine proteases, caspases, calpains, and cathepsins, which can all
      participate in apoptotic cell death. Status epilepticus increased the number of
      bromodeoxyuridine (BrdU)-positive proliferated cells in the subgranular zone of
      the dentate gyrus. At the time of maximum cell proliferation, immunohistochemical
      analyses revealed protein expression of active caspase-cleaved poly (ADP-ribose)
      polymerase (PARP) in approximately 66% of the BrdU-positive cells, while none of
      them expressed cathepsin B or the 150-kDa calpain-produced fodrin breakdown
      product. To evaluate the importance of cysteine proteases in regulating survival
      of the newly formed neurons, we administered intracerebroventricular infusions of
      a caspase inhibitor cocktail (zVAD-fmk, zDEVD-fmk and zLEHD-fmk) over a 2-week
      period, sufficient to allow for neuronal differentiation, starting 1 week after
      the epileptic insult. Increased numbers of cells double-labelled with BrdU and
      neuron-specific nuclear protein (NeuN) marker were detected in the subgranular
      zone and granule cell layer of the caspase inhibitor-treated rats. Our data
      indicate that caspase-mediated cell death pathways are active in progenitor cell
      progeny generated by status epilepticus and compromise survival during neuronal
      differentiation.

PMID- 12405960
TI  - GABA(A) receptor heterogeneity in histaminergic neurons.
AB  - Histaminergic neurons of the tuberomamillary nucleus display pacemaker
      properties; their firing rate is regulated according to behavioural state by
      gabaergic inhibition. Whole-cell recordings and single-cell RT-PCR from acutely
      isolated rat tuberomamillary neurons were used to characterize GABA -evoked
      currents and to correlate them with the expression pattern of 12 GABAA receptor
      subunits. We report differences in sensitivity to GABA and zinc as well as in the
      modulation of IPSC-decay times by zolpidem in histaminergic neurons expressing
      gamma-subunits at different levels. Immunocytochemistry and pharmacological
      analysis of whole-cell GABA-currents in these neurons revealed that all carry the
      gamma2-subunit protein and that all receptors contain at least one gamma-subunit.
      Neurons with different expression levels of gamma-subunits displayed a difference
      in cooperativity of GABA and zolpidem binding which we explain by the presence of
      one vs. two gamma-subunits in one receptor. Thus, we describe here native GABAA
      receptor function in relation to its stoichiometry.

PMID- 12405962
TI  - NMDA receptor-dependent CREB activation in survival of cerebellar granule cells
      during in vivo and in vitro development.
AB  - During both in vivo and in vitro development, cerebellar granule cells depend on
      the activity of the NMDA glutamate receptor subtype for survival and full
      differentiation. With the present results, we demonstrate that CREB activation,
      downstream of the NMDA receptor, is a necessary step to ensure survival of these
      neurons. The levels of CREB expression and activity increase progressively during
      the second week of postnatal cerebellar development and the phosphorylated form
      of CREB is localized selectively to cerebellar granule cells during the critical
      developmental stages examined. Chronically blocking the NMDA receptor through
      systemic administration of the competitive antagonist, CGP 39551, during the in
      vivo critical developmental period, between 7-11 postnatal days, results in
      increased apoptotic elimination of differentiating granule neurons in the
      cerebellum [Monti & Contestabile, Eur. J. Neurosci., 12, 3117-3123 (2000)]. We
      report here that this event is accompanied by a significant decrease of CREB
      phosphorylation in the cerebellum of treated rat pups. When cerebellar granule
      neurons are explanted and maintained in dissociated cultures, the levels of CREB
      phosphorylation increase with differentiation, similar to that which happens
      during in vivo development. When granule cells are kept in non-trophic
      conditions, their viability is affected and both CREB phosphorylation and
      transcriptional activity are decreased significantly. The neuronal viability and
      the deficiency of CREB activity, are both rescued by the pharmacological
      activation of the NMDA receptor. These results provide good circumstantial
      evidence for a functional link between the NMDA receptor and CREB activity in
      promoting neuronal survival during development.

PMID- 12405961
TI  - The putative role of vanilloid receptor-like protein-1 in mediating high
      threshold noxious heat-sensitivity in rat cultured primary sensory neurons.
AB  - High threshold noxious heat-activated currents and vanilloid receptor-like
      protein-1 expression were studied in rat cultured primary sensory neurons to find
      out the molecule(s) responsible for high threshold noxious heat-sensitivity. The
      average temperature threshold and amplitude of high threshold noxious heat
      activated currents were 51.6 +/- 0.13 degrees C and -2.0 +/- 0.1nA (at a holding
      potential of -60 mV), respectively. The current-voltage relationship of high
      threshold noxious heat-activated currents was linear at positive membrane
      potentials, while it showed a weak inward rectification at negative membrane
      potentials. The average reversal potential measured in control intracellular and
      extracellular solutions was 4.5 +/- 0.9 mV (n = 6). Ionic substitutions revealed
      that the high threshold noxious heat-activated current is a nonselective cationic
      current with calculated ionic permeabilities of Cs+ : Na+ : Ca2+ (1 : 1.3 : 4.5).
      Consecutive stimuli reduced the heat threshold from 52.2 +/- 1 to 48.4 +/- 1.4
      degrees C and then to 44 +/- 0.7 degrees C (n = 3). High threshold noxious heat
      activated currents could dose-dependently and reversibly be reduced by ruthenium
      red (100 nm-10 micro m) but not by capsazepine (10 micro m). The average longest
      diameter of high threshold noxious heat-sensitive neurons was 31.48 +/- 0.5 micro
      m (A = approximately 778 micro m2; n = 77). Twenty-three percent of the total
      neuronal population expressed vanilloid receptor-like protein-1. The average area
      of the vanilloid receptor-like protein-1-immunopositive cells was 1,696 +/- 65.3
      micro m2 (d = approximately 46 micro m). Vanilloid receptor-like protein-1
      expressing neurons did not express the vanilloid receptor 1. Comparison of our
      data with results obtained in vanilloid receptor-like protein-1-expressing non
      neuronal cells and previous immunohistochemical findings suggests that high
      threshold noxious heat-activated currents are produced by vanilloid receptor-like
      protein-1 and that high threshold heat-sensitive dorsal root ganglion neurons are
      the perikarya of type I noxious heat-sensitive fibers.

PMID- 12405963
TI  - EphB receptors influence growth of ephrin-B1-positive statoacoustic nerve fibers.
AB  - The Eph family of receptors and ligands has been implicated in a variety of
      developmental processes, including the provision of inhibitory guidance cues to
      developing nerve fibers. A unique property of the B class of receptors is that
      they are able to phosphorylate ephrin-B ligands, allowing for bi-directional, or
      reverse signalling. While most of the studies to date have focused on central
      nerve fibers, little is known about the role of Eph molecules in guiding nerve
      fibers of the peripheral nervous system. In the present study, ephrin-B1 was
      found to be highly expressed on developing peripheral nerve fibers including
      auditory and vestibular (statoacoustic) and dorsal root ganglion nerve fibers. In
      vitro assays revealed that EphB-Fc receptors inhibited further growth of
      statoacoustic nerve fibers. In contrast, EphA7-Fc and ephrin-B2-Fc did not
      prevent further growth of SAG. Together, these results suggest a role for EphB
      receptors in providing guidance signals to ephrin-B1-positive SAG nerve fibers.

PMID- 12405964
TI  - Mutation in hotfoot-4J mice results in retention of delta2 glutamate receptors in
      ER.
AB  - The orphan glutamate receptor delta2 is selectively expressed in Purkinje cells
      and plays a critical role in cerebellar function. Recently, the ataxia of hotfoot
      4J (ho-4J) mice was shown to be caused by a 170-amino acid deletion in the N
      terminal region of delta2 receptors. To understand delta2 receptor function, we
      characterized these mutant receptors (delta2ho) in Purkinje cells.
      Immunohistochemical staining showed that delta2ho receptors of the ho-4J
      homozygotes were abundantly expressed but localized to the Purkinje cell soma; in
      wild-type mice, delta2 receptors were predominantly present at distal dendrites
      of Purkinje cells. In addition, delta2ho receptors of the ho-4J mice were
      sensitive to endoglycosidase H, a finding suggesting that delta2ho receptors were
      not transported beyond the endoplasmic reticulum (ER) or cis-Golgi apparatus. To
      gain further insights into the mechanisms of this phenomenon, we characterized
      delta2ho receptors in transfected HEK293 cells. delta2ho receptors expressed in
      HEK293 cells were also sensitive to endoglycosidase H. Immunohistochemical
      staining showed that delta2ho receptors colocalized with proteins retained in the
      ER. Furthermore, delta2ho receptors were not labelled by membrane-impermeable
      biotinylation reagents. Coimmunoprecipitation assays showed that the
      intermolecular interaction of delta2ho receptors was significantly weaker than
      those of wild-type delta2 receptors, a finding suggesting that the ho-4J region
      is involved in oligomerization of delta2 receptors. Thus, delta2ho receptors were
      retained in the ER, probably by the quality control mechanism that detects
      unstable oligomers. We conclude that the absence of delta2 receptors on the cell
      surface by failed transport from the ER of Purkinje cells causes ataxia.

PMID- 12405965
TI  - Synaptic glutamate receptor clustering in mice lacking the SH3 and GK domains of
      SAP97.
AB  - Postsynaptic targeting of the Drosophila tumour suppressor discs-large (Dlg)
      critically depends on its SH3 and GK domains. Here, we asked whether these
      domains are also involved in subcellular targeting of the mammalian Dlg homolog
      SAP97 and its interacting partners in CNS cortical neurons by analysing a
      recently described mouse mutant lacking the SH3 and GK domains of SAP97. Both
      wildtype and truncated SAP97 were predominantly expressed in perinuclear regions,
      in a pattern suggesting association with the endoplasmic reticulum. Weaker
      immunoreactivity was found in neurites colocalizing with both dendritic and
      axonal markers. As SAP97 has been implicated in the early intracellular
      processing of the glutamate receptor GluR1, we studied biochemical maturation and
      subcellular localization of GluR1 in the mutants. Both the glycosylation pattern
      and synaptic clustering of GluR1 were indistinguishable from wildtype mice.
      Synaptic clustering of the guanylate kinase domain interacting protein GKAP was
      also intact. Our data demonstrate that truncation of the SH3 and GK domains of
      SAP97 in mice does neither change its subcellular distribution nor does it
      disrupt synaptic structure or protein clustering, as opposed to severe missorting
      of the respective mutant Dlg protein in Drosophila.

PMID- 12405966
TI  - Long-lasting enhancement of corticostriatal neurotransmission by taurine.
AB  - Taurine occurs at high concentrations in the forebrain and its distribution
      varies with (patho)physiological conditions; however, its role in neural function
      is poorly understood. We have now characterized its effects on corticostriatal
      synaptic transmission. Bath application of taurine (10 mm) to slices obtained
      from mice and rats exerted a biphasic action on corticostriatal field potentials.
      The fast and reversible inhibition by taurine was accompanied by a depolarization
      and conductance increase in medium spiny neurons and was sensitive to gamma
      aminobutyric acid (GABA)A and glycine receptor (GlyR) antagonists. A long-lasting
      enhancement (LLETAU) of field potentials was recorded after taurine withdrawal.
      The LLETAU was not prevented by N-methyl-d-aspartate (NMDA)- or by GABAA receptor
      antagonists, but was sensitive to the GlyR-antagonist strychnine and blocked by
      the competitive taurine uptake inhibitor guanidinoethylsulphonate (GES, 1 mm).
      GES at 10 mm evoked an enhancement of field potentials similar to LLETAU. LLETAU
      depended on protein kinase C activation as it was blocked by chelerythrine, but
      was unaffected by trifluoperazine, and thus independent of calmodulin. LLETAU was
      significantly smaller in juvenile than in mature rodents. Activation of GlyRs and
      the specific taurine transporter by taurine evoke a long-lasting enhancement of
      corticostriatal transmission.

PMID- 12405967
TI  - Differential induction and localization of mPer1 and mPer2 during advancing and
      delaying phase shifts.
AB  - The mechanism whereby brief light exposure resets the mammalian circadian clock
      in a phase dependent manner is not known, but is thought to involve Per gene
      expression. At the behavioural level, a light pulse produces phase delays in
      early subjective night, phase advances in late subjective night, and no phase
      shifts in mid-subjective night or subjective day. To understand the relationship
      between Per gene activity and behavioural phase shifts, we examined light-induced
      mPer1 and mPer2 expression in the suprachiasmatic nucleus (SCN) of the mouse, in
      the subjective night, with a view to understanding SCN heterogeneity. In the VIP
      containing region of the SCN (termed 'core'), light-induced mPer1 expression
      occurs at all times of the subjective night, while mPer2 induction is seen only
      in early subjective night. In the remaining regions of the SCN (termed 'shell'),
      a phase delaying light pulse produces no mPer1 but significant mPer2 expression,
      while a phase advancing light pulse produces no mPer2 but substantial mPer1
      induction. Moreover, following a light pulse during mid-subjective night, neither
      mPer1 nor mPer2 are induced in the shell. The results reveal that behavioural
      phase shifts occur only when light-induced Per gene expression spreads from the
      core to the shell SCN, with mPer1 expression in shell corresponding to phase
      advances, and mPer2 corresponding to phase delays. The results indicate that the
      time course and the localization of light-induced Per gene expression in SCN
      reveals important aspects of intra-SCN communication.

PMID- 12405968
TI  - Effect of melatonin administration on qPer2, qPer3, and qClock gene expression in
      the suprachiasmatic nucleus of Japanese quail.
AB  - Temporal changes of mRNA expression of three clock genes, qPer2, qPer3 and
      qClock, were studied in the suprachiasmatic nucleus (SCN) of Japanese quail under
      different light conditions, as well as under the condition of continuous
      melatonin. In addition, the expression of melatonin receptor genes, Mel1a and
      Mel1c, in the SCN were also examined. The expression of qPer2 mRNA showed robust
      oscillation during both light and dark (LD) 12:12 cycles and under constant dark
      conditions (DD), but did not exhibit circadian rhythmicity in constant light
      conditions (LL), instead being expressed at a consistently high level. Expression
      of qPer3 also showed robust oscillation under both LD and DD conditions. Unlike
      qPer2 however, qPer3 mRNA expression remained rhythmic under LL conditions.
      Contrary to the findings on the other clock genes, no remarkable rhythmicity was
      detectable in either light condition. Both Mel1a and Mel1c mRNAs were detected in
      the SCN, however, Mel1a mRNA levels were higher than Mel1c and showed daily
      rhythmicity. Although implantation of melatonin tubes caused constant high levels
      of plasma melatonin and consequently masked the endogenous daily melatonin
      rhythm, no significant differences in the expression pattern of any of the three
      clock genes were observed between birds with and without constant melatonin. In
      addition, a single injection of melatonin did not affect mRNA expression of these
      clock genes. These results suggest that melatonin does not affect transcription
      of clock genes, but may act on the mechanism of synchronization among SCN
      oscillatory cells.

PMID- 12405969
TI  - Inhibition of tonic spinal glutamatergic activity induces antinociception in the
      rat.
AB  - Inhibition of tonic activity in spino-supraspinal projection neurons induces
      heterosegmental antinociception that is mediated by opioid receptors in nucleus
      accumbens. To investigate the origin of this tonic activity, we evaluated the
      ability of inhibiting neurotransmission in the spinal cord to produce
      heterosegmental antinociception in the trigeminal nociceptive jaw-opening reflex
      (JOR) in the rat. Spinal intrathecal administration of calcium channel blockers
      attenuated the JOR, suggesting that the tonic spinal activity depends on synaptic
      input. To identify the excitatory neurotransmitter receptors involved, selective
      antagonists for AMPA/kainate, mGluR1, NMDA or NK1 receptors were administered
      intrathecally to the spinal cord. The AMPA/kainate and mGluR1 receptor
      antagonists, but not the NMDA or NK1 receptor antagonists, induced
      antinociception, which was antagonized by intra-accumbens administration of the
      selective micro -opioid receptor antagonist CTOP. Thus, inhibition of tonic
      spinal glutamatergic activity resulted in supraspinally mediated antinociception.
      As this antinociception occurred in the absence of interventions that would
      produce a facilitated nociceptive state, this tonic glutamatergic activity is
      important in setting nociceptive threshold.

PMID- 12405970
TI  - Heading encoding in the macaque ventral intraparietal area (VIP).
AB  - We recorded neuronal responses to optic flow stimuli in the ventral intraparietal
      area (VIP) of two awake macaque monkeys. According to previous studies on optic
      flow responses in monkey extrastriate cortex we used different stimulus classes:
      frontoparallel motion, radial stimuli (expansion and contraction) and rotational
      stimuli (clockwise and counter-clockwise). Seventy-five percent of the cells
      showed statistically significant responses to one or more of these optic flow
      stimuli. Shifting the location of the singularity of the optic flow stimuli
      within the visual field led to a response modulation in almost all cases. For the
      majority of neurons, this modulatory influence could be approximated in a
      statistically significant manner by a two-dimensional linear regression. Gradient
      directions, derived from the regression parameters and indicating the direction
      of the steepest increase in the responses, were uniformly distributed. At the
      population level, an unbiased average response for the stimuli with different
      focus locations was observed. By applying a population code, termed 'isofrequency
      encoding', we demonstrate the capability of the recorded neuronal ensemble to
      retrieve the focus location from its population discharge. Responses to expansion
      and contraction stimuli cannot be predicted based on quantitative data on a
      neuron's frontoparallel preferred stimulus direction and the location and size of
      its receptive field. These results, taken together with data on polymodal motion
      responses in this area, suggest an involvement of area VIP in the analysis and
      the encoding of heading.

PMID- 12405971
TI  - Visual-vestibular interactive responses in the macaque ventral intraparietal area
      (VIP).
AB  - Self-motion detection requires the interaction of a number of sensory systems for
      correct perceptual interpretation of a given movement and an eventual motor
      response. Parietal cortical areas are thought to play an important role in this
      function, and we have thus studied the encoding of multimodal signals and their
      spatiotemporal interactions in the ventral intraparietal area of macaque monkeys.
      Thereby, we have identified for the first time the presence of vestibular sensory
      input to this area and described its interaction with somatosensory and visual
      signals, via extracellular single-cell recordings in awake head-fixed animals.
      Visual responses were driven by large field stimuli that simulated either
      backward or forward self-motion (contraction or expansion stimuli, respectively),
      or movement in the frontoparallel plane (visual increments moving simultaneously
      in the same direction). While the dominant sensory modality in most neurons was
      visual, about one third of all recorded neurons responded to horizontal rotation.
      These vestibular responses were typically in phase with head velocity, but in
      some cases they could signal acceleration or even showed integration to position.
      The associated visual responses were always codirectional with the vestibular on
      direction, i.e. noncomplementary. Somatosensory responses were in register with
      the visual preferred direction, either in the same or in the opposite direction,
      thus signalling translation or rotation in the horizontal plane. These results,
      taken together with data on responses to optic flow stimuli obtained in a
      parallel study, strongly suggest an involvement of area VIP in the analysis and
      the encoding of self-motion.

PMID- 12405972
TI  - Development of two transmitter release components during the critical period for
      imprinting in the chick IMHV.
AB  - Transmitter release at an excitatory synapse has two components, fast synchronous
      and slow asynchronous transmitter release. Using the whole cell recording
      technique, we investigated the developmental properties of neurotransmitter
      release, which is composed of the two components in the intermediate and medial
      part of the hyperstriatum ventral (IMHV) of chicks during the critical period for
      imprinting. Analysis of the paired-pulse responses revealed that the depression
      of the excitatory postsynaptic currents (EPSCs), driven mainly by fast
      synchronous release, was frequently observed in P0-1 chicks but not in those at
      P5-8. The spontaneous excitatory postsynaptic currents (sEPSCs) after the paired
      pulse stimulation, which were thought to be driven by asynchronous transmitter
      releases, were observed more frequently in P0-1 chicks than P5-8 chicks.
      Furthermore, examination of Ca2+ dependency in the evoked EPSCs showed that the
      amplitudes in P5-8 chicks were more sensitive to reduction of the extracellular
      Ca2+ concentration than younger chicks. Considering that the Ca2+ dependency of
      EPSCs is defined by both Ca2+ sensitivity and the proportion of each type of
      release machineries at the release site, these results indicate that the ratio of
      fast synchronous to slow asynchronous transmitter release machinery changed
      during the critical period. These changes may play critical roles in the capacity
      of the avian brain to consolidate novel experience in the immediate period after
      hatching.

PMID- 12405973
TI  - Impaired acquisition in the water maze and hippocampal long-term potentiation
      after chronic prenatal ethanol exposure in the guinea-pig.
AB  - In the hippocampus, the CA1 region is selectively vulnerable to the effects of
      chronic prenatal ethanol exposure. In the guinea-pig, the number of CA1 pyramidal
      cells is decreased after chronic prenatal ethanol exposure. We tested the
      hypotheses that chronic prenatal ethanol exposure (through maternal ethanol
      ingestion) results in impairments in spatial learning and short- and long-term
      plasticity in the CA1 region of the postnatal guinea-pig hippocampus. Timed,
      pregnant guinea-pigs were treated with ethanol (4 g/kg maternal body weight/day),
      isocaloric sucrose/pair-feeding, or water throughout gestation. Offspring were
      studied between postnatal days 40 and 80. In the Morris water maze, animals
      exposed to ethanol prenatally showed slower acquisition of an escape response to
      a hidden platform over 5 days of training. The amplitude of the field excitatory
      postsynaptic potential in the CA1 region in response to contralateral CA3
      stimulation was decreased in offspring exposed to ethanol prenatally. Two forms
      of short-term plasticity (paired-pulse and frequency facilitation) were
      unaffected by chronic prenatal ethanol exposure. Long-term potentiation (LTP) in
      response to high-frequency CA3 stimulation was induced reliably and maintained
      over 60 min in isocaloric-sucrose and water control animals. However, LTP failed
      to be induced in the CA1 area of the hippocampus in prenatal ethanol-exposed
      offspring. These data show that chronic prenatal ethanol exposure, through
      maternal ethanol administration, impairs spatial performance and LTP in CA1
      neurons. Hippocampal dysfunction could contribute importantly to the cognitive
      and behavioural deficits resulting from chronic prenatal ethanol exposure.

PMID- 12405974
TI  - Substantia nigra pars reticulata neurons code initiation of a serial pattern:
      implications for natural action sequences and sequential disorders.
AB  - Sequences of movements are initiated abnormally in neurological disorders
      involving basal ganglia dysfunction, such as Parkinson's disease or Tourette's
      syndrome. The substantia nigra pars reticulata (SNpr) is one of the two primary
      output structures of the basal ganglia. However, little is known about how
      substantia nigra mediates the initiation of normal movement sequences. We studied
      its role in coding initiation of a sequentially stereotyped but natural movement
      sequence by recording neuronal activity in SNpr during behavioural performance of
      'syntactic grooming chains'. These are rule-governed sequences of up to 25
      grooming movements emitted in four predictable (syntactic) phases, which occur
      spontaneously during grooming behaviour by rats and other rodents. Our results
      show that neuronal activation in central SNpr codes the onset of this entire rule
      governed sequential pattern of grooming actions, not elemental grooming
      movements. We conclude that the context of sequential pattern may be more
      important than the elemental motor parameters in determining SNpr neuronal
      activation.

PMID- 12405975
TI  - The roles of the cerebellum and basal ganglia in timing and error prediction.
AB  - Recent evidence that the cerebellum and the basal ganglia are activated during
      the performance of cognitive and attention tasks challenges the prevailing view
      of their primary function in motor control. The specific roles of the basal
      ganglia and the cerebellum in cognition, however, have been difficult to
      identify. At least three functional hypotheses regarding their roles have been
      proposed. The first hypothesis suggests that their main function is to switch
      attentional set. The second hypothesis states that they provide error signals
      regarding stimuli or rewards. The third hypothesis is that they operate as an
      internal timing system, providing a precise representation of temporal
      information. Using functional magnetic resonance imaging, we tested these three
      hypotheses using a task-switching experiment with a 2 x 2 factorial design
      varying timing (random relative to fixed) and task order (unpredictable relative
      to predictable). This design allowed us to test whether switching between tasks,
      timing irregularity and/or task order unpredictability activate the basal ganglia
      and/or the cerebellum. We show that the cerebellum is primarily activated with
      timing irregularity while the anterior striatum is activated with task order
      unpredictability, supporting their distinctive roles in two forms of
      readjustment. Task order unpredictability alone, independent of reward delivery,
      is sufficient to induce striatal activation. In addition, activation of the
      cerebellum and basal ganglia were not specific to switching attention because
      these regions were both activated during switching between tasks and during the
      simultaneous maintenance of two tasks without switching between them.

PMID- 12405976
TI  - Differential expression of c-fos in subtypes of GABAergic cells following sensory
      stimulation in the cat primary visual cortex.
AB  - Recent immunocytochemical stainings on cat visual cortex, visually stimulated for
      1 h, showed a strong induction of Fos expression in cortical neurons. We
      initiated immunocytochemical double staining experiments with different
      cytochemical markers to investigate the neurochemical and morphological character
      of these activated neurons showing Fos induction after sensory stimulation.
      Double staining with Fos and glutamic acid decarboxylase (GAD) demonstrated the
      presence of Fos in the nuclei of GABAergic neurons of the primary visual cortex.
      To further subdivide this Fos/GABAergic cell population we investigated whether
      Fos colocalized with parvalbumin, calbindin or calretinin. Colocalization of Fos
      with these calcium-binding proteins delineated distinct neuronal subclasses of
      Fos-immunoreactive neurons in supra- and infragranular layers of cat area 17.
      Quantitative analysis of the proportion of immunoreactive local circuit neurons
      revealed that 35% of the GABAergic neurons showed Fos induction in supragranular
      layers, whereas in infragranular layers a mere 10% of the GABAergic cells
      revealed Fos expression. Fos coexisted in about 24% of the calbindin
      immunopositive cells within supra- and infragranular layers, but only a minority
      of the parvalbumin and the calretinin neuronal subgroups were immunopositive for
      Fos in the corresponding layers of area 17. These findings suggest that visual
      stimulation induces Fos expression in distinct subsets of inhibitory neurons in
      cat primary visual cortex.

PMID- 12405977
TI  - Bilateral parieto-frontal network for verbal working memory: an interference
      approach using repetitive transcranial magnetic stimulation (rTMS).
AB  - Verbal working memory has been attributed to a left-dominant neuronal network,
      including parietal, temporal and prefrontal cortical areas. The current study was
      designed to evaluate the contribution of these brain regions to verbal working
      memory processes and to assess possible hemispheric asymmetry. The effect of
      repetitive transcranial stimulation (rTMS) on performance in a verbal working
      memory task both during, and after an rTMS train (110% of individual motor
      threshold, 4 Hz) over nine different scalp locations was studied [bilateral
      middle frontal gyrus (MFG), bilateral supramarginal gyrus (SMG), bilateral
      inferior parietal cortex (IP) and three different midline control sites].
      Significant performance deterioration was observed during rTMS over the left and
      right MFG and left and right IP. There was no consistent interference effect
      across subjects over the left or right SMG and the three different midline
      control sites. The interference effect with the given stimulation parameters did
      not last beyond the rTMS train itself. The data provide evidence for a
      symmetrical, bilateral parieto-frontal verbal working memory network. The data
      are discussed with respect to the competing ideas of a parieto-frontal central
      executive network vs. a network that processes the inherent semantic and object
      features of the visually presented verbal stimuli in parallel.

PMID- 12405978
TI  - Expression and regulation of interleukin-10 and interleukin-10 receptor in rat
      astroglial and microglial cells.
AB  - Activated glial cells crucially contribute to brain inflammatory responses.
      Interleukin-10 (IL-10) is an important modulator of glial cell responses in the
      brain. In the present study we describe the expression of IL-10 and the IL-10
      receptor (IL-10R1) in primary cocultures of rat microglial and astroglial cells.
      Using quantitative RT-PCR and ELISA, we show that IL-10 mRNA expression and
      subsequent IL-10 secretion is time-dependently induced by lipopolysaccharide
      (LPS). IL-10R1, however, is constitutively expressed in glial cell cocultures, as
      shown by RT-PCR and immunocytochemistry. Radioligand binding studies using 125I
      IL-10 reveal that rat glial cells express a single binding site with an apparent
      affinity of approximately 600 pm for human IL-10. Observations in enriched
      cultures of either microglial or astroglial cells indicate that both cell types
      express IL-10 mRNA and are capable of secreting IL-10. Both cell types also
      express IL-10R1 mRNA and protein. However, in glial cell cocultures
      immunoreactive IL-10R1 protein is predominantly observed in astrocytes,
      suggesting that microglial expression of IL-10R1 in cocultures is suppressed by
      astrocytes. In addition, exogenous IL-10 is highly potent in down-regulating LPS
      induced IL-1beta and IL-10 mRNA, and, at a higher dose, IL-10R1 mRNA in untreated
      and LPS-treated cultures, suggesting that IL-10 autoregulates its expression and
      inhibits that of IL-1beta at the transcriptional level. Together the findings
      support the concept that IL-10, produced by activated microglial and astroglial
      cells, modulates glia-mediated inflammatory responses through high-affinity IL-10
      receptors via paracrine and autocrine interactions.

PMID- 12405979
TI  - Adaptive loss of ultraviolet-sensitive/violet-sensitive (UVS/VS) cone opsin in
      the blind mole rat (Spalax ehrenbergi).
AB  - In previous studies, fully functional rod and long-wavelength-sensitive (LWS)
      cone photopigments have been isolated from the eye of the subterranean blind mole
      rat (Spalax ehrenbergi superspecies). Spalax possesses subcutaneous atrophied
      eyes and lacks any ability to respond to visual images. By contrast this animal
      retains the ability to entrain circadian rhythms of locomotor behaviour to
      environmental light cues. As this is the only known function of the eye, the rod
      and LWS photopigments are thought to mediate this response. Most mammals are
      dichromats possessing, in addition to a single rod photopigment, two classes of
      cone photopigment, LWS and ultraviolet-sensitive/violet-sensitive (UVS/VS) with
      differing spectral sensitivities which mediate colour vision. In this paper we
      explore whether Spalax is a dichromat and has the potential to use colour
      discrimination for photoentrainment. Using immunocytochemistry and molecular
      approaches we demonstrate that Spalax is a LWS monochromat. Spalax lacks a
      functional UVS/VS cone photopigment due to the accumulation of several
      deleterious mutational changes that have rendered the gene nonfunctional. Using
      phylogenetic analysis we show that the loss of this class of photoreceptor is
      likely to have arisen from the visual ecology of this species, and is not an
      artefact of having an ancestor which lacked a functional UVS/VS cone
      photopigment. We conclude that colour discrimination is not a prerequisite for
      photoentrainment in this species.

PMID- 12405980
TI  - Indirect projections from the suprachiasmatic nucleus to the ventrolateral
      preoptic nucleus: a dual tract-tracing study in rat.
AB  - The suprachiasmatic nucleus (SCN) contains a master clock for most circadian
      rhythms in mammals, including daily sleep-wake cycles. The ventrolateral preoptic
      nucleus (VLPO) plays a key role in sleep generation and, as such, might be an
      important target of the SCN circadian signal. However, direct SCN projections to
      the VLPO are limited, suggesting that most of the SCN output to the VLPO might be
      conveyed indirectly. We examined this possibility by microinjecting selected
      known major targets of SCN efferents with biotinylated dextran-amine and/or
      cholera toxin B subunit, followed by analyses of retrograde labelling in the SCN
      and anterograde labelling in the VLPO. Retrograde labelling results confirmed
      that the medial preoptic area, subparaventricular zone, dorsomedial hypothalamic
      nucleus and posterior hypothalamic area all received projections from the SCN;
      these projections arose predominantly from the shell, as opposed to the core, of
      the SCN. Anterograde labelling results indicated that these same nuclei also
      projected to the VLPO, mainly its medial and ventral aspects. Comparison of the
      results of injections of similar sizes across different target groups indicated
      that the rostral part of the medial preoptic area and the caudal part of the
      dorsomedial hypothalamic nucleus were particularly noteworthy for the abundance
      of both SCN source neurons and efferent fibres and terminals in the VLPO. These
      results suggest that the SCN might provide indirect input to the VLPO via the
      medial preoptic area and the dorsomedial hypothalamic nucleus, and that these
      indirect neuronal pathways might play a major role in circadian control of sleep
      wake cycles.

PMID- 12405981
TI  - Characterization of large conductance Ca2+-activated K+ channels in cerebellar
      Purkinje neurons.
AB  - We investigated the role of large conductance, calcium-activated potassium
      channels (BK channels) in regulation of the excitability of cerebellar Purkinje
      neurons. Block of BK channels by iberiotoxin reduced the afterhyperpolarization
      of spontaneous action potentials in Purkinje neurons in acutely prepared
      cerebellar slices. To establish the conditions required for activation of BK
      channels in Purkinje neurons, the dependence of BK channel open probability on
      calcium concentration and membrane voltage were investigated in excised patches
      from soma of acutely prepared Purkinje cells. Single channel currents were
      studied under conditions designed to select for potassium currents and in which
      voltage-activated currents were largely inactivated. Micromolar calcium
      concentrations activated channels with a mean single channel conductance of 266
      pS. BK channels were activated by both calcium and membrane depolarization, and
      showed no sign of inactivation. At a given calcium concentration, depolarization
      over a 60-mV range increased the mean open probability (P(O)) from < 0.1 to >
      0.8. Increasing the calcium concentration shifted the voltage required for half
      maximal activation to more hyperpolarized potentials. The apparent affinity of
      the channels for calcium increased with depolarization. At -60 mV the apparent
      affinity was approximately 35 micro m decreasing to approximately 3 micro M at
      +40 mV. These results suggest that BK channels are unlikely to be activated at
      resting membrane potentials and calcium concentrations. We tested the hypothesis
      that Purkinje cell BK channels may be activated by calcium entry during
      individual action potentials. Significant BK channel activation could be detected
      when brief action potential-like depolarizations were applied to patches under
      conditions in which the sole source of calcium was flux across the plasma
      membrane via the endogenous voltage-gated calcium channels. It is proposed that
      BK channels regulate the excitability of Purkinje cells by contributing to
      afterhyperpolarizations and perhaps by shaping individual action potentials.

PMID- 12405982
TI  - Amygdala norepinephrine levels after training predict inhibitory avoidance
      retention performance in rats.
AB  - Previous findings indicate that footshock and several drugs that modulate memory
      consolidation alter norepinephrine (noradrenaline) release in the amygdala, as
      assessed by in vivo microdialysis and high-performance liquid chromatography.
      Such findings suggest that norepinephrine release in the amygdala may be critical
      for regulating memory consolidation. The present study was the first to examine
      the relationship between norepinephrine release in the amygdala assessed after
      inhibitory avoidance training and 24-h retention performance within individual
      animals. Norepinephrine levels increased to > 300% of pretraining baseline 30 min
      after training and remained elevated for 2 h. In individual rats, the increase in
      norepinephrine levels after training correlated highly with 24-h retention
      performance. These findings indicate that the degree of activation of the
      noradrenergic system within the amygdala in response to a novel, emotionally
      arousing experience predicts the extent of long-term memory for that experience.

PMID- 12405983
TI  - Cellular architecture of the nucleus reuniens thalami and its putative
      aspartatergic/glutamatergic projection to the hippocampus and medial septum in
      the rat.
AB  - Little is known about the neurochemical features of the nucleus reuniens thalami
      (RE). In the present study, immunocytochemical experiments were performed to
      characterize the expression pattern of certain neurochemical markers, e.g. the
      calcium-binding proteins calbindin and calretinin and several neuropeptides.
      Colocalization studies revealed that half of the calbindin-positive cells express
      calretinin, and numerous calretinin-immunoreactive neurons contain calbindin. In
      contrast, immunolabelling for neuropeptides did not reveal cell bodies in the RE.
      The RE establishes widespread connections with several limbic structures. To
      correlate these projection patterns with the neurochemical characteristics of RE
      neurons, the retrograde tracer [3H]D-aspartate, which is selectively taken up by
      high affinity uptake sites that use glutamate as neurotransmitter, and the
      nonselective retrograde tracer wheatgerm agglutinin-conjugated colloidal gold was
      injected into the stratum lacunosum moleculare of the hippocampal CA1 subfield
      and into the medial septum. The results provide direct anatomical demonstration
      of aspartatergic/glutamatergic projection from the RE to the hippocampus and to
      the medial septum. Nearly all of the projecting neurons proved to be calbindin
      immunopositive and many of them expressed calretinin. Both retrograde labelling
      techniques revealed that neurons projecting to the hippocampus were located in
      clusters in the dorsolateral part of the RE, whereas neurons projecting to the
      medial septum were mainly distributed in the ventromedial portion of the nucleus,
      indicating that different cell populations project to these limbic areas. These
      results suggest that neurons in the RE are heterogeneous and contribute to the
      excitatory innervation of the septo-hippocampal system.

PMID- 12405984
TI  - Evidence for a direct projection from the paraventricular nucleus of the
      hypothalamus to putative serotoninergic neurons of the nucleus
      paragigantocellularis involved in the control of erection in rats.
AB  - In the male rat, serotoninergic neurons of the ventrolateral medulla send direct
      projections onto spinal preganglionic neurons that innervate the penis. The role
      of the paraventricular nucleus of the hypothalamus in the control of penile
      erection is well recognized. Our aim was to demonstrate anatomical relation
      between paraventricular neurons and medullary serotoninergic neurons innervating
      the penis. In adult male rats, stereotaxic iontophoretic injections of Phaseolus
      vulgaris leuco-agglutinin were performed in the paraventricular nucleus. Neurons
      in the ventrolateral medulla were retrogradely labelled using transneuronal
      retrograde transport of pseudorabies virus injected in the corpus cavernosum.
      Sections of the ventro-lateral medulla were processed for double
      immunofluorescence to reveal both Phaseolus vulgaris leuco-agglutinin and
      pseudorabies virus using specific antibodies. Sections were also processed for
      the simultaneous detection of pseudorabies virus and serotonin. Pseudorabies
      virus-infected neurons in the ventrolateral medulla were present in the nucleus
      paragigantocellularis, reticular formation of the medulla, raphe pallidus and
      raphe magnus. In the nucleus paragigantocellularis, all pseudorabies virus
      infected-neurons were immunoreactive for serotonin. Some of them received
      Phaseolus vulgaris leuco-agglutinin-labelled varicose fibres that ran along the
      soma of pseudorabies virus-infected neurons. Confocal microscopy suggested the
      presence of several close appositions between them, which were demonstrated using
      three-dimensional reconstruction of serial optical sections. Our results show
      that paraventricular neurons send direct projections in the nucleus
      paragigantocellularis onto neurons that innervate the penis. They suggest a
      possible role of the paraventricular nucleus in penile erection through the
      control of descending serotoninergic raphe-spinal neurons. The neurotransmitter
      used in this pathway remains to be determined.

PMID- 12405985
TI  - The postnatal reorganization of primary afferent input and dorsal horn cell
      receptive fields in the rat spinal cord is an activity-dependent process.
AB  - The dorsal horn of the spinal cord in the newborn rat is characterized by large
      cutaneous mechanoreceptive fields, a predominance of A-fibre synaptic inputs and
      diffuse primary afferent A-fibre projections, all of which are gradually reduced
      and refined over the first postnatal weeks. This may be partly responsible for
      the reduction in cutaneous flexion reflex sensitivity of rats over the postnatal
      period. Here we show that chronic, local exposure of the dorsal horn of the
      lumbar spinal cord to the NMDA antagonist MK801 from birth prevents the normal
      functional and structural reorganization of A-fibre connections. Dorsal horn
      cells in spinal MK801-treated animals, investigated at eight weeks of age by in
      vivo electrophysiological recording, had significantly larger cutaneous
      mechanoreceptive fields and greater A-fibre evoked responses than vehicle
      controls. C-fibre evoked responses were unaffected. Chronic MK801 also prevented
      the normal structural reorganization of A-fibre terminals in the spinal cord. The
      postnatal withdrawal of superficially projecting A-fibre primary afferents to
      deeper laminae did not occur in treated animals although C-fibre afferent
      terminals and cell density in the dorsal horn were apparently unaffected. Spinal
      MK801-treated animals also had significantly reduced behavioural reflex
      thresholds to mechanical stimulation of the hindpaw compared to naive and vehicle
      treated animals, whereas noxious heat thresholds remained unaffected. The results
      indicate that the normal postnatal structural and functional development of A
      fibre sensory connectivity within the spinal cord is an activity-dependent
      process requiring NMDA receptor activation.

PMID- 12405986
TI  - Stimulation of cortical acetylcholine release following blockade of ionotropic
      glutamate receptors in nucleus accumbens.
AB  - In vivo microdialysis techniques were used to determine the ability of glutamate
      receptors within the nucleus accumbens to trans-synaptically modulate the basal
      forebrain cortical cholinergic system. Rats were implanted with a dialysis probe
      in the medial prefrontal cortex to measure changes in cortical acetylcholine
      efflux and in the ipsilateral nucleus accumbens to locally manipulate glutamate
      receptor activity. Intra-accumbens perfusion of the broad spectrum ionotropic
      glutamate receptor antagonist kynurentate (1.0, 5.0 mm) led to a dose-dependent
      increase (maximum of 200%) in cortical acetylcholine efflux. This stimulated
      efflux was reproduced with the intra-accumbens perfusion of the AMPA/kainate
      antagonist DNQX (0.1, 0.25, 2.5 mm; maximum increase of 200%) or the NMDA
      antagonist D-CPP (10.0, 100.0, 200 micro M; maximum increase of 400%). These
      results reveal a significant glutamatergic tone within the accumbens of awake
      rats and support the hypothesis that accumbens efferents to basal forebrain
      modulate the excitability of the basal forebrain cortical cholinergic system.

PMID- 12405987
TI  - Passive avoidance training enhances cell proliferation in 1-day-old chicks.
AB  - One-day-old domestic chicks were injected i.p. with bromodeoxyuridine (BrdU)
      before training on a one-trial passive avoidance task where the aversive
      experience was a bead coated with a bitter tasting substance, methyl anthranilate
      (MeA). Animals were tested 24 h later; those avoiding (if MeA-trained) or pecking
      if water (W)-trained (which they peck appetitively), along with a group of
      untrained naive chicks, were used to determine cell proliferation either 24 h or
      9 days post BrdU injection. In all three groups, BrdU positive cells were
      identified sparsely throughout the forebrain but labelling was pronounced around
      ventricular zone (VZ) surfaces at both 24 h and 9 days post-BrdU-injection.
      Double immunolabelling with neuronal specific antibodies, to either NeuN, or beta
      tubulin III, confirmed that most BrdU labelled cells appeared to be neurons.
      Unbiased stereological analysis of labelled cells in selected forebrain areas 24
      h post BrdU injection showed a significant MeA-training induced increase in
      labelled cells in both the dorsal VZ surface bordering the intermediate and
      medial hyperstriatum ventrale (IMHV) and the tuberculum olfactorium (TO). By 9
      days post-BrdU-injection, there was a significantly greater number of BrdU
      labelled cells in MeA-trained birds within the IMHV, lobus parolfactorius (LPO)
      and TO. These results demonstrate that avoidance training in 1-day-old chicks has
      a marked effect on cell proliferation, in the LPO and IMHV, regions of the chick
      previously identified as a key loci of memory formation, and in a second region
      (TO), which has olfactory functions, but has not been previously investigated in
      relation to avoidance learning.

PMID- 12405988
TI  - Astrocytes enhance lipopolysaccharide-induced nitric oxide production by
      microglial cells.
AB  - Several stimuli result in glial activation and induce nitric oxide (NO)
      production in microglial and astroglial cells. The bacterial endotoxin
      lipopolysaccharide (LPS) has been widely used to achieve glial activation in
      vitro, and several studies show that both microglial and, to a lesser extent,
      astroglial cell cultures produce NO after LPS treatment. However, NO production
      in endotoxin-treated astrocyte cultures is controversial. We characterized NO
      production in microglial, astroglial and mixed glial cell cultures treated with
      lipopolysaccharide, measured as nitrite accumulation in the culture media. We
      also identified the NO-producing cells by immunocytochemistry, using specific
      markers for the inducible NO synthase (iNOS) isoform, microglial and astroglial
      cells. Only microglial cells showed iNOS immunoreactivity. Thus, contaminating
      microglial cells were responsible for NO production in the secondary astrocyte
      cultures. We then analysed the effect of astrocytes on NO production by
      microglial cells using microglial-astroglial cocultures, and we observed that
      this production was clearly enhanced in the presence of astroglial cells. Soluble
      factors released by astrocytes did not appear to be directly responsible for such
      an effect, whereas nonsoluble factors present in the cell membrane of LPS-treated
      astrocytes could account, at least in part, for this enhancement.

PMID- 12405989
TI  - Characterization of the mouse adenylyl cyclase type VIII gene promoter:
      regulation by cAMP and CREB.
AB  - Adenylyl cyclase (AC) type VIII has been implicated in several forms of neural
      plasticity, including drug addiction and learning and memory. In the present
      study, we directly examined the role for the transcription factor CREB (cAMP
      response element binding protein) in regulating ACVIII expression by cloning a
      5.2 kilobase region upstream of the translation start site of the mouse ACVIII
      gene. Analysis of this fragment revealed consensus elements for several
      transcription factors, including a canonical cAMP response element (CRE) in close
      proximity to the transcription initiation region. Next, ACVIII promoter activity
      was studied in two neural-derived cell lines and in primary cultures of rat
      striatal neurons. Activation of the cAMP pathway by forskolin treatment increased
      promoter activity, and a series of deletion and point mutants demonstrated that
      this activation is mediated specifically via the canonical CRE site. Gel shift
      assays confirmed that this site can bind CREB and several CREB family proteins.
      Further, activation of the ACVIII promoter by forskolin was potentiated by
      expression of a constitutively active form of CREB, CREB-VP16, whereas it was
      inhibited by expression of a dominant-negative form of CREB, A-CREB. Finally,
      over-expression of CREB in vivo, by viral-mediated gene transfer, induced ACVIII
      promoter activity in the brains of ACVIII-LacZ transgenic mice. These results
      suggest that the ACVIII gene is regulated by CREB in vitro and in vivo and that
      this regulation may contribute to CREB-dependent neural plasticity.

PMID- 12405990
TI  - Postnatal innervation of the rat superior colliculus by axons of late-born
      retinal ganglion cells.
AB  - Rat retinal ganglion cells (RGCs) are generated between embryonic day (E) 13 and
      E19. Retinal axons first reach the superior colliculus at E16/16.5 but the time
      of arrival of axons from late-born RGCs is unknown. This study examined (i)
      whether there is a correlation between RGC genesis and the timing of retinotectal
      innervation and (ii) when axons of late-born RGCs reach the superior colliculus.
      Pregnant Wistar rats were injected intraperitoneally with bromodeoxyuridine
      (BrdU) on E16, E18 or E19. Pups from these litters received unilateral superior
      colliculus injections of fluorogold (FG) at ages between postnatal (P) day P0 and
      P6, and were perfused 1-2 days later. RGCs in 3 rats from each BrdU litter were
      labelled in adulthood by placing FG onto transected optic nerve. Retinas were
      cryosectioned and the number of FG, BrdU and double-labelled (FG+/BrdU+) RGCs
      quantified. In the E16 group, the proportion of FG-labelled RGCs that were BrdU+
      did not vary with age, indicating that axons from these cells had reached the
      superior colliculus by P0/P1. In contrast, for the smaller cohorts of RGCs born
      on E18 or E19, the proportion of BrdU+ cells that were FG+ increased
      significantly after birth; axons from most RGCs born on E19 were not retrogradely
      FG-labelled until P4/P5. Thus there is a correlation between birthdate and
      innervation in rat retinotectal pathways. Furthermore, compared to the earliest
      born RGCs, axons from late-born RGCs take about three times longer to reach the
      superior colliculus. Later-arriving axons presumably encounter comparatively
      different growth terrains en route and eventually innervate more differentiated
      target structures.

PMID- 12405991
TI  - Differential excitability and voltage-dependent Ca2+ signalling in two types of
      medial entorhinal cortex layer V neurons.
AB  - The entorhinal cortex (EC) is a key structure in memory formation, relaying
      sensory information to the hippocampal formation and processed information to the
      neocortex. EC neurons in the deep layers modulate the transfer of sensory
      information by the superficial layers and the dentate gyrus, and form the output
      to the neocortex. Here we characterize two types of EC layer V neurons by their
      fluorescence morphology, electrophysiology and intracellular Ca2+ signalling
      using intracellular recording and Ca2+ imaging. Pyramidal neurons show, in
      response to depolarizing current pulses, regular firing with strong adaptation
      and a fast and medium afterhyperpolarization (AHP) which are separated by a
      depolarizing notch and, with hyperpolarizing current injection, a transient sag.
      Multipolar cells respond to depolarization with delayed firing with very weak
      adaptation and have no depolarizing notch between fast and medium AHP and no sag
      with hyperpolarization. The delayed firing was blocked by 30 micro m 4
      aminopyridine, indicating mediation by the D-type potassium current. Subthreshold
      depolarization evoked membrane potential oscillations of 2-5 Hz in both cell
      types and an increase in [Ca2+]i of 37 nm in pyramidal and 59 nm in multipolar
      neurons. Repetitive firing at 10 Hz for 30 s increased [Ca2+]i in pyramidal and
      multipolar neurons by 194 and 295 nm, respectively. Differential temporal firing
      and Ca2+ signalling suggest specific information processing and synaptic memory
      storage possibilities in these two layer V cell types of the EC.

PMID- 12405992
TI  - Fibroblast growth factor-2 increases functional excitatory synapses on
      hippocampal neurons.
AB  - The effect of fibroblast growth factor-2 (FGF-2) on synapse formation was
      investigated using rat cultured hippocampal neurons. Treatment with FGF-2 (0.4-10
      ng/mL) for 6 days enhanced synaptogenesis on these neurons by approximately 50%,
      as determined by counting puncta immunostained for presynaptic- or postsynaptic
      specific proteins. This enhancement was statistically significant, and was
      abolished by a specific inhibitor of mitogen-activated protein kinase (MAPK). The
      majority of neurons expressed FGF receptors (types 1-3) abundantly on the
      membrane of somata, dendrites, and growth cones, and in these regions
      phosphorylation of MAPK was enhanced after FGF-2 application. Furthermore, our
      experiments showed that the majority of synapses formed in cultures containing
      FGF-2 were positive both for presynaptic proteins and postsynaptic excitatory
      synapse-specific proteins, and that these synapses had a similar capacity to
      recycle the fluorescent styryl dye FM4-64 as those in the control culture. These
      results indicate that: (i) FGF-2 increases excitatory synapses on hippocampal
      neurons by activating MAPK activity through FGF receptors; and (ii) synapses
      formed in FGF-2-treated culture are capable of cycling vesicles.

PMID- 12405993
TI  - Synaptic plasticity in the acoustic startle pathway: the neuronal basis for short
      term habituation?
AB  - The aim of the present study was to analyse the cellular mechanism underlying
      short-term habituation of the acoustic startle response (ASR). We explored
      distinct synapses of the neuronal startle pathway in rat brain slices by patch
      clamp recordings of giant neurons in the caudal pontine reticular formation.
      Presynaptic stimulation of auditory afferents by repeated bursts at 0.1 and 1 Hz
      led to an exponential decay of EPSC magnitudes. This homosynaptic depression
      (HSD) was reversible and repeatedly inducible after recovery. Many parameters of
      HSD in vitro match those of ASR habituation in vivo. The mechanisms underlying
      HSD are distinct from classical short-term plasticity: paired-pulse as well as
      paired-burst stimulation revealed a facilitation of the second EPSC, occurring in
      a much smaller time window up to interstimulus intervals of 200 ms.
      Pharmacological experiments demonstrated that HSD could be completely blocked by
      the group II and III metabotropic glutamate receptor antagonist MPPG. Similar
      results were obtained by CPPG, another group II and III antagonist. In contrast,
      HSD was not affected by the group I and II antagonist MCPG. We conclude that we
      found a form of synaptic depression in synapses within the primary startle
      pathway which correlates in many respects with short-term habituation of the ASR
      and which is presumably mediated by group III metabotropic glutamate receptors.

PMID- 12405994
TI  - Time course of motor cortex reorganization following botulinum toxin injection
      into the vibrissal pad of the adult rat.
AB  - The present experiment studies representation patterns in the motor cortex (M1)
      of adult rats, 1, 3, 6, and 12 days after unilateral injection of Botulinum Toxin
      (BTX) into the vibrissa pad. Intracortical microstimulation (ICMS) was used to
      evidence changes in the representation over time and in the current thresholds
      required to evoke movements inside the disconnected vibrissa region. After 1 day,
      isolated as well as contiguous negative sites were observed within the motor
      cortex corresponding to the disconnected vibrissa region. Thereafter the
      percentage of unresponsive sites decreased so that after 6 days, the number of
      unresponsive sites was not significantly higher than those in the control
      hemispheres. Within the disconnected vibrissa region, electrical stimulation
      elicited forelimb, eye, ipsilateral vibrissa and neck movements. Following BTX
      injection, the enlargement of the forelimb representation into the disconnected
      vibrissa representation began during the first day and stabilized during the
      second week after injection. In the first days, stimulation thresholds in
      expanded forelimb sites were higher than those required for similar movement in
      normal M1 forelimb representation. These thresholds then declined so that in
      approximately 6 days they were similar to normal. There was no clear evidence
      that stimulation of sites in the medial part of disconnected vibrissa-cortex
      evoked eye movements during the first 6 days after BTX injection. After this
      time, thresholds required to evoke eye movement in expanded sites were generally
      similar to, and never higher than, those needed to evoke this movement in control
      sites. Intermingled ipsilateral vibrissa and neck movement occupies part of the
      medial vibrissa region. Over the 12 days, extension of the ipsilateral vibrissa
      representation shrank while the representation of neck movement remained
      unchanged. Throughout the entire time there was no change in the excitability of
      these sites and the thresholds remained higher than that needed to elicit the
      vibrissa movement normally represented in this cortical region. No significant
      differences in threshold were found over time for any of the other movement
      categories represented in M1. These results indicate that, over time, the new
      movements inside the disconnected vibrissa region develop differently in M1
      following peripheral motor disconnection. The implications for mechanisms
      involved in cortical plasticity are discussed.

PMID- 12405995
TI  - Descending pathways controlling visually guided updating of reaching in cats.
AB  - This study uses a previously described paradigm (Pettersson et al., 1997) to
      investigate the ability of cats to change the direction of ongoing reaching when
      the target is shifted sideways; the effect on the switching latency of spinal
      cord lesions was investigated. Large ventral lesions transecting the ventral
      funicle and the ventral half of the lateral funicle gave a 20-30 ms latency
      prolongation of switching in the medial (right) direction, but less prolongation
      of switching directed laterally (left), and in one cat the latencies of switching
      directed laterally were unchanged. It may be inferred that the command for
      switching in the lateral direction can be mediated by the dorsally located
      cortico- and rubrospinal tracts whereas the command for short-latency switching
      in the medial direction is mediated by ventral pathways. A restricted ventral
      lesion transecting the tectospinal pathway did not change the switching latency.
      Comparison of different ventral lesions revealed prolongation of the latency if
      the lesion included a region extending dorsally along the ventral horn and from
      there ventrally as a vertical strip, so it may be postulated that the command for
      fast switching, directed medially, is mediated by a reticulospinal pathway within
      this location. A hypothesis is forwarded suggesting that the visual control is
      exerted via ponto-cerebellar pathways.

PMID- 12405996
TI  - The cerebellum in action: a simulation and robotics study.
AB  - The control or prediction of the precise timing of events are central aspects of
      the many tasks assigned to the cerebellum. Despite much detailed knowledge of its
      physiology and anatomy, it remains unclear how the cerebellar circuitry can
      achieve such an adaptive timing function. We present a computational model
      pursuing this question for one extensively studied type of cerebellar-mediated
      learning: the classical conditioning of discrete motor responses. This model
      combines multiple current assumptions on the function of the cerebellar circuitry
      and was used to investigate whether plasticity in the cerebellar cortex alone can
      mediate adaptive conditioned response timing. In particular, we studied the
      effect of changes in the strength of the synapses formed between parallel fibres
      and Purkinje cells under the control of a negative feedback loop formed between
      inferior olive, cerebellar cortex and cerebellar deep nuclei. The learning
      performance of the model was evaluated at the circuit level in simulated
      conditioning experiments as well as at the behavioural level using a mobile
      robot. We demonstrate that the model supports adaptively timed responses under
      real-world conditions. Thus, in contrast to many other models that have focused
      on cerebellar-mediated conditioning, we investigated whether and how the
      suggested underlying mechanisms could give rise to behavioural phenomena.

PMID- 12405997
TI  - Neural correlates of the motivational and somatic components of naloxone
      precipitated morphine withdrawal.
AB  - In morphine-dependent rats, low naloxone doses have been shown to induce
      conditioned place aversion, which reflects the negative motivational component of
      opiate withdrawal. In contrast, higher naloxone doses are able to induce a 'full'
      withdrawal syndrome, including overt somatic signs. The c-fos gene is commonly
      used as a marker of neuronal reactivity to map the neural substrates that are
      recruited by various stimuli. Using in situ hybridization, we have analysed in
      the brain of morphine-dependent rats the effects of acute withdrawal syndrome
      precipitated by increasing naloxone doses on c-fos mRNA expression. Morphine
      dependence was induced by subcutaneous implantation of slow-release morphine
      pellets for 6 days and withdrawal was precipitated by increasing naloxone doses
      inducing the motivational (7.5 and 15 micro g/kg) and somatic (30 and 120 micro
      g/kg) components of withdrawal. Our mapping study revealed a dissociation between
      a set of brain structures (extended amygdala, lateral septal nucleus, basolateral
      amygdala and field CA1 of the hippocampus) which exhibited c-fos mRNA dose
      dependent variations from the lowest naloxone doses, and many other structures
      (dopaminergic and noradrenergic nuclei, motor striatal areas, hypothalamic nuclei
      and periaqueductal grey) which were less sensitive and recruited only by the
      higher doses. In addition, we found opposite dose-dependent variations of c-fos
      gene expression within the central (increase) and the basolateral (decrease)
      amygdala after acute morphine withdrawal. Altogether, these results emphasize
      that limbic structures of the extended amygdala along with the lateral septal
      nucleus, the basolateral amygdala and CA1 could specifically mediate the negative
      motivational component of opiate withdrawal.

PMID- 12405998
TI  - Attentional demands reflect learning-induced alterations of bimanual coordination
      dynamics.
AB  - This study aimed to investigate the effects of practice on bimanual coordination
      dynamics and attentional demands. Participants were asked to perform a dual-task
      associating a cyclic antiphase bimanual pattern and a discrete reaction time
      task. A pretest determined each individual critical transition frequency. In the
      training session, participants practised 120 trials. They were instructed to
      maintain the antiphase coordination pattern at the critical transition frequency.
      The training session was interrupted and followed by an intermediate test (after
      60 trials) and a post-test (30 min after 120 trials), respectively. A retention
      test was performed 7 days after the end of the training session. Results showed
      that: (i) the number of transitions decreased as a consequence of practice; and
      (ii), subjects were able to maintain the antiphase pattern at a higher frequency
      than in the pretest. Analysis of the trade-off between relative phase variability
      and reaction time showed that participants were able to maintain a higher level
      of stability at the same (intermediate and post-test) or a lower attentional cost
      (retention test). These findings show that phase transition dynamics and pattern
      stability can be significantly modified as a result of practice. Changes in the
      trade-off between pattern stability and cost with learning confirm that the
      attentional cost incurred by the central nervous system to maintain pattern
      stability decreased with practice. In line with recent neurobiological studies,
      the present study provides new insights regarding relationships between brain
      processes, attentional demands and coordinated behaviour in learning bimanual
      patterns.

PMID- 12405999
TI  - The effects of genetic and pharmacological blockade of the CB1 cannabinoid
      receptor on anxiety.
AB  - The aim of this study was to compare the effects of the genetic and
      pharmacological disruption of CB1 cannabinoid receptors on the elevated plus-maze
      test of anxiety. In the first experiment, the behaviour of CB1-knockout mice and
      wild-type mice was compared. In the second experiment, the cannabinoid antagonist
      SR141716A (0, 1, and 3 mg/kg) was administered to both CB1-knockout and wild type
      mice. Untreated CB1-knockout mice showed a reduced exploration of the open arms
      of the plus-maze apparatus, thus appearing more anxious than the wild-type
      animals, however no changes in locomotion were noticed. The vehicle-injected CB1
      knockout mice from the second experiment also showed increased anxiety as
      compared with wild types. Surprisingly, the cannabinoid antagonist SR141716A
      reduced anxiety in both wild type and CB1 knockout mice. Locomotor behaviour was
      only marginally affected. Recent evidence suggests the existence of a novel
      cannabinoid receptor in the brain. It has also been shown that SR141716A binds to
      both the CB1 and the putative novel receptor. The data presented here supports
      these findings, as the cannabinoid receptor antagonist affected anxiety in both
      wild type and CB1-knockout mice. Tentatively, it may be suggested that the
      discrepancy between the effects of the genetic and pharmacological blockade of
      the CB1 receptor suggests that the novel receptor plays a role in anxiety.

PMID- 12406000
TI  - Decreased glucocorticoid receptor mRNA and dysfunction of HPA axis in rats after
      removal of the cholinergic innervation to hippocampus.
AB  - Excess exposure to glucocorticoids can have deleterious effects on physiology and
      cognition. Glucocorticoids acting via receptors located in hippocampal neurons
      contribute to negative feedback after stress by terminating the further release
      of glucocorticoids. The current study investigated the effects of selective
      immunolesions of septo-hippocampal cholinergic neurons on hippocampal
      corticosterone receptor mRNA and on hypothalamic-pituitary-adrenal (HPA)
      activity. As evaluated by in situ hybridization, hippocampal glucocorticoid
      receptor (GR) mRNA, but not mineralocorticoid receptor (MR) mRNA, was
      significantly decreased in lesioned rats compared to controls. In a companion
      study, the peak corticosterone response to one hour of restraint stress did not
      differ between lesion and control groups but the post-stress decline of
      corticosterone was more protracted in the lesioned rats. These findings are
      discussed in terms of their possible relevance to ageing as age-related
      degeneration of the basal forebrain cholinergic system may contribute to the
      commonly observed dysfunction of the HPA axis in older animals.

PMID- 12406005
TI  - Standard-dose anti-CD20 antibody rituximab has efficacy in chronic lymphocytic
      leukaemia: results from a Nordic multicentre study.
AB  - OBJECTIVES: This prospective multicentre study was conducted to assess the
      efficacy of the monoclonal anti-CD20 antibody rituximab in patients with chronic
      lymphocytic leukaemia (CLL). Secondary objectives were defined as the
      tolerability and feasibility of rituximab in patients with CLL. METHODS: Twenty
      four heavily pretreated patients with CLL were treated with a standard dose of
      375 mg m-2 of rituximab given once weekly for four doses. RESULTS: The overall
      response rate was 35% and all the responses were partial as defined by the
      revised NCI criteria. In 17 (85%) of 20 patients with initially measurable
      peripheral lymph nodes the size of lymph nodes decreased by at least 50%, while
      an improvement of the bone marrow infiltration was observed only in two (11%) of
      18 evaluable patients. The median duration of the overall response was 12.5 wk.
      Rituximab was relatively well tolerated. Although side-effects were common (75%)
      they were usually mild or moderate. There was only one grade 3 adverse event and
      no grade 4 events. CONCLUSIONS: Standard-dose rituximab has activity in heavily
      pretreated patients with CLL, although the response is mainly limited to the
      lymph nodes and of short duration. Since rituximab has in vitro synergism with
      chemotherapeutic agents and is well tolerated by CLL patients, it is reasonable
      to investigate rituximab in combination with other treatments.

PMID- 12406006
TI  - Relationship between the clinical manifestations of sickle cell disease and the
      expression of adhesion molecules on white blood cells.
AB  - BACKGROUND: The severity of sickle cell disease (SCD) increases with leukocyte
      count. The biological basis could be that leukocyte adherence to vascular
      endothelium mediated by adhesion molecules (AMs) facilitates vaso-occlusion, the
      basic pathological process in SCD. OBJECTIVE: To find out if there is a
      relationship between expression of AMs by leukocytes and the clinical
      manifestations of SCD. METHODS: Flow cytometry was used to study the relationship
      between leukocyte AM expression and disease manifestations in 100 patients with
      homozygous (HbSS) sickle cell disease and 34 genotype HbAA controls. The effect
      of hydroxyurea therapy on AM expression was also examined. We excluded HbSS
      patients with any other disease, pregnancy in the previous 3 months, or
      Haemogloben F (HbF) > or = 10%. RESULTS: Patients with complications of SCD
      showed high expression of alphaMbeta integrin by the neutrophils; and l-selectin
      by lymphocytes and neutrophils (P < 0.03). CD18 was highly expressed by
      neutrophils in patients with sickle nephropathy (P = 0.018), and l-selectin by
      lymphocytes in those with stroke (P = 0.03). Monocyte l-selectin increased in
      sickle cell crisis relative to steady state (P = 0.04). Expression of alphaLbeta2
      integrin by neutrophils, monocytes, and lymphocytes decreased within a month of
      hydroxyurea therapy (P < 0.05), with symptomatic improvement in the patients and
      no more than 3.3% rise in HbF level. CONCLUSIONS: The findings suggest that in
      SCD (1): High steady-state expression of alphaMbeta2 integrin and l-selectin by
      leukocytes predisposes to severe manifestations. (2) Increased leukocyte AM
      expression above steady-state levels could be important in the genesis of crisis.
      (3) The early symptomatic improvement that follows hydroxyurea therapy is
      mediated via mechanisms independent of increased HbF, and may involve reduced AM
      expression in leukocytes. (4) Other treatment modalities that reduce leukocyte AM
      expression might also confer clinical benefit.

PMID- 12406007
TI  - Band 3 as a marker of erythrocyte changes in pregnancy.
AB  - Modifications in the erythrocyte membrane protein band 3 seem to mark the cell
      for death. A decrease in band 3 high molecular weight aggregates (HMWAg) and a
      rise in its proteolytic fragments (Pfrag) were described for younger
      erythrocytes. The aim of this work was to study the band 3 profile as a marker of
      erythrocyte changes in pregnancy and postpartum. We performed a cross-sectional
      study in non-pregnant controls (n = 24), in women in the first (n = 64), second
      (n = 48) and third (n = 67) trimesters of gestation, and also in the puerperium
      (24-48 h after delivery; n = 32); we also carried out a longitudinal study (n =
      23) during the three trimesters of normal pregnancy. We evaluated the band 3
      profile (% of band 3 monomer, HMWAg, and Pfrag) and the membrane-bound
      haemoglobin. Total serum bilirrubin, glutathione peroxidase activity, red blood
      cell (RBC) count, haematocrit (Ht), haemoglobin (Hb) concentration, the
      haematimetric indices, and red cell distribution width were also evaluated.
      Similar results were found in pregnancy in both the cross-sectional and
      longitudinal studies. We found that the RBC count, Hb, and Ht decreased
      significantly in pregnancy and in puerperium. Band 3 profile in the first
      trimester of pregnancy, when compared with controls, presented significantly
      reduced HMWAg and increased Pfrag. Comparing the first with the third trimester,
      we found a significant reduction in band 3 and a significant rise in Pfrag.
      However, between these same periods, HMWAg did not decrease. Our data suggest
      band 3 profile as a marker of erythrocyte changes in pregnancy, which are
      independent of the 'physiological anaemia' of pregnancy. These changes suggest an
      increase in damaged RBCs, but also an increase in younger RBCs in the maternal
      circulation.

PMID- 12406008
TI  - Comparison of reticulated platelet count and mean platelet volume determination
      in the evaluation of bone marrow recovery after aplastic chemotherapy.
AB  - Reticulated platelet count provides an estimate of thrombopoiesis in the same way
      as reticulocyte count is a measure of erythropoiesis. We applied thiazole orange
      (TO) staining, followed by fluorescence-activated flow-cytometric analysis, to
      platelets in whole-blood samples from normal subjects and 18 aplastic patients
      after chemotherapy for haematologic malignancies. The percentage of TO-positive
      platelets in 30 control subjects was 5.7 +/- 2.4% (mean +/- 1 SD), determining
      the threshold of reticulated platelet positivity as up to 10.5% (mean + 2 SD). In
      the 18 patients studied, the mean percentage of TO-positive platelets was 4.3 +/-
      1.89% during aplasia and 23.3 +/- 9.43% during bone marrow recovery, respectively
      (P < 0.05). All patients had a percentage of TO-positive platelets of up to
      10.5%. In comparison, mean platelet volume during bone marrow recovery increased
      in 12 cases of the 18 patients studied. We conclude that flow cytometric analysis
      of reticulated platelets is a sensitive and specific test for evaluating
      thrombopoiesis recovery during aplastic chemotherapy, and platelet transfusion
      should be reconsidered in these patients.

PMID- 12406009
TI  - Acquired hemophilia: a single-center survey with emphasis on immunotherapy and
      treatment-related side-effects.
AB  - OBJECTIVES: Acquired hemophilia is a rare disease caused by the development of
      autoantibodies against factor VIII. Since 1981 we have observed 17 patients with
      this disorder in our institution. The objective of this survey was to assess the
      epidemiological features, clinical course, and mortality rate of these patients,
      with special emphasis on therapy-related side-effects. Also, we present our
      results with an immunosuppressive approach based on the severity of bleeding
      episodes. METHODS: Clinical records of all patients with acquired hemophilia due
      to factor VIII inhibitor admitted or referred to our hospital between 1981 and
      2001 were reviewed retrospectively. We collected each patient's sex, age, medical
      history, presenting symptoms, activated partial thromboplastin time, factor VIII
      activity, and inhibitor titre. Patient's clinical courses, including their
      bleeding episodes, response to therapy, and therapy-related side-effects, were
      also recorded. RESULTS: Complete and partial responses were achieved in 14 and
      one patient, respectively (overall response rate 88%) after a median time to
      complete response of 3.5 months (range 30 d - 25 months). The inhibitor-related
      and overall mortality rates were 12% and 29%, respectively. Side-effects were
      frequent: two patients had blood-borne infections, three patients had thrombotic
      complications, and nine patients had immunosuppressive therapy-related side
      effects. In five patients, discontinuation of cyclophosphamide or prednisone was
      required. CONCLUSIONS: Although our response rates were remarkable, this survey
      showed that treatment-related morbidity could also be very important. Therefore,
      it is pertinent to bear in mind these potential side-effects in order to decide
      the most appropriate therapy for each particular patient.

PMID- 12406010
TI  - Can t(8;21) oligoblastic leukemia be called a myelodysplastic syndrome?
AB  - The new World Health Organization (WHO) classification of hematologic
      malignancies has incorporated t(8;21) myelodysplastic syndromes (MDS) according
      to the French-American-British classification into the category of acute myeloid
      leukemia (AML) with t(8;21)(q22;q22), while our knowledge about
      clinicopathological features of t(8;21) oligoblastic leukemia is still limited.
      We present our experience with 12 patients meeting the FAB diagnostic criteria of
      MDS and having t(8;21), who were compared to 43 t(8;21) AML patients. The MDS and
      AML patients shared most hematomorphologic, immunophenotypic, and clinical
      features, whereas the differences lay along myeloid maturation. The MDS patients
      had higher percentages of circulating neutrophils and marrow myeloid cells beyond
      promyelocytes than the AML patients. The incidence of Auer rods in mature
      neutrophils in MDS was significantly higher than that in AML, and furthermore,
      the neutrophils in MDS more commonly contain t(8;21) than in AML. Our findings
      support the rationale for the WHO classification, and future studies on large
      patient populations should help clarify whether the spontaneous differentiation
      potential could be actively associated with a hematological manifestation of
      t(8;21) leukemias.

PMID- 12406011
TI  - Deoxycytidine kinase expression and activity in patients with resistant versus
      sensitive acute myeloid leukemia.
AB  - Resistance to cytarabine (AraC) is a major problem in treatment of patients with
      acute myeloid leukemia (AML). In contrast to in vitro AraC resistance,
      deoxycytidine kinase (dCK) mutations are rarely found in patients with refractory
      or relapsed AML. Previously we have demonstrated alternatively spliced dCK mRNA
      predominantly expressed in leukemic blasts from patients with resistant AML. In
      this study we investigated wild-type (wt) dCK expression and activity to
      elucidate the possible role of decreased dCK expression or activity in
      unresponsiveness to AraC in patients with AML. No alterations in dCK mRNA and
      protein expression or in dCK activity were detected between patients with
      clinically resistant vs. sensitive AML. In addition, wt dCK expression and
      activity were not reduced in leukemic blasts expressing alternatively spliced dCK
      forms as compared to blasts with only wt dCK. Also, no major differences in wt
      dCK expression and activity were observed between samples obtained from patients
      with AML and bone marrow or peripheral blood samples from healthy donors. These
      data implicate that in our patient group of refractory or relapsed AML cases,
      alterations in dCK expression and/or activity cannot explain unresponsiveness to
      chemotherapy including AraC.

PMID- 12406012
TI  - Hemoglobin H disease resulting from the association of the - alpha 3.7 rightward
      deletion and the (alpha alpha)MM deletion in a Brazilian patient.
AB  - A patient with Hb H disease resulting from the association of the - alpha 3.7
      rightward deletion with the rare (alpha alpha)MM deletion, which removes the
      entire alpha-major regulatory element (MRE), is reported. This is the first
      description of an alpha-thalassemic mutation resulting from deletion of the locus
      controlling sequences in the South-American population.

PMID- 12406013
TI  - Prolymphocytic leukaemia and Hodgkin's lymphoma.
AB  - We describe a case of B-prolymphocytic leukaemia (B-PLL) who, following a long
      lasting remission with fluradabine, developed a Hodgkin's lymphoma (HL) with bone
      marrow involvement. A 75-yr-old male was found to have a lymphocytosis [white
      blood cell (WBC) count = 146 x 10(9) L(-1)], small volume axillary
      lymphadenopathy, and hepatosplenomegaly. The majority of circulating lymphocytes
      had a round nucleus and prominent single nucleolus. The patient did not respond
      to chlorambucil and then received fludarabine, achieving a good response lasting
      for 5 yr, when he manifested with B symptoms and pancytopenia. A diagnosis of HL
      in the bone marrow was made based on histology (Reed-Sternberg cells) and
      immunohistochemistry (CD30+, CD15+). Epstein-Barr virus (EBV) studies were
      negative. The patient was treated with chemotherapy but died 6 months later from
      disease progression.

PMID- 12406014
TI  - Acquired amegakaryocytic thrombocytopenic purpura successfully treated with
      limited cyclosporin A therapy.

PMID- 12406015
TI  - Induction of toxic granulation in neutrophils by granulocyte colony-stimulating
      factor.

PMID- 12406016
TI  - Anti-Epo and anti-Tpo antibodies in myelodysplastic syndromes.

PMID- 12406017
TI  - Thrombotic thrombocytopenic purpura in a patient treated with clarithromycin.

PMID- 12406018
TI  - Does plasma fibrinogen increase thrombotic tendency?

PMID- 12406019
TI  - Current and adolescent levels of cardiopulmonary fitness are related to large
      artery properties at age 36: the Amsterdam Growth and Health Longitudinal Study.
AB  - BACKGROUND: High levels of cardiopulmonary fitness (VO2max) are associated with
      reduced risk of cardiovascular morbidity and mortality, but little is known to
      what extent this is related to the effects of cardiopulmonary fitness on
      atherosclerosis and arterial stiffness. Moreover, the time course of these
      relationships needs to be elucidated. We sought to investigate (i) the cross
      sectional relationship between VO2max and carotid atherosclerosis and carotid and
      femoral arterial stiffness at age 36, as well as (ii) the relationship between
      VO2max during adolescence (13-16 years) and the same arterial properties at age
      36 (prospective analyses). DESIGN: Cross-sectional analyses consisted of 351
      subjects (183 women) and the prospective analyses of a subpopulation of 154
      subjects (79 girls). Arterial properties were assessed noninvasively by
      ultrasound imaging; VO2max was measured with a maximal running text on a
      treadmill with direct measurements of oxygen uptake. RESULTS: After adjustment
      for confounding by other known risk factors, current and adolescent levels of
      VO2max were independently associated with carotid intima-media thickness (beta = 
      0.288, P = 0.004 and beta = -0.381, P = 0.012) in men, and with the diameter of
      the femoral artery (beta = 0.375, P < 0.001 and beta = 0.252, P = 0.026,
      respectively) in both sexes. Current levels of VO2max were positively associated
      with the compliance of the carotid and the femoral arteries (beta = 0.186, P =
      0.023 and beta = 0.183, P = 0.033, respectively), and with the distensibility of
      the carotid (beta = 0.162, P = 0.047) but not the femoral artery. CONCLUSION: We
      conclude that cardiopulmonary fitness is associated with large artery properties
      at age 36, and that the roots of this association may already be present in
      adolescence.

PMID- 12406020
TI  - Captopril and quinapril reduce reactive oxygen species.
AB  - BACKGROUND: Angiotensin-converting enzyme inhibitors may affect reactive oxygen
      species in humans in vitro and in vivo. In the present study we evaluated whether
      angiotensin-converting enzyme inhibitors may affect NAD(P)H oxidase activity.
      MATERIALS AND METHODS: The production of reactive oxygen species was measured
      spectrophotometrically in mononuclear leukocytes using the fluorescent dye,
      dichlorofluorescein diacetate. The effects of quinaprilat, captopril, enalaprilat
      and lisinopril on phorbol myristate acetate-induced reactive oxygen species
      generation were investigated in vitro. The effects of quinaprilat, captopril,
      enalaprilat and lisinopril on the NAD(P)H oxidase activity of the mononuclear
      leukocytes were measured photometrically. In addition, reactive oxygen species
      were measured before and 4 h after oral administration of quinapril. RESULTS: In
      vitro, the addition of quinaprilat (72 +/- 6% of control; mean +/- SEM; n= 19; P
      < 0.001) and captopril (48 +/- 2% of control; n= 19; P < 0.001) significantly
      reduced the phorbol-12-myristate-13-acetate-induced reactive oxygen species
      generation by the mononuclear leukocytes, whereas enalaprilat and lisinopril
      showed no effect. The effect of captopril on phorbol-12-myristate-13-acetate
      induced reactive oxygen species generation in vitro was concentration-dependent.
      Quinaprilat and captopril significantly inhibited the NAD(P)H oxidase activity.
      After the oral administration of 10 mg of quinapril the phorbol-12-myristate-13
      acetate-induced reactive oxygen species generation by the mononuclear leukocytes
      was significantly decreased from 1981 +/- 292% to 988 +/- 141% (n = 14; P <
      0.01). CONCLUSION: Quinapril and captopril decrease the production of reactive
      oxygen species.

PMID- 12406021
TI  - Apolipoprotein E polymorphism and serum lipid response to plant sterols in
      humans.
AB  - BACKGROUND: The apolipoprotein E polymorphism may influence the absorption of
      cholesterol from the intestine and thus the response of serum cholesterol to
      diet. We decided to use plant sterols to investigate this and studied whether the
      cholesterol-lowering effect of plant sterols differed between subjects with
      different apolipoprotein E genotyes. DESIGN: Thirty-one healthy subjects with the
      E3/4 or E4/4 genotype and 57 with the E3/3 genotype were fed sterol-enriched
      margarine or control margarine for 3 weeks each in a blind randomised cross-over
      design. The sterol margarine provided 3.2 g of plant sterols daily, was low-fat,
      and had the same fatty acid composition as the control margarine. Subjects used
      the margarines as part of their usual diet, which was fairly low in cholesterol
      (mean, 175 mg per day). The mean (+/- standard deviation) age of the subjects was
      25 (+/- 11) years. RESULTS: The apolipoprotein E polymorphism did not
      significantly affect the responses of total and LDL cholesterol. The decrease in
      total cholesterol was 0.36 mmol L-1 (7.4%) in the E3/3 subjects and 0.31 mmol L-1
      (5.7%) in the epsilon 4 subjects (P = 0.50) and that in LDL cholesterol was 0.34
      mmol L-1 (12.2%) in the E3/3 subjects and 0.32 mmol L-1 (9.8%) in the epsilon 4
      subjects (P = 0.68). CONCLUSION: The serum cholesterol response to plant sterols
      is not affected by the apolipoprotein E polymorphism in healthy subjects who
      consume a low-cholesterol diet.

PMID- 12406022
TI  - Inhibition of human primary melanoma cell proliferation by histamine is enhanced
      by interleukin-6.
AB  - BACKGROUND: Interleukin-6 (IL-6) is a bifunctional growth factor in malignant
      melanoma; its expression increases during the malignant progression of the
      disease. Histamine, detected in large amounts in normal and pathological
      proliferating tissues, is an important paracrine and autocrine regulator of
      normal and tumour cell proliferation as well. MATERIALS AND METHODS: We
      investigated the presence and function of IL-6 and histamine in the WM35 primary
      human melanoma cell line with respect to their direct role in cell proliferation
      and their regulatory interactions. RESULTS: IL-6 inhibited the proliferation of
      WM35 melanoma cells and increased significantly the expression of histidine
      decarboxylase as well as histamine production. It had dose-dependent effects on
      the proliferation: high concentration (10-5 M) was inhibitory through H1
      histamine receptors while low histamine concentration acting on H2 receptors,
      with a simultaneous increase of cAMP, enhanced colony formation in the monolayer.
      Furthermore, IL-6 increased the H1- but decreased the H2-histamine receptor
      expression of the melanoma cells. On the other hand, histamine was locally
      synthesized by the WM35 melanoma cells. CONCLUSION: We suggest that the growth
      arrest induced by IL-6 is in part mediated by its dual action on histamine: a
      shift toward H1 receptor predominance and an elevation of locally produced
      histamine with prevalent action on the inhibitory response triggered through the
      H1 receptor. These findings suggest a local cross-talk between histamine and IL-6
      in the regulation of melanoma growth.

PMID- 12406023
TI  - No increase in mortality and morbidity among carriers of the C282Y mutation of
      the hereditary haemochromatosis gene in the oldest old: the Leiden 85-plus study.
AB  - BACKGROUND: The C282Y mutation in the gene for haemochromatosis (HFE) has been
      associated with various diseases at middle age. However, recent studies indicate
      that penetrance of the C282Y mutation is low. We explored the association between
      the C282Y mutation, iron metabolism, and morbidity and mortality in participants
      of the Leiden 85-plus. STUDY DESIGN: A cross-sectional comparison and prospective
      follow-up was conducted in two unselected cohorts of 661 and 552 subjects. All
      subjects were aged 85 years and over. We determined the prevalence of C282Y
      homozygous and heterozygous subjects, and the association between the C282Y
      mutation and iron metabolism, all-cause and specific causes of death. RESULTS:
      Prevalence of C282Y homozygosity in both cohorts was 0.2% (1/661 and 1/552,
      respectively) and of C282Y heterozygosity was 12.4% (82/661) and 11.4% (63/552),
      respectively. These estimates coincide exactly with reported estimates in younger
      age groups. Median ferritin level was 97 microg L-1 (IQR 39-162) for heterozygous
      carriers and 89 microg L-1 (IQR 41-157) for noncarriers (P = 0.66). The serum
      ferritin concentration for one C282Y homozygous subject, a woman aged 86 years at
      the time of enrollment in 1986, was 392 microg L-1. Cardiovascular morbidity was
      comparable between the C282Y heterozygous subjects and the noncarriers in both
      study cohorts. All-cause and cardiovascular mortality of carriers of the C282Y
      mutation was similar to that in noncarriers. CONCLUSIONS: We found two C282Y
      homozygous subjects, illustrating that homozygosity can be compatible with
      survival in very old ages. C282Y heterozygosity was not associated with history
      of cardiovascular disease morbidity, all cause mortality, cardiovascular
      mortality, or biochemical phenotype of haemochromatosis at old age.

PMID- 12406024
TI  - G-455A polymorphism of the fibrinogen beta gene and deep vein thrombosis.
AB  - BACKGROUND: Elevated fibrinogen levels have been linked to increased risk for
      deep venous thrombosis, although it is not clear whether fibrinogen is causal or
      rather a marker for the presence of other risk factors. A common G/A polymorphism
      in the gene for the fibrinogen beta-chain (FGB G-455A) is associated with
      elevated fibrinogen levels. The present study was designed to analyze the role of
      this genetic marker for deep venous thrombosis. MATERIALS AND METHODS: We
      performed a case-control study including 307 patients with documented deep venous
      thrombosis and 316 control subjects. beta-fibrinogen genotypes were determined by
      allele-specific polymerase chain reaction. RESULTS: GG, GA and AA genotype
      frequencies were similar among the patients (53.1%, 41.0, 5.9) and controls
      (51.6%, 42.1, 6.3; P = 0.92). Fibrinogen levels of the patients (median 3.72 g l
      1; range 1.93-11.6) did not differ significantly from those of the controls
      (3.76; 2.17-9.99). Carriers of the homozygous AA genotype had significantly
      higher fibrinogen levels than noncarriers (patients: 5.32 vs. 3.59; P = 0.024;
      controls: 6.29 vs. 3.72; P = 0.048). CONCLUSION: Our data suggest that the
      fibrinogen-elevating FGB G-455A gene polymorphism is not linked to an increased
      risk for deep venous thrombosis.

PMID- 12406025
TI  - Procoagulant and inflammatory response of virus-infected monocytes.
AB  - BACKGROUND: Monocytes play a prominent role in inflammation, coagulation and
      atherosclerosis by their ability to produce tissue factor (TF) and cytokines. The
      aim of the present study was to establish whether virus-infected monocytes
      initiate coagulation. In addition, the production of cytokines by monocytes may
      accelerate the chronic process of atherosclerosis and may contribute to coronary
      syndromes by eliciting plaque instability. MATERIALS AND METHODS: Monocytes were
      isolated by Vacutainer(R), BD Biosciences, Alphen aan den Rijn, Netherlands and
      subsequent magnetic cell sorting (MACS(R), Milteny Biotec, Bergish Gladbach,
      Germany). Coagulation times in normal pooled plasma and Factor VII-deficient
      plasma were measured after infection with cytomegalovirus (CMV), Chlamydia
      pneumoniae (Cp) and influenza A?H1N1. Anti-TF antibodies were added to neutralize
      TF expressed on monocytes. Interleukins (IL) 6, 8 and 10 were measured in the
      supernatants. RESULTS: Chlamydia pneumoniae- and CMV-infected monocytes decreased
      the clotting time by 60%, and influenza-infected monocytes by 19%, as compared to
      uninfected monocytes. Procoagulant activity was absent when Factor VII-deficient
      plasma or anti-TF antibodies were used. Monocytes produced both IL-6 and IL-8
      after infection with CMV (317 pg mL-1 and 250 pg mL-1) or Cp (733 pg mL-1 and 268
      pg mL-1). Similar results were obtained for influenza virus-infected monocytes,
      but the levels of both cytokines were 3-5-fold higher (1797 pg mL-1 and 725 pg mL
      1). Interleukin-10 was not produced by infected monocytes. CONCLUSION: The
      procoagulant activity of virus-infected monocytes is TF-dependent. Although
      influenza infection did not generate a significant reduction in clotting time,
      the pronounced expression of IL-6 and IL-8 may induce local and/or systemic
      inflammatory reactions, which may be associated with plaque rupture and
      atherosclerosis. The lack of production of the anti-inflammatory cytokine IL-10
      may even accelerate these processes.

PMID- 12406026
TI  - Post-transcriptional regulation of VEGF expression by oxidised LDL in human
      macrophages.
AB  - BACKGROUND: Accumulation of oxidised low density lipoproteins (oxLDL) in
      macrophages and their subsequent transformation into lipid-filled foam cells is
      generally considered an early event in atherosclerosis. Vascular Endothelial
      Growth Factor (VEGF) may contribute to atherogenesis through increased vascular
      permeability, chemoattraction towards monocytes and intraplaque vessel formation.
      In this study we investigate the effect and regulation of VEGF expression in
      human macrophages stimulated with oxLDL. MATERIALS AND METHODS: Vascular
      Endothelial Growth Factor mRNA and protein expression was assayed using RT-PCR
      and ELISA, respectively. The activity of mitogen-activated protein kinases
      (MAPKs) was investigated using Western blots. RESULTS: In human monocyte-derived
      macrophages, oxLDL significantly increased VEGF mRNA expression and subsequent
      protein secretion in a concentration-dependent manner after 6 h and 18 h,
      respectively. Using an in vitro mRNA decay assay, we show that this oxLDL-induced
      VEGF expression partly is regulated through increased stability of the VEGF mRNA.
      Involvement of MAPKs has previously been implicated in the stabilisation of VEGF
      mRNA. Activity of the p38 MAPK, but not the c-jun-N-terminal kinase (JNK),
      increased in macrophages stimulated with oxLDL (50 micro g mL-1) for 5-15 min.
      Preincubation with SB202190 (20 micro M), a specific inhibitor of p38 MAPK,
      significantly decreased the oxLDL-induced VEGF mRNA expression by 40%. The
      prolonged half-life of VEGF mRNA, induced by oxLDL, was not inhibited by
      SB202190. CONCLUSIONS: OxLDL increases VEGF expression and p38 MAPK activity in
      human macrophages. The increased VEGF mRNA expression by oxLDL is mediated
      through at least two intracellular pathways, one involving p38 MAPK and another
      that independently of p38 MAPK activity increases VEGF mRNA stability.

PMID- 12406027
TI  - Longitudinal evolution of HIV-1-associated lipodystrophy is correlated to serum
      cortisol:DHEA ratio and IFN-alpha.
AB  - BACKGROUND: We have previously shown that lipid alterations in HIV-1-associated
      lipodystrophy (LD) are correlated with decreased serum dehydroepiandosterone
      (DHEA) and increased cortisol:DHEA ratio and IFN-alpha levels. OBJECTIVE: To
      evaluate in a longitudinal study whether steroid and cytokine modifications are
      associated with the evolution of physical changes and lipid alterations
      associated with LD. METHODS: Thirty-four HIV-1-positive men were followed during
      32.5 +/- 4.0 months and tested at four time-points. The patients were subdivided
      into five groups according to physical changes and anthropometric measurements:
      LD-negative, initially LD-negative becoming LD-positive, LD-positive unchanged,
      aggravated or improved. Serum lipids, apolipoproteins, adrenal steroids and
      cytokines were measured and compared with baseline values. RESULTS: (1) LD
      aggravation is associated with persistent elevated lipids, a decrease in serum
      DHEA, an increase in cortisol:DHEA ratio and persistent high levels of IFN-alpha.
      (2) LD improvement is associated with normalization of serum lipids, an increase
      in serum DHEA leading to normalization in cortisol:DHEA ratio, and normalization
      of IFN-alpha levels. (3) In LD-positive men evolution of VLDL cholesterol is
      negatively correlated with DHEA (r = -0.56, P < 0.01) and positively with
      cortisol:DHEA ratio (r = 0.62, P < 0.004) and with IFN-alpha (r = 0.57, P <
      0.01). (4) The switch to LD is associated with a decrease in serum DHEA. (5)
      Patients who remained LD-negative maintained normal lipids, elevated cortisol and
      DHEA, and normal cortisol:DHEA ratio and normal levels of IFN-alpha. CONCLUSIONS:
      This study indicates that cortisol:DHEA ratio and serum IFN-alpha levels are
      closely associated with clinical evolution and atherogenic lipid alterations in
      LD.

PMID- 12406028
TI  - Starvation reduces allergen-induced skin wheal responses and plasma substance P
      and vasoactive intestinal peptide in patients with atopic eczema/dermatitis
      syndrome.
AB  - The effect of starvation on allergen-induced skin wheal responses and plasma
      neuropeptide levels was not previously reported. Starvation for 24 h reduces
      allergen-induced skin wheal responses and plasma levels of substance P and
      vasoactive intestinal peptide in patients with atopic eczema/dermatitis syndrome,
      but not in control subjects. These results may have implications for the
      pathophysiology of the atopic eczema/dermatitis syndrome.

PMID- 12406029
TI  - Interferon-gamma administration to patients after major surgery influences
      cellular immunity without pro-inflammatory response.

PMID- 12406030
TI  - Diabetes in tomorrow's world: dark clouds do have silver linings.

PMID- 12406031
TI  - Adipose depot-specific effects of PPAR gamma agonists: a consequence of
      differential expression of PPAR gamma in adipose tissue depots?

PMID- 12406032
TI  - Cardiovascular risk management in primary care.

PMID- 12406033
TI  - Glyburide/metformin combination product is safe and efficacious in patients with
      type 2 diabetes failing sulphonylurea therapy.
AB  - AIM: To compare the efficacy, safety and tolerability of a fixed combination
      glyburide/metformin preparation with those of glyburide or metformin alone in
      patients with type 2 diabetes inadequately controlled by sulphonylurea, diet and
      exercise. METHODS: In this 16-week, randomized, double-blind, parallel group
      study, 639 patients with inadequate glycaemic control on at least half-maximal
      dose of sulphonylurea were randomly assigned to: glyburide 10 mg b.i.d. (n =
      164); metformin 500 mg (n = 153); glyburide/metformin 2.5 mg/500 mg (n = 160); or
      glyburide/metformin 5 mg/500 mg (n = 162). Titration was allowed to maximum doses
      of 2000 mg for metformin or 10 mg/2000 mg and 20 mg/2000 mg for
      glyburide/metformin 2.5 mg/500 mg and 5 mg/500 mg respectively. The primary
      outcome measure was HbA1c level after 16 weeks; secondary end-points included
      fasting and 2-h post-prandial plasma glucose. Adverse events (AEs) were recorded
      and summarized by treatment group. RESULTS: Both strengths of glyburide/metformin
      equally reduced mean HbA1c by 1.7% more than did glyburide alone (p < 0.001), and
      by 1.9% more than did metformin alone (p < 0.001). Final mean fasting plasma
      glucose concentrations were also lower in both glyburide/metformin groups than in
      the glyburide (-2.8 mmol/l, -51.3 mg/dl; p < 0.001) and metformin groups (-3.6
      mmol/l, -64.2 mg/dl; p < 0.001). Safety and tolerability were similar across all
      treatment groups, except for a higher incidence of gastrointestinal AEs in the
      metformin monotherapy group, and more patients reporting mild or moderate
      symptoms of hypoglycaemia while taking glyburide/metformin. CONCLUSIONS: Both
      glyburide/metformin tablet strengths produced, with equal efficacy, significantly
      better glycaemic control than monotherapy with either agent. These data also
      confirm that glycaemic efficacy does not require maximal sulphonylurea doses in
      combination with metformin.

PMID- 12406034
TI  - The influence of the Pro12Ala mutation of the PPAR-gamma receptor gene on
      metabolic and clinical characteristics in treatment-naive patients with type 2
      diabetes.
AB  - Peroxisome proliferator activated receptor-gamma is an important factor in
      adipocyte differentiation and energy metabolism and is thus a candidate gene for
      obesity, insulin resistance and dyslipidaemia. We therefore assessed the
      associations between the most common variant of the PPAR-gamma, the Pro12Ala
      (P12A) substitution in the PPAR-gamma 2 gene, with BMI, blood pressure, fasting
      plasma glucose, HbA1c, total cholesterol, LDL and HDL cholesterol and plasma
      triglyceride in 183 treatment-naive patients with type 2 diabetes (T2D). The P12A
      allele associated with lower fasting plasma glucose but had no influence on HbA1c
      or BMI. In obese patients (BMI > 29 kg/m2), the P12A substitution associated with
      elevated total and non-HDL cholesterol levels.

PMID- 12406035
TI  - Changes in risk factors for cardiovascular disease with body fat loss in obese
      women.
AB  - BACKGROUND: Current guidelines for obesity management emphasize the improvements
      in health risks associated with weight losses of 5-10% initial weight. However,
      most of the data is derived from periods of acute weight loss and may not
      represent the true effect in the longer term or in obese but otherwise healthy
      individuals. This study examines the temporal changes in risk factors for
      cardiovascular disease with weight change over 52 weeks. METHODS: In total, 57
      overweight women (age 43.7 +/- 9.1 years, mean BMI of 31.7 kg/m2, range 27.2-38.5
      kg/m2) with no other significant medical history, entered a milk-based, low
      energy weight loss programme for 12 weeks and were then monitored without further
      intervention until 52 weeks. Weight, fat mass, fasting plasma insulin, lipids and
      blood pressure were measured at 0, 12, 24 and 52 weeks. RESULTS: The mean weight
      change in sequential periods was -11.6% (p < 0.0001), +1.1% (p = 0.02) and +5.2%
      (p < 0.0001). The change from baseline to 1 year being -6.0% (p < 0.0001) an 11%
      (p < 0.0001) reduction in initial body fat mass. Initial weight loss (0-12 weeks)
      was positively correlated with greater longer term weight loss (0-52 weeks, r =
      0.75, p < 0.0001) and not with weight regain (12-52 weeks, r = 0.14, p = 0.28).
      Despite significant improvements in insulin sensitivity, lipid profile and blood
      pressure (BP) with acute weight loss, in the group overall, only benefits in BP
      were maintained after 52 weeks. However, improvements in insulin sensitivity were
      sustained in those who maintained more than 5% weight loss, and those with higher
      baseline metabolic risk had greater benefits with weight loss. Change in waist
      circumference was better than BMI or fat mass in predicting improvements in
      metabolic risk in these obese women. CONCLUSIONS: This study suggests, in
      otherwise apparently healthy obese women, the rationale of targeting individuals
      most likely to benefit from weight management. Most importantly it highlights the
      need to focus on achieving initial weight losses of greater than 10% to maintain
      longer term losses of at least 5% and the associated health benefits.

PMID- 12406036
TI  - Relationship between insulin resistance and accumulation of coronary risk
      factors.
AB  - We examined correlations between the frequency of insulin resistance and the
      accumulation of coronary risk factors in residents of rural comities in Japanese,
      using simple criteria for determination of insulin resistance based on evaluation
      by the euglycaemic-hyperinsulinaemic glucose clamp (GC) method. The subjects were
      376 men and 589 women living in two rural communities in Japan. We measured body
      mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP),
      triglyceride (TG), HDL cholesterol (HDL), and homeostasis model assessment (HOMA
      R). Correlations between HOMA-R and those parameters were examined. To assess the
      existence of insulin resistance in these subjects, we used a practical index
      based on the GC method. The subjects with value of HOMA-R >or= 1.73 have insulin
      resistance. In addition, the HOMA-R was divided into five quantiles based on the
      frequency distribution (0.60 or below, from 0.61 to 0.82, from 0.83 to 1.18, from
      1.19 to 1.69, and 1.70 or higher), to examine the concentration of risk factors
      in each group. In total, 74 (19.6%) of the men and 119 (20.3%) of the women had
      insulin resistance (HOMA-R >or= 1.73). It was found that the higher the HOMA-R,
      the higher was the number of coronary risk factors, such as hypertension,
      obesity, hypertriglyceridaemia and hypo HDL cholesterolaemia. The number of
      coronary risk factors was particular high in subjects with HOMA-R >or= 1.70. HOMA
      R in the case of no glucose loading is a useful and practical index for
      evaluation of insulin resistance and coronary risk factors in the epidemiological
      study.

PMID- 12406037
TI  - Effect of cogent db, a herbal drug, on plasma insulin and hepatic enzymes of
      glucose metabolism in experimental diabetes.
AB  - AIMS: The present study was designed to investigate the effect of cogent db, a
      polyherbal drug on blood glucose, plasma insulin and the activities of hepatic
      glucose metabolic enzymes in alloxan-induced diabetic rats. METHODS: Male Wistar
      rats body weight of 180-200 g (six normal and 18 diabetic rats) were used in this
      study. The rats were divided into four groups after the induction of alloxan
      diabetes. In the experiment, six rats were used in each group: Group 1, normal
      rats given 2 ml of saline; Group 2, diabetic control rats given 2 ml of saline;
      Group 3, diabetic rats given aqueous solution of cogent db (0.45 g/body kg
      weight); and Group 4, diabetic rats given aqueous solution of glibenclamide (600
      micro g/kg body weight). The treatment was given for 40 days. After the
      treatment, fasting blood glucose, plasma insulin, urine sugar and the activities
      of hepatic glucose metabolic enzymes were determined in normal and experimental
      animals. RESULTS: Treatment with cogent db resulted in a significant reduction in
      blood glucose and the activities of glucose-6-phosphatase and fructose-1,6
      bisphosphatase in the liver, whereas the level of plasma insulin and hepatic
      hexokinase activity were significantly increased in alloxan-diabetic rats.
      CONCLUSIONS: The present investigation suggests that cogent db controls the blood
      glucose level by increasing glycolysis and decreasing gluconeogenesis with a
      lower demand of pancreatic insulin than in untreated rats. This is possible
      because it regulates the activities of hepatic glucose metabolic enzymes.

PMID- 12406038
TI  - Orexin reverses cholecystokinin-induced reduction in feeding.
AB  - AIM: This study was designed to investigate the effect of orexin on anorexia
      induced by cholecystokinin (CCK),a peripheral satiety signal. METHODS: We
      administered orexin A (0.01-1 nmol/mouse) and CCK-8 (3 nmol/mouse) to mice. Food
      intake was measured at different time-points: 20 min, 1, 2 and 4 h post
      intracerebroventricular (i.c.v.) or intraperitoneal (i.p.) administrations.
      RESULTS: Intracerebroventricular-administered orexin significantly increased food
      intake in a dose-dependent manner. The inhibitory effect of i.p.-administered CCK
      8 on food intake was significantly negated by the simultaneous i.c.v. injection
      of orexin in a dose-dependent manner. CONCLUSIONS: Orexin reversed the CCK
      induced loss of appetite. Our results indicate that orexin might be a promising
      target for pharmacological intervention in the treatment of anorexia and cachexia
      induced by various diseases.

PMID- 12406039
TI  - Diabetic ketoacidosis associated with Metabolife: a report of two cases.
AB  - AIM: To describe two cases of diabetic ketoacidosis in newly diagnosed type 1-
      and type-2-diabetic individuals associated with Metabolife-356. METHODS: We
      report the acute hospitalizations and clinical courses of two individuals with
      diabetic ketoacidosis taking Metabolife-356. RESULTS: Both patients presented
      without a previous diagnosis of diabetes mellitus. One patient clinically has
      type 1 diabetes (positive islet cell antibodies and subnormal pancreatic beta
      cell function to glucagon stimulation) and is treated with insulin. The second
      patient, after 5 days of treatment with intravenous insulin of up to 25 units per
      hour, is now treated with oral medications. Several possible mechanisms may
      exist, including the increases in catecholamines and in blood glucose after
      ingestion of the ingredients of these supplements. Recent clinical trial data
      shows an increase in blood glucose (in non-diabetics) with these supplements
      despite significant weight loss at 8 weeks, although no association with diabetes
      mellitus has been shown in these closely monitored studies. CONCLUSIONS: Although
      no precipitating factor of diabetic ketoacidosis was found in these individuals,
      the dietary supplement Metabolife cannot be established as a precipitant.
      However, patients with diabetes should take this supplement only after
      consultation with their health care provider, as stated on the product label.
      Most individuals using this supplement meet the current criteria for screening to
      detect undiagnosed diabetes mellitus and should consider these tests.

PMID- 12406040
TI  - Impact of weight loss on the metabolic syndrome.
AB  - AIM: Individuals with the metabolic syndrome (MS), a clustering of risk factors
      [triglycerides, glucose, high-density lipoprotein cholesterol, blood pressure
      (BP), abdominal obesity] defined by the National Cholesterol Education Program
      (NCEP), are at high risk for coronary heart disease and type 2 diabetes mellitus,
      and may benefit from aggressive lifestyle modification. METHODS: We reviewed 1
      year of consecutive patients' charts to determine the prevalence of the MS in
      obese individuals enrolled in a medically supervised rapid weight loss programme,
      the correlation of weight change with the components of the MS, and response to
      diet-induced weight loss. RESULTS: Out of 185 individuals, 125 (68%) met the NCEP
      definition of the MS. A moderate decrease in weight (6.5%) induced by a very low
      calorie diet (VLCD) resulted in substantial reductions of systolic (11.1 mmHg)
      and diastolic (5.8 mmHg) blood pressure (BP), glucose (17 mg/dl), triglycerides
      (94 mg/dl) and total cholesterol (37 mg/dl) at 4 weeks (all p < 0.001). These
      improvements were sustained at the end of active weight loss (average 16.7 weeks;
      total weight loss 15.1%), with further significant reductions in BP and
      triglycerides. Weight loss was related to the changes in each criterion of the
      metabolic syndrome. CONCLUSIONS: The MS is prevalent in two-thirds of obese
      individuals enrolling in a structured weight loss programme. Moderate weight loss
      with a VLCD markedly improved all aspects of the MS.

PMID- 12406041
TI  - The effects of orlistat on body weight and glycaemic control in overweight
      patients with type 2 diabetes: a randomized, placebo-controlled trial.
AB  - AIM: To assess the long-term effects of orlistat on body weight, glycaemic
      control and cardiovascular risk factors in overweight patients with type 2
      diabetes. METHODS: This was a multicentre, randomized, placebo-controlled study
      with a 4-week placebo plus diet lead-in period and a 48-week, double-blind
      treatment period. Overweight or obese adults [body mass index (BMI) >or= 28
      kg/m2] with HbA1c of 6.5-11% and clinical type 2 diabetes were randomized to
      orlistat (120 mg t.i.d. n = 189) or placebo (n = 180) in conjunction with a low
      calorie diet. Patients had either received sulphonylurea therapy for at least 2
      months before the study or were not receiving any antidiabetic medication (the
      majority of which were drug-naive). RESULTS: After 1 year, patients in the
      orlistat group lost significantly more weight than patients in the placebo group
      (-5.4% vs. -3.6%; p = 0.006). Moreover, significantly more patients achieved
      weight loss of >or= 5% with orlistat compared with placebo (51.3% vs. 31.6%; p =
      0.0001). Patients treated with orlistat also had significantly greater
      improvements than placebo-treated patients in HbA1c (-0.9% vs. -0.4%; p < 0.001),
      fasting glucose (-1.6 vs.-0.7 mmol/l; p = 0.004) and post-prandial glucose (-1.8
      vs. -0.5 mmol/l; p = 0.003). In addition, orlistat-treated patients had a
      significantly greater reduction in LDL cholesterol compared with placebo.
      Overall, orlistat had a similar safety profile to placebo, with the exception of
      a higher incidence of generally mild and transient gastrointestinal events known
      to be associated with the mode of action of orlistat. CONCLUSIONS: Treatment with
      orlistat plus diet resulted in significant weight loss, improved glycaemic
      control and cardiovascular risk factor profile in overweight patients with type 2
      diabetes.

PMID- 12406042
TI  - Effects of metformin on bile salt transport by monolayers of human intestinal
      Caco-2 cells.
AB  - The antidiabetic biguanide metformin has been shown to increase faecal excretion
      of bile salts in type 2 diabetes. Cultured human intestinal Caco-2 cell
      monolayers provide a model of human enterocytes. These monolayers are used here
      to determine the effect of metformin on the secondary-active, sodium-linked
      transfer of 14C-glycocholate from the apical (brush border) to the basolateral
      (serosal) surface. During 24-h incubations, 10-2 mol/l metformin significantly
      reduced 14C-glycocholate transfer. This could not be attributed to alterations of
      monolayer integrity or Na+-K+ ATPase pump activity. For example, the secondary
      active transport of glucose and proline was not interrupted, and the inhibitory
      effect of metformin on bile salt transport was additive to the inhibitory effect
      of ouabain. The results suggest that metformin can act directly on intestinal
      enterocytes to reduce the active transfer of bile salts by a mechanism that is
      independent of Na+-K+ ATPase activity.

PMID- 12406043
TI  - TRP64ARG polymorphism of the beta 3-adrenergic receptor gene and obesity risk:
      effect modification by a sedentary lifestyle.
AB  - AIM: We performed a case-control study to assess the association between obesity
      risk and the Trp64Arg polymorphism of the beta 3-adrenergic receptor gene.
      METHODS: Obese subjects [n = 159; body mass index (BMI) > 30 kg/m2] and controls
      (n = 154; BMI < 25 kg/m2) were compared using multivariable logistic regression
      to control for potential confounders. RESULTS: A higher obesity risk (adjusted
      OR: 2.98; 95% CI: 1.00-8.56; p = 0.05) was associated with the Trp64Arg
      polymorphism among sedentary, but not among more active people. CONCLUSIONS: Our
      results suggest that the TRP64ARG polymorphism of the ADRB3 seems to be a risk
      factor for obesity that is dependent on a sedentary lifestyle.

PMID- 12406044
TI  - Ghrelin and cachexia.

PMID- 12406047
TI  - Neuropsychological and emotional challenges in a 38-year-old man with a brain
      tumor.

PMID- 12406048
TI  - Family perspectives of ovarian cancer.
AB  - PURPOSE: This qualitative study explored quality of life (QOL) in family
      caregivers of ovarian cancer patients to better define their needs for support.
      DESCRIPTION OF STUDY: One thousand one hundred pieces of correspondence written
      by family caregivers of ovarian cancer patients were contributed to the City of
      Hope investigators by the founder and editor of Conversations!: The International
      Newsletter for Those Fighting Ovarian Cancer. The investigators analyzed
      meaningful comments in the letters using content analysis methods. RESULTS:
      Comments by family caregivers reflected little concern for their own physical
      well-being and, instead, focused on the psychological, social, and spiritual
      aspects of their experiences. Correspondence on the psychological effects of
      caregiving demonstrated poor QOL stemming from feelings of lack of control and
      helplessness. Social data showed that family caregivers lacked support, were
      given to feelings of isolation, and experienced considerable anxiety regarding
      the genetic nature of the disease. Spiritual well-being was particularly
      important to caregivers, as they drew strength from their faith and were able to
      find positive meaning in their experiences. CLINICAL IMPLICATIONS: The study
      findings revealed that caregivers require additional support from the healthcare
      community, especially to address disease-specific needs in patients with ovarian
      cancer. The correspondence demonstrates a need in family caregivers to connect
      with others fighting the same disease. This study also identifies the need for
      support for at-risk women, as well as a continuing need for palliative-care
      services.

PMID- 12406049
TI  - Survivorship resources for post-treatment cancer survivors.
AB  - PURPOSE: The purpose of this project was to determine the scope of services and
      resources available to cancer survivors who have completed active treatment and
      their families at National Cancer Institute (NCI)-designated comprehensive cancer
      centers. DESCRIPTION OF STUDY: Patient education program contacts from the 37 NCI
      designated comprehensive cancer centers participated in a telephone interview.
      Program contacts were asked to identify the types of medical and psychosocial
      services that their respective cancer center offered. RESULTS: Telephone
      interviews were completed by patient education program contacts from all NCI
      designated comprehensive cancer centers for a total response rate of 100%.
      Services pertaining to lymphedema management were identified in 70% of cancer
      centers. Other common services identified specifically for post-treatment cancer
      survivors at cancer centers were professionally led support groups (49% of cancer
      centers), long-term medical care (38% of cancer centers), school re-entry
      programs (19% of cancer centers), nutrition counseling (14% of cancer centers),
      and counseling addressing fertility and sexual concerns (14% of cancer centers).
      CLINICAL IMPLICATIONS: Results from this project outline the range of services
      and resources that are provided to post-treatment cancer survivors by NCI
      designated comprehensive cancer centers, and can be used to develop standards of
      care for future cancer control programs.

PMID- 12406050
TI  - Adherence to moderate-intensity exercise during breast cancer therapy.
AB  - PURPOSE: The aims of this pilot study were the following: 1) to examine patterns
      of adherence to a brisk walking program in women receiving adjuvant chemotherapy
      or radiation therapy for newly diagnosed breast cancer using a prospective,
      randomized, controlled experimental design; 2) to examine the influence of
      disease symptoms and treatment side effects on exercise levels; and 3) to suggest
      methods that may improve future clinical trials of moderate-intensity exercise in
      similar populations. DESCRIPTION OF STUDY: Fifty-two patients with newly
      diagnosed breast cancer were randomly assigned to one of two treatment arms:
      usual care or usual care plus exercise. Those assigned to the exercise group
      received a standardized, self-administered, home-based brisk walking intervention
      in addition to usual care. Each day subjects completed self-report diary forms
      that elicited information about activity levels, and the occurrence of symptoms
      and side effects during cancer treatment. RESULTS: Analyses of self-reported
      daily activity levels revealed a diffusion of treatment effect. Fifty percent of
      the usual-care group reported maintaining or increasing their physical activity
      to a moderate-intensity level, while 33% of the exercise group did not exercise
      at the prescribed levels. Analyses of self-reported disease symptoms and
      treatment side effects did not reveal clinically meaningful differences between
      the two groups. CLINICAL IMPLICATIONS: The results of this study suggest that
      women who exercised regularly before receiving a breast cancer diagnosis
      attempted to maintain their exercise programs. Women who lead sedentary
      lifestyles may benefit from a structured exercise program that includes
      information and support related to exercise adherence strategies.

PMID- 12406051
TI  - Viatical settlements: effects on terminally ill patients.
AB  - PURPOSE: This study was performed to assess the knowledge, attitudes, and
      experiences with viatical settlements among hospice staff who provide financial
      counseling to terminally ill patients and their families. DESCRIPTION OF STUDY: A
      random sample of 300 hospices in the 50 states was selected from the National
      Hospice Directory. Staff members who provide financial counseling to patients and
      families were interviewed by phone using a 31-item structured questionnaire.
      RESULTS: The response rate was 80%. The results showed that only 4% of hospices
      provide information about viatical settlements to all patients, while 32% provide
      information only if asked. Only 9% of respondents rated themselves as very
      informed about viatical settlements, and 53% rated themselves as moderately
      informed. Of the 47 hospices where at least one patient had used a viatical
      settlement, 92% felt the patient had a positive experience using the resource. In
      response to a hypothetical case of a terminally ill patient considering a
      viatical settlement, 40% responded positively, while 51% were neutral. CLINICAL
      IMPLICATIONS: Among hospice financial counselors who have had experience with
      viatical settlements, most report positive experiences. When asked to respond to
      a hypothetical case, most respondents were either neutral or positive. However,
      lack of knowledge about viatical settlements may limit the availability of this
      resource for terminally ill patients and their families.

PMID- 12406052
TI  - Tapestry: a retreat program of support for persons living with cancer.
AB  - PURPOSE: In an effort to mitigate the negative psychological sequelae of a cancer
      diagnosis and cancer treatment, efforts have been made to explore a variety of
      psychosocial issues and interventions. This article describes the provision and
      preliminary evaluation of a novel psychosocial service delivery, a residential
      "retreat" program called Tapestry, which is run under the aegis of the
      established cancer care community in Alberta, Canada. OVERVIEW: Retreat programs
      offer a novel way to provide psychosocial support for those persons who are
      living with cancer. The retreats are unique in the provision of a respite and the
      opportunity to address the isolation and other existential issues arising from a
      cancer diagnosis. The program described in this article has provided such a
      service six times per year since 1998. The intervention is described, and
      preliminary evaluation data are presented. CLINICAL IMPLICATIONS: Cancer care has
      begun to move beyond a solely biomedical paradigm toward a more holistic ethos in
      service delivery and research orientation. While the face value of and demand for
      such programming continues to grow, few residential psychosocial programs are
      offered under the auspices of conventional cancer care centers, and little work
      has been done to examine the nature and possible efficacy of retreat programs as
      a valid forum for psychosocial service delivery.

PMID- 12406053
TI  - Patient and caregiver interest in internet-based cancer services.
AB  - PURPOSE: The primary goal of this study was to identify the needs for, the
      interest in, and the feasibility of the implementation of an Internet-based
      cancer services web site. Additionally, group differences (racial, patient vs
      caregiver, or rural vs urban) were identified that might influence the
      implementation of such a project. DESCRIPTION OF STUDY: Patients with cancer and
      caregivers (N = 319) in the waiting rooms of a cancer center located within a
      southeastern medical university completed questionnaires regarding their interest
      in Internet-based services. Topics included the likelihood of using Internet
      based services, interest in home healthcare services delivered via a personal
      computer, and knowledge about and use of the Internet. RESULTS: Results indicated
      that most patient and caregiver respondents were interested in Internet-based
      cancer-related services such as information related to treatment (80%),
      conversations with physicians via the Internet (70%), and online support groups
      (65%). In addition, respondents reported that they would be likely to use such
      services (70%) and were interested in home healthcare services delivered via
      personal computers (60%). No group differences were found across ethnic groups,
      geographic settings, and patient status (patient vs caregivers) on these
      variables. Minorities, older individuals, and less educated individuals were less
      likely to have knowledge of and to have used the Internet. CLINICAL IMPLICATIONS:
      Patients with cancer and their caregivers are interested in supplementing in
      person services with Internet-based services relating to their cancer treatment.
      Special efforts need to be made to reach ethnic minorities, the elderly, and
      those with less education with Internet-based programs.

PMID- 12406054
TI  - Bladder cancer: epidemiology, diagnosis, and management.
AB  - PURPOSE: The purpose of this article is to present an overview of the
      epidemiology diagnosis, and management of bladder cancer, with a focus on the
      early stage of this disease. OVERVIEW: English-language articles published
      between 1990 and 2000, as well as selected abstracts published in non-English
      languages before 1990, were reviewed. Epidemiologic data clearly indicate that
      bladder cancer is much more common in men, White persons, and the elderly.
      Cigarette smoking appears to be the most significant environmental risk factor.
      Screening for the disease is currently not standard in the United States or
      Canada. Potential tests include urine cytology, hematuria dipstick, and the
      urinary biomarkers. Diagnosis is made most often on the basis of the findings of
      cystoscopy, tumor biopsy, and urine cytology. Transurethral resection (TUR) of
      the tumor is generally the first-line treatment for superficial disease.
      Cystectomy is the "gold standard" treatment for invasive disease in many
      countries, although trimodality therapy (TUR, radiation, systemic chemotherapy)
      has shown promise as a bladder-preserving strategy. Intravesical therapy is
      effective for preventing disease recurrence, although its role in slowing disease
      progression is uncertain. Chemotherapy and radiation also can be used with
      cystectomy to treat or prevent pelvic recurrence of invasive disease or to
      prolong life in patients with metastatic disease. CLINICAL IMPLICATIONS: Bladder
      cancer is a commonly occurring disease. Prevention efforts must focus on the
      avoidance or cessation of cigarette smoking and on public education relating to
      known environmental risk factors. Patient and disease factors must be considered
      in making treatment decisions and determining prognosis. Careful follow-up after
      treatment is essential. It is hoped that ongoing research on potential tumor
      markers and tumor-specific therapies ultimately will result in improved clinical
      outcomes for patients with this malignancy.

PMID- 12406055
TI  - Cancer genetics: information sources for patients and families.

PMID- 12406056
TI  - Darbepoetin alfa: a review of its use in patients with cancer.

PMID- 12406060
TI  - Pyothorax-associated lymphoma.

PMID- 12406061
TI  - Thrombus in harvested marrow from a patient with recent heparin-induced
      thrombocytopenia.

PMID- 12406062
TI  - The investigation and management of neonatal haemostasis and thrombosis.
AB  - These guidelines address developmental aspects of neonatal haemostasis and
      thrombosis, the laboratory investigation of the neonate, and the diagnosis and
      clinical management of haemostatic and thrombotic conditions occurring in this
      period (defined as the first 4 weeks of life following birth). Relevant
      scientific papers were identified by a systematic literature review from Medline
      1975-2000 using index terms which incorporated the various component subjects of
      these guidelines. Further publications were obtained from the references cited
      and from reviews known to the members of the working party and to the Haemostasis
      and Thrombosis Task Force. Evidence and graded recommendations presented in these
      guidelines are in accordance with the US Agency for Health Care Policy and
      Research, as described in the Appendix. It will be noted that there is a lack of
      a strong evidence base for many of the recommendations suggested, as the
      appropriate clinical and laboratory trials have not been and perhaps never will
      be undertaken in neonates. Most of the recommendations are therefore of Grade C
      evidence levels IV: higher levels are mentioned specifically throughout the
      document when relevant.

PMID- 12406063
TI  - Optimization of factor VIII replacement therapy: can structural studies help in
      evading antibody inhibitors?

PMID- 12406064
TI  - Factor VIII - novel insights into form and function.

PMID- 12406065
TI  - The uptake of recombinant Factor VIII in the Netherlands.
AB  - In comparison with other biotechnology substitutions, the adoption of recombinant
      Factor VIII (rFVIII) has been relatively slow. We sent a postal questionnaire to
      all Dutch haemophilia patients and haemophilia-treating physicians, to determine
      which factors predict whether a patient uses plasma-derived FVIII (pdFVIII) or
      rFVIII and to investigate patients' and doctors' opinions on both products. Fifty
      six per cent of patients received rFVIII. This percentage varied widely between
      centres. Only one doctor would choose to use pdFVIII if he suffered from
      haemophilia A himself, and 74% would choose to use rFVIII. Younger patients,
      those not infected with the human immunodeficiency virus or hepatitis C, and
      those who did not have family members who used pdFVIII switched more often from
      pdFVIII to rFVIII. Patients who rated themselves as innovative, who had family
      members who used rFVIII, and those who were treated in a large haemophilia
      treatment centre were also more likely to have switched. For physicians and
      patients alike, the respondents generally did not see large differences between
      rFVIII and pdFVIII, except for the risk of infections and the knowledge of long
      term effects (both larger for pdFVIII). Although haemophilia patients represent
      one of the most empowered patient groups, physicians appear to have been
      influential in choosing between pdFVIII and rFVIII.

PMID- 12406066
TI  - Antibodies to factor VIIa in patients with haemophilia and high-responding
      inhibitors.
AB  - The haemostatic effect of by-passing agents such as activated prothrombin complex
      concentrates (aPCC) and recombinant factor VIIa is inadequate in some patients
      with severe haemophilia and high-responding inhibitors. Theoretically, this could
      be due to antibody reactivity to procoagulant proteins other than the deficient
      factor. To evaluate this hypothesis, immunoglobulin (Ig) fractions from six multi
      transfused patients (three haemophilia A and three haemophilia B) were purified
      on protein A sepharose and then subjected to immunoaffinity chromatography on
      factor IX sepharose and factor VIIa sepharose. All three Ig fractions from the
      haemophilia B patients, but not commercially available Ig, contained antibodies
      that bound to both gels. None of the haemophilia A patients had antibodies to
      factor IX but all three had antibodies towards factor VIIa. The immunoaffinity
      purified antifactor IX and VIIa antibodies from the haemophilia B patients
      inhibited thrombin formation in vitro using Feiba as active enzyme, but had no
      significant effect in the presence of NovoSeven. In contrast, no inhibitory
      effect was observed with the antifactor VIIa antibodies from the haemophilia A
      patients. Cross-reactivity to factor IX was seen for the antifactor VIIa
      antibodies from the patients with haemophilia B. Our findings show that antibody
      reactivity to other procoagulant factors such as factor VIIa exists in patients
      with high-responding inhibitors and that these antibodies may have an inhibitory
      potential that correlates to the amount of active enzyme present. The
      characterization of the antibody profile may facilitate an optimal treatment with
      by-passing agents in severe bleeding events.

PMID- 12406067
TI  - Human platelet alloantigen polymorphism in Glanzmann's thrombasthenia and its
      impact on the severity of the disease.
AB  - Glanzmann's thrombasthenia (GT) is an autosomal recessive disorder of platelets
      caused by the deficiency or abnormality of platelet receptors. Several platelet
      alloantigen systems reside on glycoprotein (GP) IIb and GPIIIa, of which the
      human platelet antigen 1 (HPA-1) system is important. Studies have shown that, in
      the normal population, the HPA-1b phenotype results in increased platelet
      aggregation and increased fibrinogen binding, increasing the risk of myocardial
      infarction. GT produces severe bleeding, but in a subset of patients has a
      relatively milder course. Forty-one GT patients and 100 healthy control subjects
      were genotyped for platelet alloantigens HPA-1 to HPA-6, using PCR-ASA
      (polymerase chain reaction-allele-specific amplification), and for GPIIb-IIIa
      expression and fibrinogen binding using flow cytometric techniques. Platelet
      alloantigen distributions were similar in the patient and control groups. With
      the exception of the two HPA-1b/1b homozygous patients (> 10%), 25 GT patients
      had less than 5% aggregation to 6 micro mol/l ADP, and 16 patients showed between
      5% and 10% aggregation to 6 micro mol/l ADP. Seven out of 37 patients with HPA
      1a/1a phenotype showed 1-5% fibrinogen binding and GPIIb-IIIa receptors. The two
      HPA-1b/1b patients showed 34.6% and 32% fibrinogen binding and > 10% GPIIb-IIIa
      receptors. This study determined the platelet alloantigen distribution in a large
      cohort of unrelated GT patients from western India. GT patients homozygous for
      HPA-1b/1b had higher levels of platelet aggregation and fibrinogen binding as
      well as a milder course, as evidenced by infrequent epistaxis and no transfusion
      requirement to date.

PMID- 12406068
TI  - Platelet autoantibodies and lupus-associated thrombocytopenia.
AB  - To characterize the antigenic targets of anti-platelet antibodies (APA) found in
      systemic lupus erythematosus (SLE)-associated thrombocytopenia, 48 patients with
      immune thrombocytopenia and SLE were compared with 20 patients with SLE who had
      never been thrombocytopenic. Both cases and controls were tested for circulating
      APA by an indirect platelet suspension immunofluorescence assay (PSIIFT) and by
      indirect monoclonal antibody specific immobilization of platelet antigens
      (MAIPA). A direct platelet suspension immunofluorescence assay (PSIFT) was also
      used for antibodies bound to platelets in vivo in thrombocytopenic patients; 13
      of them with high titres of platelets-bound APA were investigated by direct and
      indirect MAIPA and platelet eluate analysis. Circulating APA were detected by
      PSIIFT in 88% of cases and 55% of controls (P = 0.0066) and platelet-bound
      antibodies were detected by PSIFT in 90% of cases. Indirect MAIPA detected
      specific APA (mainly directed against GpIIbIIIa) in 36% of cases and only 5% of
      the controls (P = 0.0076). Nine out of the 13 fully investigated thrombocytopenic
      patients (69%) had a positive direct MAIPA and/or APA detected in platelet
      eluates. In conclusion, the production of specific anti-platelet autoantibodies,
      mainly directed against GpIIb/IIIa, and their binding to platelet membrane plays
      an important role in the pathogenesis of SLE-associated thrombocytopenia.

PMID- 12406069
TI  - Expression of stanniocalcin-1 in megakaryocytes and platelets.
AB  - Stanniocalcin-1 (STC) is a 56-kDa homodimeric glycoprotein hormone originally
      found in fish, in which it regulates calcium/phosphate homeostasis and protects
      against toxic hypercalcaemia. The recently characterized human STC is 80% similar
      to fish STC. We have earlier reported a high expression of STC in terminally
      differentiated human and rodent brain neurones, and found that STC contributes to
      the maintenance of their integrity. Here, we report that mature megakaryocytes
      and platelets display high STC content. K562 cells, induced to megakaryocytoid
      differentiation in vitro, acquired expression of STC, which was not seen in
      untreated K562 cells or cells induced to erythroid differentiation.

PMID- 12406070
TI  - Lupus anticoagulant testing: improvements in performance in a UK NEQAS
      proficiency testing exercise after dissemination of national guidelines on
      laboratory methods.
AB  - Laboratory screening for lupus anticoagulant (LA) has been shown to be suboptimal
      in several studies. Guidelines have recently been published by an expert group
      for the British Committee for Standards in Haematology, in an attempt to
      standardize and improve screening procedures. The value of using screening tests
      conforming with these guidelines was investigated in a United Kingdom National
      External Quality Assessment Scheme (UK NEQAS) proficiency testing exercise. The
      correct diagnosis was achieved by 97% of laboratories for a LA-negative sample.
      However, 18.3% of centres reported a false-negative result for a sample from a LA
      positive subject. A significantly higher proportion of centres that used methods
      conforming with the published guidelines achieved the correct diagnosis for this
      sample (P < 0.002, chi-square test). A wide variety of screening tests were used
      by laboratories in this study. Within-method agreement could be improved by the
      use of a common normal pooled plasma to determine ratios. However, between-method
      agreement was not improved by this procedure. We conclude that adoption of
      methods compliant with national guidelines may improve the diagnosis of LA. There
      is a need, however, for reference and standardization materials to ensure further
      improvement in the accuracy of LA methods.

PMID- 12406071
TI  - Reliability of point-of-care prothrombin time testing in a community clinic: a
      randomized crossover comparison with hospital laboratory testing.
AB  - The success in achieving therapeutic international normalized ratio (INR) targets
      in the control of warfarin using a whole-blood point-of-care testing (POCT)
      monitor (CoaguChek) in a community clinic was compared with hospital laboratory
      coagulometer prothrombin time (PT) testing in a randomized crossover study. Forty
      six patients were randomized into two groups. At each visit, capillary blood was
      taken for the POCT monitor and venous blood for the laboratory coagulometer. In
      Group 1, for 6 months, dosage was based on the CoaguChek and for the second 6
      months on the coagulometer. In the second group, the order was reversed. Dosages
      were determined using the dawn ac computer programme. Success was assessed by the
      percentage of time patients were maintained within the INR targets. Agreement
      between laboratory and monitor INR, and patient satisfaction were also assessed.
      Results with the POCT monitor compared well with the hospital coagulometer. Time
      in INR target range between the groups was similar, with 60.9% on the POCT
      monitor and 59.3% with the laboratory coagulometer in Group 1 and in Group 2,
      respectively, 64.3% and 63.4% with no significant difference in mean INR. An INR
      above 4.0 gave some discrepant results. International Sensitivity Index
      calibrations of the two test systems indicated that the INRs were dependable.
      Patient questionnaires showed greater satisfaction with community POCT
      monitoring.

PMID- 12406072
TI  - A family of textilinin genes, two of which encode proteins with antihaemorrhagic
      properties.
AB  - Two peptides, textilinins 1 and 2, isolated from the venom of the Australian
      common brown snake, Pseudonaja textilis textilis, are effective in preventing
      blood loss. To further investigate the potential of textilinins as
      antihaemorrhagic agents, we cloned cDNAs encoding these proteins. The isolated
      full-length cDNA (430 bp in size) was shown to code for a 59 amino acid protein,
      corresponding in size to the native peptide, plus an additional 24 amino acid
      propeptide. Six such cDNAs were identified, differing in nucleotide sequence in
      the coding region but with an identical propeptide. All six sequences predicted
      peptides containing six conserved cysteines common to Kunitz-type serine protease
      inhibitors. When expressed as glutathione S-transferase (GST) fusion proteins and
      released by cleavage with thrombin, only those peptides corresponding to
      textilinin 1 and 2 were active in inhibiting plasmin with Ki values similar to
      those of their native counterparts and in binding to plasmin less tightly than
      aprotinin by two orders of magnitude. Similarly, in the mouse tail vein blood
      loss model only recombinant textilinin 1 and 2 were effective in reducing blood
      loss. These recombinant textilinins have potential as therapeutic agents for
      reducing blood loss in humans, obviating the need for reliance on aprotinin, a
      bovine product with possible risk of transmissible disease, and compromising the
      fibrinolytic system in a less irreversible manner.

PMID- 12406073
TI  - C-reactive protein in the diagnosis of deep vein thrombosis.
AB  - The role of C-reactive protein (CRP) in the diagnosis of suspected deep vein
      thrombosis (DVT) and a possible advantage of its additional evaluation with D
      dimer has not been clearly evaluated. We therefore studied plasma CRP and D-dimer
      levels in 233 consecutive patients with suspected DVT; the final diagnosis was
      based on the results of colour duplex ultrasound or venography. DVT was diagnosed
      in 31.3%. CRP and D-dimer correlated significantly (r = 0.64, P < 0.01); both
      were increased significantly in patients suffering from DVT (P < 0.001).
      Multivariate analysis revealed a significant influence of the presence of DVT (P
      < 0.001), the presence of malignancy (P < 0.001) and the presence of inflammatory
      diseases (P = 0.009) on plasma CRP, while there was no significant influence of
      the duration of symptoms (P = 0.30). The sensitivity (75% vs 93%) to specificity
      (69% vs 55%) relationship showed inferior results for CRP compared with D-dimer;
      its additional evaluation did not improve the diagnostic value of D-dimer. We
      conclude that CRP can provide additional information neither for the diagnostic
      process in patients with suspected DVT nor for the differential diagnosis of DVT
      and inflammatory diseases.

PMID- 12406074
TI  - Factor VIII deficiency not induced by FVIII gene mutation in a female first
      cousin of two brothers with haemophilia A.
AB  - In this study, we reinvestigated a 20-year-old woman, the first cousin of two
      brothers with severe haemophilia A. This patient was previously assumed to be a
      carrier of haemophilia A due to her FVIII deficiency. We identified a novel FVIII
      gene mutation in the family and demonstrated that the FVIII deficiency in this
      female patient did not result from this gene mutation, but was linked to
      molecular defects in the von Willebrand factor gene.

PMID- 12406075
TI  - Analysis of factor VIII inhibitors in a haemophilia A patient with an Arg593-
      >Cys mutation using phage display.
AB  - We characterized anti-factor VIII antibodies in a mild haemophilia A patient with
      an Arg593-->Cys mutation in the A2 domain, using V gene phage-display technology.
      All isolated single-chain variable-domain antibody fragments were directed
      against residues Arg484-Ile508, a binding site for factor VIII inhibitors in the
      A2 domain. After a further period of replacement therapy, a transient rise in
      inhibitor titre was observed. These antibodies were directed against the A2
      domain. Activation of a pre-existing pool of B cells, which express antibodies
      against residues Arg484-Ile508, could explain the rapid anamnestic response.

PMID- 12406076
TI  - Severe methylenetetrahydrofolate reductase deficiency revealed by a pulmonary
      embolism in a young adult.
AB  - Deficiency in methylenetetrahydrofolate reductase (MTHFR), the enzyme involved in
      the remethylation of homocysteine to methionine using methyltetrahydrofolate as
      cofactor, induces hyperhomocysteinaemia, homocysteinuria, hypomethioninaemia and
      low methylfolate levels. Diagnosis usually occurs during infancy because of
      various neurological abnormalities. We report MTHFR deficiency diagnosed in an
      adult woman after a pulmonary embolism. Her adult sister, intellectually
      retarded, suffered from the same disease. Molecular analysis of the MTHFR gene
      exhibited four different mutations (two missense mutations, one exon skipping and
      C677T). The impact of these mutations was analysed through the biological
      abnormalities in the parents and children.

PMID- 12406077
TI  - Monensin-mediated growth inhibition in human lymphoma cells through cell cycle
      arrest and apoptosis.
AB  - Monensin, a Na+ ionophore, regulates many cellular functions, including
      apoptosis. We investigated the in vitro antiproliferative effect of monensin on
      nine human lymphoma cell lines. Monensin significantly inhibited the
      proliferation of all the lymphoma cell lines examined with a 50% inhibition
      concentration of about 0.5 micromol/l, and induced a G1 and/or a G2-M phase
      arrest in these cell lines. To address the antiproliferative mechanism of
      monensin, we examined the effect of this drug on cell-cycle-related proteins in
      CA46 cells (both G1 and G2 arrest) and Molt-4 cells (G2 arrest). Treatment with
      monensin for 72 h decreased CDK4 and cyclin A levels in CA46 cells, and cdc2
      levels in Molt-4 cells. In monensin-treated CA46 cells, increased p21-CDK2, p27
      CDK2 and p27-CDK4 complex forms were observed. And, in monensin-treated Molt-4
      cells, increased p21-cdc2 complex form was detected. Furthermore, the activities
      of CDK2- and CDK4-associated kinases were reduced in association with Rb
      hypophosphorylation in monensin-treated CA46 cells. The activity of cdc2
      associated kinase was decreased in both cell lines, which was accompanied by
      induction of Wee1. Also, monensin induced apoptosis in these cell lines, as
      evidenced by annexin V binding assay and flow cytometric detection of sub-G1 DNA
      content. This apoptotic process was associated with loss of mitochondria
      transmembrane potential (Delta(psi)m). Taken together, these results demonstrated
      for the first time that monensin potently inhibits the proliferation of human
      lymphoma cell lines via cell cycle arrest and apoptosis.

PMID- 12406078
TI  - The value of bone marrow examination in the staging of Hodgkin's lymphoma: a
      review of 955 cases seen in a regional cancer centre.
AB  - Bone marrow aspirates (BMA) and trephine biopsies (BMT) are commonly performed in
      the staging of patients with newly diagnosed Hodgkin's lymphoma (HL) but the
      value of these procedures is controversial. The purpose of this study was to
      evaluate the predictive value of the blood count and erythrocyte sedimentation
      rate (ESR) for bone marrow involvement (BMI) and the influence of BMI on stage
      and prognostic score. A retrospective analysis of 955 patients with newly
      diagnosed HL entered into clinical trials in a regional cancer centre between
      1975 and 1999 was performed. BMI was identified by BMT in 50 patients (5.2%) but
      in only five of these by BMA. The negative predictive values of a normal full
      blood count (FBC) and ESR for absence of BMI were 98.8% and 97.3%, respectively,
      and the positive predictive value of an abnormal FBC and ESR for presence of BMI
      were both 6.7%. BMT did not alter initial patient management in a single case but
      provided valuable prognostic information in certain subgroups of patients. BMA
      gave no additional staging information over BMT and abnormalities of blood count
      and ESR were poor predictors of infiltration. We conclude that BMA should be
      abandoned for staging purposes in HL and BMT restricted to patients with stage
      IIB or III disease, for whom valuable prognostic information may be obtained.

PMID- 12406079
TI  - Incidence and nature of CD20-negative relapses following rituximab therapy in
      aggressive B-cell non-Hodgkin's lymphoma: a retrospective review.
AB  - Re-treatment with rituximab for B-cell non-Hodgkin's lymphoma (NHL) relapsing
      after previous rituximab therapy has recently been shown to be clinically
      efficacious. Although the mechanism of resistance to rituximab re-treatment in
      non-responding patients is unknown, it is possible that loss of CD20 expression
      in the relapsed NHL could be important in some patients. We examined the
      incidence and nature of CD20 negative relapses following rituximab therapy in
      aggressive B-cell NHL treated at our institution. Of a total of 18 patients who
      received rituximab, 13 have relapsed, with 10 patients subsequently undergoing
      repeat tissue biopsy. Six of these 10 patients (60%) were shown to have lost CD20
      expression by either immunohistochemistry and/or flow cytometry. Furthermore,
      three of the six patients who relapsed with CD20-negative NHL also suffered
      relapses at unusual anatomical sites. We conclude that loss of CD20 expression in
      aggressive B-cell NHL relapsing post-rituximab therapy is common. As such, repeat
      tissue biopsy should be undertaken to document CD20 expression by both flow
      cytometry and immunohistochemistry prior to considering repeated courses of
      rituximab in relapsed aggressive lymphomas.

PMID- 12406080
TI  - Major histocompatibility complex abnormalities in non-Hodgkin lymphomas.
AB  - An optimal antitumoral immune response requires the participation of both CD8 and
      CD4 T lymphocytes, which are activated by peptide antigen presentation via human
      leucocyte antigen (HLA) class I and class II molecules respectively. Loss of HLA
      molecules has been observed in different malignancies, and provides a mechanism
      for escape from immune surveillance. Furthermore, HLA-G, a class Ib molecule, is
      considered to be an immune tolerance-inducing molecule. HLA-G expression on
      tumour cells could provide a further mechanism for immune escape. To determine
      the frequency and the pattern of HLA defects in non-Hodgkin lymphomas (NHL), HLA
      expression was prospectively studied in 614 NHL cases, using flow cytometry.
      Furthermore, HLA-G expression was tested in 50 cases, including 20 cases selected
      on the basis of their defective HLA class I expression. In 64 cases (10.4%),
      lymphomatous cells exhibited lower HLA class I mean fluorescence intensity
      compared with reactive cells. Their characteristics were (1) the diversity of
      histological entities; (2) the significant frequency of relapse or
      transformation; (3) the increased incidence of high-grade NHL compared with low
      grade; and (4) the severity of the class I defect in 50% of the cases, mainly in
      high-grade NHL. A defect in HLA-DR expression was always associated with a severe
      class I defect (12 cases; 2%). The HLA-G protein was detected in three class I
      defective cases. These HLA alterations frequently appeared as a secondary event
      at relapse or at transformation, suggesting a direct role in lymphomagenesis.

PMID- 12406081
TI  - Differentiation of anti-tumour cytotoxic T lymphocytes from autologous peripheral
      blood lymphocytes in non-Hodgkin's lymphomas.
AB  - We have previously reported that specific anti-tumour cytotoxic T cells (CTL) can
      be differentiated from tumour-infiltrating lymphocytes (TIL) in non-Hodgkin's
      lymphoma. We found that the combination of interleukin (IL)-1, IL-2 and IL-12 was
      very efficient for expansion of CD8+ T-cell receptor (TCR)alphabeta+ T cells and
      for development of their ability to specifically lyse tumour cells. In this
      study, we investigated whether anti-tumour T cells could be generated from the
      peripheral blood of patients using the culture protocol developed for TIL.
      Autologous T cells and tumour B cells from five patients were included in this
      study. It was found that polyclonal anti-tumour cytotoxic effector cells were
      generated when cultured in the presence of IL-1beta, IL-2 and IL-12.
      Interestingly, tumour cells were lysed by perforin/granzyme-mediated cytolysis
      and not by CD95-mediated apoptosis. By performing inhibition experiments, it was
      observed that both CD8+ and CD4+ T cells were responsible for the cytotoxic
      effect and that they were able to recognize malignant B cells by either a major
      histocompatibility complex (MHC)-restricted or MHC-non-restricted mechanism.
      Intriguingly, in addition to interferon-gamma and tumour necrosis factor-alpha,
      IL-10 was secreted continuously during culture. The source of patient T cells
      used for the generation of anti-tumour CTL should be based on the results
      obtained with peripheral blood lymphocytes and TIL.

PMID- 12406082
TI  - Hodgkin's disease in the elderly: a population-based study.
AB  - This study evaluated the incidence and outcome of Hodgkin's disease (HD) in older
      patients using a population-based approach. In total, 102 patients (52 men, 50
      women) aged >or= 60 years presented in the Northern Health Region of England
      (population of 3.09 million) between 1 January 1991 and 31 December 1998 and were
      studied prospectively. The age-specific incidence was 1.97/100,000 for those aged
      60-69 years, and 2.18/100,000 for those aged 70 years or over. The median age of
      the cohort was 70 years (range 60-91) and the median follow up was 63 months
      (range 20-113). Out of 95 treated patients, 70 (74%) obtained complete or good
      partial (> 90% response) remissions. In the 60 to 69-year-old group, the disease
      specific survival at 5 years was 100% for those presenting with early stage
      disease and 52% for those with advanced stage disease. In patients aged >70 years
      the 5 year disease-specific survival was 36% in patients with early stage and 14%
      for patients with advanced stage disease. The survival of patients with Epstein
      Barr virus (EBV)-positive tumours was significantly poorer than that of patients
      with EBV-negative tumours (P = 0.007); median survival in the former group was 20
      months versus undefined in the latter group. In total, 43 deaths were due to
      progressive HD and five were treatment-related. This study defined the incidence
      of HD in our population and demonstrated that the prognosis of elderly patients,
      particularly those with advanced stage disease, has not improved concurrently
      with that of patients aged < 60 years old. Novel approaches to assessment and
      treatment are necessary.

PMID- 12406083
TI  - Isolated parenchymal lung involvement in children with stage IV Hodgkin's
      disease: results of the UKCCSG HD8201 and HD9201 studies.
AB  - We retrospectively reviewed the case notes of 27 patients who were diagnosed with
      stage IV Hodgkin's disease (HD) because of isolated parenchymal pulmonary
      involvement on chest radiograph and computerized tomography scan (excluding
      subcategory E). Ten were boys and 15 had B symptoms. Median age at diagnosis was
      13.6 years (range 6.1-16.2). All received 6-8 cycles of ChlVPP (chlorambucil,
      vinblastine, procarbazine and prednisolone) and two had additional whole lung
      irradiation (12 Gy). Ten patients (37%) relapsed or progressed. Seven survive
      following second-line therapy while three died, two of HD and one of secondary
      acute myeloid leukaemia 4 years from diagnosis. At the time of analysis, the
      median follow-up of patients was 56 months (range 9-127). The event-free survival
      (EFS) was 58.4% (95% CI 38.5-75.8%) at both 5 and 10 years from diagnosis, and
      the overall survival (OS) was 84.2% (95% CI 61.8-94.6%) at both 5 and 10 years
      from diagnosis. We conclude that the outcome for HD patients defined as stage IV,
      because of isolated parenchymal lung involvement, is encouraging and compares
      favourably with other extra lymphatic organ involvement. Combination chemotherapy
      is effective in achieving long-term remission and whole lung irradiation is
      unnecessary.

PMID- 12406084
TI  - Prospective molecular monitoring of BCR/ABL transcript in children with Ph+ acute
      lymphoblastic leukaemia unravels differences in treatment response.
AB  - Children with Philadelphia-chromosome-positive (Ph+) acute lymphoblastic
      leukaemia (ALL) represent a subgroup at very high risk for treatment failure,
      despite intensive chemotherapy. However, recent retrospective studies showed that
      Ph+ childhood ALL is a heterogeneous disease with regard to treatment response.
      We have prospectively monitored, by reverse transcription polymerase chain
      reaction (RT-PCR) during follow-up, the presence of the BCR/ABL fusion transcript
      in Ph+ ALL children diagnosed in the Italian multicentre Associazione Italiana
      Ematologia Oncologia Pediatrica ALL-AIEOP-95 therapy protocol. To our knowledge,
      this is the first report on the evaluation of minimal residual disease (MRD) in
      childhood Ph+ ALL prospectively enrolled in an intensive, Berlin-Frankfurt
      Munster (BFM)-type treatment protocol. Twenty-seven of 36 (75.0%) Ph+ patients
      consecutively enrolled into the high-risk group of the AIEOP-ALL protocol between
      May 1995 and October 1999 were successfully analysed. Twenty were good responders
      to the pre-phase of prednisone/intrathecal methotrexate treatment (PGR) and seven
      were poor responders (PPR). Within the PPR group, the RT-PCR monitoring
      constantly showed positivity for the BCR/ABL fusion transcript and all the
      patients died of disease progression. In contrast, highly sensitive qualitative
      RT-PCR monitoring revealed heterogeneity within the PGR group of Ph+ childhood
      ALL patients. Three different subgroups could be defined, according to the
      clearance of Ph+ cells within the first 5 months of treatment. This provides
      useful information on the capability of chemotherapy to reduce the leukaemic
      clone, with prognostic implications.

PMID- 12406085
TI  - Identification of an ETV6-ABL2 fusion transcript in combination with an ETV6
      point mutation in a T-cell acute lymphoblastic leukaemia cell line.
AB  - ETV6, a member of the Ets family of transcription factors, is frequently
      rearranged to various translocation partners in human leukaemias. We previously
      described a CD3+/TCRalpha/beta+ mature T-cell acute lymphoblastic leukaemia (T
      ALL) cell line, MT-ALL, carrying a t(1;10;12)(q25; p13;p13) with cytokine
      inducible lineage switch into the myeloid lineage. Using reverse transcription
      polymerase chain reaction with primers complementary to ETV6 and ABL2, two ETV6
      ABL2 fusion transcripts were identified in MT-ALL which resulted from alternative
      splicing of an ABL2 exon. The fusion transcripts code for putative ETV6-ABL2
      fusion proteins containing the pointed domain of ETV6 and almost the complete
      ABL2 protein, including the SH2, SH3 domains and the protein tyrosine kinase
      domain (PTK). Identical ETV6-ABL2 fusion transcripts have been reported in an
      acute myeloid leukaemia (AML) M3 cell line, carrying both a t(15;17)(q22;q21) and
      a t(1;12)(q25;p13) with unusual inducible differentiation to eosinophils, and in
      a patient with AML-M4eo. Interestingly, the non-rearranged allele of ETV6 in the
      MT-ALL cell line carries an arginine to histidine (R399H) mutation which affects
      a conserved amino acid in the ets DNA binding domain.

PMID- 12406086
TI  - Autologous lymphocytes as vectors to target therapeutic radiation, using indium
      114m, in patients with lymphoid cell malignancy.
AB  - Autologous lymphocytes provide a potential vector for the delivery of a cytotoxic
      agent in patients with lymphoid cell malignancy. This report describes a phase I
      II study using autologous lymphocytes to target the radionuclide indium-114m
      ((114m)In) in patients with refractory chronic lymphocytic leukaemia or small
      lymphocytic non-Hodgkin's lymphoma. Nineteen patients, the majority of whom had
      been heavily pretreated with conventional chemotherapy and radiotherapy, received
      between 69 and 211 MBq (114m)In-labelled autologous lymphocytes. Approximately
      80% of the administered activity was localized in the liver and spleen, with
      around 5% accumulating in the bone marrow. Ten patients (53%) responded (one
      complete response and nine partial responses). The median duration of response
      was 7 months. The median survival for the responders was 14 months and for the
      non-responders was 3 months. The first notable response in every patient was a
      fall in peripheral lymphocyte count. The indium treatment was not associated with
      any subjective toxicity, although all patients suffered from myelosuppression,
      with thrombocytopenia being the dose-limiting factor. This study has demonstrated
      a significant anti-tumour effect in a group of patients with late-stage highly
      resistant disease.

PMID- 12406087
TI  - Autocrine and/or paracrine growth of adult T-cell leukaemia tumour cells by
      interleukin 15.
AB  - We previously demonstrated that interleukin 2 (IL-2) autocrine/paracrine growth
      in adult T-cell leukaemia (ATL) cells was closely correlated with clinical
      aggressiveness. In the present study, we compared the significance of IL-15 and
      IL-2 in growth of ATL cells and clinical aggressiveness. Thirty-seven patients
      with ATL were examined: 19 acute and 18 chronic. Autonomous growth and IL-2- or
      IL-15-responsive growth activities of ATL cells were measured by [3H]-thymidine
      incorporation after 24 h cultures in vitro. All of the autonomous, IL-15- and IL
      2-responsive growth activities of acute-type cells were higher than those of
      chronic type (P = 0.04, P = 0.03 and P = 0.02 respectively). IL-15- and IL-2
      responsive growth activities were highly correlated (P = 0.0001, R2 = 0.837).
      Enzyme-linked immunosorbent assay (ELISA) showed detectable serum levels of IL-15
      and IL-2 in 18 out of 19 and 14 out of 17 patients respectively. Reverse
      transcription polymerase chain reaction (RT-PCR) revealed IL-15 and IL-2 mRNA
      expression in 8 out of 11 patients' cells. Anti-IL-2 antibody partially inhibited
      autonomous growth of ATL cells; anti-IL-15 antibody was less effective. In situ
      immunochemistry detected IL-15 in cells of three patients and was consistent with
      the results of RT-PCR. These results suggest that ATL cells grow in an IL-15
      autocrine/paracrine manner and that this growth is related to disease
      aggressiveness in a manner similar to IL-2.

PMID- 12406088
TI  - Pamidronate causes apoptosis of plasma cells in vivo in patients with multiple
      myeloma.
AB  - Anti-resorptive bisphosphonates, such as pamidronate, are an effective treatment
      for osteolytic disease and hypercalcaemia in patients with multiple myeloma, but
      have also been shown to cause apoptosis of myeloma cell lines in vitro. In this
      study, we found that a single infusion of pamidronate, in 16 newly diagnosed
      patients with multiple myeloma, caused a marked increase in apoptosis of plasma
      cells in vivo in 10 patients and a minimal increase in four patients (P < 0.05).
      The nitrogen-containing bisphosphonates pamidronate and zoledronic acid also
      induced apoptosis of authentic, human bone marrow-derived plasma cells in vitro.
      Apoptosis of plasma cells in vitro was probably caused by inhibition of the
      mevalonate pathway and loss of prenylated small GTPases, as even low
      concentrations (>or= 1 micro mol/l) of zoledronic acid caused accumulation of
      unprenylated Rap1A in cultures of bone marrow mononuclear cells in vitro. GGTI
      298, a specific inhibitor of geranylgeranyl transferase I, also induced apoptosis
      in human plasma cells in vitro, suggesting that geranylgeranylated proteins play
      a role in signalling pathways that prevent plasma cell death. Our results suggest
      that pamidronate may have direct and/or indirect anti-tumour effects in patients
      with multiple myeloma, which has important implications for the further
      development of the more potent nitrogen-containing bisphosphonates, such as
      zoledronic acid, in the treatment of myeloma.

PMID- 12406089
TI  - Limitations of Gallium-67 SPECT in histological transformation of chronic
      lymphocytic leukaemia: an analysis of 13 patients with clinically suspected
      Richter's syndrome.
AB  - Gallium-67 single photon emission computerized tomography (Ga-67 SPECT) was
      performed in 13 chronic lymphocytic leukaemia (CLL) patients suspected of
      evolution into diffuse large B-cell lymphoma (DLCL) or Richter's syndrome (RS).
      Six positive and nine negative Ga-67 SPECTs were observed. Ten patients were
      biopsied (five in each group). DLCL was not detected in any Ga-67-positive
      patient, including those in whom Ga-67-positive areas were biopsied. The only
      case of DLCL was demonstrated in a Ga-67-negative patient. The tumoral
      proliferative index (Ki67 antigen expression) was moderate and similar in both
      groups of patients. These results illustrate the limitations of Ga-67 SPECT in
      identifying RS.

PMID- 12406090
TI  - Molecular cytogenetics characterization of a novel translocation involving
      chromosomes 17 and 19 in a Ph+ adult acute lymphoblastic leukaemia.
AB  - We report a case of positive Philadelphia chromosome adult acute lymphoblastic
      leukaemia with a novel unbalanced translocation t(17;19), leading to trisomy of
      17q21-qter. The patient did not obtain complete haematological response and died
      a few months after diagnosis. The significance of the 17q21-qter trisomy,
      resulting from this novel translocation, and its possible role in the progression
      of the leukaemia is discussed.

PMID- 12406091
TI  - CXCL13 (BCA-1) is produced by follicular lymphoma cells: role in the accumulation
      of malignant B cells.
AB  - Follicular lymphomas (FLs) localize in lymphoid tissues and recapitulate the
      structure of normal secondary follicles. The chemokine/chemokine receptor pair
      CXCL13/CXCR5 is required for the architectural organization of B cells within
      lymphoid follicles. In this study, we showed that CXCL13 was secreted by FL
      cells. FL cells expressed CXCR5 and migrated in response to CXCL13. Furthermore,
      we observed a synergistic effect between CXCL13 and CXCL12 (SDF-1), a chemokine
      produced by stromal cells in lymphoid tissues. The production of CXCL13 by FL
      cells and CXCL12 by stromal cells probably directs and participates in the
      accumulation of FL cells within specific anatomic sites.

PMID- 12406092
TI  - Nephrotic proteinuria associated with high-dose pamidronate in multiple myeloma.
AB  - Five patients receiving increased dose or frequency of pamidronate beyond the
      recommended dose (90 mg/monthly) exhibited nephrotic proteinuria (range 3.96-24
      g/24 h). On dose reduction or discontinuation, three of these patients showed
      decreased proteinuria to normal levels (< 1 g/24 h), and proteinuria decreased to
      4.5 g/24 h from a peak of 24 g/24 h in one patient. One patient on haemodialysis
      (hence not evaluable) had proteinuria of 2 g/24 h and elevated creatinine levels.
      One other patient continued to show elevated creatinine levels (272.8 micro
      mol/l). Renal biopsies obtained in two patients revealed focal segmental
      glomerulosclerosis.

PMID- 12406093
TI  - Influence of cell cycling and cell division on transendothelial migration of
      CD34+ cells.
AB  - The migration of haemopoietic stem and progenitor cells across endothelium lining
      bone marrow sinuses is a critical first step in the homing and successful
      engraftment of these cells. We have previously shown that freshly isolated
      mobilized peripheral blood CD34+ cells adhere to the endothelial surface but do
      not transmigrate unless activated by growth factors. The aim of this work was to
      examine the relationship between cell cycle progression, cell division and
      migration across endothelium. We now show that the enhanced migration of cytokine
      activated cells is selective for cells which are in G0G1 phase of the cell cycle.
      Thus, the transmigrated population of CD34+ cells was enriched for cells in G0G1
      phase, and sorted cells in G0G1 migrated more efficiently than those in S+G2M.
      Conversely, cells in S+G2M were more adherent to endothelium, a finding that may
      explain their reduced migration. Using the cytoplasmic dye, carboxyfluorescein
      diacetate succinimidyl ester, to track the divisional kinetics of CD34+ cells, we
      found that migration occurred preferentially in non-divided cells. Thus, although
      CD34+ cells require cytokine activation in order to migrate, cell division is not
      required for transmigration, which occurs optimally before cells enter S phase.
      The superior migratory ability of CD34+ cells in G0G1 phase of the cell cycle may
      have important implications for the homing and engraftment of ex vivo expanded
      cells.

PMID- 12406094
TI  - Developmental changes in the expression of transcription factors GATA-1, -2 and 
      3 during the onset of human medullary haematopoiesis.
AB  - Regulation of gene expression during the ontogeny of haematopoiesis in the human
      fetal bone marrow is poorly understood. Studies in mice demonstrated that GATA-1,
      -2 and -3 play pivotal roles in haematopoiesis. In this study, we identified GATA
      1-, GATA-2- and GATA-3-expressing cells in bone marrow sections and analysed the
      expression of GATA-transcription factors during the development of human fetal
      bone marrow haematopoiesis using semiquantitative reverse transcription
      polymerase chain reaction (RT-PCR). We showed that GATA-1, -2 and -3 were
      expressed only in haematopoietic cells in the bone marrow. RT-PCR analysis
      demonstrated that (1) GATA-1 expression significantly increased during gestation;
      (2) GATA-2 expression peaked at the onset of medullary haematopoiesis, declined
      thereafter, and remained at a constant level after 30 weeks post conception; and
      (3) GATA-3 expression revealed no changes during development. The results
      indicated that the onset of medullary haematopoiesis in humans is accompanied by
      high expression of GATA-2, reflecting high proliferation rates of early
      haematopoietic progenitor cells, whereas expression of GATA-1 mirrors
      haematopoietic activity.

PMID- 12406095
TI  - AC133+ umbilical cord blood progenitors demonstrate rapid self-renewal and low
      apoptosis.
AB  - Umbilical cord blood (UCB) provides immediate access to haemopoietic
      stem/progenitor cells (HSPC) but low cell number restricts use in full adult bone
      marrow reconstitution. This study investigated early ex vivo expansion kinetics
      of UCB AC133+ cells (2-4 x 10(4)/ml), mononuclear cells (MNC, 1-2 x 10(6)/ml) and
      AC133negative cells (AC133(neg), 2-4 x 10(4)/ml) in stroma-free 8 d liquid
      culture (fetal bovine serum-supplemented Iscove's-modified Dulbecco's medium
      (IMDM) with either 'K36EG'[c-Kit ligand, interleukin 3 (IL-3), IL-6,
      erythropoietin, granulocyte colony-stimulating factor] or 'TPOFL'
      (thrombopoietin, Flt-3 ligand). Cell enumeration, apoptosis assay and
      AC133/CD34/CD38 antigen immunophenotyping were performed at d 0, 3, 5 and 8. All
      three cell populations went through a proliferation lag phase between d 3 and d
      5. AC133+ cells recovered better from lag phase with significantly higher fold
      increase (FI) when compared with MNC and AC133(neg) populations (K36EG FI: 15.04
      +/- 5.46; TPOFL FI: 8.59 +/- 2.92, P < 0.05). After 8 d, populations lacking
      AC133+ cells were significantly more inclined to undergo apoptosis under
      proliferative conditions (P < 0.01). Also, when compared with K36EG, 8 d TPOFL
      expanded AC133+ cells encompassed a significantly higher percentage of AC133+ and
      CD34+ early HSPC (K36EG: 20.50 +/- 2.36; TPOFL: 47.00 +/- 7.69; P < 0.05). In
      conclusion, TPOFL synergism demonstrated the potential for AC133+ HSPC ex vivo
      expansion inducing self-renewal, early HSPC maintenance and promoting cell
      survival status.

PMID- 12406096
TI  - Reconstitution of human haematopoiesis in non-obese diabetic/severe combined
      immunodeficient mice by clonal cells expanded from single CD34+CD38- cells
      expressing Flk2/Flt3.
AB  - In the present study, we examined the expression of Flk2/Flt3, a tyrosine kinase
      receptor, on human cord blood CD34+ haematopoietic progenitor/stem cells. In flow
      cytometric analysis, Flk2/Flt3 was expressed on 80% of CD34+ cells and their
      immature subpopulations, CD34+CD33- and CD34+CD38- cells. Methycellulose clonal
      culture of sorted CD34+Flk2/Flt3+ and CD34+Flk2/Flt3- cells showed that most of
      myelocytic progenitors expressed Flk2/Flt3, but erythroid and haematopoietic
      multipotential progenitors were shared by both fractions. When 1 x 10(4) lineage
      marker-negative (Lin-)CD34+Flk2/Flt3- cells were transplanted into non-obese
      diabetic/severe combined immunodeficient (NOD/SCID) mice, none of the recipients
      possessed human CD45+ cells in bone marrow 11-12 weeks after the transplantation.
      In contrast, all recipients transplanted with 1 x 10(4) Lin-CD34+Flk2/Flt3+ cells
      showed successful engraftment. Furthermore, clonal cells expanded from single Lin
      CD34+CD38-Flk2/Flt3+ cells in the culture with Flk2/Flt3 ligand, stem cell
      factor, thrombopoietin, and a complex of interleukin 6/soluble interleukin 6
      receptor were individually transplanted into NOD/SCID mice. At 20 to 21 weeks
      after the transplantation, three out of 10 clones harvested at d 7 of culture,
      and three out of six clones at d 14 could reconstitute human haematopoiesis in
      recipient marrow. These results demonstrated that Flk2/Flt3 was expressed on a
      wide variety of human haematopoietic cells including long-term-repopulating
      haematopoietic stem cells.

PMID- 12406097
TI  - Dominant expression of interleukin 10 but not interferon gamma in CD4(-)CD8(
      )alphabetaT cells of autoimmune lymphoproliferative syndrome.
AB  - Cytokine expression in CD4-CD8- double-negative (DN) T cells of autoimmune
      lymphoproliferative syndrome (ALPS) was analysed. Two patients with DN alphabetaT
      cell expansion showed higher serum interleukin 10 (IL-10) levels than one patient
      without it. Intracellular flow-cytometric analysis indicated the IL-10-expressing
      CD3+CD4-CD8- cells in patients with lymphoproliferation. Quantitative real-time
      polymerase chain reaction revealed approximately 100 times higher IL-10, but not
      interferon-gamma or transforming growth factor-beta in DN than in single-positive
      T cells. IL-10 was exclusively expressed in DN alphabeta but not (gamma)(delta)T
      cells. Circulating DN alphabetaT cells may constitutively express IL-10 and
      contribute to the ALPS phenotype.

PMID- 12406098
TI  - Genetic hyperferritinaemia and reticuloendothelial iron overload associated with
      a three base pair deletion in the coding region of the ferroportin gene
      (SLC11A3).
AB  - Iron overload may predominantly involve parenchymal or reticuloendothelial cells,
      the prototype of parenchymal iron overload being HFE-related genetic
      haemochromatosis. We studied a family with autosomal dominant hyperferritinaemia
      in whom the proband showed selective iron accumulation in the Kupffer cells on
      liver biopsy. Analysis of L and H ferritin genes excluded mutations responsible
      for hereditary hyperferritinaemia/cataract syndrome or similar translational
      disorders. Sequence analysis of the ferroportin gene (SLC11A3) in four
      individuals with hyperferritinaemia singled out a three base pair deletion in a
      region that contains four TTG repeats. This mutation removes a TTG unit from 780
      to 791, and predicts the loss of one of three sequential valine residues 160-162.
      Denaturing high performance liquid chromatography can be used for its detection.
      SLC11A3 polymorphism analysis indicates that this probably represents a recurrent
      mutation due to slippage mispairing. Affected individuals may show marginally low
      serum iron and transferrin saturation, and young women may have marginally low
      haemoglobin concentration levels. Serum ferritin levels are directly related to
      age, but are 10-20 times higher than normal. Heterozygosity for the ferroportin
      Val 162 deletion represents the prototype of selective reticuloendothelial iron
      overload, and should be taken into account in the differential diagnosis of
      hereditary or congenital hyperferritinaemias.

PMID- 12406099
TI  - Effective binding of free iron by a single intravenous dose of human
      apotransferrin in haematological stem cell transplant patients.
AB  - Myeloablative treatment results in iron accumulation and the appearance of non
      transferrin-bound iron (NTBI) in the circulation, which may contribute to
      treatment-related organ damage and susceptibility to infections. The aim of this
      study was to investigate the efficacy of human apotransferrin in the binding of
      NTBI in patients receiving an allogeneic stem cell transplant after myeloablative
      conditioning. A single intravenous 100 mg/kg dose of apotransferrin was given to
      six adult patients on d 3 after the transplantation. Initially, all patients had
      serum transferrin saturation above 80% and NTBI in their serum. After the
      apotransferrin injection, serum NTBI became undetectable in all patients and
      transferrin saturation decreased to 30-50%. Serum transferrin increased by an
      average of 1.95 g/l. The administered apotransferrin was subsequently converted
      into monoferric and diferric transferrin forms. NTBI reappeared and transferrin
      saturation again exceeded 80% 12-48 h after the injection in four patients and
      after 6 d in one patient. NTBI remained non-detectable for the whole 12 d follow
      up period in one patient. The apotransferrin injection was well tolerated and no
      adverse events with probable association with the apotransferrin were observed.
      Repeated apotransferrin infusions might completely eliminate NTBI and iron
      induced toxicity during myeloablative therapy.

PMID- 12406100
TI  - Rapid detection of the major Mediterranean beta-thalassaemia mutations by real
      time polymerase chain reaction using fluorophore-labelled hybridization probes.
AB  - We present a new method to detect the major beta-thalassaemia mutations of the
      Mediterranean countries (IVS I-1, IVS I-6, IVS I-110, CD-37 and CD-39). The
      procedure is based upon real-time polymerase chain reaction (PCR), using specific
      fluorescently labelled hybridization probes. The melting curves for each of the
      specific probes obtained after PCR enabled the identification of different
      alleles. Genotyping of 71 patients with thalassaemia and 20 controls without
      thalassaemia by the established method and conventional allele-specific
      restriction enzyme analysis produced identical results. The established method is
      a robust, fast and straightforward assay that allows detection of the major
      Mediterranean beta-thalassaemia mutations simultaneously in less than 60 min.

PMID- 12406101
TI  - Exploring polycythaemia vera with fluorescence in situ hybridization: additional
      cryptic 9p is the most frequent abnormality detected.
AB  - Between 1986 and 2001, 220 patients with polycythaemia vera (PV) were studied
      using conventional cytogenetics. Of 204 evaluable patients, 52 (25.4%) had clonal
      abnormalities. The recurrent chromosomal rearrangements were those of chromosome
      9 (21.1%), del(20q) (19.2%), trisomy 8 (19.2%), rearrangements of 13q (13.4%),
      abnormalities of 1q (11.5%), and of chromosomes 5 and 7 (9.6%). Subsequent
      analysis of 32 patients, performed at follow-up of up to 14.8 years, revealed new
      clonal abnormalities in five patients and the disappearance of an abnormal clone
      in four. Eleven patients remained normal up to 11.5 years and seven patients
      maintained an abnormality for over 10 years. Fifty-three patients were studied
      retrospectively using interphase fluorescence in situ hybridization (I-FISH),
      utilizing probes for centromere enumeration of chromosomes 8 and 9, and for 13q14
      and 20q12 loci. Conventional cytogenetics demonstrated clonal chromosome
      abnormalities in 23% of these 53 patients. The addition of I-FISH increased the
      detection of abnormalities to 29% and permitted clarification of chromosome 9
      rearrangements in an additional 5.6% of patients. FISH uncovered rearrangements
      of chromosome 9 in 53% of patients with an abnormal FISH pattern, which
      represented the most frequent genomic alteration in this series.

PMID- 12406102
TI  - Chronic leg ulceration in homozygous sickle cell disease: the role of venous
      incompetence.
AB  - Chronic leg ulceration is a common cause of morbidity in Jamaican patients with
      homozygous sickle cell (SS) disease. Ulcers heal more rapidly on bed rest and
      deteriorate on prolonged standing, suggesting a role of venous hypertension in
      their persistence. This hypothesis has been tested by Doppler detection of venous
      competence in SS patients and in matched controls with a normal haemoglobin (AA)
      genotype in the Jamaican Cohort Study. Venous incompetence was significantly more
      frequent in SS disease [137/183 (75%)] than in non-pregnant AA controls [53/137
      (39%)]. Past or present ulceration occurred in 78 (43%) SS patients, with a
      highly significant association between leg ulceration and venous incompetence in
      the same leg (P < 0.001). Prominence and/or varicosities of the veins and
      spontaneous leg ulcers were more common among patients with multiple sites of
      incompetence. The association of venous incompetence with chronic leg ulceration
      identifies a further pathological mechanism contributing to the morbidity of SS
      disease. The cause of venous incompetence is unknown but the sluggish circulation
      associated with dependency, turbidity and impaired linear flow at venous valves,
      hypoxia-induced sickling, the rheological effects of high white cell counts, and
      activation of components of the coagulation system may all contribute. Venous
      hypertension in SS patients with leg ulceration suggests that firm elastic
      supportive dressings might promote healing of chronic leg ulcers.

PMID- 12406103
TI  - Piebaldism in diamond-blackfan anaemia: a new phenotype?

PMID- 12406104
TI  - Successful umbilical cord blood transplantation in a child with dyskeratosis
      congenita after a fludarabine-based reduced-intensity conditioning regimen.

PMID- 12406105
TI  - Hyperbaric oxygen for cyclophosphamide-induced cystitis.

PMID- 12406106
TI  - Severe increase in creatinine with hypocalcaemia in thalidomide-treated myeloma
      patients receiving zoledronic acid infusions.

PMID- 12406107
TI  - Treatment of refractory autoimmune (acquired) haemophilia with anti-CD20
      (rituximab).

PMID- 12406108
TI  - Is high expression of the chemokine receptor CXCR-4 of predictive value for early
      relapse in childhood acute lymphoblastic leukaemia?

PMID- 12406110
TI  - Intersex.

PMID- 12406111
TI  - Ureterocele: an ongoing challenge in infancy and childhood.

PMID- 12406112
TI  - Pharmacological control of the immune response in renal transplantation.

PMID- 12406113
TI  - Lower limb compartment syndrome associated with the lithotomy position: concepts
      and perspectives for the urologist.

PMID- 12406114
TI  - Understanding and evaluating qualitative research.
AB  - Qualitative research aims to address questions concerned with developing an
      understanding of the meaning and experience dimensions of humans' lives and
      social worlds. Central to good qualitative research is whether the research
      participants' subjective meanings, actions and social contexts, as understood by
      them, are illuminated. This paper aims to provide beginning researchers, and
      those unfamiliar with qualitative research, with an orientation to the principles
      that inform the evaluation of the design, conduct, findings and interpretation of
      qualitative research. It orients the reader to two philosophical perspectives,
      the interpretive and critical research paradigms, which underpin both the
      qualitative research methodologies most often used in mental health research, and
      how qualitative research is evaluated. Criteria for evaluating quality are
      interconnected with standards for ethics in qualitative research. They include
      principles for good practice in the conduct of qualitative research, and for
      trustworthiness in the interpretation of qualitative data. The paper reviews
      these criteria, and discusses how they may be used to evaluate qualitative
      research presented in research reports. These principles also offer some guidance
      about the conduct of sound qualitative research for the beginner qualitative
      researcher.

PMID- 12406115
TI  - Demoralization: its phenomenology and importance.
AB  - OBJECTIVE: Demoralization, as described by Jerome Frank, is experienced as a
      persistent inability to cope, together with associated feelings of helplessness,
      hopelessness, meaninglessness, subjective incompetence and diminished self
      esteem. It is arguably the main reason people seek psychiatric treatment, yet is
      a concept largely ignored in psychiatry. The aim here is to review and summarize
      the literature pertaining to demoralization in order to examine the validity of
      the construct. METHOD: A narrative review of demoralization and the related
      concepts of hope, hopelessness, and meaning is presented, drawing on a range of
      empirical and observational studies in the medical and psychiatric literature.
      RESULTS: An examination of the concepts of the 'Giving Up-Given Up' syndrome
      (George Engel), 'suffering' (Eric Cassell), and demoralization (Jerome Frank),
      demonstrate considerable convergence of ideas. Demoralization has been commonly
      observed in the medically and psychiatrically ill and is experienced as
      existential despair, hopelessness, helplessness, and loss of meaning and purpose
      in life. Although sharing symptoms of distress, demoralization is distinguished
      from depression by subjective incompetence in the former and anhedonia in the
      latter. Demoralization can occur in people who are depressed, cancer patients who
      are not depressed and those with schizophrenia. Hopelessness, the hallmark of
      demoralization, is associated with poor outcomes in physical and psychiatric
      illness, and importantly, with suicidal ideation and the wish to die.
      CONCLUSIONS: Demoralization is an important construct with established
      descriptive and predictive validity. A place needs to be found for it in
      psychiatric nomenclature.

PMID- 12406116
TI  - What outcomes to measure in routine mental health services, and how to assess
      them: a systematic review.
AB  - OBJECTIVE: Routine outcome assessment in adult mental health services involves
      the on-going assessment of patient-level outcomes. Use of outcomes to inform
      treatment is widely recommended, but seldom implemented. The goals of this review
      were (i) to identify principles that have been proposed for implementing routine
      outcome assessment, (ii) to identify the full range of outcome domains that have
      been proposed for assessment, and (iii) to synthesize proposals for specific
      outcome domains into emergent categories. METHOD: A systematic review of
      published and unpublished research was undertaken, using electronic databases,
      research registers, conference proceedings, expert informants and the World Wide
      Web. For goal (i) studies were included that proposed principles for implementing
      routine outcome assessment. For goal (ii) studies were included that identified
      at least two patient-level outcome domains for patients using adult mental health
      services and made some reference to a broader literature base. RESULTS: Six
      thousand four hundred publications matched initial search criteria. Seven
      distinct sets of principles for choosing patient-level outcomes were located,
      which showed a fair degree of consensus. Sixteen outcome domain proposals were
      identified, which were synthesized into seven emergent categories: wellbeing,
      cognition/emotion, behaviour, physical health, interpersonal, society and
      services. CONCLUSIONS: The findings from this review were used to develop a four
      step method for adult mental health services wishing to implement routine outcome
      assessment.

PMID- 12406117
TI  - Postdisaster emotional distress, depression and event-related variables: findings
      across child and adolescent developmental stages.
AB  - OBJECTIVE: Developmental approaches have not been widely used in child and
      adolescent posttraumatic stress disorder research, and little is known about
      developmental differences in response to postdisaster trauma. Our objective was
      to investigate postdisaster depression and emotional distress psychopathology
      across a broad child and adolescent developmental range. METHOD: Six months
      following a bushfire disaster, 2379 grade 4-12 school students -completed an
      extensive self-report battery, which included the Impact of Event Scale and the
      Birleson Depression Inventory. Generalized linear models were constructed to
      model the effects of multiple covariates on continuous outcome measures of
      depression and emotional distress. RESULTS: Significant independent predictors of
      persisting depressive symptoms were increased symptoms of emotional distress;
      increased symptoms of anxiety; evacuation experience; and school grade.
      Significant independent predictors of emotional distress were persisting
      depressive symptoms; perception of threat to self or to parents; evacuation
      experience; and school grade. Gender was not a significant predictor in either
      the depression or emotional distress multivariate models. Complex, non-linear
      relationships between depression, emotional distress and school grade were found.
      CONCLUSION: This study suggests that important developmental differences in
      postdisaster psychological responses exist across a broad spectrum of
      developmental stages in children.

PMID- 12406118
TI  - A clinical and neurobehavioural review of high-functioning autism and Asperger's
      disorder.
AB  - OBJECTIVE: To compare, contrast and review clinical and neuropsychological
      studies of high-functioning autism and Asperger's disorder. METHOD: This paper
      reviews past and contemporary conceptualizations of autism and Asperger's
      disorder, together with epidemiological information, genetic and neurobehavioural
      findings. This paper focuses on neurobehavioural studies, in particular,
      executive functioning, lateralization, visual-perceptual and motor processing,
      which have provided an important source of information about the potential
      neurobiological dissociation that may exist between autism and Asperger's
      disorder. RESULTS: The clinical profiles of autism and Asperger's disorder
      contain a mixture of psychiatric and neurological symptoms: for example, movement
      abnormalities (i.e. stereotyped behaviours, hand flapping, toe walking, whole
      body movements), atypical processing of parts and wholes, verbal and non-verbal
      deficits, ritualistic/compulsive behaviour, disturbances in reciprocal social
      interaction and associated depression and anxiety. The considerable clinical
      overlap between autism and Asperger's disorder has led many to question whether
      Asperger's disorder is merely a mild form of autism, or whether it should be
      considered as a separate clinical entity. CONCLUSION: In light of the growing
      body of epidemiological information, genetic, and neurobehavioural evidence that
      distinguishes autism from Asperger's disorder, it is premature to rule out the
      possibility that these disorders may be clinically, and possibly
      neurobiologically separate.

PMID- 12406119
TI  - Neuropsychological functioning in children with DSM-IV combined type Attention
      Deficit Hyperactivity Disorder.
AB  - OBJECTIVE: To compare the global cognitive functioning and frontal lobe
      functioning of children with and without DSM-IV combined type Attention Deficit
      Hyperactivity Disorder (ADHD). METHOD: Participants were 6 to 10 year old, clinic
      referred children diagnosed with combined type ADHD, who were medication naive;
      and an age (+/- 3 months) and sex matched group of children without behaviour
      problems. The performance of the two groups were compared on measures of
      intellectual functioning and tests designed to assess the functions of the
      frontal lobes (verbal and-non-verbal fluency, reasoning, problem solving, spatial
      working memory, attention). RESULTS: The children with ADHD obtained
      significantly lower Wechsler Intelligence Scale for Children-third edition IQ
      scores than controls and performed more poorly across the range of frontal lobe
      tests. Group differences on these tests were attenuated when IQ scores were
      included in the analyses as a covariate. CONCLUSIONS: Children with combined type
      ADHD have mild to moderate global cognitive impairment together with some
      impairment of functions subserved by the frontal lobes. Longitudinal studies are
      required to determine if the deficit in global cognitive functioning is a primary
      deficit or secondary to the deficit in frontal lobe functioning. The importance
      of neuro-psychological assessment and follow-up for children with ADHD is
      stressed. Study limitations relate to the generalizability of the findings and
      the absence of a psychiatric control group.

PMID- 12406120
TI  - A five year follow-up study of the use of clozapine in community practice.
AB  - OBJECTIVE: To present information about the value of clozapine in treatment
      resistant schizophrenia. Data is reported on the use of clozapine in an entire
      cohort of (42) patients in a community, the Australian Capital Territory. It
      extends a 3-year study of clinical and financial outcomes to 5 years. METHOD:
      Experiences during the 2 years before clozapine was prescribed and those of the 5
      years following prescription were compared by a records review, including
      hospital and hostel bed use and estimated treatment costs. Changes in dose
      levels, living circumstances and employment status were assessed, and treating
      psychiatrists reported on side-effects and their impression of clinical change
      since clozapine was prescribed. RESULTS: Ten subjects were excluded. The
      remaining cohort (32 subjects) demonstrated continuing clinical improvement and
      cost savings during follow-up. Those (22) remaining on clozapine after the five
      year period showed continuing clinical improvement, reduced hospital admissions
      and hospital bed usage and significantly large cost savings, and were moderately
      to markedly improved after 3 years. Only one patient (of 22) showed a slight
      deterioration in the next two years while 14 showed further improvement. After 5
      years, the clinical status of four of the 10 subjects who discontinued clozapine
      was unchanged or deteriorated compared with their preclozapine status. There were
      no suicides. CONCLUSION: The findings of continuing clinical improvement and
      decreased costs after long-term (5 years) use of clozapine supports the selective
      use of clozapine in community practice.

PMID- 12406121
TI  - What is duty/triage? Understanding the role of duty/triage in an area mental
      health service.
AB  - OBJECTIVE: To describe the duty/triage system within one urban area mental health
      service in Australia and to investigate the factors that affect the decision to
      organize a comprehensive assessment. METHOD: Data was collected from 3 months of
      duty/triage information and key informant interviews. Policies and procedures
      related to duty/triage were reviewed. Quantitative and qualitative analyses were
      conducted. RESULTS: Two thousand, six hundred and three contacts with duty/triage
      occurred over a -3-month period. Half of these were related to patients new to
      the service. Most contacts were self-referrals or referrals from a carer. Few
      referrals came through the primary health care sector. New patients were more
      likely to be assessed if the referral was presented in technical language and if
      it was initiated by a health professional, particularly a general practitioner,
      emergency department or other mental health service. Assessment was less likely
      if the patient or carer initiated the referral, if the problem was presented in
      vague or non-technical terms, if there was a drug or alcohol problem or if the
      person refused care. CONCLUSIONS: A substantial number of potential patients
      contact a duty/triage worker every day. However, there is little interaction with
      the primary care sector, limited documentation of risk and a lack of consistency
      in the documented reasons for the service response. Further investigation is
      needed of the conditions conducive to consistent quality decision making at the
      point of entry to a specialist mental health service.

PMID- 12406122
TI  - Barriers to optimal care for patients with coexisting substance use and mental
      health disorders.
AB  - OBJECTIVE: This paper describes qualitative research that was carried out as part
      of a project aimed at drawing up a series of guidelines for the assessment and
      management for people with coexisting substance use and mental health disorders,
      or dual diagnosis. METHOD: A core consultation team of 14 experts with experience
      in the areas of both substance use and mental health in New Zealand was
      established to advise on the development of eight clinical scenarios. The
      clinical scenarios were selected to highlight a range of real life issues in the
      treatment of people with coexisting substance use and mental health disorders and
      were presented at 12 focus groups around New Zealand. The 261 participants of the
      focus groups were asked to comment on what was optimal management for each of the
      scenarios and to identify barriers to optimal care in their region. Written notes
      were analysed for recurring and strongly stated themes and these comprise the
      results of the study. RESULTS: While there was marked regional variation in
      treatment approaches and service structures, many of the barriers to optimal care
      that were identified were common to all regions. The results are considered under
      the headings of systems issues, clinical issues and attitudes. CONCLUSIONS: A
      wide variety of barriers that impede the delivery of optimal care have been
      identified. These range from the attitudes of individual clinicians to the
      structure of the systems within which they work. A system of key principles and
      processes for organizing treatment in a way which helps overcome these barriers
      is proposed.

PMID- 12406123
TI  - Cannabis use is not associated with the development of psychosis in an 'ultra'
      high-risk group.
AB  - BACKGROUND: The association between cannabis use and the development of a first
      psychotic episode was studied in a group of 100 young people identified as being
      at very high risk for the onset of psychosis. METHOD: The 'ultra' high risk
      cohort was identified by the presence of subthreshold psychotic symptoms, or a
      combination of first-degree relative with a psychotic disorder and recent
      functional decline. Thirty-two per cent of the cohort developed an acute
      psychotic episode over the 12-month period after recruitment. As a component of a
      larger research study, the level of cannabis use by participants in the year
      prior to enrollment in the study was assessed at intake. RESULTS: Cannabis use or
      dependence in the year prior to recruitment to this study was not associated with
      a heightened risk of developing psychosis over the following 12-month period and
      therefore did not appear to contribute to the onset of a psychotic disorder.
      CONCLUSION: The results of this study suggest that cannabis use may not play an
      integral role in the development of psychosis in a high-risk group. While this
      study does not support a role for cannabis in the development of first-episode
      psychosis, we cannot conclude that cannabis use should be completely ignored as a
      candidate risk factor for onset of psychosis. A number of weaknesses of the study
      (the low level of cannabis use in the current sample, the lack of monitoring of
      cannabis use after intake) suggest that it may be premature to dismiss cannabis
      use as a risk factor for the development of psychosis and further research is
      urged in this area.

PMID- 12406124
TI  - Monitoring consumer satisfaction with inpatient service delivery: the Inpatient
      Evaluation of Service Questionnaire.
AB  - OBJECTIVE: To report on the development, testing and psychometric properties of a
      brief consumer satisfaction measure for use with psychiatric inpatients. METHOD:
      Focus group discussions with inpatients were used to develop a pool of items
      related to satisfaction with hospital stay. A second cohort of 72 inpatients was
      invited to rate the 51 items that emerged for importance in contributing to
      satisfaction. Mean importance scores highlighted 20 items that were subsequently
      framed into neutrally worded statements. A draft questionnaire comprising these
      statements was introduced, on a trial basis, in a range of inpatient facilities.
      RESULTS: Factor analysis of 356 completed questionnaires yielded three factors
      comprising a staff-patient alliance; doctor/treatment issues; and an
      environmental component. Psychometric properties include good response
      variability and high internal consistency. CONCLUSIONS: The Inpatient Evaluation
      of Service Questionnaire addresses many of the shortcomings of existing
      satisfaction measures. It was developed through extensive consumer involvement,
      it is simply worded, easy to score and appears to perform well with acute and
      rehabilitation inpatients.

PMID- 12406125
TI  - Eysenck's challenge to psychotherapy: a view of the effects 50 years on.

PMID- 12406126
TI  - Concurrent use of ECT and cholinesterase inhibitor medications.

PMID- 12406127
TI  - Methadone, morphine and PTSD.

PMID- 12406128
TI  - Venlafaxine open-label treatment of patients with obsessive-compulsive disorder.

PMID- 12406129
TI  - Clinical research and scientific creativity.

PMID- 12406130
TI  - Brain, mind and kep.

PMID- 12406131
TI  - Low rates of monitoring of mood stabilizing drugs for bipolar disorder in
      community psychiatric clinics.

PMID- 12406132
TI  - Cardiac risk of psychotropic drugs.

PMID- 12406140
TI  - Systemic consequences of ventricular assist devices: alterations of coagulation,
      immune function, inflammation, and the neuroendocrine system.
AB  - Implantable ventricular assist devices have proven efficacious as a bridge to
      transplantation and as a bridge to recovery. Although current indications for use
      of assist devices are somewhat limited, they are likely to expand in the upcoming
      years, including their use as destination therapy for end-stage heart failure.
      Recipients of assist devices, however, are prone to certain device-specific
      complications, including excessive postoperative bleeding, late propensity for
      thromboembolism, infections, and systemic inflammation, which may contribute to
      end-organ dysfunction. This article reviews the systemic biochemical alterations
      underlying these clinical phenomena. As assist devices are increasingly used,
      better understanding of these systemic perturbations is imperative.

PMID- 12406141
TI  - Powering an artificial heart: birth of the inductively coupled-radio frequency
      system in 1960.
AB  - In mid-1960, our group initiated a research program focused on studying pain-free
      electromagnetic methods of furnishing energy to an implanted heart without
      piercing the skin. During the last half of 1960, we derived a detailed
      theoretical rationale for a radio frequency system involving inductive coupling
      between a thin, small, pancake-shaped coil on the surface of the chest and a
      similar coil either within the chest or, alternatively, subcutaneously. Having an
      efficiency of about 95%, the system was evaluated in dogs at 50 and 69 W levels,
      respectively. Thus was born what is now termed the transcutaneous energy
      transformer (TET).

PMID- 12406142
TI  - Centrifugal blood pumps for various clinical needs.
AB  - During the past 10 years, different types of blood pumps were developed to
      address various clinical needs. The Nikkiso centrifugal blood pump was developed
      for cardiopulmonary bypass application. This blood pump has been widely used in
      Japan in more than 20% of the cardiopulmonary bypass procedures. The Kyocera C1E3
      Gryo pump was developed for short-term circulatory assistance and extracorporeal
      membrane oxygenation application for up to 2 weeks. This blood pump has been
      clinically used for up to 28 days without any blood clot formation. Through Phase
      I of the Japanese government New Energy and Industrial Technology Development
      Organization (NEDO) program, a chronically implanted centrifugal pump for left
      ventricular assistance was developed. This pump has already demonstrated its
      effectiveness, safety, and durability as a 2 year blood pump through in vitro and
      in vivo experiments. Currently, it is in the process of being converted from an
      experimental to a clinical device. Through Phase II of the NEDO program, a
      permanently implantable biventricular assist centrifugal blood pump system is
      under development. It has demonstrated that the previously mentioned left
      ventricular assist device blood pump is easily converted into a right ventricular
      assist pump by simply adding a spacer between the pump and the actuator. This
      communication discusses the historical development strategies for centrifugal
      blood pumps and their current status for different clinical needs.

PMID- 12406143
TI  - Pediatric physiologic pulsatile pump enhances cerebral and renal blood flow
      during and after cardiopulmonary bypass.
AB  - Controversy over benefits of pulsatile flow after pediatric cardiopulmonary
      bypass (CPB) continues. Our study objectives were to first, quantify pressure and
      flow waveforms in terms of hemodynamic energy, using the energy equivalent (EEP)
      formula, for direct comparisons, and second, investigate effects of pulsatile
      versus nonpulsatile flow on cerebral and renal blood flow, and cerebral vascular
      resistance during and after CPB with deep hypothermic circulatory arrest (DHCA)
      in a neonatal piglet model. Fourteen piglets underwent perfusion with either an
      hydraulically driven dual-chamber physiologic pulsatile pump (P, n = 7) or a
      conventional nonpulsatile roller pump (NP, n = 7). The radiolabeled microsphere
      technique was used to determine the cerebral and renal blood flow. P produced
      higher hemodynamic energy (from mean arterial pressure to EEP) compared to NP
      during normothermic CPB (13 +/- 3% versus 1 +/- 1%, p < 0.0001), hypothermic CPB
      (15 +/- 4% versus 1 +/- 1%, p < 0.0001) and after rewarming (16 +/- 5% versus 1
      +/- 1%, p < 0.0001). Global cerebral blood flow was higher for P compared to NP
      during CPB (104 +/- 12 ml/100g/min versus 70 +/- 8 ml/100g/min, p < 0.05). In the
      right and left hemispheres, cerebellum, basal ganglia, and brainstem, blood flow
      resembled the global cerebral blood flow. Cerebral vascular resistance was lower
      (p < 0.007) and renal blood flow was improved fourfold (p < 0.05) for P versus
      NP, after CPB. Pulsatile flow generates higher hemodynamic energy, enhancing
      cerebral and renal blood flow during and after CPB with DHCA in this model.

PMID- 12406144
TI  - Assessing the calf pulmonary function during a long-term biventricular assist
      device study with a centrifugal blood pump.
AB  - Pulmonary congestion due to inappropriate pump flow management is one major
      problem necessary to avoid during long-term biventricular assist device (BVAD)
      implantation. Our objective was to assess the effects of pulmonary arterial flow
      rate and flow rates of both (right and left) bypass pumps. Six healthy calves,
      which had been implanted with a BVAD system, were selected for this retrospective
      study. Pulmonary artery flows, both pump flow rates, oxygen saturation of the
      arterial blood, and pulmonary arterial pressures were assessed as parameters of
      pulmonary function as was routine clinical evaluation of respiratory rate and
      character and chest auscultation. The average pulmonary artery flow rate (PAF),
      systolic pressure of pulmonary artery (sPAP), and oxygen saturation were 148.8
      ml/kg per min, 35.1 mm Hg, and 95.3%, respectively. Pulmonary dysfunction
      occurred in one case, in which the mean PAF, sPAP, and oxygen saturation were 169
      ml/kg per min, 66.1 mm Hg, and 90.9%, respectively. The ratio for the right/left
      pump flow rate (R/L ratio) for the case having pulmonary dysfunction was 1.57
      even though the ratio for the other cases was less than 1. Maintaining an R/L
      ratio less than 1 and/or PAF less than 160 ml/kg per min and PAP less than 50 mm
      Hg is recommended as the initial conditions to target to avoid pulmonary
      dysfunction during a BVAD implantation with a beating heart condition.

PMID- 12406145
TI  - The balance of the impeller-driver magnet affects the antithrombogenicity in the
      Gyro permanently implantable pump.
AB  - The Gyro permanently implantable (PI) pump is activated magnetically when a
      double pivot bearing supported impeller is rotated at predetermined revolutions
      per minute (rpm). The male bearing shaft of the impeller is supported by the top
      and bottom female pivot bearing in a loosely mated fashion. The Gyro PI pump's
      impeller transfers to a floating condition when the rpm is increased. The design
      objective of the Gyro PI pump is to drive the impeller while maintaining a top
      contact position to prevent thrombus formation. As a left ventricular assist
      device (LVAD), the Gyro PI pumps achieved long-term survivals in calves without
      thrombus formation. However, thrombus formation occurred during a biventricular
      assist device (BVAD) implantation. Our hypothesis was that the impeller remaining
      in the bottom contact position during the BVAD experiment caused this thrombus
      formation. Therefore, a replica of the Gyro PI pump housing was fabricated from a
      transparent plastic to observe the floating conditions of the impeller. When
      simulating an LVAD animal experiment, the impeller was at a non-bottom contact
      position. However, when simulating the BVAD animal experiment, the impeller
      remained at the bottom contact position. This study shows that the magnet balance
      affects the antithrombogenicity in a Gyro PI pump.

PMID- 12406146
TI  - Physiologic control algorithms for rotary blood pumps using pressure sensor
      input.
AB  - Hierarchical algorithms have been developed for enhanced physiologic control and
      monitoring of blood pumps using pressure inputs. Pressures were measured at pump
      inlet and outlet using APEX pressure sensors (APSs). The APS is a patented, long
      term implantable, flow-through blood pressure sensor and designed to control
      implantable heart pumps. The algorithms have been tested using a Donavan
      circulatory mock-loop setup, a generic rotary pump, and LabVIEW software. The
      hierarchical algorithms control pump speed using pump inlet pressure as a primary
      independent variable and pump outlet pressure as a secondary dependent variable.
      Hierarchical control algorithms based on feedback from pressure sensors can
      control the speed of the pump to stably maintain ventricular filling pressures
      and arterial pressures. Monitoring algorithms based on pressure inputs are able
      to approximate flow rate and hydraulic power for the pump and the left ventricle.

PMID- 12406147
TI  - Incorporation of electronics within a compact, fully implanted left ventricular
      assist device.
AB  - The promise of expanded indications for left ventricular assist devices in the
      future for very long-term applications (10+ years) prompts sealed (i.e. fully
      implanted) systems and less-obtrusive and more reliable implanted components than
      their external counterparts in percutaneous configurations. Furthermore, sealed
      systems increase the fraction of total power losses dissipated intracorporeally,
      a disadvantage that must be carefully managed. We set out to incorporate the
      motor drive and levitation control electronics within the HeartMate III blood
      pump without substantially increasing the pump's size. Electronics based on a
      rigid-flex satellite printed circuit board (PCB) arrangement that could be folded
      into a very compact, dense package were designed, fabricated, and tested. The
      pump's lower housing was redesigned to accommodate these PCBs without increasing
      any dimension of the pump except the height, and that by only 5 mm. The
      interconnect cable was reduced from 22 wires to 10 (two fully redundant sets of
      5). An ongoing test of the assembled pump in vitro has demonstrated no problems
      in 5 months. In addition, a 20-day in vivo test showed only 1 degrees C
      temperature rises, equivalent to pumps without incorporated electronics at
      similar operating conditions.

PMID- 12406148
TI  - Mesenteric complications after hypothermic cardiopulmonary bypass with cardiac
      arrest: underlying mechanisms.
AB  - The aim of this study was to determine the pathophysiological mechanisms of
      postcardiopulmonary bypass (CPB) intestinal dysfunction using an in vivo canine
      model of extracorporeal circulation. Six dogs underwent a 90 min hypothermic CPB
      with continuous monitoring of mean arterial blood pressure (MAP) and mesenteric
      blood flow (MBF). Reactive hyperemia and vasodilator responses of the superior
      mesenteric artery to acetylcholine and sodium nitroprusside were determined
      before and after CPB. Mesenteric lactate production, glucose consumption,
      creatine kinase (CK) release and venous free radicals were determined. CPB
      induced a significant fall (p < 0.05) in MAP and MBF. After CPB, reactive
      hyperemia (-26 +/- 15% versus -53 +/- 2%, p < 0.05) and the response to
      acetylcholine (-42 +/- 9 versus -55 +/- 6%, p < 0.05) were significantly
      decreased. Reperfusion increased lactate production (0.8 +/- 0.09 mmol/L versus
      0.4 +/- 0.18, p < 0.05) and the CK release (446 +/- 98 U/L versus 5 +/- 19 U/L, p
      < 0.01). Endothelial dysfunction, conversion from aerobic to anaerobic
      metabolism, and intestinal cell necrosis seem to be responsible for intestinal
      complications associated with CPB.

PMID- 12406149
TI  - A magnetic suspension theory and its application to the HeartQuest ventricular
      assist device.
AB  - Motivated by the design of the HeartQuest magnetically levitated left ventricular
      assist device, closed form expressions have been developed to compute forces and
      stiffnesses of magnetic suspensions. The theory applies to any combination of
      concentric permanent magnet rings, and its accuracy and versatility were verified
      by experiments. The equations adapt to spreadsheet implementation and numerical
      optimization, providing a powerful tool of optimal design of magnetically
      levitated ventricular assist devices (VADs). The method was applied to the
      development of the HeartQuest VAD which achieved remarkable compactness and
      stable operation.

PMID- 12406150
TI  - Extracorporeal membrane oxygenator compatible with centrifugal blood pumps.
AB  - Coil-type silicone membrane oxygenators can only be used with roller blood pumps
      due to the resistance from the high blood flow. Therefore, during extracorporeal
      membrane oxygenation (ECMO) treatment, the combination of a roller pump and an
      oxygenator with a high blood flow resistance will induce severe hemolysis, which
      is a serious problem. A silicone rubber, hollow fiber membrane oxygenator that
      has a low blood flow resistance was developed and evaluated with centrifugal
      pumps. During in vitro tests, sufficient gas transfer was demonstrated with a
      blood flow less than 3 L/min. Blood flow resistance was 18 mm Hg at 1 L/min blood
      flow. This oxygenator module was combined with the Gyro C1E3 (Kyocera, Japan),
      and veno-arterial ECMO was established on a Dexter strain calf. An ex vivo
      experiment was performed for 3 days with stable gas performance and low blood
      flow resistance. The combination of this oxygenator and centrifugal pump may be
      advantageous to enhance biocompatibility and have less blood trauma
      characteristics.

PMID- 12406151
TI  - Titania gel reduces thrombin generation.
AB  - Titanium alloy (Ti) commonly is used for long-term blood pumps as a conventional
      blood contacting material. Thrombus formation in the pump, however, is still a
      critical problem. Once thrombin is generated on the Ti surface, it activates
      platelets and the coagulation cascade, leading to thrombus formation. It would be
      expected that an inhibition of thrombin generation on a blood-contacting surface
      would prevent thrombus formation. In this study, the titania gel (Ti-gel) on the
      surface of Ti was formed with chemical modification. The surface structure and
      its effects on the coagulation cascade were evaluated. Scanning electron
      microscopic study revealed numerous cracks on the dried surface of Ti-gel,
      indicating a water-enriched layer. Blood coagulation on the Ti-gel was less than
      that on the Ti. Generated thrombin on the Ti-gel was less than that on the Ti in
      both the extrinsic and intrinsic pathways. There was no statistical difference of
      thrombin degradation. These results suggest that coagulation cascade on the Ti
      surface was inhibited by the Ti-gel formation. The Ti-gel may have better
      antithrombogenic characteristics for blood pumps because of its antiblood
      coagulation effects.

PMID- 12406152
TI  - Effects of mild hypothermic cardiopulmonary bypass on blood viscoelasticity in
      coronary artery bypass grafting patients.
AB  - The purpose of this study was to determine the changes in blood viscoelasticity
      during and after coronary artery bypass grafting (CABG) and to identify
      correlations between blood viscoelasticity and patients' age, duration of
      cardiopulmonary bypass (CPB), and cross-clamp time. After Institutional Review
      Board approvals, patients (n = 10) who were subjected to mild hypothermic CPB
      were included in this study. Viscosity and elasticity were measured at strains of
      0.2, 1, and 5 using a Vilastic-3 Viscoelasticity Analyzer. Arterial blood samples
      were collected pre-CPB, on normothermic CPB, hypothermic CPB, after rewarming,
      and after CPB. Viscosity and elasticity at strains of 0.2 and 1 were altered
      significantly during and after CPB compared to the pre-CPB (p < 0.01). In
      particular, elasticity of blood was diminished during normothermic bypass and
      could not be recovered after CPB (p < 0.01). Although there were strong
      correlations between blood viscoelasticity, duration of CPB, and cross-clamp time
      on normothermic CPB, only the patients' age showed a positive correlation between
      viscosity (r = 0.61, p = 0.05), and elasticity (r = 0.89, p < 0.001) after CPB.
      These results suggest that mild hypothermic CPB alters the blood viscoelasticity
      during and after CABG.

PMID- 12406153
TI  - Online parameter identification of second-order systemic circulation model using
      the delta operator.
AB  - To develop effective medical care with the artificial heart, we proposed a new
      method that can calculate the time varying and unmeasured hemodynamics of the
      human body from measured physiological data: aortic pressure, aortic flow, and
      pump flow in real time. This method comprises first, the second order of systemic
      circulation model, which consists of aortic compliance (Ca), aortic resistance
      (Ra), aortic inertia (L), and total peripheral resistance (Rp); and second,
      system identification using the delta operator. In the computer simulation, we
      confirmed the effectiveness of this method. During the animal experiment with the
      left ventricular assist system, the physiological parameters could be identified
      online: mean Ra = 0.04 mm Hg s/ml, mean Ca = 0.65 mm Hg/ml, mean L = 0.004 mm Hg
      s(2)/ml, and mean Rp = 0.3 mm Hg s/ml. This new method efficiently identified the
      physiological parameters, which are important not only to support the medical
      care but also to develop the control method adapted to the physiological
      behavior.

PMID- 12406154
TI  - The application of quantitative oil streaking to the HeartQuest left ventricular
      assist device.
AB  - Methods of flow visualization using oil streaking are established techniques for
      investigating surface shear and near wall flow patterns. Recent studies have used
      an array of oil dots on a surface which form streaks when exposed to shear
      forces. This method is generally qualitative, but it is possible to make
      quantitative measurements of the shear if the oil streaks have been calibrated.
      This paper presents the application of a quantitative oil streak method to the
      HeartQuest left ventricular assist device (LVAD). An array of dots was applied to
      the top housing of the pump, yielding quantitative values for the shear and
      qualitative patterns of the near wall flow in that region. The results were used
      to locate regions likely to promote thrombosis, such as stagnation points or
      recirculation regions. Regions of high shear, where hemolysis might occur, also
      can be identified with this method. In addition to being an important design
      technique, quantitative oil streaking assisted in the verification of
      computational fluid dynamics results within the HeartQuest LVAD.

PMID- 12406155
TI  - Morphological changes of the arterial systems in the kidney under prolonged
      continuous flow left heart bypass.
AB  - We investigated morphological changes of the arterial systems in the kidneys
      under prolonged continuous flow left heart bypass. Twelve goats were subjected to
      2 weeks of pulsatile left heart bypass followed by 4 weeks of continuous flow
      left heart bypass (group CF). After autopsy, the kidneys underwent pathological
      evaluation. Six normal healthy goats were used as controls. The media of the
      afferent arterioles of group CF were frequently thickened by an increase in the
      number of the mature smooth muscle cells (SMCs). The juxtaglomerular areas (JGA)
      were expanded because of an increase in the number and size of SMCs and/or SMC
      like cells. Furthermore, the percentage of anti-proliferating cell nuclear
      antigen antibody-positive cells in the JGA of group CF (9.9 +/- 1.9%) was
      significantly higher (p = 0.025) than that of the control group (4.6 +/- 3.4%),
      indicating active proliferation in group CF. We concluded that prolonged
      continuous flow left heart bypass causes proliferation of SMCs and/or SMC-like
      cells in the afferent arterioles and their perivascular tissue.

PMID- 12406156
TI  - Nonlinear controller for ventricular assist devices.
AB  - This paper presents the design of a gain-scheduled proportional integral (PI)
      feedback controller for ventricular assist devices to maintain physiologically
      motivated perfusion. The selected control objective is to maintain an average
      differential pressure deltaP between the left ventricle and the aorta. Computer
      simulations for different pathological conditions, ranging from the normal heart
      to left heart asystole, and a wide range of physiological scenarios, ranging from
      rest to strenuous exercise, were used to validate the performance of the
      controller and the effectiveness of the selected control objective in ensuring
      physiologically adequate perfusion under different clinical and cardiac demand
      conditions.

PMID- 12406157
TI  - Flow rate and pressure head estimation in a centrifugal blood pump.
AB  - Considering a miniaturization of percutaneous cardiopulmonary support (PCPS)
      system, we have developed a pump system that can estimate flow rate and pressure
      head in the circuit. A commercially available centrifugal blood pump (C1E3,
      Kyocera Co., Ltd., Kyoto, Japan) with an exclusive motor driver was used in the
      experiment. In this system, the motor revolutions per minute and torque were used
      to derive an estimation equation. Taking into consideration fluid viscosity, the
      accuracy of the estimation was increased. Bovine blood was used to evaluate the
      system in vitro. The average maximum difference between the estimated flow rate
      and the measured flow rate was 0.56 L/min (for 98% accuracy). The average
      difference between the estimated pressure head and the measured pressure head was
      30.7 mm Hg (for 94.2% accuracy). Because of the stability of the estimations, we
      believe this system has the possibility of use for real-time monitoring and
      miniaturization of PCPS system.

PMID- 12406158
TI  - Centrifugal pump support for distal aortic perfusion during repair of traumatic
      thoracic aortic injury.
AB  - Paraplegia from ischemic injury of the spinal cord and renal failure from
      inadequate perfusion of the kidneys may occur from aortic cross-clamping during
      repair of traumatic thoracic aortic injuries. After Institutional Review Board
      approval, we retrospectively reviewed the charts of 26 patients surgically
      treated for traumatic transection of the descending thoracic aorta during a 14
      year period (1987-2001), using centrifugal pump (Sarns) support for distal aortic
      perfusion. The study group comprised 19 males and 7 females, whose ages ranged
      from 15 to 69 years. For all but 1 patient, who fell from a flagpole, the
      injuries were incurred in motor vehicle accidents. Aortic cross-clamp time lasted
      between 5 to 78 min (median = 40 min). Mean arterial pressure ranged from 50 to
      80 mm Hg (median = 70 mm Hg). All patients survived operation without developing
      paraplegia or renal failure. Distal centrifugal pump perfusion during repair of
      traumatic injury of the descending thoracic aorta is a valuable adjunct during
      surgical treatment and aids in preservation of spinal cord and renal function.

PMID- 12406159
TI  - Postcardiotomy centrifugal assist: a single surgeon's experience.
AB  - Because of the infrequent application of cardiac assist devices for
      postcardiotomy heart failure, most published reports include the results of
      learning curves from multiple surgeons. Between October 1986 and June 2001, a
      single surgeon used 35 Sarns Centrifugal Pumps as ventricular assist devices in
      21 patients with severe hemodynamic compromise after open heart surgery (0.88%
      incidence). Patients' ages ranged from 39 to 77 (mean, 59.6 years). Three
      patients required right ventricular assist devices, 4 left ventricular assist
      devices, and 14 had biventricular assist devices. For all, the indication for
      application was inability to wean from cardiopulmonary bypass despite multiple
      inotropes and intraaortic balloon pumping. All were expected to be intraoperative
      deaths without further mechanical assistance. Patients were assisted from 2 to
      434 h (median, 48 h). Fifteen patients (71.4%) were weaned from device(s), and 11
      patients (52.4%) were hospital survivors. Actuarial survival in those dismissed
      from the hospital was 78% at 5 years and 39% at 10 years. Patients facing certain
      demise after cardiac surgery can be salvaged with temporary centrifugal
      mechanical assist. Results are competitive with that achieved with more
      sophisticated devices. Hospital survivors enjoy reasonable longevity.

PMID- 12406160
TI  - Effects of scaling on centrifugal blood pumps.
AB  - Experimental studies on the effects of scaling on the performance of centrifugal
      blood pumps were conducted in a closed-loop test rig. For the prototype, eight
      different impellers of the same outer diameter of 25 mm were tested at 1,500,
      2,000, and 2,500 revolutions per minute (rpm) using blood analog as fluid medium.
      This corresponds to Reynolds numbers (Re) of 25,900, 34,500, and 43,200,
      respectively. The results indicated that the nondimensional pump characteristic
      is a function of Re. This is understandable since the typical operating Re for
      centrifugal blood pumps is less than 100,000. Thus, the effects of scaling cannot
      be ignored for centrifugal blood pumps. Experiments on a 5x scaled-up model have
      also indicated that the scaled-up model is more efficient than the prototype
      model. Our results showed that in the range of Re tested, the nondimensional head
      versus flow curve is a function of Re to the power of approximately 0.25. It is
      observed that the nondimensional head versus flow is a function of diameter ratio
      to the power of 0.2.

PMID- 12406161
TI  - A prototype HeartQuest ventricular assist device for particle image velocimetry
      measurements.
AB  - The objective of this study is to fully characterize the flow within the
      HeartQuest ventricular assist device (VAD), a magnetically levitated centrifugal
      VAD, using particle image velocimetry (PIV) to identify regions of potential high
      shear or stagnation and validate and refine computational models of the flow. An
      acrylic model of the pump was designed and constructed to allow optical access
      into all interior regions of the pump. The geometry of the exterior housing and
      the use of a novel working fluid make quantitative measurements of velocity
      within the exit volute, blade passage, cut-water, blade tip clearance, and pump
      inlet possible. Highly accurate velocity measurements using particle PIV have
      been made in one region (the inlet elbow), and measurements in the other critical
      regions of the pump will be made. These measurements are used for investigation
      of regions with potential for hemolysis resulting from high shear stress or with
      potential for thrombosis caused by recirculation or stagnation. Quantitative
      velocity data are also needed for comparison with computational fluid dynamics
      (CFD) models of the VAD. In this study, experiments have again proven to be an
      essential complement to CFD for thorough investigations of the flow inside the
      pump.

PMID- 12406162
TI  - The road ahead.

PMID- 12406163
TI  - Calcium: a potential central regulator in wound healing in the skin.
AB  - Calcium has an established role in the normal homeostasis of mammalian skin and
      serves as a modulator in keratinocyte proliferation and differentiation.
      Gradients of calcium concentration increasing from 0.5 mM in the basal layer to >
      1.4 mM in the stratum granulosum are consistent with migration patterns in
      response to minor abrasion (normal wear). Dermal fibroblasts require calcium but
      are approximately 100 times less sensitive than keratinocytes. Normal calcium
      metabolism in the skin is dependent on cell membrane and cytosolic calcium
      binding proteins (calmodulin, cadherins, etc.), but their modulation through
      parathyroid hormone, vitamin D or growth factors in normal or damaged tissue is
      not well documented. In wound repair, calcium is predominantly involved as Factor
      IV in the hemostatic phase, but it is expected to be required in epidermal cell
      migration and regeneration patterns in later stages of healing. Calcium alginate
      dressings are designed to liberate calcium early in the acute phase to promote
      hemostasis, but it is presently unclear whether the supplementary calcium
      influences the intracellular environment at later stages of wound repair, notably
      during the remodeling phase. Although experimental studies suggest that control
      of calcium is obligatory in wound management, we know very little as to how
      calcium in the wound bed is modulated through hormones, vitamin D, or various
      growth factors. Also, there is limited information as to how calcium released
      either from dressings, platelets, or from the circulation through the action of
      parathyroid hormone, growth factors or other modulators influences cell migration
      and remodeling in skin wounds, although experimental models suggest that
      management of calcium is essential in wound management.

PMID- 12406164
TI  - Effects of nitric oxide releasing poly(vinyl alcohol) hydrogel dressings on
      dermal wound healing in diabetic mice.
AB  - Healing of chronic wounds such as diabetic foot ulcers is a significant clinical
      problem. Methods of accelerating healing in these difficult lower extremity sites
      include use of growth factor-loaded gels, hyperbaric oxygen, grafts, and
      artificial skin replacements. Nitric oxide (NO) has been proposed as a possible
      active agent for enhancing wound healing. This study examines the in vitro and in
      vivo responses to a novel hydrogel that produces therapeutic levels of NO. A
      hydrogel wound dressing was fabricated using ultraviolet light-initiated
      polymerization from poly(vinyl alcohol) with a NO donor covalently coupled to the
      polymer backbone. NO release from the NO-modified hydrogel was shown to occur
      over a time period of up to 48 hours, and there was no associated decrease in
      fibroblast growth or viability in vitro associated with NO hydrogels. Fibroblasts
      in culture with NO hydrogels had an increased production of extracellular matrix
      compared with cells cultured without the NO hydrogels. Preliminary animal studies
      in a diabetic mouse, impaired wound healing model were conducted comparing low
      (0.5 mM) and high (5 mM) doses of NO. Time to complete closure was similar in
      control wounds and NO-treated wounds; however, at 8 days control wounds were
      significantly smaller than NO-treated wounds. By days 10 to 13 this delay was no
      longer apparent. Granulation tissue thickness within the wounds at days 8 and 15
      and scar tissue thickness after wound closure were increased in animals exposed
      to higher dose NO hydrogels. The results of this study suggest that exogenous NO
      released from a hydrogel wound dressing has potential to modulate wound healing.

PMID- 12406165
TI  - Neutral endopeptidase inhibition in diabetic wound repair.
AB  - In response to cutaneous injury, sensory nerves release substance P, a
      proinflammatory neuropeptide. Substance P stimulates mitogenesis and migration of
      keratinocytes, fibroblasts, and endothelial cells. Neutral endopeptidase (NEP), a
      cell surface metallopeptidase, degrades substance P. Chronic nonhealing wounds
      and skin from patients with diabetes mellitus show increased NEP localization and
      activity. We hypothesized that increased NEP may retard wound healing and that
      NEP inhibition would improve closure kinetics in an excisional murine wound
      model. NEP enzyme activity was measured in skin samples from mutant diabetic mice
      (db/db) and nondiabetic (db/-) littermates by degradation of glutaryl-ala-ala-phe
      4-methoxy-2-naphthylamine. Full-thickness 6-mm dorsal excisional wounds treated
      with normal saline or the NEP inhibitor thiorphan (10 microM or 25 microM) for 7
      days were followed until closure. Histological examination and NEP activity were
      evaluated in a subset of wounds. NEP activity in unwounded db/db skin (20.6 pmol
      MNA/hr/ microg) significantly exceeded activity in db/-skin (7.9 pmol MNA/hr/
      microg; p = 0.02). In db/db mice, 25 microM thiorphan shortened time to closure
      (18.0 days; p < 0.05) compared to normal saline (23.5 days). NEP inhibition did
      not alter closure kinetics in db/-mice. While the inflammatory response appeared
      enhanced in early wounds treated with thiorphan, blinded histological scoring of
      healed wounds using a semiquantitative scale showed no difference in
      inflammation. Unwounded skin from diabetic mice shows increased NEP activity and
      NEP inhibition improved wound closure kinetics without affecting contraction,
      suggesting that its principal effect was to augment epithelialization.

PMID- 12406166
TI  - Appearance of leptin in wound fluid as a response to injury.
AB  - The adiposity hormone leptin regulates food intake, body weight, reproduction and
      other metabolic and endocrine functions mainly through signaling to the
      hypothalamus. Leptin signaling to peripheral tissues other than the hypothalamus
      has been suggested for a number of processes such as immunity, bone metabolism,
      hematopoiesis, angiogenesis, and wound healing. It was previously shown that
      exogenously applied leptin accelerated wound healing and that leptin mRNA is
      expressed at the wound site, but there is no published evidence showing that it
      is translated into leptin protein that is available at the site of repair. To
      address this question we analyzed pig wound fluids collected from partial
      thickness excisional wounds during the first 9 days after injury. Leptin was
      measured using a modified culture of HEK-293 cells, expressing both the human
      leptin receptor gene and the firefly luciferase gene driven by a STAT-inducible
      promoter. Relatively high levels of leptin activity (50-250 ng/ml) were detected
      in wound fluids using the leptin receptor expressing HEK-293 cells. Our results
      suggest that leptin is normally induced (4.8- to 10.2-fold) in wound tissue
      during the first few days following injury and may operate in a paracrine or
      autocrine circuit during the wound repair process.

PMID- 12406167
TI  - Tacrolimus enhances colon anastomotic healing in rats.
AB  - Tacrolimus inhibits T-cell function and neutrophil chemotaxis during
      inflammation. We hypothesized that tacrolimus would enhance healing of a rat
      colon anastomosis by reducing the inflammatory response. Fifty-five male Sprague
      Dawley rats, 230-260 g body weight, underwent identical surgical manipulation
      consisting of a single-layer, inverted colon anastomosis and the implantation of
      osmotic pumps subcutaneously in the left flank area. The animals were randomly
      assigned to receive tacrolimus, at a dose of 0.01, 0.1, or 1.0 mg/kg/day, or only
      the control solvent solution. The animals were euthanized 4 days after surgery.
      Colon-bursting pressure (mmHg), anastomotic collagen content ( micro g
      hydroxyproline/mg wet tissue), and anastomotic type IV collagenase activity
      (mU/mg protein) were measured. Tacrolimus significantly increased colon-bursting
      pressure at all doses used (146 +/- 9, 158 +/- 10, 151 +/- 6 mmHg; 0.01, 0.1, and
      1.0 mg/kg/day, respectively) vs. control (119 +/- 7 mmHg, p < 0.01). There was no
      effect on collagen accumulation except at a dose of 0.01 mg/kg/day, which
      significantly decreased anastomotic collagen content (p < 0.05). Tacrolimus at a
      dose of 0.01 mg/kg/day increased anastomotic collagenase activity, which was not
      changed by treatment with the higher doses. Microscopic examination revealed the
      preservation of the multilayered structure, including the mucosal muscle, a
      thickened submucosa, and the proper muscle of the anastomotic site in the
      tacrolimus-treated groups. These data suggest that tacrolimus enhances wound
      strength during acute anastomotic healing despite a reduction in collagen
      content.

PMID- 12406168
TI  - c-Jun N-terminal kinase activation during warm hepatic ischemia/reperfusion
      injuries in a rat model.
AB  - Ischemia/reperfusion injuries are a major problem in liver resections and
      transplantations. Tumor necrosis factor-alpha has been widely investigated as a
      key mediator in the mechanism of ischemia/reperfusion injury. Upstream signal
      transduction mechanisms for tumor necrosis factor-alpha have not been well
      documented. Therefore, we assessed c-Jun N-terminal kinase activation during warm
      hepatic ischemia/reperfusion injuries in a rat model. Male Wistar rats were
      subjected to 30 minutes of ischemia followed by reperfusion. Hepatic enzymes,
      histological examinations, microfluorographs, and tumor necrosis factor-alpha
      protein production (in the serum and liver tissue) were analyzed during the
      course of reperfusion. c-Jun N-terminal kinase activity was measured by a
      radioisotope kinase assay. Ischemia/reperfusion injuries were characterized by an
      elevation in hepatic enzyme, the histological degeneration of hepatocytes, and an
      increase in the number of nonviable cells. Moreover, increased endothelial
      adherent leukocytes and tumor necrosis factor-alpha protein production were also
      observed. c-Jun N-terminal kinase activity at 60 minutes after reperfusion was
      12.4 times higher than the pre-ischemia level. These results suggest that c-Jun N
      terminal kinase may play some role in the mechanism of ischemia/reperfusion
      injuries.

PMID- 12406169
TI  - Analysis of mucosal regeneration and the expression profile of heat shock protein
      70 in the isolated small bowel segment.
AB  - To investigate the mechanisms underlying the regeneration of the denervated small
      bowel segment from ischemic injury, we examined the heat shock protein 70 (HSP70)
      expression profile and compared it to the histopathological and proliferative
      changes seen in an isolated bowel segment using a rabbit model. Two weeks
      following the small bowel segment transplantation to the subcutaneous space, the
      vascular pedicle was sectioned. Next, the rabbits were divided into three groups
      based on the collection time of the isolated bowel segment (3, 7, and 14 days for
      Groups A, B, and C, respectively). The unsectioned small bowel segment was
      utilized as a control for each group. Histological studies showed that no
      experimental group recovered from mucosal injury. The bromodeoxyuridine labeling
      index showed that the more severe mucosal injury group had the highest
      bromodeoxyuridine incorporation. In the experimental groups, HSP70
      immunoreactivity was intensely seen in the regenerating epithelial cells and
      inflammatory cells. In the control mucosa, HSP70 immunoreactivity was weakly seen
      in the subepithelial stromal tissue, crypt cells and not in epithelial cells. The
      present study shows that the isolated bowel segment requires longer periods for
      regeneration from ischemic injury and HSP70 may play an important role during the
      regeneration process.

PMID- 12406170
TI  - Cell proliferating effect of latent transforming growth factor-beta1 is cell
      membrane dependent.
AB  - The mechanism of in vivo activation of transforming growth factor-beta1 (TGF
      beta1), which is critical to its role in many physiological and pathological
      conditions, is not fully understood. To explore the mechanism by which dermal
      fibroblasts respond to latent TGF-beta1 directly, the efficacy of either latent
      TGF-beta1 (LTGF-beta1) alone or LTGF-beta1 plus cell membranes isolated from
      fibroblasts, mink lung, and one skin-related (Sk23) and two skin-unrelated (U251
      and D54MG) transformed cell lines was examined using the mink lung epithelial
      cell (Mv1Lu) inhibition assay. As a source of LTGF-beta1, PA317 cells were
      transfected with previously constructed pLin-TGF-beta1 or pLin vectors with no
      TGF-beta1 insert. LTGF-beta1 expressing PA317 cells were then enriched by growth
      in the presence of 0.5 mg G-418 for 6-10 days. Eight out of 53 colonies of cells
      expressing high levels of LTGF-beta1 were selected and their conditioned media
      were removed after 3 days and used to evaluate the latency and bioactivity of TGF
      beta1 using ELISA and Mv1Lu growth inhibition assay, respectively. The level of
      TGF-beta1 was 19-fold greater (21.4 +/- 0.4 vs. 1.1 +/- 0.2 ng/ml) in conditioned
      medium derived from pLin-TGF-beta1 transfected cells than that of control. These
      conditioned media were then used for the subsequent cell proliferating
      experiments. The results showed that latent TGF-beta1, which proved to be
      inactive in an Mv1Lu inhibition assay, significantly stimulates fibroblast cell
      proliferation compared to that of control in a dose-dependent fashion. In another
      set of experiments, cells were treated with either active (acidified/neutralized)
      or latent TGF-beta1 and the results showed a significant increase in cell
      proliferation in response to low concentrations of active TGF-beta1. However,
      high concentrations of active TGF-beta1 markedly suppressed fibroblast
      proliferation. These dual effects were in contrast to a steady increase in
      fibroblast proliferation found in response to latent TGF-beta1. To explore why
      LTGF-beta1 has a differential proliferating effect on epithelial and fibroblast
      cell proliferation, cell membranes from these cells were isolated and incubated
      with PA317-conditioned medium containing LTGF-beta1 and then added to mink lung
      cells. Only isolated fibroblast cell membranes incubated with LTGF-beta1
      inhibited Mv1Lu cells. To examine whether the LTGF-beta1 cell proliferating
      activity is unique to dermal fibroblasts or is a general phenomenon, in similar
      experimental conditions cell membranes from several cell lines, U251, D54MG, and
      SK23, were isolated, incubated with LTGF-beta1, and then added to an Mv1Lu
      inhibition assay. The proliferation of Mv1Lu epithelial cells was significantly
      (1547 +/- 269 vs. 3568 +/- 23) inhibited with SK23, but not U251 cell membranes
      plus LTGF-beta1 relative to that of control. The inhibitory effect of SK23 plus
      LTGF-beta1 was cell membrane dose-dependent. In conclusion, the result of this
      study shows that LTGF-beta1 may directly modulate cell proliferation of those
      cells that possess a cell membrane associated LTGF-beta1 activation mechanism.

PMID- 12406171
TI  - Fibroblast proliferation due to exposure to a platelet concentrate in vitro is pH
      dependent.
AB  - The influence of platelet-rich plasma lysates on fibroblast proliferation was
      studied in culture. Cells were exposed to platelet lysates that had been
      preincubated at different pHs (5.0, 7.1, and 7.6). Proliferation was evaluated
      with the MTT assay and incorporation of [3H]thymidine into macromolecules, while
      type I collagen production was assayed by Western blotting. Enzyme-linked
      immunosorbent assays were used to determine platelet-derived growth factor and
      transforming growth factor-beta concentrations. Platelets preincubated in an
      acidic environment (pH 5.0) induced the highest degree of fibroblast
      proliferation, and the concentration of platelet-derived growth factor in the
      different treated lysates was the highest at that particular pH. The
      concentration of transforming growth factor-beta, however, was lower after
      incubation at pH 5.0 than at either pH 7.1 or 7.6. These findings may be relevant
      to normal wound healing in vivo and useful in the treatment of wounds and delayed
      healing processes.

PMID- 12406173
TI  - Plea for better communication and interaction.

PMID- 12406174
TI  - East of the West Nile.

PMID- 12406175
TI  - Key elements for church-based health promotion programs: outcome-based literature
      review.
AB  - Although not a new concept, church-based health promotion programs have yet to be
      widely researched. Few of the initial studies used randomized and controlled
      designs. Dissemination of study results has been sporadic, with findings often
      reported in church periodicals. A renewed interest in church-based health
      promotion programs (CBHPP) is emerging. The purpose of this article is to propose
      seven key elements found in a literature review to be beneficial in establishing
      church-based community health promotion programs that demonstrated desired health
      promotion outcomes. Based on the outcomes of successful CBHPP, the following key
      elements have been identified: partnerships, positive health values, availability
      of services, access to church facilities, community-focused interventions, health
      behavior change, and supportive social relationships. An example of one program
      that embodies these elements is presented. The Heart and Soul Program, designed
      to increase physical activity in midlife women to reduce their risk of
      cardiovascular disease with advancing age, is discussed within the context of the
      elements for successful church-based programs. CBHPP have effectively promoted
      health behaviors within certain communities. To promote health and wellness in
      light of our diverse society and health needs, health promotion professionals and
      churches can be dynamic partners.

PMID- 12406176
TI  - A plan for the delegation of epinephrine administration in nonpublic schools to
      unlicensed assistive personnel.
AB  - Professional nurses in nonpublic schools address variables in their practice that
      are different from nurses in a public school setting. These may include lack of
      funds for full-time nursing, different educational requirements, incorporation of
      religious beliefs into the social milieu, and inadequate peer or union support.
      These variables are problematic when public law health statues require change in
      school/parent/student relationships. New Jersey's Public Law 1997, Chapter 368
      (N.J.S.A. 18A:40-12.5 and 12.6), hereafter referred to as P.L. 1997, c. 368, was
      enacted because school nurses may not always be available to assess students who
      are experiencing severe allergic reactions. Since allergies in the school
      population are common and can lead to anaphylaxis which is life threatening
      (Smith, 1999), P.L. 1997, c. 368, requires each educational board or chief school
      administrator/principal of public and nonpublic schools to develop a policy
      governing epinephrine administration. This article describes how public health
      nurses, the director of public health nursing, and a faculty consultant in the
      Bergen County Department of Health Services worked together to produce strategies
      for the safe implementation of this law. These strategies may provide a template
      for consideration by other public health nurses who serve the student population.

PMID- 12406177
TI  - Development and expert evaluation of "Moms on the Move," a physical activity
      intervention for WIC mothers. Women, Infants, and Children.
AB  - The purpose of this descriptive study was to develop and evaluate "Moms on the
      Move," a provider-counseled physical activity intervention for mothers enrolled
      in the Women, Infants, and Children (WIC) program. The intervention was based on
      the Transtheoretical Model (TTM) of behavior change. The evaluation occurred in
      two stages. In the first stage, physical activity behavioral experts (n=4)
      evaluated the: (a) rationale for intervention components; (b) linkages between
      behavior change constructs, intervention activities, and study outcomes; (c)
      literature support for the TTM behavior change constructs; and (d) the
      intervention brochure. The expert evaluation tool was adapted from the
      "Educational Materials Review Form." Each item in the expert evaluation met the
      <or= 3.0 mean criterion for acceptability (range, 1.33-2.67). Revisions were made
      based on expert comments before stage 2. In the second stage, WIC mothers (n=5)
      evaluated the intervention brochure. The 9-item WIC mothers' evaluation tool was
      adapted from a simple tool for community members. In the second stage evaluation,
      the mean total score for the intervention brochure evaluation was 44.0 (SD=1.22),
      which met the a priori criterion to retain as is. Mean item responses ranged from
      4.8 to 5.0 (5.0=great). This evaluation indicates that "Moms on the Move" is a
      promising physical activity intervention for WIC mothers, which should be
      implemented for efficacy testing.

PMID- 12406178
TI  - Development and pilot testing of a bicycle safety questionnaire for adult
      bicyclists.
AB  - Most deaths associated with bicycle riding are reported in those over the age of
      16 and the highest death rate per million trips is reported in those over the age
      of 50, yet most efforts to reduce deaths among bicycle riders have focused on
      children. The purpose of this study was to pilot test a new instrument designed
      to assess knowledge of bicycle laws and perception of risk related to specific
      host behaviors and agents of injury. A pilot study using a descriptive
      correlational design was conducted among a convenience sample of 104 adult
      bicycle riders. A 25-item questionnaire was administered to participants (10
      knowledge items, 15 belief items). There were no significant differences in total
      knowledge or belief score for gender, age group, riding frequency, education, or
      formal bicycle training. Significant differences were found for responses to
      individual items on both scales. Psychometric testing indicated that items on the
      knowledge scale were independent. Psychometric testing on the belief scale
      suggested three underlying constructs measuring beliefs about riding behavior,
      agents of injury, and user burden. Bicycle riders with previous safety training
      had significantly different scores on the riding behavior and user burden
      subscales.

PMID- 12406179
TI  - Selected factors associated with students' perceptions of threat in the
      community.
AB  - This study assessed nursing students' perceptions of threat in the community from
      the beginning to the completion of their first formal community health nursing
      course (inclusive of specific community health content associated with relevant
      clinical experience) and determined how perceptions of threat differed by
      residential zone and by type of program (generic day, generic weekend/evening, or
      R.N.). Undergraduate nursing students were sampled from eight National League for
      Nursing Accrediting Commission (NLNAC) accredited baccalaureate schools.
      Completed pretest data were obtained for 345 students. Completed post-test data
      were obtained for 274 students. Paired data were available for 197 students.
      Generally, students were comfortable when the environment was assessed within the
      context of daylight before and after the course. Students were not as comfortable
      with the environment when assessed within the context of nighttime either before
      they started the community course or after they completed it. Students continue
      to perceive that the community environment presents limited threats, particularly
      when viewed from the perspective of time of day. Because the community
      educational experience is not restricted to baccalaureate education (Cahill et
      al., 1998), nor is it conceptualized as a singular experience (Mellon & Nelson,
      1998), the challenge to faculty is to enhance student learning by preparing them
      in such a manner that they assess their community environment for threats and
      practice safely within that environment. The use of the Environmental Comfort
      Scale III, including the open-ended question, may be one way to achieve this
      challenge.

PMID- 12406180
TI  - Population-based osteoporosis education for older women.
AB  - With an increased focus on wellness and health promotion, there is a need for
      community-based strategies to complement traditional strategies aimed at
      improving individual and aggregate health. An educational program on the
      prevention, diagnosis, and treatment of osteoporosis was provided for 188 women
      age 60 and older in three different community settings: churches, retirement
      homes, and senior citizen centers. The major purposes of the study were to
      determine whether a community-based program might (a) contribute to older women's
      knowledge about osteoporosis and (b) promote their intent to use this knowledge.
      Each participant completed a demographic profile, the Osteoporosis Risk
      Checklist, and the Osteoporosis Knowledge Questionnaire (OKQ), with the OKQ
      serving as a pre- and post-test. Before post-testing, a 30-min educational
      program was provided. Differences among the three groups were risk factors, prior
      knowledge about osteoporosis, and knowledge at the completion of the program. A
      majority of the clients indicated an intent to increase calcium in their diet,
      discuss osteoporosis with their health care provider, check their home
      environment for safety/falls, and discuss what they had learned with others.
      Nurses need to plan educational programs in all settings to teach older clients
      about the risk factors, prevention, diagnosis, and treatment of osteoporosis.

PMID- 12406181
TI  - TB-HIV Registry Matching in Missouri, 1987-1999.
AB  - Mycobacterium tuberculosis (MTB) is an important problem for human
      immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) patients.
      This study investigated whether all cases of MTB reported to the HIV/AIDS
      Registry (HARS) in Missouri were also reported to the Tuberculosis Information
      Management System (TIMS) to determine the sensitivity of TIMS and the predictive
      value of HARS. We found 262 total MTB cases registered in HARS. Of these, 145
      (55%) were included in the TIMS. Thirty-eight of the remaining 117 were caused by
      mycobacteria other than TB leaving 79 for investigation. Chart review of the 79
      revealed 16 cases of MTB. Sensitivities and predictive values were calculated
      first including unknown/unreported group as being MTB-positive and the second
      including this group as being MTB-negative. Sensitivities for TIMS were 83 and
      90%, respectively, and predictive values for HARS were 68 and 63%, respectively.
      The fact that there were at least 16 unreported cases of MTB has significant
      public health implications for TB control in Missouri. Public health nursing
      could work with HARS surveillance staff to help improve the accuracy of case
      finding and reporting. By whatever means necessary, communications between the TB
      and HIV programs within the Missouri Department of Health should be enhanced.

PMID- 12406183
TI  - Alterations of chaperone protein expression in presenilin mutant neurons in
      response to glutamate excitotoxicity.
AB  - Mutations in the presenilin-1 (PS1) gene underlie the most common form of
      familial dementia of the Alzheimer type (DAT). We demonstrated previously that
      the expression of PS1 with a M146V mutation in transgenic mice potentiates
      glutamate toxicity to neurons, due to an altered calcium homeostasis. Here, using
      a subtractive cDNA library approach, we report the identification of several
      genes, the altered expression of which may be associated with this unique PS1
      related vulnerability to glutamate. The identified genes, including chaperonin
      subunit 2 and nucleophosmin 1/B23, are involved in the intracellular trafficking
      of proteins and ions. Northern blot analysis revealed that the effect of
      glutamate on calcium-binding proteins was augmented in neurons from PS1 mutation
      mice, compared with neurons from mice lacking other genes relevant to the
      pathogenesis of DAT (FE65 and APOE) or neurons from control wild-type mice.
      Interestingly, mRNA for two chaperone proteins were expressed at lower levels
      specifically in neurons from PS1 mutant mice. These findings suggest that PS1
      mutations may, in part, contribute to the development of DAT via altered
      expression of chaperone proteins.

PMID- 12406184
TI  - Ethics of the new biology and genetic medicine (molecular ethics): brief (re)view
      from the USA.

PMID- 12406185
TI  - Accumulation of imidazolone, pentosidine and N(epsilon)-(carboxymethyl)lysine in
      hippocampal CA4 pyramidal neurons of aged human brain.
AB  - Previous studies from our laboratory demonstrated that N(epsilon)
      (carboxymethyl)lysine (CML), one of the major advanced glycation end products
      (AGE), was accumulated in human pyramidal neurons in the hippocampus in an age
      dependent manner. This suggests a potential link between AGE-accumulation and the
      aging process in neurons. The purpose of the present study was to examine whether
      this notion could be extended to other AGE structures, such as imidazolone and
      pentosidine. This was done using 19 human brains that were not affected by
      dementia. The immunohistochemical survey on distribution in brain tissues of
      imidazolone and pentosidine was carried out with monoclonal antibodies specific
      for imidazolone and pentosidine. A parallel control experiment was carried out
      with anti-CML antibody. The results showed that pentosidine and imidazolone were
      localized in neurons in different areas of human brain tissue, especially in
      neurons of CA4 in the hippocampus. The characteristic distribution of pentosidine
      and imidazolone is very similar to that of CML. Furthermore, when the
      accumulation of these AGE structures was compared with the age of individual
      brains it was found that accumulation of imidazolone, pentosidine and CML in the
      CA4 region increased with age. These findings taken together support the notion
      that the accumulation of AGE structures in the CA4 region might be closely
      related to the aging process in neurons.

PMID- 12406187
TI  - cDNA arrays: gene expression profiles of Hodgkin's disease and anaplastic large
      cell lymphoma cell lines.
AB  - cDNA arrays are a powerful tool for the identification of differentially
      expressed genes in malignant tumors. We used this technique to study the gene
      expression profiles of anaplastic large cell lymphoma (ALCL) and Hodgkin's
      disease (HD). Gene expression of 11 lymphoma cell lines was analyzed covering
      1176 cDNA sequences. Comparing these data to the expression profiles of B- and T
      lymphocytes, we identified 27 genes that were deregulated in all cell lines or in
      a particular entity. For the establishment of gene expression profiles the 27
      genes were assigned to four groups composed of genes deregulated in (i) all
      lymphoma cell lines, (ii) ALCL and HD, (iii) only HD, and (iv) ALCL exclusively.
      Our results indicate that ALCL and HD share the differential expression of at
      least five genes. In addition, both entities are characterized by the
      differentially deregulated expression of four genes in HD and seven genes in
      ALCL. Because the expression profiling was performed on cell lines, further
      studies are needed to clarify the biological significance of the differentially
      expressed genes.

PMID- 12406186
TI  - Upregulation of alpha-synuclein by lipopolysaccharide and interleukin-1 in human
      macrophages.
AB  - Alpha-synuclein was originally identified as the presynaptic nerve terminal
      protein. Recently, we reported that alpha-synuclein is also expressed in cultured
      human astrocytes and that its levels are increased by stimulation with
      interleukin-1beta, suggesting that it may be involved in inflammatory processes.
      We therefore investigated the effect of inflammatory stimuli on alpha-synuclein
      expression in human macrophages. Alpha-synuclein mRNA and protein were detected
      in cultured human macrophages and levels of alpha-synuclein protein were
      increased by stimulation with lipopolysaccharide and interleukin-1beta in a time-
      and concentration-dependent manner. Immunofluorescent staining showed that alpha
      synuclein protein was expressed within the cytoplasm and nucleus. Furthermore,
      alpha-synuclein immunoreactivity was present in alveolar macrophages from human
      lung tissues. These findings suggest that the function of alpha-synuclein is not
      exclusive to the nervous system and that alpha-synuclein may play a role in
      inflammatory processes and immune responses.

PMID- 12406188
TI  - Analysis of immunoglobulin VH genes in CD10-positive diffuse large B-cell
      lymphoma.
AB  - CD10, a proteolytic enzyme seen in germinal center cells and in the majority of
      follicular lymphomas, is occasionally expressed in diffuse large B-cell lymphomas
      (DLBCL). To clarify the origin and cellular characteristics of CD10-positive
      DLBCL, we analyzed 36 de novo cases of DLBCL for somatic mutations of the
      immunoglobulin heavy chain variable region (VH) genes and for their
      immunophenotypes. Expression greater than that of grade 2 Bcl-6 was observed in
      11 of the 30 CD10-negative cases (37%) and in all six CD10-positive cases (100%;
      P < 0.05) without expression of CD5, CD23, cyclin D1, CD30 or CD138. The average
      mutation frequencies of the six CD10-positive and 30 CD10-negative DLBCL were
      12.9 and 9.8%, respectively. The range of SM frequencies in CD10-positive DLBCL
      (9.52-18.06) was distinctly narrower than that observed for CD10-negative DLBCL
      (0.69-26.89). These findings seem to indicate that CD10-positive DLBCL,
      originating from germinal center B cells, is a genetically and
      immunophenotypically more homogeneous group than CD10-negative DLBCL.
      Furthermore, three extranodal lymphomas, in five of the six CD10-positive DLBCL,
      showed ongoing mutation, indicating that antigen-driven, high-affinity somatic
      mutation may play an important role in clonal expansion in CD10-positive DLBCL.
      All four extranodal cases of the six CD10-positive DLBCL showed ongoing mutation
      and/or bcl-2/JH rearrangement. This result suggests that the cell origin of
      extranodal CD10-positive DLBCL may be the same as that of follicular lymphomas.

PMID- 12406189
TI  - Reassessment and clinicopathological prognostic factors of malignant fibrous
      histiocytoma of soft parts.
AB  - Recently, the category of malignant fibrous histiocytoma (MFH) has been under
      discussion and new entities resembling MFH have appeared. To clarify the recent
      situation regarding MFH, we reassessed previously diagnosed MFH cases in
      accordance with the most up-to-date diagnostic criteria, which included allied
      tumors. We carefully reassessed 428 cases that had been diagnosed in our
      institute during the past 28 years. Moreover, we searched for clinicopathological
      prognostic factors among the cases that were finally diagnosed as MFH. Among the
      428 cases, 138 cases had their diagnoses changed. The revised cases included 78
      leiomyosarcomas (57%; ordinary leiomyosarcoma, 45 cases; pleomorphic
      leiomyosarcoma, 23 cases; myxoid leiomyosarcoma, 10 cases), 12 liposarcomas (9%;
      pleomorphic liposarcoma, 11 cases; dedifferentiated liposarcoma, one case), seven
      dermatofibrosarcoma protuberans (5%), six unclassified sarcomas (4%), five
      primary or metastatic carcinomas (4%), four low-grade fibromyxoid sarcomas (3%),
      four inflammatory myofibroblastic tumors (3%), three rhabdomyosarcomas (2%),
      three malignant peripheral nerve sheath tumors (2%), three acral myxoinflammatory
      fibroblastic sarcomas (2%) and two atypical fibroxanthomas (1.5%). Among the 1974
      soft tissue sarcomas registered in our institute, MFH (428 cases) had been the
      most common sarcoma, followed by liposarcoma, leiomyosarcoma and
      rhabdomyosarcoma. However, after reassessment, leiomyosarcoma proved to be the
      most common soft tissue sarcoma (322 cases), followed by 290 MFH, 273
      liposarcomas and 202 rhabdomyosarcomas. Among these 290 cases finally diagnosed
      as MFH, survival data were available in 189 cases. Tumor location in the
      abdominal cavity, the retroperitoneum or the head and neck (P = 0.0024), tumor
      size of 5 cm or more (P < 0.0001), deep tumor location (P < 0.0001), high
      histological grade (grade 3) based on the French Federation of Cancer Centers'
      grading system (P = 0.0007), and high stage (stage III or IV) based on the
      American Joint Committee on Cancer (AJCC) staging system (P < 0.0001) were
      significantly worse prognostic factors by univariate analysis. In multivariate
      analysis, deep tumor location and high AJCC stage were independent adverse
      prognostic factors. We conclude that leiomyosarcoma is the most important
      differential diagnosis for MFH, especially pleomorphic leiomyosarcoma from
      storiform-pleomorphic type and myxoid leiomyosarcoma from myxoid type. Tumor
      depth and AJCC stage are the most important predictive prognostic factors in MFH.

PMID- 12406190
TI  - Minute pancreatic adenocarcinoma presenting with stenosis of the main pancreatic
      duct.
AB  - We describe a case of minute pancreatic ductal adenocarcinoma featuring stenosis
      of the main pancreatic duct (MPD) and associated with histological findings of
      periductal elastosis and fibroblast proliferation. A 53-year-old Japanese man
      with preoperative radiological evidence of MPD stricture and dilation of the
      distal MPD, and suspected of having pancreatic cancer, underwent successful
      resection. Neither radiological nor macroscopic examination directly disclosed
      any tumorous lesions, and a small focus of carcinoma (8 x 8 mm) was only revealed
      on microscopic examination. The tumor was a poorly differentiated, invasive
      ductal adenocarcinoma that had invaded the intrapancreatic nerves and veins.
      Interestingly, the MPD located at the edges of the tumor had not been destroyed
      by the carcinoma, but its wall had been thickened by elastic tissue and
      fibroblast proliferation, resulting in stenosis. The peripheral pancreas
      exhibited secondary obstructive pancreatitis. To date, the detection of small
      pancreatic tumor masses using imaging procedures remains difficult, and most
      patients are diagnosed on the basis of pancreatic ductal changes. However, the
      published work on small pancreatic cancers contains little information about the
      histological features of the affected MPD. The present findings suggest that MPD
      strictures are not always provoked by destruction or filling with cancer cells,
      and that they can be caused by periductal elastosis and fibroblast proliferation
      in a minute carcinoma. Such changes in the MPD may therefore be of clinical
      importance in the detection of early stage cancers.

PMID- 12406191
TI  - Regression of congenital fibrosarcoma to hemangiomatous remnant with histological
      and genetic findings.
AB  - We report a rare case of congenital fibrosarcoma (CFS) showing regression during
      the course of disease, in which the histological and genetic alterations were
      investigated. This CFS, located on the patient's right hand, was a
      hemangiopericytomatous hypervascular tumor showing frequent mitosis and necrosis.
      Small lymphocytes, predominantly cytotoxic T cells and natural killer cells,
      infiltrated the tumor. At the age of 3 months, the patient received a partial
      resection of the tumor. At the age of 1 year, the hemangiopericytomatous tumor
      with a dilated vascular lumen remained, although most of the tumor cells
      exhibited focal necrosis with calcification and no mitotic activity. Lymphocytes
      increased in number and intermingled with the tumor cells. At the age of 4 years,
      vascular tissue consisting of inner endothelial cells and surrounding
      pericytomatous actin-positive cells remained at the previous tumor locus. With
      reverse transcription-polymerase chain reaction analysis, ETV6-NTRK3 fusion
      transcripts were detected in tumor samples at 3 months and at 1 year, but not
      from those at 4 years of age. These genetic and histological changes suggest that
      the CFS either completely disappeared by apoptosis or showed mature
      transformation to hemangiomatous tissue with aging.

PMID- 12406192
TI  - Angiomyofibroblastoma-like tumor (lipomatous variant) of the inguinal region of a
      male patient.
AB  - A case of angiomyofibroblastoma-like tumor (lipomatous variant) that arose in the
      subcutis of the inguinal region of a 45-year-old man is presented. The maximum
      dimension of the tumor measured 39 mm and it was well circumscribed.
      Histopathological examination revealed a close admixture of plump spindle or
      stellate cells and mature adipocytes. These were arranged haphazardly or formed
      interconnecting thin cellular trabeculae on the myxoid or edematous background.
      The tumor was highly vascularized and contained a moderate amount of collagen
      fibers. Immunohistochemically, the tumor cells were positive for vimentin, CD34
      and the estrogen receptor, but negative for alpha-smooth muscle actin and desmin.
      The differential diagnosis between the lipomatous variant of
      angiomyofibroblastoma and cellular angiofibroma or spindle cell lipoma is
      discussed, and the pathogenetic hypotheses about the occurrence of mature
      adipocytes within benign fibroblastic or myofibroblastic neoplasms are mentioned
      briefly. It is important for surgical pathologists to be acquainted with the
      occasional presence of adipocytes in these neoplasms to avoid misinterpretation.

PMID- 12406193
TI  - Relationship between reactive nitrogen intermediates and total immunoglobulin E,
      soluble CD21 and soluble CD23: comparison between cerebral malaria and nonsevere
      malaria.
AB  - To search for evidence of a protective role of the CD23/NO pathway against
      cerebral malaria, concentrations of reactive nitrogen intermediates (RNI) and
      sCD21, total immunoglobulin (Ig)E and sCD23 were compared between 17 cases of
      cerebral malaria and 33 controls. The geometric mean of sCD23 concentration was
      higher among cerebral malaria cases than among controls (optical density
      2643/1495, P = 0.01). The ratio between sCD21 and sCD23 was significantly lower
      in cerebral malaria cases than in controls (0.67 +/- 0.02 versus 0.77 +/- 0.02,
      respectively, P = 0.009). Multiple linear regression analysis showed that, among
      cerebral malaria cases, there was a clear correlation between RNI and both IgE (P
      = 0.007) and sCD21 (P < 0.0001). Among controls, there was a strong negative
      correlation between RNI and sCD23 concentrations (r = -0.61, P < 0.0001).
      However, multivariate analysis unmasked the fact that, in controls, there was
      also a positive correlation between RNI and IgE (P = 0.045). Logistic regression
      showed that increased RNI concentrations were associated with a cerebral malaria
      adjusted odds ratio of 1.05 per unit increase [95% confidence interval (CI) 1.006
      1.1, P = 0.02] and that an increased ratio between sCD21 and sCD23 was associated
      with protection from cerebral malaria (adjusted OR = 0.00001 per unit increase
      (95% CI 0-0.03, P = 0.005). These different immunological profiles suggest that,
      among controls, the CD23/NO pathway was chronically stimulated whereas, in
      cerebral malaria, its stimulation was acute, which could explain why some
      patients developed cerebral malaria and others did not.

PMID- 12406194
TI  - Paraflagellar rod protein-specific CD8+ cytotoxic T lymphocytes target
      Trypanosoma cruzi-infected host cells.
AB  - Our previous studies show that in mice immunized with the paraflagellar rod (PFR)
      proteins of Trypanosoma cruzi protective immunity against this protozoan parasite
      requires MHC class I-restricted T cell function. To determine whether PFR
      specific CD8+ T cell subsets are generated during T. cruzi infection, potential
      CTL targets in the PFR proteins were identified by scanning the amino acid
      sequences of the four PFR proteins for regions of 8-10 amino acids that conform
      to predicted MHC class I H-2b binding motifs. A subset of the peptide sequences
      identified were synthesized and tested as target antigen in 51Cr-release assays
      with effector cells from chronically infected T. cruzi mice. Short-term cytotoxic
      T lymphocyte (CTL) lines specific for two of the peptides, PFR-1(164-171) and PFR
      3(123-130), showed high levels of lytic activity against peptide-pulsed target
      cells, secreted interferon (IFN)-gamma in response to parasite-infected target
      cells, and were found to be CD8+, CD4-, CD3+, TCRalphabeta+ cells of the Tc1
      subset. Challenge of PFR immunized CD8-/- and perforin-deficient (PKO) mice
      confirmed that while CD8+ cells are required for survival of T. cruzi challenge
      infection, perforin activity is not required. Furthermore, while lytic activity
      of PFR-specific CD8+ T cell lines derived from PKO mice was severely impaired,
      the IFN-gamma levels secreted by CTLs from PKO mice were equivalent to that of
      normal mice, suggesting that the critical role played by CD8+ T cells in immunity
      to the parasite may be secretion of type 1 cytokines rather than lysis of
      parasite infected host cells.

PMID- 12406195
TI  - Identification of an antigen from the sheep scab mite, Psoroptes ovis, homologous
      with house dust mite group I allergens.
AB  - Infestation of sheep with the ectoparasitic mite Psoroptes ovis, results in a
      severe allergic dermatitis. Currently, little is known about the
      allergens/antigens that stimulate the allergic response. We have isolated an 836
      bp cDNA from a P. ovis cDNA library which displays strong homology to cysteine
      proteases and, in particular, to the group I house dust mite allergens Der p 1,
      Der f 1 and Eur m 1. The cDNA was expressed in Escherchia coli, fused to a
      hexahistidine tag and the recombinant protein (Pso o 1) purified using a nickel
      affinity column. The recombinant Pso o 1 was tested for recognition by
      immunoglobulin (Ig)G and IgE in serum from P. ovis naive and P. ovis infested
      sheep. Using Western blots, both classes of antibody to Pso o 1 were detected in
      postinfestation serum. In enzyme-linked immunosorbent assays, a pronounced IgG
      antibody response to Pso o 1 was detected in five of five sheep 3 weeks
      postinfestation. The IgE-antibody response to whole mite extract was poor in four
      of five animals. However, a marked IgE response occurred in the fifth animal, and
      IgE anti Pso o 1 was detected in the serum.

PMID- 12406196
TI  - Diminished immunopathology in Schistosoma mansoni infection following intranasal
      administration of cholera toxin B-immunodominant peptide conjugate correlates
      with enhanced transforming growth factor-beta production by CD4 T cells.
AB  - In Schistosoma mansoni infection, CD4 T cells specific for parasite egg antigens
      mediate perioval granuloma formation in the liver and intestines. Mice of the CBA
      strain develop a severe form of disease and a significant proportion of their CD4
      T cell response is directed against the major egg antigen Sm-p40 and its
      immunodominant T cell epitope peptide 234-246. Here, we show that intranasal
      (i.n.) treatment of infected CBA mice with a fusion protein of the cholera toxin
      B subunit (CTB) with peptide 234-246 (CTB::pep) results in significant down
      modulation of hepatic granulomatous inflammation and fibrosis. Moreover, egg
      antigen-stimulated dispersed hepatic granuloma cells, as well as mesenteric lymph
      node CD4 T cells from the CTB::pep-treated mice, produced significantly more
      transforming growth factor (TGF)-beta than that produced by treated or untreated
      controls. The data demonstrate that i.n. administration of a single
      immunodominant peptide conjugated to CTB can lead to down-regulation of the
      hepatic immunopathology associated with schistosomiasis, and that this down
      regulation is, at least in part, mediated by TGF-beta.

PMID- 12406197
TI  - Production of a recombinant version of a Heligmosomoides polygyrus antigen that
      is preferentially recognized by resistant mouse strains.
AB  - Protective immunity to the mouse nematode parasite, Heligmosomoides polygyrus,
      has been characterized and found to be composed of the Th2 type. However, many
      inbred mouse strains cannot produce this protective immune response during a
      primary infection. A possible reason for this lack of protection in poor
      responding strains could be due to lack of recognition of specific protective
      antigens by these strains. Recently, evidence suggests that specific antigens
      exist that are only recognized by fast responding strains during a primary
      infection. Using monoclonal antibodies to screen an H. polygyrus cDNA library
      enabled the production of a recombinant protein, 3A4, which is antigenically
      similar to those found in the excretory/secretory antigens (E/S) of both L4 and
      adult parasites. Protein 3A4 shares approximately 70% sequence homology with an
      E/S protein that induces protection to Trichostrongylus colubriformis in guinea
      pigs. Antibodies that bind to 3A4 are preferentially produced in SWR compared to
      BALB/c mice following immunization with L4 homogenate, although both strains of
      mice were able to produce comparable levels of specific antibodies after
      immunization with 3A4 protein. It is believed that 3A4 may have considerable
      importance in dissecting out the nature of the immune response to H. polygyrus
      infection, particularly in mouse strains of differing response phenotype.

PMID- 12406198
TI  - Maxadilan, the vasodilator/immunomodulator from Lutzomyia longipalpis sand fly
      saliva, stimulates haematopoiesis in mice.
AB  - Protozoal parasites of the genus Leishmania are transmitted to their vertebrate
      host within the saliva of the sand fly during a blood meal. The saliva of the
      sand fly Lutzomyia longipalpis contains maxadilan, a potent vasodilator and
      immunomodulator. Maxadilan has been shown to enhance the virulence of L. major in
      all strains of laboratory mice when injected along with the organism. Increased
      haematopoiesis has been associated with enhanced susceptibility to Leishmania
      organisms. Here, we show that maxadilan alone stimulates bone marrow
      haematopoiesis through its ability to stimulate interleukin-6 production by bone
      marrow stromal cells. Moreover, these effects of maxadilan are mediated through
      the interaction of maxadilan with the pituitary adenylate cyclase activating
      polypeptide receptor. These data suggest that increasing haematopoiesis may be
      yet another way that maxadilan enhances susceptibility of mice to Leishmania
      infection.

PMID- 12406199
TI  - The review process.

PMID- 12406200
TI  - Prospective study of fall risk assessment among institutionalized elderly in
      Japan.
AB  - The purpose of the present study was to identify risk factors for falls among
      institutionalized elderly, using the standardized risk assessment tool developed
      by Izumi. We examined 746 patients from three types of facilities: rehabilitation
      wards in four general hospitals, three long-term care facilities, and three
      nursing homes, for up to three months. The incidence of falls within all
      facilities was 12.5%. Patterns of relative risks of falling differed among types
      of facilities. The highest relative risk of fall in long-term care facilities and
      nursing homes was nurses' prediction, followed by history of fall and altered
      mentation. In contrast, that in general hospitals was mobility. In long-term care
      facilities, history of falls (odds 3.68, 95CI: 1.47-9.23) and interaction
      (history of falls and assistance with toileting) (odds 3.13, 95CI: 1.48-6.64)
      showed significance on adjusted-odds ratios for fall. History of falls, altered
      mentation, and assistance with toileting may be used to screen patients at a high
      risk for fall at admission.

PMID- 12406201
TI  - Communication effectiveness of nurses working in a variety of settings within one
      large university teaching hospital in western Japan.
AB  - This survey study measured the communication effectiveness of 176 nurses working
      on a variety of clinical units within one large university hospital in western
      Japan. The vast majority of the nurses demonstrated fair effectiveness in their
      communication skills. Although some of the nurses did demonstrate slightly higher
      communication effectiveness scores, few of the nurses' demographic
      characteristics appeared to influence how well they communicated. The major
      limitations of the present study were the use of one hospital for data gathering,
      and the possible lack of cultural sensitivity of the communication questionnaire.

PMID- 12406202
TI  - The relationship between fear of falling, activities of daily living and quality
      of life among elderly individuals.
AB  - The purpose of the present study was to examine the relationship between
      functional disability and fear of falling during daily activities. Also examined
      was the relationship between fear of falling and health-related Quality of Life
      (QOL). Health-related QOL concepts were measured using the Short Form 36 Health
      Survey (SF-36) within an elderly day services sample. Eligible subjects were
      elderly persons using Day Service (type B) who were capable of independently
      answering a questionnaire and had no memory problems. Forty-three males and 92
      females were eligible for this study. Forty-nine (36.3%) subjects expressed no
      fear of falling, whereas 22 (16.3%) reported that they were very fearful of
      falling. Among females, walking and bathing had a highly significant relationship
      with the fear of falling. The fear of falling can contribute to psychological
      conditions such as depression, and also impacts on the health-related QOL of
      frail elderly people. Thus, it is critical to provide integrated health care
      activities for these individuals that address both psychological well-being and
      physical functioning.

PMID- 12406203
TI  - Research utilization among pediatric health professionals.
AB  - The present study investigated research use and attitudes toward research among
      pediatric health professionals. All nurses and allied health professionals in a
      pediatric teaching hospital were surveyed using previously tested and published
      measures. Over half of the participants had some formal education in research
      but, for some participants, that education was many years ago. Most participants
      reported poor or very poor understanding of research design. Two variables were
      independently associated with a positive attitude towards research: (i) better
      understanding of how to conduct a literature search; and (ii) higher level of
      education. Five variables were independently associated with research use: better
      understanding of research design; having presented at a conference in the past
      two years; sense of calling to the profession; better understanding of how to
      conduct a literature search; and attending rounds. A small proportion of variance
      in both research use and a positive attitude towards research was explained by
      the independent predicator variables. Further research is required to identify
      characteristics of the workplace environment that support research use.

PMID- 12406204
TI  - Genetic education in baccalaureate and associate degree nursing programs in
      Japan.
AB  - The purpose of the present study was to ascertain the amount and type of genetic
      content in basic nursing education programs in Japan baccalaureate degree (BSN)
      and associate degree (ADN), and to describe the qualifications of faculty members
      teaching the genetics content. A questionnaire was used to examine these. The
      sample was derived from 66 basic nursing preparatory programs. Faculty members
      from 34 out of 75 (44.7%) of the BSN programs and 32 out of 52 (61.5%) of the ADN
      programs returned completed surveys, providing a total response rate of 52%. As a
      result of the analysis of the survey data, the researchers recommend increasing
      the amount of genetic content, related to nursing practice, in the curriculum of
      Japanese baccalaureate and associate degree nursing programs. In addition, the
      researchers recommend increasing the number of nursing faculty specialising in
      genetics. Japanese nursing education must incorporate genetic knowledge into the
      curricula to produce professionals who are prepared to practise in the current
      and future genetic health care arena.

PMID- 12406205
TI  - Initiating and sustaining breastfeeding in Hong Kong: contextual influences on
      new mothers' experiences.
AB  - The research reported in the present paper was conducted as part of a larger
      longitudinal infant feeding study examining the relationship between motivational
      and situational variables, and primaparas' infant feeding behaviors. The aim of
      this investigation was to identify contextual factors that influenced first-time
      mothers' breastfeeding practices in the immediate postpartum period. Employing an
      exploratory, qualitative design, data were collected through unstructured in
      depth interviews with 19 primiparous mothers at one-month postpartum. Thematic
      analysis revealed two main themes: sociocultural and environmental influences,
      and lactation management. Although the participants wanted to succeed at
      breastfeeding, they faced many impediments in a society that was not supportive
      of lactating mothers. Health professionals' mixed messages, life stresses (short
      maternity leaves and lack of work place support for breastfeeding) and the
      participants' poor understanding of the physiological process of lactation
      presented obstacles for continued breastfeeding.

PMID- 12406206
TI  - Nurses' knowledge, attitudes and beliefs regarding substance use: a questionnaire
      survey.
AB  - A questionnaire on nurses' knowledge, attitudes, beliefs and practises regarding
      substance use was distributed to 302 nurses in Victoria. One hundred and thirty
      four returned the questionnaire, giving an overall response rate of 44.3%. The
      survey results showed that although knowledge and skill gaps exist in assessment
      and management of alcohol and drug problems, overall knowledge levels were
      adequate. Although positive attitudes towards substance use were expressed,
      specific educational programs to enhance nurses' skills in assessment and
      management of substance-related disorders may be beneficial.

PMID- 12406207
TI  - Reflective practise in clinical teaching.
AB  - The present paper describes the process of reflective practise in clinical
      teaching through a workshop entitled 'Effective Clinical Teaching'. The clinical
      teachers were invited to analyze the content of a videotape in which various
      clinical teaching scenarios were presented. Following this, they discussed a
      series of questions designed to promote reflective activities and evaluated the
      interaction among the student, the client and the clinical teachers in each
      scenario. The teachers also identified the positive and negative aspects of the
      teaching approaches portrayed on the tape. Finally, the participants made
      recommendations that would improve the interaction and suggested alternate
      teaching strategies to enhance the learning outcome. In addition, there was
      sharing of clinical teaching experiences among the clinical teachers. Through
      this process of reflection on action, the clinical teachers were able to
      understand various teaching approaches as perceived by students, and to address
      the issues that might hinder student learning in clinical settings. Different
      reflective activities have also been proposed to enhance student's reflective
      learning skills.

PMID- 12406208
TI  - The importance of first-time parent groups for new parents.
AB  - First-time parent groups are offered to all new parents in Victoria, Australia
      through the Maternal and Child Health Service, which is funded by state and local
      governments. Parents who join a group attend a series of eight sessions that
      emphasize parenting skills, relationship development and social support in order
      to increase confidence and skills in parenting. The present paper highlights the
      importance of first-time parent groups, claiming that these groups serve an
      important social support and health function amid a climate of early discharge
      policies and changing family structures. Although there are a number of
      challenges to the successful running of groups, it is argued that first-time
      parents benefit from participating in these groups in a number of ways: by
      developing social networks, gaining self confidence, and through access to
      relevant information on child health and parenting. Research indicates that first
      time parent groups provide lasting benefits not only for families, but also for
      society as a whole. Maternal and child health nurses play a key role in
      facilitating groups for first-time parents.

PMID- 12406209
TI  - Evolution of signalling in the sporulation phosphorelay.
AB  - Two-component and phosphorelay signal transduction systems are believed to
      function as environ-mental sensors that programme gene expression to the
      composition of the ecological niche in which a microbe normally resides. The
      question of how evolutionarily related bacteria that occupy different
      environments change their signal transduction pathways to adapt to such
      environments was asked of the sporulation phosphorelay of Bacillus subtilis,
      Bacillus halodurans, Bacillus anthracis and Bacillus stearothermophilus.
      Comparison of the primary amino acid sequence of phosphorelay proteins with the
      known structural and interactive properties of the B. subtilis proteins revealed
      that the amino acid residues of interaction surfaces between phosphorelay
      proteins and between a phosphorelay protein and DNA resist evolutionary change.
      The absolute conservation of interaction surfaces allowed the identification of
      sporulation sensor kinases in B. halodurans, B. anthracis and B.
      stearothermophilus. In these sensor kinases, the signal-sensing domains are
      vastly different in size and subdomain composition, with little apparent
      conservation between species, whereas the catalytic domains of these sensor
      kinases retain the high level of homology observed for the other phosphorelay
      proteins. Adaptation to new environments appears to result in rapid evolution of
      signalling domains to maximize environmental impact while maintaining identical
      protein-protein and protein-DNA contacts in the entire phosphorelay. In
      Clostridial genomes, only the Spo0A protein was found, suggesting that the
      anaerobic relatives of the Bacilli do not use a phosphorelay and phosphorylate
      Spo0A directly with sensor kinases.

PMID- 12406210
TI  - CPMK2, an SLT2-homologous mitogen-activated protein (MAP) kinase, is essential
      for pathogenesis of Claviceps purpurea on rye: evidence for a second conserved
      pathogenesis-related MAP kinase cascade in phytopathogenic fungi.
AB  - Cpmk2, encoding a mitogen-activated protein (MAP) kinase from the ascomycete
      Claviceps purpurea, is an orthologue of SLT2 from Saccharomyces cerevisiae, the
      first isolated from a biotrophic, non-appressorium-forming pathogen. Deletion
      mutants obtained by a gene replacement approach show impaired vegetative
      properties (no conidiation) and a significantly reduced virulence, although they
      retain a limited ability to colonize the host tissue. Increased sensitivity to
      protoplasting enzymes indicates that the cell wall structure of the mutants may
      be altered. As the phenotypes of these mutants are similar to those observed in
      strains of the rice pathogen, Magnaporthe grisea, that have been deprived of
      their MAP kinase gene mps1, the ability of cpmk2 to complement the defects of
      delta mps1 was investigated. Interestingly, the C. purpurea gene, under the
      control of its own promoter, was able to complement the M. grisea mutant
      phenotype: transformants were able to sporulate and form infection hyphae on
      onion epidermis and were fully pathogenic on barley leaves. This indicates that,
      despite the differences in infection strategies, which include host and organ
      specificity, mode of penetration and colonization of host tissue, CPMK2/MPS1
      defines a second MAP kinase cascade (after the Fus3p/PMK1 cascade) essential for
      fungal pathogenicity.

PMID- 12406211
TI  - The GlnD and GlnK homologues of Streptomyces coelicolor A3(2) are functionally
      dissimilar to their nitrogen regulatory system counterparts from enteric
      bacteria.
AB  - Glutamine synthetase I (GSI) enzyme activity in Streptomyces coelicolor is
      controlled post-translationally by the adenylyltransferase (GlnE) as in enteric
      bacteria. Although other homologues of the Escherichia coli Ntr system (glnK,
      coding for a PII family protein; and glnD, coding for an uridylyltransferase) are
      found in the S. coelicolor genome, the regulation of the GSI activity was found
      to be different. The functions of glnK and glnD were analysed by specific
      mutants. Surprisingly, biochemical assay and two-dimensional PAGE analysis showed
      that modification of GSI by GlnE occurs normally in all mutant strains, and
      neither GlnK nor GlnD are required for the regulation of GlnE in response to
      nitrogen stimuli. Analysis of the post-translational regulation of GlnK in vivo
      by two-dimensional PAGE and mass spectrometry indicated that it is subject to
      both a reversible and a non-reversible modification in a direct response to
      nitrogen availability. The irreversible modification was identified as removal of
      the first three N-terminal amino acid residues of the protein, and the reversible
      modification as adenylylation of the conserved tyro-sine 51 residue that is known
      to be uridylylated in E. coli. The glnD insertion mutant expressing only the N
      terminal half of GlnD was capable of adenylylating GlnK, but was unable to
      perform the reverse deadenylylation reaction in response to excess ammonium. The
      glnD null mutant completely lacked the ability to adenylylate GlnK. This work
      provides the first example of a PII protein that is modified by adenylylation,
      and demonstrates that this reaction is performed by a homologue of GlnD,
      previously described only as a uridylyltransferase enzyme.

PMID- 12406212
TI  - Two transcriptional regulators GlnR and GlnRII are involved in regulation of
      nitrogen metabolism in Streptomyces coelicolor A3(2).
AB  - Streptomyces coelicolor has an unusually large arsenal of glutamine synthetase
      (GS) enzymes: a prokaryotic GSI-beta-subtype enzyme (encoded by glnA), three
      annotated glnA-like genes of the GSI-alpha-subtype and a eukaryote-like glutamine
      synthetase II (encoded by glnII). Under all tested conditions, GSI was found to
      represent the dominant glutamine synthetase activity. A significant heat-labile
      GSII activity, which is very low to undetectable in liquid-grown cultures, was
      only detected in morphologically differentiating S. coelicolor cultures. Analysis
      of glnA and glnII transcription by S1 nuclease mapping and egfp fusions revealed
      that, on nitrogen-limiting solid medium, glnII but not glnA expression is
      upregulated. An OmpR-like regulator protein, GlnR, has previously been implicated
      in transcriptional control of glnA expression. Gel retardation analysis revealed
      that GlnR is a DNA-binding protein, which interacts with the glnA promoter. It is
      not autoregulatory and does not bind to the upstream regions of the glnA-like
      genes of the alpha-subfamily, nor to the glnII promoter in vitro. A second GlnR
      target was identified upstream of the amtB gene, encoding a putative ammonium
      transporter. amtB forms an operon with glnK (encoding a PII protein) and glnD
      (encoding a putative PII nucleotidylyltransferase) shown by S1 nuclease
      protection analysis and reverse transcription-polymerase chain reaction (RT-PCR).
      An amtB and glnA promoter alignment revealed a putative GlnR operator structure.
      Downstream of glnII, a gene encoding for another OmpR-like regulator, GlnRII, was
      identified, with strong similarity to GlnR. Gel shifts with GlnRII showed that
      the promoters recognized by GlnR are also targets of GlnRII. However, GlnRII also
      interacted with the glnII upstream region. Only inactivation of glnR resulted in
      a glutamine auxotrophic phenotype, whereas the glnRII mutant can grow on minimal
      medium without glutamine.

PMID- 12406213
TI  - High-frequency conjugative transfer of antibiotic resistance genes to Yersinia
      pestis in the flea midgut.
AB  - The acquisition of foreign DNA by horizontal transfer from unrelated organisms is
      a major source of variation leading to new strains of bacterial pathogens. The
      extent to which this occurs varies widely, due in part to lifestyle factors that
      determine exposure to potential donors. Yersinia pestis, the plague bacillus,
      infects normally sterile sites in its mammalian host, but forms dense aggregates
      in the non-sterile digestive tract of its flea vector to produce a transmissible
      infection. Here we show that unrelated co-infecting bacteria in the flea midgut
      are readily incorporated into these aggregates, and that this close physical
      contact leads to high-frequency conjugative genetic exchange. Transfer of an
      antibiotic resistance plasmid from an Escherichia coli donor to Y. pestis
      occurred in the flea midgut at a frequency of 10-3 after only 3 days of co
      infection, and after 4 weeks 95% of co-infected fleas contained an average of 103
      antibiotic-resistant Y. pestis transconjugants. Thus, transit in its arthropod
      vector exposes Y. pestis to favourable conditions for efficient genetic exchange
      with microbial flora of the flea gut. Horizontal gene transfer in the flea may be
      the source of antibiotic-resistant Y. pestis strains recently isolated from
      plague patients in Madagascar.

PMID- 12406214
TI  - Compensatory adaptation to the deleterious effect of antibiotic resistance in
      Salmonella typhimurium.
AB  - Most chromosomal mutations that cause antibiotic resistance impose fitness costs
      on the bacteria. This biological cost can often be reduced by compensatory
      mutations. In Salmonella typhimurium, the nucleotide substitution AAA42 --> AAC
      in the rpsL gene confers resistance to streptomycin. The resulting amino acid
      substitution (K42N) in ribosomal protein S12 causes an increased rate of
      ribosomal proofreading and, as a result, the rate of protein synthesis, bacterial
      growth and virulence are decreased. Eighty-one independent lineages of the low
      fitness, K42N mutant were evolved in the absence of antibiotic to ameliorate the
      costs. From the rate of fixation of compensated mutants and their fitness, the
      rate of compensatory mutations was estimated to be > or = 10-7 per cell per
      generation. The size of the population bottleneck during evolution affected
      fitness of the adapted mutants: a larger bottleneck resulted in higher average
      fitness. Only four of the evolved lineages contained streptomycin-sensitive
      revertants. The remaining 77 lineages contained mutants that were still fully
      streptomycin resistant, had retained the original resistance mutation and also
      acquired compensatory mutations. Most of the compensatory mutations, resulting in
      at least 35 different amino acid substitutions, were novel single-nucleotide
      substitutions in the rpsD, rpsE, rpsL or rplS genes encoding the ribosomal
      proteins S4, S5, S12 and L19 respectively. Our results show that the deleterious
      effects of a resistance mutation can be compensated by an unexpected variety of
      mutations.

PMID- 12406215
TI  - Critical role of the N-terminal residues of listeriolysin O in phagosomal escape
      and virulence of Listeria monocytogenes.
AB  - A putative PEST sequence was recently identified close to the N-terminus of
      listeriolysin O (LLO), a major virulence factor secreted by the pathogenic
      Listeria monocytogenes. The deletion of this motif did not affect the secretion
      and haemolytic activity of LLO, but abolished bacterial virulence. Here, we first
      tested whether the replacement of the PEST motif of LLO by two different
      sequences, with either a very high or no PEST score, would affect phagosomal
      escape, protein stability and, ultimately, the virulence of L. monocytogenes.
      Then, we constructed LLO mutants with an intact PEST sequence but carrying
      mutations on either side, or on both sides, of the PEST motif. The properties of
      these mutants prompted us to construct three LLO mutants carrying single amino
      acid substitutions in the distal portion of the PEST region (P49A, K50A and P52A;
      preprotein numbering). Our data demonstrate that the susceptibility of LLO to
      intracellular proteolytic degradation is not related to the presence of a high
      PEST score sequence and that the insertion of two residues immediately downstream
      of the intact PEST sequence is sufficient to impair phagosomal escape and abolish
      bacterial virulence. Furthermore, we show that single amino acid substitutions in
      the distal portion of the PEST motif are sufficient to attenuate bacterial 
      virulence significantly, unravelling the critical role of this region of LLO in
      the pathogenesis of L. -monocytogenes.

PMID- 12406216
TI  - Domains in the S-layer protein CbsA of Lactobacillus crispatus involved in
      adherence to collagens, laminin and lipoteichoic acids and in self-assembly.
AB  - The protein regions in the S-layer protein CbsA of Lactobacillus crispatus JCM
      5810, needed for binding to collagens and laminin, anchoring to bacterial cell
      wall, as well as self-assembly, were mapped by deletion analysis of His-tagged
      peptides isolated from Escherichia coli and by heterologous expression on
      Lactobacillus casei. Mature CbsA is 410 amino acids long, and stepwise genetic
      truncation at both termini revealed that the region 32-271 carries the infor
      mation for self-assembly of CbsA into a periodic structure. The lactobacillar S
      layer proteins exhibit sequence variation in their assembly domain, but the
      border regions 30-34 and 269-274 in CbsA are conserved in valine-rich short
      sequences. Short deletions or substitutions at these regions affected the
      morphology of His-CbsA polymers, which varied from sheet-like to cylindrical
      tubular polymers, and further truncation beyond the DNA encoding residues 32 and
      271 leads to a non-periodic aggregation. The self-assembly of the truncated
      peptides, as seen by electron microscopy, was correlated with their behaviour in
      a cross-linking study. The shorter peptides not forming a regular polymer were
      observed by the cross-linking study and mass spectrometry to form dimers, trimers
      and tetramers, whereas the other peptides were cross-linked to large multimers
      only. Binding of solubilized type I and IV collagens was observed with the His
      CbsA peptides 1-274 and 31-287, but not with the smaller peptides regardless of
      their ability to form regular polymers. Strain JCM 5810 also adheres to
      immobilized laminin and, in order to analyse the possible laminin binding by
      CbsA, cbsA and its fragments were expressed on the surface of L. casei.
      Expression of the CbsA peptides 1-274, 1-287, 28-287 and 31-287 on L. casei
      conferred adhesiveness to both laminin and collagen immobilized on glass as well
      as to laminin- and collagen-containing regions in chicken colon and ileum. The C
      terminal peptides 251-410 and 288-410 bound to L. crispatus JCM 5810 cells from
      which the S-layer had been depleted by chemical extraction, whereas no binding
      was seen with the His-CbsA peptides 1-250 or 1-269 or to cells with an intact S
      layer. The His-CbsA peptides 251-410 and 288-410 bound to teichoic acids of
      several bacterial species. The results show that CbsA is an adhesive complex with
      an N-terminal assembly domain exhibiting affinity for pericellular tissue
      components and a cationic C-terminal domain binding to negatively charged cell
      wall components.

PMID- 12406217
TI  - Cell cycle-dependent expression of an essential SMC-like protein and dynamic
      chromosome localization in the archaeon Halobacterium salinarum.
AB  - The genome of Halobacterium salinarum encodes four proteins of the structural
      maintenance of chromosomes (SMC) protein superfamily. Two proteins form a novel
      subfamily and are named 'SMC-like proteins of H. salinarum' (Sph1 and Sph2).
      Northern blot analyses revealed that sph1 and hp24, the adjacent gene, are solely
      transcribed in exponentially growing, but not in stationary phase, cells. A
      synchronization procedure was developed, which makes use of the DNA polymerase
      inhibitor aphidicolin and leads to highly synchronous cultures. It allowed us for
      the first time to study cell cycle-dependent transcription in an archaeon. The
      sph1 transcript was found to be highly cell cycle regulated, with its maximal
      accumulation around the time of septum formation. The Sph1 protein level was also
      elevated at that time, but a basal protein level was found throughout the cell
      cycle. The hp24 transcript was sharply upregulated about 1 h before sph1 and had
      already declined at the time of sph1 induction. These and additional transcript
      patterns revealed that precisely controlled transcriptional regulation is
      involved in haloarchaeal cell cycle progression. A DNA staining protocol was
      developed, which opened the possibility of following the dynamic intracellular
      localization of haloarchaeal nucleoids using synchronized cultures. After an
      initial dispersed localization, the nucleoid is condensed at mid-cell.
      Subsequently, DNA is rapidly transported to the 1/4 and 3/4 positions. All
      staining patterns were also observed in untreated exponentially growing cells,
      excluding synchronization artifacts. The Sph1 concentration is elevated when
      segregation of the new chromosomes is nearly complete; therefore, it is proposed
      to play a role in a late step of replication, e.g. DNA repair, similar to
      eukaryotic Rad18 proteins.

PMID- 12406218
TI  - Genetic analysis of functions involved in the late stages of biofilm development
      in Burkholderia cepacia H111.
AB  - Burkholderia cepacia and Pseudomonas aeruginosa often co-exist as mixed biofilms
      in the lungs of patients suffering from cystic fibrosis (CF). Here, we report the
      isolation of 13 random mini-Tn5 insertion mutants of B. cepacia H111 that are
      defective in biofilm formation on a polystyrene surface. We show that the
      screening procedure used in this study is biased towards mutants defective in the
      late stages of biofilm development. A detailed quantitative analysis of the
      biofilm structures formed by wild-type and mutant strains revealed that the
      isolated mutants are impaired in their abilities to develop a typical three
      dimensional biofilm structure. Molecular investigations showed that the genes
      required for biofilm maturation fall into several classes: (i). genes encoding
      for surface proteins; (ii). genes involved in the biogenesis and maintenance of
      an integral outer membrane; and (iii). genes encoding regulatory factors. It is
      shown that three of the regulatory mutants produce greatly reduced amounts of N
      octanoylhomoserine lactone (C8-HSL). This compound serves as the major signal
      molecule of the cep quorum-sensing system. As this density-dependent regulatory
      system is involved in the regulation of biofilm maturation, we investigated the
      interplay between the three regulatory genes and the quorum-sensing cascade. The
      results of these investigations show that the identified genes encode for
      regulatory elements that are positioned upstream of the cep system, indicating
      that the quorum-sensing system of B. cepacia is a major checkpoint for biofilm
      formation.

PMID- 12406219
TI  - Ralstonia solanacearum requires type 4 pili to adhere to multiple surfaces and
      for natural transformation and virulence.
AB  - As reported previously for Ralstonia solanacearum strain GMI1000, wild-type
      strains AW1 and K60 were shown to produce Hrp pili. AW1 and K60 mutants lacking
      Hrp pili still exhibited twitching motility, which requires type 4 pili (Tfp),
      and electron microscopy revealed that they still made flexuous polar pili.
      Twitching-positive cells had an extracellular 17 kDa protein that was associated
      with piliation, and an internal 43-amino-acid sequence of this protein was
      typical of type 4 pilins. This amino acid sequence is encoded by an open reading
      frame, designated pilA, in the genomic sequence of GMI1000. PilA is 46% identical
      to a Pseudomonas aeruginosa type 4 pilin over its entire length and has all the
      conserved residues and motifs characteristic of type 4 group A pilins. pilA
      mutants did not make the 17 kDa PilA protein and did not exhibit twitching
      motility. When compared with its parent, an AW1 pilA mutant was reduced in
      virulence on tomato plants and in autoaggregation and biofilm formation in broth
      culture. Unlike AW1, a pilA mutant did not exhibit polar attachment to tobacco
      suspension culture cells or to tomato roots; it was also not naturally competent
      for transformation. We reported previously that twitching motility ceases in
      maturing AW1 colonies and that inactivation of PhcA, a global transcriptional
      regulator, results in colonies that continue to exhibit twitching motility.
      Similarly, in broth culture, expression of a pilA::lacZ fusion in AW1 decreased
      10-fold at high cell density, but expression remained high in a phcA mutant. In
      addition, pilA::lacZ expression was positively regulated 10-fold by PehR, a
      response regulator that is known to be repressed by PhcA. This signal cascade is
      sufficient to explain why pilA expression, and thus twitching motility, decreases
      at high cell densities.

PMID- 12406220
TI  - Conjugative transfer of clostridial shuttle vectors from Escherichia coli to
      Clostridium difficile through circumvention of the restriction barrier.
AB  - Progress towards understanding the molecular basis of virulence in Clostridium
      difficile has been hindered by the lack of effective gene transfer systems. We
      have now, for the first time, developed procedures that may be used to introduce
      autonomously replicating vectors into this organism through their conjugative,
      oriT-based mobilization from Escherichia coli donors. Successful transfer was
      achieved through the use of a plasmid replicon isolated from an indigenous C.
      difficile plasmid, pCD6, and through the characterization and subsequent
      circumvention of host restriction/modification (RM) systems. The characterized
      replicon is the first C. difficile plasmid replicon to be sequenced and encodes a
      large replication protein (RepA) and a repetitive region composed of a 35 bp
      iteron sequence repeated seven times. Strain CD6 has two RM systems,
      CdiCD6I/M.CdiCD6I and CdiCD6II/M. CdiCD6II, with equivalent specificities to
      Sau96I/M. Sau96I (5'-GGNMCC-3') and MboI/M. MboI (5'-GMATC-3') respectively. A
      second strain (CD3) possesses a type IIs restriction enzyme, Cdi I, which cleaves
      the sequence 5'-CATCG-3' between the fourth and fifth nucleotide to give a blunt
      ended fragment. This is the first time that an enzyme with this specificity has
      been reported. The sequential addition of this site to vectors showed that each
      site caused between a five- and 16-fold reduction in transfer efficiency. The
      transfer efficiencies achieved with both strains equated to between 1.0 x 10-6
      and 5.5 x 10-5 transconjugants per donor.

PMID- 12406222
TI  - Characterization of the promoter regions involved in galactose- and nisin
      mediated induction of the nisA gene in Lactococcus lactis ATCC 11454.
AB  - The nisA promoter is positively regulated in Lactococcus lactis ATCC 11454 by
      autoinduction via a two-component NisRK-mediated system. However, induction of
      this promoter can also occur when introduced into the plasmid-free L. lactis
      LM0230 during growth in galactose or lactose, independent of the NisRK system. In
      this study, we also characterized this galactose-mediated induction by
      determining the nisA start site during growth in galactose, which was identical
      to the nisA start site upon nisin induction. The region involved in the galactose
      mediated induction of the nisA promoter was investigated by directed deletion
      analysis of a 200 bp region upstream of the nisA promoter in the transcription
      fusion pDOC99. The induction of the deletion derivatives by galactose and nisin
      was compared phenotypically using beta-galactosidase measurements, and the
      regions necessary for the induction were determined by sequence analysis.
      Analysis of these regions revealed two sets of a TCT direct repeat [TCT-N8-TCT]
      present at positions (-107 to -94) and (-39 to -26) relative to the transcription
      initiation site. Disruption of the upstream repeat abolished galactose induction
      and significantly reduced the nisin induction capacity, suggesting a potential
      pivotal role for these repeats in transcription induction of the nisA promoter.
      It was also observed that the galactose-mediated induction was abolished when a
      plasmid containing the phosphotransferase system (PTS), phospho-beta
      galactosidase and tagatose pathway genes was introduced into this strain. As this
      effectively made the Leloir pathway redundant, it points to some component of
      this pathway as the specific inducer of the nisA promoter.

PMID- 12406221
TI  - Overexpression of inhA, but not kasA, confers resistance to isoniazid and
      ethionamide in Mycobacterium smegmatis, M. bovis BCG and M. tuberculosis.
AB  - The inhA and kasA genes of Mycobacterium tuberculosis have each been proposed to
      encode the primary target of the antibiotic isoniazid (INH). Previous studies
      investigating whether overexpressed inhA or kasA could confer resistance to INH
      yielded disparate results. In this work, multicopy plasmids expressing either
      inhA or kasA genes were transformed into M. smegmatis, M. bovis BCG and three
      different M. tuberculosis strains. The resulting transformants, as well as
      previously published M. tuberculosis strains with multicopy inhA or kasAB
      plasmids, were tested for their resistance to INH, ethionamide (ETH) or
      thiolactomycin (TLM). Mycobacteria containing inhA plasmids uniformly exhibited
      20-fold or greater increased resistance to INH and 10-fold or greater increased
      resistance to ETH. In contrast, the kasA plasmid conferred no increased
      resistance to INH or ETH in any of the five strains, but it did confer resistance
      to thiolactomycin, a known KasA inhibitor. INH is known to increase the
      expression of kasA in INH-susceptible M. tuberculosis strains. Using molecular
      beacons, quantified inhA and kasA mRNA levels showed that increased inhA mRNA
      levels corre--lated with INH resistance, whereas kasA mRNA levels did not. In
      summary, analysis of strains harbouring inhA or kasA plasmids yielded the same
      conclusion: overexpressed inhA, but not kasA, confers INH and ETH resistance to
      M. smegmatis, M. bovis BCG and M. tuberculosis. Therefore, InhA is the primary
      target of action of INH and ETH in all three species.

PMID- 12406223
TI  - Modular domain structure in the Candida glabrata adhesin Epa1p, a beta1,6 glucan
      cross-linked cell wall protein.
AB  - The yeast pathogen Candida glabrata adheres avidly to cultured human epithelial
      cells. This interaction depends on the expression of EPA1, which encodes a lectin
      belonging to a large family of GPI-anchored glucan-cross-linked cell wall
      proteins (GPI-CWPs) found in diverse fungal species. To understand the
      relationship between different domains of EPA1 and its function, we have mapped
      functional domains of Epa1p and analysed their contribution to Epa1p function. We
      found that the N-terminal third of the protein contains the ligand-binding
      domain, and that the GPI anchor is essential both for cross-linking in the cell
      wall and for Epa1p-mediated adherence. We also found that the C-terminal Ser/Thr
      rich domain, characteristic of many GPI-CWPs, was absolutely essential for
      function. Although Epa1p derivatives lacking the Ser/Thr domain were expressed
      abundantly in the cell wall, they were localized to internal layers of the cell
      wall; such constructs were unable to mediate adherence. The outer layer of the
      yeast cell wall is known to act as a permeability barrier; we found that the C
      terminal Ser/Thr-rich region was absolutely required to project the N-terminal
      domain of Epa1p through this permeability barrier and into the external
      environment. Thus, the Ser/Thr-rich domain of Epa1p and, presumably, of other
      related GPI-CWPs serves an essential structural role in localization of the
      protein at the external surface of the yeast cell where it can interact with its
      ligand. In conclusion, Epa1p has a modular structure, with each domain serving a
      distinct and essential role in the function of the adhesin.

PMID- 12406224
TI  - Conservation of dynamic localization among MinD and MinE orthologues: oscillation
      of Neisseria gonorrhoeae proteins in Escherichia coli.
AB  - Min proteins are involved in the correct placement of division septa in many
      bacterial species. In Escherichia coli (Ec) cells, these proteins oscillate from
      pole to pole, ostensibly to prevent unwanted polar septation. Here, we show that
      Min proteins from the coccus Neisseria gonorrhoeae (Ng) also oscillate in E.
      coli. Green fluorescent protein (GFP) fusions to gonococcal MinD and MinE
      localized dynamically in different E. coli backgrounds. GFP-MinDNg moved from
      pole to pole in rod-shaped E. coli cells with a 70 +/- 25 s localization cycle
      when MinENg was expressed in cis. The oscillation time of GFP-MinDNg was reduced
      when wild-type MinENg was replaced with MinENg carrying a R30D mutation, but
      lengthened by 15 s when activated by MinEEc. Several mutations in the N-terminal
      domain of MinDNg, including K16Q and 4- and 19-amino acid truncations, prevented
      oscillation; these MinDNg mutants showed decreased or lost interaction with
      themselves and MinENg. Like MinEEc-GFP, MinENg-GFP formed MinE rings and
      oscillated in E. coli cells when MinDEc was expressed in cis. Finally, in round
      E. coli cells, GFP-MinDNg appeared to move in a plane parallel to completed
      septa. This pattern of movement is predicted to be similar in gonococcal cells,
      which also divide in alternating perpendicular planes.

PMID- 12406225
TI  - Molecular characterization and analysis of the biosynthetic gene cluster for the
      azoxy antibiotic valanimycin.
AB  - Streptomyces viridifaciens MG456-hF10 produces the antibiotic valanimycin, a
      naturally occurring azoxy compound. Valanimycin is known to be derived from
      valine and serine with the intermediacy of isobutylamine and
      isobutylhydroxylamine, but little is known about the stages in the pathway
      leading to the formation of the azoxy group. In previous studies, a cosmid
      containing S. viridifaciens DNA was isolated that conferred valanimycin
      production upon Strepto-myces lividans TK24. Subcloning of DNA from the
      valanimycin-producing cosmid has led to the identi-fication of a 22 kb segment of
      DNA sufficient to allow valanimycin production in S. lividans TK24. Sequencing of
      this DNA segment and the surrounding DNA revealed the presence of 20 genes. Gene
      disruption experiments defined the boundaries of the valanimycin gene cluster,
      which appears to contain 14 genes. The cluster includes an amino acid decar
      boxylase gene (vlmD), a valanimycin resistance gene (vlmF ), at least two
      regulatory genes (vlmE, vlmI ), two genes encoding a flavin monooxygenase (vlmH,
      vlmR), a seryl tRNA synthetase gene (vlmL ) and seven genes of unknown function.
      Overproduction and characterization of VlmD demonstrated that it catalyses the
      decarboxylation of l-valine. An unusual feature of the valanimycin gene cluster
      is that four genes involved in branched amino acid biosynthesis are located near
      its 5' end.

PMID- 12406226
TI  - Glycosylation of Pseudomonas aeruginosa 1244 pilin: glycan substrate specificity.
AB  - The structural similarity between the pilin glycan and the O-antigen of
      Pseudomonas aeruginosa 1244 suggested that they have a common metabolic origin.
      Mutants of this organism lacking functional wbpM or wbpL genes synthesized no O
      antigen and produced only non-glycosylated pilin. Complementation with plasmids
      containing functional wbpM or wbpL genes fully restored the ability to produce
      both O-antigen and glycosylated pilin. Expression of a cosmid clone containing
      the O-antigen biosynthetic gene cluster from P. aeruginosa PA103 (LPS serotype
      O11) in P. aeruginosa 1244 (LPS serotype O7) resulted in the production of strain
      1244 pili that contained both O7 and O11 antigens. The presence of the O11
      repeating unit was confirmed by matrix-assisted laser desorption ionization time
      of-flight (MALDI-TOF) mass spectrometry. Expression of the O-antigen biosynthesis
      cluster from Escherichia coli O157:H7 in strain 1244 resulted in the production
      of pilin that contained both the endogenous Pseudomonas as well as the
      Escherichia O157 O-antigens. A role for pilO in the glycosylation of pilin in P.
      aeruginosa is evident as the cloned pilAO operon produced glycosylated strain
      1244 pilin in eight heterologous P. aeruginosa strains. Removal of the pilO gene
      resulted in the production of unmodified strain 1244 pilin. These results show
      that the pilin glycan of P. aeruginosa 1244 is a product of the O-antigen
      biosynthetic pathway. In addition, the structural diversity of the O-antigens
      used by the 1244 pilin glycosylation apparatus indicates that the glycan
      substrate specificity of this reaction is extremely low.

PMID- 12406227
TI  - Intracellular translation initiation factor levels in Saccharomyces cerevisiae
      and their role in cap-complex function.
AB  - Knowledge of the balance of activities of eukaryotic initiation factors (eIFs) is
      critical to our understanding of the mechanisms underlying translational control.
      We have therefore estimated the intracellular levels of 11 eIFs in
      logarithmically growing cells of Saccharomyces cerevisiae using polyclonal
      antibodies raised in rabbits against recombinant proteins. Those factors involved
      in 43S complex formation occur at levels comparable (i.e. within a 0.5- to 2.0
      fold range) to those published for ribosomes. In contrast, the subunits of the
      cap-binding complex eIF4F showed considerable variation in their abundance. The
      helicase eIF4A was the most abundant eIF of the yeast cell, followed by eIF4E at
      multiple copies per ribosome, and eIF4B at approximately one copy per ribosome.
      The adaptor protein eIF4G was the least abundant of the eIF4 factors, with a copy
      number per cell that is substoichiometric to the ribosome and similar to the
      abundance of mRNA. The observed excess of eIF4E over its functional partner eIF4G
      is not strictly required during exponential growth: at eIF4E levels artificially
      reduced to 30% of those in wild-type yeast, growth rates and the capacity for
      general protein synthesis are only minimally affected. This demonstrates that
      eIF4E does not exercise a higher level of rate control over translation than
      other eIFs. However, other features of the yeast life cycle, such as the control
      of cell size, are more sensitive to changes in eIF4E abundance. Overall, these
      data constitute an important basis for developing a quantitative model of the
      workings of the eukaryotic translation apparatus.

PMID- 12406228
TI  - Glutathione regulates the expression of gamma-glutamylcysteine synthetase via the
      Met4 transcription factor.
AB  - Our previous studies have shown that glutathione is an essential metabolite in
      the yeast Saccharomyces cerevisiae because a mutant deleted for GSH1, encoding
      the first enzyme in gamma-l-glutamyl-l-cysteinylglycine (GSH) biosynthesis,
      cannot grow in its absence. In contrast, strains deleted for GSH2, encoding the
      second step in GSH synthesis, grow poorly as the dipeptide intermediate, gamma
      glutamylcysteine, can partially substitute for GSH. In this present study, we
      identify two high copy suppressors that rescue the poor growth of the gsh2 mutant
      in the absence of GSH. The first contains GSH1, indicating that gamma
      glutamylcysteine can functionally replace GSH if it is present in sufficiently
      high quantities. The second contains CDC34, encoding a ubiquitin conjugating
      enzyme, indicating a link between the ubiquitin and GSH stress protective
      systems. We show that CDC34 rescues the growth of the gsh2 mutant by inducing the
      Met4-dependent expression of GSH1 and elevating the cellular levels of gamma
      glutamylcysteine. Furthermore, this mechanism normally operates to regulate GSH
      biosynthesis in the cell, as GSH1 promoter activity is induced in a Met4
      dependent manner in a gsh1 mutant which is devoid of GSH, and the addition of
      exogenous GSH represses GSH1 expression. Analysis of a cis2 mutant, which cannot
      breakdown GSH, confirmed that GSH and not a metabolic product, serves as the
      regulatory molecule. However, this is not a general mechanism affecting all Met4
      regulated genes, as MET16 expression is unaffected in a gsh1 mutant, and GSH acts
      as a poor repressor of MET16 expression compared with methionine. In summary, GSH
      biosynthesis is regulated in parallel with sulphate assimilation by activity of
      the Met4 protein, but GSH1-specific mechanisms exist that respond to GSH
      availability.

PMID- 12406229
TI  - A fibrinogen receptor from group B Streptococcus interacts with fibrinogen by
      repetitive units with novel ligand binding sites.
AB  - Group B Streptococcus (GBS) is a frequent cause of bacterial sepsis and
      meningitis in neonates. During the course of infection, GBS colonizes and invades
      a number of host compartments, thereby interacting with different host proteins.
      In the present report, we describe the isolation of the fbsA gene, which encodes
      a fibrinogen receptor from GBS. The deduced FbsA protein is characterized by
      repetitive units, each 16 amino acids in length. Sequencing of the fbsA gene from
      five different GBS strains revealed significant variation in the number of repeat
      encoding units. The deletion of the fbsA gene in the genome of GBS 6313
      completely abolished fibrinogen binding, suggesting that FbsA is the major
      fibrinogen receptor in this strain. Growth of the fbsA deletion mutant in human
      blood was significantly impaired, indicating that FbsA protects GBS from
      opsonophagocytosis. In Western blot experiments with truncated FbsA -proteins,
      the repeat region of FbsA was identified as mediating fibrinogen binding. Using
      synthetic peptides, even a single repeat unit of FbsA was demonstrated to bind to
      fibrinogen. Spot membrane analysis and competitive binding experiments with
      peptides carrying single amino acid substitutions allowed the prediction of a
      fibrinogen-binding motif with the consensus sequence G-N/S/T-V-L-A/E/M/Q-R-R-X
      K/R/W-A/D/E/N/Q-A/F/I/L/V/Y-X-X-K/R-X-X.

PMID- 12406230
TI  - Characterization of a membrane-linked Ser/Thr protein kinase in Bacillus
      subtilis, implicated in developmental processes.
AB  - PrkC was shown to be a eukaryotic-like (Hanks-type) protein kinase from Bacillus
      subtilis with a structural organization similar to that of the eukaryotic sensor
      Ser/Thr or Tyr kinases (e.g. the TGF beta or PDGF receptors). The molecule
      consists of a catalytic domain located in the cytoplasm, joined by a single
      transmembrane-spanning region (TMD) to a large extracellular domain. Using a
      genetic reporter system, involving the cI repressor of lambda, evidence was
      obtained indicating that PrkC forms a dimer, involving both the TMD and the
      external domain in dimerization. The purified catalytic domain of PrkC was shown
      to autophosphorylate and to phosphorylate an external target, MBP, in both cases
      on threonine. These two functions require the completely conserved K40 residue in
      subdomain II, which is essential for enzymatic activity. Importantly, both the
      mutant deleted for prkC and a K40R mutant exhibit decreased efficiency of
      sporulation and a significant reduction in biofilm formation, demonstrating that
      the catalytic activity of PrkC is necessary for these two developmental
      processes. In addition, we showed that the product of prpC, a PPM phosphatase
      encoded by the adjacent gene, co-transcribed with prkC, is also required for
      normal biofilm and spore formation.

PMID- 12406231
TI  - Structural heterogeneity of carbohydrate modifications affects serospecificity of
      Campylobacter flagellins.
AB  - Flagellin from Campylobacter coli VC167 is post-translationally modified at > or
      = 16 amino acid residues with pseudaminic acid and three related derivatives. The
      predominant modification was 5,7-diacetamido-3,5,7,9 - tetradeoxy - l - glycero -
      l - manno - nonulosonic acid (pseudaminic acid, Pse5Ac7Ac), a modification that
      has been described previously on flagellin from Campylobacter jejuni 81-176.
      VC167 lacked two modi-fications present in 81-176 and instead had two unique
      modifications of masses 431 and 432 Da. Flagellins from both C. jejuni 81-176 and
      C. coli VC167 were also modified with an acetamidino form of pseudaminic acid
      (PseAm), but tandem mass spectrometry indicated that the structure of PseAm
      differed in the two strains. Synthesis of PseAm in C. coli VC167 requires a
      minimum of six ptm genes. In contrast, PseAm is synthesized in C. jejuni 81-176
      via an alternative pathway using the product of the pseA gene. Mutation of the
      ptm genes in C. coli VC167 can be detected by changes in apparent Mr of flagellin
      in SDS-PAGE gels, changes in isoelectric focusing (IEF) patterns and loss of
      immunoreactivity with antiserum LAH2. These changes corresponded to loss of both
      315 Da and 431 Da modifications from flagellin. Complementation of the VC167 ptm
      mutants with the 81-176 pseA gene in trans resulted in flagellins containing both
      315 and 431 Da modifications, but these flagellins remained unreactive in LAH2
      antibody, suggesting that the unique form of PseAm encoded by the ptm genes
      contributes to the serospecificity of the flagellar filament.

PMID- 12406233
TI  - Extra pair paternity in birds: a review of interspecific variation and adaptive
      function.
AB  - The application of molecular genetic techniques has revolutionized our view of
      avian mating systems. Contrary to prior expectations, birds are only very rarely
      sexually monogamous, with 'extra-pair offspring' found in approximately 90% of
      species. Even among socially monogamous species, over 11% of offspring are, on
      average, the result of extra-pair paternity (EPP). Based on over 150 molecular
      genetic studies of EPP in birds, we review two topical areas: (i) ecological
      explanations for interspecific variation in the rate of EPP; and (ii) evidence
      bearing on the adaptive function of EPP. We highlight the remaining challenges of
      understanding the relative roles of genes and ecology in determining variation
      between taxa in the rate of extra paternity, and testing for differences between
      extra-pair offspring and those sired within-pair.

PMID- 12406234
TI  - The influence of mating system, demography, parasites and colonization on the
      population structure of Biomphalaria pfeifferi in Madagascar.
AB  - Current evolutionary forces and historical processes interact to shape the
      distribution of neutral genetic variability within and among populations.
      Focusing on the genetics of recently introduced organisms offers a good
      opportunity to understand the relative importance of these factors. This study
      concerns variation at 8 polymorphic microsatellite loci in 30 populations of
      Biomphalaria pfeifferi. The sampling area spans most of the species' range in
      Madagascar where it was probably introduced recently. Extremely low variation was
      found within all populations studied, which may partly result from high selfing
      rates. However, this cannot account for the variance of variation across
      populations, which is better explained by habitat openness (that reflects
      environmental stochasticity), the prevalence of the parasitic trematode
      Schistosoma mansoni and historical demography (colonization and subsequent
      bottlenecks). Large global differentiation was also observed, suggesting that
      current gene flow among populations is limited to small distances, within
      watersheds and to few individuals. Our data set also allowed us to test several
      hypotheses regarding colonization, based on bottleneck and admixture tests. The
      observed pattern requires at least two independent introductions from slightly
      differentiated genetic sources in the western part of Madagascar. Another
      introduction, from a very different genetic origin, should also be postulated to
      explain the genetic composition of eastern populations. That this introduction
      occurred recently suggests that the colonization of Madagascar by B. pfeifferi is
      an ongoing process.

PMID- 12406235
TI  - Multilocus population structure of Tapesia yallundae in Washington State.
AB  - Population genetic structure of the fungal wheat pathogen Tapesia yallundae in
      Washington State was determined using genetically characterized amplified
      fragment length polymorphic (AFLP) markers and mating-type (MAT1-1 or MAT1-2).
      Segregation and linkage relationships among 164 AFLP markers and MAT were
      analysed using 59 progeny derived from an in vitro cross. Alleles at 158 AFLP
      loci and the mating-type locus segregated in a 1:1 ratio. Ten unlinked markers
      were chosen to determine genetic and genotypic diversity and to test the
      hypothesis of random mating and population differentiation among five
      subpopulations of T. yallundae representative of the geographical distribution of
      wheat production in eastern Washington. Among 228 isolates collected, overall
      gene diversity was high (h = 0.425) and a total of 91 unique multilocus genotypes
      (MLG) were identified, with 32 MLG occurring at least twice. The overall
      population genetic structure was consistent with random mating based on the
      segregation of mating-type, index of association (IA), parsimony tree length
      permutation test (PTLPT) and genotypic diversity analyses. However, clonal
      genotypes were found within each subpopulation and were also distributed among
      the five subpopulations. No significant differences in allele frequencies were
      found among the five subpopulations for all 10 loci based on contingency table
      analysis (G2) and Wier & Cockerham's population differentiation statistic theta
      (theta = -0.008, P = 0.722). T. yallundae appears to consist of a large
      homogeneous population throughout eastern Washington with both sexual and asexual
      reproduction contributing to the observed population genetic structure despite no
      report of sexual fruiting bodies of T. yallundae occurring under natural field
      conditions.

PMID- 12406236
TI  - Evaluating the effects of historic bottleneck events: an assessment of
      microsatellite variability in the endangered, North Atlantic right whale.
AB  - Commercial exploitation reduced the North Atlantic right whale (Eubalaena
      glacialis) population from c. 12,000 in the 11th century to around 300 by the
      21st century. We examine the effect of this population decline on levels of
      genetic variation at 16 microsatellite loci and contrast levels of variability to
      that in a closely related species (E. australis). Of the 13 loci developed from
      the E. glacialis genome, 100% were polymorphic in E. australis. In contrast, nine
      loci were polymorphic in E. glacialis and four were fixed. Both allelic diversity
      (A) and heterozygosity (H) were significantly lower in E. glacialis than E.
      australis (A = 3.2 +/- 2.6 vs. A= 6.9 +/- 3.3, P < 0.001; H= 0.31 +/- 0.25 vs. H=
      0.72 +/- 0.23, P < 0.001, respectively). Bottleneck anlayses indicate that the
      population is in mutation-drift equilibrium and that a genetic bottleneck did not
      occur during the most recent decline (18th-20th centuries). Nevertheless, low
      frequency alleles are relatively uncommon in E. glacialis, suggesting that
      genetic variability has been reduced in this population. Possible origins of low
      genetic variability are discussed, including the slow but continual erosion of
      alleles during the 800-year period of decline.

PMID- 12406237
TI  - Population genetic structure and male-biased dispersal in the queenless ant
      Diacamma cyaneiventre.
AB  - In this study we investigated the population genetic structure of the queenless
      ant Diacamma cyaneiventre. This species, lacking winged queens, is likely to have
      a restricted female dispersal. We used both mitochondrial and microsatellite
      markers to assess the consequence of such restricted female dispersal at three
      geographical scales: within a given locality (< 1 km), between localities within
      a given region (< 10 km) and between regions (> 36 km). Within a locality, a
      strong population structure was observed for mitochondrial DNA (mtDNA) whereas
      weak or nonexistent population genetic structure was observed for the
      microsatellites (around 5% of the value for mtDNA). Male gene flow was estimated
      to be about 20-30 times higher than female gene flow at this scale. At a larger
      spatial scale, very strong genetic differentiation for both markers was observed
      between localities - even within a single region. Female dispersal is nonexistent
      at these scales and male dispersal is very restricted, especially between
      regions. The phylogeographical structure of the mtDNA haplotypes as well as the
      very low genetic diversity of mtDNA within localities indicate that new sites are
      colonized by a single migration event from adjacent localities, followed by
      successive colony fissions. These patterns of genetic variability and
      differentiation agree with what is theoretically expected when colonization
      events are kin-structured and when, following colonization, dispersion is mainly
      performed by males.

PMID- 12406238
TI  - Microsatellite analysis of genetic divergence among populations of giant
      Galapagos tortoises.
AB  - Giant Galapagos tortoises represent an interesting model for the study of
      patterns of genetic divergence and adaptive differentiation related to island
      colonization events. Recent mitochondrial DNA work elucidated the evolutionary
      history of the species and helped to clarify aspects of nomenclature. We used 10
      microsatellite loci to assess levels of genetic divergence among and within
      island populations. In particular, we described the genetic structure of
      tortoises on the island of Isabela, where discrimination of different taxa is
      still subject of debate. Individual island populations were all genetically
      distinct. The island of Santa Cruz harboured two distinct populations. On
      Isabela, populations of Volcan Wolf, Darwin and Alcedo were significantly
      different from each other. On the other hand, Volcan Wolf showed allelic
      similarity with the island of Santiago. On Southern Isabela, lower genetic
      divergence was found between Northeast Sierra Negra and Volcan Alcedo, while
      patterns of gene flow were recorded among tortoises of Cerro Azul and Southeast
      Sierra Negra. These tortoises have endured heavy exploitation during the last
      three centuries and recently attracted much concern due to the current number of
      stochastic and deterministic threats to extant populations. Our study complements
      previous investigation based on mtDNA diversity and provides further information
      that may help devising tortoise management plans.

PMID- 12406239
TI  - The genetic structure of the rare lagoonal sea anemone, Nematostella vectensis
      Stephenson (Cnidaria; Anthozoa) in the United Kingdom based on RAPD analysis.
AB  - The sea anemone Nematostella vectensis occurs in lagoons in the United States and
      along the southern and eastern coasts of the United Kingdom. In the United
      Kingdom it is considered rare and is threatened, principally through the
      destruction of lagoonal habitat. Random amplified polymorphic DNA (RAPD) data
      from populations across most of the rane of N. vectensis in the United Kingdom
      revealed that 61% of individuals had an identical genotype, the frequency of
      which varied from 0.01 to 1.00. These data provide strong evidence for
      predominantly clonal reproduction and for the existence of a 'general-purpose
      genotype' in the UK populations. Alternatively, the low levels of genetic
      variation observed in some N. vectensis populations may have resulted if they
      were founded from very few successful individuals from the United States.
      Analysis of molecular variance (amova) showed significant genetic differentiation
      between lagoons with no large-scale pattern of geographical variation. This
      result is consistent with occasional passive or anthropogenic dispersal of low
      numbers of individuals between lagoons followed by asexual proliferation of
      immigrants. Transplantation of individuals of the predominant (general-purpose)
      genotype, for conservation purposes, will probably stand a good chance of
      survival given its prevalence throughout the United Kingdom.

PMID- 12406240
TI  - Population genetics of wolf spiders of fragmented habitat in the wheat belt of
      New South Wales.
AB  - Possible effects of habitat fragmentation on the population genetics of a species
      of wolf spider (Lycosidae) from remnant Callitris woodland in the wheat belt of
      central western New South Wales in Australia are examined. Single-strand
      conformational analysis of mitochondrial cytochrome oxidase (subunit 1) was used
      to characterize the haplotypes of 295 spiders in six blocks each of four woodland
      sites. DNA sequences were collected from 119 of these spiders to confirm
      haplotype scoring, allow phylogeny estimation and permit calculation of sequence
      based statistics. Intra-block tests do not suggest widespread effects of
      fragmentation. Genetic diversity is high in all blocks, with 25 haplotypes being
      identified. Nucleotide diversity is relatively low, as all of the haplotypes are
      closely related. One block had a significantly low value for the Ewens/Watterson
      test of neutrality and one block's value was nearly significantly high. Two
      blocks had nearly significant values of the Harpending Raggedness Index testing
      for recent population bottlenecks. No other intrablock tests approach
      significance. Interpopulation comparisons show significant nonhomogeneity of
      haplotype frequencies globally and in all pairwise comparisons. Relationships
      between woodland blocks based on haplotype frequencies are discordant with
      geographical proximity. Haplotype distribution patterns suggest that population
      structuring existed prior to fragmentation. We develop two measures of genetic
      distinctiveness to identify subpopulations of interest for conserving
      evolutionary processes in a species' regional population. One is based on the sum
      of pairwise FST values and one on the spatial distribution of genetic variation.
      High values of the measure suggest a subpopulation might have been recently
      perturbed and low values that it is relatively undisturbed. The two measures
      identify different blocks as being of particular interest.

PMID- 12406241
TI  - Nestmate relatedness and population genetic structure of the Australian social
      crab spider Diaea ergandros (Araneae: Thomisidae).
AB  - We characterized the population genetic structure of the Australian social spider
      Diaea ergandros using polymorphic allozyme markers. Our main objectives were to
      understand the social organization of D. ergandros and discern patterns of gene
      flow across distantly separated geographical areas. Spiders were sampled from
      nests located within 100 m wide locales, which were distributed within larger 50
      km wide regions. Our results indicated that nestmates could have been produced by
      a single mother and father in 88.9% of D. ergandros nests. The remainder of nests
      contained spiders that were probably produced by polyandrous females or were
      immigrants from foreign nests. Nestmate relatedness was relatively high (r =
      0.44) and did not differ significantly between the sexes or among juvenile,
      subadult and adult life stages. We also discovered that D. ergandros populations
      were highly structured, with significant differentiation detected among locales
      (FLR = 0.23) and regions (FRT = 0.081). Spiders within locales were also
      substantially inbred (FIL = 0.15). Overall, our data show that significant
      population subdivision exists in D. ergandros populations, and we suggest that
      the poor dispersal ability of Diaea spiders can account for the observed genetic
      structure.

PMID- 12406242
TI  - Polymerase chain reaction-single strand conformation polymorphism analyses of
      nuclear and chloroplast DNA provide evidence for recombination, multiple
      introductions and nascent speciation in the Caulerpa taxifolia complex.
AB  - Independent lines of evidence support an Australian origin for the Mediterranean
      populations of the tropical alga Caulerpa taxifolia. To complement previous
      biogeographical studies based on nuclear rDNA internal transcribed spacer (ITS),
      a new chloroplast marker was developed--the cp 16S rDNA intron-2. Sequence
      variability for both nuclear and chloroplast markers were assessed in 110
      individuals using single strand conformation polymorphism. Comparison of
      intrapopulation genetic diversity between invasive Mediterranean and 'native'
      Australian populations revealed the occurrence of two divergent and widespread
      clades. The first clade grouped nontropical invasive populations with inshore
      mainland populations from Australia, while the second clustered all offshore
      island populations studied so far. Despite our finding of nine distinct nuclear
      and five distinct chloroplast profiles, a single nucleocytoplasmic combination
      was characteristic of the invasive populations and sexual reproduction was found
      to be very rare. C. taxifolia is clearly a complex of genetically and
      ecologically differentiated sibling species or subspecies.

PMID- 12406243
TI  - Phylogeographical variation of chloroplast DNA in holm oak (Quercus ilex L.).
AB  - Variation in the lengths of restriction fragments (RFLPs) of the whole
      chloroplast DNA molecule was studied in 174 populations of Quercus ilex L.
      sampled over the entire distribution of this evergreen and mainly Mediterranean
      oak species. By using five endonucleases, 323 distinct fragments were obtained.
      From the 29 and 17 cpDNA changes identified as site and length mutations,
      respectively, 25 distinct chlorotypes were distinguished, mapped and treated
      cladistically with a parsimony analysis, using as an outgroup Q. alnifolia Poech,
      a closely related evergreen oak species endemic to Cyprus where Q. ilex does not
      grow. The predominant role of Q. ilex as maternal parent in hybridization with
      other species was reflected by the occurrence of a single very specific lineage
      of related chlorotypes, the most ancestral and recent ones being located in the
      southeastern and in the northwestern parts of the species' geographical
      distribution, respectively. The lineage was constituted of two clusters of
      chlorotypes observed in the 'ilex' morphotyped populations of the Balkan and
      Italian Peninsulas (including the contiguous French Riviera), respectively. A
      third cluster was divided into two subclusters identified in the 'rotundifolia'
      morphotyped populations of North Africa, and of Iberia and the adjacent French
      regions, respectively. Postglacial colonization probably started from three
      distinct southerly refugia located in each of the three European peninsulas, and
      a contact area between the Italian and the Iberian migration routes was
      identified in the Rhone valley (France). Chlorotypes identical or related to
      those of the Iberian cluster were identified in the populations from Catalonia
      and the French Languedoc region, which showed intermediate morphotypes, and in
      the French Atlantic populations which possessed the 'ilex' morphotype, suggesting
      the occurrence of adaptive morphological changes in the northern part of the
      species' distribution.

PMID- 12406244
TI  - Geographic pattern of genetic variation in the European globeflower Trollius
      europaeus L. (Ranunculaceae) inferred from amplified fragment length polymorphism
      markers.
AB  - The distribution of genetic variation and the phylogenetic relationships between
      18 populations of the arctic-alpine plant Trollius europaeus were analysed in
      three main regions (Alps, Pyrenees and Fennoscandia) by using dominant AFLP
      markers. Analysis of molecular variance revealed that most of the genetic
      variability was found within populations (64%), although variation among regions
      (17%) and among populations within regions (19%) was highly significant (P <
      0.001). Accordingly, the global fixation index FST averaged over loci was high
      (0.39). The among-population differentiation indicates restricted gene flow,
      congruent with limited dispersal of specific globeflower's pollinating flies
      (Chiastocheta spp.). Within-population diversity levels were significantly higher
      in the Alps (mean Nei's expected heterozygosity HE = 0.229) than in the Pyrenees
      (HE= 0.197) or in Fennoscandia (HE = 0.158). This finding is congruent with the
      species-richness of the associated flies, which is maximum in the Alps. We
      discuss the processes involved in shaping observed patterns of genetic diversity
      within and among T. europaeus populations. Genetic drift is the major factor
      acting on the small Pyrenean populations at the southern edge of T. europaeus
      distribution, while large Fennoscandian populations result probably from a
      founder effect followed by demographic expansion. The Alpine populations
      represent moderately fragmented relics of large southern ancestral populations.
      The patterns of genetic variability observed in the host plant support the
      hypothesis of sympatric speciation in associated flies, rather than recurrent
      allopatric speciations.

PMID- 12406245
TI  - Spatial pattern of chloroplast DNA variation of Cyclobalanopsis glauca in Taiwan
      and East Asia.
AB  - This study examined the spatial pattern of chloroplast DNA (cpDNA) variation in
      Cyclobalanopsis glauca (Thunb. ex Murray) Oerst. (Fagaceae) in 140 trees from
      Taiwan (25 populations), Japan (three), Ryukyus (two), Hong Kong (one) and
      Mainland China (one). By sequencing three cpDNA intergenic spacer fragments using
      universal primers (trnT-trnL, trnV-trnM, including the trnV intron, and petG
      trnP), we found a total of 1,980 bp and 15 polymorphic sites. Among them, 12
      sites were caused by point mutation, and three resulted from insertion. This
      gives rise to a total of 13 cpDNA haplotypes. The level of differentiation among
      the populations studied is relatively high (GST = 0.612). Two ancestral
      haplotypes (A and B) are distributed widely in East Asia. Interestingly, all the
      derived cpDNA variations are found only in Taiwan but not in other areas. The
      Central Mountain Ridge (CMR) of Taiwan creates an unsurpassed barrier to the east
      west gene flow of C. glauca. Among the populations on the west of CMR, only three
      separated populations, Yangmingshan, Wushe and Chinshuiying, have high haplotype
      diversity, each consisting of sister haplotypes all mutated from the same
      ancestral haplotype. Thus, they have probably originated from de novo mutation
      after the last glaciation. This inference agrees with the observation that no
      spatial autocorrelation existed on the west side. Two unrelated dominant lineages
      on the east of the CMR (haplotypes D and F) showed significant spatial genetic
      structure. Estimate of NST - GST was -0.090 and differed significantly from zero.
      Thus at the local scale, the phylogeographical component of the genetic structure
      is significant on the east of the CMR. Accompanied by published palynological
      records of the last glaciation, this study suggests the possibility that these
      two types were colonized northward from the southeastern part of Taiwan. 'Star
      like' genealogy is characterized, with all the haplotypes coalescing rapidly and
      as a general outcome of population expansion (Page & Holmes 1998). A neutrality
      test also suggested a demographic expansion recovered from a bottleneck. We
      therefore inferred that the southeastern part of Taiwan might be a potential
      refugium for C. glauca.

PMID- 12406246
TI  - The use of AFLP to find an informative SNP: genetic differences across a
      migratory divide in willow warblers.
AB  - We used the amplified fragment length polymorphism (AFLP) method to obtain
      genetic markers distinguishing two subspecies of willow warblers Phylloscopus
      trochilus that have different migratory behaviours but are not differentiated in
      mitochondrial DNA or at several microsatellite loci. With the inverse-polymerase
      chain reaction (PCR) approach we converted a dominant AFLP-marker to a codominant
      single nucleotide polymorphism (SNP). Across Scandinavia we typed 621 birds at
      the SNP locus AFLP-WW1 and we found a sigmoid change in allele frequencies
      centred around 62 degrees latitude. North of the latitudinal cline was a west
      east cline. Both clines are narrower than one would expect from dispersal
      distances in willow warblers, which suggests that these are maintained by
      selection. The latitudinal cline at the locus AFLP-WW1 is paralleled by changes
      in several other traits, all of which might be maintained by a single selective
      force. The most plausible selection factor that we have identified is selection
      against hybrids because of inferior migratory behaviour. The selective force
      maintaining the east-west cline is less obvious. We discuss alternatives to the
      selection scenario, involving colonization history and asymmetric gene flow.

PMID- 12406247
TI  - Intensive genetic assessment of the mating system and reproductive success in a
      semi-closed population of the mottled sculpin, Cottus bairdi.
AB  - Most genetic surveys of parentage in nature sample only a small fraction of the
      breeding population. Here we apply microsatellite markers to deduce the genetic
      mating system and assess the reproductive success of females and males in an
      extensively collected, semi-closed stream population of the mottled sculpin fish,
      Cottus bairdi. In this species, males guard nest rocks where females deposit the
      eggs for fertilization. The potential exists for both males and females to mate
      with multiple partners and for males to provide parental care to genetically
      unrelated offspring. Four hundred and fifty-five adults and subadults, as well as
      1,259 offspring from 23 nests, were genotyped at five polymorphic microsatellite
      loci. Multilocus maternal genotypes, deduced via genetic analyses of embryos,
      were reconstructed for more than 90% of the analysed nests, thus allowing both
      male and female reproductive success to be estimated accurately. There was no
      genetic evidence for cuckoldry, but one nest probably represents a takeover
      event. Successful males spawned with a mean of 2.8 partners, whereas each female
      apparently deposited her entire clutch of eggs in a single nest (mean fecundity =
      66 eggs/female). On average, genetically deduced sires and dams were captured 1.6
      and 9.3 metres from their respective nests, indicating little movement by
      breeders during the spawning season. Based on a 'genetic mark-recapture'
      estimate, the total number of potentially breeding adults (c. 570) was an order
      of-magnitude larger than genetically based estimates of the effective number of
      breeders (c. 54). In addition, significantly fewer eggs per female were deposited
      in single than in multidam nests. Not only were perceived high-quality males
      spawning with multiple partners, but they were receiving more eggs from each
      female.

PMID- 12406248
TI  - Complex patterns of mating revealed in a Eucalyptus regnans seed orchard using
      allozyme markers and the neighbourhood model.
AB  - The neighbourhood model apportions offspring of individual mother plants to self
      fertilization, outcrossing to males within a circumscribed area around the mother
      plant (the neighbourhood), and outcrossing to males outside the neighbourhood.
      Formerly the model was applied only to haploid pollen gametes in the offspring of
      conifers, but is extended so that it can be used with genotypic data from diploid
      offspring of both angiosperms and gymnosperms. In addition, it is shown that the
      mating parameters can be estimated without independent estimates of allele
      frequencies in the pollen pools outside the neighbourhood; thus the model might
      be applied effectively to natural populations exposed to unknown external pollen
      sources. Parameters of the neighbourhood mating model were estimated for a 10
      year-old seed orchard population of the insect-pollinated tree, Eucalyptus
      regnans, in southeast Australia, which contained a mixture of two geographical
      provenances (Victoria and Tasmania). The mating patterns revealed were complex.
      Crosses between trees of the same provenance occurred three times more often than
      crosses between trees of different provenances. Levels of self-fertilization and
      patterns of mating within neighbourhoods were influenced by provenance origin,
      crop fecundity and orchard position (central vs. edge) of mother trees. Gene
      dispersal, however, was extensive, with approximately 50% of effective pollen
      gametes coming from males more than 40 m away from mother trees (average distance
      between neighbouring trees was 7.4 m). Thus, insect pollinators are efficient
      promoters of cross-fertilization in this orchard, with the result that the
      effective number of males mating with each female is large.

PMID- 12406249
TI  - Intraspecific phylogeography of the slender madtom: the complex evolutionary
      history of the Central Highlands of the United States.
AB  - A number of different biogeographical studies of the Central Highlands of the
      United States have yielded conflicting area cladograms. We estimate the mtDNA
      phylogeny of populations of the slender madtom, Noturus exilis, a clear-water
      stream catfish. The goal is to compare population relationships to those reported
      in previous studies that used upland, stream-dwelling vertebrates. A region of
      the NADH dehydrogenase subunit 4 gene, along with adjacent tRNAs, was sequenced
      for population samples from 21 different Central Highlands rivers. Sequence
      difference among 39 haplotypes ranged from 0.1% to 4.8%. Most haplotypes were
      restricted to specific rivers and mapped well onto geography. Slender madtoms
      from different drainages contained mostly monophyletic groups of haplotypes
      genetically divergent from haplotypes found in other drainages, although a few
      haplotypes were found in well-separated drainages. The area cladogram for the
      slender madtom was not similar to any of the other cladograms for other species
      and species groups from the area. We discuss a variety of methodological and
      biological reasons for the discordance, and suggest that some of the
      discrepancies may be resolved by the sequencing of multiple genes per species. We
      recommend that more, and more extensive, intraspecific phylogeography studies
      should be conducted for species living in the Central Highlands rivers.

PMID- 12406250
TI  - Complex sociogenetic organization and reproductive skew in a primitively eusocial
      sweat bee, Lasioglossum malachurum, as revealed by microsatellites.
AB  - The sweat bees (Family Halictidae) are a socially diverse taxon in which
      eusociality has arisen independently numerous times. The obligate, primitively
      eusocial Lasioglossum malachurum, distributed widely throughout Europe, has been
      considered the zenith of sociality within halictids. A single queen heads a
      colony of smaller daughter workers which, by mid-summer, produce new sexuals
      (males and gynes), of which only the mated gynes overwinter to found new colonies
      the following spring. We excavated successfully 18 nests during the worker- and
      gyne-producing phases of the colony cycle and analysed each nest's queen and
      either all workers or all gynes using highly variable microsatellite loci
      developed specifically for this species. Three important points arise from our
      analyses. First, queens are facultatively polyandrous (queen effective mating
      frequency: range 1-3, harmonic mean 1.13). Second, queens may head colonies
      containing unrelated individuals (n = 6 of 18 nests), most probably a consequence
      of colony usurpation during the early phase of the colony cycle before worker
      emergence. Third, nonqueen's workers may, but the queen's own workers do not, lay
      fertilized eggs in the presence of the queen that successfully develop into
      gynes, in agreement with so-called 'concession' models of reproductive skew.

PMID- 12406251
TI  - Individual female clutch identification through yolk protein electrophoresis in
      the communally breeding guira cuckoo (Guira guira).
AB  - Avian communal breeding systems generate alternative behavioural strategies for
      females, resulting in differences in reproductive success. Identifying eggs of
      different females in such systems is problematic, however, due to egg destruction
      before incubation, difficulty of capturing adults, and/or inaccuracy of egg
      identification based on egg morphometry. Here, we describe a technique that uses
      electrophoresis of yolk proteins to determine egg ownership, which we applied to
      communally breeding guira cuckoos (Guira guira). Validation of the method
      included identical yolk protein banding patterns in all eggs of the same female,
      but different patterns in eggs of different females in budgerigars (Melopsittacus
      undulatus), and identical patterns in yolk follicles of the same females in guira
      cuckoos. We applied the protocol to 195 guira cuckoo eggs from 34 joint nests in
      2 years. All multiple guira cuckoo eggs laid on the same day in single nests had
      distinct banding patterns of yolk proteins, practically eliminating the
      possibility of more than one female being represented by the same pattern. Some
      identical banding patterns were repeated in different days within a nesting bout,
      indicating that some females laid several eggs in shared nests. Identical
      patterns occasionally occurred in renestings of groups, indicating that some
      females lay eggs in consecutive nestings. Yolk protein electrophoresis is a
      useful tool to identify egg maternity in other circumstances, such as polygynous
      mating systems with joint nests and intraspecific parasitism. Additionally, it is
      an alternative method for species where electrophoresis of egg white proteins
      does not show sufficient polymorphism.

PMID- 12406252
TI  - Wolbachia infections and superinfections in cytoplasmically incompatible
      populations of the European cherry fruit fly Rhagoletis cerasi (Diptera,
      Tephritidae).
AB  - Wolbachia is an obligately intracellular, maternally inherited bacterium which
      has been detected in many arthropods. Wolbachia infections disperse in host
      populations by mechanisms such as cytoplasmic incompatibility (CI). CI leads to
      embryonic mortality which occurs when infected males mate with uninfected females
      or females with a different Wolbachia strain. Populations of the European cherry
      fruit fly Rhagoletis cerasi (Diptera, Tephritidae) were found to be infected by
      two different Wolbachia strains, wCer1 and wCer2. Superinfections with both
      strains occurred throughout southern and central Europe and infections with wCer1
      were found in northern, western and eastern Europe. Strong unidirectional CI
      between European populations of R. cerasi were first reported in the 1970s. From
      the conformity in the recent geographical distribution of the Wolbachia
      infections and the CI expression patterns found 25 years ago it was deduced that
      wCer2 potentially causes CI in R. cerasi. The comparison of the geographical
      distributions indicated that wCer1 + 2 must have spread into wCer1-infected
      populations in some areas. In other regions, a spread of wCer1 + 2 was probably
      prevented by dispersal barriers. There, a sharp transition from infected to
      superinfected populations suggested regional isolation between wCer1 and wCer1 +
      2-infected populations.

PMID- 12406254
TI  - Estimating allelic richness: effects of sample size and bottlenecks.
AB  - Although differences in sampling intensity can bias comparisons of allelic
      richness (A) among populations, investigators often fail to correct estimates of
      A for differences in sample size. Methods that standardize A on the basis of the
      size of the smallest number of samples in a comparison are preferable to other
      approaches. Rarefaction and repeated random subsampling provide unbiased
      estimates of A with the greatest precision and thus provide greatest statistical
      power to detect differences in variation. Less promising approaches, in terms of
      bias or precision, include single random subsampling, eliminating very small
      samples, using sample size as a covariate or extrapolating estimates obtained
      from small samples to a larger number of individuals.

PMID- 12406253
TI  - Genetic differentiation in the winter pine processionary moth (Thaumetopoea
      pityocampa--wilkinsoni complex), inferred by AFLP and mitochondrial DNA markers.
AB  - The winter pine processionary moth has become an important pine pest in the last
      century, as a consequence of the spread of pine cultivation in the Mediterranean
      region. The pattern of genetic differentiation of this group, that includes two
      sibling species (Thaumetopoea pityocampa and Th. wilkinsoni), has been studied in
      nine populations using amplified fragment length polymorphism (AFLP) and single
      strand conformation polymorphism-sequence analysis (SSCP) of the mitochondrial
      cytochrome oxidase 1 (COI) and cytochrome oxydase 2 (COII). Results indicate the
      existence of strong genetic differentiation between the two species that became
      separated before the Quaternary ice ages. Moreover data indicate that Th.
      pityocampa has a strong geographical structure, particularly evident at the
      nuclear level, where all pairwise phiST resulted to be highly significant and
      individuals from the same population resulted to be strongly clustered when an
      individual tree was reconstructed. The estimates of the absolute number of
      migrants between populations (Nm), obtained from mitochondrial and nuclear DNA
      markers, suggest that gene flow is low and that a gender-related dispersal could
      occur in this species. The males appear to disperse more than females,
      contributing to the genetic diversity of populations on a relatively wide range,
      reducing the risks of inbreeding and the genetic loss associated with bottlenecks
      occurring in isolated populations.

PMID- 12406257
TI  - Research in medical education at the start of the century.

PMID- 12406258
TI  - Practice into theory.

PMID- 12406259
TI  - Educational research and randomised trials.

PMID- 12406260
TI  - Physician communication skills training: a review of theoretical backgrounds,
      objectives and skills.
AB  - CONTEXT: Significant shortcomings have been noted in the literature in
      communication skills training for practising doctors. Given the importance of
      competent communication to the doctor-patient relationship and health care in
      general, these shortcomings should be addressed in future research. OBJECTIVE:
      Research into physician communication skills training is examined with respect to
      the communication objectives and behaviours that are addressed. METHODS: A
      Medline search of literature from 1990 to the present was conducted. RESULTS: A
      total of 26 studies of doctor communication skills training were found. The
      majority of studies included insufficient information about the communication
      behaviours taught to participants. In several studies, there was a mismatch
      between stated behaviours and instruments or procedures used to assess them.
      CONCLUSION: Three recommendations are suggested. Firstly, future researchers
      should take greater care in matching assessment instruments with stated
      communication skills. Secondly, researchers should provide and use a theoretical
      framework for selecting communication skills to address in interventions, and
      thirdly, the timing of communication skills within the interview context should
      be part of the instruction in interventions.

PMID- 12406261
TI  - The relationship between medical students' attitudes towards communication skills
      learning and their demographic and education-related characteristics.
AB  - INTRODUCTION: The General Medical Council (GMC) has stressed the importance of
      medical students' attitudes towards learning. However, few studies have explored
      medical students' attitudes towards communication skills learning. This study
      explores the relationship between the attitudes of medical students at two
      different schools and their demographic and education-related characteristics.
      METHODS: A total of 490 medical students from the Universities of Nottingham
      (Years 1 and 2) and Leicester (Year 1) completed the 26-item Communication Skills
      Attitude Scale (CSAS) and a personal details questionnaire satisfactorily. The
      relationships between students' attitudes and their demographic and education
      related characteristics were analysed separately for Nottingham and Leicester
      students using both univariate and multivariate statistics. RESULTS: The
      attitudes of Nottingham and Leicester medical students towards communication
      skills learning were significantly associated with a number of demographic and
      education-related characteristics. Both Nottingham and Leicester students with
      more positive attitudes towards communication skills learning tended to be
      female, tended to think their communication skills needed improving and tended
      not to have parents who were doctors. Both Nottingham and Leicester students with
      more negative attitudes towards communication skills learning tended to think
      their communication skills did not need improving. DISCUSSION: The results
      indicate that medical students' attitudes towards communication skills learning
      are associated with their demographic and education-related characteristics.
      These findings have a number of implications for educational practice and further
      research and these are discussed in this paper.

PMID- 12406262
TI  - Trialling a new way to learn clinical skills: systematic clinical appraisal and
      learning.
AB  - AIM: To describe and evaluate the effectiveness of a new method of teaching
      clinical skills designed to increase students' active and self-directed learning
      as well as tutor feedback. METHODS: A total of 22 consenting Year 4 medical
      students undertaking general practice and general surgery clinical experience
      were involved in a pre- and post-test research design. In the initial period of
      the study, students were taught clinical skills in a traditional manner. In the
      second phase a clinical teaching strategy called systematic clinical appraisal
      and learning (SCAL) was utilised. This learning strategy involved active and self
      directed learning, holistic care and immediate feedback. Students independently
      saw a patient and were asked to make judgements about the patient's potential
      diagnosis, tests required, management, psychosocial needs, preventive health
      requirements, and any ethical problems. These judgements were then compared with
      those of the clinical supervisor, who saw the same patient independently.
      Students recorded details for each consultation. Comparisons were made of the two
      study periods to examine whether the use of SCAL increased the number of
      students' independent judgements, perceived student learning, tutor feedback and
      self-directed learning. RESULTS: During the SCAL learning period, students
      reported making a greater number of statistically significant independent
      judgements, and receiving significantly increased tutor feedback in both general
      practice and general surgery. The number of learning goals set by students was
      not found to differ between the two periods in surgery but significantly
      increased in general practice in the SCAL period. Students' perceptions of their
      learning significantly increased in the SCAL period in surgery but not in general
      practice. During the traditional learning period in both settings, there was
      limited student decision-making about most aspects of care, but particularly
      those relating to prevention, psychosocial issues and ethics. CONCLUSIONS: The
      SCAL approach appears to offer some advantages over traditional clinical skills
      teaching. It appears to encourage active and independent decision-making, and to
      increase tutor feedback. Further exploration of the approach appears warranted.

PMID- 12406263
TI  - Evaluation of procedural skills training in an undergraduate curriculum.
AB  - CONTEXT: A substantial proportion of medical students enter their intern year
      without any basic skills experience. Lack of experience is a significant source
      of stress for many junior doctors. OBJECTIVES: To evaluate the effect of a basic
      procedural skills tutorial for Year 3 medical students on their competence in
      relevant skills at Year 5. SUBJECTS: The control group consisted of 93 medical
      students who completed Year 3 in 1996. The intervention group consisted of 92
      medical students who completed Year 3 in 1997. The intervention group received a
      practical skills tutorial in Year 3; the control group did not. Both groups were
      assessed on their practical skills competence during Year 5. METHODS: A 3-hour
      practical tutorial on injection and suturing techniques was delivered to the
      intervention group. The effectiveness of the intervention was assessed by self
      reported experience of giving injections, inserting sutures and sustaining
      needlestick injuries, and by teacher-rated competency in four basic procedural
      skills. RESULTS: Students who received the Year 3 tutorial were significantly
      more likely to record a satisfactory assessment for their performance in all four
      basic skills compared with students who did not receive the tutorial. They were
      less likely than controls to refuse invitations to give injections, but not
      invitations to insert a suture, during Years 4 and 5. CONCLUSIONS: A single
      session of formalised teaching in procedural skills in the early stages of a
      medical degree can have long-term effectiveness in basic skills competence and
      may increase students' confidence to practise their skills.

PMID- 12406264
TI  - What is effective supervision and how does it happen? A critical incident study.
AB  - OBJECTIVES: To identify the key features of supervision from the perspectives of
      educational supervisors and specialist registrars. DESIGN: Critical incident
      study. Telephone interviews were conducted with selected informants representing
      a range of specialties. The sample comprised educational supervisors with an
      identified interest in supervision, specialist registrars and GP trainees in the
      Yorkshire region. RESULTS: Educational supervisors and specialist registrars were
      generally agreed on what constitutes effective supervision: direct supervision
      was seen as very important. Educational supervisors and specialist registrars had
      very different concerns in relation to ineffective supervision: specialist
      registrars were concerned with inadequate supervision whilst educational
      supervisors were concerned with failures in direct supervision and poorly
      performing trainees. Supervision practices varied between specialties; in this
      study there seemed to be particular problems in anaesthesia, medicine and
      paediatrics. CONCLUSIONS: Direct supervision and the quality of the supervisory
      relationship are key to effective supervision. There is a need for clear guidance
      on supervision and the establishment of appropriate procedures and mechanisms to
      resolve difficulties relating to inadequate supervision for trainees and
      performing trainees. Insufficient numbers of supervisors have received training
      in supervision.

PMID- 12406265
TI  - Medical students' personality characteristics and academic performance: a five
      factor model perspective.
AB  - OBJECTIVES: This study investigates: (1) which personality traits are typical of
      medical students as compared to other students, and (2) which personality traits
      predict medical student performance in pre-clinical years. DESIGN: This paper
      reports a cross-sectional inventory study of students in nine academic majors and
      a prospective longitudinal study of one cohort of medical students assessed by
      inventory during their first preclinical year and by university examination at
      the end of each pre-clinical year. SUBJECTS AND METHODS: In 1997, a combined
      total of 785 students entered medical studies courses in five Flemish
      universities. Of these, 631 (80.4%) completed the NEO-PI-R (i.e. a measure of the
      Five-Factor Model of Personality). This was also completed by 914 Year 1 students
      of seven other academic majors at Ghent University. Year end scores for medical
      students were obtained for 607 students in Year 1, for 413 in Year 2, and for 341
      in Year 3. RESULTS: Medical studies falls into the group of majors where students
      score highest on extraversion and agreeableness. Conscientiousness (i.e. self
      achievement and self-discipline) significantly predicts final scores in each pre
      clinical year. Medical students who score low on conscientiousness and high on
      gregariousness and excitement-seeking are significantly less likely to sit
      examinations successfully. CONCLUSIONS: The higher scores for extraversion and
      agreeableness, two dimensions defining the interpersonal dynamic, may be
      beneficial for doctors' collaboration and communication skills in future
      professional practice. Because conscientiousness affects examination results and
      can be reliably assessed at the start of a medical study career, personality
      assessment may be a useful tool in student counselling and guidance.

PMID- 12406266
TI  - 'So you row, do you? You don't look like a rower.' An account of medical
      students' experience of sexism.
AB  - INTRODUCTION: Medicine has traditionally been considered a masculine pursuit and
      its undergraduate curriculum criticised as being inherently sexist. Overt sexism,
      though diminished, still occurs and students report offensive sexual remarks,
      unwanted sexual advances and unequal learning opportunities. Sexual
      discrimination also colludes with attitudes that promote the stereotyping of the
      roles of women both in medicine and in society itself. This study aimed to
      ascertain medical students' own experience of sexism during undergraduate
      training, their understanding of these events, what effects the events had on
      them and, specifically, how they coped. METHODS: Twelve in-depth interviews, each
      focusing on a critical incident, with individual self-selecting Year 5 medical
      students took place. Initial qualitative analysis of transcripts produced themes
      that were further subsetted. RESULTS: Students described situations where they
      felt their learning had been jeopardised. Male students reported frequent
      difficulties whilst attached to obstetric and gynaecology firms. Students
      commented that their gender did sometimes affect their relationships with
      teaching staff and that affirmation from their teachers was important. Female
      students coped well with their experiences of sexism, often supporting each
      other. Male students often felt resigned to being excluded from certain learning
      opportunities and this sometimes resulted in unresolved frustration. CONCLUSIONS:
      Developing a non-sexist undergraduate curriculum should be prioritised.
      Encouraging teaching staff to reflect on their attitudes to gender, approaches to
      teaching and providing support, such as mentoring, especially for female students
      frequently lacking appropriate role models, is advised.

PMID- 12406267
TI  - Cross-year peer tutoring experience in a medical school: conditions and outcomes
      for student tutors.
AB  - AIMS: To examine the features of cross-year peer tutoring and to explore their
      relationships to learners' characteristics and educational outcomes from the
      student-tutor perspective. METHOD: The records of 447 final year medical students
      were examined to provide data on the starting terms, frequency and course targets
      of peer tutoring activity of student tutors. The relationships of these features
      with their learners' characteristics, academic achievements and selective
      clerkship pathways were analysed. SETTING: The medical education programme at the
      University of Brasilia, Brazil. RESULTS: Analysis showed that about 96% of all
      graduates had acted as student tutors at some time during the programme, with
      great variation in starting terms, numbers and types of courses tutored. The
      average number of tutored courses per tutor was four. Frequency and variety of
      tutored courses were significantly related to achievement, learning style and
      gender. Higher achievers acted as student tutors for many terms and explored
      different subjects, and there is evidence that the experience expanded their
      academic expertise. Specific tutoring in a clinical course also related to
      strength of early career preference. Furthermore, there was a significant
      correlation between the number of terms of tutoring undertaken in a clinical
      course and the proportion of students choosing selective clerkship training in
      the same area by the end of programme. CONCLUSIONS: The findings suggest that
      acting as a peer tutor can be an appealing and constructive educational
      opportunity to further students' academic development. Enhanced expertise seems
      to relate to the accumulation and breadth of tutoring experience. Moreover,
      clinical tutoring may help students in making decisions regarding choice of
      career.

PMID- 12406268
TI  - Literature and medicine: evaluating a special study module using the nominal
      group technique.
AB  - OBJECTIVES: To evaluate a special study module in literature and medicine that
      aimed for clinical relevance. METHODS: We organised a 4-week course around themes
      such as empathy, death and dying, disability, madness and creativity, addiction,
      domestic violence, ethical dilemmas, doctor/patient communication, doctors'
      emotions and end of life decisions. We used a diversity of texts and genres to
      address these themes. We explicitly encouraged the students to engage with both
      content and form when studying literature. To evaluate the course we used a
      nominal group technique. Students identified a range of items in response to open
      questions about the content and methods of the course. After clarifying and
      reducing the items generated, they ranked them in order of importance. To
      investigate perceived clinical relevance, we grouped the individual items into
      broader themes using a previously suggested taxonomy of clinical relevance.
      RESULTS: The students attached the highest importance to the insights gained into
      patients and their experience of illness. These encompassed aspects of
      understanding, knowledge and empathy. They also perceived that they had improved
      clinically relevant skills including communication, analysis, presentation,
      writing and ethical reasoning. The remaining items were more broadly concerned
      with themes of personal growth, development and pleasure. CONCLUSIONS: There are
      many objectives in studying literature. We focussed on designing a special study
      module that explicitly emphasised clinical relevance. Our evaluation shows that
      students identified clinically relevant improvements in knowledge, skills and
      attitudes from having taken the course.

PMID- 12406269
TI  - Modelling medicine.
AB  - CONTEXT: Aristotle's writing on poiesis and techne in general, and his frequent
      references to medicine in particular, suggest that medicine is instrumental,
      contingent and procedural. These 3 basic characteristics give rise to three
      questions: What do doctors do? What affects what they do? How do they do it?
      Similar questions can be applied to other professions. OBJECTIVES: This paper
      sets out a 3-dimensional model of medicine which addresses these 3 questions. The
      model can be used to explore general issues in the field such as the nature of
      general practice, the scope of evidence-based medicine and the relationship
      between medicine and cognate professions. It may help to clarify decisions about
      the scope, sequence and integration of the medical curriculum and it offers a
      framework for the concrete analysis of clinical situations and decisions.
      METHODS: The article is based on conceptual analysis rather than empirical
      investigation although there are some examples of practical applications of the
      model. CONCLUSIONS: Although the headings in the model must be treated as
      tentative, it offers one way of viewing medicine as a whole. It also offers
      potential scope for development and use in both initial and continuing medical
      education. Further work is needed to develop and refine the model for medical
      education and practice.

PMID- 12406274
TI  - Teaching of forensic medicine in the undergraduate curriculum in Sri Lanka:
      bridging the gap between theory and practice.

PMID- 12406275
TI  - Teaching teamwork to medical students: goals, roles and power.

PMID- 12406276
TI  - Self-directed learning during community-based placements.

PMID- 12406277
TI  - Voluntary student research groups in biochemical education.

PMID- 12406278
TI  - Developing communication skills for pharmacist-led clinics.

PMID- 12406279
TI  - A special study module in hospital management.

PMID- 12406280
TI  - Taking the skills lab onto the wards.

PMID- 12406281
TI  - Evaluating a teaching skills workshop for medical students.

PMID- 12406282
TI  - The influence of self-deception and impression management on surgeons' self
      assessment scores.

PMID- 12406283
TI  - 'Whose life is it anyway?' An innovative course on mental health issues.

PMID- 12406284
TI  - The ethics of teamwork in an interprofessional undergraduate setting.

PMID- 12406285
TI  - Standardised audio-visual equipment to support the corporate identity of an
      integrated curriculum.

PMID- 12406286
TI  - Current forms of psychotherapy: teaching their history, concept and application.

PMID- 12406287
TI  - A training post in women's health care for GP registrars.

PMID- 12406288
TI  - The resident as teacher of medical humanities.

PMID- 12406289
TI  - Bringing medical ethics to life: an educational programme using standardised
      patients.

PMID- 12406290
TI  - Virtual handouts for handheld computers.

PMID- 12406291
TI  - BaFa BaFa: a cross-cultural simulation experience for medical educators and
      trainees.

PMID- 12406292
TI  - Doing it well: demonstrating general competencies for resident education
      utilising the ACGME Toolbox of Assessment Methods as a guide for implementation
      of an evaluation plan.

PMID- 12406293
TI  - MammoEd: digital interactive breast imaging education.

PMID- 12406294
TI  - Through the patient's eyes.

PMID- 12406295
TI  - Increasing the instructional equivalency at a tri-clinical campus: going online
      with an Ob-Gyn clerkship.

PMID- 12406296
TI  - Conquering conflict in medicine.

PMID- 12406297
TI  - An integrated structure-function module for first year medical students:
      correlating anatomy, clinical medicine and radiology.

PMID- 12406298
TI  - Preventive health counselling for paediatric residents.

PMID- 12406299
TI  - Undergraduate training to expand regional health care: Med Experience Plus at
      Brock University.

PMID- 12406300
TI  - Who's afraid of the pre-school child? A parent and toddler programme for teaching
      pre-clerkship clinical skills.

PMID- 12406301
TI  - Integrated simulation experiences to enhance clinical education.

PMID- 12406302
TI  - Nitric oxide signalling in salivary glands.
AB  - Nitric oxide (NO) plays multiple roles in both intracellular and extracellular
      signalling mechanisms with implications for health and disease. This review
      focuses on the role of NO signalling in salivary secretion. Attention will be
      paid primarily to endogenous NO production in acinar cells resulting from
      specific receptor stimulation and to NO-regulated Ca2+ homeostasis. Due to the
      fact that NO readily crosses membranes by simple diffusion, endogenous NO may
      play a physiological role in processes as diverse as modifying the secretory
      output, controlling blood supply to the gland, modulating transmitter output from
      nerve endings, participating in the host defence barrier, and affecting growth
      and differentiation of surrounding tissue. Furthermore, the role of NO in the
      pathogenesis of human oral diseases will be considered.

PMID- 12406303
TI  - Nucleolar organizer regions (NORs) evaluation of lingual salivary glands of
      chronic alcoholics.
AB  - BACKGROUND: Chronic alcoholism has been associated with structural and
      physiological changes in salivary glands. Studies on a variety of pathologies
      have suggested that variation in number of nucleolar organizer regions (NORs)
      reveals conditions of cellular activity. The aim of this work was to examine,
      through the AgNOR technique, changes in number and size of NORs in lingual
      salivary glands of chronic alcoholics. METHODS: Samples of mucous and serous
      lingual salivary glands were obtained from tongues from autopsies of individuals
      whose cause of death was hepatic alcoholic cirrhosis. Lingual organs from
      individuals whose cause of death was accidental were used as controls. Number and
      size of the AgNORs and nuclear area, in ductal and acinar cells, were evaluated
      through a digital image analyzer. RESULTS: Statistical analysis revealed
      differences (P < or = 0.05) in number of AgNORs in mucous acini and ductal cells.
      Also, we observed changes in the area of the NORs. CONCLUSION: These results
      suggest that in alcoholics the activity of glandular cells, mainly in ductal
      epithelium, could be affected, modifying synthesis, transport and salivary
      secretions.

PMID- 12406304
TI  - Precancerous foci in pleomorphic adenoma of the salivary gland: recognition of
      focal carcinoma and atypical tumor cells by P53 immunohistochemistry.
AB  - BACKGROUND: It is still controversial if atypical tumor cells scattered in
      salivary pleomorphic adenomas are precancerous and how carcinoma arises in
      pleomorphic adenomas. METHODS: We studied clinicopathologically the frequency and
      variation of cellular atypia among tumor cells and examined the expression status
      of p53 gene products as well as proliferating cell nuclear antigen (PCNA) in 101
      surgical materials of pleomorphic adenomas. RESULTS: Histopathologically,
      atypical tumor cells were found in 51% of the cases examined. Their mode of
      distribution was classified into three groups: focal (six cases, 6%) which could
      be identified as focal carcinoma, measuring less than 1 mm in diameter; sporadic
      (15 cases, 15%) and singular (30 cases, 30%). These atypical cells were located
      mainly within sheet-like nests of tumor cells but not in chondroid or fibro
      hyaline foci. Immunohistochemically, most of the atypical cells were positive for
      p53 gene products and PCNA. CONCLUSION: The results indicated that atypical cells
      with p53 protein accumulation in their nuclei could be regarded as cells in a
      precancerous state not yet forming an apparent carcinomatous nest. Some cell
      population with these atypical cells are likely to form focal carcinomas and then
      to an apparent form of carcinoma in pleomorphic adenoma.

PMID- 12406305
TI  - Analysis of the Ki-67 antigen at the invasive tumour front of human oral squamous
      cell carcinoma.
AB  - BACKGROUND: It is hypothesised that cell proliferation, as measured by the Ki-67
      labelling index (LI) at the invasive tumour front (ITF) was directly related to
      the histological grade in human oral squamous cell carcinomas (SCCs). METHODS:
      Tissues from 42 human oral SCCs were collected and stained with an antibody
      directed against the Ki-67 antigen using an advanced polymer staining system.
      Quantitation of the immunopositive cells was performed on two parallel sections
      at the invasive tumour front (ITF), using an image analyser. The Ki-67 LI was
      expressed as the number of positive nuclei/mm2 of epithelium. The control tissue
      used was normal epithelium at the excision margin. RESULTS: The mean Ki-67 LI for
      oral SCCs at the ITF was significantly greater than that for the excision margin
      tissue (P < 0.0001). There was a positive association between increasing Ki-67 LI
      and increasing Broders' grade (P < 0.05), with a well-differentiated tumour
      having the lowest mean Ki-67 LI (1549 +/- 806) and a poorly differentiated tumour
      having the highest value (2232 +/- 771). A similar trend was observed between the
      mean Ki-67 LI and Bryne's multifactorial grading system. CONCLUSIONS: It was
      concluded from this study that cell proliferation (as measured by the Ki-67
      antigen) at the ITF had a strong positive relationship with histological grading
      in human oral SCC.

PMID- 12406306
TI  - Immunohistochemical analysis of inducible nitric oxide synthase (iNOS) and heat
      shock proteins (HSPs) in ameloblastomas.
AB  - BACKGROUND: To clarify the possible role of nitric oxide (NO) and stress proteins
      in oncogenesis and cytodifferentiation of odontogenic epithelium. Inducible NO
      synthase (iNOS) and heat shock proteins (HSPs) were analyzed in ameloblastomas as
      well as in tooth germs. METHODS: Specimens of seven tooth germs, 36 benign
      ameloblastomas and five malignant ameloblastomas were examined by
      immunohistochemistry using antibodies against iNOS and 27-, 60- and 70-kDa HSPs
      (HSP27, HSP60 and HSP70). RESULTS: Immunoreactivity for iNOS was detected in
      normal and neoplastic odontogenic epithelial cells and was higher in malignant
      ameloblastomas than in tooth germs and benign ameloblastomas. HSP27 was expressed
      constitutively in all odontogenic epithelial cells in tooth germs and benign and
      malignant ameloblastomas. Expression of HSP60 and HSP70 was detected in normal
      and neoplastic odontogenic epithelial cells and was prominent in cells
      neighboring the basement membrane. HSP60 reactivity showed no apparent difference
      between normal and neoplastic odontogenic epithelium, whereas HSP70 expression
      was slightly higher in benign and malignant ameloblastomas than in tooth germs.
      CONCLUSIONS: Activation of iNOS might be associated with malignant potential of
      epithelial odontogenic tumors. Elevated expression of HSP70 is considered to be
      involved in neoplastic transformation of odontogenic epithelial cells.

PMID- 12406307
TI  - Ameloblastomatoid, central odontogenic fibroma: an epithelium-rich variant.
AB  - Two cases are presented of a central odontogenic fibroma (OF) in the mandible of
      a middle-aged female, which posed considerable difficulty in microscopic
      diagnosis. These well-demarcated but non-encapsulated intraosseous tumors had
      hybrid features of both OF and ameloblastoma. Their clinical findings are more in
      keeping with the putative OF rather than ameloblastoma. The present lesions alert
      pathologists to this unusual type of central OF in order to avoid misdiagnosis.

PMID- 12406308
TI  - Facial pain, depression and stress - connections and directions.
AB  - Chronic facial pain is associated with depression, stress and other chronic pain
      disorders such as fibromyalgia. There is growing evidence that all these
      conditions share underlying pathophysiological processes. This review explores
      this relationship and examines the role of the main stress hormone axis, the
      hypothalamic-pituitary-adrenal axis, in the pathogenesis of facial pain including
      possible future therapeutic approaches.

PMID- 12406309
TI  - Don't follow leaders...

PMID- 12406311
TI  - Valuing 'voices from below'.
AB  - The publication of Commission for Health Improvement (CHI) reports in recent
      years have revealed that employees attempted to blow the whistle on abuse,
      corruption or malpractice but were largely ignored by senior members of staff.
      The CHI report into the North Lakeland National Health Service (NHS) Trust
      (November 2000), for instance, states that an initial failure among management to
      listen to the concerns of student nurses led to the sustained abuse of patients.
      To protect patients from incompetent and unethical practitioners and improve
      standards of care, an environment needs to be created where health care
      professionals feel able to express legitimate concerns openly and honestly to
      senior staff, safe in the knowledge that senior managers will take their concerns
      seriously and act accordingly. The government has pledged to create an 'open
      culture' in the NHS to encourage staff with genuine concerns to speak out. This
      can only be achieved if the current leadership culture characterized by conflict
      avoidance, blame and hierarchical control is replaced with openness and
      accountability. To produce the desired changes in culture and attitudes, the NHS
      needs strong leaders capable of challenging the existing social equilibrium.

PMID- 12406312
TI  - The digital portfolio: a tool for human resource management in health care?
AB  - This article discusses the current situation of human resource management (HRM)
      in Finnish health care and charts the views of nurse directors (ward sisters and
      clinical nurse managers, n = 47) on the digital portfolio as a tool of HRM. The
      study is part of an evaluation research project; this article reports on the
      findings from nurse directors' perspective. The data were collected from three
      organizations in eastern Finland: a University Hospital, a Central Hospital and a
      Social and Health Centre. The nurse directors indicated a need for information on
      their staff's skills and competencies, but the area on which they had most
      information was on staff's formal education. They did not have access to
      systematic tools and methods for monitoring the continuous education of staff
      members. The digital portfolio can be used as a tool for HRM in health care,
      although the nurse directors did not realize it could provide a tool for sharing
      expertise through the units or wards.

PMID- 12406313
TI  - The organizational implications of the role NHS Service Managers played in the
      quality process in the mid-1990s.
AB  - AIM: It is the intention of this paper to highlight the problems associated with
      the organizational implications of the role NHS Service Managers (SMs) played in
      the quality process of the mid-1990s. BACKGROUND: To provide quality care all
      staff must be committed and involved, in this study it appeared that few SMs
      played a part in the process. METHODS: Semistructured taped interviews were
      conducted with 33 SMs and three Chief Executives in seven Trusts. As part of a
      study they were asked the role SMs played in quality in their clinical
      directorate. The data was transcribed and analysed in a content-analysis
      approach. FINDINGS: Quality of care was not the SMs' primary objective. The role
      played by SMs was dependent on their background, experience and the organization
      in which they worked. Most Trusts' quality-control strategy was not standardized,
      co-ordinated or integrated, nor was the audit process regulated. For most,
      quality was seen as synonymous with professions, managers from a non-professional
      background found the monitoring of the quality of performance inherently
      difficult. Only one Trust (the most successful) appeared to undertake
      organizational learning, influenced by the philosophy of the Chief Executive.

PMID- 12406314
TI  - Irish diploma in nursing students' first clinical allocation: the views of nurse
      managers.
AB  - AIM OF THE STUDY: To ascertain the views held by some Irish general nurse
      managers of the Diploma in Nursing students' first clinical allocation.
      RATIONALE: Until 1994, nurses in Ireland were trained under a 3-year
      apprenticeship system and were employed throughout their clinical experience. In
      March 1997, the first intake of Diploma in Nursing students into one Dublin
      university were scheduled to commence their clinical placements. As this was the
      first time that supernumerary students were to be placed in the clinical areas,
      it was important to discover how effective the whole process was in terms of
      nurse managers' experiences. RESEARCH METHODS: A grounded-theory approach, using
      unstructured interviews, explored Irish nurse managers' views of the impact of
      supernumerary students in the workplace. Ethical approval was granted. All
      available nurse managers in three general teaching hospitals linked with the
      university agreed to take part (n = 10). RESULTS: Three themes emerged from the
      data, entitled 'Structure', 'Students' and 'Support'. In general, the managers
      believed that staff had had sufficient preparation for this change and that the
      whole process had been well handled. The respondents were pleasantly surprised by
      the students' abilities and interest in nursing. Minor problems were dealt with
      successfully at the local level and the support received by the students was
      found to be excellent. DISCUSSION: Preconceptions of the students as more
      intellectual and less able for practical nursing were found to be untenable. The
      students' presence was welcomed and their questioning attitude, enthusiasm and
      application of knowledge was praised. Strong clinical support was required and
      students benefited from giving care, rather than just observing care given.
      CONCLUSION: It is recommended that supernumerary students should be encouraged to
      give full care under supervision, in order to learn and to become proficient in
      all clinical skills. The next phase of change, transition to degree status for
      students from 2002, will benefit from lessons learned in the past 7 years since
      transition from certificate to diploma education.

PMID- 12406315
TI  - From conflict to collaboration? Contrasts and convergence in the development of
      nursing and management theory.
AB  - AIM: This is the first of two papers which examine the development of theory in
      the occupations of management and nursing, in order to determine where the
      similarities and differences lie. BACKGROUND: The need for the Health Service to
      be effectively managed was a prominent feature of UK health policy in the 1980s
      and early 1990s and accounts of the introduction of 'management methods' into
      health care tend to focus on the conflict between management and nursing. More
      recently, however, the policy emphasis has shifted towards collaborative and co
      operative approaches to the provision of health care. METHOD: An examination of
      the development of nursing is conducted as the first step in identifying areas of
      contrast and convergence in the development of nursing and managerial ideologies.
      In the second paper a similar approach is taken to the history of management.
      CONCLUSION: Nursing has been subject to a succession of ideologies aimed at
      advancing practice, however, many of these approaches have been accepted in an
      uncritical way. In the second paper the similarities in the development of
      management thought are examined and the implications this has for nursing
      management explored.

PMID- 12406316
TI  - Continuing competence and the regulation of nursing practice.
AB  - A study commissioned by the Australian Nursing Council Inc. sought to develop an
      approach to the maintenance of continuing competence in nursing that is broadly
      acceptable to nurses in all States and Territories. The study involved a
      comprehensive review of the international literature and this paper provides an
      overview of statutory regulation of professions with particular reference to
      regulation of the nursing profession. A definition of competence and competencies
      and a discussion of beginning and continuing professional competence are
      presented, followed by a review of current indicators of continuing professional
      competence used by a variety of professions in Australia.

PMID- 12406318
TI  - Cutaneous neurobiology.

PMID- 12406319
TI  - The human herpesviruses and pityriasis rosea: curious covert companions?

PMID- 12406320
TI  - Red skin re-read.

PMID- 12406321
TI  - Pathways to melanoma development: lessons from the mouse.
AB  - Because of subtle differences between mouse and human skin, mice have
      traditionally not been an ideal model to study melanoma development.
      Understanding of the molecular mechanisms of melanoma predisposition, however,
      has been greatly improved by modeling various pathway defects in the mouse. This
      review analyzes the latest developments in mouse models of melanoma, and
      summarizes what these may indicate about the development of this neoplasm in
      humans. Mutations of genes involved in human melanoma have been recapitulated
      with some unexpected results, particularly with respect to the role of the two
      transcripts (Ink4a and Arf) encoded by the Cdkn2a locus. Both the Ink4a/pRb and
      Arf/p53 pathways are involved in melanoma development in mice, and possible
      mechanisms of cross-talk between the two pathways are discussed. We also know
      from mouse models that Ras/mitogen-activated protein kinase pathway activation is
      very important in melanoma development, either through direct activation of Ras
      (e.g., Hras G12V), or via activation of Ras-effector pathways by other oncogenes
      (e.g., Ret, Hgf/Sf). Ras can cooperate with the Arf/p53 pathway, and probably the
      Ink4a/Rb pathway, to induce melanoma. These three growth regulation pathways
      (Ink4a/pRb, Arf/p53, and Ras/mitogen-activated protein kinase) seem to represent
      three major "axes" of melanoma development in mice. Finally, we summarize
      experiments using genetically modified mice that have given indications of the
      intensity and timing of ultraviolet radiation exposure that may be most
      responsible for melanoma development.

PMID- 12406322
TI  - Pityriasis rosea is associated with systemic active infection with both human
      herpesvirus-7 and human herpesvirus-6.
AB  - Pityriasis rosea is a common skin disease that has been suspected to have a viral
      etiology. We performed nested polymerase chain reaction to detect human
      herpesvirus-7, human herpesvirus-6, and cytomegalovirus DNA in lesional skin,
      nonlesional skin, peripheral blood mononuclear cells, serum, and saliva samples
      isolated from 14 pityriasis rosea patients. Viral mRNA expression and virion
      visualization within lesional skin were studied by in situ hybridization and
      transmission electron microscopy, respectively. By nested polymerase chain
      reaction, human herpesvirus-7 DNA was present in lesional skin (93%), nonlesional
      skin (86%), saliva (100%), peripheral blood mononuclear cells (83%), and serum
      (100%) samples, whereas human herpesvirus-6 DNA was detected in lesional skin
      (86%), nonlesional skin (79%), saliva (80%), peripheral blood mononuclear cells
      (83%), and serum (88%) samples. By contrast, cytomegalovirus DNA was not detected
      in these tissues. Control samples from 12 healthy volunteers and 10 psoriasis
      patients demonstrated rare positivity for either human herpesvirus-7 or human
      herpesvirus-6 DNA in skin or serum. By in situ hybridization, infiltrating
      mononuclear cells expressing human herpesvirus-7 and human herpesvirus-6 mRNA
      were identified in perivascular and periappendageal areas in 100% and 75%
      pityriasis rosea skin lesions, respectively, compared to herpesviral mRNA
      positivity in only 13% normal skin and psoriasis skin controls. Transmission
      electron microscopy failed to reveal herpesviral virions in pityriasis rosea
      lesional skin. Nested polymerase chain reaction and in situ hybridization enabled
      detection of human herpesvirus-7 and human herpesvirus-6 in skin and other
      tissues isolated from patients with pityriasis rosea. These results suggest that
      pityriasis rosea is associated with systemic active infection with both human
      herpesvirus-7 and human herpesvirus-6.

PMID- 12406323
TI  - Detection of hepatitis C virus RNA and core protein in keratinocytes from
      patients with cutaneous lichen planus and chronic hepatitis C.
AB  - Cutaneous lichen planus has been associated in patients with chronic hepatitis C
      virus infection. It is still unknown whether hepatitis C virus infects
      keratinocytes of lichen planus lesions. In this report we have analyzed the
      presence of genomic and anti-genomic hepatitis C virus RNA in skin biopsies from
      26 patients with chronic hepatitis C and healthy skin and from 24 patients with
      cutaneous lichen planus (five with and 19 without hepatitis C virus infection) by
      in situ hybridization. Hepatitis C virus RNA was detected in the keratinocytes of
      69% of the patients with healthy skin and chronic hepatitis C, in 100% of the
      patients with lichen planus and hepatitis C virus infection, and in none of
      lichen planus patients without hepatitis C virus infection. The percentage of
      keratinocytes showing genomic or anti-genomic hepatitis C virus RNA was
      statistically lower (p < 0.01 in all cases) in patients with healthy skin (mean
      +/- SD: 5.7 +/- 3.5% and 2.7 +/- 3.1% of keratinocytes with genomic or anti
      genomic hepatitis C virus RNA, respectively) than in those with lichen planus
      lesions (31.7 +/- 7.9% and 18.8 +/- 7.4%, mean +/- SD) or the unaffected adjacent
      skin (24.8 +/- 6.9% and 14.3 +/- 3.8%, mean +/- SD). In conclusion, we have
      demonstrated that hepatitis C virus infects keratinocytes from patients with
      lichen planus and hepatitis C virus infection.

PMID- 12406324
TI  - Enhanced expression and activity of protein-tyrosine kinases establishes a
      functional signaling pathway only in FcepsilonRIhigh Langerhans cells from atopic
      individuals.
AB  - The trimeric high-affinity IgE receptor (FcepsilonRI) on human epidermal
      Langerhans cells mediates IgE-dependent antigen uptake and subsequent antigen
      focusing. Its expression is upregulated on Langerhans cells (FcepsilonRIhigh
      Langerhans cells) and inflammatory dendritic epidermal cells (FcepsilonRIhigh
      inflammatory dendritic epidermal cells) in the skin of patients with atopic
      dermatitis. In the absence of the amplifying beta-chain in these cells,
      FcepsilonRI signaling (indicated by calcium mobilization and activation of the
      transcription factor nuclear factor-kappaB) is only detectable in FcepsilonRIhigh
      Langerhans cells from atopics, but not FcepsilonRIlow Langerhans cells from
      nonatopics. Therefore we investigated protein-tyrosine kinases putatively
      involved in FcepsilonRI signaling in Langerhans cells and asked whether
      differences in their expression and FcepsilonRI-induced activity could explain
      the dichotomic responses observed in atopic vs nonatopic individuals. First, we
      found the src protein-tyrosine kinases p53/56lyn, p59fyn, p56/59hck, p55c-fgr,
      and p60c-src to be expressed in Langerhans cells from all donors. In addition,
      whereas p56lck was lacking, p72syk and the negative regulatory p50csk were
      detected. Upon terminal maturation of Langerhans cells in vitro, no significant
      change of the protein- tyrosine kinase expression profile except downregulation
      of p56/59hck was observed. In contrast, significant upregulation of all protein
      tyrosine kinase expressed except p50csk was detected in FcepsilonRIhigh
      Langerhans cells, but not in FcepsilonRIhigh inflammatory dendritic epidermal
      cells. Finally, the important protein-tyrosine kinases substrate phospholipase C
      gamma1, which is also essential for downstream calcium mobilization, was only
      phosphorylated upon FcepsilonRI triggering in FcepsilonRIhigh Langerhans cells
      from atopics, but not in FcepsilonRIlow Langerhans cells from nonatopics.
      Therefore, upregulation of FcepsilonRI and protein-tyrosine kinase expression as
      well as subsequent protein-tyrosine kinase activity may explain, at least in
      part, that an efficient signaling pathway in terms of calcium mobilization is
      restricted to FcepsilonRIhigh Langerhans cells from atopic individuals. Key
      words:

PMID- 12406325
TI  - Arsenic induces tumor necrosis factor alpha release and tumor necrosis factor
      receptor 1 signaling in T helper cell apoptosis.
AB  - Long-term exposure to arsenic induces arsenical cancers in human beings. Arsenic
      has been shown to induce apoptosis in a variety of cell systems. Previous studies
      revealed that patients with arsenic-induced Bowen's disease showed a defective
      cell-mediated immunity and decreased percentages of T cell and T helper cell
      subpopulations in peripheral mononuclear cells. The purpose of this study was to
      investigate the effects of arsenic on T cell survival and function in mononuclear
      cells. Arsenic concentrations higher than 1 micro M induced tumor necrosis factor
      alpha release from mononuclear cells and caused a cytotoxic effect on T cells.
      When exposed to higher concentrations of arsenic, apoptosis was induced. CD4+
      cells were the major apoptoic population in mononuclear cells. Tumor necrosis
      factor receptor 1 expression on CD4+ cells, but not Fas/FasL, was significantly
      enhanced by arsenic treatment compared to other mononuclear cells. Increased
      expressions of tumor necrosis factor receptor 1 related death domain proteins and
      activated caspases were observed. These findings indicate that tumor necrosis
      factor receptor 1 signaling is the major pathway in arsenic-induced T helper cell
      apoptosis.

PMID- 12406326
TI  - Characterization of a novel isoform of alpha-nascent polypeptide-associated
      complex as IgE-defined autoantigen.
AB  - The nascent polypeptide-associated complex is required for intracellular
      translocation of newly synthesized polypeptides in eukaryotic cells. It may also
      act as a transcriptional coactivator in humans and various eukaryotic organisms
      and binds to nucleic acids. Recently, we provided evidence that a component of
      nascent polypeptide-associated complex, alpha-nascent polypeptide-associated
      complex, represents an IgE-reactive autoantigen for atopic dermatitis patients.
      By oligonucleotide screening we isolated a complete cDNA coding for a so far
      unknown alpha-nascent polypeptide-associated complex isoform from a human
      epithelial cDNA library. Southern blot hybridization experiments provided further
      evidence that alpha-nascent polypeptide-associated complex is encoded by a gene
      family. Recombinant alpha-nascent polypeptide-associated complex was expressed in
      Escherichia coli as a soluble, His-tagged protein, and purified via nickel
      affinity chromatography. By circular dichroism analysis it is demonstrated that
      purified recombinant alpha-nascent polypeptide-associated complex represents a
      folded protein of mixed alpha-helical and beta-sheet conformation with unusual
      high thermal stability and remarkable refolding capacity. Complete recombinant
      alpha-nascent polypeptide-associated complex (215 amino acids) and its 86 amino
      acid C-terminal fragment specifically bound IgE autoantibodies. Recombinant alpha
      nascent polypeptide-associated complex also inhibited IgE binding to natural
      alpha-nascent polypeptide-associated complex, demonstrating the presence of
      common IgE epitopes between the recombinant and natural protein. Furthermore,
      recombinant alpha-nascent polypeptide-associated complex induced specific
      lymphoproliferative responses in peripheral blood mononuclear cells of a
      sensitized atopic dermatitis patient. As has been proposed for environmental
      allergens it is possible that T cell responses to IgE-defined autoantigens may
      contribute to the chronic skin manifestations in atopic dermatitis.

PMID- 12406327
TI  - Isolation of a Microsporum canis gene family encoding three subtilisin-like
      proteases expressed in vivo.
AB  - Microsporum canis is the main agent of dermatophytosis in dogs and cats and is
      responsible for frequent zoonosis. The pathogenesis of the disease remains
      largely unknown, however. Among potential fungal virulence factors are secreted
      keratinolytic proteases, whose molecular characterization would be an important
      step towards the understanding of dermatophytic infection pathogenesis. M. canis
      secretes a 31.5 kDa keratinolytic subtilisin-like protease as the major component
      in a culture medium containing cat keratin as the sole nitrogen source. Using a
      probe corresponding to a gene's internal fragment, which was obtained by
      polymerase chain reaction, the entire gene encoding this protease named SUB3 was
      cloned from a M. canislambdaEMBL3 genomic library. Two closely related genes,
      termed SUB1 and SUB2, were also cloned from the library using as a probe the gene
      coding for Aspergillus fumigatus 33 kDa alkaline protease (ALP). Deduced amino
      acid sequence analysis revealed that SUB1, SUB2, and SUB3 are secreted proteases
      and show large regions of identity between themselves and with subtilisin-like
      proteases of other filamentous fungi. Interest ingly, mRNA of SUB1, SUB2, and
      SUB3 were detected by reverse transcriptase nested-polymerase chain reaction from
      hair of experimentally infected guinea pigs. These results show that SUB1, SUB2,
      and SUB3 encode a family of subtilisin-like proteases and strongly suggest that
      these proteases are produced by M. canis during the invasion of keratinized
      structures. This is the first report describing the isolation of a gene family
      encoding potential virulence-related factors in dermatophytes.

PMID- 12406328
TI  - Interleukin-10-treated dendritic cells modulate immune responses of naive and
      sensitized T cells in vivo.
AB  - Interleukin-10 is a pleiotropic cytokine known to have inhibitory effects on the
      accessory functions of dendritic cells. In vitro, interleukin-10 converts
      immature dendritic cells into tolerizing antigen- presenting cells. To assess
      whether interleukin-10-treated dendritic cells exert tolerizing effects in vivo,
      CD4+ T cells from DO11.10 ovalbumin-T cell receptor transgenic mice were
      transferred to syngeneic BALB/c recipients. Recipient animals were treated with
      ovalbumin-pulsed/unpulsed, interleukin-10-treated/untreated CD11c+ dendritic
      cells thereafter and ovalbumin-specific proliferation of lymph node cells was
      assessed by restimulation with the peptide in vitro. In prophylactic experiments,
      recipients received naive CD4+ DO11.10 T cells and were immunized with
      ovalbumin323-339 peptide in incomplete Freund's adjuvant after treatment with
      various subtypes of dendritic cells. Strong ovalbumin-specific proliferation was
      observed in animals immunized with control ovalbumin-dendritic cells. Minimal
      proliferation was found in mice treated with ovalbumin-pulsed, interleukin-10
      treated dendritic cells. In therapeutic experiments, preactivated CD4+ DO11.10 T
      cells were transferred, and recipients were treated with dendritic cells as
      described. Ovalbumin-specific proliferation was strong in recipients treated with
      ovalbumin-dendritic cells. CD4+ T cell proliferation from ovalbumin-interleukin
      10-dendritic cell treated animals was below background. When delayed type
      hypersensitivity reactions in the footpads of prophylactically or therapeutically
      vaccinated animals were tested, mice treated with ovalbumin-interleukin-10
      dendritic cells showed no footpad swelling compared with controls. Rechallenge
      with the antigen in vitro and in vivo did not alter the inhibitory effect of
      interleukin-10-treated dendritic cells. Thus, interleukin-10-treated dendritic
      cells inhibit ovalbumin-specific immune responses in naive and sensitized mice.

PMID- 12406329
TI  - A reducing microenvironment leads to the generation of FcepsilonRIhigh
      inflammatory dendritic epidermal cells (IDEC).
AB  - Inflammatory dendritic epidermal cells present in skin lesions of the atopic
      eczema/dermatitis syndrome display the highest expression of the high-affinity
      receptor for IgE (FcepsilonRI), ever detected on human antigen-presenting cells.
      Owing to the instability of the FcepsilonRI (alphagammagamma) complex and fast
      cleavage from the cell surface during the interleukin-4/granulocyte-macrophage
      colony-stimulating factor driven in vitro differentiation of monocytes, a method
      to generate inflammatory dendritic epidermal cells was not at our disposal in the
      past and the amount of ex vivo isolated inflammatory dendritic epidermal cells
      available for functional assays was limited. Therefore, information about the
      role of inflammatory dendritic epidermal cells and FcepsilonRI on this dendritic
      cell subtype in atopic and inflammatory skin diseases is completely missing. In
      this study, we were able to: (i) increase the expression of a functional
      FcepsilonRI complex on the cell surface of immature monocyte-derived dendritic
      cells from atopic donors by creating a reducing microenvironment; (ii) enhance
      significantly the intracellular pool of the FcepsilonRIgamma chains, which is the
      limiting parameter for the FcepsilonRI surface expression; and (iii) generate
      monocyte-derived dendritic cells displaying the phenotypical characteristics of
      inflammatory dendritic epidermal cells, producing high amounts of proinflammatory
      cytokines and chemokines similar to the cytokines found in lesional skin of the
      atopic eczema/dermatitis syndrome. Altogether the high expression of functional
      FcepsilonRI on these cells enables us for the first time to study inflammatory
      dendritic epidermal cells and FcepsilonRI-mediated mechanisms of inflammatory
      dendritic epidermal cells in vitro, in order to shed light on the putative role
      of this important cell type in the atopic eczema/dermatitis syndrome.

PMID- 12406330
TI  - Natural killer and dendritic cell contact in lesional atopic dermatitis skin-
      Malassezia-influenced cell interaction.
AB  - The regulation of dendritic cells is far from fully understood. Interestingly,
      several recent reports have suggested a role for natural killer cells in
      affecting dendritic cell maturation and function upon direct contact between the
      cells. It is not known if this interaction takes place also in vivo, or if a
      potential interaction of natural killer cells and dendritic cells would be
      affected by allergen exposure of the dendritic cells. The yeast Malassezia can
      act as an allergen in atopic eczema/dermatitis syndrome, and induce maturation of
      dendritic cells. Our aims were to study the distribution of natural killer cells
      in the skin from atopic eczema/dermatitis syndrome patients with the emphasis on
      possible natural killer cell-dendritic cell interaction, and to assess whether
      the interaction of Malassezia with dendritic cells would affect subsequent
      interaction between dendritic cells and natural killer cells. A few scattered
      natural killer (CD56+/CD3-) cells were found in the dermis of healthy individuals
      and in nonlesional skin from atopic eczema/dermatitis syndrome patients. In
      lesional skin and in biopsies from Malassezia atopy-patch-test-positive skin,
      however, natural killer cells were differentially distributed and for the first
      time we could show close contact between natural killer cells and CD1a+ dendritic
      cells. Dendritic cells preincubated with Malassezia became less susceptible to
      natural-killer-cell-induced cell death, suggesting a direct effect imposed by
      Malassezia upon interaction of dendritic cells with natural killer cells. These
      findings indicate that natural killer cells and dendritic cells can interact in
      the skin and that Malassezia affects the interaction between natural killer cells
      and dendritic cells. Our data suggest that natural killer cells may play a role
      in regulating dendritic cells in atopic eczema/dermatitis syndrome.

PMID- 12406331
TI  - Ultraviolet a irradiation of C57BL/6 mice suppresses systemic contact
      hypersensitivity or enhances secondary immunity depending on dose.
AB  - Ultraviolet radiation is the most common environmental carcinogen humans are
      exposed to. It is now known that in order for skin cancers to develop, both
      genetic damage and immunosuppression is required. Ultraviolet-induced
      immunosuppression is therefore a key contributor to the development of skin
      cancer. Little is known about the relative contributions of the different
      ultraviolet spectra (A and B), however. Therefore detailed ultraviolet dose
      response curves for systemic suppression of contact hypersensitivity in two mouse
      strains were determined to examine the relative contributions of each of these
      spectral components of sunlight to primary and secondary immunity. Whereas
      ultraviolet B caused a linear dose-related immunosuppression in both C57BL/6 and
      Balb/c mice, only C57BL/6 mice were immunosuppressed by medium doses of
      ultraviolet A. At higher ultraviolet A doses, C57BL/6 mice were protected from
      immunosuppression, suggesting a genetic predisposition to ultraviolet-A-induced
      immunomodulation. Surprisingly, we found that, in contrast to primary
      immunosuppression, low dose ultraviolet A enhanced the secondary immune response,
      whereas ultraviolet B caused antigen-specific tolerance. When ultraviolet A and
      ultraviolet B were combined to mimic sunlight (solar-simulated ultraviolet),
      immunosuppression and tolerance were only observed over a narrow dose range as
      the memory-enhancing effect of low dose ultraviolet A and the immunoprotective
      effect of higher dose ultraviolet A prevented the suppressive effects of
      ultraviolet B. These studies suggest that complex relationships between
      ultraviolet dose, immunomodulation, spectra, and genetic background are likely to
      be important for skin cancer induction. We also describe for the first time that
      low doses of ultraviolet A are able to enhance secondary immunity, which has
      important implications for vaccination strategies.

PMID- 12406332
TI  - Selection of mimotopes of the cell surface adhesion molecule Mel-CAM from a
      random pVIII-28aa phage peptide library.
AB  - The cell surface adhesion molecule Mel-CAM is highly expressed in advanced
      primary and metastatic melanoma. Mel-CAM was first described as an integral
      membrane glycoprotein of malignant melanoma cells. The murine monoclonal antibody
      MAd18-5D7 recognizes an epitope of the extracellular domain of Mel-CAM and is
      able to enhance Mel-CAM mediated adhesion of melanoma cells in aggregation
      assays. For the characterization of peptides that antigenically mimic surface
      exposed areas of Mel-CAM we screened a newly constructed random pVIII-28aa
      bacteriophage peptide library against MAd18-5D7. After three panning rounds a
      population of phages binding to MAd18-5D7 was enriched. Peptides expressed on the
      surface of these phages were then tested for their specificity for the antibody's
      antigen binding site. DNA sequences coding for two specific peptide ligands were
      determined. One of the deduced amino acid sequences showed similarity to a
      portion of the sequence of the third immunoglobulin-like extracellular domain of
      Mel-CAM. Both peptides blocked the interaction of MAd18-5D7 with Mel-CAM present
      in a MelJuSo melanoma cell line lysate. Phage displayed as well as synthetic
      peptides inhibited in a dose-dependent manner the binding of MAd18-5D7 to
      recombinant Mel-CAM in enzyme-linked immunosorbent assay experiments. No such
      inhibition was observed using a panel of other anti-Mel-CAM antibodies. Our
      results clearly indicate that these 28mer peptides are structural equivalents of
      the MAd18-5D7 epitope of Mel-CAM and that they will be useful tools for further
      in vitro and in vivo studies of Mel-CAM mediated cell-cell interaction.

PMID- 12406333
TI  - Dichotomic nature of atopic dermatitis reflected by combined analysis of monocyte
      immunophenotyping and single nucleotide polymorphisms of the interleukin
      4/interleukin-13 receptor gene: the dichotomy of extrinsic and intrinsic atopic
      dermatitis.
AB  - Patients with atopic dermatitis display substantial immunologic abnormalities,
      among which elevated total IgE is considered as a hallmark; however, a subgroup
      of atopic dermatitis patients exhibits normal IgE levels, but mechanisms
      contributing to the so-called "intrinsic" or "nonallergic" form of atopic
      dermatitis are obscure. In order to unravel similarities and differences of both
      atopic dermatitis subtypes, the phenotype of monocytes, total serum IgE levels,
      and serum levels of cytokines regulating the IgE production from nonatopic
      individuals and patients with allergic rhinitis, and extrinsic and intrinsic
      atopic dermatitis were measured. Concomitantly, genomic DNA probes of all
      subjects were analyzed for single nucleotide polymorphisms of candidate genes of
      structures involved in the regulation of the IgE synthesis, such as interleukin-4
      and the interleukin-4R/interleukin-13R. Our data show that the surface expression
      of the high- and low-affinity receptor for IgE (FcepsilonRI and
      FcepsilonRII/CD23) and the interleukin-4Ralpha chain were significantly elevated
      in monocytes from patients with extrinsic atopic dermatitis. Furthermore, serum
      levels of interleukin-13 were significantly increased in patients with intrinsic
      atopic dermatitis. In addition, the frequency of the interleukin-4Ralpha
      polymorphism C3223T and the interleukin-4 polymorphism C590T tended to be higher
      in extrinsic atopic dermatitis than in intrinsic atopic dermatitis. Altogether
      our findings indicate that intrinsic atopic dermatitis patients exhibit
      phenotypic and immunologic features, which differ from those of patients with
      extrinsic atopic dermatitis or other atopic disorders.

PMID- 12406334
TI  - Pimecrolimus identifies a common genomic anti-inflammatory profile, is clinically
      highly effective in psoriasis and is well tolerated.
AB  - The ascomycin macrolactam pimecrolimus is a novel inflammatory cytokine release
      inhibitor that so far has not been administered systemically to humans. In this
      phase I/II randomized double-blind, placebo-controlled, multiple rising dose
      proof of concept study psoriasis patients were treated with oral pimecrolimus or
      placebo. Gene profiling identified a common genomic profile with a downregulation
      of genes associated with inflammation but no changes in gene expression linked to
      drug-related side-effects. A steady state of pimecrolimus was reached after 5-10
      d, Cmax, and area under the curve (0-24) was 54.5 ng per ml and 589.9 ng h per
      ml, respectively, at steady state at the highest dose. There was clear clinical
      efficacy in patients receiving 20 mg pimecrolimus twice daily and 30 mg twice
      daily with a reduction of Psoriasis Area and Severity Index by 60% and 75%,
      respectively. Histopatho logically and immunopathologically there was a reversion
      of the psoriatic phenotype towards normal. There were no notable clinical,
      laboratory, kidney function, or immunologic side-effects. We conclude that
      pimecrolimus taken orally is highly effective in a concentration-dependent manner
      in patients with psoriasis and on a short-term basis it is well tolerated and
      this is confirmed by its pharmacogenomic profile. The latter also indicates that
      pimecrolimus should be equally effective in other inflammatory skin diseases.

PMID- 12406335
TI  - Keratinocyte stem cells: a commentary.
AB  - For many years it has been widely accepted that stem cells play a crucial role in
      adult tissue maintenance. The concept that the renewing tissues of the body
      contain a small subcompartment of self-maintaining stem cells, upon which the
      entire tissue is dependent, is also now accepted as applicable to all renewing
      tissues. Gene therapy and tissue engineering are driving considerable interest in
      the clinical application of such hierarchically organized cellular compartments.
      Recent initial observations have provided a tantalizing insight into the large
      pluripotency of these cells. Indeed, scientists are now beginning to talk about
      the possible totipotency of some adult tissue stem cells. Such work is currently
      phenomenologic, but analysis of data derived from genomics and proteomics,
      identifying the crucial control signals involved, will soon provide a further
      impetus to stem cell biology with far reaching applications. The epidermis with
      its relatively simple structure, ease of accessibility, and the ability to grow
      its cells in vitro is one obvious target tissue for testing stem cell
      manipulation theories. It is crucial, however, that the normal keratinocyte stem
      cell is thoroughly characterized prior to attempting to manipulate its
      pluripotency. This commentary assesses the data generated to date and critically
      discusses the conclusions that have been drawn. Our current level of
      understanding, or lack of understanding, of the keratinocyte stem cell is
      reviewed.

PMID- 12406336
TI  - Abrupt decreases in environmental humidity induce abnormalities in permeability
      barrier homeostasis.
AB  - Previous reports demonstrated that long-term exposure to extremes in humidity
      influence permeability barrier homeostasis. Here the effects of a sudden shift
      from a high humidity to a dry environment were studied. Mice were initially
      maintained in either a humid (> 80% relative humidity) or normal environment
      (relative humidity = 40-70%), and then transferred to a dry environment (< 10%
      relative humidity). Within 2 d of transfer from a humid to a dry environment a 6
      7-fold increase in transepidermal water loss occurred that returned to normal
      within 7 d. No increase in transepidermal water loss occurred in response to a
      switch from a normal to a dry environment. At a time when barrier function was
      abnormal, both stratum corneum hydration and pH were normal, indicating that the
      mechanisms that regulate these functions differ. Following transfer from a humid
      to dry environment, electron microscopy revealed a marked decrease in: (i)
      lamellar bodies in the outermost stratum granulosum; (ii) deposition of lamellar
      body contents at the stratum granulosum-stratum corneum interface; and (iii) the
      quantity of intercellular lamellae in the stratum corneum, which together could
      account for the barrier abnormality. Transfer of mice from a normal to a dry
      environment rapidly stimulated epidermal proliferation, whereas animals switched
      from a humid to a dry environment displayed a delayed increase in proliferation
      that might also contribute to the barrier abnormality. The present study
      demonstrates that sudden changes from a high to a low humidity environment
      results in abnormal barrier function, which could adversely influence the
      incidence and/or severity of skin disorders.

PMID- 12406337
TI  - Characterization of mouse profilaggrin: evidence for nuclear engulfment and
      translocation of the profilaggrin B-domain during epidermal differentiation.
AB  - Filaggrin is a keratin filament associated protein that is expressed in granular
      layer keratinocytes and derived by sequential proteolysis from a polyprotein
      precursor termed profilaggrin. Depending on the species, each profilaggrin
      molecule contains between 10 and 20 filaggrin subunits organized as tandem
      repeats with a calcium-binding domain at the N- terminal end. We now report the
      characterization of the complete mouse gene. The structural organization of the
      mouse gene is identical to the human profilaggrin gene and consists of three
      exons with a 4 kb intron within the 5' noncoding region and a 1.7 kb intron
      separating the sequences encoding the calcium-binding EF-hand motifs. A processed
      pseudogene was found embedded within the second intron. The third and largest
      exon encodes the second EF-hand, a basic domain (designated the B-domain)
      followed by 12 filaggrin repeats and a unique C-terminal tail domain. A
      polyclonal antibody raised against the conceptually translated sequence of the B
      domain specifically stained keratohyalin granules and colocalized with a
      filaggrin antibody in granular layer cells. In upper granular layer cells, B
      domain containing keratohyalin granules were in close apposition to the nucleus
      and, in some cells, appeared to be completely engulfed by the nucleus. In
      transition layer cells, B-domain staining was evident in the nucleus whereas
      filaggrin staining remained cytoplasmic. Nuclear staining of the B-domain was
      also observed in primary mouse keratinocytes induced to differentiate. This study
      has also revealed significant sequence homology between the mouse and human
      promoter sequences and in the calcium-binding domain but the remainder of the
      protein-coding region shows substantial divergence.

PMID- 12406338
TI  - Identification of platelet-activating factor acetylhydrolase II in human skin.
AB  - Platelet-activating factor acetylhydrolases are a family of specialized
      phospholipase A2 enzymes. They serve an anti-inflammatory function by converting
      the proinflammatory autocoid, PAF, into biologically inactive lyso-PAF, by the
      removal of the sn-2 acetyl group of this glycerophospholipid. Similarly, platelet
      activating factor acetylhydrolases can also degrade oxidatively modified sn-2
      polyunsaturated-fatty-acid-containing phospholipids, which are toxic to cells.
      Platelet-activating factor acetylhydrolase II is a recently cloned member of this
      family of specialized phospholipases. Consistent with a potential role of this
      intracellular enzyme in protecting membrane phospholipids against oxidative
      stress, platelet-activating factor acetylhydrolase II has been shown to
      translocate from cytosol to membranes in response to pro-oxidative stressors, and
      overexpression of this enzyme decreases the cytotoxic effects of these agents.
      The objective of this study was to assess whether platelet-activating factor
      acetylhydrolase II is involved in protecting skin against oxidative stress.
      Platelet-activating factor acetylhydrolase II protein was demonstrated in human
      skin by immunohistochemistry, with the highest levels of the enzyme found in
      sebaceous glands and lesser amounts in epidermal keratinocytes. Treatment of
      epidermal cells with t-butylhydroperoxide or ultraviolet B radiation resulted in
      platelet-activating factor acetylhydrolase II translocation from cytosol to
      membranes. To assess the role of this enzyme in epidermal function, a recombinant
      retroviral strategy was used to overexpress platelet-activating factor
      acetylhydrolase II in the human keratinocyte-derived cell line HaCaT.
      Overexpression of platelet-activating factor acetylhydrolase II protected HaCaT
      cells against apop tosis induced by oxidative stressors t-butylhydroperoxide and
      ultraviolet B radiation. Similar levels of apoptosis, however, were seen in both
      control and platelet-activating-factor-acetylhydrolase-II-over expressing HaCaT
      cells in response to C2 ceramide. These studies demonstrate the presence of
      platelet-activating factor acetylhydrolase II in a restricted pattern in human
      skin, and provide evidence that this specialized phospholipase is involved in
      protecting this organ against oxidative stress through the degradation of
      oxidatively modified bioactive phospholipids.

PMID- 12406339
TI  - A novel missense mutation affecting the human hairless thyroid receptor
      interacting domain 2 causes congenital atrichia.
AB  - Congenital atrichias represent a large and heterogeneous group of inherited hair
      disorders. In this report, we describe a patient affected with alopecia
      universalis congenita (MIM 203655). Sequence analysis revealed a G to A
      transition at cDNA position 3034 of the hairless hr gene present in a homozygous
      state in the patient and in a heterozygous state in the patient's mother, and
      absent in the patient's sister. The mutation is predicted to result in the
      substitution of an asparagine residue for an aspartate amino acid (D1012N) at a
      position previously shown in the rat to affect hairless binding to thyroid
      hormone receptor. This study presents the first evidence in humans for the
      functional importance of the hairless thyroid receptor interacting domain 2.

PMID- 12406340
TI  - Adenosine receptors as mediators of both cell proliferation and cell death of
      cultured human melanoma cells.
AB  - Adenosine displays contradictory effects on cell growth: it improves cell
      proliferation, but it may also induce apoptosis and impair cell survival.
      Following the pharmacologic characterization of adenosine receptor expression on
      the human melanoma cell line A375, we chose A375 as our cellular model to define
      how the extracellular adenosine signals are conveyed from each receptor. By using
      selective adenosine receptor agonists or antagonists, we found that A2A
      stimulation reduced cell viability and cell clone formation, whereas, at the same
      time, it improved cell proliferation. In support of this finding we demonstrated
      that the stimulation of A2A adenosine receptors stably expressed in Chinese
      hamster ovary cell clone reproduced deleterious effects observed in human
      melanoma cells. A3 stimulation counteracted A2A-induced cell death but also
      reduced cell proliferation. Furthermore, we found that A3 stimulation ensures
      cell survival. We demonstrated that adenosine triggers a survival signal via A3
      receptor activation and it kills the cell through A2A receptor inducing a
      signaling pathway that involves protein kinase C and mitogen-activated protein
      kinases.

PMID- 12406341
TI  - Serotoninergic system in hamster skin.
AB  - We have cloned the tryptophan hydroxylase cDNA from hamster pituitary and
      demonstrated its expression in the skin, melanotic and amelanotic melanomas,
      spleen, heart, and the eye. We further demonstrated that skin, melanomas, spleen,
      pituitary, and eye but not heart expressed arylalkylamine N-acetyltransferase
      mRNA. The cutaneous expression of the arylalkylamine N-acetyltransferase gene was
      accompanied by enzymatic activity for the conversion of serotonin and tryptamine
      to N-acetylserotonin and N-acetyltryptamine, respectively. There was marked
      regional variation in the serotonin N-acetyltransferase activity, which was
      higher in ear skin than in corpus skin, and was lower in melanomas than in normal
      skin. Serotonin N-acetyltransferase activity was significantly inhibited by Cole
      bisubstrate at low concentration (</= 1 micro m); this evidence in conjunction
      with arylalkylamine N-acetyltransferase mRNA expression implies an involvement of
      arylalkylamine N-acetyltransferase in serotonin metabolism in the skin. We also
      documented both the in vitro transformation of serotonin to N-acetylserotonin
      using liquid chromatography/mass spectrometry and the generation/storage of N
      acetylserotonin in cultured melanoma cells. Thus, we have uncovered a cutaneous
      pathway displaying capabilities for serotonin biosynthesis and/or its metabolism
      to N-acetylserotonin in rodent skin. As serotonin has powerful vasodilator,
      immunomodulator, and growth factor actions, this pathway could be involved in
      skin physiology and/or pathology.

PMID- 12406342
TI  - Expression of the high-affinity choline transporter, CHT1, in the neuronal and
      non-neuronal cholinergic system of human and rat skin.
AB  - Choline is an essential component in acetylcholine biosynthesis, and is involved
      in cell signaling. It is unable to permeate the cell membrane and requires a
      transporter to enter the cell. Neurons that synthesize acetylcholine take up
      choline by a recently cloned high-affinity choline transporter (choline
      transporter 1) that is Na+-dependent and can be blocked by hemicholinium-3. The
      aim of this study was to determine the expression and to analyze the distribution
      of choline transporter 1 in human and rat skin. The mRNA for choline transporter
      1 was detected in rat and human skin and in the human keratinocyte cell line
      HaCaT. A polyclonal anti-serum was developed against the N-terminal region of the
      human and rat protein. In rat and human skin, choline transporter 1
      immunoreactivity was present in nerve fibers. In addition, keratinocytes, HaCaT
      cells and cells of the internal root sheath of the hair follicle contained
      choline transporter 1 immunoreactivity. The labeling patterns of nonconfluent vs
      confluent cultured cells and the distribution of choline transporter 1 along the
      epidermal layer suggest an association of choline transporter 1 with keratinocyte
      differentiation. In conclusion, this study shows the presence of the high
      affinity choline transporter choline transporter 1 in nerve fibers and epithelial
      cells in the human and rat skin supporting the pivotal role of this transporter
      in both the neuronal and non-neuronal cholinergic system of the skin.

PMID- 12406343
TI  - Reduced skin capillary density during attacks of erythromelalgia implies
      arteriovenous shunting as pathogenetic mechanism.
AB  - Erythromelalgia is characterized by burning pain, erythema, and increased
      temperature in acral skin. The pain is aggravated by warming and relieved by
      cooling. Increased microvascular arteriovenous shunting in deep dermal plexa has
      been hypothesized as the pathogenetic mechanism of pain in affected skin,
      inducing hypoxia during pain attacks. The aim of this study was to quantify skin
      capillary density in erythromelalgic patients before and after heat provocation,
      as increased skin temperature should increase the need for nutritive blood supply
      by the capillaries. Fourteen patients and 10 healthy control subjects were
      studied using an enhanced technique of computer-assisted analysis of capillary
      bed morphology and temperature measurements before and after central body
      heating. The increase in acral skin temperature was significantly higher (p <
      0.05) in the eight patients where symptoms were induced after heat provocation,
      compared to asymptomatic patients and healthy control subjects. The number of
      visible capillaries in a field of view (1.7 mm2) decreased significantly (p =
      0.01) in erythromelalgia patients from 105 (62-137) (median with total range) to
      89 (49-118) after warming in areas with numerous arteriovenous anastomoses (nail
      bed region). In symptomatic patients an even more significant reduction was
      observed (p = 0.01). The capillary size was also significantly reduced (p < 0.05)
      from 41.0 (31.5-50.5) (arbitrary units) to 37.3 (33.0-46.0) in symptomatic
      patients. The change in capillary density in the nail bed area was significantly
      larger in erythromelalgia patients -17 (-49 to 39) compared to controls 0 (-47 to
      13) (p < 0.05), and in symptomatic patients -19 (-49 to -12) compared to
      asymptomatic patients -8 (-48 to 39) (p < 0.05) and controls (p < 0.01). The
      reduced skin capillary density after heating is compatible with increased
      microvascular arteriovenous shunting of blood and a corresponding relative
      deficit in nutritive perfusion (steal phenomenon) with skin hypoxia, causing the
      symptoms in erythromelalgia.

PMID- 12406344
TI  - Mitogenic activity of dermatofibrosarcoma protuberans is mediated via an
      extracellular signal related kinase dependent pathway.
AB  - Dermatofibrosarcoma protuberans is a malignant mesenchymal tumor originating in
      the dermis. Although it is locally aggressive and recurs unless completely
      excised, it only rarely metastasizes. In this study, we investigated the
      mechanisms of increased proliferation of dermatofibrosarcoma protuberans cells.
      The cells showed increased DNA synthesis in serum-free medium, which was
      demonstrated by the incorporation of [3H]-thymidine. Increased DNA synthesis of
      dermatofibrosarcoma protuberans cells was abolished by genistein, a tyrosine
      kinase inhibitor, or by PD98059, a specific extracellular signal related kinase
      pathway inhibitor, but not by calphostin C, a protein kinase C inhibitor.
      Immunoblotting analysis of dermatofibrosarcoma protuberans cells using a specific
      antibody against phosphorylated extracellular signal related kinase
      (Thr202/Tyr204) showed that extracellular signal related kinase was expressed as
      constitutively phosphorylated molecules in dermatofibrosarcoma protuberans cells.
      Immunofluorescence analysis showed that the kinase was constitutively located in
      the nucleus of the cells. Furthermore, transfection of the dominant negative
      mutant extracellular signal related kinase into dermatofibrosarcoma protuberans
      cells abolished the increased mitogenic activity of the cells. These results
      suggest that an extracellular signal related kinase dependent pathway is
      implicated in the increased mitogenic activity of dermatofibrosarcoma protuberans
      cells.

PMID- 12406345
TI  - An assessment of the CDKN2A variant Ala148Thr as a nevus/melanoma susceptibility
      allele.
AB  - Melanocytic nevi are the most potent risk factors for melanoma yet identified.
      Variation in the nevus phenotype within a population is predominantly genetically
      determined. Genes that determine nevus expression may therefore act as low
      penetrance melanoma susceptibility genes. Rare germline mutations in CDKN2A
      predispose to melanoma and appear to be nevogenic, although the correlation
      between nevus phenotype and mutation status is poor. It is plausible that more
      common CDKN2A variants may influence both melanoma susceptibility and nevus
      susceptibility. Ala148Thr is a G to A missense polymorphism of CDKN2A, which is
      found in 4%-6% of the general population. We have investigated the role of
      Ala148Thr as a low penetrance melanoma or nevus susceptibility allele in two
      separate groups of individuals. The first was a sample of 488 adults recruited
      from 179 families of patients with the atypical nevus phenotype and/or a family
      history of melanoma, and the second was a population-based sample of 599 women.
      Similar prevalences of Ala148Thr (4.9% and 5.2%) were found in both samples but
      significant variation in the prevalence of the polymorphism was seen across
      geographic areas within England. There was no association between Ala148Thr
      status and nevus number or history of melanoma, and therefore the results did not
      support the hypothesis that the Ala148Thr variant is a low penetrance melanoma or
      nevus susceptibility allele. A significant protective role of Ala148Thr on the
      number of atypical nevi was observed in the family sample (mean of 1 atypical
      nevus in those with the allele and 3.5 nevi in those without, p = 0.02). After
      allowing for potential confounders this was not evident in the population-based
      sample.

PMID- 12406346
TI  - Two cases of primarily palmoplantar keratoderma associated with novel mutations
      in keratin 1.
AB  - Mutations in keratin 1 were initially described in the classical form of bullous
      congenital ichthyosiform erythroderma (also known as epidermolytic
      hyperkeratosis). More recently the range of phenotypes associated with mutations
      in this gene has been extended to include annular ichthyosiform erythroderma and
      mild epidermolytic palmoplantar keratoderma. Here we present two novel mutations
      in the keratin 1 gene (KRT1): a 5' donor splice site mutation in exon 1 (591 + 2T
      > A) that predicts a 22 amino acid in-frame deletion in the keratin 1 1A domain;
      and an in-frame deletion in exon 7 (1376del24) that predicts a foreshortened 2B
      coiled-coil domain of keratin 1. In each case these mutations are associated with
      palmoplantar keratoderma and mild ichthyosis, largely limited to the flexural
      areas. These mutations appear to have a less damaging effect than previously
      reported mis-sense mutations sited in the helix boundary motifs. This report
      extends the range of phenotypes associated with mutations in KRT1.

PMID- 12406347
TI  - Somatic and germinal mosaicism for the steroid sulfatase gene deletion in a
      steroid sulfatase deficiency carrier.
AB  - Steroid sulfatase deficiency results in X-linked ichthyosis, an inborn error of
      metabolism in which the principal molecular defect is the complete deletion of
      the steroid sulfatase gene and flanking markers. Mosaicism for the steroid
      sulfatase gene has not yet been reported in X-linked ichthyosis. In this study we
      describe an X-linked ichthyosis patient with complete deletion of the steroid
      sulfatase gene and his mother with somatic and germinal mosaicism for this
      molecular defect. The family (X-linked ichthyosis patient, grandmother, mother,
      and sister) was analyzed through steroid sulfatase enzyme assay, polymerase chain
      reaction, DNA markers, and fluorescence in situ hybridization of the steroid
      sulfatase gene. Steroid sulfatase activity was undetectable in the X-linked
      ichthyosis patient, very low in the mother, and normal in the grandmother and
      sister. The X-linked ichthyosis patient showed a 2 Mb deletion of the steroid
      sulfatase gene and flanking regions from 5'DXS1139 to 3'DXF22S1. The mother
      showed one copy of the steroid sulfatase gene in 98.5% of oral cells and in 80%
      of leukocytes. The grandmother and sister showed two copies of the steroid
      sulfatase gene. The origin of the X chromosome with the deletion of the steroid
      sulfatase gene corresponded to the grandfather of the proband. We report the
      first case of somatic and germinal mosaicism of the steroid sulfatase gene in an
      X-linked ichthyosis carrier and propose DNA slippage as the most plausible
      mechanism in the genesis of this mosaicism.

PMID- 12406348
TI  - Two novel mutations in the keratin 1 gene in epidermolytic hyperkeratosis.

PMID- 12406349
TI  - The M581V mutation, associated with a mild form of congenital insensitivity to
      pain with anhidrosis, causes partial inactivation of the NTRK1 receptor.

PMID- 12406350
TI  - Interleukin-10-deficient mice are less susceptible to the induction of alopecia
      areata.

PMID- 12406351
TI  - Regeneration of a new hair follicle from the upper half of a human hair follicle
      in a nude mouse.

PMID- 12406352
TI  - Unmet expectations for care and the patient-physician relationship.
AB  - OBJECTIVE: To profile patients likely to have unmet expectations for care,
      examine the effects of such expectations, and investigate how physicians'
      responses to patients' requests affect the development of unfulfilled
      expectations. DESIGN: Patient and physician questionnaires were administered
      before and after outpatient visits. A follow-up telephone survey was administered
      2 weeks post visit. SETTING: The offices of 45 family practice, internal
      medicine, and cardiology physicians. PATIENTS: Nine hundred nine adults reporting
      a health problem or concern. MEASUREMENTS AND MAIN RESULTS: Before their visits,
      patients rated their general health and trust in the index physician. After the
      visit, patients reported upon 8 types of unmet expectations and any request they
      made. Two weeks thereafter, patients rated their visit satisfaction, improvement,
      and intention to adhere to the physician's advice. They also reported any
      postvisit health system contacts. Overall, 11.6% of patients reported >/=1 unmet
      expectation. Visits in which a patient held an unmet expectation were rated by
      physicians as less satisfying and more effortful. At follow-up, patients who
      perceived an unmet expectation for care also reported less satisfaction with
      their visits, less improvement, and weaker intentions to adhere. Patients with an
      unmet expectation related to clinical resource allocation had more postvisit
      health system contacts. Unmet expectations were typically reported by a patient
      whose request for a resource was not fulfilled. CONCLUSIONS: Unmet expectations
      adversely affect patients and physicians alike. Physicians' nonfulfillment of
      patients' requests plays a significant role in patients' beliefs that their
      physicians did not meet their expectations for care.

PMID- 12406353
TI  - Medical residents' first clearly remembered experiences of giving bad news.
AB  - CONTEXT: Communication of bad news to patients or families is a difficult task
      that requires skill and sensitivity. Little is known about doctors' formative
      experiences in giving bad news, what guidance they receive, or what lessons they
      learn in the process. OBJECTIVE: To learn the circumstances in which medical
      residents first delivered bad news to patients or families, the nature of their
      experience, and their opinions about how best to develop the needed skills.
      DESIGN: Confidential mailed survey. SETTING AND SUBJECTS: All medicine house
      officers at 2 urban, university-based residency programs in Boston. MAIN OUTCOME
      MEASURES: Details of medical residents' first clearly remembered experiences of
      giving bad news to a patient or family member; year in training; familiarity with
      the patient; information about any planning prior to, observation of, or
      discussion after their first experience; and the usefulness of such discussions.
      We also asked general questions about delivering bad news, such as how often this
      was done, as well as asking for opinions about actual and desired training.
      RESULTS: One hundred twenty-nine of two hundred thirteen surveys (61%) were
      returned. Most (73%) trainees first delivered bad news while a medical student or
      intern. For this first experience, most (61%) knew the patient for just hours or
      days. Only 59% engaged in any planning for the encounter. An attending physician
      was present in 6 (5%) instances, and a more-senior trainee in 14 (11%) others.
      Sixty-five percent of subjects debriefed with at least 1 other person after the
      encounter, frequently with a lesser-trained physician or a member of their own
      family. Debriefing focused on the reaction of those who were given the bad news
      and the reaction of the trainee. When there were discussions with more-senior
      physicians, before or after the encounter, these were judged to be helpful
      approximately 80% of the time. Most subjects had given bad news between 5 and 20
      times, yet 10% had never been observed doing so. Only 81 of 128 (63%) had ever
      observed an attending delivering bad news, but those who did found it helpful 96%
      of the time. On 7-point scales, subjects rated the importance of skills in
      delivering bad news highly, (mean 6.8), believed such skill can be improved (mean
      6.6), and thought that more guidance should be offered to them during such
      activity (mean 5.8). CONCLUSION: Medical students and residents frequently
      deliver bad news to patients and families. This responsibility begins early in
      training. In spite of their inexperience, many do not appear to receive adequate
      guidance or support during their earliest formative experiences.

PMID- 12406355
TI  - Quantitative evaluation of the diagnostic thinking process in medical students.
AB  - OBJECTIVE: To explore the diagnostic thinking process of medical students.
      SUBJECTS AND METHODS: Two hundred twenty-four medical students were presented
      with 3 clinical scenarios corresponding to high, low, and intermediate pre-test
      probability of coronary artery disease. Estimates of test characteristics of the
      exercise stress test, and pre-test and post-test probability for each scenario
      were elicited from the students (intuitive estimates) and from the literature
      (reference estimates). Post-test probabilities were calculated using Bayes'
      theorem based upon the intuitive estimates (Bayesian estimates of post-test
      probability) and upon the reference estimates (reference estimates of post-test
      probability). The differences between the reference estimates and the intuitive
      estimates, and between Bayesian estimates and the intuitive estimates were used
      for assessing knowledge of test characteristics, and ability of estimating pre
      test and post-test probability of disease. RESULTS: Medical students could not
      rule out disease in low or intermediate pre-test probability settings, mainly
      because of poor pre-test estimates of disease probability. They were also easily
      confused by test results that differed from their anticipated results, probably
      because of their inaptitude in applying Bayes' theorem to real clinical
      situations. These diagnostic thinking patterns account for medical students or
      novice physicians repeating unnecessary examinations. CONCLUSIONS: Medical
      students' diagnostic ability may be enhanced by the following educational
      strategies: 1) emphasizing the importance of ruling out disease in clinical
      practice, 2) training in the estimation of pre-test disease probability based
      upon history and physical examination, and 3) incorporation of the Bayesian
      probabilistic thinking and its application to real clinical situations.

PMID- 12406354
TI  - Stressful life events among community-living older persons.
AB  - OBJECTIVES: To identify the life events that older persons experience as most
      stressful, to evaluate older persons' perceptions of the consequences of these
      stressful events for their lives, and to evaluate the relationship of demographic
      factors and measures of health and functional status to these perceptions.
      DESIGN: Cross-sectional study. PARTICIPANTS: Seven hundred fifty-four community
      living persons aged 70 years or older. MEASURES: During a comprehensive
      assessment, participants identified the most stressful event that they had
      experienced in the past 5 years and, subsequently, rated its stressfulness and
      perceived consequences. RESULTS: Six hundred three participants (80%) identified
      a stressful life event. Of these, 18% identified a personal illness, 42% the
      death of a family member or friend, 23% the illness of a family member or friend,
      and 17% a nonmedical event. Although participants consistently rated their events
      as highly stressful, they reported widely varied consequences of these events for
      their lives. While 27% to 59% of participants across the 4 event types reported
      considerable negative consequences, 17% to 36% reported positive consequences
      such as starting new activities that have become important to them and changing
      for the better how they feel about their lives. Dependence in instrumental
      activities of daily living and depressive symptoms were independently associated
      with several negative perceived consequences. CONCLUSIONS: Older persons
      experience a wide array of stressful life events, with only a small minority
      reporting personal illnesses as the most stressful. Similar stressful events can
      have either negative or positive consequences for older persons' lives. This
      variation in response to stressful events among older persons may indicate
      different degrees of resilience, a potentially important factor underlying
      successful aging that deserves further investigation.

PMID- 12406356
TI  - Indicators of early research productivity among primary care fellows.
AB  - OBJECTIVE: Little is known about the impact of fellowship training in primary
      care on subsequent research productivity. Our goal was to identify
      characteristics of research fellows and their training associated with subsequent
      publications and research funding. DESIGN: Mail survey in 1998. SETTING AND
      PARTICIPANTS: 1988-1997 graduates of 25 National Research Service Award primary
      care research fellowships in the United States. OUTCOME MEASURES: 1) Publishing 1
      or more papers per year since the beginning of fellowship, or 2) serving as
      principal investigator (PI) on a federal or non-federal grant. RESULTS: One
      hundred forty-six of two hundred fifteen program graduates (68%) completed the
      survey. The median age was 38 years, and 51% were male. Thirty-two percent had
      published 1 or more papers per year, and 44% were PIs. Male gender (odds ratio
      [OR], 3.6; 95% confidence interval [95% CI], 1.4 to 9.2), self-reported
      allocation of 40% or more of fellowship time to research (OR, 4.4; 95% CI, 1.8 to
      11.2), and having an influential mentor during fellowship (OR, 5.0; 95% CI, 1.5
      to 17.2) were independently associated with publishing 1 or more papers per year.
      Fellows with funding as a PI were also more likely to have an influential mentor
      (OR, 3.0; 95% CI, 1.3 to 7.2). CONCLUSION: Primary care fellows who had
      influential mentors were more productive in research early after fellowship.
      Awareness of the indicators of early research success can inform the policies of
      agencies that fund research training and the curricula of training programs
      themselves.

PMID- 12406357
TI  - How far is the sternal angle from the mid-right atrium?
AB  - BACKGROUND: The central venous pressure (CVP) is commonly estimated at the
      bedside by measuring the height of the jugular venous pressure (JVP) relative to
      the sternal angle. Determining the CVP from this measure requires that the
      distance from the sternal angle to the level of the mid-right atrium be known.
      Classical clinical teaching quotes this distance as 5 cm, invariable between
      patients, and invariable with changes in the elevation of the patient's head. The
      validity of these JVP characteristics has been questioned. OBJECTIVES: To measure
      the distance from the sternal angle to the level of the mid-right atrium (SA-RA)
      and determine if the SA-RA distance varies with patient position. METHODS: Cross
      sectional study conducted at a single-center teaching hospital on ambulatory
      patients undergoing computed tomography of the chest. RESULTS: One hundred sixty
      patients were included. The median SA-RA distance with the patient lying supine
      was 5.4 cm (interquartile range, 4.7 to 6.1). Using geometric calculations to
      estimate the SA-RA distance when the patient's torso was elevated above the
      supine position, the median SA-RA distance was calculated to be 8 cm, 9.7 cm, and
      9.8 cm at 30, 45, and 60 degrees elevation respectively. The SA-RA distance
      varied extensively between patients and was independently associated with
      smoking, age, and antero-posterior chest diameter. CONCLUSIONS: The distance from
      the sternal angle to the level of the mid-right atrium varies considerably
      between individuals and with patient position. When using the JVP to calculate
      the CVP, physicians need to consider specific patient factors and the patient's
      position.

PMID- 12406358
TI  - Impoverished diabetic patients whose doctors facilitate their participation in
      medical decision making are more satisfied with their care.
AB  - OBJECTIVE: Greater participation in medical decision making is generally
      advocated for patients, and often advocated for those with diabetes. Although
      some studies suggest that diabetic patients prefer to participate less in
      decision making than do healthy patients, the empirical relationship between such
      participation and diabetic patients' satisfaction with their care is currently
      unknown. We sought to characterize the relationship between aspects of diabetic
      patients' participation in medical decision making and their satisfaction with
      care. DESIGN: Cross-sectional observational study. SETTING: A general medical
      county hospital-affiliated clinic. PARTICIPANTS: One hundred ninety-eight
      patients with type 2 diabetes. MAIN MEASURES: Interviews conducted prior to the
      doctor visit assessed patients' desire to participate in medical decision making,
      baseline satisfaction (using a standardized measure), and sociodemographic and
      clinical characteristics. Postvisit interviews of those patients assessed their
      visit satisfaction and perception of their doctor's facilitation of patient
      involvement in care. A discrepancy score was computed for each subject to reflect
      the difference between the previsit stated desire regarding participation and the
      postvisit report of their experience of participation. RESULTS: Overall, patients
      reported low postvisit satisfaction relative to national standards (mean of 70 on
      a 98-point scale). Patients perceived a high level of facilitation of
      participation (mean 88 on a 100-point scale). Facilitation of participation and
      the discrepancy score both independently predicted greater visit satisfaction. In
      particular, a 13-point (1 SD) increase in the perceived facilitation score
      resulted in a 12-point (0.87 SD) increase in patient satisfaction, and a 1.22
      point increase (1 SD) in the discrepancy score (the extent to which the patient
      was allowed more participation than, at previsit, he or she desired) resulted in
      a 6-point (0.5 SD) increase in the satisfaction score, even after controlling for
      initial desire to participate. For women, but not for men, physician facilitation
      of participation was a positive predictor of satisfaction; for men, but not
      women, desire to participate was a significant positive predictor of visit
      satisfaction. CONCLUSION: Clinicians may feel reassured that encouraging even
      initially reluctant patients with diabetes to participate in medical decision
      making may be associated with increased patient satisfaction. Greater patient
      participation has the potential to improve diabetic self-care because of the
      likely positive effect of patient satisfaction on adherence to treatment. Further
      research to assess the prospective effects of enhancing physician facilitation of
      patient participation is likely to yield important information for the effective
      treatment of chronically ill patients.

PMID- 12406359
TI  - Black-white differences in severity of coronary artery disease among individuals
      with acute coronary syndromes.
AB  - OBJECTIVE: To determine whether the extent of coronary obstructive disease is
      similar among black and white patients with acute coronary syndromes. DESIGN:
      Retrospective chart review. PATIENTS: We used administrative discharge data to
      identify white and black male patients, 30 years of age or older, who were
      discharged between October 1, 1989 and September 30, 1995 from 1 of 6 Department
      of Veterans Affairs (VA) hospitals with a primary diagnosis of acute myocardial
      infarction (AMI) or unstable angina (UnA) and who underwent coronary angiography
      during the admission. We excluded patients if they did not meet standard clinical
      criteria for AMI or UnA or if they had had prior percutaneous transluminal
      coronary angioplasty or coronary artery bypass grafting. MEASUREMENTS AND MAIN
      RESULTS: Physician reviewers classified the degree of coronary obstruction from
      blinded coronary angiography reports. Obstruction was considered significant if
      there was at least 50% obstruction of the left main coronary artery, or if there
      was 70% obstruction in 1 of the 3 major epicardial vessels or their main
      branches. Of the 628 eligible patients, 300 (48%) had AMI. Among patients with
      AMI, blacks were more likely than whites to have no significant coronary
      obstructions (28/145, or 19%, vs 10/155 or 7%, P =.001). Similarly, among
      patients with UnA, 33% (56/168) of blacks but just 17% (27/160) of whites had no
      significant stenoses (P =.012). There were no racial differences in severity of
      coronary disease among veterans with at least 1 significant obstruction. Racial
      differences in coronary obstructions remained after correcting for coronary
      disease risk factors and characteristics of the AMI. CONCLUSIONS: Black veterans
      who present with acute coronary insufficiency are less likely than whites to have
      significant coronary obstruction. Current understanding of coronary disease does
      not provide an explanation for these differences.

PMID- 12406360
TI  - The sociophysiology of caring in the doctor-patient relationship.
AB  - The emotional investment required to construct a caring doctor-patient
      relationship can be justified on humane grounds. Can it also be justified as a
      direct physiologic intervention? Two lines of evidence point in this direction.
      People in an empathic relationship exhibit a correlation of indicators of
      autonomic activity. This occurs between speakers and responsive listeners,
      members of a coherent group, and bonded pairs of higher social animals.
      Furthermore, the experience of feeling cared about in a relationship reduces the
      secretion of stress hormones and shifts the neuroendocrine system toward
      homeostasis. Because the social engagement of emotions is simultaneously the
      social engagement of the physiologic substrate of those emotions, the process has
      been labeled sociophysiology. This process can influence the health of both
      parties in the doctor-patient relationship, and may be relevant to third parties.

PMID- 12406361
TI  - Five uneasy pieces about pre-test probability.

PMID- 12406362
TI  - Dreaded conversations: moving beyond discomfort in patient-physician
      communication.

PMID- 12406363
TI  - Sexological approach to ejaculatory dysfunction.
AB  - Ejaculatory disorders include premature, deficient (delayed ejaculation and
      anejaculation) and retrograde ejaculation. A rare symptom connected to
      ejaculatory disorders is male anorgasmia. In the past, ejaculatory disorders were
      considered as typical relational and psychological symptoms. For this reason, a
      number of behavioural and psycho-relational approaches have flourished from the
      first ideas of curing sexual problems with empirical therapy, focusing on the
      symptoms of sexual pathology. Such treatment includes assessment, behavioural and
      educational components, psychotherapy in the context of the relationship and
      sexual timetables. Recent advances in understanding the importance and frequency
      of ejaculatory disorders, insights into their organic and non-organic
      pathophysiology and the efficacy of a growing arsenal of pharmacological
      therapies lead to a new challenge which can be confronted only with the
      development of new, integrated therapeutic alternatives from a modern somato
      psychic and holistic viewpoint.

PMID- 12406364
TI  - Penile vibratory stimulation and electroejaculation in the treatment of
      ejaculatory dysfunction.
AB  - The purpose of this review is to present the current understanding of penile
      vibratory stimulation (PVS) and electroejaculation (EEJ) procedures and its
      clinical use in men with ejaculatory dysfunction. Unfortunately, the record of
      treating such individuals has been quite poor, but within recent years
      development and refinement of PVS and EEJ in men with spinal cord injury (SCI)
      has significantly enhanced the prospects for treatment of ejaculatory
      dysfunction. The majority of spinal cord injured men are not able to produce
      antegrade ejaculation by masturbation or sexual stimulation. However,
      approximately 80% of all spinal cord injured men with an intact ejaculatory
      reflex arc (above T10) can obtain antegrade ejaculation with PVS.
      Electroejaculation may be successful in obtaining ejaculate from men with all
      types of SCI, including men who do not have major components of the ejaculatory
      reflex arc. Because vibratory stimulation is very simple in use, non-invasive, it
      does not require anaesthesia and is preferred by the patients when compared with
      EEJ, PVS is recommended to be the first choice of treatment in spinal cord
      injured men. Furthermore, EEJ has been successfully used to induce ejaculation in
      men with multiple sclerosis and diabetic neuropathy. Any other conditions which
      affect the ejaculatory mechanism of the central and/or peripheral nervous system
      including surgical nerve injury may be treated successfully with EEJ. Finally,
      for sperm retrieval and sperm cryopreservation before intensive anticancer
      therapy in pubertal boys, PVS and EEJ have been successfully performed in
      patients who failed to obtain ejaculation by masturbation. Nearly all data
      concerning semen characteristics in men with ejaculatory dysfuntion originate
      from spinal cord injured men. Semen analyses demonstrate low sperm motility rates
      in the majority of spinal cord injured men. The data give evidence of a decline
      in spermatogenesis and motility of ejaculated spermatozoa shortly after (few
      weeks) an acute SCI. Furthermore, it is suggested that some factors in the
      seminal plasma and/or disordered storage of spermatozoa in the seminal vesicles
      are mainly responsible for the impaired semen profiles in men with chronic SCI.
      Home insemination with semen obtained by penile vibratory and introduced
      intravaginally in order to achieve successful pregnancies may be an option for
      some spinal cord injured men and their partners. The majority of men will further
      enhance their fertility potential when using either penile vibratory or EEJ
      combined with assisted reproduction techniques such as intrauterine insemination
      or in-vitro fertilization with or without intracytoplasmic sperm injection.

PMID- 12406365
TI  - Update on medical treatment of ejaculatory disorders.
AB  - Among the treatment modalities for ejaculatory disorders pharmacological
      treatment is the least invasive option. In this review, medical treatments for
      retrograde ejaculation (RE) and anejaculation (AE) are discussed systematically.
      Thirty-six studies dealing with patients with RE and 40 with AE evaluated the use
      of medical treatment and were included in this review. In addition four articles
      dealing with prostatic massage in anejaculatory patients were considered. Sperm
      quality in patients with retrograde and AE is often impaired. In patients with RE
      no differences in response to medical treatment could be detected between the
      different underlying diagnoses. Compared with ephedrine, imipramine and
      chlorpheniramine + phenylpropanalamine showed significantly higher reversal
      rates, while differences between the other treatments were not significant.
      Regarding the reversal of AE, the alpha agonistic drugs were significantly
      inferior to treatment with parasympathetic drugs. Of the different alpha
      agonistic medical treatments for the reversal of AE, milodrin showed
      significantly better rates than imipramine (p = 0.008), pseudoephidrine (p =
      0.02) and ephedrine (p = 0.044), while all other treatments were not
      significantly different (p = 0.4). In conclusion, medical treatment for reversal
      of RE offers a realistic chance of conceiving offspring naturally and should be
      the treatment modality of first choice. In contrast, in AE, medical treatment
      cannot be recommended generally as treatment of first choice as it shows low
      overall success rates compared with electrovibration stimulation and
      electroejaculation. Under consideration of the mostly uncontrolled design of the
      majority of studies published, controlled clinical trials comparing different
      treatment options appear urgently warranted.

PMID- 12406366
TI  - Seminal plasma androgen/oestrogen balance in infertile men.
AB  - The hypothesis that the balance between oestrogen and androgen in seminal plasma
      is important for normal fertility was investigated. We determined the
      concentrations of oestradiol and testosterone in blood and seminal plasma from 62
      infertile men and 32 normozoospermic men. Infertile men were classified according
      to semen analysis (concentration, motility and morphology): asthenozoospermia,
      oligozoospermia and oligoteratoasthenozoospermia. Serum luteinizing hormone (LH)
      and follicle-stimulating hormone (FSH) were determined in all participants. For
      all subjects, mean testosterone levels were lower and mean oestradiol were higher
      in seminal plasma than in blood. Seminal plasma testosterone levels were lower in
      the infertile groups vs. control men ( p < 0.0002). Oligpzoospermic and
      oligoteratoasthenozoospermic men had significantly higher seminal plasma
      oestradiol levels compared with controls ( p < 0.03). The three infertile groups
      had significantly lower seminal plasma testosterone/oestradiol ratio than control
      men ( p < 0.001). Sperm analysis data (concentration, motility and morphology)
      significantly correlated with seminal plasma testosterone/oestradiol ratio. The
      findings of elevated seminal plasma oestradiol, decreased testosterone and
      testosterone/oestradiol ratio in infertile men, and the significant correlation
      between hormone levels and sperm analysis data suggest that the local balance
      between androgen and oestrogen is important for spermatogenesis.

PMID- 12406367
TI  - False-positive Y-microdeletion result for a fertile male caused by an alteration
      under a PCR primer.
AB  - The pathogenic relationship between the presence of Y chromosomal microdeletions
      and male infertility is unclear. Nevertheless, a causal relationship is thought
      to be probable when loci are shown to be deleted in infertile males but are
      present in fertile males. Polymerase chain reaction (PCR) analysis of the Y
      chromosome is now routinely performed in the evaluation of the infertile male,
      although, until recently, there has been no consensus on how the diagnosis should
      be performed and which loci or markers should be analysed. The European Academy
      of Andrology (EAA) published guidelines for the molecular diagnosis of Y
      chromosomal microdeletions in 1999. Following these guidelines, our laboratory
      developed assays that incorporated the suggested primer pairs for the recommended
      Sequence Tagged Sites (STS). A number of fertile (n = 117), infertile (n = 17)
      and unknown samples (n = 20) were tested in our laboratory as part of the
      validation to provide a clinical assay. Two multiplex PCR assays were optimized,
      each of which examined STS markers in the centre of the AZFa, b and c regions of
      the Y chromosome. We correctly identified all but one of the 154 samples
      (according to the expected result based on fertility or previous testing at
      another laboratory). A single equivocal result was observed for a sample obtained
      from a known fertile male who appeared to be deleted for a single marker, sY84,
      in the AZFa region but not the adjacent marker, sY86. Follow-up analysis showed
      that proximal and distal markers within the same region (sY82 and sY98) were also
      present. Sequencing the region flanking and including the sY84 primer set
      revealed a single base alteration under the reverse primer, which probably caused
      the amplification failure. Furthermore, the sY84 sequence itself was present, as
      was the flanking sequence 50 bp on either side of both primers. This observation
      underlines the importance of using at least two closely linked STS markers for
      the reliable diagnosis of Y chromosome microdeletions as proposed by the EAA
      guidelines.

PMID- 12406368
TI  - Characterization of the fertility of Kit haplodeficient male mice.
AB  - The role of the proto-oncogene Kit expression during gonadal development, then in
      differentiated spermatogonia has been thoroughly established. The present study
      was designed to investigate the consequences of a partial defect in Kit gene
      expression on sperm fertilizing ability, using Kit haplodeficient mice (kitW
      lacZ/+). Same inbred mice (kit+/+) were used as controls. Epididymal sperm
      characteristics and in vivo fertility were assessed, then in vitro-fertilization
      experiments were carried out for mice of both genotypes. Epididymal sperm count
      was drastically reduced, and sperm motility was also decreased in kitW-lacZ/+
      compared with kit+/+ males. Both in vivo or in vitro fertility were greatly
      reduced in kitW-lacZ/+ compared with kit+/+ males. By contrast, the fertility of
      kitW-lacZ/+ females was apparently unaffected. Additionally, a higher number of
      spermatozoa with undetected acrosomal contents was revealed by fluorescein
      isothiocyanate-labelled Pisum sativum agglutinin acrosomal staining after
      epididymal sperm retrieval in kitW-lacZ/+ mice, whereas no difference was
      observed after induction of acrosomal reaction in mice of either genotype. Ultra
      structural data confirmed the higher frequency of abnormal acrosome in
      spermatozoa of kitW-lacZ/+ mice. Thus, sperm production is impaired in Kit
      haplodeficient mice both on a quantitative and a qualitative basis. Finally, we
      show that one single copy of Kit gene is not sufficient to maintain genuine
      fertility in male mice.

PMID- 12406369
TI  - Tissue inhibitors of metalloproteinases 1 and 2 in human seminal plasma and their
      association with spermatozoa.
AB  - A 24-kDa heparin binding protein recently identified as tissue inhibitor of
      matrix metalloproteinases 2 (TIMP-2) in bovine seminal fluid was suggested to
      play an important role in bull fertility. As no data are present for men, the
      concentrations of tissue inhibitors of metalloproteinases 1 (TIMP-1) and TIMP-2
      were quantified in human seminal plasma of normozoospermic and azoospermic men
      using enzyme-linked immunosorbent assay methods. TIMP-1 and 2 were not
      significantly different in both groups and there were no relationships between
      the concentrations of both TIMPs and other sperm characteristics. It is assumed
      that TIMPs are released from accessory sex glands.

PMID- 12406370
TI  - Research of single mitochondrial nucleotide substitutions in male infertility
      should consider human mitochondrial haplogroups.

PMID- 12406373
TI  - Effect of IL-1ra on human dental pulp cells and pulpal inflammation.
AB  - AIM: This study was conducted to investigate the effect of interleukin-1 receptor
      antagonist (IL-1ra) on the LPS-induced interleukin-1beta (IL-1beta) synthesis in
      human dental pulp cells and to assess the role of IL-1ra in pulpal inflammation.
      METHODS: IL-1beta from human dental pulp cells (HDP) was measured by sandwich
      ELISA; IL-1ra expression in pulpal tissue was detected by immunohistochemical
      staining. RESULTS: Stimulation of HDP with increasing concentrations of FnLPS
      resulted in dose-dependent IL-1beta production. The addition of IL-1ra reduced
      FnLPS-induced IL-1beta synthesis in human dental pulp cells. Significant
      inhibition of the FnLPS-induced IL-1beta synthesis was observed when IL-1ra was
      added before treating with FnLPS for 60 min. Large numbers of IL-1ra positive
      neutrophils, plasmacytes, endothelial cells and lymphocytes were observed in
      inflamed pulp tissue. CONCLUSIONS: IL-1ra could reduce LPS-stimulated IL-1beta
      synthesis, suggesting that IL-1ra may play a role in pulpitis.

PMID- 12406374
TI  - Patients' attitudes to rubber dam.
AB  - AIM: The aims of this study were to record patients' views of their experience of
      RD use in an objective manner, and to evaluate the influence of some personal and
      clinical factors on patients' opinion. METHODOLOGY: A questionnaire was designed
      which was then distributed to patients receiving dental treatment under RD by (a)
      final-year dental students at Birmingham Dental School, and (b) general dental
      practitioners. Patients completed the confidential questionnaire anonymously
      after treatment, outside the treatment room. After 100 correctly completed forms
      were collected from group (a) and 106 from group (b), data were entered into a
      database and subsequently analyzed using SPSS. Analyses were confined to simple
      cross-tabulations of the patients' responses and potential associated factors,
      with chi-square analysis and appropriate follow-up comparisons wherever
      necessary. RESULTS: In both groups, the majority of patients said they would
      prefer RD to be used at their next appointment, and most had a positive opinion
      of the experience. No statistically significant association between age, sex,
      procedure, application time or duration of use and preference for rubber dam was
      found. Prolonged RD use showed some association with a negative opinion of the
      experience of RD. Compared with the dentists, students took longer to apply
      rubber dam and it was in place for longer. Fewer student patients preferred RD
      next time, and were less positive about its use than the dentists' patients.
      CONCLUSIONS: Further evidence is presented that (i) Patients generally are not
      averse to RD. (ii) Placement of rubber dam does not take long. (iii) Operator
      experience improves patient compliance.

PMID- 12406375
TI  - Smooth flexible versus active tapered shaft design using NiTi rotary instruments.
AB  - AIM: The aim of this study was to evaluate the influence of a smooth flexible
      versus active tapered shaft design on canal preparation by NiTi rotary
      techniques. METHODOLOGY: A XMCT-scanner (SkyScan 1072) and developed software
      (Bergmans et al. 2001) were used to nondestructively analyze the mesial canals of
      10 extracted mandibular molars in 3D with a spatial resolution of 30 microm.
      Specimens (n = 10 per group) were scanned before (PRE) and after (POST)
      preparation using Lightspeed (smooth flexible) or GT-rotary (active tapered)
      files. Numerical values for volumes, dentine removal (net) transportation and
      centring ability were obtained in addition to a visual inspection on canal
      aberrations. Data were analyzed by Shapiro Wilk test, multiway factorial anova,
      Tukey-Kramer test, Wilcoxon test and t-test. RESULTS: Results indicated that the
      active tapered shaft removed significantly more dentine in the middle to apical
      portion of the root compared to the smooth flexible design. Both groups
      demonstrated some straightening, but no significant differences were found with
      respect to instrument types. However, absolute values for net transportation and
      centering ratio were small and no canal aberrations could be found. CONCLUSIONS:
      The smooth flexible shaft design did not improve the morphological
      characteristics of canal preparation by NiTi rotary instruments when compared
      with the active tapered design. Therefore, system selection should be based upon
      other criteria.

PMID- 12406376
TI  - Is pulpitis painful?
AB  - AIM: To determine whether inflamed dental pulps progress to necrosis without
      pain. METHODOLOGY: Records of 2,202 maxillary anterior teeth endodontically
      treated at the University of Michigan were collected. Records of teeth presenting
      with periapical radiolucencies but no response to vitality tests were examined
      further to determine, from the history, whether the patient had experienced pain
      or no pain from the involved tooth. RESULTS: Approximately 40% of the teeth
      included gave no history of spontaneous or prolonged pain to a thermal stimulus.
      No statistically significant differences in the incidence of 'painless pulpitis'
      were related to either gender or tooth type. Patients aged >53 years experienced
      'painless pulpitis' more often than patients <33 years. CONCLUSIONS: Many teeth
      appear to progress to pulpal necrosis without the patient experiencing pain
      attributable to the pulp.

PMID- 12406377
TI  - Micro-tensile bond strengths of bonding agents to pulpal floor dentine.
AB  - AIM: The purpose of this study was to characterize the dentine surface of the
      pulpal floor and to determine the micro-tensile bond strengths of two dentine
      adhesive systems used in conjunction with a resin composite core material to
      pulpal floor dentine. METHODOLOGY: Thirty-six extracted human molars were cut
      horizontally with a slow-speed diamond saw to expose the pulp chamber and the
      pulp tissue was removed. Eight teeth were used to investigate characteristics of
      untreated and etched dentine surfaces of the pulpal floor using SEM. Twenty-eight
      teeth were randomly allocated to two groups, each of 14 teeth. In group 1, a 'one
      bottle' system (Prime & Bond NT) was used as dentine bonding agent and in group
      2, a self-etching-priming system (Clearfil SE Bond) was applied. Pulp chambers of
      both groups were then filled with resin composite core buildup (FluoroCore) and
      kept moist in tap water at 37 degrees C for 24 h. Samples were prepared for micro
      tensile bond testing by sectioning each tooth vertically in the mid-pulpal floor
      region and shaped to an hour-glass form of 1 +/- 0.2 mm(2) area at the bonded
      interface. Micro-tensile bond strengths were determined using a universal testing
      machine at a crosshead speed of 1 mm min-1. Fractured surfaces were examined by
      SEM. RESULTS: The intact pulpal floor showed numerous calcospherites with
      variable tubule density and few accessory canals. Etching the pulpal floor with
      34% phosphoric acid gel resulted in an irregular surface with patent dentinal
      tubules and the dome-shaped calcospherites mostly lost. With self-etching primer,
      the superficial dentine surface was less demineralized and little peritubular
      dentine matrix was removed. Mean bond strength for the self-etching-priming
      (Clearfil SE Bond) specimens was significantly greater than for 'one-bottle'
      (Prime & Bond NT) specimens (P< 0.05, Student's t-test). The fracture mode of
      Clearfil SE Bond specimens was mostly partial cohesive failure within dentine,
      whilst Prime & Bond NT specimens mostly showed partial cohesive failure in
      bonding resin/composite. CONCLUSIONS: Despite an irregular surface morphology and
      absence of a smear layer, bonding to pulpal floor dentine was weaker than
      previously reported for cut coronal dentine. The self-etching-priming system
      bonded more strongly than the 'one-bottle' system.

PMID- 12406378
TI  - Comparison of Diaket and MTA when used as root-end filling materials to support
      regeneration of the periradicular tissues.
AB  - AIM: The objective of this study was to evaluate on a comparative basis the
      potential for mineral trioxide aggregate (MTA) and Diaket to promote
      periradicular tissue regeneration when used as surgical root-end filling
      materials. METHODOLOGY: Seven dogs weighing between 15 and 25 kg were
      anesthetized prior to having the root canals of their mandibular premolars
      accessed, cleaned, shaped and obturated. Coronal access cavities were restored
      with IRM. Surgical access to the root ends was established and the root ends were
      resected and prepared with ultrasonic tips. Root-end fillings of either MTA or
      thickly mixed Diaket were randomly assigned to the preparations. Reflected
      tissues were repositioned and sutured with 4-0 vicryl sutures. Sixty days
      postsurgery, the animals were killed, perfused with 10% neutral buffered formalin
      and the third and fourth premolars removed in block sections. The specimens were
      demineralized and sectioned at 6-microm intervals for histological assessment.
      Sections were stained with either haematoxylin and eosin or Gomori's one step
      trichrome stain and examined under the light microscope. All evaluations were
      made by two calibrated examiners and gradings were scored based on established
      criteria. The raw data was evaluated statistically using anova after adjusting
      for the animal block effect. RESULTS: Statistical evaluation indicated that there
      were no statistical differences between the observed regenerative responses of
      the tissues to the two root-end filling materials. CONCLUSIONS: Both Diaket and
      MTA can support almost complete regeneration of the periradicular periodontium
      when used as root-end filling materials in periradicular surgery on noninfected
      teeth.

PMID- 12406379
TI  - Surface analysis of ProFile instruments by scanning electron microscopy and X-ray
      energy-dispersive spectroscopy: a preliminary study.
AB  - AIM: The purpose of this preliminary study was to analyze surface irregularities
      on ProFile nickel-titanium (NiTi) rotary instruments before use, after
      sterilization by two different methods and after instrumentation of molar root
      canals. METHODOLOGY: Five new ProFile NiTi rotary instruments with 0.04 taper,
      size 20, five instruments with 0.04 taper, size 25 and five with 0.06 taper, size
      20 were analyzed by scanning electron microscopy (SEM) and X-ray energy
      dispersive spectroscopy (EDS). The instruments were then divided into two groups:
      three of each taper and size were sterilized in a dry heat sterilizer, whilst two
      of each taper and size were sterilized in an autoclave. After inspection by the
      same techniques, the files were used to instrument six molar root canals, and
      again analyzed by SEM/EDS. RESULTS: Together with the usual machining defects, a
      variable amount of material containing mainly carbon and sulphur was found on the
      surface of new instruments. This material was not removed by standard cleaning
      and sterilization procedures. The use of the files for instrumentation of root
      canals eliminated a considerable amount of the adhered substance, but deposits
      rich in calcium and phosphorus accumulated on the remaining impurities.
      CONCLUSIONS: The adherence of dentine on surface deposits found on new ProFile
      instruments requires special cleaning, prior to sterilization.

PMID- 12406380
TI  - Immunohistochemical localization of cyclooxygenase-2 in radicular cysts.
AB  - AIM: The purpose of this study was to investigate the expression of
      cyclooxygenase-2 (COX-2) in radicular cysts. METHODOLOGY: Thirty biopsy specimens
      of radicular cysts were examined using immunohistochemistry. A peroxidase
      labelled streptavidin-biotin technique was used for identification of the COX-2.
      Fisher's exact test (two-tail) was used for statistical analysis of the results.
      RESULTS: The result demonstrated that COX-2 expression was significantly higher
      in radicular cysts with higher levels of inflammatory infiltrates. COX-2 stain
      was detected in the lining epithelium, subepithelial fibroblasts, macrophages and
      endothelial cells in all specimens. CONCLUSIONS: COX-2 expression is
      significantly higher in radicular cysts. COX-2 may play an important role in the
      pathogenesis of radicular cysts.

PMID- 12406381
TI  - The effects of dentine pretreatment on the adhesion of root-canal sealers.
AB  - AIM: The adhesion of five root-canal sealers to dentine and gutta-percha was
      studied. The effects of various dentine pretreatments on adhesion were also
      investigated. METHODOLOGY: Root dentine cylinders, 4 mm in diameter, were
      prepared from human teeth. The dentine surfaces were conditioned with either 37%
      H(3)PO(4) for 30 s, 25% citric acid for 30 s, 17% EDTA for 5 min or a rinse with
      10 mL distilled water (control). Gutta-percha cylinders, 4 mm in diameter, were
      prepared and their end surfaces polished flat. The dentine and gutta-percha
      surfaces were coated with freshly mixed sealer: Grossman's sealer (GS), Apexit
      (AP), Ketac-Endo (KE), AH Plus (AH), RoekoSeal Automix (RS) or RoekoSeal Automix
      with an experimental primer (RP). The surfaces were pressed together and the
      sealers allowed to set. The test specimens were subjected to a tensile force in a
      universal testing machine. RESULTS: Mean tensile bond strengths (MPa +/- SD)
      ranged from 0.07 +/- 0.01 (AP) to 1.19 +/- 0.47 (AH). Pretreatment with EDTA
      showed no effect or produced weaker bonds than controls. Phosphoric and citric
      acid pretreatments increased adhesion of GS. A primer used with RoekoSeal
      significantly enhanced its adhesion to untreated dentine. Inspection of fractured
      surfaces indicated failure of adhesion to dentine for GS and RS and to gutta
      percha for KE and RP. The failure appeared to be mainly cohesive within the
      sealer for AH and AP. CONCLUSIONS: Removal of the smear layer may impair sealer
      adhesion to dentine. Different sealer types require different dentine
      pretreatments for optimal adhesion.

PMID- 12406382
TI  - Effect of sterilization on the cutting efficiency of PVD-coated nickel-titanium
      endodontic instruments.
AB  - AIM: To investigate alterations in cutting efficiency when conventional and
      titanium nitride (TiN) coated nickel-titanium (NiTi) K-files were exposed to
      repeated sterilization using an autoclave. METHODOLOGY: A total of 96 NiTi K
      files (size 35) were randomly divided into two groups (A and B) of 48 instruments
      each. Whilst the instruments of group B were exposed to physical vapour
      deposition (PVD) creating a coating of a TiN layer, the files of group A were not
      coated. The instruments of groups A and B were randomly divided into four
      subgroups of 12 instruments each. A.1/B.1: Instruments were exposed to five
      cycles of sterilization. A.2/B.2: Instruments were exposed to 10 cycles of
      sterilization. A.3/B.3: Instruments were immersed in NaOCl for 30 min, rinsed in
      water, and exposed to five cycles of sterilization. A.C/B.C: Instruments were not
      sterilized (controls). The cutting efficiency of all files was determined by
      means of a computer-driven testing device. Special plastic samples with
      cylindrical canals were used and the maximum penetration depth of the files into
      the lumen was assessed. RESULTS: The TiN-coated instruments of groups B.1, B.2
      and B.3 showed no significant difference in comparison with the penetration
      depths of the controls (P> 0.05). The uncoated files of groups A.1, A.2 and A.3
      displayed significantly lower maximum penetration depths (P< 0.05) when compared
      to the control files. CONCLUSIONS: Repeated sterilization under autoclave or
      exposure to sodium hypochlorite (NaOCl) prior to sterilization did not alter the
      cutting efficiency of PVD-coated NiTi K-files.

PMID- 12406383
TI  - Dens invaginatus type III: report of a case and 10-year radiographic follow-up.
AB  - AIM: The purpose of this article is to report the 10-year follow-up of a right
      mandibular central incisor with 'dens invaginatus' that was root filled. SUMMARY:
      'Dens invaginatus' is a rare malformation of teeth, probably resulting from an
      infolding of the dental papilla during tooth development. It has alternatively
      been called 'dens in dente' and 'dilated composite odontome'. Radiographic
      examination may clearly demonstrate this feature, although no signs may be
      recognized clinically. If no entrance to the invagination can be detected and
      there are no signs of pulp pathosis, then no treatment is required other than
      fissure sealing of the invagination. In deep invaginations, it is likely that
      root-canal treatment may be required. Occasionally, when the tooth has an
      immature root, apexification is necessary. Root-canal treatment of a right
      mandibular central incisor with 'dens invaginatus' is described along with 10
      year follow-up. KEY LEARNING POINTS: Both clinical and radiographic examinations
      are necessary to determine morphological features of teeth before root-canal
      treatment. Sensibility testing to determine the pulp condition is critical prior
      to treatment.

PMID- 12406384
TI  - Induction of immune tolerance by dendritic cells: implications for preventative
      and therapeutic immunotherapy of autoimmune disease.
AB  - Dendritic cells (DC) have a key role in controlling the immune response, by
      determining the outcome of antigen presentation to T cells. Through costimulatory
      molecules and other factors, DC are involved in the maintenance of peripheral
      tolerance through modulation of the immune response. This modulation occurs both
      constitutively, and in inflammation, in order to prevent autoimmunity and to
      control established immune responses. Dendritic cell control of immune responses
      may be mediated through cytokine or cell-contact dependent mechanisms. The
      molecular and cellular basis of these controls is being understood at an
      increasingly more complex level. This understanding is reaching a level at which
      DC-based therapies for the induction of immune regulation in autoimmunity can be
      tested in vivo. This review outlines the current state of knowledge of DC in
      immune tolerance, and proposes how DC might control both T cell responses, and
      themselves, to prevent autoimmunity and maintain peripheral tolerance.

PMID- 12406385
TI  - Dendritic cells: making progress with tumour regression?
AB  - Due to their potent ability to activate the immune system, dendritic cells (DC)
      are showing promise as potential adjuvants for tumour immunotherapy of cancer
      patients. However, little is known about the effect tumour cells can have on DC
      function. Indeed, the discovery of different DC subsets with different
      immunological functions indicates that the relationship between tumour cells and
      tumour-infiltrating DC subtypes is likely to be complex. There remains a lot to
      be understood about the effects of tumours on DC before we can expect to benefit
      from DC-based tumour immunotherapy of cancer patients. Here we review the recent
      advances being made in understanding DC phenotype and function in relation to
      interactions with different types of tumours.

PMID- 12406387
TI  - Up-regulation of production of TGF-beta and IL-4 and down-regulation of IL-6 by
      apoptotic human bronchial epithelial cells.
AB  - Human bronchial epithelial cells secrete cytokines that play a role in immune
      responses in the lung. However, the roles of these cytokines in regulating
      epithelial repair following acute lung injury are largely unknown. Responses to
      injury include hyperplasia of epithelial cells and squamous metaplasia. The
      resolution stage is characterized by discontinuation of hyperplasia. Apoptosis is
      considered to be the most efficient mechanism of removal of unwanted cells
      without causing inflammation. The presence of TGF-beta1 increases apoptosis,
      induces squamous metaplasia and inhibits proliferation of airway epithelial
      cells. Interleukin-4 increases the ability of macrophages to phagocytose
      epithelial cells and produce inflammatory cytokines. The purpose of this study
      was to investigate the hypothesis that apoptotic lung epithelial cells produce
      cytokines, which could act in an autocrine manner to control hyperplasia and
      induce squamous differentiation following acute lung injury. A bronchial
      epithelial cell line (16 HBE) was used as an in vitro model, to study the
      production of TGF-beta, IL-4 and IL-6 by lung epithelial cells undergoing
      apoptosis. Apoptotic and live cells were sorted on the basis of bright and
      negative staining with FITC-conjugated Annexin V, respectively. Intracellular IL
      6, TGF-beta and IL-4 was measured using flow cytometric techniques. Electron
      microscopy, immunohistochemistry and ELISA were used as supportive techniques.
      Apoptotic cells produced significantly more TGF-beta and IL-4 (but less IL-6)
      than viable cells. Increased production of TGF-beta and IL-4 by epithelial cells
      undergoing apoptosis may contribute to the inhibition of proliferation, squamous
      metaplasia, and reduction of the inflammatory response in acute lung injury.

PMID- 12406386
TI  - 15-Deoxy-D12,14-prostaglandin J2 inhibits CX3CL1/fractalkine expression in human
      endothelial cells.
AB  - Peroxisome proliferator-activated receptor-gamma (PPAR-gamma)is a member of
      nuclear hormone receptor superfamily, and is knownto play a role in various
      biological processes including inflammatoryresponses and adipocyte
      differentiation. CX3CL1/fractalkineis a potent agonist for chemotaxis and
      adhesion of monocytes and lymphocytes. Endothelial cells produce fractalkine when
      stimulated with cytokinessuch as interleukin-1 (IL-1), tumour necrosis factor
      alpha andinterferon-gamma (IFN-gamma). We herein report that 15-deoxy-n12,14 
      prostaglandinJ2 (15d-PGJ2), a PPAR-gamma agonist,inhibits the expression of
      fractalkine induced by IFN-gamma orIL-1beta in human endothelial cells. Agonist
      for PPAR-alpha (WY14643)or PPAR-gamma (ciglitazone) did not inhibit the cytokine
      inducedfractalkine expression, and the effect of 15d-PGJ2 maybe independent of
      PPAR. 15-Deoxy-D12,14 prostaglandinJ2 also inhibited the adhesion of blood
      mononuclear cellsto endothelial monolayers treated with IFN-gamma or IL-1beta.
      The data suggest that 15d-PGJ2 regulates inflammatoryreactions, at least in part,
      through the inhibition of fractalkineexpression and leucocyte traffic through the
      endothelium.

PMID- 12406388
TI  - Characterization of immune responses during infection with Mycobacterium avium
      strains 100, 101 and the recently sequenced 104.
AB  - Mycobacterium avium strain 104 was chosen as the M. avium isolate to sequence, as
      it is virulent to humans, stable and readily transfectable. As this strain has
      not been widely studied we sought to investigate the pattern of 104 infection in
      mice. Bacterial growth and the immune response generated were compared with
      infection with the low virulence M. avium strain 100, and the high virulence
      common laboratory strain, 101. Mycobacterium avium strains 104 and 101 grew
      progressively within mice, while strain 100 was gradually cleared. Strains 104
      and 101 induced strong T cell activation and spleen cell cultures produced
      similar levels of IFN-gamma. In mice infected with strain 100 no significant T
      cell activation or IFN-gamma production was measured. Further, mice infected with
      strain 104 or 101 also displayed comparable inflammatory responses and similar
      granuloma formation, while only minimal inflammation was seen in mice infected
      with strain 100. Strains 101 and 104 also grew in a similar fashion in bone
      marrow-derived macrophages and induced significant levels of TNF and nitric
      oxide. Thus infection with M. avium strain 104 induced an immunological response
      comparable to M. avium strain 101 and, with the availability of its sequence,
      should be a useful tool for designing new vaccines or drugs therapies to treat
      the increasing incidence of M. avium infection in humans.

PMID- 12406390
TI  - Binding of Tamm-Horsfall protein to complement 1q and complement 1, including
      influence of hydrogen-ion concentration.
AB  - The goal of this study was to further characterize the interaction between an
      abundant urinary glycoprotein, Tamm-Horsfall protein, and complement 1q to
      determine the robustness of this reaction under different environmental
      conditions (particularly pH) and to begin to determine the specificity of this
      reaction. The influence of pH coupled with ionic strength was evaluated with an
      ELISA that demonstrated immobilized Tamm-Horsfall protein bound complement 1q
      strongly with a KD in the nmol/L range from pH 9 to pH 5.5. Increasing the ionic
      strength from 10 mmol/L sodium chloride (NaCl) to 154 mmol/L NaCl decreased the
      affinity of Tamm-Horsfall protein for complement 1q slightly (2-7-fold) at pH 9
      to pH 6.5. A resonant mirror biosensor was also utilized to evaluate the binding
      of Tamm-Horsfall protein to complement 1q at different pH values (pH 8.2-5.8).
      These studies indicated that, compared to at pH 8.2, Tamm-Horsfall protein bound
      complement 1q at pH 5.8 with an almost two-fold higher affinity (pH 8.2, KD = 5.1
      nmol/L vs at pH 5.8, KD = 2.8 nmol/L) due to a faster association rate (pH 8.2
      kass = 1.6 x 106 L/mol per s vs pH 5.8 kass = 2.9 x 106 L/mol per s).
      Surprisingly, the capacity of Tamm-Horsfall protein for complement 1q decreased
      significantly at pH 5.8, suggesting that a site for complement 1q binding to Tamm
      Horsfall protein may be lost at the acidic pH. Biosensor studies also showed that
      Tamm-Horsfall protein bound the entire complement 1 complex with binding
      affinities and association rates similar to those obtained for complement 1q
      individually. This suggested that Tamm-Horsfall protein bound complement 1q at a
      site other than the region of its collagenous tail where C1r2 and C1s2 bind. By
      western blot analysis, it was demonstrated that Tamm-Horsfall protein bound
      preferentially to the C chain of complement 1q.

PMID- 12406389
TI  - Inhibition of LPS-induced nitric oxide and TNF-alpha production by alpha-lipoic
      acid in rat Kupffer cells and in RAW 264.7 murine macrophages.
AB  - The activation of Kupffer cells represents a central mechanism of inflammatory
      liver injury involving the production of two important inflammatory mediators,
      nitric oxide and TNF-alpha. The aim of this study was to investigate the effect
      of the hepatoprotective compound alpha-lipoic acid (thioctic acid) on the
      production of nitric oxide and TNF-alpha in isolated rat Kupffer cells and RAW
      264.7 macrophages. Isolated rat Kupffer cells or RAW 264.7 were either untreated,
      treated with alpha-lipoic acid (500 micro g/mL), or activated with 1 micro g/mL
      of lipopolysaccharide in the presence or absence of alpha-lipoic acid (0.2-500
      micro g/mL). After 20 h the accumulation of nitrite was measured by the Griess
      assay. Tumour necrosis factor-alpha secretion was quantified after 4 h by L929
      bioassay. Cell viability was determined by mitochondrial reduction of 3-(4,5
      dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) test, nuclear factor
      kappaB (NF-kappaB) and activator protein-1 (AP-1) DNA binding activity by
      gelshift assays. Treatment of Kupffer cells and RAW 264.7 with alpha-lipoic acid
      alone had no effect on basal nitric oxide production. However, alpha-lipoic acid
      significantly inhibited lipopolysaccharide-induced nitrite accumulation. alpha
      Lipoic acid did not alter basal TNF-alpha secretion in Kupffer cells, whereas it
      significantly inhibited lipopolysaccharide-induced TNF-alpha production. alpha
      Lipoic acid attenuated the activation of nuclear factor-kappaB and AP-1, two
      transcription factors pivotal in induction of inducible nitric oxide synthase and
      TNF-alpha. alpha-Lipoic acid significantly inhibits lipopolysaccharide-induced
      macrophage production of nitric oxide and TNF-alpha via an attenuated activation
      of NF-kappaB and activator protein-1. The reduced production of nitric oxide and
      TNF-alpha in Kupffer cells may be involved in the hepatoprotective action
      conveyed by alpha-lipoic acid.

PMID- 12406391
TI  - The role of CD4+CD25+ immunoregulatory T cells in the induction of autoimmune
      gastritis.
AB  - A number of experimental models of organ-specific autoimmunity involve a period
      of peripheral lymphopenia prior to disease onset. There is now considerable
      evidence that the development of autoimmune disease in these models is due to the
      absence of CD4+CD25+ regulatory T cells. However, the role of CD4+CD25+
      regulatory T cells in the prevention of autoimmune disease in normal individuals
      has not been defined. Here we have assessed the affect of depletion of CD4+CD25+
      regulatory T cells in BALB/c mice on the induction of autoimmune gastritis. The
      CD4+CD25+ T cell population was reduced to 95% of the original population in
      adult thymectomized mice by treatment with anti-CD25 mAb. By 48 days after the
      anti-CD25 treatment, the CD4+CD25+ regulatory T cell population had returned to a
      normal level. Treatment of thymectomized adult mice for up to 4 weeks with anti
      CD25 mAb did not result in the development of autoimmune gastritis. Furthermore,
      we have demonstrated that depletion of CD4+CD25+ regulatory T cells, together
      with transient CD4+ T lymphopenia, also did not result in the development of
      autoimmune gastritis, indicating that peripheral expansion of the CD4+ T cell
      population, per se, does not result in autoimmunity in adult mice. On the other
      hand, depletion of CD4+CD25+ T cells in 10-day-old euthymic mice resulted in a
      30% incidence of autoimmune gastritis. These data suggest that CD4+CD25+
      regulatory T cells may be important in protection against autoimmunity while the
      immune system is being established in young animals, but subsequently other
      factors are required to initiate autoimmunity.

PMID- 12406394
TI  - [Community-acquired pneumonia: serum adenosine-deaminase activity in the
      aetiological diagnosis].
AB  - BACKGROUND: Adenosine deaminase (ADA) is a cytoplasmic enzyme which activity is
      increased in disorders that stimulate cells involved in the immune system. In
      community-acquired pneumonia (CAP), increased levels of serum ADA have been
      associated with the presence of atypical microorganisms as the source of the
      former. Previous studies have shown ADA increases in non-infectious diseases. We
      evaluated the factors that may influence plasmatic ADA (ADAp) levels in CAP
      patients. PATIENTS AND METHODS: A study with cases (245 episodes of CAP) and
      controls (49) was designed, and the differences in ADAp activity with regard to
      organisms, comorbidity factors and complications were analyzed. A logistic
      regression analysis was performed. RESULTS: CAP caused by atypical microorganisms
      were found to have increased ADAp values. Variables that independently increased
      ADAp levels were: atypical etiology (OR = 5.9), liver disease (OR = 5.8),
      diabetes mellitus (OR = 1.9), and prior antibiotic consumption (OR = 1.7).
      CONCLUSIONS: ADAp is an etiologic marker that could be useful in the empiric
      approach of the treatment of CAP.

PMID- 12406392
TI  - Identification of an I-Ad restricted peptide on the 65-kilodalton heat shock
      protein of Mycobacterium avium.
AB  - The 65 kilodalton heat shock protein (Hsp65) from mycobacterial species elicits
      immune responses and in some cases protective immunity. Here we have used a DNA
      sublibrary approach to identify antigenic fragments of Mycobacterium avium Hsp65
      and a synthetic peptide approach to delineate CD4+ T cell determinants. A panel
      of Hsp65 reactive CD4+ T cell clones was established from lymph node cells
      obtained from BALB/c mice immunized with recombinant Hsp65. The clones were
      tested for proliferative reactivity against the products of the DNA sublibrary of
      the hsp65 gene. A T cell epitope, restricted by the I-Ad molecule, was identified
      within the C-terminal region of Hsp65 and the minimal epitope (amino acid
      residues 489-503) delineated using overlapping peptides spanning the C-terminal
      fragment. Additionally, the CD4+ T cell clone recognizing this epitope also
      responded to native Hsp65 present in M. avium lysates by both proliferation and
      cytokine production, indicating that the epitope was present and processed
      similarly both in the native and the recombinant forms of Hsp65. This sequence
      identified in BALB/c mice (Hsp65 489-503) is identical in other mycobacteria,
      notably M. tuberculosis, M. bovis and M. leprae, suggesting the epitope may have
      wider application in murine models of other mycobacterial infections.

PMID- 12406395
TI  - [Cardiovascular risk factors in patients with morbid obesity: weight loss
      influence].
AB  - BACKGROUND: We studied the presence of cardiovascular risk factors in patients
      with morbid obesity and analyzed the influence of weight loss achieved through
      diet on these factors. We also evaluated the influence of gender on the presence
      of cardiovascular risk factors and on its response to diet. PATIENTS AND METHODS:
      An anthropometric evaluation was performed in patients with morbid obesity (23
      men and 36 women). The presence of cardiovascular risk factors was evaluated
      (fibrinogen, blood pressure, glucose metabolism determination by means of oral
      glucose tolerance test, complete lipid profile, sleep apnea syndrome), before and
      after following, on an alternative fashion, very-low calorie and low-calorie
      diets. The comparison was made with the t-test for paired samples. RESULTS: A
      very significant weight loss was achieved in our patients, particularly in men
      (decrease of 33.4 kg, 95% CI: 26.9 to 39.8). This was accompanied by a reduction
      in the presence of cardiovascular risk factors, particularly in men, in whom the
      body fat distribution improved significantly (decrease in waist: 24.8 cm, 95% CI
      18.4 to 36.5), as well as the lipid profile including triglycerides, VLDLc, HDLc
      and B100 apoprotein. CONCLUSIONS: Patients with morbid obesity have a high
      prevalence of cardiovascular risk factors. A significant reduction of this
      prevalence can be achieved with diet during one year. This improvement is
      particularly significant in men.

PMID- 12406396
TI  - [Health problems of foreign adopted children in Spain].
AB  - BACKGROUND: We decided to assess the health problems of internationally adopted
      children in Spain. PATIENTS AND METHODS: Retrospective study of 135 medical
      records from the Hospital Nino Jesus, Madrid. The prevalence of malnutrition,
      anemia, parasitosis and other acquired and congenital diseases was studied.
      RESULTS: 18.9% of children were considered completely healthy; 37.8% children had
      a single disease and 43.3% had two or more. 32.3% were found to have anemia,
      30.2% parasitosis and 25.2% malnutrition. CONCLUSIONS: The high morbidity figures
      observed in our study reinforces the need of special medical care in this group
      of children.

PMID- 12406397
TI  - [Accuracy of the automated oscillometric device Lohmeier B-606, for blood
      pressure measurement in hospitals].
AB  - BACKGROUND: The aim of the present study was to evaluate the accuracy of an
      automated oscillometric device, Lohmeier B-606, for clinical use in hospitals,
      according to there commendations of the European Society of Hypertension.
      METHODS: Thirty-three subjects were studied. We performed three pair of
      sequential comparisons of blood pressure in each patient, first with mercury
      sphygmomanometer, second with the oscillometric device, obtaining a whole number
      of 99 comparisons. RESULTS: From the total 99 comparisons, 55 for SBP and 66 for
      DBP showed differences 3/4 5 mmHg, 86 and 88 differences 3/4 10 mmHg and 99 for
      SBP and DBP differences 3/4 15 mmHg. Mean differences between procedures (mercury
      automatic) were 0.08 (confidence interval [IC] 95%: 14.1, 14.3) for SBP and 0.99
      (95% CI: 11.0, 13.0) for DBP. Intraclass correlation coefficients were 0.975 for
      SBP and 0.944 for DBP. CONCLUSIONS: The blood pressure measurement oscillometric
      device Lohmeier B-606 satisfies the European Society of Hypertension criteria for
      clinical use in hospitals.

PMID- 12406398
TI  - [Burn out syndrome].

PMID- 12406399
TI  - [Description of a new TP53 gene germline mutation in a family with the Li
      Fraumeni syndrome. Genetic counselling to healthy mutation carriers].
AB  - BACKGROUND: Li-Fraumeni syndrome is a dominantly inherited disorder characterized
      by early-onset breast cancer, soft-tissue sarcomas and osteosarcomas, acute
      leukemia, adrenocortical neoplasms and central nervous system tumors. Germline
      mutations in gene TP53 are identified in a percentage of affected families.
      PATIENTS AND METHOD: Eight families with aggregation of childhood sarcomas, brain
      tumors, breast cancers in pre-menopausal women, and renal tumors were screened
      for TP53 germ-line mutations. SSCP and posterior direct sequencing were performed
      for genetic analysis. We also report a previously undescribed family with the Li
      Fraumeni syndrome carrying a germline mutation. RESULTS: Seven families fulfilled
      so-called Li-Fraumeni like criteria and one fulfilled classical criteria. A new
      germ-line mutation in codon 238 at exon 7 of the gene TP53 was identified in the
      family fulfilling classical criteria. This mutation has not been previously
      reported. CONCLUSIONS: The clinical heterogeneity as well as the molecular
      complexity and consequences of mutation analysis and genetic counseling make it
      necessary to develop protocols in this area. A multidisciplinary approach is
      needed; this approach should be coordinated by a Familial Cancer Genetic
      Counseling Unit.

PMID- 12406400
TI  - [Intravascular catheter-related infection].

PMID- 12406401
TI  - [Uncommon purine lithiasis: adenine phosphoribosyltransferase (APRT) deficiency
      and hereditary xanthinuria].

PMID- 12406402
TI  - [First spontaneous reports of adverse drug reactions to the new selective COX-2
      non-steroid anti-inflammatory drugs].

PMID- 12406403
TI  - [First spontaneous reports of adverse drug reactions to the new selective COX-2
      non-steroideal anti-inflammatory drugs].

PMID- 12406404
TI  - [First spontaneous reports of adverse drug reactions to the new selective COX-2
      non-steroideal anti-inflammatory drugs].

PMID- 12406406
TI  - [Use of adequate parasitologic diagnosis techniques in a patient from Pakistan
      with chronic iron deficiency anemia].

PMID- 12406407
TI  - [The need to move].

PMID- 12406408
TI  - [Patients and quality of primary health care services. Survey of practitioners at
      the Bahia de Cadiz and La Janda health centers].
AB  - AIM: To report the opinions of practitioners at health centers on dimensions of
      quality that affect user satisfaction. DESIGN: Cross-sectional study of focus
      groups (FG). SETTING: Bahia de Cadiz and La Janda health centers in southwestern
      Spain. PARTICIPANTS: We studied 4 FG whose participants were staff members of the
      two health centers: FG1, physicians; FG2, user satisfaction service staff; FG3,
      social workers; FG4, nurses. The groups were based on the different functions of
      staff at the two centers. METHOD: The analysis was based on variables in the
      SERCAL model (an adaptation of the SERVQUAL model for the Spanish health care
      system) of opinions regarding service quality: access, comfort (tangibles),
      personalized service (courtesy), competence, and loyalty. The data were analyzed
      with version N-Vivo of the NUDIST program. RESULTS: All dimensions of the
      theoretical model were identified by practitioners as constructs of users'
      perceptions of service quality. Users' and practitioners' views contrasted with
      and complemented each other to generate a model that could be validated. Access,
      personalized service and problem-solving (responsiveness) were key variables.
      CONCLUSIONS: Practitioners' opinions provided information of use in improving the
      quality model. Differences in opinion between users and practitioners merit
      further study based on an understanding of these groups' values and interests,
      and on the care provision context. Practitioners identified access, personalized
      service and problem-solving as features that influenced users' opinions of the
      quality of the health center.

PMID- 12406409
TI  - [Commentary: The other view].

PMID- 12406410
TI  - [Evaluation of clinical competence in the postgraduate family medicine course, by
      means of the Structured Objective Clinical Test].
AB  - OBJECTIVE: To evaluate the clinical competence of first-year residents on the
      course specialising in family medicine, by applying a structured objective
      clinical test (SOCT) for simultaneous assessment of cognitive, affective and
      psychomotor areas. DESIGN: Observational and descriptive. SETTING: Family
      medicine clinics in the metropolitan area of Mexico City.Participants. 89 doctors
      on the specialist course in Family Medicine at the Autonomous University of
      Mexico (UNAM). MAIN MEASUREMENTS: After prior design of comparison lists, expert
      validation of content, and design of support material for the evaluation and
      pilot study, a SOCT with ten themes or sections, eight dynamic and two static,
      was administered. The cut-off point for competent performance was 60 out of 100,
      both in each section and in the overall average. The statistical analysis was
      univariate, using descriptive statistics. RESULTS: The overall average of scores
      in all sections was under 60. The highest average was 73, in the section for
      monitoring healthy children. In the five highest-scoring sections, the scattering
      was lower than in the other five. There were low scores in the family study
      section. CONCLUSIONS: Academic performance, as evaluated by a SOCT measuring
      clinical competence, was low. This kind of test enabled clinical competence to be
      assessed more objectively. Interval evaluation scales need to be tested so as to
      evaluate better the quality of the performance of clinical activities.

PMID- 12406411
TI  - [Economic evaluation of a new selective COX-2 NSAID, rofecoxib, in a real
      practice context].
AB  - OBJECTIVE: To evaluate the economic and health consequences of the use of a new
      COX-2 anti-inflammatory drug. DESIGN: Cost-effectiveness analysis by modelling
      three options for prescribing non-steroidal anti-inflammatories (NSAIDs) in
      patients diagnosed with arthrosis and undergoing long-term NSAID treatment.
      Option 1: NSAID prescription without gastric protection for low-risk patients,
      and with gastric protection for patients running a medium or high risk of
      developing complications (current procedure). Option 2: exclusive prescription of
      rofecoxib (25 mg/day) for all patients (high and low risk). Option 3: single
      therapy rofecoxib (25 mg/day) prescription for patients sensitive to combined
      treatment (NSAIDs and gastric protection) due to the risk of complications. In
      each case, resources and expected clinical benefits were accounted for by the
      calculation of the cost of avoidance of each moderate or high gastro-intestinal
      side-effect (GISE) (symptomatic ulcer or complication) avoided. The direct
      economic impact on the centre of passing from option 1 to any of the other two
      options was calculated. SETTINGS AND PARTICIPANTS: The study, conducted in the
      Barceloneta Primary Care Centre, included in its modelling the 124 patients
      diagnosed with arthrosis who received NSAIDs continuously during the year 2000.
      RESULTS: Option 2 supposed avoiding 1.5 cases of GISE (0.5 symptomatic ulcers and
      0.9 serious complications), to an additional cost of 336 566.78 euros. Each case
      avoided would cost 24,641.50 euros; and each serious case avoided 38,464.79
      euros. Option 3 avoided 0.25 cases of serious complication, at an additional cost
      of 9,015.18 euros. Avoiding one case would cost 37,262.75 euros. CONCLUSIONS: The
      overall health benefits arising from the universal or partial introduction of a
      selective COX-2 inhibitor NSAID involve a unit cost of 24,040.48 or 36,060.73
      euros, depending on the option. The impact on the Centre s pharmaceutical budget
      would increase by 1.3% under option 2, and by 0.35% under option 3.

PMID- 12406412
TI  - [Attitudes of health centre users to diagnoses of terminal illness].
AB  - OBJECTIVE: To calculate the prevalence of users who want to know their diagnosis
      of terminal illness and to analyse the factors determining their decision.
      DESIGN: Descriptive, observational, cross-sectional study. SETTING: Six lists
      belonging to two Health Districts in Asturias Health Area III. PARTICIPANTS: On
      demand users of the clinic, over 17 years old, selected by systematic randomized
      sampling stratified according to the number of consultations at the centre. MAIN
      MEASUREMENTS AND RESULTS: Through a questionnaire composed by the researchers and
      face-to-face interviews, social and personal variables and attitudes to a
      diagnosis of terminal illness were collected. The sample consisted of 388 people.
      A descriptive analysis and population calculations were made, with a logistical
      regression analysis to identify associated variables. RESULTS: 70.6% of those
      questioned (95% CI, 66%-75.1%) wanted to know their diagnosis, mainly on the
      basis of their right to the information (35.1%; 95% CI, 29%-40.6%). Most of these
      wanted to be informed by the doctor (81.9%; CI, 77.5%-86.5%). The variables
      significantly linked to a positive reply were: male (OR, 1.91; CI, 1.1%-3.4%),
      age (OR, 0.97; CI, 0.95%-0.99%), religious beliefs (OR, 0.2; CI, 0.1%-0.8% for
      believers), fear of pain and disability (OR, 3.8; CI, 1.2%-12%), and having
      previously thought about wanting to be informed (OR, 2.2; CI, 1.2%-4%). This last
      variable achieved the highest partial correlation coefficient (R, 0.12).
      CONCLUSIONS: Most users want to be informed of a diagnosis of terminal illness.
      The profile of the patient who wants to know the truth is: young male, non
      believer, and someone whose main fears of terminal illness are pain and
      disability. The variable with most influence on the positive reply was having
      posed the question previously.

PMID- 12406413
TI  - [Quality versus quantity in primary care: resolution or survival?].

PMID- 12406415
TI  - [Communication with terminally ill patients].

PMID- 12406417
TI  - [Should a request for an echocardiogram to study an asymptomatic murmur be
      directly from primary health care?].

PMID- 12406416
TI  - [Evaluation of the proper use of medicines in primary care. How can this be
      improved?].
AB  - INTRODUCTION: The process of medicating a patient embraces the identification of
      the health problem, the doctor's prescription to treat this indication, the
      dispensing of the medicine and its consumption. The studies of use of medicine
      analyse this process in order to detect those factors that impinge on the correct
      use of medicines. OBJECTIVE: To evaluate the quality of the prescription of
      certain primary care medicines as a function of the indication for which they
      were prescribed, detecting those features of the patients, prescribing doctors,
      primary care centre and health district that affect their inappropriate use.
      METHOD: Prescription-indication study based on the calculation of multiple-level
      models with individualised data bases for the prescriptions. These include
      characteristics of the prescriptions, patients, doctors, health centres and the
      health district involved. These models are a step forward in this kind of study,
      in that they enable analysis of the information from different levels at the same
      time as calculation of the respective degrees of responsibility for inadequacies
      of prescription. DISCUSSION: Apart from its methodological originality, which may
      serve for subsequent studies, the main interest of this study lies in the
      pioneering nature of its massive use of population micro-data to evaluate
      prescription quality. These data are taken from the computerised clinical records
      in primary care.

PMID- 12406418
TI  - [Descriptive study of Horton's headache and chronic mehiplegial migraines.
      Application to primary care].

PMID- 12406419
TI  - [Cervical whiplash syndrome?].

PMID- 12406420
TI  - [The morning-after pill: a second chance, for whom?].

PMID- 12406421
TI  - [Research studies presented by family and community medicine residents at the
      last two congresses on the speciality].

PMID- 12406423
TI  - Why is the concept of spondyloarthropathies important?
AB  - The concept of spondyloarthropathy was recognized first by clinicians based on
      the aggregation of several diseases occurring either sequentially in the same
      patient or simultaneously in a family. This concept was thereafter confirmed by
      the higher prevalence of the HLA-B27 antigen, not only in the group of patients
      suffering from an axial involvement of ankylosing spondylitis but also in other
      diseases belonging to the concept of spondyloarthropathy, i.e. psoriatic
      arthritis, reactive arthritis, inflammatory-bowel-disease-related arthritis
      and/or other clinical manifestations such as acute anterior uveitis. Recognition
      of the concept of the spondyloarthropathy is of great importance not only for
      research purposes but also in daily practice because such recognition has at
      least a threefold effect: (a) it permits earlier diagnosis, (b) it facilitates
      patients' education and monitoring, and (c) it has prognostic implications

PMID- 12406424
TI  - Reactive arthritis or post-infective arthritis?
AB  - Infective mechanisms probably underlie a wide range of inflammatory
      arthropathies. There appears to be a spectrum of mechanisms ranging from the
      frankly septic, through low-grade infection with very small numbers of
      microorganisms in the joint to arthritides in which no hard evidence for an
      infective cause exists. In the midst of the spectrum lie 'post-infective' and
      'reactive' arthritides, characterized clinically, genetically and by
      epidemiological links with infection. Identification of bacterial components
      within joint material from such patients suggested that the causes of the
      arthritis had been found. It is now clear that many bacteria are present in
      inflamed joints; establishing their significance will be of crucial importance,
      but not easy.

PMID- 12406425
TI  - Psoriatic arthritis.
AB  - Psoriatic arthritis (PsA) is a common form of arthritis, accounting for
      approximately 15% of patients attending early synovitis clinics, the second most
      common diagnostic category after rheumatoid arthritis. PsA patients exhibit
      restricted organ involvement largely confined to skin, synovial tissue and sites
      of entheseal attachment. This restricted involvement in an inflammatory response
      suggests that either a common antigen/autoantigen is present at these sites which
      is driving the immune response or that there are shared proteins or cells which
      migrate to or are resident at these sites only. This chapter explores the
      evidence for common pathogenic mechanisms in the skin and joint in PsA. Further,
      the concept of similar mechanisms operating in the various subtypes of PsA is
      also explored. While evidence presented supports the concept of PsA being one
      disease with diverse clinical manifestations, further detailed genetic and
      mechanistic studies are required before a firm conclusion can be arrived at.

PMID- 12406426
TI  - Ankylosing spondylitis and bowel disease.
AB  - Clinical studies indicate an important role for bowel inflammation in ankylosing
      spondylitis and other spondyloarthropathies whereby two different aspects have to
      be considered. First, the gut inflammation is clinically and histologically
      closely related to Crohn's disease. Recent data on subclinical immune alterations
      confirm this relationship and suggest that spondyloarthropathy is a unique human
      model for studying early Crohn's disease. Second, bowel and peripheral joint
      inflammation are clinically, histologically and pathogenetically linked. The most
      important clinical implication of these observations is that targeted therapies
      for Crohn's disease could also be effective for intestinal as well as extra
      intestinal disease manifestations in spondyloarthropathy, as evidenced by the
      recent studies on TNF-alpha blockade. Unravelling the gut-synovium axis in
      spondyloarthopathy could also contribute to the identification of new therapeutic
      targets. Finally, assessment of subclinical gut inflammation by histology,
      serology and genetics could contribute to the stratification of individual
      patients in subgroups with an optimal response to specific therapeutic
      interventions.

PMID- 12406427
TI  - The juvenile-onset spondyloarthritides: rationale for clinical evaluation.
AB  - This chapter reviews the clinical events that occur in patients with juvenile
      onset spondyloarthritides (SpA) with the purpose of developing core sets, domains
      and instruments to evaluate disease activity and disease damage. We discuss
      several aspects, from concept and classification to clinical features and
      instruments already in use for measuring adult-onset SpA and childhood
      arthritides. Similarly, comparisons between juvenile-onset SpA, its adult
      counterpart, and other forms of juvenile arthritis are made to consider the
      adaptation of existing instruments or to develop specific ones.

PMID- 12406428
TI  - Imaging and scoring in ankylosing spondylitis.
AB  - Ankylosing spondylitis (AS) is the prototype of the spondyloarthritides (SpA). AS
      is a disease subset but also a possible outcome of SpA. Early diagnosis of
      sacroiliitis, the most frequent clinical symptom frequently accompanied by
      inflammatory back pain and other inflammatory lesions of the spine such as
      spondylitis and spondylodiscitis, can be visualized early by magnetic resonance
      imaging (MRI). Spinal inflammation can be demonstrated by MRI using either the
      fat-saturating short tau inversion recovery (STIR) technique or by application of
      the contrast agent gadolinium-diethylenetriamine pentaacetic acid (DTPA). This is
      especially useful in early and active disease, in young women and in children,
      and for the differential diagnosis of septic sacroiliitis. Because of the
      efficacy of the novel biological agents directed against tumour necrosis factor
      alpha (TNF-alpha) - such as infliximab and etanercept - in SpA there is a need
      for spinal imaging techniques more sensitive than conventional X-rays. The
      available scoring tools are reviewed and novel approaches using MRI are
      presented.

PMID- 12406429
TI  - Ankylosing spondylitis: how should the disease be assessed?
AB  - The four clinical features of spondyloarthropathy, i.e. axial involvement,
      peripheral articular involvement, enthesopathy and extra-articular features, must
      be assessed in each patient suffering from spondyloarthropathy at each visit. The
      ASsessment in Ankylosing Spondylitis working group is establishing
      recommendations to facilitate the short- and long-term monitoring of patients
      suffering from spondyloarthropathies. Several relevant instruments are available
      for assessing the main domains, allowing evaluation of such patients - for
      example, pain, functional disability and spinal mobility. Other investigations
      are required in order to obtain relevant instruments for other domains, such as
      structural severity.

PMID- 12406430
TI  - Ankylosing spondylitis and current disease-controlling agents: do they work?
AB  - In contrast to rheumatoid arthritis (RA), the concept of disease modification in
      ankylosing spondylitis (AS) remains to be clarified. Endpoint measures employed
      in AS trials primarily assess features related to symptomatology while endpoints
      considered more relevant to the concept of disease modification, such as spinal
      mobility, acute-phase reactants and radiological progression, either lack
      sensitivity to change or have not been comprehensively validated. NSAIDs
      alleviate symptoms of AS but most trials have been short term, precluding
      meaningful conclusions regarding disease modification. Among disease-modifying
      therapies used in RA, sulfasalazine has been studied in several controlled trials
      mostly in patients with longstanding disease, effect sizes being small and
      limited to those with peripheral synovitis. No conclusions can be drawn from the
      limited studies evaluating methotrexate.

PMID- 12406431
TI  - Therapy for ankylosing spondylitis: new treatment modalities.
AB  - The therapeutic options for patients suffering from the more severe forms of
      spondyloarthritis (SpA) have been rather limited in recent decades. There is now
      accumulating evidence that anti-tumour necrosis factor (anti-TNF) therapy is
      highly effective in SpA, especially in ankylosing spondylitis (AS) and psoriatic
      arthritis (PsA). Based on the data recently published on more than 200 AS
      patients, and more than 100 PsA patients, this treatment seems to be even more
      effective than it is in rheumatoid arthritis (RA). The two major anti-TNF-alpha
      agents currently available, infliximab (Remicade) and etanercept (Enbrel), are
      approved for the treatment of RA in Europe and in the USA. The situation in SpA
      is different from RA because there is an unmet medical need, especially in AS,
      because disease-modifying anti-rheumatic therapy is not available for severely
      affected patients. Thus, TNF blockers might even be considered first-line
      immunosuppressive treatment in patients with active AS who are not sufficiently
      treated with non-steroidal anti-inflammatory drugs (NSAIDs). For infliximab, a
      dose of 5mg/kg was required, and intervals between 6 and 12 weeks were necessary
      for constant suppression of disease activity - a major aim also for long-term
      treatment. However, it remains to be shown whether patients benefit from long
      term therapy and whether radiological progression and ankylosis can be stopped.
      The optimal doses of infliximab might well be determined individually. Allergic
      reactions and increased susceptibility to tuberculosis are rare side-effects
      which need to be recognized early. As it stands now, the benefits of anti-TNF
      therapy in AS seem to outweigh these shortcomings. The efficacy of etanercept was
      first demonstrated in PsA. A double-blind study has now been performed in AS -
      with similar results. There is preliminary evidence that both agents also work in
      other SpA such as undifferentiated SpA. Hopefully, both agents will be approved
      soon for the short-term treatment of severe SpA. In parallel, studies should be
      performed to document the long-term efficacy and safety of this treatment.

PMID- 12406432
TI  - Spa and exercise treatment in ankylosing spondylitis: fact or fancy?
AB  - Physical therapy plays an important role in the overall treatment of ankylosing
      spondylitis. Apart from exercising at home, patients are advised to follow weekly
      group physical therapy. In addition, many patients often follow annual courses of
      in-patient physiotherapy or spa therapy in which exercises also play a central
      role. This chapter focuses on evidence for benefits of physical therapy and spa
      therapy in ankylosing spondylitis.

PMID- 12406433
TI  - Do patient self-help organizations help?
AB  - Ankylosing spondylitis (AS) patient organizations presently exist in 24
      countries. This chapter describes how these patient organizations help AS
      patients to cope with their disease and describes how patients and health
      professionals assess these contributions.

PMID- 12406434
TI  - Genetic aspects of ankylosing spondylitis.
AB  - There is substantial evidence strongly favouring a direct role for HLA-B27 in
      genetic susceptibility to ankylosing spondylitis (AS) and related
      spondyloarthropathies (SpA), although the underlying molecular basis has yet to
      be identified. HLA-B27 itself is a serologic specificity that encompasses 26
      different alleles that encode 24 different subtypes - HLA-B*2701 to B*2725, with
      the exclusion of B*2722. [The B*2722 allele was deleted as an official WHO allele
      in April 2002, with a note that the reference cell has been shown to have the
      same sequence as B*2706. Thus, from now on, with this deletion of B*2722, there
      will be a "hole" among the HLA-B*2701 to B*2725 group of alleles]. The 24 HLA-B27
      alleles (subtypes) seem to have evolved from the most widespread subtype, B*2705.
      Two B27 alleles have been reported to lack association with AS: B*2706 among
      Southeast Asian populations, and B*2709 among Sardinians. The distinction between
      the disease-associated subtypes and those that are not disease-associated may
      provide some clues to the actual role of HLA-B27 in disease pathogenesis. Genetic
      family studies in populations of European descent indicate that HLA-B27
      contributes only 16 % of the total genetic risk for the disease. The genes in the
      Major Histocompatibility Complex (MHC) as a whole, that includes HLA-B27, account
      for about half of the genetic susceptibility for AS. This clearly indicates the
      presence of additional disease predisposing genes in the MHC region on chromosome
      6, and genome-wide studies have identified many areas of interest on other
      chromosomes that may contain additional disease predisposing genes. Additional
      studies emanating from the recent mapping of the human genome is expected to lead
      to better understanding of the genetic basis of these and other rheumatic
      diseases. Genetic counselling and the use of HLA-B27 typing as an aid to
      diagnosis are also reviewed.

PMID- 12406435
TI  - Ankylosing spondylitis: what is the cost to society, and can it be reduced?
AB  - Ankylosing spondylitis is a chronic rheumatic disease leading to functional
      limitations. This has an important impact on participation in the labour force,
      with high disease-related work disability. As for cost-of-illness studies, which
      estimate the costs related to a disease, the cost of lost productivity is the
      major contributor to the total costs of ankylosing spondylitis. Because of the
      low prevalence of the disease, the costs related to ankylosing spondylitis are a
      relatively small part of the costs of all diseases to society. However, given the
      early and the important long-term functional loss, the lifetime costs and socio
      economic impact for the individual patient are likely to be high. Because poor
      physical function is the major determinant of high direct and productivity costs,
      new (biological) treatments with effects on long-term functional disability will
      potentially reduce the economic impact of the disease for society and patients.

PMID- 12406438
TI  - Pathogenesis of steatohepatitis.
AB  - Understanding the pathogenesis of non-alcoholic steatohepatitis has recently
      assumed great importance with the recognition that it has the potential to
      progress to fibrosis and cirrhosis. The 'two-hit' model of pathogenesis was
      proposed in 1998, with the first 'hit' - steatosis - increasing the sensitivity
      of the liver to the second 'hits' mediating liver injury. The main aim of this
      chapter is to review this model in the light of studies that have been published
      over the subsequent 4 years. Particular attention will be focused on the role of
      insulin resistance and recent advances in our understanding of the basic cellular
      mechanisms linking obesity and insulin resistance. Based on this information I
      will propose a modification of the two-hit model that places more emphasis on the
      role of free fatty acids. This model will provide the basis for further research
      and enable the rational design of treatment strategies.

PMID- 12406439
TI  - Animal models of steatohepatitis.
AB  - Animal models of hepatic steatosis and steatohepatitis have improved our
      understanding of the pathogenesis of non-alcoholic fatty liver disease (NAFLD).
      Three models, genetically obese ob/ob mice, lipoatrophic mice and normal rats fed
      choline-deficient, methionine-restricted diets, have been particularly
      informative. All support the multiple 'hit' hypothesis for NAFLD pathogenesis
      that suggests that fatty livers are unusually vulnerable to oxidants and develop
      steatohepatitis when secondary insults generate sufficient oxidants to cause
      liver cell death and inflammation. Steatohepatitis, in turn, increases
      sensitivity to other insults that induce hepatic fibrosis, promoting the
      evolution of cirrhosis. Early during NAFLD pathogenesis, inhibitor kappa kinase
      beta (IKKbeta), an enzyme that induces tumour necrosis factor alpha (TNFalpha)
      and other proinflammatory cytokines, is activated and this causes insulin
      resistance. Inhibition of IKKbeta or TNFalpha improves insulin sensitivity,
      steatosis and steatohepatitis in animals, suggesting novel strategies to prevent
      and treat early NAFLD in humans.

PMID- 12406440
TI  - Pathology of steatohepatitis.
AB  - Pathologists have long been involved in clinical diagnosis and investigative
      studies of various forms of liver disease, including alcoholic liver disease. The
      concept that progressive fatty liver disease may result from causes other than
      alcohol toxicity can be noted in the literature. However, acceptance of this as a
      bona fide form of liver disease has been credited to an in-depth study published
      in 1980 of patients gathered from cases in the files of the pathology department
      of the Mayo Clinic in whom liver biopsies showed histological similarities to
      alcoholic steatohepatitis, but for whom clinical evidence of alcohol use was
      absent. Subsequent studies of the natural history and pathogenesis of non
      alcoholic steatohepatitis have relied on detailed histopathological correlations.
      This chapter will elucidate the constellation of microscopic findings, the issues
      of concern for pathological evaluation and the knowledge to date of their
      significance in various forms of fatty liver disease.

PMID- 12406441
TI  - The metabolic abnormalities associated with non-alcoholic fatty liver disease.
AB  - Non-alcoholic fatty liver disease (NAFLD) is a common disorder in the Western
      hemisphere. It encompasses two histological lesions: fatty liver and
      steatohepatitis. A large body of literature indicates that insulin resistance is
      a key pathophysiological abnormality in patients with NAFLD. Insulin resistance
      results from a complex interplay between the major targets of insulin action,
      i.e. muscle, adipose tissue and liver, versus the ability of the pancreatic islet
      beta cells to compensate for insulin resistance by increasing insulin production.
      The metabolic and clinical profile associated with insulin resistance is thus
      defined by the factors that produce and maintain insulin resistance and the
      effects of decreased insulin sensitivity on various insulin-dependent pathways.
      The major metabolic defects associated with insulin resistance are increased
      peripheral lipolysis, increased hepatic glucose output due to increased
      gluconeogenesis and increased lipid oxidation. This is associated with an
      oxidative stress in the liver that may be compounded by additional
      pathophysiological abnormalities. While much work remains to be done, the current
      understanding of the pathogenesis of NAFLD provides direction for both future
      investigation and development of therapeutic trials.

PMID- 12406442
TI  - Steatohepatitis in obese individuals.
AB  - Nonalcoholic steatohepatitis (NASH), which is the most severe histological form
      of nonalcoholic fatty liver disease (NAFLD), is emerging as the most common
      clinically important form of liver disease in developed countries. Although its
      prevalence is 3% in the general population, this increases to 20-40% in obese
      patients. Since NASH is associated with obesity, prevalence has been predicted to
      increase along with the arsent epidemic of obesity and type II diabetes mellitus.
      The importance of this observation comes from the fact that NASH is a progressive
      fibrotic disease, in which cirrhosis and liver-related death occur in 25% and 10%
      in these patients respectively over a 10-year period. This is of particular
      concern given the increasing recognition of NASH in children. Treatment consists
      of treating obesity and its co-morbidities; diabetes and hyperlipidemia. Nascent
      studies suggest that a number of pharmacological therapies may be effective, but
      all remain unproven at present. Histological and laboratory improvement occurs
      with a 10% decrease in body weight. Bariatric surgery is indicated in selected
      patients.A greater understanding of the pathophysiological progression of NASH in
      obese patients must be obtained in order to develop more focused and improved
      therapy.

PMID- 12406443
TI  - Steatohepatitis in children.
AB  - Steatohepatitis in children occurs in the childhood version of non-alcoholic
      fatty liver disease (NAFLD), as a result of hepatotoxicity and with certain
      genetic/metabolic diseases. Until recently, NAFLD was considered to be rare in
      children. It is now recognized as an important childhood liver disease,
      especially because childhood obesity is much more common. Children with NAFLD may
      present as young as 4 years old; males tend to predominate; fibrosis is often
      found on liver biopsy and cirrhosis has been reported. Treatment for childhood
      NAFLD currently consists of weight reduction plus regular aerobic exercise;
      vitamin E may be an effective adjunctive therapy. Drug hepatotoxicity and
      genetic/metabolic diseases that can cause fatty liver, such as Wilson's disease
      and cystic fibrosis, must be excluded since treatment is radically different.
      Other causes of chronic hepatitis, such as chronic viral hepatitis, must also be
      excluded. Multisystemic inherited diseases with hyperinsulinaemia plus insulin
      resistance may have NAFLD as hepatic involvement and should be identified.

PMID- 12406444
TI  - Interaction of non-alcoholic fatty liver disease with other liver diseases.
AB  - Obesity-related steatosis is an increasingly common histological finding in liver
      biopsies and may co-exist with other chronic liver diseases. Although non
      alcoholic fatty liver disease (NAFLD) without true steatohepatitis is generally a
      benign condition, when another liver disease is present, steatosis may exacerbate
      the liver damage. In this review, we discuss the interaction of obesity-related
      steatosis with chronic hepatitis C, alcoholic liver disease, disorders of hepatic
      iron storage and drug-induced liver disease. The role of weight reduction in
      minimizing liver injury in patients with chronic hepatitis C is discussed.
      Finally, we discuss the problems associated with orthotopic liver transplantation
      for patients with NAFLD.

PMID- 12406445
TI  - Other disease associations with non-alcoholic fatty liver disease (NAFLD).
AB  - Non-alcoholic fatty liver disease (NAFLD) is usually seen in middle-aged women
      with obesity, non-insulin-dependent diabetes mellitus and/or hyperlipidaemia.
      NAFLD has also been associated with other conditions. Surgical procedures to
      treat obesity such as jejunoileal bypass and gastroplasty as well as massive
      small bowel resection have been associated with NAFLD. Mechanisms such as rapid
      weight loss, certain nutritional deficiencies and bacterial overgrowth have been
      proposed. Other nutritional conditions such as extreme malnutrition and total
      parenteral nutrition can also cause NASH. This can be due to abnormal glucose and
      fat metabolism, deficiencies like carnitine, essential fatty acid and choline or,
      in the case of parenteral nutrition, excess of calories, glucose or lipids.
      Several drugs have also been implicated as well as some inborn errors of
      metabolism and, more rarely, other diseases.

PMID- 12406446
TI  - Treatment of non-alcoholic steatohepatitis.
AB  - Treatment of patients with non-alcoholic steatohepatitis (NASH) has typically
      been focused on the management of associated conditions such as obesity, diabetes
      mellitus and hyperlipidaemia. NASH associated with obesity may resolve with
      weight reduction, although the benefits of weight loss have been inconsistent.
      Appropriate control of glucose and lipid levels is always recommended, but is not
      always effective in reversing the liver condition. Results of pilot studies
      evaluating ursodeoxycholic acid, gemfibrozil, betaine, N-acetylcysteine, alpha
      tocopherol, metformin and thiazolidinedione derivatives suggest that these
      medications may be of potential benefit for patients with NASH. These
      medications, however, need first to be tested in well-controlled trials with
      clinically relevant end-points and extended follow-up. A better understanding of
      the pathogenesis and natural history of NASH will help to identify the subset of
      patients at risk of progressing to advanced liver disease and, hence, those
      patients who should derive the most benefit from medical therapy.

PMID- 12406449
TI  - Epidemiology of diverticular disease.
AB  - Diverticulosis, which is an acquired condition marked by mucosal herniation
      through defects in the colonic wall, has been termed both a "disease of the 20th
      century" and a "disease of Western civilization" due to its increasing prevalence
      in modern times and its striking geographical variability. Both of these
      epidemiological observations may provide interesting insights into the
      pathophysiology of diverticulosis. This chapter will review the known
      epidemiology of diverticulosis coli and its main complications: diverticulitis
      and diverticular haemorrhage. Where possible, attempts will be made to place
      these observational reports in the context of both the cause and clinical
      behaviour of this disorder.

PMID- 12406450
TI  - The pathology of diverticular disease.
AB  - Diverticular disease is common in the elderly Western population and its
      complications are frequent clinical presentations. Despite this, the pathogenesis
      of the condition remains relatively poorly understood. Several theories have been
      developed, the most acceptable suggesting elastosis of the taeniae coli as the
      primary event, causing shortening of the sigmoid colon, with relative mucosal
      excess and subsequent mucosal herniations. A Western-type diet is implicated in
      the increased uptake of proline from the gut, leading to elastosis of the sigmoid
      colon. For pathologists, in clinical practice, the disease is most commonly seen
      in sigmoid colonic resection specimens, usually performed for complications of
      the disease. It is now realised that mucosal biopsies of the luminal mucosa, in
      the sigmoid colon affected by diverticular disease, can produce perplexing
      pathological changes. In particular diverticular colitis can mimic both
      ulcerative colitis and Crohn's disease: care should be taken when diagnosing
      chronic inflammatory bowel disease on a background of diverticular disease. For
      pathologists, diverticular disease remains something of an enigma: although
      common, its pathogenesis remains ill-defined and its complications can provide
      diagnostic difficulties, which require precise clinical and radiological
      correlation.

PMID- 12406451
TI  - Pathophysiology of diverticular disease.
AB  - There is substantial evidence that colonic diverticulosis is related to
      civilization, industrialization and a "Western" lifestyle and diet, being
      described as "a disease of Western civilization". Its increased incidence during
      the 20th century and the morbidity and mortality associated with complications,
      demand that this condition should receive greater attention in terms of
      aetiology, prevention and management. It is generally believed that low dietary
      fibre and ageing are the two main pathogenic factors involved in this disease.
      Physiological studies have also demonstrated that there is a higher intraluminal
      pressure in the large bowel with diverticula. This chapter provides the evidence
      currently available for the pathophysiology of colonic diverticulosis and
      discusses its aetiological factors, including low dietary fibre, ageing and
      intraluminal pressure as well as extracelluar matrix such as collagen and
      elastin. The difference between the left-sided diverticulosis commonly seen in
      Caucasians and the right-sided predominantly observed in Asians is also
      presented.

PMID- 12406452
TI  - Clinical features and differential diagnosis of diverticular disease.
AB  - Colonic diverticulosis occurs in the majority of Western populations with age,
      but only a small proportion of people experience symptoms. Diverticular disease
      usually presents with either haemorrhage or diverticulitis. A quarter of patients
      with diverticulitis will develop complications including perforation,
      fistulation, obstruction or stricture. This chapter deals with the natural
      history, risk factors, clinical features and differential diagnoses of
      symptomatic diverticular disease.

PMID- 12406453
TI  - Imaging diverticular disease.
AB  - Barium enema remains the gold standard for demonstrating the extent and severity
      of colonic diverticular disease. As such, barium studies have a role in
      clarifying the differential diagnosis of patients with abdominal pain and altered
      gut function. In acute diverticulitis or suspected diverticular perforation water
      soluble contrast studies are preferred to barium. An alternative in this acute
      scenario is cross-sectional imaging by ultrasound, or more usefully computed
      tomography (CT). CT is especially helpful in complicated diverticular disease.
      Diverticular disease is a common finding at colonoscopy and is often a
      complicating factor in the technical performance of the procedure. In acute
      diverticulitis, when the risk of perforation is high, colonoscopy should not be
      performed. In acute diverticular haemorrhage, colonoscopic haemostatic therapy
      with adrenaline can be effectively performed.

PMID- 12406454
TI  - Medical management of diverticular disease.
AB  - Diverticular disease is a common disorder affecting 30-55% of the population in
      the developed world. It has been described as "a deficiency disease of Western
      civilization", a theory that has been proposed since it was observed that
      diverticular disease was uncommon in African and other developing countries where
      dietary fibre consumption was high. At the turn of the century the medical
      treatment of colonic diverticulosis involved the avoidance of "roughage", which
      was felt to exacerbate the problem. However, the use of high fibre diets in the
      prevention and treatment of the symptoms of diverticular disease has now become
      commonplace, and the development of this practice is discussed in this chapter.

PMID- 12406455
TI  - Diverticular disease in adolescence.
AB  - Diverticular disease is rare in the adolescent. Acute diverticulitis is almost
      never considered as a diagnosis for a young patient presenting with abdominal
      pain. Unfortunately, unrecognized it may be associated with significant morbidity
      and mortality. Also, when present, diverticulitis in the young adult is
      considered to be more aggressive compared to diverticulitis in older adults.
      Therefore, it is important to recognize, diagnose and manage diverticular disease
      appropriately in this age group. In tis chapter we will review the available
      literature on diverticula disease in the adolescent and young adult, discuss
      epidemiology, aetiology and pathogenesis and suggest guidelines for diagnosis and
      management.

PMID- 12406456
TI  - Diverticulitis.
AB  - Although diverticular disease is common in the Western world, few patients who
      develop diverticulitis require surgery. The use of appropriate broad-spectrum
      antibiotics in uncomplicated diverticulitis can be an effective treatment,
      avoiding the need for acute surgical intervention. In the event of surgery the
      choice of procedure is dictated by the degree of contamination and the expertise
      of the operating surgeon. This chapter will outline the modern management of
      diverticulitis, from steps in diagnosis to different surgical options in each
      clinical scenario, thus aiding clinicians on a practical level.

PMID- 12406457
TI  - Complicated diverticulosis.
AB  - "Uncomplicated" diverticulitis can be prevented from progressing into
      "complicated" diverticulitis by early diagnosis and active medical treatment.
      Complicated diverticulitis develops from a peridiverticular abscess, to a
      perforation with peritonitis, to fistulation into adjacent viscera, to luminal
      narrowing by inflammation or stricture formation causing obstruction. Computer
      tomography (CT) scanning is the diagnostic imaging modality when diverticulitis
      is suspected and allows percutaneous drainage of peridiverticular abscesses that
      will enhance the effect of antibiotic therapy with resolution of the acute
      episode in 75% of patients. Thus, an emergent or urgent operation is converted to
      an elective operation and a two-stage operative procedure, namely a temporary
      stoma and a second operation, is avoided. Interventional surgery is urgent for
      perforation and obstruction. While a Hartmann's resection and temporary colostomy
      has been the favoured operative procedure, under favourable conditions resection
      with primary anastomosis is preferable. Although a temporary stoma may be
      required with primary anastomosis, and hence the procedure is a two-stage one
      similar to a Hartmann's, the closure of the stoma is less demanding and has a
      lower morbidity. A single-stage resection and anastomosis is the standard
      elective treatment for symptomatic fistulas and strictures.

PMID- 12406459
TI  - Cultural correlates of youth suicide.
AB  - Youth suicide has risen in most developed nations over the past 50 years,
      especially among males, but the increase remains to be explained. Statistical
      analyses were used to examine associations between youth suicide rates in 11-21
      mainly Western, developed nations and 32 socio-economic and cultural variables.
      The central hypothesis was that suicide rates would be correlated with various
      cultural measures of social attachment and integration, especially individualism.
      Socio-economic variables were included in the analysis to demonstrate the
      relative strength of the cultural associations. The study found a strong positive
      correlation between male youth suicide rates and subjective measures of health,
      optimism, and several indices of individualism, including personal freedom and
      control. Correlations between female youth suicide and individualism were
      smaller, attaining significance in only one instance. Male youth suicide and
      individualism were negatively correlated with older people's sense of parental
      duty. Correlations between suicide and other possibly relevant cultural variables
      -tolerance of suicide, belief in God and national pride--were not significant.
      The analysis of socio-economic variables yielded only one significant, but
      doubtful, correlation. The findings can be interpreted as supporting two very
      different hypotheses: that youth suicide represents "an island of misery in an
      ocean of happiness" or "the tip of an iceberg of suffering". In favouring the
      latter interpretation, and consistent with Durkheim's theories on suicide, it is
      argued that increased youth suicide reflects a failure of Western societies to
      provide appropriate sites or sources of social identity and attachment, and,
      conversely, a tendency to promote unrealistic or inappropriate expectations of
      individual freedom and autonomy.

PMID- 12406461
TI  - On the measurement of relative and absolute income-related health inequality.
AB  - In recent work on international comparisons of income-related inequalities in
      health, the concentration index has been used as a measure of health inequality.
      A drawback of this measure is that it is sensitive to whether it is estimated
      with respect to health or morbidity. An alternative would be to use the
      generalized concentration index that is based on absolute rather than relative
      health differences. In this methodological paper, we explore the importance of
      the choice of health inequality measure by comparing the income-related
      inequality in health status and morbidity between Sweden and Australia. This
      involves estimating a concentration index and a generalized concentration index
      for the eight-scale health profile of the Short Form 36 (SF-36) health survey. We
      then transform the scores for each scale into a measure of morbidity and show
      that whether the concentration index is estimated with respect to health or
      morbidity has an impact on the results. The ranking between the two countries is
      reversed for two of the eight dimensions of SF-36 and within both countries the
      ranking across the eight SF-36 scales is also affected. However, this change in
      ranking does not occur when the generalized concentration index is compared and
      we conclude with the implications of these results for reporting comparisons of
      income-related health inequality in different populations.

PMID- 12406460
TI  - The contribution of medical care to changing life expectancy in Germany and
      Poland.
AB  - This paper assesses the impact of medical care on changes in mortality in east
      Germany and Poland before and after the political transition, with west Germany
      included for comparison. Building upon Rutstein's concept of unnecessary untimely
      deaths, we calculated the contribution of conditions considered responsive to
      medical care or health policy to changes in life expectancy between birth and age
      75 [e(0-75)] for the periods 1980/1983-1988 and 1991/1992-1996/1997. Temporary
      life expectancy, between birth and age 75, has been consistently higher in west
      Germany, intermediate in east Germany and lowest in Poland. Although improving in
      all three regions between the early 1980s and the late 1990s, the pace of change
      differed between countries, resulting in a temporary widening of an initial east
      west gap by the late 1980s and early 1990s. In the 1980s, in east Germany, 50-60%
      of the improvement was attributable to declining mortality from conditions
      responsive to medical care (west Germany: 30-40%). A net positive effect was also
      observed in Poland, although counterbalanced by deterioration in ischaemic heart
      disease mortality.In the former communist countries, improvements attributable to
      medical care in the 1980s were due, largely, to declining infant mortality. In
      the 1990s, they benefited also adults, specifically those aged 35+ in Poland and
      55+ in Germany. A persisting east-west gap in temporary life expectancy in
      Germany was due, largely, to higher mortality from avoidable conditions in the
      east, with causes responsive to health policy contributing about half, and
      medical care 16% (men) to 24% (women) to the differential in 1997. The findings
      indicate that changes in the health care system related to the political
      transition were associated with improvements in life expectancy in east Germany
      and, to a lesser extent, in Poland. Also, differences in the quality of medical
      care as assessed by the concept of "unnecessary untimely deaths" appear to
      contribute to a persisting east-west health gap. Especially in Poland and the
      former German Democratic Republic there remains potential for further progress
      that would narrow the health gap with the west.

PMID- 12406462
TI  - Economic role of solidarity and social capital in accessing modern health care
      services in the Ivory Coast.
AB  - At the beginning of the 1990s, health service reforms were implemented in public
      health institutions in most African countries South of the Sahara. In the Ivory
      Coast, the imposition of user fees for public services was adopted in 1994. Such
      fees require each person to have adequate financial resources in order to access
      modern health care services. Many poor people--despite their poverty--are able to
      access modern health care services that have become quite expensive. The factor
      that allows this access lies within the solidarity of parents, friends or members
      of a social network. In Africa, illness is a social phenomenon and a state of
      illness is negative. The sick human being is one who cannot fully participate in
      community life. The treatment of a sick person is, then, an act, which is tied to
      the systems of life, which are produced and maintained collectively. Once the
      causes of illness are identified and consequences evaluated, it is the entire
      family or group that participates in the finances which bring about treatment. In
      this study, we show the role of social capital in the processes of financial
      solidarity for access to modern health care services that now require payment.
      Our investigation provides valuable insights on the role of social capital with
      respect to social strategies and community financing mechanisms for the
      acquisition of modern health care in Africa.

PMID- 12406463
TI  - Qualitative differences among cancer clinical trial explanations.
AB  - This paper examines how medical oncologists present to breast cancer patients the
      option of participating in experimental treatment trials. The investigation takes
      a case study approach, comparing two contrasting presentations of the clinical
      trial option. One presentation constructs the experimental trial as a locally
      organized, joint physician-patient effort to determine "best" treatments, and
      minimizes uncertainty by oversimplification of the randomization process; the
      second presentation situates the clinical trial within the larger national
      research effort, underscores the uncertainty created by randomization, and casts
      non-enrollment as a reasonable option. These observations provide initial
      evidence that physician presentation of the clinical trial varies substantially
      and provides the first detailed look at actual discourse practices used in the
      United States to recruit patients to experimental protocols.

PMID- 12406464
TI  - Lifetime risk factors for women's psychological distress in midlife.
AB  - Research on the causes of psychological distress in women in midlife has focused
      on current adversity and hormonal changes associated with menopause and paid less
      attention to possible risk factors across the life course. We examined the
      factors in childhood, adolescence and earlier adult life that show persisting
      effects on psychological symptoms reported annually over a 6 year period (47-52
      years) using prospective data on a cohort of 1500 British women who have been
      followed since their birth in 1946. Even after taking into account the powerful
      effect of recent life stress, this study found that women with a high level of
      psychological distress had different life course trajectories than those with
      less distress. They were more likely to have scored highly on the neuroticism
      scale or exhibited antisocial behaviour when they were teenagers, and to have had
      prior experience of mental and physical health problems in adult life. Those
      whose parents had divorced reported more distress in midlife, particularly if
      they too had experienced marital breakdown. These factors accounted for the
      associations between some of the adult sources of risk, particularly those to do
      with interpersonal difficulties or poor adult socioeconomic circumstances, and
      psychological distress in midlife. There was no evidence that concurrent
      menopausal status had any effect on the level of psychological symptoms except
      for those women on hormone replacement therapy who had a small and independent
      additional risk. More attention to a long term temporal perspective is warranted
      in research on the causes of psychological distress in women at midlife.

PMID- 12406465
TI  - Change in psychological and vasomotor symptom reporting during the menopause.
AB  - There remains uncertainty regarding what health symptoms can be directly
      attributed to the menopause. The association between changes in menopausal status
      and changes in vasomotor symptom and psychological symptom reporting was
      investigated and the effects of changing menopausal status were compared with
      those related to life events and difficulties. Reports of common health symptoms,
      menopausal status and life events and difficulties have been collected
      prospectively from 1572 British women followed up since their birth in 1946,
      every year between 47 and 52 years. Regression models for repeated measures were
      fitted with the change in symptom scores between consecutive years as the
      outcome. Estimates from these models were obtained using generalised estimating
      equations, thus allowing appropriately for the correlation between repeated
      measures on the same woman. Vasomotor symptoms were found to be strongly related
      to changes in menopausal status with increases being observed as women move
      through the menopause. Psychological symptoms were more strongly associated with
      current life events and difficulties, particularly those experienced in family
      life, than with menopausal status. An increase in symptoms was, however, observed
      in premenopausal and perimenopausal women starting hormone replacement therapy.
      These effects were not confounded or modified by previous psychological
      morbidity, social or behavioural factors. The findings suggest that vasomotor
      symptoms are dependent on changing hormone levels associated with the menopause,
      while psychological symptoms are not. The possibility that there is a small
      subgroup of women who experience increased psychological problems at the time of
      the menopause, and who in this cohort are identified by their use of HRT, is
      suggested. The mechanism behind this rise remains unclear. Factors other than the
      menopause should be considered, such as concurrent life events and past
      experiences and behaviours, when considering the treatment of psychological
      symptoms in women during middle life.

PMID- 12406466
TI  - Childhood and adulthood risk factors for socio-economic differentials in
      psychological distress: evidence from the 1958 British birth cohort.
AB  - Social inequalities in psychological status have been attributed to health
      selection and to social causation. We used data from the 1958 British birth
      cohort, followed over three decades, to identify causes of inequality in
      adulthood. Psychological status prior to labour market entry influenced inter
      generational mobility, but selection effects were weaker for intra-generational
      mobility, between age 23 and 33. However, selection failed to account for social
      differences in risk of distress of approximately threefold in classes IV&V
      compared with I&II. Both childhood and adult life factors appeared to contribute
      to the development of inequalities. The principal childhood factors were ability
      at age 7 for both sexes and adverse environment (institutional care for men and
      low class for women). Adult life factors varied, with stronger effects for work
      factors (job strain and insecurity) for men and qualifications on leaving school,
      early child-bearing and financial hardship for women. Gradients in psychological
      distress reflect the cumulative effect of multiple adversities experienced from
      childhood.

PMID- 12406467
TI  - Building an inter-disciplinary science of health inequalities: the example of
      lifecourse research.
AB  - Across the post-industrial world, new public health strategies are being
      developed with the goal of reducing the socio-economic gradient in health. These
      new strategies are distinguished by a commitment to tackling the macro
      determinants of health inequalities through policies informed by scientific
      evidence. The engagement with macro determinants and with scientific evidence
      presents a major challenge to the health inequality research community. This is
      not only because of the complexity of the links between distal causes, proximal
      risk factors and health outcomes. It is also and more importantly because of the
      narrow disciplinary base of health inequality research. Grounded in social
      epidemiology, health inequality research has illuminated the pathways which run
      from individual socio-economic position to health-but has left in shadow the
      factors which influence socio-economic position. Broadening the evidence base to
      include these structural processes requires a new science of health inequalities,
      resourced both by epidemiological research and by research on social inequality
      and social exclusion. The paper demonstrates how such an inter-disciplinary
      science can be constructed. Taking lifecourse research as its example and the UK
      as its case study, it nests epidemiological research within social policy
      research: setting evidence on the health consequences of cumulative exposures
      within research on lifecourse dynamics, and locating both within analyses of how
      state policies can amplify or moderate inequalities in socio-economic position.

PMID- 12406468
TI  - Exploring the determinants of health for First Nations peoples in Canada: can
      existing frameworks accommodate traditional activities?
AB  - While much research has examined First Nations peoples' health in Canada, few
      studies have explored the role of traditional activities in enhancing health.
      Using data from the 1991 Aboriginal Peoples Survey (APS), this paper incorporates
      a set of measures of traditional activities within a determinants of health
      framework for understanding First Nations peoples' health. Results from the
      analyses undertaken show that many of the determinants of health identified in
      analyses of the Canadian population in general hold for First Nations peoples.
      While only a few statistically significant relationships between health status
      and traditional activities were identified, taking into account the limitations
      of the APS and other conceptual issues, we argue that there is the potential to
      move from the analysis of traditional activities to a more nuanced analysis of
      cultural attachment.

PMID- 12406470
TI  - SWAp dynamics in a decentralized context: experiences from Uganda.
AB  - This paper examines the role of the Ministry of Health (MoH) in Uganda in the
      process of developing a Sector-Wide Approach (SWAp) within the health sector.
      Power dynamics are integral to any understanding of development assistance, and
      SWAps bring with them new opportunities for the deployment of influence. The SWAp
      process has changed the interaction between the donors and the Government, and
      the perspective of this interaction has shifted from various technical areas to
      the entire health sector. It is argued that although the decentralization of the
      public sector has transferred considerable responsibilities and duties from the
      central level to the districts, significant power, defined as a social construct,
      has been generated by the MoH in the very process of developing SWAps. The MoH
      has been able to exercise significant influence on defining the content and
      boundaries of the SWAp process, as well as the direction it is taking. This
      development has largely followed blueprints drawn by donors. Through the
      institutional framework associated with SWAps, the MoH has redefined the
      interaction between the central level and the districts as well as between the
      MoH and the donors. While the SWAp process is now moving from the planning to the
      implementation phase in Uganda, we see a number of new, changing, ambiguous and
      contradictory strategies emerging.

PMID- 12406469
TI  - Unemployment and health: contextual-level influences on the production of health
      in populations.
AB  - While there is a large and growing literature investigating the relationship
      between an individual's employment status and health, considerably less is known
      about the effect on this relationship of the context in which unemployment
      occurs. The aim of this paper is test for the presence and nature of contextual
      effects in the ways unemployment and health are related, based on a simple
      underlying model of stress, social support and health using a large population
      health survey. An individual's health can be influenced directly by own exposure
      to unemployment and by exposure to unemployment in the individual's context, and
      indirectly by the effects these exposures have on the relationship between other
      health determinants and health. Based on this conceptualization an empirical
      model, using multi-level analysis, is formulated that identifies a five-stage
      process for exploring these complex pathways through which unemployment affects
      health. Results showed that the association of individual unemployment with
      perceived health is statistically significant. Nevertheless, this study did not
      provide evidence to support the hypothesis that the association of unemployment
      with health status depends upon whether the experience of unemployment is shared
      with people living in the same environment. Above all, this study demonstrates
      both the subtlety and complexity of individual- and contextual-level influences
      on the health of individuals. Our results caution against simplistic
      interpretations of the unemployment-health relationship and reinforce the
      importance of using multi-level statistical methods for investigation of it.

PMID- 12406471
TI  - Afghan refugees and the temporal and spatial distribution of malaria in Pakistan.
AB  - Influx of refugees and establishment of camps or settlements in malaria endemic
      areas can affect the distribution and burden of malaria in the host country.
      Within a decade of the Soviet invasion of Afghanistan and the arrival of 2.3
      million Afghan refugees in Pakistan's North West Frontier Province, the annual
      burden of malaria among refugees had risen ten fold from 11,200 cases in 1981 to
      118,000 cases in 1991, a burden greater than the one reported by the Pakistan
      Ministry of Health for the entire Pakistani population. Political developments in
      the 1990s led to over half the refugee population repatriating to Afghanistan,
      and the Afghan Refugee Health Programme (ARHP) was scaled down proportionately.
      Districts in which the ARHP recorded a reduced incidence of malaria began to show
      an increased incidence in the statistics of the Pakistan government health
      programme. This and other evidence pointed to a change in health seeking
      practices of the refugees who remained in Pakistan, with many turning from ARHP
      to Pakistani health services as aid declined. Comparison of the two sources of
      data produced no evidence for the spatial distribution of malaria in NWFP having
      changed during the 1990s. Nor was there any evidence for the presence of refugees
      having increased the malaria burden in the Pakistani population, as is sometimes
      alleged. This highlights the risk of misinterpreting health trends when parallel
      health services are operating. Over the decade incidence in the refugee camps
      decreased by 25% as a result of control activities, and by 1997 the burden among
      remaining refugees had fallen to 26,856 cases per annum. These trends indicate
      that the burden would continue to fall if political conditions in Afghanistan
      were to improve and more refugees returned to their homeland.

PMID- 12406477
TI  - Fighting back against substance abuse: are community coalitions winning?
AB  - OBJECTIVE: Federal initiatives continue to provide strong support for community
      antidrug coalitions, but whether this approach actually reduces substance abuse
      is not clear. This paper examines the strategies that coalitions in a large
      national demonstration program (Fighting Back) chose to develop, the degree to
      which they implemented these strategies, and evidence regarding their effects.
      METHODS: Coalition strategy implementation was coded and ranked for 12 Fighting
      Back sites. Effect sizes (intervention over time) for outcomes related to
      substance use, alcohol and other drug treatment, and community/prevention
      indicators were also ranked by site. Using rank order correlation, three
      directional hypotheses compared strategy dose to outcomes. RESULTS: None of the
      hypotheses were supported. Strategies aimed at either youth or
      community/prevention outcomes showed no effects, while strategies to improve
      adult-focused outcomes showed significant negative effects over time, compared to
      matched controls. Coalitions with a more comprehensive array of strategies did
      not show any superior benefits, and increasing the number of high-dose strategies
      showed a significant negative effect on overall outcomes. CONCLUSIONS:
      Comprehensive community coalitions are intuitively attractive and politically
      popular, but the potential for adverse effects must be considered. Efforts to
      evaluate implementation processes as well as to correlate strategies with
      theoretically corresponding outcomes are a critical but neglected aspect of
      prevention research.

PMID- 12406478
TI  - Vaccine storage practices in primary care physician offices: assessment and
      intervention.
AB  - PURPOSE: To assess the proportion of primary care physician (PCP) offices meeting
      vaccine storage guidelines, identify factors associated with low compliance, and
      evaluate whether a quality improvement (QI) activity improves compliance.
      METHODS: We examined compliance with guidelines of 721 PCP offices contracted
      with a national managed care organization in four cities. A QI activity
      (educational materials, written feedback, and distribution of thermometers) was
      conducted at baseline and a follow-up assessment occurred within 3 months.
      RESULTS: Baseline compliance was relatively high, with >80% adherence to most
      guidelines. For example, 89% of offices had a thermometer; and 83% of
      temperatures were appropriate. Most units did not have vaccines stored in the
      door or food/biological materials in the unit (80% and 96%, respectively). Almost
      all vaccines had not expired. Multivariate analysis indicated that practice
      location, type of physician, participation in vaccine programs, and using
      guidelines were associated with compliance. For most of the compliance measures,
      pediatric offices had the highest compliance. Adherence to guidelines improved
      after the QI activity; the net change between pre- and post-intervention ranged
      from +1% to +19%. Measurements most impacted included temperature log posted (19%
      improvement in refrigerator; 16% improvement in freezer) and no vaccine stored in
      refrigerator door (14% improvement). CONCLUSIONS: Despite generally high
      compliance, there are some opportunities for improvement in how PCPs store
      vaccines. Incorporating an intervention program in existing practice activities
      can improve storage practices. Further research is needed to determine the
      possible benefits of targeting interventions to certain types of providers who
      may be less knowledgeable about recommended guidelines.

PMID- 12406479
TI  - Seatbelt use, attitudes, and changes in legislation: an international study.
AB  - BACKGROUND: The use of seat belts is among the most effective methods of reducing
      injury in motor vehicle crashes. We examined trends in seat belt use by
      university students from 13 European countries between 1990 and 2000, in relation
      to changes in legislation, attitudes, and hazardous driver behaviors. METHODS:
      Data were collected via an anonymous standardized questionnaire from university
      students in Belgium, England, France, Germany, Greece, Hungary, Iceland, Ireland,
      Italy, the Netherlands, Poland, Portugal, and Spain. There were 10,576
      respondents in 1990, and 10,294 in 2000. Data were also collected from 1672
      students in the United States in 2000. Analyses were performed in early 2002.
      RESULTS: Reported seat belt use increased from 63% to 73% in male students, and
      from 66% to 77% in female students over the decade. There were marked increases
      in seat belt use in countries with changes in legislation or enforcement from
      1990 to 2000, with 24% to 64% more respondents reporting seat belt use in 2000.
      The prevalence of use and noted changes during this period correlated with
      findings from national surveys (r= 0.91). Attitudes to seat belt use were
      associated with behavior both within and between countries. Nonuse of seat belts
      was positively related to alcohol-impaired driving and failure to obey speed
      limits. CONCLUSIONS: Legislation has a substantial impact on the use of vehicle
      seat belts, but additional gains require efforts to change attitudes within the
      university student population.

PMID- 12406480
TI  - Physical and mental health effects of intimate partner violence for men and
      women.
AB  - BACKGROUND: Few population-based studies have assessed the physical and mental
      health consequences of both psychological and physical intimate partner violence
      (IPV) among women or men victims. This study estimated IPV prevalence by type
      (physical, sexual, and psychological) and associated physical and mental health
      consequences among women and men. METHODS: The study analyzed data from the
      National Violence Against Women Survey (NVAWS) of women and men aged 18 to 65.
      This random-digit-dial telephone survey included questions about violent
      victimization and health status indicators. RESULTS: A total of 28.9% of 6790
      women and 22.9% of 7122 men had experienced physical, sexual, or psychological
      IPV during their lifetime. Women were significantly more likely than men to
      experience physical or sexual IPV (relative risk [RR]=2.2, 95% confidence
      interval [CI]=2.1, 2.4) and abuse of power and control (RR=1.1, 95% CI=1.0, 1.2),
      but less likely than men to report verbal abuse alone (RR=0.8, 95% CI=0.7, 0.9).
      For both men and women, physical IPV victimization was associated with increased
      risk of current poor health; depressive symptoms; substance use; and developing a
      chronic disease, chronic mental illness, and injury. In general, abuse of power
      and control was more strongly associated with these health outcomes than was
      verbal abuse. When physical and psychological IPV scores were both included in
      logistic regression models, higher psychological IPV scores were more strongly
      associated with these health outcomes than were physical IPV scores. CONCLUSIONS:
      Both physical and psychological IPV are associated with significant physical and
      mental health consequences for both male and female victims.

PMID- 12406481
TI  - Tobacco and alcohol use-prevention program for Hispanic migrant adolescents.
AB  - OBJECTIVE: Evaluate a community-based tobacco/alcohol use-prevention program
      group compared with an attention-control condition (first aid/home safety) group.
      METHODS: A total of 660 adolescents and 1 adult caregiver for each were recruited
      through the Migrant Education Program to participate in an 8-week intervention.
      Random assignment to the two groups occurred in 22 schools. Seventy 8-week
      intervention groups (37 tobacco/alcohol and 33 attention-control) were conducted.
      Assessments occurred at baseline, immediate post-intervention, and 1- and 2-year
      follow-ups. Susceptibility to smoking and alcohol as well as smoking and drinking
      over the past 30 days were the primary outcomes of interest. RESULTS: Following
      intervention, no between-group differences in smoking or drinking were
      significant. Thirty-day smoking started and remained at very low levels, with the
      highest group prevalence at any measurement period being 4.7% and the lowest
      2.5%. Those considered susceptible to smoking dropped by nearly 40% in the
      attention-control group and by 50% in the intervention group from baseline to the
      final follow-up. (The overall reduction from post-test to final follow-up was
      statistically significant.) Less-acculturated children were less likely to report
      drinking in the past 30 days. CONCLUSIONS: The current intervention was not
      demonstrated to be effective in preventing cigarette or alcohol consumption. This
      perhaps is due to very low baseline levels of smoking and drinking in the migrant
      youth participants.

PMID- 12406482
TI  - Do HEDIS measures reflect cost-effective practices?
AB  - PURPOSE: Whether the Health Plan Employer Data and Information Set (HEDIS)
      performance measures for managed care plans encourage a cost-effective use of
      society's resources has not been quantified. Our study objectives were to examine
      the cost-effectiveness evidence for the clinical practices underlying HEDIS 2000
      measures and to develop a list of practices not reflected in HEDIS that have
      evidence of cost effectiveness. DATA SOURCES: Two databases of economic
      evaluations (Harvard School of Public Health Cost-Utility Registry and the Health
      Economics Evaluation Database) and two published lists of cost-effectiveness
      ratios in health and medicine. STUDY SELECTION: For each of the 15 "effectiveness
      of care" measures in HEDIS 2000, we searched the data through 1998 for cost
      effectiveness ratios of similar interventions and target populations. We also
      searched for important interventions with evidence of cost-effectiveness
      (<$20,000 per life-year [LY] or quality-adjusted life year [QALY] gained), which
      are not included in HEDIS. All ratios were standardized to 1998 dollars. The data
      were collected and analyzed during fall 2000 to summer 2001. DATA EXTRACTION:
      Cost-effectiveness ratios reporting outcomes in terms of cost/LY or cost/QALY
      gained were included if they matched the intervention and population covered by
      the HEDIS measure. DATA SYNTHESIS: Evidence was available for 11 of the 15 HEDIS
      measures. Cost-effectiveness ranges from cost saving to $660,000/LY gained. There
      are numerous non-HEDIS interventions with some evidence of cost effectiveness,
      particularly interventions to promote healthy behaviors. CONCLUSIONS: HEDIS
      measures generally reflect cost-effective practices; however, in a number of
      cases, practices may not be cost effective for certain subgroups. Data quality
      and availability as well as study perspective remain key challenges in judging
      cost effectiveness. Opportunities exist to refine existing measures and to
      develop additional measures, which may promote a more efficient use of societal
      resources, although more research is needed on whether these measures would also
      satisfy other desirable attributes of HEDIS.

PMID- 12406483
TI  - Exercise training for African Americans with disabilities residing in difficult
      social environments.
AB  - OBJECTIVE: To examine the feasibility, efficacy, and safety of a structured 12
      week exercise training program for a predominantly African-American group of
      adults with multiple health conditions who reside in difficult social
      environments. METHODS: A total of 37 females and 7 males (mean age, 54.1 years)
      participated in an exercise training regimen 3 days per week for 60 minutes per
      day (cardiovascular, 30 minutes; strength, 20 minutes; and flexibility, 10
      minutes). Outcome measures included peak VO(2) (mL min(-1), mL kg(-1) min(-1));
      upper and lower body strength (strength); hand-grip strength (GS); body weight
      (BW); total skin folds (TS); waist-to-hip ratio (WHR); hamstring/low-back
      flexibility (HLBF); and shoulder flexibility (SF). RESULTS: Compared to the
      control group, the exercise group showed significant gains in peak VO(2) (p <
      0.01); strength (p < 0.01); and body composition (TS, p < 0.01). There was no
      significant difference between the exercise and control groups on BW, WHR, HLBF,
      and GS. Of a total 1116 exercise sessions (31 experimental participants x 36
      sessions), 87% of the sessions were attended. CONCLUSIONS: A structured exercise
      training program can provide substantial improvement in strength and
      cardiovascular fitness in low-income, sedentary adults with multiple chronic
      conditions and/or risk factors for chronic conditions. Future research should
      explore simple home-based and community-based physical activity interventions
      that provide ongoing support for increasing and maintaining physical activity
      participation in this cohort.

PMID- 12406484
TI  - Enhancing self-efficacy and patient care with cardiovascular nutrition education.
AB  - BACKGROUND: Provision of medical education that develops nutrition knowledge and
      self-efficacy is critical if physicians are to incorporate nutrition in
      preventive care. We studied the impact of a cardiovascular nutrition module on
      the knowledge, attitudes, and self-efficacy of fourth-year medical students and
      the relationship of these attributes to patient care practices. METHODS: Based on
      national practice guidelines and learner needs, an educational intervention
      consisting of two web-based cases, pocket reference cards, and classroom
      discussion was developed and implemented. Knowledge, attitudes, and self-efficacy
      were measured at the beginning and end of the 4-week ambulatory care rotation for
      40 control and 156 experimental students. Performance in patient care was
      approximated using a self-report; chart audits were performed for a subset of
      students. CONCLUSIONS: Knowledge scores of experimental students increased
      significantly from a mean of 10.3 to 14.4 (p<0.001), while the change for control
      students from 9.2 to 9.8 was not significant (p=0.20). The increase in self
      efficacy scores from 26.2 to 35.7 in the experimental group (p<0.001) was twice
      that of the increase from 25.8 to 29.9 in the control group (p=0.001). Small but
      significant increases in attitude scores were similar for both groups. Limited
      data on student performance revealed that students with greater cardiovascular
      nutrition self-efficacy were more likely to address nutrition with cardiovascular
      patients. CONCLUSIONS: Incorporation of cardiovascular nutrition concepts in an
      ambulatory care rotation including use of computer-based cases improved student
      knowledge and self-efficacy, which may translate to increased frequency of future
      physicians addressing nutrition with patients.

PMID- 12406485
TI  - Fighting back or fighting themselves? Community coalitions against substance
      abuse and their use of best practices.

PMID- 12406487
TI  - In response to the 2002, vol. 22, no. 4 article entitled "The rise and fall of
      occupational medicine in the United States".

PMID- 12406486
TI  - In response to the 2002, vol. 22, no. 4 article entitled "The rise and fall of
      occupational medicine in the United States".

PMID- 12406488
TI  - In Response to the 2002, vol. 22, issue 4 article entitled "The rise and fall of
      occupational medicine in the United States". The rise and fall of occupational
      medicine in the United Kingdom.

PMID- 12406489
TI  - Guidance at the many edges of evidence: position statements of the American
      College of Preventive Medicine.

PMID- 12406490
TI  - Preventing handgun injury. American College of Preventive Medicine position
      statement.

PMID- 12406491
TI  - NTP center for the evaluation of risks to human reproduction phthalates expert
      panel reports.

PMID- 12406492
TI  - NTP Center for the Evaluation of Risks to Human Reproduction: phthalates expert
      panel report on the reproductive and developmental toxicity of butyl benzyl
      phthalate.

PMID- 12406493
TI  - NTP Center for the Evaluation of Risks to Human Reproduction: phthalates expert
      panel report on the reproductive and developmental toxicity of di-n-butyl
      phthalate.

PMID- 12406494
TI  - NTP Center for the Evaluation of Risks to Human Reproduction: phthalates expert
      panel report on the reproductive and developmental toxicity of di(2-ethylhexyl)
      phthalate.

PMID- 12406495
TI  - NTP Center for the Evaluation of Risks to Human Reproduction: phthalates expert
      panel report on the reproductive and developmental toxicity of di-isodecyl
      phthalate.

PMID- 12406496
TI  - NTP Center for the Evaluation of Risks to Human Reproduction: phthalates expert
      panel report on the reproductive and developmental toxicity of di-isononyl
      phthalate.

PMID- 12406497
TI  - NTP Center for the Evaluation of Risks to Human Reproduction: phthalates expert
      panel report on the reproductive and developmental toxicity of di-n-hexyl
      phthalate.

PMID- 12406499
TI  - Expression of insulin-responsive glucose transporter GLUT4 mRNA in the rat brain
      and spinal cord: an in situ hybridization study.
AB  - Following a previous immunocytochemical study of GLUT4 in the rat brain and
      spinal cord (J. Comp. Neurol. 399 (1998) 492), we now report the distribution and
      cellular expression of GLUT4 mRNA in the CNS using reverse transcription
      polymerase chain reaction and non-radioactive in situ hybridization (ISH). The
      former technique demonstrated the expression of GLUT4 in the different regions
      examined while ISH with a specific riboprobe allowed the anatomical localization
      of GLUT4 mRNA. A strong hybridization signal was detected in the piriform and
      entorhinal cortices and in the pyramidal cell layer of the hippocampal CA1-CA3
      areas. Numerous moderately labeled cells were additionally observed in the
      dentate gyrus granular layer, subiculum and most neocortical areas, as well as in
      different nuclei of the limbic and motor systems. In contrast, positive cell
      groups were scarce in the hypothalamus. In the hindbrain, a strong expression of
      GLUT4 mRNA was observed in the large cell bodies of the red nucleus and
      cerebellar Purkinje cell layer. Moreover, different groups of moderately labeled
      cells were found in the deep cerebellar and medullary motor nuclei, in various
      reticular fields and in the ventral horn of the spinal cord. The present results
      of ISH mostly agree with the immunocytochemical data reported by our group,
      although the immunoreactive cells were generally less numerous. However, the fact
      that a high expression of GLUT4 mRNA was observed in cell bodies of the piriform
      lobe, hippocampus and substantia nigra, whereas the immunoreactivity for GLUT4
      was low in these regions, suggests the existence of post-transcriptional
      regulation of GLUT4 expression which may depend on the physiological conditions
      of the animals.

PMID- 12406498
TI  - NTP Center for the Evaluation of Risks to Human Reproduction: phthalates expert
      panel report on the reproductive and developmental toxicity of di-n-octyl
      phthalate.

PMID- 12406500
TI  - Differential effects of prenatal cocaine exposure on selected subunit mRNAs of
      the GABA(A) receptor in rabbit anterior cingulate cortex.
AB  - We have previously shown that in the dopamine-rich anterior cingulate cortex
      (ACC), significant changes in gamma-aminobutyric acid (GABA) immunoreactivity
      occur in the offspring of rabbits given intravenous injections of cocaine (3
      mg/kg) twice daily during pregnancy. In the present study, the effects of
      prenatal cocaine exposure on the developmental expression of specific GABA(A)
      receptor subunit mRNAs were investigated. We compared the distribution of the
      alpha1, beta2, and gamma2 subunit mRNAs in cocaine- and saline-treated offspring
      aged postnatal days 20 and 60 (P20, P60). At P20, prenatal cocaine exposure
      resulted in a significant increase in alpha1 subunit mRNA in ACC lamina III and a
      significant reduction in the amounts of the beta2 subunit mRNA in ACC lamina II.
      No differences between cocaine- and saline-treated controls were detected for
      gamma2 subunit mRNA levels in ACC. Although the pattern of labeling was altered
      in cocaine-exposed animals, Nissl sections revealed no differences in lamination,
      indicating that the changes in GABA(A) subunit mRNAs could not be attributed to
      abnormal cytoarchitectonics. In P60 brains, no significant differences were
      observed between cocaine- and saline-treated material, indicating that the
      observed differences were transient. Collectively, our data show that prenatal
      cocaine exposure elicits differential, lamina-specific changes in mRNA levels
      encoding selected subunits of the GABA(A) receptor. Since these changes occur
      during a critical period when fine tuning of synaptic organization is achieved by
      processes of selective elimination or stabilization of synapses, we suggest that
      specific subunit mRNAs of the GABA(A) receptor play a role in cortical
      development.

PMID- 12406501
TI  - Restricted distribution of galanin receptor 3 (GalR3) mRNA in the adult rat
      central nervous system.
AB  - Recent molecular cloning studies have established the existence of a third rat
      galanin receptor subtype, GalR3, however its precise distribution in the
      mammalian central nervous system (CNS) is not well established. In the present
      study, we examined the regional and cellular distribution of GalR3 mRNA in the
      CNS of the rat by in situ hybridization. Our findings indicate that GALR3 mRNA
      expression in the rat brain is discrete and highly restricted, concentrated
      mainly in the preoptic/hypothalamic area. Within the hypothalamus, GalR3
      expression was confined to the paraventricular, ventromedial and dorsomedial
      hypothalamic nuclei. In addition to these hypothalamic nuclei, GalR3 mRNA
      expressing cells were observed in the medial septum/diagonal band of Broca
      complex, the bed nucleus of the stria terminalis, the medial amygdaloid nucleus,
      the periaqueductal gray, the lateral parabrachial nucleus, the dorsal raphe
      nucleus, the locus coeruleus, the medial medullary reticular formation and in one
      of the circumventricular organs, the subfornical organ. In the spinal cord, a
      faint but specific ISH signal was observed over the laminae I-II with a few
      moderately labeled cells distributed in laminae V and X. The neuroanatomical
      distribution of GalR3 suggests it might be involved in mediating documented
      effects of galanin on food intake, fluid homeostasis, cardiovascular function and
      nociception.

PMID- 12406502
TI  - NADPH diaphorase activity in olfactory receptor neurons and their axons conforms
      to a rhinotopically-distinct dorsal zone of the hamster nasal cavity and main
      olfactory bulb.
AB  - NADPH diaphorase histochemical protocols were optimized for the histochemical
      labeling of olfactory receptor neurons (ORNs) in the nasal cavity and their axon
      terminals in glomeruli of the main olfactory bulb (MOB) in the Syrian hamster.
      This labeling was then used to map and quantify the spatial distribution of ORNs
      and their central projections. Diaphorase-positive ORNs were found to be
      rhinotopically restricted to dorsal-medially situated segments of sensory mucosa
      associated with central air channels in the nose, together constituting about 25%
      of the total receptor sheet. This topography closely resembles the zonal
      expression patterns of putative odorant receptor genes and cell surface
      glycoconjugates in the nose. Moreover, the projections of ORNs in the diaphorase
      positive dorsal/central zone were found to expand onto the entire dorsal half of
      the MOB, consistent with spatial patterns discerned in retrograde tract-tracing
      studies. These boundaries indicate that dorsal/central zone ORNs project to a
      disproportionately larger region of the MOB than do those in the more
      ventral/peripheral zones. The demonstration of NADPH diaphorase activity in ORNs
      is inconsistent with the expression of the best-known NADPH-dependent enzymes,
      such as nitric oxide synthase (neuronal and endothelial isoforms) and NADPH
      cytochrome P450 oxidoreductase. Understanding the spatial patterning of
      histochemical labeling in ORNs should facilitate the biochemical identification
      of this diaphorase.

PMID- 12406503
TI  - Coexistence of NMDA and AMPA receptor subunits with nNOS in the nucleus tractus
      solitarii of rat.
AB  - We previously showed that most neuronal nitric oxide synthase (nNOS)-containing
      neurons in the nucleus tractus solitarii (NTS) contain NMDAR1, the fundamental
      subunit for functional N-methyl-D-aspartate (NMDA) receptors. Likewise, we found
      that almost all nNOS-containing neurons in the NTS contain GluR1, the calcium
      permeable AMPA receptor subunit. These data suggest that AMPA and NMDA receptors
      may colocalize in NTS neurons that contain nNOS. However, other investigators
      have suggested that non-NMDA receptors are located primarily on second-order
      neurons and NMDA receptors are located predominantly on higher-order neurons in
      NTS. We now seek to test the hypothesis that NMDA receptors, AMPA receptors and
      nNOS are colocalized in NTS cells. We performed triple fluorescent
      immunohistochemical staining of nNOS, NMDAR1 and GluR1, and performed confocal
      laser scanning microscopic analysis of the NTS. The distributions of nNOS
      immunoreactivity (IR), NMDAR1-IR and GluR1-IR in the NTS were similar to those we
      reported earlier. Superimposed images revealed that almost all NMDAR1-IR cells
      contained GluR1-IR and almost all GluR1-IR cells contained NMDAR1-IR. Some double
      labeled cells were additionally labeled for nNOS-IR. All nNOS-IR neurons
      contained both GluR1-IR and NMDAR1-IR. These studies support our hypothesis that
      NMDA and AMPA receptors are colocalized in NTS neurons and are consistent with a
      role of both types of ionotropic receptors in transmission of afferent signals in
      NTS. In addition, these data provide support for an anatomical link between
      ionotropic glutamate receptors and nitric oxide in the NTS.

PMID- 12406504
TI  - Interactions of enantiomers of 2',3'-didehydro-2',3'-dideoxy-fluorocytidine with
      wild type and M184V mutant HIV-1 reverse transcriptase.
AB  - Both the beta-D-(+) and beta-L-(-)-enantiomers of 2',3'-didehydro-2',3'-dideoxy-5
      fluorocytidine (D4FC) are clinically relevant compounds because of their potent
      anti-HIV and anti-HBV activities. Cross-resistance to L-D4FC with HBV containing
      a mutation in the conserved polymerase YMDD region has been observed. In order to
      better understand the effects of stereochemistry on planar 5-fluorinated cytidine
      analogs and to gain insight into resistance caused by YMDD mutations in HIV-1
      reverse transcriptase (RT), a combination of transient kinetic studies and
      computer modeling were employed. In contrast to studies with the (+) and (-)
      isomers of 3TC-TP and FTC-TP, it was found that wild type RT had a high
      enantiomeric selectivity between the D-(+) and L-(-) isomers of D4FC-TP. While no
      resistance was conferred by the methionine 184 to valine mutation to D-D4FC-TP, L
      D4FC-TP was incorporated 50- to 70-fold less efficiently. The kinetic parameters
      of incorporation in the presence of L-D4FC-TP by RT(WT) and the mechanism of
      resistance by RT(M184V) were found to be distinct from those seen with the
      corresponding L-isomers containing an oxathiolane ring: (-)-3TC-TP and (-)-FTC
      TP. Molecular modeling suggests that L- and D-D4FC-TP are positioned in the
      active site favorably for incorporation by RT(WT) and that L-D4FC-TP, but not D
      D4FC-TP, is sterically hindered by the addition of a beta branched amino acid at
      position 184 of RT(M184V).

PMID- 12406505
TI  - Effect of antioxidants on apoptosis induced by influenza virus infection:
      inhibition of viral gene replication and transcription with pyrrolidine
      dithiocarbamate.
AB  - Influenza virus (IV) infection induced apoptotic DNA fragmentation and the
      moderate overproduction of reactive oxygen species (ROS) in primary cultured
      chorion cells prepared from human fetal membranes, and IV particles were released
      from the infected cells. The antioxidant pyrrolidine dithiocarbamate (PDTC)
      inhibited the induced DNA fragmentation, ROS overproduction and IV particle
      release. Although Trolox inhibited ROS overproduction, it did not inhibit DNA
      fragmentation or IV production. The inhibitory effect of PDTC on DNA
      fragmentation was manifested when added up to 3 h after infection or by exposing
      the infected cells to it for only 1 h after infection. PDTC inhibited IV
      hemagglutinin (HA) viral (vRNA) and complementary (cRNA and mRNA) RNAs synthesis
      until 6 h after infection and delayed and decreased HA protein synthesis.
      However, HA RNA synthesis resumed after 12 h even in the presence of PDTC. These
      results suggested that PDTC inhibited apoptosis by inhibiting viral macromolecule
      synthesis rather than through its antioxidant effect, because Trolox did not
      inhibit apoptosis or IV production, although ROS overproduction was inhibited.
      The synthesis of specific viral macromolecules at the early stage of infection
      may play a critical role in the mechanism of apoptosis induction and moderate ROS
      overproduction may not be involved in the mechanism.

PMID- 12406506
TI  - Inhibition of host kinase activity altered by the LMP2A signalosome-a therapeutic
      target for Epstein-Barr virus latency and associated disease.
AB  - Epstein-Barr virus (EBV) is a human herpesvirus that establishes a lifelong
      latent infection in the majority of the human population. The virus resides in a
      latent state in B lymphocytes and is associated with a variety of cancers in the
      human host. In normal individuals, latent infection with EBV typically poses no
      health risk, but upon immunosuppression, either following organ transplantation
      or HIV infection, malignancies and lymphoproliferative diseases can result.
      Latent membrane protein 2A (LMP2A) is a virally encoded membrane protein that is
      expressed in EBV latent infection and in most of the tumors associated with EBV
      infection. Previous studies have indicated that LMP2A expression alters the
      activity of the Src family protein tyrosine kinases, the Syk protein tyrosine
      kinase, the Btk protein tyrosine kinase, and phosphatidylinositol 3-kinase (PI3
      kinase). In this study, inhibitors of each of these kinases were tested using an
      in vitro system dependent on LMP2A expression for B cell colony formation in IL-7
      containing methylcellulose media. Of the inhibitors tested, only piceatannol, a
      Syk tyrosine kinase inhibitor, demonstrated a specific effect on LMP2A expressing
      cells and not control cells. These studies provide a basis for targeting LMP2A
      function in EBV latency and may allow for the identification of novel
      therapeutics for the treatment or eradication of EBV latent infections and
      associated proliferative disorders.

PMID- 12406507
TI  - A post-CD4-binding step involving interaction of the V3 region of viral gp120
      with host cell surface glycosphingolipids is common to entry and infection by
      diverse HIV-1 strains.
AB  - The V3-loop region in the envelope protein gp120 of HIV is critical for viral
      infection, but its interaction with the target cells is not clear. Using
      synthetic peptides, representing linear V3 sequences as reagents, we obtained
      evidence to show inhibition of infection by both T-cell- and macrophage-tropic
      strains of human immunodeficiency virus type 1 (HIV-1) (X4 and R5, respectively),
      without interfering with gp120-CD4 interaction, by the V3 peptides through
      binding to host cell membrane glycosphingolipids (GSL). Synthetic peptides
      mimicking the central 15-21 amino acid sequence of the V3-loop region in both X4
      and R5 strains of HIV-1 competed with and blocked the entry of both types of HIV
      isolates. These HIV-inhibitory V3 peptides exhibited specific binding to target
      cells that was not competed by antibodies to either the primary receptor CD4 or
      the co-receptors CXCR-4 and CCR5. However, R15K, the V3 peptide from HIV-1 IIIB
      gp120 exhibited specific binding to three distinct cell surface GSL: GM3, Gb3,
      and GalCer. Further, R15K inhibited GSL binding of gp120 from both HIV-1 IIIB
      (X4, Gb3-binding strain) and HIV-1 89.6 (X4R5, GM3-binding strain). Together,
      these results suggest a critical V3-mediated post-CD4-binding event involving
      cell surface GSL binding represented by the HIV-inhibitory V3 peptides, that is
      common for the entry of diverse HIV-1 strains and may be targeted for the
      development of novel HIV therapeutics aimed at blocking viral entry.

PMID- 12406508
TI  - Genotypic and phenotypic characterization of the thymidine kinase of ACV
      resistant HSV-1 derived from an acyclovir-sensitive herpes simplex virus type 1
      strain.
AB  - Twenty-four strains of acyclovir (ACV)-resistant (ACV(r)) herpes simplex virus
      type 1 (HSV-1) were generated from the HSV-1 TAS strain by exposure to ACV, and
      the genotype and phenotype of the thymidine kinase (TK) from these mutants were
      analyzed. The TK polypeptide of the ACV(r) HSV-1 strains was examined by Western
      blot using an anti-HSV-1 TK rabbit serum. The sensitivity of each strain to ACV,
      foscarnet and cidofovir (CDV) was also determined. A single guanine (G) insertion
      or a single cytosine (C) deletion was detected in 12 of the 24 ACV(r) strains at
      the G or C homopolymer stretches within the TK gene. Genotypic analysis predicted
      that two thirds of the ACV(r) HSV-1 strains expressed truncated TK polypeptides,
      while one third expressed viral TK polypeptide with a single amino acid
      substitution at various sites. Western blot abnormalities in the viral TK
      polypeptides were identified in 21 ACV(r) strains. There was an inverse
      correlation between the susceptibility of the HSV-1 mutant strains to ACV and
      that to CDV. Nucleotide sequencing of the TK gene and Western blot analysis of
      the viral TK polypeptides are considered to be one of the methods for predicting
      virus sensitivity to ACV and CDV.

PMID- 12406509
TI  - Macrophage protection by addition of glutathione (GSH)-loaded erythrocytes to AZT
      and DDI in a murine AIDS model.
AB  - Monocyte-macrophages play a central role in HIV-1 infection because they are
      among the first cells to be infected and because later they are important
      reservoirs for the virus. Thus, newly designed therapies should take into account
      the protection of this cell compartment. Herein, we report the results obtained
      in a murine AIDS model, by the addition to AZT+DDI of a system (GSH-loaded
      erythrocytes) able to protect macrophages against HIV-1 infection. Five groups of
      LP-BM5-infected mice were treated as follows: one group was treated by AZT, one
      group was treated by DDI, one group was treated by the combination of both,
      another by GSH-loaded erythrocytes, and finally, one by the combination of all
      three. After 10 weeks of infection the parameters of the disease were studied and
      the proviral DNA content in different organs and in macrophages of bone marrow
      and of the peritoneal cavity was quantified. The results obtained show that mice
      treated with AZT+DDI+GSH-loaded erythrocytes showed proviral DNA content in the
      brain and in macrophages of bone marrow that was significantly lower than in mice
      treated with AZT+DDI. This study may help developing strategies aimed at blocking
      HIV-1 replication in its reservoirs in the body.

PMID- 12406510
TI  - Z-isomers of 2-hydroxymethylcyclopropylidenemethyl adenine (synadenol) and
      guanine (synguanol) are active against ganciclovir- and foscarnet-resistant human
      cytomegalovirus UL97 mutants.
AB  - Emergence of drug-resistant human cytomegalovirus (HCMV) strains is a substantial
      problem during treatment of HCMV infections in immunocompromised patients. The Z
      isomers of 2-hydroxymethylcyclopropylidenemethyl adenine (synadenol) and guanine
      (synguanol) were previously shown to be potent inhibitors of AD169 and Towne HCMV
      reference strains and postulated to share a common phosphorylation pathway with
      ganciclovir (GCV) possibly involving the UL97-encoded phosphotransferase.
      Analysis of synadenol and synguanol susceptibility of a series of HCMV isolates
      from immunocompromised untreated patients and from patients with treatment
      failure due to the emergence of GCV- and foscarnet (PFA)-resistant HCMV strains
      demonstrated that synadenol and synguanol are potent inhibitors of clinical HCMV
      isolates and are highly effective against both GCV- and PFA-resistant isolates.
      These results together with those showing resistance of a UL97 knock-out HCMV
      mutant to GCV as well as synadenol and synguanol suggest the involvement of UL97
      phosphotransferase in synadenol and synguanol anabolism but with a substrate
      specificity different from that of GCV.

PMID- 12406511
TI  - Antiviral activity of Spirulina maxima against herpes simplex virus type 2.
AB  - Spirulina has been used in a variety of practical applications in biotechnology
      and medical sciences. This paper presents the antiviral activity found in a hot
      water extract (HWE) of a commercial preparation of Spirulina maxima, studied by a
      microplate inhibition assay, using several viruses. The HWE inhibited the
      infection for: herpes simplex virus type 2 (HSV-2), pseudorabies virus (PRV),
      human cytomegalovirus (HCMV), and HSV-1, and the 50% effective inhibition doses
      (ED(50)) were 0.069, 0.103, 0.142, and 0.333 mg/ml for each virus, respectively.
      For adenovirus the inhibition was less than 20%, and no inhibition was found for
      measles virus, subacute sclerosing panencephalitis virus (SSPE), vesicular
      stomatitis virus (VSV), poliovirus 1 and rotavirus SA-11, at concentrations of 2
      mg/ml of the HWE. The highest antiviral activity was for HSV-2, with a
      selectivity index of 128. The antiviral activity was not due to a virucidal
      effect. Herpesvirus infection was inhibited at the initial events (adsorption and
      penetration) of the viral cycle. To initiate the isolation and identification of
      the compound that exhibits the antiviral activity of S. maxima, some extracts
      made by using several solvents with different polarity were evaluated by
      microplate inhibition assay using HSV-2. The highest antiviral activity was
      detected in the methanol-water 3:1, which suggests that the antiviral activity is
      probably due to highly polar compounds.

PMID- 12406512
TI  - Long-term effects of neonatal pain on nociceptive systems.

PMID- 12406513
TI  - Patient-related barriers to pain management: the Barriers Questionnaire II (BQ
      II).
AB  - Patients' beliefs can act as barriers to optimal management of cancer pain. The
      Barriers Questionnaire (BQ) is a tool used to evaluate such barriers. Here, the
      BQ has been revised to reflect changes in pain management practices, resulting in
      the Barriers Questionnaire-II (BQ-II), a 27-item, self report instrument. This
      paper presents the results from two studies where the psychometric properties of
      the BQ-II were evaluated. In the first study, the responses of 27 nurses trained
      in pain management were compared to responses of a convenience sample of 12
      patients with cancer. The results indicated that patients with cancer had higher
      mean scores on the BQ-II than did nurses trained in pain management. In the
      second study, a convenience sample of 172 patients with cancer responded to the
      BQ-II and a set of pain and quality of life (QOL) measures. A factor analysis
      supported four factors. Factor one, physiological effects, consists of 12 items
      addressing the beliefs that side effects of analgesics are inevitable and
      unmanageable, concerns about tolerance, and concerns about not being able to
      monitor changes in one's body when taking strong pain medications. Factor two,
      Fatalism, consists of three items addressing fatalistic beliefs about cancer pain
      and its management. Factor three, Communication, consists of six items addressing
      the concern that reports of pain distract the physician from treating the
      underlying disease, and the belief that 'good' patients do not complain of pain.
      The fourth and final factor, harmful effects, consists of six items addressing
      fear of becoming addicted to pain medication and the belief that pain medications
      harm the immune system. The BQ-II total had an internal consistency of 0.89, and
      alpha for the subscales ranged from 0.75 to 0.85. Mean (SD) scores on the total
      scale was 1.52 (0.73). BQ-II scores were related to measures of pain intensity
      and duration, mood, and QOL. Patients who used adequate analgesics for their
      levels of pain had lower scores on the BQ-II than did patients who used
      inadequate analgesics. The BQ-II is a reliable and valid measure of patient
      related barriers to cancer pain management.

PMID- 12406514
TI  - Efficacy of systemic morphine suggests a fundamental difference in the mechanisms
      that generate bone cancer vs inflammatory pain.
AB  - Pain is the cancer related event that is most disruptive to the cancer patient's
      quality of life. Although bone cancer pain is one of the most severe and common
      of the chronic pains that accompany breast, prostate and lung cancers, relatively
      little is known about the mechanisms that generate and maintain this pain.
      Recently, we developed a mouse model of bone cancer pain and 16 days following
      tumor implantation into the intramedullary space of the femur, significant bone
      destruction and bone cancer pain-related behaviors were observed. A critical
      question is how closely this model mirrors human bone cancer pain. In the present
      study we show that, as in humans, pain-related behaviors are diminished by
      systemic morphine administration in a dose dependent fashion that is naloxone
      reversible. Humans suffering from bone cancer pain generally require
      significantly higher doses of morphine as compared to individuals with
      inflammatory pain and in the mouse model, the doses of morphine required to block
      bone cancer pain-related behaviors were ten times that required to block peak
      inflammatory pain behaviors of comparable magnitude induced by hindpaw injection
      of complete Freund's adjuvant (CFA) (1-3mg/kg). As these animals were treated
      acutely, there was not time for morphine tolerance to develop and the rightward
      shift in analgesic efficacy observed in bone cancer pain vs. inflammatory pain
      suggests a fundamental difference in the underlying mechanisms that generate bone
      cancer vs. inflammatory pain. These results indicate that this model may be
      useful in defining drug therapies that are targeted for complex bone cancer pain
      syndromes.

PMID- 12406515
TI  - Effect of intrathecal octreotide on thermal hyperalgesia and evoked spinal c-Fos
      expression in rats with sciatic constriction injury.
AB  - This study was designed to determine whether intrathecal octreotide
      (sandostatin), a synthetic octapeptide derivative of somatostatin, relieved
      thermal hyperalgesia and reduced the evoked spinal c-Fos expression in rats with
      chronic constriction injury (CCI) of the sciatic nerve. Intrathecal catheters
      were implanted in rats 7 days before CCI of the sciatic nerve over the left hind
      limb. After confirmation of the development of thermal hyperalgesia by decreased
      paw withdrawal latencies (PWL) to heat stimulation 7 days after CCI, intrathecal
      sandostatin at 20, 40, and 80 microg was administered, respectively. Rats in the
      control group received saline injections intrathecally. PWLs were evaluated at
      30, 60, 120, 180, and 240 min after drug administration. Detection of Fos-like
      immunoreactivity (Fos-LI) neurons in the dorsal horn of the spinal cord following
      drug administration was performed after mechanical stimulation (stroking of the
      hind paws) on the 14th day after CCI. The reduction of PWL was attenuated
      significantly in the groups that received intrathecal sandostatin at 20, 40, and
      80 g when compared with the saline group. However, PWL did not return to pre-CCI
      values in all groups. In the 40 microg group, PWL returned up to 76% of pre-CCI
      values 120 min after drug administration. Stroking of the hind paw in CCI-treated
      (ipsilateral) limbs induced a significantly greater expression of spinal Fos-LI
      neurons than that of non-CCI treated (contralateral) limbs in each group. The
      number of Fos-LI neurons in animals receiving intrathecal sandostatin was dose
      dependently reduced. Expression of Fos-LI neurons in the 80 microg group was
      nearly completely inhibited. These data suggest that intrathecal sandostatin
      significantly relieved thermal hyperalgesia behaviorally but with limited effects
      and dose-dependently reduced spinal Fos-LI neurons expression evoked by stroking
      stimulation, which may reflect mechanical allodynia in rats with sciatic
      constriction injury. This implies that intrathecal sandostatin was effective in
      the treatment of neuropathic pain.

PMID- 12406516
TI  - Orofacial pain-related communication patterns: sex and residential setting
      differences among community-dwelling adults.
AB  - This study documented orofacial pain-related communication patterns among
      community-dwelling dentate adults, health care providers, and persons in the
      respondent's social network. We report communication patterns for orofacial pain
      by symptom (toothache pain, pain when chewing, temperature sensitivity of the
      teeth, painful oral sores, and jaw joint pain). The subjects for the study were
      724 participants in the 42-month interview of the Florida Dental Care Study, a
      longitudinal study of oral health among dentate adults, age 45 and older at
      baseline. The data were collected using a standardized telephone interview. Pain
      was more likely to be discussed with a lay consultant (41-66% depending on the
      symptom) than a health care professional (21-62%). Consistent with studies that
      report females tend to rely on social networks to cope with pain, more female
      respondents than males reported having talked to a lay consultant about orofacial
      pain for most of the symptoms. We also found that rural Black adults were less
      likely to speak to a health care professional about their orofacial pain. The
      findings highlight the importance of family, friends, and neighbors within the
      lay consultation and support network for persons with pain. Recent interest in
      self-care and the use of complementary and alternative approaches to treatment
      suggest the importance of considering influences acting within the environment of
      persons with pain.

PMID- 12406517
TI  - Acupuncture analgesia in a new rat model of ankle sprain pain.
AB  - The lack of suitable experimental animal models for persistent pain showing clear
      acupuncture analgesia, has been the major stumbling block in the investigation of
      the physiological mechanisms of acupuncture analgesia. The present study
      developed a new rat model of ankle sprain pain and the effect of
      electroacupuncture (EA) on this model was examined. A common source of persistent
      pain in humans is the lateral ankle sprain. To model this condition, the rat's
      right ankle was bent repeatedly, overextending lateral ligaments, for 4 min under
      halothane anesthesia. The rat subsequently showed swelling of the ankle and a
      reduced stepping force of the affected limb for the next several days. The
      reduced stepping force of the limb was presumably due to a painful ankle since
      systemic injection of morphine produced temporary improvement of weight bearing.
      EA was applied to the SI-6 acupuncture point on the contralateral forelimb for 30
      min under halothane anesthesia. After the termination of EA, behavioral tests
      measuring stepping force were periodically conducted during the next 4h. EA
      produced a 40% recovery in the stepping force of the sprained foot lasting for at
      least 2h. The magnitude of this improvement was equivalent to that obtained after
      a systemic injection of 2mg/kg of morphine and this improvement of stepping
      pressure was interpreted as an analgesic effect. The analgesic effect was
      specific to the acupuncture point since (1). the analgesic effect on the ankle
      sprain pain model could not be mimicked by EA applied to a nearby point, LI-4 and
      (2). EA applied to the SI-6 point was not effective in the knee arthritis pain
      model. The analgesic effect could not be blocked by systemic injection of opioid
      antagonists naloxone or naltrexone. These data suggest that EA produces a potent
      analgesic effect on the ankle sprain pain model in the rat. This analgesic effect
      is produced by applying EA to a site remote from the painful area in a stimulus
      point-specific way. The present study provides a powerful experimental animal
      model that can be used for investigating the unique physiological mechanisms
      involved in acupuncture analgesia.

PMID- 12406518
TI  - Controlled dilatation of the uterine cervix--an experimental visceral pain model.
AB  - Pain originating from the female reproductive organs is a substantial clinical
      problem to treat. Experimental models may be a tool for the study of visceral
      pain mechanisms and hence provide information to aid in formulating new treatment
      strategies. The aim was to develop and evaluate the performance and safety of a
      model for nociceptive stimulation of the uterine cervix by balloon dilatation
      using impedance planimetry. Three consecutive (repeated) dilatations at 1 ml/min,
      an isovolumetric and a fast dilatation at 2 ml/min were performed. Pilot studies
      were conducted in vitro on hysterectomy specimens, followed by application of the
      model in 14 healthy females. Subjects indicated the quality of perception and
      pain during dilatations by verbal reports and the McGill Pain Questionnaire
      (MPQ), and the intensity by a continuous electronic visual analog scale. The pain
      location was marked on an anatomical map. The balloon cross-sectional area (CSA)
      was measured simultaneously. The experimental procedure was atraumatic. Pain was
      evoked in all subjects, with referral to the hypogastric and low back regions.
      The word descriptors on the MPQ and the areas of referred sensations were similar
      to that seen clinically in abortion, labor and menstrual pain. The pain intensity
      correlated with balloon CSA (r=0.9, P<0.001). No significant differences were
      found for the balloon volumes (4.2, 3.8 and 3.9 ml) or CSA (163, 122 and 123
      mm(2)) to pain threshold (PT) for repeated dilatations, suggesting the
      reliability of the model. There was significant correlation between the balloon
      volume and CSA to reach the PT for single and repeated cervical dilatations.
      During isovolumetric distension, greater overall pain intensity was demonstrated
      for the prolonged as compared to the shorter duration cervical stimulation. In
      conclusion, this is the first human experimental pain model for dilatation of the
      uterine cervix, providing a safe, controlled, quantifiable stimulus that evoked
      reliable pain scores. The model thus provides a new possibility to study
      gynecological pain and may lead to better characterization and treatment of
      female visceral pain syndromes.

PMID- 12406519
TI  - A comparison of placebo effects in clinical analgesic trials versus studies of
      placebo analgesia.
AB  - A previous meta-analysis of clinical analgesic trial studies showed generally low
      magnitudes of placebo analgesia (N. Engl. J. Med. 344 (2001) 1594). However, as
      studies included in their analysis used only placebo as a control condition, we
      conducted two meta-analyses, one in which 23 studies used only placebo as a
      control condition, and one in which 14 studies investigated placebo analgesic
      mechanisms. Magnitudes of placebo analgesic effects were much higher in the
      latter (mean effect size=0.95) as compared to the former (mean effect size=0.15)
      and were significantly different (P=0.003). This difference as well as
      differences in effect sizes within studies of placebo mechanisms may be
      parsimoniously explained by differences in expected pain levels produced by
      placebo suggestions and by conditioning. Furthermore, some of the studies of
      placebo analgesic mechanisms indicate that the magnitude of placebo analgesia is
      higher when the placebo analgesic effect is induced via suggestion combined with
      conditioning than via suggestion alone or conditioning alone. Based on these
      findings, we suggest that placebo analgesic effects are most optimally
      conceptualized in terms of perception of the placebo agent, and therefore a new
      definition of placebo response is proposed.

PMID- 12406520
TI  - Orofacial pain: just another chronic pain? Results from a population-based
      survey.
AB  - Features of somatisation have been shown to predict the onset of widespread body
      pain. This study aims to determine to what extent persons with orofacial pain
      syndromes share these features and to what extent they are uniquely related to
      oral mechanical factors. We have conducted a population-based cross-sectional
      survey in the South-East Cheshire area of the United Kingdom involving 2504
      individuals aged 18-65 years. All participants completed a postal questionnaire
      which enquired about the occurrence of both orofacial pain and widespread body
      pain. It also enquired about potential risk factors for one or both conditions.
      In total, 473 subjects (23%) reported orofacial pain only, 123 (6%) widespread
      pain only, while 85 (4%) reported both. The number reporting both was
      significantly higher than would be expected if the symptoms were independent
      (P<0.001). Several oral mechanical factors were significantly associated with
      both orofacial pain and widespread body pain (grinding teeth, clicking jaw,
      missing teeth), while two (facial trauma, locking jaw) were specifically related
      to orofacial pain. Both pain syndromes were associated equally with high levels
      of psychological distress, indicators of somatisation and maladaptive response to
      illness. These results suggest that orofacial pain syndromes may commonly be a
      manifestation of the process of somatisation and the excess reporting of some
      local mechanical factors amongst persons with these symptoms, may not be uniquely
      associated with pain in the orofacial region.

PMID- 12406521
TI  - Catastrophizing is related to pain ratings, but not nociceptive flexion reflex
      threshold.
AB  - Catastrophizing is reliably associated with increased reports of clinical and
      experimental pain. To test the hypothesis that catastrophizing may heighten pain
      experience by increasing nociceptive transmission through spinal gating
      mechanisms, the present study examined catastrophizing as a predictor of pain
      ratings and nociceptive flexion reflex (NFR) thresholds in 88 young adult men
      (n=47) and women (n=41). The NFR threshold was defined as the intensity of
      electrocutaneous sural nerve stimulation required to elicit a withdrawal response
      from the biceps femoris muscle of the ipsilateral leg. Participants completed an
      assessment of their NFR threshold and then provided pain ratings using both a
      numerical rating scale (NRS) and the short-form McGill pain questionnaire (SF
      MPQ). Pain catastrophizing was assessed using the catastrophizing subscale of the
      coping strategies questionnaire (CSQ). Although catastrophizing was positively
      related to both NRS and SF-MPQ pain ratings, catastrophizing was not
      significantly related to NFR threshold. These findings suggest that differential
      modulation of spinal nociceptive input may not account for the relationship
      between catastrophizing and increased pain.

PMID- 12406522
TI  - Randomized controlled trial of botulinum toxin A for chronic myogenous orofacial
      pain.
AB  - The purpose of this study was to determine whether botulinum toxin A (BTX-A) was
      efficacious for the treatment of chronic moderate to severe jaw muscle pain in
      females. This was a randomized double-blind, placebo-controlled crossover trial
      of BTX-A. Twenty five units injected into each temporalis muscle and 50 U
      injected into each masseter muscle using three sites per muscle with 0.2 cm(3)
      per site. Data were collected at baseline, 8, 16, 24 weeks, with crossover
      occurring at 16 weeks. Primary outcome variables were pain intensity and
      unpleasantness, measured by horizontal visual analog scale (VAS). Secondary
      outcome variables were maximum interincisal opening without and irrespective of
      pain, muscle palpation tenderness (12 points), and four general questions.
      Fifteen female patients were enrolled (18-45 years), but only ten completed the
      trial. Of those who finished, no statistically significant difference was found
      in pain intensity (P=0.10), unpleasantness (P=0.40), palpation muscle tenderness
      (P=0.91), or the three general questions (P=0.64, P=0.66, P=0.67). Statistical
      significance was achieved for maximum opening without pain (P=0.02) and
      irrespective of pain (P=0.005) with the BTX-A arm having a relative decreased
      opening. No statistically significant difference was observed in any outcome
      measures except maximum opening, which showed BTX-A patient opening less wide
      than placebo. The results do not support the use of BTX-A in the treatment of
      moderate to severe jaw muscle pain in this patient population.

PMID- 12406523
TI  - Tissue glucose level modulates the mechanical responses of cutaneous nociceptors
      in streptozotocin-diabetic rats but not normal rats in vitro.
AB  - The maintenance of normoglycemia has been reported to reduce painful sensations
      in diabetic subjects. This suggests that lowering the tissue glucose
      concentration might inhibit the increased cutaneous nociceptor activities seen in
      a diabetic conditin. To test this hypothesis, we studied the effect of changing
      the glucose concentration in the superfusate of in vitro preparations (high, HG:
      20 mM or normal glucose, NG: 6.7 mM) on the mechanical response of C-fiber
      polymodal receptors (C-polymodal receptors). Single fiber activities of C
      polymodal receptors were recorded from skin-nerve in vitro preparations of
      streptozotocin-induced diabetic and age-matched control rats. Pressure
      stimulation was applied to the receptive field by a servo-controlled mechanical
      stimulator. C-polymodal receptors from diabetic preparations superfused with HG
      solution showed increased spontaneous activity, lowered response threshold,
      increased response magnitude and a less adaptive response pattern to mechanical
      stimulation compared with those from control preparations superfused with NG
      solution. C-polymodal receptors from diabetic preparations superfused with NG
      solution showed no such changes. The responsiveness of C-polymodal receptors from
      control preparations was not different in NG- or HG-conditions. These data
      demonstrated that normalization of the glucose concentration normalized the
      responsiveness of C-polymodal receptors in diabetic animals. This response may be
      associated with the fact that normoglycemia reduces painful sensations in
      diabetic subjects.

PMID- 12406524
TI  - Fear-avoidance beliefs and catastrophizing: occurrence and risk factor in back
      pain and ADL in the general population.
AB  - Fear-avoidance beliefs and catastrophizing have been shown to be powerful
      cognitions in the process of developing chronic pain problems and there is a need
      for increased knowledge in early stages of pain. The objectives of this study
      were therefore, firstly, to examine the occurrence of fear-avoidance beliefs and
      catastrophizing in groups with different degrees of non-chronic spinal pain in a
      general population, and secondly to assess if fear-avoidance beliefs and
      catastrophizing were related to current ratings of pain and activities of daily
      living (ADL). The study was a part of a population based back pain project and
      the study sample consisted of 917 men and women, 35-45 years old, either pain
      free or with non-chronic spinal pain. The results showed that fear-avoidance
      beliefs as well as catastrophizing occur in this general population of non
      patients. The levels were moderate and in catastrophizing a 'dose-response'
      pattern was seen, such that more the catastrophizing was, the more was pain. The
      study showed two relationships, which were between fear-avoidance and ADL as well
      as between catastrophizing and pain intensity. Logistic regression analyses were
      performed with 95% confidence intervals and the odds ratio for fear-avoidance
      beliefs and ADL was 2.5 and for catastrophizing and pain 1.8, both with
      confidence interval above unity. The results suggest that fear-avoidance beliefs
      and catastrophizing may play an active part in the transition from acute to
      chronic pain and clinical implications include screening and early intervention.

PMID- 12406525
TI  - Increases in the phosphorylation of cyclic AMP response element binding protein
      (CREB) and decreases in the content of calcineurin accompany thermal hyperalgesia
      following chronic constriction injury in rats.
AB  - Plasticity in the spinal dorsal horn may underlie the development of chronic pain
      following peripheral nerve injury or inflammation. In this study, we examined
      whether chronic constriction injury of the sciatic nerve was associated with
      changes in the immunoreactive content of cyclic AMP response element binding
      protein (CREB), protein kinase A (PKA), and calcineurin Aalpha and Abeta in the
      spinal dorsal horn. In animals exhibiting thermal hyperalgesia as a behavioral
      sign of neuropathic pain 7 days after loose ligation of the sciatic nerve
      (chronic constriction injury), there was a significant increase in the content of
      phosphorylated (activated) CREB (pCREB). In contrast, following the typical
      disappearance of thermal hyperalgesia 28 days after loose ligation surgery, there
      were no differences in pCREB content between control and sciatic ligation
      animals. The increased CREB activation associated with thermal hyperalgesia was
      accompanied by significant decreases in the content of both calcineurin Aalpha
      and Abeta. In contrast, there were no differences in the content of non
      phosphorylated CREB, and phosphorylated or non-phosphorylated PKA between control
      and sciatic ligation animals either 7 or 28 days after surgery. These data
      established a close association in the expression of thermal hyperalgesia with
      CREB activation and decreased calcineurin content in the spinal dorsal horn. The
      data revealed a significant but reversible shift in the manner in which spinal
      neurons processed sensory information following peripheral nerve injury, and lent
      further support to the notion that plasticity in the spinal dorsal horn may have
      contributed to the development of chronic pain.

PMID- 12406526
TI  - Elastoviscous substances with analgesic effects on joint pain reduce stretch
      activated ion channel activity in vitro.
AB  - Activation by noxious mechanical stimuli of sensory nerve fibres that signal
      joint pain takes place through stretch-activated ion channels, which open in
      response to increased membrane tension. It has been suggested that the analgesic
      effect of hyaluronan solutions used for intra-articular treatment of joint pain
      in humans are mediated by a reduction of the sensitivity of mechanosensory ion
      channels of nociceptive nerve terminals. We have investigated whether cross
      linked hyaluronan solutions (hylans) of different elastoviscosities modify the
      response characteristics of stretch-activated ion channels of Xenopus laevis
      oocytes. Patch-clamp recordings on intact oocytes and in excised membrane patches
      (outside-out and inside-out configurations) were performed in Barth's solution
      (control condition) and after exposure to hylans of different elastoviscosities.
      For mechanical stimulation, monitored suction was applied through the
      microelectrode and the activity of stretch-activated channels was recorded. The
      activity of stretch-activated channels was significantly reduced in the presence
      of high elastoviscous hylan A (0.8% polymer content, molecular weight 6M) and of
      a mixture of hylan A (90% by weight) and hylan B (10% by weight), 0.9% total
      polymer content, a clinically used hylan product. In contrast, solutions of hylan
      A with the same chemical composition but reduced elastoviscosity (0.8% polymer
      content, molecular weight 96000) were found ineffective. It is concluded that
      stretch-activated channels have a decreased mechanical sensitivity in the
      presence of elastoviscous solutions of hylan, but not in the presence of non
      elastoviscous solutions of hylan of the same concentration. These data suggest
      that the analgesic effects of intra-articular injections of elastoviscous
      solutions of hylans are due to a reduction of the sensitivity to mechanical
      forces of stretch-activated channels present in the membrane of joint
      mechanonociceptors.

PMID- 12406527
TI  - The effect of high and low frequency electroacupuncture in pain after lower
      abdominal surgery.
AB  - In the present study, we examined the effects of preoperative electroacupuncture
      (EA) at classical bilateral acupuncture points (Zusanli, also known as ST-36) on
      postoperative pain and opioid-related side effects. One hundred healthy
      consenting women undergoing lower abdominal surgery were randomly assigned to
      four treatment regimens: Group I (n=25), control; Group II (n=25), sham-EA
      (needle insertion without electrical stimulation); Group III (n=25), low-EA (2 Hz
      of electrical stimulation); and Group IV (n=25), high-EA (100 Hz of electrical
      stimulation). EA groups received needle insertion with or without electrical
      stimulation 20 min prior to anesthesia. All patients received patient-controlled
      analgesia (PCA) of morphine postoperation. Postoperative pain was evaluated by
      recording (1). the time of the first required analgesic, (2). the number of PCA
      demands, (3). the total amount of morphine required by PCA, and (4) patients' VAS
      pain score. We found that the time of first analgesic requested was 10, 18, 28,
      and 28 min in the control, sham-, low-, and high-EA groups, respectively. During
      the first 24h, the total amount of morphine required was decreased by 21, 43 and
      61% in the sham-, low- and high-EA groups, respectively. The incidence of nausea
      and dizziness during the first 24h after surgery was significantly reduced in
      both the low-EA and high-EA groups compared with the control and sham-EA groups.
      We also found that sham-EA exerts a beneficial effect with respect to its pain
      relieving quality but not the side effect profiles. Our findings demonstrates
      that preoperative treatment with low-EA and high-EA can reduce postoperative
      analgesic requirements and associated side effects in patients undergoing lower
      abdominal surgery.

PMID- 12406528
TI  - Chronic pain in a biracial population of young women.
AB  - This study investigated dimensions of chronic pain and temporomandibular
      disorders (TMDs) in a census tract sampling of African-American and Caucasian
      young women enrolled (from racially congruent households) at ages 9-10 in the
      longitudinal multicenter National Heart Lung and Blood Institute's Growth and
      Health Study (NGHS). The present study, which examined participants at the
      California clinical NGHS center when they were 19-23 years old, investigates five
      commonly reported chronic pains: back, head, face/jaw, abdomen, and chest.
      Chronic pain grade (CPG) status based on pain self-reports (frequency, duration,
      severity, and interference with usual activities) is reported for each of the
      five pain sites. Results show that chronic pain is common in this population of
      young women, although based on the CPG severity scores, only a small percentage
      is dysfunctional. Racial differences were not found for back, head, abdomen or
      chest pains. However, significant racial differences were found regarding facial
      pain and symptoms related to TMDs above and beyond socioeconomic status (SES)
      (lifetime prevalence: adjusted odds ratio (aOR)=2.14 and 95% confidence interval
      (CI)=1.40-3.31; 6 month period prevalence: aOR=2.03 and 95% CI=1.16-3.64). Not
      only were facial pain and jaw symptoms reported more frequently by Caucasians
      compared to African-Americans controlling for SES, but they were also reported to
      have an earlier onset.

PMID- 12406529
TI  - Excitatory amino acid receptor antagonists and electroacupuncture synergetically
      inhibit carrageenan-induced behavioral hyperalgesia and spinal fos expression in
      rats.
AB  - The interaction between electroacupuncture and an N-methyl-D-aspartic acid (NMDA)
      receptor antagonist, (DL-2-amino-5-phosphonopentanoic acid; AP5), or an (+/-)
      alpha-Amino-3-hydroxy-5-methylisoxazole-4-propionic acid/kainite (AMPA/KA)
      receptor antagonist, (6,7-dinitroquinoxaline-2,3 (1H,4H); DNQX) administered
      intrathecally on carrageenan-induced thermal hyperalgesia and spinal c-Fos
      expression was investigated. The latency of paw withdrawal (PWL) from a thermal
      stimulus was used as a measure of hyperalgesia in awake rats. Intrathecal (i.t.)
      injection of 1 and 10 nmol AP5, but not DNQX, markedly increased the PWL of the
      carrageenan-injected paw. At a dose of 100 nmol, either AP5 or DNQX significantly
      increased the PWL of carrageenan-injected paw, with AP5 being more potent. The
      PWLs of the non-injected and normal saline (NS)-injected paws were not detectably
      affected by the administration of NMDA or AMPA/KA receptor antagonists at the
      doses tested. Unilateral electroacupuncture stimulation of the 'Zu-San-Li' (St
      36) and 'Kun-Lun' (UB 60) acupuncture points (60 and 2 Hz alternately, 1-2-3 mA)
      contralateral to the carrageenan-injected paw significantly elevated the PWLs of
      carrageenan- and NS-injected paws. Although neither i.t. injection of 0.1 nmol
      AP5 nor 1 nmol DNQX alone had an effect on the PWL of the carrageenan- and NS
      injected paws, both significantly potentiated electroacupuncture-induced
      analgesia in carrageenan-injected rats, especially 0.1 nmol AP5. Fos expression
      evoked by intraplantar (i.pl.) injection of carrageenan was examined in the
      spinal cord with immunohistochemical methods. Three hours after i.pl. injection
      of carrageenan, the number of Fos-like immunoreactive (Fos-LI) neurons was
      significantly increased in all the layers of the ipsilateral spinal cord at L(4
      5), with the highest density in laminae I-II and V-VI. Intrathecally pre
      administered AP5 (10 nmol) or DNQX (100 nmol) significantly reduced the total
      number of carrageenan-induced Fos-LI neurons. The reduction was most apparent in
      laminae I-II and IV-V. Similarly, following bilateral electroacupuncture
      stimulation of the 'Zu-San-Li' and 'Kun-Lun' acupuncture points, the numbers of
      carrageenan-induced Fos-LI neurons in laminae I-II and V-VI were also markedly
      reduced. When a combination of electroacupuncture with 10 nmol AP5 or 100 nmol
      DNQX was used, the level of Fos expression in the spinal cord induced by
      carrageenan was significantly lower than electroacupuncture or i.t. injection of
      AP5 or DNQX alone. These results demonstrate that electroacupuncture and NMDA or
      AMPA/KA receptor antagonists have a synergetic anti-nociceptive action against
      inflammatory pain. Furthermore, this study supports the idea that both NMDA and
      AMPA/KA receptors are involved in spinal nociceptive transmission in carrageenan
      inflamed rats, with the former more preferentially mediating transmission of
      nociceptive information from cutaneous tissue.

PMID- 12406530
TI  - The glycine/NMDA receptor antagonist (+)-HA966 enhances the peripheral effect of
      morphine in neuropathic rats.
AB  - Systemic opioid dosing until adequate analgesia in neuropathic pain may involve
      intolerable and untreatable side effects. Peripheral opioid receptor mechanisms
      may participate in the antinociceptive effect of systemic morphine. We evaluated
      the effect of peripherally injected morphine alone, and the ability of the
      functional antagonist at the glycine site of the N-methyl-D-aspartate (NMDA)
      receptor complex (+)-HA966 to modulate the antinociceptive effect of peripheral
      morphine in a rat model of neuropathic pain. Mononeuropathy was induced by
      placing four ligatures around the common sciatic nerve. Experiments were
      performed 2 weeks after the nerve ligature, when the pain-related behavior
      reached a stable maximum. Rats received injections of either subcutaneous (+)
      HA966 (2.5mg/kg) or saline administered 20 min before morphine (50-150 microg
      injected into the nerve-injured hindpaw). The antinociceptive effect was tested
      against mechanical (vocalization threshold to hindpaw pressure) or thermal
      (struggle latency to hindpaw immersion into a 46 degrees C hot water bath)
      stimuli. In both tests, morphine alone (100-150 microg) produced antinociception.
      Pretreatment with (+)-HA966 did not potentiate the analgesic effectiveness of the
      two highest doses of morphine, but it did produce analgesia when combined with a
      low dose of morphine (50 microg), which did not produce analgesia by itself.
      These effects were reversed by intraplantar naloxone methiodide (50 microg
      injected into the nerve-injured hindpaw) indicating a peripherally opioid
      mediated mechanism of action. The present studies suggested that combined
      administration of glycine/NMDA receptor antagonists, and peripherally acting
      morphine may be an interesting approach in the treatment of neuropathic pain.

PMID- 12406531
TI  - Topical cannabinoid agonist, WIN55,212-2, reduces cornea-evoked trigeminal
      brainstem activity in the rat.
AB  - Cannabinoids act at receptors on peripheral and central neurons to modulate
      diverse physiological functions and produce analgesia. Corneal sensory nerves
      express the CB1 cannabinoid receptor and project to two spatially discrete
      regions of the lower brainstem, the trigeminal interpolaris/caudalis (Vi/Vc)
      transition and subnucleus caudalis/upper cervical cord (Vc/C1) junction region.
      The function of CB1 expression on corneal nerves is not known. To determine if
      cannabinoid receptors in the anterior eye affect the activity of trigeminal
      brainstem neurons at the Vi/Vc and Vc/C1 the CB1 agonist, WIN55,212-2 (WIN-2),
      was applied topically prior to chemical excitation of corneal afferent fibers. In
      the first series of experiments WIN-2 was applied topically prior to excitation
      of corneal nociceptors by mustard oil (MO). WIN-2 reduced significantly the
      number of Fos-like immunoreactive neuronal nuclei (Fos-LI) at the Vi/Vc
      transition (-46.7+/-8.2%, P<0.05), while smaller non-significant reductions
      occurred at the Vc/C1 junction region (-20.3+/-7.6%). The selective CB1
      antagonist, SR141716A (1mg/kg, i.v.), prevented WIN-2-evoked reduction in Fos-LI
      after MO. Systemic administration of WIN-2 (1 or 10mg/kg, i.p.) or SR141716A
      (1mg/kg, i.v.) or topical corneal application of morphine sulfate did not affect
      Fos-LI produced by MO. In parallel experiments, topical WIN-2 reduced the
      magnitude of single unit activity recorded at the Vi/Vc transition (-80+/-7%,
      P<0.025), but not at the Vc/C1 junction region (-34+/-30%) evoked by CO(2) pulses
      applied to the cornea. Topical morphine did not alter CO(2)-evoked unit activity
      at either recording location. These results indicated that cannabinoid receptor
      agonists acted, at least in part, at CB1 receptors in the anterior eye to reduce
      corneal stimulation-evoked trigeminal brainstem neural activity. Corneal
      nociceptor-evoked activity at the Vi/Vc transition was reduced significantly by
      topical WIN-2, while activity at the Vc/C1 junction region displayed only minor
      decreases. These findings were consistent with the hypothesis that CB1 receptors
      affect the activity of corneal-responsive neurons that preferentially contribute
      to homeostasis of the anterior eye and/or reflexive aspects of nociception rather
      than the sensory-discriminative aspects of corneal nociception.

PMID- 12406532
TI  - Gabapentin in neuropathic pain syndromes: a randomised, double-blind, placebo
      controlled trial.
AB  - A double-blind, randomised, placebo-controlled 8-week study was conducted to
      evaluate the efficacy and safety of gabapentin in the treatment of neuropathic
      pain, using doses up to 2400 mg/day. The study used a novel design that was
      symptom- rather than syndrome-based; an approach that aimed to reflect the
      realities of clinical practice. Participants had a wide range of neuropathic pain
      syndromes, with at least two of the following symptoms: allodynia, burning pain,
      shooting pain, or hyperalgesia. Patients were randomised to gabapentin (n=153) or
      placebo (n=152). Gabapentin was given in three divided doses, initially titrated
      to 900 mg/day over 3 days, followed by two further increases, to a maximum of
      2400 mg/day if required by the end of week 5. The primary outcome measure was
      changed in average daily pain diary score (baseline versus final week). Over the
      8 week study, this score decreased (i.e. improved) by 1.5 (21%) in gabapentin
      treated patients and by 1.0 (14%) in placebo treated patients (P=0.048, rank
      based analysis of covariance). Significant differences were shown in favour of
      gabapentin (P<0.05) for the Clinician and Patient Global Impression of Change,
      and some domains of the Short Form-McGill Pain Questionnaire. Improvements were
      also shown in patient-reported outcomes in quality of life, as seen by
      significant differences in favour of gabapentin in several domains of the Short
      Form-36 Health Survey. Gabapentin was well tolerated and the majority of patients
      completed the study (79 versus 73% for placebo). The most common adverse events
      were mild to moderate dizziness and somnolence, most of which were transient and
      occurred during the titration phase. This study shows that gabapentin reduces
      pain and improves some quality-of-life measures in patients with a wide range of
      neuropathic pain syndromes.

PMID- 12406533
TI  - Application of a pro-inflammatory agent to the orbital portion of the rat
      infraorbital nerve induces changes indicative of ongoing trigeminal pain.
AB  - The present experiments investigated the behavioral and immunocytchemical (ICC)
      effects of applying complete Freund's adjuvant (CFA) to the orbital portion of
      the infraorbital nerve (IOn). Two control groups, the first had saline applied to
      the IOn and the second underwent sham operation, were included in the study. In
      the CFA group, significant hyper-responsiveness to von Frey (analysis of variance
      <0.05) and to pinprick stimulation (Kruskal Wallis <0.05) in the vibrissal pad
      was observed on the fourth and the fifth days post-operative (dpo). This was
      accompanied by a reduced bite force and altered bite patterns of similar
      duration. Histology of the IOn in CFA rats revealed immune cell infiltration and
      edema around and in the nerve trunk with only mild axonal damage confirmed by
      neuropeptide Y immunoreactivity in trigeminal ganglion. Histological areas of
      inconsistent and mild inflammation were observed in the saline group that were
      accompanied by similarly attenuated behavioral and ICC changes. This model of
      inflammation-induced neuropathic pain is highly applicable to the study of
      neuroinflammatory orofacial pain.

PMID- 12406534
TI  - Does acupuncture improve the orthopedic management of chronic low back pain--a
      randomized, blinded, controlled trial with 3 months follow up.
AB  - This prospective, randomised controlled trial, with three parallel groups,
      patient and observer blinded for verum and sham acupuncture and a follow up of 3
      months raises the question: "Does a combination of acupuncture and conservative
      orthopedic treatment improve conservative orthopedic treatment in chronic low
      back pain (LBP). 186 in-patients of a LBP rehabilitation center with a history of
      LBP >or=6 weeks, VAS >or=50mm, and no pending compensation claims, were selected;
      for the three random group 4 weeks of treatment was applied. 174 patients met the
      protocol criteria and reported after treatment, 124 reported after 3 months
      follow up. Patients were assorted 4 strata: chronic LBP, <or=0.5 years, 0.5-2
      years, 2-5 years, >or=5 years. Analysis was by intention to treat. Group 1
      (Verum+COT) received 12 treatments of verum acupuncture and conservative
      orthopedic treatment (COT). Group 2 (Sham+COT) received 12 treatments of non
      specific needling and COT. Group 3 (nil+COT) received COT alone. Verum- and Sham
      acupuncture were blinded against patient and examiner. The primary endpoints were
      pain reduction >or=50% on VAS 3 months after the end of the treatment protocol.
      Secondary endpoints were pain reduction >or=50% on VAS and treatment efficacy on
      a four-point box scale directly after the end of the treatment protocol and
      treatment efficacy after 3 months. In the whole sample a pain relief of >or=50%
      on VAS was reported directly after the end of treatment protocol: Verum+COT 65%
      (95%CI 51-77%), Sham+COT 34% (95%ci 22-49%), nil+COT 43% (95%ci 29-58%) - results
      are significant for Verum+COT over Sham+COT (P<or=0.02). The results after 3
      months are: Verum+COT 77% (95%ci 62-88%), Sham+COT 29% (95%ci 16-46%), nil+Cot
      14% (95%ci 4-30%) - effects are significant for Verum+COT over Sham+COT
      (P<or=0.001) and for Verum+COT over nil+COT (P<0.001). No difference was found in
      the mobility of the patients nor in the intake of NSAID diclofenac. Our
      conclusion is that acupuncture can be an important supplement of conservative
      orthopedic treatment in the management of chronic LBP.

PMID- 12406535
TI  - Pain activation of human supraspinal opioid pathways as demonstrated by [11C]
      carfentanil and positron emission tomography (PET).
AB  - The role of the supraspinal endogenous opioid system in pain processing has been
      investigated in this study using positron emission tomography imaging of [11C]
      carfentanil, a synthetic, highly specific mu opioid receptor (mu-OR) agonist.
      Eight healthy volunteers were studied during a baseline imaging session and
      during a session in which subjects experienced pain induced by applying capsaicin
      topically to the dorsal aspect of the left hand. A pain-related decrease in brain
      mu-OR binding was observed in the contralateral thalamus consistent with
      competitive binding between [11C]-carfentanil and acutely released endogenous
      opioid peptides. This decrease varied directly with ratings of pain intensity.
      These results suggest that the supraspinal mu-opioid system is activated by acute
      pain and thus may play a substantial role in pain processing and modulation in
      pain syndromes.

PMID- 12406536
TI  - Phase I safety assessment of intrathecal ketorolac.
AB  - Spinal prostaglandin synthesis has been implicated in acute pain processes and in
      generation and maintenance of central sensitization, and intrathecal injection of
      cyclo-oxygenase (COX) inhibitors produce antinociception and reduce
      hypersensitivity in animals. We herein report a Phase I safety assessment of
      intrathecal injection of the COX inhibitor, ketorolac, in healthy volunteers, and
      demonstrate no serious side effects. Preclinical studies suggest a major site of
      action of COX inhibitors for analgesia lies in the central nervous system,
      especially the spinal cord. For example, COX isoenzymes are expressed in the
      spinal cord, acute noxious stimuli and inflammation increase spinal prostaglandin
      production, and spinally administered prostaglandins excite dorsal horn
      projection neurons, induce release of excitatory neurotransmitters, and cause
      nociceptive behavior. Intrathecal injection of COX inhibitors increases thermal
      and mechanical withdrawal threshold in animals with inflammation or nerve injury
      at doses several 100-fold less than those required systemically. Following pre
      clinical neurotoxicity screening and regulatory agency approval, we examined the
      safety of intrathecal injection of a preservative-free formulation of the COX
      inhibitor, ketorolac. In an open label, dose-escalating design, 20 healthy
      volunteers received intrathecal ketorolac, 0.25, 0.5, 1, or 2mg (n=5 per group).
      Ketorolac did not alter blood pressure, although there was small (10-12%), dose
      independent reduction in heart rate for the first hour after injection when data
      from all subjects were pooled. Ketorolac did not affect sensory or motor function
      or deep tendon reflexes, and there were no subjective sensations, neurologic or
      otherwise, reported by the volunteers. Ketorolac did not reduce pain report to
      heat stimuli applied to the lateral calf. One subject had a mild headache 24h
      after study, resolving the next day. There were no long-term side effects 6
      months after study. These data suggest that intrathecal ketorolac does not
      produce a high incidence of serious adverse events, and they support further
      investigation for analgesia.

PMID- 12406537
TI  - Is tooth extraction a good model for dental pain? A critic to Sabino et al (Pain
      2002;95:175-86).

PMID- 12406539
TI  - Comment on: Doverty et al, Hyperalgesic responses in methadone maintenance
      patients (Pain 2001;90;91-6).

PMID- 12406541
TI  - Cellular mechanisms targeted during astrocytoma progression.
AB  - Astrocytomas are the commonest type of primary brain tumour. Four malignancy
      grades are recognized with very different prognosis. The most malignant and
      commonest form in adults is called glioblastoma and has a median survival with
      modern treatment of less than one year. Over the last 20 years, molecular genetic
      and cell biological data have helped identify some of the genes affected during
      oncogenesis and progression. This will be briefly reviewed. Many significant
      observations have been made but we are still far from understanding the
      neoplastic astrocyte at the molecular level. This is reflected in inconclusive
      attempts to date to use current molecular knowledge in providing additional
      prognostic information and in the design of molecular based treatments. However,
      it seems reasonable to assume that further understanding of oncogenesis and
      progression at the molecular level will provide a basis for improved clinical
      assessment and individually tailored treatment.

PMID- 12406542
TI  - Green tea: cancer preventive beverage and/or drug.
AB  - Green tea and (-)-epigallocatechin gallate (EGCG) are now acknowledged cancer
      preventives in Japan and has made it possible for us to establish the concept of
      a cancer preventive beverage. For the general population, we recommend 10 cups of
      green tea daily supplemented with green tea tablets. For cancer patients
      following treatment, we here present new evidence that green tea and a cancer
      preventive drug, sulindac, have synergistic preventive effects. An approach to
      develop green tea capsules as a cancer preventive drug in the US is discussed,
      aiming at taking full advantage of this cancer preventive beverage.

PMID- 12406543
TI  - The role of human papillomavirus oncoproteins E6 and E7 in apoptosis.
AB  - The oncogenic potential of 'high risk' human papillomaviruses can be mainly
      attributed to two small proteins called E6 and E7. Even these oncoproteins have a
      low molecular size, they are highly promiscuous and are capable to interact with
      a whole variety of host cellular regulator proteins to elicit cellular
      immortalization and ultimately complete malignant transformation. To avoid
      reiterations in summarizing the biochemical and molecular biological properties
      of E6/E7 in terms of their influence on cell cycle control, the present review is
      mainly an attempt to describe some regulatory principles by which human
      papillomavirus (HPV) oncoproteins can interfere with apoptosis in order to escape
      immunological surveillance during progression to cervical cancer. The models
      derived from these basic cellular and molecular studies are relevant to our
      understanding of HPV-induced carcinogenesis. Conversely, experimental procedures
      aimed at relieving apoptosis resistance, can facilitate the eradication of
      immunologically suspicious cells and may prevent the accumulation of cervical
      intraepithelial cell abnormalities in future prophylactic or therapeutic
      approaches.

PMID- 12406544
TI  - What's in the 'BAG'?--A functional domain analysis of the BAG-family proteins.
AB  - Bcl-2-associated athanogene (BAG)-family proteins are BAG domain-containing
      proteins that interact with the heat shock proteins 70, both constitutive Hsc70
      and inducible Hsp70. BAG-family proteins bind through the BAG domain to the
      ATPase domain of Hsc70/Hsp70. The BAG domain, approximately 110 amino acids in
      length, is a conserved region at the carboxyl terminus and consists of three anti
      parallel alpha helices based on X-ray crystallography and NMR studies. The second
      and third alpha-helices of the BAG domain interact with the ATP-binding pocket of
      Hsc70/Hsp70. Currently, six human BAG proteins have been reported, four of which
      have been shown to functionally bind Hsc70/Hsp70. BAG-family proteins regulate
      chaperone protein activities through their interaction with Hsc70/Hsp70. Over
      expression of BAG-family proteins is found in several cancers and has been
      demonstrated in the laboratory to enhance cell survival and proliferation. The
      anti-apoptotic activities of BAG-family proteins may be dependent on their
      interactions with Hsc70/Hsp70 and/or binding to Bcl-2. Both BAG-1 and BAG-3/CAIR
      1 interact with Bcl-2 and have been shown to have a supra-additive anti-apoptotic
      effect with Bcl-2. Several N-terminal domains or motifs have been identified in
      BAG-family proteins as well. These domains enable BAG-family proteins to partner
      with other proteins and potentially alter the activity of those target proteins
      by recruiting Hsc70/Hsp70. BAG-family proteins participate in a wide variety of
      cellular processes including cell survival (stress response), proliferation,
      migration and apoptosis.

PMID- 12406545
TI  - Distinction of carcinogens from mutagens by induction of liver cell foci in a
      model for detection of initiation activity.
AB  - Initiating activities of 26 chemicals were investigated in an in vivo 5 week
      initiation assay model with evaluation of the induction of glutathione S
      transferase placental form (GST-P) positive foci as end-point lesions. With the
      five genotoxic hepatocarcinogens (diethylnitrosamine, dimethylnitrosamine, 2
      acetylaminofluorene, N-bis(2-hydroxypropyl)-nitrosamine and safrole) and 11
      genotoxic non-hepatocarcinogens, (2-(2-furyl)-3-(5-nitro-2-furyl)-acrylamide,
      benzo[a]pyrene, N-butyl-N-(4-hydroxybutyl)nitrosamine, 7,12
      dimethylbenz[a]anthracene, 1,2-dimethylhydrazine, N-ethyl-N
      hydroxyethylnitrosamine, 3-methylcholanthrene, N-methyl-N-nitrosourea, N-methyl
      N'-nitro-N-nitrosoguanidine, 4-nitroquinoline 1-oxide and 8-hydroxyquinoline),
      the numbers of GST-P positive foci were significantly higher than in the
      controls. On the other hand, the mutagenic non-carcinogens (quercetin, p
      phenylenediamine dihydrochloride, 2-chloroethanol and 6-hydroquinoline) did not
      cause a significant increase. Similarly, non-genotoxic hepatocarcinogens of the
      hepatopromotor class and promotors which target organs other than the liver did
      not induce GST-P positive foci. The specificity was thus remarkable. Moreover,
      regardless of the target organ, mutagenic carcinogens were detected by this in
      vivo 5 week initiation assay, which therefore constitutes a powerful method for
      screening for carcinogenic potential, especially in the initiation stage of
      carcinogenesis.

PMID- 12406546
TI  - Rapid induction of uterine endometrial proliferative lesions in transgenic mice
      carrying a human prototype c-Ha-ras gene (rasH2 mice) given a single
      intraperitoneal injection of N-ethyl-N-nitrosourea.
AB  - In our previous study, uterine endometrial stromal sarcomas and atypical
      hyperplasias of the endometrial glands were induced in heterozygous p53 deficient
      mice (p53 (+/-) mice) of the CBA strain given a single dose of N-ethyl-N
      nitrosourea (ENU). In order to clarify whether uterine tumors can be induced in
      transgenic mice carrying a human prototype c-Ha-ras gene (rasH2 mice) that are
      very susceptible to genotoxic carcinogens, rasH2 mice and their wild-type
      littermates received an intraperitoneal injection of 120 or 0mg/kg body weight of
      ENU followed by no further treatment for 22 weeks. Eighteen and 94% of ENU
      treated rasH2 mice had uterine endometrial adenocarcinomas and atypical
      hyperplasias, respectively. Other malignant and benign tumors such as lung
      alveolar/bronchiolar adenomas and carcinomas, forestomach squamous cell
      papillomas and carcinomas, splenic hemangiomas/sarcomas, skin papillomas,
      malignant lymphomas and harderian gland adenomas were also observed in ENU
      treated rasH2 mice. The result in the present study suggests that female rasH2
      mice are very susceptible to uterine carcinogenesis, providing a useful model for
      ENU-induced uterine epithelial tumors.

PMID- 12406547
TI  - Role of the progesterone receptor (PR) in susceptibility of mouse mammary gland
      to 7,12-dimethylbenz[a]anthracene-induced hormone-independent preneoplastic
      lesions in vitro.
AB  - Glands of wild-type (WT) and progesterone receptor knockout (PRKO) mice were
      exposed to 7,12-dimethylbenz[a]anthracene (DMBA) while cultured in serum-free
      medium containing insulin, prolactin, aldosterone, and cortisol. Glands of WT but
      not PRKO mice responded to DMBA with epithelial hyperplasia after 10 days in this
      medium. After culture without prolactin and adrenocortical hormones for an
      additional 14 days, hyperplastic lesions were present only in glands of WT mice.
      We conclude that in the absence of PR, epithelial structures are resistant to the
      carcinogenic action of DMBA.

PMID- 12406548
TI  - Effects of the phosphodiesterase-IV inhibitor EMD 95832/3 on tumour growth and
      cachexia in rats bearing the Yoshida AH-130 ascites hepatoma.
AB  - Administration of the phosphodiesterase-IV inhibitor EMD 95832/3 (Merck KGaA,
      Darmstadt, Germany) to rats bearing the ascites hepatoma Yoshida AH-130, a highly
      cachectic tumour, could not prevent either the anorexia nor the massive weight
      loss (affecting both adipose and skeletal muscle tissues) present in the tumour
      bearing animals. This compound did not have any effects on the fractional rates
      of protein turnover in skeletal muscle, and did not affect circulating
      triacylglycerols or lipoprotein lipase activity in adipose tissue. Although the
      administration of EMD 95832/3 did not influence tumour growth either, it did
      increase the number of tumour cells undergoing apoptosis. It is concluded that
      the drug is unable to reverse the cachectic state in this particular experimental
      tumour model.

PMID- 12406549
TI  - Localization of tumor by chemiluminescence probe during photosensitization
      action.
AB  - As a chemiluminescence (CL) probe, 3,7-dihydro-6-[4-[2-(N'-(5-fluoresceinyl)
      thioureido)ethoxy]phenyl]-2-methylimidazo[1,2-a]pyrazin-3-one dosium salt (FCLA)
      can sensitively and specifically react with singlet oxygen ((1)O(2)) and
      superoxide (O(2)(-)). Based on the fact that photosensitization action involves
      (1)O(2) generation, this report presents a novel method for localization of tumor
      mediated by FCLA. In experiments, FCLA was used as an optical reporter of (1)O(2)
      produced from photosensitization reaction of hematoporphyrin derivative. The
      effects of azide inhibition and deuterium enhancement on photosensitized CL
      indicated that (1)O(2) molecules generated during photosensitization action could
      be measured and imaged. In vivo experiments in vivo with tumor-bearing nude mice
      showed a clear CL image of tumor. The study suggests that CL imaging method may
      be applicable to the detection of (1)O(2) and the diagnosis of superficial
      tumors.

PMID- 12406550
TI  - Synergistic inhibitory effects of transplatin and beta-hydroxyisovalerylshikon on
      carcinoma A431 cells involve epidermal growth factor receptor.
AB  - Treatment of human epidermoid carcinoma A431 cells with transplatin (trans-DDP)
      and beta-hydroxyisovalerylshikon (beta-HIVS) together had a strong inhibitory
      effect on A431 cells. By contrast, trans-DDP and beta-HIVS by themselves, at the
      same respective concentrations, had practically no effect. The tyrosine kinase
      activities of v-Src and epidermal growth factor (EGFR) were inhibited by each of
      the two agents alone and strongly inhibited by combination. The observed
      synergistic inhibitory effect on the growth of A431 cells might have resulted
      from the inhibition of EGFR by trans-DDP, as well as by beta-HIVS.

PMID- 12406551
TI  - Induction of poly(ADP-ribose) polymerase-1 cleavage by antitumor triptycene
      bisquinones in wild-type and daunorubicin-resistant HL-60 cell lines.
AB  - In contrast to their inactive parent compound triptycene (code name TT0), new
      synthetic analogs (TT code number) mimic the antitumor effects of the
      anthracycline quinone antibiotic daunorubicin (DAU) in the nM range in vitro but
      have the additional advantage of also blocking nucleoside transport and retaining
      their efficacy in multidrug-resistant (MDR) tumor cells. Since TT bisquinones may
      induce DNA fragmentation at 24 h by an active mechanism that requires RNA and
      protein syntheses and protease activities, the most cytotoxic of them, TT24, was
      tested for its ability to induce poly(ADP-ribose) polymerase-1 (PARP-1) cleavage,
      an early marker of apoptosis. PARP-1 cleavage starts at 2-3 h and is maximally
      induced at 6 h by 1.6 microM concentrations of TT24 and DAU in wild-type drug
      sensitive HL-60-S cells. However, in MDR HL-60-RV cells, PARP-1 cleavage is still
      induced by 4 microM TT24 but not by 4-10 microM DAU. The magnitude of PARP-1
      cleavage may increase with the number of quinoid rings in the triptych structure
      and, in contrast to TT0, all lead antitumor TT bisquinones share the ability to
      fully induce PARP-1 cleavage in HL-60-S cells. A 1 h pulse treatment is
      sufficient for TT24 and DAU to induce PARP-1 cleavage at 6 h. Since the abilities
      of TT24 and DAU to induce PARP-1 cleavage are inhibited by benzyloxycarbonyl-Val
      Ala-Asp-fluoromethyl ketone but not by N-tosyl-L-phenylalanine chloromethyl
      ketone, caspase-mediated apoptosis may be involved in the mechanism by which
      these quinone antitumor drugs induce the proteolytic cleavage of PARP-1 at 6 h
      and the internucleosomal fragmentation of DNA at 24 h in the HL-60 tumor cell
      system.

PMID- 12406552
TI  - Induction of apoptosis in human cancer cell lines by diospyrin, a plant-derived
      bisnaphthoquinonoid, and its synthetic derivatives.
AB  - Diospyrin, a bisnaphthoquinonoid natural product, and three synthetic derivatives
      have been tested for their action in four human cancer cell lines: acute
      myeloblastic leukemia (HL-60), chronic myelogenic leukemia (K-562), breast
      adenocarcinoma (MCF-7) and cervical epithelial carcinoma (HeLa). In cells grown
      in appropriate media several derivatives elicited cytotoxicity as assessed by
      Trypan Blue dye exclusion, 3-(4,5-dimethylthiazol-2-yl)-2,5
      diphenyltetrazoliumbromide reduction and DNA synthesis. Diethyl ether derivative
      (D7) was most effective in this regard while the parent compound diospyrin (D1)
      was least active (D7>D3>D2>D1). D7 was not cytotoxic toward normal human
      lymphocytes, suggesting its action is specific for tumor cells. On microscopic
      examination D7-treated cells exhibited characteristic morphological features of
      apoptosis, such as cell shrinkage and formation of apoptotic bodies. Fluorescent
      staining with propidium iodide revealed distinct chromatin condensation and
      nuclear fragmentation. The apoptotic index paralleled cytotoxic parameters, and
      fragmented DNA extracted free of genomic DNA displayed on gel electrophoresis a
      typical ladder pattern. D7-induced apoptosis was mediated via activation of
      caspase 3 and caspase 8.

PMID- 12406553
TI  - Glutathione-S-transferases M1 (GSTM1) and GSTT1 genotype, smoking, consumption of
      alcohol and tea and risk of esophageal and stomach cancers: a case-control study
      of a high-incidence area in Jiangsu Province, China.
AB  - To evaluate interactions between lifestyle factors and glutathione-S-transferases
      M1 (GSTM1) and GSTT1 genotypes with reference to development of esophageal and
      stomach cancers, we conducted a case-control study of 141 cases of esophageal
      cancer, 153 cases of stomach cancer and 223 population-based controls in Huaian
      City of Jiangsu Province, China. GSTM1 and GSTT1 genotypes were identified by
      multiplex polymerase chain reaction. The GSTM1 null genotype was associated with
      an increased odds ratio for esophageal cancer (2.17, 95% confidence interval=1.35
      3.50), but not for stomach cancer. A combined effect was also observed between
      smoking and the GSTM1 null genotype with regard to esophageal risk. Tea drinking
      was a protective factor for both cancers, its effect being independent of the
      GSTT1 and GSTM1 genotypes. These findings suggest the GSTM1 polymorphism is
      involved in the susceptibility to esophageal cancer development, and tea
      consumption reduces the risk of esophageal and stomach cancers.

PMID- 12406554
TI  - Polymorphic variants of NFKB1 and its inhibitory protein NFKBIA, and their
      involvement in sporadic breast cancer.
AB  - Nuclear factor kappa-beta (NF-kappaB) is a transcription factor responsible for
      modulating the expression of many genes involved in cell proliferation,
      differentiation, apoptosis and metastasis. NF-kappaB interacts with IkappaB
      inhibitory proteins to regulate gene expression. This study investigated common
      variants within the genes coding for NF-kappaB and IkappaB, NFKB1 and NFKBIA, for
      involvement in sporadic breast cancer. Genotypes were determined in a population
      of breast cancer affected individuals and age-matched controls. Results do not
      support an involvement of the tested NFKB1 and NFKBIA polymorphisms in
      susceptibility to sporadic breast cancer, in the tested Caucasian population.

PMID- 12406555
TI  - Detection of p16 hypermethylation in circulating plasma DNA of non-small cell
      lung cancer patients.
AB  - We detected tumor-associated aberrant hypermethylation of the p16 gene in plasma
      DNA from 105 non-small cell lung cancer (NSCLC) patients (65 squamous cell
      carcinoma (SCC) and 40 adenocarcinoma (ADC)) and 92 matched tumor DNA samples,
      using a modified semi-nested methylation-specific PCR (MSP). This technique
      increased the sensibility of detecting p16 hypermethylation from DNA samples in
      varying stages. p16 hypermethylation was present in 73.3% (77/105) of the plasma
      samples, and 79.3% (73/92) of the tumor samples. Among those cases with
      methylated p16 sequence in tumor samples, 87.7% (64/73) also demonstrated this
      epigenetic alteration in the corresponding plasma DNA. Only patients whose tumor
      cells had hypermethylated p16 gene exhibited aberrant methylation in their plasma
      samples. Regarding different clinical stages of SCC and ADC, the frequencies of
      p16 hypermethylation in plasma DNA were nearly the same as those in corresponding
      tumors, except for stage I ADC. Our study indicated that aberrant methylation of
      p16 may be an excellent biomarker for early diagnosis and follow-up of NSCLC
      patients, and MSP is a reliable method for these purposes.

PMID- 12406556
TI  - Molecular detection of p16 promoter methylation in the serum of colorectal cancer
      patients.
AB  - Assays based on the molecular detection of genetic changes in serum have been
      shown as potential diagnostic tools for colorectal cancer. We examined the
      methylation status of p16 in colorectal cancers using methylation-specific PCR
      (MSP). Forty-four of 94 (47%) cancer DNA exhibited abnormal promoter methylation
      of p16 gene while no corresponding normal DNA exhibited such methylation.
      Subsequently, we examined whether aberrant methylation could be detected in
      corresponding serum DNA, and found that 13 of 44 (30%) patients with p16 promoter
      methylation in tumor DNA demonstrated abnormal methylation in their serum DNA.
      Moreover, abnormal methylation was found in the serum of patients in all clinical
      stages, suggesting that early colorectal cancer could be detected using the MSP
      method.

PMID- 12406557
TI  - Mouse DAM1 regulates pro-apoptotic activity of BLK in mammary epithelial cells.
AB  - Mouse mammary gland cDNA library was screened to search for BLK-interacting
      protein using yeast two-hybrid system, and a mouse DNA amplified in mammary
      carcinoma 1 (mDAM1) was obtained. mDAM1 cDNA contained a full coding region of
      678bp encoding 225 amino acids with the predicted molecular mass of 26kDa.
      Comparison of the mouse to human DAM1 revealed 90 and 100% identities at the
      nucleotide and protein levels, respectively. A single 1.5kb transcript for mDAM1
      was expressed in NMuMG mouse mammary epithelial cells. Through in vitro protein
      binding assay, interaction between mDAM1 and BLK was also confirmed. NMuMG cells,
      stably transfected and expressing mDAM1, promoted cell death under serum
      starvation condition. Transient coexpression of mDAM1 and BLK showed increased
      cell death compared to BLK expression alone in NMuMG cells. These results
      indicate that mDAM1 promotes mammary epithelial cell death and pro-apoptotic
      function of BLK.

PMID- 12406558
TI  - Induction and superinduction of growth arrest and DNA damage gene 45 (GADD45)
      alpha and beta messenger RNAs by histone deacetylase inhibitors trichostatin A
      (TSA) and butyrate in SW620 human colon carcinoma cells.
AB  - Histone deacetylase (HDAC) inhibitors such as trichostatin (TSA) and butyrate
      have been shown to inhibit cancer cell proliferation, induce apoptosis and
      regulate the expression of genes involved in cell cycle. Although the precise
      mechanism underlying HDAC inhibitor-induced cell growth arrest is not fully
      understood, induction of cell cycle related genes such as p21(cip/waf), is
      thought to be important. Here we showed that in the SW620 human colon cancer cell
      line, TSA and butyrate induced the growth arrest and DNA damage gene 45alpha
      (GADD45alpha) and GADD45beta. Furthermore, GADD45beta and p21(cip/waf) messenger
      RNA were induced in the absence of protein synthesis, indicating that both genes
      were immediate target genes for TSA. Cyclohexamide and TSA super-induced the
      expression of GADD45alpha and beta, but not p21(cip/waf). Interestingly while
      mitogen-activated kinase (MEK) inhibitor PD98059 and p38 kinase inhibitor
      SB242235 were unable to affect GADD45 induction, two serine/threonine protein
      kinase inhibitors (H7 and H8) as well as curcumin completely blocked the super
      induction. Concomitant to the inhibition of GADD45 induction, H7 and H8 also
      blocked TSA-induced apoptosis. Taken together, these results suggest that GADD45
      induction may play important role in TSA-induced cellular effects.

PMID- 12406559
TI  - Apoptosis sensitivity is not correlated with sensitivity to proliferation
      inhibition by the histone deacetylase inhibitors butyrate and TSA.
AB  - We investigated a set of cell lines as to their sensitivity to proliferation
      inhibition, on the one side, and apoptosis induction, on the other, by the core
      histone deacetylase inhibitors butyrate and trichostatin A (TSA), respectively.
      The results can be summarized as follows: (i) the investigated cell lines can be
      classified into three groups of high, medium and low sensitivity to proliferation
      inhibition by the histone deacetylase inhibitors; (ii) there is no correlation
      between the sensitivities to proliferation inhibition and the sensitivities to
      apoptosis induction by the histone deacetylase inhibitors; (iii) a comparison of
      the relative sensitivities to butyrate versus TSA with regard to proliferation
      inhibition and apoptosis induction, respectively, revealed that besides a good
      correlation most often encountered, there are also cell lines with conspicuously
      differing relative sensitivities to the two structurally different histone
      deacetylase inhibitors.

PMID- 12406561
TI  - Lack of inhibitory effects of green tea catechins in 1,2-dimetylhydrazine-induced
      rat intestinal carcinogenesis model: comparison of the different formulations,
      administration routes and doses.
AB  - Differences in the modifying effects of green tea catechins (GTC) on intestinal
      carcinogenesis by different formulations, doses and administration routes were
      investigated in male rats pretreated with 1,2-dimethylhydrazine (DMH). One
      hundred and eighty nine F344 male rats received subcutaneous injections of DMH at
      40 mg/kg body weight twice a week for 3 weeks. Three days after completion of the
      carcinogen treatment, they were divided into nine groups. Each was administered a
      different source of 0.1% or 0.01% of GTC (Mitsui Norin Co. (M) or Taiyo Kagaku
      Co. (T)) either in the diet (D) or the drinking water (W), or basal diet and tap
      water alone without GTC for 33 weeks and then killed for autopsy. The survival
      rate tended to be lower with 0.01% MGTC (W) group than in the other groups. In
      the large intestine, although the multiplicity and/or incidences of adenomas
      showed tendencies for dose-dependent decrease in all GTC groups, and the average
      volumes of tumors tended to be decrease dose-dependently in the MGTC (W) and TGTC
      (W) groups, the multiplicity of carcinomas did not show such a trend, rather
      being significantly increased in the 0.01% MGTC (D) and 0.1% TGTC (W) groups. In
      the small intestine, the incidence and the multiplicity of tumors in all GTC
      treated groups had a tendency to decrease. On the other hand, the volume of
      tumors was increased with statistical significance in the 0.01% MGTC (W) and 0.1%
      TGTC (W) groups. Thus it can be concluded that GTC does not exert chemopreventive
      effects on intestinal carcinogenesis irrespective of its formulation, dose or
      route of administration.

PMID- 12406560
TI  - Unsaturated fatty acids bind Myc-Max transcription factor and inhibit Myc-Max-DNA
      complex formation.
AB  - Oncoprotein Myc, hetero-dimerized with Max through a b/HLH/Zip region, is a
      transcription factor that governs important cellular processes such as cell cycle
      entry, proliferation and differentiation. We found that linoleic acid, isolated
      from Pollen Typhae, and other unsaturated fatty acids have strong inhibitory
      effects on the binding of Myc-Max heterodimer to an E-box DNA site (CA(C/T)GTG).
      The interaction of a fatty acid with a protein dimer, not with DNA, is assumed to
      block the entire Myc-Max-DNA complex formation. Unsaturated fatty acids also
      showed cytotoxicity against a SNU16 human stomach cancer cell line and conjugated
      linoleic acid suppressed mRNA expression of several myc-target genes; ornithine
      decarboxylase, p53, cdc25a in the SNU16 cells.

PMID- 12406562
TI  - Potent cytotoxic effect of the trans10, cis12 isomer of conjugated linoleic acid
      on rat hepatoma dRLh-84 cells.
AB  - We evaluated the cytotoxic effect of conjugated linoleic acid (CLA) on rat
      hepatoma dRLh-84 cells in vitro. When cells were cultured in the presence of CLA,
      strong cytotoxic effect on dRLh-84 cells was recognized at 1 microM level
      compared to the control vehicle group, and trans10, cis12-CLA but not cis9,
      trans11-CLA was shown to be an active isomer for inducing this effect. Increase
      of the sub-G1 population and activation of caspase-3 and 9 accompanied with a
      time-dependent cleavage of poly(ADP-ribose) polymerase were recognized in dRLh-84
      cells treated with trans10, cis12-CLA. In addition, we could see nuclear
      fragmentation in dRLh-84 cells treated with trans10, cis12-CLA by laser scanning
      confocal microscopy observation. Cytotoxic effect of trans10, cis12-CLA on normal
      hepatocytes was weaker than on dRLh-84 cells. These data indicate trans10, cis12
      CLA has a potent cytotoxic effect on dRLh-84 cells through at least in part by an
      apoptotic pathway.

PMID- 12406563
TI  - Expression of hyaluronate and hyaluronate synthase in human primary tumours and
      their metastases in scid mice.
AB  - Hyaluronate and hyaluronate synthase expression were examined in primary tumours
      and if present in metastatic deposits of human breast, colon, ovarian and small
      cell lung cancer cell lines transplanted into scid mice using biotinylated
      hyaluronectin and immunohistochemical staining of hyaluronate synthase. Very
      intensive hyaluronate and hyaluronate synthase expression could be observed in
      peripheral areas of tumours derived from highly metastatic cell lines (HT29, MCF
      7). Even smaller lung metastases of up to 15 cells showed typically a focal
      binding of hyaluronectin predominantly at the host-tumour interface of the
      metastases, indicating that increased expression is closely correlated with the
      degree of invasiveness and metastatic potential of malignant tumours.

PMID- 12406564
TI  - Detection of disseminated cancer cells in bone marrow of gastric cancer using
      real time quantitative reverse transcriptase polymerase chain reaction.
AB  - Bone marrow is a prognostically relevant indicator organ for micrometastasis. In
      the present study, real time quantitative reverse transcriptase polymerase chain
      reaction (RT-PCR) was used to detect disseminated gastric cancer cells in bone
      marrow. We compared CEA, CK18 and CK20 expression using four gastric cancer cell
      lines and three normal tissue cell lines in order to select the most appropriate
      marker for detection of disseminated gastric cancer cell in bone marrow. CK20
      proved to be the most promising marker since the expression level of normal cell
      lines was extremely low and about 50--100-fold differences were found between
      gastric carcinoma cell lines and normal tissue cell lines. We also screened bone
      marrow RNA of 47 patients with gastric cancers, using this system. Among the
      three markers we tested, with only about CK20 could we find that 27 of 47
      patients were positive. Though long-term clinical follow up studies are needed to
      evaluate the clinical significance of this method, real time quantitative RT-PCR
      is sensitive and quantitative for detection of micrometastasis in bone marrow.

PMID- 12406565
TI  - The aberrant expression of cytosolic carbonic anhydrase and its clinical
      significance in human non-small cell lung cancer.
AB  - This study was designed to elucidate the possible relationship between the
      expression of cytosolic carbonic anhydrase (CA) and non-small cell lung cancer
      (NSCLC). The activity and protein expression patterns of carbonic anhydrase I
      (CAI) and II (CAII) of 70 NSCLC patients were analyzed by CA activity analysis,
      immunoblotting and immunohistochemical staining. The results showed that the CA
      activity and protein expression were significantly decreased in both squamous
      cell carcinoma (SCC) and adenocarcinoma (AD) (P<0.001 and P<0.001). From our
      study, it was suggested that the reduction of CAI and CAII in both SCC and AD
      patients may promote tumor cell motility and contribute to tumor growth and
      metastasis.

PMID- 12406566
TI  - Proline homozygosity in codon 72 of p53: a risk genotype for human papillomavirus
      related cervical cancer in Indian women.
AB  - The objective of the present study was to determine the codon 72 genotypic
      frequencies of p53 in Indian women and to analyze the association of this
      polymorphism with human papillomavirus (HPV) related cervical cancer (CaCx). We
      used tissues derived from 55 women diagnosed with squamous cell carcinoma of the
      cervix (of whom 46 were HPV types 16/18 positive) and cervical scrapes derived
      from 201 cytologically normal women (of whom 84 were HPV types 16/18 positive) as
      controls. The DNA isolated from these samples was genotyped for p53 polymorphism
      by polymerase chain reaction and restriction fragment length polymorphism method.
      The genotypic frequency of homozygous arginine among women with CaCx was 27% and
      this did not differ with the controls. But, proline homozygosity of 33% in the
      malignant samples was significantly higher than controls (OR=2.23; 95% CI: 1.14
      4.35; P=0.02). The associated risk of this genotype towards CaCx was more
      prominent (OR=2.67; 95% CI: 1.16-6.15; P=0.02) when analysis was restricted to
      HPV 16/18 positive women. Thus, proline homozygosity at codon 72 of p53 and not
      arginine homozygosity, could be a risk factor for development of CaCx associated
      with high risk HPV among Indian women.

PMID- 12406567
TI  - Inhibition of lung metastasis of osteosarcoma cell line POS-1 transplanted into
      mice by thigh ligation.
AB  - Using a model with external ligation of the thigh, the effect of ischemia
      reperfusion injury on tumor growth and the activity of lung metastasis was
      investigated in mice inoculated a spontaneous murine osteosarcoma cell line (POS
      1) in vivo. POS-1 cell suspension was inoculated into the right hind footpad of
      70 mice. Four weeks after inoculation, the ipsilateral thigh was ligated for 3 h
      in 15 mice and the contralateral thigh in 15 mice. Another ten mice were
      inoculated with POS-1 without ligating the thigh. The number of metastatic foci
      on the lung surface 6 weeks after inoculation was 2.29+/-0.98 (mean+/-SE)
      foci/lungs in mice with ipsilateral ligation and 6.25+/-2.41 in mice with
      contralateral ligation, which were significantly lower than control (13.40+/-1.42
      in mice no ligation) (P<0.01). The number of metastatic foci on the lung surface
      in mice with intraperitoneal injection of superoxide dismutase (SOD) and catalase
      was 3.25+/-0.65 (mean+/-SE) foci/lungs in mice with ligation which was
      significantly greater than that in mice without SOD and catalase injection 1.29+/
      0.97 (P=0.04). Cell viability was 9.12+/-4.07% with 100 microM H(2)O(2) in 3-[4,5
      dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay. It revealed that at
      concentrations of 100 microM H(2)O(2) or higher was cytotoxic to POS-1. In cell
      invasion assay, the number of invading cells with 10 microM H(2)O(2) was 2.80+/
      0.53 cells/field, which was significantly lower than control (5.93+/-0.18)
      (mean+/-SE), indicating that low-dose H(2)O(2) suppressed invasion of POS-1.
      These results suggested that reperfusion injury had selective cytotoxicity to POS
      1 through producing reactive oxygen species. Activated oxygen was considered to
      inhibit the regional growth and the ability of lung metastasis of POS-1 cells.

PMID- 12406568
TI  - Cyclin A expression in superficial squamous cell carcinoma of the esophagus and
      coexisting infiltrated lymphocyte follicle.
AB  - Cyclin A is a protein kinase to act a pivotal role in the mitotic phase of the
      cell cycle. The purpose of the current study was to elucidate the biological
      significance of immunohistochemical expression of cyclin A in superficial
      squamous cell carcinoma (SCC) of the esophagus. Immunohistochemical staining of
      cyclin A was performed for 45 samples of esophageal superficial SCCs.
      Clinicopathological features were compared between SCCs with and without cyclin A
      expression. Twenty-five superficial SCCs (55.6%) had positive expression of
      cyclin A and the other 20 (44.4%) did not. No significant difference regarding
      clinicopathological characteristics between esophageal SCCs with and without
      cyclin A expression. Infiltration of lymphocytes with germinal center cells was
      observed beneath 17 (68.0%) out of 25 superficial SCCs with cyclin A expression
      and 15 (75.0%) out of 20 superficial SCCs without cyclin A expression. Although
      16 (94.1%) out of 17 superficial SCCs with cyclin A expression were associated
      with cyclin A expression in germinal center cells in infiltrated lymphoid
      follicles beneath the tumors, only 2 (13.3%) out of 15 superficial SCCs without
      cyclin A expression coexisted with cyclin A expression in lymphoid follicles
      beneath the tumors (P<0.0001). Cyclin A expression in the germinal center cells
      of the lymphoid follicles beneath the superficial SCCs of the esophagus might be
      an immunological signal toward the proliferation and progression of the tumors.

PMID- 12406569
TI  - Gender differences in the dihydropyrimidine dehydrogenase expression of
      colorectal cancers.
AB  - Dihydropyrimidine dehydrogenase (DPD) is the initial, rate-limiting enzyme in the
      catabolism of 5-fluorouracil (5-FU). DPD expression levels are believed to
      correlate with the 5-FU sensitivity of malignant tumors. In colorectal cancer
      (CRC), a few previous studies demonstrated that females could benefit more from
      adjuvant chemotherapy. However, it is still unknown why the effectiveness of
      postoperative chemotherapy is affected by gender. The objective of this study was
      to clarify the beneficial differences in 5-FU chemotherapy between genders in
      patients with the CRC based on DPD expression. Ninety-seven tumor specimens and
      92 adjacent normal tissue specimens from 97 patients with the CRC and no prior
      therapy were obtained. The DPD expression in the tissues was quantified and
      analyzed based on clinicopathological factors. In the tumor tissue, the DPD
      expression in females was significantly lower than that in males. In the normal
      tissues, however, there were no significant differences in DPD expression between
      genders. In the treatment of CRC, cases who will benefit most because of 5-FU
      sensitivity; i.e. cases with lower DPD expression, must be given priority. Based
      on DPD expression, female gender seems to be a predictive factor for a better
      response to chemotherapy with 5-FU.

PMID- 12406570
TI  - The human SLC8A3 gene and the tissue-specific Na+/Ca2+ exchanger 3 isoforms.
AB  - We have identified the human gene for member 3 of Solute Carrier family 8
      (SLC8A3) by bioinformatic analysis of human genomic sequences. The gene is
      located on chromosome 14q24.2, and spans a region of about 150 kb. The full
      length DNA complementary to RNA encoding the Na(+)/Ca(2+) exchanger isoform 3
      (NCX3), amplified by reverse transcriptase-polymerase chain reaction (RT-PCR)
      from the human neuroblastoma SH-SY5Y RNA, includes seven exons and encodes a
      protein of about 100 kDa. RT-PCR analysis was performed in different tissues to
      determine the exon composition in the region encoding the large intracellular
      loop of the protein. The region underwent modifications by alternative tissue
      specific splicing. NCX3.2, including exon 4 but not exon 5, was found in human
      brain and in the neuroblastoma cell line. In human skeletal muscle two additional
      isoforms were identified: NCX3.3, including exons 4 and 5, and a truncated
      isoform (NCX3.4) produced by the skipping of both exons 3 and 4. The skipping
      causes a frame shift downstream of the exon 2 sequence. The new coding sequence
      of 25 amino acids terminates with a stop codon in exon 6. The NCX3.4 isoform (68
      kDa) is truncated in the C-terminal portion of the domain first found in
      Drosophila Na(+)/Ca(2+) exchanger domain (Calxbeta) and lacks the C-terminal
      hydrophobic segments.

PMID- 12406571
TI  - Transcriptional repression of the RET proto-oncogene by a mitogen activated
      protein kinase-dependent signalling pathway.
AB  - Transcription factors play important roles in regulating cell growth and
      differentiation. In this study, treatment of the MTC cell line, TT, with phorbol
      12-myristate 13-acetate (PMA) was shown to reduce neurite outgrowth which may be
      associated with de-differentiation and loss of the transformed phenotype.
      Northern blotting revealed that PMA transiently induced early growth response
      gene 1 (Egr-1) expression and decreased RET expression. Transient transfection
      analyses using 5'-deletion constructs of the basal RET promoter, demonstrated the
      requirement of a region between -70 and -33 bp for PMA-inducible expression. Gel
      shift and supershift studies demonstrated that PMA induced Egr-1 formed part of a
      complex capable of binding to the RET minimal promoter. Overexpression of Egr-1
      displaced both sephacryl and phosphocellulose protein 1 (Sp1) and Sp3 from a GC
      box element previously found to be important for RET basal expression.
      Furthermore, use of a raf-1 inducible TT cell line, that has been previously
      shown to downregulate RET expression, revealed that this downregulation may be
      linked to the induction of Egr-1. Our data suggest that regulation of RET
      expression during development and in medullary thyroid carcinoma may be
      determined, at least in part, by this complex of Sp and Egr-1 proteins.

PMID- 12406572
TI  - Genomic structure of the sponge, Halichondria okadai calcyphosine gene.
AB  - Calcyphosine is an EF-hand Ca(2+)-binding protein, which was first isolated from
      the canine thyroid. It is phosphorylated in a cyclic AMP (cAMP)-dependent manner;
      then it is thought to be implicated in the cross-signaling between the cAMP and
      calcium-phosphatidylinositol cascades. Here, we isolated the DNA complementary to
      RNA (cDNA) of an EF-hand Ca(2+)-binding protein from the sponge, Halichondria
      okadai and determined its genomic structure. The deduced sequence of the sponge
      Ca(2+)-binding protein showed significant similarity (about 40% identity) with
      those of mammal calcyphosines, and the intron positions were well conserved
      between the sponge and human calcyphosine genes. We considered that the isolated
      cDNA was that of sponge calcyphosine, and that sponge and mammalian calcyphosines
      evolved from a common ancestor gene. Recent cDNA projects have revealed that a
      calcyphosine cDNA is also expressed by human, mouse, and the ascidia. These cDNAs
      have more than 60% identity with sponge calcyphosine and each other, and all are
      composed of 208 amino acid residues. On the constructed phylogenetic trees,
      calcyphosines are essentially divided into two groups, types-I and -II
      calcyphosines. Type-I calcyphosine may be specific to mammals, and type-II is
      widely distributed among metazoan species. This suggests that type-II
      calcyphosine is a rather ancient gene with some essential function.

PMID- 12406573
TI  - In vivo functional analysis of Drosophila protein kinase casein kinase 2 (CK2)
      beta-subunit.
AB  - Protein casein kinase 2 (CK2) is a heterotetramer composed of two catalytic
      (alpha) and two regulatory (beta) subunits. In Drosophila melanogaster, four
      genes encoding for one CK2alpha (DmCK2alpha) and three CK2beta (DmCK2beta,
      DmCK2beta' and DmCK2betates) subunits have been identified. Here, we have focused
      on the role of DmCK2beta. Evaluation of DNA complementary to RNA sequences and
      Western blot analysis revealed a complex pattern of DmCK2beta transcription and
      the existence of at least three distinct DmCK2beta isoforms in adult flies. The
      phenotype of the viable DmCK2beta mutation mushroom bodies undersized(P1)
      (DmCK2beta(mbuP1)) described in this study implicates a role for DmCK2beta in
      cell proliferation or cell survival during brain development. The isolation of a
      complete loss of function allele of DmCK2beta allowed us to assay the importance
      of various structural domains for the in vivo function of DmCK2beta. Expression
      of in vitro mutagenised DmCK2beta transgenes in a DmCK2beta null mutant
      background demonstrated an absolute requirement of the beta/beta dimerisation
      motif for CK2beta function, whereas removal of all N-terminal phosphorylation
      sites of DmCK2beta resulted in reduced viability. In contrast, a mutation in the
      predicted destruction box motif did not interfere with DmCK2beta function.

PMID- 12406574
TI  - Molecular and functional analysis of the Rickettsia typhi groESL operon.
AB  - The groESL operon from an obligate, intracellular, Gram-negative bacterium
      Rickettsia typhi, the etiologic agent of murine typhus, was cloned and sequenced.
      The sequence analysis of 2229 bp of the groESL operon reveals two open reading
      frames of 288 nucleotides (groES) and 1653 nucleotides (groEL) separated by 20
      nucleotides. The deduced amino acid sequence of R. typhi GroES and GroEL shows a
      high degree of identity with other bacterial GroES and GroEL. Reverse
      transcriptase-polymerase chain reaction and Northern blot analysis indicated that
      both groES and groEL are transcribed as a single mRNA. The transcriptional start
      point at 81 nucleotides upstream of the groES start codon was determined by
      primer extension. The promoter analysis shows no regulatory CIRCE element as it
      is known for many Gram-positive and Gram-negative bacteria. However, it contains
      the sequence similar to the putative sigma(70)-dependent promoter and lacks the 
      35 sequence of the putative sigma(32)-dependent promoter. Complementation assay
      by R. typhi groESL in a temperature sensitive Escherichia coli groEL mutant
      restored significant growth ability at non-permissive temperature.

PMID- 12406575
TI  - Interactions of heterogeneous nuclear ribonucleoprotein D-like protein JKTBP and
      its domains with high-affinity binding sites.
AB  - JKTBP proteins consisting of two canonical RNA binding domains (RBDs) and a
      glycine-rich carboxyl domain are nucleocytoplasmic shuttling proteins. We studied
      in vivo and in vitro interactions between JKTBP and RNA. UV cross-linking
      experiments on HL-60 cells indicated that following RNA synthesis inhibition by
      actinomycin D, JKTBP1 accumulated in the cytoplasam is bound to poly(A)(+) RNAs.
      Recombinant JKTBP1 protein blots could bind poly(A)(+) RNAs, but not poly(A)(-)
      RNAs. For examination of RNA binding specificity of JKTBP, we enriched high
      binding sites from pools of 20 nt random sequence-containing RNAs by a
      selection/amplification method. After eight rounds of a selection and
      amplification, >20 sequences for each of JKTBPs 1 and 2 were identified. Their
      consensus high-affinity site was ACUAGC. Approximate K(d)s of JKTBPs 2 and 1 were
      estimated to be 6-12 nM for the selected sequences by filter binding assays.
      JKTBP deletion analysis indicated that not individual RBDs, both RBDs and the N
      terminal 15 amino acids of the carboxyl domain are required for sequence-specific
      and high-affinity binding. These results indicate that JKTBP is a sequence
      specific RNA binding protein differing from the related heterogeneous nuclear
      ribonucleoproteins A1 and D.

PMID- 12406576
TI  - Identification and characterization of the human long form of Sox5 (L-SOX5) gene.
AB  - The Sox (Sry-type HMG box) group of transcription factors, which is defined by a
      high-mobility group (HMG) DNA-binding domain, is categorized into six
      subfamilies. Sox5 and Sox6 belong to the group D subfamily, which is
      characterized by conserved N-terminal domains including a leucine-zipper, a
      coiled-coil domain and a Q-box. Group D Sox genes are expressed as long and short
      transcripts that exhibit differential expression patterns. In mouse, the long
      form of Sox5, L-Sox5, is co-expressed and interacts with Sox6; together, these
      two proteins appear to play a key role in chondrogenesis and myogenesis. In
      humans, however, only the short form of Sox5 has previously been identified. To
      gain insight into Sox5 function, we have identified and characterized human L
      SOX5. The human L-SOX5 cDNA encodes a 763-amino-acid protein that is 416 residues
      longer than the short form and contains all of the characteristic motifs of group
      D Sox proteins. The predicted L-SOX5 protein shares 97% amino acid identity with
      its mouse counterpart and 59% identity with human SOX6. The L-SOX5 gene contains
      18 exons and shows similar genomic structure to SOX6. We have identified two
      transcription start sites in L-SOX5 and multiple alternatively spliced mRNA
      variants that are distinct from the short form. Unlike the short form, which
      shows testis-specific expression, L-SOX5 is expressed in multiple tissues. Like
      SOX6, L-SOX5 shows strong expression in chondrocytes and striated muscles,
      indicating a likely role in human cartilage and muscle development.

PMID- 12406577
TI  - Angiomotin belongs to a novel protein family with conserved coiled-coil and PDZ
      binding domains.
AB  - Angiomotin has previously been identified in a yeast two-hybrid screen by its
      ability to bind to angiostatin, an inhibitor of novel formation of blood vessels
      (angiogenesis). Angiomotin mediates the inhibitory effect of angiostatin on
      endothelial cell migration and tube formation in vitro. Here we report that two
      human protein sequences, of which one is novel and one has been cloned
      previously, are similar to angiomotin and are members of a novel protein family,
      which we propose to call motins. These two genes have been named angiomotin-like
      1 (amotl1) and angiomotin-like 2 (amotl2). We have cloned mouse angiomotin and
      identified amotl1 and amotl2 homologs in mice. The alignment of the amino acid
      sequences encoded by these six sequences spans 455 residues of which 64% was
      conserved in all six proteins. Sequence analysis showed that these sequences all
      share putative coiled-coil domains and PDZ-binding motifs. Sequence information
      from GenBank indicate that motins can be found in several species including the
      frog Xenopus laevis, the pufferfish Fugu rubripes and the nematode Caenorhabditis
      elegans. Further phylogenetic analysis indicates that amotl2 is an evolutionary
      outgroup in relation to angiomotin and amotl1. Northern blot analysis shows
      distinct expression patterns for each motin in various mouse tissues.

PMID- 12406578
TI  - Cryptosporidium parvum: the first protist known to encode a putative polyketide
      synthase.
AB  - We are reporting a putative multifunctional Type I polyketide synthase (PKS) gene
      from the apicomplexan Cryptosporidium parvum (CpPKS1). The 40 kb intronless open
      reading frame (ORF) predicts a single polypeptide of 13,414 amino acids with a
      molecular mass of 1516.5 kDa. Sequence analysis identified at least 29 enzymatic
      domains within this protein. These domains are organized into an N-terminal
      loading unit, seven polyketide chain elongation modules, and a carboxy terminator
      unit. The loading domain consists of an acyl-CoA ligase (AL) and an acyl carrier
      protein (ACP). All seven elongation modules contain between two and five of the
      six domains required for the elongation of two-carbon (C2) acyl units, i.e.
      ketoacyl synthase, acyl transferase, dehydrase, enoyl reductase, ketoreductase
      and/or ACP. The carboxy terminator is homologous to various reductases,
      suggesting that the final elongated product is not hydrolytically released by
      thioesterases as observed in most Type I PKS and all fatty acid synthetase (FAS)
      systems, but by a reducing reaction, which has been demonstrated in some non
      ribosomal peptide synthase systems. The protein sequence and domain organization
      of CpPKS1 protein resembles a previously reported C. parvum fatty acid synthase
      (CpFAS1), which is encoded by a 25 kb ORF. Maximum likelihood phylogenetic
      analysis of acyl transferases within PKS/FAS from C. parvum and other organisms
      clearly differentiates acetate-extending clades from those incorporating
      propionate. All acyl transferase domains from CpPKS1, and a previously reported
      CpFAS1, clustered within the acetate-extending group, suggesting the likelihood
      that only non-methylated C2 units are incorporated by C. parvum polyketide and
      fatty acid synthases. The expression of CpPKS1 was confirmed by reverse
      transcription-polymerase chain reaction and immunofluorescence microscopy. Many
      polyketides are medically significant antibiotics, anticancer agents, toxins, or
      signaling molecules. Therefore, it is interesting to speculate what role CpPKS1
      might play in this apicomplexan and the disease caused by this opportunistic
      infection of AIDS patients.

PMID- 12406579
TI  - Identification and characterization of alternatively spliced variants of DNA
      methyltransferase 3a in mammalian cells.
AB  - CpG methylation is mediated by the functions of at least three active DNA
      methyltransferases (DNMTs). While DNMT1 is thought to perform maintenance
      methylation, the more recently discovered DNMT3a and DNMT3b enzymes are thought
      to facilitate de novo methylation. Murine Dnmt3a and 3b are developmentally
      regulated and a new Dnmt3a isoform, Dnmt3a2, has been recently shown to be
      expressed preferentially in mouse embryonic stem (ES) cells. Here we have
      characterized four alternatively spliced variants of human and mouse DNMT3a.
      These transcripts included a novel exon 1 (1beta) that was spliced into the same
      exon 2 acceptor splice site used by the original exon 1 (1alpha). Cloning and
      sequencing of the 5' region of the human DNMT3a gene revealed that exon 1beta was
      situated upstream of exon 1alpha and that the entire region was contained within
      a CpG island. We also identified other alternatively spliced species containing
      intron 4 inclusions that were associated with either exon 1alpha or 1beta. These
      were expressed at low levels in mouse and human cells. All transcripts were
      highly conserved between human and mouse. The levels of Dnmt3a mRNA containing
      exon 1beta were 3-25-fold greater in mouse ES cells than in various somatic cells
      as determined by semiquantitative reverse transcription-polymerase chain reaction
      analysis, while the levels of exon 1alpha-containing transcripts were slightly
      higher in human and mouse somatic cells. The preferential expression of the beta
      transcript in ES cells suggests that this transcript, in addition to Dnmt3a2, may
      also be important for de novo methylation during development.

PMID- 12406580
TI  - Genomic organization and promoter analysis of the human nicotinic acetylcholine
      receptor alpha6 subunit (CHNRA6) gene: Alu and other elements direct
      transcriptional repression.
AB  - Nicotinic acetylcholine receptors (nAChRs) form ligand-gated ion channels
      involved in fast synaptic transmission. Recently mutations in nAChR genes have
      been reported in nocturnal frontal lobe epilepsy. We performed molecular analysis
      on the human neuronal nAChR alpha6 subunit (CHRNA6) gene, a member of nAChR gene
      family, to understand its role in disease. Genomic analysis revealed that the
      gene consisted of six exons with an estimated size of 16 kb. We mapped the CHRNA6
      gene to chromosome 8p11.21-11.22 by fluorescence in situ hybridization, the same
      putative region responsible for adolescent-onset idiopathic generalized epilepsy.
      Examination of the 5'-regulatory region failed to identify either a TATA box or
      GC-rich sequences, but did highlight tandem Alu sequences, located between 910
      and 370 bp upstream from a potential cap site. Analyses of transcriptional
      activity, performed using nested deletions of the 5'-upstream region, showed that
      the downstream Alu repeat and another element(s) in the promoter region, function
      as negative regulators. Further analyses of the tandem Alu repeats, examined by
      fusing them to a different ion channel gene promoter, confirmed their role as
      transcriptional repressors regardless of their orientation and copy number. These
      data may explain the limited expression of the CHRNA6 gene in the brain.

PMID- 12406581
TI  - Development of enantioselective chemiluminescence flow- and sequential-injection
      immunoassays for alpha-amino acids.
AB  - The development of an enantioselective flow-through chemiluminescence
      immunosensor for amino acids is described. The approach is based on a competitive
      assay using enantioselective antibodies. Two different instrumental approaches, a
      flow-injection (FIA) and a sequential-injection system (SIA), are used. Compared
      to the flow-injection technique, the sequential injection-mode showed better
      repeatability. Both systems use an immunoreactor consisting of a flow cell packed
      with immobilized haptens. The haptens (4-amino-L- or D-phenylalanine) are
      immobilized onto a hydroxysuccinimide-activated polymer (Affi-prep 10) via a
      tyramine spacer. Stereoselective antibodies, raised against 4-amino-L- or D
      phenylalanine, are labeled with an acridinium ester. Stereoselective inhibition
      of binding of the acridinum-labeled antibodies to the immobilized hapten by amino
      acids takes place. Chiral recognition was observed not only for the hapten
      molecule but also for a series of different amino acids. One assay cycle
      including regeneration takes 6:30 min in the FIA mode and 4:40 min in the SIA
      mode. Using D-phenylalanine as a sample, the detection limit was found to be 6.13
      pmol/ml (1.01 ng/ml) for the flow-injection immunoassay (FIIA) and 1.76 pmol/ml
      (0.29 ng/ml ) for the sequential-injection immunoassay (SIIA) which can be
      lowered to 0.22 pmol/ml (0.036 ng/ml) or 0.064 pmol/ml (0.01 ng/ml) by using a
      stopped flow system. The intra-assay repeatability was found to be about 5% RSD
      and the inter-assay repeatability below 6% (within 3 days).

PMID- 12406582
TI  - Chiral separation of thiazide diuretics by HPLC on Chiralcel OD-RH, Chiralcel OJ
      R and Chirobiotic-T phases.
AB  - This contribution deals with comparative studies on the chiral separation of
      thiazide diuretics using cellulose tris(3,5-dimethylphenylcarbamate) (Chiralcel
      OD-RH), cellulose tris(4-methylbenzoate) (Chiralcel OJ-R) and teicoplanin
      (Chirobiotic T) phases. All columns showed good chiral recognition ability for
      this class of compounds. Out of seven compounds investigated, six were resolved
      with baseline resolution with at least one of the three columns.

PMID- 12406583
TI  - Chiral separation of bioactive cyclic Mannich ketones by HPLC and CE using
      cellulose derivatives and cyclodextrins as chiral selectors.
AB  - The chiral separation of cyclic Mannich ketones of potential pharmaceutical
      interest is investigated using HPLC and CE. These Mannich ketones show a marked
      antibacterial and antifungal activity. In HPLC, stationary phases containing
      cellulose derivatives or beta-cyclodextrin were used and in CE different
      cyclodextrins, such as beta-CD, gamma-CD, carboxymethyl-beta-CD and succinyl-beta
      CD were added to the background electrolyte as chiral selectors.

PMID- 12406584
TI  - Effects of industrially produced flavours with pro- and antioxidative properties
      on the formation of the heterocyclic amine PhIP in a model system.
AB  - PhIP (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine) is a heterocyclic aromatic
      amine belonging to a class of mutagens found in food. This project studied the
      effects of commercially available flavours of spices on the formation of PhIP,
      one of the most common heterocyclic aromatic amines in heated meat and fish
      products. The model reactions were carried out in diethylene glycol. Highest
      amounts of PhIP were obtained at 200 degrees C, a heating time of 60 min and an
      equivalent molar ratio of phenylalanine and creatinine. With this model system,
      the influence of Monascus red and flavours extracted from thyme, marjoram and
      rosemary on the formation of PhIP was tested. The flavours were added to the
      model system in different amounts. The oxidative properties were determined with
      the rancimat method. It was shown that all tested products, independent of their
      pro- or antioxidative properties, increased PhIP in the model system.

PMID- 12406585
TI  - The detection of radical scavenging compounds in crude extract of borage (Borago
      officinalis L.) by using an on-line HPLC-DPPH method.
AB  - The rapid evaluation of antioxidant activity of crude borage (Borago officinalis
      L.) extract was determined by using DPPH free radical method. This borage extract
      resulted in a rapid decrease of the absorbance and showed very high hydrogen
      donating capacity towards the 2,2'-diphenyl-1-picrylhydrazyl (DPPH) radical. A
      new HPLC-DPPH on-line method was applied for a screening of several radical
      scavenging components in this borage extract as well as for quantitative
      analysis. This on-line HPLC-DPPH method was developed using a methanolic solution
      of DPPH-stable radical. The HPLC-separated analytes reacted post-column with the
      DPPH solution in methanol. The induced bleaching was detected as a negative peak
      photometrically at 515 nm. The separation of antioxidative components was carried
      out by gradient HPLC with mobile-phase composition ranging from 2% to 80%
      acetonitrile with 2% acetic acid in water, UV detection was carried out at 280
      nm. The HPLC analysis of borage extract revealed the presence of several radical
      scavenging components in the borage extract. The results obtained from the
      chromatograms suggest that some compounds present in the extract possess high
      radical quenching ability. The dominant antioxidative compound in the crude
      extract of borage leaves was identified as rosmarinic acid.

PMID- 12406586
TI  - Determination of bone and tissue concentrations of teicoplanin mixed with
      hydroxyapatite cement to repair cortical defects.
AB  - A highly specific and sensitive isocratic reversed-phase high performance liquid
      chromatography (HPLC) method for the determination of the major component of
      teicoplanin in tissue is reported. Comparing fluorescamine and o-phthalaldehyde
      (OPA) as derivatizing agents, the derivative formed with the latter exhibits
      superior fluorescence intensity allowing detection of femtomole quantities.
      Pretreatment for tissue samples is by solid-phase extraction which uses Bakerbond
      PolarP C(18) cartridges and gives effective clean up from endogenous by-products.
      Linearity was given from 0.6 to 100 ng per injection. The coefficient of
      variation did not exceed 5.8% for both interday and intraday assays. It was found
      that when bone defects are repaired with a hydroxyapatite-teicoplanin mixture,
      the antibiotic does not degrade, even when it is in the cement for several
      months. The stability of teicoplanin in bone cement was determined
      fluorodensitometrically.

PMID- 12406587
TI  - Urinary excretion of cyanidin glycosides.
AB  - Anthocyanins, which are natural plant pigments from the flavonoid family,
      represent substantial constituents of the human diet. Several fruits
      (blackcurrant, blue berries, red grape and elderberry) are rich sources of these
      efficient antioxidant compounds. The present study was designed to determine the
      potential bioavailability in humans of the anthocyanins of elderberry, mainly
      cyanidin-3-glucoside and cyanidin-3-sambubioside, and the influence of the
      simultaneous ingestion of sucrose on the absorption of anthocyanins. Urinary
      samples from 16 healthy volunteers--8 women and 8 men--were collected before and
      over a period of 6 h with intervals of 1 h after the ingestion of 11 g elderberry
      concentrate (containing 1.9 g of anthocyanins equivalent to 235 ml of fresh
      juice) 1 day diluted with water, the other day with 30 g sucrose. Using high
      performance liquid chromatography, it was possible to quantify the two main
      anthocyanins of elderberry excreted unchanged in the urine (0.003-0.012% of the
      oral dose). The ingestion of sucrose led to a reduced excretion of anthocyanins.

PMID- 12406588
TI  - Effect of nucleotides and their analogues on essential light chains in myosin
      head.
AB  - The domain movement in myosin head plays a decisive role in the energy
      transduction process of the muscle contraction. During hydrolysis of ATP, the
      specific formation of strong binding of myosin head for actin causes
      conformational changes. As a consequence, the light chain-binding motif generates
      the powerstroke. In our work maleimide spin labels were covalently attached to
      Cys-177 residue of ELC in subfragment-1 (S1). Our goal was to study the
      orientation dependence and the motion of S1, which were incorporated into
      glycerinated skeletal muscle fibres. The electron paramagnetic resonance
      spectroscopy (EPR) spectra of the probes depended strongly on the orientation of
      the fibre axis relative to the magnetic field, indicating that the essential
      light chain (ELC) and the neck were ordered. The probes were undergoing rapid
      motion within a cone. The half-width of the cone was estimated to be 65+/-5
      degrees (SD, n=8). Addition of ADP affected little the hyperfine splitting and
      the angular spread of the probe distribution. In the presence of ADP and
      orthovanadate the intensity of the spectra decreased, which showed the
      dissociation of S1 and this was accompanied with the disappearance of the
      orientation dependence.

PMID- 12406589
TI  - Analysis of nucleotide myosin complexes in skeletal muscle fibres by DSC and EPR.
AB  - The internal dynamics and thermal unfolding of fibre bundles prepared from rabbit
      psoas muscle has been studied in the presence of nucleotides by differential
      scanning calorimetry (DSC) and electron paramagnetic resonance (EPR)
      spectroscopy. Using ADP, adenosine 5'-triphosphate (ATP), AMP.PNP and inorganic
      phosphate analogue orthovanadate (V(i)), AlF(4)(-) and BeF(3)(-), three
      intermediate states of the ATP hydrolysis cycle were simulated in glycerinated
      muscle fibres. In the main transition of the DSC pattern, three overlapping
      endotherms were detected in rigor, four in strongly as well as weakly binding
      state of myosin to actin. Deconvolution procedure showed that the transition
      temperature of 67.5 degrees C was the same for rigor and strong binding state of
      myosin. In contrast, nucleotide binding induced shift of the melting temperatures
      of 52 degrees C and 67.5 degrees C, appeared a new fourth peak at 74 and 77
      degrees C and produced changes in the calorimetric enthalpies. The changes of the
      parameters of the peak functions suggest global rearrangements of the internal
      structure in myosin heads in the intermediate states. In the presence of ADP or
      ATP plus phosphate analogue orthovanadate or beryllium fluoride, aluminium
      fluoride, the conventional EPR spectra of spin-labeled muscle fibres showed large
      changes in the ordering of the probe molecules, and a new distribution of spin
      labels appeared. ATP plus orthovanadate induced the orientation disorder of
      myosin heads; the random population of spin labels gave evidence of large local
      conformational and motional changes in the internal structure of myosin heads.
      Saturation transfer EPR measurements reported increased rotational mobility of
      spin labels in the presence of ATP plus phosphate analogues corresponding to
      weakly binding state of myosin to actin.

PMID- 12406590
TI  - Study of the thermal behavior of azidohetarenes with differential scanning
      calorimetry.
AB  - Thermal properties of azidohetarenes without reactive ortho-substituents,
      obtained by DSC analysis, were compared with the DSC data of ortho-phenyl and
      ortho-acyl substituted azidohetarenes, which give ring closure reactions either
      to indoles or to five-membered heterocycles such as isoxazoles. The reaction
      temperatures and reaction enthalpies give both information to prepare the
      reaction conditions and important safety information and were, in addition, used
      to find out relations between the temperatures or enthalpies with the three
      different reaction mechanisms.

PMID- 12406591
TI  - Anisotropy decay study on the host-guest interaction of distally dialkylated
      calix[4]arenes with 1-chloro-4-(trifluoromethyl)benzene.
AB  - The 'host' properties of distally dialkylated calix[4]arenes and 4-tert
      butylcalix[4]arenes in the presence of 1-chloro-4-(trifluoromethyl)benzene (BFT)
      were studied in chloroform solvent by intensity-independent spectrofluorometric
      method. The anisotropy decay experiments were found as suitable method to
      indicate the host-guest complex formation but it is unable to determine the
      strength of supramolecular interaction.

PMID- 12406592
TI  - Detection and relocation of rare events. A comparative study using the laser
      scanning cytometer and the Metafer/RCDetect microscope scanning system.
AB  - We compared instrumental analysis of enriched cord blood nucleated red blood
      cells (CB-NRBC) out of in vitro contamination preparations of dilutions of minute
      volumes of male cord blood into peripheral blood from nonpregnant women. This was
      done using the laser scanning cytometer (LSC) and the Metafer/RCDetect microscope
      scanning system, both allowing for relocation of positive cells defined on the
      basis of fluorescence parameters. Both instruments were efficient in performing
      scanning and relocation; a difference in the recovery of CB-NRBC was not
      significant and can be explained by the method of preparation used.

PMID- 12406593
TI  - An example of abnormal glow curves identification in personnel thermoluminescent
      dosimetry.
AB  - The personal Dosimetry Service Seibersdorf analyses monthly a large number of
      thermoluminescent dosimeters (TLD). The dosimeters consist of LiF chips, and the
      readout is carried out with an automated Harshaw 8800 reader system. In some
      cases, the luminescent glow curves of the routine analysis do not have the
      expected form as a result of external chemical contamination, hardware problems,
      poor heat transfer, etc. It is therefore necessary to investigate the reasons for
      the irregularity of these curves. An algorithm for the investigation of the
      routine curves was developed. It is based on the fact that the shape of an
      abnormal glow curve differs from the shape of a normal one. An interesting type
      of abnormal glow curves in the routine service was found. Some dosimeters of a
      certain client, a steel industry, exhibit glow curves with an atypical shape and
      very high signals. In those dosimeters, a possible chemical contamination in the
      form of a powder was discovered, which interferes with the dosimetric signal. A
      quantitative analysis of that powder was made by means of inductively coupled
      plasma emission spectroscopy (ICP-OES) after microwave dissolution. Elements like
      aluminium, barium, calcium and others were found. Such elements are used in
      different combinations as thermoluminescent materials.

PMID- 12406594
TI  - Urinary steroids in men with male-pattern alopecia.
AB  - Enzyme hydrolysis, solid phase extraction, methoxym-silyl derivatization and
      capillary gas chromatographic analysis were used to examine the changes in
      urinary steroid metabolites in men with androgenic alopecia. A total of 23 men
      with androgenic alopecia and 7 age-matched control healthy men collected 24-h
      urine. Significantly increased values were found in the metabolites of
      testosterone (T): androsterone (A) (p<0.02), and etiocholanolone (E) (p<0.05) in
      patients with androgenic alopecia, compared to the control values. Elevated
      levels of 16-hydroxy-dehydroepiandrosterone (16-OHD) (p<0.03) and cortisol (F)
      (P<0.05) were found, but the levels of cortisol metabolites were unchanged.
      Calculating the ratio of total 5 alpha/5 beta metabolites provided information on
      the activity of 5 alpha-reductase. The ratio of total 5 alpha/5 beta metabolites
      was increased in the patients showing the increased 5 alpha-reductase activity.
      The elevated 16-OHD level could be indicative of patients who had mild
      hyperadrenal activity.

PMID- 12406595
TI  - Determination and quantification of clonidine in human blood serum.
AB  - Clonidine ((2-[2,6-dichlorophenyl]amino)-2-imidazoline) preferentially stimulates
      central alpha(2)-adrenoceptors, which leads to inhibition of sympathetic tone,
      resulting in a lowering of arterial pressure and of heart rate. Additionally,
      many other desirable and undesirable effects are described, including analgesia,
      sedation and withdrawal reactions, which consist of a sudden rise in arterial
      pressure, nervousness, agitation and increased heart rate. The present study has
      the goal to develop a simple and effective method for the analysis of trace
      amounts of clonidine in human blood serum. Special emphasis is necessary to make
      application of electron impact ionization and separation of the analyte fragments
      in a quadruple mass analyzer suitable. The procedure comprises solid phase
      extraction followed by formation of the pentafluorobenzyl derivative. Further
      purification is achieved by phase transfer extraction into an acidic aqueous
      solution succeeded by re-extraction into dichloromethane. After solvent exchange,
      an aliquot is injected into the gas chromatograph equipped with a DB5 MS
      capillary column and a mass spectrometric detector. Chromatograms are recorded in
      single ion monitoring mode. Quantification is accomplished by internal
      standardization with moxonidine [4-chloro-5-(2-imidazolin-2-yl-amino)-6-methoxy-2
      methylpyridine].

PMID- 12406596
TI  - Abnormal protein patterns in blood serum and cerebrospinal fluid detected by
      capillary electrophoresis.
AB  - Capillary zone electrophoresis and high-resolution agarose gel electrophoresis
      were compared to detect protein components in serum and cerebrospinal fluid of
      patients. Both electrophoretic methods proved to be useful for detection of
      protein abnormalities (e.g., mono- and oligoclonal bands) in biological fluids,
      but capillary electrophoresis offered several important advantages, such as
      sample application without preliminary concentration, lack of staining
      procedures, and on-line evaluation of patterns. Furthermore, capillary
      electrophoresis exhibits shorter analysis time and high resolution with low
      baseline noise. The results were proven to be powerful in diagnosis and
      monitoring of dyscrasias in routine laboratory practice.

PMID- 12406597
TI  - Significant differences in capillary electrophoretic patterns of follicular
      fluids and sera from women pre-treated for in vitro fertilization.
AB  - Human ovarian follicular fluids and sera obtained from women pre-treated for in
      vitro fertilization (IVF) were investigated by capillary zone electrophoresis.
      Comparison of the matching physiological liquids showed substantial differences
      in the electrophoretic patterns. Significant decrease in the alpha(1)- and gamma
      fractions of follicular fluids of every woman were observed, whereas other
      fractions of the samples did not show such alterations. Since follicular fluid is
      a product of both, secretion by granulosa cells and diffusion from the theca
      capillaries, we can assume that the forced production of follicular fluid upon
      hormone stimulation (with gonadotropin releasing hormone (GnRH), follicle
      stimulating hormone (FSH) and corionic gonadotroph hormone (hCG)) may play role
      in the uneven presence of the proteins.

PMID- 12406598
TI  - Immunoluminometric detection of human procalcitonin.
AB  - Procalcitonin is a normal precursor of the active hormone calcitonin; however,
      its level in blood is normally undetectable. Dramatically increased levels of
      procalcitonin have been found in severe systemic bacterial infections and, today,
      this molecule is considered to be one of the earliest inflammatory markers of
      sepsis. In spite of the large body of data, it is still uncertain how and from
      which tissues procalcitonin is released into the circulation. In our experiments,
      we tested the analytical performance of a flash-type chemiluminescent
      immunoassay. The precision and accuracy of the assay was acceptable for early
      detection of sepsis and procalcitonin levels showed predictive information on the
      outcome of the infections. Using isolated leukocyte subpopulations and acridinium
      labelled anti-calcitonin monoclonal antibody, we made attempts to detect
      procalcitonin inside the cells or in surrounding medium by measuring the
      chemiluminescent signal triggered after the specific binding of the antibodies
      had occurred. Our preliminary data showed that lymphocytes did not contain
      detectable amounts of procalcitonin nor neutrophils secreted it after
      stimulation. However, neutrophils expressed chemiluminescence of intracellular
      origin. This finding suggests that neutrophil leukocytes might be a potential
      source of serum procalcitonin under in vivo conditions.

PMID- 12406599
TI  - Development and study of an amperometric biosensor for the in vitro measurement
      of low concentration of putrescine in blood.
AB  - An amperometric biosensor was developed for the in vitro determination of
      putrescine in blood samples because elevated level of putrescine in blood can be
      a diagnostic indicator of certain kinds of cancer. The electrochemical transducer
      consisted of a flat form, three electrode amperometric micro-cell fabricated with
      thin film photolithography on flexible Kapton substrate. An immobilized
      putrescine oxidase (PUO) layer provided the biocatalytic oxidation of the
      putrescine, while the generated hydrogen peroxide was detected on the platinum
      working electrode. An electropolymerized poly(m-phenylenediamine) (pPDA) size
      exclusion layer was used to protect the working electrode from fouling and to
      prevent signal generation by common electroactive interferents present in blood.
      The preparation of the biocatalytic enzyme- and outer protective layers was
      optimized for improved sensitivity and response time. A detection limit of 50 nM
      was achieved in pH-adjusted whole blood samples, which is below pathological
      levels.

PMID- 12406600
TI  - Opto-electrochemical planar wave-guide sensor for copper (II) ion.
AB  - An opto-electrochemical sensor for copper (II) ion was developed. The sensor
      consists of a planar conductive indium-tin-oxide (ITO) glass support, which was
      coated by a polymeric copper (II) sensitive membrane. The sensing membrane is
      made of plasticized polyurethane matrix containing Zincon colorimetric reagent
      immobilized as ion pair with tetraoctylammonium ion. The instrumentation used
      commonly for wave-guide sensor development was extended with a potentiostat that
      made possible the control of the electric potential of the conductive surface. In
      this way the transport rate of ionic species through the membrane-sample
      interface could be influenced. In the presence of copper (II) ions the color of
      the membrane turned from red to blue, which was monitored optically. By applying
      positive potential to the conductive surface the direction of the ion diffusion
      at the membrane/sample interface was changed. As a result the sensing layer was
      regenerated within 2 minutes and was ready for further measurement. The sensor
      measured Cu(2+) ion in a concentration range of 1-200 microM.

PMID- 12406601
TI  - Investigation of catalytic reaction with spectrofluorimetric method.
AB  - Numerous derivatives of nicotinic acid hydrazids are suitable for sensitive
      fluorescence determination of metal ions. The reaction proceeds upon ultraviolet
      illumination in the presence of an oxidizing agent and catalyst forming a
      fluorescent product. Therefore, the catalyst metal ion can be quantitatively
      determined by fluorescence methods. We have studied the reaction of nicotinic
      acid (di-pyridin-2-yl-methylene)-hydrazide (NADPMH), catalyzed by Mn(II)ion, and
      determined the optimal parameters of metal ion method.

PMID- 12406602
TI  - An improved method to discover adulteration of Styrian pumpkin seed oil.
AB  - Pumpkin seed oil is rather expensive compared to other vegetable oils. Therefore,
      it is often adulterated by the addition of cheaper oils. In contrast to other
      edible oils, the content of Delta 5-sterols is very low, while Delta 7-sterols
      are dominating. The determination of Delta 5-sterols, especially beta-sitosterol
      has proven to be a good possibility to detect admixture of cheap vegetable oils
      to a level below which the economic profit is not significant any more. The
      presented method is a variant of an analysis concept, which has been published
      previously in European Food Research and Technology by Mandl et al. [Eur. Food
      Res. Technol. 209 (1999) 400. ]. It includes saponification of the triglycerides
      as a first step followed by separation of the potassium salts of the fatty acids
      from the unsaponifiable fraction by adsorption chromatography. In order to
      enhance gas chromatographic properties of the analytes, the hydroxyl function of
      the sterols is derivatized with N-Methyl-N-(trimethylsilyl)trifluoroacetamide
      (MSTFA) to the trimethylsilylether. Finally, the analytes are separated on a
      capillary column of medium polarity (HP 35 MS) in a temperature programmed run
      within 18 min. Detection of the analytes was done by flame ionization. Special
      attention was set onto the precision and repeatability of the method.

PMID- 12406603
TI  - Optimized extraction of polycyclic aromatic hydrocarbons from contaminated soil
      samples.
AB  - A comparison of Soxhlet extraction and a new extraction technique, fluidized-bed
      extraction, has been conducted. The extraction of polycyclic aromatic
      hydrocarbons (PAHs) by this new technique has been optimized considering as
      experimental variables the variation of the number of extraction cycles and the
      holding time after reaching the heating temperature by means of a surface
      response design. The significance of the operational parameters of the fluidized
      bed extraction onto the performance characteristics has been investigated. For
      the determination of the analytes, a cleanup of the extracts followed by gas
      chromatography with mass spectrometric detection was used. The accuracy of the
      method was established by extraction and analysis of a reference material,
      supplied from the European Commission's Joint Research Centre.

PMID- 12406604
TI  - Occurrence of triazines in surface and drinking water of Liaoning Province in
      Eastern China.
AB  - The Liaoning Province in Eastern China has a prosperous economy and traditional
      agricultural background. Steadily increasing water demand implies the direct use
      of surface water for drinking water support and foodstuff production. Due to the
      extensive use, high persistence, water solubility and relatively weak
      adsorptivity, the chloro s-triazines contaminate the aquatic environment and are
      therefore regularly and most frequently detected in ground and surface water.
      Water sample enrichment procedures were performed by solid-phase extraction (SPE)
      using different materials. During a 1-year monitoring program on the Liao-He
      River, water sample enrichment was performed using C(18)-SPE cartridges. These
      SPE cartridges showed low recoveries for the atrazine metabolites, although high
      triazine values were detected. Based on these results, a pilot sampling on
      drinking water in the Liao-He region was performed. This time, in addition to the
      C(18)-SPE cartridges, a new polymer SPE sorbent made from a balance ratio of two
      monomers, the lipophilic divinylbenzene and the hydrophilic N-vinylpyrrolidone,
      was used. Both materials were characterized by establishing breakthrough curves
      for the investigated analytes and up to large volumes.

PMID- 12406605
TI  - Rapid screening of triazines and quantitative determination in drinking water.
AB  - A sensitive, rapid and inexpensive analysis method has been developed for the
      triazines most frequently used in Palestine; the method includes
      fluorodensitometric screening and densitometric determination of the individual
      substances. Terbutryn as a model substance was derivatized with dansyl chloride
      in sodium hydrogen-carbonate or phosphate buffer solution to yield a green-blue
      fluorescent compound. Derivatization occurred at 120 degrees C within maximum of
      10-min reaction time. The fluorescent compound formed was separated from excess
      reagent and other by-products on silica gel TLC plates and was then determined
      fluorodensitometrically. A linearity range between 20 and 1200 pg/spot was
      achieved. The method was also applied to other triazine herbicides such as
      ametryn, atrazine, propazine, terbuthylazine and simazine. Drinking water samples
      spiked with triazines were extracted using RP-C18 polar plus cartridges, and the
      extract could be then dansylated as a total. Recoveries were between 88% and 95%;
      the detection limit was 10 pg/spot and could be further improved to 2 pg/spot by
      a dipping solution. For quantification, each of the six triazines can be
      separated on one of three different stationary phases after solid phase
      extraction and measured densitometrically. The LOD for each individual triazine
      was 100 ng/l.

PMID- 12406607
TI  - FT-IR study of some seco- and apocarotenoids.
AB  - FT-IR spectroscopy was applied to investigate 15 different carotenoids. The
      following compounds were examined: beta-carotenone (1); semi-beta-carotenon
      epoxide (2); beta-apo-8'-carotenal (3); ethyl-beta-apo-8'-carotenoate (4); beta
      citraurin (5); 5,6-Epoxy-beta-caroten-8'-al (6); beta-citraurin-epoxide (7); apo
      10'-violaxanthal (8); persicaxanthin (9); capsylaldehyde (10); capsanthylal (11);
      retinol (12); retinal (13); retinoic acid (14); and bixin (15). Some
      characteristic functional groups (Cz.dbnd;C, Cz.dbnd;O, CHO, OH, etc.) were
      identified. We focused on the influence of conjugation of the keto-, aldehyde-
      and ester groups on the absorption of the Cz.dbnd;C bonds. This method is useful
      in the fast analysis of the biologically important carotenoids especially if
      there are small samples available.

PMID- 12406606
TI  - HPLC study on the carotenoid composition of Calendula products.
AB  - The authors report on the HPLC investigation of the carotenoid composition of the
      steams, leaves, petals and pollens of Calendula officinalis L. In the petals and
      pollens, the main carotenoids were flavoxanthin and auroxanthin while the stem
      and leaves mostly contained lutein and beta-carotene. Five different herbal tea
      and two tinctures made from the flower of C. officinalis L. were also
      investigated and the carotenoid composition of the industrial products was
      compared to the starting material.

PMID- 12406609
TI  - Revisiting the James versus Cannon debate on emotion: startle and autonomic
      modulation in patients with spinal cord injuries.
AB  - James' hypothesis that impaired peripheral physiology in patients with spinal
      cord injuries (SCI) impairs emotional processing, as manifested in the modulation
      of physiological responses and in the subjective component of emotions, was
      examined in the present study. A pilot study confirmed the utility of Lang's
      picture viewing paradigm in a group of 78 students using the Spanish norms of the
      International Affective Picture System. In the main study, 19 patients with SCI
      and 19 well controls matched for sex, age and education were examined. Results
      showed: (1) no differences between SCI and control participants in the valence
      and arousal ratings of the pictures; (2) similar heart rate modulation in both
      groups, i.e. the unpleasant pictures produced greater deceleration than the
      pleasant ones; and (3) no decrease in emotional experience in the SCI group
      compared with the control group. The implications of the results for the James
      versus Cannon controversy on the theory of emotions are discussed.

PMID- 12406610
TI  - Developmental differences in the preparatory heart rate response: childhood
      through adulthood.
AB  - The present article examines developmental differences across childhood,
      adolescence, and adulthood in the triphasic anticipatory heart rate response and
      the impact of age on the relationship between anticipatory deceleration (D2) and
      reaction time (RT). Heart rate and RT were recorded from participants ages 5-25
      during a fixed, 6 s anticipatory paradigm. The triphasic anticipatory heart rate
      response was larger in children, with the children displaying a delayed
      acceleratory component. Across this wide age range sample, D2 significantly
      predicted RT, but a model that included Age and D2 predicted significantly more
      of the RT variance. When comparing across ages on the triphasic response
      components or the relationship between D2 and RT, researchers should account for
      developmental effects.

PMID- 12406611
TI  - Evidence for the utilization of distinctive features in nonlinear discrimination
      problems.
AB  - There is evidence that in human Pavlovian conditioning positive patterning (A-, B
      , AB+) as well as negative patterning (A+, B+, AB-) are solved by applying
      abstract rules. In the present report we further investigated how humans solve
      patterning discriminations by conducting two Go/NoGo reaction time experiments
      that utilized the stimulus probability effect: stimuli presented with a low
      probability of occurrence elicit larger pupil dilations than those presented with
      a high frequency. In decreasing the ratio of compound and elemental trials from
      1/1 (24 A, 24 B, 48 AB) in Experiment 1 to 1/2 (32 A, 32 B, 32 AB) in Experiment
      2 we manipulated stimulus probability. The results of both experiments indicate
      that humans utilize distinctive features such as number information in order to
      classify the stimuli.

PMID- 12406612
TI  - Patterns of EEG coherence, power, and contingent negative variation characterize
      the integration of transcendental and waking states.
AB  - Long-term meditating subjects report that transcendental experiences (TE), which
      first occurred during their Transcendental Meditation (TM) practice, now
      subjectively co-exist with waking and sleeping states. To investigate
      neurophysiological correlates of this integrated state, we recorded EEG in these
      subjects and in two comparison groups during simple and choice contingent
      negative variation (CNV) tasks. In individuals reporting the integration of the
      transcendent with waking and sleeping, CNV was higher in simple but lower in
      choice trials, and 6-12 Hz EEG amplitude and broadband frontal EEG coherence were
      higher during choice trials. Increased EEG amplitude and coherence,
      characteristic of TM practice, appeared to become a stable EEG trait during CNV
      tasks in these subjects. These significant EEG differences may underlie the
      inverse patterns in CNV amplitude seen between groups. An 'Integration Scale,'
      constructed from these cortical measures, may characterize the transformation in
      brain dynamics corresponding to increasing integration of the transcendent with
      waking and sleeping.

PMID- 12406613
TI  - Differential effects of the hiba odor on CNV and MMN.
AB  - The aim of this study was to objectively measure some psychophysiological effects
      of odors, particularly the effects of odors on the contingent negative variation
      (CNV) and the mismatch negativity (MMN). It is generally believed that CNV
      reflects arousal processes and MMN reflects activity in an automatic detection
      system. Sixteen females were exposed to the odor of Thujopsis dolabrata (hiba), a
      conifer. CNV was obtained with a foreperiod of 2 s in a traditional click-flash
      reaction-time (RT) paradigm. Auditory MMN was measured while the subject was
      reading a book with SOA fixed at 500 ms. The amplitude of the early and late CNV
      components were significantly larger and RT to the imperative stimulus (IS) was
      shorter in the aroma condition than in the absence-of-odor condition, but there
      was no significant difference in the amplitude of MMN obtained in the two
      conditions. Our results indicate that the odor generates a high level of arousal
      within the nervous system but does not have a significant effect on automatic
      information processing.

PMID- 12406615
TI  - Separation of no-carrier-added 64Cu from a proton irradiated 64Ni enriched nickel
      target.
AB  - An ion exchange method has been developed to separate no-carrier-added 64Cu from
      irradiated Ni target. The target is first dissolved in nitric acid and the
      solution is evaporated to dryness and the residue is dissolved in an ethanol-HCl
      solution. Cu, Co and Ni in ethanol-HCl solution are then absorbed on an anion
      exchange column. Co and Ni are removed from the column by eluting with 72%
      ethanol-0.3 mol/l HCl. Finally, the 64Cu is eluted with water. For separating Ni
      from Co isotopes and recovering the 64Ni target, the eluate of 72% ethanol-0.3
      mol/l HCl is evaporated to dryness, the residue is dissolved in a concentrated
      HCl solution, and loaded to an another column, Ni is eluted by 9 mol/l HCl, while
      Co remains on the column. The procedure developed has been successfully applied
      for the production of no-carrier-added 64Cu from enriched 64Ni generated by the
      reaction 64Ni(p,n)64Cu using a cyclotron. The decontamination of Co in Cu
      fraction is higher than 99% and recoveries of 64Cu and 64Ni are higher than 95%.

PMID- 12406614
TI  - Bacterial clearance after total splenectomy and splenic autotransplantation in
      rats.
AB  - Wistar rats submitted to isolated total splenectomy or total splenectomy combined
      with splenic autotransplantation were inoculated with 99mtechnetium-labeled
      Escherichia coli. Measurement of isotope uptake in the organs of the mononuclear
      phagocytic system showed a greater bacterial bloodstream clearance in rats with
      splenic autotransplantation. Although uptake of bacteria in the spleen was higher
      in the control group, the number of bacteria remaining in the bloodstream did not
      differ between groups. These results indicate that splenic autotransplantation
      preserves the phagocytic function of the spleen.

PMID- 12406616
TI  - Neutron activation analysis of calcium/phosphorus ratio in rib bone of healthy
      humans.
AB  - The Ca/P ratio was estimated in intact rib bone samples from healthy humans, 37
      women and 45 men, aged from 15 to 55 years using instrumental neutron activation
      analysis. No statistically significant differences (p>0.05) age- or sex-related
      differences in the Ca/P ratio were observed. The mean value (M+/-SD) for the
      investigated parameter for the whole group studied, 2.33+/-0.34, was within a
      very wide range of published data and close to the median value.

PMID- 12406617
TI  - On the use of 225Ra as yield tracer and Ba(Ra)SO4 microprecipitation in 226Ra
      determination by alpha-spectrometry.
AB  - A simple procedure for the determination of 226Ra in geological samples using
      alpha-spectrometry is presented. The method uses 225Ra as yield tracer, and
      microprecipitation of Ba(Ra)SO(4) for source preparation. Extensive studies were
      performed in order to determine the chemical yield of the proposed procedure with
      precision. The method was tested on a geological reference sample, and gave
      satisfactory results and high reproducibility.

PMID- 12406619
TI  - Methodology for monitoring the residual activity in silicon rods irradiated with
      thermal neutrons.
AB  - A calibrated detection system developed for monitoring the residual activity in
      silicon rods irradiated for neutron transmutation doping is described. This
      residual activity is mainly due to 31Si and 32P, produced by thermal neutron
      capture reactions. The set-up consists of a scanning device, developed for
      positioning the rods, coupled to a GM detector for measuring beta-rays coming
      from the rod. The set-up has been calibrated using a 32P aqueous solution
      standardised in a 4pibeta gas-flow proportional counter system. The validity of
      the experimental procedure has been checked by Monte Carlo calculations. An
      additional check has been made by measuring the residual activity of a silicon
      rod irradiated in a well-known neutron fluence and the formalism used for
      calculating the activity on the basis of irradiation parameters is given. The
      results are compared to the radiological limit imposed by IAEA regulations in
      order to consider the material as exempt before it could be released for
      industrial applications.

PMID- 12406618
TI  - Estimation of mean-glandular dose from monitoring breast entrance skin air kerma
      using a high sensitivity metal oxide semiconductor field effect transistor
      (MOSFET) dosimeter system in mammography.
AB  - Estimation of mean-glandular dose (MGD) has been investigated in recent years due
      to the potential risks of radiation-induced carcinogenesis associated with the
      mammographic examination for diagnostic radiology. In this study, a new technique
      for immediate readout of breast entrance skin air kerma (BESAK) using high
      sensitivity MOSFET dosimeter after mammographic projection was introduced and a
      formula for the prediction of tube output with exposure records was developed. A
      series of appropriate conversion factors was applied to the MGD determination
      from the BESAK. The study results showed that signal response of the high
      sensitivity MOSFET exhibited excellent linearity within mammographic dose ranges,
      and that the energy dependence was less than 3% for each anode/filter combination
      at the tube potentials 25-30 kV. Good agreement was observed between the BESAK
      and the tube exposure output measurement for breasts thicker than 30 mm. In
      addition, the air kerma estimated from our prediction formula provided sufficient
      accuracy for thinner breasts. The average MGD from 120 Asian females was 1.5 mGy,
      comparable to other studies. Our results suggest that the high sensitivity MOSFET
      dosimeter system is a good candidate for immediately readout of BESAK after
      mammographic procedures.

PMID- 12406620
TI  - Dosimetric study of a new palladium seed.
AB  - In this paper, the dosimetric parameters for a new palladium seed design: the
      InterSource(103,)(1) are presented as recommended by the AAPM in the TG-43
      formalism. Measurements are made with LiF thermoluminescent dosimeters (size of
      1mm(3)) in solid water phantoms WT1 to obtain the dose constant, the radial dose
      function and the anisotropy function. The TLD were calibrated at 6 MV and an
      energy correction factor of 1.40 has been applied. The same dose parameters are
      also obtained by Monte Carlo calculations (MCNP4B) in solid water and in liquid
      water. The calculated and the measured TG-43 functions for solid water are in
      excellent agreement. In WT1, the calculated dose rate constant is 0.657+/-1% and
      the measured value is 0.672+/-7%. The calculated value for water is 0.692+/-1%.
      The comparison with the previous study (Med. Phys. 27(5) (2000)) shows a very
      good agreement for the dose rate constant. The agreement for the radial function
      is poorer. For the measurements, it can be due to the difference of TLD settings.
      For the calculations the discrepancy could come from the different cross-section
      data utilized in the different Monte Carlo codes. In conclusion, the dosimetric
      functions for the new iodine seed InterSource(103) have been determined using the
      MCNP4B Monte Carlo code and TLD measurement in solid water WT1.

PMID- 12406621
TI  - Fading behavior of X-ray induced color centers in soda-lime silicate glass.
AB  - The X-ray induced color centers in soda-lime silicate glass were unstable at room
      temperature. There was a rapid fading at short-term stage and a slow fading at
      long-term stage. In the short-term stage, both first-order and second-order
      fading kinetics played roles in the fading process, while only the first-order
      fading controlled the long-term stage fading.

PMID- 12406622
TI  - Comparison of lead attenuation and lead hardening equivalence of materials used
      in respect of diagnostic X-ray shielding.
AB  - Present interest is in the shielding of diagnostic X-ray units. Numerical
      comparison has been made of the attenuation and hardening properties of lead and
      some particular alternative materials: steel, plate glass and gypsum wallboard.
      Results show, for particular choices of thickness, that lead and steel can be
      made to provide closely similar attenuation and spectral hardening, values of
      lead attenuation equivalent (LAE) and lead hardening equivalent (LHE) thicknesses
      being nearly the same. Significant differences in the attenuation and hardening
      properties of lead are found in comparison with plate glass and gypsum wallboard.
      LAE produces better matching of exposure for lead-plate glass and lead-gypsum
      wallboard than LHE.

PMID- 12406623
TI  - Accuracy of the convolution/superposition dose calculation algorithm at the
      condition of electron disequilibrium.
AB  - Using Monte Carlo simulation and the convolution/superposition algorithm, this
      work examines percent depth dose curves of the central axis in an acrylic phantom
      (20 x 20 x 20 cm(3)) with variously sized air cavities (20 x 20 x 1.0, 20 x 20 x
      2.0, 20 x 20 x 3.0, 20 x 20 x 4.0 and 20 x 20 x 4.95 cm(3) for study of
      longitudinal electron disequilibrium (ED) and 3.6 x3.6 x 4.95, 4.5 x 4.5 x 4.95,
      5.4 x 5.4 x 4.95 and 20 x 20 x 4.95 cm(3) for study of lateral ED). Radiochromic
      film samples are also measured to verify the Monte Carlo results. The Monte Carlo
      simulation is performed using OMEGA/BEAM and DOSXYZ codes, and the
      convolution/superposition calculation relies on an ADAC commercial treatment
      planning system. Underestimating the dose kernel expansion leads to
      overestimating the dose of what was found in the air cavity of ED using the
      convolution/superposition algorithm. Consequently, the dose in the rebuild-up
      region is influenced. The influenced region is on the acrylic phantom surface to
      a depth of about 0.5 cm. The density scaling method of the
      convolution/superposition algorithm, applied to heterogeneous media, should be
      enhanced to account for the over-expansion of the dose kernel in the cavity of
      ED.

PMID- 12406624
TI  - Simultaneous use of neutron transmission and reflection techniques for the
      classification of crude oil samples.
AB  - Neutron attenuation and reflection characteristics of three crude mineral oil
      samples from West Africa were determined using 37 GBq 241Am-Be source in a single
      set-up and compared with those of paraffin (oil) and benzene, an aromatic
      compound. Based on the trends of measured data which are similar to those
      exhibited by paraffin but different from those associated with benzene, the crude
      oil samples could be classified as paraffinic. The total hydrogen content and
      weight ratios (O+C)/H and C/H determined for the crude oil samples using the
      transmission and reflection techniques are not only independent of the technique
      but are also consistent with literature values of thermal reflection technique.

PMID- 12406625
TI  - Tritium labelling and characterization of the cognition enhancing drug tacrine
      using several precursors.
AB  - Tacrine and its analogues have shown promise as cognition enhancers and potential
      chemotherapeutic agents for Alzheimer's disease. [3H]tacrine was required to
      explore its mechanism of action via receptor binding assay and the radioligand
      was prepared by means of catalytic dehalogenation of several brominated
      precursors.

PMID- 12406626
TI  - Design and synthesis of 225Ac radioimmunopharmaceuticals.
AB  - The alpha-particle-emitting radionuclides 213Bi, 211At, 224Ra are under
      investigation for the treatment of leukemias, gliomas, and ankylosing
      spondylitis, respectively. 213Bi and 211At were attached to monoclonal antibodies
      and used as targeted immunotherapeutic agents while unconjugated 224Ra chloride
      selectively seeks bone. 225Ac possesses favorable physical properties for
      radioimmunotherapy (10d half-life and 4 net alpha particles), but has a history
      of unfavorable radiolabeling chemistry and poor metal-chelate stability. We
      selected functionalized derivatives of DOTA as the most promising to pursue from
      out of a group of potential 225Ac chelate compounds. A two-step synthetic process
      employing either MeO-DOTA-NCS or 2B-DOTA-NCS as the chelating moiety was
      developed to attach 225Ac to monoclonal antibodies. This method was tested using
      several different IgG systems. The chelation reaction yield in the first step was
      93+/-8% radiochemically pure (n=26). The second step yielded 225Ac-DOTA-IgG
      constructs that were 95+/-5% radiochemically pure (n=27) and the mean percent
      immunoreactivity ranged from 25% to 81%, depending on the antibody used. This
      process has yielded several potential novel targeted 225Ac-labeled
      immunotherapeutic agents that may now be evaluated in appropriate model systems
      and ultimately in humans.

PMID- 12406627
TI  - Technetium-99m labeling of tityustoxin and venom from the scorpion Tityus
      serrulatus.
AB  - The tityustoxin, the most toxic fraction from scorpion Tityus serrulatus venom,
      has been used as a tool in several neurochemical and neuropharmacological
      studies. Biological activities of labeled and unlabeled tityustoxin and venom
      were compared. The samples were labeled in the presence of stannous chloride and
      sodium borohydride with a yield of 60-70% for the venom and 75-85% for
      tityustoxin and then chromatographed in Sephadex G-10. Biological activities of
      tityustoxin and venom were preserved after labeling.

PMID- 12406628
TI  - Efficient routine production of the 18F-labelled amino acid O-2-18F fluoroethyl-L
      tyrosine.
AB  - A convenient remotely controlled no-carrier-added synthesis of enantiomerically
      pure O-(2-[18F]fluoroethyl)-L-tyrosine (FET) is described. This allows the
      distribution of the radiotracer to other laboratories according to the satellite
      concept. The radiochemical yield obtained within 80 min is about 60%. The FET
      containing HPLC fraction can be used immediately (after adding sodium chloride)
      for human application.

PMID- 12406629
TI  - An improvement of 11C acetate synthesis--non-radioactive contaminants by
      irradiation-induced species emanating from the 11C carbon dioxide production
      target.
AB  - An existing procedure for [11C]acetate synthesis, consisting of a reaction of
      methylmagnesium chloride and [11C]carbon dioxide in tetrahydrofuran, hydrolysis
      and ion-exchange purification on small columns, has been improved. The use of
      less Grignard reagent and application of commercial cartridges instead of home
      made ones led to an increase of the overall yield from 60-65% to over 80%.
      Malfunction in pure nitrogen targets for 11C production may lead to unexpected
      contaminants. It is recommended to incorporate in the target outlet line a trap
      for removal of nitrogen oxides.

PMID- 12406630
TI  - The digital radiographic and computed tomography imaging of two types of
      explosive devices.
AB  - Two well-established medical imaging methods, digital radiography (DR) and
      computed tomography (CT), were employed to obtain images of two types of
      explosive devices, model rocket engines and shotgun shells. The images were
      evaluated from an airport security perspective. In terms of geometrical shape,
      the detection probability of the explosive devices appears to be higher with DR
      imaging, but in terms of the actual explosive compounds in the devices, CT
      appears to offer a higher detection probability. DR imaging offers a low
      detection probability for the explosive powder in the shotgun shells, but a
      rather significant detection probability for the explosive propellant in the
      model rocket engines.

PMID- 12406631
TI  - CCD saturation in high-background environments.
AB  - Charge-coupled devices (CCDs) are nowadays preferred X-ray detectors in
      environments with high-background radiation. The maximum number of X-ray counts
      per exposure in a CCD-detector is limited by saturation. The simulation of this
      effect reproduces well the measurements with a 55Fe source. In an accelerator
      area, where a large amount of charged particles is present, a strong reduction of
      X-ray recognition efficiency with increasing occupancy (percentage of hit pixels)
      is observed which depends only weakly on the specific distribution of cluster
      sizes.

PMID- 12406632
TI  - Energy response of an imaging plate exposed to standard beta sources.
AB  - Imaging plates (IPs) are a reusable media, which when exposed to ionizing
      radiation, store a latent image that can be read out with a red laser as
      photostimulated luminescence (PSL). They are widely used as a substitute for X
      ray films for diagnostic studies. In diagnostic radiology this technology is
      known as computed radiography. In this work, the energy response of a commercial
      IP to beta-particle reference radiation fields used for calibrations at the
      National Institute of Standards and Technology was investigated. The absorbed
      dose in the active storage phosphor layer was calculated following the scaling
      procedure for depth dose for high Z materials with reference to water. It was
      found that the beta particles from Pm-147 and Kr-85 gave 68% and 24% higher PSL
      responses than that induced by Sr-90, respectively, which was caused by the
      different PSL detection efficiencies. In addition, normalized response curves of
      the IPs as a function of depth in polystyrene were measured and compared with the
      data measured using extrapolation chamber techniques. The difference between both
      sets of data resulted from the continuous energy change as the beta particle
      travels across the material, which leads to a different PSL response.

PMID- 12406633
TI  - Characterization of high-sensitivity metal oxide semiconductor field effect
      transistor dosimeters system and LiF:Mg,Cu,P thermoluminescence dosimeters for
      use in diagnostic radiology.
AB  - Monitoring radiation exposure during diagnostic radiographic procedures has
      recently become an area of interest. In recent years, the LiF:Mg,Cu,P
      thermoluminescence dosimeter (TLD-100H) and the highly sensitive metal oxide
      semiconductor field effect transistor (MOSFET) dosimeter were introduced as good
      candidates for entrance skin dose measurements in diagnostic radiology. In the
      present study, the TLD-100H and the MOSFET dosimeters were evaluated for
      sensitivity, linearity, energy, angular dependence, and post-exposure response.
      Our results indicate that the TLD-100H dosimeter has excellent linearity within
      diagnostic energy ranges and its sensitivity variations were under 3% at tube
      potentials from 40Vp to 125kVp. Good linearity was also observed with the MOSFET
      dosimeter, but in low-dose regions the values are less reliable and were found to
      be a function of the tube potentials. Both dosimeters also presented predictable
      angular dependence in this study. Our findings suggest that the TLD-100H
      dosimeter is more appropriate for low-dose diagnostic procedures such as chest
      and skull projections. The MOSFET dosimeter system is valuable for entrance skin
      dose measurement with lumbar spine projections and certain fluoroscopic
      procedures.

PMID- 12406634
TI  - Monte Carlo simulation of the self-absorption corrections for natural samples in
      gamma-ray spectrometry.
AB  - Gamma-ray self-attenuation corrections in the energy range 60-2000 keV were
      evaluated by means of Monte Carlo calculations for environmental samples in a
      cylindrical measuring geometry. The dependence of the full-energy peak efficiency
      on the sample density was obtained for some particular photon energies and, as a
      result, the corresponding self-attenuation correction factors were obtained. The
      calculations were performed by assuming that natural materials have mass
      attenuation coefficients very similar to those of water in the energy range
      studied. Three different HpGe coaxial detectors were considered: an n-type
      detector with 44.3% relative efficiency and two p-type detectors of relative
      efficiencies 20.0% and 30.5%. Our calculations were in very good agreement with
      the self-attenuation correction factors obtained experimentally by other workers
      for environmental samples of different densities. This work demonstrates the
      reliability of Monte Carlo calculations for correcting photon self-attenuation in
      natural samples. The results also show that the corresponding correction factors
      are essentially unaffected by the specific coaxial detector used.

PMID- 12406635
TI  - A real-time positron monitor for the estimation of stack effluent releases from
      PET medical cyclotron facilities.
AB  - Large activities of short-lived positron emitting radiopharmaceuticals are
      routinely manufactured by modern Medical Cyclotron facilities for positron
      emission tomography (PET) applications. During radiochemical processing, a
      substantial fraction of the volatile positron emitting radiopharmaceuticals are
      released into the atmosphere. An inexpensive, fast response positron detector
      using a simple positron-annihilation chamber has been developed for real-time
      assessment of the stack release of positron emitting effluents at the Australian
      National Medical Cyclotron. The positron detector was calibrated by using a 3.0
      ml (1.50 MBq) aliquot of 18FDG and interfaced to an industrial standard
      datalogger for the real-time acquisition of stack release data.

PMID- 12406636
TI  - Experimental and theoretical excitation functions for natBr(p,x) reactions.
AB  - The excitation functions for protons incident on natBr were measured from
      threshold up to 100 MeV by means of the stacked-foil technique. Where applicable,
      the measured cross-section values are compared with previously published values.
      Theoretical cross-sections were also calculated by means of the computer code
      ALICE (IPPE) for comparison purposes.

PMID- 12406637
TI  - A simplified technique to determine the self-absorption correction for sediment
      samples.
AB  - A self-absorption correction factor is required for the determination of the
      radioactive isotope concentration in sediment samples at the low-energy region. A
      simplified technique for this correction factor for a well-type HP germanium
      detector is described. This correction is especially important when the ratio
      between the sample density and reference sample density (rho(sa.)/rho(re)) is
      greater than approximately 1.4.

PMID- 12406638
TI  - Geochemical monitoring of thermal waters in Slovenia: relationships to seismic
      activity.
AB  - Thermally anomalous fluids released in seismic areas in Slovenia were the
      subjects of geochemical monitoring. Thermal waters were surveyed from the
      seismically active area of Posocje (Bled and Zatolmin; NW Slovenia) and from
      Rogaska Slatina in eastern Slovenia. Continuous monitoring of geochemical
      parameters (radon concentration, electrical conductivity, and water temperature)
      was performed with discrete gas sampling for their (3)He/(4)He ratio. The
      observed values were correlated with meteorological parameters (rainfall,
      barometric pressure and air temperature) and with seismic activity. Only a few
      earthquakes occurred in the vicinity of the measuring sites during the monitoring
      period. Nevertheless, changes in radon concentration, water temperature,
      electrical conductivity and helium isotopic ratio were detected at the three
      thermal springs in the periods preceding the earthquakes. A close correlation was
      also observed of both water temperature and electrical conductivity with the
      Earth tide, making the observations in the selected sites a promising tool for
      addressing the widely debated question of earthquake prediction.

PMID- 12406639
TI  - Radon in groundwaters from Guarany aquifer, South America: environmental and
      exploration implications.
AB  - Groundwater and sandstone samples were analyzed for radon in Guarany aquifer,
      Parana sedimentary basin, South America. The dissolved radon ranged between 3 and
      3303pCi/l, being lognormally distributed, with a modal value of 1315pCi/l, and a
      median value of 330pCi/l. 222Rn leakage experiments for sandstones yielded a
      theoretical value of 1390pCi/l for 222Rn in water, showing that theoretical
      modeling can reliably be used to interpret laboratory and field data.

PMID- 12406640
TI  - Measurements of atmospheric 7Be properties using high-efficiency gamma
      spectroscopy.
AB  - Two 7Be-related properties have been measured using a high-efficiency germanium
      gamma spectrometer (relative efficiency of 90%), namely, the activity median
      aerodynamic diameter (AMAD) of 7Be-associated atmospheric aerosols and the
      airborne 7Be radioactivity. With time resolutions of about 1-3d correlations
      between these 7Be-related properties and different meteorological parameters were
      identified. We found that AMAD is anti-correlated to 7Be counts. It is correlated
      with the relative humidity (RH) and mean cloud cover with high confidence, but
      not with temperature. We also found that 7Be radioactivity was correlated with
      the RH with a moderate confidence, but not with the mean cloud cover or
      temperature. Furthermore, wet precipitation present in the middle of the sampling
      period decreased the 7Be activity and increased the AMAD, while wet precipitation
      before or at the beginning of the sampling period decreased both 7Be activity and
      AMAD. Finally, after a cold front passed by, the AMAD decreased and the 7Be
      activity increased. Possible explanations are also given.

PMID- 12406641
TI  - Pharmacogenetics of CYP enzymes and drug transporters: remarkable recent
      advances.

PMID- 12406642
TI  - Pharmacogenetics: is the right drug for the right patient sufficient?

PMID- 12406643
TI  - CYP2A6 genetic variation and potential consequences.
AB  - Human cytochrome P450 2A6 (CYP2A6) has been shown to have large interindividual
      and interethnic variability in levels of expression and activity. This is thought
      to be largely due to genetic polymorphisms. In recent years, 13 genetic variants
      (CYP2A6*1-*11 and the gene duplication, *1 x 2) of CYP2A6 have been identified
      and a number of these have been shown to result in altered CYP2A6 enzyme
      activity. For example, there are alleles which result in variants that are in
      inactive (e.g. due to a gene deletion), have decreased activity (e.g. altered
      enzyme structure or transcriptional activity) or have increased activity (e.g.
      due to gene duplications). The resulting interindividual variation in metabolic
      activity may affect the metabolism of CYP2A6 substrates including nicotine,
      cotinine (the major metabolite of nicotine), several tobacco-specific
      procarcinogens, coumarin and many toxins. The frequencies of the CYP2A6 alleles
      vary considerably among different ethnic populations, which may partially explain
      the interethnic variability found in CYP2A6-related metabolic activity (e.g.
      nicotine metabolism), behaviors (i.e. smoking) and disease (i.e. lung cancer).
      Investigations of the genetic variation of CYP2A6 and its resulting effects on
      metabolism and health consequences are still fairly early; this review summarizes
      what is presently known about CYP2A6, its genetic variants and their clinical
      consequences.

PMID- 12406644
TI  - CYP2C9 allelic variants: ethnic distribution and functional significance.
AB  - Cytochrome P-450 (CYP) 2C9 CYP2C9 is a polymorphically expressed enzyme
      responsible for the metabolism of several clinically important drugs, some with a
      low therapeutic index. This review summarizes the structure-function relationship
      of the CYP2C9 promoter and coding regions, known polymorphisms, the functional
      significance of various CYP2C9 alleles in vitro and in vivo, and their population
      frequencies. In addition, possible molecular mechanisms underlying ethnic
      variability in the metabolism of CYP2C9 substrate drugs are discussed.

PMID- 12406645
TI  - Genetic contribution to variable human CYP3A-mediated metabolism.
AB  - The human CYP3A subfamily plays a dominant role in the metabolic elimination of
      more drugs than any other biotransformation enzyme. CYP3A enzyme is localized in
      the liver and small intestine and thus contributes to first-pass and systemic
      metabolism. CYP3A expression varies as much as 40-fold in liver and small
      intestine donor tissues. CYP3A-dependent in vivo drug clearance appears to be
      unimodally distributed which suggests multi-genic or complex gene-environment
      causes of variability. Interindividual differences in enzyme expression may be
      due to several factors including: variable homeostatic control mechanisms,
      disease states that alter homeostasis, up- or down-regulation by environmental
      stimuli (such as smoking, drug intake, or diet), and genetic mutations. This
      review summarizes the current understanding and implications of genetic variation
      in the CYP3A enzymes. Unlike other human P450s (CYP2D6, CYP2C19) there is no
      evidence of a 'null' allele for CYP3A4. More than 30 SNPs (single nucleotide
      polymorphisms) have been identified in the CYP3A4 gene. Generally, variants in
      the coding regions of CYP3A4 occur at allele frequencies <5% and appear as
      heterozygous with the wild-type allele. These coding variants may contribute to
      but are not likely to be the major cause of inter-individual differences in CYP3A
      dependent clearance, because of the low allele frequencies and limited
      alterations in enzyme expression or catalytic function. The most common variant,
      CYP3A4*1B, is an A-392G transition in the 5'-flanking region with an allele
      frequency ranging from 0% (Chinese and Japanese) to 45% (African-Americans).
      Studies have not linked CYP3A4*1B with alterations in CYP3A substrate metabolism.
      In contrast, there are several reports about its association with various disease
      states including prostate cancer, secondary leukemias, and early puberty. Linkage
      disequilibrium between CYP3A4*1B and another CYP3A allele (CYP3A5*1) may be the
      true cause of the clinical phenotype. CYP3A5 is polymorphically expressed in
      adults with readily detectable expression in about 10-20% in Caucasians, 33% in
      Japanese and 55% in African-Americans. The primary causal mutation for its
      polymorphic expression (CYP3A5*3) confers low CYP3A5 protein expression as a
      result of improper mRNA splicing and reduced translation of a functional protein.
      The CYP3A5*3 allele frequency varies from approximately 50% in African-Americans
      to 90% in Caucasians. Functionally, microsomes from a CYP3A5*3/*3 liver contain
      very low CYP3A5 protein and display on average reduced catalytic activity towards
      midazolam. Additional intronic or exonic mutations (CYP3A5*5, *6, and *7) may
      alter splicing and result in premature stop codons or exon deletion. Several
      CYP3A5 coding variants have been described, but occur at relatively low allelic
      frequencies and their functional significance has not been established. As CYP3A5
      is the primary extrahepatic CYP3A isoform, its polymorphic expression may be
      implicated in disease risk and the metabolism of endogenous steroids or
      xenobiotics in these tissues (e.g., lung, kidney, prostate, breast, leukocytes).
      CYP3A7 is considered to be the major fetal liver CYP3A enzyme. Although hepatic
      CYP3A7 expression appears to be significantly down-regulated after birth, protein
      and mRNA have been detected in adults. Recently, increased CYP3A7 mRNA expression
      has been associated with the replacement of a 60-bp segment of the CYP3A7
      promoter with a homologous segment in the CYP3A4 promoter (CYP3A7*1C allele).
      This mutational swap confers increased gene transcription due to an enhanced
      interaction between activated PXR:RXRalpha complex and its cognate response
      element (ER-6). The genetic basis for polymorphic expression of CYP3A5 and CYP3A7
      has now been established. Moreover, the substrate specificity and product
      regioselectivity of these isoforms can differ from that of CYP3A4, such that the
      impact of CYP3A5 and CYP3A7 polymorphic expression on drug disposition will be
      drug dependent. In addition to genetic variation, other factors that may also
      affect CYher factors that may also affect CYP3A expression include: tissue
      specific splicing (as reported for prostate CYP3A5), variable control of gene
      transcription by endogenous molecules (circulating hormones) and exogenous
      molecules (diet or environment), and genetic variations in proteins that may
      regulate constitutive and inducible CYP3A expression (nuclear hormone receptors).
      Thus, the complex regulatory pathways, environmentally susceptible milieu of the
      CYP3A enzymes, and as yet undetermined genetic haplotypes, may confound
      evaluation of the effect of individual CYP3A genetic variations on drug
      disposition, efficacy and safety.

PMID- 12406646
TI  - The influence of MDR1 polymorphisms on P-glycoprotein expression and function in
      humans.
AB  - The MDR1 (ABCB1) gene product P-glycoprotein is a membrane protein, which
      functions as an ATP-dependent exporter of xenobiotics from cells. Its importance
      was first recognized because of its role in the development of multidrug
      resistance (MDR) of cultured tumor cells against various anticancer agents. It is
      now, however, well established that this transporter is not only expressed in
      tumor cells, but also in normal tissues with excretory function (intestine,
      liver, kidney). Since P-glycoprotein has a very broad substrate specificity, it
      determines disposition of a broad variety of drugs. Moreover, induction and
      inhibition of P-glycoprotein are new mechanisms for drug interactions in humans.
      Very recently, systematic screens of the MDR1 gene have identified multiple
      single nucleotide polymorphisms. Some of those appear to be associated with
      altered transporter function and expression. This review discusses the currently
      available data on the influence of MDR1 polymorphisms on P-glycoprotein tissue
      expression, drug disposition, treatment outcome and disease risk.

PMID- 12406647
TI  - Single nucleotide polymorphisms in multidrug resistance associated protein 2
      (MRP2/ABCC2): its impact on drug disposition.
AB  - Multidrug resistance associated protein 2 (MRP2/ABCC2), expressed on the bile
      canalicular membrane, plays an important role in the biliary excretion of various
      kinds of substrates. In addition, MRP2 is also expressed on the apical membrane
      of epithelial cells such as enterocytes. It is possible that the inter-individual
      difference in the function of MRP2 affects the drug disposition. In the present
      article, we will summarize the physiological and pharmacological role of MRP2,
      particularly focusing on the factors affecting its transport function such as
      single nucleotide polymorphisms and/or the induction/down regulation of this
      transporter. Mutations found in patients suffering from the Dubin-Johnson
      syndrome, along with the amino acid residues which are involved in supporting the
      transport activity of MRP2, are also summarized.

PMID- 12406648
TI  - Therapeutic and biological importance of getting nucleotides out of cells: a case
      for the ABC transporters, MRP4 and 5.
AB  - The energy dependent transport of drugs contributes to cellular resistance and is
      undoubtedly a prime suspect in chemotherapeutic failure of a variety of disease
      processes. Early studies focused on a single gene, the multidrug resistance gene,
      MDR1, as a main contributor to chemotherapeutic failure. However, the
      multifaceted nature of cellular resistance lead to the discovery of the MRP gene.
      This pivotal finding and the concurrent rapid development of gene databases lead
      to the expansion of the MRP gene family. The purpose of this review is to discuss
      two of the recently described MRP family members that were orphans until their
      role in drug resistance was discovered. This review will provide an overview of
      the current state of our understanding of MRP4 and 5.

PMID- 12406649
TI  - Pharmacogenomics of organic anion-transporting polypeptides (OATP).
AB  - The organic anion-transporting polypeptides (OATP) represent a family of proteins
      responsible for the membrane transport of a large number of endogenous and
      xenobiotic compounds with diverse chemical characteristics. OATPs are expressed
      in liver, kidney, brain and intestine suggesting that they may play a critical
      role in drug disposition. Naturally occurring polymorphisms in OATPs are
      currently being identified and for some, in vitro transport activities have been
      characterized. In this article, we review the molecular, biochemical and
      pharmacological aspects of known human OATPs including the presence and
      functional relevance of genetic polymorphisms.

PMID- 12406650
TI  - Type 1 and type 2 responses in regulation of Ig isotype expression in cattle.
AB  - Regulation of humoral immune responses is multifactorial involving appropriate
      activation, costimulation and the presence of specific soluble factors. Polarized
      type 1 or type 2 humoral responses in the laboratory mouse have been linked to
      expression of specific cytokines and thus can be used to provide insight into the
      type of response generated by infection. For example, IFN-gamma has been linked
      to IgG2a and IgG3 production, IL-4 to IgG1 and IgE production and TGF-beta to IgA
      production. Unlike the laboratory mouse, generally housed under defined
      conditions, highly skewed isotype expression patterns generally occur in cattle
      in chronic infections. A few examples of polarized responses have been noted in
      chronic experimental or naturally occurring infections including F. hepatica, M.
      paratuberculosis, C. parvum and B. abortus. In vitro studies using purified
      bovine B cells and various forms of costimulation and cytokines have demonstrated
      that isotype responses can be polarized under certain experimental conditions in
      vitro. That is, IgG1 expression is positively regulated by IL-4 and IgG2
      expression is positively regulated by IFN-gamma. Other as yet unidentified
      factors may play pivotal roles in regulating humoral immune responses in large
      ruminant species in vivo. This possibility is best exemplified by recent studies
      using DNA vaccines in cattle that have been demonstrated in the mouse to be
      generally polarizing to a type 1 response. Surprisingly, studies in cattle using
      plasmid DNA as vaccination material show an almost exclusive IgG1 response. Based
      on a number of studies using T cell clones and various biological assays, it is
      clear that the classical roles of many cytokines in the laboratory mouse do not
      extrapolate entirely or at all to cattle. Thus, the design of adjuvants and
      immune modulators should be based on studies done in cattle or using bovine
      cells. Based on studies to date, several "holes" in the cytokine repertoire exist
      and these roles may be assumed by unique factors or activities of other known
      cytokines.

PMID- 12406651
TI  - Changes in macrophages in spleen and lymph nodes during acute African swine
      fever: expression of cytokines.
AB  - To gain further insight into the pathogenesis of African swine fever (ASF), the
      cytokine expression by macrophages in spleen and lymph nodes were examined.
      Twenty-one piglets were inoculated with the highly virulent isolate Spain-70 of
      ASF virus and killed in groups at 1-7 post-inoculation days (pid). An increase in
      the immunohistochemical detection of proinflammatory monokines in spleen and
      renal and gastrohepatic lymph nodes is reported, along with an increase in the
      serum levels of TNF-alpha and IL-1 beta. The expression of these cytokines is
      detected simultaneously in time and space with the viral protein 73 (vp 73) of
      the ASF virus detection. Our results demonstrate that mononuclear phagocyte
      system cell activation results in the release of several cytokines that could
      induce apoptosis of lymphocytes and haemodynamic changes.

PMID- 12406652
TI  - Humoral immune response against Borna disease virus (BDV) in experimentally and
      naturally infected cats.
AB  - In order to investigate the peripheral and intracerebral humoral immune response
      against Borna disease virus (BDV) in cats, serum and cerebrospinal fluid (CSF)
      samples from experimentally and naturally BDV-infected cats were analysed in two
      different test systems (indirect enzyme-linked immunosorbent assay and indirect
      immunofluorescent test). The experimentally infected cats developed high antibody
      titres against the major immunogenic BDV-proteins, p24 and p40. In contrast, the
      naturally infected cats showed a comparatively weak humoral immune response. The
      experimentally infected cats were inoculated with either BDV laboratory strain V
      or a feline BDV-isolate. Some differences existed between the two groups of cats.
      The former group developed a higher response against p40, whereas the latter
      group showed, beside the p40-response, a more pronounced p24-response, similar to
      the situation in the naturally infected cats.

PMID- 12406653
TI  - Sows intramammarily inoculated with Escherichia coli at parturition: I.
      Functional capacity of granulocytes in sows affected or non-affected by clinical
      mastitis.
AB  - The objective of this study was to investigate if occurrence of clinical disease
      was related to granulocyte traits in sows. Functional capacity of granulocytes
      and plasma steroid hormone concentrations were assessed before inoculation with
      Escherichia coli in the mammary glands in sows at parturition. Blood samples were
      taken for 3 days approximately 1 week before parturition, and granulocyte
      migration, phagocytic capacity and expression of CD 18 adhesion molecules were
      determined. Inoculation was done within 36 h before partus. Thereafter, daily
      thorough clinical examinations were performed including udder health, habitus,
      appetite and rectal temperature, to assess the severity of disease. Based on the
      clinical findings four sows were classified as affected and eight as non-affected
      by clinical mastitis within 48 h after parturition.No difference (p>0.10) in pre
      inoculation chemotaxis, phagocytosis or CD 18 expression was found between
      granulocytes from the sows resisting and developing clinical mastitis,
      respectively. However, there was an effect by the individual sow (p=0.001) on the
      numbers of granulocytes and white blood cells, and on plasma concentrations of
      estradiol-17beta and progesterone. In conclusion, these data does not suggest
      that impaired chemotaxis or phagocytosis by blood granulocytes contribute to the
      development of clinical coliform mastitis in the periparturient sow.

PMID- 12406654
TI  - Sows intramammarily inoculated with Escherichia coli at parturition. II. Effects
      on the densities of MHC class II(+), CD4(+) and CD8(+) cells in the mammary
      gland.
AB  - The aim of this study was to determine the density of MHC class II, CD4 and CD8
      positive cells in mammary glands of sows around parturition, and whether the
      densities were altered following intramammary inoculation with Escherichia coli
      prior to parturition. Also, animals developing clinical disease after inoculation
      were compared with animals not developing clinical disease. Fourteen cross-bred
      primiparous sows were subject to intramammary inoculation with E. coli bacteria
      24h before estimated parturition. Mammary gland biopsies were collected and
      clinical observations were made. Four sows were categorised as clinically ill
      based on general condition, body temperature and gross mammary affection. There
      were no changes in density of MHC class II, CD4 and CD8 positive cells in non
      inoculated glands around parturition, while significant changes in densities were
      shown in inoculated glands. Here, the density of MHC class II, CD4 and CD8
      positive cells reached a peak at 72 h post-inoculation (p<0.01). In sows
      developing clinical disease, there was a tendency to an over all lower density
      (p=0.07) of MHC class II positive cells in inoculated glands compared with sows
      not developing clinical disease. When comparing the categories with respect to
      the density of CD4 and CD8 positive cells, the sows developing clinical disease
      showed a higher density (p=0.03) of CD4 and CD8 positive cells in inoculated
      glands than sows not developing disease. No differences were shown between
      categories in non-inoculated glands. It is concluded that the density of MHC
      class II, CD4 and CD8 positive cells seems to be unaltered around parturition.
      However, there is a rapid increase in density of these cells following
      intramammary inoculation with E. coli. Also, the data suggest that there is a
      difference between sows developing and sows not developing clinical disease after
      inoculation with respect to the increase in density of MHC class II, CD4 and CD8
      positive cells in the mammary gland.

PMID- 12406655
TI  - Efficacy of DNA vaccination by different routes of immunisation in sheep.
AB  - DNA vaccination, delivered through various routes, has been used extensively in
      laboratory animals. Few studies have focused on veterinary species and while
      results obtained in laboratory animals can often be extrapolated to veterinary
      species this is not always the case. In this study we have compared the effect of
      the route of immunisation with DNA on the induction of immune responses and
      protection of sheep to challenge with live Corynebacterium pseudotuberculosis.
      Intramuscular injection of plasmid DNA encoding an inactivated form of the
      phospholipase D (PLD) antigen linked to CTLA4-Ig resulted in the induction of a
      strong memory response and sterile immunity following challenge in 45% of the
      animals. In contrast, gene gun delivery or subcutaneous (SC) injection of the DNA
      vaccine induced comparatively poor responses and insignificant levels of
      protection. Thus, DNA vaccine efficacy in sheep is strongly influenced by the
      route of vaccination. Amongst intramuscular vaccinates, protected sheep had
      significantly elevated IgG2 responses compared to unprotected animals, while both
      subgroups had equivalent IgG1 levels. This suggests that the presence of IgG2
      antibodies and hence a Th1-like response, induced by the DNA vaccine gave rise to
      protective immunity against C. pseudotuberculosis.

PMID- 12406656
TI  - CXCL8((3-73))K11R/G31P antagonizes the neutrophil chemoattractants present in
      pasteurellosis and mastitis lesions and abrogates neutrophil influx into
      intradermal endotoxin challenge sites in vivo.
AB  - The ELR(+) CXC chemokines are critical for protective neutrophil responses to
      most bacterial infections, but nevertheless can contribute importantly to the
      pathogenic effects of many inflammatory responses. We recently engineered a
      series of high affinity CXCL8/IL-8 antagonists, one of which, CXCL8((3
      73))K11R/G31P, binds very strongly to neutrophils via the CXCR1 and CXCR2. Herein
      we show in competitive 125I-ligand binding assays that bovine CXCL8((3
      73))K11R/G31P has an affinity for neutrophils that is 2-3 orders of magnitude
      higher than that of CXCL8/IL-8. Furthermore, when used at approximately 0.5 nM,
      CXCL8((3-73))K11R/G31P inhibited by 50% the chemotactic responses of neutrophils
      to 129 nM CXCL8/IL-8, but it also blocked chemotactic responses to the alternate
      ELR-CXC chemokines CXCL1/GRO alpha and CXCL5/ENA-78. Furthermore, CXCL8((3
      73))K11R/G31P could inhibit by 93-97% the spectrum of neutrophil chemotactic
      activities present within wash fluids from clinical bacterial pneumonia or
      experimental endotoxin-induced mastitis lesions. Finally, intramuscular or
      subcutaneous application of CXCL8((3-73))K11R/G31P (75 micro g/kg) reduced by up
      to 97% neutrophil infiltration into intradermal endotoxin challenge sites in
      cattle, and prevented their circulating neutrophils from responding to CXCL8/IL-8
      or ENA-78 in vitro. This data thus encourages further investigation of the
      potential impact of this novel antagonist on ELR-CXC chemokine-driven
      inflammatory disorders.

PMID- 12406657
TI  - In vitro responses to purified protein derivate of caprine T lymphocytes
      following vaccination with live strains of Mycobacterium avium subsp
      paratuberculosis.
AB  - Live attenuated vaccines provide protection against intestinal lesions in goats
      infected with Mycobacterium avium subsp. paratuberculosis. To examine the role of
      different T lymphocyte subsets in the development of this protective immunity,
      CD4(+), CD8(+) and gamma delta T cell receptor (TCR)(+) cells from peripheral
      blood of goat kids vaccinated with live attenuated strains of M. a.
      paratuberculosis were studied. After in vitro stimulation with purified protein
      derivate, the expression of gamma-interferon (IFN-gamma) and the activation
      marker interleukin-2 receptor (IL-2R) was analysed by flow cytometry. A depletion
      experiment was performed, where the phenotypes and IL-2R expression was studied
      after stimulation of cultures depleted of a T lymphocyte subpopulation. Close to
      all of the IFN-gamma producing cells were of the CD4(+) subset, while only a
      small number were CD8(+) cells. The gamma delta TCR(+) cells were highly
      activated, but did not produce IFN-gamma after in vitro stimulation. Depletion of
      CD4(+) cells lead to a decrease in the percentage of total gamma delta TCR(+)
      cells and gamma delta TCR(+)IL2-R(+) cells. Removing the gamma delta TCR(+) cells
      increased the relative numbers of CD4(+), but not the CD4(+)IL-2R(+) cells.
      Insight into the in vitro recall responses of T cell subsets from animals
      vaccinated with live paratuberculosis vaccines is essential in the development of
      more efficient vaccines.

PMID- 12406658
TI  - Haemolytic complement activity, C3 and Factor B consumption in serum from
      chickens divergently selected for antibody responses to sheep red blood cells.
AB  - Antibody responses, serum complement haemolytic activity, and complement
      component C3 and Factor B consumption were studied in chickens divergently
      selected for high and low antibody responses to sheep red blood cells, and in a
      randombred control line. Significantly higher total and IgG antibody responses to
      SRBC were found after intramuscular immunisation in the high antibody responder
      (H) line versus the low antibody responder (L) line and the control (C) line.
      Also significantly higher antibody titres were found in the C line as compared to
      the L line. Ca-dependent (classical) and Ca-independent (alternative) complement
      haemolytic activity was significantly higher in the H line than in the L line.
      Also initial complement haemolytic activity and C3 levels prior to immunisation
      with SRBC were significantly higher in the H than in the L line. The L line, on
      the other hand, showed numerically higher Factor B levels. Immunisation with SRBC
      was followed by a different consumption of C3 in serum of the H line than the L
      line. The results indicated that divergent selection of chickens for specific
      antibody responses to SRBC affected complement levels and C3 consumption in these
      chickens. This suggests a genetic linkage between these two immune traits.

PMID- 12406659
TI  - Granulocyte responses to experimental injection of live and formalin-killed
      bacteria in carp (Cyprinus carpio).
AB  - The objective of the study was to investigate the dynamics of changes in number
      of granulocytes in bacterial infections of carp (Cyprinus carpio). Carp were
      inoculated with non-pathogenic or pathogenic bacteria and changes in type I
      (neutrophils) and type II granulocyte (basophils/eosinophils) counts in kidney,
      circulating blood and peritoneal cavity were assessed. After the injection of non
      pathogenic bacteria (Escherichia coli), the number of type I and II cells in
      blood increased after 6-12h, but returned to the control level after 24-48 h. In
      contrast, after the injection of pathogenic bacteria (Aeromonas hydrophila), the
      number of type I cells initially increased followed by an increase in the number
      of type II cells. The peak counts of type I and II cells were at 12 and 24h after
      the injection, respectively. When the fish were given serial-injections of
      formalin-killed bacteria at 12-h intervals, the type II cells also predominantly
      increased and remained at high levels, following the peak count of type I cells.

PMID- 12406660
TI  - Mannheimia haemolytica serotype 1 and Pasteurella trehalosi serotype 10 culture
      supernatants contain fibrinogen-binding proteins.
AB  - Fibrinogen-binding proteins were found in the culture supernatants of Mannheimia
      haemolytica serotype 1 (ATCC 43270) and Pasteurella trehalosi serotype 10 (ECO
      100). Sheep fibrinogen was biotinylated and shown to bind to proteins in the
      culture supernatants by modified western blot. Fibrinogen-binding proteins in the
      culture supernatant may be important virulence factors leading to the
      characteristic fibrinous pneumonia caused by these organisms and may be critical
      antigenic targets for immune prophylaxis.

PMID- 12406662
TI  - What's in the pipeline? Prospects for monoclonal antibodies (mAbs) as therapies
      for lung diseases.
AB  - The striking clinical results from recent studies with Remicade (infliximab, a
      monoclonal anti-TNFalpha antibody) in rheumatoid arthritis, Crohn's disease and
      psoriasis demonstrate the disease-altering potential of monoclonal antibodies
      (mAbs) in chronic inflammation. Chronic obstructive pulmonary disease (COPD) and
      asthma represent two major chronic pulmonary inflammatory diseases with
      substantial unmet medical needs. Most of the cells and mediators implicated in
      the pathophysiology of COPD and asthma are excellent targets for mAb
      intervention. Indeed, clinical trials with mAbs directed against IL-5, IgE, and
      CD4 yielded results that are critical in dissecting the pathophysiology of
      asthma, and reinforce the potential for mAbs as therapeutic agents in treating
      pulmonary diseases. Furthermore, fundamental advances in the discovery,
      manufacture and safety of mAbs underscore the enormous therapeutic value of these
      agents for chronic pulmonary diseases. Indeed, a large number of mAbs are in pre
      clinical and clinical development for treating these conditions. In this review,
      we discuss the scientific rationale for generating mAb therapies directed
      specifically toward COPD and asthma. We believe that as a therapeutic class, mAbs
      offer the opportunity to alter symptoms, progression and outcome of chronic
      pulmonary diseases.

PMID- 12406663
TI  - Anti-immunoglobulin E therapy for asthma.
AB  - The role of immunoglobulin E (IgE) in allergic asthmatic disease is well
      established. Allergen-specific IgE binds to its cognate receptors, thus
      triggering a series of cellular events. These events include presentation of
      antigen by dendritic cells and the degranulation of mast cells and basophils to
      release numerous factors that play an integral part in potentiating the disease
      symptoms. Studies in the mouse indicate that a reduction in IgE levels could lead
      to significant attenuation of the allergic inflammatory response associated with
      diseases such as asthma, making IgE a target for the development of new
      therapeutic agents. Omalizumab (Xolair, a recombinant humanized monoclonal anti
      IgE antibody that blocks the interaction of IgE with its receptors, is the first
      anti-IgE agent to undergo clinical development. Several clinical studies have
      been performed in adults and children with moderate-to-severe allergic asthma to
      evaluate the efficacy and safety of this agent. Treatment with omalizumab was
      well tolerated and showed clinical benefit in terms of a reduction in the
      frequency and number of asthma exacerbation episodes and lower usage of
      corticosteroids and other medications to control disease, along with improved
      quality of life. Such findings indicate that omalizumab represents a promising
      new treatment option for allergic asthma.

PMID- 12406664
TI  - Weight loss in chronic obstructive pulmonary disease. Mechanisms and
      implications.
AB  - Weight loss occurs frequently in patients with chronic obstructive pulmonary
      disease (COPD). Although the precise cellular mechanisms underlying weight loss
      in COPD are unclear, this is a clinically relevant phenomenon because it
      contributes to limit the exercise capacity of these patients and, therefore, it
      jeopardizes their quality of life. More importantly, it is a negative prognostic
      factor that is independent of the degree of lung function impairment present.
      Thus, weight loss in COPD constitutes a new therapeutic target. This article
      reviews the mechanisms and potential consequences of weight loss in COPD and
      highlights areas that needed future research. It is hoped that a better
      understanding of its pathogenesis may eventually contribute to the development of
      new therapeutic strategies that contribute to improve the well-being and/or long
      term prognosis of patients suffering from this devastating disease and,
      potentially, from others characterized also by unexplained weight loss.

PMID- 12406665
TI  - Pirfenidone: A novel anti-fibrotic agent and progressive chronic allograft
      rejection.
AB  - In our established model of heterotopic tracheal transplantation, at day 28
      following transplantation, obliteration of the lumen is observed, which is
      histologically similar to that seen in Obliterative Bronchiolitis (OB).
      Pirfenidone (Pir) is a novel anti-fibrotic agent that causes no
      immunosuppression, but does downregulate the production of TGF-beta and collagen
      in vitro. We hypothesized that when used in this in vivo model, that Pir may
      alter the observed luminal fibrosis and obliteration. METHODS: The treatment
      groups were: CSA, Pir and CSA, Pir only (n=6 each). Luminal supernatants and
      tissue were obtained from these groups at day 28. H&E staining was completed, as
      well as MTS proliferation assays, and TGF-beta ELISA on the fluids. RESULTS: The
      CSA-Pir combined treatment group was the least fibrogenic in vitro (p<0.001). The
      TGF-beta levels were elevated in all groups (range 203-372 pg/ml). The H&E
      staining revealed that the luminal obliteration was less organized in the
      combined CSA-Pir group. CONCLUSIONS: Our study shows that the combination of CSA
      Pir results in a less fibrogenic luminal fluid and a less dense fibrous luminal
      plug. Pir should be further studied in obliterative airways disease (OAD).

PMID- 12406666
TI  - Superoxide dismutase mimetics.
AB  - In this review we describe the potential role(s) of superoxide in inflammatory
      disorders.

PMID- 12406667
TI  - Importance of drug delivery system in steroid aerosol therapy via nebulizer.
AB  - Aim of our study was to evaluate if the type of nebulizer can influence the
      effects of steroid aerosol therapy. We considered 27 asthmatics allergic to
      grasses with FEV1<80% of the predictive value or methacholine PD20 FEV1<750 mcg.
      The patients were divided into three groups in relation to the type of nebulizer
      they used and treated 9 weeks by aerosol therapy with beclomethasone dipropionate
      bid (800 mcg). Respect to the values recorded at the beginning and at the end of
      the therapy we found different variations of spirometric indeces and PD20 values
      among the three groups. We can conclude that the type of nebulizer influences
      steroid aerosol therapy and, particularly, jet nebulizers seem more efficient
      than ultrasonic nebulizers.

PMID- 12406668
TI  - Effect of surfactant on ventilation-induced mediator release in isolated perfused
      mouse lungs.
AB  - The human acute respiratory distress syndrome (ARDS) is a severe pulmonary
      complication with high mortality rates. To support their vital functions,
      patients suffering from ARDS are mechanically ventilated. Recently it was shown
      that low tidal volume ventilation reduces mortality and pro-inflammatory mediator
      release in these patients, suggesting biotrauma as a side effect of mechanical
      ventilation. Because the application of exogenous surfactant has been proposed as
      a treatment for ARDS, we investigated the effect of surfactant on ventilation
      induced release of tumor necrosis factor (TNF), interleukin-6 (IL-6) and 6-keto
      PGF(1 alpha) (the stable metabolite of prostacyclin) in isolated perfused mouse
      lungs ventilated with high end-inspiratory pressures. Instillation of 100mg/kg
      surfactant into the lungs was well tolerated and improved tidal volume, pulmonary
      compliance and alveolar expansion. Exogenous surfactant increased the ventilation
      induced liberation of TNF and IL-6 into the perfusate, but had no effect on the
      release of 6-keto-PGF(1 alpha). The surfactant preparation used reduced baseline
      TNF production by murine alveolar macrophages, indicating that the exaggeration
      of ventilation-induced TNF release cannot be explained by a direct effect of
      surfactant on these cells. We hypothesize that ventilation-induced mediator
      release is explained by stretching of lung cells, which is reinforced by
      surfactant. The findings that in this model of ventilation-induced lung injury
      exogenous surfactant at the same time improved lung functions and enhanced
      mediator release suggest that surfactant treatment may prevent barotrauma and
      augment biotrauma.

PMID- 12406669
TI  - Comparison of the bronchodilating effects of inhaled formoterol, salmeterol and
      salbutamol in asthmatic patients.
AB  - Ten subjects with various degrees of asthma severity underwent a three-day trial,
      with the aim of evaluating the bronchodilating effect of inhaled formoterol (12
      micro g), in comparison with salbutamol (200 micro g) and salmeterol (50 micro
      g). The bronchodilation afforded by formoterol paralleled that of salbutamol in
      rapidity (mean percentage increases in functional measurements (FEV(1)) vs.
      baseline recorded 5 min after drug administration: 7.7%, 9.3%, and 0.3% for
      salbutamol, formoterol and salmeterol, respectively) and that of salmeterol in
      duration (mean percentage increases in FEV(1) vs. baseline recorded 12h after
      drug administration: 16.8% and 15.9% for formoterol and salmeterol,
      respectively). Moreover, the maximal effect of formoterol resulted to be slightly
      higher in comparison with salbutamol (P<0.001) and salmeterol (P<0.05); in this
      regard, the mean percentage increases in FEV(1) vs. baseline recorded 2h after
      salbutamol and formoterol, and 4h after salmeterol were 22.3%, 29.5%, and 24.6%,
      respectively. Therefore, these results suggest that formoterol can be used, in
      addition to its utilization as long-acting bronchodilator, also as an effective
      rescue medication for the immediate relief of asthma symptoms.

PMID- 12406670
TI  - Kinetics of airway hyperresponsiveness and airway eosinophilia in BALB/c mice and
      their modulation by different dexamethasone treatment regimens.
AB  - The mechanisms of airway hyperresponsiveness (AHR) are still poorly understood.
      In this study we have established a model of persistent AHR and eosinophilia and
      evaluated the prophylactic vs. therapeutic effects of dexamethasone on these
      parameters. Mice were immunised with ovalbumin (OVA) on day 0 and challenged
      intranasally on days 10, 11, 12 and 13 with OVA or phosphate buffer saline (PBS).
      Airway responsiveness to methacholine, measured 24-h post multiple intranasal OVA
      challenges, was significantly increased compared to time matched PBS-controls
      (P<0.05). AHR could be detected for up to 14 days after the last OVA challenge
      although the magnitude of the AHR had diminished by day 14 compared to day 1. OVA
      challenge of mice induced a significant airway eosinophilia at 24h (P<0.05); this
      persisted for 2 weeks after the challenge. Prophylactic treatment with
      dexamethasone (1mg x kg (-1)) reduced the OVA induced AHR, eosinophilia and mucus
      cell hyperplasia/metaplasia measured 24h post challenge. Therapeutic treatment,
      with dexamethasone (2 mg x kg(-1)), significantly inhibited established airway
      eosinophilia, measured at 72 h post OVA challenge, only when treatment was
      initiated at 24h but not 48 h after challenge. In contrast, AHR measured at 72 h
      post OVA challenge was significantly reduced when treatment was started at either
      24 or 48 h post challenge. Our data shows that the immunization and challenge
      procedures employed resulted in a persistent type of AHR. Prophylactic
      intervention with steroids almost completely inhibited its development; however
      therapeutic intervention only partially resolved AHR.

PMID- 12406672
TI  - Response of recombinant calcineurin to metal ions, reduction-oxidation agents,
      and enzymatic modification.
AB  - Recombinant calcineurin heterodimer with the full length delta-isoform of the
      catalytic subunit (CaN(500)) was expressed in insect cells using the baculovirus
      system and compared to native bovine brain enzyme in its response to divalent
      metal ions, redox reagents, and enzymatic modification of arginine residues. The
      response to various metal ions showed essentially the same profile as bovine
      brain calcineurin, although Co2+ and Zn2+ did not support recombinant activity as
      well. Kinetic analysis showed that metal ion and substrate binding were not
      independent, as found for the bovine brain calcineurin. Incubation with DTT or
      ascorbate alone caused similar effects on the activity of both enzymes, but
      different responses were observed when incubated with both DTT and ascorbate;
      only the recombinant enzyme showed activation. Arginine deimination of
      recombinant calcineurin by peptidylarginine deiminase resulted in the loss of 60
      80% of its phosphatase activity with protection observed if calmodulin was
      present. Recombinant calcineurin was reactivated by treatment with the protease
      clostripain, suggesting that deimination of an arginine in the carboxyl terminal
      domain may be responsible for the loss of phosphatase activity and decreased
      calmodulin binding [Arch. Biochem. Biophys. 318 (1995) 370]. Supporting this
      conclusion, a truncated variant of the catalytic subunit lacking the carboxyl
      terminus showed no loss of phosphatase activity compared to full length
      calcineurin subunit and contained lower amounts of citrulline than the full
      length subunit after deimination. These different responses of recombinant
      calcineurin are consistent with conformational differences compared to bovine
      brain calcineurin and raise questions about its utility for studying the
      mechanism of calcineurin.

PMID- 12406671
TI  - Recombinant human insulin IX. Investigation of factors, influencing the folding
      of fusion protein-S-sulfonates, biotechnological precursors of human insulin.
AB  - The peculiarities of molecular structures and the influence of reaction
      conditions on the folding efficiency of fusion proteins-biotechnological
      precursors of human insulin, expressed in Escherichia coli as inclusion bodies
      have been investigated. The fusion proteins contained proinsulin sequence with
      various leader peptides connected by an Arg residue to the insulin B-chain. The
      kind and the size of leader peptide do not have essential influence on folding
      efficiency. However, the efficiency of protein folding depends on the location of
      the (His)6 site, which is used for metal-chelating affinity chromatography. In
      our study the protein folding depends on the reaction medium composition
      (including additives), the presence of accompanied cell components, pH,
      temperature, concentrations of protein, and redox agents. A negative influence of
      nucleic acid and heavy metal ions on folding has been found. S-sulfonated fusion
      protein has proinsulin-like secondary structure (by CD-spectroscopy data) that is
      the key point for 95% efficient folding proceeding. Folded fusion proteins are
      transformed into insulin by enzymatic cleavage.

PMID- 12406673
TI  - Production of recombinant endotoxin neutralizing protein in Pichia pastoris and
      methods for its purification.
AB  - Production of recombinant Limulus endotoxin neutralizing protein (rENP) was
      attained with the GS115 methylotrophic strain of Pichia pastoris transformed with
      a plasmid, bearing multiple ENP gene copies. The synthetic gene for Limulus ENP
      was cloned into the integrative plasmid pAO815 under the control of a methanol
      inducible promoter. Clones containing a single enp insert were used to construct
      cassettes bearing 2 and 3 tandem copies of enp. These were then integrated at the
      HIS locus of P. pastoris GS115 (his4). Clones were chosen for their ability to
      produce rENP upon methanol induction in shaker flasks, and then the 1x, 2x, and
      3x-enp strains were analyzed by Southern blot for the presence of the ENP
      gene(s). Isolate 3 x 5q, containing a 3x-enp cassette, was the best producer of
      rENP. Under optimal conditions this strain grown in a fed-batch mode produced
      yields of >500 mg rENP/L with an average of 5.46 mg rENP/g DCW. Purification of
      rENP from the clarified broth resulted in a yield of 35% and a purity of >86%.
      Glycosylated rENP, the main contaminant, was removed with a concanavalin-A column
      and characterized. The pure rENP neutralized lipopolysaccharide and had the mass,
      amino-acid composition and N-terminal sequence expected from the cloned gene.

PMID- 12406674
TI  - Hispin, a novel ribosome inactivating protein with antifungal activity from hairy
      melon seeds.
AB  - A ribosome inactivating protein demonstrating a molecular mass of 21 kDa and a
      novel N-terminal sequence was isolated from seeds of the hairy melon. The
      purification procedure involved affinity chromatography on Affi-gel blue gel and
      ion exchange chromatography on CM-Sepharose and Mono S. The protein designated
      hispin inhibited translation in the cell-free rabbit reticulocyte lysate system
      with an IC50 of 165 pM and exhibited N-glycosidase activity. Antifungal activity
      was also observed.

PMID- 12406676
TI  - Production of extracellular domain of human tissue factor using maltose-binding
      protein fusion system.
AB  - Making use of the physiological process of coagulation as an anti-tumor effector
      function may be beneficial in various coagulation-mediated diseases. Preclinical
      and clinical studies with novel tissue factor targeting constructs require that
      efficient procedures for preparing large quantities of pure truncated TF (tTF)
      become available. In this study, we described a simple and rapid on-column method
      for purifying large quantities of human tTF from Escherichia coli. The coding
      region of extracellular domain of tissue factor was linked to the 3(')-end of
      maltose-binding protein (MBP) gene. The fusion protein was expressed as soluble
      form after induction by isopropylthio-beta-D-galactoside (IPTG). MBP-tTF was
      purified by amylose affinity chromatography. MBP can be removed by digestion with
      factor Xa. Expression could represent 21.5% of the total soluble protein in E.
      coli, allowing approximately 15mg of highly purified protein to be obtained per
      liter of bacterial culture. The fusion protein was recognized in Western blot by
      anti-TF monoclonal antibody and the activity was confirmed by chromogenic assay.
      This MBP-fusion system permits large-scale functional expression and purification
      of recombinant soluble proteins, providing a basis for the future study of
      structure and function of tTF.

PMID- 12406675
TI  - Overexpression of DsbC and DsbG markedly improves soluble and functional
      expression of single-chain Fv antibodies in Escherichia coli.
AB  - Single-chain Fv antibodies (scFv), a group of reconstructed molecules with
      several disulfide bonds, are prone to aggregate as inclusion bodies, the
      insoluble species of natural proteins, when expressed in Escherichia coli,
      especially at high level. Recovery of functionally active products from inclusion
      bodies is onerous and ineffective. We have increased the soluble and functional
      scFv yields by fusing either DsbC or DsbG, two E. coli disulfide isomerases with
      general chaperone function, to scFvs. Compared to the totally insoluble inclusion
      bodies of scFvs expressed separately, more than half of each fusion protein DsbC
      scFv or DsbG-scFv was soluble, according to SDS-PAGE analysis. The more effective
      solubility was obtained when the fused protein DsbG-scFv was co-expressed
      simultaneously with DsbC under the same promoter. Under this condition, the
      soluble portion of DsbG-scFv increased from about 50% to 90% measured by scanning
      SDS-PAGE gel. Co-expression of DsbC can change fusion protein CBD-scFv from
      totally insoluble when expressed in E. coli separately to a considerable portion
      of soluble CBD-scFv. Antigen-binding activity assay showed that scFvs retained
      full affinity to specific antigens. We also determined that general molecular
      chaperones GroEL and GroES had no effects on the solubility of scFvs when co
      expressed with scFv in E. coli. We propose that the correct formation of
      disulfide bonds in scFvs is the crucial factor responsible for solubility of
      scFvs.

PMID- 12406677
TI  - The preparation and characterization of an antimicrobial polypeptide from the
      loach, Misgurnus anguillicaudatus.
AB  - Using Sephadex G-50 gel filtration, DEAE-52 cellulose ion-exchange
      chromatography, and an improved polyacrylamide gel electrophoresis together with
      electroelution, a novel polypeptide with antimicrobial activity in vitro was
      isolated and characterized from loach, Misgurnus anguillicaudatus. The
      polypeptide, named MAPP, contains about 94 residues containing l0 different amino
      acids, of which cysteine was the most abundant. No alkaline residue was found in
      MAPP. MAPP is a single-chain polypeptide with Mw of about 9800Da and pI of about
      4.78; the N-terminus of MAPP was CFGWN. MAPP showed good inhibition of various
      bacteria including Bacillus subtilis, Escherichia coli, and Staphylococcus
      aureus. MAPP is thermally stable with more than 70% inhibitory bioactivity
      remaining after treatment at 60 degrees C for 30min. In addition, MAPP could
      inhibit the autoxidation of pyrogallol with a high efficiency. Similarity
      searches by comparing amino acid composition, MS-fingerprint, and the N-terminus
      of MAPP demonstrated that no protein exactly matched MAPP in databases around the
      world.

PMID- 12406678
TI  - Expression of the class 1 outer-membrane protein of Neisseria meningitidis in
      Escherichia coli and purification using a self-cleavable affinity tag.
AB  - The class 1 protein (PorA) is a major component of the outer membrane of
      Neisseria meningitidis and functions as a cationic porin. The protein is
      particularly effective in generating a bactericidal immune response following
      infection and is therefore under investigation as a potential antigen for
      inclusion in new meningococcal vaccines. Studies on the vaccine potential of PorA
      would be facilitated by the production of pure protein, free from other
      components of the meningococcal outer membrane. In the current study, PorA was
      expressed from the heterologous host Escherichia coli as a C-terminal fusion to
      an inducible protein-splicing element (intein) with an N-terminal chitin-binding
      domain (CBD) (IMPACT-TWIN system). The CBD acted as an affinity tag and allowed
      binding of the fusion protein to a chitin bead column, after which self-cleavage
      of the intein at its C-terminus was induced, resulting in the release of mature
      PorA. Cleavage of the fusion protein was temperature- and time-dependent, and was
      optimal at pH 7.0 after 5 days of storage at 4 degrees C. Efficient cleavage was
      also dependent on the addition of a minimal amino acid sequence (Gly-Arg-Ala) to
      the N-terminus of the mature PorA protein. This represented a significant
      improvement on the large N-terminal sequences introduced by other expression
      systems previously used to prepare recombinant PorA, and the yields of PorA
      purified with the IMPACT-TWIN system were similar. Thus, the IMPACT-TWIN system
      provides a facile method for producing recombinant PorA and may also be useful
      for the production of other bacterial outer-membrane proteins for vaccine
      studies.

PMID- 12406679
TI  - Production of salmon calcitonin by direct expression of a glycine-extended
      precursor in Escherichia coli.
AB  - The export of heterologous products into the conditioned medium of an Escherichia
      coli culture offers the advantages of a higher product yield, an increased
      probability of recovering an intact recombinant protein, proper folding for
      biological activity, and greater stability of a secreted product. In this report,
      we describe the development of an optimized direct expression system, designed to
      maximize the extracellular accumulation of recombinant glycine-extended salmon
      calcitonin peptide (sCTgly). We have used dual promoters, an ompA signal
      sequence, co-expression of homologous secretion factor genes, and multiple gene
      cartridges to express the sCTgly. High-density fermentation conditions have been
      developed that allow for the selective secretion and accumulation of the
      expressed sCTgly at very high levels. Purification and in vitro enzymatic
      conversion by peptidylglycine alpha-amidating monooxygenase yields authentic,
      biologically active salmon calcitonin. This recombinant production technology is
      applicable to a variety of amidated peptide hormones.

PMID- 12406680
TI  - Affinity purification of GST fusion proteins for immunohistochemical studies of
      gene expression.
AB  - Fusion proteins expressed in bacteria are often insoluble or inefficiently
      purified by standard procedures previously reported to work well for the non
      fused proteins. We report here a simple but general procedure that can be used to
      quickly customize and optimize the purification of milligram quantities of most
      GST fusion proteins. For each new protein, this procedure determines the optimal
      conditions for solubilization with detergents in a bacterial lysate, binding to
      glutathione-agarose beads, and elution with different buffers. This approach was
      applied to three GST fusion proteins containing large fragments of the Hox
      transcription factors Lox2, Lox4, and Lox6 that had low solubility and poor
      elution when purified following published procedures. After optimization,
      purified proteins were obtained at high yield and successfully used to raise and
      purify antibodies for the study of the expression patterns of these genes in
      embryonic tissues.

PMID- 12406681
TI  - Chaperonin assisted overexpression, purification, and characterisation of human
      PP2A methyltransferase.
AB  - Protein phosphatase 2A (PP2A) is a ubiquitous phosphatase found in many
      eukaryotic cell types and is involved in regulating a number of intracellular
      signalling pathways. Its activity, in turn, is regulated through covalent
      modification, involving phosphorylation and methylation reactions. The effect of
      phosphorylation on the activity of the protein is well known, but the effects of
      methylation have only recently been documented and the mechanistic details of
      methylation are lacking. Methylation, which occurs on the catalytic subunit of
      PP2A, is catalysed by PP2A methyltransferase (PP2Amt). Here, we present a method
      for the large-scale purification of human PP2Amt using an Escherichia coli host,
      coexpressing the chaperonins GroEL and GroES. Purified PP2Amt was identified by
      peptide mass mapping using MALD-MS and peptide sequencing using ESI-LC-MS/MS. The
      CD spectrum indicated that purified PP2Amt was folded, with about one-third of
      the protein adopting an alpha-helical conformation. Analytical gel filtration
      estimated the molecular weight to be 34kDa, equivalent to the monomeric form of
      the protein. Further CD analysis showed that in the presence and absence of the
      ligand S-adenosylhomocysteine, the thermal denaturation profiles were biphasic.
      However, the transition midpoints shifted to a higher temperature in the presence
      of ligand, indicating stabilisation of ligand-bound PP2Amt compared to the apo
      form. We also report on the progress made in determining the structure of PP2Amt,
      using both X-ray crystallography and NMR spectroscopy.

PMID- 12406682
TI  - Purification and characterization of progenipoietins produced in Escherichia.
      coli.
AB  - The progenipoietins (ProGPs) are a family of genetically engineered chimeric
      proteins that contain receptor agonist activity for both fetal liver tyrosine
      kinase-3 and the granulocyte colony-stimulating factor receptor. These unique
      proteins have previously been shown to induce the proliferation of multiple cell
      lineages. The characterization of two progenipoietins, ProGP-1 and ProGP-4,
      refolded and purified from an Escherichia coli expression system is described.
      These ProGP molecules differ in the orientation of the two receptor agonists and,
      in addition, ProGP-4 contains a fetal liver tyrosine kinase-3 receptor agonist
      that has been circularly permuted to modulate its activity. Static light
      scattering analyses demonstrated that both ProGP molecules exist as dimers, most
      likely through non-covalent interaction of the fetal liver tyrosine kinase-3
      receptor agonist domains. ProGP-1 and ProGP-4 have comparable secondary
      structures, as analyzed by circular dichroism; however, their tertiary
      structures, as measured by intrinsic fluorescence, were demonstrated to be
      different. Differential scanning calorimetry demonstrated that the thermal
      stability of these two proteins was indistinguishable. Interestingly, these dual
      agonist proteins yielded only a single melting temperature value that was
      intermediate between that of their individual receptor agonist components,
      indicating that these chimeric molecules behave as a single domain protein during
      thermal denaturation. This study describes the purification and physico-chemical
      properties of this class of proteins generated using an E. coli expression
      system.

PMID- 12406683
TI  - Expression, purification, and characterization of minimized chicken riboflavin
      carrier protein from a synthetic gene in Escherichia coli.
AB  - Minimized proteins have long been used to elicit immune response to particular
      regions of a protein antigen. Most efforts to derive minimized proteins have
      employed synthetic peptide fragments. Here we describe molecular cloning and
      production of a minimized chicken riboflavin carrier protein (mini-RCP) sequence
      that harbours all the four neutralizing epitopes but lacks the sequences that
      otherwise elicit undesirable antibodies. The gene encoding mini-RCP is engineered
      by contiguous alignment of nucleotide sequences coding for selected epitopes of
      chicken RCP separated by leucyl alanine residues. The gene has been constructed
      from eight oligonucleotides by employing overlapping PCR strategy and expressed
      in Escherichia coli, using the T7 promoter system. The recombinant protein could
      be purified to homogeneity by a single step Ni2+ affinity chromatography. Western
      blot experiments using epitope specific antisera confirm that the corresponding
      linear amino acid sequences are available for immunorecognition in the engineered
      protein. This methodology enables continuous production and purification in bulk
      amounts of the minimized RCP as a source of candidate immunocontraceptive vaccine
      in mammals.

PMID- 12406684
TI  - High-level expression and characterization of a secreted recombinant cation
      dependent mannose 6-phosphate receptor in Pichia pastoris.
AB  - Mannose 6-phosphate receptors (MPRs) form essential components of the lysosomal
      enzyme targeting system by binding newly synthesized acid hydrolases with high
      (nM) affinity. We report the use of Pichia pastoris as a host to efficiently
      express the extracytoplasmic ligand-binding domain of the cation-dependent
      mannose 6-phosphate receptor. A truncated and glycosylation-deficient form of the
      receptor AF-Asn(81)/Stop(155) was secreted into the culture medium, yielding
      approximately 28mg/L after purification, which is an improvement of 10-100-fold
      compared to expression in baculovirus-infected insect cells and mammalian cells,
      respectively. Enzymatic deglycosylation indicated high-mannose sugars at the
      single potential glycosylation site of Asn 81. The extent and heterogeneity of N
      glycans were revealed by applying matrix-assisted laser desorption/ionization
      time-of-flight mass spectrometry (MALDI-TOF MS). In the case of AF
      Asn(81)/Stop(155), the majority (75%) of the oligosaccharides contained chain
      lengths of Man(8-10)GlcNAc(2) while Man(11-12)GlcNAc(2) comprised the remaining
      (25%) N-linked sugars. A comparative MALDI-TOF spectra of Asn(81)/Stop(155)
      purified from insect cells indicated that Man(2-3)GlcNAc(2) and GlcNAcMan(2
      3)GlcNAc(2) share the oligosaccharide pool. The receptor isolated from yeast was
      functional with respect to ligand binding and acid-dependent dissociation
      properties, as determined by pentamannosyl phosphate-agarose affinity
      chromatography. In addition, the protein was biochemically and functionally
      similar to Asn(81)/Stop(155) expressed in insect cells concerning its oligomeric
      state and binding affinity to the lysosomal enzyme, beta-glucuronidase
      (K(d)=1.4nM). These results demonstrate that P. pastoris is a convenient system
      for the production of large quantities of functional recombinant MPRs suitable
      for structure-function studies.

PMID- 12406685
TI  - Rapid refolding and polishing of single-chain antibodies from Escherichia coli
      inclusion bodies.
AB  - An inexpensive and fast-folding strategy for single-chain antibody (scFv)
      recovered from Escherichia coli inclusion bodies has been developed. Two anti
      fluorescein single-chain antibodies, 4-4-20 and 4M5.3, were expressed as
      inclusion bodies in E. coli for use in a comparative refolding study. Active
      protein yields as well as degree of aggregation were evaluated for scFv produced
      by stepwise dialysis, redox dialysis, and a newly developed controlled dilution
      and filtration strategy. Although all three methods produced active protein for
      both 4-4-20 and 4M5.3, the extent of aggregation differed greatly among the
      methods. For 4-4-20, the controlled dilution and filtration strategy reduced
      aggregation by half, allowed batch processing times of 8h (an 18-fold
      improvement), and significantly reduced denaturant usage while increasing active
      yields by 150%. A hydroxyapatite resin polishing step was used to remove
      completely the aggregate species and inactive monomeric scFv from active scFv.

PMID- 12406686
TI  - A plasmid system for optimization of Fab' production in Escherichia coli:
      importance of balance of heavy chain and light chain synthesis.
AB  - We demonstrate the importance of optimizing the balance of light chain (LC) and
      heavy chain (HC) expression to achieve high level production of Fab' fragments in
      the Escherichia coli periplasm. The LC:HC balance has been controlled by varying
      the codon usage of the signal peptide (SP) and 5' mature domain coding regions.
      Different SP coding regions have been identified from a codon wobble-based
      library using alkaline phosphatase (AP) as a reporter gene. A plasmid system that
      enables random combination of these variant SP coding regions is used to
      construct optimized Fab' expression plasmids. These small plasmid libraries
      facilitated selection of optimal Fab' expression plasmids and resulted in
      increases of periplasmic yield, up to 580 mgL(-1) from E. coli fermentations and
      will enable rapid variable region subcloning and selection of future Fab(')
      expression plasmids.

PMID- 12406687
TI  - Expression and purification of Rhizobium leguminosarum NodD.
AB  - A Rhizobium expression system was constructed via introducing strong
      transcriptional elements to an IncP broad host range plasmid pKT230. Using this
      system, the nodD gene of Rhizobium leguminosarum biovar viciae was overexpressed
      in its own in vivo environment. Western blot showed that the NodD yield of the
      newly constructed expression vector pKNDT was much higher than that of a reported
      vector pIJ1518. Based on the result from quantitative gel retardation assay, the
      specific DNA-binding activity of NodD was estimated to increase by about 80-fold.
      Purification of NodD was performed by the sequential steps: polyethyleneimine
      treatment, ammonium sulfate fractional precipitation, and cellulose phosphate P11
      chromatography. About 26 mg NodD with a purity about 90% was obtained from 14 g
      wet weight cell pellet within 2 days.

PMID- 12406688
TI  - In vitro refolding process of urea-denatured microbial transglutaminase without
      pro-peptide sequence.
AB  - Efficient refolding process of denatured mature microbial transglutaminase (MTG)
      without pro-peptide sequence was studied in the model system using urea-denatured
      pure MTG. Recombinant MTG, produced and purified to homogeneity according to the
      protocol previously reported, was denatured with 8M urea at neutral pH and
      rapidly diluted using various buffers. Rapid dilution with neutral pH buffers
      yielded low protein recovery. Reduction of protein concentration in the refolding
      solution did not improve protein recovery. Rapid dilution with alkaline buffers
      also yielded low protein recovery. However, dilution with mildly acidic buffers
      showed quantitative protein recovery with partial enzymatic activity, indicating
      that recovered protein was still arrested in the partially refolded state.
      Therefore, we further investigated the efficient refolding procedures of
      partially refolded MTG formed in the acidic buffers at low temperature (5 degrees
      C). Although enzymatic activity remained constant at pH 4, its hydrodynamic
      properties changed drastically during the 2h after the dilution. Titration of
      partially refolded MTG to pH 6 after 2h of incubation at pH 4.0 improved the
      enzymatic activity to a level comparable with that of the native enzyme. The same
      pH titration with incubation shorter than 2h yielded less enzymatic activity.
      Refolding trials performed at room temperature led to aggregation, with almost
      half of the activity yield obtained at 5 degrees C. We conclude that rapid
      dilution of urea denatured MTG under acidic pH at low temperature results in
      specific conformations that can then be converted to the native state by
      titration to physiological pH.

PMID- 12406689
TI  - Ultrastructural properties of ciliary zonule microfibrils.
AB  - Conventional electron microscopy and rotary shadowing techniques have provided
      conflicting interpretations of microfibril ultrastructure. To address this issue,
      we have used quick-freeze deep-etch (QFDE) microscopy to obtain 3-dimensional
      surface views of microfibrils that have not been fixed, dehydrated, or stained
      with heavy metals. By this approach, microfibrils appear as tightly packed rows
      of bead-like subunits that do not display the interbead filamentous links seen by
      other methods. At regular 50-nm intervals along the microfibril length, a larger
      bead is often recognized which tends to be aligned with those from adjacent
      microfibrils when the microfibrils are in bundles. This evidence of organized
      lateral associations of microfibrils is supported by the observation of small
      filaments that span between the adjacent microfibrils. When QFDE microscopy was
      used to examine microfibrils exposed to sonication, partially dissociated
      microfibrils with the more typical "beads on a string" appearance were observed.
      Beads are also seen alone, as monomers, often with an array of small thread-like
      filaments extending from the bead in a "crab-like" manner. Our results suggest
      that the beads on a string appearance of sonicated microfibrils may result from a
      partial loss of protein components from the interbead domains, thus leading to
      exposure of a filamentous substructure. It is possible, therefore, that this
      phenomenon might also contribute to the beads on a string appearance of
      microfibrils seen using other electron microscopy techniques.

PMID- 12406690
TI  - Nuclear structure and gene activity in human differentiated cells.
AB  - The nuclear arrangement of the ABL, c-MYC, and RB1 genes was quantitatively
      investigated in human undifferentiated HL-60 cells and in a terminally
      differentiated population of human granulocytes. The ABL gene was expressed in
      both cell types, the c-MYC gene was active in HL-60 cells and down-regulated in
      granulocytes, and expression of the RB1 gene was undetectable in HL-60 cells but
      up-regulated in granulocytes. The distances of these genes to the nuclear center
      (membrane), to the center of the corresponding chromosome territory, and to the
      nearest centromere were determined. During granulopoesis, the majority of
      selected genetic structures were repositioned closer to the nuclear periphery.
      The nuclear reposition of the genes studied did not correlate with the changes of
      their expression. In both cell types, the c-MYC and RB1 genes were located at the
      periphery of the chromosome territories regardless of their activity. The
      centromeres of chromosomes 8 and 13 were always positioned more centrally within
      the chromosome territory than the studied genes. Close spatial proximity of the c
      MYC and RB1 genes with centromeric heterochromatin, forming the chromocenters,
      correlated with gene activity, although the nearest chromocenter of the silenced
      RB1 gene did not involve centromeric heterochromatin of chromosome 13 where the
      given gene is localized. In addition, the role of heterochromatin in gene
      silencing was studied in retinoblastoma cells. In these differentiated tumor
      cells, one copy of the RB1 gene was positioned near the heterochromatic
      chromosome X, and reduced RB1 gene activity was observed. In the experiments
      presented here, we provide evidence that the regulation of gene activity during
      important cellular processes such as differentiation or carcinogenesis may be
      realized through heterochromatin-mediated gene silencing.

PMID- 12406691
TI  - The structure of tomato aspermy virus by X-ray crystallography.
AB  - The three-dimensional structure of tomato aspermy virus (TAV) has been solved by
      X-ray crystallography and refined to an R factor of 0.218 for 3.4-40 A data
      (effective resolution of 4A). Molecular replacement, using cucumber mosaic virus
      (Smith et al., 2000), provided phases for the initial maps used for model
      building. The coat protein of the 280 A diameter virion has the canonical "Swiss
      roll" beta-barrel topology with a distinctive amino-terminal alpha-helix directed
      into the interior of the virus where it interacts with encapsidated RNA. The N
      terminal helices are joined to the beta-barrels of protein subunits by extended
      polypeptides of six amino acids, which serve as flexible hinges allowing movement
      of the helices in response to local RNA distribution. Segments of three
      nucleotides of partially disordered RNA interact with the capsid, primarily
      through arginine residues, at interfaces between A and B subunits. Side chains of
      cys64 and cys106 form the first disulfide observed in a cucumovirus, including a
      unique cysteine, 106, in a region otherwise conserved. A positive ion, putatively
      modeled as a Mg(+)ion, lies on the quasi-threefold axis surrounded by three quasi
      symmetric glutamate 175 side chains.

PMID- 12406692
TI  - Diffraction quality crystals of PRD1, a 66-MDa dsDNA virus with an internal
      membrane.
AB  - It has proved difficult to obtain well diffracting single crystals of
      macromolecular complexes rich in lipid. We report here the path that has led to
      crystals of the bacteriophage PRD1, a particle containing approximately 2,000
      protein subunits from 18 different protein species, around 10 of which are
      integral membrane proteins associated with a host-derived lipid bilayer of some
      12,500 lipid molecules. These crystals are capable of diffracting X-rays to Bragg
      spacings below 4A. It is hoped that some lessons learned from PRD1 will be
      applicable to other lipidic systems and that these crystals will allow, as a
      proof of principle, the determination of the structure of the virus in terms of a
      detailed atomic model.

PMID- 12406693
TI  - Two-dimensional structures of the Shiga toxin B-subunit and of a chimera bound to
      the glycolipid receptor Gb3.
AB  - The B-subunit of Shiga toxin has been demonstrated as a powerful vector for
      carrying attached peptides into cells for intracellular transport studies and for
      medical research. We have investigated the structure of the B-subunit and of a
      chimera bearing a peptide extension, bound to the membranous lipidic receptor,
      the globotriaosylceramide (Gb3). Two-dimensional crystals of both B-subunits have
      been obtained by the lipid layer method and projection maps have been calculated
      at 8.5A resolution from ice-embedded samples. The B-subunits as the chimera are
      organized in a pentameric form similar to the X-ray structure of the B-subunit
      not bound to Gb3. A difference map of both proteins has been calculated in which
      no density could be attributed to the peptide extension. Cross-correlations with
      projections of the B-subunit X-ray structure revealed that pentamers in the 2D
      crystals were oriented with their binding sites pointing to the lipid layer.
      Thus, it is likely that the peptide extension was disordered and confined to the
      surface of the pentamer opposite to the Gb3 binding sites. This location confirms
      the hypothesis that addition of peptide extension to the C-terminus conserves the
      ability of the modified B-subunit to bind the membranous receptor Gb3.

PMID- 12406694
TI  - Interaction of the Vibrio cholerae cytolysin (VCC) with cholesterol, some
      cholesterol esters, and cholesterol derivatives: a TEM study.
AB  - The Vibrio cholerae cytolysin (VCC) 63-kDa monomer has been shown to interact in
      aqueous suspension with cholesterol microcystals to produce a ring/pore-like
      heptameric oligomer approximately 8 nm in outer diameter. Transmission electron
      microscopy data were produced from cholesterol samples adsorbed to carbon support
      films, spread across the holes of holey carbon films, and negatively stained with
      ammonium molybdate. The VCC oligomers initially attach to the edge of the stacked
      cholesterol bilayers and with increasing time cover the two planar surfaces. VCC
      oligomers are also released into solution, with some tendency to cluster,
      possibly via the hydrophobic membrane-spanning domain. At the air/water
      interface, the VCC oligomers are likely to be selectively oriented with the
      hydrophobic domain facing the air. Despite some molecular disorder/plasticity
      within the oligomers, multivariate statistical analysis and rotational self
      correlation using IMAGIC-5 strongly suggest the presence of sevenfold rotational
      symmetry. To correlate the electron microscopy data with on-going biochemical and
      permeability studies using liposomes of varying lipid composition, the direct
      interaction of VCC with several cholesterol derivatives and other steroids has
      been examined. 19-Hydroxycholesterol and 7 beta-hydroxycholesterol both induce
      VCC oligomerization. beta-Estradiol, which does not possess an aliphatic side
      chain, also efficiently induces VCC oligomer formation, as does cholesteryl
      acetate. Cholesteryl stearate and oleate and the C22 (2
      trifluoroacetyl)naphthyloxy analogue of cholesterol fail to induce VCC
      oligomerization, but binding of the monomer to the surface of these steroids does
      occur. Stigmasterol has little tendency to induce oligomer formation, and
      oligomers are largely confined to the edge of the bilayers; ergosterol has even
      less oligomerization ability. Attempts to solubilize and stabilize the VCC
      oligomers from cholesterol suspensions have been pursued using the neutral
      surfactant octylglucoside. Although individual solubilized oligomers have been
      defined which exhibit a characteristic cytolysin channel conformation in the side
      on orientation, a tendency remains for the oligomers to cluster via their
      hydrophobic domains.

PMID- 12406701
TI  - Hydroxamates as substrates and inhibitors for FMN-dependent 2-hydroxy acid
      dehydrogenases.
AB  - Long-chain hydroxy acid oxydase (HAO) is a member of a flavoenzyme family with
      significant amino acid sequence similarity and strongly conserved three
      dimensional structure; in particular, active-site amino acids involved in
      catalysis are invariant, with one exception, and numerous enzymatic studies
      suggest an identical chemical mechanism involving an intermediate carbanion for
      all family members. Known physiological substrates are a variety of L-2-hydroxy
      acids. Peroxisomal HAO differs from the other family members in that its actual
      physiological substrate is not known; it was first described as an L-amino acid
      oxidase, and recently was identified as an enzyme that converts creatol
      (hydroxycreatinine) to methylguanidine (a metabolite involved in a variety of
      uremic syndromes). Creatol (2-amino-5-hydroxy-1-methyl-4(5H)imidazolone) is not a
      2-hydroxy acid. We show in this work that 2-hydroxyphenyl acetohydroxamate
      (HYPAH, the hydroxamate of mandelic acid), a compound that bears similarity both
      to mandelate (one of the best substrates known) and to creatol, is turned over by
      HAO, but between 10- and 100-fold less efficiently than mandelate itself. The
      compound also binds to the active site of homologous flavocytochrome b(2) (L
      lactate dehydrogenase). Comparative pH-rate studies for mandelate and its
      hydroxamate suggest that HYPAH may bind in its ionized form. Both pH-rate
      profiles are bell-shaped curves, as are those determined for two other family
      members, flavocytochrome b(2) and mandelate dehydrogenase; while the group with
      an acid pK(a) between 5 and 6 is most likely the active-site histidine (the
      residue which abstracts the substrate C2 proton), the identity of the basic group
      is less clear. It has been proposed to be one of the active site arginines
      (Lehoux, I., and Mitra, B. (1999) Biochemistry38, 5836-5848); we suggest as an
      alternative that it could be the lysine residue that interacts with the flavin N1
      and O2 positions and stabilizes the negative charge of reduced flavin. In
      addition to these studies, we have found that HAO is competitively inhibited by
      benzohydroxamate, which is one atom shorter than HYPAH; its affinity is nearly
      100-fold lower than that of the substrate, in contrast to the strong inhibition
      it exerts on mandelate racemase (Maurice, St. M., and Bearne, S. L. (2000)
      Biochemistry39, 13324-13335). In the latter case, the 100-fold higher affinity
      compared to mandelate was proposed to arise from the fact that the hydroxamate
      can mimic the enolic intermediate which lies on the reaction pathway after C2
      proton abstraction. Thus our results do not support the existence of a similar
      enolic intermediate for HAO (and probably its homologues), although they do not
      disprove it.

PMID- 12406702
TI  - Large-scale motions within ribosomal 50S subunits as demonstrated using
      photolabile oligonucleotides.
AB  - Photolabile oligonucleotides (PHONTs) bind to rRNA sequences to which they are
      complementary and, on photolysis, incorporate into neighboring ribosomal
      components. Here we report on photocrosslinking results obtained with PHONTs
      targeting 23S rRNA nucleotides 1882-1892, in the long lateral arm of the 50S
      subunit (PHONT 1892), and 1085-1093, in the L11 binding domain (PHONT 1093).
      Photolysis of the PHONT 1892.50S and PHONT 1093.50S complexes leads to formation
      of 'long-range' crosslinks from C1892 to U1094/A1095 and G1950, and from G1093 to
      U1712/1716 and U1926, that are clearly incompatible with published crystal
      structures of 50S subunits. These results provide strong evidence that within the
      50S subunit (a) the L11 binding domain can extend in an arm-like fashion,
      accessing large areas of the ribosome, and (b) the lateral arm can bend about the
      noncanonical helix at its center. Such motions may have functional relevance in
      identifying regions that undergo major conformational change as the ribosome
      moves through its catalytic cycle.

PMID- 12406703
TI  - Spectroscopic evidence for participation of the 1',4'-imino tautomer of thiamin
      diphosphate in catalysis by yeast pyruvate decarboxylase.
AB  - The 1',4'-iminopyrimidine tautomeric form of the coenzyme thiamin diphosphate
      (ThDP), implicated in catalysis on the basis of the conformation of enzyme-bound
      ThDP, has been observed by both ultraviolet absorption and circular dichroism
      spectroscopy. On yeast pyruvate decarboxylase, the unusual tautomer is observed
      in an active center variant in which catalysis in the post-decarboxylation regime
      of the reaction is compromised. In a model system consisting of N1-methyl-4
      aminopyrimidinium or N1-methyl-N4-n-butylpyrimidinium salts, on treatment with
      either NaOH in water, or DBU in DMSO there is an intermediate formed with
      lambda(max) near 310 nm, and this intermediate reverts back to the starting salt
      on acidification. Proton NMR chemical shifts are consistent with the intermediate
      representing the 1-methyl-4-imino tautomer. On the enzyme, the intermediate could
      be observed by rapid-scan stopped flow with UV detection when reacting holoenzyme
      of the E477Q active center variant with pyruvate, and by circular dichroism even
      in the absence of pyruvate. This represents the first direct observation of the
      imino tautomeric form of ThDP both on the enzyme and in models, although some
      years ago, this laboratory had already reported some pertinent acid-base
      properties for its formation [Jordan, F., and Mariam, Y. H. (1978) J. Am. Chem.
      Soc.100, 2534-2541]. The work also represents the first instance in which a rare
      tautomer implicated in catalysis is identified and suggests that such tautomeric
      catalysis may be more common in biology than hitherto recognized.

PMID- 12406704
TI  - A close-packed planar 4-atom motif serves as a variable-pathway mechanistic
      switching device in enzymatic catalysis.
AB  - We have found a new kind of structural motif that appears to be highly conserved
      among the pyridine nucleotide-linked alpha-amino acid dehydrogenases. This
      feature is comprised of four atoms closely packed in a planar form. Two of the
      atoms are donated by the enzyme, one is provided by the substrate (or reactive
      intermediate), a bound water molecule constitutes the fourth. This tetrad, by
      virtue of its spatial connectivity, constitutes a two-dimensional machine in
      contrast to the one-dimensional charge-relay system commonly observed at enzyme
      active sites. As such, this new motif is capable of more complex behavior
      permitting a wide variety of possible bonding patterns. Modulation of these
      potentially variable patterns can lead to qualitative differences in mechanism
      between structurally similar enzymes, and, in the case of a given enzyme, may
      constitute the core of its catalytic machinery. We offer a conjecture as to how
      such a structure may participate in enzymatic catalysis.

PMID- 12406705
TI  - The application and usefulness of the ratio k(cat)/K(M).
AB  - The ratio of two important constituents in enzyme action, k(cat) and K(M), has
      become of value and provides insight into enzymatic mechanisms and the functional
      effects of enzyme mutations. It is timely to examine how this ratio is used and
      where it can be effectively applied. It has been called on some occasions the
      "specificity constant" and on other occasions, the "performance constant," and it
      is of interest to examine which then is the most accurate and useful way to
      utilize this ratio.

PMID- 12406706
TI  - Multiparametric flow cytometry and cell sorting for the assessment of viable,
      injured, and dead bifidobacterium cells during bile salt stress.
AB  - Using a flow cytometry-based approach, we assessed the viability of
      Bifidobacterium lactis DSM 10140 and Bifidobacterium adolescentis DSM 20083
      during exposure to bile salt stress. Carboxyfluorescein diacetate (cFDA),
      propidium iodide (PI), and oxonol [DiBAC4(3)] were used to monitor esterase
      activity, membrane integrity, and membrane potential, respectively, as indicators
      of bacterial viability. Single staining with these probes rapidly and noticeably
      reflected the behavior of the two strains during stress exposure. However, the
      flow cytometry results tended to overestimate the viability of the two strains
      compared to plate counts, which appeared to be related to the nonculturability of
      a fraction of the population as a result of sublethal injury caused by bile
      salts. When the cells were simultaneously stained with cFDA and PI, flow
      cytometry and cell sorting revealed a striking physiological heterogeneity within
      the stressed bifidobacterium population. Three subpopulations could be identified
      based on their differential uptake of the probes: cF-stained, cF and PI double
      stained, and PI-stained subpopulations, representing viable, injured, and dead
      cells, respectively. Following sorting and recovery, a significant fraction of
      the double-stained subpopulation (40%) could resume growth on agar plates. Our
      results show that in situ assessment of the physiological activity of stressed
      bifidobacteria using multiparameter flow cytometry and cell sorting may provide a
      powerful and sensitive tool for assessment of the viability and stability of
      probiotics.

PMID- 12406707
TI  - A new species of Devosia that forms a unique nitrogen-fixing root-nodule
      symbiosis with the aquatic legume Neptunia natans (L.f.) druce.
AB  - Rhizobia are the common bacterial symbionts that form nitrogen-fixing root
      nodules in legumes. However, recently other bacteria have been shown to nodulate
      and fix nitrogen symbiotically with these plants. Neptunia natans is an aquatic
      legume indigenous to tropical and subtropical regions and in African soils is
      nodulated by Allorhizobium undicola. This legume develops an unusual root-nodule
      symbiosis on floating stems in aquatic environments through a unique infection
      process. Here, we analyzed the low-molecular-weight RNA and 16S ribosomal DNA
      (rDNA) sequence of the same fast-growing isolates from India that were previously
      used to define the developmental morphology of the unique infection process in
      this symbiosis with N. natans and found that they are phylogenetically located in
      the genus Devosia, not Allorhizobium or RHIZOBIUM: The 16S rDNA sequences of
      these two Neptunia-nodulating Devosia strains differ from the only species
      currently described in that genus, Devosia riboflavina. From the same isolated
      colonies, we also located their nodD and nifH genes involved in nodulation and
      nitrogen fixation on a plasmid of approximately 170 kb. Sequence analysis showed
      that their nodD and nifH genes are most closely related to nodD and nifH of
      Rhizobium tropici, suggesting that this newly described Neptunia-nodulating
      Devosia species may have acquired these symbiotic genes by horizontal transfer.

PMID- 12406708
TI  - Membranes of class IIa bacteriocin-resistant Listeria monocytogenes cells contain
      increased levels of desaturated and short-acyl-chain phosphatidylglycerols.
AB  - A major concern in the use of class IIa bacteriocins as food preservatives is the
      well-documented resistance development in target Listeria strains. We studied the
      relationship between leucocin A, a class IIa bacteriocin, and the composition of
      the major phospholipid, phosphatidylglycerol (PG), in membranes of both sensitive
      and resistant L. monocytogenes strains. Two wild-type strains, L. monocytogenes
      B73 and 412, two spontaneous mutants of L. monocytogenes B73 with intermediate
      resistance to leucocin A (+/-2.4 and +/-4 times the 50% inhibitory concentrations
      [IC50] for sensitive strains), and two highly resistant mutants of each of the
      wild-type strains (>500 times the IC50 for sensitive strains) were analyzed.
      Electrospray mass spectrometry analysis showed an increase in the ratios of
      unsaturated to saturated and short- to long-acyl-chain species of PG in all the
      resistant L. monocytogenes strains in our study, although their sensitivities to
      leucocin A were significantly different. This alteration in membrane
      phospholipids toward PGs containing shorter, unsaturated acyl chains suggests
      that resistant strains have cells with a more fluid membrane. The presence of
      this phenomenon in a strain (L. monocytogenes 412P) which is resistant to both
      leucocin A and pediocin PA-1 may indicate a link between membrane composition and
      class IIa bacteriocin resistance in some L. monocytogenes strains. Treatment of
      strains with sterculic acid methyl ester (SME), a desaturase inhibitor, resulted
      in significant changes in the leucocin A sensitivity of the intermediate
      resistance strains but no changes in the sensitivity of highly resistant strains.
      There was, however, a decrease in the amount of unsaturated and short-acyl-chain
      PGs after treatment with SME in one of the intermediate and both of the highly
      resistant strains, but the opposite effect was observed for the sensitive
      strains. It appears, therefore, that membrane adaptation may be part of a
      resistance mechanism but that several resistance mechanisms may contribute to a
      resistance phenotype and that levels of resistance vary according to the type of
      mechanisms present.

PMID- 12406709
TI  - Characterization of the adaptive response to trichloroethylene-mediated stresses
      in Ralstonia pickettii PKO1.
AB  - In Ralstonia pickettii PKO1, a denitrifying toluene oxidizer that carries a
      toluene-3-monooxygenase (T3MO) pathway, the biodegradation of toluene and
      trichloroethylene (TCE) by the organism is induced by TCE at high concentrations.
      In this study, the effect of TCE preexposure was studied in the context of
      bacterial protective response to TCE-mediated toxicity in this organism. The
      results of TCE degradation experiments showed that cells induced by TCE at 110
      mg/liter were more tolerant to TCE-mediated stress than were those induced by TCE
      at lower concentrations, indicating an ability of PKO1 to adapt to TCE-mediated
      stress. To characterize the bacterial protective response to TCE-mediated stress,
      the effect of TCE itself (solvent stress) was isolated from TCE degradation
      dependent stress (toxic intermediate stress) in the subsequent chlorinated
      ethylene toxicity assays with both nondegradable tetrachloroethylene and
      degradable TCE. The results of the toxicity assays showed that TCE preexposure
      led to an increase in tolerance to TCE degradation-dependent stress rather than
      to solvent stress. The possibility that such tolerance was selected by TCE
      degradation-dependent stress during TCE preexposure was ruled out because a
      similar extent of tolerance was observed in cells that were induced by toluene,
      whose metabolism does not produce any toxic products. These findings suggest that
      the adaptation of TCE-induced cells to TCE degradation-dependent stress was
      caused by the combined effects of solvent stress response and T3MO pathway
      expression.

PMID- 12406710
TI  - Utilization of ganglioside-degrading Paenibacillus sp. strain TS12 for production
      of glucosylceramide.
AB  - Gangliosides, sialic acid-containing glycosphingolipids, are membrane
      constituents of vertebrates and are known to have important roles in cellular
      differentiation, adhesion, and recognition. We report here the isolation of a
      bacterium capable of degrading gangliotetraose-series gangliosides and a new
      method for the production of glucosylceramide with this bacterium. GM1a
      ganglioside was found to be sequentially degraded by Paenibacillus sp. strain
      TS12, which was isolated from soil, as follows: GM1a --> asialo GM1 --> asialo
      GM2 --> lactosylceramide --> glucosylceramide. TS12 was found to produce a series
      of ganglioside-degrading enzymes, such as sialidases, beta-galactosidases, and
      beta-hexosaminidases. TS12 also produced beta-glucosidases, but glucosylceramide
      was somewhat resistant to the bacterial enzyme under the conditions used. Taking
      advantage of the specificity, we developed a new method for the production of
      glucosylceramide using TS12 as a biocatalyst. The method involves the conversion
      of crude bovine brain gangliosides to glucosylceramide by coculture with TS12 and
      purification of the product by chromatography with Wakogel C-300 HG.

PMID- 12406711
TI  - Increasing acidification of nonreplicating Lactococcus lactis deltathyA mutants
      by incorporating ATPase activity.
AB  - Lactococcus lactis MBP71 deltathyA (thymidylate synthase) cannot synthesize dTTP
      de novo, and DNA replication is dependent on thymidine in the growth medium. In
      the nonreplicating state acidification by MBP71 was completely insensitive to
      bacteriophages (M. B. Pedersen, P. R. Jensen, T. Janzen, and D. Nilsson, Appl.
      Environ. Microbiol. 68:3010-3023, 2002). For nonreplicating MBP71 the biomass
      increased 3.3-fold over the first 3.5 h, and then the increase stopped. The rate
      of acidification increased 2.3-fold and then started to decrease. Shortly after
      inoculation the lactic acid flux was 60% of that of exponentially growing MBP71.
      However, when nonspecific ATPase activity was incorporated into MBP71, the lactic
      acid flux was restored to 100% but not above that point, indicating that control
      over the flux switched from ATP demand to ATP supply (i.e., to sugar transport
      and glycolysis). As determined by growing nonreplicating cells with high ATPase
      activity on various sugar sources, it appeared that glycolysis exerted the
      majority of the control. ATPase activity also stimulated the rate of
      acidification by nonreplicating MBP71 growing in milk, and pH 5.2 was reached 40%
      faster than it was without ATPase activity. We concluded that ATPase activity is
      a functional means of increasing acidification by nonreplicating L. lactis.

PMID- 12406712
TI  - Postadaptational resistance to benzalkonium chloride and subsequent
      physicochemical modifications of Listeria monocytogenes.
AB  - Many studies have demonstrated that bacteria, including Listeria monocytogenes,
      are capable of adapting to disinfectants used in industrial settings after
      prolonged exposure to sublethal concentrations. However, the consequent
      alterations of the cell surface due to sanitizer adaptation of this pathogen are
      not fully understood. Two resistant and four sensitive L. monocytogenes strains
      from different sources were progressively subcultured with increasing sublethal
      concentrations of a surfactant, benzalkonium chloride (BC). To evaluate the
      effects of acquired tolerance to BC, parent and adapted strains were compared by
      using several morphological and physiological tests. Sensitive strains showed at
      least a fivefold increase in the MIC, while the MIC doubled for resistant strains
      after the adaptation period. The hydrophobicities of cells of parent and adapted
      strains were similar. Serological testing indicated that antigen types 1 and 4
      were both present on the cell surface of adapted cells. The data suggest that
      efflux pumps are the major mechanism of adaptation in sensitive strains and are
      less important in originally resistant isolates. A different, unknown mechanism
      was responsible for the original tolerance of resistant isolates. In an
      originally resistant strain, there was a slight shift in the fatty acid profile
      after adaptation, whereas sensitive strains had similar profiles. Electron
      micrographs revealed morphological differences after adaptation. The changes in
      cell surface antigens, efflux pump utilization, and fatty acid profiles suggest
      that different mechanisms are used by resistant and sensitive strains for
      adaptation to BC.

PMID- 12406713
TI  - Improved system for protein engineering of the hydroxylase component of soluble
      methane monooxygenase.
AB  - Soluble methane monooxygenase (sMMO) of Methylosinus trichosporium OB3b is a
      three-component oxygenase that catalyses the O(2)- and NAD(P)H-dependent
      oxygenation of methane and numerous other substrates. Despite substantial
      interest in the use of genetic techniques to study the mechanism of sMMO and
      manipulate its substrate specificity, directed mutagenesis of active-site
      residues was previously impossible because no suitable heterologous expression
      system had been found for expression in a highly active form of the hydroxylase
      component, which is an (alphabetagamma)(2) complex containing the binuclear iron
      active site. A homologous expression system that enabled the expression of
      recombinant wild-type sMMO in a derivative of M. trichosporium OB3b from which
      the chromosomal copy of the sMMO-encoding operon had been partially deleted was
      previously reported. Here we report substantial development of this method to
      produce a system for the facile construction and expression of mutants of the
      hydroxylase component of sMMO. This new system has been used to investigate the
      functions of Cys 151 and Thr 213 of the alpha subunit, which are the only
      nonligating protonated side chains in the hydrophobic active site. Both residues
      were found to be critical for the stability and/or activity of sMMO, but neither
      was essential for oxygenation reactions. The T213S mutant was purified to >98%
      homogeneity. It had the same iron content as the wild type and had 72% wild-type
      activity toward toluene but only 17% wild-type activity toward propene; thus, its
      substrate profile was significantly altered. With these results, we have
      demonstrated proof of the principle for protein engineering of this uniquely
      versatile enzyme.

PMID- 12406714
TI  - Mode of action of the antimicrobial peptide aureocin A53 from Staphylococcus
      aureus.
AB  - We investigated the mode of action of aureocin A53 on living bacterial cells and
      model membranes. Aureocin A53 acted bactericidally against Staphylococcus
      simulans 22, with >90% of the cells killed within a few minutes. Cell death was
      followed by lysis, as indicated by a clearing of the cell suspension and Gram
      staining. Aureocin A53 rapidly dissipated the membrane potential and
      simultaneously stopped biosynthesis of DNA, polysaccharides, and protein.
      Aureocin A53 induced a rapid release of preaccumulated glutamate and Rb(+).
      Experiments on model membranes demonstrated that aureocin A53 provoked
      significant leakage of carboxyfluorescein (CF) exclusively from acidic liposomes
      but only at relatively high concentrations (0.5 to 8 mol%). Thus, the
      bactericidal activity of aureocin A53 derives from membrane permeation via
      generalized membrane destruction rather than by formation of discrete pores
      within membranes. Tryptophan emission fluorescence spectroscopy demonstrated
      interaction of aureocin A53 with both acidic and neutral membranes, as indicated
      by similar blue shifts. Since there was no significant aureocin A53-induced CF
      leakage from neutral liposomes, its appears that the peptide does interact with
      neutral lipids without provoking membrane damage.

PMID- 12406715
TI  - Strain variation in Mycobacterium marinum fish isolates.
AB  - A molecular characterization of two Mycobacterium marinum genes, 16S rRNA and
      hsp65, was carried out with a total of 21 isolates from various species of fish
      from both marine and freshwater environments of Israel, Europe, and the Far East.
      The nucleotide sequences of both genes revealed that all M. marinum isolates from
      fish in Israel belonged to two different strains, one infecting marine (cultured
      and wild) fish and the other infecting freshwater (cultured) fish. A restriction
      enzyme map based on the nucleotide sequences of both genes confirmed the
      divergence of the Israeli marine isolates from the freshwater isolates and
      differentiated the Israeli isolates from the foreign isolates, with the exception
      of one of three Greek isolates from marine fish which was identical to the
      Israeli marine isolates. The second isolate from Greece exhibited a single base
      alteration in the 16S rRNA sequence, whereas the third isolate was most likely a
      new Mycobacterium species. Isolates from Denmark and Thailand shared high
      sequence homology to complete identity with reference strain ATCC 927. Combined
      analysis of the two gene sequences increased the detection of intraspecific
      variations and was thus of importance in studying the taxonomy and epidemiology
      of this aquatic pathogen. Whether the Israeli M. marinum strain infecting marine
      fish is endemic to the Red Sea and found extremely susceptible hosts in the
      exotic species imported for aquaculture or rather was accidentally introduced
      with occasional imports of fingerlings from the Mediterranean Sea could not be
      determined.

PMID- 12406716
TI  - Rapid isolation of a single-chain antibody against the cyanobacterial toxin
      microcystin-LR by phage display and its use in the immunoaffinity concentration
      of microcystins from water.
AB  - A naive (unimmunized) human semisynthetic phage display library was employed to
      isolate recombinant antibody fragments against the cyanobacterial hepatotoxin
      microcystin-LR. Selected antibody scFv genes were cloned into a soluble
      expression vector and expressed in Escherichia coli for characterization against
      purified microcystin-LR by competition enzyme-linked immunosorbent assay (ELISA).
      The most sensitive single-chain antibody (scAb) isolated was capable of detecting
      microcystin-LR at levels below the World Health Organization limit in drinking
      water (1 microg liter(-1)) and cross-reacted with three other purified
      microcystin variants (microcystin-RR, -LW, and -LF) and the related cyanotoxin
      nodularin. Extracts of the cyanobacterium Microcystis aeruginosa were assayed by
      ELISA, and quantifications of microcystins in toxic samples showed good
      correlation with analysis by high-performance liquid chromatography. Immobilized
      scAb was also used to prepare immunoaffinity columns, which were assessed for the
      ability to concentrate microcystin-LR from water for subsequent analysis by high
      performance liquid chromatography. Anti-microcystin-LR scAb was immobilized on
      columns via a hexahistidine tag, ensuring maximum exposure of antigen binding
      sites, and the performance of the columns was evaluated by directly applying 150
      ml of distilled water spiked with 4 micro g of purified microcystin-LR. The
      procedure was simple, and a recovery rate of 94% was achieved following elution
      in 1 ml of 100% methanol. Large-scale, low-cost production of anti-microcystin-LR
      scAb in E. coli is an exciting prospect for the development of biosensors and on
      line monitoring systems for microcystins and will also facilitate a range of
      immunoaffinity applications for the cleanup and concentration of these toxins
      from environmental samples.

PMID- 12406717
TI  - Diversity of Aphanizomenon flos-aquae (cyanobacterium) populations along a Baltic
      Sea salinity gradient.
AB  - Colony-forming cyanobacteria of the genus Aphanizomenon form massive blooms in
      the brackish water of the Baltic Sea during the warmest summer months. There have
      been recent suggestions claiming that the Baltic Sea Aphanizomenon species may be
      different from Aphanizomenon flos-aquae found in lakes. In this study, we
      examined variability in the morphology and 16S-23S rRNA internal transcribed
      spacer (ITS) sequences of A. flos-aquae populations along a salinity gradient
      from a string of lakes to a fjord-like extension of the Baltic Sea to the open
      Baltic Sea. Morphological differences among the populations were negligible. We
      found that the Baltic Sea was dominated (25 out of 27 sequences) by one ITS1-S
      (shorter band of ITS 1 [ITS1]) genotype, which also was found in the lakes. The
      lake populations of A. flos-aquae tended to be genetically more diverse than the
      Baltic Sea populations. Since the lake ITS1-S genotypes of A. flos-aquae are
      continuously introduced to the Baltic Sea via inflowing waters, it seems that
      only one ITS1 genotype is able to persist in the Baltic Sea populations. The
      results suggest that one of the ITS1-S genotypes found in the lakes is better
      adapted to the conditions of the Baltic Sea and that natural selection removes
      most of the lake genotypes from the Baltic Sea A. flos-aquae populations.

PMID- 12406718
TI  - Isolation and functional analysis of a gene, tcsB, encoding a transmembrane
      hybrid-type histidine kinase from Aspergillus nidulans.
AB  - We cloned and characterized a novel Aspergillus nidulans histidine kinase gene,
      tcsB, encoding a membrane-type two-component signaling protein homologous to the
      yeast osmosensor synthetic lethal N-end rule protein 1 (SLN1), which transmits
      signals through the high-osmolarity glycerol response 1 (HOG1) mitogen-activated
      protein kinase (MAPK) cascade in yeast cells in response to environmental osmotic
      stimuli. From an A. nidulans cDNA library, we isolated a positive clone
      containing a 3,210-bp open reading frame that encoded a putative protein
      consisting of 1,070 amino acids. The predicted tcsB protein (TcsB) has two
      probable transmembrane regions in its N-terminal half and has a high degree of
      structural similarity to yeast Sln1p, a transmembrane hybrid-type histidine
      kinase. Overexpression of the tcsB cDNA suppressed the lethality of a temperature
      sensitive osmosensing-defective sln1-ts yeast mutant. However, tcsB cDNAs in
      which the conserved phosphorylation site His(552) residue or the phosphorelay
      site Asp(989) residue had been replaced failed to complement the sln1-ts mutant.
      In addition, introduction of the tcsB cDNA into an sln1delta sho1delta yeast
      double mutant, which lacked two osmosensors, suppressed lethality in high
      salinity media and activated the HOG1 MAPK. These results imply that TcsB
      functions as an osmosensor histidine kinase. We constructed an A. nidulans strain
      lacking the tcsB gene (tcsBdelta) and examined its phenotype. However,
      unexpectedly, the tcsBdelta strain did not exhibit a detectable phenotype for
      either hyphal development or morphology on standard or stress media. Our results
      suggest that A. nidulans has more complex and robust osmoregulatory systems than
      the yeast SLN1-HOG1 MAPK cascade.

PMID- 12406719
TI  - The murein hydrolase of the bacteriophage phi3626 dual lysis system is active
      against all tested Clostridium perfringens strains.
AB  - Clostridium perfringens commonly occurs in food and feed, can produce an
      enterotoxin frequently implicated in food-borne disease, and has a substantial
      negative impact on the poultry industry. As a step towards new approaches for
      control of this organism, we investigated the cell wall lysis system of C.
      perfringens bacteriophage phi3626, whose dual lysis gene cassette consists of a
      holin gene and an endolysin gene. Hol3626 has two membrane-spanning domains
      (MSDs) and is a group II holin. A positively charged beta turn between the two
      MSDs suggests that both the amino terminus and the carboxy terminus of Hol3626
      might be located outside the cell membrane, a very unusual holin topology. Holin
      function was experimentally demonstrated by using the ability of the holin to
      complement a deletion of the heterologous phage lambda S holin in
      lambdadeltaSthf. The endolysin gene ply3626 was cloned in Escherichia coli.
      However, protein synthesis occurred only when bacteria were supplemented with
      rare tRNA(Arg) and tRNA(Ile) genes. Formation of inclusion bodies could be
      avoided by drastically lowering the expression level. Amino-terminal modification
      by a six-histidine tag did not affect enzyme activity and enabled purification by
      metal chelate affinity chromatography. Ply3626 has an N-terminal amidase domain
      and a unique C-terminal portion, which might be responsible for the specific
      lytic range of the enzyme. All 48 tested strains of C. perfringens were sensitive
      to the murein hydrolase, whereas other clostridia and bacteria belonging to other
      genera were generally not affected. This highly specific activity towards C.
      perfringens might be useful for novel biocontrol measures in food, feed, and
      complex microbial communities.

PMID- 12406720
TI  - Occurrence of mycobacteria in water treatment lines and in water distribution
      systems.
AB  - The frequency of recovery of atypical mycobacteria was estimated in two treatment
      plants providing drinking water to Paris, France, at some intermediate stages of
      treatment. The two plants use two different filtration processes, rapid and slow
      sand filtration. Our results suggest that slow sand filtration is more efficient
      for removing mycobacteria than rapid sand filtration. In addition, our results
      show that mycobacteria can colonize and grow on granular activated carbon and are
      able to enter distribution systems. We also investigated the frequency of
      recovery of mycobacteria in the water distribution system of Paris (outside
      buildings). The mycobacterial species isolated from the Paris drinking water
      distribution system are different from those isolated from the water leaving the
      treatment plants. Saprophytic mycobacteria (present in 41.3% of positive
      samples), potentially pathogenic mycobacteria (16.3%), and unidentifiable
      mycobacteria (54.8%) were isolated from 12 sites within the Paris water
      distribution system. Mycobacterium gordonae was preferentially recovered from
      treated surface water, whereas Mycobacterium nonchromogenicum was preferentially
      recovered from groundwater. No significant correlations were found among the
      presence of mycobacteria, the origin of water, and water temperature.

PMID- 12406721
TI  - Molecular analysis of maltotriose transport and utilization by Saccharomyces
      cerevisiae.
AB  - Efficient fermentation of maltotriose is a desired property of Saccharomyces
      cerevisiae for brewing. In a standard wort, maltotriose is the second most
      abundant sugar, and slower uptake leads to residual maltotriose in the finished
      product. The limiting factor of sugar metabolism is its transport, and there are
      conflicting reports on whether a specific maltotriose permease exists or whether
      the mechanisms responsible for maltose uptake also carry out maltotriose
      transport. In this study, radiolabeled maltotriose was used to show that
      overexpression of the maltose permease gene, MAL61, in an industrial yeast strain
      resulted in an increase in the rate of transport of maltotriose as well as
      maltose. A strain derived from W303-1A and lacking any maltose or maltotriose
      transporter but carrying a functional maltose transport activator (MAL63) was
      developed. By complementing this strain with permeases encoded by MAL31, MAL61,
      and AGT1, it was possible to measure their specific transport kinetics by using
      maltotriose and maltose. All three permeases were capable of high-affinity
      transport of maltotriose and of allowing growth of the strain on the sugar.
      Maltotriose utilization from the permease encoded by AGT1 was regulated by the
      same genetic mechanisms as those involving the maltose transcriptional activator.
      Competition studies carried out with two industrial strains, one not containing
      any homologue of AGT1, showed that maltose uptake and maltotriose uptake were
      competitive and that maltose was the preferred substrate. These results indicate
      that the presence of residual maltotriose in beer is not due to a genetic or
      physiological inability of yeast cells to utilize the sugar but rather to the
      lower affinity for maltotriose uptake in conjunction with deteriorating
      conditions present at the later stages of fermentation. Here we identify
      molecular mechanisms regulating the uptake of maltotriose and determine the role
      of each of the transporter genes in the cells.

PMID- 12406722
TI  - Biodegradation of hexahydro-1,3,5-trinitro-1,3,5-triazine and its mononitroso
      derivative hexahydro-1-nitroso-3,5-dinitro-1,3,5-triazine by Klebsiella
      pneumoniae strain SCZ-1 isolated from an anaerobic sludge.
AB  - In previous work, we found that an anaerobic sludge efficiently degraded
      hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX), but the role of isolates in the
      degradation process was unknown. Recently, we isolated a facultatively anaerobic
      bacterium, identified as Klebsiella pneumoniae strain SCZ-1, using MIDI and the
      16S rRNA method from this sludge and employed it to degrade RDX. Strain SCZ-1
      degraded RDX to formaldehyde (HCHO), methanol (CH3OH) (12% of total C), carbon
      dioxide (CO(2)) (72% of total C), and nitrous oxide (N2O) (60% of total N)
      through intermediary formation of methylenedinitramine (O(2)NNHCH(2)NHNO(2)).
      Likewise, hexahydro-1-nitroso-3,5-dinitro-1,3,5-triazine (MNX) was degraded to
      HCHO, CH3OH, and N2O (16.5%) with a removal rate (0.39 micromol. h(-1). g [dry
      weight] of cells(-1)) similar to that of RDX (0.41 micromol. h(-1). g [dry
      weight] of cells(-1)) (biomass, 0.91 g [dry weight] of cells. liter(-1)). These
      findings suggested the possible involvement of a common initial reaction,
      possibly denitration, followed by ring cleavage and decomposition in water. The
      trace amounts of MNX detected during RDX degradation and the trace amounts of
      hexahydro-1,3-dinitroso-5-nitro-1,3,5-triazine detected during MNX degradation
      suggested that another minor degradation pathway was also present that reduced 
      NO2 groups to the corresponding -NO groups.

PMID- 12406723
TI  - Ethylene production by Botrytis cinerea in vitro and in tomatoes.
AB  - A laser-based ethylene detector was used for on-line monitoring of ethylene
      released by the phytopathogenic fungus Botrytis cinerea in vitro and in tomato
      fruit. Ethylene data were combined with the results of a cytological analysis of
      germination of B. cinerea conidia and hyphal growth. We found that
      aminoethoxyvinylglycine and aminooxyacetic acid, which are competitive inhibitors
      of the 1-aminocyclopropane-1-carboxylic acid pathway, did not inhibit the
      ethylene emission by B. cinerea and that the fungus most likely produces ethylene
      via the 2-keto-4-methylthiobutyric acid pathway. B. cinerea is able to produce
      ethylene in vitro, and the emission of ethylene follows the pattern that is
      associated with hyphal growth rather than the germination of conidia. Ethylene
      production in vitro depended on the L-methionine concentration added to the
      plating medium. Higher values and higher emission rates were observed when the
      concentration of conidia was increased. Compared with the ethylene released by
      the fungus, the infection-related ethylene produced by two tomato cultivars
      (cultivars Money Maker and Daniela) followed a similar pattern, but the levels of
      emission were 100-fold higher. The time evolution of enhanced ethylene production
      by the infected tomatoes and the cytological observations indicate that ethylene
      emission by the tomato-fungus system is not triggered by the ethylene produced by
      B. cinerea, although it is strongly synchronized with the growth rate of the
      fungus inside the tomato.

PMID- 12406724
TI  - Anaerobic ammonia oxidation in the presence of nitrogen oxides (NO(x)) by two
      different lithotrophs.
AB  - The anaerobic ammonia-oxidizing activity of the planctomycete Candidatus
      "Brocadia anammoxidans" was not inhibited by NO concentrations up to 600 ppm and
      NO2 concentrations up to 100 ppm. B. anammoxidans was able to convert (detoxify)
      NO, which might explain the high NO tolerance of this organism. In the presence
      of NO2, the specific ammonia oxidation activity of B. anammoxidans increased, and
      Nitrosomonas-like microorganisms recovered an NO2-dependent anaerobic ammonia
      oxidation activity. Addition of NO2 to a mixed population of B. anammoxidans and
      Nitrosomonas induced simultaneous specific anaerobic ammonia oxidation activities
      of up to 5.5 mmol of NH4+ g of protein(-1) h(-1) by B. anammoxidans and up to 1.5
      mmol of NH4+ g of protein(-1) h(-1) by Nitrosomonas. The stoichiometry of the
      converted N compounds (NO2-/NH3 ratio) and the microbial community structure were
      strongly influenced by NO2. The combined activity of B. anammoxidans and
      Nitrosomonas-like ammonia oxidizers might be of relevance in natural environments
      and for technical applications.

PMID- 12406725
TI  - Differentiation of closely related Carnobacterium food isolates based on 16S-23S
      ribosomal DNA intergenic spacer region polymorphism.
AB  - A novel strategy for identification of Carnobacterium food isolates based on
      restriction fragment length polymorphism (RFLP) of PCR-amplified 16S-23S
      ribosomal intergenic spacer regions (ISRs) was developed. PCR amplification from
      all Carnobacterium strains studied always yielded three ISR amplicons, which were
      designated the small ISR (S-ISR), the medium ISR (M-ISR), and the large ISR (L
      ISR). The lengths of these ISRs varied from one species to another.
      Carnobacterium divergens NCDO 2763(T) and C. mobile DSM 4849(T) generated one
      major S-ISR band (ca. 400 bp) and minor M-ISR and L-ISR bands (ca. 500 and ca.
      600 bp, respectively). The ISRs amplified from C. gallinarum NCFB 2766(T) and C.
      piscicola NCDO 2762(T) were larger (S-ISR, ca. 600 bp; M-ISR, ca. 700 bp; and L
      ISR, ca. 800 bp). The L-ISR contained two tDNAs coding for tRNA(Ile) and
      tRNA(Ala) genes. The M-ISR included one tRNA(Ala) gene, and the S-ISR did not
      contain a tDNA gene. The RFLP scheme devised involves estimation of variable PCR
      product sizes together with HinfI, TaqI, and HindIII restriction analysis. Forty
      two isolates yielded four unique band patterns that correctly resolved these
      isolates into four Carnobacterium species. This method is very suitable for
      rapid, low-cost identification of a wide variety of Carnobacterium species
      without sequencing.

PMID- 12406727
TI  - Membrane-bound ATPase contributes to hop resistance of Lactobacillus brevis.
AB  - The activity of the membrane-bound H+-ATPase of the beer spoilage bacterium
      Lactobacillus brevis ABBC45 increased upon adaptation to bacteriostatic hop
      compounds. The ATPase activity was optimal around pH 5.6 and increased up to
      fourfold when L. brevis was exposed to 666 microM hop compounds. The extent of
      activation depended on the concentration of hop compounds and was maximal at the
      highest concentration tested. The ATPase activity was strongly inhibited by N,N'
      dicyclohexylcarbodiimide, a known inhibitor of FoF1-ATPase. Western blots of
      membrane proteins of L. brevis with antisera raised against the alpha- and beta
      subunits of FoF1-ATPase from Enterococcus hirae showed that there was increased
      expression of the ATPase after hop adaptation. The expression levels, as well as
      the ATPase activity, decreased to the initial nonadapted levels when the hop
      adapted cells were cultured further without hop compounds. These observations
      strongly indicate that proton pumping by the membrane-bound ATPase contributes
      considerably to the resistance of L. brevis to hop compounds.

PMID- 12406726
TI  - RNA stable isotope probing, a novel means of linking microbial community function
      to phylogeny.
AB  - Identifying microorganisms responsible for recognized environmental processes
      remains a great challenge in contemporary microbial ecology. Only in the last few
      years have methodological innovations provided access to the relationship between
      the function of a microbial community and the phylogeny of the organisms
      accountable for it. In this study stable-isotope-labeled [13C]phenol was fed into
      a phenol-degrading community from an aerobic industrial bioreactor, and the 13C
      labeled RNA produced was used to identify the bacteria responsible for the
      process. Stable-isotope-labeled RNA was analyzed by equilibrium density
      centrifugation in concert with reverse transcription-PCR and denaturing gradient
      gel electrophoresis. In contradiction with findings from conventional
      methodologies, this unique approach revealed that phenol degradation in the
      microbial community under investigation is dominated by a member of the Thauera
      genus. Our results suggest that this organism is important for the function of
      this bioreactor.

PMID- 12406728
TI  - Evaluation of the heat inactivation of Escherichia coli and Lactobacillus
      plantarum by differential scanning calorimetry.
AB  - Differential scanning calorimetry (DSC) is used to evaluate the thermal stability
      and reversibility after heat treatment of transitions associated with various
      cellular components of Escherichia coli and Lactobacillus plantarum. The
      reversibility and the change in the thermal stability of individual transitions
      are evaluated by a second temperature scan after preheating in the DSC to various
      temperatures between 40 and 130 degrees C. The viability of bacteria after a heat
      treatment between 55 and 70 degrees C in the DSC is determined by both plate
      count and calorimetric data. The fractional viability values based on
      calorimetric and plate count data show a linear relationship. Viability loss and
      the irreversible change in DSC thermograms of pretreated whole cells are highly
      correlated between 55 and 70 degrees C. Comparison of DSC scans for isolated
      ribosomes shows that the thermal stability of E. coli ribosomes is greater than
      that of L. plantarum ribosomes, consistent with the greater thermal tolerance of
      E. coli observed from viability loss and DSC scans of whole cells.

PMID- 12406729
TI  - Efficacy of UV irradiation in inactivating Cryptosporidium parvum oocysts.
AB  - To evaluate the effectiveness of UV irradiation in inactivating Cryptosporidium
      parvum oocysts, the animal infectivities and excystation abilities of oocysts
      that had been exposed to various UV doses were determined. Infectivity decreased
      exponentially as the UV dose increased, and the required dose for a 2-log(10)
      reduction in infectivity (99% inactivation) was approximately 1.0 mWs/cm(2) at 20
      degrees C. However, C. parvum oocysts exhibited high resistance to UV
      irradiation, requiring an extremely high dose of 230 mWs/cm(2) for a 2-log(10)
      reduction in excystation, which was used to assess viability. Moreover, the
      excystation ability exhibited only slight decreases at UV doses below 100
      mWs/cm(2). Thus, UV treatment resulted in oocysts that were able to excyst but
      not infect. The effects of temperature and UV intensity on the UV dose
      requirement were also studied. The results showed that for every 10 degrees C
      reduction in water temperature, the increase in the UV irradiation dose required
      for a 2-log(10) reduction in infectivity was only 7%, and for every 10-fold
      increase in intensity, the dose increase was only 8%. In addition, the potential
      of oocysts to recover infectivity and to repair UV-induced injury (pyrimidine
      dimers) in DNA by photoreactivation and dark repair was investigated. There was
      no recovery in infectivity following treatment by fluorescent-light irradiation
      or storage in darkness. In contrast, UV-induced pyrimidine dimers in the DNA were
      apparently repaired by both photoreactivation and dark repair, as determined by
      endonuclease-sensitive site assay. However, the recovery rate was different in
      each process. Given these results, the effects of UV irradiation on C. parvum
      oocysts as determined by animal infectivity can conclusively be considered
      irreversible.

PMID- 12406730
TI  - Characterization of the rRNA locus of Pfiesteria piscicida and development of
      standard and quantitative PCR-based detection assays targeted to the
      nontranscribed spacer.
AB  - Pfiesteria piscicida is a heterotrophic dinoflagellate widely distributed along
      the middle Atlantic shore of the United States and associated with fish kills in
      the Neuse River (North Carolina) and the Chesapeake Bay (Maryland and Virginia).
      We constructed a genomic DNA library from clonally cultured P. piscicida and
      characterized the nontranscribed spacer (NTS), small subunit, internal
      transcribed spacer 1 (ITS1), 5.8S region, ITS2, and large subunit of the rRNA
      gene cluster. Based on the P. piscicida ribosomal DNA sequence, we developed a
      PCR-based detection assay that targets the NTS. The assay specificity was
      assessed by testing clonal P. piscicida and Pfiesteria shumwayae, 35 additional
      dinoflagellate species, and algal prey (Rhodomonas sp.). Only P. piscicida and
      nine presumptive P. piscicida isolates tested positive. All PCR-positive products
      yielded identical sequences for P. piscicida, suggesting that the PCR-based assay
      is species specific. The assay can detect a single P. piscicida zoospore in 1 ml
      of water, 10 resting cysts in 1 g of sediment, or 10 fg of P. piscicida DNA in 1
      micro g of heterologous DNA. An internal standard for the PCR assay was
      constructed to identify potential false-negative results in testing of
      environmental sediment and water samples and as a competitor for the development
      of a quantitative competitive PCR assay format. The specificities of both
      qualitative and quantitative PCR assay formats were validated with >200
      environmental samples, and the assays provide simple, rapid, and accurate methods
      for the assessment of P. piscicida in water and sediments.

PMID- 12406731
TI  - Low-Shear modeled microgravity alters the Salmonella enterica serovar typhimurium
      stress response in an RpoS-independent manner.
AB  - We have previously demonstrated that low-shear modeled microgravity (low-shear
      MMG) serves to enhance the virulence of a bacterial pathogen, Salmonella enterica
      serovar Typhimurium. The Salmonella response to low-shear MMG involves a
      signaling pathway that we have termed the low-shear MMG stimulon, though the
      identities of the low-shear MMG stimulon genes and regulatory factors are not
      known. RpoS is the primary sigma factor required for the expression of genes that
      are induced upon exposure to different environmental-stress signals and is
      essential for virulence in mice. Since low-shear MMG induces a Salmonella acid
      stress response and enhances Salmonella virulence, we reasoned that RpoS would be
      a likely regulator of the Salmonella low-shear MMG response. Our results
      demonstrate that low-shear MMG provides cross-resistance to several environmental
      stresses in both wild-type and isogenic rpoS mutant strains. Growth under low
      shear MMG decreased the generation time of both strains in minimal medium and
      increased the ability of both strains to survive in J774 macrophages. Using DNA
      microarray analysis, we found no evidence of induction of the RpoS regulon by low
      shear MMG but did find that other genes were altered in expression under these
      conditions in both the wild-type and rpoS mutant strains. Our results indicate
      that, under the conditions of these studies, RpoS is not required for
      transmission of the signal that induces the low-shear MMG stimulon. Moreover, our
      studies also indicate that low-shear MMG can be added to a short list of growth
      conditions that can serve to preadapt an rpoS mutant for resistance to multiple
      environmental stresses.

PMID- 12406732
TI  - Pine oil cleaner-resistant Staphylococcus aureus: reduced susceptibility to
      vancomycin and oxacillin and involvement of SigB.
AB  - Mutants of Staphylococcus aureus strain COL resistant to a household pine oil
      cleaner (POC) were isolated on laboratory media containing POC. S. aureus mutants
      expressing the POC resistance (POC(r)) phenotype also demonstrate reduced
      susceptibility to the cell wall-active antibiotics vancomycin and oxacillin. The
      POC(r) phenotype is reliant on the S. aureus alternative transcription factor
      SigB, since inactivation of sigB abolished expression of elevated POC resistance
      and the reductions in vancomycin and oxacillin susceptibilities. The isolation of
      suppressor mutants of COLsigB::kan, which maintain the sigB::kan allele,
      indicates that the POC(r) phenotype can also be expressed to a lesser degree via
      a sigB-independent mechanism. These results bolster a growing body of reports
      suggesting that common disinfectants can select for bacteria with reduced
      susceptibilities to antibiotics. A series of in vitro-selected glycopeptide
      intermediate S. aureus (GISA) isolates also expressed reductions in POC
      susceptibility compared to parent strains. Viewed collectively, our evidence
      suggests that mutations leading to the POC(r) phenotype may also be involved with
      the mechanism that leads to the GISA phenotype.

PMID- 12406733
TI  - Effect of pyruvate carboxylase overexpression on the physiology of
      Corynebacterium glutamicum.
AB  - Pyruvate carboxylase was recently sequenced in Corynebacterium glutamicum and
      shown to play an important role of anaplerosis in the central carbon metabolism
      and amino acid synthesis of these bacteria. In this study we investigate the
      effect of the overexpression of the gene for pyruvate carboxylase (pyc) on the
      physiology of C. glutamicum ATCC 21253 and ATCC 21799 grown on defined media with
      two different carbon sources, glucose and lactate. In general, the physiological
      effects of pyc overexpression in Corynebacteria depend on the genetic background
      of the particular strain studied and are determined to a large extent by the
      interplay between pyruvate carboxylase and aspartate kinase activities. If the
      pyruvate carboxylase activity is not properly matched by the aspartate kinase
      activity, pyc overexpression results in growth enhancement instead of greater
      lysine production, despite its central role in anaplerosis and aspartic acid
      biosynthesis. Aspartate kinase regulation by lysine and threonine, pyruvate
      carboxylase inhibition by aspartate (shown in this study using permeabilized
      cells), as well as well-established activation of pyruvate carboxylase by lactate
      and acetyl coenzyme A are the key factors in determining the effect of pyc
      overexpression on Corynebacteria physiology.

PMID- 12406734
TI  - Food-grade delivery system for controlled gene expression in Lactococcus lactis.
AB  - A food-grade system for the delivery of desired genes to Lactococcus lactis,
      their inducible expression, and their transfer to related strains was
      established. Based on the thermosensitive pG(+)host replicon, two types of
      plasmid vectors were constructed which contained sections of either the
      chromosomal leu operon of L. lactis or the tel operon from the lactococcal sex
      factor. Genes cloned into the leu or tel sequences of these vectors were
      delivered to the homologous regions of the chromosome or the sex factor through
      two single crossovers, leading to integration of the recombinant plasmids and
      subsequent excision of the vector portions. Inducible transcription of integrated
      genes was achieved by using the nisin-controlled expression (NICE) system. To
      establish the signal transduction genes nisRK in L. lactis, the vectors pLNG1363
      (targeted to the chromosome) and pUK500 (targeted to the sex factor) were
      constructed. Fusions of six different peptidase genes (pep) from Lactobacillus
      delbrueckii with the nisin-inducible promoter P(nisA) were delivered to the sex
      factor with derivatives of the vector pUK300. Food-grade recombinants of L.
      lactis were constructed which had the nisRK genes and individual P(nisA)::pep
      fusions integrated either separately into the chromosome and the sex factor or
      simultaneously into the sex factor. With both types of recombinants, expression
      of P(nisA)::pep fusions after induction with nisin was demonstrated. Depending on
      the loci used for integration of nisRK, variable induction rates were observed.
      Furthermore, an engineered sex factor carrying a P(nisA)::pepI fusion was
      transfered by conjugation between two strains of L. lactis at a frequency of 4 x
      10(-4).

PMID- 12406735
TI  - SED1 gene length and sequence polymorphisms in feral strains of Saccharomyces
      cerevisiae.
AB  - The SED1 gene (YDR077W), coding for the major cell wall glycoprotein of
      Saccharomyces cerevisiae stationary-phase cells, contains two blocks of tandem
      repeat units located within two distinct regions of the nucleotide sequence. A
      PCR survey of the SED1 open reading frames (ORFs) of 186 previously
      uncharacterized grape must isolates of S. cerevisiae yielded 13 PCR profiles
      arising from different combinations of seven SED1 length variants in individuals
      homozygous or heterozygous for the gene. Comparison of the nucleotide sequences
      of a group of representatives of each of the seven length variants with those of
      S288C and the type strain, CBS1171, unequivocally identified them as SED1 alleles
      and provided evidence for the presence of two minisatellite-like sequences,
      variable in length, within the ORF of an S. cerevisiae gene. The segregation
      analyses of the SED1 length variants and other genetic markers in 13 isolates
      representative of each PCR profile suggested that molecular mechanisms involved
      in minisatellite expansion and contraction may be responsible for SED1
      heterozygosities within a population of homothallic must isolates of S.
      cerevisiae.

PMID- 12406736
TI  - Development of 16S rRNA-gene-targeted group-specific primers for the detection
      and identification of predominant bacteria in human feces.
AB  - For the detection and identification of predominant bacteria in human feces, 16S
      rRNA-gene-targeted group-specific primers for the Bacteroides fragilis group,
      Bifidobacterium, the Clostridium coccoides group, and Prevotella were designed
      and evaluated. The specificity of these primers was confirmed by using DNA
      extracted from 90 species that are commonly found in the human intestinal
      microflora. The group-specific primers were then used for identification of 300
      isolates from feces of six healthy volunteers. The isolates were clearly
      identified as 117 isolates of the B. fragilis group, 22 isolates of
      Bifidobacterium, 65 isolates of the C. coccoides group, and 17 isolates of
      Prevotella, indicating that 74% of the isolates were identified with the four
      pairs of primers. The remaining 79 isolates were identified by 16S ribosomal DNA
      sequence analysis and consisted of 40 isolates of Collinsella, 24 isolates of the
      Clostridium leptum subgroup, and 15 isolates of disparate clusters. In addition,
      qualitative detection of these bacterial groups was accomplished without
      cultivation by using DNA extracted from the fecal samples. The goal for this
      specific PCR technique is to develop a procedure for quantitative detection of
      these bacterial groups, and a real-time quantitative PCR for detection of
      Bifidobacterium is now being investigated (T. Requena, J. Burton, T. Matsuki, K.
      Munro, M. A. Simon, R. Tanaka, K. Watanabe, and G. W. Tannock, Appl. Environ.
      Microbiol. 68:2420-2427, 2002). Therefore, the approaches used to detect and
      identify predominant bacteria with the group-specific primers described here
      should contribute to future studies of the composition and dynamics of the
      intestinal microflora.

PMID- 12406737
TI  - Characterization of six Leuconostoc fallax bacteriophages isolated from an
      industrial sauerkraut fermentation.
AB  - Six bacteriophages active against Leuconostoc fallax strains were isolated from
      industrial sauerkraut fermentation brines. These phages were characterized as to
      host range, morphology, structural proteins, and genome fingerprint. They were
      exclusively lytic against the species L. fallax and had different host ranges
      among the strains of this species tested. Morphologically, three of the phages
      were assigned to the family Siphoviridae, and the three others were assigned to
      the family Myovidae: Major capsid proteins detected by electrophoresis were
      distinct for each of the two morphotypes. Restriction fragment length
      polymorphism analysis and randomly amplified polymorphic DNA fingerprinting
      showed that all six phages were genetically distinct. These results revealed for
      the first time the existence of bacteriophages that are active against L. fallax
      and confirmed the presence and diversity of bacteriophages in a sauerkraut
      fermentation. Since a variety of L. fallax strains have been shown to be present
      in sauerkraut fermentation, bacteriophages active against L. fallax are likely to
      contribute to the microbial ecology of sauerkraut fermentation and could be
      responsible for some of the variability observed in this type of fermentation.

PMID- 12406738
TI  - Inhibition of Candida albicans biofilm formation by farnesol, a quorum-sensing
      molecule.
AB  - Farnesol is a quorum-sensing molecule that inhibits filamentation in Candida
      albicans. Both filamentation and quorum sensing are deemed to be important
      factors in C. albicans biofilm development. Here we examined the effect of
      farnesol on C. albicans biofilm formation. C. albicans adherent cell populations
      (after 0, 1, 2, and 4 h of adherence) and preformed biofilms (24 h) were treated
      with various concentrations of farnesol (0, 3, 30, and 300 micro M) and incubated
      at 37 degrees C for 24 h. The extent and characteristics of biofilm formation
      were then assessed microscopically and with a semiquantitative colorimetric
      technique based on the use of 2,3-bis(2-methoxy-4-nitro-5-sulfo-phenyl)-2H
      tetrazolium-5-carboxanilide. The results indicated that the effect of farnesol
      was dependent on the concentration of this compound and the initial adherence
      time, and preincubation with 300 micro M farnesol completely inhibited biofilm
      formation. Supernatant media recovered from mature biofilms inhibited the ability
      of planktonic C. albicans to form filaments, indicating that a morphogenetic
      autoregulatory compound is produced in situ in biofilms. Northern blot analysis
      of RNA extracted from cells in biofilms indicated that the levels of expression
      of HWP1, encoding a hypha-specific wall protein, were decreased in farnesol
      treated biofilms compared to the levels in controls. Our results indicate that
      farnesol acts as a naturally occurring quorum-sensing molecule which inhibits
      biofilm formation, and we discuss its potential for further development and use
      as a novel therapeutic agent.

PMID- 12406739
TI  - Characterization of the melA locus for alpha-galactosidase in Lactobacillus
      plantarum.
AB  - Alpha-galactosides are abundant sugars in legumes such as soy. Because of the
      lack of alpha-galactosidase (alpha-Gal) in the digestive tract, humans are unable
      to digest these sugars, which consequently induce flatulence. To develop the
      consumption of the otherwise highly nutritional soy products, the use of
      exogenous alpha-Gal is promising. In this framework, we characterized the melA
      gene for alpha-Gal in Lactobacillus plantarum. The melA gene encodes a
      cytoplasmic 84-kDa protein whose enzymatically active form occurs as oligomers.
      The melA gene was cloned and expressed in Escherichia coli, yielding an active
      alpha-Gal. We show that melA is transcribed from its own promoter, yielding a
      monocistronic mRNA, and that it is regulated at the transcriptional level, i.e.,
      it is induced by melibiose but is not totally repressed by glucose.
      Posttranscriptional regulation by the carbon source could also occur. Upstream of
      melA, a putative galactoside transporter, designated RafP, was identified that
      shows high homology to LacS, the unique transporter for both alpha- and beta
      galactosides in Streptococcus thermophilus. rafP is also expressed as a
      monocistronic mRNA. Downstream of melA, the lacL and lacM genes were identified
      that encode a heterodimeric beta-galactosidase. A putative galM gene identified
      in the same cluster suggests the presence of a galactose operon. These results
      indicate that the genes involved in galactoside catabolism are clustered in L.
      plantarum ATCC 8014. This first genetic characterization of melA and of its
      putative associated transporter, rafP, in a lactobacillus opens doors to various
      applications both in the manufacture of soy-derived products and in probiotic and
      nutraceutical issues.

PMID- 12406740
TI  - Identification by PCR of Fusarium culmorum strains producing large and small
      amounts of deoxynivalenol.
AB  - Thirty deoxynivalenol-producing F. culmorum strains, isolated from wheat grains,
      were incubated in vitro and analyzed for trichothecene production. Seventeen
      strains produced more than 1 ppm of deoxynivalenol and acetyldeoxynivalenol and
      were considered high-deoxynivalenol-producing strains, whereas 13 F. culmorum
      strains produced less than 0.07 ppm of trichothecenes and were considered low
      deoxynivalenol-producing strains. For all strains, a 550-base portion of the
      trichodiene synthase gene (tri5) was amplified and sequenced. According to the
      tri5 data, the F. culmorum strains tested clustered into two groups that
      correlated with in vitro deoxynivalenol production. For three high-producing and
      three low-producing F. culmorum strains, the tri5-tri6 intergenic region was then
      sequenced, which confirmed the two separate clusters within the F. culmorum
      strains. According to the tri5-tri6 sequence data, specific PCR primers were
      designed to allow differentiation of high-producing from low-producing F.
      culmorum strains.

PMID- 12406741
TI  - Expression of duplicate msa genes in the salmonid pathogen Renibacterium
      salmoninarum.
AB  - Renibacterium salmoninarum is a gram-positive bacterium responsible for bacterial
      kidney disease of salmon and trout. R. salmoninarum has two identical copies of
      the gene encoding major soluble antigen (MSA), an immunodominant, extracellular
      protein. To determine whether one or both copies of msa are expressed, reporter
      plasmids encoding a fusion of MSA and green fluorescent protein controlled by 0.6
      kb of promoter region from msa1 or msa2 were constructed and introduced into R.
      salmoninarum. Single copies of the reporter plasmids integrated into the
      chromosome by homologous recombination. Expression of mRNA and protein from the
      integrated plasmids was detected, and transformed cells were fluorescent,
      demonstrating that both msa1 and msa2 are expressed under in vitro conditions.
      This is the first report of successful transformation and homologous
      recombination in R. salmoninarum.

PMID- 12406742
TI  - Seasonality of Chesapeake Bay bacterioplankton species.
AB  - Bacteria, gamma-subclass of Proteobacteria, Vibrio-Photobacterium, Vibrio
      vulnificus, Vibrio cholerae-Vibrio mimicus, and Vibrio cincinnatiensis in water
      samples collected from the Choptank River in Chesapeake Bay from 15 April to 16
      December 1996 were enumerated using a fluorescent oligonucleotide direct-counting
      (FODC) procedure. FODC results obtained using a Bacteria taxon-specific probe
      ranged from one-third the number of to the same number as that obtained by the
      acridine orange direct count (AODC) procedure. The abundance of individual taxa
      (per liter) ranged from 0.25 x 10(10) to 2.6 x 10(10) Bacteria, 0.32 x 10(8) to
      3.1 x 10(8) gamma-Proteobacteria, 0.2 x 10(8) to 2.1 x 10(8) Vibrio
      Photobacterium, 0.5 x 10(7) to 10 x 10(7) V. vulnificus, 0.2 x 10(6) to 6 x 10(6)
      V. cholerae-V. mimicus, and 0.5 x 10(5) to 8 x 10(5) V. cincinnatiensis. The
      occurrence of all taxa monitored in this study was higher in summer; however,
      these taxa made up a larger proportion of the Bacteria when the water temperature
      was low. Large fluctuations in species abundance as well as in percent
      composition of Vibrio-Photobacterium occurred from week to week, indicating that
      localized blooms of these taxa occur. The cross-Choptank River transect sample
      profile of V. vulnificus and V. cholerae-V. mimicus varied significantly in
      abundance, and trans-Choptank River transect samples revealed a patchy
      distribution.

PMID- 12406743
TI  - Bacteria of the gamma-subclass Proteobacteria associated with zooplankton in
      Chesapeake Bay.
AB  - The seasonal abundance of gamma-subclass Proteobacteria, Vibrio-Photobacterium,
      Vibrio cholerae-Vibrio mimicus, Vibrio cincinnatiensis, and Vibrio vulnificus in
      the Choptank River of Chesapeake Bay associated with zooplankton was monitored
      from April to December 1996. Large (>202- microm) and small (64- to 202- microm)
      size classes of zooplankton were collected, and the bacteria associated with each
      of the zooplankton size classes were enumerated by fluorescent oligonucleotide
      direct count. Large populations of bacteria were found to be associated with both
      the large and small size classes of zooplankton. Also, the species of bacteria
      associated with the zooplankton showed seasonal abundance, with the largest
      numbers occurring in the early spring and again in the summer, when zooplankton
      total numbers were correspondingly large. Approximately 0.01 to 40.0% of the
      total water column bacteria were associated with zooplankton, with the percentage
      of the total water column bacteria population associated with zooplankton varying
      by season. A taxonomically diverse group of bacteria was associated with
      zooplankton, and a larger proportion was found in and on zooplankton during the
      cooler months of the year, with selected taxa comprising a larger percent of the
      Bacteria in the summer. V. cholerae-V. mimicus and V. vulnificus comprised the
      bulk of the large and small zooplankton-associated Vibrio-Photobacterium species.
      In contrast, V. cincinnatiensis accounted for less than 0.1 to 3%. It is
      concluded that water column and zooplankton bacterial populations vary
      independently with respect to species composition since no correlation was
      observed between taxa occurring with highest frequency in the water column and
      those in association with zooplankton.

PMID- 12406744
TI  - Molecular characterization of cadmium resistance in Streptococcus thermophilus
      strain 4134: an example of lateral gene transfer.
AB  - Two genes (cadC(St) and cadA(St) [subscript St represents Streptococcus
      thermophilus]), located on the chromosome of S. thermophilus 4134, were shown to
      constitute a cadmium/zinc resistance cassette. The genes seem to be organized in
      an operon, and their transcription is cadmium dependent in vivo. The proposed
      product of the cadA open reading frame (CadA(St)) is highly similar to P-type
      cadmium efflux ATPases, whereas the predicted protein encoded by cadC(St)
      (CadC(St)) shows high similarity to ArsR-type regulatory proteins. The observed
      homologies and G+C content of this cassette and surrounding regions suggest that
      this DNA was derived from Lactococcus lactis and may have been introduced
      relatively recently into the S. thermophilus 4134 genome by a lateral gene
      transfer event. The complete cassette confers cadmium and zinc resistance to both
      S. thermophilus and L. lactis, but expression of cadA(St) alone is sufficient to
      give resistance. By using electrophoretic mobility shift assays it was shown that
      the CadC(St) protein is a DNA binding protein that binds specifically to its own
      promoter region, possibly to two copies of an inverted repeat, and that this
      CadC(St)-DNA interaction is lost in the presence of cadmium. Using lacZ fusion
      constructs it was shown that the cadmium-dependent expression of CadA(St) is
      mediated by the negative regulator CadC(St). A model for the regulation of the
      expression of cadmium resistance in S. thermophilus is discussed.

PMID- 12406745
TI  - Transport of Cryptosporidium parvum oocysts through vegetated buffer strips and
      estimated filtration efficiency.
AB  - Vegetated buffer strips were evaluated for their ability to remove waterborne
      Cryptosporidium parvum from surface and shallow subsurface flow during simulated
      rainfall rates of 15 or 40 mm/h for 4 h. Log(10) reductions for spiked C. parvum
      oocysts ranged from 1.0 to 3.1 per m of vegetated buffer, with buffers set at 5
      to 20% slope, 85 to 99% fescue cover, soil textures of either silty clay
      (19:47:34 sand-silt-clay), loam (45:37:18), or sandy loam (70:25:5), and bulk
      densities of between 0.6 to 1.7 g/cm(3). Vegetated buffers constructed with sandy
      loam or higher soil bulk densities were less effective at removing waterborne C.
      parvum (1- to 2-log(10) reduction/m) compared to buffers constructed with silty
      clay or loam or at lower bulk densities (2- to 3-log(10) reduction/m). The effect
      of slope on filtration efficiency was conditional on soil texture and soil bulk
      density. Based on these results, a vegetated buffer strip comprised of similar
      soils at a slope of <or=20% and a length of >or=3 m should function to remove
      >or=99.9% of C. parvum oocysts from agricultural runoff generated during events
      involving mild to moderate precipitation.

PMID- 12406747
TI  - Robust hydrocarbon degradation and dynamics of bacterial communities during
      nutrient-enhanced oil spill bioremediation.
AB  - Degradation of oil on beaches is, in general, limited by the supply of inorganic
      nutrients. In order to obtain a more systematic understanding of the effects of
      nutrient addition on oil spill bioremediation, beach sediment microcosms
      contaminated with oil were treated with different levels of inorganic nutrients.
      Oil biodegradation was assessed respirometrically and on the basis of changes in
      oil composition. Bacterial communities were compared by numerical analysis of
      denaturing gradient gel electrophoresis (DGGE) profiles of PCR-amplified 16S rRNA
      genes and cloning and sequencing of PCR-amplified 16S rRNA genes. Nutrient
      amendment over a wide range of concentrations significantly improved oil
      degradation, confirming that N and P limited degradation over the concentration
      range tested. However, the extent and rate of oil degradation were similar for
      all microcosms, indicating that, in this experiment, it was the addition of
      inorganic nutrients rather than the precise amount that was most important
      operationally. Very different microbial communities were selected in all of the
      microcosms. Similarities between DGGE profiles of replicate samples from a single
      microcosm were high (95% +/- 5%), but similarities between DGGE profiles from
      replicate microcosms receiving the same level of inorganic nutrients (68% +/- 5%)
      were not significantly higher than those between microcosms subjected to
      different nutrient amendments (63% +/- 7%). Therefore, it is apparent that the
      different communities selected cannot be attributed to the level of inorganic
      nutrients present in different microcosms. Bioremediation treatments dramatically
      reduced the diversity of the bacterial community. The decrease in diversity could
      be accounted for by a strong selection for bacteria belonging to the alkane
      degrading Alcanivorax/Fundibacter group. On the basis of Shannon-Weaver indices,
      rapid recovery of the bacterial community diversity to preoiling levels of
      diversity occurred. However, although the overall diversity was similar, there
      were considerable qualitative differences in the community structure before and
      after the bioremediation treatments.

PMID- 12406746
TI  - Construction of a shuttle vector for, and spheroplast transformation of, the
      hyperthermophilic archaeon Pyrococcus abyssi.
AB  - Our understanding of the genetics of species of the best-studied
      hyperthermophilic archaea, Pyrococcus spp., is presently limited by the lack of
      suitable genetic tools, such as a stable cloning vector and the ability to select
      individual transformants on plates. Here we describe the development of a
      reliable host-vector system for the hyperthermophilic archaeon Pyrococcus abyssi.
      Shuttle vectors were constructed based on the endogenous plasmid pGT5 from P.
      abyssi strain GE5 and the bacterial vector pLitmus38. As no antibiotic resistance
      marker is currently available for Pyrococcus spp., we generated a selectable
      auxotrophic marker. Uracil auxotrophs resistant to 5-fluoorotic acid were
      isolated from P. abyssi strain GE9 (devoid of pGT5). Genetic analysis of these
      mutants revealed mutations in the pyrE and/or pyrF genes, encoding key enzymes of
      the pyrimidine biosynthetic pathway. Two pyrE mutants exhibiting low reversion
      rates were retained for complementation experiments. For that purpose, the pyrE
      gene, encoding orotate phosphoribosyltransferase (OPRTase) of the
      thermoacidophilic crenarchaeote Sulfolobus acidocaldarius, was introduced into
      the pGT5-based vector, giving rise to pYS2. With a polyethylene glycol
      spheroplast method, we could reproducibly transform P. abyssi GE9 pyrE mutants to
      prototrophy, though with low frequency (10(2) to 10(3) transformants per micro g
      of pYS2 plasmid DNA). Transformants did grow as well as the wild type on minimal
      medium without uracil and showed comparable OPRTase activity. Vector pYS2 proved
      to be very stable and was maintained at high copy number under selective
      conditions in both Escherichia coli and P. abyssi.

PMID- 12406748
TI  - Isolation and molecular analysis of the gene cluster for the arginine deiminase
      system from Streptococcus gordonii DL1.
AB  - The arginine deiminase (AD) system (ADS) is one of two major ammonia-generating
      pathways in the oral cavity that play important roles in oral biofilm pH
      homeostasis and oral biofilm ecology. To initiate a study of the Streptococcus
      gordonii ADS, the ADS gene cluster was isolated from subgenomic DNA libraries of
      S. gordonii DL1 by using an arcB-specific probe. Nucleotide sequence analysis
      revealed six open reading frames (ORFs) that were arranged contiguously; the
      first five ORFs were transcribed in the same direction, as an apparent operon,
      and the sixth was transcribed in the opposite direction. The ORFs were found to
      share significant homologies and to correspond closely in molecular mass to
      previously characterized arc genes; thus, they were designated arcA (AD), arcB
      (ornithine carbamyltransferase), arcC (carbamate kinase), arcD (arginine
      ornithine antiporter), arcT (dipeptidase), and arcR (regulator). A putative
      sigma(70) promoter (ParcA [TTGTGT-N(19)-TAGAAT]) was mapped 5' to arcA by primer
      extension, and the expression of ParcA was shown to be inducible by arginine and
      repressible by glucose, in agreement with AD specific activities measured in the
      wild-type strain. To investigate the function of ArcR in the differential
      expression of the arc operon, arcR was insertionally inactivated by a KM
      resistance marker flanked by T4 transcription/translation termination signals,
      and the expression of ParcA was monitored by primer extension in the wild-type
      and ArcR-deficient strains. Lower levels of arcA expression, as well as lower
      levels of AD activity, were consistently observed in the ArcR-deficient strain
      compared to wild-type cells, regardless of the growth conditions. Thus, ArcR is a
      transcriptional activator that is required for induction and optimal expression
      of the S. gordonii ADS gene cluster.

PMID- 12406749
TI  - Widespread N-acetyl-D-glucosamine uptake among pelagic marine bacteria and its
      ecological implications.
AB  - Dissolved free and combined N-acetyl-D-glucosamine (NAG) is among the largest
      pools of amino sugars in the ocean. NAG is a main structural component in chitin
      and a substantial constituent of bacterial peptidoglycan and lipopolysaccharides.
      We studied the distribution and kinetics of NAG uptake by the
      phosphoenolpyruvate:NAG phosphotransferase systems (PTS) in marine bacterial
      isolates and natural bacterial assemblages in near-shore waters. Of 78 bacterial
      isolates examined, 60 took up 3H-NAG, while 18 showed no uptake. No systematic
      pattern in NAG uptake capability relative to phylogenetic affiliation was found,
      except that all isolates within Vibrionaceae took up NAG. Among 12 isolates, some
      showed large differences in the relationship between polymer hydrolysis (measured
      as chitobiase activity) and uptake of the NAG, the hydrolysis product. Pool
      turnover time and estimated maximum ambient concentration of dissolved NAG in
      samples off Scripps Pier (La Jolla, Calif.) were 5.9 +/- 3.0 days (n = 10) and
      5.2 +/- 0.9 nM (n = 3), respectively. Carbohydrate competition experiments
      indicated that glucose, glucosamine, mannose, and fructose were taken up by the
      same system as NAG. Sensitivity to the antibiotic and NAG structural analog
      streptozotocin (STZ) was developed into a culture-independent approach, which
      demonstrated that approximately one-third of bacteria in natural marine
      assemblages that were synthesizing DNA took up NAG. Isolates possessing a NAG PTS
      system were found to be predominantly facultative anaerobes. These results
      suggest the hypothesis that a substantial fraction of bacteria in natural pelagic
      assemblages are facultative anaerobes. The adaptive value of fermentative
      metabolism in the pelagic environment is potentially significant, e.g., to
      bacteria colonizing microenvironments such as marine snow that may experience
      periodic O2-limitation.

PMID- 12406750
TI  - A metalloprotease (MprIII) involved in the chitinolytic system of a marine
      bacterium, Alteromonas sp. strain O-7.
AB  - Alteromonas sp. strain O-7 secretes several proteins in addition to chitinolytic
      enzymes in response to chitin induction. In this paper, we report that one of
      these proteins, designated MprIII, is a metalloprotease involved in the chitin
      degradation system of the strain. The gene encoding MprIII was cloned in
      Escherichia coli. The open reading frame of mprIII encoded a protein of 1,225
      amino acids with a calculated molecular mass of 137,016 Da. Analysis of the
      deduced amino acid sequence of MprIII revealed that the enzyme consisted of four
      domains: the signal sequence, the N-terminal proregion, the protease region, and
      the C-terminal extension. The C-terminal extension (PkdDf) was characterized by
      four polycystic kidney disease domains and two domains of unknown function.
      Western and real-time quantitative PCR analyses demonstrated that mprIII was
      induced in the presence of insoluble polysaccharides, such as chitin and
      cellulose. Native MprIII was purified to homogeneity from the culture supernatant
      of Alteromonas sp. strain O-7 and characterized. The molecular mass of mature
      MprIII was estimated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis
      to be 115 kDa. The optimum pH and temperature of MprIII were 7.5 and 50 degrees
      C, respectively, when gelatin was used as a substrate. Pretreatment of native
      chitin with MprIII significantly promoted chitinase activity. Furthermore, the
      combination of MprIII and a novel chitin-binding protease (AprIV) remarkably
      promoted the chitin hydrolysis efficiency of chitinase.

PMID- 12406751
TI  - Enhancing transport of hydrogenophaga flava ENV735 for bioaugmentation of
      aquifers contaminated with methyl tert-butyl ether.
AB  - The gasoline oxygenate methyl tert-butyl ether (MTBE) has become a widespread
      contaminant in groundwater throughout the United States. Bioaugmentation of
      aquifers with MTBE-degrading cultures may be necessary to enhance degradation of
      the oxygenate in some locations. However, poor cell transport has sometimes
      limited bioaugmentation efforts in the past. The objective of this study was to
      evaluate the transport characteristics of Hydrogenophaga flava ENV735, a pure
      culture capable of growth on MTBE, and to improve movement of the strain through
      aquifer solids. The wild-type culture moved only a few centimeters in columns of
      aquifer sediment. An adhesion-deficient variant (H. flava ENV735:24) of the wild
      type strain that moved more readily through sediments was obtained by sequential
      passage of cells through columns of sterile sediment. Hydrophobic and
      electrostatic interaction chromatography revealed that the wild-type strain is
      much more hydrophobic than the adhesion-deficient variant. Electrophoretic
      mobility assays and transmission electron microscopy showed that the wild-type
      bacterium contains two distinct subpopulations, whereas the adhesion-deficient
      strain has only a single, homogeneous population. Both the wild-type strain and
      adhesion-deficient variant degraded MTBE, and both were identified by 16S rRNA
      analysis as pure cultures of H. flava. The effectiveness of surfactants for
      enhancing transport of the wild-type strain was also evaluated. Many of the
      surfactants tested were toxic to ENV735; however, one nonionic surfactant, Tween
      20, enhanced cell transport in sand columns. Improving microbial transport may
      lead to a more effective bioaugmentation strategy for MTBE-contaminated sites
      where indigenous oxygenate degraders are absent.

PMID- 12406752
TI  - Presence of a single genotype of the newly described species Mycobacterium
      immunogenum in industrial metalworking fluids associated with hypersensitivity
      pneumonitis.
AB  - Outbreaks of hypersensitivity pneumonitis (HP) among industrial metal-grinding
      machinists working with water-based metalworking fluids (MWF) have frequently
      been associated with high levels of mycobacteria in the MWF, but little is known
      about these organisms. We collected 107 MWF isolates of mycobacteria from
      multiple industrial sites where HP had been diagnosed and identified them to the
      species level by a molecular method (PCR restriction enzyme analysis [PRA]).
      Their genomic DNA restriction fragment length polymorphism (RFLP) patterns, as
      determined by pulsed-field gel electrophoresis (PFGE), were compared to those of
      15 clinical (patient) isolates of the recently described rapidly growing
      mycobacterial species Mycobacterium immunogenum. A total of 102 of 107 (95%) MWF
      isolates (from 10 industrial sites within the United States and Canada) were
      identified as M. immunogenum and gave PRA patterns identical to those of the
      clinical isolates. Using genomic DNA, PFGE was performed on 80 of these isolates.
      According to RFLP analysis using the restriction enzymes DraI and XbaI, 78 of 80
      (98%) of the MWF isolates represented a single clone. In contrast, none of the 15
      clinical isolates had genetic patterns the same as or closely related to those of
      any of the others. Given the genomic heterogeneity of clinical isolates of M.
      immunogenum, the finding that a single genotype was present at all industrial
      sites is remarkable. This suggests that this genotype possesses unusual features
      that may relate to its virulence and its potential etiologic role in HP and/or to
      its resistance to biocides frequently used in MWF.

PMID- 12406753
TI  - MtrB is required for proper incorporation of the cytochromes OmcA and OmcB into
      the outer membrane of Shewanella putrefaciens MR-1.
AB  - When grown under anaerobic conditions, Shewanella putrefaciens MR-1 synthesizes
      multiple outer membrane (OM) cytochromes, some of which have a role in the use of
      insoluble electron acceptors (e.g., MnO2) for anaerobic respiration. The
      cytochromes OmcA and OmcB are localized to the OM and the OM-like intermediate
      density membrane (IM) in MR-1. The components necessary for proper localization
      of these cytochromes to the OM have not been identified. A gene replacement
      mutant (strain MTRB1) lacking the putative OM protein MtrB was isolated and
      characterized. The specific cytochrome content of the OM of MTRB1 was only 36%
      that of MR-1. This was not the result of a general decline in cytochrome content,
      however, because the cytoplasmic membrane (CM) and soluble fractions were not
      cytochrome deficient. While OmcA and OmcB were detected in the OM and IM
      fractions of MTRB1, significant amounts were mislocalized to the CM. OmcA was
      also detected in the soluble fraction of MTRB1. While OmcA and OmcB in MR-1
      fractions were resistant to solubilization with Triton X-100 in the presence of
      Mg2+, Triton X-100 readily solubilized these proteins from all subcellular
      fractions of MTRB1. Together, these data suggest that MtrB is required for the
      proper localization and insertion of OmcA and OmcB into the OM of MR-1. The
      inability of MTRB1 to properly insert these, and possibly other, proteins into
      its OM likely contributes to its marked deficiency in manganese(IV) and iron(III)
      reduction. While the localization of another putative OM cytochrome (MtrF) could
      not be directly determined, an mtrF gene replacement mutant exhibited wild-types
      rates of Mn(IV) and Fe(III) reduction. Therefore, even if MtrF were mislocalized
      in MTRB1, it would not contribute to the loss of metal reduction activity in this
      strain.

PMID- 12406754
TI  - Salmonellae in avian wildlife in Norway from 1969 to 2000.
AB  - Postmortem records of wild-living birds in Norway with laboratory-confirmed
      findings of salmonella infection were summarized for the period from 1969 to
      2000. Salmonella spp. were isolated from 470 birds belonging to 26 species. The
      salmonella-positive birds included 441 small passerines, 15 gulls, 5 waterfowl, 4
      birds of prey, 3 doves, and 2 crows. The bullfinch (Pyrrhula pyrrhula) was by far
      the most frequently recorded species (54% of the cases). Salmonella enterica
      serover Typhimurium was recovered from all cases except from one hooded crow
      (Corvus corone), which yielded serovar Paratyphi-B var. Java. Variant O:4,12
      comprised 96% (451 cases) of all serovar Typhimurium isolates, including all the
      passerines, while variant O:4,5,12 accounted for the remaining 4% (18 cases). The
      occurrence of salmonellae in small passerines showed a distinct seasonality, with
      a peak in February and March. Plasmid profile analysis of 346 isolates of serovar
      Typhimurium O:4,12 detected six profiles, of which two comprised 66 and 28% of
      the isolates, respectively. Phage typing of 52 randomly selected isolates of
      serovar Typhimurium O:4,12 from passerines detected four types: DT 40 (54%), U277
      (35%), DT 99 (6%), and DT 110 (4%).

PMID- 12406755
TI  - Molecular epidemiology of Salmonella enterica serovar typhimurium isolates
      determined by pulsed-field gel electrophoresis: comparison of isolates from avian
      wildlife, domestic animals, and the environment in Norway.
AB  - The molecular epidemiology of 142 isolates of Salmonella enterica serovar
      Typhimurium from avian wildlife, domestic animals, and the environment in Norway
      was investigated using pulsed-field gel electrophoresis (PFGE) and computerized
      numerical analysis of the data. The bacterial isolates comprised 79 isolates from
      wild-living birds, including 46 small passerines and 26 gulls, and 63 isolates of
      nonavian origin, including 50 domestic animals and 13 environmental samples.
      Thirteen main clusters were discernible at the 90% similarity level. Most of the
      isolates (83%) were grouped into three main clusters. These were further divided
      into 20 subclusters at the 95% similarity level. Isolates from passerines, gulls,
      and pigeons dominated within five subclusters, whereas isolates from domestic
      animals and the environment belonged to many different subclusters with no
      predominance. The results support earlier results that passerines constitute an
      important source of infection to humans in Norway, whereas it is suggested that
      gulls and pigeons, based on PFGE analysis, represent only a minor source of human
      serovar Typhimurium infections. Passerines, gulls, and pigeons may also
      constitute a source of infection of domestic animals and feed plants or vice
      versa. Three isolates from cattle and a grain source, of which two were
      multiresistant, were confirmed as serovar Typhimurium phage type DT 104. These
      represent the first reported phage type DT 104 isolates from other sources than
      humans in Norway.

PMID- 12406756
TI  - Antibacterial activities of nisin Z encapsulated in liposomes or produced in situ
      by mixed culture during cheddar cheese ripening.
AB  - This study investigated both the activity of nisin Z, either encapsulated in
      liposomes or produced in situ by a mixed starter, against Listeria innocua,
      Lactococcus spp., and Lactobacillus casei subsp. casei and the distribution of
      nisin Z in a Cheddar cheese matrix. Nisin Z molecules were visualized using gold
      labeled anti-nisin Z monoclonal antibodies and transmission electron microscopy
      (immune-TEM). Experimental Cheddar cheeses were made using a nisinogenic mixed
      starter culture, containing Lactococcus lactis subsp. lactis biovar diacetylactis
      UL 719 as the nisin producer and two nisin-tolerant lactococcal strains and L.
      casei subsp. casei as secondary flora, and ripened at 7 degrees C for 6 months.
      In some trials, L. innocua was added to cheese milk at 10(5) to 10(6) CFU/ml. In
      6-month-old cheeses, 90% of the initial activity of encapsulated nisin (280 +/-
      14 IU/g) was recovered, in contrast to only 12% for initial nisin activity
      produced in situ by the nisinogenic starter (300 +/- 15 IU/g). During ripening,
      immune-TEM observations showed that encapsulated nisin was located mainly at the
      fat/casein interface and/or embedded in whey pockets while nisin produced by
      biovar diacetylactis UL 719 was uniformly distributed in the fresh cheese matrix
      but concentrated in the fat area as the cheeses aged. Cell membrane in lactococci
      appeared to be the main nisin target, while in L. casei subsp. casei and L.
      innocua, nisin was more commonly observed in the cytoplasm. Cell wall disruption
      and digestion and lysis vesicle formation were common observations among strains
      exposed to nisin. Immune-TEM observations suggest several modes of action for
      nisin Z, which may be genus and/or species specific and may include intracellular
      target-specific activity. It was concluded that nisin-containing liposomes can
      provide a powerful tool to improve nisin stability and availability in the cheese
      matrix.

PMID- 12406757
TI  - Expression of an anaplerotic enzyme, pyruvate carboxylase, improves recombinant
      protein production in Escherichia coli.
AB  - Anaplerotic enzyme reactions are those which replenish tricarboxylic acid
      intermediates that are withdrawn for the synthesis of biomass. In this study, we
      examined recombinant protein production in Escherichia coli containing activity
      in an additional anaplerotic enzyme, pyruvate carboxylase. In batch
      fermentations, the presence of pyruvate carboxylase resulted in 68% greater
      production of the model protein, beta-galactosidase, 41% greater cell yield, and
      57% lower acetate concentration. We discuss why these results indicate that
      acetate concentration does not limit cell growth and protein synthesis, as
      predicted by other researchers, and suggest instead that the rate of acetate
      formation represents an inefficient consumption of glucose carbon, which is
      reduced by the presence of pyruvate carboxylase.

PMID- 12406758
TI  - Bacteria belonging to the genus cycloclasticus play a primary role in the
      degradation of aromatic hydrocarbons released in a marine environment.
AB  - To identify the bacteria that play a major role in the aerobic degradation of
      petroleum polynuclear aromatic hydrocarbons (PAHs) in a marine environment,
      bacteria were enriched from seawater by using 2-methylnaphthalene, phenanthrene,
      or anthracene as a carbon and energy source. We found that members of the genus
      Cycloclasticus became predominant in the enrichment cultures. The Cycloclasticus
      strains isolated in this study could grow on crude oil and degraded PAH
      components of crude oil, including unsubstituted and substituted naphthalenes,
      dibenzothiophenes, phenanthrenes, and fluorenes. To deduce the role of
      Cycloclasticus strains in a coastal zone oil spill, propagation of this bacterial
      group on oil-coated grains of gravel immersed in seawater was investigated in
      beach-simulating tanks that were 1 m wide by 1.5 m long by 1 m high. The tanks
      were two-thirds filled with gravel, and seawater was continuously introduced into
      the tanks; the water level was varied between 30 cm above and 30 cm below the
      surface of the gravel layer to simulate a 12-h tidal cycle. The number of
      Cycloclasticus cells associated with the grains was on the order of 10(3) cells/g
      of grains before crude oil was added to the tanks and increased to 3 x 10(6)
      cells/g of grains after crude oil was added. The number increased further after
      14 days to 10(8) cells/g of grains when nitrogen and phosphorus fertilizers were
      added, while the number remained 3 x 10(6) cells/g of grains when no fertilizers
      were added. PAH degradation proceeded parallel with the growth of Cycloclasticus
      cells on the surfaces of the oil-polluted grains of gravel. These observations
      suggest that bacteria belonging to the genus Cycloclasticus play an important
      role in the degradation of petroleum PAHs in a marine environment.

PMID- 12406759
TI  - Donor substrate regeneration for efficient synthesis of globotetraose and
      isoglobotetraose.
AB  - Here we describe the efficient synthesis of two oligosaccharide moieties of human
      glycosphingolipids, globotetraose (GalNAcbeta1-->3Galalpha1-->4Galbeta1-->4Glc)
      and isoglobotetraose (GalNAcbeta1-->3Galalpha1-->3Galbeta1-->4Glc), with in situ
      enzymatic regeneration of UDP-N-acetylgalactosamine (UDP-GalNAc). We demonstrate
      that the recombinant beta-1,3-N-acetylgalactosaminyltransferase from Haemophilus
      influenzae strain Rd can transfer N-acetylgalactosamine to a wide range of
      acceptor substrates with a terminal galactose residue. The donor substrate UDP
      GalNAc can be regenerated by a six-enzyme reaction cycle consisting of
      phosphoglucosamine mutase, UDP-N-acetylglucosamine pyrophosphorylase, phosphate
      acetyltransferase, pyruvate kinase, and inorganic pyrophosphatase from
      Escherichia coli, as well as UDP-N-acetylglucosamine C4 epimerase from
      Plesiomonas shigelloides. All these enzymes were overexpressed in E. coli with
      six-histidine tags and were purified by one-step nickel-nitrilotriacetic acid
      affinity chromatography. Multiple-enzyme synthesis of globotetraose or
      isoglobotetraose with the purified enzymes was achieved with relatively high
      yields.

PMID- 12406760
TI  - Detection of cytotoxin-hemolysin mRNA in nonculturable populations of
      environmental and clinical Vibrio vulnificus strains in artificial seawater.
AB  - The objective of this study was to develop a molecular detection method that
      better estimates the potential risk associated with the presence of Vibrio
      vulnificus. For that purpose, we applied seminested reverse transcription-PCR (RT
      PCR) to viable but nonculturable (VBNC) populations of V. vulnificus and targeted
      the cytotoxin-hemolysin virulence gene vvhA. Three strains, two environmental, IF
      Vv10 and IF Vv18, and one clinical, C7184, were used in this study. Artificial
      seawater, inoculated with mid-log-phase cells, was maintained at 4 degrees C.
      VBNC cells resulted after 3, 6, and 14 days for C7184, IF Vv18, and IF Vv10,
      respectively. Our data indicate that seminested RT-PCR is sensitive for the
      detection of vvhA mRNA in artificial seawater when exclusively nonculturable
      bacteria are present. This is the first report of the expression of a toxin gene
      in VBNC V. vulnificus. Moreover, vvhA transcripts were shown to persist in
      nonculturable populations over a 4.5-month period, with a progressive decline of
      the signal over time. This result indicates that special attention should be
      given to the presence of potentially pathogenic VBNC cells in environmental
      samples when assessing public health risk.

PMID- 12406761
TI  - Gbu glycine betaine porter and carnitine uptake in osmotically stressed Listeria
      monocytogenes cells.
AB  - The food-borne pathogen Listeria monocytogenes grows actively under high-salt
      conditions by accumulating compatible solutes such as glycine betaine and
      carnitine from the medium. We report here that the dominant transport system for
      glycine betaine uptake, the Gbu porter, may act as a secondary uptake system for
      carnitine, with a K(m) of 4 mM for carnitine uptake and measurable uptake at
      carnitine concentrations as low as 10 microM. This porter has a K(m) for glycine
      betaine uptake of about 6 micro M. The dedicated carnitine porter, OpuC, has a
      K(m) for carnitine uptake of 1 to 3 microM and a V(max) of approximately 15
      nmol/min/mg of protein. Mutants lacking either opuC or gbu were used to study the
      effects of four carnitine analogs on growth and uptake of osmolytes. In strain DP
      L1044, which had OpuC and the two glycine betaine porters Gbu and BetL,
      triethylglycine was most effective in inhibiting growth in the presence of
      glycine betaine, but trigonelline was best at inhibiting growth in the presence
      of carnitine. Carnitine uptake through OpuC was inhibited by gamma-butyrobetaine.
      Dimethylglycine inhibited both glycine betaine and carnitine uptake through the
      Gbu porter. Carnitine uptake through the Gbu porter was inhibited by
      triethylglycine. Glycine betaine uptake through the BetL porter was strongly
      inhibited by trigonelline and triethylglycine. These results suggest that it is
      possible to reduce the growth of L. monocytogenes under osmotically stressful
      conditions by inhibiting glycine betaine and carnitine uptake but that to do so,
      multiple uptake systems must be affected.

PMID- 12406762
TI  - Metabolic engineering of acetaldehyde production by Streptococcus thermophilus.
AB  - The process of acetaldehyde formation by the yogurt bacterium Streptococcus
      thermophilus is described in this paper. Attention was focused on one specific
      reaction for acetaldehyde formation catalyzed by serine hydroxymethyltransferase
      (SHMT), encoded by the glyA gene. In S. thermophilus, SHMT also possesses
      threonine aldolase (TA) activity, the interconversion of threonine into glycine
      and acetaldehyde. In this work, several wild-type S. thermophilus strains were
      screened for acetaldehyde production in the presence and absence of L-threonine.
      Supplementation of the growth medium with L-threonine led to an increase in
      acetaldehyde production. Furthermore, acetaldehyde formation during fermentation
      could be correlated to the TA activity of SHMT. To study the physiological role
      of SHMT, a glyA mutant was constructed by gene disruption. Inactivation of glyA
      resulted in a severe reduction in TA activity and complete loss of acetaldehyde
      formation during fermentation. Subsequently, an S. thermophilus strain was
      constructed in which the glyA gene was cloned under the control of a strong
      promoter (P(LacA)). When this strain was used for fermentation, an increase in TA
      activity and in acetaldehyde and folic acid production was observed. These
      results show that, in S. thermophilus, SHMT, displaying TA activity, constitutes
      the main pathway for acetaldehyde formation under our experimental conditions.
      These findings can be used to control and improve acetaldehyde production in
      fermented (dairy) products with S. thermophilus as starter culture.

PMID- 12406763
TI  - Use of the alr gene as a food-grade selection marker in lactic acid bacteria.
AB  - Both Lactococcus lactis and Lactobacillus plantarum contain a single alr gene,
      encoding an alanine racemase (EC 5.1.1.1), which catalyzes the interconversion of
      D-alanine and L-alanine. The alr genes of these lactic acid bacteria were
      investigated for their application as food-grade selection markers in a
      heterologous complementation approach. Since isogenic mutants of both species
      carrying an alr deletion (Deltaalr) showed auxotrophy for D-alanine, plasmids
      carrying a heterologous alr were constructed and could be selected, since they
      complemented D-alanine auxotrophy in the L. plantarum Deltaalr and L. lactis
      Deltaalr strains. Selection was found to be highly stringent, and plasmids were
      stably maintained over 200 generations of culturing. Moreover, the plasmids
      carrying the heterologous alr genes could be stably maintained in wild-type
      strains of L. plantarum and L. lactis by selection for resistance to D
      cycloserine, a competitive inhibitor of Alr (600 and 200 micro g/ml,
      respectively). In addition, a plasmid carrying the L. plantarum alr gene under
      control of the regulated nisA promoter was constructed to demonstrate that D
      cycloserine resistance of L. lactis is linearly correlated to the alr expression
      level. Finally, the L. lactis alr gene controlled by the nisA promoter, together
      with the nisin-regulatory genes nisRK, were integrated into the chromosome of L.
      plantarum Deltaalr. The resulting strain could grow in the absence of D-alanine
      only when expression of the alr gene was induced with nisin.

PMID- 12406764
TI  - Cloning and characterization of a gene cluster involved in cyclopentanol
      metabolism in Comamonas sp. strain NCIMB 9872 and biotransformations effected by
      Escherichia coli-expressed cyclopentanone 1,2-monooxygenase.
AB  - Cyclopentanone 1,2-monooxygenase, a flavoprotein produced by Pseudomonas sp.
      strain NCIMB 9872 upon induction by cyclopentanol or cyclopentanone (M. Griffin
      and P. W. Trudgill, Biochem. J. 129:595-603, 1972), has been utilized as a
      biocatalyst in Baeyer-Villiger oxidations. To further explore this biocatalytic
      potential and to discover new genes, we have cloned and sequenced a 16-kb
      chromosomal locus of strain 9872 that is herein reclassified as belonging to the
      genus COMAMONAS: Sequence analysis revealed a cluster of genes and six potential
      open reading frames designated and grouped in at least four possible
      transcriptional units as (orf11-orf10-orf9)-(cpnE-cpnD-orf6-cpnC)-(cpnR-cpnB
      cpnA)-(orf3-orf4 [partial 3' end]). The cpnABCDE genes encode enzymes for the
      five-step conversion of cyclopentanol to glutaric acid catalyzed by cyclopentanol
      dehydrogenase, cyclopentanone 1,2-monooxygenase, a ring-opening 5-valerolactone
      hydrolase, 5-hydroxyvalerate dehydrogenase, and 5-oxovalerate dehydrogenase,
      respectively. Inactivation of cpnB by using a lacZ-Km(r) cassette resulted in a
      strain that was not capable of growth on cyclopentanol or cyclopentanone as a
      sole carbon and energy source. The presence of sigma(54)-dependent regulatory
      elements in front of the divergently transcribed cpnB and cpnC genes supports the
      notion that cpnR is a regulatory gene of the NtrC type. Knowledge of the
      nucleotide sequence of the cpn genes was used to construct isopropyl-beta-thio-D
      galactoside-inducible clones of Escherichia coli cells that overproduce the five
      enzymes of the cpn pathway. The substrate specificities of CpnA and CpnB were
      studied in particular to evaluate the potential of these enzymes and establish
      the latter recombinant strain as a bioreagent for Baeyer-Villiger oxidations.
      Although frequently nonenantioselective, cyclopentanone 1,2-monooxygenase was
      found to exhibit a broader substrate range than the related cyclohexanone 1,2
      monooxygenase from Acinetobacter sp. strain NCIMB 9871. However, in a few cases
      opposite enantioselectivity was observed between the two biocatalysts.

PMID- 12406765
TI  - Effect of soil ammonium concentration on N2O release and on the community
      structure of ammonia oxidizers and denitrifiers.
AB  - The effect of ammonium addition (6.5, 58, and 395 microg of NH4+-N g [dry weight]
      of soil(-1)) on soil microbial communities was explored. For medium and high
      ammonium concentrations, increased N2O release rates and a shift toward a higher
      contribution of nitrification to N2O release occurred after incubation for 5 days
      at 4 degrees C. Communities of ammonia oxidizers were assayed after 4 weeks of
      incubation by denaturant gradient gel electrophoresis (DGGE) of the amoA gene
      coding for the small subunit of ammonia monooxygenase. The DGGE fingerprints were
      invariably the same whether the soil was untreated or incubated with low, medium,
      or high ammonium concentrations. Phylogenetic analysis of cloned PCR products
      from excised DGGE bands detected amoA sequences which probably belonged to
      Nitrosospira 16S rRNA clusters 3 and 4. Additional clones clustered with
      Nitrosospira sp. strains Ka3 and Ka4 and within an amoA cluster from unknown
      species. A Nitrosomonas-like amoA gene was detected in only one clone. In
      agreement with the amoA results, community profiles of total bacteria analyzed by
      terminal restriction fragment length polymorphism (T-RFLP) showed only minor
      differences. However, a community shift occurred for denitrifier populations
      based on T-RFLP analysis of nirK genes encoding copper-containing nitrite
      reductase with incubation at medium and high ammonia concentrations. Major
      terminal restriction fragments observed in environmental samples were further
      described by correspondence to cloned nirK genes from the same soil. Phylogenetic
      analysis grouped these clones into clusters of soil nirK genes. However, some
      clones were also closely related to genes from known denitrifiers. The shift in
      the denitrifier community was probably the consequence of the increased supply of
      oxidized nitrogen through nitrification. Nitrification activity increased upon
      addition of ammonium, but the community structure of ammonium oxidizers did not
      change.

PMID- 12406766
TI  - Engineering of polyploid Saccharomyces cerevisiae for secretion of large amounts
      of fungal glucoamylase.
AB  - We engineered Saccharomyces cerevisiae cells that produce large amounts of fungal
      glucoamylase (GAI) from Aspergillus awamori var. kawachi. To do this, we used the
      delta-sequence-mediated integration vector system and the heat-induced
      endomitotic diploidization method. delta-Sequence-mediated integration is known
      to occur mainly in a particular chromosome, and the copy number of the
      integration is variable. In order to construct transformants carrying the GAI
      gene on several chromosomes, haploid cells carrying the GAI gene on different
      chromosomes were crossed with each other. The cells were then allowed to form
      spores, which was followed by dissection. Haploid cells containing GAI genes on
      multiple chromosomes were obtained in this way. One such haploid cell contained
      the GAI gene on five chromosomes and exhibited the highest GAI activity (5.93
      U/ml), which was about sixfold higher than the activity of a cell containing one
      gene on a single chromosome. Furthermore, we performed heat-induced endomitotic
      diploidization for haploid transformants to obtain polyploid mater cells carrying
      multiple GAI genes. The copy number of the GAI gene increased in proportion to
      the ploidy level, and larger amounts of GAI were secreted.

PMID- 12406767
TI  - In vitro and in vivo invasiveness of different pulsed-field gel electrophoresis
      types of Listeria monocytogenes.
AB  - The virulence of different pulsed-field gel electrophoresis (PFGE) types of
      Listeria monocytogenes was examined by monitoring their ability to invade Caco-2
      cells. Strains belonging to seven different PFGE types originating from both
      foods and humans were included. No significant differences in invasiveness were
      detected between strains isolated from humans and those isolated from food.
      Strains belonging to PFGE type 1 expressed a significantly lower ability to
      invade cells compared to strains belonging to other PFGE types. Although strains
      of PFGE type 2 also seemed to invade at a low level, this was not significant in
      the present study. PFGE types 1 and 2 as well as type 14 are more frequently
      found in food than the four other PFGE types examined and moreover have a
      relatively low prevalence in humans compared to their prevalence in food. Thus,
      the hypothesis that some PFGE types are less virulent than others is supported by
      this study showing that certain PFGE types of L. monocytogenes commonly found in
      food are less invasive than others to Caco-2 cells. In contrast to the
      differences in invasion, identical intracellular growth rates between the
      different PFGE types were observed. In vivo studies of the actual ability of the
      strains to invade the liver and spleen of cimetidine-treated rats following an
      oral dose of 10(9) L. monocytogenes cells were performed for isolates of PFGE
      types 1, 2, 5, and 15. After 2 days, equal amounts of bacteria were observed in
      the liver and spleen of the rats for any of the PFGE types tested.

PMID- 12406768
TI  - Characterization of serracin P, a phage-tail-like bacteriocin, and its activity
      against Erwinia amylovora, the fire blight pathogen.
AB  - Serratia plymithicum J7 culture supernatant displayed activity against many
      pathogenic strains of Erwinia amylovora, the causal agent of the most serious
      bacterial disease of apple and pear trees, fire blight, and against Klebsiella
      pneumoniae, Serratia liquefaciens, Serratia marcescens, and Pseudomonas
      fluorescens. This activity increased significantly upon induction with mitomycin
      C. A phage-tail-like bacteriocin, named serracin P, was purified from an induced
      culture supernatant of S. plymithicum J7. It was found to be the only compound
      involved in the antibacterial activity against sensitive strains. The N-terminal
      amino acid sequence analysis of the two major subunits (23 and 43 kDa) of
      serracin P revealed high homology with the Fels-2 prophage of Salmonella
      enterica, the coliphages P2 and 168, the phiCTX prophage of Pseudomonas
      aeruginosa, and a prophage of Yersinia pestis. This strongly suggests a common
      ancestry for serracin P and these bacteriophages.

PMID- 12406769
TI  - Altered Glycosylation of 63- and 68-kilodalton microvillar proteins in Heliothis
      virescens correlates with reduced Cry1 toxin binding, decreased pore formation,
      and increased resistance to Bacillus thuringiensis Cry1 toxins.
AB  - The binding and pore formation abilities of Cry1A and Cry1Fa Bacillus
      thuringiensis toxins were analyzed by using brush border membrane vesicles (BBMV)
      prepared from sensitive (YDK) and resistant (YHD2) strains of Heliothis
      virescens. 125I-labeled Cry1Aa, Cry1Ab, and Cry1Ac toxins did not bind to BBMV
      from the resistant YHD2 strain, while specific binding to sensitive YDK vesicles
      was observed. Binding assays revealed a reduction in Cry1Fa binding to BBMV from
      resistant larvae compared to Cry1Fa binding to BBMV from sensitive larvae. In
      agreement with this reduction in binding, neither Cry1A nor Cry1Fa toxin altered
      the permeability of membrane vesicles from resistant larvae, as measured by a
      light-scattering assay. Ligand blotting experiments performed with BBMV and 125I
      Cry1Ac did not differentiate sensitive larvae from resistant larvae. Iodination
      of BBMV surface proteins suggested that putative toxin-binding proteins were
      exposed on the surface of the BBMV from resistant insects. BBMV protein blots
      probed with the N-acetylgalactosamine-specific lectin soybean agglutinin (SBA)
      revealed altered glycosylation of 63- and 68-kDa glycoproteins but not altered
      glycosylation of known Cry1 toxin-binding proteins in YHD2 BBMV. The F1 progeny
      of crosses between sensitive and resistant insects were similar to the sensitive
      strain when they were tested by toxin-binding assays, light-scattering assays,
      and lectin blotting with SBA. These results are evidence that a dramatic
      reduction in toxin binding is responsible for the increased resistance and cross
      resistance to Cry1 toxins observed in the YHD2 strain of H. virescens and that
      this trait correlates with altered glycosylation of specific brush border
      membrane glycoproteins.

PMID- 12406770
TI  - Function of native OmtA in vivo and expression and distribution of this protein
      in colonies of Aspergillus parasiticus.
AB  - The activities of two enzymes, a 168-kDa protein and a 40-kDa protein, OmtA,
      purified from the filamentous fungus Aspergillus parasiticus were reported to
      convert the aflatoxin pathway intermediate sterigmatocystin to O
      methylsterigmatocystin in vitro. Our initial goal was to determine if OmtA is
      necessary and sufficient to catalyze this reaction in vivo and if this reaction
      is necessary for aflatoxin synthesis. We generated A. parasiticus omtA-null
      mutant LW1432 and a maltose binding protein-OmtA fusion protein expressed in
      Escherichia coli. Enzyme activity analysis of OmtA fusion protein in vitro
      confirmed the reported catalytic function of OmtA. Feeding studies conducted with
      LW1432 demonstrated a critical role for OmtA, and the reaction catalyzed by this
      enzyme in aflatoxin synthesis in vivo. Because of a close regulatory link between
      aflatoxin synthesis and asexual sporulation (conidiation), we hypothesized a
      spatial and temporal association between OmtA expression and conidiospore
      development. We developed a novel time-dependent colony fractionation protocol to
      analyze the accumulation and distribution of OmtA in fungal colonies grown on a
      solid medium that supports both toxin synthesis and conidiation. OmtA-specific
      polyclonal antibodies were purified by affinity chromatography using an LW1432
      protein extract. OmtA was not detected in 24-h-old colonies but was detected in
      48-h-old colonies using Western blot analysis; the protein accumulated in all
      fractions of a 72-h-old colony, including cells (0 to 24 h) in which little
      conidiophore development was observed. OmtA in older fractions of the colony (24
      to 72 h) was partly degraded. Fluorescence-based immunohistochemical analysis
      conducted on thin sections of paraffin-embedded fungal cells from time
      fractionated fungal colonies demonstrated that OmtA is evenly distributed among
      different cell types and is not concentrated in conidiophores. These data suggest
      that OmtA is present in newly formed fungal tissue and then is proteolytically
      cleaved as cells in that section of the colony age.

PMID- 12406771
TI  - Identification of DNA-synthesizing bacterial cells in coastal North Sea plankton.
AB  - We describe a method for microscopic identification of DNA-synthesizing cells in
      bacterioplankton samples. After incubation with the halogenated thymidine
      analogue bromodeoxyuridine (BrdU), environmental bacteria were identified by
      fluorescence in situ hybridization (FISH) with horseradish peroxidase (HRP)
      linked oligonucleotide probes. Tyramide signal amplification was used to preserve
      the FISH staining during the subsequent immunocytochemical detection of BrdU
      incorporation. DNA-synthesizing cells were visualized by means of an HRP-labeled
      antibody Fab fragment and a second tyramide signal amplification step. We applied
      our protocol to samples of prefiltered (pore size, 1.2 micro m) North Sea surface
      water collected during early autumn. After 4 h of incubation, BrdU incorporation
      was detected in 3% of all bacterial cells. Within 20 h the detectable DNA
      synthesizing fraction increased to >14%. During this period, the cell numbers of
      members of the Roseobacter lineage remained constant, but the fraction of BrdU
      incorporating Roseobacter sp. cells doubled, from 24 to 42%. In Alteromonas sp.
      high BrdU labeling rates after 4 to 8 h were followed by a 10-fold increase in
      abundance. Rapid BrdU incorporation was also observed in members of the SAR86
      lineage. After 4 h of incubation, cells affiliated with this clade constituted 8%
      of the total bacteria but almost 50% of the visibly DNA-synthesizing bacterial
      fraction. Thus, this clade might be an important contributor to total
      bacterioplankton activity in coastal North Sea water during periods of low
      phytoplankton primary production. The small size and low ribosome content of
      SAR86 cells are probably not indications of inactivity or dormancy.

PMID- 12406772
TI  - Sensitive in situ monitoring of a recombinant bioluminescent Yersinia
      enterocolitica reporter mutant in real time on Camembert cheese.
AB  - Bioluminescent mutants of Yersinia enterocolitica were generated by transposon
      mutagenesis using a promoterless, complete lux operon (luxCDABE) derived from
      Photorhabdus luminescens, and their production of light in the cheese environment
      was monitored. Mutant B94, which had the lux cassette inserted into an open
      reading frame of unknown function was used for direct monitoring of Y.
      enterocolitica cells on cheeses stored at 10 degrees C by quantifying
      bioluminescence using a photon-counting, intensified charge-coupled device
      camera. The detection limit on cheese was 200 CFU/cm(2). Bioluminescence of the
      reporter mutant was significantly regulated by its environment (NaCl,
      temperature, and cheese), as well as by growth phase, via the promoter the lux
      operon had acquired upon transposition. At low temperatures, mutant B94 did not
      exhibit the often-reported decrease of photon emission in older cells. It was not
      necessary to include either antibiotics or aldehyde in the food matrix in order
      to gain quantitative, reproducible bioluminescence data. As far as we know, this
      is the first time a pathogen has been monitored in situ, in real time, in a "real
      product" status, and at a low temperature.

PMID- 12406773
TI  - Mercury methylation by Desulfovibrio desulfuricans ND132 in the presence of
      polysulfides.
AB  - The extracellular speciation of mercury may control bacterial uptake and
      methylation. Mercury-polysulfide complexes have recently been shown to be
      prevalent in sulfidic waters containing zero-valent sulfur. Despite substantial
      increases in total dissolved mercury concentration, methylation rates in cultures
      of Desulfovibrio desulfuricans ND132 equilibrated with cinnabar did not increase
      in the presence of polysulfides, as expected due to the large size and charged
      nature of most of the complexes. In natural waters not at saturation with
      cinnabar, mercury-polysulfide complexes would be expected to shift the speciation
      of mercury from HgS(0)((aq)) toward charged complexes, thereby decreasing
      methylation rates.

PMID- 12406774
TI  - Uptake rates of oxygen and sulfide measured with individual Thiomargarita
      namibiensis cells by using microelectrodes.
AB  - Gradients of oxygen and sulfide measured towards individual cells of the large
      nitrate-storing sulfur bacterium Thiomargarita namibiensis showed that in
      addition to nitrate oxygen is used for oxidation of sulfide. Stable gradients
      around the cells were found only if acetate was added to the medium at low
      concentrations.

PMID- 12406776
TI  - Differential enantioselective transformation of atropisomeric polychlorinated
      biphenyls by multiple bacterial strains with different inducing compounds.
AB  - Five polychlorinated biphenyl (PCB)-degrading bacteria were tested for the
      ability to differentiate between the enantiomers of four atropisomeric PCB
      congeners (2,2',3,6-tetra-CB; 2,2',3,3',6-penta-CB; 2,2',3,4',6-penta-CB; and
      2,2',3,5',6-penta-CB) after growth in the presence of tryptone-soytone, biphenyl,
      carvone, or cymene. Enantioselectivity was shown to vary with respect to strain,
      congener, and cosubstrate.

PMID- 12406775
TI  - Large-scale production of coenzyme F420-5,6 by using Mycobacterium smegmatis.
AB  - Production of coenzyme F420 and its biosynthetic precursor FO was examined with a
      variety of aerobic actinomycetes to identify an improved source for these
      materials. Based on fermentation costs, safety, and ease of growth, Mycobacterium
      smegmatis was the best source for F420-5,6. M. smegmatis produced 1 to 3 micromol
      of intracellular F420 per liter of culture, which was more than the 0.85 to 1.0
      micromol of F420-2 per liter usually obtained with Methanobacterium
      thermoautotrophicum and approximately 10-fold higher than what was previously
      reported for the best aerobic actinomycetes. An improved chromatography system
      using rapidly flowing quaternary aminoethyl ion-exchange material and Florisil
      was used to more quickly and easily purify F420 than with previous methods.

PMID- 12406777
TI  - Diversity of diazotrophic unicellular cyanobacteria in the tropical North
      Atlantic Ocean.
AB  - We present data on the genetic diversity and phylogenetic affinities of N2-fixing
      unicellular cyanobacteria in the plankton of the tropical North Atlantic Ocean.
      Our dinitrogenase gene (nifH) sequences grouped together with a group of
      cyanobacteria from the subtropical North Pacific; another subtropical North
      Pacific group was only distantly related. Most of the 16S ribosomal DNA sequences
      from our tropical North Atlantic samples were closely allied with sequences from
      a symbiont of the diatom Climacodium frauenfeldianum. These findings suggest a
      complex pattern of evolutionary and ecological divergence among unicellular
      cyanobacteria within and between ocean basins.

PMID- 12406778
TI  - Transcript analysis of genes encoding a family 61 endoglucanase and a putative
      membrane-anchored family 9 glycosyl hydrolase from Phanerochaete chrysosporium.
AB  - Phanerochaete chrysosporium cellulase genes were cloned and characterized. The
      cel61A product was structurally similar to fungal endoglucanases of glycoside
      hydrolase family 61, whereas the cel9A product revealed similarities to
      Thermobifida fusca Cel9A (E4), an enzyme with both endo- and exocellulase
      characteristics. The fungal Cel9A is apparently a membrane-bound protein, which
      is very unusual for microbial cellulases. Transcript levels of both genes were
      substantially higher in cellulose-grown cultures than in glucose-grown cultures.
      These results show that P. chrysosporium possesses a wide array of conventional
      and unconventional cellulase genes.

PMID- 12406779
TI  - Regulation of freA, acoA, lysF, and cycA expression by iron availability in
      Aspergillus nidulans.
AB  - In the filamentous fungus Aspergillus nidulans, iron homeostasis is regulated at
      the transcriptional level by the negative-acting GATA factor SREA. In this study
      the expression of a putative heme-containing metalloreductase-encoding gene,
      freA, was found to be upregulated by iron limitation independently of SREA,
      demonstrating the existence of an iron-regulatory mechanism which does not
      involve SREA. In contrast to freA, various other genes encoding proteins in need
      of iron-containing cofactors-acoA, lysF, and cycA-were downregulated in response
      to iron depletion. Remarkably, SREA deficiency led to increased expression of
      acoA, lysF, and cycA under iron-replete growth conditions.

PMID- 12406780
TI  - High-frequency rugose exopolysaccharide production by Vibrio cholerae.
AB  - Vibrio cholerae can shift to a "rugose" phenotype, thereby producing copious
      exopolysaccharide (EPS), which promotes its environmental survival and
      persistence. We report conditions that promote high-frequency rugose EPS
      production (HFRP), whereby cells switch at high frequency (up to 80%) to rugose
      EPS production. HFRP appeared to be more common in clinical strains, as HFRP was
      found in 6 of 19 clinical strains (32%) (including classical, El Tor, and non-O1
      strains) but in only 1 of 16 environmental strains (6%). Differences were found
      between strains in rugose colony morphology, conditions promoting HFRP, the
      frequency of rugose-to-smooth (R-S) cell reversion, and biofilm formation. We
      propose that rugose EPS and HFRP provide an evolutionary and adaptive advantage
      to specific epidemic V. cholerae strains for increased persistence in the
      environment.

PMID- 12406781
TI  - Application of carbon source utilization patterns to measure the metabolic
      similarity of complex dental plaque biofilm microcosms.
AB  - Biolog technology was applied to measure the metabolic similarity of plaque
      biofilm microcosms, which model the complex properties of dental plaque in vivo.
      The choice of Biolog plate, incubation time, and incubation conditions strongly
      influenced utilization profiles. For plaque biofilm microcosms, Biolog GP2 plates
      incubated anaerobically in an H2-free atmosphere gave the clearest profile. To
      test the application of the Biolog GP2 assay, plaque microcosms were developed
      under different nutrient conditions in which the frequency of sucrose application
      was varied. Cluster analysis of Biolog GP2 data from 10 microcosm biofilms
      correlated with sucrose frequency. Aciduric bacteria (Streptococcus mutans plus
      lactobacilli) predominated in the plaques receiving high-frequency sucrose
      applications. Agreement between the Biolog GP2 groupings with nutrient and
      compositional changes suggests that Biolog analysis is a valuable technique for
      analyzing the metabolic similarity of dental plaque biofilm microcosms and other
      high-nutrient or predominantly anaerobic ecosystems.

PMID- 12406782
TI  - Serum as a factor influencing adhesion of Enterococcus faecalis to glass and
      silicone.
AB  - The purpose of this work was to analyze the effect of serum on the
      physicochemical surface properties and adhesion to glass and silicone of
      Enterococcus faecalis ATCC 29212 at 37 degrees C. As is presented using
      thermodynamics analysis, serum minimizes the interaction of cells with water,
      which correlates well with the increase in hydrophobicity and in bacterial
      adhesion to glass and silicone.

PMID- 12406784
TI  - Broadening the focus of epidemiology and public health training.

PMID- 12406785
TI  - Scientific evidence supports anthrax vaccination.

PMID- 12406786
TI  - Recognition of osteoporosis since 1997.

PMID- 12406789
TI  - "Palliatives will no longer do": the deep roots and continuing dynamic of
      community-oriented primary care.

PMID- 12406790
TI  - Community-oriented primary care: a path to community development.
AB  - Although community development and social change are not explicit goals of
      community-oriented primary care (COPC), they are implicit in COPC's emphasis on
      community organization and local participation with health professionals in the
      assessment of health problems. These goals are also implicit in the shared
      understanding of health problems' social, physical, and economic causes and in
      the design of COPC interventions. In the mid-1960s, a community health center in
      the Mississippi Delta created programs designed to move beyond narrowly focused
      disease-specific interventions and address some of the root causes of community
      morbidity and mortality. Drawing on the skills of the community itself, a
      selfsustaining process of health-related social change was initiated. A key
      program involved the provision of educational opportunities.

PMID- 12406791
TI  - The Jerusalem experience: three decades of service, research, and training in
      community-oriented primary care.
AB  - Community-oriented primary care (COPC) developed and was tested over nearly 3
      decades in the Hadassah Community Health Center in Jerusalem, Israel. Integration
      of public health responsibility with individual-based clinical management of
      patients formed the cornerstone of the COPC approach. A family medicine practice
      and a mother and child preventive service provided the frameworks for this
      development. The health needs of the community were assessed, priorities
      determined, and intervention programs developed and implemented on the basis of
      detailed analysis of the factors responsible for defined health states. Ongoing
      health surveillance facilitated evaluation, and the effectiveness of
      interventions in different population groups was illustrated. The center's
      international COPC involvement has had effects on primary health care policy
      worldwide.

PMID- 12406792
TI  - The community-oriented primary care experience in the United kingdom.
AB  - The UK National Health Service has long delivered public health programs through
      primary care. However, attempts to promote Sidney Kark's model of community
      oriented primary care (COPC), based on general practice populations, have made
      only limited headway. Recent policy developments give COPC new resonance.
      Currently, primary care trusts are assuming responsibility for improving the
      health of the populations they serve, and personal medical service pilots are
      tailoring primary care to local needs under local contracts. COPC has yielded
      training packages and frameworks that can assist these new organizations in
      developing public health skills and understanding among a wide range of primary
      care professionals.

PMID- 12406793
TI  - Roots, shoots, but too little fruit: assessing the contribution of COPC in South
      Africa.
AB  - Community-oriented primary care (COPC) originated in South Africa during the
      1940s and 1950s, where it served to inform local church-based and nongovernmental
      organization-based initiatives during the apartheid years. During the 1990s, COPC
      played an inspirational role in the process of national health policy
      formulation. Yet COPC's contribution to current health practice remains more
      symbolic than substantive. Despite a policy framework that favors the widespread
      introduction of COPC, various political, structural, managerial, and human
      resource obstacles constrain its effective implementation. Notwithstanding a
      rapidly changing health care environment and well-established health transition
      from infections and nutritional disorders to non-communicable diseases and
      injury, COPC and its variants remain abidingly relevant to South Africa's-and
      Africa's-health care reality.

PMID- 12406794
TI  - Community-oriented primary care in action: a Dallas story.
AB  - Dallas County, Texas, is the site of the largest urban application of the
      community-oriented primary care (COPC) model in the United States. We summarize
      the development and implementation of Dallas's Parkland Health & Hospital System
      COPC program. The complexities of implementing and managing this comprehensive
      community-based program are delineated in terms of Dallas County's political
      environment and the components of COPC (assessment, prioritization, community
      collaboration, health care system, evaluation, and financing). Steps to be taken
      to ensure the future growth and development of the Dallas program are also
      considered. The COPC model, as implemented by Parkland, is replicable in other
      urban areas.

PMID- 12406795
TI  - Rural health centers in the Americas.

PMID- 12406796
TI  - International efforts spotlight traditional, complementary, and alternative
      medicine.
AB  - Affordable, available, and ever more popular at home and abroad, "alternative"
      healers are finally getting positive attention from Western practitioners. This
      rapprochement has enormous implications for public health worldwide.

PMID- 12406797
TI  - Pursuing community-oriented primary care in a Russian closed nuclear city: the
      Sarov-Los Alamos community health partnership.
AB  - The Russian health care system historically has not relied on medical evidence to
      guide practice, uses centralized management, and is burdened by
      overspecialization. In 1999, a community health partnership was established
      between Sarov, Russia, and Los Alamos, NM, 2 cities linked by their nuclear
      weapons histories. Health problems addressed include asthma and diabetes,
      pediatric dental caries, low prevalence of breastfeeding, and adolescent drug
      abuse and sexually transmitted diseases. A community-oriented primary care
      approach was adopted that includes (1) implementing a "train the trainers"
      strategy to educate health professionals and lay people, (2) adapting established
      clinical practice guidelines based on local resources, (3) restricting use of
      expensive or limited resources, and (4) securing commitments from local
      government for expendable supplies and medications.

PMID- 12406798
TI  - The Pholela Health Centre: a progress report. 1952.

PMID- 12406799
TI  - Sidney Kark and John Cassel: social medicine pioneers and South African emigres.

PMID- 12406800
TI  - Community-oriented primary care: new relevance in a changing world.
AB  - Since its inception in rural, pre-apartheid South Africa, community-oriented
      primary care (COPC) has intrigued and informed public health and primary care
      leaders worldwide. COPC has influenced such programs as the US community health
      center movement, the general practice movement in the United Kingdom, and recent
      reforms in the public health system of South Africa. We provide a global overview
      of COPC, tracing its conceptual roots, reviewing its many manifestations, and
      exploring its future prospects as an organizational paradigm for the democratic
      organization of community health services. We examine the pitfalls and paradoxes
      of COPC and suggest its future utility. COPC has important values and methods to
      offer disparate but powerful movements in public health worldwide.

PMID- 12406801
TI  - Hepatitis B vaccination among research participants, Seattle, Washington.

PMID- 12406802
TI  - Studying cancer incidence and outcomes in immigrants: methodological concerns.

PMID- 12406803
TI  - Changes in HIV testing after implementation of name-based HIV case surveillance
      in New Mexico.

PMID- 12406804
TI  - The midwife as an "Instrument" of care.

PMID- 12406805
TI  - The contextual effect of the local food environment on residents' diets: the
      atherosclerosis risk in communities study.
AB  - OBJECTIVES: We studied the association between the local food environment and
      residents' report of recommended dietary intake. METHODS: Recommended intakes of
      foods and nutrients for 10 623 Atherosclerosis Risk in Communities participants
      were estimated from food frequency questionnaires. Supermarkets, grocery stores,
      and full-service and fast-food restaurants were geocoded to census tracts.
      RESULTS: Black Americans' fruit and vegetable intake increased by 32% for each
      additional supermarket in the census tract (relative risk [RR] = 1.32; 95%
      confidence interval [CI] = 1.08, 1.60). White Americans' fruit and vegetable
      intake increased by 11% with the presence of 1 or more supermarket (RR = 1.11;
      95% CI = 0.93, 1.32). CONCLUSIONS: These findings suggest the local food
      environment is associated with residents' recommended diets.

PMID- 12406806
TI  - Variability and vulnerability at the ecological level: implications for
      understanding the social determinants of health.
AB  - OBJECTIVES: We examined variability in disease rates to gain understanding of the
      complex interactions between contextual socioeconomic factors and health.
      METHODS: We compared mortality rates between New York and California counties in
      the lowest and highest quartiles of socioeconomic status (SES), assessed rate
      variability between counties for various outcomes, and examined correlations
      between outcomes' sensitivity to SES and their variability. RESULTS: Outcomes
      with mortality rates that differed most by county SES were among those whose
      variability across counties was high (e.g., AIDS, homicide, cirrhosis). Lower-SES
      counties manifested greater variability among outcome measures. CONCLUSIONS:
      Differences in health outcome variability reflect differences in SES impact on
      health. Health variability at the ecological level might reflect the impact of
      stressors on vulnerable populations.

PMID- 12406807
TI  - The impact of government policies and neighborhood characteristics on teenage
      sexual activity and contraceptive use.
AB  - OBJECTIVES: This study sought to examine the effects of government policies and
      neighborhood characteristics on adolescent female sexual behavior to better
      inform future public policy decisions. METHODS: Using a bivariate probit model
      and National Survey of Family Growth data on women aged 15 through 19 years, we
      estimated the probabilities of their being sexually active and, if sexually
      active, of their using contraceptives. RESULTS: Variables measuring the cost of
      obtaining an abortion are not good predictors of sexual activity or contraceptive
      use. However, the relationship between family planning availability and
      contraceptive use is statistically significant at conventional levels.
      CONCLUSIONS: Policymakers seem to have little leverage with regard to influencing
      the decision to become sexually active, although increased access to family
      planning services may encourage responsible contraceptive behavior. Neighborhood
      context is an important determinant of adolescent female sexual behavior.

PMID- 12406808
TI  - Provision of sexual health services to adolescent enrollees in Medicaid managed
      care.
AB  - OBJECTIVES: This Seattle project measured sexual health services provided to 1112
      Medicaid managed care enrollees aged 14 to 18 years. METHODS: Three health
      maintenance organizations (HMOs) that provide Medicaid services for a capitated
      rate agreed to participate. These included a non-profit staff-model HMO, a for
      profit independent practice association (IPA), and a non-profit alliance of
      community clinics. Analyses used health maintenance organizations' administrative
      data, chart reviews, and Medicaid encounter data. RESULTS: Health maintenance
      organizations provided primary care to 54% and well care to 20% of Medicaid
      enrollees. Girls were more likely than boys to have their sexual history taken or
      to be given condom counseling. Only 27% of sexually active girls were tested for
      chlamydia, with significantly lower rates of testing among those who spoke
      English as a second language. The nonprofit staff-model plan outperformed the for
      profit independent practice association on most measures. CONCLUSIONS:
      Substantial room for improvement exists in sexual health services delivery to
      adolescent Medicaid managed care enrollees.

PMID- 12406809
TI  - STD screening, testing, case reporting, and clinical and partner notification
      practices: a national survey of US physicians.
AB  - OBJECTIVES: This study presents results from a national survey of US physicians
      that assessed screening, case reporting, partner management, and clinical
      practices for syphilis, gonorrhea, chlamydia, and HIV infection. METHODS: Surveys
      were mailed to a random sample of 7300 physicians to assess screening, testing,
      reporting, and partner notification for syphilis, gonorrhea, chlamydia, and HIV.
      RESULTS: Fewer than one third of physicians routinely screened men or women
      (pregnant or nonpregnant) for STDs. Case reporting was lowest for chlamydia (37
      percent), intermediate for gonorrhea (44 percent), and higher for syphilis, HIV,
      and AIDS (53 percent-57 percent). Physicians instructed patients to notify their
      partners (82 percent-89 percent) or the health department (25 percent-34 percent)
      rather than doing so themselves. CONCLUSIONS: STD screening levels are well below
      practice guidelines for women and virtually nonexistent for men. Case reporting
      levels are below those legally mandated; physicians rely instead on patients for
      partner notification. Health departments must increase collaboration with private
      physicians to improve the quality of STD care.

PMID- 12406810
TI  - The burden of infectious disease among inmates of and releasees from US
      correctional facilities, 1997.
AB  - OBJECTIVES: This study developed national estimates of the burden of selected
      infectious diseases among correctional inmates and releases during 1997. METHODS:
      Data from surveys, surveillance, and other reports were synthesized to develop
      these estimates. RESULTS: During 1997, 20% to 26% of all people living with HIV
      in the United States, 29% to 43% of all those infected with the hepatitis C
      virus, and 40% of all those who had tuberculosis disease in that year passed
      through a correctional facility. CONCLUSIONS: Correctional facilities are
      critical settings for the efficient delivery of prevention and treatment
      interventions for infectious diseases. Such interventions stand to benefit not
      only inmates, their families, and partners, but also the public health of the
      communities to which inmates return.

PMID- 12406811
TI  - HIV infection and pregnancy status among adults attending voluntary counseling
      and testing in 2 developing countries.
AB  - OBJECTIVES: This study investigated the impact of HIV voluntary counseling and
      testing (VCT) on reproduction planning among 1634 adults in 2 sub-Saharan
      countries. METHODS: Data were obtained from a multisite randomized controlled
      trial. RESULTS: At 6 months post-VCT, the women more likely to be pregnant were
      younger (odds ratio [OR] = 2.5; 95% confidence interval [CI] = 1.0, 6.5), not
      using contraceptives (OR = 0.1; 95% CI = 0.1, 0.3), and HIV infected (OR = 3.0;
      95% CI = 1.3, 7.0). An interaction emerged linking pregnancy intention at
      baseline and HIV serostatus with pregnancy at follow-up (OR = 0.1; 95% CI =.0,
      0.4) Partner pregnancy rates did not differ by HIV serostatus among men.
      CONCLUSIONS: HIV diagnosis may influence reproduction planning for women but not
      for men.

PMID- 12406812
TI  - A reexamination of smoking before, during, and after pregnancy.
AB  - OBJECTIVES: This study examined the patterns and correlates of maternal smoking
      before, during, and after pregnancy. METHODS: We examined socioeconomic,
      demographic, and clinical risk factors associated with maternal smoking in a
      nationally representative cohort of women (n = 8285) who were surveyed 17 +/- 5
      months and again 35 +/- 5 months after delivery. RESULTS: Smoking rates among
      women with a college degree decreased 30% from before pregnancy to 35 months
      postpartum but did not change among the least educated women. Risk factors
      clustered, and a gradient linked the number of risk factors (0, 2, 4) to the
      percentage smoking (6%, 31%, 58%, P <.0001). CONCLUSIONS: The period of pregnancy
      and early parenthood is associated with worsening education-related disparities
      in smoking as well as substantial clustering of risk factors. These observations
      could influence the targeting and design of maternal smoking interventions.

PMID- 12406813
TI  - The relationship between periodontal disease attributes and Helicobacter pylori
      infection among adults in the United States.
AB  - OBJECTIVES: We investigated the relationship between Helicobacter pylori
      infection and abnormal periodontal conditions. METHODS: Data from the first phase
      of the third National Health and Nutrition Examination Survey were used. A total
      of 4504 participants aged 20 to 59 years who completed a periodontal examination
      and tested positive for H. pylori antibodies were examined. RESULTS: Periodontal
      pockets with a depth of 5 mm or more were associated with increased odds of H.
      pylori seropositivity (odds ratio [OR] = 1.47; 95% confidence interval [CI] =
      1.12, 1.94) after adjustment for sociodemographic factors. This association is
      comparable to the independent effects of poverty on H. pylori (OR = 1.54; 95% CI
      = 1.10, 2.16). CONCLUSIONS: Poor periodontal health, characterized by advanced
      periodontal pockets, may be associated with H. pylori infection in adults,
      independent of poverty status.

PMID- 12406814
TI  - Relationship between children's dental needs and dental care utilization: United
      States, 1988-1994.
AB  - OBJECTIVES: This study describes the relationship between dental needs and dental
      care utilization among children. METHODS: Data from the third National Health and
      Nutrition Examination Survey (1988-1994) were used to analyze dental care needs
      and dental care utilization. RESULTS: Younger children with perceived needs
      (needs perceived by the child or responsible adult) were more likely to be
      episodic users of dental care than children without perceived needs. Younger
      children with normative needs (defined by the presence of untreated caries
      diagnosed by a dentist) were less likely to be regular users. Older children with
      perceived or normative needs were more likely to be episodic users and less
      likely to have had a previous-year visit than children with no needs.
      CONCLUSIONS: Despite their presence, dental needs do not drive dental care use
      among children, and children's dental care utilization is inadequate.

PMID- 12406815
TI  - Reductions in injury crashes associated with red light camera enforcement in
      oxnard, california.
AB  - OBJECTIVES: This study estimated the impact of red light camera enforcement on
      motor vehicle crashes in one of the first US communities to employ such cameras
      Oxnard, California. METHODS: Crash data were analyzed for Oxnard and for 3
      comparison cities. Changes in crash frequencies were compared for Oxnard and
      control cities and for signalized and nonsignalized intersections by means of a
      generalized linear regression model. RESULTS: Overall, crashes at signalized
      intersections throughout Oxnard were reduced by 7% and injury crashes were
      reduced by 29%. Right-angle crashes, those most associated with red light
      violations, were reduced by 32%; right-angle crashes involving injuries were
      reduced by 68%. CONCLUSIONS: Because red light cameras can be a permanent
      component of the transportation infrastructure, crash reductions attributed to
      camera enforcement should be sustainable.

PMID- 12406816
TI  - Rearrest rates after incarceration for DWI: a comparative study in a southwestern
      US county.
AB  - OBJECTIVES: This study was undertaken to assess a 28-day detention and treatment
      program's effect, in a multiethnic county with high rates of alcohol-related
      arrests and crashes, on first-time offenders sentenced for driving while impaired
      (DWI). METHODS: We used comparison of baseline characteristics, survival curves
      of subsequent arrest, and Cox proportional hazards regression to examine
      probability of rearrest of those sentenced and those not sentenced to the
      program. RESULTS: Probability of not being rearrested was significantly higher
      for the treatment group after adjustment for covariates. At 5 years, probability
      of not being rearrested for the treatment vs the nontreatment group was 76.6% vs
      59.9%. CONCLUSIONS: Results suggest that this county's program has significantly
      affected rearrest rates for Native Americans, Hispanics, and non-Hispanic Whites.

PMID- 12406817
TI  - Ethnic differences in use of complementary and alternative medicine at midlife:
      longitudinal results from SWAN participants.
AB  - OBJECTIVES: We estimated the prevalence and longitudinal correlates of use of
      complementary and alternative medicine (CAM) at midlife among participants of the
      Study of Women's Health Across the Nation (SWAN). METHODS: Multiple logistic
      regression was used to evaluate the relationship between baseline survey-reported
      symptoms and use of herbal, spiritual, and physical manipulation therapies 1 year
      later. RESULTS: Almost half of all women had used CAM in the past year. Baseline
      psychological symptoms were associated with subsequent use of spiritual therapies
      among White and Chinese women. Baseline CAM use was a major predictor of
      subsequent use in White, Japanese, and Chinese women. CONCLUSIONS: Baseline CAM
      use, rather than presence of symptoms, was the major predictor of subsequent CAM
      use. Premenopausal health behaviors are important determinants of choice of
      therapy during midlife.

PMID- 12406818
TI  - Will screening mammography in the East do more harm than good?
AB  - OBJECTIVES: We sought to systematically review the evidence for population-based
      mammography as applied to a Chinese population. METHODS: Primary reports for meta
      analysis were identified by a search of MEDLINE and the Cochrane Library. Outcome
      measures included breast cancer-related mortality, the number needed to be
      screened to prevent 1 death, and the positive predictive value of mammography.
      RESULTS: Pooled relative risk for breast cancer-related death in the screened
      group was 0.80 (95% confidence interval = 0.71, 0.90). Applied to Hong Kong, this
      figure translates into a number needed to screen of 1 302 healthy women screened
      annually for 10 years to prevent 1 death. CONCLUSIONS: Evidence is insufficient
      to justify population-based breast cancer screening by mammography for women in
      Hong Kong and other Asian populations with low breast cancer prevalence.

PMID- 12406819
TI  - Montelukast prevents antigen-induced mucociliary dysfunction in sheep.
AB  - The cysteinyl leukotrienes are potent proinflammatory mediators that, in addition
      to their bronchospastic actions, can also contribute to mucociliary dysfunction,
      a central component of the pathophysiology of asthma. In this study, we
      determined whether montelukast, a cysteinyl leukotriene 1 receptor antagonist,
      could prevent and/or reverse antigen-induced mucociliary dysfunction in allergic
      sheep. We measured tracheal mucus velocity, a marker of mucociliary clearance,
      before and for 8 hours after antigen challenge in six animals treated with
      montelukast (0.15 mg/kg, intravenously) 30 minutes before, 1 hour after, or 4
      hours after antigen challenge. In the control trial, the sheep received 0.9%
      saline intravenously at each of the previously mentioned time points. The maximum
      decrease in tracheal mucus velocity seen in the control trial was 56 +/- 4% (mean
      +/- SE) of baseline at 8 hours. Pretreatment with montelukast significantly
      protected against this reduction. However, treatment at 1 and 4 hours neither
      protected against nor reversed the allergen-induced fall in tracheal mucus
      velocity. We conclude that the early release of cysteinyl leukotrienes may
      contribute to the fall in tracheal mucus velocity that follows acute antigen
      challenge and that pretreatment with montelukast reduces this impairment.

PMID- 12406820
TI  - Antiinflammatory effects of genistein, a tyrosine kinase inhibitor, on a guinea
      pig model of asthma.
AB  - Protein tyrosine kinase signaling cascade plays a pivotal role in the activation
      of inflammatory cells. The purpose of this study was to investigate the effects
      of genistein, a broad-spectrum protein tyrosine kinase inhibitor, on airway
      inflammation in an in vivo guinea pig model of asthma. Guinea pigs were actively
      sensitized by intraperitoneal injections of ovalbumin. Aerosolized ovalbumin
      induced acute bronchoconstriction in conscious animals in a dose-dependent
      manner. Genistein (15 mg/kg given intraperitoneally) markedly inhibited ovalbumin
      induced, but not histamine- and methacholine-induced, acute bronchoconstriction.
      In addition, genistein significantly reduced ovalbumin-induced increases in total
      cell counts and eosinophils recovered in bronchoalveolar lavage fluid, airway
      eosinophilia, and eosinophil peroxidase activity in cell-free bronchoalveolar
      lavage fluid and markedly attenuated ovalbumin-induced airway hyperresponsiveness
      to inhaled methacholine. Immunoblot analysis of lung lysates isolated from
      genistein-pretreated animals showed that epidermal growth factor-induced tyrosine
      phosphorylation in lung tissues was inhibited by genistein. These results
      implicate that inhibition of tyrosine kinase signaling cascade may have
      therapeutic potential for allergic airway inflammation.

PMID- 12406821
TI  - In vivo and in vitro effects of SAR 943, a rapamycin analogue, on airway
      inflammation and remodeling.
AB  - No current therapy is considered to be satisfactory for severe asthma, and
      alternative approaches are still required for what is a major unmet medical need.
      In this study, we compared the effect of a rapamycin derivative, SAR 943, with
      budesonide, using a murine model of lung inflammation and remodeling. Allergen
      challenge of ovalbumin-sensitized BALB/c mice induced an increase in the levels
      of interleukin-5 and interleukin-4; numbers of eosinophil, neutrophil, and
      lymphocyte; cellular fibronectin; lung epithelial cell proliferation and mucus
      hypersecretory phenotype; as well as hyperreactivity to methacholine. Both SAR
      943 and budesonide, when given intranasally 1 hour before and 24 hours after the
      aerosol challenge, inhibited all of these parameters with a similar potency
      (effective dose 50% of 1 mg/kg). In primary cultured smooth muscle cells from
      human airways, SAR 943 dose dependently inhibited epidermal growth factor-induced
      proliferation but did not affect the basal cell proliferation. Neither the basal
      nor stimulated proliferation of a human bronchial epithelial cell line (16HBE14o
      ) was affected by SAR 943. In conclusion, SAR 943 is as effective as budesonide
      in inhibiting both lung inflammation and remodeling in a murine model of asthma.
      Hence, this class of compound could offer beneficial effects in patients with
      severe asthma.

PMID- 12406822
TI  - Patient, physician, and family member understanding of living wills.
AB  - This study examines understanding of living wills by patients, family members,
      and physicians. Questionnaires were used to examine whether each cohort
      understood patients' living wills regarding endotracheal intubation and
      cardiopulmonary rescuscitation (CPR). Of 4,800 patients admitted during the study
      period, 206 reported having living wills, all of which precluded intubation and
      CPR for "terminal conditions." Of 140 admitted to the general hospital wards, 17
      (12%) wanted their living wills to preclude intubation/mechanical ventilation and
      12 (8.6%) did not want resuscitation under any circumstances. Seven of 120 (6%)
      physicians and 4 of 108 family members would not intubate or perform CPR even if
      there was a chance of recovery. Of 88 patients with complete data (including
      physicians and family members), 29 (33%) wanted their living wills to block
      intubation/mechanical ventilation only if they were deemed terminal and 46 (52%)
      wanted the living will to block intubation even if there was a 10% chance of
      recovery. Thirteen (15%) wanted to block intubation even if the chance of
      recovery was > or = 50. Results were similar for wishes regarding CPR. These data
      suggest substantial differences of patient, physician, and family member
      understanding of living wills. Living wills did not reflect fully patients'
      expectations of receiving (or not receiving) life-sustaining modalities.

PMID- 12406823
TI  - Effect of discontinuation of inhaled corticosteroids in patients with chronic
      obstructive pulmonary disease: the COPE study.
AB  - The aim of this double-blind single center study (the COPE study) was to
      investigate the effect of discontinuation of the inhaled corticosteroid
      fluticasone propionate (FP) on exacerbations and health-related quality of life
      in patients with chronic obstructive pulmonary disease. After 4 months of
      treatment with FP (1,000 microg/day), 244 patients were randomized to either
      continue FP or to receive placebo for 6 months: 123 patients continued FP (FP
      group), and 121 received placebo (placebo group). In the FP group, 58 (47%)
      patients developed at least one exacerbation compared with 69 (57%) in the
      placebo group. The hazard ratio of a first exacerbation in the placebo group
      compared with the FP group was 1.5 (95% confidence interval [CI] 1.1-2.1). In the
      placebo group 26 patients (21.5%) experienced rapid recurrent exacerbations and
      were subsequently unblinded and prescribed FP compared with 6 patients (4.9%) in
      the FP group (relative risk = 4.4; 95% CI 1.9-10.3). Over a 6-month period, a
      significant difference in favor of the FP group was observed in the total score
      (+2.48 95% CI 0.37-4.58), activity domain (+4.64 95% CI 1.60-7.68), and symptom
      domain (+4.58 95% CI 1.05-8.10) of the St. George's Respiratory Questionnaire.
      This study indicates that discontinuation of FP in patients with chronic
      obstructive pulmonary disease is associated with a more rapid onset and higher
      recurrence-risk of exacerbations and a significant deterioration in aspects of
      Health-Related Quality of Life.

PMID- 12406824
TI  - Histomorphometric analysis of bone biopsies from the iliac crest of adults with
      cystic fibrosis.
AB  - This study reports the results of quantitative analysis of iliac bone histology
      in adults with cystic fibrosis (CF) and low bone mineral density (BMD). Twenty
      patients with CF had bone biopsies taken after double tetracycline labeling.
      Histomorphometric measurements were made by image analysis, and data were
      compared with those of healthy control subjects. Cancellous bone area was lower
      in the patients with CF (p = 0.003), and there was a trend towards a decrease in
      cancellous bone connectivity. Bone formation rate at tissue level was
      significantly lower in patients with CF (p = 0.0002). Wall width, representing
      the amount of bone formed within individual remodeling units, was decreased (p <
      0.0001), as was mineralizing perimeter and mineral apposition rate. Analysis of
      resorption cavities revealed lower cavity area, reconstructed surface lengths,
      and cavity depths (p < 0.003) in patients with CF, whereas eroded surface area
      was higher (p = 0.0004). Our results demonstrate low cancellous bone volume in
      adult patients with CF with low BMD, the main cause of which appears to be low
      bone formation at tissue and cellular level. Osteomalacia was diagnosed in one
      patient. This condition should be excluded as a cause of low bone mineral density
      in patients with CF and vitamin D insufficiency corrected.

PMID- 12406825
TI  - Inhaled corticosteroids and hip fracture: a population-based case-control study.
AB  - There is accumulating evidence that the use of inhaled corticosteroids is
      associated with a dose-related reduction in bone mineral density. Whether this
      translates to an increase in fracture is unclear. We have used the General
      Practice Research Database to perform a case-control analysis, including 16,341
      cases of hip fracture (mean age of 79 years, 79% female, median period
      prescribing data 2.7 years) and 29,889 control subjects, individually matched by
      age, sex, and general practice. Data for all prescriptions for corticosteroids
      and for potential confounders, including other drug use and comorbid illnesses,
      were extracted, and the impact of inhaled corticosteroid exposure was analyzed
      using conditional logistic regression. The risk of hip fracture was associated
      with exposure to inhaled corticosteroids with an odds ratio of 1.26 (95%
      confidence interval, 1.17 to 1.36). This odds ratio was reduced after adjusting
      the model for annual courses of oral corticosteroids, the only confounder of note
      (OR 1.19; 95% CI, 1.10 to 1.28). There was a dose-response relationship between
      inhaled corticosteroid use and hip fracture even after adjusting for the annual
      number of courses of oral corticosteroids (p trend = 0.007). In older subjects,
      the recent use of inhaled corticosteroids is associated with a dose-related
      increase in hip fracture.

PMID- 12406826
TI  - Upper airway size analysis by magnetic resonance imaging of children with
      obstructive sleep apnea syndrome.
AB  - Detailed analysis of the upper airway has not been performed in children with
      obstructive sleep apnea. We used magnetic resonance imaging and automatic
      segmentation to delineate the upper airway in 20 children with obstructive sleep
      apnea and in 20 control subjects (age, 3.7 +/- 1.4 versus 3.9 +/- 1.7 years,
      respectively). We measured mean and minimal cross-sectional area, length, and
      volume of: (1) the total airway; (2) regions along the adenoid, tonsils, and
      where adenoid and tonsils overlap; and (3) 10 segments at 10% increments along
      the airway. The mean cross-sectional area of the total airway of the obstructive
      sleep apnea group was significantly smaller in comparison with the control group,
      28.1 +/- 12.6 versus 47.1 +/- 18.2 mm2, respectively (p < 0.0005). Minimal cross
      sectional area and airway volume were smaller in this group, 4.6 +/- 3.3 versus
      15.7 +/- 12.7 mm2 (p < 0.0005), and 1,129 +/- 515 versus 1,794 +/- 846 mm3 (p <
      0.005), respectively. Regional analysis suggested that the upper airway in
      children with obstructive sleep apnea is most restricted where adenoid and
      tonsils overlap. Segmental analysis demonstrated that the upper airway is
      restricted throughout the initial two-thirds of its length and that the narrowing
      is not in a discrete region adjacent to either the adenoid or tonsils, but rather
      in a continuous fashion along both.

PMID- 12406827
TI  - Effectiveness of medical resident education in mechanical ventilation.
AB  - Specific methods of mechanical ventilation management reduce mortality and lower
      health care costs. However, in the face of a predicted deficit of intensivists,
      it is unclear whether residency programs are training internists to provide
      effective care for patients who require mechanical ventilation. To evaluate these
      educational outcomes, we administered a validated 19-item case-based test and
      survey to resident physicians at 31 diverse U.S. internal medicine residency
      programs nationwide. Of 347 senior residents, 259 (75%) responded. The mean test
      score was 74% correct (SD, 14%; range, 37 to 100%). Important items representing
      evidence-based standards of critical care answered incorrectly were as follows:
      use of appropriate tidal volume in the acute respiratory distress syndrome (48%
      incorrect), identifying a patient ready for a weaning trial (38% incorrect), and
      recognizing indication for noninvasive ventilation (27% incorrect). Most
      accurately identified pneumothorax (86% correct) and increased intrathoracic
      positive end-expiratory pressure (93% correct). Better scores were associated
      with "closed" versus "open" intensive care unit organization (76 versus 71%
      correct, p = 0.001), resident perception of greater versus lesser ventilator
      knowledge (79 versus 71% correct, p = 0.001), and graduation from a U.S. versus
      international medical school (75 versus 69% correct, p = 0.033). Although overall
      training satisfaction correlated strongly with program use of learning objectives
      (r = 0.89, p < 0.0001), only 46% reported being satisfied with their mechanical
      ventilation training. We conclude that senior residents may not be gaining
      essential evidence-based knowledge needed to provide effective care for patients
      who require mechanical ventilation. Residency programs should emphasize evidence
      based learning objectives to guide mechanical ventilation instruction.

PMID- 12406828
TI  - Polymorphisms in toll-like receptor 4 are not associated with asthma or atopy
      related phenotypes.
AB  - Toll-like receptor 4 (TLR4) is the principal receptor for bacterial endotoxin
      recognition, and functional variants in the gene confer endotoxin
      hyporesponsiveness in humans. Furthermore, there is evidence that endotoxin
      exposure during early life is protective against the development of atopy and
      asthma, although this relationship remains poorly understood. It is therefore
      possible that genetic variation in the TLR4 locus contributes to asthma
      susceptibility. In this study we characterize the genetic diversity in the TLR4
      locus and test for association between the common genetic variants and asthma
      related phenotypes. In a cohort of 90 ethnically diverse subjects, we resequenced
      the TLR4 locus and identified a total of 29 single nucleotide polymorphisms. We
      assessed five common polymorphisms for evidence of association with asthma in two
      large family-based cohorts: a heterogeneous North American cohort (589 families),
      and a more homogenous population from northeastern Quebec, Canada (167 families).
      Using the transmission-disequilibrium test, we found no evidence of association
      for any of the polymorphisms tested, including two functional variants.
      Furthermore, we found no evidence for association between the TLR4 variants and
      four quantitative intermediate asthma- and atopy-related phenotypes. Based on
      these results, we found no evidence that genetic variation in TLR4 contributes to
      asthma susceptibility.

PMID- 12406829
TI  - Respiratory and cerebrovascular responses to hypoxia and hypercapnia in familial
      dysautonomia.
AB  - Although cardiorespiratory complications contribute to the high
      morbidity/mortality of familial dysautonomia (FD), the mechanisms remain unclear.
      We evaluated respiratory, cardiovascular, and cerebrovascular control by
      monitoring ventilation, end-tidal carbon dioxide (CO2-et), oxygen saturation, RR
      interval, blood pressure (BP), and midcerebral artery flow velocity (MCFV) during
      progressive isocapnic hypoxia, progressive hyperoxic hypercapnia, and during
      recovery from moderate hyperventilation (to simulate changes leading to
      respiratory arrest) in 22 subjects with FD and 23 matched control subjects.
      Subjects with FD had normal ventilation, higher CO2-et, lower oxygen saturation,
      lower RR interval, and higher BP. MCFV was also higher but depended on the higher
      baseline CO2-et. In the FD group, whereas hyperoxic hypercapnia induced normal
      cardiovascular and ventilatory responses, progressive hypoxia resulted in blunted
      increases in ventilation, paradoxical decreases in RR interval and BP, and lack
      of MCFV increase. Hyperventilation induced a longer hypocapnia-induced apneic
      period (51.5 +/- 9.9 versus 11.2 +/- 5.5 seconds, p < 0.008) with profound
      desaturation (to 75.8 +/- 3.5%), marked BP decrease, and RR interval increase.
      Subjects with FD develop central depression in response to even moderate hypoxia
      with lack of expected change in cerebral circulation, leading to hypotension,
      bradycardia, hypoventilation, and potentially respiratory arrest. Higher resting
      BP delays occurrence of syncope during hypoxia. Therapeutic measures preventing
      hypoxia/hypocapnia may correct cardiovascular accidents in patients with FD.

PMID- 12406830
TI  - Alveolar macrophages have a protective antiinflammatory role during murine
      pneumococcal pneumonia.
AB  - Alveolar macrophages (AMs) are considered major effector cells in host defense
      against respiratory tract infections by virtue of their potent phagocytic
      properties. In addition, AMs may regulate the host inflammatory response to
      infection by production of cytokines and by their capacity to phagocytose
      apoptotic polymorphonuclear cells (PMNs). To elucidate the in vivo contribution
      of AM to host defense against pneumococcal pneumonia, we depleted mice of AMs via
      pulmonary application of liposomal dichloromethylene-bisphosphonate (AM- mice)
      before inoculation with Streptococcus pneumoniae; control mice received saline
      (AM+sal) or liposomal phosphate-buffered saline (AM+lip) before bacterial
      inoculation. AM- mice displayed a significantly higher mortality compared with
      AM+ control mice, whereas bacterial clearance did not differ. Poor outcome of AM-
      mice was accompanied by a pronounced increase of local proinflammatory cytokine
      production as well as strongly elevated and prolonged pulmonary PMN accumulation.
      Closer examination of infiltrating PMN in AM- mice disclosed high proportions of
      apoptotic and secondary necrotic cells, reflecting the lack of efficient
      clearance mechanisms in the absence of AMs. Furthermore, caspase-3 staining
      showed only slightly higher activity in AM- mice, arguing against accelerated
      apoptosis per se. These data suggest that AMs are indispensable in the host
      response to pneumococcal pneumonia by means of their capacity to modulate
      inflammation, possibly via elimination of apoptotic PMNs.

PMID- 12406831
TI  - Effects of respiratory rate, plateau pressure, and positive end-expiratory
      pressure on PaO2 oscillations after saline lavage.
AB  - One of the proposed mechanisms of ventilator-associated lung injury is cyclic
      recruitment of atelectasis. Collapse of dependent lung regions with every breath
      should lead to large oscillations in PaO2 as shunt varies throughout the
      respiratory cycle. We placed a fluorescence-quenching PO2 probe in the
      brachiocephalic artery of six anesthetized rabbits after saline lavage. Using
      pressure-controlled ventilation with oxygen, ventilator settings were varied in
      random order over three levels of positive end-expiratory pressure (PEEP),
      respiratory rate (RR), and plateau pressure minus PEEP (Delta). Dependence of the
      amplitude of PaO2 oscillations on PEEP, RR, and Delta was modeled by multiple
      linear regression. Before lavage, arterial PO2 oscillations varied from 3 to 22
      mm Hg. After lavage, arterial PO2 oscillations varied from 5 to 439 mm Hg.
      Response surfaces showed markedly nonlinear dependence of amplitude on PEEP, RR,
      and Delta. The large PaO2 oscillations observed provide evidence for cyclic
      recruitment in this model of lung injury. The important effect of RR on the
      magnitude of PaO2 oscillations suggests that the static behavior of atelectasis
      cannot be accurately extrapolated to predict dynamic behavior at realistic
      breathing frequencies.

PMID- 12406832
TI  - A randomized trial of montelukast in respiratory syncytial virus
      postbronchiolitis.
AB  - Infants often develop reactive airway disease after respiratory syncytial virus
      (RSV) bronchiolitis. Cysteinyl-leukotrienes (cys-LT) are released during RSV
      infection and may contribute to the inflammation. We hypothesized that a cys-LT
      receptor antagonist would ameliorate reactive airway disease subsequent to RSV
      bronchiolitis. One hundred and thirty infants who were 3 to 36 months old,
      hospitalized with acute RSV bronchiolitis, were randomized into a double-blind,
      parallel comparison of 5-mg montelukast chewable tablets or matching placebo
      given for 28 days starting within 7 days of symptom debut. Infants with a
      suspected history of asthma were excluded. One hundred sixteen infants provided
      diary card data for the treatment period. Median age was 9 months. Infants on
      montelukast were free of any symptoms on 22% of the days and nights compared with
      4% of the days and nights in infants on placebo (p = 0.015). Daytime cough was
      significantly reduced on active treatment (p = 0.04). Exacerbations were
      significantly delayed from montelukast compared with placebo (p < 0.05). In
      conclusion, cys-LT antagonist treatment reduces lung symptoms subsequent to RSV
      bronchiolitis.

PMID- 12406833
TI  - Eosinophil's role remains uncertain as anti-interleukin-5 only partially depletes
      numbers in asthmatic airway.
AB  - The role of eosinophils as effector cells in asthma pathogenesis has been
      questioned since an anti-interleukin (IL)-5 monoclonal antibody (mepolizumab),
      which depleted blood and sputum eosinophils, failed to inhibit allergen-induced
      bronchoconstriction and airway hyperresponsiveness. However, the effect of IL-5
      blockade on tissue eosinophils was not examined. We sought to determine whether
      mepolizumab depletes airway tissue eosinophils and their products. Twenty-four
      patients with mild asthma received three intravenous doses of either 750 mg of
      mepolizumab or placebo in a randomized, double-blind, parallel-group fashion over
      20 weeks. Mepolizumab produced a median decrease from baseline of 55% for airway
      eosinophils (interquartile range, 29-89%; p = 0.009 versus placebo), 52% for bone
      marrow eosinophils (45-76%, p = 0.003), and 100% for blood eosinophils (range, 67
      100%, p = 0.02). Mepolizumab had no appreciable effect on bronchial mucosal
      staining of eosinophil major basic protein. There were no significant changes in
      clinical measures of asthma (airway hyperresponsiveness, FEV1, and peak flow
      recordings) between the mepolizumab and placebo-treated groups. Anti-IL-5
      treatment reduces but does not deplete airway or bone marrow eosinophils. The
      role of the eosinophil remains uncertain. Further clinical studies in asthma with
      more effective antieosinophil strategies are required.

PMID- 12406834
TI  - Outcome of diffuse alveolar hemorrhage in hematopoietic stem cell transplant
      recipients.
AB  - Previous studies have reported mortality rates of about 80% in hematopoietic stem
      cell transplant recipients with diffuse alveolar hemorrhage. This retrospective
      study describes the clinical course of 48 such patients: mean age 47.7 years, 52%
      autologous transplant and 67% peripheral stem cell source. The hemorrhage
      occurred within one month of transplant in 28 patients. Symptoms included dyspnea
      in 92%, fever in 67%, cough in 56%, and hemoptysis in 15%. Intensive care unit
      admission was required in 85% and mechanical ventilation in 77%. Most of the
      patients were treated with intravenous methylprednisolone 1 g daily for 3 days
      and then tapered off after a median of 22 days. The hospital mortality was 48%.
      The cause of death was respiratory failure in 15 of the 23 deaths. Mortality was
      28% in autologous compared with 70% in allogeneic transplant recipients (p =
      0.0040). The mortality rate of patients whose hemorrhage occurred within the
      first 30 days of transplant was 32% compared with 70% of those with late
      hemorrhage (p = 0.0096). This study shows that survival rate of hematopoietic
      stem cell transplant recipients with diffuse alveolar hemorrhage is better than
      previously reported, and that early onset and autologous transplant are favorable
      prognostic indicators.

PMID- 12406835
TI  - Bronchoscopic lung volume reduction using tissue engineering principles.
AB  - Bronchoscopic lung volume reduction (BLVR), a minimally invasive procedure based
      on tissue engineering principles, was performed in six sheep with papain-induced
      experimental emphysema (EMPH). Physiologic measurements, at baseline, after
      generation of EMPH, and at 3 and 9 weeks after BLVR, included lung volumes,
      diffusing capacity (DL(CO)), pressure-volume relationships for the lung and chest
      wall, pleural pressures generated during active respiratory muscle contraction,
      lung resistance and dynamic elastance. The animal model displayed hyperinflation
      (change in total lung capacity +8%; change in residual volume +66%), reduced
      DL(CO) (-21%), and elevated airway resistance (+76%) that resembled advanced
      human EMPH. BLVR was well tolerated without complications, and it reduced lung
      volumes (change in total lung capacity -16%; change in residual volume -55%) in a
      pattern that resulted in significant improvements in vital capacity (10%). At
      autopsy, well-organized, peripheral scars associated with tissue contraction were
      observed at 33 of the 36 (91%) treated sites. There was no evidence of infection,
      abscess, or granuloma formation, or allergic reaction. Scar tissue, generated by
      BLVR, replaced hyperinflated lung, reduced overall lung volume, and improved
      respiratory function safely and consistently. The BLVR technology employed in
      this study addresses the limitations identified in our prior attempt at BLVR
      therapy and appears safe and effective enough to justify a trial in humans.

PMID- 12406836
TI  - Meta-analysis of acute lung injury and acute respiratory distress syndrome trials
      testing low tidal volumes.

PMID- 12406837
TI  - Effect of ventilator mode on sleep quality in critically ill patients.
AB  - To determine whether sleep quality is influenced by the mode of mechanical
      ventilation, we performed polysomnography on 11 critically ill patients. Because
      pressure support predisposes to central apneas in healthy subjects, we examined
      whether the presence of a backup rate on assist-control ventilation would
      decrease apnea-related arousals and improve sleep quality. Sleep fragmentation,
      measured as the number of arousals and awakenings, was greater during pressure
      support than during assist-control ventilation: 79 +/- 7 versus 54 +/- 7 events
      per hour (p = 0.02). Central apneas occurred during pressure support in six
      patients; heart failure was more common in these six patients than in the five
      patients without apneas: 83 versus 20% (p = 0.04). Among patients with central
      apneas, adding dead space decreased sleep fragmentation: 44 +/- 6 versus 83 +/-
      12 arousals and awakenings per hour (p = 0.02). Changes in sleep-wakefulness
      state caused greater changes in breath components and end-tidal CO2 during
      pressure support than during assist-control ventilation. In conclusion,
      inspiratory assistance from pressure support causes hypocapnia, which combined
      with the lack of a backup rate and wakefulness drive can lead to central apneas
      and sleep fragmentation, especially in patients with heart failure.

PMID- 12406838
TI  - Lung deposition and efficiency of nebulized amikacin during Escherichia coli
      pneumonia in ventilated piglets.
AB  - Lung tissue deposition and antibacterial efficiency of nebulized and intravenous
      amikacin (AMK) were compared in anesthetized and ventilated piglets suffering
      from a bronchopneumonia produced by the intrabronchial inoculation of Escherichia
      coli. AMK was administered 24 hours after the inoculation either through an
      ultrasonic nebulizer (45 mg x kg-1, n = 10) or by intravenous infusion (15 mg x
      kg-1, n = 8). Piglets were killed 1 hour after a second AMK administration
      performed 24 hours after the first one, and lung tissue concentrations of AMK and
      lung bacterial burden were assessed on multiple lung specimens. The amount of
      nebulized AMK reaching the tracheobronchial tree represented 38 +/- 6% of the
      initial nebulizer AMK charge. After nebulization, AMK lung tissue concentrations
      were 3- to 30-fold higher than after intravenous administration and were
      influenced by the severity of lung lesions: 188 +/- 175 microg x g-1 in lung
      segments with mild bronchopneumonia versus 40 +/- 65 microg x g-1 in lung
      segments with severe bronchopneumonia (p < 0.01). Lung bacterial burden was
      significantly lower in the aerosol group than in the intravenous group (median =
      0 colony forming units. g-1 versus median = 5 x 10(2) colony forming units x g-1,
      p < 0.001). In conclusion, the deposition of AMK in infected lung parenchyma and
      the efficiency of bacterial killing were greater after nebulization than after
      intravenous administration.

PMID- 12406839
TI  - Diaphragm length during tidal breathing in patients with chronic obstructive
      pulmonary disease.
AB  - Diaphragm function is compromised in severe chronic obstructive pulmonary disease
      (COPD) by hyperinflation, but its ability to shorten and contribute to tidal
      volume is uncertain. We estimated coronal diaphragm length by measuring zone of
      apposition length with ultrasound and rib cage diameters with magnetometers, in
      10 male patients with severe COPD and 10 age- and sex-matched control subjects.
      Diaphragm length was 20% shorter in patients at residual volume (413 and 536 mm
      in patients and control subjects, respectively) and FRC (381 and 456 mm,
      respectively), but was not different at total lung capacity (312 and 336 mm,
      respectively). Zone of apposition length was reduced 50% at residual volume and
      FRC in patients, but was larger at a given absolute lung volume than in control
      subjects. There were no differences in tidal volume (0.8 L), tidal changes in
      zone of apposition length (20 mm) and diaphragm length (38 and 42 mm), and tidal
      volume displaced by the diaphragm (0.6 L), even though mean FRC in patients was
      similar to predicted total lung capacity. Although the diaphragm is shorter at
      FRC in patients with COPD, its motion and change in length during tidal breathing
      is similar to that in control subjects.

PMID- 12406840
TI  - Comparison between automatic and fixed positive airway pressure therapy in the
      home.
AB  - We tested the hypothesis that continuous positive airway pressure (CPAP) use and
      outcomes can be improved by an autotitrating CPAP device in patients with
      obstructive sleep apnea-hypopnea syndrome (OSAHS) who require higher CPAP (10 cm
      H2O or more). In this multisite randomized single-blind cross-over study, 44
      patients (mean age, 49 +/- 10 years) were randomized to 6 weeks at laboratory
      determined fixed pressure and 6 weeks on autotitrating CPAP. Average nightly use
      was greater in automatic mode (306 versus 271 minutes, p = 0.005); median and
      95th centile pressures in automatic mode were lower (p < 0.002). Automatic CPAP
      resulted in better SF-36 Vitality scores (65 +/- 20 versus 58 +/- 23, p < 0.05)
      and mental health scores (80 +/- 14 versus 75 +/- 18, p < 0.05), but no
      significant difference in Epworth score (p = 0.065). During automatic therapy,
      patients reported more restful sleep, better quality sleep, less discomfort from
      pressure, and less trouble getting to sleep for both the first week of therapy
      and for the averaged scores for Weeks 2-6 (all p values < 0.006). Patients who
      require higher fixed CPAP use autotitrating CPAP more and report greater benefit
      from this therapy.

PMID- 12406841
TI  - Comparative effects of two ventilatory modes on speech in tracheostomized
      patients with neuromuscular disease.
AB  - Many patients with respiratory failure related to neuromuscular disease receive
      chronic invasive ventilation through a tracheostomy. Improving quality of life,
      of which speech is an important component, is a major goal in these patients. We
      compared the effects on breathing and speech production of assist-control
      ventilation (ACV) and bilevel positive-pressure ventilation (BPPV) in nine
      patients with neuromuscular disease. Ventilator-delivered flow was measured using
      a pneumotachograph, and respiratory rate, inspiratory time, and ventilator
      delivered volume were measured on this flow signal. Gas exchange was assessed
      using oxygen saturation and end-tidal carbon dioxide measurement. Microphone
      speech recordings were subjected to quantitative analysis. At rest, ventilatory
      parameters were similar with both modes. Speech induced an increase in
      inspiratory time during BPPV, with a greater increase in the volume released by
      the ventilator during speech as compared with ACV (172 +/- 194 versus 26 +/- 31
      ml). Consequently, speech duration was longer during inspiration with BPPV.
      Moreover, BPPV allowed speech production to extend into expiration, and three
      patients could speak continuously during several respiratory cycles while
      receiving BPPV. Blood gas exchange was not modified by speech with BPPV or ACV.
      This study shows that BPPV provides better speech duration than ACV with no
      detectable short-term deleterious effects.

PMID- 12406842
TI  - Inspiratory muscle training in patients with chronic obstructive pulmonary
      disease: structural adaptation and physiologic outcomes.
AB  - The present study was aimed at evaluating the effects of a specific inspiratory
      muscle training protocol on the structure of inspiratory muscles in patients with
      chronic obstructive pulmonary disease. Fourteen patients (males, FEV1, 24 +/- 7%
      predicted) were randomized to either inspiratory muscle or sham training groups.
      Supervised breathing using a threshold inspiratory device was performed 30
      minutes per day, five times a week, for 5 consecutive weeks. The inspiratory
      training group was subjected to inspiratory loading equivalent to 40 to 50% of
      their maximal inspiratory pressure. Biopsies from external intercostal muscles
      and vastus lateralis (control muscle) were taken before and after the training
      period. Muscle samples were processed for morphometric analyses using monoclonal
      antibodies against myosin heavy chain isoforms I and II. Increases in both the
      strength and endurance of the inspiratory muscles were observed in the
      inspiratory training group. This improvement was associated with increases in the
      proportion of type I fibers (by approximately 38%, p < 0.05) and in the size of
      type II fibers (by approximately 21%, p < 0.05) in the external intercostal
      muscles. No changes were observed in the control muscle. The study demonstrates
      that inspiratory training induces a specific functional improvement of the
      inspiratory muscles and adaptive changes in the structure of external intercostal
      muscles.

PMID- 12406843
TI  - Developing cystic fibrosis lung transplant referral criteria using predictors of
      2-year mortality.
AB  - The first objective of our study was to develop a model identifying the best
      clinical predictors of 2-year mortality among patients with cystic fibrosis (CF),
      to assist in selection of appropriate candidates for lung transplantation. Using
      multivariate logistic regression, we found that age, height, FEV1, respiratory
      microbiology, number of hospitalizations for pulmonary exacerbations, and number
      of home intravenous antibiotic courses were all significant predictors of 2-year
      mortality among 14,572 patients in the Cystic Fibrosis Foundation National
      Patient Registry who were 6 years of age or older in 1996. The second objective
      was to compare the diagnostic accuracy of our model when used to guide referral
      for lung transplant with that of the widely used criterion of an FEV1 of less
      than 30% predicted. Surprisingly, this well-fitting model derived from the
      largest collection of data available on patients with CF provided no better
      diagnostic accuracy than the simpler FEV1 criterion. Both had high negative
      predictive values (98 and 97%, respectively) but only modest positive predictive
      values (33 and 28%, respectively). Transplant referral decisions based either on
      a multivariate logistic model or on the criterion of an FEV1 of less than 30%
      predicted are likely to result in high rates of premature referral. Better
      clinical predictors of short-term mortality among patients with CF are needed.

PMID- 12406844
TI  - Model-based assessment of autonomic control in obstructive sleep apnea syndrome
      during sleep.
AB  - Respiration, R-R interval, blood pressure, and other polysomnographic variables
      were recorded in eight normal subjects and nine patients with untreated
      obstructive sleep apnea syndrome in wakefulness and sleep. To increase
      respiratory and cardiovascular variability, a computer-controlled ventilator
      delivered randomly modulated inspiratory pressures that were superimposed on a
      baseline continuous positive airway pressure. A mathematical model allowed heart
      rate variability to be partitioned into a component mediated by respiratory
      cardiac coupling and one mediated by the baroreflexes. Respiratory-cardiac
      coupling gain was lower in patients versus normal subjects (36.9 +/- 3.3 versus
      66.1 +/- 5.6 milliseconds L-1, p < 0.03). Baroreflex gain in patients was also
      depressed relative to normal subjects (2.3 +/- 0.4 versus 4.9 +/- 0.7
      milliseconds mm Hg-1; p < 0.02). Baroreflex gain increased two- to threefold from
      wakefulness to sleep in normal subjects, but was relatively unaffected by state
      change in patients. Along with results derived from spectral analysis of
      cardiovascular variability, these findings confirm previous reports that
      obstructive sleep apnea syndrome is associated with reduced parasympathetic and
      elevated sympathetic activity. The model-based approach provides a more precise
      characterization of heart rate variability that can be employed in conjunction
      with spectral analysis for the noninvasive detection and assessment of autonomic
      cardiovascular abnormality in obstructive sleep apnea syndrome.

PMID- 12406845
TI  - Pharmacological characterization of serotonergic receptor activity in the
      hypoglossal nucleus.
AB  - State-dependent reductions in serotonin delivery to upper airway dilator
      motoneuron activity may contribute to sleep apnea. The functional significance of
      serotonin receptor subtypes implicated in excitation of dilator motor neurons was
      evaluated in anesthetized, paralyzed, mechanically ventilated adult rats (n =
      108). The effects of antagonists selective for serotonin receptor subtypes 2A,
      2C, or 7 on intrinsic hypoglossal activity and on serotonin agonist (serotonin, 5
      carboxamidotryptamine maleate, and RO-600175) dose responses were characterized.
      All drugs were injected unilaterally into the hypoglossal nucleus. The 2A
      antagonist, MDL-100907, dropped intrinsic hypoglossal nerve respiratory activity
      by 61 +/- 6% (p < 0.001) and suppressed serotonin excitation of hypoglossal nerve
      activity (p < 0.05). The 2C antagonist, SB-242084, dropped hypoglossal nerve
      activity 17 +/- 6% (p < 0.05) and suppressed the dose-response curve for the 2C
      agonist. Rapid desensitization occurred with the 2C agonist only (p < 0.05). The
      7 antagonist, SB-269970, had no effect on either intrinsic activity or agonist
      responses. We conclude that serotonin 2A is the predominant excitatory serotonin
      receptor subtype at hypoglossal motor neurons. The serotonin 2C excitatory
      effects are of lower magnitude and are associated with rapid desensitization.
      There is no evidence for serotonin 7 activity in the hypoglossal nucleus. This
      characterization of serotonin receptor subtypes in the hypoglossal nucleus
      provides a focus for the development of pharmacotherapies for sleep apnea.

PMID- 12406846
TI  - Extracellular superoxide dismutase protects lung development in hyperoxia-exposed
      newborn mice.
AB  - We tested the hypothesis that targeted transgenic overexpression of human
      extracellular superoxide dismutase (EC-SOD) would preserve alveolar development
      in hyperoxia-exposed newborn mice. We exposed newborn transgenic and wild-type
      mice to 95% oxygen (O2) or air x 7 days and measured bronchoalveolar lavage cell
      counts, and lung homogenate EC-SOD, oxidized and reduced glutathione, and
      myeloperoxidase. We found that total EC-SOD activity in transgenic newborn mice
      was approximately 2.5x the wild-type activity. Hyperoxia-exposed transgenic mice
      had less pulmonary neutrophil influx and oxidized glutathione than wild-type
      littermates at 7 days. We measured alveolar surface and volume density in animals
      exposed to 14 days more of air or 60% O2. Hyperoxia-exposed transgenic EC-SOD
      mice had significant preservation of alveolar surface and volume density compared
      with wild-type littermates. After 7 days 95% O2 + 14 days 60% O2, lung
      inflammation measured as myeloperoxidase activity was reduced to control levels
      in all treatment groups.

PMID- 12406847
TI  - Interstitial vascularity in fibrosing alveolitis.
AB  - The aim of this study was to evaluate interstitial vascularity in cryptogenic
      fibrosing alveolitis (CFA) and in fibrosing alveolitis associated with systemic
      sclerosis (FASSc). Open lung biopsies from eight patients with CFA, nine patients
      with FASSc, and normal lung from 12 patients undergoing surgery for lung cancer
      were studied. Markers for endothelial cells (CD34) and cell proliferation
      (proliferating cell nuclear antigen) were localized by sequential
      immunohistochemistry and quantified using computer-assisted analysis. Vascular
      distribution was evaluated at increasing distances (up to 160 microm) from the
      airspaces. Vessel density was markedly reduced in both FASSc (3.9%) and in CFA
      (4.5%) compared with control samples (20.4%, p < 0.0001). The percentage of
      tissue occupied by vessels decreased with increasing distance from alveoli in
      control samples but not in CFA or FASSc samples. Endothelial cell proliferation
      indices were increased in FASSc but not in CFA, compared with control samples (p
      = 0.006). In conclusion, there is net vascular ablation and redistribution of
      blood vessels in areas of interstitial thickening in both CFA and FASSc, which
      may contribute to gas exchange impairment.

PMID- 12406848
TI  - Endothelial nitric oxide synthase variants in cystic fibrosis lung disease.
AB  - Variants in the genes encoding for the nitric oxide synthases may act as disease
      modifier loci in cystic fibrosis, affecting both an individual's nitric oxide
      level and pulmonary function. In this study, the 894G/T variant in exon 7 of the
      endothelial nitric oxide synthase gene was related to exhaled nitric oxide and
      pulmonary function in 70 cystic fibrosis patients who were aged 14.8 +/- 6.9
      years (mean +/- SD), with a FEV1 of 69.4 +/- 24.8% predicted. Although there was
      no association between endothelial nitric oxide synthase genotypes and exhaled
      nitric oxide in males, nitric oxide levels were significantly higher in female
      cystic fibrosis patients with an 894T mutant allele, compared with female
      patients homozygous for the 894G wild-type allele (7.0 +/- 4.4 versus 3.6 +/- 1.9
      parts per billion, p = 0.02). Furthermore, in female patients, colonization of
      airways with Pseudomonas aeruginosa was significantly (p < 0.05) less frequent
      when carrying an 894T mutant allele as compared with wild type. These data
      suggest that the 894T variant in the endothelial nitric oxide synthase gene is
      associated with increased airway nitric oxide formation in female cystic fibrosis
      patients, possibly affecting colonization of airways with P. aeruginosa.

PMID- 12406849
TI  - Strenuous resistive breathing induces plasma cytokines: role of antioxidants and
      monocytes.
AB  - Inspiratory resistive breathing increases plasma cytokines, yet the stimulus (or
      stimuli) and source(s) remain unknown. We tested the role of reactive oxygen
      species as stimuli and of monocytes as sources of resistive breathing-induced
      cytokines. Six healthy subjects performed two resistive breathing sessions at 75%
      of maximum inspiratory pressure before and after a combination of antioxidants
      (vitamin E 200 mg, vitamin A 50,000 IU, and vitamin C 1,000 mg per day for 60
      days, allopurinol 600 mg/day for 15 days, and N-acetylcysteine 2 g/day for 3 days
      before the second session). Blood was drawn before, at the end, and at 30 and 120
      minutes after resistive breathing. Before antioxidants, plasma cytokine levels
      (determined by enzyme-linked immunosorbent assay) increased secondary to
      resistive breathing (tumor necrosis factor-alpha and interleukin [IL]-6 by
      twofold and IL-1beta by threefold). After antioxidants, plasma IL-1beta became
      undetectable. The tumor necrosis factor-alpha response to resistive breathing was
      abolished, and the IL-6 response was significantly blunted. Intracellular
      cytokine detection (by flow cytometry) showed no change in either the percentage
      of monocytes producing the cytokines or their mean fluorescence intensity both
      before and after antioxidants. We conclude that oxidative stress is a major
      stimulus for the resistive breathing-induced cytokine production and that
      monocytes play no role in this process.

PMID- 12406850
TI  - Prevalence and clinical course of pleural effusions at 30 days after coronary
      artery and cardiac surgery.
AB  - The present prospective study was designed to determine the prevalence of pleural
      effusion at approximately 28 days after cardiac surgery and their subsequent
      course. This consecutive case study included 389 patients; 312 had only coronary
      artery bypass graft surgery (CABG) surgery, 37 had both valve and CABG surgery,
      and 40 had only valve surgery. Chest radiographs were obtained approximately 28
      days postoperatively. Patients were subsequently contacted by telephone 3, 6, and
      12 months postoperatively and questioned about the presence of fluid in their
      chest and related symptoms. The prevalence of pleural effusions in the patients
      undergoing only CABG surgery (63%) or CABG surgery plus valve surgery (62%) was
      significantly (p = 0.05) higher than that in the patients undergoing valve
      surgery only (45%). The prevalence of effusions occupying more than 25% of the
      hemithorax was 9.7%. The primary symptom associated with these larger effusions
      was dyspnea. Chest pain and fever were uncommon. Over the 12-month follow-up, the
      effusions tended to resolve. In conclusion, the prevalence of pleural effusions
      occupying more than 25% of the hemithorax is approximately 10%, 28 days
      postoperatively. These larger pleural effusions produce dyspnea but not chest
      pain or fever, and most of the effusions disappear gradually over the subsequent
      months.

PMID- 12406851
TI  - Role of interleukin-10 in the intracellular sequestration of human leukocyte
      antigen-DR in monocytes during septic shock.
AB  - Monocytes from many critically ill patients show a low level of major
      histocompatibility complex type II (MHC II) expression. This phenomenon is
      believed to play a role in these patients' increased susceptibility to secondary
      infections. In the present study, we show that the level of monocyte human
      leukocyte antigen (HLA)-DR expression inversely correlates with the degree of
      severity of the sepsis syndrome. The defect of the monocyte HLA-DR expression
      resides in an intracellular sequestration of the MHC II molecules, a
      posttranslational effect. No significant decrease in the rate of transcription of
      HLA-DR, or its major transcriptional inducer, Class II transactivator, was noted.
      The levels of HLA-DR protein produced by monocytes from patients with septic
      shock were comparable to those from healthy volunteers. Plasma from patients with
      septic shock induced significant HLA-DR endocytosis resulting in decreased
      surface HLA-DR expression of normal donor monocytes. This effect was partially
      blocked by anti-interleukin (IL)-10 monoclonal antibody, but not by antagonists
      to transforming growth factor-beta1, prostaglandins, or beta-adrenergic agonists.
      Altogether, these data suggest that HLA-DR molecules are re-endocytosed and
      retained intracellularly in monocytes from patients with septic shock, and that
      this phenomenon is partially mediated by IL-10. IL-10 may represent a future
      target for immunomodulating patients with the sepsis syndrome or critically ill
      patients at risk of developing infections.

PMID- 12406852
TI  - Patient satisfaction with bronchoscopy.
AB  - We conducted a cohort study to characterize patient satisfaction with flexible
      bronchoscopy (FB) and to determine patient characteristics, care factors, and
      patient evaluations of bronchoscopy that are associated with a patient's
      willingness to return for repeat FB. Physicians and patients completed surveys
      between February 1997 and June 1998. Data from 481 patients were analyzed. Over
      80% of the patients rated physicians as very good or excellent, but they were
      least satisfied with the information that they were provided about FB, waiting
      time before and after FB, and the FB environment. Seventy-one percent of the
      patients would definitely return, and 22% would probably return for a repeat FB.
      Better health status (odds ratio [OR] 1.4; 95% confidence interval [CI], 1.1
      1.7), not being bothered by scope insertion (OR 2.0; 95% CI, 1.2-3.3), better
      rating of information quality (OR 1.2; 95% CI, 1.0-1.3), and better rating of
      physician quality (OR 1.1; 95% CI, 1.0-1.2) were associated with patients
      reporting that they would definitely return for a repeat FB. Although patient
      satisfaction with providers is high, there are specific patient and process of
      care factors that should be improved. Sicker patients may be at a risk of
      dissatisfaction with FB. Process of care measures that could improve satisfaction
      with FB include providing better information to patients and optimizing the
      experience of bronchoscope insertion.

PMID- 12406853
TI  - Increased leukotrienes in exhaled breath condensate in childhood asthma.
AB  - Cysteinyl leukotrienes (cys-LTs; LTC4, LTD4, and LTE4) are generated
      predominantly by mast cells and eosinophils and induce airway smooth muscle
      contraction, microvascular leakage, and mucous hypersecretion whereas leukotriene
      B4 (LTB4) is a potent chemoattractant of neutrophils. We measured cys-LTs and
      LTB4 in exhaled breath condensate from children aged 7-14 years including healthy
      nonatopic children (n = 11) and children with mild intermittent asthma (steroid
      naive, n = 11), mild persistent asthma (low-dose inhaled steroid treatment, n =
      13), or moderate to severe persistent asthma (high-dose inhaled steroid
      treatment, n = 13). Exhaled LTB4 levels were increased in patients with mild and
      moderate to severe persistent asthma compared with patients with mild
      intermittent asthma (126.0 +/- 8.8 and 131.9 +/- 7.1 versus 52.7 +/- 3.8 pg/ml, p
      < 0.001 and p < 0.0001) and normal subjects (126.0 +/- 8.8 and 131.9 +/- 7.1
      versus 47.9 +/- 4.1 pg/ml, p < 0.0001). Elevated exhaled cys-LT levels were found
      in patients with mild and moderate to severe persistent asthma compared with
      normal subjects (27.9 +/- 2.8 and 31.5 +/- 4.5 versus 18.5 +/- 0.5 pg/ml, p <
      0.01 and p < 0.05). There was an inverse correlation between exhaled cys-LTs and
      LTB4 in patients with mild persistent asthma. We conclude that exhaled cys-LTs
      and LTB4 may be noninvasive markers of airway inflammation in pediatric asthma.

PMID- 12406854
TI  - Simvastatin attenuates smooth muscle neointimal proliferation and pulmonary
      hypertension in rats.
AB  - Hypertensive pulmonary vascular disease is characterized by abnormal
      proliferation of vascular endothelial and smooth muscle cells, leading to
      occlusion of pulmonary arterioles, pulmonary hypertension, right ventricular
      failure, and death. Compounds with antiproliferative effects on vascular
      endothelial and smooth muscle cells, such as 3-hydroxy-3-methylglutaryl-coenzyme
      A (HMG-CoA) reductase inhibitors, may prevent the development of experimental
      hypertensive pulmonary vascular disease. Pneumonectomized rats injected with
      monocrotaline at 7 days develop severe hypertensive pulmonary vascular disease
      with neointimal formation. Rats were randomized to receive either vehicle or
      treatment with the HMG-CoA reductase inhibitor simvastatin (2 mg/kg per day). By
      Day 35, rats that received vehicle had higher mean pulmonary arterial pressures
      (53 +/- 2 mm Hg) and right ventricular hypertrophy (right ventricle/[left
      ventricle plus septum] [RV/LV+S] = 0.78 +/- 0.09) than rats in Group PMS5-35 that
      received simvastatin from Day 5 to 35 (mean pulmonary arterial pressure = 27 +/-
      3 mm Hg, RV/LV+S = 0.34 +/- 0.08; p < or = 0.001). Pulmonary vascular remodeling
      with neointimal formation consisting of vascular smooth muscle cells was more
      severe in vehicle-treated rats (vascular occlusion score, 1.98 +/- 0.02) than in
      Group PMS5-35 (vascular occlusion score, 0.59 +/- 0.46; p < 0.001). In addition,
      lung endothelial nitric oxide synthase gene expression was decreased in vehicle
      treated animals but was restored toward normal levels in simvastatin-treated
      animals. Simvastatin attenuates monocrotaline-induced pulmonary vascular
      remodeling with neointimal formation, pulmonary arterial hypertension, and right
      ventricular hypertrophy in rats.

PMID- 12406855
TI  - Secretoglobins SCGB3A1 and SCGB3A2 define secretory cell subsets in mouse and
      human airways.
AB  - Clara cell secretory protein (CCSP) is expressed abundantly within the conducting
      airway epithelium and is thought to have immunoregulatory functions. Differences
      in the localization of CCSP between mouse and human airways led us to hypothesize
      that functional homologues of CCSP may compensate for the lack of CCSP expression
      in proximal airway locations. We previously identified an expressed sequence tag
      (W82219) whose expression is induced within Clara cells of CCSP knockout mice.
      Expressed sequence tag W82219 is distantly related to CCSP and represents a
      member of a new subfamily of secretoglobins (MmSCGB3A2). Another member of the
      mouse SCGB3 family (MmSCGB3A1) as well as human orthologues (HsSCGB3A1 and
      HsSCGB3A2) that possess structural homology to CCSP were identified, suggesting
      they may share common functional properties. SCGB3A1 messenger RNA localizes to a
      subset of SCGB3A2-expressing cells within bronchi of both mouse and neonatal
      human lungs. CCSP, SCGB3A1, and SCGB3A2 were decreased in airways of neonates
      with bronchopulmonary dysplasia and in mice after airway injury. We conclude that
      secretory cells of the conducting airway epithelium express distinct members of
      the secretoglobin family in a partially overlapping fashion. Altered expression
      of secretoglobins in airway disease may contribute to immunoregulatory
      perturbations commonly seen in chronic airway disease.

PMID- 12406856
TI  - Impaired inhibition by dexamethasone of cytokine release by alveolar macrophages
      from patients with chronic obstructive pulmonary disease.
AB  - Chronic obstructive pulmonary disease (COPD) is characterized by inflammation of
      the respiratory tract in which macrophages are the predominant inflammatory cell
      and for which the efficacy of treatment with corticosteroids is controversial. We
      investigated the effect of dexamethasone on basal and interleukin (IL)-1beta or
      cigarette smoke media (CSM)-stimulated release of IL-8 and granulocyte macrophage
      colony stimulating factor (GM-CSF) by bronchoalveolar lavage macrophages from
      cigarette smokers and patients with COPD (n = 15). Basal release of IL-8 was
      approximately fivefold greater in patients with COPD than smokers, whereas GM-CSF
      was similar for each group. IL-1beta and CSM increased IL-8 and GM-CSF release by
      macrophages from both smokers and patients with COPD. Dexamethasone did not
      inhibit basal or stimulated IL-8 release from macrophages from patients with COPD
      but inhibited release in smokers. In contrast, basal and IL-1beta-stimulated GM
      CSF release, but not CSM-stimulated release, was inhibited by dexamethasone. We
      conclude that the lack of efficacy of corticosteroids in COPD might be due to the
      relative steroid insensitivity of macrophages in the respiratory tract.

PMID- 12406858
TI  - The Babel of multicenter exposure assessment.

PMID- 12406859
TI  - Assessment of the noise exposure of call centre operators.
AB  - Call centres now play a major role in the daily operations of financial,
      technology and utility companies, as well as public bodies. It is predicted that
      2002 will see 2.3% of the total British workforce employed in call centres.
      However, local authority enforcement officers, unions, voluntary organizations,
      employers and employees have all expressed concern that there are hazards to
      health and safety unique to this new and developing industry. One of the
      potential hazards reported in the press is hearing damage from using headsets. In
      a Health & Safety Executive funded project, the noise exposure of 150 call centre
      operators was evaluated, in call centres which included financial services, home
      shopping and telecommunications services. The results show that the daily
      personal noise exposure of these call centre operators is unlikely to exceed the
      85 dB(A) action level defined in the Noise at Work Regulations 1989. The risk of
      hearing damage is therefore extremely low. Exposure to higher noise levels is
      possible, for example from fax tones, holding tones and high pitched tones from
      mobile phones. However, the duration of these events is likely to be short and
      they are therefore unlikely to have a significant effect on the operators'
      overall noise exposure. A practical method of limiting exposure to unexpected
      high noises from headsets is to ensure that the headsets incorporate acoustic
      shock protection that meets the requirements of the Department of Trade and
      Industry specification 85/013. In the UK, this limiter ensures any noise above
      118 dB is not transmitted through the headset. Operators should receive regular
      training on the headset and telephone equipment they are using. This training
      should include correct use of the headset and the volume control facilities, and
      advice on how and when to clean and maintain the headsets.

PMID- 12406860
TI  - Investigation of the aerosols produced by a high-speed, hand-held grinder using
      various substrates.
AB  - Mechanical processes such as grinding are classically thought to form micrometer
      scale aerosols through abrasion and attrition. High-speed grinding has been used
      as the basis for testing the hypothesis that ultrafine particles do not form a
      substantial component of mechanically generated aerosols. A wide variety of
      grinding substrates were selected for evaluation to represent the broad spectrum
      of materials available. To characterize the particle size distribution over
      particle sizes ranging from 4.2 nm to 20.5 microm, the aerosol-laden air
      collected from an enclosed chamber was split and directed to three aerosol
      instruments operated in parallel. Transmission electron microscope samples of the
      various grinding substrates were also collected. The results demonstrate that
      ultrafine particles do have the potential to form a significant component of a
      grinding aerosol for a number of substrates. It appears that the ultrafine
      aerosols were formed by the following processes: (i) from within the grinding
      motor, (ii) from the combustion of amenable grinding substrates and (iii) from
      volatilization of amenable grinding materials at the grinding wheel/substrate
      interface.

PMID- 12406857
TI  - Characterization of high-altitude pulmonary hypertension in the Kyrgyz:
      association with angiotensin-converting enzyme genotype.
AB  - Previous studies have suggested a genetic component in susceptibility to hypoxia
      induced pulmonary hypertension. We therefore estimated the prevalence of high
      altitude pulmonary hypertension (HAPH) in a Kyrgyz population and whether the
      insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE)
      gene associates with HAPH. An electrocardiographic survey of 741 highlanders
      demonstrated electrocardiogram signs of cor pulmonale in 14% of subjects.
      Pulmonary artery hemodynamics measured in an independent group of 136 male
      highlanders with symptoms of dyspnea at altitude revealed established pulmonary
      hypertension (mean pulmonary artery pressure [MPAP] > or = 25 mm Hg) in 20%.
      However, 26% of the normal subjects demonstrated an exaggerated response (twofold
      or greater increase in MPAP) to inhalation of 11% oxygen, and were classified as
      hyperresponsive. Ten-year follow-up of this group revealed increases in the MPAP,
      but not in normal subjects. Comparison of ACE I/D genotypes in the catheterized
      group revealed a threefold higher frequency of the I/I genotype in highlanders
      with HAPH, compared with normal highlanders (chi2 = 11.59, p = 0.003). In
      addition, MPAP was higher in highlanders with the I/I genotype (26.9 +/- 4.0 mm
      Hg) compared with the I/D genotype (20.6 +/- 1.2 mm Hg) or the D/D genotype (18.3
      +/- 0.9 mm Hg) (p < 0.05). We conclude that HAPH is associated with ACE I/D
      genotype among Kyrgyz highlanders and the development of HAPH in this population
      and may be predicted by hyperresponsiveness to acute hypoxia.

PMID- 12406862
TI  - Silicosis compensation in Western Australian gold miners since the introduction
      of an occupational exposure standard for crystalline silica.
AB  - Occupational exposure limits for crystalline silica are under review worldwide
      because of the large numbers of exposed people and, especially, because of the
      recent International Agency for Research on Cancer classification of silica as a
      human carcinogen. OBJECTIVES: The aims of this study were to (i) re-examine the
      incidence of silicosis in Western Australian gold miners and, using estimates of
      the total population at risk, (ii) estimate the upper confidence limit for the
      risk of silicosis in Western Australian gold miners since 1974, when the current
      exposure standard for crystalline silica was implemented. METHODS: Work histories
      of cases compensated for pneumoconiosis after 1974 were examined. Numbers of
      workers in the total workforce likely to be exposed to crystalline silica in
      Western Australia were estimated as the population at risk. RESULTS: There were
      no cases of compensated silicosis in Western Australian miners whose first dust
      exposure began during or after 1974. The upper 95% confidence interval for this
      zero rate was estimated to be 4.8 per 100,000 person-yr. CONCLUSIONS: There have
      been no compensated cases of silicosis in Western Australia among miners first
      exposed to crystalline silica after introduction of the current exposure
      standard. A rate of compensated silicosis higher than five cases per 100,000
      person-yr is unlikely.

PMID- 12406861
TI  - Determinants of wood dust exposure in the Danish furniture industry.
AB  - This paper investigates the relation between wood dust exposure in the furniture
      industry and occupational hygiene variables. During the winter 1997-98 54
      factories were visited and 2362 personal, passive inhalable dust samples were
      obtained; the geometric mean was 0.95 mg/m(3) and the geometric standard
      deviation was 2.08. In a first measuring round 1685 dust concentrations were
      obtained. For some of the workers repeated measurements were carried out 1 (351)
      and 2 weeks (326) after the first measurement. Hygiene variables like job,
      exhaust ventilation, cleaning procedures, etc., were documented. A multivariate
      analysis based on mixed effects models was used with hygiene variables being
      fixed effects and worker, machine, department and factory being random effects. A
      modified stepwise strategy of model making was adopted taking into account the
      hierarchically structured variables and making possible the exclusion of non
      influential random as well as fixed effects. For woodworking, the following
      determinants of exposure increase the dust concentration: manual and automatic
      sanding and use of compressed air with fully automatic and semi-automatic
      machines and for cleaning of work pieces. Decreased dust exposure resulted from
      the use of compressed air with manual machines, working at fully automatic or
      semi-automatic machines, functioning exhaust ventilation, work on the night
      shift, daily cleaning of rooms, cleaning of work pieces with a brush, vacuum
      cleaning of machines, supplementary fresh air intake and safety representative
      elected within the last 2 yr. For handling and assembling, increased exposure
      results from work at automatic machines and presence of wood dust on the
      workpieces. Work on the evening shift, supplementary fresh air intake, work in a
      chair factory and special cleaning staff produced decreased exposure to wood
      dust. The implications of the results for the prevention of wood dust exposure
      are discussed.

PMID- 12406863
TI  - Accuracy and repeatability of weighing for occupational hygiene measurements:
      results from an inter-laboratory comparison.
AB  - Gravimetric analysis is a fundamental technique frequently used in occupational
      hygiene assessments, but few studies have investigated its repeatability and
      reproducibility. Four inter-laboratory comparisons are discussed in this paper.
      The first involved 32 laboratories weighing 25 mm diameter glassfibre filters,
      the second involved 11 laboratories weighing 25 mm diameter PVC filters and the
      third involved eight laboratories weighing plastic IOM heads with 25 mm diameter
      glassfibre filters. Data from the third study found that measurements using this
      type of IOM head were unreliable. A fourth study, to ascertain if laboratories
      could improve their performance, involved a selected sub-group of 10 laboratories
      from the first exercise that analysed the 25 mm diameter glassfibre filters. The
      studies tested the analytical measurement process and not just the variation in
      weighings obtained on blank filters, as previous studies have done. Graphs of
      data from the first and second exercises suggest that a power curve relationship
      exists between reproducibility and loading and repeatability and loading. The
      relationship for reproducibility in the first study followed the equation log
      s(R) = -0.62 log m + 0.86 and in the second study log s(R) = -0.64 log m + 0.57,
      where s(R) is the reproducibility in terms of per cent relative standard
      deviation (%RSD) and m is the weight of loading in milligrams. The equation for
      glassfibre filters from the first exercise suggested that at a measurement of 0.4
      mg (about a tenth of the United Kingdom legislative definition of a hazardous
      substance for a respirable dust for an 8 h sample), the measurement
      reproducibility is more than +/-25% (2sigma). The results from PVC filters had
      better repeatability estimates than the glassfibre filters, but overall they had
      similar estimates of reproducibility. An improvement in both the reproducibility
      and repeatability for glassfibre filters was observed in the fourth study. This
      improvement reduced the reproducibility RSD at the lowest loading of 0.1 mg from
      30 to 18%. Sub-groups of data from the better performing laboratories in the
      first glassfibre filter study produced similar curves to the robust data from the
      fourth study. These data are useful in estimating the likely accuracy of
      measurements from a laboratory where good analytical practices exist.

PMID- 12406864
TI  - An investigation of air inlet velocity in simulating the dispersion of indoor
      contaminants via computational fluid dynamics.
AB  - Computational fluid dynamics (CFD) is potentially a valuable tool for simulating
      the dispersion of air contaminants in workrooms. However, CFD-estimated airflow
      and contaminant concentration patterns have not always shown good agreement with
      experimental results. Thus, understanding the factors affecting the accuracy of
      such simulations is critical for their successful application in occupational
      hygiene. The purposes of this study were to validate CFD approaches for
      simulating the dispersion of gases and vapors in an enclosed space at two air
      flow rates and to demonstrate the impact of one important determinant of
      simulation accuracy. The concentration of a tracer gas, isobutylene, was measured
      at 117 points in a rectangular chamber [1 (L) x 0.3 (H) x 0.7 m (W)] using a
      photoionization analyzer. Chamber air flow rates were scaled using geometric and
      kinematic similarity criteria to represent a full-sized room at two Reynolds
      numbers (Re = 5 x 10(2) and 5 x 10(3)). Also, CFD simulations were conducted to
      estimate tracer gas concentrations throughout the chamber. The simulation results
      for two treatments of air inlet velocity (profiled inlet velocity measured in
      traverses across the air inlet and the assumption that air velocity is uniform
      across the inlet) were compared with experimental observations. The CFD-simulated
      3-dimensional distribution of tracer gas concentration using the profiled inlet
      velocity showed better agreement qualitatively and quantitatively with measured
      chamber concentration, while the concentration estimated using the uniform inlet
      velocity showed poor agreement for both comparisons. For estimating room air
      contaminant concentrations when inlet velocities can be determined, this study
      suggests that using the inlet velocity distribution to define inlet boundary
      conditions for CFD simulations can provide more reliable estimates. When the
      inlet velocity distribution is not known, for instance for prospective design of
      dilution ventilation systems, the trials of several velocity profiles with
      different source, air inlet and air outlet locations may be useful for
      determining the most efficient workroom layout.

PMID- 12406865
TI  - Alveolar macrophages as biomarkers of pulmonary irritation in kitchen workers.
AB  - OBJECTIVES: Alveolar macrophages (AM) are used as a biomarker of pulmonary
      irritation due to occupational exposure in the AM test. The aim of this study was
      to investigate whether there is a co-variation between the number of AM and
      exposure to cooking fumes. MATERIALS AND METHODS: The study group consisted of 62
      volunteers. People who worked in a kitchen preparing hot meals were considered as
      occupationally exposed (35 persons). The exposed group was further divided into
      highly and slightly exposed persons according to the levels of fat aerosols and
      aldehydes in the working atmosphere. People who were not preparing hot meals were
      considered as unexposed (27 persons). The number of AM was counted in smears
      prepared from expectorate samples from each participant. Samples were taken on
      three different days. RESULTS: Highly occupationally exposed persons had a higher
      number of AM in their samples than both slightly occupationally exposed persons
      and unexposed persons. Highly exposed smokers had a statistically significantly
      higher number of AM compared with both slightly and unexposed smokers (P < or =
      0.05). CONCLUSION: The results suggest an increase in the number of AM due to
      exposure to cooking fumes and a synergistic effect between occupational exposure
      and smoking.

PMID- 12406866
TI  - Mitochondrial ferritin expression in erythroid cells from patients with
      sideroblastic anemia.
AB  - The sideroblastic anemias are characterized by ring sideroblasts, that is, red
      cell precursors with mitochondrial iron accumulation. We therefore studied the
      expression of mitochondrial ferritin (MtF) in these conditions. Erythroid cells
      from 13 patients with refractory anemia with ring sideroblasts (RARS) and 3
      patients with X-linked sideroblastic anemia (XLSA) were analyzed for the
      distribution of cytoplasmic H ferritin (HF) and MtF using immunocytochemical
      methods. We also studied 11 healthy controls, 5 patients with refractory anemia
      without ring sideroblasts (RA), and 7 patients with RA with excess of blasts
      (RAEB). About one fourth of normal immature red cells, mostly proerythroblasts
      and basophilic erythroblasts, showed diffuse cytoplasmic positivity for HF, but
      very few were positive for MtF (0%-10%). Similar patterns were found in anemic
      patients without ring sideroblasts. In contrast, many erythroblasts from patients
      with sideroblastic anemia (82%-90% in XLSA and 36%-84% in RARS) were positive for
      MtF, which regularly appeared as granules ringing the nucleus. Double
      immunocytochemical staining confirmed the different cellular distribution of HF
      and MtF. There was a highly significant relationship between the percentage of
      MtF(+) erythroblasts and that of ring sideroblasts (Spearman R = 0.90; P <.0001).
      Reverse transcription-polymerase chain reaction studies demonstrated the presence
      of MtF mRNA in circulating reticulocytes of 2 patients with XLSA but not in
      controls. These findings suggest that most of the iron deposited in perinuclear
      mitochondria of ring sideroblasts is present in the form of MtF and that this
      latter might be a specific marker of sideroblastic anemia.

PMID- 12406867
TI  - The peripheral cannabinoid receptor Cb2, a novel oncoprotein, induces a
      reversible block in neutrophilic differentiation.
AB  - We previously identified a novel common virus integration site, Evi11, by means
      of retroviral insertional mutagenesis. We demonstrated that the gene encoding the
      peripheral cannabinoid receptor (Cb2) is the potential target, suggesting that
      Cb2 is a proto-oncogene. To elucidate a role for this G protein-coupled receptor
      (GPCR) in leukemic transformation we generated a Cb2-EGFP cDNA construct that was
      introduced into 32D/G-CSF-R cells. These cells require interleukin 3 (IL-3) to
      proliferate in vitro, whereas in the presence of granulocyte-colony-stimulating
      factor (G-CSF) they differentiate toward mature neutrophils. We demonstrate that
      32D/G-CSF-R/Cb2-EGFP cells migrate in a transwell assay in reponse to the Cb2
      ligand 2-arachidonoylglycerol (2-AG), indicating that the fusion protein was
      functional. When cultured in the presence of G-CSF neutrophilic differentiation
      of Cb2-EGFP-expressing 32D/G-CSF-R cells was completely blocked. Moreover, a Cb2
      specific antagonist fully recovered the G-CSF-induced neutrophilic
      differentiation of 32D/G-CSF-R/Cb2-EGFP cells. To investigate which signal
      transduction pathway(s) may be involved in the block of neutrophilic maturation,
      differentiation experiments were carried out using specific inhibitors of
      signaling routes. Interestingly, full rescue of G-CSF-induced neutrophilic
      differentiation was observed when cells were cultured with the mitogen-induced
      extracellular kinase (MEK) inhibitors, PD98059 or U0126, and partial recovery was
      detected with the phosphoinositide 3-kinase (PI3-K) inhibitor LY-294002. These
      studies demonstrate that the Cb2 receptor is an oncoprotein that blocks
      neutrophilic differentiation when overexpressed in myeloid precursor cells. Cb2
      appears to mediate its activity through MEK/extracellular signal-related kinase
      (ERK) and PI3-K pathways.

PMID- 12406868
TI  - HES-1 preserves purified hematopoietic stem cells ex vivo and accumulates side
      population cells in vivo.
AB  - Mouse long-term hematopoietic reconstituting cells exist in the c-Kit+Sca-1+Lin-
      (KSL) cell population; among them, CD34(low/-) cells represent the most highly
      purified population of hematopoietic stem cells in the adult bone marrow. Here,
      we demonstrate that retrovirus-mediated transduction of CD34(low/-)c-Kit+Sca
      1+Lin- (34-KSL) cells with the HES-1 gene, which encodes a basic helix-loop-helix
      transcription factor functioning downstream of the Notch receptor, and is a key
      molecule for the growth phase of neural stem cells in the embryo, preserves the
      long-term reconstituting activity of these cells in vitro. We also show that
      cells derived from the HES-1-transduced 34-KSL population produce progenies
      characterized by negative Hoechst dye staining, which defines the side
      population, and by CD34(low/-) profile in the bone marrow KSL population in each
      recipient mouse at ratios 3.5- and 7.8-fold those produced by nontransduced 34
      KSL-derived competitor cells. We conclude that HES-1 preserves the long-term
      reconstituting hematopoietic activity of 34-KSL stem cells ex vivo. Up-regulation
      of HES-1 protein in the 34-KSL population before unnecessary cell division, that
      is, without retrovirus transduction, may represent a potent approach to absolute
      expansion of hematopoietic stem cells.

PMID- 12406869
TI  - The human herpes virus 8-encoded viral FLICE inhibitory protein protects against
      growth factor withdrawal-induced apoptosis via NF-kappa B activation.
AB  - The human herpes virus 8 (HHV8)-encoded viral FLICE (Fas-associating protein with
      death domain-like interleukin-1-converting enzyme) inhibitory protein (vFLIP) is
      believed to protect cells against death receptor-mediated apoptosis. In the
      present study we demonstrate that expression of HHV8 vFLIP in a growth factor
      dependent TF-1 leukemia cell line protects against growth factor withdrawal
      induced apoptosis. Unlike vector-expressing cells, those expressing HHV8 vFLIP
      maintain their mitochondrial membrane potential upon withdrawal from growth
      factor and also exhibit a block in the activation of caspases. The protective
      effect of HHV8 vFLIP is associated with its ability to activate the nuclear
      factor-kappa B (NF-kappaB) pathway and is missing in the vFLIP encoded by equine
      herpes virus 2 that lacks this activity. Inhibition of the NF-kappaB pathway by
      IkappaB superrepressor, lactacystin, MG132, arsenic trioxide, and phenylarsine
      oxide reverse the protection against growth factor withdrawal-induced apoptosis
      conferred by HHV8 vFLIP. HHV8 vFLIP up-regulates the expression of Bcl-x(L), an
      antiapoptotic member of the Bcl2 family, which is a known target of the NF-kappaB
      pathway. Collectively, the above results suggest that HHV8 vFLIP-induced NF
      kappaB activation may contribute to cellular transformation seen in association
      with HHV8 infection by preventing the apoptosis of cells destined to die because
      of growth factor deprivation.

PMID- 12406870
TI  - BVL-1-like VL30 promoter sustains long-term expression in erythroid progenitor
      cells.
AB  - Congenital blood disorders are common and yet clinically challenging globin
      disorders. Gene therapy continues to serve as a potential therapeutic method to
      treat these disorders. While tremendous advances have been made in vivo, gene
      delivery protocols and vector prototypes still require optimization. Alternative
      cis-acting promoter elements derived from VL30 retroelements have been effective
      in expressing tissue-specific transgene expression in vivo in nonerythroid cells.
      VL30 promoter elements were isolated from ELM-I-1 erythroid progenitor cells upon
      erythropoietin (epo) treatment. These promoters were inserted into a VL30-derived
      expression vector and reintroduced into the ELM-I-1 cells. beta-Galactosidase
      reporter gene activity from the ELM 5 clone, a BVL-1-like VL30 promoter, was
      capable of expressing sustained levels of the transgene expression over a 16-week
      assay period. These findings delineate the potential utility of these
      retroelement promoters as transcriptionally active, erythroid-specific, long
      terminal repeat (LTR) components for current globin vector constructs.

PMID- 12406871
TI  - Donor CMV serostatus has no impact on CMV viremia or disease when prophylactic
      granulocyte transfusions are given following allogeneic peripheral blood stem
      cell transplantation.
AB  - We studied the impact of donor cytomegalovirus (CMV) serologic status on CMV
      viremia and disease when prophylactic granulocyte colony-stimulating factor (G
      CSF)-mobilized granulocyte transfusions (GTs) were given following allogeneic
      peripheral blood stem cell (AlloPBSC) transplantation. A cohort of 83 patients
      who received 2 prophylactic GTs from ABO-compatible stem cell donors following
      AlloPBSC transplantation was compared with a cohort of 142 patients who did not.
      AlloPBSC donors were eligible for granulocyte donation irrespective of their CMV
      serostatus. Recipients received no prophylactic therapy for CMV. Donor CMV
      serostatus had no impact on CMV viremia and disease in the 2 cohorts. Our data
      show that in an era of effective surveillance and preemptive therapy for CMV,
      AlloPBSC recipients can safely receive 2 transfusions of prophylactic G-CSF
      mobilized granulocyte components from CMV-seropositive AlloPBSC donors. This
      knowledge may help expand the donor pool in areas with a high prevalence of CMV
      in the general population.

PMID- 12406872
TI  - Transformation of follicular lymphoma to diffuse large cell lymphoma is
      associated with a heterogeneous set of DNA copy number and gene expression
      alterations.
AB  - Genomic aberrations in a series of paired biopsy samples from patients who
      presented initially with follicle center lymphoma (FCL) and subsequently
      transformed to diffuse large B-cell lymphoma (DLBCL) were measured by array
      comparative genomic hybridization (CGH). The consequences of these aberrations on
      gene expression were determined by comparison with expression analysis on these
      specimens using cDNA microarrays. A heterogeneous pattern of acquired genomic
      abnormalities was observed upon transformation, some of which were recurrent in
      small subsets of patients. Some of the genomic aberration acquired upon
      transformation, such as gain/amplification of 1q21-q24, 2p16 (REL/BCL11A gene
      loci), 3q27-q29 (including the BCL6 locus), 7q11.2-q22.1, 12pter-q12, 18q21
      (including the BCL2 locus) and Xq, and deletion of 6q22-q24, 13q14-q21 and 17p13
      (P53 locus) have been previously implicated in the FCL/DLBCL pathogenesis. In
      addition, novel genomic imbalances not previously reported in association with
      FCL transformation, such as overrepresentation of 4p12-pter, 5p12-p15, 6p12.3
      p21, 9p23, 9q13-q31, 16q, 17q21, and loss of 1p36.3, 4q21-q23, 5q21-q23, 9q31
      qter, 11q24-q25, and 15q23, were identified. We observed a differential
      expression profile of many genes within regions of gain and deletion upon
      transformation, including novel target genes associated with FCL transformation.
      However, other genes did not show deregulated expression despite their location
      within these areas. In summary, the combination of array CGH and expression
      analysis provides a more comprehensive picture of the transformation of FCL to
      DLBCL. This process is associated with the acquisition of a variable spectrum of
      genomic imbalances affecting recurrent chromosomal areas that harbor
      overexpressed or underexpressed genes targeted upon transformation.

PMID- 12406873
TI  - An intronic polymorphism in the PAR-1 gene is associated with platelet receptor
      density and the response to SFLLRN.
AB  - Protease-activated receptor 1 (PAR-1), the main thrombin receptor on vascular
      cells, plays a key role in platelet activation. We examined the range of PAR-1
      expression on platelets, obtained twice, 1 week apart, from 100 healthy subjects
      and found a 2-fold interindividual variation in receptor numbers (95% CI = 858
      1700). Because PAR-1 density was stable with time (r(2) = 76%, P <.001), we
      sought a genetic explanation for the observed variability. To validate this
      approach, we also analyzed the alpha(2)beta(1) genotype according to receptor
      density and platelet mRNA expression data. We found that the number of PAR-1
      receptors on the platelet surface is associated with the intervening sequence
      IVSn-14 A/T intronic variation. The number of receptors was also found to govern
      the platelet response to the SFLLRN agonist, in terms of aggregation and P
      selectin expression. The T allele (allelic frequency, 0.14) can be considered as
      an allele with decreased expression, because it was associated with lower PAR-1
      expression on the platelet surface and with a lower response to SFLLRN. The IVSn
      14 A/T intronic variation may therefore be clinically relevant.

PMID- 12406874
TI  - Tolerance induction to a mammalian blood group-like carbohydrate antigen by
      syngeneic lymphocytes expressing the antigen.
AB  - Tolerance induction to transplantation-associated carbohydrate antigens, such as
      blood group A or B and the alpha-gal epitope (Gal(alpha)1-3Gal(beta)1-4GlcNAc-R),
      is of clinical significance. This study demonstrates tolerance induction to the
      alpha-gal epitope in the experimental animal model of
      alpha1,3galactosyltransferanse knockout mice (KO mice) lacking alpha-gal epitopes
      by administering syngeneic lymphocytes expressing alpha-gal epitopes. Repeated
      immunization of control KO mice with pig kidney membranes (PKM) expressing many
      alpha-gal epitopes induces an extensive anti-Gal antibody response against this
      epitope. In contrast, KO mice that received as few as 2 x 10(6) wild-type (WT)
      lymphocytes were tolerized and failed to produce anti-Gal following PKM
      immunizations. Accordingly, control mice producing anti-Gal rapidly rejected
      transplanted WT hearts, whereas tolerized mice did not reject WT hearts. These
      findings suggest that autologous blood lymphocytes processed to express a
      carbohydrate antigen may induce a similar tolerance to such an antigen upon
      administration into humans.

PMID- 12406875
TI  - The 4G5G polymorphism in the gene for PAI-1 and the circadian oscillation of
      plasma PAI-1.
AB  - Plasminogen activator inhibitor type I (PAI-1) antigen concentrations follow a
      circadian oscillation peaking in the morning. Some individuals show no apparent
      circadian rhythm, while others show up to a 10-fold variation in PAI-1 over 24
      hours. Results from experimental studies suggest that a polymorphism in the
      promoter of the gene for PAI-1 (4G5G) directly influences the circadian
      expression of the PAI-1 gene. We studied whether the diurnal variation of PAI-1
      antigen differs for the genotypes of the 4G5G polymorphism. A population-based,
      cross-sectional study was performed among 263 subjects selected from the
      Rotterdam Study, a population-based cohort of 7983 men and women aged 55 years
      and older. The 4G allele was associated with a more pronounced circadian
      expression of PAI-1 antigen. Morning PAI-1 antigen concentrations were 79 ng/mL
      (95% confidence interval [CI], 68-92) in subjects homozygous for 4G, 62 ng/mL
      (95% CI, 54-72) in heterozygous subjects, and 59 ng/mL (95% CI, 49-71) in
      subjects homozygous for 5G. While respective PAI-1 antigen concentrations in the
      afternoon were 40 ng/mL (95% CI, 33-49), 41 ng/mL (95% CI, 37-47), and 40 ng/mL
      (95% CI, 49-71). These findings suggest that the morning increase in PAI-1
      antigen concentration is more pronounced among subjects homozygous for the 4G
      allele compared with the morning increase among the other genotypes.
      Additionally, these findings show that homozygosity for the 4G allele is
      associated with increased PAI-1 levels during the morning only.

PMID- 12406876
TI  - Autocrine-paracrine VEGF loops potentiate the maturation of megakaryocytic
      precursors through Flt1 receptor.
AB  - The expression/function of vascular endothelial growth factor (VEGF) receptors
      (VEGFR1/Flt1 and VEGFR2/KDR/Flk1) in hematopoiesis is under scrutiny. We have
      investigated the expression of Flt1 and kinase domain receptor (KDR) on
      hematopoietic precursors, as evaluated in liquid culture of CD34(+) hematopoietic
      progenitor cells (HPCs) induced to unilineage differentiation/maturation through
      the erythroid (E), megakaryocytic (Mk), granulocytic (G), or monocytic (Mo)
      lineage. KDR, expressed on 0.5% to 1.5% CD34(+) cells, is rapidly downmodulated
      on induction of differentiation. Similarly, Flt1 is present at very low levels in
      HPCs and is downmodulated in E and G lineages; however, Flt1 is induced in the
      precursors of both Mo and Mk series; ie, its level progressively increases during
      Mo maturation, and it peaks at the initial-intermediate culture stages in the Mk
      lineage. Functional experiments indicate that Mk and E, but not G and Mo,
      precursors release significant amounts of VEGF in the culture medium,
      particularly at low O(2) levels. The functional role of VEGF release on Mk
      maturation is indicated by 2 series of observations. (1) Molecules preventing the
      VEGF-Flt1 interaction on the precursor membrane (eg, soluble Flt1 receptors)
      significantly inhibit Mk polyploidization. (2) Addition of exogenous VEGF or
      placenta growth factor (PlGF) markedly potentiates Mk maturation. Conversely,
      VEGF does not modify Mo differentiation/maturation. Altogether, our results
      suggest that in the hematopoietic microenvironment an autocrine VEGF loop
      contributes to optimal Mk maturation through Flt1. A paracrine loop involving
      VEGF release by E precursors may also operate. Similarly, recent studies indicate
      that an autocrine loop involving VEGF and Flt1/Flk1 receptors mediates
      hematopoietic stem cell survival and differentiation.

PMID- 12406877
TI  - Successful therapy of metastatic cancer using tumor vaccines in mixed allogeneic
      bone marrow chimeras.
AB  - A frequent outcome of allogeneic stem cell transplantation (alloSCT) in the
      treatment of leukemia is the destruction of the host hematolymphoid compartment
      and, thus, the malignancy, through the combined action of high-dose
      chemoradiotherapy and a T-cell-mediated graft-versus-host effect. Unfortunately,
      alloSCT is frequently limited by toxicity, including graft-versus-host disease
      (GVHD), and has not been successful in the treatment of tumors derived from solid
      organs. Here we report a novel cooperation between host and donor T cells in the
      response to a tumor cell vaccine given after a nonmyeloablative allogeneic stem
      cell transplantation (NST) protocol that achieves stable mixed bone marrow
      chimerism. Treatment of animals with NST, posttransplantation donor lymphocyte
      infusions (DLIs), and a vaccine, comprising irradiated autologous tumor cells
      mixed with a granulocyte-macrophage colony-stimulating factor (GM-CSF)-producing
      bystander line, results in potent and specific antitumor immunity. This combined
      modality immunotherapy, administered after surgical removal of the primary tumor,
      cured metastatic mammary cancer in most animals without inducing GVHD. Cured
      animals contained tumor-specific T cells of both host and donor origin, but
      immunodeficient hosts could not be cured by NST, DLI, and vaccine administration.
      Thus, transfer of allogeneic donor T cells may help break functional tolerance of
      a host immune system to a solid tumor, thereby providing a rationale for the
      generation of mixed hematopoietic chimerism by NST prior to tumor cell
      vaccination.

PMID- 12406878
TI  - Generation and genetic modification of dendritic cells derived from mouse
      embryonic stem cells.
AB  - We developed a method to generate dendritic cells (DCs) from mouse embryonic stem
      (ES) cells. We cultured ES cells for 10 days on feeder cell layers of OP9, in the
      presence of granulocyte-macrophage colony-stimulating factor in the latter 5
      days. The resultant ES cell-derived cells were transferred to bacteriologic Petri
      dishes without feeder cells and further cultured. In about 7 days, irregularly
      shaped floating cells with protrusions appeared and these expressed major
      histocompatibility complex class II, CD11c, CD80, and CD86, with the capacity to
      stimulate primary mixed lymphocyte reaction (MLR) and to process and present
      protein antigen to T cells. We designated them ES-DCs (ES cell-derived dendritic
      cells), and the functions of ES-DCs were comparable with those of DCs generated
      from bone marrow cells. Upon transfer to new dishes and stimulation with
      interleukin-4 plus tumor necrosis factor alpha, combined with anti-CD40
      monoclonal antibody or lipopolysaccharide, ES-DCs completely became mature DCs,
      characterized by a typical morphology and higher capacity to stimulate MLR. Using
      an expression vector containing the internal ribosomal entry site-puromycin N
      acetyltransferase gene or a Cre-lox-mediated exchangeable gene-trap system, we
      could efficiently generate ES cell transfectants expressing the products of
      introduced genes after their differentiation to DCs. ES-DCs expressing invariant
      chain fused to a pigeon cytochrome C epitope presented the epitope efficiently in
      the context of E(k). We primed ovalbumin (OVA)-specific cytotoxic T lymphocytes
      in vivo by injecting mice with ES-DCs expressing OVA, thus demonstrating
      immunization with ES-DCs genetically engineered to express antigenic protein. The
      methods may be applicable to immunomodulation therapy and gene-trap
      investigations of DCs.

PMID- 12406879
TI  - Both B and T lymphocytes may be clonally involved in myelofibrosis with myeloid
      metaplasia.
AB  - A combination of magnetic cell sorting (MACS) and fluorescent in situ
      hybridization (FISH) techniques was used to detect clonal cytogenetic markers in
      different myeloid and lymphoid cell types of the peripheral blood from 4 patients
      with myelofibrosis with myeloid metaplasia (MMM) that was associated with either
      a 13q- or a 20q- karyotypic abnormality. Interphase cytogenetics studies
      demonstrated abnormal clonal FISH signal patterns in neutrophil, myeloid,
      erythroid, megakaryocyte, and B- and T-cell preparations in 3 of the 4 patients.
      In one patient, FISH results were within normal limits in T cells and slightly
      abnormal in B cells. In general, the percentage of abnormal nuclei was variable
      in both lymphocyte populations but always higher in B lymphocytes compared with T
      lymphocytes. The current study provides direct evidence for the clonal
      involvement of both B and T lymphocytes in MMM. A larger study is needed to
      clarify the relevance of the observed interpatient heterogeneity in clonal
      constitution.

PMID- 12406880
TI  - CCR4 versus CCR10 in human cutaneous TH lymphocyte trafficking.
AB  - The chemokine receptors (CCRs) CCR4 and CCR10, and the cutaneous lymphocyte
      antigen (CLA), have each been proposed as critical mediators of skin-specific TH
      lymphocyte homing in mice and humans. CLA initiates skin homing by mediating E
      selectin-dependent tethering and rolling within cutaneous venules, but the
      specific roles of CCR4 and CCR10 are unclear. We have generated an antihuman
      CCR10 monoclonal antibody (mAb; 1B5) to illuminate the individual contributions
      of these molecules. This mAb allows us to compare CCR10, CCR4, and CLA expression
      within human TH populations. The mAb 1B5 recognizes functional CCR10 expression,
      as chemotactic responsiveness to cutaneous T-cell-attracting chemokine
      (CTACK)/CCL27 (a CCR10 ligand) parallels the staining of TH subsets. We find
      CCR10 expressed by only a minority (approximately 30%) of blood-borne, skin
      homing (CLA+/CCR4+) TH cells. However, essentially all members of the relatively
      small "effector" (CLA+/CCR4+/CD27-/CCR7-) skin-homing TH population express
      CCR10. Most skin-infiltrating lymphocytes in allergic delayed-type
      hypersensitivity (DTH) and bacterial chancroid skin lesions express both CCR4 and
      CLA, but only about 10% express CCR10. This suggests for the 2 models of TH skin
      homing studied here that CCR10+ TH cells have no advantage over other CLA+/CCR4+
      TH cells in homing to cutaneous sites. We conclude that the skin-homing TH
      compartment is itself divided into distinct subpopulations, the smaller of which
      expresses both CCR4 and CCR10, and the larger of which expresses only CCR4. Thus,
      CCR10 is unlikely to be necessary for cutaneous homing of TH cells in the models
      studied here. CCR10 may instead play a role in the movement of specialized
      "effector" cutaneous TH cells to and/or within epidermal microenvironments.

PMID- 12406881
TI  - Local and systemic effects of an allogeneic tumor cell vaccine combining
      transgenic human lymphotactin with interleukin-2 in patients with advanced or
      refractory neuroblastoma.
AB  - In murine models, transgenic chemokine-cytokine tumor vaccines overcome many of
      the limitations of single-agent immunotherapy by producing the sequence of T-cell
      attraction followed by proliferation. The safety and immunologic effects of this
      approach in humans were tested in 21 patients with relapsed or refractory
      neuroblastoma. They received up to 8 subcutaneous injections of a vaccine
      combining lymphotactin (Lptn)- and interleukin-2 (IL-2)-secreting allogeneic
      neuroblastoma cells in a dose-escalating scheme. Severe adverse reactions were
      limited to reversible panniculitis in 5 patients and bone pain in 1 patient.
      Injection-site biopsies revealed increased cellularity caused by infiltration of
      CD4+ and CD8+ lymphocytes, eosinophils, and Langerhans cells. Systemically, the
      vaccine produced a 2-fold (P =.035) expansion of CD4+ T cells, a 3.5-fold (P
      =.039) expansion of natural killer (NK) cells, a 2.1-fold (P =.014) expansion of
      eosinophils, and a 1.6-fold (P =.049) increase in serum IL-5. When restimulated
      in vitro by the immunizing cell line, T cells collected after vaccination showed
      a 2.3-fold increase (P =.02) of T-helper (TH2)-type CD3+IL-4+ cells. Supernatant
      collected from restimulated cells showed increased amounts of IL-4 (11.4-fold; P
      =.021) and IL-5 (8.7-fold; P =.002). Six patients had significant increases in NK
      cytolytic activity. Fifteen patients made immunoglobulin G (IgG) antibodies that
      bound to the immunizing cell line. Measurable tumor responses included complete
      remission in 2 patients and partial response in 1 patient. Hence, allogeneic
      tumor cell vaccines combining transgenic Lptn with IL-2 appear to have little
      toxicity in humans and can induce an antitumor immune response.

PMID- 12406882
TI  - Potentiation of TRAIL-induced apoptosis in primary effusion lymphoma through
      azidothymidine-mediated inhibition of NF-kappa B.
AB  - The survival of viral mediated lymphomas depends upon constitutive nuclear factor
      kappa B (NF-kappaB) activity. AIDS-related human herpesvirus type 8-associated
      primary effusion lymphoma (PEL) responds poorly to chemotherapy and is almost
      invariably fatal. We have previously demonstrated that the antiviral combination
      of interferon alpha (IFN-alpha) and azidothymidine (AZT) induces apoptosis in PEL
      cell lines. We therefore used these agents as therapy for an AIDS patient with
      PEL. The patient had a dramatic response, with complete resolution of his
      malignant effusion in 5 days. In PEL cells, the death receptor ligand known as
      tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is markedly up
      regulated by IFN-alpha; however, signals transduced by death receptors may also
      activate an antiapoptotic response mediated by NF-kappaB. In both the primary
      tumor cells from our patient and PEL cell lines, AZT selectively blocked nuclear
      entry of the NF-kappaB heterodimer p50 and p65, an effect not seen with other
      nonthymidine antiviral nucleosides. AZT monophosphate, the principal
      intracellular metabolite, inhibited phosphorylation and degradation of IkappaB by
      the IkappaB kinase complex. AZT- and IFN-alpha-mediated apoptosis was blocked by
      expression and nuclear localization of an IkappaB-resistant form of NF-kappaB
      (the p50 subunit linked to the transactivation domain of herpes simplex virus
      VP16). The proapoptotic effect of AZT and IFN-alpha in PEL occurs through the
      concomitant activation of TRAIL and blockade of NF-kappaB and represents a novel
      antiviral therapy for a virally mediated tumor.

PMID- 12406883
TI  - Novel secreted isoform of adhesion molecule ICAM-4: potential regulator of
      membrane-associated ICAM-4 interactions.
AB  - Intercellular adhesion molecule-4 (ICAM-4), a newly characterized adhesion
      molecule, is expressed early in human erythropoiesis and functions as a ligand
      for binding alpha4beta1 and alphaV integrin-expressing cells. Within the bone
      marrow, erythroblasts surround central macrophages forming erythroblastic
      islands. Evidence suggests that these islands are highly specialized
      subcompartments where cell adhesion events, in concert with cytokines, play
      critical roles in regulating erythropoiesis and apoptosis. Since erythroblasts
      express alpha4beta1 and ICAM-4 and macrophages exhibit alphaV, ICAM-4 is an
      attractive candidate for mediating cellular interactions within erythroblastic
      islands. To determine whether ICAM-4 binding properties are conserved across
      species, we first cloned and sequenced the murine homologue. The translated amino
      acid sequence showed 68% overall identity with human ICAM-4. Using recombinant
      murine ICAM-4 extracellular domains, we discovered that hematopoietic alpha4beta1
      expressing HEL cells and nonhematopoietic alphaV-expressing FLY cells adhered to
      mouse ICAM-4. Cell adhesion studies showed that FLY and HEL cells bound to mouse
      and human proteins with similar avidity. These data strongly suggest conservation
      of integrin-binding properties across species. Importantly, we characterized a
      novel second splice cDNA that would be predicted to encode an ICAM-4 isoform,
      lacking the membrane-spanning domain. Erythroblasts express both isoforms of ICAM
      4. COS-7 cells transfected with green flourescent protein constructs of
      prototypic or novel ICAM-4 cDNA showed different cellular localization patterns.
      Moreover, analysis of tissue culture medium revealed that the novel ICAM-4 cDNA
      encodes a secreted protein. We postulate that secretion of this newly described
      isoform, ICAM-4S, may modulate binding of membrane-associated ICAM-4 and could
      thus play a critical regulatory role in erythroblast molecular attachments.

PMID- 12406884
TI  - Circulation is established in a stepwise pattern in the mammalian embryo.
AB  - To better understand the relationship between the embryonic hematopoietic and
      vascular systems, we investigated the establishment of circulation in mouse
      embryos by examining the redistribution of yolk sac-derived primitive
      erythroblasts and definitive hematopoietic progenitors. Our studies revealed that
      small numbers of erythroblasts first enter the embryo proper at 4 to 8 somite
      pairs (sp) (embryonic day 8.25 [E8.25]), concomitant with the proposed onset of
      cardiac function. Hours later (E8.5), most red cells remained in the yolk sac.
      Although the number of red cells expanded rapidly in the embryo proper, a steady
      state of approximately 40% red cells was not reached until 26 to 30 sp (E10).
      Additionally, erythroblasts were unevenly distributed within the embryo's
      vasculature before 35 sp. These data suggest that fully functional circulation is
      established after E10. This timing correlated with vascular remodeling,
      suggesting that vessel arborization, smooth muscle recruitment, or both are
      required. We also examined the distribution of committed hematopoietic
      progenitors during early embryogenesis. Before E8.0, all progenitors were found
      in the yolk sac. When normalized to circulating erythroblasts, there was a
      significant enrichment (20- to 5-fold) of progenitors in the yolk sac compared
      with the embryo proper from E9.5 to E10.5. These results indicated that the yolk
      sac vascular network remains a site of progenitor production and preferential
      adhesion even as the fetal liver becomes a hematopoietic organ. We conclude that
      a functional vascular system develops gradually and that specialized vascular
      hematopoietic environments exist after circulation becomes fully established.

PMID- 12406885
TI  - Identification of an MIP-1alpha -binding heparan sulfate oligosaccharide that
      supports long-term in vitro maintenance of human LTC-ICs.
AB  - We previously showed that heparan sulfate (HS) is required for in vitro cytokine
      + chemokine-mediated maintenance of primitive human hematopoietic progenitors.
      However, HS preparations are mixtures of polysaccharide chains of varying size,
      structure, and protein-binding abilities. Therefore, we examined whether the long
      term culture-initiating cells (LTC-IC) supportive capability of HS is
      attributable to an oligosaccharide of defined length and protein-binding ability.
      Oligosaccharides of a wide range of sizes were prepared, and their capability to
      support human marrow LTC-IC maintenance in the presence of low-dose cytokines and
      a single chemokine, macrophage inflammatory protein-1alpha (MIP-1alpha), was
      examined. LTC-IC supportive capability of HS oligosaccharides correlated directly
      with size and MIP-1alpha binding ability. A specific MIP-1alpha-binding HS
      oligosaccharide preparation of M(r) 10 kDa that optimally supported LTC-IC
      maintenance was identified. This oligosaccharide had the structure required for
      MIP-1alpha binding, which we have recently described. The present study defines
      the minimum size and structural features of LTC-IC supportive HS.

PMID- 12406886
TI  - Engraftment of human CD34+ cells leads to widespread distribution of donor
      derived cells and correction of tissue pathology in a novel murine
      xenotransplantation model of lysosomal storage disease.
AB  - A novel murine system was developed to study the in vivo localization of
      xenotransplanted human cells and assess their therapeutic effect in an authentic
      model of disease. The beta-glucuronidase (GUSB) mutation of the
      mucopolysaccharidosis type VII (MPSVII) mouse was backcrossed onto the nonobese
      diabetic/severe combined immunodeficient (NOD/SCID) xenotransplantation strain.
      The resulting NOD/SCID/MPSVII mice displayed the characteristic features of
      lysosomal storage disease because of GUSB deficiency and were also capable of
      engrafting human cells. Human CD34+ hematopoietic progenitor cells from healthy,
      GUSB+ donors engrafted NOD/SCID/MPSVII mice in a manner similar to that of
      standard NOD/SCID mice. Six to 12 weeks following transplantation, 1% to 86% of
      the host bone marrow was positive for human CD45. By using a GUSB-specific
      histochemical assay, human engraftment was detected with single-cell sensitivity
      not only in well-characterized hematopoietic tissues like bone marrow, spleen,
      lymph node, and thymus, but also in other nonhematopoietic organs like liver,
      kidney, lung, heart, brain, and eye. Quantitative measurements of GUSB activity
      confirmed this expansive tissue distribution. The GUSB-specific assays were
      validated for their accuracy in identifying human cells through colocalization of
      human CD45 expression with GUSB activity in tissues of mice receiving
      transplants. An analysis of the therapeutic effects of engrafted human cells
      revealed a reduction of pathologic storage material in host organs, including the
      bone, spleen, and liver. Such xenotransplantation experiments in the
      NOD/SCID/MPSVII mouse represent a powerful approach to both study the in vivo
      biology of human cells and gather preclinical data regarding treatment approaches
      for a human disease.

PMID- 12406887
TI  - Simian immunodeficiency virus dramatically alters expression of homeostatic
      chemokines and dendritic cell markers during infection in vivo.
AB  - Dendritic cells (DCs) are potent antigen-presenting cells that likely play
      multiple roles in human immunodeficiency virus type 1 (HIV-1) pathogenesis. We
      used the simian immunodeficiency virus (SIV)/macaque model to study the effects
      of infection on homeostatic chemokine expression and DC localization directly in
      secondary lymphoid tissues. SIV infection altered the expression of chemokines
      (CCL19/MIP-3beta, CCL21/ 6Ckine, and CCL20/MIP-3alpha) and of chemokine receptors
      (CCR7 and CCR6) that drive DC trafficking. CCL19/MIP-3beta, CCL20/MIP-3alpha,
      CCR6, and CCR7 expression increased in lymph nodes during the early systemic
      burst of viral replication (acute infection), whereas CCL21/6Ckine expression
      progressively decreased throughout disease to AIDS. Parallel with the SIV-induced
      perturbations in chemokine expression were changes in the expression of the DC
      associated markers, DC-SIGN, DC-LAMP, and DECTIN-1. During AIDS, DC-LAMP mRNA
      expression levels were significantly reduced in lymph nodes and spleen, and DC
      SIGN levels were significantly reduced in spleen. These findings suggest that the
      disruption of homeostatic chemokine expression is responsible, in part, for
      alterations in the networks of antigen-presenting cells in lymphoid tissues,
      ultimately contributing to systemic immunodeficiency.

PMID- 12406888
TI  - Heterotypic interactions between transferrin receptor and transferrin receptor 2.
AB  - Cellular iron uptake in most tissues occurs via endocytosis of diferric
      transferrin (Tf) bound to the transferrin receptor (TfR). Recently, a second
      transferrin receptor, transferrin receptor 2 (TfR2), has been identified and
      shown to play a critical role in iron metabolism. TfR2 is capable of Tf-mediated
      iron uptake and mutations in this gene result in a rare form of hereditary
      hemochromatosis unrelated to the hereditary hemochromatosis protein, HFE. Unlike
      TfR, TfR2 expression is not controlled by cellular iron concentrations and little
      information is currently available regarding the role of TfR2 in cellular iron
      homeostasis. To investigate the relationship between TfR and TfR2, we performed a
      series of in vivo and in vitro experiments using antibodies generated to each
      receptor. Western blots demonstrate that TfR2 protein is expressed strongest in
      erythroid/myeloid cell lines. Metabolic labeling studies indicate that TfR2
      protein levels are approximately 20-fold lower than TfR in these cells. TfR and
      TfR2 have similar cellular localizations in K562 cells and coimmunoprecipitate to
      only a very limited extent. Western analysis of the receptors under nonreducing
      conditions reveals that they can form heterodimers.

PMID- 12406890
TI  - T(14;18)(q32;q21) involving IGH and MALT1 is a frequent chromosomal aberration in
      MALT lymphoma.
AB  - T(11;18)(q21;q21) is the most common structural abnormality in extranodal
      marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT
      lymphoma) leading to the fusion of the apoptosis inhibitor-2 (API2) gene and the
      MALT lymphoma-associated translocation (MALT1) gene. In 2 patients with MALT
      lymphoma of the liver and skin, respectively, t(14;18)(q32;q21) was observed by
      cytogenetic analysis. Subsequent fluorescence in situ hybridization (FISH)
      studies disclosed that the immunoglobulin heavy-chain locus (IGH) and the MALT1
      gene were rearranged by this translocation. In order to screen a large series of
      MALT lymphomas for this aberration, a 2-color interphase FISH assay was
      established. Among a total of 66 cases, t(14;18)(q32;q21) involving IGH and MALT1
      was detected in MALT lymphomas of the liver (4 of 4), skin (3 of 11), ocular
      adnexa (3 of 8), and salivary gland (2 of 11), but did not occur in MALT
      lymphomas of the stomach (n = 10), intestine (n = 9), lung (n = 7), thyroid (n =
      4), or breast (n = 2). In total, 12 of 66 (18%) MALT lymphomas harbored
      t(14;18)(q32;q21); 7 additional cases of splenic marginal zone lymphoma tested
      negative. All of the 12 MALT lymphomas featuring the t(14;18)(q32;q21) were
      negative for t(11;18)(q21;q21) by reverse transcriptase-polymerase chain reaction
      (RT-PCR). However, trisomy 3 and/or 18 was found in 4 of 12 cases, suggesting
      that the t(14;18)(q32;q21) does not occur as the sole genetic abnormality. This
      study identifies IGH as a new translocation partner of MALT1 in MALT lymphomas,
      which tend to arise frequently at sites other than the gastrointestinal tract and
      lung. In contrast to t(11;18)(q21;q21)(+) MALT lymphomas, those with
      t(14;18)(q32;q21) may harbor additional genetic abnormalities.

PMID- 12406889
TI  - Insights into leukocyte adhesion deficiency type 2 from a novel mutation in the
      GDP-fucose transporter gene.
AB  - Leukocyte adhesion deficiency type 2 (LADII) is characterized by defective
      selectin ligand formation, recurrent infection, and mental retardation. This rare
      syndrome has only been described in 2 kindreds of Middle Eastern descent who have
      differentially responded to exogenous fucose treatment. The molecular defect was
      recently ascribed to single and distinct missense mutations in a putative Golgi
      guanosine diphosphate (GDP)-fucose transporter. Here, we describe a patient of
      Brazilian origin with features of LADII. Sequencing of the GDP-fucose transporter
      revealed a novel single nucleotide deletion producing a shift in the open-reading
      frame and severe truncation of the polypeptide. Overexpression of the mutant
      protein in the patient's fibroblasts did not rescue fucosylation, suggesting that
      the deletion ablated the activity of the transporter. Administration of oral L
      fucose to the patient produced molecular and clinical responses, as measured by
      the appearance of selectin ligands, normalization of neutrophil counts, and
      prevention of infectious recurrence. The lower neutrophil counts paralleled
      improved neutrophil interactions with activated endothelium in cremasteric
      venules of nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice.
      However, fucose supplementation induced autoimmune neutropenia and the appearance
      of H antigen on erythrocytes, albeit without evidence of intravascular hemolysis.
      The robust response to fucose despite a severely truncated transporter suggests
      alternative means to transport GDP-fucose into the Golgi complex.

PMID- 12406891
TI  - Evidence for naive T-cell repopulation despite thymus irradiation after
      autologous transplantation in adults with multiple myeloma: role of ex vivo CD34+
      selection and age.
AB  - Immunodeficiency following autologous CD34+-purified peripheral blood stem cell
      (PBSC) transplantation could be related to T-cell depletion of the graft or
      impaired T-cell reconstitution due to thymus irradiation. Aiming to assess the
      role of irradiated thymus in T-cell repopulation, we studied 32 adults with
      multiple myeloma, randomly assigned to receive high-dose therapy including total
      body irradiation (TBI) followed by autologous transplantation with either
      unselected or CD34+-selected PBSCs. The median number of reinfused CD3+ cells was
      lower in the selected group (0.03 versus 14 x 10(6)/kg; P =.002). Lymphocyte
      subset counts were evaluated from month 3 to 24 after grafting. Naive CD4+ T
      cells were characterized both by phenotype and by quantification of T-cell
      receptor rearrangement excision circles (TRECs). The reconstitution of CD3+ and
      CD4+ T cells was significantly delayed in the CD34+-selected group, but
      eventually led to counts similar to those found in the unselected group after
      month 12. Mechanism of reconstitution differed, however, between both groups.
      Indeed, a marked increase in the naive CD62L+CD45RA+CD4+ subset was observed in
      the selected group, but not in the unselected group in which half of the
      CD45RA+CD4+ T cells appear to be CD62L-. Age was identified as an independent
      adverse factor for CD4+ and CD62L+CD45RA+CD4+ T-cell reconstitution. Our results
      provide evidence that infusing PBSCs depleted of T cells after TBI in adults
      delays T-cell reconstitution but accelerates thymic regeneration.

PMID- 12406892
TI  - Efficient transduction of primary human B lymphocytes and nondividing myeloma B
      cells with HIV-1-derived lentiviral vectors.
AB  - We studied the transduction of primary human B lymphocytes and myeloma cells with
      lentiviral vectors. In peripheral blood B cells that had been activated with
      helper T cells (murine thymoma EL-4 B5) and cytokines, multiply attenuated HIV-1
      derived vectors pseudotyped with vesicular stomatitis virus (VSV) G-envelope
      protein achieved the expression of green fluorescence protein (GFP) in 27% +/-
      12% (mean +/- 1 SD; median, 27%) of B cells in different experiments. When
      compared in parallel cultures, the transducibility of B cells from different
      donors exhibited little variation. The human cytomegalovirus (CMV) promoter gave
      4- to 6-fold higher GFP expression than did the human elongation factor-1alpha
      promoter. A murine retroviral vector pseudotyped with VSV G protein proved
      inefficient even in mitotically active primary B cells. B cells freshly
      stimulated with Epstein-Barr virus were also transducible by HIV vectors (24% +/-
      9%), but B cells activated with CD40 ligand and cytokines resisted transduction.
      Thus, different culture systems gave different results. Freshly isolated,
      nondividing myeloma cells were efficiently transduced by HIV vectors; for 6
      myelomas the range was 14% to 77% (median, 28%) GFP(+) cells. HIV vectors with a
      mutant integrase led to no significant GFP signal in primary B or myeloma cells,
      suggesting that vector integration was required for high transduction. In
      conclusion, HIV vectors are promising tools for studies of gene functions in
      primary human B cells and myeloma cells for the purposes of research and the
      development of gene therapies.

PMID- 12406893
TI  - A chemically defined culture of VEGFR2+ cells derived from embryonic stem cells
      reveals the role of VEGFR1 in tuning the threshold for VEGF in developing
      endothelial cells.
AB  - Vascular endothelial growth factor (VEGF) is a major growth factor for developing
      endothelial cells (ECs). Embryonic lethality due to haploinsufficiency of VEGF in
      the mouse highlighted the strict dose dependency of VEGF on embryonic vascular
      development. Here we investigated the dose-dependent effects of VEGF on the
      differentiation of ES cell-derived fetal liver kinase 1 (Flk-1)/VEGF receptor
      2(+) (VEGFR2(+)) mesodermal cells into ECs on type IV collagen under a chemically
      defined serum-free condition. These cells could grow even in the absence of VEGF,
      but differentiated mostly into mural cells positive for alpha-smooth muscle
      actin. VEGF supported in a dose-dependent manner the differentiation into ECs
      defined by the expression of VE-cadherin, platelet-endothelial cell adhesion
      molecule 1 (PECAM-1)/ CD31, CD34, and TIE2/TEK. VEGF requirement was greater at
      late than at early phase of culture during EC development, whereas response of
      VEGFR2(+) cells to VEGF-E, which is a virus-derived ligand for VEGFR2 but not for
      Flt-1/VEGFR1, was not dose sensitive even at late phase of culture. Delayed
      expression of VEGFR1 correlated with increased dose dependency of VEGF. These
      results suggested that greater requirement of VEGF in the maintenance than
      induction of ECs was due to the activity of VEGFR1 sequestering VEGF from VEGFR2
      signal. The chemically defined serum-free culture system described here provides
      a new tool for assessing different factors for the proliferation and
      differentiation of VEGFR2(+) mesodermal cells.

PMID- 12406894
TI  - Neuropilin-1 on hematopoietic cells as a source of vascular development.
AB  - Neuropilin-1 (NP-1) is a receptor for vascular endothelial growth factor-165
      (VEGF165) and acts as a coreceptor that enhances the function of VEGF165 through
      VEGF receptor-2 (VEGFR-2). Studies using transgenic and knock-out mice of NP-1
      indicated that this molecule is important for vascular development as well as
      neuronal development. We recently reported that clustered soluble NP-1
      phosphorylates VEGFR-2 on endothelial cells with a low dose of VEGF165 and
      rescues the defective vascularity of the NP-1-/- embryo in vitro and in vivo.
      Here we show that NP-1 is expressed by CD45+ hematopoietic cells in the fetal
      liver, can bind VEGF165, and phosphorylates VEGFR-2 on endothelial cells. CD45+NP
      1+ cells rescued the defective vasculogenesis and angiogenesis in the NP-1-/- P
      Sp (para-aortic splanchnopleural mesodermal region) culture, although CD45+NP-1-
      cells did not. Moreover, CD45+NP-1+ cells together with VEGF165 induced
      angiogenesis in an in vivo Matrigel assay and cornea neovascularization assay.
      The extracellular domain of NP-1 consists of "a," "b," and "c" domains, and it is
      known that the "a" and "c" domains are necessary for dimerization of NP-1. We
      found that both the "a" and "c" domains are essential for such rescue of
      defective vascularities in the NP-1 mutant. These results suggest that NP-1
      enhances vasculogenesis and angiogenesis exogenously and that dimerization of NP
      1 is important for enhancing vascular development. In NP-1-/- embryos, vascular
      sprouting is impaired at the central nervous system (CNS) and pericardium where
      VEGF is not abundant, indicating that NP-1-expressing cells are required for
      normal vascular development.

PMID- 12406895
TI  - Radiosensitive SCID patients with Artemis gene mutations show a complete B-cell
      differentiation arrest at the pre-B-cell receptor checkpoint in bone marrow.
AB  - Severe combined immunodeficiency disease (SCID) can be immunologically classified
      by the absence or presence of T, B, and natural killer (NK) cells. About 30% of
      T(-)B(-)NK(+) SCID patients carry mutations in the recombination activating genes
      (RAG). Some T(-)B(-)NK(+) SCID patients without RAG gene mutations are sensitive
      to ionizing radiation, and several of these radiosensitive (RS) SCID patients
      were recently shown to have large deletions or truncation mutations in the
      Artemis gene, implying a role for Artemis in DNA double-strand break (dsb)
      repair. We identified 5 RS-SCID patients without RAG gene mutations, 4 of them
      with Artemis gene mutations. One patient had a large genomic deletion, but the
      other 3 patients carried simple missense mutations in conserved amino acid
      residues in the SNM1 homology domain of the Artemis protein. Extrachromosomal
      V(D)J recombination assays showed normal and precise signal joint formation, but
      inefficient coding joint formation in fibroblasts of these patients, which could
      be complemented by the wild-type Artemis gene. The cells containing the missense
      mutations in the SNM1 homology domain had the same recombination phenotype as the
      cells with the large deletion, indicating that these amino acid residues are
      indispensable for Artemis function. Immunogenotyping and immunophenotyping of
      bone marrow samples of 2 RS-SCID patients showed the absence of complete V(H)
      J(H) gene rearrangements and consequently a complete B-cell differentiation
      arrest at the pre-B-cell receptor checkpoint-that is, at the transition from
      CyIgmu(-) pre-B-I cells to CyIgmu(+) pre-B-II cells. The completeness of this
      arrest illustrates the importance of Artemis at this stage of lymphoid
      differentiation.

PMID- 12406896
TI  - Angiostatin selectively inhibits signaling by hepatocyte growth factor in
      endothelial and smooth muscle cells.
AB  - Angiostatin, an inhibitor of angiogenesis, contains 3 to 4 kringle domains that
      are derived from proteolytic cleavage of plasminogen. The antiangiogenic effects
      of angiostatin occur, in part, from its inhibition of endothelial cell surface
      adenosine triphosphate synthase, integrin functions, and pericellular
      proteolysis. Angiostatin has structural similarities to hepatocyte growth factor
      (HGF; "scatter factor"), a promoter of angiogenesis, that induces proliferation
      and migration of both endothelial and smooth muscle cells via its cell surface
      receptor, c-met. We hypothesized that angiostatin might block HGF-induced
      signaling in endothelial and smooth muscle cells. Angiostatin inhibited HGF
      induced phosphorylation of c-met, Akt, and ERK1/2. Angiostatin also significantly
      inhibited proliferation of human umbilical vein endothelial cells (HUVECs)
      induced by HGF. In contrast, angiostatin did not inhibit vascular endothelial
      growth factor (VEGF)-or basic fibroblast growth factor (bFGF)-induced signaling
      events or HUVEC proliferation. Angiostatin bound to immobilized truncated c-met
      produced by A431 cells and could be immunoprecipitated as a complex with soluble
      c-met. HGF inhibited the binding of (125)I-angiostatin to HUVECs. Soluble c-met,
      produced by several tumor cell lines, could inhibit the antiangiogenic effect of
      angiostatin. The disruption of HGF/c-met signaling is a novel mechanism for the
      antiangiogenic effect of angiostatin.

PMID- 12406897
TI  - High-level ectopic HOXB4 expression confers a profound in vivo competitive growth
      advantage on human cord blood CD34+ cells, but impairs lymphomyeloid
      differentiation.
AB  - Ectopic retroviral expression of homeobox B4 (HOXB4) causes an accelerated and
      enhanced regeneration of murine hematopoietic stem cells (HSCs) and is not known
      to compromise any program of lineage differentiation. However, HOXB4 expression
      levels for expansion of human stem cells have still to be established. To test
      the proposed hypothesis that HOXB4 could become a prime tool for in vivo
      expansion of genetically modified human HSCs, we retrovirally overexpressed HOXB4
      in purified cord blood (CB) CD34+ cells together with green fluorescent protein
      (GFP) as a reporter protein, and evaluated the impact of ectopic HOXB4 expression
      on proliferation and differentiation in vitro and in vivo. When injected
      separately into nonobese diabetic-severe combined immunodeficient (NOD/SCID) mice
      or in competition with control vector-transduced cells, HOXB4-overexpressing cord
      blood CD34+ cells had a selective growth advantage in vivo, which resulted in a
      marked enhancement of the primitive CD34+ subpopulation (P =.01). However, high
      HOXB4 expression substantially impaired the myeloerythroid differentiation
      program, and this was reflected in a severe reduction of erythroid and myeloid
      progenitors in vitro (P <.03) and in vivo (P =.01). Furthermore, HOXB4
      overexpression also significantly reduced B-cell output (P <.01). These results
      show for the first time unwanted side effects of ectopic HOXB4 expression and
      therefore underscore the need to carefully determine the therapeutic window of
      HOXB4 expression levels before initializing clinical trials.

PMID- 12406898
TI  - Therapeutic factor VIII levels and negligible toxicity in mouse and dog models of
      hemophilia A following gene therapy with high-capacity adenoviral vectors.
AB  - High-capacity adenoviral (HC-Ad) vectors expressing B-domain-deleted human or
      canine factor VIII from different liver-specific promoters were evaluated for
      gene therapy of hemophilia A. Intravenous administration of these vectors into
      hemophilic FVIII-deficient immunodeficient SCID mice (FVIIIKO-SCID) at a dose of
      5 x 10(9) infectious units (IU) resulted in efficient hepatic gene delivery and
      long-term expression of supraphysiologic FVIII levels (exceeding 15 000 mU/mL),
      correcting the bleeding diathesis. Injection of only 5 x 10(7) IU still resulted
      in therapeutic FVIII levels. In immunocompetent hemophilic FVIII-deficient mice
      (FVIIIKO), FVIII expression levels peaked at 75 000 mU/mL but declined thereafter
      because of neutralizing anti-FVIII antibodies and a cellular immune response.
      Vector administration did not result in thrombocytopenia, anemia, or elevation of
      the proinflammatory cytokine interleukin-6 (IL-6) and caused no or only transient
      elevations in serum transaminases. Following transient in vivo depletion of
      macrophages before gene transfer, significantly higher and stable FVIII
      expression levels were observed. Injection of only 5 x 10(6) HC-Ad vectors after
      macrophage depletion resulted in long-term therapeutic FVIII levels in the
      FVIIIKO and FVIIIKO-SCID mice. Intravenous injection of an HC-Ad vector into a
      hemophilia A dog at a dose of 4.3 x 10(9) IU/kg led to transient therapeutic
      canine FVIII levels that partially corrected whole-blood clotting time.
      Inhibitory antibodies to canine FVIII could not be detected, and there were no
      signs of hepatotoxicity or of hematologic abnormalities. These results contribute
      to a better understanding of the safety and efficacy of HC-Ad vectors and suggest
      that the therapeutic window of HC-Ad vectors could be improved by minimizing the
      interaction between HC-Ad vectors and the innate immune system.

PMID- 12406899
TI  - Outcome of donor splice site mutations accounting for congenital afibrinogenemia
      reflects order of intron removal in the fibrinogen alpha gene (FGA).
AB  - Congenital afibrinogenemia (Mendelian Inheritance in Man #202400) is a rare,
      autosomal recessive disorder characterized by the complete absence of circulating
      fibrinogen. Our recent studies on the molecular basis of the disease showed that
      the most common genetic defect is a donor splice mutation in fibrinogen alpha
      gene (FGA) intron 4, IVS4+1G>T. Two other FGA donor splice mutations, in intron 1
      (IVS1+3A>G) and intron 3 (IVS3+1_+4delGTAA), were identified in afibrinogenemia
      patients. Because it was impossible to directly study the effect of these
      mutations on mRNA splicing in patient hepatocytes, we used a transfected cell
      approach, which previously allowed us to show that the common IVS4 mutation
      causes afibrinogenemia due to the activation of multiple cryptic donor splice
      sites. In this study, analysis of the IVS3delGTAA mutation showed exon 3 skipping
      in 99% of transcripts and exons 2 and 3 skipping in 1% of transcripts. The
      different outcomes of these donor splice mutations appear to follow the model
      proposed in a study of fibrillar collagen genes, where donor splice mutations
      occurring in a rapidly spliced intron with respect to upstream introns lead in
      most cases to exon skipping, while mutations in later-spliced introns lead to
      intron inclusion or cryptic splice-site utilization. Indeed, we found that in FGA
      intron 3 was preferentially spliced first, followed by intron 2, intron 4, and
      intron 1.

PMID- 12406900
TI  - Extracellular ubiquitin inhibits the TNF-alpha response to endotoxin in
      peripheral blood mononuclear cells and regulates endotoxin hyporesponsiveness in
      critical illness.
AB  - Ubiquitin is suggested to play a key role in essential intracellular functions,
      such as heat shock response, protein breakdown, and regulation of immune
      responses. Ubiquitin has also been detected in the extracellular space, but the
      function and biologic significance is unclear. We describe a new function of
      extracellular ubiquitin and show that extracellular ubiquitin specifically
      inhibits ex vivo secretion of tumor necrosis factor-alpha (TNF-alpha) and TNF
      alpha mRNA expression from peripheral blood mononuclear cells (PBMNCs) in
      response to endotoxin in a dose-dependent manner. In contrast, the TNF-alpha
      response to zymosan or Staphylococcus aureus as well as the interleukin-6 (IL-6)
      and IL-8 responses to endotoxin were unaffected by ubiquitin. Measurement of
      serum ubiquitin levels showed a significant 5- to 7-fold increase in sepsis and
      trauma patients, to the level required for inhibition of the PBMNC TNF-alpha
      response to endotoxin by ubiquitin. Elevated ubiquitin levels in serum were
      significantly correlated with a reduced TNF-alpha production. Antibodies to
      ubiquitin were able to (1) significantly increase (2- to 5-fold) the TNF-alpha
      response to endotoxin in whole blood from trauma and sepsis patients, (2)
      completely neutralize the inhibitory effect of trauma patients' serum on healthy
      donors' TNF-alpha production, and (3) partially neutralize the inhibitory effect
      of sepsis patients' serum on healthy donors' TNF-alpha production. Ubiquitin
      depleted serum from trauma patients lost the inhibitory activity for TNF-alpha
      production, whereas extracted endogenous ubiquitin exerts the inhibitory
      activity. The results demonstrate that extracellular ubiquitin acts as a
      cytokinelike protein with anti-inflammatory properties and indicate that
      extracellular ubiquitin is involved in the regulation of immunodepression in
      critical illness.

PMID- 12406901
TI  - Granulocyte-colony stimulating factor increases CD123hi blood dendritic cells
      with altered CD62L and CCR7 expression.
AB  - Changes in blood dendritic cell (BDC) counts (CD123(hi)BDC and CD11c(+)BDC) and
      expression of CD62L, CCR7, and CD49d were analyzed in healthy donors, multiple
      myeloma (MM), and non-Hodgkin lymphoma (NHL) patients, who received granulocyte
      colony stimulating factor (G-CSF) containing peripheral blood stem cell (PBSC)
      mobilization protocols. Low-dose G-CSF in healthy donors (8-10 microg/kg/d
      subcutaneously) and high-dose G-CSF in patients (30 microg/kg/d) increased
      CD123(hi)BDC (2- to 22-fold, mean 3.7 x 10(6)/L-17.7 x 10(6)/L and 1.9 x 10(6)/L
      12.0 x 10(6)/L) in healthy donors and MM but decreased CD11c(+)BDC (2- to 10
      fold, mean 5.7 x 10(6)/L-1.6 x 10(6)/L) in NHL patients, on the day of apheresis,
      compared with steady state. After apheresis, CD123(hi)BDC counts remained high,
      whereas low CD11c(+)BDC counts tended to recover in the following 2-5 days. Down
      regulation of CD62L and up-regulation of CCR7 on CD123(hi)BDC were found in most
      healthy donors and MM patients. CD49d expression was unchanged. Thus, PBSC
      mobilization may change BDC counts by altering molecules necessary for BDC homing
      from blood into tissues.

PMID- 12406902
TI  - The protein tyrosine kinase inhibitor SU5614 inhibits FLT3 and induces growth
      arrest and apoptosis in AML-derived cell lines expressing a constitutively
      activated FLT3.
AB  - Activating mutations of the protein tyrosine kinase (PTK) FLT3 can be found in
      approximately 30% of patients with acute myeloid leukemia (AML), thereby
      representing the most frequent single genetic alteration in AML. These mutations
      occur in the juxtamembrane (FLT3 length mutations; FLT3-LMs) and the second
      tyrosine kinase domain of FLT3-TKD and confer interleukin 3 (IL-3)-independent
      growth to Ba/F3 cells. In the mouse bone marrow transplantation model, FLT3-LMs
      induce a myeloproliferative syndrome stressing their transforming activity in
      vivo. In this study, we analyzed the pro-proliferative and antiapoptotic
      potential of FLT3 in FLT3-LM/TKD-mutation-transformed Ba/F3 cells and AML-derived
      cell lines. The PTK inhibitor SU5614 has inhibitory activity for FLT3 and
      selectively induces growth arrest, apoptosis, and cell cycle arrest in Ba/F3 and
      AML cell lines expressing a constitutively activated FLT3. In addition, the
      compound reverts the antiapoptotic and pro-proliferative activity of FLT3 ligand
      (FL) in FL-dependent cells. No cytotoxic activity of SU5614 was found in leukemic
      cell lines that express a nonactivated FLT3 or no FLT3 protein. At the
      biochemical level, SU5614 down-regulated the activity of the hyperphosphorylated
      FLT3 receptor and its downstream targets, signal transducer and activator of
      (STAT) 3, STAT5, and mitogen-activated protein kinase (MAPK), and the STAT5
      target genes BCL-X(L) and p21. Our results show that SU5614 is a PTK inhibitor of
      FLT3 and has antiproliferative and proapoptotic activity in AML-derived cell
      lines that endogenously express an activated FLT3 receptor. The selective and
      potent cytotoxicity of FLT3 PTK inhibitors support a clinical strategy of
      targeting FLT3 as a new molecular treatment option for patients with FLT3-LM/TKD
      mutation(+) AML.

PMID- 12406903
TI  - A1 is a growth-permissive antiapoptotic factor mediating postactivation survival
      in T cells.
AB  - The regulation of cell death in activated naive T cells is not well understood.
      We examined the expression of A1, an antiapoptotic member of the Bcl-2 family,
      following activation of naive mouse splenocytes. A1 gene expression was strongly
      but transiently induced during the first day of activation, with a peak at 2 to 6
      hours, whereas Bcl-2 mRNA was simultaneously transiently down-regulated.
      Transgenic (Tg) overexpression of A1-a in T cells via the lck distal promoter
      resulted in decreased apoptosis following activation either with concanavalin A
      or with antibodies to CD3 and CD28 and led to a doubling of T-cell yield by 5
      days. Tg A1-a also partially protected thymocytes from several proapoptotic
      stimuli but did not protect T-cell blasts from cell death induced by reactivation
      via the T-cell receptor. Tg Bcl-2 and Tg A1-a showed a similar ability to reduce
      apoptosis in both resting and activated T cells. However, in activated splenocyte
      cultures, the increase in 5-day T-cell yield observed with Tg Bcl-2 was only half
      that produced by Tg A1-a. This difference could be attributed at least in part to
      the fact that A1, unlike Bcl-2, did not inhibit S-phase entry of activated cells.
      The A1 protein may represent an adaptation of the Bcl-2 gene family to the need
      for survival regulation in the context of a proliferative stimulus.

PMID- 12406904
TI  - Ikaros regulates neutrophil differentiation.
AB  - The Ikaros gene encodes a zinc finger transcription factor that is selectively
      expressed by all hematopoietic cells. Although Ikaros is required for lymphocyte
      differentiation, its role in the myeloid lineage is unclear. We show here that
      Ikaros expression is temporally regulated during neutrophil differentiation:
      Ikaros is primarily expressed at immature stages and significantly less so in
      mature neutrophils. Furthermore Ik(L/L) mice, harboring a hypomorphic mutation at
      the Ikaros locus, exhibit several defects during neutrophil differentiation. (1)
      Ik(L/L) fetal livers contain high numbers of neutrophil lineage cells, and this
      increase is reflected in the number of GM-CSF-dependent progenitor cells. (2) The
      migratory potential and survival of neutrophil progenitors is altered in vitro.
      (3) Expression of the Gr-1 marker is delayed and repressed. In contrast,
      neutrophil function appears normal. These data demonstrate that Ikaros regulates
      early neutrophil differentiation but is dispensable in mature neutrophils.

PMID- 12406905
TI  - CD100/Plexin-B1 interactions sustain proliferation and survival of normal and
      leukemic CD5+ B lymphocytes.
AB  - Growth and survival of chronic B-cell tumors are favored by the malignant cell's
      capacity to respond to selected microenvironmental stimuli provided by nontumoral
      bystander cells. To investigate which mechanisms operate in these crosstalks and
      whether they are malignancy-related or reproduce the mechanisms used by normal B
      cells we have studied the expression and functional role of semaphorin CD100 (now
      called Sema4D) in chronic lymphocytic leukemia (CLL) cells and normal CD5+ B
      cells. We demonstrate here that (1) leukemic and normal CD5+ B lymphocytes
      uniformly express CD100; (2) the CD100 high-affinity receptor Plexin-B1 is
      expressed by bone marrow stromal cells, follicular dendritic cells, and activated
      T lymphocytes, and is thus available to CD100+ lymphocytes in different specific
      microenvironments; and (3) upon interaction between CD100 and Plexin-B1 both CLL
      and normal CD5+ B cells increase their proliferative activity and extend their
      life span. These findings establish that Plexin-B1 is an easily accessible
      receptor for CD100 within the immune system. The encounter of CD100+ leukemic
      cells with Plexin-B1 may promote the proliferation and survival of malignant
      cells. The crosstalk operated by the CD100/Plexin-B1 interaction is not
      malignancy related but reproduces a mechanism used by normal CD5+ B cells.

PMID- 12406906
TI  - High levels of BAX, low levels of MRP-1, and high platelets are independent
      predictors of response to imatinib in myeloid blast crisis of CML.
AB  - Imatinib induces remissions in approximately 30% of patients with chronic myeloid
      leukemia (CML) in myeloid blast crisis (M-BC). Because most patients eventually
      relapse, allogeneic stem cell transplantation (SCT) in remission offers the best
      chance for cure. Remission induction with imatinib alone would seem ideal because
      it is less toxic than conventional chemotherapy. Conversely, patients unlikely to
      respond may benefit from combination therapy up front. To identify prognostic
      factors, we studied the mRNA expression of genes related to drug resistance and
      apoptosis in leukemic cells from patients with M-BC and their in vitro
      sensitivity to imatinib, and analyzed the results with other baseline factors for
      their impact on response. We show that high levels of BAX, low levels of MRP-1,
      and a high platelet count are independently predictive of response to imatinib.
      Combined into a score, these parameters may be clinically useful for risk-adapted
      patient stratification.

PMID- 12406907
TI  - The angiogenic regulator CD13/APN is a transcriptional target of Ras signaling
      pathways in endothelial morphogenesis.
AB  - Angiogenesis, the formation of new blood vessels, is a critical step for tumor
      growth and metastasis and an integral component of the pathologic inflammatory
      response in arthritis and the proliferative retinopathies. The
      CD13/aminopeptidase N (CD13/APN) metalloprotease is an important regulator of
      angiogenesis where its expression on activated blood vessels is induced by
      angiogenic signals. Here, we show that cytokine induction of CD13/APN in
      endothelial cells is regulated by distinct Ras effector pathways involving
      Ras/mitogen-activated protein kinase (MAPK) or PI-3K. Signals transduced by
      activated Ras, Raf, and mitogen-induced extracellular kinase (MEK) stimulate
      transcription from the CD13/APN proximal promoter. Inhibition of these pathways
      and extracellular signal-regulated serine/threonine kinase (ERK-2) and PI-3K by
      expression of dominant-negative proteins or chemical inhibitors prevented
      induction of CD13/APN transcription in response to basic fibroblast growth factor
      (bFGF). We show that Ras-induced signal transduction is required for growth
      factor-induced angiogenesis, because inhibition of downstream mediators of Ras
      signaling (MEK or PI-3K) abrogated endothelial cell migration, invasion, and
      morphogenesis in vitro. Reintroduction of CD13/APN, a shared downstream target of
      these pathways, overrode the suppressive effect of these inhibitors and restored
      the function of endothelial cells in migration/invasion and capillary
      morphogenesis assays. Similarly, inhibition of MEK abrogated cell invasion and
      the formation of endothelial-lined capillaries in vivo, which was effectively
      rescued by addition of exogenous CD13/APN protein. These studies provide strong
      evidence that CD13/APN is an important target of Ras signaling in angiogenesis
      and is a limiting factor in angiogenic progression.

PMID- 12406908
TI  - Total lymphoid irradiation nonmyeloablative preconditioning enriches for IL-4
      producing CD4+-TNK cells and skews differentiation of immunocompetent donor CD4+
      cells.
AB  - Preconditioning with the nonmyeloablative regimen total lymphoid irradiation
      (TLI) before hematopoietic cell transplantation facilitates the establishment of
      mixed chimerism and protects against graft-versus-host disease. We reported that
      the development of mixed chimerism requires interleukin (IL)-4 and is associated
      with increased host anti-donor TH2 cells, but the effect of TLI on the
      differentiation of immunocompetent donor cells has not been investigated. To
      examine the extent to which TLI preconditioning influences donor T cells, we
      measured responses of transgenic CD4+cells specific for ovalbumin peptide (OVA
      Tg) following in vivo and in vitro antigen stimulation in a TLI-preconditioned
      environment. OVA-Tg cells that were adoptively transferred into TLI
      preconditioned mice that express cross-reactive antigens produced more IL-4 and
      less interferon-gamma and IL-2 than controls when stimulated with OVA peptide one
      week later. OVA-Tg primed in vitro with spleen from TLI-preconditioned mice
      generated more TH2 and fewer TH1 cells when stimulated in recall enzyme-linked
      immunosorbent spot (ELISPOT) assays with OVA peptide. Naive OVA-Tg up-regulated
      CD69 and CD25 normally following stimulation with OVA peptide in the presence of
      spleen from TLI-preconditioned mice, but proliferated less and secreted less IL-2
      than controls. Surprisingly, naive OVA-Tg secreted IL-4 in primary cultures that
      were stimulated with OVA peptide in the presence of spleen from TLI
      preconditioned mice. This response depends on CD4+cells from TLI-spleen, which
      constitutively produce IL-4 and are composed primarily of CD4+-natural killer T
      (TNK) cells. Thus, TLI preconditioning enriches for IL-4-secreting and TNK-like
      CD4+cells that may function in the protection from graft-versus-host disease by
      redirecting the differentiation of immunocompetent donor CD4+cells toward TH2 and
      away from pathogenic TH1 cells.

PMID- 12406909
TI  - Induction of C/EBPalpha activity alters gene expression and differentiation of
      human CD34+ cells.
AB  - The CCAAT/enhancer binding protein alpha (C/EBPalpha) belongs to a family of
      transcription factors that are involved in the differentiation process of
      numerous tissues, including the liver and hematopoietic cells. C/EBPalpha(-/-)
      mice show a block in hematopoietic differentiation, with an accumulation of
      myeloblasts and an absence of mature granulocytes, whereas expression of
      C/EBPalpha in leukemia cell lines leads to granulocytic differentiation.
      Recently, dominant-negative mutations in the C/EBPalpha gene and down-regulation
      of C/EBPalpha by AML1-ETO, an AML associated fusion protein, have been identified
      in acute myelogenous leukemia (AML). To better understand the role of C/EBPalpha
      in the lineage commitment and differentiation of hematopoietic progenitors, we
      transduced primary human CD34(+) cells with a retroviral construct that expresses
      the C/EBPalpha cDNA fused in-frame with the estrogen receptor ligand-binding
      domain. Induction of C/EBPalpha function in primary human CD34(+) cells, by the
      addition of beta-estradiol, leads to granulocytic differentiation and inhibits
      erythrocyte differentiation. Using Affymetrix (Santa Clara, CA) oligonucleotide
      arrays we have identified C/EBPalpha target genes in primary human hematopoietic
      cells, including granulocyte-specific genes that are involved in hematopoietic
      differentiation and inhibitor of differentiation 1 (Id1), a transcriptional
      repressor known to interfere with erythrocyte differentiation. Given the known
      differences in murine and human promoter regulatory sequences, this inducible
      system allows the identification of transcription factor target genes in a
      physiologic, human hematopoietic progenitor cell background.

PMID- 12406910
TI  - Myocardial fibrosis in mice with overexpression of human blood coagulation factor
      IX.
AB  - Elevated circulatory levels of many blood coagulation factors are known to be a
      risk factor for deep vein thrombosis in humans. Here we report the first direct
      demonstration of a close association between elevated circulatory factor IX
      levels in mice with thrombosis as well as myocardial fibrosis. Transgenic mice
      overexpressing human factor IX at persistently high levels died at much younger
      ages than their cohorts expressing lower levels, or nontransgenic control
      animals. The median survival age of animals was inversely related to the
      circulatory levels of human factor IX. Prematurely dying animals had focal
      fibrotic lesions predominantly present in the left ventricular myocardium, and
      vasculatures in these lesions showed fibrin deposition. Thromboemboli were also
      present in other organs, including lung and brain. These observations support the
      hypothesis that persistently high circulatory levels of factor IX are a risk
      factor not only for thrombosis and/or thromboembolism, but also for myocardial
      fibrosis mimicking human myocardial infarction.

PMID- 12406911
TI  - Protein kinase Czeta mediated Raf-1/extracellular-regulated kinase activation by
      daunorubicin.
AB  - In light of the emerging concept of a protective function of the mitogen
      activated protein kinase (MAPK) pathway under stress conditions, we investigated
      the influence of the anthracycline daunorubicin (DNR) on MAPK signaling and its
      possible contribution to DNR-induced cytotoxicity. We show that DNR increased
      phosphorylation of extracellular-regulated kinases (ERKs) and stimulated
      activities of both Raf-1 and extracellular-regulated kinase 1 (ERK1) within 10 to
      30 minutes in U937 cells. ERK1 stimulation was completely blocked by either the
      mitogen-induced extracellular kinase (MEK) inhibitor PD98059 or the Raf-1
      inhibitor 8-bromo-cAMP (cyclic adenosine monophosphate). However, only partial
      inhibition of Raf-1 and ERK1 stimulation was observed with the antioxidant N
      acetylcysteine (N-Ac). Moreover, the xanthogenate compound D609 that inhibits DNR
      induced phosphatidylcholine (PC) hydrolysis and subsequent diacylglycerol (DAG)
      production, as well as wortmannin that blocks phosphoinositide-3 kinase (PI3K)
      stimulation, only partially inhibited Raf-1 and ERK1 stimulation. We also
      observed that DNR stimulated protein kinase C zeta (PKCzeta), an atypical PKC
      isoform, and that both D609 and wortmannin significantly inhibited DNR-triggered
      PKCzeta activation. Finally, we found that the expression of PKCzeta kinase
      defective mutant resulted in the abrogation of DNR-induced ERK phosphorylation.
      Altogether, these results demonstrate that DNR activates the classical Raf
      1/MEK/ERK pathway and that Raf-1 activation is mediated through complex signaling
      pathways that involve at least 2 contributors: PC-derived DAG and PI3K products
      that converge toward PKCzeta. Moreover, we show that both Raf-1 and MEK
      inhibitors, as well as PKCzeta inhibition, sensitized cells to DNR-induced
      cytotoxicity.

PMID- 12406912
TI  - Differential mRNA expression of Ara-C-metabolizing enzymes explains Ara-C
      sensitivity in MLL gene-rearranged infant acute lymphoblastic leukemia.
AB  - Infant acute lymphoblastic leukemia (ALL) is characterized by a high incidence of
      mixed lineage leukemia (MLL) gene rearrangements, a poor outcome, and resistance
      to chemotherapeutic drugs. One exception is cytosine arabinoside (Ara-C), to
      which infant ALL cells are highly sensitive. To investigate the mechanism
      underlying Ara-C sensitivity in infants with ALL, mRNA levels of Ara-C
      metabolizing enzymes were measured in infants (n = 18) and older children
      (noninfants) with ALL (n = 24). In the present study, infant ALL cells were 3.3
      fold more sensitive to Ara-C (P =.007) and accumulated 2.3-fold more Ara-CTP (P
      =.011) upon exposure to Ara-C, compared with older children with ALL. Real-time
      quantitative reverse trancriptase-polymerase chain reaction (RT-PCR) (TaqMan)
      revealed that infants express 2-fold less of the Ara-C phosphorylating enzyme
      deoxycytidine kinase (dCK) mRNA (P =.026) but 2.5-fold more mRNA of the
      equilibrative nucleoside transporter 1 (hENT1), responsible for Ara-C membrane
      transport (P =.001). The mRNA expression of pyrimidine nucleotidase I (PN-I),
      cytidine deaminase (CDA), and deoxycytidylate deaminase (dCMPD) did not differ
      significantly between both groups. hENT1 mRNA expression inversely correlated
      with in vitro resistance to Ara-C (r(s) = -0.58, P =.006). The same differences
      concerning dCK and hENT1 mRNA expression were observed between MLL gene
      rearranged (n = 14) and germ line MLL cases (n = 25). An oligonucleotide
      microarray screen (Affymetrix) comparing patients with MLL gene-rearranged ALL
      with those with nonrearranged ALL also showed a 1.9-fold lower dCK (P =.001) and
      a 2.7-fold higher hENT1 (P =.046) mRNA expression in patients with MLL gene
      rearranged ALL. We conclude that an elevated expression of hENT1, which
      transports Ara-C across the cell membrane, contributes to Ara-C sensitivity in
      MLL gene-rearranged infant ALL.

PMID- 12406913
TI  - Oscillation between B-lymphoid and myeloid lineages in Myc-induced hematopoietic
      tumors following spontaneous silencing/reactivation of the EBF/Pax5 pathway.
AB  - B lymphomagenesis is an uncontrolled expansion of immature precursors that fail
      to complete their differentiation program. This failure could be at least partly
      explained by inappropriate expression of several oncogenic transcription factors,
      such as Pax5 and Myc. Both Pax5 and c-Myc are implicated in the pathogenesis of
      non-Hodgkin lymphomas. To address their role in lymphomagenesis, we analyzed B
      cell lymphomas derived from p53-null bone marrow progenitors infected in vivo by
      a Myc-encoding retrovirus. All Myc-induced lymphomas invariably maintained
      expression of Pax5, which is thought to be incompatible with terminal
      differentiation. However, upon culturing in vitro, several cell lines
      spontaneously down-regulated Pax5 and its target genes CD19, N-Myc, and MB1.
      Unexpectedly, other B-cell markers (eg, CD45R) were also down-regulated, and
      markers of myeloid lineage (CD11b and F4/80 antigen) were acquired instead.
      Moreover, cells assumed the morphology reminiscent of myeloid cells. A pool of
      F4/80-positive cells as well as several single-cell clones were obtained and
      reinjected into syngeneic mice. Remarkably, pooled cells rapidly re-expressed
      Pax5 and formed tumors of relatively mature lymphoid phenotype, with surface
      immunoglobulins being abundantly expressed. Approximately half of tumorigenic
      single-cell clones also abandoned myeloid differentiation and gave rise to B
      lymphomas. However, when secondary lymphoma cells were returned to in vitro
      conditions, they once again switched to myeloid differentiation. This process
      could be curbed via enforced expression of retrovirally encoded Pax5. Our data
      demonstrate that some Myc target cells are bipotent B-lymphoid/myeloid
      progenitors with the astonishing capacity to undergo successive rounds of lineage
      switching.

PMID- 12406914
TI  - The pattern of CD38 expression defines a distinct subset of chronic lymphocytic
      leukemia (CLL) patients at risk of disease progression.
AB  - Chronic lymphocytic leukemia (CLL) has a variable clinical course. CD38
      expression and IgV(H) gene mutational status are independent predictors of
      prognosis, but their relationships and the CD38 cutoff level are unknown. Using
      cytofluorography, we analyzed CD38 in 148 patients, in 108 of whom we were able
      to evaluate IgV(H) mutations, make correlations with disease history, and assess
      cumulative survival. Three different patient groups were identified by the CD38
      expression pattern: a group homogeneously CD38(-), a group homogeneously CD38(+),
      and a group characterized by a bimodal profile, because of the concomitant
      presence of variable proportions of 2 distinct populations, one CD38(+) and one
      CD38(-). In CD38 bimodal expression patients the CD38(+) subset was significantly
      more represented in the bone marrow than in the peripheral blood. For IgV(H)
      mutations, 11.4% of CD38(-), 84.6% of CD38(+), and 68.0% of CD38 bimodal
      expression patients had no mutation. CD38 expression, IgV(H) mutational status,
      and traditional prognostic factors were concordant. The progression rate was
      12.9% for CD38(-), 75.0% for CD38(+), and 63.3% for CD38 bimodal expression
      patients. Only 25.8% of the CD38(-) patients but 63.3% of the bimodal and 75.0%
      of CD38(+) patients were treated. The presence of a CD38(+) population, albeit
      small, correlated with the development of autoimmune manifestations. The CD38(-)
      group has not yet reached the median survival, which is 183 months in the CD38(+)
      group and 156 months in the CD38 bimodal expression group, regardless of the size
      of the CD38(+) population. The presence of a distinct CD38(+) population within
      the leukemic clone, rather than a numerical cutoff definition, correlates with
      IgV(H) gene mutational status and, irrespective of its size, identifies CLL
      patients who will have progressive disease.

PMID- 12406915
TI  - The usefulness of monitoring WT1 gene transcripts for the prediction and
      management of relapse following allogeneic stem cell transplantation in acute
      type leukemia.
AB  - In acute-type leukemia, no method for the prediction of relapse following
      allogeneic stem cell transplantation based on minimal residual disease (MRD)
      levels is established yet. In the present study, MRD in 72 cases of allogeneic
      transplantation for acute myeloid leukemia, acute lymphoid leukemia, and chronic
      myeloid leukemia (accelerated phase or blast crisis) was monitored frequently by
      quantitating the transcript of WT1 gene, a "panleukemic MRD marker," using
      reverse transcriptase-polymerase chain reaction. Based on the negativity of
      expression of chimeric genes, the background level of WT1 transcripts in bone
      marrow following allogeneic transplantation was significantly decreased compared
      with the level in healthy volunteers. The probability of relapse occurring within
      40 days significantly increased step-by-step according to the increase in WT1
      expression level (100% for 1.0 x 10(-2)-5.0 x 10(-2), 44.4% for 4.0 x 10(-3)-1.0
      x 10(-2), 10.2% for 4.0 x 10(-4)-4.0 x 10(-3), and 0.8% for < 4.0 x 10(-4)) when
      WT1 level in K562 was defined as 1.0). WT1 levels in patients having relapse
      increased exponentially with a constant doubling time. The doubling time of the
      WT1 level in patients for whom the discontinuation of immunosuppressive agents or
      donor leukocyte infusion was effective was significantly longer than that for
      patients in whom it was not (P <.05). No patients with a short doubling time of
      WT1 transcripts (< 13 days) responded to these immunomodulation therapies. These
      findings strongly suggest that the WT1 assay is very useful for the prediction
      and management of relapse following allogeneic stem cell transplantation
      regardless of the presence of chimeric gene markers.

PMID- 12406917
TI  - Violence and health: the ultimate public health challenge.

PMID- 12406916
TI  - Cyclophosphamide metabolism, liver toxicity, and mortality following
      hematopoietic stem cell transplantation.
AB  - Liver toxicity caused by high-dose myeloablative therapy leads to significant
      morbidity after hematopoietic cell transplantation. We examined the hypothesis
      that liver toxicity after cyclophosphamide and total body irradiation is related
      to cyclophosphamide through its metabolism to toxins. Cyclophosphamide was
      infused at 60 mg/kg over 1 to 2 hours on each of 2 consecutive days, followed by
      total body irradiation. Plasma was analyzed for cyclophosphamide and its major
      metabolites. Liver toxicity was scored by the development of sinusoidal
      obstruction syndrome (veno-occlusive disease) and by total serum bilirubin
      levels. The hazards of liver toxicity, nonrelapse mortality, tumor relapse, and
      survival were calculated using regression analysis that included exposure to
      cyclophosphamide metabolites (as the area under the curve). Of 147 patients, 23
      (16%) developed moderate or severe sinusoidal obstruction syndrome. The median
      peak serum bilirubin level through day 20 was 2.6 mg/dL (range, 0.5-41.1 mg/dL).
      Metabolism of cyclophosphamide was highly variable, particularly for the
      metabolite o-carboxyethyl-phosphoramide mustard, whose area under the curve
      varied 16-fold. Exposure to this metabolite was statistically significantly
      related to sinusoidal obstruction syndrome, bilirubin elevation, nonrelapse
      mortality, and survival, after adjusting for age and irradiation dose. Patients
      in the highest quartile of o-carboxyethyl-phosphoramide mustard exposure had a
      5.9-fold higher risk for nonrelapse mortality than did patients in the lowest
      quartile. Engraftment and tumor relapse were not statistically significantly
      related to cyclophosphamide metabolite exposure. Increased exposure to toxic
      metabolites of cyclophosphamide leads to increased liver toxicity and nonrelapse
      mortality and lower overall survival after hematopoietic cell transplantation.

PMID- 12406918
TI  - Evaluation of a workplace cardiovascular health promotion programme in the
      Republic of Ireland.
AB  - This paper describes a comprehensive evaluation of the organizational impact of a
      workplace health promotion programme, in the context of a framework devised by
      Nutbeam in 1998. The Happy Heart at Work programme, sponsored by the Irish Heart
      Foundation, has been in existence for 10 years and aims to promote a healthy
      lifestyle through specially devised modular materials. A postal census survey of
      785 valid registered sites expressing any level of initial interest in the
      programme yielded a 40% response rate (n = 311). Of these, 194 (63%) were
      currently active and 114 were not. Active organizations were less likely to be
      Irish owned (54.5% versus 71.4%, p < 0.05), and more likely to operate in shifts
      (72.3% versus 51.1%, p < 0.05) or to have an occupational physician amongst the
      staff (36.9% versus 31%). Programme impact within active organizations, based on
      pre-defined Health Promoting Workplace parameters, was documented. There was
      agreement in the questionnaire responses that participating organizations promote
      a smoke-free environment (mean rating on five-point scale = 4.42), employee
      health and well-being (4.21) and good nutritional practice (4.11). Triangulation
      of research methods, including a telephone survey of gatekeepers from within
      organizations (n = 18), focus groups with participant employees (n = 42) and a
      review of the staff opinions of the facilitating organization on the programme,
      all showed strong concordance with respect to the strengths and weaknesses of
      Happy Heart at Work. The programme was felt to help improve employees' lifestyle
      habits and morale, as well as the company's public image. The main drawbacks of
      the programme were its relatively low profile, even in actively participating
      organizations, and the fact that it was not seen to be independently sustainable
      without intensive and ongoing support.

PMID- 12406919
TI  - Cultural context, older age and smoking in Scotland: qualitative interviews with
      older smokers with arterial disease.
AB  - This paper explores how smoking among older smokers with a smoking-related
      illness is influenced by the wider cultural context of smoking. The paper draws
      upon a Scottish qualitative interview study to explore lifecourse changes in
      smoking-related beliefs and behaviours, in current smokers between the ages of 65
      and 84 years with arterial disease. The respondents' understanding of smoking, as
      a socially acceptable behaviour of their youth, had undergone dramatic change
      over the course of their lives. While some respondents continued to associate
      their current smoking with their, albeit reduced, participation in social
      activities, others now smoked at home alone and associated smoking with
      increasing levels of isolation in their lives. Through an examination of how
      social attitudes may contribute to smoking as a solitary activity, the paper
      highlights the implications of cultural context for the adaptive strategies that
      older people use to cope with the circumstances and conditions of later life. The
      paper concludes that the wider cultural context of smoking is influential in
      shaping smoking as either an isolated 'home' activity, or as a 'social' activity
      for those whose opportunities to smoke in the private sphere are limited by
      disapproval of significant others. Within the social context, however, these
      'social' smokers experience further constraints which shape and reduce their
      smoking behaviour. The data suggest that in order to be successful with this
      group of smokers, further research is needed to identify aspects of the lives of
      older people that sustain smoking in later life. These data will be necessary to
      develop appropriate health promotion measures to successfully target aspects of
      lives that support smoking in later life.

PMID- 12406920
TI  - A stage model for assessing a community-based diabetes prevention program in
      Sweden.
AB  - Type 2 diabetes is the most common type of diabetes, with a prevalence of at
      least 4% in Sweden. Aiming at primary prevention of the disease, the Stockholm
      Diabetes Prevention Program (SDPP) was developed as a joint program between the
      Departments of Endocrinology, Social Medicine and Epidemiology at the Karolinska
      Institute. The program was designed to include three stages, i.e. a combined
      baseline and aetiological study, a community-based intervention program and a
      follow-up study after 10 years. In 1995, the intervention program was initiated
      in Stockholm County with the aim of reducing the incidence of type 2 diabetes.
      The intervention has focused on the whole adult population in three intervention
      municipalities, where the local authorities have been involved in planning,
      initiating and implementing the program. Activities to prevent diabetes, aiming
      at risk factors such as obesity, low physical activity, dietary habits and
      tobacco use, have been initiated together with people from different fields and
      backgrounds, and with different ideas and approaches to health promotion and
      diabetes prevention. This paper provides a description and reflects upon the
      development and implementation process of SDPP as well as its interaction with
      the intervention communities. The stage model that was used for planning SDPP
      will be used for describing the various phases of the program. Over the period of
      the program, interest and responsibility has grown at the municipal authorities.
      The program has been a concern for the municipalities, as the program
      intermediate goals are also important for other health promotion issues.

PMID- 12406921
TI  - Health promotion behaviors in Chinese family caregivers of patients with stroke.
AB  - The purpose of this study was to explore the relationship between and among the
      caregiver's personal factors, the care recipient's functional status, the
      caregiver's perceived self-efficacy, social support, reactions to caregiving, and
      health promotion behaviors in family caregivers of community-dwelling stroke
      patients in Taiwan. A structured home-interview survey methodology was used to
      collect data from 134 primary caregivers responsible for care of stroke patients
      in Taipei, Taiwan. The study results indicated that, in general, caregivers were
      female spousal caregivers (mean age 52 years, average caregiving period 24
      months). Regression analyses revealed that the caregiver's health status was the
      strongest positive predictor of caregiver self-efficacy. Spousal caregivers with
      a better-perceived health status were more satisfied with their resources of
      social supports. Spousal caregivers with poor perceived health status had a
      higher level of caregiving strain. Results for the overall model indicated
      caregiver's social support and the care recipient's functional status made
      significant contributions in explaining the caregiver's health promotion
      behaviors. Implications for further practice suggest establishing community
      training programs and support groups for family caregivers.

PMID- 12406922
TI  - Reorienting health services with capacity building: a case study of the Core
      Skills in Health Promotion Project.
AB  - This paper presents a case study of the application of a framework for capacity
      building [Hawe, P., King, L., Noort, M., Jordens, C. and Lloyd, B. (2000)
      Indicators to Help with Capacity Building in Health Promotion. NSW Health,
      Sydney] to describe actions aimed at building organizational support for health
      promotion within an area health service in New South Wales, Australia. The Core
      Skills in Health Promotion Project (CSHPP) arose from an investigation which
      reported that participants of a health promotion training course had increased
      health promotion skills but that they lacked the support to apply their skills in
      the workplace. The project was action-research based. It investigated and
      facilitated the implementation of a range of initiatives to support community
      health staff to apply a more preventive approach in their practice and it
      contributed to the establishment of new organizational structures for health
      promotion. An evaluation was undertaken 4 years after the CSHPP was established,
      and 2 years after it had submitted its final report. Interviews with senior
      managers, document analysis of written reports, and focus groups with middle
      managers and service delivery staff were undertaken. Change was achieved in the
      three dimensions of health infrastructure, program maintenance and problem
      solving capacity of the organization. It was identified that the critically
      important elements in achieving the aims of the project-partnership, leadership
      and commitment-were also key elements of the capacity building framework. This
      case study provides a practical example of the usefulness of the capacity
      building framework in orienting health services to be supportive of health
      promotion.

PMID- 12406923
TI  - 'Opportunity structures': urban landscape, social capital and health promotion in
      Australia.
AB  - This paper presents data from 40 in-depth interviews that were conducted as part
      of a study of social capital and health in relation to people's perceptions of
      the influence of 'place' on their participation levels and health. These data
      were used to examine features of the western suburbs of Adelaide that were
      perceived as health damaging and health promoting. The paper demonstrates that
      our Australian suburban respondents expressed a considerable concern about these
      features and the impact they have on their perception of community and their
      ability to participate in it. Safety, connectedness to the area, the reputation
      of an area and the extent and nature of community facilities are all seen as
      important to a healthy community. The research found that in the more deprived
      socioeconomic areas within the study area, there was a significant degree of
      dissatisfaction with features of the urban environment, such as availability of
      amenities, provision of public transport, and proximity of industry to private
      dwellings. The paper concludes by considering certain features of urban
      environments that might make them more supportive of health through encouraging
      contact between people. We conclude that these environments could be improved
      using the following measures: a subsidy scheme to support the viability of local
      shops and cafes (thereby providing meeting places and employment); parks with
      facilitators (who could play a role in increasing safety in the park but also
      encouraging community development); attractive places to walk; and a general
      environmental improvement program.

PMID- 12406924
TI  - Youth social action: building a global latticework through information and
      communication technologies.
AB  - New technologies and a growing global consciousness have created innovative
      opportunities for young people to connect locally, nationally and internationally
      for social action. This paper describes the dynamics of collective action in this
      new environment. Particular attention is given to how youth social action
      initiatives use information and communication technologies (ICT) to foster
      connection, action and sustainability. In-depth interviews were performed with
      five youths (aged 18-24 years) and two youth workers at two international non
      government organizations (NGOs) focusing on social justice and human rights:
      Global Youth Connect and Amnesty International Canada. Qualitative methods were
      used to code and analyze the interview tapes and notes. Three main results are
      discussed: (i) the role of connection in building a youth action movement; (ii)
      the differential use of various communication technologies; and (iii) access
      barriers to connection opportunities. ICT enables new and expanded ways of
      connecting youth to express and share their experiences, which is a key success
      factor for social action initiatives.

PMID- 12406925
TI  - National environmental health planning in Vietnam: flying some kites.
AB  - The link between environment and health has been well established, as has the
      need to develop strategies to manage the environment to protect health. The
      response of many governments to the emergence of environment as a leading concern
      of public health policy has been to fragment environment and health functions
      across many agencies, without effective coordination or communication systems,
      resulting in poor planning frameworks. There is a deepening awareness by many in
      government and international agencies of the need to develop 'national
      environmental health plans' (NEHAPS) to build and integrate environment and
      health policy and practice. To date, however, experience in the development of
      these and similar plans indicates that prescriptive 'top-down' approaches to plan
      development may yield limited success. This paper describes an ongoing project in
      Vietnam to develop a process for a national environmental health plan that
      provides a strong link between policies and practice, and utilizes a learning
      model for plan development. As environmental health is a new concept in Vietnam,
      significant attention has been given to the development of both national and
      local visions. The lessons learnt to date indicate that the use of a learning
      framework may provide a strong basis for the emergence of environmental health
      policy and its management. Facilitation of this process has required the use of a
      variety of change management tools and has placed an emphasis on using them in
      culturally sensitive ways. It is hoped that the emerging model, which gives
      environmental health its first expression at both national and provincial levels,
      will be of value to others undertaking similar policy and planning initiatives.

PMID- 12406927
TI  - Vaccination mondiale et terreur mondiale.

PMID- 12406926
TI  - Global vaccination meets global terror.

PMID- 12406929
TI  - Family medicine in decline?

PMID- 12406930
TI  - Family medicine in decline?

PMID- 12406931
TI  - Hip-fracture and stroke care: parallel problems in evidence.

PMID- 12406932
TI  - Family medicine in decline?

PMID- 12406933
TI  - Hip-fracture and stroke care: parallel problems in evidence.

PMID- 12406934
TI  - Disclosure at Pfizer Canada.

PMID- 12406935
TI  - Disclosure at Pfizer Canada.

PMID- 12406936
TI  - Drug interactions with grapefruit.

PMID- 12406937
TI  - Folic acid fortification: time for a concentrated effort.

PMID- 12406938
TI  - Folic acid fortification: time for a concentrated effort.

PMID- 12406939
TI  - Puzzling vitamin D results.

PMID- 12406940
TI  - Puzzling vitamin D results.

PMID- 12406941
TI  - Reducing antibiotic prescriptions.

PMID- 12406942
TI  - Low risk of recurrence of oculorespiratory syndrome following influenza
      revaccination.
AB  - BACKGROUND: During the 2000-2001 influenza vaccination season, a new adverse
      event associated with the influenza vaccine, called oculorespiratory syndrome
      (ORS), was identified in Canada. We examined the risk of recurrence of ORS for
      individuals affected in 2000-2001 who were revaccinated in the community setting
      in 2001-2002. METHODS: We conducted a telephone survey in May 2002 in which
      participants were asked whether they had been revaccinated in the 2001-2002
      immunization season and whether they had experienced any recurrence of ORS or any
      other adverse event. Eligible individuals (n = 609) included residents of British
      Columbia aged 18 years or more who had reported any type of adverse event
      associated with the influenza vaccine in 2000 and who had participated in a
      survey in September 2001 that characterized their adverse event experience.
      RESULTS: The response rate to this survey was 92% (561 of 609 people approached).
      Of the 561 participants, 202 were revaccinated in 2001. Among the 202
      revaccinated, 122 individuals had previously reported ORS in 2000: 40 had
      described their ORS experience in 2000 as mild (present but not bothersome), 44
      as moderate (interrupting daily activities), 35 as severe (preventing daily
      activities) and 3 did not provide specific details. Six of the 122 individuals
      experienced a recurrence of ORS following revaccination. The estimated risk of
      recurrence for ORS following revaccination in the community setting was 5% (95%
      confidence interval 2.2%-10.5%). Four of the 6 individuals described their ORS
      recurrence in 2001 as milder than the ORS they had experienced in 2000.
      INTERPRETATION: We found a low risk of recurrence of ORS for individuals
      previously affected in 2000 when they were revaccinated in 2001, including those
      whose ORS in 2000 had prevented daily activities but was not clinically severe.
      Health care providers should be confident in the safety of recommending
      revaccination of these individuals. As with all vaccines, however, a detailed
      risk-benefit assessment should be undertaken before revaccination of people whose
      previous adverse event experience may have included collapse, respiratory
      difficulty (including throat tightness) and/or chest discomfort requiring
      emergency intervention.

PMID- 12406943
TI  - The value of clock drawing in identifying executive cognitive dysfunction in
      people with a normal Mini-Mental State Examination score.
AB  - BACKGROUND: Executive cognitive dysfunction can precede the memory disturbances
      of dementia. People with executive cognitive dysfunction can have a normal Mini
      Mental State Examination (MMSE) score but still have severe functional
      limitations. We evaluated the usefulness of clock drawing in identifying people
      with executive dysfunction who have a normal MMSE score. METHODS: We reviewed the
      charts of consecutive patients referred between July 1999 and June 2000 to a
      multidisciplinary geriatric assessment clinic because of concerns about
      functional inabilities. The patients had all undergone the Executive Interview
      for the diagnosis of executive cognitive dysfunction as well as an MMSE and clock
      drawing test (scored by 2 methods: one described by Watson and colleagues [the
      Watson method] and one described by Sunderland and colleagues [the Sunderland
      method]). RESULTS: We reviewed the charts of 68 patients (40 women, 28 men);
      their mean age was 79 years (range 55-94). Thirty-six patients had an MMSE score
      of less than 24, and 32 had a "normal" MMSE score (24-30). Among those with a
      normal MMSE score, 22 had an abnormal Executive Interview score. Using the
      Executive Interview as the gold standard, the sensitivity and specificity of the
      Watson method of scoring clock drawings to predict an abnormal Executive
      Interview score were 59% and 70% respectively; the corresponding values were 18%
      and 100% for the Sunderland method. INTERPRETATION: The presence of an abnormal
      MMSE score alerts clinicians to the possibility of cognitive impairment. For
      patients referred for geriatric assessment who have a normal MMSE score, a clock
      drawing test, scored by either the Watson or the Sunderland method, is a
      moderately sensitive and specific adjunct for detecting executive cognitive
      dysfunction.

PMID- 12406944
TI  - Do family physicians with emergency medicine certification actually practise
      family medicine?

PMID- 12406945
TI  - Prevalence of infection with carcinogenic human papillomavirus among older women.

PMID- 12406946
TI  - Medical women in academia: the silences we keep.

PMID- 12406947
TI  - Searching for El Dorado: the impossibility of finding the right rate.

PMID- 12406949
TI  - Giving thanks for locally grown food.

PMID- 12406948
TI  - Antimicrobial resistance in Canada.
AB  - Antibiotic resistance has increased rapidly during the last decade, creating a
      serious threat to the treatment of infectious diseases. Canada is no exception to
      this worldwide phenomenon. Data from the Canadian Nosocomial Infection
      Surveillance Program have revealed that the incidence of methicillin-resistant
      Staphylococcus aureus, as a proportion of S. aureus isolates, increased from 1%
      in 1995 to 8% by the end of 2000, and vancomycin-resistant enterococcus has been
      documented in all 10 provinces since the first reported outbreak in 1995. The
      prevalence of nonsusceptible Streptococcus pneumoniae in Canada in 2000 was found
      to be 12%. Human antimicrobial prescriptions, adjusted for differences in the
      population, declined 11% based on the total number of prescriptions dispensed
      between 1995 and 2000. There was also a 21% decrease in beta-lactam prescriptions
      during this same period. These data suggest that systematic efforts to reduce
      unnecessary prescribing of antimicrobials to outpatients in Canada, beginning
      after a national consensus conference in 1997, may be having an impact. There is,
      however, still a need for continued concerted efforts on a national, provincial
      and regional level to quell the rising tide of antibiotic resistance.

PMID- 12406950
TI  - Facts on mercury and fish consumption.

PMID- 12406951
TI  - Mammography screening among women aged 40-49 years shows no benefit.

PMID- 12406952
TI  - Suicidal stab wound with a butter knife.

PMID- 12406953
TI  - Dubious diagnoses.

PMID- 12406954
TI  - Ron Noganosh: sculpting politics and passion.

PMID- 12406955
TI  - The right position: 

PMID- 12406956
TI  - Mitral regurgitation.

PMID- 12406957
TI  - Blood donations dwindle in US after post-Sept. 11 wastage publicized.

PMID- 12406958
TI  - Dentistry ranks first, medicine second, in tuition fees.

PMID- 12406960
TI  - Oh rats!

PMID- 12406959
TI  - Meakins accepts Oxford post.

PMID- 12406962
TI  - Remains of a day: half of New York 9/11 victims identified by ME.

PMID- 12406961
TI  - Situation tense in Quebec as physicians ordered into ERs.

PMID- 12406963
TI  - Affirmative action needed to give women fair shot at research chairs?

PMID- 12406964
TI  - Federal committee supports patenting of some life forms.

PMID- 12406965
TI  - Off-reserve Aboriginal people face daunting health problems: StatsCan.

PMID- 12406966
TI  - Surprise! Women eat healthier than men.

PMID- 12406968
TI  - "Feminization of medicine - people say it like it's a bad thing"

PMID- 12406967
TI  - Jury calls for cellphone ban for drivers.

PMID- 12406969
TI  - Deaths.

PMID- 12406970
TI  - Striving for perfection.

PMID- 12406972
TI  - Stabilization of mRNA expression in whole blood samples.
AB  - BACKGROUND: Accurate quantification of mRNA in whole blood is made difficult by
      the simultaneous degradation of gene transcripts and unintended gene induction
      caused by sample handling or uncontrolled activation of coagulation. This study
      was designed to compare a new blood collection tube (PAXgene Blood RNA System)
      and a companion sample preparation reagent set with a traditional sample
      collection and preparation method for the purpose of gene expression analysis.
      METHODS: We collected parallel blood samples from healthy donors into the new
      sample collection tubes and control EDTA tubes and performed serial RNA
      extractions on samples stored for 5 days at room temperature and for up to 90
      days at 4 and 20 degrees C. Samples were analyzed by Northern blot analysis or
      reverse transcription-PCR (RT-PCR). RESULTS: Specific mRNA concentrations in
      blood stored in EDTA tubes at any temperature changed substantially, as
      determined by high-precision RT-PCR. These changes were eliminated or markedly
      reduced when whole blood was stored in PAXgene tubes. Loss of specific mRNAs, as
      measured by RT-PCR, reflected total RNA depletion as well as specific mRNA
      destruction demonstrated by Northern blot analysis. The salutary effects of
      PAXgene on mRNA stabilization extended to blood samples from eight unrelated
      donors. CONCLUSIONS: Compared with whole blood collected in EDTA tubes and
      extracted by an organic method, the PAXgene Blood RNA System reduced RNA
      degradation and inhibited or eliminated gene induction in phlebotomy whole blood
      samples. Storage of whole blood samples in PAXgene tubes can be recommended for
      clinically related blood samples that will be analyzed for total or specific RNA
      content.

PMID- 12406971
TI  - Multiplexed, targeted gene expression profiling and genetic analysis on
      electronic microarrays.
AB  - BACKGROUND: Electronic microarrays comprise independent microelectrode test sites
      that can be electronically biased positive or negative, or left neutral, to move
      and concentrate charged molecules such as DNA and RNA to one or more test sites.
      We developed a protocol for multiplexed gene expression profiling of mRNA targets
      that uses electronic field-facilitated hybridization on electronic microarrays.
      METHODS: A multiplexed, T7 RNA polymerase-mediated amplification method was used
      for expression profiling of target mRNAs from total cellular RNA; targets were
      detected by hybridization to sequence-specific capture oligonucleotides on
      electronic microarrays. Activation of individual test sites on the electronic
      microarray was used to target hybridization to designated subsets of sites and
      allow comparisons of target concentrations in different samples. We used
      multiplexed amplification and electronic field-facilitated hybridization to
      analyze expression of a model set of 10 target genes in the U937 cell line during
      lipopolysaccharide-mediated differentiation. Performance of multiple genetic
      analyses (single-nucleotide polymorphism detection, gene expression profiling,
      and splicing isoform detection) on a single electronic microarray was
      demonstrated using the ApoE and ApoER2 genes as a model system. RESULTS: Targets
      were detected after a 2-min hybridization reaction. With noncomplementary capture
      probes, no signal was detectable. Twofold changes in target concentration were
      detectable throughout the ( approximately 64-fold) range of concentrations
      tested. Levels of 10 targets were analyzed side by side across seven time points.
      By confining electronic activation to subsets of test sites, polymorphism
      detection, expression profiling, and splicing isoform analysis were performed on
      a single electronic microarray. CONCLUSIONS: Microelectronic array technology
      provides specific target detection and quantification with advantages over
      currently available methodologies for targeted gene expression profiling and
      combinatorial genomics testing.

PMID- 12406973
TI  - Molecular and biochemical studies of acute intermittent porphyria in 196 patients
      and their families.
AB  - BACKGROUND: Acute intermittent porphyria (AIP) is a metabolic disease with
      clinical manifestations that mimic other abdominal, neurologic, or mental crises.
      We studied the diagnostic accuracy of current laboratory tests during an acute
      attack and in remission. METHODS: Since 1966, we have studied all known Finnish
      AIP patients (n = 196) and their families (n = 45) and identified the
      porphobilinogen deaminase (PBGD) mutation in each family. Diagnoses or exclusions
      of AIP were based on clinical data (including family history), biochemical tests,
      and in 239 cases, mutation testing. We retrospectively evaluated the diagnostic
      accuracy of erythrocyte PBGD activity, urinary excretion of porphobilinogen (PBG)
      and delta-aminolevulinic acid, and urinary and fecal excretion of porphyrins in
      these patients. RESULTS: Measurement of urinary PBG identified all 35 AIP
      patients studied during an acute attack. The mean excretion of PBG was 50-fold
      above the reference interval, although the intraindividual increases were modest
      (1.6- to 4.0-fold). In the mutation-screened population, urinary PBG analysis
      identified only 85% of 81 AIP patients studied during remission, but by ROC curve
      analysis it was nonetheless the best of the biochemical tests. It was increased
      <or=2-fold in 29% of healthy relatives. Erythrocyte PBGD activity was decreased
      in only 84% of AIP patients, with results within the reference interval mainly in
      the variant form of AIP; it was decreased in 23% of healthy relatives.
      CONCLUSIONS: Measurement of urinary PBG is the best biochemical test for AIP,
      although it is unspecific and does not distinguish AIP from other acute
      porphyrias. Because the acute increase in PBG is often modest, the medical
      history, signs, and symptoms must be evaluated carefully during an acute attack.
      In addition, because biochemical analyses often remain indeterminate in
      remission, mutation analysis is needed to exclude or confirm the diagnosis of
      AIP.

PMID- 12406974
TI  - Comprehensive scanning of the entire mitochondrial genome for mutations.
AB  - BACKGROUND: Definitive molecular diagnosis of mitochondrial disorders has been
      greatly hindered by the tremendous clinical and genetic heterogeneity, the
      heteroplasmic condition of pathogenic mutations, and the presence of numerous
      homoplasmic mitochondrial DNA (mtDNA) variations with unknown significance. We
      used temporal temperature gradient gel electrophoresis (TTGE) to detect
      heteroplasmic mutations from homoplasmic variations in the whole mitochondrial
      genome. METHODS: We screened 179 unrelated patients by TTGE with use of 32
      overlapping primer pairs. Mutations were identified by direct sequencing of the
      PCR products and confirmed by PCR with allele-specific oligonucleotide or
      restriction fragment length polymorphism analysis. RESULTS: We detected 71
      heteroplasmic and 647 homoplasmic banding patterns. Sequencing of the
      heteroplasmic fragments identified 68 distinct novel mutations and 132 reported
      sequence variations and mutations; most of them occurred only once. The
      deleterious nature of some of the novel mutations was established by analyzing
      the asymptomatic family members and the biochemical and molecular characteristics
      of the mutation. When the number of mutations was normalized to the size of the
      region, the occurrence of mutations was 2.4 times more frequent in the tRNA genes
      than in the mRNA (protein coding) regions. CONCLUSIONS: Screening by TTGE detects
      low proportions of mutant mtDNA and distinguishes heteroplasmic from homoplasmic
      variations. Results from comprehensive molecular analysis should be followed up
      with clinical correlation to establish a guideline for complete mutational
      analysis of the entire mitochondrial genome and to facilitate the diagnosis of
      mitochondrial disorders.

PMID- 12406975
TI  - Use of denaturing HPLC to provide efficient detection of mutations causing
      familial hypercholesterolemia.
AB  - BACKGROUND: Autosomal dominant familial hypercholesterolemia (FH) attributable to
      mutations in the LDL receptor (LDLR) gene is one of the most common genetic
      disorders associated with significant morbidity and mortality. Definitive
      diagnosis would help to initiate appropriate treatment to prevent premature
      cardiovascular disease. Currently, clinical diagnosis of FH is imprecise, and
      molecular diagnosis is labor-intensive and expensive because of the size of the
      LDLR gene and number of coding exons. METHODS: We used PCR to amplify all exons,
      including exon/intron boundaries, and the promoter of the LDLR gene. Nine
      individuals from five families with typical findings for a clinical diagnosis of
      heterozygous FH, 2 heterozygous FH cell lines, and 50 control individuals were
      screened for mutations by denaturing HPLC (DHPLC) followed by direct sequencing
      of aberrantly migrating fragments. RESULTS: Mutations that were previously
      reported to be disease causing were identified in eight of nine individuals with
      FH and both cell lines (V502M, C146X, E207X, C660X, C646Y, and delG197), but none
      were found in controls. The one individual with FH in whom no mutation was found
      had a previously unreported change in the 5'-untranslated region of unknown
      significance. In addition, we identified several previously reported polymorphism
      both in controls and individuals with FH. CONCLUSIONS: DHPLC can be used to
      detect mutations causing FH. On the basis of our current experience with DHPLC,
      this method combined with confirmatory DNA sequencing is likely to be sensitive
      and efficient.

PMID- 12406976
TI  - Screening for primary aldosteronism: implications of an increased plasma
      aldosterone/renin ratio.
AB  - BACKGROUND: The value of the ratio of plasma aldosterone concentration
      (aldosterone) to plasma renin activity (renin) to identify patients at risk for
      primary aldosteronism is controversial. We determined the sensitivity,
      specificity, and predictive value of the ratio to identify combinations of renin
      and aldosterone compatible with primary aldosteronism. METHODS: The ratio was
      calculated in 505 adults with essential hypertension (143 black women, 82 black
      men, 122 white women, and 158 white men). We used a conventional cutpoint for an
      increased ratio (i.e., 20 mL/dL x h). The primary combination of renin and
      aldosterone considered compatible with primary aldosteronism was increased
      aldosterone for the concomitant renin, defined as aldosterone in the highest
      quartile predicted by linear regression on renin. Renin was considered low if it
      was in the lowest quartile of the sample distribution. RESULTS: The sensitivity
      of the ratio to identify individuals with increased aldosterone for the
      concomitant renin was 66% (80% in blacks and 56% in whites; P = 0.009), and the
      specificity of the ratio was 67% (46% in blacks and 84% in whites; P <0.0001). In
      36% of instances of an increased ratio, it was a measure of low renin alone
      without increased aldosterone for renin (32% in blacks and 45% in whites; P =
      0.072). The positive predictive value of the ratio to identify individuals with
      increased aldosterone for the concomitant renin was 34% (49% in whites and 27% in
      blacks; P <0.002). CONCLUSION: The aldosterone/renin ratio lacks sensitivity and
      specificity and has only a modest predictive value for combinations of renin and
      aldosterone that are compatible with primary aldosteronism.

PMID- 12406977
TI  - Evaluation of coagulation markers for early diagnosis of acute coronary syndromes
      in the emergency room.
AB  - BACKGROUND: Diagnosis of acute coronary syndromes (ACS) is a major challenge for
      emergency physicians. Because soluble fibrin (sF) has been suggested as a
      potential early marker of impending myocardial ischemia, we were interested
      whether a sF bedside test could help in early identification of patients with ACS
      in the emergency department. METHODS: We evaluated plasma coagulation markers,
      including a newly developed sF bedside test, prothrombin fragment (F(1+2)), sF,
      and D-dimer, in a cross-sectional trial with 184 patients suggestive of ACS.
      RESULTS: Whereas 76% (13 of 17) of patients with unstable angina pectoris (UAP)
      had a positive sF bedside test, only 10 of 33 patients (30%) with non-ST-segment
      elevation myocardial infarction and 10 of 44 patients (23%) with ST-elevation
      myocardial infarction tested positive. Three percent of controls (1 of 33) and
      11% of patients (6 of 57) with preexisting stable angina had a positive sF
      bedside test (P <0.001 for noncardiac chest pain vs ACS), yielding an overall
      specificity of 92% and a sensitivity of 35%. The sensitivity of the established
      coagulation markers was significantly less to detect ACS (11% for F(1+2), 20% for
      thrombus precursor protein, and 18% for D-dimer; P <0.02 vs sF bedside test). The
      sF bedside test presented the earliest objective indicator of impending
      myocardial damage in the majority (10 of 13) of ACS patients with a normal or
      nondiagnostic electrocardiogram (ECG). CONCLUSIONS: A sF bedside test offers a
      specific tool for early identification of patients with ACS in an emergency
      department setting, although its sensitivity seems sufficient only for the early
      identification of patients with UAP. A sF bedside test could be useful,
      particularly in UAP patients with a nondiagnostic ECG.

PMID- 12406978
TI  - Carcinoembryonic antigen, squamous cell carcinoma antigen, CYFRA 21-1, and neuron
      specific enolase in squamous cell lung cancer patients.
AB  - BACKGROUND: Carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCC
      Ag), and CYFRA 21-1 are the most useful markers for non-small cell lung cancer
      (NSCLC), but neuron-specific enolase (NSE) is a tumor maker of choice for SCLC.
      The determination of NSE in NSCLC could allow selection of patients with
      neuroendocrine features. NSCLC patients whose tumors have neuroendocrine
      properties may be more responsive to chemotherapy; however, these tumors have
      been reported to be more aggressive. Tumor markers are not suitable for
      diagnosis; their principal applications are in monitoring of therapy and
      prognosis. METHODS: Tumor markers were measured in 200 untreated patients with
      squamous cell lung cancer (SQC) and a reference group (n = 220; 124 healthy
      persons and 96 patients with nonmalignant lung disease). CEA and SCC-Ag were
      measured by microparticle enzyme immunoassays on Abbott AxSYM and IMx analyzers.
      CYFRA 21-1 and NSE were measured by electrochemiluminescence immunoassays on the
      Roche Elecsys 2010. RESULTS: CEA, SCC-Ag, CYFRA 21-1, and NSE were increased
      above the cutoffs in 26%, 32%, 67%, and 28% of tested patients, respectively. The
      area under the ROC curve for CYFRA 21-1 was higher than those for CEA, SCC-Ag,
      and NSE (SQC vs controls). CYFRA 21-1 and CEA were significantly higher in
      advanced SQC than in early stages of disease (P <0.0001 and P <0.0004,
      respectively). In multivariate analysis of survival, CYFRA 21-1 was an
      independent but nonspecific prognostic factor in the operable group of SQC
      patients, whereas NSE was an independent prognostic factor in the advanced stages
      of disease. CONCLUSION: CYFRA 21-1 is an independent prognostic factor in earlier
      stages and NSE in the advanced stages of SQC.

PMID- 12406979
TI  - Electrophoretic variant of a lactate dehydrogenase isoenzyme and selective
      promoter methylation of the LDHA gene in a human retinoblastoma cell line.
AB  - BACKGROUND: Lactate dehydrogenase (LD), a tetrameric product of the genes LDHA
      and LDHB, may be increased in sera of cancer patients. A variant isoenzyme with
      electrophoretic mobility between LD2 and LD3 (LD2ex) has been described in
      patients, but its molecular nature is largely unknown. METHODS: A newly
      established retinoblastoma cell line, NCC-RbC-51 (R51), showed an isoenzyme
      pattern with only two bands, LD1 and LD2ex. We investigated the isoenzymes by
      Northern blot, Western blot, and methylation analysis and PCR. RESULTS: Northern
      blot analysis revealed that R51 cells expressed no wild-type/somatic LDHA mRNA,
      but did express a small amount of LDHA-related mRNA with a slightly higher
      molecular mass. Western blot analysis confirmed the anti-LDHA-reactive protein
      with a 3-kDa higher molecular mass. Treatment of R51 cells with the demethylating
      agent 5-aza-2'-deoxycytidine restored the expression of the LD2, -3, -4, and -5
      isoenzymes. PCR analysis of sodium bisulfite-treated genomic DNA revealed that
      the CpG island in the promoter region around exon a of the LDHA gene was
      completely methylated. Reverse transcription-PCR analysis and direct sequencing
      revealed that R51 cells expressed a RNA with the sequence of the human homolog of
      a murine testis-specific variant that has exon 0 as the 5' noncoding sequence.
      LDHB was expressed normally in R51 cells. CONCLUSIONS: The somatic LDHA in R51
      cells is transcriptionally silenced by promoter hypermethylation around exon a,
      leaving only LDHB to be expressed normally and a testis-specific variant
      transcript of LDHA containing exon 0. LD2ex possibly results from tetramerization
      of three wild-type LDHB molecules and one variant LDHA product.

PMID- 12406980
TI  - Differential reactivity of two homogeneous LDL-cholesterol methods to LDL and
      VLDL subfractions, as demonstrated by ultracentrifugation and HPLC.
AB  - BACKGROUND: The analytical and clinical performance of homogeneous LDL
      cholesterol assays has been reported, but their reactions with subfractions of
      LDL and VLDL have not been described in detail. METHODS: We evaluated reaction
      selectivity of two homogeneous LDL-cholesterol assays, LDLk (Kyowa Medex) and
      LDLd (Daiichi Pure Chemical), with ultracentrifugally isolated VLDL and LDL
      subfractions to identify the lipoprotein particles from which the cholesterol
      recognized by these assays originates. RESULTS: The LDLd (y) and LDLk (x) methods
      correlated highly for whole serum samples: y = 0.986x - 39.5 mg/L (r = 0.966; n =
      34). In isolated VLDL, the LDLk and the LDLd methods recovered 17.3% and 23.8% of
      cholesterol, respectively; but correlation analysis revealed differential
      reactivity to small and large VLDL particles. For the isolated LDL subfraction of
      density 1.019-1.040 kg/L, the LDLd method had significantly higher reactivity
      (95.6-98.7%) than the LDLk (88.4-92.0%). Both methods, however, demonstrated poor
      recovery (approximately 50%) for the 1.050-1.063 kg/L fraction, indicating
      incomplete reactivity with small, dense LDL. Reactivity with lipoprotein(a) was
      better (71.2-90.8%) for both methods than with small LDL. For intermediate
      density lipoprotein (IDL), there was no significant difference in recovery
      between the two methods (71.7% for LDLk and 68.9% for LDLd), but the LDLk method
      appeared to be more sensitive to IDL particle size. CONCLUSIONS: The two
      homogeneous assays for LDL-cholesterol demonstrate only partial reactivity to
      small, dense LDL and nonspecific reactions to VLDL particles. Modification will
      be required in the homogeneous methods to obtain LDL-cholesterol values
      equivalent to those obtained by ultracentrifugation.

PMID- 12406981
TI  - Effect of analytical error on the assessment of cardiac risk by the high
      sensitivity C-reactive protein and lipid screening model.
AB  - BACKGROUND: Several prospective epidemiologic studies have demonstrated that high
      sensitivity C-reactive protein (hsCRP) is an effective serum marker for cardiac
      risk assessment. When hsCRP is considered in conjunction with traditional lipid
      screening, its clinical utility is further increased. In this report, hsCRP, HDL
      cholesterol (HDLC), and total cholesterol (TC) assay imprecision is evaluated in
      terms of the impact on the cardiac risk assessment process. METHODS: Cardiac risk
      assessment events were simulated using software written in Visual Basic for
      Applications with Microsoft Excel. Representative sets of analyte concentrations
      were used for true patient cardiac marker values. Monte Carlo simulations about
      the marker values were run using assay SD estimates based on College of American
      Pathologists surveys and journal articles. RESULTS: Risk distributions for
      reasonable assay imprecision showed clinically significant variation. Estimated
      relative risks of cardiovascular disease using the Ridker-Rifai quintile model
      varied by as much as 2.5-, 3.5-, and 6-fold for conditions of low, medium, and
      high laboratory test imprecision, respectively. The true relative risks were
      underestimated by >25% in 3%, 6.7%, and 10.5% of cases under conditions of low,
      medium, and high laboratory test imprecision, respectively, and overestimated by
      >25% in 4.4%, 8.5%, and 11.1% of cases under those conditions. CONCLUSIONS: Use
      of the Monte Carlo simulation method as a tool to assess the impact of analytical
      variation on the clinical decision-making process is valuable. From this
      analysis, it is shown that multiple measurements of HDLC may reduce
      misclassifications that result from assay imprecision. This is most important
      when using HDLC assays that include sample preparation with 500 000 molecular
      weight dextran sulfate. For these assays the total assay method SDs are higher
      than for other assay methods. In addition, as demonstrated by a propagation of
      error analysis, HDLC has the largest component of overall error in the relative
      risk estimate. Under conditions of typical TC and hsCRP assay performance,
      replication of these assays is less important.

PMID- 12406982
TI  - Primary standardization of assays for anticonvulsant drugs: comparison of
      accuracy and precision.
AB  - BACKGROUND: The accuracy and precision of methods for the measurement of the
      anticonvulsants phenytoin, phenobarbital, primidone, carbamazepine, ethosuximide,
      and valproate in human serum were assessed in 297 laboratories that were
      participants in the United Kingdom National External Quality Assessment Scheme
      (UKNEQAS). METHODS: We distributed lyophilized, serum-based materials containing
      low, medium, and high weighed-in concentrations of the drugs. The 297
      participating laboratories received the materials on two occasions, 7 months
      apart. Expected concentrations were determined by gas chromatography or HPLC
      methods in five laboratories using serum-based NIST reference materials as
      calibrators. RESULTS: In general, bias was consistent across concentrations for a
      method but often differed in magnitude for different drugs. Bias ranged from 
      1.9% to 8.6% for phenytoin, -2.7% to 3.1% for phenobarbital, -2.7% to 0.5% for
      primidone, -8.6% to 0.3% for carbamazepine, -5.6% to 2.0% for ethosuximide, and 
      7.2% to 0.1% for valproate. Intralaboratory sources of imprecision significantly
      exceeded interlaboratory sources for many drug/method combinations. The mean CVs
      for intra- and interlaboratory errors for the different drugs were 6.3-7.8% and
      3.3-4.2%, respectively. CONCLUSIONS: For these long-established and relatively
      high-concentration analytes, the closed analytical platforms generally performed
      no better than open systems or chromatography, where use of calibrators prepared
      in house predominated. To improve the accuracy of measurements, work is required
      principally by the manufacturers of immunoassays to ensure minimal calibration
      error and to eliminate batch-to-batch variability of reagents. Individual
      laboratories should concentrate on minimizing dispensing errors.

PMID- 12406983
TI  - Comprehensive screening of urine samples for inborn errors of metabolism by
      electrospray tandem mass spectrometry.
AB  - BACKGROUND: Detection of abnormal metabolites in urine is important for the
      diagnosis of many inborn errors of metabolism (IEM). Rapid, comprehensive
      screening methods are needed. METHODS: We used electrospray ionization tandem
      mass spectrometry in positive- and negative-ion modes to detect selected
      metabolites in urine. For positive-ion analysis, samples were dried and
      butylated, whereas for negative-ion analysis, samples were merely diluted with
      the mobile phase. Analysis was by direct injection with multiple reaction
      monitoring for 32 metabolites in positive mode (amino acids and acylcarnitines)
      and 30 metabolites in negative mode (organic acids). Run time was 2.1 min in each
      mode. RESULTS: Interbatch CVs ranged from 4.8% to 32%, enabling quantification of
      many metabolites. The procedure was applied to controls (278 and 120 in positive-
      and negative-ion mode, respectively) and 108 IEM individuals representing 37
      different IEM. In 105 IEM individuals, representing 36 different IEM,
      concentrations of one or more diagnostic metabolites were above the 99th
      percentiles of the control values. CONCLUSIONS: The procedure is faster and less
      labor-intensive than conventional methods of testing for IEM by amino and organic
      acid profiling and has similar diagnostic sensitivity. The ability to include a
      greater range of metabolites offers the potential of a more comprehensive
      screening procedure.

PMID- 12406984
TI  - Automated time-resolved immunofluorometric assay for Toxoplasma gondii-specific
      IgM and IgA antibodies: study of more than 130,000 filter-paper blood-spot
      samples from newborns.
AB  - BACKGROUND: To screen for congenital toxoplasmosis, we developed a time-resolved
      immunofluorometric assay for the simultaneous detection of Toxoplasma gondii
      specific IgM and IgA in filter-paper samples collected from newborns 4-7 days
      after birth. METHODS: The assay was performed on the AutoDELFIA, and results were
      calculated based on the ToxoM WHO Third International Reference Serum. Comparison
      with an in-house mu-capture immunoassay was carried out retrospectively on filter
      paper samples from children with confirmed congenital toxoplasmosis.
      Prospectively the assay was compared with a mu-capture immunoassay on 68 394
      samples and a commercially available assay on another 69,467 samples. Before
      serum was requested from the newborn, positive samples were tested for IgA and
      IgM separately and in an IgM-immunosorbent agglutination assay developed for
      filter-paper samples. RESULTS: Intra- and interassay variations (CVs) were 8% and
      16%, respectively. The cutoff of 5 units/mL produced a 0.5% retest rate. The
      assay detected 13 of 18 (72%) samples from newborns diagnosed with congenital
      toxoplasmosis in the retrospective study. Prospectively, the assay identified 24
      newborns who were later diagnosed with congenital toxoplasmosis. Results for all
      24 cases were positive by the respective comparison method. No cases were
      detected solely by the IgA antibodies in the sample. CONCLUSION: Neonatal
      screening for congenital toxoplasmosis can be automated by use of purified
      europium-labeled antigen for detection of T. gondii-specific IgM and IgA eluted
      from filter-paper samples.

PMID- 12406985
TI  - Impact of subgroup prevalences on partitioning of Gaussian-distributed reference
      values.
AB  - BACKGROUND: The aims of this report were to examine how unequal subgroup
      prevalences in the source population may affect reference interval partitioning
      decisions and to develop generally applicable guidelines for partitioning
      gaussian-distributed data. METHODS: We recently proposed a new model for
      partitioning reference intervals when the underlying data distribution is
      gaussian. This model is based on controlling the proportions of the subgroup
      distributions that fall outside each of the common reference limits, using the
      distances between the reference limits of the subgroup distributions as functions
      to these proportions. We examine the significance of the unequal prevalence
      effect for the partitioning problem and quantify it for distance partitioning
      criteria by deriving analytical expressions to express these criteria as a
      function of the ratio of prevalences. An application example, illustrating
      various aspects of the importance of the prevalence effect, is also presented.
      RESULTS: Dramatic shrinkage of the critical distances between reference limits of
      the subgroups needed for partitioning was observed as the ratio of prevalences,
      the larger one divided by the smaller one, was increased from unity. Because of
      this shrinkage, the same critical distances are not valid for all ratios of
      prevalences, but specific critical distances should be used for each particular
      value of this ratio. Although proportion criteria used in determining the need
      for reference interval partitioning are not dependent on the prevalence effect,
      this effect should be accounted for when these criteria are being applied by
      adjusting the sample sizes of the subgroups to make them correspond to the ratio
      of prevalences. CONCLUSIONS: The prevalences of subgroups in the reference
      population should be known and observed in the calculations for every reference
      interval study, irrespective of whether distance or proportion criteria are being
      used to determine the need for reference interval partitioning. We present
      detailed methods to account for the prevalences when applying each of these types
      of criteria. Analytical expressions for the distance criteria, to be used when
      high precision is needed, and approximate distances, to be used in practical
      work, are derived. General guidelines for partitioning gaussian distributed data
      are presented. Following these guidelines and using the new model, we suggest
      that partitioning can be performed more reliably than with any of the earlier
      models because the new model not only offers an improved correspondence between
      the critical distances and the critical proportions, but also accounts for the
      prevalence effect.

PMID- 12406986
TI  - Comparison of procedures for evaluating laboratory performance in external
      quality assessment schemes for lead in blood and aluminum in serum demonstrates
      the need for common quality specifications.
AB  - BACKGROUND: The different scoring methods used by eight European External Quality
      Assessment Schemes (EQASs) for occupational and environmental laboratory medicine
      were compared to develop suitable quality specifications as a step toward
      harmonization. METHODS: Real results for blood lead and serum aluminum assays,
      reported by participants in Italian and United Kingdom EQASs, were evaluated
      according to individual scheme scoring criteria. The same results were then used
      to produce z scores using scheme-based between-laboratory SDs as the estimate of
      variability to determine whether simple performance-derived quality
      specifications produced better agreement among schemes. RESULTS: The schemes gave
      conflicting assessments of participants' performance, and participants judged to
      be successful by one scheme could be defined as performing inadequately by
      another. An approach proposed by Kenny et al. (Scand J Clin Lab Invest
      1999;59:585), which uses clinical inputs to set targets for analytical
      imprecision, bias, and total error allowable, was then used to elaborate quality
      specifications. CONCLUSIONS: We suggest that the CLIA '88 recommendations for
      blood lead (+/- 40 micro g/L or +/- 10% of the target concentration, whichever is
      the greater) could be used as a quality specification, although a revision to +/-
      30 micro g/L or +/- 10% is recommended. For serum aluminum, a suitable quality
      specification of +/- 5 micro g/L or +/- 20% of the target concentration,
      whichever is the greater, is suggested. These specifications may be used to
      compare laboratory performance across schemes.

PMID- 12406987
TI  - False-positive immunoassay results: a multicenter survey of erroneous immunoassay
      results from assays of 74 analytes in 10 donors from 66 laboratories in seven
      countries.
AB  - BACKGROUND: Analytical interference in immunoassays can produce serious errors,
      but it is generally considered rare with modern analytical systems. METHOD: Blood
      was collected from 10 donors with illnesses known to be associated with
      rheumatoid factor. Immunoassays for 74 analytes were performed in 66 clinical
      laboratories. Each sample was measured in duplicate, and again in duplicate after
      the addition of a proprietary heterophil blocking reagent, with the laboratory's
      routinely used reagents and equipment. Reagents were typically supplied by the
      manufacturers of the closed analytical systems. Both competitive and sandwich
      immunoassays were investigated. RESULTS: Overall approximately 8.7% of the 3445
      results were considered to be "false positive", many of them seriously so. Twenty
      one percent of the erroneously high results (1.8% of all results) were
      potentially misleading and were corrected by blocking reagent, although 49% of
      such seriously high results (4.2% of all results) were not. A further 39% of the
      false-positive results (2.6% of all results) would not necessarily have appeared
      likely to produce adverse clinical consequences but were substantially lowered by
      the addition of the blocking reagent. CONCLUSIONS: Random errors can occur with
      all types of immunoassays tested and can be difficult to identify even when
      repeated in another laboratory. Clinicians need to be aware of these limitations.

PMID- 12406988
TI  - Effects of temperature on stability of blood homocysteine in collection tubes
      containing 3-deazaadenosine.
AB  - BACKGROUND: The accuracy of homocysteine (Hcy) results is currently compromised
      by the requirement to separate the plasma within 1 h of sample collection. We
      studied the effect of temperature on the stability of plasma Hcy over a 72-h time
      course in blood collected into evacuated tubes containing either EDTA alone or
      both EDTA and 3-deazaadenosine (3DA). METHODS: We recruited 100 volunteers,
      including both diseased and healthy individuals with a range of baseline plasma
      Hcy values, from two centers. Blood samples were collected into tubes containing
      EDTA, and EDTA plus 3DA and stored at ambient temperature (20-25 degrees C) or
      refrigerated (2-8 degrees C). Aliquots of blood were centrifuged at various times
      up to 72 h, the plasma was removed, and Hcy was measured by HPLC. RESULTS: Plasma
      Hcy measurement covering the sample collection and storage conditions during the
      whole time course was possible on samples from 59 of those recruited. One-way
      ANOVA for repeated measures within subjects revealed that only samples that were
      collected into tubes containing EDTA plus 3DA and stored refrigerated were stable
      over 72 h (P = 0.2761). CONCLUSIONS: A combination of 3DA and storage at 2-8
      degrees C will allow collection of samples for plasma Hcy measurement outside of
      the hospital setting and wider population screening.

PMID- 12406989
TI  - Wrong biochemistry results: two case reports and observational study in 5310
      patients on potentially misleading thyroid-stimulating hormone and gonadotropin
      immunoassay results.
AB  - BACKGROUND: Immunoassays are used in almost all medical and surgical specialties,
      but they suffer from interference from proteins such as antibodies in some
      patients' sera. Such interferences are usually reported in the literature only as
      case reports after the introduction of a new assay. METHODS: We undertook a
      prospective observational study on 5310 patients for whom the common immunoassay
      tests for thyroid-stimulating hormone (TSH) and/or gonadotropins were requested.
      All TSH and gonadotropin results were critically assessed for a mismatch between
      the clinical details and analytical results to identify samples suspected of
      analytical unreliability. These were tested further by three approaches to screen
      for interference. RESULTS: From the 5310 sets of results, 59 patients' samples
      were identified as suspect and were tested further. Analytically incorrect
      results were found in 28 (0.53% of the total studied). The magnitude of
      interference varied, but in 23 of 28 patients (82%), it was considered large
      enough to have a potentially adverse effect on cost and/or the clinical care of
      these patients. Two cases, described in detail, illustrate the adverse effect of
      error on patient care and cost, and the second highlights the difficulties and
      limitations of current approaches for identifying interference and inaccuracy in
      immunoassays. CONCLUSIONS: Because millions of TSH/gonadotropin tests are carried
      out in UK hospital laboratories alone, our data suggest that thousands of
      patients could be adversely affected by errors from interferences. Early
      identification of interference in cases with unusual results could be valuable.

PMID- 12406990
TI  - Clinical performance of an in-line, ex vivo point-of-care monitor: a multicenter
      study.
AB  - BACKGROUND: The management of critically ill infants and neonates includes
      frequent determination of arterial blood gas, electrolyte, and hematocrit values.
      An objective of attached point-of-care patient monitoring is to provide
      clinically relevant data without the adverse consequences associated with serial
      phlebotomy. METHODS: We prospectively determined the mean difference (and SD of
      the difference) from laboratory methods of an in-line, ex vivo monitor, the VIA
      LVM Blood Gas and Chemistry Monitoring System (VIA LVM Monitor; Metracor
      Technologies, Inc.), in 100 critically ill neonates and infants at seven
      children's hospitals. In doing so, we examined monitor stability with continuous
      use. In vivo patient test results from laboratory benchtop analyzers were
      compared with those from the VIA LVM Monitor on paired samples. In a separate in
      vitro comparison, benchtop analyzer and monitor test results were compared on
      whole-blood split samples. RESULTS: A total of 1414 concurrent, paired-sample
      measurements were obtained. The mean differences (SD of differences) from
      laboratory methods and r values for the combined data for the VIA LVM Monitor
      from the seven sites were 0.001 (0.026) and 0.97 for pH, 0.7 (3.6) mmHg and 0.94
      for PCO(2), 4.2 (9.6) mmHg and 0.98 for PO(2), 0.0 (2.9) mmol/L and 0.87 for
      sodium, 0.1 (0.2) mmol/L and 0.96 for potassium, and 0.3% (2.9%) and 0.90 for
      hematocrit. Performance results were similar among the study sites with
      increasing time of monitor use and between in vivo paired-sample and in vitro
      split-sample test results. CONCLUSION: The VIA LVM Monitor can be used to assess
      critically ill neonates and infants.

PMID- 12406991
TI  - Disclosure of hidden free light chains by immunosubtraction.

PMID- 12406992
TI  - Iterative, spectrophotometric method for determination of amniotic fluid
      bilirubin concentrations: comparison with the Liley method.

PMID- 12406993
TI  - Enzymatic hydrolysis improves the sensitivity of Emit screening for urinary
      benzodiazepines.

PMID- 12406994
TI  - Liquid chromatographic-tandem mass spectrometric method for the determination of
      5-hydroxyindole-3-acetic acid in urine.

PMID- 12406995
TI  - Reliable detection of beta-thalassemia and G6PD mutations by a DNA microarray.

PMID- 12406996
TI  - Liver fatty acid-binding protein as a sensitive serum marker of acute
      hepatocellular damage in liver transplant recipients.

PMID- 12406997
TI  - Comparison of the isoelectric focusing patterns of darbepoetin alfa, recombinant
      human erythropoietin, and endogenous erythropoietin from human urine.

PMID- 12406998
TI  - Neopterin concentrations in cord blood: a single-cohort study of paired samples
      from 541 pregnant women and their newborns.

PMID- 12406999
TI  - Bias and random error in retinol measurements of laboratories in countries with
      populations with mild to severe vitamin A deficiency.

PMID- 12407000
TI  - Cobalamin status (holo-transcobalamin, methylmalonic acid) and folate as
      determinants of homocysteine concentration.

PMID- 12407001
TI  - Lack of association between increased carotid intima-media thickening and
      decreased HDL-cholesterol in a family with a novel ABCA1 variant, G2265T.
AB  - Low HDL-cholesterol (HDL-C) concentrations are inversely correlated with
      cardiovascular disease, and previous studies have demonstrated that variants in
      the ATP-binding cassette transporter, ABCA1, are responsible for a proportion of
      HDL-C deficiency states. We identified a novel variant in ABCA1 in a kindred with
      decreased HDL-C. This variant was not identified in >200 chromosomes of healthy
      individuals. The proband, a heterozygote for G2265T, developed premature coronary
      artery disease. In addition to low HDL-C, six biological family members
      heterozygous for the ABCA1 variant exhibited low HDL-C concentrations compared
      with unaffected family members (0.83 +/- 0.32 vs 1.33 +/- 0.36 mmol/L; P =
      0.009). Despite the decreased HDL-C, carotid artery B-mode ultrasound studies
      failed to reveal increased intima-media thickening in affected individuals
      compared with age- and sex-matched controls. Although these data extend previous
      observations that a single defective ABCA1 allele may lead to decreased HDL-C,
      associated evidence of early atherosclerosis was not confirmed.

PMID- 12407002
TI  - Monitoring neonatal hypoglycemia with the Accu-chek advantage II glucose meter:
      the cautionary tale of galactosemia.

PMID- 12407003
TI  - Alcohol abuse and carbohydrate-deficient transferrin analysis: are screening and
      confirmatory analysis required?

PMID- 12407004
TI  - Does centrifugation cause the ex vivo release of DNA from blood cells?

PMID- 12407005
TI  - Inherited bisalbuminemia with benign monoclonal gammopathy detected by capillary
      but not agarose gel electrophoresis.

PMID- 12407006
TI  - Reporting of cardiac troponin concentrations.

PMID- 12407007
TI  - Serologic testing for celiac disease.

PMID- 12407014
TI  - Restoration of ethanol-compromised T(h)1 responses by sodium orthovanadate.
AB  - Alcohol consumption often diminishes antigen-specific cell-mediated immunity. In
      alcohol-consuming mice IFN-gamma and delayed-type hypersensitivity (DTH)
      responses are blunted, although antigen-specific T cell proliferation and IL-2
      responses are largely unaffected, suggesting that alcohol differentially affects
      signal transduction pathways. In the present report we explore the use of the
      phosphatase inhibitor, Na3 VO4 to restore IFN-gamma secretion in the presence of
      ethanol both in vivo and in vitro. We show that Na3 VO4 restores IFN-gamma in
      vitro and antigen-specific DTH in vivo to the levels seen in alcohol non
      consuming mice. Our data support the contention that ethanol, by up-regulating
      phosphotyrosine phosphatase, diminishes the IFN-gamma signal transduction
      pathway.

PMID- 12407015
TI  - Macrophages as main inducers of IFN-gamma in T cells following administration of
      human and mouse heat shock protein 60.
AB  - Human Hsp60 (hHsp60) elicits a potent pro-inflammatory response in cells of the
      innate immune system. Here we compared the capacity of peritoneal exudate cells
      (PEC) and bone marrow-derived dendritic cells (DC) to stimulate murine T cells in
      the presence of Hsp60. Hsp60 induced a specific secretion of high amounts of IFN
      gamma in T cells with PEC as antigen-presenting cells (APC). Although DC are
      highly efficient APC, they were much less potent as inducers of IFN-gamma in the
      presence of Hsp60. The IFN-gamma-inducing effect of Hsp60 is dependent on co
      stimulatory signals provided by B7-CD28 interactions. In addition to hHsp60, we
      used syngenic murine recombinant Hsp60 (mHsp60) and show that mHsp60 also induces
      IFN-gamma in TCR transgenic T cells. These results demonstrate that mHsp60 as an
      endogenous 'self' molecule can induce an inflammatory response. Interestingly,
      mHsp60, although sharing >98% protein sequence identity with the hHsp60
      homologue, does not bind to human CD14 molecules. Taken together, our results
      indicate a finely tuned activation of cells from the innate and adaptive immune
      system by 'self' Hsp60 that depends strongly on the type of APC.

PMID- 12407016
TI  - Systemic chemokine and chemokine receptor responses are divergent in allergic
      versus non-allergic humans.
AB  - T(h)1- and T(h)2-polarized human T cell clones display distinct patterns of
      chemokine receptor expression and selective chemokine responsiveness in vitro. We
      hypothesized that natural exposure to environmental grass pollen would induce
      differential systemic chemokine and chemokine receptor expression patterns in
      individuals with allergic rhinitis compared to healthy controls with type 2- and
      type 1-dominated responses to allergen respectively. To this end, we compared
      chemokine receptor expression on peripheral blood T cells directly ex vivo and
      plasma chemokine levels between these two groups of study participants prior to
      and during the grass pollen season. T(h)1-associated CXC chemokine receptor
      (CXCR) 3 was strongly expressed on >50% CD4(+)/CD45RO(+) cells of all subjects.
      When examined longitudinally, CXCR3 expression increased over the grass pollen
      season (P < 0.0001), solely in non-allergic subjects. In contrast, for both
      allergic and non-allergic subjects, CC chemokine receptor (CCR) 5 (T(h)1
      associated) and CCR3 (T(h)2-associated) were weakly expressed on <10% of
      CD4(+)/CD45RO(+) cells both prior to and during the grass pollen season. Type 1
      chemokines CXC chemokine ligand (CXCL) 9 and CXCL10 (monokine induced by IFN
      gamma and IFN-gamma-inducible protein of 10 kDa: CXCR3 ligands), and type 2
      chemokines CC chemokine ligand (CCL) 11 (eotaxin: CCR3 ligand), CCL17 (thymus and
      activation-regulated chemokine: CCR4 ligand) and CCL22 (monocyte-derived
      chemokine: CCR4 ligand) were readily detectable in the plasma of most
      participants. Systemic CXCL9 levels decreased from pre- to grass pollen season in
      allergics (P < 0.05), whereas CCL17 decreased in non-allergics (P < 0.05) over
      the same period. Taken together, these longitudinal data suggest a systemic shift
      to more intensely type 1-dominated responses in non-allergic individuals and,
      conversely, to more type 2-dominated responses in allergic individuals upon
      natural re-exposure to grass pollen.

PMID- 12407017
TI  - Serine phosphorylation of Stat5 proteins in lymphocytes stimulated with IL-2.
AB  - Tyrosine phosphorylation regulates cytokine-induced dimerization of STAT
      proteins. Serine phosphorylation has also been found to occur in a number of STAT
      proteins, including Stat1, Sat3, Stat4, Stat5a, Stat5b and Stat6, and was shown
      to be important for maximal transcriptional activation mediated by Stat1, Stat3
      and Stat4, but not for Stat5a or Stat5b. As these latter proteins were studied in
      transiently transfected COS-7 cells stimulated with prolactin, we sought to
      further investigate the significance of their serine phosphorylation in a more
      physiologically based system in response to IL-2. Both Stat5a and Stat5b were
      rapidly phosphorylated on serine in response to IL-2 and the phosphorylation site
      in Stat5a was mapped to Ser780, which is not conserved in Stat5b. In vitro
      studies with reporter constructs, and experiments in which wild-type and mutant
      Stat5a retroviruses were used to transduce Stat5a-deficient splenocytes revealed
      that the serine mutant constructs were not diminished in their ability to mediate
      IL-2 signaling and if anything exhibited augmented proliferative capability.
      Thus, in contrast to the apparent importance of serine phosphorylation for
      transcriptional activation by Stat1, Stat3 and Stat4 in response to IFN, IL-6 and
      IL-12 respectively, serine phosphorylation of Stat5a does not enhance Stat5a
      mediated signaling in response to IL-2.

PMID- 12407018
TI  - Characterization of mac25/angiomodulin expression by high endothelial venule
      cells in lymphoid tissues and its identification as an inducible marker for
      activated endothelial cells.
AB  - Previous results have indicated that mac25/angiomodulin (AGM) is expressed in
      lymph node (LN) high endothelial venules (HEV), the specialized venules that
      support efficient lymphocyte transendothelial migration. How mac25/AGM's
      endothelial expression pattern is regulated in situ remains unknown. Here, we
      demonstrate that in mouse LN blood vessels, including HEV, mac25/AGM is
      localized, unlike previous reports, not to the luminal or lateral regions
      bordering the endothelial cells (EC), but exclusively to the basal lamina that is
      in direct association with EC. In the spleen, mac25/AGM was expressed in the
      vascular basal lamina, in direct association with smooth muscle cells and
      pericytes, but not with EC. In addition, we report herein that mac25/AGM is an
      inducible marker for activated EC. In inflamed tissues, mac25/AGM expression was
      strongly induced in the abluminal region of blood vessels. In vitro, mac25/AGM
      was readily induced in EC upon activation with pro-inflammatory cytokines such as
      tumor necrosis factor-alpha, indicating that mac25/AGM is an activated EC marker.
      mac25/AGM binds vascular endothelial growth factor and, together with its strict
      abluminal localization, it is suggested that mac25/AGM has a specific function(s)
      in the subendothelium of activated blood vessels such as capturing humoral
      factors produced in the vicinity of HEV.

PMID- 12407019
TI  - Comparison of the frequency of peptide-specific cytotoxic T lymphocytes
      restricted by self- and allo-MHC following in vitro T cell priming.
AB  - T cell recognition of antigenic peptides is thought to occur preferentially in
      the context of self-MHC. Here, we have tested the ability of four different K(b)
      peptide combinations to stimulate self- and allo-restricted CTL responses in
      three different mouse stains. Responder T cells were primed in vitro with peptide
      loaded stimulator cells, followed by limiting dilution assays to measure the
      number of peptide-specific cytotoxic T lymphocytes (CTL). For three peptides the
      number of CTL restricted by self-MHC was higher than for allo-MHC-restricted
      responses, although the difference was surprisingly small (3- to 5-fold). For the
      fourth peptide there was no detectable difference in the number of self- and allo
      restricted CTL. Peptide titration experiments revealed that high avidity CTL were
      present in both the self- and allo-restricted setting. These data showed that the
      bias for preferred peptide recognition in the context of self-MHC imposed by
      positive thymic selection seems marginal. This raised the possibility that the
      TCR repertoire is inherently biased towards MHC restriction, independent of MHC
      guided thymic selection. This was supported by the analysis of mature T cells
      generated from the thymus of MHC-deficient mice by lectin stimulation. K(b)
      restricted CTL were found amongst these T cells at numbers similar to those of
      allo-restricted CTL. In summary, the data suggest that MHC-restricted peptide
      recognition is an inherent feature of the TCR repertoire and does not require
      thymic selection by MHC molecules.

PMID- 12407020
TI  - Conserved regions of protein disulfide isomerase are targeted by natural IgA
      antibodies in humans.
AB  - Secretory IgA (sIgA) antibodies in human tears and milk were found to recognize
      protein disulfide isomerase (PDI) on a Toxoplasma gondii lysate immunoblot (IB).
      These antibodies were already detectable in tears of infants. To determine the
      epitope containing-regions on PDI, we generated truncated versions of recombinant
      PDI that differ by 8-10 amino acids in length. By IB, it was found that the sIgA
      epitopes were confined to conserved regions of PDI, including the functionally
      essential thioredoxin-like domain. This suggested the capacity of sIgA to react
      with PDI of other species, which was confirmed by recognition of human PDI by IgA
      in tears. In contrast, anti-T. gondii PDI antibodies generated by immunization
      were not able to cross-react. Binding to the thioredoxin-like domain on IB could
      be gradually abrogated by incubation with peptide constituting the same domain.
      By consecutive investigation of the function of the protein targeted by sIgA, the
      presence of antibody in relation to age and analysis of the epitope constituting
      regions on PDI we demonstrate that sIgA directed against PDI are self-reactive
      natural antibodies. Furthermore, analysis of antibody epitopes on an antigen is a
      useful method to distinguish conventional, affinity-matured antibodies from
      natural antibodies. The presence at early age and continuity of anti-PDI sIgA in
      relation to age suggests the existence of B cells secreting germline-encoded
      antibodies in human mucosa outside of the gut. Overall, the PDI-specific
      antibodies are clearly part of the natural antibody repertoire, suggesting an
      active role for these antibodies in the innate defense against pathogens.

PMID- 12407021
TI  - Efficacy of IVIG affinity-purified anti-double-stranded DNA anti-idiotypic
      antibodies in the treatment of an experimental murine model of systemic lupus
      erythematosus.
AB  - Since the idiotypic network is an important mechanism for controlling the immune
      repertoire, we tested anti-idiotypic modulation employing concentrated specific
      natural polyclonal anti-double-stranded (ds) DNA anti-idiotypic antibodies
      obtained from a commercial IVIG in the treatment of experimental systemic lupus
      erythematosus (SLE). Specific natural polyclonal anti-dsDNA anti-idiotypic
      antibodies (IVIG-ID) were affinity purified from IVIG on an anti-dsDNA-Sepharose
      column constructed from anti-dsDNA idiotypes (ID) affinity purified from 55
      patients with active SLE. NZB/W F(1) mice were treated i.v. with 3 weekly
      injections of IVIG-ID (2 mg/kg/injection) or regular IVIG (400 mg/kg/injection)
      both before (age 8 weeks) and after developing anti-dsDNA antibodies at the age
      of 21-22 weeks. The IVIG-ID-treated mice showed a decline in the titer of anti
      dsDNA antibodies during the treatment, reaching maximum suppression 1 week after
      the last injection. A significant difference in the proteinuria level in the IVIG
      ID-treated group compared to the control group was observed. Immunohistology
      showed different patterns of IgG deposition, with mesangial and capillary wall
      deposits in controls and in the IVIG-treated group, but only mesangial deposits
      in the IVIG-ID-treated group. The survival time of the IVIG-ID-treated group was
      longer than the IVIG-treated group. Treatment with concentrated specific anti
      dsDNA anti-ID prepared from commercial IVIG is more effective in suppressing the
      humoral reaction and clinical signs of SLE than native IVIG. These results point
      to the considerable regulatory role of anti-ID in the mechanism of action of IVIG
      in SLE.

PMID- 12407022
TI  - Aging and developmental transitions in the B cell lineage.
AB  - One explanation for the deterioration of the humoral immune response in elderly
      individuals is that B lymphopoiesis declines with increasing age. Recent studies
      report a dramatic decline in pre-B cell numbers in old mice. Surprisingly, the
      number of mature B cells does not decline with age. To determine if new B cells
      are made in aged animals despite the drop in pre-B cells, we used 5'-bromo-2
      deoxyuridine labeling to determine the production rate of B cells in the bone
      marrow and spleen of young and old mice. Because of the great variability in the
      number of early B lineage cells in old mice, we acquired data on >60 young and 50
      old mice throughout these experiments. The transitional and mature B cell
      compartments in the spleen have slower labeling kinetics in old mice as compared
      to young. By the end of 4 weeks of labeling, an average of only 15% of the mature
      B cell compartment consists of newly made cells compared to 30% in young mice.
      However, in contrast to an earlier report, our results indicate that there is no
      statistical difference in the rate of production of new immature B cells in the
      marrow of young and old animals. In total, our results confirm previous work
      showing that mature B cells in old mice have a slower turnover, but more
      importantly suggest that the defect in mature B cell turnover is not due to a
      decline in B lymphopoiesis, but rather an inability of the newly made cells to
      replenish the peripheral compartments.

PMID- 12407023
TI  - Cell activation by Porphyromonas gingivalis lipid A molecule through Toll-like
      receptor 4- and myeloid differentiation factor 88-dependent signaling pathway.
AB  - Porphyromonas gingivalis lipopolysaccharide (LPS) and its bioactive center, lipid
      A, are known to exhibit very low endotoxic activities and activate LPS
      hyporesponsive C3H/HeJ mice that have a point mutation in the cytoplasmic portion
      of Toll-like receptor (TLR) 4, in contrast to classical enterobacterial LPS and
      their lipid A. In the present study, we attempted to determine which TLR mediates
      the response to lipid A from P. gingivalis strain 381. P. gingivalis LPS and its
      natural lipid A fraction induced NF-kappa B activation primarily in Ba/F3 cells
      expressing mouse TLR 2 (Ba/mTLR2), rather than in those expressing mouse TLR4 and
      its accessory protein MD2 (Ba/mTLR4/mMD2). Further purification of the natural
      lipid A fraction resulted in a significant decrease of NF-kappa B activation in
      Ba/mTLR2, although not in Ba/mTLR4/mMD2. The synthetic counterpart of P.
      gingivalis strain 381-lipid A (compound PG-381) also elicited NF-kappa B
      activation in Ba/mTLR4/mMD2, but not Ba/mTLR2. Furthermore, P. gingivalis
      purified natural lipid A and compound PG-381 lacked the ability to activate
      gingival fibroblasts from C3H/HeJ, TLR4 knockout (KO) and myeloid differentiation
      factor 88 (MyD88) KO mice. These findings demonstrate that the P. gingivalis
      lipid A molecule induces cell activation via a TLR4/MD2-MyD88-dependent pathway,
      and suggest the possibility that unknown bacterial components in P. gingivalis
      LPS and its lipid A may induce cell activation via TLR2.

PMID- 12407024
TI  - HY peptides modulate transplantation responses to skin allografts.
AB  - Injection of female C57BL/6 mice with immature female bone marrow-derived
      dendritic cells (BMDC) pulsed with a single immunodominant HY(Db) Uty peptide,
      WMHHNMDLI, induces prolonged survival of syngeneic male skin grafts. In contrast,
      injection of immature female BMDC pulsed with a single MHC class I-restricted
      HY(Ab) Dby peptide, NAGFNSNRANSSRSS, causes immunization similar to that
      following injection of male cells. Tolerance induced by HY(Db) Uty peptide
      pretreatment is not characterized by clonal deletion: long-term tolerant mice
      maintain circulating HY(Db) Uty tetramer(+) T cells which expand following
      exposure to male cells in vivo or in vitro. Tolerance to male skin grafts can be
      adoptively transferred into neonatal females with splenocytes from tolerant
      donors. Tolerance is specific-third-party skin grafts are rejected. We propose
      that tolerance in this model is initiated by cognate interaction of HY(Db) Uty
      specific CD8(+) T cells with their ligand, presented either on the injected
      immature BMDC or on recipient DC. This interaction leads to incomplete activation
      of the CD8(+) T cells resulting in diminished responsiveness of CD4(+) and CD8(+)
      T cells specific for HY peptide epitopes subsequently presented on the male
      graft.

PMID- 12407026
TI  - IL-22, in contrast to IL-10, does not induce Ig production, due to absence of a
      functional IL-22 receptor on activated human B cells.
AB  - IL-22 is an IL-10 homologue that binds to and signals via the class II cytokine
      receptor (R) heterodimer IL-22RA1/CFR2-4 (IL-10R2), the latter chain being part
      of the IL-10R complex. Here, we report that, despite its structural similarity
      with IL-10, as well as its use of the common IL-10R2 chain, IL-22, in contrast to
      IL-10, is unable to induce Ig production by activated human B cells. Whereas
      culture of anti-CD40 mAb-stimulated splenic or tonsillar B cells in the presence
      of rIL-10 resulted in the production of IgG, IgG1, IgG3 and IgA, rIL-22, at
      concentrations ranging from 4 to 100 ng/ml, did not induce the production of any
      of these isotypes. Moreover, unlike rIL-10 which enhanced rIL-4-induced IgG4 and
      IgE production, rIL-22 was ineffective. Although activated B cells expressed
      transcripts for a soluble IL-22-binding protein (IL-22RA2), no mRNA for a
      transmembrane IL-22R (IL-22RA1) could be detected. The latter result was
      confirmed by the demonstration that rIL-22 failed to induce activation of STAT-3
      and -5 in resting or activated B cells. Together, these data show that IL-22, in
      contrast to its homologue IL-10, is not involved in the immunological activity of
      B cells, which is due to the absence of a functional IL-22R at the surface of
      these cells.

PMID- 12407025
TI  - A regulatory role for suppressor of cytokine signaling-1 in T(h) polarization in
      vivo.
AB  - Suppressor of cytokine signaling (SOCS)-1 is an inhibitory molecule for JAK, and
      its deficiency in mice leads to lymphocyte-dependent multi-organ disease and
      perinatal death. Crossing of SOCS-1(-/-) mice on an IFN-gamma(-/-), STAT1(-/-)
      and STAT6(-/-) background revealed that the fatal disease of SOCS-1(-/-) mice is
      also dependent on IFN-gamma/STAT1 and IL-4/STAT6 signaling pathways. Since IFN
      gamma and IL-4 are representative T(h)1 and T(h)2 cytokines respectively, here we
      investigated the role of SOCS-1 in T(h) differentiation. Freshly isolated SOCS-1(
      /-) CD4(+) T cells stimulated with anti-CD3 rapidly produced larger amounts of
      IFN-gamma and IL-4 than control cells, suggesting that these mutant T cells had
      already differentiated into T(h)1 and T(h)2 cells in vivo. In addition, SOCS-1(+/
      ) CD4(+) T cells cultured in vitro produced significantly larger amounts of IFN
      gamma and IL-4 than SOCS-1(+/+) cells. Similarly, SOCS-1(+/-) CD4(+) T cells
      produced more IFN-gamma and IL-4 than SOCS-1(+/+) cells after infection with
      Listeria monocytogenes and Nippostrongyrus braziliensis respectively. Since IL-12
      induced STAT4 and IL-4-induced STAT6 activation is sustained in SOCS-1(-/-) T
      cells, the enhanced T(h) functions in SOCS-1(-/-) and SOCS-1(+/-) mice appear to
      be due to the enhanced effects of these cytokines. These results suggest that
      SOCS-1 plays a regulatory role in both T(h)1 and T(h)2 polarizations.

PMID- 12407027
TI  - Contribution of CD3 gamma to TCR regulation and signaling in human mature T
      lymphocytes.
AB  - CD3 proteins may have redundant as well as specific contributions to the
      intracellular propagation and final effector responses of TCR-mediated signals at
      different checkpoints during T cell differentiation. We report here on the
      participation of CD3 gamma in the activation and effector function of human
      mature T lymphocytes at the antigen recognition checkpoint. Following TCR-CD3
      engagement of human CD3 gamma-deficient T cell lines, and despite their lower TCR
      CD3 surface levels compared to normal controls, mature T cell responses such as
      protein tyrosine phosphorylation and the regulation of expression of several cell
      surface molecules, including the TCR-CD3 itself, were either normal or only
      slightly affected. In contrast, other physiological responses like the specific
      adhesion and concomitant cell polarization on ICAM-1-coated dishes were
      selectively defective, and activation-induced cell death was increased. Our data
      indicate that CD3 gamma contributes essential specialized signaling functions to
      certain mature T cell responses. Failure to generate appropriate interactions may
      abort cytoskeleton reorganization and initiate an apoptotic response.

PMID- 12407028
TI  - Epigenetic risks related to assisted reproductive technologies: short- and long
      term consequences for the health of children conceived through assisted
      reproduction technology: more reason for caution?
AB  - Does the manipulation of gametes and embryos as practised in human IVF invoke
      perturbations in fetal and neonatal phenotype? There is increasing evidence that
      the answer is 'yes', although the degree of perturbation may be less acute than
      observed in other species. However, the long-term consequences are not known, and
      may prove to be considerable. There is now a substantial body of evidence from
      animal models suggesting that assisted reproductive technologies (ART) are
      associated with altered outcomes in fetal and neonatal development. Epigenetic
      modification of gene expression is an attractive hypothesis that accounts for
      these differences and is one of a number of causal pathways that may be activated
      by cellular stress invoked during manipulation. Here we widen the debate to
      propose that environment-induced cellular stress also acts to modify fetal and
      placental gene expression, potentially also contributing to phenotype skewing
      after ART.

PMID- 12407029
TI  - Embryo freezing for preventing ovarian hyperstimulation syndrome: a Cochrane
      review.
AB  - This paper is based on a Cochrane review published in The Cochrane Library, issue
      3, 2002 (see www.CochraneLibrary.net for information) with permission from The
      Cochrane Collaboration and Update Software. Cochrane reviews are regularly
      updated as new evidence emerges and in response to comments and criticisms, and
      The Cochrane Library should be consulted for the most recent version of the
      review. BACKGROUND: Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic
      condition resulting from an excessive ovarian response to superovulation
      medication. The objective of this review was to evaluate the effectiveness of
      cryopreservation (embryo freezing) when compared with human i.v. albumin infusion
      and with fresh embryo transfer for the prevention of OHSS. METHODS: This was
      based on a Cochrane Review. Randomized controlled trials in which either human
      i.v. albumin or cryopreservation of all embryos was used as a therapeutic
      approach to OHSS were included. The participants were women down-regulated by
      GnRH agonist, undergoing superovulation in IVF/ICSI cycles. The interventions
      compared were cryopreservation versus i.v. human albumin administration and
      elective cryopreservation of all embryos versus fresh embryo transfer. The
      primary outcomes were: incidence of moderate and severe OHSS versus nil/mild
      OHSS, and clinical pregnancies/woman. Statistical analysis was performed in
      accordance with the Cochrane Menstrual Disorders and Subfertility Group
      guidelines. RESULTS: Seventeen studies were identified, two of which met our
      inclusion criteria. One study was included where cryopreservation was compared
      with i.v. human albumin administration and another where elective
      cryopreservation of all embryos was compared with fresh embryo transfer. In both
      interventions no difference was found in all the outcomes examined between the
      two groups. CONCLUSIONS: This review has shown that there is insufficient
      evidence to support routine cryopreservation and insufficient evidence for the
      relative merits of i.v. albumin versus cryopreservation.

PMID- 12407030
TI  - Endometrial destruction techniques for heavy menstrual bleeding: a Cochrane
      review.
AB  - This paper is based on a Cochrane review published in The Cochrane Library, issue
      3, 2002 (see www.CochraneLibrary.net for information) with permission from The
      Cochrane Collaboration and Update Software. Cochrane reviews are regularly
      updated as new evidence emerges and in response to comments and criticisms, and
      The Cochrane Library should be consulted for the most recent version of the
      review. BACKGROUND: The objective of this review was to compare the efficacy,
      safety and acceptability of methods used to destroy the endometrium to reduce
      heavy menstrual bleeding (HMB) in premenopausal women. METHODS: We searched the
      Cochrane Controlled Trials Register, Medline, Embase, Current Contents,
      Biological Abstracts, Psyclit and CINAHL. We also searched the specialized
      register of the Cochrane Menstrual Disorders and Subfertility Group and reference
      lists of articles, and contacted pharmaceutical companies and experts in the
      field. Randomized controlled trials comparing endometrial ablation techniques in
      women with a complaint of HMB without uterine pathology were selected. The
      outcomes included reduction of HMB, improvement in quality of life, operative
      outcomes, satisfaction with outcome, complications and need for further surgery.
      The two reviewers independently selected trials for inclusion, assessed trials
      for quality and extracted data. Attempts were made to contact authors for
      clarification of data in some trials. Adverse events were only assessed if they
      were separately measured in the included trials. RESULTS: In comparing
      hysteroscopic techniques, the vaporizing electrode procedure was less difficult
      to perform [odds ratio (OR) = 0.25; 95% confidence interval (CI): 0.1, 0.7] and
      had less fluid deficit [weighted mean difference (WMD) = -258 ml; 95% CI: -342.1,
      -174.0] than transcervical resection of the endometrium (TCRE). The odds of fluid
      overload and equipment failure were higher (OR = 5.2; 95% CI: 1.5, 18.4 and OR =
      6.0; 95% CI: 1.7, 20.9 respectively) for those women having laser treatment as
      compared with TCRE. In comparing traditional hysteroscopic endometrial ablation
      with the newer second generation techniques overall, the newer techniques took
      less time to perform (WMD = -11 min; 95% CI: -18.6, -2.6) and were more likely to
      be performed under local anaesthesia (OR = 7.6; 95% CI: 1.1, 52.7) but had a
      greater chance of equipment failure (OR = 4.1; 95% CI: 1.1, 15.0). The reduction
      in HMB did not differ significantly between any of the groups. CONCLUSIONS: The
      rapid development of a number of new methods of endometrial destruction has made
      systematic comparisons between methods and with the 'gold standard' of TCRE
      difficult. Most of the newer techniques are performed blind and are technically
      easier than hysteroscopy-based methods. Overall, the existing evidence suggests
      that success rates and complication profile of newer techniques of ablation
      compare favourably with TCRE, although technical difficulties with new equipment
      need to be ironed out.

PMID- 12407031
TI  - Preimplantation genetic diagnosis for fragile Xa syndrome: difficult but not
      impossible.
AB  - BACKGROUND: In this paper, we review our clinical preimplantation genetic
      diagnosis (PGD) programme for fragile Xa syndrome, analysing if PGD for these
      couples is still a valuable option, as it is particularly difficult for two
      reasons. First, the couples have to be informative (the number of triplet repeats
      on the healthy FMR-1 allele of the mother has to be different from the number of
      repeats on the healthy FMR-1 allele of the father) and second, women with a
      premutation are at increased risk of premature ovarian failure. METHODS: A total
      of 34 couples attended our genetics department between December 1998 and July
      2001, requesting information about PGD for fragile Xa syndrome. RESULTS: Eight
      couples decided not to go further with the procedure and of the 26 remaining
      couples, 16 were informative (61.5%). Four couples have so far not started
      ovarian stimulation, one patient was totally refractive to stimulation and 11
      couples have had a total of 19 oocyte retrievals. From these, there have been 13
      embryo transfers with a clinical pregnancy rate per embryo transfer of 23%; the
      implantation rate was 13.6% and the live birth rate per couple was 27.3%.
      CONCLUSIONS: PGD for fragile Xa is feasible for a number of couples. A pre-PGD
      work-up should include a determination of the premutation or mutation carrier
      status, the maternal or paternal origin of the premutation and an estimation of
      the ovarian reserve of the patient. Fragile Xa premutation carriers should be
      advised not to postpone reproduction for too long.

PMID- 12407032
TI  - Clinical characterization of 42 oligospermic or azoospermic men with
      microdeletion of the AZFc region of the Y chromosome, and of 18 children
      conceived via ICSI.
AB  - BACKGROUND: Severe spermatogenic compromise may be the result of a Y-chromosomal
      deletion of the AZFc region. Prior studies are limited to relatively small
      numbers of AZFc-deleted men. In this study, we have fully characterized 42
      infertile men with a Y chromosome microdeletion strictly confined to the AZFc
      region, and we report on 18 children conceived through the use of ICSI. METHODS:
      A total of 42 oligospermic or azoospermic men had AZFc deletions. History,
      physical examination, karyotype, FSH, LH, testosterone, testis histology and
      results of ICSI using ejaculated or testis sperm were retrospectively accumulated
      in two academic clinical practices. RESULTS: All men were somatically healthy.
      Karyotypes were 46,XY in all but two men. FSH, LH, testosterone and testis
      histology could not differentiate those with oligospermia or azoospermia, nor
      could they predict whether sperm could be found in harvested testis tissue.
      Paternal age was not increased. Sperm production appeared stable over time. The
      results of ICSI were not affected by the AZFc deletion. All but one of the
      offspring were healthy. The sons inherited the AZFc deletion with no increase in
      length. CONCLUSIONS: AZFc-deleted men are somatically healthy, will most likely
      have useable sperm, will have stable sperm production over time and will have a
      good chance to experience biological paternity, but their sons will also be AZFc
      deleted.

PMID- 12407033
TI  - Follicular administration of a cyclooxygenase inhibitor can prevent oocyte
      release without alteration of normal luteal function in rhesus monkeys.
AB  - BACKGROUND: Prostaglandins (PG), produced by the follicle just before ovulation,
      appear to act locally to promote follicle rupture and oocyte release. METHODS: To
      determine whether administration of PG synthesis inhibitor directly into the
      primate follicle would prevent ovulatory events, serum estradiol was used to
      predict the day of the ovulatory LH surge in rhesus monkeys. On the day before or
      the day of the LH surge, vehicle (n = 9), the PG synthesis inhibitor indomethacin
      (10(-6) or 10(-5) mol/l final concentration; n = 8), or 10(-5) mol/l indomethacin
      + 1 micro g/ml PGE(2) (n = 3) was injected into the follicular fluid of the pre
      ovulatory follicle. In some animals, luteal phase estrogen and progesterone were
      measured in daily serum samples. Other animals were ovariectomized 3 days after
      follicle injection; ovaries were examined for verification of follicle rupture
      and oocyte release. RESULTS: Follicle injection of indomethacin [10(-6) mol/l (n
      = 4) or 10(-5) (n = 4) mol/l final concentration] or vehicle (n = 6) did not
      alter luteal function. Examination of serial sections of removed ovaries
      confirmed follicle rupture and the absence of oocytes in vehicle-injected
      follicles (n = 3). Trapped oocytes were observed in 4/8 indomethacin-injected
      follicles, though several ovaries with trapped oocytes had experienced follicle
      rupture. Oocytes were not detected in the ruptured, luteinizing follicles from
      indomethacin + PGE(2)-injected monkeys (n = 3). CONCLUSIONS: Follicular
      administration of indomethacin can prevent oocyte release without inhibition of
      follicle rupture or disruption of subsequent luteal function. The ability of
      PGE(2) to prevent indomethacin-induced ovulatory failure suggests a critical role
      for locally produced PGE(2) in the process of oocyte release in primates.

PMID- 12407034
TI  - Culture of menstrual endometrium with peritoneal explants and mesothelial
      monolayers confirms attachment to intact mesothelial cells.
AB  - BACKGROUND: To evaluate adhesion of menstrual endometrium (ME) to intact
      peritoneal mesothelium. METHODS: Explants of peritoneum were cultured for 1 h
      with ME (n = 6). Specimens were serially sectioned for haematoxylin and eosin
      stain and immunohistochemistry using an anti-cytokeratin antibody to label
      mesothelium. Confocal laser scanning microscopy (CLSM) was performed to identify
      an intact layer of mesothelial cells (MC) underlying sites of ME attachment.
      Also, ME and MC were labelled with Cell-Tracker dyes. ME was cultured with
      mesothelial monolayers for 1 h (n = 10). Cultures were examined with differential
      interference contrast and CLSM. Optical sections were taken and a three
      dimensional model was constructed. RESULTS: In the peritoneal explants, ME
      adhered to intact mesothelium. There was no evidence of transmesothelial
      invasion. CLSM of sections of the explants demonstrated an intact monolayer of
      cytokeratin positive cells below the sites of ME implantation. Cytokeratin
      negative and positive ME cells adhered to mesothelial cells. Likewise, the ME
      attached to cultured mesothelium. Orthogonal sections and three-dimensional
      reconstruction confirmed an intact monolayer of mesothelium underlying ME
      attachment sites. CONCLUSIONS: This study confirms that ME adheres rapidly to
      intact peritoneal mesothelium. Further studies are needed that characterize the
      mechanisms of ME adhesion to, and migration through, mesothelial cells.

PMID- 12407035
TI  - Determination of bisphenol A concentrations in human biological fluids reveals
      significant early prenatal exposure.
AB  - BACKGROUND: There is broad human exposure to bisphenol A (BPA), an estrogenic
      endocrine-disrupting chemical widely used for the production of plastic products.
      BPA is reported to affect preimplantation embryos or fetuses and alter their
      postnatal development at doses typically found in the environment. We measured
      contamination of BPA in various kinds of human biological fluids by a novel
      enzyme-linked immunosorbent assay. METHODS: Blood samples were obtained from
      healthy premenopausal women, women with early and full-term pregnancy, and
      umbilical cord at full-term delivery. Ovarian follicular fluids obtained during
      IVF procedures and amniotic fluids obtained at mid-term and full-term pregnancy
      were also subject to BPA measurements. RESULTS: BPA was present in serum and
      follicular fluid at approximately 1-2 ng/ml, as well as in fetal serum and full
      term amniotic fluid, confirming passage through the placenta. Surprisingly, an
      approximately 5-fold higher concentration, 8.3 +/- 8.7 ng/ml, was revealed in
      amniotic fluid at 15-18 weeks gestation, compared with other fluids. CONCLUSION:
      These results suggest accumulation of BPA in early fetuses and significant
      exposure during the prenatal period, which must be considered in evaluating the
      potential for human exposure to endocrine-disrupting chemicals.

PMID- 12407036
TI  - Tailoring the GnRH antagonist cetrorelix acetate to individual patients' needs in
      ovarian stimulation for IVF: results of a prospective, randomized study.
AB  - INTRODUCTION: This study was performed to evaluate whether a tailored approach to
      the administration of the GnRH antagonist cetrorelix acetate according to
      follicular size leads to a reduction in the amount of Cetrotide vials used and/or
      an increased number of monitoring visits. METHODS: Sixty patients were
      prospectively randomized (using sealed envelopes) to receive either the fixed
      multiple dose antagonist protocol starting on day 6 of stimulation (group 1), or
      an individualized protocol with the time of antagonist start according to
      follicle size (14 mm, group 2), or an individualized single dose protocol (group
      3). Recombinant human (rh)FSH was used. The primary endpoints were the number of
      Cetrotide vials and number of monitoring visits. Statistical power for the
      parameter Cetrotide vials was 80%. RESULTS: Patients in group 1 needed
      significantly more Cetrotide vials (6.81 +/- 1.61) than patients of group 2 (4.59
      +/- 1.65; P < 0.01). The number of monitoring visits was similar between the
      three groups. Surprisingly, the number of retrieved oocytes was significantly
      higher in the individualized groups as compared with group 1. Despite a
      significantly lower total amount of rhFSH used, estradiol levels were
      significantly higher in group 2 as compared with group 1. CONCLUSION: Tailoring
      of GnRH antagonist protocols leads to an optimization of ovarian stimulation with
      more oocytes retrieved despite less rhFSH used, and the same number of monitoring
      visits.

PMID- 12407037
TI  - Percentile curves of serum estradiol levels during controlled ovarian stimulation
      in 905 cycles stimulated with recombinant FSH show that high estradiol is not
      detrimental to IVF outcome.
AB  - BACKGROUND: High, normal and poor responders are usually defined by reference to
      subjectively selected estradiol E2 levels at days 4-6 and the day of hCG
      administration (d-hCG). The purpose of this study was to use E2 percentile curves
      from day 5 until d-hCG to determine high, normal and poor responders, and to
      predict IVF outcome. METHODS: In this retrospective study, 762 patients underwent
      905 cycles with a GnRH agonist/recombinant FSH short protocol. They were divided
      into three groups according to their age. Percentile E2 curves according to E2
      levels were plotted. High responders were those patients with E2 levels above the
      90th percentile, normal responders had E2 between the 10th and 90th percentiles,
      and poor responders had E2 below the 10th percentile. RESULTS: IVF outcome,
      expressed as number of oocytes, total embryos obtained and number of high grade
      embryos, was significantly better for patients with E2 above the 90th percentile
      at d-hCG for the three age groups and at day 5 for group A (<35 years). Pregnancy
      rates were higher for high responders, but the difference did not reach
      statistical significance. CONCLUSIONS: Percentile curves can be useful in
      controlled ovarian stimulation cycles to define high, normal and poor responders,
      and also to predict IVF outcome.

PMID- 12407038
TI  - Long-term follow-up of patients with polycystic ovary syndrome after laparoscopic
      ovarian drilling: endocrine and ultrasonographic outcomes.
AB  - BACKGROUND: There is considerable controversy as to how long the beneficial
      effects of laparoscopic ovarian drilling (LOD) last. This follow-up study was
      undertaken to investigate the long-term effects of LOD. METHODS: The study
      included 116 anovulatory women with polycystic ovary syndrome (PCOS) who
      underwent LOD between 1991 and 1999 (study group) and 34 anovulatory PCOS women
      diagnosed during the same period, who had not undergone LOD (comparison group).
      The hospital records were reviewed and most patients attended for a transvaginal
      ultrasound scan and blood sampling to measure the serum concentrations of LH,
      FSH, testosterone, androstenedione and sex hormone-binding globulin. The results
      before and at different intervals, short- (<1 year), medium- (1-3 years) and long
      term (4-9 years), after LOD were compared. RESULTS: The LH:FSH ratio, mean serum
      concentrations of LH and testosterone and free androgen index decreased
      significantly after LOD and remained low during the medium- and long-term follow
      up periods. The mean ovarian volume decreased significantly (P < 0.05) from 11 ml
      before LOD to 8.5 ml at medium-term and remained low (8.4 ml) at long-term follow
      up. CONCLUSION: The beneficial endocrinological and morphological effects of LOD
      appear to be sustained for up to 9 years in most patients with PCOS.

PMID- 12407039
TI  - Pregnancy outcomes among women with polycystic ovary syndrome treated with
      metformin.
AB  - BACKGROUND: We sought to determine whether metformin, which had facilitated
      conception in 72 oligoamenorrhoeic women with polycystic ovary syndrome (PCOS),
      would safely reduce the rate of first trimester spontaneous abortion (SAB) and
      increase the number of live births without teratogenicity. METHODS: Seventy-two
      oligoamenorrheic women with PCOS conceived on metformin (2.55 g/day). They were
      prospectively assessed in an outpatient clinical research centre. Outcome
      measures included number of first trimester SAB, live births, normal ongoing
      pregnancies >or=13 weeks, gestational diabetes (GD), congenital defects (CD),
      birthweight and height, as well as weight, height, and motor and social
      development during the first 6 months of life. RESULTS: Of the 84 fetuses, to
      date there have been 63 normal live births without CD (75%), 14 first trimester
      SAB (17%), and seven ongoing pregnancies >or=13 weeks with normal sonograms
      without CD (8%). Previously, without metformin, 40 of the 72 women had 100
      pregnancies (100 fetuses) with 34 (34%) live births and 62 (62%) first trimester
      SAB. In current pregnancies on metformin in these 40 women (46 pregnancies, 47
      fetuses), there have been 33 live births (70%), two pregnancies ongoing >/=13
      weeks (4%), and 12 SAB (26%) (P < 0.0001). There was no maternal lactic acidosis,
      and no maternal or neonatal hypoglycaemia. Fasting entry serum insulin was a
      significant explanatory variable for total (previous and current) first trimester
      SAB, odds ratio 1.32 (for each 5 micro U/ml rise in insulin), 95% CI 1.09-1.60 (P
      = 0.005). On metformin, GD developed in 4% of pregnancies versus 26% of previous
      pregnancies without metformin, P = 0.025. There have been no major CD in the 63
      live births or CD by sonography in the seven fetuses <or=13 weeks. In the 63 live
      births, neither weight nor height differed from the normal neonatal population.
      At 6 month follow-up, height was greater (P = 0.008) and weight did not differ
      from the normal paediatric population; motor and social development were normal.
      CONCLUSIONS: Metformin therapy during pregnancy in women with PCOS was safely
      associated with reduction in SAB and in GD, was not teratogenic, and did not
      adversely affect birthweight or height, or height, weight, and motor and social
      development at 3 and 6 months of life.

PMID- 12407040
TI  - A prospective randomized study on the measured blood loss in medical termination
      of early pregnancy by three different misoprostol regimens after pretreatment
      with mifepristone.
AB  - BACKGROUND: Prolonged vaginal bleeding is a common complaint after medical
      abortion. The effect of a 1 week course of daily oral misoprostol after medical
      abortion with mifepristone and misoprostol on the amount of post-abortal blood
      loss was studied. METHODS: A total of 150 women (gestation <or=63 days) were
      randomized to three groups using computer-generated tables. They received 200 mg
      oral mifepristone, followed 48 h later by 0.8 mg oral misoprostol and vaginal
      placebo in group A, and 0.8 mg vaginal misoprostol and oral placebo in groups B
      and C. In groups A and B, the women continued with oral misoprostol 0.4 mg twice
      daily on days 4-10, while the women in group C took placebo. The actual blood
      loss was measured by the alkaline haematin method. RESULTS: No significant
      difference in the median amount (82.8, 94.7 and 88.5 ml for A, B and C
      respectively) and duration (16, 15 and 16 days respectively) of vaginal bleeding
      was observed. The incidence of diarrhoea was significantly higher (66, 55.1 and
      12.5% respectively) in the groups with oral misoprostol after abortion.
      CONCLUSION: A 1 week course of oral misoprostol (0.4 mg twice daily) could not
      decrease the duration and amount of vaginal bleeding. Further studies with a
      larger sample size are needed to assess whether the complete abortion rate can be
      improved with this regimen.

PMID- 12407041
TI  - Investigation of hormonal male contraception in African men: suppression of
      spermatogenesis by oral desogestrel with depot testosterone.
AB  - BACKGROUND: Suppression of spermatogenesis to azoospermia is required for
      effective hormonal male contraception, but the degree of suppression varies
      between ethnic groups. We here report the first study of hormonal suppression of
      spermatogenesis in two African centres using a regimen of oral progestogen with
      depot testosterone. METHODS A total of 31 healthy men (21 black) were recruited
      in Cape Town and 21 men in Sagamu, Nigeria. Subjects were randomized to take
      either 150 or 300 micro g desogestrel daily p.o. with testosterone pellets. In
      Cape Town, desogestrel was administered for 24 weeks with 400 mg testosterone re
      administered 12 weekly. In Sagamu, desogestrel was administered for 52 weeks with
      200 mg testosterone (later increased to 400 mg) re-administered 12-weekly.
      RESULTS: In Cape Town, 22 men completed at least 20 weeks treatment. Azoospermia
      was achieved in 8/10 and 8/12 men in the 150 micro g and 300 micro g desogestrel
      groups. Four men in Sagamu withdrew. Azoospermia was achieved in all 17 men in
      the two groups. There were no significant changes in lipoprotein or haemoglobin
      concentrations in any group. CONCLUSION: These data demonstrate that the
      combination of oral desogestrel with depot testosterone is an effective regimen
      for suppression of spermatogenesis in African as in Caucasian and Chinese men,
      with azoospermia achieved in a total of 83/98 (85%) men.

PMID- 12407042
TI  - The local progestational effect of the levonorgestrel-releasing intrauterine
      system: a sonographic and Doppler flow study.
AB  - BACKGROUND: We aimed to evaluate the effect of the levonorgestrel-releasing
      intrauterine system (LNG-IUS) on the uterine vasculature and the endometrium.
      METHODS: The study was a prospective controlled study evaluating the local
      effects of LNG-IUS compared with the copper intrauterine device (IUD). Forty
      seven women carrying LNG-IUS (group A) were compared with 35 women carrying
      copper IUD in a control group (group B). Clinical measures of menstrual bleeding,
      endometrial thickness and Doppler flow of the cervical branch of the uterine
      artery and spiral artery were evaluated and compared between the two groups.
      RESULTS: Doppler flow in the cervical branch of the uterine artery did not reveal
      any changes between the groups (resistance index = 0.6 +/- 0.01 in both groups).
      Endometrial width was significantly thinner in group A (4.1 +/- 0.2 mm) compared
      with group B (7.3 +/- 0.2 mm) (P < 0.0001). Subendometrial flow in the spiral
      artery was significantly reduced in 35 women of group A (75%) and in none of
      group B (P < 0.0001). CONCLUSIONS: The present study offers an explanation for
      the oligomenorrhoea in LNG-IUS users, i.e. a local progestational effect on the
      endometrium with no change in the blood flow in the uterine artery. This should
      be presented to the women in the pre-contraceptive counselling in order to lessen
      the discontinuation rate.

PMID- 12407043
TI  - A randomized double-blind comparison of perifollicular vascularity and
      endometrial receptivity in ovulatory women taking clomiphene citrate at two
      different times.
AB  - BACKGROUND: It is still controversial whether the day of clomiphene citrate
      initiation has any impact on the pregnancy rate. This study aimed to compare the
      perifollicular vascularity and endometrial receptivity of ovulatory women who
      started clomiphene citrate on day 2 and day 5. METHODS: Thirty-five women with
      regular ovulatory cycles were first monitored in a natural cycle and then
      randomized by computer-generated random numbers put in sealed opaque envelopes to
      receive 50 mg clomiphene citrate on days 2-6 or on days 5-9. The hormonal
      profile, the number of dominant follicles, the grading of perifollicular
      vascularity, endometrial thickness and Doppler flow indices of
      uterine/subendometrial arteries were compared between both groups. RESULTS: All
      the above parameters were similar for both groups on the day of the LH surge and
      7 days after the LH surge. CONCLUSIONS: There were no differences in oocyte
      quality graded by the perifollicular vascularity and the endometrial receptivity
      assessed by endometrial thickness and Doppler flow indices of uterine and
      subendometrial vessels when clomiphene citrate was started in regularly ovulatory
      women on day 2 or on day 5.

PMID- 12407044
TI  - The usefulness of ultrasound guidance in frozen-thawed embryo transfer: a
      prospective randomized clinical trial.
AB  - BACKGROUND: Recent randomized controlled trials have shown that implantation and
      pregnancy rates were improved with ultrasound-guided embryo transfer compared
      with clinical touch in fresh IVF cycles associated with supraphysiological
      ovarian steroid levels. However, the usefulness of ultrasound guidance in frozen
      thawed embryo transfer where potential hormonal influences are lacking has not
      been appropriately investigated. METHODS: A total of 184 consecutive patients
      undergoing thawed embryo transfer cycles with hormone replacement under pituitary
      suppression were randomized by computer-generated randomization table to two
      study groups: 93 had ultrasound-guided (group 1) and 91 had clinical touch (group
      2) embryo transfer. RESULTS: There was equal distribution between the two study
      groups with respect to the main demographic and baseline characteristics of the
      patients as well as the characteristics of both prior IVF cycles from which
      embryos were generated and cryopreserved-thawed embryo transfer cycles. However,
      both pregnancy and implantation rates in group 1 (34.4 and 19.8% respectively)
      were significantly higher than the corresponding values (19.7 and 11.9%) in group
      2. CONCLUSIONS: Ultrasound guidance in frozen-thawed embryo transfer
      significantly increases pregnancy and implantation rates.

PMID- 12407045
TI  - A health-economic decision-analytic model comparing double with single embryo
      transfer in IVF/ICSI.
AB  - BACKGROUND: Single embryo transfer (SET) is the sole strategy with which to
      reduce the incidence of twins following assisted reproductive technology (ART),
      but SET may increase the number of ART cycles needed per live-born child. Its
      cost-effectiveness compared with double embryo transfer (DET) is therefore
      unknown. METHODS: A decision-analytic model comparing SET with DET was developed.
      Estimates were obtained from literature, national pregnancy registers and local
      hospital records. A sensitivity analysis was performed, using pregnancy rates
      from four published studies. The outcome measure was the cost per child born,
      calculated from IVF procedure-related, pregnancy-related and neonatal care costs.
      Neonatal mortality and long-term morbidity costs were not taken into account.
      RESULTS: Independently of the pregnancy rates used, the SET cost per child born
      was in all instances the same as with DET, varying from EURO= 9520 (SET) versus
      EURO= 9511 (DET) to EURO= 12254 (SET) versus EURO= 12934 (DET). CONCLUSIONS: More
      ART cycles are required to obtain the same numbers of children born following SET
      compared with DET. Because SET allows the avoidance of twins and thus diminishes
      pregnancy-related and neonatal care costs, there is no difference in the cost per
      child born between SET and DET. The real advantage of SET is the avoidance of the
      very high long-term costs resulting from the increased morbidity of twins after
      birth.

PMID- 12407046
TI  - The course of pregnancy and delivery and the use of maternal healthcare services
      after standard IVF in Northern Finland 1990-1995.
AB  - BACKGROUND: The objective of this study was to evaluate the course of pregnancy
      and delivery and the use of maternal healthcare after IVF. METHODS: This
      population-based cohort study included all women who had undergone IVF treatment
      in Northern Finland leading to delivery in 1990-1995 (n = 225) and control
      pregnancies derived from the Finnish Medical Birth Register (n = 671) matched for
      sex of the child, year of birth, area, maternal age, parity, social class and
      fetal plurality. The analyses were stratified by plurality. Outcome measures were
      pregnancy complications, mode of delivery, gestational length and the level of
      use of antenatal care. RESULTS: The results showed an increased risk for vaginal
      bleeding throughout pregnancy [relative risk (RR) 4.1, 95% confidence interval
      (CI) 2.5-6.7 for singletons; RR 6.9, 95% CI 2.5-19.2 for twins], threatened
      preterm birth (RR 1.8, 95% CI 1.1-2.9, singletons) and intrahepatic cholestasis
      of pregnancy (RR 3.8, 95% CI 1.0-15.0, singletons) in IVF pregnancies, as well as
      an increase in the use of specialized antenatal care. CONCLUSIONS: IVF
      pregnancies following standard, fresh ova IVF treatments are at greater risk of
      obstetric problems than spontaneously conceived pregnancies, and hence IVF
      mothers use more specialized antenatal care than others. The pregnancy
      complications after IVF are likely to be due to maternal characteristics
      regarding infertility and to a high incidence of multiple pregnancies.

PMID- 12407047
TI  - The impact of epididymal and accessory sex gland function on sperm motility.
AB  - BACKGROUND: Little is known about the regulation of sperm motility, which is an
      important predictor of male fertility. However, both testicular and post
      testicular factors may be involved, although the impact of the latter has been
      relatively poorly investigated. METHODS: In semen samples from 301 young men from
      the general Swedish population (mean +/- SD age 18.2 +/- 0.4 years), we assessed
      sperm motility by use of a manual method as well as computer-assisted sperm
      analysis (CASA) and correlated these values to seminal levels of neutral alpha
      glucosidase (NAG), prostate-specific antigen (PSA), zinc and fructose. RESULTS:
      There were significant positive correlations between seminal levels of NAG, and
      PSA and CASA percentage motile sperm (r = 0.158, P = 0.009; r = 0.155, P = 0.01
      respectively), and significant negative correlations with CASA percentage
      immotile sperm (r = -0.206, P = 0.001; r = -0.157, P = 0.009 respectively). In a
      multiple regression analysis it was found that, apart from sperm concentration,
      the level of PSA was the most significant and independent parameter in predicting
      percentage motile sperm (beta = 0.220, P = 0.037). CONCLUSION: Our study
      demonstrated the regulatory effect of post-testicular glands on the motility of
      sperm. This is to our knowledge the first study showing a direct correlation
      between the seminal PSA levels and sperm motility in a group of men representing
      the general population. In future investigations and searches for specific
      treatment modalities in male infertility, more attention should be paid to the
      epididymis and accessory sex gland function.

PMID- 12407048
TI  - Assessment of sperm DNA integrity in workers exposed to styrene.
AB  - BACKGROUND: Occupational exposure to toxic agents may cause infertility,
      congenital anomalies or death in offspring, but few studies have evaluated DNA
      integrity in germ cells of male workers. We investigated sperm DNA integrity in
      individuals occupationally exposed to styrene. METHODS AND RESULTS: Semen samples
      were obtained from 46 male workers exposed to styrene and 27 unexposed controls
      (age range 18-45 years). Exposed individuals had worked for at least 2 years in
      the last 5 years and continuously for 6 months in factories producing reinforced
      plastics. The Comet assay was performed to evaluate DNA integrity in sperm, as
      well as semen quality analysis to assess sperm concentration and morphology.
      There were no differences in the results of the standard semen analysis between
      exposed subjects and the reference group. However, we found a significant
      difference (P < 0.001) in sperm DNA damage by the Comet assay between exposed
      subjects and the reference group. CONCLUSIONS: The Comet assay proved to be
      sensitive in detecting an alteration in DNA integrity in germ cells of workers
      exposed to styrene. This finding contributes towards the understanding of the
      importance of male occupational exposure within the context of genetic risk
      assessment in humans.

PMID- 12407049
TI  - Quantitative differences in matrix metalloproteinase (MMP)-2, but not in MMP-9,
      tissue inhibitor of metalloproteinase (TIMP)-1 or TIMP-2, in seminal plasma of
      normozoospermic and azoospermic patients.
AB  - BACKGROUND: Matrix metalloproteinases (MMPs) and their inhibitors, tissue
      inhibitors of metalloproteinases (TIMPs), have been detected in reproductive
      tissues and seminal plasma. The purpose of this study was to quantify MMP-2, MMP
      9, TIMP-1 and TIMP-2 in human seminal plasma and to evaluate their association
      with sperm. METHODS: Seminal plasma was analysed using ELISA assays for all four
      analytes in 12 normozoospermic and 12 azoospermic patients and then for MMP-2
      only in another 114 men with azoospermia (n = 16), after vasectomy (n = 20) and
      with sperm counts within the following ranges: 0.3-19 x 10(6)/ml (n = 20), 20-23
      x 10(6)/ml (n = 11), 49-57 x 10(6)/ml (n = 12), 96-110 x 10(6)/ml (n = 12), 139
      161 x 10(6)/ml (n = 12) and 215-346 x 10(6)/ml (n = 11). Additional zymographic
      analyses using SDS-PAGE were performed. RESULTS: All investigated MMPs and TIMPs
      were detected. MMP-9, TIMP-1 and TIMP-2 were not significantly different in
      normozoospermia and azoospermia. Only the MMP-2 concentration was significantly
      decreased in azoospermic compared with normozoospermic patients (mean +/- SD:
      650.6 +/- 288.9 versus 1677 +/- 910.4 ng/ml respectively; P = 0.0002) and
      significantly correlated with the number of sperm (r = 0.54; P < 0.0001).
      CONCLUSION: MMP-2 in seminal plasma was strongly correlated to the sperm count in
      a linear fashion. Its origin and potential function remain to be elucidated.

PMID- 12407050
TI  - Conventional multiple or microdissection testicular sperm extraction: a
      comparative study.
AB  - BACKGROUND: Testicular sperm extraction (TESE) with ICSI is becoming the first
      line treatment for non-obstructive azoospermia (NOA). Recently, the sperm
      retrieval rate (SRR) by microdissection TESE was reported to be higher than by
      conventional TESE. However, a comprehensive comparison between multiple and
      microdissection TESE patients including histological findings has not been
      reported. METHODS: Patients with NOA who underwent microdissection TESE (n = 56)
      or multiple TESE (n = 37) were compared. Pre-operative characteristics were
      similar between groups. In addition, microscopic findings during microdissection
      TESE also were investigated. RESULTS: Operative time was significantly longer for
      microdissection TESE than for multiple TESE. Histological examination suggested
      that spermatogenesis was relatively more impaired in the microdissection TESE
      group than in the multiple TESE group. Despite this, SRR by microdissection TESE
      (42.9%) appeared higher than by conventional TESE (35.1%) although this
      observation failed to reach statistical significance. Seventeen of 26 patients
      (65.4%) with heterogeneous tubule were successful for sperm retrieval. No severe
      operative complications occurred in any patient in either group, and no patient
      required post-operative hormone replacement to treat hypogonadism. CONCLUSIONS:
      Microsurgical technique is safe and may improve SRR for TESE in a variety of
      patients with NOA, especially patients with heterogeneous testicular tubules.

PMID- 12407051
TI  - Analysis of the human sperm centrosomal function and the oocyte activation
      ability in a case of globozoospermia, by ICSI into bovine oocytes.
AB  - BACKGROUND: Centrosomal function and oocyte activation ability of human sperm
      from a case of globozoospermia was assayed by heterologous ICSI into bovine
      oocytes. METHODS: Microtubules and chromatin configuration in bovine oocytes were
      examined by immunofluorescence after heterologous ICSI with human sperm from two
      fertile donors and from a globozoospermic man. RESULTS: The microtubule array
      from the sperm centrosome, the 'sperm aster' and the male pronucleus were
      observed in bovine oocytes, following ICSI with round-headed sperm from a
      globozoospermic man. The rate of sperm aster formation and the rate of male
      pronuclear formation in the bovine oocytes injected with fertile donor sperm were
      57.9 and 92.5% respectively; the respective values for oocytes injected with
      round-headed sperm without artificial oocyte activation were 15.8 and 31.0%.
      Ethanol activation after ICSI improved male pronuclear formation (84.9%) but not
      sperm aster formation rate (32.3%) of the globozoospermic patient. CONCLUSIONS:
      These data indicated that sperm from this patient with globozoospermia have
      centrosomal dysfunction and low ability for oocyte activation compared with
      fertile donor sperm. The centrosomal dysfunction may be one of the reasons for
      infertility in this patient.

PMID- 12407052
TI  - Aspermia and chronic testicular pain after imperforate anus correction.
      Cryopreservation of sperm cells extracted from whole orchiectomized testis: case
      report.
AB  - This paper describes an unusual association of aspermia and untreatable, chronic
      testicular pain in a young man who underwent 14 surgical interventions for an
      imperforate anus. Physical examination and ultrasonography revealed left
      epididymal and vas enlargement, normal-sized testes, tubular ectasia of the left
      rete testis and a small intraprostatic paramedian left cyst. Retrograde
      ejaculation and urogenital infections were excluded, and the FSH and karyotype
      results were normal. The patient gave his consent to an exploratory intervention
      with possible radical left orchiectomy. The patency of the left distal seminal
      duct was unexpectedly normal, and no sperm were found in the epididymis or vas
      deferens despite their obstructive appearance. Sperm were only found in a
      'testicular touch' preparation. The removed testis was immediately opened and
      most of the testicular lobules were removed, thus allowing the extraction of 25 x
      10(6) sperm, which were cryopreserved in 35 straws. An 8-month follow-up
      examination documented the complete absence of pain and, during the next few
      months, it is planned to use the thawed sperm for ICSI. Radical orchiectomy plus
      the cryopreservation of sperm extracted from the whole testis must be considered
      in the case of the co-existence of chronic unilateral testicular pain and
      aspermia.

PMID- 12407053
TI  - Calcium-binding proteins and calcium-release channels in human maturing oocytes,
      pronuclear zygotes and early preimplantation embryos.
AB  - BACKGROUND: The study aim was to investigate the presence and localization of
      Ca2+-binding proteins and Ca2+-release receptor channels in human maturing
      oocytes, pronuclear zygotes and preimplantation embryos. METHODS:
      Immunocytochemical analysis, using specific antibodies against the proteins being
      studied, followed with confocal laser microscopy, was performed on human oocytes
      and embryos. RESULTS: Calreticulin and calsequestrin (the two major calcium
      storage proteins of somatic cells), two types of calcium release receptors, the
      inositol trisphosphate and ryanodine receptors (InsP(3)R-2, RyRs-1,2,3), and the
      molecular chaperone, calnexin, were identified in all investigated cell types.
      Calreticulin was predominant in the cell cortex and in the nuclear envelope,
      while calsequestrin was distributed throughout the entire cytoplasm. Generally,
      localization of the InsP(3)R-2 and RyRs was similar to that of calreticulin and
      calsequestrin respectively. Both types of receptor were enriched in the
      subplasmalemmal region of meiotic oocytes. In addition, the InsP(3)R was detected
      in the nuclear structures of oocytes and blastomeres. Calnexin distribution
      overlapped with that of calreticulin but appeared to be present in distinct
      subcompartments. CONCLUSIONS: Human oocytes and embryos express the calcium
      sequestration and release proteins in highly organized and developmentally
      regulated patterns. Fine-tuning of these proteins may play a crucial role in
      regulation of Ca2+ transience during oocyte maturation, fertilization and early
      embryo development.

PMID- 12407054
TI  - Calcium signalling in human oocytes and embryos: two-store model revival.

PMID- 12407055
TI  - Culture environment modulates maturation and metabolism of human oocytes.
AB  - BACKGROUND: The clinical use of oocytes matured in vitro for IVF is increasing,
      but little is known about the effect of culture conditions on oocyte maturation.
      METHODS: Denuded immature oocytes identified following superovulation prior to
      ICSI were individually matured in one of two commercial media: tissue culture
      medium (TCM) 199 or modified Eagle medium with Earle's modified salts (MEME).
      During maturation, depletion of pyruvate and accumulation of lactate in the
      culture medium were non-invasively measured. RESULTS: Maturing oocytes took up
      pyruvate (20-30 pmol/oocyte/h) and produced lactate (2-10 pmol/oocyte/h). Oocytes
      matured faster in MEME, with significantly more oocytes reaching metaphase II by
      24 h after oocyte retrieval compared with TCM 199 (P = 0.03). The oocytes that
      matured more quickly in MEME had significantly lower lactate production than
      oocytes that matured more slowly (P = 0.02). In TCM 199, pyruvate uptake by
      rapidly maturing oocytes was lower than by slowly maturing oocytes (P = 0.05).
      During the second incubation, from 24 to 48 h post-oocyte retrieval, pyruvate
      uptake in MEME was 30% lower than in TCM 199 (P = 0.007). Pyruvate uptake and
      lactate production differed depending on the stage of nuclear maturation:
      pyruvate uptake and lactate production were greater during germinal vesicle
      breakdown than during polar body extrusion in MEME (P < 0.05). CONCLUSIONS: We
      have shown that: (i). pyruvate is a major energy source during oocyte maturation;
      (ii). the composition of the culture medium can affect the rate of maturation;
      and (iii). the culture medium and stage of nuclear maturation can affect pyruvate
      uptake and lactate production.

PMID- 12407056
TI  - Correlation between fluorescence in-situ hybridization analyses and in-vitro
      development to blastocyst stage of embryos from Robertsonian translocation
      (13;14) carriers.
AB  - BACKGROUND: Little is known about the extent and timing of selection against the
      embryos that are carriers of unbalanced translocations. METHODS: Fluorescence in
      situ hybridization (FISH) with probes for chromosomes 13, 14 and 18 was
      performed, mostly on day 3, on 69 human embryos which were then allowed to
      develop further in culture to day 5, from five carriers of Robertsonian
      translocation (RT) t(13;14). RESULTS: Twelve normal/balanced blastocysts were
      replaced in seven consecutive cycles (day 5). Three cycles resulted in clinical
      pregnancies. The proportion of blastocysts displaying a normal/balanced karyotype
      was 56%, while only the 20% of blocked embryos were normal/balanced (chi(2): P <
      0.05). All the embryos analysed on day 5, except one, displayed mosaicism. The
      percentages of diploid cells for chromosomes 13 and 14 were significantly lower
      than for chromosome 18 (chromosome 13: 49.0 +/- 28.0; chromosome 14: 53.0 +/-
      31.8; chromosome 18: 75.7 +/- 20.4; Mann-Whitney test: P < 0.01). The embryos
      displaying vertical line 62% of diploid cells for at least two of the three
      chromosomes analysed, more frequently reached the blastocyst stage (blocked
      embryos: blastocysts chromosome 13: 43.1 +/- 30.3, 64.9 +/- 29.0; chromosome 18:
      64.9 +/- 29.0, 83.0 +/- 12.9; Mann-Whitney test: P < 0.01). CONCLUSIONS:
      Normal/balanced embryos developed better but the proportion of abnormal
      blastocysts was still high. Preimplantation genetic diagnosis is recommended to
      select normal/balanced embryos from RT t(13;14) carriers.

PMID- 12407057
TI  - Ongoing twin pregnancy after vitrification of blastocysts produced by in-vitro
      matured oocytes retrieved from a woman with polycystic ovary syndrome: Case
      report.
AB  - This case report describes an ongoing pregnancy after cryopreservation of
      blastocysts produced by in-vitro matured oocytes retrieved from a woman with
      polycystic ovary syndrome (PCOS). Oocyte retrieval was performed on day 18. The
      patient was administered 10 000 IU of hCG s.c. 36 h prior to oocyte collection. A
      total of 61 immature oocytes was obtained. Following incubation for 24-72 h in
      the YS maturation medium supplemented with 30% follicular fluid (hFF), 1 IU/ml
      FSH, 10 IU/ml hCG and 10 ng/ml rhEGF, 65.6% (40/61) of the oocytes were at the
      metaphase II stage. Thirty-eight oocytes (38/40, 95.0%) were fertilized after
      ICSI with the patient's husband's sperm and the 2PN oocytes were co-cultured with
      cumulus cells in YS medium supplemented with 10% hFF. Four embryos were
      transferred into the uterus on day 4 following oocyte retrieval but this failed
      to result in pregnancy. Eight embryos were developed to expanded blastocyst
      stage. The blastocysts were vitrified on electron microscope grids. Two years
      after cryopreservation, four blastocysts were thawed, three re-expanded and these
      frozen-thawed blastocysts were transferred to the uterus. A viable twin pregnancy
      was confirmed by ultrasound scan.

PMID- 12407058
TI  - Operative morbidity and reproductive outcome in secondary myomectomy: a
      prospective cohort study.
AB  - BACKGROUND: This prospective study was designed to evaluate the operative
      morbidity and reproductive outcome in patients who had secondary myomectomy for
      recurrent symptomatic uterine fibroids. METHODS: A total of 58 women were
      subjected to a secondary myomectomy via the abdominal route. The operative
      morbidity such as blood loss, presence of adhesions and febrile index were
      estimated and the pregnancy outcome over a 2-4 year period of follow-up. RESULTS:
      The mean age and standard deviation (+/- SD) of the women was 35 (+/- 2.4) years.
      Nineteen patients (33%) had a postoperative temperature vertical line 100 degrees
      F and the estimated blood loss ranged from 159-2500 ml (median 700 ml). Seven
      patients (12%) required blood transfusion and one had a hysterectomy due to
      haemorrhage. Nine women (15.5%) became pregnant but only five (56%) had live
      births. Those with successful pregnancies tended to be younger with a mean age of
      31.8 (+/- 2.6) years versus 35 (+/- 1.8) years, (P = 0.08, non-significant) and
      had fewer uterine leiomyomata; median with range values, 2 (1-6) versus 7 (6-15).
      The variables which best predicted the postoperative likelihood of pregnancy
      were; age, presence of tubal adhesions and the number of uterine fibroids.
      CONCLUSION: This prospective study showed a high operative morbidity and a poor
      fertility outcome after a repeat myomectomy. The factors affecting successful
      outcome in a logistic regression model were age, tubal adhesions and number of
      uterine fibroids.

PMID- 12407059
TI  - Ischaemia-reperfusion injury of rat ovary and the effects of vitamin C, mannitol
      and verapamil.
AB  - BACKGROUND: In this prospective controlled study, the aim was to examine the
      effects of vitamin C, mannitol and verapamil on adnexial ischaemia-reperfusion
      injury in the rat ovary. METHODS: Thirty-six female Wistar rats were used. In the
      controls (group 1), only laparotomy was performed. In group 2, ovarian ischaemia
      was produced and the bilateral ovaries were surgically removed 4 h later. In
      group 3, an ischaemic period of 4 h was followed by reperfusion for 1 h; the
      bilateral ovaries were then removed. In groups 4, 5 and 6, after 4 h of
      ischaemia, either vitamin C, mannitol or verapamil respectively was infused
      before reperfusion; after 1 h of reperfusion the ovaries were removed.
      Thiobarbituric acid reactive substance (TBARS) levels were measured in all ovary
      tissues. RESULTS: TBARS levels of the reperfusion group were significantly higher
      than those of groups treated with vitamin C or mannitol (P = 0.013 and P = 0.045
      respectively), but not of the verapamil group. CONCLUSIONS: Vitamin C and
      mannitol were found to be effective in reducing ischaemia-reperfusion injury of
      the ovary during its early stages, but verapamil was ineffective.

PMID- 12407060
TI  - Endometrioma of uterine serosa in a woman with mosaic Turner's syndrome receiving
      hormone replacement therapy: case report.
AB  - Endometriosis in Turner's syndrome patients has only been reported in five
      isolated cases. We present here an endometrioma on the uterine serosa and pelvic
      endometriosis arising in a mosaic Turner's patient receiving hormone replacement
      therapy (HRT). The 24 year old patient with mosaic Turner's syndrome [45,X; 46,X
      pseudo dicentric Y (q11.23)], on cyclic HRT after laparoscopic gonadectomy 5
      years previously, was found to have an adnexal mass on routine examination. Given
      her history, due to the fear of a malignant process arising from a potential
      gonadal remnant, she underwent a laparoscopy and was found to have a 5 cm serosal
      endometrioma arising on a stalk from the uterine fundal surface as well as pelvic
      endometriosis. De-novo endometrioma and endometriosis occurred in a mosaic
      Turner's patient after gonadectomy on cyclic HRT. The presentation was also
      unusual with a pedunculated endometrioma arising from the uterine serosa. Due to
      the fact that the patient did have cyclic menstrual flow, her endometriosis may
      have arisen from retrograde menstruation or coelomic metaplasia induced by
      exogenous hormones.

PMID- 12407061
TI  - Antiphospholipid antibodies (APA) and recurrent pregnancy loss: treating a unique
      APA positive population.
AB  - BACKGROUND: Recurrent pregnancy loss (RPL) has been associated with
      antiphospholipid antibodies (APA) including anticardiolipin and lupus
      anticoagulant. Therapy using heparin and aspirin has been shown to significantly
      improve the live birth rate. We evaluated whether other APA should be considered
      as a basis for treatment in women with RPL. We also assessed the efficacy of
      heparin and aspirin therapy compared with aspirin alone in these women. METHODS:
      A two-centred, prospective, cohort evaluation of 79 women with two or more
      consecutive pregnancy losses who underwent a complete evaluation for RPL that was
      negative except for positive APA. Women with RPL and APA to cardiolipin (CL),
      phosphatidyl serine (PS) and/or lupus anticoagulant (LAC) treated with heparin
      and aspirin (group 1) were compared with those with other positive APA (to
      phosphatidyl inositol, phosphatidyl glycerol and/or phosphatidyl ethanolamine)
      treated with heparin or aspirin (group 2) or treated with aspirin alone (group
      3). RESULTS: There were no significant differences in patients' demographics
      between groups. There were 19 viable infants born to 25 women (76%) in group 1,
      18 viable infants born to the 28 women (64%) in group 2, and 12 viable infants
      born to the 26 women (46%) in group 3. Only the comparison between group 1 and
      group 3 reached statistical significance (P = 0.03). CONCLUSION: APA other than
      CL, PS and LAC may be associated with RPL.

PMID- 12407062
TI  - Anxiety, depression and anger suppression in infertile couples: a controlled
      study.
AB  - BACKGROUND: Although several authors have suggested an important pathogenic role
      for psychosocial factors in 'functional' infertility, the extent to which
      depression, anxiety and expressed emotional patterns correlate to infertility is
      not yet clear. METHODS: This study included 156 infertile couples (recruited at
      intake) and 80 fertile couples, whose personal characteristics were recorded.
      They were examined using scales for the evaluation of the degree of
      psychopathology [Hamilton Anxiety Rating Scale (HAM-A), Hamilton Depression
      Rating Scale (HAM-D)], and anger expression [State-Trait Anger Expression
      Inventory (STAXI)]. The 156 infertile couples were then subdivided into groups
      based on the cause of infertility ('organic', 'functional' or 'undetermined').
      The psychometric evaluation was double-blind with respect to the causes of
      infertility. RESULTS: Differences emerged in the degree of psychopathology
      between 'organic' and 'functional' infertile subjects and fertile controls. In
      women, logistic regression identified three variables able to predict the
      diagnosis subtype; these variables are HAM-A, HAM-D, and tendency toward anger
      suppression. In men, anger did not emerge as a predictor for diagnosis, whereas
      HAM-A and HAM-D did. CONCLUSIONS: The 'functional' infertile subjects of this
      sample showed particular psychopathological and psychological features,
      independent from the stress reaction following the identification of the cause of
      infertility.

PMID- 12407063
TI  - Using attitudinal indicators to explain the public's intention to have recourse
      to gamete donation and surrogacy.
AB  - BACKGROUND: Although the donation and receipt of gametes has become an integral
      part of infertility management, previous research in the field of social
      attitudes and intention to use medical technologies is limited. This study aimed
      to investigate attitudinal indicators and their potential relationship with the
      public's intention to have recourse to gamete donation and surrogacy. METHODS: A
      total of 365 individuals of reproductive age (49.3% men and 50.7% women)
      completed a questionnaire referring to their intention to receive or donate
      sperm/oocytes and their acceptance of becoming a commissioning couple or
      surrogate mother, and also to explore their attitudes towards gamete donation and
      surrogacy. Two attitudinal indicators emerged from the principal component
      analysis identifying (i). recipients' and donors' choice for anonymity, donors'
      renunciation of parental obligations and refusal of children's rights to know
      their biological parents and (ii). favourable attitudes towards legislative and
      financial measures to be adopted by the Government for the promotion of
      reproductive technologies. RESULTS: It was found that the indicator of 'Donors
      Anonymity and Refusal of Children's Rights' (DARCR) and the 'Legislative and
      Financial Support' (LFS) scale are positively associated with intention to have
      recourse to Gamete Donation and Surrogacy (GDS) (regression coefficients 0.31 and
      1.08 respectively). Moreover, among the other variables used in the analysis only
      the 'church attendance' variable is negatively related with reported rates of
      intention to have recourse to GDS (P = 0.029), suggesting that the more religious
      respondents are less willing to use GDS. CONCLUSION: Social, legislative and
      financial implications provide a convenient rationale for adopting a favourable
      intention towards reproductive technologies. The findings of the present research
      should be given close consideration by policy makers and health education
      campaigns.

PMID- 12407064
TI  - Reported relationship between increased CTG repeat lengths in myotonic dystrophy
      and azoospermia.

PMID- 12407065
TI  - Is the benefit of IUI really evidence-based?

PMID- 12407066
TI  - Neonatal outcome and congenital malformations in children born after IVF.

PMID- 12407070
TI  - Meiosis and Klinefelter's syndrome.

PMID- 12407071
TI  - Metformin and FSH for induction of ovulation in women with polycystic ovary
      syndrome.

PMID- 12407074
TI  - Hydrolyzable ATP and PIP(2) modulate the small-conductance K+ channel in apical
      membranes of rat cortical-collecting duct (CCD).
AB  - The small-conductance K+ channel (SK) in the apical membrane of the cortical
      collecting duct (CCD) is regulated by adenosine triphosphate (ATP) and
      phosphorylation-dephosphorylation processes. When expressed in Xenopus oocytes,
      ROMK, a cloned K+ channel similar to the native SK channel, can be stimulated by
      phosphatidylinositol bisphosphate (PIP2), which is produced by phosphoinositide
      kinases from phosphatidylinositol. However, the effects of PIP2 on SK channel
      activity are not known. In the present study, we investigated the mechanism by
      which hydrolyzable ATP prevented run-down of SK channel activity in excised
      apical patches of principal cells from rat CCD. Channel run-down was
      significantly delayed by pretreatment with hydrolyzable Mg-ATP, but ATP gamma S
      and AMP-PNP had no effect. Addition of alkaline phosphatase also resulted in loss
      of channel activity. After run-down, SK channel activity rapidly increased upon
      addition of PIP2. Exposure of inside-out patches to phosphoinositide kinase
      inhibitors (LY294002, quercetin or wortmannin) decreased channel activity by 74%
      in the presence of Mg-ATP. PIP2 added to excised patches reactivated SK channels
      in the presence of these phosphoinositide kinase inhibitors. The protein kinase A
      inhibitor, PKI, reduced channel activity by 36% in the presence of Mg-ATP. PIP2
      was also shown to modulate the inhibitory effects of extracellular and cytosolic
      ATP. We conclude that both ATP-dependent formation of PIP2 through membrane-bound
      phosphoinositide kinases and phosphorylation of SK by PKA play important roles in
      modulating SK channel activity.

PMID- 12407075
TI  - Membrane potential and bicarbonate secretion in isolated interlobular ducts from
      guinea-pig pancreas.
AB  - The interlobular duct cells of the guinea-pig pancreas secrete HCO(3)(-) across
      their luminal membrane into a HCO(3)(-)-rich (125 mM) luminal fluid against a
      sixfold concentration gradient. Since HCO(3)(-) transport cannot be achieved by
      luminal Cl-/HCO(3)(-) exchange under these conditions, we have investigated the
      possibility that it is mediated by an anion conductance. To determine whether the
      electrochemical potential gradient across the luminal membrane would favor
      HCO(3)(-) efflux, we have measured the intracellular potential (V(m)) in
      microperfused, interlobular duct segments under various physiological conditions.
      When the lumen was perfused with a 124 mM Cl- -25 mM HCO(3)(-) solution, a
      condition similar to the basal state, the resting potential was approximately -60
      mV. Stimulation with dbcAMP or secretin caused a transient hyperpolarization
      (approximately 5 mV) due to activation of electrogenic Na+-HCO(3)(-) cotransport
      at the basolateral membrane. This was followed by depolarization to a steady
      state value of approximately -50 mV as a result of anion efflux across the
      luminal membrane. Raising the luminal HCO(3)(-) concentration to 125 mM caused a
      hyperpolarization (approximately 10 mV) in both stimulated and unstimulated
      ducts. These results can be explained by a model in which the depolarizing effect
      of Cl- efflux across the luminal membrane is minimized by the depletion of
      intracellular Cl- and offset by the hyperpolarizing effects of Na+-HCO(3)(-)
      cotransport at the basolateral membrane. The net effect is a luminally directed
      electrochemical potential gradient for HCO(3)(-) that is sustained during maximal
      stimulation. Our calculations indicate that the electrodiffusive efflux of
      HCO(3)(-) to the lumen via CFTR, driven by this gradient, would be sufficient to
      fully account for the observed secretory flux of HCO(3)(-).

PMID- 12407076
TI  - Tracking voltage-dependent conformational changes in skeletal muscle sodium
      channel during activation.
AB  - The primary voltage sensor of the sodium channel is comprised of four positively
      charged S4 segments that mainly differ in the number of charged residues and are
      expected to contribute differentially to the gating process. To understand their
      kinetic and steady-state behavior, the fluorescence signals from the sites
      proximal to each of the four S4 segments of a rat skeletal muscle sodium channel
      were monitored simultaneously with either gating or ionic currents. At least one
      of the kinetic components of fluorescence from every S4 segment correlates with
      movement of gating charge. The fast kinetic component of fluorescence from sites
      S216C (S4 domain I), S660C (S4 domain II), and L1115C (S4 domain III) is
      comparable to the fast component of gating currents. In contrast, the fast
      component of fluorescence from the site S1436C (S4 domain IV) correlates with the
      slow component of gating. In all the cases, the slow component of fluorescence
      does not have any apparent correlation with charge movement. The fluorescence
      signals from sites reflecting the movement of S4s in the first three domains
      initiate simultaneously, whereas the fluorescence signals from the site S1436C
      exhibit a lag phase. These results suggest that the voltage-dependent movement of
      S4 domain IV is a later step in the activation sequence. Analysis of equilibrium
      and kinetic properties of fluorescence over activation voltage range indicate
      that S4 domain III is likely to move at most hyperpolarized potentials, whereas
      the S4s in domain I and domain II move at more depolarized potentials. The
      kinetics of fluorescence changes from sites near S4-DIV are slower than the
      activation time constants, suggesting that the voltage-dependent movement of S4
      DIV may not be a prerequisite for channel opening. These experiments allow us to
      map structural features onto the kinetic landscape of a sodium channel during
      activation.

PMID- 12407077
TI  - Probing an open CFTR pore with organic anion blockers.
AB  - The cystic fibrosis transmembrane conductance regulator (CFTR) is an ion channel
      that conducts Cl- current. We explored the CFTR pore by studying voltage
      dependent blockade of the channel by two organic anions: glibenclamide and
      isethionate. To simplify the kinetic analysis, a CFTR mutant, K1250A-CFTR, was
      used because this mutant channel, once opened, can remain open for minutes. Dose
      response relationships of both blockers follow a simple Michaelis-Menten function
      with K(d) values that differ by three orders of magnitude. Glibenclamide blocks
      CFTR from the intracellular side of the membrane with slow kinetics. Both the on
      and off rates of glibenclamide block are voltage dependent. Removing external Cl-
      increases affinity of glibenclamide due to a decrease of the off rate and an
      increase of the on rate, suggesting the presence of a Cl- binding site external
      to the glibenclamide binding site. Isethionate blocks the channel from the
      cytoplasmic side with fast kinetics, but has no measurable effect when applied
      extracellularly. Increasing the internal Cl- concentration reduces isethionate
      block without affecting its voltage dependence, suggesting that Cl- and
      isethionate compete for a binding site in the pore. The voltage dependence and
      external Cl- concentration dependence of isethionate block are nearly identical
      to those of glibenclamide block, suggesting that these two blockers may bind to a
      common binding site, an idea further supported by kinetic studies of blocking
      with glibenclamide/isethionate mixtures. By comparing the physical and chemical
      natures of these two blockers, we propose that CFTR channel has an asymmetric
      pore with a wide internal entrance and a deeply embedded blocker binding site
      where local charges as well as hydrophobic components determine the affinity of
      the blockers.

PMID- 12407078
TI  - Coupling between voltage sensors and activation gate in voltage-gated K+
      channels.
AB  - Current through voltage-gated K+ channels underlies the action potential encoding
      the electrical signal in excitable cells. The four subunits of a voltage-gated K+
      channel each have six transmembrane segments (S1-S6), whereas some other K+
      channels, such as eukaryotic inward rectifier K+ channels and the prokaryotic
      KcsA channel, have only two transmembrane segments (M1 and M2). A voltage-gated
      K+ channel is formed by an ion-pore module (S5-S6, equivalent to M1-M2) and the
      surrounding voltage-sensing modules. The S4 segments are the primary voltage
      sensors while the intracellular activation gate is located near the COOH-terminal
      end of S6, although the coupling mechanism between them remains unknown. In the
      present study, we found that two short, complementary sequences in voltage-gated
      K+ channels are essential for coupling the voltage sensors to the intracellular
      activation gate. One sequence is the so called S4-S5 linker distal to the voltage
      sensing S4, while the other is around the COOH-terminal end of S6, a region
      containing the actual gate-forming residues.

PMID- 12407080
TI  - Transport function of the renal type IIa Na+/P(i) cotransporter is codetermined
      by residues in two opposing linker regions.
AB  - Two highly similar regions in the predicted first intracellular (ICL-1) and third
      extracellular loop (ECL-3) of the type IIa Na+/P(i) cotransporter (NaPi-IIa) have
      been shown previously to contain functionally important sites by applying the
      substituted cysteine accessibility method (SCAM). Incubation in
      methanethiosulfonate (MTS) reagents of mutants that contain novel cysteines in
      both loops led to full inhibition of cotransport activity. To elucidate further
      the role these regions play in defining the transport mechanism, a double mutant
      (A203C-S460C) was constructed with novel cysteines in each region. The effect of
      cysteine modification by different MTS reagents on two electrogenic transport
      modes (leak and cotransport) was investigated. MTSEA (2-aminoethyl MTS
      hydrobromide) and MTSES (MTS ethylsulfonate) led to full inhibition of
      cotransport and increased the leak, whereas incubation in MTSET (2
      [trimethylammonium]ethyl MTS bromide) inhibited only cotransport. The behavior of
      other double mutants with a cysteine retained at one site and hydrophobic or
      hydrophilic residues substituted at the other site, indicated that most likely
      only Cys-460 was modifiable, but the residue at Ala-203 was critical for
      conferring the leak and cotransport mode behavior. Substrate interaction with the
      double mutant was unaffected by MTS exposure as the apparent P(i) and Na+
      affinities for P(i)-induced currents and respective activation functions were
      unchanged after cysteine modification. This suggested that the modified site did
      not interfere with substrate recognition/binding, but prevents translocation of
      the fully loaded carrier. The time-dependency of cotransport loss and leak growth
      during modification of the double cysteine mutant was reciprocal, which suggested
      that the modified site is a kinetic codeterminant of both transport modes. The
      behavior is consistent with a kinetic model for NaPi-IIa that predicts mutual
      exclusiveness of both transport modes. Together, these findings suggest that
      parts of the opposing linker regions are associated with the NaPi-IIa transport
      pathway.

PMID- 12407079
TI  - Ser165 in the second transmembrane region of the Kir2.1 channel determines its
      susceptibility to blockade by intracellular Mg2+.
AB  - The strong inward rectification of Kir2.1 currents is reportedly due to blockade
      of the outward current by cytoplasmic magnesium (Mg(2+)(i)) and polyamines, and
      is known to be determined in part by three negatively charged amino acid
      residues: Asp172, Glu224, and Glu299 (D172, E224, E299). Our aim was to identify
      additional sites contributing to the inward rectification of Kir2.1 currents. To
      accomplish this, we introduced into wild-type Kir2.1 and its D172N and D172N &
      E224G & E299S mutants various point mutations selected on the basis of a
      comparison of the sequences of Kir2.1 and the weak rectifier sWIRK. By analyzing
      macroscopic currents recorded from Xenopus oocytes using two-electrode voltage
      clamp, we determined that S165L mutation decreases inward rectification,
      especially with the triple mutant. The susceptibility to blockade by
      intracellular blockers was examined using HEK293 transfectants and the inside-out
      patch clamp configuration. The sensitivity to spermine was significantly
      diminished in the D172N and triple mutant, but not the S165L mutant. Both the
      S165L and D172N mutants were less susceptible to blockade by Mg(2+)(i) than the
      wild-type channel, and the susceptibility was still lower in the D172N & S165L
      double mutant. These results suggest that S165 is situated deeper into the pore
      from inside than D172, where it is accessible to Mg(2+)(i) but not to spermine.
      The single channel conductance of the D172N mutant was similar to that of the
      wild-type Kir2.1, whereas the conductance of the S165L mutant was significantly
      lower. Permeation by extracellular Rb+ (Rb(+)(o)) was dramatically increased by
      S165L mutation, but was increased only slightly by D172N mutation. By contrast,
      the Rb+/K+ permeability ratio was increased equally by D172N and S165L mutation.
      We therefore propose that S165 forms the narrowest part of the Kir2.1 pore, where
      both extracellular and intracellular blockers plug the permeation pathway.

PMID- 12407081
TI  - Regulation of AE2-mediated Cl- transport by intracellular or by extracellular pH
      requires highly conserved amino acid residues of the AE2 NH2-terminal cytoplasmic
      domain.
AB  - We reported recently that regulation by intracellular pH (pH(i)) of the murine Cl
      /HCO(3)(-) exchanger AE2 requires amino acid residues 310-347 of the
      polypeptide's NH(2)-terminal cytoplasmic domain. We have now identified
      individual amino acid residues within this region whose integrity is required for
      regulation of AE2 by pH. 36Cl- efflux from AE2-expressing Xenopus oocytes was
      monitored during variation of extracellular pH (pH(o)) with unclamped or clamped
      pH(i), or during variation of pH(i) at constant pH(o). Wild-type AE2-mediated
      36Cl- efflux was profoundly inhibited by acid pH(o), with a value of pH(o50) =
      6.87 +/- 0.05, and was stimulated up to 10-fold by the intracellular
      alkalinization produced by bath removal of the preequilibrated weak acid,
      butyrate. Systematic hexa-alanine [(A)6]bloc substitutions between aa 312-347
      identified the greatest acid shift in pH(o(50)) value, approximately 0.8 pH units
      in the mutant (A)6 342-347, but only a modest acid-shift in the mutant (A)6 336
      341. Two of the six (A)6 mutants retained normal pH(i) sensitivity of 36Cl-
      efflux, whereas the (A)6 mutants 318-323, 336-341, and 342-347 were not
      stimulated by intracellular alkalinization. We further evaluated the highly
      conserved region between aa 336-347 by alanine scan and other mutagenesis of
      single residues. Significant changes in AE2 sensitivity to pH(o) and to pH(i)
      were found independently and in concert. The E346A mutation acid-shifted the
      pH(o(0) value to the same extent whether pH(i) was unclamped or held constant
      during variation of pH(o). Alanine substitution of the corresponding glutamate
      residues in the cytoplasmic domains of related AE anion exchanger polypeptides
      confirmed the general importance of these residues in regulation of anion
      exchange by pH. Conserved, individual amino acid residues of the AE2 cytoplasmic
      domain contribute to independent regulation of anion exchange activity by pH(o)
      as well as pH(i).

PMID- 12407082
TI  - Structural and functional role of the extracellular s5-p linker in the HERG
      potassium channel.
AB  - C-type inactivation in the HERG channel is unique among voltage-gated K channels
      in having extremely fast kinetics and strong voltage sensitivity. This suggests
      that HERG may have a unique outer mouth structure (where conformational changes
      underlie C-type inactivation), and/or a unique communication between the outer
      mouth and the voltage sensor. We use cysteine-scanning mutagenesis and thiol
      modifying reagents to probe the structural and functional role of the S5-P
      (residues 571-613) and P-S6 (residues 631-638) linkers of HERG that line the
      outer vestibule of the channel. Disulfide formation involving introduced cysteine
      side chains or modification of side chain properties at "high-impact" positions
      produces a common mutant phenotype: disruption of C-type inactivation, reduction
      of K+ selectivity, and hyperpolarizing shift in the voltage-dependence of
      activation. In particular, we identify 15 consecutive positions in the middle of
      the S5-P linker (583-597) where side chain modification has marked impact on
      channel function. Analysis of the degrees of mutation-induced perturbation in
      channel function along 583-597 reveals an alpha-helical periodicity. Furthermore,
      the effects of MTS modification suggest that the NH2-terminal of this segment
      (position 584) may be very close to the pore entrance. We propose a structural
      model for the outer vestibule of the HERG channel, in which the 583-597 segment
      forms an alpha-helix. With the NH2 terminus of this helix sitting at the edge of
      the pore entrance, the length of the helix (approximately 20 A) allows its other
      end to reach and interact with the voltage-sensing domain. Therefore, the "583
      597 helix" in the S5-P linker of the HERG channel serves as a bridge of
      communication between the outer mouth and the voltage sensor, that may make
      important contribution to the unique C-type inactivation phenotype.

PMID- 12407084
TI  - Occlusion and temporomandibular disorders (TMD): still unsolved question?

PMID- 12407085
TI  - Effect of perfusion with water on demineralization of human dentin in vitro.
AB  - Dentinal fluid rarely features in caries studies of dentin. The mutual effects of
      in vitro perfusion and dentin demineralization were investigated. The correlation
      between the remaining dentin thickness and demineralization was also analyzed.
      Buccal cervical dentin windows in human tooth segments were demineralized either
      with or without perfusion with water at 3.14 kPa. Transverse microradiography
      revealed that dentin perfusion reduced the amount of mineral loss from the
      lesions by 22 vol%; the reduction in lesion depth was 8%. Perfusion rate, which
      was measured throughout the demineralization process by means of a fluid
      transport model, did not change significantly. Lesions formed closer to the pulp
      exhibited increased mineral loss and lesion depth. In conclusion, dentinal fluid
      flow offers some protection against demineralization. For a better approximation
      of clinical reality, therefore, in vitro studies on dentinal caries should
      consider the effect of dentinal fluid flow.

PMID- 12407083
TI  - Control of outer vestibule dynamics and current magnitude in the Kv2.1 potassium
      channel.
AB  - In Kv2.1 potassium channels, changes in external [K+] modulate current magnitude
      as a result of a K+-dependent interconversion between two outer vestibule
      conformations. Previous evidence indicated that outer vestibule conformation (and
      thus current magnitude) is regulated by the occupancy of a selectivity filter
      binding site by K+. In this paper, we used the change in current magnitude as an
      assay to study how the interconversion between outer vestibule conformations is
      controlled. With 100 mM internal K+, rapid elevation of external [K+] from 0 to
      10 mM while channels were activated produced no change in current magnitude
      (outer vestibule conformation did not change). When channels were subsequently
      closed and reopened in the presence of elevated [K+], current magnitude was
      increased (outer vestibule conformation had changed). When channels were
      activated in the presence of low internal [K+], or when K+ flow into conducting
      channels was transiently interrupted by an internal channel blocker, increasing
      external [K+] during activation did increase current magnitude (channel
      conformation did change). These data indicate that, when channels are in the
      activated state under physiological conditions, the outer vestibule conformation
      remains fixed despite changes in external [K+]. In contrast, when channel
      occupancy is lowered, (by channel closing, an internal blocker or low internal
      [K+]), the outer vestibule can interconvert between the two conformations. We
      discuss evidence that the ability of the outer vestibule conformation to change
      is regulated by the occupancy of a nonselectivity filter site by K+. Independent
      of the outer vestibule-based potentiation mechanism, Kv2.1 was remarkably
      insensitive to K+-dependent processes that influence current magnitude (current
      magnitude changed by <7% at membrane potentials between -20 and 30 mV).
      Replacement of two outer vestibule lysines in Kv2.1 by smaller neutral amino
      acids made current magnitude dramatically more sensitive to the reduction in K+
      driving force (current magnitude changed by as much as 40%). When combined, these
      outer vestibule properties (fixed conformation during activation and the presence
      of lysines) all but prevent variation in Kv2.1 current magnitude when [K+]
      changes during activation. Moreover, the insensitivity of Kv2.1 current magnitude
      to changes in K+ driving force promotes a more uniform modulation of current over
      a wide range of membrane potentials by the K+-dependent regulation of outer
      vestibule conformation.

PMID- 12407086
TI  - Autosomal-dominant hypoplastic form of amelogenesis imperfecta caused by an
      enamelin gene mutation at the exon-intron boundary.
AB  - Amelogenesis imperfecta (AI) is currently classified into 14 distinct subtypes
      based on various phenotypic criteria; however, the gene responsible for each
      phenotype has not been defined. We performed molecular genetic studies on a
      Japanese family with a possible autosomal-dominant form of AI. Previous studies
      have mapped an autosomal-dominant human AI locus to chromosome 4q11-q21, where
      two candidate genes, ameloblastin and enamelin, are located. We studied AI
      patients in this family, focusing on these genes, and found a mutation in the
      enamelin gene. The mutation detected was a heterozygous, single-G deletion within
      a series of 7 G residues at the exon 9-intron 9 boundary of the enamelin gene.
      The mutation was detected only in AI patients in the family and was not detected
      in other unaffected family members or control individuals. The male proband and
      his brother showed hypoplastic enamel in both their deciduous and permanent
      teeth, and their father showed local hypoplastic defects in the enamel of his
      permanent teeth. The clinical phenotype of these patients is similar to that of
      the first report of AI caused by an enamelin gene mutation. Thus, heterogeneous
      mutations in the enamelin gene are responsible for an autosomal-dominant
      hypoplastic form of AI.

PMID- 12407087
TI  - Mapping brain region activity during chewing: a functional magnetic resonance
      imaging study.
AB  - Mastication has been suggested to increase neuronal activities in various regions
      of the human brain. However, because of technical difficulties, the fine
      anatomical and physiological regions linked to mastication have not been fully
      elucidated. Using functional magnetic resonance imaging during cycles of rhythmic
      gum-chewing and no chewing, we therefore examined the interaction between chewing
      and brain regional activity in 17 subjects (aged 20-31 years). In all subjects,
      chewing resulted in a bilateral increase in blood oxygenation level-dependent
      (BOLD) signals in the sensorimotor cortex, supplementary motor area, insula,
      thalamus, and cerebellum. In addition, in the first three regions, chewing of
      moderately hard gum produced stronger BOLD signals than the chewing of hard gum.
      However, the signal was higher in the cerebellum and not significant in the
      thalamus, respectively. These results suggest that chewing causes regional
      increases in brain neuronal activities which are related to biting force.

PMID- 12407088
TI  - Disturbed jaw behavior in whiplash-associated disorders during rhythmic jaw
      movements.
AB  - As shown previously, "functional jaw movements" are the result of coordinated
      activation of jaw as well as neck muscles, leading to simultaneous movements in
      the temporomandibular, atlanto-occipital, and cervical spine joints. In this
      study, the effect of neck trauma on natural jaw function was evaluated in 12
      individuals suffering from whiplash-associated disorders (WAD). Spatiotemporal
      characteristics of mandibular and concomitant head movements were evaluated for
      three different modes of rhythmic jaw activities: self-paced continuous maximal
      jaw-opening/-closing movements, paced continuous maximal jaw-opening/-closing
      movements at 50 cycles/minute, and unilateral chewing. Compared with healthy
      subjects, the WAD group showed smaller magnitude and altered coordination pattern
      (a change in temporal relations) of mandibular and head movements. In conclusion,
      these results show that neck trauma can derange integrated jaw and neck behavior,
      and underline the functional coupling between the jaw and head-neck motor
      systems.

PMID- 12407089
TI  - Human masticatory muscle volume and zygomatico-mandibular form in adults with
      mandibular prognathism.
AB  - Although several investigators have reported associations between masticatory
      muscles and skeletal craniofacial form, there is no agreement on the association.
      We tested the hypothesis that masticatory muscle volume correlates with the size
      and form of the adjacent local skeletal sites. For this purpose, we investigated
      the morphological association of the cross-sectional area and volume of temporal
      and masseter muscles with zygomatico-mandibular skeletal structures using
      computerized tomography (CT) in 25 male adults with mandibular prognathism.
      Muscle variables significantly correlated with widths of the bizygomatic arch and
      temporal fossa but not with the cranium width. Masseter volume significantly
      correlated with cross-sectional areas of the zygomatic arch and mandibular ramus.
      Masseter orientation was almost perpendicular to the zygomatic arch and
      mandibular antegonial region. The zygomatic arch angle significantly correlated
      with the antegonial angle. The results of the study suggest that the masticatory
      muscles exert influence on the adjacent local skeletal sites.

PMID- 12407090
TI  - Immunolocalization of PTCH protein in odontogenic cysts and tumors.
AB  - The human patched gene (PTCH) functions in both embryologic development and tumor
      suppression. PTCH mutations have been found in odontogenic keratocysts. However,
      the expression and localization of the protein product of the gene have not been
      determined in odontogenic tumors and cysts. We investigated 68 odontogenic
      lesions by immunohistochemistry, and compared their PTCH expression with that in
      basal cell carcinomas. All odontogenic lesions, including two keratocysts with
      truncating mutations, were positive for PTCH. Different types of lesions had
      different amounts of staining. Lack of staining was noted in the majority of
      basal cell carcinomas. Taken together, these data suggest that odontogenic
      keratocysts arise with heterozygous mutations of the PTCH gene.

PMID- 12407091
TI  - Molecular and cultural analysis of the microflora associated with endodontic
      infections.
AB  - Cultural studies have indicated that a subset of the oral microflora is
      responsible for endodontic infections. Approximately 50% of oral bacteria are
      unculturable, so it is likely that currently unknown bacteria are present in such
      infections. In this study, cultural and molecular analyses were performed on the
      microflora in aspirate samples collected from 5 infected root canals. 16S rDNA
      sequences from 261 isolates and 624 clones were identified by comparison with
      database sequences. Sixty-five taxa were identified, of which 26 were found by
      the molecular method alone. A mean of 20.2 taxa was found in each sample. A new
      species of Dialister was the only organism present in all 5 samples. Twenty-seven
      novel taxa were detected, 18 of which belonged to the phylum Firmicutes and 8 to
      Bacteroidetes. Culture-independent, molecular analysis has revealed a more
      diverse microflora associated with endodontic infections than that revealed by
      cultural methods alone.

PMID- 12407092
TI  - Effectiveness of silver diamine fluoride and sodium fluoride varnish in arresting
      dentin caries in Chinese pre-school children.
AB  - Untreated dental caries in Chinese pre-school children is common. This
      prospective controlled clinical trial investigated the effectiveness of topical
      fluoride applications in arresting dentin caries. Three hundred seventy-five
      children, aged 3-5 years, with carious upper anterior teeth were divided into
      five groups. Children in the first and second groups received annual applications
      of silver diamine fluoride solution (44,800 ppm F). Sodium fluoride varnish
      (22,600 ppm F) was applied every three months to the lesions of children in the
      third and fourth groups. For children in the first and third groups, soft carious
      tissues were removed prior to fluoride application. The fifth group was the
      control. Three hundred eight children were followed for 30 months. The respective
      mean numbers of arrested carious tooth surfaces in the five groups were 2.5, 2.8,
      1.5, 1.5, and 1.3 (p < 0.001). Silver diamine fluoride was found to be effective
      in arresting dentin caries in primary anterior teeth in pre-school children.

PMID- 12407093
TI  - Gene expression and accumulation of fibrillin-1, fibrillin-2, and tropoelastin in
      cultured periodontal fibroblasts.
AB  - The elastic system fibers consist of three types--oxytalan, elaunin, and elastic
      fibers--differing in their relative microfibril and elastin contents. All three
      types are found in human gingiva, but human periodontal ligaments contain only
      elastin-free fibers. We examined cultured human gingival fibroblasts (HGF) and
      cultured human periodontal ligament fibroblasts (HPLF) to determine the gene
      expression of fibrillin-1 and fibrillin-2 (the major components of microfibrils)
      and of tropoelastin. In addition, we assessed the degree of accumulation of these
      proteins in the extracellular matrix. Northern blot analysis revealed that the
      level of expression of fibrillin-1 and fibrillin-2 was higher in HGF than in
      HPLF. However, examination of matrix samples from HGF and HPLF cell layers showed
      that there was no difference in fibrillin-1 accumulation, although fibrillin-2
      accumulated to a much greater extent in the HGF-derived matrix. Tropoelastin was
      expressed only in and around HGF. These results show a correlation between gene
      expression and the accumulation of tropoelastin and fibrillin-2 in HGF.

PMID- 12407094
TI  - Expression profiling of periodontal ligament cells stimulated with enamel matrix
      proteins in vitro: a model for tissue regeneration.
AB  - Several studies have examined the role of enamel matrix proteins in root
      formation and periodontal regeneration, although most of these have focused on a
      few specific genes which had previously been implicated. However, recent advances
      in expressional profiling have made it possible to examine the range of genetic
      responses involved in these processes. In the present experiments, we have
      therefore utilized this technique to determine the effects of enamel matrix
      proteins on the gene activities of periodontal ligament cells in vitro. Such
      cells were found to have an elevated level of RNA synthesis compared with control
      cells. Moreover, hybridization of the cDNA prepared from this RNA to gene array
      filters showed that there was differential expression of 121 genes, most of which
      had not previously been associated with periodontal regeneration. Some of these
      selective changes in gene activity might thus reflect the fundamental events that
      underlie periodontal development.

PMID- 12407095
TI  - A DNA vaccine encoding a cell-surface protein antigen of Streptococcus mutans
      protects gnotobiotic rats from caries.
AB  - A cell-surface protein antigen (PAc) of Streptococcus mutans is considered a
      virulence factor because it may mediate initial attachment of Streptococcus
      mutans to tooth surfaces. Thus, inhibiting PAc is predicted to provide protection
      against caries. To develop vaccines against dental caries, we constructed a DNA
      vaccine, pCIA-P, which encodes two high-conservative regions of PAc. Expression
      of the recombinant protein was obtained in eukaryotic cells in vitro and in vivo.
      In this report, we provide evidence that fewer caries lesions, and high levels of
      PAc-specific salivary IgA antibody and serum IgG antibody, were observed in
      gnotobiotic rats following targeted salivary gland (TSG) administration of pCIA
      P. This study shows that the recombinant DNA vaccine pCIA-P could induce
      protective anti-caries immune responses and that TSG immunization is a promising
      strategy for the inhibition of dental caries.

PMID- 12407096
TI  - Staurosporine mobilizes Ca(2+) from secretory granules by inhibiting protein
      kinase C in rat submandibular acinar cells.
AB  - Staurosporine was previously shown to mobilize Ca(2+) from the thapsigargin
      insensitive Ca(2+) store in rat submandibular acinar cells. However, the nature
      of the store is not yet known. Therefore, in the present study, the staurosporine
      releasable intracellular Ca(2+) store was characterized. Staurosporine increased
      the cytosolic Ca(2+) concentration ([Ca(2+)](c)) after the inositol 1,4,5
      trisphosphate (IP(3))-sensitive Ca(2+) store was depleted. Ionomycin caused only
      small increases in [Ca(2+)](c) after the depletion of the IP(3)-sensitive Ca(2+)
      store, whereas ionomycin+monensin caused large increases. However,
      ionomycin+monensin did not increase [Ca(2+)](c) when added after [Ca(2+)](c) was
      increased by staurosporine, indicating that the acidic Ca(2+) store was the main
      source of Ca(2+). The acidic Ca(2+) store appeared to be associated with
      secretory granules, since ionomycin+monensin- and staurosporine-induced
      [Ca(2+)](c) increases were significantly reduced when the acinar cells were
      degranulated. The effect of staurosporine on [Ca(2+)](c) was mimicked by other
      protein kinase C inhibitors. Therefore, we conclude that staurosporine mobilizes
      Ca(2+) from secretory granules, probably through the inhibition of protein kinase
      C in rat submandibular acinar cells.

PMID- 12407097
TI  - Dental fluorosis: variability among different inbred mouse strains.
AB  - Concurrent with the decline in dental caries has been an increase in the
      prevalence of dental fluorosis, a side-effect of exposure to greater than optimal
      levels of fluoride during amelogenesis. The mechanisms that underlie the
      pathogenesis of dental fluorosis are not known. We hypothesize that genetic
      determinants influence an individual's susceptibility or resistance to develop
      dental fluorosis. We tested this hypothesis using a mouse model system
      (continuous eruption of the incisors) where genotype, age, gender, food, housing,
      and drinking water fluoride level can be rigorously controlled. Examination of 12
      inbred strains of mice showed differences in dental fluorosis
      susceptibility/resistance. The A/J mouse strain is highly susceptible, with a
      rapid onset and severe development of dental fluorosis compared with that in the
      other strains tested, whereas the 129P3/J mouse strain is least affected, with
      minimal dental fluorosis. These observations support the contribution of a
      genetic component in the pathogenesis of dental fluorosis.

PMID- 12407098
TI  - Insulin-like growth factor-1 increases skeletal muscle dihydropyridine receptor
      alpha 1S transcriptional activity by acting on the cAMP-response element-binding
      protein element of the promoter region.
AB  - Previous work from our laboratory has shown that insulin-like growth factor 1
      (IGF-1) increases the expression of the skeletal muscle dihydropyridine receptor
      (DHPR) alpha(1) subunit by regulating DHPR alpha(1S) nuclear transcription. In
      this study, we investigated the mechanism by which IGF-1 enhances expression of
      the DHPR alpha(1S) gene. To this end, the promoter region of the mouse DHPR
      alpha(1S) gene was recently cloned and sequenced and various promoter deletion
      luciferase reporter constructs were used. These constructs were transfected into
      C2C12 cells and IGF-1 effects were measured by recording luciferase activity. IGF
      1 significantly enhanced DHPR alpha(1S) transcription in those constructs
      carrying cAMP-response element-binding protein (CREB) binding site but not in
      CREB core binding site mutants. Gel mobility shift assay using a double stranded
      oligonucleotide for the CREB site in the promoter region, and competition
      experiments with excess unlabeled or mutated promoter oligonucleotide, and
      unlabeled consensus CREB oligonucleotide demonstrated that IGF-1 induces CREB
      binding to the DHPR alpha(1S) promoter. IGF-1-mediated enhancement in charge
      movement was prevented by incubating the cells with antisense but not with sense
      oligonucleotides against CREB. These results support the conclusion that IGF-1
      regulates DHPR alpha(1S) transcription in muscle cells by acting on the CREB
      element of the promoter.

PMID- 12407099
TI  - Polycystin-1 activates and stabilizes the polycystin-2 channel.
AB  - Autosomal dominant polycystic kidney disease (ADPKD) is a prevalent genetic
      disorder largely caused by mutations in the PKD1 and PKD2 genes that encode the
      transmembrane proteins polycystin-1 and -2, respectively. Both proteins appear to
      be involved in the regulation of cell growth and maturation, but the precise
      mechanisms are not yet well defined. Polycystin-2 has recently been shown to
      function as a Ca(2+)-permeable, non-selective cation channel. Polycystin-2
      interacts through its cytoplasmic carboxyl-terminal region with a coiled-coil
      motif in the cytoplasmic tail of polycystin-1 (P1CC). The functional consequences
      of this interaction on its channel activity, however, are unknown. In this
      report, we show that P1CC enhanced the channel activity of polycystin-2. R742X, a
      disease-causing polycystin-2 mutant lacking the polycystin-1 interacting region,
      fails to respond to P1CC. Also, P1CC containing a disease-causing mutation in its
      coiled-coil motif loses its stimulatory effect on wild-type polycystin-2 channel
      activity. The modulation of polycystin-2 channel activity by polycystin-1 may be
      important for the various biological processes mediated by this molecular
      complex.

PMID- 12407100
TI  - Bile acids stimulate cFLIP phosphorylation enhancing TRAIL-mediated apoptosis.
AB  - Bile acids induce hepatocyte injury by enhancing death receptor-mediated
      apoptosis. In this study, bile acid effects on TRAIL-mediated apoptosis were
      examined to gain insight into bile acid potentiation of death receptor signaling.
      TRAIL-induced apoptosis of HuH-7 cells, stably transfected with a bile acid
      transporter, was enhanced by bile acids. Caspase 8 and 10 activation, bid
      cleavage, cytosolic cytochrome c, and caspase 3 activation by TRAIL were all
      increased by the bile acid glycochenodeoxycholate (GCDCA). GCDCA (100 microm) did
      not alter expression of TRAIL-R1/DR4, TRAIL-R2/DR5, procaspase 8, cFLIP-L, cFLIP
      s, Bax, Bcl-xL, or Bax. However, both caspase 8 and caspase 10 recruitment and
      processing within the TRAIL death-inducing signaling complex (DISC) were greater
      in GCDCA-treated cells whereas recruitment of cFLIP long and short was reduced.
      GCDCA stimulated phosphorylation of both cFLIP isoforms, which was associated
      with decreased binding to GST-FADD. The protein kinase C antagonist chelerythrine
      prevented bile acid-stimulated cFLIP-L and -s phosphorylation, restored cFLIP
      binding to GST-FADD, and attenuated bile acid potentiation of TRAIL-induced
      apoptosis. These results provide new insights into the mechanisms of bile acid
      cytotoxicity and the proapoptotic effects of cFLIP phosphorylation in TRAIL
      signaling.

PMID- 12407101
TI  - HIV-1 integrase forms stable tetramers and associates with LEDGF/p75 protein in
      human cells.
AB  - We studied human immunodeficiency virus, type 1 (HIV-1) integrase (IN) complexes
      derived from nuclei of human cells stably expressing the viral protein from a
      synthetic gene. We show that in the nuclear extracts IN exists as part of a large
      distinct complex with an apparent Stokes radius of 61 A, which dissociates upon
      dilution yielding a core molecule of 41 A. We isolated the IN complexes from
      cells expressing FLAG-tagged IN and demonstrated that the 41 A core is a tetramer
      of IN, whereas 61 A molecules are composed of IN tetramers associated with a
      cellular protein with an apparent molecular mass of 76 kDa. This novel integrase
      interacting protein was found to be identical to lens epithelium-derived growth
      factor (LEDGF/p75), a protein implicated in regulation of gene expression and
      cellular stress response. HIV-1 IN and LEDGF co-localized in the nuclei of human
      cells stably expressing IN. Furthermore, recombinant LEDGF robustly enhanced
      strand transfer activity of HIV-1 IN in vitro. Our findings indicate that the
      minimal IN molecule in human cells is a homotetramer, suggesting that at least an
      octamer of IN is required to accomplish coordinated integration of both
      retroviral long terminal repeats and that LEDGF is a cellular factor involved in
      this process.

PMID- 12407102
TI  - Soluble major histocompatibility complex-peptide octamers with impaired CD8
      binding selectively induce Fas-dependent apoptosis.
AB  - Fluorescence-labeled soluble major histocompatibility complex class I-peptide
      "tetramers" constitute a powerful tool to detect and isolate antigen-specific
      CD8(+) T cells by flow cytometry. Conventional "tetramers" are prepared by
      refolding of heavy and light chains with a specific peptide, enzymatic
      biotinylation at an added C-terminal biotinylation sequence, and
      "tetramerization" by reaction with phycoerythrin- or allophycocyanin-labeled
      avidin derivatives. We show here that such preparations are heterogeneous and
      describe a new procedure that allows the preparation of homogeneous tetra- or
      octameric major histocompatibility complex-peptide complexes. These compounds
      were tested on T1 cytotoxic T lymphocytes (CTLs), which recognize the Plasmodium
      berghei circumsporzoite peptide 252-260 (SYIPSAEKI) containing photoreactive 4
      azidobenzoic acid on Lys(259) in the context of H-2K(d). We report that mutation
      of the CD8 binding site of K(d) greatly impairs the binding of tetrameric but not
      octameric or multimeric K(d)-PbCS(ABA) complexes to CTLs. This mutation abolishes
      the ability of the octamer to elicit significant phosphorylation of CD3,
      intracellular calcium mobilization, and CTL degranulation. Remarkably, however,
      this octamer efficiently activates CTLs for Fas (CD95)-dependent apoptosis.

PMID- 12407103
TI  - Trans-Golgi network and subapical compartment of HepG2 cells display different
      properties in sorting and exiting of sphingolipids.
AB  - In HepG2 cells, the subapical compartment (SAC) is involved in the biogenesis of
      membrane polarity. By contrast, direct apical transport originating from the
      trans-Golgi network (TGN), which may contribute to polarity establishment, has
      been poorly defined in these cells. Thus, although newly synthesized
      sphingolipids can be directly transported from the TGN to the apical membrane,
      numerous apical resident proteins are traveling via the transcytotic route. Here,
      we developed an in vitro transport assay and compared the molecular sorting of 6
      [N-(7-nitrobenz-2-oxa-1,3 diazol-4-yl)amino] hexanoyl-sphingomyelin (C(6)NBD-SM)
      and C(6)NBD-glucosylceramide (C(6)NBD-GlcCer) in TGN and SAC. SM is released from
      both TGN and SAC in the lumenal leaflet of transport vesicles. This holds also
      for GlcCer released from the SAC but not for a substantial fraction that departed
      from the Golgi. Distinct transport vesicles, enriched in either SM or GlcCer are
      released from SAC, consistent with their rigid sorting in this compartment.
      Different vesicle populations could not be recovered from TGN, although in situ
      experiments reveal that GlcCer is preferentially transported to the apical
      membrane, reflecting different transport mechanisms. The results indicate that in
      HepG2 cells sphingolipids are mainly sorted in the SAC membrane and that the
      release of SM from SAC and TGN is differentially regulated.

PMID- 12407104
TI  - Protein kinase C phosphorylates protein kinase D activation loop Ser744 and
      Ser748 and releases autoinhibition by the pleckstrin homology domain.
AB  - Persistent activation of protein kinase D (PKD) via protein kinase C (PKC)
      mediated signal transduction is accompanied by phosphorylation at Ser(744) and
      Ser(748) located in the catalytic domain activation loop, but whether PKC
      isoforms directly phosphorylate these residues, induce PKD autophosphorylation,
      or recruit intermediate upstream kinase(s) is unclear. Here, we explore the
      mechanism whereby PKC activates PKD in response to cellular stimuli. We first
      assessed in vitro PKC-PKD transphosphorylation and PKD activation. A PKD738-753
      activation loop peptide was well phosphorylated by immunoprecipitated PKC
      isoforms, consistent with similarities between the loop and their known substrate
      specificities. A similar peptide with glutamic acid replacing Ser(748) was
      preferentially phosphorylated by PKCepsilon, suggesting that PKD containing
      phosphate at Ser(748) is rapidly targeted by this isoform at Ser(744). When
      incubated in the presence of phosphatidylserine, phorbol 12,13-dibutyrate and
      ATP, intact PKD slowly autophosphorylated in the activation loop but only at
      Ser(748). In contrast, addition of purified PKCepsilon to the incubation mixture
      induced rapid Ser(744) and Ser(748) phosphorylation, concomitant with persistent
      2-3-fold increases in PKD activity, measured using reimmunoprecipitated PKD to
      phosphorylate an exogenous peptide, syntide-2. We also further examined
      pleckstrin homology domain-mediated PKD regulation to determine its relationship
      with activation loop phosphorylation. The high constitutive activity of the
      pleckstrin homology (PH) domain deletion mutant PKD-deltaPH was not abrogated by
      mutation of Ser(744) and Ser(748) to alanines, suggesting that one function of
      activation loop phosphorylation in the PKD activation mechanism is to relieve
      autoinhibition by the PH domain. These studies provide evidence of a direct
      PKCepsilon-PKD phosphorylation cascade and provide additional insight into the
      activation mechanism.

PMID- 12407105
TI  - Pho85 phosphorylates the Glc7 protein phosphatase regulator Glc8 in vivo.
AB  - The budding yeast Glc7 serine/threonine protein phosphatase-1 is regulated by
      Glc8, the yeast ortholog of mammalian phosphatase inhibitor-2. In this work, we
      demonstrated that similarly to inhibitor-2, Glc8 function is regulated by
      phosphorylation. The cyclin-dependent protein kinase, Pho85, in conjunction with
      the related cyclins Pcl6 and Pcl7 comprise the major Glc8 kinase in vivo and in
      vitro. Several glc7 mutations are dependent on the presence of Glc8 for
      viability. For example, glc7 alleles R121K, R142H, and R198D are lethal in
      combination with a glc8 deletion. We found that glc7-R121K is lethal in
      combination with a pho85 deletion. This finding indicates that Pho85 is the sole
      Glc8 kinase in vivo. Furthermore, glc7-R121K is also lethal when combined with
      deletions of pcl6, plc7, pcl8, and pcl10, indicating that these related cyclins
      redundantly activate Pho85 for Glc8 phosphorylation in vivo. In vitro kinase
      assays and genetic results indicate that Pho85 cyclins Pcl6 and Pcl7 comprise the
      predominant Glc8 kinase.

PMID- 12407106
TI  - Early mitochondrial activation and cytochrome c up-regulation during apoptosis.
AB  - Apoptosis induced by many stimuli requires the mitochondrial respiratory chain
      (MRC) function. While studying the molecular mechanisms underlying this MRC
      dependent apoptotic pathway, we find that apoptosis in multiple cell types
      induced by a variety of stimuli is preceded by an early induction of MRC proteins
      such as cytochrome c (which is encoded by a nuclear gene) and cytochrome c
      oxidase subunit II (COX II) (which is encoded by the mitochondrial genome).
      Several non-MRC proteins localized in the mitochondria, e.g. Smac, Bim, Bak, and
      Bcl-2, are also rapidly up-regulated. The up-regulation of many of these proteins
      (e.g. cytochrome c, COX II, and Bim) results from transcriptional activation of
      the respective genes. The up-regulated cytosolic cytochrome c rapidly
      translocates to the mitochondria, resulting in an accumulation of holocytochrome
      c in the mitochondria accompanied by increasing holocytochrome c release into the
      cytosol. The increased cytochrome c transport from cytosol to the mitochondria
      does not depend on the mitochondrial protein synthesis or MRC per se. In
      contrast, cytochrome c release from the mitochondria involves dynamic changes in
      Bcl-2 family proteins (e.g. up-regulation of Bak, Bcl-2, and Bcl-x(L)), opening
      of permeability transition pore, and loss of mitochondrial membrane potential.
      Overexpression of cytochrome c enhances caspase activation and promotes cell
      death in response to apoptotic stimulation, but simple up-regulation of
      cytochrome c using an ecdysone-inducible system is, by itself, insufficient to
      induce apoptosis. Taken together, these results suggest that apoptosis induced by
      many stimuli involves an early mitochondrial activation, which may be responsible
      for the subsequent disruption of MRC functions, loss of Deltapsi(m), cytochrome c
      release, and ultimately cell death.

PMID- 12407107
TI  - The SET protein regulates G2/M transition by modulating cyclin B-cyclin-dependent
      kinase 1 activity.
AB  - The SET protein and the cell cycle inhibitor p21(Cip1) interact in vivo and in
      vitro. We identified here the domain (157)LIF(159) of p21(Cip1) as essential for
      the binding of SET. We also found that SET contains at least two domains of
      interaction with p21(Cip1), one located in the fragment amino acids 81-180 and
      the other one in the fragment including amino acids 181-277. SET and p21(Cip1) co
      localize in the cell nucleus in a temporal manner. Overexpression of SET blocks
      the cell cycle at the G(2)/M transition in COS and HCT116 cells. Moreover, SET
      inhibits cyclin B-CDK1 activity both in vivo and in vitro in both cell types.
      This effect is specific for these complexes since SET did not inhibit either
      cyclin A-CDK2 or cyclin E-CDK2 complexes. SET and p21(Cip1) cooperate in the
      inhibition of cyclin B-CDK1 activity. The inhibitory effect of SET resides in its
      acidic C terminus, as demonstrated by the ability of this domain to inhibit
      cyclin B-CDK1 activity and by the lack of blocking G(2)/M transition when a
      mutated form of SET lacking this C terminus domain was overexpressed in COS
      cells. These results indicate that SET might regulate G(2)/M transition by
      modulating cyclin B-CDK1 activity.

PMID- 12407108
TI  - Posttranscriptional control of the expression and function of diacylglycerol
      acyltransferase-1 in mouse adipocytes.
AB  - Acyl-CoA:diacylglycerol acyltransferase-1 (DGAT1) catalyzes the final step of
      triglyceride synthesis in mammalian cells. Data obtained from DGAT1-knockout mice
      have indicated that this enzyme plays an important role in energy homeostasis. We
      investigated the regulation of the expression and function of DGAT1 in mouse 3T3
      L1 cell as a model for mammalian adipocytes. We demonstrated that the DGAT1
      protein level increased by approximately 90-fold following differentiation of 3T3
      L1 into mature adipocytes, a change that was accompanied by approximately 7-fold
      increase in DGAT1 mRNA. On the other hand, forced overexpression of DGAT1 mRNA by
      >20-fold via a recombinant adenovirus only resulted in approximately 2-fold
      increase in DGAT1 protein in mature adipocytes and little increase in
      preadipocytes. These results indicated that gene expression of DGAT1 in
      adipocytes is subjected to rigorous posttranscriptional regulation, which is
      modulated significantly by the differentiation status of 3T3-L1 cells. Protein
      stability is not a significant factor in the control of DGAT1 expression. The
      steady-state levels of DGAT1 were unaffected by blockage of proteolytic pathways
      by ALLN. However, translational control was suggested by sequence analysis of the
      5'-untranslated region of human DGAT1 (hDGAT1) mRNA. We found that the level of
      DGAT1 activity was predominantly a function of the steady-state level of DGAT1
      protein. No significant functional changes were observed when the conserved
      tyrosine phosphorylation site in hDGAT1 was mutated by a single base pair
      substitution. Despite only a approximately 2-fold increase in DGAT1 protein
      caused by recombinant viral transduction, a proportionate increase in cellular
      triglyceride synthesis resulted without affecting the triglyceride lipolysis
      rate, leading to >2-fold increase in intracellular triglyceride accumulation. No
      change in adipocyte morphology or in the expression levels of lipoprotein lipase,
      proxisomal proliferation-activating receptor-gamma, and aP2 was evident secondary
      to DGAT1 overexpression at different stages in 3T3-L1 differentiation. These data
      suggest that dysregulation of DGAT1 may play a role in the development of
      obesity, and manipulation of the steady-state level of DGAT1 protein may offer a
      potential means to treat or prevent obesity.

PMID- 12407109
TI  - The protein kinase C beta II exon confers mRNA instability in the presence of
      high glucose concentrations.
AB  - Previous studies showed that short term exposure of cells to high glucose
      destabilized protein kinase C (PKC) betaII mRNA, whereas PKCbetaI mRNA levels
      remained unaltered. Because PKCbeta mRNAs share common sequences other than the
      PKCbetaII exon encoding a different carboxyl terminus, we examined PKCbetaII mRNA
      for a cis-acting region that could confer glucose-induced destabilization. A beta
      globin/growth hormone reporter con struct containing the PKCbetaII exon was
      transfected into human aorta and rat vascular smooth muscle cells (A10) to follow
      glucose-induced destabilization. Glucose (25 mm) exposure destabilized PKCbetaII
      chimeric mRNA but not control mRNA. Deletion analysis and electrophoretic
      mobility shift assays followed by UV cross-linking experiments demonstrated that
      a region introduced by inclusion of the betaII exon was required to confer
      destabilization. Although a cis-acting element mapped to 38 nucleotides within
      the betaII exon was necessary to bestow destabilization, it was not sufficient by
      itself to confer complete mRNA destabilization. Yet, in intact cells antisense
      oligonucleotides complementary to this region blocked glucose-induced
      destabilization. These results suggest that this region must function in context
      with other sequence elements created by exon inclusion involved in affecting mRNA
      stability. In summary, inclusion of an exon that encodes PKCbetaII mRNA
      introduces a cis-acting region that confers destabilization to the mRNA in
      response to glucose.

PMID- 12407110
TI  - Identification of sequence motifs responsible for the adhesive interaction
      between exon v10-containing CD44 isoforms.
AB  - Previous studies have demonstrated that CD44 isoforms containing the
      alternatively spliced exon v10 promote cell-cell adhesion via a mechanism that
      involves the recognition of chondroitin sulfate side chains presented on the
      surface of interacting cells in association with other CD44 molecules. Sequence
      analysis revealed the presence within exon v10 of two motifs that may be relevant
      to this interaction, a B[X(7)]B motif that may contribute to the recognition and
      binding of chondroitin sulfate and a serine-glycine motif that may serve as a
      site of chondroitin sulfate attachment. To determine whether either of these two
      motifs explain the unique adhesive activity of exon v10-containing CD44 isoforms,
      each was targeted by site-directed mutagenesis, and the adhesive activity of the
      resultant mutants was determined using a quantitative cell-cell binding assay.
      The data obtained demonstrate conclusively that it is the exon v10-encoded
      B[X(7)]B motif that is solely responsible for the enhanced adhesive activity of
      exon v10-containing CD44 isoforms.

PMID- 12407111
TI  - The central domain is required to target and anchor perilipin A to lipid
      droplets.
AB  - The perilipins are the most abundant proteins coating the surfaces of lipid
      droplets in adipocytes and are found at lower levels surrounding lipid droplets
      in steroidogenic cells. Perilipins drive triacylglycerol storage in adipocytes by
      regulating the rate of basal lipolysis and are also required to maximize
      hormonally stimulated lipolysis. To map the domains that target and anchor
      perilipin A to lipid droplets, we stably expressed fragments of perilipin A in
      3T3-L1 fibroblasts. Immunofluorescence microscopy and immunoblotting of proteins
      from isolated lipid droplets revealed that neither the amino nor the carboxyl
      terminus is required to target perilipin A to lipid droplets; however, there are
      multiple, partially redundant targeting signals within a central domain including
      25% of the primary amino acid sequence. A peptide composed of the central domain
      of perilipin A directed a fused green fluorescent protein to the surfaces of
      lipid droplets. Full-length perilipin A associates with lipid droplets via
      hydrophobic interactions, as shown by the persistence of perilipins on lipid
      droplets after centrifugation through an alkaline carbonate solution. Results of
      the mutagenesis studies indicate that the sequences responsible for anchoring
      perilipin A to lipid droplets are most likely domains of moderately hydrophobic
      amino acids located within the central 25% of the protein. Thus, we conclude that
      the central 25% of the perilipin A sequence contains all of the amino acids
      necessary to target and anchor the protein to lipid droplets.

PMID- 12407112
TI  - Differential expression of tapasin and immunoproteasome subunits in adenovirus
      type 5- versus type 12-transformed cells.
AB  - Adenovirus type 12 (Ad12)-transformed baby rat kidney (BRK) cells are oncogenic
      in syngeneic immunocompetent rats in contrast to adenovirus type 5 (Ad5)
      transformed BRK cells, which are not oncogenic in these animals. A significant
      factor contributing to the difference in oncogenicity may be the low levels of
      major histocompatibility complex (MHC) class I membrane expression in Ad12
      transformed BRK cells as compared with those in Ad5-transformed BRK cells, which
      presumably results in escape from killing by cytotoxic T lymphocytes. Here we
      show that, in addition to the decreased levels of expression of the MHC class I
      heavy chain and the peptide transporter Tap-2, the expression levels of the
      chaperone Tapasin and the immunoproteasome components MECL-1, PA28-alpha, and
      PA28-beta also are much lower in Ad12- than in Ad5-transformed BRK cells. The low
      expression levels of these proteins may contribute to the escape from killing by
      cytotoxic T lymphocytes, because the generation of optimal peptides and loading
      of these peptides on MHC class I require these components. Increased levels of
      phosphorylated signal transducer and activator of transcription-1 protein and
      expression of IFN regulatory factor-7 were found in Ad5- versus Ad12-transformed
      BRK cells. Therefore, the critical alteration leading to the plethora of
      differences may be an interferon (-related) effect.

PMID- 12407113
TI  - A selective role for phosphatidylinositol 3,4,5-trisphosphate in the Gi-dependent
      activation of platelet Rap1B.
AB  - The small GTP-binding protein Rap1B is activated in human platelets upon
      stimulation of a G(i)-dependent signaling pathway. In this work, we found that
      inhibition of platelet adenylyl cyclase by dideoxyadenosine or SQ22536 did not
      cause activation of Rap1B and did not restore Rap1B activation in platelets
      stimulated by cross-linking of Fcgamma receptor IIA (FcgammaRIIA) in the presence
      of ADP scavengers. Moreover, elevation of the intracellular cAMP concentration
      did not impair the G(i)-dependent activation of Rap1B. Two unrelated inhibitors
      of phosphatidylinositol 3-kinase (PI3K), wortmannin and LY294002, totally
      prevented Rap1B activation in platelets stimulated by cross-linking of
      FcgammaRIIA, by stimulation of the P2Y(12) receptor for ADP, or by epinephrine.
      However, in platelets from PI3Kgamma-deficient mice, both ADP and epinephrine
      were still able to normally stimulate Rap1B activation through a PI3K-dependent
      mechanism, suggesting the involvement of a different isoform of the enzyme.
      Moreover, the lack of PI3Kgamma did not prevent the ability of epinephrine to
      potentiate platelet aggregation through a G(i)-dependent pathway. The inhibitory
      effect of wortmannin on Rap1B activation was overcome by addition of
      phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P(3)), but not
      PtdIns(3,4)P(2), although both lipids were found to support phosphorylation of
      Akt. Moreover, PtdIns(3,4,5)P(3) was able to relieve the inhibitory effect of
      apyrase on FcgammaRIIA-mediated platelet aggregation. We conclude that
      stimulation of a G(i)-dependent signaling pathway causes activation of the small
      GTPase Rap1B through the action of the PI3K product PtdIns(3,4,5)P(3), but not
      PtdIns(3,4)P(2), and that this process may contribute to potentiation of platelet
      aggregation.

PMID- 12407114
TI  - Cloning and characterization of a new human UDP-N-acetyl-alpha-D
      galactosamine:polypeptide N-acetylgalactosaminyltransferase, designated pp-GalNAc
      T13, that is specifically expressed in neurons and synthesizes GalNAc alpha
      serine/threonine antigen.
AB  - To date, 10 members of the UDP-N-acetyl-alpha-d-galactosamine:polypeptide N
      acetylgalactosaminyltransferase (pp-GalNAc-T) family have been cloned and
      analyzed in human. In this study, we cloned and analyzed a novel human pp-GalNAc
      T from an NT2 cell cDNA library, and we named it pp-GalNAc-T13. In amino acid
      sequences, pp-GalNAc-T13 was highly homologous, showing 84.3% identity, to pp
      GalNAc-T1. Real time PCR analysis revealed pp-GalNAc-T13 to be highly and
      restrictively expressed in the brain and present at very low or undetectable
      levels in other tissues, in contrast to the ubiquitous expression of pp-GalNAc
      T1. pp-GalNAc-T13 was abundantly expressed in all neuroblastoma cells examined
      and primary cultured neurons but not in glioblastoma cells and primary cultured
      astrocytes. pp-GalNAc-T13 exhibited much stronger activity to transfer GalNAc to
      mucin peptides, such as Muc5Ac and MUC7, than did pp-GalNAc-T1. In addition, pp
      GalNAc-T13 differed in substrate specificity to pp-GalNAc-T1. pp-GalNAc-T13 was
      able to form a triplet Tn epitope, three consecutive GalNAc-Ser/Thr structures,
      on peptides encoded in syndecan-3, a proteoglycan expressed in neurons. pp-GalNAc
      T13-deficient mice have been established in a previous work. Immunohistochemical
      study showed a remarkable decrease in Tn antigen expression in the cerebellum of
      the pp-GalNAc-T13 knockout mouse. pp-GalNAc-T13 would be a major enzyme
      responsible for the synthesis of O-glycan and specifically the Tn antigen epitope
      in neurons.

PMID- 12407115
TI  - Modulation of thrombomodulin-dependent activation of human protein C through
      differential expression of endothelial Smads.
AB  - Protein C is a plasma protease that in its active form plays a central role in
      the regulation of vascular function by modulating thrombosis, inflammation, and
      apoptosis. A central player in this pathway is the cytokine-regulated receptor
      thrombomodulin (TM), which functions as a co-factor for the thrombin-dependent
      generation of activated protein C. We have found that tumor necrosis factor-beta
      (TGF-beta)-dependent suppression of TM on endothelial cells is differentially
      regulated by endothelial Smad6s and Smad7. Overexpression of Smad6s resulted in
      activation of a TGF-beta reporter alone and enhanced TGF-beta response. Moreover,
      Smad6s overexpression suppressed TM and subsequently reduced activated protein C
      generation. Antisense inhibition of Smad6s expression enhanced the TM-dependent
      activation of protein C, whereas blocking the inhibitory Smad7 by antisense
      resulted in reduced TM-dependent activation of protein C. The effect of Smad6s
      appeared to be due, at least in part, to up-regulation of TGF-beta itself.
      Immunohistochemistry studies in normal versus atherosclerotic vessels showed that
      TM levels were suppressed in the endothelium over plaque. Consistent with the in
      vitro data, we found differential expression of Smad6s and Smad7 in normal versus
      atherosclerotic vessels, with Smad6s expression low in normal vessels but
      elevated in atherosclerotic vessels. In contrast, the opposite expression pattern
      was observed for Smad7. Overall, our results suggest that the relative balance of
      these intracellular Smads modulate the balance of endothelial function with
      regard to protein C activation.

PMID- 12407116
TI  - Glycopeptide-resistant Staphylococcus aureus.

PMID- 12407117
TI  - Probiotics in human infections.

PMID- 12407118
TI  - 3-[4'-bromo-(1,1'-biphenyl)-4-yl]-N, N-dimethyl-3-(2-thienyl)-2-propen-1-amine:
      synthesis, cytotoxicity, and leishmanicidal, trypanocidal and antimycobacterial
      activities.
AB  - Current therapies for Chagas' disease, leishmaniasis and tuberculosis are
      unsatisfactory because of the failure rates, significant toxicity and/or drug
      resistance. In this study, the compound 3-[4'-bromo-(1,1'-biphenyl)-4-yl]-N,N
      dimethyl-3-(2-thienyl)-2-propen-1-amine (IV) was synthesized and its
      trypanocidal, leishmanicidal and antimycobacterial activities were investigated.
      The cytotoxicity was determined on V79 cells with three endpoints: nucleic acid
      content, 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide reduction
      and Neutral Red uptake. This compound was active against different species of
      mycobacteria and different life cycle stages of Trypanosoma cruzi. In experiments
      with trypomastigotes performed at 4 degrees C in the presence of blood, the
      activity was 8.8-fold more active than the standard drug, Crystal Violet. Higher
      activity was achieved against Leishmania amazonensis, with an ED(50)/24 h of 3.0
      +/- 0.3 micro mol/L. The effect against trypanosomatids, which suggests high
      activity of compound IV against promastigotes of L. amazonensis and amastigotes
      of T. cruzi, stimulated further studies in vitro with amastigotes interiorized in
      macrophages and with in vivo models. Our results indicate that mammalian V79
      cells are less susceptible to the action of compound IV than promastigotes of L.
      amazonensis (8.0-13.3-fold) and axenic amastigotes of T. cruzi (3.5-5.9-fold).

PMID- 12407119
TI  - Inhibition of murine AIDS by a heterodinucleotide of azidothymidine and 9-(R)-2
      (phosphonomethoxypropyl)adenine.
AB  - Tenofovir [9-(R)-2-(phosphonomethoxypropyl)adenine (PMPA)] and zidovudine
      [azidothymidine (AZT)] are potent anti-HIV agents that have shown a strong
      synergy in in vitro studies. In this paper we have investigated both the
      potentiality of this synergy in vivo and the possibility to administer AZT and
      PMPA simultaneously as a single drug AZTpPMPA. The pharmacokinetic studies
      reported here have shown that AZTpPMPA administered intraperitoneally in mice
      performs as a prodrug, providing a slow delivery of AZT and PMPA in circulation.
      C57BL/6 mice infected with the retroviral complex LP-BM5 were used to evaluate
      the efficacy of AZTpPMPA in inhibiting disease progression. Furthermore, the
      effectiveness of the heterodinucleotide was compared with that of AZT and PMPA,
      administered as single drugs, or as a combination (AZT plus PMPA). The results
      obtained showed that AZTpPMPA is able to reduce lymphoadenopathy (88%),
      splenomegaly (64%), lymph node BM5 proviral DNA content (49%) and
      hypergammaglobulinaemia (40%). However, upon AZT plus PMPA administration,
      similar (splenomegaly and lymphoadenopathy reduction) or better results (64%
      hypergammaglobulinaemia reduction and 75% lymph node BM5 proviral DNA content
      inhibition) were obtained. Furthermore, these results overlapped those obtained
      upon PMPA administration. Thus, no synergy between PMPA and AZT was observed in
      murine AIDS and administration of AZT does not improve the antiviral results
      obtained by PMPA administration.

PMID- 12407120
TI  - Examination of single and multiple mutations involved in resistance to quinolones
      in Staphylococcus aureus by a combination of PCR and denaturing high-performance
      liquid chromatography (DHPLC).
AB  - Detection of DNA sequence variation is fundamental to the identification of the
      genomic basis of phenotypic variability. Denaturing high-performance liquid
      chromatography (DHPLC) is a novel technique that has been used to detect
      mutations in human DNA. We report on the first study to use this technique as a
      tool to detect mutations in genes encoding antibiotic resistance in bacteria.
      Three methicillin-sensitive and three methicillin-resistant clinical
      Staphylococcus aureus isolates, susceptible to ciprofloxacin (MIC <or= 0.4 mg/L),
      were used to derive mutants resistant to ciprofloxacin, levofloxacin,
      sparfloxacin, trovafloxacin and moxifloxacin. Genomic DNA from each strain was
      subjected to PCR amplification of 225-500 bp regions spanning the quinolone
      resistance determining regions of the gyrA, gyrB, grlA and grlB genes. Following
      DNA sequencing of these amplicons and identification of resistance mutations,
      DHPLC was undertaken to correlate the distinctive chromatogram with DNA sequence.
      The mutations detected by DHPLC resulted in the following amino acid
      substitutions: Ser-84-->Leu, Ser-112-->Pro, Glu-88-->Lys in GyrA, Glu-84-->Val,
      Ser-80-->Phe in GrlA, Pro-456-->Ser in GyrB and Glu-422-->Asp, Pro-451-->Ser, Asp
      432-->Gly in GrlB. Mutations could be rapidly and reproducibly identified from
      the PCR products using DHPLC, producing specific peak patterns that correlate
      with genotypes. This system facilitates the detection of resistance alleles,
      providing a rapid (5 min per sample), economic (96 sample per run) and reliable
      technique for characterizing antibiotic resistance in bacteria.

PMID- 12407121
TI  - Fitness of in vitro selected Pseudomonas aeruginosa nalB and nfxB multidrug
      resistant mutants.
AB  - Overproduction of multidrug resistance (MDR) efflux pumps is involved in the
      resistance to a wide range of compounds in bacteria. These determinants extrude
      antibiotics, but also bacterial metabolites like quorum-sensing signals. Non
      regulated extrusion of bacterial metabolites might produce a metabolic burden, so
      that MDR-overproducing mutants could have a reduced fitness when compared with
      their parental strains. To test such a possibility, we have compared the
      behaviour of two MDR Pseudomonas aeruginosa in vitro selected mutants (nalB and
      nfxB) with their isogenic parental strain with respect to some properties with
      potential relevance for the survival in the environment and the virulence of this
      bacterial species. Overproduction of the MDR determinants MexABOprM (nalB mutant)
      and MexCDOprJ (nfxB mutant) decreased the survival in water, the production of
      phenazines and proteases, and the virulence (using a Caenorhabditis elegans model
      system) of the P. aeruginosa mutants. In contrast, the capability of forming
      biofilms was not impaired. The simple models tested in the present work can
      enable the analysis of the fitness of large numbers of antibiotic-resistant
      bacteria by using more realistic approaches than the in vitro competition assays
      currently used.

PMID- 12407122
TI  - Virulence factor expression by Gram-positive cocci exposed to subinhibitory
      concentrations of linezolid.
AB  - Linezolid is a new oxazolidinone with potent antibacterial activity against Gram
      positive cocci; it uniquely inhibits bacterial translation through inhibition of
      70S initiation complex formation. The effects of sub-growth-inhibitory
      concentrations of linezolid on the expression of various structural and soluble
      virulence factors of Staphylococcus aureus and Streptococcus pyogenes were
      examined. For S. aureus, strains Wood 46 and Cowan 1 (NCTC 8532) were used to
      measure protein A, coagulase, alpha-haemolysin (hla) and delta-haemolysin (hld).
      For S. pyogenes, strain NCTC 9994 was used to measure M protein, streptolysin O
      (SLO) and DNase. Coagulase was assayed by clotting of citrated rabbit plasma, and
      hla, hld and SLO by lysis of rabbit, human and horse erythrocytes, respectively.
      Protein A and M protein were measured indirectly using bacterial susceptibility
      to phagocytic ingestion of radiolabelled bacteria by human neutrophils. When S.
      aureus was grown in 1/2, 1/4 and 1/8 MIC, linezolid, coagulase, hla and hld
      production were impaired. Susceptibility to phagocytosis was changed by growth in
      the presence of 1/2 MIC linezolid compared with that in its absence (50.8 +/-
      4.1% versus 38.9 +/- 2.9%; P <or= 0.05). When S. pyogenes was grown in 1/2, 1/4
      and 1/8 MIC linezolid, SLO and DNase production were impaired compared with that
      of bacteria grown in the absence of the drug; its susceptibility to phagocytosis
      was also increased (52.8% bacteria ingested versus 37.5%; P <or= 0.05). A
      reduction in virulence factor expression at sub-MIC linezolid concentrations may
      be of benefit in the treatment of Gram-positive infections.

PMID- 12407123
TI  - Molecular characterization of SPM-1, a novel metallo-beta-lactamase isolated in
      Latin America: report from the SENTRY antimicrobial surveillance programme.
AB  - The gene encoding the metallo-beta-lactamase SPM-1 was cloned from a genomic
      library of Pseudomonas aeruginosa strain 48-1997 A. The insert carrying spm-1
      possessed a GC content of 47%, indicating that it is of non-Pseudomonas origin.
      Upstream of spm-1 there is a small open reading frame (ORF), which is homologous
      to the LysR family of proteins (69% identity to the LysR protein from Salmonella
      enterica serovar Typhimurium). Downstream of spm-1 there is the start of an ORF,
      the product of which shows close homology with the GroEL-type proteins from
      Xanthomonas campestris. No transmissible element could be identified upstream or
      downstream of spm-1. The spm-1 gene is carried on a plasmid that can transform
      both Escherichia coli and P. aeruginosa to ceftazidime resistance. SPM-1 contains
      the classic metallo-beta-lactamase zinc-binding motif HXHXD and shows the highest
      identity (35.5%) to IMP-1. SPM-1 is a distinctly different metallo-beta-lactamase
      from VIM and IMP and, accordingly, represents a new subfamily of mobile metallo
      beta-lactamases. The predicted molecular weight of the protein was 27 515 Da,
      significantly higher than that of IMP (25 041 Da) or VIM (25 322 Da). SPM-1
      possesses a unique loop of 23 residues that accounts for the higher molecular
      mass.

PMID- 12407124
TI  - Characterization of CMY-type beta-lactamases in clinical strains of Proteus
      mirabilis and Klebsiella pneumoniae isolated in four hospitals in the Paris area.
AB  - We isolated five clinical strains (three Proteus mirabilis and two Klebsiella
      pneumoniae) with beta-lactam resistance phenotypes consistent with production of
      an AmpC-type beta-lactamase. The predicted amino acid sequences of the enzymes
      were typical of class C beta-lactamases. The enzymes were identified as CMY-2,
      CMY-4 and a new CMY-variant beta-lactamase, CMY-12. The AmpC beta-lactamases from
      the two K. pneumoniae isolates were found to be encoded on self-transferable
      plasmids. The genes encoding the AmpC-type beta-lactamase produced by the three
      P. mirabilis isolates were chromosomal. Four of the five clinical isolates were
      from patients transferred from Greece, Algeria and Egypt; one of the K.
      pneumoniae strains was recovered from a French patient. PFGE analysis and rep-PCR
      fingerprinting showed that the two P. mirabilis isolates from Greek patients were
      closely related.

PMID- 12407125
TI  - Identification and characterization of teicoplanin-intermediate Staphylococcus
      aureus blood culture isolates in NE Scotland.
AB  - The study objective was to screen both methicillin-resistant Staphylococcus
      aureus (MRSA) and methicillin-sensitive S. aureus (MSSA) isolates from blood
      cultures for reduced susceptibility to vancomycin and teicoplanin. A total of 72
      MRSA and 143 MSSA isolates were screened on brain-heart infusion agar containing
      either 4 mg/L vancomycin or 8 mg/L teicoplanin, using an inoculum of
      approximately 10(6) organisms. MICs were determined by Etest, broth microdilution
      and agar incorporation. Isolates were characterized by PFGE, mecA and nuc PCR,
      transmission electron microscopy (TEM) and analysis of cell proteins
      (proteomics). Based on British Society for Antimicrobial Chemotherapy (BSAC)
      breakpoints, seven MRSAs and seven MSSAs were teicoplanin resistant, with MICs of
      up to 16 and 24 mg/L respectively, but were vancomycin sensitive. Based on higher
      NCCLS breakpoints, five MRSAs and six MSSAs were teicoplanin intermediate,
      vancomycin sensitive. All the MRSAs belonged to the EMRSA-16 clone and subdivided
      into two groups. The MSSAs belonged to five different clones. TEM showed the
      resistant variants to have slightly thicker cell walls than sensitive variants.
      Most notably, the resistant variants possessed characteristic dark, granular
      material concentrated in the middle of the cells, believed to be chromosome.
      Proteomics showed the resistant variants to overexpress phosphoglycerate kinase.
      Both MRSA and MSSA with reduced teicoplanin susceptibility may remain vancomycin
      sensitive by NCCLS and BSAC criteria and it is important to screen clinical
      isolates of MRSA and MSSA for reduced susceptibility to both agents.

PMID- 12407126
TI  - Pharmacokinetics of lansoprazole, amoxicillin and clarithromycin after
      simultaneous and single administration.
AB  - In a randomized, double-blind, placebo-controlled, four-way crossover study,
      possible influences of the triple therapy with amoxicillin, clarithromycin and
      the proton pump inhibitor lansoprazole on the pharmacokinetics of each of the
      drugs and the active 14-OH-clarithromycin metabolite were assessed. Twelve
      Helicobacter pylori-negative healthy male volunteers (age 27 +/- 4.3 years;
      creatinine clearance 7.0 +/- 2.0 L/h) were given lansoprazole 30 mg, amoxicillin
      1 g and clarithromycin 500 mg, alone and in triple combination. Drug elimination
      intervals were at least 9 days between the dosing periods. The study medication
      was administered twice daily for 4 days. On the fifth day of each period, drugs
      were only given once in the morning, and blood and urine samples were collected
      for 12 h. The concentrations of the three substances administered, and 14-OH
      clarithromycin, were determined by validated HPLC methods. Alterations in the
      serum kinetics were found for lansoprazole and the active 14-OH-clarithromycin
      metabolite (all data expressed as mean +/- S.D.). For lansoprazole, the
      elimination half-life (t(1/2)) was significantly prolonged (1.46 versus 1.7 h, P
      < 0.05) and the area under the concentration-time curve from 0 to 8 h (AUC(0-8))
      was significantly increased (3.65 versus 4.59 mg.h/L, P < 0.05) by combination of
      the drugs. For 14-OH-clarithromycin, the peak concentration (C(max)) was 0.95
      versus 1.18 mg/L and the AUC from 0 to 12 h (AUC(0-12)) was 8.3 versus 10.5
      mg.h/L (augmented significantly, P < 0.05). The amoxicillin concentrations were
      slightly elevated by concomitant administration of lansoprazole and
      clarithromycin but without statistical significance (11.1 versus 12.6 mg/L). For
      clarithromycin, the time to maximum concentration of drug in serum (T(max)) was
      increased (2.73 versus 3.31 h, P < 0.05), whereas AUC and C(max) remained
      unchanged. Simultaneous administration of lansoprazole, amoxicillin and
      clarithromycin increases the serum concentrations of lansoprazole and the active
      14-OH-clarithromycin metabolite significantly. These effects were not so
      pronounced as to have any therapeutic influence, making dosage adjustment
      unnecessary.

PMID- 12407128
TI  - Vancomycin therapeutic drug monitoring: is there a consensus view? The results of
      a UK National External Quality Assessment Scheme (UK NEQAS) for Antibiotic Assays
      questionnaire.
AB  - This study investigated vancomycin therapeutic drug monitoring (TDM) and issues
      related to patient management. Questionnaires were distributed to 310
      participants in the UK National External Quality Assessment Scheme (NEQAS) for
      Antibiotic Assays. The response rate was 57.4%. The majority (76%) had an 'in
      house' assay service based, almost exclusively, in the microbiology department,
      and a fluorescence polarization immunoassay (FPIA) was used by 97%. Almost half
      (48.7%) had an assay service available for 24 h/day, 7 days/week and 92.7%
      expected same-day results. The majority (80%) had issued guidelines for
      vancomycin use. A 12 hourly initial dosing regimen was used by 89%. Trough assay
      samples were taken <10 min before the dose by 91.5%. For post-dose assay samples,
      44% took a sample at 1 h, 28% at 2 h and the remainder at 'other' times. For
      trough target ranges, 93% quoted <10 mg/L or 5-10 mg/L. There was no consensus
      with regard to post-dose assay sample times and 23 ranges were quoted. The
      majority (74.4%) regarded a trough level of >or=10 mg/L as 'toxic' but 13
      concentrations were quoted as toxic post-dose measurements. In conclusion, there
      was a wide variability and poor consensus with regard to post-dose vancomycin
      assay sampling times, target ranges and what constituted a toxic level.

PMID- 12407127
TI  - Single- and multiple-dose pharmacokinetics of linezolid and co-amoxiclav in
      healthy human volunteers.
AB  - In an open, randomized, two-period crossover study the pharmacokinetics of
      linezolid and co-amoxiclav were investigated after single- and multiple-dose
      administration in 12 healthy volunteers (six females and six males). Linezolid
      was given in tablets of 600 mg twice a day for 7 days and co-amoxiclav in tablets
      of 1000 mg (875 + 125 mg) once a day for 7 days. The wash-out period was 4 weeks
      between the administration of the two antibacterial agents. Blood and urine
      samples were collected on days 1 and 7 before and at different time points up to
      24 h after medication. The concentrations of the antibiotics in serum and urine
      were measured by validated high-performance liquid chromatography methods.
      Linezolid exhibited a mean C(max) of 14.5 +/- 4.6 mg/L after T(max) of 47.5 +/-
      20.1 min on day 1, with a significant increase to 24.0 +/- 6.9 mg/L on day 7 (P <
      0.01). The AUD(tot) (total area under the data) revealed a significant increase
      from 140.5 +/- 28.3 mg.h/L on day 1 to 220.2 +/- 42.6 mg.h/L on day 7 (P < 0.01).
      There were no significant differences in terminal elimination half-life between
      days 1 and 7 (9.53 +/- 2.87 versus 7.97 +/- 3.08 h) or in total clearance (71.6
      +/- 17.6 versus 81.5 +/- 14.7 ml/min.1.73 m(2)). Results are in agreement with
      the assumption of a limited accumulation of linezolid under the dosage regimen
      given. Serum linezolid concentrations in females were always higher than those in
      males. The volume of distribution V(ss)/f differed significantly between females
      and males (41.6 +/- 4.2 versus 52.2 +/- 3.3 L/70 kg; P < 0.01). Pharmacokinetic
      parameters of amoxicillin and clavulanic acid found in this study were similar to
      previously published data. No accumulation was found with co-amoxiclav. No
      serious adverse event was observed with the study drugs.

PMID- 12407129
TI  - Comparative evaluation of two different methods of inoculum preparation for
      antifungal susceptibility testing of filamentous fungi.
AB  - Two different methods of inoculum preparation for susceptibility testing were
      analysed. The first method was adjustment of inoculum size by haemocytometer
      counting. The second method was spectrophotometric adjustment at 530 nm. The
      reliability of both methods was assessed by colony counting. The overall
      agreement between colony counting and haemocytometer counts was 93.6%, and the
      intraclass coefficient correlation was 0.71 (P < 0.05). Pearson's correlation
      index between colony counts and optical density values was -0.059 (P > 0.05).
      Optical densities ranged between 0.01 and 1.2, showing less reproducibility than
      expected by the NCCLS M 38-P standard. Haemocytometer counting is a more reliable
      method of inoculum preparation for antifungal susceptibility testing.

PMID- 12407130
TI  - Characterization of a laboratory-generated variant of BPS beta-lactamase from
      Burkholderia pseudomallei that hydrolyses ceftazidime.
AB  - Burkholderia pseudomallei produces an Ambler class A beta-lactamase, known as BPS
      1. The beta-lactamase gene from a laboratory-derived, ceftazidime-resistant
      strain of B. pseudomallei (LH-1-2) was cloned and expressed in Escherichia coli.
      The beta-lactamase, named BPS-1m, had an identical isoelectric focusing point (pI
      7.7) to that of BPS-1, but differed in having a stronger hydrolytic activity
      against ceftazidime. Susceptibility testing showed that BPS-1m when expressed in
      E. coli conferred resistance to ceftazidime (MIC >or= 32 mg/L). The amino acid
      sequence of BPS-1m differed from that of BPS-1 by a Pro-to-Ser change at position
      167 in the omega loop.

PMID- 12407131
TI  - In vitro activity of sitafloxacin (DU-6859a) alone, or in combination with
      rifampicin, against Mycobacterium ulcerans.
AB  - The antimicrobial effect of sitafloxacin (DU-6859a), used either singly or in
      combination with rifampicin, was evaluated in vitro against Mycobacterium
      ulcerans. Growth of M. ulcerans was measured by plate counts and the BACTEC
      radiometric method. The MICs and MBCs of sitafloxacin for M. ulcerans were in the
      range 0.125-0.5 mg/L. The values for other fluoroquinolones were two- to four
      fold higher than for sitafloxacin. Combination of sitafloxacin and rifampicin
      exhibited synergy with five of the eight strains, whereas the combination of
      ofloxacin and rifampicin resulted in additive effects only. These results suggest
      that the combination of sitafloxacin and rifampicin has potential in the
      treatment of M. ulcerans infection.

PMID- 12407132
TI  - Nisin, alone and combined with peptidoglycan-modulating antibiotics: activity
      against methicillin-resistant Staphylococcus aureus and vancomycin-resistant
      enterococci.
AB  - OBJECTIVE: We have sought ways to circumvent resistance, by combining nisin with
      other antibiotics known to target bacterial cell wall biosynthesis. METHODS:
      Twenty strains each of methicillin-resistant Staphylococcus aureus (MRSA) and
      vancomycin-resistant enterococci (VRE) were tested in vitro by standardized
      methods against nisin alone and combined with bacitracin, ramoplanin and
      chloramphenicol. RESULTS: Ramoplanin was the most potent compound, and bacitracin
      had the least activity. Two-way synergy was observed with nisin and ramoplanin.
      However, chloramphenicol was clearly antagonistic to the activity of nisin.
      CONCLUSIONS: Observations of synergy between nisin and ramoplanin against MRSA
      and VRE offer a promising approach to the concept of combining nisin with
      inhibitors of cell wall peptidoglycan. Further investigations are needed in order
      to develop this approach as a clinical possibility.

PMID- 12407133
TI  - Comparative in vitro activities of ertapenem against bacterial pathogens from
      patients with acute pelvic infection.
AB  - This study compared the in vitro activities of ertapenem, ceftriaxone, co
      amoxiclav, ciprofloxacin and piperacillin-tazobactam against 314 aerobic bacteria
      and of ertapenem, piperacillin-tazobactam, cefoxitin, ceftriaxone,
      chloramphenicol, ticarcillin-clavulanate, ampicillin-sulbactam, clindamycin and
      metronidazole against 500 anaerobic bacteria from 212 patients with acute pelvic
      infection. Antimicrobial susceptibilities were determined by broth microdilution
      (aerobes) or agar dilution (anaerobes), following NCCLS guidelines. The most
      common isolates were Enterobacteriaceae and Peptostreptococcus spp. Ertapenem was
      the most active drug tested against Enterobacteriaceae (100% susceptible) and
      anaerobes (99.8% susceptible); the least active agents were co-amoxiclav (79% of
      Enterobacteriaceae susceptible) and ceftriaxone (85.9% of anaerobes susceptible).
      All agents tested had excellent activity against beta-haemolytic streptococci and
      methicillin-susceptible Staphylococcus aureus.

PMID- 12407134
TI  - Linezolid-resistant enterococci: report of the first isolates in the United
      Kingdom.
AB  - Linezolid, the first oxazolidinone antibacterial agent to be developed for
      clinical use, was licensed in the UK in early 2001. We report the first three
      examples of resistant enterococci (two isolates of Enterococcus faecium and one
      Enterococcus faecalis) isolated in the UK, which were obtained from patients who
      had received linezolid. The linezolid MICs for the resistant isolates were 64
      mg/L. Pulsed-field gel electrophoresis (PFGE) analysis of the linezolid
      susceptible and -resistant isolates from two of the patients, combined with
      sequence analysis of rRNA, indicated that resistance developed in previously
      susceptible strains, most probably via a point mutation in the 23S rRNA.

PMID- 12407135
TI  - Linezolid penetration into osteo-articular tissues.
AB  - Penetration of linezolid into osteo-articular tissue and fluid was studied in 10
      patients undergoing primary total knee replacement. Linezolid 600 mg 12 hourly
      was given orally over the 48 h before operation and intravenously 1 h before
      induction of anaesthesia. Mean concentrations of linezolid at 90 min after the
      final dose, in serum, synovial fluid, synovium, muscle and cancellous bone,
      assayed by HPLC, were at least twice the MIC(90) for staphylococci and
      streptococci. The concentrations obtained indicate good penetration of this
      antibiotic and support its use in the management of multidrug-resistant Gram
      positive bone, joint and deep-seated soft-tissue infections.

PMID- 12407136
TI  - Evidence for the efficacy of artesunate in asymptomatic Plasmodium malariae
      infections.
AB  - This study evaluated the efficacy and safety of a 3-day course of artesunate (4
      mg/kg/day) for asymptomatic Plasmodium malariae infections. The parasitological
      cure rates on days 7 and 56 in the group treated with artesunate were 100% and
      83%, respectively, compared with no cure in the placebo group (P < 0.0001).

PMID- 12407137
TI  - Molecular epidemiology of resistance to macrolides-lincosamides-streptogramins in
      methicillin-resistant Staphylococcus aureus (MRSA) causing bloodstream infections
      in patients admitted to Belgian hospitals.

PMID- 12407138
TI  - A survey of susceptibility testing of anaerobes in the United Kingdom.

PMID- 12407139
TI  - Comparative in vitro activities of tigecycline (GAR-936) and other antimicrobial
      agents against Stenotrophomonas maltophilia.

PMID- 12407140
TI  - In vitro activity of 21 antimicrobials against vancomycin-resistant
      Staphylococcus aureus (VRSA) and heteroVRSA (hVRSA).

PMID- 12407141
TI  - Are multiply resistant enterococci a common phenomenon in Hong Kong?

PMID- 12407142
TI  - Fulminant hepatic failure after the start of an efavirenz-based HAART regimen in
      a treatment-naive female AIDS patient without hepatitis virus co-infection.

PMID- 12407143
TI  - Gamma-interferon treatment for resistant oropharyngeal candidiasis in an HIV
      positive patient.

PMID- 12407144
TI  - TFF peptides in the human efferent tear ducts.
AB  - PURPOSE: To determine whether the lining epithelium of the human lacrimal sac and
      nasolacrimal duct synthesizes TFF peptides (formerly P-domain peptides, trefoil
      factors), a family of mucin-associated secretory peptides. METHODS: Expression of
      TFF peptides in human lacrimal sac and nasolacrimal ducts was monitored by
      reverse transcription-polymerase chain reaction and Western blot analysis.
      Antisera specific for TFF peptides were used in immunohistochemical analysis to
      determine the presence and distribution of all three TFF peptides in epithelia of
      the lacrimal passage. The samples investigated originated from tissue obtained
      during surgery (18 patients) and postmortem tissue (10 specimens). RESULTS: mRNA
      expression of TFF1 and TFF3, but not TFF2, was detected in human lacrimal sac and
      nasolacrimal duct. TFF1 was detected in only approximately 50% of the
      investigated probes, whereas TFF3 was present in all samples.
      Immunohistochemistry revealed TFF1 (if present) to be associated with goblet
      cells forming intraepithelial mucous glands. TFF3 occurred in epithelial cells of
      the lacrimal sac and the nasolacrimal duct as well as in the acinar cells of
      subepithelial serous glands, but appeared to be absent in goblet cells.
      CONCLUSIONS: The epithelium of the nasolacrimal ducts synthesizes TFF3 and in
      some cases also TFF1. In contrast to the human conjunctiva, in which TFF3 is
      detectable only in goblet cells, TFF3 of the lacrimal sac and nasolacrimal duct
      is produced in large amounts by epithelial cells as well as by serous glands, but
      not-or in small amounts only-by goblet cells. This is comparable with
      localization of TFF3 in the major salivary glands. Thus, TFF3 may have a special
      function in tear transport through the lacrimal passage comparable to its
      function on the ocular surface, because the peptide, together with TFF1, may
      contribute to the rheologic properties of the tear film. Moreover, the TFF
      peptides may also influence epithelial healing with their motogenic properties.

PMID- 12407145
TI  - Cloning and characterization of a novel all-trans retinol short-chain
      dehydrogenase/reductase from the RPE.
AB  - PURPOSE: In the photic visual cycle, retinal G protein-coupled receptor (RGR)
      isomerizes all-trans retinal to 11-cis retinal in the retinal pigment epithelium
      (RPE) after illumination. It is unclear, however, how all-trans retinal, the
      substrate for RGR, is generated in the RPE, because no all-trans retinol
      dehydrogenase (atRDH) has been identified in the RPE. This study was conducted to
      identify the atRDH that generates all-trans retinal in the RPE. METHODS: The full
      length cDNA encoding a novel atRDH, RDH10, was cloned by PCR based on an
      expressed sequence tag (EST). Cellular localization was determined at the mRNA
      level by Northern blot analysis, RT-PCR, and in situ hybridization and at the
      protein level by immunohistochemistry with an antibody specific to RDH10. The
      activity was measured by an RDH activity assay with recombinant RDH10 expressed
      in COS cells. RESULTS: The full-length RDH10 was cloned from the human, cow, and
      mouse. These cDNAs encode a protein of 341 amino acids and have significant
      sequence homology with other short-chain dehydrogenases/reductases (SDRs). The
      human RDH10 shares 100% and 98.6% amino acid sequence identity with the bovine
      and mouse proteins, respectively, suggesting a highly conserved sequence during
      evolution. RDH10 is predominantly expressed in the microsomal fraction of the
      RPE. Human RDH10 expressed in COS cells oxidized all-trans retinol to all-trans
      retinal. RDH10 displayed substrate specificity for all-trans retinol and
      preferred nicotinamide adenine dinucleotide phosphate (NADP) as the cofactor.
      CONCLUSIONS: RDH10 is a novel retinol oxidase expressed in the RPE. This enzyme
      can generate all-trans retinal from all-trans retinol and may play an important
      role in the photic visual cycle.

PMID- 12407146
TI  - Complex expression pattern of RPGR reveals a role for purine-rich exonic splicing
      enhancers.
AB  - PURPOSE: To examine the mechanism underlying transcript heterogeneity in the gene
      for the retinitis pigmentosa GTPase regulator (RPGR). METHODS: Transcript
      heterogeneity was analyzed by reverse transcription-polymerase chain reactions
      (RT-PCR), rapid amplification of cDNA ends (RACE), and transient expression of
      minigene constructs. Protein variants were identified by immunoblot analysis and
      by immunocytochemistry. RESULTS: RPGR transcripts terminated either uniformly at
      the end of exon 19, producing the constitutive transcript with few variants, or
      at variable sites downstream from exon 15. The latter transcripts resembled the
      previously described open reading frame (ORF)14/15 variant, but the ORF14/15 exon
      was not found in full length. Instead, various portions of a purine-rich region
      were removed as introns. Numerous splice site combinations were used, giving rise
      to innumerable variants. Analysis of the purine-rich region found multiple exonic
      splicing enhancers (ESEs) known to promote splicing through interaction with
      serine-arginine repeat (SR) proteins. Antibodies targeting different regions of
      RPGR detected a multitude of RPGR proteins in photoreceptors, concentrated in the
      connecting cilium. Predominant ORF14/15-encoded RPGR polypeptides migrated at
      approximately 200 kDa and were photoreceptor specific. CONCLUSIONS: The
      exceptional heterogeneity in RPGR transcript processing results primarily from a
      novel form of alternative RNA splicing mediated by multiple exonic splicing
      enhancers. RPGR is composed of a population of proteins with a constant N
      terminal core encompassing the RCC1 homology domain followed by a C-terminal
      portion of variable lengths and sequences.

PMID- 12407147
TI  - Transformations of selected carotenoids in plasma, liver, and ocular tissues of
      humans and in nonprimate animal models.
AB  - PURPOSE: To determine the stereochemistry of carotenoids in human ocular tissues
      in comparison with plasma and liver and to elucidate the possible transformations
      of dietary (3R,3'R,6'R)-lutein and (3R,3'R)-zeaxanthin in the eye. Similarly, to
      characterize the carotenoid profiles in the eye tissues, plasma, and liver of
      quails and frogs to determine whether these can serve as appropriate nonprimate
      animal models for metabolic studies. METHODS: Configurational isomers of
      carotenoids and their nondietary by-products from pooled human plasma, liver,
      retinal pigment epithelium (RPE-choroid), ciliary body, iris, and lens were
      characterized and quantified by high-performance liquid chromatography (HPLC) on
      a chiral column. Carotenoids and their nondietary by-products in pooled extracts
      from quail and frog plasma, liver, retina, RPE-choroid, iris, and lens were
      similarly characterized and quantified. RESULTS: (3R,3'R,6'R)-lutein, (3R,3'R)
      zeaxanthin, (3R,3'S; meso)-zeaxanthin, (3R,3'S,6'R)-lutein (3'-epilutein), 3
      hydroxy-beta, epsilon -carotene-3'-one, and 5Z- and all-E-lycopene were detected
      in nearly all human ocular tissues examined. (3R,3'S; meso)-zeaxanthin was not
      detected in the human plasma and liver but was present in human macula, retina,
      and RPE-choroid. (3S,3'S)-zeaxanthin was detected in human macula in minute
      quantities. The carotenoid profiles in quail and frog ocular tissues were
      somewhat similar to those in humans, with the exception that lycopene was absent.
      Frog retina, plasma, and liver revealed the presence of (3S,3'S)-zeaxanthin.
      CONCLUSIONS: The most likely transformations of carotenoids in the human eye
      involve a series of oxidation-reduction and double-bond isomerization reactions.
      Quail and frog appear to possess the appropriate enzymes for conversion of
      dietary (3R,3'R,6'R)-lutein and (3R,3'R)-zeaxanthin to the same nondietary by
      products observed in humans and thus may serve as excellent nonprimate animal
      models for metabolic studies.

PMID- 12407148
TI  - The impact of visual impairment and eye disease on vision-related quality of life
      in a Mexican-American population: proyecto VER.
AB  - PURPOSE: To describe the relationship of visual acuity impairment and eye disease
      on vision-related quality of life, as measured by the 25-item National Eye
      Institute Visual Function Questionnaire (NEI-VFQ-25), in a cross-sectional,
      population-based study of older Hispanic persons living in Arizona. METHODS: A
      random sample of block groups with Hispanic residents in Nogales and Tucson,
      Arizona, were selected for study. Participants were interviewed at home with a
      questionnaire that included the NEI-VFQ-25, an instrument measuring vision
      related quality of life. Acuity was obtained with Early Treatment Diabetic
      Retinopathy Study (ETDRS) charts and standard protocol. Cataract was determined
      by clinical examination, diabetic retinopathy was diagnosed on stereo fundus
      photographs, and glaucoma was diagnosed on the basis of clinical examination and
      visual field results. Analyses were done to determine the degree of association
      between subscale scores and acuity in the better-seeing eye, monocular visual
      impairment, and specific eye diseases, with adjustment for acuity. RESULTS: Of
      the 4774 participants in the study, 99.7% had completed questionnaires that were
      not completed by proxy. Participants with visual impairment had associated
      decrements in scores on all subscales, with a decrease in presenting acuity
      associated with a worse score (P < 0.05), after adjustment for demographic
      variables. Monocular impairment was also associated with lower scores in several
      subscales. In those with cataract, low acuity explained most of the low scores,
      but those with glaucoma or diabetic retinopathy had low scores independent of
      acuity. CONCLUSIONS: In this study of Mexican-American persons aged 40 or more,
      monocular impairment and better-eye acuity was associated with a decrease in most
      domains representing quality of life. Subjects with uncorrected refractive error,
      cataract, diabetic retinopathy, and glaucoma had associated decrements in quality
      of life, many not explained by loss of acuity. Further work on the specific
      measures of vision associated with reported decreases in quality of life, such as
      visual field or contrast sensitivity, is warranted.

PMID- 12407149
TI  - Population-based assessment of clinical characteristics predicting outcome of
      conjunctival melanoma in whites.
AB  - PURPOSE: To identify the clinical determinants of prognosis and the incidence of
      malignant conjunctival melanoma in whites. METHODS: A nationwide search
      identified 85 patients in whom primary conjunctival melanoma was diagnosed in
      Finland between 1967 and 2000, all of whom were enrolled. Data were collected
      from the Finnish Cancer and Population Registries and from patients' charts in
      all involved hospitals. The age-specific and age-adjusted incidences were
      calculated. Clinical characteristics of the tumors were recorded and time to
      local recurrence and melanoma-specific survival were analyzed by Kaplan-Meier
      analysis and univariate and multivariate extended Cox regression. RESULTS: The
      annual crude incidence of conjunctival melanoma in Finland was 0.51 per million
      inhabitants, and the age-adjusted incidence (mean, 0.54) increased from 0.4 to
      0.8 during the 34-year study period. The median age at diagnosis was 60 years
      (range, 20-90). Clinically detectable primary acquired melanosis preceded or
      accompanied the primary tumor in 61% of patients. The 5-year cumulative
      proportion of cases with local recurrence was 0.36 (95% confidence interval [CI],
      0.25-0.48). The melanoma-specific 5-and 10-year mortalities were 0.20 (95% CI,
      0.12-0.32) and 0.38 (95% CI, 0.26-0.53), respectively. By multiple-event Cox
      regression, nonlimbal location of the primary tumor predicted a short time to
      local recurrence (hazard ratio [HR] 1.81, P = 0.024). Nonlimbal location of the
      primary tumor (HR 4.08, P = 0.023) and increasing tumor thickness (HR 1.19 for
      each millimeter change, P=0.063) were associated with increased mortality. Local
      recurrence, analyzed as a time-dependent covariate, also increased mortality (HR
      1.39 for each recurrence, P = 0.014). CONCLUSIONS: The incidence of conjunctival
      melanoma in the white population of Finland increased analogous to cutaneous
      melanoma. Nonlimbal tumors recur more often and are associated with decreased
      survival, independent of their greater thickness. Local recurrence contributes to
      mortality, whereas primary acquired melanosis was not associated with either
      outcome.

PMID- 12407150
TI  - Cytoprotective effects of hyaluronic acid and Carbomer 934P in ocular surface
      epithelial cells.
AB  - PURPOSE: To investigate in vitro the cell toxicity and antioxidant effects of two
      major tear substitutes, hyaluronic acid and a widely used carbomer, with and
      without preservative. METHODS: Chang conjunctival cells were treated with
      different concentrations of unpreserved or preserved carbomer 934P (0.03% and
      0.3%), unpreserved or preserved hyaluronic acid (0.018% and 0.18%), and
      benzalkonium chloride (BAC 0.0005% and 0.005%) for 15 minutes or for 15 minutes
      with 24 hours of cell recovery, according to previously validated methods.
      Microplate cold light cytofluorometry was performed to evaluate cell viability
      (neutral red test), chromatin condensation (Hoechst 33342 test), and reactive
      oxygen species (ROS) production (dichlorofluorescein diacetate and hydroethidine
      tests). Confocal microscopy was used to explore morphologic changes. RESULTS: No
      alterations were found with unpreserved and preserved hyaluronic acid at all
      concentrations and times tested. A decrease in cell viability with chromatin
      condensation appeared with 0.3% preserved carbomer 934P at the two times tested.
      This cytotoxicity, however, was significantly less than that observed with BAC
      alone, although the same concentrations of preservative were used. Unpreserved
      carbomer 934P induced no modification of cell viability after 15 minutes but a
      significant decrease in chromatin condensation, reversible after 24 hours of cell
      recovery, when a delayed decrease in cell viability was observed. Production of
      reactive oxygen species (ROS) decreased with the four formulations of tear
      substitutes tested at their usual concentrations, whereas a significant
      production of ROS occurred with BAC. CONCLUSIONS: These two ophthalmic hydrogels
      have no cytotoxicity but possess antioxidant properties and tend to reduce the
      toxic effects of preservatives. These results may allow use of hydrogels, not
      only in dry eye but also in ocular surface disorders involving oxidative stress
      and in ophthalmic drug therapy to improve ocular tolerance.

PMID- 12407151
TI  - Partial restoration of the keratocyte phenotype to bovine keratocytes made
      fibroblastic by serum.
AB  - PURPOSE: To determine whether keratocytes made fibroblastic in vitro by addition
      of fetal bovine serum to the medium regain the keratocyte phenotype after culture
      in serum-free medium. METHODS: Collagenase-isolated keratocytes from bovine
      corneas were plated in DMEM/F-12 containing 1% horse plasma, to allow cell
      attachment, and then cultured until day 4 in either DMEM/F-12 alone, to retain
      the keratocyte phenotype, or in DMEM containing 10% fetal bovine serum, to cause
      the keratocytes to become fibroblastic. Medium for the fibroblastic cells was
      replaced on day 4 with serum-free medium, and cells were cultured until day 12.
      Cell phenotypes were determined on days 4 to 5 and 11 to 12 of culture as
      follows: (1) by the morphologic appearance on phase-contrast microscopy; (2) by
      the levels of aldehyde dehydrogenase in the cells, determined by SDS-PAGE and
      Coomassie blue staining; (3) by the relative synthesis of collagen types I and V,
      determined by (14)C-proline radiolabeling; (4) by pepsin digestion and analysis
      of collagen types by SDS-PAGE autoradiography; (5) by relative synthesis of
      cornea-specific proteoglycan core proteins determined by analysis of
      chondroitinase- or endo-beta-galactosidase-generated radiolabeled core proteins
      by SDS-PAGE autoradiography; and (6) by the relative synthesis of keratan sulfate
      and chondroitin sulfate determined by (35)SO(4) radiolabeling and measuring the
      sensitivity to endo-beta-galactosidase and chondroitinase ABC. RESULTS:
      Keratocytes cultured in serum-free medium appeared dendritic and became
      fibroblastic in appearance when exposed to medium containing serum. Keratocytes
      and fibroblasts synthesized a similar proportion of collagen types I and V.
      However, compared with the keratocytes, the fibroblasts possessed no aldehyde
      dehydrogenase and synthesized significantly higher levels of decorin and
      significantly lower levels of prostaglandin D synthase (PGDS) and keratan
      sulfate. Subsequent culture of the fibroblasts in serum-free medium did not
      restore aldehyde dehydrogenase to keratocyte levels but did restore the cell
      morphology to a more dendritic appearance and returned the synthesis of decorin,
      PGDS, and keratan sulfate to keratocyte levels. CONCLUSIONS: The results of these
      studies indicate that primary cultures of keratocytes made fibroblastic by
      exposure to serum can return to their keratocyte phenotype in synthesizing
      extracellular matrix. These results also indicate that the differences in the
      organization of the collagenous matrix produced by keratocytes and fibroblasts
      may be related more to the different proteoglycan types than to the collagen
      types produced.

PMID- 12407152
TI  - Regulation of corneal keratin-12 gene expression by the human Kruppel-like
      transcription factor 6.
AB  - PURPOSE: The keratin-12 (K12) protein is essential for the integrity of the
      corneal epithelium. This study was conducted to investigate the possible
      involvement of Kruppel-like factor 6 (KLF6) in the corneal regulation of K12 gene
      expression, in view of the presence of one KLF6 potential binding site in the
      human K12 promoter and the known role of KLF6 in regulating keratin gene
      expression. METHODS: RT-PCR, Western blot analysis, and immunolocalization
      experiments were used to investigate the expression of KLF6 mRNA and protein in
      five human total corneas. The same experimental design was used to explore human
      corneal epithelial (HCE) cells in 20 patients and a HCE cell line. The ability of
      the KLF6 protein to modulate K12 promoter activity was studied in the HCE cell
      line, by transient transfections with a KLF6 expression plasmid and promoter
      reporter gene assays. Gel-shift assays were performed to confirm the interactions
      between the KLF6 protein and specific sequences of the K12 promoter. RESULTS: The
      presence of KLF6 transcripts and proteins in human total corneal extracts was
      demonstrated. Immunohistofluorescence experiments showed positive staining
      specifically present in the corneal epithelial layer. KLF6 transcripts and
      proteins were also present in corneal epithelial cells in 20 patients and the HCE
      cell line. Transient transfections of KLF6 showed statistical transactivation of
      the K12 promoter in HCE cells. The gel-shift assay showed a physical interaction
      between KLF6 and the K12 promoter. CONCLUSIONS: The expression of KLF6 in HCE
      cells and its role in the regulation of K12 gene expression were demonstrated.

PMID- 12407153
TI  - UVB-mediated induction of interleukin-6 and -8 in pterygia and cultured human
      pterygium epithelial cells.
AB  - PURPOSE: Pterygia are common ocular surface lesions that are thought to be
      induced by exposure to ultraviolet (UV) radiation. The hypothesis tested in the
      current study is that UV radiation modulates the expression of interleukin (IL)-6
      and -8, which could promote the neovascularization and chronic inflammation
      regularly observed in pterygia. METHODS: Immunohistochemical analysis was
      performed on 10 pterygia and 14 specimens of normal conjunctiva (4 of which
      contained limbus), to identify the cellular source of these cytokines. Pterygium
      epithelial cells were exposed to UVB (0-100 mJ/cm(2)) and the expression of
      cytokine mRNA and protein was determined by reverse transcription-polymerase
      chain reaction (RT-PCR), RNase protection assay (RPA), and enzyme immunoassay.
      Similarly, pterygium tissue in organ culture was UVB irradiated and the
      supernatants analyzed for cytokine production. RESULTS: IL-6 and -8 proteins were
      abundantly expressed, predominantly by the pterygium epithelium, with additional
      IL-8 immunoreactivity associated with the vascular endothelium. In contrast,
      significantly less staining for both cytokines was observed in normal
      conjunctiva, cornea, and limbus. Expression of both IL-6 and -8 mRNA and protein
      was induced in UVB-irradiated pterygium epithelial cells in a time- and dose
      dependent manner. Similarly, IL-6 and -8 proteins were significantly elevated in
      UVB-treated compared with nonirradiated pterygia. CONCLUSIONS: This study
      provides the first direct experimental evidence that implicates UV in the
      pathogenesis of pterygia. The two proinflammatory cytokines that are induced by
      UV radiation may play a key role in the development of pterygia, by initiating
      blood vessel formation, cellular proliferation, tissue invasion, and
      inflammation. Strategies aimed at reducing ocular exposure to UV light may
      decrease the incidence and recurrence of pterygia.

PMID- 12407154
TI  - Ocular torsion during voluntary blinks in humans.
AB  - PURPOSE: Most studies on blink-induced eye movements have been restricted to
      rotations about the horizontal and vertical axes. By additionally measuring
      rotation about the torsional axis, the authors investigated whether the three
      dimensional rotation of the eye during the early phase of eyelid closure could be
      assigned to the action of a single extraocular muscle. METHODS: In five healthy
      human subjects, eye movements about all principal axes of rotation (horizontal,
      vertical, and torsional) were recorded during voluntary blinks of different
      durations (as short as possible, 0.83 seconds, and 1.67 seconds) in straight
      ahead gaze. Original dual search coils frequently rotate about the line of sight,
      because the upper eyelid touches the nasally exiting wire leads. Therefore, the
      search coils were modified so that the wires left the silicon annulus from its
      inner border at 6 o'clock. RESULTS: The earliest eye movement during blinks
      consisted of a pulselike trajectory in a direction that was always extorsional,
      downward, and inward, regardless of the duration of eyelid closure. The beginning
      of all three movement components preceded the beginning of eyelid movement; thus,
      a coil artifact is unlikely. On eyelid opening, a consistent pulselike movement
      in the intorsional, upward, and outward direction occurred. CONCLUSIONS: During
      the initial phase of voluntary eyelid closure, the eyes move in a three
      dimensional direction that is consistent with a pulselike innervation of the
      inferior rectus muscle. To obtain reliable measurement of torsional eye movements
      with dual search coils during blinks, modification of the annulus is
      indispensable.

PMID- 12407155
TI  - Comparing neural networks and linear discriminant functions for glaucoma
      detection using confocal scanning laser ophthalmoscopy of the optic disc.
AB  - PURPOSE: To determine whether neural network techniques can improve
      differentiation between glaucomatous and nonglaucomatous eyes, using the optic
      disc topography parameters of the Heidelberg Retina Tomograph (HRT; Heidelberg
      Engineering, Heidelberg, Germany). METHODS: With the HRT, one eye was imaged from
      each of 108 patients with glaucoma (defined as having repeatable visual field
      defects with standard automated perimetry) and 189 subjects without glaucoma (no
      visual field defects with healthy-appearing optic disc and retinal nerve fiber
      layer on clinical examination) and the optic nerve topography was defined by 17
      global and 66 regional HRT parameters. With all the HRT parameters used as input,
      receiver operating characteristic (ROC) curves were generated for the
      classification of eyes, by three neural network techniques: linear and Gaussian
      support vector machines (SVM linear and SVM Gaussian, respectively) and a
      multilayer perceptron (MLP), as well as four previously proposed linear
      discriminant functions (LDFs) and one LDF developed on the current data with all
      HRT parameters used as input. RESULTS: The areas under the ROC curves for SVM
      linear and SVM Gaussian were 0.938 and 0.945, respectively; for MLP, 0.941; for
      the current LDF, 0.906; and for the best previously proposed LDF, 0.890. With the
      use of forward selection and backward elimination optimization techniques, the
      areas under the ROC curves for SVM Gaussian and the current LDF were increased to
      approximately 0.96. CONCLUSIONS: Trained neural networks, with global and
      regional HRT parameters used as input, improve on previously proposed HRT
      parameter-based LDFs for discriminating between glaucomatous and nonglaucomatous
      eyes. The performance of both neural networks and LDFs can be improved with
      optimization of the features in the input. Neural network analyses show promise
      for increasing diagnostic accuracy of tests for glaucoma.

PMID- 12407156
TI  - The mechanism of increasing outflow facility during washout in the bovine eye.
AB  - PURPOSE: To investigate the relationship between outflow facility and separation
      between the inner wall of the aqueous plexus and the juxtacanalicular connective
      tissue (JCT) during washout in the bovine eye. METHODS: Facility was recorded
      during 3 hours of anterior chamber perfusion at 15 mm Hg in eight pairs of bovine
      eyes. One eye of each pair was then lowered to 0 mm Hg for 1 hour, whereas the
      fellow eye was kept at 15 mm Hg. After a brief perfusion at 15 mm Hg, both eyes
      were perfusion fixed and processed for electron microscopy. Micrographs of the
      inner wall were analyzed for separation from the JCT. To study the role of
      cellular adhesion between the inner wall and JCT, 12 additional pairs were
      perfused with integrin-binding peptide (RGD: Arg-Gly-Asp) or sham control peptide
      (RGE: Arg-Gly-Glu) at 2 micro M to 2 mM, before IOP was reduced. RESULTS: During
      the first 3 hours, facility increased in both eyes because of "washout." However,
      after 1 hour of 0 mm Hg, facility decreased by 13% (P < 0.006), whereas facility
      increased by 20% (P < 0.001) in the fellow eyes maintained at 15 mm Hg. Two types
      of separation were observed between the inner wall and JCT: cell-matrix
      separation between the endothelial cell and basal lamina and matrix-matrix
      separation between the basal lamina and JCT. A significant positive correlation
      (P = 0.042) was found between the degree of matrix-matrix separation and the
      change in outflow facility after 1 hour of 0 mm Hg. Compared with RGE control,
      RGD had no apparent effect on outflow facility (P > 0.35) or on the change in
      outflow facility after 1 hour at 0 mm Hg (P > 0.15). CONCLUSIONS: The increase in
      outflow facility that occurs during washout in the bovine eye is reversible and
      correlates with the degree of separation between the basal lamina of the inner
      wall endothelium and the JCT. Therefore, adhesions tethering the inner wall to
      the JCT may be important ultrastructural features involved in the regulation of
      aqueous humor outflow resistance.

PMID- 12407157
TI  - Signaling mechanism of TGF-beta1-induced collagen contraction mediated by bovine
      trabecular meshwork cells.
AB  - PURPOSE: To characterize the intracellular signaling mechanism that underlies the
      contraction of trabecular meshwork (TM) tissue. METHODS: The contraction of
      collagen mediated by bovine TM cells was evaluated by measuring changes in the
      diameter of collagen gels in which the cells were embedded. Changes in the
      organization of the actin cytoskeleton were examined by laser-scanning confocal
      microscopy of cells stained with fluorescent phalloidin. Cell motility was
      monitored by time-lapse video microscopy. RESULTS: Transforming growth factor
      (TGF)-beta1 induced marked TM-cell-mediated contraction of collagen gels in a
      concentration- and time-dependent manner. Inhibitors of protein kinase C (PKC)
      blocked this effect of TGF-beta1, whereas an inhibitor of PKA and -G did not. An
      inhibitor of the small guanosine triphosphatase (GTPase) Rho also inhibited TGF
      beta1-induced collagen contraction, whereas an activator of Rho promoted this
      effect of TGF-beta1. Furthermore, inhibition either of the release of Ca(2+) from
      internal stores or of the activation of myosin light-chain kinase (MLCK)
      prevented gel contraction in response to TGF-beta1. The effects of these various
      agents on TGF-beta1-induced contraction of collagen gels mediated by TM cells
      were mirrored by their effects on TGF-beta1-induced formation of actin stress
      fibers, cell spreading (the extension of cellular processes), and cell motility
      under conditions in which cell contraction was not possible. CONCLUSIONS: TGF
      beta1 induces TM-cell-mediated collagen gel contraction through activation of Rho
      and the Ca(2+)-dependent enzymes PKC and MLCK. These same signaling molecules
      contribute to TGF-beta1-induced rearrangement of the actin cytoskeleton, cell
      spreading, and cell motility.

PMID- 12407158
TI  - Gammadelta T cells in anterior chamber-induced tolerance in CD8(+) CTL responses.
AB  - PURPOSE: Delivery of antigen to the anterior chamber (AC) of the eye induces a
      systemic form of tolerance, referred to as anterior chamber-associated immune
      deviation (ACAID). ACAID is characterized by decreases in delayed-type
      hypersensitivity responses and complement-fixing antibodies on subsequent
      challenge with an immunogenic form of the antigen. The current study was designed
      to test whether priming of antigen-specific CD8(+) cytotoxic T-lymphocytes (CTLs)
      are inhibited by injection of soluble antigen into the AC and whether gammadelta
      T cells play a role in the inhibition of such responses. METHODS: Antigen was
      administered through the AC to normal gammadelta T-cell-deficient or
      reconstituted gammadelta T-cell-deficient mice. Seven days after the AC
      injection, the mice were primed with antigen in adjuvant and 10 days later, their
      spleen cells were cultured for 5 to 7 days and the CTL responses measured.
      RESULTS: CTL responses were inhibited by antigen delivered through the AC in
      normal but not gammadelta T-cell-deficient mice. Tolerance was reconstituted in
      delta-chain knockout mice by the adoptive transfer of gammadelta T cells from
      normal mice. Moreover, spleen cells and splenic gammadelta(+) T cells, but not
      gammadelta(-) T cells, from mice injected with antigen through the AC inhibited
      development of CTL responses when cultured together with primed effector T cells.
      CONCLUSIONS: These data show, for the first time, that administration of soluble
      antigen in the AC inhibits development of CD8(+) cytotoxic T-cell responses and
      that gammadelta T cells play a critical role in inhibition of CTL responses.

PMID- 12407159
TI  - Gene therapy for detached retina by adeno-associated virus vector expressing
      glial cell line-derived neurotrophic factor.
AB  - PURPOSE: To examine the protective effect of glial cell line-derived neurotrophic
      factor (GDNF) on retinal detachment (RD)-induced photoreceptor damage by using
      gene delivery. METHODS: Gene delivery to photoreceptors was achieved by
      subretinal injection of recombinant adeno-associated virus expressing GDNF (rAAV
      GDNF) in the right eyes and AAV expressing Escherichia coli LacZ (rAAV-LacZ) in
      the left eyes of Lewis rats. RD in bilateral eyes was induced with subretinal
      injection of high-density vitreous substitute in the temporal retina 3 weeks
      after gene delivery. The synthesis and accumulation of GDNF within the retina was
      monitored 3 weeks after RD by immunohistochemistry and enzyme-linked
      immunosorbent assay (ELISA), respectively. The rescue of photoreceptors was
      evaluated by monitoring the preservation of the thickness of photoreceptor outer
      segment (OS) and outer nuclear layer (ONL). Apoptosis in the photoreceptors was
      studied using the TdT-dUTP terminal nick-end labeling (TUNEL) method 2 days after
      RD. Muller cell activity was checked using the immunohistochemistry with glial
      fibrillary acidic protein (GFAP) antibody 28 days after RD. RESULTS: Gene
      delivery was demonstrated by immunohistochemical study. The results of ELISA
      confirmed that high levels of neurotrophic factors were produced in retinas.
      Photoreceptor OS degeneration and the gradual shortening of the ONL were noted
      after RD in all the eyes. However, rAAV-GDNF-treated eyes retained longer OS than
      rAAV-LacZ-treated eyes 7 (P = 0.012) and 28 days (P = 0.008) after RD. ONL was
      also longer in rAAV-GDNF-treated eyes than in rAAV-LacZ-treated eyes 7 (P =
      0.012) and 28 days (P = 0.008) after RD. GDNF-treated eyes had statistically less
      apoptotic cells than control eyes in photoreceptor layer (P = 0.043). Subretinal
      proliferation of Muller cells was suppressed in the GDNF-treated group,
      indicating less scar formation. CONCLUSIONS: GDNF is a potential factor that can
      protect photoreceptors from degeneration. In addition to preserving the OS and
      ONL structures, GDNF may exert its protective action by preventing the apoptosis
      of photoreceptors after RD. GDNF gene therapy may be a valuable adjuvant to
      current treatments in certain complicated forms of RD.

PMID- 12407160
TI  - Distinct functions of photoreceptor cell-specific nuclear receptor, thyroid
      hormone receptor beta2 and CRX in one photoreceptor development.
AB  - PURPOSE: To clarify the functions of a specific subtype of thyroid hormone
      receptor (TR), TRbeta2, and photoreceptor cell-specific nuclear receptor (PNR) in
      the development of cone photoreceptors. METHODS: The expression of short (S)- and
      medium (M)-wavelength cone opsins was analyzed by reverse transcription
      polymerase chain reaction (RT-PCR) and Northern blot analysis in mice without a
      functional PNR (rd7/rd7 mice), and levels of plasma thyroid hormones and
      expression of TRbeta2 were also examined. Concomitantly, by means of reporter
      assays, the roles of PNR and TRbeta2 in the S- and M-cone opsin expression were
      explored at the transcriptional level. RESULTS: In rd7/rd7 mice, an abnormal
      increase in cone photoreceptors was observed immediately before retinal
      maturation normally occurs. Although an increase in S-cone opsin in the retina
      was observed during and after retinal development, the expression of M-cone opsin
      expression was not perturbed during retinal maturation. Plasma concentrations of
      thyroid hormone and levels of TRbeta2 expression in the rd7/rd7 mouse retina over
      the developmental period were normal. Transcriptional studies demonstrated that
      TRbeta2, but not PNR, activated the M-cone opsin gene promoter function, while
      suppressing the S-cone opsin promoter function enhanced by CRX in a thyroid
      hormone-dependent manner. CONCLUSIONS: The results indicate that PNR may suppress
      proliferation of cone photoreceptor progenitor cells and that the regulation of S
      and M-cone opsin gene expression is mediated by TRbeta2 and CRX, but not by PNR.
      Thus, our results partly disclosed the molecular mechanism of cone photoreceptor
      development, highlighting the distinct functions of PNR and TRbeta2.

PMID- 12407161
TI  - Subconjunctival administration of bucillamine suppresses choroidal
      neovascularization in rat.
AB  - PURPOSE: Bucillamine is an antirheumatic drug with antiangiogenic properties that
      is currently used in clinical practice. Because bucillamine inhibits the
      production of VEGF, it is possible that this drug may inhibit choroidal
      neovascularization (CNV). Thus, the effect of bucillamine on the eyes of rats
      with experimental CNV was investigated in vivo by subconjunctival injection or
      oral intake. METHODS: CNV was induced in rat eyes by diode laser
      photocoagulation. The intensity of fluorescein leakage from the photocoagulated
      lesions was studied 7 and 14 days after photocoagulation. The areas of CNV
      lesions were measured histologically and studied immunohistochemically at days 4,
      7, and 14. In addition, the concentration of the drug in ocular tissue and blood
      was measured by high-performance liquid chromatography-tandem mass spectrometry
      after the drug was delivered orally or subconjunctivally. RESULTS: After
      subconjunctival injection, fluorescein leakage from the CNV lesions decreased
      significantly compared with the control eyes throughout the study period.
      Histologic and immunohistochemical analyses 4, 7, and 14 days after
      photocoagulation demonstrated that the average size of the CNV lesions was
      reduced in the bucillamine-treated eyes compared with the control eyes.
      Subconjunctival injection maximized the ocular drug concentration while
      minimizing the blood concentration of the drug compared with oral intake.
      CONCLUSIONS: Subconjunctival injection of bucillamine significantly reduced the
      leakage and size of experimental CNV. These results suggest that bucillamine may
      be beneficial in treating CNV and that further studies can be considered to
      evaluate this possibility.

PMID- 12407162
TI  - Retinal vascular development is mediated by endothelial filopodia, a preexisting
      astrocytic template and specific R-cadherin adhesion.
AB  - PURPOSE: A neonatal mouse retina developmental model was used to study
      endothelial cell guidance and subsequent formation of vascular patterns. Since
      most diseases that cause catastrophic loss of vision do so as a result of
      abnormal ocular angiogenesis, a better understanding of events regulating normal
      retinal vascular growth may provide insight into pathologic angiogenesis.
      METHODS: Development of the retinal vasculature at various postnatal and
      embryonic time points was analyzed by collagen IV immunohistochemistry and
      staining with isolectin Griffonia simplicifolia. GFAP-GFP transgenic mice were
      used to evaluate the relationship between developing vessels and retinal glial
      cells. Immunolocalization of R-cadherin and intravitreous injection of R-cadherin
      specific antibodies was performed to determine the role of R-cadherin during
      patterning of the superficial and deep retinal vascular plexuses. RESULTS: The
      characteristic honeycomb pattern of vessel formation observed in the superficial
      layer is a result of endothelial cell migration over a preexisting astrocytic
      template. Filopodial extensions associate with underlying astrocytes by
      protruding from the tips of endothelial cells at the migrating vascular front.
      Branching of vessels in the primary vascular plexus, as well as appropriate
      localization of the deep vascular network is mediated by R-cadherin, an adhesion
      molecule known to be involved in neuronal cell guidance. Injection of antibodies
      directed against R-cadherin prevents the normally extensive collateralization
      observed during formation of the superficial network. Injection of anti-R
      cadherin antibodies also dramatically affects vessels of the deep network. These
      vessels migrate beyond the normal turning point, penetrating into the deeper
      photoreceptor layer. CONCLUSIONS: . These studies suggest that angiogenesis and
      formation of vascular patterns in the retina may use many of the same
      developmental cues used by neurons in both the central and peripheral nervous
      systems. Furthermore, retinal vascular endothelial cell guidance mediated by
      filopodial extensions and neuronal guidance cues may represent a novel conceptual
      framework within which to study the establishment of vascular patterns in a
      variety of angiogenic systems.

PMID- 12407163
TI  - DNA damage and repair in light-induced photoreceptor degeneration.
AB  - PURPOSE: Intense light causes photoreceptor death that is greatest in the
      superior central retina. Short-duration treatment in a light-damage model results
      in TUNEL-positive photoreceptor nuclei within this region. However, cells lost 10
      days after light treatment are fewer than the TUNEL-labeled cells observed
      earlier. Therefore, this study was undertaken to monitor DNA fragmentation and
      cell death to explain the discrepancy. METHODS: Eyes of dark-adapted rats were
      light damaged for 4 or 5 hours. DNA fragmentation was measured by TUNEL,
      laddering, and highly repetitive short interspersed nuclear element (SINE)
      analysis in dark-adapted, nondamaged control (dark-control) retinas and in
      retinas collected at 6-hour intervals after light treatment. TUNEL-positive
      photoreceptor nuclei were counted in these samples along a superior-to-inferior
      meridian and compared with control and damaged 10-day retinas. Monocytes and DNA
      polymerase beta were monitored by immunohistochemistry. RESULTS: TUNEL-positive
      staining of photoreceptors was centered around the superior central retina. At 10
      days, photoreceptor loss had occurred in this region. In graphs of 6-hour
      interval data, two DNA-fragmentation peaks, 24 hours apart, were evident.
      Monocytes appeared after nuclear damage. Total TUNEL-positive cells under both
      peaks exceeded the number of photoreceptors lost. The DNA-repair enzyme,
      polymerase beta, was induced in the superior central retina, within photoreceptor
      inner segments, 24 hours after light treatment, but declined thereafter.
      CONCLUSIONS: One population of damaged cells may mend DNA until the repair
      mechanism is exceeded and then revert to apoptosis, or, alternatively, two
      populations may undergo DNA fragmentation 24 hours apart. Either DNA
      fragmentation is masked at midpoint by temporary repair, or two waves of damage
      occur, but repair rescues the first set, not the second. Photoreceptors lost are
      fewer than TUNEL-positive cells. Thus, both possibilities suggest photoreceptor
      DNA repair. The transient appearance of DNA polymerase beta in photoreceptors
      under these experimental conditions further suggests nuclear repair. Thus,
      maintenance of in-house DNA-repair mechanisms may provide an alternate approach
      for the rescue of photoreceptors, as well as other neurons with stress-induced
      damage. These events may provide useful drug targets to promote photoreceptor
      survival in various forms of retinal degeneration.

PMID- 12407164
TI  - Effects of homeobox genes on the differentiation of photoreceptor and
      nonphotoreceptor neurons.
AB  - PURPOSE: The homeobox genes Pax6 and Chx10 are diffusely expressed in
      proliferating, undifferentiated retina neuroepithelial cells. Distinct,
      topographically specific expression patterns emerge, however, as postmitotic
      cells become organized into layers. The hypothesis that the product of each gene
      may be necessary for the differentiation of particular nonphotoreceptor neuron
      subsets and that their absence may be required for progenitor cells to
      differentiate as photoreceptors was tested in this study. METHODS: Neural retinas
      from 5-day-old chick embryos were dissociated, cultured at low density, and
      cotransfected with a plasmid expressing the green fluorescent protein (GFP)
      reporter gene, and a plasmid expressing Pax6, Chx10, Optx2, or the control gene
      lacZ. After further culture, the cells were fixed and processed for the detection
      of cell-specific markers. RESULTS: Nonphotoreceptor neurons increased threefold
      with Chx10 and almost sixfold with Pax6, compared with cells transfected with
      lacZ. The frequency of GFP(+) cells immunoreactive with the ganglion cell
      specific antibody RA4 was unchanged by Chx10, but was increased twofold by Pax6.
      Conversely, Chx10 and Pax6 expression diminished the photoreceptor population to
      approximately 35% and 15% of control values, as determined by morphologic
      analysis, visinin immunocytochemistry, and peanut lectin binding. Optx2 had some
      inhibitory effects on photoreceptor differentiation, which were accompanied by
      marked increases in the frequency of morphologically undifferentiated cells.
      CONCLUSIONS: These results are consistent with the hypothesis that Chx10 and Pax6
      promote the differentiation of nonphotoreceptor neurons while inhibiting the
      differentiation of photoreceptor cells.

PMID- 12407165
TI  - Expression of the ETS transcription factor ELF3 in the retinal pigment
      epithelium.
AB  - PURPOSE: The ETS family of transcription factors regulate several critical
      cellular functions. They have also been implicated in invertebrate ocular
      development. This work was undertaken to determine whether epithelium-specific
      ETS transcription factors are expressed in the retinal pigment epithelium and to
      investigate the possible role of these factors in retinal diseases such as age
      related macular degeneration. METHODS: The expression of the epithelial ETS
      transcription factors ELF5, ESE3, and ELF3 was assessed by RT-PCR in the human
      RPE cell lines D407 and hTERT-RPE1. The full-length coding sequence of rat Elf3
      was isolated with 3' rapid amplification of cDNA ends (RACE) and degenerative
      primers, and its expression was determined in various rat tissues, by RT-PCR and
      real-time PCR. A polyclonal ELF3 antibody produced from a C-terminal peptide was
      used to observe the distribution of the transcription factor within the retina.
      To assess the possible ELF3 regulation of the TIMP3 promoter, transient
      transfection assays were performed. Promoter activity was determined with a
      firefly luciferase reporter gene construct. RESULTS: The epithelium-specific ETS
      transcription factor ELF3 was expressed in the D407 and hTERT-RPE1 cell lines.
      Neither ESE3 nor ELF5 was detected in the RPE. The cloning of rat Elf3 produced
      two splice variants, designated Elf3a (1786 bp) and Elf3b (1855 bp). The larger
      form, Elf3b, contained a 69-bp insert in the coding sequence, which showed high
      homology to a similar insert previously identified in murine Elf3. Both splice
      variants were expressed in rat lung, kidney, liver, and retina, but were absent
      in heart tissue. Real-time PCR analysis showed the retina to contain high levels
      of Elf3, which was subsequently localized to the RPE. Elf3 upregulated the TIMP3
      promoter, with Elf3a and -3b inducing an approximate sixfold increase in
      activity. CONCLUSIONS: The ELF3 transcription factor is highly expressed in the
      RPE and can regulate important ocular genes, such as TIMP3, in vitro. The
      specific expression of ELF3 in the RPE may reflect an important role for this
      transcription factor in retinal function. Furthermore, its regulation of TIMP3
      may have implications for degenerative retinal diseases, such as age-related
      macular degeneration.

PMID- 12407166
TI  - Elevated retinal zeaxanthin and prevention of light-induced photoreceptor cell
      death in quail.
AB  - PURPOSE: Inferential evidence indicates that macular pigments (lutein and
      zeaxanthin) protect photoreceptors and/or retard age-related macular
      degeneration. These experiments tested the hypothesis that retinal zeaxanthin
      prevents light-induced photoreceptor cell death. METHODS: Retinal damage was
      assessed in quail fed a carotenoid-deficient (C-) diet for 6 months. Groups of 16
      birds (8 male, 8 female) were fed a C- diet supplemented with 35 mg 3R,3'R
      zeaxanthin for 1, 3, or 7 days; one group was continued on C- diets. Half of each
      group was exposed to intermittent 3200-lux white light (10 1-hour intervals
      separated by 2 hours in dark). After 14 additional hours in the dark, one retina
      of each quail was collected for HPLC analysis, and the contralateral retina was
      embedded in paraffin for counts of apoptotic nuclei. RESULTS: After 7 days'
      supplementation, concentrations of zeaxanthin in serum, liver, and fat had
      increased by factors of 50.8, 43.2, and 6.5, respectively (all P < 0.001). In
      contrast, retinal zeaxanthin fluctuated significantly upward on day 3, but there
      was no net change on day 7. The number of apoptotic rods and cones in light
      damaged eyes correlated significantly and inversely with zeaxanthin concentration
      in the contralateral retina (r = -0.61; P < 0.0001 and r = -0.54; P < 0.002), but
      not with serum zeaxanthin. Similar correlations were observed with retinal
      lutein, which correlated strongly with retinal zeaxanthin (r = 0.95; P < 0.0001).
      CONCLUSIONS: Retinal zeaxanthin dose dependently reduced light-induced
      photoreceptor apoptosis; elevated serum levels did not. These data provide the
      first experimental evidence that xanthophyll carotenoids protect photoreceptors
      in vivo.

PMID- 12407167
TI  - Protection of retinal pigment epithelial cells from oxidative damage by oltipraz,
      a cancer chemopreventive agent.
AB  - OBJECTIVE: To determine whether oltipraz (4-methyl-5-pyrazinyl-3H-1,2-dithiole-3
      thione) protects against oxidative injury in cultured human retinal pigment
      epithelial (hRPE) cells. METHODS: Primary cultured hRPE cells were incubated with
      various concentrations of oltipraz followed by treatment with the chemical
      oxidant tert-butylhydroperoxide (tBH). Cell viability was assessed by release of
      lactate dehydrogenase (LDH) and cleavage of WST-1. Intracellular and
      mitochondrial levels of glutathione (GSH) were measured by HPLC. Glutathione S
      transferase (GST), NADPH-quinone reductase (NQR), and glutathione peroxidase
      (GPx) were measured by specific enzyme activity assays. RESULTS: Treatment of
      hRPE cells with oltipraz inhibited tBH-induced cell death in a concentration
      dependent manner with significant inhibition at 50 micro M. Olitpraz (50 micro M)
      increased GSH levels in hRPE cells by approximately 18% and in hRPE mitochondrial
      fractions by approximately 50% after 24 hours of exposure. Treatment with
      oltipraz increased GST and NQR activities by approximately 21% and 11%,
      respectively. CONCLUSIONS: Oltipraz protects hRPE cells against tBH induced
      injury. The mechanism of protection is likely to include increased cellular and
      mitochondrial GSH levels and induction of detoxification enzymes, including GST
      and NQR. Dietary supplementation with oltipraz or other dithiolethiones may help
      protect the hRPE against oxidant induced injury.

PMID- 12407168
TI  - The P2Y(2) receptor agonist INS37217 stimulates RPE fluid transport in vitro and
      retinal reattachment in rat.
AB  - PURPOSE: To investigate the effects of INS37217, a synthetic P2Y(2) receptor
      agonist, on intracellular calcium signaling, electrophysiology, and fluid
      transport in vitro and on experimentally induced retinal detachment in rat eyes
      in vivo. METHODS: Freshly isolated monolayers of bovine and human fetal RPE were
      mounted in Ussing chambers for measurements of cytosolic calcium levels
      ([Ca(2+)](i)), membrane voltages and resistances, and transepithelial fluid
      transport. Retinal detachments were experimentally produced in Long-Evans rats by
      injecting modified phosphate-buffered saline into the subretinal space (SRS).
      Experimental or vehicle solutions were injected into the vitreous, and the size
      of blebs in the SRS was scored under masked conditions. RESULTS: Addition of
      INS37217 to Ringer's solution bathing the apical membrane transiently increased
      [Ca(2+)](i), altered membrane voltages and resistances and generally produced
      responses that were similar in magnitude to those of uridine triphosphate (UTP).
      In fluid transport experiments performed with the capacitance probe technique,
      INS37217 significantly increased fluid absorption across freshly isolated bovine
      and fetal human RPE monolayers. All in vitro results were blocked by apical 4,4'
      diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS), which has been shown to
      block P2Y(2) receptors in the RPE. Intravitreal administration of INS37217, but
      not UTP, in the rat model of retinal detachment enhanced the removal of SRS fluid
      and facilitated retinal reattachment when compared with vehicle control.
      CONCLUSIONS: These findings indicate that INS37217 stimulates the RPE fluid
      "pump" function in vitro by activating P2Y(2) receptors at the apical membrane.
      In vivo INS37217 enhances the rates of subretinal fluid reabsorption in
      experimentally induced retinal detachments in rats and may be therapeutically
      useful for treating a variety of retinal diseases that result in fluid
      accumulation in the subretinal space.

PMID- 12407169
TI  - Effect of INS37217, a P2Y(2) receptor agonist, on experimental retinal detachment
      and electroretinogram in adult rabbits.
AB  - PURPOSE: To evaluate the effects of subretinal and intravitreal delivery of
      INS37217, a P2Y(2) receptor agonist, on subretinal fluid reabsorption in
      experimentally induced retinal detachments in rabbits, and to characterize the
      effects of INS37217 on electroretinograms (ERG) in rabbits. METHODS: A single
      retinal detachment was produced in New Zealand White rabbits by injecting
      approximately 50 micro L of modified phosphate-buffered saline (MPBS) solution
      into the subretinal space (SRS). In all experiments, one eye served as the
      INS37217-treated eye and the contralateral eye served as the vehicle control. In
      the first series of experiments, each rabbit received a SRS injection of MPBS
      solution, with or without INS37217 (1 mM). In the second series of experiments,
      each eye received an SRS injection of MPBS solution, followed by an intravitreal
      injection of MPBS solution, with or without INS37217 (12, 1.4, and 0.15 mM). A
      masked observer determined the size of blebs by indirect ophthalmoscopy at 30
      minute intervals for up to 3 hours after SRS injections. Optical coherence
      tomography (OCT) was conducted to provide cross-sectional images of the blebs.
      Cellular expression of P2Y(2) receptor mRNA was localized by nonradioisotopic in
      situ hybridization in fresh rabbit retina-RPE tissue sections. Bilateral, full
      field scotopic and photopic ERGs were made at 1, 7, and 14 days after a single
      intravitreal injection of 24 mM INS37217. RESULTS: SRS administration of 1 mM
      INS37217 significantly enhanced subretinal fluid reabsorption when compared with
      vehicle controls (P < 0.05; repeated measures ANOVA). Intravitreal administration
      of INS37217 at 12 and 1.4 mM, but not at 0.15 mM, also significantly enhanced
      subretinal fluid reabsorption (P < 0.05). P2Y(2) receptor mRNA was observed
      throughout the RPE and in discrete layers of the retina. INS37217 had no adverse
      effects on scotopic and photopic ERG amplitude and latency parameters at any of
      the postadministration time points evaluated. CONCLUSIONS: These results
      demonstrate that INS37217 enhances subretinal fluid reabsorption in experimental
      retinal detachment in rabbits and support the development of INS37217 for
      stimulating subretinal fluid reabsorption in conditions that result in retinal
      detachment or retinal edema.

PMID- 12407170
TI  - Retinal pigment epithelium is protected against apoptosis by alphaB-crystallin.
AB  - PURPOSE: The degeneration of retinal pigment epithelial (RPE) cells is considered
      to be a crucial event in the pathophysiology of age-related macular degeneration
      (AMD). Cumulative oxidative damage has been implicated in the development of the
      changes seen in AMD. The present study was undertaken to evaluate the expression
      of the small heat shock protein alphaB-crystallin in the RPE in response to
      oxidative stress and to explore whether alphaB-crystallin expression confers an
      antiapoptotic cytoprotective effect on RPE cells. METHODS: Native human RPE cells
      from the macula and retinal periphery were analyzed by RT-PCR and Western blot
      analysis for expression of alphaB-crystallin. Monolayer cultures of human RPE
      cells were stressed by heat shock (42 degrees C for 20 minutes) or oxidant
      mediated injury (50-300 micro M H(2)O(2) for 1 hour). Induction of alphaB
      crystallin and the corresponding mRNA was assessed by Western and Northern blot
      analyses. To study the cytoprotective effect of alphaB-crystallin, human RPE
      cells were transfected with either a neomycin-selectable expression vector
      containing alphaB-crystallin cDNA or a control vector without alphaB-crystallin
      cDNA. Caspase-3 activity was determined by observing the cleavage of a
      colorimetric peptide substrate. Cell viability was quantified by combined
      propidium iodide and Hoechst 33342 staining. RESULTS: alphaB-crystallin is
      constitutively expressed in RPE under in vivo and in vitro conditions. Western
      blot analysis of freshly isolated RPE showed greater baseline expression levels
      in RPE derived from the macular area than in that from the more peripheral
      regions. Heat shock treatment and oxidative stress caused a significant increase
      in alphaB-crystallin mRNA and protein. Oxidant-mediated injury in RPE cells with
      baseline expression levels of alphaB-crystallin resulted in apoptotic cell death,
      as measured by caspase-3 activity, whereas RPE cells that had been stably
      transfected with alphaB-crystallin were more resistant to H(2)O(2)-induced
      cellular injury. CONCLUSIONS: alphaB-crystallin may function as a stress
      inducible antiapoptotic protein in human RPE and is inducible by oxidative
      stress, a condition implicated in the pathogenesis of AMD. Overexpression of
      alphaB-crystallin may be an important mechanism for the RPE to prevent apoptotic
      cell death in response to cellular stress.

PMID- 12407171
TI  - Sensitivity of photoreceptor-derived cell line (661W) to baculoviral p35, Z
      VAD.FMK, and Fas-associated death domain.
AB  - PURPOSE: Rod, cone, cone-rod, and macular dystrophies eventually bring about the
      death of cone photoreceptor cells. The present study explores means of inhibiting
      apoptosis in addition to inducing a specific apoptotic pathway within a
      photoreceptor-derived cell line. METHODS: Retinal cell culture of murine 661W
      photoreceptor-derived cells was used to assess the effect of both a synthetic
      peptide inhibitor of caspases (benzyloxycarbonyl-Val-Ala-DL-Asp-[Ome]
      fluoromethylketone [Z-VAD.FMK]) and a natural inhibitor, baculoviral p35. In
      addition, the effect of transfection of Fas-associated death domain (FADD), a
      cellular protein implicated in receptor-induced apoptosis, was assessed. Assays
      were performed by transient transfection of cell cultures, and results were
      recorded by cell counting, Western blot, and spectrophotometry. RESULTS: Western
      blot analysis and chromogenic caspase substrate cleavage analysis confirmed the
      activation of caspases within 661W cells. At a concentration of 80 micro M, Z
      VAD.FMK, 72.36% +/- 0.93% of 661W cells survived cytotoxic insult compared with
      6.99% +/- 1.35% of control cells. Transient transfection of 1200 ng baculoviral
      p35 conferred a protection of 75.30% +/- 4.23%, compared with 19.61% +/-1.84% of
      control cells, and it was additionally observed that as little as 50 ng
      transfection of FADD was capable of inducing the death of 53.21% +/- 1.33% of
      cells in 661W cultures. CONCLUSIONS: Apoptotic cell death in 661W cells is
      caspase dependent and may be inhibited with both a synthetic and natural
      inhibitor of caspase function. Furthermore, 661W cells are highly sensitive to
      the FADD protein, which may suggest a number of novel therapeutic approaches to
      halt photoreceptor cell apoptosis.

PMID- 12407172
TI  - An examination of physiological mechanisms underlying the frequency-doubling
      illusion.
AB  - PURPOSE: The frequency-doubling illusion is an apparent doubling of spatial
      frequency when a sinusoidal grating is modulated rapidly in temporal
      counterphase. It has been proposed that the illusion arises from a spatially
      nonlinear ganglion cell class. The current study reexamines this possibility and
      investigates other mechanisms that may underlie the illusion. METHODS: Responses
      of macaque magnocellular (MC) retinal ganglion cells were recorded to
      counterphase-modulated sinusoidal gratings of various spatial frequencies, and
      linearity of spatial summation was assessed. Human psychophysical thresholds were
      measured for a variety of phase discrimination and matching tasks. RESULTS:
      Consistent with lateral geniculate recordings reported by other authors, no
      evidence was found of a separate nonlinear (M(y)) MC cell class. The small,
      spatially nonlinear responses found were least at the low spatial frequencies
      used in clinical testing. Further analysis showed that no spatially modulated
      signal can be expected from the nonlinear response of a ganglion cell; the
      nonlinearity of spatial summation gives a doubled response in time but not across
      space. Psychophysical performance was consistent with an inability to distinguish
      the temporal phase of counterphase-modulated gratings when the illusion occurs.
      From 4 to 40 Hz, the zero-crossings of the modulated sinusoidal grating provided
      a spatial cue and were matched to comparison patterns at twice the stimulus
      spatial frequency. CONCLUSIONS: These results are inconsistent with the
      hypothesis that spatially nonlinear (M(y)) retinal ganglion cells are the
      physiological substrate of the frequency-doubling illusion. A cortical loss of
      temporal phase discrimination may be the principle cause of the illusion.

PMID- 12407173
TI  - Female investment is retarded pending reception of allosperm in a hermaphroditic
      colonial invertebrate.
AB  - Young colonies of the bryozoan Celleporella hyalina are capable of acquiring
      water-borne allosperm and of using it to fertilize ova for a period of 3-6 weeks
      after reaching female sexual maturity. In these simultaneous hermaphrodites,
      early allocation to female modules, but not male, is greatly enhanced by the
      acquisition of allosperm. The degree of enhancement is inversely proportional to
      coancestry of the recipient and donor colonies, thus promoting outcrossing. This
      apparently novel mechanism of adjusting operational sex ratio depends on the
      uptake and storage of sperm by nonreproductive (somatic) modules and subsequent
      translocation to females.

PMID- 12407174
TI  - Evidence of hybridity in invasive watermilfoil (Myriophyllum) populations.
AB  - Invasions of nonindigenous species have caused ecological devastation to natural
      communities worldwide, yet the biological bases for invasiveness remain poorly
      understood. Our studies of invasive watermilfoil (Myriophyllum) populations
      revealed widespread polymorphisms in biparentally inherited nuclear ribosomal DNA
      sequences, which were not detected in populations of native North American
      species. Subclones of the polymorphic regions revealed the occurrence of distinct
      sequences matching those acquired from both nonindigenous and native North
      American species. Molecular data demonstrate clearly that invasive watermilfoil
      populations in North America have resulted from hybridization between
      nonindigenous and native species. These observations suggest that invasiveness in
      these aggressive aquatic weeds may be linked to heterosis maintained by
      vegetative propagation.

PMID- 12407175
TI  - Structural features of cytochrome c' folding intermediates revealed by
      fluorescence energy-transfer kinetics.
AB  - We employed fluorescence energy-transfer probes to investigate the polypeptide
      dynamics accompanying cytochrome c' folding. Analysis of fluorescence energy
      transfer kinetics from wild-type Trp-72 or Trp-32 in a crystallographically
      characterized (1.78 A) Q1A/F32W/W72F mutant shows that there is structural
      heterogeneity in denatured cytochrome c'. Even at guanidine hydrochloride
      concentrations well beyond the unfolding transition, a substantial fraction of
      the polypeptides ( approximately 50%) adopts compact conformations (tryptophan-to
      heme distance, approximately 25 A) in both pseudo-wild-type (Q1A) and mutant
      proteins. A burst phase (< or =5 ms) is revealed when stopped flow-triggered
      refolding is probed by tryptophan intensity: measurements on the Q1A protein show
      that approximately 75% of the Trp-72 fluorescence (83% for Trp-32) is quenched
      within the mixing deadtime, suggesting that most of the polypeptides have
      collapsed.

PMID- 12407176
TI  - Differentiation of Hdm2-mediated p53 ubiquitination and Hdm2 autoubiquitination
      activity by small molecular weight inhibitors.
AB  - The oncoprotein hdm2 ubiquitinates p53, resulting in the rapid degradation of p53
      through the ubiquitin (Ub)-proteasome pathway. Hdm2-mediated destabilization and
      inactivation of p53 are thought to play a critical role in a number of human
      cancers. We have used an in vitro enzyme assay, monitoring hdm2-catalyzed Ub
      transfer from preconjugated Ub-Ubc4 to p53, to identify small molecule inhibitors
      of this enzyme. Three chemically distinct types of inhibitors were identified
      this way, each with potency in the micromolar range. All three types of compounds
      display selective inhibition of hdm2 E3 ligase activity, with little or no effect
      on other Ub-using enzymes. Most strikingly, these compounds do not inhibit the
      autoubiquitination activity of hdm2. Steady-state analysis reveals that all three
      classes behave as simple reversible inhibitors of the enzyme and that they are
      noncompetitive with respect to both substrates, Ub-Ubc4 and p53. Studies of the
      effects of combinations of two inhibitory molecules on hdm2 activity indicate
      that the three types of compounds bind in a mutually exclusive fashion,
      suggesting a common binding site on hdm2 for all of these inhibitors. These
      compounds establish the feasibility of selectively blocking hdm2-mediated
      ubiquitination of p53 by small molecule inhibitors. Selective inhibitors of hdm2
      E3 ligase activity could provide a novel mechanism for the development of new
      chemotherapeutics for the treatment of human cancers.

PMID- 12407177
TI  - Laminar specificity of functional MRI onset times during somatosensory
      stimulation in rat.
AB  - The blood oxygenation level-dependent (BOLD) response to somatosensory
      stimulation was measured in alpha-chloralose-anesthetized rats. BOLD fMRI was
      obtained at 40-ms temporal resolution and spatial resolution of 200 x 200 x 2,000
      microm(3) by using a gated activation paradigm in an 11.7 T MRI. Results show a
      consistent heterogeneity of fMRI onset times and amplitudes. The earliest onset
      time (0.59 +/- 0.17 s, n = 9) corresponded anatomically to layer IV, with
      superficial and deeper layers starting significantly later (1.27 +/- 0.43 s in
      layers I-III, and 1.11 +/- 0.45 s in layer VI). The amplitude of BOLD signal
      changes also varied with the cortical depth from the pial surface. Changes in the
      supragranular layers (8.3%) were 44% bigger than changes in the intermediate
      layers (5.5%), located only approximately 700 microm below, and 144% larger than
      the bottom layer (3.5%), located approximately 1.4 mm below the pial surface. The
      data presented demonstrate that BOLD signal changes have distinct amplitude and
      temporal characteristics, which vary spatially across cortical layers.

PMID- 12407178
TI  - RNA-binding protein Musashi family: roles for CNS stem cells and a subpopulation
      of ependymal cells revealed by targeted disruption and antisense ablation.
AB  - Homologues of the Musashi family of RNA-binding proteins are evolutionarily
      conserved across species. In mammals, two members of this family, Musashi1 (Msi1)
      and Musashi2 (Msi2), are strongly coexpressed in neural precursor cells,
      including CNS stem cells. To address the in vivo roles of msi in neural
      development, we generated mice with a targeted disruption of the gene encoding
      Msi1. Homozygous newborn mice frequently developed obstructive hydrocephalus with
      aberrant proliferation of ependymal cells in a restricted area surrounding the
      Sylvius aqueduct. These observations indicate a vital role for msi1 in the normal
      development of this subpopulation of ependymal cells, which has been speculated
      to be a source of postnatal CNS stem cells. On the other hand, histological
      examination and an in vitro neurosphere assay showed that neither the embryonic
      CNS development nor the self-renewal activity of CNS stem cells in embryonic
      forebrains appeared to be affected by the disruption of msi1, but the diversity
      of the cell types produced by the stem cells was moderately reduced by the msi1
      deficiency. Therefore, we performed antisense ablation experiments to target both
      msi1 and msi2 in embryonic neural precursor cells. Administration of the
      antisense peptide-nucleotides, which were designed to specifically down-regulate
      msi2 expression, to msi1(-/-) CNS stem cell cultures drastically suppressed the
      formation of neurospheres in a dose-dependent manner. Antisense-treated msi1(-/-)
      CNS stem cells showed a reduced proliferative activity. These data suggest that
      msi1 and msi2 are cooperatively involved in the proliferation and maintenance of
      CNS stem cell populations.

PMID- 12407179
TI  - The Coprinus cinereus adherin Rad9 functions in Mre11-dependent DNA repair,
      meiotic sister-chromatid cohesion, and meiotic homolog pairing.
AB  - Mitotic sister-chromatid cohesion (SCC) is known to depend in part on conserved
      proteins called adherins, which although necessary for SCC are not themselves
      localized between sister chromatids. We have examined mitotic DNA-repair and
      meiotic chromosome behavior in the Coprinus cinereus adherin mutant rad9-1.
      Genetic pathway analysis established that Rad9 functions in an Mre11-dependent
      pathway of DNA repair. Using fluorescence in situ hybridization, we found that
      the rad9-1 mutant is defective in the establishment of meiotic homolog pairing at
      both interstitial and subtelomeric sites but in the maintenance of pairing at
      only interstitial loci. To determine the role of Rad9 in meiotic SCC, we
      hybridized nuclear spreads simultaneously with a homolog-specific probe and a
      probe that recognizes both members of a homologous pair. We found that Rad9 is
      required for wild-type levels of meiotic SCC, and that nuclei showing loss of
      cohesion were twice as likely also to fail at homolog pairing. To ask whether the
      contribution of Rad9 to homolog pairing is solely in the establishment of SCC, we
      examined a rad9-1;msh5-22 double mutant, in which premeiotic DNA replication is
      inhibited. The msh5-22 mutation partially suppressed the deleterious effects of
      the rad9-1 mutation on homolog pairing; however, pairing in the double mutant
      still was significantly lower than in the msh5-22 single mutant control. Because
      the role of Rad9 in homolog pairing is not obviated by the absence of a sister
      chromatid, we conclude that adherins have one or more early meiotic functions
      distinct from the establishment of cohesion.

PMID- 12407180
TI  - The Usher syndrome proteins cadherin 23 and harmonin form a complex by means of
      PDZ-domain interactions.
AB  - Usher syndrome type 1 (USH1) patients suffer from sensorineuronal deafness,
      vestibular dysfunction, and visual impairment. Several genetic loci have been
      linked to USH1, and four of the relevant genes have been identified. They encode
      the unconventional myosin VIIa, the PDZ-domain protein harmonin, and the putative
      adhesion receptors cadherin 23 (CDH23) and protocadherin 15 (PCDH15). We show
      here that CDH23 and harmonin form a protein complex. Two PDZ domains in harmonin
      interact with two complementary binding surfaces in the CDH23 cytoplasmic domain.
      One of the binding surfaces is disrupted by sequences encoded by an alternatively
      spliced CDH23 exon that is expressed in the ear, but not the retina. In the ear,
      CDH23 and harmonin are expressed in the stereocilia of hair cells, and in the
      retina within the photoreceptor cell layer. Because CDH23-deficient mice have
      splayed stereocilia, our data suggest that CDH23 and harmonin are part of a
      transmembrane complex that connects stereocilia into a bundle. Defects in the
      formation of this complex are predicted to disrupt stereocilia bundles and cause
      deafness in USH1 patients.

PMID- 12407181
TI  - The A14-A43 heterodimer subunit in yeast RNA pol I and their relationship to Rpb4
      Rpb7 pol II subunits.
AB  - A43, an essential subunit of yeast RNA polymerase I (pol I), interacts with Rrn3,
      a class I general transcription factor required for rDNA transcription. The pol I
      Rrn3 complex is the only form of enzyme competent for promoter-dependent
      transcription initiation. In this paper, using biochemical and genetic
      approaches, we demonstrate that the A43 polypeptide forms a stable heterodimer
      with the A14 pol I subunit and interacts with the common ABC23 subunit, the yeast
      counterpart of the omega subunit of bacterial RNA polymerase. We show by
      immunoelectronic microscopy that A43, ABC23, and A14 colocalize in the three
      dimensional structure of the pol I, and we demonstrate that the presence of A43
      is required for the stabilization of both A14 and ABC23 within the pol I. Because
      the N-terminal half of A43 is clearly related to the pol II Rpb7 subunit, we
      propose that the A43-A14 pair is likely the pol I counterpart of the Rpb7-Rpb4
      heterodimer, although A14 distinguishes from Rpb4 by specific sequence and
      structure features. This hypothesis, combined with our structural data, suggests
      a new localization of Rpb7-Rpb4 subunits in the three-dimensional structure of
      yeast pol II.

PMID- 12407182
TI  - Negative autoregulation of BCL-6 is bypassed by genetic alterations in diffuse
      large B cell lymphomas.
AB  - Thirty to forty percent of diffuse large B cell lymphomas (DLBCL) carry BCL-6
      translocations that disrupt its 5' regulatory region. This same region is also
      subject to somatic hypermutations, although only a small fraction of these
      mutations have a detectable effect on transcription. Here, we show that
      transcription of the BCL-6 gene is negatively self-regulated in multiple cell
      types. This mechanism operates by means of the interaction of two BCL-6-binding
      sites within exon 1 of the gene and the BCL-6 protein itself, which is a potent
      transcription repressor. Because the DLBCL-associated "activating mutations"
      specifically target these exon 1 binding sites, and because the entire exon 1 is
      usually removed in the BCL-6-translocated tumors, this autoregulation is bypassed
      in 30-40% of all DLBCL cases. Our results not only demonstrate an important
      mechanism governing the expression of BCL-6, but also explain how BCL-6 is
      deregulated in a large number of DLBCL patients, providing a better understanding
      of BCL-6-related lymphomagenesis.

PMID- 12407183
TI  - Genomic analysis of immediate/early response to shear stress in human coronary
      artery endothelial cells.
AB  - The involvement of shear stress in the pathogenesis of vascular disease has
      motivated efforts to define the endothelial cell response to applied shear stress
      in vitro. A central question has been the mechanisms by which endothelial cells
      perceive and respond to changes in fluid flow. We have utilized cDNA microarrays
      to characterize the immediate/early genomic response to applied laminar shear
      stress (LSS) in primary cultures of human coronary artery endothelial cells
      (HCAECs). Cells were exposed, in a parallel plate flow chamber, to 0, 15, or 45
      dyn/cm2 LSS for 1 h, and gene expression profiles were determined using human
      GEM1 cDNA microarrays. We find that a high proportion of LSS-responsive genes are
      transcription factors, and these are related by their involvement in growth
      arrest. These likely play a central role in the reprogramming of endothelial
      homeostasis following the switch from a static to a shear-stressed environment.
      LSS-responsive genes were also found to encode factors involved in
      vasoreactivity, signal transduction, antioxidants, cell cycle-associated genes,
      and markers of cytoskeletal function and dynamics.

PMID- 12407184
TI  - Exon truncation by alternative splicing of murine ICAM-1.
AB  - The murine gene for intercellular adhesion molecule-1 (ICAM-1) encodes multiple
      products, arising from alternative splicing. Full-length ICAM-1 contains five
      extracellular Ig domains, each encoded by a separate exon. Alternatively spliced
      forms have Ig domains 2, 3, and/or 4 excised as a result of exon skipping. We
      report here a novel splice variant of murine ICAM-1, resulting from exon
      truncation rather than exon skipping and affecting Ig domain 5. A 5' splice donor
      site within exon 6 generates transcripts missing 69 nucleic acids from the 3'
      terminus of the exon. This in-frame exon truncation is predicted to replace 24
      amino acids within Ig domain 5 with a single aspartic acid residue, yielding a
      structure other than an Ig domain immediately external to the membrane.
      Expression of this alternatively spliced form is induced in mouse lungs, spleen,
      and kidneys during LPS-induced pulmonary inflammation. Since the affected region
      is critical for ICAM-1 presentation, dimerization, and solubilization, this
      alternative splice variant may have unique physiological functions.

PMID- 12407185
TI  - Statistical evaluation of SAGE libraries: consequences for experimental design.
AB  - Since the introduction of serial analysis of gene expression (SAGE) as a method
      to quantitatively analyze the differential expression of genes, several
      statistical tests have been published for the pairwise comparison of SAGE
      libraries. Testing the difference between the number of specific tags found in
      two SAGE libraries is hampered by the fact that each SAGE library is only one
      measurement: the necessary information on biological variation or experimental
      precision is not available. In the currently available tests, a measure of this
      variance is obtained from simulation or based on the properties of the tag
      distribution. To help the user of SAGE to decide between these tests, five
      different pairwise tests have been compared by determining the critical values,
      that is, the lowest number of tags that, given an observed number of tags in one
      library, needs to be found in the other library to result in a significant P
      value. The five tests included in this comparison are SAGE300, the tests
      described by Madden et al. (Oncogene 15: 1079-1085, 1997) and by Audic and
      Claverie (Genome Res 7: 986-995, 1997), Fisher's Exact test, and the Z test,
      which is equivalent to the chi-squared test. The comparison showed that, for SAGE
      libraries of equal as well as different size, SAGE300, Fisher's Exact test, Z
      test, and the Audic and Claverie test have critical values within 1.5% of each
      other. This indicates that these four tests will give essentially the same
      results when applied to SAGE libraries. The Madden test, which can only be used
      for libraries of similar size, is, with 25% higher critical values, more
      conservative, probably because the variance measure in its test statistic is not
      appropriate for hypothesis testing. The consequences for the choice of SAGE
      library sizes are discussed.

PMID- 12407186
TI  - Classification and expression analysis of Arabidopsis F-box-containing protein
      genes.
AB  - F-box proteins regulate diverse cellular processes, including cell cycle
      transition, transcriptional regulation and signal transduction, by playing roles
      in Skp1p-cullin-F-box protein (SCF) complexes or non-SCF complexes. F-box
      proteins are encoded by a large gene family. Our database search revealed that at
      least 568 F-box protein genes are present in the Arabidopsis thaliana
      (Arabidopsis) genome. Domain search analysis using SMART and Pfam-A databases
      revealed that 67 of the F-box proteins contained Kelch repeats and 29 contained
      leucine-rich repeats (LRRs). Interestingly only two F-box proteins contained WD40
      repeats that are found in many F-box proteins of other organisms. Kelch repeats,
      LRRs and WD40 repeats are implicated in protein-protein interactions. This
      analysis also resulted in the finding of several unique functional domains;
      however, 448 of the F-box proteins did not contain any known domains. Therefore,
      these proteins were used to search the Pfam-B database to find novel domains, and
      three putative ones were found. These domain search analyses led us to classify
      the Arabidopsis F-box proteins into at least 19 groups based on their domain
      structures. Macro array analysis showed that several F-box protein genes are
      expressed in a tissue-specific manner.

PMID- 12407187
TI  - A vacuolar sorting receptor PV72 on the membrane of vesicles that accumulate
      precursors of seed storage proteins (PAC vesicles).
AB  - A novel vesicle, referred to as a precursor-accumulating (PAC) vesicle, mediates
      the transport of storage protein precursors to protein storage vacuoles in
      maturing pumpkin seeds. PV72, a type I integral membrane protein with three
      repeats of epidermal growth factor, was found on the membrane of the PAC
      vesicles. PV72 had an ability to bind to pro2S albumin, a storage protein
      precursor, in a Ca(2+)-dependent manner, via the C-terminal region of pro2S
      albumin, which was found to function as a vacuolar targeting signal. This implies
      that PV72 is a vacuolar sorting receptor of the storage protein. PV72 was
      specifically and transiently accumulated at the middle stage of seed maturation
      in association with the synthesis of storage proteins. Subcellular fractionation
      showed that PV72 was also accumulated in the microsomal fraction. A fusion
      protein consisting of GFP and the transmembrane domain and the cytosolic tail of
      PV72 was localized in Golgi complex. PV72 in the isolated PAC vesicles had a
      complex type of oligosaccharide, indicating that PV72 passed though the Golgi
      complex. These results suggest that PV72 is recycled between PAC vesicles and
      Golgi complex/post-Golgi compartments. PV72 appears to be responsible for
      recruiting pro2S albumin molecules from the Golgi complex to the PAC vesicles.

PMID- 12407188
TI  - Hd3a, a rice ortholog of the Arabidopsis FT gene, promotes transition to
      flowering downstream of Hd1 under short-day conditions.
AB  - Heading date 3a (Hd3a) has been detected as a heading-date-related quantitative
      trait locus in a cross between rice cultivars Nipponbare and Kasalath. A previous
      study revealed that the Kasalath allele of Hd3a promotes heading under short-day
      (SD) conditions. High-resolution linkage mapping located the Hd3a locus in a
      approximately 20-kb genomic region. In this region, we found a candidate gene
      that shows high similarity to the FLOWERING LOCUS T (FT) gene, which promotes
      flowering in Arabidopsis: Introduction of the gene caused an early-heading
      phenotype in rice. The transcript levels of Hd3a were increased under SD
      conditions. The rice Heading date 1 (Hd1) gene, a homolog of CONSTANS (CO), has
      been shown to promote heading under SD conditions. By expression analysis, we
      showed that the amount of Hd3a mRNA is up-regulated by Hd1 under SD conditions,
      suggesting that Hd3a promotes heading under the control of Hd1. These results
      indicate that Hd3a encodes a protein closely related to Arabidopsis FT and that
      the function and regulatory relationship with Hd1 and CO, respectively, of Hd3a
      and FT are conserved between rice (an SD plant) and Arabidopsis (a long-day
      plant).

PMID- 12407189
TI  - Epi-alleles in plants: inheritance of epigenetic information over generations.
AB  - Epigenetic modification of plant gene and transposon activity, which correlates
      with their methylation, is often heritable over many generations. Such heritable
      properties allow conventional genetic linkage analysis to identify the sequences
      affected in epigenetic variants. Machinery controlling the establishment of the
      epigenetic state and role of the epigenetic controls in plant development are
      also discussed.

PMID- 12407190
TI  - Dual role of triplet localization on the accessory chlorophyll in the photosystem
      II reaction center: photoprotection and photodamage of the D1 protein.
AB  - Infrared absorption and electron spin resonance studies have shown that the
      excited triplet state of chlorophyll formed by radical pair recombination in the
      PSII reaction center is mainly localized on the accessory chlorophyll, which is
      most probably located in the D1 protein (Chl(1)). This triplet localization plays
      two contrasting roles, depending on the redox state of Q(A), in the process of
      acceptor-side photoinhibition of PSII. In the early stage of photoinhibition, in
      which singly reduced Q(A) is reversibly stabilized, the triplet state of Chl(1)
      ((3)Chl(1)*) is rapidly quenched (t(1/2) = 2-20 micro s) by the interaction with
      Q(A)(-), preventing formation of harmful singlet oxygen. In the next inhibitory
      stage, in which Q(A) is doubly reduced and then irreversibly released from the
      Q(A) pocket, the lifetime of (3)Chl(1)* becomes longer by more than two orders of
      magnitude (t(1/2) = 1-3 ms). As a result, singlet oxygen is produced around
      Chl(1) in the D1 protein, causing damage preferably to the D1 protein, which
      induces subsequent proteolytic degradation. Thus, (3)Chl(1)* functions as a
      switch to change from the protective to the degradative phase of the PSII
      reaction center by sensing either reversible or irreversible inhibited state at
      the Q(A) site.

PMID- 12407191
TI  - Differential sensitivity of oleosins to proteolysis during oil body mobilization
      in sunflower seedlings.
AB  - Until now, there has been no conclusive demonstration of any in vivo oleosin
      degradation at the early stages of oil body mobilization. The present work on
      sunflower (Helianthus annuus L.) has demonstrated limited oleosin degradation
      during seed germination. Seedling cotyledon homogenization in Tris-urea buffer,
      followed by SDS-PAGE, revealed three oleosins (16, 17.5 and 20 kDa). Incubation
      of oil bodies with total soluble protein from 4-day-old seedlings resulted in
      oleosin degradation. In vitro and in vivo degradation of the 17.5-kDa oleosin was
      faster than the other two, indicating its greater susceptibility to proteolysis.
      Oleosin degradation by the total soluble protein resulted in a transient 14.5-kDa
      polypeptide, followed by an 11-kDa protease-protected fragment, which appeared
      post-germinatively and accumulated corresponding to increased rate of lipid
      mobilization. A 65-kDa protease, active at pH 7.5-9.5, was zymographically
      detected in the total soluble protein. Its activity increased along with in vivo
      accumulation of the protease-protected fragment during seed germination and
      accompanying lipid mobilization. Protease-treated oil bodies were more
      susceptible to maize lipase action. Differential proteolytic sensitivity of
      different oleosins in the oil body membranes could be a determinant of oil body
      longevity during seed germination.

PMID- 12407192
TI  - The cyanobacterial PilT protein responsible for cell motility and transformation
      hydrolyzes ATP.
AB  - The unicellular cyanobacterium, Synechocystis sp. PCC 6803 is motile. A homologue
      of the PilT protein family, required for twitching motility in Pseudomonas
      aeruginosa and social gliding motility in Myxococcus xanthus, was found to be
      necessarily associated with cyanobacterial motility. The pilT1 (slr0161) mutant
      shows a pleotropic phenotype, defects in individual cell motility, and an
      increased number of long surface pili. Furthermore, the mutant loses its ability
      of natural competency. These findings demonstrate that PilT1 is essential for
      both cell motility and competency. Since the pilT gene contains a consensus ATP
      binding motif (Walker boxes), the PilT protein is suggested for supplying energy
      for cell motility. The product of pilT1, overproduced in Escherichia coli and
      purified by Ni-affinity chromatography, hydrolyzes ATP in vitro.

PMID- 12407193
TI  - Salt-tolerant ATPase activity in the plasma membrane of the marine angiosperm
      Zostera marina L.
AB  - Plasma membrane (PM) H(+)-ATPase and H(+) transport activity were detected in PM
      fractions prepared from Zostera marina (a seagrass), Vallisneria gigantea (a
      freshwater grass) and Oryza sativa (rice, a terrestrial plant). The properties of
      Z. marina PM H(+)-ATPase, specifically, the optimal pH for ATPase activity and
      the result of trypsin treatment, were similar to those of authentic PM H(+)
      ATPases in higher plants. In V. gigantea and O. sativa PM fractions, vanadate
      sensitive (P-type) ATPase activities were inhibited by the addition of NaCl. In
      contrast, activity in the Z. marina PM fraction was not inhibited. The nitrate
      sensitive (V-type) and azide-sensitive (F-type) ATPase activities in the Z.
      marina crude microsomal fraction and the cytoplasmic phosphoenolpyruvate
      carboxylase activity, however, were inhibited by NaCl, indicating that not all
      enzyme activities in Z. marina are insensitive to salt. Although the ratio of
      Na(+) to K(+) (Na(+)/K(+)) in seawater is about 30, Na(+)/K(+) in the Z. marina
      cells was about 1.0. The salt-tolerant ATPase activity in the plasma membrane
      must play an important role in maintaining a low Na(+) concentration in the
      seagrass cells.

PMID- 12407194
TI  - Promotion of transcript accumulation of novel Zinnia immature xylem-specific HD
      Zip III homeobox genes by brassinosteroids.
AB  - We isolated three novel homeobox genes (ZeHB-10, -11 and -12) from Zinnia elegans
      to elucidate the molecular mechanism underlying vascular system formation. ZeHB
      10, -11 and -12 encode for HD-Zip proteins of the class III to which Arabidopsis
      Athb-8, -9, -14, -15 and IFL1 belong. In situ hybridization analysis demonstrated
      that the ZeHB-10, -11 and -12 mRNAs accumulated preferentially in procambium and
      immature xylem cells in 14-day-old plants. Transcripts for the three genes also
      accumulated in cultured Zinnia cells in a xylogenesis-specific manner. The
      accumulation of transcripts for all of ZeHB-10, -11 and -12 in cultured Zinnia
      cells was suppressed strongly by uniconazole, an inhibitor of brassinosteroid
      synthesis, and such suppression was reversed by the addition of brassinolide, a
      biologically active brassinosteroid. Thus the expression of ZeHB-10, -11 and -12
      may be regulated by endogenous levels of brassinosteroids. Taken together with
      the fact that ZeHB-10, -11 and -12 proteins can bind to each other in yeast, the
      roles of HD-Zip III genes in vascular development are discussed.

PMID- 12407195
TI  - Detection of singlet oxygen and superoxide with fluorescent sensors in leaves
      under stress by photoinhibition or UV radiation.
AB  - In order to understand the physiological functions of reactive oxygen species
      (ROS) generated in leaves, their direct measurement in vivo is of special
      importance. Here we report experiments with two dansyl-based ROS sensors, the
      singlet oxygen specific DanePy and HO-1889NH, which is reactive to both singlet
      oxygen and superoxide radicals. Here we report in vivo detection of (1)O(2) and
      O(2)(-*) by fluorescence quenching of two dansyl-based ROS sensors, the (1)O(2)
      specific DanePy and HO-1889NH, which was reactive with both (1)O(2) and O(2)(-*).
      The ROS sensors were administered to spinach leaves through a pinhole, and then
      the leaves were exposed to either excess photosynthetically active radiation or
      UV (280-360 nm) radiation. Microlocalization of the sensors' fluorescence and its
      ROS-induced quenching was followed with confocal laser scanning microscopy and
      with fluorescence imaging. These sensors were specifically localized in
      chloroplasts. Quenching analysis indicated that the leaves exposed to strong
      light produced (1)O(2), but hardly any O(2)(-*). On the other hand, the dominant
      ROS in UV-irradiated leaves was O(2)(-*), while (1)O(2) was minor.

PMID- 12407196
TI  - The transcript-level-independent activation of ornithine decarboxylase in
      suspension-cultured BY2 cells entering the cell cycle.
AB  - The regulation of ornithine decarboxylase (ODC) expression was studied in
      suspension-cultured tobacco (Nicotiana tabacum L.) BY2 cells. ODC activity
      increased rapidly 3 h after cells re-entered the cell cycle from the stationary
      phase, corresponding to the G1 phase, and continued to increase in the subsequent
      S phase, while the ODC transcript level increased only transiently. ODC activity
      was suppressed by sucrose-deficiency, while the ODC transcript level was not
      affected. U0126, a specific inhibitor of mammalian MAPK kinases (MEKs),
      significantly reduced ODC enzyme activity, but not the ODC transcript level.
      These results suggest that ODC activity is regulated independently of its
      transcript level in BY2 cells, and that sucrose and a U0126-sensitive protein
      kinase are required for the transcript-level-independent activation of ODC.

PMID- 12407197
TI  - Phytochrome in cotyledons regulates the expression of genes in the hypocotyl
      through auxin-dependent and -independent pathways.
AB  - To elucidate the mechanism of plant responses to shading, we identified three
      promoter/enhancer trap lines (M812, J53, J59) that exhibited reporter expression
      in the hypocotyl in response to the end-of-day far-red light treatment.
      Interestingly, we found auxin-responsive genes in the vicinities of the reporter
      insertion sites in M812 and J53. We examined the effects of auxin on the reporter
      expression in these lines together with a previously identified N35 line. The
      results indicated that the reporter expression was induced by exogenous auxin in
      N35 and J53. Furthermore, an auxin transport inhibitor inhibited the responses of
      these lines to the end-of-day far-red light treatment, suggesting the involvement
      of auxin in the responses of plants to shading. By contrast, neither auxin nor
      the transport inhibitor affected the response in M812 and J59. Interestingly, J59
      responded to ABA. Hence, ABA might be involved in the response as well. Analysis
      of the photoreceptive sites for the responses revealed the cotyledons, not the
      hypocotyl, are the major photoreceptive sites both in the auxin-responsive and
      ABA-responsive lines. Hence, some signals appeared to be transmitted from the
      cotyledons to the hypocotyl.

PMID- 12407198
TI  - Chill-induced inhibition of photosynthesis: genotypic variation within Cucumis
      sativus.
AB  - Cucumber is generally a thermophilic species; however, cultivars have been
      selected for higher yield during winter cultivation in unheated glasshouses in
      temperate regions. We tested whether photosynthesis in these varieties had
      greater chilling tolerance. There was no difference in the instantaneous
      reduction of photosynthesis at low temperature between four winter glasshouse and
      four summer field cultivars. After 5 d of 10 degrees C and 100 micro mol m(-2) s(
      1) photon flux density, the four field cultivars had a sustained depression of
      photosynthesis after returning to clement conditions. This inhibition was
      associated with reduced rates of CO(2) fixation and photosystem II (PSII)
      electron transport in the light, but not with sustained PSII photoinhibition.
      However, photosynthesis in the glasshouse genotypes was nearly identical to the
      pre-chill rates. Chill impacts on light-adapted chlorophyll fluorescence
      parameters, such as the quantum yield of PSII electron transport (phi(PSII)),
      correlated well with overall photosynthesis. This demonstrates the potential for
      using these fast and non-invasive techniques to screen for chill-tolerant
      genotypes, with the potential to further improve winter cucumber yield in
      unheated glasshouses.

PMID- 12407199
TI  - Dual roles of photosynthetic electron transport in photosystem I biogenesis:
      light induction of mRNAs and chromatic regulation at post-mRNA level.
AB  - Light regulation of photosystem I (PSI) biogenesis was studied in a unicellular
      green alga, Chlamydomonas reinhardtii. When Chlamydomonas cells were transferred
      from darkness to the light, mRNAs for both nuclear- and chloroplast-encoded PSI
      subunits were induced in concert. This light induction was inhibited by
      photosynthetic electron transport (PET) inhibitors, 3-(3,4 dichlorophenyl)-1,1
      dimethylurea and 2,5-dibromo-3-methyl-6 isopropyl-p-benzoquinone, but not by an
      uncoupler, carbonyl cyanide m-chlorophenylhydrazone. This indicated that PET
      plays a pivotal role in the light induction of PSI subunit mRNAs, but that
      photophosphorylation is not necessary. When we irradiated the Chlamydomonas cells
      with PSI-light (695 nm) or PSII-light (644 nm), which makes the plastoquinone
      pool oxidative and reductive, respectively, PSII-light caused the accumulation of
      PSI proteins more abundantly than did PSI-light. However, there was no difference
      for the PSI subunit mRNA levels between these light sources. From these results,
      we conclude that PET plays dual roles in the regulation of PSI biogenesis in
      Chlamydomonas: when cells are illuminated, PET first induces the PSI subunit
      mRNAs irrespective of the redox state of the intersystem electron carriers, and
      then their redox state fine-tunes PSI biogenesis at translational and/or post
      translational steps to fulfil the chromatic adaptation.

PMID- 12407200
TI  - An orchid (Oncidium Gower Ramsey) AP3-like MADS gene regulates floral formation
      and initiation.
AB  - cDNA for a B group MADS box gene OMADS3 was isolated and characterized from
      Oncidium Gower Ramsey, an important species of orchid. OMADS3 encoding a 204
      amino acid protein showed high sequence homology to both paleoAP3 and TM6 lineage
      of B group MADS box gene such as monocots AP3 homologue LMADS1 in lily and GDEF1
      in Gerbera hybrida. Despite the sequence homology, consensus motifs identified in
      the C-terminal region of B group genes were absent in OMADS3. Southern analysis
      indicated that OMADS3 was present in O. Gower Ramsey genome in low copy numbers.
      Different from most B group genes, OMADS3 mRNA was detected in all four floral
      organs as well as in vegetative leaves. This is similar to the expression pattern
      of GDEF1. 35S::OMADS3 transgenic plants showed novel phenotypes by producing
      terminal flowers similar to those observed in transgenic plants ectopically
      expressed A functional genes such as AP1. Ectopic expression of OMADS3 cDNA
      truncated with the MADS box or C terminal region in Arabidopsis generated novel
      ap2-like flowers in which sepals and petals were converted into carpel-like and
      stamen-like structures. Yeast two-hybrid analysis indicated that OMADS3 is able
      to strongly form homodimers. Our results suggested that OMADS3 might represent an
      ancestral form of TM6-like gene which was conserved in monocots with a function
      similar to A functional gene in regulating flower formation as well as floral
      initiation.

PMID- 12407201
TI  - Expression of the 12-oxophytodienoic acid 10,11-reductase gene in the compatible
      interaction between pea and fungal pathogen.
AB  - Suppressors produced by Mycosphaerella pinodes are glycopeptides to block pea
      defense responses induced by elicitors. A clone, S64, was isolated as cDNA for
      suppressor-inducible gene from pea epicotyls. The treatment of pea epicotyls with
      suppressor alone induced an increase of S64 mRNA within 1 h, and it reached a
      maximum level at 3 h after treatment. The induction was not affected by
      application of the elicitor, indicating that the suppressor has a dominant action
      to regulate S64 gene expression. S64 was also induced by inoculation with a
      virulent pathogen, M. pinodes, but not by inoculation with a non-pathogen,
      Ascochyta rabiei, nor by treatment with fungal elicitor. The deduced structure of
      S64 showed high homology to 12-oxophytodienoic acid reductase (OPR) in
      Arabidopsis thaliana. A recombinant protein derived from S64 had OPR activity,
      suggesting compatibility-specific activation of the octadecanoid pathway in
      plants. Treatment with jasmonic acid (JA) or methyl jasmonic acid, end products
      of the octadecanoid pathway, inhibited the elicitor-induced accumulation of PAL
      mRNA in pea. These results indicate that the suppressor-induced S64 gene
      expression leads to the production of JA or related compounds, which might
      contribute to the establishment of compatibility by inhibiting the
      phenylpropanoid biosynthetic pathway.

PMID- 12407202
TI  - Genetic control of petiole length in Arabidopsis thaliana.
AB  - Shade-avoidance syndrome is characterized by the formation of elongated petioles
      and unexpanded leaf blades under low-intensity light, but the genetic basis for
      these responses is unknown. In this study, two-dimensional mutational analysis
      revealed that the gene for phytochrome B, PHYB, had opposing effects in the leaf
      petioles and leaf blades of Arabidopsis, while the ROT3, ACL2, and GAI genes
      influenced the length of leaf petioles more significantly than the length of leaf
      blades. Anatomical analysis revealed that the PHYB and ACL2 genes control the
      length of leaf petioles exclusively via control of the length of individual
      cells, while the GAI, GA1 and ROT3 genes appeared to control both the elongation
      and proliferation of petiole cells, in particular, under strong light. By
      contrast, both the size and the number of cells were affected by the mutations
      examined in leaf blades. The differential control of leaf petiole length and leaf
      blade expansion is discussed.

PMID- 12407203
TI  - Aquaporin isoforms responsive to salt and water stresses and phytohormones in
      radish seedlings.
AB  - Aquaporins in the plasma and vacuolar membranes play a key role in the
      intercellular and intracellular water transport in plants. First, we quantitated
      the absolute amounts for mRNAs of eight aquaporin isoforms in hypocotyls of
      radish seedlings. Then, we investigated the effects of salt and water stresses
      (150 mM NaCl, 300 mM mannitol and 20% polyethylene glycol) and phytohormones
      (gibberellic acid, abscisic acid and brassinolide) on the mRNA and protein levels
      of aquaporins in the plasma membrane (RsPIP1-1, 1-2, 1-3, 2-1, 2-2 and 2-3) and
      vacuolar membrane (RsTIP1-1 and 2-1). The mRNA and protein levels of RsTIP1-1,
      RsTIP2-1, RsPIP1-1, RsPIP1-2 and RsPIP1-3 were comparatively constant. In
      contrast, mannitol treatment altered the mRNA levels of RsPIP2-1, RsPIP2-2 and
      RsPIP2-3 in roots. Immunoblot analysis showed that the RsPIP2-1 protein level was
      increased by NaCl treatment and decreased by treatment with mannitol and
      polyethylene glycol. Gibberellic acid and abscisic acid suppressed the levels of
      mRNAs of RsPIP2-1, RsPIP2-2 and RsPIP2-3 and the protein level of RsPIP2-1 in
      roots. On the other hand, the protein levels of RsPIP1-group members and RsTIPs
      were scarcely changed by these phytohormones. In the case of hypocotyls and
      cotyledons, the mRNA and protein levels of eight isoforms were not markedly
      affected by any treatment. These results indicate that aquaporins in the root,
      especially the RsPIP2 group, may be a stress responsive type of aquaporin at
      least in the protein level.

PMID- 12407204
TI  - The active site of the thioredoxin-like domain of chloroplast protein disulfide
      isomerase, RB60, catalyzes the redox-regulated binding of chloroplast poly(A)
      binding protein, RB47, to the 5' untranslated region of psbA mRNA.
AB  - RB60, a chloroplast protein disulfide isomerase, modulates the binding of RB47,
      chloroplast poly(A)-binding protein, to the 5'-UTR of the psbA mRNA using redox
      potential, allowing for a reversible switch capable of regulating psbA mRNA
      translation in a light/dark dependent manner. RB60 contains two thioredoxin-like
      domains with putative catalytic sites of -Cys-Gly-His-Cys- that are presumed to
      function as active sites for the redox-regulated changes in RNA-binding activity
      of RB47. To investigate whether these motifs are required for redox-regulated RNA
      binding, RNA-gel-mobility shift assays were performed with RB47 and mutant RB60
      proteins with single cysteines changed to serines in the -Cys-Gly-His-Cys- motif.
      The results showed that each thioredoxin-like domain has independent catalytic
      function in the reactivation of RB47 binding and that a double active site mutant
      completely lacks the ability to activate RB47 RNA binding activity.

PMID- 12407205
TI  - A truncated mutant of the extrinsic 23-kDa protein that absolutely requires the
      extrinsic 17-kDa protein for Ca2+ retention in photosystem II.
AB  - One function of the extrinsic 23-kDa protein in photosystem II (OEC23) is to
      retain Ca(2+ )and Cl(-), two essential cofactors for photosynthetic oxygen
      evolution. A truncated mutant of OEC23 (OEC23 Delta19) revealed that 19 residues
      of the N-terminus of OEC23 were necessary for Ca(2+ )retention but not for its
      proper interaction with OEC17, the extrinsic 17-kDa protein in photosystem II.
      The lost ability of OEC23 Delta19 to reconstitute the oxygen-evolving activity
      was partially restored by OEC17 binding, suggesting the involvement of OEC17 in
      Ca(2+ )retention in photosystem II.

PMID- 12407206
TI  - Cloning, functional expression, and mutational analysis of a cDNA for Lotus
      japonicus mitochondrial phosphate transporter.
AB  - A full-length cDNA encoding mitochondrial phosphate transporter was isolated from
      symbiotic nodules of Lotus japonicus, a model legume. The gene appeared to be
      single-copied and its transcript was abundant in roots, symbiotic root nodules
      and shoots, in that order. The L. japonicus transporter has a conserved N
      ethylmaleimide-reactive Cys residue. Site-directed mutagenesis and phosphate
      transport assaying in vitro showed that this Cys residue is preferable for the
      transport activity, although it can be replaced to some extent by Ser, but not by
      Ala.

PMID- 12407207
TI  - Zinc ions inhibit the protein-DNA complex formation between cyanobacterial
      transcription factor SmtB and its recognition DNA sequences.
AB  - SmtB is a trans-acting dimeric repressor of the metal-regulated smtA gene, and
      the release of SmtB from the smtA operator/promoter region is essential for the
      tolerance to Zn(2+) stress by SmtA expression. Gel retardation assaying
      demonstrated that different sizes of SmtB-DNA complexes were formed depending on
      the DNA sequences, and the amounts of these complexes decreased in the presence
      of Zn(2+). Here, we present the first direct evidence that Zn(2+ )(>4 micro M)
      inhibits the SmtB-DNA complex formation in vitro, which ensures the physiological
      functions of SmtB as a Zn(2+) sensor and a transcription factor.

PMID- 12407208
TI  - Genetic diversity and fitness in black-footed ferrets before and during a
      bottleneck.
AB  - The black-footed ferret (Mustela nigripes) is an endangered North American
      carnivore that underwent a well-documented population bottleneck in the mid
      1980s. To better understand the effects of a bottleneck on a free-ranging
      carnivore population, we used 24 microsatellite loci to compare genetic diversity
      before versus during the bottleneck, and compare the last wild population to two
      historical populations. We also compared genetic diversity in black-footed
      ferrets to that of two sibling species, the steppe polecat (Mustela eversmanni)
      and the European polecat (Mustela putorius). Black-footed ferrets during the
      bottleneck had less genetic diversity than steppe polecats. The three black
      footed ferret populations were well differentiated (F(ST) = 0.57 +/- 0.15; mean
      +/- SE). We attributed the decrease in genetic diversity in black-footed ferrets
      to localized extinction of these genetically distinct subpopulations and to the
      bottleneck in the surviving subpopulation. Although genetic diversity decreased,
      female fecundity and juvenile survival were not affected by the population
      bottleneck.

PMID- 12407209
TI  - Selection against blue mussels (Mytilus edulis L.) homozygotes under various
      stressful conditions.
AB  - Three mussel groups differing in mean multilocus heterozygosity (MLH) were used
      to examine the MLH-fitness relationship. Mussels were submitted to aerobic and
      anaerobic stressful conditions in the laboratory, and their LT(50) was measured.
      Mortality was not random in two of the three groups and affected the homozygous
      individuals more. This selective mortality caused a significant increase in the
      mean MLH of the survivors, but only for the two groups characterized by the
      lowest initial MLH and significant deficits in heterozygotes at the onset of the
      experiments. While these experiments were ongoing, the same two groups also
      suffered a 40% mortality rate in lantern nets under field conditions. This
      mortality also increased the mean MLH in survivors. All groups showed strong
      inverse relationships between MLH and standard metabolism. Our results suggest
      that the higher resistance of more heterozygous individuals is related to their
      lower metabolic needs.

PMID- 12407210
TI  - Genetic differentiation of Anopheles gambiae s.s. populations in Mali, West
      Africa, using microsatellite loci.
AB  - Anopheles gambiae sensu stricto is a principal vector of malaria through much of
      sub-Saharan Africa, where this disease is a major cause of morbidity and
      mortality in human populations. Accordingly, population sizes and gene flow in
      this species have received special attention, as these parameters are important
      in attempts to control malaria by impacting its mosquito vector. Past measures of
      genetic differentiation have sometimes yielded conflicting results, in some cases
      suggesting that gene flow is extensive over vast distances (6000 km) and is
      disrupted only by major geological disturbances and/or barriers. Using
      microsatellite DNA loci from populations in Mali, West Africa, we measured
      genetic differentiation over uniform habitats favorable to the species across
      distances ranging from 62 to 536 km. Gene flow was strongly correlated with
      distance (r(2) = 0.77), with no major differences among chromosomes. We conclude
      that in this part of Africa, at least, genetic differentiation for microsatellite
      DNA loci is consistent with traditional models of isolation by distance.

PMID- 12407211
TI  - Gene flow among geographically diverse housefly populations (Musca domestica L.):
      a worldwide survey of mitochondrial diversity.
AB  - Single-strand conformation polymorphisms at 16S2 and COII mitochondrial genes
      were surveyed in 111 housefly samples from North, Central, and South America,
      Europe, Asia, Africa, and the Western Pacific. Forty-eight phenotypes were
      detected, of which none were ubiquitous, and 21 (44%) were confined to a single
      zoogeographical region. Nei's gene diversity index (H(S)) was 0.27 and was
      heterogeneous among zoogeographical regions. Phenotypes were the most diverse in
      the Ethiopian region and least diverse in the Palearctic and Nearctic regions.
      Hierarchical partitioning of the total diversity among regions (Nei's G(RT) =
      0.49) indicated only a small proportion was shared. The differentiation of
      populations within regions (G(SR)) was 0.32. All pairwise estimates of gene flow
      between zoogeographical regions were less than 0.31 reproducing females per
      generation (mean 0.19). We conclude that housefly populations are highly
      structured even though the flies are mobile and easily capable of passive
      transport by ship and air.

PMID- 12407212
TI  - Comparisons of likelihood and machine learning methods of individual
      classification.
AB  - Classification methods used in machine learning (e.g., artificial neural
      networks, decision trees, and k-nearest neighbor clustering) are rarely used with
      population genetic data. We compare different nonparametric machine learning
      techniques with parametric likelihood estimations commonly employed in population
      genetics for purposes of assigning individuals to their population of origin
      ("assignment tests"). Classifier accuracy was compared across simulated data sets
      representing different levels of population differentiation (low and high F(ST)),
      number of loci surveyed (5 and 10), and allelic diversity (average of three or
      eight alleles per locus). Empirical data for the lake trout (Salvelinus
      namaycush) exhibiting levels of population differentiation comparable to those
      used in simulations were examined to further evaluate and compare classification
      methods. Classification error rates associated with artificial neural networks
      and likelihood estimators were lower for simulated data sets compared to k
      nearest neighbor and decision tree classifiers over the entire range of
      parameters considered. Artificial neural networks only marginally outperformed
      the likelihood method for simulated data (0-2.8% lower error rates). The relative
      performance of each machine learning classifier improved relative likelihood
      estimators for empirical data sets, suggesting an ability to "learn" and utilize
      properties of empirical genotypic arrays intrinsic to each population. Likelihood
      based estimation methods provide a more accessible option for reliable assignment
      of individuals to the population of origin due to the intricacies in development
      and evaluation of artificial neural networks.

PMID- 12407213
TI  - Association between loci with deleterious alleles and distorted sex ratios in an
      inbred line of tilapia (Oreochromis aureus).
AB  - Three microsatellite markers (UNH159, UNH231, and UNH216) were examined for
      association with both deleterious genes and sex-ratio distortions in a full-sib
      family of 222 progeny from the fourth generation of a meiogynogenetic tilapia
      line (Oreochromis aureus). The three markers were mapped previously to different
      linkage groups and were shown to be associated with genes with deleterious
      alleles in this line. A restricted maximum likelihood model was used for analysis
      of major effects and their interactions on sex ratio and viability. This model
      was based on selective mortality of genders, ignoring effects of possible sex
      determining genes. The results showed that deleterious genes linked to UNH216 and
      UNH231 exert higher lethality in females than in males (P < .0005 and P < .05,
      respectively). UNH159 was not associated directly with sex ratio distortion, but
      acts strongly as a modifier of sex ratio in combination with UNH216 and UNH231.
      Each of the three loci was found to have a significant effect on viability (P <
      .05) in the maximum likelihood analysis. The deleterious single-locus effects act
      strongly against females, while most of the epistatic interactions exert higher
      lethality in males. This contradiction results in a close to 1:1 sex ratio at
      maturity. The genetic mechanism and significance of such a balance between
      genders are still unknown. A detailed analysis of sex-specific lethality may be
      applied by screening in appropriate series of matings and fine mapping with
      additional markers. Our data suggest that UNH216 and UNH231 are linked to sex
      ratio distortion genes and that UNH159 may be linked to a modifier of these
      genes.

PMID- 12407214
TI  - New variations in intron 4 of growth hormone gene in Chinese native chickens.
AB  - Polymorphism in intron 4 of chicken growth hormone (cGH) gene was studied in 20
      Chinese native chicken populations and broiler or layer populations. A total of
      eight restriction digestion profiles were identified in intron 4 and confirmed by
      sequencing. Among 20 populations, there were distinctively different allele
      numbers and frequencies of intron 4 restriction fragment length polymorphisms
      (RFLPs) between Chinese native chickens and broilers or layers. Two new alleles,
      allele D and allele E, were identified in Taihe Silkies. Allele D was also
      identified in other Chinese native breeds and a 50 bp fragment deletion was
      identified in allele E.

PMID- 12407215
TI  - rDNA (18S-28S and 5S) colocalization and linkage between ribosomal genes and
      (TTAGGG)(n) telomeric sequence in the earthworm, Octodrilus complanatus
      (Annelida: Oligochaeta: Lumbricidae), revealed by single- and double-color FISH.
AB  - Spermatogonial and metaphase I chromosomes of the lumbricid earthworm Octodrilus
      complanatus (Annelida: Oligochaeta) were examined using fluorescent in situ
      hybridization (FISH) with three repetitive DNA probes-5S rDNA, 18S-26S rDNA, and
      (TTAGGG)(n). Single-color FISH consistently mapped one chromosome pair per spread
      using either 5S rDNA or 18S-26S rDNA as probes. Simultaneous (18S-26S)-5S and
      (18S-26S)-(TTAGGG)(n) FISH demonstrated that repeated units of the two ribosomal
      families were overlapped and closely associated with telomeric sequences.

PMID- 12407216
TI  - Conservation of (TTAGG)(n) telomeric sequences among ants (Hymenoptera,
      Formicidae).
AB  - To determine the telomere sequence in Tapinoma nigerrimum, we carried out in situ
      hybridization using TTAGGG and TTAGG repeat polymerase chain reaction (PCR)
      generated probes. No hybridization signals were found when TTAGGG was used as a
      probe. However, strong signals were observed at the end of the chromosomes with
      the TTAGG probe. Southern blot analysis carried out on genomic DNA using TTAGG as
      a probe showed a strong hybridization signal even under highly stringent
      conditions. Similar results were obtained in Southern blot analysis carried out
      on genomic DNA of 19 species of ants belonging to three different subfamilies. In
      accordance with all the results shown in this article, the TTAGG repeat seems to
      be the major component of the telomere sequence in the majority of ant species.

PMID- 12407217
TI  - Caudal spotting in the beacon fish (Hemigrammus ocellifer Characidae).
AB  - The beacon fish (Hemigrammus ocellifer) exhibits two phenotypes associated with
      spotting at the base of the caudal fin, with fish either possessing (H. o.
      ocellifer) or lacking (H. o. falsus) a prominent red spot in this region.
      Segregation patterns observed from the progenies of 15 different crosses support
      a hypothesis that caudal spotting in this species is controlled by a single gene
      with two alleles, for which the caudal spotting allele is completely dominant.

PMID- 12407218
TI  - Multiplexed systems of microsatellite markers for genetic analysis of mahogany,
      Swietenia macrophylla King (Meliaceae), a threatened neotropical timber species.
AB  - Mahogany (Swietenia macrophylla King [Meliaceae]) is the most valuable hardwood
      species in the neotropics. Its conservation status has been the subject of
      increasing concern due to overexploitation and habitat destruction. In this work
      we report the development and characterization of 10 highly variable
      microsatellite loci for S. macrophylla. Twenty-nine percent of the 126 sequenced
      mahogany clones yielded useful microsatellite loci. Three high-throughput
      genotyping systems were developed based on polymerase chain reaction (PCR)
      multiplexing of these mahogany loci. We identified a total of 158 alleles in 121
      adult individuals of S. macrophylla, with an average of 15.8 alleles (range 11
      25) per locus. All loci showed Mendelian inheritance in open-pollinated half-sib
      families. The mean expected heterozygosity was 0.84 and the mean observed
      heterozygosity was 0.73. The combined probability of identity-the probability
      that two individuals selected at random from a population would have identical
      genotypes--was 7.0 x 10(-15), and combined probability of paternity exclusion was
      0.999998 overall loci. These microsatellite loci permit precise estimates of
      parameters such as gene flow, mating system, and paternity, thus providing
      important insights into the population genetics and conservation of S.
      macrophylla.

PMID- 12407219
TI  - Genomic location of the Fw gene for resistance to Fusarium wilt race 1 in peas.
AB  - Resistance to fusarium wilt in peas (Pisumsativum L.) caused by Fusarium
      oxysporum Schlect. f. sp. pisi race 1 (van Hall) Snyd. & Hans. is conferred by a
      single dominant gene, Fw. The gene was located in the pea genome by analyzing
      progenies from crosses involving genetic markers across all pea linkage groups.
      Phenotyping of the progenies for reaction to race 1 of the fusarium wilt pathogen
      was determined by field screening in a "wilt-sick" plot in Pullman, Washington.
      Fw was shown to be located on linkage group III, about 13 map units from Lap-1
      and b and 14 map units from Td. The relatively large distances between these
      markers and Fw precludes the use of the linked markers in marker-assisted
      selection for wilt resistance. Additional markers in this region of the pea
      genome will be required if marker-assisted selection for Fw is to be successful.

PMID- 12407220
TI  - A case of chloroplast heteroplasmy in kiwifruit (Actinidia deliciosa) that is not
      transmitted during sexual reproduction.
AB  - We report the first case of plastid chimera within the Actinidia genus, where
      plastid inheritance was believed to be paternal. The heterogeneity of chloroplast
      DNA observed in the hexaploid Actinidia deliciosa cultivar D uno involves the
      presence or absence of a particular MspI restriction site in the region between
      the psbC gene and the tRNA-Ser(UGA) gene. The heterogeneity was first observed
      using restriction fragment length polymorphism and then confirmed through cloning
      and sequencing. The analysis of the cloned fragments revealed the presence of two
      haplotypes: the most frequent type was found in 123 (88.5%) out of a total of 139
      colonies screened. Partial sequences of the psbC-trnS fragment from both
      haplotypes revealed that the polymorphism occurs within the coding region of the
      psbC gene and consists of a synonymous transition. A contamination-free cross
      involving D uno as the male parent produced only plants characterized by the most
      frequent haplotype, indicating either selection bias against the rare type or
      more likely fixation of the frequent type in tissues leading to the formation of
      the male gametes. The MspI restriction profiles performed on various tissues
      suggest that the rarer type is absent from the histogenic layer LII and that D
      uno is a periclinal plastid chimera.

PMID- 12407221
TI  - RAPD analysis reveals genetic variability among sexual and Apomictic Paspalum
      dilatatum poiret biotypes.
AB  - Paspalum dilatatum is a valuable forage grass in the subtropics. This species
      consists of several sexual (tetraploid) and apomict (penta- and hexaploid)
      biotypes. It has been proposed that the presence of a genome of unknown origin,
      the X genome, is responsible for apomixis in penta- and hexaploid biotypes. Here
      we evaluated the utility of random amplified polymorphic DNA (RAPD) markers for
      discriminating sexual and apomictic P. dilatatum biotypes. DNA samples from nine
      accessions, including P. intermedium, P. juergensii, and P. dilatatum (ssp.
      flavescens, and the common and Uruguayan biotypes) were analyzed with 86 RAPD
      primers. Three hundred sixty-two fragments were scored and genetic similarity
      estimates revealed that the penta- and hexaploid biotypes were highly similar
      (S(D) > or = 0.913). Forty RAPDs were unique to the penta- and hexaploid
      biotypes. Overall RAPD markers were useful for assessing genetic variation among
      closely related P. dilatatum genotypes as well as generating putative X genome
      markers.

PMID- 12407222
TI  - The dynamic synapse: neuronal nexus for signaling.

PMID- 12407223
TI  - AMPA receptors do the electric slide.
AB  - How the synapse is organized and how its organization changes during events that
      result in long-term changes in synaptic efficacy is the subject of intense study.
      Various anchoring proteins work in concert to organize the postsynaptic side of
      the membrane, and the interactions of these proteins can be altered by synaptic
      activity. DeSouza and Ziff discuss the evidence that the reversible
      palmitoylation of the postsynaptic density protein PSD-95 may result in the
      movement of AMPA-type glutamate receptors into and out of lipid raft domains,
      ultimately controlling AMPA receptor accumulation at the postsynaptic membrane.

PMID- 12407224
TI  - Glutamate receptor trafficking in synaptic plasticity.
AB  - Ionotropic glutamate receptors mediate excitatory synaptic transmission at most
      central mammalian synapses. In addition to converting the chemical signal
      released from the presynaptic terminal to an electrical response in the
      postsynaptic neuron, these receptors are critically involved in activity
      dependent, long-term changes in synaptic strength and, therefore, are central to
      processes thought to underlie learning and memory. Several mechanisms have been
      proposed to play roles in altering synaptic strength, and it is clear that there
      are several different forms of long-term synaptic plasticity in the mammalian
      brain. Here, we review recent evidence that some forms of synaptic strengthening
      rely on the modification of the glutamate receptor complement at synapses in
      response to activity-dependent processes.

PMID- 12407226
TI  - Adolescence: a time of risk taking.

PMID- 12407227
TI  - Adolescent reproductive health interventions.

PMID- 12407228
TI  - "A single petticoat".

PMID- 12407229
TI  - Services for sexually transmitted infections in Europe and central Asia.

PMID- 12407232
TI  - Managing the very young patient: a conflict between the requirements of the
      Children Act and the VD regulations?
AB  - We describe the case of a 12 year old girl who presented requesting screening for
      sexually transmitted infections and discuss a conflict between concerns of
      clinicians to maintain confidentiality and concerns of social workers to
      investigate the possibility of sexual abuse.

PMID- 12407231
TI  - National guideline for the management of suspected sexually transmitted
      infections in children and young people.

PMID- 12407233
TI  - Attitudes about sexual disclosure and perceptions of stigma and shame.
AB  - OBJECTIVES: To determine the association between stigma and shame about having a
      sexually transmitted disease and adolescents' past STD related care seeking;
      between stigma, shame, and perceptions about disclosure of sexual behaviours to a
      doctor or nurse; and whether the association of stigma, shame, and care seeking
      was moderated by perceptions about disclosure. METHODS: A household sample of 142
      sexually active African-American youths, 13-19 years old, was questioned about
      STD related stigma (alpha = 0.89), STD related shame (alpha = 0.90), and
      perceptions about disclosure of sexual behaviours to a doctor or nurse (alpha =
      0.81). RESULTS: Among females, stigma was associated with increased anticipation
      of negative reactions to disclosure of sexual behaviours to a doctor or nurse
      (odds ratio (OR) = 0.319; 95% confidence interval (CI) =0.12 to 0.85) while shame
      was not. Stigma was also independently associated with STD related care seeking
      in the past year (OR = 0.296; 95% CI = 0.09 to 0.94) while shame was not. There
      was no association between stigma and shame with perceptions about disclosure or
      past care seeking in males. Perceived outcomes of disclosing sexual behaviours
      did not moderate the association of stigma, shame, and past STD related care
      seeking. CONCLUSIONS: Stigma about STDs may influence how female adolescents
      perceive reactions to disclosure of their sexual behaviour to healthcare
      providers. It may also be an important factor in their decision seek to STD
      related care. Perceptions about disclosure of sexual behaviour to a doctor or
      nurse do not change the relation of stigma or shame to past STD related care
      seeking.

PMID- 12407234
TI  - Knowledge about the prevention of sexually transmitted diseases: a longitudinal
      study of young women from 16-23 years of age.
AB  - OBJECTIVES: To describe knowledge and attitudes regarding sexually transmitted
      diseases (STD) in the same women followed longitudinally for 7 years from teenage
      years to early adulthood, and to relate the findings to sexual behaviour.
      METHODS: A face to face interview and a questionnaire were completed by 79 young
      women when they were 16, 18, and 23 years old. RESULTS: The questionnaire,
      testing knowledge about the mode of transmission and prevention of STD, gave a
      total score of correct answers varying between 44% and 64%, with less knowledge
      about human papilloma (HPV) and herpes viruses than about chlamydia. Awareness of
      the possibility of asymptomatic transmission was low. The highest scores were
      obtained at the age of 18 years. Experience of many partners, a history of STD,
      smoking, and more frequent use of alcohol were associated with a higher level of
      knowledge. CONCLUSIONS: Knowledge was fairly good and consistent, but was more
      often incorrect regarding viral infections and the possibility of asymptomatic
      transmission, and in total did not ensure an adequate protective behaviour. A
      higher level of knowledge was associated with a more risky behaviour, indicating
      that information was best received by those who could identify with the problem.

PMID- 12407236
TI  - Young people's views on provision of sexual health services.
AB  - OBJECTIVES: To identify the sexual health needs of young people in order to
      establish a service suited to these needs. METHODS: A peer designed questionnaire
      piloted to a small group of young people was followed by a more widely
      distributed, amended questionnaire. The questionnaire survey was delivered to 744
      pupils aged 11-18 years in six secondary schools and a pupil exclusion unit in
      central London. Factors encouraging or discouraging the use of young people's
      sexual health services were measured. RESULTS: Several findings challenged
      existing models of care for young people's sexual health services. Notably,
      pupils wanted clinics to run more frequently than the usual once a week; the
      staff attributes that were most important were attitudinal rather than to do with
      sex, age, or physical appearance; and they did not mind if the waiting room
      contained older people. Many findings, however, agreed with existing data-young
      people wanted the clinic to be open after school; girls preferred to attend with
      a friend; a confidential, walk-in service was preferred. CONCLUSIONS: Large
      financial outlays are not necessary for the establishment of effective sexual
      health services for young people. Existing facilities and staff may be utilised
      with training of these staff to be sensitive to, and aware of, the needs of young
      people. Clinic opening times should coincide with school closing times. Although
      pupils stated a preference for female staff, this was not a high priority. More
      important was feeling that staff would listen to them and take their problems
      seriously, and that confidentiality would be maintained.

PMID- 12407237
TI  - Herpes simplex virus type 1 infection: a sexually transmitted infection of
      adolescence?
AB  - OBJECTIVES: To examine the factors associated with antibodies to herpes simplex
      virus type 1 (HSV-1). DESIGN: Cross sectional study with HSV-1 antibody testing
      performed by University of Washington western blot assay. SETTING: Central London
      STD clinic (1990-1) and central London blood donation centre (1992).
      PARTICIPANTS: Representative sample of 869 new and rebooked GUM clinic attenders
      and 1494 consecutive blood donors. RESULTS: The prevalence of HSV-1 antibody
      among clinic attenders was 60.4% (95% CI 57.0 to 63.7) and among donors was 46.1%
      (95% CI 43.5 to 48.7). HSV-1 antibody was independently associated with
      increasing age in both populations (p<0.001). Among clinic attenders, HSV-1 was
      less common among heterosexual men than women and homosexual men (p<0.005), and
      was more common among black people (p=0.001) and those of lower socioeconomic
      status (p=0.05). Among blood donors, being single rather than married was
      independently associated with HSV-1 infection (p=0.03). Early age at first
      intercourse was strongly associated with presence of HSV-1 in both populations.
      The adjusted odds of HSV-1 among GUM clinic attenders was 0.37 (95% CI 0.21 to
      0.65) for someone aged 20 at first intercourse compared with someone aged <or=15.
      Among blood donors, those aged 20 had an adjusted odds of 0.64 (95% CI 0.39 to
      1.05) compared with someone aged 15. HSV-1 was not associated with increasing
      number of lifetime partners after adjustment for other factors. CONCLUSIONS:
      Genital herpes due to HSV-1 antibody is increasing in the United Kingdom,
      particularly among young people. In this study we found that HSV-1 was strongly
      associated with early age of first sexual intercourse, which may reflect the
      sexual practices of people initiating sex in this age group.

PMID- 12407238
TI  - News from the frontline: sexually transmitted infections in teenagers attending a
      genitourinary clinic in south east London.
AB  - OBJECTIVES: To define the incidence and characterise the clinical presentation of
      sexually transmitted infections (STI) in people aged <or=16 years old attending a
      genitourinary clinic in south east London. METHODS: Cross sectional analysis of
      clients aged <or=16 years attending one genitourinary clinic. A subgroup was
      identified for priority treatment. Data collected included age, reason for
      presentation, diagnosis, contraceptive use, and adherence to therapy. Diagnoses
      were compared to the KC60 codes for female attendances of all ages. RESULTS: 144
      females and 18 males with a mean age of 15.4 years attended, of whom 49% were
      symptomatic. Compared to other attenders, clients aged <or=16 years were
      significantly more likely to have an STI (64% versus 22%, p <0.00000001); 27 were
      pregnant (of whom 96% requested a termination of pregnancy); 47% did not return
      for follow up; and 12% did not adhere to treatment plan. Those diagnosed with an
      STI were significantly less likely to reattend (p<0.001). CONCLUSIONS: There is a
      high rate of STIs in 16 year olds compared to national figures and to general
      clinic attenders. Poor contraception is often overlooked within the genitourinary
      medicine clinic. Young attenders frequently fail to reattend for follow up.
      Priority treatment did not affect outcome. Further strategies are needed to
      identify ways to improve young people's access to genitourinary medicine clinics.

PMID- 12407239
TI  - Adolescent sexual health in Sweden.
AB  - In Sweden, society's attitudes towards teenage sexual relationships are liberal,
      and sexual and reproductive health issues are given high priority. Family and sex
      education has been taught in schools since the 1950s. The age of sexual consent
      is 15 years. Since 1975, abortion has been free on demand. Contraceptive
      counselling is free, easily available at family planning and youth health
      clinics. Screening for genital chlamydial infection is performed at these
      clinics, thus providing a "one stop shop" service. Condoms and oral contraception
      are available at low cost, emergency contraception is sold over the counter.
      Teenage childbearing is uncommon. However, sexual and reproductive health
      problems are on the increase among young people. During the 1990s, a period of
      economic stagnation in Sweden, schools have suffered budget cut backs. Sex
      education is taught less. Social segregation, school non-attendance, smoking, and
      drug use have increased. Teenage abortion rates have gone up, from 17/1000 in
      1995 to 22.5/1000 in 2001. Genital chlamydial infections have increased from
      14,000 cases in 1994 to 22,263 cases in 2001, 60% occurring among young people,
      and with the steepest increase among teenagers. Thus, a question of major concern
      is whether and how adolescent sexual behaviour has shifted towards more risky
      practices during the late 1990s.

PMID- 12407240
TI  - Reaching homeless youths for Chlamydia trachomatis and Neisseria gonorrhoeae
      screening in Denver, Colorado.
AB  - BACKGROUND AND RATIONALE: The availability of urine based testing for Chlamydia
      trachomatis (CT) and Neisseria gonorrhoeae (GC) provides a unique opportunity to
      screen for these pathogens outside traditional clinical settings. The researchers
      investigated the feasibility of street based CT/GC screening in the context of an
      outreach programme among street/homeless adolescents in Denver. OBJECTIVES: To
      describe the integration of urine based CT/GC screening into an existing outreach
      programme among street/homeless youths and the yield of CT/GC testing in this
      setting. METHODS: The Denver Department of Public Health (DPH) collaborated with
      outreach staff from Urban Peak (a community based organisation serving
      street/homeless youths in Denver) to offer urine based CT/GC testing to males and
      females in street settings. Tests were conducted on the street in areas where
      street/homeless youths congregate. RESULTS: Urban Peak outreach staff were
      trained by DPH staff to conduct CT testing, process urine specimens, and provide
      test results to participating youths. DPH remained responsible for treatment of
      people with CT or GC infection as well as CT/GC case reporting. CT testing
      started in January 2000; GC testing was added in July 2000. Throughout April 2002
      a total of 414 CT and 302 GC tests were conducted, respectively 11.6% and 2.7% of
      which were positive. Among first testers, 13.0% were positive for CT and 3.7% for
      GC. CONCLUSIONS: CT/GC urine testing can be incorporated into existing outreach
      programmes without considerable extra effort. Overall CT rates were high and
      suggest the need for ongoing screening in this manner. LEARNING OBJECTIVE: To
      understand the role of CT/GC screening in the context of services provided to
      street/homeless youths in outreach settings.

PMID- 12407241
TI  - Predictors of infection with Trichomonas vaginalis: a prospective study of low
      income African-American adolescent females.
AB  - OBJECTIVES: To identify psychosocial predictors of Trichomonas vaginalis
      infection among low income African-American adolescent females living in a high
      risk urban area of the United States. METHODS: Baseline plus 6 and 12 month
      follow up data collected as part of an HIV prevention intervention trial were
      utilised. The baseline sample consisted of 522 African-American females, 14-18
      years of age. Recruitment sites were located in low income neighbourhoods of
      Birmingham, Alabama, characterised by high rates of unemployment, substance
      abuse, violence, teenage pregnancy, and sexually transmitted infections. Self
      administered vaginal swab specimens were cultured for T vaginalis. Baseline
      measures collected as part of a self administered survey and face to face
      interviews were used to predict subsequent infection with T vaginalis at any of
      the three assessment periods conducted over the span of 1 year. RESULTS: At
      baseline, 12.9% were diagnosed with T vaginalis. At the 6 and 12 month follow
      ups, T vaginalis was diagnosed in 8.9% and 10.2%, respectively. The strongest
      multivariate predictor of T vaginalis infection was biologically confirmed
      marijuana use; those using marijuana were more than six times as likely to test
      positive for T vaginalis (adjusted odds ratio (AOR) = 6.2, p = 0.0003). Other
      multivariate predictors were reporting that typical sex partners were at least 5
      years older (AOR = 2.6; p = 0.005), reporting sex with non-steady partners (AOR =
      1.9; p = 0.02), and history of delinquency (AOR = 1.3; p = 0.02). The odds of
      testing positive increased by 31% for every one unit increase on a six item scale
      measure of delinquency. CONCLUSIONS: Infection with T vaginalis was common and
      significant multivariate predictors comprised a constellation of problem
      behaviours, each of which are potentially amenable to behavioural intervention.

PMID- 12407242
TI  - Post-treatment sexual and prevention behaviours of adolescents with sexually
      transmitted infections.
AB  - OBJECTIVE: To evaluate sexual behaviour (including abstinence), sex partner
      change, and condom use during the 3 month period following treatment for
      Neisseria gonorrhoeae, Chlamydia trachomatis, Trichomonas vaginalis, or non
      gonococcal urethritis. METHODS: 251 14-21 year old participants (83% female; 83%
      African-American) diagnosed with gonorrhoea, chlamydia, trichomonas, or non
      gonococcal urethritis or sexual contacts of infected partners. Participants were
      clients of a public sexually transmitted diseases clinic or primary care
      adolescent clinics. Data were collected by structured interview at treatment, 1
      month post-treatment, and 3 months post-treatment. At each visit, participants
      were asked about coital frequency and condom use for each recent partner. At 1
      month, participants were asked when coitus occurred following treatment. At each
      follow up visit, sex partners were compared to partners named at treatment and
      classified as "same partner(s)," "new partner(s)," or both "same and new
      partner(s)." RESULTS: Post-treatment abstinence was reported by 26% and 19% for
      the 1 month and 3 month visits, respectively. Abstinence was associated with
      greater likelihood of infection at enrolment although abstainers reported fewer
      lifetime STI and fewer lifetime sex partners. A substantial proportion of
      participants reported additional sexual contact with a previous partner. The
      average proportion of condom protected coital events increased from about 45% at
      enrolment to 64% at 1 month and 58% at 3 months (p<0.05). Higher levels were
      sustained for the 3 months following treatment. CONCLUSIONS: Many adolescents
      adopt, at least temporarily, risk reduction behaviours such as abstinence or
      increased condom use. Sexual re-exposure to potentially untreated previous
      partners may increase risk of subsequent reinfection.

PMID- 12407243
TI  - Provider willingness to screen all sexually active adolescents for chlamydia.
AB  - OBJECTIVES: To assess differences in provider willingness to screen all sexually
      active male and female adolescents for chlamydia and to determine whether
      concerns about cost effectiveness of screening are related to provider
      willingness to screen for chlamydia. METHODS: All primary care providers in a
      managed care organisation self administered a survey about screening all sexually
      active adolescents for chlamydia. RESULTS: Respondents were 217 physicians (MDs)
      and 121 nurse practitioners (NPs) or physician assistants (PAs). Excluding
      obstetrician/gynaecologists, more providers were willing to routinely screen
      adolescent females than males for chlamydia (67% v 49% respectively; p<0.001).
      Independent predictors of provider willingness to screen both males and females
      included belief that routine screening is cost effective and being a NP/PA v an
      MD. Belief that chlamydia screening is easier in females than males independently
      predicted less willingness to screen males. CONCLUSION: Information that reduces
      provider concern about the cost effectiveness of screening may increase provider
      willingness to screen adolescents for chlamydia. Availability of urine based
      tests may reduce provider beliefs that females are easier to screen than males
      and increase chlamydia screening in males.

PMID- 12407244
TI  - Understanding correlates of hepatitis B virus vaccination in men who have sex
      with men: what have we learned?
AB  - OBJECTIVES: Hepatitis B infection (HBV) is prevalent among men who have sex with
      men (MSM) and may lead to significant morbidity and death. Although an effective
      vaccine exists vaccination rates among MSM are low. We conducted a systematic
      review to synthesise the various findings from empirical correlational studies to
      understand HBV vaccination and series completion among MSM. METHODS: We
      systematically searched the Medline, PubMed, EMBASE, CINAHL, ERIC, and Web of
      Science databases to identify the breadth of published studies pertaining to HBV
      vaccination among MSM and to synthesise findings from these studies to better
      identify common themes that may direct future research and intervention
      approaches. RESULTS: Eight papers specifically addressed correlates of HBV
      vaccination among MSM. Six domains were identified as predictors of vaccination:
      (1) demographic variables such as younger age and higher education level; (2)
      knowledge of the vaccine; (3) access to health care; (4) level of "outness"
      regarding one's same sex sexual orientation; (5) behavioural factors including
      sexual and drug use behaviour; and (6) psychosocial variables. Three papers
      addressed predictors of vaccine series completion among MSM, observing two main
      domains: (1) demographic variables such as younger age and higher income level;
      and, (2) behavioural factors including sexual and health promotion behaviours.
      CONCLUSIONS: Continued educational efforts, creation of environments that
      facilitate proper risk factor evaluation, and access to low cost vaccine may
      facilitate vaccine uptake. Although we observed important trends in the studies
      we reviewed, there is a lack of empirical research regarding this important
      public health issue.

PMID- 12407245
TI  - Update of trichomoniasis.
AB  - Trichomoniasis remains an extremely common infection despite the fact that rates
      of other treatable sexually transmitted diseases are declining. Newer diagnostic
      techniques such as polymerase chain reaction (PCR) are documenting higher rates
      of infection in heterosexual men than have been previously found with culture.
      Although data on the association of vaginal trichomoniasis with preterm birth are
      controversial, the association of trichomoniasis with HIV acquisition seems
      clear. Despite being a readily diagnosed and treated STD, trichomoniasis is not a
      reportable infection and control of the infection has received relatively little
      emphasis from public health STD control programmes. More recently, however,
      appreciation of high rates of disease and of associations of trichomoniasis in
      women with adverse outcomes of pregnancy and increased risk for HIV infection
      suggest a need for increased control efforts.

PMID- 12407248
TI  - HIV tests in young adolescents attending a GUM clinic.

PMID- 12407246
TI  - A survey of STI policies and programmes in Europe: preliminary results.
AB  - OBJECTIVES: A survey was conducted to assess the adequacy of sexually transmitted
      infections (STI) prevention and control policies and programmes in the European
      region (including the central Asian republics). METHODS: An adapted World Health
      Organization (WHO) model questionnaire was sent to ministry of health officials
      in all 45 countries of Europe and central Asia. The questionnaire included
      questions on STI programme structure; STI case management; the different types
      and levels of services, including public and private service providers; partner
      notification and screening policies; services for vulnerable populations;
      monitoring and supervision; surveillance and research. RESULTS: Western European
      countries largely leave STI prevention and care to individual practitioners.
      Licensed providers exist at all levels of care, and access to consultations and
      treatment is usually free of charge. In the newly independent states (NIS), by
      contrast, programme efforts emphasise state guidance and supervision of local
      providers rather than individual practitioners. Access to services is limited in
      that in several NIS, only public sector specialists are licensed to treat STI.
      Formerly free of charge policies have been severely eroded. While in western
      Europe access to condoms appears to be good, in the NIS there are many fewer
      condom outlets. Regionwide, in 40% of countries the distribution of condoms is
      part of STI consultations. CONCLUSIONS: Non-availability of affordable high
      quality STI services, including STI treatment and condoms, may be one of the
      causes for the much higher STI prevalence in parts of eastern Europe and NIS than
      in western Europe.

PMID- 12407249
TI  - Sexual and reproductive health among female adolescents: preliminary results.

PMID- 12407250
TI  - Screening for STIs in individuals with HIV infection.

PMID- 12407251
TI  - Factors affecting co-infection with genital chlamydia and genital gonorrhoea in
      an urban genitourinary medicine clinic.

PMID- 12407252
TI  - Erythema nodosum induced by chancroid.

PMID- 12407253
TI  - Four layer discontinuous gradient for HIV.

PMID- 12407254
TI  - Uptake of HIV testing in patients with a confirmed sexually transmitted
      infection.

PMID- 12407255
TI  - Gonococcal perianal abscess: re-emergence after cessation of co-trimoxazole.

PMID- 12407256
TI  - Returning to the community--again.

PMID- 12407258
TI  - Use of psychotropics in two employee groups directly affected by the events of
      September 11.

PMID- 12407259
TI  - What is it about the holidays?

PMID- 12407260
TI  - Psychiatric outpatient care in Germany and the United States.

PMID- 12407261
TI  - Alcohol & drug abuse: alcohol, the "Un-Drug".

PMID- 12407262
TI  - Teaching persons with severe mental disabilities to be their own case managers.

PMID- 12407263
TI  - Transition of enrollees from a managed care organization to an academic managed
      behavioral health carve-out.

PMID- 12407265
TI  - Models of mental health services in nursing homes: a review of the literature.
AB  - OBJECTIVE: The authors review the research literature on models and outcomes of
      extrinsic mental health services in nursing homes and summarize the data on
      current practices in this area. Extrinsic mental health services are those
      delivered in the nursing home by specialists who are not full-time staff of the
      nursing home. METHODS: English-language articles providing descriptive and
      research reports on models and outcomes of extrinsic mental health services in
      nursing homes were identified through a comprehensive search of peer-reviewed
      journals, using MEDLINE and psychological literature databases. The research
      methods of the reports were also noted. RESULTS: Three primary models of mental
      health service delivery were identified: psychiatrist-centered, nurse-centered,
      and multidisciplinary team models. Uncontrolled observational studies suggested
      that mental health services may result in improved clinical outcomes and less use
      of acute services. However, few well-designed controlled intervention studies
      have been conducted. Education and training appeared to improve staff members'
      knowledge and performance and to decrease turnover. The least effective model
      involved traditional consultation-liaison service in which a lone clinician
      provided a one-time, written consultation on an as-needed basis.
      Multidisciplinary team approaches were favored as preferred service models.
      CONCLUSIONS: Few studies using an experimental design have examined the outcomes
      of mental health services in nursing homes. Program descriptions and uncontrolled
      outcome studies suggest that preferred practice includes the routine presence of
      qualified mental health clinicians in the nursing home, that optimal services are
      interdisciplinary and multidimensional, and that the most effective interventions
      blend innovative approaches to training and education with consultation and
      feedback on clinical practices.

PMID- 12407266
TI  - Use of nonpharmacologic interventions among nursing home residents with dementia.
AB  - The authors describe domains of nonpharmacologic interventions for residents with
      dementia who are receiving long-term care. Special emphasis is placed on
      interventions involving the domains of inappropriate behavior, restraint
      reduction, and cognition. Illustrations of the salubrious effects of these
      interventions are presented. For each domain, a review of the available
      information about nonpharmacologic interventions is provided, and areas in which
      additional information is needed are discussed. The authors conclude with a
      summary that emphasizes linkages and similarities among interventions across
      domains. The authors' major point is that effective nonpharmacologic
      interventions are available for a variety of behavioral problems that are
      commonly observed in long-term care settings.

PMID- 12407267
TI  - Challenges to the use of nonpharmacologic interventions in nursing homes.
AB  - The Nursing Home Reform Act, part of the Omnibus Budget Reconciliation Act of
      1987, stated that nursing homes should try nonpharmacologic interventions before
      resorting to pharmacologic agents when addressing problem behaviors among
      residents. Since that time, the use of pharmacologic agents has decreased, but
      there is little evidence to suggest that the use of nonpharmacologic
      interventions has increased. Psychosocial models describe problem behaviors as
      complex phenomena that require individualized strategies based on a resident's
      unique characteristics. Categories of intervention include social contact,
      behavior therapy, staff training, structured activities, environmental
      interventions, and a combination of therapies. This article discusses internal
      barriers to the use of nonpharmacologic interventions based on the Porras stream
      organization model: organizing arrangements, social factors, technology, and
      physical setting. Also, external barriers related to the regulatory, legal, and
      economic sectors are discussed. The authors offer recommendations for overcoming
      these barriers.

PMID- 12407268
TI  - Psychopharmacologic interventions in nursing homes: what do we know and where
      should we go?
AB  - Psychiatric symptoms are common among individuals who live in nursing homes, with
      prevalence rates ranging from 51 percent to 94 percent. Accordingly, psychotropic
      medications are widely prescribed in this setting and are the subject of
      considerable debate and regulation. Current regulations arose from public and
      governmental concerns that psychiatric medications were being prescribed
      inappropriately to frail patients. Concern has also been raised about the absence
      of evidence on which to base prescribing decisions. Nursing homes are slowly
      being recognized as complex health care settings that warrant considerable
      research attention. This article explores the origins of the regulation of the
      use of psychotropic drugs in nursing homes, reviews controlled trials of these
      drugs in nursing homes, examines the role of these agents in adverse drug events
      experienced by nursing home residents, and proposes policy and research areas
      that merit consideration.

PMID- 12407269
TI  - Regulatory oversight, payment policy, and quality improvement in mental health
      care in nursing homes.
AB  - During the past 15 years, federal regulations, survey and inspection programs,
      and payment policies have presented conflicting incentives and disincentives for
      the provision of mental health services in nursing homes in the United States.
      Policies and regulatory measures have reflected the concern that many patients in
      nursing homes are not receiving the mental health care they need, and, more
      prominently, the concern that some of the services that are provided seem to be
      inappropriate or medically unnecessary. Despite evidence that payment policy and
      regulatory oversight can be used effectively to promote quality improvement, the
      need for improved access and quality of mental health services in long-term care
      remains substantial. Recent reports issued by the Surgeon General and by the
      Institute of Medicine identify a need for refinements in the assessment process,
      the use of outcomes-based quality measures, and payment policies designed to
      improve access and quality. These elements must be coordinated to promote humane
      treatment in nursing homes, including access to medically necessary psychiatric
      care.

PMID- 12407270
TI  - Evidence-based practices in geriatric mental health care.
AB  - The past decade has seen dramatic growth in research on treatments for the
      psychiatric problems of older adults. An emerging evidence base supports the
      efficacy of geriatric mental health interventions. The authors provide an
      overview of the evidence base for clinical practice. They identified three
      sources of evidence-evidence-based reviews, meta-analyses, and expert consensus
      statements-on established and emerging interventions for the most common
      disorders of late life, which include depression, dementia, substance abuse,
      schizophrenia, and anxiety. The most extensive research support was found for the
      effectiveness of pharmacological and psychosocial interventions for geriatric
      major depression and for dementia. Less is known about the effectiveness of
      treatments for the other disorders, although emerging evidence is promising for
      selected interventions. Empirical support was also found for the effectiveness of
      community-based, multidisciplinary, geriatric psychiatry treatment teams. The
      authors discuss barriers to implementing evidence-based practices in the mental
      health service delivery system for older adults. They describe approaches to
      overcoming these barriers that are based on the findings of research on practice
      change and dissemination. Successful approaches to implementing change in the
      practices of providers emphasize moving beyond traditional models of continuing
      medical education to include educational techniques that actively involve the
      learner, as well as systems change interventions such as integrated care
      management, implementation toolkits, automated reminders, and decision support
      technologies. The anticipated growth in the population of older persons with
      mental disorders underscores the need for a strategy to facilitate the systematic
      and effective implementation of evidence-based practices in geriatric mental
      health care.

PMID- 12407271
TI  - Patients' perceptions of intensive case management.
AB  - OBJECTIVE: The authors examined patients' perceptions of their case management
      care and the factors that influenced those perceptions. METHODS: A nine-item
      patients' perceptions questionnaire was administered to 225 patients with severe
      psychosis who were enrolled in a randomized controlled trial evaluating the
      efficacy of intensive versus standard case management. RESULTS: Factor analysis
      of the responses to the perceptions questionnaire revealed two principal
      components: quality of care received (including relationship and contact with the
      case manager) and overall perception of case management. Patients had a better
      overall perception of intensive case management compared with standard case
      management, but no significant differences were noted in perceived quality of
      care. Patients with female case managers had more positive perceptions of the
      quality of the care they received than those with male case managers. Several
      clinical and social variables were strongly associated with perceived quality of
      care but less so with overall perception of case management. CONCLUSIONS:
      Patients' general perceptions of intensive case management seemed more favorable
      than patients' general perceptions of standard case management, but no difference
      was noted in their perceptions of quality of care.

PMID- 12407272
TI  - Predictive models and the effectiveness of strategies for improving outpatient
      follow-up under managed care.
AB  - OBJECTIVES: This study tested the accuracy of models for predicting
      rehospitalization in a managed behavioral health organization and tested the
      effectiveness of different care management strategies for enhancing outpatient
      treatment follow-up. METHODS: In a controlled study, patients with an inpatient
      mental health or substance use admission received one of three types of care
      management, distinguished by the level of care managers' involvement in discharge
      planning and postdischarge outreach: usual (N=31), enhanced (N=94), and intensive
      (N=74). The groups were compared with each other and with a cohort admitted in
      the year before the study that received usual care management (N=192) to
      determine whether differences existed in time to outpatient follow-up, amount of
      postdischarge care, and rehospitalization at 30, 60, and 180 days. RESULTS: No
      differences between groups were found. The majority of patients (69 percent)
      received outpatient care within 30 days of discharge. Prediction models using
      logistic regression suggested that the number of clinical and sociodemographic
      risk factors identified by care managers was related to the rate of
      rehospitalization at 60 and 180 days. Patients authorized to receive intermediate
      care (partial hospitalization or residential care) and those who failed to attend
      intermediate care if it was authorized were more likely than other patients to be
      rehospitalized at 30, 60, and 180 days. CONCLUSIONS: Outpatient follow-up after
      psychiatric hospitalization did not improve with increasingly intensive discharge
      planning and outreach. Improvement in prediction of risk of rehospitalization may
      increase opportunities to provide intensive interventions for difficult-to-engage
      patients.

PMID- 12407273
TI  - Patterns of antidepressant use among children and adolescents.
AB  - OBJECTIVE: The purpose of this study was to identify patterns of new
      antidepressant use among children and adolescents and to determine whether the
      duration of treatment was sufficient. METHODS: A retrospective 12-month analysis
      was conducted of claims data for a cohort of nine- to 18-year-old new users of
      antidepressants in an Ohio Medicaid population. Treatment duration was
      categorized into five time intervals reflecting initial treatment through various
      continuation periods. RESULTS: A total of 554 children and adolescents started an
      antidepressant regimen during a three-month period. These children were mostly
      Caucasians (78 percent), and their average age was 13 years. Boys and girls were
      equally represented. The use of antidepressants increased with age among girls
      but declined among boys. The distribution of antidepressants dispensed was
      selective serotonin reuptake inhibitors, 47 percent; tricyclic antidepressants,
      27 percent; and other antidepressants, 23 percent. The specific agent used varied
      by primary psychiatric diagnosis. The proportion of children who completed
      treatment was 94 percent for the four-week treatment period, 23.5 percent for the
      six-month period, and 12.6 percent for the whole year. CONCLUSIONS:
      Antidepressants are used in the treatment of children and adolescents who have a
      wide array of mental health problems. As with adults, continuation of treatment
      among children and adolescents declines dramatically after an initial period. In
      addition to studies of the clinical efficacy of antidepressant use among children
      and adolescents, future research is needed to assess adherence to practice
      guidelines and health outcomes in childhood and adolescent mental health.

PMID- 12407274
TI  - Preadmission care as a new mental health performance indicator.
AB  - OBJECTIVE: This study examined the relationship between receipt of preadmission
      outpatient care during the month before an episode of hospitalization and the
      patients' subsequent treatment. METHODS: A total of 37,852 psychiatric inpatients
      who were discharged from 122 Veterans Affairs medical centers between October 1,
      1997, and March 31, 1998, were studied. Linear and logistic regression were used
      to examine the relationship between receipt of preadmission outpatient care and
      length of hospital stay, use of postdischarge aftercare, and readmission.
      RESULTS: Having at least one outpatient visit in the month before admission was
      associated with a significantly shorter inpatient stay (16 days compared with 26
      days, a difference of more than 60 percent) and with significantly greater use of
      postdischarge aftercare (odds ratio=1.83). However, the number of outpatient
      visits beyond one visit in the month before admission did not increase the effect
      on length of stay. These effects were strongest among patients with
      schizophrenia. CONCLUSIONS: Patients who have received outpatient care before
      hospital admission have shorter hospital stays and are more likely to use
      postdischarge aftercare than those who have not received outpatient care in the
      month before admission. Receipt of preadmission care itself rather than the
      intensity of such care seems to be the greatest predictor of length of stay.

PMID- 12407275
TI  - Medical comorbidity and receipt of medical care by older homeless people with
      schizophrenia or depression.
AB  - OBJECTIVE: Few studies have examined medical comorbidity among middle-aged and
      older homeless people with schizophrenia. This study compared the number of
      physical health problems and receipt of physical health care services among older
      homeless people with schizophrenia and those with major depression. METHODS: The
      study was conducted at St. Vincent de Paul Village, a homeless shelter in San
      Diego, California, with an on-site free medical and psychiatric clinic. Data from
      the psychiatric clinic log for a one-year period were used to identify 47 shelter
      users older than age 45 with schizophrenia and an age- and gender-matched
      comparison group of 47 shelter users with major depression. A physician reviewed
      the patients' charts to obtain data for a comparison between groups of the number
      of clinic visits for medical problems, receipt of various components of the
      physical examination and preventive screening studies, and number of chronic
      medical disorders. RESULTS: The patients with schizophrenia had fewer medical
      visits and fewer documented medical problems than those with depression. They
      were also less likely to receive a detailed physical examination, cholesterol
      level screening, and screening for colon cancer. The documented rates of several
      chronic medical problems, including diabetes, arthritis, and hypertension, were
      lower among the shelter residents with schizophrenia. CONCLUSIONS: Middle-aged
      and older homeless people with schizophrenia received less primary and preventive
      health care and were treated for fewer chronic medical problems than a comparison
      group with depression.

PMID- 12407276
TI  - Hospitalization of patients with cocaine and amphetamine use disorders from a
      psychiatric emergency service.
AB  - OBJECTIVES: Among the illicit stimulants, cocaine and amphetamines are the most
      widely abused. Although these drugs have similar psychoactive properties and
      routes of administration, their duration of action and mechanism of action are
      different, as are the psychiatric problems that accompany their use. The authors
      explored whether these differences and results of urine drug testing were
      associated with differences in use of psychiatric inpatient services. METHODS:
      The records of 2,357 patients admitted to a large county psychiatric emergency
      service were examined to determine whether patients admitted for amphetamine
      related or cocaine-related disorders differed in rates of transfer to an
      inpatient psychiatric ward or in length of stay on the ward after transfer. The
      authors also examined whether positive or negative results of urine drug screens
      predicted transfer or length of stay. RESULTS: Patients with amphetamine-related
      disorders were more than a third more likely than patients with cocaine-related
      disorders to be transferred to the inpatient ward. Patients with negative urine
      screens were a third more likely than those with positive screens to be
      transferred and stayed slightly longer on the ward after transfer. Patients with
      cocaine-related disorders stayed slightly longer on the ward than patients with
      amphetamine-related disorders. CONCLUSIONS: Patients with amphetamine-related
      disorders have higher rates of psychiatric hospitalization than patients with
      cocaine-related disorders. Diagnostic uncertainty and other factors may also
      influence transfer rates and subsequent length of stay.

PMID- 12407277
TI  - Multiple-family groups for urban children with conduct difficulties and their
      families.
AB  - The authors present the results of two studies designed to improve treatment
      engagement among urban youths with conduct and oppositional behavioral
      difficulties. In the first study, information on attitudes about mental health
      treatment was obtained from 159 adult caregivers of children who were referred to
      an urban child mental health clinic because of disruptive behavioral
      difficulties. The caregivers listed insufficient time, lack of transportation,
      the child's not wanting to attend treatment, and the caregiver's concern that
      treatment might not help as barriers to service use. The data from study 1 were
      used to design a multiple-family group intervention to be tested in study 2. The
      families who participated in these groups attended an average of seven sessions
      during the 16-week study, compared with four sessions for families who
      participated in family therapy and three for families who participated in
      individual psychotherapy.

PMID- 12407279
TI  - Characteristics of persons who are homeless for the first time.
AB  - The Pathways Into Homelessness project in Toronto interviewed 300 unaccompanied
      adult users of homeless shelters to identify characteristics of individuals who
      are homeless for the first time. The sample reflected the total population of
      homeless shelter users in terms of age, sex, level of use, and type of shelter.
      Two fifths of the sample were homeless for the first time. There were more
      similarities than differences between those who were homeless for the first time
      and those who had been homeless previously. The prevalence of psychiatric and
      substance use disorders and the rate of previous hospitalization did not differ
      between first-time homeless persons and those who had been homeless before. The
      two groups were distinguished by some childhood experiences related to housing.
      Both groups had multiple indicators of serious problems, suggesting that the need
      for intervention is as pressing for persons who are homeless for the first time
      as it is for the larger population of homeless persons.

PMID- 12407278
TI  - Release planning for inmates with mental illness compared with those who have
      other chronic illnesses.
AB  - The authors evaluated the effort of New Jersey jails to plan for the postrelease
      treatment needs of inmates with mental illness compared with inmates with heart
      disease and HIV infection or AIDS. Seventy percent of interviewees expressed a
      belief that release planning for persons with serious mental illness is very or
      extremely important. However, virtually all the jails reported providing "no real
      release planning." A majority of the jails provide aftercare plans for fewer than
      10 percent of inmates with serious mental illness. A lack of release planning was
      noted for the other chronic conditions. Release planning for particular chronic
      problems is most common and complete in facilities with special treatment
      programs, such as a mental health unit.

PMID- 12407280
TI  - Changes in psychotropic drug use after September 11, 2001.

PMID- 12407281
TI  - Terrorism and people with mental illness.

PMID- 12407282
TI  - Cognitive skills group treatment for schizophrenia.

PMID- 12407283
TI  - Sertraline-induced akathisia and dystonia misinterpreted as a panic attack.

PMID- 12407284
TI  - [Long-term oxygen therapy for chronic respiratory failure. Rationale,
      indications, modalities].
AB  - Long-term oxygen therapy (LOT) has become quite popular over the last 20 years
      due to better knowledge of the beneficial effect (improved life expectancy,
      improved quality of life, stabilization of the pulmonary hypertension) and to
      technological progress (concentrators, liquid oxygen). Ambulatory techniques have
      greatly contributed to the widespread use of oxygen therapy as has the decision
      of the French National Health Insurance System to reimburse this costly
      treatment. Almost all the studies devoted to the clinical and functional aspects
      of LOT have concerned patients with chronic obstructive pulmonary disease (COPD).
      By extension, it is generally accepted that LOT is warranted in other forms of
      respiratory failure (diffuse fibrosis, cyphoscoliosis, cystic fibrosis, etc.)
      when blood gas criteria similar to those retained for COPD are present:
      PaO(2)<=55 mmHg during stable periods with control measurements at lest 3 weeks
      apart; PaO(2) between 56 and 60 mmHg if there is also an elevated red cell count
      or pulmonary hypertension, signs of cor pulmonale ou frank hypoxemia during
      sleep. These consensus indications are widely accepted but other indications
      remain controversial: should LOT be prescribed for moderate hypoexmia (PaO(2)
      >=60 mmHg), exercise-induced hyoxemia alone, sleep hypoxemia alone? Appropriate
      studies are lacking so systematic prescription of LOT cannot be recommended in
      these three situations. The duration of LOT should be >=16 h/d, and if possible
      >=18 h/d. It has been established that objective results (life expectancy,
      improvement in pulmonary hypertension) are better for longer daily treatment.
      Patient compliance is however often insufficient. In addition to education, the
      best way to improve patient participation is to strive for improved quality of
      life with oxygen therapy (portable device, liquid oxygen) in these patients.

PMID- 12407285
TI  - [Cystic lymphangioma of the mediastinum. Seven cases].
AB  - Cystic lymphangioma of the mediastinum is an uncommon vascular tumor frequently
      discovered incidentally on chest x-ray exams. Radiology (CT and MRI) may suggest
      the diagnosis and allow an assessment of the operatives difficulties, but
      histology of the surgical specimen is required for precise diagnosis. Complete
      resection is the only treatment; in some patients resection was incomplete
      because of the infiltrating character of these tumors, leading to recurrence. We
      report seven cases of mediastinal localization with a review of literature.

PMID- 12407286
TI  - [Rib tuberculosis: value of imaging. Report of 4 cases].
AB  - We report 4 cases of tuberculous osteitis of the ribs in patients aged 25 to 60
      years. All patients had thoracic CT scan. Two cases presented as multifocal
      tuberculosis, involving nodes and lung in one case, a costo-verebral joint and
      lung in the second case. In two patients, the aspect was a misleading pseudo
      tumor form with a primitive malignant bone tumor and infiltration of
      perivertebral and endocanalar soft tissue in one case of costo-transverse joint
      tuberculosis with neurologial disorder; in the other case, the rib affection
      presented as a breast tumor due to the involvement of anterior thoracic wall in a
      50-year-old woman. In all cases, the radiological aspect was quite extensive
      osteolysis of the rib with involvement of endo- and/or extrathoracic soft tissue
      noted as cystic or tissue density. We underline the value of CT scan for a
      complete investigation of rib lesions, which enables characterization of soft
      tissues involvement, guiding biopsies and search for associated vertebral
      lesions.

PMID- 12407287
TI  - [Retrotracheal cystic mass in the mediastinum].
AB  - We describe a case of retro-tracheal mass of the visceral compartment of the
      mediastinun in a 79-year-old woman revealed by signs of tracheal compression.
      Visualization of a vascular image coming from the cervical zone on reconstructed
      injected CT, and biological demonstration of a primary hyperparathyroidism led to
      the diagnosis of ectopic parathyroid adenoma, in spite of the cystic aspect of
      that tissular mass. Surgery by cervical approach was able to remove this mass
      without any problem. Pathological examination confirmed that it was a parathyroid
      adenoma with necrotic modifications. Follow up show a clinical and a biological
      improvement.

PMID- 12407288
TI  - [A patient with pulmonary endometriosis].
AB  - A 30-year-old woman consulted for recent repeated episodes of hemoptysis
      occurring at the onset of the menses a few months after interruption of estrogen
      progesterone treatment. This patient's only surgical history involved uterine
      curetage. She was a smoker and had cumulated 10 pack-years. Physical examination
      and chest x-rays were normal. Bronchial endoscopy and cytological examination of
      the bronchial aspiration were normal. Thoracic CT demonstrated an alveolar image
      in the right lower lobe. A second CT performed later after resolution of the
      episode of hemoptysis was normal. Laparoscopy was performed and visualized an
      endometrial nodule in the pelvis which was removed. The patient's clinical signs
      disappeared after treatment with triptoreline. Bronchopulmonary endometriosis is
      an uncommon condition. The main manifestations are catamenial hemoptysis during
      the first days of the menses. Chest pain is exceptional. Diagnosis may result
      from an incidental discovery. A traumatic intervention on the uterus is often
      found in the patient's history. The most commonly proposed pathogenic mechanism
      involves hematogenic migration following a uterine procedure. Imaging does not
      disclose specific signs and bronchial endoscopy is often normal but may
      demonstrate a tracheal or bronchial plaque of endometriosis, or exceptionally
      endometrial tissue in the endoscopy biopsies. LH-RH agonists remain the current
      treatment.

PMID- 12407289
TI  - [Concomitant pulmonary nocardiosis and Hodgkin's disease: importance of long-term
      treatment].
AB  - A 32-year-old patient taking corticosteroid therapy for 10 months for autoimmune
      hemolytic anemia developed Hodgkin's disease and concomitant acute pulmonary
      nocardiosis. After treatment with imipenen and amikacin for 15 days, which was
      adapted to susceptibility tests, multiple-drug chemotherapy using the ABVD
      protocol (doxorubicin, bleomycin, vinblastine, dacarbazine) was given without
      recurrence of the pulmonary infection. Antibiotic prophylaxis using a minocycine
      erythromycin combination was continued for 8 months. We discuss the importance of
      long-term treatment based on data in the literature.

PMID- 12407290
TI  - [Thymolipoma. A case report].
AB  - Thymolipoma is an uncommon benign tumor of the thymus. Asymptomatic, it is an
      incidental discovery. Pathogenesis remains controversial. We report a new case in
      a 36-year-old woman that was discovered on a chest x-ray ordered for pneumonia.
      The MRI findings suggested the diagnosis which was confirmed at the pathology
      examination of the surgical specimen.

PMID- 12407291
TI  - [Familial alveolar proteinosis].
AB  - Pulmonary alveolar proteinosis is a progressive disease recognized 35 years ago.
      Many etiologies have been put forward, but the pathogenesis remains obscure.
      Familial alveolar proteinosis is a rare condition, probably transmitted by
      recessive autosomal inheritance, with deficiency in surfactant apoprotein SPB or
      defective expression of the common granulocyte colony stimulating factor (GM
      CSF), IL3 and IL5 receptor. Gene therapy could be a future option for treatment
      in patients with specific gene defects.

PMID- 12407292
TI  - [Pulmonary carcinosarcoma with jejunal metastasis: complete response to
      chemotherapy].
AB  - We report a case of pulmonary carcinosarcoma with jejunal metastasis. The lung is
      an exceptional localization for carcinosarcoma, a tumor with carcinomatous and
      sarcomatous components. These two components are closely related but well-defined
      morphologically and immunohistochemically. Risk of metastasis and local
      recurrence is high. Surgery is the treatment of choice for localized forms.
      Prognosis depends on the sarcomatous component which is usually sensitive to
      chemotherapy, with at least doxorubicin and ifosfamide. This rare case
      illustrates the potential for jejunal metastasis and complete response to
      chemotherapy, proven histologically at 33 months.

PMID- 12407294
TI  - [Current concepts of autoimmunity].
AB  - Autoimmunity is physiological: in every normal individual autoreactive T cells
      and B cells which produce natural autoantibodies, exist. Auto-immunity becomes
      pathological, giving rise to an autoimmune disease, when the number of
      autoreactive cells, and particularly the avidity of their receptors for
      autoantigens increase. Triggering of the disease depends both on the increase in
      immunogenicity of the target cell, which may be secondary to a viral infection,
      and the individual's own capability to recognize the antoantigens (HLA genes, T
      cell repertoire). More rarely, the disease is caused by an infectious agent
      leading to a crossed reaction with an autoantigen (Guillain-Barre syndrome).
      Nevertheless, all these elements are not sufficient to provoke a chronic disease
      such as multiple sclerosis or myasthenia gravis. The passage to chronicity is
      usually secondary to a defect in immunoregulation. Several categories of
      regulatory T cells have been found: Th2 cells, CD25+ cells, Trl cells, NKT cells.
      It is still difficult to asses the responsibility of the defect of one of these
      populations in a given disease, or to single out the cytokines implicated,
      although an essential role is often given to interleukin 10 and/or TGFB. Even if
      the pathogenic autoimmune reaction is triggered by the autoantigens of the target
      cell, there is apparently not a unique autoantigen target. The specificity of the
      reaction spreads progressively from one antigen, which may vary among subjects,
      to the entire target cell. It is based on these notions that new
      immunotherapeutic approaches for autoimmune diseases are being developed (soluble
      autoantigens, or one of their modified peptides: (APL), cytokine, anti-CD3
      antibody).

PMID- 12407295
TI  - Inflammatory cytokines in the nervous system: multifunctional mediators in
      autoimmunity and cerebral ischemia.
AB  - Cytokines are immune mediators that orchestrate inflammatory responses. In
      autoimmune disorders of the nervous system such as the Guillain-Barre syndrome
      (GBS), and the corresponding animal model, experimental autoimmune neuritis
      (EAN), proinflammatory cytokines augment nerve infiltration by T-cells and
      contribute to macrophage-mediated demyelination. The local balance between pro-
      and antiinflammatory effects determines the clinical course. Cytokine expression
      in the nervous system is, however, not restricted to autoimmune disorders.
      Cytokines likewise contribute to infarct growth after focal cerebral ischemia,
      and under certain conditions convey neuroprotection. This short review summarizes
      selected aspects of cytokine actions during immune-mediated demyelination and
      cerebral ischemia. Elucidation of cytokine-mediated pathways of neurotoxicity and
      neuroprotection may not only improve stroke treatment, but, in addition may have
      a major impact on autoimmune diseases such as multiple sclerosis and GBS, in
      which axonal loss rather than demyelination determines long-term disability.

PMID- 12407297
TI  - Les syndromes paraneoplasiques.
AB  - Paraneoplastic syndromes affecting the nervous system are rare but devastating
      complications of systemic cancer. The neurologic disorder usually precedes
      identification of the cancer and can affect any portion of the nervous system
      including cerebral cortex, cerebellum, spinal cord, peripheral nerves,
      neuromuscular junction or muscle. A single area or cell type of the nervous
      system may be affected or the entire neuraxis may be involved. The pathogenesis
      of paraneoplastic syndromes involving the nervous system is believed to be immune
      mediated: the current hypothesis is that antigens usually expressed only in
      neurons are expressed in a cancer; the immune system recognizes the antigen in
      the cancer as foreign and mounts an immune response that slows the growth of the
      tumor but damages the nervous system. The diagnosis of a paraneoplastic syndrome
      is made either by identifying a small cancer in a patient with a neurologic
      disorder of unknown etiology or by identifying paraneoplastic autoantibodies in
      the serum of patients. The treatment involves identification and treatment of the
      causal cancer and immunosuppression to suppress both the humoral and cellular
      immune response.

PMID- 12407296
TI  - [The immune system: new therapeutic targets].
AB  - Control of the immune reaction can become a major goal, particularly in patients
      with autoimmune diseases or who express alloreactivity after organ
      transplantation. The most important side effect of this control is an
      immunodeficiency, a consequence of the wide spectrum of activity of the
      treatment. Thus, in order to limit the infectious risks, it would appear
      reasonable to try to develop new more selective strategies. A better definition
      of the cellular and molecular mechanisms implicated in the initiation and
      effector phases of autoimmune diseases authorizes the development of new
      therapeutic approaches able to target precise points of the immune system. There
      are a large number of potential targets, mainly directed at orientating the
      cytokinic response toward an antiinflammatory profile, neutralizating
      proinflammatory cytokines or their receptors, inducing regulatory lymphocytes in
      order to normalize the state of T and B cell tolerance, and modulating cellular
      cooperation and lymphocytic homing by blocking adhesion molecules. Some of these
      new approaches have already been validated in autoimmune diseases, others will
      follow soon.

PMID- 12407298
TI  - [Central nervous system and systemic vasculitides].
AB  - Central nervous system (CNS) involvement can occur in large, medium, or small
      sized vessel vasculitides. It is present in less than 10p. cent of systemic
      vasculitides. Clinical symptoms are heterogeneous and reflect the various
      mechanisms involved: vasculitis, blood hypertension, thrombosis and embolism. The
      symptoms can be present initially, at the time of relapse or occur as a treatment
      side effect. A primary angiitis of the CNS can also be observed. This
      granulomatous vasculitis is rare and isolated. Its diagnosis is difficult. The
      prognosis has improved but the disease remains severe. Diagnosis can be made by
      histology but is suggested by the association of clinical symptoms and brain
      imaging. Cognitive modifications, sometimes severe can also be observed but can
      improve with treatment. Prognosis of CNS manifestations is severe. It counts for
      one point in the Five Factor Score (FFS) which has been validated in some
      systemic vasculitides. The death rate is 12p. cent when the score is 0 and 50
      percent for 2 points. Patients should be treated with a combination of steroids
      and cyclophosphamide which improves CNS vasculitis outcome.

PMID- 12407299
TI  - [Neurological manifestations of systemic necrotizing vasculitis].
AB  - Systemic vasculitides commonly induces peripheral neuropathies. In most cases
      signs and symptoms of multisystem involvement, including polyarthritis, asthma,
      renal and skin involvement, accompany peripheral neuropathy. In approximately one
      third of the patients however peripheral neuropathy is the first and only
      manifestation of necrotizing vasculitis. Nerve and muscle biopsy is often
      necessary to confirm vasculitis, which requires histological evidence for
      diagnosis. A focal or multifocal, axonal, ischemic neuropathy often results from
      involvement of nerve trunks vasa nervorum. Outcome of the neuropathy is often
      favorable with corticosteroids but the improvement is very slow and sometimes
      only partial.

PMID- 12407300
TI  - [Neurological manifestations in cryoglobulinemia].
AB  - Cryoglobulins are immunoglobulins that persist in the serum, precipitate at cold
      temperature and resolubilize when rewarmed. Type I is often associated with
      hematological disorders. Type II and III are mixed cryoglobulins, composed of
      different immunoglobulins with a monoclonal component in type II and only
      polyclonal immunoglobulins in type III. Mixed cryoglobulins are associated with
      connective tissues or infectious diseases. Hepatitis C virus is involved in most
      of previously called "essential" mixed cryoglobulinemia. Dermatological,
      rhumatological, and nephrological manifestations are the most frequent, and
      neurological complications are found in 20 percent of cases. However, in mixed
      cryoglobulinemia with low cryoglobulins level, neurological signs may reveal the
      disease. Ischemic central nervous system complications are rare, but sensory,
      axonal, peripheral neuropathies or sensory and motor multiple mononeuropathies
      are more frequent. Prognostic and treatment depend on association with hepatitis
      C, and presence of vasculitis lesions in the nerve biopsy.

PMID- 12407301
TI  - [Neurological manifestations of Behcet's disease].
AB  - The neurological complications of Behcet's Disease are observed in 5 to 35
      percent of cases depending of series. They included vascular and central nervous
      system manifestations. Vascular involvement is dominated by cerebral venous
      thrombosis marked by benign intracerebral hypertension. Prognosis is favourable
      with steroids and anticoagulation. Arterial involvement (thrombosis or aneurysm)
      are seldomly observed but increasingly with angio-MRI. Parenchymal involvement is
      dominated by meningoencephalitis eventually associated with fever. Myelitis and
      cranial nerve palsy are seldomly encountered. Cerebrospinal fluid is abnormal
      with lymphocytosis or pleiocytosis. MRI has a high sensitivity with hypersignals
      in the brainstem, basal ganglia, internal capsule and thalamus. Prognosis of
      central nervous system involvement is severe. Initially recovery is frequent, but
      severe impairment occurs due to relapse. In our experience, therapy including
      steroids, immunosuppressive drugs and colchicine improve short term and long term
      prognosis due to significant reduction of relapse in patients with good
      observance.

PMID- 12407302
TI  - [Dermatomyositis and polymyositis].
AB  - Dermatomyositis (DM) and polymyositis (PM) are the two main forms of idiopathic
      inflammatory myopathies. They have in common a proximal muscle weakness, but skin
      manifestations, juvenile forms and increased incidence of malignancies are
      clinical characteristics of DM. The follow up of creatine-kinases is the best
      biological test in spite of their possible normality. The significance of
      antibodies titers is uncertain, except the association Jo-1 interstitial and lung
      disease indicating a poor prognosis. The association with HLA haplotypes
      expresses a genetic predisposition of a dysimmunity to develop DM or PM.
      Pathological changes are well known with a humoral immune effector mechanism in
      DM, and a muscle fibre aggression by CD8 + T cells in PM. Non inflammatory forms
      of DM and PM and rhabdomyolytic forms of PM are not very rare, they are
      recognized by the HLA class 1 immunoreactivity. Pathophysiological processes
      involve muscle fibers, inflammatory cells and endothelial cells of capillaries,
      with a complex intervention of cytokines, adhesion molecules, MHC classe 1,
      membrane attack complex, anti endothelial cells antibodies, perforin secretion
      and sometimes apoptotic Fas-mediated mechanisms. Despite these recent advances,
      causal antigens and activator processes of endothelial cell lysis and
      autoinvasive cytotoxicity of muscle fibers remain to be identified.

PMID- 12407303
TI  - Understanding the immunopathogenesis of inclusion-body myositis: present and
      future prospects.
AB  - Sporadic Inclusion Body Myositis (s-IBM) is the most common acquired inflammatory
      myopathy. It has a stereotypic clinical presentation and a predictably
      progressive course that leads to severe muscle weakness and permanent disability.
      The combination of primary endomysial inflammation with autoimmune features
      identical to those seen in Polymyositis, and degenerative features with
      vacuolization of muscle fibers and deposits of tiny speckles of amyloid, are
      characteristic for the disease. In this review, the immunopathology of IBM is
      detailed. The inflammation which is prominent even late in the disease, is
      characterized by activated, CD8+ cytotoxic T cells that secrete perforin and
      invade MHC-I-expressing muscle fibers. The autoinvasive T cells are probably
      antigen driven because of specific rearrangement of their T Cell Receptor
      profile, restriction of the CDR3 region, upregulation of co-stimulatory molecules
      and their ligands on the muscle fibers, and activation of various cytokines,
      chemokines and adhesion molecules. The disease can be seen in association with
      HIV and HTLV-I infection, but viruses have not been amplified from the muscle
      fibers and the antigen or the factors that trigger inflammation are still
      unknown. The disease is mysteriously resistant to conventional immunotherapies in
      spite of the immunopathologic similarities with PM. The cause of the vacuolar
      formation in IBM is also unknown and the role, that the tiny amyloid deposits
      play in the disease remain unclear. The treatment approaches and the prospects
      for future immunotherapeutic interventions are discussed.

PMID- 12407304
TI  - [Neuroradiological manifestations of primary Sjogren's syndrome].
AB  - Primary Sjogren's syndrome (PSS) is considered as the most frequent connective
      tissue disease. Neurological complications may affect the peripheral nervous
      system and to a lesser extent the central nervous system. Neurological
      manifestations often precede or reveal SSP. Peripheral neuropathy is the most
      common and well-known neurological complication of PSS. Its frequency is about 20
      30 percent of patients. Distal sensory or sensorimotor axonal neuropathy is the
      most frequent followed by sensory neuronopathy, the only neurological
      complication characteristic of SSP. Recently, several cases of motor neuron
      syndrome have been reported suggesting that it could be a neurological
      complication of SSP. CNS involvement consists of cerebral or spinal cord
      involvement and its frequency is debated. Cerebral dysfunction may be focal or
      multifocal according to the number and location of lesions. Its course may be
      acute, remittent or progressive. Cognitive dysfunction and psychiatric
      manifestations seem to be frequent in SSP but this needs to be confirmed by
      further studies. Spinal cord involvement consists of acute myelitis or
      progressive myelopathy. In CNS involvement, there is no correlation between
      clinical findings and results of CSF study or MRI which can be normal or disclose
      unspecific abnormalities. For all neurological complications, response to
      corticosteroids or immunosuppressive therapy is unpredictable. As neurological
      manifestations in SSP are miscellaneous, SSP diagnosis should be considered in
      any unexplained neurological setting because sicca syndrome is often mild or
      asymptomatic and immunological abnormalities or other extraglandular
      manifestations of PSS may be lacking.

PMID- 12407305
TI  - [Hashimoto's encephalitis].
AB  - Hashimoto's encephalitis was first described more than 30 years ago. The clinical
      picture is typically that of a subacute encephalopathy with a moderate to marked
      alteration of consciousness, seizures, myoclonus or tremulousness. Additional
      stroke-like episodes can occur along the course of the disease which may be
      monophasic or relapsing. The diagnosis of Hashimoto's encephalitis requires the
      presence of an elevated titer of antithyroid antibodies (mainly anti
      thyroperoxidase and also anti-thyroglobulin) which is not necessarily associated
      with obvious thyroid dysfunction. The results of neurologic investigations are
      not specific and show typically a global slowing of the EEG, a moderately high
      CSF protein content and a normal or near normal imaging except in rare cases. The
      disorder is considered autoimmune and is remarkably responsive to corticosteroids
      which must be started as soon as possible after the diagnosis has been confirmed
      biologically. The long-term prognosis is usually good but some patients may die
      or present major neurologic sequelae.

PMID- 12407306
TI  - [Neurological manifestations of IgM dysglobulinemia].
AB  - Disturbancies in neurological functions associated with paraproteinaemic states
      are well documented. In recent years increasing attention has been given to
      paraproteinemia in the absence of evidence of malignancy. In this article we
      review the main clinical and pathological features associated with IgM
      paraproteins. Neurological complications affecting the central nervous system are
      rare, while peripheral neuropathies are frequently observed. Recent advances at
      the histological and molecular level have allowed a better characterization of
      clinical syndromes and have given new insights into their pathogenesis. The most
      convincing evidence for a causal relationship can be drawn from IgM monoclonal
      gammopathies with specificities directed against carbohydrate determinants of the
      myelin associated glycoprotein (MAG). There remain, however, many unresolved
      questions such as how monoclonal anti-MAG IgM antibodies cross the blood-nerve
      barrier and trigger a chronic demyelinating polyneuropathy while the central
      nervous system is essentially spared. Current immune therapies for neuropathy
      associated with IgM paraproteins are temporarily effective in half of patients
      and are often associated with considerable side effects which limit their
      prolonged use and efficacy. The availability of safer therapies such as humanized
      monoclonal antibodies that eliminate specifically B-cell and B-cell precursors
      may open a new avenue for the management of these patients.

PMID- 12407307
TI  - Neuropathies associated with IgG and IgA monoclonal gammopathy.
AB  - Neuropathy has been frequently reported in patients with monoclonal gammopathy,
      particularly those with monoclonal gammopathy of undetermined significance
      (MGUS). While the neuropathy associated with IgM-MGUS is well characterized and
      is often associated with a reactivity of the monoclonal protein with neural
      antigens, the relationship between the neuropathy and IgG and IgA MGUS is less
      clear. We review here the clinical, electrophysiological and pathogenetic
      features of neuropathies associated with IgG and IgA M-proteins in order to
      determine whether they represent distinct clinical entities and, most
      importantly, whether the finding of an IgG or IgA monoclonal gammopathy in a
      patient with neuropathy should led to different diagnostic or therapeutical
      approaches. This review will mainly focus on neuropathies associated with MGUS
      since the disclosure of a malignant monoclonal gammopathy, including multiple or
      osteosclerotic myeloma, lymphoma or primary amyloidosis, in a patient with
      neuropathy usually divert the therapeutical decisions to the hematologist for an
      appropriate therapy of the underlying life threatening condition.

PMID- 12407308
TI  - [Neurological manifestations of Whipple disease].
AB  - Whipple disease is an uncommon chronic bacterial infection due to Tropheryma
      whipplei. Clinical manifestations are protean (joint pain, fever, weight loss,
      abdominal pain, lymphadenopathies), and the diagnosis is often delayed. Although
      previously considered a late manifestation of Whipple disease, neurological
      involvement is now frequently the initial clinical manifestation and represents
      the greatest risk for long-term disability. All patients should be treated and
      monitored as if they had central nervous system disease even if they are
      asymptomatic. Neurological manifestations include dementia (56 percent),
      abnormalities of eye movements (33p. cent), involuntary movements (28 percent),
      seizures, hypothalamic dysfunction, myelopathy, ataxia and psychiatric
      manifestations. Uveitis, retinitis, optic neuritis and papilloedema may be found.
      80 percent of the reported cases of neuro-Whipple had associated systemic
      symptoms or signs but many patients are presenting without concurrent intestinal
      manifestation. Thus, the disease may remain undiagnosed or misdiagnosed, as
      rheumatoid arthritis or sarcoidosis. Traditionally, the diagnostic procedure of
      choice is biopsy of the duodenal mucosa by demonstrating PAS-positive foamy
      macrophages. However, not all cases have small bowel infiltration and tissue
      obtained from sites clinically affected may be helpful. CT and MR images of the
      central nervous system are normal or not specific: atrophic changes, mass
      lesions, focal abnormalities and hydrocephalus. The application of a PCR assay
      against Tropheryma whipplei has transformed the diagnosis. Positive results have
      been obtained from several tissues and from CSF and PCR is more sensitive than
      other techniques. All patients must be treated with antibiotics which cross the
      blood-brain barrier. Most agree that initial treatment with a combination of
      parenteral penicillin and streptomycin for at least 14 days is appropriate,
      thereafter cotrimoxazole orally 3 times a day for at least one and probably for
      two years. Third generation cephalosporins, rifampicin and chloramphenicol have
      been used successfully. PCR is recognized to be a useful tool for monitoring
      progress but it is sometimes difficult to reverse established neurological
      defects.

PMID- 12407309
TI  - [Tick-borne neurological diseases].
AB  - Some microorganisms transmitted to man via tick bite are responsible for
      infections, which can be associated with neuro-meningeal complications. TBE virus
      is the most frequent virus associated with potentially severe neurological
      lesions. No treatment is available so far. The most frequent bacterial diseases
      in which neurological complications may appear are Lyme borreliosis, Q fever and
      some rickettsial infections. More recently ehrlichiosis have emerged as new
      infections that may be associated with neuro-meningeal complications. Appropriate
      antibiotic therapy may be used for the treatment of these bacterial infections,
      but no vaccine is available so far.

PMID- 12407311
TI  - [Fat embolism to the brain after orthopedic surgery].

PMID- 12407310
TI  - [Prion diseases].
AB  - Creutzfeldt-Jakob disease, kuru, Gerstmann Straussler Scheinker syndrome and
      fatal familial insomnia in humans, as well as scrapie and bovine spongiform
      encephalopathy, in animals, are fatal disorders of the central nervous system
      that are part of the group of transmissible spongiform encephalopathies, (TSE) or
      prion diseases. Neuronal intracellular spongiosis and the accumulation of
      abnormal, protease resistant prion protein in the nervous central system
      characterize TSE. The conformational change of a host protein, prion protein,
      into a pathological isoform is the key pathogenetic event in TSE. Despite their
      relative rarity, prion diseases have a great impact on the scientific community
      and society in general. There are two major reasons: first, the heretical
      hypothesis of a disease transmitted by an "infectious protein" in the absence of
      nucleic acid, the basis of the conformational transmissibility concept; second,
      the panic originated from the appearance of new variant Creutzfeldt-Jakob disease
      and the evidence linking it to the exposure of humans to bovine spongiform
      encephalopathy via food contaminated by affected bovine tissue. Novel therapeutic
      approaches are examined.

PMID- 12407312
TI  - [Fundamentals of lower urinary tract anatomy and function].

PMID- 12407313
TI  - [Urinary disorders, functional exploration of the urinary tract, and multiple
      sclerosis].

PMID- 12407315
TI  - [Improving training in Neurosurgery].

PMID- 12407314
TI  - [Magnetic resonance imaging in multiple sclerosis].

PMID- 12407316
TI  - [Craniopharyngioma in children: MRI study of 43 cases].
AB  - BACKGROUND AND PURPOSE: Craniopharyngiomas are intra-cranial tumors, relatively
      frequent in children, expanding in the pituitary stalk axis, from the third
      ventricle to the sphenoid body. Plain films and CT scan generally show a
      calcified lesion, deforming the sella turcica. MRI improves tumor description and
      topographic and structural analysis of the lesion. The aim of this study is to
      analyze the MRI aspect of craniopharyngiomas in a pediatric population and to
      correlate findings with surgical data. METHODS: MR and CT studies of 43 pediatric
      cases of histology-proven craniopharyngiomas were reviewed retrospectively. Tumor
      emergence, extensions and signal on different sequences were recorded. We
      searched for radio-surgical correlations. RESULTS: Craniopharyngiomas can be
      classified into two groups: intra-sellar tumors and third ventricle floor tumors
      (infundibulum and tuber cinereum). Preferential routes of extension are observed
      in each group correlated with consistency (cystic and/or solid). Surgical data
      confirmed these results. CONCLUSIONS: MRI is crucial for the pre-therapeutic
      evaluation of craniopharyngiomas allowing not only a detailed description of the
      tumor but also guiding therapeutic decisions. This series demonstrated that
      craniopharyngiomas exhibit two different types of localization and behavior.
      Embryonic development of the tumor explains the topographical differences.

PMID- 12407317
TI  - [Brain stem cavernomas in children. Nine case reports and literature review].
AB  - We report our experience with 9 cases of brain stem cavernoma in children aged 15
      years during the period 1987-2000. All patients were admitted with lesion-related
      symptoms, except in one where the brain stem cavernoma was discovered on a
      routine MR scan. A female predominance was noted in the present study. In 2
      children, brain stem cavernoma was associated with multiples lesions. All
      patients except two with multiple cavernomas underwent surgery. One child died 2
      months after surgery from recurrent hemorrhage. The eight others are alive. Among
      the 8 survivors, only one has worsened. Children with brain stem cavernoma who
      develop persistent or progressive deficit are candidates for surgery. When
      surgery is indicated, total removal is mandatory to avoid the risk of recurrence
      and rebleeding.

PMID- 12407318
TI  - [Treatment of intracranial cysts in children: peritoneal derivation or endoscopic
      fenestration?].
AB  - OBJECTIVE: The goal of this study is to evaluate the indications, benefit and
      complications of shunts and endoscopic fenestrations in the treatment of
      malformative intracranial cysts. MATERIAL AND METHOD: The records of 172
      consecutive children (mean age of 4 years) were reviewed. All had a malformative
      cyst. Dandy Walker malformation, mega cisterna magna, and cysts from tumoral or
      porencephalic origin were excluded from the study. The cysts were diagnosed
      either in utero (n=64) or postnatally (n=108). Most of them were unique (94.8%)
      and localized in the posterior fossa (26.2%) or at the convexity (23.2%).
      Indication for surgery was based on clinical symptoms (n=101; 86.3%) or size of
      the lesion (n=16; 13.7%). Endoscopy was the treatment of choice when cysts were
      in closed relationship with enlarged ventricles. Shunting procedures were
      indicated when endoscopy was not feasible and craniotomies when shunt insertion
      was unsafe or diagnosis uncertain. Fifty children underwent an endoscopic
      fenestration, 55 a shunting procedure, 7 the puncture or the external drainage of
      a pericerebral collection and 5 a direct surgical approach. The mean follow-up
      was 5.5 years. Psycho-motor, intellectual and school performances were evaluated
      in 93 children (54%). Success was defined by both the disappearance of symptoms
      of increased intra cranial pressure and regression of the cyst. RESULTS: Compared
      to shunts, endoscopic fenestrations were more frequently successful (70% vs
      61.8%), led to less complications (6% vs 61.8%) and to a lesser number of
      reoperations (in average 1.6 operation per child vs 2.2). Median developmental
      and intellectual quotients for the whole series were respectively 98 and 97 and
      did not depend upon the type of treatment. CONCLUSION: The study of this series
      shows that treatment modalities necessarily vary according to the site of the
      cysts but that endoscopic fenestrations are preferable to shunts whenever
      feasible.

PMID- 12407319
TI  - [Infections after missile head injury. Experience during the Lebanese civilian
      war].
AB  - OBJECTIVE: Establish the risk factors for infection following missile head
      injuries (MHI). METHODS: Between 1975 and 1990, 500 cases of MHI were admitted,
      with only 272 responding to inclusion criteria. After initial evaluation
      including CT scan for 177 patients, all underwent craniectomy with debridement
      and duroplasty. A retrospective study was undertaken in order to identify the
      risk factors that increase the infection rate. RESULTS: The global infection rate
      was 11.39%. Among the studied factors, those increasing the infection rate were:
      coma on admission (17.6% vs 7.6%), penetrating wounds (12.93% vs 7% for
      tangential wounds), intracerebral trajectory length over 6 cm (18.42% vs 6.32%),
      air sinuses effraction (25.8% vs 9.54%), a surgical delay over 72 hours (41.6% vs
      10.6%), inadequate duroplasty (28% vs 7.33%), cerebrospinal fluid (CSF) fistulae
      (58.62% vs 5.76%). The presence of postoperative bone fragments did not increase
      the infection rate (11.4% vs 11.2%). DISCUSSION AND CONCLUSION: Adequate
      duroplasty and aggressive treatment of CSF fistulae decrease the infection rate.
      There is no need to reoperate on residual bone fragments after adequate
      debridment. A delay of 24 to 48 hours should be considered, to facilitate the
      procedure without increasing the infection risk.

PMID- 12407320
TI  - [Postoperative intracranial seeding of craniopharyngioma. Three case reports and
      a review of the literature].
AB  - Metastasis of craniopharyngioma is uncommon. Only 10 cases have been reported in
      the literature. In this report, we describe 3 patients who presented metastases
      following operative treatment of suprasellar craniopharyngioma. All 3 patients
      (ages: 32, 11, and 9 years) underwent radical excision of a supradiaphragmatic,
      retrochiasmatic craniopharyngioma by the right frontopterional approach.
      Resection was considered as total in all cases. All patients required hormone
      replacement therapy. Local recurrence was observed in only one case. Metastasis
      occurred along the surgical route in all three patients. The interval between
      surgery and metastasis was 5 and 3 years in the first two cases. The third
      patient presented two metastases: one in the temporal space at 3 years and
      another in the frontal space at 10 years. Repeat surgery was performed in 2
      patients. The first case involved a lesion located in the right frontal space,
      and the second involved local recurrence and metastasis along the surgical route.
      The third patient was treated by puncture and radiation therapy for the temporal
      lesion and surveillance for the frontal lesions. No recurrence has been observed
      at 2 and 7 years after re-operation. Although rare, metastasis of
      craniopharyngioma has been reported up to 21 years after resection of the primary
      tumor. Metastasis often occurs along the surgical route, as in our 3 cases, but
      spreading to distant locations via cerebrospinal fluid has been observed. Regular
      follow-up is necessary, even after supposedly total resection.

PMID- 12407321
TI  - [Cerebellar primary germinoma. Case report].
AB  - Germinoma cell tumors account for 1% of all primary cerebral tumors. They occur
      in pineal and in supra-sellar regions, and rarely, in basal ganglia and thalami.
      Germinoma cell tumors originating in the posterior fossa are very rare. We report
      a case of primary germinoma found in the cerebellar hemisphere in a 45-year-old
      immunocompetent man presented with intracranial hypertension and cerebellar
      ataxia. The CT scan revealed a heterogeneous mass in the cerebellar right
      hemisphere with a cystic component. Intense and heterogeneous enhancement after
      contrast infusion was observed. Two other nodules were identified in the frontal
      and occipital lobe. The pineal region was normal. Total resection was performed.
      The histological finding were a germinoma. Extensive systemic examination
      indicated that the intracranial lesion had not metastasized from a primary
      extracranial tumor.

PMID- 12407322
TI  - [Code of professional ethics in clinical research].

PMID- 12407323
TI  - [Development of better tolerated prosthetic materials: applications in
      gynecological surgery].
AB  - Meshes have come to be widely used for surgical repair of the dysfunctional
      pelvic floor. The problem to date has been mesh intolerance. History. The first
      meshes were made with silver filigrees or stainless steel. Non-metallic and non
      absorbable synthetic prostheses include nylon, silastic, polytetrafluoroethylene
      as well as expansive polyester and polypropylene forms. Most of the absorbable
      prostheses are made of polyglycolic acid and polyglactine 910. Classification.
      Four groups of biomaterials can be described according to pore size. Mechanical
      and biological properties. The mechanical properties of meshes have been tested
      industrially for resistance, pliability, elasticity and ductile qualities. These
      properties depend on type of tissue structure (woven or knitted) and the type of
      fiber used (mono and multi-filaments). The goal is to obtain a "silent" material,
      i.e. a material which does not trigger a host tissue reaction. Introducing the
      foreign body induces a "scarring" response. This fibroblastic reaction replaces
      the inflammatory reaction, leading to progressive colonization of the prosthesis.
      The major risk is infection caused by a disturbance of the inflammatory phase and
      bacterial development. Bacteria can be trapped in fibrotic tissue, with the risk
      of delayed infection. Immunological reactions may have an additive effect. These
      problems are not encountered with absorbable meshes. An ideal implant material
      must: not undergo physical modification by tissue fluids, be chemically inert,
      not trigger inflammatory or foreign body cell response in body tissues, be
      noncarcinogenic and nonallergenic, be capable of resisting mechanical stress and
      sterilization, and be able to be manufactured in the necessary shape. Polyester,
      polypropylene and expansive polytetrafluoroethylene fulfill these criteria. The
      ideal mesh. Eleven criteria are proposed. Complications for hernia repair.
      Infection and seroma are the most frequent complications with micro-porous
      meshes. Macro-porous meshes can cause erosive phenomena and adhesions. Retraction
      of synthetic tissues is observed in 20 to 30% of cases. Meshes in gynecology. In
      gynecology surgery, meshes made their first appearance in trans-abdominal
      sacrocolpopexy and slings. A detailed review of complications found in 32
      articles studying slings and 22 studying sacrocolpopexy with approximately 10
      types of meshes shows that intolerance of slings has oscillated between 1% with
      Prolene and 31% with Gore-Tex; for abdominal sacrocolpopexy the rate was between
      1.7% with Prolene and 20% with Teflon. Rejection phenomena appear during the
      first year and are proportional to the surface area of the synthetic tissue and
      the proximity of the vaginal scar. New materials have been proposed over the last
      ten years for prolapse surgery, notably for cystocele, which accounts for 70% of
      all repair procedures. Nearly fifteen studies have reported a level of
      intolerance reaching 6%, the large majority of the meshes used being Prolene
      meshes. Our personal experience with 87 repair procedures has led us to the
      conclusion that Prolene is the most adapted mesh, allowing free tension between
      the bladder and the anterior vaginal wall. CONCLUSION: Continuous evaluation is
      needed to study these replacement materials which should in theory, improve the
      rate of recurrence, which is at present 20% with classic procedures not using a
      mesh.

PMID- 12407324
TI  - [Postmenopausal hormonal treatment: conventional hormone replacement therapy or
      tibolone? Effects on bone].
AB  - OBJECTIVE: Our purpose was to review with critical analysis, data from randomized
      controlled clinical trials comparing the effects on bone of conventional hormone
      replacement therapy (HRT) and tibolone. Their respective effects on bone were
      also reviewed and summarized. Materials and methods. Medline via PubMed was
      searched using a combination of the following key words "tibolone, estrogens and
      bone" to identify all randomized controlled trials tibolone versus HRT (1960
      2001). RESULTS: Six randomized controlled trials that have been carried out to
      compare effects of tibolone and conventional HRT on prevention of postmenopausal
      bone loss were identified. Only one of these trials has been performed with a
      correct methodology (double-blind and with an adequate duration). In this trial
      over 2 years, the highest significant increase from baseline in bone mineral
      density (BMD) at all sites was observed with HRT; in addition, HRT showed a
      significantly greater increase in BMD at lumbar spine than tibolone. Randomized
      placebo-controlled trials have demonstrated that tibolone produces positive
      effects on BMD. Nevertheless, no clinical convincing data are available to
      support its efficacy in the prevention of osteoporotic fractures. The positive
      impact on BMD of conventional HRT to prevent postmenopausal bone loss and to
      treat established osteoporosis has been shown by many randomized controlled
      trials. Regarding fracture risk prevention, some clinical and epidemiological
      data suggest that HRT initiated in early or late postmenopause may prevent
      fractures if it is administered at standard doses and continued for a long time.
      CONCLUSION: HRT is always the reference treatment of postmenopausal symptoms
      related to estrogen deficiency.

PMID- 12407325
TI  - [Obstetrics, surgical gynecology, or medical gynecology: what type of practice
      interests today's interns?].
AB  - INTRODUCTION: Two major modifications have recently changed the training program
      of interns in obstetrics and gynecology in France. The first modification is an
      important increase in the number of interns in OBGYN, allowing more lower ranked
      medical students to enter this training. The second modification is the imposed
      subdivision of the pool of interns in two distinctive branches: obstetrics and
      gynecological surgery, and medical gynecology with a 2/1 ratio. These
      modifications were decided without consulting interns on the type of practice
      they intend to have later. This study tries to determine what type of practice
      French interns in OBGYN intend to have when they have finished their training.
      MATERIAL AND METHOD: We distributed surveys to all French interns in OBGYN. The
      survey included questions on the type of practice they intend to have, and
      questions on their opinions on how OBGYN show be taught. RESULTS: Two third of
      interns wanted to have a full practice in OBGYN. This proportion was the same
      considering only first year interns. Three quarters of interns wanted to have a
      future practice that includes at least medical gynecology, and only one intern
      wanted to do solely medical gynecology later. French interns in OBGYN wanted more
      medical gynecology teaching during their training CONCLUSION: Despite recent
      modifications in the training program, French interns in OBGYN intend to have a
      full practice later. This choice is not influenced by the 5 years of training.

PMID- 12407326
TI  - [Systematic screening for Chlamydia trachomatis with the molecular biological AMP
      CT test in urine samples from young women].
AB  - OBJECTIVE: We report the results of a systematic direct detection screening
      protocol for Chlamydia trachomatis in urine samples from young women. MATERIAL
      AND METHOD: The study included 1026 patients aged 13 to 30 years. Urine samples
      were tested with a molecular biology assay: AMP-CT. RESULTS: Thirty-five patients
      (3.4%) were positive: 80% of the positive patients were aged less than 25 years,
      48.6% less than 20 years. All these patients were treated and post treatment
      controls were negative. CONCLUSION: This study suggests that national screening
      programs for Chlamydia trachomatis could be beneficial for women aged between 15
      and 25 years and that the "Calmat" law could be modified in consequence.

PMID- 12407327
TI  - [Complications, sequellae and outcome of cervical conizations: evaluation of
      three surgical technics].
AB  - OBJECTIVES: To assess complications and after-effects of conizations and follow
      up of patients treated with 3 conization methods. Materials and methods. Two
      hundred and forty-one conizations were performed for cervical dysplasia using
      cold knife (100 cases), electric knife (39 cases) or loop electrosurgical
      excision (102 cases). Residual disease, post-operative bleeding, cervical
      stenosis and recurrences were assessed. RESULTS: The height of the cone biopsy
      specimen was higher after cold knife conization (18.3 4.7 mm) and electric knife
      conization (18.4 0.7 mm) than after loop electrosurgical excision (12.8 3.5 mm)
      (P<0.001). However, the rate of positive margins for dysplasia was not
      significantly different: 7%, 8% and 14%, respectively. The rate of post-operative
      bleeding was 8%, 5% and 2%, respectively. The rate of cervical stenosis was 8%,
      27% and 3%, respectively (P<0.001). The rate of recurrences was not significantly
      different: 8%, 15% and 11%, respectively. CONCLUSION: Taking into account the
      current trend not to repeat surgery systematically after positive margin
      conizations, the risk of bleeding after cold knife conization, the risk of
      stenosis after electric knife conization and excessive depth of cone excision,
      the loop electrosurgical procedure may be recommended as a first option to treat
      cervical dysplasia.

PMID- 12407328
TI  - [The sentinal node: the Dijon experience].
AB  - OBJECTIVES: The goal of this study was to evaluate the technical feasibility of
      sentinel node biopsy in breast cancer and its capacity to predict axillary node
      status. MATERIAL AND METHODS: Between February 2000 and June 2001, 70 patients
      with invasive breast carcinomas referred to the cancer center of Dijon, underwent
      lymphatic mapping (patent blue dye and lymphoscintigraphy with a gamma probe) and
      sentinel node biopsy followed by axillary clearance (Berg's level 1 and 2).
      RESULTS: A sentinel node was identified in 94.26% of the patients. We noted 2
      false negative sentinel lymph nodes. The sentinel lymph node was involved in
      32.8% of the patients and was the only node involved in 14.2% of the patients.
      CONCLUSION: This study confirms the feasibility of sentinal node mapping,
      emphasizing the advantage of using two methods (patent blue dye and gamma probe).
      A learning curve is required. This procedure is not adapted for tumors larger
      than 3 cm because of a greater risk of sentinel node involvement and the need for
      a complete procedure with an axillary clearance.

PMID- 12407329
TI  - [Comparison of two cesarean techniques: classic versus Misgav Ladach cesarean].
AB  - OBJECTIVE: The aim of the study was to compare two cesarean section techniques
      Methodology. A prospective study was conducted UB 400 cesareans performed at the
      Gynecological and Obstetric Clinic of the Dakar Teaching Hospital between March
      2000 and August 2000. Two hundred patients underwent the classical procedure (CL
      group) and the other 200 the Misgav Ladach procedure (ML group). Per- and post
      operative data were compared between the two groups with Student's test and the
      Chi(2) test. A p-value less than 0.05 was considered statistically significant.
      RESULTS: The two groups were similar for socio-demographic and clinical data. The
      delay between the skin incision and infant delivery was significantly shorter in
      the ML group (5 minutes 26 seconds versus 6 minutes 20 seconds). The same trend
      was found for the length of operation (36 minutes 36 seconds versus 54 minutes 38
      seconds). Fewer sutures were used in the ML group (2.92 versus 4.14). There is no
      significant difference for dose of analgesia, post-operative complications and
      hospital discharge. Cost analysis demonstrated that the Misgav Ladach procedure
      was 10000 FCFA (15 euros) less costly. CONCLUSION: Misgav Ladach method is
      simple, rapid, cost-effective cesarean procedure which appears to be an
      attractive alternative to traditional cesarean section.

PMID- 12407330
TI  - [Breech presentation at term: a survey on obstetrical practice in France and a
      search for a homogeneous attitude associated with lower neonatal risk].
AB  - OBJECTIVES: 1- In order to define a "consensual attitude" in case of breech
      presentation, we queried the AUDIPOG network on obstetrical practice in search
      for the more frequently accepted criteria for normal delivery. 2- For consensual
      practices that could be identified, early neonatal complications were compared
      between women cared for in maternity wards applying these practices and those
      cared for in maternity wards not applying these practices. MATERIALS AND METHODS:
      1- A confidential survey was sent to participating obstetrics units to determine
      their practical attitude in case of breech presentation. A consensual attitude
      was established on the basis of their responses. 2- Crude and adjusted
      comparisons were made concerning neonatal results between the consensual and non
      consensual groups of obstetrics units. RESULTS: Response rate was 85% for 175
      obstetrics departments consulted. Six criteria were identified leading to
      classification of 42% of the units as consensual obstetrics units. The risk of
      major neonatal complications was lower in the consensual group than in the non
      consensual group: adjusted OR=0.27 (95% CI: 0.09-0.85). CONCLUSION: A
      questionnaire on obstetrical practice can help define consensual attitudes
      associated with lower risk of neonatal complications.

PMID- 12407331
TI  - [Vaginal hysterectomy: operative technique used at Caen].
AB  - OBJECTIVES: Describe the simplified technique we use for vaginal hysterectomy and
      report results from a retrospective series of 490 patients operated on between
      1990 and 1998. MATERIAL: and methods. The following parameters were studied:
      peroperative surgical complications, blood loss, infection, thromboembolism, and
      morbidity after one month. RESULTS: Our series demonstrated the same rate of
      complications (20.7%) as reported in the literature. CONCLUSION: This simplified
      technique for hysterectomy saves time and requires less operative assistance
      without changing outcome in terms of morbidity.

PMID- 12407332
TI  - [Cystocele repair by the vaginal route with a tension-free sub-bladder
      prosthesis].
AB  - OBJECTIVE: To describe a new vaginal approach for the repair of cystoceles,
      reinforced with a tension-free polypropylene mesh. METHODS: The vaginal procedure
      consisted of a complete dissection of the cystocele and a thorough entry from the
      vesicovaginal space under the inferior pubic ramus into the retropubic space. The
      polypropylene mesh (GyneMesh(TM), Gynecare, Ethicon France) was placed from the
      retropubic space to the inferior part of the bladder in a tension-free fashion.
      RESULTS: Forty-eight consecutive women with grade 3-4 cystoceles underwent this
      procedure between October 1999 and September 2001. Mean age was 63.9 years (41
      85). Mean follow-up is 18 months (8-32). The success rate was 97.9%. There were a
      total of four vaginal erosions of the mesh (8.3%). There were no postoperative
      infections of the mesh. CONCLUSION: The vaginal repair of severe cystocele
      reinforced with a tension-free polypropylene mesh is a simple and reproducible
      technique, with high success rate and low morbidity.

PMID- 12407333
TI  - [Ultrasonographic and pathological correlation in a fetal intracranial cyst: a
      case of "diencephalo-synapsis"].
AB  - Brain imaging now provides exquisite images of the central nervous system (CNS)
      enabling identification of CNS malformations early during pregnancy. However,
      pathogenical evaluation, necessary for genetic counselling, requires a detailed
      neuropathological analysis. Brain imaging of a female fetus at 27 weeks gestation
      disclosed a paramedial cystic formation, considered to be a porencephalic lesion.
      Neuropathological correlation after pregnancy termination disclosed partial
      atresia of the third ventricle, responsible for lateral ventricle dilatation and
      corpus callosum lamination. Atresia of the third ventricle, that we suggest could
      be called "diencephalo-synapsis", is a rare CNS malformation due to an unknown
      cause. Further neuropathological studies and phenotype-genotype correlations are
      necessary for the delineation of the entity and the comprehension of its cause
      and pathogenesis.

PMID- 12407334
TI  - ["Isthmic cerclage by laparoscopy" by P. von Theobald].

PMID- 12407335
TI  - [Reform medical training but not medicine].

PMID- 12407336
TI  - Presidential address: we have met the enemy.

PMID- 12407337
TI  - Technical and immunologic progress in simultaneous pancreas-kidney
      transplantation.
AB  - BACKGROUND: During the past few years the use of new immunosuppressants and
      refinements in surgical technique of simultaneous pancreas-kidney (SPK)
      transplantation have resulted in markedly improved outcomes. This is a
      retrospective study of 208 SPK transplants performed at Northwestern University,
      demonstrating the advances made at a single center that are reflective of the
      field at large. METHODS: An 8.5-year time span was split into 4 distinct eras
      marking sequential changes in immunosuppression and surgical technique that
      ensued. SPK transplant outcomes of patient and graft survival and rejection rates
      were compared. Also examined were end points related to the changing risk profile
      of the recipients, as well as quality of allograft function and rates of
      rehospitalizations. RESULTS: Recipients receiving tacrolimus/mycophenolate
      mofetil-based immunosuppression had patient, kidney, and pancreas survival rates
      significantly higher than those of earlier cohorts. The elimination of
      corticosteroids did not reduce survival rates or increase rejection risk. The use
      of pancreatic exocrine enteric drainage technique over bladder drainage reduced
      rehospitalizations. CONCLUSIONS: Advances in immunosuppression management
      combined with technical refinements have made SPK transplantation a safer and
      more effective treatment option for the diabetic, uremic patient.

PMID- 12407338
TI  - Improved survival in resected biliary malignancies.
AB  - BACKGROUND: For many years the prognosis for patients with biliary malignancies
      has been poor. However, recent advances in radiology and laparoscopy have
      improved staging, and active biliary stent management may improve outcome in
      these patients. In the past the goal with surgery was to excise all gross tumor.
      Now, the surgical goal is to achieve negative microscopic margins even if a major
      hepatic resection is required. Similarly, chemotherapy or radiation was
      frequently given in isolation, but chemoradiation has become the standard.
      Therefore, the aim of this analysis was to determine whether survival has
      improved with better staging, active stent management, more aggressive surgery,
      and chemoradiation. METHODS: From 1990 through 2001, 140 patients with biliary
      malignancies were treated at the Medical College of Wisconsin. One hundred eleven
      malignancies were cholangiocarcinomas (intrahepatic, 22%; perihilar, 65%; and
      distal, 13%), and 29 were gallbladder (GB) cancers. Eighty-six of the 140
      patients (61%) underwent exploration (intrahepatic, 58%; perihilar, 57%; distal,
      67%, and GB, 72%). Forty-four of these 86 patients (51%) underwent resection
      (intrahepatic, 64%; perihilar, 41%; distal, 70%; and GB, 52%). Chemoradiation
      with confocal radiation, 5-fluorouracil, and gemcitabine was used more frequently
      in the patients resected since 1998. RESULTS: Thirty-day operative mortality was
      4%. In the resected patients (n = 44) the 5-year actuarial survival was 31% and
      the median survival was 27.8 months. Patients resected between 1998 and 2001 (n =
      25) had a median survival longer than 44 months with a 3-year actuarial survival
      of 70% as compared to patients resected between 1990 and 1997 (n = 19), who had a
      median survival of 13 months and a 3-year actuarial survival of 21% (P <.01).
      CONCLUSIONS: These data suggest that (1) approximately one third of patients with
      biliary malignancies have resectable disease and (2) surgery in carefully
      selected patients with adjuvant chemoradiation has improved survival in resected
      patients. We suspect that a combination of improved staging, active biliary
      stenting, safe but extensive surgery to obtain negative margins, and newer
      techniques for chemoradiation have resulted in improved outcomes for patients
      with biliary malignancies.

PMID- 12407339
TI  - Evolution of minimally invasive bariatric surgery.
AB  - BACKGROUND: Minimally invasive Roux-en-Y gastric bypass is a procedure that is
      being performed with increasing frequency. It is an advanced laparoscopic
      procedure with a steep learning curve. With experience, it can be performed in a
      reasonable amount of time with minimal morbidity. METHODS: We first performed
      minimally invasive gastric bypass with the hand-assisted laparoscopic surgery
      (HALS) technique. After significant experience with HALS, we changed our approach
      to completely laparoscopic (LS). Our technique for all cases involves a circular
      stapled gastrojejunostomy with a 25-mm anvil passed transgastrically. RESULTS:
      From June 1998 to January 2002, 304 patients underwent minimally invasive gastric
      bypass. Our first 81 cases were with HALS, and the rest were LS. The incidence of
      early major and minor perioperative complications for the entire series was 5.6%
      and 7.9%, respectively. Early reoperation (less than 30 days) was required in
      4.6% of all patients. There was 1 leak (1.2%) in the HALS group and 4 anastomotic
      leaks (1.8%) in the LS group. Other measured outcomes were similar in each group
      with the exception of wound hernia (16% HALS vs 0.9% LS). Weight loss after 1
      year was 44% for HALS and 56% for LS. We have not had any deaths in our series.
      CONCLUSIONS: HALS may have certain advantages in selected patients and early in a
      surgeon's experience with minimally invasive gastric bypass. With experience,
      good results are possible with either approach.

PMID- 12407340
TI  - Ethanol impairs intestinal barrier defense by modulation of immunoglobulin A
      transport.
AB  - BACKGROUND: Increased epithelial permeability may contribute to septic
      complications after alcohol intoxication. Prior ethanol (EtOH) exposure leads to
      structural and functional effects on cytoskeletal components important in
      maintaining barrier integrity. The cytoskeleton is also important in the
      transcellular transport of proteins including the polymeric immunoglobulin
      receptor (pIgR) mediated transport of immunoglobulin A (IgA) to the luminal
      surface of mucosal tissues. We (1) investigated the effects of acute EtOH
      exposure on cell monolayer barrier integrity and IgA transport and (2) assessed
      the importance of microtubule function on these functions in vitro. METHODS:
      Confluent Madin-Darby canine kidney (MDCK) epithelial cells transfected with pIgR
      cDNA were exposed to 1% or 5% EtOH, and transcytosis of dimeric IgA was measured.
      Paclitaxel was used to pretreat a subset of MDCK cells. Results. EtOH exposure
      resulted in a concentration and time dependent decrease in IgA transcytosis. This
      was associated with physical derangements in the integrity of the cell monolayer.
      Pretreatment with paclitaxel completely abrogated these effects. CONCLUSIONS:
      EtOH causes both physical and immune derangement of epithelial cell barrier
      function. Decreased secretory IgA at mucosal surfaces may initiate septic
      complications after EtOH intoxication.

PMID- 12407341
TI  - Directed duct excision by using mammary ductoscopy in patients with pathologic
      nipple discharge.
AB  - BACKGROUND: Duct excision for pathologic nipple discharge (PND) often requires
      "blind" surgical resection. Intraoperative mammary ductoscopy can allow for
      direct visualization of intraductal abnormalities during surgical resection.
      METHODS: We reviewed our experience with 119 patients with PND undergoing
      ductoscopy-directed duct excision. The variables that could interfere with a
      successful procedure were analyzed. RESULTS: Cannulation of the discharging duct
      was successful in 105 of 119 (88%) of patients, and ductoscopy-directed duct
      excision could be performed in 104 of 119 (87%). A preoperative ductogram was
      obtained in 70 patients and was positive in 53 of 70 (76%). In this same group,
      ductoscopy was positive in 63 of 70 (90%). The pathologic diagnoses were as
      follows: cancer (5), papilloma (84), and hyperplasia (16), for an abnormal
      pathology yield of 88%. Hyperplasia and cancer were significant predictors of
      unsuccessful cannulation. In 22 patients, ductoscopy visualized multiple lesions
      or abnormalities beyond 4 cm. CONCLUSIONS: Mammary ductoscopy for PND is a safe,
      effective procedure that offers advantages of a high lesion localization rate and
      intraoperative guidance, therefore negating the need for a preoperative
      ductogram. Lesions deep within the ductal system can be identified and removed,
      which would likely have been missed by blind duct excision.

PMID- 12407342
TI  - A long-term analysis of 1018 patients with melanoma by classic Cox regression and
      tree-structured survival analysis at a major referral center: Implications on the
      future of cancer staging.
AB  - BACKGROUND: Traditional statistical analysis of 2 surgeons' experiences with
      resectable malignant melanoma during a 30-year period (November 1970-July 2000)
      was compared with new tree-structured recursive partitioning regression analysis.
      METHODS: A total of 1018 consecutive patients were registered and 983 patients
      were evaluable. Disease-free survival (DFS) and melanoma survival (MS) were
      calculated by Kaplan-Meier method for stage, thickness, ulceration, site, lymph
      node involvement, age, sex, and type; and compared with log-rank tests. Cox
      proportional hazards model was used for multivariate analysis. Multivariate
      predictors were used to analyze DFS and MS with a classification and regression
      tree model that partitioned patients into progressively more homogenous
      prognostic groups with significantly different Kaplan-Meier curves. RESULTS:
      Multivariate correlations were with thickness (millimeters), ulceration, age (per
      year), type, and sex in predicting DFS (relative risk = 1.18, 2.10, 1.05, 1.71,
      and 1.71, respectively). Thickness, ulceration, age, and type remained
      significant predictors of MS (relative risk = 1.14, 3.02, 1.02, and 2.30,
      respectively). Classification and regression tree analysis showed thickness, age,
      ulceration, and sex affected DFS. Only thickness and ulceration were significant
      in predicting MS. CONCLUSION: The Cox model is an important tool for analysis of
      clinical data but has flaws. New statistical technology to predict outcome should
      be considered. Classification and regression tree analysis of larger published
      series may reveal new predictors useful for staging, prognosis, and guiding
      clinical decisions.

PMID- 12407343
TI  - Radiofrequency ablation of liver tumors: influence of technique and tumor size.
AB  - BACKGROUND: Radiofrequency thermal ablation (RFA) of liver tumors is done by both
      radiologists and surgeons by using various techniques for a variety of
      indications. This report describes our initial experience with RFA in 45 patients
      with hepatic malignancies. METHODS: Patients with primary or secondary hepatic
      malignancies who were not candidates for resection underwent ultrasound-guided
      RFA under general anesthesia. End points were recurrence within or adjacent to
      the ablation zone or new hepatic or extrahepatic lesions. Product limit survival
      estimates for both ablation site recurrence-free survival and disease-free
      survival were calculated and compared for tumor size (less than 4 cm or 4 cm or
      greater), operative approach (percutaneous, laparoscopy, or open), and tumor type
      (hepatocellular cancer, colorectal cancer, or other metastatic disease). RESULTS:
      Patients with hepatocellular cancer (n = 11) and with secondary hepatic
      malignancies (n = 34) had 84 lesions ablated with a median follow-up of 12
      months. Largest ablated tumor size of 4 cm or greater (P <.001) and the
      percutaneous approach (P <.02) were associated with worse ablation site
      recurrence-free survival but not overall disease-free survival (P =.06). The 15
      patients with colorectal cancer had worse disease-free survival compared with
      other tumor types (P <.01). CONCLUSIONS: RFA of hepatic malignancies can be done
      by using a percutaneous, laparoscopic, or open approach. Local control appears
      superior for tumors less than 4 cm and when an open surgical approach is used.
      The difficulty in achieving prolonged disease-free survival, especially in
      colorectal cancer, underscores the need to investigate multimodality approaches
      that include local ablative techniques. Future RFA studies should consider tumor
      size, operative technique, and tumor type in trial design.

PMID- 12407344
TI  - Diagnosis and management of chronic compartment syndrome.
AB  - BACKGROUND: This article describes the diagnosis and management of chronic
      compartment syndrome and functional popliteal entrapment syndrome, unusual causes
      for claudication in young adults. METHODS: A total of 276 patients (<50 years
      old) with isolated muscle cramping, swelling, and plantar paresthesia were
      routinely evaluated with compartment pressures (normal < 15 mm Hg), stress
      plethysmography, and selectively evaluated with pulse volume recordings and
      arteriography. RESULTS: Patients were young (mean 28.4 years) with long-standing
      symptoms (mean 24 months), affecting 1 or both lower extremities (32% vs 68%,
      respectively). Of the patients, 84 were male (30%) and 192 were female (70%).
      Common symptoms were isolated muscle cramping (100%) or swelling (40%), and
      plantar paresthesia (20%). Of 436 treated compartments, 316 were anterolateral,
      70 deep-posterior, and 50 superficial-posterior. Mean compartment pressure was 28
      mm Hg. Resting pulse volume recordings were abnormal in 6 patients (2.5%); 82 had
      positive popliteal entrapment tests (30%), but symptoms were present in only 21
      (9.7%). Open fasciectomy was performed in all patients with chronic compartment
      syndrome or functional entrapment. Local anesthesia was used in 243 (88%) and
      general in 33 patients (12%). Mean follow-up was 60 months. Of the 276 patients,
      92% had full relief of symptoms and returned to normal daily or athletic
      activity. Eight percent obtained symptomatic relief, but activity was limited
      because of new compartment symptoms or other orthopedic injury. CONCLUSIONS: Open
      fasciectomy for chronic compartment and functional entrapment syndromes is
      effective therapy.

PMID- 12407345
TI  - Does aggressive local therapy improve survival in metastatic breast cancer?
AB  - BACKGROUND: Women with metastatic breast cancer and an intact primary tumor are
      currently treated with systemic therapy. Local therapy of the primary tumor is
      considered irrelevant to the outcome, and is recommended only for palliation of
      symptoms. METHODS: We have examined the use of local therapy, and its impact on
      survival in patients presenting with stage IV breast cancer at initial diagnosis,
      who were reported to the National Cancer Data Base (NCDB) between 1990 and 1993.
      RESULTS: A total of 16,023 patients with stage IV disease were identified in the
      NCDB during this period, of whom 6861 (42.8%) received either no operation or a
      variety of diagnostic or palliative procedures, and 9162 (57.2%) underwent
      partial (3513) or total (5649) mastectomy. The presence of free surgical margins
      was associated with an improvement in 3-year survival in partial or total
      mastectomy groups (26% vs 35%, respectively). A multivariate proportional hazards
      model identified the number of metastatic sites, the type of metastatic burden,
      and the extent of resection of the primary tumor as significant independent
      prognostic covariates. Women treated with surgical resection with free margins,
      when compared with those not surgically treated, had superior prognosis, with a
      hazard ratio of 0.61 (95% confidence interval 0.58,0.65). CONCLUSIONS: These data
      suggest that the role of local therapy in women with stage IV breast cancer needs
      to be re-evaluated, and local therapy plus systemic therapy should be compared
      with systemic therapy alone in a randomized trial.

PMID- 12407346
TI  - Prospective preoperative determination of mucinous pancreatic cystic neoplasms.
AB  - BACKGROUND: Optimal management of pancreatic cystic neoplasms includes
      identification and resection of mucinous neoplasms. This study was performed to
      assess the accuracy of preoperative variables in determining a mucinous lesion.
      METHODS: Patients referred for a cystic neoplasm were prospectively assessed by
      presenting symptoms, blinded radiologic review, and endoscopic ultrasound-guided
      cyst aspirate analysis. Patients who were symptomatic, or had aspirate findings
      of a mucinous neoplasm were resected. RESULTS: Eighty-seven patients were
      enrolled over a 22-month period ending in December 2001. There were 56 (64%)
      women and 31 (36%) men, with a mean age of 63 (27-86) years. Thirty-five (40%)
      patients were resected including 24 (69%) women and 11 (31%) men with a mean age
      of 58 years. Twenty-eight (80%) patients who had resection were symptomatic.
      Specimen histology included 18 (51%) mucinous neoplasms, 8 (23%) serous
      neoplasms, 4 (11%) ductal or neuroendocrine carcinomas, and 3 (9%) pseudocysts.
      The positive predictive value (PPV) for cyst-aspirate extracellular mucin (83%)
      was significant in predicting a mucinous neoplasm (P =.009). No other aspirate
      variables (amylase, carcinoembryonic antigen, CA15-3, viscosity), or patient
      characteristics were predictive of final histology. Diagnostic agreement between
      all 3 radiologists was 8% (P =.98). At a median follow-up of 12 months, no
      patients who were observed required resection. CONCLUSIONS: Patients with
      suspected pancreatic cystic neoplasms can be selectively treated on the basis of
      symptoms and cyst-aspirate mucin analysis. Symptomatic and mucin containing
      lesions should be resected.

PMID- 12407347
TI  - Maintaining outcomes in a surgical residency while complying with resident
      working hour regulations.
AB  - BACKGROUND: Regulatory requirements for resident working hours were designed to
      improve patient care. Compliance challenges a training program to meet procedural
      and clinical requirements. This is a retrospective study of a 5-year experience
      in addressing the challenges and studying the impact of compliance on resident
      caseload and board performance. METHODS: Our surgical program adopted strict
      start/stop working hours for clinical contact. Program leadership modified the
      program to establish procedural and performance criteria. Procedures were
      prioritized and assignments were changed to maximize clinical and procedural
      experience while reducing redundancy of experience. Procedural activity was
      monitored frequently. Compliance with working hour regulations was monitored and
      behavior modified where necessary. A web based computer program was developed to
      improve measurement of compliance and provide feedback. Outcome measures included
      both the number of procedures as reported by the ACGME and performance on the
      American Board of Surgery, Qualifying Examination. RESULTS: Working hour
      compliance is greater than 95%. First time pass rate on the Qualifying
      examination is 90% (45/50). There is no significant difference in the procedural
      activity. CONCLUSION: Complying with working hour regulations improves the
      quality of a resident's life and can be achieved while maintaining procedural
      experience and guaranteeing academic development.

PMID- 12407348
TI  - Examination of the role of abdominal computed tomography in the evaluation of
      victims of trauma with increased aspartate aminotransferase in the era of focused
      abdominal sonography for trauma.
AB  - BACKGROUND: Current evaluation of patients with negative findings on a focused
      abdominal sonography for trauma scan and an isolated increase of admission
      hepatic enzymes includes abdominal computed tomography (CT). Many of these
      patients do not have clinically important hepatic injuries. The purpose of this
      study was to establish the admission aspartate aminotransferase (AST) level below
      which patients do not need an abdominal CT for injury evaluation and treatment.
      METHODS: Patients who were hemodynamically stable, had a focused abdominal
      sonography for trauma scan with negative findings, and an AST level greater than
      200 IU/L were identified over a 1-year period. Medical records were reviewed for
      demographics, injuries sustained, mechanism, evaluation, interventions, and
      complications. RESULTS: A total of 67 patients, mostly with blunt trauma, were
      identified; 42 (63%) had an AST level < 360 IU/L, and 25 (37%) had an AST level >
      360 IU/L. Patients with an AST level > 360 IU/L had a 88% chance of having any
      hepatic injury and a 44% chance of having an injury of grade III or greater (P
      =.0001). Patients with an AST level of < 360 IU/L only had a 14% chance of having
      a liver injury and no chance of having an injury of grade III or greater (P
      =.036). CONCLUSIONS: Clinically important hepatic injuries are not missed if an
      abdominal CT is only performed for patients with a focused abdominal sonography
      for trauma scan with negative findings and an AST level of > 360 IU/L.
      Eliminating unnecessary CT allows for more cost-effective use of resources.

PMID- 12407349
TI  - The results of ultrasound-guided fine-needle aspiration biopsy for evaluation of
      nodular thyroid disease.
AB  - BACKGROUND: The purpose of this study was to determine whether ultrasonography
      (US) improves the accuracy and reduces the rate of nondiagnostic fine-needle
      aspiration biopsy (FNAB) of thyroid nodules. METHODS: A review of 536 consecutive
      patients evaluated for nodular thyroid disease from 1990 to 2001 was completed to
      determine the results for US vs palpation-guided FNAB. RESULTS: FNAB was used to
      evaluate 458 patients. US-guided FNAB was performed in 66 (12%) patients: 48 with
      a nonpalpable nodule, 14 with nondiagnostic standard FNAB, and 4 with a palpable
      nodule. US-guided FNAB was nondiagnostic in 15 (23%) patients. There were no
      false-positive or false-negative results. Standard FNAB was performed in 407
      patients, 57 (14%) of whom had a nondiagnostic result. There were 2 (3%) false
      positive and 3 (1.6%) false-negative results. In 14 patients with a nondiagnostic
      standard FNAB, US-guided FNAB yielded an adequate specimen in 7 (50%). Nodules
      evaluated by standard FNAB were 4.1 +/- 0.1 cm (mean +/- SEM) in size compared
      with 2.5 +/- 0.1 cm for nodules evaluated by US-guided FNAB (P <.05).
      CONCLUSIONS: US improves the diagnostic yield in selected patients with
      nondiagnostic standard FNAB. The higher frequency of nondiagnostic US-guided FNAB
      was related to its selective use in patients with smaller nodules.

PMID- 12407351
TI  - Patient outcomes for segmental colon resection according to surgeon's training,
      certification, and experience.
AB  - Background. We examined patient outcomes for colon resection to determine if they
      varied according to surgeon-specific factors including: (1) American Board of
      Surgery (ABS) certification, (2) colorectal surgery subspecialty certification,
      (3) site of residency training (university-based vs nonuniversity-based), and (4)
      years of experience since ABS certification. Methods. We performed a
      retrospective study of 15,427 admissions of northern Illinois residents who
      underwent segmental colon resection as their primary operation from 1994 to 1997
      at 76 nonfederal Illinois hospitals. There were 514 surgeons. Main outcome
      measures were inpatient mortality, complications, and hospital length of stay.
      Regression analyses with mixed effects were used to assess the significance of
      surgeon-specific variables as a predictor of outcomes after risk adjustment for
      patient age, gender, emergency admission, surgeon volume, hospital site, colon
      pathology, and comorbid illnesses. Results. ABS-certification was associated with
      reduced mortality and morbidity. Increasing years of experience was associated
      with reduced mortality. Colorectal surgery certification and site of residency
      training did not significantly affect outcomes. Conclusion. We were able to link
      patient outcomes with surgeon's training. Certification was an important
      determinant of patient outcomes for colon resection. Increasing surgeon
      experience also had a favorable effect on outcomes, suggesting a continued
      learning curve subsequent to residency. (Surgery 2002;132:663-72).

PMID- 12407350
TI  - Portal vein thrombi after restorative proctocolectomy.
AB  - BACKGROUND: Restorative proctocolectomy (RP) has been the surgical procedure of
      choice for surgical management of mucosal ulcerative colitis since 1978. This
      study was undertaken to investigate the clinical presentation and implications of
      portal vein thrombi (PVT). METHODS: We reviewed all patients undergoing RP in our
      institution in the 4 years from January 1997 to December 2000. As the diagnosis
      of PVT was made on computed tomography (CT) scan in all cases, we confined our
      incidence estimate to those patients having an abdominal CT scan postoperatively.
      All scans were reviewed by an experienced radiologist. Patient demographics,
      symptoms, and clinical course were recorded. RESULTS: A total of 702 patients
      underwent RP, of whom 94 had a CT scan within the postoperative period. PVT was
      diagnosed in 42 of the 94 patients (45%). PVT was diagnosed at initial reading of
      the scan in 11 patients, and on review in 31. The indications for CT scan
      included abdominal pain, fever, leukocytosis, and delayed bowel function. Septic
      complications of RP caused these symptoms and signs in 45 patients, 20 of whom
      had PVT. Twenty-two patients were found to have had PVT without evidence of any
      septic source. CONCLUSION: PVT can be found in a high proportion of patients
      undergoing abdominal CT scan after RP. It is often associated with pain, fever,
      nausea vomiting, tenderness, and leukocytosis. This study shows that PVT subtle
      enough to go undiagnosed has no serious consequences, even when not treated.
      Also, patients treated with anticoagulation recover completely.

PMID- 12407352
TI  - Omega-3 fatty acids in immune-enhancing enteral diets selectively increase blood
      flow to the ileum by a bile acid dependent mechanism.
AB  - BACKGROUND: The immune-enhancing diet (IED) (Impact, Novartis Corp, Minneapolis,
      Minn) initiates a delayed and sustained increase in blood flow to the ileum and
      gut-associated lymphoid tissue. The immune-enhancing benefits of Impact (Novartis
      Corp) are attributed to the addition of L-arginine, fish oil (FO), and RNA
      fragments to a standard enteral diet. The sustained increase in blood flow to the
      gut-associated lymphoid tissue during IED exposure might account for these immune
      effects. We hypothesized that the increase in ileal blood flow with IED might be
      a result of ileal omega-3 fatty acid absorption in the ileum by a bile-dependent
      mechanism. METHODS: Male Sprague-Dawley rats (200 g-230 g) were anesthetized and
      cannulated for microsphere measurement of whole organ blood flow. Rats received
      gastric gavage (2 mL) with either IED, an isocaloric, isonitrogenous control diet
      (CD) (Boost, Mead-Johnson, Evansville, Ind), CD plus menhaden FO (CD+FO), or
      CD+FO plus bile duct ligation (BDL). Blood flow was determined at baseline and
      30, 60, and 120 minutes after short-term gavage. RESULTS: Baseline blood flow and
      central hemodynamics were comparable in all groups. In the ileum, at 120 minutes
      postgavage, blood flow was increased by IED and CD+FO compared with baseline and
      CD. BDL prevented the increase in blood flow in the CD+FO+BDL rats. All groups
      exhibited differences in splanchnic blood flow distribution after gavage: CD and
      CD+FO+BDL increased blood flow compared with baseline early in the proximal gut
      and spleen. IED and CD+FO produced a delayed, sustained hyperemia to the distal
      gut. CONCLUSIONS: Gastrointestinal blood flow distribution after feeding is
      dependent on nutrient composition. These findings suggest that omega-3 fatty
      acids are the components of the enteral IED, Impact (Novartis Corp), which
      produce the increased blood flow to the terminal ileum and its contiguous gut
      associated lymphoid tissue. Our data suggests that an intact enterohepatic bile
      pathway is needed for the IED blood flow effect.

PMID- 12407353
TI  - Maternity policy and practice during surgery residency: how we do it.
AB  - BACKGROUND: Pregnancy during general surgery residency has traditionally been
      discouraged. METHODS: In 2001, using an approved protocol, we anonymously
      surveyed 25 residents (PGY3 level or greater) concerning their experiences
      working with each other during episodes of resident pregnancy and maternity
      leave. RESULTS: From 1995 to 2001, 13 of 59 residents in general surgery were
      female (22%). While training, 6 of 13 residents reported 8 pregnancies with 2
      miscarriages. Five residents (39%) gave birth to 6 children and adopted 1 child.
      Residents worked until the day of term delivery in 5 of 6 cases; 1 pregnancy was
      complicated by placental abruption at 33 weeks. Residents were off work
      postpartum for a median of 6 weeks (range 2-6). Nursing was universal for > or =
      3 months but at-work problems with privacy and stress were frequent. On survey,
      all resident mothers believed they had been treated very fairly, and 94% of
      surveyed male peers stated that the coworker's status had no effect or a positive
      effect on their own work life. Fatherhood was reported to occur during residency
      by 42% of male respondents. CONCLUSIONS: Parenthood during residency is frequent.
      The complexities of resident maternity can be handled with mutual safety, equity,
      and satisfaction by the residents and faculty of a surgical training program.

PMID- 12407354
TI  - Hand-assisted laparoscopic splenectomy in patients with splenomegaly or prior
      upper abdominal operation.
AB  - BACKGROUND: Laparoscopic splenectomy (LS) in patients with significant
      splenomegaly or prior upper abdominal operation is technically challenging with a
      high conversion rate to open operation. We hypothesized that hand-assisted
      laparoscopic splenectomy (HLS) in this setting would improve operative (OR)
      outcomes without impacting post-OR ileus, length of stay, morbidity, or
      mortality, compared with LS. METHODS: All patients with splenomegaly (spleen
      weight > or = 500 g) or prior upper abdominal operation undergoing LS or HLS
      between March 1996 and June 2001 were reviewed. Nonparametric continuous
      variables were expressed as median and intraquartile range with statistical
      significance determined by Wilcoxon rank sum test. RESULTS: Of 41 patients
      reviewed, 22 underwent HLS, whereas 19 underwent LS. Median OR time for HLS was
      significantly less than for LS (161 minutes vs 212 minutes, P =.004). HLS was
      associated with a lower conversion rate (13.6% vs 36.8%, P =.08) and blood loss
      (325 mL vs 550 mL, P =.18) than LS, which approached statistical significance.
      HLS did not increase post-OR ileus, length of stay, morbidity, or mortality.
      CONCLUSIONS: HLS in patients with significant splenomegaly or prior upper
      abdominal operation significantly shortens OR time compared with LS without
      adversely impacting post-OR ileus, length of stay, morbidity, or mortality. In
      addition, HLS may be associated with a lower conversion rate and decreased blood
      loss.

PMID- 12407355
TI  - Surgical outcomes of isolated caudate lobe resection: a single series of 19
      patients.
AB  - BACKGROUND: Isolated caudate lobe resection is a complex surgical procedure that
      requires technical expertise and knowledge of the surgical anatomy. METHODS: All
      consecutive patients who were operated on for isolated caudate lobe resections by
      the senior author were studied. En bloc resections with adjacent hepatic
      parenchyma (as part of extended hepatectomies) or partial resections of the
      caudate lobe were excluded. Follow-up was completed by outpatient evaluation and
      mail correspondence. RESULTS: Nineteen patients met the inclusion criteria (6
      male, 13 female). Mean age (+/-SD) was 52 (+/-3) years. Primary diagnoses were
      colorectal metastases, hemangioma, hepatocellular carcinoma, adenoma, and
      neuroendocrine metastases. Margins were negative in all but 1 patient. One
      patient needed inferior vena cava resection. Pringle's maneuver was used in 1
      patient (5%). Mean (+/-SD) operative time was 211 (+/-15) minutes, and estimated
      blood loss was 760 (+/-150) mL. Median blood transfusion was 0 U (range, 0-4).
      Complications (bile leak) were seen in 1 patient (5%). Median length of stay was
      7 days (range, 4-14). There were no perioperative deaths. CONCLUSIONS: Isolated
      caudate lobe resection is a feasible procedure that can be done with low
      morbidity/mortality. Sound surgical judgment and detailed knowledge of the
      caudate lobe anatomy are keys for a safe performance of this procedure.

PMID- 12407356
TI  - Pelvic fracture in the elderly is associated with increased mortality.
AB  - OBJECTIVE: The elderly population is currently the fastest growing sector in
      America. The purpose of this study was to examine the age-related outcome in
      patients after blunt pelvic injury. METHODS: All patients admitted with a pelvic
      fracture during a 5-year period were identified from the trauma registry. Data
      retrieval included: demographics, shock (BP < 90 mm Hg) on admission, injury
      severity score (ISS), abbreviated injury score (AIS) for head, chest, and
      abdomen, intensive care unit (ICU) length of stay (LOS), hospital LOS, and
      mortality. All pelvic fracture patterns were classified. Patient data were then
      stratified by age for comparison: young (< 55 years) and elderly (> or = 55
      years). Statistical analysis was performed using the Student t test, Wilcoxon
      rank-sum test, multiple logistic regression analysis, and chi-square test with
      significance set at P <.05. RESULTS: Three hundred five patients sustained a
      pelvic fracture (young [n = 248, 81.3%]; elderly [n = 57, 18.7%]). The only
      predictor of mortality was age. The 2 groups differed by gender (elderly = 54.4%
      females; young = 62.5% males) but not frequency of shock, ISS, or AIS for head,
      chest, and abdomen. Motor vehicle collision was the most common mechanism of
      injury (elderly = 68.4%; young = 73.8%). Lateral compression was the most common
      fracture pattern in both groups (elderly = 54.4%; young = 45.6%). There was no
      difference in transfusion (elderly = 2.5 +/- 0.7 vs young = 2.0 +/- 0.3; ns) but
      the elderly group was more frequently admitted to the ICU (elderly = 61.4% vs
      young = 46.8%; P =.065). Significantly more of the elderly group had a diagnosis
      of cardiovascular disease (43.9% vs 10.1%, P <.001) and diabetes mellitus (10.5%
      vs 2.4%, P <.014). Mortality was significantly greater in the elderly group
      (12.3% vs 2.3%). CONCLUSION: Elderly patients sustaining a pelvic fracture were
      more likely to have a lateral compression fracture pattern, longer hospital LOS,
      and die despite aggressive resuscitation. This difference in outcome should help
      trauma surgeons recognize that the elderly patient sustaining a pelvic fracture
      is at increased risk of death.

PMID- 12407357
TI  - Floppy Dor fundoplication after esophagocardiomyotomy for achalasia.
AB  - BACKGROUND: When esophagocardiomyotomy (ECM) is performed for achalasia, a
      complementary antireflux procedure of the surgeon's choice is usually performed
      to minimize postoperative gastroesophageal reflux. This retrospective analysis
      describes patients after laparoscopic ECM, most of whom had a modified Dor
      fundoplication. METHODS: Between 1994 and 2001, 81 patients with achalasia of the
      esophagus had laparoscopic ECM. We have previously described the use of
      intraoperative endoscopy to verify completion of ECM in a cohort of 48 patients
      who had either Toupet fundoplication (n = 25) or floppy Dor fundoplication (n =
      23). Since then floppy Dor fundoplication has been the preferred antireflux
      procedure for ease of performance and safety reasons. This article describes the
      floppy Dor fundoplication as we have performed it since 1997, anchoring the wrap
      to both crura of the hiatus. In addition, the anterior gastric wall is sutured to
      the anterior rim of the esophageal hiatus, avoiding creation of the
      paraesophageal hernia that occurs if the gastric wall abuts the entire the length
      of a long ECM. RESULTS: During the 1- to 70-month follow up period (mean 45
      months), patients who were symptomatic were evaluated by radiographic,
      manometric, or endoscopic methods; pH studies were not done systematically. The
      70% of patients who could be evaluated had postoperative quality of life and
      symptom assessment interviews that revealed willingness to repeat the operation.
      Overall satisfaction was high (8.4/10 where 10 is perfect); moderate dysphagia
      was seen in 11 (16%) 3 to 16 months postoperatively, but patients reverted to a
      satisfaction score of 8.2 after endoscopic dilation. Occasional heartburn was
      present in 15 (26%) patients with regular, 5-use proton pump inhibitors (PPI),
      including 1 with Barrett's esophagus. Others use these medications for gastric
      disorders. No patient has had cancer of the esophagus develop, but endoscopic
      surveillance has been inconstant. CONCLUSIONS: Swallowing was improved in
      patients without sigmoid esophagus and overall satisfaction was high. New-onset
      heartburn is an unpredictable problem that can be treated in most patients.
      Endoscopic dilatation may be required at intervals after ECM-fundoplication for
      bridging fibrosis at the cardia, but has not required reoperation, as a rule.
      Laparoscopic ECM is an attractive operation for achalasia.

PMID- 12407358
TI  - Long-term data indicate a progressive loss in efficacy of adjustable silicone
      gastric banding for the surgical treatment of morbid obesity.
AB  - BACKGROUND: Many short-term follow-up reports on the efficacy of the adjustable
      silicone gastric band (ASGB) and its modification for laparoscopic insertion (Lap
      Band) for the surgical treatment of morbid obesity have been reported in the
      surgical literature. However, long-term studies are lacking. METHODS: Between
      March 17, 1992, and January 7, 1997, 45 females and 17 males consecutively
      entered this prospective study. Forty ASGB and 22 Lap-Band were implanted. Mean
      age was 34 years (range 19-51); mean height was 171 cm (range 152-190); mean
      weight was 145 kg (range 100-214). Weight loss and adverse events associated with
      the device were observed over time. RESULTS: There was no operative mortality.
      Thirty intra-abdominal reoperations were necessary to correct complications
      related to the implanted ASGB and the Lap-Band. In the ASGB cohort, the body mass
      index (BMI) decreased from 50 to 36 over a 3-year period and then increased to 44
      at 8 years after operation. In the Lap-Band cohort the BMI decreased from 47 to
      40 at 1 year and then increased to 43 at 6 years after operation. Twenty-seven
      implantable devices (18 ASGB, 9 Lap-Band) have been removed to date. CONCLUSION:
      The results of this study do not support the use of ASGB devices for the surgical
      treatment of morbid obesity. The Lap-Band is less effective than ASGB.

PMID- 12407359
TI  - Current management of common bile duct stones: is there a role for laparoscopic
      cholecystectomy and intraoperative endoscopic retrograde cholangiopancreatography
      as a single-stage procedure?
AB  - BACKGROUND: Although laparoscopic cholecystectomy (LC) and therapeutic endoscopic
      retrograde cholangiopancreatography (ERCP) have revolutionized the management of
      secondary common bile duct (CBD) stones, the use of these modalities as a single
      stage procedure remains controversial. The aim of this study is to determine
      whether LC and intraoperative ERCP as a single procedure has any advantages to LC
      and either preoperative or postoperative therapeutic ERCP performed in 2 stages.
      METHODS: A retrospective 5-year review involved all patients undergoing both LC
      and ERCP for management of CBD stones from January 1997 to December 2001.
      Patients were categorized into 3 groups: (1) preoperative ERCP, followed by LC
      (ERCP then LC); (2) LC, followed by postoperative ERCP (LC then ERCP); and (3) LC
      with intraoperative ERCP as a single procedure (LC/ERCP). RESULTS: Sixty-seven
      patients were treated for secondary CBD stones. Forty-three patients underwent
      ERCP then LC, 10 underwent LC then ERCP, and 14 patients underwent LC/ERCP. There
      were no differences among the groups in terms of patient demographics or overall
      complication rates. CBD access and stone clearance was achieved in all 67 (100%)
      patients, with 1 mild ERCP-related complication in the ERCP-then-LC group.
      Overall complication rates, hospital length of stay, and total hospital charges
      were not statistically different among the 3 groups. CONCLUSION: Single-stage
      LC/ERCP provides efficacious therapy for CBD stones and may be beneficial in
      select patients who may not tolerate a second anesthetic procedure.

PMID- 12407360
TI  - Vascular complications associated with pancreaticoduodenectomy adversely affect
      clinical outcome.
AB  - BACKGROUND: Early survival after pancreaticoduodenectomy has improved, but its
      morbidity remains high. The purpose of this study is to determine how the intra
      operative (OR) occurrence of major vascular complications affects the outcome of
      pancreaticoduodenectomy. METHODS: The medical records of 180 consecutive patients
      having pancreaticoduodenectomy from 1991 to 2001 were reviewed. Vascular
      complications were defined as "an unanticipated injury or thrombosis of a major
      vessel necessitating intervention." Age, sex, type of pancreaticoduodenectomy,
      tumor size, estimated blood loss, OR time, time in intensive care, post-OR
      hospitalization, and survival were compared. RESULTS: Eighteen vascular
      complications were identified. Differences in age, sex, and type of resection
      between patients with or without vascular complications were not significant. OR
      time, estimated blood loss, blood transfusions, tumor size, time in intensive
      care, and post-OR hospitalization were all significantly greater in patients with
      vascular complications. Median survival for patients with vascular complications
      was significantly shorter than for patients without vascular complications.
      Thirty-day mortality was greater in patients with vascular complications.
      CONCLUSION: Vascular complications significantly affect the outcome of
      pancreaticoduodenectomy increasing OR time, estimated blood loss, blood
      transfusion requirements, time in intensive care, post-OR hospitalization, and
      mortality.

PMID- 12407361
TI  - Surgical management of duodenal injuries in children.
AB  - BACKGROUND: The goal of this study was to review current injury characteristics,
      severity, intervention, and outcome of duodenal injuries from a single, pediatric
      trauma facility. METHODS: A retrospective review was performed of duodenal
      injuries in children less than 16 years of age from 1990 to 2000. RESULTS: Twelve
      children had duodenal injuries as a result of blunt abdominal trauma. Six
      injuries were the result of motor vehicle crashes. Nonaccidental trauma (2) and
      contact injury (4) provided the remaining cases. Diagnosis was achieved by
      abdominal computed tomography. Severity of duodenal injury included grade I (1),
      II (8), and III (3). Seven patients had associated visceral or neurologic
      injuries. Average Injury Severity Score was 18. Duodenal repair was required in 9
      of the 10 patients explored. Treatment included observation (3); primary repair,
      alone, (2) or with proximal decompression (4); and pyloric exclusion with
      gastrojejunostomy (3). Exclusion techniques had fewer complications (0% vs 57%)
      and fewer hospital days (19 vs 23). CONCLUSIONS: Blunt abdominal trauma remains
      the most prevalent mechanism for pediatric duodenal injuries. Patients undergoing
      pyloric exclusion for severe duodenal trauma had a lesser morbidity and a shorter
      hospital stay in this small series. Pyloric exclusion remains an alternative for
      the treatment of severe duodenal injuries in selected children.

PMID- 12407362
TI  - Incidental diagnosis of gastric cancer in transplant recipients improves patient
      survival.
AB  - BACKGROUND: Gastric cancer in the United States is often diagnosed at advanced
      stages, resulting in dismal outcomes. In the immunosuppressed transplant
      recipient population, little is known about the clinical staging and outcome of
      these compromised patients. METHODS: All US cases reported to the Israel Penn
      International Transplant Tumor Registry were retrospectively examined for patient
      demographics, immunosuppressive therapy, tumor characteristics, therapeutic
      modalities, and mortality. Statistical analysis was performed with Students t
      test, chi-square analysis, and log-rank analysis by the method of Kaplan-Meier.
      RESULTS: Gastric cancer was identified in 34 recipients: 28 (82%) were male; 24
      (71%) were white. Mean age at diagnosis was 58 +/- 11 years. Twenty-four (71%)
      patients received kidney transplants, 7 (21%) received heart transplants, and 3
      (9%) received liver transplants. Fifty percent received induction therapy,
      whereas 94% were maintained on calcineurin inhibitors and corticosteroids. Thirty
      five percent of patients were diagnosed during evaluation for gastrointestinal
      symptoms, with the remaining cases discovered incidentally during endoscopy (53%)
      or during computed tomography (12%) performed for other reasons. Stage varied at
      presentation as follows: stage I (n = 6), stage II (n = 11), stage III (n = 13),
      and stage IV (n = 4). Incidental diagnoses resulted in a lower stage malignancy
      (P <.001) and greater 1-year and 5-year survivals (P <.05) compared with those
      patients whose were diagnosed after being evaluated of gastrointestinal symptoms.
      CONCLUSION: In the United States, because gastric cancer in the transplant
      recipient is frequently identified at an earlier stage (50% were stages I and II)
      than in the general population, survivals are equivalent despite continued
      administration of immunosuppression. This early identification may be attributed
      to more frequent presymptom diagnosis and staging, resulting from incidental
      detection of these malignancies during posttransplant upper endoscopy or computed
      tomography. Early detection has resulted in a 29% 5-year survival for the entire
      transplant recipient group compared with a 5% to 15% 5-year survival in the
      general population.

PMID- 12407363
TI  - The effect of intraoperative duplex on the management of postoperative stroke.
AB  - BACKGROUND: Stroke after carotid endarterectomy (CEA) may be a result of
      intraoperative ischemia, embolism, or thrombosis at the operative site.
      Intraoperative duplex should eliminate the occurrence of a severe internal
      carotid artery (ICA) thrombosis and, thus, negate the benefit of reoperation.
      This article will detail the results of our evolving treatment algorithm for
      immediate versus delayed post-CEA neurologic deficit (ND). METHODS: We studied
      patients who had an ND after CEA from 1988 to 2000. Results. Thirty-two patients
      (3.2%) had a post-CEA ND (26 related stroke or transient ischemic attack, 6
      other); 31 had a satisfactory intraoperative duplex post-CEA, 1 was not tested.
      Fifteen patients awoke from operation with a related deficit, 5 of whom were re
      explored and all had a patent ICA. One patient without lateralizing signs who was
      not re-explored had extensive thrombosis at postmortem. The remaining 9 all had a
      duplex-proven patent ICA. Ten patients had a lucid interval before their related
      ND. Six patients were re-explored and all had thrombosed ICAs; 5 of the 6
      improved postthrombectomy. Four patients were not re-explored for various
      reasons; a carotid thrombosis was not later diagnosed in any of these patients.
      CONCLUSIONS: Intraoperative and postoperative duplex has modified our treatment
      of post-CEA stroke. No longer are all patients re-explored. Patients with a
      normal intraoperative duplex who awaken with an immediate stroke do not usually
      have occlusive thrombus and routine re-exploration does not benefit these
      patients. Patients who have an ND develop after a lucid period may have a
      thrombosed ICA despite a normal intraoperative duplex, and unless there is a
      timely normal duplex, re-exploration is recommended and appears to benefit these
      patients.

PMID- 12407364
TI  - Hospital costs and risk factors associated with complications of the ileal pouch
      anal anastomosis.
AB  - BACKGROUND: The purpose of this study was to estimate the costs associated with
      the most common complications of the ileal pouch anal anastomosis (IPAA) and
      identify factors that predispose to them. METHODS: Hospital costs of 135 patients
      undergoing the IPAA were combined with information abstracted from charts.
      Logistic and linear regression modeling were used to estimate the marginal costs
      for the most common IPAA complications and determine factors predisposing to
      their occurrence. RESULTS: The average overall cost for the IPAA was $20,865.
      Just more than half (53%) of patients experienced complications, the 3 most
      common being small-bowel obstruction (24.4%), pelvic/abdominal sepsis (6.7%), and
      dehydration (5.9%). The average cost to treat an episode of small-bowel
      obstruction was $6709. Treatment of pelvic/abdominal sepsis averaged $9268 per
      occurrence, whereas dehydration averaged $4860. Steroid use > 3 months before
      colectomy significantly increased the risk for any complication (P =.02). No
      factors were found to be good predictors of bowel obstruction. However, age > 42
      years and low patient hematocrit were significant predictors of dehydration as a
      complication (P <.05). Trending toward significance were urgent operation and
      weight loss greater than 5%. CONCLUSIONS: The most common complications of the
      IPAA are small-bowel obstruction, pelvic/abdominal sepsis, and dehydration.
      Complications were responsible for approximately 44% of the overall cost of an
      IPAA. Factors that increase risk of IPAA complications are steroid use, low
      hematocrit, age > 42 years, nonelective procedures, and preoperative weight loss.

PMID- 12407365
TI  - The long-term survival and causes of death in patients who survive at least 1
      year after liver transplantation.
AB  - BACKGROUND: The purpose of this study was to examine the long-term survival and
      causes of death in patients who survive the first year after liver
      transplantation. METHODS: The focus of the analysis was 433 patients who survived
      for at least 1 year after liver transplantation between November 1, 1984, and
      December 31, 2001. A total of 586 liver transplants were performed in 542
      patients during this time period. The overall 1-, 5-, and 10-year survivals and
      the 5- and 10-year survivals for those patients who lived for a year were
      analyzed on the basis of Kaplan-Meier survival estimates. Factors examined
      included diagnosis, sex, age, and retransplantation. The causes of death were
      also analyzed. RESULTS: The overall 1-, 5-, and 10-year survivals were 85%, 73%,
      and 55%, respectively. The 5- and 10-year survivals for those patients who lived
      for a year were 86% and 65%, respectively. Fifty-one percent of the causes of
      late death were graft-related, 71% from recurrent primary disease. Cardiovascular
      events and de novo malignancies were responsible for 65% of the nongraft-related
      deaths. CONCLUSIONS: The long-term survival in patients who survive for the first
      year after liver transplantation is excellent. Recurrent primary disease is
      responsible for the majority of graft-related deaths. Cardiovascular events and
      de novo malignancy cause most of the nongraft-related deaths.

PMID- 12407366
TI  - Thoracic outlet syndrome.

PMID- 12407367
TI  - Basic science review: the helix and the heart.

PMID- 12407368
TI  - Video comes to the Journal.

PMID- 12407369
TI  - The Dor procedure: what has changed after fifteen years of clinical practice?

PMID- 12407370
TI  - Letter to Hans Georg Borst.

PMID- 12407371
TI  - Management of intramural hematoma of the ascending aorta: still room for debate.

PMID- 12407372
TI  - Is medical therapy still the optimal treatment strategy for patients with acute
      type B aortic dissections?
AB  - OBJECTIVE: The optimal treatment of patients with acute type B dissections
      continues to be debated. METHODS: A 36-year clinical experience of medical and
      surgical treatments in 189 patients was retrospectively analyzed (multivariable
      Cox proportional hazards model) with respect to three outcome end points: all
      deaths, freedom from reoperation, and freedom from late aortic complications or
      death. Propensity score analysis identified 2 quintiles (quintiles I and II,
      consisting of 142 comparable patients) for further comparison of the effects of
      surgical versus medical treatment. RESULTS: Shock (hazard ratio 14.5, 95%
      confidence interval 4.7-44.5, P <.001) and visceral ischemia (hazard ratio 10.9,
      95% confidence interval 3.9-30.3, P <.001) largely predominated as determinants
      of death, along with 6 other risk factors (arch involvement, rupture, stroke,
      previous sternotomy, and coronary or lung disease), which roughly doubled the
      hazard of death. Female sex was a significant but weaker predictor of death.
      Renal dysfunction, year of presentation, age, and mode of therapy (medical vs
      surgical) had no important bearing on overall survival. The actuarial survival
      estimates for all patients were 71%, 60%, 35%, and 17% at 1, 5, 10, and 15 years,
      respectively, and were similar for the medical and surgical patients. Reoperation
      and late aortic complications were predicted by the presence of Marfan syndrome.
      For the propensity-matched patients in quintiles I and II, survival, freedom from
      reoperation, and freedom from aortic complications were almost identical in the
      medically treated and surgical subsets. CONCLUSIONS: The prognosis for patients
      with acute type B aortic dissection is bleak and determined primarily by
      dissection-related and patient-specific risk factors, which do not appear to be
      readily modifiable.

PMID- 12407373
TI  - Determinants and assessment of regurgitation after mitral valve repair.
AB  - OBJECTIVES: The ability to detect residual regurgitation is important in the
      management of patients after mitral valve repair. We performed a study of 264
      patients to determine the risk factors and to compare the accuracy of clinical
      assessment with that of echocardiography. METHODS: Operative details and valve
      pathologic data were obtained from individual patient case notes. Clinical
      assessment consisted of history, examination, and electrocardiography. The
      presence of regurgitation was ranked in 7 grades, from none to severe.
      Transthoracic echocardiography was performed blinded to and independently of
      clinical assessment on the same visit and was graded similarly. Univariate
      analyses of demographic, etiologic, and operative variables were performed.
      Significant factors were entered into a multivariate logistic regression model.
      Sensitivities and specificities were calculated for each diagnostic modality, and
      the kappa statistic was used to express agreement. RESULTS: Mean (+/- SE)
      freedoms from regurgitation at 1 and 5 years were 91.5% +/- 1.7% and 47.5% +/-
      3.2%. Factors independently associated with postoperative regurgitation were poor
      ventricular function (P =.04), increased age (P =.01), and chordal procedures (P
      =.006). When assessing the presence of regurgitation, auscultation conferred a
      specificity of 78%, a sensitivity of 77%, and a kappa of 0.43 relative to
      echocardiography. Electrocardiographic criteria for left ventricular hypertrophy
      were superior, with a complete specificity of 100% but a low sensitivity of 15%.
      Agreement within 7 grades of severity was moderate, with a weighted kappa value
      of 0.42. CONCLUSIONS: The hazard function for regurgitation after mitral repair
      increases steadily after the third year, with ventricular function, age and
      chordal procedures as independent risks. Clinical assessment and
      electrocardiography are excellent in identifying regurgitation, but their
      agreement is less when grading severity.

PMID- 12407374
TI  - Management of patients with intramural hematoma involving the ascending aorta.
AB  - OBJECTIVE: Although intramural hematoma of the aorta is considered a unique
      pathologic entity, the management of intramural hematoma involving the ascending
      aorta (type A) has not been well established. The purpose of this study was to
      establish the optimal mode of management of type A intramural hematoma. METHODS:
      We treated patients with type A intramural hematoma as follows. Early operation
      was carried out only for patients with cardiac tamponade, impending rupture, or
      rupture. Other patients were treated medically, but patients with progression of
      intramural hematoma during medical follow-up had their treatment converted to
      surgery. From February 1992 to March 2001, a total of 33 patients with type A
      intramural hematoma were treated as described here. Patients were divided
      according to initial treatment into an early surgery group (n = 9) and a medical
      treatment group (n = 24). Clinical profiles and in-hospital and long-term
      survival rates were compared between the groups. RESULTS: Compared with the early
      surgery group, the medical treatment group was younger (64.2 +/- 7.0 years vs
      71.7 +/- 8.5 years, P =.0319) and had a greater number of involved segments (3.6
      +/- 0.6 vs 3.0 +/- 0.9, P =.0395). Eight patients in the medical treatment group
      were switched to surgery during follow-up because of progression of intramural
      hematoma. In-hospital mortality rates in the early surgery and medical groups
      were 11% and 5% (P =.477), respectively. Cumulative 1- and 2-year survivals were
      89% and 89%, respectively, in the early surgery group, and 92% and 81%,
      respectively, in the medical group (P =.49). CONCLUSION: We concluded that about
      70% of type A intramural hematomas could be managed expectantly, and more than
      50% could be treated medically alone.

PMID- 12407375
TI  - Effect of mechanical aortic valve orientation on coronary artery flow: comparison
      of tilting disc versus bileaflet prostheses in pigs.
AB  - OBJECTIVE: Orientation for optimal systolic performance of tilting disc and
      bileaflet aortic valves was defined in previous studies. The present study
      investigates the influence of valve orientation on coronary artery flow in an
      animal model. METHODS: A rotation device holding either a Medtronic Hall tilting
      disc (n = 4; Medtronic, Inc, Minneapolis, Minn), a St Jude Medical bileaflet (n =
      4; St Jude Medical, Inc, St Paul, Minn), or a Medtronic Advantage bileaflet (n =
      3) aortic valve was implanted. The device allowed rotation of the valve without
      reopening the aorta. Flow through the left anterior descending coronary artery
      was measured preoperatively and at normal versus high cardiac output after
      weaning from extracorporeal circulation. Measurements were performed at the best
      and worst hemodynamic position, as defined previously. RESULTS: Coronary flow
      rates were similar in all animals preoperatively (26 +/- 4.1 mL/min). After
      aortic valve replacement, left anterior descending flow increased significantly
      to 58.2 +/- 10.6 mL/min. Highest flow rates at normal cardiac output were found
      in the optimum orientation, especially for the Medtronic valves (Medtronic Hall,
      64 +/- 8.7 mL/min; Medtronic Advantage, 64.6 +/- 11.6 mL/min; St Jude Medical,
      48.3 +/- 10.3 mL/min), whereas the worst position demonstrated significantly
      lower left anterior descending flow, with no differences among valves (Medtronic
      Hall, 37.5 +/- 1.3 mL/min; St Jude Medical, 35.7 +/- 10.7 mL/min; Medtronic
      Advantage, 39.8 +/- 10 mL/min). Left anterior descending artery flow increased
      significantly with higher cardiac output. CONCLUSIONS: Coronary blood flow was
      significantly influenced by mechanical aortic valve implantation and the
      orientation of prostheses. For both valve designs, the previously defined optimum
      orientation with respect to pressure gradients and turbulence demonstrated the
      highest left anterior descending flow rates. Even in its optimum orientation, the
      St Jude Medical valve showed significantly lower coronary flow than the other
      valves.

PMID- 12407376
TI  - Lipopolysaccharide pretreatment attenuates myocardial infarct size: A possible
      mechanism involving heat shock protein 70-inhibitory kappaBalpha complex and
      attenuation of nuclear factor kappaB.
AB  - OBJECTIVE: Lipopolysaccharide pretreatment is known to reduce myocardial infarct
      size, but the mechanism has not been elucidated. We hypothesized that heat shock
      protein 70, induced by lipopolysaccharide pretreatment, formed complexes with
      inhibitory kappaBalpha, thereby inhibiting degradation and attenuating activation
      of nuclear factor kappaB and cellular injury in rat myocardium. METHODS: Fifteen
      Sprague-Dawley rats were given saline solution (control group) or
      lipopolysaccharide. After 48 hours, 5 hearts in each group were excised without
      ischemia for examination of heat shock protein 70 and inhibitory kappaBalpha
      levels and detection of heat shock protein 70-inhibitory kappaBalpha complexes.
      Myocardium from the remaining 10 rats in each group was exposed to 30 minutes of
      ischemia and 30 minutes of reperfusion (n = 5) to evaluate nuclear factor kappaB
      activity or to 24 hours of reperfusion (n = 5) to evaluate infarct size. RESULTS:
      Infarct size was reduced in the lipopolysaccharide group (P <.05). Nuclear factor
      kappaB was activated in the control ischemia group and attenuated in the
      lipopolysaccharide group (P <.05). Heat shock protein 70 levels were increased in
      the lipopolysaccharide group (P <.05), but inhibitory kappaBalpha levels were
      similar in both groups. Heat shock protein 70-inhibitory kappaBalpha complexes
      were detected only in the lipopolysaccharide group. Colocalization of the 2
      proteins was observed in the lipopolysaccharide group. CONCLUSIONS: Heat shock
      protein 70, induced by lipopolysaccharide pretreatment, forms complexes with
      inhibitory kappaBalpha and attenuates activation of nuclear factor kappaB and
      myocardial infarct size. Our results suggest that attenuation of nuclear factor
      kappaB through a mechanism forming heat shock protein 70-inhibitory kappaBalpha
      complexes might protect the myocardium from ischemia-reperfusion injury.

PMID- 12407377
TI  - Cardioprotective effects of the serine protease inhibitor aprotinin after
      regional ischemia and reperfusion on the beating heart.
AB  - OBJECTIVE: Early coronary reperfusion of the ischemic myocardium is a desired
      therapeutic goal to preserve myocardium. However, reperfusion itself contributes
      to an additional myocardial injury (ie, reperfusion injury), which has been
      attributed to neutrophil infiltration with subsequent release of proteases and
      oxygen-derived radicals. We studied the effects of the serine protease inhibitor
      aprotinin (Trasylol) on myocardial ischemia and reperfusion in a rat model.
      METHODS: The effects of aprotinin (5000 and 20,000 U/kg) were examined in vivo in
      a rat model of regional myocardial ischemia (20 minutes) and long-term
      reperfusion (24 hours). Cardioprotecive effects were determined by means of
      measurement of creatine kinase and myeloperoxidase activity within the
      myocardium, as well as histochemical analysis. RESULTS: Aprotinin (20,000 U/kg)
      administrated 2 minutes before reperfusion significantly attenuated myocardial
      injury expressed as creatine kinase washout compared with that seen in vehicle
      treated rats (65 +/- 25 vs 585 +/- 98 creatine kinase difference in units per 100
      mg, P <.01). Administration of 5000 U/kg of the protease inhibitor resulted in
      partial inhibition of myocardial reperfusion injury. Moreover, cardiac
      myeloperoxidase activity in the ischemic myocardium, a marker of neutrophil
      accumulation, was significantly reduced after aprotinin treatment. Histologic
      analysis of the reperfused myocardium demonstrated reduced polymorphonuclear
      leukocyte infiltration and reduced tissue injury. Furthermore, aprotinin
      treatment resulted in decreased induction of cardiac myocyte apoptosis compared
      with that seen in vehicle-treated rats. CONCLUSIONS: Inhibition of serine
      proteases with aprotinin appears to be an effective means of preserving ischemic
      myocardium from reperfusion injury, even after 24 hours of reperfusion. Aprotinin
      might exert cardioprotection through inhibition of polymorphonuclear leukocyte
      induced myocardial injury and inhibition of reperfusion-induced apoptosis of
      cardiac myocytes.

PMID- 12407378
TI  - An external, oversized, porous polyester stent reduces vein graft neointima
      formation, cholesterol concentration, and vascular cell adhesion molecule 1
      expression in cholesterol-fed pigs.
AB  - BACKGROUND: Reducing neointima formation and atherosclerosis are key goals in
      preventing late vein graft failure. Although pharmacologic and mechanical
      solutions have been proposed, the demonstration that these influence both aspects
      of vein graft pathology have been lacking. Supporting grafts externally with an
      oversized, highly porous polyester stent dramatically reduces neointima formation
      in normocholesterolemic pigs. However, its effects in the presence of
      hypercholesterolemia are unknown. METHODS: We compared wall thickening,
      cholesterol concentration, foam-cell formation, and the expression of the
      leukocyte adhesion molecule vascular cell adhesion molecule 1 after 3 months in
      stented and unstented saphenous vein interposition grafts into the carotid
      arteries of pigs fed cholesterol to cause modest hypercholesterolemia (11.2 +/-
      1.2 mmol/L). RESULTS: Stenting reduced neointima formation from 5.6 +/- 0.4 to
      1.2 +/- 0.2 mm(2) (n = 7; P <.00002, paired t test) and graft cholesterol
      concentration from 4.7 +/- 1.2 to 2.1 +/- 1.3 mg/g wet weight (P <.02). Foam
      cells were observed in unstented grafts (mean, 1.5% +/- 0.5% of all cells) but
      never in stented grafts. Vascular cell adhesion molecule 1 was strongly expressed
      in 53% +/- 8% of intimal and medial cells in unstented grafts but was weakly
      expressed in only 19% +/- 3% (n = 4, P <.05) of stented grafts. CONCLUSIONS: We
      conclude that external stenting with polyester favorably influences both
      neointima formation and early atherosclerosis, both of which are key aspects of
      vein graft disease, and that decreased expression of vascular cell adhesion
      molecule 1 is part of the underlying mechanism.

PMID- 12407379
TI  - Gene transfection of hepatocyte growth factor attenuates cardiac remodeling in
      the canine heart: A novel gene therapy for cardiomyopathy.
AB  - OBJECTIVE: Hepatocyte growth factor, a potent angiogenic agent, is unique in
      having the effects of antiapoptosis and antifibrosis. In the present study we
      used the rapid pacing-induced heart failure canine model to investigate the
      effect of gene transfection of hepatocyte growth factor on the failing heart.
      METHODS: Four weeks after onset of rapid pacing, either the human hepatocyte
      growth factor gene (160 microg; hepatocyte growth factor group, n = 7) or empty
      vector (control group, n = 7) was directly injected into the left ventricular
      myocardium by means of the hemagglutinating virus of Japan liposome method.
      RESULTS: At 4 weeks after gene transfection, the left ventricular global
      function, assessed by means of pressure-volume loop analysis, was improved in the
      hepatocyte growth factor group as preload-recruitable stroke work (percentage of
      baseline: 80% +/- 20% from 38% +/- 15% before gene transfection, P =.005),
      whereas it was not changed in the control group (50% +/- 18% from 50% +/- 18%).
      Weekly echocardiography showed that this improvement began in the week after gene
      transfer. The hearts in the hepatocyte growth factor group had a large wall
      thickness, large myocyte diameter, high capillary density, low fibrotic area
      fraction, and low density of apoptotic nuclei revealed by means of histologic
      analysis compared with that in the control group. Myocardial perfusion flow,
      assessed with color microspheres, was increased in the hepatocyte growth factor
      group (percentage of baseline: 79% +/- 16% from 48% +/- 14%, P =.010), whereas it
      was reduced in the control group (30% +/- 12% from 45% +/- 17%). CONCLUSIONS:
      Gene transfection of hepatocyte growth factor promoted angiogenesis, improved
      perfusion, decreased fibrosis and apoptosis, promoted recovery from myocyte
      atrophy, and thereby attenuated cardiac remodeling and improved myocardial
      function in the failing heart. It is a novel gene therapy for human heart
      failure.

PMID- 12407380
TI  - Right ventricular diastolic relaxation in conscious dog models of pressure
      overload, volume overload, and ischemia.
AB  - OBJECTIVE: Limitations in clinical understanding of right ventricular relaxation
      can be attributed to the paucity of information from basic studies in animal
      models of right ventricular disease. This study examined, in the conscious state,
      right ventricular relaxation dynamics under normal conditions (n = 15) and in
      subacute (2-5 weeks) canine models of right ventricular pressure overload (n =
      6), volume overload (n = 7), and free wall ischemia (n = 7). METHODS: Right-heart
      micromanometric measurements were obtained by using multisensor catheters. A new
      algorithm was developed to obtain representative ensemble averages of hemodynamic
      waveform data sets. Right ventricular relaxation was analyzed by using an
      exponential model with 3 parameters: P(0), tau, and P(b). Significant changes
      versus control values were determined by means of analysis of variance and the
      Student unpaired t test with Bonferroni's adjustment. RESULTS: In the state of
      pressure overload, right ventricular pressure decay exhibits an increased P(0)
      (56.2 +/- 19.1 vs 13.1 +/- 5.1 mm Hg [mean +/- SD]) and prolonged tau (57.1 +/-
      2.8 vs 27.8 +/- 3.9 ms); there is also a decreased P(b) (-7.9 +/- 1.5 vs 0.28 +/-
      1.8 mm Hg). The only significant change in volume overload is an increased
      asymptote, P(b) (5.3 +/- 2.9 mm Hg). In right ventricular ischemia, prolongation
      of tau (41.4 +/- 13.0 ms) and decreased P(b) (-1.95 +/- 1.1 mm Hg) attain high
      significance. CONCLUSIONS: Distinctive abnormalities in right ventricular
      relaxation dynamics accompany pressure overload, volume overload, and ischemia
      and may contribute to clinical right ventricular dysfunction.

PMID- 12407381
TI  - Adenosine A2A receptor activation decreases reperfusion injury associated with
      high-flow reperfusion.
AB  - INTRODUCTION: High pulmonary artery flow rates can result in severe reperfusion
      injury after lung transplantation. Our hypothesis was that selective activation
      of the adenosine A(2A) receptor with a highly specific analog (ATL-146e) would
      inhibit leukocyte activation and decrease reperfusion injury after high-flow
      reperfusion. METHODS: Using our isolated, ventilated, blood-perfused rabbit lung
      model, all groups (n = 8 per group) underwent lung harvest, 4 hours of cold
      storage, and blood reperfusion for 30 minutes. Measurements of pulmonary artery
      pressure (in millimeters of mercury), arterial oxygenation (in millimeters of
      mercury), myeloperoxidase, peak inspiratory pressure, and wet/dry weight ratio
      were obtained. Groups 1 (high flow) and 2 (high flow ATL-146e) underwent
      reperfusion at 120 mL/min for 30 minutes. Groups 3 (controlled high flow) and 4
      (controlled high flow ATL-146e) underwent controlled reperfusion with an initial
      reperfusion of 60 mL/min for the first 5 minutes, followed by a rate of 120
      mL/min for 25 minutes. During reperfusion, groups 2 and 4 received ATL-146e at 4
      microg. kg(-1). min(-1). RESULTS: ATL-146e significantly improved lung
      physiologic measurements under both high-flow (group 1 vs group 2) and controlled
      high-flow (group 3 vs group 4) conditions after 30 minutes. CONCLUSIONS: The
      adenosine A(2A) receptor analogue ATL-146e significantly decreases the severity
      of reperfusion injury in the setting of both high-flow and controlled high-flow
      reperfusion.

PMID- 12407382
TI  - Predictors of pericardial effusion after orthotopic heart transplantation.
AB  - OBJECTIVES: Pericardial effusion occurs frequently after orthotopic heart
      transplantation, but the causes of this complication have not been well
      described. This study was designed to identify factors predisposing toward the
      development of significant postoperative pericardial effusions in a large, single
      institution population of orthotopic heart transplant recipients. METHODS: A
      retrospective review of more than 90 preoperative, intraoperative, and
      postoperative variables was conducted for 241 patients undergoing orthotopic
      heart transplantation from September 1988 to December 1999. Patients who had
      significant postoperative pericardial effusions develop were identified from
      postoperative echocardiograms by standard criteria. Factors associated with the
      development of significant pericardial effusions were determined by multivariate
      logistic regression analysis. RESULTS: Echocardiographic data were available for
      203 of 241 transplant recipients. Forty-two patients (21%) had significant
      effusions develop. According to multivariate analysis, pericardial effusions were
      less likely to occur in recipients with a history of previous cardiac surgery
      (odds ratio 0.13, 95% confidence interval 0.05-0.36, P <.0001) and with greater
      weight (odds ratio 0.96, 95% confidence interval 0.94-0.99, P <.0048).
      Pericardial effusions were more likely to occur in patients who had received
      aminocaproic acid during the operation (odds ratio 5.92, 95% confidence interval
      2.23-15.72, P <.0008). Patient survival and hospital length of stay did not
      differ between patients with and without postoperative pericardial effusions.
      CONCLUSIONS: Postoperative pericardial effusions develop in approximately 20% of
      patients undergoing orthotopic cardiac transplantation. On the basis of the risk
      factors identified in this study, prevention may prove difficult, although
      avoidance of the intraoperative use of aminocaproic acid may be helpful.

PMID- 12407383
TI  - The morphologic nature of noncommitted ventricular septal defects in specimens
      with double-outlet right ventricle.
AB  - BACKGROUND: Lev's contribution to the understanding of the morphology of hearts
      with double-outlet right ventricle and the surgical feasibility for correction is
      important and remains in current use. However, the term noncommitted ventricular
      septal defect remains enigmatic. The aim of this study was to elucidate the
      morphologic nature of the noncommitted ventricular septal defect in view of its
      surgical implications. METHODS: We examined 67 specimens with double-outlet right
      ventricle, focusing on the relationship of the ventricular septal defect to the
      semilunar orifices. RESULTS: The defect was subaortic, subpulmonary, or doubly
      committed in 55 specimens. In a further 8 specimens, the defect opened into the
      outlet portion of the right ventricle, but the distance between the ventricular
      septal defect and the semilunar orifice was extensive, either because of extreme
      dextroposition of the aorta or a broad ventriculoinfundibular fold, which, in
      some cases, was associated with a long-outlet septum. A truly noncommitted
      ventricular septal defect was found in the inlet in the remaining 4 specimens. An
      atrioventricular septal defect without extension to the outlet was present in 3
      cases, and a ventricular septal defect limited to the inlet was found in another
      case. The ventriculoinfundibular fold, part of the outlet septum and septal band
      or septomarginal trabeculation, had fused to form a crestlike structure. The
      septomarginal trabeculation is a useful landmark in the right ventricle to
      differentiate the inlet from the outlet in different forms of double-outlet right
      ventricle. CONCLUSION: We do not suggest to discard the Lev terminology but
      rather to differentiate the noncommitted ventricular septal defect into 2 types:
      the truly noncommitted defect of the inlet type and the not-directly-committed
      defect, which does open into the outlet portion of the right ventricle. The
      implication for the surgeon is 2-fold. The tricuspid valve or right part of the
      atrioventricular valve is interposed between the noncommitted ventricular septal
      defect and the semilunar orifice. The not-directly-committed defect opens into
      the outlet portion of the right ventricle but is not directly subaortic or
      subpulmonary.

PMID- 12407384
TI  - Tumor necrosis factor and clinical and metabolic courses after cardiac surgery in
      children.
AB  - OBJECTIVE: This study was undertaken to determine the relationship between plasma
      tumor necrosis factor concentrations and hemodynamic and metabolic parameters
      during the postoperative clinical course in children undergoing cardiac surgery.
      METHODS: Tumor necrosis factor levels of 10 consecutive children undergoing
      surgery for repair of congenital heart defects were analyzed in blood samples
      drawn at predetermined time points during surgery and up to 24 hours thereafter.
      Clinical data were collected at these times for correlation to tumor necrosis
      factor levels. RESULTS: All the patients survived. Tumor necrosis factor was
      detected in all 10 children. Tumor necrosis factor levels declined after
      induction of general anesthesia (201 +/- 65 pg/mL) steadily decreasing during
      surgery, reaching 80 +/- 50 pg/mL at 24 hours after the operation. Tumor necrosis
      factor levels were found to be inversely correlated with mean blood pressure
      values and indicators of acidosis (bicarbonate levels and base excess, P <.03).
      They were not correlated with the durations of cardiopulmonary bypass and aortic
      crossclamping. CONCLUSIONS: Tumor necrosis factor released into the circulation
      during and after pediatric cardiac surgery under cardiopulmonary bypass may be
      related to the hemodynamic and acid-base changes observed after cardiac surgery.
      Elucidation of the relationship between tumor necrosis factor and patient outcome
      in high-risk patients awaits further studies.

PMID- 12407385
TI  - Reversible pulmonary trunk banding. II. An experimental model for rapid pulmonary
      ventricular hypertrophy.
AB  - OBJECTIVE: An experimental model with a reversible pulmonary trunk banding device
      was developed with the aim of inducing rapid ventricular hypertrophy. The device
      consists of an insufflatable cuff connected to a self-sealing button. METHODS:
      The right ventricles of 7 young goats (average weight, 8.7 kg) were submitted to
      systolic overload and evaluated according to the hemodynamic, echocardiographic,
      and morphologic aspects. Baseline biopsy specimens were taken from the myocardium
      for microscopic analysis. The device was implanted on the pulmonary trunk and
      inflated so that a 0.7 right ventricular/left ventricular pressure ratio was
      achieved. Echocardiographic and hemodynamic evaluations were performed every 24
      hours. Systolic overload was maintained for 96 hours. The animals were then
      killed for morphologic study. Another 9 goats (average weight, 7.7 kg) were used
      for control right ventricular weight. RESULTS: The systolic right
      ventricular/pulmonary trunk pressure gradient varied from 10.1 +/- 4.3 mm Hg
      (baseline) to 60.0 +/- 11.0 mm Hg (final). Consequently, the right
      ventricular/left ventricular pressure ratio increased from 0.29 +/- 0.06 to 1.04
      +/- 0.14. The protocol group showed a 74% increase in right ventricular mass when
      compared with the control group. Serial 2-dimensional echocardiography showed a
      66% increase in right ventricular wall thickness. There was a 24% increase in the
      mean myocyte perimeter, and the myocyte area increased 61%. CONCLUSIONS: The
      device is easily adjustable percutaneously, enabling right ventricular
      hypertrophy in 96 hours of gradual systolic overload. This study suggests that
      the adjustable pulmonary trunk banding might provide better results for the 2
      stage Jatene operation and for the failed atrial switch operations to convert to
      the double-switch operation.

PMID- 12407386
TI  - Pulmonary metastasectomy for 165 patients with colorectal carcinoma: A prognostic
      assessment.
AB  - OBJECTIVE: The purpose of this study was to analyze our entire experience with
      pulmonary resection for metastatic colorectal carcinoma to determine prognostic
      factors and critically evaluate the potential role of extended metastasectomy.
      METHODS: We analyzed the postoperative survival of 165 patients who underwent
      curative pulmonary surgery at eight institutions in the Kansai region of western
      Japan (Kansai Clinical Oncology Group) from 1990 to 2000. RESULTS: Overall
      survivals at 5 and 10 years were 39.6% and 37.2%, respectively. Cumulative
      survival of patients who underwent simultaneous bilateral metastasectomy was
      significantly lower than that of the patients who underwent unilateral
      metastasectomy or sequential bilateral metastasectomy (P =.048). Five-year
      survival was 53.6% for patients without hilar or mediastinal lymph node
      metastasis, versus 6.2% at 4 years for patients with metastases (P <.001). Five
      year survival of patients with a prethoracotomy carcinoembryonic antigen level
      less than 10 ng/mL was 42.7%, versus 15.1% at 4 years for patients with a
      carcinoembryonic antigen level 10 ng/mL or greater (P <.0001). Twenty-one
      patients underwent a second or third thoracotomy for recurrent colorectal
      carcinoma. Overall 5-year survival from the date of the second thoracotomy was
      52.1%. The 34.1% 10-year survival for the 26 patients with hepatic metastasis
      resected before thoracotomy did not differ significantly from that of patients
      without hepatic metastases (P =.38). CONCLUSIONS: The status of the hilar or
      mediastinal lymph nodes and prethoracotomy carcinoembryonic antigen level were
      significant independent prognostic factors. Patients with pulmonary metastases
      potentially benefit from pulmonary metastasectomy even when there is a history of
      solitary liver metastasis. Careful follow-up is warranted, because patients with
      recurrent pulmonary metastases can undergo repeat thoracotomy with acceptable
      long-term survival. Simultaneous bilateral metastasectomy confers no survival
      benefit. Prospective studies may determine the significance of this type of
      pulmonary metastasectomy.

PMID- 12407387
TI  - Computed tomographic image comparison between mediastinal and lung windows
      provides possible prognostic information in patients with small peripheral lung
      adenocarcinoma.
AB  - OBJECTIVES: The purpose of this study was to determine whether the ratio of the
      area of the mediastinal computed tomographic image to that of the lung computed
      tomographic image can be a prognostic factor of small peripheral lung
      adenocarcinoma. METHODS: We studied the computed tomographic images of 143
      patients with primary peripheral lung adenocarcinoma of 30 mm or less in maximum
      diameter. Two groups were categorized according to the tumor's ratio of the area
      of the mediastinal computed tomographic image to that of the lung computed
      tomographic image (tumor's area in the mediastinal computed tomographic
      image/tumor's area in lung computed tomographic image x 100%), both faint density
      type (<50%) and solid-type images (>/=50%). Clinical factors and prognoses of the
      2 groups were analyzed. RESULTS: There were 58 patients with the solid-type tumor
      image and 85 patients with the faint density-type tumor image. The number of
      patients with tumor size of less than 20 mm in the faint density-type tumor group
      (n = 30) was significantly higher than that in the solid-type tumor group (n = 8,
      P =.008). The 5-year survival of patients with faint density-type tumors was
      74.1%, whereas that in patients with solid-type tumors was 54.2% (P =.013).
      Furthermore, the survival curve of patients with the solid-type computed
      tomographic image combined with ground-glass opacity was similar to that of
      patients with the faint density-type image. Multivariate analysis revealed the
      prognostic influence of the ratio of the area of the mediastinal computed
      tomographic image to that of the lung computed tomographic image on survival (P
      =.029, relative risk = 0.48) and showed to be of second highest influence after
      the N factor. CONCLUSIONS: It is suggested that the ratio of the area of the
      mediastinal computed tomographic image to that of the lung computed tomographic
      image can be a prognostic factor in patients with small peripheral lung
      adenocarcinoma.

PMID- 12407388
TI  - Single-stage bilateral minimally invasive approach for pulmonary hydatid disease:
      an alternative technique.

PMID- 12407389
TI  - Benign expectoration of a surgical clip through a pneumonectomy stump.

PMID- 12407390
TI  - Less pain with flexible fluted silicone chest drains than with conventional rigid
      chest tubes after cardiac surgery.

PMID- 12407391
TI  - A simple maneuver to detect air leaks on the operating table after needlescopic
      video-assisted thoracic surgery.

PMID- 12407392
TI  - Thoracoscopic repair of cervical lung hernia.

PMID- 12407393
TI  - Placement of self-expandable metallic stents with a laryngeal mask and a
      fiberoptic flexible bronchoscope for obstructive tracheobronchial lesions.

PMID- 12407394
TI  - Cardiopulmonary bypass-induced myocardial reoxygenation injury in pediatric
      patients with cyanosis.

PMID- 12407395
TI  - Successful treatment with intraluminal fibrinogen injection of serous leakage
      from a polytetrafluoroethylene Blalock-Taussig shunt.

PMID- 12407396
TI  - Bovine jugular vein thrombosis in the Fontan circulation.

PMID- 12407397
TI  - Saphenous vein homograft containing a valve as a right ventricle-pulmonary artery
      conduit in the modified Norwood operation.

PMID- 12407398
TI  - Early calcification of a Carpentier-Edwards Perimount mitral valve in an elderly
      woman.

PMID- 12407399
TI  - Combined right atrial and ventricular reduction operation: case report of
      unrolling-rolling of the right ventricle to preserve ventricular muscle
      orientation.

PMID- 12407400
TI  - Aortic root reimplantation for successful repair of an insufficient pulmonary
      autograft valve after the Ross procedure.

PMID- 12407401
TI  - Spiral arterial switch operation in transposition of the great arteries.

PMID- 12407402
TI  - Spatial orientation of the ventricular muscle band.

PMID- 12407403
TI  - Alternate explanation of the hypothermic prolonged induction of heat shock
      protein.

PMID- 12407404
TI  - Hide and seek.

PMID- 12407405
TI  - Immunology taught by Darwin.

PMID- 12407406
TI  - Cancer immunoediting: from immunosurveillance to tumor escape.
AB  - The concept that the immune system can recognize and destroy nascent transformed
      cells was originally embodied in the cancer immunosurveillance hypothesis of
      Burnet and Thomas. This hypothesis was abandoned shortly afterwards because of
      the absence of strong experimental evidence supporting the concept. New data,
      however, clearly show the existence of cancer immunosurveillance and also
      indicate that it may function as a component of a more general process of cancer
      immunoediting. This process is responsible for both eliminating tumors and
      sculpting the immunogenic phenotypes of tumors that eventually form in
      immunocompetent hosts. In this review, we will summarize the historical and
      experimental basis of cancer immunoediting and discuss its dual roles in
      promoting host protection against cancer and facilitating tumor escape from
      immune destruction.

PMID- 12407408
TI  - Viral evasion of natural killer cells.
AB  - Viruses have evolved mechanisms to avoid the host immune system, including means
      of escaping detection by both the innate and adaptive immune responses. Natural
      killer (NK) cells are a central component of the innate immune system and are
      crucial in defense against certain viruses. To attain a state of chronic
      infection, some successful viruses have developed specific mechanisms to evade
      detection by and activation of NK cells. These NK cell-specific evasion
      mechanisms fall into distinct mechanistic categories used in numerous virus
      families.

PMID- 12407407
TI  - Natural selection of tumor variants in the generation of "tumor escape"
      phenotypes.
AB  - The idea that tumors must "escape" from immune recognition contains the implicit
      assumption that tumors can be destroyed by immune responses either spontaneously
      or as the result of immunotherapeutic intervention. Simply put, there is no need
      for tumor escape without immunological pressure. Here, we review evidence
      supporting the immune escape hypothesis and critically explore the mechanisms
      that may allow such escape to occur. We discuss the idea that the central engine
      for generating immunoresistant tumor cell variants is the genomic instability and
      dysregulation that is characteristic of the transformed genome. "Natural
      selection" of heterogeneous tumor cells results in the survival and proliferation
      of variants that happen to possess genetic and epigenetic traits that facilitate
      their growth and immune evasion. Tumor escape variants are likely to emerge after
      treatment with increasingly effective immunotherapies.

PMID- 12407409
TI  - To kill or be killed: viral evasion of apoptosis.
AB  - In the struggle between virus and host, control over the cell's death machinery
      is crucial for survival. Viruses are obligatory intracellular parasites and, as
      such, must modulate apoptotic pathways to control the lifespan of their host in
      order to complete their replication cycle. Many of the counter-assaults mounted
      by the immune system incorporate activation of the apoptotic pathway-particularly
      by members of the tumor necrosis factor cytokine family-as a mechanism to
      restrict viral replication. Thus, apoptosis serves as a powerful selective
      pressure for the virus to evade. However, for the host, success is harsh and
      potentially costly, as apoptosis often contributes to pathogenesis. Here we
      examine some of the molecular mechanisms by which viruses manipulate the
      apoptotic machinery to their advantage and how we (as vertebrates) have evolved
      and learned to cope with viral evasion.

PMID- 12407410
TI  - Viral interference with antigen presentation.
AB  - CD8+ T cells play an important role in immunity to viruses. Just how important
      these cells are is demonstrated by the evolution of viral strategies for blocking
      the generation or display of peptide-major histocompatibility complex class I
      complexes on the surfaces of virus-infected cells. Here, we focus on viral
      interference with antigen presentation; in particular we consider the importance
      (and difficulty) of establishing the evolutionary significance (that is, the
      ability to enhance viral transmission) of viral gene products that interfere with
      antigen presentation in vitro.

PMID- 12407411
TI  - Chronic bacterial infections: living with unwanted guests.
AB  - Some bacterial pathogens can establish life-long chronic infections in their
      hosts. Persistence is normally established after an acute infection period
      involving activation of both the innate and acquired immune systems. Bacteria
      have evolved specific pathogenic mechanisms and harbor sets of genes that
      contribute to the establishment of a persistent lifestyle that leads to chronic
      infection. Persistent bacterial infection may involve occupation of a particular
      tissue type or organ or modification of the intracellular environment within
      eukaryotic cells. Bacteria appear to adapt their immediate environment to favor
      survival and may hijack essential immunoregulatory mechanisms designed to
      minimize immune pathology or the inappropriate activation of immune effectors.

PMID- 12407412
TI  - Bacterial strategies for overcoming host innate and adaptive immune responses.
AB  - In higher organisms a variety of host defense mechanisms control the resident
      microflora and, in most cases, effectively prevent invasive microbial disease.
      However, it appears that microbial organisms have coevolved with their hosts to
      overcome protective host barriers and, in selected cases, actually take advantage
      of innate host responses. Many microbial pathogens avoid host recognition or
      dampen the subsequent immune activation through sophisticated interactions with
      host responses, but some pathogens benefit from the stimulation of inflammatory
      reactions. This review will describe the spectrum of strategies used by microbes
      to avoid or provoke activation of the host's immune response as well as our
      current understanding of the role this immunomodulatory interference plays during
      microbial pathogenesis.

PMID- 12407413
TI  - Evasion of innate immunity by parasitic protozoa.
AB  - Parasitic protozoa are a major cause of global infectious disease. These
      eukaryotic pathogens have evolved with the vertebrate immune system and typically
      produce long-lasting chronic infections. A critical step in their host
      interaction is the evasion of innate immune defenses. The ability to avoid attack
      by humoral effector mechanisms, such as complement lysis, is of particular
      importance to extracellular parasites, whereas intracellular protozoa must resist
      killing by lysosomal enzymes and toxic metabolites. They do so by remodeling the
      phagosomal compartments in which they reside and by interfering with signaling
      pathways that lead to cellular activation. In addition, there is growing evidence
      that protozoan pathogens modify the antigen-presenting and immunoregulatory
      functions of dendritic cells, a process that facilitates their evasion of both
      innate and adaptive immunity.

PMID- 12407415
TI  - Antigen receptor signaling under the Tuscan sun.

PMID- 12407416
TI  - When ligand becomes receptor--tolerance via B7 signaling on DCs.

PMID- 12407417
TI  - Slick signaling.

PMID- 12407420
TI  - Post-intervention vessel remodeling.
AB  - By-pass surgery and percutaneous transluminal (coronary) angioplasty, PT(C)A, are
      standard techniques for the treatment of vascular occlusions. Their usefulness is
      limited by by-pass graft failure and restenosis occurring after the procedures.
      Twenty percent of patients treated with PTCA/PTA need a new revascularization
      procedure within 6 months, despite a successful procedure. Stents are used to
      prevent restenosis in selected lesions, but in-stent restenosis also remains an
      important clinical problem. In this review we discuss progress of gene therapy
      for the treatment of post-PT(C)A restenosis, in-stent restenosis and by-pass
      graft stenosis over the last 2 years (2000-2002).

PMID- 12407421
TI  - Hypothalamic delivery of doxycycline-inducible leptin gene allows for reversible
      transgene expression and physiological responses.
AB  - Our purpose was to incorporate regulation into the recombinant adeno-associated
      virus encoding leptin by introducing a tet-inducible promotor. This system, TET
      Ob, allows for control of leptin gene expression via doxycycline in drinking
      water. F344XBN rats (aged 4 months) were given a hypothalamic injection of TET-Ob
      or control virus. During 34 days of doxycycline (doxy) administration to all rats
      (STAGE 1), TET-Ob rats gained 50.7% less mass, ate 10.4% less food, and had a
      77.5% reduction in serum leptin as compared with controls. Doxy was then
      withdrawn from half of the TET-Ob rats for 32 days (TET-Ob-OFF), while half
      continued to receive doxy (TET-Ob-ON) (stage 2). During stage 2, TET-Ob-ON rats
      gained 44.8% less mass than TET-Ob-OFF and ate significantly less food than both
      TET-Ob-OFF and controls. Serum leptin increased to 83.4% of control values in TET
      Ob-OFF, but remained very low in the in TET-Ob-ON. At death, visceral adiposity
      was 14.5% of controls in TET-Ob-ON animals, but had risen to 76.9% of controls in
      TET-Ob-OFF. A reversible increase in both leptin signal transduction in the
      hypothalamus and uncoupling protein expression in brown adipose was recorded.
      This system allows for more precise regulation of gene therapy-mediated fat loss.

PMID- 12407422
TI  - Size and topology of exogenous DNA as determinant factors of transgene
      transcription in mammalian cells.
AB  - We prepared a series of linearized DNA duplexes of various lengths in order to
      examine the effects of topology and the size of exogenous, plasmid-derived DNAs
      on transgene expression. These linearized DNA duplexes were capped at each end
      with a highly stable loop (5'-GCGAAGC-3') to produce a dumbbell-shaped construct
      that is refractory to exonuclease digestion in comparison to the analogous
      uncapped DNA duplexes. Intranuclear microinjection of the DNA dumbbells into
      simian COS-7 cells allowed the expression of the green fluorescent protein (GFP)
      gene on the linearized molecules, which was expressed five- to 10-fold more than
      that on the circular DNA of the same size. In addition, the expression by the
      dumbbell DNA was higher than that by the circular plasmid for at least 14 days.
      Interestingly, the size of the dumbbell DNA affected the transgene expression
      upon their microinjection into cell nuclei. The GFP expression efficiency
      increased with decreasing DNA size below a DNA size of 5.7 kb. The effects of
      topology and size on the expression of DNAs transfected with cationic lipids are
      similar to those of DNAs microinjected into cell nuclei. In contrast,
      microinjection into the cytosol showed the inverse size dependency over a range
      of 2.3 to 9.4 kb. Thus, transcription of a transgene in the nucleus, but not
      endocytosis or nuclear entry, was influenced by the exogenous DNA structure, and
      this was the primary determinant of transgene expression upon transfection under
      our conditions. These results indicate that small, linearized DNA duplexes that
      are end-capped with a highly stable loop (dumbbell-shaped DNA) would be very
      useful for nonviral gene therapy.

PMID- 12407423
TI  - Inhibition of cartilage destruction by double gene transfer of IL-1Ra and IL-10
      involves the activin pathway.
AB  - The objective of the study was to determine the effects and the molecular
      background of interleukin-1 receptor antagonist (IL-1Ra) and vIL-10 double gene
      transfer into human synovial fibroblasts from patients with rheumatoid arthritis
      (RA) using the SCID mouse model for cartilage erosion in RA. RA synovial
      fibroblasts were transduced with retro- or adenoviruses encoding IL-1Ra and/or
      viral IL-10 (vIL-10). SCID mice were engrafted subcutaneously with IL-1Ra and vIL
      10 transduced human rheumatoid synovial fibroblasts and normal cartilage. In
      parallel, gene expression analysis before and after gene transfer using RNA
      arbitrarily primed PCR in combination with cDNA array was performed. vIL-10 and
      IL-1Ra double gene transfer resulted in inhibition of cartilage invasion and
      degradation by RA synovial fibroblasts when compared with control transduced and
      non-transduced implants. Expression of key genes that were altered after double
      gene transfer were related to the activin pathway. The results demonstrate not
      only that virus-based gene transfer using a combination of two joint-protective
      genes is a feasible approach to inhibit cartilage degradation by activated RA
      synovial fibroblasts, but also that the underlying molecular effects include
      modulation of the activin pathway.

PMID- 12407424
TI  - Persistent hepatic expression of human apo A-I after transfer with a helper-virus
      independent adenoviral vector.
AB  - Gene transfer with 'gutted' vectors is associated with persistent transgene
      expression and absence of hepatotoxicity, but the requirement of helper viruses
      hampers efficient production and leads to contamination of viral batches with
      these helper-viruses. In the present study, gene transfer with a helper-virus
      independent E(1)/E(3)/E(4)-deleted adenoviral vector induced persistent
      expression of human apo A-I (200 +/- 16 mg/dl at day 35, 190 +/- 15 mg/dl at 4
      months, 170 +/- 16 mg/dl at 6 months) and stable transgene DNA levels (3.5 +/-
      0.60 at day 35, 3.3 +/- 0.39 at 4 months, 3.1 +/- 0.47 mg/dl at 6 months) in
      C57BL/6 mice in the absence of significant toxicity. The vector contained the 1.5
      kb human alpha(1)-antitrypsin promoter in front of the genomic human apo A-I
      sequence and four copies of the human apo E enhancer (hAAT.gA-I.4xapoE) and was
      deleted in E(1), E(3) and E(4). Reintroduction of E(4) ORF 3 and E(4) ORF 4 in
      the viral backbone caused a more than four-fold decline of transgene DNA between
      day 35 and 4 months after transfer both in wild-type and in C57BL/6 SCID and
      C57BL/6 Rag-1(-/-) mice, indicating that the effect of E(4) ORF 3 and E(4) ORF 4
      is independent of a cellular immune response against viral epitopes. Co-injection
      of an E(1)-deleted vector containing no expression cassette and the
      E(1)/E(3)/E(4)-deleted vector containing the hAAT.gA-I.4xapoE expression cassette
      indicated that E(4) gene products destabilize transgene DNA in trans. Gene
      transfer with an E(1)/E(3)/E(4)-deleted vector containing only E(4) ORF 3 and the
      hAAT.gA-I.4xapoE expression cassette was associated with transgene DNA decline,
      but not with hepatotoxicity, indicating that transgene DNA persistence and
      hepatotoxicity are dissociated processes. After transfer with E(1)/E(3)/E(4)
      deleted vectors containing expression cassettes with a different promoter or a
      different position of the apo E enhancers, transgene DNA levels were less stable
      than after transfer with the vector containing hAAT.gA-I.4xapoE, indicating that
      the expression cassette is an important determinant of episomal stability. In
      conclusion, gene transfer with an E(1)/E(3)/E(4)-deleted vector containing the
      hAAT.gA-I.4xapoE expression cassette induces persistent expression of human apo A
      I in the absence of hepatotoxicity. Transgene DNA turnover is independent of an
      adaptive cellular immune response against viral epitopes and of hepatotoxicity.
      E(1)/E(3)/E(4)-deleted vectors containing transgenes under control of the hAAT
      promoter in combination with four copies of the human apo E enhancer may be
      suitable for hepatocyte-specific overexpression of transgenes after gene
      transfer. doi:10.1038/sj.gt.3301824

PMID- 12407425
TI  - Possible mechanism of gene transfer into early to mid-gestational mouse fetuses
      by tail vein injection.
AB  - Our aim is to develop a simple gene transfer method into egg cylinder and mid
      gestational murine embryos. We examined whether plasmid/lipid complexes injected
      into the tail veins of pregnant transgenic mice can be transferred to fetuses at
      E 4.5-13.5. When pregnant CETZ-17 mice carrying a transgene consisting of a
      ubiquitous promoter, floxed EGFP/CAT and the LacZ gene, were injected with a Cre
      expression vector DNA/lipid complex, Cre-mediated excision of the transgenes, as
      evaluated by X-gal staining, occurred in 10-50% of fetuses treated at E 11.5
      13.5. Although younger embryos remained unstained, PCR analysis revealed low
      levels of the Cre vector DNA and recombined transgene. To examine the fate of a
      solution given intravenously, we injected trypan blue or fluorescence-labeled
      plasmid DNA/lipid complexes into females at E 5.5-11.5 and E 6.5, respectively.
      Both collected in the visceral endoderm (VE) lineage, but were undetectable in
      the embryo proper. These findings suggest that substances in maternal blood are
      delivered to post-implantation embryos via cells of the VE lineage and placenta,
      but that most are trapped in the VE. If significantly improved, gene transfer to
      fetuses by injection into the maternal circulation may become a promising tool in
      fetal gene therapy and embryological studies.

PMID- 12407426
TI  - Folate-targeted, cationic liposome-mediated gene transfer into disseminated
      peritoneal tumors.
AB  - A folate-targeted, cationic lipid based transfection complex was developed and
      found to specifically transfect folate receptor-expressing cells and tumors.
      These liposomal vectors were comprised of protamine-condensed plasmid DNA, a
      mixture of cationic and neutral lipids, and a folic acid-cysteine
      polyethyleneglycol-phosphatidylethanolamine (FA-Cys-PEG-PE) conjugate. Pre
      optimization studies revealed that inclusion of low amounts (0.01 to 0.03%) of FA
      Cys-PEG-PE yielded the highest binding activity of
      dioleoylphosphatidylcholine/cholesterol liposomes to folate receptor-bearing
      cells. In contrast, higher amounts (>0.5%) of FA-Cys-PEG-PE progressively
      decreased cellular binding of the liposomes. In vitro studies with cationic
      lipid/dioleoylphosphatidylethanolamine formulations indicated that as little as
      0.01 to 0.3% of FA-Cys-PEG-PE was needed to produce optimal targeted expression
      of plasmid DNA. Similarly, using a disseminated intraperitoneal L1210A tumor
      model, maximum in vivo transfection activity occurred with intraperitoneally
      administered formulations that contained low amounts (0.01 mol%) of the FA-Cys
      PEG-PE targeting lipid. Overall, folate-labeled formulations produced an eight-
      to 10-fold increase in tumor-associated luciferase expression, as compared with
      the corresponding non-targeted cationic lipid/DNA formulations. These results
      collectively indicate that transfection of widespread intraperitoneal cancers can
      be significantly enhanced using folate-targeted techniques.

PMID- 12407427
TI  - Efficient transduction and long-term retroviral expression of the melanoma
      associated tumor antigen tyrosinase in CD34(+) cord blood-derived dendritic
      cells.
AB  - Differentiation of genetically modified CD34(+) hematopoietic stem cells into
      dendritic cells (DCs) will contribute to the development of immunotherapeutic
      anticancer protocols. Retroviral vectors that have been used for the transduction
      of CD34(+) cells face the problem of gene silencing when integrated into the
      genome of repopulating stem cells. We reasoned that a high copy number of
      retroviral DNA sequences might overcome silencing of transgene expression during
      expansion and differentiation of progenitor cells into functional DCs. To prove
      this, we utilized a retroviral vector with bicistronic expression of the melanoma
      associated antigen tyrosinase and the enhanced green fluorescent protein (EGFP).
      Human cord blood CD34(+) cells were transduced with vesicular stomatitis virus G
      protein (VSV-G) pseudotyped Moloney murine leukemia virus (MoMuLV) particles
      using 100-150 multiplicity of infection. During expansion of transduced cells
      with immature phenotype, transgene expression was strongly silenced, but upon
      differentiation into mature DCs, residual transgene expression was retained.
      Intracellular processing of the provirally expressed tyrosinase was tested in a
      chromium release assay utilizing a cytotoxic T cell clone specific for a HLA
      A*0201-restricted tyrosinase peptide. We suggest that retroviral transduction of
      tumor-associated antigens in hematopoietic progenitor cells and subsequent
      differentiation into DCs is a suitable basis for the development of potent anti
      tumor vaccines.

PMID- 12407428
TI  - New concepts about graft-versus-host and graft-versus-leukaemia-reactions. A
      summary of the 5th International Symposium held in Munich, 21 and 22 March 2002.
AB  - The Fifth International Symposium on Graft-versus-Host and Graft-versus-Leukemia
      Reactions was held on 21 and 22 March 2002 in the University Hospital (Klinikum
      Grosshadern) of the University of Munich. As in previous years, it was dedicated
      to the encounter of scientists and clinicians involved in hematopoietic cell
      transplantation. This year's symposium focused on the characterization of stem
      cells potentially expanding the use of hematopoietic stem cells and on gene
      therapy. The immunology section dealt with mechanisms of tolerance, and the
      characterization of minor histocompatibility antigens presented by major
      histocompatibility molecules. Further important topics were cytokines and
      dendritic cells. In 1 and 1/2 days of intense work, the invited speakers,
      chairmen, authors and an active audience experienced an exciting exchange of
      ideas and collaboration. Again, new impulses were given for basic research and
      clinical transplantation. The authors would like to express their deep
      appreciation and thanks to all participants of this symposium.

PMID- 12407429
TI  - Cobblestone area-forming cells, long-term culture-initiating cells and NOD/SCID
      repopulating cells in human neonatal blood: a comparison with umbilical cord
      blood.
AB  - Our prior study demonstrated that neonatal blood (NB) contained hematopoietic
      stem and progenitor cells that declined rapidly after birth. To validate that NB
      is a source of functional stem cells, we characterized this population in terms
      of cobblestone area-forming cells (CAFC), long-term culture-initiating cells (LTC
      IC) and NOD/SCID mouse repopulating cells (SRC) in NB and umbilical cord blood
      (CB). Our data demonstrated that the frequencies of CAFC (30.2 vs 37.1, P = 0.14)
      and LTC-IC (28.6 vs 31.0, P = 0.49) in 1 x 10(5) mononuclear cells (MNC) of NB
      and CB were similar, suggesting that these cells were preserved in the
      circulation of the neonates shortly after birth. Sublethally irradiated NOD/SCID
      mice were transplanted with CD34(+) cells enriched from thawed NB and CB. At 6
      weeks post transplant, human (hu)CD45(+) cells were detected in the bone marrow
      (BM), spleen and peripheral blood (PB) of the mice as demonstrated by flow
      cytometric and DNA analysis. Levels of huCD45(+)cells and colony forming units
      (CFU) appeared to be dependent on the infusion cell dose and were higher in
      animals receiving CB cells when compared with those of the NB group. The
      transplanted cells were capable of differentiation into multi-lineage progenitor
      cells (CD34(+) cells and differential CFU), as well as mature myeloid (CD14(+),
      CD33(+)), B lymphoid (CD19(+)) and megakaryocytic (CD61(+)) cells in the
      recipients. NB cells, subjected to ex vivo culture in an optimized preclinical
      condition, were significantly expanded to early and committed progenitor cells.
      Expanded NB contained SRC at a reduced quantity but with high proportions of
      CD14(+) cells and CD33(+) cells. Our study confirms that NB contains pluripotent
      hematopoietic stem and progenitor cells capable of homing and engrafting the
      NOD/SCID mice.

PMID- 12407430
TI  - Possible benefits of high-dose chemotherapy and autologous stem cell
      transplantation for adults with recurrent medulloblastoma.
AB  - In an attempt to improve the dismal prognosis of adults with recurrent
      medulloblastoma, six patients were treated with aggressive salvage therapy
      including high-dose chemotherapy (HDCT) and autologous stem cell transplantation
      (ASCT). At relapse, all patients underwent surgical debulking followed by
      HDCT/ASCT and then radiotherapy when possible. The treatment plan included two
      cycles of HDCT/ASCT; first with cyclophosphamide, etoposide and carboplatin
      (CECb) and then 2 months later with cyclophosphamide and thiotepa (CT). Three of
      the six patients received the planned therapy. One patient experienced severe
      toxicity requiring life-sustaining therapy. This patient developed multi-organ
      dysfunction including multiple enhancing lesions in both cerebral hemispheres
      that slowly resolved over several months. Two other patients did not mobilize
      sufficient stem cells for two ASCT procedures. They received one ASCT conditioned
      with cyclophosphamide, thiotepa and carboplatin (CTCb). Three of six patients had
      a complete response (CR); the other three had a partial response (PR). Following
      the first ASCT, median duration of response was 13.5 months (range 9-29 months)
      and median survival was 21.5 months (range 12-42 months). There was no treatment
      related mortality. We conclude that HDCT/ASCT with CECb-CT or CTCb is active
      against recurrent medulloblastoma in adults and may be associated with prolonged
      remissions. Multiple enhancing cerebral lesions on brain MRI early post-HDCT/ASCT
      may be a consequence of the treatment rather than metastatic disease.

PMID- 12407431
TI  - Administration of low-dose interleukin-2 plus G-CSF/EPO early after autologous
      PBSC transplantation: effects on immune recovery and NK activity in a prospective
      study in women with breast and ovarian cancer.
AB  - This study evaluated the effects of low-dose IL-2 plus G-CSF/EPO on post-PBSC
      transplantation (PBSCT) immune-hematopoietic reconstitution and NK activity in
      patients with breast (BrCa) and ovarian cancer (OvCa). To this end, two
      consecutive series of patients were prospectively assigned to distinct post-PBSCT
      cytokine regimens (from day +1 to day +12) which consisted of G-CSF (5
      microg/kg/day) plus EPO (150 IU/kg/every other day) in 17 patients (13 BrCa and 4
      OvCa) or G-CSF/EPO plus IL-2 (2 x 10(5) IU/m(2)/day) in 15 patients (10 BrCa and
      5 OvCa). Hematopoietic recovery and post-transplantation clinical courses were
      comparable in G-CSF/EPO- and in G-CSF/EPO plus IL-2-treated patients, without
      significant side-effects attributable to IL-2 administration. In the early and
      late post-transplant period a significantly higher PMN count was observed in G
      CSF/EPO plus IL-2-treated patients (P = 0.034 and P = 0.040 on day +20 and +100,
      respectively). No significant differences were found between the two groups of
      patients in the kinetics of most lymphocyte subsets except naive CD45RA(+) T
      cells which had a delayed recovery in G-CSF/EPO plus IL-2 patients (P = 0.021 on
      day +100). No significant difference was observed between NK activity in the two
      different groups, albeit a significantly higher NK count was observed in G
      CSF/EPO plus IL-2 series on day +20 (P = 0.020). These results demonstrate that
      low-dose IL-2 can be safely administered in combination with G-CSF/EPO early
      after PBSCT and that it exerts favorable effects on post-PBSCT myeloid
      reconstitution, but not on immune recovery.

PMID- 12407432
TI  - Allogeneic bone marrow transplantation (BMT) for adults with acute lymphoblastic
      leukemia (ALL): predictive role of minimal residual disease monitoring on
      relapse.
AB  - We developed a PCR-based method to monitor clonogenic IgH VDJ rearrangement as a
      possible predictor of relapse in patients with acute B-ALL after allogeneic bone
      marrow transplantation (BMT). We studied 23 patients at diagnosis, before and
      after BMT. At the time of BMT, 13 patients were in first complete remission,
      eight in second complete remission and two in relapse. Four patients were PCR
      negative before BMT and remained PCR negative also after BMT (-/- pattern). They
      are still in remission after a median follow-up of 41 months. Nineteen patients
      were MRD-positive before BMT: three were PCR negative at first determination
      after BMT (+/- pattern) and maintain remission. Sixteen patients were PCR
      positive at first determination after BMT (+/+ pattern): five became PCR negative
      (+/+/- pattern) (four with chronic graft-versus-host disease (GVHD) and two after
      donor lymphocyte infusions (DLI)). Nine patients remained PCR-positive (+/+/+
      pattern) (four remain in remission, and six relapsed); two patients died before
      transplant. In conclusion, PCR negative patients before BMT remained negative
      post-BMT; many pre-BMT positive patients had initial MRD positivity after BMT:
      37% of them achieved a molecular remission with cGVHD or DLI.

PMID- 12407433
TI  - A multivariable analysis of factors influencing mucositis after autologous
      progenitor cell transplantation.
AB  - Mucositis is a common and vexing complication of autologous progenitor cell
      transplantation (ABMT). A modified oral mucositis assessment scale (OMAS) has
      been found to be a reproducible and effective tool for monitoring mucositis after
      radiation therapy or chemotherapy. We utilized the modified OMAS scale to study
      clinical parameters associated with the development of mucositis in 79 patients
      undergoing ABMT. Median patient age was 52; 61% had non-Hodgkin's lymphoma (NHL),
      23% multiple myeloma and 14% Hodgkin's disease. Patients were mobilized with G
      CSF alone or the combination of etoposide plus G-CSF. Univariable correlates of
      worse mucositis were prior radiation therapy (P = 0.004), a diagnosis of NHL (P =
      0.014), progenitor cell mobilizing regimen containing etoposide (P = 0.001), and
      ABMT preparative regimen containing etoposide (P = 0.006). Multivariable
      regression analysis revealed that NHL diagnosis (P = 0.007), prior radiation
      therapy (P = 0.001), and etoposide in the mobilizing regimen (P = 0.034) were
      associated with worse post-transplant mucositis. Worsening mucositis correlated
      with a longer inpatient length of stay. We conclude that several variables
      contribute to worsening mucositis during autologous transplantation, including
      etoposide in the progenitor cell mobilizing regimen.

PMID- 12407434
TI  - Relationship between irreversible alopecia and exposure to cyclophosphamide,
      thiotepa and carboplatin (CTC) in high-dose chemotherapy.
AB  - Reversible alopecia is a commonly observed, important and distressing
      complication of chemotherapy. Permanent alopecia, however, is rare after standard
      dose therapy, but has occasionally been observed after high-dose chemotherapy
      with cyclophosphamide, thiotepa and carboplatin (CTC). We evaluated the
      relationships between total exposure to these three compounds and their different
      metabolites in the high-dose CTC regimen, and the subsequent development of
      irreversible alopecia. Twenty-four patients received two or three courses of high
      dose CTC, each followed by peripheral blood progenitor cell transplantation.
      Plasma levels of cyclophosphamide, its active metabolite 4
      hydroxycyclophosphamide, thiotepa, its active metabolite tepa, and carboplatin
      were determined, and the area-under-the-plasma concentration-versus-time curves
      (AUC) of the compounds were calculated. Eight of the 24 patients included in the
      study developed permanent alopecia, while seven had normal hair regrowth and nine
      patients developed incomplete and/or thin hair regrowth. The carboplatin AUC and
      the summed AUC of thiotepa and tepa were both significantly associated with
      increasing irreversibility of hair loss. These results suggest that high exposure
      to carboplatin and the sum of the thiotepa and tepa exposure may lead to the
      development of permanent alopecia. This knowledge could guide therapeutic drug
      monitoring in order to prevent the occurrence of permanent alopecia and thereby
      improve the patients' quality of life.

PMID- 12407435
TI  - Pulmonary function abnormalities after allogeneic marrow transplantation: a
      systematic review and assessment of an existing predictive instrument.
AB  - Pulmonary function testing (PFT) is used to characterize non-infectious pulmonary
      complications after allogeneic BMT. Identifying high-risk patients could
      facilitate preventive or early therapeutic measures. The objectives of the study
      were first, to review available data on PFT changes after BMT and second, to
      validate a previously published predictive index for PFT obstruction in patients
      transplanted at one center. For the systematic review, frequency, severity and
      time course of PFT changes after BMT and for the validation study, retrospective
      cohort comparing predicted with observed PFT, and calculation of indices of
      predictive accuracy were summarized. The validation study involved 434 patients
      from Princess Margaret Hospital, Toronto, Canada, who received their first BMT
      between 1980 and 1997, survived for at least 6 months and had adequate PFT follow
      up. The systematic review included 20 studies. After BMT, decreased diffusion and
      total lung capacity were common and partially reversible. Obstruction was less
      common. The validation study of a previously published index, performed in 434
      patients, found a sensitivity and specificity of 48% and 68% for identifying
      patients who develop obstruction. We concluded that PFT changes after BMT are
      common. A published predictive index is not sufficiently accurate to identify
      high-risk patients for potential preventive or early therapeutic strategies.

PMID- 12407436
TI  - Cognitive and psychosocial functioning of pediatric hematopoietic stem cell
      transplant patients: a prospective longitudinal study.
AB  - A prospective longitudinal study of cognitive and psychosocial functioning in
      pediatric hematopoietic stem cell transplant (HSCT) patients was conducted on
      three occasions: pre-HSCT, 1 year post-HSCT, and 2 years post-HSCT. In contrast
      to the previous hypothesis that cognitive declines would occur as a result of
      HSCT treatment, it was hypothesized that (1) global cognitive functioning (IQ
      scores), as well as specific areas would remain stable over time; (2) pre
      transplant functioning would be predictive of later functioning; and (3) age
      would be negatively related to cognitive functioning. Based on previous research
      it was further hypothesized: that (4) while declines in psychosocial functioning
      might be seen at 1 year, functioning would improve by 2 years. 153 children and
      adolescents were evaluated pre-HSCT and at 1 year, with 2 year data available for
      74 children. Longitudinal analyses of Wechsler IQ data were completed on 100
      children (longitudinal exact test) and 52 children (repeated measures analysis of
      variance. Results of cognitive assessment indicated (1) stability of IQ scores
      over time; and (2) that the strongest predictor was pre-HSCT cognitive
      functioning. Psychosocial assessment results indicated: (1) a low prevalence of
      behavioral and social problems; (2) stability in functioning over time; (3) pre
      HSCT functioning strongly predictive of later functioning.

PMID- 12407437
TI  - Long-term outcome and quality of life of patients who are alive and in complete
      remission more than two years after allogeneic and syngeneic stem cell
      transplantation.
AB  - We assessed long-term outcome in 155 patients who had undergone an
      allogeneic/syngeneic stem cell transplant (SCT) and were in complete remission
      for more than 2 years after transplant. Probability of late transplant-related
      mortality was 6%, and affected only patients with chronic graft-versus-host
      disease (cGVHD). Thirteen percent of patients experienced relapse. Overall
      survival projected at 10 and 15 years was 83% and 76%, respectively. Secondary
      malignancies occurred in two patients, 7.5 and 11 years after SCT. Three female
      and four male patients parented children 19 to 84 months after SCT. Quality of
      life (QoL) was assessed in a cross-sectional study by the means of a 30-item
      questionnaire (QLQ-C30) of the EORTC. The questionnaire was sent to 127 patients
      remaining alive and answered by 106 patients. Seventy-three percent reported a
      good to very good QoL within 5 years after SCT and 78% after this time point.
      However, patients with cGVHD had significant impairment of physical, role and
      social functioning and only 60% of them were fit for work. These results from
      long-term survivors show that high cure rates with good to very good QoL can be
      achieved by allogeneic or syngeneic SCT.

PMID- 12407439
TI  - The hypercoagulable state of malignancy: pathogenesis and current debate.
AB  - A hypercoagulable or prothrombotic state of malignancy occurs due to the ability
      of tumor cells to activate the coagulation system. It has been estimated that
      hypercoagulation accounts for a significant percentage of mortality and morbidity
      in cancer patients. Prothrombotic factors in cancer include the ability of tumor
      cells to produce and secrete procoagulant/fibrinolytic substances and
      inflammatory cytokines, and the physical interaction between tumor cell and blood
      (monocytes, platelets, neutrophils) or vascular cells. Other mechanisms of
      thrombus promotion in malignancy include nonspecific factors such as the
      generation of acute phase reactants and necrosis (i.e., inflammation), abnormal
      protein metabolism (i.e., paraproteinemia), and hemodynamic compromise (i.e.,
      stasis). In addition, anticancer therapy (i.e., surgery/chemotherapy/hormone
      therapy) may significantly increase the risk of thromboembolic events by similar
      mechanisms, e.g., procoagulant release, endothelial damage, or stimulation of
      tissue factor production by host cells. However, not all of the mechanisms for
      the production of a hypercoagulable state of cancer are entirely understood. In
      this review, we attempt to describe what is currently accepted about the
      pathophysiology of the hypercoagulable state of cancer. We also discuss whether
      or not to screen patients with idiopathic deep venous thrombosis for an
      underlying malignancy, and whether this would be beneficial to patients. It is
      hoped that a better understanding of these mechanisms will ultimately lead to the
      development of more targeted treatment to prevent thromboembolic complications in
      cancer patients. It is also hoped that antithrombotic strategies may also have a
      positive effect on the process of tumor growth and dissemination.

PMID- 12407440
TI  - Combination of endostatin and a protein kinase Calpha DNA enzyme improves the
      survival of rats with malignant glioma.
AB  - Malignant gliomas are refractory to conventional therapies, including surgery,
      radiotherapy and chemotherapy. Thus, a variety of therapies such as the
      inhibition of angiogenesis and signal transduction pathways have been attempted.
      In the present study, we have evaluated the combined effect of endostatin, an
      inhibitor of angiogenesis, and a DNA enzyme targeting the protein kinase Calpha
      (PKCalpha) gene expression. Inhibition of PKCalpha by a nuclease-resistant DNA
      enzyme eliminated PKCalpha gene expression and induced apoptosis in most glioma
      cells. To assess the efficacy of endostatin and the PKCalpha DNA enzyme in vivo,
      rats bearing the intracranial tumor BT(4)C were given a combined treatment of
      endostatin and the PKCalpha enzyme. Survival was significantly enhanced by
      continuous delivery of endostatin (P<.0004) and rats treated with a single
      injection of the active DNA enzyme lived significantly longer than those treated
      with the inactive form (P<.045). Interestingly, a single injection of the
      PKCalpha DNA enzyme in combination with continuous delivery of endostatin
      significantly improved animal survival compared with PKCalpha (P<.0009) or
      endostatin (P<.025) alone. Thus, the combined treatment may represent an
      attractive therapeutic strategy against malignant gliomas.

PMID- 12407441
TI  - MRI of mouse models for gliomas shows similarities to humans and can be used to
      identify mice for preclinical trials.
AB  - Magnetic resonance imaging (MRI) has been utilized for screening and detecting
      brain tumors in mice based upon their imaging characteristics appearance and
      their pattern of enhancement. Imaging of these tumors reveals many similarities
      to those observed in humans with identical pathology. Specifically, high-grade
      murine gliomas have histologic characteristics of glioblastoma multiforme (GBM)
      with contrast enhancement after intravenous administration of gadolinium
      diethylenetriamine pentaacetic acid (Gd-DTPA), implying disruption of the blood
      brain barrier in these tumors. In contrast, low-grade murine oligodendrogliomas
      do not reveal contrast enhancement, similar to human tumors. MRI can be used to
      identify mice with brain neoplasms as inclusion criteria in preclinical trials.

PMID- 12407442
TI  - Ultraviolet radiation-induced apoptosis is mediated by Daxx.
AB  - UV irradiation and other stress-activated signals activate the Jun N-terminal
      kinase (JNK, SAPK) pathway. The induction of JNK activity results in the
      activation of proto-oncogene c-Jun and activator protein-1 (AP-1) transcriptional
      activity. Data presented here show that UV mediated the activation of JNK
      correlated with UV-induced apoptosis and that overexpression of a dominant
      negative JNK blocked UV-induced apoptosis. However, the molecular events that
      lead to JNK activation in response to UV treatment are not clear. In this report,
      we provide evidence that a Fas receptor binding protein, Daxx, mediates UV
      induced JNK activation and apoptosis. A dominant negative Daxx, coding for the C
      terminal region (112 amino acids) of Daxx, was constructed and used in the
      experiments. Our data show that overexpression of the dominant negative Daxx
      partially inhibits UV-induced JNK phosphorylation in 293 cells. Inhibition of JNK
      phosphorylation resulted in the inhibition of c-Jun activation upon UV
      irradiation. Our data also show that the inhibition of JNK activation by dominant
      negative Daxx correlates with the reduced rate of apoptotic death of 293 cells
      after UV irradiation. Surprisingly, overexpression of wild-type Daxx also
      inhibited UV-induced apoptosis, suggesting that Daxx competes for Fas receptor
      binding sites with other proapoptotic factors such as FADD. In addition,
      overexpression of a dominant negative mutant of FADD did not affect UV-induced
      JNK activation but does inhibit UV-induced apoptosis. These results suggest that
      UV-induced JNK activation is not sufficient but required for induction of
      apoptosis.

PMID- 12407443
TI  - Cooperation of hTERT, SV40 T antigen and oncogenic Ras in tumorigenesis: a cell
      transplantation model using bovine adrenocortical cells.
AB  - Expression of TERT, the reverse transcriptase component of telomerase, is
      necessary to convert normal human cells to cancer cells. Despite this,
      "telomerization" by hTERT does not appear to alter the normal properties of
      cells. In a cell transplantation model in which bovine adrenocortical cells form
      vascularized tissue structures beneath the kidney capsule in scid mice,
      telomerization does not perturb the functional tissue-forming capacity of the
      cells. This cell transplantation model was used to study the cooperation of hTERT
      with SV40 T antigen (SV40 TAg) and oncogenic Ras in tumorigenesis. Only cells
      expressing all three genes were tumorigenic; this required large T, but not small
      t, antigen. These cells produced a continuously expanding tissue mass; they were
      invasive with respect to adjacent organs and eventually destroyed the kidney.
      Cells expressing only hTERT or only Ras produced minimally altered tissues. In
      contrast, SV40 TAg alone produced noninvasive nodules beneath the kidney capsule
      that had high proliferation rates balanced by high rates of apoptosis. The use of
      cell transplantation techniques in a cell type that is able to form tissue
      structures with or without full neoplastic conversion allows the phenotypes
      produced by individual cooperating oncogenes to be observed.

PMID- 12407444
TI  - Detection of spontaneous schwannomas by MRI in a transgenic murine model of
      neurofibromatosis type 2.
AB  - Spontaneous schwannomas were detected by magnetic resonance imaging (MRI) in a
      transgenic murine model of neurofibromatosis type 2 (NF2) expressing a dominant
      mutant form of merlin under the Schwann cell-specific P0 promoter. Approximately
      85% of the investigated mice showed putative tumors by 24 months of age.
      Specifically, 21% of the mice showed tumors in the intercostal muscles, 14% in
      the limb muscles, 7% in the spinal cord and spinal ganglia, 7% in the external
      ear, 14% in the muscle of the abdominal region, and 7% in the intestine; 66% of
      the female mice had uterine tumors. Multiple tumors were detected by MRI in 21%
      of mice. The tumors were isointense with muscle by T1-weighted MRI, showed strong
      enhancement following administration of gadolinium-DTPA, and were markedly
      hyperintense by T2-weighted MRI, all hallmarks of the clinical manifestation.
      Hematoxylin and eosin staining and immunohistochemistry indicated that the tumors
      consisted of schwannomas and Schwann cell hyperplasias. The lesions stained
      positively for S-100 protein and a marker antigen for the mutated transgenic NF2
      protein, confirming that the imaged tumors and areas of hyperplasia were of
      Schwann cell origin and expressed the mutated NF2 protein. Tumors were highly
      infectable with a recombinant herpes simplex virus type 1 vector, hrR3, which
      contains the reporter gene, lacZ. The ability to develop schwannoma growth with a
      noninvasive imaging technique will allow assessment of therapeutic interventions.

PMID- 12407445
TI  - Met-HGF/SF signal transduction induces mimp, a novel mitochondrial carrier
      homologue, which leads to mitochondrial depolarization.
AB  - Met-hepatocyte growth factor/scatter factor (HGF/SF) signaling plays an important
      role in epithelial tissue morphogenesis, lumen formation, and tumorigenicity. We
      have recently demonstrated that HGF/SF also alters the metabolic activity of
      cells by enhancing both the glycolytic and oxidative phosphorylation pathways of
      energy production. Using differential display polymerase chain reaction, we
      cloned a novel gene, designated mimp (Met-Induced Mitochondrial Protein), which
      is upregulated in NIH-3T3 cells cotransfected with both HGF/SF and Met (HMH
      cells). Northern and Western blot analyses showed that mimp is induced in several
      Met-expressing cell lines following treatment with HGF/SF. Mimp encodes a 33-kDa
      protein that shows sequence homology to the family of mitochondrial carrier
      proteins (MCPs). Murine Mimp (mMimp) is expressed in a wide variety of tissues,
      exhibiting an expression pattern similar to Met. Predominant expression is seen
      in liver, kidney, heart, skeletal muscle, and testis. Using immunostaining for HA
      tagged mMimp and a GFP-mMimp chimeric protein as well as subcellular
      fractionation, we determined that Mimp is primarily localized to the
      mitochondria. Ectopic expression of mMimp in the Met-responsive adenocarcinoma
      cell line, DA3, reduced the mitochondrial membrane potential (uncoupling
      activity). The extent of the mitochondrial depolarization positively correlated
      with the level of Mimp expression. Our results demonstrate that Mimp is a novel
      mitochondrial carrier homologue upregulated by Met-HGF/SF signal transduction,
      which leads to mitochondrial depolarization, and suggest novel links among
      tyrosine kinase signaling, mitochondrial function, and cellular bioenergetics.

PMID- 12407446
TI  - MRI of transgene expression: correlation to therapeutic gene expression.
AB  - Magnetic resonance imaging (MRI) can provide high-resolution 3D maps of
      structural and functional information, yet its use of mapping in vivo gene
      expression has only recently been explored. A potential application for this
      technology is to noninvasively image transgene expression. The current study
      explores the latter using a nonregulatable internalizing engineered transferrin
      receptor (ETR) whose expression can be probed for with a superparamagnetic Tf
      CLIO probe. Using an HSV-based amplicon vector system for transgene delivery, we
      demonstrate that: 1) ETR is a sensitive MR marker gene; 2) several transgenes can
      be efficiently expressed from a single amplicon; 3) expression of each transgene
      results in functional gene product; and 4) ETR gene expression correlates with
      expression of therapeutic genes when the latter are contained within the same
      amplicon. These data, taken together, suggest that MRI of ETR expression can
      serve as a surrogate for measuring therapeutic transgene expression.

PMID- 12407447
TI  - DNA amplification by breakage/fusion/bridge cycles initiated by spontaneous
      telomere loss in a human cancer cell line.
AB  - The development of genomic instability is an important step in generating the
      multiple genetic changes required for cancer. One consequence of genomic
      instability is the overexpression of oncogenes due to gene amplification. One
      mechanism for gene amplification is the breakage/fusion/bridge (B/F/B) cycle that
      involves the repeated fusion and breakage of chromosomes following the loss of a
      telomere. B/F/B cycles have been associated with low-copy gene amplification in
      human cancer cells, and have been proposed to be an initiating event in high-copy
      gene amplification. We have found that spontaneous telomere loss on a marker
      chromosome 16 in a human tumor cell line results in sister chromatid fusion and
      prolonged periods of chromosome instability. The high rate of anaphase bridges
      involving chromosome 16 demonstrates that this instability results from B/F/B
      cycles. The amplification of subtelomeric DNA on the marker chromosome provides
      conclusive evidence that B/F/B cycles initiated by spontaneous telomere loss are
      a mechanism for gene amplification in human cancer cells.

PMID- 12407448
TI  - Enhanced uptake of ifosfamide into GH3 prolactinomas with hypercapnic hyperoxic
      gases monitored in vivo by (31)P MRS.
AB  - Previously, (31)P magnetic resonance spectroscopy (MRS) has been used to detect
      ifosfamide (IF) in vivo and to show that breathing carbogen (5% CO(2)/95% O(2))
      enhances the uptake and increases the efficacy of IF in rat GH3 prolactinomas
      [Rodrigues LM, Maxwell RJ, McSheehy PMJ, Pinkerton CR, Robinson SP, Stubbs M, and
      Griffiths JR (1997). In vivo detection of ifosfamide by (31)P MRS in rat tumours;
      increased uptake and cytotoxicity induced by carbogen breathing in GH3
      prolactinomas. Br J Cancer 75, 62-68]. We now show that other hypercapnic and/or
      hyperoxic (5% CO(2) in air, 2.5% CO(2) in O(2)) gas mixtures also increase the
      uptake of IF into tumors, measured by (31)P MRS. All gases caused an increased
      uptake (C(max)) of IF compared to air breathing, with carbogen inducing the
      largest increase (85% (P<.02) compared to 46% with 2.5% CO(2) in O(2) (P<.004)
      and 48% with 5% CO(2) in air (P<.004)). The T(max) (time of maximum concentration
      in tumor posintravenous injection of IF) was significantly (P<.04) later in the
      cohort that breathed 5% CO(2) in air. The increased uptake of IF with carbogen
      breathing was selective to tumor tissue and there were no significant increases
      in any of the normal tissues studied, suggesting that any host tissue toxicity
      would be minimal. Carbogen breathing by patients causes breathlessness. There was
      no significant difference in IF uptake between breathing carbogen and 2.5% CO(2)
      in O(2) and, therefore, the ability of 2.5% CO(2) in O(2) to also increase IF
      uptake may be clinically useful as it causes less patient discomfort.

PMID- 12407449
TI  - A mortality gene(s) for the human adenocarcinoma line HeLa maps to a 130-kb
      region of human chromosome 4q22-q23.
AB  - Human chromosome 4 was previously shown to elicit features of senescence when
      introduced into cell lines that map to complementation group B for senescence,
      including HeLa cells. Subsequently, a DNA segment encoding the pseudogene
      Mortality Factor 4 (MORF4) was shown to reproduce some of the effects of the
      intact chromosome 4 and was suggested to be a candidate mortality gene. We have
      identified multiple MORF4 alleles in several cell lines and tissues by sequencing
      and have failed to detect any cancer-specific mutations in three of the
      complementation group B lines (HeLa, T98G, and J82). Furthermore, MORF4 was
      heterozygous in these lines. These results question whether MORF4 is the
      chromosome 4 mortality gene. To map other candidate mortality gene(s) on this
      chromosome, we employed microcell-mediated monochromosome transfer to introduce
      either a complete copy, or defined fragments of the chromosome into HeLa cells.
      The introduced chromosome 4 fragments mapped the mortality gene to a region
      between the centromere and the marker D4S2975 (4q27), thus excluding MORF4, which
      maps to 4q33-q34.1. Analysis of microsatellite markers on the introduced
      chromosome in 59 immortal segregants identified a frequently deleted region,
      spanning the markers BIR0110 and D4S1557. This defines a new candidate interval
      of 130 kb at 4q22-q23.

PMID- 12407450
TI  - Defining characteristics of Types I and II apoptotic cells in response to TRAIL.
AB  - Type I cells have been defined to be independent of mitochondria for the
      induction of Fas death receptor-mediated apoptosis, whereas Type II cells are
      mitochondria-dependent. Knock-out studies in mice show that thymocytes are Type I
      and liver cells are Type II. We have previously shown that primary human
      hepatocytes and HCT116 human colon carcinoma cells behave like Type II cells
      because TRAIL-induced apoptosis can be blocked by the caspase 9 inhibitor, Z-LEHD
      FMK. On the other hand, caspase 9 inhibition does not allow survival of TRAIL
      treated SW480 colon cancer cells, which is predicted for Type I cells.
      Investigating the differences in TRAIL-induced apoptotic pathways in HCT116 and
      SW480 cells revealed that although FADD, BID, and procaspase 3 protein levels are
      higher in SW480 cells, and although procaspase 8 and FLIP processing is more
      efficient at the TRAIL-DISC of SW480 cells, BID, procaspase 3, XIAP, and PARP
      cleavages occur more rapidly in HCT116, despite the higher levels of BCL-2 and
      HSP70. Cytochrome c release from the mitochondria to the cytoplasm is more
      efficient in HCT116 cells. These results suggest BID cleavage as a possible
      limiting factor in the involvement of mitochondria in TRAIL-induced cell death.
      Thus, regulation of BID cleavage may define if a cell is mitochondria-dependent
      or -independent in response to TRAIL death receptor-induced apoptosis.

PMID- 12407453
TI  - Enhanced activity by poly(ethylene glycol) modification of Coriolopsis gallica
      laccase.
AB  - We are studying the enzymatic modification of polycyclic aromatic hydrocarbons
      (PAHs) by the laccase from Coriolopsis gallica UAMH 8260. The enzyme was produced
      during growth in a stirred tank reactor to 15 units ml(-1), among the highest
      levels described for a wild-type fungus; the enzyme was the major protein
      produced under these conditions. After purification, it exhibited characteristics
      typical of a white rot fungal laccase. Fifteen azo and phenolic compounds at 1 mM
      concentration were tested as mediators in the laccase oxidation of anthracene.
      Higher anthracene oxidation was obtained with the mediator combination of ABTS
      and HBT, showing a correlation between the oxidation rate and the mediator
      concentration. Reactions with substituted phenols and anilines, conventional
      laccase substrates, and PAHs were compared using the native laccase and enzyme
      preparations chemically modified with 5000 MW-poly(ethylene glycol). Chemically
      modified laccase oxidized a similar range of substituted phenols as the native
      enzyme but with a higher catalytic efficiency. The k(cat) increase by the
      chemical modification may be as great as 1300 times for syringaldazine oxidation.
      No effect was found of chemical modification on mediated PAH oxidation. Both
      unmodified and PEG-modified laccases increased PAH oxidation up to 1000 times in
      the presence of radical mediators. Thus, a change of the protein surface improves
      the mediator oxidation efficiency, but does not affect non-enzymatic PAH
      oxidation by oxidized mediators.

PMID- 12407452
TI  - Alginate production by Azotobacter vinelandii mutants altered in poly-beta
      hydroxybutyrate and alginate biosynthesis.
AB  - Mutant AT268 of Azotobacter vinelandii - showing diminished production of poly
      beta-hydroxybutyrate (PHB) due to a mutation in phbR (the gene coding for the
      transcriptional activator of the phbBAC biosynthetic operon); mutant CNT26,
      containing a mutation (muc26) that increases the transcription of gene algD
      (encoding GDP mannose dehydrogenase, the key enzyme in alginate biosynthesis);
      and mutant DM, carrying both phbR and muc26 mutations - were characterised in
      terms of alginate production, broth viscosity, and molecular weight of the
      alginate. All the mutants evaluated produced 25% less alginate with respect to
      that produced by the wild type. Unexpectedly and with no apparent relation to the
      phbR and muc26 mutations, mutant DM exhibited the highest molecular weight ever
      reported for a bacterial alginate (up to 4 x 10(6) Da), with a very low
      polydispersity index (1.3). Acetyl content in the alginate produced by this
      strain was low (1.4-2.6%). These characteristics make this mutant a very valuable
      source for producing alginates with improved properties.

PMID- 12407454
TI  - Fermentation of sugar mixtures using Escherichia coli catabolite repression
      mutants engineered for production of L-lactic acid.
AB  - Conversion of lignocellulose to lactic acid requires strains capable of
      fermenting sugar mixtures of glucose and xylose. Recombinant Escherichia coli
      strains were engineered to selectively produce L-lactic acid and then used to
      ferment sugar mixtures. Three of these strains were catabolite repression mutants
      (ptsG(-)) that have the ability to simultaneously ferment glucose and xylose. The
      best results were obtained for ptsG(-) strain FBR19. FBR19 cultures had a yield
      of 0.77 (g lactic acid/g added sugar) when used to ferment a 100 g/l total equal
      mixture of glucose and xylose. The strain also consumed 75% of the xylose. In
      comparison, the ptsG(+) strains had yields of 0.47-0.48 g/g and consumed 18-22%
      of the xylose. FBR19 was subsequently used to ferment a variety of glucose (0-40
      g/l) and xylose (40 g/l) mixtures. The lactic acid yields ranged from 0.74 to
      1.00 g/g. Further experiments were conducted to discover the mechanism leading to
      the poor yields for ptsG(+) strains. Xylose isomerase (XI) activity, a marker for
      induction of xylose metabolism, was monitored for FBR19 and a ptsG(+) control
      during fermentations of a sugar mixture. Crude protein extracts prepared from
      FBR19 had 10-12 times the specific XI activity of comparable samples from ptsG(+)
      strains. Therefore, higher expression of xylose metabolic genes in the ptsG(-)
      strain may be responsible for superior conversion of xylose to product compared
      to the ptsG(+) fermentations.

PMID- 12407455
TI  - Multimethod assessment of commercial nisin preparations.
AB  - Nisin is a GRAS preservative effective against several Gram-positive organisms
      including Listeria monocytogenes. Commercial preparations are usually
      fermentation products containing 2.5% pure nisin along with insoluble material
      which, in this study, was found to influence the quantification and activity of
      nisin under different conditions. Commercially available samples of nisin were
      tested for efficacy using various methods, such as well diffusion, time to
      turbidity, and GUS (where a reporter compound is induced in response to nisin).
      SDS-PAGE detected a single peptide band, corresponding with the molecular weight
      of nisin. Protein quantified using the Bradford method indicated that the carrier
      of some samples was proteinaceous. Though the activity of commercially available
      nisin preparations is indicated on the label, end users should determine the
      effect of changing their source of nisin.

PMID- 12407456
TI  - A luxCDABE-based bioluminescent bioreporter for the detection of phenol.
AB  - A bioluminescent reporter strain, Acinetobacter sp. DF4-8, was constructed for
      the detection of phenol by inserting a mopR-like promoter upstream of the Vibrio
      fischeri bioluminescent luxCDABE gene cassette in a modified mini-Tn5 construct.
      When introduced into the chromosome of Acinetobacter sp. DF4, the bioreporter
      produced a sensitive bioluminescent response to phenol at concentrations ranging
      from 2.5 to 100 ppm. This response was linear (R(2)=0.986) in the range from 20
      to 90 ppm. A significant bioluminescent response was also recorded when strain
      DF4-8 was incubated with slurries from aged, phenol-contaminated soil.

PMID- 12407457
TI  - Chloroxylenol- and triclosan-tolerant bacteria from industrial sources.
AB  - Potential development of bacterial tolerance to biocides in the industrial
      environment is examined in this study. Bacteria tolerant to the phenolic-type
      agent para-chloro-meta-xylenol (PCMX) and the bis-phenol 2,4,4'-trichloro-2'
      hydroxydiphenylether (triclosan) were isolated from industrial sources and
      identified. Minimum inhibitory concentrations (MICs) were determined and compared
      with those of culture collection (standard) strains. Of around 100 isolates
      originally obtained, most were naturally tolerant species such as Pseudomonas
      spp., or showed low tolerance levels. PCMX-tolerant isolates of Pseudomonas
      stutzeri and triclosan-tolerant isolates of Citrobacter freundii and
      Acinetobacter johnsonii were retained for further study. Of these, only P.
      stutzeri and A. johnsonii showed elevated tolerance compared with the standard
      strains. There was no evidence of tolerance to the other biocide except for
      Pseudomonas aeruginosa (an intrinsically tolerant microorganism), and tolerances
      were stable in the absence of selective pressure except for A. johnsonii.
      Attempts to select or generate increased tolerance in the standard strains were
      unsuccessful. High tolerances in terms of MIC were not reflected in terms of
      lethal effects. This study did not produce any evidence suggesting that the
      presence of residual biocide concentrations in the industrial environment
      promotes the emergence of bacterial tolerance for them.

PMID- 12407458
TI  - Chemical and microbiological changes in laboratory incubations of nitrate
      amendment "sour" produced waters from three western Canadian oil fields.
AB  - Nitrate addition to oil field waters stops the biogenic formation of sulfide
      because the activities of nitrate-reducing bacteria (NRB) suppress the activities
      of sulfate-reducing bacteria (SRB). In general, there are two types of NRB - the
      heterotrophic NRB and the chemolithotrophic NRB. Within the latter group are the
      nitrate-reducing, sulfide-oxidizing bacteria (NR-SOB). To date, no study has
      specifically addressed the roles of these different NRB in controlling sulfide
      concentrations in oil field produced waters. This study used different culture
      media to selectively enumerate heterotrophic NRB and NR-SOB by most probable
      number (MPN) methods. Produced waters from three sulfide-containing western
      Canadian oil fields were amended with nitrate as an electron acceptor, but no
      exogenous electron donor was added to the serum bottle microcosms. Changes in the
      chemical and microbiological characteristics of the produced waters were
      monitored during incubation at 21 degrees C. In less than 4 days, the sulfide was
      removed from the waters from two of the oil fields (designated P and C), whereas
      nearly 27 days were required for sulfide removal from the water from the third
      oil field (designated N). Nitrate addition stimulated large increases in the
      number of the heterotrophic NRB and NR-SOB in the waters from oil fields P and C,
      but only the NR-SOB were stimulated in the water from oil field N. These data
      suggest that stimulation of the heterotrophic NRB is required for rapid removal
      of sulfide from oil field-produced waters.

PMID- 12407459
TI  - Isolation and characterization of a feather-degrading bacterium from the poultry
      processing industry.
AB  - A Flavobacterium sp. producing a high keratinolytic activity was isolated from a
      poultry industry after growth on selective feather meal agar. This bacterium grew
      on feather meal broth, producing keratinase, and was also capable of complete
      degradation of raw feathers. The proteolytic activity was assessed in the
      presence of specific protease inhibitors. The crude enzyme showed mainly
      metalloprotease character. This novel isolate would have potential
      biotechnological use in processes involving keratin hydrolysis.

PMID- 12407460
TI  - Comparative studies on extracellular protease secretion and glucoamylase
      production by free and immobilized Aspergillus niger cultures.
AB  - The effects of cell immobilization on the secretion of extracellular proteases
      and glucoamylase production by Aspergillus niger were investigated under a
      variety of immobilization techniques and culture conditions. Immobilization was
      achieved by means of cell attachment on metal surfaces or spore entrapment and
      subsequent growth on porous Celite beads. Free-suspension cultures were compared
      with immobilized mycelium under culture conditions that included growth in shake
      flasks and an airlift bioreactor. Cell attachment on metal surfaces minimized the
      secretion of proteases while enhancing glucoamylase production by the fungus.
      Growth on Celite beads in shake-flask cultures reduced the specific activity of
      the secreted proteases from 128 to 61 U g(-1), while glucoamylase specific
      activity increased from 205 to 350 U g(-1). The effect was more pronounced in
      bioreactor cultures. A reduction of six orders of magnitude in protease specific
      activities was observed when the fungus grew immobilized on a rolled metal
      screen, which served as the draft tube of an airlift bioreactor.

PMID- 12407461
TI  - Bioconversion of acid- and gamma-ray-treated sweet potato residue to microbial
      protein by mixed cultures.
AB  - Sweet potato residue, a starchy agricultural waste, was used as a substrate to
      produce microbial protein by Fusarium moniliforme and Saccharomyces cerevisiae in
      submerged fermentation. Acid- and gamma-irradiation-pretreated sweet potato
      residue enhanced the biomass yield and protein production when the residue was
      fermented with F. moniliforme and S. cerevisiae. A mixed culture of F.
      moniliforme and S. cerevisiae efficiently and rapidly utilized free sugars; the
      maximal biomass yield (13.96 g/l) and protein production (65.8%) were obtained
      after 3 days fermentation. Lower carbon utilization by the two microbial strains
      occurred in the waste-containing media as compared to control, increasing the
      economic value of the waste usage.

PMID- 12407462
TI  - Effect of nickel deprivation on methanol degradation in a methanogenic granular
      sludge bioreactor.
AB  - The effect of omitting nickel from the influent on methanol conversion in an
      Upflow Anaerobic Sludge Bed (UASB) reactor was investigated. The UASB reactor (30
      degrees C, pH 7) was operated for 261 days at a 12-h hydraulic retention time
      (HRT) and at organic loading rates (OLRs) ranging from 2.6 to 7.8 g COD l
      reactor(-1) day(-1). The nickel content of the sludge decreased by 66% during the
      261-day reactor run because of washout and doubling of the sludge bed volume.
      Nickel deprivation initially had a strong impact on the methanogenic activity of
      the sludge with methanol; e.g., after 89 days of operation, this activity was
      doubled by adding 2 micro M nickel. Upon prolonged UASB reactor operation,
      methanol and VFA effluent concentrations decreased whereas the sludge lost its
      response to nickel addition in activity tests. This suggests that a less nickel
      dependent methanol-converting sludge had developed in the UASB reactor.

PMID- 12407463
TI  - Use of Chlorella vulgaris for CO(2) mitigation in a photobioreactor.
AB  - Carbon dioxide (CO(2)) is a colorless gas that exists at a concentration of
      approximately 330 ppm in the atmosphere and is released in great quantities when
      fossil fuels are burned. The current flux of carbon out of fossil fuels is about
      600 times greater than that into fossil fuels. With increased concerns about
      global warming and greenhouse gas emissions, there have been several approaches
      proposed for managing the levels of CO(2) emitted into the atmosphere. One of the
      most understudied methods for CO(2) mitigation is the use of biological processes
      in engineered systems such as photobioreactors. This research project describes
      the effectiveness of Chlorella vulgaris, used in a photobioreactor with a very
      short gas residence time, in sequestering CO(2) from an elevated CO(2) airstream.
      We evaluated a flow-through photobioreactor's operational parameters, as well as
      the growth characteristics of the C. vulgaris inoculum when exposed to an
      airstream with over 1850 ppm CO(2). When using dry weight, chlorophyll, and
      direct microscopic measurements, it was apparent that the photobioreactor's algal
      inoculum responded well to the elevated CO(2) levels and there was no build-up of
      CO(2) or carbonic acid in the photobioreactor. The photobioreactor, with a gas
      residence time of approximately 2 s, was able to remove up to 74% of the CO(2) in
      the airstream to ambient levels. This corresponded to a 63.9-g/m(3)/h bulk
      removal for the experimental photobioreactor. Consequently, this photobioreactor
      shows that biological processes may have some promise for treating point source
      emissions of CO(2) and deserve further study.

PMID- 12407464
TI  - Optimization of galacto-oligosaccharide production by Bifidobacterium infantis RW
      8120 using response surface methodology.
AB  - Oligosaccharide (OS) production, cell concentration (2 x 10(9) colony-forming
      unit/ml), lactose concentration (25% wt/vol), reaction time (6 h), and
      temperature (50 degrees C) were chosen as the central condition of the central
      composite design (CCD) for optimizing the production process using
      Bifidobacterium infantis RW-8120 in skim milk. Statistical analysis (P<0.01)
      revealed that the most relevant variable concerning OS production and yield was
      the lactose concentration. The coefficient of determination (R(2)) is good for
      the second-order OS production model (0.92) and fairly good for the second-order
      nonlinear OS yield model (0.816). An increase of lactose concentration and
      temperature resulted in a higher OS production. The optimal values for OS
      production appear to be near the area associated with the central points of the
      modeling design except for the lactose concentration, which was 40% (wt/vol) of
      the final volume.

PMID- 12407465
TI  - Effect of starvation length upon microbial activity in a biomass recycle reactor.
AB  - The kinetics of substrate degradation and bacterial growth was determined in a
      microbial community from a biomass recycle reactor that had been deprived of
      substrate feed for 0-32 days. Starvation caused changes in bacterial numbers,
      community composition, and physiological state. Substrate starvation for less
      than 1 day resulted in modest (less than threefold) changes in endogenous
      respiration rate, ATP content, and biomass level. During a starvation period of
      32 days, there were substantial changes in microbial community composition, as
      assessed by denaturing gradient gel electrophoresis (DGGE) fingerprinting of PCR
      amplicons of a portion of the 16S rDNA or by phospholipid fatty acid (PLFA)
      analysis. When the starved communities were stimulated with organic nutrients,
      the growth kinetics was a function of the length of the starvation period. For
      starvation periods of 2-8 days prior to nutrient addition, there was a phase of
      suboptimal exponential growth (S-phase) in which the exponential growth rate was
      about 30% of the ultimate unrestricted growth rate. S-phase lasted for 2-8 h and
      then unrestricted growth occurred at rates of 0.3-0.4 h(-1). At starvation times
      of 12 and 20 days, a lag phase preceded S-phase and the unrestricted growth
      phase.

PMID- 12407466
TI  - Optimization of submerged culture conditions for the production of angiotensin
      converting enzyme inhibitor from Flammulina velutipes.
AB  - The angiotensin-converting enzyme (ACE) inhibitory effect was tested in the
      culture broth from submerged mycelial cultures of 20 basidiomycetes. The ACE
      inhibitory effect of culture broth from Flammulina velutipes strain 414 was the
      highest (52.8%), followed by Lentinus edodes strains 2 (44.4%) and 16 (41.3%).
      Nutritional requirements for the production of ACE inhibitory substance from F.
      velutipes were studied. Sucrose, ammonium acetate, and glutamic acid were chosen
      for the maximum production of ACE inhibitory substance. The optimal medium
      composition was (g/l): sucrose 20, ammonium acetate 5, glutamic acid 2,
      KH(2)PO(4) 3, MgSO(4).7H(2)O 0.8, and yeast extract 0.5. Under optimal culture
      conditions, the ACE inhibitory effect was more than 80%.

PMID- 12407467
TI  - Indirect conductimetric assay of antibacterial activities.
AB  - The applicability of indirect conductimetric assays for evaluation of
      antibacterial activity was examined. The minimal inhibitory concentration (MIC)
      obtained by the indirect method was consistent with that by the direct
      conductimetric assay and the turbidity method. The indirect assay allows use of
      growth media, which cannot be used in the direct conductimetric assay, making it
      possible to evaluate the antibacterial activity of insoluble or slightly soluble
      materials with high turbidity, such as antibacterial ceramic powders.

PMID- 12407469
TI  - The relationship between mean birth weight and poverty using the Townsend
      deprivation score and the Super Profile classification system.
AB  - Super Profiles have been used as alternative methods of characterising the
      deprivation of an area. Some reports suggest that Super Profiles are as accurate
      as established indices such as the Townsend score (TS). This was a test of this
      assertion.A total of 138 696 live born singleton births to Birmingham residents
      born between 1986 and 1996 (inclusive) were allocated to enumeration districts
      (EDs) by linkage from the postcode. We allocated the TS of the individual's ED.
      We allocated a Lifestyle and Target Market (TM) from Super Profiles by linkage to
      the ED. We examined the gradient between mean birth weight and the 10 Super
      Profile Lifestyles and compared this to the gradient between 10 Townsend groups
      and mean birth weight. We repeated this approach using the 40 TMs and 40 Townsend
      groups. We used both the median income and a census-derived deprivation measure
      to rank Lifestyles and TMs. The gradient between mean birth weight and area
      deprivation was linear for Townsend groups but not linear using either Lifestyles
      or TMs whichever method of ranking Lifestyles or TMs was used. Where Lifestyles
      or TMs were out of line with their neighbours, the TS of that group mostly
      explained this. As Super Profiles are generated using nationally representative
      data, applying the affluence ranking to small areas can lead to inaccuracies, as
      shown in this data. We conclude that Super Profiles are probably unsuitable as
      measures of deprivation of small areas.

PMID- 12407470
TI  - Adjusted mortality rates: a tool for creating more meaningful league tables for
      stillbirth and infant mortality rates.
AB  - A number of problems associated with league tables of performance indicators have
      been discussed in the literature. This paper attempts to address these problems
      for stillbirth and infant mortality rates in order to produce meaningful and
      useful information for the government, general public and health professionals.
      Composite stillbirth and infant mortality rates, low birth-weight and very low
      birth-weight rates were determined for the 100 English Health Authorities for
      1996-1997. Townsend deprivation scores for these districts were also obtained.
      The mortality rates were adjusted by multiple regression for very low birth
      weight and Townsend score separately and together. Confidence intervals were
      calculated for the dual-adjusted rates. Almost 60% of the variability in
      mortality rates were explained by Townsend score and very low birth-weight rates
      together. Adjusted league tables showed how the individual and combined
      predictors affect the individual mortality rates for each Health Authority. There
      was considerable overlap in the confidence intervals for the adjusted rates
      although there were a few Health Authorities whose mortality rates were clearly
      below most others. We conclude that fairer and more useful information is
      provided by geographically based league tables which give both crude rates and
      rates adjusted for single and multiple predictor variables. The inclusion of
      confidence intervals aids interpretation of annual random variations and
      knowledge of differences in the effects of the individual predictors enables
      better resource targeting.

PMID- 12407471
TI  - Attitudes towards euthanasia among physicians, nurses and the general public in
      Finland.
AB  - The object of this study was to investigate the attitudes of physicians, nurses
      and the general public to physician-assisted suicide (PAS), active voluntary
      euthanasia (AVE) and passive euthanasia (PE) in Finland. Respondents received a
      postal questionnaire to evaluate the acceptability of euthanasia in five
      scenarios, which were imaginary patient cases. Age, severity of pain and
      prognosis of the disease were presented as background factors in these scenarios.
      This work was carried out in Finland in 1998. The respondents include a random
      selection of 814 physicians (506 responded, 62%), 800 nurses (582 responded, 68%)
      and 1000 representatives of the general public (587 responded, 59%).Thirty-four
      percent of the physicians, 46% of the nurses and 50% of the general public agreed
      that euthanasia would be acceptable in some situations. Of the scenarios, PE was
      most often considered acceptable in cases of severe dementia (physicians 88%,
      nurses 79% and general public 64%). In the same scenario, 8% of physicians, 23%
      of nurses and 48% of general public accepted AVE. In the scenario of an incurable
      cancer, 20% of the physicians, 34% of the nurses and 42% of the general public
      accepted PAS. All forms of euthanasia were generally more acceptable in older,
      than in younger, scenario patients. This paper conclude that PE was largely
      accepted among Finnish medical professionals and the general public. Only a
      minority favored AVE and PAS.

PMID- 12407472
TI  - A longitudinal study through adolescence to adulthood: the Young Hearts Project,
      Northern Ireland.
AB  - The Young Hearts (YH) Project is an ongoing study of biological and behavioural
      risk factors for cardiovascular disease in a representative sample of young
      people from Northern Ireland, a region of high coronary mortality. This article
      describes the cross-sectional clinical, dietary and lifestyle data obtained from
      individuals (aged 20-25 y) who participated in phase 3 of the project (YH3). A
      total of 489 individuals (251 males, 238 females) participated in YH3 (48.2%
      response rate). Some 31.1% of participants at YH3 were overweight (BMI >25
      kg/m(2)) with 4.4% of males and 8.0% of females were obese (BMI >30 kg/m(2)).
      More females than males had a very poor fitness (55.0 vs 22.1%, chi-squared
      51.70, d.f. 1, P<0.001) and did not participate in any sporting or exercise
      activity (38.4 vs 24.9%, chi-squared 10.26, d.f. 1, P=0.001). Over 20% of
      participants had a raised total serum cholesterol (>5.2 mmol/l). More females had
      a raised serum LDL-cholesterol (>3.0 mmol/l) than males (44.6 vs 34.6%, chi
      squared 4.39, d.f. 1, P<0.05). Over 46% of participants reported energy intakes
      from fat above recommended levels, and 68.5% of participants had saturated fat
      intakes above those recommended (Dietary reference values for food energy and
      nutrients for the United Kingdom. HMSO: London, 1991). Just over half of the
      study population reported alcohol intakes in excess of recommended sensible
      limits set by the Royal College of Physicians (A great and growing evil: the
      medical consequences of alcohol abuse. Tavistock: London, 1987), with 36.7% of
      males and 13.4% of females reporting intakes over twice these recommended limits.
      A total of 37% of the study population smoked. During young adulthood,
      individuals may be less amenable to attend a health-related study and recruitment
      of participants to the current phase of the study proved a major problem.
      However, these data constitute a unique developmental record from adolescence to
      young adulthood in a cohort from Northern Ireland and provide additional
      information on the impact of early life, childhood and young adulthood on the
      development of risk for chronic disease.

PMID- 12407473
TI  - Sexual differences in smoking behaviour and dental caries experience in young
      adults.
AB  - Smokers have been reported to exhibit a low awareness of their health. However,
      oral health awareness in smokers has not been fully studied. Having adequate oral
      care and high awareness of oral health from youth is necessary to prevent the
      deterioration of oral health in middle and old age. The aim of this study was to
      investigate the oral health status and oral health behaviour in young smokers. A
      survey composed of a questionnaire and an oral examination was administrated to
      adults aged 20-29 y who consulted dentists. The relationship between smoking
      behaviour and oral health status and oral health behaviour in subjects was
      analysed. In women, though no significant relationship between smoking behaviour
      and the number of decayed, missing, and filled teeth was seen, current smokers
      had significantly more decayed teeth, missing teeth and fewer filled teeth than
      ex-smokers and non-smokers. Current smokers tended to practice less oral health
      behaviour than non-smokers. In men, there was no significant relationship between
      smoking behaviour and each oral health status item. These findings suggested that
      the smoking group had lower oral health awareness than the non-smoking group in
      women.

PMID- 12407474
TI  - Smoking behavior, initiating and cessation factors among Japanese nurses: a
      cohort study.
AB  - The prevalence of smoking among Japanese nurses, specially in their twenties, is
      higher than that among the general female population. To examine smoking
      behavior, smoking initiating and cessation factors, we conducted a cohort study
      through questionnaire survey, targeting nurses (n=1572) working at 11 hospitals
      located in Tokyo metropolitan area. The first survey was conducted using a
      confidential questionnaire on smoking, followed by a second survey conducted in
      the same manner on the same subjects two years later. As to smoking status after
      two years, 8% (95%CI=1.5%) started smoking and 6% (95%CI=1.4%) quitted resulting
      in a 2% increase in the prevalence of current smoking. The average nicotine
      dependence for nurses who were smokers in the two surveys rose from 3.9 to 4.3
      (P<0.05). Smoking behavior of mother, friends, or superiors at work had a
      significant influence on smoking behavior of nurses. As to smoking cessation
      factors, the idea that women and medical workers should not smoke, and living
      with family each had a significant influence. Considering the fact that 6% of
      nurses in this study succeeded in quitting smoking within two years, it is
      required that anti-smoking education be conducted at medical institutions to
      decrease the prevalence of current smoking among the nurses in Japan.

PMID- 12407475
TI  - Exploring the effects of population mobility on cervical screening coverage.
AB  - London has the lowest cervical screening coverage in England and in 1998/1999
      accounted for 11 of the 13 health authorities that fell below the national 80%
      coverage target. There are several factors which may contribute to the difference
      in coverage between the capital and the rest of the country. London's population
      is much more diverse, there is greater deprivation and there are well-established
      structural differences in primary care. London has high levels of population
      mobility which will also affect the ability of GPs to achieve high population
      coverage. This paper explores the possible size of the effect that population
      mobility is likely to have on coverage of the cervical screening programme in
      London. The analysis estimates the size of 'missing populations' that may not
      receive an invitation for a smear test, or artificially inflate the list size of
      registered patients. A simple model suggests that in some London Health
      Authorities up to 14% of residents, and 11% of patients on GP lists, may miss out
      on invitations for screening as a result of population mobility. Moreover the
      large differences between list and resident populations in some areas mean that
      the current government target of 80% coverage of the registered population will
      be largely unattainable for many London Health Authorities and Primary Care
      Trusts. Moving towards a resident-based system, whereby the numbers screened are
      related to the number of residents, avoids some of the problems associated with
      list inflation and gives a fairer picture of coverage of the eligible population.

PMID- 12407476
TI  - Did the London Initiative Zone investment programme affect general practice
      structure and performance in East London? A time series analysis of cervical
      screening coverage and asthma prescribing.
AB  - A programme of incentives was set up in the London Initiative Zones to improve
      primary care in inner London based on the findings of the Tomlinson Enquiry in
      1992. This descriptive study is a 4-y time series analysis of changes in general
      practice structure in East London as the result of London Initiative Zone
      investment, and an exploration of the possible effect of investment on practice
      performance. We used routinely available administrative data for the whole
      analysis. General practice characteristics and two selected performance
      indicators: the asthma prophylaxis to bronchodilator ratio and cervical cytology
      screening rate, for all practices in the East London and the City Health
      Authority for 4 y, 1993-1996, were used. Both reflect practice efficiency, but
      relate to different aspects of practice performance. The prescribing indicator is
      more indicative of the quality of clinical practise, whereas cervical screening
      coverage relates more to the characteristics of the practice population and to
      practice organisation. Repeated measures analyses were used to identify trends
      and to explore the relationship between changes in practice characteristics and
      performance. Graphical methods were used to compare East London trends with the
      rest of England. There were significant improvements in practice structure as the
      consequence of London Initiative Zone investment. There was a positive
      association with improvements in practice performance, but East London still
      lagged some way behind national patterns. The findings suggest that while
      improvements in asthma prescribing follow the national trend, practices have
      difficulty in achieving and sustaining the 80% target for cervical cytology
      screening, and that an overall population coverage of 80% may be in
      doubt.Increased investment in practice staffing may be influential in improving
      some aspects of performance. However, in common with other inner cities, a
      greater effort and more innovative strategies may be needed to achieve a standard
      of performance equal to the best.

PMID- 12407477
TI  - Appropriate and inappropriate use of day-hospital care in Italy.
AB  - This study describes the extent of inappropriate day-hospital assistance and the
      effect of different variables on such inappropriateness. A random sample of
      patients admitted to pediatric and adult day-hospital care during the period
      Janurary--December 2000 in three hospitals located in the area of Catanzaro,
      Italy were reviewed. Assessment of appropriateness was made for the first access
      and for each of the following accesses in day-hospital. A total of 826 patients
      were reviewed. Overall, 23.8% of the first access in day-hospital care was judged
      to be inappropriate and 49.7% of the sample showed at least one inappropriate
      access for day-hospital care with a mean of 1.4 inappropriate accesses. Multiple
      logistic regression analysis indicated that the inappropriateness of the first
      access significantly increased with relation to lower distance from hospital to
      patient's home; admission to general medicine wards; first access from Monday to
      Thursday; lower number of patient's diagnostic procedures and medical
      examinations in the first access. Stepwise multiple linear regression analysis
      showed that the number of inappropriate accesses was significantly higher for
      general medicine and surgery and trauma/orthopedics wards; in patients who the
      first access was inappropriate; in those who received a lower number of
      diagnostic procedures and medical examinations; in patients who showed a higher
      length of care in day-hospital. The findings suggest the need for standardized
      diagnostic and therapeutic guidelines for day-hospital care.

PMID- 12407478
TI  - Improvement in malaria services in an urban setting: role of staff motivation.
AB  - Urban health centres and the private clinics (PCs) providing malaria services in
      an urban setting were compared on seven utilization-determining factors to assess
      why people preferred one over the other. On the other hand, motivation level of
      the technical staff of the corporation in the malaria services was studied to
      find out the extent to which the motivation level of the staff was responsible
      for the observed mean scores of the factors studied. It was found that PCs fared
      better on all of them. However, the two differed mostly on wait-in period at the
      outlet, distance from residence, ambience of the outlet, and getting relief. The
      study further showed that for the doctors and the primary health workers, the
      opportunity of influencing people was the strongest motivation to work in the
      corporation and for the subsanitary inspectors, it was affiliation. Based on
      this, a model is suggested to introduce changes based on motivation mix of the
      malaria staff.

PMID- 12407479
TI  - Sero-epidemiology of tetanus antibody among the children in eastern Turkey.
AB  - The aim of the study was to determine immunity status of children to tetanus, and
      to assess the Expanded Programme on Immunization. A total of 840 children aged 0
      71 months were randomly selected from three provinces in eastern Turkey by using
      cluster-sampling method. Blood samples were collected and enzyme linked
      immunoassay test was used to measure antibody levels. The percentage of the
      children who had antibody titres above the minimum protective level (0.01 IU/ml)
      was 80.0%. Only 10.6% of the children had antibody titres above the fully
      protective level (0.1 IU/ml). Antibody levels of children in rural areas were
      higher than those of children in urban areas. In children whose fathers were
      literate the levels were also higher than the others. Antibody level increased
      with the number of vaccine applications. Antibody levels were not consistent with
      immunization history obtained from parents. In this regard, our suggestion is
      that wound care management should not depend on immunization history obtained
      from parents if the vaccination programs are not effectively implemented. Most of
      the children in this study had antibody titres below the fully protective level.

PMID- 12407483
TI  - Liver biopsy in HIV-infected patients with chronic hepatitis C: pros and cons.
AB  - Liver biopsy was a common procedure in patients with chronic hepatitis C who
      planned to begin treatment with interferon. The greater response rates seen with
      the use of dual combination therapy with interferon plus ribavirin and the almost
      universal recognition of fibrosis and faster progression to cirrhosis seen in HIV
      HCV coinfected patients does not justify the request of a liver biopsy before
      prescribing anti-HCV therapy in this population, outside clinical trials.

PMID- 12407484
TI  - Impact of antiretroviral regimen switches on adherence.
AB  - PURPOSE: An understanding of the situations in which adherence lapses occur is
      critical to the design of effective interventions to enhance adherence. We
      investigated whether a switch in antiretroviral medications affected adherence by
      examining a prospective observational cohort of 128 patients who began a new
      antiretroviral regimen. METHOD: Adherence was measured using electronic devices,
      pill counts, and self-reports, which were combined into a composite adherence
      measure and expressed as the proportion of prescribed medication taken. RESULTS:
      During 1,056 person-months of follow-up, 129 medication regimen changes occurred
      among 84 patients (66% of participants). Among the 89 analyzable switches
      (representing 66 patients), the most common reasons for switch included pill to
      liquid ritonavir (n = 26), gastrointestinal intolerance (n = 11), virologic
      failure (n = 8), and peripheral neuropathy (n = 7). Overall, mean adherence prior
      to regimen switch exceeded mean adherence after regimen switch (0.75 vs. 0.70; p
      =.035). Among subgroups of switches, adherence decreased significantly after
      switching from pill to liquid ritonavir (0.83 vs. 0.68; p <.001). When this group
      was excluded, there was no change in adherence after switches (0.72 vs. 0.71; p
      =.74). CONCLUSION: Antiretroviral regimen changes are not associated with
      adherence improvement and may be associated with declining adherence when a new
      regimen is unpalatable. Antiretroviral regimen changes should trigger
      reassessment of adherence and, when appropriate, adherence intervention.

PMID- 12407485
TI  - Lamivudine 300 mg QD versus continued lamivudine 150 mg BID with stavudine and a
      protease inhibitor in suppressed patients.
AB  - PURPOSE: To compare the efficacy (sustained virologic suppression) and
      safety/tolerability of a switch to lamivudine 300 mg once daily (QD) versus
      continued lamivudine 150 mg twice daily (BID) in virologically suppressed
      patients (HIV-1 RNA <400 copies/mL for > or =3 months) on stable (> or =6 months)
      therapy with lamivudine 150 mg BID plus stavudine and either indinavir or
      nelfinavir. METHOD: Eighty-nine suppressed patients > or =18 years old with CD4
      counts >50 cells/mm(3) were enrolled in this phase II, open-label, multicenter,
      randomized, stratified (by pretrial protease inhibitor [PI]), parallel-group
      clinical trial. Eighty-one patients received either lamivudine 300 mg QD (n = 39)
      or 150 mg BID (n = 42) with their pretrial stavudine/PI regimens for 24 weeks.
      RESULTS: A high rate of virologic suppression was sustained with both regimens
      throughout the trial. At week 24, intent-to-treat:exposed (missing = failure)
      analyses showed no statistically significant differences in the percentage of
      patients with HIV-1 RNA <400 copies/mL (95% [QD] vs. 90% [BID]) or <50 copies/mL
      (82% [QD] vs. 81% [BID]) or in the median change from baseline in CD4 counts (+42
      cells/mm(3) [QD] vs. +22 cells/mm(3) [BID]). Both regimens were well tolerated.
      No patient experienced virologic failure, clinical disease progression, or a drug
      related serious adverse event during the trial. Self-reported medication
      adherence was high in both groups. CONCLUSION: Patients who experience virologic
      suppression with a regimen of lamivudine 150 mg BID in combination with
      stavudine/PI can maintain that suppression by continuing their regimen or
      switching to lamivudine 300 mg QD and continuing the other components. Adverse
      event profiles were comparable among treatment regimens, and no new safety
      concerns were raised.

PMID- 12407486
TI  - Simpler regimens may enhance adherence to antiretrovirals in HIV-infected
      patients.
AB  - BACKGROUND: Optimal adherence to highly active antiretroviral therapy (HAART) is
      necessary to achieve the best and the most durable benefit. Many factors may
      influence compliance to such demanding regimens, and their identification may
      help in the design of strategies to enhance adherence. PURPOSE: To assess the
      factors associated with lower compliance to therapy, the causes of nonadherence,
      and the relation of nonadherence with virologic response. METHOD: We performed an
      observational, cross-sectional study on HIV-infected patients (pts) receiving
      unrestricted HAART and attending our clinic from January to May 2001. Pts
      completed a self-administered (ACTG modified) questionnaire on adherence to their
      therapy. Virologic response was defined as undetectable viral load at the time of
      interview. A regression model was used to determine predictors of adherence.
      RESULTS: 597 out of 623 pts (95.8%) completed the survey. Mean age was 38.2 years
      (range, 18-79). A total of 448 pts (75.0%) were men, 323 (54.1%) were intravenous
      drug users, 196 (32.8%) were heterosexuals, 76 (12.7%) were men who have sex with
      men. Mean time on therapy was 49.3 months (range, 4-145). All pts were on stable
      therapy (> 4 months), 173 pts (29%) were on their first HAART regimen, 309 pts
      (51.7%) were on NNRTI-based regimen, and 288 pts (48.2%) were on a PI-containing
      treatment. A total of 304 pts (50.9%) were categorized as adherent (p = .024).
      Multiple logistic regression showed that older age (p = .002), lower number of
      pills (p = .024), fewer daily doses (p = .002), and shorter time on therapy (p <
      .001) were factors associated with adherent behavior. Forgetfulness (59.3%),
      being away from home (50.2%), and problems with schedule (37.6%) were the most
      frequent causes of nonadherence. Adherent pts were more likely to have
      undetectable viral load than nonadherent pts (76.5% vs. 55.3%; p <.0001).
      CONCLUSION: Younger age, higher number of pills, higher frequency of doses, and
      longer time on therapy were predictors of nonadherent behavior. Optimal adherence
      correlated with the best virologic response. Simpler regimens with a lower number
      of pills and doses may help patients' compliance to therapy.

PMID- 12407487
TI  - Efficacy of alcohol-based and alcohol-free melaleuca oral solution for the
      treatment of fluconazole-refractory oropharyngeal candidiasis in patients with
      AIDS.
AB  - PURPOSE: To evaluate the efficacy of alcohol-based and alcohol-free melaleuca
      oral solution in patients with AIDS and fluconazole-refractory oropharyngeal
      candidiasis. METHOD: We performed a prospective, single-center, open-label study
      in a university-based inner city HIV/AIDS clinic. The study included 27 patients
      with AIDS and oral candidiasis clinically refractory to fluconazole. Patients
      were randomized 1:1 to receive either alcohol-based or alcohol-free melaleuca
      oral solution four times daily for 2-4 weeks. Thirteen patients were enrolled
      into cohort 1, and 14 patients were enrolled into cohort 2. The main outcome
      measure was resolution of clinical lesions of oral candidiasis. Evaluations were
      performed at 2 and 4 weeks for clinical signs and symptoms of oral candidiasis
      and quantitative yeast cultures. RESULTS: All C. albicans isolates showed some
      degree of in vitro resistance to fluconazole. Overall, using a modified intent-to
      treat analysis, 60% of patients demonstrated a clinical response to the melaleuca
      oral solution (7 patients cured and 8 patients clinically improved) at the 4-week
      evaluation. CONCLUSION: Both formulations of the melaleuca oral solution appear
      to be effective alternative regimens for patients with AIDS suffering from
      oropharyngeal candidiasis refractory to fluconazole.

PMID- 12407488
TI  - Subcutaneous injection survey: psychometric evaluation of a treatment
      satisfaction instrument associated with a novel HIV medication.
AB  - PURPOSE: The 20-item Subcutaneous Injection Survey (SIS) was developed to assess
      patients' experience with subcutaneous self-injection of an innovative anti-HIV
      fusion inhibitor (T-20). It measures ease of use and impact of treatment on daily
      life. This study presents the results of a psychometric evaluation of the SIS.
      METHOD: The SIS and MOS-HIV data (N = 547) from two multinational, phase III
      clinical trials of optimized background therapy (OBT) vs. OBT + T-20 were
      utilized for this evaluation. Item performance and internal consistency
      reliability were assessed. Exploratory factor analysis was used to identify
      subscales. Pearson correlations were used to examine the relationship between the
      SIS and the MOS-HIV scores. RESULTS: Patients were predominately white males. SIS
      items had low rates of missing data (0.9%-5.5%) and with two exceptions were not
      redundant, as indicated by generally moderate item-to-item correlations. Three
      factors were identified: daily functioning, ease of injections, and activities of
      daily living. The SIS also includes three individually scored items on overall
      injection interference with daily activities, effect of injections on daily
      activities, and satisfaction with personal appearance. Cronbach's alphas ranged
      from 0.71 to 0.87. Correlations between SIS and MOS-HIV subscales were low to
      moderate. CONCLUSION: The SIS is a reliable instrument for measuring patients'
      assessment of self-injection in HIV clinical trials. Patients' experiences with
      self-injection are not strongly associated with health-related quality of life.

PMID- 12407489
TI  - Infection with retroviruses other than HIV-1 in Spain: a retrospective analysis
      for HIV-2, HTLV-I, and/or HTLV-II.
AB  - HIV-2, human T-cell lymphotropic virus (HTLV)-I, and HTLV-II infections are
      currently circulating in Spain with no evidence of an increase in the number of
      reported cases over time. Up to June 2002, a total of 106, 53, and 460 cases of
      HIV-2, HTLV-I, and HTLV-II infection, respectively, have been identified in
      Spain. Most HIV-2-infected and HTLV-I-infected individuals are immigrants who
      come from endemic areas or are Spaniards with a past history of travel to or
      sexual contacts with persons originating in those areas. In contrast, HTLV-II
      infection is mainly limited to native intravenous drug users who are frequently
      coinfected with HIV-1.

PMID- 12407490
TI  - Resistance to antiretroviral agents in individuals with HIV-1 non-B subtypes.
AB  - Naturally occurring polymorphisms at positions involved in resistance to
      antiretroviral agents are frequently seen in HIV-1 non-B subtypes. Although they
      do not seem to affect significantly the susceptibility to antiretroviral drugs in
      vitro, they may facilitate the selection of different pathways and/or a more
      rapid emergence of drug resistance and treatment failure under not fully
      suppressive treatment regimens.

PMID- 12407491
TI  - The evolving role of antiretroviral drug resistance testing in HIV-infected
      individuals.
AB  - Scientific advances have made HIV resistance testing routinely available to
      clinicians and other HIV caregivers. However, interpretation of HIV resistance
      results is complicated by the lack of knowledge of the clinical consequences of
      specific genotypic and phenotypic results for most antiretroviral agents.
      Limitations of viral genotype and phenotype HIV resistance testing include
      factors such as lack of uniform quality assurance, turn around time, cost, and
      insensitivity to those mutant strains present in less than 20% to 30% of the
      viral population. Since there are currently no multicenter prospective data that
      compare and support the use of one type of resistance testing over another,
      clinicians who are caring for HIV-infected individuals should become familiar
      with the pros and cons of the available assays. Clinicians will need to watch for
      new developments in HIV resistance testing that are on the horizon and will
      become available in years to come.

PMID- 12407492
TI  - Comment to the editorial: Liver biopsy in HIV-infected patients with chronic
      hepatitis C: pros and cons, by Vincent Soriano and Javier Garcia-Samaniego.

PMID- 12407493
TI  - Selected topics from the Centers for Disease Control and Prevention Sexually
      Transmitted Diseases Treatment Guidelines 2002.

PMID- 12407494
TI  - [The relationship of adverse childhood experiences to adult health: Turning gold
      into lead].
AB  - The Adverse Childhood Experiences (ACE) Study is a long term, in-depth analysis
      of over 17,000 adult Americans, matching their current health status against
      adverse childhood experiences that occurred on average a half-century earlier. We
      found that such adverse childhood experiences are quite common although typically
      concealed and unrecognized; that they still have a profound effect a half century
      later, although now transmutated from psychosocial experience into organic
      disease; and that they are the main determinant of the health and social well
      being of the nation. Our findings are of direct importance to the everyday
      practice of medicine and psychiatry because they indicate that much of what is
      recognized as common in adult medicine is the result of what is not recognized in
      childhood. The ACE Study challenges as superficial the current conceptions of
      depression and addiction, showing them to have a very strong dose-response
      relationship to antecedent life experiences.

PMID- 12407495
TI  - [The prevalence of childhood sexual abuse, physical abuse and emotional neglect
      in Europe].
AB  - This paper concentrates on the prevalence of childhood sexual abuse, physical
      abuse and emotional neglect in Europe. It includes studies published in
      international journals or in easily accessible books. Data bases, specifically
      MEDLINE, PubMed, Psyndex and PsycInfo were used to find papers on this topic.
      Taking a broad view there is an incidence of sexual abuse experiences of 6-36 %
      in girls under the age of 16 years and of 1-15 % in boys under the age of 16. The
      incidence of physical abuse ranges from 5 to 50 % in Europe. There is a need for
      studies dealing with the prevalence of emotional neglect or psychological abuse.
      These figures are in line with those found in North America. However, due to the
      large differences in definitions and data gathering techniques, more precise
      conclusions are currently not possible.

PMID- 12407496
TI  - [The long-term influence of socio-economic disadvantage on the psychosocial
      adjustment of women].
AB  - On the basis of a prospective longitudinal study of over 15,000 women this paper
      examines the long-term influences of socio-economic disadvantages on psychosocial
      adjustment. The study draws on data from two British cohort studies carried out
      12 years apart from each other. A contextual developmental perspective is adopted
      to analyse the pathways linking childhood experiences to adult functioning in a
      changing socio-historical context. The study suggests a causal chain process
      linking the early and persisting experience of socio-economic adversity to
      behavioural maladjustment of girls during childhood and adolescence. Socio
      economic adversity and behavioural maladjustment in adolescence, in turn, predict
      the development of depressive symptoms in adulthood. The influence of socio
      economic adversity on individual development, however, also depends on the wider
      socio-historical context in which development takes place. It is concluded that
      for a better understanding of psychosocial adjustment across the lifespan we have
      to consider the interactions of a changing individual in a changing context.

PMID- 12407497
TI  - [Maladaptative parenting and the association between parental and offspring
      psychiatric disorders].
AB  - A longitudinal study was conducted to investigate the role of maladaptive
      parental behavior and the association between parent and offspring psychiatric
      disorders. Psychosocial and psychiatric interviews were carried out in a
      representative community sample of 593 biological parents and their offspring
      from two counties in the state of New York in 1975, 1983, 1985-86, and 1991-93.
      In 1975, the mean age of offspring was 6 years. Maladaptive parental behavior was
      assessed in 1975, 1983, and 1985-86. Parent and offspring psychiatric symptoms
      were assessed in 1983, 1985-86, and 1991-93. Maladaptive parental behavior
      substantially mediated a significant association between parental and offspring
      psychiatric symptoms. Parents with psychiatric disorders had higher levels of
      maladaptive behavior in the household than did parents without psychiatric
      disorders. Maladaptive parental behavior, in turn, was associated with increased
      offspring risk for psychiatric disorders during adolescence and early adulthood.
      Most of the youths that experienced high levels of maladaptive parental behavior
      during childhood had psychiatric disorders during adolescence or early adulthood,
      independent of whether or not their parents had psychiatric disorders. In
      contrast, the offspring of parents with psychiatric disorders were not at
      increased risk for psychiatric disorders unless there was a history of
      maladaptive parental behavior. Maladaptive parental behavior is associated with
      increased risk for the development of psychiatric disorders among the offspring
      of parents with and without psychiatric disorders. Maladaptive parental behavior
      appears to be an important mediator of the association between parental and
      offspring psychiatric symptoms.

PMID- 12407498
TI  - [Long-term effects of adverse childhood experiences - Actual evidence and needs
      for research1/2].
AB  - There is evidence from some prospective and several retrospective studies that
      early biological and psychosocial stress in childhood is associated with long
      term vulnerability to various mental and physical diseases. In the last few years
      research findings have accumulated on those emotional, behavioural and
      psychobiological factors which are responsible for the mediation of these
      lifelong consequences. They are the cause of an increased risk of somatization
      and other mental disorders. Particularly anxiety, depression and personality
      disorders often result in high-risk behaviour that itself is associated with
      physical disease (cardiovascular disorders, stroke, viral hepatitis, type 2
      diabetes, chronic lung diseases) as well as with aggressive behaviour. A survey
      on the current knowledge of how these various factors interact is presented and a
      bio-psychopathological model of vulnerability is educed. Implications for future
      research are outlined and contrasted to actual political trends in Germany.

PMID- 12407500
TI  - Laparoscopic fundoplication and gastrostomy.
AB  - Minimally invasive surgical approaches to various pediatric surgical disease
      processes are becoming the standard of care. Laparoscopic Nissen fundoplication
      is transitioning toward the preferred method for the surgical correction of
      gastroesophageal reflux (GER) disease in infants and children that do not respond
      to medical management or have complications from their GER. This approach offers
      a shorter hospitalization, reduced discomfort, and cosmetic advantages when
      compared with the open operation. This report discusses the pathophysiology of
      GER, its clinical manifestations, and the diagnostic evaluation for this
      disorder. Also, the laparoscopic Nissen fundoplication technique currently
      utilized at Children's Mercy Hospital is described.

PMID- 12407501
TI  - Laparoscopic-assisted pull-through for Hirschsprung's disease.
AB  - There appears to be a trend in the management of Hirschsprung's disease toward a
      one-stage surgical correction in the newborn period. After the development of the
      one-stage laparoscopic-assisted endorectal pull-through in 1995, the minimally
      invasive approaches have come to dominate the surgical management of this
      disease. The laparoscopic-assisted pull-through is ideally suited for those
      patients with aganglionosis confined to the rectum, sigmoid, or proximal left
      colon. At the time of the operation, a laparoscopic biopsy is recommended to
      identify, with certainty, the site of the transition zone before performing the
      colonic mobilization. Advantages of this approach include reduced discomfort, the
      early initiation of defecation through a normally positioned ganglionic colon and
      rectum, and reduced postoperative hospitalization.

PMID- 12407502
TI  - Laparoscopic segmental intestinal resection.
AB  - There are numerous disease processes in the pediatric population that require
      segmental intestinal resection with primary anastomosis. These include intestinal
      strictures from necrotizing enterocolitis in neonates, resection of congenital
      lesions such as a Meckel's diverticulum or intestinal webs, and strictures from
      inflammatory bowel disease. Whereas the treatment of these lesions previously
      required a major laparotomy, they now can be approached using a minimally
      invasive surgical (MIS) approach. Techniques from laparoscopic intestinal
      mobilization with extracorporeal resection and anastomosis to complete
      intracorporeal resection and anastomosis have been successfully developed for
      pediatric patients. The benefits are similar to those achieved from other
      laparoscopic procedures and include decreased postoperative pain and morbidity,
      reduced postoperative hospitalization and faster return to normal activity. Early
      experience suggests that the minimally invasive approach is acceptable and,
      perhaps, favorable in the treatment of segmental intestinal disease in infants
      and children.

PMID- 12407503
TI  - Laparoscopic repair of high imperforate anus.
AB  - Numerous laparoscopic operations have replaced the traditional open procedure in
      both adults and children. These new procedures have allowed access to body
      cavities without significantly traumatizing intervening tissue. The
      laparoscopically assisted anorectal pull-through (LAARP) for high anorectal
      malformations (ARM) uses fundamental concepts learned from decades of high ARM
      repair and incorporates modern technologic advancements in surgical
      instrumentation and techniques. This laparoscopic approach offers good
      visualization of an infant's deep pelvis with a reconstruction technique that
      minimizes trauma to important surrounding structures. The laparoscopic repair can
      be completed in one stage, 2 stages, or 3 stages. Currently, either the 2-stage
      or 3-stage operation is recommended. With the 3-stage approach, a temporary
      colostomy is created initially followed by LAARP in several weeks to months. The
      colostomy then is closed several months later.

PMID- 12407504
TI  - Laparoscopic splenectomy.
AB  - The laparoscopic technique for splenectomy has become the preferred method for
      splenectomy at many institutions over the last 10 years. The advantages of
      laparoscopic splenectomy include a shortened postoperative hospitalization,
      improved cosmesis, and less analgesic requirements. It is associated with longer
      operating times, a steep learning curve, and may be difficult in cases of
      splenomegaly. A careful search should be made for accessory spleens, and capsular
      disruption must be avoided. New techniques and smaller instruments have
      facilitated recent advances in the technical aspects of laparoscopic splenectomy.

PMID- 12407505
TI  - Laparoscopic-assisted total colectomy with pouch reconstruction.
AB  - Whether in adults or children, benign diseases of the colon are ideally suited
      for laparoscopic-assisted resection. In children, the most frequent diseases
      leading to colectomy and pull-through include Hirschsprung's disease, ulcerative
      colitis, and familial polyposis. Laparoscopic proctocolectomy with J-pouch
      reconstruction is an ideal approach for children and adolescents who are
      generally stable but suffer from unremitting symptoms of ulcerative colitis. An
      early experience with this technique at the Children's Hospital in Alabama is
      described for children with ulcerative colitis.

PMID- 12407506
TI  - Laparoscopic adrenalectomy and esophagomyotomy.
AB  - Recent improvements in laparoscopic equipment, technique, and skills have
      contributed to advancement of the laparoscopic approach to even relatively rare
      pediatric surgical diseases. Two invasive operations that now may be approached
      laparoscopically are adrenalectomy and esophagomyotomy. Both techniques,
      initially described in the early 1990s, are particularly well suited for the
      laparoscopic approach and have become accepted as the preferred technique among
      general surgeons. Despite infrequent indications for either of these operations
      in children, pediatric surgeons experienced in minimally invasive techniques may
      apply the laparoscopic approach in a safe and effective manner. Furthermore,
      regarding achalasia in the pediatric population specifically, the offering of a
      less-invasive surgical approach may contribute toward more primary definitive
      surgical management being offered initially rather than after prolonged
      supportive medical care. The goal of this article is to familiarize the reader
      with the current laparoscopic approach to benign pediatric adrenal conditions and
      esophageal motility disorders in children.

PMID- 12407507
TI  - Systemic chemotherapy for the treatment of metastatic melanoma.
AB  - The role of systemic chemotherapy in the treatment of patients with metastatic
      melanoma remains of questionable benefit. Despite encouraging phase II data from
      multiple institutions that suggested an improved overall response rate for
      patients treated with the Dartmouth regimen, recently completed phase III trials
      have failed to demonstrate a significant benefit in survival. Of concern is the
      fact that there have been relatively few new chemotherapeutic agents in the past
      several years that have demonstrated any activity in this disease. More recently
      there has been a shift away from combination chemotherapy to biochemotherapy.
      However, this approach has yet to be clearly defined as superior. The basis for
      optimism in the future in this field resides in the realm of molecular oncology.
      As mechanisms of resistance are identified, new molecules such as antisense
      oligonucleotides may provide the basis for increasing the sensitivity of melanoma
      to chemotherapeutic and/or immunotherapeutic treatments.

PMID- 12407509
TI  - Biochemotherapy of melanoma.
AB  - Despite the evaluation of many different chemotherapy and immunotherapy drugs,
      the median survival in metastatic melanoma remains in the range of 6 to 9 months.
      Combination chemotherapy or combination immunotherapy has not produced a
      significant advantage over single-agent therapy but is associated with greater
      toxicity. Based on the potential for additive or synergistic activity with the
      combination of chemotherapy and biotherapy, many investigators have evaluated
      biochemotherapy in patients with advanced melanoma. Aggregate results suggest
      that biochemotherapy is tolerable and produces a response rate in the range of
      50% with a complete response rate of 10%. Although these phase II results appear
      superior to previous results with chemotherapy or immunotherapy alone, the true
      benefits of biochemotherapy can only be determined with the results of randomized
      phase III trials; therefore, biochemotherapy should be considered an as yet
      experimental therapy. Many other issues regarding biochemotherapy, such as
      sequence, outpatient administration, and use in the adjuvant setting, for stage
      III melanoma are being actively evaluated.

PMID- 12407508
TI  - Metastatic melanoma: chemotherapy.
AB  - The incidence of cutaneous melanoma has been rapidly increasing, with an estimate
      of 47,700 new cases diagnosed in 2000 in the United States. In the early phase of
      its natural history, melanoma is cured in most cases by surgery, but once the
      metastatic phase develops, it is almost always fatal. The treatment of metastatic
      melanoma remains unsatisfactory. Systemic therapy has not been successful up to
      now, with very low response rates to single-agent chemotherapy. Polychemotherapy
      has increased the response rate (RR), without a significant improvement in
      overall survival. Immunotherapy alone is able to induce only a few durable
      complete responses (CRs). New chemotherapeutic and biologic agents are now
      available and promising combined approaches targeting the tumor by several
      different mechanisms are desirable and will probably represent the future
      modality of treatment.

PMID- 12407510
TI  - Biochemotherapy for advanced melanoma.
AB  - The outcome of chemotherapy for patients with stage IV melanoma is
      unsatisfactory, since durable responses are rarely achieved. More experimental
      treatments, such as vaccine approaches, antibody treatments, and gene therapy are
      being developed and are of high scientific interest; however, their efficacy in
      advanced melanoma patients has so far been very limited. Based on the observation
      of a small proportion of long-term responses, the use of biotherapy or
      biochemotherapy is currently preferred in many institutions as first-line
      treatment in stage IV melanoma. Various interleukin-2 (IL-2) dosing schedules and
      combinations with interferon alpha (IFN-alpha) have been tested in patients with
      advanced melanoma during the past decade. The response rates reported with IL-2
      as a single agent or in combination with IFN-alpha varies from 10% to 41%, with a
      small, but remarkable proportion of durable responses. Subsequently,
      biochemotherapy regimens combining IL-2, IFN-alpha, and chemotherapy have been
      evaluated in phase II trials, which have suggested improved response rates.
      Recent randomized trials have investigated the role of biochemotherapy as
      compared to biotherapy alone or as compared to chemotherapy for the treatment of
      advanced melanoma. So far, none of the approaches has been proven to confer a
      survival benefit and thus the uniform desire is to include as many patients as
      possible in controlled clinical trials.

PMID- 12407511
TI  - Antibody-based vaccines for the treatment of melanoma.
AB  - Malignant melanoma remains a difficult clinical problem. Chemotherapy is not
      effective and immunotherapy has long been contemplated as the preferred approach
      to this disease. Extensive passive and active immunotherapy trials have been
      conducted. Active vaccination with whole cells or defined antigens, administered
      with a panoply of techniques to increase immunogenicity, has yielded inconsistent
      results. The development of antibody-based vaccines has allowed vaccination
      without the need for tumor tissue material or purified antigens. The idiotype
      network theory originally proposed by Lindemann and by Jerne provided the basis
      for the development of anti-idiotype (anti-Id) antibody vaccines, which mimic the
      internal image of the epitope targeted for immunization. Preclinical and phase I
      clinical data are available for various malignancies. In melanoma, some of the
      anti-Id vaccines have targeted gangliosides. One of these vaccines, TriGem, has
      been successful in generating a robust and specific humoral immunity in melanoma
      patients. Phase II data suggest this anti-Id vaccine has clinical activity.

PMID- 12407512
TI  - European approach to antibody-based immunotherapy of melanoma.
AB  - In the past two decades, the worldwide steadily rising incidence of melanoma, its
      dismal prognosis when locally advanced or metastatic, and the absence of
      clinically effective therapeutic options have prompted studies that generated
      extensive preclinical knowledge on the biology of melanoma cells and their
      interaction with the host's immune system. As a consequence, among solid tumors,
      melanoma represents a "model malignancy" to design and apply in the clinic new
      bioimmunotherapeutic approaches, that are eventually translated to solid tumors
      of different histotypes. Despite its waxing and waning appeal as a therapeutic
      strategy, antibody treatment still represents a promising clinical approach to
      melanoma. Europe is no exception in the clinical interest for antibodies as
      therapeutic tools in melanoma patients; European researchers have also focused on
      preclinical issues that may improve current antibody-based therapeutic approaches
      on the one hand, while providing novel clinical strategies on the other hand.

PMID- 12407513
TI  - Melanoma vaccines.
AB  - The incidence of malignant melanoma is increasing faster than that of any other
      malignancy in the United States, and therefore this disease represents a
      significant health threat now and in the future. The impact of conventional
      systemic therapy for metastatic melanoma is minimal, with best response rates for
      conventional therapy nearing only 30% and cure rates well below 10%. This
      justifies the development of immunotherapy as a new treatment modality for
      patients with melanoma. This review summarizes the most recent findings and the
      newest approaches in the design of vaccines for melanoma. The antigens associated
      with melanoma and their uses in the vaccine development are described. Possible
      clinical applications of the new vaccines for melanoma and future directions for
      their development are also discussed.

PMID- 12407514
TI  - Peptide-based cancer vaccines.
AB  - The characterization of tumor antigens recognized by T lymphocytes has provided
      the opportunity to immunize cancer patients with well-defined peptides.
      Differentiation and tumor-specific antigens are expressed in a significant
      proportion of patients with cancer. Pilot studies have involved many patients
      with melanoma. No major toxicity has been reported after peptide vaccination. The
      clinical efficacy of peptide vaccines is limited to a minority of patients and
      the response rate is less than 20%. Some regressions have been complete and long
      lasting. The development of this approach, and that of other methods to deliver
      tumor antigens, depends on clinical empirism to improve the therapeutic efficacy
      of the vaccine as well as the accurate understanding of the immune mechanisms
      involved in vivo.

PMID- 12407515
TI  - Gene-based therapy of malignant melanoma.
AB  - Melanoma continues to present a major therapeutic challenge to oncologists,
      oncologic surgeons, and dermatologists. Recent advances in molecular genetics and
      improvement in our understanding of immune responses to tumors have generated an
      interest in using gene-based treatment strategies to fight melanoma. Several
      basic strategies have emerged: (1) strengthening of the immune response against
      tumors by genetic modification of some target cell populations of the host using
      immunostimulatory genes such as cytokines and by genetic immunization with the
      genes coding for melanoma-associated antigens recognized by cytotoxic T cells;
      (2) interference with signaling cascades; and (3) suicide gene strategies. This
      article reviews these novel strategies and summarizes the most recent data
      generated by European groups either in experimental studies or in clinical
      trials.

PMID- 12407516
TI  - Brain metastases in melanoma: a European perspective.
AB  - CNS involvement is a common feature of metastatic melanoma. Despite this, there
      is little evidence upon which clinicians can base decisions about treatment. The
      short prognosis and significant symptoms usually associated with melanoma brain
      metastases have excluded these patients from clinical trials. In Europe the
      standard treatment involves whole brain radiotherapy, although selected centers
      offer other modalities, including surgery, radiosurgery, and chemotherapy.

PMID- 12407517
TI  - The treatment of brain metastases from malignant melanoma.
AB  - Metastasis to the CNS develops in nearly half of patients with advanced melanoma;
      in 15% to 20% of these patients, the CNS is the first site of relapse. While
      systemic therapy for metastatic melanoma produces objective responses in 15% to
      50% of patients, the available drugs do not penetrate well into the CNS, and
      these patients rarely benefit from systemic therapy. Although brain metastasis
      may be treated with surgery and/or stereotactic radiosurgery (SRS) when disease
      is limited to approximately one to three lesions, treatment for patients with
      large or multiple metastases is limited to whole brain irradiation (WBRT). While
      formal response and survival analyses of the impact of WBRT in melanoma have not
      been reported, the estimated median survival time for unselected patients with
      CNS metastases is only 2 to 4 months, with 1-year survival rates of less than
      13%. In a selected population of patients with limited CNS involvement, surgical
      resection alone or in combination with WBRT appears to prolong median survival.
      More recently, SRS has been shown to be an effective local treatment for selected
      patients with brain metastases. In several retrospective reports of patients with
      melanoma CNS metastases, treatment with surgical resection alone or in
      combination with WBRT has been demonstrated to prolong median survival. More
      recently, SRS has been shown to be an effective local treatment for selected
      patients with brain metastases. In several retrospective reports, patients with
      CNS metastases from melanoma treated with a combination of WBRT plus SRS or SRS
      alone had median survivals and rates of control in the CNS superior to published
      reports for traditional WBRT. Most of these patients died from progressive
      extracranial disease with locally controlled CNS disease. Investigation of the
      contribution of newer systemic agents to the control of melanoma metastatic to
      the CNS has been based on the identification of drugs that have antitumor
      activity and the ability to cross the blood-brain barrier. Fotemustine is a
      nitrosourea that produced similar activity in CNS metastasis as in systemic
      disease, with a response rate of about 25%. Temozolomide (TMZ) is an oral
      alkylating agent that acts via the same mechanism as dacarbazine (DTIC), the most
      active single agent in melanoma. TMZ, which is highly active in brain tumors, has
      also been associated with activity in systemic and CNS metastases in melanoma
      patients, also in the 25% range. Efforts are underway to assess the additive
      benefit of TMZ and other drugs to WBRT or focused radiotherapy in this disease.

PMID- 12407520
TI  - Laparoscopic antireflux procedures in children: evaluating the evidence.
AB  - A growing number of the pediatric antireflux procedures are performed
      laparoscopically. Although there are no prospective randomized studies comparing
      conventional open surgery to laparoscopic surgery, there are retrospective and
      anecdotal data suggesting that the laparoscopic approach is at least as good and,
      in many cases, better than the open procedure. Once the significant learning
      curve is achieved, one may attain similar operative times with the benefit of
      magnification and enhanced visualization of the operative field compared to open
      surgery. The greatest benefits of laparoscopic antireflux surgery are the
      cosmetic result, a decrease in postoperative analgesia requirements, and an
      earlier return to normal daily life for both parents and their children.

PMID- 12407521
TI  - Indications for laparoscopic antireflux procedures in children.
AB  - The decision for antireflux surgery is often made on an individual basis. How
      symptom patterns and therapeutic suggestions relate is debatable. There is a long
      list of differential diagnoses for vomiting not caused by disturbances of the
      lower esophageal sphincter. Guidelines for the clinical practice in
      gastroesophageal reflux have been established for children and for adult patients
      by the Genval Workshop Report and the Trondheim Consensus statement. Endoscopy is
      indicated if macroscopically visible lesions are to be expected. Routine
      endoscopic biopsy is not used in the diagnosis of gastroesophageal reflux disease
      (GERD). pH monitoring is performed in 33 to 77% of patients. If the most
      prominent symptoms are respiratory, radiographic studies and pH monitoring prove
      that the symptoms are really related to GERD. Best results with drugs are
      achieved by effective initial therapy. The effects of long-term treatment are
      little known. Failed long-term therapy, complications of esophagitis, recurrent
      aspiration, apnea or "near miss" sudden infant death syndrome, failure to thrive
      and anatomical abnormalities are indications for surgery. The superiority of
      laparoscopic antireflux surgery over open surgery depends on the experience of
      the surgeon. Some surgeons choose a "tailored approach", ie, perform a partial
      wrap in children with normal peristalsis, an extrashort "floppy" Nissen or a
      partial wrap for those with impaired peristalsis, and a slightly tighter 360
      degree wrap in neurologically impaired children. Partial wraps allow vomiting,
      which is considered risky in neurologically impaired children.

PMID- 12407522
TI  - Laparoscopic Nissen procedure in children.
AB  - Fundoplication is among the most frequently performed procedures in infants and
      children. The Nissen fundoplication is the most commonly performed anti-reflux
      procedure done in the pediatric population. The broad indications include
      respiratory compromise, failure to thrive, neurologic impairment, and severe
      esophagitis. Over the last decade the application of a minimally invasive
      surgical technique to this procedure has received widespread acceptance among
      adult and pediatric surgeons and should now be considered the technique of
      choice.

PMID- 12407523
TI  - Laparoscopic Nissen-Rossetti fundoplication in children.

PMID- 12407524
TI  - Laparoscopic Toupet's fundoplication in children.
AB  - Laparoscopic fundoplication is performed commonly in children, and it represents
      "the gold standard" in children with gastroesophageal reflux disease (GERD)
      refractory to medical therapy. We present a single surgeon's experience with a
      posterior partial valve. Between May 1993 and May 2002, we operated on 574
      children using Toupet's procedure. Among the patients, 24 were younger than 1
      year of age, and 17 others were neurologically impaired. The average duration of
      the surgery was 1 hour. Complications were limited to 3 eviscerations of omentum
      through the port wounds. Relapse of GERD secondary to valve failure occurred in 6
      patients, 1 neurologically impaired and 1 with mucoviscidosis. All six patients
      have been reoperated on laparoscopically, and Toupet fundoplication was performed
      again with good results. We think that the 270-degree posterior valve, according
      to Toupet, is a good procedure to adopt in children with GERD with a low rate of
      recurrence at long-term follow-up.

PMID- 12407525
TI  - Long-term results after laparoscopic Thal procedure in children.
AB  - As the laparoscopic approach to gastroesophageal reflux disease (GERD) was
      introduced in pediatric surgery in the last decade of the 20th century, it became
      apparent that this approach was beneficial. The favorable results have led to a
      more general acceptance and implementation of this type of surgery at the
      beginning of the 21st century. We give an overview of the first decade of
      laparoscopic antireflux procedures in children with an emphasis on the
      laparoscopic Thal fundoplication and its implication on morbidity and cure of
      GERD in the long term both for normal and mentally handicapped children. Between
      1993 and 2002, 149 children with GERD underwent 157 laparoscopic antireflux
      procedures, of whom 48% were mentally handicapped. Follow-up ranged from 6 months
      to 9 years (median age 4.5 years). Nineteen children died. All but one were not
      related to the antireflux procedure. Immediate relief of symptoms occurred in 120
      children (80.5%). In 29 children, the results were less than optimal. Eight
      patients underwent a laparoscopic redo procedure (5.4%). However, none of the
      children with a follow-up of more than 5 years show any symptoms anymore. In
      conclusion, the laparoscopic Thal fundoplication is a safe procedure, and results
      in the long term are favorable, irrespective of the nature of the cause, ie,
      mental retardation.

PMID- 12407526
TI  - Results of laparoscopic antireflux procedures in neurologically normal infants
      and children.
AB  - Most children treated for gastroesophageal reflux have been neurologically
      impaired. With the recent growth of laparoscopic surgery, neurologically normal
      children are being referred for fundoplication. We review the presentation
      diagnostic workup and surgical therapy for children with gastroesophageal reflux
      unresponsive to medical management. Although many techniques are available for
      surgical correction of gastroesophageal reflux in children, the laparoscopic
      Nissen fundoplication remains the standard for correction of gastroesophageal
      reflux. The technique is performed through five trocars, and emphasis is placed
      on obtaining at least 3 cm of intra-abdominal esophagus and holding the esophagus
      in this position with sutures between the crura and the esophagus. The
      fundoplication should be loose and no longer than 2 cm in length. Long-term
      follow-up has shown recurrence to be low in children who are neurologically
      normal as long as they do not gag and retch recurrently.

PMID- 12407527
TI  - Laparoscopic reoperation following unsuccessful antireflux surgery in childhood.
AB  - We determine the feasibility of laparoscopic revision surgery in children
      following previous open and laparoscopic antireflux operations. To give an
      objective overview about this topic, we analyzed the outcome of 15 children (8
      girls and 7 boys) who had undergone attempted laparoscopic revision between 4 and
      72 months (median 16 months) after a previous antireflux operation. Seven
      patients had previously undergone an open antireflux procedure (4 Nissen
      fundoplication; 3 Thal procedure) and 8 a laparoscopic procedure (5 Nissen; 3
      Toupet's procedure). Two of these children were mentally handicapped. The
      indications for revision were: recurrent reflux, 5; valve migration, 5; valve
      dismount, 5. Eight procedures comprised construction of a new Nissen
      fundoplication and in 7 cases a Toupet's procedure was performed. Revision was
      successfully completed laparoscopically in 10 cases, 7 of 8 patients following a
      previous laparoscopic procedure and in 3 of 7 following a previous open
      operation. Operating time ranged between 70 and 140 minutes (median 90 minutes).
      No perioperative complications occurred in either group. All patients were
      discharged within 3 to 4 days after the redo procedure. Follow-up time varied
      between 6 months and 7 yrs. Preoperative symptoms were relieved in all patients
      and all antireflux medication has been discontinued, except in two cases that
      still had rare symptoms. Although technically challenging, laparoscopic
      reoperation for recurrent gastroesophageal reflux disease can be performed safely
      and with good results, in the hands of experienced endoscopic surgeons.
      Reoperation is likely to be more difficult following failure of an open procedure
      than after failure of a laparoscopic one. Concerning the type of procedure, redo
      surgery is more difficult to perform after Nissen's than after Toupet's or Thal's
      procedure.

PMID- 12407528
TI  - Gastroesophageal reflux disease in neurologically impaired children: the role of
      the gastrostomy tube.
AB  - We review our experience with gastrostomy techniques in neurologically impaired
      (NI) children, with or without a Nissen fundoplication. The records of 130 NI
      children who had a gastrostomy tube (GT) placed between January 1999 and October
      2001 were reviewed. Data collected included: demographics, neurological status,
      operative time, time to first feed, postoperative stay, analgesic requirements,
      follow-up, mortality and complication rates. Open GTs were placed using the
      standard Stamm gastrostomy technique through a midline incision and were combined
      with a standard open Nissen fundoplication when indicated. Laparoscopic GTs were
      placed after institution of carbon dioxide pneumoperitoneum using a 2-port
      technique, a Mic-key G device of appropriate size and anchored to the anterior
      abdominal wall with 2 "U" stitches. The laparoscopic Nissen fundoplication (LNF)
      procedures were performed using a 5-port technique. Patients were divided into 4
      groups: group I (n = 12) laparoscopic GT alone, group II (n = 44) open GT alone,
      Group III (n = 44) laparoscopic GT with LNF and Group IV (n = 30) open GT with
      Nissen fundoplication. Based on their similar characteristics, Groups I and II
      and Groups III and IV were compared together. Data were analysed using Student's
      t test, and internal review board approval was obtained. Patients ranged in age
      between 10 days and 17.7 years (mean 3.64 years). Their weight was between 1.2
      and 63.4 kg (mean 12.8 kg). The compared groups showed similar characteristics
      with regard to age, weight, cause of mental impairment, and the reason for
      placement of the GT. The operative time for group III was significantly longer
      than that of group IV (P < 0.05). Time to first feed was significantly shorter
      for group I when compared to group II. The postoperative analgesic requirements
      were not statistically different. The overall short- and long-term complication
      rates were not statistically different when the related groups were compared,
      however, site-related complications and feeding problems were significantly less
      in group I compared to group II. Only 1 operative mortality occurred in group
      III. Follow-up showed less long-term morbidity and fewer complications with the
      laparoscopic GT compared to the open one as regard to admissions, surgery, and
      emergency department visits related to GT problems as well as frequency of GT
      change. Based on our experience, laparoscopic placement of a low-profile GT in NI
      children appears to be associated with less morbidity, permits earlier enteral
      nutrition, and has a cosmetic advantage. We believe that the laparoscopic
      technique should be the procedure of choice for GT placement in these children
      even when a Nissen fundoplication is deemed necessary.

PMID- 12407529
TI  - Results of laparoscopic antireflux procedures in neurologically impaired
      children.
AB  - Although laparoscopic fundoplication is now performed commonly in children, its
      long-term results in neurologically impaired (NI) children is unknown. We present
      a single surgeon's experience. During an 8.5 year period, 54 consecutive NI
      children (age 5 months to 16 years; weight 2.7 to 42 kg) who had failed medical
      treatment for severe gastroesophageal reflux (GER) underwent laparoscopic Nissen
      fundoplication without (7) or with (47) gastrostomy. Indications for surgery
      included failure to thrive and feeding difficulties in all, major vomiting in 42,
      recurrent chest infections in 44, and inability to take oral medication in 14.
      Hiatus hernia was present in 14 and delayed gastric emptying in 6 patients. Eight
      (15%) had undergone previous abdominal surgery. Access was modified according to
      individual anatomy and 4 or 5 cannulae were used in each patient. Postoperative
      epidural/morphine analgesia was used in the first 12 to 24 hours, and fluid
      intake and feeding were started on day 1 and 2, respectively. The average
      operating time for fundoplication was 2.2 hours (range 1.05 to 3) and for
      fundoplication and gastrostomy 2.3 hours (range 1.22 to 4.10). Three patients had
      conversion to open surgery (1 perforated esophagus, 1 hypercarbia and
      hepatomegaly, 1 camera failure). There were no other operative complications or
      mortality. One child with Down syndrome developed a food bolus obstruction 3 days
      postoperatively. The vast majority of patients were discharged home 3 to 4 days
      following fundoplication and 5 to 7 days following fundoplication and
      gastrostomy. Postoperative gas bloat was common, diarrhea developed in 4, dumping
      in 3, and major gastrostomy infection in 1 case. During follow-up (median 5.2,
      range 3 months to 8.6 years), 9 (16%) children showed signs of
      persistent/recurrent problems. Investigations showed a recurrent hiatus hernia in
      1 (requiring re-operation) and minor reflux in 3 patients. To date 6 (11%)
      children have died of their background conditions. In NI children, laparoscopic
      fundoplication is safe and successful. Awareness of the differences in access and
      risks for NI and normal children is important. Compared with historical data for
      open technique, laparoscopic fundoplication produces lower mortality and
      morbidity and similar intermediate and long-term results.

PMID- 12407531
TI  - An exclusively intraabdominal distal esophageal segment prevents primary delayed
      anastomosis in children with pure esophageal atresia.
AB  - PURPOSE: The aim of this study was to evaluate the outcome of children with pure
      esophageal atresia (EA) managed by the strategy of delayed primary anastomosis
      and to find parameters to identify which of these children will have satisfactory
      esophageal growth to permit a successful primary esophageal anastomosis. METHODS:
      Sixteen children with pure EA were treated by delayed anastomosis strategy from
      June 1992 to May 2001 at the Instituto da Crianca-University of Sao Paulo Medical
      School. The treatment consisted of creating an early feeding gastrostomy,
      continuous upper pouch suction, and periodic radiologic/endoscopic assessments of
      the gap between the superior and inferior esophageal pouches. The first
      assessment was done 4 weeks after the initial gastrostomy. Subsequent assessments
      were done, when necessary, 4 to 10 weeks after the first one. Children with the
      gap between the pouches corresponding to 2 vertebral bodies or less were
      considered for primary repair. RESULTS: The waiting period ranged from 8 to 14
      weeks. Five children were considered for primary repair (31.3%). All of them had
      an end-to-end esophageal anastomosis performed without tension. Eleven children
      (68.7%) did not show significant esophageal growth after the waiting period and
      were not considered for primary esophageal anastomosis. Eight of them (50%)
      showed an entirely intraabdominal distal pouch at the first assessment.
      CONCLUSIONS: (1) Infants with an exclusively intraabdominal distal pouch at the
      first evaluation will not reach sufficient elongation of the pouches and should
      be considered early as a candidate for esophageal replacement. (2) Combined
      radiologic/endoscopic assessment and the measurement of the gap in terms of
      vertebral bodies is a practical and reliable method to predict the feasibility of
      primary anastomosis. (3) Using these criteria, primary anastomosis could be
      accomplished in less than a third of cases.

PMID- 12407532
TI  - Esophageal motility changes in acute and late periods of caustic esophageal burns
      and their relation to prognosis in children.
AB  - BACKGROUND/PURPOSE: Esophageal burns as a result of accidental swallowing of
      caustic material are seen frequently in children. Severe motor function disorders
      of the esophagus after caustic burns are already reported covering the late
      periods. The aim of this study was to detect, follow, and report the clinical
      results of esophageal motility changes in acute as well as the late periods of
      caustic esophageal insult and its relation with prognosis in children. METHODS:
      Esophageal motility was studied in 20 children aged 1.5 to 11 years (mean, 3.8).
      In the study group, motility of the esophagus was investigated on the fifth day
      of the burn (after decrease of the edema) and repeated at the end of the third
      month. To standardize the results, the amplitude and the duration of the pressure
      waves were recorded at 3 cm above the lower esophageal sphincter (LES), and the
      velocity in the distal esophagus was calculated. Then the mean values of
      amplitude, duration, and velocity of 15 swallows were obtained for each patient.
      RESULTS: At the end of the fifth day, peristaltic response of the esophagus to
      swallowing was followed in 13 patients. Seven patients were able to swallow
      water, but no peristaltic response was detected. Therefore, the subjects were
      divided into 2 groups as motility (+) and motility (-), and each were compared
      with the control group separately. The amplitude of the pressure wave in the
      motility (-) group was significantly low when compared with the control group.
      All the subjects in this group had NaOH burns, and development of severe
      strictures was detected at the endoscopic examinations after 3 weeks. In motility
      (+) group, no pathologies were detected except significant decrease in the
      velocity of the peristaltic wave. Eleven of the subjects in this group had acid
      burns, and 2 had NaOH burns, and, at the follow-up endoscopic examination after 3
      weeks, only one acid burn patient had a slight stricture. Motility measurements
      conducted at the end of the third month showed that the initial motility (-)
      group had no changes. No peristaltic response was detected after swallowing, and
      amplitude of the pressure wave measured at the distal esophagus was significantly
      lower than the controls. However, in the motility (+) group, decrease in the
      velocity of the peristaltic wave had disappeared, and there were no differences
      when compared with the control group. CONCLUSION: It is suggested that the
      manometric studies of the esophagus give important data about the severity of the
      initial esophageal injury and have an important role in determining the
      prognosis.

PMID- 12407533
TI  - Follow-up studies of anorectal malformations after posterior sagittal
      anorectoplasty.
AB  - BACKGROUND/PURPOSE: There are few follow-up studies comparing posterior sagittal
      anorectoplasty (PSARP) with conventional procedures for patients with anorectal
      malformations (ARM). The authors have examined retrospectively postoperative
      anorectal function of patients with ARM treated with PSARP compared with those
      treated with conventional methods. METHODS: Anorectal function in 23 patients
      with high and intermediate type anorectal malformations (PSARP group), who
      underwent PSARP more than 4 years previously, were assessed by Kelly's clinical
      scoring system and objective studies. These results were compared with those in
      14 cases (5 high and 9 intermediate type cases; control group), who underwent
      other conventional surgical procedures. RESULTS: Using Kelly's clinical scoring
      system, scores of the PSARP group compared with the control group were good in
      48% versus 21%, fair in 48% versus 58%, and poor in 4% versus 21%, respectively.
      Barium enema studies suggested better anorectal sphincteric function in patients
      with high anorectal malformation in the PSARP group. Magnetic resonance imaging
      (MRI) studies showed more correct placement of the rectum through the striated
      muscle complex in the PSARP group at the I-line level. Manometric studies showed
      no difference in maximum resting pressure, anal canal length, and the incidence
      of anorectal reflex between the two groups. CONCLUSIONS: The favorable results of
      MRI and barium enema studies can be explained by direct visualization of the
      striated muscle complex with the aid of electrical stimulation as well as no
      harmful effects of amputation of the sphincter muscle in PSARP. However,
      manometric studies suggest anorectal function in patients with high and
      intermediate anorectal malformations is limited even after PSARP. Long-term
      postoperative follow-up with adequate bowel management is required for all
      patients with high or intermediate anorectal malformation.

PMID- 12407534
TI  - Peritoneal drainage as primary management in necrotizing enterocolitis: a
      prospective study.
AB  - BACKGROUND/PURPOSE: The use of peritoneal drainage (PD) in neonates with
      necrotizing enterocolitis (NEC) is controversial. The authors began to perform it
      successfully in infants with pneumoperitoneum, and subsequently they extended its
      use to infants with peritonitis and advanced NEC before radiologic evidence of
      peritoneal free air. To analyze the efficacy of PD they began a prospective
      study. METHODS: A prospective study was conducted in 6 neonatal intensive care
      units (NICU) in Spain: neonates with pneumoperitoneum or peritonitis and advanced
      NEC were all included, whatever the birth weight and gestational age (GA).
      RESULTS: PD was performed in 47 infants, but 3 of them were excluded because
      pneumoperitoneum was caused by pathologies other than NEC. In a cohort of 44
      infants, 86% improved after PD, and 64% survived after only PD. After PD, 54% of
      infants needed delayed surgery. Overall survival rate was 82%; 57% infants with
      birth weight under 1,000 g, and 95% in infants over 1,000 g at birth. The main
      cause of mortality was massive NEC in the tiniest babies. Only one infant had a
      short bowel syndrome. CONCLUSIONS: From the authors' point of view, PD is the
      first step in treating neonates with pneumoperitoneum or overwhelming NEC,
      regardless of birth weight and GA. Laparotomy, if it is necessary, always must be
      performed after clinical stability is achieved. Mortality rates remain higher in
      the tiniest babies because of massive NEC.

PMID- 12407535
TI  - Does colonization of Helicobacter pylori in the heterotopic gastric mucosa play a
      role in bleeding of Meckel's diverticulum?
AB  - BACKGROUND/PURPOSE: Helicobacter pylori is a microorganism known to colonize in
      gastric type of mucosa and is associated with gastritis and peptic ulceration.
      The aim of the study was to determine whether colonization of H pylori in
      heterotopic gastric mucosa plays a role in bleeding of Meckel's diverticulum.
      METHODS: Histopathologic slides of patients who had undergone resection of
      Meckel's diverticulum in recent 5 years were reexamined for the presence of H
      pylori in heterotopic gastric mucosa. Polimerase chain reaction (PCR) test was
      used to trace the genetic material of urease gene and 16s rDNA amplifications for
      H pylori. RESULTS: Thirteen of the 30 histopathologic slides of Meckel's
      diverticula had heterotopic gastric mucosa. Ten of the 13 patients presented with
      acute bleeding of the diverticula, whereas 3 of them were asymptomatic. None of
      the 13 gastric mucosa bearing diverticula were colonized with H pylori. PCR was
      unable to show any trace of genetic material for H pylori. CONCLUSION: Although
      the role of H pylori is well established in the gastric mucosal ulceration, its
      presence is not essentially required to induce "heterotopic gastritis" that may
      result in bleeding of the Meckel's diverticulum. .

PMID- 12407536
TI  - Glutathione S-transferase: a potential new marker of intestinal ischemia.
AB  - BACKGROUND/PURPOSE: The accurate and early diagnosis of intestinal ischemia
      remains difficult chiefly because of a lack of a suitable marker that is
      noninvasive and easy to use. The glutathione S-transferases (GST) are a family of
      cytosolic enzymes involved in detoxification and released from a variety of cells
      when the cell membrane is damaged. The enzymes are distributed widely in the
      intestine and show isoform specificity in their distribution throughout the
      intestinal tract. Several previous reports have shown the utility of these
      enzymes in the diagnosis of liver and renal graft damage during and after organ
      transplantation. The object of this study was to determine if GST levels
      correlated with histologic changes of intestinal ischemia in a controlled animal
      model of mesenteric intestinal ischemia. METHODS: Control and experimental male
      Sprague-Dawley rats underwent laparotomy and ligation of the Superior Mesenteric
      Artery (SMA) and both control and experimental animals were studied at 30, 60,
      90, 120, and 240 minutes. Blood taken from the Inferior Vena Cava (IVC) and
      Portal Vein (PV) and jejunal and ileal perfusates were assayed for alpha and mu
      isoforms of GST using a commercially available enzyme immunoassay. In addition,
      jejunal and ileal segments were sampled and reviewed by a histopathologist
      blinded to the group being studied. RESULTS: A reproducible pattern of intestinal
      ischemia was noted with worsening grades of injury observed with greater ligation
      times. Luminal alpha and mu GST release (as measured by the appearance in luminal
      perfusate) increased with increasing ischemia times. Increased ischemia times
      resulted in increased levels of alpha and mu GST in both portal and systemic
      venous samples but lagged behind the appearance of raised luminal GST values.
      CONCLUSIONS: The results suggest that GST may be an interesting and useful marker
      in the early detection of intestinal ischemia. Its detection in peripheral blood
      has implications for a more detailed study design to determine the sensitivity
      and specificity of this marker in more diverse clinical conditions such as
      necrotizing enterocolitis and superior mesenteric artery occlusion.

PMID- 12407537
TI  - Familial intussusception.
AB  - Intussusception, although a common cause of emergency in pediatric surgery,
      occurs rarely in more than one member in the same family. A genetic
      predisposition has been suggested in some cases. The authors report on 4 members
      of a family in 3 generations who suffered each an episode of idiopathic ileocolic
      intussusception over a period of 52 years. This is the only instance we found
      after reviewing 99 cases of intussusception in our hospital during the last 10
      years. There was no recurrence of intussusception in any case, and no underlying
      anatomic abnormality was found in the 2 patients who underwent surgery.

PMID- 12407538
TI  - Groin exploration for nonpalpable testes: laparoscopic approach.
AB  - PURPOSE: Diagnostic laparoscopy (DL) is the technique of choice for exploration
      of nonpalpable testes (NPT). Nevertheless, groin exploration is necessary to
      evaluate the cord and gonadal structures entering the internal ring. This
      retrospective analysis evaluates our hypothesis that hypoplastic cord structures
      entering the internal ring predicts absence of a viable testicle and a
      laparoscopic groin exploration in these cases can reduce the number of
      unnecessarily performed open groin exploration (OGE). MATERIALS: A retrospective
      review was performed of 23 boys with 26 NPTs who were operated on from June 1998
      to October 2000 to evaluate our protocol for NPT using DL and OGE. RESULTS: Of 26
      NPTs in 23 boys, 3 bilateral intraabdominal testis were detected (2 Fowler
      Stephens; 1 standard orchidopexy). Twenty cord structures entered the internal
      ring. Three appeared normal at DL with a viable testis followed by an
      orchidopexy. Seventeen were hypoplastic without patent processus. During LGE no
      viable testis was detected: blind-ending cords, no biopsy (n = 4); testicular
      regression syndromes (n = 3), early fetal regression (n = 6), no residual
      testicular structures (n = 4). CONCLUSIONS: This experience confirms the authors'
      hypothesis and criteria for LGE in all cases. The authors conclude that LGE is a
      helpful tool in the diagnostic workup of NPT to avoid unnecessary OGE and is a
      further step in the minimally invasive approach to all kinds of findings of NPT.

PMID- 12407539
TI  - Indications, complications, and surgical techniques for pediatric tracheostomies-
      an update.
AB  - BACKGROUND: With the decrease of life-threatening obstructive upper airway
      infections and the ongoing improvement of intensive care medicine, the role of
      tracheostomy in children has been changing considerably, until now. The aim of
      this study was to establish data regarding indications, complications, and
      techniques of pediatric tracheostomy, which would reflect the current state of
      science. METHODS: The authors analyzed the international literature as well as
      their own experience with 25 children less than 6 years of age who were operated
      on between 1980 and 1996. RESULTS: Literature proved to be very heterogeneous in
      terms of terminology, patient groups, operation techniques, indications, and
      complications. Within the past decades, long-term intubation and congenital
      anomalies of the upper respiratory tract have become increasingly prevalent,
      whereas inflammatory diseases were less and less an indication for tracheostomy.
      Endotracheal intubation as an alternative has resulted in less frequent
      tracheostomies in general. Today, children can be ventilated for months without
      considerable complications. However, individual, clinical, and fiberoptical
      controls are necessary. Tracheostomy-related complications have not changed
      significantly. Fatalities are mostly caused by the underlying disease. The most
      frequent causes of tracheostomy-related death are cannula obstruction and
      accidental decannulation. The most frequent early complications are
      pneumomediastinum, pneumothorax, wound complications, and bleedings. Subsequent
      complications most often are granulations and tracheal stenosis. CONCLUSIONS: The
      authors' research agreed widely with that in the literature. However, no
      tracheostomy-related death occurred. Possibly, this was because of their
      operative technique. In the opinion of the authors, establishing a cartilage
      window facilitates cannula exchange and reduces the risk of a fatal accidental
      decannulation.

PMID- 12407540
TI  - Antenatal dexamethasone enhances endothelin-1 synthesis and gene expression in
      the heart in congenital diaphragmatic hernia in rats.
AB  - BACKGROUND/PURPOSE: Although high levels of endothelin-1 (ET-1) in plasma may be
      relevant in certain pathophysiologic states, such as pulmonary hypertension
      accompanying congenital diaphragmatic hernia (CDH), experimental evidence favors
      a local, paracrine, or autocrine role for ET-1 in most tissues. Evidence of ET-1
      production has been documented in fetal heart tissue where it exerts growth
      enhancing and mitogenic effects. ET-1 also has a potent positive inotrope action
      on cardiac muscle. ET-1 -/- homozygous mice display a wide variety of cardiac
      anomalies, which also are features of the human and of the experimental CDH.
      Autopsy reports have shown that total heart weight is reduced significantly in
      the presence of CDH, and animal models have documented the presence of cardiac
      hypoplasia associated with CDH. Experimental and clinical studies have shown that
      prenatal exposure to corticosteroids improves cardiovascular function in the
      immediate newborn period. The aim of this study was to determine cardiac gene
      expression of ET-1 and of its receptor ET(A) and the cardiac ET-1 content in the
      heart of nitrofen-induced CDH in rats and to evaluate the effect of antenatal
      Dexamethasone (Dex) treatment. METHODS: A CDH model was induced in pregnant rats
      after administration of 100 mg of nitrofen on day 9.5 of gestation (term, 22
      days). Dex (0.25 mg/kg) was given by intraperitoneal injection on days 18.5 and
      19.5 of gestation. Cesarean section was performed on day 21 of gestation. The
      fetuses were divided into 3 groups: group I, control (n = 8); group II, nitrofen
      induced CDH (n = 8); group III, nitrofen-induced CDH with antenatal Dex treatment
      (n = 8). ET-1 protein was measured using ELISA. RT-PCR was performed to evaluate
      the relative amount of ET-1 and ET(A) mRNA expression. RESULTS: There was a
      reduction in ET-1 mRNA (P <.05) and in ET(A) mRNA (P <.01) in the heart of CDH
      group compared with controls. ET-1 protein level also was reduced in heart of CDH
      compared with controls. Antenatal Dex treatment increased significantly both ET-1
      mRNA and protein levels in the heart of CDH animals (P <.05 and P <.01,
      respectively). CONCLUSIONS: The reduced cardiac ET-1 gene expression and ET-1
      synthesis may be responsible for the heart hypoplasia associated with CDH.
      Prenatal corticosteroids increase the cardiac production of ET-1, and this may
      enhance heart growth and cardiac inotropism at birth.

PMID- 12407541
TI  - Choledochal cysts: age of presentation, symptoms, and late complications related
      to Todani's classification.
AB  - PURPOSE: The aim of this study was to compare presentation, complications,
      diagnosis, and treatment of choledochal cysts in pediatric and adult patients.
      METHODS: Forty-two patients were analyzed after subdivision into 3 groups: group
      A, less than 2 years (n = 10); group B, 2 to 16 years (n = 11); group C, greater
      than 16 years (n = 21). RESULTS: The cysts were classified as extrahepatic (n =
      33), intrahepatic (n = 5), and combined (n = 4). Seventy-six percent of patients
      presented with abdominal pain, (20 of 21 group C), and 57% with jaundice, (10 of
      10 group A). Cholangiocarcinoma occurred in 6 patients, 4 of whom had previously
      undergone internal drainage procedures. Excision of the extrahepatic cyst was
      performed in 27 of 37 patients. Five patients, of whom, 4 had cholangiocarcinoma,
      were beyond curative treatment at the time of diagnosis. Six patients had died at
      the closure of this study, 5 of them had carcinoma. CONCLUSIONS: Presenting
      symptoms are age dependent with jaundice prevailing in children and abdominal
      pain in adults. In view of the high risk of cholangiocarcinoma, early resection
      and not internal drainage is the appropriate treatment of extrahepatic cysts.
      Patients who had undergone internal drainage in the past still should undergo
      resection of the cyst.

PMID- 12407542
TI  - The role of surgery in stage IV neuroblastoma.
AB  - BACKGROUND/PURPOSE: The importance of primary tumor resection in stage IV
      neuroblastoma is controversial. The authors analyzed prospectively the role of
      surgery in a multicentric series of stage IV neuroblastoma patients. METHODS:
      Patients were studied according to the International Neuroblastoma Staging System
      (INSS) recommendations. Age, sex, location of the tumor, type of metastases, time
      of resection (initial or delayed), extension of resection, surgical
      complications, pathology, N-myc and Shimada classification results, relapses, and
      outcome were studied. After diagnosis, children received induction chemotherapy
      followed by delayed surgery and autologous stem cell transplantation or
      maintenance chemotherapy. Resection was classified as complete (C), greater than
      90% (P1), greater than 50% (P2), less than 50% (P3), and biopsy (B). RESULTS:
      Ninety-eight stage IV children were admitted in the study from June 1992 to July
      1999. Seventy-six were older than one year, and in 78 the primary tumor was
      abdominal. Bone was the most common metastatic site followed by bone marrow.
      Initial biopsy was performed in 74 patients, and resection in 6, with one
      complication in each group. N-myc was amplified in 20 of 80 tumors, and Shimada
      was unfavorable in 45 of 67. Delayed surgery was performed in 70 cases, achieving
      gross total resection in 55 (79%); there were minor complications in 10%. Mean
      survival rate time was 50 months. Event-free survival rate (EFS) at 5 years for
      the entire series is 0.32, but 0.0 for children having biopsy only, 0.25 for less
      than 50% resection, 0.31 for 50% to 90% resection, 0.44 for greater than 90%
      resection, and 0.33 for complete resection. Differences were statistically
      significant only when compared with the biopsied group. EFS rate for infants was
      0.56, but, again, there was no difference in relation to the type of resection.
      There were 46 relapses, 12 of them local, 7 of 20 N-myc-amplified tumors, and 4
      of 60 not amplified (P <.005). CONCLUSIONS: Biopsies of stage IV neuroblastoma
      allow safe assessment of N-myc and other biological factors on tumor tissue.
      Delayed surgery after chemotherapy is performed with a low rate of complications,
      achieving a good local control of disease. N-myc-amplified tumors have higher
      local relapse rates than nonamplified and therefore would need more intensive
      local treatment. The final outcome in these patients is determined more by
      metastatic relapses than by the degree of resection.

PMID- 12407543
TI  - MDR1 modulators improve the chemotherapy response of human hepatoblastoma to
      doxorubicin in vitro.
AB  - PURPOSE: P-glycoprotein, a membrane efflux pump encoded by the MDR1 gene, plays
      an important role in the development of multidrug resistance in human
      hepatoblastoma (HB). Chemosensitizers antagonize the efflux action of P
      glycoprotein. This study investigates the effects of 3 chemosensitizers (the
      cyclosporin analogue SDZ PSC 833 (PSC 833), the acridone carboxamide derivative
      GG 918, and verapamil) on the chemotherapy of HB in vitro. METHODS: The
      doxorubicin (DOXO) concentration that produces 50% growth inhibition (IC50) in a
      HB cell line was determined and additional effects of PSC 833, GG 918, and
      verapamil were investigated in a cytotoxicity assay. The MDR1 gene expression
      after treatment was determined in a semiquantitative reverse transcription
      polymerase chain reaction approach. RESULTS: The IC50 of DOXO is 2.5 microg/mL,
      0.61 microg/mL for DOXO + PSC 833, 1.17 microg/mL for DOXO + verapamil, and 1.47
      microg/mL for DOXO + GG 918. In combination with DOXO, cell growth was inhibited
      4.1-fold by PSC 833, 2.1-fold by verapamil, and 1.9-fold by GG 918. The MDR1 gene
      expression was enhanced significantly in all treated cells, with and without
      modulator. CONCLUSIONS: MDR1 modulators significantly improve the response of HB
      to DOXO in vitro. The combination of anticancer agents and MDR1 modulators might
      be a possible contribution to overcome multidrug resistance in HB.

PMID- 12407544
TI  - Hirschsprung's disease in cartilage-hair hypoplasia has poor prognosis.
AB  - PURPOSE: Cartilage-hair hypoplasia (CHH) is a chondrodysplasia with growth
      failure, impaired immunity, and high incidence of Hirschsprung disease (HD). This
      study describes the outcome of CHH patients with HD. METHODS: Among 147 patients
      with CHH, 13 were identified to have HD. Their medical records were analyzed for
      treatment, outcome, and complications of HD and compared with a control group of
      169 patients with HD but not CHH. RESULTS: Eight CHH patients had classic HD with
      rectosigmoid involvement, 2 had long segment colonic disease, and 3 patients had
      total colonic aganglionosis. Six of the 13 CHH patients (46%) had episodes of
      enterocolitis before the first surgery. Enterocolitis was complicated by colonic
      perforation in 2 cases. Eleven CHH patients (85%) had at least one episode of
      postoperative enterocolitis. Five patients (38%) with CHH and HD had died; 4 of
      enterocolitis-related septic infection and one of non-Hodgkin's lymphoma. In the
      control group, preoperative enterocolitis occurred in 14% and postoperative
      enterocolitis in 8%. Two controls (1.2%) had died. CONCLUSIONS: HD associated
      with CHH has poor prognosis in terms of postoperative morbidity and risk of
      death. These patients require particular attention during postoperative follow-up
      to detect potentially lethal complications.

PMID- 12407545
TI  - Effects of amnio-allantoic fluid exchange on bowel contractility in chick embryos
      with gastroschisis.
AB  - BACKGROUND/PURPOSE: Intestinal damage in patients with gastroschisis is
      characterized by bowel wall thickening, intestinal dilatation, mesenteric
      shortening, and a fibrous peel. The prevention of intestinal damage in
      gastroschisis by amnio-allantoic fluid (AAF) exchange has been reported using
      histologic and macroscopic evaluation of intestines, but the effects of this
      treatment on bowel contractility have not been investigated. The current study
      was performed to determine the effect of AAF exchange on the intestinal
      contractility in chick embryos with gastroschisis. METHODS: Thirteen-day-old
      fertilized chick eggs were used. Gastroschisis was created through amnio
      allantoic cavity. There were 3 study groups: control group, gastroschisis-only
      group, and gastroschisis-plus-exchange group. The bowels were evaluated by an in
      vitro muscle strip technique, and the response was expressed as a percentage of
      the maximum acetylcholine evoked contraction (E(max)) in each tissue obtained.
      Additionally, parasympathetic ganglion cells per 10 plexus at the intestinal wall
      were counted. Differences between groups were analyzed by analysis of variance
      (ANOVA) followed by Tukey-Kramer. Probabilities of less than 5% were considered
      significant. RESULTS: The intestines were thickened and covered by fibrous peel
      in the gastroschisis-only group when compared with the control group and the
      gastroschisis exchange group morphologically. There was a statistically
      significant decrease in contractility in the gastroschisis-only group compared
      with the control group (P <.05). It exerted 42.03 +/- 46.73% contraction of
      control group's E(max). This decrease in contractility was significantly reversed
      in the exchange group (P <.05; E(max) value of gastroschisis plus exchange group
      was 71.45 +/- 23.54% of control group's E(max)). Although the number of ganglia
      per 10 plexus was 76.7 +/- 4.3 in the control group, it was measured 28% less in
      the gastroschisis-only group (P <.05). There was no significant difference
      between the ganglion numbers of control and exchange groups. CONCLUSIONS:
      Prenatal AAF exchange treatment prevents decreased bowel contractility in
      gastroschisis. Gastroschisis does not affect intestinal ganglia morphology, but
      the number of ganglion cells decreases. AAF exchange prevents these functional
      and morphologic adverse effects of disease. By these findings the expectancy of a
      better clinical result in gastroschisis with intrauterine pretreatment by
      amniotic fluid exchange increases.

PMID- 12407546
TI  - Morbidity and quality of life in adult patients with a congenital abdominal wall
      defect: a questionnaire survey.
AB  - BACKGROUND: In children with congenital abdominal wall defects (CAWD), surgical
      treatment of the abdominal defect and the associated anomalies cause considerable
      morbidity in the first years of life. Afterward, most of the CAWD patients with
      correctable anomalies develop as other children. The morbidity and quality of
      life (QoL) of CAWD patients who have reached their adulthood is less well known
      and the subject of this study. METHODS: A 3-part questionnaire was sent to 75
      former patients with CAWD, aged 17 years or more. The first part included
      questions about health, symptoms, and education; the second part consisted of 3
      tests of psychosocial functioning; and the third part was a SF-36 questionnaire
      measuring the QoL. RESULTS: Of the 75 patients, 57 (76%) answered: (25 males, 32
      females); omphalocele (n = 16) gastroschisis (n = 11); median age, 27 (range, 17
      to 48) years. With the exception of rheumatoid arthritis (in 7% of patients), the
      prevalence of acquired diseases in CAWD patients was comparable with that of the
      general population; 50 of 57 (88%) considered their health good. The most
      frequent causes of morbidity were disorders in the abdominal scar in 21 (37%)
      patients, and functional gastrointestinal disorders in 29 (51%) of patients. Low
      self-esteem was found in 12% of patients, but the QoL and educational level of
      CAWD patients were not different from that of the general population.
      CONCLUSIONS: In CAWD patients the morbidity from acquired disorders is similar to
      morbidity in the general population. Disorders with the abdominal scar and
      various functional gastrointestinal disorders are common, but they rarely cause
      serious problems. The majority of CAWD patients have a quality of life not
      different from the general population.

PMID- 12407547
TI  - Amniotic fluid beta-endorphin: a prognostic marker for gastroschisis?
AB  - PURPOSE: The aim of this work was to study amniotic fluid beta-endorphin as a
      potential predictor for postnatal morbidity in gastroschisis. METHODS: Beta
      endorphin was assayed in 43 amniotic fluid samples from 13 pregnant women with
      fetal gastroschisis undergoing diagnostic amniocentesis or therapeutic
      amnioinfusion and compared with 33 controls. Within the gastroschisis group, the
      authors investigated the relationship between postnatal morbidity and the peak
      value of amniotic fluid beta-endorphin (AFBE). RESULTS: Ten AFBE values in 6
      cases of gastroschisis were above the upper limit of the 95% confidence interval
      derived from controls. Postnatal morbidity was significantly higher when peak
      AFBE exceeded 10 microg/L (n = 4 pregnancies) compared with below 5 microg/L (n =
      9 pregnancies), as shown by mean duration of mechanical ventilation (15.2 v 3
      days; P =.01), of parenteral feeding (77 v. 18.7 days; P =.04), and of
      hospitalization (84 v 32.2 days; P =.04). There was no statistically significant
      association between postnatal morbidity markers and prenatal dilation of fetal
      bowel. CONCLUSIONS: The most severe cases of gastroschisis are associated with
      high levels of AFBE. The authors speculate that this fetal hormonal response
      could result from stress or pain caused by prenatal bowel damage.

PMID- 12407548
TI  - Primary cutaneous mucormycosis in infants and neonates: case report and review of
      the literature.
AB  - A case of angioinvasive cutaneous mucormycosis in a premature infant, eventually
      requiring extracorporeal membrane oxygenation therapy, is described. The fungal
      infection began at the site of a brachial artery catheter that had been covered
      with an adhesive dressing in the left antecubital fossa. The infection progressed
      rapidly over a 5-day period, and a left arm amputation was required. Fungal
      hyphae were present at the margins of resection. The patient eventually had
      disseminated mucormycosis and died. A second case of cutaneous mucormycosis in
      another premature infant also is presented. This infant had the infection at an
      intravenous catheter site. Rapid initiation of surgical debridement of the wound
      and amphotericin B therapy resulted in patient survival. Eighteen reported cases
      of cutaneous mucormycosis in neonates were found and are reviewed. Prematurity,
      low birth weight, broad-spectrum antibiotics, corticosteroid therapy, and local
      trauma to the skin site were common risk factors. Only 7 of the 18 patients
      survived. Therapy consisted of local debridement and intravenous amphotericin B.
      High index of suspicion, early diagnosis, and rapid institution of therapy can
      improve survival rate. The key to prevention appears to be appropriate skin care.

PMID- 12407549
TI  - Nonoperative management of blunt extrahepatic biliary duct transection in the
      pediatric patient: case report and review of the literature.
AB  - An 11-year-old boy sustained a grade IV liver injury and complete disruption of
      the left hepatic duct (LHD) secondary to a sledding accident. Although he became
      hemodynamically stable after initial resuscitation in the emergency department
      and the intensive care unit (ICU), serial paracentesis procedures were necessary
      to manage abdominal compartment syndrome (ACS). The fluid initially was
      serosanguinous but subsequently became bile stained. A bile leak was confirmed by
      a technetium 99m dimethyliminodiacetic acid (HIDA) scan and an endoscopic
      retrograde cholangiogram (ERCP). The LHD transection was treated with
      percutaneous drainage of the subhepatic space and a transampullary biliary stent.
      The leak sealed within 8 days, and follow-up ERCP as an outpatient showed no
      extravasation but could not visualize the LHD. Repeat computed tomography (CT)
      scan 3(1/2) months after injury showed the liver laceration to be healed with
      atrophy of the left lobe and no ductal dilatation. The patient has had a complete
      recovery, resumed all activities, and currently is 20 months after his injury
      with no sequelae.

PMID- 12407550
TI  - Adnexal torsion in children may have a catastrophic sequel: asynchronous
      bilateral torsion.
AB  - BACKGROUND/PURPOSE: Adnexal torsion is a serious condition that frequently may
      result in ovarian removal, and there always is a risk of castration if the
      contralateral ovary undergo torsion as well. In this study, the authors present
      their experience with adnexal torsion in 15 children and describe a catastrophic
      event, asynchronous bilateral adnexal torsion, with review of the literature.
      METHODS: Between November 1993 and November 2000, 15 children under 15 years of
      age who had undergone operation because of torsion of uterine adnexal structures
      were evaluated. Two illustrative cases with asynchronous bilateral adnexal
      torsion are presented. RESULTS: Fourteen cases were associated with additional
      adnexal pathology, whereas in 1 case the torsion was of normal uterine adnexa.
      Sonographic studies improved the preoperative diagnosis. Hemorrhagic necrosis of
      the adnexa secondary to the torsion was found in all cases except 3 and
      necessitated adnexal resection. In only 3 cases preservation of the adnexa was
      possible. Asynchronous adnexal torsion occurred in 2 patients in the time course.
      Both were treated by laparotomy and adnexal untwisting and fixation by permanent
      multiple interrupted sutures. In their final evaluation at 40 and 8 months after
      the operation, they were found to have good ovarian function. CONCLUSION:
      Considering the risk of subsequent contralateral torsion and its impact on future
      fertility, the authors believe that conservative management (untwisting the ovary
      and pexing, both retained detorsed and contralateral, ovaries) should be
      considered in cases of ovarian torsion in children.

PMID- 12407551
TI  - Nontraumatic myositis ossificans with an unusual location: case report.
AB  - Myositis ossificans is a pathologic entity rarely met, but still it must be kept
      in mind in differential diagnosis of a tender soft tissue swelling. The authors
      present an 8-year old boy with nontraumatic myositis ossificans circumscripta in
      the left paravertebral muscle. In diagnostic workup, ultrasonography and computed
      tomography (CT)-scan showed a well marginated, regular, ossified mass in the
      paravertebral muscle, but we were not able to exclude malignancy on the clinical
      grounds. The mass was excised totally, and the histopathologic examination found
      myositis ossificans. The authors suggest that surgical intervention may be an
      option for diagnosis and treatment in unusual cases when diagnosis is not
      certain.

PMID- 12407552
TI  - A rare association of urogenital duplication and anorectal malformation.
AB  - An unusual case of urogenital duplication in association with anorectal
      malformation is presented. A 3-year-old girl was referred to the authors'
      hospital with double vagina, double urethra, double sacrum, double ureters on the
      right side, multiple vertebral anomalies, together with anorectal malformation.
      Successful surgical reconstruction was performed.

PMID- 12407553
TI  - A case of transverse colon volvulus in a child and a review of the literature in
      Japan.
AB  - A case of transverse colon volvulus in a child with mental retardation and
      epilepsy is described. Previously reported cases in Japanese children are
      reviewed. A 540 degrees, counterclockwise volvulus of the transverse colon caused
      ischemia requiring resection. Possible factors related to pathogenesis are
      discussed, and diagnostic and therapeutic measures are outlined. Volvulus of the
      transverse colon is extremely rare in children.

PMID- 12407554
TI  - Thoracoscopic resection of extralobar sequestration in a neonate.
AB  - The authors report a case of extralobar pulmonary sequestration (ELS) located at
      the right costophrenic recessus and resected thoracoscopically in a 22-day-old
      girl. Prenatally, spontaneous resolution of a cystic adenomatoid lung lesion
      (CCAM) occurring independently in the upper right hemithorax was observed. ELS
      with preceding complete resolution of CCAM in the ipsilateral hemithorax has not
      been reported before. This is the first neonate reported with ELS treated by
      thoracoscopy.

PMID- 12407555
TI  - Fournier's gangrene as a complication of varicella in a 15-month-old boy.
AB  - An inguinal and perianal localization of Fournier's gangrene (FG) in a 15-month
      old boy as a complication of the varicella infection is discussed. This is the
      first presentation of the disease as a complication of the varicella rashes.
      There were already 57 pediatric FG cases resulting from other causes that had
      been presented in the medical literature.

PMID- 12407556
TI  - Primary surgical repair of combined gastroschisis and bladder exstrophy.
AB  - The combination of bladder exstrophy and gastroschisis has not been reported
      previously. The authors describe this rare combination of congenital anomalies,
      as well as the successful multidisciplinary management of this unusual problem.

PMID- 12407557
TI  - 'High' anorectal malformation in boys: need for clarity of definition and
      management.
AB  - Posterior sagittal anorectoplasty is purported to be the approach of choice for
      the treatment of both intermediate and high variety of anorectal malformations.
      The authors describe their devastating experiences with 2 cases of high variety
      of anorectal malformations in which defects were repaired thorough the posterior
      sagittal approach. In the first case, because of the high level of the rectal
      pouch, complete urethrovesical disconnection was done along with inadvertent
      mobilization and pull-through of urinary bladder. The patient subsequently
      required major reconstructive procedures. In another case, the bladder was
      partially mobilized before the mistake was realized; the high-lying rectum was
      later identified, and a pull-through was performed without any ill consequences.
      The authors infer that only the patients with rectal pouches ending caudal to the
      third sacral vertebra should have their definitive surgery performed through
      posterior sagittal approach. They suggest that PS3 line should be the watershed
      in management of anorectal malformation in boys.

PMID- 12407558
TI  - Management of Budd-Chiari syndrome by hepatic vein stenting after extended right
      hepatectomy.
AB  - Massive splenomegaly and ascites production with hypoproteinemia and
      hypocoagulability was observed in a 15-year-old boy after extended right
      hepatectomy for hepatocellular carcinoma (HCC). Angiography disclosed a kinking
      of the left hepatic vein immediately before the junction with the inferior vena
      cava. Ascites disappeared completely, and laboratory values normalized after
      placement of a 3-cm long balloon expandable stent. The current case shows that
      Budd-Chiari syndrome caused by hepatic outflow obstruction after major hepatic
      surgery can be managed effectively by percutaneous stent placement.

PMID- 12407559
TI  - Double intussusception in an infant.
AB  - Intussusception is a common surgical disorder in infancy. Double intussusception
      (DI), however, is an extremely rare form of this pathology. The authors report a
      case of idiopathic DI in an 8-month-old girl, which is the third case of
      idiopathic DI in childhood in the English-language literature.

PMID- 12407560
TI  - Intraoperative colonic lavage in a premature infant: a case report.
AB  - Left-sided colonic obstruction in the neonate traditionally is managed with a
      multistaged defunctioning colostomy and resection. In adults, one-stage primary
      anastomosis has become increasingly popular with the use of on-table antegrade
      colonic lavage. In infants, and especially in premature neonates, enterostomies
      pose significant morbidity. O'Connor and Sawin reported a 68% complication rate
      in 50 infants with necrotizing enterocolitis who had survived until the time of
      enterostomal closure. This case discusses a modified application of on-table
      colonic lavage in the management of an obstructing sigmoid stricture in a
      premature infant.

PMID- 12407561
TI  - Pediatric surgical images: PET evaluation of papillary thyroid carcinoma
      recurrence.

PMID- 12407562
TI  - Spigelian and inguinal hernias in a neonate.

PMID- 12407564
TI  - Use of intraluminal stents in multiple intestinal atresia.
AB  - Multiple intestinal atresia presents a difficult technical problem because of
      extreme loss of intestinal length, disparity of residual bowel wall size, and
      discontinuity of multiple short intestinal segments. The authors report on a
      3,000-g infant with gastroschisis complicated by intrauterine volvulus and
      multiple intestinal atresias who was treated successfully with intraluminal
      stenting and sutureless anastomoses. A total of 25 cm of small bowel was salvaged
      including 13 segments each measuring 1 to 8 cm in length. Subsequent radiographic
      studies showed spontaneous anastomosis with a compartmental configuration of the
      residual bowel and decreased transit time. Five months postoperatively, the
      patient was weaned off total parenteral nutrition completely and one year later
      is growing and gaining weight with 4 to 6 bowel movements per day.

PMID- 12407565
TI  - Perforated congenital diverticulum of the sigmoid colon.
AB  - A case of perforation of a congenital sigmoid diverticulum producing diffuse
      peritonitis in a 4-year-old boy is presented. Physical examination showed an
      acute abdomen despite a normal computed tomography study. Successful surgical
      treatment was achieved by excision of the diverticulum, adjacent bowel, and an
      end-to-end anastomosis.

PMID- 12407566
TI  - Slide cricotracheoplasty: a novel surgical technique for congenital cricotracheal
      stenosis.
AB  - PURPOSE: The aim of this study was to introduce a new surgical technique for the
      correction of congenital cricotracheal stenosis. METHODS: A 5-day-old girl
      presented with esophageal atresia and congenital cricotracheal stenosis. After
      successfully correcting her esophageal atresia, the authors chose to use a type
      of slide cricotracheoplasty, which was a modification of slide tracheoplasty and
      anterior cricoid split. RESULTS: The postoperative period was remarkably
      uneventful except for minor subcutaneous emphysema, and the midterm results were
      excellent. CONCLUSIONS: Slide cricotracheoplasty produced a good result and
      offered the same advantages as slide tracheoplasty. The authors believe that the
      described technique offers an efficient surgical procedure for the single-staged
      correction of congenital cricotracheal stenosis.

PMID- 12407567
TI  - Acid-secreting rectal duplication cyst with associated peptic ulcer eroding
      through the anal sphincters.
AB  - A rectal duplication cyst with heterotopic gastric mucosa that resulted in a
      trans-sphincteric peptic ulcer on the opposite wall of the anus of a child is
      described. The management and outcome and a review of the literature is
      presented.

PMID- 12407568
TI  - Communicating bronchopulmonary foregut malformation involving a mixed
      sequestration/cystic adenomatoid malformation: a case report.
AB  - The authors report the case of a baby girl with an unusual communicating
      bronchopulmonary foregut malformation consisting of extralobar pulmonary
      sequestration and cystic adenomatoid malformation. A well-formed bronchus was the
      communication between the sequestration and lower esophagus.

PMID- 12407569
TI  - Complete cervical tracheal rupture in children after closed trauma.
AB  - The authors report the case of a 5-year-old boy who received a blow from a heavy
      metallic bar on the front of the neck and presented with a complete rupture of
      the cervical trachea. Such a rupture is exceptional in children because of the
      consistency of the cartilage but can occur when the neck is in extension and the
      glottis is closed. A rigid endoscopy allowed the rupture to be diagnosed, to
      restore the airway, to prepare the cervicotomy, and the suturing of the trachea.
      He presented with a stenosis 50 days after the suturing which was treated by
      dilatation.

PMID- 12407570
TI  - Repyloromyotomy for recurrent infantile hypertrophic pyloric stenosis after
      successful first pyloromyotomy.
AB  - The authors report on a male infant aged 4(1/2) weeks who underwent a
      pyloromyotomy for hypertrophic pyloric stenosis. After an uncomplicated
      postoperative course with normal feeding and weight gain, projectile vomiting
      reoccurred. The boy underwent a repyloromyotomy for recurrent hypertrophic
      pyloric stenosis. The underlying cause of a recurrent hypertrophic pyloric
      stenosis after a successful pyloromyotomy may be explained by the natural history
      of the disease.

PMID- 12407571
TI  - National Institutes of Health Consensus Development Conference: management of
      hepatitis C: 2002.

PMID- 12407572
TI  - National Institutes of Health Consensus Development Conference Statement:
      Management of hepatitis C: 2002--June 10-12, 2002.

PMID- 12407573
TI  - Course and outcome of hepatitis C.
AB  - The hepatitis C virus (HCV) is a small enveloped RNA virus belonging to the
      family flaviviridae and genus hepacivirus. The HCV RNA genome is 9,600
      nucleotides in length and encodes a single polyprotein that is post
      translationally cleaved into 10 polypeptides including t3 structural (C, E1, and
      E2) and multiple nonstructural proteins ([NS] NS2 to NS5). The NS proteins
      include enzymes necessary for protein processing (proteases) and viral
      replication (RNA polymerase). The virus replicates at a high rate in the liver
      and has marked sequence heterogeneity. There are 6 genotypes and more than 90
      subtypes of HCV, the most common in the United States being 1a and 1b
      (approximately 75%), 2a and 2b (approximately 15%), and 3 (approximately 7%).
      Acute hepatitis C is marked by appearance of HCV RNA in serum within 1 to 2 weeks
      of exposure followed by serum alanine aminotransferase (ALT) elevations, and then
      symptoms and jaundice. Antibody to HCV (anti-HCV) tends to arise late. In acute
      resolving hepatitis, HCV RNA is cleared and serum ALT levels fall to normal.
      However, 55% to 85% of patients do not clear virus, but develop chronic hepatitis
      C. Chronic hepatitis C is often asymptomatic, but is usually associated with
      persistent or fluctuating elevations in ALT levels. The chronic sequelae of
      hepatitis C include progressive hepatic fibrosis, cirrhosis, and hepatocellular
      carcinoma. Extra-hepatic manifestations include sicca syndrome, cryoglobulinemia,
      glomerulonephritis, and porphyria cutanea tarda. Knowledge of the course and
      outcome of hepatitis C is important in developing approaches to management and
      therapy.

PMID- 12407574
TI  - The burden of hepatitis C in the United States.
AB  - According to the third National Health and Nutrition Examination Survey (NHANES),
      3.9 million of the U.S. civilian population have been infected with hepatitis C
      virus (HCV), of whom 2.7 million (74%) have chronic infection. Hepatitis C virus
      infection is most common among non-Caucasian men, ages 30 to 49 years. Moreover,
      the prevalence of antibody to hepatitis C virus in groups not represented in the
      NHANES sample, such as the homeless or incarcerated, may be as high as 40%. The
      age-adjusted death rate for non-A, non-B viral hepatitis increased from 0.4 to
      1.8 deaths per 100,000 persons per year between 1982 and 1999. In 1999, the first
      year hepatitis C was reported separately, there were 3,759 deaths attributed to
      HCV, although this is likely an underestimate. There was a 5-fold increase in the
      annual number of patients with HCV who underwent liver transplantation between
      1990 and 2000. Currently, more than one third of liver transplant candidates have
      HCV. Inpatient care of HCV-related liver disease has also been increasing. In
      1998, an estimated 140,000 discharges listed an HCV-related diagnosis, accounting
      for 2% of discharges from non-federal acute care hospitals in the United States.
      The total direct health care cost associated with HCV is estimated to have
      exceeded $1 billion in 1998. Future projections predict a 4-fold increase between
      1990 and 2015 in persons at risk of chronic liver disease (i.e., those with
      infection for 20 years or longer), suggesting a continued rise in the burden of
      HCV in the United States in the foreseeable future.

PMID- 12407575
TI  - Natural history of chronic hepatitis C.
AB  - Much controversy surrounds the issue of the natural history of hepatitis C virus
      (HCV) infection. Many authorities view the disease as inexorably progressive with
      a high probability of advancing over time to cirrhosis and occasionally
      hepatocellular carcinoma (HCC) and, therefore, likely to be responsible for
      causing death. Others regard chronic hepatitis C as having a variable outcome,
      the majority of infected persons not dying from the disease, but more likely from
      the comorbid conditions that so often accompany infection by this agent, or from
      more common medical conditions. Disagreements probably derive from the manner of
      conduct of the study and the populations studied. Efforts to determine natural
      history are handicapped by the primary characteristics of the disease, namely
      that its onset rarely is recognized and its course is prolonged exceedingly.
      Thus, different outcomes have come from retrospective rather than from
      prospective studies, but both have concluded that at least 20% of chronically
      infected adults develop cirrhosis within 20 years. More recent studies that used
      a retrospective/prospective approach, focusing largely on young infected
      individuals, have produced different results. Among these young people,
      particularly young women, spontaneous resolution of the viral infection is more
      common than previously thought and cirrhosis has been identified in 5% or fewer
      of them. The major failing for all groups studied, young and old, is that natural
      history studies have rarely exceeded the first 2 decades, so that outcome beyond
      this time is not known, other than through modeling. Several host-related and
      extraneous factors probably affect the natural history.

PMID- 12407576
TI  - Fibrosis and disease progression in hepatitis C.
AB  - The progression of fibrosis in chronic hepatitis C determines the ultimate
      prognosis and thus the need and urgency of therapy. Fibrogenesis is a complex
      dynamic process, which is mediated by necroinflammation and activation of
      stellate cells. The liver biopsy remains the gold standard to assess fibrosis.
      Scoring systems allow a semiquantitative assessment and are useful for cross
      sectional and cohort studies and in treatment trials. The rate at which fibrosis
      progresses varies markedly between patients. The major factors known to be
      associated with fibrosis progression are older age at infection, male gender, and
      excessive alcohol consumption. Viral load and genotype do not seem to influence
      significantly the progression rate. Progression of fibrosis is more rapid in
      immunocompromised patients. Hepatic steatosis, obesity, and diabetes may also
      contribute to more rapid progression of fibrosis. There are no tests that
      reliably predict the rate of progression of fibrosis in an individual patient.
      High serum alanine aminotransferase (ALT) levels are associated with a higher
      risk of fibrosis progression, and worsening of fibrosis is uncommon in patients
      with persistently normal serum aminotransferase levels. Serum markers for
      fibrosis are not reliable and need to be improved and validated. Liver biopsy
      provides the most accurate information on the stage of fibrosis and grade of
      necroinflammation, both of which have prognostic significance. Repeating the
      liver biopsy, 3 to 5 years after an initial biopsy is the most accurate means of
      assessing the progression of fibrosis.

PMID- 12407577
TI  - Noninvasive monitoring of patients with chronic hepatitis C.
AB  - Hepatic fibrosis is the main determinant of clinical outcomes of chronic
      hepatitis C. Liver histology is frequently considered the gold standard for
      assessing hepatic fibrosis. However, liver biopsy is associated with sampling
      error, interobserver variability, and potential complications. Thus, there is a
      need for simple, inexpensive, and reliable noninvasive means to assess disease
      severity in patients with chronic hepatitis C. Clinical examination is unreliable
      in differentiating different stages of compensated liver disease. Among the
      routine laboratory tests, decreased platelet count, increase in the ratio of
      aspartate to alanine aminotransferase (AST/ALT), and prolonged prothrombin time
      are the earliest indicators of cirrhosis and portal hypertension. Individual
      serum fibrosis markers have limited accuracy in predicting hepatic fibrosis.
      Indices composed of a panel of markers correlate better with histological
      fibrosis, but their reliability requires further validation. Currently,
      noninvasive monitoring of patients with chronic hepatitis C relies on clinical
      evaluation, routine laboratory tests, and ultrasound and endoscopic surveillance
      in patients with cirrhosis. Initial evaluation should focus on assessment of
      activity and stage of liver disease for prognostication and decisions regarding
      treatment, and to rule out coinfections and other causes of liver disease.
      Subsequent follow-up should focus on detection of liver disease progression and
      the need for treatment. The frequency of monitoring and the tests used will
      depend on the patient's age, stage of liver disease, and comorbid conditions.
      There is an urgent need to develop and validate noninvasive tests that can
      accurately reflect the full spectrum of hepatic inflammation and fibrosis in
      chronic hepatitis C.

PMID- 12407578
TI  - Use and interpretation of virological tests for hepatitis C.
AB  - Four virological markers of hepatitis C virus (HCV) infection are used clinically
      for management of patients with hepatitis C, namely the HCV genotype, HCV RNA,
      HCV core antigen, and antibody to HCV (anti-HCV). The diagnosis of acute and
      chronic hepatitis C is based on both anti-HCV detection using enzyme immunoassays
      (EIA) and HCV RNA detection using a sensitive molecular biology-based technique.
      Other virological tools, including HCV genotype determination and HCV RNA
      quantification, are now used to tailor treatment to the individual patient and to
      determine its efficacy. This article reviews the kinetics of HCV markers during
      acute and chronic HCV infection, together with current assays and their practical
      use in the management of HCV-infected patients.

PMID- 12407579
TI  - Hepatocellular carcinoma and hepatitis C in the United States.
AB  - Chronic infection with hepatitis C virus (HCV) is a major risk factor for
      development of hepatocellular carcinoma (HCC). In general, HCC develops only
      after 2 or more decades of HCV infection and the increased risk is restricted
      largely to patients with cirrhosis or advanced fibrosis. Factors that predispose
      to HCC among HCV-infected persons include male sex, older age, hepatitis B virus
      (HBV) coinfection, heavy alcohol intake, and possibly diabetes and a transfusion
      related source of HCV infection. Viral factors play a minor role. The likelihood
      of development of HCC among HCV-infected persons is difficult to determine
      because of the paucity of adequate long-term cohort studies; the best estimate is
      1% to 3% after 30 years. Once cirrhosis is established, however, HCC develops at
      an annual rate of 1% to 4%. Successful antiviral therapy of patients with HCV
      related cirrhosis may reduce the future risk for HCC. The incidence of and
      mortality caused by all HCC has doubled in the United States over the past 25
      years, an increase that has affected all ethnic groups, both sexes, and younger
      age groups. Given the current prevalence of HCV infection among persons 30 to 50
      years of age, the incidence and mortality rates of HCC are likely to double in
      the United States over the next 10 to 20 years. Future research should focus on
      improving understanding of the incidence and risk factors for HCC, causes of HCV
      related carcinogenesis, means of early detection, and better treatment for HCC.

PMID- 12407580
TI  - Screening tests for hepatocellular carcinoma in patients with chronic hepatitis
      C: a systematic review.
AB  - This systematic review addresses the following questions: (1) What is the
      efficacy of using screening tests for hepatocellular carcinoma (HCC) in improving
      outcomes in chronic hepatitis C, and (2) what are the sensitivity and specificity
      of screening tests for HCC in chronic hepatitis C? The search strategy involved
      searching Medline and other electronic databases between January 1985 and March
      2002. Additional articles were identified by reviewing pertinent articles and
      journals and by querying experts. Articles were eligible for review if they
      reported original human data from studies of screening tests that used
      virological, histological, pathologic, or clinical outcome measures. Data
      collection involved paired reviewers who assessed the quality of each study and
      abstracted data. One nonrandomized prospective cohort study suggested that HCC
      was detected earlier and was more often resectable in patients who had twice
      yearly screening with serum alpha-fetoprotein (AFP) and hepatic ultrasound than
      in patients who had usual care. Twenty-four studies, which included patients with
      chronic hepatitis C or B or both, addressed the sensitivities and specificities
      of screening tests. They were relatively consistent in showing that the
      sensitivity of serum AFP for detecting HCC usually was moderately high at 45% to
      100%, with a specificity of 70% to 95%, for a threshold of between 10 and 19
      ng/mL. The few studies that evaluated screening with ultrasound reported high
      specificity, but variable sensitivity. In conclusion, screening of patients with
      chronic hepatitis C with AFP and ultrasound may improve detection of HCC, but
      studies are needed to determine whether screening improves clinical outcomes.

PMID- 12407581
TI  - Prevention of spread of hepatitis C.
AB  - Hepatitis C virus (HCV) is transmitted by percutaneous or permucosal exposure to
      infectious blood or blood-derived body fluids. Based on the results of cohort and
      acute case control studies, risk factors associated with acquiring HCV infection
      in the United States have included transfusion of blood and blood products and
      transplantation of solid organs from infected donors, injecting drug use,
      occupational exposure to blood (primarily contaminated needle sticks), birth to
      an infected mother, sex with an infected partner, and multiple heterosexual
      partners. Nosocomial and iatrogenic transmission of HCV primarily are recognized
      in the context of outbreaks, and primarily have resulted from unsafe injection
      practices. Transmission from HCV-infected health care workers to patients is
      rare. Transfusions and transplants have been virtually eliminated as sources for
      transmission, and most (68%) newly acquired cases of hepatitis C are related to
      injecting drug use. The primary prevention of illegal drug injecting will
      eliminate the greatest risk factor for HCV infection in the United States. Other
      prevention strategies that need to be widely implemented include risk reduction
      counseling and services and review and improvement of infection control practices
      in all types of health care settings. Testing for HCV infection should be
      routinely performed for persons at high risk for infection or who require
      postexposure management. There are no recommendations for routine restriction of
      professional activities for HCV-infected health care workers, and persons should
      not be excluded from work, school, play, and child care or other settings on the
      basis of their HCV infection status.

PMID- 12407582
TI  - Sexual activity as a risk factor for hepatitis C.
AB  - The accumulated evidence indicates that hepatitis C virus (HCV) can be
      transmitted by sexual contact but much less efficiently than other sexually
      transmitted viruses, including hepatitis B virus and human immunodeficiency virus
      (HIV). However, because sex is such a common behavior and the reservoir of HCV
      infected individuals is sizable, sexual transmission of HCV likely contributes to
      the total burden of infection in the United States. Risk of HCV transmission by
      sexual contact differs by the type of sexual relationship. Persons in long-term
      monogamous partnerships are at lower risk of HCV acquisition (0% to 0.6% per
      year) than persons with multiple partners or those at risk for sexually
      transmitted diseases (0.4% to 1.8% per year). This difference may reflect
      differences in sexual risk behaviors or differences in rates of exposure to
      nonsexual sources of HCV, such as injection drug use or shared razors and
      toothbrushes. In seroprevalence studies in monogamous, heterosexual partners of
      HCV-infected, HIV-negative persons, the frequency of antibody-positive and
      genotype-concordant couples is 2.8% to 11% in Southeast Asia, 0% to 6.3% in
      Northern Europe, and 2.7% in the United States. Among individuals at risk for
      sexually transmitted diseases (STDs), the median seroprevalence of antibody to
      HCV (anti-HCV) is 4% (range, 1.6% to 25.5%). HIV coinfection appears to increase
      the rate of HCV transmission by sexual contact. Current recommendations about
      sexual practices are different for persons with chronic HCV infection who are in
      steady monogamous partnerships versus those with multiple partners or who are in
      short-term sexual relationships.

PMID- 12407583
TI  - Maternal-infant transmission of hepatitis C virus infection.
AB  - Mother-to-infant transmission of hepatitis C virus (HCV) is comparatively
      uncommon. The prevalence of antibody to HCV (anti-HCV) in pregnant women is 0.1%
      to 2.4%, although in some endemic areas it is much higher. The proportion of
      women with anti-HCV who have active infection with viremia is 60% to 70%.
      Transmission of HCV occurs only when serum HCV RNA is detectable and may be
      related to higher levels (above 10(6) copies per mL). The rate of mother-to
      infant transmission is 4% to 7% per pregnancy in women with HCV viremia. Co
      infection with human immunodeficiency virus (HIV) increases the rate of
      transmission 4 to 5 fold. The actual time and mode of transmission are not known.
      Elective Cesarean section is not recommended for women with chronic HCV infection
      alone. The role of treatment to prevent transmission is limited by the fetal
      toxicity of currently available medications for hepatitis C. Breast feeding poses
      no important risk of HCV transmission if nipples are not traumatized and maternal
      hepatitis C is quiescent. Pregnant women at high risk for HCV infection should be
      screened for anti-HCV, and HCV RNA testing should be performed if anti-HCV is
      positive. Infants of women with hepatitis C should be tested for HCV RNA on two
      occasions, between the ages of 2 and 6 months and again at 18 to 24 months, along
      with serum anti-HCV. The natural history of mother-to-infant hepatitis C remains
      uncertain, especially the course in the first year of life when some infants
      appear to have spontaneous resolution.

PMID- 12407584
TI  - Introduction to therapy of hepatitis C.
AB  - Since the 1997 National Institutes of Health Consensus Development Conference on
      management of hepatitis C there have been several important advances that
      significantly impact its therapy; notably the availability of sensitive,
      specific, and standardized assays for identifying hepatitis C virus (HCV) RNA in
      the serum, the addition of ribavirin to alpha interferon, the pegylation of alpha
      interferon, and the demonstration that sustained virological response (SVR) is
      the optimal surrogate endpoint of treatment. Using pegylated interferon and
      ribavirin, virological response with relapse and nonresponse are less common, but
      remain poorly understood. Current studies are evaluating nonvirological endpoints
      of treatment, namely biochemical response and histological response. To date,
      definitive treatment trials have primarily been conducted in adult patients with
      elevated aminotransferase levels, clinically compensated chronic liver disease,
      and no other significant medical disorder. Limited data are available from
      studies of other patient populations, and the safety of interferon-based
      treatment has not yet been established in several patient groups. Future research
      is needed to elucidate the mechanisms of viral response and clearance, to develop
      effective therapies for interferon nonresponse or intolerance, to define the role
      of complementary and alternative medicine and other nonspecific therapies, and to
      develop strategies for the optimal management and treatment of special patient
      populations who probably represent the majority of persons with chronic hepatitis
      C in the United States.

PMID- 12407585
TI  - Optimal therapy of hepatitis C.
AB  - The highest response rates to antiviral therapy for the treatment of chronic
      hepatitis C have been achieved using the combination of peginterferon and
      ribavirin. Recently completed controlled trials have reported rates of sustained
      virological response (SVR) between 50% and 60% in patients treated with higher
      doses of peginterferon and ribavirin, which was 5% to 10% higher with standard
      doses of interferon alfa and ribavirin. The major determinant of outcome of
      therapy is hepatitis C virus (HCV) genotype. With the combination of
      peginterferon and ribavirin, patients with genotype 1 achieve response rates of
      40% to 45%, compared with rates approaching 80% with genotypes 2 or 3.
      Importantly, patients with HCV genotype 1 achieve higher rates of response with
      48 weeks than with 24 weeks of therapy, whereas patients with genotypes 2 and 3
      are adequately treated with a 24-week course. Furthermore, patients with
      genotypes 2 and 3 require only 800 mg of ribavirin daily to achieve optimal
      response rates, whereas 1,000 to 1,200 mg daily is needed for patients with
      genotype 1. Future studies should focus on optimizing the dose of peginterferon
      and ribavirin by patient characteristics, particularly on resolving the issue of
      weight-based dosing. For patients with good prognostic factors, a lower dose and
      shorter course of peginterferon may be adequate for full effect. Importantly,
      research is needed to show how treatment regimens can best be applied to other
      patient groups with hepatitis C, such as patients with acute hepatitis, human
      immunodeficiency virus coinfection, renal disease, solid-organ transplant,
      neuropyschiatric disease, autoimmunity, and alcohol or substance abuse.

PMID- 12407586
TI  - Retreatment of patients with chronic hepatitis C.
AB  - Significant advances have been made in the treatment of chronic hepatitis C virus
      (HCV) infection during the past 5 years. As a consequence, there is continuing
      enthusiasm for retreating patients who did not achieve sustained virological
      response (SVR) with previous therapy. Retreatment of non-responders to standard
      interferon monotherapy using interferon and ribavirin has yielded SVR rates of
      12% to 15%. Retreatment with peginterferon and ribavirin has been more effective;
      achieving SVR rates of 34% to 40%. Retreatment of patients who relapsed after
      interferon monotherapy using standard interferon and ribavirin yielded SVR rates
      of 47%, whereas retreatment with peginterferon and ribavirin resulted in an SVR
      rate of about 60%. The major factors associated with a higher likelihood of an
      SVR after retreatment include previous relapse, previous treatment with
      interferon monotherapy, HCV genotypes 2 or 3, lower serum levels of HCV RNA, and
      having a significant decrease in HCV RNA levels during the initial course of
      therapy. These results help to focus retreatment with peginterferon and ribavirin
      on subsets of patients who are most likely to benefit.

PMID- 12407587
TI  - Treatment of chronic hepatitis C: a systematic review.
AB  - This systematic review addressed 3 issues regarding current treatments for
      chronic hepatitis C: (1) efficacy and safety in treatment-naive patients; (2)
      efficacy and safety in selected subgroups of patients; and (3) effects on long
      term clinical outcomes. Electronic databases were searched for articles from
      January 1996 to March 2002. Additional articles were identified by searching
      references in pertinent articles and recent journals and by questioning experts.
      Articles were eligible for review if they reported original human data from a
      study that used virological, histological, or clinical outcome measures. For data
      collection, paired reviewers assessed the quality of each study and abstracted
      data. This systematic review found that the combination of high-dose
      peginterferon and ribavirin was more efficacious than standard interferon and
      ribavirin in persons infected with hepatitis C virus (HCV) genotype 1 (sustained
      virologic response [SVR] rate: 42% vs. 33%) and that ranges of SVR rates were
      higher with peginterferon than standard interferon monotherapy in naive patients
      (10% to 39% vs. 3% to 19%). Reports were consistent in showing treatment with
      interferon and ribavirin was more efficacious than interferon monotherapy in
      treatment-naive persons and previous nonresponders and relapsers. Studies were
      moderately consistent in showing that treatment decreases the risk for
      hepatocellular carcinoma (HCC). The evidence on treatment in important subgroups
      was limited by a lack of randomized controlled trials. Thus, the combination of
      peginterferon and ribavirin was the most efficacious treatment in patients with
      HCV genotype 1. Long-term outcomes were improved in patients with hepatitis C who
      achieved an SVR with treatment.

PMID- 12407588
TI  - Monitoring of viral levels during therapy of hepatitis C.
AB  - Alpha interferon therapy of chronic hepatitis C is typically accompanied by a
      biphasic decrease in hepatitis C virus (HCV) RNA levels: an initial rapid decline
      during the first 24 to 48 hours, and a second more gradual decline during the
      following weeks. The rate of second-phase decline correlates with ultimate
      response to interferon treatment. Thus, assessment of early virological response
      (EVR) may predict outcome. Data from 2 large clinical trials of peginterferon and
      ribavirin were combined and analyzed to determine the optimal definition of an
      EVR which, if not achieved, was associated with a low likelihood of a sustained
      virological response (SVR). A fall in HCV RNA level to undetectable or by at
      least 2 log(10) units after 12 weeks was found to be the optimal definition of an
      EVR. Among 965 patients, 778 (80%) achieved an EVR by week 12, including all
      except 1 patient with genotypes 2 or 3. Among 187 patients without an EVR, only 3
      (1.6%) had an SVR. These findings suggest that patients with genotype 1 who do
      not achieve an EVR should stop treatment after 12 weeks. Use of an early stopping
      rule reduces treatment costs by at least 16% and avoids the inconvenience and
      side effects of treatment in the 19% of patients without an EVR who have little
      chance of a lasting virological response.

PMID- 12407589
TI  - The role of liver biopsy in chronic hepatitis C.
AB  - The report of the 1997 National Institutes of Health Consensus Development
      Conference on hepatitis C endorsed pretreatment liver biopsy. We revisit the
      following questions: Does liver histology help determine the urgency of, and
      predict the likelihood of response to, antiviral therapy, and can surrogate
      markers supplant histological assessment? Because the rate of progression of
      chronic hepatitis C is influenced by baseline histological grade/stage, patients
      can be stratified into those with moderate to severe hepatitis, who merit
      imminent therapy, and those with mild hepatitis, in whom therapy can be postponed
      until more effective/tolerable treatments become available. Less advanced
      baseline histology has been shown to be an independent predictor of
      responsiveness to antiviral therapy. Although the predictive value of biopsy is
      insufficient to withhold therapy from patients with advanced fibrosis, baseline
      biopsy helps gauge expectations for the outcome of therapy. Reports have been
      published recently suggesting that laboratory markers can predict distinctions
      between low-grade fibrosis and therapy-indicating septal fibrosis/cirrhosis.
      These indices, however, are insufficiently reliable to predict histological
      distinctions in populations with varying prevalences of fibrosis/cirrhosis or to
      provide anything more than broad qualitative distinctions, far short of the
      potential information in a liver biopsy. For most patients, the value of
      pretreatment liver biopsy outweighs its risks, provides information about the
      urgency of treatment, and should be retained. Studies to identify noninvasive
      laboratory markers of histological activity and stage, especially genetic
      predictors of accelerated disease progression, command a high priority.

PMID- 12407590
TI  - Role of liver biopsy in management of chronic hepatitis C: a systematic review.
AB  - This systematic review addresses 2 questions pertinent to the need for
      pretreatment liver biopsy in patients with chronic hepatitis C: how well do liver
      biopsy results predict treatment outcomes for chronic hepatitis C? How well do
      biochemical blood tests and serologic measures of fibrosis predict the biopsy
      findings in chronic hepatitis C? Medline and other electronic databases were
      searched from January 1985 to March 2002. Additional articles were sought in
      references of pertinent articles and recent journals and by querying experts.
      Articles were eligible for review if they reported original human data from a
      study that used virological, histological, pathologic, or clinical outcome
      measures. Paired reviewers assessed the quality of each eligible study and
      abstracted data. Studies suggested that advanced fibrosis or cirrhosis on initial
      liver biopsy is associated with a modestly decreased likelihood of a sustained
      virological response (SVR) to treatment. Also, studies relatively consistently
      showed that serum aminotransferases have modest value in predicting fibrosis on
      biopsy; that extracellular matrix tests hyaluronic acid and laminin may have
      value in predicting fibrosis, and that panels of tests may have the greatest
      value in predicting fibrosis or cirrhosis. Biochemical and serologic tests were
      best at predicting no or minimal fibrosis, or at predicting advanced
      fibrosis/cirrhosis, and were poor at predicting intermediate levels of fibrosis.
      Thus, evidence suggests that liver biopsy may have some usefulness in predicting
      efficacy of treatment in patients with chronic hepatitis C, and biochemical blood
      tests and serologic tests currently have only modest value in predicting fibrosis
      on liver biopsy.

PMID- 12407591
TI  - Children with hepatitis C.
AB  - An estimated 240,000 children in the United States have antibody to hepatitis C
      virus (HCV) and 68,000 to 100,000 are chronically infected with HCV. Acute HCV
      infection is rarely recognized in children outside of special circumstances such
      as a known exposure from an HCV-infected mother or after blood transfusion. Most
      chronically infected children are asymptomatic and have normal or only mildly
      abnormal alanine aminotransferase levels. Although the natural history of HCV
      infection acquired in childhood seems benign in the majority of instances, the
      infection takes an aggressive course in a proportion of cases leading to
      cirrhosis and end-stage liver disease during childhood; the factors responsible
      for a more aggressive course are unidentified. An optimal approach to management
      of hepatitis C in children would be prevention, particularly of perinatal
      transmission, which is now the major cause of new cases of hepatitis C in
      children. Obstetrical factors may be important determinants of transmission,
      which, if confirmed, should lead to changes in the care of infected women.
      Therapy of HCV infection in children is also not well defined. There have been no
      large randomized, controlled trials of therapy in children with chronic hepatitis
      C. Small heterogeneous studies of interferon monotherapy have reported sustained
      virological response rates of 35% to 40%. There are few data regarding the use of
      combination therapy with interferon and ribavirin in children and no information
      on the use of peginterferon. Clearly, there are important needs for future
      epidemiologic and clinical research on hepatitis C in childhood.

PMID- 12407592
TI  - Treatment of patients with hepatitis C and normal serum aminotransferase levels.
AB  - Approximately 30% of patients with chronic hepatitis C have normal serum alanine
      aminotransferase (ALT) levels and another 40% have ALT levels that are less than
      twice the upper limit of the normal range. Most patients with normal ALT levels
      have mild degrees of inflammation with mild or no fibrosis, and the rate of
      disease progression is reduced compared with that in patients with elevated ALT
      levels. Some patients with normal ALT levels have advanced fibrosis and cirrhosis
      on liver biopsy. Treatment of patients with normal ALT levels with either
      interferon monotherapy or interferon/ribavirin combination therapy has shown
      sustained virological response (SVR) rates that are equivalent to those achieved
      for patients with elevated ALT levels. Thus, patients with chronic hepatitis C
      should not be excluded from therapy based on ALT levels alone. The decision to
      initiate therapy with interferon and ribavirin should be based on a combination
      of factors independent of ALT levels including amount of fibrosis on liver
      biopsy, hepatitis C virus (HCV) genotype and viral level, patient age and
      motivation, and co-morbid illness, and the presence of other complicating
      conditions.

PMID- 12407593
TI  - Treatment of patients with hepatitis C and cirrhosis.
AB  - Recommendations for treatment of hepatitis C in patients with cirrhosis are
      difficult. Few prospective studies have focused on treatment of patients with
      advanced disease, and response rates appear to be lower and serious side effects
      more frequent in patients with cirrhosis. In patients with compensated cirrhosis,
      combination therapy with interferon alfa (3 million units [MU] 3 times a week)
      and ribavirin (1,000 or 1,200 mg/d) results in a sustained virological response
      (SVR) in 33% to 41% of patients. Responses to combination therapy are not
      significantly higher using peginterferon alfa 2a (180 microg/wk; 43%) or
      peginterferon alfa 2b (1.5 microg /kg/wk; 44%) compared with standard interferon.
      In using peginterferon in combination therapy, the benefits of once weekly dosing
      need to be weighed against the higher risks of cytopenias and greater costs with
      the pegylated formulations. Combination therapy results in some degree of
      histological improvement even in patients who are virological non-responders.
      These findings provide the scientific basis for ongoing studies of maintenance
      therapy with peginterferon to prevent complications of cirrhosis in non-responder
      patients with hepatitis C. Recommendations for management of decompensated
      cirrhosis and of recurrent hepatitis C after liver transplantation are difficult
      because of limitations of data, most of which are derived from uncontrolled case
      series. Combination therapy is poorly tolerated in both groups and rates of
      response are low. Thus, while the medical need is great, treatment of patients
      with decompensated cirrhosis or with recurrent hepatitis C after transplantation
      should be undertaken cautiously and only within the confines of prospective
      clinical trials.

PMID- 12407594
TI  - Therapy of acute hepatitis C.
AB  - Acute hepatitis C has a high propensity to become chronic, which provides the
      rationale for treating patients with acute disease attempting to prevent
      chronicity. Almost all published studies on therapy of acute hepatitis C have
      been small in size, uncontrolled, and highly heterogeneous as to patient
      features, dose and duration of treatment, follow-up evaluation, and criteria used
      to define efficacy and safety. The published studies on treatment of acute
      hepatitis C have used standard alfa or beta interferon monotherapy: none have
      evaluated combination therapy of interferon and ribavirin or peginterferon.
      Several meta-analyses of published studies have concluded that initiation of
      interferon monotherapy during the acute phase of hepatitis C virus (HCV)
      infection significantly reduces (by 30% to 40%) evolution to chronic hepatitis.
      The tolerability of interferon in acute hepatitis C has been excellent, even in
      symptomatic and icteric patients; the side effects and adverse events being
      similar in type and frequency to those seen when treating chronic cases. Thus,
      currently available data support treatment of patients with acute hepatitis C,
      but data are insufficient to draw firm conclusions about which patients to treat,
      when therapy should be started, or what regimen is optimal. Future studies of
      adequate size and design should focus on efficacy and tolerability of
      peginterferons and whether therapy should be started immediately after diagnosis
      or delayed for 2 to 4 months to avoid treatment of patients who spontaneously
      recover.

PMID- 12407595
TI  - Hepatitis C and human immunodeficiency virus infection.
AB  - In the United States, an estimated 200,000 persons are infected with both
      hepatitis C virus (HCV) and human immunodeficiency virus (HIV). As the lives of
      HIV-infected persons have been prolonged by use of highly active antiretroviral
      therapy, liver disease has emerged as an important, and in some settings, the
      leading cause of morbidity and mortality. Human immunodeficiency virus infection
      appears to adversely affect all stages of hepatitis C infection, leading to
      increased viral persistence and accelerated progression of HCV-related liver
      disease. In turn, hepatitis C may affect the management of HIV infection,
      increasing the incidence of liver toxicity caused by antiretroviral medications.
      The medical management of hepatitis C in HIV-infected persons remains
      controversial, in part because of the complexity of both infections and potential
      drug interactions, but chiefly because there is so little published information.
      Nonetheless, the burden of liver disease is too high to delay management of
      HIV/HCV-coinfected persons while awaiting better data. Instead, the management of
      hepatitis C today must be based on data generated on persons without HIV and an
      understanding of both infections. Properly designed studies of therapy in HIV/HCV
      coinfected persons are needed to help guide management of these patients in the
      future.

PMID- 12407596
TI  - Prevention and treatment of hepatitis C in injection drug users.
AB  - Injection drug users constitute the largest group of persons infected with the
      hepatitis C virus (HCV) in the United States, and most new infections occur in
      drug users. Controlling hepatitis C in the U.S. population, therefore, will
      require developing, testing, and implementing effective prevention and treatment
      strategies for persons who inject drugs. Fortunately, a substantial body of
      research and clinical experience exists on the prevention and management of
      chronic viral diseases among injection drug users. The need to implement
      interventions to stop the spread of HCV among drug users is critical. The
      capacity of substance-use treatment programs need to be expanded to accommodate
      all who want and need treatment. Physicians and pharmacists should be educated in
      how to provide access to sterile syringes and to teach safe injection techniques,
      both of which are lifesaving interventions. The treatment of hepatitis C in drug
      users requires an interdisciplinary approach that brings together expertise in
      treating hepatitis and caring for drug users. Treatment decisions should be made
      individually by patients with their physicians, based on a balanced assessment of
      risks and benefits and the patient's personal values. Physicians should carefully
      assess, monitor, and support adherence and mental health in all patients,
      regardless of whether drug use is known or suspected. Research is needed to
      better understand how best to prevent and treat hepatitis C in substance users.
      In the meantime, substantial progress can be made if existing knowledge and
      resources are brought to bear.

PMID- 12407597
TI  - Alcohol use and hepatitis C.
AB  - Excess alcohol consumption can worsen the course and outcome of chronic hepatitis
      C. It is important to distinguish between alcohol abuse, which must be treated on
      its own merits, and the effect of alcohol use on progression, severity, and
      treatment of hepatitis C. Most studies on the effects of alcohol on hepatitis C
      have focused on patients with high levels of daily alcohol intake. Indeed, the
      adverse effects of light and moderate amounts of alcohol intake on hepatitis C
      virus (HCV) infection have not been clearly shown, and only limited studies have
      been performed. Sex differences exist in the effect of alcohol on fibrosis as
      well as on the severity of hepatitis C. Alcohol use has been reported to be
      associated with lower responses to therapy and, in some studies, higher HCV RNA
      levels and increased HCV quasi-species. Few studies address the treatment of
      hepatitis C in the alcoholic individual or determine the effect of continued
      light or moderate alcohol use on the outcome of treatment response. In summary,
      many critical questions remain regarding the interactions between alcohol and
      hepatitis C. Currently, the evidence from the literature shows that heavy alcohol
      intake worsens the outcome of HCV infection. The literature is inadequate to
      provide definitive recommendations regarding the effect of light to moderate
      alcohol use in patients with hepatitis C.

PMID- 12407598
TI  - Understudied populations with hepatitis C.
AB  - Managing patients with hepatitis C virus (HCV) infection consists primarily of
      antiviral treatment, currently with peginterferon and ribavirin. Unfortunately,
      treatment recommendations derive largely from trials that have focused on highly
      selected patient populations. As a consequence of the strict inclusion and
      exclusion criteria in these studies, more than half of all HCV-infected patients
      would be ineligible for enrollment. Even among the selected patients enrolled
      into studies, only 50% achieve a sustained virological response (SVR). Patients
      not eligible for current therapies include those with mild disease and normal
      alanine aminotransferase (ALT) levels, patients with advanced and decompensated
      liver disease, children, the elderly, patients with ongoing or recent alcohol and
      substance abuse, renal disease, human immunodeficiency virus (HIV) infection,
      severe psychiatric or neurologic illness, autoimmune disorders, solid organ
      transplant, and other significant comorbid conditions. Because these patients
      have been excluded from most clinical trials, little is known about the safety or
      efficacy of therapy in these populations. The expense and side effects of therapy
      are also an impediment to treatment of patients who are on public assistance, in
      prisons, and in institutions. Clearly, new efforts and new approaches are needed
      to expand the eligibility for antiviral therapy of hepatitis C and make treatment
      more available for understudied populations with this disease.

PMID- 12407599
TI  - Side effects of therapy of hepatitis C and their management.
AB  - Interferon and ribavirin combination therapy for chronic hepatitis C produces a
      number of well-described side effects that are dominated by fatigue, influenza
      like symptoms, hematologic abnormalities, and neuropsychiatric symptoms.
      Combination therapy with pegylated interferons (peginterferon alfa-2a and alfa
      2b) yields an adverse event profile similar to standard interferon, although the
      frequency of certain adverse events may vary by preparation. Premature withdrawal
      from therapy due to adverse events was required in 10% to 14% of participants in
      registration trials of these agents. Most adverse events were safely and
      effectively managed by dose reduction using predetermined criteria. The most
      common indications for dose reduction were hematologic abnormalities, such as
      anemia and neutropenia, with the latter more frequent in peginterferon treatment
      arms. Recent data suggest that maintaining adherence to a prescribed treatment
      regimen can enhance antiviral response. Strategies to maximize adherence are
      being developed and, in the future, may include early identification of and
      therapy for depression and the selective use of hematopoietic growth factors to
      ameliorate hematologic abnormalities.

PMID- 12407600
TI  - Future therapy of hepatitis C.
AB  - Currently available therapies for the treatment of chronic hepatitis C are
      effective in half of patients, but are expensive, often poorly tolerated, and
      unsuitable for certain patient populations. The ideal therapy would be highly
      effective, orally bioavailable, have minimal side effects, be cost effective, and
      suitable for the majority of patients with hepatitis C. Recent advances in
      understanding the replication cycle of hepatitis C virus (HCV) and structural,
      crystallographic definitions of components of the viral polyprotein have improved
      the prospects for development of novel therapies. The lack of a small animal
      model of HCV infection continues to hamper progress in the preclinical evaluation
      of new antivirals and vaccines. Strategies to enhance response to current
      therapies include the development of novel interferons and delivery systems,
      nucleoside analogues that have reduced hemolysis compared with ribavirin, inosine
      5' monophosphate dehydrogenase inhibitors, and other immunomodulators that are
      being evaluated as adjunctive therapy to interferon-based regimens. Compounds in
      preclinical or early phase human trials include small molecules that inhibit
      virus specific enzymes (such as the serine proteases, RNA polymerase and
      helicase), or those that prevent translation initiation (such as antisense
      molecules and ribozymes). Antifibrotic agents are also being developed in an
      attempt to prevent disease progression in patients in whom HCV RNA cannot be
      eradicated. While the advent of these newer compounds represent an exciting phase
      in the treatment of HCV, their safety and efficacy need to be established. Most
      of these newer therapies are unlikely to be available for routine clinical use in
      the next 3 to 5 years.

PMID- 12407601
TI  - Blood transfusion for cardiopulmonary bypass: the need to answer a basic
      question.

PMID- 12407602
TI  - Mechanisms behind operating room blood transfusions in coronary artery bypass
      graft surgery patients with insignificant bleeding.
AB  - OBJECTIVE: To investigate situations in cardiac surgery when transfusions are
      sometimes used for indications other than to compensate for surgical bleeding.
      DESIGN: Retrospective study. SETTING: Cardiac surgery unit at a university
      teaching hospital. PARTICIPANTS: Patients scheduled for coronary artery bypass
      graft surgery (n = 2,469). INTERVENTIONS: A subgroup of patients with surgical
      bleeding of < or = 400 mL (n = 982) was selected to identify mechanisms leading
      to perioperative erythrocyte transfusion. MEASUREMENTS AND MAIN RESULTS: Bleeding
      of >400 mL triggered transfusion. At less than this bleeding volume, other
      indications were noted: unstable angina, use of blood cardioplegia, and bad
      surgical outcome, such as inotropic support. After exclusion of these predictors
      and anemic patients, the strongest predictors were female gender (p < 0.001),
      weight < or = 70 kg (p < 0.001), cardiopulmonary bypass (CPB) time > or = 90
      minutes (p = 0.002), CPB cooling < or = 32 degrees C (p = 0.038), and advanced
      age (p < 0.001). Results from a more detailed study of medical records showed
      that within its normal concentration range, the operating room-transfused
      patients had lower hemoglobin levels. When followed postoperatively in the
      intensive care unit and ward, these patients continued to receive more
      transfusions (p < 0.05) even though their bleeding in the intensive care unit did
      not differ from the control subjects. CONCLUSION: Some patients are transfused
      because of institutional bias of an anticipated need rather than for true
      surgical bleeding. A concern of hemodilution from standard CPB circuits suggests
      a possible advantage with low-priming volume for smaller adult female patients.

PMID- 12407603
TI  - Prediction of excessive bleeding after coronary artery bypass graft surgery: the
      influence of timing and heparinase on thromboelastography.
AB  - OBJECTIVE: To compare the ability of thromboelastography, when done at either 10
      or 60 minutes after protamine reversal of heparin, to predict excessive bleeding
      after coronary artery bypass graft (CABG) surgery and to investigate, with the
      use of heparinase, whether heparin contamination was responsible for the
      difference, if any. DESIGN: Prospective study. SETTING: University hospital,
      single institution. PARTICIPANTS: Patients undergoing elective CABG surgery (n =
      40). INTERVENTIONS: Blood samples for thromboelastography and routine coagulation
      tests were collected before induction of anesthesia and at 10 and 60 minutes
      after protamine reversal of heparin. Blood loss and blood product use were
      recorded postoperatively. MEASUREMENTS AND MAIN RESULTS: Of 40 patients
      undergoing elective CABG surgery, 10 fulfilled the criteria for excessive
      postoperative bleeding. The sensitivity of thromboelastography to identify
      patients who bled was better at 60 minutes than at 10 minutes after protamine
      reversal of heparin (100% v 70%). There was greater specificity (83% v 40% at 10
      minutes; 73% v 20% at 60 minutes) and positive predictive value (58% v 28% at 10
      minutes; 55% v 29% at 60 minutes) when heparinase was added. At both times,
      thromboelastography showed only moderate correlation with total blood loss and
      the use of fresh frozen plasma or platelets or both. Conventional coagulation
      tests did not predict excessive postoperative bleeding. CONCLUSION: This study
      suggests that timing and the use of heparinase influence the predictive ability
      of thromboelastography, but its usefulness as a sole predictor of post-CABG
      surgery bleeding is limited.

PMID- 12407604
TI  - Differences in arterial and venous thromboelastography parameters: potential
      roles of shear stress and oxygen content.
AB  - OBJECTIVE: To investigate potential mechanisms for the differences in
      thromboelastography variables observed between arterial blood samples and venous
      blood samples. DESIGN: Prospective cohort study. SETTING: University hospital.
      PARTICIPANTS: Patients undergoing cardiac surgery (n = 33). INTERVENTIONS: After
      the withdrawal of 10 mL of discarded blood (>3 deadspace volumes), 3 blood
      samples were withdrawn simultaneously from the central venous port of the
      pulmonary artery catheter (CVP), the radial arterial catheter (ART), and the side
      port of the 9F sheath introducer (SI). MEASUREMENTS AND MAIN RESULTS:
      Thromboelastography was done simultaneously on each sample. All
      thromboelastography analyses were performed with 1% celite and heparinase
      according to the manufacturer's guidelines. A total of 80 ART, SI, and CVP
      comparisons were obtained. Mean hematocrit values were not different between
      sampling sites (27 +/- 4 v 27 +/- 4 v 27 +/- 3). Thromboelastography R time
      values (mean +/- SD) were CVP, 8 +/- 3; ART, 10 +/- 3; and SI, 13 +/- 5 (p =
      0.004). Thromboelastography maximal amplitude (MA) values (mean +/- SD) were CVP,
      60.4 +/- 11.7; ART, 56.2 +/- 11.4; and SI, 50.5 +/- 13.2 (p = 0.008). Calculated
      maximal shear stresses were CVP, 48 dyne/cm(2); ART, 36 dyne/cm(2); and SI, 0.3
      dyne/cm(2). Blood samples obtained from the CVP (highest shear stress) resulted
      in faster (shorter R) and stronger (larger MA) coagulation compared with the
      arterial site (intermediate shear stress) and sheath introducer (lowest shear
      stress). CONCLUSION: These data show that differences exist in
      thromboelastography values between arterial and venous blood samples and, more
      importantly, show that the differences observed are not related to differences in
      oxygen content. These differences seem to be related to differences in catheter
      lumen diameter and, presumably, shear forces.

PMID- 12407605
TI  - Perflubron emulsion (AF0144) augments harvesting of autologous blood: a phase II
      study in cardiac surgery.
AB  - OBJECTIVE: To assess tolerance and preliminary efficacy of a perfluorocarbon
      emulsion (AF0144) used with acute normovolemic hemodilution to reduce allogeneic
      blood transfusion for patients undergoing coronary artery bypass graft (CABG)
      surgery with cardiopulmonary bypass (CPB). DESIGN: Controlled, single-blind,
      parallel-group phase II dose escalation trial. SETTING: Single-institution
      university medical center. PARTICIPANTS: Adult patients undergoing elective CABG
      surgery (n = 36). INTERVENTIONS: A calculated volume of autologous whole blood
      was harvested for each patient with a target on-bypass hematocrit of 20% to 22%.
      Placebo, low-dose (1.8 g/kg) AF0144, or high-dose (2.7 g/kg) AF0144 was infused.
      During CPB, blood was transfused at protocol-defined triggers (hematocrit <15%,
      PvO(2) <30 mmHg, SvO(2) <60%). After CPB, all autologous whole blood was
      reinfused. Allogeneic red blood cells were transfused if a trigger was reached.
      MEASUREMENTS AND MAIN RESULTS: Safety assessments (vital signs, hematology, blood
      chemistry, coagulation, and adverse events) were monitored through postoperative
      day 21. Efficacy endpoints included percentage of patients reaching a transfusion
      trigger and number of allogeneic units of red blood cells transfused. During CPB,
      <25% of subjects reached a transfusion trigger. During hospitalization,
      significantly fewer (p < 0.01) high-dose subjects (33%) reached a trigger than
      did control patients (91%). Allogeneic red blood cell transfusion did not differ
      significantly among groups. Safety assessments indicated AF0144 was well
      tolerated. CONCLUSION: The data suggest that AF0144 when used with acute
      normovolemic hemodilution is well tolerated and may be effective when used to
      enhance oxygen delivery for patients undergoing CABG surgery. Confirmation of
      safety and efficacy in a larger phase III clinical trial is warranted.

PMID- 12407606
TI  - Hypothermia augments polymorphonuclear leukocyte degranulation and interleukin-8
      production from human umbilical vein endothelial cells and increases
      lipopolysaccharide-induced polymorphonuclear leukocyte-endothelial cell
      interaction when followed by normothermia.
AB  - OBJECTIVE: To determine if hypothermia followed by normothermia (rewarmed to 37
      degrees C) changes the inflammatory response of polymorphonuclear leukocytes
      (PMNs) and human umbilical vein endothelial cells (HUVEC). DESIGN: Prospective,
      controlled, in vitro study. SETTING: University laboratory. PARTICIPANTS: PMNs
      from 4 healthy volunteers and HUVEC. MEASUREMENTS AND MAIN RESULTS: PMNs and
      HUVEC were incubated for 3 hours at 20 degrees C, 30 degrees C, or 37 degrees C
      followed by 37 degrees C again. PMN degranulation, cytokine production from
      HUVEC, and PMN-HUVEC interaction were compared among the 3 experimental
      temperatures. Interleukin (IL)-8-induced PMN degranulation measured by
      myeloperoxidase concentrations was significantly higher in the 20 degrees C and
      30 degrees C groups than the 37 degrees C groups. Bacterial lipopolysaccharide
      (LPS)-induced IL-8 production from HUVEC, measured by enzyme-linked immunosorbent
      assay, was significantly higher in the 20 degrees C group than the other 2
      groups; however, tumor necrosis factor-alpha was not detectable in any of the
      groups. LPS-induced cell injury measured by cellular (51)Cr release was
      significantly higher in the 20 degrees C and 30 degrees C groups than in the 37
      degrees C groups. This injury was significantly inhibited by IL-8 antibody.
      CONCLUSION: Hypothermic (20 degrees C and 30 degrees C) incubation followed by
      rewarming augmented IL-8-induced PMN degranulation and LPS-induced IL-8
      production from HUVEC and LPS-induced PMN-endothelial interaction. IL-8 plays an
      important role in this increased injury. This increased inflammatory response may
      support the positive outcomes of normothermic CPB.

PMID- 12407607
TI  - Current practice of internal jugular venous cannulation in a university
      anesthesia department: influence of operator experience on success of cannulation
      and arterial injury.
AB  - OBJECTIVE: To describe current cannulation of the internal jugular vein (CIJV)
      practice in a university anesthesia department. DESIGN: Prospective,
      observational, and not randomized. SETTING: Operating rooms of the Hospital of
      the University of Pennsylvania. PARTICIPANTS: Elective surgical patients
      requiring CIJV (n = 426). INTERVENTIONS: CIJV performed by real-time ultrasound
      visualization (U-CIJV) or by anatomic landmarks (AL-CIJV). MEASUREMENTS AND MAIN
      RESULTS: A total of 462 procedures were studied in 426 patients. Overall
      cannulation failure was 2.1% with U-CIJV and 13.8% with AL-CIJV (p = 0.0001).
      Cumulative CIJV success by the sixth needle pass was 94.0%, regardless of
      technique. Junior operators performed 75.3% of CIJV, of which 86.8% was U-CIJV.
      First-pass success across operators was 60% to 70% for U-CIJV and 50% to 80% for
      AL-CIJV. Arterial puncture rates averaged 7.0%, regardless of technique (p =
      0.45). The junior operator may be more at risk for arterial puncture during U
      CIJV. CONCLUSION: U-CIJV offers incomplete protection against arterial injury in
      this practice compared with the literature. A possible solution is the ultrasound
      needle guide, which may minimize arterial injury, especially with junior
      operators.

PMID- 12407608
TI  - Does ultrasound imaging before puncture facilitate internal jugular vein
      cannulation? Prospective randomized comparison with landmark-guided puncture in
      ventilated patients.
AB  - OBJECTIVE: To investigate whether prepuncture ultrasound evaluation of vascular
      anatomy facilitates internal jugular vein cannulation compared with landmark
      guided puncture. DESIGN: Prospective randomized study. SETTING: Single community
      hospital. PARTICIPANTS: Adult patients undergoing general anesthesia (n = 240).
      INTERVENTIONS: The right internal jugular vein was cannulated using either
      anatomic landmarks or prepuncture ultrasound (3.75/7.5 MHz) guidance. In the
      landmark group, respiratory jugular venodilation was used as the primary landmark
      for locating the vein. Results of cannulation and the incidence of complications
      were compared. MEASUREMENTS AND MAIN RESULTS: Patients were randomly assigned to
      the ultrasound or landmark group. Respiratory jugular venodilation was identified
      in 188 patients (78.3%), in whom results of cannulation did not differ between
      the 2 techniques with respect to the venous access rate (cannulated at the first
      attempt: 83.5% in the landmark v 85.7% in the ultrasound group), the success rate
      (cannulated within 3 attempts: 96.9% v 95.6%), and the incidence of arterial
      puncture (1.0% v 3.3%). In the remaining 52 respiratory jugular venodilation
      unidentified patients, the access rate (30.4% v 86.2%, p < 0.001) and the success
      rate (78.3 v 100%, p < 0.05) were significantly better in the ultrasound group,
      and no arterial puncture was recorded in the ultrasound group, whereas the
      incidence was 13.0% in the landmark group. The results were similar regardless of
      the ultrasound frequency used. CONCLUSION: Prepuncture ultrasound evaluation did
      not improve the result of right internal jugular vein cannulation compared with
      the respiratory jugular venodilation-guided approach. When the landmark was not
      observed, however, the prepuncture ultrasound guidance was helpful in
      facilitating the cannulation.

PMID- 12407609
TI  - Clinical evaluation of reflectance spectrophotometry for the measurement of
      gastric microvascular oxygen saturation in patients undergoing cardiopulmonary
      bypass.
AB  - OBJECTIVE: To evaluate the impact of cardiopulmonary bypass (CPB) on gastric
      mucosal oxygen saturation assessed by reflectance spectrophotometry in patients
      undergoing coronary artery bypass graft surgery. DESIGN: Prospective,
      observational study. SETTING: A division of cardiothoracic anesthesia in a
      university hospital. PARTICIPANTS: Twelve consecutive patients undergoing CPB.
      INTERVENTIONS: Monitoring, anesthesia, surgical procedure, and CPB for the
      patients followed routine clinical protocol as established in the departments.
      Microvascular oxygen saturation in gastric mucosa was assessed by reflectance
      spectrophotometry before, during, and after CPB. MEASUREMENTS AND MAIN RESULTS:
      Gastric mucosal oxygen saturation averaged 65 +/- 7% (mean +/- SD) before CPB,
      decreased significantly to 57 +/- 9% during CPB (p < 0.01), and was 59 +/- 8%
      after CPB. These changes in regional oxygen saturation were not mirrored in
      variables of systemic oxygenation. Gastric mucosal oxygen saturation always
      showed instantaneous reactions to various surgical and pharmacologic
      interventions. CONCLUSION: Reflectance spectrophotometry allowed the authors to
      assess gastric mucosal oxygen saturation with a high repetition rate, regardless
      of spontaneous circulation with pulsatile flow or nonpulsatile flow during CPB.
      This technique provided the means to monitor on-line the course of tissue oxygen
      saturation throughout the operative procedure. Reflectance spectrophotometry is
      an appropriate and sensitive assessment tool to monitor gastric mucosal oxygen
      saturation in patients undergoing CPB.

PMID- 12407610
TI  - Anesthetic implications of primary cardiac tumors in infants and children.
AB  - OBJECTIVE: To determine the degree of hemodynamic and airway compromise in
      infants and children undergoing anesthesia for primary cardiac tumors. DESIGN:
      Retrospective study. SETTING: Tertiary-care, academic children's hospital.
      PARTICIPANTS: Patients <18 years old who had undergone anesthesia and surgery for
      resection or biopsy of a primary cardiac tumor (n = 25). INTERVENTIONS: None.
      MEASUREMENTS AND MAIN RESULTS: Charts were reviewed for intraoperative
      complications, defined as (1) hypotension (20% decrease from baseline) during or
      after induction; (2) failure to gain airway control by insertion of an airway or
      endotracheal intubation, inability to ventilate after administration of a muscle
      relaxant, need for change in patient position, rigid bronchoscopy, or
      cardiopulmonary bypass for adequate oxygenation; and (3) new arrhythmias.
      Hypotension during induction occurred in 4 patients (16%), 3 of whom were
      hemodynamically unstable preoperatively. Hypotension after induction was found in
      2 (8%) patients. Hypotension occurred more frequently in patients with
      obstruction to blood flow and arrhythmia (n = 3), obstruction to blood flow only
      (n = 1), and arrhythmia only (n = 1). No patient had airway difficulty related to
      the tumor, although one intrapericardial tumor mimicked an anterior mediastinal
      mass. New arrhythmias occurred in 3 (12%) patients. CONCLUSIONS: The subgroup of
      patients at greatest risk are patients with a combination of obstruction to blood
      flow and arrhythmias. Despite the alarming diagnosis, the intraoperative course
      tends to be fairly stable in most cases. Extensive pericardial tumors may produce
      the same airway concerns as anterior mediastinal masses, but airway complications
      do not seem to be a problem with intrachamber tumors.

PMID- 12407611
TI  - Transesophageal echocardiography for cardiac surgery in children.
AB  - OBJECTIVE: To evaluate the usefulness of transesophageal echocardiography (TEE)
      for cardiac surgery in children. DESIGN: Prospective clinical study. SETTING:
      Nagoya City University Hospital. PARTICIPANTS: Children who had cardiac surgery
      from January 1998 to December 2000 (n = 90). INTERVENTIONS: TEE was used to the
      extent permitted by the probe size and the position of the patient during
      surgery. MEASUREMENTS AND MAIN RESULTS: TEE monitoring was performed safely
      without any complications in 88 of the patients. Based on the TEE findings, the
      anesthesiologists conferred with the surgeon about the efficacy of the surgical
      procedures in 11 patients (11 of 88 [12.5%]). The cardiac surgeons altered the
      surgical repair in 2 patients based on the TEE findings (2 of 88 [2.4%]).
      CONCLUSION: TEE is a valuable diagnostic tool for monitoring during cardiac
      surgery in children. The person who performs the TEE should use it carefully
      after obtaining thorough knowledge of the pathophysiology of pediatric cardiac
      diseases, their surgical indications, and how specific surgical procedures are
      done.

PMID- 12407612
TI  - Assessment of cardiac output, intravascular volume status, and extravascular lung
      water by transpulmonary indicator dilution in critically ill neonates and
      infants.
AB  - OBJECTIVE: To assess cardiac output, intrathoracic blood volume, global end
      diastolic volume, and extravascular lung water in critically ill neonates and
      small infants using transpulmonary indicator dilution. DESIGN: Prospective,
      observational, clinical study. SETTING: Pediatric intensive care unit in a
      university hospital. PARTICIPANTS: Critically ill neonates and small infants
      suffering from severe heart failure, respiratory failure, or sepsis (n = 10).
      INTERVENTIONS: A total of 194 transpulmonary indicator dilution measurements were
      done. Global end-diastolic volume, intrathoracic blood volume, and stroke volume
      were measured and compared with standard hemodynamic parameters during the
      clinical course and before and after volume loading (16 +/- 3.7 mL/kg of 10%
      albumin solution) in 8 of 10 patients. MEASUREMENTS AND MAIN RESULTS: A positive
      correlation was found for stroke volume index versus global end-diastolic volume
      (r = 0.76, p < 0.001) and intrathoracic blood volume (r = 0.56, p < 0.001). In
      contrast, no correlation was observed for stroke volume index versus central
      venous pressure. Volume loading resulted in significant increases in stroke
      volume index (p < 0.01), global end-diastolic volume (p < 0.01), and
      intrathoracic blood volume (p < 0.01); whereas central venous pressure, heart
      rate, mean arterial pressure, and extravascular lung water remained unchanged.
      CONCLUSION: Transpulmonary indicator dilution enables measurement of cardiac
      output and intravascular volume status in critically ill neonates and infants at
      the bedside. The effects of volume loading on cardiac preload and effective
      change in stroke volume can be monitored by this technique, whereas central
      venous pressure was not indicative of changes in intravascular volume status.

PMID- 12407613
TI  - A comparison of the chronotropic and dromotropic actions between adenosine
      triphosphate and edrophonium in patients undergoing coronary artery bypass graft
      surgery.
AB  - OBJECTIVE: To compare the effects of the stimulation of adenosine receptors and
      acetylcholine receptors in the cardiac conduction system in patients with
      ischemic heart disease. DESIGN: Prospective. SETTING: University hospital.
      PARTICIPANTS: Patients scheduled for coronary artery bypass graft surgery (n =
      37). INTERVENTIONS: The patients were divided into 3 groups: control group (n =
      9), adenosine triphosphate (ATP) group (n = 12), and edrophonium group (n = 16).
      ATP (10 mg) or edrophonium (0.25 mg/kg) followed by saline or the same amount of
      saline was injected through a central venous catheter. MEASUREMENTS AND MAIN
      RESULTS: ATP induced atrioventricular block in 10 of 12 patients (83%). The ATP
      injection produced a more prominent prolongation in the PQ duration (P-R
      interval) (139%) than in the P-P interval (105%) at the last beat before the
      development of atrioventricular block. The prolongation in the P-P interval (11%,
      average 85 msec) and PQ duration during atrioventricular block disappeared
      immediately after the restoration of atrioventricular conduction. After
      edrophonium, the maximal prolongation in P-P (118%, p < 0.01) and PQ (120%, p <
      0.01) intervals was the same. P-P interval remained prolonged (p < 0.01) after PQ
      interval returned to baseline. Neither ATP nor edrophonium affected the QRS
      duration. CONCLUSION: These findings suggest that ATP predominantly inhibited
      atrioventricular conduction rather than the firing rate of sinoatrial nodes, and
      edrophonium inhibited both proportionally even with prolonged inhibitory action
      on the sinoatrial nodes. An injection of ATP is needed only when a transient
      cardiac standstill is requested, such as in endovascular grafting surgery.
      Edrophonium may be used to slow heart rate during coronary artery bypass graft
      surgery.

PMID- 12407615
TI  - Comparison between repeat bolus intrathecal morphine and an epidurally delivered
      bupivacaine and fentanyl combination in the management of post-thoracotomy pain
      with or without cyclooxygenase inhibition.
AB  - OBJECTIVE: To compare the analgesic efficacy of a traditional epidurally
      delivered bupivacaine/fentanyl combination with a repeat bolus intrathecal
      morphine technique in the management of post-thoracotomy pain and to assess
      further the effect of cyclooxygenase (COX) inhibition on both modalities. DESIGN:
      Prospective, randomized, blinded study. SETTING: University teaching hospital.
      PARTICIPANTS: Patients having thoracic surgery. INTERVENTIONS: Epidural and
      intrathecal catheters were inserted. Blood and urine samples were collected for
      analysis. COX-1 and COX-2 inhibition with ibuprofen and nimesulide (COX-2
      selective) was instituted. MEASUREMENTS AND MAIN RESULTS: Pain was assessed at
      rest and coughing by visual analog scale. Peak expiratory flow rate, patient
      satisfaction rating, sedation score, analgesic requirements, and preoperative and
      postoperative urinary creatinine levels were measured. The spinal and nimesulide
      combination showed the lowest pain scores (p < 0.001), least reduction in peak
      expiratory flow rate (p < 0.001), and highest patient satisfaction rating (p =
      0.02). COX inhibition did not affect analgesic requirements in the epidural group
      or increase urinary creatinine in any group. CONCLUSION: The intrathecal morphine
      and nimesulide combination offered significantly better analgesia than any other
      combination studied. The efficacious interaction between opioids and nonsteroidal
      anti-inflammatory drugs may be COX-2 mediated.

PMID- 12407614
TI  - Postoperative oral amiodarone as prophylaxis against atrial fibrillation after
      coronary artery surgery.
AB  - OBJECTIVE: To assess the prophylactic effect of postoperative oral amiodarone on
      the incidence and severity of atrial fibrillation (AF) after coronary artery
      surgery. DESIGN: Prospective, randomized, blinded, controlled study. SETTING:
      University hospital. PARTICIPANTS: Patients who had coronary artery surgery (n =
      200). INTERVENTIONS: Patients in group 1 (n = 100) received oral amiodarone, 15
      mg/kg, 4 hours after arrival in the intensive care unit, followed by 7 mg/kg/d
      until hospital discharge. Patients in group 2 (n = 100) received placebo.
      MEASUREMENTS AND MAIN RESULTS: Incidence, duration, and recurrence of new
      episodes of AF and maximal ventricular rate response were recorded from day 0
      until hospital discharge. Side effects related to amiodarone and complications
      induced by new-onset AF were noted. The incidence of new-onset AF (12% v 25%) and
      maximal ventricular rate response (120 +/- 21 beats/min v 135 +/- 24 beats/min)
      were significantly lower in the amiodarone group. There were no side effects
      related to the administration of amiodarone. The incidence of complications
      induced by AF was comparable between the 2 groups. CONCLUSION: Postoperative
      prophylactic oral amiodarone after coronary artery surgery is safe and effective
      in reducing the incidence of new-onset AF and maximal ventricular rate response.

PMID- 12407616
TI  - Correction of a coagulopathy using recombinant factor VII before removal of an
      intra-aortic balloon pump.

PMID- 12407617
TI  - Successful treatment of refractory bleeding with recombinant factor VIIa after
      redo coronary artery bypass graft surgery.

PMID- 12407618
TI  - Percutaneous bypass cannulae can interfere with rapid infusion during liver
      transplantation.

PMID- 12407619
TI  - Usefulness of intraoperative transesophageal echocardiography in removing
      vegetation attached to a ventricular pacing lead implanted in a patient with
      dilated cardiomyopathy.

PMID- 12407620
TI  - Laparoscopic pericardial window: anesthetic implications.

PMID- 12407621
TI  - Management of atrial fibrillation after cardiac surgery-part II: prevention and
      treatment.

PMID- 12407622
TI  - Case 5--2002. Selective bronchial blockade in patients with previous
      contralateral lung surgery.

PMID- 12407623
TI  - Pro: cerebrospinal fluid drainage protects the spinal cord during
      thoracoabdominal aortic reconstruction surgery.

PMID- 12407624
TI  - Con: cerebrospinal fluid drainage does not protect the spinal cord during
      thoracoabdominal aortic reconstruction surgery.

PMID- 12407625
TI  - A different kind of aneurysm.

PMID- 12407626
TI  - Myocardial infarction with chest pain and paraplegia.

PMID- 12407627
TI  - How much cardiac output is enough?

PMID- 12407628
TI  - Magnetic resonance imaging evidence of spinal cord ischemia after coronary artery
      bypass graft surgery using cardiopulmonary bypass.

PMID- 12407629
TI  - The central anticholinergic syndrome: a rare cause of uncontrollable agitation
      after coronary artery bypass graft surgery.

PMID- 12407630
TI  - Hyperoxygenation of the operating field can prevent hypoxia during open surgery
      of the distal airway under high-frequency jet ventilation.

PMID- 12407631
TI  - Acute renal failure in the intensive care unit: a systematic review of the impact
      of dialytic modality on mortality and renal recovery.
AB  - BACKGROUND: There is controversy about which dialytic modality should be used for
      the treatment of acute renal failure (ARF) in the intensive care unit. We
      performed a systematic review and meta-analysis to determine the relative risks
      (RRs) of mortality and renal recovery associated with intermittent hemodialysis
      (IHD) therapy compared with continuous renal replacement therapy (CRRT) in
      critically ill adults with ARF. METHODS: Four databases (MEDLINE, Cochrane
      Library, Database of Abstracts and Reviews, and Science Citation Index), hand
      searching of conference proceedings and journals, manual review of bibliographies
      from identified articles, and contact with experts were used. All randomized
      trials (published or unpublished in any language) that compared mortality between
      intermittent and continuous treatments were eligible. Trials for which an RR for
      mortality could not be calculated or with multiple experimental interventions
      were excluded. Data were extracted separately by two authors and recorded on a
      standardized form. Disagreements were resolved by consensus. RESULTS: Six
      eligible trials were identified; four of these provided data on renal outcomes.
      RR (mortality) for IHD was 0.96 (95% confidence interval [CI], 0.85 to 1.08; P =
      0.50), RR (renal death) was 1.02 (95% CI, 0.89 to 1.17; P = 0.78), and RR
      (dialysis dependence) in survivors was 1.19 (95% CI, 0.62 to 2.27; P = 0.60; all
      compared with continuous therapy). Several sensitivity analyses did not change
      these results. Of the outcomes studied, the risk for dialysis dependence in
      survivors would be most sensitive to the addition of new trials. CONCLUSIONS: In
      comparison to IHD therapy, CRRT does not improve survival or renal recovery in
      unselected critically ill patients with ARF. Future studies should focus on well
      defined subgroups of such patients using lessons learned from the trials in this
      meta-analysis. The high cost of chronic dialysis therapy and the relative
      instability of the RR for dialysis dependence suggest that future trials also
      should evaluate differences in renal recovery between dialytic modalities.

PMID- 12407632
TI  - Preventing bacterial infections and antimicrobial resistance in dialysis
      patients.
AB  - Antimicrobial use, in concert with patient-to-patient transmission of resistant
      strains, has caused a rapid increase in the prevalence of antimicrobial
      resistance in recent years. This increase is a particular threat to dialysis
      patients, who often have been in the forefront of the epidemic of resistance. In
      this report, which was written in collaboration between the American Society of
      Nephrology and the Centers for Disease Control and Prevention and has been
      endorsed by the Executive Council of the Infectious Diseases Society of America,
      we review and summarize existing clinical practice guidelines and recommendations
      concerning the prevention, diagnosis, and treatment of certain bacterial
      infections in dialysis patients and present four strategies to limit the spread
      of antimicrobial resistance in dialysis patients. First, preventing infection
      eliminates the need for antimicrobials, thereby reducing selection pressure for
      resistant strains. Efforts to prevent infection include avoidance of hemodialysis
      catheters, when possible, and meticulous care of hemodialysis and peritoneal
      catheters and other hemodialysis vascular access sites. Second, diagnosing and
      treating infections appropriately can facilitate the use of narrower spectrum
      agents, rapidly decrease the number of infecting organisms, and reduce the
      probability of resistance emerging. This entails the collection of indicated
      specimens for culture and avoidance of contamination of cultures with common skin
      microorganisms. Third, optimizing antimicrobial use helps protect the efficacy of
      such critical agents as vancomycin. Published guidelines for the use of
      vancomycin should be followed, and alternate agents should be used when
      infections with beta-lactam-resistant bacteria are unlikely or not documented.
      Fourth, preventing transmission in health care settings is important to limit the
      spread of resistant organisms. In this regard, such basic measures as glove use
      and hand hygiene are most important.

PMID- 12407633
TI  - Association of kidney function with serum lipoprotein(a) level: the third
      National Health and Nutrition Examination Survey (1991-1994).
AB  - BACKGROUND: Elevated lipoprotein(a) (Lp[a]) levels have been observed in patients
      on dialysis therapy. However, few studies explored the relationship between
      kidney function and Lp(a) levels in patients with mild to moderate chronic kidney
      disease. METHODS: We examined the association of estimated glomerular filtration
      rate (GFR) with Lp(a) level in 7,675 participants in the second phase of the
      Third National Health and Nutrition Examination Survey. RESULTS: There was no
      association between Lp(a) level and estimated GFR in the overall sample
      (geometric mean, 10.4 mg/dL [95% confidence interval (CI), 9.2 to 11.8] in the
      group with a GFR of 90 to 149 mL/min/1.73 m2 versus 9.3 mg/dL [95% CI, 7.9 to
      11.0] in the group with a GFR of 60 to 89 mL/min/1.73 m2 versus 12.1 mg/dL [95%
      CI, 9.0 to 15.9] in the group with a GFR of 15 to 59 mL/min/1.73 m2; P = 0.77 for
      linear trend) or non-Hispanic whites (geometric mean, 8.9 mg/dL [95% CI, 7.8 to
      10.2] versus 8.5 mg/dL [95% CI, 7.1 to 10.2] versus 10.9 mg/dL [95% CI, 8.1 to
      14.7]; P = 0.54 for linear trend). However, non-Hispanic blacks (geometric mean,
      30.4 mg/dL [95% CI, 28.0 to 33.0] versus 35.2 mg/dL [95% CI, 31.4 to 39.4] versus
      40.2 mg/dL [95% CI, 27.7 to 58.2]; P = 0.01 for linear trend) and Mexican
      Americans (geometric mean, 6.2 mg/dL [95% CI, 5.3 to 7.2] versus 7.4 mg/dL [95%
      CI, 6.4 to 8.5] versus 11.0 mg/dL [95% CI, 5.7 to 20.3]; P = 0.04 for linear
      trend) showed modestly, but significantly, greater Lp(a) levels with lower GFRs.
      In a weighed quantile regression model adjusted for age, sex, and race, a lower
      GFR was associated with greater 95th percentile serum Lp(a) values in the overall
      sample and non-Hispanic whites and with greater median Lp(a) levels in Mexican
      Americans. CONCLUSION: In a cross-section of the US population, a low GFR is
      associated with only moderately greater Lp(a) levels, and this association may
      differ by race-ethnicity.

PMID- 12407634
TI  - Association of hyperhomocysteinemia with plasma sulfate and urine sulfate
      excretion in patients with progressive renal disease.
AB  - BACKGROUND: Plasma total homocysteine (tHcy) level is increased in patients with
      renal disease, parallel to serum creatinine concentration. In renal failure, the
      final product of sulfated amino acid metabolism, sulfate, also accumulates as
      renal function declines. We hypothesized that the elevation in sulfate level
      could cause hyperhomocysteinemia and tested the relation between tHcy level and
      both urinary excretion and plasma levels of sulfate. METHODS: Forty patients with
      renal disease were divided into three groups: patients without renal failure
      (nRF; creatinine clearance [CCr] > or = 80 mL/min/1.73 m2 [> or =1.33 mL/s/1.73
      m2]), patients with mild renal failure (mRF; 80 > CCr > or = 25 mL/min/1.73 m2
      [1.33 > CCr >/ or 0.42 mL/s/1.73 m2]), and patients with severe renal failure
      (sRF; CCr < 25 mL/min/1.73 m2 [<0.42 mL/s/1.73 m2]). Daily urinary excretion and
      plasma levels of tHcy, total cysteine (tCys), and sulfate were measured. A
      healthy control (HC) group also was tested. Serum methionine, taurine, vitamin
      B12, and folate levels also were determined in patients with renal disease.
      RESULTS: Plasma tHcy and sulfate concentrations in the groups with mRF and sRF
      were greater than in the HC group. Plasma tCys concentrations in the mRF and sRF
      groups were greater than in the nRF group. Daily urinary Hcy and Cys excretion
      did not differ among the four groups. Daily urine sulfate and urea nitrogen
      excretion in the sRF group were significantly less than in the HC and nRF groups.
      Multiple regression analyses showed that plasma creatinine (beta = 0.40) and
      sulfate (beta = 0.43) levels were independently associated with plasma Hcy level;
      among urine parameters, only daily urine sulfate excretion (beta = -0.52) was
      independently associated with plasma Hcy level. CONCLUSION: The elevated plasma
      sulfate level, in accordance with renal function, is associated with plasma tHcy
      level. Decreased sulfate excretion, which might parallel the intake of sulfated
      amino acid or protein, may increase tHcy levels.

PMID- 12407635
TI  - Relationship of renal function to homocysteine and lipoprotein(a) levels: the
      frequency of the combination of both risk factors in chronic renal impairment.
AB  - BACKGROUND: Total homocysteine (tHcy) and lipoprotein(a) [Lp(a)] levels have been
      recognized as risk factors for vascular disease. The combination of elevated tHcy
      and Lp(a) levels may be particularly atherogenic, although no study has examined
      the prevalence of the combination of both risk factors in patients with chronic
      renal impairment. METHODS: One hundred ninety-seven patients with renal
      impairment were studied. Patients had glomerular filtration rate (GFR) measured
      by clearance of chromium 51-labeled EDTA. Blood was obtained for the
      determination of tHcy, Lp(a), and apolipoprotein(a) [apo(a)] isoform levels.
      RESULTS: Patients were divided into five groups according to GFR. Mean tHcy
      levels in the five groups were as follows: GFR less than 10 mL/min, 30.2 +/- 9.8
      (SD) micromol/L; GFR of 10 to 20 mL/min, 26.6 +/- 10.5 micromol/L; GFR of 20 to
      30 mL/min, 23.9 +/- 8.6 micromol/L; GFR of 30 to 45 mL/min, 22.2 +/- 8.6
      micromol/L; and GFR of 45 to 75 mL/min, 18.2 +/- 9.1 micromol/L compared with
      control levels of 12.7 +/- 4.6 micromol/L. There was a progressive increase in
      median Lp(a) levels with declining renal function: median Lp(a) levels for those
      with a GFR less than 10 mL/min were 37.1 mg/dL (range, 0.6 to 156.0 mg/dL); GFR
      of 10 to 20 mL/min, 30.3 mg/dL (range, 2.6 to 163.7 mg/dL); GFR of 20 to 30
      mL/min, 26.1 mg/dL (range, 0.0 to 164.0 mg/dL); GFR of 30 to 45 mL/min, 20.9
      mg/dL (range, 0.0 to 99.8 mg/dL), and GFR of 45 to 75 mL/min, 16.8 mg/dL (range,
      2.1 to 81.0 mg/dL) compared with control values of 12.5 mg/dL (range, 0.0 to 88.7
      mg/dL). CONCLUSION: Defining hyperhomocysteinemia as tHcy levels greater than the
      90th percentile of controls and elevated Lp(a) level as greater than 30 mg/dL,
      the frequency of the combination increased with declining renal function. Fifty
      eight percent of patients with a GFR less than 10 mL/min had both
      hyperhomocysteinemia and elevated Lp(a) levels, and even in patients with mild
      renal impairment, 20% of patients had both risk factors present.

PMID- 12407636
TI  - Safety and efficacy of sodium ferric gluconate complex in patients with chronic
      kidney disease.
AB  - BACKGROUND: We hypothesized that intravenous iron will improve hemoglobin (Hgb)
      concentrations in anemic patients with chronic kidney disease (CKD), and the
      response would be greater if the underlying erythropoietin deficiency also was
      treated. METHODS: Charts of 58 CKD veterans (glomerular filtration rate < 80
      mL/min) administered at least 125 mg of sodium ferric gluconate complex in
      sucrose (SFGC) during a period of 1 year for the primary outcome of an increase
      in Hgb level by at least 0.5 g/dL were reviewed. RESULTS: Mean Hgb level at
      baseline was 10.5 +/- 1.4 (SD) g/dL (105 +/- 14 g/L) in the 30 patients
      administered recombinant human erythropoietin (rHuEPO) plus SFGC and 10.1 +/- 1.3
      g/dL (101 +/- 13 g/L) in the 28 patients administered SFGC alone (P = not
      significant). The primary event occurred in 83% of the rHuEPO-plus-SFGC group at
      31 days compared with 60% at 62 days in the group administered SFGC alone (P =
      0.037, Cox F test). In patients administered SFGC alone, mean maximal Hgb level
      was 11.4 +/- 0.9 g/dL (114 +/- 9 g/L) in contrast to 12.4 +/- 1.7 g/dL (124 +/-
      17 g/L) in the combination group, which remained significantly different even
      after adjustment for biologically important covariates (P = 0.01, analysis of
      covariance). Of the 240 doses of SFGC administered for which infusion records
      were available, 237 doses were well tolerated; three hypotensive episodes
      occurred in 2 patients, which did not result in discontinuation of the drug in
      either case. CONCLUSION: Correction of anemia with parenteral iron alone suggests
      a high prevalence of iron deficiency in patients with CKD. Treatment of
      concomitant iron deficiency with SFGC was well tolerated in patients with CKD and
      appears to optimize management of anemia.

PMID- 12407637
TI  - Homocysteine, cysteine, and B vitamins as predictors of kidney disease
      progression.
AB  - BACKGROUND: Pathological similarities between atherosclerosis and
      glomerulosclerosis suggest that risk factors for the two processes may be
      similar. Elevated total homocysteine (tHcy) levels and low B vitamin levels are
      risk factors for atherosclerosis, but have not been evaluated sufficiently as
      risk factors for the progression of kidney disease. METHODS: Frozen samples from
      the Modification of Diet in Renal Disease Study were assayed for serum tHcy,
      cysteine, pyridoxal 5-phosphate (PLP), folate, and vitamin B12 levels in 804
      participants. These factors were evaluated in both continuous and categorical
      analyses as risk factors for glomerular filtration rate (GFR) decline by using
      univariate and multivariable analyses. RESULTS: At baseline, mean tHcy levels in
      study A (GFR, 25 to 55 mL/min/1.73 m2) and study B (GFR, 13 to 24 mL/min/1.73 m2)
      were 16.9 micromol/L (median, 15.6 micromol/L) and 23.0 micromol/L (median, 20.5
      micromol/L), respectively. Mean follow-up was 2.2 years. Mean GFR declines were 
      4.35 and -3.65 mL/min/y in studies A and B, respectively. There was no
      significant association between change in GFR with baseline level of tHcy in
      univariate (-0.26 mL/min/y per 1-SD unit increase in tHcy level; 95% confidence
      interval [CI], -0.67 to 0.15) or multivariable (-0.18 mL/min/y per 1-SD unit
      increase in tHcy level; 95% CI, -0.53 to 0.17) analysis in study A or univariate
      (0.07 mL/min/y per 1-SD unit increase in tHcy level; 95% CI, -0.36 to 0.51) or
      multivariable (0.24 mL/min/y per 1-SD unit increase in tHcy level; 95% CI, -0.16
      to 0.64) analysis in study B. Similarly, higher cysteine levels and lower B
      vitamin levels were not associated with faster rates of GFR decline in
      multivariable analysis in either study. CONCLUSION: Higher tHcy or cysteine
      levels and lower folate, PLP, and vitamin B12 levels are not independent risk
      factors for progression of nondiabetic kidney disease.

PMID- 12407638
TI  - Hyponatremia as a complication of cardiac catheterization: a prospective study.
AB  - BACKGROUND: A decrease in plasma sodium (P(Na)) concentration is common after
      surgery and attributed to the secretion of antidiuretic hormone in response to
      such nonosmotic stimuli as pain or nausea. In this setting, acute hyponatremia
      may lead to seizures, coma, and permanent neurological damage. Sporadic case
      reports have described severe neurological symptoms caused by hyponatremia
      occurring within hours after cardiac catheterization. We evaluated the
      prevalence, contributing clinical circumstances, and course of hyponatremia in
      patients undergoing cardiac catheterization. METHODS: We prospectively studied
      309 consecutive patients scheduled for an elective cardiac catheterization.
      Plasma and urine electrolytes and urine osmolarity were measured at baseline and
      again 1 to 4 hours and 24 hours after the procedure. RESULTS: P(Na) level was
      139.4 +/- 2.3 mEq/L at baseline. At 1 to 4 hours, P(Na) level decreased to 134.2
      +/- 3.6 mEq/L (P < 0.0001). Mild (> or =5 to 10 mEq/L), moderate (11 to 14
      mEq/L), and severe (> or =15 mEq/L) reductions in P(Na) levels occurred in 50%,
      5%, and 0.3% of patients, respectively. At the 24-hour point, P(Na) level
      increased to 137.3 +/- 2.4 mEq/L, but was significantly lower compared with
      baseline (P < 0.0001). In hyponatremic patients at the 1- to 4- and 24-hour
      points, mean urine osmolarity values were 428 +/- 139 and 420 +/- 204 mOsm/kg,
      respectively; almost every urine sample was inappropriately concentrated.
      Multivariate logistic regression identified the amount of electrolyte-free water
      administered to be a predictor for the development of hyponatremia (3.7-fold
      incremental risk for every 1 L administered to a 70-kg patient). CONCLUSION: An
      acute reduction in P(Na) level commonly occurs shortly after cardiac
      catheterization. The cause of hyponatremia appears to be related to the
      administration of hypotonic fluids, together with impaired urinary dilutional
      capacity. Although symptomatic hyponatremia is rare, the diagnosis should be
      entertained when neurological symptoms develop in this setting.

PMID- 12407639
TI  - Dynamic renal blood flow measurement by positron emission tomography in patients
      with CRF.
AB  - BACKGROUND: Positron emission tomography (PET) is a functional imaging device
      that allows dynamic regional blood flow measurements. We performed a study to
      test whether PET could detect acute changes in renal blood flow (RBF) in patients
      with chronic renal failure (CRF). METHODS: RBF was measured by means of PET (PET
      RBF) using oxygen 15-labeled water (H2(15)O) in eight men with hypertension and
      moderate CRF before and 5, 40, 80, and 120 minutes after the injection of
      quinaprilat (10 mg intravenously). Effective renal plasma flow (ERPF) and
      glomerular filtration rate (GFR) were measured simultaneously by para
      aminohippuric acid (PAH-ERPF) and inulin clearances before and 20, 60, 100, and
      140 minutes after quinaprilat injection. RESULTS: Baseline RBF and ERPF were
      decreased in all patients (221 +/- 20 mL/min/100 g and 225 +/- 38 mL/min/1.73 m2,
      respectively). PET-RBF increased significantly after quinaprilat injection (+15%,
      +26%, +19%, and +23% versus baseline; P < 0.003). PAH-ERPF did not increase
      significantly (-6%, +12%, +20%, and +15% versus baseline; P = 0.15). GFR (50.1 +/
      8.9 mL/min/1.73 m2 at baseline) did not change significantly after quinaprilat
      injection; however, filtration fraction (GFR-ERPF ratio) decreased significantly
      from 0.23% +/- 0.02% to 0.20% +/- 0.02% (P = 0.0004). Mean arterial pressure
      decreased significantly after quinaprilat injection (P < 0.005). CONCLUSION: This
      study dynamically measured RBF by means of PET in patients with CRF for the first
      time. It showed that RBF rapidly increased after quinaprilat injection. PET using
      H2(15)O is a powerful method for the noninvasive measurement of dynamic changes
      in RBF that remain undetected by PAH clearance.

PMID- 12407640
TI  - Prevalence and progression of CRF in Iceland: a population-based study.
AB  - BACKGROUND: The prevalence of end-stage renal disease (ESRD) is lower in Europe
      than in the United States. The purpose of this study was to examine whether this
      difference results from a lower prevalence or slower progression of chronic renal
      failure (CRF) in a European cohort. METHODS: We studied 18,912 subjects (9,773
      women, 9,139 men) aged 33 to 81 years who participated in the Reykjavik Study
      between 1967 and 1991. Subjects with serum creatinine (SCr) levels of 1.7 mg/dL
      (150 micromol/L) or greater were considered to have CRF. We determined the crude
      prevalence of CRF, as well as age-standardized prevalence for 5-year age groups,
      in individuals aged 30 to 79 years. Progression of CRF was defined as a decrease
      in estimated glomerular filtration rate greater than 1 mL/min/1.73 m2/y. RESULTS:
      Of 49 individuals who had an SCr of 1.7 mg/dL (150 micromol/L) or greater at
      entry, 41 individuals (26 men, 15 women) had a persistent elevation in SCr
      levels. Thirty-four individuals had mild CRF (SCr, 1.7 to 2.8 mg/dL [150 to 250
      micromol/L]), 6 individuals had moderate CRF (SCr, 2.8 to 5.6 mg/dL [250 to 500
      micromol/L]), and 1 individual had ESRD. The crude prevalence of CRF was 0.22%
      (220/100,000); 0.15% among women and 0.28% among men. The age-standardized
      prevalence was 0.23% (95% confidence interval [CI], 0.04 to 0.42) for women and
      0.42% (95% CI, 0.18 to 0.66) for men. Eighty-five percent of patients with CRF
      were 50 years or older. Twenty-seven subjects had progressive renal failure, 17
      of whom progressed to ESRD during a median of 7 years (range, 3 to 21 years).
      CONCLUSION: The prevalence of CRF is markedly lower in Iceland than in the United
      States. Furthermore, 27% of subjects did not show progression of their renal
      failure. These factors may explain in part the difference in ESRD prevalence
      between European countries and the United States.

PMID- 12407641
TI  - Differential expression of nephrin in acquired human proteinuric diseases.
AB  - BACKGROUND: The slit-diaphragm protein nephrin is an essential component of the
      glomerular filtration barrier. It is not clear whether renal injury in patients
      with acquired proteinuric diseases is associated with altered regulation of the
      nephrin gene or protein. METHODS: We examined expression patterns of nephrin
      protein and messenger RNA (mRNA) in renal biopsy specimens from patients with
      minimal lesion (n = 7), focal segmental glomerulosclerosis (FSGS; n = 14), or
      membranous nephropathy (MN; n = 7) and controls (n = 8) by immunohistochemistry,
      immunoelectron microscopy, in situ hybridization, and polymerase chain reaction
      (PCR) amplification of nephrin complementary DNA. RESULTS: In normal kidney,
      nephrin staining showed a diffuse interrupted linear pattern along the glomerular
      basement membrane (GBM). Nephrin staining in minimal lesion specimens showed a
      finely granular pattern along the GBM and was positive in cell bodies of visceral
      glomerular epithelial cells. Nephrin staining was most disrupted in FSGS
      specimens. Immunoelectron microscopy showed that nephrin-specific gold particles
      were almost absent in effaced foot processes in proteinuric patients. An in situ
      hybridization study showed significantly decreased nephrin mRNA-expressing cells
      in cases of FSGS and MN compared with controls. Reverse-transcription PCR showed
      significantly lower levels of nephrin mRNA in cases of FSGS and MN than controls,
      but no significant difference between minimal lesion cases and controls. Relative
      levels of glomerular nephrin mRNA correlated inversely with percentage of
      glomeruli with sclerosis in proteinuric diseases. CONCLUSION: These results
      suggest that nephrin-expression patterns in proteinuric diseases are different
      according to the specific glomerular disease or severity of glomerular damage.

PMID- 12407642
TI  - Effects of the creation of arteriovenous fistula for hemodialysis on cardiac
      function and natriuretic peptide levels in CRF.
AB  - BACKGROUND: Cardiac failure occasionally is caused by the creation of vascular
      access for hemodialysis. However, the influence of an arteriovenous (AV) fistula
      on cardiac function has not been fully elucidated. The present study investigated
      serial changes in cardiac function and hormonal levels after the AV fistula
      operation. METHODS: Sixteen patients with chronic renal failure underwent
      echocardiographic studies before and 3, 7, and 14 days after the AV fistula
      operation. Plasma atrial natriuretic peptide (ANP) and brain natriuretic peptide
      (BNP) concentrations were measured before and 1, 3, 6, 10, and 14 days after the
      operation. RESULTS: Creation of an AV fistula produced significant elevations in
      left ventricular (LV) end-diastolic diameter (+4%), fractional shortening (+8%),
      and cardiac output (CO; +15%). In LV inflow velocities measured by Doppler
      echocardiography, deceleration time of the early diastolic filling wave shortened
      (-12%) and the ratio of the peak velocity of early diastolic to atrial filling (E
      A ratio) increased (+18%). The difference in duration of LV inflow and pulmonary
      venous flow at atrial contraction, a marker of LV end-diastolic pressure,
      significantly shortened day 14 after the operation (-37%). That is, creation of
      an AV fistula induced LV diastolic dysfunction toward a restrictive filling
      pattern. Both ANP and BNP levels increased after the operation, and maximal
      percentages of increase were observed after 10 days (ANP, +48%; BNP, +68%). In
      the relationship between cardiac function and hormonal response, the increase in
      CO was associated with elevation of ANP levels (r = 0.61; P = 0.01), but not BNP
      levels. Conversely, the increase in E-A ratio correlated only with BNP level
      elevation (r = 0.60; P = 0.01). CONCLUSION: Our observations indicate that
      creation of an AV fistula has significant effects on cardiac systolic and
      diastolic performance, and ANP release is induced by volume loading, but BNP
      release is stimulated by LV diastolic dysfunction.

PMID- 12407643
TI  - Serum markers of periodontal disease status and inflammation in hemodialysis
      patients.
AB  - BACKGROUND: Hemodialysis (HD) patients face a 25% annual mortality rate, with 50%
      of reported deaths attributed to cardiovascular disease. All-cause and
      cardiovascular mortality correlate with such acute-phase proteins as C-reactive
      protein (CRP). Hepatic CRP synthesis is upregulated by inflammation; however,
      elevated CRP values frequently are found in the absence of apparent infection or
      inflammation. Because destructive periodontal diseases have been associated with
      elevated CRP levels, we questioned whether destructive periodontal diseases could
      contribute to elevated CRP values in HD populations. METHODS: Sera from 86
      consecutive dentate HD patients were assayed for levels of immunoglobulin G (IgG)
      antibody to six periodontal species by means of an enzyme-linked immunosorbent
      assay. RESULTS: CRP values for the subject population ranged from less than 6.9
      to 159 mg/L (median, 8.2 mg/L). Univariate comparisons between subjects with or
      without elevated CRP levels (>10 mg/L) showed that CRP level elevation was
      associated significantly (P < 0.05) with greater doses of human recombinant
      erythropoietin and lower levels of hemoglobin, serum iron, transferrin saturation
      (TSat), albumin averaged over the 3 preceding months, total cholesterol, and
      triglycerides. Log serum IgG antibody levels to Porphyromonas gingivalis also
      were significantly greater in the group with elevated CRP levels (P = 0.013).
      Subsequent multivariate logistic regression showed that log serum antibody levels
      to P gingivalis remained significant (P = 0.02) after controlling for
      nonperiodontal sources of elevated CRP, hemoglobin, TSat, and triglyceride
      values. CONCLUSION: These results suggest that elevated levels of IgG antibody to
      bacterial species associated with destructive periodontal diseases are associated
      with elevated CRP values in HD populations.

PMID- 12407644
TI  - Pharmacokinetic studies of dalteparin (Fragmin), enoxaparin (Clexane), and
      danaparoid sodium (Orgaran) in stable chronic hemodialysis patients.
AB  - BACKGROUND: Low molecular weight heparins (LMWHs) and danaparoid are an
      alternative to unfractionated heparin (UH) for anticoagulation during
      hemodialysis. Few data are available concerning their duration of action and
      whether drug accumulation occurs with continued use. We performed a prospective
      randomized study of the pharmacokinetics of dalteparin and enoxaparin plus
      danaparoid in 21 hemodialysis patients. METHODS: Patients were randomly assigned
      to administration of enoxaparin, 40 mg; dalteparin, 2,500 U; or danaparoid, 34
      U/kg, for 4 weeks. Antifactor Xa levels were measured at the end of weeks 1 and 4
      immediately before the injection and at prescribed intervals up to 48 hours
      postinjection. RESULTS: No bleeding or thrombotic episodes occurred during the
      study. Mean antifactor Xa activities 4 hours postinjection were 0.2 +/- 0.035
      (SEM), 0.38 +/- 0.028, and 0.54 +/- 0.051 U/mL week 1 and 0.26 +/- 0.038, 0.40 +/
      0.055, and 0.64 +/- 0.050 U/mL week 4 for dalteparin, enoxaparin, and
      danaparoid, respectively. Both weeks 1 and 4, antifactor Xa activity 3 hours
      postdose was significantly greater for danaparoid sodium compared with enoxaparin
      and dalteparin. There were no significant differences between antifactor Xa
      activity week 4 versus week 1 for enoxaparin and dalteparin; however, danaparoid
      sodium levels during dialysis were significantly greater after 4 weeks of
      treatment (P = 0.0328, 1 hour; P = 0.003, 2 hours; P = 0.0128, 3 and 4 hours).
      CONCLUSION: Dalteparin and enoxaparin provide adequate anticoagulation for
      hemodialysis using single bolus injections at relatively low doses. Danaparoid
      sodium at the current recommended dosage resulted in greater anticoagulation than
      enoxaparin or dalteparin and may have an

PMID- 12407645
TI  - Online monitoring of cerebral hemodynamics during hemodialysis.
AB  - BACKGROUND: Several factors, including anemia, diabetes, and hypertension,
      potentially could disturb the cerebral autoregulation mechanism in hemodialysis
      (HD) patients. This study examined the effect of hemodynamic and rheological
      changes on mean cerebral blood flow (CBF) velocity (MV) during HD. METHODS:
      Continuous online monitoring of MV and pulsatility index in the middle cerebral
      artery were performed in 18 HD patients by transcranial Doppler ultrasound during
      the entire HD period (range, 3 to 4 hours). In addition, blood pressure,
      hematocrit (Hct), and relative decrease in blood volume were continuously
      monitored. Blood samples were obtained at the beginning and end of HD to measure
      hemorheological variables. RESULTS: After HD, Hct increased significantly from
      33.6% +/- 5.9% to 41.4% +/- 5.7% (P < 0.001). Blood and plasma viscosity
      increased significantly from 3.33 +/- 0.77 to 4.36 +/- 1.3 mPa.s (P < 0.001) and
      from 1.35 +/- 0.29 to 1.54 +/- 0.38 mPa.s (P < 0.001), respectively. The change
      in MV (DeltaMV) was not significantly different from zero and correlated
      significantly with change in Hct. During HD, mean arterial pressure (MAP) in 15
      patients changed within the normal range (group I), whereas 3 patients developed
      hypotension (group II) and their MAP decreased from 99 +/- 5 to 60 +/- 8 mm Hg (P
      < 0.05). In both groups, DeltaMV were not significant. CONCLUSION: Results of
      this study suggest that CBF does not appear to be diminished significantly during
      HD.

PMID- 12407646
TI  - Induction of protein oxidation by intravenous iron in hemodialysis patients: role
      of inflammation.
AB  - BACKGROUND: Oxidative stress and inflammation contribute to the high prevalence
      and severity of atherosclerosis, infections, and beta2-microglobulin amyloidosis;
      and thus, to reduced survival rate and quality of life in hemodialysis (HD)
      patients. Inflammation induces oxidative stress by production of the oxidants:
      superoxide anion, hydrogen peroxide, and hypochlorite. Intravenous iron (IVIR),
      administered in HD patients to correct anemia, can release free iron, that may
      react with hydrogen peroxide to produce the strong oxidant hydroxyl radical.
      Inflammation-induced lipid and protein oxidation and IVIR-induced lipid oxidation
      were shown in HD patients. However, IVIR-induced protein oxidation and a
      relationship between inflammation and IVIR-induced oxidative stress have not been
      reported to date. METHODS: We examined the effect of IVIR administration on
      markers of protein oxidation in HD patients (advanced oxidation protein products
      [AOPPs], thiol, and dityrosine) in relation to such inflammatory markers as C
      reactive protein (CRP) and tumor necrosis factor-alpha (TNF-alpha). Iron
      saccharate, 100 mg, was administered to 19 HD patients for 1 hour after 3.5 hours
      of high-flux dialysis. Blood samples were drawn pre-HD, pre-IVIR, and post-IVIR
      for iron, transferrin, TNF-alpha, AOPP, thiol, total antioxidant capacity (TEAC),
      and dityrosine levels and pre-HD for ferritin and CRP levels. RESULTS: IVIR
      administration induced a 37% increase in AOPP level (P < 0.001), which correlated
      positively with pre-HD CRP level (r = 0.72; P < 0.05) and was greater in patients
      with a greater pre-HD TNF-alpha level (P < 0.05). IVIR administration did not
      affect TEAC, thiol, dityrosine, or TNF-alpha levels. CONCLUSION: IVIR
      administration induced an increase in protein oxidation (AOPP levels) that was
      related to the degree of inflammation.

PMID- 12407647
TI  - Psychosocial variables, quality of life, and religious beliefs in ESRD patients
      treated with hemodialysis.
AB  - BACKGROUND: Religious and spiritual aspects of quality of life (QOL) have not
      been fully assessed in patients with end-stage renal disease (ESRD) treated with
      hemodialysis (HD), but psychosocial factors are associated with patient survival.
      METHODS: To investigate interrelationships between religious beliefs and
      psychosocial and medical factors, we studied 53 HD patients. Psychosocial and
      medical variables included perception of importance of faith (spirituality),
      attendance at religious services (religious involvement), the Beck Depression
      Inventory, Illness Effects Questionnaire, Multidimensional Scale of Perceived
      Social Support, McGill QOL Questionnaire scores, Karnofsky scores, dialysis dose,
      and predialysis hemoglobin and albumin levels. RESULTS: Eighty-seven percent of
      participants were African-American. Men had higher depression scores, perceived
      lower social support, and had higher religious involvement scores than women. No
      other parameters differed between sexes. Perception of spirituality and
      religiosity did not correlate with age, Karnofsky score, dialysis dose, or
      hemoglobin or albumin level. Greater perception of spirituality and religiosity
      correlated with increased perception of social support and QOL and less negative
      perception of illness effects and depression. A one-question global QOL measure
      correlated with depression, life satisfaction, perception of burden of illness,
      social support, and satisfaction with nephrologist scores, but not with age or
      Karnofsky score. CONCLUSION: Religious beliefs are related to perception of
      depression, illness effects, social support, and QOL independently of medical
      aspects of illness. Religious beliefs may act as coping mechanisms for patients
      with ESRD. The relationship between religious beliefs and clinical outcomes
      should be investigated further in patients with ESRD.

PMID- 12407648
TI  - ACE inhibitors and survival of hemodialysis patients.
AB  - BACKGROUND: Cardiovascular disease is a leading cause of death in patients with
      end-stage renal disease (ESRD). Hypertension is a major risk factor for
      cardiovascular complications in these patients. Angiotensin-converting enzyme
      (ACE) inhibitors are an effective treatment for hypertension in patients with
      ESRD and are known to improve prognosis in patients with chronic renal failure.
      We investigated their effect on mortality in patients undergoing long-term
      hemodialysis therapy. METHODS: Clinical data for patients on hemodialysis therapy
      between 1994 and 2000 were reviewed. Patients were grouped according to whether
      they had been treated with ACE inhibitors. RESULTS: Sixty patients had been
      treated with ACE inhibitors (treated group) and 66 patients had not (untreated
      group). Blood pressure reduction was not significantly different between the
      treated and untreated groups. Nevertheless, comparing the treated group with the
      untreated group, mortality was decreased significantly in the treated group, with
      a risk reduction of 52% (rate ratio [RR], 0.482; confidence interval [CI], 0.25
      to 0.91; P < 0.0019). In treated patients 65 years or younger, the absolute risk
      reduction of mortality was 79% (RR, 0.211; CI, 0.08 to 0.58; P < 0.0006).
      CONCLUSION: Although further research is needed, these preliminary findings
      suggest that ACE inhibitors, independently of their antihypertensive effect, may
      dramatically reduce mortality among chronic hemodialysis patients 65 years or
      younger.

PMID- 12407649
TI  - Relapsing culture-negative peritonitis in peritoneal dialysis patients exposed to
      icodextrin solution.
AB  - BACKGROUND: Icodextrin is a new peritoneal dialysis fluid, with maltose polymers
      providing the osmotic drive, that may extend time on peritoneal dialysis in
      situations in which use of conventional glucose-based peritoneal dialysis fluid
      (Dianeal) has led to loss of ultrafiltration. Although cutaneous reactions have
      been reported, we report a new phenomenon of aseptic peritonitis that has arisen
      in our unit associated with icodextrin use. METHODS: Icodextrin was first
      introduced in our unit in 1997 and was used extensively beginning in late 1999.
      From a combination of an observational study of 141 patients in our unit in whom
      icodextrin was used over 3.5 years and our unit 2000 and 2001 peritonitis audits,
      we identified an increase in the incidence of culture-negative peritonitis (CNP).
      RESULTS: The rate in 2000 of 12.3% rose to 17% in 2001, but this increase was
      seen only in patients on icodextrin (Percentage changes 2000 audit > 2001 audit:
      icodextrin patients, 14%--31% increase; Dianeal alone, 12%--10% increase; P <
      0.05). Six patients were affected in the period 2000 to 2001 out of a total of
      141 patients exposed to icodextrin (4.3%). Two index cases of relapsing CNP
      responded after withdrawal of the icodextrin. We then adopted a protocol of
      cessation and rechallenge with icodextrin when dealing with CNP, which
      successfully confirmed the phenomenon and led to resolution of relapsing CNP
      after icodextrin withdrawal. All these patients had been on icodextrin for some
      time, and none had had an immediate reaction or any skin reaction. Eosinophils
      were reported in the peritoneal effluent from two patients. All patients
      continued Dianeal without further CNP episodes. CONCLUSION: Icodextrin use
      carries the risk of CNP, and we suggest a cessation and rechallenge protocol in
      all patients on icodextrin who have CNP.

PMID- 12407650
TI  - Derived equations are not precise enough to predict the adequacy of creatinine
      clearance in peritoneal dialysis patients.
AB  - BACKGROUND: Most renal units assess dialysis adequacy in peritoneal dialysis (PD)
      patients by formal 24-hour collections of urine and effluent dialysate. We sought
      a reliable method of predicting dialysis adequacy that allows a decrease in the
      frequency of these formal and cumbersome measurements. METHODS: We created a
      formula for estimating total creatinine clearances, then assessed the clinical
      utility of this formula and other published formulae in predicting adequate and
      inadequate dialysis in PD patients. We collected data over a 6-month period in
      2001 from 288 PD patients from 9 centers in Scotland. Four out of every 5
      patients were selected at random to create a formula for estimating total
      creatinine clearance per week, and the fifth patient was used to form a
      validation group. We plotted creatinine excretion against age, and the resultant
      linear regression equation was transformed to produce a formula for predicting
      total creatinine clearance per week, based on patient sex, weight, and serum
      creatinine. We used the data from the validation subgroup to calculate predictive
      values for our derived formula and data from all of the patients to calculate
      predictive values for the Cockcroft and Gault, Jones, and Modification of Diet in
      Renal Disease Study formulae. RESULTS: Neither our derived formula nor the three
      published formulae were sufficiently powerful to predict accurately either
      adequate or inadequate PD clearance. Receiver operator characteristic curves
      showed that no significant improvement in these predictive values could be
      achieved by altering either the sensitivity or the specificity. CONCLUSION:
      Prediction formulae are not accurate enough to detect underdialysis in PD
      patients.

PMID- 12407651
TI  - Effect of diabetes on peritoneal function assessed by personal dialysis capacity
      test in patients undergoing CAPD.
AB  - BACKGROUND: We evaluated differences in individual peritoneal membrane transport
      function and nutritional status in patients with diabetes mellitus (DM) and
      nondiabetic (non-DM) patients on continuous ambulatory peritoneal dialysis
      (CAPD). METHODS: We used a newly developed peritoneal function test, personal
      dialysis capacity, in 88 patients (44 DM and 44 non-DM) on CAPD for 1 to 210
      months. Sex, age, past history of peritonitis, and duration of CAPD were matched
      in DM and non-DM patients. RESULTS: Serum albumin (mean +/- SEM) was lower in DM
      compared with non-DM patients: 3.0 +/- 0.1 g/dL (30 +/- 1 g/L) versus 3.5 +/- 0.1
      g/dL (35 +/- 1 g/L), P < 0.001. Peritoneal area and dialysis protein loss were
      greater in DM versus non-DM patients. In multiple linear regression analysis, the
      only independent predictor of serum albumin in patients with DM was dialysis
      protein loss. In contrast, age, past history of peritonitis, duration of CAPD,
      caloric intake, protein nitrogen appearance and protein catabolic rate, and
      residual renal function did not correlate with serum albumin in DM patients. In
      non-DM patients, age, duration of CAPD, and past history of peritonitis, but not
      dialysis protein loss, were independent predictors of serum albumin. There was a
      significant correlation in DM patients, but not in non-DM CAPD patients, between
      dialysis protein loss and urinary excretion of protein (r = 0.866, P = 0.0005).
      CONCLUSION: In this multicenter study, peritoneal membrane transport and
      peritoneal protein permeability were significantly higher in DM than in non-DM
      patients. Hypoproteinemia in DM patients is attributable to the high permeability
      of the peritoneal membrane undergoing CAPD.

PMID- 12407652
TI  - A randomized controlled trial to evaluate the efficacy and safety of icodextrin
      in peritoneal dialysis.
AB  - BACKGROUND: This article presents the results of two randomized, double-blind,
      controlled studies conducted to compare the efficacy and long-term safety of
      icodextrin and 2.5% dextrose for the once-daily long dwell in continuous
      ambulatory peritoneal dialysis (CAPD) and automated peritoneal dialysis (APD).
      METHODS: Both studies were active-control comparisons of 7.5% icodextrin and 2.5%
      dextrose for the once-daily long dwell. The efficacy study was a 4-week
      evaluation of net ultrafiltration and peritoneal clearances of creatinine and
      urea nitrogen in 175 CAPD patients. The 52-week study in CAPD and APD patients
      examined the long-term safety of icodextrin and longer term effects, such as body
      weight and quality of life. RESULTS: Mean net ultrafiltration (587.2 versus 346.2
      mL, P < 0.001) and clearances of urea nitrogen (4.5 versus 4.1 mL/min, P < 0.001)
      and creatinine (4.0 versus 3.5 mL/min, P < 0.001) were increased significantly
      with icodextrin. Patients receiving icodextrin had no increase in weight after 52
      weeks, in contrast to a weight gain of almost 2 kg in the dextrose group (P <
      0.05). There were significantly fewer patients reporting edema in the icodextrin
      group compared with the dextrose group (6.3% versus 17.9%, P < 0.01). There were
      no statistically significant differences between groups for the incidence and
      severity of adverse events. There were small decreases in sodium and chloride and
      increases in alkaline phosphatase with icodextrin. CONCLUSION: Icodextrin
      provides patients with greater fluid removal and small solute clearance, no
      weight gain over 52 weeks, and a decreased risk of edema.

PMID- 12407653
TI  - Development of lumbar bone mineral density in the late course after kidney
      transplantation.
AB  - BACKGROUND: Rapid bone loss is a frequent finding early after kidney
      transplantation. Only limited data are available on the bone mineral density
      (BMD) in long-term kidney transplant recipients. METHODS: In 26 kidney transplant
      recipients (13 men and 13 women, age 45.3 +/- 12.3 years), serum biochemical
      markers of bone metabolism and BMD at the lumbar vertebrae L2-4 were evaluated
      prospectively in three serial examinations (E1, E2, E3; method: dual-energy X-ray
      absorptiometry). Examinations were performed at 47 +/- 2 months, 59 +/- 2 months,
      and 71 +/- 2 months after transplantation. All patients received standard dual or
      triple immunosuppression including prednisolone. RESULTS: The mean BMD was
      significantly lower (P < 0.001) than in sex-matched young controls: T-score was 
      1.43 +/- 1.49 (E1), -1.39 +/- 1.40 (E2), and -1.44 +/- 1.30 (E3). The BMD did not
      change significantly (Delta BMD, -0.5 +/- 5.9%) from E1 to E3. Regression
      analysis did not show significant associations between Delta BMD and biochemical
      parameters or prednisolone dosage. No clinically apparent new lumbar vertebral
      fracture occurred. The mean intact parathyroid hormone was 110.1 +/- 97.5 pg/mL
      (E1), 121 +/- 102.7 pg/mL (E2), and 134.5 +/- 128.6 pg/mL (E3). Serum creatinine
      was 1.44 +/- 0.45 (128 +/- 40) mg/dL (micromol/L) (E1), 1.44 +/- 0.47 (127 +/-
      42) mg/dL (micromol/L) (E2), and 1.45 +/- 0.70 (128 +/- 62) mg/dL (micromol/L)
      (E3). Ten patients (38.5%) showed an increase of BMD (+5.7 +/- 3.2%) and 15
      patients (57.7%) showed a decrease of -4.7 +/- 3.2% (P < 0.0001). Both groups
      were different in T-scores at E1 (-2.29 +/- 1 versus -0.88 +/- 1.5); intact
      parathyroid hormone, creatinine, vitamin D levels, and prednisolone dosage were
      not significantly different. CONCLUSION: This study shows that lumbar BMD is
      reduced in long-term kidney transplant recipients. During our 24-month
      observation period, overall lumbar BMD remained stable.

PMID- 12407654
TI  - Glomerular hypertrophy is associated with hyperinsulinemia and precedes overt
      diabetes in aging rhesus monkeys.
AB  - BACKGROUND: Rhesus monkeys have a high prevalence of obesity and spontaneous type
      2 diabetes mellitus after the age of 10 years. These monkeys go through a
      defined, sequential set of metabolic phases, including fasting hyperinsulinemia,
      impaired glucose tolerance, and fasting hyperglycemia. Using these monkeys, we
      addressed the hypothesis that renal structural features characteristic of
      diabetic nephropathy might precede the appearance of overt diabetes. METHODS: We
      carried out a quantitative analysis of renal tissue, using light microscopy and
      electron microscopy, from 6 metabolically normal young monkeys, 7 metabolically
      normal aged monkeys, 7 hyperinsulinemic monkeys, and 18 diabetic monkeys.
      RESULTS: Glomerular volume was increased significantly in hyperinsulinemic
      monkeys and diabetic monkeys compared with aged normal monkeys. In the normal
      monkey, glomerular basement membrane (GBM) width rises with age but reaches a
      plateau at about 20 years of age; the presence of diabetes was associated with
      markedly increased GBM width. Glomerular tuft volume and GBM width were
      correlated most closely with age and with glucose tolerance. CONCLUSION: Diabetic
      monkey kidneys are characterized by glomerular enlargement, glomerulosclerosis,
      and thickening of the GBM. Glomerular hypertrophy begins in the prediabetic
      hyperinsulinemic phase. This finding suggests that early intervention may be
      required in human patients to preserve normal glomerular structure.

PMID- 12407655
TI  - Nephrotic syndrome and interstitial nephritis associated with celecoxib.
AB  - Nonsteroidal anti-inflammatory drugs (NSAIDs) are well known to cause fluid and
      electrolyte abnormalities and renal failure. NSAIDs also may cause an acute
      allergic interstitial nephritis (AIN) and the nephrotic syndrome, characterized
      by histologic pathology consistent with minimal change disease in patients with
      previously normal renal function. The nephrotoxic potential of cyclooxygenase 2
      (COX-2) inhibitors has not been established because AIN associated with nephrotic
      syndrome has not been reported secondary to the COX-2 inhibitors. This case
      report describes the first case of AIN associated with nephrotic syndrome in a
      patient treated with the selective COX-2 inhibitor, celecoxib.

PMID- 12407656
TI  - Renal involvement in monoclonal (type I) cryoglobulinemia: two cases associated
      with IgG3 kappa cryoglobulin.
AB  - Renal involvement has been described rarely in monoclonal (type I)
      cryoglobulinemia, although this complication is frequent among patients with
      mixed (type II or III) cryoglobulin. We report two patients with
      glomerulonephritis and monoclonal IgGkappa cryoglobulin. Both patients presented
      with nephrotic syndrome, microscopic hematuria, and impaired renal function.
      Hepatitis C serology was negative, bone marrow aspiration was normal, and the
      renal biopsy specimen showed membranoproliferative glomerulonephritis with
      glomerular subendothelial deposits of monoclonal IgGkappa. In both cases,
      circulating cryoglobulin and monotypic tissue deposits were found to be
      IgG3kappa, suggesting that this isotype may have a particular propensity to cause
      this type of membranoproliferative glomerulonephritis. Although 18 cases of type
      I cryoglobulinemia with biopsy-proven glomerulonephritis have been reported to
      date, this is the first characterization of immunoglobulin heavy-chain isotype in
      this disease.

PMID- 12407657
TI  - Intermittent hemodialysis and/or continuous renal replacement therapy: are they
      complementary or alternative therapies?

PMID- 12407658
TI  - ACE inhibitors in hemodialysis patients: does survival improve?

PMID- 12407659
TI  - A rare infectious cause of renal allograft dysfunction.

PMID- 12407660
TI  - High incidence of pulmonary embolus in hemodialysis patients?

PMID- 12407662
TI  - Continuity of research outcomes: the correlation of bench toxicity mechanisms to
      clinical outcomes--are they dependable?

PMID- 12407664
TI  - Error, not iron, generates cytotoxicity.

PMID- 12407666
TI  - Pseudohyperphosphatemia in a hyperphosphatemic hemodialysis patient.
AB  - Hyperphosphatemia is a predictable consequence of end-stage renal disease.
      Pseudohyperphosphatemia is a spurious elevation of serum phosphate in samples
      containing a substance that interferes with the laboratory assay for phosphate.
      The most common cause is a paraprotein in disorders such as Waldenstrom's
      macroglobulinemia and multiple myeloma. We report here a case of
      pseudohyperphosphatemia in a hyperphosphatemic patient with end-stage renal
      disease on long-term hemodialysis caused by a saline solution containing
      phosphorus used to dilute the patient's serum sample in the clinical chemistry
      laboratory. Investigations showed that the phosphorus most likely was introduced
      at the time of saline manufacture. Pseudohyperphosphatemia resulting from the
      manufacture and distribution of saline-containing phosphorus could be a cause of
      abnormally high serum phosphate measurements in hyperphosphatemic dialysis
      patients whose serum samples must be diluted in the laboratory. Such spuriously
      elevated results can lead to inappropriate changes in medications and subject
      patients to additional hemodialysis treatments.

PMID- 12407667
TI  - On the chemiluminescence in the oxidation of tetravalent uranium to the uranyl
      ion by dimethyldioxirane.
AB  - The reaction of the tetravalent uranium [U(IV)] with dimethyldioxirane (DMD) in
      strongly acidic water-acetone solutions is accompanied by chemiluminescence (CL)
      in the visible (Vis) and infra-red (IR) regions. At least three independent
      reaction pathways are involved in the U(IV)-DMD oxidation: the first entails the
      non-chemiluminescent oxidation of U(IV) to the uranyl ion (UO(2) (2+)); the
      second involves the catalytic decomposition of DMD by U(IV) to afford singlet
      oxygen, as manifested by its characteristic IR-CL; and in the third process, slow
      Vis-CL (510-540 nm) is emitted, following DMD consumption.

PMID- 12407668
TI  - Effects of some trivalent metal ions on the fluoride-induced chemiluminescence
      from a phenylphosphate-substituted dioxetane Lumigen PPD.
AB  - The chemiluminescence generated from the reaction of a thermally stable
      phenylphosphate-substituted dioxetane Lumigen PPD at ambient temperature was
      studied in DMSO solution. The presence of trivalent metal ions Cr(3+), Ga(3+),
      Fe(3+) and Al(3+) was found to quench the resulting chemiluminescence
      dramatically. The system resulted in nice Stern-Volmer plots in the quencher
      concentration range 1.5 x 10(-4)-1.8 x 10(-3) mol/L. The K(Q) values decreased in
      the order Cr(3+) > Ga(3+) > Fe(3+) > Al(3+).

PMID- 12407669
TI  - Synthesis of 5-tert-butyl-1-(3-tert-butyldimethylsiloxy)phenyl-4,4-dimethyl-2,6,7
      trioxabicyclo[3.2.0]heptanes and their fluoride-induced chemiluminescent
      decomposition: effect of a phenolic electron donor on the CIEEL decay rate in
      aprotic polar solvent.
AB  - Four bicyclic dioxetanes bearing a phenolic substituent, 3-tert
      butyldimethylsiloxy-4-chlorophenyl (3a), 5-tert-butyldimethylsiloxy-4-chloro-2
      ethylphenyl (3b), 5-tert-butyldimethylsiloxy-2-ethylphenyl (3c), and 3-tert
      butyldimethylsiloxy-4-ethylphenyl (3d), were synthesized. All dioxetanes 3a-3d
      gave intense blue light on treatment with tetrabutylammonium fluoride (TBAF) in
      DMSO or acetonitrile. Kinetic study on the fluoride-induced CIEEL decay of these
      dioxetanes 3a-3d and the parent dioxetane 2b revealed that the para-substitution
      with chlorine on the phenolic moiety of dioxetane increases free energy of
      activation (DeltaG++), while the para-substitution with ethyl on the aryl
      decreases DeltaG++. On the other hand, substitution with an ethyl at the ortho
      position instead of the para-position was found to increase DeltaG++ and to
      suppress the CIEEL decay. This fact is attributed to the steric factor of the
      ortho-ethyl group which would prevent the aromatic ring from rotating freely
      around the axis joined to the peroxide ring, and supports the suggestion for a
      CIEEL-active dioxetane bearing a phenolic moiety that an intramolecular electron
      transfer occurs preferentially from the phenolic donor to O-O of the dioxetane
      ring, when the aromatic ring lies in a certain conformation(s).

PMID- 12407670
TI  - Kinetic studies on the peroxyoxalate chemiluminescence reaction: determination of
      the cyclization rate constant.
AB  - Although more currently utilized as analytical tool because of its high
      sensitivity and good reproducibility, the mechanism of the peroxyoxalate system,
      a chemiluminescence reaction with quantum yields only comparable to
      bioluminescence systems, has been extensively studied. The light emission
      mechanism can be divided in the pathway before chemiexcitation, which contains
      the rate-limiting steps, and the fast and kinetically non-observable
      chemiexcitation step. In this work, we obtain information on the mechanism of the
      slow pathways, attribute values to several rate constants prior to
      chemiexcitation and suggest a mechanistic scheme that could help optimization of
      conditions when the peroxyoxalate reaction is used as analytical tool.

PMID- 12407671
TI  - Protein structure and bioluminescent spectra for firefly bioluminescence.
AB  - Modern theory on general and specific effects of microenvironment on emission
      spectra was used for explanation of spectral differences for both natural and
      mutant forms of beetle luciferases, as well as for bioluminescence emitter
      oxyluciferin in model systems. For the analysis, both authors' and other
      published data were used. It was shown that active site mutations that resulted
      in spectral shifts of bioluminescence as a rule caused substantial decrease in
      the catalytic activity of the enzyme. At the same time, mutations in the
      conservative regions of the protein amino acid sequence that were in the
      periphery of the protein globe resulted in red shift of the bioluminescence
      spectra without affecting catalytic activity. Correlation was observed between
      the value of spectral shift and polarizability of the introduced amino acid
      residue: the higher the polarizability, the larger was the red shift of
      bioluminescence.

PMID- 12407672
TI  - Bibliography. Luminescence literature. Obelia, Renilla, Aequorea and Gonyaulax.
AB  - The journal provides comprehensive literature searches on all aspects of
      luminescence which will be published in most issues. These lists have been
      produced regularly since 1986-some by year and some by specialized topic. This
      survey of papers on Obelia, Renilla, Aequorea and Gonyaulax is drawn from the
      2000 literature and covers the biology of these organisms and the applications of
      genes and proteins from these organisms in analysis.

PMID- 12407673
TI  - Bibliography. Luminescence literature. Chemiluminescent and bioluminescent
      immunoassays.
AB  - The Journal provides comprehensive literature searches on all aspects of
      luminescence, which will be published in most issues. These lists have been
      produced regularly since 1986-some by year and some by specialized topic. This
      survey of papers on chemiluminescent and bioluminescent immunoassays is drawn
      from the 2000 literature and covers reagents, assay development and validation,
      and applications.

PMID- 12407674
TI  - Dealing with competing risks: testing covariates and calculating sample size.
AB  - It is universally agreed that Kaplan-Meier estimates overestimate the probability
      of the event of interest in the presence of competing risks. Kalbfleisch and
      Prentice recommend using the cumulative incidence as an estimate of the
      probability of an event of interest. However, there is no consensus on how to
      test the effect of a covariate in the presence of competing risks. Using
      simulations, this paper illustrates that the Cox proportional hazards model gives
      valid results when employed in testing the effect of a covariate on the hazard
      rate and when estimating the hazard ratio. A method to calculate the sample size
      for testing the effect of a covariate on outcome in the presence of competing
      risks is also provided.

PMID- 12407675
TI  - Detecting dose-response using contrasts: asymptotic power and sample size
      determination for binomial data.
AB  - Recently, Stewart and Ruberg proposed the use of contrast tests for detecting
      dose-response relationships. They considered in particular bivariate contrasts
      for healing rates and gave several possibilities of defining adequate sets of
      coefficients. This paper extends their work in several directions. First,
      asymptotic power expressions for both single and multiple contrast tests are
      derived. Secondly, well known trend tests are rewritten as multiple contrast
      tests, thus alleviating the inherent problem of choosing adequate contrast
      coefficients. Thirdly, recent results on the efficient calculation of
      multivariate normal probabilities overcome the traditional simulation-based
      methods for the numerical computations. Modifications of the power formulae allow
      the calculation of sample sizes for given type I and II errors, the spontaneous
      rate, and the dose-response shape. Some numerical results of a power study for
      small to moderate sample sizes show that the nominal power is a reasonably good
      approximation to the actual power. An example from a clinical trial illustrates
      the practical use of the results.

PMID- 12407676
TI  - Aggregate data meta-analysis with time-to-event outcomes.
AB  - In a meta-analysis of randomized controlled trials with time-to-event outcomes,
      an aggregate data approach may be required for some or all included studies.
      Variation in the reporting of survival analyses in journals suggests that no
      single method for extracting the log(hazard ratio) estimate will suffice. Methods
      are described which improve upon a previously proposed method for estimating the
      log(HR) from survival curves. These methods extend to life-tables. In the
      situation where the treatment effect varies over time and the trials in the meta
      analysis have different lengths of follow-up, heterogeneity may be evident. In
      order to assess whether the hazard ratio changes with time, several tests are
      proposed and compared. A cohort study comparing life expectancy of males and
      females with cerebral palsy and a systematic review of five trials comparing two
      anti-epileptic drugs, carbamazepine and sodium valproate, are used for
      illustration.

PMID- 12407677
TI  - Regression analysis based on pairwise ordering of patients' clinical histories.
AB  - When a medical treatment influences a variety of outcomes, describing the global
      effect of treatment can be difficult. Traditional approaches specify how
      treatment affects each separate outcome. This can be done with separate models
      for each outcome, or by using a combined multivariate model. Describing the
      overall effect of a treatment thus requires combining these separate effects in
      some fashion and can be difficult to explain. In this paper, I specify a
      regression model for use with multiple outcomes where the outcome histories for
      each pair of patients are ranked. Pairs of patients with different lengths of
      follow-up are evaluated solely over the common follow-up interval. The logit of
      the probability that the outcome for patient i is better than that of patient j
      is assumed to depend on a linear function of the difference of the covariate
      vectors (for example, treatment indicators) for persons i and j. Thus covariates
      directly affect the entire clinical history, rather than directly affecting
      specific outcomes that comprise the history. The idea is that ranking outcomes is
      more relevant and interpretable than statistically combining separate effects. An
      estimating equations approach for estimation is described and an example of a
      clinical trial involving patients with heart failure is provided.

PMID- 12407678
TI  - Assessing chronic disease progression using non-homogeneous exponential
      regression Markov models: an illustration using a selective breast cancer
      screening in Taiwan.
AB  - Previous research on estimation of the progression of chronic disease, from the
      normal preclinical screen-detectable phase (PCDP) to the final clinical phase,
      has usually assumed constant transition rates and has rarely addressed how
      relevant covariates affect multi-state transitions. The present study proposes
      two non-homogeneous models using the Weibull distribution and piecewise
      exponential model, together with covariate functions of the proportional hazard
      form, to tackle these problems. We illustrate the models by application to a
      selective breast cancer screening programme. The results of the Weibull model
      yield estimates of scale and shape parameters for annual preclinical incidence
      rate as 0.0000058 (SE=0.0000019) and 2.4755 (SE=0.1153), the latter being
      significantly higher than 1. Annual transition rate was estimated as 0.3153
      (SE=0.1385). Relative risks for the effects of late age at first pregnancy (AP)
      and high body mass index (BMI) on preclinical incidence rate were 1.98 and 2.59,
      respectively. The corresponding figures on the transition from the PCDP to
      clinical phase were 1.56 and 1.99, respectively. Non-homogeneous Markov models
      proposed in this study can be easily applied to rates of progression of chronic
      disease with increasing or decreasing rates with time and to model the effect of
      relevant covariates on multi-state transition rates.

PMID- 12407679
TI  - Choice of stratification in Poisson process analysis of recurrent event data with
      environmental covariates.
AB  - The Poisson process approach for studying the association between environmental
      covariates and recurrent events depends on the stratification of study period
      into intervals within which the baseline intensities are assumed constant. In
      this work we investigate the problem of bias and variance due to misspecification
      of this stratification. We suggest a cross-validation approach to choosing a
      stratification model to balance the trade-off between bias and variance. We also
      establish a connection between the Poisson process approach and case cross-over
      studies.

PMID- 12407680
TI  - Binary partitioning for continuous longitudinal data: categorizing a prognostic
      variable.
AB  - We investigate a binary partitioning algorithm in the case of a continuous
      repeated measures outcome. The procedure is based on the use of the likelihood
      ratio statistic to evaluate the performance of individual splits. The procedure
      partitions a set of longitudinal data into two mutually exclusive groups based on
      an optimal split of a continuous prognostic variable. A permutation test is used
      to assess the level of significance associated with the optimal split, and a
      bootstrap confidence interval is obtained for the optimal split.

PMID- 12407681
TI  - Use of statistical models for evaluating antibody response as a correlate of
      protection against varicella.
AB  - In vaccine clinical trials, humoral antibody responses are often used to measure
      the effect of a vaccine because they correlate with a vaccine's protective
      efficacy against the target disease. While the concept of a correlate of
      protection usually refers to establishing a protective level of antibody titre,
      identifying a clear-cut value is often impossible because vaccine efficacy is not
      related solely to the antibody titre. We propose examining the relationship
      between disease protection and the whole distribution of antibody responses
      rather than a single cut-off level. In particular, we use failure-time models to
      estimate the relationship between long-term disease breakthroughs and primary
      antibody responses after vaccination. We apply these models to show that the
      varicella antibody response measured by glycoprotein enzyme-linked immunosorbent
      assay 6 weeks after vaccination strongly correlate with protection against
      varicella (chickenpox); we used 7-year follow-up data from children who received
      one dose of a live attenuated varicella (Oka/Merck) vaccine. In addition, we
      explore the potential use of these models to predict long-term disease
      breakthrough rates and to estimate the predicted vaccine efficacy of a similar
      varicella vaccine made with a modified manufacturing process.

PMID- 12407682
TI  - Assessing intrarater, interrater and test-retest reliability of continuous
      measurements.
AB  - In this paper we review the problem of defining and estimating intrarater,
      interrater and test-retest reliability of continuous measurements. We argue that
      the usual notion of product-moment correlation is well adapted in a test-retest
      situation, whereas the concept of intraclass correlation should be used for
      intrarater and interrater reliability. The key difference between these two
      approaches is the treatment of systematic error, which is often due to a learning
      effect for test-retest data. We also consider the reliability of a sum and a
      difference of variables and illustrate the effects on components. Further, we
      compare these approaches of reliability with the concept of limits of agreement
      proposed by Bland and Altman (for evaluating the agreement between two methods of
      clinical measurements) and show how product-moment correlation is related to it.
      We then propose new kinds of limits of agreement which are related to intraclass
      correlation. A test battery to study the development of neuro-motor functions in
      children and adolescents illustrates our purpose throughout the paper.

PMID- 12407683
TI  - Two approaches to mutation detection based on functional data.
AB  - A new technique, denaturing high-performance liquid chromatography (dHPLC),
      allows for detection of any heterozygous sequence variation in a gene without
      prior knowledge of the precise location of the sequence change. The results of a
      dHPLC analysis are recorded in real-time in the form of a chromatogram that is
      sequence-specific. In this paper we present methods to classify an individual,
      based on the observed chromatogram, as a homozygous wild-type or a carrier of a
      specific variant for the given DNA segment by comparison to representative
      chromatograms that are obtained from the training set of individuals with known
      variant status. The first approach consists of finding a parsimonious parametric
      model and then classifying each newly observed curve based on comparing the most
      discriminating characteristic, the main mode, to the main mode of the training
      curves. The second approach consists of finding empirical estimates of the modes
      of each chromatogram and using a bootstrap test for equality with the
      corresponding estimates of the training curves. We apply both methods to data on
      the breast cancer susceptibility gene BRCA1 and test the performance of the
      methods on independent samples.

PMID- 12407684
TI  - Block principal component analysis with application to gene microarray data
      classification.
AB  - We propose a block principal component analysis method for extracting information
      from a database with a large number of variables and a relatively small number of
      subjects, such as a microarray gene expression database. This new procedure has
      the advantage of computational simplicity, and theory and numerical results
      demonstrate it to be as efficient as the ordinary principal component analysis
      when used for dimension reduction, variable selection and data visualization and
      classification. The method is illustrated with the well-known National Cancer
      Institute database of 60 human cancer cell lines data (NCI60) of gene microarray
      expressions, in the context of classification of cancer cell lines.

PMID- 12407685
TI  - Local likelihood analysis of the latency distribution with interval censored
      intermediate events.
AB  - The distribution of time between an intermediate event and a terminal event is
      frequently of interest both in studying the behaviour of populations and in
      predicting outcomes for individuals. Current methods for estimating this latency
      distribution have either imposed assumptions on the hazard for the terminal event
      following the occurrence of the intermediate event or on the parametric form of
      the hazards. Here, local likelihood estimation is applied to the underlying
      hazard functions of a three-state process in which the time of the intermediate
      event may be interval censored and the time of the terminal event is either
      observed or right censored. Smooth non-parametric estimates of the latency
      distribution, along with bootstrap confidence intervals, are calculated, and
      tests for the comparison of two latency distributions are presented. The method
      is applied to two studies: a cohort of haemophiliacs who were infected with HIV
      by contaminated blood factor and followed for AIDS onset, and an AIDS clinical
      trial in which the intermediate event is the time to 50 per cent drop in CD4
      count and the terminal event is AIDS or death. Simulations are presented to
      assess the performance of the estimation procedure.

PMID- 12407686
TI  - Comparing proportional hazards and accelerated failure time models for survival
      analysis.
AB  - This paper describes a method proposed for a censored linear regression model
      that can be used in the context of survival analysis. The method has the
      important characteristic of allowing estimation and inference without knowing the
      distribution of the duration variable. Moreover, it does not need the assumption
      of proportional hazards. Therefore, it can be an interesting alternative to the
      Cox proportional hazards models when this assumption does not hold. In addition,
      implementation and interpretation of the results is simple. In order to analyse
      the performance of this methodology, we apply it to two real examples and we
      carry out a simulation study. We present its results together with those obtained
      with the traditional Cox model and AFT parametric models. The new proposal seems
      to lead to more precise results.

PMID- 12407687
TI  - Estimation and projections of cancer prevalence from cancer registry data.
AB  - A method, PIAMOD (Prevalence, Incidence, Analysis MODel), which allows the
      estimation and projection of cancer prevalence patterns by using cancer registry
      incidence and survival data is presented. As a first step the method involves the
      fit of incidence data by an age, period and cohort model to derive incidence
      projections. Prevalence is then estimated from modelled incidence and survival
      estimates. Cancer mortality is derived as a third step from modelled incidence,
      prevalence and survival. An application to female breast cancer is given for the
      Connecticut State by using data from the Connecticut Tumor Registry (CTR), 1973
      1993. The age, period and cohort model fitted incidence quite well and allowed us
      to derive long-term projections up to 2030. Patients' survival was also projected
      to future years according to a scenario approach based on two extreme hypotheses:
      steady, that is, no more improvements after 1993 (conservative), and continuously
      improving at the same rate as during the observation period. Age-standardized
      estimated incidence shows a changing trend around the year 2005, when it starts
      decreasing. Age-standardized prevalence is expected to increase and change trend
      at a later date. Breast cancer mortality is projected as decreasing, as the
      combined result of no further increase in incidence and improving cancer
      patients' survival. An easy-to-use PIAMOD software package, on which work is in
      progress, will be made available to individual cancer registries and/or health
      planning institutions or authorities once it is developed. The use of the PIAMOD
      method for cancer registries will allow them to provide results of paramount
      importance for the whole community involved in the assessment of future disease
      burden scenarios in an evolving society.

PMID- 12407688
TI  - An adaptive test of significance for a subset of regression coefficients.
AB  - An F-test for a subset of regression coefficients is often used in order to
      compare two nested linear models. An adaptive test is proposed that has higher
      power than this F-test for many non-normal distributions of error terms. The
      adaptive test uses a weighted least squares procedure with weights determined
      from the Studentized deleted residuals from a linear model. A permutation method
      is then used so that the resulting test maintains its size near the nominal
      value. Results from several simulation studies are used to compare the power of
      the adaptive test to the F-test. The adaptive test is recommended as a way of
      increasing the power of many common tests when used with models that have few
      parameters whenever the distribution of errors is non-normal and the number of
      observations exceeds 20.

PMID- 12407689
TI  - Cytogenetics and molecular genetics of human cancer.

PMID- 12407690
TI  - Hereditary chronic lymphocytic leukemia: an extended family study and literature
      review.
AB  - Leukemia is manifested in about 1-2% of people in Western industrialized nations.
      The most common form of leukemia is B-cell chronic lymphocytic leukemia (B-CLL),
      which accounts for approximately 30% of all cases. While CLL's etiology remains
      elusive, there is increasing evidence that substantially supports the role of
      hereditary factors in a subset of cases of this disease. Our purpose is to
      describe an extremely well documented CLL family wherein the disease has been
      verified in a father and his four sons; two of the sons are identical twins. The
      family history, including available medical records and pathology reports, was
      gathered and reviewed. Peripheral blood lymphocytes were used for cytogenetic and
      fluorescence in situ hybridization analyses. The family reported herein shows
      classic findings in support of an autosomal dominant mode of genetic transmission
      of CLL. Given the explosive developments in molecular genetics during the past
      decade, it is certain that families of this type will provide important clues to
      the etiology, pathogenesis, and ultimate prevention of CLL.

PMID- 12407691
TI  - Methodologies in cancer cytogenetics and molecular cytogenetics.
AB  - Various types of cytogenetic and molecular cytogenetic approaches, including
      conventional banding, fluorescence in situ hybridization (FISH), fiber-FISH,
      comparative genomic hybridization (CGH), matrix array CGH, chromosome
      microdissection, and microcell-mediated chromosome transfer are summarized. The
      rationale, advantage, and limitations of each approach are discussed with respect
      to research and clinical applications in human neoplasia.

PMID- 12407692
TI  - Chromosome breakage syndromes and cancer.
AB  - There exist numerous genetic disorders, marked by chromosome instability, that
      are strikingly associated with various cancers. Both the chromosomal
      instabilities and neoplastic outcomes are related to abnormalities of DNA
      metabolism, DNA repair, cell-cycle governance, or control of apoptosis. Among
      these diseases are ataxia telangectasia and Nijmegen breakage syndrome, with
      increased incidences of lymphomas. Bloom syndrome, Werner syndrome, and Rothmund
      Thompson syndrome, each characterized by a DNA helicase defect, are associated
      with early incidences of different cancers. Other diseases combining the
      phenotype of chromosomal instabilities and neoplastic development are Fanconi
      anemia and breast cancers associated with mutant BRCA1 and BRCA2 genes. The
      cloning of the encoding genes and the characterization of their products have
      resulted in partial understanding of the pathways of cellular DNA surveillance
      and maintenance of genomic rectitude. The exact pathways fully linking the
      genetic defect mechanisms to the eventual development of various neoplasias
      remain to be elucidated, but progress in defining the molecular genetics of these
      entities suggests that many of them are disorders of DNA recombination. Each
      defect involves a separate protein in these complex pathways.

PMID- 12407693
TI  - Molecular cytogenetic aspects of hematological malignancies: clinical
      implications.
AB  - The field of molecular cytogenetics has had a great impact on many aspects of
      medical and basic sciences. During the past 30 years, the application of
      molecular cytogenetic methodologies has resulted in remarkable advances in the
      field of cancer genetics and cytogenetics. These advances have led to the
      establishment of chromosome patterns as diagnostic and prognostic indexes in an
      array of acute and chronic leukemias and lymphomas, as key information in BMT,
      and as guides for the localization of oncogenes and tumor suppressor genes that
      are apparently responsible for the development of neoplastic states. With such
      information, the physician is in a more favorable position to devise therapy,
      appraise diagnosis, and plan follow-up.

PMID- 12407694
TI  - Chromosome and gene alterations in breast cancer as markers for diagnosis and
      prognosis as well as pathogenetic targets for therapy.
AB  - Chromosomal abnormalities have been implicated in cancer development since the
      turn of the last century. Only during the past two decades, with advances in
      cytogenetics and molecular biology, has the genetic basis of neoplasia been
      firmly established, however, with chromosomal alterations being recognized as
      critical in the pathogenesis of human cancer. Recurrent chromosomal alterations
      provide cytological and molecular markers for the diagnosis and prognosis of
      disease. They also facilitate the identification of genes that are important in
      carcinogenesis and, ultimately, may lead to the development of targeted therapy.
      In breast cancer, the most prevalent malignancy among females, substantial
      progress has been achieved in identifying genes located at sites of recurrent
      chromosomal alterations and in profiling gene expression through the application
      of powerful cytogenetic and functional genomic techniques. Characterization of
      the molecular pathologic characteristics and gene-expression profiles of breast
      cancer should provide new clinical tools for the accurate diagnosis and
      prediction of prognosis as well as new targets for the development of therapeutic
      agents.

PMID- 12407695
TI  - Cytogenetics and molecular genetics of cancer of the prostate.
AB  - Prostate cancer remains the most common male malignancy in Western countries and
      the second-leading cause of death from cancer in males. Progress in the
      understanding of molecular and genetic mechanisms leading to this disease has
      only recently begun to offer a glimpse of the genes, chromosomal sites, and
      proteins implicated in the development and progression of prostate tumors. This
      brief review addresses some of the key issues in prostate cancer research,
      including a discussion of both hereditary and sporadic cancers as well as
      specific genes and chromosomal loci that likely play a part in the etiology of
      this disease.

PMID- 12407696
TI  - Cytogenetics and molecular genetics of ovarian cancer.
AB  - Genetic alterations identified in human ovarian tumors by conventional banding,
      fluorescence in situ hybridization, comparative genomic hybridization, chromosome
      microdissection, loss of heterozygosity, chromosome microcell-mediated chromosome
      transfer, and microarray gene expression analysis are summarized and correlated.
      The significance of these findings with respect to pathologic classification and
      clinical application are discussed.

PMID- 12407697
TI  - Renal cancer: cytogenetic and molecular genetic aspects.
AB  - To date, much progress has been made in the fields of cytogenetics and molecular
      genetics of renal tumors. The previous and recent findings have delineated the
      characteristics of the various tumors, particularly the cytogenetic and molecular
      differences that exist between papillary and nonpapillary clear cell renal cell
      carcinomas (RCCs). At the same time, new cytogenetic subtypes have emerged [e.g.,
      t(X;1)] in subtypes of RCC, while in others (e.g., Wilms tumors) several new
      cytogenetic abnormalities and consequent molecular involvement have been found.
      In addition to Wilms tumor, papillary RCC, and clear-cell RCC, cytogenetic and
      fluorescence in situ hybridization analyses have been performed on several other
      tumors of the kidney, including chromophobic carcinoma, metanephric adenoma,
      collecting duct carcinoma, transitional cell carcinoma, congenital mesoblastic
      nephroma, and malignant rhabdoid tumors of the kidney. This review is therefore
      intended to present a concise update on the cytogenetic and molecular data on
      renal tumors, focusing mainly on the clinical usefulness of the findings reported
      in the literature.

PMID- 12407698
TI  - Cytogenetics and molecular genetics of bladder cancer: a personal view.
AB  - The cytogenetic and molecular genetic aspects that may be involved in the
      pathogenesis of bladder cancer are presented. Although anomalies of chromosome 9
      may play an initial causative role in this cancer, the subsequent events,
      involving a succession of genetic changes, are less established or understood.
      This presentation is a distillation of what generally are considered to be the
      cytogenetic and molecular genetic events that constitute the array of changes
      underlying bladder cancer.

PMID- 12407699
TI  - Cytogenetics and molecular genetics of lung cancer.
AB  - The development and progression of lung cancer is a multistep process
      characterized by the accumulation of numerous genetic and epigenetic alterations,
      some of which occur early in the course of disease. In this review, we summarize
      cytogenetic imbalances and molecular genetic/epigenetic changes seen in human
      small-cell and non-small-cell lung cancer. Alterations of tumor suppressor genes
      and oncogenes leading to perturbations of key cell-regulatory and growth-control
      pathways are highlighted. The translational implications of molecular biomarkers
      for risk assessment, early detection, and monitoring of chemoprevention trials
      are discussed.

PMID- 12407700
TI  - Cytogenetics and molecular genetics of bone and soft-tissue tumors.
AB  - The cytogenetic and molecular findings in bone and soft-tissue sarcomas are
      summarized. A table presenting all such tumors, with their specific
      translocations and the genes involved, is included, along with a list of those
      tumors that most likely result from a stepwise process of numerous genetic
      changes.

PMID- 12407701
TI  - Genetic alterations associated with adult diffuse astrocytic tumors.
AB  - Astrocytic tumors make up a wide range of neoplasms that differ in their location
      in the central nervous system, morphologic features, progressive and invasive
      behaviors, and the age and gender of people they affect. This report reviews the
      cytogenetic, molecular cytogenetic, and molecular genetic abnormalities
      associated with diffuse infiltrating astrocytomas in adults. This group of tumors
      is subdivided into low-grade astrocytomas (WHO grade II), anaplastic astrocytomas
      (WHO grade III), and glioblastoma multiforme (WHO grade IV).

PMID- 12407702
TI  - Usefulness of high-resolution comparative genomic hybridization (CGH) for
      detecting and characterizing constitutional chromosome abnormalities.
AB  - Comparative genomic hybridization (CGH) is a technique for detection of
      chromosomal imbalances in a genomic DNA sample. We here report the application of
      the recently developed method of high-resolution CGH on DNA samples from 66
      children having various degrees of delayed psychomotor development with or
      without clear dysmorphic features and congenital malformations. In 5 of 50
      patients with apparently normal karyotypes, a deletion or duplication was
      revealed by CGH. Only one of these cases had a subtelomeric rearrangement. In one
      of seven cases with a de novo apparently balanced translocation, deletions were
      found. In all nine cases where the origin of a marker chromosome or additional
      chromosomal material was difficult to determine, CGH gave a precise
      identification. The following findings were from cases having a deletion or
      duplication as the sole chromosomal imbalance; dup(2)(p16p21), del(4)(q21q21),
      del(6)(q14q15), del(6)(p12p12), dup(6)(q24qter), and dup(15)(q11q13). One case
      had dup(9)(p11pter) combined with a very small subtelomeric deletion on 6q. In
      our hands, CGH is highly useful not only for identifying known chromosomal
      imbalances, but also for finding elusive deletions or duplications in the large
      group of children with developmental delay with or without congenital
      abnormalities. In such cases, the diagnostic yield of CGH appears to be higher
      than what has been reported from subtelomeric FISH screening.

PMID- 12407703
TI  - Genetic testing for hearing loss: different motivations for the same outcome.
AB  - The recent discoveries of genes involved in deafness open new options for
      families and individuals with hearing loss. Our aim was to learn if parents of
      children with hearing loss will benefit from these new possibilities. A total of
      139 parents answered questionnaires aimed at evaluating their intentions as well
      as their reasons to opt for or against genetic testing and prenatal diagnosis for
      hearing loss. A very high interest (87%) in genetic testing was found among
      Israeli Jewish parents of deaf and hard-of-hearing children. Although the Jewish
      population in Israel is very diverse in its religious beliefs, this high interest
      was similar across all religious sectors (secular, traditional, orthodox, and
      ultraorthodox); however, some of the reasons for undertaking such a test were
      very different between them. Reasons related to family planning and prenatal
      diagnosis were significantly less important to parents from the ultraorthodox
      sector, but the possibility to utilize genetic testing for matchmaking the
      children with hearing loss and their hearing siblings was an important factor in
      motivating them to undertake the test. Parents from all religious sectors wished
      testing would shed light on the cause of the hearing loss. We conclude that
      genetic testing would be welcomed by a wide range of communities, including those
      that usually do not apply for genetic counseling and testing, if it is offered in
      accordance with their cultural norms and beliefs.

PMID- 12407704
TI  - Delimitation of duplicated segments and identification of their parental origin
      in two partial chromosome 3p duplications.
AB  - Two chromosome 3 short arm duplications identified through G-banding were further
      investigated using fluorescence in situ hybridization (FISH) and polymerase chain
      reaction (PCR) of microsatellite markers, aiming at mapping breakpoints and
      disclosing mechanisms of origin of these chromosome aberrations. Patient 1 was
      found to be a mosaic: a 3p12 --> 3p21 duplication was observed in most of his
      cells, and a normal cell line occurred with a frequency of about 3% in blood. In
      situ hybridization of chromosome 3 short- and long-arm libraries confirmed the
      short-arm duplication. Using FISH of short-arm sequences, the YAC 961_h_3 was
      shown to contain the proximal breakpoint (3p12.1 or 3p12.2), and the distal
      breakpoint was located between the YACs 729_c_3 and 806_h_2, which are adjacent
      in the WC 3.10 contig (3p21.1). In Patient 2, G-banding indicated a 3p21 --> 3p24
      duplication, without mosaicism. In situ hybridization of chromosome 3 short- and
      long-arm libraries confirmed the duplication of short-arm sequences. FISH of
      chromosome 3 sequences showed that the YAC 749_a_7 spanned the proximal
      breakpoint (3p21.33). The distal breakpoint mapped to the interval between YACs
      932_b_6 (3p24.3) and 909_b_6 (3p25). In both cases, microsatellite genotyping
      pointed to a rearrangement between paternal sister chromatids.

PMID- 12407705
TI  - Gender differences in psychosocial reactions to cystic fibrosis carrier testing.
AB  - Gender differences involving genetic testing have become a topic of research as
      feminist critiques assert that women may be affected differently, and possibly
      more significantly, than men by genetic carrier testing information. It is
      possible that men and women differ in their reactions to learning whether they
      are or are not a carrier of a specific mutation. It is also possible that men and
      women may differ in their reactions to different methods of genetic testing. Data
      on gender differences in reactions to cystic fibrosis (CF) carrier testing in a
      high-risk population and to gender differences in reactions to home-based as
      opposed to clinic-based testing are reported. This analysis suggests that at
      least for CF carrier testing, men and women do differ in terms of their risk
      perceptions, negative psychological affect, perceptions about themselves, and the
      convenience of testing. However, there was only one difference between men's and
      women's reactions to the method of testing. A better understanding of gender
      differences in response to carrier testing, as well as to interactions between
      gender and methods of genetic testing, may inform better approaches to carrier
      testing and to considering alternative methods of such testing.

PMID- 12407706
TI  - Limitations of stratifying sib-pair data in common disease linkage studies: an
      example using chromosome 10p14-10q11 in type 1 diabetes.
AB  - IDDM10 on chromosome 10p11-q11 has been identified as a putative diabetes
      susceptibility locus through affected sib-pair (ASP) linkage analysis in UK
      nuclear families [Davies et al., 1994: Nature 371:130-136; Reed et al., 1997: Hum
      Mol Genet 6:1011-1016; Mein et al., 1998: Nat Genet 19:297-300]. We extended
      analysis of linkage to type 1 diabetes in this region by typing a total of 61
      markers in a maximum of 418 UK sib-pairs (UK418; peak MLS = 3.84). We then
      stratified the dataset based on analyses performed previously by both our group
      [Mein et al., 1998: Nat Genet 19:297-300] and others [Paterson et al., 1999: Hum
      Hered 49:197-204; Paterson and Petronis, 1999a: Am J Med Genet 84:15-19; Paterson
      and Petronis, 2000a: J Med Genet 37:186-191; Paterson and Petronis, b: Eur J Hum
      Genet 8:145-148] and used a permutation procedure to assess the significance of
      the results. We conclude that the results obtained had a high probability of
      occurring by chance alone. These data highlight the limitations of stratifying
      small datasets (n < 500) by additional criteria and the recurrent problems of
      multiple testing in genetic analysis.

PMID- 12407708
TI  - Postnatal overgrowth by 15q-trisomy and intrauterine growth retardation by 15q
      monosomy due to familial translocation t(13;15): dosage effect of IGF1R?
AB  - We report a 4-year-old boy, a 6-month-old girl, and a 17-week-old fetus all with
      a chromosomal imbalance derived from a balanced translocation t(13;15)(q34;q26.1)
      of their father. The boy had a partial trisomy for 15q26.1-qter
      (46,XY,der(13)t(13;15)(q34;q26.1)) and postnatal overgrowth, as well as
      craniosynostosis, facial anomalies, and finger joint contractures, while the girl
      with the same chromosomal aberration did not show overgrowth, although she had
      similar craniofacial and skeletal abnormalities. The fetus had a partial monosomy
      for 15q26.1-qter and intrauterine growth retardation (IUGR). Fluorescence in situ
      hybridization (FISH) analysis with a BAC clone covering the insulin-like growth
      factor 1 receptor gene (IGF1R) that is located to 15q25-q26 revealed three copies
      in the boy, one copy in the fetus, and two copies in their phenotypically normal
      father. Since deletion of IGF1Rhas repeatedly been reported to be associated with
      IUGR, it is tempting to speculate that the dosage of IGF1R may have determined
      growth in these children.

PMID- 12407707
TI  - Constitutional deletion of chromosome 20q in two patients affected with albright
      hereditary osteodystrophy.
AB  - Albright hereditary osteodystrophy (AHO) results from heterozygous inactivation
      of G(s)alpha, encoded by the GNAS1 locus on the distal long arm of chromosome 20.
      This autosomal dominant condition is characterized by short stature, obesity,
      shortening of the metacarpals and metatarsals, and variable mental retardation
      and may also include end-organ resistance to multiple hormones. Small insertions
      and deletions or point mutations of GNAS1 are found in approximately 80% of
      patients with AHO. The remainder may be accounted for by larger genomic
      rearrangements, but none have been reported to date. We now describe two patients
      with constitutional 20q deletions and features of AHO. Such deletions are rare in
      the published literature and have not previously been associated with AHO.
      Molecular genetic analysis confirmed complete deletion of GNAS1 in both patients.
      Parental origin could be determined in both cases and provides further support
      for the parent-of-origin effect on the biochemical status of patients with AHO.

PMID- 12407709
TI  - Mutational analysis of the RNX gene in congenital central hypoventilation
      syndrome.
AB  - Congenital central hypoventilation syndrome (CCHS) is a rare syndrome
      characterized by failure of autonomic respiratory control, often presenting with
      other dysfunctions of the autonomic nervous system. Segregation analysis
      suggested a complex model of inheritance with a major locus involved. Disruption
      of the Rnx gene, a member of the Hox11 family of homeobox genes, in embryonic
      stem cells produced mice showing a phenotype similar to CCHS. Based on this
      observation, we have carried out mutation screening of the RNX gene in a set of
      13 patients affected with CCHS, 2 of whom showing association with Hirschsprung
      disease. Single-strand conformational polymorphism analysis and direct sequencing
      of the whole coding portion of the RNX gene and of 1,311 bp of 5' flanking region
      were performed. No sequence variant was identified, with the exception of a
      private nucleotide change at position -874 bp from the ATG codon in two siblings
      affected with isolated CCHS. A functional test, performed by using the luciferase
      gene reporter system, has not shown any significant difference in the activity of
      the promoter region carrying this latter nucleotide change with respect to the
      wild-type allele. We conclude that RNX, and presumably its expression, are not
      altered in our index cases of CCHS.

PMID- 12407710
TI  - Simvastatin treatment in the SLO syndrome: a safe approach?
AB  - Soon after the discovery of reduced cholesterol synthesis in the Smith-Lemli
      Opitz syndrome (SLOS), several trials with dietary supplementation were initiated
      with the aim of increasing cholesterol and reducing the de novo synthesis and
      accumulation of 7- and 8-dehydrocholesterol (DHC). Dietary cholesterol raises
      cholesterol levels in the circulation with only marginal effects on levels of
      DHC. Photosensitivity and polyneuropathy have been reported to be improved by the
      treatment, but other effects have been difficult to evaluate. In order to see
      whether inhibition of hydroxymethylglutaryl CoA reductase is of benefit, two of
      our patients have been treated with simvastatin in addition to the long-term
      treatment with cholesterol and bile acids. Absolute as well as relative levels of
      DHC were reduced. In one patient, creatine kinase increased moderately after 2
      months of treatment. In the other patient, the treatment had to be interrupted
      because of hepatotoxic side effects with a marked increase in alanine
      aminotransferase and aggravation of the hypocholesterolemia and photosensitivity.
      We conclude that even if the levels of accumulated intermediates can be reduced,
      treatment with a statin may be harmful in some patients with SLOS.

PMID- 12407711
TI  - De novo pericentric inversion of chromosome 4, inv(4)(p16q12) in a boy with
      piebaldism and mental retardation.
AB  - An 8-year-old boy who was diagnosed to have piebaldism had moderate growth and
      mental retardation. Chromosome analysis from peripheral blood showed pericentric
      inversion 4(p16q12). The inversion was further confirmed by fluorescence in situ
      hybridization using whole chromosome painting and centromeric probes. Chromosomal
      analysis of parents revealed de novo inheritance of this inversion. This is the
      first report of pericentric inversion associated with piebald trait.

PMID- 12407712
TI  - Grebe-Quelce-Salgado chondrodystrophy: prenatal diagnosis of two new cases in
      unrelated families in Southern Brazil.
AB  - Grebe-Quelce-Salgado chondrodystrophy is an autosomal recessive non-lethal
      skeletal dysplasia. Affected individuals have normal head, neck, and trunk
      skeleton, relatively normal humeri and femora, short and deformed radii, ulnae,
      tibiae, and fibulae, and severe abnormalities of hands and feet. Polydactyly is
      frequent. Digits present as globular appendages and are characteristic of the
      condition. The disease is caused by a missense mutation in the gene encoding
      cartilage-derived morphogenetic protein-1 (CDMP-1). Most cases described in the
      literature are from Brazil and, among these, all had ancestors from a particular
      region in the state of Bahia. We describe two cases of Grebe-Quelce-Salgado
      chondrodystrophy visualized by prenatal ultrasound. The patients presented in
      this report do not descend from the population of Bahia and, to our knowledge,
      case two is the only case with prenatal clinical diagnosis in a family with no
      previously affected children.

PMID- 12407713
TI  - Craniosynostosis associated with ocular and distal limb defects is very likely
      caused by mutations in a gene different from FGFR, TWIST, and MSX2.
AB  - Craniosynostosis caused by genetic factors includes a heterogeneous group of over
      100 syndromes, most with autosomal dominant inheritance. Mutations in five genes
      (FGFR1-, -2, -3, TWIST, and MSX2) causing craniosynostosis as the main clinical
      feature were described. In most of these conditions, there are also limb
      malformations. We report a two-generation kindred segregating microcornea, optic
      nerve alterations and cataract since childhood, craniosynostosis, and distal limb
      alterations, with a great clinical intrafamilial variability. The
      ophthalmological problems here described seem to be unique to this genealogy
      while similar feet alterations were apparently only described in two other
      affected siblings with acro-cranial-facial dysostosis syndrome (ADS). However,
      ADS has an autosomal recessive inheritance instead of the dominant pattern of the
      present genealogy. The candidate exons of the five genes previously mentioned
      were tested through sequencing analysis presenting normal results in all cases.
      Therefore, clinical and laboratory analyses in our patients suggest that their
      phenotype represents a new syndrome very likely caused by mutation in a gene
      different from those studied.

PMID- 12407714
TI  - Molecular cytogenetic characterization of a 10p14 deletion that includes the DGS2
      region in a patient with multiple anomalies.
AB  - We report on a prenatally diagnosed four-month-old boy with DiGeorge-like
      phenotype and a deletion of chromosome 10pter --> 14. Fluorescence in situ
      hybridization (FISH) experiments using phage artificial chromosome (PAC) and
      yeast artificial chromosome (YAC) clones indicated that the chromosomal
      breakpoint was located at the proximal boundary of the DiGeorge syndrome 2 (DGS2)
      critical region. The patient demonstrated a high forehead, high arched eyebrows,
      short palpebral fissures, sparse eyelashes, prominent nose with bulbous tip,
      small mouth, receding chin, round ears with deficient helices, cardiac defects
      atrial septal defect (ASD), ventricular septal defect (VSD), mild
      brachytelephalangy, mild syndactyly, hypoplastic left kidney, undescended testes,
      muscular hypertonia, dorsally flexed big toes, and developmental delay. The
      phenotype corresponded well with the clinical signs of 10p deletion of this
      region that were described previously. The facial features appeared different
      from the typical face with the 22q11 deletion.

PMID- 12407715
TI  - Provisional new syndrome of MR/MCA with evolving phenotype.
AB  - We report on a 10-year-old patient with a provisionally new syndrome of MR/MCA
      with an evolving phenotype. Major findings at birth included short umbilical
      cord; striking hypotonia and cutis laxa with increased OFC; facial abnormalities
      with epicanthal folds, telecanthus, mild hypertelorism, wide flat nasal bridge,
      hypoplastic nose with upturned nostrils, and low-set dysplastic ears; asymmetric
      deformed chest with prominent sternum and winged scapulae; wider thumbs and
      halluces; left cryptorchidism and unusual perianal creases. Chromosomal and
      metabolic studies were normal. With aging, the phenotype has changed
      significantly: cutis laxa disappeared, the perianal creases and hypotonia are
      much milder, the initial apparent macrocephaly turned out to be true
      microcephaly, broad thumbs are less evident, but skeletal anomalies are more
      striking. Unsuccessful extensive diagnostic searches since birth and presentation
      in meetings suggest the presence of a private syndrome.

PMID- 12407716
TI  - Pure partial trisomy 7q: two new patients and review.
AB  - We report on two new cases with a pure partial trisomy of the long arm of
      chromosome 7. Patient 1 was a female who showed cleft palate with retrognathia,
      cardiomyopathy, and pulmonary hypertension. Patient 2 was a male who showed
      microretrognathia, cleft palate, micropenis, camptodactyly, and clynodactyly.
      High-resolution G-bands (550-850) karyotype showed that patient 1 had an extra
      chromosome, which resulted from the adjacent 3:1 segregation from a maternal
      balanced reciprocal translocation, and patient 2 had an abnormaly Y chromosome.
      Fluorescent in Situ Hybridization (FISH) analysis with a whole chromosome
      painting confirmed in the first patient that the extra chromosome was from
      chromosome 7, and in patient 2 the abnormal Y chromosome had extra material of
      chromosome 7 origin. Three different clinical entities have been described as the
      product of the partial trisomy of three different 7q regions, although some
      authors have found no karyotype-phenotype correlations. Of the patients presented
      here, patient 1 had trisomy of those three regions, and patient 2 had trisomy of
      two of those regions.

PMID- 12407717
TI  - Rapid SMN1 deletion test using DHPLC to screen patients with spinal muscular
      atrophy.

PMID- 12407718
TI  - Symmetrical tetraphocomelia without associated congenital malformations: a
      nosological dilemma.

PMID- 12407719
TI  - Breast cancer testing: what is appropriate?

PMID- 12407720
TI  - 5- and 10-year survival in cancer patients aged 90 and older: a study of 37,318
      patients from SEER.
AB  - BACKGROUND AND OBJECTIVES: Uncertainty exists about the value of cancer therapy
      in patients aged 90 years and older. Because of the relative paucity of these
      patients, as well as the possibility of selection bias in any one institution,
      the use of a large, total population-based cancer registry was employed. METHODS:
      The Surveillance, Epidemiology, and End Results (SEER) program of the National
      Cancer Institute (NCI) offers a large, total population-based cancer registry. It
      includes more than 2,000,000 cases in the nine registry data from 1973 to 1998;
      37,318 of these are 90 or older and are eligible for follow-up studies. A cross
      sectional study of relative survival of all these cases, along with younger age
      groups for comparison, was carried out. RESULTS: After the first year after
      diagnosis, the annual relative survival is not affected by a patient's age for up
      to 10 years. CONCLUSIONS: Age alone is not a contraindication to cancer treatment
      in the most elderly and, other than in the first year, one can expect the same
      relative survival in these oldest patients as one does for younger patients.

PMID- 12407722
TI  - Adenocarcinoma of the stomach in patients age 35 years and younger: no impact of
      early diagnosis on survival outcome.
AB  - BACKGROUND AND OBJECTIVES: Patients aged 35 years and younger with gastric
      adenocarcinoma constitute a group of patients who have been observed to have low
      survival rates as compared with older gastric adenocarcinoma patients. A low
      index of suspicion for gastric cancer in this age group has been suspected to
      result in a delay in diagnosis. The use of computed tomography (CT) scanning and
      endoscopy has become much more common during the past 15 years. We hypothesized
      that early diagnosis would result in improved survival for these patients.
      METHODS: We performed a retrospective study of 127 patients aged 35 years and
      younger with gastric (median follow-up, 9 months). RESULTS: High proportions of
      female patients and Hispanic patients were observed. Overall survival of this
      group of patients was poor, with a median survival of only 8 months. Comparison
      of patients diagnosed within 2 months of the onset of symptoms with those
      diagnosed later revealed no survival advantage to early diagnosis. Similarly,
      diagnosis within 2 months of presentation to a physician conferred no survival
      advantage. CONCLUSIONS: Long-term survival is rare, with a short overall median
      survival. Early diagnosis conferred no survival advantage. This group of patients
      should be considered for protocol based multi-modality therapy, even with
      potentially resectable disease.

PMID- 12407724
TI  - Lymphatic spread among women with primary peritoneal carcinoma.
AB  - BACKGROUND AND OBJECTIVES: Our knowledge regarding the pathologic lymphatic
      spread pattern of primary peritoneal carcinoma (PPC) is limited. The aim of this
      study was to compare the incidence and the pathologic patterns of pelvic and para
      aortic lymph node metastases among women with PPC and those with papillary serous
      ovarian carcinoma (PSOC). METHODS: We conducted a prospective study over the last
      4 years among women with FIGO stage III and IV PPC and PSOC who had optimal
      primary cytoreductive surgery (<1 cm residual). The same surgeon performed pelvic
      and para-aortic lymphadenectomy on all the patients using a similar technique.
      The same pathologist reviewed all lymph nodes and recorded nodal involvement with
      cancer, diameter of the largest nodal tumor, capsular integrity, and pattern of
      immune response (lymphocyte predominant, germinal cell predominant, unstimulated,
      or lymphocyte depletion). Both groups were compared in their characteristics,
      FIGO stage, tumor grade, number of lymph nodes, proportion of lymph nodes with
      metastases, and the pathologic characteristics of the positive lymph nodes.
      RESULTS: Eleven women had PPC and 27 had PSOC. Patients with PPC were older than
      those with PSOC (mean age: 63.2 years +/- 11.0 vs. 57.4 +/- 13.4, P = 0.181).
      There was no difference in FIGO stage or tumor grade between both groups. There
      was no difference among the mean numbers of pelvic and para-aortic lymph nodes
      between women with PPC and those with PSOC (10.8 +/- 7.3 vs. 11.0 +/- 6.7 and 3.0
      +/- 3.3 vs. 3.4 +/- 2.1, P = 0.768 and 0.706, respectively). The incidences of
      pelvic, para-aortic, and pelvic and/or para-aortic lymph node metastases were
      similar among women with PPC and those with PSOC (72.7% vs. 66.6%, P = 0.701,
      72.7% vs. 48.1%, P = 0.172, and 72.7% vs. 77.8%, P = 0.736, respectively).
      Similarly, pelvic and para-aortic nodal tumor size, capsular integrity, and
      immune response were similar in both groups. The incidence of significant
      complications related to lymphadenectomy was low among women with PPC and those
      with PSOC (9.1% vs. 7.4%, respectively). CONCLUSIONS: PPC and PSOC exhibit
      similar pathologic lymphatic spread patterns. Pelvic and para-aortic
      lymphadenectomy should be considered among women with PPC in whom the tumor could
      be optimally cytoreduced.

PMID- 12407725
TI  - Does systematic lymphadenectomy have a benefit on survival of suboptimally
      debulked patients with stage III ovarian carcinoma? A DEGOG* Study.
AB  - BACKGROUND AND OBJECTIVES: The aim of this study was to investigate whether
      systematic lymphadenectomy is necessary in suboptimally cytoreduced patients with
      stage III ovarian carcinoma. METHODS: Prognostic significance and the effect on
      survival of systematic pelvic and para-aortic lymphadenectomy were investigated
      retrospectively in 61 suboptimally debulked patients with stage III ovarian
      carcinoma. All patients received platinum-based chemotherapy after surgery; 51
      patients had been followed for > or =1 year, or until death. Survival curves were
      calculated according to the Kaplan-Meier method and were evaluated by log-rank
      test. RESULTS: Most patients had stage IIIC disease (60.7%), poorly
      differentiated tumor (45.9%), and serous histological type (59%). Systematic
      pelvic and para-aortic lymphadenectomy was performed in 29 patients (47.5%).
      Lymph node metastases were found in 17 (58.6%) patients; the median number of
      metastatic nodes was 7 (5-10). Lymph node metastasis was significantly higher in
      patients with residual disease of >2 cm (P < 0.05). Both univariate and
      multivariate analyses showed that systematic pelvic and para-aortic
      lymphadenectomy was not a significant prognostic factor (P > 0.05). In lymph node
      dissected patients, survival was significantly longer in patients with minimal
      residual tumor than in those with residual tumor size >2 cm (P = 0.005).
      CONCLUSIONS: Lymphadenectomy seems not to have an evident prognostic value and a
      benefit on survival in suboptimally debulked patients with stage III ovarian
      carcinoma.

PMID- 12407726
TI  - Phase II study of gemcitabine combined with radiation therapy in patients with
      localized, unresectable pancreatic cancer.
AB  - BACKGROUND AND OBJECTIVES: Gemcitabine is an active agent in pancreatic cancer,
      with known radiosensitizing properties. Therefore, a phase II study was conducted
      to evaluate the efficacy of gemcitabine combined with radiation therapy in
      patients with localized unresectable adenocarcinoma of the pancreas. METHODS:
      Weekly gemcitabine at a dose of 1,000 mg/m(2) for 7 weeks was given as an
      induction phase. Patients who showed both clinical benefit response (CBR) and
      reduced or stable tumor size on computed tomography (CT) scan entered the
      chemoradiotherapy phase of the treatment. This consisted of gemcitabine 400
      mg/m(2) weekly x3 every 28 days for 2 cycles, given concurrently with
      radiotherapy, for a total dose of 50.4 Gy in 28 fractions. After completion of
      radiotherapy, gemcitabine was continued as maintenance. RESULTS: Twenty patients
      entered this study. Ten patients (50%) achieved CBR to gemcitabine in the
      induction phase; these patients had no objective tumor progression and were
      therefore enrolled in the chemoradiotherapy phase. Four patients (20%) had a
      partial response, and three patients (15%) underwent pancreatectomy. Two patients
      had negative surgical margins, and in one patient histologic examination of the
      residual mass showed only fibrosis. The median survival for the entire group was
      8 months, and the median survival has not yet been reached for the
      chemoradiotherapy group. CONCLUSIONS: Treatment with gemcitabine concomitant with
      radiation therapy according to the present schedule is well tolerated and can
      provide prolonged CBR and disease stabilization in patients with localized,
      unresectable pancreatic cancer.

PMID- 12407727
TI  - Aggressive resection of retroperitoneal sarcoma is superior to simple excision:
      an animal study using a novel model for retroperitoneal sarcoma.
AB  - BACKGROUND AND OBJECTIVES: Retroperitoneal sarcomas constitute a difficult
      management problem. The need for, and extent of, aggressive surgery continues to
      be debated. The aim of our study was to compare the impact of radical en bloc
      resection of retroperitoneal sarcoma with complete resection of the tumor alone
      in a rat model. METHODS: Under laparoscopic guidance, a fibrosarcoma cell line
      suspension was injected into the left paranephric space of a rat, resulting in
      the development of a macroscopic retroperitoneal tumor. Ten days after
      inoculation, 50 rats were randomized into three groups: (1) local resection, (2)
      radical resection, and (3) follow-up only. Groups 1 and 2 were further randomized
      for sacrifice 1 month after surgery or were followed up for 2 months. RESULTS:
      Local recurrence: 46% of group 1, while none in group 2 developed local
      recurrence during the same follow-up period (P = 0.02). Survival: 33% of group 1
      were alive after 2 months, as compared with 54.5% of group 2. (P = 0.04). All
      rats in the control group died within <25 days. CONCLUSIONS: Our results suggest
      that aggressive en bloc resection of retroperitoneal sarcomas with adjacent
      viscera, even when macroscopically uninvolved with disease, has an advantage over
      complete local resection alone.

PMID- 12407728
TI  - Quantitative analysis of heparanase messenger RNA expression in hepatocellular
      carcinoma.
AB  - BACKGROUND AND OBJECTIVES: In the process of tumor invasion, cancer cells secrete
      enzymes including heparanase that degrade extracellular matrices and basement
      membranes of blood vessels. In the present study, the clinical importance of
      enhanced expression of heparanase messenger RNA (mRNA) in hepatocellular
      carcinoma (HCC) was evaluated. METHODS: Fresh tumor and noncancerous liver tissue
      adjacent to a tumor were obtained from 50 patients with HCC immediately after
      hepatic resection. The expression levels of heparanase mRNA were analyzed
      quantitatively, using the real-time reverse transcriptase-polymerase chain
      reaction (RT-PCR) method, and were compared with clinicopathological findings.
      RESULTS: Relative heparanase mRNA expression level in HCC was significantly lower
      than that of noncancerous liver tissue (P < 0.001). Tumor heparanase expression
      did not correlate with tumor differentiation, tumor stage, or patient prognosis.
      CONCLUSIONS: Enhanced heparanase mRNA expression may not be a good biological
      marker in HCC. J. Surg. Oncol. 2002;81:148-154.

PMID- 12407730
TI  - Giant pleomorphic adenoma of the parotid gland involving the parapharyngeal space
      treated by a totally extraoral transparotid approach.

PMID- 12407732
TI  - Molecular and genetic aspects of lung cancer.

PMID- 12407733
TI  - Molecular alterations in lung cancer. Impact on prognosis.
AB  - There are multiple molecular abnormalities that can occur in lung cancer. Based
      on the aberrancies described previously, many investigators and drug companies
      are designing novel therapies. The molecular markers can also be used as
      prognostic variables for future clinical trials and therapeutic interventions. It
      will not be an easy task to make an impact on lung cancer using these methods,
      since multiple pathways are abnormal in its pathogenesis. It is hoped that with
      the advent of novel and directed therapeutics, we may soon show some impact on
      the survival of this devastating disease.

PMID- 12407734
TI  - Cellular predictive factors of drug resistance in non-small cell lung carcinomas.

PMID- 12407735
TI  - Clinical implications of p53 mutations in lung cancer.
AB  - The process of bronchial carcinogenesis is characterized by accumulated genetic
      abnormalities which ultimately lead to malignant transformation of bronchial
      epithelial cells, followed by invasion and metastasis. One of the most common and
      consistent of these genetic lesions is inactivation of the p53 tumor suppressor
      gene by mutation or deletion. The frequency of p53 alterations in lung cancer is
      highest in those subtypes of bronchial carcinomas that are most consistently
      associated with smoking, especially SCLC and squamous cell carcinomas. The
      frequency is lower in adenocarcinomas, in which the association with smoking,
      although present, is not as strong. The frequency of p53 abnormalities is higher
      in patients with greater cumulative tobacco exposure. Tobacco-specific
      carcinogens, in particular BPDE, cause a unique spectrum of p53 mutations, quite
      distinct from those found in cancers that are not associated with smoking. This
      characteristic genetic "signature" may persist even decades following smoking
      cessation. The prognostic significance of p53 mutations in lung cancer is not
      entirely clear despite the multitude of clinical studies that have been carried
      out. Nevertheless, the majority of clinical studies suggest that lung cancers
      with p53 alterations carry a worse prognosis. Furthermore, those tumors with
      mutant p53 may be relatively more resistant to chemotherapy and radiation. An
      understanding of the role of p53 in human lung cancer may lead to more rational
      targeted approaches for treating this disease. For example, the observation that
      the introduction of wild-type p53 into lung cancer cells with mutant or deleted
      p53 may reverse the malignant phenotype despite the presence of multiple other
      genetic abnormalities (14) suggests that replacement of this gene may be an
      effective clinical strategy. Preclinical and early clinical studies indicate that
      this is a promising approach, but clearly more effective means of gene delivery
      to the tumor cells are required (127-129), as discussed elsewhere in this volume.

PMID- 12407736
TI  - An epidemiologic and clinicopathologic overview of AIDS-associated pulmonary
      Kaposi's sarcoma.

PMID- 12407737
TI  - Myeloperoxidase promoter region polymorphism and lung cancer risk.
AB  - Historically, myeloperoxidase activity and subsequent production of hypochlorous
      acid has been associated with the killing of host-invading microorganisms
      (bacteria, viruses, and fungi). Currently, there is a wealth of evidence that the
      MPO polymorphism and enzyme activity is associated with a wide range of
      pathological and biological processes, including lung cancer carcinogenesis.
      Although the molecular epidemiology reports reviewed in this chapter are not in
      complete agreement on all aspects of their findings, it is evident that the MPO
      polymorphism contributes to the modulation of overall lung cancer risk. Four of
      the five molecular epidemiologic studies reviewed in this chapter utilized
      similar case-control study designs with quite different sources of populations.
      These studies all demonstrate that the MPO variant genotype modulates overall
      lung cancer risk. However, these studies are not in agreement regarding age and
      gender effects, and gene-environmental interactions. The nested case control
      study designed utilized by Misra et al. (35) is a valid and sound approach, but
      their results found no evidence of an association. Certainly, heterogeneity in
      study populations can contribute to the variability between these studies.
      Additionally, epidemiologic issues such as case-control matching and sources of
      control populations may contribute to the conflicting findings. Thus, the
      publication of inconsistent or null studies as well as other positive findings is
      certainly encouraged to elucidate the range of effects associated with the MPO
      polymorphism and lung cancer risk.

PMID- 12407738
TI  - Clinical utility of tumor markers in the management of non-small cell lung
      cancer.

PMID- 12407739
TI  - Detection of chromosomal aberrations in lung tissue and peripheral blood
      lymphocytes using interphase fluorescence in situ hybridization (FISH).

PMID- 12407740
TI  - In situ analysis of telomerase RNA gene expression as a marker for tumor
      progression.

PMID- 12407741
TI  - A high-throughput methodology for identifying molecular targets overexpressed in
      lung cancers.

PMID- 12407742
TI  - Expression profiling of lung cancer based on suppression subtraction
      hybridization (SSH).

PMID- 12407743
TI  - Comparative genomic hybridization of human lung cancer.

PMID- 12407744
TI  - Sensitive assays for detection of lung cancer. Molecular markers in blood
      samples.

PMID- 12407745
TI  - Fluorescent microsatellite analysis in bronchial lavage as a potential diagnostic
      tool for lung cancer.

PMID- 12407746
TI  - Southern Blotting of genomic DNA from lung and its tumors. Application to
      analysis of allele loss on chromosome 11p15.5.

PMID- 12407747
TI  - Assessment of insulin-like growth factors and mutagen sensitivity as predictors
      of lung cancer risk.

PMID- 12407748
TI  - Comparative multiplex PCR and allele-specific expression analysis in human lung
      cancer. Tools to facilitate target identification.

PMID- 12407749
TI  - Detection of K-ras point mutations in sputum from patients with adenocarcinoma of
      the lung by point-EXACCT.

PMID- 12407750
TI  - Detection of K-ras and p53 mutations by "mutant-enriched" PCR-RFLP.

PMID- 12407751
TI  - Detection of small cell lung cancer by RT-PCR for neuropeptides, neuropeptide
      receptors, or a splice variant of the neuron restrictive silencer factor.

PMID- 12407752
TI  - Utilization of thyroid transcription factor-1 immunostaining in the diagnosis of
      lung tumors.

PMID- 12407753
TI  - Molecular biologic substaging of stage I NSCLC through immunohistochemistry
      performed on formalin-fixed, paraffin-embedded tissue.

PMID- 12407754
TI  - A sensitive immunofluorescence assay for detection of p53 protein in the sputum.

PMID- 12407755
TI  - SPR1. An early molecular marker for bronchial carcinogenesis.

PMID- 12407756
TI  - Determination of biological parameters on fine-needle aspirates from non-small
      cell lung cancer.

PMID- 12407757
TI  - Detection and analysis of lung cancer cells from body fluids using a rare event
      imaging system.

PMID- 12407758
TI  - Reconstruction of geno-phenotypic evolutionary sequences from intracellular
      patterns of molecular abnormalities in human solid tumors.

PMID- 12407759
TI  - Surgical treatment of lung cancer. Past and present.

PMID- 12407760
TI  - Recent advances and dilemmas in the radiotherapeutic management of locally
      advanced non-small cell lung cancer.

PMID- 12407761
TI  - Photodynamic therapy in lung cancer. A review.
AB  - PDT utilizes photosensitizing agents that are selectively retained by tumors.
      These agents have high resulting tumor:tissue concentrations but are inactive by
      themselves. When activated by light, they generate free radicals, resulting in
      membrane injury, vascular injury, and immune-mediated injury with relatively
      selective cytotoxicity to tumor cells. Clinically, PDT can be used to treat CIS
      as well as more advanced lung cancers with endobronchial obstruction. PDT should
      be viewed as one tool of many that can be used to deal with airway problems in
      patients with lung cancer and it will often need to be used in conjunction with
      other techniques, such as airway stenting, Nd-YAG, or cryotherapy. For PDT to be
      effective, it must be integrated into a multimodality approach, including
      chemotherapy and radiation therapy.

PMID- 12407762
TI  - Gene therapy for lung cancer. An introduction.
AB  - Incremental progress will likely continue to be made in the treatment of lung
      cancer using the conventional treatment modalities. However, there is now hope
      that the development of noncross-resistant modalities that can be accomplished
      using the technology of gene transfer may hasten the progress made in this
      disease. Although significant progress has been made, the practical application
      of the various strategies to the treatment of cancer patients in clinical trials
      has yielded only very limited results. For the strategies of introducing suicide
      genes, replacing defective tumor-suppressor genes, and inactivating oncogenes,
      considerable progress will need to be made particularly with regard to the
      ability of vectors to selectively and efficiently target tumor cells in order for
      many of these strategies to become effective. With regard to the application of
      gene therapy to immunotherapy, major responses are not likely at this time since
      these innovative therapies are being developed in patients with advanced disease.
      However, it is very likely that these pioneering clinical trials will provide
      important clinical and immunological information that will be the basis for
      future attempts to effectively harness the immune system against lung cancer.

PMID- 12407763
TI  - Identifying obstacles to viral gene therapy for lung cancer. Malignant pleural
      effusions as a paradigm.

PMID- 12407764
TI  - Topical gene therapy for pulmonary diseases with PEI-DNA aerosol complexes.

PMID- 12407765
TI  - Targeted delivery of expression plasmids to the lung via macroaggregated
      polyethylenimine-albumin conjugates.

PMID- 12407766
TI  - Preparation of retroviral vectors for cell-cycle-targeted gene therapy of lung
      cancer.

PMID- 12407767
TI  - Aerosol gene therapy for metastatic lung cancer using PEI-p53 complexes.

PMID- 12407768
TI  - Clinical development of antisense oligonucleotides as anti-cancer therapeutics.

PMID- 12407769
TI  - Antisense oligonucleotides targeting RI alpha subunit of protein kinase A. In
      vitro and in vivo anti-tumor activity and pharmacokinetics.

PMID- 12407770
TI  - Use of antisense oligonucleotides for therapy. Manipulation of apoptosis
      inhibitors for destruction of lung cancer cells.

PMID- 12407771
TI  - Induction of programmed cell death with an antisense Bcl-2 oligonucleotide.

PMID- 12407772
TI  - Tumor vaccination with cytokine-encapsulated microspheres.

PMID- 12407773
TI  - Adoptive immunotherapy.

PMID- 12407774
TI  - Intratumoral therapy with cytokine gene-modified dendritic cells in murine lung
      cancer models.

PMID- 12407775
TI  - Cyclooxygenase 2-dependent regulation of antitumor immunity in lung cancer.

PMID- 12407776
TI  - Chemoprevention of lung cancer.

PMID- 12407777
TI  - Assessing the interaction of particulate delivery systems with lung surfactant.

PMID- 12407778
TI  - Chemopreventive therapeutics. Inhalation therapies for lung cancer and bronchial
      premalignancy.
AB  - The lung cancer epidemic is not expected to abate in the next two decades.
      Smoking cessation campaigns have not been successful in reducing the prevalence
      of smoking to < 25% of the adult population in the US. Among high school
      students, the prevalence of smoking is increasing (27.5% in 1991; 36.4% in 1997)
      (43). In addition, only 1 in 8 heavy smokers develop lung cancer and about 20% of
      patients with lung cancer have no history of active or passive smoking, thus
      indicating that genetic predisposing factors and other unidentified carcinogens
      play a crucial role in the etiology of this disease. The bronchial epithelium is
      like an internal skin where lung cancer originates after chronic exposure to
      airborne carcinogens in a predisposed host. Although the bronchial epithelium is
      not readily examinable, it is easily accessible to therapeutic intervention by
      using inhaled therapeutics. We hope to extend our findings using direct wild-type
      p53 gene replacement via intratracheal and aerosolized administrations in mice to
      NSCLC patients with p53 mutations. We also plan on utilizing aerosolized chemical
      agents to activate endogenous mechanisms of cytoprotection. If, in clinical
      trials, evidence of effective cytoprotection is observed in the absence of
      intolerable side effects, further exploration of this new strategy for the
      control and prevention of a neoplastic disease that accounts for a third of all
      cancer-related deaths will be fully justified.

PMID- 12407779
TI  - [The treatment of arterial hypertension: is it a simple routine?].

PMID- 12407780
TI  - [Pulse pressure and coronary disease].
AB  - The concept of pulse pressure has been developed over the past 10 years. Large
      observational studies in the general population have shown a link between pulse
      pressure and risk of late coronary events. The correlation between pulse pressure
      and coronary events appears particularly strong in the elderly. More limited data
      have shown that a high level of pulse pressure was related to angiographically
      documented coronary artery disease; recently, a correlation between pulse
      pressure and a high level of C reactive protein has been evidenced in the NHANES
      cohort. In patients with known coronary artery disease, pulse pressure is a
      prognostic factor, both after myocardial infarction with left ventricular
      dysfunction (SAVE trial) and after myocardial revascularization by coronary
      surgery or angioplasty (BARI randomised trial and registry). In addition, two
      small-sized studies have shown a strong correlation between pulse pressure and
      restenosis after conventional percutaneous transluminal coronary angioplasty.

PMID- 12407782
TI  - [Hypertension and microcirculation].
AB  - The importance of the microcirculation (comprising the smallest arteries,
      arterioles, capillaries and venules) in hypertension and other cardiovascular
      diseases is well known. The small resistance arteries develop structural changes
      such as an increase in the wall/lumen ratio and the capillary networks of
      different vascular beds become rarefied in response to increased blood pressure.
      These changes not only contribute to hypertensive lesions of target organs but
      also maintain or amplify the increased blood pressure by increasing peripheral
      resistances, so creating a vicious circle. Microvascular changes in hypertension
      may also lead to an increased reflection of the pressure wave towards the heart
      from the peripheral reflecting sites. This reflected wave also increases systolic
      blood pressure without increasing the diastolic pressure, thereby increasing the
      pulse pressure. A high pulse pressure may induce lesions of the vessel walls and
      of the endothelium of the large arteries, and this is known to be a significant
      independent risk factor for cardiovascular mortality, especially in the elderly.
      Microvascular rarefaction could possibly be reversed by therapeutic angiogenesis
      with cytokines but this treatment is difficult to deliver to the myocardium and
      is not yet available in clinical practice. Some conventional antihypertensive
      therapies, including the association of a low dose angiotensin converting enzyme
      inhibitor, perindopril, and a diuretic, indapamide, may have a beneficial effect
      on the microcirculation. It has been demonstrated clinically that these drugs
      specifically reduce the pulse pressure, probably by decreasing the reflected
      pressure wave, and, therefore, additional benefits in terms of a reduction of
      cardiovascular risk can be expected.

PMID- 12407781
TI  - [Combination of low-dose perindopril/indapamide versus atenolol in the
      hypertensive patient. Effects on systolic pressure and arterial hemodynamics.
      REASON Study].
AB  - In hypertension, consideration of systolic blood pressure (SBP) and pulse
      pressure (PP) is now well recognized from epidemiological and therapeutical
      points of view, after numerous years of interest in only diastolic blood
      pressure. SBP, and also PP, are tightly linked to mechanical properties of large
      arteries. It is now possible to investigate precisely, with very good
      repeatability, these mechanic properties. The REASON study is an international
      multicenter randomised, controlled, parallel-groups study in essential
      hypertensives. The very low dose perindopril/indapamide combination (Per/Ind: 2
      mg/0.625 mg) was compared with atenolol (50 mg) for a 12-month active treatment
      period in terms of blood pressure reduction efficiency and change in large artery
      hemodynamics to attempt to relate changes in pressure and changes in arterial
      mechanics. 471 patients suffering from hypertension were included, 406 benefitted
      from the treatment for one year (per-protocol analysis) and 96 benefitted from
      arterial investigations (pulse wave velocity and aortic wave reflection with
      applanation tonometry). Changes in brachial and central SBP and PP were higher
      with Per/ind than with atenolol. The reduction in pulse wave velocity was similar
      with both drugs, but aortic wave reflections were more reduced with Per/Ind than
      with atenolol. The very low dose perindopril/indapamide decreases SBP and PP to a
      larger extent than does a betablocker after a 12-month treatment. Changes in
      arterial mechanics, non invasively measured, were the same (pulse wave velocity)
      or in favour of Per/Ind vs atenolol (higher reduction in aortic wave reflection,
      with higher reductions in central systolic and pulse pressures).

PMID- 12407783
TI  - Visiting the virus veteran. Interview by Philip Siekman.

PMID- 12407784
TI  - The last taboo. It's not sex. It's not drinking. It's stress--and it's soaring.

PMID- 12407785
TI  - Love (and aging). Italian-style.

PMID- 12407786
TI  - Alzheimer's unease.

PMID- 12407787
TI  - Inflexible-spending accounts.

PMID- 12407788
TI  - [Drug-eluding stents: bis repetita?].

PMID- 12407789
TI  - [Value of type B natriuretic peptide in the emergency management of patients with
      suspected cardiac failure. Report of 125 cases].
AB  - Shortness of breath is a common cause of consultation in the emergency unit.
      Therefore, it is essential to diagnose cases of cardiac failure. This may be
      difficult in some cases. The authors set out to assess the value of measuring
      brain natiuretic peptide in this context. Brain natiuretic peptide (BNP) was
      measured by an ultrafast method (Biosite/BMD) on arrival of 125 patients to the
      emergency unit. The results were then compared with the diagnoses made in the
      emergency unit and those of the hospital discharge summary. Nearly 18% of
      patients were wrongly classified in the emergency room; 1/3 were falsely
      diagnosed as cardiac failure and 2/3 were not recognised initially as having
      cardiac failure. In 90% of patients, in particular in the group wrongly
      considered as not having cardiac failure, BNP measurement could have helped
      correct the mistake. The optimal threshold value of BNP for diagnosis of cardiac
      failure in this study was 300 pg/mL, with positive and negative predictive values
      of 92.4 and 90.2%, respectively.

PMID- 12407790
TI  - [Retrospective study of hospitalizations for heart failure in elderly patients in
      a cardiology service of a general hospital center].
AB  - The results of a retrospective study of patients over 70 years of age admitted to
      the cardiology department of Meaux Hospital for cardiac failure in 1997 are
      reported. The cases of 143 patients were analysed with respect to two age groups:
      70-79 years, and over 80 years of age. The principal aetiology of cardiac failure
      in all ages was ischaemic heart disease. Hypertensive heart disease was observed
      in younger patients and valvular heart disease in the more elderly. No
      significant gender differences were observed in those affected by this pathology
      or by left ventricular systolic or diastolic dysfunction between the younger and
      older patients, men having more systolic dysfunction than women. The main causal
      factor of decompensation in all ages was supraventricular arrhythmias. From the
      therapeutic point of view, the prescription of ACE inhibitors was relatively
      common but at low doses. Re-hospitalisation for cardiac failure was common and
      observed mainly in patients with low ejection fractions. The average hospital
      stay was 12.58 days. The hospital mortality was high: 15%. Two year survival was
      41% with no difference between patients with systolic or diastolic dysfunction.
      Pluridisciplinary management should reduce the number of re-hospitalisation,
      improve the quality of life and, perhaps, improve survival.

PMID- 12407791
TI  - [Biochemical markers of myocardial ischemia and necrosis].
AB  - The biochemical markers of myocardial ischaemia have to be interpreted according
      to their kinetics; their interests depend on the clinical presentation. They are
      helpful to orient to a myocardial ischaemia in front of undefined chest pain, to
      stratify the outcome of acute coronary syndrome without ST segment elevation, to
      evaluate the amount of myocardial damage following infarction, to detect the
      failure of thrombolysis therapy and probably to stratify the post percutaneous
      coronary intervention outcome.

PMID- 12407792
TI  - [Iatrogenic lesions of the left main coronary artery].
AB  - Reoccurrence of ischemic events several months after a percutaneous
      transcutaneous coronary angioplasty is usually due to a restenosis. Coronary
      angiography rarely shows a new stenosis on another site or on the left main
      coronary artery. In this series, we report 5 cases of left main coronary artery
      stenosis which have occurred from 3 to 12 months after a prior percutaneous
      angioplasty. This phenomenon which has previously been described after direct
      cannulation of the coronaries ostia during aortic valve replacement in the 70'.
      This complication is related to intimal damage caused by traumatic manipulation
      of the left main, which can be either already minimally altered or normal. This
      complication is rare after percutaneous transcutaneous coronary angioplasty (0.2
      1.7%) according to various series. We compare our cases to the published cases in
      the literature.

PMID- 12407793
TI  - [Clinical implications of blood pressure variability].
AB  - There are many variations in blood pressure, ranging from that observed between
      systole and diastole (pulse pressure) to slower daily or seasonal variations.
      This variability has many facets, for example the simple concept of variation
      around the mean blood pressure and the more complex spectral, chaos or fractal
      analysis... Some of these concepts are still the subject of fundamental research
      and have no current clinical applications. Others, however, are already part of
      our evaluation of hypertensive patients or used as prognostic factors in cardiac
      failure or myocardial infarction. Blood pressure variability, either the pulse
      pressure or 24 hour variability, is associated with a higher incidence of
      cardiovascular complications. Although the causality of the relationship is
      uncertain, patients with the greatest variability seem to be at higher risk. In
      addition to this prognostic impact, the study of changes in blood pressure by
      spectral analysis may also provide indices of adrenergic tone or sympathovagal
      equilibrium which may be useful clinically. Finally, the combined study of blood
      pressure variability and heart rate lead to the baroreflex, the sensitivity of
      which integrates major risk factors such as blood pressure, age, heart rate and
      serum cholesterol. This baroreflex could be a useful parameter for stratification
      of cardiovascular risk. This has already been demonstrated in patients at high
      risk, such as those with cardiac failure or myocardial infarction.

PMID- 12407794
TI  - [Dynamic echocardiography in mitral insufficiency].
AB  - Mitral insufficiency can have a dynamic character, correlating to an intermittent
      increase in the area of the regurgitant orifice and the regurgitant volume. Among
      the various stress methods, echocardiography during effort on a bicycle in the
      semisitting position appears to be the technique of choice for evaluating this
      dynamic character. Thanks to the improvement of the Doppler signal quality,
      quantification of the regurgitant volume variations can be obtained in a
      reproducible manner at rest and during effort by applying the "PISA" method.

PMID- 12407795
TI  - [Smoking cessation: practice guidelines].
AB  - Smoking is a habit sustained and amplified by dependency on nicotine. Despite
      knowing the risks to their health, smokers have great difficulty in stopping. The
      syndrome of nicotine withdrawal and the related complications when stopping
      smoking: depression, weight gain, are adequate justifications of the many
      failures to stop smoking. However, we have now come out of the empiricism,
      effective treatment is available and scientifically validated international
      recommendations have been established. They involve: the practice of minimal
      advice which consists of questioning every patient about smoking habits and
      encouraging them to stop; the treatments of nicotine substitution, patch, chewing
      gum, tablets or inhaler, used at effective dosage and sometimes in association
      with each other; more recently, Bupropion (Zyban, LP), a psychotropic inhibitor
      of Dobutamine and Noradrenalin recapture; behavioural and cognitive therapies,
      alone or in association with pharmacological therapy. The measurement of the
      score of tobacco dependency with the Fagerstrom test enables definition of a
      therapeutic strategy. Of course, these treatments are only effective in smokers
      motivated to stop smoking. The decision to stop smoking should only be taken
      after a period of reflection during which the role of information and advice
      given by all health professionals is primordial. Also, the long-term follow-up
      and counsel are essential to prevent relapse, especially during the first year.

PMID- 12407796
TI  - [Oxidative stress, atherogenesis and cardiovascular risk factors].
AB  - Cardiovascular diseases are the main cause of mortality in the western world. It
      is widely accepted that atherosclerosis, the first etiology, is influenced by
      free radicals and the oxidizing stress that they cause. In the oxidative theory
      of atherosclerosis, the atheromatous lesion is initiated by oxidation of two
      density lipoproteins (LDL), a process still known as lipid peroxidation. Oxidized
      LDL have many effects on the cells of the vessel wall which, provide an
      explanation to most of the cellular and tissular changes observed in the plaque.
      The vascular complications of hypercholesterolaemia, diabetes,
      hyperhomocysteinemia, hypertension and smoking may, in part, be secondary to
      oxidizing stress that impairs endothelial function and modify the lipids in the
      intima of the vessels. The aim of this paper is to review the modes of free
      radical production, to determine the role of oxidizing stress in the development
      of atherosclerosis and to show how the different risk factors may initiate
      atheroma through oxidizing stress.

PMID- 12407797
TI  - Functional disturbances due to structural remodeling in the failing human heart.
AB  - In severely hypertrophied hearts structural remodeling occurs continuously and
      finally leads to heart failure. The remodeling process involves all structural
      components of the cardiomyocyte and all protein families and it consists of
      cellular enlargement accompanied by degeneration in addition to the occurrence of
      fibrosis. Nuclei are increased in size but the nuclear volume/cell volume ratio
      is reduced. Transcription and translation are downregulated for contractile and
      sarcomeric skeleton proteins but both are upregulated for cytoskeletal and
      membrane-associated proteins. The connexin43 content is significantly reduced.
      Chronic degeneration finally leads to cell death by ubiquitin-related autophagy,
      and acute ischemic cell death (oncosis) is also observed. Apoptosis seems to be
      of minor importance. The morphological alterations described here are the
      structural correlate of the typical clinical characteristics of heart failure in
      human patients: of reduced contractile function, of increased ventricular
      stiffness represented by an increased left end-diastolic pressure and of
      ventricular arrhythmia.

PMID- 12407799
TI  - Atrial fibrillation: the tip of the iceberg.
AB  - Atrial fibrillation (AF) usually results from profound alterations of the
      functional properties and structure of the atrial myocardium. For instance, at
      the cellular level AF is associated with a marked shortening of the action
      potential (AP) also seen in dilated atria in sinus rhythm. Drastic down
      regulation of the I-type Ca2+ current that activates during the plateau phase is
      one of the main mechanisms responsible for this AP shortening. The down
      regulation could be due to a variety of mechanisms including decreased channel
      expression and alteration of their camp-dependent phosphorylation. There are also
      alterations of repolarizing currents such as the transient outward potassium
      current or acetylcholinegated-inward rectifier potassium current. The electrical
      remodeling of diseased atria is most often associated with severe tissular and
      cellular alterations including: fibrosis, myocyte dystrophy with myolysis and
      dedifferentiation, apoptosis and gap junction disorganization. These
      abnormalities could result from a common and non specific adaptive response to
      changes in the working conditions of the atrial myocardium. The main goal of
      research in this field is now to link up the various abnormalities observed
      during AF and to determine their respective roles in atrial vulnerability to
      arrhythmia.

PMID- 12407798
TI  - Emerging concepts of neurohumoral modulation in the treatment of congestive heart
      failure.
AB  - The angiotensin converting enzyme (ACE), endothelin (ET) converting enzyme (ECE)
      and neutral endopeptidase (NEP) are all zinc-metallopeptidases expressed in
      almost all the organs, such as heart, vessels and kidneys. While ACE and ECE are
      respectively involved in the transformation of angiotensin I and Big-ET into
      angiotensin II and ET-1 respectively, which possess vasoconstrictor and mitogenic
      properties, NEP is involved in the degradation of atrial natriuric factor (ANF),
      which possesses vasorelaxant, diuretic/natriuretic and antihypertrophic
      properties. These three systems are activated in heart failure and modulate the
      progression of heart failure. This article will discuss preliminary date
      concerning simultaneous inhibition of ACE, ECE and/or NEP and their therapeutic
      potential interest in the treatment of heart failure.

PMID- 12407800
TI  - [Chloroquine cardiomyopathy revealed by complete atrio-ventricular block. A case
      report].
AB  - We describe a rare case of chloroquine cardiomyopathy occurring during long term
      (7 years) treatment for rheumatoid polyarthritis in a 42 year old woman. There
      was an isolated acute severe conduction defect, which is particularly rare.
      Histological study with the electron microscope allowed confirmation of this
      diagnosis. We report here the secondary cardiological effects of this frequently
      used synthetic antimalarial.

PMID- 12407801
TI  - [Continuous nodal reciprocal rhythm and Steinert's disease: treatment by double
      chamber stimulation. A case report].
AB  - We report a case of continuous supraventricular tachycardia in a patient affected
      by Steinert's myotonic dystrophy. The investigation of this tachycardia showed
      that there was a "slow-fast" common nodal re-entry, rendered continuous by the
      existence of significant conduction defects in the fast pathway and the slow
      anterograde pathway. Implantation of a double chamber cardiac stimulator,
      necessary for conduction defects present in the basal state in this patient
      allowed, with the evolution of the conduction defects, the complete eradication
      of reciprocal rhythm entry, without resorting to ablation.

PMID- 12407802
TI  - [National observational study of diagnostic and interventional cardiac
      catheterization by the French Society of Cardiology: list and definition of basic
      data].

PMID- 12407803
TI  - [Update of recommendations for nuclear cardiology stress tests in adults and
      children].

PMID- 12407804
TI  - The Atlantis Components Abutment: simplifying the tooth implant procedure.

PMID- 12407805
TI  - Nailing down pre-op clearance exams.

PMID- 12407806
TI  - How to get the lowdown on EMR software.

PMID- 12407807
TI  - Assisted suicide? Pain control? Where's the line?

PMID- 12407808
TI  - Medical errors. Is honesty ever optional?

PMID- 12407809
TI  - Abortion. A right or an outrage?

PMID- 12407810
TI  - Managed care. Can lying be good medicine?

PMID- 12407811
TI  - Patients' rights. Who should know what?

PMID- 12407812
TI  - Cloning. Where are the limits?

PMID- 12407813
TI  - Impaired physicians. Speak no evil?

PMID- 12407814
TI  - Gifts. What's all the fuss about?

PMID- 12407815
TI  - My toughest choice.

PMID- 12407816
TI  - Rxs when a patient is away from home.

PMID- 12407817
TI  - Yellow fever, Senegal--update.

PMID- 12407818
TI  - WHO Global Influenza Programme: survey on capacities of national influenza
      centres, January-June 2002.

PMID- 12407819
TI  - Heart rate variability as a clinical tool.
AB  - Power spectrum analysis of cardiovascular signal variability, and in particular
      of the RR period (heart rate variability), is a widely used procedure for the
      investigation of autonomic cardiovascular control and/or target function
      impairment. However, a correct methodology is essential to extract the
      information embedded in the frequency domain. This article has the main purpose
      of proposing a still wider clinical use of the spectral methodology. Indeed, with
      this procedure the state of the sympathovagal balance modulating the sinus node
      pacemaker activity can be quantified in a variety of physiological and
      pathophysiological conditions. Changes in the sympathovagal balance can be often
      detected in basal conditions; however, a reduced responsiveness to an excitatory
      stimulus is the most common feature that characterizes numerous
      pathophysiological states. Moreover, the attenuation of an oscillatory pattern or
      its impaired responsiveness to a given stimulus can also reflect an altered
      target function and thus can furnish interesting prognostic markers.

PMID- 12407820
TI  - Off-pump coronary surgery in a single center experience: from selective to
      systematic use.
AB  - BACKGROUND: The feasibility of the systematic use of the off-pump technique for
      myocardial revascularization was investigated. METHODS: From September 1997 to
      June 2001, 1221 isolated coronary artery bypass grafting operations were
      performed consecutively: 771 (group A) were completed with cardiopulmonary
      bypass, and 450 (group B) without. Since July 2000 all patients were considered
      as potential candidates for off-pump coronary artery bypass. In group B, a
      specific original instrumentation was used for coronary stabilization. RESULTS:
      The differences in the preoperative data were: a higher age, a higher incidence
      of chronic obstructive pulmonary disease and a left ventricular ejection fraction
      < 30% in group B; a higher incidence of critical left main stenosis in group A.
      More grafts per patient were completed in group A (3.0 +/- 1.4 vs 2.2 +/- 0.9, p
      < 0.001). The hospital mortality (group A 1.0%, group B 0.7%) and the incidence
      of perioperative myocardial infarction (group A 2.5%, group B 1.1%) and that of
      cerebrovascular accidents (group A 1.4%, group B 0.9%) were comparable. Bleeding
      (610 +/- 370 vs 496 +/- 215 ml, p < 0.001), the transfusion rate (36 vs 19.7%, p
      < 0.001), the intubation time (13.4 +/- 3.5 vs 8.3 +/- 5 hours, p < 0.001), the
      intensive care unit stay (1.7 +/- 2.7 vs 1.2 +/- 2.1 days, p < 0.001) and the
      hospital stay (5.8 +/- 3 vs 5.1 +/- 3.2 days, p < 0.001) were lower in group B.
      At follow-up, the mortality (2.5 vs 1.1%), the rate of recurrence of angina (2.5
      vs 2.0%), and those of re-angiography (4.1 vs 5.3%) and of new revascularization
      (1.6 vs 1.1%) were similar. The actuarial survival rates were 99.8, 98.6 and
      96.3% in group A, and 98.8, 96.7 and 96.7% in group B at 1, 2 and 3 years of
      follow-up respectively (log rank p = 0.3387). CONCLUSIONS: The increase in the
      use of off-pump coronary artery bypass up to its systematic empolyment is
      feasible. The early and intermediate results are satisfactory.

PMID- 12407821
TI  - The extent of late in-stent neointima formation is modified by treatment with
      pravastatin: a preliminary study with intravascular ultrasound.
AB  - BACKGROUND: The aim of the present comparative, non-randomized intravascular
      ultrasound (IVUS) study was to test the effect of pravastatin on late neointima
      formation in stented de novo lesions. METHODS: The treatment group consisted of
      28 consecutive patients in whom 31 stents were deployed; all patients were
      prescribed 40 mg daily of pravastatin for a mean follow-up period of 14 +/- 3
      months (group 1). The control group consisted of 27 consecutive patients in whom
      30 stents were deployed; lipid-lowering treatment was not prescribed; the mean
      follow-up period for this group of patients was 13 +/- 3 months (group 2). At
      follow-up IVUS images were acquired at a continuous 0.5 mm/s speed. IVUS
      measurements of the lumen area, stent area and neointima area were calculated
      within the stent at 0.5 mm intervals. RESULTS: The stent dimensions and technique
      of implantation were similar in the two groups. At follow-up the minimal lumen
      diameter at quantitative coronary angiography was slightly larger in group 1 than
      in group 2 (2.43 +/- 0.58 vs 2.17 +/- 0.59 mm, p = NS), while the late loss
      tended to be lower in group 1 than in group 2 (0.28 +/- 0.39 vs 0.63 +/- 0.37 mm,
      p = NS). At IVUS evaluation, the lumen and stent areas were similar in the two
      groups whereas the percent neointima area was significantly lower in group 1 than
      in group 2 (21 +/- 11 vs 29 +/- 11% respectively, p < 0.03). CONCLUSIONS:
      Pravastatin treatment was associated with a significantly reduced late in-stent
      neointima formation as assessed at IVUS.

PMID- 12407822
TI  - Age, a predictive factor for the reduction in the mean transmitral pressure
      gradient after percutaneous balloon mitral valvotomy.
AB  - BACKGROUND: The aim of this study was to evaluate the changes in mitral valve
      area and mean transmitral pressure gradient before and after percutaneous balloon
      mitral valvotomy and at 2 years of follow-up. We hypothesized that the patient's
      age would be an important determinant for the success of balloon valvotomy.
      METHODS: We studied 24 patients with mitral stenosis (6 men and 18 women with an
      average age of 58 years, range 39 to 80 years), who underwent percutaneous
      balloon mitral valvotomy. Two-dimensional and Doppler echocardiographic
      examinations were taken before, immediately after and at a mean follow-up of 24
      months (range 12 to 73 months). The correlation between the changes in the mitral
      valve area or mean transmitral pressure gradient and age was assessed with rank
      correlation and with stepwise multiple linear regression analysis correcting for
      sex, days of follow-up, heart rate score, pulmonary hypertension, mitral
      regurgitation and Wilkins score at follow-up. RESULTS: Changes in the mitral
      valve area did not correlate with age. The reduction in mean transmitral pressure
      gradient at follow-up was associated with age with a 20.6% less reduction in mean
      transmitral pressure gradient (95% confidence interval 3.5-40.4%, p < 0.021) for
      every other year of the patients' age. When comparing changes in mean transmitral
      pressure gradient before and after percutaneous balloon mitral valvotomy, the
      strength and consistency of the association with age appeared similar (mean
      transmitral pressure gradient -0.9 +/- 3.0 vs -2.8 +/- 3.4 mmHg). CONCLUSIONS:
      Age is a predictive factor for the reduction in mean transmitral pressure
      gradient after percutaneous balloon mitral valvotomy. This suggests that a better
      outcome is to be expected in younger patients, independently of the list of
      factors taken into consideration in our study.

PMID- 12407823
TI  - Efficacy of a short-course intensive rehabilitation program in patients with
      moderate-to-severe intermittent claudication.
AB  - BACKGROUND: Many rehabilitation programs for intermittent claudication include
      physical training for several months, since the outcome of short-course protocols
      is still unclear. The aim of this study was to evaluate the efficacy of a short
      course of exercise therapy in patients with moderate-to-severe intermittent
      claudication in terms of walking distance variations. METHODS: Twenty-six
      patients (males 88%, mean age 59 +/- 8 years, ankle-brachial index < or = 0.8 and
      < or = 0.5 before and after exercise respectively) were evaluated. Moderate-to
      severe stenoses or occlusions were localized at color Doppler scanning of the
      abdominal aorta/iliac arteries and femoral/popliteal/tibial arteries in 15 and
      31% of patients respectively, while in 54% of cases both the proximal and distal
      sites were involved. The initial and absolute claudication distances were
      recorded by means of the constant treadmill test (3 km/hour speed, 0% grade) at
      the time of presentation and after a short-course comprehensive rehabilitation
      program (4 week duration) including physical training, educational intervention,
      psychological support, and cardiovascular risk management. RESULTS: At the end of
      the program, 1 patient (4%) became asymptomatic (walked > 1000 m without pain).
      In 25 patients who still developed pain, the average increase in the initial
      claudication distance was 132% (from 75 to 174 m). Among these, 20 patients (77%)
      were still unable to complete the treadmill test due to maximal claudication
      pain, but the absolute claudication distance increased by 87% from 204 to 381 m
      (p < 0.05). No cardiovascular complication occurred during the study period.
      Major clinical variables failed to predict an unsatisfactory increase in walking
      capacity. CONCLUSIONS: Short-course training programs enhance the walking ability
      even in patients with moderate-to-severe intermittent claudication and seem to be
      well tolerated, supporting their widespread use in rehabilitation centers.

PMID- 12407824
TI  - A cosmetic access for minimally invasive aortic valve replacement without
      sternotomy in women.
AB  - BACKGROUND: Different methods of replacing the aortic valve via a minimally
      invasive access have been reported in the recent literature. Although these
      strategies have clear advantages in terms of reduced surgical trauma, no further
      refinements in terms of cosmetic results have been made for women. METHODS:
      Aortic valve replacement was performed in 4 women via a right anterior submammary
      minithoracotomy without rib resection. The incision was made along the breast
      fold. The extracorporeal circulation was connected through the same access.
      Standard surgical technique and equipment were employed. RESULTS: No
      intraoperative complications or hospital deaths occurred. The 4 patients could be
      discharged home on the sixth postoperative day. The cosmetic result was excellent
      and the wound completely disappeared within the breast fold. CONCLUSIONS: The
      advantages of the present method include the preservation of sternal integrity,
      early mobilization and rehabilitation and an excellent cosmetic result for women.

PMID- 12407825
TI  - Heart transplantation in X-linked dilated cardiomyopathy.
AB  - BACKGROUND: X-linked dilated cardiomyopathy (DCM) is a clinical phenotype of
      dystrophinopathy characterized by preferential myocardial involvement without
      overt signs of skeletal muscle disease. X-linked DCM is a familiar myocardial
      disease characterized by ventricular dilation resulting in progressive heart
      failure and/or sudden death, and it may be differentiated from other DCMs. The
      aim of this retrospective study was to assess that patients with end-stage X
      linked DCM can safely undergo heart transplantation. METHODS: Between August 1989
      and January 2000, 7 patients presenting with X-linked DCM underwent heart
      transplantation for end-stage disease at our Institution. The patients' age
      ranged from 16 to 31 years (mean 24.4 years) and all were in NYHA functional
      class IV. RESULTS: The mean follow-up was 44 months (range 22-66 months). Only
      one sudden death occurred at 66 months of follow-up; all the other patients are
      doing well and are in NYHA functional class I. CONCLUSIONS: Our data suggest that
      heart transplantation can be considered as the treatment of choice for refractory
      cardiac failure in X-linked DCM.

PMID- 12407827
TI  - Attempted retrograde reopening of an occluded left main stent.
AB  - Percutaneous revascularization is generally considered to be the treatment of
      choice for patients with recurrence of symptoms following coronary artery bypass
      surgery. Protected left main disease is usually approached in an antegrade way.
      However, if the left main coronary artery is occluded, such an approach is often
      very challenging, and alternative strategies are adopted. We present a case of
      attempted retrograde reopening of an occluded left main stent through the right
      coronary artery, a sequential radial graft from the right coronary artery to the
      marginal branch and eventually in a retrograde way to the left main coronary
      artery. Although this case was unsuccessful it demonstrates how technological
      developments are allowing interventionists to tackle a vast range of challenging
      cases, which only few years ago would have been considered impossible.

PMID- 12407826
TI  - Amyloidosis of epicardial and intramural coronary arteries as an unusual cause of
      myocardial infarction and refractory angina pectoris.
AB  - The present case report refers to a 65-year-old male patient with subocclusion of
      the right coronary artery who had an inferior myocardial infarction that was
      treated with coronary angioplasty. The patient subsequently developed intractable
      angina pectoris in the absence of critical coronary stenosis at serial coronary
      angiography. Doppler wire velocity demonstrated an impaired coronary flow
      reserve. The patient died of cardiogenic shock. Postmortem examination revealed
      amyloid involvement of the media of the epicardial coronary arteries and severe
      amyloid deposition in the media and adventitia with obstruction of the lumen of
      the intramyocardial coronary arteries. Widespread ischemic areas were present in
      the myocardium with only slight amyloid deposition. In this patient myocardial
      infarction and unstable angina were a rare initial manifestation of primary
      amyloidosis.

PMID- 12407828
TI  - Thrombus in the right atrial appendage during pulmonary and paradoxical embolism:
      a case report.
AB  - We report the case of a 56-year-old woman who was admitted because of left
      pulmonary embolism. An episode of ischemic stroke occurred during
      hospitalization. Transesophageal echocardiography revealed a right atrial
      appendage thrombus and a patent foramen ovale with right to left shunting. This
      suggested paradoxical embolism across a patent foramen ovale as the most
      reasonable explanation of the ischemic stroke in this patient, in the presence of
      right cardiac overload secondary to the hemodynamically significant pulmonary
      embolism. The patient's clinical conditions dramatically improved after
      anticoagulant therapy.

PMID- 12407829
TI  - Dissection of the ascending aorta mimicking an acute coronary syndrome:
      usefulness of transthoracic echocardiography for the differential diagnosis.
AB  - We describe the case of 2 patients presenting with chest pain and
      electrocardiographic signs of myocardial ischemia, in whom a transthoracic
      echocardiogram, performed urgently at the bedside, allowed a diagnosis of
      dissection of the ascending aorta. Prompt recognition of this condition avoided
      inappropriate aggressive medical treatments and permitted emergency surgical
      intervention. Aortic dissection can mimic other conditions including an acute
      coronary syndrome. When the diagnosis is unclear it may be useful to perform a
      transthoracic echocardiogram before starting any aggressive medical treatment
      because in such cases thrombolytic or anticoagulant therapy and antithrombotic
      treatment with platelet glycoprotein IIb/IIIa receptor antagonists can results in
      serious side effects. On the other hand, transthoracic echocardiography can
      confirm the suspicion of an acute coronary syndrome or suggest other diagnoses
      such as aortic dissection.

PMID- 12407830
TI  - A rare left ventricular mass: intramuscular hemangioma of the left ventricle.

PMID- 12407831
TI  - Limited measles outbreak, Tunisia, 2002.

PMID- 12407832
TI  - Recommended composition of influenza virus vaccines for use in the 2003 influenza
      season.

PMID- 12407833
TI  - [Intervention strategies in refractory heart failure].
AB  - Although the additional therapies with beta-blockers and spironolactone have
      recently proved to be significantly beneficial for the treatment of advanced
      heart failure, in the end stages of this disease the prognosis remains quite
      poor. Moreover, the quality of life of patients with advanced heart failure is
      still heavily influenced by symptoms and by a high rate of hospitalizations. In
      selected patients heart transplantation constitutes the only chance, but the low
      availability of donors limits a wider diffusion of this procedure. Mechanical
      left ventricular assistance is still considered a bridge to heart transplantation
      and, at present, technical reasons limit the long-term utilization of these
      devices. Xenotransplantation and regeneration of cardiac myocytes from bone
      marrow stem cells remain the greatest hopes for the future. Several other
      possibilities of offering broader opportunities to patients with end-stage heart
      failure are under investigation. The expectations regarding the antagonism of
      cytokines and endothelin were not confirmed by the recent results of several
      studies. The association between beta-blockers and non-adrenergic inotropes could
      have a rationale, but needs to be investigated with appropriate trials. Other
      surgical procedures, such as myocardial revascularization in case of severe
      ischemic left ventricular dysfunction or repair of severe secondary mitral
      regurgitation, represent surgical options the use of which may be more
      widespread, but their indications are still based on a rather empirical approach.
      The preliminary results of the electrical therapy of ventricular
      resynchronization are encouraging, but the selection of patients and the long
      term advantages need to be defined further on. Moreover, advanced heart failure
      has a major impact on health costs and organization. This makes mandatory the
      definition of operative hospital- and home-care models, the use of which in
      clinical practice is to be proposed.

PMID- 12407834
TI  - [Refractory heart failure. Antagonism of tumor necrosis factor alpha and
      endothelin in humans: 2 promises still to be honored].
AB  - Excessive biohumoral activation participates in the pathophysiology and
      progression of congestive heart failure (CHF). Pharmacological inhibition of the
      renin-angiotensin-aldosterone and beta-adrenergic systems improves the mortality
      and morbidity of this disease. Among other detrimental molecules, two local
      factors, tumor necrosis factor (TNF)-alpha and endothelin (ET) both contribute to
      the worsening of CHF. TNF-alpha can induce many of the cellular modifications
      typically associated with CHF, such as myocyte death, interstitial tissue
      derangement and negative inotropism. On the other hand ET promotes
      vasoconstriction, and cell growth and proliferation. On the premise of some
      favorable experimental studies, selective antagonism of TNF-alpha or ET has been
      tested in clinical trials in order to control the progression of or even reverse
      CHF. However, contrasting results have been obtained so far with either approach,
      in accordance with other unfavorable data from animal models of heart failure.
      Etanercept (Enbrel, a recombinant dimer of two p75sTNFR molecules fused to the Fc
      fragment of human IgG1) has proved to be useful and effective in basic and animal
      experiments, while contrasting data have been reported on humans. The Randomized
      EtaNErcept Worldwide evALuation (RENEWAL) trial has recently been prematurely
      stopped due to impossibility of showing statistically significant results with
      the pre-specified sample size. Results of phase II to III clinical trials on
      different ET receptor antagonists in CHF have yielded conflicting results, so
      that none of the agents of this class have been labeled for CHF. The mechanisms
      by which TNF-alpha and ET might exert their negative biological actions are
      discussed together with an analysis of the possible reasons why they have failed
      so far in human CHF.

PMID- 12407835
TI  - [Refractory heart failure. Positive inotropes and beta blockers: alternative or
      complementary treatments?].
AB  - Both beta-blockers as well as positive inotropic drugs may be indicated for the
      treatment of patients with advanced or refractory heart failure. When tolerated,
      beta-blocker therapy is able to counteract the adverse biologic effects produced
      by the chronic activation of the sympathetic nervous system and, therefore, to
      delay the progression of the disease. Conversely, although the long-term
      administration of positive inotropic agents is not recommended, these drugs may
      be required to face episodes of acute hemodynamic deterioration, which frequently
      occur in patients who are so severely impaired. Beta-blocker and positive
      inotropic therapies are currently viewed as alternative strategies for the
      management of severe heart failure patients. However, both the theoretical
      background and preliminary clinical evidences about the combined use of these two
      drug classes are suggestive of the potential for cumulative benefits and of the
      mutual attenuation of deleterious effects.

PMID- 12407836
TI  - [Refractory heart failure. Myocardial revascularization as alternative to heart
      transplantation].
AB  - Coronary artery disease is the most common cause of heart failure in the western
      world. Due to shortage of donors, heart transplantation is not a realistic
      treatment for the great majority of patients with heart failure, while surgical
      revascularization is a valuable alternative in selected patients. Several
      variables have to be taken into account in order to appropriately identify
      patients with severe left ventricular dysfunction who are likely to benefit from
      myocardial revascularization. The recovery of cardiac function can be expected
      only in patients with sufficiently large areas of hibernating myocardium,
      particularly when the contractile reserve is documented. The anatomy of the
      coronary arteries should be suitable for coronary bypass grafting and provide a
      good run-off. Patients with an excessively dilated heart, with signs and symptoms
      of right heart failure and significant pulmonary hypertension are not candidates
      for myocardial revascularization. An appropriate surgical strategy, also
      including the reduction of the left ventricular volume and/or the correction of
      mitral insufficiency if needed, is the key factor for a successful
      revascularization procedure in patients with coronary artery disease and heart
      failure as the predominant symptom.

PMID- 12407837
TI  - [Refractory heart failure. Surgery of the left ventricle and mitral
      insufficiency].
AB  - The high number of patients with advanced heart failure despite optimal medical
      therapy and the limited availability of radical therapeutic solutions (including
      heart transplantation) increase the interest in alternative surgical procedures.
      In this paper, the correction of secondary mitral valve regurgitation, left
      ventriculectomy, and aneurysmectomy/ventriculoplasty will be reviewed. Secondary
      mitral valve regurgitation worsens both symptoms and prognosis in patients with
      left ventricular dysfunction of ischemic and non-ischemic etiology. Its
      correction, mostly by conservative repair, can be performed with an acceptable
      perioperative risk in patients with compensated heart failure. Concomitant
      correction of mitral insufficiency is advisable in patients with significant
      regurgitation undergoing revascularization surgery. On the other hand, data
      regarding the improvement in clinical and objective parameters after mitral valve
      surgery in patients with severe mitral regurgitation and idiopathic or ischemic
      cardiomyopathy who are unsuitable for revascularization are discordant. In view
      of its feasibility and presumed efficacy, partial left ventriculectomy or the
      Batista operation seemed attractive but the expectations were not met: success
      cannot be predicted in individual patients, the initial improvement may be of
      short duration, and the peri and postoperative mortalities are relevant.
      Postinfarction surgical reconstruction and reshaping of the left ventricle is
      performed mostly together with revascularization surgery; the surgical
      experience, indications and results reported in various studies are however
      discordant. In conclusion, multicenter cooperation including randomized studies
      or registries is worthwhile in order to define the role of surgery of the mitral
      valve and left ventricle in patients with advanced heart failure.

PMID- 12407838
TI  - [Refractory heart failure. Multisite stimulation].
AB  - The pathophysiological background of cardiac resynchronization therapy is
      represented by the intraventricular conduction delay such as left bundle branch
      block, present in about one third of patients with dilated cardiomyopathy.
      Intraventricular conduction block, with or without atrioventricular delay,
      adversely influences ventricular function due to unsynchronized contraction and
      is associated with a poor prognosis. Contractile dyssynchrony and abnormal
      atrioventricular delay can be corrected by non-conventional stimulation
      modalities such as left ventricular pacing or biventricular pacing associated
      with preexcitation to restore the physiological atrioventricular timing. Over the
      last decade several studies have reported the short- or long-term favorable
      effects of resynchronization therapy on the left ventricular function and
      remodeling, the quality of life, the functional capacity, the adrenergic
      activity, and the reduced rehospitalization rate. The most significant results
      have been reported in patients with a QRS duration > or = 150 ms, while the
      InSync Italian Registry has shown improvement even in patients with a QRS
      duration < 150 ms as well as in patients with atrial fibrillation. On the basis
      of such data it may be argued that the activation sequence of the different walls
      of the left ventricle is likely more important than the QRS duration. Inclusion
      criteria commonly used in the published or ongoing trials are: moderate to severe
      congestive heart failure (NYHA functional class III-IV) on optimized
      pharmacological treatment; left ventricular ejection fraction < or = 35%; left
      ventricular diastolic diameter > 60 mm; end-diastolic mitral regurgitation; no
      need of conventional pacing. While with regard to the surrogate endpoints the
      results of published trials are very encouraging, we do not yet know whether
      resynchronization therapy prolongs the life expectancy of patients with heart
      failure. Studies able to provide important answers to these problems are near
      completion. In the meanwhile, in agreement with the guidelines of the European
      Society of Cardiology, it seems prudent to employ such a therapy only in case of
      patients satisfying the above-mentioned criteria.

PMID- 12407839
TI  - [Refractory heart failure. Models of hospital, ambulatory, and home management].
AB  - Chronic heart failure is an enormous and growing public health problem and is
      reaching epidemic proportions. Its economic impact is dramatic; two thirds of
      expenses are for hospitalizations and relatively little is being spent for
      medications and outpatient visits. Most of the hospitalizations, deaths and costs
      are incurred by a relatively small minority of patients who may be described as
      having "complex", "advanced", "refractory" or "end-stage" heart failure; however,
      in essence they are patients who have severe symptoms and/or recurrent
      hospitalizations and/or emergency department visits despite maximal oral therapy.
      Many of the recommendations regarding the management of these patients are based
      more on experience than on evidence from controlled trials. This, because such
      patients require an individualized therapy which limits their inclusion in large
      trials and because support is less easily available when testing specific
      strategies than when testing specific agents. Improving the treatment of this
      group of patients by optimizing their medical regimen, aggressive monitoring and
      providing early intervention to avert heart failure can reduce their morbidity,
      mortality and costs of care. Refractory heart failure is not a single disease and
      it is extremely unlikely that all patients should be treated in a similar manner;
      before selecting the appropriate therapy, the clinician must categorize and
      profile the patient. The first step should be a re-evaluation of the previous
      treatment because many patients are treated suboptimally. It is also important to
      identify reversible or precipitating factors. For patients with advanced heart
      failure, the initial goal of therapy is to improve symptoms; the next goal is to
      maintain the improvement and to prevent later deterioration. The appropriate
      treatment plan will reflect the presence of comorbidities, the patients' history
      regarding previous responses to therapy, their own expectations with regard to
      daily life. The most common symptoms causing hospitalizations are those related
      to congestion; the distinction between the rising filling pressures and low
      cardiac output puts the focus on the adjustment of further medical therapy. The
      persistence of congestion confers a worse prognosis and urgency for the
      consideration of surgical therapies. It has been repeatedly shown that in case of
      heart failure, fewer hospitalizations and lower costs are necessary after
      referral to programs that provide multidisciplinary care. This care includes
      heart failure physician specialists with specifically trained clinical nurses.
      Other important components of a comprehensive management program for advanced
      heart failure are patient education, rehabilitation and the availability of
      adequate social service. We have entered a difficult era marked by a collision
      course between increasing scientific discoveries and restricted resources; a
      better care for heart failure, integrating improved medical practice with the
      necessity of bearing the financial pressures in mind, constitutes a great
      opportunity for medicine.

PMID- 12407840
TI  - [Use of bar codes of biomedical products in a catheterization laboratory. A
      required step to improve quality and reduce costs].
AB  - The technology of bar coding has been recommended because of the ability to
      increase efficiency. The relative widths of both the bars and spaces code the
      data stored in the bar code. The Health Industry Business Communications Council
      (HIBCC) is a non-profit organization aimed at developing appropriate standards to
      improve exchange among all health care trading partners. According to these
      recommendations all health care products should be labeled with a primary symbol
      identifying the labeler and the product code and a secondary one that is useful
      to distributors and providers. The efficacy of bar code technology depends on the
      ease of use and the incorporation of user workflow into the system. Despite
      problems depending on industry factors as well as the lack of standards, resource
      factors associated with costs for the implementation of the new technology and
      human factors for cultural exchange that facilitate adoption, it is outstanding
      that bar code technology improves patient safety and increases organization
      productivity reducing manual-consuming steps and allowing for more accurate and
      complete data collection.

PMID- 12407841
TI  - [Isolated non-compaction of left ventricle in childhood: clinical experience with
      5 cases].
AB  - BACKGROUND: Isolated noncompaction of the left ventricular myocardium, a rare
      congenital disorder, is thought to be due to an arrest of myocardial
      morphogenesis. It is characterized by an excessively prominent trabecular
      meshwork and by deep intertrabecular recesses. The aim of this study was to
      clarify the late outcome of this malformation, reporting our experience on 5
      pediatric patients observed for a period of 11 years. METHODS: We describe the
      clinical, electrocardiographic and echocardiographic findings of 5 pediatric
      cases, with an age ranging from 1 month to 10 years. The mean follow-up was 4.5
      years (> 10 years in 1 patient). RESULTS: In no case did life-threatening
      ventricular arrhythmias or systemic embolic events occur. Four patients who
      developed heart failure have been submitted to digoxin, diuretic, angiotensin
      converting enzyme and anticoagulant therapy. One of them is still asymptomatic
      and in good health. One patient died while on the waiting list for cardiac
      transplantation. CONCLUSIONS: The appropriate and early diagnosis and treatment
      of this disorder can improve the outcome even though further studies will be
      needed to elucidate its long-term prognosis. At the same time, in view of the
      high incidence of a positive family history, evaluation of all members of the
      family is warranted.

PMID- 12407842
TI  - [Guidelines for the performance of electrophysiologic study: are they still
      current?].
AB  - The aim of the present study was to reevaluate the indications to
      electrophysiological study after the observation of various clinical trials such
      as MADIT, AVID and MUSTT. In this perspective, the guidelines of 1995 surely
      appear to be outdated. The present paper concludes that the indications which
      still appear acceptable are those which support catheter ablation, those
      regarding syncope of unexplained origin and, until the conclusions of MADIT-II
      are universally accepted, the indication included in the MADIT study.

PMID- 12407843
TI  - [Thrombocytopenia associated with massive cardiac thrombosis during treatment
      with non-fractionated heparin: description of a clinical case].
AB  - Thrombosis associated with a drop in the platelet count may occur in 33-50% of
      the patients who develop heparin-induced thrombocytopenia (HIT) during treatment
      with unfractionated heparin; the deep veins are commonly involved while cardiac
      thrombosis is considered as a rare complication. We report the case of a 64-year
      old woman who was treated with unfractionated heparin following a myocardial
      infarction and an episode of deep vein thrombosis which occurred 13 days after
      myocardial revascularization including triple coronary artery bypass grafting; a
      drop in the patient's platelet count was documented and a transesophageal
      echocardiogram revealed massive thrombosis of the four cavities of her heart. The
      diagnosis of HIT was supported by high blood levels of PF4-antiheparin
      antibodies. Heparin infusion was stopped and the patient was started on sodium
      warfarin therapy; the platelet count promptly returned to normal and the size of
      the clots slowly decreased, although they were still detectable 1 month later.
      Aspirin (325 mg daily) was then prescribed as an adjunct to warfarin and 6 months
      later we documented the total disappearance of the thrombotic masses without
      embolic complications.

PMID- 12407844
TI  - [Long QRS tachycardia secondary to Aconitum napellus alkaloid ingestion].
AB  - The roots and seeds of the aconite (Aconitum napellus) contain alkaloids with
      modulatory activity on the sodium voltage-dependent channels; most fatal cases
      have been determined by ventricular tachycardia and respiratory paralysis. The
      only established treatment is supportive. We report a case of poisoning from
      Aconitum napellus, ingested by a husband and wife who thought the plant was
      "mountain chicory". They both had tachyarrhythmias, but the husband had more
      malignant episodes of hemodynamically unstable wide QRS tachycardia and
      respiratory paralysis requiring mechanical ventilation.

PMID- 12407845
TI  - Magnetic resonance coronary angiography: present clinical applications.
AB  - Coronary angiography is presently considered the gold standard test for the
      assessment of coronary artery disease. However, owing to the exposure to ionizing
      radiations, the invasiveness, and the incidence of major complications (0.3
      1.1%), investigators are attempting to develop safer, non-invasive techniques.
      Cardiovascular magnetic resonance proved to be an extremely safe tool with a wide
      range of clinical applications. Its flexibility and non-invasiveness allow the
      evaluation of the heart and coronary arteries in one single setting, with the
      possibility of quantifying several cardiac physiological parameters. Multiple
      techniques have been applied to overcome the substantial difficulties in coronary
      artery imaging: respiration artifacts are suppressed by breath-holding or
      respiratory gating, cardiac motion artifacts are reduced by diastolic gating with
      ultra fast sequences and the signal-to-noise ratio can be increased with contrast
      agents. In several clinical trials, magnetic resonance coronary angiography has
      been successfully used to assess coronary artery stenoses, coronary artery bypass
      grafts and anomalous coronary artery origins and course. Considering the
      continuing developments in magnet coils, in software technology and in innovative
      imaging approaches, it is likely that magnetic resonance coronary angiography
      will in the future play an important role in the evaluation of coronary artery
      disease.

PMID- 12407846
TI  - Post-infarction microvascular integrity predicts myocardial viability and left
      ventricular remodeling after primary coronary angioplasty. A study performed with
      intravenous myocardial contrast echocardiography.
AB  - BACKGROUND: After acute myocardial infarction the preservation of the
      microvasculature is a pre-requisite for myocardial viability, limited ventricular
      remodeling and a better prognosis. Intracoronary myocardial contrast
      echocardiography after acute myocardial infarction can detect the extent of
      microvascular damage. We hypothesized that intravenous myocardial contrast
      echocardiography after acute myocardial infarction treated with primary coronary
      angioplasty can predict the contractile reserve at low-dose dobutamine
      echocardiography, myocardial functional recovery and left ventricular remodeling.
      METHODS: We studied 37 patients with a first acute myocardial infarction and
      submitted to primary coronary angioplasty. All patients underwent
      echocardiography on the day they had the acute myocardial infarction, intravenous
      myocardial contrast echocardiography with power Doppler imaging 2.9 +/- 0.5 days
      later and dobutamine echocardiography 3.7 +/- 1.2 days after the acute myocardial
      infarction. In all cases, an echocardiography was performed at 3 months of follow
      up. RESULTS: At intravenous myocardial contrast echocardiography, 25 patients
      showed contrast enhancement (reflow) and 12 a sizeable contrast defect (no
      reflow). Reflow patients were found to have a regional wall motion score index
      similar to that of the no-reflow patients on the first day echocardiogram (2.6 +/
      0.4 vs 2.8 +/- 0.2, p = NS), but this parameter was smaller than that of the no
      reflow patients at dobutamine echocardiography (1.5 +/- 0.4 vs 2.6 +/- 0.2, p <
      0.0001) and at follow-up echocardiography (1.5 +/- 0.5 vs 2.6 +/- 0.2, p <
      0.0001). The sensitivity and specificity of intravenous myocardial contrast
      echocardiography in identifying myocardial functional recovery at follow-up were
      80 and 64%, while the sensitivity and specificity of dobutamine echocardiography
      were 85 and 76%. In no-reflow patients the left ventricular volumes increased
      from the acute to the chronic phase (end-diastolic volume from 71.9 +/- 14.1 to
      100.9 +/- 40.6 ml/m2, p < 0.0001, +28%; end-systolic volume from 43.1 +/- 10.1 to
      61.1 +/- 30.1 ml/m2, p < 0.0001, +29%), while they remained constant in reflow
      patients (end-diastolic volume from 71.8 +/- 20.1 to 71.1 +/- 15.4 ml/m2, p = NS,
      -1%; and end-systolic volume from 39.9 +/- 11.9 to 36.3 +/- 12.8 ml/m2, p = NS, 
      8%). CONCLUSIONS: Intravenous myocardial contrast echocardiography is capable of
      identifying patients with a post-infarction contractile reserve and myocardial
      functional recovery; it also allows the early identification of patients prone to
      late left ventricular dilation, thus permitting a more aggressive diagnostic and
      therapeutic strategy.

PMID- 12407847
TI  - Trends in hypertension control and left ventricular hypertrophy over three years.
AB  - BACKGROUND: The aim of this study was to describe trends in blood pressure (BP)
      control and in the prevalence of left ventricular hypertrophy (LVH) during 3
      years of follow-up in a representative sample of treated hypertensive patients
      seen in our out-patient hypertension hospital clinic. METHODS: Four hundred and
      sixty-four hypertensive treated patients who took part in a clinical survey at
      our out-patient clinic during the year 1997 and who had been submitted to a
      routine follow-up visit 3 years later were included in the study. All patients
      were subjected to the following procedures: an accurate medical history, physical
      examination, electrocardiogram, clinical BP measurement. For the diagnosis of LVH
      we used two different ECG criteria: the Solokow-Lyon voltage and the gender
      specific Cornell voltage. RESULTS: During the first survey, 15% of treated
      patients had a clinical BP < 130/85 mmHg, 25.1% > or = 130/85 mmHg and < 140/90
      mmHg, 33.6% > or = 140/90 and < 150/95 mmHg, 26.3% > or = 150/95 mmHg. The
      corresponding figures in the second survey were 19, 26.7, 33.2 and 21.1%,
      respectively. Overall, from the first to the second survey the prevalence of an
      effective BP control (< 140/90 mmHg) rose from 40.1 to 46.7% (p < 0.01). At
      baseline, 40 patients had ECG LVH (8.6%); at the second visit, LVH was found to
      have regressed in 19 of these patients. Among the 424 patients with a normal
      baseline electrocardiogram, 3 developed LVH during follow-up. Hence, the
      prevalence of LVH decreased from 8.6 to 5.1% (p < 0.01). In terms of treatment,
      the prevalence of combination therapy regimens increased from 68.6 to 79.7% (p <
      0.05). CONCLUSIONS: This study demonstrates that in hypertensive patients managed
      in a hypertension hospital clinic, BP control improved during the long-term
      follow-up and that this trend was associated with a significant regression in ECG
      LVH.

PMID- 12407848
TI  - Evaluation of the left anterior descending coronary artery flow velocity by
      transthoracic echo-Doppler without contrast enhancement.
AB  - BACKGROUND: The evaluation of the coronary flow velocity and coronary flow
      reserve (CFR) can provide important information on the functional significance of
      stenoses and of abnormalities of the coronary microcirculation. To date, the
      potential of echo-Doppler in the noninvasive evaluation of the coronary flow has
      been mainly reported for small groups of patients with stenoses of the left
      anterior descending coronary artery (LAD), eventually treated with percutaneous
      coronary angioplasty. The great majority of publications report the use of echo
      Doppler together with contrast enhancement for an optimal visualization of the
      LAD. The aim of our study was to evaluate the feasibility of echo-Doppler
      examination of the LAD with a high-frequency probe and without the use of
      contrast enhancement. METHODS: We studied, in basal conditions, a group of 116
      consecutive patients with a wide range of cardiovascular diseases. CFR was
      evaluated during infusion of adenosine in a subgroup of patients with a recent
      coronary artery bypass graft and left ventricular dysfunction (ejection fraction
      < 40%). RESULTS: The LAD was visualized in 105 out of 116 patients (90%), with no
      difference between the various cardiac pathologies. The mean diameter of the LAD
      was 1.8 +/- 0.4 mm. The peak systolic flow velocity was 16.3 +/- 6 cm/s and the
      peak diastolic flow velocity 28.5 +/- 10 cm/s. The mean CFR was 1.9 +/- 0.8.
      CONCLUSIONS: The coronary flow of the LAD can be evaluated at transthoracic
      Doppler echocardiography without contrast enhancement in a wide range of cardiac
      pathologies. The noninvasive evaluation of the CFR with transthoracic echo
      Doppler should be borne in mind during the clinical and instrumental work-up of
      cardiac patients.

PMID- 12407849
TI  - Resolution of myocardial ischemia due to coronary microcirculatory
      vasoconstriction in a patient with mixed angina.
AB  - Vasoconstriction of collateral vessels has been previously reported as a
      mechanism of spontaneous transient ischemic episodes and after the administration
      of ergonovine. This case report describes a 47-year-old woman with mixed angina
      and a right coronary artery occlusion supplied by a collateral system related to
      the left anterior descending artery. Angina and ECG changes at rest were present
      for more than 1 year and also provoked by intracoronary ergonovine which induced
      collateral vasoconstriction. To the best of our knowledge, this report is the
      first demonstration that the reopening of the right coronary artery and the
      disappearance of collateral vessels may definitively relieve angina and ECG
      changes occurring at rest, thus confirming small coronary vessel constriction as
      the main cause of the disease status.

PMID- 12407850
TI  - Constrictive pericarditis associated with hydrops fetalis.
AB  - We report a rare case of constrictive pericarditis coexistent with a unique heart
      malformation in a fetus. Cardiac abnormalities, possibly due to a transplacental
      viral infection, were responsible for severe hydrops fetalis.

PMID- 12407851
TI  - Angiographic evidence of myocardial channels after percutaneous transmyocardial
      laser treatment.
AB  - The available clinical reports on percutaneous transmyocardial laser
      revascularization do not provide data on the visibility of the channels after the
      procedures. We present the case of a patient who had clear angiographic evidence
      of the presence of myocardial channels immediately after percutaneous
      transmyocardial laser revascularization.

PMID- 12407852
TI  - Apical ventricular septal defect with reverse bidirectional transseptal flow: a
      sign of restriction within the right ventricle.
AB  - Apical ventricular septal defects (VSD) may spontaneously become restricted or
      may even close following tissue outgrowth within the right ventricle in the
      region of the apical muscle bundles. We report a case of spontaneous restriction
      of an apical VSD localized within the right ventricle in the region of prominent
      apical trabeculae, in which pulsed Doppler interrogation showed an unusual
      pattern of bidirectional blood flow across the VSD, with right to left flow in
      systole and left to right in diastole. Angiography confirmed these unusual
      aspects. This reverse bidirectional transseptal flow is due to the physiological
      incorporation of the apical part of the right ventricular cavity in the left
      ventricle and may be, in the absence of right outflow obstruction, a sign of
      restriction of the VSD inside the right ventricle.

PMID- 12407853
TI  - A fenestrated fossa ovalis aneurysm mimicking an atrial septal defect: correct
      diagnosis and treatment by intracardiac echocardiography.

PMID- 12407854
TI  - Papillary fibroelastoma on the pulmonary valve.

PMID- 12407855
TI  - Double orifice mitral valve.

PMID- 12407856
TI  - The new definition of myocardial infarction: analysis of the ESC/ACC Consensus
      Document and reflections on its applicability to the Italian Health System.
AB  - The recent document of the ESC/ACC Committee for the redefinition of myocardial
      infarction (MI) has introduced the measurement of cardiac troponin as the
      biochemical standard for the diagnosis of MI. This change has been mainly driven
      by the demonstration that any amount of myocardial damage, as detected by cardiac
      troponins, implies a worse long-term outcome of the patient. The results of
      several studies consistently show that there is a continuous relationship between
      the degree of troponin elevation and the patient's prognosis. The new definition
      has important consequences on the diagnostic and therapeutic approaches to
      patients with acute coronary syndromes; in fact, patients with increased
      troponins, i.e. patients with MI, necessitate more aggressive treatment than
      those without troponin elevations, i.e. patients with unstable angina. The
      application of the new definition is expected to increase the number of cases of
      MI by about 30% and to decrease mortality. We believe that several aspects of the
      new definition need to be discussed before the new criteria for MI are used in
      clinical practice in Italy. The most relevant issues are the following: 1) the
      definition of troponin elevation should meet the analytical performance of the
      available assays, the diagnostic cutoff of which is frequently too imprecise. We
      propose that troponin elevations be defined as values exceeding the concentration
      corresponding to a total analytical imprecision of 10%. We disclose such a
      concentration for the currently available assays and suggest its use in clinical
      practice to mitigate the possibility of false-positive values; 2) the number of
      samples required for the diagnosis should be sufficient for the assessment of the
      changes in concentration over time. When only one sample is available, or when
      the temporal pattern of the changes in marker concentration is not consistent
      with the time elapsed from the onset of symptoms, we suggest that objective
      evidence that myocardial ischemia is the likely cause of myocardial damage should
      be obtained; 3) the diagnosis of MI after a percutaneous coronary intervention
      represents a unique situation. In contrast with myocardial damage occurring
      during spontaneous ischemia, available data do not support the concept that any
      troponin elevation is associated with an adverse prognosis. In the absence of
      conclusive studies, we suggest that the diagnosis of MI after a percutaneous
      coronary intervention be based on conventional criteria. Finally, we propose this
      summary with the aim of overcoming some of the more controversial aspects of the
      ESC/ACC redefinition of MI: Criteria for acute, evolving or recent MI. Either one
      of the following criteria satisfies the diagnosis for an acute, evolving or
      recent MI: 1) elevation of biochemical markers of myocardial necrosis (preferably
      troponin) with at least one of the following: a) ischemic symptoms; b)
      development of pathologic Q waves on the ECG; c) ECG changes indicative of
      ischemia (ST segment elevation or depression); d) coronary artery intervention
      (e.g., coronary angioplasty). Marker elevations should be accompanied by
      objective evidence that myocardial ischemia is the likely cause of myocardial
      damage when: a) only one blood sample is available; b) marker changes over time
      are not consistent with the onset of symptoms; 2) pathologic findings of an acute
      MI. Criteria for established MI. Anyone of the following criteria satisfies the
      diagnosis for established MI: 1) development of new pathologic Q waves on serial
      ECGs. The patient may or may not remember previous symptoms. Biochemical markers
      of myocardial necrosis may have normalized, depending on the length of time that
      has passed since the infarct developed; 2) pathologic findings of a healed or
      healing MI.

PMID- 12407857
TI  - [Atrial fibrillation and heart failure: cause or effect?].
AB  - The association between atrial fibrillation and heart failure is well documented.
      Heart failure is one of the established predisposing conditions for the
      development of atrial fibrillation; conversely, heart failure is a common
      condition in patients with atrial fibrillation. In patients with heart failure
      the atrial electrophysiologic properties might be modified by hemodynamic
      overloading and neurohumoral activation. Atrial fibrillation promotes heart
      failure with multiple mechanisms including uncontrolled heart rate, loss of
      atrioventricular synchrony, irregularity in the ventricular rhythm, valvular
      regurgitation and neurohormonal effects. Treatment includes correction of
      neurohumoral activation, prevention of thromboembolism, maintenance of sinus
      rhythm, and pharmacologic and interventional control of ventricular rate. The
      results of recent trials (PIAF-Pharmacological Intervention in Atrial
      Fibrillation, RACE-RAte Control versus Electrical cardioversion for persistent
      atrial fibrillation, AFFIRM-Atrial Fibrillation Follow-up Investigation of Rhythm
      Management) suggest that a rate control strategy can be better than rhythm
      control, particularly in patients at high risk of relapse, like those with left
      ventricular dysfunction.

PMID- 12407858
TI  - [Muscle changes and exercise intolerance in congestive heart failure: main role
      of the periphery].
AB  - Chronic heart failure (CHF) patients are characterized by a reduction in
      functional capacity, which appears to have only a weak relation with central
      hemodynamic parameters. Recent studies suggest that changes in the periphery,
      like those occurring in the skeletal muscles of patients with CHF, might play an
      important role in the origin of symptoms and exercise intolerance in this
      condition. It has been shown that biochemical and histological changes in the
      skeletal muscles of CHF patients relate with the degree of exercise intolerance,
      as expressed by peak oxygen consumption (pVO2) better than resting hemodynamic
      parameters. A reduction in skeletal muscle mass represents another important
      determinant of exercise intolerance in CHF patients. In a recent study, in fact,
      it has been shown that the total skeletal muscle mass, as assessed by total body
      X-ray absorptiometry, is a significant predictor of pVO2 in a population of
      ambulatory CHF patients independently of NYHA functional class and neurohormonal
      activation. The relation between skeletal muscle mass and pVO2 might also
      contribute to explain the differences in exercise capacity observed between men
      and women. This relation is not surprising, as oxygen uptake during exercise
      occurs in the metabolically active tissues, i.e. the skeletal muscles. For the
      same reason, the correction of pVO2 for skeletal muscle mass instead of total
      body weight would represent a more physiological approach. This correction might
      also contribute to improve the prognostic power of pVO2 in those groups of
      patients, like women and obese patients, in whom it is still not clear. Finally,
      the relationship between skeletal muscle changes and exercise intolerance
      suggests the possibility to modify the peripheral changes in order to improve
      functional capacity in CHF patients. Recent studies have shown that the
      administration of ACE-inhibitors and angiotensin II receptor blockers can improve
      the properties of the skeletal muscles in animal and human models. Another
      important tool to improve exercise capacity in CHF patients is represented by
      rehabilitation. Exercise training, in fact, allows to obtain an improvement in
      pVO2, which parallels important biochemical and histological changes in the
      skeletal muscles.

PMID- 12407859
TI  - [Genetic modulation in the inflammatory process of ischemic cardiopathy].
AB  - Inflammatory mechanisms and infectious agents, in association with "classic"
      cardiovascular risk factors, may be involved in the development of coronary
      atherosclerosis; moreover, recent studies demonstrated a direct role of
      inflammation in the pathogenesis of acute coronary syndromes, in which the
      intensity of the individual response to potential environmental inflammatory
      stimuli seems to influence the magnitude of the inflammatory reaction and the
      clinical outcome. The variability of this response may be modulated by genetic
      determinants, in particular by functional polymorphisms of the genes codifying
      for molecules involved in the inflammatory process. In this review we discuss the
      association between these polymorphisms and various aspects of ischemic heart
      disease. Although the association between this syndrome and genetic factors may
      be confounded by several elements (variable penetrance, different prevalence in
      different populations and age groups, interaction with environmental risk
      factors), presently available findings suggest that the inflammatory process in
      ischemic heart disease might be, at least in part, genetically mediated.

PMID- 12407860
TI  - [Brugada's syndrome: epidemiology, risk stratification, and clinical management].
AB  - Brugada syndrome is an arrhythmogenic disease, characterized by syncope and
      sudden cardiac death, with a typical electrocardiographic pattern: right bundle
      branch block and ST segment elevation in the right precordial leads. Only
      recently, the first gene causing Brugada syndrome has been demonstrated by the
      identification of mutations in SCN5A, the gene encoding for the cardiac sodium
      channel, also responsible for the LQT3 subtype of long QT syndrome. Despite the
      knowledge on Brugada syndrome has dramatically improved in the recent years, the
      clinical management is still often empirical and limited by the lack of
      pharmacological therapies. Therefore, the implantable cardioverter-defibrillator
      (ICD) is the only life-saving option for high-risk patients. However, life-long
      implant in young individuals may have a major impact on the quality of life and
      it is not free from complications. Therefore, the identification of a robust risk
      stratification algorithm is of outmost importance to limit the use of ICD to the
      higher risk individuals. Programmed electrical stimulation has been proposed but
      this approach appears to have a low positive predictive value, thus leading to
      implants in many asymptomatic patients. Recently, we analyzed data from 200
      Brugada syndrome patients, one of the largest groups so far reported, and we
      showed that the best predictor of cardiac events is the presence of a spontaneous
      abnormal ECG pattern associated with history of syncope. In the present article
      we will review the clinical characteristic of Brugada syndrome and point out a
      possible risk stratification scheme.

PMID- 12407861
TI  - [Diagnosis of heart failure in general medicine: role of cerebral natriuretic
      peptide. Results of a pilot study of a population sample from Calabria].
AB  - BACKGROUND: The aim of this study was to evaluate the usefulness of brain
      natriuretic peptide (BNP) in diagnosing congestive heart failure (CHF), in an
      unselected population. METHODS: Eighty-three patients (47 men, 36 women, mean age
      70 +/- 10 years) were referred to our hospital ambulatory from their general
      practitioners, with a diagnosis of CHF. RESULTS: Clinical-instrumental evaluation
      confirmed diagnosis in 45 patients (54%) (group A), and excluded it in the
      remaining 38 (46%) (group B). There were no differences between groups regarding
      age, weight, height, heart rate, blood pressure. Statistically significant
      differences between groups were found regarding ejection fraction (44 +/- 10%
      group A vs 60 +/- 7% group B, p < 0.01), and BNP blood concentration (162 +/- 226
      pg/ml group A vs 73 +/- 23 pg/ml group B, p < 0.01). Forty-two patients in group
      A (93%) and 25 in group B (65%) had a BNP value > 20 pg/ml (p < 0.05). Using this
      cut-off value, sensitivity was 93%, specificity 34%, negative predictive value
      81% and positive predictive value 62%. Forty-two patients in group A (93%) and 14
      in group B (36%) had an "abnormal" electrocardiogram (p < 0.01). The presence of
      electrocardiographic abnormalities showed a sensitivity for the diagnosis of CHF
      of 93%, specificity of 63%, negative predictive value of 89% and positive
      predictive value of 77%. CONCLUSIONS: In our population BNP dosage confirms the
      high negative predictive value reported in the literature and may be useful to
      exclude diagnosis of CHF in patients with suspect signs and symptoms.

PMID- 12407862
TI  - [Markers of myocardial damage in the diagnosis of acute myocardial infarction:
      the Italian reality in the year 2000].
AB  - BACKGROUND: The Joint European Society of Cardiology and the American College of
      Cardiology Committee has recently reviewed the criteria to diagnose myocardial
      infarction, focusing on the central role of biochemical criterium and indicating
      the cardiac troponins as the reference marker. However, at present, little is
      known upon how "old" and "new" biochemical markers of myocardial damage are
      utilized in daily clinical practice. METHODS: We performed a survey across the
      whole set of Italian coronary care units (CCUs) to evaluate the actual behavior
      of the clinicians in detecting myocardial necrosis with the biomarkers. A simple
      and brief questionnaire was used to pursue such purpose. RESULTS: The feedback
      from CCUs was positive in 87.6% (303/346). The creatine kinase-MB is the most
      frequently used biomarker, however the "mass concentration" method was utilized
      in a minority of centers (38%). More than 60% of the CCUs are still measuring
      obsolete biomarkers as lactic dehydrogenase or aspartate transaminase. Cardiac
      troponins are measured only in 70% of the centers, and almost always in
      conjunction with the "old" biomarkers. Additionally, 14.5% of the Italian CCUs
      had written guidelines upon how to use the biomarkers to pose diagnosis of
      myocardial infarction. Biochemical criteria widely differed from center to
      center, regardless of the biomarker selected as reference standard. CONCLUSIONS:
      The results of our survey show a high degree of difference in the choice as well
      as in the application criteria of biochemical markers for diagnosing myocardial
      infarction among the Italian CCUs. A great deal of confusion has been
      accumulating over the years among Italian cardiologists, and this situation was
      antecedent to the recently released revised criteria for detecting myocardial
      necrosis.

PMID- 12407863
TI  - ["Cure" and "tactics" interventional strategies in unstable angina/non-Q
      infarction].
AB  - Early risk stratification and an invasive approach (coronary angiography and
      reperfusion if indicated) have recently emerged as the treatment of choice in non
      ST elevation acute coronary syndromes. An aggressive pharmacologic therapy, i.e.
      glycoprotein IIb/IIIa antagonists, is also more effective in case of risk
      assessment at the time of the admission of the patient in the coronary care unit.
      Recent data have assessed the advantages of abciximab over tirofiban in unstable
      patients submitted to percutaneous coronary intervention (PCI), whereas non
      anticorpal molecules (tirofiban, integrilin) are indicated for the medical
      treatment of high-risk patients in order to reduce myocardial necrosis during the
      acute phase. A good platelet inhibition with the oral tienopiridine derivative
      clopidogrel, resulted in a lower incidence of major cardiovascular events at
      follow-up both in patients treated conservatively as well as in patients
      submitted to PCI (CURE and PCI-CURE trials). The early risk of myocardial
      necrosis before coronary revascularization was also reduced by clopidogrel in
      patients submitted to PCI, an effect already demonstrated with tirofiban and
      integrilin ("small molecules like" effect). A new therapeutic scheme including,
      at the time of admission, oral clopidogrel for platelet inhibition, an early risk
      assessment and the subsequent use of abciximab in the cath lab, if indicated is
      proposed for the treatment of unstable angina. The advantages associated with the
      proposed treatment have to be validated by ad hoc studies.

PMID- 12407864
TI  - [Typical electrocardiogram in atypical context. Or, when history and
      electrocardiogram are conclusive for a complex diagnosis].
AB  - A case of sudden death in an old female carrier of Duchenne muscular dystrophy is
      reported. Typical electrocardiographic features were registered without other
      signs or symptoms of heart involvement. In particular, cardiomyopathy was
      excluded by echocardiographic evaluation. We believe that in case of a typical
      electrocardiogram of Duchenne muscular dystrophy, a careful family medical
      history should be undertaken to exclude a carrier condition.

PMID- 12407865
TI  - [Closure of coronary fistula with the Amplatzer duct occluder system].
AB  - We describe a case of a 54-year-old woman with a history of palpitations due to
      recurrent atrial fibrillation. The diagnosis of a coronary artery fistula between
      the right coronary artery and right atrium was made after the detection of a
      continuous cardiac murmur. In view of the patient symptoms and owing to the
      aneurysmatic dilation of the fistula, she was submitted to percutaneous closure.
      The anatomic features of the fistula and the closure device used demonstrate the
      peculiarity of the intervention. An artery-venous loop crossing the coronary
      fistula was created via the femoral vein and artery; the Amplatzer duct occluder
      was then advanced through this loop up to the fistula neck and successfully
      delivered. At 1-month follow-up the patient was totally asymptomatic. Cardiac
      auscultation revealed that the murmur was no longer detectable. Current
      guidelines for the treatment of coronary fistulas and on their percutaneous
      closure are discussed.

PMID- 12407866
TI  - [New definition of myocardial infarction: analysis of the consensus document
      ESC/ACC and thoughts about applicability to the Italian health situation].
AB  - The recent document of the ESC/ACC Committee for the redefinition of myocardial
      infarction (MI) has introduced the measurement of cardiac troponin as the
      biochemical standard for the diagnosis of MI. This change has been mainly driven
      by the demonstration that any amount of myocardial damage, as detected by cardiac
      troponins, implies a worse long-term outcome of the patient. The results of
      several studies consistently show that there is a continuous relationship between
      the degree of troponin elevation and the patient's prognosis. The new definition
      has important consequences on the diagnostic and therapeutic approaches to
      patients with acute coronary syndromes; in fact, patients with increased
      troponins, i.e. patients with MI, necessitate more aggressive treatment than
      those without troponin elevations, i.e. patients with unstable angina. The
      application of the new definition is expected to increase the number of cases of
      MI by about 30% and to decrease mortality. We believe that several aspects of the
      new definition need to be discussed before the new criteria for MI are used in
      clinical practice in Italy. The most relevant issues are the following: 1) the
      definition of troponin elevation should meet the analytical performance of the
      available assays, the diagnostic cut-off of which is frequently too imprecise. We
      propose that troponin elevations be defined as values exceeding the concentration
      corresponding to a total analytical imprecision of 10%. We disclose such a
      concentration for the currently available assays and suggest its use in clinical
      practice to mitigate the possibility of false-positive values; 2) the number of
      samples required for the diagnosis should be sufficient for the assessment of the
      changes in concentration over time. When only one sample is available, or when
      the temporal pattern of the changes in marker concentration is not consistent
      with the time elapsed from the onset of symptoms, we suggest that objective
      evidence that myocardial ischemia is the likely cause of myocardial damage should
      be obtained; 3) the diagnosis of MI after a percutaneous coronary intervention
      represents a unique situation. In contrast with myocardial damage occurring
      during spontaneous ischemia, available data do not support the concept that any
      troponin elevation is associated with an adverse prognosis. In the absence of
      conclusive studies, we suggest that the diagnosis of MI after a percutaneous
      coronary intervention be based on conventional criteria. Finally, we propose this
      summary with the aim of overcoming some of the more controversial aspects of the
      ESC/ACC redefinition of MI: Criteria for acute, evolving or recent MI. Either one
      of the following criteria satisfies the diagnosis for an acute, evolving or
      recent MI: 1) elevation of biochemical markers of myocardial necrosis (preferably
      troponin) with at least one of the following: a) ischemic symptoms; b)
      development of pathologic Q waves on the ECG; c) ECG changes indicative of
      ischemia (ST segment elevation or depression); d) coronary artery intervention
      (e.g., coronary angioplasty). Marker elevations should be accompanied by
      objective evidence that myocardial ischemia is the likely cause of myocardial
      damage when: a) only one blood sample is available; b) marker changes over time
      are not consistent with the onset of symptoms; 2) pathologic findings of an acute
      MI. Criteria for established MI. Anyone of the following criteria satisfies the
      diagnosis for established MI: 1) development of new pathologic Q waves on serial
      ECGs. The patient may or may not remember previous symptoms. Biochemical markers
      of myocardial necrosis may have normalized, depending on the length of time that
      has passed since the infarct developed; 2) pathologic findings of a healed or
      healing MI.

PMID- 12407867
TI  - [Coronary microembolization in acute coronary syndrome].

PMID- 12407868
TI  - The "ART" of the Blue FACT.

PMID- 12407869
TI  - Your Jaws--Your Life.

PMID- 12407870
TI  - Interview with Dr. Derek Mahony. 1999 AAFO clinician of the year.

PMID- 12407871
TI  - [Physicians and sexuality].

PMID- 12407872
TI  - [Four years with psyche and soma].

PMID- 12407873
TI  - [The sexual life of Danes illuminated by population studies].
AB  - The sexual life is multitudinous and sexual dysfunctions should be interpreted in
      this complexity. Broader descriptive sexological studies based on normal
      populations are thus of relevance in medical science. The aim of this review was
      to describe existing Danish studies on sexuality in normal populations. A total
      of 34 studies based on a representative material were identified. However, only
      three studies were nationwide, including both genders and several age groups. The
      studies elucidate sex education, sexual activity, and sexual practices in regard
      to risk behavior related to AIDS, whereas sexual desire is is insufficiently
      examined. In several studies, the frequency of sexual dysfunctions has been
      examined, but most studies have methodological shortcomings. This review
      demonstrates the need for representative, national cross-sectional studies and
      prospective studies in the area.

PMID- 12407874
TI  - [Sexual side effects of treatment with psychopharmaceuticals].
AB  - The majority of psychotropic drugs entail sexual side effects. The sexual side
      effects may reduce the quality of life and may give rise to non-compliance. For
      example, 30-60 per cent of patients treated with antidepressants are known to
      develop a sexual dysfunction. However, some psychotropic drugs with no or very
      few sexual side effects have begun to emerge. The treatment of sexual side
      effects induced by psychotropic drugs may consist of: modified sexual habits,
      reduction in dosage, switching to an alternative medication, possibly in
      combination with different psychotropic agents, other varieties of
      pharmacologically active substances or specific products for the treatment of
      sexual dysfunction such as sildenafil. Above all, it should be acknowledged that
      relatively few data are available in this field and in particular that there is a
      lack of controlled studies.

PMID- 12407875
TI  - [Female sexual dysfunction as adverse effect of pharmacological treatment].
AB  - This review describes female sexual dysfunction (FSD) as an adverse effect to
      pharmacological treatment. FSD covers libido, arousal, orgasm, and pain problems.
      The existing knowledge of the influence of medication upon female sexual function
      is very sparse. Treatment with SSRIs and other antidepressants may cause
      decreased libido and organism problems. Antipsychotic treatment often causes
      libido, lubrication, and orgasm problems. Spironolactone may cause decreased
      libido and impaired lubrication. Whether antihypertensives, H2-receptor
      antagonists and sex hormones have sexual adverse effects has not been clarified
      properly. Some drugs, such as bupropion and sildenafil, may enhance the sexual
      function, but further studies have to be carried out. The need for further
      research on the topic is stressed.

PMID- 12407876
TI  - [Incidence and treatment of sexual dysfunction in heart disease].
AB  - Several links have been established between sexual dysfunction and heart disease.
      Indeed, many risk factors for developing sexual dysfunction are shared by
      coronary artery disease: age, smoking, diabetes, hypertension, and
      hypercholesterolaemia. It should also be borne in mind that in men several
      cardiac drugs are responsible for erectile dysfunction (ED). Lastly it should be
      remembered that treatment of ED may be associated with cardiovascular side
      effects. Data from the literature show that men with coronary artery disease,
      hypertension or diabetes have an up to fourfold higher risk of developing ED than
      have age-matched controls. Thiazide diuretics and beta-blockers are the most
      common drugs that produce ED. Current therapies for ED are safe and effective in
      the large majority of patients with cardiovascular disease. However, the
      concomitant use of nitrates and sildenafil may be life-threatening, and nitrate
      therapy is therefore contra-indicated in patients taking sildenafil--and vice
      versa.

PMID- 12407877
TI  - [Sexual function in patients with spinal cord injuries].
AB  - A spinal cord lesion (SCL) changes most functions below the level of lesion,
      including sexual function. Most women had sexual intercourse after the lesion,
      but describe practical problems. Many of them are capable of achieving organism,
      and are normally fertile. During pregnancy there is an increased risk of urinary
      tract infection. Delivery can take place vaginally. In the case of lack of
      progression or severe autonomic dysreflexia, cesarean section may be necessary.
      For erectile dysfunction in men with SCL, oral sildenafil may be used,
      alternatively intracavernous injection with prostaglandin E1. To obtain
      ejaculation penile vibratory stimulation (PVS) is used, and if this fails then
      electroejaculation. Impaired sperm quality with low motility is observed. Vaginal
      insemination at home with sperm obtained by PVS is possible. The fertility
      potential may be enhanced with assisted reproduction techniques, like
      intrauterine insemination and in vitro fertilisation.

PMID- 12407878
TI  - [Sexually transmitted infections and sexual violence against women. Guidelines
      for examination, prophylactic treatment and follow-up].
AB  - Based upon a literature search, but also considering the situation in Denmark,
      guidelines for examination, prophylactic treatment and follow-up of female
      victims of sexual assault have been prepared. A pragmatic attitude, looking upon
      the victim's situation and fear of having acquired a sexually transmitted
      infection, has been prevailing in order to avoid unnecessary examinations and
      treatments. The guidelines are directed towards female victims in whom the
      assault has included vaginal, oral, and/or anal penetration or attempt of
      penetration. It is concluded that all victims should be screened for and offered
      prophylactic treatment for chlamydia. Screening for gonorrhea initially and at
      follow-up is recommended but treatment only if an infection has been established.
      All victims should be screened for hepatitis B initially and again after three
      months and vaccination offered if any information indicates that the assailant
      has an increased risk of hepatitis B. All victims should be screened for HIV
      initially and again after one and three months. In single cases antiviral HIV
      prophylaxis must be considered.

PMID- 12407879
TI  - [Sexual dysfunction in torture victims].
AB  - Sexual dysfunction is seen in up to 51% of torture victims. The torture victim
      seldom reports anything about having been tortured but often consults the health
      care system because of a somatic problem which may seem unrelated to torture.
      Therefore, it is important that doctors are aware of the possible correlation.
      Symptoms and findings may be both physical and psychical. The torture may be both
      sexual and non-sexual as well as physical and non-physical. Social, cultural and
      individual factors also influence the development of sexual dysfunction in a
      torture victim. The factors that cause sexual dysfunction and the identification
      of any direct causal relations are discussed. There are indications that sexual
      torture has a greater impact on the development of sexual dysfunction than other
      types of torture and it seems that sexual dysfunction is a result of many
      factors.

PMID- 12407880
TI  - [Sexuality of the elderly].

PMID- 12407881
TI  - [Erectile dysfunction].

PMID- 12407882
TI  - [Surgical aspects of sexual dysfunction in men].

PMID- 12407883
TI  - [Sexual dysfunction in women after certain surgical interventions].

PMID- 12407884
TI  - [Sexual dysfunction in diabetes mellitus].

PMID- 12407885
TI  - [Sexual dysfunction among patients with epilepsy].

PMID- 12407886
TI  - [Pharmacological treatment of sexual dysfunction in women].

PMID- 12407888
TI  - [Sexual dysfunction after rape].

PMID- 12407887
TI  - [Gynecologic cancer and sexuality. Evidence and research perspectives].

PMID- 12407889
TI  - [Psychotherapeutic treatment of sexual dysfunction--or from sex therapy to
      marital therapy].

PMID- 12407890
TI  - [What do Danish physicians learn about the incidence and treatment of sexual
      dysfunction?].

PMID- 12407891
TI  - [Sexual knowledge, attitudes and behavior among young Danes. A questionnaire
      study].
AB  - INTRODUCTION: The aim of this study was to present selected key figures
      concerning the sexual knowledge, attitudes, and behaviour among Danish teenagers.
      MATERIAL AND METHODS: 7355 Danish adolescents (aged 13-25) participated in a
      comprehensive questionnaire survey concerning sexual knowledge, attitudes, and
      behaviour. RESULTS: The median age at coital debut was 16.8 and in all age groups
      > 13, girls were more experienced and active than boys. The coital frequency was
      increased by age, as was girls' experience with orgasm in the years following
      their debut. The prevalence of same-gender sex appeared to be modest, and anal
      sex was reported by less than 10 per cent. A significant and increasing amount of
      youngsters did not discuss sexual matters at home, whereas the vast majority had
      received sexual education in school. One fourth of the girls regarded doctors as
      desired sexual interlocutors. Almost one fourth of the youngsters did not use
      contraception at their sexual debut, and 7 per cent of the sexually experienced
      girls had had an induced abortion. 9 per cent of the girls and 5 per cent of the
      boys had been infected with chlamydia, and 17 per cent of those sexually active
      had taken at least one HIV test. DISCUSSION: The age at coital debut seems to be
      stable, whereas the prevalences of unsafe sex and STDs are still high. New
      didactic methods are incessantly needed, just as supplementary empirical studies
      are encouraged.

PMID- 12407892
TI  - [Naked on the lawn. The sexual life of 60-year-old Danish women].
AB  - INTRODUCTION: The sexuality of older women has attracted little scientific
      interest. In a literature search only 29 fairly representative cross-sectional
      studies were found. There was a single population study of elderly Danish women.
      The aim of our study was to describe the sexual life of a group of 60-year-old
      women from the Copenhagen area. MATERIAL AND METHODS: A random sample of 122
      women was taken from a cohort found to be fairly representative of 60-year-old
      women in the County of Copenhagen. The women were asked about their attitudes and
      sexual experiences in a semi-structured interview. Socio-demographic data were
      collected. RESULTS: Half the women felt sexual desire once a month or more and
      had intercourse once a month or more. Two thirds had had no more than three
      sexual partners, and 85 per cent had a regular partner at the time of the study.
      The most common dysfunction was vaginal dryness, which one third had. 25 per cent
      said they seldom or never achieved orgasm. Most of the women had experienced
      different sexual practices and were tolerant toward prostitution and pornography,
      but took exception to a number of perversions. DISCUSSION: These elderly women
      have developed and maintained their sexual life in step with the changes in the
      sexual norms occurring during their adult life, despite prejudices against
      elderly people's sexuality.

PMID- 12407893
TI  - [The sexual life of 60-year-old Danish men].
AB  - INTRODUCTION: The sexuality of men is influenced by many factors, and there are
      changes throughout life. In a literature search only 35 fairly representative
      cross-sectional studies of elderly men were found. There is no population study
      of elderly Danish men's sexuality. The aim of our study was to describe the
      sexual life of a group of 60-year-old men from the Copenhagen area. MATERIAL AND
      METHODS: The material is a random sample of 66 men from a cohort found to be
      fairly representative of 60-year-old men in the County of Copenhagen. The men
      were interviewed using structured guidelines, which also included open questions.
      RESULTS: Around half of the men felt sexual desire once a week or more. Around
      one third had had fewer than four sexual partners throughout their lives, and six
      per cent did not have a partner at the time of the interview. Slightly more than
      half had intercourse once a month or more. Two thirds masturbated. One tenth had
      problems with the erection. Two thirds were satisfied with their sexual life.
      DISCUSSION: This study reveals a large variation in the sexual life of elderly
      Danish men.

PMID- 12407894
TI  - [Magnesium to pregnant women with pre-eclampsia?].

PMID- 12407895
TI  - [Celecoxib and the CLASS trial].

PMID- 12407896
TI  - [Utility of MRCP].

PMID- 12407897
TI  - [Is methadone therapy inexpensive?].

PMID- 12407898
TI  - Replacement ratio redux.
AB  - Disconnects between what employees need and expect to receive during retirement
      and what employer-sponsored plans provide can create workforce issues with
      important implications. By creating a model that analyzes the spend-down phase of
      retirement, the authors provide a framework for better understanding what
      employees will need to save during their working lifetimes.

PMID- 12407899
TI  - Preemption--HMOs--independent physician review of medical necessity. Moran v.
      Rush Prudential HMO, Inc., 230 F.3d 959 (7th Cir. 2000), cert. granted,--U.S.-
      150 L.Ed.2d 749 (2001).

PMID- 12407900
TI  - Photocatalytic degradation of actual textile industrial wastewater in aqueous
      suspensions of polycrystalline TiO2.
AB  - Heterogeneous photocatalytic oxidation of contaminants present in wastewater
      produced by a textile industry was carried out. The samples were withdrawn from
      the plant before and after a traditional biological treatment. The effluents were
      named A and A' (before the biological treatment), B and B' (after the biological
      treatment). Polycrystalline TiO2 (Degussa P25) was used as the catalyst in a
      batch photoreactor with immersed lamp. An almost complete decolorization was
      observed after about 0.5 divided by 1 hours for both kinds of effluents, but the
      decrease of the total organic carbon (TOC) concentration occurred more slowly.
      The influence of some chemical oxidants, i.e. ozone, hydrogen peroxide and
      peroxydisulfate on the photo-oxidation rate was also investigated. After addition
      of H2O2 or S2O8(2-) TOC decreased more quickly only for B and B'. The runs
      performed by using O3 as bubbling gas showed a mineralization rate higher than
      that observed in the presence of O2.

PMID- 12407901
TI  - Thermodynamic analysis of the province of Ravenna (Italy).
AB  - This is a thermodynamic analysis of the Province of Ravenna (Italy) and its
      districts (Ravenna, Faenza and Lugo) and an evaluation of entropy waste
      production based on a balance sheet of greenhouse gases. The method used is
      energy analysis. The results show that the Province and Ravenna are characterized
      by a heavy exploitation of local non renewable resources, Faenza strikes a good
      balance between economic development and environment conservation and Lugo is
      less sustainable than the others. The greenhouse gas balance shows that the
      Province emits 10.5 times the quantity of greenhouse gases that it adsorbs and
      that the emissions reduction is required in the energy sector, which is
      responsible for 92% of the total.

PMID- 12407902
TI  - An EPR study on wastewater disinfection by peracetic acid, hydrogen peroxide and
      UV irradiation.
AB  - EPR spectroscopy was applied to obtain qualitative and quantitative information
      on the radicals produced in disinfection processes of wastewater for agricultural
      reuse. The DEPMPO spin trap was employed to detect hydroxyl and carbon-centered
      short living radicals in two different peracetic acid solutions and a hydrogen
      peroxide solution used for water disinfection either in the absence or in the
      presence of UV-C irradiation. Moreover, three different kinds of water
      (wastewater, demineralized water, distilled water) were analysed in order to
      assess the contribution of Fenton reactions to the radical production. The
      spectroscopic results were discussed in relation to the efficiency of the
      different oxidizing agents and UV irradiation in wastewater disinfection
      evaluated as Escherichia Coli, Faecal and Total Coliforms inactivation.

PMID- 12407903
TI  - "High specific activity" radiotracers for metallo-toxicological studies:
      cyclotron and nuclear reactor production, radiochemical separation and "quality
      control": platinum, iridium, gold, copper and gallium.
AB  - Very High Specific Activity RadioNuclides, HSARN, are a powerful tool to label a
      wide variety of chemical elements and compounds present in the biosphere in ultra
      trace amounts. Medium and high Z radionuclides, can be produced by irradiation in
      light-ions accelerator and sometimes nuclear reactor. If the nuclear reaction
      product has atomic number different from irradiated target, it is possible
      separating the radioactive nuclide from irradiated target, without addition of
      isotopic carrier. These kinds of radionuclides are named No Carrier Added, NCA,
      and their specific activity is very high and can reach values close to the
      theoretical Carrier Free one. The true specific activity must be determined by
      use of very sensitive radioanalytical techniques. If a low isotopic dilution
      factor is obtained, these radiotracers are used to label inorganic species and
      complexes of elements, which are presently introduced into the echo-systems by
      human activities. New production methods for NCA Pt, Ir, Au, Cu and Ga
      radiotracers are presented, with some details on radiochemistry and quality
      controls.

PMID- 12407904
TI  - Collection and analytical characterisation of the atmospheric particulate in the
      city of Bari.
AB  - In this paper an application of new procedures for atmospheric particulate
      analysis is illustrated. PM10, PAHs (benzo[a]anthracene (BaA),
      benzo[b]fluoranthene (BbF), benzo[j]fluoranthene (BjF), benzo[k]fluoranthene
      (BkF), benzo[a]pyrene (BaP), indeno[1, 2, 3-cd]pyrene (Ip), dibenzo[a,
      h]anthracene (DbA)) and heavy metals (Cu, Ni, Zn, Co, Mn, Cd, Fe and Pb) were
      investigated. PM10 determination was performed by gravimetric method, PAHs were
      measured by GC-MS, and heavy metals by HPIC. An air quality monitoring campaign
      on the territory of Bari municipality has been organised, and its results are
      shown.

PMID- 12407905
TI  - Vehicle emissions, urban air quality and current Italian legislation: the case of
      Messina. V.
AB  - In the current program for the preparation of an urban air map, this paper
      reports data obtained by the five base stations in the period 1997-2000 regarding
      traditional pollutants and gives the first results obtained in determining
      continuously benzene, toulene and PM10. Additional measurements have been carried
      out by a mobile station at the falcate zone, never tested before, which has very
      low traffic but with the presence of some small metal industries and, under
      favourable meteorological conditions, the effects of the harbour. A statistical
      study on the hourly-trend of particulate suspended matter in two zones of the
      city which have different traffic volume for the period 1995-1997 is also
      reported. The ozone characteristic peak at 15.00 is fully confirmed in all
      stations and over all the period contrarily to most Italian cities, which present
      the peak about three hours earlier. PM10 annual mean value during 1999 was a
      little higher than the legal one. Base stations "Archimede" and "Minissale" still
      present some risk of a stop or limitation of traffic even with respect to
      traditional or "new" pollutants. Statistical analysis of particulate suspended
      matter confirm the very different characteristics of the base stations under
      consideration.

PMID- 12407906
TI  - The use of leaves of Rosmarinus officinalis L. as samplers for polycyclic
      aromatic hydrocarbons. Assessment of air quality in the area of Palermo.
AB  - The quantitative analysis of polycyclic aromatic hydrocarbons (PAHs) in
      vegetables and animals allows us to evaluate the quality of air, in a determined
      geographic area, without the need of making long samplers with complicate
      instrumentation. In this work, Rosmarinus officinalis leaves have been used as
      passive samplers. In particular, this plant was chosen because it is widespread
      in the Mediterranean area and it is commonly found both in the metropolitan and
      in the peripheral areas of the city of Palermo. Results for the concentration of
      total polycylic aromatic hydrocarbons (the sum of the 22 compounds) and the PAHs
      distribution in leaves from Rosmarinus officinalis are presented. Purified
      extracts were analyzed by GC-MS.

PMID- 12407907
TI  - A new microbial assay for the toxicity detection of contaminated soils.
AB  - A comparative study to detect toxicity prior to bioremediation treatment was set
      in order to investigate dehydrogenase activity inhibition of a common soil
      bacterium caused by soil contaminated with Cu, Pb, and As. A spectrophotometric
      test with Pseudomonas fluorescens strain ATCC 13525 utilising the 2,3,5-triphenyl
      tetrazolium chloride (TTC) reduction by microbial dehydrogenase has been adapted
      for this purpose. Soil samples are incubated for 48 hours at 30 +/- 1 degrees C
      in 18-ml tubes in the presence of TTC as an artificial electron-acceptor. The
      reduced TTC forms a reddish colour substance named triphenyl formazan (TPF),
      which can be extracted from the microbial cells and measured colorimetrically.
      The rapid response of biological activity in microorganisms and the reported
      sensitivity to the toxicants in the contaminated samples are reflected by the TTC
      reduction method, which is a sensitive tool for toxicity screening of
      contaminated sites, routine monitoring of bioremediation processes, as well as
      for feasibility studies of bioremediation treatments, in order to assess whether
      a specific pollutant or any other substance at a site location could inhibit the
      microbiological processes.

PMID- 12407908
TI  - Monitoring of inorganic species distribution in water and sediments of Aso river.
AB  - Analytical results are reported for the determination of inorganic species in
      water and sediments sampled in the Aso river ecosystem. The species determined
      are Cd, Co, Cr, Cu, Fe, Mn, Ni, Zn, Hg, F-, NO3-, SO4--, Na, K, Ca, Mg, NH4+ in
      water, and Cd, Co, Cr, Cu, Fe, Mn, Ni, Zn, Hg in sediments. For all the elements,
      in addition to detection limits, precision and accuracy are given: the former,
      expressed as relative standard deviation (Sr), and the latter, expressed as
      relative error (e), were good, being in all cases lower than 6%.

PMID- 12407910
TI  - Thermodynamic indicators for environmental certification.
AB  - The Earth is an open thermodynamic system, that remains in a steady state far
      from the equilibrium, through energy and matter exchanges with the surrounding
      environment. These natural constraints, which prevent the system from maximizing
      its entropy, are threatened by human action and our ecosystem needs urgent
      protection. In this viewpoint the environmental certification was born, according
      to international standards ISO 14001, ISO 14040, and European Regulation EMAS.
      These are voluntary adhesions to a program of environmental protection by
      companies, administrations and organizations which, starting from the respect of
      the existing environmental laws and regulations, decide to further improve their
      environmental performance. To obtain and maintain certification of a system is
      necessary to apply some indicators to evaluate its environmental performance and
      to demonstrate its progressive improvement. Here we propose to use for this
      purpose the thermodynamic indicators produced from energy analysis by Odum. The
      case study is Montalcino city (Italy) and energy indicators are used to evaluate
      environmental performance of this system where exist different activities, from
      agricultural productions, to tourism. Results show that energy analysis could
      become a valid standard monitoring method for environmental certification,
      especially in consideration of its wide application field.

PMID- 12407911
TI  - Carbon and nitrogen distribution in the sediments of lagoon of Ravenna (Italy).
AB  - The distribution and the origin of carbon and nitrogen in sediments of an Italian
      lagoon--located north-east of Ravenna town--were investigated. From 1957 to 1976,
      the lagoon had been affected by a strong industrial pollution due to an important
      petrochemical complex. At present, industrial and domestic waste waters undergo a
      treatment process before being discharged into the lagoon. Sediment samples from
      10 locations throughout the lagoon were analysed, in order to document the
      spatial and vertical distribution of C and N. Data show a very strong variability
      (organic carbon content varies between 8.9% and 0.14%) and the highest values
      were found in the immediate vicinity of the industrial discharge. Sediment
      organic matter shows allochthonous origin in proximity of industrial discharge
      and autochthonous origin in the remaining areas.

PMID- 12407912
TI  - Stability of a NDIR analyser for CO2 at atmospheric concentration.
AB  - Carbon dioxide monitoring is significant in the environmental field since this
      gas plays an important role in the greenhouse effect. In order to determine CO2
      concentration and to develop simulation models, it is necessary to carry out
      measurements which are accurate and comparable in time and space, i.e. SI
      traceable. Non-dispersive infrared (NDIR) analysers are employed for CO2
      measurements, as they are precise and stable. In order to achieve traceability,
      such instruments have to be characterized and calibrated. At the Istituto di
      Metrologia "G. Colonnetti"--CNR, a procedure for calibrating NDIR analysers for
      CO2 at atmospheric level was developed, which enables to calculate a correction
      for the analyser output. In addition, a complete uncertainty analysis was carried
      out and a correct traceability chain was established. The goal of the present
      work is the study of the stability of a NDIR analyser by repeating calibrations
      during three years and comparing the correction curves obtained to identify a
      proper re-calibration interval for such analysers. The investigated instrument
      has good repeatability and reproducibility, hence satisfactory stability during
      time, as shown by the short-term and long-term compatibility of calibration
      curves.

PMID- 12407909
TI  - European Union strategies for the protection of the environment and sustainable
      development.
AB  - Currently there are three main parallel processes aiming either to improve the
      environment or to achieve sustainable development within the European Union (EU):
      the 6th Environmental Action Programme (6th EAP), the Cardiff Process and the
      Strategy for Sustainable Development (SDS). The 6th EAP provides key
      environmental objectives and the framework to set other environmental strategies.
      The Cardiff Process plays a fundamental role in the progression of environmental
      integration, as an essential tool to implement the EAP and to achieve sustainable
      development. Sustainable development is a major political mandate for the EU and
      the SDS aims to provide long-term objectives and measures to promote and
      implement it. The EU Chemicals policy is an example of a European policy
      extracting and using some new approaches and principles characterising the
      political processes described above. The aim of this paper is to analyse these
      political processes, their reciprocal interactions, highlight their innovative
      approaches, as well as providing concrete example of sectoral policy implementing
      them.

PMID- 12407913
TI  - Fly ash with high sulphate and chloride content: solidification and stabilisation
      using hydraulic lime.
AB  - This paper examines the solidification/stabilisation treatment of two fly ash
      samples from a Municipal Solid Waste (MSW) incineration plant using a lime
      pozzolan binder. The two examined fly ash samples were characterised by a high
      chloride and sulphate content and by a significant concentration of heavy metals.
      The effective development of hydrate phases during hydration of hydraulic lime
      fly ash mixtures allows us to stabilise numerous pollutants in hardened pastes.
      The release of pollutants into the leachants is limited and decreases with the
      curing period of the pastes.

PMID- 12407914
TI  - Determination of urinary t-t muconic acid as biomarker of environmental benzene
      intake and its interference factors.
AB  - The target of our study was the determination of urinary t,t muconic acid
      concentration, as a biomarker of benzene intake in a population. Urinary samples
      of 101 subjects, males and females were obtained to whom. Information regarding
      modification and confounding factors were recorded by questionnaire. The samples
      were analysed by HPLC, after extraction of trans,trans muconic acid on strong
      anionic exchange cartridges. In these analytical conditions the detection limit
      with good care is 10 micrograms/l. A concentration range from 10 to 1300
      micrograms/l was found. High levels found in the population could explained by
      confounding factors present. The obtained results were correlated with sex, age
      and smoking or non smoking. There was a significant difference in mean
      concentrations between heavy smokers (160 micrograms/l) and non smokers (110
      micrograms/l), that showed tobacco as an interference factor. The study showed
      that it is strictly necessary carry out a thorough anamnesis before sampling with
      the objective of finding eventual interference factors such as smoking, diet and
      drugs taken.

PMID- 12407915
TI  - Phenol photonitration.
AB  - This paper presents some new data on nitrophenol formation from phenol under
      illumination, and reviews the studies performed on phenol photonitration, from
      its discovery in 1988 to the very recent elucidation of its reaction pathway by
      the authors. Recent experimental results account for the pH effect on phenol
      photonitration. The nitrogen sources so far investigated are nitrate and nitrite,
      which undergo photolysis upon absorption of near-UV light. These studies have
      given a relevant information on the role of both nitrate and nitrite as
      environmental factors. Such processes can take place both in natural waters and
      in atmospheric hydrometeors.

PMID- 12407916
TI  - Polycyclic aromatic hydrocarbon (PAHS) degradation by soil microorganisms.

PMID- 12407917
TI  - [Anniversary of the Comenius University School of Pharmacy in Bratislava].

PMID- 12407918
TI  - [Immunopathogenesis of psoriasis and its current therapy ].
AB  - Psoriasis is a partly inflammatory hyperproliferative skin disease. Its origin
      has not been clarified yet, but numerous immunologic, bioregulatory, and
      biochemical changes accompanying this disease are known. Many cell types and a
      number of immunity system factors forming a perfectly interlinked network are
      involved in the immunity processes in the psoriasis-affected skin. This network
      is a common place where antipsoriatics operate. There is no therapeutic means
      known which guarantees permanent elimination of psoriasis symptoms. External as
      well as internal therapeutic methods having effect on the pathogenetic processes
      at various levels are combined. UV radiation treatment (SUP), sometimes combined
      with psoralens (PUVA), tar, and dithranol are some of the classical methods of
      psoriasis treatment. Topical medicamentous treatment with corticoids, vitamin D
      derivatives, salicylic acid, urea, and tar plays an important part here.

PMID- 12407919
TI  - [Mycophenolate mofetil, a possible new immunosuppresant].
AB  - The mycophenolate mofetil, a prodrug of mycophenolic acid, is a new
      immunosuppressive drug with a specific mechanism of action consisting in the
      inhibition of T- and B-lymphocytes proliferation. A series of animal experiments
      showed efficiency of the mycophenolate mofetil administered in monotherapy or in
      combination with other immunosuppressants to prolong the survival of different
      allo- and xenotransplanted grafts. In clinical trials, the mycophenolate mofetil,
      cyclosporine, and steroids demonstrated high efficacy in the prevention of acute
      rejection in the solid allotransplanted organs. The mycophenolate mofetil seems
      to be a suitable candidate for the treatment of many other, e.g., autoimmune and
      inflammatory diseases.

PMID- 12407920
TI  - [Advances in the development of antifungal agents].
AB  - The present review paper deals with novel antifungal drugs. The lack of new
      antifungal drugs ascend proportionally to the increasing occurrence of serious
      infections caused by yeast and fungi mainly at immunocompromised or in other way
      sensitive patients. The topical state of pharmacotherapy is briefly drawn out;
      most attention is given to newly developed active entities. Established agents do
      not satisfy the medical need completely, azoles are fungistatic and vulnerable to
      resistance, whereas polyenes cause serious host toxicity. Drugs in clinical
      development include modified azoles and a new class of echinocandins and
      pneumocandins. Other promising novel agents in preclinical development include
      several inhibitors of fungal protein, lipid and cell wall syntheses.

PMID- 12407921
TI  - [Effect of fractal dimensions of powdered pharmaceutical aids on their flow
      rate].
AB  - Fractal dimension of the particles of powdered auxiliary substances expresses the
      raggedness of their surface, which can influence both the bulk density and their
      flow rate through the opening of the powder funnel. In the size fractions of 0.20
      0.25 mm of six powdered auxiliary substances, their linear fractal dimensions
      within a range of 1.031 to 1.109 and the corresponding flow rates through the
      circular openings of the powder funnel of diameters of 6; 8; 10, and 12 mm were
      found. A significant correlation has been demonstrated between the flow rate
      expressed in volume (cm3/s) and the fractal dimension, which after an increase by
      one unit characterizes the surface of the particles. With increasing fractal
      dimension, the porosity of freely poured layer of powdered auxiliary substances
      is increased and simultaneously also their flow rate expressed in volume. For the
      usually reported flow rate expressed in weight (g/s), such influence is not
      significant.

PMID- 12407922
TI  - [Cholesterol inhibits peroxidation of egg phosphatidylcholine in multilamellar
      liposomes].
AB  - The effect of cholesterol (CHOL) on the rate of autoperoxidation of
      chromatographically pure phosphatidylcholine from hen egg yolks (EYPC) in aerated
      multilamellar liposomes was examined at eight CHOL:EYPC molar ratios from 0.1 up
      to 1.0 at 45 degrees C. Autoperoxidation was measured as conjugated diene (CD)
      formation by UV-VIS spectrophotometry. In the presence of cholesterol, the
      initiation and propagation phases of autoperoxidation were prolonged, the
      autoperoxidation rate in the propagation phase was decreased, and the CD
      concentration in the termination phase was lowered. The inhibition of EYPC
      autoperoxidation by cholesterol can originate a) from the increased lateral
      separation of polyunsaturated EYPC acyl chains caused by intercalation of
      cholesterol between EYPC molecules, b) from the increased molecular packing of
      both the bilayer polar and hydrophobic regions due to the reduced bilayer
      hydration, c) from the decreased concentration of the molecular oxygen in the
      bilayer interior, and d) from the cholesterol epoxidation and hydroperoxidation
      induced by the oxidation products of EYPC polyunsaturated acyl chains.

PMID- 12407923
TI  - [The role of moistening on the extrusion and spheronization process].
AB  - The pellet is an important oral dosage form, interesting because of its numerous
      technological and pharmacotherapeutic advantages. Extrusion/spheronization is one
      of the most frequently employed technologies of pellet manufacture. Similarly as
      other technologies, also this process of manufacture influences a number of
      manufacturing and formulating parameters, which are then reflected in the final
      properties of produced pellets. The present experimental paper is concerned with
      the role of the moistening agent in the process of extrusion/spheronization and
      the examination of its effect on the size, density, shape, and mechanical and
      flow properties of pellets.

PMID- 12407924
TI  - [Effect of sodium chloride on elasticity of silicone matrices].
AB  - An increase in the availability of the active ingredient from silicone matrices
      can be achieved by using sodium chloride as the filler. An addition of sodium
      chloride also influences the mechanical properties of silicone systems. The
      temperature dependence of real Young's model E' of addition silicone systems with
      sodium chloride was measured. With increasing NaCl concentration in the silicone
      system, the values of Young's module E are increased. The increase is also
      influenced by the particle size of NaCl. The values of the module are moderately
      increased also with increasing temperature, which corresponds to the kinetic
      theory of caoutchouc elasticity. A significant increase in E takes place at NaCl
      concentrations higher than 20%. With a 50% NaCl content in the system, E is
      increased approximately 3.5 times in comparison with an unfilled sample. Various
      theories of elastic behaviour of composites can be employed for the description
      of the effect of the filler on the mechanical properties of silicone systems
      under small deformations. The effect of chloride is best described by the
      relation proposed by Nielsen. The value of the constant A in Nielsen's relation,
      dependent on the shape of the filler particles and Poisson's constant of the
      unfilled matrix, decreases with increasing particle size. With a change in
      particle size, a certain change in particle shape takes place. Hydrodynamic
      theory provides good results for sodium chloride particle size of 102.5 microns,
      but for particle sizes of 20 microns and 60 microns it is less successful than
      Nielsen's relation.

PMID- 12407925
TI  - [Biodistribution of low-molecular-weight proteins and technetium (99mTc) labeled
      peptides in an animal model of inflammation].
AB  - The aim of this study was to evaluate accumulation of the low molecular peptides
      and proteins labelled with 99mTc in rat inflammatory/infection foci. Peptides
      (human leukocyte dialysate--HLD, thymosin fraction 5--TF5, aprotinin--APT),
      proteins (human IgG-HIG) were labelled with 99mTc using a redox polymer. The
      labelling efficiency was evaluated using paper, TLC and/or column chromatography
      and electrophoresis. The biodistribution of the labelled substances was evaluated
      in Wistar rats with Staphylococcus aureus infection or with sterile kaolin
      suspension-induced inflammation in the left inguinal region 24 h after abscess
      induction. Accumulation of 99mTc activity was determined both by external gamma
      camera imaging and by counting dissected tissues 1-4 hours after administration.
      The evaluated peptides and proteins show a high labelling efficiency (99mTc-HLD >
      98%, 99mTc-TF5 > 95%, 99mTc-APT > 98%, 99mTc-HIG > 95%). Use of redox polymer for
      labelling raises the stability of 99mTc-labelled substances so that the labelling
      efficiency remains to be virtually the same (95-98%) after 8 hours at least. In
      experimentally induced inflammation, the amount of 99mTc-peptides and 99mTc-HIG
      activity accumulated is 2.5-6.5 and 5.3-10.6 times, respectively, that in control
      tissue. A comparison of two types of model inflammations(inflammation induced by
      kaolin and Staphylococcus-induced inflammation) revealed the values measured with
      99mTc-peptides are more than a double that induced by kaolin suspension. The
      studied low molecular peptides labelled with 99mTc allow rapid localisation of
      infection foci in the animal model. 99mTc labelled HIG seems to be useful for the
      detection of both infections and inflammatory lesions.

PMID- 12407926
TI  - [Optimal conditions for determination of L-cystine using capillary
      isotachophoresis].
AB  - The compound L-cystine was determined using the method of capillary
      isotachophoresis in two electrolyte systems. Precision, correctness, linearity,
      robustness, and selectivity of ITP were evaluated. The results of ITP
      measurements were compared with the results obtained by means of the standard
      pharmacopoeial methods.

PMID- 12407927
TI  - Rational decision making in the treatment of renal artery stenosis.

PMID- 12407928
TI  - [Sildenafil--adverse effects, complications and safety].

PMID- 12407929
TI  - Hematopoietic stem cell transplantation in the treatment of autoimmune diseases.

PMID- 12407930
TI  - [Traveler's thrombosis: incidence, etiology, prevention].
AB  - The number of persons traveling by airplane, railway or bus is on the increase.
      Recently, there has been a growing number of reports on travel-related disorders
      after long journeys, especially long-haul flights (i.e. deep venous thrombosis
      (DVT) and pulmonary thromboembolism (VTE), also known as "economy class syndrome"
      or "traveler's thrombosis"). The exact incidence of travel related thrombosis is
      not known. Contributing factors for DVT and VTE are sitting in a cramped position
      for hours, low humidity and lowered oxygen pressure in the aircraft cabin,
      reduced fluid intake and dehydration, as well as individual risk factors. In this
      review article definitions for risk groups (low, moderate and high risk for DVT
      and VTE) and recommendations for prevention (leg exercise, fluid intake,
      compression stockings and application of low molecular weight heparins) of travel
      related thrombosis, based on the outcome of a recent expert meeting, are
      presented.

PMID- 12407931
TI  - Renal artery PTA and stent implantation: immediate and late clinical and
      morphological outcome.
AB  - BACKGROUND: Renal artery stenosis (RAS) is a potentially curable cause of
      secondary hypertension, but the indications for interventional treatment of
      renovascular hypertension are still a matter of debate. The aim of the study was
      to investigate immediate and long-term results of percutaneous renal artery
      revascularization (PTRA). Primary technical success, peri-intervention
      complications, patency, the course of arterial hypertension and renal function
      were analyzed. METHODS: 32 renal interventions in 24 consecutive patients (15
      PTA, 17 stents) were investigated in a retrospective cohort study. Comorbidities,
      interventional data and serum creatinine were recorded. Patients were followed
      for a median period of 45 months (IQR, 32 to 68). Clinical evaluation of the
      course of blood pressure, serum creatinine, Doppler ultrasound evaluation and
      multi-slice spiral-CT angiography were performed at follow-up. RESULTS: Primary
      technical success was achieved in 30 interventions (94%), and in 2 patients
      during a secondary intervention. The rate of complications was 16% (n = 5). Three
      major complications were encountered (9%): 1 renal artery thrombosis and 2 acute
      renal failures. Three patients developed late renal failure after 1, 4 and 37
      months, but the overall serum creatinine levels remained stable during the
      observation period. Hypertension was improved after intervention in 17 patients
      (71%). However, recurrent hypertension was found in 9 patients (38%) after a
      median period of 49 months (IQR, 47 to 96). Patency rates at 12, 24 and 72 months
      were 94%, 94% and 64%, respectively. CONCLUSION: Renal artery PTA can be
      performed with an acceptable rate of major complications and good long term
      morphological results. However, clinical outcome in terms of sustained
      improvement of hypertension is moderate.

PMID- 12407932
TI  - Leukocyte scintigraphy with 99mTc-exametazime-labeled leukocytes is not useful
      for follow-up of systemic vasculitis.
AB  - BACKGROUND: The prognosis of systemic vasculitis, for instance Wegener's
      granulomatosis (WG), was greatly improved by the introduction of
      immunosuppressive treatment. However, relapses are frequent and predictors are
      scarce. 111In-leukocytes have been found to indicate unknown manifestations of WG
      and to predict later relapse. We prospectively investigated the value of 99mTc
      Exametazime (99mTc-HMPAO)-labeled leukocytes with regard to specific patterns and
      for their usefulness in the follow-up of patients with WG. METHODS: The
      vasculitis group consisted of 8 patients with WG and 2 with idiopathic
      necrotizing glomerulonephritis (ING). Seven patients with different inflammatory
      diseases served as controls. Leukocyte labeling with 99mTc-HMPAO was done using a
      slightly modified Hammersmith protocol. Cell viability after labeling was
      verified in vivo by the exclusion of early lung and splenic uptake and in vitro
      by means of propidium iodide and FACS analysis. Static gamma camera images from
      the head, chest, abdomen, and pelvis were obtained up to 18 hours after injection
      of approximately 300 MBq 99mTc-HMPAO-labeled leukocytes. Scintigrams were
      analyzed visually; for semiquantitative analysis ROIs were drawn over the nasal
      region, the right lung, kidneys, and liver. RESULTS: Increased nasal leukocyte
      accumulation was found in 7/8 patients with WG and in 2/2 patients with ING. Of 2
      patients who had a relapse 6 months later, one presented with, and one without
      nasal uptake. The kidney/liver ratio was higher in controls (0.24 +/- 0.07 vs.
      0.37 +/- 0.11, p < 0.05). Distinct to moderate lung uptake was observed in 2
      patients with WG and in one with ING. No correlation was found between
      scintigraphic results, medication, ANCA status or cretinine levels. CONCLUSION:
      Nasal leukocyte accumulation is increased in systemic vasculitis, independent of
      the immunosuppressive treatment and later clinical course. However, this finding
      is not specific for vasculitis. 99mTc-HMPAO leukocyte scintigraphy failed to
      indicate or exclude a later relapse and is therefore not suitable as a diagnostic
      tool in the management of patients with systemic vasculitis.

PMID- 12407933
TI  - [Functional assessment before and after interventions on the optic chiasm
      system].
AB  - OBJECTIVES: In the course of a tumor in the area of the optic chiasm the
      optochiasmal system is often exposed to compressive and vascular irritations.
      This study deals with the functional results (visual acuity and visual field)
      before and after surgery based on the primary situation and morphology of the
      tumor in order to give a prognosis on this matter. METHODS: 62 patients (41
      female, 21 male) suffering from tumors in the area of the optic chiasm were
      retrospectively reviewed. The duration of the follow-up was an average of 25.82
      months, +/- 20.04. Among the tumors investigated there were 36 pituitary
      adenomas, 20 meningiomas, 4 craniopharyngiomas, one histiozytosis X and one
      gangliozytoma. For visual field examination the Humphrey Field Analyzer, program
      30-2, was used. 34 tumors (54.8%) were excised by the transsphenoidal approach,
      28 patients (45.2%) underwent transcranial surgery. RESULTS: As for visual
      acuity, of the 124 eyes 53 eyes (42.8%) improved after surgery, 64 eyes (51.6%)
      remained unchanged, 7 eyes (5.6%) deteriorated. Of the patients who underwent
      transsphenoidal surgery, 28 eyes (41.2%) improved after operation, 36 eyes
      (52.9%) remained unchanged, and 4 eyes (5.9%) worsened. In case of transcranial
      surgery, 25 eyes (44.6%) improved, 28 eyes (50.0%) remained unchanged, whereas 3
      eyes (5.4%) worsened. There was a postoperative improvement in 53.2% of the
      visual fields, 37.1% remained unchanged, whereas 9.7% deteriorated. CONCLUSION:
      Both the transsphenoidal and transcranial approaches showed excellent visual
      outcome. Our experience indicates an excellent prognosis for improvement of
      visual acuity and visual fields provided an adequate procedure. Results depend,
      however, on the primary functional and morphological situation. In the case of a
      large supra-/parasellar tumor component a postoperative deterioration of vision
      may occur.

PMID- 12407934
TI  - [Non-extrapyramidal motor side-effects in long-term therapy with neuroleptics: an
      analysis of 99 patients].
AB  - Compliance is the degree of adherence to medical advice. Therapeutic success,
      especially in long-term therapy, largely depends on the patient's compliance.
      Advances in psychopharmacology have led to the production of medications with
      substantial efficacy in the treatment of schizophrenia. The tolerability profile
      of these atypical antipsychotic drugs shows a lower incidence of extrapyramidal
      motor side effects. However, other, perhaps more trivial, side effects impair
      their good tolerability and may severely reduce compliance. We assessed the
      acceptance of these side effects in 99 patients under neuroleptic long term
      treatment. Difficulties to concentrate, weight gain, dizziness, vision
      impairment, and headache were found to be the subjectively most distressing side
      effects. Female patients may be at particular risk of discontinuing medication
      due to side effects (especially weight gain). Our results suggest that non
      compliance as a clinical problem should lead to an individualized treatment,
      which is best developed in the context of an ongoing physician-patient
      relationship. Furthermore the assessment of other neuroleptic side effects
      besides motor disturbances seems to be of outstanding importance.

PMID- 12407935
TI  - Surgery and adjuvant radiation therapy of endometrial stromal sarcoma.
AB  - OBJECTIVE: In the treatment of endometrial stromal sarcoma, it is still not clear
      whether adjuvant radiation therapy improves the outcome. We wish to summarize the
      experiences we gathered from treating 15 patients over a period of 18 years, and
      to compare these to results from literature. PATIENTS AND METHODS: According to
      the 1989 FIGO classification for endometrial carcinoma, 11 (73%) of the 15
      patients analyzed presented stage I, 1 presented stage II, and 3 presented stage
      III sarcoma. Of these, 11 patients (73%) had high grade stromal sarcoma and 4 had
      low grade stromal sarcoma. All patients were treated with surgery and adjuvant
      radiation therapy. Total abdominal hysterectomy and bilateral salpingo
      oophorectomy was performed on 11 patients (73%), vaginal hysterectomy and
      bilateral salpingo-oophorectomy on 2 patients, and total abdominal hysterectomy
      on 2 patients. Combined radiotherapy was performed on 13 patients (93%), while
      isolated brachytherapy and isolated external beam therapy were each performed on
      1 patient. External beam therapy was administrated in daily fractions of 1.6-2.0
      Gy up to a total dose of 37-57 Gy to the pelvis. RESULTS: Follow up ranged from
      23 to 170 months (mean: 80 mths). 10 patients (67%) are still alive without
      tumor, and 5 patients have died. Of these, one died due to intercurrent disease,
      one due to breast-cancer, and 3 due to endometrial stromal sarcoma, presenting
      distant metastases within one year after therapy. Only one patient presented with
      an additional local recurrence. The overall actuarial survival and the disease
      specific survival rate was 72% and 79% respectively after 5 years, and 60% and
      79% after 10 years. The overall local control rate was 93% after 5 years. There
      were no severe acute side effects and no late side effects. CONCLUSION: In our
      experience, the most effective treatment for patients with endometrial stromal
      sarcoma is total abdominal hysterectomy and bilateral salpingo-oophorectomy
      followed by adjuvant radiation therapy, due to the excellent local monitoring
      possibilities in all stages of disease, and a good disease specific survival in
      early stages.

PMID- 12407936
TI  - Outcome of pregnancies after non-amniocentesis-induced premature rupture of
      membranes at 14 to 23 weeks' gestation.
AB  - OBJECTIVE: To evaluate the outcome of singleton pregnancies after non
      amniocentesis-induced premature rupture of membranes (PROM) at 14 to 23 weeks'
      gestation. STUDY DESIGN: We reviewed the hospital records of 53 consecutive
      pregnant women with PROM at 14 to 23 weeks' gestation at our institution from
      1991 to 1996; the pregnancies were not associated with amniocentesis or multiple
      gestation. RESULTS: The median interval between PROM and delivery was 1 day
      (range 0-90; mean 5.2 days). Fifty-two (98%) of the 53 neonates were stillborn or
      died within 4 days. One neonate (2%), a 720-gram male delivered vaginally at 23
      weeks' gestation, survived. The infant had Apgar scores of 6 at 1 minute and 2 at
      5 minutes, and showed normal physical and neurological development at age 5
      months. CONCLUSION: The outcome of pregnancies with non-amniocentesis-induced
      PROM at 14 to 23 weeks' gestation is almost uniformly poor.

PMID- 12407937
TI  - Vestibular symptoms as a complication of sildenafil: a case report.
AB  - Potential vasodilator side effects of sildenafil such as headache, flushing,
      dyspepsia, heartburn, nasal congestion, dizziness and visual changes have been
      frequently observed. We report a 79-year-old man who developed severe vestibular
      neuritis-like symptoms (horizontal nystagmus with rotatory components and
      vomiting) two hours after taking 50 mg sildenafil. Additionally, the patient
      complained of tinnitus in both ears. Internal and neurological examination
      revealed no pathological findings and the patient had no history of
      cardiovascular disease. The symptoms lasted for 24 hours and then resolved
      completely. All of the patient's complaints indicated a drug-related phenomenon.
      This drug related adverse reaction should be included in the long list of
      potential side effects of sildenafil.

PMID- 12407938
TI  - Benign fibrous histiocytoma of bone: a report of ten cases and review of
      literature.
AB  - The benign fibrous histiocytoma is a rare tumor with only a few descriptions. In
      order to better define the optimal therapeutic procedure and the necessity of
      surgery we retrospectively analyzed the patients of the orthopedic department.
      Benign fibrous histiocytoma occurred in the femur (n = 3), pelvis (n = 2),
      humerus, tibia, fibula, rib and spine. Pain as the cardinal symptom and a median
      age of 28 years are factors that differentiate benign fibrous histiocytoma from
      other metaphyseal fibrous lesions such as the nonossifying fibroma. Radiographic
      investigation of this entity showed osteolytic lesions with eccentric thinning of
      the cortex and small fissures. To a variable extent, sclerosis was found in the
      margin of the lesions. Computer tomography revealed dense soft tissue in the
      lesions, but one lesion was filled with fluid. The tumor was restricted to bone,
      with no periosteal or soft tissue reaction. Magnetic resonance imaging showed
      enhancement of the tumor after administration of contrast medium. All lesions had
      uniform histological findings. Although no pathologic fracture occurred in any
      case, local expansion of the tumor was indicated by cortical thinning, small
      fissures and pain. This implied that the patients needed prophylactic curettage
      and bone grafting. Surgery restricted to the osteolytic area was sufficient to
      prevent recurrence.

PMID- 12407939
TI  - [Contribution to the history of endoscopy: improvements of Bozzini's light
      conductor by Johann Georg Ilg at the Vienna Jesophinian Medical-Surgical
      Academy].
AB  - One of the first "modern" endoscopes was the so called "light conductor"
      developed by Bozzini. In spite of repeated indications that certain modifications
      of this device had been carried out in the Josephinian Academy in Vienna in 1806
      and 1807, no details were known on these improvements. With the discovery of the
      original report written by Dr. Johann Georg Ilg, who was prosector at the
      Josephinian Academy in Vienna at that time, an extensive description of this
      "Viennese model" and the performed changes is available for the first time. The
      detailed knowledge of these two early devices should now allow the identification
      and classification of both types of endoscopes in the context of the further
      development of endoscopy. This document of Ilg's report also reveals that the
      "modified light conductor" of Ilg ("Viennese model") already contains
      characteristics of endoscopes that first became available for clinical use in the
      second half of the 19th century.

PMID- 12407940
TI  - Cranio-cervical posture: a factor in the development and function of the
      dentofacial structures.
AB  - Many practitioners will recognize that subjects with a large mandibular plane
      inclination are characterized by an extended head posture and a forward inclined
      cervical column, i.e. an extended cranio-cervical posture. It is also typical
      that subjects with a short-face morphology often carry their heads somewhat
      lowered, and have a markedly backward-curved upper cervical spine, i.e. cervical
      lordosis. The aim of the paper is to link together the findings of a series of
      studies that attempt to clarify this relationship, and bring into focus cranio
      cervical posture, which is a functional factor that seems to be involved in many
      clinical orthodontic problems. To provide a background for the article, the
      concept of standardized posture of the head and the cervical column is developed,
      and procedures for recording this posture, as well as categories of cephalometric
      variables that express the different postural relationships, are described.
      Findings that relate cranio-cervical posture to upper airway obstruction, to
      craniofacial morphology, and to malocclusion are surveyed, and a post-natal
      developmental mechanism that explains the findings and leads to further questions
      is discussed. Recent findings of a relationship between extended cranio-cervical
      posture and signs and symptoms of temporomandibular disorders further emphasize
      the biological importance of this functional parameter.

PMID- 12407941
TI  - Natural head posture--considerations of reproducibility.
AB  - This three-part study investigated the reproducibility of natural head posture
      (NHP) using radiographs and photographs. In part 1, reproducibility of
      cephalograms 1 year after the introduction of NHP was investigated and found to
      be less favourable (Dahlberg coefficient of 2.99 degrees) than most other
      previous investigations. In order to minimize radiation exposure of patients,
      reproducibility of photographs and method agreement between photographs and
      cephalograms were investigated in part 2. Reproducibility of the two photographs
      was poor (2.71 degrees). However, method agreement between cephalograms and the
      photographs taken at the same time was good (1.39 degrees). Replacement of the
      radiographic method with the photographic method for assessing NHP
      reproducibility appeared justified. Changing the protocol for achieving NHP in
      part 3 of the study improved reproducibility substantially (1.41 degrees).
      Various statistical methods were used to assess reproducibility and method
      agreement. Bland and Altman's graphical representation was found to be the most
      appropriate for method agreement. The Dahlberg coefficient, commonly used to
      assess NHP repeatability/reproducibility, does not provide an extreme enough
      interval to allow a sufficient clinical assessment of a method to be undertaken,
      compared with the reproducibility coefficient. That is, the latter provides a 95
      per cent range, compared with 52 per cent with Dahlberg.

PMID- 12407942
TI  - Post-operative stability of the maxilla treated with Le Fort I and horseshoe
      osteotomies in bimaxillary surgery.
AB  - In this study, the post-operative change of the maxilla in six non-cleft patients
      who underwent combination (Le Fort I and horseshoe) osteotomy for superior
      repositioning of the maxilla was investigated. In all patients, the maxilla was
      first osteotomized and fixed with four Luhr plates. No iliac bone graft was
      applied to the maxilla. A bilateral sagittal split ramus osteotomy of the
      mandible (BSSRO) was then carried out and titanium screw fixation was performed.
      No maxillo-mandibular fixation (MMF) with stainless steel wire was used post
      operatively in any patient. Lateral cephalograms were obtained pre-operatively, 5
      days post-operatively, and 3, 6, and 12 months after surgery. The changes in
      anterior nasal spine (ANS), point A, upper incisor (U1), and point of maxillary
      tuberosity (PMT) were examined. The maxillae in the six subjects were
      repositioned nearly in their planned positions during surgery and no significant
      post-operative changes in the examined points of the maxilla were found. These
      results suggest that a combination of a Le Fort I and horseshoe osteotomy is a
      useful technique for reliable superior repositioning of the maxilla. The post
      operative change in the maxilla using this combination osteotomy is comparatively
      stable.

PMID- 12407943
TI  - Properties of the ANB angle and the Wits appraisal in the skeletal estimation of
      Angle's Class III patients.
AB  - The aims of the present study were: (1) to investigate the statistical
      differences in jaw relationship assessments with the ANB angle and the Wits
      appraisal in Angle Class III children, and (2) to suggest guidelines for the use
      of these two parameters in this group of children. Seventy-five Angle Class I
      children with anterior crowding (male, 37; female, 38) and 96 Angle Class III
      children with anterior crossbite (male, 38; female, 58) were examined. All had
      undergone treatment that started at 8 or 9 years of age. Pre-treatment lateral
      cephalograms were used cross-sectionally for the analysis. The mean age was 8
      years 7 months +/- 9 months in the Class I subjects, and 9 years 0 month +/- 7
      months in the Class III subjects. To compare the assessments using ANB angle and
      the Wits appraisal in the Angle's Class III subjects, nine measured values from
      each individual subject were converted into Z scores in relation to the means and
      standard deviations of the two parameters in the Angle Class I subjects. The jaw
      discrepancy is assessed more severely using the ANB angle than by the Wits
      appraisal in these Angle Class III subjects. The paired t-test showed that the Z
      score of the ANB angle was significantly smaller than that of the Wits appraisal
      (P < 0.001). In Angle Class III subjects with a counter-clockwise mandibular
      rotation and a flattened occlusal plane, the ANB angle is a more critical
      cephalometric parameter than the Wits appraisal.

PMID- 12407944
TI  - Proportional changes in cephalometric distances during Twin Block appliance
      therapy.
AB  - The aim of the study was to evaluate the cephalometric changes produced by the
      Twin Block appliance. Lateral cephalometric radiographs were taken before and
      after Twin Block appliance treatment on 30 consecutive patients (14 male, 16
      female, mean age 12 years 6 months). Published normative data tables were used to
      produce control data, which were individually matched to the test group for age,
      sex, and treatment time. Alteration in shape was assessed by measuring percentage
      change in linear dimensions as opposed to change in cephalometric angles used in
      previous investigations. The differential average percentage change was
      calculated by subtracting the control value from the Twin Block value. Clinically
      significant changes (2 per cent and greater) were found in lower anterior (6.6
      per cent) and posterior (4.6 per cent) face heights, upper incisor to maxillary
      plane (4.9 per cent), i.e. upper incisor retraction, and increase in mandibular
      length (Co-B 3.3 per cent, Co-Po 2.6 per cent, Ar-B 3.5 per cent, Ar-Po 2.2 per
      cent).

PMID- 12407945
TI  - Craniofacial differences between Japanese and British Caucasian females with a
      skeletal Class III malocclusion.
AB  - The racial differences in the craniofacial structures of 28 Japanese and 24
      British Caucasian females with Class III malocclusions associated with a severe
      skeletal pattern were examined using lateral cephalograms. The mean age of the
      Japanese and Caucasian patients was 19.6 +/- 3.5 and 20.2 +/- 3.8 years (+/- SD),
      respectively. The mean values of 14 linear and 13 angular cephalometric
      parameters were compared between the two groups. The results showed that the
      Japanese females had a significantly reduced anterior cranial base (P < 0.01), a
      more retrusive midfacial component (P < 0.05), and a significantly increased
      lower anterior facial height (P < 0.01) associated with a more obtuse gonial
      angle (P < 0.05) compared with the Caucasians. Analysis of the dento-alveolar
      component in Japanese patients indicated more proclined upper incisors (P < 0.01)
      compared with those of Caucasian subjects. The reduced anterior cranial base and
      midfacial component, and the high-angle facial pattern in the Japanese
      population, may be morphological features based on race, and these skeletal
      features seem to be less favourable for a skeletal Class III growth pattern
      compared with the Caucasian population.

PMID- 12407946
TI  - The extraction of permanent second molars and its effect on the dentofacial
      complex of patients treated with the Tip-Edge appliance.
AB  - The aim of this investigation was to assess the dentofacial changes in a group of
      patients consecutively treated with Tip-Edge appliances and the extraction of
      four permanent second molars by one specialist orthodontic practitioner. Before
      and after treatment lateral cephalograms and study cast measurements of 45
      individuals, 26 females (mean age 13.8 years) and 19 males (mean age 13.9 years),
      were collated and statistically analysed. Cephalometric variables that exhibited,
      before treatment, significant sex differences, included SNA, SNB (both smaller in
      males, P < 0.05) and U1-NA degrees (P < 0.05), nasolabial angle (P < 0.05), and
      upper lip length P < 0.01 (all larger in males). After treatment, sex differences
      were demonstrated for SNA (smaller in males, P < 0.05), mandibular length (P <
      0.01), upper face height (P < 0.05), lower face height (P < 0.01), anterior face
      height (P < 0.001), posterior face height (P < 0.01), nasolabial angle (P <
      0.05), and upper lip length and thickness (P < 0.001; all larger in males). For
      the cast analysis, before treatment differences indicated larger values for males
      than females for lower arch inter-canine, premolar, and molar widths, arch depth
      (all P < 0.05), tooth size, and arch length (P < 0.01). Similar findings were
      noted in the upper arch except for inter-canine and premolar arch width. Despite
      most arch variables displaying sex differences, no gender effect was found for
      irregularity or crowding parameters. The same variables exhibited significant sex
      differences and changes after treatment (except tooth size, lower arch depth, and
      upper arch inter-canine width). Overall, the pattern of correction exhibited by
      the subjects included dental, skeletal, and soft tissue changes. Males tended to
      have greater mean increases in mandibular skeletal and soft tissue variables
      compared with females. Both males and females had increases in most dental arch
      variables measured from the study casts. Both sexes demonstrated a small
      uprighting, but statistically non-significant distalizing of the buccal segments.
      The lower incisors in the sagittal plane revealed a mean tendency to remain in
      their pre-treatment positions, with some individual variation. Overall, the
      treatment results were considered favourable, but case selection appeared to bias
      towards Angle Class I skeletal patterns of average to slightly reduced facial
      height, overbite and overjet < or = 4 mm, lip competence, no incisor protrusion,
      and moderate tooth size to arch length discrepancy (3-3.5 mm lower arch, 1 mm
      upper arch). Further evaluation of third molar eruption responses may provide
      insight into appropriate timing of second molar extractions.

PMID- 12407947
TI  - Shear bond strength of a new dental adhesive used to bond brackets to unetched
      enamel.
AB  - The aims of the present study were to measure the shear bond strength of a new
      multipurpose dental adhesive, IntegraCem, for direct bonding of stainless steel
      and ceramic brackets to unetched enamel, and to determine the mode of bond
      failure. Both stainless steel and ceramic brackets (GAC) were bonded with
      IntegraCem to unetched extracted human premolars. After bonding, the teeth were
      either stored in a water bath at 37 degrees C for 3 days or passed 2500
      thermocycles from 6 to 60 degrees C. Debonding was then performed with a shearing
      force using an Instron universal testing machine. The force was recorded at bond
      failure. The results showed that the shear bond strength achieved was between 6.7
      and 10.8 megapascals (MPa). Bond failure occurred at the enamel-adhesive
      interface, enabling more efficient enamel clean up. The shear bond strengths
      measured suggest that IntegraCem adhesive may be effectively used in orthodontic
      treatment.

PMID- 12407948
TI  - Casebook: assessing confusion.

PMID- 12407949
TI  - Sexual problems in elderly patients.

PMID- 12407950
TI  - Using antipsychotics in elderly patients.

PMID- 12407951
TI  - CHF: a GP guide to management.

PMID- 12407952
TI  - Better stroke management.

PMID- 12407953
TI  - Current management of atopic eczema.

PMID- 12407955
TI  - Unusual presentation of hepatocellular carcinoma: a case report.
AB  - Hepatocellular carcinoma is the seventh most common cancer in men and ninth in
      women. The authors describe a case of an 83-year old man with a history of
      cryptogenic cirrhosis and a remote history of tuberculosis who presented with
      sudden onset of dyspnea. Screening ultrasound of the abdomen and alpha
      fetoprotein levels three months before this acute presentation were not
      suggestive of hepatocellular carcinoma. Chest roentgenogram showed a miliary
      pattern of pulmonary nodules and the patient was admitted with the diagnosis of
      miliary tuberculosis. Biopsy established the diagnosis of hepatocellular
      carcinoma with pulmonary metastases.

PMID- 12407954
TI  - Hemorrhagic angiomyolipoma and tuberous sclerosis complex: a case report.
AB  - Tuberous sclerosis was first described in 1862 by von Recklinghausen. Since then
      there have been many advances in our understanding of the diagnosis,
      pathogenesis, and treatment of this disease complex, especially after it was
      characterized genetically. While many patients who have tuberous sclerosis
      present with the classic triad of mental retardation, seizures, and facial
      "adenoma sebaceum," most do not because of its variable penetrance. The
      diagnostic criteria have been revised to include patients with tuberous sclerosis
      who do not match the classic pattern. Here we describe a 44-year-old female
      without a prior diagnosis who did not have the classic triad but who presented
      with flank pain. Hemorrhagic angiomyolipoma was diagnosed by computerized
      tomography scan and she was treated by an embolization procedure. We review
      tuberous sclerosis and underscore the need to consider this diagnosis for the
      following reasons: 1. it is not uncommon (slightly more than one in 6,000 live
      births); 2. its presentation is protean; 3. once the diagnosis is made, search
      can be made for associated findings that may lead to additional morbidity if not
      carefully managed, e.g., if an angio-myolipoma is diagnosed, it can be followed
      and possibly treated; and 4. owing to its autosomal dominant pattern of
      inheritance, members of the family can be screened appropriately.

PMID- 12407956
TI  - Antipsychotics and QTc interval prolongation.

PMID- 12407957
TI  - Man has an inborn craving for medicine.

PMID- 12407959
TI  - Re: there's no such thing as a free meal.

PMID- 12407958
TI  - Malpractice premiums: making sense of it all.

PMID- 12407960
TI  - Weapon carrying among rural southern Illinois elementary school children.

PMID- 12407961
TI  - Enhancing rural economic development: crafting a health care revolving loan fund.
AB  - Community development efforts in economically depressed rural areas are often
      hampered by poor access to health care. One barrier to rural provider
      availability is the difficulty of obtaining capital for rural health care
      infrastructure development. Commercial lending institutions are limited in their
      ability to respond to these needs due to traditional lending criteria-
      creditworthiness, equity, experience, management ability, and profits or cash
      flow. This paper describes a rural health care revolving loan fund crafted to
      address these needs for capital while addressing the goal of improving health
      care access in rural Arkansas. The Arkansas Rural Health Revolving Loan Fund is a
      model for other states interested in two processes that work synergistically: (1)
      increasing access to capital to strengthen the rural primary health care
      infrastructure and (2) making health care more economically viable by integrating
      the fund's efforts with those of other community development initiatives.

PMID- 12407962
TI  - Compliance rates and predictors of cancer screening recommendations among
      Appalachian women.
AB  - High rates of morbidity and mortality in the Appalachian region of the country
      warrant examination of the preventive care behavior of its residents. This study
      determined compliance rates for breast and cervical cancer screening
      recommendations for women residing in Appalachian states and identified
      predictors of such compliance using the Behavioral Risk Factor Surveillance
      System data (1995-97). Healthy People 2000 goals were used as benchmarks for
      progress. Appalachian women have made good progress toward goals pertaining to
      breast and cervical cancer screening. Compliance with other preventive services,
      having insurance coverage, residing in urban areas, better self-reported health,
      and higher education were independently associated with increased odds of
      compliance with annual-screening recommendations. Risk factors of obesity and
      smoking were associated with decreased odds of compliance. Findings should be
      useful to health care providers, policy makers, and researchers in their efforts
      to educate, encourage, and promote preventive care behavior among residents of
      Appalachia.

PMID- 12407963
TI  - Breast cancer detection and outcomes in a disability beneficiary population.
AB  - Women with disabilities may be at higher risk of late-stage breast cancer. Using
      the 1991-93 Medicare-Surveillance Epidemiology and End Results (SEER)-linked data
      set, the authors compared stage at diagnosis and mortality, for Social Security
      Disability Insurance (SSDI)-qualifying women and similarly aged non-SSDI
      qualifying women. Disabled patients were diagnosed at a later American Joint
      Committee on Cancer stage. Disabled patients had higher all-cause mortality rates
      but had similar breast cancer-specific mortality. Disabled women belonging to
      Medicare HMOs tended to have earlier stage diagnosis and better survival compared
      to Medicare fee-for-service (FFS) insurance. In conclusion, disabled patients
      tended to be diagnosed with breast cancer at a later stage and to have higher
      mortality. These findings were more pronounced in Medicare FFS than in Medicare
      HMOs.

PMID- 12407965
TI  - Latino adults' health insurance coverage: an examination of Mexican and Puerto
      Rican subgroup differences.
AB  - Lack of health insurance is a serious problem in the United States. Using data
      from the 1996 Medical Expenditure Panel Survey, this paper examines how insurance
      varies between black, white, and Latino adults. Because Latino subgroups are not
      homogeneous, the paper also compares the factors associated with health insurance
      status for Mexican and Puerto Rican adults. Results indicate that access to
      private health insurance for Latino adults was more closely associated with
      workplace characteristics than employment itself. Time lived in the United States
      was a major factor associated with being uninsured for Mexican adults, while
      language barriers were a major factor limiting Puerto Rican individuals' access
      to private health insurance. The paper suggests two approaches for decreasing
      uninsurance among Latino adults: (1) strengthening the link between employment
      and private health insurance and (2) addressing disparities in access to public
      coverage for racial and ethnic groups, including recent immigrants.

PMID- 12407966
TI  - Race and sex differences in the use of cardiac procedures for patients with
      ischemic heart disease in Maryland.
AB  - This study analyzes administrative data from the Maryland Health Services Cost
      Review Commission to compare differences by race and sex in the use of cardiac
      procedures performed in hospitals in Maryland. African Americans discharged from
      Maryland hospitals were less likely than whites to have received cardiac
      procedures after controlling for age, insurance status, and the number of
      comorbidities (e.g., hypertension and diabetes). Overall, the general pattern of
      care suggests that African American women may receive high-technology cardiac
      treatment significantly less often than all other race and sex categories.

PMID- 12407967
TI  - Explores the social nature of early development and the way in which social and
      cognitive development interacts.

PMID- 12407964
TI  - Socioeconomic, cultural, and behavioral factors affecting Hispanic health
      outcomes.
AB  - Evidence suggests that social and economic factors are important determinants of
      health. Yet, despite higher porverty rates, less education, and worse access to
      health care, health outcomes of many Hispanics living in the United States today
      are equal to, or better than, those of non-Hispanic whites. This paradox is
      described in the literature as the epidemiological paradox or Hispanic health
      paradox. In this paper, the authors selectively review data and research
      supporting the existence of the epidemiological paradox. They find substantial
      support for the existence of the epidemiological paradox, particularly among
      Mexican Americans. Census undercounts of Hispanics, misclassification of Hispanic
      deaths, and emigration of Hispanics do not fully account for the epidemiological
      paradox. Identifying protective factors underlying the epidemiological paradox,
      while improving access to care and the economic conditions among Hispanics, are
      important research and policy implications of this review.

PMID- 12407968
TI  - Cognitive and social factors in the development of infants with Down syndrome.
AB  - Infants and young children with Down syndrome can be engaging and affectionate.
      It seems that in the early months of life their personal relations may be
      relatively 'spared' the effects of limitations in their capacities for
      information-processing. Yet how far is this the case as development proceeds? In
      this paper we discuss some ways in which social and cognitive development
      interact and mutually influence one another over the first year or so of life,
      and present preliminary findings from a longitudinal study of infants with and
      without Down syndrome. The evidence suggests that the development of 'triadic'
      (person-person-world) social interactions may be affected by limited information
      processing capacities in infants with Down syndrome, through a complex socially
      mediated developmental trajectory.

PMID- 12407969
TI  - A 'positive' approach to supporting a pupil with Down syndrome during 'dedicated
      numeracy time'?
AB  - This exploratory study has been designed to consider how mainstream staff can
      most effectively support pupils with Down syndrome in numeracy. The study is
      partly based on the work of Wishart (1996, 2001), looking at motivation and
      learning styles in young children with Down syndrome. An individual case study
      was carried out during 'dedicated numeracy time', a central part of the National
      Numeracy Strategy framework, in a reception class. Background information was
      collected from the educational records of the pupil, initial unstructured
      observations and semi-structured interviews with the class teacher and Learning
      Support Assistant. Structured observations were carried out across individual,
      group and whole class settings. The findings, from this single case study,
      revealed that, contrary to the expectations of staff, the pupil demonstrated less
      inappropriate behaviour in the whole class setting, in comparison to individual
      and group settings. However, the pupil was more successful in his independent
      attempts at tasks in individual and group settings, in comparison with the whole
      class setting. The report concludes that it is important to provide pupils with
      appropriate support to avoid failure, particularly during the early stages of
      learning. It also recommends that the pupil is able to work within the mainstream
      classroom and participate, with the appropriate support, in the whole class
      'mentral maths' session and plenary on a more regular basis. This is a small
      scale study and the findings tentative. It does however indicate the need for
      further research in this area.

PMID- 12407971
TI  - Gender differences in coping strategies of parents of children with Down
      syndrome.
AB  - Little research has been conducted on the reactions of parents, and fathers in
      particular, following the birth of a child with Down syndrome. Previous studies
      suggest that gender differences exist in coping strategies and a number of
      theories have supported this. The current study is informed by Pleck's (1981)
      Gender Role Strain model which attempts to explain the different socialisation
      processes males encounter which influence their development in our society.
      Questionnaires from Carver, Scheier and Weintraub's COPE inventory (1989) were
      given to parents (n = 150) to measure coping strategies and a number of gender
      differences were found. Females scored significantly higher than males in seeking
      instrumental and emotional support; in focusing on and venting emotions; and
      suppression of competing activities. An additional analysis carried out on
      parents of young children (n = 74) yielded similar results. The overall findings
      from the study provides mixed implications for Pleck's theory. Gender differences
      were found but no value can be ascribed to these different coping strategies.

PMID- 12407970
TI  - Reading with Abby: a case study of individual tutoring with a young adult with
      Down syndrome.
AB  - This case study examined the impact of a series of tutoring sessions on the
      literacy development of a young woman with Down syndrome. The sessions were
      conducted within the LATCH-ON (Literacy and Technology-Hands On) program at the
      Schonell Special Education Centre at the University of Queensland and made use of
      technology resources in addition to other methods of instruction. The first
      author assumed the role of participant observer through the reported sessions and
      acted as an individual tutor to the young woman. Data obtained from an initial
      screening indicated that the young woman had only limited word decoding
      strategies when reading text, and consequently, had significant problems with
      comprehension. Instruction during individual tutoring sessions focused primarily
      on phonics instruction, as well as other decoding strategies, such as sight word
      recognition. Specific instructional strategies employed by the first author are
      discussed. Within the context of the LATCH-ON program, the impact of individual
      instruction on the development of literacy is examined and discussed.

PMID- 12407972
TI  - Work stress and people with Down syndrome and dementia.
AB  - This study aimed to assess how staff ratings of challenging behaviour for people
      with Down syndrome and dementia affected the self-reported well-being of care
      staff. Data were collected from 60 care staff in 5 day centres in a large city in
      England. The data were collected by use of a questionnaire. There was no
      significant difference between those who cared for individuals with Down syndrome
      and dementia and those caring for service users with other non-specified learning
      disabilities without dementia, regarding their self-reported well-being. Self
      reported well-being did correlate with staff rating of challenging behaviour in
      both those who cared for people with Down syndrome and dementia and those who did
      not care for such service users, with well-being declining as perceived
      challenging behaviour increased. The findings indicate that challenging behaviour
      prevention and reduction may be of benefit to both service users and care staff
      well-being.

PMID- 12407973
TI  - Oxidative stress in Portuguese children with Down syndrome.
AB  - BACKGROUND: Individuals with Down syndrome have an accelerated process of ageing
      which is thought to be associated with oxidative stress. AIM: Since Zn/Cu
      superoxide dismutase is increased by about 50% in children with Down syndrome,
      glutathione and other less known antioxidant mechanisms were studied to determine
      whether there were changes in reactive oxygen species. METHODS: Plasma reduced
      and oxidised glutathione and red blood cells enzymes including acid phosphatase,
      methemoglobin reductase and transmembrane reductase were evaluated in Portuguese
      children with Down syndrome and their siblings, who were used as a control group.
      RESULTS: No significant differences were found between the study and control
      groups. A negative correlation was noted between total glutathione and acid
      phosphatase in the siblings without Down syndrome, but not in the children with
      Down syndrome. CONCLUSION: Although it is claimed that the production of hydrogen
      peroxide is enhanced in children with Down syndrome, their antioxidant mechanisms
      do not seem to be significantly different compared with their siblings. This may
      result in an excess of reactive oxygen species that could help to explain
      accelerated ageing in children with Down syndrome. Further studies will be needed
      to shed light on these mechanisms.

PMID- 12407975
TI  - Associated postmortem dental findings as an aid to personal identification.
AB  - The use of the unique features of the human dentition to aid in personal
      identification is well accepted within the forensic field. Indeed, despite
      advances in DNA and other identification methodologies, comparative dental
      identifications still play a major role in identifying the victims of violence,
      disaster or other misfortune. The classic comparative dental identification
      employs the use of postmortem and antemortem dental records (principally written
      notes and radiographs) to determine similarities and exclude discrepancies. In
      many cases the tentative identification of the individual is unknown and
      therefore antemortem records cannot be located. In such a situation a dental
      profile of the individual is developed to aid the search for the individual's
      identity. With such a profile a forensic odontologist can identify and report
      indicators for age at time of death, race (within the four major ethnic groups)
      and sex. In addition to these parameters the forensic dentist may be able to give
      more insight into the individual. This paper outlines, for the non-expert, some
      of the additional personal information that can be derived from the teeth of the
      deceased, and which may assist in their ultimate identification.

PMID- 12407981
TI  - A case of fatal poisoning with the aconite plant: quantitative analysis in
      biological fluid.
AB  - In recent years recorded cases of plant poisoning have become rare, this may in
      part be due to the possibility of plant ingestion not being indicated at the
      beginning of an investigation. Aconitum napellus (aconite, Wolfsbane, Monkshood)
      is one of the most poisonous plants in the UK. It contains various potent
      alkaloids such as aconitine, isoaconitine, lycaconitine and napelline. Ingestion
      of Aconitum plant extracts can result in severe, potentially fatal toxic effects.
      This paper describes the analytical findings in a recent death in the UK.
      resulting from deliberate ingestion of Aconitum napellus extract. The
      concentrations of aconitine measured by HPLC-DAD in the post mortem femoral blood
      and urine were 10.8 micrograms/L and 264 micrograms/L, respectively. The
      aconitine concentration in the ante mortem urine was 334 micrograms/L and was
      estimated to be 6 micrograms/L in the ante mortem serum. Hence, accidental,
      suicidal or homicidal poisoning due to the ingestion of plant material remains a
      possibility and should be borne in mind when investigating sudden or unexplained
      death.

PMID- 12407986
TI  - Longitudinal assessment of ADL ability of partially dependent elderly people:
      examining the utility of the index and characteristics of longitudinal change in
      ADL ability.
AB  - The present study aimed to evaluate the utility of the activities of daily living
      (ADL) index for partially dependent elderly people (ADL-PDI) when applied
      longitudinally to an institutionalized partially dependent (PD) group, and to
      determine the characteristics of the longitudinal change in ADL ability of the PD
      group. The subjects were ten Japanese PD living at welfare institutions for the
      aged such as accredited nursing homes and health facilities (mean age was 82.2 +/
      2.32 years in total; 84.3 +/- 4.18 years for five males; 80.3 +/- 2.33 years for
      five females). The questionnaire consisted of the ADL-PDI, the Barthel index
      (BI), physical independence, dementia independence, anamnesis, body impairments,
      use of assisting devices, the institutionalized period, and type of medical
      rehabilitation and medical treatment, and was administered to the subjects twice
      during their institutionalized period. All testers were staff working at the
      subjects' institution, such as occupational therapists, physiotherapists and
      nurses. The result of the longitudinal ADL assessment was that ADL-PDI may
      evaluate the longitudinal change in ADL ability on a unidimensional scale. The
      utility of the standard for discriminating the functional level of the elderly
      using the ADL-PDI score, which was indicated in our previous study (Sato et al.,
      2001), was supported by longitudinal data. Furthermore, the BI was superior to
      the ADL-PDI in evaluating the disabled elderly with lower functional levels.
      However, the ADL-PDI was better than the BI in evaluating the disabled elderly
      with a higher functional level and was considered to have wider applications in
      evaluating the ADL ability of the elderly.

PMID- 12407987
TI  - Heart rate response and perceived exertion in college students during riding a
      scooter.
AB  - The purpose of this research is to examine the heart rate responses and the
      perceived exertion in college students during scootering, and to examine if
      scootering possibly makes heart rate increase up to the level that can contribute
      to maintaining or developing cardiorespiratory fitness. Five male students (20-23
      yrs) participated in this research, mainly assigned to scooter on an official 400
      m-tartan track. Each session of scootering was six minutes. Each subject did
      three sessions of scootering at different speeds, slow, ordinary, and very fast.
      During the scootering, heart rate was measured using a Polar Vantage XL.
      Immediately after each session, the subjects were questioned about their
      perceived exertion. To evaluate heart rate during scootering on the track,
      maximal heart rate was measured in advance with graded maximal tests. In each
      speed in the track trial, the mean heart rates and the standard deviations were
      106 +/- 5.9, 129 +/- 4.2, and 179 +/- 13.7 beats/min respectively. They
      correspond to 54.0 +/- 4.2%, 65.8 +/- 4.2%, and 91.2 +/- 5.5% of the maximal
      heart rate respectively. The mean and standard deviation of perceived exertion
      based on Borg's scale in each scootering session were 7.2 +/- 0.45, 10.2 +/-
      1.10, and 16.6 +/- 2.79 respectively. Conclusively, at ordinary speed, the heart
      rates of the college students on a tartan track were situated around the level of
      the lower boundary which the American College of Sports Medicine recommended to
      develop and maintain cardiorespiratory fitness for apparently healthy people. If
      people have places to ride a scooter briskly, their heart rate could rise above
      the minimum level.

PMID- 12407988
TI  - The relationship and its change with aging between ADL and daily life
      satisfaction characteristics in independent Japanese elderly living at home.
AB  - The purposes of this study were to examine the characteristics of the
      relationship between ADL ability and daily life satisfaction and the pattern
      change with aging in independent Japanese elderly, and to compare these
      tendencies between males and females. The characteristics of ADL ability and
      daily life satisfaction of 482 subjects (213 males, 269 females) were
      investigated in a self-response survey. Seventy-four ADL items, considered from
      previous studies, were selected from nine ADL domains of 1) movement, 2) going up
      and down stairs, 3) changing and holding posture, 4) bathing, 5) toileting, 6)
      dressing, 7) grooming, 8) eating, and 9) manual activities, and nine items of
      daily life satisfaction were selected from physical, psychological and
      sociological factors. Both ADL ability and life satisfaction of independent
      elderly tended to decline with aging. From correlation analysis, since life
      satisfaction of the elderly was higher with high ADL ability level, it was
      considered that ADL ability level is one of the important factors in providing
      for life satisfaction of independent elderly. The subjective symptoms of
      inconvenience in the lower extremity and lumbar region increased from the 70s in
      both genders, and the use of assisting devices for movement remarkably increased
      in the 80s in both genders. The use of assisting devices closely related to the
      activity area in daily life and influenced the characteristics of life
      satisfaction and its age-related change in the relationship between ADL ability
      and life satisfaction. The relationship between ADL ability and satisfaction with
      physical function was similar in both genders, while the relationship between ADL
      ability and satisfaction with sociological and psychological factors was
      different between males and females. Since the relationship between ADL ability
      and life satisfaction of independent elderly is influenced by a combination of
      personal, cultural, and environmental factors, additional study must investigate
      in detail the influence of these factors.

PMID- 12407989
TI  - Nutrient intake of highly competitive male and female collegiate karate players.
AB  - Nutrient intake of 29 male (M Group) and 16 female (F Group) highly competitive
      collegiate karate players were compared. The results were also compared with the
      daily energy expenditure (DEE), Japanese recommended dietary allowances (RDAs) or
      adequate dietary intakes (ADIs). Dietary information was collected using a 3
      weekday diet record. Although the M Group showed significantly higher mean %RDAs
      or %ADIs in iron, vitamin B1, phosphorus, magnesium, and sodium than the F Group,
      many of the mean %RDAs or %ADIs were below RDAs or ADIs in both groups. The
      subjects who skipped meals tended to show lower mean %DEE, Japanese %RDAs or
      %ADIs in minerals and vitamins than the subjects who did not skip in both M and F
      Groups. The consumption of green and other vegetables and milk and dairy products
      in both M and F Groups were low. It is concluded that the male and female highly
      competitive karate players studied in the present study may be at risk of sub
      optimal nutrient intake, which increases the potential for nutrient deficiency.
      The subjects were advised not to skip meals, and to consume a balanced high
      carbohydrate, moderate-protein, low-fat diet with increasing green and other
      vegetables and milk and dairy products to increase mineral, vitamin and dietary
      fiber intakes.

PMID- 12407990
TI  - Snowballs in hell.

PMID- 12407991
TI  - The future of the dental profession: perspectives from Oral Health in America: a
      report of the Surgeon General.
AB  - "The intent of this first-ever Surgeon General's Report on Oral Health is to
      alert Americans to the full meaning of oral health and its importance to general
      health and well-being" (US Department of Health and Human Services, 2000). Thus
      began the introductory message from the Secretary for Health and Human Services
      to Oral Health in America: A Report of the Surgeon General, released in May 2000.
      The centerpiece of the charge was to "define, describe, and evaluate the
      interaction between oral health and general health and well-being through the
      life span in the context of changes in society" (US Department of Health and
      Human Services, 2000). To address this charge, the report was science-based,
      prevention and health promotion-oriented, and focused on all life stages.
      Although the report stressed oral health, not the dental profession, the report's
      messages and themes are relevant to current and future dental practice,
      education, research, and to dentistry's role in the healthcare system.

PMID- 12407992
TI  - The Future of Dentistry: a synopsis.
AB  - The American Dental Association commissioned the Future of Dentistry report in
      1999. A sixteen-member oversight committee and six expert panels developed the
      report. It was presented to the American Dental Association's House of Delegates
      in October 2001. The Future of Dentistry report was intended to describe the
      current status of the U. S. dental profession, observe trends that will influence
      the profession, envision challenges that the profession will confront in the next
      five to fifteen years, and make recommendations regarding how to meet those
      challenges. The report concludes that the profession is strong and healthy.
      Revolutionary changes are not necessary. However concerted effort to address the
      areas of concern is important to assure the American people access to the finest
      dental health care possible. This effort will require the cooperation of all
      involved in the dental care--the profession, industry, policy-makers and the
      public.

PMID- 12407993
TI  - Conducting and putting science into practice: the future of oral health research,
      dental education, and dental practice.
AB  - Popular attention has focused on connections between single nucleotide
      polymorphisms (SNPs) where single genome irregularities are associated with
      biological deficiencies. The more significant and more difficult work will come
      through seeking to understand the proteonomics--the way sets of genes are
      expressed as proteins, and ultimately in larger and more complex entities. Future
      developments will take place at the interfaces among various disciplines. We are
      already seeing the introduction of diagnostic tests based on the new genomics in
      dental offices. New skills will be needed to bring these emerging developments
      into practice.

PMID- 12407994
TI  - A new format for dental education.
AB  - Three trends that have been with dental education for a number of years are
      identified: a crowded curriculum, promising growth in the biological
      understudying of oral conditions, and disparities in access to oral health care
      among Americans. To address these influences, a restructuring of dental education
      in the U. S. is proposed. Among the changes called for are bringing biomedical
      science education in the first two years of dental school to parity with medical
      school education, increasing the time and quality of extramural clinical
      education, and adding a mandatory year of postdoctoral education.

PMID- 12407995
TI  - External forces impacting U.S. health care: implications for future of dental
      practice.
AB  - Prognostication requires extrapolation of existing conditions and trends into the
      future. Alternative perspectives and starting points will suggest alternative
      futures. Since dentistry does not exist independently of the larger health care
      environment, it is useful to start by considering external forces that impact the
      overall health care system in order to anticipate both short-term and long-term
      changes in the dental profession. This contribution to the Future of the Dental
      Profession symposium considers dentistry's role within the larger health care
      environment, examines a variety of forces influencing health care--specifically
      demography, equity, population health, and social determinants of health,
      identifies likely demands on the profession, and iterates nine likely changes in
      the profession.

PMID- 12407996
TI  - The future of dental practice.
AB  - This paper is intended to describe several broad areas of change that will affect
      dental practice as we enter the early portion of the 21st century. The four major
      topic areas are: The changing status of American and world society, the
      demographic changes in the patient and provider communities, technology, and the
      development of evidenced-based dental practice. The article presents a digest of
      other issues that are encompassed in these four major topic areas that will
      affect dental practice in the future.

PMID- 12407997
TI  - Challenges and opportunities for dental education, research, and service in the
      21st century.
AB  - The recent advances in research, technology, and levels of oral health are
      expected to continue at an accelerated pace. This will place pressures on the
      curricula, students, and faculty of dental schools; our research infrastructure;
      and the way we serve diverse segments of the population. Although it is easy to
      forecast that improvements will come at ever quicker rates, it is less certain
      how we will react to them.

PMID- 12407998
TI  - Dental ethics for the 21st century: learning from the Charter on Medical
      Professionalism.
AB  - At chairside the dentist is obligated to act primarily in the patients'
      interests, to fully and honestly inform patients, enable them to make their own
      treatment choices, and provide competent, continually improving care. Dentists
      must also recognize that they have a responsibility to reduce existing barriers
      to access to care in their communities. These long-standing principles of health
      care practice have found a new expression in the "Charter of Medical
      Professionalism." The charter is the work of an international consortium that has
      reviewed the applicability of existing ethical standards to the challenges facing
      21st century practitioners and has revised and restated the fundamental
      principles of ethical health care practice to effectuate a code of conduct for
      the new century. The author will review professional ethics in the context of the
      historical doctor-patient relationship, explore how the transition to modern
      treatment modalities has affected the professional-patient relationship, and will
      appraise the charter as a valuable resource in redefining dental professionalism
      for the future.

PMID- 12407999
TI  - Measured success.
AB  - Some practices "wing it," some pick outcomes after the fact in order to look
      good. But neither of these approaches creates much confidence that next year will
      be okay, let alone better. Using measurement to improve practice requires
      understanding the interplay among mission, vision, core values, key success
      factors, and performance indicators. Combined intelligently, these five elements
      drive strategic planning and budgeting. They also lead to monitoring progress
      toward success. This is best done with a balanced scorecard that includes leading
      and lagging indicators of mission and vision. Indicators should be sampled to
      represent the practice and monitored against targets to propel the practice
      toward success.

PMID- 12408000
TI  - [Epidemiology as a discipline in the Italian national health service].

PMID- 12408001
TI  - [Preventive strategies and environmental risks].

PMID- 12408002
TI  - [Prevalence studies on tumors and society epidemiology].

PMID- 12408003
TI  - [Subjective non-specific symptoms related with electromagnetic fields:
      description of 2 cases].
AB  - In Italy, as in other countries, an apparently increasing number of subjects is
      reporting a variety of subjective symptoms that the subjects themselves refer to
      the exposure to electric, magnetic or electromagnetic fields (EMF) from nearby
      electric appliances, cellular phones, antennas, etc. Terms like electricity
      hypersensitivity (EHS), EMF hypersensitivity, or other similar, are frequently
      adopted to describe such symptoms; nevertheless, up to now, these terms are not
      entered the medical terminology. No accepted diagnostic criteria or procedures
      for the diagnosis of EHS are currently available. Furthermore, apart from the
      subject's self-attribution of the symptoms to EMFs, no direct cause-effect
      relationship between EHS symptoms and electromagnetic fields has been proved;
      additionally, evidence of a possible pathogenetic mechanism is lacking. In this
      paper, two cases developing symptoms of EHS ascribed to overhead power line in
      the proximity of their house are discussed. Nervous system (asthenia, depression,
      paraesthesias etc.), cardiovascular system (cardiac palpitations) and the skin
      (tingling, itching, etc.), are mostly (but not exclusively) involved. Based on
      available scientific knowledge, the rationale for an approach to subjects
      claiming for EHS is discussed. The establishment of a National archive for the
      collection of cases is communicated.

PMID- 12408004
TI  - [Estimates of cancer incidence in Tuscany, year 2000. Between method accuracy and
      communication appropriateness].
AB  - This study applies a method for the estimation and temporal projection of cancer
      incidence. The estimates are disaggregated to the Local Health Units; they refer
      to Tuscany for the year 2000 and to the incidence of cancer at three specific
      sites (lung, breast, prostate). The mortality data derive from the Regional
      Mortality Registry and the incidence data from the Tuscan Cancer Registry, which
      includes two provinces: Florence and Prato. The choice of method is discussed and
      a validation of the estimates obtained, using the incidence data observed in the
      province of Prato. The estimates and the temporal projections are required for
      accurate health planning, and they present the means to overcome health planning
      based on the historical data of medical care only. We suggest that appropriate
      communication of these estimates should address their limits, due to the
      uncertainty of the temporal prediction on the one hand and the possibility (only
      partially verifiable) of the violation of the assumptions on which any method for
      the estimation of cancer incidence is based.

PMID- 12408005
TI  - [Evaluation of the capacity of the APR-DRG classification system to predict
      hospital mortality].
AB  - Inpatient mortality has increasingly been used as an hospital outcome measure.
      Comparing mortality rates across hospitals requires adjustment for patient risks
      before making inferences about quality of care based on patient outcomes.
      Therefore it is essential to dispose of well performing severity measures. The
      aim of this study is to evaluate the ability of the All Patient Refined DRG
      system to predict inpatient mortality for congestive heart failure, myocardial
      infarction, pneumonia and ischemic stroke. Administrative records were used in
      this analysis. We used two statistics methods to assess the ability of the APR
      DRG to predict mortality: the area under the receiver operating characteristics
      curve (referred to as the c-statistic) and the Hosmer-Lemeshow test. The database
      for the study included 19,212 discharges for stroke, pneumonia, myocardial
      infarction and congestive heart failure from fifteen hospital participating in
      the Italian APR-DRG Project. A multivariate analysis was performed to predict
      mortality for each condition in study using age, sex and APR-DRG risk mortality
      subclass as independent variables. Inpatient mortality rate ranges from 9.7%
      (pneumonia) to 16.7% (stroke). Model discrimination, calculated using the c
      statistic, was 0.91 for myocardial infarction, 0.68 for stroke, 0.78 for
      pneumonia and 0.71 for congestive heart failure. The model calibration assessed
      using the Hosmer-Leme-show test was quite good. The performance of the APR-DRG
      scheme when used on Italian hospital activity records is similar to that reported
      in literature and it seems to improve by adding age and sex to the model. The APR
      DRG system does not completely capture the effects of these variables. In some
      cases, the better performance might be due to the inclusion of specific
      complications in the risk-of-mortality subclass assignment.

PMID- 12408006
TI  - [Epidemiologic studies on electromagnetic fields: evidence of risk and
      indications for prevention].

PMID- 12408007
TI  - [Will epidemiology succeed in saving the tumor registries?].
AB  - The present paper focuses on the Italian registries: their actual achievements,
      future developments and the possible critical states. The present setting is
      analysed in perspective with the international and European framework of cancer
      registries. Given the recent development of new cancer registries in Italy, and
      their participation to traditional and new international publication of their
      data, there is an increasing delay in publication time, both in Italy and abroad
      International and national institutions played an important role in helping and
      supporting registries' development, but delays in publications and some
      uncertainty in coordinating incidence and survival analyses in a unique framework
      is posing an unavoidable challenge.

PMID- 12408008
TI  - [Estimates of short-term effects of air pollutants in Italy].

PMID- 12408009
TI  - [Methodologic problems in the analysis of competing risks].

PMID- 12408011
TI  - [Data war on the emissions of Radio Vaticana: what people think].

PMID- 12408012
TI  - [The Evidence-Based Prevention initiative in Italy. A project for public health
      reform. Guide to community preventive services].

PMID- 12408010
TI  - [Molecular epidemiology and informed consent].

PMID- 12408022
TI  - [Structure prediction for peptides capable of inducing antibody formation in
      mice].
AB  - A simple method for the sequence prediction of peptides capable of the in vivo
      stimulation of antibody production in mice without conjugation with protein
      carriers was proposed on the basis of literature data on the structure of T
      helper epitopes active in vivo. According to this approach, a potentially active
      peptide should contain a nine-membered sequence with a hydrophobic amino acid
      residue in the first position and a positively charged residue in the ninth
      position. The efficiency of this approach was confirmed by the presence of such
      sequences in the previously described synthetic peptides with immune activities,
      by the application of this approach to the choice of immunogenic fragments within
      the sequences of various proteins that exhibited further the specific activity,
      and by the construction of immunogenic peptides on the basis of inactive natural
      sequences.

PMID- 12408024
TI  - [An analysis of methyltransferase SsoII-DNA contacts in the enzyme-substrate
      complex].
AB  - The functional groups of the DNA methylation site that are involved in the DNA
      interaction with methyltransferase SsoII at the recognition stage were
      identified. The contacts in the enzyme-substrate complex were analyzed in the
      presence of S-adenosyl-L-homocysteine using the interference footprinting assay
      with formic acid, hydrazine, dimethyl sulfate, or N-ethyl-N-nitrosourea as a
      modifying reagent. It was shown that the replacement of the central A.T by the
      G.C pair in the methylation site did not affect the enzyme-DNA interaction,
      whereas the use of a substrate with one chain methylated (monomethylated
      substrate) instead of the unmethylated substrate dramatically changes the DNA
      contacts. The binding constants of unmethylated and monomethylated substrates
      with methyltransferase SsoII in the presence of S-adenosyl-L-homocysteine were
      calculated.

PMID- 12408023
TI  - [Synthesis and antibacterial activity of analogues of the N-terminal fragment of
      the sarcotoxin IA antimicrobial peptide].
AB  - Three 18-membered analogues of the N-terminal fragment of the sarcotoxin IA
      cationic antimicrobial peptide were synthesized by the solid phase method of
      peptide synthesis with the use of swellographic monitoring. The ability of these
      peptides to inhibit the growth of various bacteria in culture medium and their
      hemolytic activity in experiments on human erythrocytes were studied. The
      analogue completely corresponding to the N-terminal amino acid sequence of the
      natural sarcotoxin IA with the amide group on its C-terminus exhibited higher
      antibacterial activity. The presence of carboxyl group on the C-terminus or the
      substitution of Tyr for Trp2 resulted in a decrease in the antimicrobial activity
      of the peptide. Our results indicate that the amphiphilic N-terminal peptide
      corresponding to the 1-18 sequence of sarcotoxin IA involves the moieties
      responsible for the antimicrobial activity of the antibiotic.

PMID- 12408025
TI  - [Mitochondrial H+-ATPase: identification of subunits of the F0 subcomplex
      contacting with membrane lipids].
AB  - The subunits of the F0 membrane sector of bovine heart mitochondrial H(+)-ATPase
      that contact the lipids of the mitochondrial inner membrane were identified with
      the use of specially synthesized proteoliposomes that contained active
      mitochondrial H(+)-ATPase and a photoreactive lipid, which was 1-acyl-2-[12
      (diazocyclopentadiene-2-carbonylamino)-[12-14C]dodecanoyl]-sn- glycero-3
      phosphocholine, 1-acyl-2-[11-([125I]diazoiodocyclopentadiene-2
      carbonyloxy)undecanoyl]-sn- glycero-3-phosphocholine, or 1-acyl-2-[12
      (diazocyclopentadiene-2-carbonylamino)dodecanoyl]-sn-glycero- 3-phosphocholine,
      where acyl is a mixture of the residues of palmitic (70%) and stearic (30%)
      acids. An analysis of the cross-linked products obtained upon the UV-irradiation
      of these proteoliposomes indicated that subunits c and a of the F0 membrane
      sector contact the lipids. The cross-linked products were identified by SDS-PAGE
      and MALDI mass spectrometry.

PMID- 12408027
TI  - [Hydrophobic formate dehydrogenase from Pseudomonas sp. 101 in the system of
      reverse micelles of aerosol OT in octane].
AB  - NAD(+)-dependent formate dehydrogenase (FDH) was hydrophobized with palmitoyl
      chloride to give the samples with various modification degrees (2-10). The native
      and modified FDHs were comparatively studied in the system of reverse micelles of
      Aerosol OT in octane. Like the native, the modified enzyme displayed three maxima
      in the curve of dependence of its catalytic activity on the degree of surfactant
      hydration (the micelle size), which reflect the enzyme functioning in the form of
      a monomer, dimer, or octamer. The peak corresponding to the functioning of the
      FDH dimer was found to decrease along with an increase in the modification
      degree. Thus, the modified enzyme mainly functions in the form of monomer and
      octamer. The modified FDH displayed membranotropy and revealed the dependence of
      catalytic activity on surfactant concentration.

PMID- 12408026
TI  - [Hexameric, trimeric, dimeric, and monomeric forms of inorganic pyrophosphatase
      from Escherichia coli].
AB  - The conditions were found for obtaining trimeric, dimeric, and monomeric forms of
      the Escherichia coli inorganic pyrophosphatase from its native hexameric form.
      Interconversions of the oligomers were studied, and rate constants for their
      dissociation and association were determined. All forms were found to be
      catalytically active, with the activity decreasing in the order: hexamer-trimer
      dimer-monomer. The activity of trimeric and dimeric forms was high enough to
      study and to compare their catalytic properties. The monomeric form of the enzyme
      was unstable.

PMID- 12408028
TI  - [Deletion mutants of human granulocyte-macrophage colony-stimulating factor].
AB  - To study the structure-function relationship of the human granulocyte-macrophage
      colony-stimulating factor (GM-CSF), genes were constructed that encode its three
      deletion mutants: D1, a mutant with the deletion of six amino acid residues (37
      42) some of which are a part of a beta-structural region; D2, a mutant with the
      deletion of the unstructured six-aa sequence of a loop (45-50); and D3, a mutant
      with the deletion of 14 aa residues (37-50) corresponding to the A-B loop and
      encoded by the second exon of the gmcsf gene. The expression products of these
      genes in E. coli were accumulated in a fraction of insoluble proteins. The
      secondary structures of the mutant proteins were similar to that of the full-size
      GM-CSF, but the biological activity of the deletion mutants was 130 times lower
      than that of the GM-CSF: they stimulated the proliferation of the TF-1 cell line
      at 3 ng/ml concentration. The resulting proteins displayed antagonistic
      properties toward the full-size GM-CSF, with the inhibition degree of its colony
      stimulating activity being 27%. A decrease in the mutant activity in the row D2 >
      D1 > D3 implies the importance of the conserved hydrophobic residues involved in
      the formation of the beta-structure for the formation of the GM-CSF functional
      conformation.

PMID- 12408029
TI  - [Theoretical study of antagonists and inhibitors of mammalian adenosine
      deaminase. II. Isomeric aza-deazaanalogues of adenosine].
AB  - Isomeric aza-deazaanalogues of adenosine and their N1-protonated forms (except
      for that of 8-aza-1-deazaadenosine) were studied by computer modeling to find a
      relationship between their molecular structures and the properties as substrates
      for the mammalian adenosine deaminase. The atomic charge distribution and maps of
      the electrostatic potential around their van der Waals molecular surface were
      calculated using the ab initio STO-3G method. The conformational studies were
      carried out by the MM+ method of molecular mechanics. The previously proposed
      mechanism of the substrate acceptance in the active site of mammalian adenosine
      deaminase was refined, and the potential substrate properties were predicted for
      two previously unstudied adenosine analogues, 5-aza-9-deazaadenosine and 8-aza-3
      deazaadenosine.

PMID- 12408030
TI  - [4'-Thio-5-ethyl-2'-deoxyuridine 5'-phosphonates: synthesis and antiviral
      activity].
AB  - A number of new 5'-phosphonate derivatives of 4'-thio-5-ethyl-2'-deoxyuridine
      (TEDU) were synthesized. These compounds displayed a low cytotoxicity and, except
      for TEDU 5'-fluorophosphate, antiherpes activity similar to that of 9-[(2
      hydroxyethoxy)methyl]guanine (acyclovir) and 9-(4-hydroxy-3-hydroxymethylbut-1
      yl)guanine (pencyclovir). 5'-Ethoxycarbonylphosphonate and 5'
      aminocarbonylphosphonate of TEDU were also found to suppress the reproduction of
      herpes simplex type 1 virus, which is resistant to acyclovir.

PMID- 12408031
TI  - [Synthesis of alpha- and beta-glycosyl donors with a disaccharide beta-D-Gal-(1-
      >3)-D-GalNAc backbone].
AB  - The synthesis of thioglycosyl donors with a disaccharide beta-D-Gal-(1-->3)-D
      GalNAc backbone was studied using the glycosylation of a series of suitably
      protected 3-monohydroxy- and 3,4-dihydroxyderivatives of phenyl 2-azido-2-deoxy-1
      thio-alpha- and 1-thio-beta-D-galactopyranosides by galactosyl bromide, fluoride,
      and trichloroacetimidate. In the reaction with the monohydroxylated glycosyl
      acceptor, the process of intermolecular transfer of thiophenyl group from the
      glycosyl acceptor onto the cation formed from the molecule of glycosyl donor
      dominated. When glycosylating 3,4-diol under the same conditions, the product of
      the thiophenyl group transfer dominated or the undesired (1-->4), rather than (1-
      >3)-linked, disaccharide product formed. The aglycone transfer was excluded when
      4-nitrophenylthio group was substituted for phenylthio group in the galactosyl
      acceptor molecule. This led to the target disaccharide, 4-nitrophenyl 2-azido-4,5
      O-benzylidene-2-deoxy-3-O-(2,3,4,6-tetra-O-acetyl-beta-D- galactopyranosyl)-1
      thio-beta-D-galactopyranoside, in 57% yield. This disaccharide product bears
      nonparticipating azide group in position 2 of galactosamine and can hence be used
      to form alpha-glycoside bond. 2-Azide group and the aglycone nitro group were
      simultaneously reduced in this product and then trichloroacetylated, which led to
      the beta-glycosyl donor, 4-trichloroacetamidophenyl 4,6-O-diacetyl-2-deoxy-3-O
      (2,3,4,6-tetra- O-acetyl-beta-D-galactopyranosyl)-1-thio-2-trichloroacetamido
      beta-D- galactopyranoside, in 62% yield. The resulting glycosyl donor was used in
      the synthesis of tetrasaccharide asialo-GM1.

PMID- 12408032
TI  - [1H-NMR analysis of the heteroassociation of caffeine with the antibiotic
      actinocyl-bis(3-dimethylaminopropylamine) in aqueous solution].
AB  - The heteroassociation of caffeine (CAF) and the synthetic antibiotic actinocyl
      bis(3-dimethylaminopropylamine) (ACT) was studied in aqueous solution by one- and
      two-dimensional 1H NMR spectroscopy at 500 MHz. The equilibrium reaction
      constants, thermodynamic parameters (delta H and delta S) of ACT
      heteroassociation with CAF, the limiting values of proton chemical shifts of
      their molecules in the heteroassociation complex, and the spatial structure of
      the ACT-CAF complex were determined from the experimental dependences of proton
      chemical shifts of the aromatic molecules on concentration and temperature. The
      parameters of CAF heteroassociation with the phenoxazone antibiotic actinomycin D
      and its synthetic analogue ACT were comparatively analyzed and conclusions were
      made on the crucial role of stacking interactions of the chromophores of CAF and
      the phenoxazone antibiotics in the formation of the heterocomplexes in aqueous
      solution.

PMID- 12408033
TI  - Why sex, really? To get pregnant, women may need to be 'inoculated' by men first.

PMID- 12408034
TI  - Too much caring. Doubts about advanced ambulance care.

PMID- 12408035
TI  - Under the (virtual) knife.

PMID- 12408036
TI  - Tiny hands talking. Aiming for higher IQs and fewer tantrums, parents are
      teaching 'baby signing' to infants.

PMID- 12408037
TI  - Portrait: Steven Pinker. Nature's son.

PMID- 12408038
TI  - Weight Watchers. When it comes to fat, they're huge.

PMID- 12408039
TI  - Bitter medicine.

PMID- 12408040
TI  - The coming crash in health care.

PMID- 12408041
TI  - Breast cancer fix.

PMID- 12408042
TI  - Stopping cancer in its tracks.

PMID- 12408043
TI  - Hormones of choice.

PMID- 12408044
TI  - B cell anergy and systemic lupus erythematosus.

PMID- 12408045
TI  - BLyS and B cell autoimmunity.

PMID- 12408046
TI  - Apoptosis and B cell tolerance.

PMID- 12408047
TI  - Signaling mutations and autoimmunity.
AB  - Mutations in a number of signaling components in mice can lead to strong
      autoimmune phenotypes. In some cases, these mutations likely compromise important
      feedback inhibitory pathways that downregulate antigen receptor signaling. For
      example, a deficiency of Lyn leads to a severe lupus-like autoimmunity. This
      autoimmunity may result from loss of a feedback inhibitory pathway in which Lyn
      phosphorylates CD22, triggering recruitment of the tyrosine phosphatase SHP-1 to
      the plasma membrane, which then dampens BCR signaling. Loss of Lyn also
      compromises an inhibitory pathway involving Fc gamma RIIb and SHIP, an inositol
      phosphatase. Mutation of Fyn exacerbates the autoimmunity caused by loss of Lyn.
      This may be due in part to a nonimmunological compromise in the integrity of the
      podocytes in the kidney, which may make the kidneys more susceptible to immune
      complex-induced damage. Fyn-deficient mice exhibit a number of immunological
      abnormalities and also exhibit some autoimmunity, although this is less severe
      than what is seen in Lyn-deficient mice. Recently a gain of function mutation in
      CD45 that may enhance activity of Src family tyrosine kinases has also been found
      to cause autoimmune disease, suggesting that the level of Src family tyrosine
      kinase activity is an important determinant of immune tolerance. Finally, several
      studies suggest that there is a significant interaction between Src family
      tyrosine kinases and the Fas pathway that is important for self-tolerance.
      Although these studies are still at an early stage, it seems clear that
      alterations in regulators of antigen receptor signaling can contribute to
      autoimmunity.

PMID- 12408048
TI  - Abnormal B cell signal transduction in systemic lupus erythematosus.

PMID- 12408049
TI  - Toll-like receptors and activation of autoreactive B cells.

PMID- 12408051
TI  - Role of complement in the development of autoimmunity.
AB  - B cell complement receptors have been shown to be important in the generation of
      normal humoral immune responses, and they likely also participate in the
      development of autoimmunity. Complement component and receptor deficiencies have
      been associated with SLE in both animal models and patients with disease. Recent
      data suggest that Cr2 is a lupus susceptibility gene in the NZM2410 mouse model
      for lupus, as it generates complement receptors that are structurally and
      functionally altered. Complement deficiency may result in autoimmune disease
      because of the inability to appropriately clear immune complexes or apoptotic
      cells or by the impaired generation of C3-coated autoantigens for CR1/CR2. In
      turn, CR1/CR2 may participate in the maintenance of B cell tolerance by lowering
      the threshold for negative selection of autoreactive B cells, by targeting
      autoantigen to FDCs in secondary lymphoid organs, or by regulating autoreactive T
      cell function. The effect of CR2 has not been dissected from that of CR1 in the
      animal studies performed to date. Furthermore, the effects of CR1/CR2 dysfunction
      or partial deficiency, which are found in the NZM2410 mouse model and in patients
      with SLE respectively, have not been delineated from those of complete
      deficiency, which has been studied in several animal models of autoimmunity and
      tolerance. Although CR1/CR2 dysfunction or deficiency may confer only a modest
      phenotype in isolation, it is likely that when combined with other disease
      susceptibility genes it will result in a fully penetrant end-stage disease
      phenotype. Understanding the mechanisms by which these receptors participate in
      the maintenance of B cell tolerance will be critical in developing appropriate
      therapeutic interventions for patients with autoimmune diseases such as SLE.

PMID- 12408050
TI  - Affinity maturation and autoimmunity to DNA.

PMID- 12408052
TI  - Rheumatoid factors in health and disease: structure, function, induction and
      regulation.

PMID- 12408053
TI  - Development of VH11+ B cells: a model for selection of B cells producing natural
      autoantibodies.

PMID- 12408054
TI  - The role of B lymphocytes as key antigen-presenting cells in the development of T
      cell-mediated autoimmune type 1 diabetes.

PMID- 12408055
TI  - The chronic graft-versus-host model of systemic autoimmunity.

PMID- 12408056
TI  - Do B cells take advantage of 'missing self' recognition?

PMID- 12408058
TI  - Molecular diagnosis of hereditary hearing impairment.

PMID- 12408057
TI  - Understanding inner ear physiology at the molecular level.

PMID- 12408059
TI  - Developments in cochlear gene therapy.

PMID- 12408060
TI  - Auditory phenotype of DFNA1.

PMID- 12408061
TI  - DFNA2/KCNQ4 and its manifestations.

PMID- 12408062
TI  - DFNA3.

PMID- 12408064
TI  - Clinical presentation of DFNA8-DFNA12.

PMID- 12408063
TI  - Clinical features of DFNA5.

PMID- 12408065
TI  - DFNA9/COCH and its phenotype.

PMID- 12408066
TI  - DFNA10/EYA4--the clinical picture.

PMID- 12408068
TI  - The phenotype of DFNA13/COL11A2.

PMID- 12408067
TI  - Clinical presentation of DFNA11 (MYO7A).

PMID- 12408069
TI  - The clinical presentation of DFNA15/POU4F3.

PMID- 12408070
TI  - Clinical presentation of the DFNA loci where causative genes have not yet been
      cloned. DFNA4, DFNA6/14, DFNA7, DFNA16, DFNA20 and DFNA21.

PMID- 12408071
TI  - Auditory phenotype of DFNA17.

PMID- 12408072
TI  - Clinical presentation of DFNB1.

PMID- 12408073
TI  - The clinical presentation of DFNB2.

PMID- 12408074
TI  - DFNB3, spectrum of MYO15A recessive mutant alleles and an emerging genotype
      phenotype correlation.
AB  - We have now identified seven MYO15A mutations that cause congenital profound
      neurosensory hearing loss and a possible hypomorphic allele of MYO15A associated
      with moderately-severe hearing loss in 1 of 8 SMS patients. Because myosin XVA is
      encoded by 66 exons, screening for mutations in hearing-impaired individuals is
      expensive and labor-intensive in comparison to a screen for mutations in GJB2
      (Cx26), for example, which has only a single protein coding exon. Among
      consanguineous families segregating profound, congenital hearing loss from
      Pakistan, approximately 10% are consistent with linkage to DFNB3 (11 of 112 DFNB
      families). In one-half of these DFNB3 families, we found a homozygous mutation in
      1 of the 66 exons of MYO15A [25]. This suggests that mutations of MYO15A are
      responsible for at least 5% of recessively inherited, profound hearing loss in
      Pakistan. However, without the benefit of a pre-screen for linkage to DFNB3, it
      will be a challenge to determine the extent to which mutations of MYO15A
      contribute to hereditary hearing loss among isolated cases and small families in
      other populations.

PMID- 12408075
TI  - Pendred syndrome redefined. Report of a new family with fluctuating and
      progressive hearing loss.

PMID- 12408076
TI  - DFNB9.

PMID- 12408077
TI  - Clinical presentation of DFNB12 and Usher syndrome type 1D.

PMID- 12408078
TI  - DFNB21.

PMID- 12408079
TI  - Clinical manifestations of DFNB29 deafness.

PMID- 12408081
TI  - Clinical phenotype of DFN2, DFN4 and DFN6.

PMID- 12408080
TI  - X-linked mixed deafness syndrome with congenital fixation of the stapedial
      footplate and perilymphatic gusher (DFN3).

PMID- 12408082
TI  - The clinical spectrum of maternally transmitted hearing loss.

PMID- 12408083
TI  - Hearing impairment in Usher's syndrome.

PMID- 12408084
TI  - The branchio-oto-renal syndrome.

PMID- 12408085
TI  - Clinical features of the Waardenburg syndromes.

PMID- 12408086
TI  - Hearing loss in the Treacher-Collins syndrome.
AB  - About 50% of patients with the TCS have conductive hearing loss, caused by
      characteristic major and/or minor ear anomalies. It is also common for these
      patients to have microtia or severe malformation of the pinna. The results of
      [figure: see text] reconstructive surgery to improve hearing are usually moderate
      to poor, because of combinations of anomalies. In general, it is recommended to
      start hearing rehabilitation at the earliest possible stage. Owing to the above
      described anomalies, rehabilitation usually involves fitting a BAHA, whether or
      not in combination with a pinna epithesis.

PMID- 12408087
TI  - Hearing impairment in Stickler syndrome.

PMID- 12408088
TI  - Genetic modifiers of hereditary hearing loss.

PMID- 12408089
TI  - Genetic evaluation and counseling for congenital deafness.

PMID- 12408090
TI  - Bad breath: a brief update.

PMID- 12408091
TI  - Teeth and Torah: Jewish law and the requirement to wait between eating meat and
      milk.

PMID- 12408092
TI  - Medical police and the history of public health.

PMID- 12408093
TI  - The Lunacy Commissioners and the East London Guardians, 1845-1867.

PMID- 12408094
TI  - 'That senescence itself is an illness': a transitional medical concept of age and
      ageing in the eighteenth century.

PMID- 12408095
TI  - The St Andrews Institute for clinical research: an early experiment in
      collaboration.

PMID- 12408097
TI  - Sick cities: getting the measure of urban public health. Essay review.

PMID- 12408096
TI  - A J E Terzi and L W Sambon: early Italian influences on Patrick Manson's
      "Tropical medicine", entomology, and the art of entomological illustration in
      London.

PMID- 12408098
TI  - AIDS virus lurks in fat cells, French study finds.

PMID- 12408099
TI  - Diaphragm put to test against HIV.

PMID- 12408100
TI  - Lipodystrophy: lack of agreement on definition and etiology presents a challenge
      to research and therapy.

PMID- 12408101
TI  - Case report. Hepatitis B virus and HIV coinfection.
AB  - Coinfection with HIV and hepatitis B virus (HBV) is more common than that with
      HIV and hepatitis C virus (HCV), although more attention has been given to HCV
      coinfection as a result of its higher frequency of chronic disease. Natural
      history studies with HIV-HCV coinfection have also shown more rapid progression
      of liver disease, and end-stage liver disease due to hepatitis C is now a leading
      cause of death in HIV-infected patients. Like HCV infection, HBV infection can
      also be associated with significant morbidity and mortality in patients with HIV
      infection. Fortunately, treatment options of hepatitis B are expanding and may
      have a clinical impact on slowing disease progression. A case study of a patient
      with severe HBV-HIV coinfection is presented to illustrate what is known about
      this increasingly problematic disease state.

PMID- 12408102
TI  - Editorial comment: a tale of two viruses.

PMID- 12408103
TI  - Case report. Severe cutaneous ulceration secondary to cytomegalovirus inclusion
      disease during successful immune reconstitution with HAART.
AB  - Restoration of the immune system following HAART is not without its adverse
      effects. We describe a case of severe cutaneous ulceration secondary to
      cytomegalovirus (CMV) infection in an HIV-1-seropositive man following the
      initiation of HAART in the absence of active CMV retinitis and discuss the likely
      mechanisms associated with its development.

PMID- 12408104
TI  - Activating mutations of the lutropin choriogonadotropin receptor in precocious
      puberty.
AB  - The human receptor for lutropin and chorionic gonadotropin (LHR) is a member of
      the G-protein-coupled receptor superfamily and plays a key role in normal and
      abnormal reproductive physiology. Naturally occurring mutations of the LHR gene
      that lead to hormone-independent signaling are associated with abnormal Leydig
      cell growth and precocious puberty in boys. These mutations affect 13 different
      residues in the LHR, with the majority clustered in the cytoplasmic half of
      transmembrane helix 6. Germline LHR mutations that produce constitutive
      activation of the Gs pathway are found in cases of Leydig cell hyperplasia, while
      a unique somatic LHR mutation capable of activating both the Gs and Gq signaling
      pathways has been identified in Leydig cell tumors. The newly determined crystal
      structure of bovine rhodopsin provides a useful framework for interpreting the
      effects of these disease-associated LHR mutations in the context of conserved
      structural motifs in helix 3 and helix 7 that are known to be involved in
      receptor activation. As with rhodopsin, conformational signaling appears to
      depend on the rearrangement of key electrostatic, hydrogen-bond, and hydrophobic
      interactions that normally serve to stabilize the inactive LHR conformation.

PMID- 12408105
TI  - [Malaria in Milan and the surrounding areas. 1901].

PMID- 12408107
TI  - Safety and stability of nightguard vital bleaching: 9 to 12 years post-treatment.
AB  - PURPOSE: The purposes of this retrospective case series study were to evaluate
      safety issues and determine participants' perceptions of a nightguard vital
      bleaching (NGVB) technique approximately 10 years post-treatment (average, 118
      mo; range, 108-144 mo). MATERIALS AND METHODS: The study sample included 30 (79%)
      of 38 participants who had completed a previous NGVB study using a 10% carbamide
      peroxide solution (Proxigel or Gly-Oxide) in a custom tray for 6 weeks.
      Participants were asked whether there had been any change in the shade of their
      teeth post-treatment and, if so, to quantify the change on a verbal scale. In
      addition, 19 participants had gingival index and tooth vitality evaluated
      clinically, external cervical root anatomy evaluated radiographically, and enamel
      surface changes evaluated microscopically. RESULTS: Thirty-five (92%) of the
      original 38 participants had successful lightening of their teeth. At
      approximately 10 years post-treatment (average, 118 mo; range, 108-144 mo),
      external cervical resorption was not diagnosed and gingival index and tooth
      vitality findings were considered within the normal expectations for the sample
      studied, suggesting minimal clinical post-NGVB side effects at approximately 10
      years. Scanning electron microscopic observations did not reveal substantial
      differences between treated and nontreated surfaces. Color stability, as
      perceived by 43% of the participants, may last approximately 10 years (average,
      118 mo; range, 108-144 mo) post-treatment. CLINICAL SIGNIFICANCE: Nightguard
      vital bleaching using 10% carbamide peroxide is safe and effective, with no
      noticeable side effects, at approximately 10 years (average, 118 mo; range, 108
      144 mo) post-treatment. Color stability, as perceived by 43% of the participants,
      may last 108 to 144 months post-whitening.

PMID- 12408108
TI  - Management of post-anopexy rectal stricture.

PMID- 12408109
TI  - Study involving patients with posterior rectocele.

PMID- 12408110
TI  - Bibliography. Current world literature. Adult and pediatric gynecology.

PMID- 12408111
TI  - Bibliography. Current world literature. Urogynecology.

PMID- 12408112
TI  - Requiem or renaissance for the law reform commission of Canada?
AB  - From 1975 to 1992, the protection of life project of the Law Reform Commission of
      Canada sought to help society answer some of the legal and bioethical riddles
      posed by the biomedical revolution, particularly as these developments affected
      the protection of human life, public safety and fundamental values. A focus on
      the risks, benefits, rights and duties associated with biomedical sciences and
      technology provided the project both a means of inquiry into pressing health law
      and bioethics questions, and a methodology of law reform. The inquiry was often
      applied through a transdisciplinary perspective, to such topics as the
      redefinition of death, medically assisted procreation, behavioral alteration,
      human experimentation, organ transplantation, consent, and the criminal law. Amid
      recent initiatives to resurrect the Commission, the contributions of the
      protection of life project are likely to be judged by the bioethico-legal
      decision-making, dispute resolution, legislative or regulatory enactments and
      court decisions influenced by its corpus of thought.

PMID- 12408113
TI  - Vogt-Koyanagi-Harada syndrome.

PMID- 12408114
TI  - Towards an improved understanding of the international human right to health.

PMID- 12408115
TI  - Human cloning: a success story or a tempest in a petri dish?

PMID- 12408116
TI  - High-sensitivity fluorescence detector fluorescein isothiocyanate derivatives of
      amino acids separated by capillary zone electrophoresis.
AB  - A fluorescence detector has been developed for capillary zone electrophoresis
      that produces a ten-fold improvement in precision compared with the previous
      state-of-the-art in fluorescence detection. This instrument, which is based on a
      sheath-flow cuvette flow chamber and a 0.05-W argon ion laser beam, combines a
      high numerical aperture collection optic, N.A = 0.65, with a high quantum yield
      photomultiplier tube, phi approximately = 0.15 at the wavelength of maximum
      emission. Detection limits (3 sigma) range from the injection of 1.7 . 10(-21)
      mol (1.3 . 10(-12) M) of fluorescein isothiocyanate (FITC)-labeled arginine, the
      best case, to 6 . 10(-21) mol (5.6 . 10(-12) M) of FITC-cysteine, the worse case.
      Signal linearity extends for at least five orders of magnitude from the detection
      limit to greater than 10(-16) mol (10(-7) M) injected.

PMID- 12408117
TI  - Genetic investigation of healthy subjects.

PMID- 12408118
TI  - Parental autonomy and immunisation: a true choice?

PMID- 12408119
TI  - Conflicts of interest in immunisation.

PMID- 12408120
TI  - What is in Maria's best interests?

PMID- 12408121
TI  - Competent patients decide their treatment.

PMID- 12408122
TI  - Retained organs.
AB  - The Retained Organs Commission, set up in April last year in response to the
      Alder Hey scandal, has issued a consultation paper. It seeks views on the use and
      disposal of unclaimed and unidentified organs, and a framework for the regulation
      of all types of collections of human organs and tissues. The following are the
      questions to which the Commission seeks answers, which could equally be the basis
      for some interesting seminars, and the ethical principles and values behind them.
      Responses are needed by 10 June 2002.

PMID- 12408124
TI  - The new genetics: promise or threat to children?
AB  - What will treating children as consumer artefacts, to be changed genetically at
      parental or medical whim, do to our understanding of human existence, of human
      identity, or of intergenerational obligations? These issues are explored in a
      paper based on a lecture given recently at a New Zealand conference.

PMID- 12408123
TI  - Milla en plaque: an unusual localisation.

PMID- 12408125
TI  - Genetics and insurance.
AB  - Both the membership and terms of reference of the Genetics and Insurance
      Committee (GAIC) are under review. The Department of Health is currently seeking
      twelve new members of the committee, as part of its response to a Select
      Committee report last year on the use of genetic tests by the insurance industry.
      This article reproduces the Select Committee's recommendations and some of the
      Government's response, and sets them in context.

PMID- 12408126
TI  - [Studies of the Chinese crude drug "Fangji" (1) herbological studies of name].
AB  - The Japanese Pharmacopoeia standardizes a Chinese crude drug "Bou-i" as the woody
      stem of Sinomenium acutum Rherder et Wilson of the family Menispermaceae. The
      Chinese Pharmacopoeia writes about the same drug under the name of "Fang-ji". The
      present herbological studies resulted in learning that the original written
      character for this drug is in China. The ancient Japanese misread it as "--"
      because of confusion between "--" and "--" in old Chinese herbals. The reason for
      changing "--" to "--" in China is presumed to be because the pronunciation of
      these characters changed in the Yuan dynasty, to "--" from "zi" to "si", and to "
      -" from "ki" to "tsi." That is, the original name "Fang-ji," written in today's
      Chinese phonetic symbols, can be used without big changes by switching the
      character from "--" to "--".

PMID- 12408127
TI  - Ethics and genetics: susceptibility testing in the workplace.
AB  - Genetic testing in the workplace is a technology both full of promise and fraught
      with ethical peril. Though not yet common, it is likely to become increasingly
      so. We survey the key arguments in favour of such testing, along with the most
      significant ethical worries. We further propose a set of pragmatic criteria,
      which, if met, would make it permissible for employers to offer (but not require)
      workplace genetic testing.

PMID- 12408128
TI  - Considering practising geriatric nursing.

PMID- 12408129
TI  - Quality of life: home comforts for lab animals create problems for researchers.

PMID- 12408130
TI  - The patient's revenge.

PMID- 12408131
TI  - Hidden dragon: American biotech has nothing to fear from China's clones.

PMID- 12408132
TI  - The race for a cure: who will benefit from the rapid advances in therapeutic
      cloning?

PMID- 12408133
TI  - Corporate science v the right to know: is the rise of the private sector bringing
      down a cloak of secrecy?

PMID- 12408134
TI  - Gagged and bound.

PMID- 12408135
TI  - Reputations at stake.

PMID- 12408136
TI  - Grave expectations: rumours of a human clone pregnancy spark health fears and
      horrors.

PMID- 12408137
TI  - Vaccine cost-effective, but underused.

PMID- 12408138
TI  - New housing loans.

PMID- 12408139
TI  - Male nurses leaving profession faster than females.

PMID- 12408140
TI  - JCAHO announces 6 patient safety goals.

PMID- 12408141
TI  - Life of Craig: he was so curious about himself, he sequenced his own DNA.

PMID- 12408142
TI  - Because it's there.

PMID- 12408143
TI  - Say hello to the RoboRat.

PMID- 12408145
TI  - Protecting fetuses from certain harm.
AB  - Deborah Mathieu's proposal for state intervention in the lives of pregnant
      substance abusers in order to prevent serious harm to their future children
      sparked a lively debate in this journal. The present discussion characterizes the
      three main arguments offered against her proposal as (a) the "uncertainty
      principle"--the inability to predict which fetuses will be affected, (b) the
      "father factor"--gender bias with respect to prenatal damage, and (c) "critical
      periods"--the vulnerability of the embryo/fetus at different times of pregnancy.
      Each of these arguments is examined in the specific context of fetal alcohol
      syndrome (FAS). Since the birth of a child with FAS is a virtual certainty if a
      woman has previously given birth to a child with FAS, since no father has ever
      sired a child with FAS unless his spouse is an alcoholic, and since the most
      damaging effects are those associated with exposure throughout and especially
      late in pregnancy, none of the arguments offered against Mathieu's proposal are
      relevant in this particularly narrow set of circumstances. While Mathieu's
      proposal seems pertinent in this situation, her proposal would be even more
      effective if modified as suggested here.

PMID- 12408144
TI  - The search for perfection.

PMID- 12408146
TI  - Statement on the health information management work force.

PMID- 12408147
TI  - Ethical debates in genetic engineering: U.S. scientists' attitudes on patenting,
      germ-line research, food labeling, and agri-biotech issues.
AB  - A 1995 survey of 1,257 scientists working in the field of recombinant DNA
      research indicates wide areas of agreement as well as some noteworthy divisions
      when it comes to such thorny questions as patenting, germ-line research, food
      labeling, and biodiversity. In general, the scientists surveyed approve of
      patenting living organisms that result from rDNA research, but vary significantly
      on what should be patentable. They advocate human germ-line therapy, yet have
      reservations about using it for any but serious diseases. They oppose mandatory
      labeling of biologically engineered food products, but understand that the public
      has a right to know and advocate openness. Finally, they favor development of
      threats to biodiversity and maintain that publicly funded researchers should be
      legally obligated to consider the potential environmental effects of their
      research. Some clear differences arise between scientists working in industry and
      those in academia and between men and women.

PMID- 12408148
TI  - Pneumococcal vaccination for cochlear implant recipients.

PMID- 12408149
TI  - Ethical aspects of human tissue banking.

PMID- 12408150
TI  - Agency seeks approval of financial disclosure steps for researchers.

PMID- 12408151
TI  - Protection of human subjects in "third party" experiments.

PMID- 12408152
TI  - Status of "third party" research subjects.

PMID- 12408153
TI  - University failed to have adequate IRB policies and procedures in place.

PMID- 12408155
TI  - U.S health care: limited access?

PMID- 12408154
TI  - Lawsuit says university, hospitals, and researchers caused death of research
      subject.

PMID- 12408157
TI  - Abuse and ACTH response to corticotropin-releasing factor.

PMID- 12408159
TI  - Ethics teaching and learning in pediatric training: development of a curriculum.
AB  - The Royal College of Physicians and Surgeons of Canada has stated that residency
      programs "must provide opportunities for residents to gain an understanding of
      the basic principles of biomedical ethics as it relates to the specialty." This
      article presents the steps taken to develop a curriculum for teaching and
      learning biomedical ethics in Canadian pediatric residency programs, and to
      provide a model for teaching ethics in this context. Using literature reviews,
      and opinion surveys of departmental chairpersons, pediatric residents, and
      practising pediatricians across Canada, we have developed a teachers' handbook to
      help faculty members in teaching ethics. It can also be used as a tool to enhance
      faculty development in ethics. The manual is to be distributed to all pediatric
      training programs throughout Canada in 1997, and its use will be evaluated over
      the subsequent year. It offers a prototype that is adaptable to Royal College
      programs other than pediatrics.

PMID- 12408160
TI  - The cultural context of ethical problems.

PMID- 12408161
TI  - The altruistic medical researcher.

PMID- 12408162
TI  - Pediatricians' experience of ethical dilemmas in practice: implications for
      education.
AB  - OBJECTIVE: To determine Canadian pediatricians' experience with ethical dilemmas,
      to relate this information to proposed curriculum for residency training in
      Canada, and to determine pediatricians' self-assessment of adequacy of training
      in ethical issues and the means used in practice to resolve dilemmas. METHOD: A
      single-pass questionnaire was mailed to all 1,220 pediatrician members of the
      Canadian Pediatric Society. RESULTS: From the 363 questionnaires (30 per cent)
      that were returned, 43 per cent of respondents had received formal ethics
      education in their training. Approximately half of respondents judged their
      training as adequate. Responses confirmed the themes of futile treatment, demands
      for and refusal of treatment by parents, uncertainty regarding withdrawing or
      withholding treatments, conflicts over judgments about the right thing to do, and
      dilemmas regarding the role of the child and adolescent. Respondents relied
      mainly on informal discussion with colleagues to resolve their dilemmas in
      practice. CONCLUSIONS: Core residency and continuing physician education need a
      valid epidemiological description of ethical issues encountered in practice.
      Educational approaches to the development of ethical knowledge, skills, and
      attitudes must be validated as there is a tendency to rely on case precedent and
      peer judgment. Perceived competence in handling ethical issues and dilemmas must
      be tested against accepted standards. Emerging ethical issues such as resource
      allocation, peer review, managed care, and technological and scientific advances
      must be regularly incorporated into both residency education and continuing
      medical education.

PMID- 12408163
TI  - Southern Africa food crises deepens, UN says.

PMID- 12408164
TI  - Celebrating the value of HIM.

PMID- 12408165
TI  - Commentary on Cadaveric-donor organ recovery at a hospital-independent facility.

PMID- 12408166
TI  - The views of adolescents and nurses on the provision of health care in hospitals
      in England.

PMID- 12408167
TI  - [An analysis of the frequency of formulations and crude drugs described in Shan
      Han-Lun].
AB  - A systematic database was constructed to investigate the frequency of reporting
      formulations and crude drugs described in Shang-Han-Lun, a famous formulary in
      traditional Chinese medicine. It contains 112 kinds of genuine formulations, but
      because of overlapping or repetition, the number of formulations total as many as
      430. The best two frequently mentioned in the formulary were Da-cheng-qi-tang and
      Guizhi-tang. Da-cheng-qi-tang, which is Dai-joki-to in Japanese, is a formulation
      composed mainly of Rhizoma Rhei and Cortex Magnoliae used for the treatment of
      interior heat- and excess-syndrome. Guizhi-tang, Keishi-to, contains Radix
      Glycyrrhizae, Ramulus Cinnamoni, and Radix Paeoniae as major crude drugs and is
      used for the treatment of exterior cold- and deficiency-syndrome. It was revealed
      that Shang-Han-Lun explained directions for using 112 formulations prescribed for
      acute febrile diseases and the associated syndromes by revealed clinical cases
      treated with Da-cheng-qi-tang and Guizhi-tang.

PMID- 12408168
TI  - To have and have not.

PMID- 12408169
TI  - Differences in treatment preferences between persons who enrol and do not enrol
      in a clinical trial.
AB  - OBJECTIVE: To quantitatively compare preferences for treatment between persons
      who enrolled in a randomized controlled trial (RCT) and those who were eligible
      but chose not to enrol. INTERVENTIONS: Participants' thresholds for treatment
      were determined using a probability trade-off technique. Pertinent health states
      were described. If not taking Aspirin, the probabilities of stroke, myocardial
      infarction (MI), and major bleeding were given. Given the risks and benefits of
      chronic Aspirin therapy, a systematic approach was used to determine patients'
      thresholds for treatment (the smallest reduction in stroke or MI risk of which
      patients were willing to take Aspirin). RESULTS: Of 54 participants, 42 enrolled
      in the RCT, and 12 did not. Compared with persons who enrolled, those who did not
      enrol required significantly greater increments in treatment benefit to be
      willing to take Aspirin. CONCLUSIONS: This study shows differences in thresholds
      for treatment between persons who enrolled in a clinical trial and those who
      chose not to. Such attitudinal differences may lead to difficulty in the
      interpretation of clinical trials, especially those using health-related quality
      of-life measures. More studies are needed to determine whether the attitudinal
      differences affect the generalization of results from clinical trials.

PMID- 12408170
TI  - The US-Japan Cooperative Medical Science Program Tuberculosis and Leprosy Panel's
      36th Annual Research Conference, New Orleans, Louisiana, USA, 15-17 July 2001.
      Abstracts.

PMID- 12408171
TI  - Challenges of an aging population.
AB  - With the growing number of elderly persons in the developed world, the need for
      adequate health care, and social and financial resources will increase. Health
      and social-service professionals must be aware of the clinical and ethical issues
      involved. As medical advances in the treatment of debilitating conditions such as
      dementia, stroke, Parkinson's disease, depression, and osteoporosis are made, it
      is expected that the elderly will have a greater potential for longer and more
      fulfilling lives. Medical schools must take steps to ensure that all physicians
      understand the issues related to aging so that they can meet the challenges
      ethically, humanely, and respectfully.

PMID- 12408173
TI  - Quiz page. Mesangial lupus nephritis, WHO IIb, and severe acute tubular necrosis,
      secondary to gentamycin toxicity.

PMID- 12408174
TI  - Anal sphincter injury after vaginal delivery in primiparous females.

PMID- 12408175
TI  - Population-based study of factors influencing occurrence and prognosis of local
      recurrence after surgery for rectal cancer.

PMID- 12408176
TI  - Effect of preoperative radiochemotherapy on lymph node retrieval after resection
      of rectal cancer.

PMID- 12408177
TI  - Induction of apoptosis and inhibition of DNA topoisomerase-I in K-562 cells by a
      marine microalgal polysaccharide.

PMID- 12408178
TI  - [A morphological study of the cellular biocompatability of a new bone-matrix
      material in vitro].

PMID- 12408179
TI  - Needs or wants?

PMID- 12408180
TI  - Professional responsibility.

PMID- 12408181
TI  - A heavy disposal.

PMID- 12408182
TI  - Piercing and tooth jewellery.

PMID- 12408183
TI  - Phenylketonuria in adulthood: a collaborative study.
AB  - During 1967-1983, the Maternal and Child Health Division of the Public Health
      Services funded a collaborative study of 211 newborn infants identified on
      newborn screening as having phenylketonuria (PKU). Subsequently, financial
      support was provided by the National Institute of Child Health and Human
      Development (NICHD). The infants were treated with a phenylalanine (Phe)
      restricted diet to age 6 years and then randomized either to continue the diet or
      to discontinue dietary treatment altogether. One hundred and twenty-five of the
      211 children were then followed until 10 years of age. In 1998, NICHD scheduled a
      Consensus Development Conference on Phenylketonuria and initiated a study to
      follow up the participants from the original Collaborative Study to evaluate
      their present medical, nutritional, psychological, and socioeconomic status.
      Fourteen of the original clinics (1967-1983) participated in the Follow-up Study
      effort. Each clinic director was provided with a list of PKU subjects who had
      completed the original study (1967-1983), and was asked to evaluate as many as
      possible using a uniform protocol and data collection forms. In a subset of
      cases, magnetic resonance imaging and spectroscopy (MRI/MRS) were performed to
      study brain Phe concentrations. The medical evaluations revealed that the
      subjects who maintained a phenylalanine-restricted diet reported fewer problems
      than the diet discontinuers, who had an increased rate of eczema, asthma, mental
      disorders, headache, hyperactivity and hypoactivity. Psychological data showed
      that lower intellectual and achievement test scores were associated with dietary
      discontinuation and with higher childhood and adult blood Phe concentrations.
      Abnormal MRI results were associated with higher brain Phe concentrations. Early
      dietary discontinuation for subjects with PKU is associated with poorer outcomes
      not only in intellectual ability, but also in achievement test scores and
      increased rates of medical and behavioural problems.

PMID- 12408184
TI  - Elevated plasma phenylalanine concentrations may adversely affect bone status of
      phenylketonuric mice.
AB  - Children with phenylketonuric (PKU) are at risk for fractures. This study used a
      PKU murine model (PAH(enu-2)) to evaluate effects of moderate dietary protein
      restriction and elevated plasma phenylalanine concentration impact upon bone
      status. Fifty-four male weanling PKU and control mice were assigned to either an
      elemental phenylalanine (Phe)-restricted diet (treated) or Phe-unrestricted diet
      (untreated) with low or normal protein levels for 56 days. Untreated mice and
      control mice received equal amounts of dietary Phe; treated mice consumed
      prescribed dietary Phe to maintain plasma Phe concentrations between 120 and
      480micromol/L. Plasma Phe, osteocalcin, and urine deoxypyridinoline
      (DPD)/creatinine were analysed at baseline and at days 28 and 56. Femur strength,
      bone mineral density (BMD) and bone mineral content (BMC) were analysed at day
      56. Moderate protein restriction did not significantly affect bone status. Mean
      plasma Phe concentrations were significantly greater in untreated vs treated and
      control mice (p < 0.0001). Total body weight was significantly less in untreated
      vs control mice (p < 0.01). Mean femur weight was reduced in untreated mice vs
      both treated and control mice (p < 0.03). Untreated mice had smaller mean femur
      length than control mice (p < 0.002). Femur strength was greater in treated mice
      compared to control mice (p < 0.01) but not compared to untreated mice. No
      significant difference among groups was found in BMD and BMC. At day 56 there was
      a statistical trend (p < 0.056) towards higher urine DPD/creatinine excretion in
      untreated mice than in treated mice. Plasma Phe concentration was positively
      correlated with urine DPD/creatinine. These data suggested that
      hyperphenylalaninaemia may adversely affect bone status in PKU mice.

PMID- 12408185
TI  - Identification of two novel mutations in OCTN2 from two Saudi patients with
      systemic carnitine deficiency.
AB  - Systemic carnitine deficiency (CDSP) (McKusick 212140) is a rare autosomal
      recessive disease caused by defective plasma membrane uptake of carnitine. The
      disease is characterized by Reye syndrome, progressive cardiomyopathy, skeletal
      myopathy, hypoglycaemia and hyperammonaemia. CDSP is a treatable disease provided
      an early diagnosis is made and prompt treatment with L-carnitine is initiated.
      The biochemical diagnosis of the disease is based on the findings of very low
      plasma and tissue carnitine concentrations. Recently, a human gene, SLC22A5,
      encoding a sodium-dependent high-affinity carnitine transporter OCTN2 was cloned
      from human kidney and shown to be mutated in systemic carnitine deficiency. Here
      we report two unrelated Saudi CDSP patients who were detected by tandem mass
      spectrometric analysis (MS/MS) of blood spots. Studies in skin fibroblasts from
      the two patients showed a severely reduced carnitine uptake. Subsequent molecular
      studies led to the identification of two novel missense mutations in the OCTN2
      gene in the two patients.

PMID- 12408186
TI  - Reversible fulminant lactic acidosis and liver failure in an infant with hepatic
      cytochrome-c oxidase deficiency.
AB  - Cytochrome-c oxidase (COX) is the most common respiratory chain complex involved
      in liver failure, either as a single enzyme deficiency or as part of multiple
      enzyme deficiencies. We describe an infant who presented with fulminant lactic
      acidosis in the neonatal period. The lactic acidosis resolved spontaneously but
      liver and pancreatic insufficiency ensued. Isolated cytochrome-c oxidase
      deficiency was found in liver but not in muscle and fibroblasts. mtDNA
      rearrangements or depletion were ruled out. By the age of one year, liver and
      pancreatic functions have normalized completely and neurodevelopment is normal.

PMID- 12408187
TI  - A secondary respiratory chain defect in a patient with Fanconi-Bickel syndrome.
AB  - A North African boy, the son of consanguineous parents, presented at 8 years of
      age with hypophosphataemic rickets due to De Toni-Debre-Fanconi syndrome.
      Hepatomegaly and abnormalities of carbohydrate metabolism were suggestive of
      Fanconi-Bickel syndrome. This was confirmed by the detection of a mutation within
      GLUT2, the gene encoding the liver-type facilitative glucose transporter. The
      study of the respiratory chain revealed a deficiency of complexes I, III and IV
      in muscle. Mechanisms responsible for an impairment ofmitochondrial function,
      which we interpret as a secondary phenomenon, are discussed.

PMID- 12408188
TI  - Identification of novel mutations in the NPC1 gene in German patients with
      Niemann-Pick C disease.
AB  - Niemann-Pick disease type C (NPC) is an inherited neuro-degenerative disorder
      associated with intracellular cholesterol trafficking defects. Mutations in two
      distinct genes, NPC1 and HE1, have recently been shown to cause this disease. We
      have analysed the NPC1 gene in five German patients with NPC from four unrelated
      families. We identified a total of five novel mutations in the coding region of
      the NPC1 gene (G231V, D874V, 1642M, 11094T and R116stop). All affected
      individuals displayed compound heterozygosity. The mutated alleles were
      transmitted by the nonaffected parents with the exception of one patient, in whom
      a de novo mutation (G231V) had occurred. Interestingly, the G231V/P237S NPC1
      genotype in this individual is associated with an early-onset form of NPC. In
      contrast, we found that the D874V/D948N genotype, observed in another NPC
      patient, is characterized by a late onset of clinical symptoms that presents with
      a pronounced white-matter disease. Our results will contribute to defining the
      association between the clinical phenotypes and the genetic abnormalities in
      Niemann-Pick C disease.

PMID- 12408189
TI  - Pamidronate treatment improves bone mineral density in children with Menkes
      disease.
AB  - Menkes disease is a severe multisystem disorder due to defective bioavailability
      and transport of copper at the cellular level. Deficient activity of lysyl
      oxidase, a copper-dependent enzyme, causes defective collagen cross-linking
      leading to osteoporosis and pathological fractures in these children. The
      objective of the study was to evaluate the changes in bone mineral density
      following pamidronate treatment in children with Menkes disease. The study design
      was an open observational study of three children with Menkes disease and
      significant osteoporosis with or without pathological fractures, all of whom
      received pamidronate treatment for 1 year. There were 34-55% and 16-36% increases
      in lumbar spine bone mineral content and areal bone mineral density,
      respectively, following 1 year of treatment with pamidronate. There were no
      further fractures in two of the three children treated. No adverse effects of
      pamidronate treatment were noted. Pamidronate treatment was associated with an
      increase in bone mineral density and may be an effective treatment modality for
      the management of osteoporosis in children with Menkes disease.

PMID- 12408190
TI  - Clinical, enzymatic, and molecular genetic characterization of a biochemical
      variant type of argininosuccinic aciduria: prenatal and postnatal diagnosis in
      five unrelated families.
AB  - A biochemical variant of argininosuccinate lyase deficiency, found in five
      individuals, is introduced. In comparison to classical patients, the variant
      cases of argininosuccinate lyase deficiency were characterized by residual enzyme
      activity as measured by the incorporation of [14C]citrulline into proteins. The
      five patients of different ethnic backgrounds presented with relatively mild
      clinical symptoms, variable age of onset, marked argininosuccinic aciduria and
      severe, but not complete, deficiency of argininosuccinate lyase. [14C]Citrulline
      incorporation into proteins, which is completely blocked in classical
      argininosuccinic aciduria, was only partially reduced in fibroblasts of these
      patients. Further investigation showed that previous standard conditions of the
      assay were not optimal. Higher concentrations of citrulline in the incubation
      medium strongly stimulated 14C incorporation in normal cells, but not in the
      patients; as a result, the relative incorporation level in the patients dropped
      to 6-28% compared to 18-75% of normal in the original procedure. Prenatal
      diagnosis was successfully performed in three of the families. Affected
      pregnancies were indicated by (partial) deficiency of [14C]citrulline
      incorporation in chorionic villi and/or increased levels of argininosuccinate in
      amniotic fluid. Analysis of the ASL gene in the five patients revealed a
      considerable allelic heterogeneity. Three novel mutations--R385C (2 patients),
      V178M and R379C--were detected in homozygous states, whereas one patient was
      compound heterozygous for the known mutations R193Q and Q286R. In conclusion,
      there are patients of different ethnic backgrounds who are characterized by
      residual activity of argininosuccinate lyase and who present with less severe
      clinical courses. In addition, we present an improved biochemical assay for
      accurate prenatal and postnatal diagnosis.

PMID- 12408191
TI  - Cytochrome oxidase deficiency in Lowe syndrome.
AB  - We report on a patient with complex IV deficiency who in later clinical course
      was diagnosed as a Lowe syndrome. Mitochondrial abnormalities can be present in
      Lowe syndrome and might lead to misdiagnosis, additionally because clinical
      features can be overlapping.

PMID- 12408192
TI  - Lipoprotein lipase deficiency and transient diabetes mellitus in a neonate.
AB  - Lipoprotein lipase deficiency (LPLD) represents a rare ( < 1:100000), life
      threatening neonatal condition, and a challenge for dietary management. We
      describe a neonate who developed diabetes mellitus as a feature of LPLD, without
      evidence of pancreatitis.

PMID- 12408193
TI  - A novel FUCA1 mutation causing fucosidosis in a Chinese boy.
AB  - We report a 6-year-old boy with an intermediate form of fucosidosis.

PMID- 12408194
TI  - National efforts to promote behavior-change research: views from the Office of
      Behavioral and Social Sciences Research.

PMID- 12408195
TI  - The Behavior Change Consortium: setting the stage for a new century of health
      behavior-change research.
AB  - The Behavior Change Consortium (BCC), a collective of 15 National Institutes of
      Health-funded behavior-change projects, was conceived with the goal of evaluating
      the efficacy and effectiveness of novel ways of intervening in diverse
      populations to reduce tobacco dependence, and improve physical activity,
      nutrition and other health behaviors. The purpose of this article is to provide a
      general introduction and context to this theme issue by: (1) reviewing the
      promises and challenges of past efforts related to promoting change for three key
      health behaviors; (2) reviewing successful intervention strategies and principles
      of health behavior change; (3) discussing major theoretical approaches for
      obtaining successful behavior change; (4) setting BCC activities within the
      context of recent recommendations for the behavioral and social sciences; and (5)
      providing an organizational framework for describing each of the projects within
      this consortium. In addition to the rich database on behavioral outcomes for
      tobacco dependence, physical activity and diet, the BCC represents a unique
      opportunity to share data and address cross-cutting intervention research issues
      critical for strengthening the field of behavior change research.

PMID- 12408196
TI  - Self-determination, smoking, diet and health.
AB  - A Clinical Trial will test (1) a Self-Determination Theory (SDT) model of
      maintained smoking cessation and diet improvement, and (2) an SDT intervention,
      relative to usual care, for facilitating maintained behavior change and
      decreasing depressive symptoms for those who quit smoking. SDT is the only
      empirically derived theory which emphasizes patient autonomy and has a validated
      measure for each of its constructs, and this is the first trial to evaluate an
      SDT intervention. Adult smokers will be stratified for whether they are at
      National Cholesterol Education Program (1996) recommended goal for low-density
      lipoprotein cholesterol (LDL-C). Those with elevated LDL-C will be studied for
      diet improvement as well as smoking cessation. Six-month interventions involve a
      behavior-change counselor using principles of SDT to facilitate autonomous
      motivation and perceived competence for healthier behaving. Cotinine-validated
      smoking cessation and LDL-C-validated dietary recall of reduced fat intake, as
      well as depressive symptoms, will be assessed at 6 and 18 months. Structural
      equation modeling will test the model for both behaviors within the intervention
      and usual-care conditions.

PMID- 12408197
TI  - The Challenge study: theory-based interventions for smoking and weight loss.
AB  - Both smokers and overweight persons report frequent efforts to change their
      behavior. Long-term success, however, is achieved by few. Interventions are
      needed to improve long-term success in smoking cessation and weight loss. Our
      research program is designed to address this need and to test a novel
      conceptualization of health behavior change that is based on the premise that the
      initiation and the maintenance of behavior change involve different decision
      processes. Positive expectations about the consequences of behavior change are
      thought to guide decisions to initiate behavior change, whereas satisfaction with
      the outcomes afforded by one's behavior guides decisions about maintenance. In
      the first phase of our research program, we are evaluating the effect people's
      expectations about the benefits of behavior change have on immediate and long
      term behavioral outcomes. Specifically, participants are assigned to either an
      'optimistic' treatment condition that emphasizes positive expectations for
      outcomes or a 'balanced' treatment condition that gives equal weight to the
      benefits and costs associated with behavior change. The impact of manipulating
      people's expectations about behavior change will be examined in the areas of
      smoking cessation and weight loss. Results of these studies will advance research
      on health behavior change by informing practical and theoretical understanding of
      the factors that control decisions to initiate a new pattern of behavior and to
      maintain it.

PMID- 12408198
TI  - Design of an intervention addressing multiple levels of influence on dietary and
      activity patterns of low-income, postpartum women.
AB  - Low-income, multi-ethnic women are at elevated risk for obesity and chronic
      diseases, yet influences at different levels may act as barriers to changing risk
      behaviors. Following the birth of a child, childrearing and social isolation can
      exacerbate these influences. The social ecological framework integrates behavior
      change strategies at different levels, providing a strong theoretical base for
      developing interventions in this high-risk population. The primary purpose of
      this randomized controlled trial is to test the efficacy of an educational model
      delivered by community-based paraprofessionals in improving diet, activity and
      weight loss among new mothers over a 12-month postpartum period and a 6-month
      maintenance period. This model fosters institutional change to support behavior
      changes influenced at intrapersonal and interpersonal levels, through
      collaboration with federal programs for low-income families: the Special
      Supplemental Food Program for Women, Infants and Children (WIC), and the Expanded
      Food and Nutrition Education Program (EFNEP). Participants are randomized to the
      Usual Care, e.g. WIC nutrition and breastfeeding education, or Enhanced EFNEP
      intervention arm, consisting of Usual WIC Care plus a sustained, multi-component
      intervention including home visits, group classes and monthly telephone
      counseling. If shown to be efficacious, this program will be readily sustainable
      through existing federal agencies.

PMID- 12408199
TI  - Healthy youth places promoting nutrition and physical activity.
AB  - To reduce the risk for chronic disease, adolescents should eat at least five
      servings of fruit and vegetables and be physically active daily. The Healthy
      Youth Places Project will test if an intervention strategy that implements school
      environmental change--with adult leader and youth participation--will influence
      and maintain adolescent fruit and vegetable consumption and physical activity.
      Using an experimental design, middle schools will be randomized (eight
      intervention and eight control schools), and the health behavior of a cohort of
      adolescents will be assessed during Grades 6 (baseline), 7 and 8 (intervention),
      and 9 (follow-up). The project uses an ecologically informed social cognitive
      model to inform a place-based intervention that encourages participation in the
      process of planning and implemented environmental change in targeted adolescent
      physical and social environments (school lunch place and after school program
      place). Environmental change is defined as implemented practices, programs and
      policies that promote critical elements (connection, autonomy, skill-building and
      healthy norms) in places. These critical elements are hypothesized environmental
      antecedents of social cognitive mediators of behavior change. The Project
      develops a place-based dissemination model of multiple levels (project, school
      and place) that are hypothesized to build the skills and efficacy of leaders
      (school staff and youth) that implement environmental changes.

PMID- 12408200
TI  - The Study of Exercise and Nutrition in Older Rhode Islanders (SENIOR):
      translating theory into research.
AB  - Innovative and effective health promotion interventions targeted on older adults
      within a public health framework will be increasingly important as the US
      population ages dramatically. The benefits of healthier lifestyles for older
      adults include increased functional ability and improved quality of life. The
      Study of Exercise and Nutrition in Older Rhode Islanders (SENIOR) Project is a
      multibehavioral health promotion intervention for community-dwelling older adults
      focusing on increasing exercise and fruit and vegetable consumption. Intervention
      materials are stage-tailored for each individual, and include manuals,
      newsletters, expert system assessments and reports, and telephone coaching. The
      primary purpose of the SENIOR Project is to investigate the relative
      effectiveness of a multiple-behavior intervention-based on a single theoretical
      framework-compared to single-behavior interventions. The secondary purposes are
      to investigate the intervention's effects on both functional ability and general
      health outcomes, and how older adults move along a continuum of changing health
      behaviors. The Transtheoretical Model of Health Behavior Change, the conceptual
      framework for the SENIOR Project, was chosen for the following reasons:
      performance potential with older adults, individual tailoring on a stage basis,
      technological features, and interdisciplinary research base and community
      partnership.

PMID- 12408201
TI  - Healthy Body/Healthy Spirit: a church-based nutrition and physical activity
      intervention.
AB  - African-Americans (AAs) are significantly less likely to be physically active
      than other Americans, and, like all Americans, they consume fewer than the
      recommended five fruit and vegetable (F & V) servings per day. This study, titled
      Healthy Body/Healthy Spirit, has two primary aims: (1) to test the effectiveness
      of a culturally tailored self-help dietary (focusing on F & V intake) and
      physical activity (PA) intervention compared to standard health education
      materials, and (2) to test the effectiveness of using Motivational Interviewing
      (MI), delivered by telephone, to modify PA and dietary habits. The study is a
      randomized effectiveness trial with three experimental conditions. Group 1
      (comparison) will receive standard (existing commercial) nutrition and PA
      intervention materials, Group 2 (TX1) will receive a culturally tailored self
      help nutrition and PA intervention of similar intensity as Group 1, and Group 3
      (TX2) will receive the same intervention as Group 2, plus four telephone
      counseling calls based on MI. Participants will be AA adults recruited through
      local black churches. Despite the extensive use of MI to modify addictive
      behaviors, this represents one of the first controlled field trials to employ MI
      to address diet and PA. Secondly, this is one of the first studies to test the
      effectiveness of a self-help diet and PA intervention tailored for an African
      American church population.

PMID- 12408202
TI  - Enhancing support for health behavior change among women at risk for heart
      disease: the Mediterranean Lifestyle Trial.
AB  - This paper describes a randomized study to evaluate the effects of a
      comprehensive lifestyle management intervention for 279 postmenopausal women with
      type 2 diabetes who are at elevated risk for coronary heart disease (CHD). The
      intervention, called the Mediterranean Lifestyle Trial, is focused on dietary
      factors, physical activity, social support and stress management. The
      Mediterranean Lifestyle Trial relies on a synthesis of Social Cognitive Theory
      and Social Ecologic Theory, as well as goal-systems theory, to explicitly inform
      the lifestyle intervention and to address maintenance. Thus, the trial should
      help illuminate the theoretical mechanisms responsible for lifestyle change.
      Primary outcome variables are dietary, stress management and physical activity
      behavior change, quality of life, and CHD-related biological risk factors.
      Hypothesized mediating variables include self-efficacy, coping, and social and
      environmental support. Following the initial 6-month intervention, participants
      in the intervention condition are randomized to one of two groups designed to
      enhance maintenance of effects: either a peer-led support group or a personalized
      multilevel community resources maintenance condition. Unlike the peer group, the
      personalized approach focuses on multiple levels of community resources to
      promote healthful lifestyle change. Because this research focuses on issues of
      generalization and translation to practice, the RE-AIM evaluation framework is
      being used to evaluate Reach, Effectiveness, Adoption, Implementation and
      Maintenance. This framework will help to translate research into practice by
      directing researchers' attention to important but seldom-investigated strategies
      for enhancing longer-term maintenance. Specifically, the study tests how long
      term maintenance may be improved through the use of existing community resources,
      an intervention based on multiple environmental factors and multiple lifestyle
      behaviors, and lay leaders versus personalized professional support.

PMID- 12408203
TI  - Promoting Healthy Lifestyles: Alternative Models' Effects (PHLAME).
AB  - The Promoting Healthy Lifestyles: Alternative Models' Effects (PHLAME) study
      evaluates the efficacy of two intervention strategies for improving nutrition and
      physical activity practices in fire fighters: a team-centered program and a one
      on-one format targeting the individual. PHLAME compares these two behavior change
      models (the team-based versus the one-on-one approaches) against a usual-care
      control group. As a group, fire fighters have a concentration of the same harmful
      behaviors and health risks commonly afflicting the US population. Fire fighters
      have a unique work structure which is ideal for a team-centered model of behavior
      change. This strategy, based on Social Learning Theory, focuses on a team of fire
      fighters who work together on the same shift. If this team-centered model proves
      successful, it could provide a cost-effective method to impact behavior, and be
      disseminated among fire bureaus and in other team settings. The one-on-one
      intervention incorporates the Transtheoretical Model of behavior change, uses
      Motivational Interviewing for its counseling strategy and could be used in the
      more typical provider-client clinic setting. Findings from PHLAME will provide
      information about the process and outcomes of these models' ability to achieve
      health behavior change.

PMID- 12408204
TI  - Partners for Life: a theoretical approach to developing an intervention for
      cardiac risk reduction.
AB  - Long-term maintenance of behavioral change to reduce health risk factors is
      essential to producing a positive effect on medical outcomes. This study examines
      whether an ongoing, long-term relationship can be used to help patients diagnosed
      with coronary artery disease adhere to a risk-reducing behavioral intervention
      and maintain healthy behavioral changes. One hundred and sixty patients with
      diagnosed coronary artery disease will be randomized to a standard behavioral
      treatment group or to a standard behavioral treatment group including a couples
      intervention and followed for 18 months. The treatment in both groups follows
      tenets of cognitive behavioral and Self-Determination Theories as well as the
      Transtheoretical Model of Behavior Change. In addition, the couples intervention
      is designed to (1) change the patient's environment to facilitate cardiac risk
      reducing behavioral changes, (2) optimize social reinforcement and motivation for
      behavior change, and (3) decrease relationship stress. Behavioral outcomes
      assessed include adherence to an exercise regimen, adherence to dietary
      recommendations and adherence to lipid-lowering medication. Lipid values,
      psychological variables and relationship variables are assessed throughout the
      study and at follow-up. While we expect both groups of cardiac patients to
      successfully adapt new health behaviors, we expect the couples intervention to be
      superior in helping maintain long-term health behaviors.

PMID- 12408205
TI  - Improving health behaviors and outcomes after angioplasty: using economic theory
      to inform intervention.
AB  - Patients who have been relieved of cardiac symptoms following angioplasty may not
      be sufficiently motivated to initiate behavior changes that can reduce risk of
      subsequent cardiac events. Finding an effective means to help patients modify
      their behavior thus presents a unique challenge. This paper describes an
      innovative behavioral intervention whose theoretical underpinning is net-present
      value economic theory. This intervention is being evaluated in a randomized
      controlled trial in which all patients complete a computerized baseline health
      assessment of 14 cardiovascular risk factors. Each patient is presented with an
      individualized risk-factor profile and asked to choose risk factors for
      modification. In the experimental group, each risk factor is presented with a
      corresponding numerical biologic age value that represents the relative potential
      to benefit from modifying each risk factor. Risk reduction for these patients is
      framed as the opportunity to reduce present biologic age (the net-present value),
      and improve current health status and quality of life. In the control group, risk
      reduction is framed in the standard risk-factor approach as the value of
      preventing future health problems. We hope to demonstrate that economic theory is
      a plausible perspective from which to design interventions aimed at communicating
      risk and facilitating change in health behaviors.

PMID- 12408206
TI  - Tailored interventions for multiple risk behaviors.
AB  - The prevention and management of chronic disease necessitates the effective
      treatment of health risk behaviors. Evaluating methods for maximizing change
      among individuals with a combination of these behaviors is an area of continued
      research. The University of Michigan's Health Media Research Laboratory, in
      collaboration with the Henry Ford Health System (HFHS), is testing a computer
      based tailored print material intervention and complementary telecounseling
      intervention among individuals served by the HFHS. Both interventions are
      informed by theoretical constructs, particularly those derived from the
      Transtheoretical Framework and the Health Belief Model. Through a randomized, 2x2
      factorial trial, we intend to determine effectiveness of the two interventions in
      achieving behavior change of three health risk behaviors: cigarette smoking, low
      vegetable consumption and sedentary behavior. Participants with at least two of
      these behavioral risk factors will receive four treatments over an 18-week
      intervention period. Follow-up at 3 and 12 months will assess both short- and
      long-term behavioral effects of the individual and combined treatments against a
      group receiving generic print materials. Through this research, we intend to
      develop a better understanding of how the presence of multiple risk behaviors
      affects the probability of behavior change and to evaluate the joint action of
      these behaviors.

PMID- 12408207
TI  - Harnessing motivational forces in the promotion of physical activity: the
      Community Health Advice by Telephone (CHAT) project.
AB  - Physical inactivity among middle- and older-aged adults is pervasive, and is
      linked with numerous chronic conditions that diminish health and functioning.
      Counselor-directed physical activity programs may enhance extrinsic motivation
      (reflected in social influence theories, such as self-presentation theory) and,
      in turn, physical activity adherence, while the counselor is in charge of program
      delivery. However, external influences can undermine intrinsic motivation, making
      it more difficult to maintain physical activity once counselor-initiated contact
      ends. In contrast, programs that diminish the socially evaluative and controlling
      aspects of the counseling interchange may promote intrinsic motivation (described
      in cognitive evaluation theory), and, thus, physical activity maintenance, even
      when counselor-initiated contact ceases. The objective of the Community Health
      Advice by Telephone (CHAT) project is to compare these two theories by conducting
      a randomized controlled trial evaluating the effects of a telephone-administered
      counseling program delivered by a person (social influence enhancement) or
      computer (cognitive evaluation enhancement) on physical activity adoption and
      maintenance over 18 months. Healthy, sedentary adults (n = 225) aged 55 years and
      older are randomized to one of these programs or to a control arm. This study
      will contribute to advancing motivational theory as well as provide information
      on the sustained effectiveness of interventions with substantial public health
      applicability.

PMID- 12408208
TI  - Health Opportunities with Physical Exercise (HOPE): social contextual
      interventions to reduce sedentary behavior in urban settings.
AB  - Physical activity interventions targeting social and physical environments of the
      urban poor hold promise in improving health outcomes in underserved communities.
      This study randomly assigned overweight, sedentary, economically disadvantaged
      adults to one of three intervention conditions at The Hope and Healing Center, a
      large inner-city health facility providing numerous options for exercise. Within
      the tenets of Social Action Theory, the Health Opportunities with Physical
      Exercise (HOPE) trial will test the efficacy of two behavior change models,
      social support and patient-provider interaction, to increase physical activity.
      In addition to a standard care condition, in which patients have open access to
      Hope and Healing physical activity programming, patients were assigned to one of
      two behavior change interventions. Those assigned to patient-peer receive face-to
      face, systematic and scheduled encouragement from study-trained 'peer'
      interventionists at the facility. Patients assigned to patient-provider receive
      face-to-face, systematic and scheduled encouragement provided by study-trained
      'provider' interventionists also at the facility. The primary outcomes of change
      in exercise behavior will be documented by self-reported physical activity and
      confirmed by fitness testing at baseline, 6, 12 and 24 months during the 1 year
      of active intervention and 1 year of relapse prevention follow-up. Intervention
      conditions will be compared on psychosocial mediators including motivational
      appraisals, ratings of social support, rapport, problem solving and self-efficacy
      for overcoming barriers to increased physical activity. Novel aspects of this
      intervention include: (1) delivery of socially based physical activity
      interventions to an economically disadvantaged urban population, (2) reduction of
      environmental barriers to be physically active and (3) emphasis on social
      interactions influencing health habit change. Results of this study have the
      potential to identify mechanisms of behavior change that could be adopted by
      physical activity interventions aimed at reducing sedentary behavior and health
      disparities in high-risk, underserved populations.

PMID- 12408209
TI  - Evaluating the components of the Exercise Plus Program: rationale, theory and
      implementation.
AB  - Recovery following a hip fracture is facilitated by participation in regular
      exercise. Despite the benefits of exercise, it is difficult to get older adults
      to initiate and adhere to regular exercise programs. The Attribution Theory of
      Achievement Motivation suggests that an individual's future involvement in an
      activity is based on assessments of prior experience with the activity.
      Conversely, the Theory of Self-efficacy states that self-efficacy expectations
      and outcome expectations are not only influenced by behavior, but also by verbal
      encouragement, physiological sensations and exposure to role models or self
      modeling. These expectations then determine the individual's willingness to
      initiate and engage in a given activity. Using a 2x2 factorial design, the
      primary aim of this study is to compare these two theories. The effectiveness of
      the Exercise Plus Program will be compared to the individual components of the
      program (Exercise Training and Plus components) on both self-efficacy and outcome
      expectations, exercise behavior, activity, and specific physical and
      psychological outcomes. A total of 240 older women post hip fracture will be
      recruited from five different acute care facilities. This study will add to
      current knowledge by examining the impact of a combined exercise training/social
      learning intervention approach versus either alone.

PMID- 12408210
TI  - Motivating parents of kids with asthma to quit smoking: the PAQS project.
AB  - The Parents of Asthmatics Quit Smoking (PAQS) project contrasts two theory-based
      smoking cessation interventions for parents of children with asthma, and compares
      mechanisms of behavior change within and across theoretical perspectives. We
      hypothesize that enhancing the perception of risk to self and child will motivate
      smoking cessation more than standard approaches that emphasize building self
      efficacy and coping skills for quitting in a population that is largely not
      motivated to quit smoking. Smokers (n = 288) and their asthmatic children who
      receive nurse-delivered in-home asthma education (as part of the insurance
      carrier's standard of care) are randomized into one of two treatment conditions:
      (1) the Behavioral Action Model (BAM), in which nurses emphasize goal setting and
      skill building to enhance self-efficacy to quit smoking, or 2) the Precaution
      Adoption Model (PAM), in which nurses tailor the intervention to the smoker's
      readiness to quit and incorporate biomarker feedback [i.e. level of carbon
      monoxide exposure to the smoker and level of environmental tobacco smoke (ETS)
      exposure to the child] in order to increase risk perception in smokers. In both
      conditions, smokers who are ready to quit receive the nicotine patch. Analyses
      will examine (1) quit rates, ETS level and motivation to quit as the primary
      dependent variables, (2) mediators of behavior change between and within
      conditions, and (3) relations between parent smoking outcomes and child asthma
      morbidity (i.e. ER visits and asthma symptoms) post-treatment. Results will help
      tailor interventions to this population, and identify mechanisms of behavior
      change that result in adaptive health outcomes for smokers and their children who
      have asthma.

PMID- 12408211
TI  - Theory-comparison and multiple-behavior research: common themes advancing health
      behavior research.
AB  - Research that seeks to compare and contrast theories of behavior change and
      assess the utility of a particular theoretical model for changing two or more
      health-related behaviors is critical to advancing health behavior research.
      Theory-comparison can help us learn more about the processes by which people
      change and maintain health behaviors than does study of any single theory alone
      and thus has the potential to better guide the development of intervention.
      Multiple-behavior interventions promise to have much greater impact on public
      health than single-behavior interventions. However, theory-comparison and
      multiple-behavior research presents several emerging challenges. These include
      finding new ways to enhance recruitment and retention, especially among diverse
      populations; improving treatment fidelity; developing common metrics across
      behaviors that can be used to advance the measurement and assessment of
      behavioral change; and expanding the reach and translation of intervention
      approaches that have demonstrated efficacy. This paper discusses the rationale
      for conducting theory-comparison and multiple-behavior research and presents
      several common themes that have emerged from the work of the National Institutes
      of Health Behavior Change Consortium (BCC). The activities of each BCC workgroup
      and the potential contribution of each to these common themes to advance health
      behavior research are also described.

PMID- 12408212
TI  - The peer review process (aka peer reviewology).

PMID- 12408213
TI  - Changes in nutritional status and postoperative outcomes in elderly CABG
      patients.
AB  - OBJECTIVES: To systematically examine the pattern of nutritional status over time
      in older people undergoing elective coronary artery bypass grafting (CABG) and
      the extent to which nutritional status affects health outcomes postdischarge.
      DESIGN: The sample consisted of 91 community-dwelling English-speaking persons >
      or = 65 (72.27 +/- 4.85) years of age with normal cognitive function and no
      active cancer. Data collected prospectively at 3 time points (preoperatively,
      postoperatively on day 5, and 4 to 6 weeks postdischarge) included serum albumin,
      transferrin, and calculated Body Mass Index (BMI). The Short-Form 36 Health
      Status Survey Questionnaire was administered 4 to 6 weeks postdischarge as a
      primary health outcome measure. RESULTS: Nutritional status changed over time.
      For albumin and transferrin, the pattern of change corresponded to the phases of
      surgical stress (P = 0.001). The BMI decreased from preoperative to 4 to 6 weeks
      postdischarge (P = 0.001), and this decrease explained 13.8% of the variance in
      physical health 4 to 6 weeks postdischarge (P = 0.008). The change in the BMI
      corresponds to an average weight loss of 5% from preoperative to postdischarge.
      CONCLUSIONS: Older people undergoing CABG who lose significant weight from
      preoperative to postdischarge are more likely to have lower self-reported
      physical health.

PMID- 12408214
TI  - The physiological response in patients with acute myocardial infarction to the
      administration of psychological instruments.
AB  - The administration of psychologically provocative research instruments could
      serve as a transient source of stress and spuriously affect results. To determine
      whether the administration of selected psychosocial instruments activates the
      stress response, we examined the physiological stress response of stable patients
      post-myocardial infarction (MI) to completing the Beck Depression Inventory, the
      Illness Perception Questionnaire, and the Spielberger State Anxiety Inventory 24
      to 48 hours post-acute event. Salivary cortisol, heart rate variability (HRV),
      heart rate, and mean arterial pressure (MAP) were measured prior to instrument
      administration and 30 minutes after as indicators of the stress response. Twenty
      four subjects (16 men) completed the study. Mean baseline measures of salivary
      cortisol (0.558 mcg/dL), heart rate (86 bpm), and MAP (86 mm Hg) were within
      normal ranges. A repeated-measures analysis of variance demonstrated no
      significant difference in salivary cortisol, F(1, 23) = 2.59, NS; HRV, F(1, 18) =
      0.27, NS; heart rate, F(1, 23) = 4.29, NS; or MAP, F(1, 22) = 0.859, NS, from
      preinterview to postinterview. These results suggest that completing these
      selected psychological instruments in thefirst 24 to 48 hoursfollowing MI was not
      a stressful event, at least for those who were stable post-percutaneous
      transluminal coronary angioplasty.

PMID- 12408215
TI  - Stress hormones: how do they measure up?
AB  - Stress as a stimulus is integral to dynamic homeostatic functioning. However,
      evidence of its potentially deleterious effects on health is mounting. The
      impetus to understand the mechanisms that underlie stress-related negative health
      outcomes and prevent the development of stress-related disorders has never been
      greater. Symptom severity and subjective levels of stress, although frequently
      assessed in studies of stress in nursing research, may not provide adequate data
      to fully understand the pervasive effects of chronic or overwhelming stress
      associated with stress disorders. The measurement of stress hormones such as
      cortisol can help identify bodily changes that are stressor specific, people at
      risk for development of stress-related disorders, and the efficacy of
      interventions aimed at stress reduction. Cortisol, as the peripheral output of
      one of the major stress response systems, possesses several properties that make
      its measurement highly useful for investigations of stress. This article
      discusses some of the biological mechanisms involved in the stress response, why
      cortisol is commonly measured, and issues and approaches in cortisol measurement.

PMID- 12408216
TI  - The effect of therapeutic touch on agitated behavior and cortisol in persons with
      Alzheimer's disease.
AB  - Agitated behavior in persons with Alzheimer's disease (AD) presents a challenge
      to current interventions. Recent developments in neuroendocrinology suggest that
      changes in the hypothalamic-pituitary-adrenal (HPA) axis alter the responses of
      persons with AD to stress. Given the deleterious effects of pharmacological
      interventions in this vulnerable population, it is essential to explore
      noninvasive treatments for their potential to decrease a hyperresponsiveness to
      stress and indirectly decrease detrimental cortisol levels. This within-subject,
      interrupted time-series study was conducted to test the efficacy of therapeutic
      touch on decreasing the frequency of agitated behavior and salivary and urine
      cortisol levels in persons with AD. Ten subjects who were 71 to 84 years old and
      resided in a special care unit were observed every 20 minutes for 10 hours a day,
      were monitored 24 hours a day for physical activity, and had samples for salivary
      and urine cortisol taken daily. The study occurred in 4 phases: 1) baseline (4
      days), 2) treatment (therapeutic touch for 5 to 7 minutes 2 times a day for 3
      days), 3) posttreatment (11 days), and 4) post- "wash-out" (3 days). An analysis
      of variance for repeated measures indicated a significant decrease in overall
      agitated behavior and in 2 specific behaviors, vocalization and pacing or
      walking, during treatment and posttreatment. A decreasing trend over time was
      notedfor salivary and urine cortisol. Although this study does not provide direct
      clinical evidence to support dysregulation in the HPA axis, it does suggest that
      environmental and behavioral interventions such as therapeutic touch have the
      potential to decrease vocalization and pacing, 2 prevalent behaviors, and may
      mitigate cortisol levels in persons with AD.

PMID- 12408217
TI  - Major histocompatibility complex (MHC) tetramer technology: an evaluation.
AB  - Single-cell assays are currently favored to quantitate T-cell responses. Staining
      antigen-specific T-cells with fluorescently labeled tetrameric major
      histocompatibility complex (MHC)/peptide complexes has greatly enhanced the
      ability to assess the cellular dynamics of an immune response at the single-cell
      level. This article reviews MHC tetramer technology, defining it, discussing how
      MHC tetramers are made, outlining the benefits of this technology, comparing and
      contrasting it to other methods for evaluating immune responses, and describing
      current applications.

PMID- 12408219
TI  - New strategies for treating ear infections in children.

PMID- 12408218
TI  - A critical reexamination of the morphology, neurovasculature, and fiber
      architecture of knee extensor muscles in animal models and humans.
AB  - The purposes of the present study were to resolve a number of major
      inconsistencies found in the literature on the structure of the quadriceps
      femoris muscle and to extend knowledge of its structure using descriptive,
      qualitative methodology. The quadriceps femoris muscle was investigated in 41
      cats, and the findings were confirmed in 6 human cadavers. Two aponeuroses with
      major biomechanical functions (rectus-vastus and vastus aponeurosis), neither of
      which had been previously described in the literature, were characterized in both
      species. The study also resolved many major inconsistencies in the literature:
      The muscle sometimes described as vastus intermedius (VI) was found to be the
      articularis genu, the muscle sometimes described as vastus medialis (VM) was
      found to be the VI, the rectus femoris head was found to have an additional
      proximal nerve branch not previously recognized, no anomalous 5th head was
      everfound, and the distal VM were not found to have 2 heads (in either cats or
      humans). The authors' anatomical descriptions and bimechanical models of the
      muscles, tendons, and neurovascular should provide a helpful foundation for
      future studies on the quadriceps. Two general recommendations are made: 1) that
      the feline model be considered a viable model to elucidate human knee
      pathomechanics; and 2) that regardless of the anatomical structure of interest,
      orthopedic nurses, orthopedic surgeons, and research investigators should
      routinely use the research literature for anatomical guidance instead of standard
      anatomical textbooks.

PMID- 12408220
TI  - Strategies for decreasing multidrug antibiotic resistance: role of ototopical
      agents for treatment of middle ear infections.
AB  - Change in the susceptibility of bacterial pathogens to antimicrobial agents is
      constant. The efficacy of a new drug may change as it is used in clinical
      settings, and resistant bacterial clones result from the encounter of drug and
      organism. Soon after the introduction of the sulfonamides in the mid-1930s, the
      first effective agents of the antimicrobial era, resistance of pneumococci and
      group A streptococci was evident. In each of the following decades, a different
      problem in multidrug resistance occurred among common bacterial pathogens: beta
      lactamase-producing staphylococci in the 1950s; highly resistant gram-negative
      enteric bacteria in the 1960s; beta-lactamase-producing Haemophilus influenzae
      and Moraxella catarrhalis in the 1970s; and multidrug-resistant pneumococci in
      the 1980s. Antimicrobial resistance among respiratory pathogens is now a common
      clinical problem throughout the world, and its management is a part of routine
      office practice. Currently in the United States, about 25% of pneumococci are
      resistant to penicillin, and 25% of H influenzae and 90% of M catarrhalis produce
      beta-lactamase and would be inactivated by organisms producing the enzyme. The
      emergence of penicillin and multidrug-resistant pneumococci and beta-lactamase
      producing strains of H influenzae and M catarrhalis have special importance for
      the management of infections of the middle ear. The widespread use of oral and
      parenteral antimicrobial drugs for appropriate and inappropriate uses has driven
      the emergence and spread of resistant organisms. This article discusses current
      susceptibility patterns of organisms involved in middle ear infections, risk
      factors associated with development of resistant strains, strategies for limiting
      the incidence and spread of resistant organisms and, as part of the strategy, use
      of ototopical rather than systemic antimicrobial drugs for chronic suppurative
      otitis media (CSOM) and acute otitis media (AOM) in children with tympanostomy
      tubes. Although many ototopical agents are approved by the Food and Drug
      Administration for the indication of otitis externa, only ofloxacin otic is
      approved for treatment of CSOM in patients older than 12 years of age and AOM in
      children with tympanostomy tubes who are 1 year of age or older.

PMID- 12408221
TI  - Ototopical agents in the treatment of the draining ear.
AB  - Otorrhea is the result of several pathologic conditions of the ear, including
      bacterial, fungal, and viral acute external otitis (AOE), acute otitis media with
      perforation (AOM), posttympanostomy tube otorrhea (PTTO), and chronic suppurative
      otitis media (CSOM). The significant differences among these conditions
      necessitate a thorough knowledge of the pathogenesis of each prior to the
      selection of a treatment regimen likely to succeed. Consideration must be given
      to the accelerating process of antimicrobial resistance, rising concern over
      ototoxicity, and limits on the resources available for healthcare in general.
      This article reviews the pathophysiology of AOE, AOM, PTTO, and CSOM and proposes
      treatment options that demonstrate the value of ototopical therapy as the first
      line treatment option for AOE, PTTO, and CSOM with consideration given to
      efficacy as well as cost effectiveness. The growing concern with ototoxicity and
      resultant recent litigation issues are also discussed.

PMID- 12408222
TI  - Asymmetric growth of models of avascular solid tumours: exploiting symmetries.
AB  - In this paper a mathematical model of avascular tumour growth is studied.
      Attention focuses on the stability of radially symmetric model solutions to
      perturbations involving spherical harmonics Ylm (theta, phi). Linear theory is
      used to identify bifurcation points at which the radially symmetric steady state
      loses stability. The first modes to become unstable are shown to correspond to
      the l = 2 spherical harmonics. Results from group theory and weakly nonlinear
      analysis indicate the structure of the l = 2 bifurcation point is a transcritical
      bifurcation in which all nontrivial solution branches are unstable. By proceeding
      to third order and focusing on a special set of parameter values for which the
      quadratic terms are negligible, it is shown that the system's behaviour in a
      neighbourhood of the l = 2 bifurcation point is governed by a subcritical
      bifurcation. In consequence, the nontrivial asymmetric solution branches in a
      neighbourhood of the bifurcation point are unstable. The branches of asymmetric
      solutions bound the domain of attraction of the radially symmetric tumour
      configuration where it is locally stable. The analytical results that are derived
      lead us to conjecture that any stable asymmetric tumour structures will involve
      spherical harmonics of order l > or = 3.

PMID- 12408223
TI  - Fluid flow in the anterior chamber of a human eye.
AB  - A simple model is presented to analyse fluid flow in the anterior chamber of a
      human eye. It is shown that under normal conditions such flow inevitably occurs.
      The flow, whose reduced Reynolds number is small, is viscosity dominated and is
      driven by buoyancy effects which are present because of the temperature
      difference between the front and back of the anterior chamber. In cases of severe
      eye trauma or as a result of certain diseases and medical conditions, particulate
      matter may be introduced into the anterior chamber. The motion and distribution
      of such particles is analysed and it is shown that the model is capable of
      predicting well-established and observed features that may be present in a
      traumatized eye such as hyphemas, keratic precipitates, hypopyons and Krukenberg
      spindles.

PMID- 12408224
TI  - Modelling the transmission dynamics of Ross River virus in Southwestern
      Australia.
AB  - During the 1995-1996 Australian financial year, over 1300 notifications of Ross
      River (RR) virus disease were notified in humans from Southwestern Australia. Due
      to the mild symptoms of the disease, it is difficult to diagnose and subclinical
      infections are common. However, these subclinical infections do give rise to
      immunity. For planning and control, it is important for public health authorities
      to estimate the true number of people who have contracted the disease and to
      assess the impact of key epidemiological parameters. A mathematical model was
      developed to describe the transmission of RR virus between its hosts (humans and
      kangaroos) and its vectors (mosquitoes). For this model, the threshold conditions
      and relative removal rates were calculated and interpreted. Finally, a computer
      program was written to simulate the model in order to estimate the total number,
      both clinical and sub clinical human infections given known and hypothetical
      epidemiological parameter values. Within this simulation sensitivity of the
      results to changes in the parameters were examined. The analysis of the threshold
      conditions conformed well to established principles of arboviral transmission and
      control. It was observed that conditions which can prevent an outbreak occuring
      include reducing the number of susceptibles in host and vector populations,
      reducing the infection rates between hosts and vectors and shortening the
      duration of viraemia. Results on the sensitivity analysis showed that some
      parameters such as the extrinsic incubation period, mosquito mortality rate in
      winter and the proportion of Western Grey Kangaroos in the marsupial population
      have little effect on human incidence. However, the transmission rate between
      hosts and vectors, vector-mortality rate in summer and the proportion of
      infectious vectors among infected vectors have pronounced effects. The simulation
      results on the ratio of clinical to subclinical human infections predicted a
      minimum ratio of 1:2 and a maximum ratio of 1:65, which is consistent with data
      obtained during previous sero-epidemiological studies.

PMID- 12408225
TI  - Neuropathology and neuroimaging--two solitudes, or two sides of the same coin?

PMID- 12408226
TI  - Excitatory amino acid transporter EAAT-2 in tangle-bearing neurons in Alzheimer's
      disease.
AB  - The excitatory amino acid transporter EAAT-2 is physiologically expressed in
      astrocytes. This study demonstrates that distinct subclasses of neurons exhibited
      EAAT-2 immunoreactivity in cases with Alzheimer's disease (AD). EAAT-2 was
      identified in the following types of neurons: Cortical pyramidal cells, fascia
      dentata granule cells, neurons of the basal nucleus of Meynert, the substantia
      nigra, the paraventricular nucleus of the hypothalamus, oral and central raphe
      nuclei, locus coeruleus, parabrachial nucleus, and neurons of the reticular
      formation of the brain stem. All EAAT-2-positive neurons displayed cytoskeletal
      abnormalities with abnormal tau-protein and often showed condensed and shrunken
      nuclei. None of the control cases without AD-related pathology showed EAAT-2
      immunoreactive neurons. These results indicate that AD-related neurodegeneration
      is associated with the expression of the glutamate transporter EAAT-2 in altered
      neurons. Since an aberrant expression of EAAT-1 in neurons has recently been
      described, the finding of a neuronal expression of EAAT-2 strongly supports the
      hypothesis that abnormalities in glutamate transport play an important role in
      the pathogenesis of AD.

PMID- 12408227
TI  - Vitamin D and its analog EB1089 induce p27 accumulation and diminish association
      of p27 with Skp2 independent of PTEN in pituitary corticotroph cells.
AB  - Disruption of the gene for the cyclin dependent kinase inhibitor (CDKI) p27/kip1
      results in pituitary corticotroph hyperplasia while diminished expression of this
      protein has been described in aggressive human pituitary tumors. We have
      previously shown that 1,25-vitamin D3 (VD) hypophosphorylates p27 and interferes
      with the degradation of this CDKI in thyroid carcinoma cells. In this study we
      investigated whether VD/EB1089 can induce p27 accumulation and cause growth
      arrest of pituitary corticotroph cells. VD and EB1089 exhibited a significant
      reduction in AtT20 corticotroph but not PRL235 lactotroph cell growth. These
      changes were accompanied by selective accumulation of p27 in AtT20 but not in
      PRL235 cells. As p27 levels are highly dependent on protein degradation, we
      examined the effect of VD/EB1089 on p27 association with factors that target this
      CDKI to the proteasome. VD/EB1089 significantly restricted the association of p27
      with Skp2 as well as with cyclin dependent kinase 2 (CDK2). As the tumor
      suppressor and phosphatase PTEN has been implicated in p27 regulation, we tested
      whether the effects of VD/EB1089 on p27 accumulation in corticotrophs could be
      mediated through this pathway. VD/EB1089 did not appreciably alter PTEN
      expression. Moreover, transfection of PTEN did not influence the effect of VD on
      p27 accumulation in corticotrophs. We conclude that VD/EB1089 can selectively
      arrest pituitary corticotroph growth and induce p27 accumulation.This effect is
      mediated at least partially through diminished p27 association with Skp2 and with
      CDK2. In contrast to other cell systems, PTEN does not participate in the
      regulation of corticotroph p27 and is not involved in mediating the effect of VD
      on p27 in these cells. Our findings highlight p27 and VD analogs as targets for
      manipulation and drug development respectively in the treatment of inoperable
      corticotroph adenomas.

PMID- 12408228
TI  - The critical role of IL-12p40 in initiating, enhancing, and perpetuating
      pathogenic events in murine experimental autoimmune neuritis.
AB  - Interleukin 12 (IL-12) is a proinflammatory cytokine with important
      immunoregulatory activities and is critical in determining the differentiation
      and generation of Th1 cells. For the present study, we investigated the role of
      endogenous IL-12 in the pathogenesis of experimental autoimmune neuritis (EAN),
      which is a CD4+ T-cell mediated autoimmune inflammatory disease of the peripheral
      nervous system. EAN is used as an animal model for Guillain-Barre syndrome of
      humans. Here, EAN was established in IL-12 p40 deficient mutant (IL-12-/-)
      C57BL/6 mice by immunization with P0 peptide 180-199, a purified component of
      peripheral nerve myelin, and Freund's complete adjuvant. In these IL-12-/- mice
      the onset of clinical disease was delayed, and the incidence and severity of EAN
      were significantly reduced compared to that in wild-type mice.The former group's
      clinical manifestations were associated with less P0-peptide 180-199 induced
      secretion of interferon-gamma (IFN-gamma) by splenocytes in vitro and low
      production of anti-P0-peptide 180-199 IgG2b antibodies in serum. Fewer IFN-gamma
      and TNF-alpha producing cells, but more cells secreting IL-4, were found in
      sciatic nerve sections from IL-12-/- mice, consistent with impaired Th1 functions
      and response. However, the IL-12 deficiency appeared not to affect P0 peptide 180
      199-specific T-cell proliferation. These results indicate that IL-12 has a major
      role in the initiation, enhancement and perpetuation of pathogenic events in EAN
      by promoting a Th1 cell-mediated immune response and suppressing the Th2
      response. This information augments consideration of IL-12 as a therapeutic
      target in Guillain-Barre syndrome and other T-cell-mediated autoimmune diseases.

PMID- 12408229
TI  - Caspase-cleaved amyloid precursor protein in Alzheimer's disease.
AB  - Caspase-3 mediated cleavage of the amyloid precursor protein (APP) has been
      proposed as a putative mechanism underlying amyloidosis and neuronal cell death
      in Alzheimer's disease (AD). We utilized an antibody that selectively recognizes
      the neo epitope generated by caspase-3 mediated cleavage of APP (alphadeltaC(csp)
      APP) to determine if this proteolytic event occurs in senile plaques in the
      inferior frontal gyrus and superior temporal gyrus of autopsied AD and age
      matched control brains. Consistent with a role for caspase-3 activation in AD
      pathology, alphadeltaC(csp)-APP immunoreactivity colocalized with a subset of
      TUNEL-positive pyramidal neurons in AD brains. AlphadeltaC(csp)-APP
      immunoreactivity was found in neurons and glial cells, as well as in small- and
      medium-size particulate elements, resembling dystrophic terminals and condensed
      nuclei, respectively, in AD and age-matched control brains. There were a larger
      number of alphadeltaC(csp)-APP immunoreactive elements in the inferior frontal
      gyrus and superior temporal gyrus of subjects with AD pathology than age-matched
      controls. AlphadeltaC(csp)-APP immunoreactivity in small and medium size
      particulate elements were the main component colocalized with 30% of senile
      plaques in the inferior frontal gyrus and superior temporal gyrus of AD brains.
      In some control brains, alphadeltaC(csp)-APP immunoreactivity appeared to be
      associated with a clinical history of metabolic encephalopathy. Our results
      suggest that apoptosis contributes to cell death resulting from amyloidosis and
      plaque deposition in AD.

PMID- 12408230
TI  - Human brain parenchymal microglia express CD14 and CD45 and are productively
      infected by HIV-1 in HIV-1 encephalitis.
AB  - Microglia are endogenous brain macrophages that show distinct phenotypes such as
      expression of myeloid antigens, ramified morphology, and presence within the
      neural parenchyma. They play significant roles in a number of human CNS diseases
      including AIDS dementia. Together with monocyte-derived (perivascular)
      macrophages, microglia represent a major target of HIV-1 infection. However, a
      recent report challenged this notion based on findings in SIV encephalitis. This
      study concluded that perivascular macrophages can be distinguished from
      parenchymal microglial cells by their expression of CD14 and CD45, and that
      macrophages, but not microglia, are productively infected in SIV and HIV
      encephalitis. To address whether parenchymal microglia are productively infected
      in HIV encephalitis, we analyzed expression of CD14, CD45 and HIV-1 p24 in human
      brain. Microglia were identified based on their characteristic ramified
      morphology and location in the neural parenchyma. We found that parenchymal
      microglia are CD14+ (activated), CD45+ (resting and activated), and constitute
      approximately two thirds of the p24+ cells in HIV encephalitis cases. These
      results demonstrate that microglia are major targets of infection by HIV-1, and
      delineate possible differences between HIVE and SIVE. Because productively
      infected tissue macrophages serve as the major viral reservoir, these findings
      have important implications for AIDS.

PMID- 12408231
TI  - Collagen XVIII: a novel heparan sulfate proteoglycan associated with vascular
      amyloid depositions and senile plaques in Alzheimer's disease brains.
AB  - Heparan sulfate proteoglycans (HSPGs) may play a role in the formation and
      persistence of senile plaques and neurofibrillary tangles in Alzheimer's disease
      brains. Recently, it has been demonstrated that the human extracellular matrix
      associated molecule collagen XVIII is the first collagen carrying heparan sulfate
      side-chains. Two variants of collagen XVIII with both different signal peptides
      and N-terminal domains have been described and are referred to as the short and
      long form. To investigate the distribution of these variants we performed an
      immunohistochemical analysis by using specific well-characterized polyclonal
      antibodies. Anti-long huXVIII, a polyclonal antibody directed against the long
      variant of collagen XVIII, weakly stained large cortical and leptomeningeal
      vessels, whereas small cortical vessels remained unstained. Interestingly, all
      amyloid-laden vessels and classic senile plaques were strongly stained. Anti-all
      huXVIII, a polyclonal antibody directed against an epitope common to both
      collagen XVIII variants, intensely stained all types of cerebral blood vessels,
      cerebral amyloid angiopathy-affected vessels and classic senile plaques. Collagen
      XVIII expression was absent in neurofibrillary tangles. We conclude that collagen
      XVIII is a novel heparan sulfate proteoglycan associated with vascular A beta and
      classic senile plaques and that at least the long form of collagen XVIII
      accumulates in amyloid-laden vessels and classic senile plaques.

PMID- 12408232
TI  - Oligodendrocyte progenitor cells in the adult rat CNS express myelin
      oligodendrocyte glycoprotein (MOG).
AB  - While the effects of high dose X-irradiation on mitotically active progenitor
      cells and remyelination are well-documented, its effects on myelinating
      oligodendrocytes are less clear, due in part to divergent views on their mitotic
      capacity. To examine the effect of X-irradiation on oligodendrocytes, the spinal
      cord of rats was exposed to 40 Gy of X-irradiation and the number of
      oligodendrocytes and oligodendrocyte progenitors in the dorsal funiculi at T12
      and L1 was determined by in situ hybridization using cRNA-probes for platelet
      derived growth factor alpha receptor (PDGFRalpha) (to identify oligodendrocyte
      progenitors), exon 3b of proteolipid protein (PLP) (to identify mature
      oligodendrocytes) and myelin oligodendrocyte glycoprotein (MOG). X-irradiation
      resulted in no change in the number of PLP positive cells and no loss of myelin
      internodes, but caused an almost complete loss of PDGFRalpha-expressing cells,
      and a reduction in the number of MOG positive cells to a number similar to that
      found using the PLP exon 3b probe. Importantly, the number of radiation-sensitive
      MOG-expressing cells was similar to the number of PDGFRalpha positive cells. To
      determine if the radiation-sensitive MOG positive cells were the same population
      as the radiation sensitive PDGFRalpha-expressing cells, MOG and PDGFRalpha
      expressing cells were isolated from the adult CNS using antibody coated magnetic
      beads. Twelve to thirteen percent of MOG positive cells were PDGFRalpha positive
      and nearly all the PDGFRa isolated cells were MOG and galactocerebroside
      positive. Double immunofluorescence revealed colocalization of NG2 and MOG on
      cells in the normal adult rat spinal cord. These results show that in situ in the
      adult rat spinal cord white matter oligodendrocyte progenitors are MOG positive
      and indicates that expression of MOG cannot be regarded a marker that only
      identifies mature myelin-supporting oligodendrocytes in tissue.

PMID- 12408233
TI  - Introduction: A coming of age for molecular neurotoxicology.

PMID- 12408234
TI  - Astrocyte modulation of neurotoxic injury.
AB  - Astrocytes produce trophic factors, regulate neurotransmitter and ion
      concentrations, and remove toxins and debris from the extracellular space of the
      CNS, maintaining an extracellular milieu that is optimally suited for neuronal
      function. Consequently, astrocytic functional impairments, as well as
      physiological reactions of astrocytes to injury have the potential to induce
      and/or exacerbate neuronal dysfunction. This mini-review showcases contemporary
      evidence provoking reformulation of concepts of the inter-dependence between
      astrocytes and neurons and advances several mechanisms used by astrocytes in
      potentiating or nullifying the final pathway of neuropathologic injury. Though
      clearly possessing an array of protective systems and upregulating a large number
      of protective molecules in response to xenobiotic exposure, recent evidence also
      invokes astrocytes in secondary amplification of cell injury in multiple
      neurodegenerative disorders.

PMID- 12408235
TI  - The mammalian striatum and neurotoxic injury.

PMID- 12408236
TI  - Drug-induced apoptotic neurodegeneration in the developing brain.
AB  - Physiological cell death (PCD), a process by which redundant or unsuccessful
      neurons are deleted by apoptosis (cell suicide) from the developing central
      nervous system, has been recognized as a natural phenomenon for many years.
      Whether environmental factors can interact with PCD mechanisms to increase the
      number of neurons undergoing PCD, thereby converting this natural phenomenon into
      a pathological process, is an interesting question for which new answers are just
      now becoming available. In a series of recent studies we have shown that 2 major
      classes of drugs (those that block NMDA glutamate receptors and those that
      promote GABAA receptor activation), when administered to immature rodents during
      the period of synaptogenesis, trigger widespread apoptotic neurodegeneration
      throughout the developing brain. In addition, we have found that ethanol, which
      has both NMDA antagonist and GABAmimetic properties, triggers a robust pattern of
      apoptotic neurodegeneration, thereby deleting large numbers of neurons from many
      different regions of the developing brain. These findings provide a more likely
      explanation than has heretofore been available for the reduced brain mass and
      lifelong neurobehavioral disturbances associated with the human fetal alcohol
      syndrome (FAS). The period of synaptogenesis, also known as the brain growth
      spurt period, occurs in different species at different times relative to birth.
      In rats and mice it is a postnatal event, but in humans it extends from the sixth
      month of gestation to several years after birth. Thus, there is a period in pre-
      and postnatal human development, lasting for several years, during which immature
      CNS neurons are prone to commit suicide if exposed to intoxicating concentrations
      of drugs with NMDA antagonist or GABAmimetic properties. These findings are
      important, not only because of their relevance to the FAS, but because there are
      many agents in the human environment, other than ethanol, that have NMDA
      antagonist or GABAmimetic properties. Such agents include drugs that may be
      abused by pregnant mothers (ethanol, phencyclidine [angel dust], ketamine
      [Special K], nitrous oxide [laughing gas], barbiturates, benzodiazepines), and
      many medicinals used in obstetric and pediatric neurology (anticonvulsants), and
      anesthesiology (all general anesthetics are either NMDA antagonists or
      GABAmimetics).

PMID- 12408237
TI  - Mechanistic approaches to Parkinson's disease pathogenesis.
AB  - Parkinson's disease (PD) is a progressive neurological disorder marked by
      nigrostriatal dopaminergic degeneration and development of cytoplasmic
      proteinaceous aggregates known as Lewy bodies. Although the pathogenic mechanisms
      responsible for PD are not completely understood, many clues have come from
      biochemical, epidemiological, and genetic studies. Mutations in certain genes
      found in rare, familial cases of PD, such as alpha-synuclein and parkin, suggest
      a role for the ubiquitin-proteosome system and aberrant protein aggregation.
      Biochemical analyses have implicated mitochondrial dysfunction in PD.
      Epidemiological and animal model studies point to a role for environmental
      toxins, some of which are mitochondrial inhibitors. Mitochondrial dysfunction,
      resulting from either genetic defects, environmental exposures or an interaction
      between the two, may cause alpha-synuclein aggregation or neurodegeneration
      through oxidative stress or excitotoxicity. A better understanding of the
      mechanisms underlying PD should reveal novel therapeutic targets.

PMID- 12408238
TI  - The 12th International Symposium on ALS/MND: scientific advancements in
      amyotrophic lateral sclerosis. November 18-20, 2001, Oakland, Calif.

PMID- 12408239
TI  - April 2002: 35-year-old healthy man with enlarging right parotid mass.
AB  - The April 2002 Case of the Month (COM). 35-year-old healthy man developed a mass
      in the right parotid gland. A superifical parotidectomy was performed for a 4.5 x
      1.5 x 1.5 cm mass involving the intraparotid facial nerve. Grossly the tumor was
      multinodular, smooth and yellow with normal surrounding salivary gland.
      Microscopically, the tumor showed expanding nodules composed of proliferating
      fibroblasts, Schwann cells, and perineural-like cells in a myxoid stroma. Normal
      peripheral nerve twigs were identified in the periphery of the tumor. There was
      no increased mitotic activity, cellularity or nuclear pleomorphism. S-100
      immunohistochemical stain was positive. The tumor was diagnosed as a solitary
      plexiform neurofibroma. Plexiform neurofibromas in this area have been described
      in children with von Recklinghausen's disease or neurofibromatosis 1 (NF 1).
      Plexiform neurofibromas typically involve deep seated nerve trunks and is
      considered pathognomonic for NF 1. This unusual case represents a solitary
      variant of plexiform neurofibroma presenting as a parotid mass in an adult
      patient without a personal stigmata or family history of NF 1.

PMID- 12408240
TI  - May 2002: 38-year-old man and 69-year-old woman with dural based masses.
AB  - The May 2002 COM. A 38-year-old man presented with new onset seizures and a 69
      year-old woman presented with bilateral headaches and episodes of syncope. Both
      were found to have extra-axial masses that were contrast-enhancing and thought to
      be meningiomas. Both had complete resection. Microscopic examination revealed an
      inflammatory lesion composed of plasma cells, scattered lymphocytes and numerous
      large histocytic cells, which exhibited emperi polesis and were CD1 a negative,
      but positive for CD68 and S100. The diagnosis of Destombes-Rosai-Dorfman Disease
      (DRDD) was rendered. Both cases had good long-term outcome. The differential
      diagnosis of inflammatory masses in the dura (plasmacytoma, lymphomas, plasma
      cell fibroma, angiofollicular hyperplasia [Castleman's-disease] and Langerhan's
      cell histiocytosis) are discussed.

PMID- 12408241
TI  - June 2002: 57-year-old male with leptomeningeal and liver tumors.
AB  - The June 2002 COM. A male patient presented at the age of 57 years with a benign
      meningeal melanocytoma. Eight years later, the patient had a local recurrence of
      the tumor, cerebral metastases and liver metastases. This demonstrates that a
      correct diagnosis of melanocytic CNS tumors remains a challenge together with
      elucidating predictive markers for biological behavior. To the best of our
      knowledge, this is the first case of a melanocytoma associated with hepatic
      metastasis.

PMID- 12408242
TI  - What we do not know about juvenile sexual reoffense risk.
AB  - States have increasingly subject juvenile sexual offenders to sex offender
      registration and commitment under sexual predator laws in recent years. These
      statutes assume that sexual offenders present a sustained risk to recommit
      sexually violent crimes over an extended time period. Implicit in this assumption
      is that criminal sexual behavior is a product of some form of stable trait or
      condition that continues to push the juvenile toward sexually violent behaviors
      as they get older. This article examines these assumptions in light of the
      available research on the stability of sexually offending behavior in juveniles.
      The difficulties attendant to applying adult offender risk assessment models to
      juvenile sexual offenders are addressed. The available evidence indicates that
      the development and persistence of sexually criminal behavior is poorly
      understood, making the prediction of sustained sexual offending in juveniles that
      is required by some sexual predator statutes a particularly difficult task.

PMID- 12408243
TI  - Emotional abuse in children: variations in legal definitions and rates across the
      United States.
AB  - Child emotional abuse has an intangible quality that has resulted in confusion
      regarding both medical and legal definitions. This retrospective review of
      emotional, physical, sexual abuse, and neglect rates reported by the National
      Center for Child Abuse and Neglect Data System revealed a 300-fold variation in
      the rate of emotional abuse across state boundaries. By contrast, the rates of
      physical and sexual abuses, which are much easier to define, were significantly
      more consistent. To better understand the potential reasons for the unique
      variability of emotional abuse, an analysis of sociodemographic factors was
      performed and no correlations were found. However, a systematic review of state
      laws on child emotional abuse revealed that states having inclusive civil and/or
      inclusive caretaker culpability statutes were more likely to report higher rates
      of child emotional abuse. This study supports a need for child maltreatment
      researchers and advocates to develop clear consensus definitions to aid the legal
      community in adopting uniform inclusive statutes to protect children from
      emotional abuse.

PMID- 12408244
TI  - A comparison of two forms of hearsay in child sexual abuse cases.
AB  - The present study was designed to compare two forms of hearsay: videotaped
      hearsay and hearsay supplied by an adult witness. In elaborately staged, mock
      child sexual abuse trials, jurors were presented with (a) videotaped forensic
      interviews of children who, in actual legal cases, disclosed abuse or (b) a
      police officer who repeated the children's videotaped statements. In addition, a
      subset of jurors who viewed the videotape during trial were allowed access to the
      videotape during deliberations. Findings indicated that manner of presentation of
      children's testimony had an indirect effect on verdicts. Jurors in the videotape
      conditions were more likely to believe that the child fully disclosed during the
      forensic interview, which in turn influenced ratings of child believability. The
      latter ratings were the strongest predictor of defendant-guilt judgments.

PMID- 12408245
TI  - Intracranial hemorrhage and rebleeding in suspected victims of abusive head
      trauma: addressing the forensic controversies.
AB  - Does an expanded subarachnoid space predispose to subdural bleeding? What does
      heterogeneity in the appearance of a subdural collection on CT or MRI imaging
      indicate? Spontaneous rebleeding? Minor re-injury? Major re-injury? In some
      specific cases, answers to these questions have important forensic implications.
      To conclude objectively that an infant's intracranial hemorrhage or rebleeding
      resulted from inflicted injury or re-injury requires an in-depth understanding of
      the pathogenesis of posttraumatic subdural and subarachnoid collections. The
      authors present two cases of indoor, accidental, pediatric, closed-head trauma
      that resulted in intracranial rebleeding. Both accidental cranial impacts
      occurred in medical settings and were independently witnessed by medical
      personnel. In addition, the authors summarize the relevant medical literature
      regarding pediatric intracranial bleeding and rebleeding.

PMID- 12408246
TI  - The co-occurrence of child maltreatment and domestic violence: examining both
      neglect and child physical abuse.
AB  - Research supports a substantial overlap between domestic violence and child
      maltreatment. However, few studies examine the characteristics of families in
      which both domestic violence and child maltreatment are present, with most
      studies exploring only child physical abuse. This study examined differences in
      demographic characteristics, parental problems, and maltreatment characteristics
      for families involving physical abuse or neglect and woman battering compared to
      families with the same type of maltreatment but no known woman battering present.
      Descriptive analyses found more differences between families with domestic
      violence and neglect and neglect-only than between co-occurring physical abuse
      and physical abuse-only families. Analyses looking at the association or
      interaction between the type of maltreatment and presence of domestic violence
      found a significant association between marital status, father's biological
      relationship to the child, mother-as-perpetrator, and age of the children with co
      occurrence of domestic violence for neglect but not for physical abuse.

PMID- 12408248
TI  - A comparison of abusive and nonabusive mothers of abused children.
AB  - A majority of the approximately 240,000 children in this country who were
      physically maltreated in 1997 live with their mothers, regardless of whether
      their mothers committed the abuse. This study compared service use and
      functioning at intake for families of physically abused children as a function of
      the mother's offender status. Analyses found few differences in the initial
      functioning and subsequent services received by abusive and nonabusive mothers
      and their children. Abusive mothers did receive fewer services overall and were
      significantly less likely to receive individual parent services as compared to
      nonabusive mothers. This was true, despite abusive mothers receiving less
      positive parent ratings by their children at intake as compared to nonabusive
      mothers. Results from this study highlight the similarities among abusive
      families, whether or not the mother perpetrated the abuse. Future research should
      include abusive families in the control group to have the greatest impact on
      developing effective identification and prevention programs. These results also
      emphasize the importance of collecting data from multiple informants. The only
      significant difference in maternal functioning was found on a child-completed
      rating. Mothers involved in child protective services may be less likely to
      reveal negative information about their own functioning.

PMID- 12408247
TI  - The neglect scale: confirmatory factor analyses in a low-income sample.
AB  - The Neglect Scale is an easy-to-administer, retrospective, self-report measure of
      neglect. Research conducted by Straus and colleagues with college students
      indicates that this scale has a high level of internal consistency reliability
      and moderate construct validity. The purpose of this article is to examine the
      reliability and validity of the Neglect Scale when used with a low-income, inner
      city sample. The sample included 151 women who were participating in a neglect
      prevention demonstration project. The Neglect Scale was completed as part of a
      computer-administered baseline interview before services were provided. To assess
      whether the 20-item, four-factor structure reported by Straus et al. fit the data
      from this sample, a confirmatory factor analysis was performed; the model did not
      fit the data well. Additional analyses identified a model that did fit the data
      well and suggest that the Neglect Scale is a promising self-report measure.

PMID- 12408249
TI  - Factors that facilitate or impede physicians who perform evaluations for child
      maltreatment.
AB  - Physicians are needed to evaluate children for the possibility of maltreatment.
      In many communities, physicians are reluctant to evaluate children who may have
      been maltreated. Because it is unclear which factors facilitate and impede
      physicians' involvement in evaluations for child maltreatment, physicians were
      surveyed to identify these factors. The biggest obstacles identified were the
      time involved in doing an evaluation, scheduling cases, and problems dealing with
      the legal, judicial, and social service systems. Medical information, training,
      and follow-up about the disposition of cases would help physicians who
      participate in evaluations. Interventions that enhance communication and training
      across disciplines could also be effective in increasing physician involvement in
      child abuse evaluations.

PMID- 12408250
TI  - Congenital complete atrioventricular block. A pace in time saves lives (?).

PMID- 12408251
TI  - Long-term follow up of children with congenital complete atrioventricular block
      and the impact of pacemaker therapy.
AB  - AIMS: This study assessed survival, morbidity and impact of pacemaker (PM)
      therapy in children with Congenital Complete Atrioventricular Block (CCAVB).
      METHODS AND RESULTS: Data of 32 children, diagnosed as showing CCAVB at a median
      age of 0.4 years (range foetal-10 years), were retrospectively analysed. For
      comparison of clinical data patients were separated into two groups: CCAVB
      without structural heart disease (group 1; n = 23) and with structural heart
      disease (group 2; n = 9). Median follow-up time was 10.2 years. Pacemakers (PM)
      were implanted in 17 group 1 and all group 2 children. Frequency of PM therapy,
      age and symptoms before PM implantation did not differ significantly between the
      groups. Indications for PM implantation were bradycardia in 15, decreased
      exercise tolerance in 6, syncope in 3 and heart failure in 2 children. PM system
      related complications occurred in 11/26 (42%) children. Although 1 child died due
      to PM exit block no further CCAVB related symptoms were recorded in children with
      PM. CONCLUSION: PM therapy reduces mortality and morbidity in children with CCAVB
      when compared with natural history data. Although children with PM are free from
      CCAVB related symptoms limited morbidity remains due to PM system related
      complications.

PMID- 12408252
TI  - The application of a standardized strategy of evaluation in patients with syncope
      referred to three syncope units.
AB  - BACKGROUND: The appropriate diagnostic work-up of patients with syncope is not
      well defined. We applied the guidelines of Italian 'Associazione Nazionale Medici
      Cardiologi Ospedalieri' to a group of consecutive patients with syncope referred
      to three Syncope Units. The aim of the study was to evaluate the applicability of
      those guidelines in the 'real world' and their impact on the use of the tests.
      METHODS: We evaluated 308 consecutive patients with syncope (mean age 61 +/- 20
      years; median of three syncopal episodes per patient). The hierarchy and
      appropriateness of diagnostic tests and the definitions of the final diagnosis
      followed standardized predefined criteria. In brief, all patients underwent
      initial evaluation consisting of history, physical examination, supine and
      upright blood pressure measurement and standard electrocardiogram (ECG) (only in
      patients > 45 years or with history of heart disease). Any subsequent
      investigations were based on the findings of the initial evaluation. Priority was
      given to cardiological tests (prolonged ECG monitoring, exercise test,
      electrophysiological study), or to neurally mediated tests (carotid sinus
      massage, tilt test, ATP test), or to neuro-psychiatric tests, as appropriate.
      FINDINGS: The initial evaluation alone was diagnostic in 72 patients (23%). One
      further test was necessary for diagnosis in 65 patients (21%), > or = 2 tests in
      64 (21%) and > or = 3 tests in 50 (16%). The diagnostic yield was 10% for ECG, 3%
      for echocardiogram, 16% for Holter, 5% for exercise test, 27% for
      electrophysiological study, 57% for carotid sinus massage, 52% for tilt testing
      and 15% for ATP test. At the end of the work-up the mechanism of syncope remained
      unexplained in 57 patients (18%). CONCLUSIONS: When standardized criteria based
      on the appropriateness of indications are used, few simple tests are usually
      needed for diagnosis of syncope.

PMID- 12408253
TI  - A standardized conventional evaluation of the mechanism of syncope in patients
      with bundle branch block.
AB  - BACKGROUND: The finding of bundle branch block in patients with syncope suggests
      that paroxysmal AV block may be the cause of syncope, even though its prevalence
      is unknown. METHODS: We evaluated 55 consecutive patients with syncope and bundle
      branch block (mean age 75 +/- 8 years; median of two syncopal episodes per
      patient) referred to three Syncope Units. The hierarchy and appropriateness of
      diagnostic tests and the definitions of the final diagnoses followed standardized
      predefined criteria. RESULTS: Cardiac syncope was diagnosed in 25 patients (45%):
      AV block in 20, sick sinus syndrome in 2, sustained ventricular tachycardia in 1,
      aortic stenosis in 2. Neurally mediated syncope was diagnosed in 22 (40%):
      carotid sinus syndrome in 5, tilt-induced syncope in 15, adenosine-sensitive
      syncope in 2. Syncope remained unexplained in 8 (15%). CONCLUSIONS: Less than
      half of the patients with bundle branch block have a final diagnosis of cardiac
      syncope; in these patients, paroxysmal AV block is the most frequent but not the
      only mechanism supposed.

PMID- 12408254
TI  - How reproducible is the cardioinhibitory response to carotid sinus massage in
      fallers?
AB  - AIMS: To ascertain the reproducibility of the cardioinhibitory subtype of carotid
      sinus hypersensitivity (CICSH) in fallers. METHODS AND RESULTS: One hundred and
      seventy-five subjects with CICSH and unexplained or recurrent falls were
      randomized to pacemaker implantation or control. Sixty-four control subjects (61%
      female, mean age 71.8 years, median 2 falls in the previous year) completed one
      year follow-up and had carotid sinus massage (CSM) performed on 4 occasions
      (twice before randomization, at 6 months and 1 year following randomization). CSM
      was performed sequentially on the right and then left sides, initially supine and
      then upright at 70 degrees head-up tilt by the same investigator. On each
      occasion CSM was discontinued once CICSH was demonstrated. CICSH was demonstrated
      on 82% of occasions, 75% on right CSM and 77% whilst the subject was supine.
      Before randomization, and at 6 months and 1 year, 91%, 67%, and 70% of subjects
      had reproducible CICSH respectively. Half had CICSH on all 4 occasions. Only 17%
      had a consistent response on the same side in the same position. CONCLUSIONS: In
      the majority of subjects CICSH is reproducible and this is more likely shortly
      after the initial response. However the cardioinhibitory response to CSM is
      inconsistent both in side elicited and subject position.

PMID- 12408255
TI  - Reproducibility of asystole during head-up tilt testing in patients with neurally
      mediated syncope.
AB  - Tilt induced prolonged asystole has been considered to identify a distinct
      subgroup of patients with neurally mediated syncope and management including
      permanent pacemaker implantation has been suggested. To evaluate the
      reproducibility of asystolic response during head-up tilt testing (HUT), 33
      patients with neurally mediated syncope and asystolic response (> or = 3 seconds)
      during HUT prospectively underwent two consecutive tests 13 +/- 15 days apart. On
      repeat tilt testing asystole was reproduced in 12 patients (36%), while 8
      patients still had a positive HUT, but without asystole. Remarkably, 13 patients
      (40%) had a negative repeat HUT. Among 12 patients with asystole on both HUTs
      there was no significant difference in duration of asystole (14 371 +/- 11 430 ms
      vs 13 707 +/- 10 470 ms, P = ns) and time to syncope (36 +/- 20 min vs 37 +/- 20
      min, P = ns) during initial and repeat HUTs. In conclusion, asystole during tilt
      testing does not seem to be a reproducible response.

PMID- 12408256
TI  - Comparative study of cerebral blood flow between postural tachycardia and
      neurocardiogenic syncope, during head-up tilt test.
AB  - We assessed the cerebral blood flow velocity response to head-up tilt test in
      patients with typical neurocardiogenic syncope compared with patients showing
      postural tachycardia. Fifty patients (21 men) with history of orthostatic
      intolerance, younger than 50 years (mean 27 +/- 10), participated in the study.
      Transcranial Doppler sonography of the middle cerebral artery, heart rate and
      brachial blood pressure were recorded during a head-up tilt test. According to
      the outcome of the test, patients were categorized in two groups:
      neurocardiogenic syncope (29 patients) and postural tachycardia (21 patients).
      The clinical history of the two groups was similar. During baseline in the supine
      position, no differences in haemodynamic parameters were observed. From the first
      min of tilt, the heart rate was higher in patients with postural tachycardia than
      in patients with neurocardiogenic syncope. Although, during tilt, the absolute
      values of the cerebral blood flow parameters were similar in the two groups,
      throughout tilt, continuous observation of the Doppler recording in patients with
      postural tachycardia showed intermittent fluctuation of the blood flow velocity,
      with an oscillatory pattern, which were not observed in the recordings in
      patients with neurocardiogenic syncope. Comparison of patients with
      neurocardiogenic syncope, and those with postural tachycardia also showed larger
      variations of the pulsatility index (P < 0.05) in the postural tachycardia group.
      These findings support the possibility that abnormalities within the central
      nervous system play a pivotal role in the pathogenesis of postural tachycardia.

PMID- 12408257
TI  - Multiple AV nodal pathways in patients with AV nodal reentrant tachycardia--more
      common than expected?
AB  - AIMS: It was the purpose of this study to determine the incidence of more than
      two AV nodal pathways in patients with AVNRT. METHODS AND RESULTS: In 78
      consecutive patients with AV-nodal reentrant tachycardias (AVNRT) (50 females, 28
      males, mean age 52.8 +/- 14.6 years), the number of sudden AH increases by 50 ms
      or more (AH-jump) was analysed during atrial extrastimulation. The incidence of
      two AV nodal pathways was accepted to be present in patients with AVNRT without
      an AH-jump ('smooth curve'). The following forms of tachycardia were induced: a
      typical AVNRT (slow-fast) in 67 patients, an atypical AVNRT (fast-slow) in 12
      patients and a slow-slow-AVNRT in 4 patients. Five patients had two forms of
      AVNRT. 47 patients (60.3%) showed two AV nodal pathways, 27 patients (34.6%) had
      three AV-nodal pathways and 4 patients (5.1%) exhibited four AV-nodal pathways.
      For successful catheter ablation of AVNRT in patients with more than two
      pathways, more radiofrequency energy applications were required (9.2 +/- 6.3)
      compared with patients with only two pathways (6.7 +/- 4.8). Furthermore, in
      patients with more than two AV-nodal pathways, the catheter intervention resulted
      more frequently in a modulation of slow pathway conduction than in an ablation of
      the slow pathway(s). CONCLUSION: The incidence of more than two AV-nodal pathways
      in patients with AVNRT was unexpectedly high at about 40%. Thus, these
      tachycardias require a meticulous electrophysiological evaluation for successful
      ablation.

PMID- 12408258
TI  - Atrial fibrillation threshold predicted long-term efficacy of pharmacological
      treatment of patients without structural heart disease.
AB  - AIMS: To ascertain if an electrophysiological study could predict long-term
      efficacy of anti-arrhythmic drugs in the treatment of lone atrial fibrillation.
      METHODS AND RESULTS: Forty-four patients (36 males, 8 females, age 55.5 +/- 10.6)
      with paroxysmal atrial fibrillation were enrolled to undergo serial
      electrophysiological studies at the bedside. Two quadripolar catheters were
      inserted via the subclavian vein. Disopyramide (D: 2 mg/kg iv), cibenzoline (C:
      1.4 mg/kg iv), aprindine (A: 2 mg/kg iv), pilsicainide (P: 2 mg/kg po) and
      flecainide (F: 3 mg/kg po) were tested. Atrial fibrillation threshold (AFT) was
      measured as the lowest current amplitude of rapid pacing (50 Hz for 1 s) to
      induce atrial fibrillation lasting more than 30 s. Before drug treatment, AFT was
      3.9 +/- 0.3 mA. Pharmacological treatment raised AFT as follows: D 5.9 +/- 0.9
      mA, C 7.6 +/- 1.2 mA, A 8.1 +/-1.1 mA, P 6.0 +/- 0.8 mA, F 7.3 +/- 1.1 mA.
      Recurrence of atrial fibrillation was observed during 1-year follow-up in 12% of
      cases when they were treated with a drug that raised AFT by 5 mA or more. On the
      other hand, the recurrence rate was 87% when patients were treated with a drug
      that raised AFT by less than 5 mA (P = 0.001). CONCLUSION: AFT was a good
      predictor of long-term efficacy of pharmacological treatment against atrial
      fibrillation.

PMID- 12408259
TI  - Ablation of pulmonary vein foci for the treatment of atrial fibrillation;
      percutaneous electroanatomical guided approach.
AB  - AIMS: To evaluate the usefulness of three-dimensional (3D) electroanatomical
      mapping of the pulmonary veins (PV) for guiding radiofrequency (RF) ablation of
      focal atrial fibrillation (AF) in a single session and to correlate the
      electrophysiological results with the six month clinical outcome. METHODS AND
      RESULTS: Sixteen consecutive patients with idiopathic paroxysmal AF (more than 1
      episode/month) were studied. A non-fluoroscopic mapping system was used to
      generate 3D electroanatomic maps of the left atrium and deliver RF energy. In
      patients with frequent ectopies, mapping was performed using the 'hot-cold'
      approach (looking for the earliest electrogram in the 3D reconstruction). In
      patients with infrequent/no ectopies, double/ multiple potentials recorded at the
      PV were tagged. Pacing at these sites to test for inducibility of ectopy or
      atrial fibrillation was used to define PV foci. The therapeutic endpoint was
      defined as suppression of premature beats, dissociation of PV potentials and
      inability to induce AF. Twenty-five foci were identified (multiple foci in 38%).
      In the 4 pts with frequent ectopies, Group A, these were suppressed by 4 +/- 4.7
      applications. In the 12 pts with infrequent/no ectopies, Group B, an average 4.7
      +/- 1.8 applications were delivered per focus; the endpoint was achieved in eight
      of the patients (13 of 21 foci). By 180 days follow-up, 11 patients were free of
      symptoms and in sinus rhythm, two had paroxysmal AF episodes and 3 have
      symptomatic ectopies and are receiving antiarrhythmic drugs. The overall success
      rate at six months was thus 69%, 100% for group A and 58% for group B.
      CONCLUSION: Electroanatomic guided RF ablation of paroxysmal AF was highly
      successful in patients with frequent ectopies. The use of electroanatomical
      mapping for precise anatomical localization of multiple potentials and for
      guiding the PV ostia isolation allowed successful RF ablation in 50% of pts with
      infrequent/no ectopies.

PMID- 12408260
TI  - Ventricular activation and recovery measured in electrocardiographic limb leads
      correlate with measurements from specific areas in body surface mapping.
AB  - AIMS: Dispersion of ventricular depolarization-repolarization in 12-lead
      electrocardiograms (ECGs) has been reported to provide noninvasive information on
      arrhythmogenicity. However, there are two methods to calculate the dispersion
      from ECGs including and excluding limb leads. The aim of this study was to
      examine whether temporal parameters from limb leads represent activation and
      repolarization of a particular part of the body surface. METHODS AND RESULTS: We
      compared the temporal parameters of activation time (AT), activation-recovery
      interval (ARI), and recovery time (RT) from limb leads of ECGs with those from an
      87-lead body surface maps. The study population consisted of 50 normal subjects
      (25 men and 25 women, 19.4 +/- 1.6 years). The temporal parameters in leads I,
      II, and III were highly (r > 0.9) correlated with those in unipolar leads over
      the left lateral, left lower, and right lower chest, respectively. The temporal
      parameters in leads aVR, aVL, and aVF showed a significant correlation (r > 0.8)
      with those in unipolar leads over the right upper, left upper, and lower anterior
      chest, respectively. The mean AT, ARI, and RT from each limb lead of ECG were
      almost the same as those of unipolar leads over the corresponding areas of the
      body surface. CONCLUSIONS: These findings suggest that ATs, ARIs, and RTs from
      limb leads may represent those from unipolar leads of particular areas over the
      body surface in normal subjects. The temporal parameters from limb leads of ECGs
      may provide information on activation and repolarization as well as the
      precordial leads of ECGs.

PMID- 12408261
TI  - Decremental intravenous pulse propagation during extrastimulus pacing: relevance
      for catheter ablation of focal atrial fibrillation.
AB  - We report a case study demonstrating delayed circumferential intrapulmonary
      venous conduction characteristics during coronary sinus extrastimulus pacing.
      This phenomenon allowed the unmasking and discrimination of a localized left
      atrial to PV breakthrough from secondarily activated PV muscle in a common left
      sided PV ostium. Thus, this pacing manoeuvre may serve to guide RF delivery in
      the treatment of focal AF.

PMID- 12408262
TI  - A 12-month quality of life assessment of cardiac arrest survivors treated with or
      without an implantable cardioverter defibrillator.
AB  - BACKGROUND: Previous studies indicate that the implantable cardioverter
      defibrillator (ICD) has a large impact on the quality of life of patients. The
      effects of having an ICD over longer periods of times has been less studied.
      OBJECTIVE: To assess the quality of life and well-being of cardiac arrest
      survivors who have received an implantable cardioverter defibrillator (ICD) or
      other treatment. METHODS: 168 patients were monitored for 1 year and completed
      four questionnaires. RESULTS: No differences were found between the two
      treatments regarding quality of life (except for pain, ICD patients perceived
      less pain) and well-being. A significant improvement in physical and social
      function, and in mental health was found in the first 6 months. Older patients
      (60 years or older) perceived less improvement in their health than younger
      patients. Women reported having poorer social function. The prevalence of anxiety
      and probable depression was high irrespective of the treatment received: anxiety
      and depressive symptoms did not change significantly between 1 and 12 months
      after discharge. Patients with higher anxiety scores experienced less improvement
      in health and patients with more depressive symptoms experienced poorer social
      function. CONCLUSIONS: The prevalence of anxiety and probable depression was high
      in cardiac arrest survivors. Probable depression affected social function. Those
      patients who felt anxious experienced less health improvement. Quality of life
      and well-being were not affected by the type of treatment. We conclude that
      surviving an out-of-hospital cardiac arrest has a greater impact on patients than
      the treatment received.

PMID- 12408263
TI  - Inappropriate high-rate ventricular pacing in a patient with a defibrillator.
AB  - We describe a patient who presented with high rate ventricular pacing secondary
      to dysfunction of his implantable cardioverter defibrillator (ICD). The device
      was also unable to communicate with the programmer and unable to treat
      ventricular fibrillation. Immediate disconnection of the ICD from the leads was
      the only effective recourse. Subsequent detailed technical analysis of the device
      revealed a different electrical circuit problem from that found in typical cases
      of runaway pacing. To our knowledge this is the first description of a
      malfunction of precisely this nature.

PMID- 12408264
TI  - The electromechanical effects of pacing at different sites within the right
      atrium.
AB  - AIMS: To compare high right atrium (HRA) with right atrial appendage (RAA) pacing
      with respect to atrial electromechanical function. METHODS: Eleven patients
      undergoing elective electrophysiological studies were studied in order directly
      to compare atrial conduction acutely associated with HRA and RAA pacing. Twenty
      five patients with chronically implanted, active fixation leads in the HRA were
      compared with an age and sex matched group of 25 patients with chronically
      implanted, passive fixation leads in the RAA. For both studies recordings were
      taken in sinus rhythm then repeated when paced. Measured time intervals were
      intra- and interatrial activation times. P wave duration and time to onset of
      atrial systolic blood flow. RESULTS: Right atrial pacing, when compared with
      sinus rhythm, significantly prolongs the interatrial activation time, the P wave
      duration and the time to onset of right and left atrial blood flow irrespective
      of site paced. Comparing the RAA group with the HRA group, there were no
      statistical differences for any of the measured parameters. CONCLUSION: High
      right atrial free wall or the right atrial appendage pacing, when compared with
      sinus rhythm, is significantly detrimental to atrial electromechanical function.
      There is, however, no demonstrable difference between the two sites.

PMID- 12408265
TI  - Testing a new mechanism for left interventricular septal pacing: the transseptal
      route; a feasibility and safety study.
AB  - AIMS: To prove the feasibility and safety of left interventricular septal pacing.
      BACKGROUND: Right ventricular apical pacing is an established but
      haemodynamically less favourable pacing method compared with transvenous left
      ventricular pacing. Alternatively, we propose a simple septal screw-in lead for
      left interventricular septal pacing. METHODS: A pacemaker lead with a long
      insulated screw with the two distal windings forming an active tip was implanted
      from the right side of the interventricular septum to the subendocardial left
      side in six goats. A special guiding sheath enabled stable, easy, and swift
      implantation of the lead. The implantation was performed using fluoroscopy
      together with. normal and contrast echocardiography (via the long pre-shaped
      sheath) and electrocardiographic signals (His-bundle recordings in conjunction
      with atrial and ventricular intracardiac signals). The screw was also positioned
      at other locations along the free wall, and at the interventricular septum to
      assess possible adverse effects at other sites. RESULTS: An average of 2.2 +/-
      1.5 positions per goat was attempted. No adverse effects were noticed during
      implantation or at necropsy. In two goats, the final position was at the junction
      of the right ventricular wall and the interventricular septum. Parameters at the
      final positions were as follows: the pacing threshold was 1.3 +/- 1.0 V at 0.5
      ms; the pacing impedance was 1022 +/- 463 omega at 4.8 V and 0.5 ms. R-wave
      amplitudes were 17.6 +/- 7.6 mV. CONCLUSION: Left interventricular septal pacing
      is feasible. In our study it was safely performed in six goats. The pacing
      threshold was low, and the stability of the lead system was good. Implantations
      in humans and animals and haemodynamic evaluations are needed to reveal the
      potential benefits of this new form of left interventricular septal pacing.

PMID- 12408266
TI  - Reversed remodelling of dilated left sided cardiomyopathy after upgrading from
      VVIR to VVIR biventricular pacing.
AB  - AIMS: To show reversed remodelling of the left ventricle and left atrium after
      upgrading to biventricular pacing in a patient with worsening heart failure due
      to VVIR pacing. To review the literature concerning reversed remodelling after
      upgrading to biventricular pacing. METHODS AND RESULTS: In a 61-year-old man,
      with cardiomyopathy and worsening heart failure and mitral insufficiency
      following conventional pacing after His-bundle ablation, upgrading to
      biventricular pacing showed left sided reversed remodelling of the heart with
      decrease in mitral regurgitation in 6 months. The literature is reviewed by a
      Medline search between 1966-2001. CONCLUSION: The occasionally observed
      progressive heart failure after right ventricular pacing following His-bundle
      ablation can be reversed by upgrading to VVIR biventricular pacing and under
      these circumstances upgrading should be considered.

PMID- 12408267
TI  - Ebstein's anomaly, atrial paralysis and atrio-ventricular block: an uncommon
      association.
AB  - We report here the case of a 22-year-old female patient with an incomplete
      Ebstein's anomaly, complete heart block and atrial standstill. Atrial paralysis
      associated with Ebstein's anomaly is the most important feature, since there is a
      report of familial Ebstein's anomaly associated with atrial standstill but
      isolated cases have not been described. The patient presented with atypical chest
      pain and a symptomatic bradycardia of 37 beats per minute. A VVIR pacemaker was
      implanted. She has subsequently been symptom free.

PMID- 12408268
TI  - Diabetes mellitus: hope or despair.

PMID- 12408269
TI  - Dietary patterns and glucose intolerance among rural Indian populations.
AB  - Dietary data obtained by application of uniform methodology in rural diabetes
      surveys conducted near Delhi, Ahmedabad, Trivandrum and Cuttack (441 normal
      persons and 142 subjects ascertained as abnormal following oral glucose tolerance
      test), at Kalpa (30 normal, 14 abnormal) in Himachal Pradesh state, and near
      Kottayam (3588 normal, 37 abnormal) in Kerala state, were summarised. Average
      nutrients intake in rural Indians were between 53% and 69% as carbohydrates, 55%
      and 70% (of total carbohydrates) as complex carbohydrates, 0% and 8% as free
      sugars, 11% and 16% as proteins, 16% and 46% (of total proteins) as animal
      proteins, 17% and 32% as fats and, 30% and 54% (of total fats) as animal fats.
      There were no consistent differences in the total energy intake and, proportions
      of total or complex carbohydrates, free sugars, total or animal proteins and
      total or animal fats between subjects with normal and abnormal glucose tolerance.
      Complex carbohydrates constituted major source of carbohydrates even in those
      with abnormal glucose tolerance, and there was also evidence to suggest that
      animal fat was favoured within India too. Of the Indian dietary habits, it is
      difficult to identify any specific dietary pattern to relate with diabetes.
      Qualitative and not quantitative nutrients intake alone needs more detailed
      analysis for their relationship with glucose tolerance.

PMID- 12408270
TI  - Incidence of cardiac autonomic neuropathy and its correlation with retinopathy,
      micro-albuminuria and glycated haemoglobin in non-insulin dependent diabetes
      mellitus.
AB  - Forty non-insulin dependent diabetes mellitus (NIDDM patients were subjected to
      bedside evaluation of cardiovascular autonomic reflexes. Autonomic neuropathy was
      detected in 23 patients (57.5%); orthostatic hypotension in 6 (15%), abnormal
      blood pressure response to sustained handgrip in 8 (20%), abnormal Valsalva ratio
      in 10 (25%), abnormal heart rate response to deep breathing in 12 (30%) and
      abnormal heart rate response to standing in 11 patients (27.5%). Incidence of
      parasympathetic neuropathy was 57.5% in comparison to 20% sympathetic neuropathy
      One abnormal cardiac reflex was seen in 6 (15%), 2 in 13 (32.5%) and 3 or more in
      4 patients (10%). Raised glycated haemoglobin was seen in 17 patients,retinopathy
      in 3 and micro-albuminuria in 11 patients with autonomic dysfunction and in 13, 0
      and 3 patients respectively in NIDDM patients without autonomic neuropathy.
      Positive correlation of cardiac autonomic neuropathy was seen with retinopathy
      and micro-albuminuria.

PMID- 12408271
TI  - Epidemiology of diabetes in India--current perspective and future projections.
AB  - Diabetes is the singlemost important metabolic disease which can affect nearly
      every organ system in the body. It has been projected that 300 million
      individuals would be affected with diabetes by the year 2025. In India it is
      estimated that presently 19.4 million individuals are affected by this deadly
      disease, which is likely to go up to 57.2 million by the year 2025. The reasons
      for this escalation are due to changes in lifestyle, people living longer than
      before (ageing) and low birth weight could lead to diabetes during adulthood.
      Diabetes related complications are coronary artery disease, peripheral vascular
      disease, neuropathy, retinopathy, nephropathy, etc. People with diabetes are 25
      times more likely to develop blindness, 17 times more likely to develop kidney
      disease, 30-40 times more likely to undergo amputation, two to four times more
      likely to develop myocardial infarction and twice as likely to suffer a stroke
      than non-diabetics. Lifestyle modifications, inclusive of dietary modification,
      regular physical activity and weight reduction are indicated for prevention of
      diabetes.

PMID- 12408272
TI  - Current diagnostic criteria and their impact on outcome and management.
AB  - The 1997 American Diabetes Association (ADA) Expert Committee on the Diagnosis
      and Classification of Diabetes Mellitus and the Provisional Report of the WHO
      Consultation focus on a fasting plasma glucose (FPG) that is 126 mg/dl or greater
      and confirmed on a subsequent day as the preferred criterion for the diagnosis of
      diabetes mellitus. This criterion is supported by studies demonstrating that this
      threshold accurately differentiates between non-diabetic and diabetic populations
      and is associated with the development of specific diabetic microvascular
      complications. It corrects for the inequivalence of the FPG and 2- hour post
      glucose (2hPG) criteria of the previous National Diabetes Data Group (NDDG) and
      WHO diagnostic schemes and recognises that oral glucose tolerance tests (OGTTs)
      rarely are performed in clinical practice. Although the new and the previous
      criteria produce similar estimates of the prevalence of diabetes, there may be a
      considerable degree of reclassification. Preliminary studies suggest that the new
      criteria favour the diagnosis of diabetes in younger and more obese individuals,
      whereas the older criteria increase the likelihood of diagnosis in older, leaner
      individuals.

PMID- 12408273
TI  - Diabetic retinopathy: need for awareness amongst physicians.
AB  - The physician as a general practitioner, endocrinologist, nephrologist,
      cardiologist sees a diabetic patient first, much before the ophthalmologist, and
      so it is he who can help them a lot in case of diabetic retinopathy which is a
      highly specific vascular complication of both type 1 and type 2 diabetes.
      Progression of retinopathy advances step by step and ultimately loss of vision
      takes place. Laser photocoagulation is beneficial in preventing further vision
      loss. There is a need to educate diabetic patient about the devastating effects
      of the disease and guide them to an ophthalmologist - preferably a retina
      specialist.

PMID- 12408274
TI  - Diabetic foot: magnitude of the problem.
AB  - Of total diabetic population, 15-20% have foot problems and 30% have peripheral
      vascular disease. The fundamental strategy for foot salvaging is 'early
      conservative amputation and radical debridement' of diabetic foot infection. For
      this strategy, concept of foot spaces is to be well understood. Guidelines for
      'early conservative amputation and radical debridment' are discussed in this
      article. As regarding diabetic foot care ten valuable points are to be remembered
      which are also discussed.

PMID- 12408275
TI  - Diabetic nephropathy--prevention and treatment.
AB  - Diabetic nephropathy is a major cause of end stage renal failure. Non-insulin
      dependent diabetes mellitus (NIDDM) is more prevalent in our country than insulin
      dependent diabetes mellitus (IDDM). Nephropathy can be classified in IDDM
      patients in 5 stages which have been elaborated here. The major intervention to
      prevent or reduce the rate of progress in diabetic nephropathy is control of
      blood sugar, control of blood pressure, use of angiotensin converting enzyme
      inhibitors, restricting dietary protein intake, treatment with inhibitors of the
      formation of advanced glycosylation end products, treatment with aldose reductase
      inhibitors and treatment of dyslipidaemia. Once the patient of diabetic
      nephropathy reaches the end stage renal disease, renal replacement therapy is
      needed. The different modalities of renal replacement therapy are: Haemodialysis,
      continuous ambulatory peritoneal dialysis, kidney transplantation and kidney and
      pancreas transplantation. Renal replacement therapy in diabetics has to be
      individualised from patient to patient. Kidney transplantation is at present the
      option of choice.

PMID- 12408276
TI  - Hypoglycaemic: prevention, consequences and management.
AB  - Hypoglycaemia is one of the most commonly encountered acute complications of
      diabetes. This is caused due to overdosage of insulin or oral hypolgycaemic
      agents. The signs and symptoms of hypoglycaemia can be divided into those due to
      autonomic hyperactivity and those resulting from neuroglycopenia. If detected
      early, hypoglycaemia is reversible and can be prevented. Hypoglycaemia may be
      misdiagnosed as hyperglycaemia and if not treated promptly may lead to death. The
      treatment of choice in hypoglycaemia is to give 25-50 ml of 50% glucose solution
      over 2-3 minutes. Where peripheral veins are collapsed, i.v. glucagon injection
      is preferable. Adequate education of diabetic patients and their relatives is
      necessary so that hypoglycaemia can be avoided or treated effectively.

PMID- 12408277
TI  - In defence of animal insulins.
AB  - The term 'human insulin' is a misnomer, as its source is not human pancreas but
      the pork pancreas from where insulin is humanised by modern techniques of genetic
      engineering. With the use of purified animal insulin, untoward effects occur
      infrequently. Porcine insulin is different from human insulin in only one amino
      acid. They have also been found to be equal in terms of effect on plasma glucose,
      glycated haemoglobin and insulin dose requirements. A lesser written fact is that
      while human insulin can produce all the problems encountered with animal insulin,
      there are certain more serious additional problems experienced with use of human
      insulin.

PMID- 12408278
TI  - Rational choice of oral antihyperglycaemic agents.
AB  - Until 1995 sulphonylureas and metformin formed the mainstay of oral
      pharmacotherapy of type 2 diabetes mellitus. Since then many new insulin
      secretagogues and new classes of oral antihyperglycaemic agents have been
      launched. This has improved the management of type 2 diabetes mellitus. Oral
      agents available currently in Indian market are: Those predominantly targeting
      beta cell dysfunction, those predominantly targeting insulin resistance and those
      inhibit carbohydrate absorption. Strategies for treatment with oral
      antihyperglycaemic agents are: Targeting fasting hyperglycaemia, targeting
      postprandial hyperglycaemia, minimising cost therapy, minimising weight gain and
      minimising patient effort strategies. Special situations where antihyperglycaemic
      agents used are: Teenage diabetes, elderly diabetes, persons with erratic
      lifestyle, persons with cardiac disease, renal disease and in pregnancy.

PMID- 12408279
TI  - Lifestyle modification in management of diabetes mellitus.
AB  - India has the largest diabetic population in the world. Change in eating habits,
      increasing weight and decreased physical activity are major factors leading to
      increased incidence of type 2 diabetes. Obesity is the most important modifiable
      risk factor. Smoking is an independent risk factor for type 2 diabetes mellitus.
      Diet and exercise are primary therapeutic options for its management. Dietary
      management should not only aim to achieve glycaemic control but to normalise
      dyslipidaemia. Smoking cessation reduces the risk of morbidity and mortality in
      CAD. Exercise improves the condition of a diabetic patient. Exercise includes
      yoga practices which have a role to play in the prevention of type 2 diabetes.

PMID- 12408280
TI  - Current and future perspective in the management of diabetes.
AB  - Diabetes mellitus has attained epidemic proportions worldwide. It is suggested
      that resistin (also called Fizz 3), a cysteine. rich-protein may represent a link
      between obesity and insulin resistance. Uncoupling proteins are candidate genes
      for human obesity or type 2 diabetes mellitus. Amylin has a vital role in
      regulating blood glucose concentration following meals. Gluco watch biographers
      are safe and effective device to measure glucose every 20 minutes. Islet
      transplantation has had a remarkable preliminary success. Protein kinase Cbeta
      inhibitor was shown to reduce albuminuria and decrease statement of TGFbeta and
      various extracellular matrix proteins in diabetic rats.

PMID- 12408281
TI  - Continuous ambulatory peritoneal dialysis: Indian scenario.
AB  - Chronic peritoneal dialysis (CPD) has been initiated as a treatment modality for
      chronic renal failure patients in the Indian subcontinent since 1990. Over a
      period of 9 years both continuous ambulatory peritoneal dialysis (CAPD) and
      continuous cyclic peritoneal dialysis (CCPD) have emerged as accepted forms of
      renal replacement therapy in our country. Although there were government
      restrictions on import of dialysis fluid until 1993, the availability of locally
      manufactured fluid in collapsible bags had facilitated the expansion of the
      programme to the far corners of the country and in neighbouring countries.
      Initially majority (78%) of the patients who were started on this programme were
      diabetics with other comorbid conditions who were drop-outs from haemodialysis
      and unfit for transplantation. Both CAPD and CCPD have been used for all age
      groups and for men and women. Majority of the patients do 3 x 2 l exchanges a day
      on CAPD; 8-10 l using a cycler at night those who are onCCPD. Peritonitis rate
      was 1 episode every 18 patient months. With the introduction of new connection
      and disposable sets the incidence of peritonitis is dropping down. The major
      cause of drop-out is cardiovascular death followed by peritonitis. Malnutrition
      is a major problem in both CAPD and haemodialysis patients. The programme has
      been expanded and there are over one thousand patients on this treatment in the
      country. The introduction of CPD had a major impact on the treatment of renal
      failure in India.

PMID- 12408282
TI  - Electrocardiographic changes in craniocerebral trauma--could they serve as
      prognostic indicators?
AB  - Electrocardiographic (ECG) changes were analysed in one hundred patients of
      craniocerebral injuries irrespective of age and sex. Males comprised 82% of
      patients and most vulnerable age group was 15-40 years (66%). Although the
      overall mortality was 17%, the maximum mortality (44.44%) was observed in the age
      group of 41-60 years. Computed tomographic scan proved lesions in intracerebral
      haemorrhage, subdural haematoma, mixed lesions and extradural haematoma were
      associated with mortality rates in 66.66, 33.33, 20 and 11.11 per cent
      respectively. ECG changes of some or the other type were present in almost all
      patients (99%) but ST-segment shift, sinus tachycardia/bradycardia, T-wave
      changes and prolonged QTc-interval (> 440 msec) carried high mortality rates of
      60, 34.6/27.3, 19.6 and 17.3 per cent respectively, especially if these changes
      persisted for long duration. Occurrence of supraventricular tachycardia and nodal
      arrhythmia, although associated with high (50%) mortality rates, were probably
      terminal events rather than the cause of increased mortality. There was, however,
      no direct correlation between the type of craniocerebral injury and specific ECG
      changes.

PMID- 12408284
TI  - Current perspective in insulin therapy in the management of diabetes mellitus.
AB  - Insulin therapy since its discovery in 1922 is effective in restoring
      normoglycaemia, suppressing ketogenesis, delaying or arresting diabetic
      complications. The commonest indication for regular insulin therapy in type-2
      diabetes is oral hypoglycaemic agent (OHA) failure. Regular insulin therapy is
      also indicated in patients of diabetes associated with renal or hepatic disease
      where OHA is contra-indicated. Different types and species of insulin have
      different pharmacological properties. There are several methods of insulin
      administration. Efficacy of human insulin has been proved beyond doubt. However,
      there is no reason to believe that animal insulin is inferior to human insulin.

PMID- 12408283
TI  - Effect of an immunomodulator containing Mycobacterium w on sputum conversion in
      pulmonary tuberculosis.
AB  - Sputum conversion is an important milestone in the management of pulmonary
      tuberculosis. Early sputum conversion is desirable. A controlled study was done
      to improve sputum conversion rate of current short course chemotherapy using
      immunomodulator containing mycobacterium w. The immunomodulator is very potent
      and freely available. It shares antigens with Mycobacterium tuberculosis. In a
      randomised pattern 69 of 134 patients suffering from pulmonary tuberculosis
      received the immunomodulator intradermally every 15 days along with chemotherapy.
      The use of the immunomodulator results in preponement of sputum conversion. The
      sputum conversion rate obtained by chemotherapy at 60 days was achieved latest by
      30 days when mycobacterium w containing immunomodulator was used as an adjuvant
      therapy. This was found irrespective of bacterial load (1 +, minimal or 3+,
      maximal) in sputum or category (fresh or retreatment) of disease. The therapy was
      well tolerated.

PMID- 12408285
TI  - Gyrate atrophy of choroid and retina.
AB  - Gyrate atrophy of choroid and retina is a rare disorder of autosomal recessive
      nature. There occurs patchy and progressive atrophy of the choroid and retina at
      the equatorial region with central area being less affected. Here in this case
      report, one woman of about 47 years attended at the retina clinic, Tenennt
      Institute of Ophthalmology, Glasgow University with the history of gradual loss
      of vision. On fundus examination, sharply defined bizarre shaped atrophic areas
      of fundus was seen in both the eyes. Velvet like fine granular pigments were
      present in the macula, the zone of healthy retina and the periphery. The
      colourless, elongated, glittering crystals were scattered over the dark brown
      pigments visible through 90 dioptre lens. Bone corpuscles pigments were not
      found. Fluorescein angiography showed hyperfluorescence in the area of gyrate
      atrophy. Her plasma ornithine level and plasma tiramine level were 1 90 U mol/l
      and 357 U mol/l. respectively. A rigid schedule of low protein diet including
      near total elimination of arginine with supplementation of essential amino acids
      was advised since the diagnosis was established.

PMID- 12408286
TI  - Mature teratoma of the mesentery.
AB  - Teratoma of the mesentery is an extremely rare tumour of the germ cells and
      imposes diagnostic dilemma in clinical practice and is reported because of its
      very uncommon occurrence. With the advent of modern imaging modalities like
      ultrasonography, computerised tomography (CT) and magnetic resonance imaging
      (MRI), it is now confidently diagnosed and rarely requires diagnostic laparotomy.
      CT shows characteristic appearance (Rokitansky sign).

PMID- 12408287
TI  - Palindromic rheumatism.
AB  - A 27-year-old male presented with the complaints of recurring attacks of painful
      inflammation affecting finger joints of both hands for last one year. There were
      no constitutional features of weight loss, fever, anaemia, itching or burning
      sensation over the joints. It was diagnosed to be a case of palindromic
      rheumatism clinically and treated with hydroxychloroquine. The case is discussed
      in detail with reference to similar cases reported by others.

PMID- 12408288
TI  - Treatment of AIDS.

PMID- 12408289
TI  - Our decimating daughters.

PMID- 12408290
TI  - Muscle cramps.

PMID- 12408291
TI  - Efficacy and safety of losartan-amplodipine combination--an Indian postmarketing
      surveillance experience.
AB  - The present study was conducted among 719 patients enrolled by 109 doctors to
      evaluate the efficacy and tolerability of the combination of losartan potassium
      and amlodipine besylate in Indian patients with mild to moderate hypertension.
      Out of them 11 patients were dropped out. Of these 708 patients 643 patients
      received once daily dosage of the combination whereas 10 patients received 1/2
      daily, 13 patients received 1 1/2 daily and 42 patients received 1 twice daily
      dosage of the combination. The mean SBP in the study was 172.89 +/- 19.18 mm Hg
      baseline. After the 10-day treatment, the mean SBP had significant reduction ie,
      13.1% from basal and at the end of day 20 of the treatment, the reduction was
      19.13% from the baseline which was significant. Similarly mean DBP was 105.42 +/-
      10.85 mm Hg at baseline. After treatment, the mean DBP had significant reduction.
      After 10- day treatment, there was 12.7% reduction from the baseline and at the
      end of the treatment ie, after day 20, the reduction was 17.70% from basal, which
      was significant. Global evaluation of efficacy was done by the physicians; 93.8%
      of the cases had excellent to good response and 4.9% patients had fair response.
      Details of any adverse event reported or noted during the treatment with the
      combination were recorded in the appropriate section of the case record form,
      whether considered treatment related or not, as reported by the patients. The
      severity of an adverse event was graded on a 3-point scale as mild, moderate and
      severe. The most common side-effects reported were oedema of feet (5.08%), ankle
      oedema (1.98%). Remaining adverse events included some cardiovascular events such
      as palpitations, gastro-intestinal events such as constipation, miscellaneous
      events, muscular pain, weakness, generalised swelling, etc. CNS events included
      giddiness, headache, insomnia, etc.

PMID- 12408292
TI  - Evaluation of a miniature electromagnetic position tracker.
AB  - The advent of miniaturized electromagnetic digitizers opens a variety of
      potential clinical applications for computer aided interventions using flexible
      instruments; endoscopes or catheters can easily be tracked within the body. With
      respect to the new applications, the systematic distortions induced by various
      materials such as closed metallic loops, wire guides, catheters, and ultrasound
      scan heads were systematically evaluated in this paper for a new commercial
      tracking system. We employed the electromagnetic tracking system Aurora
      (Mednetix/CH, NDI/Can); data were acquired using the serial port of a PC running
      SuSE Linux 7.1 (SuSE, Gmbh, Nurnberg). Objects introduced into the digitizer
      volume included wire loops of different diameters, wire guides, optical tracking
      tools, an ultrasonic (US) scan head, an endoscope with radial ultrasound scan
      head and various other objects used in operating rooms and interventional suites.
      Beyond this, we determined the influence of a C-arm fluoroscopy unit. To quantify
      the reliability of the system, the miniaturized sensor was mounted on a
      nonmetallic measurement rack while the transmitter was fixed at three different
      distances within the digitizer range. The tracker was shown to be more sensitive
      to distortions caused by materials close to the emitter (average distortion error
      13.6 mm +/- 16.6 mm for wire loops positioned at a distance between 100 mm and
      200 mm from the emitter). Distortions caused by materials near the sensor
      (distances smaller than 100 mm) are small (typical error 2.2 mm +/- 1.9 mm). The
      C-arm fluoroscopy unit caused considerable distortions and limits the reliability
      of the tracker (distortion error 18.6 mm +/- 24.9 mm). Distortions resulting from
      the US scan head are high at distances smaller than about 100 mm from the
      emitter. The distortions also increase when the scan head is positioned
      horizontally and close to the sensor (average error 4.1 mm +/- 1.5 mm when the
      scan head is positioned within a distance of 100 mm from the sensor). The
      distortions are slightly higher when the ultrasound machine is switched on. We
      also evaluated the influence of common medical instruments on distance
      measurements. For these measurements the average deviation from the known
      distance of 200 mm amounted to 3.0 mm +/- 1.5 mm (undistorted distance
      measurement 1.5 mm +/- 0.3 mm). The deviations also depend on the relative
      orientation between emitter and sensor. The results demonstrate that the
      miniature tracking system opens up new perspectives with regard to surgery
      applications where a flexible instrument is to be tracked within the body.
      Significant distortions caused by metallic objects only occur in the worst cases,
      for example, in the presence of a closed, unisiolated wire loop or a C-arm
      fluorescence unit close to the emitter and which can be avoided by suitable
      usage.

PMID- 12408293
TI  - Light and electron radiation fields' coincidence at extended distance.
AB  - Light field is routinely used for matching electron fields with adjacent photon
      fields and also positioning an ion chamber for cutout output measurements. At
      extended distance, however, the peripheral aspects of a radiation field are
      shifted with respect to their light shadow by up to 10 mm at SSD of 115 cm. This
      is mostly due to a difference in positions of light and virtual electron sources;
      however loss of the lateral scatter equilibrium, electron scatter in air, and
      partial transmission through cutout edges can also contribute to the effect. For
      the aperture sizes large enough for the lateral scatter equilibrium to be
      achieved, a simple geometrical formula allows one to calculate the misalignment
      at off-axis locations if the virtual electron source position is known. If the
      source position is not known or the aperture is too small for the lateral scatter
      equilibrium to be established, then a light-radiation coincidence test using a
      ready-pack film at dmax can be used to measure the light and electron radiation
      fields coincidence.

PMID- 12408294
TI  - Diffraction enhanced imaging contrast mechanisms in breast cancer specimens.
AB  - We have investigated the contrast mechanisms of the refraction angle, and the
      apparent absorption images obtained from the diffraction enhanced imaging
      technique (DEI) and have correlated them with the absorption contrast of
      conventional radiography. The contrast of both the DEI refraction angle image and
      the radiograph have the same dependence on density differences of the tissues in
      the visualization of cancer; in radiography these differences directly relate to
      the contrast while in the DEI refraction angle image it is the density difference
      and thickness gradient that gives the refraction angle. We show that the density
      difference of fibrils in breast cancer as measured by absorption images correlate
      well with the density difference derived from refraction angle images of DEI. In
      addition we find that the DEI apparent absorption image and the image obtained
      with the DEI system at the top of the reflectivity curve have much greater
      contrast than that of the normal radiograph (x8 to 33-fold higher). This is due
      to the rejection of small angle scattering (extinction) from the fibrils
      enhancing the contrast.

PMID- 12408295
TI  - Reshapable physical modulator for intensity modulated radiation therapy.
AB  - A new method of generating beam intensity modulation filters for intensity
      modulated radiation therapy (IMRT) is presented. The modulator was based on a
      reshapable material, which is not compressible but can be deformed under
      pressure. A two-dimensional (2D) piston array was used to repeatedly shape the
      attenuating material. The material is a mixture of tungsten powder and a silicon
      based binder. The linear attenuation coefficient of the material was measured to
      be 0.409 cm(-1) for a 6 MV x-ray beam. The maximum thickness of the physical
      modulator is 10.2 cm, allowing a transmission of 1.5%. A 16 x 16 square piston
      array was used to generate a depth pattern in the deformable attenuating
      material. Each piston has a cross section of 6.37 x 6.37 mm2. The modulator was
      placed 65 cm from the radiation source of the linear accelerator in the position
      of the shielding tray. At this position, each piston projects to a 1.0 x 1.0 cm2
      area at the isocenter, giving a treatment field of 16 x 16 cm2. The percent depth
      dose curve and output factor measurement show a slight beam hardening and a 1%-4%
      increase in scatter fraction when 2.2-4.4 cm uniform thickness filters are in the
      beam. The surface dose was decreased with the filter in the beam. Ion chamber and
      verification films were used to verify the entrance dose. The measured absolute
      and relative doses were compared with the calculated dose. The agreement of
      measurements and calculations is within 3%. In order to verify the spatial
      modulation of dose, 1-D dose profiles were obtained using dose calculations.
      Calculated and measured profiles were compared. The 20%-80% penumbra of the
      modulator was measured to be 5.5-10 mm. The results show that a physical
      modulator formed using a 16 x 16 piston array and a deformable attenuation
      material can provide intensity modulation for IMRT comparable with those provided
      by currently available commercial MLC techniques.

PMID- 12408296
TI  - Matching PET and CT scans of the head and neck area: development of method and
      validation.
AB  - Positron emission tomography (PET) provides important information on tumor
      biology, but lacks detailed anatomical information. Our aim in the present study
      was to develop and validate an automatic registration method for matching PET and
      CT scans of the head and neck. Three difficulties in achieving this goal are (1)
      nonrigid motions of the neck can hamper the use of automatic ridged body
      transformations; (2) emission scans contain too little anatomical information to
      apply standard image fusion methods; and (3) no objective way exists to quantify
      the quality of the match results. These problems are solved as follows: accurate
      and reproducible positioning of the patient was achieved by using a radiotherapy
      treatment mask. The proposed method makes use of the transmission rather than the
      emission scan. To obtain sufficient (anatomical) information for matching, two
      bed positions for the transmission scan were included in the protocol. A mutual
      information-based algorithm was used as a registration technique. PET and CT data
      were obtained in seven patients. Each patient had two CT scans and one PET scan.
      The datasets were used to estimate the consistency by matching PET to CT1, CT1 to
      CT2, and CT2 to PET using the full circle consistency test. It was found that
      using our method, consistency could be obtained of 4 mm and 1.3 degrees on
      average. The PET voxels used for registration were 5.15 mm, so the errors
      compared quite favorably with the voxel size. Cropping the images (removing the
      scanner bed from images) did not improve the consistency of the algorithm. The
      transmission scan, however, could potentially be reduced to a single position
      using this approach. In conclusion, the represented algorithm and validation
      technique has several features that are attractive from both theoretical and
      practical point of view, it is a user-independent, automatic validation technique
      for matching CT and PET scans of the head and neck, which gives the opportunity
      to compare different image enhancements.

PMID- 12408297
TI  - Dosimetry comparison of 192Ir sources.
AB  - 192Ir sources besides being widely utilized in the field of conventional
      brachytherapy also find use in contemporary peripheral and coronal intravascular
      applications. In this study, the same Monte Carlo simulation code and input data
      were used to investigate differences between the dose rate distributions of the
      most commonly used 192Ir sources in the cm and mm distance range. Findings are
      discussed in view of differences in source and encapsulation dimensions as well
      as structural details. Results are presented in the AAPM TG-43 formalism, as
      generalized by AAPM TG-60, for five 192Ir HDR source designs as well as an LDR
      seed and an LDR wire source. Dose rate constants of the sources at r0 = 1 cm and
      r0 = 2 mm were found proportional to the corresponding geometry factors along the
      transverse source bisectors and an equation of the form lambda r0(cGyh(-1) U(-1))
      = 1.12 x G(r0,90 degrees) provides results within clinical accuracy (less than
      2%) for any 192Ir source. Radial dose functions do not depend significantly on
      source and encapsulation geometry and agree within 2% with that of a point 192Ir
      source. Anisotropy is of importance for accurate dosimetry at the cm distance
      range but it does not affect dose rate in the mm distance range significantly. At
      such short radial distances the source geometry factor defines the shape of
      isodose lines. Dose uniformity at given distances from the sources is strongly
      dependent on source dimensions as indicated by dose rate profiles in polar and
      Cartesian coordinates.

PMID- 12408298
TI  - Dosimetric aspects of a national survey of diagnostic and interventional
      radiology in Switzerland.
AB  - The effective dose delivered to the patient was determined, by modeling, for 257
      types of examinations covering the different modalities of diagnostic and
      interventional radiology. The basic operational dosimetric quantities considered
      were obtained from the parameters of the examinations on the basis of dosimetric
      models. These models required a precise characterization of each examination. The
      operational dosimetric quantities were converted into doses to organs and
      effective doses using appropriate conversion factors. The determination of the
      collective effective dose to the Swiss population requires a number of
      corrections to account for the variability of several parameters: sensitivity of
      the detection system, age, gender, and build of the patient. The use of various
      dosimetric models is illustrated in this paper for a limited number of
      examination types covering the different radiological modalities, for which the
      established typical effective doses are given. With regard to individual doses,
      the study indicated that the average effective doses per type of examination can
      be classified into three levels: (a) the weakly irradiating examinations (less
      than 0.1 mSv), which represent 78% of the examinations and 4% of the collective
      dose, (b) the moderately irradiating examinations (between 0.1 mSv and 10 mSv),
      which represent 21% of the examinations and 72% of the collective dose, (c) the
      strongly irradiating examinations (more than 10 mSv), which represent 1% of the
      examinations and 24% of the collective dose.

PMID- 12408299
TI  - Choice of phantom materials for dosimetry of Leksell Gamma Knife unit: a Monte
      Carlo study.
AB  - In calculations for the Leksell Gamma Knife, GammaPlan employs a tissue
      equivalent material without the presence of a skull bone, while dosimetry work is
      based on a polystyrene phantom. The compatibility of these dose distributions is
      uncertain. The Monte Carlo technique was employed to determine the radial dose
      distributions from a single 14 mm collimator helmet in 160 mm diam phantoms with
      different materials. The materials studied were polystyrene, perspex, water, and
      water with skull bone. Results showed no significant differences among the radial
      doses in different phantom materials for the 14 mm collimator helmet. The Monte
      Carlo simulation was repeated with the inclusion of all 201 sources. Again, no
      significant differences were observed.

PMID- 12408300
TI  - An investigation of a new amorphous silicon electronic portal imaging device for
      transit dosimetry.
AB  - The relationship between the pixel value and exit dose was investigated for a new
      commercially available amorphous silicon electronic portal imaging device. The
      pixel to dose mapping function was established to be linear for detector
      distances between 116.5 cm to 150 cm from the source, radiation field sizes from
      5 x 5 cm2 to 20 x 20 cm2 and beam energies of 6 to 18 MV. Coefficients in the
      mapping function were found to be dependent on beam energy and field size. Open
      and wedged field profiles measured with the device showed agreement to a maximum
      of 5% and 8%, respectively, as compared to film. A comparison of relative
      transmission measurements between the EPID and ion chamber indicate a maximum
      deviation of 6% and 2% at 6 and 18 MV, respectively, for an attenuator thickness
      of 21 cm and SDD > or = 130 cm. It was found that accuracies of better than 1%
      could be obtained if detector position and field size specific fitting parameters
      were used to generate unique mapping functions for each configuration.

PMID- 12408301
TI  - Clinical implementation of AAPM TG61 protocol for kilovoltage x-ray beam
      dosimetry.
AB  - Historically, there have been a variety of dosimetry protocols used for
      kilovoltage x-ray therapy beams with a set of conversion factors and correction
      factors taken from different references. Corresponding to the continued
      installation and use of kilovoltage machines, the American Association of
      Physicists in Medicine (AAPM) presented a unified protocol developed by Task
      Group 61 (TG61). TG61 determines the absorbed dose to water with an ionization
      chamber calibrated in air in terms of air kerma (Nk). TG61 presents both an in
      air method and an in-phantom method. In this work we only examine the TG61 in-air
      method. Our traditional dosimetry procedure, which is based upon NCRP Report 69
      and on material found in standard medical physics texts, has been compared to the
      TG61. A variety of kilovoltage beam energies were examined with a set of various
      field sizes and source to surface distances. TG61 published updated data for the
      mass absorption coefficient ratios, backscatter factors, and the average energy
      per ion pair factor. The following conclusions have been reached: (1) Our
      traditional procedures and the TG61 protocol for in-air measurements are
      equivalent. (2) The conversion and correction factors used in TG61 are different
      by up to 4.5% compared to the old factors that we have used. (3) The application
      of the TG61 factors can result in up to 5% differences in the determination of
      the absorbed dose.

PMID- 12408302
TI  - Development of high quantum efficiency flat panel detectors for portal imaging:
      intrinsic spatial resolution.
AB  - Recently developed flat panel detectors have been proven to have a much better
      image quality than conventional electronic portal imaging devices (EPIDs). They
      are, however, not yet the ideal systems for portal imaging application due to the
      low x-ray absorption, i.e., low quantum efficiency (QE), which is typically on
      the order of 2-4% as compared to the theoretical limit of 100%. The QE of current
      flat panel systems can be improved by significantly increasing the thickness of
      the energy conversion layer (i.e., amorphous selenium or phosphor screen). This,
      however, will be at the expense of a decrease in spatial resolution mainly due to
      x-ray scatter in the conversion layer (and also the spread of optical photons in
      the case of phosphor screen). In this paper, we investigate theoretically the
      intrinsic spatial resolution of a high QE flat panel detector with a new energy
      conversion layer that is much denser and thicker than that of current flat panel
      systems. The modulation transfer function (MTF) of the system is calculated based
      on a theoretical model using a novel approach, which uses an analytical
      expression for absorbed dose. It is found that if appropriate materials are used
      for the conversion layer, then the intrinsic MTF of the high QE flat panel is
      better than that of current EPIDs, and in addition they have a high QE (e.g.,
      approximately 60%). Some general rules for the design of the conversion layer to
      achieve both high QE and high resolution as well as high DQE are also discussed.

PMID- 12408303
TI  - Evaluation of the imaging properties of two generations of a CCD-based system for
      digital chest radiography.
AB  - Two generations of a CCD-based detector system with lens-based optical coupling
      for digital chest radiography were evaluated in terms of presampling MTF, NPS,
      NEQ, DQE, linearity in response, and SNR over the detector area. Measurements
      were performed over a wide exposure range and at several different beam
      qualities. Neither the presampling MTF nor the DQE showed any general strong beam
      quality dependence, whereas the NPS and NEQ did when compared at specific
      entrance air kerma values. The exposure dependency for the DQE was found to be
      considerable, with the detectors showing low DQE at low exposures, and higher DQE
      at higher exposures. It was found that the second generation has been
      substantially improved compared to its predecessor regarding all the relevant
      parameters. The DQE(0) at an entrance air kerma of 5 microGy increased from 9% to
      15%, mainly due to a better system gain (including optical coupling efficiency
      and matching of the energy of the emitted light photons to the sensitivity of the
      CCD camera). The first generation of detectors was found to have problems with
      bad peripheral resolution [MTF(muN/2) <0.1]. This problem was nonexistent for the
      second generation for which uniform resolution has been obtained
      [MTF(muN/2)=0.3]. A theoretical calculation of the DQE of two model systems
      similar to the ones evaluated was also performed, and the results were comparable
      to the experimentally determined data at high exposures. The model shows that
      both systems suffer from low optical coupling efficiency due to the large
      demagnification used. The main conclusion is that although the second generation
      has been improved, there is still a problem with low system gain leading to
      relatively modest DQE values, especially at low exposures.

PMID- 12408304
TI  - Beyond bixels: generalizing the optimization parameters for intensity modulated
      radiation therapy.
AB  - Intensity modulated radiation therapy (IMRT) treatment planning systems optimize
      fluence distributions by subdividing the fluence distribution into rectangular
      bixels. The algorithms typically optimize the fluence intensity directly, often
      leading to fluence distributions with sharp discontinuities. These
      discontinuities may yield difficulties in delivery of the fluence distribution,
      leading to inaccurate dose delivery. We have developed a method for decoupling
      the bixel intensities from the optimization parameters; either by introducing
      optimization control points from which the bixel intensities are interpolated or
      by parametrizing the fluence distribution using basis functions. In either case,
      the number of optimization search parameters is reduced from the direct bixel
      optimization method. To illustrate the concept, the technique is applied to two
      dimensional idealized head and neck treatment plans. The interpolation algorithms
      investigated were nearest-neighbor, linear and cubic spline, and radial basis
      functions serve as the basis function test. The interpolation and basis function
      optimization techniques were compared against the direct bixel calculation. The
      number of optimization parameters were significantly reduced relative to the
      bixel optimization, and this was evident in the reduction of computation time of
      as much as 58% from the full bixel optimization. The dose distributions obtained
      using the reduced optimization parameter sets were very similar to the full bixel
      optimization when examined by dose distributions, statistics, and dose-volume
      histograms. To evaluate the sensitivity of the fluence calculations to spatial
      misalignment caused either by delivery errors or patient motion, the doses were
      recomputed with a 1 mm shift in each beam and compared to the unshifted
      distributions. Except for the nearest-neighbor algorithm, the reduced
      optimization parameter dose distributions were generally less sensitive to
      spatial shifts than the bixel optimization. These results indicate that
      significant reductions in optimization parameter sets can be accomplished with a
      negligible reduction in dose distribution quality. The decreased parameters can
      result in a reduced optimization time, or can be used to allow an improved and
      consequently more computation-intensive dose calculation for more accurate dose
      calculations during the optimization process. The basis functions may be
      generalized to model the accelerator motion for direct computation of the
      accelerator motion sequence, removing the need for developing an independent leaf
      sequence step.

PMID- 12408305
TI  - The effect of set-up uncertainties, contour changes, and tissue inhomogeneities
      on target dose-volume histograms.
AB  - Understanding set-up uncertainty effects on dose distributions is an important
      clinical problem but difficult to model accurately due to their dependence on
      tissue inhomogeneities and changes in the surface contour (i.e., variant
      effects). The aims are: (1) to evaluate and quantify the invariant and variant
      effects of set-up uncertainties, contour changes and tissue inhomogeneities on
      target dose-volume histograms (DVHs); (2) to propose a method to interpolate
      (variant) DVHs. We present a lung cancer patient to estimate the significance of
      set-up uncertainties, contour changes and tissue inhomogeneities in target DVHs.
      Differential DVHs are calculated for 15 displacement errors (with respect to the
      isocenter) using (1) an invariant shift of the dose distribution at the
      isocenter, (2) a full variant calculation, and (3) a B-spline interpolation
      applied to sparsely sampled variant DVHs. The collapsed cone algorithm was used
      for all dose calculations. Dosimetric differences are quantified with the root
      mean square (RMS) deviation and the equivalent uniform dose (EUD). To determine
      set-up uncertainty effects, weighted mean EUDs, assuming normally distributed
      displacement errors, are used. The maximum absolute difference and RMS deviation
      in the integral DVHs' relative dose between (1) the invariant and calculated
      curves are 65.2% and 5.8% and (2) the interpolated and calculated curves are
      16.9% and 2.5%. Similarly, the maximum absolute difference and RMS deviation in
      mean EUD as a function of the set-up uncertainty's standard deviation between (1)
      the invariant and calculated curves are 0.02 and 0.01 Gy; and (2) the
      interpolated and calculated curves are 0.01 and 0.006 Gy. Since a "worst-case"
      example is selected, we conclude that, in the majority of clinical cases, the
      variant effects of contour changes, tissue inhomogeneities and set-up
      uncertainties on EUD are negligible. Interpolation is a valid, efficient method
      to approximate DVHs.

PMID- 12408306
TI  - Theoretical and experimental quantification of carotid plaque volume measurements
      made by three-dimensional ultrasound using test phantoms.
AB  - An accurate technique that exhibits low variability has practical importance for
      the quantification of carotid plaque volume. Such a technique is necessary to
      monitor plaque progression or regression that may result in response to
      nonsurgical therapy. In this study, we investigate the accuracy and variability
      of plaque volume measurement by three-dimensional ultrasound using vascular
      plaque phantoms over a range of 68.2 mm3 to 285.5 mm3. The agar plaques
      maintained a consistent cylindrical geometry with variations in the height,
      length, and echogenicity. The volume of each plaque was determined by water
      displacement. The three-dimensional (3D) ultrasound (US) images were acquired
      with a mechanical scanning system which creates a 3D US Cartesian volume, that
      was manipulated and viewed in any orientation, from a collection of conventional
      parallel two-dimensional (2D) US images. The plaque volumes were measured by
      serial 2D manual planimtery. The mean accuracy in plaque volume measurement was
      3.1+/-0.9%. Variability in plaque volume measurement was calculated to be 4.0+/
      1.0% and 5.1+/-1.4% for intraobserver and interobserver measurements,
      respectively. We have also developed a theoretical description for the variance
      in measurement of plaque volume using manual planimetry. Root-mean-square
      difference between experimentally and theoretically determined values of plaque
      volume fractional variance was 9%.

PMID- 12408307
TI  - The medical-irradiation characteristics for neutron capture therapy at the Heavy
      Water Neutron Irradiation Facility of Kyoto University Research Reactor.
AB  - At the Heavy Water Neutron Irradiation Facility of the Kyoto University Research
      Reactor, the mix irradiation of thermal and epi-thermal neutrons, and the solo
      irradiation of epi-thermal neutrons are available additionally to the thermal
      neutron irradiation, and then the neutron capture therapy (NCT) at this facility
      became more flexible, after the update in 1996. The estimation of the depth dose
      distributions in NCT clinical irradiation, were performed for the standard
      irradiation modes of thermal, mixed and epi-thermal neutrons, from the both sides
      of experiment and calculation. On the assumption that the 10B concentration in
      tumor part was 40 ppm and the ratio of tumor to normal tissue was 3.5, the
      advantage depth were estimated to 5.4, 6.0, and 8.0, for the respective standard
      irradiation modes. It was confirmed that the various irradiation conditions can
      be selected according to the target-volume conditions, such as size, depth, etc.
      Besides, in the viewpoint of the radiation shielding for patient, it was
      confirmed that the whole-body exposure is effectively reduced by the new clinical
      collimators, compared with the old one.

PMID- 12408308
TI  - Controllability of depth dose distribution for neutron capture therapy at the
      Heavy Water Neutron Irradiation Facility of Kyoto University Research Reactor.
AB  - The updating construction of the Heavy Water Neutron Irradiation Facility of the
      Kyoto University Research Reactor has been performed from November 1995 to March
      1996 mainly for the improvement in neutron capture therapy. On the performance,
      the neutron irradiation modes with the variable energy spectra from almost pure
      thermal to epi-thermal neutrons became available by the control of the heavy
      water thickness in the spectrum shifter and by the open-and-close of the cadmium
      and boral thermal neutron filters. The depth distributions of thermal, epi
      thermal and fast neutron fluxes were measured by activation method using gold and
      indium, and the depth distributions of gamma-ray absorbed dose rate were measured
      using thermo-luminescent dosimeter of beryllium oxide for the several irradiation
      modes. From these measured data, the controllability of the depth dose
      distribution using the spectrum shifter and the thermal neutron filters was
      confirmed.

PMID- 12408309
TI  - Improved treatment planning for boron neutron capture therapy for glioblastoma
      multiforme using fluorine-18 labeled boronophenylalanine and positron emission
      tomography.
AB  - Boron neutron capture therapy (BNCT) is a cancer brachytherapy based upon the
      thermal neutron reaction: 10B(n,alpha)7Li. The efficacy of the treatment depends
      primarily upon two conditions being met: (a) the preferential concentration of a
      boronated compound in the neoplasm and (b) an adequate fluence of thermal
      neutrons delivered to the neoplasm. The boronated amino acid, para
      boronophenylalanine (BPA), is the agent widely used in clinical trials to deliver
      10B to the malignancy. Positron emission tomography (PET) can be used to generate
      in vivo boron distribution maps by labeling BPA with the positron emitting
      nuclide fluorine-18. The incorporation of the PET-derived boron distribution maps
      into current treatment planning protocols is shown to provide improved treatment
      plans. Using previously established protocols, six patients with glioblastoma had
      18BPA PET scans. The PET distribution maps obtained were used in the conventional
      BNCT treatment codes. The isodose curves derived from the PET data are shown to
      differ both qualitatively and quantitatively from the conventional isodose curves
      that were derived from calculations based upon the assumption of uniform uptake
      of the pharmaceutical in tumor and normal brain regions. The clinical course of
      each of the patients who eventually received BNCT (five of the six patients) was
      compared using both sets of isodose calculations. The isodose contours based upon
      PET derived distribution data appear to be more consistent with the patients'
      clinical course.

PMID- 12408310
TI  - Intensity modulated arc deliveries approximated by a large number of fixed gantry
      position sliding window dynamic multileaf collimator fields.
AB  - The intensity modulated arc has been proposed as an alternative to tomotherapy.
      Treatment planing systems more typically model the conventional step and shoot or
      sliding window dynamic multileaf collimator (DMLC) deliveries, and may not
      support intensity modulated arc therapy (IMAT). As well, another potential
      drawback to this technique is that increasing the number of intensity levels
      required to achieve certain dose distributions necessitates increasing the number
      of gantry passes, as may occur if the desired dose distribution is complex (e.g.,
      concave or bifurcated), potentially increasing the overall treatment time. A
      technique is presented here for the delivery of tomotherapy like dose
      distributions in a single gantry pass by the use of a large number of fields
      modulated by a sliding window DMLC technique from fixed equally spaced gantry
      positions. This serves as a good approximation to either IMAT or tomotherapy
      deliveries. The planning of these fields is achieved using iterative filtered
      back projection. Measured results of deliveries of varying degrees of complexity
      on a homogeneous phantom are compared to desired distributions.

PMID- 12408311
TI  - Accelerating Monte Carlo simulations of radiation therapy dose distributions
      using wavelet threshold de-noising.
AB  - The Monte Carlo dose calculation method works by simulating individual energetic
      photons or electrons as they traverse a digital representation of the patient
      anatomy. However, Monte Carlo results fluctuate until a large number of particles
      are simulated. We propose wavelet threshold de-noising as a postprocessing step
      to accelerate convergence of Monte Carlo dose calculations. A sampled rough
      function (such as Monte Carlo noise) gives wavelet transform coefficients which
      are more nearly equal in amplitude than those of a sampled smooth function.
      Wavelet hard-threshold de-noising sets to zero those wavelet coefficients which
      fall below a threshold; the image is then reconstructed. We implemented the
      computationally efficient 9,7-biorthogonal filters in the C language. Transform
      results were averaged over transform origin selections to reduce artifacts. A
      method for selecting best threshold values is described. The algorithm requires
      about 336 floating point arithmetic operations per dose grid point. We applied
      wavelet threshold de-noising to two two-dimensional dose distributions: a dose
      distribution generated by 10 MeV electrons incident on a water phantom with a
      step-heterogeneity, and a slice from a lung heterogeneity phantom. Dose
      distributions were simulated using the Integrated Tiger Series Monte Carlo code.
      We studied threshold selection, resulting dose image smoothness, and resulting
      dose image accuracy as a function of the number of source particles. For both
      phantoms, with a suitable value of the threshold parameter, voxel-to-voxel noise
      was suppressed with little introduction of bias. The roughness of wavelet de
      noised dose distributions (according to a Laplacian metric) was nearly
      independent of the number of source electrons, though the accuracy of the de
      noised dose image improved with increasing numbers of source electrons. We
      conclude that wavelet shrinkage de-noising is a promising method for effectively
      accelerating Monte Carlo dose calculations by factors of 2 or more.

PMID- 12408312
TI  - Energy-loss straggling algorithms for Monte Carlo electron transport.
AB  - A new method is presented for the modeling of the electron (positron) energy-loss
      straggling in Monte Carlo transport simulations. First, the Vavilov energy-loss
      distribution is calculated for electrons and positrons using the Moller and
      Bhabha collision cross-sections, respectively. The maximum energy transfer in a
      single collision (E(S)) is considered as variable. Binding effects from low
      energy collisions are modeled using the Blunck and Westphal model. Secondly, new
      algorithms are developed to fit the Vavilov distribution. These algorithms are
      based on the first three moments of the energy-loss distribution. They are
      suitable for rapid random sampling of the energy loss. The new algorithms are
      validated against the Vavilov distribution for electrons and positrons, water and
      lead, kinetic energy E0 of 0.1, 1, and 10 MeV and several values of E(S) (10, 50,
      100, and 200 keV). The developed algorithms are incorporated in a new version of
      the GEPTS Monte Carlo code called GEPTS(III). Collisions involving energy
      transfers larger than E(S) are simulated individually and the energy loss due to
      soft collisions (energy transfers less than E(S)) is sampled using the new
      algorithms. The straggling effect is therefore taken into account whatever the
      chosen E(S) value. GEPTS(III) and EGSnrc are used for the calculation of (1)
      electron dose distributions in water and (2) energy spectra for electrons passing
      through water and tungsten slabs. Electron beams of 1, 2, 5, 10, and 20 MeV along
      with varying E(S) values are considered. Electron dose distributions in water are
      rather insensitive to the soft collision straggling. The use of the new
      algorithms results in a slight gain in computation time when relatively large
      E(S) values are used (e.g., E(S) = 1 MeV for 10 MeV electrons). However, the
      calculation of electron energy spectra is very sensitive to the soft collision
      straggling. GEPTS(III) (E(S) = 200 keV) is about 5 and 11 times faster than
      EGSnrc (E(S) = 1 keV) for the case of 2 and 20 MeV electrons passing through
      0.025 and 0.25 cm water slabs, respectively. Contrary to EGSnrc, GEPTS(III)
      accounts for the energy-spectrum broadening due to the binding effects. The
      resulting differences between the two codes are significant for 5 and 10 MeV
      electrons passing through a 0.01 cm tungsten slab. Gains in GEPTS(III)
      computation times (approximately a factor 5) are also observed for tungsten. In
      short, GEPTS(III) provides significant advantages (rapidity and accuracy) for
      electron transport simulations, especially those dealing with energy-spectrum
      calculations, as encountered in clinical electron beam modeling studies. In other
      respects, the developed approach is more suitable than class-II codes for the use
      of accurate electron cross sections (numerical data) at low energy (<100 keV).

PMID- 12408313
TI  - Rapid radiographic film calibration for IMRT verification using automated MLC
      fields.
AB  - A method for measuring a film sensitometric curve using a single sheet of film
      exposed with a two field step-and-shoot MLC treatment was developed and tested
      with Kodak XV2 and EDR2 films. With this technique a film sensitometric curve can
      be completed in only 10 minutes, making it practical to generate new film
      calibrations daily. This method is applicable to film calibrations for all
      purposes, but is particularly useful in IMRT treatment verification due to the
      method's use of small fields. This method agrees with the traditional large-field
      multifilm calibration within 0.5% and will produce sensitometric curves with
      errors less than 1% throughout the dose range, including uncertainties in dose
      delivery, film response, and optical density measurements. OD values for XV2 and
      EDR2 films were consistent in the middle of exposure areas at high depths, but
      the XV2 film penumbra regions showed large amounts of over-response as the
      calibration depth increased. If XV2 film is used for IMRT treatment verification,
      it is necessary to reduce the fluence of low energy photons in areas around the
      film by using thin lead shields. EDR2 film was shown to have minimal energy
      dependence, as it accurately represented penumbra areas and yielded identical
      sensitometric curves generated with 6 and 18 MV photons. However, its darker tint
      may make it more sensitive to scanning laser film digitizers' horizontal
      nonuniformities. This single film method proved to be superior to the traditional
      calibration method and allows fast daily calibrations of films for highly
      accurate IMRT delivery verifications.

PMID- 12408314
TI  - Pathophysiological effects of radiation on atherosclerosis development and
      progression, and the incidence of cardiovascular complications.
AB  - Radiation therapy while important in the management of several diseases, is
      implicated in the causation of atherosclerosis and other cardiovascular
      complications. Cancer and atherosclerosis go through the same stages of
      initiation, promotion, and complication, beginning with a mutation in a single
      cell. Clinical observations before the 1960s lead to the belief that the heart is
      relatively resistant to the doses of radiation used in radiotherapy.
      Subsequently, it was discovered that the heart is sensitive to radiation and many
      cardiac structures may be damaged by radiation exposure. A significantly higher
      risk of death due to ischemic heart disease has been reported for patients
      treated with radiation for Hodgkin's disease and breast cancer. Certain cytokines
      and growth factors, such as TGF-beta1 and IL-1 beta, may stimulate radiation
      induced endothelial proliferation, fibroblast proliferation, collagen deposition,
      and fibrosis leading to advanced lesions of atherosclerosis. The treatment for
      radiation-induced ischemic heart disease includes conventional pharmacological
      therapy, balloon angioplasty, and bypass surgery. Endovascular irradiation has
      been shown to be effective in reducing restenosis-like response to balloon
      catheter injury in animal models. Caution must be exercised when radiation
      therapy is combined with doxorubicin because there appears to be a synergistic
      toxic effect on the myocardium. Damage to endothelial cells is a central event in
      the pathogenesis of damage to the coronary arteries. Certain growth factors that
      interfere with the apoptotic pathway may provide new therapeutic strategies for
      reducing the risk of radiation-induced damage to the heart. Exposure to low level
      occupational or environmental radiation appears to pose no undue risk of
      atherosclerosis development or cardiovascular mortality. But, other radiation
      induced processes such as the bystander effects, abscopal effects, hormesis, and
      individual variations in radiosensitivity may be important in certain
      circumstances.

PMID- 12408315
TI  - Prospects for quantitative computed tomography imaging in the presence of foreign
      metal bodies using statistical image reconstruction.
AB  - X-ray computed tomography (CT) images of patients bearing metal intracavitary
      applicators or other metal foreign objects exhibit severe artifacts including
      streaks and aliasing. We have systematically evaluated via computer simulations
      the impact of scattered radiation, the polyenergetic spectrum, and measurement
      noise on the performance of three reconstruction algorithms: conventional
      filtered backprojection (FBP), deterministic iterative deblurring, and a new
      iterative algorithm, alternating minimization (AM), based on a CT detector model
      that includes noise, scatter, and polyenergetic spectra. Contrary to the dominant
      view of the literature, FBP streaking artifacts are due mostly to mismatches
      between FBP's simplified model of CT detector response and the physical process
      of signal acquisition. Artifacts on AM images are significantly mitigated as this
      algorithm substantially reduces detector-model mismatches. However, metal
      artifacts are reduced to acceptable levels only when prior knowledge of the metal
      object in the patient, including its pose, shape, and attenuation map, are used
      to constrain AM's iterations. AM image reconstruction, in combination with object
      constrained CT to estimate the pose of metal objects in the patient, is a
      promising approach for effectively mitigating metal artifacts and making
      quantitative estimation of tissue attenuation coefficients a clinical
      possibility.

PMID- 12408316
TI  - Development of contrast digital mammography.
AB  - Development of breast tumors is often accompanied by angiogenesis--the formation
      of new blood vessels. It is possible to image the effects of this process by
      tracking the uptake and washout of contrast agents in the vicinity of a lesion.
      In this article, a method for carrying out contrast subtraction mammography on a
      full-field digital mammography unit is described. Spectral measurements and
      modeling were performed to optimize the choice of x-ray target, kilovoltage and x
      ray beam filtration for contrast digital mammography (CDM) on an available
      digital mammography system. Phantom studies were carried out to determine the
      sensitivity of CDM to iodine. Detection of iodine area densities of 0.3 mg/cm2 is
      possible for a circular object with a radius of 1.3 mm, which allows detection of
      uptake levels in the breast typically seen with cancer and some benign breast
      conditions. It was found that with a molybdenum anode x-ray tube, copper
      filtration could be used to effectively shape the x-ray spectrum to maximize the
      proportion of x rays with energies above the k edge of iodine. Simple logarithmic
      subtraction was found to be adequate in suppressing background signals dependent
      on the x-ray beam intensity and background thickness of the breast. The total x
      ray dose from the procedure ranges between 1 and 3 mGy, similar to that from a
      conventional single view film mammogram. A clinical pilot study is currently
      being carried out to evaluate this technique.

PMID- 12408317
TI  - Attenuation of 4-20 MV x rays by a new compensator material of cement.
AB  - The properties of a new cement based material for production of compensators are
      presented. Broad beam attenuation of 4-20 MV x rays by slabs of the material have
      been measured at various field sizes and depths in a large water phantom. For
      comparison the attenuation of aluminum was determined at some of the photon
      energies and it was found that the attenuation properties of the cement based
      material are very close to those of aluminum. At 6 and 18 MV, a comparison of
      different phantoms for attenuation measurements was carried out. For this
      investigation the ionization chamber was placed in a 50x50x50 cm3 water phantom,
      a 20x20x20 cm3 water equivalent plastic phantom, and a cylindrical mini-phantom.
      Agreement was obtained between the measurements in the large water phantom and in
      the water equivalent plastic phantom. The measurements carried out with the mini
      phantom in a 6 MV x-ray beam gave a higher transmission versus absorber thickness
      than the transmission found with the water phantom resulting in a lower value of
      the effective attenuation coefficient. At 18 MV x rays the difference between the
      measurements in the water phantom and in the mini-phantom was less. This shows
      that a water equivalent plastic phantom with an area comparable with the largest
      field size applied can be used for measurements of effective attenuation
      coefficients, whereas a mini-phantom cannot be used directly, especially at low
      photon energies.

PMID- 12408318
TI  - Experimental determination of dosimetric characterization of a newly designed
      encapsulated interstitial brachytherapy source of 103Pd-model Pd-1.
AB  - A newly designed encapsulated 103Pd source has been introduced (BrachySeed-Pd
      103, also named Model Pd-1, manufactured by DRAXIMAGE Inc. and distributed by
      Cytogen Corp.) for interstitial brachytherapy to provide more isotropic dose
      distributions. In this work, the dosimetric characteristics of the 103Pd source
      were measured with micro LiF TLD chips and dosimetry parameters were
      characterized based upon the American Association of Physicists in Medicine
      (AAPM) Task Group No. 43 formalism. The dose rate constant of the sources was
      determined to be 0.66 +/-0.05 cGy h(-1) U(-1). The radial dose function was
      measured and was found to be similar to that of the Theragenics Model 200 103Pd
      source. The anisotropy constant for the Model Pd-1 source was determined to be
      1.03.

PMID- 12408319
TI  - High energy electron beams shaped with applied magnetic fields could provide a
      competitive and cost-effective alternative to proton and heavy-ion radiotherapy.
      For the proposition.

PMID- 12408321
TI  - Dosimetry of therapeutic photon beams using an extended dose range film.
AB  - For intensity modulated radiation therapy (IMRT) dose distribution verification,
      multidimensional measurements are required to quantify the steep dose-gradient
      regions. High resolution, two-dimensional dose distributions can be measured
      using radiographic film. However, the photon energy response of film is known to
      be a function of depth, field size, and photon beam energy, potentially reducing
      the accuracy of dose distribution measurements. The dosimetric properties of the
      recently developed Kodak EDR2 film were investigated and compared to those of
      Kodak XV film. The dose responses of both film types to 6 MV and 18 MV photon
      beams were investigated for depths of 5 cm, 10 cm, and 15 cm and field sizes of
      4x4 cm2 and 15x15 cm2. This analysis involved the determination of sensitometric
      curves for XV and EDR2 films, the determination of dose profiles from exposed XV
      and EDR2 films, and comparison of the film-generated dose profiles to ionization
      chamber measurements. For the combinations of photon beam energy, depth, and
      field size investigated here, our results indicate that the sensitometric curves
      are nearly independent of field size and depth of calibration. For a field size
      of 4x4 cm2, a single sensitometric curve for either EDR2 and XV film can be used
      for the determination of relative dose profiles. For the larger field size, the
      sensitometric curve for EDR2 film is superior to XV film in regions where the
      dose falls below 20% of the central axis dose, due to the effects that the
      increased low energy scattered photon contributions have on film response. The
      limited field size and depth dependence of sensitometric data measured using EDR2
      film, along with the inherently wide linear dose-response range of EDR2 film,
      makes it better suited to the verification of IMRT dose distributions.

PMID- 12408322
TI  - Parameter dependence of the MCNP electron transport in determining dose
      distributions.
AB  - In this paper, a detailed study of the electron transport in MCNP is performed,
      separating the effects of the energy binning technique on the energy loss rate,
      the scattering angles, and the sub-step length as a function of energy. As this
      problem is already well known, in this paper we focus on the explanation as to
      why the default mode of MCNP can lead to large deviations. The resolution
      dependence was investigated as well. An error in the MCNP code in the energy
      binning technique in the default mode (DBCN 18 card = 0) was revealed, more
      specific in the updating of cross sections when a sub-step is performed
      corresponding to a high-energy loss. This updating error is not present in the
      ITS mode (DBCN 18 card = 1) and leads to a systematically lower dose deposition
      rate in the default mode. The effect is present for all energies studied (0.5-10
      MeV) and depends on the geometrical resolution of the scoring regions and the
      energy grid resolution. The effect of the energy binning technique is of the same
      order of that of the updating error for energies below 2 MeV, and becomes less
      important for higher energies. For a 1 MeV point source surrounded by homogeneous
      water, the deviation of the default MCNP results at short distances attains 9%
      and remains approximately the same for all energies. This effect could be
      corrected by removing the completion of an energy step each time an electron
      changes from an energy bin during a sub-step. Another solution consists of
      performing all calculations in the ITS mode. Another problem is the resolution
      dependence, even in the ITS mode. The higher the resolution is chosen (the
      smaller the scoring regions) the faster the energy is deposited along the
      electron track. It is proven that this is caused by starting a new energy step
      when crossing a surface. The resolution effect should be investigated for every
      specific case when calculating dose distributions around beta sources. The
      resolution should not be higher than 0.85*(1-EFAC)*CSDA, where EFAC is the energy
      loss per energy step and CSDA a continuous slowing down approximation range. This
      effect could as well be removed by determining the cross sections for energy loss
      and multiple scattering at the average energy of an energy step and by sampling
      the cross sections for each sub-step. Overall, we conclude that MCNP cannot be
      used without a caution due to possible errors in the electron transport. When
      care is taken, it is possible to obtain correct results that are in agreement
      with other Monte Carlo codes.

PMID- 12408324
TI  - A vision for a healthy industry.

PMID- 12408323
TI  - National concerns, local impacts.

PMID- 12408325
TI  - Controlling movement to control disease.

PMID- 12408326
TI  - Experiences of University of Liverpool veterinary students during the 2001
      epidemic of foot-and-mouth disease.
AB  - The 2001 epidemic of foot-and-mouth disease disrupted the teaching of practical
      farm animal work for much of that year. Many students in their clinical years in
      the Faculty of Veterinary Science at the University of Liverpool, went to help to
      control the disease, both in place of some normal term-time activities and as
      part of their extramural studies out of term time. This paper, which is based on
      a questionnaire survey of the students, describes their experiences, the types of
      work they did, the skills they acquired and their views on the effects of the
      epidemic on their studies. The vast majority of students felt they had benefited
      from their experiences and had contributed to combating the epidemic.

PMID- 12408327
TI  - Biomarkers of exposure to cyanogens in horses with grass sickness.
AB  - To test the hypothesis that equine grass sickness may be associated with the
      ingestion of cyanogenic glycosides from white clover (Trifolium repens), the
      concentrations of whole blood cyanide, and plasma and urinary thiocyanate, the
      main metabolite of cyanide, were measured in 12 horses with acute grass sickness
      and 10 horses with subacute grass sickness, and in 43 control horses, of which 21
      were co-grazing with cases of acute grass sickness, 12 grazed pastures where
      grass sickness had not been reported, and 10 were stabled horses. The healthy
      horses which grazed with cases of acute grass sickness had higher concentrations
      of blood cyanide, and plasma and urinary thiocyanate than the other control
      horses, consistent with an increased exposure to cyanogens. The horses with grass
      sickness had no evidence of a recent intake of cyanogens, but may have been
      exposed to increased levels of cyanogens before they became anorexic.

PMID- 12408328
TI  - Position of the abomasum in dairy cows during the first six weeks after calving.
AB  - The position of the abomasum in six cows was examined by ultrasonography at
      regular intervals for six weeks after they had calved. Its position was
      established by determining the distance between the margin of the left side of
      the abomasum and the ventral midline at two sites. During the last weeks of
      pregnancy, the abomasum was positioned in a small region of the left ventral side
      of the abdominal cavity. At parturition it was positioned high on the left side
      and then descended. The abomasum was furthest from the midline immediately after
      parturition. Its position was related to the interval after calving, the cow's
      feed intake, and the pH and osmotic pressure of the rumen fluid. There was
      considerable variation between the cows in the position of the abomasum, which
      was in part due to analytical variation, and in individual cows it had a
      circadian rhythm.

PMID- 12408329
TI  - Incidence of antibodies to selected bacterial pathogens in wild turkeys
      (Meleagris gallopavo) in Kansas, USA.

PMID- 12408330
TI  - Preliminary epidemiological analyses of the first 16 cases of BSE born after July
      31, 1996, in Great Britain.

PMID- 12408331
TI  - Preliminary study of short-term preservation of ovine ovarian tissue containing
      preantral follicles in saline solution of TCM199.

PMID- 12408332
TI  - Antimicrobial drug resistance and veterinary therapeutics.

PMID- 12408333
TI  - European bat lyssavirus type 2 in a bat found in Lancashire.

PMID- 12408334
TI  - Policies on FMD.

PMID- 12408335
TI  - Competition Commission inquiry into POMs.

PMID- 12408336
TI  - Competition Commission inquiry into POMs.

PMID- 12408337
TI  - Chromosomal translocations and their role in the pathogenesis of non-Hodgkin's
      lymphomas.
AB  - The discovery that non-Hodgkin's lymphomas are monoclonal and that recurrent
      chromosomal translocations are involved in their pathogenesis has greatly
      revolutionised their diagnosis and improved our understanding of these diseases.
      In the last decades, many genes deregulated by such recurrent chromosomal
      translocations have been identified. However, we have also learned that these
      genetic alterations are apparently insufficient, in themselves, to cause
      neoplastic cell transformation and that more complex genetic events must be
      involved. This review examines the involved genes in chromosomal translocations
      and current evidence and postulated mechanisms for their role in the pathogenesis
      of non-Hodgkin's lymphomas.

PMID- 12408338
TI  - Atypical ductal hyperplasia and atypia of uncertain significance in core biopsies
      from mammographically detected lesions: correlation with excision diagnosis.
AB  - AIMS: To assess: (1) the prevalence of reporting of atypical ductal hyperplasia
      (ADH) and intraductal atypia of uncertain significance (AUS) in a series of core
      biopsies from mammographically detected lesions, (2) the proportion of cases
      where excision revealed breast carcinoma, and (3) whether any diagnoses should be
      revised on review. METHODS: Breast core biopsy reports from the Sir Charles
      Gairdner Hospital Breast Assessment Centre for the years 1999-2000 were
      retrieved. Slides from cases reported as ADH or AUS were reviewed as well as
      slides from the excision biopsies. RESULTS: There were 1048 core biopsies from
      911 women. Breast carcinoma was diagnosed in 197 samples (18.8%) including 88
      with invasive carcinoma (8.4%), 109 with ductal carcinoma in situ (DCIS) (10.4%).
      Three biopsies (0.3%) 'suspicious' of invasive carcinoma proved to be so. Of 52
      samples (5.0%) with a diagnosis of ADH or AUS, 46 were excised, showing seven
      invasive carcinomas, 15 DCIS, 11 ADH, two lobular carcinoma in situ (LCIS), nine
      fibrocystic change (FCC), one mucocoele-like lesion and one fibroadenoma. The 22
      malignancies represented 47.8% of the excised lesions. On review, seven of the 52
      original core diagnoses were downgraded to benign hyperplasia. Five underwent
      excision, revealing two FCC, one complex sclerosing lesion, and two incidental
      lesions unrelated to the mammographic abnormality, including a microscopic
      tubular carcinoma and a focus of LCIS. In one case reviewed as unsatisfactory,
      excision showed invasive carcinoma. Lesions of particular interest included a
      case of high-grade DCIS with local regression in the core biopsy (so-called 'bumt
      out DCIS'), and one case diagnosed on excision as micropapillary ADH, where the
      review diagnosis was micropapillary DCIS. CONCLUSIONS: ADH and AUS were reported
      in 5.0% of biopsies. There was a high rate of carcinoma (47.8%) in subsequent
      excisions. Very few diagnoses were revised on review. Current protocols for
      excision of lesions with a 14-gauge core biopsy diagnosis of ADH/AUS appear
      justified. Literature review suggests that vacuum-assisted core sampling with 11
      gauge needles will not remove the need for excision. Further study of local
      regression of DCIS and micropapillary lesions will be worthwhile.

PMID- 12408339
TI  - Pathology of hepatocellular carcinoma and its precursors using proton magnetic
      resonance spectroscopy and a statistical classification strategy.
AB  - AIM: Apply the statistical classification strategy (SCS) to magnetic resonance
      spectroscopy (MRS) data from liver biopsies and test its potential to
      discriminate between normal liver, cirrhotic nodules and nodules of
      hepatocellular carcinoma with a high degree of accuracy. METHODS: Liver tissue
      specimens from 54 patients undergoing either partial (hemi) or total hepatectomy
      were analysed by one-dimensional proton MRS at 8.5 Tesla. Histologically, these
      specimens were confirmed as normal (n=31), cirrhotic (n=59), and hepatocellular
      carcinoma (HCC, n=32). Diagnostic correlation was performed between the MR
      spectra and histopathology. An SCS was applied consisting of pre-processing MR
      magnitude spectra to identify spectral regions of maximal discriminatory value,
      and cross-validated linear discriminant analysis. RESULTS: SCS applied to MRS
      data distinguished normal liver tissue from HCC with an accuracy of 100%. Normal
      liver tissue was distinguished from cirrhotic liver with an accuracy of 92% and
      cirrhotic liver was distinguished from HCC with an accuracy of 98%. CONCLUSIONS:
      SCS applied to proton MRS of liver biopsies provides a robust method to
      distinguish, with a high degree of accuracy, HCC from both cirrhotic and normal
      liver.

PMID- 12408340
TI  - Hep Par 1 in gastric and bowel carcinomas: an immunohistochemical study.
AB  - AIMS: Hep Par 1 has been described as a specific marker of hepatocellular
      differentiation and its immunohistochemical use has been suggested as a helpful
      tool for hepatocellular carcinoma (HCC) diagnosis. Most metastatic liver tumours
      come from the gastrointestinal tract and usually can be distinguished from HCC
      only through histology. We evaluated by immunohistochemistry the specificity of
      Hep Par 1, studying the presence of the epitope that reacts with Hep Par 1 in
      primary gastric and colorectal cancers. METHODS: A series of 39 cases of primary
      gastric and 18 cases of colorectal carcinoma were selected. Twenty-six of the 39
      gastric carcinomas were of the intestinal type, six of the diffuse type, three of
      the mixed type and five had hepatoid differentiation. Two of the 18 colorectal
      adenocarcinomas were well differentiated, 14 moderately differentiated, one
      poorly differentiated and one was of the mucinous type. Five-microm sections were
      stained by immunohistochemistry using Hep Par 1 as primary antibody. RESULTS:
      Immunohistochemical staining was observed in 26 gastric carcinomas (69%) and nine
      large bowel carcinomas (50%). Fifteen of the 26 positive-stained gastric cancers
      were of intestinal type, four of diffuse type and two of mixed type cases. All of
      the five hepatoid type cases stained positively. Two of the nine positively
      stained colorectal cancers were well differentiated, six were moderately
      differentiated and one was a mucinous type adenocarcinoma. The staining pattern
      was cytoplasmic and granular as described in benign and malignant hepatocytes.
      The percentage of immunostained cells was graded as follows: 0 (no staining); 1
      (>0-5%); 2 (> 5-50%); 3 (> 50%). Of the 26 positive gastric tumours, 13 showed a
      staining score of 1, eight scored 2, and five scored 3. Four of the nine positive
      intestinal carcinomas showed a staining score of 1, and five scored 2.
      CONCLUSIONS: Our results show that Hep Par 1 is a highly sensitive marker of
      hepatocellular differentiation as demonstrated by the expression in gastric
      tumours with hepatoid histotype. However, the frequent reaction with neoplastic
      cells of gastric and bowel carcinomas shows a low grade of specificity of this
      antibody.

PMID- 12408341
TI  - Prognostic implication of nm23-H1 expression in colorectal carcinomas.
AB  - AIMS: Expression of nm23 has been identified as a potential metastatic
      suppressor. In this study, nm23-H1 expression, clinicopathological parameters and
      influences on clinical outcomes were investigated in colorectal carcinoma
      patients. METHODS: Immunostaining was performed on 185 colorectal carcinomas
      using a polyclonal anti-nm23-H1 antibody. RESULTS: The nm23-H1 immunoreactivity
      was weak in 31 (17%), moderate in 48 (26%) and strong in 106 (57%) cases. The
      well differentiated adenocarcinomas showed significantly strong staining for nm23
      H1 compared with the moderately and poorly differentiated adenocarcinomas (chi2
      test, P<0.001). Advanced tumour stages were associated with reduced nm23-H1
      expression (P<0.001). There was an inverse correlation with angiolymphatic
      invasion, nodal metastasis and liver metastasis (univariate logistic regression
      analysis, P<0.001). In univariate analysis, patients with reduced expression of
      nm23-H1 had significantly shorter overall and disease-free survival than the
      strong expression group (log-rank test for trend, P=0.002 and P=0.003,
      respectively). CONCLUSIONS: Our results indicated that reduced nm23-H1 expression
      showed poor prognosis in colorectal carcinomas. As a result, nm23-H1 expression
      might be a useful marker to predict outcome while planning treatment.

PMID- 12408342
TI  - Comparison of the endothelial surface and subjacent elastic lamina of anterior
      descending coronary arteries at the location of atheromatous lesions with
      internal thoracic arteries of the same subjects: a scanning electron microscopic
      study.
AB  - AIM: Current theories fail to explain the localisation of atheromatous lesions or
      their variable incidence in different arteries of the same subject. The objective
      of this study was to compare by scanning electron microscopy (SEM) the
      endothelial surface and the subjacent elastic lamina of human coronary arteries
      at the location of areas showing infiltration by lipid and cells, with the same
      components of internal thoracic arteries of the same subjects. METHODS: The
      endothelial surface and the subjacent elastic lamina of localised atheromatous
      areas of 146 anterior descending coronary arteries were compared with the same
      structural components of the internal thoracic arteries of the same subjects,
      using SEM, transverse paraffin sections and freeze-fracture. Some arteries were
      digested with formic acid to destroy the endothelium and interstitial tissue, and
      reveal the elastin fibre structure of the elastic laminae. RESULTS: Coronary
      arteries showed localised defects of the endothelial surface and of the elastin
      fibre structure of the subjacent elastic membrane, with the presence of lipid and
      cells in transverse sections of the intima. Internal thoracic arteries showed
      such changes only rarely, more particularly in older age groups. CONCLUSIONS: In
      localised areas of the coronary arteries showing infiltration of the wall by
      lipid and cells, there were imperfections of the endothelial surface and of the
      elastin fibre structure of the subjacent elastic lamina. These imperfections were
      not in general present in the endothelial surface, or subendothelial elastic
      lamina of the internal thoracic arteries in age groups below 50, and only rarely
      in older subjects.

PMID- 12408343
TI  - Flow cytometric DNA analysis of benign hyperfunctioning parathyroid glands:
      significant difference in the S phase fraction and proliferative index between
      adenomas and hyperplasias.
AB  - AIMS: Flow cytometric DNA analysis was performed to measure the DNA content of
      benign parathyroid tumours in patients with primary hyperparathyroidism. METHODS:
      DNA analysis of paraffin-embedded parathyroid samples was performed on 51
      parathyroid glands from 29 patients after parathyroidectomy. Histopathology
      showed parathyroid adenoma in 25 cases and hyperplasia in four patients. DNA
      ploidy status, DNA index (DI), percentage of cells in S phase and proliferative
      index (PI) were determined. RESULTS: Normal cells from normal glands were all
      diploid. DNA cytometry showed 12 aneuploid and 13 diploid adenomas. There were 12
      diploid and four aneuploid hyperplastic glands. Incidence of aneuploid DNA
      histograms did not show a statistically significant difference between adenomas
      and hyperplasias (P=0.216). Mean S phase fraction was 3.45% in adenomas and 1.53%
      in hyperplasias (P= 0.015). Mean PI was 6.48% in adenomas and 2.78% in
      hyperplastic parathyroid glands. This difference was statistically significant
      (P=0.006). Diploid cases had a mean PI of 4.78% and aneuploid glands a mean PI of
      7.7% (P=0.08). Aneuploid DNA content did not reveal statistically significant
      correlation with age, gender, pre-operative Ca, alkaline phosphatase, i-PTH
      levels, and tumour size. The mean S phase fraction and PI were 2.25% and 4.78% in
      diploid glands, and 4.5% and 7.7% in aneuploid cases. CONCLUSION: Aneuploid DNA
      content may be present in benign parathyroid diseases, but not in normal
      parathyroid glands. Aneuploid DNA histograms and higher PI occur more often in
      adenomas compared with hyperplasias, but the nuclear DNA analysis is unable to
      make a distinction between adenomas and hyperplasias.

PMID- 12408344
TI  - Frequent presence of subtype A virus in Epstein-Barr virus-associated
      malignancies.
AB  - AIMS: Epstein-Barr virus (EBV) is associated with many human malignancies. It is
      implicated in a pathogenetic role in some of these tumours. Two subtypes, type A
      and B have been identified on the basis of DNA sequence divergence in the nuclear
      protein genes (EBNA) 2, 3, 4 and 6. They differ in their transforming efficiency
      and prevalence pattern in different geographical locations. We aimed to identify
      the virus subtype infection pattern in our EBV-associated diseases. METHODS:
      Paraffin-embedded tissue from 38 lymphomas (17 Hodgkin's, 14 Burkitt's, four T
      cell and 3 B cell non-Hodgkin's lymphomas) and 14 nasopharyngeal carcinomas (NPC)
      were studied, with 12 reactive lymph nodes and tonsils as normal control. EBER in
      situ hybridisation was performed to confirm EBV association in the tumour cells.
      A nested polymerase chain reaction (PCR) protocol was employed using two pairs of
      consensus primers which flanked a 105-bp deletion in the type A virus. U2 region
      encoding for EBNA-2 was chosen as the target of amplification, with cell lines
      B95.8 and AG876 serving as positive controls for types A and B virus,
      respectively. RESULTS: All cases showed presence of type A virus, consistently
      detected with nested PCR protocol but not with single step PCR. There was no type
      B virus or mix infections detected. CONCLUSIONS: Nested PCR technique has
      successfully increased the sensitivity of EBV subtype detection, and type A virus
      is the prevalent strain associated with human diseases in Malaysia.

PMID- 12408345
TI  - Soft tissue myoepithelioma: a case report.
AB  - Myoepitheliomas are tumours composed predominantly or exclusively of
      myoepithelial cells. They are well described, especially within the salivary
      gland, but their occurrence in soft tissues is less well known and this often
      results in diagnostic problems. We report a case involving the deep soft tissues
      of the lower neck behind the clavicle. Grossly, the tumour was well circumscribed
      with solid and cystic areas. Histology showed a richly vascularised tumour
      composed of bland round, ovoid or spindle-shaped cells. Various growth patterns
      were present including solid, nested, microcystic and trabecular arrangements. In
      some areas there was an alveolar pattern with tumour cells lining fibrous septae.
      Immunohistochemistry showed diffuse strong positivity for S100 protein, calponin,
      vimentin and glial fibrillary acidic protein and focal positivity for epithelial
      membrane antigen, 34betaE12 and AE1/AE3, in keeping with myoepithelial
      differentiation. Electron microscopy revealed tumour cells surrounded by basal
      lamina with subplasmalemmal densities and containing cytoplasmic myofilaments.
      This case report highlights the rare occurrence of myoepitheliomas in deep soft
      tissues. Pathologists should be aware of this and should consider a
      myoepithelioma in the differential diagnosis of a soft tissue spindle cell
      neoplasm.

PMID- 12408346
TI  - Primitive neuroectodermal tumours of the uterus: a case report with cytological
      correlation and review of the literature.
AB  - A case of primitive neuroectodermal tumour (PNET) co-existing with endometrial
      adenocarcinoma of the uterus is reported in a 48-year-old female. Histologically,
      the neoplastic cells formed neuroectodermal rosettes and displayed ependymal
      differentiation. Focal positive immunohistochemical staining for synaptophysin,
      chromogranin A, CD57 and cytokeratins was noted. Merging imperceptibly with the
      neuroectodermal component were areas of endometrial adenocarcinoma and, to the
      best of our knowledge, this report represents the second case of a uterine PNET
      with an admixed mullerian component. The patient was disease-free 6 months
      following surgical resection of the tumour. The literature on this uncommon
      entity is critically reviewed and the histogenesis, differential diagnoses and
      cytomorphological features of PNET are also discussed.

PMID- 12408347
TI  - Susceptibility of Erysipelothrix rhusiopathiae to antimicrobial agents and home
      disinfectants.
AB  - AIM: Erysipelothrix rhusiopathiae causes the occupationally-related infection
      erysipeloid in humans, and may be responsible for infections in lobster fishermen
      in Western Australia. There are little recent data pertaining to antimicrobial
      susceptibility, or susceptibility to disinfectants that might be used in the
      environment. The aim of this study was to determine the susceptibility of E.
      rhusiopathiae from human, animal and environmental sources to various
      antimicrobial agents and disinfectants. METHODS: The susceptibility of 60 E
      rhusiopathiae isolates was determined using a recommended agar dilution
      procedure. Susceptibility to disinfectants was achieved using a broth
      microdilution method. RESULTS: Penicillin and ceftriaxone, with low minimum
      inhibitory concentrations (MICs) (MIC90 0.03 mg/l and 0.125 mg/l, respectively),
      remained active against E. rhusiopathiae and should continue to be recommended
      for treatment. Ciprofloxacin MICs were particularly low (MIC90 0.06 mg/l),
      offering an alternative agent for the penicillin allergic patient. Erysipelothrix
      rhusiopathiae is still resistant to vancomycin (MIC90 64 mg/l), highlighting the
      importance of early diagnosis of E. rhusiopathiae infection in cases of
      endocarditis. In addition, 31 E. rhusiopathiae isolates were tested against
      several commercially available home disinfectants. Most were effective in killing
      E. rhusiopathiae with minimum bactericidal concentrations of 0.001% for Pine O
      Cleen, and 0.03% for Domestos, Linely and the Wheelie Bin Phenyl Cleanser.
      CONCLUSIONS: There appeared to be no new emergence of antibiotic resistance in E.
      rhusiopathiae. Various disinfectants could be used following mechanical cleaning
      of work environments, such as fishing boats, and equipment, to reduce the risk of
      infection with E. rhusiopathiae.

PMID- 12408348
TI  - Test and teach. Diagnosis: Subcutaneous Rosai-Dorfman disease.

PMID- 12408349
TI  - Pathology in East Timor.
AB  - East Timor is the newest nation in Southeast Asia and, with its recent turbulent
      history, also one of the poorest. Infectious and parasitic diseases such as
      tuberculosis and malaria are endemic, and the poor infrastructure in the wake of
      Indonesia's sudden withdrawal has left the country with enormous health
      challenges. Australia's key role in the emergence of East Timor as an independent
      country brings with it a long-term interest in the future development of its
      health services, including pathology.

PMID- 12408350
TI  - Giant lamellar bodies in a case of Mycobacterium avium complex lung disease.

PMID- 12408351
TI  - Epithelial-myoepithelial carcinoma arising from clear cell myoepithelioma of the
      parotid.

PMID- 12408352
TI  - Granulomatous osteomyelitis caused by bacteria other than mycobacteria: a report
      of two cases.

PMID- 12408353
TI  - CD83 in Hodgkin and Reed-Sternberg cells.

PMID- 12408354
TI  - Lymph node sampling for flow cytometric analysis.

PMID- 12408355
TI  - Tiger snake envenomation and disseminated intravascular coagulation (DIC).

PMID- 12408356
TI  - Expression of NK2 homologous transcripts during zebrafish development.
AB  - Expression of NK2 homologous transcripts during Zebrafish development was
      investigated by in situ hybridization technique. NK2 mRNA expression was first
      detected in a cluster of cells at the embryonic shield stage, and subsequently in
      the heart field of the 5-8-somite embryo. By the 15-17 somite stages, NK2
      expressing cells were revealed in the midline of the developing embryo, and by 48
      hpf within the heart tube of the larva. By 72 hpf, NK2 transcripts appeared in
      the jaw bones, pharyngeal arches, the cranium with minimal expression in striated
      muscle.

PMID- 12408357
TI  - Culture and co-culture of DU145 prostate carcinoma, osteoblasts and HT-29 colon
      carcinoma cells on a fabricated type III collagen matrix.
AB  - DU145 prostate carcinoma cells cultured on type III collagen possessed a highly
      migratory potential which was twice as much as HT-29 colon carcinoma cells. Prior
      to attachment to collagen, DU145 cells were highly reactive for fibronectin and
      after attachment clear zones between cells and collagen suggested protease
      activity. HT-29 cells attached to type III collagen forming dome-like polyps,
      however, tight and/or gap junctions were not observed. hFob osteoblasts were co
      cultured with DU145 to establish a prostate cancer-collagen matrix barrier-bone
      cell metastasis model. Osteoblasts maintained their differentiated osteoblastic
      characteristics on one side of the collagen barrier, demonstrating high alkaline
      phosphatase, osteocalcin and insulin growth factor (IGF) activities. hFob cell
      growth was prominent adjacent to demineralized bone matrix particles (BMPs)
      embedded in type III collagen. The collagen matrix was deteriorated on the DU145
      side of the collagen barrier. The DU145-collagen III-hFob model will allow an
      evaluation of the influence of the matrix on prostate cancer-bone cell
      interaction and regulation by growth factors.

PMID- 12408358
TI  - Analysis of IL-2, IFN-gamma and TNF-alpha production, alpha5 beta1 integrins and
      actin filaments distribution in peritoneal mouse macrophages treated with
      homeopathic medicament.
AB  - The newer forms of immune modulatory therapy are aimed at specific cells or
      cytokines that contribute to the immune response. These forms of immunotherapy
      have been referred to as 'biological response modifiers'. Our lab was interested
      in investigating if a homeopathic medicament 'Metodo Canova' (MC), sold in
      homeopathic drugstores, does enhance immunological system responses acting
      through macrophages pathway. Mice peritoneal macrophages were cultivated with or
      without homeopathic medicament for 24 h for alpha5, beta1 and actin filaments
      distribution analyses through immunolabelling for confocal microscopy. To detect
      the IL-2, IFN-gamma and TNF-alpha production these cells were cultivated for 48 h
      with or without medicament, followed by analyses of these cytokines in
      supernatant culture with ELISA kits. It was observed differences in morphology
      and molecular distribution (alpha5 and beta1 integrins, actin filaments and Fc
      receptors) between the groups control and treated with MC. In control group
      macrophages had the morphology of resident cells and in MC treated group
      macrophages were more spread, had many cellular projections and a substantial
      increase in cytoplasmic volume. In addition, macrophages culture with two doses
      of MC showed that TNF-alpha production decreased when compared with control
      group.

PMID- 12408359
TI  - Morphology and histoenzymology of eosinophilic granulocytes in the circulating
      blood of the turtle (Chrysemys dorbignih).
AB  - The studies on the characterization of eosinophils and neutrophils/heterophils of
      turtles are contradictory. Some authors have pointed out the existence of two
      distinct cell types: eosinophils and heterophils. Other authors have proposed
      that eosinophils and heterophils may be the same cells in different stages of
      maturation. These interpretations are based only on a morphological analysis. In
      the blood of the turtle (Chrysemys dorbignih), a South American freshwater
      species, there are two types of granulocytes with eosinophilic staining pattern:
      the first with round cytoplasmic granules and the second with ellipsoidal
      cytoplasmic granules. In the present study by using histoenzymological methods
      for the analyses of enzymological cellular content, we found that the cells with
      round cytoplasmic granules were positive for nonspecific esterase and the cells
      with ellipsoidal granules were positives for acid phosphatase, alkaline
      phosphatase, nonspecific esterase and peroxidase. The results show that these
      cells are distinct cells and that the cells with ellipsoidal cytoplasmic granules
      have the same histoenzymological characteristics as the neutrophils/heterophils
      of mammalians and other vertebrates.

PMID- 12408360
TI  - Rodlet cells in teleosts: new ultrastructural observations on the distribution of
      the cores in trout (Oncorhynchus mykiss, Salmo trutta L.).
AB  - The distribution of released rodlet cores was ultrastructurally analysed in the
      epithelia of intestine, kidney tubules and gill of trout (Oncorhynchus mykiss,
      Salmo trutta L.). In all three tissues, membrane -- bounded cores extruded from
      the rodlet cells were observed undissolved at the surface of the epithelia, often
      attached to or between the microvillar borders. Occasionally, in the medium zone
      of the comparatively high intestinal epithelium, rodlet cells were seen to shed
      their rodlet sacs into neighbouring intestinal cells. At the epithelial surface
      the released cores displayed often a conspicuously undulating limiting membrane
      apparently developing tubular elements (psi 25-30 nm). Additionally, discharged
      cores were observed in the apical cytoplasm or even in nuclei of damaged or
      apoptotic cells and in an intraepithelial lymphocyte. In these cases, the cores
      were often lacking the membrane but showed association with the mentioned tubular
      elements. In developing rodlet cells the cores originated near or in contact with
      the nuclear envelope and displayed a polygonal outline and crystalloid
      substructure. The observed distribution and morphology is unusual assuming the
      current interpretation of the rodlet cell as defensive, possibly blood-cell
      derived secretory cell correlated to stress. As crystalline inclusions and
      undulating, tubulo-reticular endoplasmic reticulum are typical e.g., in excessive
      protein synthesis, alternative explanations seem worth while considering.

PMID- 12408361
TI  - Ultrastructural histochemical studies of secretory granule replenishment in rat
      submandibular granular tubules after cyclocytidine-induced secretion.
AB  - Rat submandibular glands have been examined electron microscopically at various
      times after degranulating the granular tubules by injecting cyclocytidine (75
      mg/kg i.p.), to study events in the reformation of secretory granules in these
      cells. The changes were progressive but not synchronous in the cells. The first
      evidence of recovery was the re-appearance of glycogen particles 6 h after
      injection. Residual secretory granules were small and located periluminally at
      that time. More granules were present at 15 h after injection but they were still
      small and placed periluminally. There was more glycogen in the cells and some was
      present in aggregates. At 1 day after injection there were more secretory
      granules and they tended to be larger than previously. The secretory granules
      increased in size and number progressively thereafter and the cells appeared like
      normal controls by day 7. During the recovery, fusion profiles were seen between
      granules from 2 days onwards. Throughout, few Golgi complexes were detected and
      this may be related with the low glycosylation of the secretory proteins in these
      cells. The results confirm that the reformation of the secretory granules in
      granular tubule cells is a slow process that involves fusions of smaller
      granules.

PMID- 12408362
TI  - Ultrastructural analyses of the Caenorhabditis elegans DR 847 bli-1(n361) mutant
      which produces abnormal cuticle blisters.
AB  - The bli-1 gene of Caenorhabditis elegans has been previously described as a
      mutation which disrupts the structure of the adult-stage cuticle causing the
      formation of fluid-filled blisters. We investigated the blistering phenotype
      exhibiting n361 allele and observed a gradual blister formation in adult
      nematodes. In the course several fine changes occurred including a high electron
      density granulous material filling the intermediate layer, alterations on struts
      structure, and finally the total disappearance of the fibrous and basal layers.
      With the ethanolic phosphotungstic acid technique (E-PTA), which localizes basic
      proteins, reaction product was observed in the cortical layer of the wild strain,
      whereas in the mutant strain an irregular labelling pattern was observed in this
      region. The granulous material inside the intermediate layer of the mutant strain
      showed also a strong reaction. An imidazole-buffered osmium tetroxide solution
      was used to visualize lipids at ultrastructural level, however no dense product
      was detected in the cuticle of both strains of C. elegans. Based on these results
      we postulated that the blistering phenotype is due to an altered function of bli
      1 gene, which is probably enzymatic.

PMID- 12408363
TI  - Study of the tail fin rays of rainbow trout (Oncorhynchus mykiss) infected with
      the parasite Myxobolus cerebralis.
AB  - A light, transmission and scanning microscope study of the rays (lepidotrichia)
      forming the tail fin of rainbow trout (Oncorhynchus mykiss) fingerlings infected
      with the parasite Myxobolus cerebralis showed that triactinomyxon adherence to
      the tail fin of host fingerlings occurred 10 min after infection. After 2 h of
      exposure, it was possible to observe triactinomyxon spores in the epidermis.
      Although the characteristic symptoms of the disease, such as a black tail and a
      change in tail morphology, were observed, there was no attack against the tissue
      forming the tail fin rays and triactinomyxon spores were not observed inside the
      leptotrichial matrix at any stage, indicating that the spores do not reach the
      rays or that their observation was not possible under the conditions of the
      present study.

PMID- 12408364
TI  - Mouse extensor digitorum longus and soleus show distinctive ultrastructural
      changes induced by veratrine.
AB  - We investigated whether veratrine (5 microl, 10 ng/kg) injected into the mouse
      extensor digitorum longus (EDL) (fast-twitch) and soleus (SOL) (slow-twitch)
      muscles provokes distinctive ultrastructural disturbances 15, 30 and 60 min
      later. The mitochondria in SOL were affected earlier (within 15 min) than in EDL.
      Swelling of the sarcoplasmic reticulum terminal cisternae was more marked in EDL
      than in SOL and caused distortion of sarcomeres so that fragmentation of
      myofilaments was more pronounced in EDL. Hypercontracted sarcomeres were seen
      mainly in SOL and veratrine caused infoldings of the sarcolemma only in this
      muscle. In both muscles, the T-tubules remained unaffected and by 60 min after
      veratrine most of the above alterations had reverted to normal. Pretreatment with
      tetrodotoxin prevented the alterations induced by veratrine. This suggests that
      most of the alterations resulted from the enhanced influx of Na+ into muscle
      fibers. These results emphasize the importance of considering the type of muscle
      when studying the action of myotoxic agents.

PMID- 12408365
TI  - Differential long-term subcellular responses in heart and liver to adriamycin
      stress. Exogenous L-carnitine cardiac and hepatic protection.
AB  - In order to evaluate the heart and liver responses after adriamycin (ADR) toxic
      aggression, with and without exogenous L-carnitine (CAR) protection, female
      Sprague-Dawley rats, body weight 40-60 g, were randomized into four groups: CON,
      ADR, CAR and CAR-ADR. ADR was injected i.v. at a dose of 15-18 mg/kg body wt (0.1
      ml). CAR was administered i.v. at a dose of 20 mg (0.1 ml) before each subdose of
      ADR, and then orally at 180 mg/kg body wt daily for 12 weeks. Long-term cardiac
      and hepatic subcellular damage were determined by transmission electron
      microscopic analysis of ultrathin sections. The ADR-induced long-term cardiac
      subcellular pathology included loss, disruption and disassembly of myofibrils,
      and mitochondrial swelling and condensation. On the other hand, the ADR-induced
      subcellular hepatic alterations consisted of polymorphic mitochondria,
      cytoplasmic vacuolization and accumulation of lipid droplets. Apparently, cardiac
      tissue was more affected by ADR toxic aggression than hepatic tissue. However,
      these alterations were of less severity in protected groups, in both heart and
      liver, suggesting CAR as a possible hepatoprotector agent against ADR toxicity.
      Because of the liver-L-carnitine-heart relationship, studying ADR-hepatotoxicity
      could be helpful in the further understanding of severe ADR-cardiotoxicity.

PMID- 12408366
TI  - The thrombocyte aggregation process in the turtle Phrynopys hilarii (Chelonia).
      An ultrastructural study.
AB  - This study investigates the thrombocyte aggregation process in the South American
      fresh water turtle (Phrynopys hilarii) using electron microscopy. Blood was taken
      from surgically exposed lateral neck vessels of ten turtles Phrynopys hilarii
      during the spring and summer seasons, when the mean temperature is 37 degrees C.
      Blood samples were fixed with Karnovsky solution for processing by transmission
      electron microscopy. The turtle thrombocytes were spindle-shaped with lobulated
      nuclei. Prominent vesicles and canaliculi were found throughout the cytoplasm.
      The cytoplasm organelles showed an agranular endoplasmatic reticulum, Golgi
      complex near the centrioles and scattered free ribosomes. These cells are similar
      to bird thrombocytes but distinct from fish and frog thrombocytes. Blood clotting
      time was 5 min +/- 30 sec measured by the Lee and White method. Structural
      alterations resulting from the aggregation process occurred after activation.
      Thrombocytes developed numerous filopodial projections, an increased number of
      vacuoles and changed from spindle to spherical shape. P. hilarii thrombocytes
      have different morphologic characteristics compared to other non-mammalian
      vertebrate cells. These cells can participate in the aggregation process, as
      observed in birds.

PMID- 12408367
TI  - Effects of repeated exposures to xenon on rat adrenal cortex ultrastructure.
AB  - Xenon has many properties of the ideal anaesthetic and it has been proposed to
      replace classic volatile anaesthetics. Although some studies demonstrated that
      xenon does not induce gross morphological changes in major organs, little is
      known on its possible ultrastructural effects. The present study investigates the
      subcellular effects of repeated exposures to 70% xenon on rat adrenal cortex in
      comparison with N2O. Animals were divided into four groups: xenon-exposed, N2O
      exposed, sham-exposed and controls. Exposed rats were placed into a sealed cage
      to breathe the respective gas mixture for 2.5 h/day for a week. Specimens of
      adrenal cortex for electron microscopy and blood samples for determination of
      corticosterone plasma levels were taken at the end of the last exposure or one
      week after the last exposure (recovery). Adrenal cortex from N2O- and sham
      exposed rats mainly showed dilation of endoplasmic reticulum, whereas xenon
      exposed rats also exhibited several cells with lipid droplets appearing
      subdivided into smaller droplets, irregular in shape and size. In all
      experimental groups, corticosterone plasma levels increased in comparison to
      controls. Both ultrastructural and hormonal changes were not detected anymore
      after one week from the last exposure. These findings indicate that xenon is able
      to induce subcellular changes in rat adrenal cortex, mainly at the level of lipid
      structures. The transient changes induced by xenon suggest that this gas can be
      regarded as a safer anaesthetic.

PMID- 12408368
TI  - In vitro rapid organization of rabbit meniscus fibrochondrocytes into chondro
      like tissue structures.
AB  - We described the behaviour of 120 days rabbit knee-meniscus cells in monolayer
      culture. The cells were grown forming cellular aggregates resembling true
      cellular nodules. Three stages of development of these nodules could be observed:
      formation of the cellular nodules between days 1 and 3; nodular growth, with
      their maximal at day 5; and nodular regression beginning at day 8.
      Ultrastructural analysis of the extracellular matrix of these cellular nodules
      was assessed on days 3, 5 and 8. At the formation stage, we could observe
      striated collagen fibrils and small bundles of tubular microfibrils either
      interspersed with very low quantities of amorphous elastin, being morphologically
      identical to elaunin fibers, or without only trace of elastin, being
      morphologically identical to oxytalan fibers. By day 5, fibrillar elements with
      100 nm periodic ladder-like collagen VI fibrillar aggregates could also be
      detected. At day 8, the striated collagen fibrils and oxytalan fibers could not
      be observed. During this same period, there was an increase of a dense matrix
      comprised of collagen VI and mature elastic fibers. Chondroitin/dermatan sulfate
      proteoglycans were synthesized and became essential for the arrangement of
      collagen type VI, since chondroitinase ABC treatment of the culture disrupted
      collagen VI assembly, associated with the large spaces near the cell surface. In
      addition, the cells lost their fusiform morphology and changed into rounded
      cells. The results show that primary cultures of rabbit meniscus
      fibrochondrocytes maintain their capacity to form chondro-like structures in
      vitro. The organization process was rapid and uniform throughout the entire
      culture presuming that the normal signal transduction pathways are maintained
      intact and that essential factors in some phases of tissue organization are
      present.

PMID- 12408369
TI  - Ultrastructural study of the cheek oral mucosa of rats submitted to experimental
      chronic alcoholism.
AB  - Ultrastructural features of the cheek oral mucosa of rats (Rattus norvegicus)
      submitted to experimental chronic alcoholism were studied by transmission
      electron microscopy. Sixty male rats aged three months and with a mean body
      weight of 250 g were divided into two experimental groups. The control group
      received a solid diet (Purina rat chow) and tap water ad libitum. The alcoholic
      group received the same solid diet but was only allowed to drink sugar cane
      liquor dissolved in 30 degrees Gay Lussac (v/v). The animals of the two groups
      were weighed and sacrificed after 60, 120, and 180 days of treatment. Samples of
      the oral mucosa from the cheek region were dissected and processed for
      ultrastructural analysis. The results showed cell alterations in the basal and
      intermediate layer of the mucosal epithelium. The most frequent alterations
      observed were an increased intercellular space, the presence of lipid droplets in
      the cytoplasm, and irregular nuclei with a pyknotic aspect.

PMID- 12408370
TI  - Influence of Cimicifuga racemosa on the proliferation of estrogen receptor
      positive human breast cancer cells.
AB  - Hormone replacement therapy, which is a common menopausal treatment, is
      contraindicated in women with breast cancers due to concerns regarding the
      potential for breast cell proliferation. As such, there is a need for alternative
      methods for treating menopausal symptoms. To determine the influence of one such
      alternative, black cohosh (Cimicifuga racemosa [CR]), on estrogen-dependent
      mammary cancers, we conducted an in vitro investigation of the effect of an
      isopropanolic CR-extract on the proliferation of estrogen receptor-positive
      breast cancer cells. The experiments were performed using the human breast
      adenocarcinoma (MCF-7) cell test system, an established in vitro model for
      estrogen-dependent tumors. The influence of CR-extract on the proliferation of
      the MCF-7 cells was determined by measuring the incorporation of radioactively
      labeled thymidine. Under estrogen-deprived conditions, the CR-extract (10(-3)-10(
      5) dilutions) significantly inhibited MCF-7 cell proliferation. Additionally,
      application of the CR-extract inhibited estrogen-induced proliferation of MCF-7
      cells. Moreover, the proliferation-inhibiting effect of tamoxifen was enhanced by
      the CR-extract. Such data that suggest a non-estrogenic, or estrogen-antagonistic
      effect of CR on human breast cancer cells lead to the conclusion that CR
      treatment may be a safe, natural remedy for menopausal symptoms in breast cancer.

PMID- 12408371
TI  - T1 breast cancer: identification of patients at low risk of axillary lymph node
      metastases.
AB  - OBJECTIVE: The status of the axillary lymph nodes is one of the most important
      prognostic factors in patients with breast cancer. A panel of molecular markers
      of tumor aggressiveness in addition to conventional clinical and histopathologic
      features were analyzed in an attempt to identify a subgroup of patients with a
      low risk of axillary lymph node metastases. MATERIAL AND METHODS: Data from 358
      patients with T1 breast cancer who underwent level I/II axillary lymph node
      dissection (ALND) were investigated. Hormone receptor status, Ki-67, S-phase
      fraction, DNA ploidy, HER-2/neu, p53, epidermal growth factor receptor, urokinase
      type plasminogen activator, plasminogen activator inhibitor-1, bone marrow
      micrometastases as well as patient age, menopausal status, tumor site, tumor
      size, histologic type, tumor grade, carcinoma in situ, multifocality, and lymph
      vascular invasion (LVI) were studied to predict axillary lymph node status.
      RESULTS: In a multivariate logistic regression analysis LVI (present v.s. not
      present), Ki-67 (> or = 18% v.s. < 18%), tumor size (1.1-2 cm v.s. < or = 1 cm),
      and histologic grade (G3 v.s. G1/2) were identified as independent predictive
      factors of axillary lymph node metastases. Approximately 13% of patients (n = 47)
      with well or moderately differentiated tumors less than or equal to 1 cm, no
      lymph vascular invasion, and a low Ki-67 staining were identified as having a low
      risk of axillary lymph node metastases of 4.3%. However, 20 patients with all
      four unfavorable predictive factors had a 75% incidence of axillary lymph node
      involvement. CONCLUSION: Primary tumor characteristics can be used to identify a
      subgroup of patients with a low risk of axillary lymph node metastases in T1
      breast cancer. Preoperative risk assessment might be used to omit routine ALND in
      those patients at low risk of axillary lymph node metastases.

PMID- 12408372
TI  - Breast cancers found by screening: earlier detection, lower malignant potential
      or both?
AB  - A population-based study was performed to compare the characteristics of
      clinically detected breast cancers and cancers detected by the Dutch screening
      program. To determine whether differences are most likely to be explained by
      earlier diagnosis or by the detection of biologically different cancers in the
      screening program, comparisons were stratified according to tumor size. Data were
      obtained from the population-based Eindhoven Cancer Registry. During the period
      1996-1999, 568 screen-detected and 630 clinically detected invasive breast
      cancers were available for analysis. Compared with patients with clinically
      detected breast cancer, women with screen-detected breast cancer had smaller
      tumors (P < 0.0001), were more likely to have negative lymph nodes (P < 0.0001),
      tumors with a positive estrogen (P = 0.007) or progesterone (P = 0.019) receptor
      status and a lower mitotic activity index (P = 0.009). In the group with cancers
      < or = 1.0 cm the screen-detected were more likely to have negative estrogen
      receptors (P = 0.027). The group with screen-detected tumors 1.1-2.0 cm across
      were more likely to have positive estrogen and progesterone receptors (P = 0.005
      and P = 0.044, respectively) and tended to have a lower mitotic activity index (P
      = 0.078). No significant differences were found between screen-detected and
      clinically detected breast cancers of 2.1-3.0 cm across. After adjustments for
      tumor size, most of the differences between clinically detected and screen
      detected breast cancers disappeared, suggesting that screen-detected breast
      cancers represent tumors in an earlier phase of their development, not a
      biologically different class.

PMID- 12408373
TI  - Estrogen receptor breast cancer phenotypes in the Surveillance, Epidemiology, and
      End Results database.
AB  - BACKGROUND: Researchers question whether estrogen receptor alpha-negative (ERN)
      and -positive (ERP) represent different stages of one disease or different breast
      cancer types. OBJECTIVE: To further examine ERalpha phenotypes, we stratified
      incident tumor characteristics in the Surveillance, Epidemiology, and End Results
      (SEER) Database (n = 82,488) by ERN and ERP. METHODS: Study variables included
      black-white race, age-at-diagnosis, and standard incident tumor characteristics.
      These characteristics were arbitrarily dichotomized into good versus poor
      prognostic factor groups, for example, good (tumor size < or = 2.0 cm, negative
      axillary lymph nodes, and good histologic grade) versus poor (tumor size > 2.0
      cm, positive nodes, and poor grade). Age frequency density plots were generated
      from the corresponding age-at-diagnosis frequency histograms. Average annual age
      specific incidence rates (or risks) were adjusted to the 1970 United States
      standard female population. RESULTS: Age frequency density plots demonstrated
      bimodal premenopausal and postmenopausal breast cancer populations. ERN was
      correlated with premenopausal disease, black race, and poor prognostic factor
      groups, whereas ERP was associated with postmenopausal disease, white race, and
      favorable tumor characteristics. ERN rates increased premenopausally and then
      flattened to a nearly constant level after 50 years of age. ERP risk rose for
      most of a woman's lifetime with the greatest risk occurring between 75 and 79
      years. CONCLUSIONS: ERalpha exhibited bimodal age frequency distribution with a
      dichotomous pattern for age-specific rates, racial, and prognostic factor
      profiles. Menopause had a greater effect on ERN than ERP. Possible implications
      for breast carcinogenesis and cancer prevention are discussed in the text.

PMID- 12408374
TI  - Prognostic value of residual node involvement in operable breast cancer after
      induction chemotherapy.
AB  - The purpose of this retrospective study was to evaluate the influence of axillary
      disease on patients' survival after neoadjuvant chemotherapy and to assess
      patient and tumor characteristics associated with post-chemotherapy axillary
      involvement. After six induction cycles, 277 patients with operable breast cancer
      (stage II-III) underwent surgery with axillary dissection, followed by
      radiotherapy (n = 267) or additional chemotherapy (n = 63) and adjuvant tamoxifen
      therapy (n = 138). At a median follow-up of 8.5 years, overall survival (OS) and
      disease-free survival (DFS) were analyzed as a function of node involvement. The
      differences in OS and DFS according to the number of positive nodes were highly
      statistically significant with a decreased survival associated with the
      increasing number of nodes (p = 5 x 10(-6) and 9 x 10(-7), respectively). Upon
      multivariate analysis, the node number after chemotherapy appeared as the most
      significant prognostic factor (p = 7 x 10(-4) for OS and p = 3 x 10(-5) for DFS).
      All the other classical prognostic factors were insignificant, except post
      chemotherapy Scarff-Bloom-Richardson (SBR) grading for OS (p = 8 x 10(-4)) and
      adjuvant hormonotherapy for DFS (p = 1 x 10(-2)). Although constituting a
      different parameter from primary surgery data, the number of positive nodes after
      chemotherapy could still remain a valuable prognostic factor at secondary
      surgery, raising the question for high risk patients of a second non-cross
      resistant adjuvant regimen, or high dose chemotherapy with peripheral blood stem
      cells support.

PMID- 12408375
TI  - Docetaxel plus vinorelbine as salvage chemotherapy in advanced breast cancer: a
      phase II study.
AB  - PRECIS: Administration of a combined regimen of docetaxel plus vinorelbine every
      4 weeks is feasible and shows activity in heavily pretreated patients with
      advanced breast cancer. PURPOSE: To determine the activity and tolerance of
      docetaxel plus vinorelbine in heavily pretreated patients with advanced breast
      cancer. METHODS: Thirty-five metastatic breast cancer patients with ECOG
      performance status of 0-2 received docetaxel (80 mg/m2 given intravenously) on
      day 1 and vinorelbine (30 mg/m2 given intravenously) on days 1 and 14, every 4
      weeks. The median number of prior chemotherapy regimens was 2 (range: 1-4).
      Twenty-five patients (71.4%) had been treated previously using intensive therapy
      approaches with peripheral blood-derived stem cell (PBSC) support, including high
      dose chemotherapy (11 patients), multicyclic dose-intensive chemotherapy
      supported with repeated PBSC infusions (seven patients), or both (seven
      patients). Twenty-eight patients (80%) received previous chemotherapy for
      metastatic disease. Adjuvant therapy in the remaining seven patients consisted of
      high-dose chemotherapy and PBSC support or an anthracycline-containing regimen.
      RESULTS: The total number of courses was 229, and the median number of courses
      per patient was 6 (range: 1-16). There was one toxic death (2.8%). Grade 3-4
      toxicities included mucositis (17.1%), neutropenia (37.1%), anemia (5.7%),
      vomiting (2.9%), and asthenia (14.3%). Eighteen patients (58%; 95% CI: 40.6
      75.4%) achieved an objective response, including four complete responses (12.9%)
      and 14 partial responses (45.1%). Overall response rate was 51.4% (95% CI: 34.8
      67.9%). After a median follow-up of 20 months (range: 2-42), overall survival was
      20 months (95% CI: 16-24), and median time to progression was 13 months (95% CI:
      7-19). CONCLUSION: This combination shows activity and an acceptable toxicity
      profile in patients with advanced breast cancer.

PMID- 12408376
TI  - Cyclooxygenase inhibitors block cell growth, increase ceramide and inhibit cell
      cycle.
AB  - We have shown previously in a model of metastatic breast cancer that murine
      mammary tumor cells express both cyclooxygenase-1 (Cox-1) and Cox-2 isoforms.
      Growth and metastasis of these tumors in syngeneic hosts are inhibited by either
      selective Cox-1 (SC560) or selective Cox-2 (celecoxib) inhibitors. To gain
      insight into the relevant mechanisms involved in the therapeutic response, we
      determined the effect of Cox inhibitors on tumor cell behavior in vitro. We now
      report that either selective Cox-1 or Cox-2 drugs inhibited cell replication, but
      only at concentrations that are no longer selective for either isoform. Growth
      delay by either nonselective or selective inhibitors was associated with changes
      in cell morphology including cell rounding; these changes were reversed upon
      removal of drug. Unlike many other cell types examined, treatment of these
      mammary tumor cells with Cox inhibitors was not associated with detectable
      apoptosis. Growth inhibition, induced by either selective or nonselective Cox
      inhibitors, was accompanied by increased intracellular levels of the sphingolipid
      ceramide by 1.7-2.6-fold in comparison to vehicle-treated cells. Ceramide changes
      are associated with cell cycle arrest and we observed that all the Cox inhibitors
      examined increased significantly the number of cells in G0/G1 and reduced the S
      phase fraction. Likewise, addition of a cell-permeable form of ceramide (C6
      ceramide) could mimic the effect of Cox inhibitors on both cell cycle and cell
      growth inhibition. Thus, mammary tumor cells are growth restricted by Cox
      inhibitors. These effects are associated with changes in ceramide levels and a
      block in cell cycle progression.

PMID- 12408377
TI  - Progesterone receptor quantification as a strong prognostic determinant in
      postmenopausal breast cancer women under tamoxifen therapy.
AB  - There is now an emerging body of evidence that shows there is a relationship
      between the survival of breast cancer patients and the expression level of
      steroid receptors. The aim of this study was to determine the relationship
      existing between estrogen receptors (ER) and progesterone receptors (PR)
      cytosolic content and the prognosis of postmenopausal breast cancer women under
      tamoxifen therapy. Two hundred and nineteen postmenopausal patients, without
      neoadjuvant chemotherapy and treated postoperatively with tamoxifen for at least
      2 years, were followed up in our Cancer Center. We used flexible regression
      modeling and log likelihood methods for determining optimum cut-off values for
      steroid receptors, which allows the separation of patients into significantly
      different categories in term of survival. For PR, 3 categories were defined
      (category 1: PR < 10, category 2: 10 < or = PR < 60 and category 3: PR > or = 60
      fmol/mg P). Univariate analysis at 8 years indicated that significant differences
      in event-free survival (EFS) were found for tumor size (T) (p = 0.005), lymph
      node status (N) (p = 0.003), histological Scarff, Bloom and Richardson grade (p =
      0.003), ER values divided into 5 categories (p = 0.02) and PR values divided into
      3 categories (p = 1 x 10(-5)). Eight-year EFS rate for the 3 PR categories,
      adjusted for N, were 39, 66 and 81%, respectively. Multivariate Cox analysis
      indicated that only T, N and PR values were significant variables for EFS.
      Patients with PR values > or = 60 present significantly greater EFS rates than
      patients with PR < 60 (p < 0.001). Our results show that the PR level in ER
      positive postmenopausal women is a strong prognostic marker in postmenopausal
      breast cancer women under tamoxifen therapy.

PMID- 12408378
TI  - Predictors of sensitivity of clinical breast examination (CBE).
AB  - Clinical breast examination (CBE) is one of the most common breast cancer
      screening modalities, but factors that affect its sensitivity are not well
      understood. We examined the association between CBE sensitivity and tumor, breast
      and personal characteristics among members of a managed care organization's
      Breast Cancer Screening Program (BCSP). The study population was 468 screened
      women 40 years and older diagnosed with invasive breast cancer between 1988 and
      1994 within 1 year of a screening CBE. Logistic regression was used to evaluate
      the likelihood of a true positive versus a false negative CBE result, after
      adjustment for age, body weight and tumor size. CBE sensitivity increased with
      larger tumor size (17% for tumors < or = 0.5 cm and 58% for tumors > or = 2.1 cm,
      adjusted p for trend < 0.001) and decreased with higher body weight (48 and 23%
      for the lowest and highest quartiles, adjusted p for trend < 0.001). CBE was more
      sensitive in Asian women compared to white women (88% v.s. 35%, adjusted p =
      0.04) and in current users of estrogen and progesterone combination therapy
      compared to never/former users (52% v.s. 33%, adjusted p = 0.08). There was an
      inverted U-shaped association between age and CBE sensitivity (40-49: 26%, 50-59:
      48%, 60-69: 36%, 70-79: 33%, 80+: 18%, significant for oldest and youngest groups
      v.s. age 50-59 years). These findings suggest certain groups of women, for
      example, obese women and younger women, receive less benefit from CBE.

PMID- 12408379
TI  - Effect of spinal disease on successful arthrodesis in lumbar pedicle screw
      fixation.
AB  - OBJECT: Pedicle screw fixation with transverse process fusion has gained
      widespread acceptance since its inception. Improved rates of arthrodesis have
      been demonstrated when this technique is used. The authors present one of the
      largest series of patients to undergo this procedure at a single center; one of
      the goals was to correlate construct length and spinal disease with rates of
      successful arthrodesis by conducting a prospective analysis of lumbar fusion in
      which pedicle screws were placed. METHODS: During a 7-year period, the senior
      author performed pedicle screw fixation with posterolateral fusion in 457
      patients; the mean follow-up period was 28.4 months. Indications for fusion
      included metastatic tumor, single-level degenerative disc disease (DDD), trauma,
      degenerative scoliosis, and translational vertebral instability. Successful
      fusion was based on the radiographic demonstration of a bilateral contiguous
      osseous bridge over the transverse processes and absence of movement on dynamic x
      ray films. Fusion rates were lowest in cases of tumors (54%) and highest in cases
      of trauma (96%). In patients with single-level DDD the rate was 91%, and in those
      with translational instability it was 89%. Fusion rates, however, declined
      steeply in relation to each additional motion segment in the translational
      instability group. In this group a strong linear trend for proportion was
      demonstrated (p < 0.001). The overall fusion rate in patients with degenerative
      scoliosis was 70%. The overall fusion rate for the entire group was 86%.
      CONCLUSIONS: The data in this study can be used as a benchmark with which to
      compare newer technologies. Although overall pedicle screw-assisted fusion rate
      in cases of trauma or selected degenerative lesions approached 90%, the
      arthrodesis rates are not uniform for the different diagnoses. This appears to be
      related to the underlying spinal disease and the number of segments included in
      the fusion.

PMID- 12408380
TI  - Degenerative lumbar spondylolisthesis-induced radicular compression: nonfusion
      related decompression in selected patients without hypermobility on flexion
      extension radiographs.
AB  - OBJECT: The authors conducted a study to determine the results of decompressive
      surgery without fusion in selected patients who presented with radicular
      compression syndromes caused by degenerative lumbar spondylolisthesis and in whom
      there was no evidence of hypermobility on flexion-extension radiographs. METHODS:
      The medical records and radiographs obtained in 49 patients were reviewed
      retrospectively. Clinical status was quantified by summing self-assessed Prolo
      Scale scores. All 49 patients (55% female, mean age 68.7 years) presented with
      leg pain accompanied by lumbalgia in 85.7% of the cases. Preoperatively the
      median sum of Prolo Scale scores was 4. The mean preoperative degree of forward
      vertebral displacement was 13.5% and was located at L-4 in 67% of the cases.
      Osseous decompression alone was performed in 53%, and an additional discectomy at
      the level of displacement was undertaken in the remaining patients because of
      herniated discs. Major complications (deep wound infection) occurred in 2%.
      During a mean follow-up period of 3.73 years, 10.2% of the patients underwent
      instrumentation-assisted lumbar fusion when decompression alone failed to resolve
      symptoms. At last follow up the median overall Prolo Scale score was 8. Excellent
      and good results were demonstrated in 73.5% of the patients. Prolonged back pain
      (r = 0.381) as well as the preoperative degree of displacement (r = 0.81) and
      disc space height (r = 0.424) influenced outcome (p < or = 0.05); additional
      discectomy for simultaneous disc herniation at the displaced level did not
      influence outcome (p > 0.05). CONCLUSIONS: These results appear to support a less
      invasive approach in this subgroup of elderly patients with degenerative lumbar
      spondylolisthesis-induced radicular compression syndromes and without
      radiographically documented hypermobility. Additional discectomy for simultaneous
      disc herniation of the spondylolisthetic level did not adversely influence the
      outcome. Complication rates are minimized and fusion can eventually be performed
      should decompression alone fail. A prospective controlled study is required to
      confirm these results.

PMID- 12408382
TI  - Preoperative embolization and intraoperative cryocoagulation as adjuncts in
      resection of hypervascular lesions of the thoracolumbar spine.
AB  - OBJECT: The purpose of this study was twofold. First the authors evaluated
      preoperative embolization alone to reduce estimated blood loss (EBL) when
      resecting hypervascular lesions of the thoracolumbar spine. Second, they compared
      this experience with intraoperative cryotherapy alone or in conjunction with
      embolization to minimize further EBL. METHODS: Twelve patients underwent 13
      surgeries for hypervascular spinal tumors. In 10 cases the surgeries were
      augmented by preoperative embolization alone. In one patient, two different
      surgeries involved intraoperative cryocoagulation, and in one patient surgery
      involved a combination of preoperative embolization and intraoperative
      cryocoagulation for tumor resection. When cryocoagulation was used, its extent
      was controlled using intraoperative ultrasonography or by establishing physical
      separation of the spinal cord from the tumor. In the 10 cases in which
      embolization alone was conducted, intraoperative EBL in excess of 3 L occurred in
      five. Mean EBL was of 2.8 L per patient. In one patient, who underwent only
      embolization, excessive bleeding (> 8 L) required that the surgery be terminated
      and resulted in suboptimum tumor resection. In another three cases,
      intraoperative cryocoagulation was used alone (in two patients) or in combination
      with preoperative embolization (in one patient). In all procedures involving
      cryocoagulation of the lesion, adequate hemostasis was achieved with a mean EBL
      of only 500 ml per patient. No new neurological deficits were attributable to the
      use of cryocoagulation. CONCLUSIONS: Preoperative embolization alone may not
      always be satisfactory in reducing EBL in resection of hypervascular tumors of
      the thoracolumbar spine. Although experience with cryocoagulation is limited, its
      use, in conjunction with embolization or alone, suggests it may be helpful in
      limiting EBL beyond what can be achieved with embolization alone. Cryocoagulation
      may also assist resection by preventing spillage of tumor contents, facilitating
      more radical excision, and enabling spinal reconstruction. The extent of
      cryocoagulation could be adequately controlled using ultrasonography or by
      establishing physical separation between the tumor and spinal cord. Additionally,
      somatosensory evoked potential monitoring may provide early warning of spinal
      cord cooling.

PMID- 12408381
TI  - Percutaneous transpedicular vertebroplasty with calcium phosphate cement in the
      treatment of osteoporotic vertebral compression and burst fractures.
AB  - OBJECT: Osteoporotic vertebral fractures occasionally lead to late-onset
      collapse, kyphosis, persistent back pain, and disability. The authors describe a
      series of patients in whom they performed percutaneous vertebroplasty by using
      calcium phosphate cement (CPC) to obtain early pain relief and improve the
      integrity of the osteoporotic vertebral body (VB). METHODS: Between August 2000
      and February 2001, they performed 17 percutaneous transpedicular CPC-assisted
      vertebroplasty procedures in 16 patients who harbored thoracic or lumbar
      osteoporotic vertebral fractures. Following repositioning and curettage of the
      pathological soft tissues, CPC-assisted vertebroplasty was percutaneously
      performed in four patients with osteoporotic burst fracture and pseudarthrosis
      (Procedure A). In situ CPC-assisted vertebroplasty was performed in 12 patients
      with fresh vertebral compression fractures due to osteoporosis (Procedure B).
      Back pain and low-back pain were evaluated using a visual analog scale (VAS). The
      deformity index of the VB was measured on a lateral radiograph as the ratio of
      the VB's height (sum of measurements at anterior, middle, and posterior regions)
      to its longitudinal diameter. Based on VAS scores, pain was decreased in all
      patients immediately after surgery, and pain relief was maintained at the last
      follow up. The mean preoperative deformity index score of the VB was 1.43 in
      Procedure A and 1.67 in Procedure B; postoperatively scores improved to 1.59 and
      1.93, respectively. At the 6-month follow-up examination, the mean deformity
      index score rebounded to 1.52 in Procedure A and 1.79 in Procedure B. Bone union
      was documented in all patients. Complications, such as a temporary respiratory
      insufficiency and a small amount of CPC leakage into the spinal canal, were
      observed in patients who underwent Procedure B. CONCLUSIONS: Percutaneous
      transpedicular CPC-assisted vertebroplasty is a minimally invasive procedure that
      provides early relief of pain and prevents vertebral collapse and pseudarthrosis
      in patients with osteoporotic vertebral fracture.

PMID- 12408383
TI  - Surgical treatment of superior sulcus tumors with spinal and brachial plexus
      involvement.
AB  - OBJECT: Non-small cell lung carcinomas with spinal and brachial plexus
      involvement have traditionally been considered to be Stage IIIb lesions and
      therefore unresectable. Advances in spinal surgery, the application of magnetic
      resonance (MR) imaging, and improvements in neoadjuvant therapy require a
      reassessment of the potential for complete resection. METHODS: The authors
      conducted a retrospective review of all procedures involving the resection of
      superior sulcus tumors with spinal or brachial plexus involvement performed
      between 1985 and 1999. Assessment or resectability and operative planning were
      based on an MR imaging classification scheme in which the extent of spinal
      involvement was considered. Class A tumors involved the periosteum of the
      vertebral body (VB) (16 patients); Class B, distal neural foramen without
      epidural compression (eight patients); Class C, proximal neural foramen with
      epidural compression (four patients); and Class D, bone involvement (VB or
      posterior elements) with or without epidural involvement (14 patients). Brachial
      plexus involvement was present in 21 patients, including 17 with T-1 nerve root
      only and four with C-8 or lower-trunk infiltration. Complete tumor resection was
      achieved in 27 patients and incomplete resection in 15. Complications occurred in
      14 patients, two of which were related to instrumentation failures. The overall
      median survival was 1.44 years. The median survival for the complete and
      incomplete resection groups were 2.84 and 0.79 years, respectively (p = 0.0001).
      There was no statistical difference in survival among classification groups.
      CONCLUSIONS: Complete tumor resection of superior sulcus tumors is possible in
      selected patients in whom involvement of the spinal column and/or brachial plexus
      is present. Preoperative MR imaging is essential for evaluation of the spine and
      surgical planning. Survival and cure are dependent on complete resection,
      regardless of the extent of spinal involvement.

PMID- 12408384
TI  - Surgical treatment of spinal deformities associated with neurofibromatosis type
      1. Report of 12 cases.
AB  - OBJECT: In 10 to 50% of cases with neurofibromatosis, skeletal disorders are
      present, mainly as various deformities of the spine. These deformities can be
      divided into dystrophic and nondystrophic groups depending on the absence or
      presence of bone dystrophy. The nondystrophic curves are highly similar to those
      in idiopathic scoliosis, whereas the dystrophic curves are manifested early and,
      by progressing inexorably, may lead to neurological symptoms. In this article the
      authors report on a series of 12 patients (11 with dystrophic and one with
      nondystrophic deformities) who underwent surgical treatment. METHODS: In the case
      with a nondystrophic curve, posterolateral instrumentation-assisted fusion was
      performed. A curvature correction of 70% was achieved in the frontal plane, and
      at the 2-year follow-up examination neither bone dysplasia nor pseudarthrosis was
      observed. In the cases with dystrophic curves, preoperative traction for 3 weeks
      was applied; anterior surgical release was then performed, as was two-stage
      posterior instrumentation-assisted fusion. In the cases of thoracic
      kyphoscoliosis in which this treatment protocol was performed, the mean scoliosis
      correction was 66%, whereas the mean decrease in kyphotic angle was 34.5 degrees.
      In the cases with thoracolumbar and lumbar curves, the mean correction in the
      frontal plane was 69.8 degrees, whereas the mean preoperative lumbar kyphosis of
      42 degrees was corrected to a mean lordotic angle of 23 degrees. Postoperatively,
      no hook dislocation was detected. A neurological complication was observed in one
      case. CONCLUSIONS: The surgical treatment of dystrophic curves always included
      360 degrees fusion and the use of a tibial corticocancellous graft, which must be
      placed on the concave side of the curve in the frontal plane, the graft thereby
      providing biomechanical support.

PMID- 12408385
TI  - Syringomyelia associated with foramen magnum arachnoiditis.
AB  - OBJECT: Syringomyelia is often linked to pathological lesions of the foramen
      magnum. The most common cause is hindbrain herniation, usually referred to as
      Chiari I or II malformation. Foramen magnum arachnoiditis without either Chiari I
      or II malformation is a rare cause of syringomyelia. The authors undertook a
      retrospective analysis of 21 patients with foramen magnum arachnoiditis (FMA) and
      syringomyelia treated between 1978 and 2000 to determine clinical course and
      optimum management. METHODS: In the review of records, 21 patients with FMA and
      syringomyelia were documented. A stable clinical course was demonstrated in three
      patients in whom surgery was not performed, and one patient refused surgical
      intervention. Seventeen patients underwent 23 operations to treat progressive
      neurological disease. Of these 23 operations, 18 involved opening of the foramen
      magnum, arachnoid dissection, and placement of a large dural graft. One patient
      underwent insertion of a ventriculoperitoneal shunt for treatment of accompanying
      hydrocephalus, one patient received a cystoperitoneal shunt for an accompanying
      arachnoid cyst; two syringoperitoneal and one syringosubarachnoid shunts were
      also inserted. Hospital and outpatient files, neuroimaging studies, and
      intraoperative photographic and video material were analyzed. Additional follow
      up information was obtained by telephone interview and questionnaires. Standard
      and cardiac-gated magnetic resonance imaging studies are the diagnostic
      procedures of choice in these patients. Sensory disturbances, dysesthesias, and
      pain were the only symptoms likely to improve after foramen magnum surgery. Motor
      weakness and gait disturbances, which were severe in a considerable number of
      patients, and swallowing disorders tended to remain unchanged. As a consequence
      of the rather severe arachnoid lesions in most patients, clinical recurrences
      were observed in 57% over a 5-year period. CONCLUSIONS: Surgery for FMA and
      syringomyelia has to provide clear cerebrospinal fluid pathways between the
      cerebellopontine cisterns, spinal canal, and fourth ventricle. If this can be
      achieved successfully, the syrinx decreases in size and the clinical course of
      the patient may even improve. In patients with severe and widespread areas of
      arachnoiditis, however, multiple operations may be required at least to stabilize
      the clinical course.

PMID- 12408386
TI  - Hydroxyapatite laminar spacers and titanium miniplates in cervical laminoplasty.
AB  - OBJECTIVE: The authors describe a new surgical technique for cervical
      laminoplasty that was performed in 25 patients. The posterior elements along with
      the various ligaments are removed en bloc and are stabilized in a lift-up
      position by placing hydroxyapatite (HA) laminar spacers and titanium miniplates
      and screws. The procedure and clinical results are discussed. METHODS: The
      posterior spinal elements, including the lamina(e), spinous process(es), and
      various attached ligaments, are removed en bloc by incising the lamina in its
      lateral aspect. Trapezoid-shaped HA spacers are placed between the cut ends of
      the laminae or between the laminae and lateral masses bilaterally at each level.
      Malleable titanium miniplates and screws are used for fixation of the spacers.
      The fixation of transected laminae was judged to be successful. Postoperative
      care included application of a soft neck collar for 1 week but no further
      restriction of activity. Surgery-related outcome was assessed in the 21 patients
      who attended more than 6 months of follow up after laminoplasty. There were 18
      men and three women who ranged in age from 27 to 81 years. Cervical stenotic
      myelopathy was demonstrated in 15 patients who underwent decompressive and
      expansive laminoplasty, and spinal tumors were documented in six patients who
      underwent a nonexpansive laminoplasty. Postoperative and follow-up computerized
      tomography scans demonstrated no hardware failure. Bone formation around the
      spacers was observed either at 6- or at 9-month follow-up examination in all 21
      patients. Fusion of the reconstructed laminae was found to be completed at 12
      months in all 18 patients able to attend follow up for this duration. Spinal
      alignment and the range of motion of the cervical spine were well preserved. In
      patients with stenotic cervical myelopathy, neurological and anatomical outcome
      of canal expansion were satisfactory. CONCLUSIONS: This technique enables rigid
      laminoplasty while maintaining anatomical and biomechanical integrity of
      posterior elements of cervical spine. Expansive and nonexpansive laminoplasty
      procedures are possible.

PMID- 12408387
TI  - Preliminary experience with the DOC dynamic cervical implant for the treatment of
      multilevel cervical spondylosis.
AB  - OBJECT: Despite the wide use of anterior cervical instrumentation in the
      management of multilevel cervical spondylosis, the incidences of pseudarthrosis
      and instrument-related failure remain high. The use of a dynamic implant may aid
      in the prevention of these complications. The purpose of this study was to
      evaluate the DOC dynamic cervical implant in the treatment of multilevel cervical
      spondylosis. METHODS: The authors evaluated 34 cases in which anterior multilevel
      cervical decompression and fusion were performed using the DOC Ventral Cervical
      Stabilization System. Postoperatively, and at each follow-up visit, the sagittal
      angle and the degree of subsidence that developed were measured. Fusion rates and
      clinical outcomes were also evaluated. The mean postoperative sagittal angle was
      14 degrees of lordosis. The mean change in the sagittal angle during the follow
      up period was 0.4 degrees of lordosis. By 6 months postoperatively some
      subsidence had occurred in most patients, with no subsidence occurring in only
      15%. By 3 months greater than or equal to 2 mm of subsidence was demonstrated in
      61% of cases. The overall fusion rate was 91%. In the majority of patients (79%)
      symptoms were judged to be improved or resolved. CONCLUSIONS: The DOC dynamic
      cervical implant permitted controlled subsidence and prevented progression of
      kyphotic deformity. There was one construct failure (related to a motor vehicle
      accident) and an overall fusion rate of 91%. The DOC implant is a safe and
      effective cervical construct for multilevel spondylotic disease.

PMID- 12408389
TI  - Quantitative anatomy of the transverse ligament tubercles.
AB  - OBJECT: The medial tubercles of the atlas serve as the attachments of the
      transverse ligament and provide an important anchoring site for which no
      discussion of their fine anatomy is published in the literature. In this study
      the authors examine this anatomy along with its osseous relationships. METHODS:
      One hundred dry cadaveric atlantal tubercles were assessed for size and
      relationship to nearby anatomical osseous structures. In addition, eight
      cadaveric specimens were evaluated for their anatomy in this area. All specimens
      exhibited atlantal tubercles for the attachment of the transverse portion of the
      cruciate ligament of the atlas. Right-sided tubercles tended to be of a larger
      caliber. Overall, right-sided vertical distances between these tubercles and the
      superior articular facets and inferior articular facets were greater, although
      distances from each tubercle to the lateral margin of the dental facets
      anteriorly were found to be constant, as were intertubercular distances. The mean
      angle formed between both tubercles and the dental facet was 75 degrees.
      CONCLUSIONS: The data derived in this study should be useful to the clinician for
      whom the craniocervical junction is a vital anatomical area.

PMID- 12408388
TI  - Surgical approach to anterior compression in the upper thoracic spine.
AB  - OBJECT: The anterior upper thoracic spine (T1-3) is difficult to access because
      most neurosurgeons are unfamiliar with the anatomy. This study was performed to
      evaluate the different surgical options by retrospectively analyzing data on
      operations performed for anterior upper thoracic compression at the authors'
      institution. METHODS: Eighteen patients underwent surgery between November 1993
      and May 2001. There were eight men and 10 women; their mean age was 55 years
      (range 28-80 years). All patients presented with pain and/or neurological
      deficits. The causes of anterior compression were diverse, although metastatic
      spinal tumor was most common. The approach chosen was primarily dictated by the
      axial involvement of the lesion. Anterior approaches, mainly the transmanubrium
      approach, were performed in six and posterior approaches in 12. In all cases
      except one, in which only an iliac bone graft was placed, instrumentation was
      used. The mean follow-up period was 11.4 months (range 1-57 months). One
      postoperative death occurred. Postoperative follow-up imaging studies, especially
      plain radiography, demonstrated no instrumentation failure. Improvement was shown
      in eight patients, an aggravation of symptoms in one, and stable clinical status
      in eight. CONCLUSIONS: Decompression may be achieved on the anterior side of the
      upper thoracic spine if the operative approach is scrupulously chosen; this
      choice involves consideration of the locations of the lesion, the nature of the
      primary disease, and the surgery-related risk.

PMID- 12408390
TI  - Biomechanical properties of expander compared with conventional screws.
AB  - OBJECT: A pullout strength biomechanical study was performed in 20 fresh swine
      vertebral bodies in which titanium expander (Group 1) and conventional screws
      (Group 2) were placed. METHODS: The screws were inserted into the anterosuperior
      portion of the anterior spine, and assessment was performed after application of
      loads. The expander screw is composed of two parts: 1) a cover with an external
      portion comprising tight thin threads; and 2) a compact internal screw inserted
      through the cover that allows expansion. In the comparative study between the
      screws in Groups 1 and 2 maximum load was assessed, and the intergroup difference
      was significant (p = 0.00001 [t-test]); regarding load at the elasticity
      threshold, a significant difference was also observed (p = 0.0063). With regard
      to rigidity (stiffness), there was a tendency in both groups toward significance
      (p = 0.069). With regard to absorbed energy in the elastic phase, statistical
      analysis showed a significant intergroup difference (p = 0.00439). The expander
      screw showed a greater load-bearing capacity than the conventional screw.
      Adhesion to bone in relation to the applied load and displacement was greater
      (significant tendency) in the expander screw group than in the conventional screw
      group. CONCLUSIONS: The expander screws exhibited a greater capacity to absorb
      energy in the elastic phase. They adhered better to bone, were easy to insert,
      and, if necessary, were simple to remove.

PMID- 12408391
TI  - Beta-tricalcium phosphate as a substitute for autograft in interbody fusion cages
      in the canine lumbar spine.
AB  - OBJECT: An interbody fusion cage has been introduced for cervical anterior
      interbody fusion. Autogenetic bone is packed into the cage to increase the rate
      of union between adjacent vertebral bodies. Thus, donor site-related
      complications can still occur. In this study a synthetic ceramic, beta-tricalcium
      phosphate (TCP), was examined as a substitute for autograft bone in a canine
      lumbar spine model. METHODS: In 12 dogs L-1 to L-4 vertebrae were exposed via a
      posterolateral approach, and discectomy and placement of interbody fusion cages
      were performed at two intervertebral disc spaces. One cage was filled with
      autograft (Group A) and the other with TCP (Group B). The lumbar spine was
      excised at 16 weeks postsurgery, and biomechanical, microradiographic, and
      histological examinations were performed. Both the microradiographic and
      histological examinations revealed that fusion occurred in five (41.7%) of 12
      operations performed in Group A and in six (50%) of 12 operations performed in
      Group B. The mean percentage of trabecular bone area in the cages was 54.6% in
      Group A and 53.8% in Group B. There were no significant intergroup differences in
      functional unit stiffness. CONCLUSIONS: Good histological and biomechanical
      results were obtained for TCP-filled interbody fusion cages. The results were
      comparable with those obtained using autograft-filled cages, suggesting that
      there is no need to harvest iliac bone or to use allo- or xenografts to increase
      the interlocking strength between the cage and vertebral bone to achieve anterior
      cervical interbody fusion.

PMID- 12408392
TI  - Intraoperative angiography to prevent vertebral artery injury during reduction of
      a dislocated hangman fracture. Case report.
AB  - The authors report on a 38-year-old woman with a dislocated hangman fracture
      associated with unilateral vertebral artery (VA) occlusion. The patient presented
      with a mild central cord syndrome, as well as anterior subluxation of the C-2
      vertebral body upon C-3, bilateral neural arch fractures, and a unilateral locked
      facet joint. Digital subtraction angiography revealed occlusion of the right VA,
      with the posterior cerebral circulation entirely dependent on the left VA.
      Intraoperative angiography demonstrated that complete reduction of the
      dislocation would have caused severe stenosis of the left VA; partial reduction
      and anterior fixation were performed instead, with excellent neurological
      outcome. In this case, intraoperative angiography was particularly useful for
      preventing brain-related ischemic complications during reduction.

PMID- 12408393
TI  - Spinal cord compression by multistrand cables after solid posterior atlantoaxial
      fusion. Report of three cases.
AB  - The sublaminar wiring procedure has been commonly used for stabilizing the
      atlantoaxial complex. Multistrand braided cables were introduced in the early
      1990s. In previous biomechanical studies these cables were demonstrated to be
      superior to monofilament wires in terms of their flexibility, mechanical
      strength, and fatigue-related characteristics. To the authors' knowledge, they
      are the first to describe clinically the occurrence of delayed spinal cord
      compression resulting from multistrand cables after the completion of rigid
      spinal arthrodesis in the upper cervical spine. Three patients underwent
      posterior atlantoaxial fusion in which two sublaminar multistrand cables were
      placed. Between 15 and 48 months postoperatively, they suffered from upper- and
      lower-extremity numbness as well as gait disturbance. Plain radiography and
      computerized tomography myelography revealed spinal cord compression caused by
      the sublaminar cables, although fusion was complete and physiological alignment
      was maintained at the fused segment. The radiographs obtained immediately after
      surgery demonstrated that the initial cable placement had been properly
      performed. The shape of the cable at the initial surgery was oval and then
      gradually became circular. The anterior arc of the circular shape of the cable in
      fact led to the spinal cord compression. Considering the mechanism of this late
      complication, a cable tends to spring open because of its high flexibility and
      becomes circular shaped even after the complete arthrodesis. When applying
      multistrand cables for intersegmental fixation at the atlantoaxial complex,
      delayed complications related to bowing of the cables is possible.

PMID- 12408394
TI  - Delayed management of traumatic bilateral cervical facet dislocation: surgical
      strategy. Report of three cases.
AB  - Postinjury cervical spine instability typically requires surgical treatment in
      the acute or semiacute stage. The authors, however, report on three patients with
      older (> 8 weeks) untreated bilateral cervical facet dislocation. In two patients
      they attempted a classic anterior-posterior-anterior approach but failed. The
      misalignment in the second stage of the procedure could not be corrected, and
      they had to add a fourth, posterior, stage. To avoid the fourth stage, thereby
      reducing operating time and risk of neurological damage while turning the
      patient, they propose the following sequence: 1) a posterior approach to perform
      a complete facetectomy bilaterally with no attempt to reduce the dislocation; 2)
      an anterior microscopic discectomy with reduction of the dislocation and anterior
      fixation; and 3) posterior fixation. This sequence of procedures was successfully
      performed in the third patient. Based on this experience, they suggest that in
      cases of nonacute bilateral cervical facet dislocations the operating sequence
      should be posterior-anterior-posterior.

PMID- 12408395
TI  - Syringomyelia caused by loosening of multistrand cables following C1-2 Brooks
      type fusion in the rheumatoid cervical spine. Case report.
AB  - The authors report a very rare case of syringomyelia caused by loosening of
      multistrand cable wires following C1-2 Brooks-type fusion in a 36-year-old woman
      with a 13-year history of rheumatoid arthritis (RA). The syrinx vanished
      immediately after removal of the cables, and 2 years later no recurrence of
      symptoms or deterioration has occurred. The authors contend that multistrand
      titanium cables should not be used to fix a graft-assisted C1-2 construct in
      patients with RA, although this material is good for fixing rods. The phenomenon
      observed in this case adds to our understanding of the pathogenesis of
      noncommunicating syringomyelia.

PMID- 12408396
TI  - Thoracic idiopathic spinal cord herniation at the vertebral body level: a
      subgroup with a poor prognosis? Case reports and review of the literature.
AB  - The authors present two cases of thoracic idiopathic spinal cord herniation
      (TISCH) occurring at the vertebral body (VB) level in whom adequate surgical
      reduction failed to reverse symptoms. In the second case, in which TISCH occurred
      into a VB cavity, presentation was atypical (subacute spinal cord syndrome) and
      there was persistent postoperative deterioration. In both cases, adequate
      surgical reduction was achieved via a posterior midthoracic laminectomy, and
      reduction was maintained by closure of the anterior dural defect by using
      prosthetic material. Thoracic idiopathic spinal cord herniation occurring at a VB
      level may be technically well treated by surgical reduction, but the outcome
      appears less predictable. Herniation that occurs directly into a VB cavity may
      form a distinct subgroup in which the presentation is atypical and the prognosis
      worse.

PMID- 12408397
TI  - Dural arteriovenous fistula and progressive conus medullaris syndrome as
      complications of lumbar discectomy. Case report.
AB  - A case of a dural arteriovenous fistula (DAVF) that developed at the site of
      nerve root sleeve damage as a result of lumbar disc extrusion is reported. A 60
      year-old man who had undergone lumbar discectomy 3 years previously for severe
      left-sided sciatica and L5-S1 disc herniation presented with progressive gait
      disturbance. After the initial surgery, the symptoms resolved. Fourteen months
      after the operation, however, he started to experience dysesthesias in both legs
      and progressive gait and urinary disturbances. Physical examination revealed a
      weakness of the anterior tibialis and the gastrocnemius muscles, as well as
      decreased contractility of the anal sphincter and marked sacral hypesthesia.
      Magnetic resonance (MR) imaging revealed swelling and a T2 signal elongation in
      the conus medullaris; angiography demonstrated arteriovenous dural shunting
      between the left lateral sacral artery and the left S-1 radicular vein at the
      site of the previous operation. Surgery was conducted to excise the DAVF on the S
      1 nerve root sleeve and an arterialized intradural vein on the root. The
      procedure resulted in resolution of the symptoms and disappearance of the
      abnormal angiographically and MR imaging-documented anomalies. This is the first
      report of a DAVF in which progressive conus myelopathy developed after a lumbar
      discectomy.

PMID- 12408398
TI  - Spontaneous osteoporotic fractures of the sacrum causing neurological damage.
      Report of three cases.
AB  - Although osteoporotic fractures of the sacrum seem to be a well-known entity,
      their associated rate of neurological complications has not been assessed in the
      literature. The authors report three such cases of nerve root compromise in
      elderly women and conduct a literature review. Based on their review, they
      estimate the incidence to be approximately 2%. The true incidence is probably
      higher because many case reports provide only scant information on symptoms;
      furthermore, sphincter dysfunction and lower-limb paresthesias are the most
      common symptoms and can readily be overlooked or misinterpreted in elderly
      patients with multiple health problems. The neurological manifestations were
      delayed in some cases. A full recovery is the rule. The characteristics of the
      sacral fracture are not consistently related with the risk of neurological
      compromise. In most reviewed cases the authors found no displacement and in many
      the foramina were not involved. The pathophysiology of the neurological
      manifestations remains unclear. The authors suggest that patients with sacral
      osteoporotic fractures should be carefully monitored for neurological
      manifestations.

PMID- 12408399
TI  - Total cervical spondylectomy for primary osteogenic sarcoma. Case report and
      description of operative technique.
AB  - The authors describe a technique for total spondylectomy for lesions involving
      the cervical spine. The method involves separately staged anterior and posterior
      approaches and befits the unique anatomy of the cervical spine. The procedure is
      described in detail, with the aid of radiographs, intraoperative photographs, and
      illustrations. Unlike in the thoracic and lumbar spine--for which methods of
      total en bloc spondylectomy have previously been described--a strictly en bloc
      resection is not possible in the cervical spine because of the need to preserve
      the vertebral arteries and the nerve roots supplying the upper limbs. Although
      the resection described in this case is by definition intralesional, it is
      oncologically sound, given the development of effective neoadjuvent
      chemotherapeutic regimens for osteosarcoma.

PMID- 12408400
TI  - Traumatic neuroma of the anterior cervical nerve root with no subjective episode
      of trauma. Report of four cases.
AB  - The authors report four cases of traumatic neuroma in the cervical nerve root in
      patients with no history of trauma. In one case the patient presented with
      intractable pain in the left upper extremity and motor paresis of the left
      shoulder, and in another case the patient suffered neuropathic pain in the left
      forearm. In both cases, magnetic resonance (MR) imaging revealed an intradural
      extramedullary mass lesion in the ipsilateral cervical nerve root; these MR
      imaging signals were similar to the intensity of the spinal cord.
      Intraoperatively, fusiform enlargement of the anterior cervical nerve root was
      detected in the subarachnoid space. Histological examination showed a meandering
      change of axons accompanied by mild axonal swelling and a thin myelin sheath,
      which are consistent with the typical pathological features of traumatic neuroma.
      Postoperatively, pain resolved in both cases. The authors also investigated two
      traumatic neuromas of the anterior cervical nerve root in autopsy cases in which
      there was no history of trauma and no significant neurological signs suggestive
      of traumatic neuroma. The authors conclude that traumatic neuroma of the anterior
      cervical nerve root may develop following an unnoticed minor brachial plexus
      injury at birth or a forgotten traction injury of the upper extremity in
      childhood, and the lesion may be accompanied by various case-specific clinical
      features.

PMID- 12408401
TI  - Unusual thigh fistulas from tuberculous spondylitis. Case illustration.

PMID- 12408402
TI  - "Twinning" of a cervical nerve root mimicking a neoplasm. Case illustration.

PMID- 12408403
TI  - Posterior longitudinal ligament cyst causing radiculopathy. Case illustration.

PMID- 12408404
TI  - A bone and cable girth-hitch technique for atlantoaxial fusion in pediatric
      patients. Technical note.
AB  - A new technique for performing a posterior rib and multistranded cable
      atlantoaxial fusion in children is described. The technique has been used
      successfully, in two patients 22 and 18 months of age, respectively. In both
      cases, fusion was used to augment C1-2 transarticular screw fixation, and solid
      arthrodesis was achieved without a halo orthosis.

PMID- 12408405
TI  - Reconstruction of the thoracal spine with an anterior interbody fixator and
      methylmethacrylate. Technical note and case report.

PMID- 12408406
TI  - Correction addendum to: Late recovery following spinal cord injury.

PMID- 12408407
TI  - Long-term consequences of type 2 diabetes mellitus: economic impact on society
      and managed care.
AB  - Type 2 diabetes is the most common form of diabetes in the United States and is
      associated with significant long-term morbidity and increased mortality. Patients
      with diabetes are at much higher risk for development of both microvascular and
      macrovascular complications, including peripheral neuropathy, nephropathy,
      ophthalmic abnormalities, and cardiovascular disease. Not surprisingly, direct
      and indirect healthcare costs associated with diabetes totaled $98 billion in
      1997. Studies have shown that improving glycemic control leads to reductions in
      healthcare utilization and a decrease in overall costs. Notably, early and
      aggressive treatment may delay or even prevent many of the complications
      associated with diabetes, leading to improved quality of life and reduced
      expenditures in patients with type 2 diabetes. This article will provide a review
      of recent findings on the impact of diabetes on healthcare costs.

PMID- 12408408
TI  - Understanding type 2 diabetes mellitus and associated cardiovascular disease:
      linked by insulin resistance.
AB  - Type 2 diabetes mellitus is a prevalent disorder diagnosed by the presence of
      hyperglycemia, although insulin resistance frequently precedes the onset of
      hyperglycemia. Metabolic abnormalities, such as dyslipidemia, increased markers
      of atherosclerotic and inflammatory states, and increased free fatty acid flux,
      also precede the detection of hyperglycemia in many patients. Not surprisingly,
      clinical morbidities from complications of type 2 diabetes often are present at
      the time of diagnosis; these complications include both microvascular and
      macrovascular disease. The macrovascular complications of type 2 diabetes are
      associated with a variety of risk factors for cardiovascular disease. Insulin
      resistance appears to be the risk factor that best correlates with metabolic
      abnormalities prior to diagnosis and is fundamentally linked to development of
      cardiovascular disease in patients with type 2 diabetes. This article will review
      the unifying finding of insulin resistance in type 2 diabetes with both metabolic
      and cardiovascular consequences.

PMID- 12408409
TI  - Current treatment approaches to type 2 diabetes mellitus: successes and
      shortcomings.
AB  - Diabetes mellitus affects approximately 17 million adults in the United States
      and has profound implications in terms of long-term microvascular and
      macrovascular complications and their associated costs. In type 2 diabetes,
      insulin resistance and a relative beta-cell defect are the underlying pathologic
      problems leading to hyperglycemia. Notably, insulin resistance is also associated
      with obesity, dyslipidemia, and hypertension. Diabetes can be defined as a
      disease of accelerated cardiovascular deterioration associated with elevated
      blood glucose levels. Glycemic control has been shown to reduce the long-term
      complications associated with diabetes. Although medical nutrition therapy and
      appropriately prescribed increased physical activity are important components of
      a diabetes management plan, most patients need medication to lower glucose to
      near-normal levels. Therapeutic options for treating hyperglycemia include
      sulfonylureas and other insulin secretagogues, biguanides, alpha-glucosidase
      inhibitors, thiazolidinediones, and insulin. An antidiabetic agent that improves
      insulin sensitivity is an excellent choice for early treatment of type 2 diabetes
      because it may delay or prevent complications associated with this disease.
      Because of the progressive nature of type 2 diabetes, aggressive intervention
      early in the course of the disease, including combination therapy, is often
      necessary.

PMID- 12408410
TI  - Effects of thiazolidinediones for early treatment of type 2 diabetes mellitus.
AB  - The thiazolidinediones (TZDs) are a new class of oral antidiabetic agents used in
      the treatment of type 2 diabetes mellitus. TZDs are selective and potent agonists
      of peroxisome proliferator-activated receptor-gamma, which is expressed in target
      tissues for insulin action and in a variety of cells that play an important role
      in atherosclerosis. TZDs primarily improve glycemic control by reducing insulin
      resistance in target tissues. Evidence also suggests that the TZDs may have a
      direct, beneficial effect on beta-cell function. In patients with impaired
      glucose tolerance (prediabetics), treatment with a TZD improves insulin secretory
      responses and proinsulin concentrations. These beta-cell-specific effects may
      result in prolongation of beta-cell function and the enduring glycemic control
      necessary to prevent microvascular complications. Durable glycemic control has
      not been clearly demonstrated with other antihyperglycemic agents. The TZDs may
      prevent or delay the macrovascular complications associated with type 2 diabetes.
      TZDs improve the characteristic dyslipidemia of type 2 diabetes, promote
      decreases in blood pressure, and enhance fibrinolysis. In addition, they exert
      direct effects on the vasculature, including the ability to decrease the intimal
      medial thickness and inhibit transendothelial migration of monocytes. These
      demonstrated antiatherogenic effects may reduce the cardiovascular complications
      commonly associated with type 2 diabetes. TZDs also reduce microalbuminuria to a
      greater extent than other agents. Use of a TZD early in the course of therapy may
      reduce the risk of development of many of the long-term microvascular and
      macrovascular complications associated with type 2 diabetes.

PMID- 12408411
TI  - Thiazolidinediones in the treatment of managed care patients with type 2
      diabetes.
AB  - Insulin resistance and progressive beta-cell failure are fundamental defects in
      type 2 diabetes. Treatments that improve insulin sensitivity and beta-cell
      function can improve these defects and improve glycemic control. The
      thiazolidinediones (TZDs) improve insulin sensitivity, fasting and postprandial
      plasma glucose levels, and glycosylated hemoglobin (HbA1c) levels. These agents
      can be used as monotherapy, and they have been successfully combined with other
      antidiabetic therapies. The TZDs have also been associated with improvements in
      various cardiovascular risk factors, including hypertension, the dyslipidemic
      profile often observed in patients with diabetes or insulin resistance, aspects
      of endothelial dysfunction, abnormal hemostasis, and levels of several
      inflammatory markers. Studies are currently under way to evaluate the effects of
      TZDs on cardiovascular event rates. Accumulating evidence suggests that TZDs may
      enhance or preserve beta-cell function and thus may have a more durable
      therapeutic effect than some of the other oral antidiabetic agents. Using TZDs as
      monotherapy or as a component of combination therapy will contribute to improved
      glycemic control and should reduce the risk of diabetic complications. A number
      of studies have shown that a strategy of aggressive use of pharmacologic agents
      to achieve glycemic control is associated with cost benefits.

PMID- 12408412
TI  - Resident hours: reform is at hand.

PMID- 12408413
TI  - Recommendation for modified metered-dose inhaler.

PMID- 12408414
TI  - Treatment of tobacco dependence.

PMID- 12408415
TI  - Should patients be referred for endoscopy?

PMID- 12408416
TI  - Techniques and tips for lipoma excision.

PMID- 12408417
TI  - Screening for osteoporosis in postmenopausal women: recommendations and
      rationale.

PMID- 12408418
TI  - Evaluation of clumsiness in children.
AB  - Parents and physicians often dismiss seemingly minor motor difficulties in
      children. Approximately 6 percent of school-aged children have coordination
      problems serious enough to interfere with academic performance and social
      integration. These problems often arise during the early school years and
      manifest in difficulties with such simple motor tasks as running, buttoning, or
      using scissors. Increasing evidence shows that rather than improving over time,
      these motor difficulties remain stable throughout adolescence and adulthood.
      While these children are initially singled out for motor difficulties, their
      problems are rarely limited to poor motor coordination. Many of them have a range
      of associated deficits, such as attention-deficit/hyperactivity disorder,
      learning disabilities, poor handwriting and drawing skills, and emotional
      immaturity. Associated problems magnify with time, and as teenagers, these
      children have higher rates of educational, social, and emotional problems.
      Diagnosis is determined by taking a careful history that includes a review of
      fine motor, visual, adaptive, and gross motor milestones, and performing a
      physical examination. Formal standardized testing may be indicated. Referral to
      occupational therapy that is appropriately individualized to the needs of each
      child appears to be effective. To aid in management, the family physician must be
      aware of this condition, as well as the associated coexisting deficits.

PMID- 12408419
TI  - Childhood discipline: challenges for clinicians and parents.
AB  - Although childhood discipline is an important issue for parents, this topic is
      seldom emphasized by family physicians during well-child examinations. Behavior
      problems are relatively common but frequently under-recognized by physicians.
      Opportunities to counsel parents about safe, effective methods of discipline are
      therefore missed. Discipline should be instructive and age-appropriate and should
      include positive reinforcement for good behavior. Punishment is only one aspect
      of discipline and, in order to be effective, it must be prompt, consistent, and
      fair. Time-out is frequently used to correct younger children, but because it is
      often enforced improperly, it loses its effectiveness. Corporal punishment is a
      controversial but common form of discipline that is less effective than some
      other types of punishment. Its use is linked to child and spouse abuse, as well
      as to future substance use, violent crime, poor self-esteem, and depression.
      Despite the possible negative effects of corporal punishment, it is still widely
      accepted in our society. Since discipline plays an important role in the social
      and emotional development of children, physicians should be trained to discuss
      this issue with parents during routine well-child examinations.

PMID- 12408420
TI  - Information from your family doctor. How to teach good behavior: tips for
      parents.

PMID- 12408421
TI  - Preoperative care of patients with kidney disease.
AB  - Patients with chronic kidney disease often require surgical interventions for
      vascular access and for medical problems related to comorbid conditions.
      Perioperative morbidity and mortality rates are increased in these patients.
      Preoperative attention to common medical problems that occur in patients with
      impaired renal function can lower some surgical risks. Hyperkalemia can be
      temporarily improved by the intravenous administration of an insulin-dextrose
      combination or bicarbonate, and polystyrene binding resins or dialysis can remove
      excess stores of potassium. Increased bleeding related to uremic platelet
      dysfunction can be managed by the administration of desmopressin,
      cryoprecipitate, or estrogens, and by avoiding the use of medications with
      antiplatelet effects close to the time of surgery. Transfusions of red blood
      cells should be reserved for use in patients with clinically significant anemia,
      because antibody formation may decrease the likelihood of successful renal
      transplantation in the future. Cardiovascular disease is the most common cause of
      death in patients with renal disease. Patients with chronic kidney disease may
      have hypertension and hypoglycemia in the perioperative period. Preoperative
      testing may be necessary in patients with cardiac risk factors. If future
      vascular access grafting is contemplated, intravenous line placement and blood
      draws should be avoided in a patient's nondominant arm.

PMID- 12408422
TI  - What to do when SSRIs fail: eight strategies for optimizing treatment of panic
      disorder.
AB  - Selective serotonin reuptake inhibitors (SSRIs) are the drug of choice for
      treatment of patients with panic disorder. Most patients have a favorable
      response to SSRI therapy; however, 30 percent will not be able to tolerate these
      drugs or will have an unfavorable or incomplete response. Strategies to improve
      management of such patients include optimizing SSRI dosing (starting at a low
      dose and slowly increasing the dose to reach the target dose) and ensuring an
      adequate trial before switching to a different drug. Benzodiazepines should be
      avoided but, when necessary, may be used for a short duration or may be used long
      term in patients for whom other treatments have failed. Slower-onset, longer
      acting benzodiazepines are preferred. All patients should be encouraged to try
      cognitive behavior therapy. Augmentation therapy should be considered in patients
      who do not have a complete response. Drugs to consider for use in augmentation
      therapy include benzodiazepines, buspirone, beta blockers, tricyclic
      antidepressants, and valproate sodium.

PMID- 12408423
TI  - Epilepsy in women.
AB  - Epilepsy in women raises special reproductive and general health concerns.
      Seizure frequency and severity may change at puberty, over the menstrual cycle,
      with pregnancy, and at menopause. Estrogen is known to increase the risk of
      seizures, while progesterone has an inhibitory effect. Many antiepileptic drugs
      induce liver enzymes and decrease oral contraceptive efficacy. Women with
      epilepsy also have lower fertility rates and are more likely to have anovulatory
      menstrual cycles, polycystic ovaries, and sexual dysfunction. Irregular menstrual
      cycles, hirsutism, acne, and obesity should prompt an evaluation for reproductive
      dysfunction. Children who are born to women with epilepsy are at greater risk of
      birth defects, in part related to maternal use of antiepileptic drugs. This risk
      is reduced by using a single antiepileptic drug at the lowest effective dose and
      by providing preconceptional folic acid supplementation. Breastfeeding is
      generally thought to be safe for women using antiepileptic medications.

PMID- 12408425
TI  - Information from your family doctor. Joint aspiration and injection.

PMID- 12408424
TI  - Knee joint aspiration and injection.
AB  - Knee joint aspiration and injection are performed to aid in diagnosis and
      treatment of knee joint diseases. The knee joint is the most common and the
      easiest joint for the physician to aspirate. One approach involves insertion of a
      needle 1 cm above and 1 cm lateral to the superior lateral aspect of the patella
      at a 45-degree angle. Once the needle has been inserted 1 to 1 1/2 inches,
      aspiration aided by local compression is performed. Local corticosteroid
      injections can provide significant relief and often ameliorate acute
      exacerbations of knee osteoarthritis associated with significant effusions. Among
      the indications for arthrocentesis are crystal-induced arthropathy, hemarthrosis,
      unexplained joint effusion, and symptomatic relief of a large effusion.
      Contraindications include bacteremia, inaccessible joints, joint prosthesis, and
      overlying infection in the soft tissue. Large effusions can recur and may require
      repeat aspiration. Anti-inflammatory medications may prove beneficial in reducing
      joint inflammation and fluid accumulations.

PMID- 12408426
TI  - Information from your family doctor. How to care for your ankle sprain.

PMID- 12408427
TI  - Information from your family doctor. Knee bracing: what works?

PMID- 12408428
TI  - Information from your family doctor. Cast care.

PMID- 12408429
TI  - American Cancer Society releases guidelines on nutrition and physical activity
      for cancer prevention.

PMID- 12408430
TI  - Resident education and patient safety.

PMID- 12408431
TI  - Probiotics in the third millennium.
AB  - Probiotics are "living microorganisms which upon ingestion in certain numbers
      exert health benefits beyond inherent general nutrition". Since 1987, when the
      first publication on the properties of the Lactobacillus GG was done, overall,
      there have been over 200 publications in peer-reviewed scientific journals. This
      paper will report the status and the prospectus of probiotics research at the
      beginning of the Third Millennium. Probiotics have proven benefits in treatment
      and prevention of rotavirus diarrhoea in children and reduction of antibiotic
      associated intestinal side-effects. Interesting results have recently been
      published regarding food allergies and atopic eczema in children. Prevention of
      vaginitis and of travellers' diarrhoea have also been reported. Promising results
      are being reported in patients with inflammatory bowel disease, cystic fibrosis,
      dental caries and irritable bowel syndrome. It has also been suggested that
      probiotics could enhance oral vaccine administration, and that they may help
      treatment against Helicobacter pylori infection, but further studies are needed.
      Future areas of research regard probiotics' role in the process of
      carcinogenesis, given their influence on the gut microflora, and as immune
      modulators in autoimmune disorders. The possibility of introducing appropriate
      genes to the probiotics to make them produce various compounds is also under
      investigation. However, there is still confusion in the minds of the authorities
      over whether a probiotic is a drug, a food, or a dietary supplement. The
      challenge is to continue research to define the appropriate uses of probiotics
      and discover new applications which will bring benefit to humankind.

PMID- 12408432
TI  - Probiotics: clinics and/or nutrition.
AB  - The primary claim of probiotics is their beneficial influence on the intestinal
      ecosystem, which, in turn, may provide protection against gastro-intestinal
      infections. The positive actions on human health include antagonistic activity
      against pathogens, anti-allergic effects and other effects on the immune system.
      In recent years, the concept of probiotics evolved from food with beneficial,
      even if not clearly established, effects on well-being, to the new area of the
      nutraceuticals or functional foods. This concept was developed further into the
      biotherapeutics, which are the clinical applications of probiotic microorganisms
      originally selected for food use. Whereas several of these health claims remain
      controversial, well-planned clinical trials increasingly support the claims for
      some carefully selected probiotic strains. Aim of this review is to provide a
      first attempt to evaluate these two areas of use of probiotics and to draw a
      borderline between them. Only a more in-depth knowledge of the mechanisms
      underlying the probiotic effects will allow a clear discrimination between the
      food use and the clinical use.

PMID- 12408433
TI  - Variation in human intestinal microbiota with age.
AB  - The large intestinal microbiota plays an important role in normal bowel function
      and the maintenance of host health, through the formation of short chain fatty
      acids, modulation of immune system reactivity and development of colonisation
      resistance. However, the effects of ageing on bacterial community structure in
      the colon are not well documented. Aim of this study is to assess bacterial
      species diversity in the human faecal microbiota with respect to age and
      Clostridium difficile infection. Bacterial populations were quantified from stool
      samples obtained from children (16 months to seven years), young adults (21-34
      years), healthy elderly people (67-88 years) and patients diagnosed with
      Clostridium difficile-associated diarrhoea (68-73 years). Microbial diversity was
      assessed to species level for samples from the latter three subject groups.
      Marked interindividual variations occurred in microbial composition at genus and
      species levels. The faecal microbiota of children was found to be
      bacteriologically less complex whilst advancing age was associated with decreased
      bifidobacteria and increased bacteroides species diversity. Changes in microbial
      composition with age or disease will alter the metabolic capacity of the gut
      microbiota and has important implications for therapies aimed at modulating the
      large intestinal microbiota.

PMID- 12408434
TI  - Gastrointestinal tract and the elderly: functional foods, gut microflora and
      healthy ageing.
AB  - Advances in science and medicine as well as improved living standards have led to
      a steady increase in life expectancy. Yet ageing is associated with increased
      susceptibility to degenerative or infectious diseases, which may be exacerbated
      by a poor nutritional status. The intestinal microflora will mediate crucial
      events towards the protection or degradation of health. It is hence essential and
      timely that strategies of preventive nutrition aimed at maintaining or improving
      the quality of life of the ageing population be developed. "CROWNALIFE" is a
      newly funded EuropeanUnion project, so called because of its emphasis on the
      preservation of the period of independence of the elderly, recognised as the
      "crown of life". The project aims at assessing age-related alterations and
      exploring strategies to restore and maintain a balanced healthy intestinal
      environment. Current knowledge on the composition and function of the human
      intestinal microflora is still improving with the use of better methodologies and
      yet their evolution with ageing has not been investigated in detail. There have
      been a few reports that putatively protective lactic acid bacteria, in general,
      and bifidobacteria, in particular, seem less represented in the elderly faecal
      flora. We have also observed an increase in species diversity of the dominant
      faecal microflora with ageing. This certainly warrants confirmation and is being
      addressed by the investigation of age-related changes in the structure and
      function of the intestinal flora of the elderly in countries across Europe.
      Ensuing results will constitute a baseline for functional-food based strategies
      aimed at providing health benefits for the elderly.

PMID- 12408435
TI  - Novel probiotics for the management of allergic inflammation.
AB  - Several pathologies of the gastrointestinal tract, particularly food allergy, are
      due to an exaggerated and imbalanced response of the gut mucosal immune system.
      The intestinal microflora is an important constituent of the gut mucosal barrier
      against food allergens and there is increasing evidence that one important
      acquired factor predisposing to food allergy in infants is the gut microflora.
      Indeed, the balance of bifidobacteria versus Clostridia in the neonatal flora
      appears to determine the allergic status in infants. In earlier studies, it was
      shown that the higher prevalence of allergies in infants fed standard formulas,
      compared to breast-fed infants, correlated with lower frequencies of
      bifidobacteria in their faeces. Certain Lactobacillus probiotic strains can have
      an inhibitory impact on allergic inflammation. The mechanisms implicated are
      still unclear, but it seems that they can involve both proteolytic and/or
      immunomodulatory functions. One challenge will be to find a probiotic strain that
      elicits all these functions and that fulfills all safety criteria.

PMID- 12408436
TI  - Interactions between novel micro-organisms and intestinal flora.
AB  - Microbial strains traditionally used to ferment food have a long history of safe
      use and are, therefore, considered as generally recognised as safe. Many of these
      micro-organisms have also functional attributes and are included among
      probiotics. New species and strains of bacteria with desirable technological and
      functional properties are constantly being identified; in addition, micro
      organisms can be engineered by recently developed biotechnological tools in order
      to accelerate strain improvement. Although the potentialities of novel micro
      organisms with better probiotic and technological properties are promising, it
      cannot be assumed that they share the safety record of traditional micro
      organisms, since they may pose unique challenges for human health. The risk
      assessment and safety evaluation of novel micro-organisms must focus, primarily,
      on their potential harmful effects, both direct and indirect, upon host resident
      intestinal microflora. Genetically modified micro-organisms need further
      assessment for the complete characterisation of the DNA rearrangement and of the
      final product, in order to establish the "substantial equivalence" with the
      parental strain.

PMID- 12408437
TI  - Cytoskeletal proteins and resident flora.
AB  - Recent observations demonstrate that enteropathogenetic and enterohaemorrhagic
      bacteria, as well as other non enteropathogenetic bacteria (Listeria, Coxiella
      Burnetii), may subvert the host cell cytoskeleton. Models from enteropathogenic
      bacteria demonstrate that cytoskeletal proteins are required for bacteria binding
      to the enterocytes and that they play a role in the immune response of the host
      to intestinal bacteria. The cytoskeletal protein family Tropomyosins is present
      in all eukaryotic cells, with multiple isoforms regulated by multiple genes. Of
      the different Tropomyosin isoforms, TM5 has been shown to be expressed in colonic
      and jejunal epithelial cells, while TM1 in colonic and jejunal smooth muscle. In
      vitro studies have shown the presence of serum and mucosal IgG against TM5 in
      almost two thirds of patients with ulcerative colitis, suggesting: a. a possible
      autoimmune response to Tropomyosin in these patients; b. the hypothesis that the
      development of pouchitis may be related to the expression of TM5 in the ileal
      pouch; c. the use of probiotics in the treatment of pouchitis. Overall, the new
      expression of cytoskeletal proteins on the cell surface appears to be possibly
      induced by several mechanisms, including intestinal bacteria and apoptosis. The
      expression of cytoskeletal proteins on the cell surface may induce tolerance or
      autoimmune response on target cells. Further investigations are, however needed
      on the possible role of cytoskeletal proteins in human diseases.

PMID- 12408438
TI  - Resident bacterial flora and immune system.
AB  - The "controlled inflammation" of the normal human gut is a closely controlled
      phenomenon and any change in the cell type number and/or functions, including the
      release of soluble mediators can lead to an "uncontrolled" inflammation. The
      physiological inflammation in the human gut plays a crucial role in maintaining a
      local immune response that is appropriate, efficiently protective and which
      respects the gut structure and function. The intestinal mucosa represents a
      considerable proportion of the human immune system. Disregulation of the mucosal
      immune response can switch a "controlled" toward an "uncontrolled" intestinal
      inflammation. A key role in the maintenance of an adequate balance between
      antigenic stimulation and host immune response is played by the immunoregulatory
      molecules released by activated immunocytes in the human gut. The role of the
      host immune system in the maintenance of an adequate balance between luminal
      antigens, including the resident bacterial flora and host immune response, is
      strongly supported by animal models of uncontrolled intestinal inflammation.
      Besides the aetiology of inflammatory bowel disease, luminal antigens (including
      food, viral and bacterial antigens) contribute to the maintenance of the
      inflammatory process in inflammatory bowel disease, by stimulating the
      immunocompetent cells in the intestinal mucosa. Of the luminal antigens, the
      resident bacterial flora seems to play a major role in the development of animal
      models of "uncontrolled" intestinal inflammation. Recent evidence also suggest
      that bacterial flora can modulate the function of the intestinal mucosal cells.
      These observations support the role of the intestinal bacterial flora in the
      induction of an uncontrolled inflammation in the human gut, leading to tissue
      damage. Probiotics, defined as living micro-organisms which, when taken in
      appropriate amounts, improve the health status, have been proposed in the
      treatment of inflammatory bowel disease, but their mechanisms of action still
      remain to be fully elucidated.

PMID- 12408439
TI  - New therapeutic approach in the management of intestinal disease: probiotics in
      intestinal disease in paediatric age.
AB  - Current evidence supports the view that oral administration of probiotics may be
      of therapeutic usefulness in several clinical disorders by reestablishing normal
      flora in the gastrointestinal tract. These entities include inflammatory and
      infectious diseases of the gut as well as extraintestinal disorders (such as
      atopic eczema) in which a defective intestinal permeability plays a role. The
      probiotic effects are attributed to restoration to normal of increased intestinal
      permeability, unbalanced gut microecology, improved immunological gut barrier
      function, downregulation of the intestinal inflammatory responses with reduced
      generation of proinflammatory cytokines. Entities for which the impact of
      probiotic administration can be considered as proven are Rotavirus diarrhoea,
      Clostridium difficile diarrhoea, post-antibiotic diarrhoea, allergic diseases. On
      the other hand, entities for which administration of probiotics is considered
      under investigation are inflammatory bowel disease, necrotizing enterocolitis,
      cystic fibrosis, small bowel bacterial contamination, functional gastrointestinal
      disorders. The value of probiotics as therapy for a variety of gastrointestinal
      disorders in childhood still needs to be investigated in detail, through well
      controlled and rigorous studies, including a placebo group and strict criteria of
      randomisation. Much work needs to be done in this area by clearly defining
      indications, delivery system, costs, safety long-term effects.

PMID- 12408440
TI  - Intestinal microflora and oral bacteriotherapy in irritable bowel syndrome.
AB  - On the basis of many clinical and experimental observations, it would appear
      feasible to hold that the characteristics of the luminal milieu, the
      relationship, the balance between luminal prokaryotic cells and mucosal
      eukaryotic cells and the consequent immunological and humoral local and systemic
      responses take part in the pathophysiology of several diseases and, consequently
      bacteriotherapy can play a relevant role in the treatment and prevention of
      irritable bowel syndrome and more in general, of the intestinal functional
      disorders. The irritable bowel syndrome is characterised by sudden and
      unforeseeable changes in the two main symptoms, constipation and diarrhoea, even
      within a few days. The amount and composition of proximal colon microflora,
      increasing with regard to the above-mentioned factors, and the time in which this
      development occurs, are, in our opinion, elements taking part, together with
      colon dysmotility and alterations of visceral perception, in the onset of the
      variability in stool frequency, typical of these patients. The present open
      noncontrolled trial is the first observation showing a clinical improvement
      related to changes in the composition of the faecal bacterial flora and in faecal
      biochemistry and, remarkably, in the colonic motility pattern, all of which
      induced by administration of probiotics, in patients with functional diarrhoea.

PMID- 12408441
TI  - Bile salts, intestinal microflora and enterohepatic circulation.
AB  - Use of probiotic therapy implies an attempt to maintain the normal bacterial
      flora or to alter the bacterial flora so that organisms beneficial to the host
      are nurtured. We also know that the bacterial flora are essential in the
      deconjugation and transformation of bile acid metabolism. The relationships of
      the bile acids to intestinal bacteria and their recurrent exposure in the
      enterohepatic circulation are discussed.

PMID- 12408442
TI  - Probiotics--role in inflammatory bowel disease.
AB  - The aetiology of inflammatory bowel disease is still unclean. Whilst a specific
      pathogen agent associated with these diseases has not been found, the rationale
      for probiotic therapy in inflammatory bowel disease is based on convincing
      evidence involving intestinal bacteria in their pathogenesis. Encouraging results
      have been obtained with probiotic therapy in several animal models of
      experimental colitis. The administration of highly concentrated probiotic
      preparations represents a valid approach both for the prevention of pouchitis
      onset and relapses. The encouraging results obtained in ulcerative colitis and
      Crohn's disease need to be further assessed in large double-blind trials.

PMID- 12408443
TI  - Use of Lactobacillus-GG in paediatric Crohn's disease.
AB  - The potential role of luminal bacteria in initiating the abnormal immune response
      seen in inflammatory bowel disease is stressed by many observations. A defect in
      mucosal barrier function could allow luminal bacterial antigens to initiate the
      chronic relapsing inflammation in Crohn's disease. The potential role of luminal
      bacteria in initiating the abnormal immune response seen in inflammatory bowel
      disease is stressed by many observations. A pilot study to investigate the
      possible effect of Lactobacillus GG in children with active Crohn's disease was
      conducted. Four male patients were enrolled, median age 14.5 years (range 10-18).
      In terms of clinical outcome, the patients showed significant improvement. In
      three patients on Lactobacillus GG, it was possible to taper the dose of
      steroids. Thus, although our data are obviously very preliminary, Lactobacillus
      GG appears to be effective in improving the clinical status of children with
      Crohn's disease. A multicentre study is currently being carried out in 7 US
      University centres in a randomized, double-blind, placebo-controlled fashion to
      establish the efficacy of this probiotic in children with Crohn's disease.

PMID- 12408444
TI  - Probiotics and Crohn's disease.
AB  - Antibiotics are often employed in the treatment of Crohn's disease, with
      interesting results. However indiscriminate suppression of intestinal bacteria
      may be harmful and long-term use of antibiotics is burdened by side-effects and
      by the risk of developing bacterial resistance. Manipulation of enteric flora
      with probiotic compounds would be a possible and appealing alternative. First aim
      of our study has been to investigate the efficacy of this probiotic in reducing
      the endoscopic recurrence rate or in reducing the severity of recurrent lesions
      at 1 year after surgery. Secondary goal has been the reduction of the clinical
      recurrence rate. Forty-five patients have been randomised to receive
      Lactobacillus rhamnosus strain GG or placebo for 12 months. The results have
      shown no differences in endoscopic and clinical remission between the two groups.

PMID- 12408445
TI  - Probiotics and atopic dermatitis. A new strategy in atopic dermatitis.
AB  - Over the last few decades, the prevalence of atopic dermatitis has been
      increasing from 2% to 100%, with 90% of cases within 5 years of age versus 6%
      between 6 and 10 years and 2% after 10 years, and environmental factors may
      possibly play an important role in this increase as in other atopic diseases.
      Many findings suggest an important role of atopy in atopic dermatitis; moreover,
      40% of children with atopic dermatitis have food allergy and the removal of the
      food allergen from the patient's diet leads to a significant clinical
      improvement. In a possible scenario, IgE-bearing dendritic cells are likely to
      process allergens acquired in the gastrointestinal tract, circulate to the skin
      and activate local T cells. Cultures of beneficial live microorganisms
      characteristic of the commensal microflora are administered with probiotic
      functional foods in order to provide a microbial challenge for the maturation of
      gut-associated lymphoid tissue, which the infant often lacks. The probiotic
      effects are attributed to normalisation of the increased intestinal permeability
      and balancing gut microecology, improvement of the immunological defence barrier
      (IgA) of the intestine, alleviation of the intestinal inflammatory response, and
      downregulation of proinflammatory cytokines characteristic of local and systemic
      allergic inflammation.

PMID- 12408446
TI  - Consequences of Helicobacter pylori infection on the absorption of
      micronutrients.
AB  - Recent studies have suggested a relationship between Helicobacter pylori
      infection and various important micronutrients, including iron and vitamin B12,
      suggesting likely biological factors in the association between Helicobacter
      pylori and microcytic or macrocytic anaemia. There is some evidence that direct
      or indirect consequences of Helicobacter pylori gastritis on acid secretion
      account for the role of the bacterium in the absorption process of iron and
      Vitamin B12. The plasma, intragastric and mucosal concentration of different
      antioxidant compounds such as ascorbic acid, a-tocopherol and beta-carotene is
      also affected by Helicobacter pylori gastritis supporting the possible role of
      Helicobacter pylori in the multistep cascade leading to gastric carcinogenesis.
      The relationship between Helicobacter pylori infection and micronutrients is,
      therefore, a promising and, until now, poorly investigated field of research.

PMID- 12408447
TI  - Probiotics in antibiotic-associated diarrhoea.
AB  - Antibiotic-associated diarrhoea is a common event. In some cases, it could
      represent a life-threatening event. Clostridium difficile colitis is a further
      distinct complication of antibiotic administration. Treatment options for
      antibiotic-associated diarrhoea and Clostridium difficile colitis include
      supplementation with several types of probiotics, as overviewed in this paper.
      Three randomised, double-blind, controlled clinical trials show a therapeutic
      effect of Saccharomyces boulardii in antibiotic-associated diarrhoea. The
      efficacy of Lactobacillus acidophilus and bulgaricus has also been ascertained in
      two double-blind controlled studies. Other studies focusing on Lactobacillus as a
      new preventive agent for antibiotic-associated diarrhoea are not double-blind.
      Among these, a positive effect of Lactobacillus rhamnosus GG, Bifidobacterium
      longum and Enterococcus faecium SF68 has been reported. Effectiveness of
      probiotics in antibiotic-associated diarrhoea has, therefore, a consistent
      scientific rationale, however few studies have performed an assessment of
      bacterial recovery in stools, and this approach may be helpful in deciding a more
      rigorous dose standardisation.

PMID- 12408448
TI  - Probiotics and Helicobacter pylori eradication.
AB  - The need for new strategies for Helicobacter pylori eradication, alternative or
      complementary to antibiotic therapy, has recently claimed the attention of many
      investigators. Pre-clinical studies have shown the inhibition of Helicobacter
      pylori growth by Lactobacilli and the anti-Helicobacter pylori action of
      Lactobacillus salivarius, Lactobacillus acidophilus and Lactobacillus casei
      subspecies rhamnosus strains, possibly due to the production of lactic acid or to
      the secretion of an autolysin. Clinical studies have demonstrated a persistent
      reduction in delta over baseline values at the 13C urea breath test independently
      of omeprazole administration with Lactobacillus acidophilus La1, the eradication
      in 6 out of 14 patients with Lactobacillus acidophilus alone, positive results in
      patients in which a standard Helicobacter pylori triple therapy was randomly
      supplemented with Lactobacillus acidophilus.

PMID- 12408449
TI  - Prophylaxis of diarrhoea in patients submitted to radiotherapeutic treatment on
      pelvic district: personal experience.
AB  - Diarrhoea is a severe side-effect of radiotherapy on the pelvic area. It is due
      to acute enteric damage. We aimed at determining the ability of a highly
      concentrated freeze-dried living bacteria compound (VSL/3) to reduce these side
      effects in 190 patients receiving radio therapy on the pelvic area. A total of 95
      patients received radiotherapy alone and 95 were also administered VSL/3 bags, at
      doses of one bag three times a day beginning on the first day of the radiotherapy
      treatment. The same diet was indicated for both groups. All patients were
      irradiated for 6 to 7 weeks, with Linac X-6 MV or 15 MV through a box multiportal
      technique with the lower limit of the fields below the obturator foramina, upper
      limit at L5-S1, lateral limit 1.5 cm beyond the innominate hip. The total
      radiated dose ranged from 60 to70 Gy for a daily dose of 180 cGy. Gastroenteric
      toxicity was rated in WHO degrees. Two patients receiving radiotherapy alone had
      to discontinue the treatment due to acute enteritis. Toxicity was found in 52
      (50.6%) patients with radiotherapy alone vs 36 (30.5%) patients receiving VSL/3.
      None of them had to discontinue radiotherapy. Toxicity of degrees 3 or 4 was
      found in 28 patients receiving radiotherapy alone vs 7 with VSL/3. These
      preliminary data suggest the effectiveness of VSL/3 in preventing the occurrence
      of diarrhoea in patients submitted to radiotherapy with a direct and indirect
      improvement of their quality of life and a good tolerance.

PMID- 12408450
TI  - Biotherapeutics and biotherapy of surgical enteropathies.
AB  - Probiotic agents are living micro-organisms that, upon ingestion, exert health
      benefits beyond inherent general nutrition. In this context, we must
      differentiate between biotherapeutics as approved drugs and dietary supplements
      and food products containing prebiotic bacteria that are not considered drugs. At
      present, the only biotherapeutic agent which is prescribable in some European
      countries, indicated to relieve specific diseases, is the yeast Saccharomyces
      boulardii. In this review, we consider the various pre-clinical and clinical
      aspects of biotherapeutics as basic drugs and the biotherapeutic powers of their
      use in the treatment of some surgical enteropathies.

PMID- 12408451
TI  - European Union-funded research on probiotics, prebiotics and new foods.
AB  - At the beginning of 1999, the European Commission launched the Fifth Framework
      Programme for Research, Technological Development and Demonstration (1998-2002),
      which has been conceived to help solve problems and to respond to major socio
      economic challenges facing the European Union. Within its thematic programme
      'Quality of life and management of living resources', Key Action 1 covers the
      subject 'Food, nutrition and health' with a total budget of 290 million euro. The
      key action concentrates on consumer needs, the competitiveness of the European
      food industry, the role of nutrition in health and well-being, and the safety and
      integrity of the food supply. Within this framework, research on probiotics,
      prebiotics and new foods is an important focus of the funding activities of the
      European Commission at present and in future.

PMID- 12408452
TI  - Functional food concept and its application to prebiotics.
AB  - A food can be regarded as functional if it is satisfactorily demonstrated to
      affect beneficially one or more target functions in the body, beyond adequate
      nutritional effects, in a way which is relevant to either the state of wellbeing
      and health or the reduction of the risk of a disease. A food can be made
      functional by increasing the concentration, adding or improving the
      bioavailability of a particular component. Functional food science will serve to
      establish claims based either on enhanced function or disease risk reduction.
      Inulin and oligofructose are functional food ingredients present in miscellaneous
      edible plants. They are non-digestible oligosaccharides classified as dietary
      fibres. The target for their functional effects is the colonic microflora that
      ferment them and for which they serve as selective "fertilizers"; the
      gastrointestinal physiology; the immune functions; the bioavailability of
      minerals; the metabolism of lipids; and colonic carcinogenesis. The scientific
      data available on the nutritional effects of inulin and oligofructose provide
      strong evidence for a prebiotic effect (i.e., selective stimulation of growth of
      bifidobacteria in colonic microbiota), improvement of bowel habit (both stool
      frequency and stool weight) and improved calcium bioavailability.

PMID- 12408453
TI  - Nutritional aspects of short-chain fructooligosaccharides: natural occurrence,
      chemistry, physiology and health implications.
AB  - Short-chain fructooligosaccharides occur in a number of edible plants, such as
      chicory, onions, asparagus, wheat... They are a group of linear fructose
      oligomers with a degree of polymerisation ranging from n = 1 up to 5
      (oligosaccharides). Short-chain fructooligosaccharides, to a large extent, escape
      digestion in the human upper intestine and reach the colon where they are totally
      fermented mostly to lactate, short chain fatty acids (acetate, propionate and
      butyrate), and gas, like dietary fibres. As a consequence of their fermentation,
      their caloric value is approximately 2 Kcal/g. A faecal bulking effect of
      fructooligosaccharides has been observed in humans. An important property of
      short-chain fructooligosaccharides is the stimulation of bifidobacterial growth
      specifically while suppressing the growth of potentially harmful species such as,
      for example, Clostridium perfringens in the colon. It is associated with a
      decrease in faecal pH, an increase in faecal or colonic organic acids, a decrease
      in the production of nitrogenous end products in urine and stools, a decrease in
      faecal bacterial enzymatic activities and a modification in faecal neutral
      sterols. The short-chain fructooligosaccharides enhance magnesium absorption in
      humans and have been shown, in animal models, to reduce colon tumour development
      by enhancing both colon butyrate concentrations and local immune system
      effectors.

PMID- 12408454
TI  - Fibres and colorectal cancer: should we change our dietary advice on prevention?
AB  - Evidence from epidemiological studies overwhelmingly indicates that fruit,
      vegetables and cereals prevent cancer at a wide range of sites in the body, not
      just the large bowel. However, recent important papers have shown that an
      intervention diet rich in fruit, vegetables and fibre failed to decrease the risk
      of new colorectal adenoma formation. The adenoma-cancer sequence and the role of
      diet are discussed in the light of these new findings.

PMID- 12408455
TI  - Prebiotics in infant formulas: biochemical characterisation by thin layer
      chromatography and high performance anion exchange chromatography.
AB  - BACKGROUND: Breast-fed infants, unlike bottle-fed babies, have a microbic
      intestinal flora characterised by a marked predominance of bifidobacteria and
      lactic acid bacteria. This is essentially due to the prebiotic effect of
      oligosaccharides in human milk. Recently, oligosaccharides with a prebiotic
      effect have been added to formulas. Aim. To characterise the mixture of
      oligosaccharides contained in these new formulas. MATERIALS AND METHODS: The
      characterisation of oligosaccharides was performed using thin layer
      chromatography as well as high performance anion exchange chromatography.
      RESULTS: The mixture of oligosaccharides used in the formulas analysed was made
      up of oligosaccharides with low molecular weight (transgalactosylated
      oligosaccharides) and polysaccharides with high molecular weight (inulin).
      CONCLUSION: With the methods employed, it was possible to characterise the
      mixture of oligosaccharides used as prebiotics in the formulas now available on
      the market.

PMID- 12408456
TI  - Effects of guar gum, ispaghula and microcrystalline cellulose on abdominal
      symptoms, gastric emptying, orocaecal transit time and gas production in healthy
      volunteers.
AB  - BACKGROUND: Dietary fibres are carbohydrates that resist hydrolysis by human
      intestinal enzymes but are fermented by colonic microflora. Soluble dietary
      fibres are fermented by anaerobic bacteria with production of gases, short chain
      fatty acids and other metabolic products believed to cause symptoms such as
      bloating, abdominal distension, flatulence. Insoluble fibres are only partially
      fermented, serving almost exclusively as bulking agents that result in shorter
      transit time and increased faecal mass. AIMS: To evaluate effect of a
      supplementation of a single 5 g dose of dietary fibre to a solid meal on gastric
      emptying, orocaecal transit time, gas production and symptom genesis, in healthy
      volunteers. Three different dietary fibres were tested, two soluble (guar gum and
      ispaghula] and one insoluble (microcrystalline cellulose). PATIENTS AND METHODS:
      After a 24-hour low fibre diet, 10 healthy subjects had a standard meal
      consisting of white bread and one 70 g egg the yolk of which was mixed with 100
      mg of 13C octanoic acid and fried. Breath samples were collected for 13CO2
      measurements with a mass spectrophotometer and excretion curve (Tlag, T1/2)
      evaluation. Further breath samples were collected and analysed with a gas
      chromatograph for the evaluation of H2 and CH4 production and orocaecal transit
      time. Each evaluation was repeated adding to standard meal, diluted in 300 ml tap
      water, respectively: a single 5 g dose of microcrystalline cellulose, guar gum or
      ispaghula. Subjects were asked to report all symptoms experienced from time of
      meal ingestion over 24 hours, evaluating the intensity. RESULTS: Dietary fibres
      did not significantly change gastric emptying (Tlag, T1/2) and orocaecal transit
      time of standard meal. Subjects experienced more symptoms when meals were
      supplemented with guar gum (p=0.009 vs standard meal) and ispaghula (p=0.048 vs
      standard meal). There was a poor, but significant, correlation between gas
      production and symptoms (r=0. 38, p=0. 01). CONCLUSIONS: Addition of different
      dietary fibres to a solid meal did not influence gastric emptying and orocaecal
      transit time. Microcrystalline cellulose caused fewer symptoms than guar gum and
      ispaghula probably due to the insoluble nature and the dimensions of the
      particles of this micronised cellulose.

PMID- 12408457
TI  - Clinical, physiopathological and dietetic aspects of metabolic syndrome.
AB  - Hypertriglyceridaemia, diabetes, hypertension and obesity are the deadly quartet
      indicating a syndrome at high risk for cardiovascular disease for which, in 1998,
      WHO proposed the definition of Metabolic Syndrome, related to an elevated degree
      of insulin resistance. Treatment will often include behavioural changes that
      reduce body weight and increase physical activity A high-carbohydrate/low-fat
      diet with complex carbohydrates and mainly unsaturated fat is recommended.
      Replacing refined grain products and potatoes with minimally processed plant
      based foods such as whole grains, fruit, and vegetables, and reducing the intake
      of high glycaemic load beverages may offer a simple strategy for reducing the
      incidence of coronary heart disease.

PMID- 12408458
TI  - Dietary fibre in treatment of diabetes: myth or reality?
AB  - Diabetes is a plurimetabolic disease characterised mainly by glucose metabolism
      abnormalities that lead to the development of acute and long-term complications.
      Long-term complications are rapidly increasing, which explains the higher
      mortality due to cardiovascular events in diabetic patients compared to the
      general population. A poor blood glucose control is known to be an important risk
      factor for the development of cardiovascular complications, and dietary fibre -
      particularly the soluble type - plays an important role in controlling plasma
      glucose concentrations and other risk factors associated with diabetes.
      Nevertheless, there are still some doubts as to whether it is possible to
      achieve, in free-living diabetic patients, good compliance to a high fibre diet
      without using fibre supplements or foods fortified with fibre, and whether the
      beneficial effects of this diet on blood glucose control, observed in acute or in
      medium-term studies, are clinically relevant also in the longterm. Recently, a
      wealth of convincing evidence has confirmed the hypothesis that, in diabetic
      patients, dietary fibre decreases postprandial plasma glucose, insulin and
      triglyceride concentrations, and has a clinically relevant hypocholesterolaemic
      effect. These data also show that: 1) it is possible to increase dietary fibre by
      consuming exclusively natural foods, with a satisfactory compliance in free
      living diabetic patients also in the long-term, due to its minimal side-effects;
      and 2) the beneficial metabolic effects of dietary fibre are long-lasting and
      clinically relevant, as shown by the lower plasma glycosylated haemoglobin
      levels, reduced rate of hypoglycaemic episodes and improved cardiovascular
      profile both in type 1 and type 2 diabetic patients.

PMID- 12408459
TI  - Fibre consumption, metabolic effects and prevention of complications in diabetic
      patients: epidemiological evidence.
AB  - The EURODIAB Complications Study, a clinic based epidemiological project
      including 3250 individuals with type 1 diabetes from 31 European centres analysed
      the natural dietary fibre intake and possible benefits for patients with
      diabetes. The mean intake of natural dietary fibre in the cohort of patients with
      type 1 diabetes was 17.3 g/day for all centres with a centre range of 13.9-21.9
      g/day. The fibre consumption was lowest in patients from Eastern European centres
      compared to patients from centres in Southern and North-Western Europe. The fibre
      density was highest in patients from Southern Europe. Total fibre intake was
      significantly inversely related to HbA1c levels; severe ketoacidosis risk fell
      significantly with higher fibre intakes. Higher intakes of total fibre were
      independently associated with significantly higher levels of high density
      lipoprotein-cholesterol in male and in female patients. Fibre intakes in men with
      diabetes were also inversely related to ratios of total cholesterol to high
      density lipoprotein-cholesterol and to levels of low density lipoprotein
      cholesterol. Higher fibre intakes are also associated with decreases in plasma
      oestradiol and oestrone levels. A protective effect of total fibre intake against
      cardiovascular disease was observed in females but not in males with diabetes.

PMID- 12408460
TI  - Coeliac disease.
AB  - In the last few decades, the comprehension of epidemiological, pathogenic and
      clinical aspects of coeliac disease has increasingly improved. Serological
      screening studies on the general population have shown that the true coeliac
      disease prevalence in Europe is higher than previously reported. It has become
      clear that tissue transglutaminase has a crucial role in the pathogenesis of
      coeliac disease pathogenesis, and there is evidence that substitution of
      deamidated amino acidic residues at a critical position along the gliadin
      sequence dramatically increases immunological activation. The toxicity of many
      gluten epitopes has been investigated, so far, but recent studies have indicated
      the region 57-75 of alpha gliadin as a possible candidate epitope in the
      pathogenesis of coeliac disease. However, the wide heterogeneity of gliadin and
      glutenin molecules complicate any attempts to identify the toxic epitope, and the
      fascinating idea to produce detoxified grains will represent a great challenge in
      the near future. From a clinical point of view, there is now evidence of a broad
      spectrum of gluten conditions. Extra-intestinal signs, i.e., alopecia,
      unexplained neurological disorders, cryptic hypertransaminasaemia, increased red
      cell width, frequently constitute the only clinical manifestation at the
      diagnosis.

PMID- 12408461
TI  - Genetic improvement of plant for coeliac disease.
AB  - Wheat, rye and barley are toxic for patients with coeliac disease. Toxicity has
      been found to result, respectively, from proteins such as gliadins, secalins and
      hordeins. Agglutination of in vitro cultured human myelogenous leukaemia K 562
      (S) cells proved to be a suitable model for detection of toxic components of
      proteins. Five toxic peptides derived from an A-gliadin protein have been found
      to agglutinate the K 565 (S) cells. Triticum monococcum is a diploid wheat
      species widely grown during the Bronze Age. Proteins from monococcum are unable
      to agglutinate the K 562 (S) cells.

PMID- 12408462
TI  - Effect of acute load of grapefruit juice on urinary excretion of citrate and
      urinary risk factors for renal stone formation.
AB  - The effect of citrus fruit juice ingestion on the risk of calcium oxalate stone
      formation is still debated. The present study was undertaken to investigate
      changes in urinary stone risk factors after administration of a soft drink
      containing grapefruit juice. Seven healthy subjects, with no history of kidney
      stones, were submitted to an acute oral load (20 ml/kg body weight over 60 min)
      of a soft drink containing grapefruit juice diluted (10%) in mineral water. After
      a 7-day wash-out period, each subject underwent an oral load with mineral water
      alone under the same conditions. Urine specimens were collected before (for 120
      min) and after each oral fluid load (for 180 min). Urinary flow was significantly
      increased after both grapefruit juice (46+/-26 vs 186+/-109 ml/h, p = 0.01) and
      mineral water (42+/-16 vs 230+/-72 ml/h, p=0.001) compared to baseline. Compared
      to mineral water, grapefruit juice significantly (p=0.021) increased urinary
      excretion of citrate (25.8+/-9.3 vs 18.7+/-6.2 mg/h), calcium (6.7+/-4.3 vs 3.3+/
      2.3 mg/h, p=0.015) and magnesium (2.9+/-1.5 vs 1.0+/-0.7 mg/h, p=0.003). Citrus
      fruit juices could represent a natural alternative to potassium citrate in the
      management of nephrolithiasis, because they could be better tolerated and cost
      effective than pharmacological calcium treatment. However, in order to obtain a
      beneficial effect in the prevention of calcium renal stones a reduced sugar
      content is desirable to avoid the increase of urinary calcium due to the effect
      of sugar supplementation.

PMID- 12408463
TI  - Pitfalls and drawbacks in research concerning diagnostic tests.

PMID- 12408464
TI  - The impact of intraoperative manipulation of the prostate on total and free
      prostate-specific antigen.
AB  - OBJECTIVES: It is well documented that mechanical manipulation of the prostate
      can elevate total PSA (t-PSA) levels in serum. However, less is known about its
      effects on free PSA (f-PSA) and the free-to-total PSA ratio (f/t-PSA). We
      therefore examined the impact of prostate manipulation on t-PSA and f-PSA during
      surgical procedures involving the prostate. METHODS: Intraoperative blood samples
      for t-PSA and f-PSA measurement (Hybritech) were collected every 15 min during 14
      radical retropubic prostatectomies (RRP) and 10 radical cystoprostatectomies
      (RCP). RESULTS: Prostatic manipulation induced significant elevations in t-PSA
      and f-PSA during RRP and RCP. Postmanipulatory peaks were markedly higher for f
      PSA than for t-PSA. The mean maximum f-PSA levels showed a 4.3- (RRP) and 7.9
      fold (RCP) increase, followed by a rapid decline after prostate removal. t-PSA
      increased 1.2- (RRP) and 1.3-fold (RCP), and declined more slowly.
      Postmanipulatory f/t-PSA ratios also increased significantly, reaching mean
      elevations of +0.29 and +0.28 over preoperative ratios during RRP and RCP,
      respectively. CONCLUSIONS: Prostate manipulation can induce transient increases
      in t-PSA, f-PSA and f/t-PSA in benign and malignant prostates. The extent of
      these alterations and their course over time must be taken into account when
      postmanipulatory changes in PSA forms are investigated. Timing of
      postmanipulatory venipunctures and the molar response ratio of t-PSA assays used
      (equimolar versus nonequimolar) seem to have substantial impact on the results of
      such studies.

PMID- 12408465
TI  - Prostate-specific antigen levels among cirrhotic patients.
AB  - PURPOSE: The aim of this study was to determine serum prostate-specific antigen
      (PSA) levels in patients with liver cirrhosis. PATIENTS AND METHODS: Between
      January 1995 and August 2001, 216 men with cirrhosis were evaluated. The extent
      of their liver disease was classified according to the Child-Pugh classification.
      Serum PSA levels were measured with the Hybritech Tandem-R RIA method and matched
      with age-related reference PSA levels. Digital rectal examination (DRE) was
      performed in all patients. Patients with elevated PSA levels and/or abnormal DRE
      were recommended to undergo further assessment including transrectal
      ultrasonography (TRUS) and biopsy performed by an urologist. RESULTS: Two hundred
      and sixteen men (mean age 54.09 +/- 9.09 years, range 25-76) with cirrhosis were
      examined. Their mean PSA value was 0.57 +/- 0.84 ng/mL and tended to be lower
      than in the normal population. The degree of PSA decrease was found to parallel
      the severity of the liver disease (p=0.002). The mean serum PSA level increased
      with each age decade in a statistically significant manner (p<0.001). Four
      patients (three with elevated PSA values) underwent prostate biopsy. Three
      biopsies were positive for prostate cancer, the other showed evidence of benign
      prostatic hyperplasia (BPH). CONCLUSION: Serum PSA is influenced by the severity
      of liver disease and its levels tend to be lower in cirrhotic patients than in
      the normal population. However, serum PSA can still be considered a reliable
      marker in the clinical management of prostatic disease in patients with
      cirrhosis.

PMID- 12408466
TI  - Cathepsin D expression in colorectal adenocarcinomas and adenomas.
AB  - The aim of this study was to investigate the role of cathepsin D in colorectal
      cancer. For this purpose cathepsin D expression was evaluated by means of
      immunohistochemistry in stromal and tumor cells of 31 colorectal carcinomas and
      29 adenomas. Cytoplasmic cathepsin D expression of tumor cells was present in
      90.3% of the carcinoma cases and various degrees of stromal cell cathepsin D
      expression were present in all cases. In the adenomas, the epithelial cells and
      stromal cells expressed cathepsin D in 68.96% and 96.55% of cases, respectively.
      The staining intensity was always weaker in the adenomas. When the stromal and
      tumor cell cathepsin D expression in the adenocarcinoma and adenoma cases were
      compared, a statistically significant difference was observed in the staining of
      stromal cells. Furthermore, stromal cathepsin D expression in the adenocarcinomas
      was related to tumor stage when the carcinomas were divided into low and high
      stage. Cathepsin D expression in stromal cells may be an important indicator of
      poor prognosis in colorectal adenocarcinomas.

PMID- 12408467
TI  - Prognostic significance of tissue-type plasminogen activator (tPA) content in
      gastric cancer and surrounding mucosa.
AB  - AIMS: We analyzed the tPA content in primary gastric carcinomas and surrounding
      mucosa in order to assess the relationship between tPA content,
      clinicopathological tumor characteristics, and estrogen and progesterone receptor
      content. We evaluated the prognostic value of this serine protease in gastric
      cancer patients. PATIENTS AND METHODS: 122 resected gastric neoplasms and 95
      adjacent mucosa samples were studied. The tPA content was measured in cytosol by
      an ELISA method. Cytosolic ER and PgR were measured with a solid phase enzyme
      immunoassay. RESULTS: Cytosolic tPA levels in neoplastic tissues (median 1.0
      ng/mg prot) were significantly lower (p=0.002) than those found in paired mucosa
      samples (median 2.3 ng/mg prot). There was no significant association between tPA
      levels and clinicopathological parameters or PgR content, but tPA levels were
      significantly correlated with ER content. The intermediate-tPA-content group,
      corresponding to samples with between 0.3 and 1.70 ng/mg protein, proved to have
      a significantly high risk of relapse. CONCLUSIONS: We found a wide variability in
      tPA levels in gastric carcinoma and adjacent mucosa samples, with significantly
      decreased levels in tumors and a significantly positive relationship between tPA
      levels and ER status. There was a non-monotonic relationship between tPA levels
      and prognosis in patients with gastric cancer.

PMID- 12408468
TI  - Osteoprotegerin and receptor activator of nuclear factor-kappaB ligand (RANKL) in
      the serum of healthy adults.
AB  - AIMS: Osteoprotegerin and the receptor activator of the nuclear factor-kappaB
      ligand (RANKL) are decisive factors for maintaining the balance between bone
      formation and bone resorption. As new, sensitive ELISAs have been developed
      recently, reference serum ranges should be established to use these analytes for
      possible diagnostic purposes. METHODS: Measurements were performed in serum
      samples of 142 healthy adults (82 women, 60 men) between 20 and 70 years of age
      (mean age: 46 years) using ELISA kits from Immundiagnostik, Bensheim, Germany.
      RESULTS: Serum concentrations of osteoprotegerin were age and gender independent
      and showed a Gaussian distribution, while RANKL concentrations were also age
      independent but differed between males and females, with a non-Gaussian
      distribution. For osteoprotegerin a gender-independent upper 97.5 percentile
      limit of 3.6 pmol/L was calculated while the corresponding limits for RANKL and
      the ratio of RANKL to osteoprotegerin amounted to 3.29 pmol/L and 2.78 in women
      and 1.66 pmol/L and 2.18 in men, respectively. CONCLUSIONS: Both osteoprotegerin
      and RANKL were quantifiable in serum of healthy adults, which means that these
      compounds can be used as potential diagnostic tools.

PMID- 12408469
TI  - Quantitative analysis of urinary daidzein and equol by gas chromatography after
      solid-phase extraction and high-performance liquid chromatography.
AB  - Daidzein and its main metabolite equol are isoflavone phytoestrogens. Several
      studies have suggested that intake of an isoflavone-rich diet may prevent hormone
      related cancer and estrogen-related disorders (cardiovascular disease,
      osteoporosis and menopausal symptoms). To better understand the role of
      isoflavones in preventing such severe disease, several methods have been
      developed to measure these compounds in biological fluids. However, the
      analytical procedures to measure isoflavones are often time-consuming and require
      highly skilled technicians. In this paper we describe a method for urinary
      daidzein and equol measurement that combines solid phase extraction and HPLC
      purification before gas chromatographic determination. The specificity of the
      method was confirmed by the gas chromatography-mass spectrometry technique. The
      mean recovery of daidzein and equol was 94.6% and 97.0%, respectively. The
      repeatability of the method was in the range of 2.0-7.4% for daidzein and 1.3
      4.9% for equol. A linear relationship between observed and expected values was
      found in the dilution (r2=0.9983 for daidzein; r2=0.9982 for equol) and addition
      (r2=0.9984 for daidzein; r2=0.9989 for equol) assays. The method is suitable to
      measure changes in the urinary excretion of isoflavones and to investigate
      urinary isoflavonoids as biomarkers of isoflavone exposure.

PMID- 12408470
TI  - Thrombin is present in the lungs of patients with primary extremity osteosarcoma
      and pulmonary metastases.
AB  - Osteosarcoma is a rare cancer, which metastasizes to the lung in up to 80% of
      cases. Thrombin is involved in metastasis and is present in the lungs of patients
      with pulmonary metastases (PM). To identify its role in PM and osteosarcoma, we
      measured thrombin levels in the bronchoalveolar lavage fluid (BALF) of 15
      patients. BALF was collected at different stages of the disease and correlated
      with the diagnosis of PM. We also assessed fibrinogen overexpression in the
      tumors. We found that 11/15 (73%) patients with high thrombin levels in the lungs
      developed PM within the first 12 months from primary surgery. The median thrombin
      concentration in the BALF of these patients increased up to 8x10(-9) M (range,
      3x10(-9)M-15x10(-9)M), which represents a more than 100-fold increase compared to
      patients without PM (p<0.0001). Eight of 15 (53%) primary and 11/15 (73%)
      metastatic samples showed fibrinogen overexpression. A significant difference
      between high thrombin levels, fibrinogen overexpression and PM was found compared
      to patients without PM (p=0.00073 and p=0.025). These results show that thrombin
      levels are increased in the lungs of patients with primary osteosarcoma and a
      high risk of developing PM. They suggest that thrombin may be involved in the
      development of PM.

PMID- 12408471
TI  - Natural history of estrogen receptor-negative, progesterone receptor-positive
      breast cancer.
AB  - The biological significance of estrogen receptor-negative but progesterone
      receptor-positive breast carcinomas is not clear. In the present study the
      aggressiveness of breast carcinomas in relation to ER and PgR status has been
      investigated. The probability of disease-free survival in 297 node-negative
      breast carcinoma patients was monitored during a follow-up ranging from six to 96
      months (median 45 months). Steroid hormone receptor content was assayed with the
      biochemical method recommended by the EORTC. The probability of disease-free
      survival was significantly worse for patients with ER-negative, PgR-positive
      carcinomas compared to the other three steroid hormone receptor phenotypes. Our
      results suggest that ER-negative, PgR-positive breast carcinomas are biologically
      different in terms of aggressiveness from the other steroid hormone receptor
      phenotypes.

PMID- 12408473
TI  - Human insulin-like growth factor receptor 1 in serum: can it be evaluated by
      ELISA?

PMID- 12408472
TI  - Quality control for biomarker determination in oncology: the experience of the
      Italian Network for Quality Assessment of Tumor Biomarkers (INQAT).
AB  - Biomarker analysis and evaluation in oncology is the product of a number of
      processes (including managerial, technical and interpretation steps) which need
      to be monitored and controlled to prevent and correct errors and guarantee a
      satisfactory level of quality. Several biomarkers have recently moved to clinical
      validation studies and successively to clinical practice without any definition
      of standard procedures and/or quality control (QC) schemes necessary to guarantee
      the reproducibility of the laboratory information. In Italy several national
      scientific societies and single researchers have activated -- often on a pilot
      level -- specific external quality assessment protocols, thereby potentially
      jeopardizing the clinical reality even further. In view of the seriousness of the
      problem, in 1998 the Italian Ministry of Health sponsored a National Survey
      Project to coordinate and standardize the procedures and to develop QC programs
      for the analysis of cancer biomarkers of potential clinical relevance. Twelve QC
      programs focused on biomarkers and concerning morphological, immunohistochemical,
      biochemical, molecular, and immunoenzymatic assays were coordinated and
      implemented. Specifically, external QC programs for the analytical phase of
      immunohistochemical p53, Bcl-2, c-erb-2/neu/HER2, and microvessel density
      determination, of morphological evaluation of tumor differentiation grade, and of
      molecular p53 analysis were activated for the first time within the project.
      Several hundreds of Italian laboratories took part in these QC programs, the
      results of which are available on the web site of the Network
      (www.cqlaboncologico.it). Financial support from the Italian Government and the
      National Research Council (CNR) will guarantee the pursuit of activities that
      will be extended to new biomarkers, to preanalytical phases of the assays, and to
      revision of the criteria of clinical usefulness for evaluating the cost/benefit
      ratio.

PMID- 12408474
TI  - A basic study of some normoxic polymer gel dosimeters.
AB  - Polymer gel dosimeters offer a wide range of potential applications in the three
      dimensional verification of complex dose distribution such as in intensity
      modulated radiotherapy (IMRT). Until now, however, polymer gel dosimeters have
      not been widely used in the clinic. One of the reasons is that they are difficult
      to manufacture. As the polymerization in polymer gels is inhibited by oxygen, all
      free oxygen has to be removed from the gels. For several years this was achieved
      by bubbling nitrogen through the gel solutions and by filling the phantoms in a
      glove box that is perfused with nitrogen. Recently another gel formulation was
      proposed in which oxygen is bound in a metallo-organic complex thus removing the
      problem of oxygen inhibition. The proposed gel consists of methacrylic acid,
      gelatin, ascorbic acid, hydroquinone and copper(II)sulphate and is given the
      acronym MAGIC gel dosimeter. These gels are fabricated under normal atmospheric
      conditions and are therefore called 'normoxic' gel dosimeters. In this study, a
      chemical analysis on the MAGIC gel was performed. The composition of the gel was
      varied and its radiation response was evaluated. The role of different chemicals
      and the reaction kinetics are discussed. It was found that ascorbic acid alone
      was able to bind the oxygen and can thus be used as an anti-oxidant in a polymer
      gel dosimeter. It was also found that the anti-oxidants N-acetyl-cysteine and
      tetrakis(hydroxymethyl)phosphonium were effective in scavenging the oxygen.
      However, the rate of oxygen scavenging is dependent on the anti-oxidant and its
      concentration with tetrakis(hydroxymethyl)phosphonium being the most reactive
      anti-oxidants. Potentiometric oxygen measurements in solution provide an easy way
      to get a first impression on the rate of oxygen scavenging. It is shown that
      cupper(II)sulphate operates as a catalyst in the oxidation of ascorbic acid. We,
      therefore, propose some new normoxic gel formulations that have a less
      complicated chemical formulation than the MAGIC gel.

PMID- 12408475
TI  - A fluence-convolution method to calculate radiation therapy dose distributions
      that incorporate random set-up error.
AB  - The International Commission on Radiation Units and Measurements Report 62 (ICRU
      1999) introduced the concept of expanding the clinical target volume (CTV) to
      form the planning target volume by a two-step process. The first step is adding a
      clinically definable internal margin, which produces an internal target volume
      that accounts for the size, shape and position of the CTV in relation to
      anatomical reference points. The second is the use of a set-up margin (SM) that
      incorporates the uncertainties of patient beam positioning, i.e. systematic and
      random set-up errors. We propose to replace the random set-up error component of
      the SM by explicitly incorporating the random set-up error into the dose
      calculation model by convolving the incident photon beam fluence with a Gaussian
      set-up error kernel. This fluence-convolution method was implemented into a Monte
      Carlo (MC) based treatment-planning system. Also implemented for comparison
      purposes was a dose-matrix-convolution algorithm similar to that described by
      Leong (1987 Phys. Med. Biol. 32 327-34). Fluence and dose-matrix-convolution
      agree in homogeneous media. However, for the heterogeneous phantom calculations,
      discrepancies of up to 5% in the dose profiles were observed with a 0.4 cm set-up
      error value. Fluence-convolution mimics reality more closely, as dose
      perturbations at interfaces are correctly predicted (Wang et al 1999 Med. Phys.
      26 2626-34, Sauer 1995 Med. Phys. 22 1685-90). Fluence-convolution effectively
      decouples the treatment beams from the patient. and more closely resembles the
      reality of particle fluence distributions for many individual beam-patient set
      ups. However, dose-matrix-convolution reduces the random statistical noise in MC
      calculations. Fluence-convolution can easily be applied to
      convolution/superposition based dose-calculation algorithms.

PMID- 12408476
TI  - Speed versus accuracy in a fast convolution photon dose calculation for conformal
      radiotherapy.
AB  - A convolution dose calculation for megavoltage photon beams is described and the
      compromise between speed and accuracy examined. The algorithm is suitable for
      treatment planning optimization, where the need is for a fast, flexible method
      requiring minimal beam data but providing an accurate result. The algorithm uses
      a simple tabular beam model, together with a discrete scatter kernel. These beam
      parameters are fitted either to a measured dose distribution, or to a dose
      distribution calculated using a more accurate dose calculation algorithm. The
      calculation is then applied to pelvic and thoracic conformal plans, and the
      results compared with those provided by a commercial radiotherapy treatment
      planning system (Pinnacle3, Philips Radiation Oncology Systems, Milpitas, CA),
      which has been verified against measurements. The calculation takes around 4 s to
      compute a 100 x 100 mm field, and agreement of the dose-volume histograms with
      the commercial treatment planning system is to within 5% dose or 8% volume. Use
      of a grid resolution coarser than 5 x 5 x 5 mm is found to be inaccurate, whereas
      calculating primary dose on a coarse grid and interpolating is found to increase
      speed without significantly reducing accuracy. Kernel resolution influences the
      speed and accuracy, but using 12 discrete points provides a fast result with a
      limited error. Thus, the algorithm is suitable for optimization applications.

PMID- 12408477
TI  - Examination of the effect of increasing the number of radiation beams on a
      radiation treatment plan.
AB  - Within the confines of least-squares operations, it is possible to quantify the
      effect of the addition of treatment fields or beamlets to a treatment plan. Using
      linear algebra and eigenvalue perturbation theory, the effect of the increase in
      number of treatments is shown to be equivalent to adding a perturbation operator.
      The effect of adding additional fields will be negligible if the perturbation
      operator is small. The correspondence of this approach to an earlier work in beam
      orientation optimization is also demonstrated. Results are presented for
      prostate, spinal and head and neck cases, and the connection to beam-orientation
      optimization is examined.

PMID- 12408478
TI  - Segmentation of MR images for computer-assisted surgery of the lumbar spine.
AB  - This paper describes a segmentation algorithm designed to separate bone from soft
      tissue in magnetic resonance (MR) images developed for computer-assisted surgery
      of the spine. The algorithm was applied to MR images of the spine of healthy
      volunteers. Registration experiments were carried out on a physical model of a
      spine generated from computed tomography (CT) data of a surgical patient.
      Segmented CT, manually segmented MR and MR images segmented using the developed
      algorithm were compared. The algorithm performed well at segmenting bone from
      soft tissue on images taken of healthy volunteers. Registration experiments
      showed similar results between the CT and MR data. The MR data, which were
      manually segmented, performed worse on visual verification experiments than both
      the CT and semi-automatic segmented data. The algorithm developed performs well
      at segmenting bone from soft tissue in MR images of the spine as measured using
      registration experiments.

PMID- 12408479
TI  - Quantitative imaging and correction for cascade gamma radiation of 76Br with 2D
      and 3D PET.
AB  - Several positron emitting nuclides with applications in PET, such as 76Br, 124I,
      110In and 86Y, also emit gamma radiation in their decays. Measured coincidences
      between annihilation photons and this cascade gamma radiation are essentially
      true coincidences and the standard PET corrections do not account for them. We
      investigated the performance of 76Br in 2D and 3D PET, the effect of the gamma
      radiation emitted by 76Br on quantitative accuracy and the distribution of
      cascade gamma radiation coincidences in 2D and 3D PET sinograms. A correction
      method for cascade gamma radiation coincidences was implemented and evaluated.
      Count rate linearity was affected by the gamma radiation from the 76Br decay.
      Spatial resolution and sphere recovery were slightly worse for 76Br compared to
      18F. Correction for cascade gamma radiation coincidences by subtraction of a
      linear projection tail fit improved total correction accuracy to similar values
      as for positron-only emitters such as 18F, and improved image contrast
      significantly.

PMID- 12408480
TI  - Effect of 176Lu background on singles transmission for LSO-based PET cameras.
AB  - We explore how the radioactive background from naturally occurring 176Lu affects
      single photon transmission imaging for lutetium orthosilicate (LSO) scintillator
      based PET cameras by estimating the transmission noise equivalent count rate
      (NECR) including this background. Assuming a typical PET camera geometry (80 cm
      detector ring diameter), we use a combination of measurement and analytic
      computation to estimate the counting rates due to transmission, scatter and
      background events as a function of singles transmission source strength. We then
      compute a NECR for singles transmission. We find that the presence of radiation
      from the naturally occurring 176Lu reduces the NECR by 60% or higher for source
      strengths less than 10 mCi, and that a 25% reduction of the NECR can occur even
      with a source strength of 40 mCi.

PMID- 12408481
TI  - Is the increased relative biological effectiveness of high LET particles due to
      spatial or temporal effects? Characterization and OER in V79-4 cells.
AB  - The efficiency of producing biological damage varies with radiation quality.
      Conventional explanations rely on spatial differences in the radiation track
      structure; generally however there are also very large temporal differences in
      delivery of the radiation at the cellular level. High-LET radiation normally
      deposits substantial amounts of energy by individual heavily ionizing tracks on a
      timescale of the order of picoseconds. By contrast each low-LET radiation track
      deposits a small amount of energy. Many of these tracks, distributed over the
      whole cell, are required to deliver an equivalent dose to a high-LET track and
      they are usually delivered over much longer timescales (typically seconds) during
      which chemical, biochemical and biological processes are occurring. In this paper
      the design, characterization and initial application of a high-brightness, laser
      plasma ultrasoft x-ray source is described. This has been used to investigate the
      importance of the temporal differences by irradiating mammalian cells with an
      energy deposition with spatial properties of low-LET radiation and temporal
      properties similar to high-LET radiation. The present system delivers a typical
      dose, to the incident surface of the cells, of 0.12 Gy per pulse delivered in <10
      ps. The capabilities of the x-ray source were tested by determining the survival
      of V79-4 hamster cells irradiated with picosecond pulses of ultrasoft x-rays
      under aerobic and anaerobic conditions, which were found to be consistent with
      previously published non pulsed data with x-rays of similar energy. These results
      support the expectation that the disappearance of an oxygen effect for high-LET
      radiation particles is due to their spatial properties rather than the very short
      timescale of each particle traversal. For other effects, particularly non
      targeted phenomena such as induced genomic instability, expectations may be less
      clear cut.

PMID- 12408482
TI  - Investigation into the thermal distribution of microwave helical antennas
      designed for the treatment of Barrett's oesophagus.
AB  - A set of helical microwave antennas was designed to investigate their potential
      use in thermal therapy of Barrett's oesophagus. The antennas had a diameter of up
      to 3.3 mm and various lengths between 20 and 37 mm; these were designed to
      operate at 915 MHz. Sets of polytetrafluoroethylene (PTFE) formers were
      constructed to improve the repeatability and reproducibility of the helix
      manufacture. Small diameter copper wire was wound over the formers and connected
      to the coaxial cable at the inner and outer conductor junctions. The power
      deposition profiles of the antennas were measured in a muscle-equivalent phantom
      using an infrared camera. The effects of antenna length and coil spacing were
      characterized. It was observed that uniform temperature profiles along the
      antenna length were achieved with a length of wire of 99 mm +/- 2 mm. The
      effective heating length (length of the antenna that exhibits > 50% of the
      maximum temperature rise) was comparable to the antenna length. The radial
      penetration depth of 50% of the antenna surface temperature for the optimum 20 mm
      antenna was 2.5 mm from the antenna outer surface.

PMID- 12408483
TI  - Use of a blood glucose meter for radiochromic film analysis in blood irradiation.
AB  - The use of a diabetic blood glucose meter for radiochromic film dosimetry in
      blood irradiation using x-ray beams on a medical linear accelerator has been
      investigated. The glucose meter provides optical density analysis in the visible
      and infrared region using a reflectance measurement technique. By comparing the
      'blood sugar' level output with standard calibration gafchromic films a
      calibration curve is produced for quantitative analysis. Results show that a
      reproducible dose to meter output curve can be fitted using a second order
      polynomial function and that blood irradiation doses in vitro were measured to
      within 7.9% mean error (as compared to ionization chamber results) using the
      blood glucose meter. This level of accuracy falls below that measured with a
      standard densitometer (4.3%); however, results show that the blood glucose meter,
      which would be available in any haematology department, produces an adequate
      measure of gafchromic film optical density for blood irradiation dosimetry.

PMID- 12408484
TI  - Tools for the analysis of dose optimization: II. Sensitivity analysis.
AB  - Dose optimization requires that the treatment goals be specified in a meaningful
      manner, but also that alterations to the specification lead to predictable
      changes in the resulting dose distribution. Within the framework of constrained
      optimization, it is possible to devise a tool that quantifies the impact on the
      objective of target volume coverage of any change to a dosimetric constraint of
      normal tissue or target dose homogeneity. This sensitivity analysis relies on
      properties of the Lagrange function that is associated with the constrained
      optimization problem, but does not depend on the method used to solve this
      problem. It is useful particularly in cases with multiple target volumes and
      critical normal structures, where constraints and objectives can interact in a
      non-intuitive manner.

PMID- 12408485
TI  - Is there an elevated risk of brain cancer among physicians performing
      interventional radiology procedures?

PMID- 12408486
TI  - Study of a selection of 10 historical types of dosemeter: variation of the
      response to Hp(10) with photon energy and geometry of exposure.
AB  - An international collaborative study of cancer risk among workers in the nuclear
      industry is tinder way to estimate direetly the cancer risk following protracted
      low-dose exposure to ionising radiation. An essential aspect of this study is the
      characterisation and quantification of errors in available dose estimates. One
      major source of errors is dosemeter response in workplace exposure conditions.
      Little information is available on energy and geometry response for most of the
      124 different dosemeters used historically in participating facilities.
      Experiments were therefore set up to assess this. using 10 dosemeter types
      representative of those used over time. Results show that the largest errors were
      associated with the response of early dosemeters to low-energy photon radiation.
      Good response was found with modern dosemeters. even at low energy. These results
      are being used to estimate errors in the response for each dosemeter type, used
      in the participating facilities, so that these can be taken into account in the
      estimates of cancer risk.

PMID- 12408487
TI  - Bayesian analysis of overdispersed chromosome aberration data with the negative
      binomial model.
AB  - The usual assumption of a Poisson model for the number of chromosome aberrations
      in controlled calibration experiments implies variance equal to the mean.
      However, it is known that chromosome aberration data from experiments involving
      high linear energy transfer radiations can be overdispersed, i.e. the variance is
      greater than the mean. Present methods for dealing with overdispersed chromosome
      data rely on frequentist statistical techniques. In this paper. the problem of
      overdispersion is considered from a Bayesian standpoint. The Bayes Factor is used
      to compare Poisson and negative binomial models for two previously published
      calibration data sets describing the induction of dicentric chromosome
      aberrations by high doses of neutrons. Posterior densities for the model
      parameters, which characterise dose response and overdispersion are calculated
      and graphed. Calibrative densities are derived for unknown neutron doses from
      hypothetical radiation accident data to deterimine the impact of different model
      assumptions on dose estimates. The main conclusion is that an initial assumption
      of a negative binomial model is the conservative approach to chromosome dosimetry
      for high LET radiations.

PMID- 12408488
TI  - Patient effective dose from endovascular brachytherapy with 192Ir sources.
AB  - The growing use of endovascular brachytherapy has been accompanied by the
      publication of a large number of studies in several fields, but few studies on
      patient dose have been found in the literature. Moreover, these studies were
      carried out on the basis of Monte Carlo simulation. The aim of the present study
      was to estimate the effective dose to the patient undergoing endovascular
      brachytherapy treatment with 112Ir sources, by means of experimental
      measurements. Two standard treatments were taken into account: an endovascular
      brachytherapy of the coronary artery corresponding to the activity x time product
      of 184 GBq.min and an endovascular brachytherapy of the renal artery (898
      GBq.min). Experimental assessment was accomplished by thermoluminescence
      dosemeters positioned in more than 300 measurement points in a properly adapted
      Rqndo phantom. A method has been developed to estimate the mean organ doses for
      all tissues and organs concerned in order to calculate the effective dose
      associated with intravascular brachytherapy. The normalised organ doses resulting
      from cronary treatment were 2.4 x 10(-2) mSv.GBq(-1).min(-1) for lung, 0.9 x 10(
      2) mSv.GBSq(-1).min(-1) for oesophagus and 0.48 x 10(-2) mS.GBq(-1).min(-1) for
      bone marrow. During brachytherapy of the renal artery, the corresponding
      normalised doses were 4.2 x 10(-2) mS.GBq(-1).min(-1) for colon, 7.8 x 10(-2)
      mSv.GBq(-1).min(-1) for stomach and 1.7 x 10(-2) mSv.GBq(-1).min(-1) for liver.
      Coronary treatment iJnvlled an efl'fective dose of (0.046 mSv.GBq(-1).min(-1),
      whereas the treatment of the renal artery resulted in an effective dose of 0.15
      mSv.GBq(-1).min(-1); there were many similarities with data from former studies.
      Based on these results it can be concluded that the dose level of patients
      exposed during brachytherapy treatment is low.

PMID- 12408489
TI  - Biological half-life of iodine in adults with intact thyroid function and in
      athyreotic persons.
AB  - A joint project between the Human Monitoring Laboratory (HML) and the Ottawa
      Hospital has measured the retention of 131I in patients who have received the
      radioiodine diagnostically. Thirty-nine subjects with intact thyroid glands and
      nine athyreotic subjects were measured in the HML's whole-body/thyroid counter to
      determine the retention of 131I following its medical administration. The average
      biological half-life of 131I in 26 euthyroid subjects was found to be 66.1+/-6.3
      days which may he statistically significantly lower than the ICRP recommended
      value of 80 days. Nine hyperthyroid patients had a mean biological half-life of
      38.2+/-8.6 days and in three hypothyroid patients the corresponding value was
      29.3+/-8.8 days. Thyroid 131I uptake was measured in a conventional clinical
      fashion at the Ottawa Hospital Civic campus 24 h after oral administration of the
      radioiodine using a collimated thick sodium iodide detector placed over the neck
      anteriorly. Measured values were 10.144+/-0.009, 0.314+/-0.035 and 0.045+/-0.010
      of the administered dose in euthyroid, hyperthyroid and hypothyroid patients
      respectively. The euthyroid range at the hospital is 0.06 - 0.22. Uptake was
      significantly lower for the euthyroid group than the ICRP value of 0.3. The
      radioiodine retention in athyreotic subjects followed a two compartment model
      with biological half-lives of 1.0+/-1.2 days and 18.4+/-1.1 days.

PMID- 12408490
TI  - Early faecal excretion of inhaled plutonium.
AB  - Special individual monitoring has been performed for suspected cases of
      inhalation of plutonium at the Tokai Works of the Japan Nuclear Cycle Development
      Institute (JNC). Some experimental data obtained from this special individual
      monitoring during the past 20 years are presented and discussed in this paper.
      Our experience suggests the following conclusions. The daily plutonium excretion
      rate, normalised to the total excretion for the first 5 days after inhalation,
      was approximately in agreement with the latest ICRP 78 dosimetric model. Maximum
      faccal excretion is observed on the second day after inhalation of plutonium
      compounds. On the other hand, the activity ratio for total alpha activity
      observed in early faeces to that detected in nasal swabs showed a wide
      distribution range, and it was proven that variations in this ratio followed a
      log-normal distribution. The logarithmic mean probability is about 2.1 for PuO2
      and about 15.7 for Pu(NO3)4. In practice, a conservative dose assessment from
      nasal swabs can be performed on the basis of these experimental ratios.

PMID- 12408491
TI  - Development of an automated shielded chair whole-body monitor.
AB  - A standard shielded chair whole-body monitor has been developed as a computer
      controlled, unattended, walk-in-type of whole-body monitor for internal dosimetry
      of radiation workers. A radiation worker enters his personal computer code
      through the attached computer terminal and follows a few instructions on the
      screen. The chair door then opens automatically and after the worker has
      positioned himself into the counting geometry in the chair, the door closes. At
      the end of the whole-body monitoring for a pre-set time, the chair door opens
      again and the worker moves out. The monitoring data acquired on a 4K-MCA is saved
      in the computer memory automatically and the chair door closes again making it
      available for monitoring the next worker. The system also gives audio
      instructions to the worker to occupy the chair and to move out after the counting
      is over. A system supervisor can come at any convenient time and get a print out
      of the monitoring report in the standardised format or carry out any detailed
      analysis if required. The system has the software for calculating intakes and the
      committed effective doses using the latest ICRP methodologies, from the measured
      retained activities of the various important fission and activation products like
      137Cs, 131I, 60Co, 125Sb etc. This type of system with trained staff is also
      expected to be of value in case of emergencies as a quick monitoring system.

PMID- 12408492
TI  - Is diffusion, thermodiffusion, or advection a primary mechanism of indoor radon
      entry?
AB  - Revision of the current theory of indoor radon entry is given. It is shown that
      there is insufficient evidence to accept the pressure-driven mechanism as the
      dominant mechanism of radon infiltration in homes. The criticism of the US
      Environmental Protection Agency's policy is presented. The similitude theory of
      gas transfer in Knudsen's and transition zones is developed. Comparison of the
      theory with experimental data confirms the validity of the assumptions made.
      Application of the theory to air flow in clay is shown. This theory allows the
      average pore radius in the clay sample to be estimated. That radius was found to
      be of the order of the mean free path of air molecules at atmospheric pressure.
      It is shown that thermodiffusion gas flow in clay and concrete can greatly exceed
      the pressure-driven flow. The necessity of including thermodiffusion gas flow in
      a general model of radon indoor entry is substantiated.

PMID- 12408493
TI  - A passive radon dosemeter suitable for workplaces.
AB  - The results obtained in different international intercomparisons on passive radon
      monitors have been analysed with the aim of identifying a suitable radon
      monitoring device for workplaces. From this analysis, the passive radon device,
      first developed for personal dosimetry in mines by the National Radiation
      Protection Board, UK (NRPB), has shown the most suitable set of characteristics.
      This radon monitor consists of a diffusion chamber, made of conductive plastic
      with less than 2 cm height, containing a CR-39 film (Columbia Resin 1939), as
      track detector. Radon detectors in workplaces may be exposed only during the
      working hours, thus requiring the storage of the detectors in low-radon zones
      when not exposed. This paper describes how this problem can be solved. Since
      track detectors are also efficient neutron dosemeters, care should be taken when
      radon monitors are used in workplaces, where they may he exposed to neutrons,
      such as on high altitude mountains, in the surroundings of high energy X ray
      facilities (where neutrons are produced by (gamma, n) reactions) or around high
      energy particle accelerators. To this end, the response of these passive radon
      monitors to high energy neutron fields has been investigated.

PMID- 12408494
TI  - Assessment of gamma dose rate over a suspected uranium mineralisation area of
      Jebel Mun, Western Sudan.
AB  - This study was conducted at the request of authorities in western Darfour State,
      to address the public concern about the levels of radioactivity in the area of
      Jebel Mun situated at Sudan-Chad international boundaries. It has been identified
      as a high background radiation area through aerial geological surveys conducted
      in late 1970s. The ambient gamma dose in the area was measured with the aid of a
      hand-held dose rate meter (Mini-Rad, Series 1000) and the surface rock samples
      were collected and analysed for their radioactivity content using a high
      resolution gamma spectrometry equipped with HPGe with relative efficiency of 18%.
      The activity concentrations of 238U, 232Th and 40K were found to range from 39
      253 Bq.kg(-1), 41-527 Bq.kg(-1) and 77-3027 Bq.kg(-1), respectively. From the
      values of the standard deviation it was concluded that the activity concentration
      of the considered primordial radionuclides was highly scattered (localised) which
      in turn indicates non-uniformity in the geological features and/or formations.
      238U activity concentration corresponds to equivalent mass concentration of
      7.77+/-6.12 ppm (3.19-20.73 ppm), which is of no economic importance. Samples are
      enriched in thorium relative to uranium as reflected by the Th:U mass ratio which
      ranges from 3 to 17. The absorbed dose rate in air as estimated from the measured
      activity concentrations of the primordial radionuclides using the DRCFs (dose
      rate conversion factors) falls within the range of 70-522 nGy.h(-1) with an
      average of 221+/-130 nGy.h(-1). It corresponds to an annual effective dose
      equivalent averaged of 0.27 mSv. The regression analysis has shown that the
      correlation between calculated and the measured ambient dose rate is marginally
      significant (r2 = 0.59). The 232Th series is the major producer of the surface
      radioactivity followed by 40K as they contribute 48% and 32% of the total
      absorbed dose, respectively.

PMID- 12408495
TI  - 226Ra, 228Ra and 228Th in scale and sludge samples from the Campos Basin oilfield
      E&P activities.
AB  - More than 40 scale and sludge samples from the Campos Basin oilfield were
      analysed in terms of 226Ra, 228Ra and 228Th. Although the exact origin of the
      samples was not known, scale samples derived from production pipes and sludge
      samples from water-oil separation units. Reported values ranged from 0.13 to 331
      kBq.kg(-1) for 226Ra, from 0.10 to 245 kBq.kg(-1) for 228Ra and <0.10 to 272
      kBq.kg(-1) for 228Th in sludge samples. The concentrations in scales were much
      more regular than in sludges and ranged from 16.2 to 93.2 kBq.kg(-1) for 226Ra,
      from 4.0 to 36.9 kBq.kg(-1) for 228Ra and from 4.5 to 18.5 kBq.kg(-1) for 228Th.
      Based on the Basic Safety Standards recommendations and on the derived results,
      these activities cannot be regarded as exempted and specific procedures should be
      designed for their radiological control.

PMID- 12408496
TI  - Surveillance in Barrett's oesophagus: a critical reappraisal.
AB  - BACKGROUND: Current recommendations are for endoscopic surveillance of patients
      with Barrett's oesophagus to detect dysplasia and to diagnose carcinoma at an
      early and possibly treatable stage. However, observations suggest that these
      current practice guidelines are thwarted by many factors often not taken into
      account. These observations stem from general surveillance aspects as well from
      specific data on Barrett's oesophagus. This review therefore aims at discussing
      data on the current surveillance strategy in conjunction with general
      surveillance aspects relevant for their interpretation. METHODS: Literature
      survey of published articles. RESULTS: A critical reappraisal of the literature
      shows that the current surveillance strategy is hampered by multiple problems
      with the marker dysplasia, cost-ineffectiveness, an overrated cancer risk and an
      astonishing lack of prospective, randomized data showing a clear benefit in terms
      of a greater life expectancy. Moreover, the decisive study is unlikely ever to be
      performed because of the large number of patients needed and the required length
      of follow-up. As a result, protocols are being carried out that have never been
      critically tested prior to large-scale clinical implementation. CONCLUSIONS:
      Although these findings should not lead to therapeutic nihilism, the data raise
      the issue of whether or not surveillance protocols should be restricted to
      specialized referral centres with particular research efforts aimed at improving
      existing and developing new techniques that lack most of the described pitfalls
      and problems. Since it is foreseen that matters will not change rapidly in the
      (near) future, the clinician has no other choice than to rely on individually
      tailored arguments to survey taking into account for example family history, age
      and anxiety about potential long-term effects.

PMID- 12408497
TI  - Barrett's oesophagus: new diagnostic and therapeutic techniques.
AB  - BACKGROUND: Barrett's oesophagus is associated with an increased risk of
      developing adenocarcinoma. Cancer development is preceded by dysplastic changes.
      Yet, detection of these microscopic changes has remained beyond the reach of
      routine endoscopy. Endoscopic screening in Barrett's therefore relies mainly on
      extensive random biopsy sampling. METHODS: Update on new endoscopic diagnostics
      techniques for Barrett's oesophagus. RESULTS: Application of new optical
      techniques has the potential to enhance our ability to detect dysplasia during
      endoscopic procedures and take targeted biopsies. Spectral information can be
      obtained either by point measurements using an optical fibre ('spectral biopsy')
      or by imaging a broad tissue field. Light-induced fluorescence techniques are
      based on the observation that tissue when excited by light of shorter wavelength
      will emit fluorescent light of a longer wavelength. This concept can be used to
      image tissue in vivo, based on minimal biochemical and structural changes of the
      (sub)mucosa. Elastic scattering spectroscopy is a spectral biopsy technique that
      can be exploited even to detect low-grade dysplasia, based on structural
      information of the mucosa, in which the size and crowding of nuclei in the
      epithelial layer play a key role. Optical coherence tomography uses reflection of
      light at optically scattering structures for cross-sectional tissue imaging.
      Compared to B-scan ultrasonography, optical coherence tomography offers a much
      higher resolution (10-20 micron), without the need for tissue contact or acoustic
      coupling. These spectral techniques, although still in their infancy, have
      already shown the ability to detect early cancer, high-grade dysplasia and in
      some cases even low-grade dysplasia with a promising degree of sensitivity. As
      the instruments and the techniques will be further refined, they are likely to
      become an important part of endoscopic screening. Advances in endoscopic
      treatment techniques make early malignancies, for which surgical resection is the
      only accepted therapy, amenable for minimally invasive endoscopic treatment.
      Endoscopic mucosal resection is a minimally invasive endoscopic technique that
      can be used in patients with circumscribed mucosal carcinomas. The technique is
      also useful as a diagnostic procedure by obtaining a full-thickness mucosal
      specimen for histologic examination. Photodynamic therapy using the prodrug 5
      aminolevulinic acid is an ablative therapy that destroys the oesophageal mucosa,
      leaving the deeper layers of the oesophageal wall intact. Cell damage is achieved
      by the action of light on the photosensitizing agent protoporphyrin IX in the
      mucosa, with skin photosensitivity of less than 48 h. Such mucosal ablation,
      however, can also be accomplished with more common thermal techniques like argon
      plasma coagulation. In all these ablative procedures, squamous regeneration is
      obtained by rigorous antacid therapy. In selected patients, these endoscopic
      ablation methods, although still experimental, might already offer an alternative
      to oesophagectomy. The need for further improvement, in conjunction with the lack
      of long-term follow-up data, however, limits the use of these techniques to
      expert centres. CONCLUSION: New endoscopic techniques are likely to change the
      diagnostic and therapeutic procedures for Barrett's oesophagus in the near
      future.

PMID- 12408498
TI  - Helicobacter pylori and gastro-oesophageal reflux disease: association and
      clinical implications. To treat or not to treat with anti-H. pylori therapy?
AB  - BACKGROUND: It has been reported that patients are at risk of developing reflux
      oesophagitis after successful anti-Helicobacter pylori therapy, and the presence
      of the bacterium might be protective against the development of reflux
      oesophagitis. METHODS: Review of the literature. RESULTS: H. pylori is relevant
      to the management of oesophagitis because it increases the pH-elevating effect of
      proton-pump inhibitors. which increase the tendency of H. pylori gastritis to
      progress to atrophic gastritis, and because eradication of H. pylori increases
      the likelihood of oesophagitis. H. pylori increases basal gastrin levels, basal
      acid output, meal-stimulated maximal acid output and 24-h intragastric acidity.
      The effects on gastric acid production depend on the distribution of gastritis in
      the stomach. CONCLUSION: H. pylori eradication may induce or exacerbate gastro
      oesophageal reflux by its influence on gastric acidity and the antisecretory
      action of proton-pump inhibitors.

PMID- 12408499
TI  - Helicobacter pylori and functional dyspepsia. What to do after the Maastricht II
      consensus meeting?
AB  - BACKGROUND: Despite many clinical studies, there is still much discussion on the
      relation between Helicobacter pylori and functional dyspepsia. METHODS: Critical
      review of recommendations for H. pylori eradication in dyspepsia. RESULTS: The
      debate can be separated into three major problems. First, how to identify the
      dyspeptic patient suffering from H. pylori infection. Second, is H. pylori
      infection causative for complaints in this patient? Third, what is the clinical
      course of functional dyspepsia after successful H. pylori eradication? In the
      recent Maastricht II consensus, it is strongly recommended that H. pylori
      positive patients with functional dyspepsia should be treated with anti-H. pylori
      therapy. In this review, the pros and cons of H. pylori eradication in patients
      with functional dyspepsia are discussed. The reader can decide what is the best
      management of an individual patient. CONCLUSIONS: This review gives the relevant
      background information allowing clinicians to decide what the best management is
      in individual H. pylori-positive patients with dyspepsia.

PMID- 12408500
TI  - The serological gastric biopsy: a non-endoscopical diagnostic approach in
      management of the dyspeptic patient: significance for primary care based on a
      survey of the literature.
AB  - BACKGROUND: Measurement of the serum concentration of the secretory products of
      the gastric mucosa, pepsinogen A (PgA), pepsinogen C (PgC) and gastrin is called
      the serological gastric biopsy. Additional measurement of Helicobacter pylori
      antibodies and antibodies to parietal cells and intrinsic factor supports the non
      invasive diagnostic value of the serum markers. In many clinical studies, the
      diagnostic potential of the serum markers in predicting the topography and
      severity of gastric mucosal disorders has been established. The aim was to assess
      the diagnostic value of the serological gastric biopsy for primary care. METHOD:
      Survey of the literature. RESULTS: The cell-physiological background of the
      serological gastric biopsy, the interpretation of the outcome of serum markers
      and the relation of these parameters to various gastric mucosal disorders are
      described. Measurement of PgA is a reliable way to discriminate between mucosal
      gastritis and functional dyspepsia. PgA is raised in duodenal, gastric and
      pyloric ulcer even though gastrin is normal. Both PgA and gastrin are raised in
      renal insufficiency and the Zollinger-Ellison syndrome. A low PgA is indicative
      of mucosal atrophy and a good indicator for gastric hypoacidity. An additional
      low PgA:C ratio is indicative of atrophic gastritis or extensive intestinal
      metaplasia of the stomach. A hypopepsinogenaemia can also be an alarm symptom for
      gastric cancer. A low PgA and a high gastrin is indicative of corpus atrophy.
      CONCLUSION: In primary care, the serological gastric biopsy might be a feasible
      and appropriate diagnostic method for management of the dyspeptic patient.
      Further research in general practice has to be done to validate the predictive
      value of the serological gastric biopsy and to define a diagnostic strategy.

PMID- 12408501
TI  - Gastric lymphoma: the revolution of the past decade.
AB  - BACKGROUND: Gastric MALT type lymphomas are distinct lymphomas that may develop
      after chronic antigenic stimulation caused by infection with Helicobacter pylori.
      An early antigen-dependent phase precedes the development of an antigen
      independent phase. METHODS: Narrative review. RESULTS: The causative relationship
      between a chronic H. pylori infection and gastric MALT lymphomas has been based
      on epidemiological, histological, experimental and therapeutic studies. H. pylori
      eradication leads to a histological remission in +/- 70% of patients in early
      stage low-grade MALT lymphoma. There is no basis for therapeutic consequences in
      the case of persistent monoclonality. Full thickness invasion of the gastric wall
      and lymph node involvement and/or high-grade lymphoma denote the transition to an
      antigen-independent phase and calls for conventional treatment modalities.
      Molecular findings show a specific translocation in low-grade MALT lymphomas:
      t(11,18) and nuclear expression of bcl-10 that are highly indicative of the
      transition of the antigen-dependent into the antigen-independent phase. Other
      chromosomal and molecular findings are probably also involved. CONCLUSION: The
      multistep pathogenesis of chronic H. pylori gastritis into low-grade gastric MALT
      lymphoma and tumour progression to a higher stage and grade are characterized by
      multiple molecular biological events. Antigen-dependency during the early phase
      of this malignancy is proven by the results of H. pylori eradication.

PMID- 12408502
TI  - Blockade of NF-kappaB activation and donation of nitric oxide: new treatment
      options in inflammatory bowel disease?
AB  - BACKGROUND: Inhibition of NF-kappaB activation has been suggested as an anti
      inflammatory treatment strategy in inflammatory bowel disease (IBD). However, NF
      kappaB regulated genes like inducible nitric oxide synthase (iNOS) are also
      involved in cell survival mechanisms. METHODS: Review of the literature on NF
      kappaB activation and iNOS induction in IBD. RESULTS: In patients with IBD the
      mucosal immune response is derailed. The nuclear transcription factor NF-kappaB
      is a key regulator of the inducible expression of many genes involved in immune
      and inflammatory responses in the gut. Stimuli like oxidative stress, cytokines
      (IL-1, IL-6, TNF-alpha), bacteria and viruses can release NF-kappaB from their
      inactive cytoplasmatic form to the nucleus. Drugs like corticosteroids,
      sulphasalazine, mesalazine and inhibitory cytokines (e.g. IL-10, IL-11) can
      prevent the activation of NF-kappaB. New, more potent and selective treatment
      strategies with anti-sense p65, proteasome inhibitors and viral IkappaBalpha
      expression vectors aim at the prevention of NF-kappaB activation in mucosal
      macrophages and T lymphocytes. However, NF-kappaB regulated genes are also
      involved in survival responses of epithelial cells. For example, inhibition of
      the NF-kappaB mediated induction of iNOS in epithelial cells could block
      important anti-apoptotic and anti-microbial survival mechanisms. Nitric oxide may
      also serve in a negative feedback loop to antagonize prolonged activation of NF
      kappaB, thereby limiting chronic inflammation. CONCLUSION: Luminal donation of
      nitric oxide could block NF-kappaB activation. Selective inhibition of NF-kappaB
      activation in inflammatory cells could be a treatment option in IBD.

PMID- 12408503
TI  - Role of mesalazine in acute and long-term treatment of ulcerative colitis and its
      complications.
AB  - BACKGROUND: Sulfasalazine, consisting of 5-aminosalicylic acid bound to
      sulfapyridine by a diazo bond, was first used for treatment of ulcerative colitis
      in the early 1940s and later found effective in placebo-controlled trials for
      acute disease and for long-term maintenance of remission. Later studies found
      that the active moiety is 5-ASA (mesalazine, mesalamine) and the sulfapyridine
      moiety acts as a carrier molecule but causes many of the symptomatic adverse
      reactions. METHODS: Review of the literature. RESULTS: The finding that 5-ASA in
      the active motility led to the development of mesalazine prodrugs, olsalazine
      (Dipentum) and balsalazide (Colazide, Colazal), and targeted release mesalazine
      preparations, such as Asacol, Pentasa, and Salofalk, as well as enemas and
      suppository preparations for distal disease. Most patients with adverse effects
      from sulfasalazine will tolerate mesalazine. Mesalazine has been shown equivalent
      or superior to sulfasalazine, and superior to placebo, with a dose-response
      benefit, in inducing remission of acute disease. and comparable to sulfasalazine
      and superior to placebo for long-term maintenance of remission. Better tolerance
      of mesalazine and the ability to use higher doses favor its use in patients
      intolerant of sulfasalazine and in patients failing to respond to usual doses of
      sulfasalazine. Adverse effects from mesalazine are uncommon, but include
      idiosyncratic worsening of the colitis symptoms and renal toxicity. Mesalazine is
      safe to use during pregnancy and for nursing mothers. As maintenance therapy,
      mesalazine may reduce the risk of developing colorectal carcinoma. CONCLUSION:
      Mesalazine represents effective and well-tolerated first-line therapy for mildly
      to moderately acute disease as well as for the long-term maintenance treatment in
      the patient with ulcerative colitis.

PMID- 12408504
TI  - Malignancies in inflammatory bowel disease: fact or fiction?
AB  - BACKGROUND: The association between ulcerative colitis (UC), Crohn disease (CD)
      and colorectal cancer (CRC) has been confirmed in several studies. The aim of
      this study was critical analysis of the relation between IBD and malignancy.
      METHODS: Review of the literature. RESULTS: In UC, the extent of the disease, its
      duration and start at a young age are risk factors for the development of CRC.
      Primary sclerosing cholangitis and colonic strictures are additional risk factors
      for development of CRC. The relation between azathioprine or 6-MP and the
      development of lymphomas is a subject of debate. The administration of anti-TNF
      alpha has produced some concern about the development of lymphomas in CD.
      However, at present there is no evidence of lymphomas caused by anti-TNF-alpha in
      CD. On the contrary, some drugs seem to have a preventive effect on CRC
      development in UC. 5-aminosalicylic acid in particular and to a lesser extent
      sulphasalazine have prevented the development of CRC significantly in
      retrospective studies. In CD, there is no strong relationship between the disease
      and the development of CRC or other malignancies. Only the development of small
      bowel carcinoma is reported with a much higher frequency. CONCLUSIONS: There is a
      correlation with UC and the development of CRC. For CD, this correlation is less
      firmly established. There is a possible, but not proven, relation between AZA/6
      MP use and the development of lymphoma in IBD. There is also a probable
      relationship between CD and the development of small-bowel carcinoma. In some
      retrospective studies, the use of 5-aminosalicylic or sulphasalazine has been
      shown to prevent the development of CRC in UC.

PMID- 12408505
TI  - Laparoscopic surgery for inflammatory bowel disease: current concepts.
AB  - BACKGROUND: The aim of a laparoscopic approach is reduced pain scores, early
      mobilization, virtual absence of wound sepsis, rapid return of gastrointestinal
      function, early discharge from hospital and return to normal activity and
      improved cosmetics. Potential advantages are fewer complications due to adhesion
      formation, viz. small-bowel obstruction, infertility and chronic abdominal pain
      advantages that are of particular importance to patients with inflammatory bowel
      disease (IBD) since they are young and in the middle of building up their socio
      economic life. This review highlights the current status of laparoscopic surgery
      for patients with IBD. METHODS: Virtually all abdominal procedures carried out in
      patients with IBD can be done laparoscopically, and vary from stoma formation to
      restorative proctocolectomy. RESULTS: Conversion rates and operating times depend
      on the surgical expertise and patient-related factors, viz. prior laparotomy, the
      presence of intestinal fistula or inflammatory masses. Morbidity rates are
      similar to those of open surgery provided that the procedures are done by expert
      laparoscopic surgeons. The observed earlier recovery contributed to laparoscopic
      surgery has not been proved in well-conducted trials; however, an advantage can
      be expected. A very obvious feature of laparoscopic surgery is the improved
      cosmetics, which might turn out to be the most important advantage of the
      laparoscopic approach in this relatively young patient group. CONCLUSION: The
      laparoscopic approach can be considered the procedure of first choice in patients
      with IBD provided the surgery is done by expert laparoscopists ensuring low
      conversion rates, acceptable operating times and low morbidity.

PMID- 12408506
TI  - Coeliac disease: changing views on gluten-sensitive enteropathy.
AB  - BACKGROUND: The continuing flow of scientific development in coeliac disease in
      the past decade points to the need for the formulation of a new concept of
      pathophysiology and clinical approach to the coeliac condition. Immunogenetic
      studies have shown a correlation of the disease to the HLA region on the short
      arm of chromosome 6; immunological research has led to the concept of a T-cell
      driven immunologic response of the small intestine, with the identification of
      highly sensitive and specific antibodies; and our understanding of the
      histopathology of coeliac disease has changed dramatically, initiated by the
      proposition of a spectrum of gluten-sensitive enteropathy by Marsh in 1992.
      Clinical studies report a significant change in patient characteristics and
      epidemiology. The incidence of the disease has shifted to a majority of adult
      coeliacs, and it may present with less severe symptoms of malabsorption.
      Screening studies suggest an overall prevalence of up to 1 in 200-300. METHODS:
      Update on histopathology concentrating on the work of our research group.
      RESULTS: We specifically describe the work of our group in Arnhem concerning the
      identification and validation of the spectrum of intestinal histopathology in
      gluten-sensitive enteropathy, i.e. lymphocytic enteritis (Marsh I lesion),
      lymphocytic enteritis with crypt hyperplasia (Marsh II lesion), and villous
      atrophy, subdivided into partial villous atrophy (Marsh IIIA), subtotal villous
      atrophy (Marsh IIIB) and total villous atrophy (Marsh IIIC). Special attention is
      given to a subgroup of 'refractory coeliacs', including the identification of
      (pre-)malignant aberrant T cells in the intestinal mucosa of these patients.
      CONCLUSION: New data on immunogenetics, epidemiology, histopathology and patient
      characteristics point to a significant change of view on coeliac disease.

PMID- 12408507
TI  - Carcinoid heart disease: an update.
AB  - BACKGROUND: Carcinoid tumours are a poorly defined collection of lesions,
      histopathologically indistinguishable from gastroentero-pancreatic neuroendocrine
      tumours. In this report, we discuss epidemiology and survival, clinical
      presentation, carcinoid valvular heart disease (CVHD), histopathological
      considerations and treatment options. METHODS: Review and update of the
      literature. RESULTS: The term carcinoid suggests a disease entity, but with
      increasing knowledge it becomes progressively confusing. To avoid further
      confusion, it is advisable to define these tumours using differentiation, stage,
      primary site, known tumour products and an associated clinical syndrome.
      Incidence varies between 0.8 and 1.9/100,000 population. About 20% present with
      metastases, with a 5-year survival varying between 15% and 35%. Metastatic
      disease frequently accompanies the carcinoid syndrome (flushing, diarrhoea,
      wheezing and CVHD). CVHD incidence is about 50%, and seems unrelated to disease
      duration and tumour mass. An aetiological relation of CVHD with urinary 5-HIAA
      remains to be confirmed. Resection is the only curative option. Surgery can also
      offer prolonged palliation and is needed to restore bowel transit in
      obstructive/ischaemic bowel problems. Adequate palliation of hormone-related
      symptoms can also be achieved by somatostatin analogues, meta-iodo-benzyl
      guanidine preparations and interferon-alpha formulations, all with a 70% response
      rate. Embolization of liver metastases has led to objective responses in about
      50% of patients, but is accompanied by significant side effects. CONCLUSIONS:
      Most patients are cured by surgery. Symptom relief is the main target in
      metastatic disease and can be achieved by a range of equally potent biologically
      active medications, debulking surgery and hepatic embolization.

PMID- 12408508
TI  - Second-line treatment for faecal incontinence.
AB  - BACKGROUND: In the treatment of faecal incontinence, more than 30% of patients
      experience continuation of their problem. We discuss new therapeutic procedures
      for dealing with faecal incontinence. METHODS: Discussion of authors' own work in
      relation to the literature. RESULTS: First-line care includes diets, constipating
      drugs, biofeedback therapy, anal repair and operations for prolapse and fistulas.
      For the failures of these first-line treatments there is hope with second-line
      therapies. Creation of a neosphincter is possible with a dynamic graciloplasty
      (DGP) or an artificial bowel sphincter (ABS). A DGP is a conventional
      graciloplasty with the addition of implanted electrodes and a stimulator that
      transforms the muscle into an automatic contracting sphincter. ABS comprises an
      inflatable cuff around the anus that is filled from a pressure-regulating
      balloon. The cuff can be emptied with an implanted pump. CONCLUSIONS: DGP and ABS
      give good results in 56%-88% of cases. For patients with an anatomical intact but
      nonfunctioning sphincter there is a new treatment: sacral nerve stimulation. This
      gives continence in a high percentage of cases, but experience is rather limited.
      Second-line treatment for faecal incontinence is successful and should be
      considered in cases where initial therapies fail.

PMID- 12408509
TI  - Robotics in laparoscopic surgery: current status and future perspectives.
AB  - BACKGROUND: Laparoscopic surgery has been introduced to limit the burden of
      surgical damage to the abdominal wall and peritoneum. METHODS: Description of
      procedure and results of robotic laparoscopic surgery. RESULTS: Laparoscopic
      surgery has resulted in reduction of postoperative pain, surgery-related
      complications and scarring. Laparoscopic techniques, however, are challenging for
      the surgeon owing to the disadvantages of inverted and restricted manipulation
      and the indirect two-dimensional view. In order to solve these problems, robotic
      telemanipulation systems were developed and introduced to the market at the end
      of the past decade. This article describes and discusses the current status and
      future perspectives of robotic systems in endoscopic surgery. CONCLUSION: Robotic
      laparoscopic surgery overcomes some of the disadvantages of conventional
      laparoscopic surgery.

PMID- 12408510
TI  - A liver tumour as an incidental finding: differential diagnosis and treatment.
AB  - BACKGROUND: A liver tumour is occasionally found by coincidence during upper
      abdominal imaging. The diagnostic and therapeutic strategy for incidental liver
      tumours is discussed. METHODS: Review of the literature. RESULTS: When a liver
      tumour is found by coincidence, the questions to be answered are whether a
      definite diagnosis can be reached by imaging alone, and whether treatment is
      indicated. To answer the first question we have to know the characteristics of
      the various liver tumours with different imaging techniques, and the added value
      of more invasive diagnostic procedures. For an answer to the second question,
      information on the natural course of the specific tumour and on the risks and
      benefit of treatment is required. Of course, the a priori chance of certain
      diagnoses depends on the presence or absence of risk factors. Using simple
      imaging techniques, liver lesions can be categorized as single or multiple and as
      cystic or solid. Cystic lesions are usually benign, either congenital or
      parasitic. Solid lesions can be benign or malignant. The most common benign
      lesions are haemangioma, focal nodular hyperplasia and hepatocellular adenoma.
      Malignant tumours arising in the normal liver can be primary, in the form of
      hepatocellular carcinoma, or secondary, resulting from dissemination of a primary
      tumour outside the liver. All these tumour types can present with typical
      features in various imaging studies. A definite diagnosis based on imaging alone,
      however, is not always possible. On the other hand, even histological examination
      of biopsy samples sometimes does not differentiate between benign and malignant
      tumours. In the case of an asymptomatic liver tumour the main indication for
      treatment is proven or suspected malignancy. Large adenomas form a notable
      exception, these should be removed if they are over 5 cm in diameter or when they
      grow during follow-up, especially during pregnancy. Therapy will usually consist
      of liver resection, either partial or, when this is not possible, complete
      resection followed by liver transplantation. An important caveat is that a
      surgical procedure without morbidity and mortality does not exist. For
      symptomatic benign liver tumours the options are the same, but there may be
      equally effective and less risky alternatives in specific cases, such as
      embolization for focal nodular hyperplasia and irradiation for haemangioma.
      CONCLUSION: The diagnostic and therapeutic approach to incidental liver tumours
      depends on several factors, including size, aspect and number of the tumours, the
      clinical background, the a priori chance of a certain type of tumour and
      especially the risk of malignancy.

PMID- 12408511
TI  - New strategies for the treatment of gallstone disease.
AB  - BACKGROUND: Symptomatic gallstones are generally accepted as being the indication
      for cholecystectomy. Generally, severe abdominal pain in epigastrium and in the
      right upper abdominal quadrant, and lasting for more than 15 min, is thought to
      be caused by gallstones. However, many patients with other abdominal complaints
      undergo cholecystectomy and are satisfied with the outcome of surgery. Possible
      ways to improve the results of cholecystectomy are discussed. METHODS: Review of
      previous work by the authors. RESULTS: The introduction of laparoscopic
      cholecystectomy has even led to an increase in cholecystectomies; in a higher
      complication rate; and in increased costs of the treatment of gallstone disease.
      Because of faster recovery, 70% of symptomatic gallstone patients are able and
      willing to undergo laparoscopic cholecystectomy in day care. Cholecystectomy
      after sphincterotomy and stone extraction in patients who have stones in the
      gallbladder was demonstrated to prevent gallstone-related symptoms in at least
      40% of patients. If the gallbladder had to be removed later for symptomatic
      disease, however, this did not result in a higher rate of conversions and
      complications. Because of shortage in operation capacity in The Netherlands,
      there is a considerable delay between the diagnosis of symptomatic stones and
      cholecystectomy. Better selection of patients for cholecystectomy will not only
      improve the results of cholecystectomy, it will also reduce the number of
      cholecystectomies and patients on waiting lists. Delay of cholecystectomy is
      associated with more complications, longer operative times, higher conversion
      rates to open cholecystectomy and prolonged hospitalization. The efficacy of the
      bile salt ursodeoxycholic acid in preventing gallstone-related pain attacks and
      complications in patients with contraindications for operation or waiting to
      undergo cholecystectomy should be investigated further, since two retrospective
      studies have demonstrated favourable outcomes for this strategy. CONCLUSION: The
      results of cholecystectomy are likely to be improved by better selection of
      patients, prevention of delay of the procedure and possibly treatment with
      ursodeoxycholic acid.

PMID- 12408512
TI  - Genetic basis of chronic pancreatitis.
AB  - BACKGROUND: Pancreatitis has a proven genetic basis in a minority of patients.
      METHODS: Review of the literature on genetics of pancreatitis. RESULTS: Ever
      since the discovery that in most patients with hereditary pancreatitis a mutation
      in the gene encoding for cationic trypsinogen (R122H) was found that results in a
      gain of trypsin function', many other mutations in the cationic trypsinogen gene,
      as well as in the gene encoding for pancreatic secretory trypsin inhibitor, have
      been found in patients with chronic pancreatitis. Furthermore, mutations in other
      genes, like the mucoviscoidosis-gene encoding for a chloride channel, and in
      genes encoding for enzymes involved in the metabolism of ethanol, have been
      linked to chronic pancreatitis. This article reviews the highlights that have
      been achieved in this field of pancreatic research. CONCLUSIONS: Recent data
      suggest that genetics may play a role in the pathogenesis of pancreatitis.

PMID- 12408513
TI  - Bioinformatics and rational drug design: tools for discovery and better
      understanding of biological targets and mode of action of drugs.
AB  - BACKGROUND: With the advent of modern high throughput technologies in both
      genomics and biological screening, and at the same time the enormous advances in
      computer technology, it is now feasible to use these tools in rational approaches
      in the search for new medicines. The role of bioinformatics in the search for new
      medicines is discussed. METHODS: Discussion of the author's own work on
      bioinformatics in drug research in future perspective. RESULTS: The emerging
      discipline of Bioinformatics plays a central role in the concert of technologies
      of the 'biological revolution' because it allows for handling of the enormous
      data load that comes with sequencing efforts and subsequent analyses of whole
      genomes, with mRNA profiling techniques and, last but not least, at a later stage
      of drug discovery the up-to-date application of rational drug design techniques
      to 3D structures of target proteins. This article covers and explains parts of
      the steps used in modern pharmaceutical research by means of a small number of
      examples. CONCLUSION: Bioinformatics is likely to play a pivotal role in the
      rational approaches for the search of new medicines.

PMID- 12408514
TI  - Eosinophils in gastrointestinal inflammation: from innocent bystanders to
      offenders.

PMID- 12408515
TI  - Relationship between gastric localization of hepatitis C virus and mucosa
      associated lymphoid tissue in Helicobacter pylori infection.
AB  - BACKGROUND: Hepatitis C virus (HCV) has been localized in several extra-hepatic
      sites. Recent evidence suggests that the stomach can harbour HCV. We therefore
      evaluated the prevalence of gastric localization of HCV and its possible
      relationship with the chronic inflammatory response to Helicobacter pylori
      infection. METHODS: Sixty patients with HCV infection (group A) and 60 subjects
      without HCV infection (control group), who underwent upper endoscopy for
      dyspeptic symptoms, were consecutively enrolled. Biopsy specimens of gastric
      mucosa obtained from each patient were assessed for H. pylori and chronic
      inflammatory infiltrates (classified as mild, moderate or marked). Furthermore,
      polymerase chain reaction (PCR) analyses were performed on the gastric biopsies
      to detect HCV and immunoglobulin heavy-chain (IgH) gene rearrangements of mucosal
      B cells. RESULTS: In group A, 24 of 36 patients with H. pylori infection and 6 of
      24 without H. pylori hosted HCV in their stomach (P = 0.0017). In these subjects,
      the presence of both HCV in the gastric mucosa and H. pylori was significantly
      associated with marked or moderate inflammatory infiltrates. Oligoclonal IgH gene
      rearrangements were detected in three group A patients who harboured both H.
      pylori and HCV in their stomach. In the control group, PCR analyses failed to
      find HCV in the gastric mucosa, and polyclonal patterns were detected in all
      individuals. CONCLUSIONS: HCV is frequently localized in the stomach and is
      associated with the chronic lymphocytic inflammatory response to H. pylori. H.
      pylori and HCV, when both present, may favour the selection of clonal B cells.

PMID- 12408516
TI  - Involvement of cholecystokinin receptor in the inhibition of gastrointestinal
      motility by estradiol in ovariectomized rats.
AB  - BACKGROUND: The effects of estradiol benzoate (EB) on gastric emptying,
      gastrointestinal transit and plasma levels of cholecystokinin (CCK) were studied
      in ovariectomized rats. METHODS: Gastrointestinal motility was assessed in rats
      15 min after intragastric instillation of a test meal containing charcoal and Na2
      51CrO4. Gastric emptying was determined by measuring the amount of radiolabeled
      chromium contained in the small intestine as a percentage of the initial amount
      received. Gastrointestinal transit was evaluated by calculating the geometric
      center of distribution of the radiolabeled marker. Blood samples were collected
      for E2 and CCK radioimmunoassay. RESULTS: After treatment of EB (4-25 microg/kg),
      gastric emptying and gastrointestinal transit were inhibited, whereas plasma
      concentrations of E2 and CCK were increased in a dose-dependent manner. The
      selective CCK(A) receptor antagonists, devazepide and lorglumide, effectively
      attenuated the EB-induced inhibition of gastric emptying and gastrointestinal
      transit. L-365,260, a selective CCK(B) receptor antagonist, did not alter the EB
      induced inhibition of gastric emptying and gastrointestinal transit. CONCLUSIONS:
      The results suggest that EB inhibits gastric emptying and gastrointestinal
      transit in ovariectomized rats via a mechanism involving CCK stimulation and
      CCK(A) receptor activation.

PMID- 12408517
TI  - Provocation of transient lower esophageal sphincter relaxations during continuous
      gastric distension.
AB  - BACKGROUND: Transient lower esophageal sphincter relaxations (TLESRs) are
      triggered by gastric distension. The aim of the study was to investigate TLESRs
      during controlled prolonged gastric distensions using the barostat technique.
      METHODS: Twelve healthy volunteers (4 M, 8 F, age range 19-42 years) were studied
      under fasting conditions with combined esophageal manometry (Dentsleeve) and
      gastric barostat. Randomized isobaric distensions at 0 (control), 10, 12 and 14
      mmHg were performed each period for 30 min with 30-min recovery periods in
      between. RESULTS: The frequency of TLESR was significantly (P < 0.05) higher
      during all distension periods compared to control periods (4.0 +/- 0.4 TLESR/30
      min versus 2.6 +/- 0.4 TLESR/30 min). The frequency of TLESR in the first 15-min
      period of distension was significantly (P < 0.001) higher compared to the second
      15-min period pointing to adaptation (2.7 +/- 0.3 TLESR/15 min versus 1.3 +/- 0.2
      TLESR/15 min, respectively). The frequency of TLESR correlated significantly with
      intragastric pressure (r = 0.47; P < 0.01) and wall tension (r = 0.48; P < 0.01),
      but not with intragastric volume. TLESR characteristics such as duration were not
      related to pressure or wall tension. CONCLUSIONS: Acute gastric distension
      increases the frequency of TLESR but adaptation occurs rapidly. The frequency of
      TLESR during distension is related to pressure and wall tension rather than to
      intragastric volume.

PMID- 12408518
TI  - Electrogastrography before and after a high-caloric, liquid test meal in healthy
      volunteers and patients with severe functional dyspepsia.
AB  - BACKGROUND: The cutaneous recording of gastric electric rhythm, so-called
      electrogastrography (EGG), has been purported as a non-invasive method for
      studying patients with functional dyspepsia and unexplained nausea and vomiting.
      The aims of this study were to determine normal values for EGG characteristics
      before and after a liquid, high-caloric test meal and to investigate whether EGG
      could discriminate between patients with functional dyspepsia and normal
      controls. METHODS: In studying 20 healthy volunteers and 10 patients with
      functional dyspepsia, we recorded gastric electrical activity during the 30 min
      before and after a liquid 1.0-1.5 kcal/ml test meal. Satiety before and after the
      meal was estimated on a 10-point scale. EGG was analysed regarding dominant
      frequency, instability of the dominant frequency, power ratio and percentage
      activity in the normal frequency range. RESULTS: The mean (+/-s) caloric intake
      in patients with functional dyspepsia (286 +/- 160 kcal) was significantly lower
      (P < 0.001) than in healthy volunteers (610 +/- 211 kcal). The patients reported
      a more pronounced feeling of satiety before the test meal (5.6 +/- 3.2) compared
      to healthy volunteers (3.6 +/- 1.2, P < 0.05), but at the end of the test meal
      there was no difference in satiety (7.9 +/- 2.5 versus 7.7 +/- 1.0). However,
      none of the EGG parameters showed any difference between patients and healthy
      volunteers. CONCLUSIONS: EGG before and after a high-caloric test meal showed
      large variation in healthy subjects and seemed to be of little value for
      differentiating between healthy individuals and patients with functional
      dyspepsia.

PMID- 12408519
TI  - Gastrectomy has no effect on bone regeneration in rats despite a decrease in bone
      mass.
AB  - BACKGROUND: Gastrectomy, specifically the removal of the acid-producing part of
      the stomach (fundectomy), is known to cause osteopenia. This effect has been
      ascribed to the elimination of a hypothetical osteotropic peptide hormone,
      presumably produced in the oxyntic mucosa. Since osteopenia is due to a disturbed
      balance between bone formation and resorption, we assessed the effect of
      gastrectomy on osteogenesis, more specifically mandibular orthotopic bone
      regeneration. METHODS: Adult rats were either gastrectomized or sham-operated.
      Two weeks later, unilateral 5-mm transosseous defects were made in the mandibles
      and covered with microporous barrier membranes (GORE-TEX Membrane). After 6 weeks
      of healing. bone-bridging of the defects was analyzed by computerized light
      microscopic image analysis. Furthermore, bone mass was analyzed in the
      contralateral untreated mandibular side, in calvarial bone, and in femora by
      morphometry and dry/ash weights. RESULTS: While gastrectomy resulted in a clearly
      decreased bone mass, manifested as increased marrow spaces in all bones and as
      decreased dry and ash weights in femora, no difference in mandibular bone healing
      rate was found between the groups. CONCLUSIONS: Since secluding of the defect
      space by membrane barriers implies that osteogenic cells have to be recruited
      primarily from intra-osseous stem cells by their proliferation and
      differentiation into actively bone-forming osteoblasts, the results indicate that
      gastrectomy has no effect on these processes. The findings thus imply that the
      disturbed balance in bone remodeling caused by gastrectomy, resulting in
      osteopenia, may be due to stimulated bone resorption rather than to reduced bone
      formation.

PMID- 12408520
TI  - Ulcerative colitis, seronegative spondyloarthropathies and allergic diseases: the
      search for a link.
AB  - BACKGROUND: Allergic diseases and seronegative spondyloarthropathies are
      frequently observed in ulcerative colitis (UC). In this report we have
      investigated possible relationships between IgE-mediated allergic disease (AD),
      allergic contact dermatitis (ACD) and seronegative spondyloarthropathy (SpA) in
      UC patients at different grades and extensions of mucosa inflammation. METHODS:
      Forty-five UC consecutive outpatients were graded according to clinical,
      endoscopic and histologic activity scores. SpA was diagnosed according to the
      European Spondyloarthropathy Study Group criteria. AD was detected by skin prick
      tests and confirmed by specific provocation tests, while ACD was diagnosed using
      the European standard series of patch tests. Thirty-seven patients' spouses or
      partners served as controls. RESULTS: Fourteen patients and 1 control subject
      showed SpA (P = 0.001). Diagnosis of rhinitis, conjunctivitis or asthma was made
      in 19 patients and in 5 controls (P = 0.004), while ACD was found in 10 and in 4
      (P = 0.17), respectively. In UC, AD coexisted with SpA in 2 cases (P = 0.01), AD
      with ACD in 1 case (P = 0.03) and ACD with SpA in 5 (P = 0.24). CONCLUSIONS:
      Notwithstanding the high frequency of AD and SpA found in UC, the concurrence of
      AD with SpA or ACD is an unusual finding, while SpA and ACD may coexist. These
      data suggest that, in UC, atopy and seronegative arthritis, as well as atopy and
      delayed-type allergy, are strongly polarized conditions tending to mutual
      exclusion. In UC, the presence of AD without SpA or ACD, and of SpA or ACD
      without AD may indicate subgroups of patients in which T-helper-2 cell or T
      helper-1 cell responses predominate.

PMID- 12408521
TI  - Quality of life in patients with inflammatory bowel disease: translation, data
      quality, scaling assumptions, validity, reliability and sensitivity to change of
      the Norwegian version of IBDQ.
AB  - BACKGROUND: The use of quality of life (QoL) questionnaires in clinical medicine
      must be based on instruments that are reliable and valid. The aim of this study
      was to describe the translation of the Inflammatory Bowel Disease Questionnaire
      (IBDQ) into Norwegian, its scaling assumptions and the psychometric properties of
      the translated questionnaire. METHOD: All patients included were recruited from
      an ongoing epidemiological study started in 1990 (the IBSEN trial), based on the
      registration of undiagnosed cases of Crohn disease (CD) or ulcerative colitis
      (UC) in subjects permanently residing in the study area the year before
      registration. At the 5-year follow-up visit in the hospital, all patients between
      18 and 75 years of age were invited to participate in this QoL study, and those
      willing were interviewed and asked to complete the two QoL questionnaires, IBDQ
      and SF-36, on two different occasions separated by 6 months. The IBDQ was tested
      for validity, reliability and responsiveness. RESULTS: In total, 497 patients
      (93%) completed the IBDQ questionnaire at visit 1, and 493 (92%) completed SF-36.
      The mean age was 43.3 years, 48% were female. We found that the Norwegian version
      of the IBDQ (N-IBDQ) consists of five underlying dimensions in contrast to the
      four dimensions previously reported. Psychometric testing of the N-IBDQ indicates
      that the questionnaire is valid, reliable, has a high degree of responsiveness
      and that the results are comparable to those reported from other groups, even
      though our findings are based on a different factorial structure than the
      original McMaster version. CONCLUSION: The N-IBDQ consists of five different
      dimensions in contrast to the four dimensions previously reported. Good item
      internal consistency, validity, reliability and responsiveness were demonstrated.

PMID- 12408522
TI  - Appendectomy in adulthood and the risk of inflammatory bowel diseases.
AB  - BACKGROUND: There is controversy as to whether appendectomy protects against the
      development of ulcerative colitis, but the possible impact of appendectomies
      performed in adulthood has not been systematically investigated. METHODS: We
      conducted a large case-control study based on inpatient records from Veterans
      Affairs hospitals in the United States for the period 1969-96. We identified
      6,172 male patients with ulcerative colitis (age range 19-101 years, mean 57.4
      years) and 4,498 male patients with Crohn disease (age range 18-99 years, mean
      52.9 years). Each of these case patients was individually age- and race-matched
      to five other male veterans without recorded history of inflammatory bowel
      disease. We compared records of prior appendectomies in adulthood for the matched
      case-control sets using conditional logistic regression. RESULTS: Overall, both
      ulcerative colitis (odds ratio (OR) = 1.6, 95% confidence interval (CI): 1.3-2.1)
      and Crohn disease (OR = 2.5, 95% CI: 2.0-3.3) were significantly and positively
      associated with history of appendectomy in adulthood. However, risks were not
      increased at intervals of 15 years or more between appendectomy and inflammatory
      bowel disease (ulcerative colitis: OR = 0.9, 95% CI: 0.4-2.1; Crohn disease: OR =
      1.2. 95% CI: 0.5-2.5). CONCLUSIONS: The elevated risk of inflammatory bowel
      disease, notably Crohn disease, after appendectomy probably reflects differential
      diagnostic difficulties in patients with abdominal pain. Appendectomy carried out
      during adulthood seems not to confer protection against ulcerative colitis.

PMID- 12408523
TI  - The value of routinely performed ultrasonography in patients with Crohn disease.
AB  - BACKGROUND: In active Crohn disease (CD), abdominal ultrasound can demonstrate
      morphological changes in the bowel wall. By contrast, the role of ultrasonography
      in periods with no disease activity has never been evaluated. In this prospective
      study we investigated the outcome of routinely performed abdominal
      ultrasonography in CD patients irrespective of symptoms and disease activity.
      METHODS: 255 consecutive patients with chronic CD (117 M, 138 F, mean age (+/-s)
      38 +/- 14) were evaluated by high-resolution ultrasonography of the bowel wall
      and abdomen. The findings were graded with respect to further diagnostic and/or
      therapeutic implications. In addition, the CD activity index (CDAI) was
      determined. In patients with pathological sonographic findings, complementary
      procedures (e.g. endoscopy, computed tomography, biopsy or operation) were
      performed to validate the suspected diagnosis. RESULTS: In 46/255 (18%) patients
      with CD, the diagnosis of a transmural inflammatory reaction (TMR) with or
      without fistula was made by ultrasonography. In respect of CDAI, 29/46 (63%) of
      these patients were graded as active disease (CDAI > 150) and 17/46 (37%) as
      inactive disease (CDAI < or = 150). Of the 17 patients with a TMR and CDAI < or =
      150, 4 patients revealed interenteric fistula, 7 patients mesenteric or
      perirectal fistula, whereas 6 patients presented with a transmural mesenteric
      inflammatory reaction without fistula. All fistulae were confirmed by
      radiography. Ultrasonography of the remaining abdominal organs revealed
      pathological findings with further diagnostic implications in 25/255 (10%)
      patients and with therapeutic implications in 9/255 (4%) patients. CONCLUSION:
      Routinely performed ultrasonography of the abdomen reveals pathological findings
      with therapeutic implications not only in symptomatic but also in asymptomatic
      patients with CD. It can therefore be recommended as a screening tool for this
      group of patients.

PMID- 12408524
TI  - APC and CTNNB1 mutations in a large series of sporadic colorectal carcinomas
      stratified by the microsatellite instability status.
AB  - BACKGROUND: Adenomatous polyposis coli (APC) and beta-catenin (encoded by CTNNB1)
      are important components in the WNT signalling pathway, a pathway altered in
      nearly all colorectal tumours. Conflicting results are reported on whether APC
      mutations are less common in tumours with a high degree of microsatellite
      instability (MSI-H) than in microsatellite stable (MSS) ones, and whether
      mutations in the regulatory domain of CTNNB1 substitute for APC mutations in the
      MSI-H tumours. METHODS: A consecutive series of 218 primary colorectal
      carcinomas, stratified by MSI status, were analysed for mutations in the APC gene
      (by the protein truncation test) and in the CTNNB1 gene (by single-strand
      conformation polymorphism). RESULTS: APC mutations detected in 66% of the
      patients were significantly more frequent in the MSS and MSI-L (low) tumours than
      in the MSI-H tumour group (P < 0.001). The MSI-H tumours tended to have more
      frameshift mutations than the MSS/MSI-L tumours. The majority of the APC
      mutations were located in the mutation cluster region (MCR). Patients that had
      lost all beta-catenin binding sites of the APC gene showed a shorter survival
      time than patients who retained some or all of these binding sites (P = 0.045).
      Two mutations were found in the CTNNB1 gene, but neither of them was located in
      the regulatory domain in exon 3. CONCLUSION: This study confirms that APC
      mutations are less frequent in MSI-H tumours than in MSS and MSI-L tumours.
      However, CTNNB1 mutations do not substitute for APC mutations in MSI-H tumours in
      these Norwegian patients.

PMID- 12408525
TI  - Human telomerase reverse transcriptase, p53 and Ki-67 expression and apoptosis in
      colorectal serrated adenoma.
AB  - BACKGROUND: Serrated adenoma (SA) has recently been proposed as a distinct
      histological lesion of the colorectum. However, no definite histopathologic
      criteria for SA have been established, and its histogenesis and natural history
      remain unclear. METHODS: We analysed 25 hyperplastic polyps (HPs), 26 low-grade
      SAs (LG-SAs), 32 high-grade SAs (HG-SAs), 18 low-grade tubular adenomas (LG-TAs),
      16 high-grade TAs (HG-TAs) and 20 carcinoma in situ (CIS). To clarify molecular
      features of SA, we used in situ hybridization to examine the expression of human
      telomerase reverse transcriptase (hTERT), immunohistochemistry to examine the
      expressions of p53 and Ki-67, and in situ DNA nick end labeling to detect
      apoptotic cells. RESULTS: The incidence of hTERT expression was 1 (4.0%) of 25
      for HP, 12 (46.2%) of 26 for LG-SA, 18 (56.3%) of 32 for HG-SA, 6 (33.3%) of 18
      for LG-TA, 7 (43.8%) of 16 for HG-TA, 12 (80.0%) of 15 for CIS, respectively. The
      incidence of hTERT expression in SA was significantly higher than that in HP.
      Seventeen (29%) of the 58 SAs were regarded as positive for p53 protein, but none
      of the HPs showed p53 immunoreactivity. Ki-67 labeling index in SA, TA and CIS
      was significantly higher than that in HP. The apoptototic index was not
      significantly different between HP, SA, TA and CIS. In HG-SA, the incidence of
      hTERT expression in p53-positive lesions was significantly higher than that in
      p53-negative lesions. CONCLUSIONS: These results suggest that hTERT and p53
      expression increase in the early stages of carcinogenesis in SA and that SA has a
      malignant transformation similar to that of TA. It may be useful to investigate
      hTERT and p53 expression for differential diagnosis of SA from HP.

PMID- 12408526
TI  - Quality of life after anterior resection versus abdominoperineal extirpation for
      rectal cancer.
AB  - BACKGROUND: Abdominoperineal extirpation has been assumed to put patients at
      higher risk of disruption to quality of life than sphincter-preserving surgery in
      rectal cancer surgery. The aim of this study was to investigate quality of life
      in patients after anterior resection versus abdominoperineal extirpation for
      rectal cancer and to evaluate the psychometrics of the Danish version of a
      symptom-specific Fecal Incontinence Quality of Life Scale. METHODS: Fourteen
      patients undergoing abdominoperineal extirpation and 26 undergoing anterior
      resection. The generic quality of life instrument SF-36 together with a new
      symptom-specific Fecal Incontinence Quality of Life Scale were used. Psychometric
      analysis of the symptom-specific scale was carried out. RESULTS: The only
      significant difference between the two groups was found in the total score of the
      symptom-specific scale in favour of anterior resection (P = 0.02). Psychometric
      evaluation of the symptom-specific fecal incontinence questionnaire proved it
      reliable and valid. CONCLUSIONS: The present study shows that a stoma influences
      quality of life only slightly, while a relatively high anterior resection does
      not. However, a few appropriate newer studies indicate that the cost of spinchter
      preserving techniques in the form of incontinence disturbances may influence the
      quality of life seriously, which should be borne in mind when low anterior
      resection is intended. Further studies in this field are necessary and could
      benefit from use of the Fecal Incontinence Quality of Life Scale, including its
      total score.

PMID- 12408527
TI  - Cholangiocarcinoma in primary sclerosing cholangitis: risk factors and clinical
      presentation.
AB  - BACKGROUND: Primary sclerosing cholangitis (PSC) confers a high risk of
      cholangiocarcinoma (CC) development. Since patients at risk of CC may be selected
      for early liver transplantation, it is a challenge to identify any predisposing
      factors. We compared the presentation and natural history of a large number of
      PSC patients with and without later CC development to identify features
      associated with risk of CC. METHODS: Clinical and laboratory data from
      presentation and follow-up were collected from 394 PSC patients from five
      European countries. The cohort included 48 (12.2%) patients with CC. RESULTS: CC
      was diagnosed within the first year after diagnosis of PSC in 24 (50%) cases and
      in 13 (27%) patients at intended liver transplantation. Jaundice, pruritus,
      abdominal pain and fatigue were significantly more frequent at diagnosis of PSC
      in the group that developed CC, but not after exclusion of cases diagnosed within
      the first year. Inflammatory bowel disease was diagnosed at least 1 year before
      PSC more often among patients with CC development than among those without (90%
      and 65%, respectively: P = 0.001). The duration of inflammatory bowel disease
      before diagnosis of PSC was significantly longer in patients who developed CC
      than in the remaining group (17.4 years and 9.0 years, respectively: P=0.009 in
      multivariate analysis). CONCLUSIONS: A high proportion of CC cases is diagnosed
      within the first year after diagnosis of PSC. A long history of inflammatory
      bowel disease is a risk factor for CC development.

PMID- 12408528
TI  - Benefit of population-based screening for phenotypic hemochromatosis in young
      men.
AB  - BACKGROUND: Hereditary hemochromatosis (HH) is a common genetic disease leading
      to accumulation of iron in the body, most notably in the liver. More men than
      women become clinically ill. The prognosis is excellent if phlebotomy treatment
      is started before liver cirrhosis develops. Screening has been recommended, but
      the benefit of population-based screening has never been shown in a randomized
      clinical trial. In this article, we estimate the benefit of screening young men,
      using a theoretical model. METHODS: A phenotypic screening scenario was modelled
      using a decision tree. Gain of quality-adjusted life-years was used as a measure
      of benefit, and estimated using Markov processes. Data on the accuracy of the
      screening tests, the prevalence of HH and the risk of liver cirrhosis were mainly
      derived from a cross-sectional study on the prevalence and morbidity of HH in
      30509 men. Data on the excess mortality of cirrhosis were taken from relevant
      literature. Sensitivity analysis was done for important variables. RESULTS:
      Assuming basal case values for variables, screening a cohort of 1000 men aged 30
      years for phenotypic HH would gain about 8 quality-adjusted life-years, compared
      to awaiting symptomatic disease. Based on actual costs of our cross-sectional
      study, the screening cost was US$250 per quality-adjusted life-year gained. The
      prevalence of phenotypic HH, the excess mortality of liver cirrhosis, the quality
      of life in non-cirrhotic HH patients, and the fractions of patients compliant
      with treatment were the most important variables in the sensitivity analysis.
      CONCLUSION: Incorporating screening for phenotypic HH in health survey programmes
      for young men may be worthwhile.

PMID- 12408529
TI  - Influence of the spleen on portal haemodynamics: a non-invasive study with
      Doppler ultrasound in chronic liver disease and haematological disorders.
AB  - BACKGROUND: Splanchnic haemodynamic parameters for the differential diagnosis of
      splenomegalies of different origins are still suboptimal and the role of spleen
      enlargement in cirrhosis remains controversial. In an attempt to elucidate these
      questions, we assessed splanchnic haemodynamics in chronic liver diseases and
      various other disorders with splenomegaly. METHODS: Study groups comprised: (i)
      patients with chronic liver disease (89 with cirrhosis, 35 with chronic
      hepatitis), (ii) patients with splenomegaly without relevant portal hypertension
      (14 with haematological splenomegaly and 25 liver transplant recipients without
      complications), (iii) 15 patients with arterial hypertension, (iv) 22 healthy
      controls. In all subjects, spleen size, portal flow parameters and splenic artery
      resistance index were measured using duplex-Doppler ultrasound. RESULTS: Splenic
      artery resistance index was significantly and selectively increased in patients
      with cirrhosis (0.63, whereas all other group means ranged between 0.53 and 0.56;
      P < 0.01). Portal flow velocity was significantly decreased in cirrhosis (P <
      0.01). The combination of these two parameters provided an accuracy of 87.5% in
      distinguishing portal hypertensive from haematological splenomegaly. In patients
      with cirrhosis, the degree of spleen enlargement was positively correlated with
      increasing portal flow volume, portal vein diameter and variceal size, whereas
      splenic resistance index and portal velocity did not differ in connection with
      spleen size. CONCLUSIONS: Splenoportal Doppler sonography provides specific
      findings in cirrhosis and may therefore be a useful tool in differentiating
      between splenomegaly of portal hypertensive or haematological origin. In patients
      with cirrhosis, the presence of splenomegaly is associated with the presence of
      larger oesophageal varices.

PMID- 12408530
TI  - Viral kinetics and treatment response in patients with hepatitis C during
      induction and standard interferon therapy in combination with ribavirin.
AB  - BACKGROUND: The early decline of hepatitis C virus (HCV) RNA levels during
      therapy may predict the outcome and can be utilized to improve treatment
      regimens. We studied the HCV RNA levels during induction and standard interferon
      (IFN) and ribavirin treatment. METHODS: Patients received IFN 3 MU daily for 14
      days followed by 3 MU three times a week (induction group; n = 10), or IFN 3 MU
      three times a week from start (standard group; n = 21), in combination with
      ribavirin 1000-1200 mg/day. HCV RNA was quantified day 0, 1, 2, 3, 7, 14, 28, 56
      and 84 during treatment, and tested qualitatively at the end of treatment and at
      follow-up. RESULTS: The initial viral load decline was more pronounced in the
      induction group, and in patients infected with genotype non-1. The sustained
      response rate was not significantly different between the study groups. At day 1,
      the mean viral load decline from baseline was significantly greater in patients
      who became sustained responders than in those who became non-responders; 1.4 log
      (96%) versus 0.3 log (55%) (P < 0.05). All sustained responders had a viral load
      decline of at least 0.7 log (79%) after the first IFN dose. CONCLUSIONS: Our
      short-term induction treatment did not improve the long-term treatment outcome
      significantly, although a trend was seen. An absent or low initial viral load
      decline can be used to predict non-response in the individual patient.

PMID- 12408531
TI  - Liver fibrosis: what's the beginning of autonomic deficit?

PMID- 12408532
TI  - Presentation of an unusual benign liver tumor: primary hepatic glomangioma.
AB  - Glomus organs are small arteriovenous anastomoses chiefly responsible for
      thermoregulation of the distal portion of the extremities. Glomangiomas are
      benign tumors of these bodies. They occur preferentially in the fingers and toes,
      but some case reports describe primary glomangiomas in the respiratory or
      gastrointestinal tract and genitals. To date, no glomangiomas of the liver have
      been reported. We report on a 61-year-old patient in whom routine ultrasound
      disclosed a subcapsular well-defined mass in the liver. Further imaging showed
      that the mass did not correspond to any of the usual liver tumors. Biopsy finally
      revealed it to be a primary glomangioma of the liver. Clinically, there was lack
      of appetite and weight loss over a period of several months. Owing to the
      possibility of malignant transformation of glomangiomas, as described in the
      literature, the tumor was excised under existing clinical symptoms and continued
      slow growth. Further histological evaluation of the tumor did not reveal
      malignancy. Primary glomangioma of the liver is a new differential diagnosis for
      benign liver neoplasms. Because there is a potential for malignant
      transformation, the existence of clinical symptoms and continuing growth are
      indications for resection.

PMID- 12408533
TI  - Gender selection: cultural and religious perspectives.
AB  - OBJECTIVE: To review the current developments in the field of preconceptual sex
      selection and to discuss the cultural and religious perspectives as that
      accompany the scientific progress. DESIGN: A survey of the major publications in
      Judaism, Christianity and Islam regarding the issue of gender selection.
      Examination of current methods of preconceptual gender selection revealed that in
      vivo methods such as timing of intercourse, the use of ovulation induction
      medications, and artificial insemination do not appear to affect the sex ratio to
      a clinically significant degree. In vitro separation of X- and Y-bearing
      spermatozoa by gradient techniques have been reported to alter significantly the
      sex ratio at birth. However, these trials were not controlled, and molecular
      biological techniques could not validate that these methods indeed change the Y-
      to X bearing spermatozoa ratio sufficiently for clinical use. Nevertheless recent
      scientific advances have made highly reliable preconceptual sex selection
      possible by using preimplantation diagnosis (PGD) or sperm separation by flow
      cytometry combined with AIH or IVF. At present, these methods have been used to
      avoid sex-linked disorders. Both involve the invasive procedure of IVF and thus
      are held by most as inappropriate for nonmedical indications. However,
      improvement in flow cytometry output of sexed spermatozoa might provide in the
      near future sufficient sorted gametes for artificial insemination. It may be that
      in the near future, an improvement in flow cytometry output of sexed spermatozoa
      will provide sufficient sorted gametes for artificial insemination. In such a
      case, the medical community will be forced to take a stand, whether this reliable
      noninvasive method of sexing will be allowed for social purposes and even if the
      practice of PGD should be allowed for nonmedical indications. CONCLUSION: The
      requirement for a man to procreate by having a minimum of two children-a boy and
      a girl-is obligatory according to Jewish law. According to both schools, Beit
      Shamai and Beit Hillel, in order to fulfill the obligation of procreation at
      least one son is required. Therefore the application of sex preselection for
      nonmedical indications may by of practical importance using the method of sperm
      separation or sex selection of pre-embryo by PGD. According to Christian view,
      especially the one of the Catholic Church, gender preselection even for medical
      indications is forbidden. Islamic legal viewpoint is that fetal sex selection is
      lawful when it is practiced on an individual basis, to fulfill the wish of a
      married couple to have a boy or a girl through available medical means.

PMID- 12408534
TI  - The 50 million missing women.
AB  - The epidemic of gender selection is ravaging countries like India & China.
      Approximately fifty million women are "missing" in the Indian population.
      Generally three principle causes are given: female infanticide, better food and
      health care for boys and maternal death at childbirth. Prenatal sex determination
      and the abortion of female fetuses threatens to skew the sex ratio to new highs.
      Estimates of the number of female fetuses being destroyed every year in India
      vary from two million to five million. This review from India attempts to
      summarize all the currently available methods of sex selection and also
      highlights the current medical practice regards the subject in south-east Asia.

PMID- 12408535
TI  - Gender selection: is there a European view?
AB  - There is no European view on gender selection. Conclusions of the ESHRE Ethics
      Task force are reported.

PMID- 12408536
TI  - Ethical considerations on indications for gender selection in Japan.
AB  - Gender selection is a matter of great concern to a cohort of parents. To what
      extent the methods available are ethically acceptable at present differs
      depending upon the society and times the couples live in. In the present
      communication, the current situation in Japan in use for gender selection by
      empirical methods without sperm separation, conventional methods with sperm
      separation and preimplantation genetic diagnosis of human embryos has been
      provided and considered in the light of human dignity as well as human right.

PMID- 12408537
TI  - Gender selection in China: its meanings and implications.
AB  - With the advancement of assisted reproduction technologies, people are offered
      wider choices to choose the gender of their offspring and to construct 'ideal
      typed' families with specific gender structure. Gender selection is welcomed by
      many societies with gender-specific preference, especially those patriarchal
      societies such as Chinese communities. It is not only a medical procedure but
      also a social orientation, which reveals much of the underlying preference
      towards gender. This paper explores the cultural dimensions to gender selection
      and its psychosocial meanings and implications in Chinese societies, especially
      after the establishment of One Child Policy in China. Problems associated with
      son preference in the culture with strong gender stereotyping are addressed. We
      believe that gender selection for social reasons should not be allowed since
      undesirable outcomes will be resulted under such strict population control
      program.

PMID- 12408538
TI  - Is any form of gender selection ethical?
AB  - In later years, sex selection has become of importance for prevention of X-linked
      diseases in families at risk. There is today a potential to perform sperm
      selection before fertilization by taking advantage of the chromosomal heterogamy
      of spermatozoa, and before implantation by preimplantation genetic diagnosis
      (PGD). The methods of sex determination by separating sperrmatozoa are, in our
      opinion, still not safe enough for routine clinical use. Apart from the technical
      problems and possible associated risks, which first must be better evaluated, the
      most critical questions are ethical or legal. We support the use of sex selection
      by PGD in X-linked severe disease, but due to the potential risks of misuse, we
      are not prepared to support a more liberal attitude as long as the discriminated
      sex in nearly all parts of the world are women.

PMID- 12408539
TI  - Preimplantation genetic diagnosis for elective sex selection, the IVF market
      economy, and the child--another long day's journey into night?
AB  - The promise of medical innovation has long evoked social commentary, particularly
      when personal reproductive autonomy may be involved. Development of the oral
      contraceptive, effective and safe surgical sterilization, and later IVF and ICSI
      are among the revolutionary developments where the initial reactions were dubious
      but were accorded mainstream status with sufficient clinical experience. In each
      instance, debate about the moral and social implications of these treatments
      accompanied their introduction into the medical marketplace. This pattern appears
      to be repeating itself in connection with the use of preimplantation genetic
      diagnosis (PGD) for elective sex selection of human embryos. As with prior
      challenges in reproductive medicine, the development of meaningful "guidelines"
      for this latest controversy has proven to be a contentious task. Indeed, the
      progression of ethics committee reports from the American Society for
      Reproductive Medicine seems to echo the ambivalence within society at large
      regarding this issue. In this report, we chronicle sex selection claims based on
      sperm sorting, and describe how flow cytometry and especially PGD have
      facilitated this selection at the gamete and embryo stage, respectively. In doing
      so, we also explore market forces and practitioner considerations associated with
      the application of PGD for this; related ethical issues with particular emphasis
      on the progeny derived from such treatment are also reviewed.

PMID- 12408540
TI  - Is gender selection an appropriate use of medical resources?
AB  - Gender selection by PGD is an appropriate use of medical resources. Children
      borne through PGD for gender determination would be welcome and would come into a
      couple's life at a planned, opportune time. If the practice were made more
      available through insurance coverage, the size and makeup of families could
      become a matter of choice rather than chance for couples favoring this approach.

PMID- 12408541
TI  - Preimplantation social sexing: a problem of proportionality and decision making.
AB  - Sex selection by sperm sorting seems ethically acceptable for social reasons. Sex
      selection after preimplantation embryo sexing results in the use of non-trivial
      means (discard healthy embryos) to fulfill a trivial desire. In this case,
      proportionality between means and ends is missing, and cultural reasons should
      not be accepted to justify its use.

PMID- 12408543
TI  - Analysis of sex chromosomes in preimplantation genetic diagnosis for X-chromosome
      linked disorders.
AB  - Preimplantation genetic diagnosis (PGD) is diagnostic tool to avoid inheritance
      of genetic disease by transferring unaffected embryos. Recently, PCR and FISH
      have been mainly applied to the diagnosis of single gene disorders and
      chromosomal abnormalities, respectively. Since with PGD, only a few cells are
      available for genetic tests, both gene and chromosomes analysis have to be
      obtained from the same, limited material. Cell recycling makes it possible to
      obtain the information on genes as well as chromosomes from the same cells.
      Therefore cell recycling is an acceptable strategy where in PGD targets large
      proportions of embryos severe chromosomal abnormalities. The responsible genes of
      the X-linked disorder and numerical abnormalities of sex chromosomes should be
      analyzed simultaneously. Gender information is definitely useful because only
      male affected embryos should be avoided for transfer.

PMID- 12408542
TI  - Gender selection: ethical, scientific, legal, and practical issues.
AB  - PURPOSE: This work offers an overview of the technology available and assisted
      reproductive technology (ART) practitioner attitudes to human reproductive sex
      preselection in either sperm with the use of flow cytometry (FC) or in embryos by
      means of preimplantational genetic diagnose (PGD) together with an analysis of
      Spanish legal environment. METHODS: A review of the legal, ethical and technical
      literature of the methods to select the sex in the offspring is performed.
      RESULTS: Sex selection in humans has different utilities to be employed depending
      on each country's law. Moreover, different ethical concerns are raised depending
      on the type of sex selection, in sperm or embryos. Both methodologies to pre
      select the sex are trustworthy, with a high predictive power in the determination
      of the sex, but nevertheless, PGD is better than FC selection in this aspect.
      CONCLUSIONS: After a careful analysis of ethical, legal, and scientific features
      of gender selection, FC combined with PGD appears to be the most acceptable way
      to select the sex of the progeny whatever the circumstances are.

PMID- 12408544
TI  - Give me your tired, your poor, your huddled masses...

PMID- 12408545
TI  - The relationship between corneal oxygen tension and hypoxic corneal edema.
AB  - PURPOSE: We sought to develop a direct, noninvasive measurement of tear oxygen
      tension behind soft contact lenses, and to use the tear oxygen tension data to
      determine if subjects with greater comeal oxygen consumption experience more
      comeal edema under hypoxic conditions. The relationship between tear oxygen
      tension and comeal thickness was also analyzed to determine if thicker comeas
      have higher metabolic rates. METHODS: Tear oxygen tension measurement was based
      on the quenching of a phosphorescent dye by oxygen. By coating a soft contact
      lens with the dye and placing it in the eye, the rate of decay of phosphorescence
      could be measured and the tear oxygen tension calculated. Corneal oxygen
      consumption could then be calculated from the tear oxygen tension. Central
      corneal swelling was measured after 3 hours of hypoxia induced by contact lens
      wear under closed-eye conditions. RESULTS: Seven right eyes of seven subjects
      were tested. Baseline central corneal thickness ranged from 517 to 616 microns.
      After 3 hours of hypoxia, central corneal swelling ranged from 24.5 to 74.3
      microns (3.9% to 13.4%). Steady-state open-eye tear PO2 behind the lens varied
      between 42.7 and 67.1 torr Pearson correlation suggested possible inverse
      relationship between open-eye tear oxygen tension and central comeal swelling
      during hypoxia (r = -0.711, p = 0.0734). CONCLUSIONS: Phosphorescent-based
      measurements provided a measure of tear oxygen tension in human beings. Low tear
      film oxygen tensions (high corneal metabolic demand) appeared to predict greater
      amounts of swelling in subjects' corneas. No relation was found between corneal
      thickness and tear oxygen tension, suggesting that epithelial and endothelial
      metabolic rates are more important than stromal thickness in determination of
      comeal oxygen demand.

PMID- 12408546
TI  - Enhancing RGP contact lens performance: comparing back surface options.
AB  - BACKGROUND: In some cases, rigid gas-permeable (RGP) contact lenses may be the
      best--or only--means of refractive correction. High Dk RGP materials have
      markedly reduced hypoxia under those lenses. With aspheric lens back surface
      designs, post-lens circulation may be enhanced as well by maximizing the
      provision of nutrients and the clearance of metabolic by-products, toxins, and
      debris, while minimizing the risk of lens binding. METHODS: Performances of four
      aspheric back surface RGP designs were compared with a spherical optic zone and
      peripheral curve back surface reference design. Oxygen uptake rates were measured
      for each of 40 wearing combinations (five lens designs fitted to each of eight
      eyes) under non-blink and blink conditions for their effectiveness in reduction
      of post-lens hypoxia. Hypoxic reductions with blinking were scaled in exchange
      efficiency (EE) units, and used as relative indicators of post-lens tear
      exchange. RESULTS: Combined exchange efficiency index (EE) scores (averaged
      responses across all eight eyes) for each of the five lens back surface designs
      ranged from a best overall performance of +13.9 EE units down to only +2.5 EE
      units, with the spherical reference design averaging +8.9 EE units. Tear pump
      efficiency of each of the eight eyes (averaged responses across all five lens
      designs) ranged from a high of +12.3 EE units down to -9.8 EE units (i.e., worse
      than the non-blink condition of 0 EE units). Among the 40 eye-lens back surface
      design combinations studied here, the highest exchange efficiency score
      registered was +28.4 EE units, the lowest being -13.8 EE units. CONCLUSIONS:
      Aspheric lens back surface and/or peripheral curve designs were found to vary
      significantly in their post-lens exchange efficiency performances, but no
      "universal problem-solver" design was found among the five we investigated.

PMID- 12408547
TI  - A cost analysis of the prostaglandin analogs.
AB  - BACKGROUND: The efficacy, ease of use, and favorable side effect profile has
      increased the popularity of the prostaglandin analogs for topical treatment of a
      variety of glaucoma types. We undertook a cost analysis study of all the
      prostaglandin analogs. METHODS: Mean number of drops per bottle, mean drop
      volume, total bottle volume, percent overfill per bottle, mean national bottle
      cost, daily cost of therapy, and yearly cost of therapy were calculated for all
      four of the prostaglandin analogs. RESULTS: Yearly cost of monocular therapy was
      $230.68 for latanoprost, $219.37 for travoprost, $211.34 for bimatoprost, and
      $178.85 for unoprostone. Unoprostone was by far the least expensive of the
      prostaglandin analogs tested. Bimatoprost, latanoprost, and travoprost were
      essentially the same price, varying in yearly cost to the patient by less than
      twenty dollars. Bimatoprost had the most expensive bottle price, unoprostone the
      least expensive. Bimatoprost also had the largest percentage of overfill from
      labeled volume. Unoprostone had the most monocular treatment days per bottle.
      CONCLUSION: Cost, in addition to efficacy and side affect profile, should be
      considered when determining which prostaglandin analog to prescribe to glaucoma
      patients.

PMID- 12408548
TI  - Hypotonous maculopathy and normal visual acuity secondary to post-traumatic
      cyclodialysis cleft.
AB  - BACKGROUND: Post-traumatic cyclodialysis clefts commonly lead to profound visual
      loss secondary to hypotonous maculopathy. Current literature regarding
      cyclodialysis clefts definitively outlines the management of visual loss
      resulting from hypotonous maculopathy. Because hypotonous maculopathy with normal
      visual acuity is rarely reported, management is less well defined. Management
      guidelines for individuals with and without visual loss secondary to hypotonous
      maculopathy are reviewed. CASE REPORT: A 32-year-old man came to us with symptoms
      of blur and glare in his left eye following airbag trauma two-and-a-half years
      earlier Best-corrected visual acuities measured 20/15 O.D. and O.S. A small iris
      sphincter tear was noted inferiorly and gonioscopic evaluation revealed a
      corresponding cyclodialysis cleft O.S. Intraocular pressures measured 10 mmHg
      O.D. and 2 mmHg O.S. Funduscopic evaluation of the left eye reveal optic disk
      edema, chorioretinal folds within the papillomacular bundle, venous tortuosity,
      and peripheral hemorrhages. Anticholinergic therapeutic management for hypotony
      was unsuccessful. Surgical intervention was not recommended. Visual function
      remains unchanged. CONCLUSION: Identification of a cyclodialysis cleft is
      imperative after blunt trauma. Therapeutic and/or surgical intervention remains
      the treatment of choice when hypotonous maculopathy affects visual outcome.
      Conservative management may be indicated in those cases in which visual function
      is not impaired.

PMID- 12408549
TI  - An unusual case of stabbing eye pain: a case report and review of trigeminal
      neuralgia.
AB  - BACKGROUND: Trigeminal neuralgia is a painful neurological disorder that affects
      one or more of the divisions of the trigeminal nerve. It is characterized by
      brief attacks of stabbing pain that can be excruciating. These attacks may be
      triggered by a light touch, shaving, or even eating. There has been much debate
      over the exact etiology of trigeminal neuralgia. One of the main theories is
      vascular compression of the trigeminal nerve as it leaves the brainstem. Another
      theory suggests that intracranial tumors--particularly those located in the
      posterior fossa--may be the cause. Trigeminal neuralgia is also associated with
      multiple sclerosis. CASE REPORT AND REVIEW: A 79-year-old man came to the eye
      clinic with signs and symptoms consistent with trigeminal neuralgia involving the
      ophthalmic and maxillary divisions of the nerve. A neurological evaluation
      confirmed the diagnosis, and proper medical treatment was subsequently
      implemented to relieve his pain. CONCLUSION: Patients who manifest symptoms
      consistent with trigeminal neuralgia should be referred for a neurological
      evaluation, including MRI. With the proper medical and/or surgical treatment, the
      quality of life of these patients can increase dramatically.

PMID- 12408550
TI  - The modified HIPAA Privacy Rule. Health Insurance Portability and Accountability
      Act.

PMID- 12408552
TI  - Guide helps ODs find answers on employment, affiliation.

PMID- 12408551
TI  - A simple approach to developing business strategy.

PMID- 12408553
TI  - How to offer the best UV protection for patients' eyes.

PMID- 12408554
TI  - National Diabetes Month.

PMID- 12408555
TI  - BCA-225 immunostain: is it of value in liver fine needle aspiration?
AB  - OBJECTIVE: To determine the utility of BCA-225 immunostain in differentiating
      hepatocellular carcinoma (HCC) from other malignant tumors in liverfine needle
      aspiration specimens. STUDY DESIGN: Cell block materialfrom 87fine needle
      aspirates of liver lesions, including 25 HCCs, 9 neuroendocrine carcinomas, 12
      adenocarcinomas metastatic from the colon, 19 other metastatic adenocarcinomas,
      13 other metastatic tumors and 2 cholangiocarcinomas, were immunostained with BCA
      225 antibody using both the EnVision avidin-biotin method (Dako U.S.A.,
      Carpinteria, California, U.S.A.), and the traditional avidin-biotin method,
      without antigen retrieval. Three independent observers evaluated the cases, and a
      consensus was reached. RESULTS: Strong immunostaining for BCA-225 in at least 10%
      of malignant cells was considered positive. Two of 25 HCCs, 9 of 19
      adenocarcinoma metastases, 1 of 9 neuroendocrine carcinomas, 4 of 13 other
      metastases and 1 of 2 cholangiocarcinomas were positive. No colon metastases were
      considered positive. CONCLUSION: BCA-225 may help exclude the diagnoses of
      metastatic colon adenocarcinoma, neuroendocrine carcinoma and well- to moderately
      differentiated HCC in this cytologic setting.

PMID- 12408556
TI  - Prognostic role of natural killer cells in pediatric mixed cellularity and
      nodular sclerosing Hodgkin's disease.
AB  - OBJECTIVE: To study natural killer cells' spontaneous cytotoxic capacity against
      tumor cells and their prognostic significance in classical Hodgkin's disease.
      STUDY DESIGN: Thirty-eight pediatric mixed cellularity and nodular sclerosing
      Hodgkin's disease patients were included in the study. Immunohistochemical
      staining was performed for natural killer cells in the background using the
      monoclonal antibody CD57 in serial sections of B5-formalin-fixed, paraffin
      embedded tissue blocks. CD57-positive cells were counted with an immersion
      objective among 5,000 cells on representative areas of the tumors. The degree of
      natural killer cells was classified as low (<150 cells) or high (> or = 150
      cells). Multivariate regression analysis was performed to determine the
      differences between patients with and without relapse. RESULT: The mean of CD57
      positive cell numberfor all the cases was 173.42 +/- 117.34 (range, 20-500). CD57
      positive cells were high in 21 cases and low in 17. The mean of CD57-positive
      cell numbers was 191.85 +/- 115.33 in the disease-free group and 84.44 +/- 57.90
      in the relapsing group. Log rank analysis showed statistical significance between
      event-free survival and number of CD57-positive cells (P = .0207). CONCLUSION: In
      multivariate analysis, CD57 expression proved to be a prognostic factor
      independent from otherfactors. As a result, CD57 expression by background natural
      killer cells may be used as a prognostic parameter in mixed cellularity and
      nodular sclerosing Hodgkin's disease.

PMID- 12408557
TI  - Prognostic value of p53 overexpression in head and neck carcinomas: a pilot
      study.
AB  - OBJECTIVE: To correlate p53 overexpression in squamous cell carcinoma of the head
      and neck region with the outcome of treatment. STUDY DESIGN: Twenty-five biopsy
      proven squamous cell carcinomas of the head and neck region, locally advanced and
      untreated, were studied. Before treatment, all patients underwent fine needle
      aspiration from primary and/or metastatic lesions. Smears were prepared from the
      aspirate for immunostaining, and p53 overexpression was measured
      semiquantitatively. All patients received a radical dosage of radiation
      equivalent to 60 Gy for 6 weeks in 30 fractions from a 6-MV linear accelerator.
      Local-regional disease control was studied, and the mean follow-up duration was
      one year. The pretreatment values of p53 overexpression were correlated with the
      outcome of treatment. RESULTS: Overexpression of p53 was found in 36% patients.
      At the end of 1 year, 6/9 patients showing overexpression were disease free as
      compared to 5/16 patients without overexpression. The difference was not
      significant (chi2 test, P>.05). CONCLUSION: Response to radiation therapy is not
      dependent on p53 overexpression in squamous cell carcinoma of the head and neck
      region. However, this was only a pilot study, and a large number of cases are
      needed to establish the prognostic value of p53 overexpression in locally
      advanced head and neck squamous cell carcinoma.

PMID- 12408558
TI  - Machine scoring of Her2/neu immunohistochemical stains.
AB  - OBJECTIVE: To establish the feasibility of a machine scoring method for her2/neu
      immunohistochemistry in samples of breast carcinoma. STUDY DESIGN: A total of 65
      consecutive cases of breast carcinoma with immunohistochemical stainingfor
      her2/neu by the Herceptest (Dako Corp., Carpinteria, California, U.S.A.) method
      (DAB chromogen with hematoxylin counterstain) were analyzed using an Extended
      Slide Wizard (Tripath Imaging, Inc., Burlington, North Carolina, U.S.A.)
      workstation running prototype software. Representative fields of view from the
      positive control, negative control and up to 10 fields from the stained tumor
      sample were captured interactively with a phased alternating line 3 CCD color
      camera. To determine the amount of specific membrane staining, chromogen
      separation of nuclear counterstain and membrane-positive stain was performed
      based on their respective absorption coefficients in the three color channels.
      The amount of specific membrane staining was scored based on a training set
      covering the rangefrom 0 to 3 + staining scores according to Dako. Manual scores
      of 2 + were tested for amplification by fluorescence in situ hybridization.
      RESULTS: The automated scoring results correlated highly with the manual scores
      obtained per the Herceptest (Dako) instructions (R2>.92). The results were
      obtained in real time in the interactive mode. CONCLUSION: Machine scoring of
      immunohistochemical stains is practical, rapid and inherently reproducible,
      especially for samples with 1+ and 2+ manual scores.

PMID- 12408559
TI  - Pathobiology of testicular germ cell tumors: views and news.
AB  - Human germ cell tumors (GCTs) are a heterogeneous group of neoplasms. They can
      occur in different anatomic locations, predominantly in the gonads (both ovary
      and testis) and in the midline of the body, including the retroperitoneal,
      mediastinal and hypothalamus/pineal gland regions. This distribution has been
      related to the migration routefollowed by primordial germ cells from the yolk sac
      to the genital ridge. The clinical behavior of these tumors depends on the sex of
      the patient, the age at clinical presentation and the histology of the tumor,
      Within the testis, three groups of GCTs can be distinguished; (I) yolk sac tumors
      and teratomas of neonates and infants; (II) seminomas and nonseminomas of
      adolescents and adults, the so-called testicular germ cell tumors; and (III)
      spermatocytic seminomas. This review discusses the histology, epidemiology and
      chromosomal constitution of GCT, in particular of the seminomas and nonseminomas
      of the adult testis, including their precursor, carcinoma in situ. In addition,
      the available data on the molecular basis of treatment sensitivity and resistance
      of GCT are reviewed.

PMID- 12408560
TI  - An objective measure of architectural complexity and proliferative index in
      Gleason pattern 3 prostate cancer.
AB  - OBJECTIVE: To objectively characterize the architectural spectrum of Gleason
      pattern 3 prostate cancer (PCA) in a biologically meaningful manner. STUDY
      DESIGN: We define an objective architectural feature of PCA, "pinch point
      density" (PPD), and explore its relationship to proliferative index (PI). A pinch
      point (PP) is a site where the epithelium of two neighboring glandular structures
      is contiguous in one histologic section but not in an adjacent serial section.
      Seventeen radical prostatectomy specimens with areas of pure Gleason pattern 3
      were studied. PPD was measured with computer aid using digital images of serial
      sections. PI was measured by computer-aided counting of Ki-67-positive cells.
      RESULTS: PPD correlated inversely with PI (PPD vs. log [PI], P < .004).
      Characteristics not significantly correlated with PI included total number of
      malignant glands, PP per gland and total number of malignant cells. Subjectively,
      tumors with high PPD and low PI tended to contain a larger number of smaller
      glands as compared to tumors with low PPD and high PI. This impression was
      confirmed analytically. CONCLUSION: PPD is an objective architectural feature of
      possible biologic significance. This is an early step toward identifying
      objective features of growth pattern in Gleason pattern 3 PCA that may be
      clinically meaningful.

PMID- 12408561
TI  - Color image analysis of cervical neoplasia using RGB computer color
      specification.
AB  - OBJECTIVE: To establish quantitative color image analysis for cytology, red,
      green and blue (RGB) color specification was applied to Papanicolaou-stained
      cervical smears. STUDY DESIGN: Cell samples used in this study was those from 300
      cervical specimens. We analyzed the color tone of nuclei and cytoplasm of the
      squamous cells in the cervical smear by means of computer image analysis.
      RESULTS: Papanicolaou stained nuclei displayed basophilic blue to purple. When
      they were hyperchromatic and deeply stained, B and G values decreased in value.
      The RGB values of cytoplasm and nuclei decreased significantly (P < .01) as their
      degree of cellular atypia increased. CONCLUSION: Using RGB color specification to
      analyze Papanicolaou-stained cervical smears, a significant difference was
      perceived in the nucleus and cytoplasm between different groups of squamous
      cells, from normal, dysplastic and squamous cell carcinoma. These findings may
      help to establish automated cytology.

PMID- 12408562
TI  - Distribution of injected MRI contrast agents in mouse livers studied by confocal
      and SIMS microscopy.
AB  - OBJECTIVE: To localize magnetic resonance imaging (MRI) contrast agents injected
      intravenously into mouse livers. STUDY DESIGN: Parallel studies were performed on
      fluorescent europium and nonfluorescent, paramagnetic gadolinium and on a product
      combining nanoparticles of Fe and Texas Red to obtain combined information on the
      distribution of these molecules inside the liver. The distribution of different
      superparamagnetic iron oxides was also studied because the size of these new
      compounds is not always convenientfor microcirculation studies. RESULTS: Europium
      and Texas Red can be detected by confocal microscopy. Europium, iron and
      gadolinium can be detected by secondary ion mass spectrometry (SIMS) microscopy.
      Studies confirmed the complementarity of both microscopies. They also confirmed
      the possibility of using europium as a model of gadolinium to analyze thefate of
      MRI contrast agents. CONCLUSION: The methodology can be used on mice injected
      intravenously and analyzed by confocal and SIMS microscopy to localize MRI
      contrast agents inside cellular and tissue specimens of mice.

PMID- 12408563
TI  - A possible new principle for adjuvant treatment of cancer in humans revealed by
      image analysis cytology.

PMID- 12408564
TI  - The role of biological research in supporting policy needs.
AB  - Within the UK, the Department for Environment, Food and Rural Affairs (DEFRA) is
      one of several government departments which undertakes research in support of its
      policy aims. For example, DEFRA has responsibility for licensing the deposit of
      materials in the sea in order to protect the environment, public health and
      prevent interference with other uses of the sea. This includes assessment of
      pollutant responses in marine organisms. The objectives include assessment of the
      sub-lethal effect that pollutants have at the cellular, organ and individual
      level, for example in normal genetic, behavioural and reproductive activity and
      extrapolation of the potential impact of pollutants to populations. This work
      helps DEFRA to establish whether individually or in combination, pollutants have
      an adverse effect on the environment. This paper gives some examples of the
      research undertaken and demonstrates how biological research can provide cost
      effective solutions to analytical problems and an opportunity to predict the way
      in which proposed disposal operations may have an impact on the marine
      environment. The way such research may influence policy is also discussed.

PMID- 12408565
TI  - Recovery of polluted ecosystems: the case for long-term studies.
AB  - Recovery of marine ecosystems from pollution has tended to receive less attention
      than the study of new or continuing impacts, but such studies are important in
      charting recovery from acute incidents and following legislation to deal with
      chronic contamination. Recovery is inevitably a long-term process, and where such
      studies have been made they are often too short-lived. Interest quickly wanes
      following an acute incident and governmental bodies rapidly switch to new
      legislative priorities for chronic inputs. We review three case studies: recovery
      of dogwhelk populations after local extinction by tributyl tin leachates from
      anti-fouling paints; recovery of rocky shore communities from oil spills; and
      recovery of estuarine ecosystems from industrial and urban development. We then
      make some generalisations about recovery processes before making a plea for long
      term studies of polluted areas.

PMID- 12408566
TI  - Assessing the impact of pollution on aquatic systems at a global and regional
      level.
AB  - In developing a methodology for the ongoing Global International Waters
      Assessment, major gaps have become apparent in our ability to make comparative
      assessments of pollution. A pragmatic impacts scoping methodology has been
      developed and tested. A more effective assessment protocol however, requires a
      better knowledge of the relationship between pollution sources and biological
      effects with less reliance on chemical monitoring.

PMID- 12408567
TI  - Implications from a field study regarding the relationship between polycyclic
      aromatic hydrocarbons and glutathione S-transferase activity in mussels.
AB  - An aluminium smelter on the west coast of Scotland discharges an aqueous effluent
      containing polycyclic aromatic hydrocarbons (PAHs) at the head of Loch Leven. The
      loch also supports two mussel (Mytilus edulis) farms. Data are presented on
      burdens of PAHs in the soft tissues of mussels and the effect of these
      contaminants on glutathione S-transferase (GST) activity in mussel
      hepatopancreas. GST activity is shown to be correlated with total PAH burden and
      also with the concentrations of certain individual PAHs. These field data show
      that high molecular weight PAHs are closely correlated to GST activity, whereas
      low molecular weight PAHs are not. This suggests that 5- and 6-ring PAHs have a
      more pronounced role than 2- to 4-ring compounds in inducing GST activity in
      mussels from Loch Leven. It is proposed that it may be more appropriate to link
      GST activity with 5- and 6-ring compounds only, rather than with the total PAH
      burden.

PMID- 12408568
TI  - Effects of three fungicides alone and in combination on glutathione S-transferase
      activity (GST) and cytochrome P-450 (CYP 1A1) in the liver and gill of brown
      trout (Salmo trutta).
AB  - In order to evaluate the gill glutathione S-transferase (GST) activity as a
      biomarker of effect of fungicide exposure in juvenile brown trout (Salmo trutta),
      the fungicides propiconazole [(R,S)-1-[2-(2,4-diclophenyl)-4-propyl-1,3-dioolan-2
      ylmetyl]-1H-1,2,4-triazole] and fenpropimorph [(+/-)-cis-4-[3-(4-tert
      butylphenyl)-2-metyl propyl]-2,6 dimetylmorfolinc] were administrated in the
      water separately and together in a static system (80 microg/l for each pesticide)
      for 5 days. The combined fungicides gave a significant decrease in gill GST
      activity towards 1-chloro-2,4-dinitrobenzene (CDNB), whilst hepatic GST-activity
      was not significantly changed. Furthermore, continuous exposure to 540 ug/l
      thiabendazole[2-(thiazol-4'-yl)benzimidazole] in a flow-through system for 4 days
      significantly increased the gill glutathione S-transferase (GST) activity towards
      CDNB, whilst hepatic GST and cytochrome P450 (CYP 1A) activities were not
      increased by the treatment.

PMID- 12408569
TI  - Effects of furadan in the brown mussel Perna perna and in the mangrove oyster
      Crassostrea rhizophorae.
AB  - Furadan is a carbamate pesticide used widely to combat agricultural pests.
      However little information is available about the toxicity of furadan in aquatic
      macroinvertebrates. The in vivo effects of furadan were evaluated in mussels,
      Perna perna, and oysters, Crassostrea rhizophorae. Glutathione S-transferase
      (GST), catalase (CAT) and cholinesterase (ChE) activities were measured in the
      gills of both species exposed to furadan (100 microg/l) for 96 h. No changes were
      observed in GST activity in the exposed groups. CAT activity was higher (9%) in
      the oysters exposed to furadan. ChE activity was inhibited by 64 and 35%,
      respectively, in C. rhizophorae and P. perna exposed to furadan, suggesting that
      the former is more susceptible to the toxic effects of furadan.

PMID- 12408570
TI  - Evidence for resistance to benzo[a]pyrene and 3,4,3'4'-tetrachlorobiphenyl in a
      chronically polluted Fundulus heteroclitus population.
AB  - Halogenated aromatic hydrocarbons (HAHs) and polynuclear aromatic hydrocarbons
      (PAHs) are major environmental contaminants. Fish species that are chronically
      exposed to these compounds can develop resistance to their toxic effects. In all
      fish species studied to date, toxicant resistance has been accompanied by
      decreased inducibility of the xenobiotic metabolizing enzyme, cytochrome P450 1A
      (CYPIA). CYP1A induction is mediated through the Aryl Hydrocarbon Receptor (AHR).
      Although these compounds mediate their effects through this pathway, there have
      been resistant populations in which one chemical class cannot induce CYPIA
      expression (HAHs) while the other (PAHs) can. Resistance to PAHs was examined in
      a HAH-resistant population of Fundulus heteroclitus collected from a site
      contaminated with both compound classes (Newark Bay, NJ). Fish were injected
      intraperitoneally with the HAH 3,4,3',4'-tetrachlorobiphenyl (PCB77),
      benzo[a]pyrene (B[a]P, a PAH) or vehicle and sacrificed after 2 (B[a]P) or 5 days
      (PCB77, vehicle). We found no significant increase in CYP1A mRNA levels in
      resistant Newark Bay F. heteroclitus treated with either B[a]P or PCB77, while
      there was a 3.9 fold (PCB77) and 4.2 fold (B[a]P) increase in CYP1A mRNA in Flax
      fish relative to controls. AHR labeling studies revealed significantly (P < 0.05)
      lower levels of hepatic AHR in Newark fish (1,770 +/- 1,693.2 DPM) relative to
      Flax fish (6,082.5 +/- 1,709.9 DPM). Overall, these data suggest Newark F.
      heteroclitus are resistant to both PAHs and HAHs at the level of CYP1A mRNA,
      which might be mediated, in part, though lower expression of AHR. We are
      currently studying the promoter sequence to determine its role in chemical
      resistance.

PMID- 12408571
TI  - Molecular evidence for multiple UDP-glucuronosyltransferase gene familes in fish.
AB  - The presence of multiple distinct UGT genes in fish was derived by analysis of
      DNA sequence data derived the zebrafish EST project, confirming indications from
      previous protein purification studies in another fish species, the plaice, for a
      diversity of isoforms in lower vertebrates. At least 10 different UGTs can be
      identified from nucleotide sequence data in zebrafish. Phylogenetic analysis of
      exon 1 sequences of the zebrafish, plaice and human UGTs indicates that six of
      these genes are related to the 1A, 1B and 2 families and that a further four
      genes were of more ancient lineage. Importantly data for the 3' sequences of the
      zebrafish clones, both from the database and our own sequences of the publicly
      available clones did not provide any evidence for elaboration of family 1A genes
      by alternative splicing in this lower vertebrate.

PMID- 12408572
TI  - Allelic variations in the plaice UGT1B1 gene.
AB  - We have shown that there are large internanimal variations in hepatic phenol UDP
      glucuronosyltransferase (UGT) activity in the plaice which may affect their
      capacity to detoxify metabolites of carcinogenic PAHS such as benzo(a)pyrene with
      obvious implications for their health and survival. By molecular studies we have
      only been able to identify one copy of the UGT1B1 gene coding for the major
      phenol-UGT in the diploid plaice genome and found that it is highly polymorphic
      about this locus. Sequencing of multiple UGT1B1 cDNA clones derived from RT-PCR
      revealed the existence of clustered SNPs, however, from their positions we
      contend that this is not sufficient to explain the observed phenotypic
      variability. We discovered a heterozygous null genotype derived from a
      dinucleotide deletion (and also found preliminary evidence for a corresponding
      phenotype) which has a much greater implication for survival not only in polluted
      environments but for embryonic survival if the gene product has an essential
      endogenous role. We propose that the observed interanimal variations are
      attributable to a combination of factors including genotypic variations and
      differential expression.

PMID- 12408573
TI  - Evidence from heterologous expression of glutathione S-transferases A and A1 of
      the plaice (Pleuronectes platessa) that their endogenous role is in
      detoxification of lipid peroxidation products.
AB  - cDNA clones for glutathione S-transferases A (GST-A) and A1 (GST-A1) from plaice
      (Pleuronectes platessa) were expressed as N-terminally 6XHis tagged proteins in
      Escherichia coli and purified to homogeneity from Ni-NTA silica. GST-A was an
      efficient catalyst for conjugation of unsaturated alkenals derived from
      peroxidation of polyunsaturated fatty acids with the highest activity observed
      with trans-non-2-enal (8 micromol min(-1) mg(-1)). GST-A1 was a very efficient Se
      independent glutathione peroxidase with an activity towards cumene hydroperoxide
      of 25 micromol min(-1) mg(-1). Although the enzymes exhibited moderately high
      activities towards the model substrate 1-chloro-2,4-dinitrobenzene (CDNB) they
      exhibited little or no activity towards other common prototypical xenobiotic
      substrates. Together with data for ontogeny, tissue distribution and inducibility
      of these enzymes, we contend that a primary function of these enzymes is
      protection from the harmful effects of lipid peroxidation products generated
      naturally or exacerbated by xenobiotic exposure.

PMID- 12408574
TI  - Application of real time PCR determination to assess interanimal variabilities in
      CYP1A induction in the European flounder (Platichthys flesus).
AB  - In both laboratory experiments and field investigations with fish a large
      interanimal variability in CYP1A expression has been observed which may be
      attributed to variations in environmental inducer exposure and/or inducer
      response. We are carrying out laboratory investigations to assess the
      contribution of a potential genetic component in inducer response of flounder
      (Platichthy sflesus) CYP1A to PCB exposure and in this paper we report
      development of a sensitive quantitative RT-PCR procedure (real time PCR) where
      accumulation of the intercalated dye SYBR Green I is followed during cycling.
      Preliminary experiments using this procedure with artificially reared Arochlor
      1254-treated flounders showed large interanimal differences in response for a
      single family group indicating that variability does have a genetic basis.

PMID- 12408575
TI  - Effect of intertidal compared to subtidal exposure on the uptake, loss and
      oxidative toxicity of water-born benzo[a]pyrene in the mantle and whole tissues
      of the mussel, Mytilus edulis L.
AB  - Blue mussels (Mytilus edulis, L.) were exposed to a single dose of 1 ppb
      benzo[a]pyrene (BaP) under subtidal (SC) or tidal conditions (TC; 6 h immersion,
      6 h emersion) in order to follow its bioaccumulation in whole mussel and mantle
      tissue, and to compare BaP-mediated toxicity on lipids (malonaldehyde formation,
      MDA) in the mantle. Rapid uptake of BaP (70-80% of BaP initially introduced in
      tanks) was observed in both conditions after 12 h, but subsequent depuration in
      clean water was slower in TC mussels. BaP levels decreased in whole tissue in
      both conditions between 12 and 24 h, but increased in mantle. The mantle BaP
      levels were similar during the first 4 days in SC and TC, but whereas they
      decreased in SC after 7 days. BaP was retained at high levels in mantle in TC
      until the end of the study (14 days). In both conditions, significant increases
      (P < 0.05) in lipid peroxidation were observed after 4 days, but MDA levels were
      approximately 3 times higher in the mantle of TC than SC mussels, although BaP
      tissue concentrations were similar. These observations suggested that increased
      BaP-mediated toxicity in mantle lipid was due to the interactive effect of the
      tidal cycle of immersion/emersion on BaP-mediated oxidative damage.

PMID- 12408576
TI  - Effect of cortisol and urea on flavin monooxygenase activity and expression in
      rainbow trout, Oncorhynchus mykiss.
AB  - Expression of flavin-containing monooxygenase(s) (FMO) correlates with salinity
      exposure in certain species of euryhaline fish, such as the rainbow trout,
      Oncorhynchus mykiss. The mechanism(s) by which salinity regulates FMO is unclear.
      Adult rainbow trout were infused through the dorsal aorta with either cortisol or
      urea. At 500 ng/ml, cortisol caused a significant increase in FMO-catalyzed
      thiourea oxidase activity in gill and liver microsomes. FMOI expression, however,
      was significantly increased by the high cortisol dose only in gill microsomes.
      The levels of TMAO and urea were not altered by cortisol. In the liver, urea
      infusion caused an increase in hepatic FMO activity. FMO expression and activity
      correlated with elevated tissue urea levels, but TMAO concentrations were not
      related. These results indicate that FMO expression and activity may be partially
      controlled by the osmoregulatory/stress hormone. cortisol, and concentrations of
      the organic osmolyte, urea, in the rainbow trout.

PMID- 12408577
TI  - Effects of single and combined exposures to benzo(a)pyrene and 3,3'4,4'5
      pentachlorobiphenyl on EROD activity and development in Fundulus heteroclitus.
AB  - The goal of this study was to assess the interactive effects of a polynuclear
      aromatic hydrocarbon (PAH), benzo(a)pyrene (BaP), and a co-planar halogenated
      aromatic hydrocarbon (HAH), 3,3'4,4'5-pentachlorobiphenyl (PCB 126) on
      ethoxyresorufin-O-deethylase (EROD) activity and occurrence of deformities in
      Fundulus heteroclitus. While each compound administered alone elicited dose
      dependent increases in EROD activity, the combined treatment of these two
      compounds generally did not elicit an additive EROD response. There was a
      significant correlation between deformity occurrence and EROD induction in
      embryos dosed with PCB alone but not for embryos dosed with BaP alone, or a
      combination of BaP and PCB 126.

PMID- 12408578
TI  - cDNA cloning of an aryl hydrocarbon receptor from Baikal seals (Phoca sibirica).
AB  - Species differences in sensitivity to related planar halogenated aromatic
      hydrocarbons (PHAH) add significant uncertainty in assessing the ecological risk
      to aquatic mammals. To investigate mechanisms of PHAH sensitivity in aquatic
      mammals, we cloned and sequenced the cDNA of Baikal seal aryl hydrocarbon
      receptor (AHR), an intracellular protein that initiates PHAH-mediated effects.
      The Baikal seal AHR cDNA has an open reading frame of 843 amino acid residues
      with a predicted molecular mass of 94.6 kDa. Comparison of AHR amino acid
      sequences indicated a high degree of sequence conservation (98%) between Baikal
      and harbor seals. The high conservation of AHRs between Baikal and harbor seals
      indicates that these seals express AHR proteins closely related structurally. In
      our previous report (Kim & Hahn, 2002), the dioxin-binding affinity of the harbor
      seal AHR was at least as high as that of the AHR from a dioxin-sensitive strain
      of mice, suggesting that this seal species may be sensitive to PHAH effects. This
      implies that Baikal seal may also be sensitive to dioxin effects.

PMID- 12408579
TI  - Conjugation of 4-hydroxynonenal by largemouth bass (Micropterus salmoides)
      glutathione S-transferases.
AB  - The glutathione S-transferases (GST) are a major group of conjugative enzymes
      involved in the detoxification of electrophilic compounds and products of
      oxidative stress. We have previously described the kinetics of hepatic GST
      conjugation in largemouth bass using a variety of synthetic GST reference
      substrates. In the present study, we investigated the ability of largemouth bass
      hepatic GSTs to conjugate 4-hydroxynon-2-enal (4HNE), a mutagenic and cytotoxic
      alpha-beta-unsaturated aldehyde produced during oxidative injury. Hepatic
      cytosolic fractions from largemouth bass rapidly catalyzed GSH-dependent 4HNE
      conjugation, with the rate of GST-4HNE conjugation in bass liver exceeding those
      of several other mammalian and aquatic species. No apparent sex-related
      differences in GST-4HNE activity were observed among adult bass. SDS-PAGE and
      Western blotting analysis of GSH affinity-purified bass liver cytosolic GST
      revealed the presence of two major GST subunits of approximately 30 and 27 KDa
      that exhibited slight cross-reactivity when probed with a rat alpha class GST
      antibody, but not to rat mu, pi or theta class GST. The rapid conjugation of 4HNE
      by hepatic GST suggests an important role for GSTs in protecting against
      peroxidation of polyunsaturated fatty acids in bass liver.

PMID- 12408580
TI  - Effects of vehicle, diet and gender on the expression of PMP70- and CYP2K1/2M1
      like proteins in the mummichog.
AB  - The mummichog (Fundulus heteroclitus) has been shown to be responsive to
      peroxisome proliferating agents (PPAs). Peroxisomes function as important sites
      for fatty acid beta-oxidation. Peroxisome proliferation by PPAs or starvation can
      lead to changes in the size and number of peroxisomes and the expression of omega
      hydroxylases (CYP2K1/2M1 in rainbow trout). Mummichogs were subjected to 96 h
      fasting or 96 h recovery from fasting. Expression of PMP70- and CYP2K1/2M1-like
      proteins in vehicle-treated or non-treated controls was compared in both males
      and females. Fasting and vehicle produced decreases in PMP70- and CYP2K1/2M1-like
      proteins in both males and females. In reproductive females, decreases due to
      fasting and vehicle treatment were greater than in female fish that were not
      gravid. Recovery from fasting resulted in levels of CYP2K1/2M1 near control
      levels in males while in recovered females, about 2-fold higher levels compared
      to controls were noted. These results indicate that gender, reproductive status
      and diet can produce changes in the expressed levels of peroxisomal PMP70 and
      microsomal CYP2K1/2M1-like proteins in the mummichog.

PMID- 12408581
TI  - Behavioural responses of estuarine mysids to hypoxia and disruption by cadmium.
AB  - Neomysis integer (Peracarida: Mysidacea) occupies the upper, low-salinity regions
      of estuaries in Europe, where it can experience periods of reduced oxygen
      concentration associated with the maximum turbidity zone. The present study
      reports the distribution of N. integer in response to gradients of dissolved
      oxygen in combination with environmentally realistic cadmium concentrations (0.1,
      0.5 and 1.0 microg Cd2+ l(-1). Control and 0.1 microg Cd2+ l(-1) mysids were
      distributed evenly along a flume containing an oxygen gradient, and demonstrated
      no avoidance to hypoxia (down to 30% air saturation). In contrast, mysids exposed
      to 1.0 microg Cd2+ l(-1) migrated away from areas of low dissolved oxygen and,
      after 90 min, no mysids were found in regions of <75% air saturation. These
      results indicate that cadmium poses an increased risk to estuarine organisms
      inhabiting upper estuarine areas subjected to reduced dissolved oxygen
      concentrations.

PMID- 12408582
TI  - Release into the environment of metals by two vascular salt marsh plants.
AB  - Metals in contaminated salt marshes are mainly locked in the anaerobic layer of
      sediments, where they are tightly bound as sulfides and organic complexes.
      Vascular plants survive in saturated soils in part by pumping O2 into their root
      zones, changing their microenvironment to an oxic one. This, along with chelating
      exudates, mobilizes metals, allowing uptake by the roots. We compared the common
      reed Phragmites australis and cordgrass Spartina alterniflora in lab and field
      studies for ways in which they handle trace metals. Both plants store most of
      their metal burden in their roots, but some is transported to aboveground
      tissues. Spartina leaves contain approximately 2-3 x more Cr, Pb, and Hg than
      Phragmites leaves, but equivalent Cu and Zn. Furthermore, Spartina leaves have
      salt glands, so leaf excretion of all metals is twice that of Phragmites. In
      depth studies with Hg indicate that Hg excretion correlates with Na release but
      not with transpiration, which is 2.2 x higher in Phragmites; and that more Hg
      accumulates in early-appearing leaves than in upper (i.e. later) leaves in both
      species. Spartina thus makes more metals available to salt marsh ecosystems than
      Phragmites by direct excretion and via dead leaves which will enter the food web
      as detritus.

PMID- 12408583
TI  - Concentrations of Cd, Zn and Cu in sediments and brown shrimp (Crangon crangon
      L.) from the Severn Estuary and Bristol Channel, UK.
AB  - Cd, Zn and Cu levels were determined in sediments and Crangon crangon from 9
      sites in the Severn Estuary/Bristol Channel during winter 1999. Metal levels in
      both shrimp and sediments varied significantly between sites and were related to
      proximity of input and/or sediment type. In the upper Estuary, Cd levels in
      shrimp were 100x higher than other reported values whereas sediment Cd
      contamination was comparable. It is suggested that high Cd levels in shrimp are
      due to the high inputs and enhanced bioavailability of metal during winter.

PMID- 12408584
TI  - Characterization of zebrafish metallothionein gene promoter in a zebrafish caudal
      fin cell-line, SJD. 1.
AB  - Metallothioneins (MTs) are low molecular weight metal binding proteins that are
      implicated in heavy metal detoxification processes, and their quantification are
      commonly used as biomarkers of exposure to heavy metal ions. To verify the use of
      zebrafish MT gene promoter for aquatic toxicology studies, an 835 bp zebrafish MT
      (zMT) gene promoter with four putative metal regulatory elements (MREs) was
      isolated by DNA walking method and characterized for metal induction of gene
      transcription using transient expression assays in a zebrafish caudal fin cell
      line, SJD.1. The cloned promoter was linked upstream to a luciferase reporter
      gene and found to be responsive to administrations of Zn2+, Cd2+, and Cu2+ in
      SID.1 cell-line, but Hg2+, Ni2+, Pb2+, and Co2+ showed no significant induction
      of zMT gene transcription.

PMID- 12408585
TI  - Assumption and elimination of trace elements in Adelie penguins from Antarctica:
      a preliminary study.
AB  - The concentration and distribution of some trace elements were determined in
      stomach contents, excreta and feathers of Adelie penguins (Pygoscelis adeliae)
      breeding at Edmonson Point (Terra Nova Bay-Antarctica). In these materials
      obtained by non-destructive methods, concentrations of mercury, cadmium and lead
      measured were used to establish natural levels of these metals in the penguins'
      diet. An intake-excretion hypothesis was formulated.

PMID- 12408586
TI  - Development of symbiosis-specific genes as biomarkers for the early detection of
      cnidarian-algal symbiosis breakdown.
AB  - Coral bleaching, i.e. the loss of dinoflagellate symbionts from cnidarian hosts,
      is occurring globally at increasing rates, scales, and severity. The significance
      of these bleaching events to the health of coral reef ecosystems is extreme, as
      bleached corals exhibit high mortality, reduced fecundity and productivity and
      increased susceptibility to disease. This decreased coral fitness leads to reef
      degradation and ultimately to the breakdown of the coral reef ecosystem. To date
      there has been little work describing the application of biomarkers to assess
      coral health. The most commonly applied biomarker is, in fact, the bleaching
      event itself. We are interested in developing early warning biomarkers that can
      detect coral stress before bleaching occurs. Recently, several genes that are
      likely to function in regulating interactions between cnidarians and their
      symbionts have been characterized, using the temperate sea anemone Anthopleura
      elegantissima as a model species. One "symbiosis gene" identified from the host
      genome, sym32, is expressed as a function of anemone symbiotic-state, where sym32
      expression is higher in symbiotic cf. aposymbiotic (symbiont-free) anemones. Real
      time quantitative RT-PCR suggested that the level of sym32 expression was
      correlated with the abundance of algae in the host. Furthermore, laboratory
      exposures of anemones to low levels of cadmium (0, 20, 100 microg(-1) CdCl2; 14
      days), which caused no change in algal cell numbers, resulted in a down
      regulation of sym32 compared to controls, indicating that sym32 expression may
      serve as a new sensitive early warning biomarker of cnidarian-algal symbiosis
      breakdown.

PMID- 12408587
TI  - A study of Cu turnover in proteins of the visceral complex of Littorina littorea
      by stable isotopic analysis using coupled HPLC-ICP-MS.
AB  - A two-dimensional HPLC system, tandemly coupled to an ICP-MS, has been used to
      study copper accumulation and turnover in the visceral complex cytosol of the
      gastropod, Littorina littorea. Animals were exposed for 8 weeks to NTA-buffered
      seawater containing stable isotopic 65Cu and then transferred to media containing
      stable isotopic 63Cu. The free ion activity of each isotope was maintained at 10(
      11) M. Size exclusion (SE) HPLC showed Cu associated with haemocyanin (HC) and
      metallothionein-like (MT) proteins in two ligand pools with apparent molecular
      weights of >300 kDa and approximately 17 kDa, respectively. The MT pool was
      inducible by Cu, could assimilate the metal from both intrinsic and extrinsic
      sources and showed a higher rate of Cu accumulation and turnover than the HC
      pool. The induction of this pool also caused the sequestration and cytosolic
      redistribution of Zn, Cd, Pb, Mn and Co. Further fractionation of the MT pool by
      ion-exchange (IE) HPLC revealed that the Cu was associated with a single, major
      isoform of the protein that was Cu inducible and also bound trace quantities of
      Zn and Pb. A number of additional metal containing proteins were also resolved by
      IE. the most prominent of which also bound Pb, Mn and minor quantities of Zn. The
      significance of these findings in metal homeostasis and detoxification is
      discussed.

PMID- 12408588
TI  - Effects of water-borne copper on metallothionein and lipid peroxidation in the
      marine amphipod Gammarus locusta.
AB  - The aim of the current work was to determine over 10 days the effects of water
      borne exposure of the marine amphipod Gammarus locusta to 4 microgCu l(-1) on the
      metallothionein (MT; measured by differential pulse polarography) protection
      system and lipid peroxidation (LP: thiobarbituric acid-reactive malondialdehyde
      equivalents) as a measure of oxidative damage. MT levels in exposed animals
      increased significantly at day 2 (36% > control; P < 0.001) and remained high at
      days 6 and 10 (55 and 38%, respectively, P < 0.001). The maximum level of MT at
      day 6 coincided with the highest Cu body-burden. LP increased within I day of
      exposure, indicative of Cu as an oxidative stressor. However, in contrast to MT,
      the highest LP level was seen at day 4 (68% > control, P < 0.001) before
      returning to control values by day 6, indicating a protective role of MT against
      the pro-oxidant effects of Cu.

PMID- 12408589
TI  - Effect of temperature and size on metallothionein synthesis in the gill of
      Mytilus galloprovincialis exposed to cadmium.
AB  - Although the degree of metal contamination is expected to be a primary
      determinant of metallothionein (MT) induction in marine mussels, at least at
      polluted sites, variability caused by temperature, and biotic factors such as
      size, may need to be considered when interpreting field data. To test the effects
      of these variables, mussels, Mytilus galloprovincialis, of different sizes
      (small: 3.5 +/- 0.5 cm and large: 5.2 +/- 0.7 cm) were exposed to Cd (100 microg
      l(-1)) at different water temperatures (5, 18 and 25 degrees C) for 34 days.
      Resultant Cd and MT concentrations in gills were shown to be size dependent and
      increased significantly with temperature. At the highest temperature tested (25
      degrees C) there appears to be a disproportionate effect on Cd accumulation,
      which raises MT synthesis to exceptionally high levels. The effect of size on MT
      concentrations was also temperature-dependent: at 18 and 25 degrees C, large
      mussels exhibited higher MT levels than smaller individuals, whilst at 5 degrees
      C there were no significant differences between contaminated and control mussels,
      in either size-group, as a result of the reduced level of MT production at this
      temperature. When considering the use of MT levels in mussels as a biochemical
      indicator of metal contamination, the potential influence of factors such as size
      and temperature on MT-metal relationships needs to be considered. Samples should
      be of uniform size as far as possible, and collection should be limited to a
      fixed season (avoiding climatic extremes) to ensure that the effects of these
      factors on baseline levels of MT is minimised.

PMID- 12408590
TI  - Protein expression signatures: an application of proteomics.
AB  - The methods of proteomics, the study of the protein complement of the genome, are
      applicable to environmental testing. Sets of proteins specific to different
      stressors can be isolated using computer imaging software. Individual proteins
      can be identified by mass spectrometry. The Protein Expression Signatures (PES)
      obtained have potential in diagnosing adverse factors in the environment. The
      challenge is to demonstrate their feasibility in complex environments. We have
      shown that PES for three endocrine disrupting compounds in trout (Onchorhynchus
      mykiss), can be detected in mixed sewage effluent. Other studies support these
      results. As protein databases expand, identification becomes routine, and capture
      molecules specific to each protein are developed, the possibility of simple field
      tests for multiple stressors becomes real.

PMID- 12408592
TI  - Cloning and sequencing of cytochrome P450 2X1 from channel catfish (Ictalurus
      punctatus).
AB  - Previous purification and immunochemical studies in livers of channel catfish
      indicated the presence of at least four cytochrome P450 (CYP) 2-like isoforms.
      Sequencing of the first 18 amino acids of one purified form indicated a CYP2
      isoform. From this N-terminal sequence and other published CYP2 sequences from
      fish, primers were designed and a full-length CYP cDNA was identified from
      reverse-transcribed catfish liver mRNA. 5' and 3' RACE was used to obtain an open
      reading frame of 1470 bp encoding a 490 amino acid protein (approximately 57 kD).
      CYP2X1 was most identical to Fundulus heteroclitus CYP2P2 (41%); CYP2N2 (40%):
      and CYP2N1 (39%).

PMID- 12408591
TI  - Identification of differentially expressed genes in Dreissena polymorpha exposed
      to contaminants.
AB  - Development of transcriptome analysis methods such as differential display PCR
      and construction of subtractive libraries now makes it possible to profile gene
      expression in response to xenobiotic exposure. As an example of application of
      these methods, zebra mussels (Dreissena polymorpha) were treated with various
      contaminants such as Aroclor 1254, 3-methylcholanthrene, chrysene and atrazine. A
      total of 242 mRNAs were identified as differentially expressed. Analysis of these
      mRNAs should provide valuable information regarding detoxification mechanisms in
      this bivalve species. In addition, the use of cDNA array technology applied to
      these gene products may constitute a multi-marker approach to monitor the effect
      of contamination on this aquatic species.

PMID- 12408593
TI  - Array technology as a tool to monitor exposure of fish to xenoestrogens.
AB  - A variety of anthropogenic chemicals are capable of binding to the estrogen
      receptor of vertebrate species. Binding of these compounds can interfere with
      homeostasis by disrupting normal gene expression patterns. The purpose of this
      study was to investigate the feasibility of applying array technology as a
      monitoring tool for detecting the presence and distribution of estrogenic
      compounds in coastal habitats using sheepshead minnows as our model. cDNA clones
      that were isolated from differential display, including vitellogenin alpha and
      beta, vitelline envelope protein (ZP2), and transferrin, among others, were
      spotted on the macroarray. The results of these experiments demonstrate a
      characteristic expression pattern of estrogen responsive genes in sheepshead
      minnows exposed to 17 beta-estradiol (E2).

PMID- 12408594
TI  - Zinc concentration effect at the organismal, cellular and subcellular levels in
      the eastern oyster.
AB  - The purpose of this research was to demonstrate a concentration effect of zinc
      exposure at organismal, cellular and sub-cellular levels in the eastern oyster
      and to find associated protein expression signatures (PES) for each concentration
      of zinc. Oysters were exposed to six concentrations of zinc for 48 h in a
      controlled environment. At the organismal level, fecal material was observed as a
      measure of physiological health during metal exposures. At the cellular level,
      lysosomal destabilization was measured using hemolymph. This cellular response
      was significant only at the highest concentration, when the fecal index was
      lowest. Protein responses were monitored in the oyster following exposure to
      zinc. Gill tissue was excised and homogenized, and then analyzed using two
      dimensional polyacrylamide gel electrophoresis (2D-PAGE) and digital image
      analysis. Protein expression signatures were found to be specific to each
      concentration. The protein responses were linked to the other biological
      parameters measured, each of which followed a concentration gradient of zinc.

PMID- 12408595
TI  - Response of antioxidant systems to copper in the gills of the clam Ruditapes
      decussatus.
AB  - Copper (Cu) is an essential element for biological systems, however, when present
      in excess, is toxic. Metallothioneins can play an important role in Cu
      homeostasis and detoxification. Moreover, Cu can catalyse the production of toxic
      hydroxyl radicals that cause lipid peroxidation but defence systems in the cells
      can limit the oxidative damage. The present study was performed to investigate
      the effect of three Cu concentrations (0.5, 2.5 and 25 microg l(-1)) on the
      response of antioxidant enzyme activities (superoxide dismutase (SOD), catalase
      (CAT), selenium-dependent glutathion peroxidase and total glutathion peroxidase),
      total proteins, metallothioneins (MT), malondialdehyde (MDA) concentrations in
      the gills of the clam, Ruditapes decussatus. The activity of antioxidant enzymes
      and total proteins, MT and MDA concentrations were measured in the gills of the
      clams after 1, 3, 7, 14, 21 and 28 days of Cu exposure. Results indicate that Cu
      only induces an imbalance in the oxygen metabolism during the first week of Cu
      exposure due to a decrease in mitochondrial SOD and CAT, selenium-dependent and
      total glutathion peroxidase activities. Cu also causes lipid peroxidation,
      measured by the MDA formation, that was Cu dependent. In the gills of clams
      exposed to 25 microg Cu/l, the excess of Cu triggers the induction of MT
      synthesis after 3 days of exposure.

PMID- 12408596
TI  - Oxidative stress in ecotoxicology: from the analysis of individual antioxidants
      to a more integrated approach.
AB  - An integrate approach will be discussed for investigations on oxidative stress in
      xenobiotic toxicity. While the analysis of individual antioxidants is useful for
      their sensitivity and to understand the mode of action of a stressor, the
      integration with the analysis of the total antioxidant capacity provides a more
      holistic assessment of the overall biological significance of such variations.
      TOSC has a greater predictive value on the health condition of the organisms and
      allows to discriminate the different role of specific ROS in oxidative stress
      syndrome.

PMID- 12408597
TI  - Total oxyradical scavenging capacity and cell membrane stability of haemocytes of
      the Arctic scallop, Chlamys islandicus, following benzo(a)pyrene exposure.
AB  - Industrial activities, notably oil and gas industries, are expanding in the
      Arctic. Most of the biomarkers were developed using temperate organisms living at
      temperatures above 10 degrees C. Little is known about the biomarker responses of
      organisms living between -1.88 and 5 degrees C. Therefore, assessment of the
      toxicity of chemicals to cold-water adapted species is required. In this study,
      the Arctic scallop, Chlamys islandicus, was selected as a key species for bio
      monitoring because of wide distribution in Arctic waters and its commercial
      value. Test animals, stored in seawater at 2 degrees C, were injected with
      benzo(a)pyrene (diluted in cod liver oil 5 mg ml(-1)) in the adductor muscle
      every 24 h for four days giving a final dose of 0, 74 and 90.6 mg kg(-1) wet
      weight for control, low and high dose, respectively. The biomarkers used were
      total oxyradical scavenging capacity (TOSC) in the digestive gland and cell
      membrane stability of haemocytes. TOSC values were significantly reduced (ca.
      30%) in exposed groups (P < 0.05), indicating a depletion in oxyradical molecular
      scavengers. The antioxidant defences appeared to be overwhelmed by the reactive
      oxygen species as the plasma membranes of haemocytes were destabilised (P < 0.05)
      probably due to lipid peroxidation. These data indicate that reactive oxygen
      species (ROS) were produced by Arctic scallops via the metabolisation of
      benzo(a)pyrene at 2 degrees C.

PMID- 12408598
TI  - Oxygen radicals production and actin filament disruption in bivalve haemocytes
      treated with benzo(a)pyrene.
AB  - Haemocytes play an essential role in the internal defence of molluscs. It has
      been reported that organic xenobiotics commonly found as pollutants in the marine
      environment impair defence capabilities of haemocytes. The purpose of the present
      study was to investigate the effects of benzo(a)pyrene [B(a)P] on the integrity
      of the actin cytoskeleton and on endocytosis in haemocytes and to see if these
      effects are related to generation of reactive oxygen species. Haemocytes were
      exposed in vitro to B(a)P (0.5-40 microg/ml) for 1 h. Cell viability (using 2,3
      bis[2-methoxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5-carboxanilide or XTT assay)
      indicated that selected doses were sublethal. Uptake of neutral red was
      significantly decreased in a dose-dependent manner in B(a)P-treated haemocytes.
      Distribution of actin filaments, labeled with rhodamine-conjugated phalloidin,
      was altered in haemocytes treated with 20 or 40 microg/ml B(a)P. These effects
      could be related to an increased production of superoxide anion during B(a)P
      metabolism, as detected by the nitroblue tetrazolium (NBT) reduction assay in
      haemocytes treated with > or = 10 microg/ml B(a)P.

PMID- 12408599
TI  - Rhodamine exclusion activity in primary cultured turbot (Scophthalmus maximus)
      hepatocytes.
AB  - Cellular detoxification by direct processes has been investigated in fish by
      studying the ability of hepatocytes prepared from juvenile aquarium-reared turbot
      (Scophthalmus maximus) to actively exclude the fluorescent dye rhodamine B (RB).
      Cell viability was studied by measurements of non-specific esterase activity
      using fluorescein diacetate. This revealed that turbot hepatocytes can be
      cultured for a few days with a viability decreasing to 38% after 24 h. The 24-h
      cultured cells have been used to study the rhodamine B exclusion activity using
      confocal laser microscopy. Hepatocytes accumulated the dye in a competitive
      manner with verapamil, thus suggesting that they express a transport system
      similar to the P-glycoprotein-mediated multixenobiotic resistance process.
      Incubation of cells with 1 microM RB and 20 microM verapamil led to a 26%
      increase of cellular fluorescence as compared to the accumulation in absence of
      competitor. Rhodamine B accumulated in the whole cytoplasm, with more
      concentrated areas that might correspond to the lysosomal compartment and the
      cell membrane.

PMID- 12408600
TI  - Measurement of the activity of multixenobiotic resistance mechanism in the common
      carp Cyprinus carpio.
AB  - The multixenobiotic resistance (MXR) mechanism, mediated by activity of the
      transmembrane P-glycoprotein, represents a basic biological defence system in
      aquatic organisms. Here we investigate the MXR transport activity in an aquatic
      vertebrate, the common carp (Cyprinus carpio). We measured the accumulation rate
      of a model MXR substrate, the fluorescent dye rhodamine B (RB), in gills, lateral
      muscles, liver and bile. Results obtained using this method showed a significant
      increase of RB accumulation in tissues of fish exposed for I h to 3 microM RB in
      the presence of the model MXR inhibitors cyclosporin A (CA, 5 microM) or
      verapamil (VER, 10 microM), when compared with specimens exposed without
      inhibitors. The highest increase in RB accumulation detected in the liver (VER
      54%, CA 170%) indicates that among the tissues analysed within this study, liver
      is the most prominent candidate organ for the functional detection of MXR
      activity in C. carpio.

PMID- 12408601
TI  - Expression and activity of a multixenobiotic resistance system in the Pacific
      oyster Crassostrea gigas.
AB  - The multidrug resistance (MDR) mechanism corresponds to a defence system relying
      on the expression of high molecular membrane proteins that can actively lower the
      intracellular concentration of a wide variety of toxins, thus maintaining them
      below their toxic level. Using RT-PCR, expression levels of a gene belonging to
      the class I of mammalian mdr genes, has been assessed in different developmental
      stages of the oyster Crassostrea gigas. While no expression was found in the
      oocyte or the trocophore stage, a rise of mRNA content was observed from the
      veliger stage to the juvenile stage, thus indicating the induction of the system
      as the animal is developing in the environment. The incubation of gill fragments
      in the dye rhodamine B and subsequent measurements of intracellular fluorescence
      using a microplate reader indicates that the system can effectively decrease the
      accumulation of the test compound in a competitive manner with known inhibitors
      or environmental contaminants as observed in vertebrate cells. The oyster MXR
      system is thus becoming active in adult oyster and could be of importance in
      environmentally contaminated areas.

PMID- 12408602
TI  - Comet assays to assess DNA damage and repair in grass shrimp embryos exposed to
      phototoxicants.
AB  - Exposure of grass shrimp (Palaemonetes pugio) embryos to four compounds
      (anthracene, pyrene, alpha-terthienyl, methylene blue) along with solar exposure
      resulted in extensive DNA strand damage using the comet assay. DNA tail moments
      of embryos exposed to these chemicals in the dark ranged from 1.8 to 4.3, while
      exposure to chemicals and solar resulted in tail moments of 14.3-15.3. Reduction
      of DNA tail moments when solar exposed embryos were transferred to the dark,
      suggested DNA repair systems were active. The comet assay can be used to follow
      both DNA damage and repair following exposure to phototoxic chemicals.

PMID- 12408603
TI  - Use of the Comet assay to assess DNA damage in hemocytes and digestive gland
      cells of mussels and clams exposed to water contaminated with petroleum
      hydrocarbons.
AB  - Oil spills can result in the deposition of large quantities of petroleum
      hydrocarbons into intertidal and shallow waters seriously impacting bivalve
      populations. Petroleum hydrocarbons are enriched in polycyclic aromatic
      hydrocarbons (PAH) and PAH analogs many of which may have potential to damage
      DNA. The Comet assay is useful for assessing DNA damage and has been used to a
      limited degree with aquatic organisms, but mostly with studies in vitro. We have
      carried out studies with the Comet assay to assess the DNA damaging potential of
      complex mixtures of petroleum hydrocarbons for bivalves. Experiments were carried
      out with mussels (Mytilus edulis) and clams (Mya arenaria) with dispersions and
      water soluble fractions of an Arabian crude oil which was also chemically
      characterized in detail by GC-MS. Pilot studies were first conducted to evaluate
      test performance and reproducibility. An interindividual coefficient of variation
      ranging from 17 to 30% was established for the assay with hemocytes and digestive
      gland cells of both species. Exposure to hydrocarbon fractions had no significant
      impact on clams. However, an increase in DNA damage was observed at P < 0.1 with
      digestive gland cells of mussels exposed to aqueous fractions of a light crude
      oil. These studies have demonstrated a potential for DNA damage in bivalves
      exposed to oil spills in inshore waters as well as potential for interspecies
      sensitivity.

PMID- 12408604
TI  - Genotoxic impacts in Klaipeda Marine port and Butinge oil terminal areas (Baltic
      Sea).
AB  - Genotoxic effects were evaluated in the somatic and gonadal cells of bivalve and
      gastropod molluscs inhabiting different sites of Klaipeda port area in Lithuania.
      The occurrence of aneuploidy and polyploidy of cells, meiotic injures, centromere
      dissociation and fragmented polyploid nuclei as cytogenetic indicators of
      environmental stressors was assessed in snails Lymnaea ovata . The highest level
      of environmental genotoxicity (in 43.2 and 46.2% of studied cells) was observed
      in the tissues of snails inhabiting Malku Bay in 1995 and 1996. Dredging and thus
      removal of contaminated sediments from Malku Bay resulted in significant decrease
      (up to 27.2% in 1999) of cytogenetic injures in molluscs studied over the period
      from 1997 to 1999. However, the frequency of cytogenetic disturbances in molluscs
      from Vilhelmo Channel was increasing (1.8 times) from 1995 to 1999. Therefore,
      the ecological safety of the biggest drinking water supply for Klaipeda
      population became questionable. Assessment of cytogenetic damage in Mytilus
      edulis (MN test) and the crustacean, Balanus improvisus, (aneugenic effects)
      inhabiting the Baltic Sea at Butinge oil terminal has shown the highest
      genotoxicity level in the zone of sewage effluents from Palanga town and
      Mazeikiai oil refinery plant. Extensive cytogenetic injuries in gonadal cells
      indicated the potential long-term hazards of pollutants to ecological health and
      integrity of aquatic species.

PMID- 12408605
TI  - DNA adducts in mussels and fish exposed to bulky genotoxic compounds.
AB  - Biological and procedural factors can influence DNA adduct detection in aquatic
      organisms. Among them, functional structure and metabolic traits represent major
      biological determinants for adducts formed by lipophilic pro-mutagenic
      contaminants. In detecting DNA adducts through the 32P-postlabelling assay,
      efficiency in DNA purification, digestion, labelling, as well as adduct
      enrichment and quantification may explain differences between independent
      studies. Reference DNA adducts have been used to verify some 32P-postlabelling
      aspects. Data obtained for mussels and fish treated with benzo[a]pyrene (B[a]P)
      and environmentally exposed to genotoxins confirm the above assertions. Although
      the 32P-postlabelling assay cannot be proposed for routine biomonitoring it
      appears a reliable and very sensitive index of exposure to genotoxic pollutants
      in both fish and mollusks.

PMID- 12408606
TI  - Susceptibility to genetic damage and cell types in Mediterranean mussels.
AB  - Micronucleus (MN) frequency is generally accepted as a marker of chromosomal
      damage and has been studied in a variety of cells and species. In previous work,
      we detected significant dose-related MN increases in the epithelial-like gill
      cells and agranular haemocytes of Mytilus galloprovincialis treated with
      benzo[a]pyrene, a well-known mutagenic pollutant. In addition, we have studied
      micronuclei and other nuclear abnormalities in mussels collected from the Venice
      lagoon (Italy). Frequency changes, possibly related to genotoxic/toxic stress, in
      both granular and micronucleated cells from gills and haemolymph, were detected.
      Environmental data suggest the effect of genotoxic pollutants and the importance
      of cell replication in the interpretation of micronucleus frequencies.

PMID- 12408607
TI  - Different levels of mussel (Mytilus edulis) DNA strand breaks following chronic
      field and acute laboratory exposure to polycyclic aromatic hydrocarbons.
AB  - Levels of polycyclic aromatic hydrocarbons (PAHs) including benzo[a]pyrene
      (B[a]P) were at least seven-fold higher in mussels sampled from a polluted site
      (Loch Leven, in Scotland, UK) compared to a nearby clean reference site (Loch
      Etive) throughout the year 2000. Levels of DNA strand breaks (alkaline COMET
      assay) using both gill and digestive gland nuclei were similar at both sites
      despite the difference in contaminant load (total PAH). In contrast, mussels
      collected from a reference site (Port Quin, Cornwall, UK) had an increase in DNA
      strand breaks in digestive gland cells following laboratory exposure to B[a]P
      dosed Isochrysis galbana. However, after 14 days high dose (20 ppb-exposed diet)
      animals had returned to levels similar to the controls. There was no evidence of
      increased necrosis or apoptosis after treatments. The results from these two
      studies suggest that an adaptive response may prevent ongoing DNA damage in
      mussels exposed to high levels of B[a]P and PAH contamination.

PMID- 12408608
TI  - In vitro mechanistic differences in benzo[a]pyrene-DNA adduct formation using
      fish liver and mussel digestive gland microsomal activating systems.
AB  - Turbot (Scophthalmus maximus) and mussel (Mytilus edulis) microsomes were
      incubated with DNA to examine if microsomal in vitro metabolism of BaP could
      result in DNA adducts detected by 32P-postlabelling. Turbot DNA was incubated
      with benzo[a]pyrene (BaP), NADPH and microsomal activating systems prepared from
      either livers of unexposed turbot, turbot exposed to BaP or beta-naphthoflavone
      (beta-NF) or digestive glands from mussels. The beta-NF activating system
      generated the highest levels of DNA adducts detected in this study (451.7 adducts
      per 10(8) nucleotides) and were distributed in three discrete adduct TLC spots,
      one of which (97% of the total adducts) co-migrated with the 32P-postlabelled BaP
      7,8-diol, 9,10-epoxide-N2-guanine adduct. Fewer adducts (P < 0.05) were generated
      by BaP-induced microsomes (9.4-30.6 adducts per 108 nucleotides) but levels were
      higher (P <0.05) than those generated from untreated fish (3.5 adducts per 10(8)
      nucleotides). Co-incubation with 500 microM alpha-naphthoflavone (alpha-NF)
      resulted in 97-99% inhibition in adduct formation implicating cytochrome P450
      dependent (CYP) bioactivation however there was some evidence for carry over of
      BaP in the liver microsomal preparations from BaP injected fish. In contrast to
      the fish activating systems, no DNA adducts were observed when mussel microsomes
      were incubated with BaP, DNA and NADPH.

PMID- 12408609
TI  - Elevation of cytochrome P450-immunopositive protein and DNA damage in mussels
      (Mytilus edulis) transplanted to a contaminated site.
AB  - Mytilus edulis were collected from a reference site (Port Quin) and an
      urban/industrial contaminated site (New Brighton) in the UK during June 1999.
      Levels of PCBs (sigma7 congeners) and CB-138 were determined to be, respectively,
      21 fold and 16 fold higher in the mussel digestive glands from New Brighton.
      Levels of CYPIA-immunopositive protein were 1.5 fold higher (P < 0.05) at the
      polluted site but the levels of DNA strand breaks were 1.3 fold higher (P<0.05)
      at the reference site. Mussels from Port Quin were placed in cages at both sites
      and both transplanted and indigenous populations sampled in September (13 weeks).
      Mussels transplanted from the reference site to the industrial site, reported
      elevated levels of CYP1A-immunopositive protein (1.4 fold; P < 0.05) and higher
      levels of DNA damage (1.2 fold; P < 0.05) compared to caged populations at the
      reference site and a PCB loading similar to the populations from the polluted
      site. Moreover, transplanted mussels had DNA damage 1.8 fold greater (P < 0.05)
      than indigenous mussels at the transplant site. These changes were small but
      significant when compared to the observed temporal changes in the indigenous
      populations.

PMID- 12408610
TI  - Correlative changes in metabolism and DNA damage in turbot (Scophthalmus maximus)
      exposed to benzo[a]pyrene.
AB  - Juvenile turbot (Scophthalmus maximus) were injected intraperitoneally with
      either corn oil or 5 mg/kg benzo[a]pyrene (BaP) dissolved in corn oil and sampled
      I and 3 days after injection. After 1 day, no elevation of 7-ethoxyresorufin O
      deethylase (EROD) activity was observed, however bile metabolites (BaP-7,8
      dihydrodiol representing 70% of the total metabolites) and a single hepatic DNA
      adduct spot (0.47 adducts/10(8) nucleotides) identified by 32P-postlabelling were
      formed. No BaP metabolites or DNA adducts were observed in either control or
      carrier control fish. Fish sampled after 3 days reported 5-fold higher (P < 0.05)
      levels of EROD activity, a shift in the bile metabolite profile towards BaP
      phenol formation (1OH and 30H BaP comprising up to 60% of total metabolites
      detected) and the formation of two adduct spots (0.86 and 0.71 adducts/10(8)
      nucleotides). These results show that BaP can be metabolised and form hydrophobic
      DNA adducts in turbot without EROD elevation. Following EROD elevation, a shift
      in the profile of both BaP metabolites and BaP metabolite-DNA interactions occurs
      indicative of other oxidative processes.

PMID- 12408611
TI  - Induction of DNA strand breakage and apoptosis in the eel Anguilla anguilla.
AB  - The ability of benzo[a]pyrene, Aroclor 1254, 2-3-7-8-tetrachlorodibenzo-p-dioxin
      and beta-naphthoflavone to induce DNA strand breaks (SB) and apoptosis in
      erythrocytes of the European eel (Anguilla anguilla) was investigated following
      by in vivo exposure. DNA damage was evaluated by the Comet assay, while the
      diffusion assay was used to investigate the induction of apoptosis 7 days after a
      single intraperitoneal administration. 2-3-7-8-Tetrachlorodibenzo-p-dioxin
      induced the highest genotoxic effect, followed by benzo[a]pyrene, while the other
      two substances had limited effects. A significant induction of apoptosis was
      observed at the highest doses after exposure to benzo[a]pyrene, when DNA damage
      was also elevated. The occurrence of apoptotic cells after exposure to Aroclor, 2
      3-7-8-tetrachlorodibenzo-p-dioxin and beta-naphthoflavone was quite variable and
      did not show clear dose-related responses. The role of oxidative stress in
      mediating DNA damage was also discussed.

PMID- 12408612
TI  - Genetic responses to metal contamination in two clams: Ruditapes decussatus and
      Ruditapes philippinarum.
AB  - Coastal ecosystems are subjected to a wide variety of disturbances, including
      those due to xenobiotics of agricultural and industrial origin. These pollutants
      as heavy metals can modify the genetic diversity of populations by favouring or
      counter-selecting certain alleles or genotypes by differential mortality. In the
      present study, two genetic markers (phosphoglucomutase and glucosephosphate
      isomerase) and a protein marker (metallothionein) were monitored in order to
      determine the impact of heavy metals in different clam populations. Analysis of
      the genetic structure of the clam populations examined reveals that those
      inhabiting environments contaminated by heavy metals exhibit a higher allelic
      diversity and possess alleles at PGM loci that could be selected by the presence
      of heavy metals. The evaluation of metallothionein levels using a specific
      polyclonal antibody developed in the Pacific oyster (Crassostrea gigas)
      demonstrated the existence of a relationship between metallothionein
      concentrations and the level of metal pollution for clam populations sampled from
      different sites. An inter-specific difference was also detected between Ruditapes
      decussatus and Ruditapes philippinarum living in sympatry at the same site,
      suggesting a differential response of these two species upon exposure to an
      identical heavy metal concentration.

PMID- 12408613
TI  - Hepatic histopathology in two populations of the mummichog, Fundulus
      heteroclitus.
AB  - The pollution-tolerant mummichog, Fundulus heteroclitus, inhabits a heavily
      contaminated estuary, Piles Creek (PC), in Linden, NJ. PC contaminants include
      PAHs, PCBs and many metals, including high Hg and Pb. PC mummichog livers and
      kidneys were compared with those from a pristine estuary in Tuckerton (TK), NJ,
      by standard histopathological methods, with quantification by computerized image
      analysis. PC livers had > 2 x the lipid ratios of TK livers. Cell sizes and
      shapes were not different between populations. TK livers had a 25% incidence of
      basophilic areas and an age-related 30% incidence of macrophage aggregates; PC
      livers had none of these lesions. PC livers had a 100% incidence of necrotic
      foci, compared with 55% of TK livers. Inflammation was noted in 50% of TK livers
      but only 27% of PC livers. Curiously, the TK livers had a 45% incidence of
      metacercarial cysts of a digenetic trematode, while none were found in the PC
      livers. The TK focal necrosis and macrophage aggregates coincided with parasite
      infestation. There were no observed kidney lesions in either population. Positive
      biomarkers in this species thus included high hepatic lipid content, possibly
      necrosis, but no other lesions. The lack of trematode cysts in PC livers may
      reflect the lack of an intermediate host in this low biodiversity estuary.

PMID- 12408614
TI  - Histopathological observations on liver, kidney and gonad of plaice (Pleuronectes
      platessa) taken from the Mersey estuary.
AB  - The Mersey estuary is the most contaminated estuary in British waters. Detailed
      studies are underway on the pathology of flounder (Platichthys flesus) from the
      Mersey and on flounder from the nearby, but less contaminated, Dee estuary.
      Flounder breed offshore but spend a lot of time in the estuaries, penetrating
      into freshwater. These flatfish are in close contact with sediments and will be
      exposed to exenobiotic stored in the sediments. Plaice (Pleuronectes platessa)
      are flatfish which enter the Mersey with the tidal flow but spend less time in
      the estuary than flounder and are less likely to show evidence of pollutant
      exposure. Over 20 plaice were collected from the Mersey. Samples of the liver,
      kidney and gonad were fixed in 10% formal saline, processed into paraffin wax and
      5 microm sections cut and stained with haematoxylin and eosin. Liver changes
      consisted of variable amounts of glycogen/lipid storage product, minor
      perivenular and perivascular fibrosis, and helminth parasitisation. No tumours or
      foci of cellular alteration, necrosis and inflammation were seen. In the gonad
      only changes consistent with normal gonadal cycling was seen. These studies
      provide evidence that plaice show little or no evidence of toxic pathological
      damage resulting from their stay in the estuary.

PMID- 12408615
TI  - Bacterial killing by Mytilus hemocyte monolayers as a model for investigating the
      signaling pathways involved in mussel immune defence.
AB  - The signaling pathways involved in mussel immune defence were investigated
      utilizing a model of killing of Escherichia coli by Mytilus galloprovincialis
      hemocytes in a co-culture setting. In particular, the role played by different
      mitogen activated protein kinases (MAPKs) and by the production of eicosanoids
      were investigated utilising specific cell permeant, pharmacological enzyme
      inhibitors. Hemocyte pretreatment with the p38 MAPK inhibitor SB203580
      significantly reduced bacterial killing, whereas PD98059 (an inhibitor of ERK-
      extracellularly regulated kinase--MAPK activation) had no significant effect.
      Wortmannin also inhibited bacterial killing, indicating a crucial role for PI3
      kinase activation in the immune response. Killing of E. coli was also reduced by
      inhibitors of both PLA2 and cyclooxygenase activities, indicating that eicosanoid
      production is involved in mediating the response to bacterial challenge. The
      results demonstrate that bacterial killing by mussel hemocytes is particularly
      sensitive to inhibitors of the key steps involved in the transduction of
      bacterial signals into the host cell. Moreover, these data indicate that the
      hemocyte bactericidal activity can be suitably utilized not only for identifying
      the signaling pathways involved in the response to bacterial infection, but also
      as a potential investigative-toxicology model to test drugs and contaminants for
      their effect on the overall mussel immune defence.

PMID- 12408616
TI  - Utilizing in vivo nuclear magnetic resonance spectroscopy to study sublethal
      stress in aquatic organisms.
AB  - In vivo nuclear magnetic resonance spectroscopy (NMR) is a powerful technique for
      characterizing the sublethal actions of physical and chemical stressors in live,
      intact organisms. In particular, 31P NMR is ideal for observing perturbations to
      cellular energetics since critical metabolite concentrations, including
      phosphagens, ATP and inorganic phosphate (Pi), can be measured non-invasively and
      in real time. This technique's versatility is demonstrated not only in the
      diversity of organisms that can be studied, but also in its broad-ranging
      applicability to environmental research. Illustrative studies include the actions
      of copper in adult red abalone (Haliotis rufescens) and changes in energetically
      important metabolites in developing medaka embryos (Oryzias latipes). Advantages
      and disadvantages of in vivo NMR will be discussed.

PMID- 12408618
TI  - The Japanese medaka (Oryzias latipes) model: applicability for investigating the
      immunosuppressive effects of the aquatic pollutant benzo[a]pyrene (BaP).
AB  - Despite the fact that BaP is a carcinogen, mammalian immunosuppressant, and
      ubiquitous aquatic pollutant, knowledge regarding the effects of BaP on the
      immune system of fish is still lacking. To begin to fill this gap, studies were
      conducted in medaka to examine the effects and mechanisms by which BaP exposure
      might alter host immunocompetence. Fish, exposed by IP injection of BaP (2-600
      microg/g BW), were examined after 48 h for effects upon immune function and CYP1A
      expression/activity. Benzo[a]pyrene, at a concentration below that which
      increased levels of CYPIA expression/activity (2 microg BaP/g BW) suppressed
      lymphocyte proliferation. Concentrations of BaP at 20 and 200 microg/g BW.
      suppressed antibody-forming cell (AFC) numbers, superoxide production, and host
      resistance against bacteria. In contrast, exposure to the low affinity aryl
      hydrocarbon receptor (AhR) agonist, benzo[e]pyrene (BeP), neither induced CYP1A
      expression nor altered immune function. Given the lack of immunosuppressive
      effects produced by BeP, and the fact that exposure to the AhR antagonist (and
      CYP1A inhibitor) alpha-naphthoflavone (ANF) ameliorated the suppressive effects
      of BaP upon AFC numbers, the AhR pathway (including CYP1A-mediated production of
      reactive BaP metabolites) appears important in mediating BaP-induced
      immunotoxicity in fish, as in mammals. In the past, the medaka has proven a
      successful model for assessing carcinogenic agents. These studies have
      demonstrated its utility for also determining the immunosuppressive effects of an
      important aquatic contaminant.

PMID- 12408617
TI  - Impact of polychlorinated biphenyls (PCBs) on the immune function of fish: age as
      a variable in determining adverse outcome.
AB  - Polychlorinated biphenyls (PCBs) are a major contaminant of global extent in
      water resources and aquatic biota. Due to its high lipid solubility, PCBs fail to
      be degraded and, therefore, continue to bioaccumulate throughout the environment
      and food chain. To determine the impact of PCBs on the immune system of aged and
      juvenile Japanese medaka (Oryzias latipes), fish were injected with the coplanar
      PCB congener 126 and examined after 3 and 14 days. PCB 126 produced oxidative
      stress in both age groups of fish 14 days post-injection; however, juvenile
      medaka appeared more susceptible than aged fish. Humoral immunity, as determined
      by antibody forming cell (AFC) numbers, was significantly depressed for up to 14
      days post-injection in both age groups. These results demonstrate the sensitivity
      of the fish immune response for predicting PCB-induced immunotoxicity and
      identify age as a variable in determining adverse outcome.

PMID- 12408619
TI  - Disorder and recovery of environmental health monitored by means of lysosomal
      stability in liver of European flounder (Platichthys flesus L.).
AB  - From 1995 to 2000 biological effects were studied in liver of flounder
      (Platichtysflesus L.) from the German Bight. During the study period deleterious
      consequences of acute discharges of DDT and PCBs in early spring 1996 and after
      1998 due to remobilization of contaminants from riverbed deepening of the River
      Elbe became evident. As core biomarker which reflects toxically induced liver
      pathologies and integrates effects of various classes of pollutants we measured
      the integrity of lysosomal membranes in individual flounder liver. During the
      study period, twice statistically significant disturbances of lysosomal function
      was detected in fish from the River Elbe: in summer 1996 and in spring 1999. Yet,
      the detrimental contaminant effects were not only restricted to individuals from
      the Elbe but expanded to those flounder inhabiting formerly less polluted
      reference areas. In contrast to flounder of the Elbe, their ability to recover
      from the lysosomal disorders were limited. While in autumn 2000 Elbe individuals
      showed clear signs of recovery, those fish caught in areas more distant to the
      source of toxicant input still maintained significantly decreased lysosomal
      membrane integrity. It can be speculated that fish populations which are not
      continuously exposed to chronic anthropogenic stress may have a lower potential
      or need a longer period to recover from the effects of pollution.

PMID- 12408620
TI  - Direct comparison of enzyme histochemical and immunohistochemical methods to
      localize an enzyme.
AB  - Immunohistochemical localization of enzymes is compared directly with
      localization of enzyme activity with (catalytic) enzyme histochemical methods.
      The two approaches demonstrate principally different aspects of an enzyme. The
      immunohistochemical method localizes the enzyme protein whether it is active or
      not whereas the catalytic method visualizes the functionally active enzyme only.
      Furthermore, enzyme histochemical methods appear to be highly sensitive in
      comparison with immunohistochemical methods. Finally, the catalytic methods are
      simple and last 5-60 min at room temp, whereas immunohistochemical methods take
      hours at least. It can be concluded that enzyme histochemical methods are the
      methods of choice to localize enzymes because they detect the functional activity
      of an enzyme, they are relatively simple and their sensitivity is high.

PMID- 12408621
TI  - A computational model of the digestive gland epithelial cell of marine mussels
      and its simulated responses to oil-derived aromatic hydrocarbons.
AB  - This paper describes a computational model of digestive gland epithelial cells
      (digestive cells) of marine mussels. These cells are the major environmental
      interface for uptake of contaminants, particularly those associated with natural
      particulates that are filtered from seawater by mussels. Digestive cells show
      well characterised reactions to exposure to lipophilic xenobiotics, such as oil
      derived aromatic hydrocarbons (AHs), which accumulate in these cells with minimal
      biotransformation. The simulation model is based on processes associated with the
      flux of carbon through the cell. Physiological parameters such as fluctuating
      food concentration, cell volume, respiration, secretion/excretion, storage of
      glycogen and lipid, protein/organelle turnover (autophagy/resynthesis) and export
      of carbon to other tissues of the mussel are all included in the model. The major
      response to AHs is induction of increased autophagy in these cells. Simulations
      indicate that the reactions to AHs and food deprivation correspond well with
      responses measured in vivo.

PMID- 12408623
TI  - Development of thyroid abnormalities in mummichogs, Fundulus heteroclitus, from a
      polluted site.
AB  - Previous studies showed that adult and 6-month-old young-of-year Fundulus
      heteroclitus from a polluted site have enlarged thyroid follicles and (in adults)
      higher thyroxine levels compared to fish from an unpolluted reference site. This
      study's purpose was to discover when in development these differences begin to
      appear. For 15-20 mm fish, the average follicle size of the polluted population
      was significantly larger than that of the reference population, similar to the
      pattern found in older fish. However, for the smaller size (12-14.5 mm), the
      average follicle size of fish from the polluted site was significantly smaller.
      Although not statistically significant, radioimmunoassay measurements of
      thyroxine levels were consistent with follicle differences: in larger sizes (20
      25 and 15-20 mm) fish from the polluted site had higher thyroxine levels but the
      smaller size (12-14.5 mm) had lower levels. Therefore, the thyroid abnormalities
      seen in adults begin when the fish are approximately 15-20 mm long. However, the
      follicle size reversal for the 12-14.5 mm range may also indicate abnormality at
      that developmental stage.

PMID- 12408622
TI  - Xenobiotic-induced immunomodulation in the European flat oyster, Ostrea edulis.
AB  - The presence of chemical contaminants in marine coastal waters is a major subject
      of concern since many molecules are potentially immunotoxic, even at low
      concentration. During the last decade, studies in sentinel species, such as the
      blue mussel, Mytilus edulis, or the Pacific oyster, Crassostrea gigas, have
      revealed that immunosuppressive responses can be related to xenobiotic exposure,
      in the laboratory and in the field. In the present study, European flat oysters
      were experimentally exposed to heavy metals, to investigate possible alterations
      of their immune function. Several hematological and functional parameters of
      hemocytes were measured by flow cytometry, a technique allowing rapid, sensitive,
      cell-by-cell measurements in large cell populations. Results reveal a depression
      of phagocytosis and several subcellular, physiological changes in oysters exposed
      to cadmium alone or to cadmium and copper, suggesting an overall alteration of
      the phagocytic function.

PMID- 12408624
TI  - Selenium-induced teratogenicity in Sacramento splittail (Pogonichthys
      macrolepidotus).
AB  - Selenium is a potent reproductive and teratogenic environmental contaminant and
      there are concerns over possible reproductive effects of selenium on the
      Sacramento splittail (Pogonichthys macrolepidotus) population, a threatened
      species, in California, USA. In this study, the teratogenic effects of selenium
      were examined in splittail embryos exposed to 0.0, 5.0, and 15.0 mg l(-1) sodium
      selenite for 48-h at 18.0 degrees C under static conditions, with renewal every
      12 h. Embryo development was evaluated daily for abnormalities from initiation of
      exposure (stage 27) to initiation of exogenous feeding. At the end of evaluation,
      prelarvae were preserved for histological analysis. There were no significant
      differences in mortality or hatching success between control and exposed embryos.
      Exposed fish had pericardial edema and deformities of skeletal tissues (loss of
      tail, lordosis, scoliosis, and kyphosis). Other histological alterations were
      limited to dysplasia, hyperplasia and metaplasia of skeletal tissues in the
      deformed fish. This study showed that a short exposure of embryos during somite
      development has significant effects on the musculoskeletal development.

PMID- 12408625
TI  - Effects of dietary exposure to the pyrethroid pesticide esfenvalerate on medaka
      (Oryzias latipes).
AB  - The pyrethroid insecticide esfenvalerate is widely used on orchard crops
      throughout California. In the aquatic environment, this compound is likely to
      accumulate in sediments, food particles and benthic organisms due to its
      lipophilicity and environmental persistence. This pilot project tested the
      hypothesis that esfenvalerate is toxic to medaka (Oryzias latipes) when taken up
      with the diet. For 7 days fish were fed diets, which contained esfenvalerate in
      three different concentrations (4, 21, 148 mg/kg, measured). Endpoints measured
      were mortality, fecundity, fertilization and hatching success of embryos,
      viability of larvae and cellular stress protein (hsp60, hsp70, hsp90) levels. The
      toxicity of aqueous exposure of medaka to esfenvalerate was also determined.
      Whereas the 96-h LC50 in the aqueous exposure was <9.4 microg/l, the dietary
      exposure did not cause mortality. Possible effects of dietary esfenvalerate were
      seen on fertilization and hatching success and the number of non-viable larvae.
      Expression of hsp60 and hsp90 showed a dose-dependent response pattern.

PMID- 12408626
TI  - Effects of sewage-impacted sediment on reproduction in the benthic crustacean
      Leptocheirus plumulosus.
AB  - Several organic contaminants in sewage effluent have been shown to elicit an
      estrogenic response in juvenile fish. Comparatively little emphasis has been
      placed on assessing these effects in marine invertebrates, particularly benthic
      organisms inhabiting sediment where lipophilic contaminants tend to persist. The
      present study examined reproductive effects in the benthic crustacean
      Leptocheirus plumulosus exposed to sewage-impacted sediment from Jamaica Bay, New
      York. Data from chronic 28-day tests showed a 50% reduction in the average number
      of young (juveniles + embryos) produced per surviving female in exposures to
      sediment from Jamaica Bay (JB). Nonylphenol ethoxylate ('NPEO) concentrations at
      this site were measured at 44.2 microg/g dw, concentrations two orders of
      magnitude higher than reference site concentrations in central Long Island Sound
      (CLIS). Dose-response studies with nonylphenol (NP) amended reference sediment,
      however, did not significantly affect reproduction suggesting that other
      contaminants may have contributed to the effects observed.

PMID- 12408627
TI  - Patterns of heritability of decreased EROD activity and resistance to PCB 126
      induced teratogenesis in laboratory-reared offspring of killifish (Fundulus
      heteroclitus) from a creosote-contaminated site in the Elizabeth River, VA, USA.
AB  - Killifish (Fundulus heteroclitus) from a highly contaminated site on the
      Elizabeth River are resistant to the acute toxicity and the cytochrome P4501A
      (CYP1A)-inducing activity of both the sediments from the site and chemically pure
      polycyclic aromatic hydrocarbons (PAHs). These effects are highly heritable for
      one generation, but heritable to a lesser degree by subsequent generations, in
      clean conditions in the laboratory. We show that offspring of this population of
      Elizabeth River killifish are also resistant to the teratogenicity and P4501A
      inducing activity of PCB congener 126, a prototypical coplanar halogenated
      aromatic hydrocarbon (HAH). Furthermore, the pattern of greater resistance to
      acute toxicity and P4501A-inducing activity in the first generation and less in
      subsequent generations is also observed upon exposure to PCB-126.

PMID- 12408628
TI  - Phototoxicity of pyrene and benzo[a]pyrene to embryo-larval stages of the Pacific
      oyster Crassostrea gigas.
AB  - There is a growing body of evidence to suggest that certain polycyclic aromatic
      hydrocarbons (PAHs) pose a greater hazard to aquatic organisms than previously
      demonstrated, due to their potential to cause photo-induced toxicity when exposed
      to ultraviolet (UV) radiation. The consequences of photo-induced toxicity are
      reported here for embryo-larval stages of the pacific oyster Crassostrea gigas,
      following exposure to pyrene and benzo[a]pyrene. During laboratory
      investigations, significant increases in toxicity were observed in the presence
      of environmentally attainable levels of UV-radiation, compared with embryos
      exposed to PAH alone, at levels previously deemed to have little acute biological
      effect. The phototoxicity of pyrene and benzo[a]pyrene completely inhibited the
      development to the D-shell larval stage when embryos were simultaneously exposed
      to 5 microg l(-1) PAH and ultraviolet light (UVB = 6.3 +/- 0.1 microW/cm2 and UVA
      = 456.2 +/- 55 microW/cm2). A linear relationship was also demonstrated for
      benzo[a]pyrene phototoxicity with decreasing UV light intensity.

PMID- 12408629
TI  - The impact of oestrogenic and androgenic contamination on marine organisms in the
      United Kingdom--summary of the EDMAR programme. Endocrine Disruption in the
      Marine Environment.
AB  - This paper summarises results of the EDMAR programme which is investigating
      oestrogenic and androgenic endocrine disruption in UK coastal waters. Most of the
      data concern fish. Four species (flounder, viviparous blenny and two sand gobies)
      are experiencing feminisation in industrialised estuaries. In males this includes
      vitellogenin (VTG) synthesis, ovotestis induction and/or feminised sexual
      characteristics. Although reproductive success may be impaired in some cases,
      implications for fish populations are still unclear. Suspected causative
      contaminants include natural oestrogenic substances and synthetic oestrogen
      mimics. The majority of the oestrogenic activity is adsorbed to sediments, and
      routes of exposure may include benthic food chain transfer. Some natural
      androgenic substances are also being discharged to estuaries, but their activity
      appears low.

PMID- 12408630
TI  - Intersex in feral marine and freshwater fish from northeastern Germany.
AB  - A histopathological assessment of the gonad of male fish was performed as part of
      biological field studies carried out in coastal waters and small rivers in
      Mecklenburg-Western Pomerania, northeastern Germany. In the marine environment
      the eelpout (Zoarces viviparus) was selected as sentinel species. The three
      spined stickleback (Gasterosteus aculeatus) and perch (Perca fluviatilis) were
      chosen at freshwater locations. Histopathology of the testis revealed the
      presence of intersexuality in specimens of all three species. The intersex
      condition was defined by the simultaneous presence of primary oocytes within the
      apparently normal testis tissue. In comparison to stickleback and perch the
      eelpout exhibited the highest intersex prevalence and the most severe
      histological alterations. Fish with intersex were found at contaminated marine
      and freshwater stations as well as at sites with apparently little pollution. The
      findings suggest that feminised male fish were exposed to endocrine disrupting
      substances in the aquatic environment.

PMID- 12408631
TI  - Dumpton syndrome reduces the tributyltin (TBT) sterilising effect on Nucella
      lapillus (L.) by limiting the development of the imposed vas deferens.
AB  - TBT induces imposex and sterilisation in female Nucella lapillus. Interestingly,
      there are populations where individuals (both males and imposexed females) may
      suffer from a genetic aberration [Dumpton Syndrome (DS)] which results in the
      development of no penis (i.e. aphally). This anomaly confers a so far unexplained
      protection against TBT. Six populations with contrasting DS frequency were
      sampled; the imposex stage in females and the mean calibre of every vas deferens
      (VDC) were assessed. While the sex ratio in the 600 specimens examined was close
      to 1, aphally was more frequent in females than in males (31 and 7%,
      respectively). VDC was significantly higher in normal than in aphallic (DS)
      specimens, independently of sex and/or site. It is concluded that the vas
      deferens imposed by TBT onto DS females is less prone to develop thick enough so
      as to interfere with normal egg laying.

PMID- 12408632
TI  - Cytochrome P450 differences in normal and imposex-affected female whelk Buccinum
      undatum from the open North Sea.
AB  - Normal and imposex-affected female Buccinum undatum were sampled from the open
      North Sea at three locations, one with low, and two with high shipping densities.
      Cytochrome P450 components and P450 aromatase activity were determined in the
      microsomal fractions isolated from pooled digestive gland/gonads. Cytochrome P450
      aromatase activity was significantly higher (P < 0.05) in normal females
      collected in the low shipping density area (1,325 +/- 295 fmol/h/mg protein) than
      levels from imposex animals from a high shipping density area (620 +/- 287
      fmol/h/mg protein). A negative correlation was found between aromatase activity
      and organotin body burden (r = -0.99). Levels of CYP450, cytochrome b5 and NADPH
      cytochrome c reductase activity did not show differences among groups. This is
      the first field evidence of depressed aromatase activity in imposex affected
      females, although additional research under laboratory controlled conditions is
      required to fully understand the mechanisms underlying the development of imposex
      in this species.

PMID- 12408633
TI  - Biomarkers for endocrine disruptors in three species of Mediterranean large
      pelagic fish.
AB  - The hypothesis that Mediterranean top predator species, such as large pelagic
      fish, are potentially at risk due to endocrine disrupting chemicals (EDCs), is
      investigated. The potential estrogenic effects of PHAHs in three fish species of
      commercial interest, the top predators bluefin tuna (Thunnus thynnus thynnus),
      swordfish (Xiphias gladius), and Mediterranean spearfish (Tetrapturus belone),
      were investigated using vitellogenin (Vtg), zona radiata proteins (Zrp) and mixed
      function oxidases (EROD, BPMO) as diagnostic tools. High induction of Vtg and Zrp
      was detected by western blot and ELISA techniques in adult males of X. gladius
      and T. thynnus thynnus, suggesting that these species are at high toxicological
      risk in the Mediterranean sea. Comparison of BPMO and EROD activities in the
      three species indicated, both in male and female, much higher MFO activity in
      bluefin tuna. This data suggests high exposure of this species to lipophilic
      xenobiotic contaminants in the Mediterranean environment.

PMID- 12408634
TI  - Preliminary investigations on vitellogenin m-RNA induction in some bioindicator
      Mediterranean fish species.
AB  - This paper describes the development of a RT-PCR method for assaying Vtg gene
      expression in different marine fish as a potentially valuable and sensitive
      biomarker of exposure to estrogenic chemicals. The levels of Vtg mRNA have been
      analyzed using primers specifically designed for the various species and the
      procedures have been standardized relative to actine mRNA expression levels.
      Different species were analyzed including organisms with a great potential as
      bioindicators in the Mediterranean (i.e. the red mullet Mullus barbatus, the
      striped mullet Mugil cephalus, the European eel Anguilla anguilla) or exposed to
      biomagnification of halogenated hydrocarbons and with elevated commercial value
      (the bluefin tuna Thunnus thynnus). The analysis of vitellogenin mRNA levels has
      been standardized in feral fish providing suitable indications for a future
      development of this approach.

PMID- 12408635
TI  - Tributyltin and triphenyltin induce spermatogenesis in ovary of female abalone,
      Haliotis gigantea.
AB  - Two-month flow-through exposure experiments of tributyltin (TBT) and triphenyltin
      (TPhT) were conducted with abalone, Haliotis gigantea. Nominal concentrations of
      100 ng TBT/l and 100 ng TPhT/l caused significant spermatogenesis in ovaries of
      exposed females. There were also significantly more contracted primary oocytes
      observed in females exposed to either TBT or TPhT than controls. The incidence of
      two types of unknown cells was also significant in females exposed to TPhT. No
      significant histological changes were observed in testis of exposed males. This
      ovarian spermatogenesis caused by TBT and/or TPhT resembles gastropod imposex.
      Remarkably high concentrations of TBT and TPhT were observed in the head
      (including central nervous system ganglia), compared to muscles concentrations.
      Accumulation of TBT and TPhT in the head may disturb reproductive hormonal
      regulators through neuropeptides released from ganglia. This, as well as possible
      aromatase inhibition, may be one of the inducers for spermatogenesis in the
      abalone ovaries.

PMID- 12408636
TI  - Residues of 14C-4n-nonylphenol in mosquitofish (Gambusia holbrooki) oocytes and
      embryos during dietary exposure of mature females to this xenohormone.
AB  - In order to assess in fish the maternal transfer of alkylphenolic compounds to
      the progeny, the identification and quantification of the labelled compounds
      present in oocytes and embryos was conducted after dietary exposure of mature
      female mosquitofish to 14C-4n-nonylphenol during vitellogenesis and embryogenesis
      respectively. Radioactivity found in bile and liver extracts accounted for 0.9
      0.6 and 0.2-0.1% of ingested radioactivity for females exposed during
      vitellogenesis and embryogenesis respectively. The amount of extractable
      radioactivity present in oocytes and embryos was 0.19 and 0.07% of the ingested
      dose respectively. The radio-HPLC profiles obtained from bile, liver, oocyte and
      embryo extracts were similar. They showed the presence of 4n-NP-glucuronide as
      the major metabolite and traces of unchanged 4n-NP. The other metabolites
      corresponded to 8-hydroxynonylphenol, 9-(4-hydroxyphenyl)-nonanoic acid and para
      hydroxybenzoic acid which is the final product of the alkyl chain oxidation. Our
      results indicate that exposure of ovoviviparous female fish to 4-NP during
      vitellogenesis and embryogenesis leads to the contamination of the progeny by 4
      NP and its metabolites.

PMID- 12408637
TI  - Estrogenic responses of larval sunshine bass (Morone saxatilis x M. Chrysops)
      exposed to New York City sewage effluent.
AB  - To determine the estrogenicity of effluents from sewage treatment plants (STPs)
      to larval fish, 2-day-old sunshine bass were exposed to effluents from three STPs
      serving New York City (NYC), varying in size and treatment level. Estrogenic
      response was evaluated by measuring vitellogenin (VTG) and estrogen receptor (ER)
      expression in cytosolic fractions of whole body homogenates. Concentrations of
      the presumptive endocrine disruptors in the effluents were also measured. VTG and
      ER levels in sewage-exposed fish were 3-5 times that observed in controls.
      Combined concentrations of estradiol and estrone ranged from 5 to 13 ng/l and
      nonylphenol-ethoxylate metabolites (NPEOs: 4-nonylphenol, and 1-, 2-, and 3
      nonylphenol-ethoxylates) ranged from 180 to 470 microg/l in chlorinated effluent.
      Results indicate that both ER and VTG can be used as biomarkers for endocrine
      disruption in larval fish, and that 4-day exposure to sewage effluent is
      sufficient to elicit significant expression of these markers in sunshine bass
      larvae. The extremely higher concentrations of NPEOs found in effluent relative
      to hormones (approximately 40,000-fold) indicates that surfactant metabolites may
      be contributing significantly to the estrogenic effects observed.

PMID- 12408638
TI  - Environmental estrogens interact with and modulate the properties of plasma sex
      steroid-binding proteins in juvenile Atlantic salmon (Salmo salar).
AB  - Environmental chemicals may modulate the endocrine system through interaction
      with plasma sex steroid-binding proteins (SBP) and SBP-regulated processes. Some
      of these chemicals, which are known to interact with the estrogen receptor (ER),
      were found to bind competitively to the Atlantic salmon (Salmo salar) SBP and
      potentially disrupt the endocrine function of these proteins. Furthermore, both
      weakly acting (di-n-butyl phthalate) and potent estrogen mimics
      (ethynylestradiol), were able to induce a substantial up-regulation of
      circulating levels of SBP in vivo. Interestingly, modulation of SBP-levels was
      found to be a more sensitive endpoint than chemically induced interference with
      classical ER-mediated mechanisms for weakly acting estrogen mimics like di-(n
      butyl) phthalate. Interference with the endocrine function of SBPs may thus
      introduce a novel mechanism for endocrine disruption. and give additional answers
      to the question why some weakly acting xenoestrogens are causing "estrogen-like"
      reproductive disturbances in developing males.

PMID- 12408639
TI  - O,p'-DDT induction of vitellogenesis and its inhibition by tamoxifen in Nile
      tilapia (Oreochromis niloticus).
AB  - In order to investigate the mechanism by which o,p'-DDT disrupts endocrine
      functioning of Nile tilapia in vivo, the estrogenicity of o,p'-DDT was
      investigated in conjunction with 17beta-estradiol (E2) and tamoxifen. Mature,
      male tilapia were treated intraperitoneally with o,p'-DDT (60 mg/kg, one dose) or
      E2 (5 mg/kg, four doses) in the presence or absence of tamoxifen (5 mg/kg, six
      doses) for 12 days and then plasma vitellogenin (Vtg) (measured as alkaline
      labile phosphorous), E2, and testosterone (T) were measured. Vtg levels were
      increased dramatically by E2 (1,744 +/- 171 microg/ml) and moderately by o,p'-DDT
      (82 +/- 15 microg/ml) compared with controls (23 +/- 3.5 microg/ml). Tamoxifen
      alone had no effect on Vtg production, but inhibited both E2 and o,p'-DDT
      stimulated vitellogenesis. T levels were reduced with E2 administration (1,688 +/
      383 pg/ml) and declined further with the combined treatment of E2 and tamoxifen
      (281 +/- 70 pg/ml), compared with controls (6,558 +/- 1,438 pg/ml). Tamoxifen or
      o,p'-DDT alone did not affect T levels, but their combined treatment did (2,069
      +/- 647 pg/ml). The results of this study suggest that o,p'-DDT is weakly
      estrogenic in male tilapia, and that this activity may be mediated through the
      estrogen receptor.

PMID- 12408640
TI  - Assessment of putative endocrine disrupters in an in vivo crustacean assay and an
      in vitro insect assay.
AB  - Concern over endocrine disrupters in coastal ecosystems has stimulated global
      efforts to understand their potential impacts on fish and invertebrate
      communities. Given that marine crustaceans are sensitive to the effects of
      alkylphenols and other xenobiotics, we are currently investigating whether these
      responses may be caused via an endocrine mechanism. Tisbe battagliai (Copepoda:
      Harpacticoida) is representative of an ecologically important group of meiofauna,
      is sensitive to toxicants and is used as an international test species in marine
      ecotoxicology. A 21-day life-cycle test that incorporates assessment of survival,
      development, reproduction and sex ratios, has shown that populations of T.
      battagliai are not significantly affected by environmentally relevant levels of
      steroidal oestrogen agonists, or by related synthetic receptor agonists. The
      absence of in vivo effects due to these steroid agonists and antagonists prompted
      in vitro studies of ecdysteroid receptor activity of a range of reference
      compounds and environmental contaminants with an ecdysteroid receptor (EcR/USP)
      based screening assay derived from the BII haemocyte line of Drosophila
      melanogaster. The implications for environmental monitoring of endocrine
      disrupters are discussed.

PMID- 12408641
TI  - Mechanisms of imposex induction in the mud snail, Ilyanassa obsoleta: TBT as a
      neurotoxin and aromatase inhibitor.
AB  - The occurrence of imposex, imposition of male sex characteristics on female
      snails, has been extensively documented throughout the world. Tributyltin (TBT)
      and other organotins have been causally linked to imposex induction at levels as
      low as 2 ng/l. There are several proposed mechanisms of action. First, TBT has
      been shown to be neurotoxic and to accumulate in snail ganglia. Peptide hormones
      control sexual differentiation in gastropods, and one hypothesis is that TBT acts
      as a neurotoxin to abnormally release the peptide hormone Penis Morphogenic
      Factor (PMF). However, PMF has not been characterized to date. The neuropeptide
      APGWamide significantly induces imposex in the mud snail, Ilyanassa obsoleta, at
      10(-16) moles sub-cutaneous (SQ) injection over 2 weeks, and could be the PMF in
      this species. A second hypothesis is that TBT inhibits aromatase activity leading
      to increased testosterone levels and decreased estradiol. In vitro studies with
      snail digestive gland microsomes showed that TBT-dosed snails not exhibiting
      imposex had a 52% reduction in aromatase activity. Although the role of
      vertebrate sex steroids is not known in gastropods, it is possible that the
      combination of changes in peptide and steroid hormones may lead to imposex
      induction at extremely low doses of TBT.

PMID- 12408642
TI  - The expression of CYP1A, vitellogenin and zona radiata proteins in Atlantic
      salmon (Salmo salar) after oral dosing with two commercial PBDE flame retardant
      mixtures: absence of short-term responses.
AB  - The short-term effects of the commercial PBDE flame retardant mixtures Penta-BDE
      and cta-BDE on the expression of cytochrome P450 1A (CYP1A), vitellogenin (Vtg)
      and zona radiata proteins (Zrp) were investigated in juvenile salmon (Salmo
      salar). For this purpose, groups of fish were dosed twice (oral intake at days I
      and 4) with 10 and 50 mg/kg body weight of both commercial mixtures. The fishes
      were sacrificed at day 7 (n = 5 for each group) and 14 (n = 6 for each group),
      and blood, liver, fillet, and brain were collected. Blanks and positive controls
      were also part of the experiment. The expressions of Vtg, Zrp, and CYPIA were
      measured with several techniques (EROD, ELISA, Western, Northern and Slot Blot).
      The values in the groups of fish treated with Penta-BDE or Octa-BDE did not
      significantly differ from the reference group for any of the parameters tested.
      In contrast, the positive control groups treated with estradiol-17beta for Vtg
      and Zrp expression, and beta-naphthoflavone for CYP1A expression did show a
      significant response, indicating the potential sensitivity of the fishes for the
      parameters measured. Since the results of the chemical analyses showed
      concentrations of a number of PBDE congeners in liver, fillet, and brain that
      were about three orders of magnitude above those of fish from the North Sea, it
      is concluded that the short-term toxicity of both commercial PBDE mixtures for
      these endpoints was low.

PMID- 12408643
TI  - The potential of the three-spined stickleback (Gasterosteus aculeatus L.) as a
      combined biomarker for oestrogens and androgens in European waters.
AB  - The majority of endocrine disruption studies in Europe have been on non
      indigenous species (some of them tropical!)--and none of which has traits that
      make them suitable for the detection of androgenic compounds. To overcome these
      problems, we have been developing the stickleback as a model biomarker for
      testing the effect of endocrine disrupters in European waters. Its advantages
      are: it is the only fish with a quantifiable in vivo androgen and anti-androgen
      endpoint (the production of the glue protein, spiggin, by the kidney); it is the
      only fish in which it will be possible to simultaneously test oestrogenic and
      androgenic properties of compound; it has a genetic sex marker; it is found in
      all EU countries; it survives and breeds in both seawater and freshwater; it is
      extremely robust and can be readily deployed in situ; it displays a variety of
      pronounced reproductive behaviours; it has a simple and short life cycle, low
      fecundity and high egg/fry survival rates.

PMID- 12408644
TI  - 4-tert-octylphenol and 17beta-estradiol applied by feeding to flounder
      Platichthys flesus: induction of vitellogenin and accumulation in tissues.
AB  - In order to simulate a possible natural administration route of xenoestrogens
      male flounder Platichthys flesus were exposed via the diet to the alkylphenol 4
      tert-octylphenol. Treatment with 4-tert-octylphenol (10, 50 and 100 mg OP kg(-1)
      BW) or 17beta-estradiol (0.05 mg kg(-1) BW) every second day during a period of
      11 days resulted in a significant increase in plasma vitellogenin (Vtg)
      concentrations. The induction of Vtg was greatest in the fish receiving 50 mg OP
      kg-' BW. A significant accumulation of 4-tert-octylphenol was found in liver and
      muscle tissue of the OP treated groups. The tissue concentrations of 4-tert
      octylphenol and the plasma vitellogenin concentration were positively correlated.
      The results show that 4-tert-octylphenol accumulates in liver and muscles of
      flounder P. flesus, and exerts estrogenic effects such as vitellogenin induction.

PMID- 12408645
TI  - Effects of an environmental estrogen, 17alpha-ethinyl-estradiol, on the maternal
      fetal trophic relationship in the eelpout Zoarces viviparus (L).
AB  - In the present experiment pregnant eelpout Zoarces viviparus females were exposed
      to 0, 5, 10, 50, 500 ng/l of the synthetic estrogen ethinylestradiol (EE2) and to
      500 ng/l estradiol-17beta (E2) under flow-through conditions during 3 weeks and
      the maternal-fetal trophic response was investigated. The circulating yolk
      precursor protein vitellogenin, measured by ELISA, increased from a mean control
      value of 0.017-36 mg/ml in the plasma of the motherfish exposed to the highest
      concentration of EE2 This increase in vitellogenin was also depicted by a 288%
      increase in circulating calcium levels. During pregnancy the ovary represents a
      new route of calcium loss from the maternal blood for the growth of the embryos.
      However, a significant decrease (120% in the group exposed to the highest
      concentration of EE2) in the calcium level in the ambient medium of the embryos,
      the ovarian fluid, was observed concomitant with the increase in maternal plasma
      calcium in the EE2-exposed females. In contrast, the level of circulating amino
      acids decreased in the maternal blood, with a slight concomitant increase in the
      ovarian fluid of the exposed fish. These and other metabolic observations
      indicate that exposure to different doses of EE2 and to estradiol-17beta affects
      the maternal-fetal trophic relationship.

PMID- 12408646
TI  - Esterases as biomarkers in Nereis (Hediste) diversicolor exposed to temephos and
      Bacillus thuringiensis var. israelensis used for mosquito control in coastal
      wetlands of Morbihan (Brittany, France).
AB  - Since 1998, a biomonitoring programme has been implemented to assess the
      potential impact of chemical mosquito control on macroinvertebrates of the
      coastal wetlands of Morbihan (Brittany, France). Acetylcholinesterase and
      carboxylesterases were used as biomarkers to assess the effects of Abate 500e
      (a.i. temephos) and Vectobac 12 AS (a.i. endotoxins of Bacillus thuringiensis
      var. israelensis, Bti) in Nereis (Hediste) diversicolor. Esterase inhibition
      revealed a marked impact of temephos, suggesting preferential contamination of
      the worms through the food. In Bti-exposed N. diversicolor, random variations of
      esterase activities were observed, that could not be attributed to the larvicide.
      However, esterases only reflected indirect physiological effects of Bti, and
      further investigations are needed to identify biomarkers more specific of Bti
      endotoxins.

PMID- 12408647
TI  - Multi-trial biomarker approach in Meganyctiphanes norvegica: a potential early
      indicator of health status of the Mediterranean "whale sanctuary.".
AB  - The aim of this study was to propose a suite of biomarkers (BPMO activity, NADPH
      cytocrome c reductase, NADH-ferricyanide reductase. esterases, porphyrins,
      vitellogenin and zona radiata proteins) and residue levels (organochlorines, PAHs
      and heavy metals) in the zooplanktonic euphausiid Meganyctiphanes norvegica as a
      potential multi-disciplinary diagnostic tool for assessment of the health status
      of the Mediterranean "whale sanctuary". Very little difference in BPMO was
      detected between sites, with values ranging from 0.75 to 2.68 U.A.F./mg prot/h.
      On the other hand larger differences between sites were found for reductase
      activities. Esterases (AChE), porphyrins (Copro-, Uro-, Proto-porphyrins)
      vitellogenin and zona radiata proteins were also detectable in this zooplanctonic
      species. Hg showed mean levels of 0.141 ppm d.w., Cd 0.119 ppm d.w. and Pb 0.496
      ppm d.w. Total PAHs ranged from 860.7 to 5,037.9 ng/g d.w., carcinogenic PAHs
      from 40.3 to 141.7 ng/g d.w., HCB from 3.5 to 11.6 ng/g d.w., DDTs from 45.3 to
      163.2 ng/g d.w. and the PCBs from 84.6 to 210.2 ng/g d.w.

PMID- 12408648
TI  - The use of porphyrins as a non-destructive biomarker of exposure to contaminants
      in two sea lion populations.
AB  - This study was carried out in two populations of Otariaflavescens, living in a
      polluted and in a reference site, in order to validate the use of porphyrins as a
      non-destructive biomarker of exposure to environmental contaminants. Analysis of
      porphyrins was carried out in the feces, blood and fur of free ranging sea lions
      and in the liver and kidney of stranded specimens. The results show that: (a) all
      biological materials used were useful for porphyrin determinations; (b) no clear
      seasonal variations in porphyrin accumulation and excretion were found; (c)
      differences in fecal porphyrin levels existed between the two colonies.

PMID- 12408649
TI  - Biochemical indicators of contaminant exposure in spotted pigfish (Orthopristis
      ruber) caught at three bays of Rio de Janeiro coast.
AB  - The initial sampling in the Marine Monitoring Program (MOMAM), coordinated by the
      Ministry of Marine Affairs (IEAPM), was performed along the southeast coast of
      Brazil. Orthopristis ruber samples were collected at Guanabara, Sepetiba and Ilha
      Grande Bays. Microsomal CYP1A levels and cytosolic cholinesterase (ChE), catalase
      (CAT) and glutathione S-transferase (GST) activities were measured in the liver
      of these fish according to established procedures. CAT activity and CYP1A content
      were significantly higher (P < or = 0.05) in fish caught at Guanabara Bay, which
      might be due to higher levels of peroxisome proliferators and Ah receptor
      agonists, respectively, at this site compared to the other sites. Also, lower GST
      activity was observed in fish from this site, which may possibly be related to
      the presence of oxidative-stress inducing compounds.

PMID- 12408650
TI  - Kinetic and toxicological characteristics of acetylcholinesterase from the gills
      of oysters (Crassostrea rhizophorae) and other aquatic species.
AB  - The aim of this work was to characterize the cholinesterases from gills of
      Crassostrea rhizophorae in order to use them as biomarkers. Gills were
      homogenized and then centrifuged (9,000 x g, 4 degrees C, 30 min). S9 and Triton
      X-100 S9 treated (TX S9) fractions were employed as enzyme source. Km(ap) and
      Vmax were estimated, using acetylthiocholine iodide as substrate. Inhibition
      assays were performed with iso-OMPA and eserine. The Km(ap) for S9 and TX S9
      fractions were 0.05 and 0.06 mM, whereas the Vmax were 1.92 and 5.84 nmol/min/mg
      protein. respectively. No inhibition was detected when the samples were incubated
      with iso-OMPA, suggesting the presence of acetylcholinesterases (AChE) in oyster
      gill homogenates. Sensitivity to eserine inhibition of AChE in the gills of
      oysters is intermediate when compared with other aquatic species.

PMID- 12408651
TI  - The phthalate diesters DEHP and DBP do not induce lauric acid hydroxylase
      activity in rainbow trout.
AB  - Aquatic organisms are extensively exposed to phthalate esters. We have
      investigated in trout the effects of diethylhexylphthalate (DEHP) and
      dibutylphthalate (DBP) on xenobiotic metabolizing enzymes which have been
      suggested as possible environmental biomarkers. Rainbow trout (Oncorhynchus
      mykiss) were waterborne exposed to DEHP (1 mg/l) or DBP (0.1 or 1 mg/l) for 72 h.
      Another group of rainbow trout received daily for 3 days an intraperitoneal
      injection of 50 mg/kg of DEHP or DBP. Laurate hydroxylation, ethoxyresorufin-o
      deethylation, UDP-glucuronyltransferase activity and glutathione-S-transferase
      activity were measured in liver and extrahepatic tissues. The phthalate esters
      have been found not to induce these enzymes; in particular, the results do not
      support the previously described induction of lauric acid hydroxylase in sea bass
      treated with DEHP [Comp. Biochem. Physiol. B122 (1999) 253.].

PMID- 12408652
TI  - Seasonal variation in lysosomal destabilization in oysters, Crassostrea
      virginica.
AB  - Lysosomal destabilization assays have been used as valuable biomarkers of
      pollutant exposures in a variety of bivalve and fish species. The responses of
      oysters, Crassostrea virginica, deployed at and native to various reference and
      degraded sites were evaluated for lysosomal destabilization during both summer
      and winter seasons. In both native and deployed oysters, lysosomal
      destabilization rates tended to be higher during the winter at both reference and
      polluted sites. There are at least two hypothetical explanations. Greater
      lysosomal destabilization rates may be related to physiological changes
      associated with mobilization of nutrient reserves during the winter and
      gametogenesis. However, lysosomal destabilization in deployed oysters was
      correlated with tissue metal concentrations. These data also support a second
      hypothesis that seasonal differences in physico-chemical factors (such as reduced
      levels of acid volatile sulfides) may increase the bioavailability of metals
      during the winter so that adverse effects are more pronounced.

PMID- 12408653
TI  - Evaluation of acetylcholinesterase activity in several zooplanktonic crustaceans.
AB  - Zooplankton are an essential component of the marine and estuarine food chains.
      The ecotoxicological risk to zooplanktonic communities, estimated through the use
      of the biomarkers, can be used as an early warning signal of a potential
      alteration of the ecosystem health. The aim of this project was to evaluate the
      potential use of several biomarkers (esterases, mixed function oxidases,
      porphyrins) in zooplanktonic organisms. The acetylcholinesterase activity (AChE)
      was determined in homogenates of whole organisms of 10 different zooplanktonic
      crustaceans. Mean activity of AChE was 10.05 micromol/min/g for Acartia
      margalefi; 3.30 for Acartia latisetosa; 79.70 for Siriella clausi; 49.97 for
      Diamysis bahirensis; 7.48 for Siriella armata; 14.20 for Mysidopsis gibbosa; 4.49
      for Euphausia crystallorophias; 1.66 for Euphausia superba; 2.74 for Streetsia
      challengeri; 13.26 for Meganycthiphanes norvegica. The species moreover showed a
      linear increase in enzyme activity in relation to the increase in sample
      concentration. The key result of this study concerns the different AChE activity
      basal values of the crustaceans' different species.

PMID- 12408654
TI  - Tolerance and hormesis--increased resistance to copper in hydroids linked to
      hormesis.
AB  - Cultured clones of the colonial hydroid Laomedeaflexuosa have been used over some
      years as an experimental model to study the dynamics of growth control [J. Mar.
      Biol. Ass. UK (1981a) 61, 35; Aquatic Toxicology (1981b) 1, 227; Journal of
      Applied Toxicology (2000a) 20, 93]. Exposure to toxic agents has been an
      essential element of the approach, providing the stimulus to elicit adaptive
      control system responses. While the work has provided interpretations of
      physiological interest, it has also given insights to some toxicological
      phenomena. It is proposed that hormesis, as a stimulation of growth due to
      exposure to low concentrations of copper (1-10 microg l(-1)), is due to increases
      in the preferred rate of the growth control mechanism. This increases the
      capacity to counteract inhibition and confers intolerance to the inhibitor, while
      overcorrections to low concentrations cause hormesis.

PMID- 12408655
TI  - Field application of biochemical markers and a physiological index in the mussel,
      Mytilus galloprovincialis: transplantation and biomonitoring studies in the
      lagoon of Venice (NE Italy).
AB  - A number of biochemical markers and a physiological index were measured in
      mussels, Mytilus galloprovincialis, transplanted or native to five different
      contaminated sites in the lagoon of Venice. Mussels from Pellestrina, a reference
      site in the adjacent Adriatic Sea, were transplanted for 6 weeks to areas of the
      lagoon where indigenous mussels were also collected. As biochemical indices,
      superoxide dismutase (SOD), catalase, aldehyde dehydrogenase (ADH) and NADPH
      cytochrome c reductase (NADPHcred) were measured in mussel digestive gland;
      survival in air as a physiological index was also determined. Biomarker responses
      varied among sites and between indigenous and transplanted animals. Significant
      induction of catalase and SOD was shown in animals transplanted to the urban
      sites of Salute and Chioggia, respectively. In indigenous mussels, induction of
      SOD and NADPHcred was seen in animals from the polluted site of Treporti and the
      heavily contaminated industrial area of Marghera. The overall biochemical data
      indicate significantly higher activity for ADH in transplanted animals in
      comparison with indigenous ones which, in contrast, present an increase in SOD.
      As regard survival in air, control mussels did not seem to be healthier in
      comparison either with transplanted or indigenous ones, suggesting that pollution
      has no effect on this parameter.

PMID- 12408656
TI  - Field application of lysosomal destabilisation indices in the mussel Mytilus
      galloprovincialis: biomonitoring and transplantation in the Lagoon of Venice
      (north-east Italy).
AB  - A field study was carried out in the Lagoon of Venice (north-east Italy) with the
      aim of evaluating the potential use of lysosomal destabilisation as a biomarker
      of anthropogenic stress in the autochthonous mussel Mytilus galloprovincialis.
      Two different approaches were adopted in biomonitoring six sites in the Lagoon,
      evaluating indigenous populations of mussels and organisms transplanted from a
      reference site and checked at several points in time. Lysosomal membrane
      stability was investigated by means of two tests: neutral red retention assay
      (NRRA) for evaluating haemocyte lysosomes and lysosomal latency test (LLT) for
      digestive cell lysosomes. Results indicate that the lysosomal response measured
      in haemocytes according to NRRA is a more valuable biomarker of anthropogenic
      stress in the framework both of passive and active biomonitoring in marine
      coastal environments.

PMID- 12408657
TI  - A non-destructive assessment of the exposure of crabs to PAH using ELISA analyses
      of their urine and haemolymph.
AB  - Urine and haemolymph can be repeatedly sampled from crabs with no (or limited)
      damage to the organism. Their analysis offers a measure of the animals' exposure
      to biologically available contaminants. Shore crabs (Carcinus maenas) were
      exposed to the PAHs phenanthrene and pyrene at concentrations ranging from 20 to
      200 microg l(-1). After 48 h, urine and haemolymph samples were taken and
      analysed using ELISA and UV-fluorescence spectrophotometry. High correlations
      were recorded between the two sets of results from the urine analyses (r2 = 0.83
      for phenanthrene and r2 = 0.88 for pyrene). Contaminant concentrations were much
      lower in haemolymph than in the urine. Analyses of urine taken from crabs
      collected from clean and contaminated sites confirm the suitability of these
      analyses for environmentally exposed organisms. Again, a good correlation was
      recorded between the ELISA and spectrofluorimetric analysis (r2 = 0.83). In this
      instance, difficulties were experienced with haemolymph analyses owing to a lack
      of sensitivity.

PMID- 12408658
TI  - Data on the preservation of Leishmania DNA from clinical samples during the pre
      analytic phase of polymerase chain reaction.

PMID- 12408659
TI  - Pyrimethamine/sulfadoxine combination in the treatment of uncomplicated
      falciparum malaria: relation between dihydropteroate synthase/dihydrofolate
      reductase genotypes, sulfadoxine plasma levels, and treatment outcome.
AB  - Several in vitro studies have shown the correlation between mutations in dhfr and
      dhps genes and resistance to pyrimethamine/sulfadoxine (PYR/SDX) combination, but
      the in vivo correlates of these mutations with PYR/ SDX efficacy have not been
      investigated fully. We assessed PYR/SDX efficacy in relation to the frequency of
      dhfr and dhps mutations in 37 Plasmodium falciparum isolates sampled before
      treatment. Plasma levels of SDX measured at days 0, 3, 7, and 14 ascertained drug
      absorption. Point mutations were detected only at codons 51 and 108 of dhfr and
      codon 436 of dhps. The frequency of dhfr 51/108 and dhps 436 mutations was 79%
      and 8%. The plasma levels of SDX indicated adequate drug absorption by all
      patients. The presence of Ile 51 and Asn 108 mutations among parasites that
      cleared after treatment indicates that these mutations alone are insufficient to
      cause in vivo resistance. In all recrudescent parasites, however, the presence of
      Ile 51/Asn 108 dhfr mutations was coupled with the dhps Ala 436. The findings
      suggest that the presence of Ile 51/Asn 108 dhfr mutations and Ala 436 dhps
      confers decreased susceptibility of P. falciparum to PYR/SDX in areas of low
      endemicity.

PMID- 12408660
TI  - Cerebral involvement in benign tertian malaria.
AB  - Although Plasmodium vivax usually causes benign uncomplicated malaria, it can
      occasionally result in severe disease with life-threatening, end-organ
      involvement generally seen with falciparum malaria. We report a case of cerebral
      malaria caused by P. vivax and review the literature on this subject.

PMID- 12408661
TI  - Monitoring the chromosome 2 intraerythrocytic transcriptome of Plasmodium
      falciparum using oligonucleotide arrays.
AB  - To test the feasibility of using short oligonucleotide probes to monitor
      transcript levels in Plasmodium falciparum, a microarray was manufactured
      containing 4,167 (25 base single-stranded) probes derived from the predicted
      coding region of P. falciparum chromosome 2. RNA samples from three asexual
      stages (rings, trophozoites, and schizonts) were labeled and hybridized to the
      arrays. These results were reproducible, and transcripts were detected for 69% of
      the 210 genes on chromosome 2. In addition, of the 145 expressed genes, 1/3
      appeared to be differentially transcribed during the asexual cycle. Some regions
      of the chromosome appeared to be transcriptionally silent. Results were confirmed
      by Northern blot analysis and by quantitative reverse transcriptase-polymerase
      chain reaction. These data validate the use of relatively short 25-mers for
      monitoring the expression of a genome that is 82% AT rich.

PMID- 12408662
TI  - Roof gutters: a key container for Aedes aegypti and Ochlerotatus notoscriptus
      (Diptera: Culicidae) in Australia.
AB  - The contribution of roof gutters to Aedes aegypti (L.) and Ochlerotatus
      notoscriptus (Skuse) pupal populations was quantified for the first time in
      Cairns, Australia. Concurrent yard and roof surveys yielded an estimated 6,934
      mosquito pupae, comprising four species. Roof gutters were an uncommon but
      productive source of Ae. aegypti in both wet season (n = 11) and dry season (n =
      2) surveys, producing 52.6% and 39.5% of the respective populations. First story
      gutters accounted for 92.3% of the positive gutters. Therefore, treatment of roof
      gutters is a critical element in Ae. aegypti control campaigns during dengue
      outbreaks. In wet season yards, the largest standing crops of Ae. aegypti
      occurred in garden accoutrements, discarded household items, and rubbish (36.4%,
      28.0%, and 20.6%, respectively). In dry season yards, rubbish produced 79.6% of
      the Ae. aegypti pupae. The number of Ae. aegypti pupae/person was 2.36 and 0.59
      for the wet and dry season surveys, respectively.

PMID- 12408663
TI  - Dengue and its vectors in Thailand: introduction to the study and seasonal
      distribution of Aedes larvae.
AB  - A study was conducted from 1989 to 1994 that included surveillance for dengue and
      its mosquito vectors in 3 villages and 2 schools in Chachoengsao Province, 100 km
      east of Bangkok, Thailand. The study is introduced, and results of larval surveys
      for Aedes mosquitoes (predominantly Aedes aegypti (L.)), with 94, 86, and 90% of
      positive containers infested by this species in the hot, wet, and cool seasons,
      respectively), are described. These surveys were conducted in 1990-1991 during
      each of the 3 principal seasons: hot (February-April), rainy (May-October), and
      cool (November-January). Indoor maximum and minimum temperatures were
      consistently greater than outdoor temperatures. The differences between maximum
      and minimum temperatures both indoors and outdoors varied seasonally, with the
      greatest differences in the cool season and the least differences in the rainy
      season. The most rain fell in September and October and the least rain in
      December, January, and February. The number of Aedes larvae in each container was
      categorized (no larvae, 1-9 larvae, 10-50 larvae, > 50 larvae) by dipping with a
      fishnet or by visual examination (for drinking water). A larval index was
      calculated for each house and school by summing the estimations from each
      container. These indexes showed that one village had more larvae in every season
      (mean larval index per house = 117) than the other 2 villages (larval indexes of
      86 and 70). The larval index of each house was mapped for each season, and the
      distribution was spatially analyzed by producing kriged estimates of interpolated
      data. These analyses showed that larvae were significantly concentrated in
      particular areas of the villages, especially during the wet season. Even when
      larvae were least abundant, every part of each village had at least some larvae.
      The results of the study imply that dengue vector control programs in Southeast
      Asian villages could increase their efficiency by applying their most energetic
      efforts on schools and areas with the greatest abundance of larvae, as measured
      by calculation of larval indexes.

PMID- 12408664
TI  - Growth characteristics of ChimeriVax-DEN2 vaccine virus in Aedes aegypti and
      Aedes albopictus mosquitoes.
AB  - The chimeric yellow fever (YF) 17D-dengue type 2 (ChimeriVax-DEN2) vaccine virus
      developed by Acambis, Inc. (Cambridge, MA) contains the prM and E genes of wild
      type (wt) dengue 2 (DEN-2) (strain PUO-218) virus in the YF vaccine virus (strain
      17D) backbone. The potential of ChimeriVax-DEN2 virus to infect and be
      transmitted by Aedes aegypti, the principal DEN and YF virus mosquito vector, and
      Aedes albopictus, a species that occurs in areas of active transmission of YF and
      DEN viruses, was evaluated. Mosquitoes were intrathoracically (IT) inoculated
      with virus or were fed a virus-laden blood meal, and the replication kinetics of
      ChimeriVax-DEN2 were compared with the wt DEN-2 and YF 17D vaccine viruses.
      Replication of YF 17D virus is attenuated in cultured Ae. albopictus C6/36
      mosquito cells and in Ae. aegypti and Ae. albopictus mosquitoes. Growth of
      ChimeriVax-DEN2 virus similarly was restricted in C6/36 cells and in mosquitoes.
      ChimeriVax-DEN2 replicated in 56% of IT inoculated Ae. aegypti, and virus
      disseminated to head tissue in 36%, with a mean viral titer of 1.8 log10
      PFU/mosquito. Of mosquitoes, 16% of Ae. aegypti and 24% of Ae. albopictus were
      infected 14 days after a blood meal containing ChimeriVax-DEN2, but virus did not
      disseminate to head tissue. In contrast, DEN-2 replicated in all IT inoculated
      and orally infected Ae. aegypti (mean titer 5.5 log10 PFU/mosquito), and virus
      disseminated to head tissue in 95%. Of Ae. albopictus, 84% were infected after a
      blood meal containing DEN-2 virus; dissemination occurred in 36%. Replication of
      ChimeriVax-DEN2 virus in mosquitoes corresponded to that of YF 17D vaccine virus,
      which is restricted in its ability to infect and replicate in mosquitoes.
      Therefore, transmission of ChimeriVax-DEN2 virus by vector mosquitoes is
      unlikely.

PMID- 12408665
TI  - Lymphatic filariasis elimination and schistosomiasis control in combination with
      onchocerciasis control in Nigeria.
AB  - This paper describes a pilot initiative to incorporate lymphatic filariasis (LF)
      elimination and urinary schistosomiasis (SH) control into a mature onchocerciasis
      control program based on community-directed ivermectin treatment in central
      Nigeria. In the same districts having onchocerciasis we found LF (as determined
      by blood antigen testing in adult males) in 90% of 149 villages with a mean
      prevalence of 22.4% (range 0-67%). Similarly, SH, as determined by dipstick
      reagent testing for blood in urine from school children, was found in 91% of 176
      villages with a mean orevalence in school age children of 24.4% (range 0-87%).
      Health education and treatment interventions for SH resulted in 52,480 cumulative
      praziquantel treatments, and 159,555 combined onchocerciasis and LF treatments
      (with ivermectin and albendazole) as of the end of 2000. Treatments for
      onchocerciasis and LF were separated by at least 1 week from treatments for SH.
      There was no negative impact on the coverage of the onchocerciasis program by the
      addition of LF and SH activities.

PMID- 12408666
TI  - Activity of azithromycin against Leishmania major in vitro and in vivo.
AB  - Azithromycin, an azalide antibiotic of the macrolide family, concentrates in the
      tissues and especially in macrophages. Because Leishmania parasites reside in
      these cells, we tested this antibiotic for a possible antileishmanial activity in
      vitro and in vivo. Azithromycin decreased the Leishmania major promastigote count
      in cell-free cultures at log phase approximately 50-fold. In macrophage cultures
      infected with L. major amastigotes, azithromycin caused a significant decrease in
      parasite levels with an ED50 of 12 microg/ml. The activity in vivo was evaluated
      after infection of the footpads of susceptible BALB/cByJ mice and resistant
      C57BL/6J mice with L. major. Treatment of BALB/cByJ mice with azithromycin, 100
      to 200 mg/kg/d, resulted in a significant decrease in lesion size and in the
      number of parasites per lesion, whereas no effect was seen in the treated
      C57BL/6J mice. Azithromycin has activity against L. major in vitro and in vivo.
      Given the severity of the disease and the limitations of the available
      therapeutic agents, azithromycin may have a significant role in the treatment of
      this group of diseases.

PMID- 12408667
TI  - The importance of leptospirosis in Southeast Asia.
AB  - The importance of leptospirosis in Southeast Asia was assessed in conjunction
      with other studies supported by the U.S. Naval Medical Research Unit No. 2 (US
      NAMRU-2), Jakarta, Republic of Indonesia. These included studies of hospital
      based, acute clinical jaundice in Indonesia, Lao PDR, and Socialist Republic of
      Vietnam; nonmalarial fever in Indonesia; and hemorrhagic fever in Cambodia.
      Background prevalence estimates of leptospiral infection were obtained by a cross
      sectional, community-based study in Lao PDR. Laboratory testing methods involved
      serology, microscopic agglutination test, and reverse-transcriptase polymerase
      chain reaction. Suggestive evidence of recent leptospiral infections was detected
      in 17%, 13%, and 3% of patients selected on the basis of non-hepatitis A through
      E jaundice, nonmalarial fever, and hemorrhagic fever (in the absence of acute,
      dengue viral infections). Leptospiral IgG antibody, reflective of prior
      infections, was detected in 37% of human sera, collected in Lao PDR. The
      predominant leptospiral serogroups identified from cases with clinical jaundice
      were Hurstbridge, Bataviae, and Icterohaemorrhagiae tonkini LT 96 69. Among the
      nonmalarial febrile cases, Bataviae was the most frequently recognized serogroup.
      Pyrogenes and Hurstbridge were the principal serogroups among the hemorrhagic
      fever case subjects. These findings further attest to the relative importance of
      clinical leptospirosis in Southeast Asia. The wide spectrum of clinical signs and
      symptoms associated with probable, acute, leptospiral infections contributes to
      the potential of significant underreporting.

PMID- 12408668
TI  - Multiple cerebral infarctions following a snakebite by Bothrops caribbaeus.
AB  - Bothrops caribbaeus, a species of the Bothrops complex, is found only in the
      island of Saint Lucia, West Indies. Snakebite from this pitviper is very rare. We
      report the case of a healthy 32-year-old Saint Lucian man who developed multiple
      cerebral infarctions following envenoming by this snake. This patient developed
      signs and symptoms very similar to those observed in patients envenomed by
      Bothrops lanceolatus, a snake found only in Martinique, the neighbor island of
      Saint Lucia. This clinical presentation differs dramatically from coagulopathies
      and systemic bleeding observed with the Central and South American bothropic
      envenomings. The exact mechanism of this thrombogenic phenomenon, leading to a
      unique envenoming syndrome, remains unknown.

PMID- 12408669
TI  - Novel primer sequences for polymerase chain reaction-based detection of
      Trypanosoma brucei gambiense.
AB  - Progress in diagnosis, treatment, and epidemiology of human African
      trypanosomiasis (sleeping sickness) depends on the existence of specific and
      sensitive diagnostic tools. Inherent shortcomings of serologic and parasitologic
      diagnostic methods can be overcome by molecular techniques. Therefore, we have
      developed a new polymerase chain reaction (PCR) test using primers derived from
      the recently identified sequence of the Trypanosoma brucei gambiense-specific
      glycoprotein (TgsGP). The specificity of the TgsGP-PCR was evaluated on DNA
      extracted from 73 different trypanosome populations belonging to diverse
      taxonomic groups that were isolated from various host species, and from different
      geographic origins. The TgsG-PCR was shown to be specific for T. b. gambiense and
      was suitable for detection of trypanosome DNA in blood samples of patients with
      confirmed sleeping sickness.

PMID- 12408670
TI  - Short report: molecular genetic characterization of an unusually severe case of
      hydatid disease in Alaska caused by the cervid strain of Echinococcus granulosus.
AB  - Distinct Echinococcus granulosus life cycle patterns have been described in North
      America: domestic and sylvatic. Gene sequences of the sylvatic E. granulosus
      indicate that it represents a separate variant. Case-based data have suggested
      that the course of sylvatic disease is less severe than that of domestic disease,
      which led to the recommendation to treat cystic echinococcosis patients in the
      Arctic by careful medical management rather than by aggressive surgery. We
      recently reported the first two documented E. granulosus human cases in Alaska,
      with accompanying severe sequelae. Here we describe the results of molecular
      genetic analysis of the cyst material of one of the subjects that supported
      identification of the parasite as the sylvatic (cervid) strain and not the
      domestic (common sheep strain), which was initially thought to be implicated in
      these unusually severe Alaskan cases.

PMID- 12408671
TI  - Enterocytozoon bieneusi among children with diarrhea attending Mulago Hospital in
      Uganda.
AB  - The prevalence of Enterocytozoon bieneusi in the general population is unknown.
      Using genetic tools, we investigated its prevalence and contribution to diarrhea
      and malnutrition in hospitalized children in Uganda. A cross-sectional, case
      control study involving diarrheic children who were matched for age and sex (3:1)
      with control children. Measurements included anthropometry and clinical
      assessment. A total of 17.4% of 1,779 children with diarrhea were infected with
      E. bieneusi compared with 16.8% of 667 control children (CHI2 = 0.137, P =
      0.712). Prevalence was highest during the rainy seasons. There was no significant
      relationship between infection with E. bieneusi and stunting, being underweight,
      wasting, or acute diarrhea. However, children who were E. bieneusi-positive by a
      polymerase chain reaction (PCR) had diarrhea for a longer period (15.15 versus
      9.67 days; F = 12.02; P = 0.001) compared with children who were either
      uninfected or were E. bieneusi-positive by a nested PCR. We conclude that E.
      bieneusi is widespread among children 3-36 months of age in Uganda, and that in a
      cross-sectional study, there was no clear association of E. bieneusi with poor
      nutrition or diarrhea. Since E. bieneusi is closely linked with persistent
      diarrhea and wasting in adults who are positive for human immunodeficiency
      virus/acquired immunodeficiency syndrome (HIV/AIDS), the outcome of follow-up
      studies involving children who are HIV/AIDS-positive and severely malnourished
      children may be entirely different and warrants further study.

PMID- 12408672
TI  - Comparison of autofluorescence and iodine staining for detection of Isospora
      belli in feces.
AB  - To evaluate the sensitivity of autofluorescence for detection of Isospora
      oocysts, wet preparations of 192 stool samples from patients with chronic
      diarrhea were examined by fluorescence microscopy and by light microscopy after
      iodine staining used for routine screening for ova and parasites. Silicon
      chambered glass coverslips were used for fluorescence microscopy. Isospora
      oocysts were detected in 46 iodine-stained concentrated stool samples; 91 samples
      were positive by autofluorescence. According to the maximum likelihood estimates,
      examination by fluorescence (95.7%; 95% confidence interval [CI], 85.2-99.5) was
      significantly more sensitive than iodine staining (48.4%; 95% CI, 37.7-59.1).
      Examination for autofluorescence is a simple, highly sensitive, inexpensive, and
      easily applicable method to detect Isospora spp. oocysts in feces.

PMID- 12408673
TI  - Molecular characterization of California serogroup viruses isolated in Russia.
AB  - Nucleotide sequencing was used to characterize unidentified California (CAL)
      serogroup virus isolates from Russia. These viruses were isolated from mosquitoes
      and humans during epidemiologic investigations on the role of CAL serogroup
      viruses in the increased incidence of arboviral encephalitis in Russia. Most of
      the isolates were identified serologically as snowshoe hare (SSH), Inkoo (INK),
      and Tahyna (TAH) viruses, but some of the isolates were difficult to classify
      serologically, suggesting that they could be reassortant viruses. There is
      evidence that at least 2 of these viruses are not reassortant viruses. Sequence
      analysis revealed that the Russian viruses differ from other Eurasian and North
      American CAL serogroup viruses in all of the segments analyzed. They are most
      closely related to SSH virus. Whether they differ sufficiently to be considered a
      new group of SSH-like viruses remains to be determined.

PMID- 12408674
TI  - Infection dynamics of Sin Nombre virus after a widespread decline in host
      populations.
AB  - Many researchers have speculated that infection dynamics of Sin Nombre virus are
      driven by density patterns of its major host, Peromyscus maniculatus. Few, if
      any, studies have examined this question systematically at a realistically large
      spatial scale, however. We collected data from 159 independent field sites within
      a 1 million-hectare study area in Nevada and California, from 1995-1998. In 1997,
      there was a widespread and substantial reduction in host density. This reduction
      in host density did not reduce seroprevalence of antibody to Sin Nombre virus
      within host populations. During this period, however, there was a significant
      reduction in the likelihood that antibody-positive mice had detectable virus in
      their blood, as determined by reverse-transcriptase polymerase chain reaction.
      Our findings suggest 2 possible causal mechanisms for this reduction: an apparent
      change in the age structure of host populations and landscape-scale patterns of
      host density. This study indicates that a relationship does exist between host
      density and infection dynamics and that this relationship concurrently operates
      at different spatial scales. It also highlights the limitations of antibody
      seroprevalence as a metric of infections, especially during transient host
      density fluctuations.

PMID- 12408675
TI  - Epizootic activity of Murray Valley encephalitis virus in an aboriginal community
      in the southeast Kimberley region of Western Australia: results of cross
      sectional and longitudinal serologic studies.
AB  - Murray Valley encephalitis (MVE) virus is a mosquito-borne flavivirus causing
      severe encephalitis with a resultant high morbidity and mortality. In the period
      1989-1993, we undertook a cross-sectional and longitudinal study by annually
      screening members of a small remote Aboriginal community in northwestern
      Australia for MVE virus antibodies. Of the estimated 250-300 people in the
      community, 249 were tested, and 52.6% had positive serology to MVE. The
      proportion testing positive increased with increasing age group, and males were
      slightly more likely to be positive than females. During the study period, a high
      proportion of the population seroconverted to MVE; the clinical/subclinical ratio
      seems to be lower than previously reported. Although MVE is mostly asymptomatic,
      the devastating consequences of clinical illness indicate that advice should be
      provided regarding the avoidance of mosquito bites. Our longitudinal study showed
      that the risk of seroconversion was similar for each age group, not just the
      young.

PMID- 12408676
TI  - Contrasting sylvatic foci of Venezuelan equine encephalitis virus in northern
      South America.
AB  - The ecology of Venezuelan equine encephalitis (VEE) virus transmission was
      compared at three enzootic foci: two forest sites in the Catatumbo region of
      western Venezuela that have yielded small numbers of virus isolates since the
      1970s, and another focus in the middle Magdalena Valley of Colombia that has
      consistently yielded many VEE virus isolates. Our results demonstrated dramatic
      differences in VEE virus isolation rates from sentinel hamsters, as well as
      differences in mosquito species composition and captured mammals with antibodies
      to VEE virus, between the Colombian and Venezuelan study sites. The higher
      isolation rate of enzootic VEE virus in the Colombian site was associated with a
      more abundant fauna of spiny rats (Proechimys spp.), known reservoir hosts of
      enzootic VEE virus. Mosquito collections demonstrated that the Colombian forest
      had a higher mosquito diversity and species evenness than either of the
      Venezuelan forests. The Colombian focus was especially richer in its Culex
      (Melanoconion) spp. fauna, a subgenus that includes all proven enzootic vectors
      for VEE virus. Our results suggest that the greater abundance, diversity, and
      stability of enzootic vector populations, combined with the greater density of
      rodent reservoir hosts, explains the higher levels of VEE virus circulation in
      the Colombian focus compared with the Venezuelan forests.

PMID- 12408677
TI  - Cholesterol attenuates the membrane perturbing properties of beta-amyloid
      peptides.
AB  - Growing evidence indicates a significant linkage between Abeta and cholesterol
      metabolism, although the exact role of cholesterol in brain aging and in the
      pathogenesis of AD is still unknown. Recently, in vitro and in vivo modification
      of cell cholesterol and its effect on Abeta-generation became a straight focus in
      the research of AD. In the present study, we discretely modulated the cholesterol
      contents of neuronal membranes from mice of different ages in vivo and in vitro
      using lovastatin and methyl-beta-cyclodextrin, respectively. The aim of the study
      was to investigate whether this modulation results in altered physico-chemical
      membrane properties. Therefore, we performed membrane fluidity measurements using
      three fluorescent dyes labeling different membrane regions. Furthermore, we
      evaluated the effects of cholesterol modulation on the membrane disturbing
      properties of Abeta. Modulation of membrane cholesterol content in vivo and in
      vitro was linked to changes in membrane properties. Very interestingly,
      cholesterol content of in vitro modulated neuronal membranes was negatively
      correlated with the membrane perturbing effects of Abeta.

PMID- 12408678
TI  - Proinflammatory cytokines but not acute phase serum amyloid A or C-reactive
      protein, downregulate paraoxonase 1 (PON1) expression by HepG2 cells.
AB  - The expression of paraoxonase1 (PON1) during inflammation has been investigated
      in vitro. The alteration of steady state PON1 mRNA in HepG2 cells by interleukin
      1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha), was investigated
      relative to acute-phase serum amyloid A (A-SAA) mRNA. PON1 mRNA expression by
      HepG2 cells was decreased within three hours of stimulation by IL-1beta or TNF
      alpha. Relative to PON1 mRNA expression, the pattern of steady state A-SAA mRNA
      expression was altered reciprocally and inversely by IL-1beta. These findings
      suggested that the decrease in serum PON activity after abdominal surgery in our
      previous clinical study may be ascribed to a decrease in steady state PON1 mRNA
      expression by liver with proinflammatory cytokines.

PMID- 12408679
TI  - AL amyloidosis treated with induction chemotherapy with VAD followed by high dose
      melphalan and autologous stem cell transplantation.
AB  - High dose melphalan (HDM) followed by reinfusion of autologous blood stem cells
      (ASCT) has been applied in AL amyloidosis. Vincristine, doxorubicin, and
      dexamethasone (VAD) rapidly decrease light chain production in multiple myeloma.
      In a Phase I/II study of VAD followed by HDM and ASCT in AL amyloidosis,
      toxicity, feasibility, and response to this regimen were evaluated. Over a 5-year
      period 38 patients with AL amyloidosis were seen of which 12 out of 18 eligible
      patients participated in the study. VAD induced a distinct clonal response in 50%
      (6/12) of the patients, but without clinical improvement. In 11 patients HDM and
      ASCT was applied. Six months after ASCT 78% (7/9) of the surviving patients
      showed partial clonal response and none responded completely. Clinical condition
      evidently improved in 67% (6/9) of survivors, whereby clonal response, clinical
      response, performance score, and SAP scintigraphs were concordant. Therefore a
      complete clonal response is not a prerequisite for clinical improvement. With
      median follow-up after ASCT of 25 months, 75% of the study group patients were
      alive. Mortality was strongly depending on the number of organs involved Patients
      treated with HDM and ASCT had better survival than those not eligible (P <
      0.0005).

PMID- 12408680
TI  - Association of the MCP-1 gene polymorphism A-2518G with carpal-tunnel syndrome in
      hemodialysis patients.
AB  - Carpal-tunnel syndrome (CTS) in long-term hemodialysis patients is caused by the
      deposition of amyloid as well as by the local inflammatory process. The
      recruitment of monocytes/macrophages in the tenosynovium, promoted by chemokines
      such as monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory
      protein-1alpha (MIP-1alpha), is thought to play an important role in CTS
      development. The genetic polymorphism of these chemokines has been identified and
      their clinical function has been partly revealed We attempted to analyze the
      relationship between these polymorphisms and their susceptibility to CTS. The
      subjects of this study were 366 patients who underwent hemodialysis. Ninety-five
      patients received surgery for CTS. No significant difference was observed in the
      genotype distributions of MCP-1 or MIP-1alpha between patients who received CTS
      surgery and those that did not. However, with the use of a logistic regression
      model, the MCP-1 GG genotype was identified as a risk factor for the development
      of CTS, in addition to the duration and the age of initiation of dialysis, as
      confirmed by a Cox proportional hazards model. In conclusion, homozygosity for G
      at -2518 in the MCP-1 gene might be a candidate for the genetic marker of CTS
      development in Japanese hemodialysis patients.

PMID- 12408681
TI  - Amyloid deposition in ocular tissues of patients with familial amyloidotic
      polyneuropathy (FAP).
AB  - It is known that the severity of ocular symptoms does not always correlate with
      the systemic symptoms in patients with familial amyloidotic polyneuropathy (FAP
      ATTR V30M). The ocular tissues may have their own TTR metabolic system. The aim
      of this study is to clarify the distribution of amyloid deposition in the ocular
      tissues and to investigate the relationship between ocular symptoms and
      histopathological changes. We analyzed histopathologically 9 autopsied eyes taken
      from 3 Japanese and 6 Swedish patients with FAP ATTR V30M. Localization of
      amyloid deposition varied among the different cases, but there were some
      tendencies in the distribution. The degree of amyloid deposition in the ocular
      tissues was not always correlated with the duration of the disease. The frequency
      of amyloid deposition in the conjunctiva, iris, trabecular meshwork and vitreous
      body were 88.9%, 44.4%, 11.1% and 11.1% respectively in the 9 patients. These
      frequencies in the histopathological changes correlated with the frequencies in
      the clinical ocular manifestations as previously reported.

PMID- 12408682
TI  - Pulmonary low-grade MALT-lymphoma associated with localized pulmonary
      amyloidosis. A case report.
AB  - We report on a female patient, who, at the age of 63 years, was found to suffer
      from low-grade MALT-lymphoma localized at her right upper eyelid. At the time of
      initial diagnosis, clinical staging showed no further organ involvement. Within
      the following two months, nodular infiltrates occurred in both lungs.
      Histopathological investigation of the pulmonary lesions showed pulmonary
      involvement by the low-grade MALT-lymphoma associated with large globular amyloid
      deposits of lambda-light chain origin. Since the tumor cells of the MALT-lymphoma
      showed restriction to lambda-light chain the amyloid deposits in this case were
      interpreted as being related to the MALT-lymphoma.

PMID- 12408683
TI  - No evidence of de novo amyloidosis in recipients of domino liver transplantation:
      12 to 40 (mean 24) month follow-up.
AB  - Domino liver transplantation (DLT) has been performed for selected recipients at
      several centers, but de novo amyloidosis in recipients of livers from patients
      with familial amyloid polyneuropathy (FAP) remains a serious concern. AIM: To
      evaluate the occurrence of de novo amyloidosis in recipients of DLT. PATIENTS AND
      METHODS: Seven recipients of FAP livers were followed for clinical and
      electroneuromyographic signs of FAP and also for de novo amyloid deposition in
      the gut. RESULTS: No signs and symptoms of de novo FAP nor any evidence of
      amyloid deposits in the gut were observed in recipients of DLT after a mean
      follow-up of 24 [12-40] months. CONCLUSIONS: Signs and symptoms of FAP do not
      occur early in recipients of DLT. These livers could therefore be offered to
      patients suitable for conventional LT, particularly older subjects in whom the
      event of de novo amyloidosis would seem improbable.

PMID- 12408685
TI  - Liver transplantation: an effective treatment for familial ATTR amyloidosis.

PMID- 12408684
TI  - Amyloid fibril protein nomenclature -- 2002.

PMID- 12408686
TI  - AL amyloidosis, a curable disease?

PMID- 12408687
TI  - 16th Amyloidforum organized by the German Society of Amyloid Diseases, April
      2002, Vienna, Austria.

PMID- 12408688
TI  - Sequence and expression analysis of the beta-2-microglobulin gene in dialysis
      patients.

PMID- 12408689
TI  - Addressing the Health Insurance Portability and Accountability Act. Part III--A
      strategy for achieving compliance: transaction code sets, privacy and security.

PMID- 12408690
TI  - A challenge to the makers of pharmaceuticals.

PMID- 12408691
TI  - Racial and geographic disparities in timing of bidirectional Glenn and Fontan
      stages of single-ventricle palliation.
AB  - OBJECTIVE: In adults, race-based disparity in access to cardiovascular care has
      been documented. Racial differences in cardiac care for children have not been
      evaluated previously. METHODOLOGY: We analyzed timing of single-ventricle
      palliation as a function of race and geography at Duke University Medical Center
      (DUMC) from 1997-2000. RESULTS: African American children underwent bidirectional
      Glenn (BDG) at a median age of 11 months (13.8 +/- 10.8, n = 11); white children
      at five months (5.6 +/- 2.3, n = 29), p = 0.01. African American children
      underwent Fontan at 60 months (106.8 +/- 84.0, n = 9); white children at 36
      months (45.6 +/- 36.0, n = 18), p = 0.005. CONCLUSIONS: African American children
      at DUMC underwent palliation at a later age and with more variability in age than
      did white children. Further investigation is needed to determine possible causes
      of these race-associated differences in health care delivery.

PMID- 12408692
TI  - Confirmatory analysis of the adolescent obsessive compulsive drinking scale (A
      OCDS): a measure of 'craving' and problem drinking in adolescents/young adults.
AB  - The A-OCDS was modeled after the Obsessive Compulsive Drinking Scale (OCDS) to
      establish an instrument appropriate for use in adolescent/young adult
      populations. Initial exploratory analysis of the A-OCDS revealed two factors,
      namely "irresistibility" and "interference," which were specific and sensitive to
      identifying problematic drinking. The study objective was to administer the A
      OCDS to obtain data for confirmatory analyses regarding the dimensionality of the
      scale, its reliability and its sensitivity and specificity in identifying problem
      drinkers. The confirmatory factor analysis supported the two previously
      identified factors. Using logistic regression to predict drinking
      classifications, the predictive value of the subscale scores for predicting
      problem drinking was statistically significant (irresistibility p = 0.0001, and
      interference p = 0.0001). We concluded that the A-OCDS was confirmed as a scale
      for identifying certain dimensions of "craving" and problematic drinking in
      adolescents/young adults. This scale may be useful as a screening tool, as well
      as monitoring change over time.

PMID- 12408693
TI  - Treatment of pseudofolliculitis barbae in very dark skin with a long pulse Nd:YAG
      laser.
AB  - BACKGROUND: Pseudofolliculitis barbae affects some individuals with coarse curly
      hair. Currently available treatment modalities are often ineffective. In some
      studies, lasers have been shown to be potentially helpful in mitigating disease
      severity by reducing the number and/or thickness of hair shafts. METHODS: This
      was a side-by-side interventional study conducted at a military tertiary medical
      facility. The study group included 26 patients (skin types IV, V, and VI)
      referred from primary care physicians with a diagnosis of pseudofolliculitis
      barbae refractory to medical therapy. A neodymium YAG laser was used to treat one
      half of the neck. One month later, shaving bumps were counted and compared to
      their preoperative levels on both sides. RESULTS: Mean postoperative papule
      counts were 11.6 +/- 6 (SD) and 30.1 +/- 19 (SD) on the treated side and
      untreated sides, respectively. CONCLUSION: Neodymium YAG laser treatment
      represents a safe and effective option for reducing papule formation in patients
      with pseudofolliculitis barbae.

PMID- 12408694
TI  - Self-reported differences in daily raw vegetable intake by ethnicity in a breast
      screening program.
AB  - PURPOSE: While the literature has no conclusive causal relationship between
      nutrition and breast cancer, diet is believed to play a role in the development
      of breast cancer. This investigation focuses on differences of dietary practice
      between Caucasians and African Americans in a cohort of women presenting for
      breast cancer screening. METHODS: Over a one-year period, 675 women presenting to
      the Breast Health Center at Tulane University Medical Center for an initial visit
      were given a self-reported health behavior questionnaire. Included in this survey
      were questions concerning the frequency of raw vegetable consumption and fat/oil
      intake. MAIN FINDINGS: The overall proportion of women who presented for breast
      cancer screening that reported daily raw vegetable consumption in the study group
      was 40%. There were statistically significant differences between proportions of
      Caucasian women's and African American women's consumption of daily raw vegetable
      (51% versus 29%, respectively; P < 0.0001). These differences were not seen in
      daily fat/oil intake. No differences were seen in socioeconomic measures.
      CONCLUSIONS: There is a substantial difference in the consumption of potentially
      protective foods among major ethnic groups. These dietary differences should be
      taken into account when investigating the ethnic differences in women with breast
      cancer, as well as the relationship between breast cancer and nutrition.

PMID- 12408695
TI  - Hemicrania continua in African Americans.
AB  - OBJECTIVE: The first six cases of hemicrania continua and episodica in African
      Americans are reported, differences from previous accounts noted, and important
      diagnostic features described. BACKGROUND: Hemicrania continua is an indomethacin
      responsive chronic daily headache. Mild to moderate daily headache is strictly
      unilateral, constant but fluctuating. Superimposed severe headache attacks occur,
      last seconds to days, and are associated with ipsilateral orbital-nasal autonomic
      dysfunction. RESULTS: Severe headache attacks are usually pulsatile, occur one to
      four times daily, and last 40 minutes to three days. Daily unilateral background
      headache was typically of a pressure, sharp, dull or pulling quality. Ipsilateral
      orbital-nasal autonomic symptoms were noted in all. Serious concomitant medical
      illnesses, e.g. coronary artery disease, diabetes, and hypertension, were
      frequent in this population. CONCLUSIONS: This is the first report of hemicrania
      continua and episodica in African Americans and the second in persons of African
      descent in the world's literature. Late age of onset, frequent serious medical
      illnesses, and family history of migraine differentiate this series from previous
      reports. The lack of reports in African Americans most likely reflects
      misdiagnosis rather than true prevalence. Thus, whenever any patient presents
      with chronic daily unilateral headache, ipsilateral autonomic symptoms should be
      assessed during severe headache attacks, and an indomethacin trial considered.

PMID- 12408696
TI  - Glaucoma: our role in reducing the burden of blindness.

PMID- 12408697
TI  - Isolated recurrent renal cell carcinoma metastatic to the bladder.

PMID- 12408699
TI  - Passing the scalpel.

PMID- 12408698
TI  - Scarred atrophic thyroid after I-131 therapy for Graves' disease documented at
      autopsy.
AB  - Radioiodine is used as the definitive treatment of choice in most patients with
      Graves' hyperthyroidism. Most patients with Graves' disease eventually develop
      hypothyroidism following I-131 therapy and require thyroid hormone replacement
      therapy. We present a patient with aortic stenotic cardiac disease and coronary
      artery disease who suffered from fatigue, weight loss and atrial fibrillation.
      The patient's radionuclide study, as well as the T4 and TSH, confirmed Graves'
      disease and he received I-131 therapy. Our patient's development of
      hypothyroidism following 5 mCi I-131 therapy after seven days later was
      considered as unusual; in addition, our patient, at autopsy, had documented
      histopathologic changes confirming atrophy and fibrosis of the thyroid gland.

PMID- 12408700
TI  - Corrections health care the road we should not take.

PMID- 12408701
TI  - WHO medical information denied to Taiwan.

PMID- 12408702
TI  - Obtaining journal reprints: the 'dos' and 'don'ts'.
AB  - In a search for knowledge, and to expand their own work, scientists and
      academicians have depended on the work of colleagues with similar interests.
      While attending conferences enables one to acquire useful knowledge, the
      information so gained is unlikely to be lasting. Furthermore, many persons learn
      better by reading than by listening, and reading can be done at one's own
      convenience. These and many other reasons account for the increasing number of
      reprints requested by researchers, and in medicine, by practicing clinicians.

PMID- 12408703
TI  - 1-Benzyl-3-(5'-hydroxymethyl-2'-furyl)indazole (YC-1) derivatives as novel
      inhibitors against sodium nitroprusside-induced apoptosis.
AB  - Antiapoptotic agents based on 1-benzyl-3-(5'-hydroxymethyl-2'-furyl)indazole (22,
      YC-1) derivatives were explored for effective treatment of sepsis and septic
      shock. We found that compound 22, 1-benzyl-3-(5'-methoxymethyl-2'-furyl)indazole
      (27), and 1-phenyl-3-(5'-hydroxymethyl-2'-furyl)indazole (23) were the most
      effective inhibitors of sodium nitroprusside-induced vascular smooth muscle cell
      apoptosis. These three compounds are proposed as potential therapeutic agents for
      the treatment of sepsis.

PMID- 12408704
TI  - Discovery of the first nonpeptide agonist of the GPR14/urotensin-II receptor: 3
      (4-chlorophenyl)-3-(2- (dimethylamino)ethyl)isochroman-1-one (AC-7954).
AB  - A functional cell-based screen identified 3-(4-chlorophenyl)-3-(2
      (dimethylamino)ethyl)isochroman-1-one hydrochloride (AC-7954, 1) as a nonpeptidic
      agonist of the urotensin-II receptor. Racemic 1 had an EC50 of 300 nM at the
      human UII receptor and was highly selective. Testing of the enantiopure (+)- and
      (-)- 1 revealed that the UII receptor activity of racemic 1 resides primarily in
      (+)-1. Being a selective nonpeptidic druglike UII receptor agonist, (+)-1 will be
      useful as a pharmacological research tool and a potential drug lead.

PMID- 12408705
TI  - Discovery of gamma-lactam hydroxamic acids as selective inhibitors of tumor
      necrosis factor alpha converting enzyme: design, synthesis, and structure
      activity relationships.
AB  - New gamma-lactam TACE inhibitors were designed from known MMP inhibitors. A
      homology model of TACE was built and examined to identify the S1' site as the key
      area for TACE selectivity over MMPs. Rational exploration of the P1'-S1'
      interactions resulted in the discovery of the 3,5-disubstituted benzyl ether as a
      TACE-selective P1' group. Further optimization led to the discovery of IK682 as a
      selective and orally bioavailable TACE inhibitor.

PMID- 12408706
TI  - Aza-peptide epoxides: a new class of inhibitors selective for clan CD cysteine
      proteases.
AB  - Aza-peptide epoxides, a new class of irreversible protease inhibitors, are
      specific for the clan CD cysteine proteases. The inhibitors have second-order
      rate constants up to 10(5) M(-1) s(-1), with the most potent epoxides having the
      S,S stereochemistry. The aza-Asn derivatives are effective legumain inhibitors,
      while the aza-Asp epoxides were specific for caspases. The inhibitors have little
      or no inhibition with other proteases such as chymotrypsin, papain, or cathepsin
      B.

PMID- 12408707
TI  - Novel tricyclic poly(ADP-ribose) polymerase-1 inhibitors with potent anticancer
      chemopotentiating activity: design, synthesis, and X-ray cocrystal structure.
AB  - A series of novel compounds have been designed that are potent inhibitors of
      poly(ADP-ribose) polymerase-1 (PARP-1), and the activity and physical properties
      have been characterized. The new structural classes, 3,4,5,6-tetrahydro-1H
      azepino[5,4,3-cd]indol-6-ones and 3,4-dihydropyrrolo[4,3,2-de]isoquinolin-5-(1H)
      ones, have conformationally locked benzamide cores that specifically interact
      with the PARP-1 protein. The compounds have been evaluated with in vitro cellular
      assays that measure the ability of the PARP-1 inhibitors to enhance the effect of
      cytotoxic agents against cancer cell lines.

PMID- 12408708
TI  - Novel short chain chloroquine analogues retain activity against chloroquine
      resistant K1 Plasmodium falciparum.
AB  - A series of short chain chloroquine (CQ) derivatives have been synthesized in one
      step from readily available starting materials. The diethylamine function of CQ
      is replaced by shorter alkylamine groups (4-9) containing secondary or tertiary
      terminal nitrogens. Some of these derivatives are significantly more potent than
      CQ against a CQ resistant strain of Plasmodium falciparum in vitro. We conclude
      that the ability to accumulate at higher concentrations within the food vacuole
      of the parasite is an important parameter that dictates their potency against CQ
      sensitive and the chloroquine resistant K1 P. falciparum.

PMID- 12408709
TI  - Synthesis, solution structure, and biological evaluation of urokinase type
      plasminogen activator (uPA)-derived receptor binding domain mimetics.
AB  - Tumor cell migration and metastasis in cancer are facilitated by interaction of
      the serine protease urokinase type plasminogen activator (uPA) with its receptor
      uPAR (CD 87). Overexpression of uPA and uPAR in cancer tissues is associated with
      a high incidence of disease recurrence and early death. In agreement with these
      findings, disruption of the protein-protein interaction between uPAR present on
      tumor cells and its ligand uPA evolved as an attractive intervention strategy to
      impair tumor growth and metastasis. For this, the uPAR antagonist cyclo[19,31][D
      Cys(19)]-uPA(19)(-)(31) was optimized to efficiently interrupt binding of uPA to
      cellular uPAR. First, the disulfide bridge of this lead compound was shifted and
      then the modified peptide was shortened from the amino and carboxy terminus to
      generate cyclo[21,29][Cys(21,29)]-uPA(21)(-)(30). Next, cyclo[21,29][D
      Cys(21)Cys(29)]-uPA(21)(-)(30) was yielded by changing the chirality of Cys(21)
      to D-Cys(21). For analysis of uPAR binding activity, we employed competitive flow
      cytofluorometric receptor binding assays, using FITC-uPA as the ligand and U937
      promyeloid leukemia cells as the cellular source of uPAR. As demonstrated for
      cyclo[21,29][D-Cys(21)Cys(29)]-uPA(21)(-)(30), the achieved peptide modifications
      maintained receptor binding activity (IC(50) = 0.04 microM), which is close in
      order to that of the parent protein ligand, uPA (IC(50) = 0.01 microM). A
      detailed NMR analysis with restrained and free molecular dynamics calculations in
      explicit H(2)O exhibits a well-defined structure with characteristic features
      such as an omega-loop with two betaI-turns about Lys(3), Tyr(4), Ser(6), and
      Asn(7). Hydrophobic clustering of the side chains of Tyr(4), Phe(5), Ile(8), and
      Trp(10) is observed. Side chain mobility is analyzed with time-dependent distance
      restraints. The NMR structure of cyclo[21,29][D-Cys(21)Cys(29)]-uPA(21)(-)(30) is
      very similar to the previously reported structure of the amino terminal fragment
      of uPA. Systematic point mutations led to cyclo[21,29][D-Cys(21)Nle(23)Cys(29)]
      uPA(21)(-)(30), which still binds to uPAR but is resistant to proteolytic
      cleavage, e.g., by the tumor-associated serine proteases uPA and plasmin, and is
      stable in blood serum or plasma. In conclusion, small cyclic peptides were
      created, which mimic the structure and activity of the binding epitope of uPA to
      uPAR and which may serve as novel therapeutic agents in cancer metastasis.

PMID- 12408710
TI  - Thrombin inhibition by novel benzamidine derivatives: a free-energy perturbation
      study.
AB  - Thrombin is a serine protease responsible for blood coagulation. Since thrombin
      inhibitors appear to be effective in the treatment and prevention of thrombotic
      and embolic disorders, considerable attention has been focused on the structure
      and interactions of this enzyme. In this work, to evaluate the relative free
      energies of hydration and binding to thrombin for some benzamidine derivatives,
      we used the finite difference thermodynamic integration (FDTI) algorithm within
      the Discover program of MSI. By this method, two possible orders of hydration for
      the candidates were obtained: p-amidinophenylpyruvate > p-(2-oxo-1
      propyl)benzamidine > p-methylbenzamidine > p-ethylbenzamidine > p-(1
      propyl)benzamidine > benzamidine and p-amidinophenylpyruvate > p-(2-oxo-1
      propyl)benzamidine > p-methylbenzamidine > p-ethylbenzamidine > benzamidine > p
      (1-propyl)benzamidine. We also obtained the following order for thrombin binding:
      p-(2-oxo-1-propyl)benzamidine > p-ethylbenzamidine > p-(1-propyl)benzamidine > p
      methylbenzamidine > benzamidine > p-amidinophenylpyruvate.

PMID- 12408711
TI  - Identification of potent and selective small-molecule inhibitors of caspase-3
      through the use of extended tethering and structure-based drug design.
AB  - The design, synthesis, and in vitro activities of a series of potent and
      selective small-molecule inhibitors of caspase-3 are described. From extended
      tethering, a salicylic acid fragment was identified as having binding affinity
      for the S(4) pocket of caspase-3. X-ray crystallography and molecular modeling of
      the initial tethering hit resulted in the synthesis of 4, which reversibly
      inhibited caspase-3 with a K(i) = 40 nM. Further optimization led to the
      identification of a series of potent and selective inhibitors with K(i) values in
      the 20-50 nM range. One of the most potent compounds in this series, 66b,
      inhibited caspase-3 with a K(i) = 20 nM and selectivity of 8-500-fold for caspase
      3 vs a panel of seven caspases (1, 2, and 4-8). A high-resolution X-ray cocrystal
      structure of 4 and 66b supports the predicted binding modes of our compounds with
      caspase-3.

PMID- 12408712
TI  - Efficient synthesis and cell-transfection properties of a new multivalent
      cationic lipid for nonviral gene delivery.
AB  - Lipid-mediated delivery of DNA into cells holds great promise both for gene
      therapy and basic research applications. This paper describes the efficient and
      facile synthesis and the characterization of a new multivalent cationic lipid
      with a double-branched headgroup structure for gene delivery applications. The
      synthetic scheme can be extended to give cationic lipids of different charge,
      spacer, or lipid chain length. The chemical and physical properties of self
      assembled complexes of the cationic liposomes (CLs) with DNA give indications of
      why multivalent cationic lipids possess superior transfection properties. The
      lipid bears a headgroup with five charges in the fully protonated state, which is
      attached to an unsaturated double-chain hydrophobic moiety based on 3,4
      dihydroxybenzoic acid. Liposomes consisting of the new multivalent lipid and the
      neutral lipid 1,2-dioleoyl-sn-glycerophosphatidylcholine (DOPC) were used to
      prepare complexes with DNA. Investigations of the structures of these complexes
      by optical microscopy and small-angle X-ray scattering reveal a lamellar
      L(alpha)(C) phase of CL-DNA complexes with the DNA molecules sandwiched between
      bilayers of the lipids. Experiments using plasmid DNA containing the firefly
      luciferase reporter gene show that these complexes efficiently transfect
      mammalian cells. When compared to the monovalent cationic lipid 2,3
      dioleyloxypropyltrimethylammonium chloride (DOTAP), the higher charge density of
      the membranes of CL-DNA complexes achievable with the new multivalent lipid
      greatly increases transfection efficiency in the regime of small molar ratios of
      cationic to neutral lipid. This is desired to minimize the known toxicity effects
      of cationic lipids.

PMID- 12408713
TI  - Design, synthesis and biological evaluation of novel N-alkyl- and N-acyl-(7
      substituted-2-phenylimidazo[1,2-a][1,3,5]triazin-4-yl)amines (ITAs) as novel A(1)
      adenosine receptor antagonists.
AB  - Prompted by pharmacophore and docking based models, we have synthesized and
      tested a number of N-alkyl and N-acyl-(7-substituted-2-phenylimidazo[1,2
      a][1,3,5]triazin-4-yl)amines (ITAs, 7) designed as a new class of A(1) adenosine
      receptor (A(1)AR) antagonists. Binding affinities at the A(1)AR, A(2A)AR, and
      A(3)AR were determined using bovine cerebral membranes. Most of the compounds
      displayed K(i) values at the A(1)AR in the submicromolar or even in the low
      nanomolar range, thus confirming the rationale leading to their synthesis. All or
      most of the ligands turned out to be selective for the A(1)AR over the A(2A)AR
      and A(3)AR subtypes, respectively. Structure-affinity relationships at the A(1)AR
      were rationalized by docking simulations in terms of putative ligand/receptor
      interactions. Among the ITAs investigated, 1-[(7-methyl-2-phenylimidazo[1,2
      a][1,3,5]triazin-4-yl)amino]acetone (7j) exhibited the best combination of
      affinity at the A(1)AR (K(i) = 12 nM) and selectivity over the A(2A)AR and A(3)AR
      subtypes (K(i)s > 10000 nM).

PMID- 12408714
TI  - Antitumor agents. 217. Curcumin analogues as novel androgen receptor antagonists
      with potential as anti-prostate cancer agents.
AB  - A number of curcumin analogues were prepared and evaluated as potential androgen
      receptor antagonists against two human prostate cancer cell lines, PC-3 and DU
      145, in the presence of androgen receptor (AR) and androgen receptor coactivator,
      ARA70. Compounds 4 [5-hydroxy-1,7-bis(3,4-dimethoxyphenyl)-1,4,6-heptatrien-3
      one], 20 [5-hydroxy-1,7-bis[3-methoxy-4-(methoxycarbonylmethoxy)phenyl]-1,4,6
      heptatrien-3-one], 22 [7-(4-hydroxy-3-methoxyphenyl)-4-[3-(4-hydroxy-3
      methoxyphenyl)acryloyl]-5-oxohepta-4,6-dienoic acid ethyl ester], 23 [7-(4
      hydroxy-3-methoxyphenyl)-4-[3-(4-hydroxy-3-methoxyphenyl)acryloyl]5-oxohepta-4,6
      dienoic acid], and 39 [bis(3,4-dimethoxyphenyl)-1,3-propanedione] showed potent
      antiandrogenic activities and were superior to hydroxyflutamide, which is the
      currently available antiandrogen for the treatment of prostate cancer. Structure
      activity relationship (SAR) studies indicated that the bis(3,4-dimethoxyphenyl)
      moieties, the conjugated beta-diketone moiety, and the intramolecular symmetry of
      the molecules seem to be important factors related to antiandrogenic activity.
      The data further suggest that the coplanarity of the beta-diketone moiety and the
      presence of a strong hydrogen bond donor group were also crucial for the
      antiandrogenic activity, which is consistent with previous SAR results for
      hydroxyflutamide analogues. When the pharmacophoric elements of
      dihydrotestosterone (DHT) and compound 4 are superposed, the resulting construct
      implies that the curcumin analogues may function as a 17alpha-substituted DHT.
      Compounds 4, 20, 22, 23, and 39 have been identified as a new class of
      antiandrogen agents, and these compounds or their new synthetic analogues could
      be developed into clinical trial candidates to control androgen receptor-mediated
      prostate cancer growth.

PMID- 12408715
TI  - Synthesis and biological evaluation of 7,8,9,10-tetrahydroimidazo[1,2
      c]pyrido[3,4-e]pyrimdin-5(6H)-ones as functionally selective ligands of the
      benzodiazepine receptor site on the GABA(A) receptor.
AB  - Benzodiazepines are allosteric modulators of the GABA(A) receptor. The
      traditionally prescribed benzodiazepines are nonselective and suffer from
      numerous side effects. Upon the identification of receptor subtypes, we set out
      to discover selective agents with the anticipation that these agents would have
      superior therapeutic potential. Herein, we describe the synthesis and biological
      evaluation of substituted 7,8,9,10-tetrahydroimidazo[1,2-c]pyrido[3,4-e]pyrimidin
      5(6H)-ones and disclose that these compounds exhibit functional selectivity at
      the benzodiazepine receptor of GABA(A) receptor subtypes. The alpha(2)/alpha(3)
      selective partial agonist 42 exhibited potent in vivo activity.

PMID- 12408716
TI  - Synthesis and biological activity of strongly fluorescent tricyclic analogues of
      acyclovir and ganciclovir.
AB  - In search of strongly fluorescent tricyclic analogues of acyclovir (ACV, 1) and
      ganciclovir (GCV, 2), derivatives of the 3,9-dihydro-9-oxo-5H-imidazo[1,2
      a]purine system, several 6-[4-(acyloxy)phenyl], 6-[4-(acylamino)phenyl], and 6-[4
      (phenoxycarbonyloxy)phenyl]-substituted TACV and TGCV analogues were synthesized
      and evaluated for their activity against herpes simplex virus types 1 and 2 in
      cell culture. All TACV and TGCV analogues showed strong fluorescence (quantum
      yield of 30-65% vs 2-aminopurine 100%). The 6-[4-(phenoxycarbonyloxy)phenyl]
      substituted compounds 11 and 19 displayed the best combination of the
      fluorescence and antiviral potency.

PMID- 12408717
TI  - Syntheses and antitumor targeting G1 phase of the cell cycle of
      benzoyldihydroisoquinolines and related 1-substituted isoquinolines.
AB  - A series of 1-substituted 3,4-dihydroisoquinolines were synthesized and tested in
      vitro against the leukemia L 1210 cell line to evaluate their ability to perturb
      the cell cycle by arresting cells in the G1 phase. 1-Benzoylimines, 1
      phenylimines, and 1-alkylimines were synthesized. The most powerful cytotoxic
      derivatives, 1-benzoyl-3,4-dihydroisoquinolines (1-26), were obtained from amides
      I via 1-benzyl-3,4-dihydroisoquinoline in good yield by a direct selective
      oxidation of the benzylic carbon of the corresponding imines through 10% Pd/C in
      acetonitrile. SAR studies let us to identify the essential structural features
      for cytotoxic activity. The most bioactive compounds (with IC(50) < 5 microM)
      were BzDHIQ (13, 22, 21, 8, 9, 11, 1, 20, 6, and 19), and they are characterized
      by the following: (i) An alpha-ketoimine moiety is necessary for potent
      antiproliferative activity (1-phenyl- and 1-alkyl-3,4-dihydroisoquinoline
      derivatives, 34-40, are less active). (ii) An hydrophobic, benzyloxy, alkyloxy,
      or allyloxy group at the C-6 position seems to be relevant for cytotoxicity.
      (iii) Regarding the influence of the benzoylic moiety, both the unsubstituted
      (13, 8, 9, 11, 1, and 6) and the 3'-monosubstituted (22, 21, 20, and 19)
      compounds were more potent than compounds with other substitutions.

PMID- 12408718
TI  - Multiobjective optimization in quantitative structure-activity relationships:
      deriving accurate and interpretable QSARs.
AB  - Deriving quantitative structure-activity relationship (QSAR) models that are
      accurate, reliable, and easily interpretable is a difficult task. In this study,
      two new methods have been developed that aim to find useful QSAR models that
      represent an appropriate balance between model accuracy and complexity. Both
      methods are based on genetic programming (GP). The first method, referred to as
      genetic QSAR (or GPQSAR), uses a penalty function to control model complexity.
      GPQSAR is designed to derive a single linear model that represents an appropriate
      balance between the variance and the number of descriptors selected for the
      model. The second method, referred to as multiobjective genetic QSAR (MoQSAR), is
      based on multiobjective GP and represents a new way of thinking of QSAR.
      Specifically, QSAR is considered as a multiobjective optimization problem that
      comprises a number of competitive objectives. Typical objectives include model
      fitting, the total number of terms, and the occurrence of nonlinear terms. MoQSAR
      results in a family of equivalent QSAR models where each QSAR represents a
      different tradeoff in the objectives. A practical consideration often overlooked
      in QSAR studies is the need for the model to promote an understanding of the
      biochemical response under investigation. To accomplish this, chemically
      intuitive descriptors are needed but do not always give rise to statistically
      robust models. This problem is addressed by the addition of a further objective,
      called chemical desirability, that aims to reward models that consist of
      descriptors that are easily interpretable by chemists. GPQSAR and MoQSAR have
      been tested on various data sets including the Selwood data set and two different
      solubility data sets. The study demonstrates that the MoQSAR method is able to
      find models that are at least as good as models derived using standard
      statistical approaches and also yields models that allow a medicinal chemist to
      trade statistical robustness for chemical interpretability.

PMID- 12408719
TI  - Synthesis and structure-activity relationships of an orally available and long
      acting analgesic peptide, N(alpha)-amidino-Tyr-D-Arg-Phe-MebetaAla-OH (ADAMB).
AB  - A novel dermorphin tetrapeptide N(alpha)-amidino-Tyr-D-Arg-Phe-MebetaAla-OH
      (ADAMB) was designed based on the structures of several dermorphin tetrapeptide
      analogues, including N(alpha)-amidino-Tyr-D-Arg-Phe-Gly-OH (ADA-DER), H-Tyr-D-Arg
      Phe-betaAla-OH (TAPA), and H-Tyr-D-Arg-Phe-Sar-OH (DAS-DER). These parent
      compounds were known to show a weak oral analgesic activity in animals and/or to
      possess a different mechanism of analgesia from other mu-opioid peptides. Six
      analogues of ADAMB were also synthesized to investigate the effect on potency of
      N-terminal amidination and N-methyl-beta-alanine (MebetaAla) substitution at
      position 4. Compounds were assessed using the tail pressure test in mice after
      subcutaneous and oral administration. Among the peptides tested, ADAMB showed the
      strongest oral antinociceptive activity, with an ED(50) of 5.8 vs 22.2 mg/kg for
      morphine, as well as a 38-fold stronger activity after subcutaneous
      administration. ADAMB also showed long-lasting antinociceptive activity, with 50%
      of the maximum effect persisting in the tail pressure test at 10 h after oral
      administration (10 mg/kg). In contrast, orally administered morphine (80 mg/kg)
      showed a rapid decrease of activity in the same test and its antinociceptive
      effect disappeared within 4 h. When the antinociceptive effect of ADAMB was
      compared with that of analogues possessing betaAla(4) (1) or Sar(4) (2), as well
      as analogues with N-substitution (3-6), it was found that both the N(alpha)
      amidino substitution and the MebetaAla(4) were synergistically involved in
      creating ADAMB's exceptionally high antinociceptive activity.

PMID- 12408720
TI  - Novel p53 inactivators with neuroprotective action: syntheses and pharmacological
      evaluation of 2-imino-2,3,4,5,6,7-hexahydrobenzothiazole and 2-imino-2,3,4,5,6,7
      hexahydrobenzoxazole derivatives.
AB  - Tumor suppressor protein, p53, is an intracellular protein that is critical
      within the biochemical cascade that leads to cell death via apoptosis. Recent
      studies identified the tetrahydrobenzothiazole analogue, pifithrin-alpha (2), as
      a p53 inhibitor that was effective in protecting neuronal cells against a variety
      of lethal insults and reducing the side effects of anticancer drugs. As up
      regulation of p53 has been described as a common feature of several
      neurodegenerative disorders, including Alzheimer's disease, 2 and novel analogues
      (3-16) were synthesized to (i) assess the value of tetrahydrobenzothiazole
      analogues as neuroprotective agents and (ii) define the structural requirements
      for p53 inactivation. Not only did 2 exhibit neuroprotective activity in both
      tissue culture and in vivo stroke models but also compounds 6, 7, 10, 13, 15, and
      16 proved to be highly potent in protecting PC12 cells and compounds 3, 4, and 6
      were highly potent in protecting primary hippocampal cells against death induced
      by the DNA-damaging agent, camptothecin.

PMID- 12408721
TI  - Effect of spermine conjugation on the cytotoxicity and cellular transport of
      acridine.
AB  - Polyamines are believed to be potent vectors for the selective delivery of
      chemotherapeutic agents into cancer cells. In this paper, we report the effect of
      spermine conjugation on the cytotoxic and transport properties of acridine. Six
      derivatives, composed of a spermine chain attached at its N(1) position to an
      acridine via an aliphatic chain, were synthesized. The aliphatic linker,
      comprised of 3-5 methylene units, was connected to the position-9 of the
      heterocycle through either an amide (amidoacridines 8-10) or an amine
      (aminoacridines 11-13) linkage. Independently of their architecture, all ligands
      showed a high affinity for DNA binding but a limited DNA sequence selectivity. In
      a whole cell assay with L1210 and Chinese hamster ovary (CHO) cells, the
      aminoacridines (IC(50) values around 2 microM) were more potent than the
      amidoacridines (IC(50) values between 20 and 40 microM). This was related to a
      less efficient transport for the latter. As determined from competitive uptake
      studies with [(14)C]spermidine, all conjugates had a high affinity for the
      polyamine transport system (PTS). However, on the basis of competitive studies
      with an excess of spermidine and on the differential effect on cell growth and
      accumulation in CHO and in the mutant PTS deficient CHO-MG cells, the
      accumulation of the conjugates through the PTS was found to be poor but still
      more efficient for the aminoacridines. alpha-Difluoromethylornithine (DFMO), an
      inhibitor of ornithine decarboxylase, which induces an up-regulation of the
      activity of the PTS, enhanced accumulation of all acridine conjugates through the
      PTS and had a synergistic effect on the potency of the acridine conjugates to
      inhibit cell growth. Despite their high affinity for the PTS, the low amount of
      derivatives transiting through the PTS is likely to be related to their ability
      to repress rapidly and efficiently the activity of the PTS and, consequently, to
      inhibit their own uptake via this system.

PMID- 12408722
TI  - Synthesis and evaluation of analogues of 5'-([(Z)-4-amino-2-butenyl]methylamino)
      5'-deoxyadenosine as inhibitors of tumor cell growth, trypanosomal growth, and
      HIV-1 infectivity.
AB  - A well-defined series of 5'-([(Z)-4-amino-2-butenyl]methylamino)-5'
      deoxyadenosine analogues was designed and synthesized in order to further
      ascertain the optimal structural requirements for S-adenosylmethionine
      decarboxylase inhibition and potentially to augment and perhaps separate their
      antiproliferative and antitrypanosomal activities. Most structural modifications
      had a deleterious affect on both the antitrypanosomal and antineoplastic activity
      of 5'-([(Z)-4-amino-2-butenyl]methylamino)-5'-deoxyadenosine. However, di-O
      acetylation of the parent compound produced a potential prodrug that caused
      markedly pronounced inhibition of trypanosomal and neoplastic cell growth and
      viability. Moreover, the acetylated derivative of 5'-([(Z)-4-amino-2
      butenyl]methylamino)-5'-deoxyadenosine did inhibit HIV-1 growth and infectivity,
      whereas the parent compound did not.

PMID- 12408723
TI  - In vitro photodynamic properties of chalcogenopyrylium analogues of the
      thiopyrylium antitumor agent AA1.
AB  - Several series of chalcogenopyrylium dyes were prepared with one or two 4-anilino
      substituents at the 2- and 6-positions and with phenyl, 4-N,N-dimethylanilino, or
      4-(N-morphilino)phenyl substituents at 2- and/or 4-positions. The dye series are
      all related in structure to AA1, a thiopyrylium dye that targets mitochondria.
      The chalcogenopyrylium nuclei included sulfur, selenium, and tellurium at the 1
      position. Key intermediates in the dye synthesis were the corresponding Delta-4H
      chalcogenopyran-4-ones. All of the dyes of this study were evaluated for dark and
      phototoxicity toward Colo-26 cells in vitro. There was no correlation of dark
      toxicity with either the reduction potential of the chalcogenopyrylium dye or the
      n-octanol/water partition coefficient, log P. Several of the dyes of this study
      (thiopyrylium dyes 1-S and 13-S, selenopyrylium dyes 1-Se, 2-Se, 3-Se, 4-Se, 13
      Se, 14-Se, and 27-Se, and telluropyrylium dye 13-Te) showed added phototoxicity
      upon irradiation. Dyes with the highest therapeutic ratio as measured by dark
      toxicity/phototoxicity (15 J cm(-2) of 360-800-nm light) had values of log P of
      1.0-1.2. Studies of cytochrome c oxidase activity in whole R3230AC cells
      suggested that dyes 1-S and 3-Se, with values of log P of 2.2 and 1.7,
      respectively, were localized in the mitochondria. Cytocrome c oxidase activity in
      whole cells was inhibited by 1-S and 3-Se in the dark. Chalcogenopyrylium dyes 2
      Se, 4-Se, 13-Te, and 14-Se inhibited whole-cell cytochrome c oxidase activity
      only following irradiation, which suggests that these dyes relocalized to
      mitochondria following irradiation.

PMID- 12408724
TI  - New pyridobenzodiazepine derivatives: modifications of the basic side chain
      differentially modulate binding to dopamine (D(4.2), D(2L)) and serotonin (5
      HT(2A)) receptors.
AB  - A series of new pyridobenzodiazepines with variation of the basic side chain were
      synthesized and evaluated for their binding to D(4.2), D(2L), and 5-HT(2A)
      receptors in comparison with clozapine, haloperidol, and two parent compounds
      previously described, 8-chloro-6-(4-methyl-1-piperazinyl)-11H-pyrido[2,3
      b][1,4]benzodiazepine (8) and 8-methyl-6-(4-methyl-1-piperazinyl)-11H-pyrido[2,3
      b][1,4]benzodiazepine (9). In the piperazine series, replacing the N-methyl group
      by a N-phenyl moiety (15-17, 30-32) provided a dramatic decrease of affinity for
      all receptors (K(i) > 1000 nM). A N-cyclohexyl group (20, 35) restored some
      affinity. Compounds with a N-benzyl (18, 33) or N-phenethyl side chain (19, 34)
      had significant affinities at D(4.2) and 5-HT(2A) receptors. Homologation of the
      piperazine nucleus (29, 44) led to a significant decrease of the affinity at all
      receptors investigated. In the 4-aminopiperidine series, N-methyl derivatives
      (21, 36) possessed less affinity in comparison with the N-methylpiperazine
      analogues (8, 9) while the N-benzyl congeners (22, 37) showed similar affinities.
      The rigidification of piperidine nucleus as obtained in azabicyclo[3.2.1]octane
      derivatives (23, 38) involved a slight reduction of the affinity at D(4.2) and 5
      HT(2A) receptors while the affinity at D(2L) receptors was dramatically
      increased. The introduction of N-substituted aminoalkylamines to replace N
      methylpiperazine generally led to a significant decrease in the affinity for
      D(4.2) receptors but some of these molecules (24, 25, 41) presented a significant
      5-HT(2A) binding affinity. The presence of a more flexible side chain induced an
      increased conformational freedom. Consequently, the preferential position of the
      distal nitrogen or its basicity in piperazine derivatives was greatly modified.
      19 with a high D(4.2) and 5-HT(2A) affinity (K(i) = 40 and 103 nM, respectively)
      did not induce cataleptic phenomenon in the paw test in rats but significantly
      reduced the immobility time in Porsolt's test in mice suggesting antidepressant
      properties.

PMID- 12408725
TI  - Synthesis and evaluation of no-carrier-added 8-cyclopentyl-3-(3
      [(18)F]fluoropropyl)-1-propylxanthine ([(18)F]CPFPX): a potent and selective A(1)
      adenosine receptor antagonist for in vivo imaging.
AB  - This report describes the precursor synthesis and the no-carrier-added (nca)
      radiosynthesis of the new A(1) adenosine receptor (A(1)AR) antagonist [(18)F]8
      cyclopentyl-3-(3-fluoropropyl)-1-propylxanthine (CPFPX), 3, with fluorine-18
      (half-life = 109.6 min). Nucleophilic radiofluorination of the precursor tosylate
      8-cyclopentyl-3-(3-tosyloxypropyl)-7-pivaloyloxymethyl-1-propylxanthine, 2, with
      nca [(18)F]KF under aminopolyether-mediated conditions (Kryptofix
      2.2.2/K(2)CO(3)) followed by deprotection was straightforward and, after
      formulation, gave the radioligand ready for injection with a radiochemical yield
      of 45 +/- 7%, a radiochemical purity of >98% and a specific radioactivity of >270
      GBq/micromol (>7.2 Ci/micromol). Preparation time averaged 55 min. The synthesis
      proved reliable for high batch yields ( approximately 7.5 GBq) in routine
      production (n = 120 runs). The radiotracer was pharmacologically evaluated in
      vitro and in vivo and its pharmacokinetics in rodents determined in detail. After
      iv injection a high accumulation of radioactivity occurred in several regions of
      mouse brain including thalamus, striatum, cortex, and cerebellum. Antagonism by
      the specific A(1)AR antagonists 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) and
      N(6)-cyclopentyl-9-methyladenine (N-0840), but not with the A(2)AR antagonist 3,7
      dimethyl-1-propargylxanthine (DMPX), indicated specific and reversible binding of
      the radioligand to A(1)AR in cortical and subcortical regions of interest. In
      mouse blood at least two polar metabolites formed rapidly (50% at 5 min after
      tracer application). However, chromatographic analyses of brain homogenate
      extracts taken 60 min pi showed that >98% of radioactivity was unchanged
      radioligand. Chromatographic isolation and reinjection of peripherally formed
      radioactive metabolites revealed no accumulation of radioactivity in mouse brain,
      probably due to the polarity of the metabolites. These preliminary results
      suggest that nca [(18)F]CPFPX is a useful radioligand for the noninvasive imaging
      of the brain A(1)AR.

PMID- 12408726
TI  - CycloSal-BVDUMP pronucleotides: how to convert an antiviral-inactive nucleoside
      analogue into a bioactive compound against EBV.
AB  - Novel cycloSal-BVDUMP triesters 2-4 5-[(E)-2-bromovinyl]-2'-deoxyuridine (BVDU,
      1) have been studied with regard to their potential anti-EBV activity. In
      addition to the 3'-unmodified cycloSal-BVDUMP triesters 2a-f, the 3'-hydroxyl
      function has been esterified with different aliphatic carboxylic acids (3a-g) and
      alpha-amino acids having natural and nonnatural Calpha-configuration (4a-m). In
      addition to the synthesis of these compounds, different physicochemical
      properties of the new derivatives will be reported, i.e., lipophilicity and
      hydrolysis behavior. It could be proven that the monophosphate BVDUMP and not
      3',5'-cyclic BVDUMP was delivered from most of the compounds by chemical
      hydrolysis in phosphate buffers at pH 6.8 and 7.3 as well as P3HR-1 cell
      extracts. Finally, the new compounds were tested for their anti-EBV activity. As
      a result, the prototype compounds and particularly triesters 2c,d exhibited
      pronounced anti-EBV activity making these compounds promising candidates for
      further development. However, the 3'-ester derivatives were devoid of any
      antiviral activity while the 3'-aminoacyl derivatives showed an antiviral
      activity dependent upon the amino acid and the Calpha-configuration

PMID- 12408727
TI  - Synthesis of classical and nonclassical, partially restricted, linear, tricyclic
      5-deaza antifolates.
AB  - Seven novel 2,4-diamino-5-deaza-6,7,8,9-tetrahydropyrido[3,4-g]pteridine
      derivatives 3-9 with different benzyl and a benzoyl substitution at the N7
      position were designed and synthesized, as classical and nonclassical, partially
      restricted, linear tricyclic 5-deaza antifolates. The purpose was to investigate
      the effect of conformational restriction of the C6-C9 (tau(1)) and C9-N10
      (tau(2)) bonds via an ethyl bridge from the N10 to the C7 position of 5-deaza
      methotrexate (MTX) on the inhibitory potency against dihydrofolate reductase
      (DHFR) from different sources and on antitumor activity. The synthetic
      methodology for most of the target compounds was a concise five-step total
      synthesis to construct the tricyclic nucleus, 2,4-diamino-5-deaza-7H-6,7,8,9
      tetrahydropyrido[3,4-g]pteridine (23), followed by regioselective alkylation of
      the N7 nitrogen. Biological results indicated that this partial conformational
      modification for the classical analogue N-[4-[(2,4-diamino-5-deaza-6,7,8,9
      tetrahydropyrido[3,4-g]pteridin-7-yl)methyl]benzoyl]-L-glutamic acid 3 was
      detrimental to DHFR inhibitory activity as well as to antitumor activity compared
      to MTX or 5-deaza MTX. However, the classical analogue 3 was a better substrate
      for folypolyglutamate synthetase (FPGS) than MTX. These results show that a
      classical 5-deaza folate partially restricted via a bridge between the N10 and C7
      positions retains FPGS substrate activity and that the antitumor activity of
      classical tricyclic analogues such as 3 would be influenced by FPGS levels in
      tumor systems. Interestingly, the nonclassical analogues 4-9 showed moderate to
      good selectivity against DHFR from pathogenic microbes compared to recombinant
      human DHFR. These results support the idea that removal of the 5-methyl group of
      piritrexim along with restriction of tau(1) and tau(2) can translate into
      selectivity for DHFR from pathogens.

PMID- 12408728
TI  - Spectral and crystallographic study of pyridinic analogues of nimesulide:
      determination of the active form of methanesulfonamides as COX-2 selective
      inhibitors.
AB  - Compound 7, N-(3-phenoxy-4-pyridinyl)trifluoromethanesulfonamide, showed in vitro
      (whole blood assay) a strong inhibitory activity on the two cyclooxygenase (COX)
      enzymes (IC(50)(COX-1) = 2.2 microM and IC(50)(COX-2) = 0.4 microM), being more
      active but less COX-2-selective than nimesulide. Physicochemical studies and
      structural analyses indicated that the anionic sulfonamidate species seemed to be
      the active form of methanesulfonamides, which optimally interacted with the COX
      enzymes' active sites.

PMID- 12408730
TI  - Tolerabilities of antiretrovirals in paediatric HIV infection.
AB  - Data on the efficacy and tolerability of antiretrovirals in children are limited
      as, in contrast to adult studies, large paediatric cohort studies are lacking.
      Thus, data pertaining to adults are often extrapolated to children despite the
      acknowledgement that children are not little adults. This review summarises
      information gathered from existing reports and focuses on the tolerabilities of
      antiretrovirals in children infected with HIV-1. The efficacy of antiretrovirals
      is not included in the scope of the discussion. Taste of antiretrovirals should
      be an important factor when considering the tolerability of antiretrovirals in
      children. However, antiretroviral options are often limited in young children as
      only some of the antiretrovirals are available as paediatric formulations. All
      antiretrovirals have been associated with toxicities in children, but in general,
      they are relatively well tolerated. The gastrointestinal system including hepatic
      system is most prone to being affected by these drugs. Skin rashes and
      hypersensitivity reactions are also associated with antiretroviral use,
      particularly with the non-nucleoside reverse transcriptase inhibitors.
      Mitochondrial toxicities that lead to impairment of liver function, pancreatic
      function and lactic acidosis are associated with most of the nucleoside
      analogues. Haematological toxicity is often a dose limiting adverse effect
      especially of the nucleoside analogues, in particular zidovudine. The protease
      inhibitors are associated with gastrointestinal intolerance (diarrhoea) and
      metabolic derangements that can lead to hypercholesterolaemia and
      hypertriglyceridaemia, which in turn and can lead to changes in body habitus. The
      renal system is also affected by several drugs, the most important of which is
      indinavir, which has been associated with renal stones and damage to the renal
      tubules. Fortunately, with lower incidence of major toxicity and with the range
      of drugs now available for paediatric use, toxicities are usually not a barrier
      to effect antiretroviral therapy in children.

PMID- 12408731
TI  - Indinavir-induced retinoid-like effects: incidence, clinical features and
      management.
AB  - Since 1998, many cases of antiretroviral therapy-related paronychia of the toes
      or fingers and ingrown toenails have been reported. Most of them were related to
      indinavir. Other indinavir-induced mucocutaneous disorders resembling the adverse
      effects of systemic retinoid therapy have also been reported. Although there is
      some uncertainty in the literature regarding a cause-effect relationship, results
      of several epidemiological and in vitro studies, together with cumulated clinical
      experience leave no doubt that indinavir causes a retinoid-like effect and nail
      alterations. Indeed, indinavir is the only antiretroviral drug that produces
      these disorders, although ritonavir may enhance indinavir-induced retinoid-like
      effects through pharmacokinetic interactions leading to increased plasma
      indinavir concentrations. Approximately 30% of patients receiving indinavir show
      two or more retinoid-like manifestations and 4-9% develop paronychia. These
      adverse effects are not related to other epidemiological variables such as the
      patient's sex, age or other risk factors or immune status. They seem to be
      exposure dependent and, therefore, largely dose-dependent. Chronic paronychia is
      considered generally to be caused by contact irritants and candidal infection.
      Nevertheless, indinavir is currently the most frequent cause of chronic or
      recurrent paronychia in HIV-infected patients. In addition, retinoid-like
      manifestations such as cutaneous xerosis and cheilitis are frequent mucocutaneous
      adverse effects related to indinavir. The exact mechanism of indinavir-induced
      retinoid-like effects is unclear. Hypotheses for pathogenesis include
      interference with retinoid metabolism by enhancing the retinoic acid signalling
      pathway, or by increasing retinoic acid synthesis, or by reducing cytochrome p450
      mediated retinoic acid oxidative metabolism. Replacement of therapy by an
      antiretroviral regimen not containing indinavir, while retaining other protease
      inhibitors and lamivudine, resolves retinoid-like manifestations without
      recurrences.

PMID- 12408732
TI  - The use and safety of non-allopathic Indian medicines.
AB  - Non-allopathic Indian medicines, referred to elsewhere in the world as
      complementary and alternative medicine have gathered increasing recognition in
      recent years with regard to both treatment options and health hazards. Ayurveda,
      Siddha, Unani and homeopathy are practiced in India as non-allopathic systems.
      These systems comprise a wide range of therapeutic approaches that include diet,
      herbs, metals, minerals, precious stones and their combinations as well as non
      drug therapies. Ayurveda is the oldest system of medicine in the world and by far
      the most commonly practiced form of non-allopathic medicine in India,
      particularly in rural India, where 70% of the population lives. The difference
      between modern medicine and these systems stems from the fact that the knowledge
      base of many of the above systems, unlike Western medicine, is based on years of
      experience, observations, empiricism and intuition and has been handed down
      generations both through word of mouth and treatises. The focus on non-allopathic
      systems of medicine in India can be attributed to various causes including a need
      to revive a rich tradition, the dependency of 80% of the country's population on
      these drugs, their easy availability, increasing worldwide use of these
      medicines, the lack of focused concerted scientific research and the abuse of
      these systems by quacks. Elsewhere, the increasing use of herbal products
      worldwide and the growth of the herbal product industry has led to increasing
      concern regarding their safety. The challenges in these non-allopathic systems
      relate to the patient, physician, regulatory authorities, the abuse/misuse of
      these medicines, quality and purity issues. Safety monitoring is mandated by a
      changing ecological environment, the use of insecticides, new manufacturing
      techniques, an as yet unregulated pharmaceutical industry, the availability of
      combinations of herbs over the counter and not mentioned in ancient Ayurvedic
      texts, and the need to look at the active principles of these medicines as
      potential chemotherapeutic agents. The Indian traditional medicine industry has
      come a long way from the times when it was considered unnecessary to test these
      formulations prior to use, to the introduction of Good Manufacturing Practice
      guidelines for the industry. However, we still have a long way to go. The
      conflict between the traditional practitioners and the purists demanding evidence
      of safety and efficacy needs to be addressed. There is an urgent need for the
      practitioners of the allopathic and non-allopathic systems to work together to
      optimise the risk-benefit profile of these medicines.

PMID- 12408733
TI  - Gastrointestinal safety of an extended-release, nondeformable, oral dosage form
      (OROS: a retrospective study.
AB  - BACKGROUND: The OROS osmotic (OSM) dosage form optimises extended-release oral
      administration by controlling the rate of drug release for a predetermined time,
      providing constant, patterned, or pulsed delivery profiles. OSM products include
      prescription medications for urology, CNS, and cardiovascular indications, as
      well as over-the-counter nasal/sinus congestion medications. METHODS: This
      retrospective study examines US gastrointestinal (GI) safety data for the OROS
      dosage form following nearly two decades of use. Although GI injury and
      obstruction are known effects of oral medications, some reports have suggested
      that extended-release products pose a greater risk of GI injury and obstruction
      than other oral dosage forms. Products incorporating OROS technology are being
      prescribed to an expanding range of patients; a review of the GI safety data for
      this dosage form thus seemed timely and appropriate. US safety information was
      obtained from three sources: English language literature published from 1982
      until June 1, 2000 from five major biomedical databases;postmarketing safety
      reports from January 1, 1983 until June 1, 2000 available through the Freedom of
      Information Act; andcommercial safety information obtained directly from ALZA
      Corporation's in-house safety database for those OSM products for which ALZA has
      reporting responsibility. US distribution data from IMS National Prescription
      Audit trade mark Plus data were used to estimate cumulative product distribution
      totals. These totals were combined with numbers of unique GI events to determine
      the estimated frequency of events. RESULTS: Nearly 13 billion OSM tablets are
      estimated to have been distributed in the US. The incidence of all clinically
      significant GI adverse events for OSM products (including intestinal, gastric,
      and oesophageal irritation, injury, and obstruction) reported in the US was
      approximately one case in >76 million tablets distributed. The majority (78%;
      estimated incidence: one case in 29 million tablets) of cases were reported in
      patients taking Procardia XL (nifedipine). Oesophageal and lower GI obstruction
      were reported primarily in patients with pre-existing abnormalities or disease of
      the GI tract. Among paediatric patients, one obstruction was reported in an
      estimated 37.7 million tablets distributed. Reports of GI irritation associated
      with OSM products were consistent with known effects of the same drug substances
      in other dosage forms. CONCLUSION: A review of long-term safety experience with
      products using OSM controlled-release technology yields a low incidence of
      clinically significant GI events. Properly prescribed, extended-release products
      provide substantial therapeutic and convenience benefits without additional risk.

PMID- 12408734
TI  - Assessing the feasibility of using an adverse drug reaction preventability scale
      in clinical practice: a study in a French emergency department.
AB  - OBJECTIVE: To assess the preventability of adverse drug reactions (ADRs) leading
      to hospital admissions and to investigate the feasibility of the use of a
      standardised preventability scale in clinical practice. DESIGN: The study was a
      prospective pharmacovigilance study. All patients more than 15 years old admitted
      to an emergency department during a period of 4 weeks were included.
      Characteristics of patients admitted for a suspected ADR (cases) were compared to
      those admitted for other reasons (controls). Preventability was assessed in two
      different ways: (i). by using a standardised preventability scale; and (ii). by
      the assessment of four reviewers without the scale. Results of the two methods
      were compared. PATIENTS: In total, 671 patients were admitted to an emergency
      department during the study period. RESULTS: Overall, 44 ADRs were identified
      involving 41 patients. The incidence of hospital admissions for ADRs was 6.1 per
      100 admissions (95% CI 4.4-8.3). According to the French causality assessment
      method, 71% of ADRs were 'possible', 18% were 'plausible' and 11% were 'likely'.
      Using the standardised preventability scale, one-third of all ADRs were
      considered as being preventable (9% 'definitely' and 25% 'potentially'
      preventable). Reviewers found that 54.5% of ADRs were 'preventable'.
      Discrepancies between the two methods concerned mainly cases defined as not
      preventable by the scale. In general, reviewers overestimated the preventability
      of ADR compared with the scale. CONCLUSIONS: These results emphasise that ADRs
      leading to hospitalisation are frequent, with one-third of them likely to be
      preventable. Moreover, the risk of ADRs mainly involved a small number of drugs.
      Our experience suggests that there is a need for further studies to validate the
      French standardised scale of preventability assessment.

PMID- 12408735
TI  - Short course in pharmacoepidemiology and pharmacovigilance at the London School
      of Hygiene and Tropical Medicine.
AB  - Demand for education in pharmacoepidemiology is widespread, and has resulted in
      the short course at the London School of Hygiene and Tropical Medicine. This
      course is designed as an introduction but requires some scientific background to
      understand it. The course occurs annually, and covers basics of epidemiology,
      statistics and drug surveillance systems as applied particularly to drug safety
      issues. A successful completion results in a certificate from the University of
      London, and the course is accredited for continuing pharmacy and medical
      education purposes.

PMID- 12408736
TI  - Meningococcal vaccines: a progress report.
AB  - Neisseria meningitidis causes a wide range of human disease and remains a common
      cause of septicaemia and meningitis. Meningococcal serogroups A, B, C and Y cause
      the majority of cases of invasive disease in the US and throughout the world,
      with epidemics usually caused by serogroups A and C. Most patients with
      meningococcaemia, with or without meningitis, respond to standard antimicrobial
      therapy with either penicillin or ampicillin, but the recent emergence of
      meningococcal strains that are intermediately resistant to penicillin may alter
      these recommendations in the future. Given the devastating nature of
      meningococcal disease and emergence of these resistant strains, prevention
      (specifically through vaccination) remains the best approach to control this
      serious infection. A polysaccharide meningococcal vaccine is efficacious against
      disease caused by serogroups A, C, Y and W135, but is not effective in infants
      and children aged <2 years, and the duration of efficacy decreases markedly
      during the first 3 years after a single dose of the vaccine. Conjugate
      meningococcal vaccines have been developed to address these concerns. Initial
      studies with the meningococcal C conjugate vaccine have shown that the vaccine is
      safe and immunogenic and provides a T cell-dependent antigen that can be boosted
      by further doses of vaccine, or following exposure to the homologous organism or
      cross-reacting antigens. The UK recently implemented routine vaccination with the
      meningococcal C conjugate vaccine to all infants, and to all persons aged >1 year
      in a catch-up programme to immunise all school-aged children and young adults up
      to 20 years of age. Early postlicensure data indicate that this vaccine has shown
      significant efficacy in reduction of invasive meningococcal disease in these age
      groups. The full impact of vaccination will be determined once all age groups are
      immunised.

PMID- 12408737
TI  - Bacterial genomics: potential for antimicrobial drug discovery.
AB  - The sequencing of entire bacterial genomes is becoming increasingly routine,
      promising to revolutionise approaches to identifying putative antimicrobial drug
      targets. In silico methods can be used to identify putative gene products by
      comparing sequences of biochemically characterised enzymes and proteins with data
      produced by sequencing projects. Comparative genomics between a pathogenic
      bacterium versus nonpathogen as well as pathogen versus host can identify
      molecular targets that would be ideal for future investigation. The aim of these
      comparisons would be to identify genes that code for pathogenicity factors in the
      bacterium or genes essential for bacterial survival. The latter set of genes
      includes those that are nonfunctional or redundant in the host as well as genes
      absent from the host but essential in the pathogen. The products of these genes
      would be ideal targets for antimicrobial compounds. If compounds could be
      generated that disrupt the pathogen's ability to thrive but not affect the host,
      since there is a lack of the targeted protein, they could prove to be powerful
      therapeutics. An elegant example illustrating the power of comparative genomics
      involves comparison of the pathways of bacterial and eukaryotic aminoacyl-tRNA
      synthesis. Comparison of pathogenic bacterial genomes shows that many bacteria
      lack the genes encoding either one or two specific aminoacyl-tRNA synthetases,
      enzymes involved in ensuring correct aminoacylation of tRNA for subsequent
      translation of the genetic code. Bacteria have an alternative pathway by which
      amide aminoacyl-tRNAs are formed. Comparative genomics has demonstrated that this
      pathway is uniquely prokaryotic/archaeal and also relatively widely found in
      pathogenic bacteria, indicating the potential of the catalytic enzymes of the
      pathway as targets for novel antimicrobial drugs.

PMID- 12408738
TI  - Iontophoresis-based transdermal delivery systems.
AB  - Transdermal iontophoresis is the administration of ionic therapeutic agents
      through the skin by the application of a low-level electric current. This article
      presents an overview of transdermal iontophoretic delivery of drugs, including
      peptides and oligonucleotides. Recent advances in the area of iontophoretic
      delivery, including devices, hydrogel formulations, safety, clinical relevance
      and future prospects, are discussed. Electroporation, another method of
      electrically assisted drug delivery, is also briefly reviewed. Transdermal
      iontophoresis appears to be a promising technique for the delivery of a variety
      of compounds in a controlled and preprogrammed manner. Transdermal iontophoresis
      would be particularly useful in the delivery of hydrophilic drugs produced by
      biotechnology (peptides and oligonucleotides). However, because of the complex
      physicochemical properties of peptides, many factors must be carefully considered
      for the proper design of an iontophoretic drug delivery system for peptides.
      Iontophoresis has been successfully used in the delivery of small peptides, such
      as leuprolide and calcitonin analogues, in humans. However, it appears that
      transdermal iontophoresis may not be a suitable method for the systemic delivery
      of larger peptides (>7,000D). The combined use of iontophoresis and
      electroporation may be more effective in the delivery of peptides, proteins,
      genes and oligonucleotides. The long-term safety of iontophoresis, patient
      compliance with the technique and the commercial success of this technology are
      yet to be demonstrated. Iontophoretic delivery of drugs would be beneficial in
      the treatment of certain skin disorders such as skin cancer, psoriasis,
      dermatitis, venous ulcers, keloid and hypertrophic scars. Investigations on
      reverse iontophoresis may yield interesting results that would be useful in the
      noninvasive measurement of clinically important molecules in the body.

PMID- 12408739
TI  - Potential of interferon-alpha in solid tumours: part 2.
AB  - The second part of this review examines the use of recombinant interferon-alpha
      (rIFNalpha) in the following solid tumours: superficial bladder cancer, Kaposi's
      sarcoma, head and neck cancer, gastrointestinal cancers, lung cancer,
      mesothelioma and ovarian, breast and cervical malignancies. In superficial
      bladder cancer, intravesical rIFNalpha has a promising role as second-line
      therapy in patients resistant or intolerant to intravesical bacille Calmette
      Guerin (BCG). In HIV-associated Kaposi's sarcoma, rIFNalpha is active as
      monotherapy and in combination with antiretroviral agents, especially in patients
      with CD4 counts >200/mm(3), no prior opportunistic infections and nonvisceral
      disease. rIFNalpha has shown encouraging results when used in combination with
      retinoids in the chemoprevention of head and neck squamous cell cancers. It is
      effective in the chemoprevention of hepatocellular cancer in hepatitis C
      seropositive patients. In neuroendocrine tumours, including carcinoid tumour, low
      dosage (</=3 MU) or intermediate-dosage (5 to 10 MU) rIFNalpha is indicated as
      second-line treatment, either with octreotide or alone in patients resistant to
      somatostatin analogues. Intracavitary IFNalpha may be useful in malignant pleural
      effusions from mesothelioma. Similarly, intraperitoneal IFNalpha may have a role
      in the treatment of minimal residual disease in ovarian cancer. In breast cancer,
      the only possible role for IFNalpha appears to be intralesional administration
      for resistant disease. IFNalpha may have a role as a radiosensitising agent for
      the treatment of cervical cancer; however, this requires confirmation in
      randomised trials. On the basis of current evidence, the routine use of rIFNalpha
      is not recommended in the therapy of head and neck squamous cell cancers, upper
      gastrointestinal tract, colorectal and lung cancers, or mesothelioma. Pegylated
      IFNalpha (peginterferon-alpha) is an exciting development that offers theoretical
      advantages of increased efficacy, reduced toxicity and improved compliance.
      Further data from randomised studies in solid tumours are needed where rIFNalpha
      has activity, such as neuroendocrine tumours, minimal residual disease in ovarian
      cancer, and cervical cancer. A better understanding of the biological mechanisms
      that determine response to rIFNalpha is needed. Studies of IFNalpha-stimulated
      gene expression, which are now feasible, should help to identify molecular
      predictors of response and allow us to target therapy more selectively to
      patients with solid tumours responsive to IFNalpha.

PMID- 12408741
TI  - Virulizin.
AB  - Virulizin, a biological response modifier, is a mixture of proteins and peptides
      that have been extracted from bovine reticuloendothelial tissue that activates
      macrophages. It is being developed by Lorus Therapeutics (formerly Imutec Pharma)
      for the treatment of various cancers and had completed phase II clinical trials
      in Canada for the treatment of pancreatic cancer and advanced malignant melanoma.
      The commencement of phase III clinical trials in Canada, for the treatment of
      pancreatic cancer, was delayed due to quality control problems with batches of
      virulizin and all clinical trials of virulizin were suspended as Lorus underwent
      a major restructuring programme. However, phase I/II clinical trials are now
      underway again in Canada in HIV-positive patients with Kaposi's sarcoma and for
      the treatment of pancreatic cancer. A phase I/II clinical trial is also underway
      in patients with pancreatic cancer in the USA. Lorus announced in June 2000 that
      it had completed a meta analysis of three phase I/II studies of virulizin that
      showed the drug increased survival and improved quality of life for pancreatic
      cancer patients. Based on these positive results, Lorus initiated a phase III
      trial to be conducted at 40 sites in North America in November 2001. The study
      aims to enrol 350 patients with advanced pancreatic cancer and will test the
      effectiveness of virulizin as first- and second-line treatment of pancreatic
      cancer. The study will compare virulizin + gemcitabine with gemcitabine alone as
      first-line therapy, while second-line treatment will involve patients who have
      failed to respond to gemcitabine. Some of these patients will receive virulizin +
      fluorouracil while another group will receive only fluorouracil. The study is
      scheduled to complete in 2004 or early 2005. Virulizin received orphan drug
      status for this indication from the US FDA in February 2001. Lorus received fast
      track designation from the FDA in June 2002 for virulizin for the treatment of
      pancreatic cancer. Virulizin is registered for the treatment of malignant
      melanoma in Mexico and is due to be launched there in 2002. Lorus has entered
      into an exclusive 7-year distribution agreement with Faulding Canada Inc., giving
      Faulding (now part of Mayne Group) the right to market and sell virulizin in
      Mexico for the treatment of melanoma. Lorus will receive royalties from sales of
      the product and will be responsible for its manufacture. In April 2002, Mayne
      exercised its option to acquire the distribution rights for virulizin in Brazil.
      Lorus Therapeutics has signed a collaborative agreement with NaPro
      BioTherapeutics, USA, to study the efficacy of virulizin in combination with
      paclitaxel for the treatment of lung adenocarcinoma. Lorus is conducting
      preclinical studies of virulizin in human breast cancer, lung, ovarian and
      prostate cancer, and has reported successful activity of the agent in these
      indications. Lorus was awarded a patent by the US Patent and Trademark Office to
      protect the only known process used to create virulizin. This patent, in
      conjunction with the patents issued in Australia, South Africa, New Zealand,
      Korea and Singapore, broadens and strengthens the protection of Lorus'
      intellectual property rights regarding the process, composition and use of
      virulizin.

PMID- 12408742
TI  - BMP 2--Genetics Institute/ Medtronic-Sofamor Danek/Integra. Bone morphogenetic
      protein 2--Genetics Institute/ Medtronic-Sofamor Danek/Integra, INFUSE Bone
      Graft, recombinant human bone morphogenetic protein 2--Genetics
      Institute/Medtronic-Sofamor Danek/Integra, RhBMP 2--Genetics Institute/Medtronic
      Sofamor Danek/Integra.
AB  - Genetics Institute (Wyeth) is collaborating with Medtronic-Sofamor Danek (which
      specialises in spinal reconstruction) and Integra Life Sciences to develop a BMP
      2 product [INFUSE Bone Graft] for use in spinal reconstruction in North America.
      The INFUSE Bone Graft product has been approved for use in lumbar interbody
      spinal fusion procedures in the USA and is in phase III trials for use in lumbar
      posterolateral spinal fusion procedures. During the procedure, damaged disc is
      replaced with a collagen sponge (Integra's Absorbable Collagen Sponge) soaked
      with BMP 2, which is held in place within an implanted cage device (LT-CAGE
      Lumbar Tapered Fusion Devise); the fusion process subsequently requires several
      months to complete. However, the patient is able to leave hospital the day after
      the operation, whereas in conventional spinal surgery a longer recovery time is
      required. The procedure supersedes the use of autograft bone as it uses a
      recombinant human bone morphogenic protein, rhBMP-2, which induces the body to
      grow its own bone where required. Genetics Institute has cloned and expressed
      bone morphogenic proteins 1-7 and established manufacturing processes by
      recombinant DNA technology. Bone morphogenic proteins may be useful in the
      treatment of osteoporosis and orthopaedic trauma. BMP 2 is also being developed
      for bone regeneration as an implanted device and as an injectable formulation.
      Genetics Institute is also collaborating with Integra LifeSciences to develop a
      formulation of BMP 2 with Integra's absorbable collagen-based structures for
      fracture treatment, which is awaiting approval in the USA.

PMID- 12408743
TI  - Amediplase: CGP 42935, K2tu-PA, MEN 9036.
AB  - Amediplase [CGP 42935, MEN 9036, K2tu-PA] is a recombinant chimeric plasminogen
      activator, consisting of the kringle 2 domain from the A-chain of tissue
      plasminogen activator (t-PA) and the carboxy terminal region of pro-urokinase.
      Amediplase was the outcome of a collaborative project with Ciba Geigy (now
      Novartis), but subsequent preclinical and clinical development has been completed
      by Menarini. Menarini is currently investigating amediplase in phase III clinical
      trials in Europe as a thrombolytic given as a single bolus to patients with
      myocardial infarction. In June 2002, Prometic Life Sciences announced that its
      collaboration with Menarini Biotech had resulted in the discovery of a scaleable
      manufacturing process for amideplase, based on Prometic's Mimetic Ligand-
      technology; amideplase manufactured by this process is expected to be used in the
      phase III studies.

PMID- 12408744
TI  - Omalizumab: anti-IgE monoclonal antibody E25, E25, humanised anti-IgE MAb, IGE
      025, monoclonal antibody E25, Olizumab, Xolair, rhuMAb-E25.
AB  - Omalizumab [anti-IgE monoclonal antibody E25, E25, humanised anti-IgE MAb, IGE
      025, monoclonal antibody E25, olizumab, rhuMAb-E25, Xolair] is a chimeric
      monoclonal antibody. It binds specifically to the Cepsilon3 domain of
      immunoglobulin E (IgE). Cepsilon3 is the site of high-affinity IgE receptor
      binding. IgE plays a major role in allergic disease by causing the release of
      histamine and other inflammatory mediators from mast cells. Omalizumab binds to
      and neutralises circulating IgE by preventing IgE from binding to its high
      affinity mast-cell receptor. In addition, omalizumab does not bind to or induce
      histamine release from basophils, nor does it bind to or recognise IgG. The
      immune complexes formed between IgE and omalizumab in vivo are relatively small
      (molecular weight <1 million) and are therefore unlikely to cause organ damage.
      COLLABORATION BETWEEN GENETECH NOVARTIS AND TANOX: omalizumab is very similar to
      the Tanox product CGP 51901. Genentech (Roche), Novartis and Tanox (formerly
      Tanox Biosystems) were developing both antibodies in phase II studies, with an
      agreement to collaborate on phase III development of the most promising one. The
      Genentech product, omalizumab, was selected for further development. Tanox has
      marketing rights to the drug in some Asian markets. Novartis and Genentech have
      marketing rights in the USA. Roche has an option to participate in the
      commercialisation of omalizumab and other anti-IgE products of the collaboration
      in Japan and Europe. Roche may exercise this option if specific events relating
      to commercialisation of the product occur; Roche has waived this option for
      omalizumab in Japan. If Genentech withdraws from the collaboration, Roche has an
      option to assume its place. Either Novartis or Genentech may withdraw from the
      collaboration on short notice, in which case rights to omalizumab revert to Tanox
      and the remaining collaborator unless Roche exercises its option in the event of
      withdrawal by Genentech. PATENTS: Protein Design Labs holds fundamental antibody
      humanisation patents. Protein Design Labs stated in its Annual Report for 2000
      that Genentech may elect to take a patent licence for Xolair under a 1998 patent
      rights agreement. CLINICAL TRIALS: Phase III clinical trials of omalizumab for
      the treatment of allergic rhinitis and allergic asthma were in progress with
      Genentech (Roche) in the USA, Canada, Europe and Japan, and are now completed. In
      New Zealand, the antibody was investigated in clinical trials for the treatment
      of allergic asthma at the Wellington School of Medicine. In the phase III trials,
      omalizumab was administered as a subcutaneous injection. It may also be
      administered intravenously. In additional phase I and II studies, the safety and
      efficacy of aerosol administration for allergic asthma was tested. Initial
      results of these studies indicated that aerosol administration is less effective
      than intravenous or subcutaneous administration. TEMPORARY SUSPENSION OF TRIALS:
      In September 2000, the US FDA requested that Genentech and Novartis suspend new
      trials of omalizumab. Existing long-term trials, however, could continue. The
      hold on new trials was due to concerns about the preclinical toxicity of
      omalizumab and the follow-up antibody E26. Thrombocytopenia was reported in
      studies in monkeys for omalizumab at 5-27 times the maximum clinical dose and for
      E26 at 3-15 times the maximum dose. In response to FDA requests, Novartis and
      Genentech carried out additional preclinical trials so that a specific
      explanation of the toxicity could be obtained; Novartis suspected a species
      specificity for the adverse events, as no thrombocytopenic events occurred in the
      completed phase III clinical trials. The supplementary data were submitted to the
      FDA and the hold on clinical trials was lifted in November 2000. REGULATORY
      FILINGS: in June 2000, Genentech, Novartis and Tanox submitted a Biologics
      Licence Application (BLA) to the US FDA for approval of omalizumab for the
      treatment of allergic asthma and allergic rhinitis. Novartis fileiled for
      marketing approval of omalizumab in the European Union, Switzerland, Australia
      and New Zealand. INDICATION NARROWED TO ADULT ALLERGIC ASTHMA: In July 2001, the
      FDA requested additional data, both preclinical and clinical, for Xolair, as well
      as more detailed information concerning the effect of prolonged action of the
      drug. Genentech is to satisfy the FDA's request with data from the ALTO platelet
      monitoring safety study and with ongoing open-label studies. Genentech, Novartis
      and Tanox believe that substantial information can be provided from continuing
      trials, but additional trials on specific subgroups may be necessary. The new
      data will be submitted to both the US FDA and the EMEA in the European Union. The
      application for approval of Xolair that was submitted to the EMEA was withdrawn
      when it became clear that there would be a delay in approval in the USA. Tanox
      had originally anticipated that Xolair would be launched in mid-2001 in the USA
      and Europe. In November 2001, Genentech and Novartis stated that an amended BLA
      would be submitted to the FDA in the fourth quarter of 2002. The amended approval
      application will focus on the use of Xolair in adults only with allergic asthma.
      The original application was for treatment of both adults and children, and
      included allergic rhinitis. Genentech has stated that it will first pursue the
      narrower indication before filing supplemental BLAs. Approval of the drug in the
      USA may now be delayed until as late as the end of 2003. In Europe, Novartis is
      planning to develop Xolair for use only in asthmatic patients who are classed as
      being 'at risk', i.e. those who have been hospitalised or have visited an
      emergency department. Clinical studies are to be carried out, with submission for
      regulatory approval planned for 2003. APPROVAL IN AUSTRALIA: In June 2002, Xolair
      was approved by the Therapeutic Goods Administration in Australia for the
      treatment of adults and adolescents with moderate allergic asthma. This is the
      first marketing approval for Xolair.

PMID- 12408745
TI  - Exploring perspectives on transition of youth with disabilities: voices of young
      adults, parents, and professionals.
AB  - Qualitative research methods were used to examine transition experiences of (a).
      9 young adults with severe disabilities during their last year of high school,
      (b). their parents, and (c). professionals from schools and adult service
      agencies. Students were remarkably articulate about plans following graduation
      but had few opportunities to meaningfully fulfill them. Parents hoped their
      child's talents and abilities would allow them to achieve fulfilling adult lives,
      but faced uncertain outcomes and unfamiliar procedures. Professionals managed the
      process and approached transition by matching needs to available programs;
      however, these programs fostered dependency and denied students a genuine
      opportunity to achieve full adult status. Although both parents and professionals
      worked for the betterment of young adults, the inability to recognize diverse
      perspectives seriously impeded the quality of the transition process.

PMID- 12408746
TI  - Prevalence of physical inactivity and recommended physical activity in community
      based adults with mental retardation.
AB  - Little information has been reported on the leisure time physical activity (LTPA)
      habits of adults with mental retardation. Prevalence of physical inactivity and
      recommended LTPA of adults with mild to moderate mental retardation who live in
      community settings was described. Adults with mental retardation (76 men, 74
      women) reported their physical activity habits. Overall, men and women who
      resided in community settings were similarly inactive, with 47% to 51% of
      individuals participating in little to no LTPA. Forty-two to 47% of them reported
      participation in moderate to vigorous LTPA five or more times per week.
      Limitations to quantifying physical activity through questionnaire process is
      discussed and development and implementation of programs designed to increase
      physical activity levels recommended.

PMID- 12408747
TI  - Subjective and objective quality of life assessment: responsiveness, response
      bias, and resident:proxy concordance.
AB  - Low language ability and response bias are frequently cited as impediments to
      valid responding to items on interview schedules. Structured interviews with a
      random sample of 154 adults with mental retardation showed that around two thirds
      of respondents were either unable to respond or exhibited response bias. There
      was a significant difference in scores on the Adaptive Behavior Scale between
      those who exhibited response bias and those who did not. In cases of nonresponse
      or response bias, the substitution of the respondent with a proxy respondent has
      been proposed as an alternative method of gathering subjective data. In this
      study concordance between individuals' responses and those of proxies was low on
      a subjective measure and high on an objective scale.

PMID- 12408748
TI  - Conceptualization, measurement, and application of quality of life for persons
      with intellectual disabilities: report of an international panel of experts.
AB  - In this article a number of issues involving the concept of quality of life as
      applied to persons with intellectual disabilities are summarized, and a number of
      agreed-upon principles regarding its conceptualization, measurement, and
      application are presented. We realize that the concepts and models presented in
      this article will vary potentially from country to country, and even from area to
      area within countries. The cross-cultural understanding of the concept of quality
      of life is in its infancy, and we hope that the discourses resulting from the
      material presented in this article will facilitate both cross-cultural
      understanding and collaborative work. The article reflects current thought about
      the conceptualization, measurement, and application of this increasingly
      important and widely used concept in the field of intellectual disabilities and
      sets the stage for its continuing development.

PMID- 12408749
TI  - Glutaminase isoform expression in cell lines derived from human colorectal
      adenomas and carcinomas.
AB  - This paper describes some properties of glutamine oxidation and glutaminase
      isoform expression in cell lines derived from human colorectal adenomas and
      carcinomas. The slow-growing adenoma-derived cell line AA/C1, and the rapidly
      proliferating carcinoma cell line HT29, both required glutamine for growth. The
      rate of (14)CO(2) production from [U-(14)C]glutamine was faster in AA/C1 cells
      than in HT29 cells. Conversely HT29 cells showed faster rates of glucose
      oxidation and lactate production. The activity of glutaminase was 3 times higher
      in AA/C1 cell extracts than in extracts of HT29 cells. Glutaminase activity in
      the two cell lines had similar K(m) values for glutamine, but the activity in
      AA/C1 cells had a higher K(0.5) for activation by phosphate. Glutaminase activity
      in extracts of both cells was inhibited by glutamate. Western blotting showed the
      presence, in both cell lines, of isoform(s) of glutaminase with an molecular mass
      of 63 kDa, intermediate between that of kidney glutaminase and liver glutaminase.
      PCR-based analysis showed that an mRNA species identical to the kidney-type
      isoform glutaminase C was present in both cell types as was an additional mRNA
      species identical to the liver-type glutaminase isoform from human breast tumour
      cells. Northern blotting using isoform-specific cDNA probes demonstrated that
      mRNA for both glutaminase isoforms was expressed at significant levels in both
      cell types. Similar results to those in AA/C1 cells and HT29 cells were obtained
      in two further adenoma and carcinoma cell lines respectively. These results
      contrast with those reported previously in hepatocyte/hepatoma model systems with
      respect to fuel selection, glutaminase activity and isoform expression. They also
      constitute the first demonstration of simultaneous expression of two glutaminase
      isoforms in a single cell type.

PMID- 12408750
TI  - Control of human carnitine palmitoyltransferase II gene transcription by
      peroxisome proliferator-activated receptor through a partially conserved
      peroxisome proliferator-responsive element.
AB  - The expression of several genes involved in fatty acid metabolism is regulated by
      peroxisome proliferator-activated receptors (PPARs). To gain more insight into
      the control of carnitine palmitoyltransferase (CPT) gene expression, we examined
      the transcriptional regulation of the human CPT II gene. We show that the 5'
      flanking region of this gene is transcriptionally active and binds PPARalpha in
      vivo in a chromatin immunoprecipitation assay. In addition, we characterized the
      peroxisome proliferator-responsive element (PPRE) in the proximal promoter of the
      CPT II gene, which appears to be a novel PPRE. The sequence of this PPRE contains
      one half-site which is a perfect consensus sequence (TGACCT) but no clearly
      recognizable second half-site (CAGCAC); this part of the sequence contains only
      one match to the consensus, which seems to be irrelevant for the binding of
      PPARalpha. As expected, other members of the nuclear receptor superfamily also
      bind to this element and repress the activation mediated by PPARalpha, thus
      showing that the interplay between several nuclear receptors may regulate the
      entry of fatty acids into the mitochondria, a crucial step in their metabolism.

PMID- 12408752
TI  - Identification and functional analysis of enzymes required for precorrin-2
      dehydrogenation and metal ion insertion in the biosynthesis of sirohaem and
      cobalamin in Bacillus megaterium.
AB  - In Bacillus megaterium, the hemAXBCDL genes were isolated and were found to be
      highly similar to the genes from Bacillus subtilis that are required for the
      conversion of glutamyl-tRNA into uroporphyrinogen III. Overproduction and
      purification of HemC (porphobilinogen deaminase) and -D (uroporphyrinogen III
      synthase) allowed these enzymes to be used for the in vitro synthesis of
      uroporphyrinogen III from porphobilinogen. A second smaller cluster of three
      genes (termed sirABC) was also isolated and found to encode the enzymes that
      catalyse the transformation of uroporphyrinogen III into sirohaem on the basis of
      their ability to complement a defined Escherichia coli (cysG) mutant. The
      functions of SirC and -B were investigated by direct enzyme assay, where SirC was
      found to act as a precorrin-2 dehydrogenase, generating sirohydrochlorin, and
      SirB was found to act as a ferrochelatase responsible for the final step in
      sirohaem synthesis. CbiX, a protein found encoded within the main B. megaterium
      cobalamin biosynthetic operon, shares a high degree of similarity with SirB and
      acts as the cobaltochelatase associated with cobalamin biosynthesis by inserting
      cobalt into sirohydrochlorin. CbiX contains an unusual histidine-rich region in
      the C-terminal portion of the protein, which was not found to be essential in the
      chelation process. Sequence alignments suggest that SirB and CbiX share a similar
      active site to the cobaltochelatase, CbiK, from Salmonella enterica.

PMID- 12408753
TI  - Expression of inflammation related enzymes during experimental rat lung
      carcinogenesis.
AB  - OBJECTIVE: To investigate the expression of two inflammation related enzymes -
      cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) during the
      experimental rat lung carcinogenesis. METHODS: Eighty Wistar rats were instilled
      with 3-methylcholanthrene (MCA) and diethylinitrosamine (DEN) into the left lobar
      branchus to induce lung squamous cell carcinoma. To obtain specimen in every
      pathological phase during the carcinogenesis, these rats were sacrificed at
      different intervals. The expression of COX-2 and iNOS in every pathological phase
      during the carcinogenesis were examined by immunohistochemical method. The
      immunohistochemical scores (IHS) were calculated by combining an estimate of the
      percentage of immunoreactive cells with that of the stain intensity. RESULTS: 155
      specimens of every pathological phase during the carcinogenesis showed:
      hyperplasia 14, squamous metaplasia 25, dysplasia 33, carcinoma in situ 12,
      infiltrating carcinoma 54 and metastasis 17. Inflammation and elevated
      expressions of COX-2 and iNOS were shown in the precancerous lesions. The COX-2
      IHS was significantly increased in dysplasia, carcinoma in situ and metastasis (P
      < 0.01, P < 0.05, P < 0.01 respectively). The iNOS IHS significantly increased in
      hyperplasia and metastasis (P < 0.05, P < 0.01 respectively). There was a
      positive correlation between the expression of COX-2 and iNOS (gamma = 0.601 6, P
      < 0.001). CONCLUSION: COX-2 and iNOS, two inflammation related enzymes, playing
      important roles in the carcinogenesis of MCA and DEN, induce rat lung squamous
      cell carcinoma as well as its metastasis. The relation between inflammation and
      carcinogenesis may partly be explained by the elevated expression of these two
      enzymes. Nonsteroidal antiinflammatory drug (COX-2 inhibitors) and iNOS
      inhibitors may possess antitumor activities because of their prevention of
      bronchial dysplasia, carcinogenesis and metastasis.

PMID- 12408754
TI  - Molecular mechanism of enhanced apoptotic response in U937 cells mediated by
      sodium butyrate.
AB  - OBJECTIVE: To study the effects of sodium butyrate (NaBu) on cell cycle
      checkpoint and the apoptosis sensitivity in U937 cells. METHODS: Two mutant U937
      cell lines, U937-ASPI3K (ATM negative) and U937-pZeosv2(+) (ATM wild-type), were
      used as the cell model system. Immunoprecipitation and kinase assay were used to
      examine the p38 MAPK and ERK1 kinase activities. Western blot was used to analyze
      the phosphorylation of Bad protein. RESULTS: U937-pZeosv2(+) pretreated with NaBu
      exhibited enhanced apoptotic response in a NaBu dose dependent fashion upon
      (137)Cs irradiation, which could be abolished by olomoucine (OLM), a p38 MAPK
      specific inhibitor. On the other hand, Cyclin dependent kinase 2 (CDK2) specific
      inhibitor CDK2-I and p34cdc2/cyclinB inhibitor alsterpaullone (ALP) failed to
      block the effects of NaBu. Similar results were also observed in U937-ASPI3K. The
      effect of irradiation on p38 MAPK and ERK1 was strikingly potentiated by NaBu.
      Furthermore, inactivation of irradiated Bad protein via phosphorylation on serine
      136 was also enhanced. CONCLUSION: NaBu is able to enhance the apoptotic response
      in U937 cells, which is mediated by p38 MAPK activation but not ATM status.

PMID- 12408751
TI  - Ceramide: second messenger or modulator of membrane structure and dynamics?
AB  - The physiological role of ceramide formation in response to cell stimulation
      remains controversial. Here, we emphasize that ceramide is not a priori an
      apoptotic signalling molecule. Recent work points out that the conversion of
      sphingomyelin into ceramide can play a membrane structural (physical) role, with
      consequences for membrane microdomain function, membrane vesiculation,
      fusion/fission and vesicular trafficking. These processes contribute to cellular
      signalling. At the Golgi, ceramide takes part in a metabolic flux towards
      sphingomyelin, diacylglycerol and glycosphingolipids, which drives lipid raft
      formation and vesicular transport towards the plasma membrane. At the cell
      surface, receptor clustering in lipid rafts and the formation of endosomes can be
      facilitated by transient ceramide formation. Also, signalling towards
      mitochondria may involve glycosphingolipid-containing vesicles. Ceramide may
      affect the permeability of the mitochondrial outer membrane and the release of
      cytochrome c. In the effector phase of apoptosis, the breakdown of plasma
      membrane sphingomyelin to ceramide is a consequence of lipid scrambling, and may
      regulate apoptotic body formation. Thus ceramide formation serves many different
      functions at distinct locations in the cell. Given the limited capacity for
      spontaneous intracellular diffusion or membrane flip-flop of natural ceramide
      species, the topology and membrane sidedness of ceramide generation are crucial
      determinants of its impact on cell biology.

PMID- 12408755
TI  - Combined IL-2 and IL-12 gene therapy for murine head and neck squamous cell
      carcinoma.
AB  - OBJECTIVE: To evaluate the efficacy of combined interleukin (IL)-2 gene and IL-12
      gene therapy in murine model with head and neck squamous cell carcinoma (HNSCC).
      METHODS: HNSCC model was established in the mouth floor of C3H/HeJ mice with
      SCCVII cell line. Lipid-IL2 and lipid-IL12 plasmid complexes were introduced
      either alone or in combination into the tumor by direct intratumor gene
      injection. Tumor size was measured before and after the treatment to evaluate the
      response of the different treatment and control groups. Enzyme-linked
      immunosorbent assay (ELISA) was used to measure the IL-2 and IL-12 expression.
      Lactic dehydrogenase (LDH) assay was used to evaluate the activity of Cytotoxic T
      Lymphocyte (CTL) and natural killer (NK) cells. RESULTS: Growth of HNSCC was
      significantly inhibited in combined IL-2 and IL-12 gene therapy group as compared
      with the other groups (P < 0.01). Increased level of IL-2 and IL-12 protein
      expression was found in both combined and single treatment groups. Greater
      activity of CTL and NK was also observed in these two groups as compared with the
      controls. CONCLUSION: Both IL-2 and IL-12 gene therapy is able to inhibit the
      growth of HNSCC and induce the host antitumor immune response efficiently in the
      murine model. Combination of the two in gene therapy may be additive or
      synergistic in antitumor effect.

PMID- 12408756
TI  - Major histocompatibility complex class II antigen and costimulatory molecule
      expression on the surface of breast cancer cells.
AB  - OBJECTIVE: To study the major histocompatibility complex class II (MHC II)
      antigen and costimulatory molecules expression on the surface of breast cancer
      cells. METHODS: MHC II antigen and costimulatory molecule expression on five
      breast cancer cell lines including MCF-7, SK-BR-3, T47D, MDA-MB-435 and ZR-75-30
      were detected through flow cytometery analysis, with their expression level
      compared with that of normal mammary cell line HBL-100. RESULTS: The MHC II
      expression level of the five breast cancer cell lines were significantly
      different from that of HBL-100 (P < 0.05). MHC II antigen expression of MCF-7
      cells which was about 20 percent of HBL-100 was the lowest. MDA-MB-435 and ZR-75
      30 cell expression levels were twice as much as that of HBL-100, with the
      fluorescence intensity of MDA-MB-435 the highest of all cells. CD40 molecule
      expression on the surface of MDA-MB-435 cells was the lowest, which was nearly
      ten percent of that of MCF-7 and HBL-100 cells. CD80 and CD86 molecule expression
      showed no difference in MDA-MB-435 or HBL-100 cell (P > 0.05), and those of the
      other four breast cancer cells were lower than that of HBL-100 (P < 0.05).
      CONCLUSION: MHC II antigen and costimulatory molecule expression on the surface
      of breast cancer cells is abnormal, with different molecule expression in
      different cells. Breast cancer cells can escape immune surveillance through
      abnormal molecule expression.

PMID- 12408757
TI  - Pre-clinical study on tumor vasoactive intestinal peptide receptor scintigraphy.
AB  - OBJECTIVE: To develop a tumor imaging agent for vasoactive intestinal peptide
      (VPAC) receptor and evaluate its biological activity and pharmacokinetics of
      radiolabeled peptide. METHODS: VIP(28) was modified at the carboxyl terminal by
      the addition of His-tag which was the chelating site of (99m)Tc(I) and the
      general purification tag for immobilized metal ion affinity chromatography.
      Biological activity of the modified VIP(28) analogue MY34 was examined in vitro
      by radiological cell-binding assay, rabbit internal anal sphincter (IAS) smooth
      muscle relaxing assay and immunocytochemical stain. The pharmacokinetics of this
      labeled peptide was examined in C57 mice. RESULTS: MY34 could relax the IAS
      smooth muscle and bind VPAC receptors on tumor cell membranes. (99m)Tc- MY34,
      with a yield of about 90%, was stable enough for practical use. Both MY34 and
      VIP(28) could inhibit the binding between the labeled peptide and VPAC receptor.
      The pharmacokinetics of [(99m)Tc(H(2)O)(3)(CO)(3)]-MY34 was studied in mice
      conformed well with the two-compartment model (Wi = 1/C(2)), with a t(1)/(2alpha)
      of 16.35 min and a t(1)/(2beta) of 1013.56 min. CONCLUSION: MY34 possesses
      physiological activities and specific receptor binding characteristics similar to
      those of natural VIP(28).

PMID- 12408758
TI  - Overexpression of Bax up-regulates the sensitivity of HCC-9204 cell apoptosis
      induced by adriamycin.
AB  - OBJECTIVE: To investigate whether Bax could regulate the sensitivity of human HCC
      9204 cells to adriamycin. METHODS: Overexpression of Bax was induced through
      inducible system and MT-II regulatory system, with addition of ZnSO(4) (100 micro
      mol L(-1)) as external inducer. Stable transfecting inducible expression vector
      containing Bax gene was performed. Apoptotic cells were measured by morphological
      criteria, and detection of apopto tic DNA fragmentation by TUNEL assay and flow
      cytometry. The ability of Bax to lower clonogenic cell survival rate was studied
      by colony-forming assay, while decrease of cell viability was assessed by MTT
      assay. RESULTS: HC-9204 cells treated with adriamycin (20 micro mol/L) showed
      extensive cell death with nucleus fragmentation detected by TUNEL assay. FACS
      analysis showed a significant sub-G(1) peak and apoptosis in 31% cells 24 hr
      after treatment. Bax was able to significantly decrease clonogenic survival rate
      in adriamycin treatment group, showing time dependence. Bax could selectively
      sensitize HCC-9204 cells to cell death induced by DNA damaging agent-adriamycin.
      CONCLUSION: Overexpression of Bax is able to sensitize HCC-9204 cell apoptosis
      induced by a driamycin.

PMID- 12408759
TI  - Arsenic trioxide in the mechanism of drug resistance reversal in MCF-7/ADM cell
      line of human breast cancer.
AB  - OBJECTIVE: To investigate the effect of drug resistance by arsenic trioxide
      (As(2)O(3)) and its possible mechanism in human breast cancer cell line MCF
      7/ADM. METHODS: Cytotoxicity of As(2)O(3) and the sensibility to adriamycin (ADM)
      in MCF-7/ADM cell line, a ADM-resistance cell line of human breast cancer, were
      studied through MTT assay. The concentration of intracellular ADM was detected by
      spectrofluorometry. With MCF-7/ADM cells treated with As(2)O(3) in combination
      with ADM, the glutathione-s-transferase (GST) activity was measured by
      biochemical method. The expression of GST-pi mRNA was assessed by RT-PCR.
      RESULTS: The non-cytotoxic dose of As(2)O(3) was 0.2 micro mol/L and the low
      cytotoxic dose was 0.8 micro mol/L to MCF-7/ADM cell line. 0.2 micro mol/L
      As(2)O(3) could significantly increase the intracellular accumulation of ADM in
      MCF-7/ADM cell line (P < 0.05). The medium inhibition concentration (IC(50)) was
      obviously reduced from 53.74 micro mol/L to 25.0 micro mol/L, with a reversal
      ratio of 2.1 as compared to its parental cell line. Before and after 0.2 micro
      mol/L, 0.8 micro mol/L As(2)O(3) were given, GST activities were decreased from
      29.68 +/- 0.29 U/ml to 19.29 +/- 2.10 U/m l and 12.66 +/- 2.78 U/ml (P < 0.05).
      In addition, MCF-7/ADM cell line had overexpression of GST-pi mRNA. A significant
      down regulation of GST-pi mRNA was observed in MCF-7/ADM cells when As(2)O(3) and
      ADM (21.55 micro mol/L) were given for 24 hours. CONCLUSION: As(2)O(3) is able to
      enhance the cytotoxicity of ADM and partly reverse the ADM resistance of MCF
      7/ADM cell line of human breast cancer, which may be related to the variation of
      GST-pi enzyme.

PMID- 12408760
TI  - Concentration change of chemotherapeutic agents in plasma and tissue after
      intraarterial and intravenous injection.
AB  - OBJECTIVE: To study the concentration change of chemotherapeutic agents in plasma
      and tissue after intraarterial and intravenous injection. METHODS: Ten mature
      female New Zealand rabbits were divided randomly into two groups. Fluorouracil,
      etopiside, and cisplatin were injected into the rabbits through the ear vein in
      one group and through the internal iliac artery in the other group. Blood samples
      and the uterus tissue specimens were collected at various time points after
      injection. Drug concentration in plasma and tissue was determined by high
      performance liquid chromatography (HPLC) method. The data were analyzed by the
      pharmacokinetic program 3P97. RESULTS: Regular concentration change of the three
      drugs in plasma and tissue was observed after the intravenous and intraarterial
      injection, which met the two - compartment model. The pharmacokinetic parameters
      of the three drugs after intravenous and intraarterial injection were different.
      The peak concentration in plasma after intraarterial injection was lower than
      that after intravenous injection and the peak concentration and area under curve
      (AUC) value in tissue after intraarterial injections were higher than those after
      intravenous injection. CONCLUSION: Intraarterial chemotherapy has advantages to
      intravenous chemotherapy in fluorouracil, etopiside and cisplatin. These
      advantages depend on the drug pharmacological properties.

PMID- 12408761
TI  - Anticancer activities of curcumin on human Burkitt's lymphoma.
AB  - OBJECTIVE: To study the anticancer activities of curcumin on human Burkitt's
      lymphoma and their molecular mechanism. METHODS: The effect of curcumin on the
      growth of CA46 cells and apoptosis were studied through Trypan blue exclusion,
      MTT assay, cell cycle, DNA fragmentation analysis and detection of TdT-mediated
      dUTP nick end labeling (TUNEL). The effect of curcumin on the expression of c
      myc, bcl-2, mutant-type p53 and Fas protein and mRNA was studied by flow
      cytometry (FCM) and reverse transcription-polymerase chain reaction (RT-PCR).
      RESULTS: 1. Curcumin inhibited proliferation of CA46 cells in a time- and dose
      dependent manner, 2. CA46 cells treated with curcumin showed G(0)/G(1) or G(2)/M
      phase increase and S phase decrease, 3. CA46 cells apoptosis induced by curcumin
      was confirmed by DNA fragmentation and TUNEL and 4. The expression of c-myc, bcl
      2, mutant-type p53 protein and mRNA was decreased sharply in CA46 cells treated
      with curcumin, while Fas protein and mRNA was increased. CONCLUSION: Curcumin is
      able to inhibit the proliferation of CA46 cells and induce the cell apoptosis by
      down-regulating the expression of c-myc, bcl-2, mutant-type p53 and up-regulating
      the expression of Fas.

PMID- 12408762
TI  - Overexpression of cyclin A in hepatocellular carcinoma and its relationship with
      HBx gene integration.
AB  - OBJECTIVE: To investigate the frequency of cyclin A overexpression in
      hepatocellular carcinoma (HCC) and its relationship with clinical significance
      and HBx gene integration. METHODS: PCR, RT-PCR and Western blot were used to
      detect the gene, mRNA and protein level of cyclin A in the tumor and nontumorous
      tissue. PCR and Southern blot were used to detect the integration of HBx gene in
      HCC. RESULTS: Amplification of cyclin A gene was found in 1 of 35 patients;
      overexpression of cyclin A mRNA and protein was found in 16 of 35, 21 of 35
      patients, respectively. Overexpression of cyclin A protein was correlated with
      patient's age, tumor size and HBx integration. CONCLUSION: Overexpression of
      cyclin A occurs in the early stage of HCC carcinogenesis. It may be one of the
      important approaches by which HBV affects the normal cell cycle of hepatocyte.

PMID- 12408763
TI  - Enhancing the efficiency of Epstein-Barr viral serologic test in the diagnosis of
      nasopharyngeal carcinoma.
AB  - OBJECTIVE: To investigate the efficiency of concurrent application of VCA-IgA, EA
      IgA and EA-IgG serological tests in diagnosing nasopharyngeal carcinoma (NPC).
      METHODS: The sera of 266 untreated NPC patients and 347 healthy adults were
      collected. In addition to the conventional immunoenzymatic method of VCA-IgA
      test, enzyme-linked immunosorbent assay (ELISA) was adopted as an alternative to
      test the antibody level of EA-IgG and EA-IgA. A new statistical formula was used
      to evaluate the odds ratio of different combinations of these three tests.
      RESULTS: The sensitivity and specificity of VCA-IgA, EA-IgG and EA-IgA
      concurrently were as high as 95.11% and 97.41%, respectively, which were higher
      than those of single test (90.60% and 94.52% for VCA-IgA, 93.98% and 93.66% for
      EA-IgG, 89.84% and 88.18% for EA-IgA). Furthermore, the odds ratio of 3-test
      positivity (1 912.5) was higher than those of 2-test positivity (27.903 2 for VCA
      IgA and EA-IgG, 11.169 0 for EA-IgG and EA-IgA, 8.032 8 for VCA-IgA and EA-IgA),
      which were even higher than those of 1-test positivity (0.121 4 for VCA-IgA,
      0.170 5 for EA-IgG and 0.048 8 for EA-IgA). CONCLUSION: ELISA is more accurate in
      reflecting the antibody level of EA-IgG and EA-IgA than the conventional
      immunoenzymatic method. The concurrent application of VCA-IgA, EA-IgG and EA-IgA
      test can markedly improve the sensitivity, specificity and odds ratio as well,
      thus resulting in enhancing the efficiency of diagnosing nasopharyngeal carcinoma
      serologically.

PMID- 12408764
TI  - Expression of extracellular signal-regulated kinase and its relationship with
      clinicopathological characteristics of breast cancer.
AB  - OBJECTIVE: To investigate the expression of extracellular signal-regulated kinase
      (ERK) and its relationship with clinicopathological characteristics of breast
      cancer as well as the effect of preoperative chemotherapy on ERK expression.
      METHODS: Expression of ERK-1 and ERK-2 protein was examined by Western blot in
      the breast cancer and normal breast (control) tissue of 48 patients, of whom 8
      had received preoperative chemotherapy of 5'-deoxy-5-fluorouridine (5'-DFUR),
      with distribution of ERKs protein detected by immunohistochemical method.
      RESULTS: Expression of ERK-1 and ERK-2 protein was increased in tumor specimen as
      compared with control tissue (P < 0.01). A positive correlation was observed
      between ERK-1 and ERK-2 (r = 0.457, P < 0.01). Protein level of ERK-1 and ERK-2
      was higher in stage III patients than in stage I and stage II patients (P <
      0.05). Expression of both ERK-1 and ERK-2 in the carcinoma tissue was decreased
      in patients who had received preoperative chemotherapy of 5'-DFUR. ERK-1 and ERK
      2 proteins were mainly located in the cytoplasm. CONCLUSION: The hyperexpression
      of ERK may play an important role in the initiation and development of human
      breast cancer. Preoperative chemotherapy of 5'-DFUR is able to partially inhibit
      ERK expression.

PMID- 12408765
TI  - Clinical significance of dual color-dual fusion translocation fluorescence in
      situ hybridization in the detection of bcr/abl fusion gene.
AB  - OBJECTIVE: To study the expression of bcr/abl hybridized gene in chronic myeloid
      leukemia (CML), acute lymphatic leukemia (ALL) and polycythemia vera (PV), and
      its clinical significance. METHODS: The bcr/abl hybridized gene of interphase
      metaphase cells of bone marrow in 67 such patients were investigated with a probe
      of dual color-dual fusion translocation fluorescence in situ hybridization (D
      FISH). RESULTS: In 38 CML patients, 34 (89.5%) were positive, with one having a
      typical t (9; 22) at first, which changed into negative after having been treated
      with interferon for 38 months. In another patient, 60 days after post-allogeneic
      peripheral blood stem cell transplantation (PBSCT), the cytomorphology and
      cytogenetics were in completely remission. But 3% cells were bcr/abl positive as
      detected by D-FISH. Six (25%) of 24 ALL patients were positive for Bcr/abl fusion
      gene, which was negative in 2 PV patients. Three patients suspected of having CML
      were also negative and one of these three was finally diagnosed as suffering from
      primary thrombocythemia and one, acute myeloid leukemia (M(2a)) as detected by
      ETO/AML(1) gene, though the other one was still not confirmed. Two (67%) of the 3
      bcr/abl negative CML patients and 5 (87%) of the 6 bcr/abl positive ALL patients
      had refractory leukemia. CONCLUSION: bcr/abl hybridized gene is accurately
      detected by a probe of dual color-dual fusion translocation fluorescence in situ
      hybridization, which can serve as an effective index for clinical diagnosis,
      estimation of prognosis and monitor of minimal residual disease in some
      hematopathies.

PMID- 12408766
TI  - Multiple factors analysis on liver metastasis from colorectal cancer.
AB  - OBJECTIVE: To investigate the clinical factors related with liver metastasis from
      colorectal cancer. METHODS: 1 312 colorectal cancer patients treated from 1988 to
      1997 were collected to set up the database. Binary and multinomial logistic
      regression (SPSS 10.0 for windows) and then correlation analysis were used to
      evaluate the factors concerned. RESULTS: Sex, disease course, gross tumor type,
      differentiation degree, pathological grade, infiltration depth and lymph node
      metastasis were related with liver metastasis by single factor analysis. Only
      sex, infiltration depth and lymph node metastasis were related with liver
      metastasis by multiple factor analysis. More male than female were observed in
      patients with liver metastasis from colorectal cancer (1.9:1, P = 0.006). Liver
      metastasis in colorectal cancer was positively related to the infiltration depth
      into the intestine wall (r = 0.926, P = 0.024). However, the correlation between
      the distance of lymph node metastasis and liver metastasis in colorectal cancer
      had no statistical significance (r = 0.748, P = 0.252). CONCLUSION: Sex, depth of
      infiltration and lymph node metastasis are the main clinical factors related with
      liver metastasis from colorectal cancer. Male colorectal cancer patients are apt
      to develop liver metastasis. The deeper the tumor infiltrates, the more the liver
      metastasis. Age, blood type, symptoms, course, complications, tumor size and site
      are not related with liver metastasis in colorectal carcinoma.

PMID- 12408767
TI  - Expression and clinical implication of soluble resistance-associated calcium
      binding protein gene and multi-drug resistance gene in leukemia.
AB  - OBJECTIVE: To study the relationship between soluble resistance-related calcium
      binding protein (sorcin) gene and multidrug resistance gene (mdr1), and their
      significance in clinical drug resistance and prognosis of acute myeloid leukemia
      (AML). METHODS: Amplification of sorcin gene and mdr1 gene in K562/A02 cell
      detected by Northern blot, were monitored by semi-quantitative reverse
      transcription polymerase chain reaction (RT-PCR) in 65 AML patients and 27 normal
      controls, with their relationship and clinical outcame analyzed. RESULTS: The
      amplification of sorcin gene and mdr1 gene in AML patients were significantly
      higher than that in the normal control, which were related to clinical drug
      resistance and prognosis. The amplification of sorcin gene was related to the
      amplification of mdr1 gene in the two groups. The clinical drug resistance
      incidence rate and complete remission rate were 92.9% and 7.1% in
      sorcin(+)/mdr1(+) group. They were 8.6% and 91.4% in the sorcin(-)/mdr1(-) group
      (P < 0.001). CONCLUSION: The co-amplification of sorcin and mdr1 gene can be
      taken as a good indicator of clinical drug resistance and prognosis of AML.

PMID- 12408768
TI  - Acute biphenotypic leukemia in the adults.
AB  - OBJECTIVE: To study the clinical, biological features and prognosis of acute
      biphenotypic leukemia (BAL) in the adults. METHODS: Bone marrow specimens of 63
      BAL patients were evaluated to prove the diagnosis and the classification by
      morphologic, cytochemical, immunologic and cytogenetic (MIC) examinations. These
      patients were treated with protocols suitable for acute myeloid leukemia (AML),
      or acute lymphoblastic leukemia (ALL), or both. RESULTS: No significant
      difference in clinical features was observed between BAL, AML or ALL.
      Morphologically, the subtypes of M(5), M(1) and M(2) were predominant in AML, as
      L(2) and L(1) were in ALL. Immunologically, coexpression of myeloid and B lineage
      associated antigens was predominant and CD(34) was hyperexpressed in BAL, which
      suggested that BAL might originate from malignant transformation of earlier
      hematopoietic cells. Cytogenetically, Ph chromosome was observed in 25.5% (13/51)
      of BAL patients. Prognostically, both the treatment response and the overall
      survival of BAL patients were poor. CONCLUSION: Patients with BAL have unique
      clinical, biological and prognostic features.

PMID- 12408769
TI  - Relationship between tissue factor expression and hepatic metastasis and
      prognosis in rectal cancer.
AB  - OBJECTIVE: To investigate the correlation between tissue factor (TF) expression
      and hepatic metastasis and prognosis in rectal cancer. METHODS: TF expression was
      retrospectively studied by immunohistochemical method in specimens of 40 rectal
      cancer, 3 hepatic metastasis and 6 benign adenoma with relation to their
      clinicopathologic data. RESULTS: 1. TF expression was detected in 20 (50%) of the
      40 primary rectal cancer specimens and all the 3 hepatic metastatic specimens,
      but not in the 6 benign adenoma or normal mucosa of rectum, 2. Significant
      correlation was observed between TF expression and synchronic hepatic metastasis
      (P = 0.002) and heterochronic hepatic metastasis (P = 0.001) and 3. TF was a risk
      factor for the prognosis of primary rectal cancer (P = 0.024). CONCLUSION: Tissue
      factor expression may play a role in the process of developing hepatic
      metastasis. It may be considered as a new clinical indicator for monitor of
      hepatic metastasis and prognosis of primary rectal cancer.

PMID- 12408770
TI  - Endoscopic study on cancer of gastric cardia in the high incidence areas of
      China.
AB  - OBJECTIVE: Endoscopy was used to study the high incidence area of cancer of
      gastric cardia. METHODS: 417 patients with early cardiac cancer and 451 patients
      with advanced lesions were analyzed to the high incidence point of cardiac
      cancer. Verifying endoscopic screening of 205 subjects was performed later in the
      high incidence area of esophageal cancer. RESULTS: 327 of 417 (78.4%) of early
      cardiac cancer patients and 336 of 451 (74.5%) of advanced lesions were proved to
      have developed their origin at the root of the mucosal fold in the gastric
      cardia. Eleven cardiac cancer patients were found by the verifying endoscopic
      screening, among whom 9 patients (81.8%) developed the primary focus at the root
      of mucosal fold in the cardia. CONCLUSION: The root of mucosal fold in the
      gastric cardia is proved to be the high incidence point of cancer of gastric
      cardia, which is very important clinically.

PMID- 12408771
TI  - Thyroid transcription factor-1 in the histogenesis of plumonary sclerosing
      hemangioma.
AB  - OBJECTIVE: To investigate the significance of thyroid transcription factor-1 (TTF
      1) in the histogenesis of pulmonary sclerosing hemangioma (PSH). METHODS: With
      clinicopathologic data of 36 PSH patients obtained, all specimens were stained by
      immunohistochemical method with a panel of antibodies including TTF-1, SpA, CK,
      EMA, F-VIII, CD34, Claretinin, HBME, synaptophsin, chromogranin, actin and S-100.
      RESULTS: The patients were mostly women with a mean age of 46.7 years and a
      median age of 48 years. All lesions were solitary and well circumscribed with a
      mean size of 3.3 cm and a median size of 3 cm. No multiple or metastasis was
      found. Surface cells (SC) and round cells (RC) were showed in PSH, with more than
      90% showing TTF-1 and EMA by immunohistochemical method. CK and SpA were showed
      in SC, which were not showed in RC. Neuroendocrine cells scattered within RC of
      PSH were detected in a few cases. Mesothelial, vascular endothelial,
      neuroendocrine, and myoepithelial markers by immunohistochemical method were
      negative. CONCLUSION: Pulmonary sclerosing hemangioma, a benign tumor, originates
      from the alveolar pneumocytes. Its surface cells are more mature, while the round
      cells, being primitive respiratory epithelia, may undergo phenotypic
      differentiation and evolve into mucinous glands or neuroendocrine structure among
      other components.

PMID- 12408772
TI  - Percutaneous microwave coagulation therapy for lung cancer.
AB  - OBJECTIVE: To evaluate the clinical effect, CT image changes and side-effects of
      percutaneous microwave coagulation therapy for lung cancer. METHODS: CT-guided
      percutaneous puncture was performed using a needle mono-pole microwave antenna
      with 65W, 2 450 MHz microwave delivered in 60 seconds to 20 peripheral lung
      cancer patients, including 8 suffering from primary lung cancer and 12 metastatic
      lung cancer (totally 28 lesions). RESULTS: Sixteen patients were alive after
      having been followed-up for 3 approximately 24 months. All patients showed
      nodules decreased in size. Diminution of over 50% was observed in 13 nodules and
      3, completely disappeared. The overall response rate was 57.1%. Ellipsoid shadow
      3.5 cm x 2.5 cm across was observed by CT in lesions immediately after
      coagulation. Gasification within the coagulated area was observed in a week with
      a high density in the peripheral region. Consolidation was observed in 3 months
      and the lesion disappeared 1 year later. Complete tumor necrosis was proved by
      biopsy. No side-effects or complications were observed. CONCLUSION: Percutaneous
      microwave coagulation therapy is a new safe treatment for lung cancer, giving
      marked effect but minimum trauma.

PMID- 12408773
TI  - Combined transcatheter arterial chemoembolization and beta-ultrasound guided
      portal vein embolization in the treatment of hepatocellular carcinoma.
AB  - OBJECTIVE: To study the effect of transcatheter arterial chemoembolization (TACE)
      combined with beta-ultrasound guided portal vein embolization (PVE) through fine
      needle liver puncture for hepatocellular carcinoma. METHODS: 209 patients with
      primary hepatocellular carcinoma were divided into TACE group (104 patients) and
      TACE + PVE group (105 patients). RESULTS: The response rates (CR + PR) were 37.5%
      in TACE group and 57.2% in TACE + PVE group (P < 0.01). Tumor thrombi became
      lessened or resolved in the portal vein with incidences of 22.2% in TACE group
      and 68.8% in TACE + PVE group (P < 0.01). The 1-, 2- and 3-year survival rates
      were 65.1%, 36.3% and 20.5% in TACE group and 95.6%, 59.6% and 39.1% in TACE +
      PVE group (P < 0.05). CONCLUSION: The effect of TACE combined with PVE is much
      more effective than TACE alone for hepatocellular carcinoma. Beta-ultrasound
      guided portal vein embolization through fine-needle liver puncture is effective,
      easy, safe and should be widely practiced.

PMID- 12408774
TI  - Diagnosis and surgical treatment of esophageal leiomyoma.
AB  - OBJECTIVE: To study the characteristics of diagnosis and surgical treatment of
      esophageal leiomyoma. METHODS: Preoperative radiology, esophagoscopy and results
      of surgical treatment were retrospectively analyzed in 141 patients with
      esophageal leiomyoma. RESULTS: Dysphagia (64.5%) and chest or epigastric pain
      (20.6%) were the most common presenting symptoms with a mean duration of 15.7
      months. Eleven patients had been misdiagnosed as malignant esophageal disease,
      mediastinal or retroperitoneal tumor before operation. Thirteen patents received
      partial esophageal resection, including 2 patients with gigantic tumor, 3 still
      misdiagnosed as malignancy in the operation theater and 8 accompanied with
      esophageal or gastric cardiac carcinoma. 128 patients were treated with tumor
      removal only, among whom the esophageal mucosa was ruptured and sutured in 13
      patents. The tumor was single in 130 patients and multiple in 11 patients. The
      tumor shape was either oval, horseshoe-or ginger-like. Tumor surrounded the
      esophagus less than half circumference in 75 patients, more than half in 59
      patients and involved the whole circumference in 7 patients. The tumor was
      polypoid and intraluminal in one patient. It was extraluminal in 2 patients and
      was intramural in all the others. The morbidity and 30-day mortality rates were
      3.6% and 0%. CONCLUSION: Preoperative differentiation of esophageal leiomyoma is
      important for it may be misdiagnosed as esophageal malignant disease or
      mediastinal tumor. Tumor removal only is indicated if possible. Biopsy is
      inadvisable if leiomyoma has been suspected by esophagoscopy. The incidence of
      esophageal carcinoma complicating esophageal leiomyoma is high, of which the
      reason needs further study.

PMID- 12408775
TI  - Retrospective comparison between CHOP-PVP and CHOP protocols for non-Hodgkin's
      lymphoma.
AB  - OBJECTIVE: To compare the therapeutic effects between CHOP-PVP and CHOP protocols
      for non-Hodgkin's lymphoma (NHL). METHODS: Of 79 NHL patients, 40 received CHOP
      PVP and 39 received CHOP protocol. Kaplan-Meier method was used for survival rate
      and Cox regression model for prognostic factors. RESULTS: The complete remission
      rate and overall response rate were 57.5% (23/40) and 87.5% (35/40) in CHOP-PVP
      group and they were 33.3% (13/39) and 69.2% (27/39) in CHOP group. There was a
      significant difference (P < 0.05) in the complete remission rate and overall
      response rate between the two groups. The main toxicity was myelosuppression. The
      leukocytopenia rate was 82.5% in CHOP-PVP group and 71.8% in CHOP group (P >
      0.05) with no fatality in either group. CONCLUSION: CHOP-PVP protocol may be more
      effective for non-Hodgkin's lymphoma than CHOP protocol without increasing
      toxicity.

PMID- 12408776
TI  - Clinicophathologic characteristics and treatment of small cell carcinoma of
      uterine cervix.
AB  - OBJECTIVE: To study the clinicopathologic characteristics, prognostic factors,
      response to chemotherapy, chemotherapy-caused disease-free interval and overall
      survival of small cell carcinoma of uterine cervix (SCCUC). METHODS: Twelve
      patients with SCCUC were treated from 1995 to 1999, with their clinic
      ophathologic data retrospectively analyzed. Their stages were I b(1) 2, I b(2) 4,
      II a 3, II b 1, III b 1 and IV b1. All 12 samples were assessed through
      immunohistochemical methods including epithelial cell markers and neuroendocrine
      cell markers, showing positive results in all. Nine early stage patients
      underwent radical hysterectomy with pelvic lymphadenectomy. Five of these 9
      patients had received neoadjuvant chemotherapy (NCH) once or twice before
      operation, three patients received adjuvant chemotherapy (ACH) once to six times
      after operation. Three patients with advanced lesions received concurrent
      chemotherapy twice to four times. RESULTS: 44.4% (4/9) of patients treated by
      pelvic lymphadenectomy showed positive lymph node metastasis. The average disease
      free intervals of patients who showed positive or negative pelvic lymph node were
      16.1 and 25.7 months, overall survival of 19 and 32 months. The success rate of
      surgery in the NCH group was 100%, 60% of whom showed chemotherapy response
      pathologically. They showed overall response rates of 80% (4/5), 20% CR (1/5) and
      60% PR (3/5). CONCLUSION: Poor prognosis of small cell carcinoma of uterine
      cervix, even the early lesions, is due to its high incidence of pelvic lymph
      metastasis. The risk factor of this lesion is high sensitivity to chemotherapy,
      but chemotherapeutic long-term survival should be studied further with more
      allotted material.

PMID- 12408777
TI  - Gemcitabine or gemcitabine plus cisplatin for in 42 patients with locally
      advanced or metastatic pancreatic cancer.
AB  - OBJECTIVE: A multi-center randomized phase III clinical trial was designed to
      evaluate the efficacy, clinical benefit response (CBR) and toxicity profile of
      germcitabine (GEM) or GEM plus cisplatin (CDDP) for locally advanced (LAPC) or
      metastatic pancreatic cancer (MPC). METHODS: From July 2000 to May 2001, 42
      untreated patients with LAPC or MPC were collected and randomized into two
      groups: Arm A-GEM 20 patients and Arm B-GEM + CDDP 22 patients. Eligibility
      criteria were: cytologically and pathologically proven pancreatic carcinoma,
      Karnosky performance status (KPS) 60 - 80, age 18 - 75 yrs, adequate
      hematological, renal and liver function, measurable disease, and controllable
      pain. For Arm A patients, weekly dose of GEM 1 000 mg/m(2)/w for 7 times followed
      by a week rest. Then weekly GEM at the same dose for 3 times every 4 weeks. Arm B
      patients were given weekly dose of GEM 1 000 mg/m(2)/w for 3 times every 4 weeks
      combined with CDDP 60 mg/m(2) on D15 for 3 cycles. RESULTS: Thirty-four patients
      were available for objective response (Arm A 16 and Arm B 18) and 36 (Arm A 16
      and Arm B 20) for CBR evaluation. In Arm A and Arm B, PR 1 (6.3%) and 2 (11%), MR
      4 (25%) and 3 (16.7%), SD 7 (43.8%) and 8 (44.4%), PD 4 (25%) and 5 (27.8%), PR +
      MR 31.3% and 27.8%, PR + MR + SD 75% and 72.2% were observed. Positive CBR was
      14/16 (87.5%) in Arm A and 14/20 (70.0%) in Arm B. The negative results was 2/16
      (12.5%) in Arm A and 6/20 (30.0%) in Arm B. The median time of disease
      progression was not yet available at present. The 3-month survival rate of both
      Arm A and B was 100%, the 6-month survival rates of Arm A and B were 81.3% and
      61.6% and the 12-month survival rates of Arm A and B was 31.3% and 11.1%, with
      median survivals of 273 and 217 days. The incidence of hematological and non
      hematological toxicity of Arm A was lower than that of Arm B without statistical
      significance. The toxicity ranging from being mild to moderate was manageable.
      CONCLUSION: GEM or GEM plus CDDP is able to lead to a moderate objective response
      rate, also significantly improve the quality of life in patients with locally
      advanced or metastatic pancreatic cancer patients, prolonging the survival time
      with tolerable toxicity.

PMID- 12408778
TI  - Alcoholic Hepatitis.
AB  - Alcoholic hepatitis is a common clinical problem confronting gastroenterologists
      and hepatologists alike. The fundamental issue regarding treatment of this
      disease is its recognition on the part of the physician. Chronic alcohol abuse,
      fever, leukocytosis, jaundice, and encephalopathy are key symptoms and signs that
      should prompt consideration of this diagnosis. Nutrition and abstinence from
      alcohol are the cornerstones of therapy. In addition, management of seriously
      ill, hospitalized patients should include prophylaxis for withdrawal and delirium
      tremens. Alcoholic hepatitis (AH) induces a profound catabolic state, resulting
      in net negative nitrogen balance. In part, because of malnutrition, AH carries a
      considerably high mortality rate. Therefore, nutrition remains a key aspect of
      therapy. In the absence of encephalopathy and in the presence of a functioning
      gastrointestinal tract, oral intake or nasogastric feedings should be given. If
      the gastrointestinal tract cannot be used (ie, because of paralytic ileus), then
      total parenteral nutrition is absolutely essential for recovery. A select subset
      of patients, based on multiple clinical trials and several meta-analyses, can be
      treated with corticosteroids provided that the patient does not have active
      gastrointestinal bleeding and does not have an active infection. The subset of
      patients with AH who should receive corticosteroids is based on calculation of a
      modified Maddrey discriminant function, which incorporates the patient's
      prothrombin time and total serum bilirubin as variables in this equation.
      Generally, a 4-week course of prednisone or prednisolone is administered. d
      penicillamine, colchicine, anabolic steroids, propylthiouracil, and antioxidants
      have not been shown to be effective in AH and cannot be recommended. After acute
      illness, patients should be discharged to an inpatient alcohol rehabilitation
      unit to ensure continued abstinence.

PMID- 12408779
TI  - Therapeutic Options in Nonalcoholic Fatty Liver Disease.
AB  - Nonalcoholic fatty liver disease, an entity that includes nonalcoholic
      steatohepatitis, is typically a benign, indolent condition. However, in a subset
      of patients, the clinical course may progress to advanced cirrhosis, end-stage
      liver disease, or hepatocellular carcinoma. Unfortunately, the pathogenesis,
      natural history, and potential therapies for these disorders remain poorly
      understood. Identifying patients who should be targeted for potential treatment
      remains difficult. Liver biopsy should be considered to assess the degree of
      hepatic inflammation and fibrosis, because physical examination findings,
      biochemical parameters, and the results of radiographic studies have been shown
      to correlate poorly with the severity of steatohepatitis and fibrosis. Although
      there is some evidence suggesting that obesity, diabetes mellitus, older age, and
      perhaps an aspartate transaminase:alanine aminotransaminase ratio higher than 1
      may be predictors of more advanced fibrosis, histology remains the gold standard.
      Most patients with simple hepatic steatosis appear to follow a benign course and
      probably do not require aggressive therapy. Conversely, patients with
      steatohepatitis with extensive inflammation and fibrosis are the patients who are
      most likely to benefit from effective therapies. The most commonly recommended
      treatment is weight loss. Existing data suggest that rapid weight loss may
      promote hepatic inflammation and fibrosis; therefore, gradual weight loss should
      be recommended. Large, randomized, controlled trials evaluating the long-term
      histologic impact and clinical outcomes of weight loss strategies are lacking.
      Potentially promising pharmacologic therapies include insulin-sensitizing oral
      hypoglycemic agents such as metformin and the thiazolidenediols,
      antihyperlipidemic agents such as gemfibrozil or 3-hydroxy-3-methylglutaryl
      coenzyme A reductase inhibitors, vitamin E and other antioxidants,
      ursodeoxycholic acid, and betaine. As with weight loss, data regarding the
      efficacy of these pharmacologic options are limited. In addition, there are no
      widely accepted guidelines to help direct the clinician in the optimal use of
      these agents in patients with nonalcoholic fatty liver diseases.

PMID- 12408780
TI  - Pyogenic Liver Abscess.
AB  - Pyogenic liver abscess is an important and often life-threatening disorder. It is
      commonly caused by underlying disease of the biliary system, but more frequently,
      no predisposing disorder can be identified. Its diagnosis requires a high index
      of suspicion and imaging of the liver. The optimal treatment of pyogenic liver
      abscess is percutaneous drainage and intravenous broad-spectrum antibiotics with
      activity against enteric aerobic and anaerobic bacteria. Blood and abscess
      cultures should be obtained and amebic liver abscess carefully eliminated when
      the diagnosis is in doubt. Surgical drainage, preferably laparoscopic, is
      reserved for patients with complicated abscesses or after failure of response to
      initial medical therapy. Possible primary predisposing conditions to pyogenic
      liver abscess, such as biliary tract disorders, should be sought and managed
      accordingly. Intravenous antibiotics should be administered for a period of 2
      weeks, followed by a more prolonged course of oral antibiotics. The choice and
      duration of antibiotic therapy, and the need for further intervention are
      determined by microbiologic data, the patient's clinical response, and repeated
      imaging studies.

PMID- 12408781
TI  - Amebic Liver Abscess.
AB  - Amebic liver abscess should be suspected in travelers returning from endemic
      areas or in immunocompromised patients who present with fever, right upper
      quadrant pain, hepatomegaly, and a liver lesion on an imaging study. Rapid
      initiation of therapy without serologic confirmation of infection, if necessary,
      is important to minimize complications. Metronidazole is given orally or
      intravenously for 14 days. The drug is generally well tolerated and leads to
      resolution of symptoms in most patients within 2 to 3 days. It is effective
      against luminal cysts in only 50% of patients and, therefore, must be followed by
      a course of treatment with paromomycin (Humatin; Parke-Davis, Morris Plains, NJ)
      or another luminal antiamebic agent to eradicate the parasite. Image-guided
      drainage of an amebic liver abscess is indicated in patients who do not respond
      to antimicrobial therapy or who are at risk of abscess rupture. Surgery is
      reserved for patients with a ruptured abscess. Although medical therapy is
      generally successful in the treatment of infection caused by Entamoeba
      histolytica, the development of potent vaccines will be needed for worldwide
      eradication of disease attributable to E. histolytica.

PMID- 12408782
TI  - Prevention of Viral Hepatitis.
AB  - Despite the availability of vaccines against hepatitis A and B, acute viral
      hepatitis due to these agents continues to be among the most commonly reported
      notifiable infectious diseases in the United States. Currently available
      hepatitis A and B vaccines are highly immunogenic and well tolerated, but vaccine
      coverage needs to be expanded. Use of the hepatitis A vaccine in children age 2
      years and older should be more widespread than is currently the case. Hepatitis A
      vaccine has been shown to be cost effective when given to children in regions
      with high attack rates and to patients with chronic hepatitis C. Routine newborn
      immunization against hepatitis B has been a successful approach to disease
      control and is among the most cost-effective interventions. Use of the hepatitis
      B vaccine for all sexually active individuals with more than one sex partner
      should be recommended for this sexually transmitted disease. The availability of
      a combined hepatitis A and B vaccine should facilitate vaccine coverage in those
      individuals at risk for both infections. For those hepatitis infections for which
      no vaccine is currently available, namely hepatitis C, D, and E, reducing
      exposure risk by modifying lifestyle behaviors is the only control measure
      available. Early education and counseling about high-risk behaviors for the
      acquisition of blood-borne hepatitis viruses needs to be expanded to young
      children and adolescents. The eventual eradication of hepatitis virus infections
      through universal immunization is plausible for those agents for whom human
      beings are the only host and effective vaccines have been developed. If hepatitis
      E is shown to be a zoonosis with an extensive reservoir in pigs, eradication of
      this agent may be very difficult.

PMID- 12408783
TI  - Veno-occlusive Disease.
AB  - Therapy for veno-occlusive disease of the liver (VOD) occurring after bone marrow
      transplantation should be directed at those with moderate or severe disease who
      will not recover on their own. Thrombolytic therapy may have a role in severe VOD
      as long as there is no renal or lung impairment. However, the risk of bleeding
      complications, including the risk of cerebral hemorrhage, must be considered in
      these patients. Defibrotide has shown promise for treatment of severe VOD but is
      not yet widely available in the United States. Therapy directed at reducing
      portal hypertension such as transjugular intrahepatic portosystemic shunts helps
      reduce ascites but has no effect on mortality. Liver transplantation has been
      reported but should be considered only in patients with severe liver failure who
      would have a good outcome in the absence of liver disease or have undergone bone
      marrow transplantation for benign disease. The most important advances in VOD has
      been in the prevention of this syndrome by recognizing the risk factors for it
      and changes in conditioning regimens before bone marrow transplantation.

PMID- 12408784
TI  - Variceal Bleeding.
AB  - Primary prophylaxis: Patients with cirrhosis who have esophageal varices but who
      have never had a bleeding episode may be treated medically or endoscopically.
      Without treatment, approximately 30% of cirrhotic patients with varices bleed and
      this risk is reduced by approximately 50% with therapy. Medical therapy includes
      nonselective beta blockers with or without nitrates. Compliance and side effects
      limit efficacy. Primary prophylaxis with endoscopic sclerotherapy is not
      warranted because of evidence suggesting that complications outweigh benefits.
      Studies of endoscopic therapy with ligation (endoscopic banding) demonstrate that
      in select patients (those with large varices), endoscopic banding may reduce the
      risk of first bleeding episode when compared with propranolol. Patients with
      large varices may benefit from a combination of banding with nonselective beta
      blockers. Secondary prophylaxis: After an initial variceal bleed, the risk of a
      second bleed is high and therapy is warranted to reduce the risk of rebleeding.
      The options are similar to those for primary prophylaxis, and in addition to
      medical and endoscopic therapy, transjugular intrahepatic portosystemic shunts
      (TIPS) and surgical shunts are therapeutic options. The combination of endoscopic
      therapy with medical therapy is the initial approach to prevent variceal
      rebleeding. Endoscopic banding is preferred to sclerotherapy because banding is
      associated with lower bleeding rates and fewer complications. TIPS is useful in
      cases refractory to endoscopic therapy or in uncontrolled variceal hemorrhage.
      Surgical shunts are typically reserved for patients in whom TIPS cannot be
      performed for technical reasons or for well-compensated cirrhotic patients. Acute
      variceal bleeding: Acute bleeding from esophageal varices requires an endoscopic
      evaluation and therapeutic intervention. Technically, endoscopic banding may not
      be possible because of limited visualization from bleeding and sclerotherapy is
      used because it is easier to perform in this setting. A continuous intravenous
      drip of octreotide should be initiated if variceal bleeding is suspected. If
      variceal bleeding cannot be controlled, then a Minnesota tube or Sengstaken
      Blakemore tube should be placed by someone with experience. TIPS is effective
      rescue therapy for controlling acute variceal hemorrhage in circumstances when
      other methods fail.

PMID- 12408785
TI  - Spontaneous Bacterial Peritonitis.
AB  - Spontaneous bacterial peritonitis (SBP) is the prototypical ascitic fluid
      infection occurring in patients with advanced liver disease and ascites. The key
      to successful treatment of SBP is a knowledge of appropriate antibiotic regimens
      and an understanding of the setting in which infection develops, particularly
      those individuals at high risk for infection. A high index of suspicion should
      lead to early diagnostic paracentesis and ascitic fluid analysis. Treatment of
      SBP involves the use of non-nephrotoxic broad-spectrum antibiotics expected to
      cover the typical bacterial flora associated with SBP. SBP typically involves
      infection with a single organism, with Escherichia coli, Klebsiella spp, and
      Streptococcus spp responsible for nearly three fourths of cases. The treatment of
      choice is cefotaxime 2 g given intravenously every 8 hours for a total of 5 days.
      The antibiotic regimen is adjusted based on the results of ascitic fluid
      cultures. Other antibiotic regimens for SBP are less well studied. Given the
      significant morbidity and mortality rates associated with SBP, efforts to prevent
      its development and recurrence with antibiotic prophylaxis are warranted. The
      most extensively studied form of prophylaxis involves selective intestinal
      decontamination (SID) with the oral fluoroquinolone norfloxacin. Individuals with
      low-protein ascites (ascitic fluid total protein < 1g/dL) benefit from SID with
      norfloxacin 400 mg daily during times of hospitalization. Long-term primary
      prophylaxis during outpatient management of individuals awaiting liver
      transplantation with severe ascites and advanced liver failure should also be
      considered. Patients with cirrhosis and upper gastrointestinal bleeding should
      receive norfloxacin 400 mg twice daily for 1 week following their bleed. Those
      individuals surviving an episode of SBP should be treated with norfloxacin 400 mg
      daily until the risk of SBP is removed by definitive resolution of the ascites or
      liver transplantation surgery. Although the infection-related mortality
      associated with SBP has decreased to less than 10%, hospitalization-related
      mortality remains as high as 30% as a result of the severe underlying liver
      disease in which the infection arises and the marked generation of cytokines and
      nitric oxide resulting from the infection. Recently, the simultaneous
      administration of intravenous albumin and antibiotics for SBP has been shown to
      result in the decreased development of azotemia and hospitalization-related
      mortality. Further improvement in the outcomes of SBP will require treatments
      targeting this cytokine cascade rather than the development of more potent
      antibiotics.

PMID- 12408786
TI  - Adult-to-adult Right Hepatic Lobe Living Donor Liver Transplantation.
AB  - Adult-to-adult right hepatic lobe living donor liver transplantation (LDLT) has
      rapidly emerged as an accepted treatment option for selected patients with end
      stage liver disease. The two most important determinants in patient outcome are
      the careful selection of recipients, and the technical skill and experience of
      the surgical team. The most appropriate candidates for LDLT are patients who
      require an expedited transplant. Also, the candidate must not have significant
      comorbid conditions that could jeopardize the success of the procedure. The
      initial outcomes of LDLT recipients are similar to recipients with a cadaveric
      liver. However, direct comparison may not be possible, because LDLT recipients
      are currently selected for favorable outcomes. Most LDLT donors are able to
      undergo right-sided hepatectomy without significant morbidity. However, the risk
      of death associated with donation is estimated to be 1/300; approximately 20%
      have a measurable complication.

PMID- 12408787
TI  - Hypertrophic Cardiomyopathy.
AB  - When an individual is diagnosed with hypertrophic cardiomyopathy (HCM), all
      relatives potentially affected by Mendelian autosomal-dominant inheritance should
      be evaluated with an electrocardiogram (ECG) and echocardiogram. Genetic testing
      should be considered in high-risk mutations where there are diagnostic
      uncertainties. Symptom relief depends on beta-blockers as first-line therapy. If
      the disease is nonobstructive, then calcium channel blockers can be added or used
      alone. If there is a significant left ventricular outflow tract (LVOT) gradient
      then disopyramide can be used, ideally in combination with a beta-blocker.
      Verapamil should be used with care due to potential exacerbation of the LVOT
      gradient. Nonmedical therapy for obstructive disease consists of surgical
      myectomy, alcohol septal ablation, or dual-chamber pacing. Surgery is the gold
      standard, although in experienced hands and directed appropriately, septal
      ablation achieves good results. Pacing is generally less effective. The
      development of atrial fibrillation (AF) or left atrial enlargement carries a
      significant risk of thromboembolism. All patients should be closely observed for
      AF and thromboembolic risk, and the threshold for initiation of anticoagulation
      should be low in patients with sustained palpitations, atrial enlargement, and
      nonsustained supraventricular arrhythmia on Holter. All patients with HCM should
      be assessed for their risk of sudden death regardless of severity of symptoms or
      morphology. The factors predictive of risk are 1) previous cardiac arrest; 2)
      unexplained syncope; 3) family history of premature sudden death; 4) abnormal
      blood pressure response to exercise; 5) nonsustained ventricular tachycardia; and
      6) severe left ventricular hypertrophy >/= 30 mm.

PMID- 12408788
TI  - Myocarditis.
AB  - Myocarditis and its sequela, dilated cardiomyopathy (DCM), cause substantial
      morbidity and mortality, especially in children and young adults. Physicians
      should include myocarditis in the differential diagnosis of all patients who have
      new symptoms of heart failure, arrhythmia, or chest pain syndromes of unclear
      cause, and should strongly consider performing endomyocardial biopsy (EMB) to
      establish the diagnosis. It may be necessary to perform multiple or serial
      biopsies to increase sensitivity. Patients with myocarditis and symptomatic heart
      failure, chest pain, or arrhythmias need hospitalization for evaluation and
      treatment. Patients with symptomatic left ventricular dysfunction should be
      treated with conventional heart failure therapy, including angiotensin-converting
      enzyme (ACE) inhibitors, digitalis, diuretics, and beta-blockers. Patients with
      arrhythmias or syncope may require electrophysiologic evaluation. In addition to
      conventional therapy, physicians should consider a course of immunosuppressive
      therapy in selected patients. The clinical course, response to therapy, and left
      ventricular function need close monitoring. Patients with myocarditis and rapidly
      progressive heart failure or cardiogenic shock should be referred early to an
      advanced heart failure center for implantation of a ventricular assist device and
      consideration for cardiac transplantation.

PMID- 12408789
TI  - Arrhythmias in Patients with Heart Failure.
AB  - Both atrial and ventricular arrhythmias are very common in patients with
      congestive heart failure, and their presence is associated with symptoms,
      significant morbidity, and mortality. Studies have attempted to determine the
      prognostic significance of atrial and ventricular arrhythmias in patients with
      heart failure. Whether atrial fibrillation is an independent risk factor of
      mortality remains controversial. The presence of ventricular arrhythmias in
      patients with ischemic cardiomyopathy identifies patients at high risk for sudden
      death. However, in patients with nonischemic cardiomyopathy there is not a strong
      correlation between ventricular arrhythmias and increased risk for sudden death.
      Multiple trials using antiarrhythmic drugs, pharmacologic therapy, and
      implantable cardioverter defibrillators have been performed in an attempt to
      improve survival in patients 1) post-myocardial infarction; 2) with congestive
      heart failure, with and without nonsustained ventricular tachycardia; and 3) with
      sustained ventricular tachycardia and those who have survived an out-of-hospital
      cardiac arrest. The purpose of this article is to present an overview of
      arrhythmias in patients with heart failure and discuss the prevalence, prognostic
      significance, complications, mechanisms, and trials that have formed the current
      therapies presently used.

PMID- 12408790
TI  - Pericardial Diseases.
AB  - Pericardial diseases have multiple clinical presentations with acute and chronic
      complications. Early diagnosis and prompt treatment markedly enhance the chance
      of complete resolution of the hemodynamic complications of pericardial disease.
      The treatment of patients with acute idiopathic pericarditis is mainly to
      alleviate symtoms of chest pain. A nonsteroidal anti-inflammatory agent such as
      indomethacin is our first drug of choice. Therapy is effective and symptoms
      resolve within 24 to 48 hours. In patients with chronic recurrent idiopathic
      pericarditis, we advise the use of colchicine at 1 mg/d. Constrictive
      pericarditis is a progressive disease and surgical pericardiectomy is the only
      definite treatment. It should be performed early in the disease process before
      myocardial fibrosis occurs. Cardiac tamponade is a cardiac emergency and patients
      should be treated promptly. We often start with volume expansion with intravenous
      fluid in preparation for transcutaneous pericardiocentesis. Echocardiographically
      guided, transcutaneous pericardiocentesis is the procedure of choice. Patients
      with asymptomatic pericardial effusion are followed with serial echocardiography,
      and reserve drainage for enlarging effusions if there are signs of cardiac
      compression.

PMID- 12408791
TI  - Myocardial and Pericardial Disease in HIV.
AB  - Cardiovascular complications are frequently encountered in the HIV-infected
      population. Cardiac care providers should implement appropriate preventive,
      screening, and therapeutic strategies to maximize survival and quality of life in
      this increasingly treatable, chronic disease. All HIV-infected individuals should
      undergo periodic cardiac evaluation, including echocardiography, in order to
      identify subclinical cardiac dysfunction. Left ventricular (LV) dysfunction can
      result from, or be exacerbated by, a variety of treatable infectious, endocrine,
      nutritional, and immunologic disorders. Aggressive diagnosis and treatment of
      these conditions may lead to improvement or even normalization of myocardial
      function. Endomyocardial biopsy should be considered to direct etiology-specific
      therapy. Standard measures for the prevention and treatment of congestive heart
      failure are recommended for HIV-infected patients. Afterload reduction with
      angiotensin-converting enzyme inhibitors may be indicated for patients with
      elevated afterload and preclinical LV dysfunction diagnosed by echocardiogram.
      However, judicious drug selection and titration are necessary in this cohort of
      patients with frequent autonomic dysfunction, at risk for a number of potentially
      lethal drug interactions. Carnitine, selenium, and multivitamin supplementation
      should be considered, especially in those with wasting or diarrhea syndromes.
      Monthly intravenous immunoglobulin (IVIG) infusions have been demonstrated to
      preserve LV parameters in HIV-infected children; ventricular recovery has been
      documented in some children with recalcitrant HIV-related cardiomyopathy
      following IVIG infusion. We support the use of immunomodulatory therapy in the
      pediatric population, and look forward to further study into the efficacy and
      broader application of this approach. Highly active antiretroviral therapy
      (HAART) may be associated with dyslipidemia and the metabolic syndrome. This
      should be treated with dietary and possibly with pharmacologic interventions.
      Drug interactions need to be considered when instituting pharmacologic therapies.
      Pericardial effusions are often seen in patients with advanced HIV infection.
      Asymptomatic effusions are most often nonspecific in nature, related to the
      proinflammatory milieu found in advanced AIDS. Nonspecific effusions are a marker
      of advanced disease and do not require exhaustive etiologic evaluation. In
      contrast, large or symptomatic effusions are often associated with infection or
      malignancy, and warrant thorough investigation and etiology-specific treatment.

PMID- 12408792
TI  - End-stage Heart Failure: Surgical Therapy and Implantable Devices.
AB  - Despite recent advances in medical therapy, mortality remains high following the
      diagnosis of heart failure (HF). Cardiac transplantation is still the standard
      surgical treatment option for highly selected patients with severe end-stage HF;
      however, it is available only to a small percentage of patients. The small number
      of available donor hearts is an inherent limitation on the ability of cardiac
      transplantation to greatly impact the management of advanced HF. The increased
      incidence and prevalence of HF in an ever aging and medically complex population
      has paved the way for alternative surgical and device treatment strategies. Some
      of these treatment options include ventricular reduction and remodeling surgery,
      mitral valve repair, mechanical ventricular assist device implantation,
      implantable cardioverter defibrillators, and cardiac resynchronization therapy.
      Several recent trials have demonstrated effectiveness of these therapies with
      regard to improvement in physiologic end points, HF symptoms, and survival.
      Surgical and device techniques are usually combined with optimal medical
      management of HF. The total cost and actual cost-effectiveness of employing these
      new therapeutic modalities in a growing population of HF patients remain to be
      determined.

PMID- 12408793
TI  - Management of Mitral Regurgitation Due to Mitral Prolapse.
AB  - Notable advances have been made in the treatment of mitral regurgitation,
      especially the advances resulting from prolapse of the mitral valve with or
      without a flail leaflet. Prosthetic mitral valve replacement results in a high
      incidence of postoperative left ventricular systolic dysfunction. Recognition of
      the importance of the subvalvular apparatus for preserving contractile function
      has fostered development of new repair techniques that preserve native valve
      tissue and reduce or eliminate postoperative systolic dysfunction and the need
      for anticoagulation. Vasoactive medications have a very limited role in the
      management of patients with primary mitral regurgitation. Better screening tools
      enable detection of early ventricular decompensation, and appropriate operative
      interventions continue to significantly reduce the morbidity and mortality
      associated with mitral regurgitation. Mortality associated with ischemic mitral
      regurgitation resulting from annular ring dilatation or structural damage
      associated with rupture of a papillary muscle continues to be high, and the
      simplest and most expeditious operative intervention is emphasized.

PMID- 12408794
TI  - The molecular basis of photoperiodism.
AB  - A recent study has demonstrated that an external coincidence mechanism, based on
      the endogenous circadian control of a transcription factor expression (CO) and
      the modulation of CO function by light, constitutes the molecular basis for the
      regulation of flowering time by photoperiod.

PMID- 12408795
TI  - Viral interactions with receptors in cell junctions and effects on junctional
      stability.
AB  - Several viruses can use, as entry receptors, cell adhesion molecules that
      localize to junctional complexes of epithelial cells and other cell types. A
      recent publication in Cell describes how adenovirus can disrupt cell junctions,
      thereby effecting its release from basal surfaces of an infected epithelium to
      the apical or external environment.

PMID- 12408796
TI  - Whole-genome expression profiles identify gene batteries in Drosophila.
AB  - Microarray studies make it possible to obtain gene expression data on a whole
      genome scale. Arbeitman et al. present microarray data generated at multiple time
      points throughout Drosophila melanogaster development, and identify new genes
      engaged in a broad spectrum of processes, including the patterning of the early
      embryo and senescence in adults.

PMID- 12408798
TI  - Three-dimensional structure of a COPII prebudding complex.
AB  - The coat protein complex II (COPII) catalyzes transport vesicle formation from
      the endoplasmic reticulum. Crystallographic analysis of a Sec23/24-Sar1
      prebudding complex of COPII now provides a molecular view of this GTPase-directed
      coat assembly mechanism.

PMID- 12408797
TI  - The (theoretical) yin and yang of spindle mechanics.
AB  - Antiparallel overlap of microtubules is central to the morphogenesis of bipolar
      mitotic spindles. How does this overlap arise, and how is it maintained? A recent
      theoretical study uses computer simulations to investigate whether motor protein
      complexes can achieve this task. The "virtual" results reveal that a mixed
      polarity motor complex is needed to do the job.

PMID- 12408799
TI  - Temporal and spatial regulation of chemotaxis.
AB  - The ability to sense and respond to shallow gradients of extracellular signals is
      remarkably similar in Dictyostelium discoideum amoebae and mammalian leukocytes.
      Chemoattractant receptors and G proteins are fairly evenly distributed along the
      cell surface. Receptor occupancy generates local excitatory and global inhibitory
      processes that balance to control the chemotactic response. Uniform stimuli
      transiently recruit PI3Ks to, and release PTEN from, the plasma membrane, while
      gradients of chemoattractant cause the two enzymes to bind to the membrane at the
      front and back of the cell, respectively. Interference with PI3Ks alters
      chemotaxis, and disruption of PTEN broadens PI localization and actin
      polymerization in parallel. Thus, counteracting signals from the upstream
      elements of the pathway converge to regulate the key enzymes of PI metabolism,
      localize these lipids, and direct pseudopod formation.

PMID- 12408800
TI  - Plant development makes strides in Vermont.
AB  - Plants are an excellent system for studying developmental biology. Depending on
      the species, they can be easily transformed and mutagenized, undergo grafts,
      tolerate changes in chromosome number, and provide fertile offspring after wide
      species crosses. Most importantly, they are perpetually embryonic, and thus
      development unfolds throughout the life of a plant. At a recent FASEB meeting,
      scientists shared their discoveries about plant development, covering topics that
      ranged from the evolution of form to cellular differentiation. The meeting
      demonstrated that the genetic and cellular basis of plant development is
      currently an exciting and growing field of research.

PMID- 12408801
TI  - Specificity of Distalless repression and limb primordia development by abdominal
      Hox proteins.
AB  - In Drosophila, differences between segments, such as the presence or absence of
      appendages, are controlled by Hox transcription factors. The Hox protein
      Ultrabithorax (Ubx) suppresses limb formation in the abdomen by repressing the
      leg selector gene Distalless, whereas Antennapedia (Antp), a thoracic Hox
      protein, does not repress Distalless. We show that the Hox cofactors
      Extradenticle and Homothorax selectively enhance Ubx, but not Antp, binding to a
      Distalless regulatory sequence. A C-terminal peptide in Ubx stimulates binding to
      this site. However, DNA binding is not sufficient for Distalless repression.
      Instead, an additional alternatively spliced domain in Ubx is required for
      Distalless repression but not DNA binding. Thus, the functional specificities of
      Hox proteins depend on both DNA binding-dependent and -independent mechanisms.

PMID- 12408802
TI  - Plzf mediates transcriptional repression of HoxD gene expression through
      chromatin remodeling.
AB  - The molecular mechanisms that regulate coordinated and colinear activation of Hox
      gene expression in space and time remain poorly understood. Here we demonstrate
      that Plzf regulates the spatial expression of the AbdB HoxD gene complex by
      binding to regulatory elements required for restricted Hox gene expression and
      can recruit histone deacetylases to these sites. We show by scanning forced
      microscopy that Plzf, via homodimerization, can form DNA loops and bridge distant
      Plzf binding sites located within HoxD gene regulatory elements. Furthermore, we
      demonstrate that Plzf physically interacts with Polycomb proteins on DNA. We
      propose a model by which the balance between activating morphogenic signals and
      transcriptional repressors such as Plzf establishes proper Hox gene expression
      boundaries in the limb bud.

PMID- 12408803
TI  - A genomic switch at the transition from cell proliferation to terminal
      differentiation in the Drosophila eye.
AB  - Organogenesis involves cell proliferation followed by complex determination and
      differentiation events that are intricately controlled in time and space. The
      instructions for these different steps are, to a large degree, implicit in the
      gene expression profiles of the cells that partake in organogenesis. Combining
      fluorescence-activated cell sorting and SAGE, we analyzed genomic expression
      patterns in the developing eye of Drosophila melanogaster. Genomic activity
      changes as cells pass from an uncommitted proliferating progenitor state through
      determination and differentiation steps toward a specialized cell fate. Analysis
      of the upstream sequences of genes specifically expressed during the
      proliferation phase of eye development implicates the transcription factor DREF
      and its inhibitor dMLF in the control of cell growth in this organ.

PMID- 12408804
TI  - Receptor-dependent and tyrosine phosphatase-mediated inhibition of GSK3 regulates
      cell fate choice.
AB  - Asymmetric body axis formation is central to metazoan development. Dictyostelium
      establishes an anterior/posterior axis utilizing seven-transmembrane cAMP
      morphogen receptors (CARs) and GSK3-mediated signal transductions that has a
      parallel with metazoan Wnt/Frizzled-GSK3 pathways. In Dictyostelium, GSK3
      promotes posterior cell patterning but inhibits anterior cell differentiation.
      Tyrosine kinase ZAK1 mediates GSK3 activation. We now show that CAR4 regulates a
      tyrosine phosphatase that inhibits GSK3 activity. We have also identified
      essential phosphotyrosines in GSK3, confirmed their role in activated/deactivated
      regulation and cell fate decisions, and relate them to the predicted 3D structure
      of GSK3beta. CARs differentially regulate GSK3 activity by selectively activating
      a tyrosine phosphatase or kinase for pattern formation. The findings may provide
      a comparative understanding of CAR-GSK3 and Wnt/Frizzled-GSK3 pathways.

PMID- 12408805
TI  - Local extrinsic signals determine muscle and endothelial cell fate and patterning
      in the vertebrate limb.
AB  - Both the muscle and endothelium of the vertebrate limb derive from somites. We
      have used replication-defective retroviral vectors to analyze the lineage
      relationships of these somite-derived cells in the chick. We find that myogenic
      precursors in the somites or proximal limb are not committed to forming slow or
      fast muscle fibers, particular anatomical muscles, or muscles within specific
      proximal/distal or dorsal/ventral limb regions. Somitic endothelial precursors
      are uncommitted to forming endothelium in particular proximal/distal or
      dorsal/ventral limb regions. Surprisingly, we also find that myogenic and
      endothelial cells are derived from a common somitic precursor. Thus, local
      extrinsic signals are critical for determining muscle and endothelial patterning
      as well as cell fate in the limb.

PMID- 12408806
TI  - The newt ortholog of CD59 is implicated in proximodistal identity during
      amphibian limb regeneration.
AB  - The proximodistal identity of a newt limb regeneration blastema is respecified by
      exposure to retinoic acid, but its molecular basis is unclear. We identified from
      a differential screen the cDNA for Prod 1, a gene whose expression in normal and
      regenerating limbs is regulated by proximodistal location and retinoic acid: Prod
      1 is the newt ortholog of CD59. Prod 1/CD59 was found to be located at the cell
      surface with a GPI anchor which is cleaved by PIPLC. A proximal newt limb
      blastema engulfs a distal blastema after juxtaposition in culture, and engulfment
      is specifically blocked by PIPLC, and by affinity-purified antibodies to two
      distinct Prod 1/CD59 peptides. Prod 1 is therefore a cell surface protein
      implicated in the local cell-cell interactions mediating positional identity.

PMID- 12408807
TI  - Regulated proteolysis of Xom mediates dorsoventral pattern formation during early
      Xenopus development.
AB  - To identify a regulatory role for proteolysis during early Xenopus development,
      we developed a biochemical screen for proteins that are degraded in an embryonic
      stage-specific manner. We found that Xom, a homeobox transcriptional repressor of
      dorsal-specific genes, was degraded precipitously during early gastrulation. Xom
      degradation is regulated by phosphorylation at a GSK3-like consensus site and is
      most likely mediated by the SCF-beta-TRCP complex. Expression of nondegradable
      Xom represses transcription of dorsal genes much more effectively than wild-type
      Xom and results in a more strongly ventralized phenotype. We propose that
      regulated Xom proteolysis plays an essential role in the establishment of the
      dorsoventral axis, by converting a gradient in BMP abundance into a sharp
      dorsoventral pattern.

PMID- 12408808
TI  - Talin is essential for integrin function in Drosophila.
AB  - We show that the Drosophila gene rhea, isolated because its wing blister
      phenotype is typical of mutants affecting integrin function, encodes talin.
      Embryos deficient in talin have very similar phenotypes to integrin (betaPS) null
      embryos, including failure in germ band retraction and muscle detachment. We
      demonstrate that talin is not required for the presence of integrins on the cell
      surface or their localization at muscle termini. However, talin is required for
      formation of focal adhesion-like clusters of integrins on the basal surface of
      imaginal disc epithelia and junctional plaques between muscle and tendon cells.
      These results indicate that talin is essential for integrin function and acts by
      stably linking clusters of ECM-linked integrins to the cytoskeleton.

PMID- 12408809
TI  - An immune-responsive Serpin regulates the melanization cascade in Drosophila.
AB  - In arthropods, the melanization reaction is associated with multiple host defense
      mechanisms leading to the sequestration and killing of invading microorganisms.
      Arthropod melanization is controlled by a cascade of serine proteases that
      ultimately activates the enzyme prophenoloxidase (PPO), which, in turn, catalyzes
      the synthesis of melanin. Here we report the biochemical and genetic
      characterization of a Drosophila serine protease inhibitor protein, Serpin-27A,
      which regulates the melanization cascade through the specific inhibition of the
      terminal protease prophenoloxidase-activating enzyme. Our data demonstrate that
      Serpin-27A is required to restrict the phenoloxidase activity to the site of
      injury or infection, preventing the insect from excessive melanization.

PMID- 12408810
TI  - Pseudomonas aeruginosa anaerobic respiration in biofilms: relationships to cystic
      fibrosis pathogenesis.
AB  - Recent data indicate that cystic fibrosis (CF) airway mucus is anaerobic. This
      suggests that Pseudomonas aeruginosa infection in CF reflects biofilm formation
      and persistence in an anaerobic environment. P. aeruginosa formed robust
      anaerobic biofilms, the viability of which requires rhl quorum sensing and nitric
      oxide (NO) reductase to modulate or prevent accumulation of toxic NO, a byproduct
      of anaerobic respiration. Proteomic analyses identified an outer membrane
      protein, OprF, that was upregulated approximately 40-fold under anaerobic versus
      aerobic conditions. Further, OprF exists in CF mucus, and CF patients raise
      antisera to OprF. An oprF mutant formed poor anaerobic biofilms, due, in part, to
      defects in anaerobic respiration. Thus, future investigations of CF pathogenesis
      and therapy should include a better understanding of anaerobic metabolism and
      biofilm development by P. aeruginosa.

PMID- 12408811
TI  - The long and short of siRNAs.
AB  - A recent work identifies a distinct class of siRNAs derived from transgenes and
      endogenous retroelements in plants (Hamilton et al., 2002). This class has slower
      electrophoretic mobility than previously characterized siRNAs and may play an
      important role in transgene-induced systemic silencing and in methylation of
      endogenous retroelement DNA.

PMID- 12408812
TI  - Measuring the immeasurable.
AB  - Many bacterial pathogens turn on virulence genes at host body temperature. In the
      September 6, 2002, issue of Cell, Johansson et al. show that the Listeria
      monocytogenes thermosensor is an RNA structure in the 5' untranslated region of
      the mRNA for the virulence-activating transcription factor PrfA. The stem-loop
      structure blocks translation initiation at 30 degrees C but melts away at 37
      degrees C.

PMID- 12408813
TI  - Duplicating dangerously: linking centrosome duplication and aneuploidy.
AB  - Centrosomes are far more fascinating than the first explorers of this organelle a
      century ago could ever have imagined. Recent evidence indicates that deregulation
      of centrosome duplication affects centrosome number and promotes aneuploidy,
      features characteristic of human tumors.

PMID- 12408814
TI  - On the road to repair: PCNA encounters SUMO and ubiquitin modifications.
AB  - The molecular events and targets regulated by the RAD6 pathway, which mediates
      postreplication DNA repair, have remained elusive. Now, ubiquitin and SUMO
      modification of proliferating cell nuclear antigen (PCNA) is shown to be induced
      by DNA damage and linked to components of the RAD6 pathway.

PMID- 12408815
TI  - The HtrA family of proteases: implications for protein composition and cell fate.
AB  - Cells precisely monitor the concentration and functionality of each protein for
      optimal performance. Protein quality control involves molecular chaperones,
      folding catalysts, and proteases that are often heat shock proteins. One quality
      control factor is HtrA, one of a new class of oligomeric serine proteases. The
      defining feature of the HtrA family is the combination of a catalytic domain with
      at least one C-terminal PDZ domain. Here, we discuss the properties and roles of
      this ATP-independent protease chaperone system in protein metabolism and cell
      fate.

PMID- 12408816
TI  - Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles
      in cell growth control.
AB  - The target of rapamycin (TOR) proteins in Saccharomyces cerevisiae, TOR1 and
      TOR2, redundantly regulate growth in a rapamycin-sensitive manner. TOR2
      additionally regulates polarization of the actin cytoskeleton in a rapamycin
      insensitive manner. We describe two functionally distinct TOR complexes. TOR
      Complex 1 (TORC1) contains TOR1 or TOR2, KOG1 (YHR186c), and LST8. TORC2 contains
      TOR2, AVO1 (YOL078w), AVO2 (YMR068w), AVO3 (YER093c), and LST8. FKBP-rapamycin
      binds TORC1, and TORC1 disruption mimics rapamycin treatment, suggesting that
      TORC1 mediates the rapamycin-sensitive, TOR-shared pathway. FKBP-rapamycin fails
      to bind TORC2, and TORC2 disruption causes an actin defect, suggesting that TORC2
      mediates the rapamycin-insensitive, TOR2-unique pathway. Thus, the distinct TOR
      complexes account for the diversity, specificity, and selective rapamycin
      inhibition of TOR signaling. TORC1 and possibly TORC2 are conserved from yeast to
      man.

PMID- 12408817
TI  - The (beta)gamma subunits of G proteins gate a K(+) channel by pivoted bending of
      a transmembrane segment.
AB  - The molecular mechanism of ion channel gating remains unclear. Using approaches
      such as proline scanning mutagenesis and homology modeling, we localize the gate
      of the K(+) channels controlled by the (beta)gamma subunits of G proteins at the
      pore-lining bundle crossing of the second transmembrane (TM2) helices. We show
      that the flexibility afforded by a highly conserved glycine residue in the middle
      of TM2 is crucial for channel gating. In contrast, flexibility introduced
      immediately below the gate disrupts gating. We propose that the force produced by
      channel-G(beta)gamma interactions is transduced through the rigid region below
      the helix bundle crossing to bend TM2 at the glycine that serves as a hinge and
      open the gate.

PMID- 12408818
TI  - Control of Smad7 stability by competition between acetylation and ubiquitination.
AB  - Smad proteins regulate gene expression in response to TGFbeta signaling. Here we
      present evidence that Smad7 interacts with the transcriptional coactivator p300,
      resulting in acetylation of Smad7 on two lysine residues in its N terminus.
      Acetylation or mutation of these lysine residues stabilizes Smad7 and protects it
      from TGFbeta-induced degradation. Furthermore, we demonstrate that the acetylated
      residues in Smad7 also are targeted by ubiquitination and that acetylation of
      these lysine residues prevents subsequent ubiquitination. Specifically,
      acetylation of Smad7 protects it against ubiquitination and degradation mediated
      by the ubiquitin ligase Smurf1. Thus, our data suggest that competition between
      ubiquitination and acetylation of overlapping lysine residues constitutes a novel
      mechanism to regulate protein stability.

PMID- 12408819
TI  - Multiple associated proteins regulate proteasome structure and function.
AB  - We have identified proteins that are abundant in affinity-purified proteasomes,
      but absent from proteasomes as previously defined because elevated salt
      concentrations dissociate them during purification. The major components are a
      deubiquitinating enzyme (Ubp6), a ubiquitin-ligase (Hul5), and an uncharacterized
      protein (Ecm29). Ecm29 tethers the proteasome core particle to the regulatory
      particle. Proteasome binding activates Ubp6 300-fold and is mediated by the
      ubiquitin-like domain of Ubp6, which is required for function in vivo. Ubp6
      recognizes the proteasome base and its subunit Rpn1, suggesting that proteasome
      binding positions Ubp6 proximally to the substrate translocation channel.
      ubp6Delta mutants exhibit accelerated turnover of ubiquitin, indicating that
      deubiquitination events catalyzed by Ubp6 prevent translocation of ubiquitin into
      the proteolytic core particle.

PMID- 12408820
TI  - Negative regulation of the mammalian UV response by Myc through association with
      Miz-1.
AB  - The Myc oncoprotein represses initiator-dependent transcription through the POZ
      domain transcription factor Miz-1. We now show that transactivation by Miz-1 is
      negatively regulated by association with topoisomerase II binding protein
      (TopBP1); UV irradiation downregulates expression of TopBP1 and releases Miz-1.
      Miz-1 binds to the p21Cip1 core promoter in vivo and is required for upregulation
      of p21Cip1 upon UV irradiation. Using both c-myc(-/-) cells and a point mutant of
      Myc that is deficient in Miz-1 dependent repression, we show that Myc negatively
      regulates transcription of p21Cip1 upon UV irradiation and facilitates recovery
      from UV-induced cell cycle arrest through binding to Miz-1. Our data implicate
      Miz-1 in a pathway that regulates cell proliferation in response to UV
      irradiation.

PMID- 12408821
TI  - Structure of a Sir2 enzyme bound to an acetylated p53 peptide.
AB  - Sir2 proteins are NAD(+)-dependent protein deacetylases that play key roles in
      transcriptional regulation, DNA repair, and life span regulation. The structure
      of an archaeal Sir2 enzyme, Sir2-Af2, bound to an acetylated p53 peptide reveals
      that the substrate binds in a cleft in the enzyme, forming an enzyme-substrate
      beta sheet with two flanking strands in Sir2-Af2. The acetyl-lysine inserts into
      a conserved hydrophobic tunnel that contains the active site histidine.
      Comparison with other structures of Sir2 enzymes suggests that the apoenzyme
      undergoes a conformational change upon substrate binding. Based on the Sir2-Af2
      substrate complex structure, mutations were made in the other A. fulgidus
      sirtuin, Sir2-Af1, that increased its affinity for the p53 peptide.

PMID- 12408822
TI  - Evidence that siRNAs function as guides, not primers, in the Drosophila and human
      RNAi pathways.
AB  - In Drosophila, two features of small interfering RNA (siRNA) structure--5'
      phosphates and 3' hydroxyls--are reported to be essential for RNA interference
      (RNAi). Here, we show that as in Drosophila, a 5' phosphate is required for siRNA
      function in human HeLa cells. In contrast, we find no evidence in flies or humans
      for a role in RNAi for the siRNA 3' hydroxyl group. Our in vitro data suggest
      that in both flies and mammals, each siRNA guides endonucleolytic cleavage of the
      target RNA at a single site. We conclude that the underlying mechanism of RNAi is
      conserved between flies and mammals and that RNA-dependent RNA polymerases are
      not required for RNAi in these organisms.

PMID- 12408823
TI  - RNAi in human cells: basic structural and functional features of small
      interfering RNA.
AB  - We investigated the mechanism of RNA interference (RNAi) in human cells. Here we
      demonstrate that the status of the 5' hydroxyl terminus of the antisense strand
      of a siRNA determines RNAi activity, while a 3' terminus block is tolerated in
      vivo. 5' hydroxyl termini of antisense strands isolated from human cells were
      phosphorylated, and 3' end biotin groups were not efficiently removed. We found
      no requirement for a perfect A-form helix in siRNA for interference effects, but
      an A-form structure was required for antisense-target RNA duplexes. Strikingly,
      crosslinking of the siRNA duplex by psoralen did not completely block RNA
      interference, indicating that complete unwinding of the siRNA helix is not
      necessary for RNAi activity in vivo. These results suggest that RNA amplification
      by RNA-dependent RNA polymerase is not essential for RNAi in human cells.

PMID- 12408824
TI  - The crystal structure of the beta-catenin/ICAT complex reveals the inhibitory
      mechanism of ICAT.
AB  - Beta-catenin is a multifunctional protein involved in both cell adhesion and
      transcriptional activation. Transcription mediated by the beta-catenin/Tcf
      complex is involved in embryological development and is upregulated in various
      cancers. We have determined the crystal structure at 2.5 A resolution of a
      complex between beta-catenin and ICAT, a protein that prevents the interaction
      between beta-catenin and Tcf/Lef family transcription factors. ICAT contains a 3
      helix bundle that binds armadillo repeats 10-12 and a C-terminal tail that,
      similar to Tcf and E-cadherin, binds in the groove formed by armadillo repeats 5
      9 of beta-catenin. We show that ICAT selectively inhibits beta-catenin/Tcf
      binding in vivo, without disrupting beta-catenin/cadherin interactions. Thus, it
      should be possible to design cancer therapeutics that inhibit beta-catenin
      mediated transcriptional activation without interfering with cell adhesion.

PMID- 12408825
TI  - ICAT inhibits beta-catenin binding to Tcf/Lef-family transcription factors and
      the general coactivator p300 using independent structural modules.
AB  - In the canonical Wnt signaling pathway, beta-catenin activates target genes
      through its interactions with Tcf/Lef-family transcription factors and additional
      transcriptional coactivators. The crystal structure of ICAT, an inhibitor of beta
      catenin-mediated transcription, bound to the armadillo repeat domain of beta
      catenin, has been determined. ICAT contains an N-terminal helilical domain that
      binds to repeats 11 and 12 of beta-catenin, and an extended C-terminal region
      that binds to repeats 5-10 in a manner similar to that of Tcfs and other beta
      catenin ligands. Full-length ICAT dissociates complexes of beta-catenin, Lef-1,
      and the transcriptional coactivator p300, whereas the helical domain alone
      selectively blocks binding to p300. The C-terminal armadillo repeats of beta
      catenin may be an attractive target for compounds designed to disrupt aberrant
      beta-catenin-mediated transcription associated with various cancers.

PMID- 12408826
TI  - Tat stimulates cotranscriptional capping of HIV mRNA.
AB  - Here we investigated how capping and methylation of HIV pre-mRNAs are coupled to
      Pol II elongation. Stable binding of the capping enzyme (Mce1) and cap
      methyltransferase (Hcm1) to template-engaged Pol II depends on CTD
      phosphorylation, but not on nascent RNA. Both Mce1 and Hcm1 travel with Pol II
      during elongation. The capping and methylation reactions cannot occur until the
      nascent pre-mRNA has attained a chain length of 19-22 nucleotides. HIV pre-mRNAs
      are capped quantitatively when elongation complexes are halted at promoter
      proximal positions, but capping is much less efficient during unimpeded Pol II
      elongation. Cotranscriptional capping of HIV mRNA is strongly stimulated by Tat,
      and this stimulation requires the C-terminal segment of Tat that mediates its
      direct binding to Mce1. Our findings implicate capping in an elongation
      checkpoint critical to HIV gene expression.

PMID- 12408827
TI  - Functional coupling of capping and transcription of mRNA.
AB  - In humans, 5' m(7)G cap addition is accomplished cotranscriptionally by the
      sequential action of the capping enzyme (Hce1) and the cap methyltransferase
      (Hcm1). We found that guanylylation and methylation occur efficiently during
      transcription with t(1/2)'s of less than 15 and 70 s, respectively. A two to four
      order of magnitude increase was found in the rate of guanylylation of RNA in
      transcription complexes compared to free RNA. This stimulation required only the
      RNA polymerase II elongation complex and Hce1. Capping activity was weakly
      associated with elongation but not preinitiation complexes. The CTD was not
      required for functional coupling but stimulated the rate of capping 4-fold.
      Inhibition of Cdk7 but not Cdk9 similarly slowed the rate of capping.

PMID- 12408828
TI  - The sigma(70) subunit of RNA polymerase is contacted by the (lambda)Q
      antiterminator during early elongation.
AB  - The Q protein of bacteriophage lambda is a transcription antiterminator that
      modifies the elongation properties of E. coli RNA polymerase (RNAP). To do this,
      DNA-bound (lambda)Q must first engage a paused elongation complex. Here we show
      that this engagement of (lambda)Q with RNAP involves an interaction between
      (lambda)Q and sigma(70), demonstrating that sigma(70) can be a target of
      regulation during elongation. Furthermore, we provide evidence that this
      interaction between (lambda)Q and sigma(70) stabilizes a conformation of RNAP
      that requires the disengagement of a segment of sigma(70) from the core enzyme.
      Recent structure-based models posit that the transition from the initiation to
      the elongation phase of transcription involves the staged displacement of
      sigma(70) from the RNAP core. Our findings provide support for this proposal.

PMID- 12408829
TI  - Swing-gate model of nucleotide entry into the RNA polymerase active center.
AB  - Each elementary step of transcription involves translocation of the 3' terminus
      of RNA in the RNA polymerase active center, followed by the entry of a nucleoside
      triphosphate. The structural basis of these transitions was studied using RNA
      protein crosslinks. The contacts were mapped and projected onto the crystal
      structure, in which the "F bridge" helix in the beta' subunit is either bent or
      relaxed. Bending/relaxation of the F bridge correlates with lateral movements of
      the RNA 3' terminus. The bent conformation is sterically incompatable with the
      occupancy of the nucleotide site, suggesting that the switch regulates both the
      entry of substrates and the translocation of the transcript. The switch occurs as
      part of a cooperative transition of a larger structural domain that consists of
      the F helix and the supporting G loop.

PMID- 12408830
TI  - A recombinant RNA polymerase II-like enzyme capable of promoter-specific
      transcription.
AB  - RNA polymerases (RNAPs) are core components of the cellular transcriptional
      machinery. Progress with functional studies of eukaryotic RNAPs has been delayed
      by the fact that it has not yet been possible to assemble active enzymes from
      individual subunits. Archaeal RNAPs are directly comparable to eukaryotic RNAPII
      in terms of primary sequence homology and quaternary structure. Here we report
      the successful in vitro assembly of a recombinant archaeal RNAP from purified
      subunits. The recombinant enzyme displays full activity in transcription assays
      and is capable, in the presence of two other basal factors, of promoter-specific
      transcription. The assembly of mutant enzymes yielded several unexpected insights
      into the structural and functional contributions of various subunits toward
      overall RNAP activity.

PMID- 12408831
TI  - DnaB drives DNA branch migration and dislodges proteins while encircling two DNA
      strands.
AB  - DnaB is a ring-shaped, hexameric helicase that unwinds the E. coli DNA
      replication fork while encircling one DNA strand. This report demonstrates that
      DnaB can also encircle both DNA strands and then actively translocate along the
      duplex. With two strands positioned inside its central channel, DnaB translocates
      with sufficient force to displace proteins tightly bound to DNA with no resultant
      DNA unwinding. Thus, DnaB may clear proteins from chromosomal DNA. Furthermore,
      while encircling two DNA strands, DnaB can drive branch migration of a synthetic
      Holliday junction with heterologous duplex arms, suggesting that DnaB may be
      directly involved in DNA recombination in vivo. DnaB binds to just one DNA strand
      during branch migration. T7 phage gp4 protein also drives DNA branch migration,
      suggesting this activity generalizes to other ring-shaped helicases.

PMID- 12408832
TI  - The Mu three-site synapse: a strained assembly platform in which delivery of the
      L1 transposase binding site triggers catalytic commitment.
AB  - The Mu DNA transposition reaction proceeds through a three-site synaptic complex
      (LER), including the two Mu ends and the transpositional enhancer. We show that
      the LER contains highly stressed DNA regions in the enhancer and in the L1
      transposase binding site. We propose that the L1 site acts as the keystone for
      assembly of a catalytically competent transpososome. Delivery of L1 through HU
      mediated bending completes LER assembly, provides the trigger for necessary
      conformational transitions in transpososome formation, and allows target capture
      to occur. Relief of the stress at L1 and the enhancer may help drive Mu A
      tetramerization and engagement of the Mu ends by the transposase active site.

PMID- 12408833
TI  - Crystal structure of the RuvA-RuvB complex: a structural basis for the Holliday
      junction migrating motor machinery.
AB  - We present the X-ray structure of the RuvA-RuvB complex, which plays a crucial
      role in ATP-dependent branch migration. Two RuvA tetramers form the symmetric and
      closed octameric shell, where four RuvA domain IIIs spring out in the two
      opposite directions to be individually caught by a single RuvB. The binding of
      domain III deforms the protruding beta hairpin in the N-terminal domain of RuvB
      and thereby appears to induce a functional and less symmetric RuvB hexameric
      ring. The model of the RuvA-RuvB junction DNA ternary complex, constructed by
      fitting the X-ray structure into the averaged electron microscopic images of the
      RuvA-RuvB junction, appears to be more compatible with the branch migration mode
      of a fixed RuvA-RuvB interaction than with a rotational interaction mode.

PMID- 12408834
TI  - BRCA2 homolog required for proficiency in DNA repair, recombination, and genome
      stability in Ustilago maydis.
AB  - In a screen for DNA repair-defective mutants in the fungus Ustilago maydis, a
      gene encoding a BRCA2 family member, designated here as Brh2, was identified. A
      brh2 null allele was found to be defective in allelic recombination, meiosis, and
      repair of gaps and ionizing radiation damage to the same extent as rad51.
      Frequent marker loss in meiosis and diploid formation suggested that genomic
      instability was associated with brh2. This notion was confirmed by molecular
      karyotype analysis, which revealed gross chromosomal alterations associated with
      brh2. Yeast two-hybrid analysis indicated interaction between Brh2 and Rad51.
      Recapitulation in U. maydis of defects in DNA repair and genome stability
      associated with brh2 means that the BRCA2 gene family is more widespread than
      previously thought.

PMID- 12408835
TI  - The bound leading the bound: target-derived receptors act as guidance cues.
AB  - Developing axons are guided to their targets by chemoattractive and
      chemorepulsive ligands. Ledda et al., in this issue of Neuron, demonstrate that
      the target-derived receptor glial cell line-derived neurotrophic factor receptor
      alpha1 (GFRalpha1) can also act in trans as an axon guidance molecule for
      neurons.

PMID- 12408836
TI  - Spinsters, synaptic defects, and amaurotic idiocy.
AB  - In this issue of Neuron, Sweeney and Davis present a beautiful characterization
      of Drosophila mutants in a gene named spinster. The results indicate a function
      of the endocytic pathway in regulating transforming growth factor-beta (TGF-beta)
      signaling at the Drosophila motor synapse. This study provides important new
      information at an intersection of several disciplines, including membrane
      traffic, lipid organization, synaptic signaling, and neurodegenerative lysosomal
      storage disease.

PMID- 12408837
TI  - mRNA at synapses, synaptic plasticity, and memory consolidation.
AB  - Miller et al. (this issue of Neuron) report that deletion of the 3'UTR of alpha
      CaMKII mRNA prevents dendritic delivery of the mRNA in transgenic mice and thus
      local synthesis of alpha-CaMKII protein in dendrites. 3'UTR mutant mice exhibit
      decreases in alpha-CaMKII protein in postsynaptic densities, and deficits in late
      phase LTP and in memory consolidation.

PMID- 12408838
TI  - Systems-level reconsolidation: reengagement of the hippocampus with memory
      reactivation.
AB  - Certain types of memories are dependent on the hippocampus for a short period of
      time following training, after which they are no longer susceptible to
      hippocampal manipulations. Having completed this initial consolidation process, a
      memory may once again engage the hippocampus (undergo reconsolidation) when
      recalled. Two studies in the current issue of Neuron make important advances in
      our understanding of reconsolidation but reach different conclusions about the
      modifiability of old memories.

PMID- 12408839
TI  - Nogo on the go.
AB  - Growth inhibition in the central nervous system (CNS) is a major barrier to axon
      regeneration. Recent findings indicate that three distinct myelin proteins,
      myelin-associated glycoprotein (MAG), Nogo, and oligodendrocyte-myelin
      glycoprotein (OMgp), inhibit axon growth by binding a common receptor, the Nogo66
      receptor (NgR), and likely converge on a common signaling cascade.

PMID- 12408840
TI  - The cortical control of movement revisited.
AB  - Recently, we found that electrical stimulation of motor cortex caused monkeys to
      make coordinated, complex movements. These evoked movements were arranged across
      the cortex in a map of spatial locations to which the hand moved. We suggest that
      some of the subdivisions previously described within primary motor and premotor
      cortex may represent different types of actions that monkeys tend to make in
      different regions of space. According to this view, primary and premotor cortex
      may fit together into a larger map of manual space.

PMID- 12408841
TI  - Fleeting activation of ionotropic glutamate receptors sensitizes cortical neurons
      to complement attack.
AB  - Insidious attack of cortical neurons by complement has been implicated in
      Alzheimer's and other neurodegenerative diseases. Excitotoxicity, triggered by
      excessive activation of glutamate receptors, has been implicated in neuronal
      death following diverse insults, including ischemia and seizures. Clinical
      studies suggested that a minimal excitotoxic insult might sensitize neurons to
      complement attack. We found that fleeting activation of ionotropic glutamate
      receptors sensitizes neurons but not astrocytes to complement attack. The
      complement molecule effecting cytotoxicity was the membrane attack complex. The
      site within the complement cascade at which sensitization was effected was the
      membrane attack pathway. Sensitization mediated by glutamate receptor activation
      required Ca(2+)(o) and generation of reactive oxygen species. These in vitro
      findings predict that a fleeting excitotoxic insult could act synergistically
      with complement to destroy cortical neurons and accelerate neurological
      deterioration.

PMID- 12408843
TI  - Target-derived GFRalpha1 as an attractive guidance signal for developing sensory
      and sympathetic axons via activation of Cdk5.
AB  - Immobilized and diffusible molecular cues regulate axon guidance during
      development. GFRalpha1, a GPI-anchored receptor for GDNF, is expressed as both
      membrane bound and secreted forms by accessory nerve cells and peripheral targets
      of developing sensory and sympathetic neurons during the period of target
      innervation. A relative deficit of GFRalpha1 in developing axons allows exogenous
      GFRalpha1 to capture GDNF and present it for recognition by axonal c-Ret
      receptors. Exogenous GFRalpha1 potentiates neurite outgrowth and acts as a long
      range directional cue by creating positional information for c-Ret-expressing
      axons in the presence of a uniform concentration of GDNF. Soluble GFRalpha1
      prolongs GDNF-mediated activation of cyclin-dependent kinase 5 (Cdk5), an event
      required for GFRalpha1-induced neurite outgrowth and axon guidance. Together with
      GDNF, target-derived GFRalpha1 can function in a non-cell-autonomous fashion as a
      chemoattractant cue with outgrowth promoting activity for peripheral neurons.

PMID- 12408842
TI  - ProNGF induces p75-mediated death of oligodendrocytes following spinal cord
      injury.
AB  - The neurotrophin receptor p75 is induced by various injuries to the nervous
      system, but its role after injury has remained unclear. Here, we report that p75
      is required for the death of oligodendrocytes following spinal cord injury, and
      its action is mediated mainly by proNGF. Oligodendrocytes undergoing apoptosis
      expressed p75, and the absence of p75 resulted in a decrease in the number of
      apoptotic oligodendrocytes and increased survival of oligodendrocytes. ProNGF is
      likely responsible for activating p75 in vivo, since the proNGF from the injured
      spinal cord induced apoptosis among p75(+/+), but not among p75(-/-),
      oligodendrocytes in culture, and its action was blocked by proNGF-specific
      antibody. Together, these data suggest that the role of proNGF is to eliminate
      damaged cells by activating the apoptotic machinery of p75 after injury.

PMID- 12408844
TI  - Unrestricted synaptic growth in spinster-a late endosomal protein implicated in
      TGF-beta-mediated synaptic growth regulation.
AB  - In a genetic screen for genes that control synapse development, we have
      identified spinster (spin), which encodes a multipass transmembrane protein. spin
      mutant synapses reveal a 200% increase in bouton number and a deficit in
      presynaptic release. We demonstrate that spin is expressed in both nerve and
      muscle and is required both pre- and postsynaptically for normal synaptic growth.
      We have localized Spin to a late endosomal compartment and present evidence for
      altered endosomal/lysosomal function in spin. We also present evidence that
      synaptic overgrowth in spin is caused by enhanced/misregulated TGF-beta
      signaling. TGF-beta receptor mutants show dose-dependent suppression of synaptic
      overgrowth in spin. Furthermore, mutations in Dad, an inhibitory Smad, cause
      synapse overgrowth. We present a model for synaptic growth control with
      implications for the etiology of lysosomal storage and neurodegenerative disease.

PMID- 12408845
TI  - Molecular analysis of gene expression in the developing pontocerebellar
      projection system.
AB  - As an approach toward understanding the molecular mechanisms of neuronal
      differentiation, we utilized DNA microarrays to elucidate global patterns of gene
      expression during pontocerebellar development. Through this analysis, we
      identified groups of genes specific to neuronal precursor cells, associated with
      axon outgrowth, and regulated in response to contact with synaptic target cells.
      In the cerebellum, we identified a phase of granule cell differentiation that is
      independent of interactions with other cerebellar cell types. Analysis of pontine
      gene expression revealed that distinct programs of gene expression, correlated
      with axon outgrowth and synapse formation, can be decoupled and are likely
      influenced by different cells in the cerebellar target environment. Our approach
      provides insight into the genetic programs underlying the differentiation of
      specific cell types in the pontocerebellar projection system.

PMID- 12408846
TI  - Dynamics and regulation of clathrin coats at specialized endocytic zones of
      dendrites and spines.
AB  - Endocytosis is a fundamental mechanism by which neurons control intercellular
      signaling, nutrient uptake, and synaptic transmission. This process is carried
      out by the assembly of clathrin coats and the budding of clathrin-coated vesicles
      from the neuronal plasma membrane. Here, we demonstrate that in young neurons,
      clathrin assembly and disassembly occur rapidly, locally, and repeatedly at "hot
      spots" throughout dendrites and at the tips of dendritic filopodia. In contrast,
      clathrin coats in mature dendrites reside in stable, long-lasting zones at sites
      of endocytosis, where clathrin undergoes continuous exchange with local cytosolic
      pools. In dendritic spines, endocytic zones lie lateral to the postsynaptic
      density (PSD) where they develop and persist independent of synaptic activity,
      akin to the PSD itself. These results reveal the presence of a novel
      specialization dedicated to endocytosis near the postsynaptic membrane.

PMID- 12408847
TI  - Activity-dependent regulation of HCN pacemaker channels by cyclic AMP: signaling
      through dynamic allosteric coupling.
AB  - Signal transduction in neurons is a dynamic process, generally thought to be
      driven by transient changes in the concentration of second messengers. Here we
      describe a novel regulatory mechanism in which the dynamics of signaling through
      cyclic AMP are mediated by activity-dependent changes in the affinity of the
      hyperpolarization-activated, cation nonselective (HCN) channels for cAMP, rather
      than by changes in cAMP concentration. Due to the allosteric coupling of channel
      opening and ligand binding, changes in cellular electrical activity that alter
      the opening of the HCN channels modify the binding of static, basal levels of
      cAMP. These changes in ligand binding produce long-lasting changes in channel
      function which can contribute to the regulation of rhythmic firing patterns.

PMID- 12408848
TI  - Transmission of olfactory information between three populations of neurons in the
      antennal lobe of the fly.
AB  - Three classes of neurons form synapses in the antennal lobe of Drosophila, the
      insect counterpart of the vertebrate olfactory bulb: olfactory receptor neurons,
      projection neurons, and inhibitory local interneurons. We have targeted a
      genetically encoded optical reporter of synaptic transmission to each of these
      classes of neurons and visualized population responses to natural odors. The
      activation of an odor-specific ensemble of olfactory receptor neurons leads to
      the activation of a symmetric ensemble of projection neurons across the
      glomerular synaptic relay. Virtually all excited glomeruli receive inhibitory
      input from local interneurons. The extent, odor specificity, and partly
      interglomerular origin of this input suggest that inhibitory circuits assemble
      combinatorially during odor presentations. These circuits may serve as dynamic
      templates that extract higher order features from afferent activity patterns.

PMID- 12408849
TI  - Kainate receptors differentially regulate release at two parallel fiber synapses.
AB  - Presynaptic kainate receptors (KARs) facilitate or depress transmitter release at
      several synapses in the CNS. Here, we report that synaptically activated KARs
      presynaptically facilitate and depress transmission at parallel fiber synapses in
      the cerebellar cortex. Low-frequency stimulation of parallel fibers facilitates
      synapses onto both stellate cells and Purkinje cells, whereas high-frequency
      stimulation depresses stellate cell synapses but continues to facilitate Purkinje
      cell synapses. These effects are mimicked by exogenous KAR agonists and
      eliminated by blocking KARs. This differential frequency-dependent sensitivity of
      these two synapses regulates the balance of excitatory and inhibitory input to
      Purkinje cells and therefore their excitability.

PMID- 12408850
TI  - Autophosphorylation of alphaCaMKII is required for ocular dominance plasticity.
AB  - Experience is a powerful sculptor of developing neural connections. In the
      primary visual cortex (V1), cortical connections are particularly susceptible to
      the effects of sensory manipulation during a postnatal critical period. At the
      molecular level, this activity-dependent plasticity requires the transformation
      of synaptic depolarization into changes in synaptic weight. The molecule alpha
      calcium-calmodulin kinase type II (alphaCaMKII) is known to play a central role
      in this transformation. Importantly, alphaCaMKII function is modulated by
      autophosphorylation, which promotes Ca(2+)-independent kinase activity. Here we
      show that mice possessing a mutant form of alphaCaMKII that is unable to
      autophosphorylate show impairments in ocular dominance plasticity. These results
      confirm the importance of alphaCaMKII in visual cortical plasticity and suggest
      that synaptic changes induced by monocular deprivation are stored specifically in
      glutamatergic synapses made onto excitatory neurons.

PMID- 12408851
TI  - Inhibitory autophosphorylation of CaMKII controls PSD association, plasticity,
      and learning.
AB  - To investigate the function of the alpha calcium-calmodulin-dependent kinase II
      (alphaCaMKII) inhibitory autophosphorylation at threonines 305 and/or 306, we
      generated knockin mice that express alphaCaMKII that cannot undergo inhibitory
      phosphorylation. In addition, we generated mice that express the inhibited form
      of alphaCaMKII, which resembles the persistently phosphorylated kinase at these
      sites. Our data demonstrate that blocking inhibitory phosphorylation increases
      CaMKII in the postsynaptic density (PSD), lowers the threshold for hippocampal
      long-term potentiation (LTP), and results in hippocampal-dependent learning that
      seems more rigid and less fine-tuned. Mimicking inhibitory phosphorylation
      dramatically decreased the association of CaMKII with the PSD and blocked both
      LTP and learning. These data demonstrate that inhibitory phosphorylation has a
      critical role in plasticity and learning.

PMID- 12408852
TI  - Disruption of dendritic translation of CaMKIIalpha impairs stabilization of
      synaptic plasticity and memory consolidation.
AB  - Local protein translation in dendrites could be a means for delivering synaptic
      proteins to their sites of action, perhaps in a spatially regulated fashion that
      could contribute to plasticity. To directly test the functional role of dendritic
      translation of calcium/calmodulin-dependent protein kinase IIalpha (CaMKIIalpha)
      in vivo, we mutated the endogenous gene to disrupt the dendritic localization
      signal in the mRNA. In this mutant mouse, the protein-coding region of
      CaMKIIalpha is intact, but mRNA is restricted to the soma. Removal of dendritic
      mRNA produced a dramatic reduction of CaMKIIalpha in postsynaptic densities
      (PSDs), a reduction in late-phase long-term potentiation (LTP), and impairments
      in spatial memory, associative fear conditioning, and object recognition memory.
      These results demonstrate that local translation is important for synaptic
      delivery of the kinase and that local translation contributes to synaptic and
      behavioral plasticity.

PMID- 12408853
TI  - Temporally graded requirement for protein synthesis following memory
      reactivation.
AB  - Learning of new information is transformed into long-lasting memory through a
      process known as consolidation, which requires protein synthesis. Classical
      theory held that once consolidated, memory was insensitive to disruption.
      However, old memories that are insensitive to protein synthesis inhibitors can
      become vulnerable if they are recalled (reactivated). These findings led to a new
      hypothesis that when an old memory is reactivated, it again becomes labile and,
      similar to a newly formed memory, requires a process of reconsolidation in order
      to be maintained. Here, we show that the requirement for protein synthesis of a
      reactivated memory is evident only when the memory is recent. In fact, memory
      vulnerability decreases as the time between the original training and the recall
      increases.

PMID- 12408855
TI  - Cognitive mechanisms of nicotine on visual attention.
AB  - Understanding nicotine's neurobiological and cognitive mechanisms may help
      explain both its addictive properties and potential therapeutic applications. As
      such, functional MRI was used to determine the neural substrates of nicotine's
      effects on a sustained attention (rapid visual information-processing) task.
      Performance was associated with activation in a fronto-parietal-thalamic network
      in both smokers and nonsmokers. Along with subtle behavioral deficits, mildly
      abstinent smokers showed less task-induced brain activation in the parietal
      cortex and caudate than did nonsmokers. Transdermal nicotine replacement improved
      task performance in smokers and increased task-induced brain activation in the
      parietal cortex, thalamus, and caudate, while nicotine induced a generalized
      increase in occipital cortex activity. These data suggest that nicotine improves
      attention in smokers by enhancing activation in areas traditionally associated
      with visual attention, arousal, and motor activation.

PMID- 12408854
TI  - Cellular and systems reconsolidation in the hippocampus.
AB  - Cellular theories of memory consolidation posit that new memories require new
      protein synthesis in order to be stored. Systems consolidation theories posit
      that the hippocampus has a time-limited role in memory storage, after which the
      memory is independent of the hippocampus. Here, we show that intra-hippocampal
      infusions of the protein synthesis inhibitor anisomycin caused amnesia for a
      consolidated hippocampal-dependent contextual fear memory, but only if the memory
      was reactivated prior to infusion. The effect occurred even if reactivation was
      delayed for 45 days after training, a time when contextual memory is independent
      of the hippocampus. Indeed, reactivation of a hippocampus-independent memory
      caused the trace to again become hippocampus dependent, but only for 2 days
      rather than for weeks. Thus, hippocampal memories can undergo reconsolidation at
      both the cellular and systems levels.

PMID- 12408856
TI  - Endocytosis: driving membranes around the bend.
AB  - When a nascent vesicle buds, the membrane must curve. Several mechanisms have
      been proposed for curvature creation or stabilization. Structural analysis of the
      ENTH domain of the endocytic protein epsin has suggested a new mechanism, in
      which the ENTH domain pushes its way into membranes, thus bending them into
      shape.

PMID- 12408857
TI  - Dueling activities of AIF in cell death versus survival: DNA binding and redox
      activity.
AB  - Apoptosis-inducing factor (AIF) was originally discovered as a mitochondrial
      protein that, like cytochrome c, is released into the cytoplasm during cell
      death. New evidence suggests, however, that a redox-active enzymatic region of
      AIF may be antiapoptotic while a DNA binding region is proapoptotic.

PMID- 12408858
TI  - Setting the boundaries of chromatin domains and nuclear organization.
AB  - The nuclear architecture of the interphase nucleus is established by laying down
      an intricate three-dimensional framework of higher-order chromatin structure.
      This arrangement is essential for the integration of complex biological processes
      such as DNA replication, RNA processing, and transcription. Boundary or insulator
      elements are emerging as key players in the establishment and maintenance of this
      organization.

PMID- 12408859
TI  - Nutrient-regulated protein kinases in budding yeast.
AB  - The ability of cells to react appropriately to nutritional cues is of fundamental
      importance, and in budding yeast, a small number of intracellular protein
      kinases, PKA, Snf1p/AMP-activated kinase, TOR, Gcn2p, and the cyclin-dependent
      kinase Pho85p have key roles. A recently characterized enzyme, PAS kinase, may be
      a new member of this group of nutritional transducers.

PMID- 12408860
TI  - A chromosome RNAissance.
AB  - In RNA-mediated interference (RNAi), double-stranded RNAs (dsRNAs) target
      complementary mRNAs for degradation. New work demonstrates that essential
      chromosomal functions are mediated through RNAi protein components and short
      RNAs, which alter chromosome function at specific DNA loci via histone
      modification.

PMID- 12408861
TI  - Phospho-regulation of kinetochore-microtubule attachments by the Aurora kinase
      Ipl1p.
AB  - The Aurora kinase Ipl1p plays a crucial role in regulating kinetochore
      microtubule attachments in budding yeast, but the underlying basis for this
      regulation is not known. To identify Ipl1p targets, we first purified 28
      kinetochore proteins from yeast protein extracts. These studies identified five
      previously uncharacterized kinetochore proteins and defined two additional
      kinetochore subcomplexes. We then used mass spectrometry to identify 18
      phosphorylation sites in 7 of these 28 proteins. Ten of these phosphorylation
      sites are targeted directly by Ipl1p, allowing us to identify a consensus
      phosphorylation site for an Aurora kinase. Our systematic mutational analysis of
      the Ipl1p phosphorylation sites demonstrated that the essential microtubule
      binding protein Dam1p is a key Ipl1p target for regulating kinetochore
      microtubule attachments in vivo.

PMID- 12408862
TI  - Targeted stimulation of meiotic recombination.
AB  - Meiotic recombination in Saccharomyces cerevisiae is initiated by programmed DNA
      double-strand breaks (DSBs), a process that requires the Spo11 protein. DSBs
      usually occur in intergenic regions that display open chromatin accessibility,
      but other determinants that control their frequencies and non-random chromosomal
      distribution remain obscure. We report that a Spo11 construct bearing the Gal4
      DNA binding domain not only rescues spo11Delta spore inviability and catalyzes
      DSB formation at natural sites but also strongly stimulates DSB formation near
      Gal4 binding sites. At GAL2, a naturally DSB-cold locus, Gal4BD-Spo11 creates a
      recombinational hotspot that depends on all the other DSB gene functions, showing
      that the targeting of Spo11 to a specific site is sufficient to stimulate meiotic
      recombination that is under normal physiological control.

PMID- 12408863
TI  - Drosophila enhancer of Zeste/ESC complexes have a histone H3 methyltransferase
      activity that marks chromosomal Polycomb sites.
AB  - Enhancer of Zeste is a Polycomb Group protein essential for the establishment and
      maintenance of repression of homeotic and other genes. In the early embryo it is
      found in a complex that includes ESC and is recruited to Polycomb Response
      Elements. We show that this complex contains a methyltransferase activity that
      methylates lysine 9 and lysine 27 of histone H3, but the activity is lost when
      the E(Z) SET domain is mutated. The lysine 9 position is trimethylated and this
      mark is closely associated with Polycomb binding sites on polytene chromosomes
      but is also found in centric heterochromatin, chromosome 4, and telomeric sites.
      Histone H3 methylated in vitro by the E(Z)/ESC complex binds specifically to
      Polycomb protein.

PMID- 12408864
TI  - Histone methyltransferase activity of a Drosophila Polycomb group repressor
      complex.
AB  - Polycomb group (PcG) proteins maintain transcriptional repression during
      development, likely by creating repressive chromatin states. The Extra Sex Combs
      (ESC) and Enhancer of Zeste [E(Z)] proteins are partners in an essential PcG
      complex, but its full composition and biochemical activities are not known. A SET
      domain in E(Z) suggests this complex might methylate histones. We purified an ESC
      E(Z) complex from Drosophila embryos and found four major subunits: ESC, E(Z),
      NURF-55, and the PcG repressor, SU(Z)12. A recombinant complex reconstituted from
      these four subunits methylates lysine-27 of histone H3. Mutations in the E(Z) SET
      domain disrupt methyltransferase activity in vitro and HOX gene repression in
      vivo. These results identify E(Z) as a PcG protein with enzymatic activity and
      implicate histone methylation in PcG-mediated silencing.

PMID- 12408865
TI  - The UCH-L1 gene encodes two opposing enzymatic activities that affect alpha
      synuclein degradation and Parkinson's disease susceptibility.
AB  - The assumption that each enzyme expresses a single enzymatic activity in vivo is
      challenged by the linkage of the neuronal enzyme ubiquitin C-terminal hydrolase
      L1 (UCH-L1) to Parkinson's disease (PD). UCH-L1, especially those variants linked
      to higher susceptibility to PD, causes the accumulation of alpha-synuclein in
      cultured cells, an effect that cannot be explained by its recognized hydrolase
      activity. UCH-L1 is shown here to exhibit a second, dimerization-dependent,
      ubiquityl ligase activity. A polymorphic variant of UCH-L1 that is associated
      with decreased PD risk (S18Y) has reduced ligase activity but comparable
      hydrolase activity as the wild-type enzyme. Thus, the ligase activity as well as
      the hydrolase activity of UCH-L1 may play a role in proteasomal protein
      degradation, a critical process for neuronal health.

PMID- 12408866
TI  - Dual regulation of NMDA receptor functions by direct protein-protein interactions
      with the dopamine D1 receptor.
AB  - Dopamine D1-like receptors, composed of D1 and D5 receptors, have been documented
      to modulate glutamate-mediated fast excitatory synaptic neurotransmission. Here,
      we report that dopamine D1 receptors modulate NMDA glutamate receptor-mediated
      functions through direct protein-protein interactions. Two regions in the D1
      receptor carboxyl tail can directly and selectively couple to NMDA glutamate
      receptor subunits NR1-1a and NR2A. While one interaction is involved in the
      inhibition of NMDA receptor-gated currents, the other is implicated in the
      attenuation of NMDA receptor-mediated excitotoxicity through a PI-3 kinase
      dependent pathway.

PMID- 12408867
TI  - Energetics of pore opening in a voltage-gated K(+) channel.
AB  - Voltage-dependent gating in K(+) channels results from the mechanical coupling of
      voltage sensor movements to pore opening. We used single and double mutations in
      the pore of the Shaker K(+) channel to analyze a late concerted pore opening
      transition and interpreted the results in the context of known K(+) channel
      structures. Gating sensitive mutations are located at mechanistically informative
      regions of the pore and are coupled energetically across distances up to 15 A. We
      propose that the pore is intrinsically more stable when closed, and that to open
      the pore the voltage sensors must exert positive work by applying an outward
      lateral force near the inner helix bundle.

PMID- 12408868
TI  - The beta-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal
      cancer cells.
AB  - The transactivation of TCF target genes induced by Wnt pathway mutations
      constitutes the primary transforming event in colorectal cancer (CRC). We show
      that disruption of beta-catenin/TCF-4 activity in CRC cells induces a rapid G1
      arrest and blocks a genetic program that is physiologically active in the
      proliferative compartment of colon crypts. Coincidently, an intestinal
      differentiation program is induced. The TCF-4 target gene c-MYC plays a central
      role in this switch by direct repression of the p21(CIP1/WAF1) promoter.
      Following disruption of beta-catenin/TCF-4 activity, the decreased expression of
      c-MYC releases p21(CIP1/WAF1) transcription, which in turn mediates G1 arrest and
      differentiation. Thus, the beta-catenin/TCF-4 complex constitutes the master
      switch that controls proliferation versus differentiation in healthy and
      malignant intestinal epithelial cells.

PMID- 12408869
TI  - Beta-catenin and TCF mediate cell positioning in the intestinal epithelium by
      controlling the expression of EphB/ephrinB.
AB  - In the small intestine, the progeny of stem cells migrate in precise patterns.
      Absorptive, enteroendocrine, and goblet cells migrate toward the villus while
      Paneth cells occupy the bottom of the crypts. We show here that beta-catenin and
      TCF inversely control the expression of the EphB2/EphB3 receptors and their
      ligand ephrin-B1 in colorectal cancer and along the crypt-villus axis. Disruption
      of EphB2 and EphB3 genes reveals that their gene products restrict cell
      intermingling and allocate cell populations within the intestinal epithelium. In
      EphB2/EphB3 null mice, the proliferative and differentiated populations
      intermingle. In adult EphB3(-/-) mice, Paneth cells do not follow their downward
      migratory path, but scatter along crypt and villus. We conclude that in the
      intestinal epithelium beta-catenin and TCF couple proliferation and
      differentiation to the sorting of cell populations through the EphB/ephrin-B
      system.

PMID- 12408870
TI  - Evidence that Armadillo transduces wingless by mediating nuclear export or
      cytosolic activation of Pangolin.
AB  - Secreted proteins of the Wnt family have profound organizing roles during animal
      development and are transduced via the activities of the Frizzled (Fz) class of
      transmembrane receptors and the TCF/LEF/Pangolin class of transcription factors.
      beta-catenins, including Drosophila Armadillo (Arm), link activation of Fz at the
      cell surface to transcriptional regulation by TCF in the nucleus. The consensus
      view is that Wnt signaling induces beta-catenin to enter the nucleus and combine
      with TCF to form a transcription factor complex in which TCF binds DNA and the C
      terminal domain of beta-catenin activates transcription. Here, we present
      findings, which challenge this view and suggest instead that beta-catenin may
      transduce Wnt signals by exporting TCF from the nucleus or activating it in the
      cytoplasm.

PMID- 12408871
TI  - Prolonged hypoxia accelerates the posttranscriptional process of collagen
      synthesis in cultured fibroblasts.
AB  - Molecular oxygen is essential for metazoan life. Hypoxia, a reduced oxygen
      condition, induces systemic and cellular responses for acclimation to the limited
      oxygen availability. Multicellularity of metazoans is maintained on extracellular
      matrices. Previously, we demonstrated that acute hypoxia up-regulated the prolyl
      4-hydroxylase alpha(I) subunit, the rate-limiting subunit for the hydroxylation
      of proline residues of procollagens (Y. Takahashi, S. Takahashi, Y. Shiga, T.
      Yoshimi, and T Miura, 2000, J. Biol. Chem., 275, 14139-14146). The formation of
      hydroxyproline is an essential posttranscriptional process for stabilization of
      the helical trimer of procollagen polypeptides at physiological temperature. In
      this present study, we cultured fetal rat lung fibroblasts for up to 9 days and
      examined the effects of prolonged hypoxia on the level of procollagen mRNA in the
      cells and the posttranscriptional steps of collagen synthesis. Hypoxia
      accelerated the deposition of collagen molecules. These enhancements in hypoxic
      cultures were observed with or without ascorbic acid in the culture medium. The
      steady-state level of procollagen alpha1(I) mRNA was not affected by the
      prolonged hypoxia. In contrast, the mRNA and protein levels of the prolyl 4
      hydroxylase alpha(I) subunit were increased by hypoxic culture under both
      ascorbic acid-sufficient and -deficient conditions. These results suggest that
      hypoxic enhancement of the posttranscriptional step of collagen synthesis
      contributed to the accelerated deposition of collagen fibrils.

PMID- 12408872
TI  - L-DOPA oxidation products prevent H2O2-induced oxidative damage to cellular DNA.
AB  - Using the single-cell gel electrophoresis ("Comet") assay, we show that
      tyrosinase-generated L-DOPA oxidation products prevent H2O2-induced oxidative DNA
      damage in cultured tissue cells. We propose that these oxidation products trigger
      cellular processes that up-regulate the overall antioxidant status of the cell,
      and could be incorporated into treatments of pathological conditions associated
      with elevated oxidative DNA damage and other manifestations of increased
      oxidative stress.

PMID- 12408873
TI  - Prevention of chronic alcohol and nicotine-induced azospermia, sterility and
      decreased libido, by a novel tri-substituted benzoflavone moiety from Passiflora
      incarnata Linneaus in healthy male rats.
AB  - Excessive long term consumption of alcohol and nicotine have serious detrimental
      effects upon the libido, fertility, and sperm count in male species. The present
      work describes the beneficial effects of a novel tri-substituted benzoflavone
      moiety (BZF) isolated from Passiflora incarnata Linneaus, the phyto-chemical
      isolation, spectroscopic elucidation, and multifarious biological activities of
      which have recently been reported by the authors. The BZF moiety has been
      reported to increase libido, sperm count, and sexual fertility in 2 years old
      male rats at 10 mg/kg, po dose, in the one of our previous studies. Presently,
      the BZF moiety has been evaluated against chronic ethanol- and nicotine-induced
      decrease in libido, sexual fertility and mating efficiency in healthy male rats.
      The male rats were given ethanol (3 g/kg, po) A, nicotine (2 mg/kg, sc) N,
      alcohol-nicotine combinations (AN) alone, and also with 10 mg/kg po dose of BZF
      (concurrent administrations). These treatments were given for 30 days. At the end
      of treatments, it was observed that rat groups A, N, and AN had no libido
      (evaluated by mounting behaviour), declined sperm count, and consequently no
      mating efficiency or fertility (upon pairing with pro-estrus female rats).
      However, the rats which were given 10 mg/kg BZF along-with nicotine (NP group),
      alcohol (AP group), and alcohol-nicotine combination (ANP) exhibited significant
      libido-oriented mounting behaviour, increased sperm count (significantly
      comparable to the control group), and increased fertilization potential. The rats
      having decreased sperm count, libido and fertilization potential due to chronic
      administration of alcohol, nicotine and alcohol-nicotine combinations, i.e., rats
      of A, N, and AN groups were again subdivided and were given 10 mg/kg BZF for 7
      days. This treatment confirmed that BZF speeds up the restoration of sexuality in
      rats upon cessation of the administration of substances like alcohol, nicotine
      and alcohol-nicotine combinations, which have severe detrimental effects upon
      male sexuality, fertility and vigour. BZF, the strongest inhibitor of aromatase
      enzyme, when administered concurrently with substances like alcohol and nicotine
      restores sexual virility, libido and vigour in male rats by maintaining the blood
      testosterone levels to be high.

PMID- 12408874
TI  - Relationship of bursal anti-steroidogenic peptide (BASP) and histone H1.
AB  - Previous in vitro research from our laboratory has demonstrated the existence of
      a protein purified from the chicken bursa of Fabricius, with potent
      antisteroidogenic and antiproliferative action on granulose cells and
      lymphocytes, respectively called Bursal anti-steroidogenic peptide (BASP). This
      protein is heat-labile, basic, and amino- and carboxy-terminus blocked. In highly
      purified form, the protein presents as a doublet on SDS-PAGE electrophoresis with
      an apparent MW of approximately 29 and approximately 32 kDa. Recently, Nanoflow Q
      TOF Mass Spectrometry amino acid sequencing allowed determination of a convincing
      partial amino acid sequence, strongly suggesting a probable relationship of BASP
      with histone H1. Bursal cDNA expression library screening, using an antibody
      produced against BASP, also identified a clone with a sequence matching histone
      H1. Presently, we have demonstrated that SDS-PAGE electrophoresis of highly
      purified and bioactive BASP, and commercially-available calf thymus derived
      histone H1, produced similar doublets at approximately the same apparent MW, and
      that the electrophoretic profile of these 2 preparations were strikingly similar
      following 2 dimensional gel electrophoresis. The BASP doublet produced on SDS
      PAGE was recognized by a commercially available monoclonal antibody recognizing a
      highly conserved region of histone H1. Furthermore, calf thymus histone H1 was
      found to suppress mitogen-stimulated chicken B-cell proliferation in a
      concentration-related manner, similar to the action of BASP. These data indicate
      that BASP shares substantial structural homology with, and may be identical to,
      histone H1.

PMID- 12408875
TI  - Effect of olvanil (N-vanillyl-cis-9-octadecenoamide) on cytosolic Ca2+ increase
      in renal tubular cells.
AB  - In canine renal tubular cells, effect of olvanil, a presumed cannabinoid and
      vanilloid receptor modulator, on intracellular Ca2+ concentration ([Ca2+]i) was
      measured by using fura-2. Olvanil (5-100 microM) caused a rapid and sustained
      [Ca2+]i rise in a concentration-dependent manner. Olvanil-induced [Ca2+]i rise
      was prevented by 70 and 90% by removal of extracellular Ca2+ and La3+,
      respectively, but was not changed by dihydropyridines, verapamil and diltiazem.
      In Ca2+-free medium, thapsigargin, an inhibitor of the endoplasmic reticulum Ca2+
      ATPase, caused a monophasic [Ca2+]i rise, after which the increasing effect of
      olvanil on [Ca2+]i was abolished; also, pretreatment with olvanil partly reduced
      thapsigargin-induced [Ca2+]i rise. U73122, an inhibitor of phoispholipase C,
      abrogated ATP-, but partly inhibited olvanil-, induced [Ca2+]i rise. Two
      cannabinoid receptor antagonists (AM251 and AM281; 5 microM) and a vanilloid
      receptor antagonist (capsazepine; 100 microM) did not alter olvanil (50 microM)
      induced [Ca2+]i rise. These results suggest that olvanil rapidly increases
      [Ca2+]i in renal tubular cells, by stimulating both extracellular Ca2+ influx and
      intracellular Ca2+ release via mechanism(s) independent of stimulation of
      cannabinoid and vanilloid receptors.

PMID- 12408876
TI  - Resveratrol-induced limitation of dysfunction of mitochondria isolated from rat
      brain in an anoxia-reoxygenation model.
AB  - Resveratrol protection on the main functions of purified rat brain mitochondria
      submitted to anoxia-reoxygenation was investigated. Resveratrol (<0.1 microM)
      reversed partly (23.3%) the respiratory control ratio (RCR) decrease by
      protecting both states 3 and 4. This effect was both observed when resveratrol
      was added before anoxia or reoxygenation. Resveratrol fully inhibited the release
      of cytochrome c in a concentration-dependent manner and significantly decreased
      the superoxide anion (O2(0-)) production at a concentration of 1 nM. The
      mitochondrial membranes damaged after the anoxia-reoxygenation were partly
      protected (about 70%) by resveratrol at 0.1 microM. The oxygen consumption of
      mitochondria in presence of NADH and cytochrome c was significantly inhibited by
      resveratrol with a low EC50 of 18.34 pM. Resveratrol inhibited the CCCP-induced
      uncoupling from about 20%. The effects of resveratrol on oxidative
      phosphorylation parameters were also investigated in rats after pretreatment
      (0.4, 2 and 10 mg/kg/day) for one week. After the isolation of brain
      mitochondria, the RCR was significantly less decreased in the resveratrol group
      compared to the control group. These results showed that resveratrol could
      preserve the mitochondrial functions with at least three mechanisms: antioxidant
      properties, action on complex III and a membrane stabilizing effect.

PMID- 12408877
TI  - Toxicologic and pharmacokinetic study of low doses of verapamil combined with
      doxorubicin.
AB  - The effect of a chronic treatment with low oral doses of verapamil, a calcium
      channel blocker commonly employed in cardiovascular therapy, on doxorubicin
      toxicity, was evaluated in CD1 mice. Verapamil, administered at a dosage
      corresponding to a typical cardiovascular posology in humans, significantly
      increased doxorubicin toxicity. In particular the mortality was significantly
      higher and earlier and histological analysis revealed an increase in the severity
      of lesions in the liver, kidney and small bowel of verapamil pretreated animals.
      The pharmacokinetic profiles revealed that verapamil treated group had higher
      doxorubicin peak plasma and tissue levels and AUCs. This study shows that
      verapamil, administered at low doses, dramatically increases doxorubicin
      toxicity, probably through an interaction between the two drugs, both P
      glycoprotein substrates, on the protein expressed in normal tissues, and suggests
      caution in the use of the calcium channel blocker for cardiovascular pathologies
      in patients who have to be treated with antineoplastic agents, substrates of P
      glycoprotein.

PMID- 12408878
TI  - Changes in the inhibitory responses to electrical field stimulation of intestinal
      smooth muscle from Trichinella spiralis infected rats.
AB  - Functional motor changes and morphological alterations have been associated with
      intestinal inflammation. The aim of this work was to study functional motor
      changes in inflamed and non-inflamed intestinal segments of Trichinella spiralis
      infected rats. Thickness of muscle layers and cell infiltration during infection
      were also evaluated. Segments of rat jejunum and ileum were placed in organ bath
      and relaxations of the longitudinal muscle in response to electrical field
      stimulation (EFS) were recorded. During the post-infection (PI) period EFS
      induced relaxations in ileum were decreased. Maximal decreases in relaxation were
      found on day 14-23 PI for ileum, whereas non significant changes were observed in
      jejunal samples throughout the experimental period. The sensitivity of the EFS
      induced relaxations to the NO synthase inhibitor Nomega-nitro-L-arginine (L-NNA)
      and to the soluble guanylate cyclase inhibitor oxadiazolo-quinoxalin-1-one (ODQ)
      was decreased on day 14 PI for jejunum, whereas in the ileum it lasted from day
      14-23 PI. The sensitivity of EFS-induced relaxations to apamin (a small
      conductance calcium activated potassium channel blocker) disappeared between day
      6-23 PI for both jejunum and ileum. In contrast, the sensitivity of the EFS
      induced relaxations to the K(+) channel blockers tetraethylamonium (TEA) and
      tetrapenthylammonium (TPEA) chloride was similar for healthy tissue and for
      tissue obtained form infected animals. Distribution and density of NADPH
      diaphorase positive neurons was similar in tissue obtained form healthy and
      infected animals. In conclusion, intestinal inflammation induces functional and
      structural changes in both worm-free and worm-positive intestinal segments.
      Increased muscle thickness was similar for both inflamed and noninflamed segments
      but the most prominent functional changes i.e. a long-lasting decrease of EFS
      induced relaxation was found in non-inflamed ileal segments.

PMID- 12408879
TI  - Development and validation of a highly sensitive RIA for zoledronic acid, a new
      potent heterocyclic bisphosphonate, in human serum, plasma and urine.
AB  - Zoledronic acid is a new, highly potent bisphosphonate drug under clinical
      evaluation. A radioimmunoassay has been developed to determine zoledronic acid
      concentration in human serum, plasma, and urine. The assay utilizes rabbit
      polyclonal antisera against a zoledronic acid-BSA conjugate and a
      [125I]zoledronic acid derivative as tracer in a competitive format adapted to
      microtiter plates. The assay shows a LLOQ 0.4 ng/ml in serum or plasma
      (interassay%CV=17%, accuracy 97%), 5 ng/ml in urine (21%, 98%). In 23 patients
      receiving 4, 8 or 16 mg of zoledronic acid, drug concentrations in plasma were
      dose proportional and showed a multiphasic profile, followed by a prolonged
      gradual decline to concentrations near the LLOQ. Zoledronic acid disposition in
      plasma and the recovery of only 40-50% of the dose in urine are consistent with
      the rapid and extensive uptake by and slow release from bone in parallel with
      renal clearance, typically shown by bisphosphonates.

PMID- 12408880
TI  - New approaches for quantifying hyaluronic acid in pharmaceutical semisolid
      formulations using HPLC and CZE.
AB  - HA was quantified in pharmaceutical formulations using HPLC-UV-detector and
      spectrophotometrically after the digestion with concentrated H(2)SO(4). Intact HA
      was quantified by capillary zone electrophoresis (CZE) using direct and indirect
      methods. The results were compared with the carbazole reaction established by
      Bitter et al. (Anal. Biochem. 4 (1997) 330) and with established method from
      Plazer et al. (J. Pharm. Biomed. Anal. 21 (1997) 491) regarding detection limits,
      linearity, reproducibility and simplicity. The present results show that the
      investigation using HPLC and CZE led to a considerable improvement of the
      detection limit [0.3 ng/ml (HPLC1), 1 microgram/ml (HPLC2) and 5 microgram/ml (CE
      D1)] compared with other methods (10 microgram/ml).

PMID- 12408881
TI  - Determination of verapamil by adsorptive stripping voltammetry in urine and
      pharmaceutical formulations.
AB  - A sensitive reduction peak of verapamil is obtained by adsorptive stripping
      voltammetry in 0.01 M phosphate (pH 7.4) at an accumulation time of 30 s. The
      peak potential is -1.81 V (vs. Ag/AgCl). The peak current is directly
      proportional to the concentration of verapamil (1x10(-8)-1x10(-6) M), with a
      3sigma detection limit of 5x10(-10) M (0.246 ng/ml). The R.S.D. at the 1x10(-7) M
      level is 1.8%. The interference of some metal ions, and some amino acids, and the
      application of the method to analysis of urine, and pharmaceutical formulations
      are described. The method is simple (no extraction), rapid (30 s accumulation
      time), sensitive (the detection limit of verapamil is 0.491 ng/ml),
      reproducible(within day R.S.D. of 1.28-1.8%), and suitable for routine analysis
      of verapamil, urine, and pharmaceutical formulation.

PMID- 12408882
TI  - A sequential injection analysis system for potassium clavulanate determination
      using two potentiometric detectors.
AB  - Two almost independent potentiometric methods were implemented in a multi-task
      flow system based on the concept of sequential injection analysis for the
      analytical control of potassium clavulanate in pharmaceutical formulations. In
      addition to in-line preparation of the solutions submitted to the analysis, the
      system simultaneously detected the clavulanate anion and the potassium cation
      using two potentiometric detectors selective to each of the species referred. For
      the two determinations, the system developed presented an analytical range of 2
      mM-0.1 M. Relative standard deviations of 0.5 and 0.6%, respectively, for
      clavulanate and potassium, were calculated from the signals obtained for 10
      consecutive injections of a solution of 5x10(-3) M potassium clavulanate. The
      frequency of sampling was 53 samples h(-1). The quality of results supplied was
      evaluated by comparison with the reference procedure revealing relative errors
      less than 2% for the two determinations. The simultaneous attainment of two
      measurements permitted the standardisation of results in real time, the detection
      of faults in the procedure and monitoring the chemical stability of clavulanate.

PMID- 12408883
TI  - Anti- and pro-oxidant activity of water soluble compounds in Cichorium intybus
      var. silvestre (Treviso red chicory).
AB  - The anti- and pro-oxidant activity of water soluble components in Cichorium
      intybus var. silvestre was investigated. This vegetable is domestically known as
      Treviso red chicory recalling its cultivation in the area of Treviso (Italy). The
      vegetable juices, obtained by centrifugation of the vegetable and treated at 2
      and 102 degrees C, were assessed for their antioxidant activity (AA) using the
      micellar model system linoleic acid-beta-carotene. The obtained juice at 2
      degrees C possessed either anti- or pro-oxidant activity. The boiled juice showed
      only strong AA, proving that the vegetable pro-oxidant components were thermally
      instable. Juice components were fractionated by sequential dialysis (1000-300000
      Da membrane cut-off), SPE, GFC, and RP-HPLC techniques showing the presence of
      several highly antioxidant components with different molecular weight (MW), and
      polar features in Treviso red chicory. The pro-oxidant fraction capable of
      masking the presence of the antioxidant components in the vegetable juice is
      retained by a MW>300000 Da dialysis membrane.

PMID- 12408884
TI  - Determination of undecylenic and sorbic acids in cosmetic preparations by high
      performance liquid chromatography with electrochemical detection.
AB  - A highly sensitive and selective method for the determination of sorbic (SA) and
      undecylenic acid (UA) in cosmetic formulations by a high performance liquid
      chromatography method with electrochemical detection (ECD) is described. The pre
      column derivatizations of SA and UA and the internal standard (cyclohexanoic acid
      (cHA)) were carried out using 1-(2,5-dihydroxyphenyl)-2-bromoethanone (2,5-DBE)
      as an electroactive labeling reagent previously synthesized in our lab. The
      resulting electroactive esters were separated by isocratic elution of a 5
      micrometer Hypersil CN column with acetonitrile-acetate buffer eluent. The
      compounds were detected by a porous graphite electrode set at an oxidation
      potential of +0.45 V. The analytical method developed in this study is suitable
      for quality control assays of complex cosmetic formulations containing sorbic
      and/or UA.

PMID- 12408885
TI  - Determinations of zidovudine/didanosine/nevirapine and
      zidovudine/didanosine/ritonavir in human serum by micellar electrokinetic
      chromatography.
AB  - Micellar electrokinetic chromatography methods were developed and validated to
      separate and quantitate anti-HIV drug mixtures containing
      zidovudine(AZT)/didanosine(ddI)/nevirapine (mixture A) and AZT/ddI/ritonavir
      (mixture B) in human serum. Serum samples were prepared using a solid-phase
      extraction procedure. The effects of various factors such as buffer type, buffer
      and surfactant concentrations, and pH on the separations were investigated. The
      optimized resolution was achieved with a run buffer containing 18 mM sodium
      dodecylsulfate in 15 mM phosphate and borate buffer (pH 9.0). An uncoated 52 cm
      (effective length 30 cm)x50 micrometer ID fused-silica capillary operated at 30
      degrees C was used in the analysis with UV detection at 210 nm. Aprobarbital was
      chosen as the internal standard. All analytes were separated within 14 min with a
      voltage of +15 kV and a current around 30 microA. The methods were validated over
      the range of 0.5-25.0 microgram/ml for AZT, 0.8-18.5 microgram/ml for ddI, 0.5
      22.8 microgram/ml for nevirapine in mixture A and the range of 0.5-25.0
      microgram/ml for AZT, 0.8-18.5 microgram/ml for ddI, 1.2-28.8 microgram/ml for
      ritonavir in mixture B. Intra-day and inter-day accuracy was less than 12.4% and
      intra-day and inter-day precision was less than 13.9% for both mixtures.
      Extraction recoveries of all analytes from serum were higher than 75.9%. The
      assay should be applicable to pharmacokinetic studies and routine monitoring of
      these drugs in serum.

PMID- 12408886
TI  - Determination of moxifloxacin in human plasma by liquid chromatography
      electrospray ionization tandem mass spectrometry.
AB  - Moxifloxacin is an advanced-generation, 8-methoxy fluoroquinolone that is active
      against a broad spectrum of pathogens, including antibiotic resistant
      Streptococcus pneumoniae. Development of a rapid, sensitive and selective method
      for the determination of moxifloxacin in human plasma is essential for
      understanding the pharmacokinetics of the drug when administered orally or
      intravenously. Solid phase extraction (SPE) using Oasis(R) HLB was used to
      extract moxifloxacin and the internal standard lomefloxacin from plasma. A method
      based on liquid chromatography electrospray ionization tandem mass spectrometry
      (LC/ESI-MS/MS) was developed and validated to quantitate moxifloxacin in human
      plasma. The precursor and major product ion of the analyte was monitored on a
      triple quadrupole mass spectrometer with positive ion electrospray ionization
      (ESI) in the multiple reaction monitoring (MRM) mode. Mechanisms for the
      formation of collision-induced dissociation (CID) products of moxifloxacin are
      proposed. Linear calibration curves were generated from 1 to 1000 ng/ml with
      coefficients of determination greater than 0.999. The inter-day and intra-day
      precision (% CV) was less than 11.3% and accuracy (% error) was less than 10.0%
      for moxifloxacin. The limit of detection (LOD) for the method was 50 pg/ml based
      on a signal to noise ratio of 3.

PMID- 12408887
TI  - HPLC analysis of the novel antipsychotic drug quetiapine in human plasma.
AB  - A precise and feasible high-performance liquid chromatographic (HPLC) method for
      the analysis of the novel antipsychotic drug quetiapine in plasma has been
      developed. The analysis was carried out on a C8 (150x4.6 mm i.d., 5 micrometer)
      reversed-phase column, using a mixture of acetonitrile, methanol and pH 1.9
      phosphate buffer as the mobile phase; triprolidine was used as the internal
      standard. Careful pretreatment of the biological samples was implemented by means
      of solid-phase extraction (SPE). A good linearity was found in the 4-400 ng ml(
      1) quetiapine plasma concentration range. The application to some plasma samples
      of patients treated with Seroquel(R) tablets gave satisfactory results. The
      accuracy was good (quetiapine mean recovery=92%), as well as the precision (mean
      RSD=3.3%). The method seems to be suitable for the clinical monitoring of
      patients treated with quetiapine.

PMID- 12408888
TI  - Determination of diminazene aceturate in pharmaceutical formulations by HPLC and
      identification of related substances by LC/MS.
AB  - A validated, reversed-phase, isocratic high-performance liquid chromatographic
      method for the simultaneous assay of diminazene aceturate, antipyrine (excipient)
      and diminazene impurities in pharmaceutical formulations is described. The
      chromatographic system consisted of a Lichrospher-60 RP-select B column with a
      mobile phase composition of acetonitrile-methanol-ammonium formate (pH 4.0, 20
      mM) (10:10: 80 v/v/v) and UV detection at 254 nm. The method is specific, precise
      and accurate for the determination of diminazene in the presence of its
      manufacturing and degradation impurities with a limit of detection and
      quantification of 50 ng/ml and 10 microgram/ml (RSD<3.0%), respectively. The
      major manufacturing impurity [1-(4 amidino phenyl)3-(4 carbamoyl phenyl)
      triazene] and a degradant (p-aminobenzamidine) of diminazene aceturate have been
      resolved and identified by liquid chromatography/electrospray ionization-mass
      spectrometry operated in a positive ion mode.

PMID- 12408889
TI  - Simple determination of propranolol in pharmaceutical preparations by heavy atom
      induced room temperature phosphorescence.
AB  - The applicability of heavy atom induced room temperature phosphorescence in real
      samples is demonstrated in this work. In this methodology only two reagents,
      potassium iodide as heavy atom salt and sodium sulphite as oxygen scavenger, were
      used to obtain phosphorescent signal of propranolol in solution. Thus a new
      simple, rapid and selective phosphorimetric method is proposed for propranolol
      determination in pharmaceutical preparations. The phosphorescence intensity was
      measured at 492 nm exciting at 294 nm. Phosphorescence was fully developed
      instantly, obtaining a linear concentration range between 0 and 500 ng ml(-1)
      with a detection limit of 14.4 ng ml(-1), an analytical sensitivity of 6.7 ng ml(
      1) and a standard deviation of 1.4% at a 300 ng ml(-1) concentration level. The
      method has been successfully applied to the analysis of propranolol in an
      antidepressive pharmaceutical preparation and it was validated using standard
      addition methodology.

PMID- 12408891
TI  - LC/MS determination of the enaminones E139, DM5 and DM27 in rat serum.
AB  - Enaminones, E139, DM5 and DM27, have been recently recognized as potential
      anticonvulsant compounds. The molecular masses of these enarminones were proven
      using ion trap Finnigan mass spectrometer. For conduction of biological studies
      in animals, a sensitive and selective high-performance liquid chromatography-mass
      spectrometry (LC/MS) was developed for the determination of the selected
      enaminones in rat serum. A simple protein precipitation procedure was followed
      for cleaning up the serum samples before analysis. LC/MS determinations were
      performed using an APCI probe at 430 degrees C. Positive ions (M+1)(+) were
      acquired in MS/MS-SRM mode at m/z 308.1 (parent m/z 340.2) for E139 and m/z 262.1
      (parent m/z 294.1) for DM5. On the other hand, DM27 and E118 (internal standard)
      were measured in SIM mode at m/z 236.5 and 222.5, respectively. Quantitation was
      based on measurement of the peak area ratio of enaminones (E139, DM5, DM27) and
      E118 as an internal standard. Calibration curves were linear (r>0.9989) over the
      concentration range 100-1000 ngml(-1) and were free from serum interference.
      Precision and accuracy studies of control samples showed intra-day and inter-day
      %RSD <10.1 and % deviation from nominal concentrations (%DEV) from -4.3 to +10.1.
      Recoveries of E139, DM5 and DM27 from quality control rat serum samples using
      protein precipitation method were 92.3, 89.4 and 89.6%, respectively. The
      reported data suggest the utility of this developed method for structural
      elucidation and for performing pharmacokinetics studies on the selected
      enaminones in rats.

PMID- 12408890
TI  - Simultaneous LC determination of tiazofurin, its acetyl and benzoyl esters and
      their active metabolite thiazole-4-carboxamide adenine dinucleotide in biological
      samples.
AB  - A rapid and sensitive HPLC-RP method for simultaneous determination of
      tiazofurin, its 5'-O acetyl and benzoyl esters and their active metabolite
      thiazole-4-carboxamide adenine dinucleotide was developed and validated. The
      method allowed determination and quantification of nanomolar quantities of these
      substances in cell extracts of treated cells, and was also used in kinetic
      studies of cellular uptake of tiazofurin and its esters from the cultivation
      medium. Separation of the analyzed substances from unidentified peaks from both
      biological materials was achieved by gradient elution, thus reducing the
      possibility of interference. The mobile phase consisted of a 0.1 M sodium
      hydrogen phosphate, pH 5.1 and methanol. Run time was 22 min, with 5 min
      equilibration time.

PMID- 12408892
TI  - Sensitive determination of nefopam and its metabolite desmethyl-nefopam in human
      biological fluids by HPLC.
AB  - Nefopam (NEF) and desmethyl-nefopam (DMN) were assayed simultaneously in plasma,
      globule and urine samples using imipramine as internal standard. A liquid-liquid
      extraction procedure was coupled with a reverse phase high-performance liquid
      chromatography system. This system requires a mobile phase containing buffer (15
      mM KH(2)PO(4) with 5 mM octane sulfonic acid: pH 3.7) and acetonitrile (77:33,
      v/v) through (flow rate=1.5 ml/min) a C(18) Symmetry column (150x4.6 I.D., 5
      micrometer particle size: Waters) and a UV detector set at 210 nm. Internal
      standard was added to 1 ml of plasma or globule sample or 0.5 ml of urine sample,
      prior to the extraction under alkaline ambiance with n-hexane. The limits of
      quantification were 1 and 2 ng/ml for both molecules in plasma and globule,
      respectively; 5 and 10 ng/ml for NEF and DMN in urine, respectively. The method
      proved to be accurate and precise: the relative error at three concentrations
      ranged from -13.0 to +12.3% of the nominal concentration for all molecule and
      biological fluid; the within-day and between-day precision (relative standard
      deviation %) ranged from 1.0 to 10.1% for all the molecules and biological
      fluids. The method was linear between 1 and 60 ng/ml for both molecules in the
      plasma; 2 and 25 ng/ml for both molecules in the globule; 25 and 250 ng/ml for
      NEF and 50 and 500 ng/ml for DMN in the urine: correlation coefficients of
      calibration curves (determined by least-squares regression) of each molecule were
      higher than 0.992 whatever the biological fluid and during the pre-study and in
      study validations. This method was successfully applied to a bio-availability
      study of NEF in healthy subjects.

PMID- 12408893
TI  - Triiodide ion and alizarin red S as two new reagents for the determination of
      clotrimazole and ketoconazole.
AB  - The reactions of a triiodide ion and alizarin red S with two important antifungal
      drugs containing an imidazole ring (ketoconazole (KC) and clotrimazole (CT)) have
      been studied for the development of two simple, rapid, sensitive and accurate
      indirect titrimetric and extractive-spectrophotometric methods for determining
      the concentration of these drugs. Spectroscopic studies and chemical analysis
      showed that the protonated forms of KC and CT react with triiodide ion forming
      highly stable and insoluble ion-pair products such as (KCH(2))(I(3))(2) and
      (CTH)I(3). Formation of ion-association complexes have been applied to the
      development of an indirect visual titrimetric method for the determination of KC
      and CT over the range 10(-5)-10(-2) M. The extractive-spectrophotometric method
      is based on the formation of (1:1) ion-association complexes between drugs and
      alizarin red S as chromogenic reagent in acidic citrate buffer that are
      extractable into chloroform with an absorption maximum at 425 nm. The system
      obeyed Beer's law in the concentration range 2.5-50 and 2.7-80 microgram ml(-1)
      for CT and KC, respectively. The proposed methods were applied for the analysis
      of the studied drugs in pure forms and their commercial preparations. Results are
      in good agreement with those obtained by official methods.

PMID- 12408894
TI  - Determination of ketoprofen enantiomers in human serum by capillary zone
      electrophoresis: man pharmacokinetic studies after administration of rac
      ketoprofen tablets.
AB  - A rapid and stereospecific capillary zone electrophoresis (CZE) method to
      quantify ketoprofen (KTP) enantiomers was developed. The KTP enantiomers and (+)
      S-naproxen [(+)-S-NPX] as an internal standard (IS) were extracted with methylene
      chloride from serum acidified. Recovery of both enantiomers was in the range of
      85-91%. The enantiomers were determined using a background electrolyte (BGE),
      consisting of 0.05 M heptakis 2,3,6-tri-O-methyl-beta-cyclodextrin (TMbetaCD) in
      a phosphate-triethanolamine buffer, which filled a fused silica capillary of 75
      micrometer i.d. The linear range of calibration curves was between 0.25 and 50 mg
      l(-1), with detection limit of 0.1 mg l(-1) (signal-to-noise baseline ratio (S/N)
      >4). Intra- and interday precision and accuracy of the calibration curves,
      expressed by the coefficient of variation (CV), did not exceed 15.0%. The
      validated method has been successfully applied for pharmacokinetic studies of KTP
      enantiomers from tablets with rac-KTP in man.

PMID- 12408895
TI  - Determination of sugars in Chinese traditional drugs by CE with amperometric
      detection.
AB  - A simple, fast and reliable method, based on capillary zone electrophoresis with
      amperometric detection, for the separation and determination of sucrose, glucose,
      and fructose in Chinese traditional drugs, namely Astragalus Membranceus (Fish.)
      Bge, Angelica and Codonopsis pilosula (Franch.) Nannf. was described in this
      paper. A copper disk electrode was used as working electrode. The optimal
      conditions of separation and detection were 0.05 mol/l sodium hydroxide buffer
      (pH 12.7), 5 kV for the separation voltage and +0.65 V (vs. Ag/AgCl) for the
      detection potential. The linear ranges were from 5.0x10(-6) to 5.0x10(-4) mol/l
      for all three sugars. The all regression coefficients were more than 0.999. The
      detection limits were 1.0x10(-6) mol/l for glucose and fructose, and 4.0x10(-6)
      mol/l for sucrose. The method built in this paper was directly applied to the
      separation and determination of the three sugars in three Chinese traditional
      drugs without prior derivatization, and the content for every sugar in the drugs
      was first assayed. The assay results were satisfactory.

PMID- 12408896
TI  - Direct determination of ranitidine and famotidine by CE in serum, urine and
      pharmaceutical formulations.
AB  - A simple and sensitive capillary electrophoresis method using UV detection has
      been developed for the direct determination of ranitidine (RANT) and famotidine
      (FAMT) in serum, urine and pharmaceutical formulations. A buffer consisting of 60
      mM phosphate buffer adjusted to pH 6.5 was found to provide a very efficient and
      stable electrophoretic system for the analysis of both drugs. The detection
      limits obtained were 0.088 microgram ml(-1) for RANT and 0.16 microgram ml(-1)
      for FAMT.

PMID- 12408897
TI  - Determination of doxorubicin and its metabolites in rat serum and bile by LC:
      application to preclinical pharmacokinetic studies.
AB  - A simple, accurate and precise high-performance liquid chromatographic method was
      developed and validated for the simultaneous determination of doxorubicin and its
      three metabolites, including doxorubicinol, doxorubicinolone and doxorubicinone,
      in rat serum and bile. Following a single protein precipitation step,
      chromatographic separation was accomplished using a C-18 column with a mobile
      phase consisting of 50 mM sodium phosphate buffer-acetonitrile-1-propanol
      (65:25:2, v/v), pH 2.0. The analytes were measured by fluorescence detection with
      excitation wavelength of 480 nm and emission wavelength of 560 nm. The lower
      limits of quantitation were 10 ng/ml for doxorubicin, and 5 ng/ml for the three
      metabolites. The calibration curves were linear over a concentration range of 10
      2500 ng/ml for doxorubicin, and 5-1250 ng/ml for its three metabolites. The
      average recoveries were greater than 89% for all analytes. The within-day and
      between-day coefficients of variation were generally less than 13%. Doxorubicin
      and its metabolites were stable in the precipitated serum and bile samples at
      room temperature in darkness for at least 48 h. This method permitted the
      analysis of samples without the presence of the anticoagulant sodium citrate and
      thus was applied to serum and bile samples collected from rats that were
      administered doxorubicin intravenously in a pharmacokinetic study.

PMID- 12408898
TI  - Monitoring of ampicillin and its related substances by NMR.
AB  - A 1H NMR procedure for the monitoring of ampicillin (Amp) and its main related
      substance in different media, has been developed. The characteristics peak of
      Amp, 6-aminopenicillanic acid (6-APA), phenylglycine (PhG), and penicilloic acid
      in the range of 0.5-0.9 and 3.0-4.5 ppm were used for their identification in
      drugs and serum samples. The quantitative works were performed based on the
      intensity of protons of the methyl group link to the beta-lactam cyclic of Amp
      and 6-APA and the aromatic protons of PhG relative to the protons of methylene
      group of maleic acid, as internal standard, at constant temperature. The
      resulting data are compared with those obtained with an HPLC method proposed by
      British Pharmacopoeia. Statistical studies show that, at a confidence limit of
      %95, there is no significant difference between the two methods. In comparison
      with the HPLC method, the proposed NMR method does not require any sample
      pretreatment, standard solution preparation, long analysis time and use of any
      carcinogenic solvent. The method was applied to the determination of Amp and its
      related substances in synthetic mixtures, drug powders and serum samples.

PMID- 12408899
TI  - 19F NMR spectrometric determination of the partition coefficients of some
      fluorinated psychotropic drugs between phosphatidylcholine bilayer vesicles and
      water.
AB  - A simple 19F NMR spectrometric method was proposed for the determination of the
      partition coefficients of fluorinated psychotropic drugs, trifluoperazine (TFPZ),
      flunitrazepam (FNZ) and flurazepam (FZ) between phosphatidylcholine (PC) bilayer
      of small unilamellar vesicles (SUVs) and water (buffer). Each 19F NMR spectrum of
      these drugs in the presence of PC SUV showed a single signal accompanying a PC
      concentration-depending shift change and broadening, which indicated a fast
      exchange of these drugs between the water phase and the PC bilayer of SUV. From
      the relationship between the 19F chemical shift change (Deltadelta) of each drug
      and the PC concentration, the molar partition coefficients (K(p)'s) were
      calculated and obtained with a good precision of RSD below 6%. The fractions of
      the partitioned drugs calculated by using the obtained K(p)-values were in a good
      agreement with the experimental values. The results demonstrate that the 19F NMR
      method can be usefully applied to the determination of partition coefficients of
      many drugs having fluorine atom(s) without any separation procedure, especially
      for drugs which do not have absorption in the ultraviolet or visible region, or
      those having absorption but show insignificant spectral changes according to
      their incorporation to PC bilayers (e.g. FNZ).

PMID- 12408900
TI  - Analysis of beta-lactam antibiotics by high performance liquid chromatography
      atmospheric pressure chemical ionization mass spectrometry using bromoform.
AB  - The novel identification method for a heat-unstable antibiotic, FC/TA-891 and its
      active metabolite (FCE22101) by high-performance liquid chromatography (HPLC)
      atmospheric pressure chemical ionization mass spectrometry (APCI-MS) employing
      bromoform as an ionization acceleration solvent, was applied to eight penicillins
      and 13 cephalosporins which are groups of beta-lactam antibiotics. The conditions
      of HPLC-APCI-MS were examined with ampicillin. Bromoform or chloroform was added
      to the mobile phase in HPLC to compare the difference between bromine and
      chlorine adducted ions. For all penicillins except sulbenicillin, both chlorine
      adducted and bromine adducted ions were observed with a flow injection method.
      The results indicated that the relative sensitivity ratios of bromine adducted
      ions to [M-H](-) were higher than those of chlorine adducted ions. These bromine
      adduct ions could be clearly distinguished from other ions due to its isotopical
      ratio (1:1), leading to an easy identification of the compounds. For 13
      cephalosporins, bromine adducted ions were detected in nine compounds, and
      chlorine adducted ions were detected in four compounds. The separation of four
      antibiotics was investigated with an HPLC column to apply this technique to the
      actual analysis. The capability was equal as in the flow injection method and it
      found that this technique, i.e. APCI-MS with bromoform could be applicable in the
      separation analysis.

PMID- 12408901
TI  - Determination of the antibacterial ofloxacin in human urine and serum samples by
      solid-phase spectrofluorimetry.
AB  - A method for the determination of trace amounts of ofloxacin has been developed,
      based on solid-phase spectrofluorimetry. The relative fluorescence intensity of
      ofloxacin fixed on Sephadex SP C-25 gel was measured directly after packing the
      gel beads in a 1-mm silica cell, using a solid-phase attachment. The wavelengths
      of excitation and emission were 294 and 494 nm, respectively. The linear
      concentration range of application was 0.5-16.0 ng ml(-1) of ofloxacin, with a
      relative standard deviation of 1.1% (for a level of 8.0 ng ml(-1)) and a
      detection limit of 0.14 ng ml(-1). The method was applied to the determination of
      ofloxacin in human urine and serum samples. It was validated applying the
      standard addition methodology and using HPLC as a reference method. Recovery
      levels of the method reached 100% in all cases.

PMID- 12408902
TI  - Quantitative determination of polymorphic composition in intact compacts by
      parallel-beam X-ray powder diffractometry.
AB  - This paper details the development of a method using parallel-beam X-ray powder
      diffractometry as a novel means of determining polymorphic composition in intact
      compacts. Two polymorphic systems, chlorpropamide and glycine, were selected. The
      polymorphic components were weighed, mixed, and compressed using a Carver press
      with 3/8-in. concave tooling. The compacts were then analyzed using parallel-beam
      X-ray powder diffractometry in transmission geometry. The data were processed
      using the profile-fitting module in the Shimadzu XRD-6000 software V 4.1 (for NT
      4.0/98). The integrated intensity ratio of a selected peak for each crystal form
      was used for quantitation of each polymorph. Excellent linear correlation was
      observed for both polymorphic systems. The convex shape of the compact surface
      had no effect on the XRD patterns. Since parallel-beam X-ray diffractometry is
      not sensitive to the shape of the sample surface, it provides a simple method for
      quantifying polymorphs in intact compacts. Further work to extend this to
      formulated tablets is ongoing. The relatively larger variation in one of the
      peaks in the chlorpropamide study was found to be consistent with the
      computational analysis of the slip behavior of the stable polymorph. This method
      provides the first reported non-invasive X-ray diffraction pattern quantitation
      of crystal forms in intact compacts.

PMID- 12408903
TI  - Simultaneous determination of amiloride hydrochloride and hydrochlorothiazide in
      synthetic samples and pharmaceutical formulations by multivariate analysis of
      spectrophotometric data.
AB  - The use of multivariate spectrophotometric calibration for the simultaneous
      analysis of synthetic samples and commercial tablet preparations containing
      hydrochlorothiazide (HCT) and amiloride hydrochloride (AMH) is reported. Partial
      least squares (PLS-1) analysis of electronic absorption spectral data allowed the
      rapid and accurate resolution of mixtures in which the analyte ratios were
      approximately 10:1, without the need of a previous separation step and without
      interference from other sample constituents. The method, validated by the
      analysis of synthetic mixtures of both drugs, where accuracy over the linear
      working range as well as inter- and intra-assay precision were determined, was
      used in the concentration ranges of 21.7-30.4 mg l(-1) for HCT and 1.8-3.0 mg l(
      1) for AMH. The proposed method was successfully applied to the evaluation of the
      stability of the stock solutions of the analytes in MeOH-H(2)O and to the
      elaboration of drug dissolution profiles of commercial tablets, results being
      concordant with those furnished by the USP technique. The method was also
      employed for the determination of drug content in two different pharmaceutical
      formulations, providing results that were in excellent agreement with those
      obtained by HPLC.

PMID- 12408904
TI  - Spectrophotometric determination of omeprazole, lansoprazole and pantoprazole in
      pharmaceutical formulations.
AB  - The compensation method and other chemometric methods (derivative, orthogonal
      function and difference spectrophotometry) have been applied to the direct
      determination of omeprazole, lansoprazole and pantoprazole in their
      pharmaceutical preparations. The methods have been validated; the limits of
      detection were found to be 3.3x10(-2), 3.0x10(-2) and 3.5x10(-2) microgram ml(-1)
      for the three drugs, respectively. The repeatabililty of the methods were found
      to be 0.3-0.5%. The linearity ranges were found to be 0.5-3.5 microgram ml(-1).
      The proposed methods have been applied to the determination of the three drugs in
      their grastro-resistant formulations. The difference spectrophotometric (DeltaA)
      method is unaffected by the presence of acid induced degradation products; hence
      can be used as a stability indicating assay.

PMID- 12408905
TI  - Quantitative and structural determination of pseudoephedrine sulfate and its
      related compounds in pharmaceutical preparations using high-performance liquid
      chromatography.
AB  - A simple isocratic reversed-phase high performance liquid chromatograghic method
      for the separation of pseudoephedrine and its related compounds in pharmaceutical
      formulations is described. The separation is achieved in less than 35 min on a C
      18 column (4.6 mm I.D. x 25 cm length, 5-micrometer particle size) using a mobile
      phase consisting of a mixture of ammonium acetate and methanol. The results
      described in this report demonstrate that the method is sensitive and selective.
      Structural elucidation of two new pseudoephedrine degradation products is
      described. On the basis of structural analysis by liquid chromatography-mass
      spectrometry (LC-MS) and liquid chromatography-nuclear magnetic resonance
      spectroscopy (LC-NMR), the two newly elucidated degradation products were
      identified to be 2-(carboxyamino)propiophenone (molecular ion of m/z=194) and 2
      formyl-2-(methylamino)-acetophenone (molecular ion of m/z=178).

PMID- 12408906
TI  - LC-MS/MS determination of a farnesyl transferase inhibitor in human plasma and
      urine.
AB  - To support clinical pharmacokinetic studies in cancer patients, sensitive and
      specific methods for measuring 4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-1-(3
      chlorophenyl) piperazinone (I), a farnesyl transferase inhibitor (FTI), in human
      plasma and urine were developed and validated. The methods are based on high
      performance liquid chromatography (HPLC) with atmospheric pressure chemical
      ionization (APCI) and tandem mass spectrometric (MS/MS) detection in the positive
      ion mode using a heated nebulizer interface. Drug and internal standard were
      isolated from plasma or basified urine using automated solid-phase extraction on
      cyano cartridges. The organic extracts were dried, reconstituted in aqueous
      acetonitrile and injected into the system. Chromatographic separation of I and
      internal standard (IS) was achieved using a BDS Hypersil C8 analytical column,
      with a mobile phase consisting of acetonitrile:methanol:water (50:4:46) and
      trifluoroacetic acid (0.05%) at a flow rate of 0.6 ml/min. MS/MS detection was
      performed on a PE-Sciex API 300 tandem mass spectrometer operated in selected
      reaction monitoring mode. The parent-->product ions monitored were m/z 406-->195
      for analyte I and m/z 448-->195 for the internal standard. Unusual in this method
      is that quantitation is accomplished using a secondary product ion, m/z 195, of
      drug I and IS. The assays were validated over the concentration range of 0.5-1000
      ng/ml (1.2 nM to 2.5 microM, respectively) in plasma, and 2.5-500 ng/ml (6.2 nM
      to 1.23 microM) in urine. Accuracy was within +/-10% of nominal concentration at
      all levels in urine, and all but the lowest standard in plasma (+/-14% at 0.5
      ng/ml). Intraday precision (expressed as coefficients of variation, CVs) for
      standard replicates and interday precision for quality control (QC) samples were
      less than 8% at all concentrations in both matrices. Detailed descriptions of the
      extraction procedure and analytical methodology used in the assay of I in plasma
      and urine are presented. This procedure may have utility in the quantitation of
      other imidazole-based FTIs with cyanobenzyl substructures.

PMID- 12408907
TI  - Assessment of solid-state interactions of naproxen with amorphous cyclodextrin
      derivatives by DSC.
AB  - A microcalorimetric method based on differential scanning calorimetry (DSC) of
      drug-additive binary systems to assess kneading-induced interactions was applied
      to naproxen (NAP) in combinations with amorphous hydroxypropyl beta-cyclodextrin
      (HPbetaCd), beta-cyclodextrin sulfobutyl ether, sodium salt ((SBE)(7m)-betaCd),
      acetyl beta-cyclodextrin (AcbetaCd) and acetyl gamma-cyclodextrin (AcgammaCd).
      Modifications of thermal parameters of NAP in DSC curves of physical mixtures
      indicate heating-induced interactions which resulted in a broadening of the NAP
      melting endotherm in the combinations with HPbetaCd, AcbetaCd and AcgammaCd. The
      effect of kneading on the interaction was particularly pronounced for the NAP
      HPbetaCd and NAP-(SBE)(7m)-betaCd systems, which show a similar drug-to-carrier
      interaction ratio (1:2 by weight) as that of the other systems. Drug-to-carrier
      ratios, calculated considering the amount of NAP which recrystallizes from the
      melted mixtures equivalent to NAP not bound to the carrier, show a distinctly
      lower affinity in solid-state of the drug for the anionically charged (SBE)(7m)
      betaCd with respect to other neutral carriers. The similar affinity of NAP for
      AcbetaCd and AcgammaCd demonstrates that the geometry of the cavity, which is a
      determinant factor for the inclusion complexation in liquid state, does not
      influence the interaction process in solid-state.

PMID- 12408908
TI  - Comparative studies of the influence of cyclodextrins on the stability of the
      sunscreen agent, 2-ethylhexyl-p-methoxycinnamate.
AB  - The effects of beta-cyclodextrin (beta-CD) and hydroxypropyl-beta-cyclodextrin
      (HP-beta-CD) on the base-catalyzed degradation and light-induced decomposition of
      the sunscreen agent, trans-2-ethylhexyl-p-methoxycinnamate (trans-EHMC) were
      investigated. Reversed-phase liquid chromatography was used to study the
      interaction between natural and modified cyclodextrins, added to the mobile
      phase, and the sunscreen. Among the available cyclodextrins (beta-CD, HP-beta-CD,
      hydroxypropyl-alpha-cyclodextrin and hydroxypropyl-gamma-cyclodextrin), only HP
      beta-CD and beta-CD produced a significant decrease in the chromatographic
      retention of trans-EHMC. The complexation of the sunscreen agent with HP-beta-CD
      and beta-CD was confirmed by thermal analysis and nuclear magnetic resonance
      spectroscopy. beta-CD depressed the decomposition of trans-EHMC in alkaline
      solutions more effectively than HP-beta-CD. Moreover, the irradiation-induced
      degradation of the sunscreen agent in emulsion vehicles was reduced by
      complexation with beta-CD (the extent of degradation was 26.1% for the complex
      compared to 35.8% for free trans-EHMC) whereas HP-beta-CD had no significant
      effect. Therefore, the complex of beta-CD with trans-EHMC enhances the chemical-
      and photo-stability of the sunscreen agent. Moreover, it limits adverse
      interactions of the UV filter with other formulation ingredients.

PMID- 12408909
TI  - Spectrofluorometric determination of labetolol in pharmaceutical preparations and
      spiked human urine through the formation of coumarin derivative.
AB  - A simple, sensitive and specific spectrofluorimetric method has been developed
      for the determination of labetalol (LBT). The method is based on the reaction
      between LBT and ethylacetoacetate in the presence of sulphuric acid to give
      yellow fluorescent product with excitation wavelength of 312 nm and emission
      wavelength of 432 nm. The reaction conditions were studied and optimized. The
      fluorescence intensity-concentration plot is rectilinear over the range 1-15
      microgram/ml with minimum detectability limit of 0.8 microgram/ml (2.16 x 10(-6)
      M). The proposed method was successfully applied to commercial tablets containing
      LBT, the percentage recoveries agreed well with those obtained using the official
      methods. Hydrochlorothiazide, which is frequently co-formulated with LBT did not
      interfere with the assay. The method was further extended to the in-vitro
      determination of LBT in spiked human urine samples. The percentage recovery was
      101.50+/-6.18 (n=6). A proposal of the reaction pathway was postulated.

PMID- 12408910
TI  - Derivation of system suitability test limits from a robustness test on an LC
      assay with complex antibiotic samples.
AB  - A System Suitability Test (SST) is a test to verify the adequate working of the
      equipment used for analytical measurements. In pharmaceutical analysis, SSTs are
      performed at least at the beginning of a series of routine analyses. The most
      generally applied SST considers the precision of the analysis, i.e. the
      repeatability standard deviation must not exceed a predefined value.
      Additionally, a SST can also consider responses indicative for the quality of the
      technique used, e.g. resolutions between peaks or peak asymmetry in high
      performance liquid chromatography. The system is then only declared suitable if
      the response is within given limits. However, it is not always evident how to
      define the SST limits to be fulfilled for a newly developed method. Robustness
      tests have been proposed as a starting point in a strategy to deduce these
      limits. Here, it is examined how such a strategy can be applied for complex
      samples of microbial origin.

PMID- 12408911
TI  - Simultaneous LC determination of trimethoprim and sulphamethoxazole in
      pharmaceutical formulations.
AB  - In the present study, a simple, sensitive, precise and rapid reversed-phase high
      performance liquid chromatographic (HPLC) method with ultraviolet detection for
      the simultaneous analysis of trimethoprim (TMP) and sulphamethoxazole (SPM) is
      developed and applied to the determination in commercial pharmaceutical
      preparations. These compounds are well separated on a Bondapak C(18) reverse
      phase column using a mobile phase consisted of a mixture of methanol:water
      (60:40; v/v) adjusted to pH 3 with 10% orthophosphoric acid at a flow rate of 1.8
      ml min(-1). The proposed method was linear in the range 2.0-10.0 microgram ml(-1)
      for TMP and 10.0-50.0 microgram ml(-1) for SPM. The limit of detection were 0.45
      and 1.21 microgram ml(-1) for TMP and SPM, respectively. The method which is
      rapid, simple and does not require any separation step, has been successfully
      applied to the assay of commercial tablet and oral suspension dosage forms
      containing TMP and SPM.

PMID- 12408912
TI  - Electrochemical behaviour and determination of acrivastine in pharmaceuticals and
      human urine.
AB  - The differential pulse polarography, DC-tast polarography and cyclic voltammetry
      behaviour of acrivastine was studied in Britton-Robinson buffer solutions (pH 2
      11.7). In acidic media, a non-reversible diffusion controlled reduction process
      involving four electrons takes place. Two reduction waves appear at a E(1/2)=-0.6
      and -0.99 V. The reduction mechanism is discussed. The linear relationship
      between peak current height and acrivastine concentration allowed the
      differential pulse polarographic determination of acrivastine over a wide
      concentration range, from 0.35 to 26.1 mg l(-1)at pH 2.5. The procedure was
      applied to determination of the drug in pharmaceutical formulations and human
      urine samples.

PMID- 12408913
TI  - Infrared imaging of laser-induced heating during Raman spectroscopy of
      pharmaceutical solids.
AB  - Raman spectroscopy is finding increasing popularity as an analytical technique
      for the analysis of pharmaceutical powders and solid dosage forms. It is well
      known that illumination by the high intensity lasers used in Raman spectrometers
      can result in sample heating, however, the extent of the problem has not been
      assessed for pharmaceutically relevant materials. Using direct thermal imaging of
      compressed powders, the extent of heating for microcrystalline cellulose (MCC),
      vanillin, ibuprofen and stearic acid was measured as a function of laser
      intensity. MCC was found to be the most susceptible to sample heating while
      ibuprofen was least sensitive. At high laser powers (1.5 W), samples were heated
      by between 38 and 60 degrees C while at more moderate laser powers (0.7 W) the
      degree of heating was between 20 and 30 degrees C. The kinetics of the heating
      process were mathematically modeled for MCC and the derived constants were used
      to predict the rotation speed necessary to prevent a solid state transition in a
      heat sensitive compound, theophylline monohydrate. Experimental measurements at
      different rotation speeds verified that the estimated rotation speed reduced
      sample heating by the desired amount. In conclusion, the extent of heating is
      clearly of some concern for pharmaceutical materials but can be substantially
      reduced by sample rotation.

PMID- 12408914
TI  - Use and validation of NMR assays for the identity and O-acetyl content of
      capsular polysaccharides from Neisseria meningitidis used in vaccine manufacture.
AB  - We describe a validated NMR (nuclear magnetic resonance) spectroscopic assay for
      the identity of the capsular polysaccharides (CPSs) from Neisseria meningitidis
      Groups A, C, W135 and Y used in vaccine manufacture, and to determine the
      proportion of residues carrying an O-acetyl substituent. Proof of structural
      identity and quantitation of the O-acetyl content are key control parameters for
      these vaccines. The meningococcal CPSs have variable levels of O-acetylation,
      present at multiple sites in the repeat unit, leading to complex NMR spectra.
      Base-catalysed de-O-acetylation of the Groups A, C, W135 and Y CPSs yields
      simplified and reproducible spectra suitable for comparison with reference data.
      The degree of O-acetylation of the original CPS can be determined by integration
      of the acetate anion resonance and a suitable resonance from the saccharide
      moiety. The assay was validated using 46 independent samples from five
      manufacturers, and is shown to be robust and reproducible.

PMID- 12408915
TI  - A high performance liquid chromatography method for simultaneous determination of
      albendazole metabolites in human serum.
AB  - A simple assay for albendazole (ABZ) main metabolites-albendazole sulphoxide (ABZ
      SO), albendazole sulphone (ABZ-SO(2)) and albendazole amino sulphone (ABZ-SO(2)
      NH(2))-in serum using high performance liquid chromatography was developed. The
      method involves liquid-liquid extraction of the serum by ethyl acetate, clean up
      with n-hexane and re-extraction with ethyl acetate, followed by separation on RP
      C(8) column with a mixture of methanol: acetonitrile: acetic acid: water
      (40:1:10:49) as the eluting solvent. ABZ-SO and mebendazole-used as internal
      standard-were detected by UV (lambda=286 nm), and ABZ-SO(2) and ABZ-SO(2)-NH(2)
      with fluorescence spectrophotometer at (Excitation=286 nm, Emission=333 nm) and
      (Excitation=286 nm, Emission=315 nm), respectively. The assay was accurate and
      reproducible with a detection limit of 10 ng/ml for ABZ-SO, 2 ng/ml for ABZ-SO(2)
      and 4 ng/ml for ABZ-SO(2)-NH(2). Disregarding ABZ determination, which is not of
      pharmacokinetic importance as it is not found in human plasma after oral
      administration, the proposed method is appropriate for further pharmacokinetic
      and metabolism study of this drug.

PMID- 12408916
TI  - Simultaneous determination of dexamethasone and trimethoprim by liquid
      chromatography.
AB  - A reverse phase high performance liquid chromatography (HPLC) method to determine
      dexamethasone phosphate and trimethoprim is described in this paper. The
      separation was made in a LichrCART(R) C18 column using an acetonitrile
      NaH(2)PO(4) (10 mM) (70:30, v/v) (pH 3) buffer solution as mobile phase. The
      mobile-phase flow rate and the sample volume injected were 1 ml/min and 20
      microliter, respectively. The limits of quantification were about 0.25 mg/l for
      each compound. The method was applied in synthetic mixtures and in pharmaceutical
      formulations. Analyses were made by preparing test (from the stock solution)
      method whose results were compared with those obtained by means of the standard
      addition method. Both methods showed similar results, and then it was proved that
      some pharmaceuticals claimed levels were in agreement with the obtained results
      by using our analytical method.

PMID- 12408917
TI  - Evaluation of essential parameters in the chromatographic determination of
      cyclosporin A and metabolites using a D-optimal design.
AB  - The extensive use of routine monitoring of cyclosporin A (INN, ciclosporin) whole
      blood levels of patients undergoing such therapy has resulted in a wide variety
      of chromatographic conditions for analysing this drug. The aim of this study was
      to evaluate the importance of essential parameters in the chromatographic
      determination of cyclosporin A and its main metabolites, AM1, AM9 and AM4N. A D
      optimal design was used to evaluate the effect of type and amount of organic
      modifier, temperature, flow rate, pH and gradient steepness. The optimal
      chromatographic conditions were determined by multi-linear regression. In the
      final chromatographic method separation of the compounds was carried out on a
      reversed phase C(8) column maintained at 80 degrees C. The mobile phase consisted
      of a linear gradient with two mobile phases containing acetonitrile and water.
      The flow rate was set at 0.8 ml/min. UV detection was carried out at 214 nm.
      Validation of the analytical method showed linearity over the range 25-1000 ng/ml
      (r>0.997). The detection limits of cyclosporin A, AM1, AM9 and AM4N were 1.3 pmol
      on column. The within-day and between-day relative standard deviations were <15%
      for cyclosporin A at all concentrations and for the metabolites at 250 and 1000
      ng/ml, and <21% for the metabolites at limit of quantification (25 ng/ml).

PMID- 12408918
TI  - LC determination of moclobemide and three metabolites in plasma.
AB  - Moclobemide and three metabolites were quantified using 1 ml of plasma and solid
      phase extraction with Bakerbond CN column after the addition of nadolol as the
      internal standard (I.S.). Separation and detection the analysed substances were
      achieved isocratically with acetonitrile-methanol-0.067 M phosphate buffer pH
      2.65-0.4% triethylamine (12.7:1.9:85:0.4, v/v/v/v), a Nova-pak C(8) column and UV
      detection at 230 nm. The lower limits of quantitation for moclobemide was 10 ng
      ml(-1), for M1 (Ro 16-3177)-8 ng ml(-1), for M2 (Ro 12-5637)-10 ng ml(-1) and for
      M3 (Ro 12-8095)-15 ng ml(-1) (as the metabolites). Accuracies calculated of three
      concentrations in each of three separate runs were between 84.55 and 93.68 for
      moclobemide, 83.28 and 92.30 for M1, 86.31 and 92.66 for M2 and 88.42 and 93.40
      for M3. Precision data within day were between 5.71 and 7.50 for moclobemide,
      2.91 and 6.58 for M1, 4.98 and 6.40 for M2 and 0.94 and 4.73 for M3.

PMID- 12408919
TI  - Photostability profiles of the experimental antimetastatic ruthenium complex NAMI
      A.
AB  - NAMI-A is a novel ruthenium complex with selective activity against metastases
      currently in Phase I clinical trials in The Netherlands. The photostability of
      this new agent in solid state and in solution has been investigated utilizing a
      stability-indicating reversed-phase high performance liquid chromatographic
      (HPLC) assay and ultraviolet/visible (UV/VIS) light spectrophotometry. In solid
      state, NAMI-A proved to be photostable. In solution, however, the compound
      degraded rapidly, in a pH-independent manner in the pH range of 2-5. At alkaline
      pH, the degradation rate was higher than at acidic pH. The type of buffer species
      had little influence. NAMI-A concentration was inversely related to the
      photostability. Addition of photostabilizers (5% DMSO, 2% benzyl alcohol, 0.001%
      curcumin) marginally increased the half-life. NAMI-A's photostability in solution
      was influenced to the greatest extent by addition of an alcohol, with the least
      polar solvent system (50% propylene glycol) providing the most stable medium.
      Based on the presented results, it is recommended to store NAMI-A solutions in
      the dark.

PMID- 12408920
TI  - Optimisation of collection, storage and preparation of rat plasma for 1H NMR
      spectroscopic analysis in toxicology studies to determine inherent variation in
      biochemical profiles.
AB  - Biofluid 1H NMR spectroscopy has been assessed as a tool for toxicological
      investigations for almost two decades, with most studies focussing on urinary
      changes. This study has examined variations in the 1H NMR spectroscopy spectra of
      plasma collected from control rats at different times of the day. The collection,
      preparation and storage of samples were optimised and potential sources of
      variation in samples taken for toxicology studies identified. Plasma samples were
      collected into heparinised containers and analysed following a standard dilution
      with D(2)O. The value of deproteinising plasma with acetonitrile to look at low
      molecular weight metabolites has also been assessed. Variations in lactate and
      citrate levels in whole blood plasma were found and are consistent with the
      observation that lactate is one of the most variable metabolites in human plasma.
      Lipids levels also varied, in particular higher levels of lipids were found in
      spectra from male rats compared to female rats, and in samples collected in the
      morning following the feeding period. No significant changes were identified in
      samples which were snap-frozen and stored for up to 9 months at -80 degrees C.
      More changes were observed after storage at 4 degrees C or room temperature,
      including an increase in glycerol and choline levels, which may have resulted
      from lipid hydrolysis.

PMID- 12408921
TI  - Direct determination of praziquantel in pharmaceutical formulations and human
      plasma by cathodic adsorptive stripping differential-pulse voltammetry.
AB  - The polarographic and cyclic voltammetric behaviour of praziquantel was studied
      in B.R. buffers of different pH values. Contradictory to that mentioned in a
      previously published work, praziquantel is an electro-active compound. Its
      polarogram exhibited a single 2-electron irreversible reduction wave in B.R.
      buffer of pH 5, the wave height decreased on the increase of pH till it
      disappeared in solution of pH >7. This wave was attributed to the reduction of
      the Cz.dbnd6;O double bond. The quantitative trace determination of bulk
      praziquantel was studied at a hanging mercury drop electrode by cathodic
      adsorptive stripping differential-pulse voltammetry. A fully validated sensitive
      procedure based on controlled adsorptive accumulation of the drug onto a HMDE was
      developed for its direct determination without derivatization. Accumulation of
      praziquantel was found to be optimized in 0.1 M Na(2)SO(4) solution as supporting
      electrolyte under the following conditions: accumulation potential, -1.2 V (vs.
      Ag/AgCl/KCl(s)); accumulation time, 30 s; scan rate, 10 mV/s and pulse height 100
      mV. The proposed procedure was applied successfully for determination of
      praziquantel in its pharmaceutical formulations and human plasma. The mean
      recoveries of the drug were 98.85-99.42% and 99.12-100.47% with RSD of 0.49-0.95%
      and 0.45-0.52% in pharmaceutical formulations and human plasma, respectively.
      Limits of detection and quantitation of 1.14x10(-9) and 3.80x10(-9) M
      praziquantel, respectively, were achieved.

PMID- 12408922
TI  - Determination of bioequivalence of lomefloxacin tablets using urinary excretion
      data.
AB  - The present study describes development of a sensitive and simple HPTLC method
      for estimation of lomefloxacin (LMF) in human urine. The drug was extracted using
      chloroform after adjusting the pH of urine to 7.0. Chloroform extract was spotted
      on silica gel 60 F(254) TLC plate and was developed in a mixture of n-butanol
      methanol-ethyl acetate-6 M ammonia (4:2:3:2, v/v/v/v) as the mobile phase and
      scanned at 290 nm. The peak for LMF resolved at R(F) of 0.40+/-0.02. The method
      was validated in terms of linearity (50-600 microgram/ml), precision, specificity
      and accuracy. The limit of detection and limit of quantification for LMF in urine
      were found to be 20 and 50 microgram/ml, respectively. The average recovery of
      LMF from urine was 91.93%. The proposed method was applied to generate urinary
      excretion data for LMF after administration of two market LMF tablet formulations
      (400 mg, Formulation R and Formulation T) to six healthy human volunteers in a
      two-treatment, open, crossover design. Various pharmacokinetic parameters like
      peak excretion rate ((dAU/dt)(max)), time for peak excretion rate (t(max)), AUC(0
      48), AUC(0- infinity ), cumulative amount and % cumulative amount of LMF
      excreted, elimination half-life (t(1/2)), terminal elimination rate constant
      (k(el)) and overall elimination rate constant (K), were calculated for both the
      formulations. The average cumulative amounts of LMF excreted in urine after
      administration of Formulation R and Formulation T were found to be 321.60 mg
      (80.40% of dose) and 296.51 mg (74.13% of dose), respectively. The urinary
      excretion profiles of LMF upto 48 h for both the formulations were found to be
      similar. Statistical comparison (90% confidence intervals of ratio) of various
      pharmacokinetic parameters of Formulation T with that of Formulation R revealed
      that Formulation T is bioequivalent with Formulation R.

PMID- 12408923
TI  - Determination of capsaicinoids in topical cream by liquid-liquid extraction and
      liquid chromatography.
AB  - A reversed-phase liquid chromatography (LC) method has been developed, optimised
      and validated for the separation and quantitation of capsaicin (CP) and
      dihydrocapsaicin (DHCP) in a topical cream formulation. Sample preparation
      involves liquid-liquid extraction prior to LC analysis. The method uses a
      Hypersil C(18) BDS, 5 micrometer, 250x4.6 mm I.D. column maintained at 35 degrees
      C. The mobile phase comprises methanol, water, acetonitrile (ACN) and acetic acid
      (47:42:10:1, v/v/v/v) at a flow rate of 1.0 ml/min. Robustness was evaluated by
      performing a central composite face-centred design (CCF) experiment. The method
      shows good selectivity, linearity, sensitivity and repeatability. The conditions
      allow the separation and quantitation of CP and DHCP without interference from
      the other substances contained in the cream.

PMID- 12408924
TI  - Electrochemical biosensor for the interaction of DNA with the alkylating agent
      4,4'-dihydroxy chalcone based on guanine and adenine signals.
AB  - The interaction of an alkylating agent, 4,4'-dihydroxy chalcone (DHC) with calf
      thymus double stranded DNA (dsDNA) and calf thymus single stranded DNA (ssDNA)
      was studied electrochemically based on the oxidation signals of guanine and
      adenine by using differential pulse voltammetry (DPV) at carbon paste electrode
      (CPE). As a result of the alkylation of DHC between the base pairs in dsDNA, the
      voltammetric signal of guanine and adenine greatly decreased. After the
      interaction of DHC with ssDNA, a higher decrease in the oxidation signals of
      guanine and adenine was observed under the same conditions. The partition
      coefficients of DHC at dsDNA and ssDNA modified CPEs were calculated. The
      interactions of DHC with synthetic polynucleotides, such as polyguanylic acid and
      polyadenylic acid were also observed. In addition, the detection limit and the
      reproducibility were determined by using DPV. The interaction of DHC with dsDNA
      in solution-phase was also investigated and the results were compared with the
      ones obtained by surface immobilized dsDNA. The application of electrochemical
      DNA biosensor for monitoring the DNA-alkylating agent interactions was explored.

PMID- 12408925
TI  - Colorimetric determination of beta-blockers in pharmaceutical formulations.
AB  - A simple, accurate, precise and sensitive colorimetric method for the
      determination of some beta-blockers as atenolol (Ateno), metoprolol (Metop),
      sotalol (Sot) and nadolol (Nad) is described. This method is based on the
      formation of charge transfer complex with 4-chloro-7-nitro-2,1,3-benzoxadiazole
      (NBD-Cl) in methanolic-aqueous (for Ateno and Metop) or acetone-aqueous (for Sot
      and Nad) medium [30% (v/v)]. The orange color products are measured at 485, 470,
      465 and 462 nm for Ateno, Metop, Sot and Nad, respectively. The optimization of
      various experimental conditions is described. Beer's law is obeyed in the range
      0.4-60 microgram ml(-1) while that obtained applying Ringbom is 0.8-56 microgram
      ml(-1). The molar absorptivity, Sandell sensitivity, detection and quantification
      limits are calculated. The results obtained showed good recoveries of 99.5+/-1.1,
      100.3+/-1.2, 100.5+/-1.0 and 99.3+/-1.1% with relative standard deviations of
      0.74, 0.98, 1.15 and 0.87% for Ateno, Metop, Sot and Nad, respectively.
      Applications of the proposed method to representative pharmaceutical formulations
      are successfully presented.

PMID- 12408926
TI  - Simultaneous determination of ibuprofen and hydroxypropylmethylcellulose (HPMC)
      using HPLC and evaporative light scattering detection.
AB  - Ibuprofen may be crystallised in the presence of hydroxypropylmethylcellulose
      (HPMC) to improve its physical properties. This, however, creates problems with
      the simultaneous analysis of each ingredient. The analytical method developed
      utilised high performance liquid chromatography (HPLC) with a stationary phase
      designed for carbohydrate separation (GylcoSep N) and a mobile phase comprising
      methanol and water. Evaporative light scattering detection (ELSD) proved a
      suitable method for the analysis of both HPMC and ibuprofen. Data showed that
      HPMC and ibuprofen could be quantified in each other's presence. Validation
      studies indicated that the method was adequately accurate and precise. Baseline
      resolution was achieved between the two components. HPMC (1.1% w/w) was retained
      in ibuprofen crystals obtained from alcoholic HPMC suspensions.

PMID- 12408927
TI  - Determination of taltirelin, a new stable thyrotropin-releasing hormone analogue,
      in human plasma by high-performance liquid chromatography turbo-ionspray
      ionization tandem mass spectrometry.
AB  - A rapid, selective and sensitive assay of taltirelin, a novel thyrotropin
      releasing hormone analogue, in human plasma has been developed. This method is
      based on a rapid sample preparation and high-performance liquid chromatography
      (HPLC) turbo-ionspray ionization tandem mass spectrometry (MS-MS). Analytes were
      purified from human plasma by SPE cartridge and separated by gradient HPLC. Turbo
      ionspray ionization and MS-MS analyses were carried out by PE-Sciex API 3000
      tandem mass spectrometer. Taltirelin was separated from its metabolite (acid
      form) on a semi-micro ODS column in methanol - 0.1% (v/v) formic acid. The
      selected reaction monitoring by precursor-->product ion combination of m/z 406-
      >264, was used for determination of taltirelin. The linearity was confirmed in
      the concentration range of 17-4137 pg/ml in human plasma, and the precision of
      this assay, expressed as a relative deviation, was less than 9.8% over the entire
      concentration range with adequate assay accuracy. The results obtained by the
      HPLC-MS-MS method correlated well with those of the radioimmunoassay method
      reported previously. Therefore, the HPLC-MS-MS method is useful for the
      determination of taltirelin with sufficient selectivity and sensitivity on
      pharmacokinetic studies in human.

PMID- 12408928
TI  - Determination of the 5-fluorouracil and N1(2'-furanidyl)uracil in the presence of
      tegafur by zero-crossing first derivative spectrometry.
AB  - A first derivative spectrometric method has been developed for the determination
      of the 5-fluorouracil and N1(2'-furanidyl)uracil related substances and
      degradation products of tegafur. The wavelengths selected for the determination
      of 5-fluorouracil and N1(2'-furanidyl)uracil were 298 and 288 nm, respectively.
      At this wavelength, the calibration graphs between the amplitude of the signals
      and the concentration of each compound were linear up to 24.75 mg l(-1) for 5
      fluorouracil and up to 20.20 mg l(-1) for N1(2'-furanidyl)uracil. The detection
      limits were 0.40 and 0.050 mg l(-1) for 5-fluorouracil and N1(2'
      furanidyl)uracil, respectively. The method is simple and rapid and does not
      require any preliminary treatment of the sample. The method was validated.

PMID- 12408929
TI  - A new second-derivative spectrophotometric method for the determination of
      permethrin in shampoo.
AB  - Permethrin, a highly effective insecticide agent, has been widely used for the
      pest control in agriculture and the treatment of lice in human. A fast and
      reliable method for the determination of permethrin was highly desirable to
      support formulation screening and quality control. A second-derivative UV
      spectroscopic method was developed for the determination of permethrin in the
      shampoo dosage form after extraction. The second-derivative spectrum recorded
      between 250 and 310 nm, and a zero-crossing technique for second-derivative
      measurement at 279 nm was selected. It is found that the selectivity and
      sensitivity of the method to be in desirable range. In comparison with the direct
      UV method, second-derivative UV spectroscopy eliminates the interference from UV
      absorbing excipients. This method is also fast and economical in comparison with
      the more time-consuming GC method regularly used for formulation screening and
      quality control and can be used routinely by any laboratory possessing a
      spectrophotometer with a derivative accessory. The linear concentration ranges
      were 0.25-1.5 ppm (D2=0.00042Conc.+0.0018, r=0.9972, n=10). Between day of
      CV%</=2.81, within day of CV%</=3.50, and an analytical recovery close to 95-100%
      shows the suitability of the method for determination in quality control.

PMID- 12408930
TI  - Spectrophotometric determination of phenylephrine HCl and orphenadrine citrate in
      pure and in dosage forms.
AB  - A simple and rapid spectrophotometric methods have been estimated for the
      microdetermination of phenylephrine HCl (I) and orphenadrine citrate (II). The
      proposed methods are based on the formation of ion-pair complexes between the
      examined drugs with alizarine (Aliz), alizarine red S (ARS), alizarine yellow G
      (AYG) or quinalizarine (Qaliz), which can be measured at the optimum lambda(max).
      The optimization of the reaction conditions is investigated. Beer's law is obeyed
      in the concentration ranges 2-36 microgram ml(-1), whereas optimum concentration
      as adopted from Ringbom plots was 3.5-33 microgram ml(-1). The molar
      absorptivity, Sandell sensitivity, and detection limit are also calculated. The
      correlation coefficient was >/=0.9988 (n=6) with a relative standard deviation of
      </=1.7, for six determinations of 20 microgram ml(-1). The proposed methods are
      successfully applied to the determination of drugs I and II in their dosage forms
      using the standard addition technique.

PMID- 12408931
TI  - On-line coupling of SEC and RP-LC for the determination of structurally related
      enkephalins in cerebrospinal fluid.
AB  - On-line coupled analytical techniques can be advantageous in the assay of smaller
      peptides in complex biological matrices such as plasma, cerebro-spinal fluid
      (CSF) and tissues. The present study shows the feasibility of the recently
      reported on-line coupled size exclusion chromatography (SEC) and reversed phase
      liquid chromatography (RP-LC) separation system for the quantitation of
      structural related peptides in biological matrices, as demonstrated for a number
      of enkephalins in CSF. The degradation of the peptides, caused by endogenous
      peptidases in the matrix, could sufficiently be inhibited with imipramine HCL to
      allow an assay with satisfactory linearity and intraday (0.70-4.9%) precision.
      The sensitivity of the method, with a concentration limit of quantitation (LOQ)
      of 2 microgram/ml is comparable with other kinds of assays for peptides and
      sufficient for the quantitation of peptide drugs with higher therapeutic ranges
      in biological matrices. However, for the assay of low concentrations of peptides,
      such as endogenous components of a biological matrix, the sensitivity may need
      improvement. The LOQ cannot be improved by increasing the sample amount, because
      of interference of other endogenous components of the CSF. This indicates that a
      larger selectivity is desired. The LOQ may be improved by using more sensitive
      and selective detection methods such as mass spectrometry or fluorescence after
      post-column derivatization. Miniaturization of the system, combined with on-line
      trapping may also contribute to a better sensitivity.

PMID- 12408932
TI  - An optimized method for the simultaneous determination of vitamins B1, B6, B12 in
      multivitamin tablets by high performance liquid chromatography.
AB  - A simple, precise, rapid and selective HPLC-RP method has been developed for the
      simultaneous determination of thiamine hydrochloride (B(1)) 150 mg, pyridoxine
      hydrochloride (B(6)) 150 mg, and hydroxocobalamine chloride (B(12)) 0.150 mg in
      multivitamin tablets. The method uses a Hypersil-BDS C(18) reversed phase column
      and gradient elution. The aqueous mobile phase contained 0.015% triethylamine
      adjusted to pH 2.7 with 1 N sulfuric acid and acetonitrile. Separation and
      quantitation was achieved by changing the proportion of the system linearly with
      a time-schedule programme. Detection was carried out using a dual-beam UV
      detector set at 280, 350 nm. Good linearity was observed between the
      concentration of the analytes and peak area (r=0.9999, 0.9998). Sample
      preparation was relatively simple whereas excipients present in the dosage forms
      did not interfere with the peaks of interest. Recovery of the compound from the
      B(1), B(6), B(12) was quantitative.

PMID- 12408933
TI  - Method development for determining the antibacterial linezolid in human serum by
      micellar electrokinetic capillary chromatography.
AB  - A precise method for determining linezolid concentration in human serum by
      micellar electrokinetic capillary chromatography has been developed and
      validated. Serum was deproteinized with acetonitrile and etofylline was used as
      an internal standard. A borate buffer (pH 10.0; 25 mM) containing sodium dodecyl
      sulfate (80 mM) was used as a running buffer. Detection was performed at UV253 nm
      by applying 25 kV voltage to a fused-silica capillary tube. Migration time of
      linezolid was approximately 14 min. Good linearity (0-100 mg/l) was obtained and
      the limit of detection was 0.5 mg/l (S/N=3). This technique covered the clinical
      concentration (4 mg/l) measurement of this drug enough. The intra- and inter-day
      reproducibility was good. Serum recovery was 95-102%. No interference from other
      anti-microbial agents was observed. Linezolid after serum deproteinization showed
      high stability. This method was easy to operate as well as economical as a method
      for determining linezolid in serum.

PMID- 12408934
TI  - Differential-pulse polarography determination of pipamperone in pharmaceutical
      formulations.
AB  - The electrochemical reduction of pipamperone has been carried out in aqueous
      solution in KNO(3) (0.1 mol l(-1)) by differential-pulse polarography (DPP).
      Pipamperone exhibits a well-defined irreversible reduction peak at -1.3 V/ref.
      The influence of pH on the reduction of pipamperone was studied in Britton
      Robinson buffer (pH range 2-10). A method for the analysis of pipamperone in
      KNO(3) (0.1 mol l(-1)), which allows quantification over the range 1.6x10(-5)
      2.0x10(-4) mol l(-1), was proposed and successfully applied to the determination
      of pipamperone in tablets with mean recovery and relative standard deviation
      (R.S.D.) of 100.35 and 0.49%, respectively.

PMID- 12408935
TI  - Differential pulse cathodic stripping voltammetric determination of selenium in
      pharmaceutical products.
AB  - The aim of this paper is to determine selenium from pharmaceutical products by
      differential pulse cathodic stripping voltammetry. Firstly, were established the
      optimum parameters for voltammetric determination of selenium (electrolyte,
      deposition time, pulse duration, pulse amplitude, etc.) and secondly, the content
      of selenium was determined in five pharmaceutical products. The drug samples were
      treated with a mixture of 6 ml HNO(3) and 1 ml H(2)O(2) in the microwave oven.
      Due to the matrix effects the method of addition is preferred. The peak potential
      is -0.545 V vs. Ag/AgCl, and the calibration curve is linear up to 0.125 ng/ml,
      but selenium was determined from pharmaceutical products used the calibration
      curve in the range 8-64 ng/ml, due to the concentration of selenium in these
      tablets.

PMID- 12408936
TI  - Viscosity behavior of some alpha-amino acids and their groups in water-sodium
      acetate mixtures.
AB  - Viscosities of glycine, DL-alpha-alanine, DL-alpha-amino-n-butyric acid, DL
      valine and DL-leucine have been determined in water-sodium acetate mixtures at
      298.15 and 308.15 K. The viscosity B-coefficients have been calculated. The
      corresponding activation free energies (Deltamu(2)(0 not equal )) for viscous
      flow have been evaluated with the help of the Feakins equation. The contributions
      of the charged end group (NH(3)(+),COO(-)) and CH(2) groups of the amino acids to
      B-coefficient and Deltamu(2)(0 not equal) have been also determined using the
      linear correlation between B-coefficient or Deltamu(2)(0 not equal) and the
      number of carbon atoms in alkyl chains of the amino acids. The results have been
      interpreted in the light of the solute-solvent interactions in aqueous media.

PMID- 12408937
TI  - Effect of hydrophobic surfactant protein SP-C on binary phospholipid monolayers.
      Molecular machinery at the air/water interface.
AB  - Fluorescent and modified dark-field microscopies were used to investigate the
      phase behavior of physiologically relevant lipid/protein monomolecular films
      containing surfactant protein C(SP-C). Synthetic human SP-C(1-34) was labeled at
      its N-terminus using the fluorescent probe 6-(((4(4,4-difluoro-5-(2-thienyl)-4
      bora-3a,4a-diaza-s-indacene-3-yl)phenoxy)acetyl)amino)hexanoic acid (BODIPY/TR
      X). Using dual fluorescent labeling (lipid and protein) in the monolayers, we
      have correlated (at physiologically small concentrations of the protein) the
      lipid phase separation and protein distribution in situ. A comparison of the
      lipid and protein dye fluorescent micrographs indicates that SP-C(1-34) is
      preferentially associated with the disordered lipid phase. Three concepts arise
      from our results. (1) The presence of SP-C alone does not result in the complete
      dissolution of condensed phase domains in a fashion that we have previously
      reported for the entire hydrophobic surfactant protein (SP-B/C) fraction
      (Biophys. J. 77 (1999) 903). Rather, the use of relatively high amounts (
      approximately 10 wt.%) of the labeled SP-C protein is needed to reproduce the
      fluorescence monolayer morphology previously observed for small concentrations (
      approximately 1 wt.%) of the natural SP-B/C mixture. (2) Scattered light, dark
      field microscopy performed using grazing angle laser illumination reveals the
      presence of surface-associated, three-dimensional (3D) structures of micrometer
      sized dimensions when the labeled BODIPY/TR-X:SP-C(1-34) protein is included in
      the monolayer, as previously observed with the naturally isolated SP-B/C mixture.
      The 3D structures are associated exclusively with the presence of the SP-C
      protein in disordered monolayer phases. (3) To explain these results, we have
      derived a molecular model accounting for the structure and physico-chemical
      properties of the SP-C protein in terms of its energetics. The molecular events
      involved in the SP-C-mediated production of the 3D surface particles are
      explained using the analogy of a simple molecular machine, namely a loaded
      spring. This interpretation is supported by an energetic analysis that suggests
      the major factor contributing to the formation of the 3D particles is the energy
      liberated by re-expansion of the surrounding phospholipid film into the area
      vacated by the SP-C protein as it re-orients away from the surface.

PMID- 12408938
TI  - Spectroscopic evidence for a preferential location of lidocaine inside
      phospholipid bilayers.
AB  - We examined the effect of uncharged lidocaine on the structure and dynamics of
      egg phosphatidylcholine (EPC) membranes at pH 10.5 in order to assess the
      location of this local anesthetic in the bilayer. Changes in the organization of
      small unilamellar vesicles were monitored either by electron paramagnetic
      resonance (EPR)-in the spectra of doxyl derivatives of stearic acid methyl esters
      labeled at different positions in the acyl chain (5-, 7-, 12- and 16-MeSL)-or by
      fluorescence, with pyrene fatty-acid (4-, 6-, 10- and 16-Py) probes. The largest
      effects were observed with labels located at the upper positions of the fatty
      acid acyl-chain. Dynamic information was obtained by 1H-NMR. Lidocaine protons
      presented shorter longitudinal relaxation times (T(1)) values due to their
      binding, and consequent immobilization to the membrane. In the presence of
      lidocaine the mobility of all glycerol protons of EPC decreased, while the
      choline protons revealed a higher degree of mobility, indicating a reduced
      participation in lipid-lipid interactions. Two-dimensional Nuclear Overhauser
      Effect experiments detected contacts between aromatic lidocaine protons and the
      phospholipid-choline methyl group. Fourier-transform infrared spectroscopy
      spectra revealed that lidocaine changes the access of water to the glycerol
      region of the bilayer. A "transient site" model for lidocaine preferential
      location in EPC bilayers is proposed. The model is based on the consideration
      that insertion of the bulky aromatic ring of the anesthetic into the glycerol
      backbone region causes a decrease in the mobility of that EPC region (T(1) data)
      and an increased mobility of the acyl chains (EPR and fluorescence data).

PMID- 12408939
TI  - Substrate-induced deformation and adhesion of phospholipid vesicles at the main
      phase transition.
AB  - The physiochemical properties of phospholipid vesicle, e.g. permeability,
      elasticity, etc., are directly modulated by the chain-melting transition of the
      lipid bilayer. Currently, there is a lack of understanding in the relationship
      between thermotropic transition, mechanical deformation and adhesion strength for
      an adherent vesicle at temperature close to main phase transition temperature
      T(m). In this study, the contact mechanics of dimyristoyl-phosphatidylcholine
      (DMPC) vesicle at the main phase transition are probed by confocal reflectance
      interference contrast microscopy in combination with phase contrast microscopy.
      It is shown that DMPC vesicles strongly adhere on pure fused silica substrate at
      T(m) and the degree of deformation as well as the adhesion energy is a decreasing
      function against the mid-plane diameter of the vesicles. Furthermore, an increase
      of osmotic pressure at the gel/liquid crystalline phase co-existence imposes
      insignificant changes in both the degree of deformation and adhesion energy of
      adherent vesicles when the lipid bilayer permeability is maximized. With the
      reverse of substrate charge, the mechanical deformation and adhesion strength for
      larger vesicles (mid-plane diameter >18 microm) are significantly reduced. By
      monitoring the parametric response of substrate-induced vesicle adhesion during
      main phase transition, it is shown that the degree of deformation and adhesion
      energy of adhering vesicle is increased and unchanged, respectively, against the
      increase of temperature.

PMID- 12408940
TI  - Simulations of temperature sensitivity of the peroxidase-oxidase oscillator.
AB  - The influence of temperature on the oscillatory kinetics of the peroxidase
      oxidase reaction was studied theoretically. Assuming Q(10)=2 for elementary
      reactions, the effect of multiplying the rate constants of the model by factors
      between 0.5 and 2 (corresponding to a 10 degrees C decrease and increase,
      respectively, of temperature) was investigated. First, the individual rate
      constants were successively multiplied by 0.5 or 2 while all other rate constants
      were kept unchanged. This resulted in either a longer or a shorter period,
      depending on the rate constant being changed. Multiplication by 0.5 or by 2
      generally resulted in opposite effects on the period length. However, the
      absolute value of this deviation differed. Also, the dynamics changed when
      halving the dimerization rate of NAD* as well as when doubling the rate constant
      for the reduction of ferric peroxidase by NAD*. Next, simulations were performed
      multiplying all rate constants by one and the same factor, which increased
      progressively from 0.5 to 2. Intervals were found corresponding to temperature
      dependency, compensation, and over-compensation, respectively.

PMID- 12408941
TI  - Concentration-dependent behavior of nisin interaction with supported bilayer
      lipid membrane.
AB  - Nisin is a positively charged antibacterial peptide that binds to the negatively
      charged membranes of gram-positive bacteria. The initial interaction of the
      peptide with the model membrane of negatively charged DPPG
      (dipalmitoylphosphatidylglycerol) was studied by cyclic voltammetry and a.c.
      impedance spectroscopy. Nisin could induce pores in the supported bilayer lipid
      membrane, thus, it led to the marker ions Fe(CN)(6)(3-/4-) crossing the lipid
      membrane and giving the redox reaction on the glassy carbon electrode (GCE).
      Experimental results suggested that the pore formation on supported bilayer lipid
      membrane was dependent on the concentration of nisin and it included three main
      concentration stages: low, middling, high concentration.

PMID- 12408942
TI  - Membrane topology modulates beta-galactosidase activity against soluble
      substrates.
AB  - The effect of bio-surfaces of contrasting curvature, on the kinetic parameters of
      ortho-nitrophenyl-beta-D-galactopiranoside hydrolysis catalyzed by E. coli beta
      galactosidase, was investigated. The self-aggregating state and structure of the
      amphiphiles (Phosphatidylcholine, Lubrol-PX, Triton X-100, DocNa, SDS and CTAB)
      were inferred from their c.m.c. values and light-scattering measurements. Low
      curvature phosphatidylcholine or mixed phosphatidylcholine-detergent vesicles
      increased V(max) without affecting K(M). High curvature micellar structures
      containing ionic detergents modulated negatively the enzyme activity (decreased
      or abolished V(max) and increased K(M)). Neither micelles containing non-ionic
      detergents nor the amphiphiles in a monomeric form, affected enzyme activity.
      CTAB at a concentration below its c.m.c but incorporated into a bilayer, became
      an activator (K(M) decreased respect to the control). Non-enzymatic interfacial
      hydrolysis of the substrate was discarded. Enzyme-membrane interaction and
      membrane elasticity, were evaluated using monomolecular layers at the air-water
      interface. Beyond particular molecular structures, topology affected the
      direction of the modulatory effects exerted by these amphiphiles on beta
      galactosidase activity.

PMID- 12408943
TI  - Habitat destruction in a simple predator-prey patch model: how predators enhance
      prey persistence and abundance.
AB  - We model a metapopulation of predator-prey patches using both spatially implicit
      or mean-field (MF) and spatially explicit (SE) approaches. We show that in the MF
      model there are parameter regimes for which prey cannot persist in the absence of
      predators, but can in their presence. In addition, there are parameter regimes
      for which prey may persist in isolation, but the presence of predators will
      increase prey patch density. Predators may thus enhance prey persistence and
      overall abundance. The key mechanism responsible for this effect is the
      occurrence of prey dispersal from patches that are occupied by both prey and
      predators. In addition, these patches should be either long-lived, such as that
      occurs when predators keep prey from overexploiting its local resource, or the
      presence of a predator on a patch should significantly enhance the prey dispersal
      out of that patch. In the SE approach these positive effects of predators on prey
      persistence and abundance occur for even larger parameter ranges than in the MF
      model. Prey dispersal from predator-prey patches may thus be important for
      persistence of both species as a community, independent of the modeling framework
      studied. Comparison of the MF and SE approaches shows that local dispersal
      constraints can have the edge over global dispersal for the persistence of the
      metapopulation in regimes where the two species have a beneficial effect on each
      other. In general, our model provides an example of feedback in multiple-species
      metapopulations that can make the implementation of conservation schemes based on
      single-species arguments very risky.

PMID- 12408944
TI  - Hardy-Weinberg equilibrium diagnostics.
AB  - We propose two diagnostics for the statistical assessment of Hardy-Weinberg
      equilibrium. One diagnostic is the posterior probability of the complement of the
      smallest highest posterior density credible region that includes points in the
      parameter space consistent with the hypothesis of equilibrium. The null
      hypothesis of equilibrium is to be rejected if this probability is less than a
      pre-selected critical level. The second diagnostic is the proportion of the
      parameter space occupied by the highest posterior density credible region
      associated with the critical level. These Bayesian diagnostics can be interpreted
      as analogues of the classical types I and II error probabilities. They are
      broadly applicable: they can be computed for any hypothesis test, using samples
      of any size generated according to any distribution.

PMID- 12408945
TI  - The impact of resource limitation and the phenology of parasitoid attack on the
      duration of insect herbivore outbreaks.
AB  - Fluctuations in resource quality and quantity, and changes in mortality due to
      predators and parasites are thought to be of prime importance in the regular
      fluctuations of forest insects. We examine how food limitation and parasitoids
      with different phenologies of attack regulate the population cycles of insect
      hosts. Our analysis of the limit cycle of a model with a biologically realistic
      form of density dependence in the host yields two novel predictions. First,
      outbreaks will typically last for only 2 generations after parasitoids begin to
      reduce the host population below the maximum density. Second, host growth rate is
      important in determining cycle length only when parasitoids attack before the
      impacts of resource limitation affect the host. The robustness of these
      predictions are tested using a more general form of density dependence in the
      host, revealing that our predictions are valid as long as density dependence in
      the host is not too overcompensatory.

PMID- 12408946
TI  - Diversity-stability relationships in community ecology: re-examination of the
      portfolio effect.
AB  - In plant communities, the portfolio effect, also called "statistical averaging
      effect", expresses the fact that stability in aggregate community properties such
      as biomass productivity generally rises with species diversity, simply because of
      the statistical averaging of the fluctuations in species' properties. This paper
      essentially upgrades the previous formulations of the portfolio effect, first
      developed by Doak and collaborators and then by Tilman. It uses a theoretical
      approach based on simple statistical relationships and some simplifying
      assumptions proposed by these authors. The new formulation presented extends and
      improves the previous relationships in the sense that it takes into account
      simultaneously a varying scaling power of the variance, the interaction effect
      between species, the heterogeneity in species productivity and interspecies
      correlated responses to the environment. It appears that the simple statistical
      averaging, as inferred from this formulation, does not necessarily lead to a
      positive correlation between species diversity and community stability.

PMID- 12408947
TI  - The impact of consumer-resource cycles on the coexistence of competing consumers.
AB  - This article seeks to determine the extent to which endogenous consumer-resource
      cycles can contribute to the coexistence of competing consumer species. It begins
      with a numerical analysis of a simple model proposed by Armstrong and McGehee.
      This model has a single resource and two consumers, one with a linear functional
      response and one with a saturating response. Coexistence of the two consumer
      species can occur when the species with a saturating response generates
      population cycles of the resource, and also has a lower resource requirement for
      zero population growth. Coexistence can be achieved over a wide range of relative
      efficiencies of the two consumers provided that the functional response of the
      saturating consumer reaches its half-saturation value when the resource
      population is a small fraction of its carrying capacity. In this case, the range
      of efficiencies allowing coexistence is comparable to that when two competitors
      have stable dynamics and a high degree of resource partitioning. A variety of
      modifications of this basic model are analyzed to investigate the consequences
      for coexistence of different resource growth equations, different functional and
      numerical response shapes, and other factors. Large differences in functional
      response shape appear to be the most important factor in producing robust
      coexistence via resource cycles. If the unstable species has a concave numerical
      response, this greatly expands the conditions allowing coexistence. If the stable
      consumer species has a convex (accelerating) functional and/or numerical
      response, the range of conditions allowing coexistence is also expanded. We argue
      that large between-species differences in functional response form can often be
      produced by between-consumer differences in the adaptive adjustments of foraging
      effort to food density. Consumer-resource cycles can also expand the conditions
      allowing coexistence when there is resource partitioning, but do so primarily
      when resource partitioning is relatively slight; this makes the ease of
      coexistence relatively independent of consumer similarity.

PMID- 12408948
TI  - Effects of local interactions and local migration on stability.
AB  - Mathematical models can help to resolve the longstanding question of whether more
      diverse communities are more stable. Here, I focus on how local dispersal and
      local interactions--hallmarks of spatial communities--affect stability in a
      spatially implicit model with demographic stochasticity. The results are based on
      a novel way to analyze moment equations. The main conclusion is that the type and
      strength of density-dependent factors, such as fecundity and competition,
      determine whether local dispersal and local interactions increase or decrease
      stability. Local dispersal has a stabilizing effect when fecundity is high,
      interspecific competition is either low or high, and the number of species is
      small. Effects of local migration on stability are amplified when space is
      explicit.

PMID- 12408950
TI  - Response of rats to low levels of sarin.
AB  - The purpose of this study was to determine whether exposure to levels of sarin
      causing no overt clinical signs would cause more subtle, adverse health effects
      that persisted after the exposure ended. Inhalation exposures of male Fischer 344
      rats to 0, 0.2, or 0.4 mg/m(3) of sarin for 1 h/day for 1, 5, or 10 days under
      normal (25 degrees C) and heat-stressed (32 degrees C) conditions were completed
      and observations were made at 1 day and 1 month after the exposures. The sarin
      exposures had no observed effects on body weight, respiration rate, and minute
      volume during exposure nor in body temperature and activity during the 30-day
      recovery period. There was no evidence of cellular changes in brain determined by
      routine histopathology nor of any increase in apoptosis. Brain mRNA for
      interleukin (IL)-1beta, tumor necrosis factor-alpha, and IL-6 was increased in a
      dose-dependent manner. Autoradiographic studies demonstrated that M1 cholinergic
      receptor site densities were unchanged at 1 day after repeated exposures with or
      without heat stress. At 30 days, there was a decrease in M1 receptors in the
      olfactory tubercle (with and without heat), and, with heat stress, M1 sites also
      decreased in a dose-dependent manner in the frontal cortex, anterior olfactory
      nucleus, and hippocampus. M3 receptor sites were not affected by sarin exposure
      alone. In the presence of heat stress, there was an upregulation in binding site
      densities in the frontal cortex, olfactory tubercle, anterior nucleus, and
      striatum immediately after exposure, and these effects persisted at 30 days.
      Although red blood cell acetylcholinesterase (AChE) was not greatly inhibited by
      the 1-day exposure, there were 30 and 60% inhibitions after repeated exposures at
      the low and high doses, respectively. Histochemical staining for AChE
      demonstrated that sarin exposure alone reduced AChE in the cerebral cortex,
      striatum, and olfactory bulb. Sarin exposure under heat stress reduced AChE
      staining in the hippocampus, an area important for memory function. Thus,
      repeated exposures under heat-stress conditions, to levels of sarin that would
      not be noticed clinically, resulted in delayed development of brain alterations
      in cholinergic receptor subtypes that may be associated with memory loss and
      cognitive dysfunction.

PMID- 12408951
TI  - Effects of sarin on temperature and activity of rats as a model for gulf war
      syndrome neuroregulatory functions.
AB  - Coexposure to subclinical levels of nerve gas and to heat stress may have induced
      some of the clinical symptoms of the Gulf War Syndrome. We tested the hypothesis
      that single or repeated subclinical exposure to sarin, particularly under
      conditions of heat stress, would impair regulation of body temperature and
      locomotor activity. Male F344 rats were housed at 25 degrees C or under mild heat
      stress at 32 degrees C and were exposed 1 h/day for 1, 5, or 10 days to 0, 0.2,
      or 0.4 mg/m(3) of sarin in a nose-only exposure system. Body temperature and
      activity were monitored continuously by telemetry during exposure and 1 month
      postexposure. Exposed rats showed no clinical symptoms of toxicity such as
      tremors, despite evidence of reduced red blood cell cholinesterase activity. Heat
      stress consistently elevated body temperature in unexposed animals, particularly
      during the dark period when animals are most active. Inhalation of sarin gas at
      the two subclinical levels did not affect body temperature acutely in a
      biologically meaningful manner after the first exposure nor after 5 or 10
      repeated exposures, either at thermoneutral ambient temperature or during chronic
      heat stress. There were no consistent effects of sarin or housing temperature on
      activity. The data suggest that subclinical levels of sarin have minimal effects
      on temperature regulation and locomotor activity under these observation
      conditions.

PMID- 12408952
TI  - Subclinical doses of the nerve gas sarin impair T cell responses through the
      autonomic nervous system.
AB  - The nerve gas sarin is a potent cholinergic agent, and exposure to high doses may
      cause neurotoxicity and death. Subclinical exposures to sarin have been
      postulated to contribute to the Gulf War syndrome; however, the biological
      effects of subclinical exposure are largely unknown. In this communication,
      evidence shows that subclinical doses (0.2 and 0.4 mg/m(3)) of sarin administered
      by inhalation to F344 rats for 1 h/day for 5 or 10 days inhibited the anti-sheep
      red blood cell antibody-forming cell response of spleen cells without affecting
      the distribution of lymphocyte subpopulations in the spleen. Moreover, sarin
      suppressed T cell responses, including the concanavalin A (Con A) and the anti
      alphabeta-T cell receptor (TCR) antibody-induced T cell proliferation and the
      rise in the intracellular calcium following TCR ligation. These concentrations of
      sarin altered regional but not total brain acetylcholinesterase activity.
      Interestingly, serum corticosterone levels of the sarin-treated animals were
      dramatically lower than the control animals, indicating that sarin-induced
      immunosuppression did not result from the activation of the hypothalamus
      pituitary-adrenal (HPA) axis. Pretreatment of animals with the ganglionic blocker
      chlorisondamine abrogated the inhibitory effects of sarin on spleen cell
      proliferation in response to Con A and anti-TCR antibodies. These results suggest
      that the effects of sarin on T cell responsiveness are mediated via the autonomic
      nervous system and are independent of the HPA axis.

PMID- 12408953
TI  - Bleomycin induces E-selectin expression in cultured umbilical vein endothelial
      cells by increasing its mRNA levels through activation of NF-kappaB/Rel.
AB  - Treatment with bleomycin (BLM) often results in the development of acute lung
      injury and subsequent fibrosis by mechanisms that are not well understood. It is
      hypothesized that active oxygen species and proteases generated by inflammatory
      cells that accumulate in the bronchoalveolus are responsible and that BLM-induced
      E-selectin expression on the endothelial surface has an essential role as a
      trigger in the accumulation of inflammatory cells. We aimed to understand the
      mechanisms of BLM-induced E-selectin expression in endothelial cells. The E
      selectin antigen was induced on the surface of cultured human umbilical vein
      endothelial cells (HUVECs) exposed to BLM in a dose- and time-dependent manner,
      with an increase in mRNA levels. The binding of nuclear proteins to
      oligonucleotides containing the NF-kappaB/Rel or AP-1 binding motif of the
      promoter of the human E-selectin gene significantly increased in BLM-treated
      HUVECs compared with control cells. The increased E-selectin antigen levels
      induced by BLM were abrogated by pretreatment with MG132 (10 microM) or PDTC (100
      microM), in parallel with inhibition of the NF-kappaB/Rel activation and nuclear
      translocation, although no inhibition of the AP-1 activation was observed.
      Supershift assays indicated that NF-kappaB/Rel bound with the NF-kappaB/Rel
      binding motif contained p65, p50, and c-Rel subunits. The AP-1 activation by BLM
      was inhibited by pretreatment of the cells with SB203580, although BLM-induced
      expression of E-selectin was not attenuated. These results suggest that BLM can
      directly induce E-selectin expression with an increase in transcription in
      endothelial cells through activation and nuclear translocation of NF-kappaB/Rel
      without mediation of inflammatory cytokines.

PMID- 12408954
TI  - Surface components of airborne particulate matter induce macrophage apoptosis
      through scavenger receptors.
AB  - Epidemiology studies have linked mortality, increased asthma morbidity, and other
      respiratory disorders in urban areas to increases in fine airborne particulate
      matter (PM) concentrations. However, neither the bioactive components of PM nor
      the biological mechanisms of the reported health effects have been elucidated. A
      number of studies have implicated soluble metals, the strong acid fraction,
      and/or other components of PM as possible bioactive mediators. Alveolar
      macrophage (AM) apoptosis, mediated through scavenger receptors (SR), may be
      important in the response to inflammatory particles. Therefore, this study
      explores the hypothesis that organic and metallic components of PM induce
      apoptosis by interacting with SR. Freshly isolated AM from Balb/c mice were
      incubated with PM 1648 samples untreated or extracted with Milli-Q water,
      acetone, or cyclohexane, acid digested, or heated at 100 or 500 degrees C. Cell
      viability was assessed by trypan blue exclusion and apoptosis was demonstrated by
      examination of cell morphology and cell death ELISA. Untreated PM induced
      necrosis and apoptosis in AM. Treatment of PM by organic extraction, acid
      digestion, or high heat modified the particle surface composition and apoptosis
      was decreased. Apoptosis induced by untreated, acetone extracted, and high heat
      treated PM was blocked by polyinosinic acid or 2F8 antibody. These results
      demonstrate that PM-induced apoptosis is mediated by Class A Type I/II SR.
      Altering the surface characteristics of PM interferes with recognition by SR,
      resulting in decreased apoptosis of AM. Therefore, altering the surface chemistry
      by removal of one or more PM components, such as the various treatments conducted
      in this study, is sufficient to alter PM bioactivity. These results may also help
      explain why PM from many different sources, with differences in composition, are
      all bioactive, since it is the overall matrix that is important, not just one
      component.

PMID- 12408955
TI  - Characterization of a rat in vitro ovarian culture system to study the ovarian
      toxicant 4-vinylcyclohexene diepoxide.
AB  - Repeated daily dosing of rats with the occupational chemical 4-vinylcyclohexene
      diepoxide (VCD) causes selective depletion of the smallest preantral ovarian
      follicles (primordial and primary). These targeted populations are difficult to
      study because they comprise very little of the overall mass of ovarian tissue.
      Additionally, they are randomly distributed throughout the ovary. Therefore, a
      neonatal rat ovarian culture system containing predominantly primordial and
      primary follicles was developed and its susceptibility to VCD was assessed. The
      in vivo sensitivity of neonatal rats to VCD dosing was first confirmed by daily
      injection of VCD (80 mg/kg/day ip) on postnatal days (PND) 4-19. On PND 19,
      depletion of primordial and small primary follicles was evident. Ovarian cultures
      were then established utilizing a floating organ culture system to treat ovaries
      from PND 4 Fischer 344 rats in vitro. Initial follicle populations in cultured
      ovaries consisted of primordial (81%) and small primary (19%) follicles, whereas
      larger-sized preantral follicles had developed after 15 days in culture (67%
      primordial, 31% small primary, and 2% large primary). Cultured rat ovaries were
      sensitive to follicle depletion by incubation with VCD (> or =30 microM), and
      follicle loss occurred in a time-dependent manner (8-15 days). Evidence for
      apoptosis in VCD-exposed ovaries, as demonstrated in vivo, was obtained using
      immunohistochemistry. There was significantly more staining for apoptosis
      associated active caspase-3 and TUNEL in ovaries incubated with VCD (30 microM,
      15 days) compared with matched controls. These results demonstrate that small
      preantral follicles of cultured neonatal rat ovaries are sensitive to VCD
      exposure. The similarities between VCD's effects in vitro and in vivo demonstrate
      the usefulness of this system for future mechanistic studies related to ovarian
      follicle loss induced by VCD or other ovotoxic chemicals.

PMID- 12408956
TI  - Biomonitoring of exposure to chemical warfare agents: a review.
AB  - In this report an overview of the methods currently available for detection of
      exposure to a number of chemical warfare agents (CWA), i.e., sulfur mustard,
      lewisite and nerve agents, is presented. Such methods can be applied for various
      purposes, e.g., diagnosis and dosimetry of exposure of casualties, confirmation
      of nonexposure, verification of nonadherence to the Chemical Weapons Convention,
      health surveillance, and forensic purposes. The methods are either based on mass
      spectrometric or immunochemical analysis of CWA adducts with DNA or proteins or
      based on mass spectrometric analysis of urine or plasma metabolites that result
      from hydrolysis and/or glutathione conjugation. Several of the methods have been
      successfully applied to actual cases.

PMID- 12408957
TI  - Effects of minority status in the classroom on children's intergroup attitudes.
AB  - Three studies examined the effects of relative group size on the development of
      children's intergroup attitudes. The studies employed a novel group paradigm in
      which elementary school children attending a summer school program were assigned
      to larger (i.e., majority) or smaller (i.e., minority) novel groups in their
      classroom (denoted by colored tee-shirts). In each study, relative group size was
      situated within a different classroom context. Study 1 examined the effects of
      relative group size when teachers made functional use of the novel groups and
      were themselves members of the novel groups. Study 2 examined the effects of
      relative group size in the absence of functional use. Study 3 examined the
      effects of relative group size when the classroom environment contained implicit
      messages about group status. In each study, children's intergroup attitudes
      (e.g., trait ratings, group evaluations) were assessed following several weeks in
      the classroom. The effect of relative group size on in-group bias was complex,
      varying as a function of (a) the relative size and salience of groups, (b) the
      measure used to assess intergroup attitudes, (c) group status (higher or lower),
      and (d) children's age.

PMID- 12408958
TI  - Relations among musical skills, phonological processing, and early reading
      ability in preschool children.
AB  - We examined the relations among phonological awareness, music perception skills,
      and early reading skills in a population of 100 4- and 5-year-old children. Music
      skills were found to correlate significantly with both phonological awareness and
      reading development. Regression analyses indicated that music perception skills
      contributed unique variance in predicting reading ability, even when variance due
      to phonological awareness and other cognitive abilities (math, digit span, and
      vocabulary) had been accounted for. Thus, music perception appears to tap
      auditory mechanisms related to reading that only partially overlap with those
      related to phonological awareness, suggesting that both linguistic and
      nonlinguistic general auditory mechanisms are involved in reading.

PMID- 12408959
TI  - Examining the efficacy of truth/lie discussions in predicting and increasing the
      veracity of children's reports.
AB  - This study investigated whether children's ability to reason about truths and
      lies influenced their truth-telling behavior. Four-six-year-old children (n=118)
      played a game that was intended to motivate children to use deception to hide a
      minor transgression. Next, an interviewer gave children one of four preliminary
      discussions. Children received a typical forensic truth/lie discussion (TLD), a
      developmentally appropriate and more elaborate TLD, or one of two discussions
      that controlled for the time spent conversing with children. Children were
      interviewed about the event. The results revealed that children's performance on
      the truth/lie questions did not predict their truth-telling behavior. Regardless
      of their performance on truth/lie questions, children who received TLD's gave
      more honest reports than children who did not receive TLD's. These results
      suggest that discussing truths and lies with children may promote truth-telling
      behavior. However, the results cast doubt on the validity of using children's
      performance on truth/lie questions as a measure of competency.

PMID- 12408960
TI  - A novel endogenous retrovirus-related element in the human genome resembles a DNA
      transposon: evidence for an evolutionary link?
AB  - A significant fraction of the human genome is composed of various types of
      transposable elements, which are divided into two broad classes based on their
      mehcanism of transposition: via an RNA intermediate (retroelements) or via a DNA
      intermediate (DNA transposons). The retroelements, which include endogenous
      retroviruses, are the more prominent group in humans and seem to be restricted to
      eukaryotes. DNA transposons are known in almost all well-studied organisms,
      including bacteria. In the human genome, they exist as mere fossils and seem to
      have been inactive for millions of years. We report here an element in the human
      genome that is the product of a recent retrotransposition event, yet apparently,
      by a novel mechanism of reverse transcription, has acquired inverted repeats more
      characteristic of DNA transposons.

PMID- 12408961
TI  - Identification and characterization of novel members of the CREG family, putative
      secreted glycoproteins expressed specifically in brain.
AB  - The cellular repressor of E1A-stimulated genes, CREG, is a secreted glycoprotein
      that enhances differentiation of pluripotent stem cells. Here we report two novel
      members of the CREG family, human CREG2 and mouse Creg2 cDNAs. The predicted
      human and mouse protein sequences exhibit 35% identity with CREG protein.
      Northern blot analyses demonstrate specific CREG2 and Creg2 transcription in
      brain-in the case of CREG2, mainly in the limbic system of the brain. Both mouse
      and human CREG2 fused to the carboxy terminus of EGFP in NIH3T3 cells localize to
      the perinuclear region, which demonstrates implicit endoplasmic reticulum and
      Golgi localization. Human and mouse CREG2 are N-glycosylated in HeLa cells and
      deletion of amino-terminal sequences completely abolishes N-glycosylation,
      indicating that the N termini of both proteins may function as signal sequences.
      Thus, human and mouse CREG2 are putative secreted glycoproteins and may be novel
      neuronal extracellular molecules.

PMID- 12408962
TI  - Ahl2, a second locus affecting age-related hearing loss in mice.
AB  - Inbred mouse strains with age-related hearing loss (AHL) provide valuable models
      for studying the genetic basis of human presbycusis. Here we report the genetic
      mapping of a second AHL locus in mice (designated Ahl2) that is a major
      contributor to the 8- to 10-month difference in hearing loss onset times between
      NOD/LtJ and C57BL/6J mice. A whole-genome linkage scan of 110 progeny from a
      (C57BL/6JxNOD/LtJ)xNOD/LtJ backcross revealed statistically significant
      associations of ABR thresholds with markers on chromosome 5, with a peak lod
      score of 5.5 for D5Mit309. At 6 months of age, backcross progeny that inherited
      two copies of the recessive NOD/LtJ-derived allele at this locus (genotype
      ahl2/ahl2) exhibited ABR thresholds that were on average 26 decibels above those
      of heterozygous mice. Analysis of a (CAST/EixNOD/LtJ)xNOD/LtJ backcross, which
      segregates strain-specific alleles at both Ahl2 and the Ahl locus on chromosome
      10, showed that the hearing loss attributable to Ahl2 is dependent on a
      predisposing Ahl genotype. The statistically significant effect of Ahl2 observed
      in crosses with NOD/LtJ was not seen in crosses involving three other strains
      with early onset AHL: A/J, BUB/BnJ, and SKH2/J.

PMID- 12408963
TI  - Identification of FOXC1 as a TGF-beta1 responsive gene and its involvement in
      negative regulation of cell growth.
AB  - We cloned the forkhead box C1 (FOXC1) gene, a member of the forkhead/winged-helix
      transcription factor family, as a transforming growth factor-beta1 (TGF-beta1)
      responsive gene. We showed that TGF-beta1 upregulated transcription of FOXC1 in
      several human cancer cell lines. Ectopic expression of FOXC1 cDNA in HeLa cells,
      which lack both copies of the FOXC1 allele, restores the potential of TGF-beta1
      to inhibit cell growth by arresting cells in the G0/G1 phase. In addition,
      screens of primary endometrial and ovarian cancers revealed homozygous deletion
      of FOXC1 in 6.7% of them, one nonsense and one missense mutation of FOXC1, and
      transcriptional silencing in 11.7% of primary cancers. Evidence that a
      significant fraction of primary cancers exhibited somatic mutations suggests that
      FOXC1 functions as a tumor suppressor through TGF-beta1 mediated signals.

PMID- 12408964
TI  - The nesprins are giant actin-binding proteins, orthologous to Drosophila
      melanogaster muscle protein MSP-300.
AB  - Nesprin-1 and nesprin-2 (also known as Syne-1 and Syne-2,) are large (
      approximately 3300-residue) vertebrate proteins associated with emerin and lamin
      A at the nuclear envelope of muscle cells and other cell types. We show that the
      previously described nesprins are short isoforms of giant proteins comprising an
      actin-binding amino-terminus connected to a carboxy-terminal klarsicht-related
      transmembrane domain by a massive ( approximately 6000-8000 amino acid) spectrin
      like rod domain, making full-length nesprin-1, at one megadalton, the largest non
      titin protein hitherto described in humans. We find that MSP-300, a 7000-residue
      Drosophila melanogaster protein whose disruption results in defects of muscle
      development, corresponds to the N-terminal two-thirds of the Drosophila nesprin
      ortholog. A nesprin-like protein is also encoded by the nematode genome.
      Moreover, we demonstrate that the larger isoforms of nesprin-1, like MSP-300, are
      localized to the sarcomeric Z-line of both skeletal and cardiac muscle. The
      recognition that a characteristic muscle-specific mutant phenotype in the fly
      results from a disruption of its nesprin ortholog reinforces the candidacy of the
      human proteins for involvement in genetic diseases of skeletal and cardiac
      muscle.

PMID- 12408965
TI  - Isolation and characterization of the mouse ortholog of the Fukuyama-type
      congenital muscular dystrophy gene.
AB  - Fukuyama-type congenital muscular dystrophy (FCMD) is a severe autosomal
      recessive muscular dystrophy accompanied by brain malformation. Previously, we
      identified the gene responsible for FCMD through positional cloning. Here we
      report the isolation of its murine ortholog, Fcmd. The predicted amino acid
      sequence of murine fukutin protein encoded by Fcmd is 90% identical to that of
      its human counterpart. Radiation hybrid mapping localized the gene to 2.02 cR
      telomeric to D4Mit272 on chromosome 4. Northern blot analysis revealed ubiquitous
      expression of Fcmd in adult mouse tissues. Through in situ hybridization, we
      observed a wide distribution of Fcmd expression throughout embryonic development,
      most predominantly in the central and peripheral nervous systems. We also
      detected high Fcmd expression in the ventricular zone of proliferating neurons at
      13.5 days post-coitum. Brain malformation in FCMD patients is thought to result
      from defective neuronal migration. Our data suggest that neuronally expressed
      Fcmd is likely to be important in the development of normal brain structure.

PMID- 12408966
TI  - The human and mouse replication-dependent histone genes.
AB  - The multigene family encoding the five classes of replication-dependent histones
      has been identified from the human and mouse genome sequence. The large cluster
      of histone genes, HIST1, on human chromosome 6 (6p21-p22) contains 55 histone
      genes, and Hist1 on mouse chromosome 13 contains 51 histone genes. There are two
      smaller clusters on human chromosome 1: HIST2 (at 1q21), which contains six
      genes, and HIST3 (at 1q42), which contains three histone genes. Orthologous Hist2
      and Hist3 clusters are present on mouse chromosomes 3 and 11, respectively. The
      organization of the human and mouse histone genes in the HIST1 cluster is
      essentially identical. All of the histone H1 genes are in HIST1, which is spread
      over about 2 Mb. There are two large gaps (>250 kb each) within this cluster
      where there are no histone genes, but many other genes. Each of the histone genes
      encodes an mRNA that ends in a stemloop followed by a purine-rich region that is
      complementary to the 5' end of U7 snRNA. In addition to the histone genes on
      these clusters, only two other genes containing the stem-loop sequence were
      identified, a histone H4 gene on human chromosome 12 (mouse chromosome 6) and the
      previously described H2a.X gene located on human chromosome 11. Each of the 14
      histone H4 genes encodes the same protein, and there are only three histone H3
      proteins encoded by the 12 histone H3 genes in each species. In contrast, both
      the mouse and human H2a and H2b proteins consist of at least 10 non-allelic
      variants, making the complexity of the histone protein complement significantly
      greater than previously thought.

PMID- 12408967
TI  - Widely spaced alternative promoters, conserved between human and rodent, control
      expression of the Opitz syndrome gene MID1.
AB  - Mutations in the gene MID1 are responsible for the X-linked form of Opitz
      syndrome, a genetic disorder that primarily affects the development of midline
      structures. Several mRNA isoforms with variant 5' ends have been reported for
      MID1, suggesting the presence of alternative transcription initiation sites.
      However, the genomic organization and expression pattern of the heterogeneous
      MID1 5'-untranslated regions (UTRs), as well as the promoter regions regulating
      their transcription, have not been determined. We now report the characterization
      of alternative MID1 first exons and their associated promoters in human and other
      species. Multiple transcription initiation sites, dispersed over 250 kb on Xp22,
      were found to give rise to five MID1 isoforms in human that differed in their 5'
      UTRs, but contained identical coding sequence. These alternative MID1 transcripts
      showed distinct expression patterns with the most 5' first exon being adipose
      specific and another exon being placenta-selective, whereas other 5'-UTRs seemed
      to be ubiquitous. Consistent with the expression data, the putative promoter
      regions upstream of the variant first exons also varied in their strength and
      tissue specificity in transfection experiments. Similar to the human gene,
      heterogeneous Mid1 isoforms were also identified in mouse and rat by 5'-RACE,
      which revealed that three of the five alternative first exons isolated in human
      are also used in rodent. Comparison of MID1 promoter regions from several mammals
      indicated a high level of identity suggesting evolutionary conservation.
      Together, these results suggest that alternative promoters are important in the
      complex transcriptional regulation of MID1 expression in several species.

PMID- 12408968
TI  - The gene CSTF2T, encoding the human variant CstF-64 polyadenylation protein
      tauCstF-64, lacks introns and may be associated with male sterility.
AB  - Messenger RNA polyadenylation in male germ cells does not seem to require the
      AAUAAA polyadenylation signal required in all other cell types. To account for
      this difference, we found a variant form of the polyadenylation protein, the
      64,000 Mr protein of the cleavage stimulation factor (CstF-64), in mouse meiotic
      and postmeiotic germ cells. This protein is a candidate to alter polyadenylation
      in those cells. More recently, we reported the cloning from mouse pachytene
      spermatocytes of mouse tauCstF-64 (gene symbol Cstf2t), which is a homolog of
      CstF-64 fitting the criteria we expected for the variant CstF-64 protein. Here we
      report the cloning and mapping of the human ortholog of mouse tauCstF-64. The
      human tauCstF-64 cDNA (gene symbol CSTF2T) is 2324 bp in length and encodes a
      protein of 616 amino acids (64,442.90 Da). Although most highly related to mouse
      tauCstF-64 (89.8% identity), human tauCstF-64 is also related to the human and
      mouse somatic CstF-64 (74.9% and 73.4% identity, respectively). Alignment of
      human tauCstF-64 with human genome sequence from chromosome 10 shows that CSTF2T
      lacks introns. Radiation hybrid mapping places the human tauCstF-64 gene at 10q22
      q23, which is the site of a translocation that has been associated with human
      neurological problems and male infertility.

PMID- 12408969
TI  - The murine alpha(1)-proteinase inhibitor gene family: polymorphism, chromosomal
      location, and structure.
AB  - alpha(1)-Proteinase inhibitor (alpha(1)-PI) is a member of the serpin superfamily
      of serine proteinase inhibitors, which function in maintaining homeostasis
      through regulation of numerous proteolytic processes. In laboratory mice (Mus
      musculus domesticus), alpha(1)-PI occurs in multiple isoforms encoded by a family
      of three to five genes that are polymorphic among inbred strains and that are
      located at the Serpina1 locus on chromosome 12. In the present study, we have
      characterized the alpha(1)-PI gene family of inbred mice in more detail. We show
      that mice express seven isoforms, all of which are encoded by genes that map to
      the Serpina1 locus. In addition, polymorphism at the locus is defined by three
      haplotypes (Serpina1(b), Serpina1(c), and Serpina1(l)) that differ with regard to
      both the number and identity of alpha(1)-PI genes. Finally, we present the
      complete sequence of an 84-kb region of Serpina1 containing a tandem repeat of
      two alpha(1)-PI genes.

PMID- 12408970
TI  - Investigating the mechanism of chromosomal deletion: characterization of 39
      deletion breakpoints in introns 47 and 48 of the human dystrophin gene.
AB  - The region of the dystrophin gene containing introns 45-50 is characterized by a
      high rate of recombination events that give rise to large deletions causing
      dystrophinopathy. The nucleotide sequence of this intronic region has recently
      been released in GenBank. With the aim of further understanding the mechanism
      favoring the occurrence of these deletions, we have characterized the
      distribution of introns 47 and 48 deletion endpoints in 39 dystrophinopathy
      patients. In 14 of these patients we were able to sequence the break junction. On
      these sequences we were able to identify several intronic motifs that could
      predispose to DNA double-strand breaks. Our results, combined with other
      literature data, show that unequal homologous recombination is a very poorly
      represented event in the dystrophin gene, whereas junction features are
      suggestive of a model of recombination in which DNA double-strand breaks are
      incorrectly repaired by a nonhomologous end-joining mechanism. The correlation
      among recombination rate, deletion frequency, and percentage of repetitive
      elements is discussed.

PMID- 12408971
TI  - Characterization of the genomic and transcriptional structure of the CRX gene:
      substantial differences between human and mouse.
AB  - We have previously shown that there is a temporal difference in human CRX: gene
      expression compared with that of mouse Crx. We have now characterized these genes
      at the genomic and transcriptional levels and here we expand on this earlier
      report. Human CRX: spans 25 kb and has six exons, and mouse CRX: spans 15 kb and
      has four exons. We isolated seven human and two mouse mRNAs generated by
      alternative splicing of a variable 5' untranslated region. The human and mouse
      genes share an evolutionarily conserved promoter, which contains OTX/CRX type and
      SP1/AP2 binding sites and drives expression of two conserved transcripts in both
      species. Additionally, the human gene has a second human-specific promoter, which
      has OTX/CRX type binding sites and drives expression of five other transcripts.
      Band shift assays have shown that six of the seven candidate OTX/CRX elements
      bind CRX in vitro, possibly implying that the gene can regulate its own
      expression. These data may account for the differences in temporal expression IN
      VIVO: we have previously reported between these two species.

PMID- 12408972
TI  - Discovery of gene families and alternatively spliced variants by RecA-mediated
      cloning.
AB  - Probing the functional complexity of the human genome will require new gene
      cloning techniques, not only to discover intraspecies gene homologs and
      interspecies gene orthologs, but also to identify alternatively spliced gene
      variants. We report homologous cDNA cloning methods that allow cloning of gene
      family members, genes from different species, and alternatively spliced gene
      variants. We cloned human 14-3-3 gene family members using DNA probes with as
      much as 35% sequence divergence, cloned alternatively spliced gene forms of
      Rad51D, and cloned a novel splice form of the human 14-3-3 theta gene with a
      unique expression pattern. Interspecies gene cloning was demonstrated for the
      mouse Rad51C and mouse beta-actin genes using human gene probes. The gene family
      cloning method is fast, efficient, and free from PCR errors; moreover, it
      exploits the abilities of RecA protein to pair homologous or partially homologous
      DNA sequences stably in kinetically trapped, multistranded DNA hybrids that can
      be used for subsequent gene clone enrichment.

PMID- 12408973
TI  - Phytochrome-mediated signal transduction pathways in plants.
AB  - Phytochromes are photoreceptors that regulate plant growth and development in
      response to the solar radiation environment. Recent studies reveal how
      phytochrome-mediated light signals can be transduced to the cells for their
      responses. The possible signal transduction pathways of phytochromes include: (a)
      direct regulation of gene transcription and (b) typical kinase-involved signaling
      pathways and its regulation by phosphorylation, dephosphorylation, and
      proteolytic degradation. This review highlights some of the recent findings.

PMID- 12408974
TI  - Attenuated signaling associated with immune activation in HIV-1-infected
      individuals.
AB  - Chronic immune activation is associated with impaired signal transduction. Since
      such activation is commonly found during HIV-1 infection, we studied cellular
      responses to non-specific T-cell receptor stimulation of PBMC obtained from 20
      HIV-1 non-infected individuals and 23 highly or partially immune activated HIV-1
      infected individuals. PBMC proliferation and ERK-1/2 phosphorylation following
      anti-CD3 stimulation, and constitutive levels of Cbl-b, were determined.
      Increased levels of Cbl-b, decreased proliferation, and lower ERK-1/2
      phosphorylation were found in PBMC of highly immune activated HIV-1 infected
      individuals. The elevated expression of Cbl-b and impaired phosphorylation of ERK
      1/2 associated with immune activation probably contribute to the attenuated
      proliferative and cellular responses characteristic of HIV-1 infection.
      Therefore, targeting immune negative modulators, such as Cbl-b, may serve as a
      novel approach for controlling HIV-1 disease progression.

PMID- 12408975
TI  - Oxidation products of phospholipid-containing delta-9 fatty acids specifically
      impair the activity of tissue factor pathway inhibitor.
AB  - In the present study, we explored the active components in oxidized low-density
      lipoprotein (ox-LDL) that reduce the catalytic activity of tissue factor pathway
      inhibitor (TFPI), a Kunitz-type protease inhibitor of the extrinsic blood
      coagulation pathway. The active fraction was extracted from the phospholipid
      fraction of ox-LDL and separated. The oxidation products of 1- and/or 2-oleoyl
      phosphatidylcholine (PC) or phosphatidylethanolamine were the most potent
      compounds, while those of arachidonyl PC possessed only a weak inhibitory effect
      on the TFPI activity. These oxidized phospholipids associated strongly with rTFPI
      containing the carboxyl-terminal domain. When rTFPI was incubated with purified
      oxononanoyl PC (9CHO-PC) and its carboxylic form (9COOH-PC), the catalytic
      activity was specifically impaired, though neither oxovaleroyl PC (5CHO-PC) nor
      lyso-phospholipids reduced the TFPI activity. We conclude that the oxidation
      products of delta-9 unsaturated phospholipid in the lipoproteins are the active
      components that impair the anti-coagulation activity of TFPI.

PMID- 12408976
TI  - Elevated phospholipase D activity induces apoptosis in normal rat fibroblasts.
AB  - Elevated expression of phospholipase D (PLD) in rat fibroblasts overexpressing a
      tyrosine kinase leads to cell transformation. However, it has been difficult to
      get elevated expression of PLD in normal rat fibroblasts. Using transient
      transfection and an inducible expression system, we were able to get elevated
      expression of PLD1 and PLD2 in 3Y1 rat fibroblasts. Elevated expression of either
      PLD1 or PLD2 in 3Y1 cells led to apoptosis in the absence of serum. Elevated PLD
      expression resulted in reduced cell viability and the cleavage of the caspase 3
      substrates poly-ADP-ribose polymerase (PARP) and protein kinase C delta. Elevated
      PLD expression also stimulated cytochrome c release, indicating that the
      mitochondrial apoptosis pathway was activated. Thus, while elevated PLD
      expression can transform cells with elevated tyrosine kinase expression, elevated
      expression of PLD activity in normal cells renders cells sensitive to apoptotic
      insult.

PMID- 12408977
TI  - Binding symmetry of extracellular divalent cations to conduction pore studied
      using tandem dimers of a CNG channel.
AB  - Cyclic nucleotide-gated (CNG) channels are composed of the tetramer of alpha
      subunit alone or alpha- and beta-subunits. The alpha-subunits of these channels
      have a conserved glutamate (Glu) residue within the pore-forming region and the
      residue determines the selectivity as well as the affinity for the extracellular
      divalent cations. Using the high-affinity mutant (E363D) of bovine retinal CNG
      channel in which the Glu at position 363 was replaced to Asp, we constructed
      tandem dimers and investigated the binding characteristics of divalent cations to
      the site. The gating and permeation characteristics of individual homomeric
      tandem dimers are indistinguishable to those of homo-tetramers formed by parental
      monomers. The heteromeric tandem dimers showed the binding affinity for Sr(2+)
      identical to the geometric mean of the affinities for two parent channels,
      indicating the energy additive and thus the simultaneous interaction. On the
      other hand, the binding affinity for Mg(2+) followed the harmonic mean of those
      parent channels indicating that Mg(2+) interacts more strongly with the subunit
      bearing Asp residue at the position. Thus the results strongly suggest that the
      Glu363 residues in the CNG channel pore be flexible enough to adapt different
      binding symmetries for different divalent cations. Moreover, the simultaneous
      interaction between the four Glu residues and Sr(2+) provides an important
      structural constraint to the CNG channel outer vestibule of unknown structure.

PMID- 12408978
TI  - In vitro selection of specific RNA inhibitors of NFATc.
AB  - NFAT (nuclear factor of activated T cells) plays a pivotal role in inducible gene
      transcription during the immune response and functions as a major target for
      immunosuppressive drugs such as cyclosporin A and FK-506. However, due to toxic
      effects of these drugs, which arise from their ability to inhibit calcineurin in
      non-immune cells, development of agents that directly target NFAT without toxic
      effects is warranted. Here, we present an in vitro selection of RNA aptamer to
      NFATc DNA binding domain (DBD) from a combinatorial RNA library with 41
      nucleotide-long random sequences using the SELEX technique. The selected (SE) RNA
      was found to specifically and avidly bind NFATc DBD based on immunoprecipitation
      and competitive gel retardation assay. SE RNA also efficiently and specifically
      inhibited DNA binding capacity of NFATc, but not NFATp. Furthermore, transient
      RNA transfection studies show that only SE RNA can selectively and efficiently
      inhibit the NFATc- but neither the NFkappaB- nor NFATp-driven promoter activity
      in cells. These results suggest that SE RNA identified in this study is a
      specific inhibitor of NFATc activation, and hence, can be used not only for the
      study of NFAT functions but for the development of potent immune modulating
      agents.

PMID- 12408979
TI  - Dual effects of the homeobox transcription factor Csx/Nkx2-5 on cardiomyocytes.
AB  - A homeobox-containing transcription factor Csx/Nkx2-5 is an important regulator
      of cardiac development. Many different human CSX/NKX2-5 mutations have been
      reported to cause congenital heart disease. We here examined the effects of three
      representative CSX/NKX2-5 mutations on cardiomyocyte differentiation and death
      with the use of the P19CL6 cardiomyogenic cell lines. Stable overexpression of
      wild-type CSX/NKX2-5 enhanced expression of cardiac-specific genes such as MEF2C
      and MLC2v, the promoter activity of the atrial natriuretic peptide gene, and the
      terminal differentiation of P19CL6 into cardiomyocytes, while all CSX/NKX2-5
      mutants attenuated them by different degrees. When exposed to H(2)O(2) or
      cultured without change of the medium, many differentiated P19CL6 cells
      overexpressing the mutants, especially the mutant which lacks the carboxyl
      terminal region just after the homeodomain, were dead, while most of the cells
      overexpressing wild-type CSX/NKX2-5 survived. Overexpression of the carboxyl
      terminus-deleted mutant down-regulated expression of an anti-apoptotic protein
      Bcl-x(L) and up-regulated that of a pro-apoptotic protein CAS, while in the cells
      overexpressing wild-type CSX/NKX2-5, expression of a pro-apoptotic protein RIP
      was reduced. Furthermore, overexpression of wild-type CSX/NKX2-5 decreased the
      number of H(2)O(2)-induced TUNEL-positive cultured cardiomyocytes of neonatal
      rats, whereas overexpression of the mutants enhanced it. These results suggest
      that Csx/Nkx2-5 not only regulates expression of cardiac-specific genes but
      protects cardiomyocytes from stresses and that cell death may be another cause
      for the cardiac defects induced by human CSX/NKX2-5 mutations.

PMID- 12408980
TI  - Identification of an alternatively spliced isoform of the fyn tyrosine kinase.
AB  - Two isoforms of the src-family tyrosine kinase p59fyn have been shown to arise
      through alternative splicing of exon 7 of the fyn gene. These isoforms have been
      designated fynT, expressed in hematopoietic cells, and fynB, expressed in the
      brain. Here, we describe a novel isoform, fynDelta7, in which exon 7 is absent.
      FynDelta7 mRNA transcripts have been identified in peripheral blood mononuclear
      cells from all individuals tested thus far and semi-quantitative RT-PCR indicates
      that this fyn transcript is expressed at near wild-type levels. Transcripts
      coding for the fynDelta7 isoform can be detected in purified B cells, T cells, NK
      cells, and monocytes, indicating that it is not lineage specific. We further show
      that the message isolated is functional using an in vitro expression system and
      by its expression in COS cells.

PMID- 12408981
TI  - Electroporation in combination with a plasmid vector containing SV40 enhancer
      elements results in increased and persistent gene expression in mouse muscle.
AB  - Gene transfer into muscle upon injection of plasmid DNA is feasible but occurs
      with low frequency. However, by using electroporation after injection of plasmid
      DNA into mouse muscle it has been demonstrated that gene expression can be
      increased more than 150-fold. In this communication, we have used this technique
      in combination with plasmids containing a tandem repeat of three 72-bp DNA
      elements from the SV40 enhancer to study gene expression. Our results show that
      the combination of electroporation and a plasmid vector carrying these DNA
      elements results in increased and more persistent gene expression of the
      luciferase reporter gene in BALB/c mouse muscle. At 14 days after gene delivery,
      the gene expression was 16-fold higher in muscles injected and electroporated
      with the plasmid carrying the SV40 enhancers than with control plasmid. We have
      also studied the effects of the vehicle in which the plasmid was delivered, and
      the DNase inhibitor aurintricarboxylic acid (ATA), on gene expression. By
      combining ATA with 150 mM sodium phosphate buffer we were able to obtain a 2-fold
      increase in gene expression compared to delivery of the plasmid in physiological
      saline. These results are of importance for the development of efficient delivery
      techniques for naked DNA.

PMID- 12408982
TI  - Novel interaction of cortactin with endothelial cell myosin light chain kinase.
AB  - Inflammatory mediators such as thrombin evoke increases in vascular permeability
      through activation of endothelial contractile mechanisms which involve increased
      levels of MLC phosphorylation catalyzed by Ca(2+)/calmodulin-dependent myosin
      light chain kinase (MLCK). We previously noted that the high molecular weight
      endothelial MLCK isoform (EC MLCK) is stably associated with a complex containing
      p60(src) and 80kDa cortactin, an actin-binding protein and known p60(src) target.
      In this study we have utilized in vitro binding assays to confirm specific
      interaction between EC MLCK and cortactin. Tyrosine phosphorylation of either EC
      MLCK (Y(464), Y(471)) or cortactin (Y(421), Y(466), and Y(482)) by p60(src)
      significantly increased this direct association. Site-specific antibody and
      peptide studies subsequently confirmed EC MLCK AA #972-979 and 1019-1025 as sites
      of cortactin interaction. EC MLCK-cortactin interaction in vitro failed to
      modulate MLCK enzymatic activity but appeared to inhibit EC MLCK binding to F
      actin, while EC MLCK abolished cortactin-mediated augmentation of Arp2/3
      stimulated actin polymerization. These data suggest that cortactin-EC MLCK
      interaction may be a novel determinant of endothelial cortical actin-based
      cytoskeletal rearrangement.

PMID- 12408983
TI  - Release of regulators of angiogenesis following Hypocrellin-A and -B photodynamic
      therapy of human brain tumor cells.
AB  - Photodynamic therapy (PDT) is an innovative strategy for the treatment of solid
      neoplasms of the brain. Aside from inducing cell death in tumor cells, PDT
      induces endothelial cell death and promotes formation of blood clots; however,
      exact mechanisms that trigger these phenomena remain largely unknown. We now used
      Western blotting to analyze secretion of regulators of angiogenesis to the
      supernatants of one glioma, one macrophage, and one endothelial cell line
      following Hypocrellin-A and -B photodynamic therapy. We observed induction of
      proangiogenic VEGF (vascular endothelial growth factor) and of antiangiogenic
      sFlt-1, angiostatin, p43, allograft inflammatory factor-1, and connective tissue
      growth factor. Release of thrombospondin-1 was diminished in a glioma cell line
      supernatant. Endostatin release was induced in glioma cells and reduced in
      macrophages and endothelial cells. These data show that a wide range of
      antiangiogenic factors are secreted by brain tumor cells following Hypocrellin
      photochemotherapy. However, VEGF release is also induced thus suggesting both
      favorable and deleterious effects on tumor outgrowth.

PMID- 12408984
TI  - pCLCA1 becomes a cAMP-dependent chloride conductance mediator in Caco-2 cells.
AB  - Members of the CLCA protein family are expressed in airway and intestinal
      epithelium, where they may participate in secretory activity as mediators of
      chloride conductance. A calcium-dependent chloride conductance has been observed
      upon expression of CLCA proteins in non-epithelial cell lines. The pCLCA1 gene,
      cloned in our laboratory, codes for a product containing a unique A-kinase
      consensus acceptor site not found in other CLCA proteins. Calcium-dependent, but
      not cAMP-dependent, chloride conductance increased when pCLCA1 was expressed in
      NIH/3T3 fibroblasts. We transfected the Caco-2 human colon carcinoma cell line
      with pCLCA1 to investigate the regulation of CLCA-associated chloride conductance
      in this differentiated epithelial cell line. Expression of pCLCA1 in the Caco-2
      cell line enhanced cAMP-responsive 36Cl efflux, short circuit current, and whole
      cell chloride current in these cells. This cAMP-dependent chloride conductance
      was localized to the apical membrane of polarized Caco-2 cells.

PMID- 12408985
TI  - Effects of cisplatin on expression of DNA ligases in MiaPaCa human pancreatic
      cancer cells.
AB  - The effect of the broad-spectrum anticancer agent, cisplatin, on the expression
      of DNA ligase I in human pancreatic carcinoma MiaPaCa cells was examined in this
      study, since DNA ligase I is known to be involved in various DNA repair pathways.
      Upon exposure of MiaPaCa cells to cisplatin at near IC(50) value (2.5-5 microM),
      about 2-3-fold increase of DNA ligase I levels was observed within 24h, while
      levels of other DNA ligases (III and IV) remained unchanged or slightly
      decreased. The same fold-increase in DNA ligase I levels was also observed in
      MiaPaCa cells exposed to cytostatic concentrations, but not cytotoxic
      concentrations of cisplatin, which significantly reduced the number of cells.
      Flow cytometric analysis revealed that normal cell cycle progression was
      disrupted in the cells treated with cisplatin, resulting in an initial arrest of
      the cells in the S-phase, concomitant with a decrease of cells in G0/G1-phase.
      With time elapsing, the transition from S- to G2 + M-phase was observed, but
      further progression into G0/G1-phase was blocked. Overall, the increase of DNA
      ligase I expression seems to correlate well with the arrest of the cell cycle
      between the S- and G2-phases in response to cisplatin treatment. Interestingly,
      the cisplatin-induced DNA ligase I increase was abrogated by caffeine treatment
      in MiaPaCa cells, suggesting that caffeine sensitive kinases might be important
      mediators in the pathway, leading to the increase of DNA ligase I levels in
      response to cisplatin. We propose that the increase of DNA ligase I expression
      after exposure to cisplatin might be required for aiding the cells to recover
      from the damage by facilitating the repair process.

PMID- 12408986
TI  - Identification and characterization of two novel low-molecular-weight dual
      specificity phosphatases.
AB  - We have cloned and characterized two novel human low molecular weight dual
      specificity phosphatases (LMW-DSPs). Both genes are expressed exclusively in the
      testis, but are not altered in any of several disease states examined.
      Transfection into COS cells indicates that both proteins are expressed in the
      nucleus and the cytoplasm. Both proteins are able to dephosphorylate the
      phosphotyrosine analog pNPP in vitro and can be inhibited by sodium
      orthovanadate. In vitro experiments also demonstrate that both DSPs can
      dephosphorylate single and diphosphorylated synthetic MAPK peptides, with
      preference for the phosphotyrosine and diphosphorylated forms over
      phosphothreonine. However, when co-transfected with MAPKs into COS cells, the
      novel DSPs exhibited no detectable in vivo activity against MAPKs under our
      conditions. Our data suggest that these novel LMW-DSPs might belong to a new
      subclass of testis-specific proteins that act independently of the MAPK signal
      transduction cascade and do not depend on N-terminal docking regions for
      substrate binding.

PMID- 12408987
TI  - The in vitro and in vivo protective activity of monoclonal antibodies directed
      against Hantaan virus: potential application for immunotherapy and passive
      immunization.
AB  - Hantaan virus (HTNV), a member of the genus Hantavirus, family Bunyaviridae, is
      an etiologic agent causing a serious human disease, hemorrhagic fever with renal
      syndrome (HFRS), with a mortality as high as 15% and is also a potential
      bioterrorism agent. It is urgently needed to develop anti-HTNV-neutralizing
      monoclonal antibodies (MAbs) for treatment and prevention of HTNV infection. In
      the present study, 18 murine MAbs directed against HTNV strain Chen were
      generated and characterized. Among these MAbs, 13 were directed against viral
      nucleocapsid protein (NP), four recognized the viral envelope glycoprotein G2 and
      one reacted with both NP and G2. Only those MAbs that recognize the epitopes on
      G2 were positive in hemagglutination inhibition (HI) test and had in vitro virus
      neutralizing activity and in vivo protective activity against HTNV infection of
      susceptible mice. Since all the mice were protected by administration of the
      virus-neutralizing MAbs one day before and two days after HTNV challenge, these
      neutralizing MAbs are potentially useful for pre- and post-exposure prophylaxis
      and for immunotherapy of HTNV infection. Phase II clinical trials of these
      neutralizing MAbs for emergent treatment of patients with HTNV infection in early
      stages of HRFS are carried out in endemic areas in China.

PMID- 12408988
TI  - Cell surface expression of a GPI-anchored form of mouse acetylcholinesterase in
      Klpmr1Delta cells of Kluyveromyces lactis.
AB  - The mouse acetylcholinesterase AChE(H) was expressed in the yeast Kluyveromyces
      lactis. The AChE(H) activity was detectable in intact cells whereas it was absent
      in the culture media. Glucanase treatment and immunoelectron microscopy data
      indicated that AChE(H) is anchored to plasma membrane and that the mouse GPI
      signaling is compatible with the K. lactis targeting machinery. The AChE(H) was
      also expressed in a K. lactis strain carrying an inactivated allele of KlPMR1,
      the gene coding for a P-type Ca(2+)-ATPase of the Golgi apparatus. This mutant
      displays changes in protein glycosylation and cell wall structure. The AChE(H)
      activity detected in Klpmr1Delta cells was more than twofold higher than that
      observed in wild-type cells. The combination of AChE expression and anchoring
      with the characteristics of Klpmr1Delta strain of K. lactis resulted in yeast
      cells displaying high AChE activity. This could be regarded as a novel sensing
      unit to be employed for detecting AChE inhibitors as pesticides.

PMID- 12408989
TI  - Functional improvement of antibody fragments using a novel phage coat protein III
      fusion system.
AB  - Functional expressions of proteins often depend on the presence of host specific
      factors. Frequently recombinant expression strategies of proteins in foreign
      hosts, such as bacteria, have been associated with poor yields or significant
      loss of functionality. Improvements in the performance of heterologous expression
      systems will benefit present-day quests in structural and functional genomics
      where high amounts of active protein are required. One example, which has been
      the subject of considerable interest, is recombinant antibodies or fragments
      thereof as expressions of these in bacteria constitute an easy and inexpensive
      method compared to hybridoma cultures. Such approaches have, however, often
      suffered from low yields and poor functionality. A general method is described
      here which enables expressions of functional antibody fragments when fused to the
      amino-terminal domain(s) of the filamentous phage coat protein III. Furthermore,
      it will be shown that the observed effect is neither due to improved stability
      nor increased avidity.

PMID- 12408990
TI  - Ionic interaction of the HIV-1 V3 domain with CCR5 and deregulation of T
      lymphocyte function.
AB  - We have reported that the principal neutralizing domain of V3 of the HIV-1 gp120
      induces an antigen-specific activation apoptosis of responding effector CD4+ T
      lymphocytes, a phenomenon inhibited by RANTES, an agonist of CCR5. Here,
      addressing the question of how a hypervariable region could induce such a
      selective reaction, we demonstrated that the magnitude of the activation phase
      was dependent on the number of basic amino acids present in the V3 peptide, an
      observation confirmed by using V3 peptides with appropriate basic amino acid
      substitutions. The relative position of the amino acids in the V3 peptide did not
      affect the biological phenomenon. Using surface plasmon resonance biosensor
      analysis, we also provided direct evidence of the influence of basic amino acids
      in the interaction between V3 and the amino terminal domain of CCR5. Sulphation
      of tyrosines in the CCR5 peptide was essential. Our results confirm gp120
      modelling predictions and demonstrate simple molecular ionic interactions as
      capable of affecting key cell events, the wider biological implications of which
      need to be further explored.

PMID- 12408991
TI  - Diverse eukaryotic transcripts suggest short tandem repeats have cellular
      functions.
AB  - Previously thought "junk" DNA, short tandem repeats consisting of (GATA)n, or its
      compliment, were found in varied metazoan eukaryotic genomes but were rare in
      yeast and bacterial genomes. The (GATA)n sequence was found in cDNAs encoding
      mRNAs with known functions. At least 16 of 18 such transcripts encode membrane
      associated proteins including: plasma membranes, synapses, mitochondrial
      membranes, nuclear envelopes, and brush border membranes. Flanking sequences were
      diverse but (GATA)n sequences clustered around 500 bases from stop codons. The
      (GATA)n sequences occurred in both orientations and showed constrained
      polymorphism. In sets of splice variants with and without (GAUA)n, the STR
      containing transcripts were the most abundant. These observations suggest that
      (GATA)n sequences probably function. In many cases, the function may be to encode
      post-transcriptional signals for mRNAs encoding membrane-associated proteins.

PMID- 12408992
TI  - In vitro transfer of antisense oligodeoxynucleotides into coronary endothelial
      cells by ultrasound.
AB  - Since antisense oligodeoxynucleotides (AS-ODNs) have been recognized as a new
      generation of putative therapeutic agents, we established a delivery technique
      that could transfect AS-ODNs, which are designed for endothelin type B receptor
      (ETB), into cultured human coronary endothelial cells (HCECs) by exposure to
      ultrasound in the presence of echo contrast microbubbles. Ultrasound offers
      several advantages such as being nontoxic, nonantigenic and providing rapid gene
      transfer. We standardized the optimal conditions, which consisted of 2 x 10(6)
      cells suspended in phosphate buffer with 900nM ODN, 50 microl of echo contrast
      microbubbles (Optison), and ultrasound exposure (1.0 W/cm(2), 10% duty cycle, and
      10s duration). The percentage of transfected cells was 25.2+/-2.0% after
      ultrasound treatment. This is the first demonstration of the use of the
      ultrasound exposure technique in conjunction with microbubbles in HCECs.

PMID- 12408993
TI  - Visualization of intracellular trafficking of exogenous DNA delivered by cationic
      liposomes.
AB  - To visualize the intracellular trafficking of exogenous DNAs delivered by
      cationic liposomes, rhodamine-labeled DNAs were transfected into NIH3T3 cells and
      observed by confocal laser microscopy. After 0.5- to 1-h incubations, the DNAs
      reached the nucleus with a much higher frequency than that expected from the cell
      division rate. This result suggests that DNAs can enter the nucleus in the
      presence of the nuclear membrane. Interestingly, some DNAs appeared to extend
      through the nuclear membrane in the aggregated form which were much larger than
      the nuclear pore complex. The DNAs which have passed through the nuclear membrane
      were stained with SYTO 24, a DNA labeling reagent. The stained part may be
      "naked" DNA that is free of lipids or proteins. This observation indicates that a
      complex containing DNA fuses with the nuclear membrane and then naked DNA is
      released into the nucleus.

PMID- 12408994
TI  - The domain-swapped dimer of cyanovirin-N contains two sets of oligosaccharide
      binding sites in solution.
AB  - The binding of high-mannose oligosaccharides to the domain-swapped dimeric form
      of the potent HIV-inactivating protein cyanovirin-N (CV-N) was investigated in
      solution by NMR, complementing recent structural studies by X-ray crystallography
      on similar complexes [J. Biol. Chem. 277 (2002) 34336]. The crystal structures of
      CV-N dimer complexed with Man-9 and hexamannoside revealed two carbohydrate
      binding sites on opposite ends of the molecule. No binding was observed at site
      1, previously identified on the solution monomer of CV-N [Structure 9 (2001) 931;
      Shenoy et al., Chem. Biol. 9 (2002) 1109]. Here, we report the presence of four
      sugar binding sites on the CV-N dimer in solution, identified by chemical shift
      mapping with hexamannoside and nonamannoside, synthetic substructures of Man-9.
      Our results demonstrate that in solution the domain-swapped CV-N dimer, like the
      CV-N monomer, contains two types of sites that are available for carbohydrate
      binding, suggesting that the occlusion of the primary sites in the crystal is due
      to specific features of the solid state.

PMID- 12408995
TI  - Ganoderma lucidum suppresses motility of highly invasive breast and prostate
      cancer cells.
AB  - A dried powder from basidiomycetous fungi, Ganoderma lucidum, has been used in
      East Asia in therapies for several different diseases, including cancer. However,
      the molecular mechanisms involved in the biological actions of Ganoderma are not
      well understood. We have recently demonstrated that phosphatidylinositol 3-kinase
      (PI 3-kinase) and nuclear factor-kappaB (NF-kappaB) regulate motility of highly
      invasive human breast cancer cells by the secretion of urokinase-type plasminogen
      activator (uPA). In this study, we investigated the effect of G. lucidum on
      highly invasive breast and prostate cancer cells. Here we show that spores or
      dried fruiting body of G. lucidum inhibit constitutively active transcription
      factors AP-1 and NF-kappaB in breast MDA-MB-231 and prostate PC-3 cancer cells.
      Furthermore, Ganoderma inhibition of expression of uPA and uPA receptor (uPAR),
      as well secretion of uPA, resulted in the suppression of the migration of MDA-MB
      231 and PC-3 cells. Our data suggest that spores and unpurified fruiting body of
      G. lucidum inhibit invasion of breast and prostate cancer cells by a common
      mechanism and could have potential therapeutic use for cancer treatment.

PMID- 12408996
TI  - Cloning and localization of rgpr85 encoding rat G-protein-coupled receptor.
AB  - In an attempt to isolate genes involved in the brain development using ordered
      differential display PCR, we cloned rgpr85 which encodes rat G-protein-coupled
      receptor with high degree of identity to the amine-like neurotransmitter
      receptors. This gene was found to be localized at rat chromosome 4q21. In situ
      hybridization demonstrated that rgpr85 was predominantly expressed in the
      developing brain and spinal cord. Hybridization signal was especially abundant
      within the embryonic cortical plates where postmitotic cortical neurons are
      localized. In the cerebral cortex, the expression of rgpr85 was gradually
      decreased postnatally and became undetectable by P18. However, weak but
      significant expression of rgpr85 was maintained in the adult hippocampal
      formation, olfactory bulb, and cerebellum. Interestingly, rgpr85 expression was
      transiently induced in the adult hippocampal formation, piriform cortex, and
      amygdaloid complex by kainic acid (KA) treatment. Thus, dynamic regulation of
      rgpr85 expression suggests an importance of rgpr85-mediated signaling in the
      development of cerebral cortex and in the KA-induced responses in the adult
      brain.

PMID- 12408997
TI  - Calmodulin-dependent regulation of hypotonicity-induced translocation of ENaC in
      renal epithelial A6 cells.
AB  - Hypotonicity stimulates translocation of epithelial Na(+) channel (ENaC) to the
      apical membrane from the intracellular store site of ENaC by activating protein
      tyrosine kinase (PTK) in renal epithelial A6 cells. Based upon the fact that
      calmodulin shows its action on other enzymes through PTK caused phosphorylation
      of tyrosine residues of calmodulin itself, we studied whether a calmodulin
      dependent pathway is involved in the action of hypotonicity on ENaC. W7, an
      antagonist of calmodulin, diminished the stimulatory action of hypotonicity on
      ENaC, irrespective of W7 treatment before or after application of hypotonicity.
      Calmodulin is known to regulate three pathways: (1) protein phosphatase 2B
      (PP2B), (2) Ca(2+)/calmodulin-dependent protein kinase II (CaMK II), and (3)
      myosin light chain kinase (MLCK). Pretreatment with cyclosporin A, an inhibitor
      of PP2B, did not influence the hypotonicity action on ENaC. The hypotonicity
      action on ENaC was partially inhibited by pretreatment with KN93, an inhibitor of
      CaMK II, but not by addition of KN93 after hypotonic stimulation had been
      applied. ML-7, an inhibitor of MLCK, showed the action similar to KN93. These
      observations indicate that: (1) the hypotonicity-induced translocation of ENaC
      depends on CaMK II and MLCK and (2) ENaC translocated to the apical membrane by
      hypotonicity is maintained in its activity and/or stability at the apical
      membrane through a calmodulin-dependent pathway.

PMID- 12408998
TI  - Antagonists of platelet fibrinogen receptor are less effective in carriers of
      Pl(A2) polymorphism of beta(3) integrin.
AB  - The polymorphism Leu(33)-->Pro (platelet-specific antigen; Pl(A1/A2)) of platelet
      GPIIIa is a potential risk factor for arterial thrombosis. However, its influence
      on platelet function remains controversial and little is known about its impact
      on platelet sensitivity to GPIIb-IIIa antagonists. Our objective was to compare
      the effectiveness of various GPIIb-IIIa antagonists in Pl(A2)(+) and Pl(A2)(-)
      carriers. Platelet aggregation was monitored in healthy donors including Pl(A2)(
      ) (N=31) and Pl(A2)(+) subjects (N=27; 23 Pl(A1/A2), 4 Pl(A2)/(A2)) using the
      impedance and turbidimetric aggregation techniques. We evaluated the inhibition
      of ADP- and collagen-induced aggregation by disintegrins, kistrin and echistatin,
      and the low-molecular-weight blockers, GR144053F ((4-[4-[4-(aminoiminomethyl]-1
      piperazinyl]-1-piperidineacetic acid, hydrochloride trihydrate) and eptifibatide
      (N(6)-(aminoiminomethyl)-N(2)-(3-mercapto-1-oxopropyl-L-lysylglycyl-L-alpha
      aspartyl-L-tryptophyl-L-propyl-L-cysteinamide, cyclic (1-->6)-disulfide). Kistrin
      (10-30 nmol/l) inhibited ADP- and collagen-induced aggregation stronger in
      Pl(A2)(-) donors than in Pl(A2)(+) donors; there was a significant difference
      between 50% inhibitory concentrations (IC(50)). The same tendency occurred with
      moderate concentrations of eptifibatide (40-100 nmol/l) and also at low
      concentrations of GR144053F (5-10 nmol/l) and high concentrations of echistatin
      (80-150 nmol/l), although in the case of the two latter inhibitors, the estimated
      IC(50) values were not significantly different. In conclusion, GPIIb-IIIa
      blockers representing various classes are less effective inhibitors of platelet
      aggregation in Pl(A2)(+) carriers; however, the effect of the genotype is both
      agonist- and antagonist-dependent.

PMID- 12408999
TI  - Single-nucleotide polymorphisms in the lipoprotein lipase gene associated with
      coronary heart disease in Chinese.
AB  - Coronary heart disease is a complex disease reflecting the interaction of
      multiple genes with the environment (e.g. diet, life style). Lipoprotein lipase
      (LPL) plays an important role in lipid metabolism and the pathogenesis of
      coronary atherosclerosis. Recent associations between single-nucleotide
      polymorphisms in the LPL gene and heart disease have been reported, but little is
      known in Chinese. The LPL gene spans >26 kb, with an mRNA of 3549 bp. In the
      present study, we screened 5155 bp (565 bp of 5' flanking region, nine exons and
      donor- and acceptor-splice sites, and some intronic bases) in 160 Chinese
      patients with confirmed coronary heart disease and 150 age- and gender-matched
      controls. Thirteen of the sixteen single-nucleotide polymorphisms that we found
      have not been previously reported. In males, significant (P<0.05) differences
      between the coronary heart disease patients and controls were found for five
      single-nucleotide polymorphisms: -421G>A (5' flanking region); +13,577C>A (intron
      2); +16,052G>A, R192Q (exon 5); +16,173C>G and +16,177T>C (intron 5). In females,
      significant differences between the patients with coronary heart disease and
      controls were found for only the -421G>A and +16,052G>A (R192Q) mutations. Among
      the coronary heart disease males, significant (P<0.05) associations were found
      between the low-HDL high-triglyceride (LHDL/HTG) phenotype and the non-LHDL/HTG
      trait for the 5' flanking-421G, the intron 2+13,577C, and the exon 5+16,052G
      mutations, with odds-ratios (ORs)[confidence intervals] of 3.90[1.12-13.66],
      3.38[1.22-9.40], and 3.22[1.04-10.01], respectively; no corresponding
      associations were found in females. There were 69, 51, 57 and 41 unphased
      haplotype patterns in male coronary heart disease, male control, female coronary
      heart disease and female control groups, respectively; the computer program PM
      Plus found the heterogeneity model by far the best fit (P<0.0001 in males, >0.01
      in females). These data show that some single-nucleotide polymorphisms in the LPL
      gene among Chinese are associated with abnormal lipid and lipoprotein profiles
      and predisposition to coronary heart disease, a genetically heterogeneous complex
      disease, and that they are gender-specific.

PMID- 12409000
TI  - The kappa-opioid agonist (+/-)-bremazocine elicits peripheral antinociception by
      activation of the L-arginine/nitric oxide/cyclic GMP pathway.
AB  - In view of the scarce information about the analgesic mechanism of kappa-opioid
      receptor agonists, the objective of the present study was to determine whether
      nitric oxide (NO) is involved in the peripheral antinociception of bremazocine, a
      kappa-opioid receptor agonist. Three drugs all interfering with the L
      arginine/NO/cyclic GMP pathway were tested using the rat paw model of carrageenan
      induced (250 microg) hyperalgesia: (a) N(G)-nitro-L-arginine (a nonselective NO
      synthase inhibitor), (b) methylene blue (a guanylate cyclase inhibitor), and (c)
      zaprinast (a cyclic GMP phosphodiesterase inhibitor). Intraplantar administration
      of bremazocine (20, 40 and 50 microg) caused a dose-dependent peripheral
      antihyperalgesia against carrageenan-induced hyperalgesia. The possibility of the
      higher dose of bremazocine (50 microg) having central or systemic effect was
      excluded since administration of the drug into the left paw did not elicit
      antinociception in the contralateral paw. However, when the dose of bremazocine
      was increased to 100 microg, a significant increase in the nociceptive threshold
      was observed, as measured in the hyperalgesic contralateral paw. Peripheral
      antihyperalgesia induced by bremazocine (50 microg) was significantly reduced in
      a dose-dependent manner when N(G)-nitro-L-arginine (6, 9, 12 and 25 microg) or
      methylene blue (250, 375 and 500 microg) was injected before. Previous treatment
      with 50 microg of zaprinast (which had no effect when administered alone)
      potentiated the antihyperalgesic effect of bremazocine (20 microg). Our data
      suggest that bremazocine elicits peripheral antinociception by activation of the
      L-arginine/NO/cyclic GMP pathway and that nitric oxide is an intermediary in this
      mechanism, forming cyclic GMP.

PMID- 12409001
TI  - The binding of BmK abT, a unique neurotoxin, to mammal brain and insect Na(+)
      channels using biosensor.
AB  - The binding properties of BmK abT (a novel neurotoxic polypeptide abT from
      Chinese scorpion Buthus martensi Karsch), a unique neurotoxin from Chinese
      scorpion, on mammal brain and insect sodium channels were investigated using the
      BIAcore assay. Results showed that BmK abT could bind to rat brain synaptosomes
      with an association rate constant of about 2.49 x 10(6) M(-1) s(-1) and a
      dissociation rate constant of about 1.57 x 10(-4) s(-1), and to Heliothis nerve
      cord synaptosomes with an association rate constant of about 1.21 x 10(7) M(-1)
      s(-1) and a dissociation rate constant of about 0.99 x 10(-3) s(-1). The binding
      of BmK abT to rat brain synaptosomes could be partially inhibited by increasing
      the membrane potential, but not by BmK AS (a novel active polypeptide AS from B.
      martensi Karsch), BmK IT2 (a depressant insect-selective toxin IT2 from B.
      martensi Karsch), and BmK I (an alpha-like anti-mammal toxin I from B. martensi
      Karsch). Binding was not modulated by veratridine. In addition, the binding of
      BmK abT to Heliothis nerve cord synaptosomes was significantly enhanced by
      increasing the membrane potential and veratridine concentration and was inhibited
      by BmK IT2, but not by BmK AS or BmK I. The results suggest that BmK abT binds to
      a distinct receptor site on mammal brain Na(+) channels and associates with a
      related site for depressant insect-selective toxins on insect sodium channels.

PMID- 12409002
TI  - Transducing system operated by adenosine A(2A) receptors to facilitate
      acetylcholine release in the rat hippocampus.
AB  - Although molecular biology studies indicate the presence of adenosine A(2A)
      receptors in the rat hippocampus, the pharmacological characterization of
      adenosine A(2A) receptor binding and of its putative facilitatory effects has
      revealed features essentially different from these found for adenosine A(2A)
      receptors in most preparations. We now confirmed that activation of adenosine
      A(2A) receptors with 2-[4-(2-p-carboxyethyl)phenylamino]-5'-N
      ethylcarboxamidoadenosine (CGS 21680, 1-30 nM) or 2-hexynyl-5'-N
      ethylcarboxamidoadenosine (HENECA, 3-100 nM) facilitated the veratridine-evoked
      [3H]acetylcholine release from hippocampal synaptosomes with a maximal effect of
      14+/-2% and 16+/-2%, respectively. These effects were prevented by the adenosine
      A(2A) receptor antagonists, 4-(2-[7-amino-2-[2-furyl][1,2,4]
      triazolo[2,3a][1,3,5]triazin-5-yl-amino]ethyl)phenol (ZM 241385, 20 nM) and 5
      amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5
      c]pyrimidine (SCH 58261, 20 nM), but not by the adenosine A(1) receptor
      antagonist, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, 20 nM). Adenosine A(2A)
      receptors may activate adenylate cyclase and protein kinase A since CGS 21680 (10
      nM) facilitation of [3H]acetylcholine release was occluded by 8-bromo-cAMP (0.5
      mM) and forskolin (10 microM) and prevented by H-89 (1 microM), but unaffected by
      phorbol-12,13-didecanoate (250 nM) or bisindolylmaleimide I (1 microM). The
      existence of adenosine A(2A) receptors in hippocampal nerve terminals was further
      confirmed by a Western blot immunoreactivity qualitatively identical to that
      found in the striatum. This constitutes the first pharmacological identification
      of canonical adenosine A(2A) receptors coupling to the expected cAMP/protein
      kinase A pathway in the hippocampus with the expected immunoreactivity.

PMID- 12409003
TI  - Carbon monoxide and metabotropic glutamate receptors in rat nucleus tractus
      solitarii: participation in cardiovascular effect.
AB  - Carbon monoxide (CO) has been identified as an endogenous biological messenger in
      the brain. Heme oxygenase catalyzes the metabolism of heme to biliverdin and CO.
      Recent studies have demonstrated that CO is involved in central cardiovascular
      regulation and modulates the baroreflex in the nucleus tractus solitarii of rats.
      The purpose of the present study was to investigate the possible interaction of
      CO and excitatory amino acids in the nucleus tractus solitarii. In anesthetized
      male Sprague-Dawley rats, unilateral intranucleus tractus solitarii
      microinjection of hematin, a heme molecule cleaved by heme oxygenase to yield CO,
      or excitatory amino acids L-glutamate produced depressor and bradycardiac
      effects. Similar cardiovascular effects were observed with several agonists for
      ionotropic glutamate receptors such as N-methyl-D-aspartate (NMDA), (+/-)-alpha
      amino-3-hydroxyl-5-methylisoxazole-4-propanoic acid (AMPA), kainic acid and for
      metabotropic glutamate (mGlu) receptors, trans-(+/-)-1-amino-(1S,3R)
      cyclopentanedicarboxylic acid (ACPD). Among these agonists, prior administration
      of the heme oxygenase inhibitor, zinc deuteroporphyrin 2,4-bis glycol (ZnDPBG) (1
      nmol), significantly attenuated the cardiovascular effects of hematin, L
      glutamate and ACPD. Furthermore, the cardiovascular effects of ACPD were
      prevented by the selective mGlu receptors antagonist L-2-amino-3
      phosphonoprionate (L-AP3). However, pretreatment with ZnDPBG failed to prevent
      the cardiovascular responses to microinjection of NMDA, AMPA and kainic acid. On
      the other hand, prior administration of the NMDA receptor antagonist,
      diazocilpine (MK-801), or (+/-)-2-amino-5-phosphonopentanoic acid (APV)
      attenuated the depressor and bradycardiac effect of hematin. These results
      demonstrated that mGlu receptors may couple to the activation of heme oxygenase
      via the liberation of CO to participate in central cardiovascular regulation.
      They also suggested that CO and excitatory amino acids may interact in the
      nucleus tractus solitarii of rats.

PMID- 12409004
TI  - Differential action of ondansetron and dexamethasone to modify cisplatin-induced
      acute and delayed kaolin consumption ("pica") in rats.
AB  - The ability of cisplatin to induce acute (0-24 h) and delayed (24-48 and 48-72 h)
      phases of kaolin ingestion (pica) was investigated in the rat. Cisplatin 3 mg/kg,
      i.p., induced kaolin consumption during the 0-24- (P<0.001) and 48-72-h (P<0.05)
      periods that was antagonised by dexamethasone 1 mg/kg, i.p., administered every
      12 h alone or in combination with ondansetron 2 mg/kg, i.p., administered every
      12 h (P<0.05). As a single treatment, ondansetron 2 mg/kg, i.p., administered
      every 12 h potentiated cisplatin-induced kaolin consumption by 41% (P<0.05)
      during the 0-24-h period but had no action to modify the delayed response
      (P>0.05). Dexamethasone 1 mg/kg, i.p., administered every 12 h and cisplatin 3
      and 6 mg/kg, i.p., but not ondansetron 2 mg/kg, i.p., administered every 12 h
      (P>0.05) reduced food consumption and decreased rat weight. The highest dose of
      cisplatin 6 mg/kg, i.p., induced acute (P<0.001) but not delayed kaolin ingestion
      (P>0.05). The action of cisplatin to induce acute and delayed pica is complicated
      and may be affected by drugs that modify appetite.

PMID- 12409005
TI  - Antagonistic effects of CompB on orphanin FQ-induced colonic contractions in
      rats.
AB  - Orphanin FQ has been shown to stimulate colonic contraction without affecting
      upper gastrointestinal motility in rats. We studied whether a new putative
      orphanin FQ receptor antagonist, 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4
      piperidyl]-3-ethyl-1, 3-dihydro-2H-benzimidazol-2-one (CompB), has antagonistic
      effects on orphanin FQ-induced colonic contractions in vivo and in vitro in rats.
      Orphanin FQ-(1-17) and orphanin FQ-(1-13) caused contractions of the circular
      muscle of the distal colon in a concentration dependent manner (10(-10)-10(-6) M)
      in vitro. CompB (10(-7)-10(-6) M) caused a significant inhibition on orphanin FQ
      (1-17) and orphanin FQ-(1-13)-induced contractions without affecting the
      spontaneous contractions. Orphanin FQ-(1-17) also caused contractions of the
      distal colon in vivo. ED(50) dose of orphanin FQ-(1-17) (400 pmol/kg)-induced
      contractions were significantly antagonized by CompB (30-300 nmol/kg) in a dose
      dependent manner. In contrast, CompB had no inhibitory effects on dynorphin A
      induced contractions in vivo and in vitro. These indicate that CompB is a
      selective orphanin FQ receptor antagonist of the rat colon.

PMID- 12409006
TI  - Different responses to drugs against overactive bladder in detrusor muscle of
      pig, guinea pig and mouse.
AB  - Direct comparison of experimental data for drugs commonly used in the treatment
      of overactive bladder is difficult because of possible species differences. In
      this study, we compare the effects of atropine, propiverine, oxybutynin and
      tolterodine in strips of pig, guinea pig and mouse detrusor muscle. In the three
      species, we observed slight differences in potency of carbachol-induced biphasic
      contractile responses between the species (guinea pig>pig>mouse). Cumulative
      concentration-response curves for carbachol were shifted to the right by
      atropine, propiverine, oxybutynin and tolterodine. However, at higher
      concentrations of the latter three antagonists, the maximum response to carbachol
      was also reduced. Therefore, propiverine, oxybutynin and tolterodine must have
      additional pharmacological actions beyond competitive antagonism at muscarinic
      receptors. Electric field stimulation (30 Hz) of detrusor strips led to
      contraction amplitudes, which remained constant over time (210 min) in pig,
      decreased by 17+/-5% in guinea pig, and increased by 28+/-9% in mouse detrusor
      muscle. Electric field stimulation-evoked contractions were suppressed to 18% of
      pre-drug control by high concentrations of atropine (10 microM) in pig, but to a
      much lesser extent in guinea pig and mouse (to 46% and 70%, respectively). In all
      three species, a myogenic component of contraction was observed in the presence
      of tetrodotoxin (1 microM). Compared to atropine, the bladder spasmolytic agents
      propiverine, oxybutynin and tolterodine also reduced electrically evoked
      contractions in the three species, though higher concentrations were required.
      The differences in the reported effects of the spasmolytic agents commonly used
      for treating overactive bladder suggest that drug action is strongly dependent on
      the species. Thus, a comparison of drug effects is only feasible in the same
      animal model and the results cannot easily be transferred to humans.

PMID- 12409007
TI  - Activation of melanocortin MC(4) receptors increases erectile activity in rats ex
      copula.
AB  - Melanocortin peptide agonists, alpha-melanocyte stimulating hormone (alpha-MSH)
      and melanotan-II, stimulate erectile activity in a variety of species, including
      man. Since neither peptide discriminates amongst melanocortin receptors, it is
      not clear which subtype mediates these pro-erectile effects. Here, we present
      data that melanocortin-induced erectogenesis is mediated by melanocortin MC(4)
      receptors. Systemic administration of a melanocortin MC(4) receptor agonist (N
      [(3R)-1,2,3,4-tetrahydroisoquinolinium-3-ylcarbonyl]-(1R)-1-(4-chlorobenzyl)-2-[4
      cyclohexyl-4-(1H-1,2,4-triazol-1ylmethyl)piperidin-1-yl]-2-oxoethylamine; THIQ)
      with high selectivity over other melanocortin receptors enhanced intracavernosal
      pressure and stimulated erectile activity in rats ex copula. THIQ dose
      dependently (1-5 mg/kg, i.v.) increased the total number of erections, to an
      extent comparable or greater than that produced by apomorphine (0.025 mg/kg,
      s.c.). Central administration of THIQ (20 microg, intracerebroventricular
      (i.c.v.)) increased the number of reflexive penile erections; whereas
      administration of both a nonselective endogenous melanocortin MC(4) receptor
      antagonist (agouti-related protein (AgRP), 5.5. microg, i.c.v.) and a
      melanocortin MC(4) receptor preferring antagonist (MPB10, 1 mg/kg, i.v.) blocked
      THIQ-induced erectogenesis. These pro-erectile effects were also attenuated by
      systemic or central administration of an oxytocin antagonist (L-368899, 1 mg/kg,
      i.v.). Thus, melanocortin MC(4) receptor activation is sufficient for
      erectogenesis and these effects may involve oxytocinergic pathways.

PMID- 12409008
TI  - Preventive effect of long-chain fatty alcohol on ischemia--reperfusion injury in
      the rat bladder.
AB  - We attempted in the present study to clarify the preventive effects of
      cyclohexenonic long-chain fatty alcohol on ischemia-reperfusion injury in the rat
      bladder. Rat bladders were exposed to 30 min of ischemia and a subsequent 30 min
      of reperfusion with or without several doses of cyclohexenonic long-chain fatty
      alcohol (0.5, 2, 8 mg/kg). Muscle-bath studies were performed, and malonaldehyde
      concentrations were measured in the bladder. Bladder dysfunction and lipid
      peroxidation caused by ischemia-reperfusion were prevented by cyclohexenonic long
      chain fatty alcohol in a dose-dependent manner. Our data indicate that
      cyclohexenonic long-chain fatty alcohol can prevent the production of free
      radicals and ischemia-reperfusion injury in the bladder.

PMID- 12409010
TI  - Effects of the imidazoline ligands efaroxan and KU14R on blood glucose
      homeostasis in the mouse.
AB  - The putative imidazoline I(3) receptor antagonist 2-(2-ethyl-2,3
      dihydrobenzo[b]furan-2-yl)-1H-imidazole (KU14R) has been shown to block the
      effects of the atypical I(3) agonist efaroxan at the level of the ATP-sensitive
      K(+) (K(ATP)) channel in isolated pancreatic islet beta cells, but its effects in
      vivo are not known. We have therefore investigated the effects of KU14R on blood
      glucose and insulin level in vivo. When KU14R was administered before or after a
      hypoglycaemic dose of efaroxan, the fall in blood glucose was at least additive.
      When the antihyperglycaemic imidazoline ligand S22068 was administered after a
      dose of KU14R, it did not alter the hypoglycaemic response. In the mouse isolated
      vas deferens preparation, neither rauwolscine (at concentrations which
      competitively antagonised the inhibitory response to 5-bromo-6-(2-imidazolin-2
      ylamino)-quinoxaline (UK14304)) nor KU14R affected inhibition produced by S22068.
      At 10(-4) M, KU14R had weak alpha(2)-adrenoceptor antagonist activity. We
      conclude that KU14R does not act as an antagonist of either efaroxan or S22068 at
      an imidazoline site in vivo.

PMID- 12409009
TI  - KF24345, an adenosine uptake inhibitor, ameliorates the severity and mortality of
      lethal acute pancreatitis via endogenous adenosine in mice.
AB  - Adenosine protects against cellular damage and dysfunction under several adverse
      conditions including inflammation and ischemia. In this study, we examined the
      effects of 3-[1-(6,7-diethoxy-2-morpholinoquinazolin-4-yl)piperidin-4-yl]-1,6
      dimethyl-2,4(1H,3H)-quinazolinedione hydrochloride (KF24345), an adenosine uptake
      inhibitor, on experimental acute pancreatitis induced by choline-deficient and
      ethionine-supplemented diet in mice. KF24345, administered with the diet onset
      and every 24 h thereafter, prevented hyperamylasemia, acinar cell injury and
      serum tumor necrosis factor-alpha elevation and ultimately decreased mortality.
      Therapeutic treatment with KF24345, which started 32 h after the diet onset, also
      decreased mortality. The beneficial effect of KF24345 on mortality was abolished
      by the pretreatment with 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3
      a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM 241385), a selective adenosine A(2A)
      receptor antagonist. An intravenous injection of KF24345 at 48 h after the diet
      onset increased plasma adenosine concentrations in mice with acute pancreatitis.
      These results suggest that KF24345 shows anti-pancreatitis effects via endogenous
      adenosine and adenosine A(2A) receptors. The adenosine uptake inhibition could be
      a new therapeutic approach for acute pancreatitis.

PMID- 12409011
TI  - Attenuation of spontaneous opiate withdrawal in mice by the anandamide transport
      inhibitor AM404.
AB  - The endogenous cannabinoid, anandamide, has been shown to attenuate naloxone
      precipitated opiate withdrawal in rodents. Here we show that the spontaneous, but
      not the naloxone-precipitated withdrawal syndrome in morphine-dependent mice is
      attenuated by the inhibitor of carrier-mediated anandamide transport N-(4
      hydroxyphenyl) arachidonylethanolamide (AM404) (2 and 10 mg/kg, i.p.). These
      results suggest that spontaneous but not opioid antagonist-precipitated
      withdrawal is associated with dynamic changes in endogenous cannabinoid
      signaling.

PMID- 12409013
TI  - The in vivo nitrogen isotope discrimination among organic plant compounds.
AB  - The bulk delta 15 N-value of plant (leaf) biomass is determined by that of the
      inorganic primary nitrogen sources NO(3)(-), NH(4)(+) and N(2), and by isotope
      discriminations on their uptake or assimilation. NH(4)(+) from these is
      transferred into "organic N" mainly by the glutamine synthetase reaction. The
      involved kinetic nitrogen isotope effect does not become manifest, because the
      turnover is quantitative. From the product glutamine any further conversion
      proceeds in a "closed system", where kinetic isotope effects become only
      efficient in connection with metabolic branching. The central and most important
      corresponding process is the GOGAT-reaction, involved in the de novo nitrogen
      binding and in recycling processes like the phenylpropanoid biosynthesis and
      photorespiration. The reaction yields relatively 15N-depleted glutamate and
      remaining glutamine, source of 15N-enriched amide-N in heteroaromatic compounds.
      Glutamate provides nitrogen for all amino acids and some other compounds with
      different 15N-abundances. An isotope equilibration is not connected to
      transamination; the relative delta 15 N-value of individual amino acids is
      determined by their metabolic tasks. Relative to the bulk delta 15 N-value of the
      plant cell, proteins are generally 15N-enriched, secondary products like
      chlorophyll, lipids, amino sugars and alkaloids are depleted in 15N. Global delta
      15 N-values and 15N-patterns of compounds with several N-atoms can be calculated
      from those of their precursors and isotope discriminations in their biosyntheses.

PMID- 12409014
TI  - Behavior of phosphatase isoforms during sclerotium formation in Physarum
      polycephalum.
AB  - The behavior of phosphatase isoforms under dark-starvation from plasmodium of
      Physarum polycephalum were investigated to determine their possible roles in
      sclerotium formation. Two and a half days after dark-starvation, approximately
      95% of plasmodia plates formed sclerotia. Specific phosphatase activity increased
      markedly up to ca. two-fold within the first day of starvation, after which the
      enzymatic activity decreased rapidly to a level less than the initial level
      within 2 days of the starvation period. Among the two isoforms of enzyme detected
      just before sclerotization under dark-starvation conditions, the enzymatic
      activity of the major isoform (Rm value of 0.6) decreased gradually within 1.5
      days of starvation, then linearly to less than 20% of that at the beginning of
      the observation. Those of other major isoform (Rm value of 0.7) increased up to
      ca. two-fold within the first day of starvation, then decreased linearly to
      levels less than that of the first 2 days of the starvation period. Behavior of
      this isoform strongly suggests that it initiates the formation of sclerotium
      under dark-starvation conditions.

PMID- 12409015
TI  - Substrate selectivity of plant and microbial lysophosphatidic acid
      acyltransferases.
AB  - Linoleic acid (18:2) is found in a large variety of plant oils but to date there
      is limited knowledge about the substrate selectivity of acyltransferases required
      for its incorporation into storage triacylglycerols. We have compared the
      incorporation of oleoyl (18:1) and linoleoyl (18:2) acyl-CoAs onto
      lysophosphatidic acid acceptors by sub-cellular fractions prepared from a variety
      of plant and microbial species. Our assays demonstrated: (1). All
      lysophosphatidic acid acyltransferase (LPA-AT) enzymes tested incorporated 18:2
      acyl groups when presented with an equimolar mix of 18:1 and 18:2 acyl-CoA
      substrates. The ratio of 18:1 to 18:2 incorporation into phosphatidic acid varied
      between 0.4 and 1.4, indicating low selectivity between these substrates. (2).
      The presence of either stearoyl (18:0) or oleoyl (18:1) groups at the sn-1
      position of lysophosphatidic acid did not affect the selectivity of incorporation
      of 18:1 or 18:2 into the sn-2 position of phosphatidic acid. (3). All LPA-AT
      enzymes tested incorporated the saturated palmitoyl (16:0) acyl group from
      equimolar mixtures of 16:0- and 18:1-CoA. The ratios of 18:1 to 16:0
      incorporation are generally much higher than those of 18:1 to 18:2 incorporation,
      varying between 2.1 and 8.6. (4). The LPA-AT from oil palm kernel is an exception
      as 18:1 and 16:0 are utilised at comparable rates. These results show that, in
      the majority of species examined, there is no correlation between the final sn-2
      composition of oil or membrane lipids and the ability of an LPA-AT to use 18:2 as
      a substrate in in vitro assays.

PMID- 12409016
TI  - Purification and characterization of soluble peroxidase from oil palm (Elaeis
      guineensis Jacq) leaf.
AB  - Soluble peroxidase (POD) from oil palm leaf was purified by (NH(4))(2)SO(4)
      precipitation, anion exchange chromatography and molecular exclusion
      chromatography. The purification grade obtained was 429 yielding 54% of the
      enzyme activity. Electrophoresis of purified enzyme under denatured conditions
      revealed M(r) of 48+/-2 kDa. It has an optimum pH of 5 and it exhibited very high
      pH and thermal stabilities. K(m) for guaiacol, ABTS and pyrogallol were 3.96, 1
      and 0.84 mM, respectively. Immunocytochemical localization studies showed that
      soluble POD was mainly located in the vascular bundles and epidermis of leaf.

PMID- 12409017
TI  - Purification and characterization of urease from dehusked pigeonpea (Cajanus
      cajan L) seeds.
AB  - Urease has been purified from the dehusked seeds of pigeonpea (Cajanus cajan L.)
      to apparent electrophoretic homogeneity with approximately 200 fold purification,
      with a specific activity of 6.24 x10(3) U mg(-1) protein. The enzyme was purified
      by the sequence of steps, namely, first acetone fractionation, acid step, a
      second acetone fractionation followed by gel filtration and anion-exchange
      chromatographies. Single band was observed in both native- and SDS-PAGE. The
      molecular mass estimated for the native enzyme was 540 kDa whereas subunit values
      of 90 kDa were determined. Hence, urease is a hexamer of identical subunits.
      Nickel was observed in the purified enzyme from atomic absorption spectroscopy
      with approximately 2 nickel ions per enzyme subunit. Both jack bean and soybean
      ureases are serologically related to pigeonpea urease. The amino acid composition
      of pigeonpea urease shows high acidic amino acid content. The N-terminal sequence
      of pigeonpea urease, determined up to the 20th residue, was homologous to that of
      jack bean and soybean seed ureases. The optimum pH was 7.3 in the pH range 5.0
      8.5. Pigeonpea urease shows K(m) for urea of 3.0+/-0.2 mM in 0.05 M Tris-acetate
      buffer, pH 7.3, at 37 degrees C. The turnover number, k(cat), was observed to be
      6.2 x 10(4) s(-1) and k(cat)/K(m) was 2.1 x 10(7) M(-1) s(-1). Pigeonpea urease
      shows high specificity for its primary substrate urea.

PMID- 12409018
TI  - A cDNA clone for beta-caryophyllene synthase from Artemisia annua.
AB  - An homology-based cloning strategy yielded a full-length cDNA from Artemisia
      annua that encoded a protein of 60.3 kDa which resembled a sesquiterpene synthase
      in sequence. Heterologous expression of the gene in Escherichia coli provided a
      soluble recombinant enzyme capable of catalyzing the divalent metal ion-dependent
      conversion of farnesyl diphosphate to beta-caryophyllene, a sesquiterpene olefin
      found in the essential oil of A. annua. In reaction parameters and kinetic
      properties, beta-caryophyllene synthase resembles other sesquiterpene synthases
      of angiosperms. The beta-caryophyllene synthase gene is expressed in most plant
      tissues during early development, and is induced in mature tissue in response to
      fungal elicitor thus suggesting a role for beta-caryophyllene in plant defense.

PMID- 12409019
TI  - Cyclic nucleotide content of tobacco BY-2 cells.
AB  - The cyclic nucleotide content of cultured tobacco bright yellow-2 (BY-2) cells
      was determined, after freeze-killing, perchlorate extraction and sequential
      chromatography, by radioimmunoassay. The identities of the putative cyclic
      nucleotides, adenosine 3',5'-cyclic monophosphate (cyclic AMP), guanosine 3',5'
      cyclic monophosphate (cyclic GMP) and cytidine 3',5'-cyclic monophosphate (cyclic
      CMP) were unambiguously confirmed by tandem mass spectrometry. The potential of
      BY-2 cell cultures as a model system for future investigations of cyclic
      nucleotide function in higher plants is discussed.

PMID- 12409020
TI  - Exudation of fluorescent beta-carbolines from Oxalis tuberosa L roots.
AB  - Root fluorescence is a phenomenon in which roots of seedlings fluoresce when
      irradiated with ultraviolet (UV) light. Soybean (Glycine max) and rye grass
      (Elymus glaucus) are the only plant species that have been reported to exhibit
      this occurrence in germinating seedling roots. The trait has been useful as a
      marker in genetic, tissue culture and diversity studies, and has facilitated
      selection of plants for breeding purposes. However, the biological significance
      of this occurrence in plants and other organisms is unknown. Here we report that
      the Andean tuber crop species Oxalis tuberosa, known as oca in the highlands of
      South America, secretes a fluorescent compound as part of its root exudates. The
      main fluorescent compounds were characterized as harmine (7-methoxy-1-methyl-beta
      carboline) and harmaline (3, 4-dihydroharmine). We also detected endogenous root
      fluorescence in other plant species, including Arabidopsis thaliana and
      Phytolacca americana, a possible indication that this phenomenon is widespread
      within the plant kingdom.

PMID- 12409021
TI  - C6-Green leaf volatiles trigger local and systemic VOC emissions in tomato.
AB  - In response to insect feeding, tomato plants (Lycopersicon esculentum) release
      elevated levels of volatile organic compounds; that is, monoterpenes and
      sesquiterpenes are released both locally and systemically with wounding while
      C(6) green leaf volatiles are released only from damaged leaves. With the
      exogenous application (100 nmol) of the C(6)-tomato-volatile (E)-2-hexenal, an
      increase in the release of local and systemic terpenes was observed, while an
      equimolar amount of methyl jasmonate triggered only local emissions of terpenes.
      Labeling studies with 13CO(2) showed that de novo synthesis was not required for
      monoterpene or sesquiterpene release immediately following chemical treatment or
      insect feeding. Comparative measurements were made between aldehyde doses applied
      to the plant and levels naturally released from leaves with insect damage.

PMID- 12409022
TI  - Development of environmentally-benign wood preservatives based on the combination
      of organic biocides with antioxidants and metal chelators.
AB  - Wood extractives can be envisaged to protect heartwood by at least three
      different mechanisms, i.e. fungicide, free radical scavengers/antioxidants and as
      metal chelators. In short-term laboratory decay tests using two different wood
      species and decay fungi, the combination of different organic fungicides with
      various antioxidants and/or metal chelators gave enhanced activity as compared to
      the organic biocide alone, with the best results usually obtained with all three
      compounds. Outdoor ground-contact stakes treated with a biocide and antioxidant
      combination and exposed for 30 months also gave enhanced protection against both
      decay fungi and termites. It was concluded that the combination of an organic
      biocide with metal chelating and/or antioxidant additives gives enhanced
      protection to wood against fungi as compared to the biocide alone and,
      consequently, it may be possible to develop environmentally-benign wood
      preservative systems based on this idea.

PMID- 12409023
TI  - Antibacterial cyclopeptide alkaloids from the bark of Condalia buxifolia.
AB  - The cyclopeptide alkaloid, named condaline-A, was isolated from the root bark of
      Condalia buxifolia Reissek (Rhamnaceae), along with the known compounds adouetine
      Y', scutianine-B, and scutianine-C. Their structures were determined by
      spectroscopic analyses, with their antibacterial activities being evaluated by
      use of a direct bioautography method.

PMID- 12409024
TI  - Chemical and anti-platelet constituents from Formosan Zanthoxylum simulans.
AB  - A pyrrole alkaloid, pyrrolezanthine [5-hydroxymethyl-1-[2-(4-hydroxyphenyl)
      ethyl]-1H-pyrrole-2-carbaldehyde]; a lignan, (-)-simulanol [4- [3-hydroxymethyl-5
      ((E)-3-hydroxypropenyl)-7-methoxy-2,3-dihydrobenzofuran-2-yl]-2,6-dimethoxy
      phenol] and a monocyclic gamma-pyrone, zanthopyranone [3,5-dimethoxy-2-methyl
      pyran-4-one], together with 28 known compounds were isolated from the stem wood
      of Formosan Zanthoxylum simulans. Their structures were determined through
      spectral analyses. Among the isolates, 11 compounds showed anti-platelet
      aggregation activity in vitro.

PMID- 12409025
TI  - Potential allelochemicals from the essential oil of Ruta graveolens.
AB  - The essential oil of aerial parts of Ruta graveolens was obtained by
      hydrodistillation with a 0.74% yield on a dry weight basis. Thirty-eight
      components were identified by GC and GC-MS analyses. 2-Ketones predominated in
      the essential oil, with undecan-2-one (46.8%) and nonan-2-one (18.8%) as the main
      constituents. The essential oil and some of its constituents were tested for
      their allelopathic activity in vitro on radish germination and radicle growth in
      light and darkness. The essential oil and some of its minor constituents were
      effective and dose-dependent inhibitors of both the germination and radicle
      growth; 2-ketones are not active. The possible allelopathic activity of rue
      essential oil and some its isolated constituents is reported.

PMID- 12409026
TI  - Very long-chain phenylpropyl and phenylbutyl esters from Taxus baccata needle
      cuticular waxes.
AB  - The cuticular wax of Taxus baccata L. needles was found to contain four different
      classes of long-chain esters that were identified by various chemical
      transformations with product assignment employing GC-MS. Homologous series of (1)
      3-(4'-hydroxyphenyl)-propyl esters of C(20)-C(36) fatty acids, (2) 4-(4'
      hydroxyphenyl)-2-butyl esters of C(18)-C(28) fatty acids, (3) 3-(3',4'
      dihydroxyphenyl)-propyl esters of C(20)-C(32) fatty acids, and (4) 4-(3',4'
      dihydroxyphenyl)-2-butyl esters of C(18)-C(28) fatty acids were identified. The
      four compound classes amounted to 0.1-3.6 micro g/cm(2) of needle surface area,
      corresponding to 0.2-7.6% of the wax mixture, respectively. While both
      phenylpropyl ester series had a maximum for the homolog containing tetracosanoic
      acid, in the phenylbutyl esters homologs containing eicosanoic and docosanoic
      acids predominated.

PMID- 12409027
TI  - Blazeispirane and protoblazeispirane derivatives from the cultured mycelia of the
      fungus Agaricus blazei.
AB  - Two blazeispirane derivatives including blazeispirols G and I were isolated from
      the cultured mycelia of the fungus Agaricus blazei Murill and were established to
      be (20S, 22S, 23R, 24S)-14 beta,22: 22,25-diepoxy-5-methoxy-des-A-ergosta-5,7,9
      triene-11 alpha,23-diol and (20S, 22S, 23R, 24S)-14 beta,22:22,25-diepoxy-5
      methoxy-des-A-ergosta-5,7,9,11-tetraene-23,28-diol by comparison of extensive 1D
      and 2D NMR spectral data with that of blazeispirol A. Furthermore, four
      blazeispirol derivatives blazeispirols, U, V, V(1) and Z(1) were isolated form
      the same source described above. Their structures were determined to be (20S,
      22S, 23R, 24S)-14 beta,22:22,25-diepoxy-23-hydroxyergosta-4,6,8,11-tetraen-3-one,
      (20S, 22S, 23R, 24S)-14 beta,22:22,25-diepoxy-6 alpha,7 alpha,23
      trihydroxyergosta-4,8,11-trien-3-one, (20S, 22S, 23R, 24S)-14 beta,22:22,25
      diepoxy-6 beta,7 alpha,23-trihydroxyergosta-4,8,11-trien-3-one and (20S, 22S,
      23R, 24S)-14 beta,22:22,25-diepoxy-23-hydroxy-4,5-seco-ergosta-6,8-diene-3,5
      dione by extensive 1 D and 2D NMR spectral data.

PMID- 12409028
TI  - Food for thought.

PMID- 12409030
TI  - Mosquito-net makers forced to renege on zero-VAT policy.

PMID- 12409031
TI  - USA firms up smallpox vaccine plans.

PMID- 12409032
TI  - Call to tackle sepsis.

PMID- 12409033
TI  - Drug companies asked to deliver on a low-cost meningitis vaccine.

PMID- 12409036
TI  - US infectious disease research leaders set out new priorities.

PMID- 12409037
TI  - CWD and neurological disease cluster link investigated.

PMID- 12409041
TI  - Early-onset group B streptococcal disease: a continuing challenge.

PMID- 12409042
TI  - Infection in an ageing world.

PMID- 12409043
TI  - Monitoring HIV treatment in the developing world.

PMID- 12409044
TI  - Plasmodium falciparum genetic diversity and ancestry.

PMID- 12409046
TI  - Ageing and infection.
AB  - Average life expectancy throughout developed countries has rapidly increased
      during the latter half of the 20th century and geriatric infectious diseases have
      become an increasingly important issue. Infections in the elderly are not only
      more frequent and more severe, but they also have distinct features with respect
      to clinical presentation, laboratory results, microbial epidemiology, treatment,
      and infection control. Reasons for increased susceptibility include
      epidemiological elements, immunosenescence, and malnutrition, as well as a large
      number of age-associated physiological and anatomical alterations. Moreover,
      ageing may be the cause of infection but infection can also be the cause of
      ageing. Mechanisms may include enhanced inflammation, pathogen-dependent tissue
      destruction, or accelerated cellular ageing through increased turnover. In most
      instances, treatment of infection leads to a satisfactory outcome in the elderly.
      However, in palliative care situations and in patients with terminal dementia,
      the decision whether or not to treat an infectious disease is becoming a
      difficult ethical issue.

PMID- 12409047
TI  - Controlling infection by tuning in and turning down the volume of bacterial small
      talk.
AB  - As the prevalence of bacterial resistance to multiple antibiotics increases it is
      becoming progressively more difficult to treat infections and, in many cases, the
      available therapeutic options are severely limited. Hence, there is a growing
      urgency to the search for novel targets and the development of new
      antimicrobials. To infect a host and cause disease bacteria produce an array of
      virulence determinants that contribute to pathogenesis. It is now known that many
      different Gram-positive and Gram-negative pathogens communicate via the
      production and sensing of small, diffusible signal molecules, to coordinate
      virulence determinant production. As a consequence, this event, now termed quorum
      sensing, represents a novel therapeutic target offering the opportunity to
      attenuate virulence, and thus control infection, by blocking cell-to-cell
      communication.

PMID- 12409048
TI  - Pathogenesis of infections due to coagulase-negative staphylococci.
AB  - As a group, the coagulase-negative staphylococci (CoNS) are among the most
      frequently isolated bacteria in the clinical microbiology laboratory and are
      becoming increasingly important, especially as causes of hospital-acquired
      infections. These bacteria are normal inhabitants of human skin and mucous
      membranes and, therefore, one of the major challenges of daily diagnostic work is
      to distinguish clinically significant CoNS from contaminant strains. This
      overview addresses current knowledge of the pathogenesis of infections due to
      CoNS and particularly focuses on virulence factors of the species Staphylococcus
      epidermidis. S epidermidis has been identified as a major cause of nosocomial
      infections, especially in patients with predisposing factors such as indwelling
      or implanted foreign polymer bodies. Most important in the pathogenesis of
      foreign-body-associated infections is the ability of these bacteria to colonise
      the polymer surface by the formation of a thick, multilayered biofilm. Biofilm
      formation takes place in two phases. The first phase involves the attachment of
      the bacteria to polymer surfaces that may be either unmodified or coated with
      host extracellular matrix proteins. In the second phase, the bacteria proliferate
      and accumulate into multilayered cell clusters that are embedded in an
      extracellular material. The bacterial factors involved in both phases of biofilm
      formation are discussed in this review. In addition, the most important aspects
      of the pathogenic potential of S saprophyticus, S lugdunensis, and S schleiferi
      are described, although, compared with S epidermidis, much less is known in these
      species concerning their virulence factors.

PMID- 12409050
TI  - Testosterone therapy in HIV wasting syndrome: systematic review and meta
      analysis.
AB  - Many HIV patients develop weight loss, which increases morbidity and mortality.
      We aimed to assess the effects of testosterone therapy on lean body mass, total
      body weight, over-all exercise functional capacity, and perceived quality of life
      in patients with HIV wasting syndrome and its adverse effects. We systematically
      reviewed randomised, placebo-controlled trials that compared the effects of
      testosterone therapy with placebo in HIV patients with wasting. Eight trials met
      the inclusion criteria and 417 randomised patients were included. Only six trials
      used lean-body mass, fat-free mass, or body-cell mass as outcome measures. The
      meta-analysis of the six trials showed a difference in the lean body mass between
      the testosterone group and placebo group of 1.22 kg (95% CI 0.23-2.22) for the
      random effect model and 0.51 kg (0.09-0.93) for fixed effect. However, the
      difference was much greater in the three trials that used the intramuscular route
      3.34 kg in the post-hoc analysis. All eight trials included total body weight as
      an outcome measure, the meta-analysis of which showed a difference of 1.04 kg (
      0.01-2.10) between testosterone group and placebo group by random effect and 0.63
      kg (-0.01-1.28) for fixed effect models. Over-all, the incidence of adverse
      effects is similar in both groups. Testosterone therapy has been shown in this
      review to increase lean body mass more than placebo. The increase is even greater
      if the therapy is given intramuscularly. There is also a small positive effect in
      total body weight. The study is, however, limited by the small numbers and
      heterogeneity of the population, which potentially introduced bias into the
      methods and results. Testosterone therapy may be considered in patients with HIV
      wasting syndrome to reverse muscle loss, but there is a concern about the adverse
      metabolic effects of long-term testosterone administration and long-term follow
      up for these patients is needed.

PMID- 12409049
TI  - Q fever in children.
AB  - Q fever is a zoonosis caused by Coxiella burnetii. Farm animals and pets are the
      main reservoirs of infection, and transmission to human beings is mainly
      accomplished through inhalation of contaminated aerosols. This illness is
      associated with a wide clinical spectrum, from asymptomatic or mildly symptomatic
      seroconversion to fatal disease. Q fever in children has been rarely reported. We
      reviewed published work on this topic. Seroepidemiological studies show that
      children are frequently exposed to C burnetii. However, children are less
      frequently symptomatic than adults following infection, and may have milder
      diseases. Using the standard diagnostic criteria, we identified 46 published
      paediatric cases only. Self-limited febrile illness and pneumonia were the most
      common manifestations of acute Q fever. Chronic disease manifested as
      endocarditis and osteomyelitis. A history of exposure to possible sources of
      infection with C burnetii in a child with a compatible infectious syndrome should
      prompt testing for Q fever. Studies are required to determine the spectrum of
      morbidity associated with Q fever during childhood.

PMID- 12409051
TI  - Concomitant bilateral herpes zoster opthalmicus.

PMID- 12409052
TI  - Behind the swinging doors with David Talan interviewed by Pam Das.

PMID- 12409055
TI  - Viral heart ache.

PMID- 12409056
TI  - Endocrine treatment and prevention of breast and gynaecological cancers.

PMID- 12409057
TI  - Written report of presented lectures: endocrine treatment and prevention of
      breast and gynaecological cancers. The scientific basis of endocrine prevention.

PMID- 12409058
TI  - Prophylactic oophorectomy in BRCA1 and BRCA2 mutation carriers.

PMID- 12409059
TI  - Tamoxifen for primary breast cancer prevention in BRCA heterozygotes.

PMID- 12409060
TI  - Tamoxifen versus raloxifene in the prevention of breast cancer.

PMID- 12409061
TI  - Rationale for a study adding tamoxifen to HRT.

PMID- 12409062
TI  - Endocrine prevention of breast: any role for tibolone?

PMID- 12409063
TI  - New SERMs in development.

PMID- 12409064
TI  - The origin of postmenopausal oestrogens.

PMID- 12409065
TI  - Pathways of carcinogenesis and prevention in the human breast.

PMID- 12409066
TI  - Oestrogen receptor determination in breast and gynaecological tissue. What is the
      best approach to reproducible measurement?

PMID- 12409067
TI  - SERMs: how do they work?

PMID- 12409068
TI  - Tamoxifen versus toremifene in the adjuvant treatment of breast cancer.

PMID- 12409069
TI  - Role of LHRH agonists in premenopausal women with oestrogen receptor-positive
      breast cancer: the ZEBRA experience.

PMID- 12409070
TI  - Adjuvant hormone therapy following primary therapy for endometrial cancer.

PMID- 12409071
TI  - LHRH-agonist versus chemotherapy in premenopausal breast cancer?

PMID- 12409072
TI  - Aromatase inhibitors and inactivators for breast cancer treatment.

PMID- 12409073
TI  - Anastrozole versus progestins/tamoxifen.

PMID- 12409074
TI  - Letrozole's superiority over progestins and tamoxifen challenges standards of
      care in endocrine therapy for metastatic breast cancer.

PMID- 12409075
TI  - Arzoxifene in breast cancer.

PMID- 12409076
TI  - Fulvestrant versus anastrozole as second-line treatment of advanced breast cancer
      in postmenopausal women.

PMID- 12409077
TI  - How do endogenous oestrogens affect breast cancer?

PMID- 12409078
TI  - Selective oestrogen receptor downregulator.

PMID- 12409079
TI  - An update on non-gynaecological effects of SERM's and aromatase inhibitors.

PMID- 12409080
TI  - An update on non-uterine gynaecological effects on raloxifene.

PMID- 12409081
TI  - Endometrial evaluation is a very important tool in the management of breast
      cancer patients.

PMID- 12409082
TI  - The effect of continuous combined 17beta-oestradiol and dihydrodydrogesterone on
      apoptotic cell death and proliferation of human breast cancer cells in vitro.

PMID- 12409083
TI  - Loss of progesterone receptor may lead to an invasive phenotype in human
      endometrial cancer.

PMID- 12409084
TI  - No rules without exception: a long-term complete remission observed in a study
      using a LH-RH agonist in platinum-refractory ovarian cancer.

PMID- 12409085
TI  - Expression of oestrogen receptor alpha and beta in uterine endometrial and
      ovarian cancers.

PMID- 12409086
TI  - IL-1alpha gene expression in human endometrial cancer is independent of ovarian
      steroid receptor expression.

PMID- 12409087
TI  - The influence of hormone replacement therapy on the ultrasound features of the
      endometrium: a prospective study.

PMID- 12409090
TI  - 11-Oxygenated androgens in female teleosts: prevalence, abundance, and life
      history implications.
AB  - Although 11-ketotestosterone (11-KT) has been found in blood of females of
      several diadromous fish species, the importance, abundance, and prevalence of
      this and related 11-oxygenated androgens in females have not been investigated.
      To address this issue and to determine whether the differences among androgen
      profiles relate to specific life history strategies, particularly diadromous
      migrations, fish (males and females) of around 30 species were sampled and 5
      androgens were measured by radioimmunoassay. Levels of 17beta-estradiol and
      cortisol were also determined to evaluate ovarian and interrenal activity at the
      time of sampling. Testosterone (T) was the predominant androgen in most sexually
      recrudescent females. Only in female eel and sturgeon were 11-oxygenated
      androgens present in levels as high as, or higher than, those of T, although
      substantial amounts were also found in blood of mullet and salmonids. 11-KT was
      generally the most abundant 11-oxyandrogen, levels being higher than those of
      11beta-hydroxytestosterone or 11beta-hydroxyandrostenedione. It is concluded that
      11-oxygenated androgens are quantitatively minor steroids in most female fish.
      There was no convincing evidence to support the notion that the presence of 11
      oxygenated androgens in blood is an adaptation specific to migratory fishes.

PMID- 12409091
TI  - Latitudinal variation in plasma testosterone levels in birds of the genus
      Zonotrichia.
AB  - Birds breeding in northern latitudes generally have elevated plasma testosterone
      levels throughout the breeding season with a peak at the onset of the breeding
      season. In contrast, tropical birds tend to have extremely low plasma
      testosterone levels year round with only a slight increase during breeding. While
      these patterns have been consistent in the species investigated, closely related
      species have not been investigated across a range of latitudes. Birds of the
      genus Zonotrichia present an ideal opportunity to investigate latitudinal
      variation in plasma testosterone levels as breeding populations occur from
      northern Alaska to southern Argentina. We studied three taxa of Zonotrichia: (1)
      Gambel's white-crowned sparrows, Zonotrichia leucophrys gambelii, breeding at
      high latitude in northern Alaska, (2) Puget Sound white-crowned sparrows, Z. l.
      pugetensis, breeding at mid-latitude in Washington state, and (3) an equatorial
      population of the rufous-collared sparrow, Z. capensis, in Ecuador. To compare
      both baseline breeding and maximal testosterone levels, males from the three taxa
      were either bled immediately upon capture during the breeding season or first
      challenged with gonadotropin-releasing hormone (GnRH) and then bled. As a
      control, another group of birds experienced a saline challenge. Two-way ANCOVA,
      with treatment and taxa as factors and testis volume as a covariate, showed a
      significant effect of treatment on plasma testosterone levels. There was also a
      significant interaction between taxa and treatment. Contrary to expectations, the
      equatorial species exhibited greater plasma testosterone levels in response to
      the GnRH challenge than the high latitude species. There were no differences
      between the mid- and high-latitude species. The equatorial species had the
      smallest average testis size and within each taxa there were no relationships
      between plasma testosterone and testis size. These data suggest that latitudinal
      clines in plasma testosterone levels in Zonotrichia do not follow previously
      described patterns and that tropical birds can have levels of testosterone
      similar to northern latitude species.

PMID- 12409092
TI  - Expression profiles of Dax1, Dmrt1, and Sox9 during temperature sex determination
      in gonads of the sea turtle Lepidochelys olivacea.
AB  - Sex determination is controlled either by genetic or environmental factors. In
      mammals Sry initiates determination but no homologue of this gene exists in non
      mammalian species. Other genes of the mammalian sex-determining pathway have been
      identified in gonads of different vertebrates. Sox9, Dax1, and Dmrt1 are
      expressed at the onset of gonadal development in birds and reptiles. In the sea
      turtle Lepidochelys olivacea, a species with temperature sex determination (TSD),
      Sox9 is expressed in undifferentiated gonads at male- (MPT) or female-promoting
      temperatures (FPT). At MPT, Sox9 remains expressed in male gonads, but at FPT it
      is downregulated coinciding with the onset of the ovarian morphologic
      differentiation and female sex determination. At MPT however, male sex is
      determined early than at FPT in still undifferentiated gonads suggesting that
      other genes maintain Sox9 expression in testis. Here we used RT-PCR to study the
      expression profiles of Dax1, Dmrt1, and Sox9 in gonads of embryos of L. olivacea
      incubated at MPT or at FPT. The profiles were correlated with sex determination
      during and after the temperature-sensitive period (TSP). Dax1 maintained similar
      levels at both temperatures during the TSP. The Dax1 expression level increased
      significantly in ovaries compared to testes at stage 27, once they were
      morphologically distinct. The expression levels of Dmrt1 were higher at MPT than
      at FPT at all stages, in contrast with Sox9 levels which were similar at both
      temperatures at stages 23-25. Together, current results suggest that, whereas
      Dax1 is not involved in TSD in L. olivacea, upregulation of Dmrt1 and
      downregulation of Sox9 may play a role in male and female sex determination,
      respectively.

PMID- 12409093
TI  - Ovarian steroidogenesis in white sturgeon (Acipenser transmontanus) during oocyte
      maturation and induced ovulation.
AB  - Ovarian follicles and plasma were collected from two female white sturgeon,
      Acipenser transmontanus, injected with sturgeon pituitary homogenate followed 12h
      later with GnRHa to induce ovulation. The oocytes of one female underwent
      germinal vesicle breakdown (GVBD) but ovulation did not occur in response to
      hormonal stimulation (Female 1), while the oocytes of the other female underwent
      GVBD and ovulation (Female 2). Follicles collected 12h after the first injection
      to induce ovulation were incubated with radioinert pregnenolone (P5) or tritiated
      P5 ([3H]P5) plus radioinert P5. Steroids were extracted from media and intact
      follicles, and the extracts were fractionated by high performance liquid
      chromatography (HPLC). Fractions from the incubation with radioinert precursor
      were used in a bioassay to determine the potency of the steroid products to
      induce GVBD. Plasma levels of testosterone (T), estradiol, and 17,20beta
      dihydroxy-4-pregnen-3-one (17,20beta-P) were measured by radioimmunoassay during
      induced ovulation, and plasma collected at the time of ovulation (actual or
      expected) was analyzed by HPLC. A peak in plasma 17,20beta-P was detected at the
      time of the second injection to induce ovulation in Female 2 (the time at which
      follicles were collected for incubation with [3H]P5). The HPLC analysis revealed
      several progestins in the plasma of Female 2 at ovulation that were not present
      in Female 1 at the time of expected ovulation. A variety of C19 and C21 steroids
      were produced in vitro by ovarian follicles from both females. The "suggestive"
      identities of the major metabolites were 11-deoxycortisol, androstenedione, 17
      hydroxyprogesterone (17OHP), and 17,20beta-P in Female 1 and cortisol, 17,20beta,
      21-trihydroxyprogesterone (20beta-S), 11-deoxycortisol, T, 17OHP, and 17,20beta-P
      in Female 2. Several of the steroids were active in a GVBD bioassay, but the
      fractions that contained the steroid coeluting the authentic 11-deoxycortisol on
      the HPLC and 17,20beta-P (positively identified by gas chromatography-mass
      spectrometry) were found to be the most potent. The results from this study
      combined with the results of Webb et al. (2001b) suggest the potential roles of
      11-deoxycortisol, 17,20beta-P, 20beta-S, and P4 as maturation-inducing steroids
      in sturgeon.

PMID- 12409094
TI  - Age dependent changes in plasma anti-Mullerian hormone concentrations in the
      bovine male, female, and freemartin from birth to puberty: relationship between
      testosterone production and influence on sex differentiation.
AB  - To understand the behaviour of the gonads, in terms of hormonal secretion, in a
      model of intersexual development naturally occurring in mammals, we determined
      plasma concentrations of testosterone, progesterone, and anti-Mullerian hormone
      (AMH) in bovine freemartins, and compared them to normal levels measured in males
      and females from birth to puberty. We found that newborn males and freemartins
      have very high concentrations of AMH (over 700ng/ml). Conversely, plasma AMH
      concentration is always below 120ng/ml in females. While values remain stable in
      males for the first five months of life, they sharply decrease in the freemartins
      within the first fortnight, and reach female levels, which demonstrates that AMH
      is essentially originated in the male twin. In young bulls the trend of plasma
      testosterone concentrations is opposite to that of the AMH. The rise in
      testosterone production at puberty corresponds to a sharp decline in AMH
      concentrations. Bovine plasma concentrations of AMH are surprisingly higher than
      those measured in other mammals, including man and mouse. The results obtained
      are discussed in reference to comparative aspects of endocrine functions.

PMID- 12409096
TI  - Murine leptin injections increase intracellular fatty acid-binding protein in
      green sunfish (Lepomis cyanellus).
AB  - Green sunfish (Lepomis cyanellus) were injected daily with either murine leptin,
      phosphate-buffered saline (PBS), or simply handled without injection for 14 days.
      At the end of the experiment, fish were assayed for intracellular indicators of
      fatty acid metabolism. Intracellular fatty acid-binding protein (FABP) expression
      in heart ventricle was twofold higher in the leptin treated group (87.2+/-5.6
      Leptin; 47.2+/-6.8 PBS; 28.9+/-3.9 Handled; percent relative expression,
      Prob.>F<0.001). Two other indicators of intracellular fat metabolism, carnitine
      palmitoyl transferase activity (CPT) in liver and 3-hydroxyacyl-CoA dehydrogenase
      (HOAD) in heart were not significantly different among groups, although the trend
      is for higher values in the leptin treatment (CPT: 0.23+/-0.04 Leptin, 0.11+/
      0.04 PBS, 0.10+/-0.03 Handled; U/gm wet weight; Prob.>F=0.08; HOAD: 1.34+/-0.28
      Leptin, 0.76+/-0.12 PBS, 0.86+/-0.25 Handled; U/gm wet weight; Prob.>F=0.18).
      Percent change in total weight, body fat (as a percent of dry weight),
      cardiosomatic index, and hepatosomatic index were not significantly different
      among treatments. These results suggest that fish respond to murine leptin
      injections by increasing fat metabolism, however many of the hallmarks of leptin
      treatment in mammals (loss of total weight and body fat) were not observed. This
      lack of response may be due to incompatibility of mouse leptin with fish
      receptors or an inadequate dose of leptin. We also suggest that leptin's action
      may be slower in ectotherms due to their lower metabolic rate.

PMID- 12409095
TI  - Cloning and mRNA expression of the Ca2+-binding DREAM protein in the pituitary.
AB  - It is well recognized that the level of intracellular calcium governs several
      cellular processes such as gene expression and secretion in the pituitary.
      Recently, a novel gene has been identified in neuroendocrine cells that encodes
      DREAM, a calcium-binding protein that acts as a transcriptional repressor by
      binding specific downstream regulatory elements (DRE) on DNA. To explore the
      possibility that DREAM may be expressed in the rat pituitary and may function in
      endocrine activity, we analyzed its mRNA expression by RT-PCR. Using
      oligonucleotide primers derived from the mouse DREAM cDNA, we amplified, cloned,
      and characterized a 852-bp RT-PCR product from rat pituitary tissue. Two splice
      variants of the rat DREAM gene differing by four nucleotides (tetramer ACAG) were
      identified. The ACAG(+) variant (ORF1) consisted of 768bp encoding a protein of
      256 residues with an estimated molecular weight of 29.5kDa. Amino acid sequence
      analysis of ORF1 indicated 92.6% and 98.1% identity to the DREAM gene product
      from human and mouse, respectively. The second variant, ACAG(-) (ORF2), was 567
      bp long and was predicted to encode a peptide of 189 residues with a molecular
      mass of about 20.8kDa. To determine which endocrine pituitary cells were
      expressing DREAM, we evaluated several different clonal populations containing
      cells that expressed specific pituitary hormones. We found that both DREAM splice
      variants were expressed in each pituitary cell types examined, which included the
      mammotropes (MMQ cells), somatotropes (GC cells), mammosomatotropes (GH(3)
      cells), gonadotropes (LbetaT2 cells), thyrotropes (TalphaT1 cells), and
      corticotropes (AtT-20 cells). Interestingly, the levels of the two variants
      differed between the cell types tested with the ACAG(+) variant comprising about
      two-thirds of the DREAM expression for the mammotropes, somatotropes,
      mammosomatotropes, and corticotropes as compared to less than one-half for the
      thyrotropes and the gonadotropes. Our initial attempts to identify pituitary
      specific genes regulated by DREAM revealed that prolactin gene expression was not
      influenced by DREAM suggesting that an action of DREAM may involve other
      pituitary hormones or be mediated by other cell processes. When taken together,
      our findings of DREAM expression in the pituitary in a manner specific to
      pituitary endocrine cell type raises the possibility that this protein may play a
      role in determining specific pituitary cell function.

PMID- 12409097
TI  - Annual variations and sex-related differences of estradiol-17beta levels in the
      anthozoan Renilla koellikeri.
AB  - In the sea pansy Renilla koellikeri, estradiol-17beta (E(2)) levels exhibited an
      annual pattern of secretion that correlated with the reproductive cycle, and
      displayed sex-specific and tissue-specific differences. The E(2) levels were low
      during the non-reproductive period extending from autumn to winter. A first rise
      of E(2) concentrations occurred in March when gonad maturation resumed, as
      indicated by an increase in lipid storage. This suggests that E(2) may influence
      the beginning of gonad maturation in the sea pansy. Estradiol-17beta returned to
      basal levels in April and May when lipids rose sharply. A second, more
      significant surge of E(2) levels occurred in June when spawning was initiated and
      it was more marked in female than in male colonies. This suggests that E(2) may
      participate in synchronising of oocyte maturation around spawning time to
      optimise the probability of fertilisation. The higher E(2) levels in somatic
      tissues (peduncle and polyps) than in eggs during the March peak revealed a non
      reproductive origin for E(2) and the need for transport of E(2) through the
      gastrovascular cavity to reach reproductive tissues. Further analyses are
      required to determine the relative contribution of E(2) to reproductive events
      and its pathway of synthesis in this colonial anthozoan.

PMID- 12409098
TI  - Identification of new pisatin demethylase genes (PDA5 and PDA7) in Nectria
      haematococca and non-Mendelian segregation of pisatin demethylating ability and
      virulence on pea due to loss of chromosomal elements.
AB  - Previous studies have shown that high virulence on pea in Nectria haematococca
      Mating Population VI is linked to the ability to detoxify the pea phytoalexin,
      pisatin, via demethylation (Pda). To test this linkage further, a highly virulent
      Pda(+) isolate (34-18) was used as the recurrent parent in backcrosses to Pda(-)
      isolates, but most of the progeny were low in virulence on pea, and tetrad
      analysis gave conflicting ratios for the genetic control of Pda. Southern
      analysis of 34-18 and progeny showed that 34-18 carries a gene similar to PDA1
      (PDA1-2), two new PDA genes, PDA5 and PDA7, and that all three genes can be lost
      during meiosis. Southern analysis of electrophoretic karyotypes showed that PDA1
      2 is on a 1.5-Mb dispensable chromosome in 34-18 and that PDA5 and PDA7 are on a
      4.9-Mb chromosome in 34-18 but are found on variably sized chromosomes in
      progeny. Loss of PDA5 or PDA7 in progeny was not generally associated with
      morphological phenotypes, except in progeny from some crosses between PDA5
      parents. Loss of PDA5 was associated with growth abnormalities in these crosses,
      suggesting that in some genetic backgrounds at least a portion of the PDA5/PDA7
      chromosome is essential for normal growth. All highly virulent progeny had PDA1-2
      or a combination of PDA5 and PDA7 while isolates that lacked the three genes were
      low in virulence, supporting the hypothesis that Pda, or genes linked to PDA
      genes, are necessary for virulence on pea. However, low virulence isolates with
      PDA genes were also identified, suggesting that there are pathogenicity genes
      that can segregate independently of PDA genes.

PMID- 12409099
TI  - The polyketide synthase gene pks4 from Gibberella fujikuroi encodes a key enzyme
      in the biosynthesis of the red pigment bikaverin.
AB  - The ascomycete Gibberella fujikuroi mating population C (MP-C) is well known for
      the production of gibberellins, but also produces many other secondary
      metabolites, including the red polyketide pigment bikaverin. Here, we used a
      differential display method to clone a polyketide synthase gene pks4 responsible
      for the first step of bikaverin biosynthesis. Sequence analysis indicated that
      pks4 encoded a 2009-amino acid polypeptide consisting of four functional domains:
      beta-ketoacyl synthase (KS), acyltransferase (AT), acyl carrier (ACP), and
      thioesterase (TE). Disruption of pks4 resulted in the loss of both pks4
      transcripts and bikaverin biosynthesis in G. fujikuroi cultures. Expression of
      pks4 is strongly repressed by high amounts of ammonium and basic pH.
      Unexpectedly, pks4 was overexpressed in mutants of the regulatory gene, areA,
      which is responsible for the activation of nitrogen assimilation genes. Three
      additional polyketide synthase genes have been cloned from G. fujikuroi MP-C by
      heterologous hybridization. The presence of these four PKS genes demonstrates the
      diversity of polyketide biosynthetic pathways in this fungus.

PMID- 12409100
TI  - Bud morphogenesis and the actin and microtubule cytoskeletons during budding in
      the corn smut fungus, Ustilago maydis.
AB  - Ustilago maydis is a dimorphic Basidiomycete fungus with a yeast-like form and a
      hyphal form. Here we present a comprehensive analysis of bud formation and the
      actin and microtubule cytoskeletons of the yeast-like form during the cell cycle.
      We show that bud morphogenesis entails a series of shape changes, initially a
      tubular or conical structure, culminating in a cigar-shaped cell connected to the
      mother cell by a narrow neck. Labelling of cells with concanavalin A demonstrated
      that growth occurs at bud tip. Indirect immunofluorescence studies revealed that
      the actin cytoskeleton consists of patches and cables that polarize to the
      presumptive bud site and the bud tip and an actin ring that forms at the neck
      region. Because the bud tip corresponds to the site of active cell wall growth,
      we hypothesize that actin is involved in secretion of cell wall components. The
      microtubule cytoskeleton has recently been shown to consist of a cytoplasmic
      network during interphase that disassembles at mitosis when a spindle and astral
      microtubules are formed. We have carried out studies of U. maydis cells
      synchronized by the microtubule-depolymerizing drug thiabendazole which allow us
      to construct a temporal sequence of steps in spindle formation and spindle
      elongation during the cell cycle. These studies suggest that astral microtubules
      may be involved in early stages of spindle orientation and migration of the
      nucleus into the bud and that the spindle pole bodies may be involved in
      reestablishment of the cytoplasmic microtubule network.

PMID- 12409101
TI  - The effects of ropy-1 mutation on cytoplasmic organization and intracellular
      motility in mature hyphae of Neurospora crassa.
AB  - We have used light and electron microscopy to document the cytoplasmic effects of
      the ropy (ro-1) mutation in mature hyphae of Neurospora crassa and to better
      understand the role(s) of dynein during hyphal tip growth. Based on video
      enhanced DIC light microscopy, the mature, growing hyphae of N. crassa wild type
      could be divided into four regions according to cytoplasmic organization and
      behavior: the apical region (I) and three subapical regions (II, III, and IV). A
      well-defined Spitzenkorper dominated the cytoplasm of region I. In region II,
      vesicles ( approximately 0.48 micro m diameter) and mitochondria maintained
      primarily a constant location within the advancing cytoplasm. This region was
      typically void of nuclei. Vesicles exhibited anterograde and retrograde motility
      in regions III and IV and followed generally parallel paths along the
      longitudinal axis of the cell. A small population of mitochondria displayed rapid
      anterograde and retrograde movements, while most maintained a constant position
      in the advancing cytoplasm in regions III and IV. Many nuclei occupied the
      cytoplasm of regions III and IV. In ro-1 hyphae, discrete cytoplasmic regions
      were not recognized and the motility and/or positioning of vesicles,
      mitochondria, and nuclei were altered to varying degrees, relative to the wild
      type cells. Immunofluorescence microscopy revealed that the microtubule
      cytoskeleton was severely disrupted in ro-1 cells. Transmission electron
      microscopy of cryofixed cells confirmed that region I of wild-type hyphae
      contained a Spitzenkorper composed of an aggregation of small apical vesicles
      that surrounded entirely or partially a central core composed, in part, of
      microvesicles embedded in a dense granular to fibrillar matrix. The apex of ro-1
      the hypha contained a Spitzenkorper with reduced numbers of apical vesicles but
      maintained a defined central core. Clearly, dynein deficiency in the mutant
      caused profound perturbation in microtubule organization and function and,
      consequently, organelle dynamics and positioning. These perturbations impact
      negatively on the organization and stability of the Spitzenkorper, which, in
      turn, led to severe reduction in growth rate and altered hyphal morphology.

PMID- 12409102
TI  - Chromosome-based molecular characterization of pathogenic and non-pathogenic
      wheat isolates of Pyrenophora tritici-repentis.
AB  - The ToxA gene of Pyrenophora tritici-repentis encodes a host-selective toxin (Ptr
      ToxA) that has been shown to confer pathogenicity when used to transform a non
      pathogenic wheat isolate. Major karyotype polymorphisms between pathogenic and
      non-pathogenic strains, and to a lesser extent among pathogenic strains, and
      among non-pathogenic strains were identified. ToxA was localized to a 3.0 Mb
      chromosome. PCR-based subtraction was carried out with the ToxA chromosome as
      tester DNA and genomic DNA from a non-pathogenic isolate as driver DNA. Seven of
      8 single-copy probes that originated from the 3.0 Mb chromosome could be assigned
      to a 2.75 Mb chromosome of a non-pathogenic isolate. Nine different repetitive
      DNA probes originated from the 3.0 Mb chromosome, including sequences that
      correspond to known fungal transposable elements. Two additional single-copy
      probes that originated from a 3.4 Mb chromosome were unique to the pathogens and
      they correspond to a peptide synthetase gene. Our findings suggest substantial
      differences between pathogenic and non-pathogenic isolates of P. tritici
      repentis.

PMID- 12409103
TI  - Regulation by carbon and nitrogen sources of a family of cellulases in
      Aspergillus nidulans.
AB  - The total amount of Aspergillus nidulans secreted cellulases is affected by both
      the carbon and nitrogen source present in the medium, and is regulated directly
      and/or indirectly by the carbon metabolism regulators, CreA, CreB, and CreC, and
      the global nitrogen metabolism regulator, AreA. We have characterized two A.
      nidulans genes that encode exo-cellulases, and one gene that encodes an endo
      cellulase which is additional to the previously described endo-cellulase encoding
      gene, eglA. The putative regulatory regions 5(') of all the genes contain
      potential binding sites for the global carbon and nitrogen regulatory proteins,
      CreA and AreA. The sequences 5(') of eglA and eglB also contain potential
      consensus binding sites for XlnR which is involved in induction in Aspergillus
      niger, but none of the 5(') sequences contains an exact copy of the AceII DNA
      binding consensus sequence involved in induction in Trichoderma reesei, and thus
      it is likely that they may be induced by different pathway specific regulatory
      proteins.

PMID- 12409105
TI  - Imaging of haemorrhagic stroke.
AB  - Computed tomography (CT) is the reference standard for the imaging of acute non
      traumatic intracranial haemorrhage. The sensitivity with which CT detects
      haemorrhage falls with time and lumber puncture remains mandatory for the
      exclusion of subarachnoid haemorrhage (SAH). Magnetic resonance (MR) imaging is,
      however, superior to CT in the subacute and chronic stages after haemorrhage. MR
      in addition offers pathophysiological information that can help with assessment
      of both the aetiology of and complications arising from both SAH and intra
      parenchymal haemorrhage.

PMID- 12409104
TI  - Identification of conidial-enriched transcripts in Aspergillus nidulans using
      suppression subtractive hybridization.
AB  - We have isolated and sequence-identified 12 genes whose transcripts are
      significantly enriched in Aspergillus nidulans conidia. To identify these genes,
      we used the method of suppressive subtraction hybridization (SSH). One of the 12
      genes is similar to plant thaumatin-like proteins that have antifungal
      properties. Four genes encode metabolic enzymes crucial in the synthesis of
      glucose, carbohydrates, nucleic acid, and amino acid precursors. The rest are of
      unknown function. We have analyzed the pattern of expression of the 12 conidial
      enriched transcripts in wild-type and mutant strains of A. nidulans blocked at
      different stages of conidial development. Our results indicate that the conidial
      enriched transcripts can be divided into four classes based on their expression
      pattern in the wild-type and mutant strains. Study of the genes identified in
      this report may enhance our understanding of the process of conidial formation
      and germination.

PMID- 12409106
TI  - MRI of the post-discectomy lumbar spine.
AB  - Laminectomy and discectomy are common procedures in the management of symptomatic
      lumbar disc herniation. Complications of such surgery include recurrent/residual
      disc herniation, epidural scar formation, discitis, arachnoiditis and pseudo
      meningocele. Gadolinium-enhanced MRI is the technique of choice for investigating
      recurrent symptoms following discectomy. This article reviews the normal early
      and late post-laminectomy MR appearances, as well as the pathological findings
      associated with the above-mentioned complications.

PMID- 12409107
TI  - Subspecialist radiology.

PMID- 12409108
TI  - Special interest radiology improves the perceived preoperative stage of gastric
      cancer.
AB  - AIM: The aim of this study was to compare the accuracy of spiral computed
      tomography (CT) performed by a specialist radiologist within a multi disciplinary
      team (MDT) framework with that of radiologists working outside of this framework.
      MATERIALS AND METHODS: One hundred and ten patients [median age 70 (35-86)yr,
      71m] underwent either a preoperative CT performed by the MDT specialist
      consultant radiologist (n=60) or a CT performed by one of 13 other consultant
      radiologists (n=50). The strength of the agreement between the CT stage and the
      histopathological stage was determined by the weighted Kappa statistic (Kw).
      RESULTS: Sensitivity for T, N and M stage were 64%, 65% and 25% for MDT
      specialist CT, compared with 24%, 24% and 5% for control CT. Specificity for T, N
      and M stage were 68%, 59% and 95% for MDT specialist CT compared with 79%, 94%
      and 93% for control CT. Kw for T, N and M stage were 0.314, 0.350 and 0.255 for
      MDT specialist CT compared with 0.088, 0.102 and -0.019 for control CT.
      Unsuspected metastases were found in 12 patients staged by MDT specialist CT
      compared with 19 patients staged by control CT (Chi2=4.366, df=1,p =0.037).
      CONCLUSION: Improved patient selection for surgery should maximize use of limited
      resource.

PMID- 12409109
TI  - MR urography: evaluation of different techniques in non-dilated tracts.
AB  - OBJECTIVE: To assess the effectiveness of different MRI sequences for the
      visualisation of the different components of the non-dilated urinary tract.
      METHOD: 20 asymptomatic individuals were prospectively evaluated using 2
      different heavily T2 weighted sequences, and after the injection of 2 different
      doses of gadolinium (Gd-DTPA). Images were independently scored. RESULTS: The low
      dose Gd-DTPA enhanced MR urography (MRU) sequence was the best overall sequence
      for the visualisation of both the pelvicalyceal systems and ureters. The
      combination of information from the other sequences was additive. CONCLUSIONS:
      Combined use of heavily T2 weighted and Gd-DTPA enhanced MRU produces diagnostic
      images and does not require pre-imaging preparation other than oral hydration.

PMID- 12409110
TI  - Identification of inguinal lymph node metastases from vulval carcinoma by
      magnetic resonance imaging: an initial report.
AB  - AIM: Magnetic Resonance Imaging (MRI) has the potential to assess inguinal lymph
      nodes more accurately than palpation and less invasively than surgical
      exploration. The objective of this study was to measure the accuracy of MRI in
      identifying inguinal metastases by demonstrating abnormal lymph node morphology.
      MATERIALS AND METHODS: 10 women with vulval malignancy underwent T1- and fat
      suppressed T2-weighted surface coil MRI of both groins before surgery. Each groin
      was prospectively categorised as normal or as having metastatic lymphadenopathy
      using criteria established in normal volunteers. Histopathological findings in
      patients undergoing groin dissection for invasive vulval carcinoma were used as
      validation. RESULTS: MRI had a positive predictive value of 89%, negative
      predictive value of 91%, sensitivity of 89%, specificity of 91% and accuracy of
      90%. The most useful observations on MRI to identify metastatic lymphadenopathy
      were those of lymph node contour irregularity, cystic change in a lymph node,
      short axis diameter exceeding 10mm and abnormal long: short axis diameter ratio.
      CONCLUSION: High resolution MRI of the inguinal regions has potential to screen
      for lymph node metastases in patients with vulval cancer, with the aim of
      reducing the number of women who have to undergo groin dissection.

PMID- 12409111
TI  - Granulomatous mastitis: imaging findings with histopathologic correlation.
AB  - OBJECTIVE: The purpose of this study is to evaluate the mammographic and
      ultrasonographic characteristics of granulomatous mastitis and to correlate the
      imaging features with the histologic findings. MATERIALS-METHODS: 15 patients
      with diagnosis of idiopathic granulomatous mastitis were examined with
      mammography and ultrasonography. The clinical, pathologic and imaging features
      were retrospectively reviewed and correlated in all patients. RESULTS:
      Mammographic examination showed an asymmetric density with no distinct margins in
      8 patients and an ill-defined mass in 3 patients. In 4 cases, no abnormal finding
      was detected on the mammography. Sonographic examination demonstrated an
      irregular mass with tubular connections in 5 patients, single or multiple
      hypoechoic tubular/nodular structures in 6, and focally or segmentally decreased
      parenchymal echogenity with acoustic shadowing in 4 patients. The imaging
      findings suggested a malignant tumor in 7 patients, while an inflammatory process
      or intraductal papilloma was considered in the differential diagnosis of the
      other patients. CONCLUSION: Granulomatous mastitis usually presents with clinical
      findings mimicking a carcinoma. The most common mammographic appearance of the
      lesion is an asymmetrically increased density, which is not characteristic for
      this entity. Sonographic patterns of the disease are varied and appear to relate
      to the histologic features. Findings include a mass-like appearance,
      tubular/nodular hypoechoic structures and focal decreased parenchmal echogenicity
      with acoustic shadowing. With awareness of the findings granulomatous mastitis
      can be considered in the differential diagnosis.

PMID- 12409112
TI  - Eliciting a terminology for mammographic calcifications.
AB  - AIM: Two studies were carried out to establish, validate and assess descriptors
      for use in the differential diagnosis for mammographic calcifications. METHODS:
      In Study 1, eleven radiologists were asked to 'think out loud' as they
      interpreted 20 sets of calcifications. Participants used 159 terms to describe
      calcifications. We used this data to design a scheme with 50 descriptors. In
      Study 2, ten radiologists used the scheme to describe 40 sets of calcifications.
      We assessed the capacity of the terms to discriminate between benign and
      malignant calcifications, testing them against radiologists' assessments of
      malignancy and follow-up data. RESULTS: All descriptors were used by at least 5
      radiologists. Five additional descriptors were required. With some exceptions,
      properties that discriminated between benign and malignant outcomes were highly
      correlated with radiologists' assessment of risk. Many descriptors have a fairly
      low sensitivity but high specificity. CONCLUSIONS: Our data suggest that
      radiologists consider a wide range of features than is included in existing
      reporting schemes. Our scheme allows a richer characterization of calcifications,
      potentially improving the reporting and understanding of these abnormalities.

PMID- 12409113
TI  - Elastography in the detection of prostatic cancer.
AB  - We describe a simple, practical technique for producing elastography images of
      the prostate. Our standard technique for the detection of prostatic cancer is
      ultrasound guided systematic biopsy of the prostate, with extra targeted biopsies
      of any abnormal areas detected by grey-scale ultrasound. The aim of this study to
      determine whether adding elastography imaging with targeted biopsies of abnormal
      areas detects more cancers. The results of elastography imaging were evaluated
      against grey-scale images and biopsy data in 100 patients. Elastography detected
      an additional 5 cancers in the 100 patients and detected an extra 3 patients with
      cancer at the expense of 8 extra biopsies. This represents a significant
      improvement in the detection rate of prostatic cancer.

PMID- 12409114
TI  - Haemosuccus pancreaticus: treatment by arterial embolization.
AB  - AIM: Haemosuccus pancreaticus is bleeding into the pancreatic duct from a
      peripancreatic artery. This condition most commonly follows pseudoaneurysm
      formation secondary to acute or chronic pancreatitis. It is a rare disorder,
      challenging in both diagnosis and therapy. We present an eight-year experience of
      managing these patients using endovascular embolization as the primary therapy.
      MATERIALS AND METHODS: We retrospectively reviewed the imaging, laboratory
      results and clinical notes of the five patients who presented to this institution
      between 1991-1999 with gastrointestinal bleeding subsequently found to be
      haemosuccus pancreaticus. RESULTS: There were four men and one women aged 38-75
      years. All had a history of gastrointestinal haemorrhage and had acute (n=1) or
      chronic pancreatitis with a complicating pseudoaneurysm. All underwent
      embolization as the primary therapy for the pseudoaneurysm. There was immediate
      technical success in all cases without major complication. No patient required
      operative surgery for the pseudoaneurysm. Follow-up ranged from 18 months to 7
      years. One patient died four years after embolization due to hepatic failure but
      the other four remain well without further gastrointestinal bleeding. CONCLUSION:
      Endovascular embolization is an effective and safe treatment for haemosuccus
      pancreaticus.

PMID- 12409116
TI  - Non-functioning adrenocortical adenomas containing fat components.

PMID- 12409115
TI  - Self-expandable metal stents in the management of cervical oesophageal and/or
      hypopharyngeal strictures.
AB  - AIM: To assess the usefulness of self-expandable metal stents in the
      recanalization of cervical and/or hypopharyngeal strictures. MATERIALS AND
      METHODS: We report our experience in 10 patients with inoperable cervical and/or
      hypopharyngeal strictures treated by implantation of 11 uncovered self-expandable
      metal stents inserted perorally under fluoroscopic guidance. The stent was placed
      in the hypopharynx and cervical oesophagus in 3 patients and cervical oesophagus
      alone in 7. There were 8 men and 2 women, mean age 70.2 years, range 45-85 years.
      All patients but two had malignant stricture caused by squamous cell carcinoma,
      in one case there was a benign postoperative stenosis secondary to laryngectomy,
      and in the last patient a local recurrence from thyroid cancer. RESULTS: Eleven
      stents were placed in 10 patients: technical success was achieved in 9 cases
      while clinical improvement was obtained in 8 cases. Seven of ten patients had a
      rapid improvement of dysphagia. One patient had a distal misplacement of the
      prosthesis, while in the other two cases stent position was very proximal and
      interfered with swallowing. A mean 9-month follow-up was obtained (range 3-24
      months). Four patients with malignant stricture developed proliferation of
      neoplastic tissue after 2-5 months. The only patient treated for a benign
      stricture developed inside proliferation of granulation tissue after 4 months.
      CONCLUSION: Despite several technical difficulties and a high rate of late
      complications, recanalization of cervical oesophageal strictures by self
      expandable metal stents allowed good palliation of symptoms. Stents proved to be
      effective and well tolerated palliative treatment also for hypopharyngeal
      stenoses.

PMID- 12409117
TI  - Intravenous leiomyomatosis diagnosed by plain radiographs.

PMID- 12409118
TI  - Improved diagnosis of a temporal lobe abscess in a post-irradiated nasopharyngeal
      carcinoma patient using diffusion-weighted magnetic resonance imaging.

PMID- 12409122
TI  - Income inequality, residential poverty clustering and infant mortality: a study
      in Rio de Janeiro, Brazil.
AB  - In this paper, we propose an approach to investigate the hypothesis that the
      residential concentration of poverty affects health status more deeply than when
      poverty is randomly scattered in a given geographical area. To characterize the
      geographic pattern of poverty in the city of Rio de Janeiro, Brazil, an index
      that measures the heterogeneity of poverty concentration among sub-areas was
      proposed. We used census data and defined poverty by means of the household head
      monthly income. The 153 neighborhoods that compose the city were used as the
      geographic units, and the census tracts as the sub-areas. The proposed index
      measures differences of poverty concentration across census tracts within a
      neighborhood. The effects of geographic poverty clustering on infant mortality
      related variables (early neonatal mortality rate; post-neonatal mortality rate;
      proportion of adolescent mothers; and fertility rate among adolescents) were
      estimated by partial correlation coefficients, controlling for the neighborhood
      poverty rate. Our study revealed that intra-city variations of the post-neonatal
      mortality rate are associated with geographic patterns of poverty, and that
      pregnancy in adolescence is strongly and contextually correlated with intra
      neighborhood poverty clustering, even after adjustment for the poverty rate. The
      evidence of relevant health differences associated with the spatial concentration
      of poverty supports the hypothesis that properties of the environment of
      residence contextually influence health. Our findings suggest that prevention of
      some infant mortality related problems has to be focused directly on features of
      communities, considering their physical, cultural and psychosocial
      characteristics, being of particular concern the health of communities segregated
      from the society at large by extreme poverty.

PMID- 12409123
TI  - Puerto Rican understandings of child disability: methods for the cultural
      validation of standardized measures of child health.
AB  - Validating the cultural context of health is important for obtaining accurate and
      useful information from standardized measures of child health adapted for cross
      cultural applications. This paper describes the application of ethnographic
      triangulation for cultural validation of a measure of childhood disability, the
      Pediatric Evaluation of Disability Inventory (PEDI) for use with children living
      in Puerto Rico. The key concepts include macro-level forces such as geography,
      demography, and economics, specific activities children performed and their key
      social interactions, beliefs, attitudes, emotions, and patterns of behavior
      surrounding independence in children and childhood disability, as well as the
      definition of childhood disability. Methods utilize principal components analysis
      to establish the validity of cultural concepts and multiple regression analysis
      to identify intracultural variation. Findings suggest culturally specific
      modifications to the PEDI, provide contextual information for informed
      interpretation of test scores, and point to the need to re-standardize normative
      values for use with Puerto Rican children. Without this type of information,
      Puerto Rican children may appear more disabled than expected for their level of
      impairment or not to be making improvements in functional status. The methods
      also allow for cultural boundaries to be quantitatively established, rather than
      presupposed.

PMID- 12409124
TI  - Birth spacing, sibling rivalry and child mortality in India.
AB  - The detrimental impact of short preceding birth intervals on infant and early
      childhood mortality is well documented in demographic literature, although the
      pathways of influence within the relationship remain an area of debate. This
      paper examines the impact of the length of the preceding birth interval on under
      two mortality in India, and examines the pathways through which short preceding
      birth intervals may lead to an increased risk of mortality. Three mortality
      periods are examined: neonatal, early post neonatal and late post-neonatal and
      toddler, using the 1992 Indian National Family Health Survey. A multilevel
      modelling approach is used to account for the hierarchical nature of the data.
      The determinants of infants following a short or long birth interval are also
      examined. The results show that short preceding birth intervals (< 18 months) are
      associated with an increased risk of mortality in all three age groups, and the
      effect is particularly marked in the early post-neonatal period. Significant
      interactions were found between the length of the preceding birth interval and
      maternal education, gender and the survival status of the previous child. The
      significance of these interactions varied with the age of the child. The results
      highlight the diluting effect that a higher level of maternal education has on
      the relationship between short preceding birth intervals and mortality risk.
      There is evidence to suggest that sibling rivalry is a pathway through which
      short birth intervals influence mortality, with the death of the previous sibling
      removing the competition for scarce resources, and resulting in lower risks of
      mortality than if the previous sibling was still alive. The greatest risks of an
      infant following a short birth interval are among those whose previous sibling
      died, high parities, those with young mothers, and those whose previous sibling
      was breastfed for a short duration.

PMID- 12409125
TI  - Investigating starting-point bias: a survey of willingness to pay for insecticide
      treated nets.
AB  - The objective of this study was to investigate the existence of starting-point
      bias in the bidding game contingent valuation elicitation technique when
      determining the willingness to pay (WTP) for insecticide-treated nets (ITNs) and
      ITNs re-treatment in rural Nigeria. Of all existing contingent techniques, the
      bidding game most closely mimics the normal price taking behaviour in local
      markets in Nigeria. Three different starting-points (low, medium and high) were
      used to determine WTP for large and small ITNs, and for ITNs re-treatment,
      respectively. The respondents were randomly assigned to any of the starting
      points and a pre-tested interviewer-administered questionnaire used to elicit
      WTP. Non-parametric tests and the Tobit model were used to analyse the data for
      evidence of starting-point bias. Plots of respondents' cumulative density
      functions by starting-points were also examined to show the pattern of responses.
      The non-parametric tests showed no statistically significant differences between
      the three starting points in WTP for large ITNs (p = 0.262) and for ITNs re
      treatment (p = 0.412). However, there was a statistical significant difference in
      WTP for small ITNs (p = 0.045). Nevertheless, in this instance, the high starting
      point group had a lower mean WTP than the low group, and also had the lowest
      median WTP amongst the three groups. However, using the conditional WTP (only
      males), there were no differences among the three starting-points for all goods.
      The multiple regression analyses using the Tobit model confirmed the results of
      the non-parametric tests. The plots of cumulative densities were also similar for
      the three starting-points for the three products. However, the high starting
      point group had those more willing to pay higher amounts for large and small
      nets. There was no conclusive evidence of starting-point bias. Future research is
      required in order to gain a deeper understanding on factors determining peoples'
      valuation of goods and services, reasons for any type of starting-point bias, and
      how the bidding game can be improved.

PMID- 12409126
TI  - Amyotrophic lateral sclerosis and hopelessness: psychosocial factors.
AB  - The purpose of this study was to investigate the relationship of psychosocial
      factors to the presence of hopelessness among patients with amyotrophic lateral
      sclerosis (ALS). Secondary cross-sectional analyses were conducted with data
      collected from 136 ALS patients. Primary research questions were examined using
      hierarchical multiple regression procedures. Results showed that health locus of
      control and purpose in life were significant predictors of hopelessness among ALS
      patients. Other factors, including socioeconomic and demographic variables,
      variables measuring length and severity of illness, and additional psychosocial
      variables (social support satisfaction and degree to which spiritual beliefs help
      to cope with ALS) were not significant predictors of hopelessness. Results are
      discussed in light of the benefit to ALS patients of psychosocial interventions
      in disease management.

PMID- 12409127
TI  - Perceptions of philosophic and practice differences between US osteopathic
      physicians and their allopathic counterparts.
AB  - Data were gathered through a random national mail survey of 3000 US osteopathic
      physicians. Nine hundred and fifty-five questionnaires were usable for analysis.
      Through open-ended questions, osteopathic physicians identified philosophic and
      practice differences that distinguished them from their allopathic counterparts,
      and whether they believed the use of osteopathic manipulative treatment (OMT), a
      key identifiable feature of the osteopathic profession, was appropriate in their
      specialty. Seventy-five percent of the respondents to the question regarding
      philosophic differences answered positively, and 41 percent of the follow-up
      responses indicated that holistic medicine was the most distinguishing
      characteristic of their profession. In response to the question on practice
      differences, 59 percent of the respondents believed they practiced differently
      from allopathic physicians, and 72 percent of the follow-up responses indicated
      that the osteopathic approach to treatment was a primary distinguishing feature,
      mainly incorporating the application of OMT, a caring doctor-patient
      relationship, and a hands-on style. More respondents who specialized in
      osteopathic manipulative medicine and family practice perceived differences
      between them and their allopathic counterparts than did other practitioners.
      Almost all respondents believed OMT was an efficacious treatment, but 19 percent
      of all respondents felt use of OMT was inappropriate in their specialty. Thirty
      one percent of the pediatricians and 38 percent of the non-primary care
      specialists shared this view. Eighty-eight percent of the respondents had a self
      identification as osteopathic physicians, but less than half felt their patients
      identified them as such. When responses are considered in the context of all
      survey respondents (versus only those who provided open-ended responses) not a
      single philosophic concept or resultant practice behavior had concurrence from
      more than a third of the respondents as distinguishing osteopathic from
      allopathic medicine. Rank and file osteopathic practitioners seem to be
      struggling for a legitimate professional identification. The outcome of this
      struggle is bound to have an impact on health care delivery in the US.

PMID- 12409128
TI  - The role of adaptation to disability and disease in health state valuation: a
      preliminary normative analysis.
AB  - Chronically ill and disabled patients generally rate the value of their lives in
      a given health state more highly than do hypothetical patients imagining
      themselves to be in such states. Much of this difference may be due to actual
      patients' adaptation to their health states, a phenomenon that would not
      typically affect the ratings of persons who only hypothetically imagine
      themselves to be patients. This article pursues a non-empirical, normative
      question: does such adaptation render actual patients' ratings of quality of life
      morally questionable for purposes of resource allocation? Distinguishing the
      different basic elements in patient adaptation reveals why, and in what respects,
      people are pulled strongly in opposite directions in responding to this question.
      Several more explicit moral arguments against using adapted patients' ratings
      have been articulated by economists and philosophers, and others are developed by
      the authors. While most of these arguments do not survive careful analysis,
      several do. Given the subsequent complexity of the matter, it is argued that: (1)
      Neither solely actual nor solely hypothetical patient perspectives should be used
      for rating quality of life. (2) Even if representatives of the general public
      acting as hypothetical patients provide ultimately the best perspective from
      which to discern societal values about health states, patients' values that are
      often influenced by adaptation must still be conveyed to and clearly understood
      by public representatives as a critically important fact about health-related
      quality of life. The article also points to the need for much additional work on
      adaptation, both empirical research and normative analysis.

PMID- 12409129
TI  - The impact of the changing marital structure on fertility of Hong Kong SAR
      (Special Administrative Region).
AB  - Hong Kong SAR has experienced an especially rapid fall in fertility over the
      course of just two decades. The total fertility rate (TFR) fell steadily from the
      replacement level (i.e. two children per woman) to 0.83 in 1999, which is the
      lowest in the world. (United Nations Population Division. Replacement migration:
      is it a solution to declining and ageing populations? United Nations, New York,
      2000.) An important question is whether the dramatic decline in the TFR results
      from a decline in the fertility of married women or from changes in the
      proportion ever married. Are married women having fewer children, or are there
      simply fewer married women of prime childbearing age? In this paper, the effects
      of the changing marital structure on the conventional TFR are identified so that
      the underlying trends in fertility can be assessed. The study shows that the
      large decline in the TFR between 1981 and 1999 was in great part distorted by
      tempo effects, distortions caused by changes in the timing of childbearing and
      the changing marital structure. Without the distortion induced by the decreasing
      proportion of women marrying in the prime childbearing years, the decline in
      fertility was essentially less significant over the 20-year period. A
      continuation in the downward trend in the proportion married is a strong
      probability in the light of marriage habits prevalent among the population. This
      will exert a continuing downward driving force on the TFR. Hong Kong will
      experience its fertility rate decline further in the short to medium term. The
      study investigates the effect of long-lasting below-replacement level fertility
      with a view to gaining some analytical insight into the situation should the
      population experience such a striking demographic process.

PMID- 12409130
TI  - Differences in low-birthweight among documented and undocumented foreign-born and
      US-born Latinas.
AB  - In the USA foreign-born women tend to have fewer low-birthweight births than US
      born women from the same ethnicity. This "healthy migrant" effect could be caused
      by immigration of the fittest or by healthy people being deliberately selected in
      the immigration process. This study tests these hypotheses by comparing self
      reported history of low-birth-weight among foreign-born documented and
      undocumented Latinas and US-born Latinas. The sample includes 2398 (57.5%)
      documented foreign-born Latinas, 782 (18.7%) undocumented foreign-born Latinas,
      and 993 (23.4%) US-born Latinas who initiated prenatal care at MIC-Women's Health
      Services/MHRA in New York City during 1996-1997. Only women who reported previous
      live births were included in the sample. Documented foreign-born Latinas were
      less likely than US-born Latinas to have low-birth-weight babies taking into
      account parity, age, risk, and education. There were no significant differences
      between rates of low-birthweight for undocumented foreign-born Latinas and US
      born Latinas, or documented foreign-born Latinas. There was, however, a
      significant trend for rates of low-birthweight to increase from documented
      foreign-born to undocumented foreign-born to US-born women. This suggests that
      both official screening and migration of the fittest play a role in lower rates
      of low-birthweight among foreign-born Latinas compared to US-born Latinas.

PMID- 12409131
TI  - Determinants of and inequalities in self-perceived health in Ukraine.
AB  - Ukraine is the second most populous of the former Soviet Republics and since
      transition its economy has fared even more poorly than Russia. Although the
      impact of the collapse of the former Soviet Union on health in Russia has been
      investigated, little is known of its impact in other post-Soviet republics. We
      report a cross-sectional study undertaken in Ukraine in March 2000. A multi-stage
      random sampling technique was used and 1600 interviews completed (72% response
      rate) with a representative national sample of Ukrainian adults. We investigated
      socioeconomic and psychosocial determinants of self-perceived health, which has
      been shown to be a valid and reliable measure of overall health and predictive of
      mortality. Odds ratios for less than good physical health were calculated using
      logistic regression. The self-rated health of Ukrainians was poor, 25% of men and
      43% of women rated their health as poor or very poor. This is worse than levels
      recorded in Russia and considerably worse than levels seen in western Europe.
      Marked gender, geographical and socioeconomic inequalities in health were
      recorded. Women are at increased risk of poor self-rated health compared with men
      (OR 3.58, 2.50-5.14) as are women living in villages compared with those in
      cities (OR 3.24, 1.30-8.07). Socioeconomic factors including poor material
      situation (OR 1.64, 1.01-2.67), and psychosocial factors including low control
      over life (OR 1.89, 1.15-3.11) were identified as independent health
      determinants. Control over life was found to account for the negative impact of
      low social position on health. Good family relations protected against poor
      health. The findings suggest that a decrease in control, arising from an
      increasingly uncertain political and economic environment, a reduction in
      material wealth and the stress of change may all have contributed to the decline
      in life expectancy seen with transition.

PMID- 12409132
TI  - Drawing lines in the sand: the boundaries of the HIV pandemic in perspective.

PMID- 12409133
TI  - From retreat to health centre: legislation, commercial opportunity and the
      repositioning of a Victorian private asylum.
AB  - This paper examines the interplay of commercial imperatives and health care
      legislation in the survival of a privately owned psychiatric hospital in Guelph,
      Ontario, Canada. Using documentary and archival evidence, we show how the
      Homewood Retreat (later Sanitarium, and eventually Health Centre) was able to
      respond to and anticipate legislative developments through the agency of
      successive medical superintendents and the structural positioning of the
      institution as an inextricably integrated element in local and provincial mental
      health provision. Our case study is used to draw out wider lessons concerning
      agency, legislative context and treatment modality in the determination of
      organizational histories. We conclude by noting the important role of the private
      sector in ensuring the continued provision of an asylum form of mental health
      care.

PMID- 12409134
TI  - Catching waves: the historical geography of the general practice fundholding
      initiative in England and Wales.
AB  - General practitioner fundholding is often represented as one of the more
      successful elements of the 1989/90 Conservative reforms of the UK National Health
      Service (NHS). Successive annual 'waves' of fundholding practices were approved
      from 1990 through to 1997 and, over time, the initiative came to involve some 50%
      of UK general practitioners. Fundholding is known to have had a strong regional
      geography that changed with evolving fundholding eligibility criteria. Further,
      there have been persistent allegations that fundholding tended to occur
      disproportionately in areas of higher social status. Past studies of fundholding
      have tended to consider single waves or the overall impact of the initiative
      rather than its development over time. They have also tended to work at a single
      geographic scale or through single-region case studies when exploring the
      statistical regularities underlying the uptake of fundholding. Using multilevel
      analysis, this paper seeks to enhance understanding of fundholding through an
      examination of the interaction of district health authority and practice
      characteristics across all implemented waves for all general medical practices in
      England and Wales. We conclude that wave mattered on a national scale, that
      deprivation was relatively unimportant and that there were certain types of area
      that exhibited persistent but unexpected high uptake.

PMID- 12409135
TI  - Strategies to improve adherence to recommended chloroquine treatment regimes: a
      quasi-experiment in the context of integrated primary health care delivery in
      Ghana.
AB  - This paper presents the results of an intervention study carried out as part of
      the activities of a District Health Management Team responsible for integrated
      primary health care delivery in a rural district in Ghana. The aim was to test
      the impact of a combination of improved information provision to patients and
      drug labeling on adherence to recommended anti-malarial treatment regimens
      focusing on oral chloroquine, for the outpatient management of acute
      uncomplicated malaria. The study had a quasi-experimental pre-test post-test
      control group design with partly random allocation by clinic. The results show
      that the intervention resulted in an improved flow of information to clients
      prescribed chloroquine, and better labeling of drugs for the home treatment of
      acute clinical episodes of malaria in the intervention area. Improvements in
      adherence occurred in all clinics. However, improvements in adherence were most
      marked in the clinic that was worst performing at the start of the intervention.
      Implications of the results for improving adherence to chloroquine therapy on an
      outpatient basis are discussed.

PMID- 12409136
TI  - The social and psychological impact of the chemical contamination incident in
      Weston Village, UK: a qualitative analysis.
AB  - This paper contributes to the literature on community response to the
      announcement of well-established chemical contamination close to their homes. It
      describes a study of residents' views of chemical contamination on a close and
      long-standing community in the context of impacts on everyday life. This followed
      the discovery early in 2000 that houses in Weston Village, in the County of
      Cheshire, England, were contaminated by the chemical hexachlorobutadiene which
      was seeping from a sealed chemical waste quarry owned by Imperial Chemical
      Industries, one of the world's largest chemical companies. Qualitative methods
      were used for the study. A total of 23 people from the village were interviewed
      in 15 focused, semi-structured interviews. This study highlights the importance
      of attention to secondary, community-level and interpersonal-level health impacts
      in the face of epidemiological uncertainty.

PMID- 12409137
TI  - Race/ethnicity and depressive symptoms: a cross-cultural/ethnic comparison among
      university students in East Asia, North and South America.
AB  - To examine manifestations of depressive symptomatology among undergraduate
      students in East Asia, North and South America, responses to the Center for
      Epidemiologic Studies Depression Scale (CES-D) were compared across Japanese (n =
      310), Anglo-American (n = 377), Native American (n = 353), and Argentinean (n =
      110) undergraduate students. Japanese reported a significantly higher level of
      low positive affect, leading to significantly higher total CES-D scores, whereas
      their negative symptoms score was comparable to scores of Anglo-Americans and
      Argentineans. Although Native Americans were more likely to endorse negative
      symptoms, their low positive affect score was comparable to those of
      Argentineans. Argentineans appear to suffer less from depressive symptoms.
      Results from a Differential Item Functioning analysis, using Anglo-Americans as
      the reference group, indicated that: (1) the manifestation of depressive symptoms
      seemed to be similar for Anglo-Americans and Argentineans, except for low
      positive affect; (2) Native Americans tended to favor somatic symptoms over
      affective (depressive) symptoms; (3) responses to positive affect questions could
      possibly be biased not only for Japanese but also for people in North America;
      i.e., the expression of positive affect might be enhanced in North American
      culture, while inhibited in Japanese culture.

PMID- 12409138
TI  - Health care reform in Russia: a survey of head doctors and insurance
      administrators.
AB  - In keeping with the introduction of market-oriented reforms since the collapse of
      the Soviet Union, Russia's health care system has undergone a series of sweeping
      changes since 1992. These reforms, intended to overhaul socialized methods of
      health care financing and delivery and to replace them with a structure of
      competitive incentives to improve efficiency and quality of care, have met with
      mixed levels of implementation and results. This article probes some of the
      sources of support for and resistance to change in Russia's system of health care
      financing and delivery. It does so through a national survey of two key groups of
      participants in that system: head doctors in Russian clinics and hospitals, and
      the heads of the regional-level quasi-governmental medical insurance Funds. The
      survey results demonstrate that, on the whole, both head doctors and health
      insurance Fund directors claim to support the recent health care system reforms,
      although the latter's support is consistently statistically significantly
      stronger than that of the former. In addition, the insurance Fund directors'
      responses to the survey questions tend consistently to fall in the shape of a
      standard bell curve around the average responses, with a small number of
      respondents more in agreement with the survey statements than average, and a
      similarly small number of respondents less so. By contrast, the head doctors,
      along a wide variety of reform measures, split into two camps: one that strongly
      favors the marketization of health care, and one that would prefer a return to
      Soviet-style socialized medicine. The survey results show remarkable national
      consistency, with no variance according to the respondents' geographic location,
      regional population levels or other demographic or health characteristics, age of
      respondents, or size of health facility represented. These findings demonstrate
      the emergence of well-defined bureaucratic and political constituencies, their
      composition mixed depending on the particular element of reform under discussion,
      for and against specific avenues of continuity and change in Russia's health
      policy. As Russia struggles to devise policy strategies and tactics that balance
      access, equity, quality, and efficiency, it confronts not only policy choices but
      also political challenges that look not dissimilar to those faced by health
      reformers elsewhere in the world.

PMID- 12409139
TI  - Using the DATCAP and ASI to estimate the costs and benefits of residential
      addiction treatment in the State of Washington.
AB  - Funding agencies and policy makers often criticize residential addiction
      treatment because the cost of residential services is typically higher than for
      outpatient services and it is unclear whether the outcomes are significantly
      better for most clients. To address these concerns, proponents of residential
      treatment require economic evidence to justify further investments in this
      modality over less intensive and less costly options. Recent studies have
      developed methods and empirical guidelines for using the drug abuse treatment
      cost analysis program (DATCAP) and the addiction severity index (ASI) in a
      comprehensive economic evaluation of addiction treatment. The present study
      applied these methods and guidelines to estimate the economic costs and benefits
      of residential addiction treatment at five programs in the State of Washington,
      USA that serve publicly funded clients. Program- and client-specific economic
      cost estimates were derived using data collected on-site with the DATCAP along
      with opportunity cost estimates associated with treatment attendance. Economic
      benefits were calculated from client self-reported information at treatment entry
      and at 6 months post discharge using the ASI. Outcome categories included
      inpatient services, employment, medical and psychiatric conditions, and criminal
      activity. Results indicate that average weekly economic cost of treatment
      services at the five programs ranged from 463 dollars to 703 dollars. Average
      (per client) economic cost of treatment was 4912 dollars (composed of 3650
      dollars in program cost and 1262 dollars in client cost) for all subjects that
      completed both a baseline and follow-up questionnaire (N = 222; 82%). Average
      (per client) total economic benefit was 21,329 dollars, leading to estimates of
      16,418 dollars for average net benefit and 4.34 for the benefit-cost ratio. Total
      and net economic benefits were significantly related to gender, race, religious
      preference, and baseline ASI composite scores for drug use and legal status. A
      detailed sensitivity analysis did not alter the qualitative findings. This study
      provides conclusive evidence that, for this sample of programs in Washington
      State, the economic benefits of residential addiction treatment significantly
      exceeded the economic costs. Although the results are not necessarily
      generalizable to private-paying clients or clients from other States in the US,
      the methods are based on widely used data collection instruments and well
      accepted economic principles. Thus, extensions of this research to other clients,
      States, and modalities should be feasible and straightforward.

PMID- 12409140
TI  - 23-Hydroxybetulinic acid-mediated apoptosis is accompanied by decreases in bcl-2
      expression and telomerase activity in HL-60 Cells.
AB  - 23-Hydroxybetulinic acid, a derivative of betulinic acid, was investigated for
      its apoptotic effect and the associated telomerase activity in human leukemia HL
      60 cells. Apoptosis and bcl-2 were determined by flow cytometry analysis. A PCR
      based telomeric repeat amplification protocol assay was used to detect telomerase
      activity. Results showed that 23-hydroxybetulinic acid induced growth arrest and
      apoptotic cell death in HL-60 cells. The apoptotic events were associated with
      concurrent down-regulation of bcl-2 and the telomerase activity. Our data suggest
      that 23-hydroxybetulinic acid may be a potential cytotoxic agent for treatment of
      cancer.

PMID- 12409141
TI  - A novel anti-proliferative property of clusterin in prostate cancer cells.
AB  - Clusterin is a ubiquitous secretory glycoprotein that is known to suppress
      certain forms of apoptosis. Since apoptosis and proliferation are two opposing
      cellular events, it remains unclear if clusterin has any effect on cellular
      proliferation. The objective of the present study was to examine the effects of
      clusterin on proliferation in a prostate cancer cell line, LNCaP. We found that
      clusterin inhibited EGF-mediated proliferation in these cells, as measured by
      (3)H-thymidine incorporation and by cell counting. Clusterin did not bind with
      EGF nor did it block phosphorylation of the EGF receptor. Treatment of LNCaP
      cells with EGF resulted in a transient increase in the expression of both c-Fos
      and c-Jun. Addition of clusterin to these cultures significantly down-regulated
      the protein level of c-Fos, but not c-Jun. These results demonstrated a novel
      biological role for clusterin. Clusterin is not only anti-apoptotic but also anti
      proliferative. The anti-proliferative event maybe associated with a down
      regulation of c-Fos.

PMID- 12409142
TI  - Resveratrol- induced apoptosis is mediated by p53-dependent pathway in Hep G2
      cells.
AB  - Resveratrol, a phytoalexin found in many plants, has been reported to possess a
      wide range of pharmacological properties and is one of the promising
      chemopreventive agents for cancer. Here, we examined the antiproliferation effect
      of resveratrol in two human liver cancer cell lines, Hep G2 and Hep 3B. Our
      results showed that resveratrol inhibited cell growth in p53-positive Hep G2
      cells only. This anticancer effect was a result of cellular apoptotic death
      induced by resveratrol via the p53-dependent pathway. Here we demonstrated that
      the resveratrol-treated cells were arrested in G1 phase and were associated with
      the increase of p21 expression. In addition, we also illustrated that the
      resveratrol-treated cells had enhanced Bax expression but they were not involved
      in Fas/APO-1 apoptotic signal pathway. In contrast, the p53-negative Hep 3B cells
      treated with resveratrol did not show the antiproliferation effect neither did
      they show significant changes in p21 nor Fas/APO-1 levels. In summary, our study
      demonstrated that the resveratrol effectively inhibited cell growth and induced
      programmed cell death in Hepatoma cells on a molecular basis. Furthermore, these
      results implied that resveratrol might also be a new potent chemopreventive drug
      candidate for liver cancer as it played an important role to trigger p53-mediated
      molecules involved in the mechanism of p53-dependent apoptotic signal pathway.

PMID- 12409143
TI  - Possible degradative process of cholecystokinin analogs in rabbit jejunum brush
      border membrane vesicles.
AB  - Our recent work on the intestinal metabolism and absorption of cholecystokinin
      analogs, sulfated C-terminal octapeptide (CCK8; Asp-Tyr(SO(3)H)-Met-Gly-Trp-Met
      Asp-Phe(NH(2)) = DY(SO(3)H)MGWMDF(NH(2))) and tetrapeptide (CCK4; Trp-Met-Asp
      Phe(NH(2)) = WMDF(NH(2))), was extended to investigate the degradative process of
      these analogs using rabbit jejunum brush-border membrane vesicles and to find a
      better enzyme-inhibitor system for intestinal absorption of peptide drugs.
      Various enzyme inhibitors and a lower pH buffer were applied to discover the
      major enzyme(s) involved in each process. Metabolic pathways showing degradative
      processes were proposed for both analogs. The major cleavage site occurs at the
      W(1)-M(2) for CCK4. At least three metabolic pathways occur independently for
      CCK8 and appear at peptides bonds between G(4)-W(5), M(6)-D(7), and D(7)
      F(NH(2))(8). Many different enzymes of aminopeptidase, endopeptidase, angiotensin
      converting enzyme, metalloenzyme, and others were involved in each process.
      Identification of more specific yet safe enzyme inhibitors and co-administration
      of various these inhibitors may lead to further enhancement in intestinal peptide
      absorption when administered orally.

PMID- 12409144
TI  - Mitochondrial cytochrome c oxidase as a target site for cephalosporin antibiotics
      in renal epithelial cells (LLC-PK(1)) and renal cortex.
AB  - We reported previously that treatment of the pig kidney proximal tubular
      epithelial cell line LLC-PK(1) with cephaloridine (CLD) decreased the activity of
      cytochrome c oxidase in the mitochondria of the cells followed by increases in
      lipid peroxidation and cell necrosis. In this study, we investigated the effects
      of CLD on the activity of cytochrome c oxidase in mitochondria isolated from LLC
      PK(1) cells and purified the enzyme from mitochondria of the rat renal cortex.
      The activity of cytochrome c oxidase in the isolated mitochondria from LLC-PK(1)
      cells was significantly decreased from 1 h after addition of 1 mM CLD. Other
      cephalosporin antibiotics, cefazolin and cefalotin, also decreased the activity
      of cytochrome c oxidase in the isolated mitochondria. The activity of cytochrome
      c oxidase purified from the mitochondria of the rat renal cortex was also
      decreased from 2 h after addition of 1 mM CLD in a non-competitive manner. These
      results suggest that the direct inhibition of cytochrome c oxidase activity in
      the mitochondrial electron transport chain by cephlosporins may result from the
      observed nephrotoxicity.

PMID- 12409145
TI  - Glucose upregulates plasminogen activator inhibitor-1 gene expression in vascular
      smooth muscle cells.
AB  - We investigated the effects of high concentrations of glucose on plasminogen
      activator inhibitor-1 (PAI-1) gene expression in cultured rat vascular smooth
      muscle cells (VSMC). In response to a high glucose concentration (27.5 mM), PAI-1
      mRNA increased within 2 h, peaked at 4 h, remained elevated for another 4 h, then
      decreased to basal levels at 24 h. On the other hand, mannose at the same
      concentration (22.5 mM mannose plus 5.5 mM glucose) as an osmotic control had
      little effect on PAI-1 mRNA expression. The expression of PAI-1 mRNA that was
      also increased by H(2)O(2), angiotensin II, or phorbol myristate acetate, was
      reversed by the MAPK kinase (MEK) inhibitor PD98059 or the specific protein
      kinase C (PKC) inhibitor GF109203X. High glucose appeared to activate MAPK and
      PKC in VSMC judging from Elk-1 and AP-1 activation, respectively. PD98059
      inhibited and GF109203X prevented subsequent PAI-1 induction by glucose. These
      results suggest that glucose at high concentrations induces PAI-1 gene expression
      in VSMC at least partially via MAPK and PKC activation. This direct effect of
      glucose might have important implications for the increased plasma concentrations
      of PAI-1 and possibly atherosclerosis that are associated with diabetes.

PMID- 12409146
TI  - Saiko-ka-ryukotsu-borei-to, an herbal medicine, prevents chronic stress-induced
      disruption of glucocorticoid negative feedback in rats.
AB  - Exposure to stress is known to precipitate or exacerbate many neuropsychiatric
      disorders such as depression. Abnormality of the neuroendocrine system, as shown
      by increased adrenal weight and attenuated glucocorticoid negative feedback, is
      frequently seen in depression. The aim of the present study is to clarify the
      usefulness of saiko-ka-ryukotsu-borei-to, an herbal medicine, in the treatment of
      abnormality of the neuroendocrine system using an experimental stress-depression
      model. Rats were subjected to water immersion and restraint for 2 h daily for 4
      weeks (chronic stress), followed by recovery for 10 days. Saiko-ka-ryukotsu-borei
      to was administered during the stress and recovery periods (100, 300, or 1000
      mg/kg daily, p.o.) or only during the recovery period (1000 mg/kg). After the
      recovery period, the adrenal weight was measured, and glucocorticoid feedback
      ability was evaluated by a dexamethasone suppression test using 30 microg/kg
      dexamethasone. The administration of saiko-ka-ryukotsu-borei-to during the stress
      and recovery periods prevented the stress-induced increase in adrenal weight or
      the attenuated negative feedback in a dose-dependent manner. The administration
      of saiko-ka-ryukotsu-borei-to during the recovery period alone also ameliorated
      the abnormality of the neuroendocrine system. These results indicate that saiko
      ka-ryukotsu-borei-to is effective against chronic stress-induced abnormality of
      the neuroendocrine system. Because some symptoms and symptomatic relapses in
      depressives are attributed to dysfunction of the hypothalamo-pituitary-adrenal
      axis, the present findings provide information important for prevention and
      treatment of depression.

PMID- 12409147
TI  - Hypercapnic and hypoxic ventilatory responses in long-term streptozotocin
      diabetic rats during conscious and pentobarbital-induced anesthetic states.
AB  - To clarify the diabetes mellitus (DM)-associated changes in the respiratory
      neuronal control system, acute ventilatory responses to progressively increasing
      hypercapnia (6%) and hypoxia (10%) were compared between normal (N) and
      streptozotocin (60 mg/kg, i.v.) -DM rats for a long period up to 28 weeks. The
      same comparison was conducted during the anesthetic state induced with
      pentobarbital (35 mg/kg, i.p.). During the conscious state, basic ventilatory
      parameters, such as respiratory rate, tidal volume and minute ventilation, were
      not impaired in DM rats, but ventilatory responses to hypercapnia and hypoxia
      were reduced significantly at 16 weeks and later after streptozotocin injection.
      The reduced responses in DM rats were not recovered by insulin treatment (5-6
      U/body, s.c., daily). During the anesthetic state, both hypoxic and hypercapnic
      responses were depressed more intensely in N rats than in DM rats, resulting in
      an equivalent level of the response in the two groups. The present study
      demonstrated that ventilatory responses to hypercapnia and hypoxia were reduced
      in a long-term DM condition. This may be derived from the impairment of the
      peripheral and central chemosensitivity. The reduction in ventilatory responses
      was exaggerated during the anesthetic state.

PMID- 12409148
TI  - Anticonflict effects of rose oil and identification of its active constituents.
AB  - The present study investigates the pharmacologically active constituents of rose
      oil, which possesses anti-conflict effects. Analysis using GC/MS revealed that
      rose oil contains 9 substances that were identified as myrcene, benzyl alcohol, 2
      phenethyl alcohol, citronellol, geraniol, citronellyl acetate, eugenol, geranyl
      acetate and methyl eugenol. We examined the effects of each of these substances
      using the Geller and Vogel conflict tests in ICR mice. Myrcene, benzyl alcohol
      and citronellyl acetate did not produce any effects in either tests. Geranyl
      acetate and methyl eugenol produced no effect in the Geller conflict test.
      Geraniol and eugenol decreased the response rate during the safe period of the
      Geller conflict test, but did not affect the response rate during the alarm
      period. In contrast, 2-phenethyl alcohol and citronellol, like rose oil, produced
      an increasing effect on the response rate during the alarm period in the Geller
      conflict test. In addition, both chemicals increased the number of electric
      shocks mice received in the Vogel conflict test in a manner similar to that of
      rose oil. Given that 2-phenethyl alcohol and citronellol produced the same anti
      conflict effects in both tests as rose oil, we concluded that they are the
      pharmacologically active constituents of anti-anxiety-like effect of rose oil.

PMID- 12409149
TI  - Effects of Rho-kinase inhibitor on vasopressin-induced chronic myocardial damage
      in rats.
AB  - The aim of this study was to develop a new model of vasopressin-induced chronic
      myocardial damage based on sustained ST-segment depression in electrocardiogram
      (ECG) with progression of myocardial fibrosis in rats. Furthermore, using this
      model, we examined the prophylactic potential of fasudil, a Rho-kinase inhibitor,
      against myocardial damage induced by vasopressin. In 10-week old male Donryu
      rats, intravenous administration of arginine vasopressin (0.5 iu/kg) induced
      significant ST-segment depression. Two days and one week after the administration
      of vasopressin, ST-segment depression was -0.19 +/- 0.02 and -0.14 +/- 0.02 mV,
      respectively. Fasudil (10 and 30 mg/kg, p.o.) significantly attenuated the ST
      segment depression induced by vasopressin. One week after the administration of
      vasopressin, the percent area of myocardial fibrosis in control animals (0.42 +/-
      0.11%, p < 0.01) was significantly greater than that in normal animals (0.05 +/-
      0.01%). Fasudil (10 and 30 mg/kg) significantly prevented the development of the
      fibrosis. We present a new model of chronic myocardial damage based on sustained
      ST-segment depression with progression of myocardial fibrosis in rats, and
      suggest that this model may be useful to investigate the treatment of chronic
      angina. Inhibition of Rho-kinase is efficacious in preventing the ECG change and
      development of fibrosis induced by vasopressin in this model.

PMID- 12409150
TI  - Studies of individuals with schizophrenia never treated with antipsychotic
      medications: a review.
AB  - A review of 65 studies of individuals with schizophrenia who had never been
      treated with antipsychotic medications indicates significant abnormalities in
      brain structure and function. Neurological and neuropsychological measures show
      the most consistent and largest group differences between those affected and
      normal controls. Measures of structural differences and cerebral metabolic
      function are significant but less impressive. Electrophysiological differences
      also are found, but most such studies are older and have methodological problems.
      The brain abnormalities implicate a variety of interrelated brain regions,
      primarily the medial temporal, prefrontal, thalamic, and basal ganglia areas. It
      is concluded that schizophrenia is a brain disease in the same sense that
      Parkinson's disease and multiple sclerosis are, and that the brain abnormalities
      in schizophrenia are inherent in the disease process and not medication-related.
      The challenge for the future is to use the new molecular techniques to study
      these brain areas and elevate our understanding of schizophrenia's etiology to
      the next level.

PMID- 12409151
TI  - 31P-spectroscopy of frontal lobe in schizophrenia: alterations in phospholipid
      and high-energy phosphate metabolism.
AB  - Studies using 31P-magnetic resonance spectroscopy (MRS) reported on abnormalities
      in frontal lobe metabolism in schizophrenia. The most consistent findings were a
      reduction in the resonances of phosphomonoesters (PME) and/or increased
      phosphodiesters (PDE), which are, respectively, the precursors and the
      metabolites of membrane phospholipids, thus suggesting an accelerated
      phospholipid metabolism in the disease. Other studies reported increased high
      energy phosphates (ATP-adenosine triphosphate and PCr-phosphocreatine) in
      schizophrenia, reflecting decreased use of energy in the frontal lobe. We
      investigated 53 schizophrenic patients (DSM-IV) and 35 healthy controls. Eighteen
      from these patients were drug nai;ve and the remaining 35 were drug-free for an
      average of 6 months. Phospholipid metabolism and high-energy phosphates were
      assessed in the left frontal lobe using 31P-MRS. Psychopathological evaluation
      was done with the Brief Psychiatric Rating Scale (BPRS) and the Negative Symptoms
      Rating Scale (NSRS). Neuropsychological evaluation was performed with the
      Wisconsin Card Sorting Test (WCST), Stroop Test and Wechsler Adult Intelligence
      Scale. Drug-nai;ve patients showed reduced PDE in the left frontal lobe compared
      to controls and to previously medicated patients (p<0.05). No differences among
      the three groups were found regarding the other spectroscopy parameters. In
      healthy controls, but not in schizophrenics, a negative (and probably
      physiological) correlation was found between PME and PDE (p<0.01). In
      schizophrenic patients, ATP was correlated with negative symptoms and with
      neuropsychological impairment (p<0.01). The lack of a correlation between PME and
      PDE, as well as the reduction of PDE in schizophrenia, suggest a disrupted
      phospholipid metabolism in the disease, albeit on a contrary direction of that
      reported in literature. The relationships of ATP with negative symptoms and
      neuropsychological deficit suggest an alteration of energetic demand in the
      frontal lobe of schizophrenic patients, which is in line with the hypofrontality
      hypothesis of the disease.

PMID- 12409153
TI  - Magnetic resonance imaging of the thalamus in male patients with schizophrenia.
AB  - Thalamic abnormalities have been hypothesized to explain much of the
      psychopathology in schizophrenia, however, quantitative magnetic resonance
      imaging (MRI) studies have yielded discrepant results as to whether there are
      thalamic volume alterations. The current study utilized high resolution MRI and
      an axial voluming protocol to determine if there was a significant reduction in
      the volume of the thalamus in patients with schizophrenia. Quantitative analysis
      was performed on magnetic resonance images of the brain in 41 male medicated
      schizophrenic patients and 39 male normal control subjects similar in age,
      education and handedness. There were no group differences in thalamic volumes
      between controls and patients with schizophrenia, even after adjusting for
      intracranial volume, total brain tissue volume, and gray matter volume. There
      were also no significant correlations between thalamic volume and either current
      neuroleptic dose or illness duration. However, there was a significant right
      greater than left thalamic volume asymmetry in schizophrenics and controls, and
      the degree of thalamic volume asymmetry was similar in both groups. The failure
      to detect any significant difference in thalamic volumes may be due to the
      heterogeneity of the schizophrenic population and as yet undetermined chronic
      effects of neuroleptic medication on the thalamus. However, another reasonable
      explanation for the study findings is that quantitative MRI voluming of the
      entire thalamus may not be sensitive enough to detect more subtle regional
      neuropathology within the thalamus.

PMID- 12409152
TI  - An MRI study of temporal lobe abnormalities and negative symptoms in chronic
      schizophrenia.
AB  - Previous magnetic resonance imaging (MRI) studies have reported various subtle
      brain abnormalities in schizophrenic patients, including temporal lobe
      abnormalities, which are of particular interest given the role of this brain
      region in auditory and language processing, and the characteristic deficits in
      these processes in schizophrenia. Subjects in this study were 16 male patients
      diagnosed with chronic schizophrenia and 15 healthy male comparison subjects.
      These patients were characterized by negative symptoms. High spatial resolution
      coronal MRI 1.5-mm-thick slices were used to measure the gray matter volume of
      the superior temporal gyrus, anterior and posterior amygdala/hippocampal complex,
      and parahippocampal gyrus. Patients, relative to normal comparison subjects,
      evinced a reduction of gray matter volume in bilateral superior temporal gyri and
      anterior amygdala/hippocampal complex. The reduction in gray matter of the
      superior temporal gyrus in patients with schizophrenia is consistent with
      previous findings, and is noteworthy in that it was found in this group of
      patients with predominantly negative symptoms. The reduction in the anterior
      amygdala/hippocampal complex was an additional temporal lobe finding. These
      results underscore the role of temporal lobe structures in the pathophysiology of
      schizophrenia.

PMID- 12409154
TI  - Non-reduction in hippocampal volume is associated with higher risk of psychosis.
AB  - Previous research using MRI scans has shown reduced hippocampal volumes in
      chronic schizophrenia and first-episode psychosis compared to well subjects.
      There are few MRI volumetric studies of high-risk cohorts and no studies that
      have compared structural measures between high-risk subjects who later developed
      a psychotic illness and those who did not. Therefore, the question of whether
      structural changes to the hippocampi precede the onset of an acute psychotic
      episode has not been answered. Hippocampal and whole brain volumes of 60 people
      at ultra high-risk (UHR) of developing a psychotic episode (identified through
      state and trait criteria) were obtained through MRI scan and compared with
      subjects with first episode psychosis (FEP: n=32), and no mental illness (n=139).
      Thirty-three percent (n=20) of the UHR cohort developed a psychotic disorder
      during the 12-month period following the MRI scan. The UHR group as a whole, like
      the FEP group, had significantly smaller left and right hippocampal volumes than
      the normal comparison group. Contrary to our initial hypothesis, the left
      hippocampal volume of the UHR subjects who developed a psychotic disorder was
      larger than the UHR-non-psychotic subgroup and the FEP group, but no differences
      were found between the UHR-psychotic and normal groups. The right hippocampus of
      the UHR-non-psychotic group was significantly smaller than the Normal group but
      not different to the FEP group. Furthermore, a larger left hippocampal volume of
      the UHR cohort at intake was associated with the subsequent development of acute
      psychosis rather than smaller volumes. These results contradicted the expected
      outcomes, which had been influenced by the neurodevelopmental model of the
      development of psychosis and an earlier study comparing hippocampal volumes of
      first episode, chronic schizophrenia and normal populations. One implication of
      these results is that a process of dynamic central nervous system change may
      occur during the onset phase of schizophrenia and related disorders, rather than
      earlier in life as suggested by the neurodevelopmental model. Alternatively,
      selection factors associated with the UHR cohort may have created a bias in the
      results. Replication of these results is required in other high-risk cohorts.

PMID- 12409155
TI  - A functional anatomic study of emotion in schizophrenia.
AB  - Using salient pictures with aversive (AV) and non-aversive (NA) content, we
      probed limbic-emotional function in schizophrenia, testing specific hypotheses
      that the amygdala would exhibit abnormal activity and a relationship with
      positive symptoms. Fourteen schizophrenic patients and 13 healthy comparison
      subjects viewed pictures during [15O] water positron emission tomography (PET).
      Both groups reported identical subjective experience of the aversive stimuli and
      both activated right insula (AV-NA). The schizophrenic group showed greater
      activation of the medial prefrontal cortex (MPFC) for the AV-NA comparison.
      Control subjects activated bilateral amygdaloid and orbitofrontal regions for NA
      relative to a blank condition (simple visual fixation, BL), whereas schizophrenic
      subjects only activated left orbitofrontal cortex. Activity in the left amygdala
      correlated with positive symptoms in the patients. Both groups activated visual
      cortex, and the schizophrenic subjects exhibited less modulation throughout
      visual cortex for NA-BL, as well as more focused deficits in the left fusiform
      and left mid-occipital gyrus for AV-NA, possibly related to decreased eye
      movements in the schizophrenic patients. Overall, the data are consistent with a
      general failure to process salient stimuli in schizophrenia, and the findings
      support the involvement of the amygdala in the positive symptoms of
      schizophrenia.

PMID- 12409156
TI  - Decreased left amygdala and hippocampal volumes in young offspring at risk for
      schizophrenia.
AB  - Abnormalities in the structural integrity and connectivity of the medial temporal
      and the prefrontal cortex are well documented in schizophrenia, but it is unclear
      if they represent premorbid indicators of neuropathology. Studies of young
      relatives at high-risk for schizophrenia (HR) provide an opportunity to clarify
      this question. We herein provide data from a magnetic resonance imaging (MRI)
      study of these structures in young offspring of schizophrenia patients. A series
      of 17 young HR offspring of schizophrenic patients were compared with 22 healthy
      comparison subjects (HC). Morphometric comparisons of the right and left
      dorsolateral prefrontal cortex (DLPFC), and the anterior and posterior amygdala
      hippocampal (A-H) complex were conducted using high-resolution whole brain T(1)
      weighted brain images. Compared with the HC group, HR subjects had significant
      decreases in intracranial volume. The volumes of the left anterior and posterior
      A-H complex were reduced in the HR subjects after adjusting for intracranial
      volume. HR subjects also showed a significant leftward (Right>Left) asymmetry of
      the anterior A-H complex compared to the HC subjects. No significant changes were
      seen in the DLPFC. Thus, lateralized alterations in the volume of the left A-H
      complex are evident in unaffected young offspring of schizophrenia patients and
      may be of neurodevelopmental origin. Follow-up studies are needed to examine the
      predictive value of these measures for future emergence of schizophrenia in at
      risk individuals.

PMID- 12409157
TI  - Caudate volume changes in first episode psychosis parallel the effects of normal
      aging: a 5-year follow-up study.
AB  - We investigated whether the caudate nuclei volume (CNV) of 15 first episode
      psychosis patients increased after 5 years of treatment with either atypical
      antipsychotics or low doses of typical antipsychotics. Caudate volumes were
      measured from magnetic resonance imaging (MRI) scans in 15 patients and 10
      healthy controls. Both groups demonstrated a significant 9% decline in caudate
      volume. We were unable to replicate previous reports of caudate enlargement in
      patients receiving antipsychotic treatment.

PMID- 12409158
TI  - Spontaneous, slow and fast magnetoencephalographic activity in patients with
      schizophrenia.
AB  - A 2* 37 channel biomagnetic system (Magnes II) was used to record spontaneous
      magnetic activity for the frequency ranges 2-6 Hz and 12.5-30 Hz in 30 patients
      with schizophrenia (23 men and 17 women) and 30 healthy volunteers in both
      hemispheres during a resting condition. The dipole localization was calculated by
      the dipole density plot (DDP) method, which is a spatial averaging in order to
      decrease the influence of the nonfocal activity. The quantified DDP results were
      superimposed to T2-weighted MR-images of each patient's head as isocontour lines.
      To superimpose the MEG results to 3-D MRI data, the scanned head data set was
      fitted to the reconstructed MRI head shape using a surface fit programme
      developed by our department. The absolute dipole values were correlated with the
      psychopathological findings and the cumulative neuroleptic dosage for each
      patient. The group of patients with schizophrenia differed overall from the
      healthy subjects in the elevation of absolute dipole values measured in both
      hemispheres. For the region of slow dipole activity (2-6 Hz), a high correlation
      was found between the intensity of dipole concentration and productive psychotic
      symptoms (PANSS, P1-P7). Dipole localization (for both frequency ranges) showed a
      concentration effect (DCE) in the temporoparietal region in patients with
      schizophrenia.

PMID- 12409159
TI  - Phosphorus metabolite changes in temporal lobes of subjects with schizotypal
      personality disorder.
AB  - Using in vivo (31)P magnetic resonance spectroscopy, phosphorus metabolite levels
      were measured in the temporal lobes of 11 neuroleptic-free subjects with
      schizotypal personality disorder (SPD) and 20 age-matched healthy subjects. SPD
      subjects showed smaller amounts of phosphomonoesters in the left temporal lobe
      than healthy subjects. Membrane phospholipid abnormalities in the left temporal
      lobe may be a common pathophysiologic feature in schizophrenia spectrum
      disorders.

PMID- 12409161
TI  - Panic attacks in schizophrenia.
AB  - OBJECTIVE: To determine the association between panic attacks and comorbid mental
      disorders, psychiatric symptomotology, service utilization, and suicidality among
      individuals with schizophrenia in the community. METHOD: Data were drawn from the
      Epidemiologic Catchment Area (ECA) Study (n=20, 291). Differences in comorbid
      mental disorders, symptomotology, service use, and suicidality were determined
      between individuals with schizophrenia, with and without panic attacks. RESULTS:
      Panic attacks (lifetime) were common among almost half (45%) of those with
      schizophrenia. Individuals with schizophrenia and panic attacks had significantly
      elevated rates of co-occurring mental disorders, psychotic symptoms, suicidality,
      and mental health service utilization compared with individuals with
      schizophrenia who did not suffer from panic attacks. CONCLUSIONS: Panic attacks
      are common among individuals with schizophrenia in the community and are
      associated with higher rates of other co-occurring mental disorders, service
      utilization and suicidality. These results suggest that concurrent treatment for
      both panic and schizophrenia may be indicated for optimal outcomes. Future
      research is needed to determine the direct and indirect cost benefit in providing
      mental health treatment for panic among individuals with schizophrenia in the
      community.

PMID- 12409160
TI  - Limbic cortical injury sustained during adulthood leads to schizophrenia-like
      syndrome.
AB  - Within 1 year of severe trauma to the left anterior temporal lobe and minor
      injury to the frontal lobes, a 35-year-old individual developed classic positive
      and negative symptoms of schizophrenia. His antipsychotic drug-induced
      parkinsonism was greater on the left side, suggesting increased left striatal
      dopaminergic transmission. The authors propose that even in adulthood,
      significant and selective disruption of fronto-temporal connectivity is
      sufficient to produce a phenocopy of schizophrenia.

PMID- 12409162
TI  - Women with schizophrenia: pregnancy outcome and infant death among their
      offspring.
AB  - Schizophrenia in the mother may imply an increased risk of adverse pregnancy
      outcome. However, inconclusive findings, unknown pathological mechanisms and
      possible confounding by social factors and smoking requests further explorations.
      The aim of this study were to (1) examine non-optimal pregnancy outcome using
      data from a population-based cohort, controlling for covariates known to
      influence fetal growth; and (2) perform separate analyses of women diagnosed
      before childbirth and women hospitalized for schizophrenia during pregnancy. The
      study sample comprised 2096 births by 1438 mothers diagnosed with schizophrenia
      (of whom 696 mothers were antenatal diagnosed and 188 admitted during pregnancy)
      and 1,555,975 births in the general population. We found significantly increased
      risks for stillbirth, infant death, preterm delivery, low birth weight, and small
      for-gestational-age among the offspring of women with schizophrenia. Women with
      an episode of schizophrenia during pregnancy had the highest risks (e.g., low
      birth weight; OR 4.3, 95% CI 2.9-6.6 and stillbirth; OR 4.4, 95% CI 1.4-13.8).
      Controlling for a high incidence of smoking during pregnancy among schizophrenic
      women (51% vs. 24% in the normal population) and other maternal factors (single
      motherhood, maternal age, parity, maternal education, mothers' country of birth
      and pregnancy-induced hypertensive diseases) in a multiple regression model,
      reduced the risk estimates markedly. However, the risks for adverse pregnancy
      outcomes were even after adjustments generally doubled for women with an episode
      of schizophrenia during pregnancy compared to women in the control group (e.g.,
      low birth weight; OR 2.3, 95% CI 1.5-3.5, preterm delivery; OR 2.4, 95% CI 1.5
      3.8 and stillbirth; OR 2.5, 95% CI 0.8-7.9). The risks for preterm delivery and
      low birth weight were significantly elevated throughout the analyses. We conclude
      that schizophrenia in the mother implies an increased risk for poor perinatal
      outcome, not fully explained by maternal factors, and a need to consider a common
      familial (probably genetic) vulnerability for pre- and perinatal stress and
      schizophrenia.

PMID- 12409163
TI  - Positive and negative thought disorder and psychopathology in childhood among
      subjects with adulthood schizophrenia.
AB  - The New York High-Risk Project (NYHRP) is a longitudinal study of offspring of
      parents with schizophrenia or affective disorder and normal controls.
      Neuropsychological deficits had been observed at about age 9 in subjects with
      adulthood schizophrenia. We explored whether in these subjects, early signs of
      clinical schizophrenia-related symptoms, such as thought disorder or behavioral
      abnormalities, could also be observed. METHODS: We rated thought disorder and
      symptoms from videotaped interviews at age 9, using the Scale for the Assessment
      of Thought, Language and Communication (TLC), and the Mental Health Assessment
      Form (MHAF). With factor analyses we examined the structure of the ratings, and
      from interpretable factors, scales were assembled. MANOVAs were used to examine
      the effect of parental risk and adulthood psychiatric diagnosis (schizophrenia
      related psychosis (SRP), major affective disorder (MAD), no disorder/other
      (NoDx/other)) as independent variables (IV) on thought disorder and symptoms as
      dependent variables. RESULTS: Global, positive and negative thought disorder, and
      negative symptoms were significantly higher in subjects with adulthood
      schizophrenia-related psychosis than both comparison groups. A significant
      interaction between the two IVs was effective with respect to positive thought
      disorder. This scale was particularly elevated among subjects with adulthood
      schizophrenia-related psychosis at parental risk for affective disorder (all of
      whom had adulthood schizoaffective disorder). CONCLUSIONS: We were able to show
      that global, negative and positive thought disorder and negative symptoms were
      present in subjects with adulthood schizophrenia already at mid-childhood, years
      before onset of psychosis. Further, we found a particularly high propensity to
      positive symptoms in subjects with adulthood schizophrenia who have also an
      affective component in their symptoms. This association, previously reported in
      acute schizophrenia, was here observed years before the first psychotic episode.

PMID- 12409164
TI  - Neurological soft signs in schizophrenic patients and their nonpsychotic
      siblings.
AB  - OBJECTIVE: (a) To investigate the prevalence of neurological soft signs (NSS) in
      schizophrenic patients and their nonpsychotic siblings and (b) to examine the
      clinical correlates of NSS in the schizophrenic group. METHODS: Ninety-nine
      schizophrenic patients, 80 of their nonpsychotic siblings and 59 healthy controls
      were included in the study. NSS were assessed with the Neurological Evaluation
      Scale (NES). Psychiatric assessment of the patients was conducted with the
      Positive and Negative Syndrome Scale (PANSS). Siblings and the control group were
      evaluated with Schedules for Clinical Assessment in Neuropsychiatry (SCAN) to
      determine the presence of any past or current psychotic disorder. RESULTS:
      Schizophrenic patients had significantly higher scores overall and on each
      subscale of NES than the sibling and control groups. The sibling group's scores
      were intermediate between those of the schizophrenic patients and those of the
      healthy controls. All subscale scores and the total NES scores correlated
      positively with the negative symptoms subscale scores of PANSS. The general
      psychopathology subscale scores of PANSS also showed a positive correlation with
      all subscale scores of NES, except the 'sequencing of complex motor acts'
      subscale. The total NES scores of the patients as well as their scores for the
      'sequencing of complex motor acts' and 'others' subscales were significantly
      correlated with the respective scores of their own siblings. CONCLUSIONS: These
      results support the findings of previous studies suggesting that there might be
      common genetic and/or environmental factors in the pathogenesis of neurological
      impairment in schizophrenic patients and their siblings. They also indicate that
      neurological soft signs in schizophrenic patients are associated with prominent
      negative symptoms.

PMID- 12409165
TI  - Depressive symptoms at baseline predict fewer negative symptoms at follow-up in
      patients with first-episode schizophrenia.
AB  - There is uncertainty regarding the prognostic value of depressive symptoms in
      schizophrenia, having previously been associated with both favourable and poor
      outcome. This study investigated the relationship between baseline depressive
      symptoms and treatment outcome at 6, 12 and 24 weeks in 80 subjects with first
      episode schizophrenia or schizophreniform disorder in terms of PANSS total and
      subscale score changes. No significant association was found between baseline
      PANSS depression factor scores and PANSS total and subscore changes. However, a
      significant inverse correlation between baseline depression scores and negative
      scores at 6, 12 and 24 weeks was found (p=0.044, 0.023 and 0.012, respectively).
      Multiple regression analysis indicated that this finding could not be explained
      on the basis of age, gender or duration of untreated psychosis. These findings
      support previous work suggesting that high baseline depressive scores predict
      favourable outcome.

PMID- 12409166
TI  - Circumstances of suicide among individuals with schizophrenia.
AB  - Very little is known about the circumstances surrounding suicides in people with
      schizophrenia. Between September 1989 and August 1998, 15 and 100 suicide victims
      with and without schizophrenia, respectively, were examined from the Maryland
      Brain Collection (MBC). Next-of-kin interview and medical record review following
      death collected demographic and clinical characteristics, family history,
      psychiatric symptoms, and variables surrounding the suicide. Individuals with
      schizophrenia exhibited significantly more lifetime depressive symptoms than
      those without schizophrenia. Jumping from a height was the most frequently used
      method among people with schizophrenia (40%), whereas gunshot wounds were most
      common among persons without schizophrenia (37%). A trend was noted for a smaller
      proportion of those with schizophrenia (20%) to plan the suicide, compared to 47%
      of those without the disorder. Suicide in schizophrenia is a significant clinical
      problem; thus, prior suicidal activity and depressive symptoms should be
      addressed because opportunities to intervene immediately before the act are
      limited.

PMID- 12409167
TI  - Neurological soft-signs in psychosis: threshold criteria for discriminating
      normal controls and for predicting cognitive impairment.
AB  - It is well established that psychotic patients obtain higher scores on
      neurological soft-sign (NSS) examinations than normal controls, and also that
      their cognitive performance is poorer. The aims of the present study were to find
      threshold criteria that distinguish between normal individuals and patients
      suffering from psychosis, and to investigate the predictive power of NSS for
      cognitive impairment. The sample was composed of 56 patients suffering from
      psychosis and 26 normal controls. Neurological assessment was carried out by
      means of the Neurological Evaluation Scale (NES), and neuropsychological
      assessment comprised executive, memory, visuospatial abilities, and attention
      tests. Receiver operating characteristic analysis was used to assess the
      diagnostic and predictive efficiency of NSS.A total score of 3 or over on the NES
      scale, or presence of three or more NSS, proved to be good threshold points for
      defining 'abnormality' in psychosis patients in comparison with normal controls.
      NSS presented greater predictive power for cognitive impairment than
      psychopathological dimensions. Moreover, an NES total score of 8 or higher or, to
      a lesser extent, the presence of six or more NSS in this scale seemed to be valid
      cut-off points for predicting severe cognitive impairment in individuals with
      psychosis.NSS were highly efficient predictors of the presence of severe
      cognitive impairment related to psychosis. However, their ability to discriminate
      between individuals with psychosis and normal controls was modest.

PMID- 12409168
TI  - Premorbid personality and psychopathological dimensions in first-episode
      psychosis.
AB  - BACKGROUND: Broadening our knowledge of the relationship between personality and
      psychopathological dimensions in psychosis would provide insights into the nature
      of their underlying pathophysiology. Research, to date, has been carried out in
      chronic samples and the possibility that the personality assessment may have been
      contaminated by the psychotic episode cannot be ruled out. The aim of this study
      was to examine the relationships between personality and psychopathology in a
      'first-episode psychosis' sample using a dimensional approach. METHOD: Premorbid
      personality dimensions of 94 consecutively admitted 'first-episode psychosis'
      patients were assessed through the information collected from parents or a close
      biological relative. A semi-structured interview (Premorbid Assessment Schedule;
      [Tyrer, P., 1988. Personality Disorders: Diagnosis, management and course.
      Wright, London]) was used by a rater, blind to the patients' psychopathological
      symptoms. Associations between dimensions of premorbid personality and
      psychopathology were examined through Pearson correlation coefficients. RESULTS:
      The negative dimension was strongly associated with higher scores on the schizoid
      dimension. Additionally, trends towards significant direct associations were
      found between the negative dimension and both the passive-dependent and the
      schizotypic dimensions, between the hostility/suspiciousness dimension and both
      sociopathic and passive-dependent dimensions, and between the manic dimension and
      the obsessional dimension. Canonical correlation analysis demonstrated that
      premorbid personality dimensions explained 17% of the variance of
      psychopathological dimensions. CONCLUSIONS: Our results suggest that premorbid
      personality dimensions may shape the expression of psychosis. Moreover, we
      hypothesize that certain personality dimensions, such as the schizoid dimension,
      should be considered nonspecific risk factors for expression of higher levels of
      negative symptomatology at the beginning of psychosis.

PMID- 12409169
TI  - Interpersonal control, expressed emotion, and change in symptoms in families of
      persons with schizophrenia.
AB  - This study examined the relationships of expressed emotion (EE), change in
      symptoms in schizophrenia, and interpersonal control patterns in relatives over a
      2-year period. Subjects were 56 persons with schizophrenia and their relatives
      who participated in the NIMH Treatment Strategies in Schizophrenia (TSS)
      longitudinal study. The relationships among EE, interpersonal control as measured
      by the Relational Control Coding System (RCCS), and levels of symptoms at each
      assessment point were analyzed longitudinally with hierarchical linear modeling
      (HLM). No relationship was found between EE and symptoms, nor did control appear
      to contribute to symptoms. High-EE relatives reacted more strongly to symptom
      change than low-EE relatives and in opposite directions. EE may be an indicator
      of responsiveness rather than either a cause or result of symptoms. Understanding
      how EE attitudes impact the struggles patients and relatives have in coping with
      schizophrenia is crucial to knowing how clinicians can support these families
      most effectively.

PMID- 12409170
TI  - An evaluation of a stress management program for individuals with schizophrenia.
AB  - Vulnerability-stress models suggest that training in specific stress management
      techniques should yield benefits to those suffering from schizophrenia and
      related disorders. In this paper, we describe an evaluation of the impact of
      adding a stress management program to other medical and psychosocial
      interventions for such patients. Outcomes were compared for 121 patients randomly
      assigned to receive either a 12-week stress management program with follow-up
      sessions or participation in a social activities group. The two treatment
      conditions did not differ in levels of symptoms, perceived stress or life skills
      immediately after completion of treatment or at 1-year follow-up. Patients who
      received the stress management program did have fewer hospital admissions in the
      year following treatment. This effect of stress management was most apparent for
      those who showed high levels of attendance for treatment sessions. It was
      concluded that training in stress management may provide patients with skills for
      coping with acute stressors and reduce the likelihood of subsequent acute
      exacerbation of symptoms with need for hospitalization.

PMID- 12409171
TI  - Association between relative temporal and prefrontal sulcal cerebrospinal fluid
      and illness duration in schizophrenia.
AB  - Changes in sulcal cerebrospinal fluid (CSF) volume have been related to the
      neurodegeneration hypothesis in schizophrenia. Fifty-three (24 neuroleptic-naive)
      schizophrenics and a control group (n=26) were studied with MRI to assess
      regional sulcal CSF values relative to the total volume of brain lobes
      (prefrontal, orbital, temporal, parietal, and occipital). Segmentation of brain
      structures was performed using an automatic Talairach-based method. Relative CSF
      volumes were adjusted for age by means of linear regression from normal subjects;
      the corrected values were used to assess their relationship with illness duration
      and age of onset (AOS). The volume of sulcal CSF on prefrontal and temporal lobes
      (bilateral) was significantly greater in schizophrenic patients and showed a
      significant positive correlation with illness duration not found in the other
      regions studied. No significant association between CSF volumes and AOS was found
      in any region. Our findings support the existence of a degenerative process in
      schizophrenia located in prefrontal and temporal areas.

PMID- 12409173
TI  - Schizophrenia and tobacco smoking in a Spanish psychiatric hospital.

PMID- 12409172
TI  - Longitudinal follow-up of neurochemical changes during the first year of
      antipsychotic treatment in schizophrenia patients with minimal previous
      medication exposure.
AB  - Reduced frontal N-acetylaspartate (NAA) has been repeatedly found in chronic
      schizophrenia and suggests neuronal loss or dysfunction. However, the potential
      confounding effect of antipsychotic drugs on NAA has not been resolved. The few
      studies of antipsychotic-nai;ve patients are inconclusive. A recent report
      suggests that antipsychotic drugs may increase NAA in the dorsolateral prefrontal
      cortex (DLPFC). We studied 10 minimally treated (less than 3 weeks lifetime
      exposure) schizophrenia patients and 10 normal controls with single-voxel proton
      magnetic resonance spectroscopy (1H-MRS) of the left frontal and occipital lobes.
      Concentrations of NAA, Cho, and Cre were determined and corrected for the
      proportion of cerebrospinal fluid (CSF) in the voxel. Patients were treated in a
      randomized-controlled double-blind design with either haloperidol or quetiapine.
      1H-MRS was repeated within a year. There were no differences in frontal or
      occipital NAA between patients and controls at baseline. However, frontal NAA was
      reduced in the schizophrenia group within the first year of treatment. Patients
      had a clear clinical response to treatment but changes in frontal NAA were not
      correlated with symptom improvement. The well-described reduced frontal NAA in
      schizophrenia may not be a trait of the illness but may represent medication
      effect or progression of the disease.

PMID- 12409174
TI  - Unilateral auditory hallucinations in schizophrenia after damage to the right
      hippocampus.

PMID- 12409175
TI  - "Normalization" of brain activation in schizophrenia. An fMRI study.

PMID- 12409176
TI  - Pro-inflammatory cytokines and motor neuron dysfunction: is there a connection in
      post-polio syndrome?

PMID- 12409177
TI  - Prior poliomyelitis-evidence of cytokine production in the central nervous
      system.
AB  - In order to study the role of a possible inflammatory reaction in the post-polio
      syndrome (PPS) four key cytokines were determined by means of mRNA expression in
      mononuclear cells from cerebrospinal fluid (CSF) and peripheral blood of 13
      patients. Data were compared with those of samples from eight non-inflammatory
      control persons. The PPS-patients displayed increased numbers of CSF cells
      expressing mRNA for TNF-alpha (p<0.02), IFN-gamma (p<0.02), IL-4 (p<0.001) and IL
      10 (p<0.05), in comparison to the non-inflammatory controls. As positive
      controls, samples from patients with Multiple Sclerosis (MS) were examined. We
      conclude that there is a chronic intra CNS expression of inflammatory cytokines
      in PPS, in the range of that in MS, a well known neuroinflammatory disease.
      However, the pathogenic significance of this is unclear.

PMID- 12409178
TI  - Short-term effect of cigarette smoking on CO(2)-induced vasomotor reactivity in
      man: a study with near-infrared spectroscopy and tanscranial Doppler sonography.
AB  - Cigarette smoking is a major risk factor for stroke, and quitting reduces the
      stroke risk within a few years. The aim of our study was to clarify whether CO(2)
      induced vasomotor reactivity (VMR) is impaired in smokers after smoking a
      cigarette as a possible factor of an increased stroke risk. We compared VMR of 23
      healthy smokers assessed at baseline, immediately, and 30 min after smoking a
      cigarette (1.2 mg nicotine) with values from nonsmoking, age-matched controls
      (n=24), obtained at identical time intervals. Cerebral blood flow velocities
      (CBFV) of both middle cerebral arteries (transcranial Doppler sonography),
      changes in concentration of cerebral oxygenated, deoxygenated, and total
      hemoglobin (HbO(2), Hb, and HbT, near-infrared spectroscopy), mean arterial blood
      pressure (MAP), and skin blood flow were recorded during normo- and hypercapnia.
      VMR was calculated as percentage change in CBFV and as micromolar change in
      concentration of HbO(2), Hb, and HbT per 1% increase in endtidal CO(2). CBFV in
      smokers was increased at baseline (left, p<0.05; right, p=0.05), immediately
      (p<0.01), and 30 min after smoking (p<0.05) as compared with nonsmokers. MAP rose
      immediately after smoking (p<0.01) and declined after 30 min. VMR in smokers at
      baseline did not differ from controls, decreased immediately after smoking
      (p<0.05), and normalized after 30 min (p>0.05). Increased baseline CBFV in
      smokers after smoking might be due to arteriolar dilation, increased MAP, and
      possibly constriction of basal cerebral arteries. Impaired VMR for about 30 min
      after smoking reflects endothelial dysfunction. This might contribute to the
      enhanced stroke risk in smokers.

PMID- 12409179
TI  - Acetazolamide challenge test using semiquantitative 123 I-IMP SPECT for detection
      of cerebral misery perfusion.
AB  - The accuracy of the acetazolamide (ACZ) challenge test using semiquantitative
      SPECT in detecting Stage II hemodynamic failure, i.e. cerebral misery perfusion,
      in patients so diagnosed with PET has yet to be determined. This study was
      carried out in 53 patients who had a unilateral occlusion or severe stenosis of
      their cerebral artery. Asymmetry index (AI) was used to determine relative CBF
      distribution on each SPECT image. DeltaAI (regional vasodilatory capacity) values
      were compared with the values of several PET parameters. We also repeated SPECT
      and PET studies in 15 patients after a mean interval of 2.6 years from entry. The
      correlation between changes in DeltaAI and PET data were examined. The DeltaAI
      value closely correlated with the ipsilateral OEF value (r=-0.64, p<0.001).
      Sensitivity-specificity curve analysis revealed that the optimal cut-off value
      for detecting Stage II hemodynamic failure was -13.5% of DeltaAI, at which point
      the diagnostic accuracy was 82%. In follow-up studies, changes in DeltaAI
      correlated significantly with changes in OEF values (r=-0.68, p<0.01).
      Semiquantitative SPECT examination with ACZ challenge detects Stage II
      hemodynamic failure with a diagnostic accuracy of 82%. An improvement in reduced
      vasodilatory capacity as determined by SPECT coincides with a reduction in OEF
      values.

PMID- 12409180
TI  - Intracerebral hemorrhage and postpartum cerebral vasculopathy.
AB  - INTRODUCTION: Intracerebral hemorrhage (ICH) associated with pregnancy commonly
      occurs in the postpartum period in the setting of preeclampsia/eclampsia. We
      describe the clinical course of two patients with ICH due to postpartum cerebral
      vasculopathy in the absence of toxemia. METHODS: We reviewed two cases with ICH
      and postpartum vasculopathy in our hospital (1996-2001) and compared them with
      seven similar case reports from the literature. RESULTS: Mean age of all patients
      is 28.7+/-5.6 years (mean+/-S.D.). Toxemia of pregnancy was absent in all cases.
      ICHs were cortical in eight and putaminal in one patient. Erythrocyte
      sedimentation rate was elevated in two. Two cases rehemorrhaged during the same
      admission. No cerebral infarctions were reported. All patients had diffuse
      vasculopathy on conventional catheter angiography, with no clinical
      manifestations or laboratory data supportive of extracerebral or systemic
      vasculitis. Eight patients were treated with corticosteroids, two with additional
      cytotoxic agents and one with nimodipine alone. Improvement on follow-up cerebral
      angiography (catheter or MRA) and transcranial Doppler ultrasonography (TCD) was
      noted in eight cases. One did not have follow-up cerebral imaging but had an
      excellent clinical outcome. All cases had good to excellent functional recovery.
      CONCLUSIONS: Postpartum ICH in the absence of toxemia may be associated with
      isolated cerebral vasculopathy. The clinical course and functional outcome is
      good to excellent. This entity appears to be distinct from cerebral vasculitis,
      which is usually associated with poor outcome.

PMID- 12409181
TI  - Event-related potentials in different subtypes of multiple sclerosis--a cross
      sectional study.
AB  - Impairment of cognitive skills is found in up to 65% of patients suffering from
      multiple sclerosis (MS). Little is known concerning the natural history or
      characteristics of progression of these cognitive dysfunctions. Furthermore, it
      has not been investigated to date whether there are differences in the course of
      cognitive impairment with respect to different diagnostic subgroups of MS. Event
      related potentials (ERP) are an objective tool to evaluate cognitive processing.
      We performed a cross-sectional study on 179 consecutive patients suffering from
      MS (107 relapsing-remitting MS; 17 primary progressive MS; 50 secondary
      progressive MS; 5 undetermined). ERP were measured by a visual oddball paradigm,
      latencies of P3 components were correlated with demographic and clinical data. We
      found pathologically increased P3 latencies in 56% of all patients. Patients with
      secondary progressive MS showed significantly increased P3 latencies as compared
      to the other subgroups. There was a significant correlation between expanded
      disability status scale (EDSS) score and P3 latency (r=0.48; p<0.001). We
      conclude that ERP are an appropriate method to follow up cognitive dysfunction in
      MS and that cognitive dysfunction as measured by ERP is progressively impaired in
      the course of MS, in particular in the secondary progressive subtype.

PMID- 12409182
TI  - Segregation of the ND4/11778 and the ND1/3460 mutations in four heteroplasmic
      LHON families.
AB  - Leber hereditary optic neuropathy (LHON) is an ocular disease associated with
      mutations in the mitochondrial DNA (mtDNA). The level of heteroplasmy in the
      mtDNA mutations ND4/11778 and ND1/3460 was followed over a period of 4-12 years
      in blood samples taken from nine members of four heteroplasmic LHON families. In
      addition, hair follicle and urinary tract epithelium samples of one individual
      were studied. The quantification of heteroplasmy was performed using the solid
      phase minisequencing method. Only minor and random shifts in the heteroplasmy
      levels were observed over time, but there were no systematic changes towards an
      increasing or decreasing proportion of either LHON mutant in the individuals.
      This indicates that there is no selection for either mtDNA genotype but the
      segregation of the wild-type mtDNAs and those carrying LHON mutations is a
      stochastic process governed by random genetic drift. In this respect, LHON
      mutations seem to behave like neutral polymorphisms.

PMID- 12409183
TI  - An assessment of the association between IL-2 gene polymorphisms and Japanese
      patients with multiple sclerosis.
AB  - Interleukin-2 (IL-2) is a cytokine intimately involved with both the function and
      regulation of the immune system. Genetic analysis of experimental autoimmune
      encephalomyelitis (EAE) provides strong evidence supporting the candidacy of IL-2
      as a susceptibility gene. We investigated the association of two single
      nucleotide polymorphisms (SNPs) at position -384 in the promoter region and +114
      in the first exon of the IL-2 gene through a case-control study involving 113
      Japanese patients with multiple sclerosis (MS) and 118 healthy controls. Our
      results showed no significant differences in the distribution of the two
      polymorphisms between MS patients and controls. Furthermore, no association was
      observed between IL-2 gene polymorphisms and clinical characteristics, such as
      clinical course and age at disease onset. Together, our findings suggest that IL
      2 gene polymorphisms do not influence the susceptibility to MS or the clinical
      characteristics of MS in Japanese patients.

PMID- 12409184
TI  - Quality of life in patients with multiple sclerosis: the impact of fatigue and
      depression.
AB  - Quality of Life (QOL) is impaired in multiple sclerosis (MS) in part due to
      physical disability. MS-associated fatigue (MSF) and depression (MSD) are common
      and treatable features of MS, which could also impact on QOL, independent of
      physical disability. We prospectively studied 60 consecutive patients with MS.
      QOL was assessed using Multiple Sclerosis Quality of Life (MSQOL)-54. Group
      differences in QOL scores were assessed after adjusting for Expanded Disability
      Status Scale (EDSS), Fatigue Severity Scale (FSS) and Hamilton Depression
      Inventory scores. MS patients were grouped into relapsing-remitting (RR) or
      secondary-progressive (SP), MSF (FSS> or =5) or MS-nonfatigue (MSNF) (FSS< or
      =4), and MSD or MS-nondepression (MSND). After accounting for disability and
      depression, fatigue was associated with impaired QOL with respect to health
      perception (p=0.03) and limitations due to physical dysfunction (p=0.008). After
      accounting for disability and fatigue, depression was associated with lower QOL
      with respect to health perception (p=0.02), sexual dysfunction (p=0.03), health
      distress (p=0.03), mental health (p=0.006), overall QOL (p=0.006), emotional
      dysfunction (p=0.04), and limitations due to emotional dysfunction (p=0.03). This
      study demonstrates that fatigue and depression are independently associated with
      impaired QOL in MS, after accounting for physical disability, suggesting that
      their recognition and treatment can potentially improve QOL.

PMID- 12409185
TI  - Botulinum toxin A and the cutaneous nociception in humans: a prospective, double
      blind, placebo-controlled, randomized study.
AB  - Aside from temporary chemodenervation of skeletal muscle and potential anti
      inflammatory effects, a genuine peripheral antinociceptive effect of Botulinum
      Neurotoxin Type A (BoNT/A) has been suspected. To evaluate the effect of BoNT/A
      on cutaneous nociception in humans, 50 healthy volunteers received subcutaneous
      injections of 100 mouse units (MU) BoNT/A (Dysport) and placebo. Both forearms of
      each subject were treated in a double-blind fashion, one with verum, one with
      placebo. Heat and cold pain thresholds within the treated skin areas were
      measured with quantitative sensory testing (QST) and pain thresholds were
      evaluated with local electrical stimulation (ES). The tests were done before
      treatment, and after 4 and 8 weeks. No major side effects were noted. All
      participants completed the study. Heat and cold pain thresholds increased from
      baseline to week 4 by 1.4 degrees C for verum and by 1.1 degrees C for placebo.
      From baseline to week 8, the thresholds increased by 2.7 degrees C for verum and
      by 1.2 degrees C for placebo. Electrically induced pain thresholds shifted from
      baseline to week 4 by -0.07 mA for verum and by 0.01 mA for placebo. From
      baseline to week 8, the thresholds increased by 0.10 mA for verum and by 0.11 mA
      for placebo. None of these differences was statistically significant. The study
      shows that there is no direct peripheral antinociceptive effect of BoNT/A in
      humans. The efficacy of BoNT/A in various pain syndromes must be explained by
      other pathways such as chemodenervation or anti-inflammatory effects.

PMID- 12409186
TI  - Expression of the costimulatory molecule BB-1 and its receptors in patients with
      scleroderma-polymyositis overlap syndrome.
AB  - We investigated expression of costimulatory molecules BB-1, B7-1 (CD80), B7-2
      (CD86), and their counter-receptors CD28 and CTLA-4 (CD152) in muscle biopsy
      specimens of patients with scleroderma-polymyositis overlap syndrome (SSc-PM),
      primary polymyositis (PM), and other related diseases to examine whether the
      muscle fibers in patients with SSc-PM behave as antigen-presenting cells (APCs).
      The major histocompatibility (MHC) class II-positive muscle fibers of SSc-PM
      patients reacted with monoclonal antibodies (mAb) against BB-1 but not against B7
      1 or B7-2. The CD4+ T cells expressed the counter-receptors CD28 and CTLA-4, and
      bound with the BB-1-positive muscle fibers in cell-to-cell contact. Our findings
      show that muscle fibers in patients with SSc-PM function as "professional" APCs
      in a way distinct from muscle fibers in patients with primary PM.

PMID- 12409187
TI  - Acute effects of cigarette smoking on cerebral oxygenation and hemodynamics: a
      combined study with near-infrared spectroscopy and transcranial Doppler
      sonography.
AB  - Cigarette smoking has been shown to increase cerebral blood flow velocity (CBFV)
      and reduce vasomotor reactivity temporarily. The aim of our study was to clarify
      whether this results from dilation of resistance vessels alone with subsequent
      increase in regional cerebral blood flow (rCBF), or an additional constriction of
      basal cerebral arteries. In 24 healthy smokers (mean age+/-S.D., 32.7+/-10.5
      years), cerebral oxygenation and hemodynamics were monitored by transcranial
      Doppler sonography and near-infrared spectroscopy before, during, and after
      smoking a cigarette (nicotine 0.9 mg). We simultaneously recorded CBFV of both
      middle cerebral arteries, mean arterial blood pressure, skin blood flow, end
      tidal CO(2), changes in concentration of cerebral oxyhemoglobin, deoxyhemoglobin,
      and total hemoglobin (micromol/l), and a cerebral tissue oxygenation index.
      Smoking increased CBFV (p<0.01), oxyhemoglobin (p<0.01), and total hemoglobin
      (p<0.01). After smoking, the increase in CBFV and total hemoglobin persisted
      (p<0.01), while oxyhemoglobin returned to baseline. Deoxyhemoglobin and cerebral
      tissue oxygenation index did not change during the whole procedure. During, but
      not after smoking, CBFV increase was correlated to ipsilateral changes in
      oxyhemoglobin and total hemoglobin (p<0.05). The increase in oxyhemoglobin only
      during smoking and the lack of changes in deoxyhemoglobin and cerebral tissue
      oxygenation index indicate that smoking did not substantially increase rCBF. The
      smoking-induced elevation in CBFV might therefore be due to an additional
      constriction of the middle cerebral artery. The combined effects of smoking on
      basal cerebral arteries and arterioles might contribute to the increased stroke
      risk in smokers.

PMID- 12409188
TI  - Role of fluorodeoxyglucose positron emission tomography in the diagnosis of
      neurosarcoidosis.
AB  - A 45-year-old man developed seizures and myelopathy. MRI showed bitemporal and
      cervical spinal cord hyperintense lesions on T2-weighted and FLAIR images that
      contrast-enhanced. Initial evaluation for sarcoidosis was negative, including
      serum angiotensin converting enzyme (ACE) and chest X-ray. Whole body
      fluorodeoxyglucose positron emission tomography (FDG-PET) revealed multiple
      hypermetabolic hilar and mediastinal foci and spinal cord hypermetabolism at the
      site of MRI abnormality. Temporal lobe MRI lesions were hypometabolic.
      Mediastinal lymph node biopsy was consistent with sarcoidosis. The brain, spinal
      cord, and chest metabolic abnormalities together with the clinical presentation
      were interpreted as being most consistent with sarcoidosis. FDG-PET helped target
      the site of biopsy that subsequently confirmed the diagnosis histologically. In
      patients with perplexing neurologic presentations, whole body FDG-PET can help
      secure a timely and minimally invasive diagnosis of neurosarcoidosis.

PMID- 12409189
TI  - Acute isolated bulbar palsy with anti-GT1a IgG antibody subsequent to
      Campylobacter jejuni enteritis.
AB  - We describe a patient with acute isolated bulbar palsy following enteritis. A 29
      year-old man developed dysphagia and nasal voice without limb weakness, ataxia,
      or areflexia. High titres of serum anti-GT1a and anti-Campylobacter jejuni IgG
      antibodies were detected. He was treated with plasmapheresis, resulting in rapid
      clinical improvement. This case suggests that an acute isolated bulbar palsy may
      be caused by a pathology relating to Guillain-Barre syndrome (GBS), in which anti
      GT1a IgG antibody may have a role.

PMID- 12409190
TI  - Scoring of contrast sensitivity on Vistech charts.

PMID- 12409191
TI  - Membrane protein structure.

PMID- 12409192
TI  - Bacteriorhodopsin: a high-resolution structural view of vectorial proton
      transport.
AB  - Recent 3-D structures of several intermediates in the photocycle of
      bacteriorhodopsin (bR) provide a detailed structural picture of this molecular
      proton pump in action. In this review, we describe the sequence of conformational
      changes of bR following the photoisomerization of its all-trans retinal
      chromophore, which is covalently bound via a protonated Schiff base to Lys216 in
      helix G, to a 13-cis configuration. The initial changes are localized near the
      protein's active site and a key water molecule is disordered. This water molecule
      serves as a keystone for the ground state of bR since, within the framework of
      the complex counter ion, it is important both for stabilizing the structure of
      the extracellular half of the protein, and for maintaining the high pK(a) of the
      Schiff base (the primary proton donor) and the low pK(a) of Asp85 (the primary
      proton acceptor). Subsequent structural rearrangements propagate out from the
      active site towards the extracellular half of the protein, with a local flex of
      helix C exaggerating an early movement of Asp85 towards the Schiff base, thereby
      facilitating proton transfer between these two groups. Other coupled
      rearrangements indicate the mechanism of proton release to the extracellular
      medium. On the cytoplasmic half of the protein, a local unwinding of helix G near
      the backbone of Lys216 provides sites for water molecules to order and define a
      pathway for the reprotonation of the Schiff base from Asp96 later in the
      photocycle. A steric clash of the photoisomerized retinal with Trp182 in helix F
      drives an outward tilt of the cytoplasmic half of this helix, opening the proton
      transport channel and enabling a proton to be taken up from the cytoplasm.
      Although bR is the first integral membrane protein to have its catalytic
      mechanism structurally characterized in detail, several key results were
      anticipated in advance of the structural model and the general framework for
      vectorial proton transport has, by and large, been preserved.

PMID- 12409194
TI  - Structural studies on rhodopsin.
AB  - Bovine rhodopsin is the prototypical G protein coupled receptor (GPCR). It was
      the first GPCR to be obtained in quantity and studied in detail. It is also the
      first GPCR for which detailed three dimensional structural information has been
      obtained. Reviewed here are the experiments leading up to the high resolution
      structure determination of rhodopsin and the most recent structural information
      on the activation and stability of this integral membrane protein.

PMID- 12409193
TI  - Crystal structure of rhodopsin: a template for cone visual pigments and other G
      protein-coupled receptors.
AB  - The crystal structure of rhodopsin has provided the first three-dimensional
      molecular model for a G-protein-coupled receptor (GPCR). Alignment of the
      molecular model from the crystallographic structure with the helical axes seen in
      cryo-electron microscopic (cryo-EM) studies provides an opportunity to
      investigate the properties of the molecule as a function of orientation and
      location within the membrane. In addition, the structure provides a starting
      point for modeling and rational experimental approaches of the cone pigments, the
      GPCRs in cone cells responsible for color vision. Homology models of the cone
      pigments provide a means of understanding the roles of amino acid sequence
      differences that shift the absorption maximum of the retinal chromophore in the
      environments of different opsins.

PMID- 12409195
TI  - Structural basis for sensory rhodopsin function.
AB  - The crystal structure of sensory rhodopsin II from Natronobacterium pharaonis was
      recently solved at 2.1 A resolution from lipidic cubic phase-grown crystals. A
      critical analysis of previous structure-function studies is possible within the
      framework of the high-resolution structure of this photoreceptor. Based on the
      structure, a molecular understanding emerges of the efficiency and selectivity of
      the photoisomerization reaction, of the interaction of the sensory receptor and
      its cognate transducer protein HtrII, and of the mechanism of spectral tuning in
      photoreceptors. The architecture of the retinal binding pocket is compact,
      representing a major determinant for the selective binding of the chromophore,
      all-trans retinal to the apoprotein, opsin. Several chromophore-protein
      interactions revealed by the structure were not predicted by previous mutagenesis
      and spectroscopic analyses. The structure suggests likely mechanisms by which
      photoisomerization triggers the activation of sensory rhodopsin II, and
      highlights the possibility of a unified mechanism of signaling mediated by
      sensory receptors, including visual rhodopsins. Future investigations using time
      resolved crystallography, structural dynamics, and computational studies will
      provide the basis to unveil the molecular mechanisms of sensory receptors
      mediated transmembrane signaling.

PMID- 12409196
TI  - Protein-lipid interactions in the purple bacterial reaction centre.
AB  - The purple bacterial reaction centre uses the energy of sunlight to power energy
      requiring reactions such as the synthesis of ATP. During the last 20 years, a
      combination of X-ray crystallography, spectroscopy and mutagenesis has provided a
      detailed insight into the mechanism of light energy transduction in the bacterial
      reaction centre. In recent years, structural techniques including X-ray
      crystallography and neutron scattering have also been used to examine the
      environment of the reaction centre. This mini-review focuses on recent studies of
      the surface of the reaction centre, and briefly discusses the importance of the
      specific protein-lipid interactions that have been resolved for integral membrane
      proteins.

PMID- 12409197
TI  - Wolinella succinogenes quinol:fumarate reductase-2.2-A resolution crystal
      structure and the E-pathway hypothesis of coupled transmembrane proton and
      electron transfer.
AB  - The structure of the respiratory membrane protein complex quinol:fumarate
      reductase (QFR) from Wolinella succinogenes has been determined by X-ray
      crystallography at 2.2-A resolution [Nature 402 (1999) 377]. Based on the
      structure of the three protein subunits A, B, and C and the arrangement of the
      six prosthetic groups (a covalently bound FAD, three iron-sulfur clusters, and
      two haem b groups), a pathway of electron transfer from the quinol-oxidising
      dihaem cytochrome b in the membrane to the site of fumarate reduction in the
      hydrophilic subunit A has been proposed. The structure of the membrane-integral
      dihaem cytochrome b reveals that all transmembrane helical segments are tilted
      with respect to the membrane normal. The "four-helix" dihaem binding motif is
      very different from other dihaem-binding transmembrane four-helix bundles, such
      as the "two-helix motif" of the cytochrome bc(1) complex and the "three-helix
      motif" of the formate dehydrogenase/hydrogenase group. The gamma-hydroxyl group
      of Ser C141 has an important role in stabilising a kink in transmembrane helix
      IV. By combining the results from site-directed mutagenesis, functional and
      electrochemical characterisation, and X-ray crystallography, a residue was
      identified which was found to be essential for menaquinol oxidation [Proc. Natl.
      Acad. Sci. U. S. A. 97 (2000) 13051]. The distal location of this residue in the
      structure indicates that the coupling of the oxidation of menaquinol to the
      reduction of fumarate in dihaem-containing succinate:quinone oxidoreductases
      could in principle be associated with the generation of a transmembrane
      electrochemical potential. However, it is suggested here that in W. succinogenes
      QFR, this electrogenic effect is counterbalanced by the transfer of two protons
      via a proton transfer pathway (the "E-pathway") in concert with the transfer of
      two electrons via the membrane-bound haem groups. According to this "E-pathway
      hypothesis", the net reaction catalysed by W. succinogenes QFR does not
      contribute directly to the generation of a transmembrane electrochemical
      potential.

PMID- 12409198
TI  - Structural model of the transmembrane Fo rotary sector of H+-transporting ATP
      synthase derived by solution NMR and intersubunit cross-linking in situ.
AB  - H(+)-transporting, F(1)F(o)-type ATP synthases utilize a transmembrane H(+)
      potential to drive ATP formation by a rotary catalytic mechanism. ATP is formed
      in alternating beta subunits of the extramembranous F(1) sector of the enzyme,
      synthesis being driven by rotation of the gamma subunit in the center of the F(1)
      molecule between the alternating catalytic sites. The H(+) electrochemical
      potential is thought to drive gamma subunit rotation by first coupling H(+)
      transport to rotation of an oligomeric rotor of c subunits within the
      transmembrane F(o) sector. The gamma subunit is forced to turn with the c
      oligomeric rotor due to connections between subunit c and the gamma and epsilon
      subunits of F(1). In this essay we will review recent studies on the Escherichia
      coli F(o) sector. The monomeric structure of subunit c, determined by NMR, shows
      that subunit c folds in a helical hairpin with the proton carrying Asp(61)
      centered in the second transmembrane helix (TMH). A model for the structural
      organization of the c(10) oligomer in F(o) was deduced from extensive cross
      linking studies and by molecular modeling. The model indicates that the H(+)
      carrying carboxyl of subunit c is occluded between neighboring subunits of the
      c(10) oligomer and that two c subunits pack in a "front-to-back" manner to form
      the H(+) (cation) binding site. In order for protons to gain access to Asp(61)
      during the protonation/deprotonation cycle, we propose that the outer, Asp(61)
      bearing TMH-2s of the c-ring and TMHs from subunits composing the inlet and
      outlet channels must turn relative to each other, and that the swiveling motion
      associated with Asp(61) protonation/deprotonation drives the rotation of the c
      ring. The NMR structures of wild-type subunit c differs according to the
      protonation state of Asp(61). The idea that the conformational state of subunit c
      changes during the catalytic cycle is supported by the cross-linking evidence in
      situ, and two recent NMR structures of functional mutant proteins in which
      critical residues have been switched between TMH-1 and TMH-2. The structural
      information is considered in the context of the possible mechanism of rotary
      movement of the c(10) oligomer during coupled synthesis of ATP.

PMID- 12409199
TI  - Ca2+ -ATPase structure in the E1 and E2 conformations: mechanism, helix-helix and
      helix-lipid interactions.
AB  - The determination of the crystal structure of the Ca(2+)-ATPase of sarcoplasmic
      reticulum (SR) in its Ca(2+)-bound [Nature 405 (2000) 647] and Ca(2+)-free forms
      [Nature 418 (2002) 605] gives the opportunity for an analysis of conformational
      changes on the Ca(2+)-ATPase and of helix-helix and helix-lipid interactions in
      the transmembrane (TM) region of the ATPase. The locations of the ends of the TM
      alpha-helices on the cytoplasmic side of the membrane are reasonably well defined
      by the location of Trp residues and by the location of Lys-262 that snorkels up
      to the surface. The locations of the lumenal ends of the helices are less clear.
      The position of Lys-972 on the lumenal side of helix M9 suggests that the
      hydrophobic thickness of the protein is only about 21 A, rather than the normal
      30 A. The experimentally determined TM alpha-helices do not agree well with those
      predicted theoretically. Charged headgroups are required for strong interaction
      of lipids with the ATPase, consistent with the large number of charged residues
      located close to the lipid-water interface. Helix packing appears to be rather
      irregular. Packing of helices M8 and M10 is of the 3-4 ridges-into-grooves or
      knobs-into-holes types. Packing of helices M5 and M7 involves two Gly residues in
      M7 and one Gly residue in M5. Packing of the other helices generally involves
      just one or two residues on each helix at the crossing point. The irregular
      packing of the TM alpha-helices in the Ca(2+)-ATPase, combined with the diffuse
      structure of the ATPase on the lumenal side of the membrane, is suggested to lead
      to a relative low activation energy for changing the packing of the TM alpha
      helices, with changes in TM alpha-helical packing being important in the process
      of transfer of Ca(2+) ions across the membrane. The inhibitor thapsigargin binds
      in a cleft between TM alpha-helices M3, M5 and M7. It is suggested that this and
      other similar clefts provide binding sites for a variety of hydrophobic molecules
      affecting the activity of the Ca(2+)-ATPase.

PMID- 12409200
TI  - Recent advances in ion channel research.
AB  - The field of ion channels has entered into a rapid phase of development in the
      last few years, partly due to the breakthroughs in determination of the crystal
      structures of membrane proteins and advances in computer simulations of
      biomolecules. These advances have finally enabled the long-dreamed goal of
      relating function of a channel to its underlying molecular structure. Here we
      present simplified accounts of the competing permeation theories and then discuss
      their application to the potassium, gramicidin A and calcium channels.

PMID- 12409201
TI  - The structure of the M2 channel-lining segment from the nicotinic acetylcholine
      receptor.
AB  - The structures of functional peptides corresponding to the predicted channel
      lining M2 segment of the nicotinic acetylcholine (AChR) were determined using
      solution NMR experiments on micelle samples, and solid-state NMR experiments on
      bilayer samples. The AChR M2 peptide forms a straight transmembrane alpha-helix,
      with no kinks. M2 inserts in the lipid bilayer at an angle of 12 degrees relative
      to the bilayer normal, with a rotation about the helix long axis such that the
      polar residues face the N-terminus of the peptide, which is assigned to be
      intracellular. A molecular model of the AChR channel pore, constructed from the
      solid-state NMR 3-D structure of the AChR M2 helix in the membrane assuming a
      pentameric organization, results in a funnel-like architecture for the channel
      with the wide opening on the N-terminal intracellular side. A central narrow pore
      has a diameter ranging from about 3.0 A at its narrowest, to 8.6 A at its widest.
      Nonpolar residues are predominantly on the exterior of the bundle, while polar
      residues line the pore. This arrangement is in fair agreement with evidence
      collected from permeation, mutagenesis, affinity labeling and cysteine
      accessibility measurements. A pentameric M2 helical bundle may, therefore,
      represent the structural blueprint for the inner bundle that lines the channel of
      the nicotinic AChR.

PMID- 12409202
TI  - Potassium channels: structures, models, simulations.
AB  - Potassium channels have been studied intensively in terms of the relationship
      between molecular structure and physiological function. They provide an
      opportunity to integrate structural and computational studies in order to arrive
      at an atomic resolution description of mechanism. We review recent progress in K
      channel structural studies, focussing on the bacterial channel KcsA. Structural
      studies can be extended via use of computational (i.e. molecular simulation)
      approaches in order to provide a perspective on aspects of channel function such
      as permeation, selectivity, block and gating. Results from molecular dynamics
      simulations are shown to be in good agreement with recent structural studies of
      KcsA in terms of the interactions of K(+) ions with binding sites within the
      selectivity filter of the channel, and in revealing the importance of filter
      flexibility in channel function. We discuss how the KcsA structure may be used as
      a template for developing structural models of other families of K channels.
      Progress in this area is explored via two examples: inward rectifier (Kir) and
      voltage-gated (Kv) potassium channels. A brief account of structural studies of
      ancillary domains and subunits of K channels is provided.

PMID- 12409203
TI  - The structure of bacterial outer membrane proteins.
AB  - Integral membrane proteins come in two types, alpha-helical and beta-barrel
      proteins. In both types, all hydrogen bonding donors and acceptors of the
      polypeptide backbone are completely compensated and buried while nonpolar side
      chains point to the membrane. The alpha-helical type is more abundant and occurs
      in cytoplasmic (or inner) membranes, whereas the beta-barrels are known from
      outer membranes of bacteria. The beta-barrel construction is described by the
      number of strands and the shear number, which is a measure for the inclination
      angle of the beta-strands against the barrel axis. The common right-handed beta
      twist requires shear numbers slightly larger than the number of strands. Membrane
      protein beta-barrels contain between 8 and 22 beta-strands and have a simple
      topology that is probably enforced by the folding process. The smallest barrels
      form inverse micelles and work as enzymes or they bind to other macromolecules.
      The medium-range barrels form more or less specific pores for nutrient uptake,
      whereas the largest barrels occur in active Fe(2+) transporters. The beta-barrels
      are suitable objects for channel engineering, because the structures are simple
      and because many of these proteins can be produced into inclusion bodies and
      recovered therefrom in the exact native conformation.

PMID- 12409204
TI  - TonB-dependent receptors-structural perspectives.
AB  - Plants, bacteria, fungi, and yeast utilize organic iron chelators (siderophores)
      to establish commensal and pathogenic relationships with hosts and to survive as
      free-living organisms. In Gram-negative bacteria, transport of siderophores into
      the periplasm is mediated by TonB-dependent receptors. A complex of three
      membrane-spanning proteins TonB, ExbB and ExbD couples the chemiosmotic potential
      of the cytoplasmic membrane with siderophore uptake across the outer membrane.
      The crystallographic structures of two TonB-dependent receptors (FhuA and FepA)
      have recently been determined. These outer membrane transporters show a novel
      fold consisting of two domains. A 22-stranded antiparallel beta-barrel traverses
      the outer membrane and adjacent beta-strands are connected by extracellular loops
      and periplasmic turns. Located inside the beta-barrel is the plug domain,
      composed primarily of a mixed four-stranded beta-sheet and a series of
      interspersed alpha-helices. Siderophore binding induces distinct local and
      allosteric transitions that establish the structural basis of signal transduction
      across the outer membrane and suggest a transport mechanism.

PMID- 12409205
TI  - Colicin crystal structures: pathways and mechanisms for colicin insertion into
      membranes.
AB  - The X-ray structures of the channel-forming colicins Ia and N, and
      endoribonucleolytic colicin E3, as well as of the channel domains of colicins A
      and E1, and spectroscopic and calorimetric data for intact colicin E1, are
      discussed in the context of the mechanisms and pathways by which colicins are
      imported into cells. The extensive helical coiled-coil in the R domain and
      internal hydrophobic hairpin in the C domain are important features relevant to
      colicin import and channel formation. The concept of outer membrane translocation
      mediated by two receptors, one mainly used for initial binding and second for
      translocation, such as BtuB and TolC, respectively, is discussed. Helix
      elongation and conformational flexibility are prerequisites for import of soluble
      toxin-like proteins into membranes. Helix elongation contradicts suggestions that
      the colicin import involves a molten globule intermediate. The nature of the open
      channel structure is discussed.

PMID- 12409206
TI  - Structural aspects of oligomerization taking place between the transmembrane
      alpha-helices of bitopic membrane proteins.
AB  - Recent advances in biophysical methods have been able to shed more light on the
      structures of helical bundles formed by the transmembrane segments of bitopic
      membrane proteins. In this manuscript, I attempt to review the biological
      importance and diversity of these interactions, the energetics of bundle
      formation, motifs capable of inducing oligomerization and methods capable of
      detecting, solving and predicting the structures of these oligomeric bundles.
      Finally, the structures of the best characterized instances of transmembrane
      alpha-helical bundles formed by bitopic membrane proteins are described in
      detail.

PMID- 12409207
TI  - Proceedings of the 5th International Meeting: VIP, PACAP, Secretin, Glucagon and
      Related Peptides. November 4-8, 2001. Santa Barbara, California, USA.

PMID- 12409208
TI  - Comparative distribution of VIP in the central nervous system of various species
      measured by a new radioimmunoassay.
AB  - Vasoactive intestinal polypeptide (VIP) occurs in high concentrations throughout
      the gut and the nervous system. The presence of VIP has been shown in a number of
      species, mainly by immunohistochemistry. The aim of the present study was to
      develop a new, highly specific VIP radioimmunoassay to investigate the
      distribution of VIP in the central nervous system of various vertebrate and
      invertebrate species. Different areas of the brain and spinal cord were removed
      from rats, chickens, turtles, frogs and fishes. The cerebral ganglia and the
      ventral ganglionic chain were investigated in the earthworm. The tissue samples
      were processed for VIP radioimmunoassay. Our results show that the antiserum used
      in the radioimmunoassay turned to be C-terminal specific, without significant
      affinity to other members of the VIP peptide family. Detection limit of the assay
      was 0.1 fmol/ml. Highest concentrations were found in the turtle diencephalon,
      followed by other brain areas in the turtle and rat. All other brain areas in the
      examined species contained significant levels of VIP. Immunoreactivity was also
      shown in the cerebral and ventral ganglia of the earthworm. In summary, our
      results show comparative quantitative distribution in representative species of
      the phylogenetic line, using the same experimental conditions.

PMID- 12409209
TI  - Influence of pinealectomy on levels of PACAP and cAMP in the chicken brain.
AB  - One of the recently found functions of pituitary adenylate cyclase activating
      polypeptide (PACAP) is the modulation of circadian rhythms. Widespread
      distribution of PACAP-containing neurons and receptors has been shown in the
      chicken. Recently, we have demonstrated that PACAP levels oscillate in a
      circadian manner in the chicken brain. Daily variation in PACAP levels might be
      influenced by several regulatory mechanisms. Among the structures that may
      regulate PACAP levels, one candidate is the pineal gland. Therefore, in the
      present study, we investigated the effect of pinealectomy on the levels of PACAP
      in the chicken brain. Animals were kept under 12:12-h light-dark schedule.
      Pinealectomy was performed at 3 weeks of age; sham-operated animals were used as
      controls. The animals were sacrificed at 15 and 24 h 1 week after pinealectomy.
      The brainstem and diencephalon were removed, and tissue samples were processed
      for PACAP and cAMP radioimmunoassay (RIA).PACAP and cAMP levels showed nighttime
      elevations in both the sham-operated and pinealectomized animals, except for the
      PACAP content in the diencephalon of pinealectomized chicken. PACAP levels of
      pinealectomized animals were significantly higher in the diencephalon and
      brainstem as compared to the control animals at both time-points. Levels of cAMP
      correlated well with levels of PACAP. The present results provide evidence that
      the pineal gland has an inhibitory impact on PACAP-neurons in the chicken
      brainstem and diencephalon.

PMID- 12409210
TI  - Comparative distributions of pituitary adenylyl cyclase-activating polypeptide
      and its selective type I receptor mRNA in the frog (Xenopus laevis) brain.
AB  - The detailed mRNA distributions of pituitary adenylyl cyclase-activating
      polypeptide (PACAP) and its selective type I receptor (PAC(1)) were
      systematically compared in the brain of the frog Xenopus laevis. PACAP mRNA
      expression overlapped with that of PAC(1) in many brain areas such as the
      pallium, hypothalamic preoptic area, ventral hypothalamic nuclei, habenular
      nucleus, most thalamic nuclei, the cerebellular nucleus, and nuclei of isthmi. In
      some structures, PACAP and PAC(1) gene transcripts were present in anatomically
      distinct cell layers. For example, in the olfactory bulb, PACAP mRNA was present
      in the mitral cell layer, whereas gene transcripts for the receptor were observed
      in the granule layer. In a number of regions, expression showed no obvious
      overlap. PAC(1) but not PACAP mRNA was present at moderate levels in the Purkinje
      cell layer of the cerebellum and distal lobe of the pituitary. Conversely, PAC(1)
      gene expression was absent in the spinal cord while PACAP mRNA signals were
      observed in the medial portion of the ventral horn and deep portion of the dorsal
      horn. The granule and molecular cell layer of the cerebellum, alpha-motor neurons
      in the spinal cord, and reticular nucleus of isthmi showed neither PACAP nor
      PAC(1) gene transcripts. These localized patterns of ligand and receptor gene
      expression suggest possible PACAP projection and target fields in the frog brain.

PMID- 12409211
TI  - Pituitary adenylate cyclase-activating polypeptide and growth hormone-releasing
      hormone-like peptide in sturgeon, whitefish, grayling, flounder and halibut: cDNA
      sequence, exon skipping and evolution.
AB  - To better understand the evolution of pituitary adenylate cyclase-activating
      polypeptide (PACAP) and growth hormone-releasing hormone (GHRH), we isolated the
      cDNAs encoding these peptides from the brains of five species of fish: sturgeon,
      whitefish, grayling, flounder and halibut. Both hormones are encoded in tandem in
      full-length cDNAs. We compared the phylogenetic relationship among these and
      other known sequences encoding PACAP. In closely related species, transcripts
      encoding PACAP and GHRH are strongly conserved in the hormone coding regions,
      moderately conserved in the signal peptide, cryptic peptide and 3'-untranslated
      regions, but are most varied in the 5'-untranslated regions.Next, we compared the
      deduced amino acid sequences for the peptides to known sequences. Sturgeon and
      whitefish have a PACAP(38) peptide sequence that is 92% conserved compared to
      human PACAP(38), the highest for a fish reported to date. GHRH is the lesser
      conserved of the two peptides with only 39% to 45% conservation between fish and
      human.Each of the five fish species had a second cDNA encoding a short precursor
      lacking GHRH(1-32), the bioactive portion of GHRH. This suggests that exon
      skipping in GHRH-PACAP transcripts may be an important mechanism for regulating
      the ratio of PACAP to GHRH peptides.

PMID- 12409212
TI  - Influence of VIP on prolactinemia in turkey anterior pituitary cells: role of
      cAMP second messenger in VIP-induced prolactin gene expression.
AB  - Vasoactive intestinal peptide (VIP) is the avian prolactin (PRL)-releasing
      factor. In the turkey, hypothalamic VIP immunoreactivity and mRNA content, as
      well as VIP levels in hypophyseal portal blood, are closely related to the state
      of prolactinemia and the reproductive stage. The present study investigated the
      role of VIP on prolactinemia in turkey anterior pituitary (AP) cells through PRL
      gene expression and the role of a cAMP second messenger system on VIP-induced PRL
      expression. In primary AP cells harvested from hens in different prolactinemic
      states, steady state promoter activities were positively correlated with secreted
      PRL levels. VIP increased PRL promoter activities in AP cells from hens with
      intermediate PRL levels (laying), but not in AP cells from hypoprolactinemic hens
      (nonphotostimulated reproductively quiescent). However, in AP cells from
      hyperprolactinemic hens (incubating), PRL promoter activity was down-regulated by
      VIP. PRL mRNA steady state levels were significantly decreased by the cAMP
      analogue, 8-bromo-cyclic adenosine monophosphate (8-Br-cAMP), and PRL secretion
      was down-regulated by the phosphodiesterase blocker, 3-isobutyl-1-methylxanthine
      (IBMX) in a dose-dependent manner, suggesting that the cAMP second messenger
      system might be involved in the inhibitory action of dopamine upon VIP-stimulated
      PRL secretion and gene expression at the pituitary level. In a study of VIP
      immediate and long-term effects on c-fos expression in relation to PRL
      expression, VIP dramatically induced c-fos mRNA expression within 5 min,
      suggesting that VIP-induced c-fos expression might be involved in VIP-stimulated
      PRL secretion and gene expression. These results provide additional evidence of
      the functional significance of VIP in PRL gene expression and suggest that
      changes in PRL promoter activity by VIP may be one of the important inductive
      mechanisms leading to prolactinemia.

PMID- 12409213
TI  - Defects in reproductive functions in PACAP-deficient female mice.
AB  - Pituitary adenylate cyclase-activating polypeptide (PACAP) is a highly conserved
      neuropeptide and widely expressed in both brain and peripheral tissues, including
      several reproductive organs (e.g., testis and ovary). PACAP stimulates syntheses
      of several sexual hormones and steroids, suggesting it has possible roles in
      reproductive function. In this study, the role of PACAP in female reproductive
      functions such as fertility, mating behavior and maternal behaviors were
      investigated by using mice lacking PACAP (PACAP(-/-)). PACAP(-/-) females showed
      reduced fertility (the number of parturitions relative to the number of
      pairings). Mating experiments using vasectomized males revealed that mating
      frequency and its intervals in some PACAP(-/-) females were quite different (zero
      to eight times/4 weeks), whereas the frequency was relatively constant (two to
      three times/4 weeks) in wild-type females. In PACAP(-/-) females, maternal
      crouching behavior tended to decrease compared to wild-type females, although the
      influence of litter size on maternal behavior needs to be considered. These data
      suggest a role for endogenous PACAP in female reproductive processes.

PMID- 12409214
TI  - Neonatal PACAP administration in rats delays puberty through the influence of the
      LHRH neuronal system.
AB  - The onset of puberty is a concerted action of many factors which leads to cyclic
      LHRH release in rats. It has been demonstrated that; in common with vasoactive
      intestinal polypeptide (VIP), pituitary adenylate cyclase activating polypeptide
      (PACAP) is also involved in the differentiation of the central nervous system. In
      our previous work, it was shown that a single PACAP injection into neonatal
      female rats delayed puberty. In the present work, neonatal administration of
      PACAP delayed the vaginal opening and decreased the weight of anterior
      pituitaries, the number of expelled ova at the first ovulation and the intensity
      of LHRH immunostaining in the septo-preoptico-infundibular system. PACAP
      antiserum had a reverse effect on LHRH immunoreactivity. The other studied
      parameters in the latter group remained unchanged compared to control rats. It
      was concluded that neonatal PACAP administration delayed the onset of puberty
      through the influence of the LHRH neuronal system.

PMID- 12409215
TI  - The effects of pituitary adenylate cyclase-activating polypeptide on acute and
      chronic morphine actions in mice.
AB  - The effects of pituitary adenylate cyclase-activating polypeptide (PACAP) on pain
      sensitivity, on morphine analgesia, on morphine tolerance and withdrawal were
      investigated in mice. The heat-radiant tail-flick test was used to assess
      antinociceptive threshold. Intracerebroventricular (i.c.v.) administration of
      PACAP alone had no effect on pain sensitivity but in a dose of 500 ng, it
      significantly diminished the analgesic effect of a single dose of morphine (2.25
      mg/kg, s.c.). PACAP (500 ng, i.c.v.) significantly increased the chronic
      tolerance to morphine and enhanced the naloxone (1 mg/kg, s.c.)-precipitated
      withdrawal jumping. Theophylline (1 mg/kg, i.p.) pretreatment significantly
      enhanced the effect of PACAP on morphine analgesia but the effects of PACAP on
      tolerance and withdrawal were unaffected upon theophylline administration. On the
      grounds of our previous studies with vasoactive intestinal polypeptide (VIP), it
      appears that different receptors are involved in the effects of PACAP in acute
      and chronic morphine actions. Our results indicate that PACAP-induced actions
      likely participate in acute and chronic effects of morphine and suggest a
      potential role of PACAP in opioid analgesia, tolerance and withdrawal.

PMID- 12409216
TI  - Dopamine- and cyclic AMP-regulated phosphoprotein-immunoreactive neurons
      activated by acute stress are innervated by fiber terminals immunopositive for
      pituitary adenylate cyclase-activating polypeptide in the extended amygdala in
      the rat.
AB  - The bed nuclei of the stria terminalis (BST) and the central nucleus of the
      amygdala are highly heterogeneous structures, which form one functional unit, the
      so-called extended amygdala. Several studies described increased c-fos expression
      following acute stress in this brain area, confirming its central role in the
      modulation/regulation of stress responses. The oval nucleus of the BST and the
      central amygdala exhibit a dense network of pituitary adenylate cyclase
      activating polypeptide (PACAP)-immunoreactive (ir) fiber terminals. In addition,
      several dopamine- and cyclic AMP-regulated phosphoprotein (DARPP-32)
      immunoreactive neurons were also observed here. Because the extended amygdala
      plays an important role in the central autonomic regulation during stress and the
      distribution of PACAP-ir and that of DARPP-32-ir nervous structures overlap, the
      aims of this study were to investigate the possible activation of DARPP-32-ir
      neurons following acute systemic stress and to demonstrate synaptic interactions
      between DARPP-32-ir neurons and fiber terminals immunopositive for PACAP.In
      summary, this study provided morphological evidence that acute stress resulted in
      the activation of DARPP-32 neurons, which were innervated by PACAP-ir neuronal
      structures in the extended amygdala. Furthermore, interaction between
      neuropeptides/neurotransmitters and phosphoproteins was also demonstrated.

PMID- 12409217
TI  - PACAP inhibits anoxia-induced changes in physiological responses in horizontal
      cells in the turtle retina.
AB  - Pituitary adenylate cyclase activating polypeptide (PACAP) has neurotrophic and
      neuroprotective effects against various cytotoxic agents in vitro, and ischemia
      in vivo. Anoxia tolerance is most highly developed in some species of turtles.
      Recently, we have demonstrated high levels of PACAP38 in the turtle brain,
      exceeding those in corresponding rat and human brain areas by 10- to 100-fold.
      The aim of the present study was to investigate with electrophysiological methods
      the protective effects of PACAP in anoxia-induced neuronal damage of turtle
      retinal horizontal cells. Adult turtles (Pseudemys scripta elegans) were used for
      the experiments. After decapitation, half of the isolated eyecup slices were
      placed into a non-oxygenated Ringer solution, the other half into 0.165 microM
      PACAP solution. Intracellular recordings were obtained from horizontal cells 18,
      22, 42 and 46 h after removal of the eyes. The amplitudes of light responses with
      the exception of the 0-h measurement, were larger at all time-points in PACAP
      incubated slices than in control retinal slices. After both 18 and 22 h, the
      response amplitudes of PACAP-treated cells exceeded those taken from control
      horizontal cells by 1.2-fold. At later times, this difference became larger than
      2-fold. In summary, the present results provide evidence that PACAP has
      neuroprotective effects on the anoxic retinal cells in the turtle.

PMID- 12409218
TI  - Cell immunoblot assay study demonstrating the release of PACAP from individual
      anterior pituitary cells of rats and the effect of PACAP on LH release.
AB  - The presence of pituitary adenylate cyclase activating polypeptide (PACAP) was
      previously demonstrated in the anterior pituitary by radioimmunoassay,
      immunohistochemistry, and reverse transcript-polymerase chain reaction (RT-PCR).
      With the use of cell immunoblot assay (CIBA), when the pituitary cells were
      cultured on nitrocellulose membrane, the release of PACAP by individual anterior
      pituitary cells was observed. The released peptide, trapped by the nitrocellulose
      membrane forming a blot around the cells, was demonstrated by
      immunocytochemistry. Double labeling revealed that a part of PACAP-immunoreactive
      cells can release LH as well. With the use of sandwich enzyme immunoassay (S
      EIA), it was found that the concentration of PACAP in the anterior pituitaries is
      10(-10) M. In cell culture in a similar concentration, PACAP stimulated the LH
      release from female gonadotropes, but did not influence it from male ones. The
      stimulated release of LH was indicated by the enhancement in the diameter of LH
      blots compared to the untreated control cultures. We concluded that PACAP may be
      released from the anterior pituitary cells in a concentration which would be able
      to influence LH release not only in vitro but under in vivo conditions as well.
      The effect of PACAP on LH release was different in female and male pituitary
      cultures.

PMID- 12409219
TI  - Pituitary adenylate cyclase-activating polypeptide (PACAP) prevents hippocampal
      neurons from apoptosis by inhibiting JNK/SAPK and p38 signal transduction
      pathways.
AB  - We have demonstrated that ischemic neuronal death (apoptosis) of rat CA1 region
      of the hippocampus was prevented by infusing pituitary adenylate cyclase
      activating polypeptide (PACAP) either intracerebroventricularly or intravenously.
      We have also demonstrated that the activity of mitogen-activated protein (MAP)
      kinase family members, including ERK (extracellular signal-regulated kinase), Jun
      N-terminal kinase (JNK)/stress-activated protein kinase (SAPK) and p38, was
      increased in the hippocampus within 1-6 h after brain ischemia. The molecular
      mechanisms underlying the PACAP anti-apoptotic effect were demonstrated in this
      study. Ischemic stress had a strong influence on MAP kinase family, especially on
      JNK/SAPK and p38. PACAP inhibited the activation of JNK/SAPK and p38 after
      ischemic stress, while ERK is not suppressed. These findings suggest that PACAP
      inhibits the JNK/SAPK and p38 signaling pathways, thereby protecting neurons
      against apoptosis.

PMID- 12409220
TI  - Regulation of neurotrophic peptide expression in sympathetic neurons:
      quantitative analysis using radioimmunoassay and real-time quantitative
      polymerase chain reaction.
AB  - The regulated expression of the peptide and transcript levels of the neurotrophic
      peptides, pituitary adenylate cyclase-activating polypeptide (PACAP), galanin and
      vasoactive intestinal peptide (VIP) were examined in sympathetic neurons of the
      rat superior cervical ganglion (SCG). Real-time quantitative PCR methods were
      developed to assess modulation of neuronal peptide precursor protein transcript
      levels following experimental paradigms of neuropeptidergic plasticity.
      Oligonucleotide primer, fluorogenic probe and amplification conditions were
      optimized for maximal assay sensitivity. Depolarization of primary cultured
      sympathetic neurons stimulated PACAP, galanin, and VIP peptide contents and
      releases with differing magnitudes and temporal profiles. The rank order of
      increased neuronal peptide content paralleled the augmented peptide release
      (VIP>galanin>PACAP). Maximal cellular PACAP and VIP levels were achieved by 72
      and 96 h, respectively; galanin levels did not plateau during the treatment
      period. PACAP transcript elevation was rapid and transient; PACAP mRNA expression
      diminished at longer depolarization times, which diverged markedly from the
      sustained high peptide production levels. By contrast, VIP and galanin mRNAs
      reached maximal levels at later times, and appeared to correlate more closely
      with peptide production. We previously described multiple proPACAP mRNA variants
      resulting from alternative 3' untranslated region cleavage and polyadenylation.
      The shorter depolarization-induced PACAP transcripts exhibit longer half-lives,
      suggesting that the short proPACAP mRNA variant may function to impart PACAP
      translational efficiency and sustain PACAP peptide production.

PMID- 12409221
TI  - Distribution of PACAP and its mRNA in several nonneural tissues of rats
      demonstrated by sandwich enzyme immunoassay and RT-PCR technique.
AB  - The presence of PACAP in various organs was previously demonstrated using
      immunohistochemistry and radioimmunoassay. The aim of our work was to get
      information whether the presence of immunoreactive PACAP in various organs,
      mainly in the gastric mucosa, also indicates the place of its synthesis. The
      immunoreactive PACAP and its mRNA were measured in parallel assays using sandwich
      enzyme immunoassay (S-EIA) and RT-PCR technique. PACAP and its mRNA were
      demonstrated in the pancreas, testes, adrenal glands, ovaries, and in the oxyntic
      mucosa of the stomach. These results support our previous observation that PACAP
      is present not only in the nervous system and endocrine glands, but might be
      synthetized in the oxyntic mucosa of the stomach as well.

PMID- 12409222
TI  - The effect of pituitary adenylate cyclase activating polypeptide on cultured rat
      cardiocytes as a cardioprotective factor.
AB  - In the cardiovascular system, pituitary adenylate cyclase activating polypeptide
      (PACAP) exhibits not only vasodilation but also positive inotropic action by
      increasing cardiac output. Then the effect of PACAP in cultured cardiovascular
      cells was examined. In neonatal rat myocytes, PACAP evoked concentration
      dependent increase in intracellular cyclic AMP content more potently than
      vasoactive intestinal polypeptide (VIP). However, in neonatal rat nonmyocytes,
      PACAP and VIP showed equal potency. The characterization of the subtype of
      PACAP/VIP receptors by RT-PCR analysis revealed that PAC1 receptor mRNA is
      dominantly present in the myocytes, but VPAC2 receptor mRNA is abundant in the
      nonmyocytes. In the myocytes, PACAP did not change the protein synthesis
      stimulated by endothelin or by itself. However, PACAP moderately stimulated the
      secretion of atrial natriuretic polypeptide (ANP). On the other hand, PACAP
      inhibited the protein synthesis and DNA synthesis of the nonmyocytes. These
      indicate that PACAP might be involved in the regulation of cardiac hypertrophy
      and fibrosis as a cardioprotective factor.

PMID- 12409224
TI  - In vitro and in vivo treatment of colon cancer by VIP antagonists.
AB  - Vasoactive intestinal peptide (VIP) is secreted from many cancer lines and VIP
      binding was observed in many tumors. We have shown before that VIP antagonists
      are potent inhibitors of neoplastic growth of neuroblastoma, lung and breast
      cancer cells in vitro. Here, the cultured colon cancer cell line HCT-15 that
      exhibited VIP receptor expression was treated with the VIP hybrid antagonist
      neurotensin(6-11)VIP(7-28). The antineoplastic activity was assessed by thymidine
      incorporation. Neurotensin(6-11)VIP(7-28) efficiently inhibited cancer growth
      with a maximal effect at nanomolar concentrations. Once the inhibitory properties
      of the VIP antagonist on colon cancer cells were established, the in vivo
      curative effects were analyzed. Sprague-Dawley rats were injected with
      azoxymethane (AOM) (15 mg/kg/week) for 2 weeks, providing artificial induction of
      colon tumors. The rats were then allocated into four experimental groups: (1)
      receiving no treatment; (2) receiving treatment with saline; (3, 4) receiving
      treatment with 10 or 20 microg of neurotensin(6-11)VIP(7-28), respectively. After
      10 weeks of daily injections, rats were sacrificed and tumors assessed for stage,
      volume, location, differentiation and lymphocytic infiltrate. Embedded mucosa was
      assessed for dysplastic crypts. Results showed that the antagonist treatment
      reduced the tumor volume, staging, lymphocyte infiltrate and the number of
      dysplastic crypts. Thus, neurotensin(6-11)VIP(7-28) could serve as an effective
      cancer treatment and a preventing agent.

PMID- 12409223
TI  - PAC1 and PACAP expression, signaling, and effect on the growth of HCT8, human
      colonic tumor cells.
AB  - The pituitary adenylate cyclase-activating polypeptide (PACAP) type 1 receptor
      (PAC1) is a heptahelical, G protein-coupled receptor that has been shown to be
      expressed by non-squamous lung cancer and breast cancer cell lines, and to be
      coupled to the growth of these tumors. We have previously shown that PACAP and
      its receptor, PAC1, are expressed in rat colonic tissue. In this study, we used
      polyclonal antibodies directed against the COOH terminal of PAC1, as well as
      fluorescently labeled PACAP, Fluor-PACAP, to demonstrate the expression of PAC1
      on HCT8 human colonic tumor cells, using FACS analysis and confocal laser
      scanning microscopy. Similarly, anti-PACAP polyclonal antibodies were used to
      confirm the expression of PACAP hormone by this cell line. We then investigated
      the signal transduction properties of PAC1 in these tumor cells. PACAP-38
      elevated intracellular cAMP levels in a dose-dependent manner, with a half
      maximal (EC(50)) stimulation of approximately 3 nM. In addition, PACAP-38
      stimulation caused an increase in cytosolic Ca(2+) concentration [Ca(2+)](i),
      which was partially inhibited by the PACAP antagonist, PACAP-(6-38). Finally, we
      studied the potential role of PACAP upon the growth of these tumor cells. We
      found that PACAP-38, but not VIP, increased the number of viable HCT8 cells, as
      measured by MTT activity. We also demonstrated that HCT8 cells expressed the Fas
      receptor (Fas-R/CD95), which was subsequently down-regulated upon activation with
      PACAP-38, further suggesting a possible role for PACAP in the growth and survival
      of these tumor cells. These data indicate that HCT8 human colon tumor cells
      express PAC1 and produce PACAP hormone. Furthermore, PAC1 activation is coupled
      to adenylate cyclase, increase cytosolic [Ca(2+)](i), and cellular proliferation.
      Therefore, PACAP is capable of increasing the number of viable cells and
      regulating Fas-R expression in a human colonic cancer cell line, suggesting that
      PACAP might play a role in the regulation of colon cancer growth and modulation
      of T lymphocyte anti-tumoral response via the Fas-R/Fas-L apoptotic pathway.

PMID- 12409225
TI  - PACAP-27 tyrosine phosphorylates mitogen activated protein kinase and increases
      VEGF mRNAs in human lung cancer cells.
AB  - The effects of pituitary adenylate cyclase activating polypeptide (PACAP) on
      human lung cancer cell line NCI-1299 mitogen activated protein kinase (MAPK)
      tyrosine phosphorylation and vascular endothelial cell growth factor (VEGF)
      expression were investigated. PACAP-27 (100 nM) increased MAPK tyrosine
      phosphorylation 3-fold, 5 min after addition to NCI-H1299 cells. PACAP caused
      tyrosine phosphorylation in a concentration-dependent manner being half-maximal
      at 10 nM PACAP-27. PACAP-27 or PACAP-38 (100 nM) but not PACAP28-38 or VIP caused
      increased MAPK tyrosine phosphorylation using NCI-H1299 cells. Also, the increase
      in MAPK tyrosine phosphorylation caused by PACAP-27 was totally inhibited by 10
      microM PACAP(6-38), a PAC(1) receptor antagonist or 10 microM PD98059, a MAPKK
      inhibitor. These results suggest that PAC(1) receptors regulate tyrosine
      phosphorylation of MAPK in a MAPKK-dependent manner. PACAP-27 (100 nM) caused
      increased VEGF mRNA in NCI-H1299 cells after 8 h. The increase in VEGF mRNA
      caused by PACAP-27 was partially inhibited by PACAP(6-38), PD98059 and H-89.
      Addition of VIP to NCI-H1299 cells caused increased VEGF mRNA, which was totally
      inhibited by H89, a PKA inhibitor. These results suggest that PAC(1) and VPAC(1)
      receptors regulate VEGF expression in lung cancer cells.

PMID- 12409226
TI  - GRP receptor-mediated immediate early gene expression and transcription factor
      Elk-1 activation in prostate cancer cells.
AB  - Bombesin (BN) and its mammalian homologue gastrin-releasing peptide (GRP) have
      been shown to play an important role in human cancer as autocrine and paracrine
      growth factors. Prostatic neuroendocrine cells are thought to secrete these
      regulatory peptides and they may therefore interact with their specific,
      aberrantly expressed GRP receptor (GRP-R) in prostate cancer. In this study, we
      investigated the effect of BN on immediate early gene expression in two androgen
      independent prostate cancer cell lines DU-145 and PC-3 with functional GRP
      receptor. We found that BN induced c-fos mRNA expression in both cell lines in a
      time-dependent manner. In contrast, c-jun mRNA was only modestly induced in DU
      145 cells but not at all in PC-3 cells. On the protein level, we detected BN
      induced stimulation of the c-fos gene product but not of c-jun protein. Sustained
      increase of the c-myc gene product was detectable in PC-3 but not in DU-145
      cells. Concurrently, we demonstrated BN-dependent activation of the transcription
      factor Elk-1 and significant increase of cell proliferation in both prostate
      cancer cell lines. Taken together, these data suggest that BN acts as a mitogen
      in prostate cancer and this might be associated with the activation of the
      transcription factor Elk-1 and the immediate early gene c-fos.

PMID- 12409227
TI  - Involvement of intracellular Ca2+ elevation but not cyclic AMP in PACAP-induced
      p38 MAP kinase activation in PC12 cells.
AB  - We have recently shown that in PC12 cells, pituitary adenylate cyclase-activating
      polypeptide (PACAP) and NGF synergistically stimulate PACAP mRNA expression
      primarily via a mechanism involving a p38 mitogen-activated protein kinase (MAPK)
      dependent pathway. Here we have analyzed p38 MAPK activation by PACAP and the
      mechanism underlying this action of PACAP in PC12 cells. PACAP increased
      phosphorylation of p38 MAPK with a bell-shaped dose-response relationship and a
      maximal effect was obtained at 10(-8) M. PACAP (10(-8) M)-induced p38 MAPK
      phosphorylation was already evident at 2.5 min, maximal at 5 min, and rapidly
      declined thereafter. PACAP-induced p38 MAPK phosphorylation was potently
      inhibited by depletion of Ca(2+) stores with thapsigargin and partially inhibited
      by the phospholipase C inhibitor U-73122, L-type voltage-dependent calcium
      channel inhibitors nifedipine and nimodipine, and the Ca(2+) chelator EGTA,
      whereas the protein kinase C inhibitor calphostin C, the protein kinase A
      inhibitor H-89, the cAMP antagonist Rp-cAMP, and the nonselective cation channel
      blocker SKF96365 had no effect. These results indicate that PACAP activates p38
      MAPK in PC12 cells through activation of a phospholipase C, mobilization of
      intracellular Ca(2+) stores, and Ca(2+) influx through voltage-dependent Ca(2+)
      channels, but not cyclic AMP-dependent mechanisms.

PMID- 12409228
TI  - Suppression of tumorigenicity in neuroblastoma cells by upregulation of human
      vasoactive intestinal peptide receptor type 1.
AB  - We hypothesize that vasoactive intestinal peptide (VIP) promotes neural crest
      differentiation through VIP receptor type I (VPAC1). In order to test this
      hypothesis, SKNSH neuroblastoma cells were stably transfected with VPAC1 and
      receptor expression was verified by real-time RT-PCR. Overexpression of VPAC1 in
      SKNSH cells resulted in upregulation of endogenous retinoic acid receptor
      expression for both RARalpha and RXRalpha with no change in expression of
      RARbeta. Transfected cells demonstrated high affinity binding of VIP (K(D)=0.2
      nM) and VIP-mediated stimulation of adenylate cyclase and a shift in cell cycle
      kinetics to a near triploid DNA index in G1. SKNSH/VPAC1 cells treated with VIP
      were observed to express a more differentiated phenotype compared to wild type
      cells as characterized by an increase in tissue transglutaminase II and a
      decrease in bcl-2 immunostaining. VIP-induced differentiation effects were
      potentiated by retinoic acid. This differentiation resulted in decreased
      proliferative potential in a xenograft model. Whereas, wild type SKNSH cells
      induced tumor growth in 100% of nude mice within 13 days post-injection, SKNSH
      transfected with VPAC1 demonstrated no tumor formation in xenografts followed for
      6 months. Taken together, these data support the hypothesis that VIP modulation
      of neural crest differentiation is mediated via VPAC1 and that high expression of
      VPAC1 induces differentiation in and decreases tumorigenicity of neuroblastoma
      cells.

PMID- 12409229
TI  - What may be the anatomical basis that secretin can improve the mental functions
      in autism?
AB  - Autism was first described and characterized as a behavioral disorder more than
      50 years ago. The major abnormality in the central nervous system is a cerebellar
      atrophy. The characteristic histological sign is a striking loss or abnormal
      development in the Purkinje cell count. Abnormalities were also found in the
      limbic system, in the parietal and frontal cortex, and in the brain stem. The
      relation between secretin and autism was observed 3 years ago. Clinical
      observations by Horvath et al. [J. Assoc. Acad. Minor. Physicians 9 (1998) 9]
      supposed a defect in the role of secretin and its receptors in autism. The aim of
      the present work was to study the precise localization of secretin
      immunoreactivity in the nervous system using an immunohistochemical approach. No
      secretin immunoreactivity was observed in the forebrain structures. In the brain
      stem, secretin immunoreactivity was observed in the mesencephalic nucleus of the
      trigeminal nerve, in the superior olivary nucleus, and in scattered cells of the
      reticular formation. The most intensive secretin immunoreactivity was observed in
      the Purkinje cells of the whole cerebellum and in some of the neurons of the
      central cerebellar nuclei. Secretin immunoreactivity was also observed in a
      subpopulation of neurons in the primary sensory ganglia. This work is the first
      immunohistochemical demonstration of secretin-immunoreactive elements in the
      brain stem and in primary sensory ganglia.

PMID- 12409230
TI  - GIP, a G-protein-coupled receptor interacting protein.
AB  - A novel protein was cloned while screening for partners interacting with the
      second intracellular loop of the V2 vasopressin receptor (V2R). The protein was
      named GIP as in G-protein-coupled receptor Interacting Protein; the corresponding
      gene was located on the 17th chromosome where three exons encode for a 379-amino
      acid protein.GIP subcellular localization was studied by immunocytochemistry and
      also using a biotinylating agent. The protein was found to be localized, at least
      in part, on the plasma membrane, probably in the form of a trimer. The results
      indicated that GIP is a transmembrane protein and the most part of the molecule
      is intracellular. Sequence homology inferred that GIP cytosolic domain is folded
      as a collagen-like helix followed by a globular domain. The interaction of the
      globular domain with the V2R was confirmed by pull-down experiments indicating
      that this structural motif can also interact with cytosolic proteins.

PMID- 12409231
TI  - Development of a biologically active secretin analogue incorporating a
      radioiodinatable photolabile p-(4-hydroxybenzoyl)phenylalanine in position 10.
AB  - Photoaffinity labeling is a powerful approach for direct elucidation of residue
      residue approximations as a ligand is bound to its receptor, providing important
      constraints for molecular modeling. Probes utilized for this need to incorporate
      photolabile sites of covalent attachment and an indicator, such as a radiolabel.
      Radioiodine provides a particularly useful high specific radioactivity label, but
      due to its size, can only be accommodated in limited positions within a peptide
      ligand. In this work, we attempted to develop a probe for the secretin receptor
      that would directly provide spatial approximation data for position 10 of
      secretin, its site of radiolabeling. This was achieved by incorporation into a
      secretin analogue of the radioiodinatable and photolabile benzophenone moiety, p
      (4-hydroxybenzoyl)phenylalanine (OH-Bpa). An unintended additional modification
      of secretin in synthesizing this probe was the elimination of Gly(4). This probe
      was shown to bind to the secretin receptor specifically and saturably
      (K(i)=25.3+/-6.0 nM). It represented a full agonist, stimulating intracellular
      cAMP in a concentration-dependent manner (EC(50)=4.2+/-0.7 nM). It was also able
      to affinity label the secretin receptor in a specific and efficient manner. This
      probe should provide the opportunity to identify the region of the secretin
      receptor in spatial approximation with position 10, within the pharmacophore of
      secretin, leading to refinement of molecular conformational models of this
      agonist-bound receptor.

PMID- 12409232
TI  - Age-dependent levels of plasma neuropeptides in normal children.
AB  - Several neuropeptides are secreted in high amounts in pediatric tumors such as
      neuroblastoma and have been used as markers of residual or recurrent disease.
      Plasma levels of neuropeptides might be expected to change during development,
      but have not been determined in normal children. We have obtained fresh plasma
      from cord blood of six full-term infants and from peripheral blood in 41 healthy
      children, ages 1 month to 21 years. Levels of six neuropeptides, vasoactive
      intestinal peptide (VIP), somatostatin, gastrin releasing peptide (GRP),
      substance P, pancreastatin and neuropeptide Y (NPY) were measured by
      radioimmunoassay along with insulin-like growth factor-1 (IGF-1) whose plasma
      levels are known to vary during development. A child with neuroblastoma was
      treated with the somatostatin analogue, octreotide, and the effect on plasma
      neuropeptides quantified. Octreotide doses of 2-3 microg/kg daily resulted in a
      40-60% decrease in plasma levels of IGF-1, pancreastatin and GRP. These results
      are the first publication of plasma neuropeptide levels in normal children.

PMID- 12409233
TI  - Specific interaction between the hop1 intracellular loop 3 domain of the human
      PAC(1) receptor and ARF.
AB  - The PAC(1), VPAC(1) and VPAC(2) receptors are members of the secretin (Group II)
      family of G protein-coupled receptors. All members of this family activate
      adenylate cyclase and several have also been shown to activate phospholipase C.
      We have recently reported that the rat VPAC(1), VPAC(2) and PAC(1) receptors
      activate phospholipase D and that distinct pathways are utilised by two
      intracellular loop 3 splice variants of PAC(1), one of which is ARF-dependent.
      Phospholipase D activation by the hop1, but not the null (short), form of the
      PAC(1) receptor is sensitive to brefeldin A, an inhibitor of GTP exchange at ARF.
      We have expressed the null and hop1 intracellular loop 3 domains of the human
      PAC(1) receptor in bacteria as GST-fusion proteins and used them as peptide
      affinity matrices to determine whether a functional interaction exists between
      these domains and ARF. Using this GST pull-down assay, we have shown binding of
      the small G protein ARF6 to the hop1 but not the null domain of this receptor.

PMID- 12409234
TI  - Immunoeffector and immunoregulatory activities of vasoactive intestinal peptide.
AB  - Vasoactive intestinal peptide (VIP) and its two G protein-coupled receptors,
      VPAC1R and VPAC2R, are prominent in the immune system and potently affect T cells
      and macrophages. VPAC1Rs are expressed constitutively by blood and tissue T
      cells, with an order of prevalence of Th2>Th1>>Ts, and transmit signals
      suppressive for migration, proliferation and cytokine production. Immune
      activation of T cells downregulates VPAC1Rs and upregulates VPAC2Rs. VPAC2Rs
      mediate T cell chemotaxis, stimulation of some Th2-type cytokines, and inhibition
      of some Th1-type cytokines. A tentative hypothesis that the VIP-VPAC2R axis is
      the major neuroregulator of Th2/Th1 balance has been confirmed by finding an
      increased ratio in CD4 T cells of transgenic (TG) mice, expressing high levels of
      VPAC2Rs, and a decreased ratio in CD4 T cells of VPAC2R-null (K/O) mice. VPAC2R
      TG mice exhibit an allergic phenotype, whereas the K/O mice are hypoallergic and
      have heightened delayed-type hypersensitivity. The mechanisms of VIP-VPAC2R
      effects include decreased Th2 apoptosis, increased Th2-type cytokine production,
      and greater generation of Th2 memory cells. VPAC2R antagonists are being
      developed to alleviate allergic diseases and strengthen effector Th1 cell
      mediated immunoprotection.

PMID- 12409235
TI  - Characteristics of polycyclic aromatic hydrocarbons and total suspended
      particulate in indoor and outdoor atmosphere of a Taiwanese temple.
AB  - Incense burning, a common and popular practice among many families and in most
      temples in Taiwan, can result in indoor pollution-related health problems. This
      exploratory study was aimed at characterizing human exposure to polycyclic
      aromatic hydrocarbons (PAHs) and total suspended particulate (TSP) inside and
      around a Taiwanese temple, and to compare the indoor levels with levels outside.
      Additionally, three types of commonly used unburned incense and incense ash were
      analyzed in order to evaluate the relationship between incense composition and
      PAH emissions.Standard methods were used to determine air concentrations of 21
      PAHs and TSP inside and around a chosen temple. Indoor mean total-PAH
      concentration, particle-bound PAH concentration and TSP concentration were 6258
      ng/m(3), 490 micro g/g and 1316 micro g/m(3), respectively; values for outdoor
      readings were 231 ng/m (3), 245 micro g/g and 73 micro g/m(3), for outdoors,
      respectively indicating PAH and TSP concentrations inside 27 and 18 times
      greater, respectively than outdoors. With respect to concentrations of individual
      PAHs (particulate+gas phase), the five highest concentrations were of
      acenaphthylene (AcPy) (3583 ng/m(3)), naphthalene (Nap) (1264 ng/m(3)),
      acenaphthene (Acp) (349 ng/m(3)), fluoranthene (FL) (243 ng/m(3)) and
      phenanthrene (PA) (181 ng/m(3)). Median values for indoor/outdoor (I/O) ratios of
      individual PAHs ranged from 5.7 to 387.9, which implied that the temple was a
      significant PAH source. Moreover, PAH content of the tested stick incense and ash
      was very low. PAH levels inside the temple were much higher than those measured
      in the vicinity and inside residential houses; and were in fact close to levels
      measured at a local traffic intersection in Tainan, Taiwan, and those in a
      graphite-electrode producing plant during the graphitization process. It is
      obvious that such substantially high concentrations of PAHs and TSP constitute a
      potential health hazard to people working in or visiting the temple.

PMID- 12409236
TI  - Effect of air in the thermal decomposition of 50 mass% hydroxylamine/water.
AB  - This paper presents experimental measurements of 50 mass% hydroxylamine
      (HA)/water thermal decomposition in air and vacuum environments using an
      automatic pressure tracking adiabatic calorimeter (APTAC). Overall kinetics,
      onset temperatures, non-condensable pressures, times to maximum rate, heat and
      pressure rates versus temperature, and mixture vapor pressures for the
      experiments in vacuum were similar when compared to the corresponding data for HA
      decomposition in air. Determined was an overall activation energy of 119+/-8
      kJ/mol (29+/-2 kcal/mol), which is low compared to 257 kJ/mol (61.3 kcal/mol)
      required to break the H(2)N-OH bond reported in the literature. The availability
      of oxygen from air did not affect detected runaway decomposition products, which
      were H(2), N(2), N(2)O, NO, and NH(3), for samples run in vacuum or with air
      above the sample. A delta H(rxn) of -117 kJ/mol (28 kcal/mol) was estimated for
      the HA decomposition reaction under runaway conditions.

PMID- 12409237
TI  - A comparative study of the removal of trivalent chromium from aqueous solutions
      by bentonite and expanded perlite.
AB  - Local bentonite and expanded perlite (Morocco) have been characterised and used
      for the removal of trivalent chromium from aqueous solutions. The kinetic study
      had showed that the uptake of Cr(III) by bentonite is very rapid compared to
      expanded perlite. To calculate the sorption capacities of the two sorbents, at
      different pH, the experimental data points have been fitted to the Freundlich and
      Langmuir models, respectively, for bentonite and expanded perlite. For both
      sorbents the sorption capacity increases with increasing the pH of the
      suspensions. The removal efficiency has been calculated for both sorbents
      resulting that bentonite (96% of Cr(III) was removed) is more effective in
      removing trivalent chromium from aqueous solution than expanded perlite (40% of
      Cr(III) was removed). In the absence of Cr(III) ions, both bentonite and expanded
      perlite samples yield negative zeta potential in the pH range of 2-11. The
      changes of expanded perlite charge, from negative to positive, observed after
      contact with trivalent chromium(III) solutions was related to Cr(III) sorption on
      the surface of the solid. Thus, it was concluded that surface complexation plays
      an important role in the sorption of Cr(III) species on expanded perlite. In the
      case of bentonite, cation-exchange is the predominate mechanism for sorption of
      trivalent chromium ions, wherefore no net changes of zeta potential was observed
      after Cr(III) sorption. X-ray photoelectron spectroscopy measurements, at
      different pH values, were also made to corroborate the zeta potential results.

PMID- 12409238
TI  - Chemical stabilization of MSW incinerator fly ashes.
AB  - In this work, the relationship between heavy metal content of fly ash and that of
      the solid wastes incinerated was correlated and compared. It is found that the
      former is a function of the latter. Hence, it is important to prevent heavy metal
      rich wastes from being incinerated in order to reduce the content of toxic metals
      in the fly ash. The leachability of fly ash from incineration was usually beyond
      the scope of toxicity standard and must be properly treated before discharge.
      Secondly, chemical stabilization for the heavy metals in fly ash was explored.
      Among the chemicals used, it was found that sodium hydroxide was not suitable for
      the adequate extraction of the heavy metals from the fly ash.
      Ethylenediaminetetraacetic acid disodium salt (EDTA) was also tested and seems to
      be effective for the leaching of toxic metals from the fly ash. On the other
      hand, sodium sulfide and thiourea are one of excellent chemicals for the
      effective treatment of fly ashes, since they convert soluble and leachable toxic
      metals into non-leachable and insoluble forms such as lead and zinc sulfide or
      their similar forms of thiourea. These chemical species are supposed to be stable
      in nature. A comparison between chemical stabilization noted above and cement or
      asphalt solidification methods is made. Chemical stabilization processes,
      especially using sodium sulfide as the chemical agent, are strongly recommended
      for the practical uses, in terms of the volume expansion and environmental safety
      of the stabilized products and cost balances, in comparison with the traditional
      cement or asphalt solidification methods.

PMID- 12409239
TI  - Lab scale experiments for permeable reactive barriers against contaminated
      groundwater with ammonium and heavy metals using clinoptilolite (01-29B).
AB  - Batch tests and column tests were performed to determine the design factors for
      permeable reactive barriers (PRBs) against the contaminated groundwater by
      ammonium and heavy metals. Clinoptilolite, one of the natural zeolites having
      excellent cation exchange capacity (CEC), was chosen as the reactive material. In
      the batch tests, the reactivity of clinoptilolite to ammonium, lead, and copper
      was examined by varying the concentration of cations and the particle size of
      clinoptilolite. One gram of clinoptilolite showed removal efficiencies of more
      than 80% against those contaminants in all cases except in very high initial
      concentrations of ammonium (80 ppm) and copper (40 ppm). The effect of particle
      size of clinoptilolite was not noticeable. In the column tests, permeability was
      examined using a flexible-wall permeameter by varying particle sizes of
      clinoptilolite. When the washed clinoptilolite having the diameter of 0.42-0.85
      mm was mixed with Jumunjin sands in 20:80 ratio (w/w), the highest permeability
      of 2 x 10(-3) to 7 x 10(-4)cm/s was achieved. The reactivity and the strength
      property of the mixed material were investigated using a fixed-wall column,
      having eight sampling ports on the wall, and the direct shear test, respectively.
      Clinoptilolite was found to be a suitable material for PRBs against the
      contaminated groundwater with ammonium and/or heavy metals.

PMID- 12409240
TI  - Catalytic oxidation of gaseous reduced sulfur compounds using coal fly ash.
AB  - Activated carbon has been shown to oxidize reduced sulfur compounds, but in many
      cases it is too costly for large-scale environmental remediation applications.
      Alternatively, we theorized that coal fly ash, given its high metal content and
      the presence of carbon could act as an inexpensive catalytic oxidizer of reduced
      sulfur compounds for "odor" removal. Initial results indicate that coal fly ash
      can catalyze the oxidization of H(2)S and ethanethiol, but not dimethyl sulfide
      (DMS) and dimethyl disulfide (DMDS) at room temperature. In batch reactor
      systems, initial concentrations of 100-500 ppmv H(2)S or ethanethiol were reduced
      to 0-2 ppmv within 1-2 and 6-8 min, respectively. This was contrary to control
      systems without ash in which concentrations remained constant. Diethyl disulfide
      was formed from ethanethiol substantiating the claim that catalytic oxidation
      occurred. The presence of water increased the rate of adsorption/reaction of both
      H(2)S and ethanethiol for the room temperature reactions (23-25 degrees C).
      Additionally, in a continuous flow packed bed reactor, a gaseous stream
      containing an inlet H(2)S concentration of 400-500 ppmv was reduced to 200 ppmv
      at a 4.6s residence time. The removal efficiency remained at 50% for
      approximately 4.6h or 3500 reactor volumes. These results demonstrate the
      potential of using coal fly ash in reactors for removal of H(2)S and other
      reduced sulfur compounds.

PMID- 12409241
TI  - Biodegradation of RDX within soil-water slurries using a combination of differing
      redox incubation conditions.
AB  - Biodegradation of 14C-tagged hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) was
      studied in aerobic, anaerobic, and anaerobic/aerobic slurries to identify the
      conditions maximizing RDX-mineralization in Cornhusker Army Ammunition Plant
      (CAAP, NE) groundwater. Supplementation with phosphate and adequate quantities of
      acetate caused 25% mineralization of RDX in 3 weeks by microorganisms native to
      CAAP. Under anaerobic conditions, the same supplementation resulted in 20%
      mineralization in 3 weeks and 30% mineralization in 6 weeks. The highest degree
      of mineralization (50%) was obtained under aerobic conditions when the
      contaminated groundwater was augmented with a consortium of three microbes
      isolated from another RDX contaminated soil (Hastings, NE) in addition to
      supplemented with phosphate and acetic acid. Use of complex organic sources
      (potato or corn starch) slowed down the rates of mineralization under anaerobic
      conditions, but rapid mineralization ensued as soon as the aerobic conditions
      were created. Final RDX concentrations in aqueous phase were below detection
      limit under most conditions. Assimilation of RDX by the cells was negligible.

PMID- 12409242
TI  - Physical properties of a soil substitute derived from an aluminum recycling by
      product.
AB  - Disposal of highly saline industrial by-products in landfills is not permitted in
      member states of the European Union, such as Germany. Large amounts of such by
      products thus have to be disposed of in alternative ways. In many countries bare
      potash mining residue mounds, consisting almost entirely of rock salt (NaCl),
      pose environmental problems. Covering such mounds with soil or soil-like material
      could help to reduce the yearly amount of briny runoff. A fine-granular saline
      aluminum recycling by-product (ALRP) has been proposed as a soil substitute to
      cover rock salt residue mounds. Use of this by-product as a combined soil
      substitute and surface barrier is not considered to be a landfill disposal, but
      as a beneficial by-product reuse. To judge the feasibility of ALRP for this
      purpose, its properties must be known. In this study physical characteristics of
      an industrially produced ALRP, mixed with the flue gas desulfurization by-product
      (FGDP) of a coal combustion power plant, were determined. It was found that the
      texture of both ALRP and ALRP-FGDP mix was silt loam. Bulk densities of ALRP and
      ALRP-FGDP were 0.93 and 0.88 Mg x m(-3) and the corresponding salt contents were
      50.0 and 35.5%, respectively. The erodibility factor K of pure ALRP was estimated
      as 0.65 Mg h x ha (-1)N(-1). Because of the stabilizing effect of FGDP, this
      factor was reduced considerably in ALRP-FGDP. The water-holding capacity of
      unwashed ALRP was 44.5% and of washed ALRP-FGDP 61.8%. In view of its physical
      properties, ALRP-FGDP seems to be suitable as an evaporation enhancing, runoff
      reducing cover material for potash mine residue mounds, even on steep slopes. Use
      of ALRP, mixed with FGDP, as a soil substitute in a surface barrier, thus seems
      to be environmentally meaningful. However, the high salt content initially
      prevents plant growth. With time, after the salt has been leached, the material
      seems able to support plant growth, which would further reduce runoff. The
      physical and hydraulic parameters determined in this study may serve future users
      of similar by-products.

PMID- 12409243
TI  - Effects of pure and dyed PCE on physical and interfacial properties of remedial
      solutions.
AB  - Hydrophobic dyes have been used to visually distinguish dense non-aqueous phase
      liquid (DNAPL) contaminants from background aqueous phases and soils. The
      objective of this study was to evaluate the effects of a dyed DNAPL, 0.5 g Oil
      Red-O/l of PCE, on the physical properties of remedial solutions: water, co
      solvents (50, 70, and 90% (v/v) ethanol), and surfactants (4% (w) sodium dihexyl
      sulfosuccinate). This study compared the densities, viscosities, and interfacial
      tensions (IFTs) of the remedial solutions in contact with both dyed and undyed
      PCE. The presence of the dye in PCE substantially alters the IFTs of water and
      ethanol solutions, while there is no apparent difference in IFTs of surfactant
      solutions. The remedial solutions saturated with PCE showed higher viscosities
      and densities than pure remedial solutions. Solutions with high ethanol content
      exhibited the largest increases in liquid density. Because physical properties
      affect the flow of the remedial solutions in porous media, experiments using dyed
      DNAPLs should assess the influence of dyes on fluid and interfacial properties
      prior to remediation process analysis.

PMID- 12409244
TI  - The role of sawdust in the removal of unwanted materials from water.
AB  - Sawdust, a relatively abundant and inexpensive material is currently being
      investigated as an adsorbent to remove contaminants from water. Chemical
      substances including dyes, oil, toxic salts and heavy metals can be removed very
      effectively with the organic material. This article presents a brief review on
      the role of sawdust in the removal of contaminants. Studies on the adsorption of
      various pollutants by different sawdust materials are reviewed and the adsorption
      mechanism, influencing factors, favorable conditions, etc. discussed in this
      paper. Some valuable guidelines can be drawn for either scientific research or
      industrial design.

PMID- 12409245
TI  - Landfill leachate treatment by a coagulation-photooxidation process.
AB  - This experimental study was conducted to investigate the effect of treatment of
      landfill leachate by a coagulation-photooxidation process. The effects of
      different dosages of coagulant and different pH values on the coagulation
      processes were compared. The effect of different concentrations of sodium oxalate
      (Na(2)C(2)O(4)) on the treatment process was also studied after the coagulation
      was performed using FeCl(3).6H(2)O. The experimental results show that in the pH
      range of 3-8, the lower the pH value, the higher the efficiency of the treatment.
      A 24% removal of COD (chemical oxygen demand, mg(O(2)) x l(-1)) can be attained
      by the addition of 1000 mg x l(-1) FeCl(3). A 31% removal of COD can be attained
      after 4h of irradiation alone, and a 64% removal of COD can be attained after 4h
      irradiation at pH 3 with the addition of 500 mg x l(-1) FeCl(3).6H(2)O.

PMID- 12409246
TI  - The photocatalytic degradation of trichloroethane by chemical vapor deposition
      method prepared titanium dioxide catalyst.
AB  - The purpose of the investigation was to study the photocatalytic reaction of
      trichloroethane using a TiO(2) catalyst deposited in an annular reactor by the
      chemical vapor deposition (CVD) method. The experimental results indicated the
      highest decomposition rate of the trichloroethane was 2.71 micro mol/(sm(2)) and
      the conversion ratio reached a maximum of 99.9%. When the humidity was below 154
      micro M, the reaction rate slightly increased with increasing humidity. However,
      the reaction rate decreased as the humidity increased >154 micro M. Oxygen played
      a role as an electron acceptor in the reaction, and reduced the recombination of
      the photogenerated electron-hole pairs. Therefore, the reaction rate rose as the
      oxygen concentration increased. Nevertheless, after the oxygen concentration
      reached 12%, the reaction rate reached it maximum and was constant in spite of
      increasing oxygen concentration. As the initial reactant concentration increased,
      the reaction rate increased, but the conversion ratio dropped. An increase of
      light intensity resulted in an increase in the number of photons and thus
      increased the reaction rate. Accordingly the decomposition of trichloroethane
      could be fitted by the semi-empirical bimolecular Langmuir-Hinshelwood model.
      Moreover, the reaction rate was proportional to the 0.48-order of the light
      intensity.

PMID- 12409247
TI  - Photodegradation of 1-nitropyrene in solution and in the adsorbed state.
AB  - The photodegradation of the 1-nitropyrene (NPy) has been studied using
      conventional (Xe and medium pressure Hg lamps) and laser sources (XeCl excimer
      and Nd-YAG UV). Low energy monochromatic light sources were used to study the
      early stages of degradation (up to 50% conversion). The medium pressure Hg lamp
      was used for longer periods of irradiation (up to 6h) and for greater degradation
      of NPy. The results of our work confirm that degradation occurs by radical
      mechanism. Aromatic hydroxymethyl, methoxy, hydroxy and nitroso derivatives of
      pyrene (Py) are created by low energy UV irradiation. After a massive UV
      irradiation, the Py aromatic system is destroyed and more polar low-molecular
      compounds are generated. The photochemical method described in this paper, based
      on irradiation by UV lamp, is therefore, suitable for degradation of fused
      benzene ring(s) and thus should also be effective for degradation of other
      nitrated polycyclic aromatic compounds.

PMID- 12409248
TI  - Evaluation of assisting agents for electrodialytic removal of Cd, Pb, Zn, Cu and
      Cr from MSWI fly ash.
AB  - Different assisting agents (0.25 M ammonium citrate/1.25% NH(3), 0.25 M Na
      citrate, 2.5% NH(3), DI water) have been used for aiding the removal of heavy
      metals during electrodialytic treatment of municipal solid waste incineration
      (MSWI) fly ash. In this study, the effectiveness of the different agents was
      evaluated. The heavy metal speciation in solution was discussed and simulated at
      the different conditions using the geochemical equilibrium model Visual MINTEQ.
      The heavy metals examined were Cd, Pb, Zn, Cu and Cr. The 2.5% NH(3) solution was
      the best assisting agent for removal of Cd, probably due to formation of stable
      tetraammine complexes; whereas the best Pb removal was obtained with 0.25 M Na
      citrate (Pb forms very stable chelates with citrate). The best compromise for
      removal of all five metals was obtained with the 0.25 M ammonium citrate/1.25%
      NH(3) solution.

PMID- 12409249
TI  - Simultaneous removal of ethyl acetate and toluene in air streams using compost
      based biofilters.
AB  - Biofitration was successfully applied to treat air streams containing a mixture
      of ethyl acetate and toluene. The experiment was performed by two identical bench
      scale biofilters, which were acclimated by ethyl acetate and toluene,
      respectively. During a 3 month steady-state performance, the two biofilters
      showed equivalent elimination capacity (EC) for toluene (50 g/m(3) bed/h of pure
      toluene). However, the biofilter acclimated with ethyl acetate showed a much
      higher EC for ethyl acetate (400 g/m(3) bed/h of pure ethyl acetate) than that
      acclimated with toluene (250 g/m(3) bed/h). The concurrent biofiltration of
      toluene was inhibited by the presence of ethyl acetate. The results also showed
      that more nitrogen and phosphorus were consumed in the process of the
      biofiltration of toluene compared with the treatment of ethyl acetate. After the
      3 month experiment, the pH of the media treating ethyl acetate dropped from 6.71
      to 5.50, whereas the pH of the media treating toluene increased from 6.71 to
      7.08.

PMID- 12409250
TI  - Electrochemical treatment in relation to pH of domestic wastewater using Ti/Pt
      electrodes.
AB  - This paper describes an electrochemical treatment of domestic wastewater (DW)
      using 0.8% (w/v) sodium chloride as electrolyte. In this technique, DW was passed
      through an electrolytic cell using Ti/Pt as anode and Stainless Steel 304 as
      cathode. Due to the strong oxidizing potential of the chemicals produced
      (chlorine, oxygen, hydroxyl radicals and other oxidants), the organic pollutants
      and nutrients (organic nitrogen, phosphorous) were wet oxidized to carbon
      dioxide, and nitrogen as well as phosphorous was precipitated as Ca(3)(PO(4))(2).
      Experiments were run in a continuous, laboratory-scale, pilot plant, at 40
      degrees C and the efficiency of oxidation was studied in relation to pH. It was
      found that in alkaline conditions the electrolysis was more efficient. At pH 9,
      NaCl concentration 0.8% (w/v), current density 0.075 A/cm(2) and for 1h of
      electrolysis, COD was reduced by 89%, volatile suspended solids (VSS) by 90%,
      ammonia nitrogen by 82% and total phosphorous by 98%. The efficiency of
      electrolysis went up to 35 g COD(r)/(hm(2)A) and the energy consumption to 12.4
      kWh/kg COD(r). It is concluded that the application of electrolytic oxidation of
      DW is more advantageous compared to conventional biological treatment especially
      for small works.

PMID- 12409253
TI  - Success and setback: another adverse event.

PMID- 12409254
TI  - Targeting retroviral integration?

PMID- 12409255
TI  - Transcutaneous ultrasound augments naked DNA transfection of skeletal muscle.
AB  - This study was designed to test the hypothesis that transcutaneous ultrasound
      (US) exposure may augment the transfection efficiency and biological outcome
      associated with nonviral DNA gene transfer. Hindlimb muscles of New Zealand White
      rabbits were transfected with the reporter plasmid pCMV-beta, with or without US
      exposure. Optimization studies employed US exposure at various frequencies,
      mechanical indices, duty cycles, durations of exposure, and exposure time points.
      Based on these results, we explored the effect of US exposure on nonviral gene
      transfer of vascular endothelial growth factor (VEGF, phVEGF165) to promote
      neovascularization of ischemic hindlimbs. Ultrasound at 1 MHz, 100 W/cm(2), 6%
      duty cycle, and 5 minutes exposure time, applied immediately following DNA
      injection, was found to be the most effective among the settings tested,
      increasing beta-galactosidase expression approximately 20 fold. Compared with US
      exposure alone, or phVEGF165 only, phVEGF165 + US exposure yielded a
      statistically significant improvement in revascularization, as determined by calf
      blood pressure ratio, angiographic score, intravascular Doppler blood flow, and
      capillary/myocyte ratio. These data demonstrate that ultrasound, when applied
      directly after intramuscular gene transfer, significantly increases transfection
      efficiency in vivo. The biological significance of this finding was confirmed by
      augmented limb perfusion in response to US exposure and naked VEGF DNA.

PMID- 12409256
TI  - Effective treatment of established mouse collagen-induced arthritis by systemic
      administration of dendritic cells genetically modified to express FasL.
AB  - Previous reports have demonstrated the ability of antigen-presenting cells
      (APCs), genetically modified to express Fas ligand (FasL), to inhibit T-cell
      responses through the induction of apoptosis of antigen-specific T cells. Here we
      have examined the ability of primary mouse bone marrow-derived dendritic cells
      (DCs), genetically modified by adenoviral infection to express FasL, to inhibit
      progression of established collagen-induced arthritis (CIA) in DBA/1 mice.
      Systemic injection of DC/FasL into mice with established CIA resulted in
      substantial disease amelioration as determined by analysis of paw swelling,
      arthritic index, and number of arthritic paws. Moreover, a single injection of
      DC/FasL resulted in extended suppression of disease. We also demonstrate that
      treatment of arthritic mice with DC/FasL suppressed interferon-gamma (IFN-gamma)
      production from spleen-derived lymphocytes and reduced T-cell proliferation
      following collagen stimulation without affecting the levels of anti-collagen
      antibody isotypes. These results demonstrate that systemic administration of
      DC/FasL is able to suppress collagen-reactive T cells, resulting in effective and
      sustained treatment of established CIA.

PMID- 12409257
TI  - Ex vivo gene delivery of IL-1Ra and soluble TNF receptor confers a distal
      synergistic therapeutic effect in antigen-induced arthritis.
AB  - Intra-articular expression of antagonists of interleukin-1beta (IL-1beta) and
      tumor necrosis factor-alpha (TNF-alpha) in arthritic rabbit knee and mouse ankle
      joints by direct adenoviral-mediated intraarticular delivery results in
      amelioration of disease pathology in both the treated and contralateral untreated
      joints. Previous experiments suggest that direct adenoviral infection of resident
      antigen-presenting cells (APCs) and subsequent traveling of these cells to other
      sites of inflammation and lymph nodes might be responsible for this
      "contralateral effect." To determine whether genetic modification of APCs is
      required for the contralateral effect, we have used an ex vivo approach utilizing
      genetically modified fibroblasts to express IL-1 receptor antagonist protein (IL
      1Ra) and soluble TNF-alpha receptor (sTNFR) locally in arthritic joints.
      Retroviral vectors carrying IL-1Ra, sTNFR-Ig, or both genes together were used to
      stably infect autologous rabbit fibroblasts that were then injected intra
      articularly into arthritic rabbit knee joints. The intra-articular delivery of
      either IL-1Ra- or sTNFR-Ig-expressing fibroblasts was antiinflammatory and
      chondro-protective in both the injected and noninjected contralateral joints. In
      addition, we demonstrate that the co-delivery of both antagonists in combination
      results in a synergistic effect in disease amelioration in both the treated and
      nontreated joints. These ex vivo results suggest that trafficking of vector
      modified inflammatory cells is not the main mechanism responsible for the
      observed distal spread of the therapeutic effect. Moreover, the results
      demonstrate that local, ex vivo gene therapy for arthritis could be effective in
      blocking pathologies within untreated, distant arthritic joints.

PMID- 12409258
TI  - Glycogen stored in skeletal but not in cardiac muscle in acid alpha-glucosidase
      mutant (Pompe) mice is highly resistant to transgene-encoded human enzyme.
AB  - Although many lysosomal disorders are corrected by a small amount of the missing
      enzyme, it has been generally accepted that 20-30% of normal acid alpha
      glucosidase (GAA) activity, provided by gene or enzyme replacement therapy, would
      be required to reverse the myopathy and cardiomyopathy in Pompe disease. We have
      addressed the issue of reversibility of the disease in the Gaa(-/-) mouse model.
      We have made transgenic lines expressing human GAA in skeletal and cardiac muscle
      of Gaa(-/-) mice, and we turned the transgene on at different stages of disease
      progression by using a tetracycline-controllable system. We have demonstrated
      that levels of 20-30% of normal activity are indeed sufficient to clear glycogen
      in the heart of young Gaa(-/-) mice, but not in older mice with a considerably
      higher glycogen load. However, in skeletal muscle-a major organ affected in
      infantile and in milder, late-onset variants in humans-induction of GAA
      expression in young Gaa(-/-) mice to levels greatly exceeding wildtype values did
      not result in full phenotypic correction, and some muscle fibers showed little or
      no glycogen clearance. The results demonstrate that complete reversal of
      pathology in skeletal muscle or long-affected heart muscle will require much more
      enzyme than previously expected or a different approach.

PMID- 12409259
TI  - The organotypic multicellular spheroid is a relevant three-dimensional model to
      study adenovirus replication and penetration in human tumors in vitro.
AB  - The use of adenoviruses for gene transfer and as oncolytic agents is currently
      receiving widespread attention. As specific constraints to adenovirus
      distribution and spread cannot be studied in cell cultures, there is a need for
      an in vitro three-dimensional (3D) model mimicking the in vivo biology of tumors.
      We studied the interactions between tumor and adenoviruses using multicellular
      spheroids grown from primary brain tumor material. Using beta-galactosidase and
      luciferase reporter genes expressed by replication-defective adenoviruses, we
      showed that infection was restricted to the first layer of cells. Using a
      replication-competent adenovirus expressing the luciferase gene, we showed that
      transgene expression in the spheroid was considerably enhanced and that viral
      spreading deep into the 3D structure took place. In addition, a tetrazolium salt
      based metabolic assay could be used to compare the oncolytic activity of
      different concentrations of replication-competent adenoviruses. We can conclude
      that organotypic spheroids offer a versatile in vitro system for studying
      distribution, spread, and oncolysis by adenoviruses in a clinically relevant
      model.

PMID- 12409260
TI  - Molecular evidence of lentiviral vector-mediated gene transfer into human self
      renewing, multi-potent, long-term NOD/SCID repopulating hematopoietic cells.
AB  - A major challenge in gene therapy is to achieve efficient transduction of
      hematopoietic stem cells (HSC). It has previously been shown that lentiviral
      vectors (LV) transduce efficiently human cord blood-derived NOD/SCID mouse
      repopulating cells (SRC). Here we studied the effect of cytokines during the
      short ex vivo incubation with vector. Although SRC transduction was efficient
      without stimulation, the presence of cytokines significantly improved it. The
      treatment did not affect the engraftment level or the SRC frequency, but seemed
      to enhance SRC susceptibility to LV. SRC transduced in both conditions
      repopulated primary and secondary recipients, maintaining stable multi-lineage
      transgene expression. Using linear amplification-mediated PCR, we then analyzed
      vector integration in the bone marrow and CFC of the engrafted mice to monitor
      the clonal activity of the transduced SRC in vivo. We showed polyclonal
      engraftment, multi-lineage differentiation, and propagation to secondary
      recipients of individual SRC. We observed multiple integrations in most clones.
      These results provide the first formal demonstration that primitive human HSC
      with self-renewal and multi-lineage repopulation capacities were transduced by
      LV. Our findings are relevant for the design of clinical protocols that exploit
      this system to reach significant engraftment by genetically modified HSC in the
      absence of in vivo selection or strong conditioning regimens.

PMID- 12409261
TI  - Development of anti-tumor immunity against a non-immunogenic mammary carcinoma
      through in vivo somatic GM-CSF, IL-2, and HSVtk combination gene therapy.
AB  - Gene therapy for cancer using suicide genes such as the herpes simplex virus
      thymidine kinase gene (HSVtk) has been explored extensively in preclinical and
      clinical studies. We have improved the use of HSVtk by combining it with two
      cytokine genes encoding granulocyte/macrophage-colony-stimulating factor (GM-CSF)
      and interleukin-2 (IL-2), and determined their additive/synergistic effects on
      tumor regression and inhibition of metastases in the non-immunogenic,
      spontaneously metastatic mammary tumor model, 4T1. Two adenoviral vectors (AV)
      were constructed, one carrying HSVtk (AV-TK) and the second (AV-GM/IL2) carrying
      Gm-CSf and Il2. Only the combination of AV-TK/GCV and AV-GM/IL2 showed a
      significant decrease in tumor growth and reduction of distant metastases with 25%
      of the tumors undergoing complete regression. When surgical excision of primary
      tumors was included in the regimen, local treatment with AV-TK/GCV plus AV-GM/IL2
      further enhanced long-term survival. A fraction of the treated mice developed
      anti-tumor immunity and survived a second challenge with 4T1. Functional analyses
      demonstrated infiltration of lymphocytes within the tumor and a strong tumor
      specific cytotoxic T lymphocyte response in TK- plus cytokine-treated animals.
      These data indicate that the coexpression of GM-CSF and IL-2 can augment the
      effect of HSVtk suicide gene therapy.

PMID- 12409262
TI  - Adenovirus-mediated mda-7 gene expression radiosensitizes non-small cell lung
      cancer cells via TP53-independent mechanisms.
AB  - We examined the ability of adenoviral-mediated expression of the melanoma
      differentiation associated gene-7 (Ad-mda-7), to radiosensitize non-small cell
      lung cancer (NSCLC) cell lines (A549 (wt-TP53/wt-RB1) and H1299 (del-TP53/wt
      RB1)), and normal human lung fibroblast (NHLF) lines (CCD-16 and MRC-9). Results
      of clonogenic assays indicated that Ad-mda7 enhanced the radiosensitivity of the
      NSCLC cells independent of their TP53 gene status. On the other hand, the NHLF
      cell lines seemed to be relatively resistant to the cytotoxic effects of Ad-mda7
      and were not radiosensitized compared with the NSCLC cells. We further examined
      the basis for this difference in the ability of Ad-mda7 to radiosensitize NSCLC
      cells compared with normal cells. Radiation-induced apoptosis was restored in the
      NSCLC lines, but not in the normal lines. Western blot analysis revealed that Ad
      mda7 enhances radiosensitivity independently of any ability to upregulate the
      expression of Fas or Bax in NSCLC cells. Further analysis indicated that
      phosphorylated c-Jun expression was increased by Ad-mda7 in both A549 and H1299
      cells, but not in CCD-16 cells. These results support the use of gene replacement
      with Ad-mda7 in combination with radiotherapy for the treatment of NSCLC.

PMID- 12409263
TI  - Expression from second-generation feline immunodeficiency virus vectors is
      impaired in human hematopoietic cells.
AB  - Vectors based on the feline immunodeficiency virus (FIV) have been developed as
      an alternative to those based on another lentivirus, human immunodeficiency virus
      1 (HIV-1), because of theoretical safety advantages. We compared the efficiency
      of gene transfer and expression in human and feline hematopoietic progenitors
      using second-generation HIV-1 and FIV-based vectors. Vector pairs were tested
      using either human cytomegalovirus or murine phospho-glycerate kinase (PGK)
      internal promoters and were pseudotyped with the vesicular stomatitis virus G
      protein (VSV-G). Vector proviral copy numbers were similar in human and feline
      hematopoietic primary cells and cell lines transduced by HIV-1 or FIV vectors,
      demonstrating that both vectors are able to transfer genes efficiently to these
      cell types. HIV-1 vectors were well expressed in human primary hematopoietic
      cells and cell lines. However, transgene expression from FIV vectors was almost
      undetectable in human hematopoietic cells. In contrast, the FIV vector was
      expressed well in primary hematopoietic feline cells and human non-hematopoietic
      cells, demonstrating that low transgene expression from the FIV vector is a
      phenomenon specific to human hematopoietic cells. Northern blot analysis
      demonstrated decreased vector transcript levels in human CEM cells transduced
      with FIV relative to cells transduced with HIV-1, despite high vector copy
      numbers. No evidence of vector transcript instability was seen in studies of
      transduced CEM cells treated with actinomycin D. We conclude that FIV vectors can
      transfer genes into human hematopoietic cells as effectively as HIV-1 vectors,
      but that unknown elements in the current FIV backbone inhibit expression from FIV
      vectors in human hematopoietic cells.

PMID- 12409264
TI  - Long-term and tight control of gene expression in mouse skeletal muscle by a new
      hybrid human transcription factor.
AB  - Diseases requiring frequent and lifelong injections of recombinant proteins would
      be more efficaciously treated by intramuscular delivery of genes encoding
      secretable proteins. However, the success of this approach largely depends on our
      capability to temporally regulate transcription of delivered genes. Therefore, we
      sought to generate a humanized transcription factor to regulate transgene
      expression in muscle. A novel 4-hydroxytamoxifen (4-OHT)-dependent
      transcriptional regulator (called HEA-3) was constructed by fusing in-frame the
      DNA binding domain of the human hepatocyte nuclear factor-1alpha (HNF1alpha),
      which is not expressed in muscle cells, a G(521)R mutant of the ligand binding
      domain of human estrogen receptor-alpha (ERalpha), and the activation domain
      derived from human nuclear factor-kappaB p65 subunit (NF-kappaB p65). We
      demonstrate that an artificial promoter containing multimeric HNF1alpha binding
      sites is silent in muscles and in cell lines that lack endogenous HNF1alpha. HEA
      3 stimulated transcription from this target promoter in a stringent 4-OHT
      dependent manner. The dynamic range of transgene regulation was high, because of
      the low basal activity and high inducibility of the system. Ex vivo, HEA-3
      increased expression of the transfected reporter gene by more than 1000-fold in a
      ligand-dependent manner. In vivo, HEA-3 stimulated by more than 100-fold, the
      expression of secreted alkaline phosphatase after delivery as plasmid DNA into
      mouse muscles. Moreover, long-term modulation of the expression of
      intramuscularly delivered mouse erythropoietin was achieved in immunocompetent
      mice.

PMID- 12409265
TI  - An angiogenic, endothelial-cell-targeted polymeric gene carrier.
AB  - Targeting is one of the primary considerations in designing a specific and
      efficient gene delivery system. Here, an angiogenic endothelial cell-targeted
      polymeric gene delivery carrier was developed by conjugating an
      alpha(v)beta3/alpha(v)beta5 integrin-binding RGD peptide, ACDCRGDCFC, into the
      cationic polymer polyethyleneimine (PEI) via a hydrophilic poly(ethylene glycol)
      (PEG) spacer. The incorporation of PEG into PEI improved the poor physicochemical
      properties of PEI-DNA complexes. At a neutral charge ratio, DNA complexes with
      PEI were polydisperse and substantially aggregated, whereas DNA complexes with
      PEI-g-1PEG-RGD were homogeneous with 100-200 nm effective diameter. Their surface
      charge was also significantly reduced due to the charge shielding effect of PEG.
      However, the extensive grafting of PEI with PEG was shown to inhibit the DNA
      condensation process, significantly decreasing transfection efficiency. In in
      vitro transfection experiments with angiogenic endothelial cells, PEI-g-1PEG-RGD
      showed an approximately fivefold increase in transfection efficiency over PEI,
      due to an integrin-mediated internalization pathway. PEI-g-1PEG-RGD also
      exhibited high specificity to angiogenic endothelial cells compared with normal
      endothelial cells, which was confirmed by in vitro transfection experiments with
      non-targeting PEI-g-1PEG-RAE in angiostatic endothelial cells.

PMID- 12409266
TI  - Carnitine membrane transporter deficiency: a long-term follow up and OCTN2
      mutation in the first documented case of primary carnitine deficiency.
AB  - Three older patients were diagnosed with systemic carnitine deficiency in
      childhood nearly a generation ago and have together been treated for more than 50
      patient years. Treatment improved tissue carnitine stores (proven in two) and
      eliminated most of the signs and symptoms of carnitine deficiency. All three have
      continued to respond to carnitine therapy and remain well except for the
      irreversible sequelae of the pretreatment illnesses. We demonstrate here that
      transformed lymphocytes from the first documented case of plasma membrane
      carnitine transporter deficiency fail to take up carnitine from the medium. The
      analysis of the cDNA of this patient and his parents revealed a homozygous
      frameshift mutation, 1027delT in exon 4. The resulting polypeptide terminates
      after amino acid 295. His parents are heterozygous for this mutation. The
      deletion resulted in predominately abnormal mRNA splicing with either a 13 or
      19bp insertion between the junction of exons 3 and 4. The 13/19bp insertions were
      found in both parents, predominantly in cis with the deletion, and rarely seen
      with normal alleles from either parents or controls.

PMID- 12409267
TI  - Infantile citrullinemia caused by citrin deficiency with increased dibasic amino
      acids.
AB  - In an infant who suffered from prolonged icterus and hepatocellular dysfunction
      we detected an increase of citrulline and dibasic amino acids in plasma and
      urine. The amino acid levels along with all the abnormal liver tests normalized
      upon replacing breast-milk by formula feeding; there was no relapse after human
      milk was tentatively reintroduced. A novel mutation, a approximately 9.5-kb
      genomic duplication, was identified in the citrin gene (SLC25A13) resulting in
      the insertion of exon 15. No mutation was detected in the CAT2A specific exon of
      the SLC7A2 gene which encodes for the liver transporter of cationic amino acids.
      This is the first report of infantile citrin deficiency in non-Asian patients.

PMID- 12409268
TI  - Molecular analysis of PCCB gene in Korean patients with propionic acidemia.
AB  - Propionic acidemia (PA) is an autosomal recessive inborn error in the catabolism
      of methionine, isoleucine, threonine, and valine, odd-numbered chain length fatty
      acids and cholesterol. Clinical symptoms are very heterogeneous and present as a
      severe neonatal-onset or a late-onset form. It is caused by a deficiency of
      propionyl-CoA carboxylase (PCC, EC 6.4.1.3), a biotin-dependent enzyme that
      catalyzes the carboxylation of propionyl-CoA to D-methylmalonyl-CoA. PCC is a
      heteropolymeric enzyme composed of alpha- and beta-subunits. A greater
      heterogeneity is observed in the PCCA gene, while for the PCCB gene, a limited
      number of mutations is responsible for the majority of the alleles characterized
      in both Caucasian and Oriental populations. We identified eight Korean patients
      with PA by organic acid analysis confirmed in five patients by the PCC enzyme
      assay in the lymphoblasts. Two neonatal-onset patients showed undetectable PCC
      activities while three cases with residual enzyme activities had relatively late
      manifestations. In the molecular analysis, we identified five novel mutations,
      Y439C, 1527del3, 1357insT, IVS12-8T-->A, and 31del10, and one known mutation,
      T428I in PCCB gene. Alleleic frequency of T428I in Korean patients with PA was
      56.3% in this study. Two neonatal-onset patients with null enzyme activities were
      homozygotes with 1527del3 and T428I, respectively. This finding implies that
      T428I and 1527del3 mutation could be responsible for their severe clinical
      courses and null enzyme activities. The mRNA of PCCB gene in T428I and 1527del3
      homozygotes were normal but in Western blot analysis, the betaPCC-subunit was
      only absent in 1527del3 homozygote patient suggesting different molecular
      pathology.

PMID- 12409269
TI  - Biochemical defects in eight SRY missense mutations causing XY gonadal
      dysgenesis.
AB  - Sex determining Region of the Y chromosome (SRY) is the Y-borne gene required for
      male sex determination. Many XY females with complete gonadal dysgenesis carry
      SRY mutations. We describe here the effects of eight clinically isolated point
      mutations on the DNA-binding and -bending functions of SRY. We found that the
      seven mutations in the HMG domain affected the protein's DNA-binding and -bending
      activities to varying degrees, although all cause complete gonadal dysgenesis.
      DNA binding was abolished by the R75N and L94P mutations, severely disrupted by
      the F67V mutation and reduced by the M64R (6-fold), R76P (4-fold), A113T (3
      fold), and M78T (1.7-fold) mutations. Of these, variant M64R showed no DNA
      bending activity, while M78T caused a mild reduction in DNA bending. The S18N
      mutation, a familial mutation that lies outside the HMG domain and caused partial
      gonadal dysgenesis in one patient, had minimal effect on DNA binding and bending.
      Analysis of the NMR solution structure of the SRY HMG domain bound to DNA
      suggests that mutations disrupt the protein's conformation (helicity, packing),
      or interactions at the DNA interface. The degree to which mutations causing
      complete gonadal dysgenesis affect the DNA-binding activity varies. We propose
      that there is a threshold level of SRY activity or expression required for testis
      determination, as we observe that familial mutations have the least effect on SRY
      activity.

PMID- 12409270
TI  - Association of the acid phosphatase (ACP1) gene with triglyceride levels in obese
      women.
AB  - The acid phosphatase (ACP1) locus codes for a low molecular weight protein
      tyrosine phosphatase (LMPTP) that is found ubiquitously in human tissues. The *A
      allele of the ACP1 gene is associated with lower total enzymatic activity than
      the *B and *C alleles. An association between the *A allele and extreme values of
      body-mass-index (BMI) and dyslipidemia has previously been described in several
      samples of obese subjects from the Italian population. In the present study, we
      investigated the relationship between ACP1 *A allele genotypes (*A/*A, *A/*B, and
      *A/*C) and non-*A allele genotypes (*B/*B, *B/*C, and *C/*C) and metabolic
      variables in 277 Caucasian post-menopausal subjects consisting of 82 non-obese
      subjects (BMI</=29), 60 moderately obese (BMI 30-34) and 135 very obese
      (BMI>/=35) subjects. ACP1 genotypes were found to be significantly associated
      with total cholesterol (p</=0.002) and triglyceride (p</=0.001) levels in the
      obese and very obese women only. The significantly lower levels of triglycerides
      in *A carriers in this group suggest a protective effect of the *A allele against
      hypertriglyceridemia. It has been unclear why some individuals who gain weight
      develop dyslipidemia and other aspects of the metabolic syndrome while others do
      not. The present study suggests that those who gain weight and carry the ACP1 *A
      allele may be partially protected against developing the metabolic syndrome. The
      confirmation of ACP1 as a modifier gene of the metabolic complications could open
      the door to the prevention of the lethal complications of obesity.

PMID- 12409271
TI  - Oxygen-induced metabolic changes and transdifferentiation in immature fetal rat
      lung lipofibroblasts.
AB  - Preterm infants lack adequate surfactant production and often require oxygen
      support for adequate oxygenation. Prolonged oxygen treatment leads to the
      development of bronchopulmonary dysplasia (BPD), a disease process characterized
      by the blunting of alveolarization and proliferation of myofibroblasts. In the
      present study, we investigated metabolic adaptive changes in cultured fibroblasts
      isolated from immature (d18) and near-term (d21), fetal rat lungs in response to
      normoxic (21%) and hyperoxic (95%) exposures. We used the [1,2-13C2]D-glucose
      tracer and gas chromatography/mass spectrometry to characterize glucose carbon
      redistribution between the nucleic acid ribose, lactate, and palmitate synthetic
      pathways, and reverse transcriptase-polymerase chain reaction to assess adipose
      differentiation related protein (ADRP) mRNA expression in response to hyperoxic
      exposure. Exposure to hyperoxia at each passage caused decrease (*, p<0.05 vs.
      21% O2) in ADRP mRNA expression in the d18 fibroblasts. This passage-dependent
      transdifferentiation is accompanied by a moderate (9-20%) increase in the
      synthesis of nucleic acid ribose from glucose through the non-oxidative steps of
      the pentose cycle. In contrast, d18 fibroblasts showed over an 85% decrease in
      the de novo synthesis of palmitate from glucose, while d21 fibroblasts showed a
      less pronounced 32-38% decrease in de novo lipid synthesis in hyperoxia-exposed
      cultures. It can be concluded from these studies that: (1) there is a maturation
      dependent sensitivity to hyperoxia; (2) transdifferentiation of flbroblast as
      demonstrated by changes in ADRP expression is accompanied by metabolic enzymes
      changes affecting ribose acid synthesis from glucose, and (3) hyperoxia
      specifically inhibits lipogenesis from glucose. Hyperoxia-induced metabolic
      changes thus play a key role in the transdifferentiation of lung fibroblasts to
      myofibroblasts and the pathogenesis of BPD.

PMID- 12409272
TI  - Metabolism of platelet activating factor by intrapulmonary vascular smooth muscle
      cells. Effect of oxygen on phospholipase A2 protein expression and activities of
      acetyl-CoA acetyltransferase and cholinephosphotransferase.
AB  - We have demonstrated that platelet activating factor (PAF) plays an important
      physiological role in the maintenance of high pulmonary vascular tone in fetal
      lambs, a role attributable to increased PAF receptor binding (J. Appl. Physiol.
      85 (1998) 1079; Am J. Physiol. 278 (2000) H1168). In this study, we examined the
      possibility that increased PAF synthesis via de novo and remodeling pathways as
      well as decreased PAF catabolism in hypoxic state of fetal lungs may account for
      the PAF action in vivo. We investigated effect of oxygen tension on PAF synthesis
      by ovine fetal intrapulmonary venous (PV) and arterial (PA) smooth muscle cells
      pulsed with [3H]choline (de novo), or [3H]acetate (remodeling), while PAF
      catabolism was studied by assay of acetylhydrolase (PAF-Ah) activity. Hypoxia
      stimulated PAF synthesis by choline incorporation (pmol/10(6)cells) in both PVSMC
      (1.14+/-0.13 vs 0.53+/-0.05) and PASMC (0.39+/-0.12 vs 0.22+/-0.04). Hypoxia
      stimulated PAF synthesis via remodeling pathway only in PVSMC (408+/-32 vs 225+/
      17) which was 5-fold greater than in PASMC (77+/-15 vs 105+/-24), however, with
      A23187 in remodeling pathway, PAF synthesis increased 5-fold compared to baseline
      conditions and then synthesis in hypoxia was greater than in normoxia in both
      cell types. Phospholipase A2 protein expression was significantly higher in
      hypoxia in both cells and was approximately 2-fold higher in PVSMC. PAF-Ah
      activity (nmol lyso-PAF/min/mg protein) was greater in hypoxia vs normoxia in
      PVSMC (0.81+/-0.24 vs 0.44+/-0.088), but in PASMC activity was less in hypoxia vs
      normoxia (1.68+/-0.24 vs 3.93+/-0.44). Compared to PVSMC PAF-Ah activity in PASMC
      was 4-fold higher in hypoxia. Our data demonstrate that (1) PAF synthesis in
      intrapulmonary SMC of fetal lambs occurs by both de novo studied by choline
      incorporation and remodeling pathways, the latter being predominant. (2) There is
      heterogeneity in PAF synthetic and catabolic activities in lung vasculature of
      fetal lambs. We conclude that increased PAF synthesis in veins by the two
      synthetic pathways coupled with decreased catabolism will result in a higher
      venous PAF levels in the hypoxic environment of fetal lungs. We speculate that in
      vivo, a high PAF level in veins will make more PAF available for binding to its
      receptors so as to sustain the desired high venous tone in the fetal pulmonary
      circulation.

PMID- 12409273
TI  - Novel missense mutation (Y24H) in the G6PT1 gene causing glycogen storage disease
      type 1b.
AB  - We describe a Chinese patient with glycogen storage disease type 1b presenting
      with failure to thrive and protuberant abdomen. The neutropenia was mild and the
      patient did not have fasting hypoglycemia. Direct DNA sequencing of the G6PT1
      gene revealed the patient to be a compound heterozygote of a novel missense
      mutation, Y24H, and another missense mutation, P191L, which we had described
      previously. The mother is heterozygous for the Y24H mutation and the father is
      heterozygous for the P191L mutation. Y24H and P191L may be ethnic-specific
      mutations as they have not been reported in other populations. The DNA-based
      diagnosis of GSD 1b will enable us to make an accurate determination of carrier
      status and to perform prenatal diagnosis of this disease.

PMID- 12409274
TI  - Four novel mutations associated with autosomal recessive inclusion body myopathy
      (MIM: 600737).
AB  - Recently, mutations in the gene encoding for the bi-functional enzyme UDP-N
      acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE/MNK), symbol GNE or
      GLCNE (MIM: 603824) [EC 5.1.3.14], were associated with IBM2 (MIM: 600737). IBM2
      is a recessively inherited vacuolar myopathy with a prevalence rate of 1-2/1000
      amongst people of Iranian-Jewish descent. Seven missense mutations were
      previously described by Eisenberg et al. All families tested from Iranian and
      Middle Eastern Jewish ancestry have the same homozygous mutation (bp2186t>c).
      Here we review the mutations in GNE associated with IBM2, and we describe
      additional four mutations found in individuals suffering from clinically similar
      disorder who are not of Iranian or Jewish descent. These findings further confirm
      that homozygous or compound heterozygous mutations of GNE/MNK gene associated
      with IBM2 are not confined to any single specific region of the enzyme outside
      its negative feedback regulatory domain located at codons 249-275.

PMID- 12409275
TI  - Analysis of the coxsackievirus B-adenovirus receptor gene in patients with
      myocarditis or dilated cardiomyopathy.
AB  - Myocarditis and dilated cardiomyopathy (DCM) are common causes of morbidity and
      mortality in children and adults, most commonly due to infection with
      coxsackievirus B or adenovirus. Increased expression of the common human
      coxsackievirus B-adenovirus receptor (CAR) has been reported in patients with
      DCM. We investigated the CAR gene in patients with acquired or familial
      myocarditis/DCM for mutations/polymorphisms. Several polymorphisms or intronic
      substitutions, distant from the intron-exon boundaries, were identified but no
      mutations. Based upon these data it appears that CAR gene mutations are not a
      major host determinant in the development of myocarditis and DCM.

PMID- 12409276
TI  - Two novel genetic lesions and a common BH4-responsive mutation of the PAH gene in
      Italian patients with hyperphenylalaninemia.
AB  - Hyperphenylalaninemia (HPA), due to a deficiency of phenylalanine hydroxylase
      (PAH) enzyme, is caused by mutations in the PAH gene. Molecular analysis in 23
      Italian patients with PAH deficiency identified two novel (P281R, L287V) and 20
      previously described genetic lesions in the PAH gene. The detection of the A403V
      amino acid substitution in combination with null mutations in patients with BH4
      responsive PAH deficiency leads us to correlate it with BH4 responsiveness.

PMID- 12409277
TI  - Chronic hyperosmolarity mediates constitutive expression of molecular chaperones
      and resistance to injury.
AB  - Renal medullary cells are exposed to elevated and variable osmolarities and low
      oxygen tension. Despite the harsh environment, these cells are resistant to the
      effects of many harmful events. To test the hypothesis that this resistance is a
      consequence of these cells developing a stress tolerance phenotype to survive in
      this milieu, we created osmotically tolerant cells [hypertonic (HT) cells] by
      gradually adapting murine inner medullary collecting duct 3 cells to hyperosmotic
      medium containing NaCl and urea. HT cells have a reduced DNA synthesis rate, with
      the majority of cells arrested in the G(0)/G(1) phase of the cell cycle, and show
      constitutive expression of heat shock protein 70 that is proportional to the
      degree of hyperosmolarity. Unlike acute hyperosmolarity, chronic hyperosmolarity
      failed to activate MAPKs. Moreover, HT cells acquired protein translational
      tolerance to further stress treatment, suggesting that HT cells have an
      osmotolerant phenotype that is analogous to thermotolerance but is a permanent
      condition. In addition to osmotic shock, HT cells were more resistant to heat,
      H(2)O(2), cyclosporin, and apoptotic inducers, compared with isotonic murine
      inner medullary duct 3 cells, but less resistant to amphotericin B and cadmium.
      HT cells demonstrate that in renal medullary cells, hyperosmotic stress activates
      biological processes that confer cross-tolerance to other stressful conditions.

PMID- 12409278
TI  - Dissociation of spectrin-ankyrin complex as a basis for loss of Na-K-ATPase
      polarity after ischemia.
AB  - The polarized distribution of Na-K-ATPase at the basolateral membranes of renal
      tubule epithelial cells is maintained via a tethering interaction with the
      underlying spectrin-ankyrin cytoskeleton. In this study, we have explored the
      mechanism underlying the loss of Na-K-ATPase polarity after ischemic injury in
      Madin-Darby canine kidney (MDCK) cells, utilizing a novel antibody raised against
      a recently described kidney-specific isoform of ankyrin. In control MDCK cells,
      ankyrin was colocalized with Na-K-ATPase at the basolateral membrane. ATP
      depletion resulted in a duration-dependent mislocation of Na-K-ATPase and ankyrin
      throughout the cytoplasm. Colocalization studies showed a partial overlap between
      the distribution of ankyrin and Na-K-ATPase at all periods after ATP depletion.
      By immunoprecipitation with anti-ankyrin antibody, the mislocated Na-K-ATPase
      remained bound to ankyrin at all time points after ATP depletion. However, the
      interaction between ankyrin and spectrin was markedly diminished within 3 h of
      ATP depletion and was completely lost after 6 h. In solution binding assays using
      a fusion peptide of glutathione S-transferase with the ankyrin binding domain of
      Na-K-ATPase, a complex with ankyrin was detected at all time points after ATP
      depletion, but spectrin was lost from the complex in a duration-dependent manner.
      The loss of spectrin binding was not attributable to spectrin degradation but was
      associated with hyperphosphorylation of ankyrin. The results suggest that a
      dissociation of the membrane-cytoskeleton complex at the spectrin-ankyrin
      interface may contribute to the loss of Na-K-ATPase polarity after ischemic
      injury and reaffirm a critical adapter role for ankyrin in the normal maintenance
      of Na-K-ATPase polarity.

PMID- 12409279
TI  - Renal expression of novel Na+/H+ exchanger isoform NHE8.
AB  - Although Na(+)/H(+) exchanger isoform 3 (NHE3) mediates most Na(+)/H(+) exchange
      in the proximal tubule, studies of NHE3/NHE2 null mice suggest residual Na(+)
      dependent proton secretion (Choi JY, Shah M, Lee MG, Schultheis PJ, Shull GE,
      Muallem S, and Baum M. J Clin Invest 105: 1141-1146, 2000). To characterize
      additional NHE isoforms that might be expressed in the kidney, we identified the
      partial sequence of a novel NHE. PCR was used to define the 5'- and 3'-ends, and
      a cDNA encoding the complete open reading frame was amplified from mouse kidney.
      The predicted protein of 576 amino acids, which we have named NHE8, has 30-35%
      amino acid identity to known mammalian isoforms (NHE1-7) but has >50% identity to
      Drosophila melanogaster "NHE1," suggesting it is the mammalian ortholog of this
      ancient invertebrate isoform. Northern blot of mouse tissues revealed ubiquitous
      expression. Western blot using anti-NHE8 antibodies demonstrated protein
      expression in apical membranes purified from rat renal cortex by divalent cation
      precipitation. In situ hybridization revealed that NHE8 message was present in
      both cortex and medulla. In the cortex, NHE8 was present in the majority of
      cortical tubules, consistent with proximal tubule (S1 and S2) localization. In
      the medulla, NHE8 message was most highly expressed in the proximal tubules (S3)
      of the outer stripe of the outer medulla. Thus NHE8 is expressed in the proximal
      tubule, where it may contribute to apical membrane ion transport.

PMID- 12409280
TI  - Expression of 5-HT3 receptors by extrinsic duodenal afferents contribute to
      intestinal inhibition of gastric emptying.
AB  - Intestinal perfusion with carbohydrates inhibits gastric emptying via vagal and
      spinal capsaicin-sensitive afferent pathways. The aim of the present study was to
      determine the role of 1) 5-hydroxytryptamine (5-HT)(3) receptors (5-HT(3)R) in
      mediating glucose-induced inhibition of gastric emptying and 2) 5-HT(3)R
      expression in vagal and spinal afferents in innervating the duodenum. In awake
      rats fitted with gastric and duodenal cannulas, perfusion of the duodenum with
      glucose (50 and 100 mg) inhibited gastric emptying. Intestinal perfusion of
      mannitol inhibited gastric emptying only at the highest concentration (990
      mosm/kgH(2)O). Pretreatment with the 5-HT(3)R antagonist tropisetron abolished
      both glucose- and mannitol-induced inhibition of gastric emptying. Retrograde
      labeling of visceral afferents by injection of dextran-conjugated Texas Red into
      the duodenal wall was used to identify extrinsic primary afferents.
      Immunoreactivity for 5-HT(3)R, visualized with an antibody directed to the COOH
      terminus of the rat 5-HT(3)R, was found in >80% of duodenal vagal and spinal
      afferents. These results show that duodenal extrinsic afferents express 5-HT(3)R
      and that the receptor mediates specific glucose-induced inhibition of gastric
      emptying. These findings support the hypothesis that enterochromaffin cells in
      the intestinal mucosa release 5-HT in response to glucose, which activates 5
      HT(3)R on afferent nerve terminals to evoke reflex changes in gastric motility.
      The primary glucose sensors of the intestine may be mucosal enterochromaffin
      cells.

PMID- 12409281
TI  - High-fat diet effects on gut motility, hormone, and appetite responses to
      duodenal lipid in healthy men.
AB  - There is evidence that gastrointestinal function adapts in response to a high-fat
      (HF) diet. This study investigated the hypothesis that an HF diet modifies the
      acute effects of duodenal lipid on appetite, antropyloroduodenal pressures,
      plasma CCK and plasma glucagon-like peptide-1 (GLP-1) levels in humans. Twelve
      healthy men were studied twice in randomized, crossover fashion. The effects of a
      90-min duodenal lipid infusion (6.3 kJ/min) on the above parameters were assessed
      immediately following 14-day periods on either an HF or a low-fat (LF) diet.
      After the HF diet, pyloric tonic and phasic pressures were attenuated, and the
      number of antropyloroduodenal pressure-wave sequences was increased when compared
      with the LF diet. Plasma CCK and GLP-1 levels did not differ between the two
      diets. Hunger was greater during the lipid infusion following the HF diet, but
      there was no difference in food intake. Therefore, exposure to an HF diet for 14
      days attenuates the effects of duodenal lipid on antropyloroduodenal pressures
      and hunger without affecting food intake or plasma hormone levels.

PMID- 12409282
TI  - Mechanisms underlying increases in SR Ca2+-ATPase activity after exercise in rat
      skeletal muscle.
AB  - Prolonged exercise followed by a brief period of reduced activity has been shown
      to result in an overshoot in maximal sarcoplasmic reticulum (SR) Ca(2+)-ATPase
      activity [maximal velocity (V(max))] in rat locomoter muscles (Ferrington DA,
      Reijneveld JC, Bar PR, and Bigelow DJ. Biochim Biophys Acta 1279: 203-213, 1996).
      To investigate the functional significance and underlying mechanisms for the
      increase in V(max), we analyzed Ca(2+)-ATPase activity and Ca(2+) uptake in SR
      vesicles from the fast rat gastrocnemius muscles after prolonged running (RUN)
      and after prolonged running plus 45 min of low-intensity activity (RUN+) or no
      activity (REC45) and compared them with controls (Con). Although no differences
      were observed between RUN and Con, both V(max) and Ca(2+) uptake were higher (P <
      0.05) by 43 and 63%, respectively, in RUN+ and by 35 and 34%, respectively, in
      REC45. The increase in V(max) was accompanied by increases (P < 0.05) in the
      phosphorylated enzyme intermediate measured by [gamma-(32)P]ATP. No differences
      between groups for each condition were found for the fluorescent probes FITC and
      (N-cyclohexyl-N(1)-dimethylamino-alpha-naphthyl)carbodiimide, competitive
      inhibitors of the nucleotide-binding and Ca(2+)-binding sites on the enzyme,
      respectively. Similarly, no differences for the Ca(2+)-ATPase were observed
      between groups in nitrotyrosine and phosphoserine residues, a measure of
      nitrosylation and phosphorylation states, respectively. Western blots indicated
      no changes in relative isoform content of sarcoendoplasmic reticulum (SERCA)1 and
      SERCA2a. It is concluded that the increase in V(max) of the Ca(2+)-ATPase
      observed in recovery is not the result of changes in enzyme nitroslyation or
      phosphorylation, changes in ATP and Ca(2+)-binding affinity, or changes in
      protein content of the Ca(2+)-ATPase.

PMID- 12409283
TI  - Characterization and identification of steroid sulfate transporters of human
      placenta.
AB  - Human trophoblasts depend on the supply of external precursors, such as
      dehydroepiandrosterone-3-sulfate (DHEA-S) and 16 alpha-OH-DHEA-S, for synthesis
      of estrogens. The aim of the present study was to characterize the uptake of DHEA
      S by isolated mononucleated trophoblasts (MT) and to identify the involved
      transporter polypeptides. The kinetic analysis of DHEA-(35)S uptake by MT
      revealed a saturable uptake mechanism (K(m) = 26 microM, V(max) = 428 pmol x mg
      protein(-1) x min(-1)), which was superimposed by a nonsaturable uptake mechanism
      (diffusion constant = 1.2 microl x mg protein(-1) x min(-1)). Uptake of
      [(3)H]DHEA-S by MT was Na(+) dependent and inhibited by sulfobromophthalein
      (BSP), steroid sulfates, and probenecid, but not by steroid glucuronides,
      unconjugated steroids, conjugated bile acids, ouabain, p-aminohippurate (PAH),
      and bumetanide. MT took up [(35)S]BSP, [(3)H]estrone-sulfate, but not (3)H
      labeled ouabain, estradiol-17beta-glucuronide, taurocholate, and PAH. RT-PCR
      revealed that the organic anion-transporting polypeptides OATP-B, -D, -E, and the
      organic anion transporter OAT-4 are highly expressed, and that OATP-A, -C, -8,
      OAT-3, and Na(+)-taurocholate cotransporting polypeptide (NTCP) are not or are
      only lowly expressed in term placental tissue and freshly isolated and cultured
      trophoblasts. Immunohistochemistry of first- and third-trimester placenta
      detected OAT-4 on cytotrophoblast membranes and at the basal surface of the
      syncytiotrophoblast. Our results indicate that uptake of steroid sulfates by
      isolated MT is mediated by OATP-B and OAT-4 and suggest a physiological role of
      both carrier proteins in placental uptake of fetal-derived steroid sulfates.

PMID- 12409284
TI  - External mechanical strain regulates membrane targeting of Rho GTPases by
      controlling microtubule assembly.
AB  - Transmission of externally applied mechanical forces to the interior of a cell
      requires coordination of biochemical signaling pathways with changes in
      cytoskeletal assembly and organization. In this study, we addressed one potential
      mechanism for this signal integration by applying uniform single external
      mechanical strains to aortic smooth muscle cells (SMCs) via their adhesion
      substrate. A tensile strain applied to the substrate for 15 min significantly
      increased microtubule (MT) assembly by 32 +/- 7%, with no apparent effect on the
      cells' focal adhesions as revealed by immunofluorescence and quantitative
      analysis of Triton X-100-insoluble vinculin levels. A compressive strain
      decreased MT mass by 24 +/- 9% but did not influence the level of vinculin in
      focal adhesions. To understand the decoupling of these two cell responses to
      mechanical strain, we examined a redistribution of the small GTPases RhoA and
      Rac. Tensile strain was found to decrease the amount of membrane-associated RhoA
      and Rac by 70 +/- 9% and 45 +/- 11%, respectively, compared with static controls.
      In contrast, compressive strain increased membrane-associated RhoA and Rac levels
      by 74 +/- 17% and 36 +/- 13%, respectively. Disruption of the MT network by
      prolonged treatments with low doses of either nocodazole or paclitaxel before the
      application of strain abolished the redistribution of RhoA and Rac in response to
      the applied forces. Combined, these results indicate that the effects of
      externally applied mechanical strain on the distribution and activation of the
      Rho family GTPases require changes in the state of MT polymerization.

PMID- 12409285
TI  - Site of action of fatty acids and other charged lipids on BKCa channels from
      arterial smooth muscle cells.
AB  - Fatty acids and other negatively charged single-chain lipids increase large
      conductance Ca(2+)-activated K(+) (BK(Ca)) channel activity, whereas sphingosine
      and other positively charged single-chain lipids suppress activity. Because these
      molecules are effective on both inside-out and outside-out patches and because
      they can flip across the bilayer, the location of their site of action is
      unclear. To identify the site of action of charged lipids on this channel, we
      used two compounds that are unlikely to flip across the lipid bilayer. Palmitoyl
      coenzyme A (PCoA) was used to identify the site of action of negatively charged
      lipids, and a positively charged myristoylated pentapeptide (myr-KPRPK) was used
      to investigate the site of action of positively charged lipids. The effect of
      these compounds on channel activity was studied in excised patches using patch
      clamp techniques. In "normal" ionic strength solutions and in experiments where
      high-ionic strength solutions were used to shield membrane surface charge, PCoA
      increased channel activity only when applied to outside-out patches, suggesting
      that the site of action of negatively charged lipids is located on the outer
      surface of the membrane. A decrease in activity, similar to that of other
      positively charged lipids, was observed only when myr-KPRPK was applied to
      outside-out patches, suggesting that positively charged lipids suppress activity
      by also acting on the outer membrane surface. Some channel blockade effects of
      myr-KPRPK and KPRPK are also described. The sidedness of action suggests that
      modulation of channel activity by single-chain lipids can occur by their
      interaction with the channel protein.

PMID- 12409286
TI  - A type 1 diabetes-related protein from wheat (Triticum aestivum). cDNA clone of a
      wheat storage globulin, Glb1, linked to islet damage.
AB  - The development of autoimmune type 1 diabetes involves complex interactions among
      several genes and environmental agents. Human patients with type 1 diabetes show
      an unusually high frequency of wheat gluten-sensitive enteropathy; T-cell
      response to wheat proteins is increased in some patients, and high concentrations
      of wheat antibodies in blood have been reported. In both major models of
      spontaneous type 1 diabetes, the BioBreeding (BB) rat and non-obese diabetic
      mouse, at least half of the cases are diet-related. In studies of BB rats fed
      defined semipurified diets, wheat gluten was the most potent diabetes-inducing
      protein source. A major limitation in understanding how wheat or other dietary
      antigens affect type 1 diabetes has been the difficulty in identifying specific
      diabetes-related dietary proteins. To address this issue, we probed a wheat cDNA
      expression library with polyclonal IgG antibodies from diabetic BB rats. Three
      clones were identified, and the intensity of antibody binding to one of them,
      WP5212, was strongly associated with pancreatic islet inflammation and damage.
      The WP5212 putative protein has high amino acid sequence homology with a wheat
      storage globulin, Glb1. Serum IgG antibodies from diabetic rats and humans
      recognized low molecular mass (33-46 kDa) wheat proteins. Furthermore, antibodies
      to Glb1 protein were found in serum from diabetic patients but not in age-, sex-,
      and HLA-DQ-matched controls. This study raises the possibility that in some
      individuals, type 1 diabetes may be induced by wheat proteins. Also, it provides
      a first candidate wheat protein that is not only antigenic in diabetic rats and
      human patients but is also closely linked with the autoimmune attack in the
      pancreas.

PMID- 12409287
TI  - Molecular cloning and characterization of spurt, a human novel gene that is
      retinoic acid-inducible and encodes a secretory protein specific in upper
      respiratory tracts.
AB  - Retinoids, such as all-trans-retinoic acid, play an essential role in the
      regulation of airway epithelial cell growth, differentiation, and gene
      expression. Using cDNA microarray, we identified a clone, DD4, that contains the
      cDNA of a novel gene, spurt (secretory protein in upper respiratory tracts) that
      was significantly induced by all-trans-retinoic acid in primary cultured human
      tracheobroncheal epithelia. Two alternatively spliced spurt transcripts of 1090
      and 1035 base pairs exist that contain the same open reading frame expressing a
      256-amino acid peptide. The full-length spurt cDNA sequence spans a genomic DNA
      fragment of 7,313 bp, and the gene is located on chromosome 20q11.21. spurt mRNA
      is notably expressed at high levels in human nasal, tracheal, and lung tissues.
      In situ hybridization demonstrated that spurt message is often present in
      secretory cell types. The human spurt gene product is a secretory protein that
      contains a distinct signal peptide sequence in its first 19 amino acids. Mono
      specific antibodies were generated to characterize spurt expression. Our data
      demonstrate that spurt is secreted onto the apical side of primary human airway
      epithelial cultures and is present in clinical sputum samples. spurt gene
      expression is higher in sputum and tissue samples obtained from patients with
      chronic obstructive lung disease. Our results provide the cloning and
      characterization of this tissue-specific novel gene and its possible relationship
      with airway diseases.

PMID- 12409288
TI  - Spectroscopic observations of ferric enterobactin transport.
AB  - We characterized the uptake of ferric enterobactin (FeEnt), the native
      Escherichia coli ferric siderophore, through its cognate outer membrane receptor
      protein, FepA, using a site-directed fluorescence methodology. The experiments
      first defined locations in FepA that were accessible to covalent modification
      with fluorescein maleimide (FM) in vivo; among 10 sites that we tested by
      substituting single Cys residues, FM labeled W101C, S271C, F329C, and S397C, and
      all these exist within surface-exposed loops of the outer membrane protein. FeEnt
      normally adsorbed to the fluoresceinated S271C and S397C mutant FepA proteins in
      vivo, which we observed as quenching of fluorescence intensity, but the ferric
      siderophore did not bind to the FM-modified derivatives of W101C or F329C. These
      in vivo fluorescence determinations showed, for the first time, consistency with
      radioisotopic measurements of the affinity of the FeEnt-FepA interaction; K(d)
      was 0.2 nm by both methods. Analysis of the FepA mutants with AlexaFluor(680), a
      fluorescein derivative with red-shifted absorption and emission spectra that do
      not overlap the absorbance spectrum of FeEnt, refuted the possibility that the
      fluorescence quenching resulted from resonance energy transfer. These and other
      data instead indicated that the quenching originated from changes in the
      environment of the fluor as a result of loop conformational changes during ligand
      binding and transport. We used the fluorescence system to monitor FeEnt uptake by
      live bacteria and determined its dependence on ligand concentration, temperature,
      pH, and carbon sources and its susceptibility to inhibition by the metabolic
      poisons. Unlike cyanocobalamin transport through the outer membrane, FeEnt uptake
      was sensitive to inhibitors of electron transport and phosphorylation, in
      addition to its sensitivity to proton motive force depletion.

PMID- 12409289
TI  - Alternative core promoters regulate tissue-specific transcription from the
      autoimmune diabetes-related ICA1 (ICA69) gene locus.
AB  - Islet cell autoantigen 69-kDa (ICA69), protein product of the human ICA1 gene, is
      one target of the immune processes defining the pathogenesis of Type 1 diabetes.
      We have characterized the genomic structure and functional promoters within the
      5'-regulatory region of ICA1. 5'-RNA ligase-mediated rapid amplification of cDNA
      ends evaluation of ICA1 transcripts expressed in human islets, testis, heart, and
      cultured neuroblastoma cells reveals that three 5'-untranslated region exons are
      variably expressed from the ICA1 gene in a tissue-specific manner. Surrounding
      the transcription initiation sites are motifs characteristic of non-TATA, non
      CAAT, GC-rich promoters, including consensus Sp1/GC boxes, an initiator element,
      cAMP-responsive element-binding protein (CREB) sites, and clusters of other
      putative transcription factor sites within a genomic CpG island. Luciferase
      reporter constructs demonstrate that the first two ICA1 exon promoters
      reciprocally stimulate luciferase expression within islet- (RIN 1046-38 cells)
      and brain-derived (NMB7) cells in culture; the exon A promoter exhibits greater
      activity in islet cells, whereas the exon B promoter more efficiently activates
      transcription in neuronal cells. Mutation of a CREB site within the ICA1 exon B
      promoter significantly enhances transcriptional activity in both cell lines. Our
      basic understanding of expression from the functional core promoter elements of
      ICA1 is an important advance that will not only add to our knowledge of the ICA69
      autoantigen but will also facilitate a rational approach to discover the function
      of ICA69 and to identify relevant ICA1 promoter polymorphisms and their potential
      associations with disease.

PMID- 12409290
TI  - How does the eye breathe? Evidence for neuroglobin-mediated oxygen supply in the
      mammalian retina.
AB  - Visual performance of the vertebrate eye requires large amounts of oxygen, and
      thus the retina is one of the highest oxygen-consuming tissues of the body. Here
      we show that neuroglobin, a neuron-specific respiratory protein distantly related
      to hemoglobin and myoglobin, is present at high amounts in the mouse retina
      (approximately 100 microm). The estimated concentration of neuroglobin in the
      retina is thus about 100-fold higher than in the brain and is in the same range
      as that of myoglobin in the muscle. Neuroglobin is expressed in all neurons of
      the retina but not in the retinal pigment epithelium. Neuroglobin mRNA was
      detected in the perikarya of the nuclear and ganglion layers of the neuronal
      retina, whereas the protein was present mainly in the plexiform layers and in the
      ellipsoid region of photoreceptor inner segment. The distribution of neuroglobin
      correlates with the subcellular localization of mitochondria and with the
      relative oxygen demands, as the plexiform layers and the inner segment consume
      most of the retinal oxygen. These findings suggest that neuroglobin supplies
      oxygen to the retina, similar to myoglobin in the myocardium and the skeletal
      muscle.

PMID- 12409291
TI  - The Cdc42 binding and scaffolding activities of the fission yeast adaptor protein
      Scd2.
AB  - The small GTP-binding protein Cdc42, the guanine nucleotide exchange factor Scd1,
      the p21-activated kinase Shk1, and the adaptor protein Scd2 are involved in the
      Cdc42-dependent signaling cascade in fission yeast. In the present study, we
      analyzed the Cdc42 binding and scaffolding activities of Scd2 by co-precipitation
      assays. We found that two SH3-containing regions, amino acid residues 1-87 (CB1
      (Cdc42-binding region 1)) and 110-266 (CB2), of Scd2 can bind to the GTP-bound
      form of Cdc42. CB2 is cryptic because of the intramolecular binding between the
      SH3 domain in CB2 (SH3(C)) and the PX domain and binds to Cdc42 only when the
      Scd2 PB1 domain binds to the PC motif-containing region (residues 760-872) of
      Scd1. This CB2.Cdc42 association, which would stabilize the open configuration of
      Scd2, enables the SH3(C) domain to bind to the polyproline motif of Shk1. We also
      found that the GTP-bound form of Cdc42 binds to the CRIB motif of Shk1 more
      strongly than to Scd2. Thus, Scd2 functions as a scaffold to form a protein
      complex, and the GTP-bound Cdc42 might be transferred effectively from the
      upstream activator Scd1 to the downstream effector Shk1 via Scd2.

PMID- 12409292
TI  - Glucagon-like peptide-1 receptor signaling modulates beta cell apoptosis.
AB  - Glucagon-like peptide-1 (GLP-1) stimulates insulin secretion and augments beta
      cell mass via activation of beta cell proliferation and islet neogenesis. We
      examined whether GLP-1 receptor signaling modifies the cellular susceptibility to
      apoptosis. Mice administered streptozotocin (STZ), an agent known to induce beta
      cell apoptosis, exhibit sustained improvement in glycemic control and increased
      levels of plasma insulin with concomitant administration of the GLP-1 agonist
      exendin-4 (Ex-4). Blood glucose remained significantly lower for weeks after
      cessation of exendin-4. STZ induced beta cell apoptosis, which was significantly
      reduced by co-administration of Ex-4. Conversely, mice with a targeted disruption
      of the GLP-1 receptor gene exhibited increased beta cell apoptosis after STZ
      administration. Exendin-4 directly reduced cytokine-induced apoptosis in purified
      rat beta cells exposed to interleukin 1beta, tumor necrosis fator alpha, and
      interferon gamma in vitro. Furthermore, Ex-4-treated BHK-GLP-1R cells exhibited
      significantly increased cell viability, reduced caspase activity, and decreased
      cleavage of beta-catenin after treatment with cycloheximide in vitro. These
      findings demonstrate that GLP-1 receptor signaling directly modifies the
      susceptibility to apoptotic injury, and provides a new potential mechanism
      linking GLP-1 receptor activation to preservation or enhancement of beta cell
      mass in vivo.

PMID- 12409293
TI  - 20 S proteasome from Saccharomyces cerevisiae is responsive to redox
      modifications and is S-glutathionylated.
AB  - The 20 S proteasome core purified from Saccharomyces cerevisiae is inhibited by
      reduced glutathione (GSH), cysteine (Cys), or the GSH precursor gamma
      glutamylcysteine. Chymotrypsin-like activity was more affected by GSH than
      trypsin-like activity, whereas the peptidylglutamyl-hydrolyzing activity (caspase
      like) was not inhibited by GSH. Cys-sulfenic acid formation in the 20 S core was
      demonstrated by spectral characterization of the Cys-S(O)-4-nitrobenzo-2-oxa-1,3
      diazole adduct, indicating that 20 S proteasome Cys residues might react with
      reduced sulfhydryls (GSH, Cys, and gamma-glutamylcysteine) through the oxidized
      Cys-sulfenic acid form. S-Glutahionylation of the 20 S core was demonstrated in
      vitro by GSH-biotin incorporation and by decreased alkylation with
      monobromobimane. Compounds such as N-ethylmaleimide (-S-sulfhydril H alkylating),
      dimedone (-SO sulfenic acid H reactant), or 7-chloro-4-nitrobenzo-2-oxa-1,3
      diazole (either -SH or -SOH reactant) highly inhibited proteasomal chymotrypsin
      like activity. In vivo experiments revealed that 20 S proteasome extracted from
      H(2)O(2)-treated cells showed decreased chymotrypsin-like activity accompanied by
      S-glutathionylation as demonstrated by GSH release from the 20 S core after
      reduction with NaBH(4). Moreover, cells pretreated with H(2)O(2) showed decreased
      reductive capacity assessed by determination of the GSH/oxidized glutathione
      ratio and increased protein carbonyl levels. The present results indicate that at
      the physiological level the yeast 20 S proteasome is regulated by its sulfhydryl
      content, thereby coupling intracellular redox signaling to proteasome-mediated
      proteolysis.

PMID- 12409294
TI  - Ca2+/cAMP response element-binding protein (CREB)-dependent activation of Per1 is
      required for light-induced signaling in the suprachiasmatic nucleus circadian
      clock.
AB  - Light is a prominent stimulus that synchronizes endogenous circadian rhythmicity
      to environmental light/dark cycles. Nocturnal light elevates mRNA of the Period1
      (Per1) gene and induces long term state changes, expressed as phase shifts of
      circadian rhythms. The cellular mechanism for Per1 elevation and light-induced
      phase advance in the suprachiasmatic nucleus (SCN), a process initiated primarily
      by glutamatergic neurotransmission from the retinohypothalamic tract, was
      examined. Glutamate (GLU)-induced phase advances in the rat SCN were blocked by
      antisense oligodeoxynucleotide (ODN) against Per1 and Ca(2+)/cAMP response
      element (CRE)-decoy ODN. CRE-decoy ODN also blocked light-induced phase advances
      in vivo. Furthermore, the CRE-decoy blocked GLU-induced accumulation of Per1
      mRNA. Thus, Ca(2+)/cAMP response element-binding protein (CREB) and Per1 are
      integral components of the pathway transducing light-stimulated GLU
      neurotransmission into phase advance of the circadian clock.

PMID- 12409295
TI  - Folding and function of the troponin tail domain. Effects of cardiomyopathic
      troponin T mutations.
AB  - Troponin contains a globular Ca(2+)-binding domain and an elongated tail domain
      composed of the N terminus of subunit troponin T (TnT). The tail domain anchors
      troponin to tropomyosin and actin, modulates myosin function, and is a site of
      cardiomyopathy-inducing mutations. Critical interactions between tropomyosin and
      troponin are proposed to depend on tail domain residues 112-136, which are highly
      conserved across phyla. Most cardiomyopathy mutations in TnT flank this region.
      Three such mutations were examined and had contrasting effects on peptide TnT-(1
      156), promoting folding and thermal stability assessed by circular dichroism
      (F110I) or weakening folding and stability (T104V and to a small extent R92Q).
      Folding of both TnT-(1-156) and whole troponin was promoted by replacing bovine
      TnT Thr-104 with human TnT Ala-104, further indicating the importance of this
      cardiomyopathy site residue for protein folding. Mutation F110I markedly
      stabilized the troponin tail but weakened binding of holo-troponin to actin
      tropomyosin 8-fold, suggesting that loss of flexibility impairs troponin tail
      function. The effect of the F110I mutation on troponin-tropomyosin binding to
      actin was much less, indicating this flexibility is particularly important for
      the interactions of troponin with tropomyosin. We suggest that most
      cardiomyopathic mutations in the troponin tail alter muscle function indirectly,
      by perturbing interactions between troponin and tropomyosin requisite for the
      complex effects of these proteins on myosin.

PMID- 12409296
TI  - Antitumor effects of photodynamic therapy are potentiated by 2-methoxyestradiol.
      A superoxide dismutase inhibitor.
AB  - Photodynamic therapy (PDT), a promising therapeutic modality for the management
      of solid tumors, is a two-phase treatment consisting of a photosensitizer and
      visible light. Increasing evidence indicates that tumor cells in regions exposed
      to sublethal doses of PDT can respond by rescue responses that lead to
      insufficient cell death. We decided to examine the role of superoxide dismutases
      (SODs) in the effectiveness of PDT and to investigate whether 2-methoxyestradiol
      (2-MeOE(2)), an inhibitor of SODs, is capable of potentiating the antitumor
      effects of this treatment regimen. In the initial experiment we observed that PDT
      induced the expression of MnSOD but not Cu,Zn-SOD in cancer cells. Pretreatment
      of cancer cells with a cell-permeable SOD mimetic, Mn(II)-tetrakis(4-benzoic
      acid)porphyrin chloride, and transient transfection with the MnSOD gene resulted
      in a decreased effectiveness of PDT. Inhibition of SOD activity in tumor cells by
      preincubation with 2-MeOE(2) produced synergistic antitumor effects when combined
      with PDT in 3 murine and 5 human tumor cell lines. The combination treatment was
      also effective in vivo producing retardation of the tumor growth and prolongation
      of the survival of tumor-bearing mice. We conclude that inhibition of MnSOD
      activity by 2-MeOE(2) is an effective treatment modality capable of potentiating
      the antitumor effectiveness of PDT.

PMID- 12409297
TI  - Dissociation of intact Escherichia coli ribosomes in a mass spectrometer.
      Evidence for conformational change in a ribosome elongation factor G complex.
AB  - We used mass spectrometry to identify proteins that are released in the gas phase
      from Escherichia coli ribosomes in response to a range of different solution
      conditions and cofactor binding. From solution at neutral pH the spectra are
      dominated by just 4 of the 54 ribosomal proteins (L7/L12, L11, and L10). Lowering
      the pH of the solution leads to the gas phase dissociation of four additional
      proteins as well as the 5 S RNA. Replacement of Mg(2+) by Li(+) ions in solutions
      of ribosomes induced the dissociation of 17 ribosomal proteins. Correlation of
      these results with available structural information for ribosomes revealed that a
      relatively high interaction surface area of the protein with RNA was the major
      force in preventing dissociation. By using the proteins that dissociate to probe
      their interactions with RNA, we examined different complexes of the ribosome
      formed with the elongation factor G and inhibited by fusidic acid or
      thiostrepton. Mass spectra recorded for the fusidic acid-inhibited complex reveal
      subtle changes in peak intensity of the proteins that dissociate. By contrast gas
      phase dissociation from the thiostrepton-inhibited complex is markedly different
      and demonstrates the presence of L5 and L18, two proteins that interact
      exclusively with the 5 S RNA. These results allow us to propose that the ribosome
      elongation factor-G complex inhibited by thiostrepton, but not fusidic acid,
      involves destabilization of 5 S RNA-protein interactions.

PMID- 12409298
TI  - Gamma 1 subunit interactions within the skeletal muscle L-type voltage-gated
      calcium channels.
AB  - Voltage-gated calcium channels mediate excitationcontraction coupling in the
      skeletal muscle. Their molecular composition, similar to neuronal channels,
      includes the pore-forming alpha(1) and auxiliary alpha(2)delta, beta, and gamma
      subunits. The gamma subunits are the least characterized, and their subunit
      interactions are unclear. The physiological importance of the neuronal gamma is
      emphasized by epileptic stargazer mice that lack gamma(2). In this study, we
      examined the molecular basis of interaction between skeletal gamma(1) and the
      calcium channel. Our data show that the alpha(1)1.1, beta(1a), and alpha(2)delta
      subunits are still associated in gamma(1) null mice. Reexpression of gamma(1) and
      gamma(2) showed that gamma(1), but not gamma(2), incorporates into gamma(1) null
      channels. By using chimeric constructs, we demonstrate that the first half of the
      gamma(1) subunit, including the first two transmembrane domains, is important for
      subunit interaction. Interestingly, this chimera also restores calcium
      conductance in gamma(1) null myotubes, indicating that the domain mediates both
      subunit interaction and current modulation. To determine the subunit of the
      channel that interacts with gamma(1), we examined the channel in muscular
      dysgenesis mice. Cosedimentation experiments showed that gamma(1) and
      alpha(2)delta are not associated. Moreover, alpha(1)1.1 and gamma(1) subunits
      form a complex in transiently transfected cells, indicating direct interaction
      between the gamma(1) and alpha(1)1.1 subunits. Our data demonstrate that the
      first half of gamma(1) subunit is required for association with the channel
      through alpha(1)1.1. Because subunit interactions are conserved, these studies
      have broad implications for gamma heterogeneity, function and subunit association
      with voltage-gated calcium channels.

PMID- 12409299
TI  - Crystal structures of the Pyrococcus abyssi Sm core and its complex with RNA.
      Common features of RNA binding in archaea and eukarya.
AB  - The Sm proteins are conserved in all three domains of life and are always
      associated with U-rich RNA sequences. Their proposed function is to mediate RNA
      RNA interactions. We present here the crystal structures of Pyrococcus abyssi Sm
      protein (PA-Sm1) and its complex with a uridine heptamer. The overall structure
      of the protein complex, a heptameric ring with a central cavity, is similar to
      that proposed for the eukaryotic Sm core complex and found for other archaeal Sm
      proteins. RNA molecules bind to the protein at two different sites. They interact
      specifically inside the ring with three highly conserved residues, defining the
      uridine-binding pocket. In addition, nucleotides also interact on the surface
      formed by the N-terminal alpha-helix as well as a conserved aromatic residue in
      beta-strand 2 of the PA-Sm1 protein. The mutation of this conserved aromatic
      residue shows the importance of this second site for the discrimination between
      RNA sequences. Given the high structural homology between archaeal and eukaryotic
      Sm proteins, the PA-Sm1.RNA complex provides a model for how the small nuclear
      RNA contacts the Sm proteins in the Sm core. In addition, it suggests how Sm
      proteins might exert their function as modulators of RNA-RNA interactions.

PMID- 12409300
TI  - Lock and key binding of the HOX YPWM peptide to the PBX homeodomain.
AB  - HOX homeodomain proteins bind short core DNA sequences to control very specific
      developmental processes. DNA binding affinity and sequence selectivity are
      increased by the formation of cooperative complexes with the PBX homeodomain
      protein. A conserved YPWM motif in the HOX protein is necessary for cooperative
      binding with PBX. We have determined the structure of a PBX homeodomain bound to
      a 14-mer DNA duplex. A relaxation-optimized procedure was developed to measure
      DNA residual dipolar couplings at natural abundance in the 20-kDa binary complex.
      When the PBX homeodomain binds to DNA, a fourth alpha-helix is formed in the
      homeodomain. This helix rigidifies the DNA recognition helix of PBX and forms a
      hydrophobic binding site for the HOX YPWM peptide. The HOX peptide itself shows
      some structure in solution and suggests that the interaction between PBX and HOX
      is an example of "lock and key" binding. The NMR structure explains the
      requirement of DNA for the PBX-HOX interaction and the increased affinity of DNA
      binding.

PMID- 12409301
TI  - Ca2+ activates cystic fibrosis transmembrane conductance regulator- and Cl- 
      dependent HCO3 transport in pancreatic duct cells.
AB  - Pancreatic duct cells secrete bicarbonate-rich fluids, which are important for
      maintaining the patency of pancreatic ductal trees as well as intestinal
      digestive function. The bulk of bicarbonate secretion in the luminal membrane of
      duct cells is mediated by a Cl(-)-dependent mechanism (Cl(-)/HCO(3)(-) exchange),
      and we previously reported that the mechanism is CFTR-dependent and cAMP
      activated (Lee, M. G., Choi, J. Y., Luo, X., Strickland, E., Thomas, P. J., and
      Muallem, S. (1999) J. Biol. Chem. 274, 14670-14677). In the present study, we
      provide comprehensive evidence that calcium signaling also activates the same
      CFTR- and Cl(-)-dependent HCO(3)(-) transport. ATP and trypsin evoked
      intracellular calcium signaling in pancreatic duct-derived cells through the
      activation of purinergic and protease-activated receptors, respectively. Cl(
      )/HCO(3)(-) exchange activity was measured by recording pH(i) in response to [Cl(
      )](o) changes of the perfusate. In perfusate containing high concentrations of
      K(+), which blocks Cl(-) movement through electrogenic or K(+)-coupled pathways,
      ATP and trypsin highly stimulated luminal Cl(-)/HCO(3)(-) exchange activity in
      CAPAN-1 cells expressing wild-type CFTR, but not in CFPAC-1 cells that have
      defective (DeltaF508) CFTR. Notably, adenoviral transfection of wild-type CFTR in
      CFPAC-1 cells completely restored the stimulatory effect of ATP on luminal Cl(
      )/HCO(3)(-) exchange. In addition, the chelation of intracellular calcium by 1,2
      bis(2-aminophenoxy)ethane-N,N,N,N'-tetraacetic acid (BAPTA) treatment abolished
      the effect of calcium agonists on luminal Cl(-)/HCO(3)(-) exchange. These results
      provide a molecular basis for calcium-induced bicarbonate secretion in pancreatic
      duct cells and highlight the importance of CFTR in epithelial bicarbonate
      secretion induced by various stimuli.

PMID- 12409302
TI  - A nucleophilic catalysis step is involved in the hydrolysis of aryl phosphate
      monoesters by human CT acylphosphatase.
AB  - Acylphosphatase, one of the smallest enzymes, is expressed in all organisms. It
      displays hydrolytic activity on acyl phosphates, nucleoside di- and
      triphosphates, aryl phosphate monoesters, and polynucleotides, with acyl
      phosphates being the most specific substrates in vitro. The mechanism of
      catalysis for human acylphosphatase (the organ-common type isoenzyme) was
      investigated using both aryl phosphate monoesters and acyl phosphates as
      substrates. The enzyme is able to catalyze phosphotransfer from p-nitrophenyl
      phosphate to glycerol (but not from benzoyl phosphate to glycerol), as well as
      the inorganic phosphate-H(2)18O oxygen exchange reaction in the absence of
      carboxylic acids or phenols. In short, our findings point to two different
      catalytic pathways for aryl phosphate monoesters and acyl phosphates. In
      particular, in the aryl phosphate monoester hydrolysis pathway, an enzyme
      phosphate covalent intermediate is formed, whereas the hydrolysis of acyl
      phosphates seems a more simple process in which the Michaelis complex is attacked
      directly by a water molecule generating the reaction products. The formation of
      an enzyme-phosphate covalent complex is consistent with the experiments of
      isotope exchange and transphosphorylation from substrates to glycerol, as well as
      with the measurements of the Bronsted free energy relationships using a panel of
      aryl phosphates with different structures. His-25 involvement in the formation of
      the enzyme-phosphate covalent complex during the hydrolysis of aryl phosphate
      monoesters finds significant confirmation in experiments performed with the H25Q
      mutated enzyme.

PMID- 12409303
TI  - Massive telomere loss is an early event of DNA damage-induced apoptosis.
AB  - Chromosomal stability and cell viability require a proficient telomeric end
      capping function. In particular, telomere dysfunction because of either critical
      telomere shortening or because of mutation of telomere-binding proteins results
      in increased apoptosis and/or cell arrest. Here, we show that, in turn, DNA
      damage-induced apoptosis results in a dramatic telomere loss. In particular,
      using flow cytometry for simultaneous detection of telomere length and apoptosis,
      we show that cells undergoing apoptosis upon DNA damage also exhibit a rapid and
      dramatic loss of telomeric sequences. This telomere loss occurs at early stages
      of apoptosis, because it does not require caspase-3 activation, and it is induced
      by loss of the mitochondrial membrane potential (Deltapsi(m)) and production of
      reactive oxygen species. These observations suggest a direct effect of
      mitochondrial dysfunction on telomeres.

PMID- 12409304
TI  - Identification of an allosteric binding site for Zn2+ on the beta2 adrenergic
      receptor.
AB  - The activity of G protein-coupled receptors (GPCRs) can be modulated by a diverse
      spectrum of drugs ranging from full agonists to partial agonists, antagonists,
      and inverse agonists. The vast majority of these ligands compete with native
      ligands for binding to orthosteric binding sites. Allosteric ligands have also
      been described for a number of GPCRs. However, little is known about the
      mechanism by which these ligands modulate the affinity of receptors for
      orthosteric ligands. We have previously reported that Zn(II) acts as a positive
      allosteric modulator of the beta(2)-adrenergic receptor (beta(2)AR). To identify
      the Zn(2+) binding site responsible for the enhancement of agonist affinity in
      the beta(2)AR, we mutated histidines located in hydrophilic sequences bridging
      the seven transmembrane domains. Mutation of His-269 abolished the effect of
      Zn(2+) on agonist affinity. Mutations of other histidines had no effect on
      agonist affinity. Further mutagenesis of residues adjacent to His-269
      demonstrated that Cys-265 and Glu-225 are also required to achieve the full
      allosteric effect of Zn(2+) on agonist binding. Our results suggest that bridging
      of the cytoplasmic extensions of TM5 and TM6 by Zn(2+) facilitates agonist
      binding. These results are in agreement with recent biophysical studies
      demonstrating that agonist binding leads to movement of TM6 relative to TM5.

PMID- 12409305
TI  - Glycogen synthase kinase 3beta phosphorylates tau at both primed and unprimed
      sites. Differential impact on microtubule binding.
AB  - Glycogen synthase kinase 3beta (GSK3beta) phosphorylates substrates, including
      the microtubule-associated protein tau, at both primed and unprimed epitopes.
      GSK3beta phosphorylation of tau negatively regulates tau-microtubule
      interactions; however the differential effects of phosphorylation at primed and
      unprimed epitopes on tau is unknown. To examine the phosphorylation of tau at
      primed and unprimed epitopes and how this impacts tau function, the R96A mutant
      of GSK3beta was used, a mutation that prevents phosphorylation of substrates at
      primed sites. Both GSK3beta and GSK3beta-R96A phosphorylated tau efficiently in
      situ. However, expression of GSK3beta-R96A resulted in significantly less
      phosphorylation of tau at primed sites compared with GSK3beta. Conversely,
      GSK3beta-R96A phosphorylated unprimed tau sites to a significantly greater extent
      than GSK3beta. Prephosphorylating tau with cdk5/p25 impaired the ability of
      GSK3beta-R96A to phosphorylate tau, whereas GSK3beta-R96A phosphorylated
      recombinant tau to a significantly greater extent than GSK3beta. Moreover, the
      amount of tau associated with microtubules was reduced by overexpression of
      GSK3beta but only when tau was phosphorylated at primed sites, as phosphorylation
      of tau by GSK3beta-R96A did not negatively regulate the association of tau with
      microtubules. These results demonstrate that GSK3beta-mediated phosphorylation of
      tau at primed sites plays a more significant role in regulating the interaction
      of tau with microtubules than phosphorylation at unprimed epitopes.

PMID- 12409306
TI  - Identification of a novel protein kinase mediating Akt survival signaling to the
      ATM protein.
AB  - We identified a novel human AMP-activated protein kinase (AMPK) family member,
      designated ARK5, encoding 661 amino acids with an estimated molecular mass of 74
      kDa. The putative amino acid sequence reveals 47, 45.8, 42.4, and 55% homology to
      AMPK-alpha1, AMPK-alpha2, MELK, and SNARK, respectively, suggesting that it is a
      new member of the AMPK family. It has a putative Akt phosphorylation motif at
      amino acids 595-600, and Ser(600) was found to be phosphorylated by active Akt
      resulting in the activation of kinase activity toward the SAMS peptide, a
      consensus AMPK substrate. During nutrient starvation, ARK5 supported the survival
      of cells in an Akt-dependent manner. In addition, we also demonstrated that ARK5,
      when activated by Akt, phosphorylated the ATM protein that is mutated in the
      human genetic disorder ataxia-telangiectasia and also induced the phosphorylation
      of p53. On the basis of our current findings, we propose that a novel AMPK family
      member, ARK5, is the tumor cell survival factor activated by Akt and acts as an
      ATM kinase under the conditions of nutrient starvation.

PMID- 12409307
TI  - Protein kinase C (PKC) phosphorylation of the Ca2+ o-sensing receptor (CaR)
      modulates functional interaction of G proteins with the CaR cytoplasmic tail.
AB  - The extracellular calcium (Ca(2+)(o))-sensing receptor (CaR) activates Ca(2+)
      influx independent of the release of intracellular Ca(2+) stores. The latter can
      be negatively regulated by protein kinase C (PKC) through phosphorylation of Thr
      888 of the CaR. In this study, we substituted Thr-888 with various amino acid
      residues or a stop codon to understand how PKC phosphorylation of the CaR
      inhibits receptor-mediated release of intracellular Ca(2+) stores. Substitutions
      of Thr-888 with hydrophobic and hydrophilic amino acid residues had various
      effects on CaR-mediated release of intracellular Ca(2+) stores as well as
      activation of Ca(2+) influx. Several point mutations, such as T888D, had marked
      negative effects on CaR-mediated release of intracellular Ca(2+) stores but not
      on phorbol myristate acetate-insensitive activation of Ca(2+) influx. Presumably,
      the negatively charged aspartate mimics phospho-threonine. Interestingly,
      truncating the receptor at 888 had an even more pronounced negative effect on CaR
      elicited release of intracellular Ca(2+) stores without significantly affecting
      CaR-mediated activation of Ca(2+) influx. Therefore, truncation at position 888
      of the CaR affects the activity of the receptor in a manner that resembles PKC
      phosphorylation of the CaR. This in turn suggests that PKC phosphorylation of the
      CaR prevents G protein subtypes from interacting with the region of the receptor
      critical for releasing Ca(2+) stores, which is missing in the truncated receptor.

PMID- 12409308
TI  - Salicylic acid reverses phorbol 12-myristate-13-acetate (PMA)- and tumor necrosis
      factor alpha (TNFalpha)-induced insulin receptor substrate 1 (IRS1) serine 307
      phosphorylation and insulin resistance in human embryonic kidney 293 (HEK293)
      cells.
AB  - Salicylates, including aspirin, have been shown to improve insulin sensitivity
      both in human and animal models. Although it has been suggested that salicylates
      sensitize insulin action by inhibiting IkappaB kinase beta (IKKbeta), the
      detailed mechanisms remain unclear. Protein kinase C isoforms and tumor necrosis
      factor alpha (TNFalpha) signaling pathways are well described mediators of
      insulin resistance; they are implicated in the activation of IKKbeta and the
      subsequent inhibition of proximal insulin signaling via insulin receptor
      substrate 1 (IRS1) and Akt. This study investigated the effect of salicylic acid
      on phorbol 12-myristate 13-acetate (PMA)- and TNFalpha-induced insulin resistance
      in a human embryonic kidney 293 (HEK293) cell line stably expressing recombinant
      human IRS1. The results showed that both PMA and TNFalpha inhibited insulin
      induced Akt phosphorylation and promoted IRS1 phosphorylation on Ser-307.
      Salicylic acid pretreatment completely reversed the effects of PMA and TNFalpha
      on both Akt and IRS1. Whereas PMA activated protein kinase C isoforms and
      IKKbeta, TNFalpha activated neither. On the other hand, both PMA and TNFalpha
      activated the c-Jun N-terminal kinase (JNK), which has been reported to directly
      phosphorylate IRS1 Ser-307. SP600125, a JNK inhibitor, prevented PMA and TNFalpha
      induced IRS1 Ser-307 phosphorylation. Finally, salicylic acid inhibited JNK
      activation induced by both PMA and TNFalpha. Taken together, these observations
      suggest that salicylic acid can reverse the inhibitory effects of TNFalpha on
      insulin signaling via an IKKbeta-independent mechanism(s), potentially involving
      the inhibition of JNK activation. The role of JNK in salicylic acid-mediated
      insulin sensitization, however, requires further validation because the JNK
      inhibitor SP600125 appears to have other nonspecific activity in addition to
      inhibiting JNK activity.

PMID- 12409309
TI  - Crystal structure of the (R)-specific enoyl-CoA hydratase from Aeromonas caviae
      involved in polyhydroxyalkanoate biosynthesis.
AB  - The (R)-specific enoyl coenzyme A hydratase ((R)-hydratase) from Aeromonas caviae
      catalyzes the addition of a water molecule to trans-2-enoyl coenzyme A (CoA),
      with a chain-length of 4-6 carbons, to produce the corresponding (R)-3
      hydroxyacyl-CoA. It forms a dimer of identical subunits with a molecular weight
      of about 14,000 and is involved in polyhydroxyalkanoate (PHA) biosynthesis. The
      crystal structure of the enzyme has been determined at 1.5-A resolution. The
      structure of the monomer consists of a five-stranded antiparallel beta-sheet and
      a central alpha-helix, folded into a so-called "hot dog" fold, with an
      overhanging segment. This overhang contains the conserved residues including the
      hydratase 2 motif residues. In dimeric form, two beta-sheets are associated to
      form an extended 10-stranded beta-sheet, and the overhangs obscure the putative
      active sites at the subunit interface. The active site is located deep within the
      substrate-binding tunnel, where Asp(31) and His(36) form a catalytic dyad. These
      residues are catalytically important as confirmed by site-directed mutagenesis
      and are possibly responsible for the activation of a water molecule and the
      protonation of a substrate molecule, respectively. Residues such as Leu(65) and
      Val(130) are situated at the bottom of the substrate-binding tunnel, defining the
      preference of the enzyme for the chain length of the substrate. These results
      provide target residues for protein engineering, which will enhance the
      significance of this enzyme in the production of novel PHA polymers. In addition,
      this study provides the first structural information of the (R)-hydratase family
      and may facilitate further functional studies for members of the family.

PMID- 12409310
TI  - alpha 1-Adrenergic receptor subtypes differentially control the cell cycle of
      transfected CHO cells through a cAMP-dependent mechanism involving p27Kip1.
AB  - Three distinct subtypes of alpha(1)-adrenergic receptors (alpha(1)A-, alpha(1)B-,
      and alpha(1)D-AR) play a prominent role in cell growth. However, little is known
      about subtype-specific effects on cell proliferation. The activation of alpha(1)A
      or alpha(1)B-AR inhibits serum-promoted cell proliferation, whereas alpha(1)D-AR
      activation does not show such an inhibitory effect. Notably, cell-cycle
      progression was blocked at G(1)/S transition after activation of
      alpha(1)A/alpha(1)B-AR but not of alpha(1)D-AR. In agreement with the
      differential cell proliferation effect, cAMP production was increased after
      activation of alpha(1)A/alpha(1)B-AR but not alpha(1)D-AR, whereas all alpha(1)
      AR subtypes are associated with inositol 1,4,5-trisphosphate production and
      mitogen-activated protein kinase activation in a similar fashion. Furthermore,
      the serum-induced reduction in the levels of the cyclin-dependent kinase
      inhibitor, p27(Kip1), was blocked after activation of alpha(1)A/alpha(1)B-AR but
      not alpha(1)D-AR. These results show that alpha(1)-AR subtypes differentially
      activate the cAMP/p27(Kip1) pathway and thereby have differential inhibitory
      effects on cell proliferation. Subtype-dependent effects should be taken into
      consideration when assessing the physiological response of native cells where
      alpha(1)-AR subtypes are generally co-expressed.

PMID- 12409311
TI  - Glyceroneogenesis comes of age.
AB  - Glyceroneogenesis is a generally ignored metabolic pathway that occurs in adipose
      tissues and liver of mammalian species. This short review highlights a series of
      recent discoveries showing that glyceroneogenesis is important in lipid
      homeostasis.

PMID- 12409312
TI  - Patterns of gene expression in atrophying skeletal muscles: response to food
      deprivation.
AB  - During fasting and many systemic diseases, muscle undergoes rapid loss of protein
      and functional capacity. To define the transcriptional changes triggering muscle
      atrophy and energy conservation in fasting, we used cDNA microarrays to compare
      mRNAs from muscles of control and food-deprived mice. Expression of >94% of genes
      did not change, but interesting patterns emerged among genes that were
      differentially expressed: 1) mRNAs encoding polyubiquitin, ubiquitin extension
      proteins, and many (but not all) proteasome subunits increased, which presumably
      contributes to accelerated protein breakdown; 2) a dramatic increase in mRNA for
      the ubiquitin ligase, atrogin-1, but not most E3s; 3) a significant suppression
      of mRNA for myosin binding protein H (but not other myofibrillar proteins) and
      IGF binding protein 5, which may favor cell protein loss; 4) decreases in mRNAs
      for several glycolytic enzymes and phosphorylase kinase subunits, and dramatic
      increases in mRNAs for pyruvate dehydrogenase kinase 4 and glutamine synthase,
      which should promote glucose sparing and gluconeogenesis. During fasting,
      metallothionein mRNA increased dramatically, mRNAs for extracellular matrix
      components fell, and mRNAs that may favor cap-independent mRNA translation rose.
      Significant changes occurred in mRNAs for many growth-related proteins and
      transcriptional regulators. These transcriptional changes indicate a complex
      adaptive program that should favor protein degradation and suppress glucose
      oxidation in muscle. Similar analysis of muscles atrophying for other causes is
      allowing us to identify a set of atrophy-specific changes in gene expression.

PMID- 12409313
TI  - In vivo lipid-derived free radical formation by NADPH oxidase in acute lung
      injury induced by lipopolysaccharide: a model for ARDS.
AB  - Intratracheal instillation of lipopolysaccharide (LPS) activates alveolar
      macrophages and infiltration of neutrophils, causing lung injury/acute
      respiratory distress syndrome. Free radicals are a special focus as the final
      causative molecules in the pathogenesis of lung injury caused by LPS. Although in
      vitro investigation has demonstrated radical generation after exposure of cells
      to LPS, in vivo evidence is lacking. Using electron spin resonance (ESR) and the
      spin trap alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone (POBN), we investigated
      in vivo free radical production by rats treated with intratracheal instillation
      of LPS. ESR spectroscopy of lipid extract from lungs exposed to LPS for 6 h gave
      a spectrum consistent with that of a POBN/carbon-centered radical adduct
      (aN=14.94+/-0.07 G and abetaH=2.42+/-0.06 G) tentatively assigned as a product of
      lipid peroxidation. To further investigate the mechanism of LPS-initiated free
      radical generation, rats were pretreated with the phagocytic toxicant GdCl3,
      which significantly decreased the production of radical adducts with a
      corresponding decrease in neutrophil infiltration. NADPH oxidase knockout mice
      completely blocked phagocyte-mediated, ESR-detectable radical production in this
      model of acute lung injury. Rats treated intratracheally with LPS generate lipid
      derived free radicals via activation of NADPH oxidase.

PMID- 12409314
TI  - Insulin-like growth factor binding protein 2 (IGFBP-2) separates hypertrophic and
      hyperplastic effects of growth hormone (GH)/IGF-I excess on adrenocortical cells
      in vivo.
AB  - GH and IGF-I are capable of inducing cellular hypertrophy and/or hyperplasia.
      Chronic overexpression of GH in transgenic mice results in systemically and
      locally increased IGF-I levels and in disproportionate overgrowth, including
      adrenocortical enlargement and corticosterone hypersecretion. Using PEPCK-bovine
      GH transgenic (G) mice, we demonstrate that adrenal enlargement involves both
      hypertrophy (44%) and hyperplasia (50%) of zona fasciculata cells. To clarify
      whether IGFBP-2 affected cell volume and number, we crossed hemizygous G mice
      with hemizygous CMV-IGFBP-2 transgenic (B) mice, generating G mice, B mice, GB
      double transgenic mice, and nontransgenic controls (C). The absolute weight of
      the adrenal glands was significantly increased in 5-wk- and 4-month-old G mice
      vs. C and B mice. IGFBP-2 overexpression in GB mice reduced this effect of GH
      excess by 26% and 37% in 5-wk- and 4-month-old animals, respectively. GH-induced
      hypertrophy of zona fasciculata cells was completely abolished by IGFBP-2
      overexpression in GB mice whereas hyperplasia was not affected. Basal and ACTH
      induced plasma corticosterone levels of 4-month-old G mice, but not of GB mice,
      were two- to threefold increased compared with C mice. Plasma ACTH levels were
      similar in all groups. Our data show that IGFBP-2 potently separates hypertrophic
      and hyperplastic effects of GH/IGF-I excess on adrenocortical cells.

PMID- 12409315
TI  - TNF-alpha signal transduction in rat neonatal cardiac myocytes: definition of
      pathways generating from the TNF-alpha receptor.
AB  - Cardiomyocyte hypertrophy and apoptosis have been implicated in the loss of
      contractile function during heart failure (HF). Moreover, patients with HF have
      been shown to exhibit increased levels of tumor necrosis factor alpha (TNF-alpha)
      in the myocardium. However, the multiple signal transduction pathways generating
      from the TNF-alpha receptor in cardiomyocytes and leading preferentially to
      apoptosis or hypertrophy are still unknown. Here we demonstrate in neonatal rat
      cardiomyocytes that 1) TNF-alpha induces phosphorylation of AKT, activation of NF
      kappaB, and the phosphorylation of JUN kinase; 2) blocking AKT activity prevents
      NF-kappaB activation, suggesting a role for AKT in regulating NF-kappaB function;
      3) AKT and JUN are both critical for the hypertrophic effects of TNF-alpha, since
      dominant-negative mutants of these genes are capable of inhibiting TNF-alpha
      induced ANF-promoter up-regulation and increase in cardiomyocyte cell size, and
      4) blocking NF-kappaB, AKT, or JUN alone or in combination does not sensitize
      cardiomyocytes to the proapoptotic effects of TNF-alpha, in contrast to other
      cell types, suggesting a cardiac-specific pathway regulating the anti-apoptotic
      events induced by TNF-alpha. Altogether, the data presented evidence the role of
      AKT and JUN in TNF-alpha-induced cardiomyocyte hypertrophy and apoptosis.

PMID- 12409316
TI  - High glucose-induced oxidative stress and mitochondrial dysfunction in neurons.
AB  - The current study examines the association between glucose induction of reactive
      oxygen species (ROS), mitochondrial (Mt) depolarization, and programmed cell
      death in primary neurons. In primary dorsal root ganglion (DRG) neurons, 45 mM
      glucose rapidly induces a peak rise in ROS corresponding to a 50% increase in
      mean Mt size at 6 h (P<0.001). This is coupled with loss of regulation of the Mt
      membrane potential (Mt membrane hyperpolarization, followed by depolarization,
      MMD), partial depletion of ATP, and activation of caspase-3 and -9. Glucose
      induced activation of ROS, MMD, and caspase-3 and -9 activation is inhibited by
      myxothiazole and thenoyltrifluoroacetone (P<0.001), which inhibit specific
      components of the Mt electron transfer chain. Similarly, MMD and caspase-3
      activation are inhibited by 100 microM bongkrekic acid (an inhibitor of the
      adenosine nucleotide translocase ANT). These results indicate that mild increases
      in glucose induce ROS and Mt swelling that precedes neuronal apoptosis.
      Glucotoxicity is blocked by inhibiting ROS induction, MMD, or caspase cleavage by
      specific inhibitors of electron transfer, or by stabilizing the ANT.

PMID- 12409317
TI  - Prevention of spontaneous mammary adenocarcinoma in HER-2/neu transgenic mice by
      foreign DNA.
AB  - Unmethylated CpG-oligodeoxynucleotides (CpG-ODNs) are recognized as a 'danger
      signal' and are potent immunostimulators. To test whether tumors might be
      prevented by maintaining the innate immune system on continuous alert, proto-neu
      transgenic female mice, which develop spontaneous mammary tumors, were
      systemically treated with CpG-ODNs at 10-day intervals. Tumor incidence and
      number of tumors/mouse were significantly lower in treated mice compared with the
      control group. Moreover, CpG-ODN systemic treatment significantly reduced lung
      metastases induced by intravenous inoculation of N202.1A cells derived from a
      spontaneous mammary carcinoma. Growth of established tumors was modestly
      inhibited after CpG-ODN systemic treatment but strongly on peritumoral
      application. Our data indicate that systemic repeated injection of CpG-ODN to
      maintain the innate immune system on continuous alert prevents the onset of
      genetically determined tumors and confers tumor protection when the tumor load is
      low.

PMID- 12409318
TI  - Overexpression of interleukin-15 prevents the development of murine retrovirus
      induced acquired immunodeficiency syndrome.
AB  - LP-BM5 murine leukemia virus (MuLV) infection causes murine acquired
      immunodeficiency syndrome (MAIDS), a disease characterized by varied functional
      abnormalities of immunocompetent cells. We found that MAIDS progression was
      severely retarded in IL-15 transgenic (Tg) mice constructed with cDNA encoding
      secretable IL-15 under the control of an MHC class I promoter. Several immune
      defects, including impaired natural killer activity, depressed IFN-gamma
      production by T cells stimulated with anti-T cell receptor cross-linking, and
      increased susceptibility to Mycobacterium bovis infection, were prevented in IL
      15 Tg mice inoculated with LP-BM5 MuLV. Cytotoxic T lymphocyte response to a
      highly antigenic 10-mer peptide encoded by LP-BM5-defective virus gag p12 gene
      was detected in the spleen and peritoneal exudate cells from IL-15 Tg mice
      infected with LP-BM5 MuLV. Intramuscular injection of cDNA encoding secretable IL
      15 also prevented the development of MAIDS. These results indicate that IL-15
      prevents the progression of MAIDS and may provide insight into an
      immunotherapeutic approach using the IL-15 gene for controlling retrovirus
      induced immunodeficiency.

PMID- 12409319
TI  - A fluorescent Tie1 reporter allows monitoring of vascular development and
      endothelial cell isolation from transgenic mouse embryos.
AB  - Tie1 is an endothelial receptor tyrosine kinase essential for development and
      maintenance of the vascular system. Here we report generation of transgenic mice
      expressing enhanced green fluorescent protein (EGFP) or a chimeric protein
      consisting of a Zeosin resistance marker and EGFP under the control of mouse Tie1
      promoter. Intravital monitoring of fluorescence showed that the EGFP reporter
      recapitulates the Tie1 expression pattern in the developing vasculature, and flow
      cytometry using EGFP allowed the isolation of essentially pure Tie1-expressing
      endothelial cells from transgenic mouse embryos. However, EGFP and LacZ
      transgenic markers were strongly down-regulated in the adult vasculature; unlike
      the Tie1-LacZ knock-in locus, the promoter was not reactivated during tumor
      neovascularization, indicating the presence of additional regulatory elements in
      the Tie1 locus. Starting at midgestation, Tie1 promoter activity became stronger
      in the arterial than in the venous endothelium; in adult mice, promoter activity
      was observed in arterioles, capillaries, and lymphatic vessels, indicating a
      significant degree of specificity in different types of endothelial cells. Our
      results establish Tie1-Z/EGFP transgenic mice as a useful model to study
      embryonic vascular development and a convenient source for the isolation of
      primary endothelial cells.

PMID- 12409320
TI  - Concomitant S-, N-, and heme-nitros(yl)ation in biological tissues and fluids:
      implications for the fate of NO in vivo.
AB  - There is growing evidence for the involvement of nitric oxide (NO) -mediated
      nitrosation in cell signaling and pathology. Although S-nitrosothiols (RSNOs)
      have been frequently implicated in these processes, it is unclear whether NO
      forms nitrosyl adducts with moieties other than thiols. A major obstacle in
      assessing the significance of formation of nitrosated species is the limited
      reliability of available analytical techniques for measurements in complex
      biological matrices. Here we report on the presence of nitrosated compounds in
      plasma and erythrocytes of rats, mice, guinea pigs, and monkeys under basal
      conditions, in immunologically challenged murine macrophages in vitro and
      laboratory animals in vivo. Besides RSNOs, all biological samples also contained
      mercury-stable nitroso species, indicating the additional involvement of amine
      and heme nitros(yl)ation reactions. Significant differences in the amounts and
      ratios of RSNOs over N- and heme-nitros(yl)ated compounds were found between
      species and organs. These observations were made possible by the development of a
      novel gas-phase chemiluminescence-based technique that allows detection of
      nitroso species in tissues and biological fluids without prior extraction or
      deproteinization. The method can quantify as little as 100 fmol bound NO and has
      been validated extensively for use in different biological matrices.
      Discrimination between nitrite, RSNOs, and N-nitroso or nitrosylheme compounds is
      accomplished by use of group-specific reagents. Our findings suggest that NO
      generation in vivo leads to concomitant formation of RSNOs, nitrosamines, and
      nitrosylhemes with considerable variation between rodents and primates,
      highlighting the difficulty in comparing data between different animal models and
      extrapolating results from experimental animals to human physiology.

PMID- 12409321
TI  - Loss of sarcolemma nNOS in sarcoglycan-deficient muscle.
AB  - nNOS, anchored to the sarcolemma through its interactions with the dystrophin
      glycoprotein complex, is dramatically reduced in dystrophin-deficient mdx mice
      and Duchenne muscular dystrophy patients. Recent evidence suggests that loss of
      nNOS in dystrophin-deficient muscle may contribute significantly to the
      progression of muscle pathology through a variety of mechanisms. To investigate
      whether nNOS plays a role in other forms of muscular dystrophy, we analyzed
      protein expression of nNOS in several sarcoglycan-deficient animal models of
      muscular dystrophy as well as patients with primary mutations in the sarcoglycan
      genes. Primary mutations in alpha-, beta-, delta-, and gamma-sarcoglycan result
      in autosomal recessive limb girdle muscular dystrophy (AR-LGMD). We report that
      loss of the sarcoglycan-sarcospan complex in muscle causes a dramatic reduction
      in the levels of nNOS expression at the membrane, even in the presence of normal
      dystrophin and syntrophin expression. Furthermore, we show that expression of
      three out of four sarcoglycans is not sufficient to maintain nNOS at the
      sarcolemma. Our data suggest that loss of nNOS may contribute to muscle pathology
      in AR-LGMD with primary mutations in the sarcoglycans.

PMID- 12409322
TI  - Two's company, three's a crowd: can H2S be the third endogenous gaseous
      transmitter?
AB  - Bearing the public image of a deadly "gas of rotten eggs," hydrogen sulfide (H2S)
      can be generated in many types of mammalian cells. Functionally, H2S has been
      implicated in the induction of hippocampal long-term potentiation, brain
      development, and blood pressure regulation. By acting specifically on KATP
      channels, H2S can hyperpolarize cell membranes, relax smooth muscle cells, or
      decrease neuronal excitability. The endogenous metabolism and physiological
      functions of H2S position this gas well in the novel family of endogenous gaseous
      transmitters, termed "gasotransmitters." It is hypothesized that H2S is the third
      endogenous signaling gasotransmitter, besides nitric oxide and carbon monoxide.
      This positioning of H2S will open an exciting field-H2S physiology-encompassing
      realization of the interaction of H2S and other gasotransmitters, sulfurating
      modification of proteins, and the functional role of H2S in multiple systems. It
      may shed light on the pathogenesis of many diseases related to the abnormal
      metabolism of H2S.

PMID- 12409323
TI  - CEACAM1: a marker with a difference or more of the same?

PMID- 12409324
TI  - The multifunctional, multi-institutional, and sometimes even global phase I
      study: a better life for phase I evaluations or just "living large"?

PMID- 12409325
TI  - Expression of CEACAM1 in adenocarcinoma of the lung: a factor of independent
      prognostic significance.
AB  - PURPOSE: To evaluate the prognostic relevance of CEACAM1 and sialyl Lewis X
      expression in adenocarcinomas of the lung. PATIENTS AND METHODS: Paraffin wax
      sections of 93 patients with adenocarcinomas of the lung who underwent surgery
      between 1990 and 1995 were immunohistochemically investigated using monoclonal
      anti-CEACAM1 and sialyl Lewis X antibodies. The clinical course of all patients
      was followed up for a minimum of 5 years. RESULTS: Sixty-one tumors were
      classified as CEACAM1-positive, and 32 were classified as CEACAM1-negative.
      Patients with CEACAM1-positive tumors had a significantly poorer overall (P
      =.00025) and relapse-free (P =.00029) survival than those with CEACAM1-negative
      tumors. Only three patients did not express the sialyl Lewis X glycotope, whereas
      90 tumors (97%) were sialyl Lewis X-positive. In multivariate Cox regression
      analysis, next to tumor stage and sex, only the expression of CEACAM1 was a
      significant independent prognostic factor for survival. CONCLUSION: Expression of
      CEACAM1 was an independent prognostic factor in our patient population and can be
      used to stratify patients with adenocarcinomas of the lung into low-risk and high
      risk groups. In contrast, the expression of sialyl Lewis X was of no prognostic
      relevance because it was expressed in 97% of all investigated tumors, and most
      likely has no influence on the function of CEACAM1 in this tumor entity.

PMID- 12409326
TI  - Phase III randomized trial comparing three platinum-based doublets in advanced
      non-small-cell lung cancer.
AB  - PURPOSE: To evaluate whether two commonly used newer platinum-based regimens
      offer any advantage over vinorelbine-cisplatin (reference regimen) in response
      rate for patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND
      METHODS: Chemotherapy-naive patients were randomized to receive gemcitabine 1,250
      mg/m(2) days 1 and 8 plus cisplatin 75 mg/m(2) day 2 every 21 days (GC arm), or
      paclitaxel 225 mg/m(2) (3-hour infusion) then carboplatin (area under the
      concentration-time curve of 6 mg/mL x min), both on day 1 every 21 days (PCb
      arm), or vinorelbine 25 mg/m(2)/wk for 12 weeks then every other week plus
      cisplatin 100 mg/m(2) day 1 every 28 days (VC arm). RESULTS: Six hundred twelve
      patients were randomized to treatment (205 GC, 204 PCb, and 203 VC). Overall
      response rates for the GC (30%) and PCb (32%) arms were not significantly
      different from that of the VC arm (30%). There were no differences in overall
      survival, time to disease progression, or time to treatment failure. Median
      survival for the GC, PCb, and VC groups was 9.8, 9.9, and 9.5 months,
      respectively. Neutropenia was significantly higher on the VC arm (GC 17% or PCb
      35% v VC 43% of cycles, P <.001), as was thrombocytopenia on the GC arm (GC 16% v
      VC 0.1% of cycles, P <.001). Alopecia and peripheral neurotoxicity were most
      common on the PCb arm, as was nausea/vomiting on the VC arm (P <.05). CONCLUSION:
      Efficacy end points were not significantly different between experimental and
      reference arms, although toxicities showed differences. These findings suggest
      that chemotherapy in NSCLC has reached a therapeutic plateau.

PMID- 12409327
TI  - Phase I safety, pharmacokinetic, and pharmacodynamic trial of ZD1839, a selective
      oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with
      five selected solid tumor types.
AB  - PURPOSE: To establish the safety and tolerability of ZD1839 (Iressa), a selective
      epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, and to explore
      its pharmacokinetic and pharmacodynamic effects in patients with selected solid
      tumor types. PATIENTS AND METHODS: This was a phase I dose-escalating trial of
      oral ZD1839 150 mg/d to a maximum of 1,000 mg/d given once daily for at least 28
      days. Patients with either advanced non-small-cell lung, ovarian, head and neck,
      prostate, or colorectal cancer were recruited. RESULTS: Eighty-eight patients
      received ZD1839 (150 to 1,000 mg/d). At 1,000 mg/d, five of 12 patients
      experienced dose-limiting toxicity (grade 3 diarrhea [four patients] and grade 3
      somnolence [one patient]). The most frequent drug-related adverse events (AEs)
      were acne-like rash (64%) and diarrhea (47%), which were generally mild (grade
      1/2) and reversible on cessation of treatment. No change in ZD1839 safety profile
      was observed with prolonged administration. Pharmacokinetic analysis showed
      steady-state exposure to ZD1839 in 98% of patients by day 7. Nineteen patients
      had stable disease and received ZD1839 for >or= 3 months; seven of these patients
      remained on study drug for >or= 6 months. Serial skin biopsies taken before
      treatment and at approximately day 28 revealed changes indicative of inhibition
      of the EGFR signaling pathway. CONCLUSION: ZD1839 was generally well tolerated,
      with manageable and reversible AEs at doses up to 600 mg/d and dose-limiting
      toxicity observed at 1,000 mg/d. ZD1839 treatment resulted in clinically
      meaningful disease stabilization across a range of tumor types and doses.
      Pharmacodynamic changes in skin confirmed inhibition of EGFR signaling, which was
      predicted from the mode of action of ZD1839.

PMID- 12409328
TI  - Dosage adjustment and pharmacokinetic profile of irinotecan in cancer patients
      with hepatic dysfunction.
AB  - PURPOSE: To determine the recommended dose (RD) and the pharmacokinetic profile
      of irinotecan and its metabolites in cancer patients with hyperbilirubinemia.
      PATIENTS AND METHODS: Patients were assigned to four treatment groups according
      to their baseline total bilirubin level. Patients in group I (bilirubin within
      normal range) and group II (bilirubin 1.0 to 1.5 times upper limit of normal
      [ULN]) received a dose of 350 mg/m(2) every 3 weeks. Patients in groups III
      (bilirubin 1.51 to 3.0 times ULN) and IV (bilirubin > 3.1 times ULN) received
      starting doses of 175 and 100 mg/m(2), respectively. RDs were defined according
      to the dose-limiting toxicity (DLT) experienced at cycle 1. RESULTS: Thirty-three
      patients including 21 gastrointestinal cancers were included. Grade 4 febrile
      neutropenia and diarrhea were common DLTs in patients with hyperbilirubinemia. At
      a dose of irinotecan 350 mg/m(2), DLTs were observed in two of seven and one of
      five patients in groups I and II, respectively. In group III, escalated doses of
      irinotecan 175, 200, and 240 mg/m(2) were associated with DLTs in one of seven,
      one of five, and three of six patients, respectively. No DLT was observed in
      group IV. High bilirubin and alkaline phosphatase levels were associated with an
      exponential decrease in the clearance of irinotecan. Pharmacokinetic analysis
      showed that the relative increase in exposure was likely caused by reduced
      biliary excretion. CONCLUSION: We showed that baseline total bilirubin level
      could be used to determine the appropriate dose of irinotecan in cancer patients
      with hepatic dysfunction. Doses of 350 mg/m(2) and 200 mg/m(2) were considered
      RDs in patients with bilirubin values <or= 1.5 times ULN and 1.51 to 3.0 times
      ULN, respectively.

PMID- 12409329
TI  - Randomized trial of influenza vaccine with granulocyte-macrophage colony
      stimulating factor or placebo in cancer patients.
AB  - PURPOSE: To determine whether granulocyte-macrophage colony-stimulating factor
      (GM-CSF) would improve response to influenza vaccination in cancer patients.
      PATIENTS AND METHODS: In a randomized, patient-blinded, placebo-controlled trial
      carried out in 1997 to 2000, 133 patients were stratified into five groups of
      treatment and disease. Single doses of standard split trivalent influenza vaccine
      and either placebo or 250 micro g of GM-CSF were administered at the same time.
      Hemagglutination inhibition assay titers were measured before and 4 weeks after
      vaccination. RESULTS: Standard analyses, which define response as at least a four
      fold increase in titers, detect no effect of GM-CSF for any of the three
      influenza subtypes in the trivalent vaccines (P >or=.12). Analysis that includes
      the magnitude of the change in titers and combines responses of the subtypes
      suggests that the placebo group had the greater response (P =.051), thus
      indicating that GM-CSF does not improve response. Ancillary analyses show that
      response declines both with increasing age and with higher initial titers. The
      fraction of patients with at least a four-fold increase in titers was 0.36 (95%
      confidence interval, 0.29 to 0.42) CONCLUSION: A single 250- micro g dose of GM
      CSF administered with the influenza vaccine does not improve response to
      vaccination. Response in cancer patients is low and declines as age and initial
      titer increase.

PMID- 12409330
TI  - Combination therapy with thalidomide plus dexamethasone for newly diagnosed
      myeloma.
AB  - PURPOSE: Multiple myeloma is a malignancy of plasma cells and is characterized by
      increased marrow angiogenesis. Thalidomide, an agent with antiangiogenic
      properties, is effective in relapsed myeloma. We report the results of a study
      combining thalidomide and dexamethasone as initial therapy for myeloma. PATIENTS
      AND METHODS: Fifty patients with newly diagnosed myeloma were studied.
      Thalidomide was given at a dose of 200 mg/d orally. Dexamethasone was given at a
      dose of 40 mg/d orally on days 1 to 4, 9 to 12, and 17 to 20 (odd cycles) and 40
      mg/d on days 1 to 4 (even cycles), repeated monthly. RESULTS: Of all 50 patients,
      a confirmed response was seen in 32 patients yielding a response rate of 64% (95%
      confidence interval, 49% to 77%). Thirty-one patients (62%) proceeded to stem
      cell collection after four cycles of therapy including 26 who underwent stem-cell
      transplantation and five who chose stem-cell cryopreservation. Major grade 3 or 4
      toxicities were observed in 16 patients (32%), and the most frequent were deep
      vein thrombosis (six patients), constipation (four patients), rash (three
      patients), and dyspnea (two patients). Three deaths occurred during active
      therapy because of a pancreatitis, pulmonary embolism, and infection. CONCLUSION:
      We conclude that the combination of thalidomide plus dexamethasone is a feasible
      and active regimen in the treatment of multiple myeloma. It merits further study
      as an oral alternative to infusional chemotherapy with vincristine, doxorubicin,
      and dexamethasone and other intravenous regimens currently used as
      pretransplantation induction therapy for myeloma.

PMID- 12409331
TI  - Relevance of bone marrow cell dose on allogeneic transplantation outcomes for
      patients with acute myeloid leukemia in first complete remission: results of a
      European survey.
AB  - PURPOSE: Many attempts have been made to improve the results of allogeneic bone
      marrow transplantation (alloBMT) for patients with acute myeloid leukemia (AML)
      in first complete remission (CR1). Bone marrow cell dose has been reported to be
      an important factor in alloBMT; however, its true impact on relapse incidence
      (RI), leukemia-free survival (LFS), and nonrelapse mortality (NRM) in a large
      cohort of patients is unknown. PATIENTS AND METHODS: From January 1992 to
      December 1999, 572 bone marrow transplantation recipients reported to the
      European Blood and Marrow Transplantation (EBMT) registry underwent allografting
      from an HLA-identical sibling donor with an unmanipulated bone marrow for AML in
      CR1. RESULTS: The median number of nucleated cells (NCs) infused was 2.6 x
      10(8)/kg. Estimated 5-year NRM, LFS, and RI for patients receiving more or less
      than 2.6 x 10(8) NCs/kg were, respectively, 18% +/- 5% v 30% +/- 5% (P =.001),
      68% +/- 3% v 46% +/- 3% (P <.00001), and 14% +/- 4% v 24% +/- 5% (P =.004). The
      association of cell dose with the above outcomes was confirmed in multivariate
      analyses for NRM (relative risk [RR], 0.53; P =.0007), for LFS (RR, 0.53; P
      =.00008), and for RI (RR, 0.57; P =.02). The cell dose was also an important
      factor for neutrophil (RR, 0.76; P =.009) and platelet (RR, 0.77; P =.03)
      recoveries; however, it did not statistically influence the incidence of acute
      graft-versus-host disease. CONCLUSION: This study shows that marrow cell dose is
      one of the most important factors influencing relapse, NRM, and LFS after alloBMT
      for patients with AML in CR1. Therefore, increasing the marrow cell dose should
      substantially improve the survival of these patients.

PMID- 12409332
TI  - Low sensitivity of the ki-ras polymerase chain reaction for diagnosing pancreatic
      cancer from pancreatic juice and bile: a multicenter prospective trial.
AB  - PURPOSE: Early detection of pancreatic cancer using molecular markers may improve
      outcome. Mutations of the ki-ras oncogene are detected in 70% to 90% of
      pancreatic adenocarcinomas. A prospective, partially blinded, multicenter
      diagnostic trial was performed to test the sensitivity and specificity of the ki
      ras polymerase chain reaction (PCR) analysis of pancreatic juice and bile
      specimens. PATIENTS AND METHODS: Specimens of pancreatic juice and bile were
      collected from 532 consecutive patients. Mutations in codon 12 of the ki-ras gene
      were identified by two independent enrichment PCRs and confirmed by direct
      sequencing. RESULTS: One hundred seventy-four of 532 patients were excluded from
      the final analysis (reasons: no amplifiable DNA, no specimen or only duodenal
      juice sent, lost to follow-up). Sixty-three of 358 patients had ductal pancreatic
      cancer. In 24 (38.1%) of 63 patients, a mutated ki-ras gene was identified in
      pancreatic juice and/or bile. Ki-ras mutations were found in four (8%) of 50
      cases of chronic pancreatitis, in 10 (18.7%) of 53 cases of other malignancies of
      the pancreaticobiliary tree, and in 14 (7.3%) of 192 cases of benign diseases or
      normal findings. Sensitivity and specificity of the ki-ras PCR analysis for the
      detection of pancreatic cancer was 38.1% and 90.5%, respectively. CONCLUSION: In
      this prospective trial performed in nonselected patients, mutations of the ki-ras
      gene were detected in 38.1% of cases with pancreatic cancer. This test in its
      present form is not appropriate to confirm or screen for pancreatic cancer. More
      sensitive and/or quantitative PCR tests may improve the molecular diagnosis of
      pancreatic cancer.

PMID- 12409333
TI  - Immunomagnetic enrichment and detection of micrometastases in colorectal cancer:
      correlation with established clinical parameters.
AB  - PURPOSE: Micrometastatic disease in bone marrow is of prognostic significance in
      colorectal cancer patients. However, detection rates of standard immunocytology
      are relatively low. We used magnetic activated cell sorting (MACS), a highly
      sensitive method, to increase detection rates and correlated the presence of
      cytokeratin (CK)-expressing cells with clinical parameters. PATIENTS AND METHODS:
      Bone marrow was obtained from 51 consecutive patients with newly diagnosed
      colorectal adenocarcinoma who underwent primary surgery and 18 control subjects.
      International Union Against Cancer (UICC) stage I disease was diagnosed in 11
      patients, stage II disease was diagnosed in 14 patients, stage III disease was
      diagnosed in 12 patients, and stage IV disease was diagnosed in 14 patients. CK
      positive cells were enriched and stained with magnetically labeled CAM 5.2
      antibodies directed to CK 7 and 8. RESULTS: CK-positive cells were found in 33
      (65%) patients and were absent in 18 (35%). Four of 11 (36%) patients with UICC
      stage I disease, nine of 14 (64%) with stage II diease, eight of 12 (67%) with
      stage III disease, and 12 of 14 (86%) with stage IV disease were CK-positive.
      Epithelial cells were more frequently found in pT3/4 (72%) than in pT1/2 (36%)
      tumors (P =.026), but there was no difference for lymph node status. CK-positive
      patients had a higher chance for elevated carcinoembryonic antigen (85% v 15%, P
      = NS) and CA 19-9 levels (92% v 8%, P =.019). There were no significant
      differences in CA 72-4, sex, age, tumor grading, or tumor localization regarding
      the presence of CK-positive cells. All control subjects were CK-negative.
      CONCLUSION: In searching for micrometastases in colorectal cancer patients, we
      have achieved high detection rates by using MACS. The presence of these cells
      correlated significantly with tumor stage, tumor extension, and the tumor marker
      CA 19-9.

PMID- 12409334
TI  - Primary adult soft tissue sarcoma: time-dependent influence of prognostic
      variables.
AB  - PURPOSE: To define prognostic factors for postrelapse survival and their time
      dependent influence for adult soft tissue sarcoma (STS). PATIENTS AND METHODS: We
      analyzed 2,123 patients with completely resected localized primary STS treated
      from 1982 to 1999. Variables studied included tumor site, size, depth, grade, and
      resection margin but not treatment other than resection. Landmark time frames
      were used to assess the influence of disease-free interval (DFI) on disease
      specific survival (DSS). DSS was estimated with the Kaplan-Meier method.
      Univariate and multivariate analyses were performed using log-rank test and the
      Cox proportional hazards regression model. Time-dependent stepwise regression
      analysis evaluated the time-dependent influence of each variable. RESULTS: Two
      thirds of recurrences developed within 2 years of initial resection. Tumor size
      (P <.001), grade (P <.001), and microscopic resection margin (P <.001)
      independently predicted DSS for all STS. Size and grade independently predicted
      early (DFI <or= 3 years) and margin late (DFI > 3 years) DSS. Risk of tumor
      related death was the same across all sites 3 years postresection and decreased
      significantly for extremity/trunk STS when DFI exceeded 3 years (P <.001).
      Influence of initial high-risk factors for tumor-related mortality in
      extremity/trunk STS decreased by 40% 3 years postresection, but their influence
      over DSS for non-extremity/trunk sites remained constant over time. Likelihood of
      complete resection after recurrence (all sites) increased with DFI (9% and 33%
      for DFI < 6 and > 36 months, respectively). CONCLUSION: Tumor size, grade, and
      resection margin predict outcome for completely resected STS, and their influence
      for DSS is time- and site-dependent. The influence of prognostic factors changes
      over the natural history of extremity/trunk STS. Time to recurrence exerts
      significant influence over complete resection rates for recurrent disease.

PMID- 12409335
TI  - The case identification challenge in measuring quality of cancer care.
AB  - PURPOSE: The delivery of quality care to all patients with cancer has been named
      as a national priority within the American health care system. This article
      addresses the issues critical to case identification in cancer quality
      measurement and recommends possible strategies for accurately identifying a
      population of cancer patients. METHODS: We present the measurement issues
      associated with the basic challenges of case identification strategies for
      quality measurement. We discuss two basic challenges: (1) accurately identifying
      all patients with the defining characteristics (eg, a diagnosis of breast
      cancer), and (2) identifying only patients with these characteristics. RESULTS:
      Possible options for identifying newly diagnosed patients include using claims or
      other administrative data, cancer registries, cancer registry rapid case
      ascertainment, pathology laboratories, and physicians' offices. In the published
      literature, the sensitivity of claims varies from 75% to 95%, whereas central
      registries must have a 90% completeness rate to be certified. Most of these
      approaches, however, involve limitations to obtaining valid and comparable data
      across multiple settings. CONCLUSION: Using an existing data collection system
      staffed by skilled data collectors and managers should result in substantially
      more accurate and timely data. Registry officials and the government agencies
      that provide their support should be encouraged to adopt quality-of-care analyses
      as an important purpose of the registry system and to enhance their capacity to
      rapidly ascertain cases, collect the appropriate identifying information needed
      for patient contact, and verify stage at diagnosis. In order to meet the growing
      demand for timely, accurate information about quality of care, registries are
      likely to require additional support so they can enhance their capacity to
      rapidly ascertain cases, collect the appropriate identifying information needed
      for patient contact, and verify stage at diagnosis.

PMID- 12409336
TI  - Pain and quality of life after treatment in patients with locally recurrent
      rectal cancer.
AB  - PURPOSE: Because survival in patients with locally recurrent rectal cancer (LRRC)
      is limited, pain control and quality of life (QOL) are important parameters. The
      purpose of this study was to assess the prevalence of posttreatment pain and QOL
      of patients with LRRC treated with nonsurgical palliation or resection and
      identify predictors of poor outcome. PATIENTS AND METHODS: Posttreatment pain
      severity and QOL were prospectively assessed in 45 patients with LRRC using the
      Brief Pain Inventory and Functional Assessment of Cancer Therapy-Colorectal
      questionnaire. RESULTS: Fifteen patients received nonsurgical palliation, and 30
      patients underwent resection of their pelvic tumors. There was a significant
      association between higher posttreatment pain scores and worse QOL (P <.001).
      Patients treated with nonsurgical palliation reported moderate to severe pain
      beyond the third month of treatment. Resected patients reported comparable levels
      of pain during the first 3 postoperative years, particularly after bony
      resections; long-term survivors (beyond 3 years), however, reported minimal pain
      and good QOL. Female sex, pelvic/sciatic pain at presentation, total pelvic
      exenteration, and bony resection were associated with higher rates of moderate to
      severe posttreatment pain (P =.04, P <.001, P =.04, and P =.02, respectively).
      Pain at presentation was an independent predictor of posttreatment pain (odds
      ratio, 7.4 [95% confidence interval, 1.8 to 30.3]; P =.006). CONCLUSION: Patients
      with LRRC treated with nonsurgical palliation or resection experience significant
      levels of pain after treatment. Close posttreatment pain monitoring is warranted
      in patients presenting with pelvic pain, and more aggressive pain management
      strategies may improve posttreatment QOL.

PMID- 12409337
TI  - Vascular permeability factor/vascular endothelial growth factor: a critical
      cytokine in tumor angiogenesis and a potential target for diagnosis and therapy.
AB  - Vascular endothelial growth factor A (VEGF-A), the founding member of the
      vascular permeability factor (VPF)/VEGF family of proteins, is an important
      angiogenic cytokine with critical roles in tumor angiogenesis. This article
      reviews the literature with regard to VEGF-A's multiple functions, the mechanisms
      by which it induces angiogenesis, and its current and projected roles in clinical
      oncology. VEGF-A is a multifunctional cytokine that is widely expressed by tumor
      cells and that acts through receptors (VEGFR-1, VEGFR-2, and neuropilin) that are
      expressed on vascular endothelium and on some other cells. It increases
      microvascular permeability, induces endothelial cell migration and division,
      reprograms gene expression, promotes endothelial cell survival, prevents
      senescence, and induces angiogenesis. Recently, VEGF-A has also been shown to
      induce lymphangiogenesis. Measurements of circulating levels of VEGF-A may have
      value in estimating prognosis, and VEGF-A and its receptors are potential targets
      for therapy. Recognized as the single most important angiogenic cytokine, VEGF-A
      has a central role in tumor biology and will likely have an important role in
      future approaches designed to evaluate patient prognosis. It may also become an
      important target for cancer therapy.

PMID- 12409338
TI  - Quality of breast cancer care: what do we know?
AB  - PURPOSE: To critically review studies that describe patterns of care for breast
      cancer patients and to examine the data sources used for case identification and
      determining patterns of care. METHODS: We searched the MEDLINE database (National
      Library of Medicine, Bethesda, MD) in August 2001 for studies of breast cancer
      care published from January 1985 to June 2001. Thirty-eight articles, describing
      32 studies, met the inclusion criteria for this review. RESULTS: According to the
      patterns of care literature, approximately 10% of women do not have an axillary
      lymph node dissection, 11% to 26% do not have their hormone receptor status
      reported, 20% do not receive radiation after breast-conserving surgery, and 30%
      to 70% of women with lymph node-positive breast cancer are not prescribed
      tamoxifen. Twenty-five (78%) of the studies relied on cancer registries for case
      identification. Cancer registries (47%) and the medical record (38%) were the
      most frequent sources of data on process of care. Twenty percent of the articles
      reported using more than one data source to determine patterns of care.
      CONCLUSION: Although more patterns of care research has taken place in breast
      cancer than in any other oncologic condition, we found the available data had
      many limitations. These limitations highlight the challenges of quality-of-care
      research. To track changes in the quality of cancer care that may result from our
      rapidly transforming health care system, we need reliable data on the quality of
      current practice.

PMID- 12409339
TI  - Unusual sites of involvement in non-Hodgkin's lymphoma: Case 1. Isolated orbit
      relapse after allogeneic bone marrow transplantation for malignant lymphoma.

PMID- 12409340
TI  - Unusual sites of involvement in non-Hodgkin's lymphoma: Case 2. Isolated
      meningeal anaplastic large-cell lymphoma.

PMID- 12409341
TI  - Unusual sites of involvement in non-Hodgkin's lymphoma: Case 3. Intussusception
      as a rare complication of mantle-cell lymphoma.

PMID- 12409342
TI  - Parents with cancer: who's looking after the children?

PMID- 12409343
TI  - Revisiting truth and consequences: what to do when the patient doesn't want to
      know.

PMID- 12409344
TI  - Increased risk of malignant mullerian tumor of the uterus among women with breast
      cancer treated by tamoxifen.

PMID- 12409345
TI  - Nail toxicity related to weekly taxanes: an important issue requiring a change in
      common toxicity criteria grading?

PMID- 12409346
TI  - Very-long-term survival rates of patients with cancer.

PMID- 12409347
TI  - Clinical microbiology in the year 2025.

PMID- 12409348
TI  - Comparison of Staphylococcus aureus isolates from bovine and human skin, milking
      equipment, and bovine milk by phage typing, pulsed-field gel electrophoresis, and
      binary typing.
AB  - Staphylococcus aureus isolates (n = 225) from bovine teat skin, human skin,
      milking equipment, and bovine milk were fingerprinted by pulsed-field gel
      electrophoresis (PFGE). Strains were compared to assess the role of skin and
      milking equipment as sources of S. aureus mastitis. PFGE of SmaI-digested genomic
      DNA identified 24 main types and 17 subtypes among isolates from 43 herds and
      discriminated between isolates from bovine teat skin and milk. Earlier, phage
      typing (L. K. Fox, M. Gershmann, D. D. Hancock, and C. T. Hutton, Cornell Vet.
      81:183-193, 1991) had failed to discriminate between isolates from skin and milk.
      Skin isolates from humans belonged to the same pulsotypes as skin isolates from
      cows. Milking equipment harbored strains from skin as well as strains from milk.
      We conclude that S. aureus strains from skin and from milk can both be
      transmitted via the milking machine, but that skin strains are not an important
      source of intramammary S. aureus infections in dairy cows. A subset of 142
      isolates was characterized by binary typing with DNA probes developed for typing
      of human S. aureus. Typeability and overall concordance with epidemiological data
      were lower for binary typing than for PFGE while discriminatory powers were
      similar. Within several PFGE types, binary typing discriminated between main
      types and subtypes and between isolates from different herds or sources. Thus,
      binary typing is not suitable as replacement for PFGE but may be useful in
      combination with PFGE to refine strain differentiation.

PMID- 12409349
TI  - Molecular epidemiology of pneumococcal carriage among children with upper
      respiratory tract infections in Hanoi, Vietnam.
AB  - To investigate the molecular epidemiology of pneumococcal nasopharyngeal carriage
      in Hanoi, Vietnam, we studied 84 pneumococcal strains retrieved from children
      with upper respiratory tract infections. Serotypes 23F (32%), 19F (21%), 6B
      (13%), and 14 (10%) were found most often. A significant number of strains were
      antibiotic resistant. Fifty-two percent of the strains were (intermediate)
      resistant to penicillin, 87% were (intermediate) resistant to co-trimoxazole, 76%
      were resistant to tetracycline, 73% were resistant to erythromycin, and 39% were
      (intermediate) resistant to cefotaxime. Seventy-five percent were resistant to
      three or more classes of antibiotics. A high degree of genetic heterogeneity
      among the penicillin resistance genes was observed. In addition, the tetracycline
      resistance gene tet(M) and the erythromycin resistance gene erm(B) were
      predominantly observed among the isolates. Molecular analysis of the 84 isolates
      by restriction fragment end labeling (RFEL) revealed 35 distinct genotypes.
      Twelve of these genotypes represented a total of eight genetic clusters with 61
      isolates (73%). The two largest clusters contained 24 and 12 isolates, and the
      isolates in those clusters were identical to the two internationally spreading
      multidrug-resistant clones Spain 23F-1 and Taiwan 19F-14, respectively. The
      remaining RFEL types were Vietnam specific, as they did not match the types in
      our reference collection of 193 distinct RFEL types from 16 countries.
      Furthermore, 57 of the 61 horizontally spreading isolates (93%) in the eight
      genetic clusters were covered by the seven-valent conjugate vaccine, whereas this
      vaccine covered only 43% of the isolates with unique genotypes. According to the
      serotype distribution of the nasopharyngeal pneumococcal isolates, this study
      suggests a high potential benefit of the seven-valent pneumococcal conjugate
      vaccine for children in Hanoi.

PMID- 12409350
TI  - Increased risk of parvovirus B19 infection in young adult cancer patients
      receiving multiple courses of chemotherapy.
AB  - An increased human parvovirus B19 infection rate has been observed in
      immunocompromised hosts. In this study, we sought to determine the prevalence of
      parvovirus B19 infection in adult cancer patients receiving multiple courses of
      systemic chemotherapy. From March 1999 through April 2000, 59 men and 68 women,
      with a median age of 49 (18 to 79) years, were enrolled in this study. They had
      received an average of 7.1 (4 to 32) courses of systemic chemotherapy. The median
      duration from the date of starting chemotherapy to the date of blood sampling was
      11 (4 to 88) months. Serum B19 immunoglobulin G (IgG) and IgM levels were
      examined by an enzyme-linked immunosorbent assay, and B19 DNA was examined by a
      nested PCR. A group of 400 healthy blood donors served as the control group. The
      overall prevalences of anti-B19 IgG in adult cancer patients and healthy blood
      donors were 61.4 and 25.0%, respectively (P < 0.01). Anti-B19 IgM and B19 DNA
      were not detectable in these anti-B19 IgG-seropositive individuals. A further age
      stratified comparison revealed that only patients younger than 40 years had a
      significantly higher anti-B19 IgG seropositivity rate than the controls (19 of 39
      versus 53 of 310; P < 0.001). The increased prevalence of B19 infection in these
      39 adult patients younger than 40 years might be clinically significant, since
      unexplained anemia, a common sequela of B19 infection, was detected in 3 of 20
      seronegative patients (15.0%) and in 12 of 19 seropositive patients (63.2%) (P <
      0.005). The results of this study suggest that adult patients younger than 40
      years and receiving multiple courses of systemic chemotherapy may have a
      significantly increased risk of B19 infection. Prospective studies to define the
      time course and clinical consequence of B19 infection in this group of patients
      are needed.

PMID- 12409351
TI  - Alafosfalin as a selective agent for isolation of salmonella from clinical
      samples.
AB  - The selectivity of a range of culture media for the detection of Salmonella was
      assessed using 435 strains of gram-negative bacteria. These media showed limited
      ability to inhibit non-Salmonella strains found in stool samples. We report the
      evaluation of alafosfalin as a selective agent for isolation of Salmonella from
      stool samples. Susceptibility studies with this agent showed that non-typhi
      Salmonella strains were relatively resistant (mean MIC, 10.2 mg/liter) compared
      to many coliforms including Escherichia coli (mean MIC, 0.7 mg/liter). A
      chromogenic medium, ABC medium, was modified to incorporate alafosfalin and was
      compared with standard ABC medium and Hektoen enteric agar for the isolation of
      Salmonella from 1,000 stool samples. On direct culture, modified ABC medium
      showed higher recovery of Salmonella (53.6%) compared with either ABC medium
      (35.7%) or Hektoen enteric agar (48.2%). We conclude that alafosfalin is a useful
      selective agent for the isolation of Salmonella from stool samples.

PMID- 12409352
TI  - Rates of detection of Neisseria meningitidis in tonsils differ in relation to
      local incidence of invasive disease.
AB  - Nasopharyngeal swabbing substantially underestimates carriage of Neisseria
      meningitidis. Real-time PCR assays were employed to examine the presence of a
      broad range of bacteria and of N. meningitidis groups B and C, respectively, in
      tonsils from 26 individuals from Oxford, England, and 72 individuals from Zurich,
      Switzerland. The detection limit of each PCR system was DNA from one bacterial
      cell per reaction mixture. Tonsillar DNA did not inhibit amplification of
      meningococcal gene sequences, and N. meningitidis was detected in tonsils exposed
      to the bacterium. Whereas in both sets of patients other bacteria were detected,
      N. meningitidis group B and group C were only found in tonsils from Oxford where
      the incidence of invasive meningococcal disease is much higher than in Zurich.
      These observations suggest that PCR-based methods could be used for the detection
      of meningococcal carriage and that difference in disease incidence could be
      explained by different transmission rates in the community rather than host
      genetics or coexisting infections.

PMID- 12409353
TI  - Real-time PCR method for detection of Encephalitozoon intestinalis from stool
      specimens.
AB  - The prevalence of microsporidiosis is likely underestimated due to the labor
      intensive, insensitive, and nonspecific clinical laboratory methods used for the
      diagnosis of this disease. A real-time PCR assay was designed to assess DNA
      extraction methods and to detect three Encephalitozoon species in feces.
      Modifications of the MagNA Pure LC DNA isolation kit protocol (Roche Applied
      Sciences, Indianapolis, Ind.) were compared by using the automated MagNA Pure LC
      instrument (Roche) and fecal specimens spiked with Encephalitozoon intestinalis
      spores. Extracted DNA was amplified by the LightCycler (Roche) PCR assay. Assay
      sensitivity, reproducibility, and efficiency were assessed by comparing threshold
      crossover values achieved with different extraction and storage conditions
      (fresh, refrigerated, frozen, and preserved specimens). Optimal extraction
      conditions were achieved by using a commercial buffer, tissue lysis buffer
      (Roche), as the specimen diluent. LightCycler PCR results were compared to those
      obtained from routine stool microscopy with trichrome blue stain. The lower limit
      of detection for the LightCycler PCR assay varied by storage conditions from
      10(2) to 10(4) spores/ml of feces, a value which represented a significant
      improvement over that achieved by staining (> or =1.0 x 10(6) spores/ml). Melting
      temperature analysis of the amplicons allowed for the differentiation of three
      Encephalitozoon species (E. intestinalis, E. cuniculi, and E. hellem). The assay
      is readily adaptable to the clinical laboratory and represents the first real
      time PCR assay designed to detect Encephalitozoon species.

PMID- 12409354
TI  - Validation of performance of the gen-probe human immunodeficiency virus type 1
      viral load assay with genital swabs and breast milk samples.
AB  - Human immunodeficiency type 1 (HIV-1) continues to spread at an alarming rate.
      The virus may be transmitted through blood, genital secretions, and breast milk,
      and higher levels of systemic virus in the index case, as measured by plasma RNA
      viral load, have been shown to correlate with increased risk of transmitting HIV
      1 both vertically and sexually. Less is known about the correlation between
      transmission and HIV-1 levels in breast milk or genital secretions, in part
      because reliable quantitative assays to detect HIV-1 in these fluids are not
      available. Here we show that the Gen-Probe HIV-1 viral load assay can be used to
      accurately quantify viral load in expressed breast milk and in cervical and
      vaginal samples collected on swabs. Virus could be quantified from breast milk
      and swab samples spiked with known amounts of virus, including HIV-1 subtypes A,
      C, and D. As few as 10 copies of HIV-1 RNA could be detected above background
      threshold levels in > or =77% of assays performed with spiked breast milk
      supernatants and mock swabs. In genital swab samples from HIV-1-infected women,
      similar levels of HIV-1 RNA were consistently detected in duplicate swabs taken
      from the same woman on the same clinic visit, suggesting that the RNA values from
      a single swab sample can be used to measure genital viral load.

PMID- 12409355
TI  - "Actinobaculum massiliae," a new species causing chronic urinary tract infection.
AB  - We report on a new Actinobaculum species, "Actinobaculum massiliae," isolated
      from the urine of an elderly woman with recurrent cystitis. Its phenotypic
      pattern was similar to those of both of the other Actinobaculum species described
      to date. On 16S rRNA sequencing, the Marseille isolate shared 95% homology with
      Actinobaculum suis, 92 to 93% homology with Actinobaculum schaalii, 91 to 92%
      homology with Arcanobacterium spp., and 87 to 90% homology with Actinomyces
      species. A bootstrap value of 99% supports the node separating the Actinobaculum
      sp. from its closest neighbor (A. suis). In conclusion, on the basis of
      phenotypic, genotypic, and phylogenetic assessments, we show that the Marseille
      isolate is a previously unrecognized organism within the Actinobaculum genus, and
      we propose placement of the organism in the taxon "Actinobaculum massiliae."

PMID- 12409357
TI  - Both urinary and rectal Escherichia coli isolates are dominated by strains of
      phylogenetic group B2.
AB  - To compare the genetic structures of uropathogenic and commensal Escherichia coli
      populations, a total of 181 urinary and rectal E. coli isolates were classified
      into intraspecies phylogenetic groups by PCR amplifications of phylogenetic
      markers. The genetic variability of these isolates within phylogenetic groups was
      further assessed by enterobacterial repetitive intergenic consensus (ERIC)
      typing. The distributions of 10 known virulence factors were also examined. In
      contrast with most reports, phylogenetic group B2 not only accounted for the
      majority of urinary isolates from young women with urinary tract infections (69%)
      but also was the dominant group among the rectal isolates from healthy young
      women (48%). Such difference may be explained by geographic variation, difference
      in host population characteristics, or differences in sampling method, or a
      combination of the three. Strains with known virulence factors most frequently
      belonged to phylogenetic groups B2 and D. Additionally, group B2 and D rectal
      isolates were more heterogeneous than urinary isolates. Two subclusters existed
      within group B2 strains by ERIC typing. These subclusters were not evenly
      distributed between rectal and urine isolates and differed in virulence gene
      distribution.

PMID- 12409356
TI  - Dissemination of Streptococcus pneumoniae clone Colombia(5)-19 in Latin America.
AB  - Streptococcus pneumoniae serotype 5 is the third most common capsular type
      causing invasive diseases in children younger than 5 years in Latin America.
      Preliminary data on Colombian serotype 5 isolates indicated a common clonal
      origin associated with resistance to tetracycline (TET) and chloramphenicol
      (CHL). We studied 172 S. pneumoniae serotype 5 invasive isolates from Argentina,
      Brazil, Colombia, Guatemala, Mexico, and Uruguay and confirmed the presence of
      the Colombia(5)-19 clone throughout Latin America. Fifteen subtypes of a pulsed
      field gel electrophoresis pattern and 4 electrophoretic types (ET) were obtained.
      Most of the isolates from different geographical regions belonged to pattern A
      (34.3%), subtype A5 (41.9%), and ET1 (91.1%). The A pattern (n = 59) was
      resistant to TET and had variable resistance to CHL; it was present in Brazil
      (10.2%), Colombia (78%), Guatemala (8.5%), and Mexico (3.4%). Subtype A5 with
      variable susceptibility to TET and sensitive to CHL was found in Argentina
      (29.2%), Mexico (8.3%), and Uruguay (62.5%). Subtypes A1-A4, A7-A8, and A9-A11
      (closely related to A) also shared ET1, while subtype A6 was assigned to ET1,
      ET2, and ET3. Eleven subtypes (n = 21) were found to be specific for one country
      each. In summary, the S. pneumoniae serotype 5 isolates from Latin American are
      genetically closely related but show different patterns of antibiotic resistance,
      probably as a result of horizontal transfer.

PMID- 12409358
TI  - Protocol for real-time PCR identification of anthrax spores from nasal swabs
      after broth enrichment.
AB  - A mass-screening protocol for the diagnosis of anthrax from nasal swabs based on
      an enrichment step in liquid medium was devised. Incubation for growth was
      performed in autoclavable vials and racks which allow real-time PCR analysis of
      sterilized cultures. A dual-color PCR was set up with primers and probes for the
      chromosomal marker rpoB and the plasmid marker lef. Specific primer and probe
      sets were designed for the differentiation of Bacillus anthracis from B. cereus
      and for the differentiation of the Sterne vaccine strain from field isolates and
      the Ames strain, which was used in the recent anthrax bioterrorist attack. The
      present protocol thus combines the high specificity and sensitivity of real-time
      PCR with excellent biosafety and the low hands-on time necessary for the
      processing of large numbers of samples, which is extremely important during
      control programs involving the processing of large numbers of samples.

PMID- 12409359
TI  - Extrapulmonary and pulmonary tuberculosis in antananarivo (madagascar): high
      clustering rate in female patients.
AB  - Antananarivo, the capital city of Madagascar, has an endemic focus of
      tuberculosis (TB). We specifically studied patients with extrapulmonary TB (EPTB)
      and grouped patients according to infected body site. The strains were
      characterized by IS6110 fingerprinting and compared with those isolated from
      patients with pulmonary TB (PTB) during the same period in order to determine the
      possible association between the genotype and the clinical expression of TB. A
      total of 316 TB patients were included in this study: 151 individuals with EPTB,
      10 with both PTB and EPTB, and 155 with PTB alone. Pleural TB was the major EPTB
      localization (77%) and was found more often in older patients, while PTB or EPTB
      in which the localization was other than pleural (other EPTB) was found in
      younger patients. The male-to-female ratio was slightly higher in pleural TB
      patients (3.06:1) than in patients with other EPTB (1.35:1). There was no
      significant difference in the BCG status among patients with PTB, pleural TB, and
      other EPTB. Analysis of IS6110 patterns showed that 167 patients (52.8%) were
      assigned to 37 clusters of 2 to 34 patients. Analysis of the IS6110 clusters and
      the IS6110 families did not show any association with a particular clinical
      expression of the disease. Patients with PTB or other EPTB were more likely to
      have strains with one IS6110 copy than patients with pleural TB. The clustering
      rate was found to be significantly higher in female patients (62%) than in male
      patients (48%) (P = 0.029), suggesting that Malagasy women were more likely to
      progress to disease after infection than men.

PMID- 12409360
TI  - mecA gene is widely disseminated in Staphylococcus aureus population.
AB  - Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most important
      causes of hospital infections worldwide. High-level resistance to methicillin is
      caused by the mecA gene, which encodes an alternative penicillin-binding protein,
      PBP 2a. To determine the clonal relationships between methicillin-susceptible S.
      aureus (MSSA) and MRSA, we typed 1,069 S. aureus isolates (493 MSSA isolates and
      576 MRSA isolates), collected mainly in North American and European hospitals
      between the 1960s and the year 2000, using pulsed-field gel electrophoresis and
      ribotyping. Of 10 widespread S. aureus lineages recognized, 8 had corresponding
      mecA-positive strains. Multiresistant MRSA strains are found in hospitals
      worldwide, while unrelated and more susceptible strains represent less than 1% of
      the MRSA population. This supports the hypothesis that horizontal transfer plays
      an important role in the dissemination of the mecA gene in the S. aureus
      population.

PMID- 12409361
TI  - Multicenter evaluation of ethambutol susceptibility testing of mycobacterium
      tuberculosis by agar proportion and radiometric methods.
AB  - Reproducibility of ethambutol (EMB) susceptibility test results for Mycobacterium
      tuberculosis has always been difficult for a variety of reasons, including the
      narrow range between the critical breakpoint for EMB resistance and the MIC for
      susceptible strains, borderline results obtained with the BACTEC 460TB method,
      the presence of microcolonies determined using the agar proportion (AP) method,
      and a lack of agreement between these two testing methods. To assess the
      frequency of these problems, M. tuberculosis drug susceptibility data were
      collected in a multicenter study involving four laboratories. Resistant,
      borderline, and susceptible isolates were shared among the laboratories to
      measure interlaboratory test agreement. Half of isolates determined by BACTEC
      460TB to be resistant were determined to be susceptible by the AP method.
      Isolates determined to be resistant to EMB by both BACTEC 460TB and AP methods
      were almost always resistant to isoniazid. Results from isolates tested by the
      BACTEC 460TB method with an EMB concentration of 3.75 micro g/ml in addition to
      the standard 2.5 micro g/ml did not show improved agreement by the AP method.
      While these results do not indicate that the AP method is more accurate than the
      BACTEC 460TB method, laboratories should not report EMB monoresistance based on
      BACTEC 460TB results alone. Monoresistance to EMB should only be reported
      following confirmation by the AP method. Microcolonies could not be confirmed as
      resistant by the BACTEC 460TB method or by repeat testing with the AP method and
      do not appear to be indicative of resistance.

PMID- 12409362
TI  - Serotype and phage type distribution of salmonella strains isolated from humans,
      cattle, pigs, and chickens in the Netherlands from 1984 to 2001.
AB  - We studied serotypes and phage types of Salmonella strains isolated from humans
      and animals in The Netherlands over the period 1984 to 2001. All human strains (n
      = 59,168) were clinical isolates. The animal strains (n = 65,567) were from
      clinical and nonclinical infections. All isolates were serotyped, and Salmonella
      enterica serovar Typhimurium and serovar Enteritidis strains were further phage
      typed. The most prevalent serotypes were as follows: in humans, serovars
      Typhimurium and Enteritidis; in cattle, serovars Typhimurium and Dublin; in pigs,
      serovar Typhimurium; and in chickens, serovars Enteritidis, Infantis, and
      Typhimurium. Serovar Enteritidis phage type 4 (pt 4) was the most common phage
      type in humans and chickens. Serovar Typhimurium pt 510 was the most prevalent
      serovar Typhimurium phage type in humans and pigs, pt 200 was the most prevalent
      serovar Typhimurium phage type in cattle, and pt 150 was the most prevalent
      serovar Typhimurium phage type in chickens. Analysis of the distribution of sero-
      and phage types during the study period indicated that types shifted over time in
      humans and animals. Serovar Typhimurium DT 104 emerged in 1991 in humans, cattle,
      pigs, and chickens and became the most common serovar Typhimurium phage type in
      2001. In general, similar sero- and phage types were found in humans and animals,
      although distinct types were more common in animals. Between the animal species,
      the sero- and phage type distributions varied considerably.

PMID- 12409363
TI  - Comparison of quantitative competitive PCR with LightCycler-based PCR for
      measuring Epstein-Barr virus DNA load in clinical specimens.
AB  - The aim of this study was to develop a LightCycler-based real-time PCR assay for
      monitoring the Epstein-Barr virus (EBV) DNA load in unfractionated whole blood.
      This assay was compared with quantitative competitive PCR (Q-PCR) for EBV. The
      LightCycler-based assay was highly sensitive and reproducible when quantifying
      plasmid DNA in either the presence or absence of healthy donor blood DNA.
      Amplifying plasmid DNA in DNA backgrounds from different donors slightly
      increased the variation of quantification, indicating that clinical specimen DNA
      has an influence on quantification. In most transplant recipients, a good
      correlation was observed between EBV DNA load dynamics determined by LightCycler
      and Q-PCR in follow-up samples, although the correlation between absolute values
      of EBV DNA loads was weak and occasional samples were false negative in the
      LightCycler assay. In 253 cross-sectional blood samples from patients with
      Burkitt's lymphoma, infectious mononucleosis, or human immunodeficiency virus
      infection, a weak but significant correlation between the two methods was found
      (r(2) = 0.37, P < 0.001). Our results indicate that the clinical specimen DNA
      background may influence the absolute values of EBV DNA load in LightCycler
      analyses but that this effect is rare. LightCycler PCR is very well suited for
      monitoring of EBV DNA load dynamics, and its diagnostic value is comparable to
      that of Q-PCR. To avoid false negativity or underestimation of viral load, future
      internal calibration of the LightCycler is recommended. This would also enhance
      EBV load assay standardization and interinstitute comparisons.

PMID- 12409364
TI  - Virologic and serologic identification of minute virus of canines (canine
      parvovirus type 1) from dogs in Japan.
AB  - Minute virus of canines (MVC), also known as canine parvovirus type 1, was
      initially believed to be a nonpathogenic agent, since it was first isolated from
      canine fecal specimens in the late 1960s. However, subsequent pathological as
      well as epidemiological studies suggested that MVC is a pathogen of neonatal
      puppies and is widely distributed among domestic dogs in the United States. The
      virus also has been shown to cause fetal deaths. Nevertheless, the virus was not
      detected in dogs outside the United States until recently, presumably because of
      a lack of widespread availability of the only susceptible canine cell line,
      WRCC/3873D, used for MVC isolation. We examined 470 clinical specimens from 346
      dogs by PCR and detected MVC-specific gene fragments from four diseased puppies
      (positive rate, 1.2%). Viruses were recovered from three PCR-positive rectal
      specimens by using WRCC/3873D and MDCK cells. The isolates possessed antigenic
      and genomic properties similar to those of the U.S. reference strain GA3 and were
      identified as MVC. In addition, seroepidemiological evidence that 5.0% of dogs
      possessed anti-MVC antibodies also indicated the presence of MVC infection among
      dogs in Japan. From this study and several recent European reports describing MVC
      field cases, it is evident that MVC is distributed among domestic dogs worldwide.

PMID- 12409365
TI  - Collaborative evaluation of optimal antifungal susceptibility testing conditions
      for dermatophytes.
AB  - A multicenter study was conducted to define the most suitable testing conditions
      for antifungal susceptibility of dermatophytes. Broth microdilution MICs of
      clotrimazole, itraconazole, and terbinafine were determined in three centers
      against 60 strains of dermatophytes. The effects of inoculum density (ca. 10(3)
      and 10(4) CFU/ml), incubation time (3, 7, and 14 days), endpoint criteria for MIC
      determination (complete [MIC-0] and prominent [MIC-2] growth inhibition), and
      incubation temperature (28 and 37 degrees C) on intra- and interlaboratory
      agreement were analyzed. The optimal testing conditions identified were an
      inoculum of 10(4) CFU/ml, a temperature of incubation of 28 degrees C, an
      incubation period of 7 days, and MIC-0.

PMID- 12409366
TI  - False-positive mycobacterium tuberculosis cultures in 44 laboratories in The
      Netherlands (1993 to 2000): incidence, risk factors, and consequences.
AB  - False-positive Mycobacterium tuberculosis cultures are a benchmark for the
      quality of laboratory processes and patient care. We studied the incidence of
      false-positive cultures, risk factors, and consequences for patients during the
      period from 1993 to 2000 in 44 peripheral laboratories in The Netherlands. The
      national reference laboratory tested 8,889 M. tuberculosis isolates submitted by
      these laboratories. By definition, a culture was false positive (i) if the DNA
      fingerprint of the isolate was identical to that of an isolate from another
      patient processed within 7 days in the same laboratory, (ii) if the isolate was
      taken from a patient without clinical signs of tuberculosis, and/or (iii) if the
      false-positive test result was confirmed by the peripheral laboratory and/or the
      public health tuberculosis officer. We identified 213 false-positive cultures
      (2.4%). The overall incidence of false-positive cultures decreased over the
      years, from 3.9% in 1993 to 1.1% in 2000. Laboratories with false-positive
      cultures more often processed less than 3,000 samples per year (P < 0.05). Among
      110 patients for whom a false-positive culture was identified from 1995 to 1999,
      we found that for 36% of the patients an official tuberculosis notification had
      been provided to the appropriate public health services, 31% of the patients were
      treated, 14% of the patients were hospitalized, and a contact investigation had
      been initiated for 16% of the patients. The application of DNA fingerprinting to
      identify false-positive M. tuberculosis cultures and the provision of feedback to
      peripheral laboratories are useful instruments to improve the quality of
      laboratory processes and the quality of medical care.

PMID- 12409367
TI  - Molecular detection and seroepidemiology of the Chlamydia pneumoniae
      bacteriophage (PhiCpn1).
AB  - Recent whole-genome analysis has demonstrated limited genetic variation in
      Chlamydia pneumoniae, with one strain (AR39) containing a 4,524 nucleotide single
      stranded DNA bacteriophage, PhiCpn1. Using PCR, reverse transcription (RT)-PCR,
      and Western blotting, we confirmed the presence and functional expression of
      PhiCpn1 in C. pneumoniae strain AR39 and its absence in strain CWL029. Six
      additional epidemiologically distinct clinical isolates of C. pneumoniae also did
      not contain PhiCpn1. We generated recombinant viral protein 1 (Vp1) from PhiCpn1
      in Escherichia coli and showed that Vp1 antigen is highly immunogenic in mice and
      that murine antisera readily recognize native Vp1 from C. pneumoniae strain AR39
      elementary bodies (EB). We developed an enzyme-linked immunosorbent assay (ELISA)
      to measure antibodies to recombinant Vp1 in human sera collected from 32 patients
      with abdominal aortic aneurysm (AAA) and 40 controls. Among the 72 subjects, 61
      had C. pneumoniae EB antibodies shown by ELISA. Antibodies to Vp1 were found in
      39 of the 61 (64%) seropositive individuals and were significantly correlated
      with AAA (adjusted odds ratio, 13.9; 95% confidence interval, 1.1 to 175). Our
      studies indicate that phage-containing strains of C. pneumoniae are uncommonly
      found by isolation but may commonly infect individuals with vascular disease.

PMID- 12409368
TI  - Precision and accuracy of a procedure for detecting recent human immunodeficiency
      virus infections by calculating the antibody avidity index by an automated
      immunoassay-based method.
AB  - We evaluated the precision and accuracy of a procedure for detecting recent human
      immunodeficiency virus (HIV) infections, specifically, the avidity index (AI)
      calculated using a method based on an automated AxSYM HIV 1/2gO assay (Abbott).
      To evaluate precision, we performed multiple replicates on eight HIV-positive
      serum samples. To evaluate the accuracy in identifying recent infections (i.e.,
      within 6 months of seroconversion), we used 216 serum samples from 47 persons
      whose dates of seroconversion were known. To evaluate the sensitivity and
      specificity of the procedure for different AI cutoff values, we performed
      receiver operating characteristic (ROC) analysis. To determine the effects of
      antiretroviral treatment, advanced stage of the disease (i.e., low CD4-cell
      count), and low HIV viral load on the AI, we analyzed 15 serum samples from 15
      persons whose dates of seroconversion were unknown. The precision study showed
      that the procedure was robust (i.e., the total variance of the AI was lower than
      10%). Regarding accuracy, the mean AI was significantly lower for samples
      collected within 6 months of seroconversion, compared to those collected
      afterwards (0.68 +/- 0.16 versus 0.99 +/- 0.10; P < 0.0001), with no overlap of
      the 95% confidence intervals. The ROC analysis revealed that an AI lower than 0.6
      had a sensitivity of 33.3% and a specificity of 98.4%, compared to 87.9 and
      86.3%, respectively, for an AI lower than 0.9. Antiretroviral treatment, low CD4
      cell count, and low viral load had no apparent effect on the AI. In conclusion,
      this procedure is reproducible and accurate in identifying recent infections; it
      is automated, inexpensive, and easy to perform, and it provides a quantitative
      result with different levels of sensitivity and specificity depending on the
      selected cutoff.

PMID- 12409369
TI  - Genetic characterization and sequence heterogeneity of a canadian isolate of
      Swine hepatitis E virus.
AB  - Swine hepatitis E virus (HEV) is a newly identified potentially zoonotic agent
      that is possibly transmitted to humans from pigs. Swine HEV is prevalent in pig
      populations and does not cause abnormal clinical symptoms in infected pigs,
      further implicating a likelihood of a risk of transmission to humans by normal
      contact. To date in North America, only one strain of swine HEV (strain US swine)
      has been fully sequenced. In the present study, we identified a swine HEV isolate
      from pigs in Canada, designated the Arkell strain, and determined the full length
      of the genomic sequence. The genome of Canadian strain Arkell consisted of 7,242
      nucleotides, excluding the poly(A) tail of at least 15 A residues. The genome
      contained three open reading frames (ORFs), ORF1, ORF2, and ORF3, which had
      coding capacities for proteins of 1,708, 660, and 122 amino acids, respectively.
      Comparative analysis of the full-length genomic sequence indicated that the
      sequence of strain Arkell was distinct from those of all other known HEV isolates
      by 13 to 27% and shared the highest degrees of identity with human HEV isolates
      US-1 and US-2, HEV isolate US swine, and the human and swine HEV isolates
      recently isolated in Japan. On the basis of sequence similarities and
      phylogenetic analyses, HEV strain Arkell was grouped into genotype 3. The
      sequence of the Arkell swine HEV isolate differed from those of HEV isolate US
      swine and HEV isolate Japan swine by 13 and 14%, respectively. To date, two
      isolates of swine HEV (isolates Arkell and SK3 [D. Yoo et al., Clin. Diagn. Lab.
      Immunol. 8:1213-1219, 2001]) have been identified in Canadian pigs, and their
      sequences also differ from each other by 11.8%. Our studies indicate that, as
      with human HEV strains, swine HEV isolates exhibit extensive genetic
      heterogeneity.

PMID- 12409370
TI  - Identification and broad dissemination of the CTX-M-14 beta-lactamase in
      different Escherichia coli strains in the northwest area of Spain.
AB  - During the course of a molecular epidemiology study of mechanisms of antibiotic
      resistance in the area served by our hospital (516,000 inhabitants), we isolated
      the gene encoding CTX-M-14 beta-lactamase. Thirty clinical strains (27
      Escherichia coli and 3 Klebsiella pneumoniae isolates) with a phenotype of
      extended-spectrum beta-lactamase were collected from January to October 2001 and
      studied for the presence of the CTX-M-14 beta- lactamase gene. By isoelectric
      point determination, PCR, and nucleotide sequencing, we detected the presence of
      this gene in 17 E. coli strains belonging to 15 different genotypes (REP-PCR)
      causing infections in 17 different patients. Epidemiological studies based on
      medical records did not suggest any relationship between the patients infected
      with these E. coli strains and, interestingly, 7 of 30 patients harboring strains
      with extended-spectrum beta-lactamases never had contact with the hospital
      environment before the clinical E. coli isolation. Conjugation experiments
      revealed that this gene was plasmid mediated in the 17 E. coli strains, and
      plasmid restriction fragment length polymorphisms showed 9 different patterns in
      the 17 E. coli strains. By PCR, the sequence of the tnpA transposase gene of the
      insert sequence ISEcp-1 was detected in all the plasmids harboring the CTX-M-14
      gene. These results strongly suggest that plasmid dissemination between different
      E. coli strains in addition to a mobile element (transposon) around the beta
      lactamase gene may be involved in the spreading of the CTX-M-14 gene. This study
      reinforces the hypothesis that the epidemiology of the prevalence of the beta
      lactamase genes is changing and should alert the medical community to the
      increase in the emergence of the CTX-M beta-lactamases worldwide.

PMID- 12409371
TI  - Severe acquired toxoplasmosis in immunocompetent adult patients in French Guiana.
AB  - The most common presentation of symptomatic postnatally acquired toxoplasmosis in
      immunocompetent patients is painless cervical adenopathy. Acute visceral
      manifestations are associated in rare cases. We report 16 cases of severe primary
      toxoplasmosis diagnosed in French Guiana during a 6.5-year period. All of the
      subjects were immunocompetent adults hospitalized with clinical presentations
      consisting of a marked, nonspecific infectious syndrome accompanied by an altered
      general status with at least one visceral localization, mainly pulmonary
      involvement (14 cases). Acute toxoplasmosis was diagnosed according to the
      results of serological tests suggestive of recent primary infection and the
      absence of an alternative etiology. Recovery was rapid following specific
      antitoxoplasmosis treatment. Thirteen of the 16 patients had consumed game in the
      2 weeks before the onset of the symptoms, and in eight cases the game was
      considered to have been undercooked. Toxoplasma strains, which were virulent in
      mice, were isolated from three patients. Microsatellite analysis showed that all
      of these isolates exhibited an atypical multilocus genotype, with one allele
      found only for isolates of this region.

PMID- 12409372
TI  - Use of epitope mapping to identify a PCR template for protein amplification and
      detection by enzyme-linked immunosorbent assay of bovine herpesvirus type 1
      glycoprotein D.
AB  - Infection with bovine herpesvirus type 1 (BHV-1) occurs worldwide and causes
      serious economic losses due to the deaths of animals, abortions, decreased milk
      production, and loss of body weight. BHV-1 is frequently found in bovine semen
      and is transmitted through natural service and artificial insemination. The
      detection of BHV-1 in bovine semen is a long-standing problem in veterinary
      virology which is important in disease control schemes. In the present study,
      ordered deletions of the full-length BHV-1 glycoprotein open reading frame were
      used to identify an epitope recognized by a specific monoclonal antibody (MAb). A
      glycoprotein D fragment containing this epitope was then amplified using an in
      vitro protein amplification assay developed previously (J. Zhou, J. Lyaku, R. A.
      Fredrickson, and F. S. Kibenge, J. Virol. Methods 79:181-189, 1999), and the
      resulting peptide was detected by indirect enzyme-linked immunosorbent assay
      (ELISA) with the specific MAb. This method detected 0.0395 50% tissue culture
      infective dose of BHV-1 in raw bovine semen, which was 1,000-fold more sensitive
      than traditional PCR. We therefore conclude that this in vitro protein
      amplification assay combined with ELISA has superior sensitivity for direct virus
      detection in clinical samples.

PMID- 12409373
TI  - Nosocomial infections caused by multidrug-resistant isolates of pseudomonas
      putida producing VIM-1 metallo-beta-lactamase.
AB  - Successful carbapenem-based chemotherapy for the treatment of Pseudomonas
      infections has been seriously hindered by the recent appearance of IMP- and VIM
      type metallo-beta-lactamases, which confer high-level resistance to carbapenems
      and most other beta-lactams. Recently, multidrug-resistant Pseudomonas putida
      isolates for which carbapenem MICs were >/=32 micro g/ml were recovered from
      cultures of urine from three inpatients in the general intensive care unit of the
      Ospedale di Circolo, Varese, Italy. Enzyme assays revealed production of a
      metallo-beta-lactamase activity, while molecular analysis detected in each
      isolate a bla(VIM-1) determinant carried by an apparently identical medium-sized
      plasmid. Conjugation experiments were unsuccessful in transferring the beta
      lactamase determinant to Escherichia coli or Pseudomonas aeruginosa.
      Macrorestriction analysis by pulsed-field gel electrophoresis demonstrated that
      the isolates were of clonal origin. PCR mapping and sequencing of the variable
      region of the plasmid-borne class 1 integron carrying the bla(VIM-1) determinant
      (named In110) showed that the bla(VIM-1)-containing cassette was identical to
      that previously found in strains of different species from other Italian
      hospitals and that the cassette array of In110 was not identical but clearly
      related to that of In70 (a bla(VIM-1)-containing plasmid-borne integron from an
      Achromobacter xylosoxidans isolate), pointing to a common origin of this cassette
      and to a related evolutionary history of their cognate integrons.

PMID- 12409374
TI  - Confirmation by 16S rRNA PCR of the COBAS AMPLICOR CT/NG test for diagnosis of
      Neisseria gonorrhoeae infection in a low-prevalence population.
AB  - The COBAS AMPLICOR CT/NG test is widely used for the diagnosis of Neisseria
      gonorrhoeae infection using genital swabs or urine samples. Although highly
      specific, cross-reactivity occurs with some nonpathogenic strains of Neisseria
      and Lactobacillus species. In low-prevalence populations, even highly specific
      assays may require confirmatory testing of positive results. We assessed the
      positive predictive value (PPV) of this test in a low-prevalence (0.5%) setting.
      Genital and urine specimens testing positive using the COBAS AMPLICOR NG test
      were retested using an investigational 16S rRNA PCR assay. Additionally, 737
      specimens were tested in parallel by both culture and the above PCR protocol. Of
      9,772 specimens tested in-house, 168 were positive by the AMPLICOR test; in
      addition, 62 AMPLICOR-positive specimens were referred to our laboratory for
      confirmatory testing, yielding 230 positive specimens. Of these, 72 were
      confirmed positive by 16S rRNA PCR, yielding a specificity of 98.7% and a PPV of
      31.3%. Specificity was similar for all specimen types, whereas PPV varied with
      prevalence: specimens from males, females, urine specimens, and genital swabs had
      PPVs of 70.8, 13.3, 51.9, and 20.1%, respectively. The PPV was higher when the
      initial AMPLICOR optical density (OD) was > or =3.5 versus initial and repeat OD
      readings in an equivocal zone of > or =0.2 to <3.5 (65.1 versus 10.1%; P <
      0.001). On repeat testing of specimens with ODs in the equivocal zone, 54 gave
      ODs of > or =0.2 and <2.0, 35 gave ODs of > or =2.0 and <3.5, and 12 gave ODs of
      > or =3.5, with 3.7, 20, and 33.3% confirmed positive, respectively (P = 0.004).
      Comparing PCR to culture as the "gold standard," specificity increased from 96.8
      to 99.9% when 16S rRNA PCR was performed on specimens positive by the COBAS
      AMPLICOR NG test. Confirmatory testing with a more specific method such as 16S
      rRNA PCR should be considered in low-prevalence populations, especially for
      specimens with an OD in the equivocal zone.

PMID- 12409375
TI  - Analysis of the genetic variability of genes encoding the RNA III-activating
      components Agr and TRAP in a population of Staphylococcus aureus strains isolated
      from cows with mastitis.
AB  - The expression of Staphylococcus aureus virulence proteins is under the control
      of RNA III, a central pleiotropic regulator transcribed from the agr locus. RNA
      III is activated by at least two two-component systems, one encoded by the agr
      locus (AgrC-AgrA) and another encoded outside of this locus (TRAP-RAP). In this
      work, we developed new typing methods based on genes encoding these two systems,
      which we used to characterize a nonclonal population of S. aureus bovine mastitis
      isolates. Twelve agr restriction types were identified in this population, but
      the majority of strains (56.3%) were grouped in the R III-A1 type. No strain
      isolated from humans, whose agr sequence is available from GenBank, was found to
      belong to this major type. Restriction maps constructed for all of those agr
      variants allowed the linking of all types in an evolution scheme and their
      grouping in one of the four agr interference groups. This analysis indicates that
      groups 2, 3, and 4 probably evolved from the more frequently encountered type,
      which belongs to group 1. agr group 1 was also found to be the most prevalent
      (69.0% of the strains) and the most polymorphic interference group. By developing
      an agr group-specific multiplex PCR, we confirmed the above classification of
      strains in the agr interference groups. Four allelic variants of trap were also
      identified, indicating that this two-component system is also polymorphic. The
      majority of strains was grouped in the trap 1 type (71.8%). Whereas no
      relationships between agr group and trap types were found, strains of similar agr
      restriction type were also of similar trap type (with the exception of strains
      belonging to the agr R IV-A5 and R VI-A8 types). Our analysis indicates that S.
      aureus isolated from cows has predominantly a clonal structure and that the
      highly prevalent agr R III-A1, trap 1 type (56.3% of the strains) probably
      possesses a genetic background which endows it with superior ability to infect
      the bovine mammary gland.

PMID- 12409376
TI  - Occult hepatitis B virus infection and clinical outcomes of patients with chronic
      hepatitis C.
AB  - Although occult hepatitis B virus (HBV) infections in individuals without
      detectable hepatitis B surface antigen (HBsAg) may occur and have been reported
      to be common in patients with chronic hepatitis C, the clinical relevance remains
      controversial. We searched for serum HBV DNA in 210 HBsAg-negative patients with
      hepatitis C virus (HCV)-related liver disease (110 patients with chronic
      hepatitis, 50 patients with cirrhosis, and 50 patients with hepatocellular
      carcinoma) by PCR. Most of the patients had detectable antibodies to HBsAg or HBV
      core antigen. All of the 110 chronic hepatitis C patients were treated with a
      combination therapy consisting of interferon plus ribavirin. In addition, 100
      HBsAg-negative healthy adults served as controls. Thirty-one of the 210 patients
      (14.8%) had HBV DNA in their sera, as did 15 of the 100 healthy controls (15%).
      HBV DNA was not detected in the sera of those negative for serological markers of
      HBV infection. In patients with chronic HCV infection, the prevalence of occult
      HBV infection did not parallel the severity of liver disease (14.5% in patients
      with chronic hepatitis, 8% in patients with liver cirrhosis, and 22% in patients
      with hepatocellular carcinoma). In addition, the sustained response to
      combination therapy against hepatitis C was comparable between patients with and
      without occult HBV infection (38 versus 39%). In conclusion, these data suggest
      that occult HBV infection does not have clinical significance in chronic
      hepatitis C patients residing in areas where HBV infection is endemic.

PMID- 12409377
TI  - Experimental versus in silico fluorescent amplified fragment length polymorphism
      analysis of Mycobacterium tuberculosis: improved typing with an extended fragment
      range.
AB  - Whole-genome fingerprinting fluorescent amplified fragment length polymorphism
      (FAFLP) data were compared with in silico data for the sequenced strains of
      Mycobacterium tuberculosis (H37Rv and CDC1551). For this G+C-rich genome, many
      predicted fragments were not detected experimentally. For H37Rv, only 108 (66%)
      of the 163 predicted EcoRI-MseI fragments between 100 and 500 bp were visualized
      in vitro. FAFLP was also used to identify polymorphism in 10 clinical isolates of
      M. tuberculosis characterized previously by IS6110 typing, examining fragments of
      up to 1,000 bp in size rather than up to 500 bp as was done previously. Five
      isolates had unique IS6110 profiles and were not known to be epidemiologically
      related, two isolates were the same single-band IS6110 type but were not known to
      be epidemiologically related, and the remaining three isolates were
      epidemiologically related with identical IS6110 profiles. Analysis of fragments
      in the 500- to 1,000-bp range using nonselective primers differentiated better
      between strains than analysis of fragments in the 50- to 500-bp range using a set
      of four selective primers. Seventeen polymorphic fragments were identified
      between 500 and 1,000 bp in size compared with nine polymorphic fragments between
      50 and 500 bp. Using the 500- to 1,000-bp analysis, a level of discrimination
      similar to that of IS6110 typing was achieved which, unlike the IS6110 typing,
      was able to differentiate the two M. tuberculosis strains, each of which had only
      a single copy of IS6110.

PMID- 12409378
TI  - Method for inactivating and fixing unstained smear preparations of mycobacterium
      tuberculosis for improved laboratory safety.
AB  - The inactivation of smears that contain Mycobacterium tuberculosis for microscopy
      before removal of the material from a biosafety cabinet is an important safety
      factor in preventing the potential transmission of tuberculosis to laboratory
      workers. The fixing and inactivating properties of heat flaming, 70% ethanol, and
      1, 3, and 5% phenol in ethanol for smears containing M. tuberculosis were
      investigated. Heat flaming failed to inactivate the smear material, whereas 5%
      phenol in ethanol successfully fixed and inactivated all smears containing M.
      tuberculosis both from concentrated sputum samples and from culture material.

PMID- 12409379
TI  - Remarkable genetic polymorphism among Entamoeba histolytica isolates from a
      limited geographic area.
AB  - In order to understand genetic polymorphisms among Entamoeba histolytica strains
      in a limited geographic area and among restricted social populations, we studied
      nucleotide polymorphism in DNA regions that do not encode proteins (locus 1-2 and
      locus 5-6) and in genes coding for chitinase and for serine-rich E. histolytica
      protein. Thirty E. histolytica isolates from domestically infected Japanese
      amebiasis patients (male homosexuals and residents in institutions for the
      mentally handicapped) and four reference strains were examined. PCR revealed
      remarkable polymorphisms in both the number and size of the PCR fragments
      containing these loci. Polymorphisms in lengths, types, and numbers of internal
      repeat units were observed in locus 1-2 and the repeat-containing region of
      serine-rich E. histolytica protein among the Japanese isolates. In contrast,
      polymorphism at locus 5-6 was observed almost exclusively in the number of
      repeats of a 16-nucleotide unit. The repeat-containing region of chitinase
      appeared to be the least polymorphic among the four loci with a single dominant
      genotype representing 66% (20 out of 30) of all of the isolates. Isolates
      obtained from male homosexuals showed a more complex genetic polymorphism than
      those from residents in institutions. Considering all four polymorphic loci
      together, all 19 Japanese isolates from male homosexuals were distinct. In
      contrast, all isolates obtained from mass-infection cases at a single institution
      had an identical genotype, suggesting that these cases were caused by a single E.
      histolytica strain. No significant correlation was found between genotypes and
      zymodemes or between genotypes and clinical presentations, e.g., colitis or liver
      abscess. Certain genotypes were observed with higher frequencies in male
      homosexuals or residents of institutions. These data indicate that genotyping of
      the E. histolytica isolates by using these four polymorphic loci could serve as a
      tool to fingerprint individual isolates. We propose that genotyping of ameba
      isolates should help to determine geographic origins of isolates and routes of
      transmission.

PMID- 12409380
TI  - Sensitive detection of RNA viruses associated with gastroenteritis by a hanging
      drop single-tube nested reverse transcription-PCR method.
AB  - The detection of the human RNA viruses, calicivirus and astrovirus, requires high
      sensitivity and broad reactivity. A novel single-tube nested reverse
      transcription-PCR (RT-PCR) method is described here, in which all of the required
      reagents are included in the one tube; however, those required for the nested
      amplification are separated in a "hanging drop" in the cap to be introduced by
      centrifugation after the RT and first-round cDNA amplification steps. Broad
      reactivity was obtained by using primer cocktails covering the published sequence
      variation in the primer targets. The method was evaluated with clinical fecal
      samples from outbreak and sporadic cases. Norwalk-like virus types 1 and 2 and
      rotavirus were the causal agents in 10 of 12 outbreaks. A viral agent was
      detected in 44% of 197 samples from sporadic infections in patients presenting to
      community health centers and a children's hospital. Interestingly, whereas
      rotavirus was more common than astrovirus in patients presenting to the hospital
      (33 and 7.6%, respectively), the reverse was true for patients presenting to
      community health centers (4.2 and 34%, respectively).

PMID- 12409381
TI  - Estimation of the rate of unrecognized cross-contamination with mycobacterium
      tuberculosis in London microbiology laboratories.
AB  - Isolates from patients with confirmed tuberculosis from London were collected
      over 2.5 years between 1995 and 1997. Restriction fragment length polymorphism
      (RFLP) analysis was performed by the international standard technique as part of
      a multicenter epidemiological study. A total of 2,779 samples representing 2,500
      individual patients from 56 laboratories were examined. Analysis of these samples
      revealed a laboratory cross-contamination rate of between 0.54%, when only
      presumed cases of cross-contamination were considered, and 0.93%, when presumed
      and possible cases were counted. Previous studies suggest an extremely wide range
      of laboratory cross-contamination rates of between 0.1 and 65%. These data
      indicate that laboratory cross-contamination has not been a common problem in
      routine practice in the London area, but in several incidents patients did
      receive full courses of therapy that were probably unnecessary.

PMID- 12409382
TI  - Human cytomegalovirus DNA in plasma and serum specimens of renal transplant
      recipients is highly fragmented.
AB  - Quantitation of cytomegalovirus (CMV) DNA in plasma and serum by PCR is
      increasingly used to identify patients at risk for developing CMV disease and to
      monitor the efficacy of antiviral therapy. Although CMV DNA levels are generally
      interpreted as viral loads, the exact nature of the viral DNA in these specimens
      is unknown. We studied the state of CMV DNA in plasma and serum specimens
      obtained from three renal transplant recipients at peak viral DNA levels during
      primary CMV infection. For this purpose, DNA isolated from these specimens was
      fractionated by size, and CMV DNA levels in the resulting DNA fractions were
      measured by quantitative PCR targeted at large (578-bp) and small (134-bp)
      amplicons. These experiments showed that the molecular sizes of DNA fragments
      from which CMV DNA is amplified were small (<2,000 bp), indicating that CMV DNA
      in plasma and serum is highly fragmented. Furthermore, CMV DNA levels were
      consistently higher when targeted at the smaller amplicon, providing additional
      evidence for the fragmentation of viral DNA. In conclusion, the first results
      with three patients have shown that CMV DNA in plasma and serum is highly
      fragmented and does not necessarily reflect the amount of infectious virus. These
      observations have potential consequences for understanding CMV pathogenesis and
      interpreting CMV DNA levels in individual patient management.

PMID- 12409383
TI  - Incidence of human astrovirus in central Australia (1995 to 1998) and comparison
      of deduced serotypes detected from 1981 to 1998.
AB  - The incidence of astrovirus infection was determined among infants and young
      children admitted to Alice Springs Hospital (central Australia) with
      gastroenteritis from 1995 to 1998. Astrovirus was detected by reverse
      transcription-PCR in 33 of 495 stool samples, and this represented 4.3% of a
      total of 774 stool samples tested for astrovirus, rotavirus, and Norwalk-like
      viruses. Astrovirus incidence was substantially lower than that of rotavirus but
      higher than that of Norwalk-like viruses both overall and in each of the 4 years
      individually. Over the period from 1981 to 1998, including the period from 1981
      to 1994 during which astrovirus was identified only by electron microscopy,
      astrovirus serotypes (deduced from genotypes) 1, 2, 3, and 4 were identified.
      Deduced serotypes 1, 3, and 4 all appeared regularly over this 18-year period.
      Also over this period, nucleotide variation (in some cases substantial) in a
      section of the capsid protein precursor region of the virus genome was evident
      among strains of all four of the deduced central Australian serotypes. Consequent
      amino acid changes were, however, only evident among deduced serotype 3 strains.
      Geographic variation at both the genome and the resultant amino acid levels was
      evident among strains of all four of the deduced central Australian serotypes and
      their respective prototypes isolated in the United Kingdom.

PMID- 12409384
TI  - Detection of gyrA mutations in quinolone-resistant Salmonella enterica by
      denaturing high-performance liquid chromatography.
AB  - Denaturing high-performance liquid chromatography (DHPLC) was evaluated as a
      rapid screening and identification method for DNA sequence variation detection in
      the quinolone resistance-determining region of gyrA from Salmonella serovars. A
      total of 203 isolates of Salmonella were screened using this method. DHPLC
      analysis of 14 isolates representing each type of novel or multiple mutations and
      the wild type were compared with LightCycler-based PCR-gyrA hybridization
      mutation assay (GAMA) and single-strand conformational polymorphism (SSCP)
      analyses. The 14 isolates gave seven different SSCP patterns, and LightCycler
      detected four different mutations. DHPLC detected 11 DNA sequence variants at
      eight different codons, including those detected by LightCycler or SSCP. One of
      these mutations was silent. Five isolates contained multiple mutations, and four
      of these could be distinguished from the composite sequence variants by their
      DHPLC profile. Seven novel mutations were identified at five different loci not
      previously described in quinolone-resistant salmonella. DHPLC analysis proved
      advantageous for the detection of novel and multiple mutations. DHPLC also
      provides a rapid, high-throughput alternative to LightCycler and SSCP for
      screening frequently occurring mutations.

PMID- 12409385
TI  - Single-tube nested PCR for detection of tritrichomonas foetus in feline feces.
AB  - Tritrichomonas foetus, a venereal pathogen of cattle, was recently identified as
      an inhabitant of the large intestine in young domestic cats with chronic
      diarrhea. Recognition of the infection in cats has been mired by unfamiliarity
      with T. foetus in cats as well as misdiagnosis of the organisms as
      Pentatrichomonas hominis or Giardia sp. when visualized by light microscopy. The
      diagnosis of T. foetus presently depends on the demonstration of live organisms
      by direct microscopic examination of fresh feces or by fecal culturing. As T.
      foetus organisms are fastidious and fragile, routine flotation techniques and
      delayed examination and refrigeration of feces are anticipated to preclude the
      diagnosis in numerous cases. The objective of this study was to develop a
      sensitive and specific PCR test for the diagnosis of feline T. foetus infection.
      A single-tube nested PCR was designed and optimized for the detection of T.
      foetus in feline feces by using a combination of novel (TFITS-F and TFITS-R) and
      previously described (TFR3 and TFR4) primers. The PCR is based on the
      amplification of a conserved portion of the T. foetus internal transcribed spacer
      (ITS) region (ITS1 and ITS2) and the 5.8S rRNA gene. The absolute detection limit
      of the single-tube nested PCR was 1 organism, while the practical detection limit
      was 10 organisms per 200 mg of feces. Specificity was examined by using P.
      hominis, Giardia lamblia, and feline genomic DNA. Our results demonstrate that
      the single-tube nested PCR is ideally suited for (i) diagnostic testing of feline
      fecal samples that are found negative by direct microscopy and culturing and (ii)
      definitive identification of microscopically observable or cultivated organisms.

PMID- 12409386
TI  - Detection of antibodies directed against human herpesvirus 6 U94/REP in sera of
      patients affected by multiple sclerosis.
AB  - The association between human herpesvirus 6 (HHV-6) and multiple sclerosis (MS)
      is controversial. In fact, it is difficult to establish a causative role of HHV
      6, due to the high prevalence of latently infected individuals in the healthy
      population. Therefore, the presence of virus sequences in tissue biopsy does not
      support a viral role, and serological assays do not show significant differences
      between MS patients and control populations. The only viral gene expressed during
      latency is U94/rep. Therefore, we have developed a serological assay for the
      detection of antibodies specifically directed against U94/REP protein. Different
      populations were analyzed by enzyme-linked immunosorbent assay, including healthy
      controls, MS patients, and subjects with diseases unrelated to HHV-6 infection,
      including other neurological diseases. The results show statistically significant
      differences (P > 0.01) between MS patients and control groups, both in antibody
      prevalence (87 and 43.9%, respectively) and in geometric mean titer (1:515 and
      1:190, respectively). The detection of antibodies specific for HHV-6 U94/REP
      shows that the immune system is exposed to this antigen during natural infection.
      The higher prevalence and higher titers of antibodies to U94/REP suggest that MS
      patients and control groups might experience different exposures to HHV-6.

PMID- 12409387
TI  - Performance assessment of two commercial amplification assays for direct
      detection of Mycobacterium tuberculosis complex from respiratory and
      extrapulmonary specimens.
AB  - The new BDProbeTec ET Mycobacterium tuberculosis Complex Direct Detection Assay
      (DTB) was compared with the enhanced M. tuberculosis Amplified Direct Test
      (AMTDII). The system is an automated walkaway system characterized by
      simultaneous DNA amplification (strand displacement amplification) and real-time
      fluorometric detection. It also contains an internal amplification control (IAC)
      designed to identify inhibition from the processed samples. The AMTDII assay
      amplifies rRNA by transcription-mediated amplification; it uses hybridization
      with a chemoluminescent probe as a detection system and is entirely manual. A
      total of 515 N-acetyl-L-cysteine-sodium hydroxide-decontaminated respiratory (n =
      331) and extrapulmonary (n = 184) sediments (from 402 patients) were tested in
      parallel by both assays. The results were compared with those of acid-fast
      staining and culture (solid plus liquid media), setting the combination of
      culture and clinical diagnosis as the "gold standard." Culture results from the
      tested specimens were as follows: 121 Mycobacterium tuberculosis complex (MTB)
      (98 smear-positive), 46 nontuberculous mycobacteria (38 smear-positive), and 338
      culture-negative results. After resolution of the discrepant results, the percent
      sensitivity, percent specificity, and positive and negative likelihood ratios for
      AMTDII were 88%, 99.2%, 110, and 0.11 for respiratory specimens and 74.3%, 100%,
      740, and 0.26 for extrapulmonary specimens, respectively. The corresponding
      values for DTB were 94.5%, 99.6%, 235, and 0.05 for respiratory specimens and
      92.3%, 100%, 920, and 0.07 for extrapulmonary specimens, respectively. The
      cumulative difference for all tuberculosis-positive extrapulmonary specimens was
      significant (P = 0.03). The overall inhibition rate for DTB was 5% (26
      specimens). We conclude that both amplification assays proved to be rapid and
      specific for the detection of MTB in clinical samples and particularly feasible
      for a routine laboratory work flow. DTB combines a labor-intensive specimen
      preparation procedure with a completely automated amplification and detection.
      Finally, differences between AMTDII and DTB sensitivities were associated with
      the presence of inhibitory samples that the former assay, lacking IAC, could not
      detect.

PMID- 12409388
TI  - Rapid and specific detection of Mycobacterium tuberculosis from acid-fast
      bacillus smear-positive respiratory specimens and BacT/ALERT MP culture bottles
      by using fluorogenic probes and real-time PCR.
AB  - A real-time PCR assay using the LightCycler (LC) instrument for the specific
      identification of Mycobacterium tuberculosis complex (MTB) was employed to detect
      organisms in 135 acid-fast bacillus (AFB) smear-positive respiratory specimens
      and in 232 BacT/ALERT MP (MP) culture bottles of respiratory specimens. The LC
      PCR assay was directed at the amplification of the internal transcribed spacer
      region of the Mycobacterium genome with real-time detection using fluorescence
      resonance energy transfer probes specific for MTB. The results from the
      respiratory specimens were compared to those from the Amplicor M. tuberculosis
      PCR test. Specimens from MP culture bottles were analyzed by Accuprobe and
      conventional identification methods. MTB was cultured from 105 (77.7%)
      respiratory AFB smear-positive specimens; 103 of these samples were positive by
      LC PCR and Amplicor PCR. Two samples negative in the LC assay contained rare
      numbers of organisms; both were positive in the Amplicor assay. Two separate
      samples negative by Amplicor PCR contained low and moderate numbers of AFB,
      respectively, and both of these were positive in the LC assay. There were 30 AFB
      smear-positive respiratory specimens that grew mycobacteria other than
      tuberculosis (MOTT), and all tested negative in both assays. Of the 231 MP
      culture bottles, 114 cultures were positive for MTB and all were positive by the
      LC assay. The remaining 117 culture bottles were negative in the LC assay and
      grew various MOTT. This real-time MTB assay is sensitive and specific; a result
      was available within 1 h of having a DNA sample available for testing.

PMID- 12409389
TI  - Molecular characterization of hepatitis a virus isolates from a transcontinental
      shellfish-borne outbreak.
AB  - One hundred eighty-four serologically confirmed cases of hepatitis A were
      reported in eastern Spain in 1999. A matched case-control study implicated
      imported coquina clams complying with European Union shellfish standards as the
      source of infection; this implication was confirmed by the detection by reverse
      transcription-PCR of hepatitis A virus (HAV) RNA in shellfish samples. In spite
      of the recognized low variability of HAV, genetic characterization of the
      complete capsid region of virus isolates from patient serum samples revealed the
      existence of both synonymous and nonsynonymous variants. Two antigenic variants
      were detected, one in a discontinuous epitope defined by monoclonal antibody K3
      4C8 and a second in a linear VP1 epitope of the virus. In spite of these
      antigenic variants, all isolates were assigned to genotype IB, providing further
      evidence that the outbreak originated from a common source, although multiple
      strains were likely to be involved.

PMID- 12409390
TI  - Increasing genetic diversity of Salmonella enterica serovar typhi isolates from
      papua new guinea over the period from 1992 to 1999.
AB  - Pulsed-field gel electrophoresis (PFGE) of XbaI-digested chromosomal DNA was
      performed on 133 strains of Salmonella enterica serovar Typhi obtained from Papua
      New Guinea, with the objective of assessing the temporal variation of these
      strains. Fifty-two strains that were isolated in 1992 and 1994 were of one phage
      type, D2, and only two predominant PFGE profiles, X1 and X2, were present.
      Another 81 strains isolated between 1997 and 1999 have shown divergence, with
      four new phage types, UVS I (n = 63), UVS (n = 5), VNS (n = 4), and D1 (n = 9),
      and more genetic variability as evidenced by the multiple and new PFGE XbaI
      profiles (21 profiles; Dice coefficient, F = 0.71 to 0.97). The two profiles X1
      and X2 have remained the stable, dominant subtypes since 1992. Cluster analysis
      based on the unweighted pair group method using arithmetic averages algorithm
      identifies two main clusters (at 87% similarity), indicating that the divergence
      of the PFGE subtypes was probably derived from some genomic mutations of the X1
      and X2 subtypes. The majority of isolates were from patients with mild and
      moderate typhoid fever and had various XbaI profiles. A single isolate from a
      patient with fatal typhoid fever had a unique X11 profile, while four of six
      isolates from patients with severe typhoid fever had the X1 pattern. In addition,
      12 paired serovar Typhi isolates recovered from the blood and fecal swabs of
      individual patients exhibited similar PFGE patterns, while in another 11
      individuals paired isolates exhibited different PFGE patterns. Three pairs of
      isolates recovered from three individuals had different phage types and PFGE
      patterns, indicating infection with multiple strains. The study reiterates the
      usefulness of PFGE in assessing the genetic diversity of S. enterica serovar
      Typhi for both long-term epidemiology and in vivo stability and instability
      within an individual patient.

PMID- 12409391
TI  - Evaluation of an enzyme-linked immunosorbent assay (ELISA) with affinity-purified
      Em18 and an ELISA with recombinant Em18 for differential diagnosis of alveolar
      echinococcosis: results of a blind test.
AB  - Alveolar echinococcosis (AE) is the most potentially lethal parasitic zoonosis of
      the nontropical areas in the northern hemisphere, where cystic echinococcosis
      (CE) is also endemic. Both AE and CE are highly endemic in China, and both
      serologic detection of echinococcosis, either AE or CE, and differentiation of AE
      from CE are crucial problems. Evaluation of Western blot analysis (WB) and enzyme
      linked immunosorbent assay (ELISA) for the Em18 antigen, using affinity-purified
      and recombinant Em18, was carried out "blindly" using 60 human sera from patients
      diagnosed in France. The results were compared with those obtained using a
      commercially available Echinococcus WB immunoglobulin G (IgG) kit developed in
      France. The Em18 WB and Echinococcus WB IgG showed very similar results for
      detection of AE. Both affinity-purified Em18 or a recombinant Em18 WB and
      Echinococcus WB IgG seem useful for identification of AE, and the latter seems
      appropriate for both AE and CE, whereas affinity-purified Em18 ELISA and the
      newly developed recombinant Em18 ELISA appear to be suitable for detection of AE,
      especially for epidemiological surveys.

PMID- 12409392
TI  - Evaluation of the ICT malaria P.f/P.v and the OptiMal rapid diagnostic tests for
      malaria in febrile returned travellers.
AB  - Rapid diagnostic tests (RDTs) are less reliant on expert microscopy and have the
      potential to reduce errors in malaria diagnosis but have not been extensively
      evaluated in nonimmune persons or in countries where infection is not endemic. We
      evaluated the ICT P.f/P.v (ICT-Amrad, Sydney, Australia) and OptiMal (Flow Inc.,
      Portland, Oreg.) assays prospectively for the diagnosis of malaria in 158
      specimens from 144 febrile returned travellers in Australia by using expert
      microscopy and PCR as reference standards. Malaria was diagnosed in 93 specimens
      from 87 patients by expert microscopy, with 3 additional specimens from recently
      treated patients testing positive for Plasmodium falciparum by PCR. For the
      diagnosis of asexual-stage P. falciparum malaria, the sensitivity and specificity
      of the ICT P.f/P.v assay were 97 and 90%, respectively, and those of the OptiMal
      assay were 85 and 96%, respectively. The ICT P.f/P.v assay missed one infection
      with a density of 45 parasites/ micro l, whereas the OptiMal assay missed
      infections up to 2,500/ micro l; below 1,000/ micro l, its sensitivity was only
      43%. For the diagnosis of P. vivax malaria, the sensitivity and specificity of
      the ICT P.f/P.v assay were 44 and 100%, respectively, and those of the OptiMal
      assay were 80 and 97%, respectively. Both assays missed infections with parasite
      densities over 5,000/ micro l: up to 10,000/ micro l with the former and 5,300/
      micro l with the latter. Despite the high sensitivity of the ICT P.f/P.v assay
      for P. falciparum malaria, caution is warranted before RDTs are widely adopted
      for the diagnosis of malaria in nonimmune patients or in countries where malaria
      is not endemic.

PMID- 12409393
TI  - Single and combination antibiotic susceptibilities of planktonic, adherent, and
      biofilm-grown Pseudomonas aeruginosa isolates cultured from sputa of adults with
      cystic fibrosis.
AB  - Evidence suggests that Pseudomonas aeruginosa bacteria form biofilms within the
      airways of adults with cystic fibrosis (CF). The objective of this study was to
      determine whether clinical isolates of P. aeruginosa recovered from adults with
      CF have similar susceptibilities to individual antibiotics and to antibiotic
      combinations when grown as adherent monolayers or as biofilms compared to when
      they are grown using planktonic methods. Twelve multiresistant P. aeruginosa
      isolates, one mucoid and one nonmucoid from each of six CF patients, were grown
      conventionally under planktonic conditions, as adherent bacterial monolayers, and
      as biofilms. Each bacterial isolate remained genotypically identical despite
      being cultured under planktonic, adherent, or biofilm growth conditions. Isolates
      grown as adherent monolayers and as biofilms were less susceptible to
      bactericidal killing by individual antibiotics compared to those grown
      planktonically. More importantly, biofilm-grown bacteria, but not adherent
      monolayer-grown bacteria, were significantly less susceptible to two- and three
      drug combinations of antibiotics than were planktonically grown bacteria (P =
      0.005). We conclude that biofilm-grown bacteria derived from patients with CF
      show decreased susceptibility to the bactericidal effects of antibiotic
      combinations than do adherent and planktonically grown bacteria.

PMID- 12409394
TI  - Epidemiological features of invasive Kingella kingae infections and respiratory
      carriage of the organism.
AB  - The age, sex, and seasonal distributions of invasive Kingella kingae infections
      in southern Israel were examined and compared to the epidemiology of respiratory
      carriage of the organism. Medical records of all patients diagnosed between 1988
      and 2002 were reviewed, and 2,044 oropharyngeal specimens were cultured on
      selective media during two periods (February to May and October to December) in
      2001. Invasive infections significantly affected children (73 of 74 patients
      [98.6%] were younger than 4 years), 50 patients (67.8%) were males (P = 0.045),
      and 55 episodes (74.3%) occurred between July and December (P = 0.004). Carriage
      was higher in the 0- to 3-year-old group and decreased with increasing age (P for
      trend = 0.0008). Carriage rates were similar in both sexes and did not
      significantly differ between the February-to-May and October-to-December periods.
      The highest rate of carriage of K. kingae coincided with the age (less than 4
      years) at which invasive infections were especially frequent. The peculiar sex
      and seasonal distributions of invasive disease, however, cannot be readily
      explained by the epidemiology of respiratory carriage. Viral infections and other
      yet-to-be-defined cofactors may play a role in the causation of invasive K.
      kingae infections.

PMID- 12409395
TI  - Rate of occurrence and pathogenic effect of enteroaggregative Escherichia coli
      virulence factors in international travelers.
AB  - One or more putative enteroaggregative Escherichia coli (EAEC) virulence factors
      (aggA, aggR, aspU, or aafA) were identified in 60 (70%) of 86 EAEC isolates from
      travelers with diarrhea compared with a rate of 7 (8%) of 90 in patients with
      diarrhea who were infected with nonadherent E. coli (odds ratio, 27.36; 95%
      confidence interval, 11.30 to 65.91). The presence of aggR or one or more
      virulence factors in EAEC from patients with diarrhea was associated with a
      statistically increased concentration of interleukin-8 (IL-8) in feces compared
      with that in EAEC negative for these factors: for aggR positive (9 of 12 [75%];
      median, 800 pg/ml) versus aggR negative (5 of 18 [28%]; median, 0), P < 0.05; and
      for isolates positive for > or =1 virulence factor (13 of 21 [62%]; median, 360
      pg/ml) versus those negative for > or =1 virulence factor (1 of 9 [11%]; median,
      0), P < 0.05. Other fecal cytokines (IL-1beta and IL-1ra) were found in increased
      concentrations (P < 0.05 when at least one EAEC virulence factor was present
      compared with the concentrations when EAEC negative for multiple virulence
      factors was found in patients with diarrhea. Putative virulence factors were
      commonly found in EAEC from patients with diarrhea, and the pathogenicity of many
      strains was suggested by showing an association between the presence of plasmid
      borne virulence factors and the presence of fecal cytokines. The different
      patterns of virulence factors of EAEC revealed several clusters demonstrating
      diversity among the isolates from the various regions.

PMID- 12409396
TI  - Novel allelic variants of Mycobacteria isolated in Brazil as determined by PCR
      restriction enzyme analysis of hsp65.
AB  - Human isolates of Mycobacterium collected in 16 different states of Brazil were
      submitted to PCR-restriction analysis (PRA) of a 439-bp fragment of the hsp65
      gene with HaeIII and BstEII. Fourteen allelic variants not described in clinical
      isolates so far were observed among 36 (10%) of 356 Brazilian strains, including
      a new pattern for Mycobacterium scrofulaceum, M. intracellulare, and M.
      flavescens, two new patterns for M. fortuitum, three new patterns each for M.
      gordonae and M. terrae, and one new pattern for M. avium complex-like strains.
      Two unidentified strains each also presented a new pattern, strongly suggesting
      that Mycobacterium genotypes are distributed biogeographically. The PRA procedure
      was also performed with 43 reference isolates belonging to 34 species, adding a
      further six new patterns to the identification algorithm. A database containing
      the normalized restriction patterns of both enzymes was constructed. Patterns
      available on the Internet can be introduced into this database, which will make
      possible the comparison of genotypes from isolates from different parts of the
      world.

PMID- 12409397
TI  - Heterogeneity and seroprevalence of a newly identified avian hepatitis e virus
      from chickens in the United States.
AB  - We recently identified and characterized a novel virus, designated avian
      hepatitis E virus (avian HEV), from chickens with hepatitis-splenomegaly syndrome
      (HS syndrome) in the United States. Avian HEV is genetically related to but
      distinct from human and swine HEVs. To determine the extent of genetic variation
      and the seroprevalence of avian HEV infection in chicken flocks, we genetically
      identified and characterized 11 additional avian HEV isolates from chickens with
      HS syndrome and assessed the prevalence of avian HEV antibodies from a total of
      1,276 chickens of different ages and breeds from 76 different flocks in five
      states (California, Colorado, Connecticut, Virginia, and Wisconsin). An enzyme
      linked immunosorbent assay using a truncated recombinant avian HEV ORF2 antigen
      was developed and used to determine avian HEV seroprevalence. About 71% of
      chicken flocks and 30% of chickens tested in the study were positive for
      antibodies to avian HEV. About 17% of chickens younger than 18 weeks were
      seropositive, whereas about 36% of adult chickens were seropositive. By using a
      reverse transcription-PCR (RT-PCR) assay, we tested 21 bile samples from chickens
      with HS syndrome in California, Connecticut, New York, and Wisconsin for the
      presence of avian HEV RNA. Of the 21 bile samples, 12 were positive for 30- to 35
      nm HEV-like virus particles by electron microscopy (EM). A total of 11 of the 12
      EM-positive bile samples and 6 of the 9 EM-negative bile samples were positive
      for avian HEV RNA by RT-PCR. The sequences of a 372-bp region within the helicase
      gene of 11 avian HEV isolates were determined. Sequence analyses revealed that
      the 11 field isolates of avian HEV had 78 to 100% nucleotide sequence identities
      to each other, 79 to 88% identities to the prototype avian HEV, 76 to 80%
      identities to chicken big liver and spleen disease virus, and 56 to 61%
      identities to other known strains of human and swine HEV. The data from this
      study indicated that, like swine and human HEVs, avian HEV isolates are
      genetically heterogenic and that avian HEV infection is enzoonotic in chicken
      flocks in the United States.

PMID- 12409398
TI  - Molecular methods for cytomegalovirus surveillance in bone marrow transplant
      recipients.
AB  - Two different methods for detection of cytomegalovirus (CMV), PCR and hybrid
      capture (HC), were compared by using plasma, peripheral blood leukocytes (PBLs),
      and whole blood (WB) from allogeneic bone marrow transplant recipients. One
      hundred specimens were obtained from nine children over an 18-month surveillance
      period. PCR of plasma for CMV was used for clinical management. The proportions
      of samples positive for CMV DNA by PCR with plasma, HC with WB, and PCR with PBLs
      were 21, 28, and 37%, respectively. Among 44 samples that were tested by all
      three methods, 68% had concordant results. By using a robust definition of true
      positive samples (positivity by two or more methods or positivity of sequential
      samples by one method), the sensitivities of PCR with plasma, HC with WB, and PCR
      with PBLs were 50, 67, and 83%, respectively, and the specificities were 100, 96,
      and 96%, respectively. Two patients developed CMV-associated end-organ disease
      (one developed respiratory disease, and one developed gastrointestinal disease).
      CMV DNA was not detected in the plasma 1 week prior to the development of
      symptoms in either patient, whereas HC with WB was positive for both patients and
      PCR with PBLs was for one patient. These data suggest that WB or PBLs might be
      the preferred sample for use for surveillance for CMV in immunocompromised
      patients.

PMID- 12409399
TI  - Performance characteristics and utilization of rapid antigen test, DNA probe, and
      culture for detection of group a streptococci in an acute care clinic.
AB  - Group A streptococcus (GAS) antigen testing has become a routine point-of-care
      (POC) test in acute care settings. Concern about performance parameters (PP) of
      these tests as well as inappropriate antibiotic use has resulted in various
      recommendations regarding diagnosis of GAS. There were two objectives in this
      study. The first was to evaluate the rapid GAS antigen test presently in use
      (Thermo BioStar, Boulder, Colo.) and the GAS Direct probe test (Gen-Probe, San
      Diego, Calif.) compared to culture. The second was to define the optimal use of
      these technologies in a large acute care pediatric clinic. A total of 520
      consecutive pediatric patients presenting with symptoms of pharyngitis at any of
      three Lahey Clinic acute care facilities were evaluated. Pharyngeal specimens
      were collected using a double-swab collection device (Copan, Corona, Calif.). One
      swab was used for the antigen test, the second was used for the probe test, and
      the pledget was placed in the collection device for culture on 5% sheep blood
      agar, incubated for 48 h anaerobically, and subsequently placed in Todd-Hewitt
      broth. After discrepant analysis, sensitivity, specificity, and positive and
      negative predictive values were as follows: 94.8, 100, 100, and 96.9% for the
      probe test and 86.1, 97.1, 93.7, and 93.4% for the antigen test, respectively.
      Sensitivity using an enhanced culture technique was 99.4% (163 of 164). False
      positive (FP) antigen results were often seen from patients previously diagnosed
      and/or treated for GAS. No FP results were seen with the probe test. Colony
      counts for the false-negative (FN) antigen tests were higher than those for the
      FN probe tests. Compared to culture and DNA probe, the rapid antigen test (RAT)
      offered a result at the time of the patient's visit, with acceptable PP when
      prevalence of disease is high. Follow-up testing with the RAT of GAS patients who
      previously tested as positive should be avoided due to increased FP results. The
      probe test was comparable to culture in performance. Results indicate the probe
      test can be used as the primary test or as a backup to negative antigen tests.
      The probe test offers the advantage over culture of same-day reporting of a final
      result but, in contrast to a POC test, necessitates follow-up communication to
      the patient. Preliminary data show the specificity of the probe test to be
      greater than that of the RAT for patients previously diagnosed with GAS.

PMID- 12409400
TI  - Optimal DNA isolation method for detection of bacteria in clinical specimens by
      broad-range PCR.
AB  - Broad-range amplification of bacterial DNA from clinical specimens has proved
      useful for the diagnosis of various bacterial infections, especially during
      antimicrobial treatment of the patient. Optimal sample processing protocols for
      diagnostic broad-range bacterial PCR should release DNA from an array of target
      organisms with equal efficiencies and wash out inhibitory factors from various
      sample types without introducing bacterial DNA contamination to the amplification
      reaction. In the present study, two physical cell wall disintegration methods,
      bead beating and sonication, for enhanced detection of organisms with difficult
      to-lyse cell walls were studied. The analytical sensitivities of several
      commercially available DNA purification kits, which were used with and without
      additional cell disintegration steps, were compared by using dilution series of
      model bacteria. Selected purification methods were used to process routine
      clinical specimens in parallel with the standard phenol-ether DNA extraction, and
      the results obtained by bacterial PCR and sequencing with the two template
      preparations were compared. The method with the DNA isolation kit with the lowest
      detection limits from the bacterial suspensions (Masterpure) did not prove to be
      superior to the standard method when the two methods were applied to 69 clinical
      specimens. For another set of 68 clinical specimens, DNA purified with a glass
      fiber filter column (High Pure) with an additional sonication step yielded
      results well in accord with those obtained by the standard method. Furthermore,
      bacterial DNA was detected in four samples that remained PCR negative by the
      standard method, and three of these contained DNA from gram-positive pathogens.
      Three samples were positive by the standard method only, indicating the
      limitations of applying any single method to all samples.

PMID- 12409401
TI  - Human rhinovirus 87 and enterovirus 68 represent a unique serotype with
      rhinovirus and enterovirus features.
AB  - It has recently been reported that all but one of the 102 known serotypes of the
      genus Rhinovirus segregate into two genetic clusters (C. Savolainen, S.
      Blomqvist, M. N. Mulders, and T. Hovi, J. Gen. Virol. 83:333-340, 2002). The only
      exception is human rhinovirus 87 (HRV87). Here we demonstrate that HRV87 is
      genetically and antigenically highly similar to enterovirus 68 (EV68) and is
      related to EV70, the other member of human enterovirus group D. The partial
      nucleotide sequences of the 5' untranslated region, capsid regions VP4/VP2 and
      VP1, and the 3D RNA polymerase gene of the HRV87 prototype strain F02-3607 Corn
      showed 97.3, 97.8, 95.2, and 95.9% identity to the corresponding regions of EV68
      prototype strain Fermon. The amino acid identities were 100 and 98.1% for the
      products of the two capsid regions and 97.9% for 3D RNA polymerase. Antigenic
      cross-reaction between HRV87 and EV68 was indicated by microneutralization with
      monotypic antisera. Phylogenetic analysis showed definite clustering of HRV87 and
      EV68 with EV70 for all sequences examined. Both HRV87 and EV68 were shown to be
      acid sensitive by two different assays, while EV70 was acid resistant, which is
      typical of enteroviruses. The cytopathic effect induced by HRV87 or EV68 was
      inhibited by monoclonal antibodies to the decay-accelerating factor known to be
      the receptor of EV70. We conclude that HRV87 and EV68 are strains of the same
      picornavirus serotype presenting features of both rhinoviruses and enteroviruses.

PMID- 12409402
TI  - Comparison of serum hepatitis C virus RNA and core antigen concentrations and
      determination of whether levels are associated with liver histology or affected
      by specimen storage time.
AB  - An enzyme immunoassay has recently been developed for the hepatitis C virus (HCV)
      core antigen. To evaluate the possible association between core antigen and HCV
      RNA levels with regards to the change in liver histology over time as well as
      study the effect of duration of storage on viral load results, sequential sera
      were analyzed from 45 patients with chronic HCV infection who had undergone two
      or more liver biopsies. A relatively strong association was found between the
      core antigen and HCV RNA concentrations (r(s) = 0.8), with a core antigen level
      of 1 pg/ml corresponding to approximately 1,000 IU/ml. All 42 sera with
      detectable HCV RNA at the time of the second biopsy had core antigen
      concentrations above 1 pg/ml, and the three sera without detectable HCV RNA had
      concentrations below 1 pg/ml. No association was found between HCV RNA or core
      antigen levels and the stage of fibrosis in biopsy samples, progression of
      fibrosis, necro-inflammatory grade, steatosis, genotype, alanine aminotransferase
      level, or alcohol consumption. A significant association was demonstrated between
      the storage time of the samples and both the HCV RNA and core antigen
      concentrations. The median log HCV RNA concentrations (international
      units/milliliter) were 3.92 for the sera obtained at the time of the first biopsy
      (median storage time, 13.0 years) and 4.41 for the sera obtained at the time of
      the second biopsy (median storage time, 6.6 years) compared to 5.96, the median
      for 102 different routine clinical patient samples.

PMID- 12409403
TI  - Identification of the causative organism of tuberculous lymphadenitis in ethiopia
      by PCR.
AB  - Tuberculous lymphadenitis (TBLN) is a common form of extrapulmonary tuberculosis
      with multiple differential diagnoses. Demonstration of the etiologic agent by
      smear microscopy or culture of fine needle aspirate (FNA) specimens is often
      unsuccessful. FNA specimens from 40 patients presenting at a rural health center
      in South Ethiopia and diagnosed as positive for TBLN on the basis of clinical and
      cytological criteria were analyzed for mycobacterial DNA by PCR. Thirty (75%) had
      cervical lymphadenitis and 11 (27.5%) were seropositive for human
      immunodeficiency virus (HIV). Three primer sets were initially used to identify
      the causative agent at the genus (antigen 85 complex), complex (IS6110 insertion
      sequence), and species (pncA gene and allelic variation) levels. Among the forty
      TBLN cases, 35 (87.5%) were positive by PCR at the genus and complex levels.
      Based on PCR for detection of allelic variation at position 169, 24 (68.6%) of
      the 35 were positive for Mycobacterium tuberculosis and 6 (17.1%) were positive
      for M. bovis. These six were positive in additional PCR assays using the JB21
      JB22 primer set, which is highly specific for M. bovis. Five (14.1%) showed
      amplification for both M. tuberculosis and M. bovis with the allele-specific
      primer set. Cooccurrence of pyrazinamide (PZA)-sensitive and -resistant M.
      tuberculosis in those five cases was indicated, since all were negative in assays
      with the JB21-JB22 primer set. This feature was seen in 3 of 11 HIV-positive and
      2 of 29 HIV-negative individuals (P < 0.001). CONCLUSION: among 35 PCR-positive
      cases of TBLN from southern Ethiopia, 29 (82.9%) were caused by M. tuberculosis
      and six (17.1%) were caused by M. bovis.

PMID- 12409404
TI  - Serological diagnosis of ovine enzootic abortion by enzyme-linked immunosorbent
      assay with a recombinant protein fragment of the polymorphic outer membrane
      protein POMP90 of Chlamydophila abortus.
AB  - Ovine enzootic abortion (OEA) resulting from infection of sheep and goats with
      Chlamydophila abortus is of major economic importance worldwide. Over the last 50
      years the serological diagnosis of infection has been based mainly on the
      complement fixation test (CFT), which lacks both sensitivity and specificity
      because of cross-reactive antibodies to other gram-negative bacteria, including
      another common chlamydial pathogen of sheep, Chlamydophila pecorum. In the
      present study, a series of overlapping recombinant antigens representing the
      polymorphic outer membrane protein POMP90 of C. abortus was assessed by enzyme
      linked immunosorbent assay (ELISA) with a panel of 143 serum samples from sheep
      experimentally infected with C. abortus, from sheep clinically free of OEA, and
      from specific-pathogen-free lambs experimentally infected with different subtypes
      of C. pecorum. The results were compared to those obtained by CFT and another
      recently described test, an indirect ELISA (iELISA) with the recombinant OMP91B
      (rOMP91B) fragment (rOMP91B iELISA) (D. Longbottom, E. Psarrou, M. Livingstone,
      and E. Vretou, FEMS Microbiol. Lett. 195:157-161, 2001). The rOMP90-3 and rOMP90
      4 ELISAs were identified as being more sensitive and specific than CFT. Assays
      with both fragments were evaluated further with a panel of 294 field serum
      samples from flocks with documented histories of abortion, from flocks with no
      clinical histories of abortion but which had a high proportion of samples
      seropositive by CFT, and from animals with no histories of abortion but from
      which various C. pecorum subtypes had been isolated. ELISAs with both POMP90
      fragments outperformed CFT with serum samples from C. pecorum-infected animals,
      producing no false-positive results. However, the ELISA with the rOMP90-4
      fragment appeared to be more sensitive than the one with rOMP90-3, as it
      identified more of the OEA-positive samples. The ELISA with the rOMP90-4 fragment
      was also able to identify apparently healthy animals that were infected with an
      enteric strain of C. abortus in flocks that were probably infected with both
      enteric C. abortus and C. pecorum strains. The identification of animals infected
      with enteric C. abortus is extremely important in controlling the spread of OEA.
      Overall, the new rOMP90-4 ELISA was found to be a more sensitive and specific
      test than CFT for differentiating animals infected with C. abortus from those
      infected with C. pecorum.

PMID- 12409405
TI  - Development of a peptide-mediated capture PCR for detection of Mycobacterium
      avium subsp. paratuberculosis in milk.
AB  - Based on phage display technology, a peptide-mediated magnetic separation
      technique was developed to facilitate selective isolation of Mycobacterium avium
      subsp. paratuberculosis (M. paratuberculosis) from bulk milk of naturally
      infected dairy herds. Nine recombinant bacteriophages binding to M.
      paratuberculosis were isolated from a commercial phage-peptide library encoding
      random 12-mer peptides. Nucleotide sequencing revealed the deduced sequence of
      the binding peptides. One peptide with the sequence NYVIHDVPRHPA, designated
      aMP3, was chemically synthesized with an amino-terminal biotin residue attached
      via an amino-hexacarbonic acid spacer molecule. Paramagnetic beads coated with
      the phage or with peptide aMP3 enabled the capture of M. paratuberculosis from
      milk. Combining this peptide-mediated magnetic separation with an ISMav2-based
      PCR allowed the detection of M. paratuberculosis in artificially spiked milk down
      to a concentration of 10(1) ml(-1). Experiments using milk from naturally
      infected cows and bulk milk samples from infected herds demonstrated that the
      peptide-mediated capture PCR is sufficiently sensitive to detect single strong
      shedders in pooled milk samples. The method, for the first time, applies phage
      display technology to microbial diagnostics and has potential value as a
      completely standardizable tool for the routine M. paratuberculosis screening of
      bulk milk samples at acceptable costs.

PMID- 12409406
TI  - Improved monitoring of cytomegalovirus infection after allogeneic hematopoietic
      stem cell transplantation by an ultrasensitive plasma DNA PCR assay.
AB  - Cytomegalovirus (CMV) DNA amplification assays in plasma have shown limited
      sensitivity compared to the detection of pp65 antigen in leukocytes. Our goal was
      to increase the sensitivity of a commercial CMV DNA PCR quantitative assay. After
      modification, the new assay was able to reproducibly detect 20 CMV DNA copies/ml
      of plasma. We compared this new ultrasensitive PCR assay with the standard PCR
      and the pp65 test for CMV detection and quantification in 22 consecutive
      allogeneic hematopoietic stem cell recipients. CMV infection or reactivation was
      detected in 84 of 319 (26%) samples by the ultrasensitive PCR assay compared to
      38 of 319 (12%) samples by the pp65 assay (P < 0.01). All samples positive by the
      pp65 assay were positive by the ultrasensitive PCR, and CMV episodes were
      detected on average 4 days earlier and 7 days later than the first and the last
      pp65-positive test, respectively. In addition, during CMV episodes, the
      ultrasensitive assay identified positive samples that were inconsistently
      detected by the pp65 assay. The ultrasensitive assay was also much more sensitive
      than the standard PCR, with 26 versus 12% of CMV DNA-positive samples (P < 0.01).
      This assay improved the monitoring of CMV infection or reactivation in
      hematopoietic allogeneic stem cell recipients.

PMID- 12409408
TI  - Virus diversity in a winter epidemic of acute diarrhea in France.
AB  - In France, an epidemic peak of acute diarrhea is observed each winter. Previous
      results suggested a viral etiology for these winter epidemics. We investigated
      the role of enteric viruses in acute diarrhea and their molecular diversity. One
      hundred sixty-one patients with acute diarrhea and 45 healthy patients (controls)
      from the general population were given a standardized questionnaire between
      December 1998 and May 1999. Stool specimens were screened for group A and C
      rotaviruses, human caliciviruses, astroviruses, and adenovirus types 40 and 41 by
      reverse transcription-PCR and/or enzyme immunoassay. Virologic analysis was
      positive for 63 cases (39%). Caliciviruses and group A rotaviruses were the most
      frequent (19 and 17% of cases, respectively). Two control stool specimens were
      found positive for group A rotavirus, and one was found positive for astrovirus.
      Molecular characterization of the strains disclosed a cocirculation of P[8],G1,
      P[8],G4, and P[4],G2 rotaviruses; type 1, 2, 3, 4, and 8 astroviruses; and
      Sapporo-like and Norwalk-like human caliciviruses. These four types of viruses
      accounted for an attributable risk of acute diarrhea of 34.7% for the general
      population, under the assumption of a causal role of these viruses.

PMID- 12409407
TI  - OspE-related, OspF-related, and Elp lipoproteins are immunogenic in baboons
      experimentally infected with Borrelia burgdorferi and in human lyme disease
      patients.
AB  - Presently, the rhesus macaque is the only nonhuman primate animal model utilized
      for the study of Lyme disease. While this animal model closely mimics human
      disease, rhesus macaques can harbor the herpes B virus, which is often lethal to
      humans; macaques also do not express the full complement of immunoglobulin G
      (IgG) subclasses found in humans. Conversely, baboons contain the full complement
      of IgG subclasses and do not harbor the herpes B virus. For these reasons,
      baboons have been increasingly utilized as the basis for models of infectious
      diseases and studies assessing the safety and immunogenicity of new vaccines.
      Here we analyzed the capability of baboons to become infected with Borrelia
      burgdorferi, the agent of Lyme disease. Combined culture and PCR analyses of tick
      and syringe-infected animals indicated that baboons are a sufficient host for B.
      burgdorferi. Analysis of the antibody responses in infected baboons over a 48
      week period revealed that antibodies are generated early during infection against
      many borrelial antigens, including the various OspE, OspF, and Elp paralogs that
      are encoded on the ubiquitous 32-kb circular plasmids (cp32s). By using the
      baboon sera generated by experimental infection it was determined that a
      combination of two cp32-encoded lipoproteins, OspE and ElpB1, resulted in highly
      specific and sensitive detection of B. burgdorferi infection. An expanded
      analysis, which included 39 different human Lyme disease patients, revealed that
      a combination of the OspE and ElpB1 lipoproteins could be the basis for a new
      serodiagnostic assay for Lyme disease. Importantly, this novel serodiagnostic
      test would be useful independent of prior OspA vaccination status.

PMID- 12409409
TI  - Disseminated mycotic infection caused by Colletotrichum acutatum in a Kemp's
      ridley sea turtle (Lepidochelys kempi).
AB  - Colletotrichum acutatum is a cosmopolitan plant pathogen with a wide host range.
      While the organism's phytopathogenic potential has been well documented, it has
      never been reported as an etiologic agent of disease in either animals or humans.
      In this case, a juvenile Kemp's ridley sea turtle, Lepidochelys kempi, probably
      with immune compromise following cold stunning (extended hypothermia), developed
      a disseminated mycotic infection in the lungs and kidneys. Prophylactic treatment
      with oral itraconazole did not prevent or cure the infection. This report of a
      Colletotrichum acutatum infection in an animal extends the range of disease
      caused by this organism beyond that of a phytopathogen.

PMID- 12409410
TI  - Presumptive identification of Candida kefyr on levine formulation of eosin
      methylene blue agar.
AB  - Three hundred thirty-one yeast and yeast-like isolates were cultivated on eosin
      methylene blue agar. While the sensitivity rate for Candida kefyr isolates
      producing a metallic green sheen was 81.8%, the high positive predictive value
      (100%) for yeast isolates with this phenotype belonging to C. kefyr suggests that
      these isolates can be presumptively identified as C. kefyr.

PMID- 12409411
TI  - Modification of dienes mutual inhibition test for epidemiological
      characterization of Pseudomonas aeruginosa isolates.
AB  - Pseudomonas aeruginosa is an important cause of community-associated and
      nosocomial infections related to exposure to aqueous environments. Such
      infections often occur in the setting of a common-source outbreak, in which case
      epidemiological characterization of isolates may be necessary. In this
      preliminary study, a modification of the Dienes mutual inhibition test,
      ordinarily used to assess the relatedness of swarming Proteus mirabilis strains,
      was used to study 15 P. aeruginosa isolates, with the results compared to those
      obtained by ribotype analysis. Complete concordance was noted between the results
      of the Dienes test and those of ribotyping. These observations suggest that
      further studies are warranted to assess the utility of the modified Dienes test
      as a simple, inexpensive, and reliable means for epidemiological typing of P.
      aeruginosa.

PMID- 12409412
TI  - Dissemination of new methicillin-resistant Staphylococcus aureus clones in the
      community.
AB  - Multiple methicillin-resistant Staphylococcus aureus (MRSA) clones carrying type
      IV staphylococcal cassette chromosome mec were identified in the community
      acquired MRSA strains of both the United States and Australia. They multiplied
      much faster than health-care-associated MRSA and were resistant to fewer non-beta
      lactam antibiotics. They seem to have been derived from more diverse S. aureus
      populations than health-care-associated MRSA strains.

PMID- 12409413
TI  - Direct detection and identification of African trypanosomes by fluorescence in
      situ hybridization with peptide nucleic acid probes.
AB  - We have developed a rapid and easy to perform fluorescence in situ hybridization
      test that allows specific identification of trypanosomes from the subgenus
      Trypanozoon, using peptide nucleic acid probes. Probes were designed to target
      subgenus-specific sequences on the multiple-copy 18S rRNA, greatly facilitating
      the detection of a single trypanosome.

PMID- 12409414
TI  - Detection of oxazolidinone-resistant Enterococcus faecalis and Enterococcus
      faecium strains by real-time PCR and PCR-restriction fragment length polymorphism
      analysis.
AB  - A real-time PCR assay identified linezolid-resistant Enterococcus faecalis and
      Enterococcus faecium isolates with a G2576U rRNA mutation. PCR-restriction
      fragment length polymorphism analysis of ribosomal DNA amplicons with NheI also
      detected this mutation. Both assays detected isolates heterozygous at this
      position. Recognition of isolates with what is presently the most frequent
      oxazolidinone resistance mutation may aid surveillance and individual case
      management.

PMID- 12409415
TI  - Cryopreserved cell monolayers for rapid detection of herpes simplex virus and
      influenza virus.
AB  - Cryopreserved cell monolayers are a new cell culture technology intended to
      ensure the availability of cells in the laboratory for virus detection. Two
      cryopreserved cell monolayers, ELVIS for the detection of herpes simplex virus
      (HSV) and R-Mix for the detection of influenza virus, were evaluated. The results
      indicated that fresh and cryopreserved cell monolayers are comparable in
      sensitivity for the detection of HSV and influenza virus. The cells retain the
      same level of sensitivity for up to 4 months at -80 degrees C.

PMID- 12409416
TI  - Real-time PCR for detection and differentiation of gram-positive and gram
      negative bacteria.
AB  - We developed a consensus real-time PCR protocol that enables us to detect spiked
      bacterial 16S DNA from specimens such as water, urine, plasma, and sputum. The
      technique allows an exact Gram stain classification of 17 intensive care unit
      relevant bacteria by means of fluorescence hybridization probes. All tested
      bacteria were identified correctly, and none gave a false-positive signal with
      the opposite Gram probe.

PMID- 12409417
TI  - Rapid identification and differentiation of Candida albicans and Candida
      dubliniensis by capillary-based amplification and fluorescent probe
      hybridization.
AB  - We developed a rapid genotypic assay to differentiate the germ tube-positive
      yeasts Candida albicans and Candida dubliniensis. Fluorescently labeled nucleic
      acid probe binding and subsequent denaturation from the target site in the PCR
      amplicons produced characteristic peak melting temperatures (T(m)) that
      identified each species. Peak T(m)s of C. albicans (n = 69) and C. dubliniensis
      (n = 28) isolates produced in the presence of their respective probes were 61.04
      +/- 0.64 degrees C and 60.52 +/- 1.01 degrees C (averages +/- standard
      deviations). No signal was generated when the C. albicans or C. dubliniensis
      probes were tested against DNA from their counterparts. Both probes reacted with
      Candida tropicalis DNA, but the T(m) was 51.85 +/- 0.05 degrees C with the C.
      albicans probe and 51.92 +/- 0.10 degrees C with the C. dubliniensis probe,
      differentiating C. tropicalis DNA from C. albicans and C. dubliniensis. A novel
      hybrid probe was designed to identify both species in a single reaction based on
      a 4 degrees C difference in peak T(m)s. Our assay is rapid (</=2 h) and allows
      reliable detection and differentiation of the two germ tube-positive Candida spp.

PMID- 12409418
TI  - Rapid assessment of phenotypic resistance to protease inhibitors in human
      immunodeficiency virus type 1 group O.
AB  - A bacteriophage lambda-based method was used to investigate the development of
      resistance to protease inhibitors (PI) in one subject infected with human
      immunodeficiency virus (HIV) type 1 group O who underwent multiple treatment
      regimens over a period of 4 years. A reduction in the susceptibility to indinavir
      of 6-fold and a reduction in the susceptibility to saquinavir of 24-fold were
      recognized after long exposure to these drugs with respect to baseline. The
      emergence of PI resistance corresponded to the selection of amino acid changes
      L10V, G48M, F53L, I54V, and L90M at the protease. The results were concordant
      with those obtained by a drug susceptibility assay with primary HIV isolates.

PMID- 12409419
TI  - Serological differentiation of infections with dengue virus serotypes 1 to 4 by
      using recombinant antigens.
AB  - The B domains of dengue virus serotypes 1 to 4 were expressed in Escherichia
      coli. The purified proteins were applied to immunoblot strips to detect serotype
      specific antibodies in paired serum samples from 41 patients with primary and
      secondary dengue infections. A close correlation between the results obtained
      with the immunoblot strips and by type-specific reverse transcription-PCR (T.
      Laue, P. Emmerich, and H. Schmitz, J. Clin. Microbiol. 37:2543-2547, 1999) was
      observed.

PMID- 12409420
TI  - Development of a hexaplex PCR assay for rapid detection of virulence and
      regulatory genes in Vibrio cholerae and Vibrio mimicus.
AB  - We have developed a hexaplex PCR assay for rapid detection of the virulence and
      regulatory genes for cholera toxin enzymatic subunit A (ctxA), zonula occludens
      toxin (zot), accessory cholera enterotoxin (ace), toxin-coregulated pilus (tcpA),
      outer membrane protein (ompU), and central regulatory protein ToxR (toxR) in
      Vibrio cholerae and Vibrio mimicus. This hexaplex PCR proved successful in
      screening pathogenic-toxigenic and nonpathogenic-nontoxigenic V. cholerae and V.
      mimicus strains from both clinical and environmental sources.

PMID- 12409421
TI  - 5' exonuclease assay for detection of serogroup Y Neisseria meningitidis.
AB  - The incidence of serogroup Y meningococcal disease has increased recently in the
      United States. Here, we describe the development of a 5' exonuclease assay for
      the detection of serogroup Y Neisseria meningitidis and demonstrate the
      usefulness of this assay for resolving serogroup identification of strains that
      are resistant to conventional serogrouping and for the nonculture identification
      of serogroup Y meningococcal disease.

PMID- 12409422
TI  - Evaluation of methods to increase the sensitivity and timeliness of detection of
      Streptococcus agalactiae in pregnant women.
AB  - Direct culture of rectovaginal specimens on Granada agar was compared to culture
      on sheep blood agar plate (SBAP) and AccuProbe detection of group B streptococcus
      from overnight LIM broth enhancement cultures (LIM-SBAP). Both broth-enhanced
      methods demonstrated excellent sensitivity (97.5% for LIM-SBAP and 93.5% for
      AccuProbe), while Granada agar demonstrated a sensitivity of only 40.3%.

PMID- 12409423
TI  - Impact of modified nonmeningeal Streptococcus pneumoniae interpretive criteria
      (NCCLS M100-S12) on the susceptibility patterns of five parenteral
      cephalosporins: report from the SENTRY antimicrobial surveillance program (1997
      to 2001).
AB  - The revised interpretive criteria for Streptococcus pneumoniae recently published
      in the NCCLS M100-S12 informational supplement provide two sets of breakpoints
      for some cephalosporins: one set for meningeal infection isolates and a new set
      for nonmeningeal infection isolates. The net effect of these changes was to
      increase the reported rates of susceptibility of S. pneumoniae to the more active
      parenteral cephalosporins, such as cefepime, cefotaxime, and ceftriaxone, by 9.1
      to 13.0%, bringing their in vitro rates much closer to those of amoxicillin
      (modified in an earlier NCCLS publication). These revised breakpoints will assist
      the rational prescribing of antimicrobial agents for the treatment of
      pneumococcal infections for specific types of infection and establish a greater
      correlation with clinical outcomes.

PMID- 12409424
TI  - Expanded-spectrum cephalosporin-resistant salmonella strains in Romania.
AB  - Thirteen Salmonella enterica serotype Typhimurium and one Salmonella enterica
      serotype Heidelberg strain resistant to expanded-spectrum cephalosporins were
      isolated from October 2000 to February 2001 from infants with gastroenteritis in
      Iasi, Romania. In all but one serotype Typhimurium isolate, resistance was due to
      the production of a CMY-2 cephalosporinase encoded by a nonconjugative plasmid.
      The remaining isolate produced an SHV-5-type beta-lactamase. Typing by pulsed
      field gel electrophoresis indicated that the CMY-2-producing serotype Typhimurium
      isolates were related.

PMID- 12409425
TI  - Nasal swab versus nasopharyngeal aspirate for isolation of respiratory viruses.
AB  - To determine the usefulness of nasal swabs as a simple method for detection of
      respiratory viruses, we compared nasal swabs and nasopharyngeal aspirates
      obtained at the same time from the opposite nostrils of 230 children with upper
      respiratory infection. The sensitivity of nasal swabs was comparable to that of
      nasopharyngeal aspirates for the detection of all major respiratory viruses
      except respiratory syncytial virus.

PMID- 12409426
TI  - Assessment of the nasopharyngeal bacterial flora of rhesus macaques: moraxella,
      Neisseria, haemophilus, and other genera.
AB  - The nasopharyngeal bacterial flora of healthy rhesus macaques was surveyed for
      the presence of Neisseria and Haemophilus species, as well as Moraxella
      catarrhalis. M. catarrhalis was found both in healthy rhesus macaques and in
      possibly immunocompromised rhesus macaques. Several Haemophilus spp. that are
      part of the normal nasopharyngeal bacterial flora of humans were found in many
      animals; these Haemophilus species included H. parahaemolyticus, H. segnis, and
      H. parainfluenzae. While Haemophilus influenzae was not identified, it is
      possible that the identification of H. influenzae types may have been thwarted by
      the growth of less fastidious species. A number of animals harbored Neisseria
      spp. such as N. sicca. However, Neisseria meningitidis was not found. In summary,
      it appears as though the rhesus macaque may be used as a model for M. catarrhalis
      infections. Moreover, in view of the susceptibility of macaques to organisms of
      the Haemophilus and Neisseria genera, it is possible that these animals may also
      accurately model nontypeable H. influenzae and N. meningitidis infections.

PMID- 12409427
TI  - Real-time fluorescence-based PCR for detection of malaria parasites.
AB  - A fluorescence-based real-time 5' nuclease PCR capable of detecting all four
      human malaria parasites was developed to screen large numbers of samples during
      an outbreak to prevent further transmission of malaria. The effectiveness of
      antimalarial therapy for malaria patients can be monitored by determining the
      reduction of parasitemia by this method.

PMID- 12409428
TI  - Quantification of hepatitis C virus in human liver and serum samples by using
      LightCycler reverse transcriptase PCR.
AB  - A highly sensitive, non-probe-based, real-time quantitative reverse transcriptase
      PCR was developed for viral load measurements in both serum and liver samples
      from patients with hepatitis C virus (HCV) infection. With synthetic RNA, the
      linearity of the approach was conserved over a wide range of HCV copy numbers.
      There was a strong correlation between hepatic and serum viral load measurements
      (r = 0.689, P = 0.004, n = 15), indicating that the level of viremia reflected
      the amount of virus present in the liver.

PMID- 12409429
TI  - In vitro susceptibilities of the Bacteroides fragilis group species: change in
      isolation rates significantly affects overall susceptibility data.
AB  - A comparison of antimicrobial susceptibility data of species of the Bacteroides
      fragilis group for 1989-1990 and 1998-1999 studies showed statistically
      significant increases or decreases in in vitro activity. Overall significant
      increases in resistance were noted for ampicillin-sulbactam and clindamycin,
      while significant decreases in resistance were noted for ertapenem and cefoxitin.
      Susceptibilities to piperacillin-tazobactam, imipenem, meropenem, and
      trovafloxacin remained virtually the same for the two studies. Importantly, a
      change in the rates of isolation of the various species showed the B. fragilis
      species comprised 58% of the isolates in 1989 to 1990 and 45% of the isolates in
      1998 to 1999. This change in rates of isolation of B. fragilis versus non-B.
      fragilis species had an overall effect on susceptibility data.

PMID- 12409430
TI  - Practical and sensitive screening strategy for detection of influenza virus.
AB  - This study evaluated the performance of Directigen FluA combined with a 3-day flu
      screening culture for the detection of influenza virus. This abbreviated protocol
      was a useful and effective tool and resulted in a substantial reduction in time,
      effort, and money spent, while not compromising sensitivity of influenza virus
      detection.

PMID- 12409431
TI  - High rate of transmission of penicillin-resistant Streptococcus pneumoniae
      between parents and children.
AB  - Transmission of Streptococcus pneumoniae between children and their parents was
      evaluated in 29 pairs from 25 families. The serotypes of 35 pneumococcal isolates
      from 18 (62.1%) of 29 child-parent pairs were identical. Of the 35 isolates, 23
      showed intermediate resistance and 10 were fully resistant to penicillin G. PCR
      indicated that all 35 strains had at least one alteration in penicillin-binding
      protein genes pbp1a, pbp2x, and pbp2b and 33 strains had macrolide resistance
      genes mef(A) and/or erm(B). As a result, the PCR patterns of 16 of 18 pairs were
      identical. Molecular typing by pulsed-field gel electrophoresis showed that 12
      pairs were indistinguishable, 3 pairs were closely related, 2 pairs were possibly
      related, and only one pair was different. Our data indicate the presence of a
      high rate of transmission of penicillin-resistant S. pneumoniae between children
      and their parents.

PMID- 12409432
TI  - PCR-based detection of Bacillus anthracis in formalin-fixed tissue from a patient
      receiving ciprofloxacin.
AB  - We demonstrate that Bacillus anthracis may be detected from a formalin-fixed,
      paraffin-embedded biopsy specimen, even after the patient has received antibiotic
      treatment. Although traditional PCR methods may not be sufficiently sensitive for
      anthrax detection in such patients, cycle numbers can be increased or PCR can be
      repeated by using an aliquot from a previous PCR as the template.

PMID- 12409433
TI  - Outbreak of nosocomial hepatitis C virus infection resolved by genetic analysis
      of HCV RNA.
AB  - In July 2000, symptomatic acute hepatitis C was diagnosed in five patients who
      had attended the emergency room of a municipal hospital on the same day, about 6
      weeks before. Investigation of the remaining 65 patients visited at the emergency
      room on that day disclosed that 8 patients had a positive anti-hepatitis C virus
      (anti-HCV) test and 4 of them had biochemical evidence of acute anicteric
      hepatitis. HCV RNA was detected in 12 of the 13 anti-HCV-positive patients.
      Phylogenetic analysis of the nonstructural 5A (NS5A) and E2 regions showed that
      10 patients, including all 9 with acute hepatitis, were infected with a closely
      related HCV strain, while the remaining 2 patients harbored unrelated strains.
      Flushing of intravenous catheters with heparin retrieved from a multidose heparin
      solution in saline was carried out for all the patients involved in the hepatitis
      outbreak but in only 1 of 23 (4%) matched controls recruited among HCV
      noninfected patients attending the emergency room on the same day, and this was
      the only significant difference concerning risk factors for HCV infection between
      patients and controls. Thus, accidental contamination of a multidose heparin
      solution with blood from an unrecognized HCV carrier was identified as the source
      of this nosocomial outbreak of hepatitis C.

PMID- 12409434
TI  - Immune responses of sheep to quadrivalent double emulsion foot-and-mouth disease
      vaccines: rate of development of immunity and variations among other ruminants.
AB  - Despite representing the majority of the world's foot-and-mouth disease (FMD)
      susceptible livestock, sheep and goats have generally been neglected with regard
      to their epidemiological role in the spread of FMD. In the present
      investigations, FMD virus quadrivalent double emulsion (Montanide ISA 206)
      vaccines were tested in sheep. The oil adjuvant elicited a better immune response
      at any time than did aluminum hydroxide gel vaccine, and the response developed
      quicker. The animals maintained their neutralizing antibody titers at >3 log(10)
      for the duration of the trial (90 days). Sheep were found to be late responders
      to serotypes A, C, and Asia-1; a clear upward shift in titer was observed at 60
      days postvaccination. However, development of the immune response to serotype O
      in sheep was superior to that in cattle and goats.

PMID- 12409435
TI  - Comparison of two silver staining techniques for detecting lipopolysaccharides in
      polyacrylamide gels.

PMID- 12409436
TI  - Characteristics of rare or recently described corynebacterium species recovered
      from human clinical material in Canada.
AB  - Nineteen new Corynebacterium species or taxa described since 1995 have been
      associated with human disease. We report the characteristics of 72 strains
      identified as or most closely resembling 14 of these newer, medically relevant
      Corynebacterium species or taxa, as well as describe in brief an isolate of
      Corynebacterium bovis, a rare pathogen for humans. The bacteria studied in this
      report were nearly all derived from human clinical specimens and were identified
      by a polyphasic approach. Most were characterized by nearly full 16S rRNA gene
      sequence analysis. Some isolates were recovered from previously unreported
      sources and exhibited unusual phenotypes or represented the first isolates found
      outside Europe. Products of fermentation, with emphasis on the presence or
      absence of propionic acid, were also studied in order to provide an additional
      characteristic with which to differentiate among phenotypically similar species.

PMID- 12409437
TI  - Detection of cell wall galactomannoprotein Afmp1p in culture supernatants of
      Aspergillus fumigatus and in sera of aspergillosis patients.
AB  - Mannoproteins are important and abundant structural components of fungal cell
      walls. The AFMP1 gene encodes a cell wall galactomannoprotein of Aspergillus
      fumigatus. In the present study, we show that Afmp1p is secreted into the cell
      culture supernatant at a level that can be detected by Western blotting. A
      sensitive enzyme-linked immunosorbent assay (ELISA) developed with antibodies
      against Afmp1p was capable of detecting this protein from the cell culture
      supernatant of A. fumigatus. The anti-Afmp1p antibody is specific since it fails
      to react with any protein from lysates of Aspergillus flavus, Aspergillus niger,
      Aspergillus terreus, Penicillium marneffei, Candida albicans, Cryptococcus
      neoformans, Blastomyces dermatitidis, and Histoplasma capsulatum by Western
      blotting. In addition, this Afmp1p antigen-based ELISA is also specific for A.
      fumigatus since the cell culture supernatants of the other eight fungi gave
      negative results. Finally, a clinical evaluation of sera from invasive
      aspergillosis patients indicates that 8 of 15 (53%) patients are Afmp1p antigen
      test positive. Furthermore, an Afmp1p antibody test was performed with these
      serum specimens. The combined antibody and antigen tests for invasive
      aspergillosis carry a sensitivity of 86.7% (13 of 15). The specificities of the
      tests are high since none of the 138 control sera, including 100 from normal
      blood donors, 20 from patients with penicilliosis marneffei, 6 from patients with
      candidemia, 8 from patients with typhoid fever, and 4 from patients with
      melioidosis, was positive by either test. In conclusion, the combined Afmp1p
      antibody and antigen tests are highly sensitive and specific for A. fumigatus
      invasive aspergillosis.

PMID- 12409438
TI  - Simple microdilution test for detection of metallo-beta-lactamase production in
      Pseudomonas aeruginosa.
AB  - A microdilution test measuring imipenem MICs in the presence or absence of a
      mixture of EDTA plus 1,10-phenanthroline was developed and tested on 190
      Pseudomonas aeruginosa isolates, including 18 VIM- and 4 IMP-type metallo-beta
      lactamase (MBL) producers. The chelator mixture reduced by fourfold or more the
      imipenem MICs for MBL producers, while a lower effect or no effect was usually
      observed with MBL nonproducers.

PMID- 12409439
TI  - Late prosthetic hip joint infection with Actinomyces israelii in an intravenous
      drug user: case report and literature review.
AB  - Late infections with Actinomyces israelii have been described for prosthetic hip
      joints but not in association with intravenous drug use. We present a case of a
      43-year-old intravenous drug user who developed A. israelii infection in
      connection with a hip prosthesis 11 years after implantation, and we review four
      previously reported cases of Actinomyces prosthetic joint infections.

PMID- 12409440
TI  - High frequency of competitive inhibition in the Roche Cobas AMPLICOR multiplex
      PCR for Chlamydia trachomatis and Neisseria gonorrhoeae.

PMID- 12409441
TI  - False-negative results of PCR assay with plasma of patients with severe viral
      hemorrhagic fever.

PMID- 12409442
TI  - Prevalence of esp, encoding the enterococcal surface protein, in Enterococcus
      faecalis and Enterococcus faecium isolates from hospital patients, poultry, and
      pigs in Denmark.

PMID- 12409443
TI  - Antigenic and genotypic relationships between Bartonella henselae strains.

PMID- 12409444
TI  - Real-time PCR assay for rapid detection of Bacillus anthracis spores in clinical
      samples.

PMID- 12409445
TI  - Oxacillin resistance screening agar base for detection of methicillin-resistant
      Staphylococcus aureus.

PMID- 12409446
TI  - Human immunodeficiency virus (HIV) antigen-antibody combination assays:
      evaluation of HIV seroconversion sensitivity and subtype detection.

PMID- 12409447
TI  - Global genome removal of thymine glycol in Escherichia coli requires endonuclease
      III but the persistence of processed repair intermediates rather than thymine
      glycol correlates with cellular sensitivity to high doses of hydrogen peroxide.
AB  - Using a monoclonal antibody that specifically recognizes thymine glycol (Tg) in
      DNA, we measured the kinetics of the removal of Tg from the genomes of wild-type
      and repair gene mutant strains of Escherichia coli treated with hydrogen
      peroxide. Tg is rapidly and efficiently removed from the total genomes of repair
      proficient cells in vivo and the removal of Tg is completely dependent on the nth
      gene that encodes the endonuclease III glycosylase. Hence, it appears that little
      redundancy in the repair of Tg occurs in vivo, at least under the conditions used
      here. Moreover, previous studies have found that nth mutants are not sensitive to
      killing by hydrogen peroxide but xth mutant strains (deficient in the major AP
      endonuclease, exonuclease III) are sensitive. We find that cell death correlates
      with the persistence of single-strand breaks rather than the persistence of Tg.
      We attempted to measure transcription-coupled removal of Tg in the lactose operon
      using the Tg-specific monoclonal antibody in an immunoprecipitation approach but
      were not successful in achieving reproducible results. Furthermore, the analysis
      of transcription-coupled repair in the lactose operon is complicated by potent
      inhibition of beta-galactosidase expression by hydrogen peroxide.

PMID- 12409448
TI  - Temperature-dependent splicing of beta-globin pre-mRNA.
AB  - A T-->G mutation at nucleotide 705 of human beta-globin intron 2 creates an
      aberrant 5' splice site and activates a cryptic 3' splice site upstream. In
      consequence, the pre-mRNA is spliced via aberrant splice sites, despite the
      presence of the still functional correct sites. Surprisingly, when IVS2-705 HeLa
      or K562 cells were cultured at temperatures below 30 degrees C, aberrant splicing
      was inhibited and correct splicing was restored. Similar temperature effects were
      seen for another beta-globin pre-mRNA, IVS2-745, and in a construct in which a
      beta-globin intron was inserted into a coding sequence of EGFP. Temperature
      induced alternative splicing was affected by the nature of the internal aberrant
      splice sites flanking the correct sites and by exonic sequences. The results
      indicate that in the context of thalassemic splicing mutations and possibly in
      other alternatively spliced pre-mRNAs, temperature is one of the parameters that
      affect splice site selection.

PMID- 12409449
TI  - A versatile communication module for controlling RNA folding and catalysis.
AB  - To exert control over RNA folding and catalysis, both molecular engineering
      strategies and in vitro selection techniques have been applied toward the
      development of allosteric ribozymes whose activities are regulated by the binding
      of specific effector molecules or ligands. We now describe the isolation and
      characterization of a new and considerably versatile RNA element that functions
      as a communication module to render disparate RNA folding domains interdependent.
      In contrast to some existing communication modules, the novel 9-nt RNA element is
      demonstrated to function similarly between a variety of catalysts that include
      the hepatitis delta virus, hammerhead, X motif and Tetrahymena group I ribozymes,
      and various ligand-binding domains. The data support a mechanistic model of RNA
      folding in which the element is comprised of both canonical and non-canonical
      base pairs and an unpaired nucleotide in the active, effector-bound conformation.
      Aside from enabling effector-controlled RNA function through rational design, the
      element can be utilized to identify sites in large RNAs that are susceptible to
      effector regulation.

PMID- 12409451
TI  - Human telomeric DNA: G-quadruplex, i-motif and Watson-Crick double helix.
AB  - Human telomeric DNA composed of (TTAGGG/CCCTAA)n repeats may form a classical
      Watson-Crick double helix. Each individual strand is also prone to quadruplex
      formation: the G-rich strand may adopt a G-quadruplex conformation involving G
      quartets whereas the C-rich strand may fold into an i-motif based on intercalated
      C*C+ base pairs. Using an equimolar mixture of the telomeric oligonucleotides
      d[AGGG(TTAGGG)3] and d[(CCCTAA)3CCCT], we defined which structures existed and
      which would be the predominant species under a variety of experimental
      conditions. Under near-physiological conditions of pH, temperature and salt
      concentration, telomeric DNA was predominantly in a double-helix form. However,
      at lower pH values or higher temperatures, the G-quadruplex and/or the i-motif
      efficiently competed with the duplex. We also present kinetic and thermodynamic
      data for duplex association and for G-quadruplex/i-motif unfolding.

PMID- 12409450
TI  - The malaria parasite Plasmodium falciparum encodes members of the Puf RNA-binding
      protein family with conserved RNA binding activity.
AB  - A novel class of RNA-binding proteins, Puf, regulates translation and RNA
      stability by binding to specific sequences in the 3'-untranslated region of
      target mRNAs. Members of this protein family share a conserved Puf domain
      consisting of eight 36 amino acid imperfect repeats. Here we report two Puf
      family member genes, PfPuf1 and PfPuf2, from the human malaria parasite
      Plasmodium falciparum. Both genes are spliced with four and three introns
      clustered within or near the Puf domains, respectively. Northern and RT-PCR
      analysis indicated that both genes were differentially expressed in gametocytes
      during erythrocytic development of the parasite. Except for similarities in the
      Puf domain and expression profile, the deduced PfPuf1 and PfPuf2 proteins differ
      considerably in size and structure. PfPuf1 has 1894 amino acids and a central Puf
      domain, whereas PfPuf2 is much smaller with a C-terminal Puf domain. The presence
      of at least two Puf members in other Plasmodium species suggests that these
      proteins play evolutionarily similar roles during parasite development. Both in
      vivo studies using the yeast three-hybrid system and in vitro binding assays
      using the recombinant Puf domain of PfPuf1 expressed in bacteria demonstrated
      intrinsic binding activity of the PfPuf1 Puf domain to the NRE sequences in the
      hunchback RNA, the target sequence for Drosophila Pumilio protein. Altogether,
      these results suggest that PfPufs might function during sexual differentiation
      and development in Plasmodium through a conserved mechanism of translational
      regulation of their target mRNAs.

PMID- 12409452
TI  - Human mitochondrial DNA with large deletions repopulates organelles faster than
      full-length genomes under relaxed copy number control.
AB  - Partially-deleted mitochondrial DNA (DeltamtDNA) accumulates during aging of
      postmitotic tissues. This accumulation has been linked to decreased metabolic
      activity, increased reactive oxygen species formation and the aging process.
      Taking advantage of cell lines with heteroplasmic mtDNA mutations, we showed
      that, after severe mtDNA depletion, organelles are quickly and predominantly
      repopulated with DeltamtDNA, whereas repopulation with the wild-type counterpart
      is slower. This behavior was not observed for full-length genomes with pathogenic
      point mutations. The faster repopulation of smaller molecules was supported by
      metabolic labeling of mtDNA with [3H]thymidine during relaxed copy number control
      conditions. We also showed that hybrid cells containing two defective mtDNA
      haplotypes tend to retain the smaller one as they adjust their normal mtDNA copy
      number. Taken together, our results indicate that, under relaxed copy number
      control, DeltamtDNAs repopulate mitochondria more efficiently than full-length
      genomes.

PMID- 12409453
TI  - In vivo and in vitro interaction between human transcription factor MOK2 and
      nuclear lamin A/C.
AB  - The human and murine MOK2 proteins are factors able to recognize both DNA and RNA
      through their zinc finger motifs. This dual affinity of MOK2 suggests that MOK2
      might be involved in transcription and post-transcriptional regulation of MOK2
      target genes. The IRBP gene contains two MOK2-binding elements, a complete 18 bp
      MOK2-binding site located in intron 2 and the essential core MOK2-binding site (8
      bp of conserved 3'-half-site) located in the IRBP promoter. We have demonstrated
      that MOK2 can bind to the 8 bp present in the IRBP promoter and repress
      transcription from this promoter by competing with the CRX activator for DNA
      binding. In this study, we identify a novel interaction between lamin A/C and
      hsMOK2 by using the yeast two-hybrid system. The interaction, which was confirmed
      by GST pull-down assays and co-immunolocalization studies in vivo, requires the N
      terminal acidic domain of hsMOK2 and the coiled 2 domain of lamin A/C.
      Furthermore, we show that a fraction of hsMOK2 protein is associated with the
      nuclear matrix. We therefore suggest that hsMOK2 interactions with lamin A/C and
      the nuclear matrix may be important for its ability to repress transcription.

PMID- 12409454
TI  - A Cajal body-specific pseudouridylation guide RNA is composed of two box H/ACA
      snoRNA-like domains.
AB  - Site-specific post-transcriptional conversion of uridines to pseudouridine in
      ribosomal RNAs and small nuclear RNAs (snRNAs) is directed by guide RNAs which
      possess the conserved box H and ACA sequence elements and fold into the consensus
      'hairpin-hinge-hairpin-tail' secondary structure. Here, we describe an unusual
      mammalian pseudouridylation guide RNA, called U93, that is composed of two
      tandemly arranged box H/ACA RNA domains. The U93 RNA therefore carries two H and
      two ACA box motifs, all of which are essential for accumulation of the full
      length RNA. The human U93 RNA accumulates in Cajal (coiled) bodies and it is
      predicted to function in pseudouridylation of the U2 spliceosomal snRNA. Our
      results lend further support to the notion that modification of the RNA
      polymerase II-transcribed spliceosomal snRNAs takes place in Cajal bodies.

PMID- 12409455
TI  - Domains of human U4atac snRNA required for U12-dependent splicing in vivo.
AB  - U4atac snRNA forms a base-paired complex with U6atac snRNA. Both snRNAs are
      required for the splicing of the minor U12-dependent class of eukaryotic nuclear
      introns. We have developed a new genetic suppression assay to investigate the in
      vivo roles of several regions of U4atac snRNA in U12-dependent splicing. We show
      that both the stem I and stem II regions, which have been proposed to pair with
      U6atac snRNA, are required for in vivo splicing. Splicing activity also requires
      U4atac sequences in the 5' stem-loop element that bind a 15.5 kDa protein that
      also binds to a similar region of U4 snRNA. In contrast, mutations in the region
      immediately following the stem I interaction region, as well as a deletion of the
      distal portion of the 3' stem-loop element, were active for splicing. Complete
      deletion of the 3' stem-loop element abolished in vivo splicing function as did a
      mutation of the Sm protein binding site. These results show that the in vivo
      sequence requirements of U4atac snRNA are similar to those described previously
      for U4 snRNA using in vitro assays and provide experimental support for models of
      the U4atac/U6atac snRNA interaction.

PMID- 12409457
TI  - An analysis of the sequence requirements of EDEN-BP for specific RNA binding.
AB  - EDEN-BP (embryo deadenylation element-binding protein) binds specifically to the
      EDEN motif in the 3'-untranslated regions of maternal mRNAs and targets these
      mRNAs for deadenylation and translational repression in Xenopus laevis embryos.
      EDEN-BP contains three RNA recognition motifs (RRMs) and is related to the elav
      family of RNA-binding proteins. In the present study we show that the two N
      terminal RRMs of EDEN-BP are necessary for the interaction with EDEN as well as a
      part of the linker region (between RRM2 and RRM3). Using a band shift assay we
      show that two different complexes are formed according to the size and,
      therefore, the functional nature of the EDEN motif. Finally, we show that EDEN-BP
      can form a dimer in a two-hybrid assay. Accordingly, we suggest that the
      functional configuration of EDEN-BP is a dimer.

PMID- 12409456
TI  - The curved DNA structure in the 5'-upstream region of the light-responsive genes:
      its universality, binding factor and function for cyanobacterial psbA
      transcription.
AB  - A unique DNA curvature, the CIT, has been found in the 5'-upstream region of the
      psbA2 gene, which exhibits basal, light-responsive and circadian rhythmic
      transcription, in a unicellular photosynthetic cyanobacterium, Microcystis
      aeruginosa K-81. In this study, we report the universality of curvatures found in
      5'-upstream regions in the psbA family and the function of the curvature in gene
      expression. Intrinsic curvatures were identified within 1000 bp upstream from the
      psbA genes in another cyanobacterium, a red alga and in plants (monocot and
      dicot). Mutagenized curvatures were constructed and confirmed to have disrupted
      architecture by gel electrophoresis and atomic force microscopy. Relatively small
      amounts but light-responsive transcripts of psbA2 were observed in cyanobacterial
      transformants harboring the mutagenized curvature under light/dark and light/high
      light conditions. This shows that the curvature is important for basal
      transcription. In vitro primer extension and DNA mobility shift assay revealed
      that factors which might bind to the region upstream from the bending center
      contribute to the effective basal transcription of psbA2.

PMID- 12409458
TI  - Multicopy genes uniquely amplified in the Y chromosome-specific repeats of the
      liverwort Marchantia polymorpha.
AB  - Sex of the liverwort Marchantia polymorpha is determined by the sex chromosomes Y
      and X, in male and female plant, respectively. Approximately half of the Y
      chromosome is made up of unique repeat sequences. Here, we report that part of
      the Y chromosome, represented by a 90-kb insert of a genomic clone pMM2D3,
      contains five putative genes in addition to the ORF162 gene, which is present
      also within the Y chromosome-specific repeat region. One of the five putative
      genes shows similarity to a male gamete-specific protein of lily and is expressed
      predominantly in male sex organs, suggesting that this gene has a male
      reproductive function. Furthermore, Southern blot analysis revealed that these
      five putative genes are amplified on the Y chromosome, but they also probably
      have homologs on the X chromosome and/or autosomes. These observations suggest
      that the Y chromosome evolved by co-amplifying protein-coding genes with unique
      repeat sequences.

PMID- 12409459
TI  - Development and comparison of procedures for the selection of delta ribozyme
      cleavage sites within the hepatitis B virus.
AB  - Delta ribozyme possesses several unique features related to the fact that it is
      the only catalytic RNA known to be naturally active in human cells. This makes it
      attractive as a therapeutic tool for the inactivation of clinically relevant
      RNAs. However, several hurdles must be overcome prior to the development of
      useful gene-inactivation systems based on delta ribozyme. We have developed three
      procedures for the selection of potential delta ribozyme target sites within the
      hepatitis B virus (HBV) pregenome: (i) the use of bioinformatic tools coupled to
      biochemical assays; (ii) RNase H hydrolysis with a pool of oligonucleotides; and
      (iii) cleavage assays with a pool of ribozymes. The results obtained with delta
      ribozyme show that these procedures are governed by several rules, some of which
      are different from those both for other catalytic RNAs and antisense
      oligonucleotides. Together, these procedures identified 12 sites in the HBV
      pregenome that can be cleaved by delta ribozymes, although with different
      efficiencies. Clearly, both target site accessibility and the ability to form an
      active ribozyme-substrate complex constitute interdependent factors that can best
      be addressed using a combinatorial library of either oligonucleotides or
      ribozymes.

PMID- 12409460
TI  - Site-specific incorporation of an unnatural amino acid into proteins in mammalian
      cells.
AB  - A suppressor tRNA(Tyr) and mutant tyrosyl-tRNA synthetase (TyrRS) pair was
      developed to incorporate 3-iodo-L-tyrosine into proteins in mammalian cells.
      First, the Escherichia coli suppressor tRNA(Tyr) gene was mutated, at three
      positions in the D arm, to generate the internal promoter for expression.
      However, this tRNA, together with the cognate TyrRS, failed to exhibit suppressor
      activity in mammalian cells. Then, we found that amber suppression can occur with
      the heterologous pair of E.coli TyrRS and Bacillus stearothermophilus suppressor
      tRNA(Tyr), which naturally contains the promoter sequence. Furthermore, the
      efficiency of this suppression was significantly improved when the suppressor
      tRNA was expressed from a gene cluster, in which the tRNA gene was tandemly
      repeated nine times in the same direction. For incorporation of 3-iodo-L
      tyrosine, its specific E.coli TyrRS variant, TyrRS(V37C195), which we recently
      created, was expressed in mammalian cells, together with the B.stearothermophilus
      suppressor tRNA(Tyr), while 3-iodo-L-tyrosine was supplied in the growth medium.
      3-Iodo-L-tyrosine was thus incorporated into the proteins at amber positions,
      with an occupancy of >95%. Finally, we demonstrated conditional 3-iodo-L-tyrosine
      incorporation, regulated by inducible expression of the TyrRS(V37C195) gene from
      a tetracycline-regulated promoter.

PMID- 12409462
TI  - Translational fusions with the engrailed repressor domain efficiently convert
      plant transcription factors into dominant-negative functions.
AB  - Evidence is provided that plant transcription factors can be efficiently
      reprogrammed to dominant- negative functions by the use of a repressor domain of
      the engrailed (en) gene from Drosophila. Ectopic expression of translational
      fusions between the en(298) N-terminus and the complete coding regions of the
      SHOOTMERISTEMLESS, APETALA3, PISTILLATA and KNAT1 transcription factors results
      in trans-dominant functions which phenocopy loss-of-function mutants. The
      combination of the dominant-negative en(298)-STM function with the hormone
      binding domain of the glucocorticoid receptor provides strong evidence that
      phenocopies rely on the incorporation of the chimeric protein into the nuclear
      compartment. By this dominant-negative approach KNAT1 was rapidly identified to
      be encoded by the BREVIPEDICELLUS locus. Dominant-negative chimeric proteins may
      be of wide use to elucidate biological functions of plant transcriptional
      activators and may be suitable to study protein-protein interactions in planta.

PMID- 12409461
TI  - Vanadate inhibits the ATPase activity and DNA binding capability of bacterial
      MutS. A structural model for the vanadate-MutS interaction at the Walker A motif.
AB  - MutS, a member of the ABC ATPases superfamily, is a mismatch DNA-binding protein
      constituent of the DNA post-replicative mismatch repair system (MMRS). In this
      work, it is shown that the ATPase activity of Pseudomonas aeruginosa and
      Escherichia coli MutS is inhibited by ortho- and decavanadate. Structural
      comparison of the region involved in the ATP binding of E.coli MutS with the
      corresponding region of other ABC ATPases inhibited by vanadate, including the
      myosin- orthovanadate-Mg complex, showed that they are highly similar. From these
      results it is proposed that the orthovanadate inhibition of MutS ATPase can take
      place by a similar mechanism to that described for other ATPases. Docking of
      decavanadate on the ATP-binding region of MutS showed that the energetically more
      favorable interaction of this compound would take place with the complex MutS-
      ADP-Mg, suggesting that the inhibitory effect could be produced by a steric
      impediment of the protein ATP/ADP exchange. Besides the effect observed on the
      ATPase activity, vanadate also affects the DNA-binding capability of the protein,
      and partially inhibits the oligomerization of MutS and the temperature-induced
      inactivation of the protein. From the results obtained, and considering that
      vanadate is an intracellular trace component, this compound could be considered
      as a new modulator of the MMRS.

PMID- 12409463
TI  - Scanning confocal fluorescence microscopy for single molecule analysis of
      nucleotide excision repair complexes.
AB  - We used scanning confocal fluorescence microscopy to observe and analyze
      individual DNA- protein complexes formed between human nucleotide excision repair
      (NER) proteins and model DNA substrates. For this purpose human XPA protein was
      fused to EGFP, purified and shown to be functional. Binding of EGFP-labeled XPA
      protein to a Cy3.5-labeled DNA substrate, in the presence and absence of RPA, was
      assessed quantitatively by simultaneous excitation and emission detection of both
      fluorophores. Co-localization of Cy3.5 and EGFP signals within one diffraction
      limited spot indicated complexes of XPA with DNA. Measurements were performed on
      samples in a 1% agarose matrix in conditions that are compatible with protein
      activity and where reactions can be studied under equilibrium conditions. In
      these samples DNA alone was freely diffusing and protein-bound DNA was immobile,
      whereby they could be discriminated resulting in quantitative data on DNA
      binding. On the single molecule level approximately 10% of XPA co-localized with
      DNA; this increased to 32% in the presence of RPA. These results, especially the
      enhanced binding of XPA in the presence of RPA, are similar to those obtained in
      bulk experiments, validating the utility of scanning confocal fluorescence
      microscopy for investigating functional interactions at the single molecule
      level.

PMID- 12409464
TI  - The fission yeast pfh1(+) gene encodes an essential 5' to 3' DNA helicase
      required for the completion of S-phase.
AB  - The Cdc24 protein plays an essential role in chromosomal DNA replication in the
      fission yeast Schizosaccharomyces pombe, most likely via its direct interaction
      with Dna2, a conserved endonuclease-helicase protein required for Okazaki
      fragment processing. To gain insights into Cdc24 function, we isolated cold
      sensitive chromosomal suppressors of the temperature-sensitive cdc24-M38 allele.
      One of the complementation groups of such suppressors defined a novel gene,
      pfh1(+), encoding an 805 amino acid nuclear protein highly homologous to the
      Saccharomyces cerevisiae Pif1p and Rrm3p DNA helicase family proteins. The
      purified Pfh1 protein displayed single-stranded DNA-dependent ATPase activity as
      well as 5' to 3' DNA helicase activity in vitro. Reverse genetic analysis in
      S.pombe showed that helicase activity was essential for the function of the Pfh1
      protein in vivo. Schizosaccharomyces pombe cells carrying the cold-sensitive pfh1
      R20 allele underwent cell cycle arrest in late S/G2-phase of the cell cycle when
      shifted to the restrictive temperature. This arrest was dependent upon the
      presence of a functional late S/G2 DNA damage checkpoint, suggesting that Pfh1 is
      required for the completion of DNA replication. Furthermore, at their permissive
      temperature pfh1-R20 cells were highly sensitive to the DNA-alkylating agent
      methyl methanesulphonate, implying a further role for Pfh1 in the repair of DNA
      damage.

PMID- 12409465
TI  - 1H NMR determination of base-pair lifetimes in oligonucleotides containing single
      base mismatches.
AB  - Proton nuclear magnetic resonance (NMR) spectroscopy is employed to characterize
      the kinetics of base-pair opening in a series of 9mer duplexes containing
      different single base mismatches. The imino protons from the different
      mismatched, as well as fully matched, duplexes are assigned from the imino-imino
      region in the WATERGATE NOESY spectra. The exchange kinetics of the imino protons
      are measured from selective longitudinal relaxation times. In the limit of
      infinite exchange catalyst concentration, the exchange times of the mismatch
      imino protons extrapolate to much shorter lifetimes than are commonly observed
      for an isolated GC base pair. Different mismatches exhibit different orders of
      base-pair lifetimes, e.g. a TT mismatch has a shorter base-pair lifetime than a
      GG mismatch. The effect of the mismatch was observed up to a distance of two
      neighboring base pairs. This indicates that disruption in the duplex caused by
      the mismatch is quite localized. The overall order of base-pair lifetimes in the
      selected sequence context of the base pair is GC > GG > AA > CC > AT > TT.
      Interestingly, the fully matched AT base pair has a shorter base-pair lifetime
      relative to many of the mismatches. Thus, in any given base pair, the exchange
      lifetime can exhibit a strong dependence on sequence context. These findings may
      be relevant to the way mismatch recognition is accomplished by proteins and small
      molecules.

PMID- 12409466
TI  - Highly conserved modified nucleosides influence Mg2+-dependent tRNA folding.
AB  - Transfer RNA structure involves complex folding interactions of the TPsiC domain
      with the D domain. However, the role of the highly conserved nucleoside
      modifications in the TPsiC domain, rT54, Psi55 and m5C49, in tertiary folding is
      not understood. To determine whether these modified nucleosides have a role in
      tRNA folding, the association of variously modified yeast tRNA(Phe) T-half
      molecules (nucleosides 40-72) with the corresponding unmodified D-half molecule
      (nucleosides 1-30) was detected and quantified using a native polyacrylamide gel
      mobility shift assay. Mg2+ was required for formation and maintenance of all
      complexes. The modified T-half folding interactions with the D-half resulted in
      K(d)s (rT54 = 6 +/- 2, m5C49 = 11 +/- 2, Psi55 = 14 +/- 5, and rT54,Psi55 = 11 +/
      3 microM) significantly lower than that of the unmodified T-half (40 +/- 10
      microM). However, the global folds of the unmodified and modified complexes were
      comparable to each other and to that of an unmodified yeast tRNA(Phe) and native
      yeast tRNA(Phe), as determined by lead cleavage patterns at U17 and nucleoside
      substitutions disrupting the Levitt base pair. Thus, conserved modifications of
      tRNA's TPsiC domain enhanced the affinity between the two half-molecules without
      altering the global conformation indicating an enhanced stability to the complex
      and/or an altered folding pathway.

PMID- 12409467
TI  - PipeOnline 2.0: automated EST processing and functional data sorting.
AB  - Expressed sequence tags (ESTs) are generated and deposited in the public domain,
      as redundant, unannotated, single-pass reactions, with virtually no biological
      content. PipeOnline automatically analyses and transforms large collections of
      raw DNA-sequence data from chromatograms or FASTA files by calling the quality of
      bases, screening and removing vector sequences, assembling and rewriting
      consensus sequences of redundant input files into a unigene EST data set and
      finally through translation, amino acid sequence similarity searches, annotation
      of public databases and functional data. PipeOnline generates an annotated
      database, retaining the processed unigene sequence, clone/file history,
      alignments with similar sequences, and proposed functional classification, if
      available. Functional annotation is automatic and based on a novel method that
      relies on homology of amino acid sequence multiplicity within GenBank records.
      Records are examined through a function ordered browser or keyword queries with
      automated export of results. PipeOnline offers customization for individual
      projects (MyPipeOnline), automated updating and alert service. PipeOnline is
      available at http://stress-genomics.org.

PMID- 12409468
TI  - Heterogeneity in the modification and involvement of chromatin components of the
      CpG island of the silenced human CDH1 gene in cancer cells.
AB  - The structural alteration of chromatin has a key role in regulating gene
      expression. The alteration of chromatin is mediated by modification of its
      components. Detailed understanding of the relationship between these
      modifications, notably, methylation of the full-length CpG island, the
      association of methyl-CpG binding proteins (MBPs), and the acetylation and
      methylation of histones in gene silencing is vitally important. Currently,
      however, the manner in which chromatin components, associated with a specific
      gene, are modified is poorly understood. Here we provide in vivo evidence in
      cancer cells of the differential association between CpG methylation, MBPs, and
      histone modification in the entire CpG island of the human E-cadherin (CDH1)
      gene. Of the cell lines with CDH1 transcriptional repression, the distribution of
      methyl-CpGs in the CpG island differed markedly. In a cell line with gene
      silencing, the promoter region was almost methylation-free. Chromatin
      immunoprecipitation analysis revealed that the acetylation status of histone H4
      differed between cell lines. However, deacetylated histone H3 was associated with
      the CpG island in all silenced cell lines. Binding of MeCP2 was also detected in
      all silenced cell lines. Additional binding of MBD1 protein was detected in a
      cell line in which the promoter region was poorly methylated and only histone H3
      was deacetylated. Binding of MBD2 protein was detected in all other silenced cell
      lines. Histone H3 lysine 9 was methylated in all silenced cells, while histone H3
      lysine 4 was methylated in some silenced cell lines. These results demonstrate
      that chromatin components associated with inactive CDH1 chromatin is
      heterogeneously modified and suggests the presence of multiple pathways for the
      formation of inactive chromatin.

PMID- 12409469
TI  - The severe slow growth of Deltasrs2 Deltarqh1 in Schizosaccharomyces pombe is
      suppressed by loss of recombination and checkpoint genes.
AB  - Our interest in the Schizosaccharomyces pombe RecQ helicase, rqh1+, led us to
      investigate the function of a related putative DNA helicase, srs2+. We identified
      the srs2+ homolog in S.pombe, and found that srs2+ is not essential for cell
      viability. A Deltasrs2 Deltarqh1 double mutant grows extremely slowly with
      aberrant shaped cells and low viability. This slow growth does not appear to be
      related to stalled replication, as Deltasrs2 Deltarqh1 cells showed higher
      survival rates, compared with Deltarqh1, when stalled forks were increased by UV
      irradiation or hydroxy urea treatment. Consistent with this result, we found that
      Deltasrs2 Deltarqh1 cells progress through S-phase with a slight delay, but
      undergo a checkpoint-dependent arrest presumably at G2/M. Further, we found that
      Deltasrs2 Deltarqh1 slow growth is related to recombination, as loss of either
      the rhp51+ or rhp57+ recombination genes improves cell growth in the double
      mutant. Deltasrs2 is also synthetic lethal with Deltarhp54, another homologous
      recombination gene. This lethality is suppressed in a Deltarhp51 background.
      Together, these results demonstrate a clear genetic interaction between rqh1+,
      srs2+ and the genes of the homologous recombination pathway.

PMID- 12409470
TI  - Hydrazide oligonucleotides: new chemical modification for chip array attachment
      and conjugation.
AB  - We report the synthesis of new phosphoramidite building blocks and their use for
      the modification of oligonucleotides with hydrazides. The reaction of these
      hydrazide oligonucleotides with active esters and aldehydes is demonstrated for
      solution conjugation and immobilization. Compared with the established amino
      modified oligonucleotides, hydrazides show enhanced reactivity at neutral and
      acidic buffer conditions. One method to introduce hydrazides is using amidites
      with preformed, protected hydrazides. A completely novel approach is the
      generation of the hydrazide functionality during the oligonucleotide cleavage and
      deprotection with hydrazine. Therefore, building blocks for the introduction of
      esters as hydrazide precursors are described. For the enhanced attachment on
      surfaces branched modifier amidites, which introduce up to four reactive groups
      to the oligonucleotide, are applied. The efficiency of branched hydrazide
      oligonucleotides compared with standard amino modified oligonucleotides for the
      immobilization of DNA on active electronic Nanogen chips is demonstrated.

PMID- 12409471
TI  - The apical stem-loop of the hepatitis B virus encapsidation signal folds into a
      stable tri-loop with two underlying pyrimidine bulges.
AB  - Reverse transcription of hepatitis B virus (HBV) pregenomic RNA is essential for
      virus replication. In the first step of this process, HBV reverse transcriptase
      binds to the highly conserved encapsidation signal, epsilon (epsilon), situated
      near the 5' end of the pregenome. epsilon has been predicted to form a bulged
      stem-loop with the apical stem capped by a hexa- loop. After the initial binding
      to this apical stem- loop, the reverse transcriptase synthesizes a 4 nt primer
      using the bulge as a template. Here we present mutational and structural data
      from NMR on the apical stem-loop of epsilon. Application of new isotope-labeling
      techniques (13C/15N/2H-U-labeling) allowed resolution of many resonance overlaps
      and an extensive structural data set could be derived. The NMR data show that,
      instead of the predicted hexa-loop, the apical stem is capped by a stable UGU tri
      loop closed by a C-G base pair, followed by a bulged out C. The apical stem
      contains therefore two unpaired pyrimidines (C1882 and U1889), rather than one as
      was predicted, spaced by 6 nt. C1882, the 3' neighbour to the G of the loop
      closing C-G base pair, is completely bulged out, while U1889 is at least
      partially intercalated into the stem. Analysis of 205 of our own HBV sequences
      and 1026 strains from the literature, covering all genotypes, reveals a high
      degree of conservation of epsilon. In particular, the residues essential for this
      fold are either totally conserved or show rare non-disruptive mutations. These
      data strongly indicate that this fold is essential for recognition by the reverse
      transcriptase.

PMID- 12409473
TI  - Synthesis and evaluation of phosphorescent oligonucleotide probes for
      hybridisation assays.
AB  - Monofunctional, p-isothiocyanatophenyl-derivatives of platinum (II)
      coproporphyrin-I (PtCP-NCS) were evaluated as phosphorescent labelling reagents
      for synthetic oligonucleotides containing a 3'- or 5'-amino modification.
      Synthesis and purification conditions were optimised to generate high yields and
      purity of PtCP-labelled oligonucleotide probes. Phosphorescent properties of the
      PtCP label have been shown to be largely unaffected by conjugation to
      oligonucleotides of various length, GC composition and label attachment site. 5'
      PtCP-labelled oligonucleotides were shown to work efficiently as primers in a
      standard PCR. A dedicated 532 nm laser-based time-resolved fluorescence plate
      reader enabled highly sensitive detection of PtCP-labelled oligonucleotides and
      PCR products, both in solution and in agarose gels, with limits of detection in
      the order of 0.3 pM. A model system employing two complementary oligonucleotides
      labelled with PtCP and QSY 7 dye (dark quencher) showed strong (approximately 20
      fold) and specific proximity quenching of PtCP label upon hybridisation in
      solution. The potential applications of PtCP-labelled probes in hybridisation
      assays were discussed.

PMID- 12409472
TI  - Advanced modular self-inactivating lentiviral expression vectors for multigene
      interventions in mammalian cells and in vivo transduction.
AB  - In recent years, lentiviral expression systems have gained an unmatched
      reputation among the gene therapy community for their ability to deliver
      therapeutic transgenes into a wide variety of difficult-to-transfect/transduce
      target tissues (brain, hematopoietic system, liver, lung, retina) without
      eliciting significant humoral immune responses. We have cloned a construction kit
      like self-inactivating lentiviral expression vector family which is compatible to
      state-of-the-art packaging and pseudotyping technologies and contains, besides
      essential cis-acting lentiviral sequences, (i) unparalleled polylinkers with up
      to 29 unique sites for restriction endonucleases, many of which recognize 8 bp
      motifs, (ii) strong promoters derived from the human cytomegalovirus immediate
      early promoter (P(hCMV)) or the human elongation factor 1alpha (P(hEF1)(alpha)),
      (iii) P(hCMV-) or P(PGK-) (phosphoglycerate kinase promoter) driven G418
      resistance markers or fluorescent protein-based expression tracers and (iv)
      tricistronic expression cassettes for coordinated expression of up to three
      transgenes. In addition, we have designed a size-optimized series of highly
      modular lentiviral expression vectors (pLenti Module) which contain, besides the
      extensive central polylinker, unique restriction sites flanking any of the 5'U3,
      R-U5-psi+-SD, cPPT-RRE-SA and 3'LTR(DeltaU3) modules or placed within the 5'U3 (
      78 bp) and 3'LTR(DeltaU3) (8666 bp). pLentiModule enables straightforward
      cassette-type module swapping between lentiviral expression vector family members
      and facilitates the design of Tat-independent (replacement of 5'LTR by
      heterologous promoter elements), regulated and self-excisable proviruses
      (insertion of responsive operators or LoxP in the 3'LTR(DeltaU3) element). We
      have validated our lentiviral expression vectors by transduction of a variety of
      insect, chicken, murine and human cell lines as well as adult rat cardiomyocytes,
      rat hippocampal slices and chicken embryos. The novel multi-purpose construction
      kit-like vector series described here is compatible with itself as well as many
      other (non-viral) mammalian expression vectors for straightforward exchange of
      key components (e.g. promoters, LTRs, resistance genes) and will assist the gene
      therapy and tissue engineering communities in developing lentiviral expression
      vectors tailored for optimal treatment of prominent human diseases.

PMID- 12409474
TI  - Stable and efficient cassette exchange under non-selectable conditions by
      combined use of two site-specific recombinases.
AB  - Work of the last decade has proven the 'one gene- one product-one function'
      hypothesis an oversimplification. To further unravel the emerging 'one gene
      multiple products-even more functions' concept, new methods (such as subtle knock
      in and tightly regulated conditional mutations) for the analysis of gene function
      in health and disease are required. Another class of improvements (such as
      tetraploid fusion and cassette exchange) addresses the efficiency with which
      targeted mutant strains can be generated. Recombinase-mediated cassette exchange
      (RMCE), which in theory is well suited for the rapid generation of multiple
      alleles of a given locus, is hampered by its low efficiency in the absence of
      selection and, especially in vivo, by the promiscuity of the participating
      recombinase recognition sites. Here we present a novel approach which circumvents
      this problem by the use of two independent recombinase systems. The strategy,
      which uses loxP on one and FRT on the other side of the cassette together with a
      Cre/Flpe expression vector, prevents excisive events and results in higher rates
      of cassette integration without selection than previously described. This method
      has a huge potential for the generation of allelic series in embryonic stem cells
      and, importantly, in pre-implantation embryos in vivo.

PMID- 12409475
TI  - A common reference for cDNA microarray hybridizations.
AB  - Comparisons of expression levels across different cDNA microarray experiments are
      easier when a common reference is co-hybridized to every microarray. Often this
      reference consists of one experimental control sample, a pool of cell lines or a
      mix of all samples to be analyzed. We have developed an alternative common
      reference consisting of a mix of the products that are spotted on the array.
      Pooling part of the cDNA PCR products before they are printed and their
      subsequent amplification towards either sense or antisense cRNA provides an
      excellent common reference. Our results show that this reference yields a
      reproducible hybridization signal in 99.5% of the cDNA probes spotted on the
      array. Accordingly, a ratio can be calculated for every spot, and expression
      levels across different hybridizations can be compared. In dye-swap experiments
      this reference shows no significant ratio differences, with 95% of the spots
      within an interval of +/-0.2-fold change. The described method can be used in
      hybridizations with both amplified and non-amplified targets, is time saving and
      provides a constant batch of common reference that lasts for thousands of
      hybridizations.

PMID- 12409476
TI  - Simultaneous determination of different DNA sequences by mass spectrometric
      evaluation of Sanger sequencing reactions.
AB  - All currently available DNA sequencing protocols rest fundamentally upon the
      homogeneity of the template. In this paper we describe the parallel DNA
      sequencing of various templates in one sample by a combination of the Sanger
      method and MALDI-TOF mass spectrometric analysis of the products. PCR-amplified
      hypervariable 16S rDNA fragments of the bacterium Escherichia coli DF1020 and
      cDNA of the 6-phosphofructo-1-kinase isoenzymes (PFK-1, EC 2.7.1.11) in rat brain
      were chosen as model systems for essentially heterogeneous templates. Avoiding
      cloning of the inhomogeneous PCR products we were able to read three sequences
      for both the 16S rDNA fragment of E.coli DF1020 and the cDNA of 6-phosphofructo-1
      kinase from the peak lists of the Sanger sequencing reactions. Short sequences
      with a length between 21 and 25 nt were sufficient to reflect the heterogeneity
      of the 16S rDNA genes in E.coli and the existence of three isoenzymes of PFK-1 in
      rat brain.

PMID- 12409477
TI  - BACFinder: genomic localisation of large insert genomic clones based on
      restriction fingerprinting.
AB  - We have developed software that allows the prediction of the genomic location of
      a bacterial artificial chromosome (BAC) clone, or other large genomic clone,
      based on a simple restriction digest of the BAC. The mapping is performed by
      comparing the experimentally derived restriction digest of the BAC DNA with a
      virtual restriction digest of the whole genome sequence. Our trials indicate that
      this program identified the genomic regions represented by BAC clones with a
      degree of accuracy comparable to that of end-sequencing, but at considerably less
      cost. Although the program has been developed principally for use with
      Arabidopsis BACs, it should align large insert genomic clones to any fully
      sequenced genome.

PMID- 12409478
TI  - Production of combinatorial libraries of fused genes by sequential transposition
      reactions.
AB  - The use of in vivo and in vitro transposition reactions to perform non
      combinatorial manipulation of DNAs in molecular biology is widespread. In this
      work we describe a technique that utilizes two sequential, directed transposition
      reactions in order to carry out combinatorial DNA manipulations. The methodology
      relies on the use of two different mutant Tn5 transposase proteins that have
      different transposon end recognition specificities. We demonstrate that the
      technique can be used to create large libraries of random fusions between two
      genes. These transpositional fusions are defined by insertion of a 32 bp linker
      sequence. We applied the technique to a model system, chloramphenicol acetyl
      transferase, to create functional fusions from N- and C-terminally truncated, non
      functional genes. Comparative structural analysis suggests that both sides of the
      linker are inserted into disordered regions in functional proteins.

PMID- 12409480
TI  - EZ-Retrieve: a web-server for batch retrieval of coordinate-specified human DNA
      sequences and underscoring putative transcription factor-binding sites.
AB  - The availability of a draft human genome sequence and ability to monitor the
      transcription of thousands of genes with DNA microarrays has necessitated the
      need for new computational tools that can analyze cis-regulatory elements
      controlling genes that display similar expression patterns. We have developed a
      tool designated EZ-Retrieve that can: (i) retrieve any particular region of human
      genome sequence from the NCBI database and (ii) analyze retrieved sequences for
      putative transcription factor-binding sites (TFBSs) as they appear on the
      TRANSFAC database. The tool is web-based, user-friendly and offers both batch
      sequence retrieval and batch TFBS prediction. A major application of EZ-Retrieve
      is the analysis of co-expressed genes that are highlighted as expression clusters
      in DNA microarray experiments.

PMID- 12409479
TI  - Designing gene libraries from protein profiles for combinatorial protein
      experiments.
AB  - Protein combinatorial libraries provide new ways to probe the determinants of
      folding and to discover novel proteins. Such libraries are often constructed by
      expressing an ensemble of partially random gene sequences. Given the intractably
      large number of possible sequences, some limitation on diversity must be imposed.
      A non-uniform distribution of nucleotides can be used to reduce the number of
      possible sequences and encode peptide sequences having a predetermined set of
      amino acid probabilities at each residue position, i.e., the amino acid sequence
      profile. Such profiles can be determined by inspection, multiple sequence
      alignment or physically-based computational methods. Here we present a
      computational method that takes as input a desired sequence profile and
      calculates the individual nucleotide probabilities among partially random genes.
      The calculated gene library can be readily used in the context of standard DNA
      synthesis to generate a protein library with essentially the desired profile. The
      fidelity between the desired profile and the calculated one coded by these
      partially random genes is quantitatively evaluated using the linear correlation
      coefficient and a relative entropy, each of which provides a measure of profile
      agreement at each position of the sequence. On average, this method of
      identifying such codon frequencies performs as well or better than other methods
      with regard to fidelity to the original profile. Importantly, the method
      presented here provides much better yields of complete sequences that do not
      contain stop codons, a feature that is particularly important when all or large
      fractions of a gene are subject to combinatorial mutation.

PMID- 12409481
TI  - Efficiencies of fluorescence resonance energy transfer and contact-mediated
      quenching in oligonucleotide probes.
AB  - An important consideration in the design of oligonucleotide probes for
      homogeneous hybridization assays is the efficiency of energy transfer between the
      fluorophore and quencher used to label the probes. We have determined the
      efficiency of energy transfer for a large number of combinations of commonly used
      fluorophores and quenchers. We have also measured the quenching effect of
      nucleotides on the fluorescence of each fluorophore. Quenching efficiencies were
      measured for both the resonance energy transfer and the static modes of
      quenching. We found that, in addition to their photochemical characteristics, the
      tendency of the fluorophore and the quencher to bind to each other has a strong
      influence on quenching efficiency. The availability of these measurements should
      facilitate the design of oligonucleotide probes that contain interactive
      fluorophores and quenchers, including competitive hybridization probes, adjacent
      probes, TaqMan probes and molecular beacons.

PMID- 12409482
TI  - AarI, a restriction endonuclease from Arthrobacter aurescens SS2-322, which
      recognizes the novel non-palindromic sequence 5'-CACCTGC(N)4/8-3'.
AB  - A new type II restriction endonuclease AarI has been isolated from Arthrobacter
      aurescens SS2-322. AarI recognizes the non-palindromic heptanucleotide sequence
      5'-CACCTGC(N)4/8-3' and makes a staggered cut at the fourth and eighth bases
      downstream of the target duplex producing a four base 5'-protruding end. AarI
      activity is stimulated by oligodeoxyribonucleotide duplexes containing an enzyme
      specific recognition sequence.

PMID- 12409484
TI  - Adaptive responses of vertebrate neurons to hypoxia.
AB  - The damage caused to mammalian neurons during ischaemic events in the brain (e.g.
      following a stroke), is an area of major interest to neuroscientists. The neurons
      of hypoxia-tolerant vertebrates offer unique models for identifying new
      strategies to enhance the survival of hypoxia-vulnerable neurons. In this review,
      we describe recent advances in our understanding of how hypoxia-tolerant neurons
      detect decreases in oxygen and create signals that have immediate and long-term
      effects on cell function and survival. Sensing and adapting to low oxygen tension
      involves numerous modalities with different times of activation and effect.
      Sensors include membrane proteins such as ionotropic ion channels, membrane or
      cytosolic heme proteins, mitochondrial proteins and/or oxygen sensitive
      transcription factors such as HIF-1alpha and NFkappaB. Signaling molecules
      involved in O(2) sensing include mitogen-activated protein kinases, ions such as
      Ca(2+) and metabolites such as adenosine. These signals act rapidly to reduce the
      conductance of ion channels (ion flux arrest) and production of energy (metabolic
      arrest), and slowly to activate specific genes. The ability to construct an
      energy budget, illustrating which physiological processes are depressed during
      both long-term and acute metabolic suppression in hypoxia-tolerant neurons, would
      be of significant value in devising new strategies for neuroprotection.
      Additionally it is not known how metabolism is regulated at 'pilot-light' levels
      at which energy-producing and energy-consuming processes are balanced. The
      regulation of organelle and cell fate during long-term hypoxia is almost
      completely unexplored, and whether programmed cell death and regeneration of lost
      neurons occur following protracted dormancy is also of considerable interest.

PMID- 12409485
TI  - Temperature and acid-base balance in ectothermic vertebrates: the imidazole
      alphastat hypotheses and beyond.
AB  - The 'imidazole alphastat hypothesis' states that intracellular and extracellular
      pH, partly via buffering by imidazole groups, change with temperature in a way
      that keeps imidazole and protein ionization constant, thus maintaining cell
      function and minimizing shifts of base equivalents and total CO(2), while
      adjustment of P(CO(2)) involves imidazole-based receptors. 'The hypothesis',
      which is actually several hypotheses, has been variously perceived and judged,
      but its underlying conceptual framework remains largely valid, and is
      reformulated using differential equations requiring less information input than
      their integral equivalents. Their usefulness is illustrated with published data
      on temperature responses in fish cells and whole tetrapods. Mathematical
      modelling allows general principles to be explored with less immediate concern
      for uncertainties in experimental data and other information. In tetrapods, it
      suggests that warming is followed by a loss of base equivalents from the body,
      and that this loss is due to metabolic adjustments that are not part of pH
      homeostasis. Uncertainties include intracellular buffer values, local variations
      in P(CO(2)) within the body, the possible role of buffering by bone mineral, and
      the temperature dependence of pK values for CO(2)/HCO(3)(-) and imidazole groups.
      The equations utilize a single, notional, temperature-dependent pK value for all
      non-bicarbonate buffers in a given body compartment. This approximates to the
      'passive component' of pH adjustment to temperature change as measured by the
      homogenate technique. Also discussed are the diversity of cell responses within
      individual animals, relevant aspects of the control of ventilation, metabolism
      and transmembrane transport, and the basis of optimum pH-temperature
      relationships.

PMID- 12409486
TI  - Aerobic capacities in the skeletal muscles of Weddell seals: key to longer dive
      durations?
AB  - In contrast to terrestrial animals that function under hypoxic conditions but
      display the typical exercise response of increasing ventilation and cardiac
      output, marine mammals exercise under a different form of hypoxic stress. They
      function for the duration of a dive under progressive asphyxia, which is the
      combination of increasing hypoxia, hypercapnia and acidosis. Our previous studies
      on short-duration, shallow divers found marked adaptations in their skeletal
      muscles, which culminated in enhanced aerobic capacities that are similar to
      those of athletic terrestrial mammals. The purpose of the present study was to
      assess the aerobic capacity of skeletal muscles from long-duration divers.
      Swimming and non-swimming muscles were collected from adult Weddell seals,
      Leptonychotes weddelli, and processed for morphometric analysis, enzymology,
      myoglobin concentrations and fiber-type distribution. The results showed that the
      skeletal muscles of Weddell seals do not have enhanced aerobic capacities
      compared with those of terrestrial mammals but are adapted to maintain low levels
      of an aerobic lipid-based metabolism, especially under the hypoxic conditions
      associated with diving. The lower aerobic capacity of Weddell seal muscle as
      compared with that of shorter-duration divers appears to reflect their energy
      conserving modes of locomotion, which enable longer and deeper dives.

PMID- 12409487
TI  - Electroreception in juvenile scalloped hammerhead and sandbar sharks.
AB  - The unique head morphology of sphyrnid sharks might have evolved to enhance
      electrosensory capabilities. The 'enhanced electroreception' hypothesis was
      tested by comparing the behavioral responses of similarly sized carcharhinid and
      sphyrnid sharks to prey-simulating electric stimuli. Juvenile scalloped
      hammerhead sharks Sphyrna lewini and sandbar sharks Carcharhinus plumbeus
      oriented to dipole electric fields from the same maximum distance (approximately
      30 cm) and thus demonstrated comparable behavioral-response thresholds (<1 nV cm(
      1)). Despite the similarity of response threshold, the orientation pathways and
      behaviors differed for the two species. Scalloped hammerheads typically
      demonstrated a pivot orientation in which the edge of the cephalofoil closest to
      the dipole remained stationary while the shark bent its trunk to orient to the
      center of the dipole. By contrast, sandbars swam in a broader arc towards the
      center of the dipole. The different orientation patterns are attributed to the
      hydrodynamic properties of the cephalofoil, which enables the hammerheads to
      execute sharp turns at high speed. The greater trunk width of the sandbar sharks
      prevented them from demonstrating the same degree of flexibility. Therefore,
      although the sphyrnid head morphology does not appear to confer a greater
      sensitivity to prey-simulating dipole electric fields, it does provide (1). a
      greater lateral search area, which may increase the probability of prey
      encounter, and (2). enhanced maneuverability, which may aid in prey capture.

PMID- 12409488
TI  - Differential partitioning of maternal fatty acid and phospholipid in neonate
      mosquito larvae.
AB  - In animals, lipids are a source of energy, cell membrane components, signaling
      pathway modulators and emulsifying agents. In egg-laying animals, maternal yolk
      lipids, imported into the egg before laying, are metabolized or distributed in
      the developing embryo to serve these functions. Studies with birds, reptiles and
      insects have described lipid metabolism in adults and in eggs, but no studies
      have addressed how lipids are distributed in developing organs in the embryo.
      Here we show that maternal fatty acid and phospholipids segregate differently in
      tissues of newly hatched mosquito larvae. In the mother, both lipids are
      colocalized in yolk granules of developing oocytes and distributed evenly. In
      neonate larvae, however, the maternal fatty acid is stored along the side of the
      body, especially at the base of the body hair, and in the thorax, where the
      muscles are located, probably to provide energy for the rapid movements needed to
      find food immediately after birth. Most maternal phospholipids, however, are
      concentrated in the motile intestinal gastric caeca, from which they are released
      into the gut lumen where they may act as emulsifiers, probably to facilitate
      assimilation of the food the neonate ingests. Similar phenomena were observed in
      both Anopheles gambiae and Aedes aegypti mosquitoes, suggesting that such
      differential segregation of lipids is common to both insects. This study may lead
      to improved delivery of larvicidal agents and to efficient killing of newly
      hatched mosquito larvae as a control strategy for mosquito-borne diseases.

PMID- 12409489
TI  - Temperature dependence of cardiac sarcoplasmic reticulum function in rainbow
      trout myocytes.
AB  - To explore how the cardiac sarcoplasmic reticulum (SR) functions over a range of
      temperatures, we used whole-cell voltage clamp combined with rapid caffeine
      application to study SR Ca(2+) accumulation, release and steady-state content in
      atrial myocytes from rainbow trout. Myocytes were isolated from rainbow trout
      acclimated to 14 degrees C, and the effect of varying stimulation pulse number,
      frequency and experimental temperature (7 degrees C, 14 degrees C and 21 degrees
      C) on SR function was studied. To add physiological relevance, in addition to 200
      ms square (SQ) voltage pulses, myocytes were stimulated with temperature-specific
      action potentials (AP) applied at relevant frequencies for each test temperature.
      We found that the SR accumulated Ca(2+) more rapidly and to a greater
      concentration (1043+/-189 micromol l(-1) Ca(2+), 1138+/-173 micromol l(-1)
      Ca(2+), and 1095+/-142 micromol l(-1) Ca(2+) at 7 degrees C, 14 degrees C and 21
      degrees C, respectively) when stimulated with physiological AP waveforms at
      physiological frequencies compared with 200 ms SQ pulses at the same frequencies
      (664+/-180 micromol l(-1) Ca(2+), 474+/-75 micromol l(-1) Ca(2+) and 367+/-42
      micromol l(-1) Ca(2+) at 7 degrees C, 14 degrees C and 21 degrees C,
      respectively). Also, and in contrast to 200 ms SQ pulse stimulation, temperature
      had little effect on steady-state SR Ca(2+) accumulation during AP stimulation.
      Furthermore, we observed SR-Ca(2+)-dependent inactivation of the L-type Ca(2+)
      channel current (I(Ca)) at 7 degrees C, 14 degrees C and 21 degrees C, providing
      additional evidence of maintained SR function in fish hearts over an acute range
      of temperatures. We conclude that the waveform of the AP may be critical in
      ensuring adequate SR Ca(2+) cycling during temperature change in rainbow trout in
      vivo.

PMID- 12409491
TI  - GABA-like immunoreactivity in nonspiking interneurons of the locust metathoracic
      ganglion.
AB  - Nonspiking interneurons are important components of the premotor circuitry in the
      thoracic ganglia of insects. Their action on postsynaptic neurons appears to be
      predominantly inhibitory, but it is not known which transmitter(s) they use.
      Here, we demonstrate that many but not all nonspiking local interneurons in the
      locust metathoracic ganglion are immunopositive for GABA (gamma-aminobutyric
      acid). Interneurons were impaled with intracellular microelectrodes and were
      shown physiologically to be nonspiking. They were further characterized by
      defining their effects on known leg motor neurons when their membrane potential
      was manipulated by current injection. Lucifer Yellow was then injected into these
      interneurons to reveal their cell bodies and the morphology of their branches.
      Some could be recognised as individuals by comparison with previous detailed
      descriptions. Ganglia were then processed for GABA immunohistochemistry. Fifteen
      of the 17 nonspiking interneurons studied were immunopositive for GABA, but two
      were not. The results suggest that the majority of these interneurons might exert
      their well-characterized effects on other neurons through the release of GABA but
      that some appear to use a transmitter other than GABA. These nonspiking
      interneurons are therefore not an homogeneous population with regard to their
      putative transmitter.

PMID- 12409490
TI  - Effects of temperature on intracellular Ca2+ in trout atrial myocytes.
AB  - Acute temperature change can be cardioplegic to mammals, yet certain ectotherms
      maintain their cardiac scope over a wide temperature range. To better understand
      the acute effects of temperature on the ectothermic heart, we investigated the
      stimulus-induced change in intracellular Ca(2+) concentration ([Ca(2+)](i);
      cytosolic Ca(2+) transient) in isolated rainbow trout myocytes at 7 degrees C, 14
      degrees C and 21 degrees C. Myocytes were voltage-clamped and loaded with Fura-2
      to measure the L-type Ca(2+) channel current (I(Ca)) and [Ca(2+)](i) during
      physiological action potential (AP) pulses at frequencies that correspond to
      trout heart rates in vivo at 7 degrees C, 14 degrees C and 21 degrees C.
      Additionally, [Ca(2+)](i) and I(Ca) were examined with square (SQ) pulses at slow
      (0.2 Hz) and physiologically relevant contraction frequencies. The amplitude of
      [Ca(2+)](i) decreased with increasing temperature for both SQ and AP pulses,
      which may contribute to the well-known negative inotropic effect of warm
      temperature on contractile strength in trout hearts. With SQ pulses, [Ca(2+)](i)
      decreased from 474+/-53 nmol l(-1) at 7 degrees C to 198+/-21 nmol l(-1) at 21
      degrees C, while the decrease in [Ca(2+)](i) with AP pulses was from 234+/-49
      nmol l(-1) to 79+/-12 nmol l(-1), respectively. Sarcolemmal Ca(2+) influx was
      increased slightly at cold temperatures with AP pulses (charge transfer was
      0.27+/-0.04 pC pF(-1), 0.19+/-0.03 pC pF(-1) and 0.13+/-0.03 pC pF(-1) at 7
      degrees C, 14 degrees C and 21 degrees C, respectively). At all temperatures,
      cells were better able to maintain diastolic Ca(2+) levels at physiological
      frequencies with AP pulses compared with 500 ms SQ pulses. We suggest that
      temperature-dependent modulation of the AP is important for cellular Ca(2+)
      regulation during temperature and frequency change in rainbow trout heart.

PMID- 12409492
TI  - Developmental changes in the cone visual pigments of black bream Acanthopagrus
      butcheri.
AB  - The spectral absorption characteristics of the visual pigments in the
      photoreceptors of the black bream Acanthopagrus butcheri Munro (Sparidae,
      Teleostei), were measured using microspectrophotometry. A single cohort of fish
      aged 5-172 days post-hatch (dph), aquarium-reared adults and wild-caught
      juveniles were investigated. During the larval stage and in juveniles younger
      than 100 dph, two classes of visual pigment were found, with wavelengths of
      maximum absorbance (lambda(max)) at approximately 425 nm and 535 nm. Following
      double cone formation, from 40 dph onwards, the short wavelength-sensitive
      pigment was recorded in single cones and the longer wavelength-sensitive pigment
      in double cones. From 100 dph, a gradual shift in the lambda(max) towards longer
      wavelengths was observed in both cone types. By 160 dph, and in adults, all
      single cones had a lambda(max) at approximately 475 nm while the lambda(max) in
      double cones ranged from 545 to 575 nm. The relationships between the lambda(max)
      and the ratio of bandwidth:lambda(max), for changes in either chromophore or
      opsin, were modelled mathematically for the long-wavelength-sensitive visual
      pigments. Comparing our data with the models indicated that changes in
      lambda(max) were not mediated by a switch from an A(1) to A(2) chromophore,
      rather a change in opsin expression was most likely. The shifts in the
      lambda(max) of the visual pigments occur at a stage when the juvenile fish begin
      feeding in deeper, tanninstained estuarine waters, which transmit predominantly
      longer wavelengths, so the spectral sensitivity changes may represent an
      adaptation by the fish to the changing light environment.

PMID- 12409493
TI  - Hovering flight mechanics of neotropical flower bats (Phyllostomidae:
      Glossophaginae) in normodense and hypodense gas mixtures.
AB  - Existing estimates of flight energetics in glossophagine flower bats, the
      heaviest hovering vertebrate taxon, suggest disproportionately high expenditure
      of mechanical power. We determined wingbeat kinematics and mechanical power
      expenditure for one of the largest flower bats (Leptonycteris curasoae Martinez
      and Villa) during hovering flight in normodense and hypodense gas mixtures.
      Additional experiments examined the effects of supplemental oxygen availability
      on maximum flight performance. Bats failed to sustain hovering flight at normoxic
      air densities averaging 63% that of normodense air. Kinematic responses to
      hypodense aerodynamic challenge involved increases in wing positional angles and
      in total stroke amplitude; wingbeat frequency was unchanged. At near-failure air
      densities, total power expenditure assuming perfect elastic energy storage was 17
      42% greater than that for hovering in normodense air, depending on the assumed
      value for the profile drag coefficient. Assuming a flight muscle ratio of 26%,
      the associated muscle-mass-specific power output at the point of near-failure
      varied between 90.8 W kg(-1) (profile drag coefficient of 0.02) to 175.6 W kg(-1)
      (profile drag coefficient of 0.2). Hyperoxia did not enhance hovering performance
      in hypodense air, and, with the exception of a small increase (10%) in stroke
      plane angle, yielded no significant change in any of the kinematic parameters
      studied. Revised energetic estimates suggest that mechanical power expenditure of
      hovering glossophagines is comparable with that in slow forward flight.

PMID- 12409494
TI  - Elevated dietary intake of L-tryptophan counteracts the stress-induced elevation
      of plasma cortisol in rainbow trout (Oncorhynchus mykiss).
AB  - Juvenile rainbow trout were isolated in individual compartments and allowed to
      acclimate for 1 week, during which they were fed commercial trout pellets. The
      feed was then replaced by pelleted feed supplemented with L-tryptophan (TRP) at
      two, four or eight times the concentration in the commercial feed. Fish were fed
      these supplemented feeds daily to satiety for 1 week, after which half of the
      fish were stressed, by lowering the water level for 2 h, while the remaining fish
      were left undisturbed. In undisturbed fish, supplementary dietary TRP resulted in
      slightly elevated plasma cortisol levels. In response to the stress, fish that
      had been fed control feed showed elevated plasma cortisol levels, but fish fed
      the TRP-supplemented feed displayed a significant reduction in this stress
      induced elevation of plasma cortisol levels. Plasma and brain TRP levels were
      elevated in fish fed TRP-supplemented feed. TRP is the precursor of the monoamine
      neurotransmitter serotonin. Brain serotonergic activity was elevated by stress
      and also tended to be increased by elevated dietary TRP intake. The central
      serotonergic system is involved in the control of the hypothalamic-pituitary
      interrenal axis, the action of serotonin being to stimulate or inhibit this
      neuroendocrine axis through different projections.

PMID- 12409495
TI  - Swim speed and movement patterns of gravid leatherback sea turtles (Dermochelys
      coriacea) at St Croix, US Virgin Islands.
AB  - Swim speed, dive behavior and movements were recorded for seven female
      leatherback sea turtles (Dermochelys coriacea Vandelli 1761) during a single
      internesting interval near St Croix in the US Virgin Islands. Modal speeds ranged
      from 0.56 to 0.84 m s(-1), maximum speed range 1.9-2.8 m s(-1). Turtles swam
      continuously throughout the day and night. There were two swim-speed patterns;
      the most common was slightly U-shaped, with high speeds at the initiation and
      conclusion of the dive, and the less common was continuous high-speed swimming.
      The U-shaped speed patterns were coincident with vertical diving by the turtles,
      while the second pattern occurred most frequently during the daytime, with the
      turtle swimming within 2 m of the surface. This latter swim behavior appeared to
      be designed to maximize efficiency for long-distance travel. The hypothesis that
      leatherbacks rest or bask at midday during their internesting interval is refuted
      by this study.

PMID- 12409496
TI  - Physiological changes of sturgeon Acipenser naccarii caused by increasing
      environmental salinity.
AB  - The possible repercussions of osmoregulatory processes on some indicators of
      classical and oxidative stress were examined during gradual acclimation of
      sturgeons (Acipenser naccarii) to full seawater (35% salinity) and after a period
      of 20 approximately days at this salinity. Erythrocyte constants and levels of
      cortisol, protein and glucose in the plasma were determined. In addition, plasma
      osmolality and muscle-hydration values, as well as liver and heart protein, were
      determined. Catalase, glutathione peroxidase and superoxide dismutase activities
      and lipidperoxidation levels were measured in blood (plasma and red blood cells)
      and tissue (liver and heart). A number of physiological responses, such as
      disturbance in body fluid, activation of osmoregulatory mechanisms, augmented
      antioxidant defences in blood and alteration of energy metabolites, were detected
      with increasing environmental salinity. After 20 days at 35% salinity, plasma
      osmolality, erythrocyte constants and muscle water content all returned to values
      usual for low environmental salinity, indicating that osmoregulatory processes
      have achieved their objective. However, cortisol values, antioxidant enzyme
      activities in the blood (plasma and red blood cells), lipid peroxidation in
      plasma, and hepatic proteins did not return to initial values, showing that
      osmoregulatory processes cause major physiological changes in the fish.

PMID- 12409497
TI  - Changes in locomotor activity parameters with variations in cycle time in larval
      lamprey.
AB  - In larval lamprey, locomotor activity recorded from whole animals and in vitro
      brain/spinal cord preparations was analyzed to determine how two parameters of
      locomotor activity, burst proportion (BP; relative duration of motor burst
      activity) and intersegmental phase lag (phi; normalized delay of burst activity
      along one side of the body), vary with changes in cycle time (T). In individual
      animals, the slopes of BP and phi versus T were compared using linear regression
      analysis, followed by statistical analysis of the slopes to determine whether the
      parameters changed significantly with variations in cycle time. For locomotor
      muscle activity in whole animals, the BP values increased significantly with
      decreases in T (i.e. negative slopes), while the slopes for phi values versus T
      were not significantly different from zero. For locomotor activity in
      preparations in vitro, the mean slopes for BP values versus T, although negative,
      were not significantly different from zero, and phase lags were also relatively
      constant with changes in cycle time. Increases in BP with decreases in cycle time
      and increases in swimming speed can be expected to generate proportionately more
      force per cycle, presumably to compensate for the increase in viscous resistance
      of moving the body more rapidly through water. By contrast, constant
      intersegmental phase lags will ensure that the relative timing of locomotor burst
      activity is constant and that an approximately single S-wave along the body is
      retained during different swimming speeds.

PMID- 12409498
TI  - Mechanical work for step-to-step transitions is a major determinant of the
      metabolic cost of human walking.
AB  - In the single stance phase of walking, center of mass motion resembles that of an
      inverted pendulum. Theoretically, mechanical work is not necessary for producing
      the pendular motion, but work is needed to redirect the center of mass velocity
      from one pendular arc to the next during the transition between steps. A
      collision model predicts a rate of negative work proportional to the fourth power
      of step length. Positive work is required to restore the energy lost, potentially
      exacting a proportional metabolic cost. We tested these predictions with humans
      (N=9) walking over a range of step lengths (0.4-1.1 m) while keeping step
      frequency fixed at 1.8 Hz. We measured individual limb external mechanical work
      using force plates, and metabolic rate using indirect calorimetry. As predicted,
      average negative and positive external mechanical work rates increased with the
      fourth power of step length (from 1 W to 38 W; r(2)=0.96). Metabolic rate also
      increased with the fourth power of step length (from 7 W to 379 W; r(2)=0.95),
      and linearly with mechanical work rate. Mechanical work for step-to-step
      transitions, rather than pendular motion itself, appears to be a major
      determinant of the metabolic cost of walking.

PMID- 12409499
TI  - Stimulatory effects on Na+ transport in renal epithelia induced by extracts of
      Nigella arvensis are caused by adenosine.
AB  - Effects of the extract of Nigella arvensis (NA) seeds on transepithelial Na(+)
      transport were studied in cultured A6 toad kidney cells by recording short
      circuit current (I(sc)), transepithelial conductance (G(T)), transepithelial
      capacitance (C(T)) and fluctuation in I(sc). Apical application of NA extract had
      merely a small stimulatory effect on Na(+) transport, whereas basolateral
      administration markedly increased I(sc), G(T) and C(T). A maximal effect was
      obtained at 500 microll(-1) of lyophilized NA extract. The increase in C(T)
      suggests that the activation of I(sc) occurs through the insertion of transport
      sites in the apical membrane. In experiments performed in the absence of Na(+)
      transport [apical Na(+) was replaced by N-methyl-D-glucamine (NMDG(+))],
      basolateral NA extract did not affect I(sc) and G(T), indicating that Cl(-)
      conductance was not influenced. Noise analysis of I(sc) using 6-chloro-3,5
      diaminopyrazine-2-carboxamide (CDPC) showed that NA extract reduced single
      channel current (i(Na)) and decreased channel open probability (P(o)) but evoked
      a threefold increase in channel density (N(T)), which confirms the insertion of
      Na(+) channels. The separation of the compounds in the crude extract of NA was
      performed by fast protein liquid chromatography (FPLC) on a Superdex 200 gel
      filtration column and by reverse-phase high-pressure liquid chromatography
      (RPHPLC) on an micro RPC C2/C18 SC2.1/10 column connected to a SMART system.
      Analysis of the purified active fraction by mass spectrometry demonstrated the
      presence of adenosine as the single organic compound in the extract that had a
      stimulatory effect on Na(+) transport. In a separate series of experiments, we
      confirmed that 1 micromol l(-1) adenosine had similar effects on the parameters
      of Na(+) transport as did the NA extract. The action of adenosine was further
      identified by experiments in which NA extract was added after adenosine. In these
      experiments, NA extract did not affect I(sc), G(T) or C(T). These results clearly
      demonstrate an essential role of adenosine in the stimulatory action of NA
      extract.

PMID- 12409500
TI  - Gliclazide increases insulin receptor tyrosine phosphorylation but not p38
      phosphorylation in insulin-resistant skeletal muscle cells.
AB  - Sulfonylurea drugs are used in the treatment of type 2 diabetes. The mechanism of
      action of sulfonylureas is to release insulin from pancreatic cells and they have
      been proposed to act on insulin-sensitive tissues to enhance glucose uptake. The
      goal of the present study was to test the hypothesis that gliclazide, a second
      generation sulfonylurea, could enhance insulin signaling in insulin-resistant
      skeletal muscle cells. We demonstrated that gliclazide enhanced insulin
      stimulated insulin receptor tyrosine phosphorylation in insulin-resistant
      skeletal muscle cells. Although insulin receptor substrate-1 tyrosine
      phosphorylation was unaffected by gliclazide treatment, phosphatidylinositol 3
      kinase activity was partially restored by treatment with gliclazide. No increase
      in 2-deoxyglucose uptake in insulin-resistant cells by treatment with gliclazide
      was observed. Further investigations into the mitogen-activated protein kinase
      (MAPK) pathway revealed that insulin-stimulated p38 phosphorylation was impaired,
      as compared with extracellular-signal-regulated kinase (ERK) and c-Jun N-terminal
      kinase (JNK), which were phosphorylated normally in insulin-resistant cells.
      Treatment with gliclazide could not restore p38 phosphorylation in insulin
      resistant cells. We propose that gliclazide can regulate part of the insulin
      signaling in insulin-resistant skeletal muscle, and p38 could be a potential
      therapeutic target for glucose uptake to treat insulin resistance.

PMID- 12409501
TI  - Different colors reveal different information: how nutritional stress affects the
      expression of melanin- and structurally based ornamental plumage.
AB  - Avian plumage colors have emerged recently as model systems for investigating the
      types of information that can be signaled by showy sexual displays in animals. In
      many species, the brightness of carotenoid-based plumage reflects the health and
      condition of individuals and is used in mate selection. The information contained
      in melanin-based and structurally based ornamental colors in birds is less well
      resolved, however. We subjected male house sparrows Passer domesticus and brown
      headed cowbirds Molothrus ater to stressful nutritional conditions during molt to
      test the hypothesis that melanin- and structurally based plumage colors are
      nutritionally condition-dependent. We restricted food access for treatment males
      during randomized 6 h periods on 4 days per week, while allowing control birds
      access to food ad libitum throughout the course of the molt. We found that the
      size and brightness of the melanin-based throat badges in male house sparrows
      were not affected by nutritional stress. Similarly, there were no differences
      between treatment and control male cowbirds in the size or brightness of the
      melanin-based brown hood. However, the structurally based iridescent plumage of
      cowbirds was indicative of the nutritional condition of males during molt.
      Nutritionally stressed cowbirds grew significantly less colorful plumage than did
      males with access to food ad libitum. These results are consistent with
      observations in other avian species that different types of plumage color
      communicate different sets of information. Melanin ornaments are less sensitive
      to nutritional conditions during molt and instead may reflect the hormonal status
      and/or competitive ability of males, whereas structural coloration appears to be
      an accurate signal of health and condition.

PMID- 12409502
TI  - Pharmacological blockade of the dive response: effects on heart rate and diving
      behaviour in the harbour seal (Phoca vitulina).
AB  - While diving, harbour seals (Phoca vitulina) manage their oxygen stores through
      cardiovascular adjustments, including bradycardia, a concurrent reduction in
      cardiac output, and peripheral vasoconstriction. At the surface, post-dive
      tachycardia facilitates rapid reloading of oxygen stores. Although harbour seals
      can tolerate >20 min of submergence, the majority of their natural dives are only
      2-6 min and are usually followed by surface intervals that are <1 min, so they
      spend approximately 80% of their time submerged. Given that harbour seals meet
      their ecological needs through repetitive short aerobic dives, we were interested
      in the functional role, if any, of the dive response during these short dives.
      During voluntary diving in an 11 m deep tank, the cardiovascular responses to
      submergence of five harbour seals were manipulated using specific pharmacological
      antagonists, and the effects on diving behaviour were observed. Effects of
      pharmacological blockade on heart rate were also examined to assess the autonomic
      control of heart rate during voluntary diving. Heart rate was recorded using
      subcutaneous electrodes and data loggers, while diving behaviour was monitored
      using a video camera. The muscarinic blocker methoctramine blocked diving
      bradycardia, the alpha-adrenergic blocker prazosin blocked diving
      vasoconstriction, and the beta-adrenergic blocker metoprolol blocked post-dive
      tachycardia. Heart-rate analysis indicated that diving bradycardia is primarily
      modulated by the vagus, while post-dive tachycardia results from parasympathetic
      withdrawal as well as increased sympathetic stimulation of the heart. None of the
      pharmacological blockers had any effect on average dive or surface interval
      duration. Seals maintained a high percentage of time spent diving in all
      treatments. Thus, harbour seals do not appear to need the dive response during
      short dives in order to maintain an efficient dive strategy.

PMID- 12409504
TI  - Congenital disorders of glycosylation: a review.
AB  - Congenital disorders of glycosylation (CDGs) are a rapidly growing group of
      inherited disorders caused by defects in the synthesis and processing of the
      asparagine(ASN)-linked oligosaccharides of glycoproteins. The first CDG patients
      were described in 1980. Fifteen years later, a phosphomannomutase deficiency was
      found as the basis of the most frequent type, CDG-Ia. In recent years several
      novel types have been identified. The N-glycosylation pathway is highly conserved
      from yeast to human, and the rapid progress in this field can largely be
      attributed to the systematic application of the knowledge of yeast mutants. Up to
      now, eight diseases have been characterized, resulting from enzyme or transport
      defects in the cytosol, endoplasmic reticulum, or Golgi compartment. CDGs affect
      all organs and particularly the CNS, except for CDG-Ib, which is mainly a hepatic
      intestinal disease.

PMID- 12409505
TI  - Epithelial cell chloride channel activity correlates with improved airway
      function in cystic fibrosis patients with the major mutant: Delta F508.

PMID- 12409506
TI  - Normal function of the cystic fibrosis conductance regulator protein can be
      associated with homozygous (Delta)F508 mutation.
AB  - Cystic fibrosis (CF) is caused by mutations of the gene encoding for the CFTR (CF
      transmembrane conductance regulator) protein. The most frequent mutation, the
      (Delta)F508 mutation, results in a defective cAMP-regulated chloride transport in
      the epithelial cells. The spectrum of clinical manifestations in patients bearing
      homozygous (Delta)F508 mutations can vary considerably, suggesting that, in the
      patients with a mild disease, CFTR could be partly functional. To test this
      hypothesis, we explored in nasal ciliated epithelial cells (NCC) of 9 control
      subjects and 23 (Delta)F508 homozygous patients the anion conductive pathway by a
      halide sensitive fluorescent dye assay SPQ (6-methoxy-N-3'
      sulfopropylquinolinium) and the CFTR transcript levels by RT-PCR. As 50%
      represented the lowest fraction of the control subjects NCC demonstrating a cAMP
      dependent conductance, a CF patient was considered as "cAMP responder" if at
      least 50% of the NCC tested displayed a cAMP-dependent conductive pathway.
      According to these criteria, 8 of the 23 patients were considered as cAMP
      responders. They had a significantly less severe disease considering the
      respiratory function and infectious status. The amount of CFTR mRNA did not
      differ between the control subjects and the patients. No statistical correlation
      could be found between the transcript level and the expression of a cAMP
      conductive pathway. This cAMP-dependent Cl(-) conductance detected in homozygous
      NCC could be due to a residual CFTR activity and may explain the mild phenotypes
      observed in some (Delta)F508 homozygous patients.

PMID- 12409507
TI  - Apoptosis induced by Pseudomonas aeruginosa in antigen presenting cells is
      diminished by genetic modification with CD40 ligand.
AB  - Persistent colonization with Pseudomonas aeruginosa (PA) is a hallmark of the
      lung disease associated with cystic fibrosis (CF). Based on the concept that PA
      is not cleared from the lung by the host response in individuals with CF, we
      analyzed the capacity of PA to induce cell death in human alveolar macrophages
      (AM) and murine dendritic cells (DC), antigen presenting cells that play a
      central role in the initiation of pulmonary host defenses against pathogens, and
      evaluated if genetic modification can lead to protection against PA induced cell
      death. AM and DC were susceptible to cell death induced by the laboratory PA
      isolates PAO1, PAK and PA103, as well as a mucoid derivative of PAO1 and PA
      isolates derived from sputum of individuals with CF. Apoptosis, analyzed by TUNEL
      assay, was detectable in AM and DC as early as 3 h after infection with PA. In
      contrast, the same strains and doses of PA had little effect on the lung
      epithelial cell line A549 and primary cultures of human bronchial epithelial
      cells in vitro. Pretreatment of DC with the caspase inhibitors VAD-fmk and YVAD
      cmk reduced PA induced cell death (p < 0.05). Finally, genetic modification of DC
      to express CD40L using an adenovirus vector decreased the susceptibility of DC to
      cell death induced by PAO1 compared with DC infected with a control Ad vector (p
      < 0.01). The data demonstrate that DC and AM are susceptible to apoptosis induced
      by PA and that this response can be partially reversed by genetic modification
      with CD40L, a CD4+ T cell molecule that plays a central role in activating
      antigen presenting cells. These observations suggest a potential mechanism
      contributing to the persistence of PA in CF and suggest that genetic manipulation
      of antigen presenting cells with anti-apoptotic genes may be able to strengthen
      host defenses in CF.

PMID- 12409508
TI  - Increased biosynthesis of glycosphingolipids in congenital disorder of
      glycosylation Ia (CDG-Ia) fibroblasts.
AB  - Congenital disorder of glycosylation Ia (CDG-Ia) is an autosomal recessive
      disease, characterized by the impaired biosynthesis of the N-linked
      oligosaccharide chains of proteins due to a deficiency of phosphomannomutase
      (PMM), the enzyme converting mannose-6-phosphate into mannose-1-phosphate. We
      investigated the consequences of the altered N-linked glycoprotein (GP)
      biosynthesis on the quantity and quality of glycosphingolipids (GSLs) in
      fibroblasts of CDG-Ia patients. First, we found that CDG-Ia fibroblasts contain
      an increased amount of total GSLs when compared with normal fibroblasts. Further,
      we assessed by metabolic labeling of CDG-Ia fibroblasts with radioactive sugar
      precursors, including galactose and N-acetylmannosamine, that a diminished
      biosynthesis of cellular GPs is antagonized by an increased biosynthesis of GSLs.
      An increased GSL biosynthesis was also observed by means of radiolabeled lipid
      precursors including sphingosine and lactosylceramide. Notably, also the
      degradation of GLSs is slowed down in CDG-Ia fibroblasts. Finally, when we
      labeled normal human fibroblasts and CHO cells with radioactive galactose in the
      presence and absence of deoxymannojirimycin (dMM), an inhibitor of N-glycan
      processing, we found that this cellular model mimics what occurs in CDG-Ia
      fibroblasts. Since an inverse relationship between GP expression and GSL content
      does exist, we assume that increased glycosphingolipid biosynthesis is secondary
      to protein hypoglycosylation. Altogether, our data suggest that the cell
      metabolic machinery may be able to partially re-equilibrate protein
      hypoglycosylation with increased biosynthesis of glycosphingolipids, possibly to
      preserve the overall physico-chemical equilibrium of the outer layer of the
      plasma membrane.

PMID- 12409510
TI  - Shift of serum osteocalcin components between cord blood and blood at day 5 of
      life.
AB  - Vitamin K deficiency is a relatively common condition in neonates. However, the
      role of vitamin K in neonatal bone metabolism remains to be determined.
      Osteocalcin (OC) is the most abundant noncollagenous protein in bone, and is
      regulated to be gamma-carboxylated by vitamin K. In this study, we measured gamma
      carboxylated osteocalcin (Gla-OC) and non- or undercarboxylated osteocalcin (Glu
      OC) separately, and examined the effects of vitamin K on osteocalcin metabolism.
      Eighteen full-term healthy neonates were enrolled in this study. In the cord and
      d-5 blood samples, the OC levels were determined by three different methods to
      examine the intact OC by immunoradiometric assay (IRMA), Gla-OC, and Glu-OC.
      Serum vitamin K fractions, hepaplastin test, and type 1 procollagen carboxyl
      extension peptide were also determined. Urine samples were also collected from
      the first voiding and on d 5 to determine urinary pyridinoline,
      deoxypyridinoline, and gamma-carboxylated glutamic acid. Serum levels of
      phylloquinone (PK) and menaquinone (MK)-4 increased on d 5 following vitamin K
      administration and increased intake in breast milk and/or formula. The OC levels
      determined by IRMA did not change between cord and d-5 blood samples, but the Gla
      OC level increased remarkably and Glu-OC reduced to a negligible level. OC in
      cord blood is mainly Glu-OC, and Glu-OC is replaced with Gla-OC within 5 d of
      life after vitamin K supplement. The IRMA assay fails to distinguish Gla-OC from
      Glu-OC and caution is needed to estimate bone turnover with this method in the
      perinatal period.

PMID- 12409509
TI  - Natal and neonatal teeth in relation to environmental toxicants.
AB  - Infants born to mothers heavily exposed to polychlorinated biphenyls (PCBs) and
      dibenzofurans (PCDFs) have earlier been reported to have increased prevalences of
      natal and neonatal teeth. Some tendency toward higher prevalence figures of natal
      and neonatal teeth can be seen in the literature in normal child populations
      during the last 40 y. We therefore decided to determine the present prevalence of
      these teeth in a Finnish population and to evaluate whether infants with natal
      and neonatal teeth are more exposed to PCBs, PCDFs, and polychlorinated dibenzo-p
      dioxins (PCDDs) than infants on average. A total of 34,457 infants born in 1997
      2000 in four hospitals in southern Finland were examined for natal and neonatal
      teeth. The exposure of the infant to PCBs and PCDD/Fs was evaluated by measuring
      the levels of 17 most toxic PCDD/F and 36 PCB congeners in his or her mother's
      milk sample when the child was 4-8 wk old. A total of 34 infants had one or two
      natal (29 infants) or neonatal teeth (five infants). The milk analyses showed
      that the median level of PCDD/Fs as toxic equivalent (World Health Organization
      recommended 2,3,7,8-tetrachlorodibenzo-p-dioxin equivalent quantity for PCDD/Fs
      in fat) was 11.9 pg/g in fat, and that of PCBs (World Health Organization
      recommended 2,3,7,8-tetrachlorodibenzo-p-dioxin equivalent quantity for PCBs) was
      7.24 pg/g in fat. These levels corresponded to the prevailing levels. The results
      showed that the prevalence of natal and neonatal teeth was 1:1000. No association
      was found between pollutant levels and occurrence of natal and neonatal teeth,
      indicating that the prevailing levels of PCDD/Fs and PCBs are likely to be below
      the threshold to cause perinatal eruption of teeth.

PMID- 12409511
TI  - Alendronate treatment for infants with osteogenesis imperfecta: demonstration of
      efficacy in a mouse model.
AB  - Recent non-placebo-controlled studies of the bisphosphonate pamidronate have
      shown it to be effective in reducing fractures and improving bone density in
      infants and children with osteogenesis imperfecta (OI). To evaluate the effects
      of bisphosphonate treatment in a controlled study, the oim/oim mouse model of OI
      was studied. Nursing infant mouse pups (approximately 2 wk old) with moderate to
      severe OI (oim/oim mouse) and age- and background-matched control mice (+/+) were
      treated either with the third-generation bisphosphonate alendronate (ALN), or
      with saline. Fracture risk, bone quality, and growth were evaluated over a 12-wk
      treatment period. ALN at a dose of 0.03 mg/kg/d or saline was administered via
      s.c. injection to infant oim/oim and wild-type (+/+) mice from 2 to 14 wk of age
      (n = 20 per subgroup). The average number of fractures sustained by the ALN
      treated oim/oim mice was reduced significantly compared with the untreated
      oim/oim mice (0.7 +/- 0.7 fractures/mouse versus 2.0 +/- 0.2 fractures/mouse).
      Bone density increased significantly in the femur and the spine with treatment
      (2.0 +/- 0.5 versus 1.2 +/- 0.5 in femur and 2.1 +/- 0.5 versus1.6 +/- 0.5 in
      spine). Histologic evaluation revealed the percentage of metaphyseal tibial bone
      increased significantly with treatment in both +/+ and oim/oim mice. Mechanical
      testing revealed an increase in structural stiffness for both treated +/+ and
      oim/oim mice compared with untreated animals. None of the material properties
      examined were significantly altered with treatment, nor was spinal curvature
      affected. Weight gain and long bone growth were comparable in the treated and
      untreated oim/oim mice. In wild-type mice, femur lengths were significantly
      shorter in the treated mice compared with untreated counterparts. This animal
      study demonstrates that treatment of OI in mice as early as 2 wk of age with ALN
      appears to be effective in reducing fractures and increasing bone properties.
      Based on the data from this study, ALN therapy in infants with OI should prove to
      be effective.

PMID- 12409512
TI  - The risk of mortality or cerebral palsy in twins: a collaborative population
      based study.
AB  - The purpose of the paper was to describe demographic and clinical factors
      associated with fetal or neonatal death or cerebral palsy (CP) in twins. Vital
      statistics from five populations in the United States and Australia, which
      included information on CP diagnosed after 1 y of age. Information on zygosity
      was not available. In 1,141,351 births, 25,772 of whom were twins, significant
      secular trends from 1980 to 1989 included increasing prevalence of twins,
      increasing proportion of unlike-sex twins, and increasing maternal age. Overall,
      twins were at an approximately 5-fold increased risk of fetal death, 7-fold
      increased risk of neonatal death, and 4-fold increased risk of CP compared with
      singletons. However, at birth weight <2500 g, twins generally did better than
      singletons, both with respect to mortality and to CP rates. Second-born twins and
      twins from same-sex pairs were at increased risk of early death but not of CP.
      Twins from growth-discordant pairs and twins whose co-twin died were at increased
      risk of both mortality and CP. The highest rates of CP were in surviving twins
      whose co-twin was still-born (4.7%), died shortly after birth (6.3%) or had CP
      (11.8%). In this large data set spanning a 10-y period, overall rates of death or
      cerebral palsy were higher in twins than singletons, although small twins
      generally did better than small singletons. Co-twin death was a strong predictor
      of CP in surviving twins. This risk was the same for same- and different-sex
      pairs, and observed both for preterm and term infants.

PMID- 12409513
TI  - Gender difference in breast tissue size in infancy: correlation with serum
      estradiol.
AB  - Breast tissue in newborn infants is considered to be physiologic and mainly
      related to exposure to maternal hormones in utero or through breast-feeding.
      However, controversy exists as to whether breast tissue in later infancy is under
      the influence of endogenous hormones. Children at 2-4 mo of age have a surge of
      reproductive hormones, including estradiol, which may affect the mammary gland.
      In a prospective cohort study of 1126 healthy, 3-mo-old infants, breast tissue
      size and reproductive hormones were measured. We found that palpable breast
      tissue (diameter >or=3 mm) is a common physiologic condition present in 78.9% of
      children, significantly more frequent (p < 0.001) and larger (p < 0.001) in girls
      than in boys. Girls had significantly higher median estradiol levels than boys
      (30.0 versus 21.0 pmol/L, p < 0.001). In a multiple regression model including
      breast tissue size given as quartiles as the dependent variable and weight for
      gestational age, subscapular skinfold, weight at 3 mo of age and serum estradiol
      as independent variables, a gender difference was shown. In girls, the estradiol
      level was positively (p < 0.03) correlated to breast quartile. In boys, no
      correlations were found. Whether the stimulation of the mammary gland in infancy
      represents a developmental window that is of biologic significance for breast
      development and pathology in adulthood remains to be defined.

PMID- 12409514
TI  - Positive association of maternal G protein beta3 subunit 825T allele with reduced
      head circumference at birth.
AB  - G protein beta3 subunit C825T polymorphism, which has previously been studied in
      association with common disorders in adults such as hypertension and obesity, has
      been focused upon recently for a possible important role in fetal metabolism.
      Japanese are characterized by having equal allele frequencies for this
      polymorphism. In this study, we determined the maternal and infantile genotypes
      in 342 pairs of normal healthy mothers and their infants, and compared the
      genotype frequencies with various infantile somatoscopic characteristics
      converted into SD units according to sex, parity and gestational weeks. We
      observed an association of the maternal (but not infantile) G protein beta3
      subunit 825T allele with reduced head circumference but not with reduced birth
      weight of the neonate. No association was observed between G protein beta3
      subunit C825T polymorphism and various maternal somatoscopic characteristics.
      Although detailed mechanism of this association requires further research, our
      results suggest that expression of the beta3 subunit 825T allele in the mother
      may exert influence on fetal metabolic environment, perhaps through changes in
      the maternal uterine environment, or on maternal metabolism.

PMID- 12409515
TI  - The influence of litter size on brain damage caused by hypoxic-ischemic injury in
      the neonatal rat.
AB  - Hypoxic ischemia is a common cause of brain injury in the human neonate. This can
      be mimicked in the neonatal rat, but produces variable injury. The present study
      investigated the influence of litter size on the severity and variability of
      damage caused by hypoxic-ischemic injury in neonatal rats. Groups of 7-d-old pups
      from birth-sized litters (13-15 pups), or from litters culled to 10 on postnatal
      d 2, and 8- and 9-d-old pups from birth-sized litters, were exposed to common
      carotid artery occlusion and then, 3 h later, hypoxia (2 h 15 min, 8% oxygen).
      Damage was assessed histologically 72 h after injury, and graded (I-IV) according
      to severity. In nonculled litters, similar numbers of animals had each grade of
      injury. Most pups (70%) from culled litters had grade III or IV damage, and
      severity was significantly greater than in nonculled litters (p < 0.001). Pups
      from culled litters were heavier (17.6 +/- 0.4 g) than pups from nonculled
      litters (14.7 +/- 0.3 g, p < 0.0001). To determine whether this indicated that
      culled litters were more similar to older pups in their response to hypoxic
      ischemic injury, we examined injury in 8- and 9-d-old pups of similar body weight
      to 7-d-old pups from culled litters. The severity and distribution of damage in
      the older pups was different from damage in the 7-d-old pups from culled litters.
      These data suggest that in 7-d-old rats, litter size influences damage caused by
      hypoxic-ischemic injury, and that the relationship between body weight, brain
      development, and susceptibility to hypoxic-ischemic injury is complex.

PMID- 12409516
TI  - Influence of 24-hour sleep deprivation on respiration in lambs.
AB  - The aim of this study was first to examine the effects of 24-h sleep deprivation
      on apnea index and duration in lambs. The effects on sleep architecture and sigh
      and swallowing indices were also studied. The impact of postnatal maturation on
      all measured variables was assessed by studying two different age groups. Twelve
      lambs (six aged 1-2 d and six aged 23-24 d on the day of surgery) were
      chronically instrumented for polysomnographic recordings including sleep state
      assessment, nasal flow, diaphragm electromyogram, and glottal constrictor muscle
      electromyogram. Two recordings, one control and one after 24-h sleep deprivation,
      were performed in all lambs. Results show that the effects of sleep deprivation
      predominate in rapid eye movement sleep in the younger group, with increased
      rapid eye movement sleep proportion and apnea, sigh, and swallowing index. Our
      results in lambs suggest that the consequences of sleep deprivation upon
      respiration are predominant early after birth. Although the potential
      relationship of these observations to neonatal apneas and sudden infant death
      syndrome has yet to be defined, awareness of the effects of sleep deprivation is
      important for neonatal care.

PMID- 12409517
TI  - Antenatal dexamethasone: effect on ovine placental 11beta-hydroxysteroid
      dehydrogenase type 2 expression and fetal growth.
AB  - Antenatal glucocorticoids are routinely given to women at risk for preterm
      delivery. The fetus is protected from excessive glucocorticoids by the placental
      enzyme 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD-2), which catalyzes
      the conversion of cortisol to its biologically inactive metabolite, cortisone. We
      examined the effects of antenatal dexamethasone on the expression of placental
      11beta-HSD-2 in fetal sheep. Ewes were randomized to receive repeated or single
      courses of dexamethasone or placebo beginning at 76-78 or 104-106 d of gestation,
      respectively. In the single course group, the ewes received dexamethasone (6 mg,
      n = 7) or placebo (n = 6) as four intramuscular injections over 48 h up to 18 h
      before placental harvest. In the repeated course group, the ewes received the
      same treatment (dexamethasone, n = 10, or placebo, n = 9) once a week for 5
      consecutive weeks starting at 76-78 d of gestation. Placental harvest occurred at
      106-108 d of gestation in the four groups. By semi-quantitative RT-PCR, we found
      that placental 11beta-HSD-2 expression was lower in the fetuses of ewes exposed
      to a single course of dexamethasone than placebo (p < 0.05). Placental 11beta-HSD
      2 expression did not differ significantly between fetuses of ewes treated with
      repeated courses of dexamethasone compared with placebo, or a single course of
      dexamethasone. Fetuses of dexamethasone treated ewes weighed less than those of
      placebo treated ewes (ANOVA, main effects for dexamethasone versus placebo
      treatment: F = 14.5, p = 0.007). Fetuses of ewes exposed to repeated courses of
      dexamethasone weighed less than those of ewes exposed to placebo or a single
      course of dexamethasone (p < 0.05). We conclude that maternal antenatal
      dexamethasone treatment reduces placental 11beta-HSD-2 expression and fetal
      weight at mid-gestation in the ovine pregnancy.

PMID- 12409518
TI  - Placental and other perinatal risk factors for chronic lung disease in very low
      birth weight infants.
AB  - To clarify the relationship between chorioamnionitis and chronic lung disease
      (CLD) in very low birth weight (VLBW) infants, we performed a retrospective
      cohort study of all inborn patients between 1995-1997 with gestational age (GA)
      less than 32 wk, birth weight less than 1.5 kg, survival to 36 wk adjusted GA,
      and placentas submitted to pathology (n = 371). Racial distribution as defined by
      the mother was 40% white/60% nonwhite. Prevalence of CLD, defined as O(2)
      dependence at 36 wk adjusted GA, was 30%. In a preliminary analysis GA and birth
      weight for GA (standard deviations from the mean, Z-score), considered together,
      were inversely related to CLD. After adjustment for GA and Z-score, other risk
      factors for CLD were white race, acute respiratory distress, pulmonary air leak,
      patent ductus arteriosus, and septicemia. Two placental lesions were inversely
      related to CLD: histologic chorioamnionitis and acute atherosis (a placental
      indicator of preeclampsia). Following multivariate analysis, independent risk
      factors for CLD were GA (OR, 0.6; 95% CI = 0.5, 0.7), birthweight for GA (OR,
      0.4; 95% CI = 0.3, 0.6), white race (OR, 1.9; 95% CI = 1.0, 3.3), patent ductus
      arteriosus (OR, 2.0; 95% CI = 1.0, 3.5), and pulmonary air leak (OR, 3.0; 95% CI
      = 1.3, 7.1). Acute atherosis was inversely related to CLD (OR, 0.2; 95% CI = 0.1,
      0.8). Chorioamnionitis was stratified by subtype and again no association with
      CLD was seen in the population as a whole. Finally, chorioamnionitis of all
      subtypes tended to be increased in white infants and decreased in black infants
      with CLD. This dichotomy was not explained by differences in death rates, acute
      respiratory distress, intubation on d 2 of life, or total duration of assisted
      ventilation. We conclude that while chorioamnionitis was not a risk factor for
      CLD in our total population, racial differences in its relationship to CLD are
      worthy of further study.

PMID- 12409519
TI  - Acylcarnitine profiles of preterm infants over the first four weeks of life.
AB  - Measurement of free carnitine and acylcarnitines allows the detection of several
      inborn errors of metabolism in neonatal screening. Because available data for
      premature infants is limited, we studied longitudinal changes in acylcarnitine
      profiles of full-term and preterm neonates over the first 4 weeks of life. One
      hundred twenty infants were divided into four groups of 30: A, gestational age 22
      to 27 wk; B, 28 to 31 wk; C, 32 to 36 wk; and D, 37 to 41 wk. Blood samples
      spotted on a Guthrie card were taken on days 5 and 28. Additional specimens
      (groups A and B only) were collected on days 1, 3, 7, and 14. Carnitine and its
      acyl esters were detected by looking for the precursor ions of m/z = 85 using a
      PE Sciex API 365 electrospray ionization tandem mass spectrometer. Concentrations
      of free carnitine and most acylcarnitines were significantly higher in group A
      compared with group D postnatally. Groups B and C displayed intermediate values.
      Carnitine levels in infants from group A and B decreased steadily from day 1 to
      day 7, and recovered up to day 14 in group B only. On day 28 carnitine
      concentrations had further decreased in group A, while reaching postnatal levels
      again in group B. Postnatal carnitine levels are higher in very immature preterm
      infants compared with full-term infants, but become lower on day 28. However, the
      commonly used metabolite ratios should still allow the detection of inborn errors
      of metabolism.

PMID- 12409520
TI  - Surfactant phosphatidylcholine half-life and pool size measurements in premature
      baboons developing bronchopulmonary dysplasia.
AB  - Because minimal information is available about surfactant metabolism in
      bronchopulmonary dysplasia, we measured half-lives and pool sizes of surfactant
      phosphatidylcholine in very preterm baboons recovering from respiratory distress
      syndrome and developing bronchopulmonary dysplasia, using stable isotopes,
      radioactive isotopes, and direct pool size measurements. Eight ventilated
      premature baboons received (2)H-DPPC (dipalmitoyl phosphatidylcholine) on d 5 of
      life, and radioactive (14)C-DPPC with a treatment dose of surfactant on d 8.
      After 14 d, lung pool sizes of saturated phosphatidylcholine were measured. Half
      life of (2)H-DPPC (d 5) in tracheal aspirates was 28 +/- 4 h (mean +/- SEM). Half
      life of radioactive DPPC (d 8) was 35 +/- 4 h. Saturated phosphatidylcholine pool
      size measured with stable isotopes on d 5 was 129 +/- 14 micro mol/kg, and 123 +/
      11 micro mol/kg on d 14 at autopsy. Half-lives were comparable to those obtained
      at d 0 and d 6 in our previous baboon studies. We conclude that surfactant
      metabolism does not change during the early development of bronchopulmonary
      dysplasia, more specifically, the metabolism of exogenous surfactant on d 8 is
      similar to that on the day of birth. Surfactant pool size is low at birth,
      increases after surfactant therapy, and is kept constant during the first 2 wk of
      life by endogenous surfactant synthesis. Measurements with stable isotopes are
      comparable to measurements with radioactive tracers and measurements at autopsy.

PMID- 12409521
TI  - Intravenous dipyridamole enhances the effects of inhaled nitric oxide and
      prevents rebound pulmonary hypertension in piglets.
AB  - Inhaled nitric oxide (NO) is increasingly used in the treatment of pulmonary
      hypertension, despite its potential toxicity and the risk of life-threatening
      rebound pulmonary hypertension upon its discontinuation. We investigated whether
      i.v. dipyridamole, a cGMP phosphodiesterase inhibitor, increased the effects of
      inhaled NO and prevented rebound pulmonary hypertension. In 14 anesthetized and
      mechanically ventilated piglets, pulmonary hypertension was induced with U-46619,
      a thromboxane A(2) analogue. Response to NO and rebound pulmonary hypertension
      were evaluated without and with i.v. dipyridamole. Low-dose dipyridamole (10
      micro g/kg/min) increased cardiac output and augmented the effects of inhaled NO
      on pulmonary vascular resistance, with marginal additive effect on mean pulmonary
      artery pressure. Pulmonary vascular resistance decreased from 904 to 511 (20
      parts per million NO) (p < 0.0005) and 358 dyne s cm(-5) (20 parts per million NO
      + dipyridamole) (p < 0.001 versus NO alone), and mean pulmonary artery pressure
      decreased from 29.0 to 20.5 (p < 0.0001) and 19.3 mm Hg (NS versus NO),
      respectively. Mean arterial pressure decreased from 85 to 74 mm Hg (dipyridamole
      + NO) (p < 0.01). High-dose dipyridamole (100 micro g/kg/min) with inhaled NO
      reduced pulmonary vascular resistance to 334 dyne s cm(-5) but also decreased
      mean arterial pressure to 57 mm Hg. Eight piglets developed rebound pulmonary
      hypertension. Two died of acute right ventricular failure and, in five, rebound
      pulmonary hypertension was prevented by low-dose dipyridamole. In conclusion, low
      dose i.v. dipyridamole augments the effects of inhaled NO on right ventricular
      afterload with moderate changes in systemic hemodynamics, and can prevent rebound
      pulmonary hypertension.

PMID- 12409522
TI  - Differentiated thyroid carcinoma that express sodium-iodide symporter have a
      lower risk of recurrence for children and adolescents.
AB  - The sodium-iodide symporter (NIS) is expressed by papillary (PTC) and follicular
      (FTC) thyroid carcinoma, and is essential for iodine uptake. We hypothesized that
      PTC and FTC with detectable NIS immunostaining would be more amenable to
      radioactive iodine ((131)I) treatment and follow a more benevolent course. To
      test this, we determined NIS expression by immunohistochemistry in 23 PTC, 9 FTC,
      and 12 benign thyroid lesions from children and adolescents. NIS expression was
      determined by two blinded examiners and graded as absent = 0, minimal = 1,
      moderate = 2, intense = 3, and very intense = 4. NIS was detected in 35% (eight
      of 23) of PTC, 44% (four of 9) of FTC, 25% (two of eight) of benign tumors, and
      100% (four of four) of autoimmune lesions. The intensity of NIS expression was
      similar in PTC (0.61 +/- 0.24), FTC (0.56 +/- 0.24), and benign tumors (0.50 +/-
      0.33) but was more intense in autoimmune lesions (3.0 +/- 0.7, p < 0.005).
      Distant metastases were found only among PTC with undetectable NIS (two of 15,
      13%), and recurrence developed exclusively from PTC and FTC with undetectable NIS
      (four of 20, 20% versus zero of 12, p = 0.043). The dose of iodine 131 required
      to achieve remission in the five patients with PTC who had undetectable NIS
      (213.3 +/- 53 mCi) was greater than that required by patients with similar age
      and extent of disease for whom NIS expression is unknown (109 +/- 22 mCi, p =
      0.06). We conclude that NIS expression is associated with a lower risk of
      recurrence for PTC and FTC of children and adolescents.

PMID- 12409523
TI  - Exhaled nitric oxide measurements in childhood asthma: comparison of two sampling
      techniques.
AB  - Nitric oxide (NO) is being increasingly used to assess airway inflammation in
      childhood. The method recommended by the American Thoracic Society workshop is
      for a prolonged expiration against a resistance. However, this is very difficult
      to apply in young children. As a result there have been a number of studies in
      which mixed expired gas has been collected and analyzed for NO content as this
      requires very little cooperation. This method has, however, yet to be fully
      validated. The aims of this study were to compare the two sampling techniques of
      exhaled NO concentrations in asthmatic and healthy children and to assess the
      correlation between NO levels and spirometry values in asthmatic children We
      studied 25 control children, mean age 11.5 y, and 20 asthmatics, mean age 12 y.
      The exhaled NO was sampled using both the single breath technique (SB) and by
      measuring the NO content in mixed expired air after 1 min tidal breathing (ME).
      Forced expiratory volume in 1 s (FEV(1)) and expiratory flow rates at 25%, 50%,
      and 75% of vital capacity (FEF(25), FEF(50), FEF(75), respectively) were measured
      by compact II spirometer (best of three) in the 20 asthmatic children. The NO
      level was significantly higher in the asthmatics versus the control children when
      measured by SB (p = 0.0015) but not when measured by ME (p = 0.1913). The NO
      results measured by SB were significantly higher than ME results in the asthmatic
      children (p = 0.008). The NO levels were negatively correlated to FEV(1),
      FEF(25), FEF(50), and FEV(75) when measured by SB (p < 0.02) but not when
      measured by ME. The SB but not the ME method for measuring expired NO
      discriminates between asthmatic and control children and correlates well with the
      degree of airway obstruction. The use of the ME technique remains unproven.

PMID- 12409524
TI  - Intrauterine growth restriction is associated with changes in polyunsaturated
      fatty acid fetal-maternal relationships.
AB  - Fetuses with intrauterine growth restriction (IUGR) are at increased risk of
      death and disease during neonatal, pediatric, and adult life. Postnatal deficits
      in essential fatty acids have been associated with the neural and vascular
      complications of premature neonates. We studied whether fetal-maternal fatty acid
      relationships are already impaired in utero in IUGR fetuses. Fetal (F) and
      maternal (M) fatty acid profiles were determined in utero in 11 normal
      [appropriate for gestational age (AGA)] and in 10 IUGR fetuses by fetal blood
      sampling (FBS) between 19 and 39 wk. Total plasma fatty acid concentrations were
      significantly higher in M than in F of both AGA (M: 2.03 +/- 0.53 mg/mL; F: 0.64
      +/- 0.29 mg/mL; p < 0.001) and IUGR (M: 2.16 +/- 0.59 mg/mL; F: 0.73 +/- 0.17
      mg/mL; p < 0.001). The F/M ratio was significantly higher for linoleic acid (AGA:
      0.36 +/- 0.09; IUGR: 0.52 +/- 0.12; p < 0.01) and significantly lower for the
      long-chain polyunsaturated fatty acid docosahexaenoic acid (AGA: 1.94 +/- 0.32;
      IUGR: 1.25 +/- 0.19; p < 0.05) and arachidonic acid (AGA: 2.35 +/- 0.35%; IUGR:
      2.04 +/- 0.3%; p < 0.05) in IUGR compared with AGA pregnancies. The differences
      observed in the relative amounts but not in total plasma concentrations of fatty
      acid fetal-maternal relationships in pregnancies associated with IUGR could be
      related to inadequate transplacental supply as well as to a fetal lack of the
      enzymes necessary for elaboration of these metabolically relevant conditionally
      essential fatty acids. These differences might have a role in determining the
      biochemical environment leading to the neural and vascular complications
      associated with IUGR.

PMID- 12409525
TI  - Inflammation inhibits muscarinic signaling in in vivo canine colonic circular
      smooth muscle cells.
AB  - We investigated the effects of experimental colitis on the muscarinic signaling
      properties and contractile behavior of canine colonic circular smooth muscle. The
      hypotheses that inflammation 1) inhibits in vivo muscarinic receptor mediated
      contractions, and 2) alters receptor density or receptor-binding affinities were
      tested. Muscarine was infused close-intra-arterially in seven conscious dogs
      during normal and experimental colitis states. Colonic circular muscle
      contractions were recorded via surgically attached strain gauge transducers.
      Muscarine stimulated phasic contractions in a dose-dependent manner, whereas
      colitis was inhibited. The inhibitory concentration 50% dose of M(3) receptor
      inhibitor was several times lower than that of M(1), M(2), and M(4) inhibitors
      during normal and colitis. However, inflammation induced a significant leftward
      shift in the circular muscle inhibitory dose-response curve of M(2) inhibitor.
      Muscarinic receptor density and binding analyses in isolated circular muscle
      cells was done in normal and colitis states. Inflammation significantly decreased
      maximum binding from 4082 fmol/mg to 2708 fmol/mg, whereas affinity constant
      remained unaffected. The conclusions were that 1) spontaneous and muscarine
      activated in vivo phasic contractile activity of colonic circular muscle cells is
      primarily mediated by M(3) receptors; 2) inflammation was associated with a shift
      in M(2) receptor potency, due chiefly to a decrease in receptor density; and 3)
      this inhibitory effect was seen in normal and inflamed states, suggesting the
      importance of M(2) receptor. These findings suggest that changes in muscarinic
      response during colitis may contribute to the abnormal motility seen with
      inflammatory bowel disease.

PMID- 12409526
TI  - Perinatal nicotine attenuates the hypoxia-induced up-regulation of tyrosine
      hydroxylase and galanin mRNA in locus ceruleus of the newborn mouse.
AB  - The effect of perinatal nicotine exposure on the hypoxic response in the newborn
      mouse was examined, with special reference to the catecholaminergic system. We
      studied transcripts for the catecholamine synthesizing enzyme tyrosine
      hydroxylase (TH) and the neuropeptide galanin (GAL) in locus ceruleus (LC) and
      adrenal medulla at different times after birth and postnatal hypoxia. We
      thereafter investigated how perinatal nicotine affected these mRNA levels, as
      well as the ability of the newborn to survive severe hypoxia. TH mRNA levels
      increased postnatally in both LC and adrenals, reaching peak values at 24 h
      postnatally and thereafter stabilizing at lower levels. GAL mRNA also increased
      in the LC but did not decrease after 24 h. Acute hypoxia (5% O(2) for 60 min)
      elicited increases in TH and GAL mRNA levels in the LC after 24 h. However, TH
      mRNA levels in the adrenals did not change. Perinatal nicotine exposure increased
      mortality after hypoxia (from 0% to 16.9%). Moreover, hypoxia-induced increases
      in TH and GAL mRNA levels in the LC were not observed in nicotine-treated pups.
      Nicotine also decreased basal TH mRNA levels in the adrenals. The present results
      suggest (1) that the postnatal increases in adrenal TH mRNA levels are not
      directly due to hypoxia at birth, and (2) that the increased mortality seen after
      hypoxia in nicotine pups concurs with a perturbed LC function in these animals. A
      deficient catecholamine synthesis in the adrenals may also contribute to the
      detrimental effect of prenatal exposure to nicotine on the response to hypoxia.

PMID- 12409527
TI  - The development of pediatric nephrology.
AB  - Pediatric nephrology, as a discipline, arose from descriptive studies of
      childhood glomerulonephritis in Europe and the field of pediatric metabolism in
      the United States. While pediatric scientists before 1950 were concerned with
      fluid and electrolyte metabolism, regulation of intracellular and extracellular
      fluid, acid-base homeostasis, and parenteral fluid therapy, the defined field of
      nephrology developed after the Second World War around six major advances: ACTH
      and glucocorticoid therapy for nephrotic syndrome; renal biopsy to diagnose
      glomerular disease; the role of immunologic factors in glomerular injury; the use
      of dialysis as renal replacement therapy; renal transplantation as the optimal
      form of therapy in children with end stage renal failure; and recognition of
      renal disease in the etiology of 80% of cases of childhood hypertension. These
      discoveries led to focused research, the definition of specific training in
      nephrology, establishment of an American, European, and an International Society
      of Pediatric Nephrology, as well as an American Sub-Board of Pediatric
      Nephrology, and the inception of a journal, Pediatric Nephrology, now in its 15th
      year. Major research themes have included developmental nephrology,
      transplantation immunology, and concerns about growth in children with renal
      disease. Many clinical entities have been described in detail, some of which are
      almost confined to children. The scientific basis of pediatric nephrology,
      ongoing patient care needs, and its technical aspects - renal biopsy, dialysis
      and transplantation - assure its continuing future as a major pediatric
      discipline on all continents.

PMID- 12409528
TI  - Silicosis in the twenty first century.

PMID- 12409529
TI  - Exposure-response analysis and risk assessment for silica and silicosis mortality
      in a pooled analysis of six cohorts.
AB  - AIMS: To study the relation between exposure to crystalline silica and silicosis
      mortality. Although mortality is an important endpoint for regulators, there have
      been no exposure-response studies for silicosis mortality, because of the
      relative rareness of silicosis as an underlying cause of death, and the limited
      availability of quantitative exposure estimates. METHODS: Data from six
      occupational cohorts were pooled with good retrospective exposure data in which
      170 deaths from silicosis were reported. Standard life table analyses, nested
      case-control analyses, and risk assessment were performed. RESULTS: The rate of
      silicosis mortality in the combined data was 28/100 000 py, increasing in nearly
      monotonic fashion from 4.7/100 000 for exposure of 0-0.99 mg/m(3)-years to
      233/100 000 for exposure of >28.1 mg/m(3)-years. The estimated risk of death up
      to age 65 from silicosis after 45 years of exposure at 0.1 mg/m(3) silica (the
      current standard in many countries) was 13 per 1000, while the estimated risk at
      an exposure of 0.05 mg/m(3) was 6 per 1000. Both of these risks are above the
      risk of 1 per 1000 typically deemed acceptable by the US OSHA. CONCLUSION: The
      findings from this pooled analysis add further support to the need to control
      silica exposure and to lower the occupational standards. Our estimates of
      lifetime silicosis mortality risk are probably underestimates as, in addition to
      exposure misclassification, our study might have suffered from outcome
      misclassification in that silicosis deaths might have been coded to other related
      causes, such as tuberculosis or chronic obstructive pulmonary disease.

PMID- 12409530
TI  - Ineffective disability management by doctors is an obstacle for return-to-work: a
      cohort study on low back pain patients sicklisted for 3-4 months.
AB  - AIMS: To determine obstacles for return-to-work in disability management of low
      back pain patients sicklisted for 3-4 months. METHODS: A cohort of 467 low back
      pain patients sicklisted for 3-4 months was recruited. A questionnaire was sent
      to their occupational physicians (OPs) concerning the medical management,
      obstacles to return-to-work, and the communication with treating physicians.
      RESULTS: The OPs of 300 of 467 patients participated in this study. In many cases
      OPs regarded the clinical waiting period (43%), duration of treatment (41%), and
      view (25%) of the treating physicians as obstacles for return-to-work.
      Psychosocial obstacles for return-to-work such as mental blocks, a lack of job
      motivation, personal problems, and conflicts at work were all mentioned much less
      frequently by OPs. In only 19% of the patients was there communication between OP
      and treating physician. Communication almost always entailed an exchange of
      information, and less frequently an attempt to harmonise the management policy.
      Surprisingly communication was also limited, when OPs felt that the waiting
      period (32%), duration of treatment (30%), and view (28%) of treating physicians
      inhibited return-to-work. Communication was significantly associated with the
      following obstacles for return-to-work: passivity with regard to return-to-work
      and clinical waiting period; adjusted odds ratios were 3.35 and 2.23,
      respectively. CONCLUSIONS: Medical management of treating physicians is often an
      obstacle for return to work regarding low back pain patients sicklisted for 3-4
      months, in the opinion of OPs. Nevertheless communication between OPs and the
      treating physicians in disability management of these patients is limited. More
      attention to prevention of absenteeism and bilateral communication is needed in
      medical courses.

PMID- 12409531
TI  - Lead induced increase of blood pressure in female lead workers.
AB  - AIMS: Although lead exposure has, in the absence of mathematical modelling, been
      believed to elevate blood pressure in females, it is necessary to clarify the
      relation between lead and blood pressure by eliminating confounding factors in
      the analysis. METHODS: Blood lead was measured in 193 female workers, including
      123 lead exposed workers. Possible confounding factors were controlled by
      multiple regression analyses. RESULTS AND CONCLUSIONS: Blood lead above 40 micro
      g/dl was found to be the most potent factor for elevating systolic/diastolic
      blood pressure. Aging, urine protein, and plasma triglyceride also contributed to
      systolic/diastolic/pulse pressure increase, but hypertensive heredity did not.
      Data suggested that lead induced changes in lipoprotein metabolism may play an
      important role in the lead induced blood pressure increase in female workers.

PMID- 12409532
TI  - Different responses of Ross River virus to climate variability between coastline
      and inland cities in Queensland, Australia.
AB  - AIMS: To examine the potential impact of climate variability on the transmission
      of Ross River virus (RRv) infection, and to assess the difference in the
      potential predictors of RRv incidence in coastline and inland regions,
      Queensland, Australia. METHODS: Information on the RRv cases notified between
      1985 to 1996 was obtained from the Queensland Department of Health. Climate and
      population data were supplied by the Australian Bureau of Meteorology and the
      Australia Bureau of Statistics, respectively. The function of cross correlations
      was used to compute a series of correlations between climate variables (rainfall,
      maximum temperature, minimum temperature, relative humidity, and high tide) and
      the monthly incidence of RRv disease over a range of time lags. Time series
      Poisson regression models were performed to adjust for the autocorrelations of
      the monthly incidences of RRv disease and the confounding effects of seasonality,
      the case notification time, and population sizes. RESULTS: The cross correlation
      function shows rainfall, maximum temperature, minimum temperature, and relative
      humidity at a lag of 1-2 months and high tide in the current month were
      significantly associated with the monthly incidence of RRv in the coastline
      region. Relative humidity and rainfall at a lag of two months was also
      significantly associated with the monthly incidence of RRv in the inland region.
      The results of Poisson regressive models show that the incidence of RRv disease
      was significantly associated with rainfall, maximum temperature, minimum
      temperature, relative humidity, and high tide in the coastline region, and with
      rainfall and relative humidity in the inland region. There was a significant
      interaction between climate variables and locality in RRv transmission.
      CONCLUSIONS: Climate variability may have played a significant role in the
      transmission of RRv. There appeared to be different responses of RRv to climate
      variability between coastline and inland cities in Queensland, Australia. Maximum
      temperature appeared to exhibit a greater impact on the RRv transmission in
      coastline than in inland cities. Minimum temperature and relative humidity at 3
      pm inland seemed to affect the RRv transmission more than at the coastline.
      However, the relation between climate variables and RRv needs to be viewed within
      a wider context of other social and environmental factors, and further research
      is needed.

PMID- 12409533
TI  - Myocardial infarction risk and occupational categories in Kaunas 25-64 year old
      men.
AB  - AIMS: To investigate the risk of a first time myocardial infarction (MI) among
      different occupational categories in 25-64 year old men in Kaunas, Lithuania, a
      country in a transition market economy. METHODS: Case-control study among men
      aged 25-64 who were residents in Kaunas between 1997 and 2000. First time, non
      fatal MI cases (n = 448) were identified from the MI hospital register
      (International Classification of Diseases, 10th revision, code I21). Controls (n
      = 1777) were selected and matched on age, gender, and city district of residence.
      Information was obtained on occupation, smoking, hypertension, psychosocial, and
      behavioural factors. The International Standard Classification of Occupations
      (ISCO) was used to code for occupational categories. The relation between MI and
      occupational categories was evaluated by logistic regression analysis, adjusting
      for a number of selected risk factors. RESULTS: Legislators, senior officials,
      and managers (1st ISCO category) had a twofold increased risk for MI compared to
      craft and related trades workers (7th ISCO category) after adjustment for age,
      district, smoking, hypertension, obesity, stress, education, and employment
      duration. An increased risk for professionals (2nd ISCO category) and plant and
      machine operators and assemblers (8th ISCO category) was also observed.
      Employment duration in the last occupation for 20 years and more almost doubled
      the risk of MI in the whole population. We also found an increased risk for other
      traditional IHD risk factors such as smoking and arterial hypertension.
      CONCLUSIONS: Differences in first time MI risk among occupational categories were
      found. Legislators, senior officials, and managers (1st ISCO category),
      professionals (2nd ISCO category), and plant and machine operators and assemblers
      (8th ISCO category) were at an increased risk. Differences in psychosocial
      factors in transition market economy countries may contribute to observed
      results.

PMID- 12409534
TI  - Mortality and cancer morbidity of production workers in the UK flexible
      polyurethane foam industry: updated findings, 1958-98.
AB  - AIMS: To describe cause specific mortality and site specific cancer morbidity
      among workers employed in factories that produce polyurethane foams, and to
      determine if any part of the experience may be caused by occupation, in
      particular to investigate any association between respiratory disease (malignant
      and non-malignant) and exposure to diisocyanates. METHODS: The mortality (1958
      98) and cancer morbidity (1971-94) experienced by a cohort of 8288 male and
      female employees from 11 factories in England and Wales engaged in the
      manufacture of flexible polyurethane foams were investigated. All employees were
      employed for at least six months with some period of employment in the period
      1958-79. Two analytical approaches were used, indirect standardisation and
      Poisson regression. RESULTS: Compared with the general population of England and
      Wales, mortality from lung cancer in female employees was significantly increased
      (observed (Obs) 35, expected (Exp) 19.4, standardised mortality ratio (SMR) 181).
      A similar excess was not found for male employees (Obs 134, Exp 125.0, SMR 107).
      There were no significantly increased cause specific SMRs among the subcohort (n
      = 1782) with some period of isocyanate exposed employment. No significant
      positive trends were found between risks of lung cancer or risks of non-malignant
      diseases of the respiratory system and durations of "lower" or "higher" exposures
      to diisocyanates. CONCLUSIONS: The study has been unable to link isocyanate
      exposed employment either with risks of lung cancer or with risks of non
      malignant diseases of the respiratory system. The increased SMR for female lung
      cancer is most likely caused by factors unrelated to the industry under study.

PMID- 12409535
TI  - Are women more sensitive than men to 2-propanol and m-xylene vapours?
AB  - AIMS: To evaluate possible differences between men and women in acute health
      effects after controlled short term chamber exposure to vapours of two common
      organic solvents. METHODS: Fifty six healthy volunteers (28 per sex) were exposed
      to 150 ppm 2-propanol, 50 ppm m-xylene, and clean air for two hours at rest. The
      subjects rated symptoms on a visual analogue scale before, during, and after the
      exposure. Blinking frequency was measured continuously during exposure. Pulmonary
      function, nasal swelling, inflammatory markers (lysozyme, eosinophilic cationic
      protein, myeloperoxidase, albumin) in nasal lavage and colour vision (Lanthony D
      15 desaturated panel) were measured before and at 0 and 3 hours after the
      exposure. RESULTS: There were no significant sex differences in response to
      solvent exposure with respect to blinking frequency, lung diffusing capacity,
      nasal area and volume, inflammatory markers in nasal lavage, and colour vision.
      Increased symptoms were rated by both sexes for nearly all 10 questions during
      exposure to 2-propanol or m-xylene, most increases being significant at one time
      point at least. The rating of "discomfort in the throat or airways" increased
      more in women during exposure to 2-propanol or m-xylene. During exposure to 2
      propanol the rating of "fatigue" was more increased in men after one hour, but
      more increased in women after two hours of exposure. With regard to pulmonary
      function, women had small but significant decreases in FVC, FEV(1)/FVC, and
      FEF(75) three hours after exposure to m-xylene, but only the decrease in FVC was
      significantly different from that in men. CONCLUSION: Our results suggest that
      women are slightly more sensitive than men to the acute irritative effects of 2
      propanol and m-xylene vapours.

PMID- 12409536
TI  - Hazard potential ranking of hazardous waste landfill sites and risk of congenital
      anomalies.
AB  - BACKGROUND: A 33% increase in the risk of congenital anomalies has been found
      among residents near hazardous waste landfill sites in a European collaborative
      study (EUROHAZCON). AIMS: To develop and evaluate an expert panel scoring method
      of the hazard potential of EUROHAZCON landfill sites, and to investigate whether
      sites classified as posing a greater potential hazard are those with a greater
      risk of congenital anomaly among nearby residents relative to more distant
      residents. METHODS: A total of 1270 cases of congenital anomaly and 2308 non
      malformed control births were selected in 14 study areas around 20 landfill
      sites. An expert panel of four landfill specialists scored each site in three
      categories-overall, water, and air hazard-based on readily available, documented
      data on site characteristics. Tertiles of the average ranking scores defined low,
      medium, and high hazard sites. Calculation of odds ratios was based on distance
      of residence from the sites, comparing a 0-3 km "proximate" with a 3-7 km
      "distant" zone. RESULTS: Agreement between experts measured by intraclass
      correlation coefficients was 0.50, 0.44, and 0.20 for overall, water, and air
      hazard before a consensus meeting and 0.60, 0.56, and 0.53 respectively after
      this meeting. There was no evidence for a trend of increasing odds ratios with
      increasing overall hazard or air hazard. For non-chromosomal anomalies, odds
      ratios by water hazard category showed an increasing trend of borderline
      statistical significance (p = 0.06) from 0.79 in the low hazard category, 1.43 in
      the medium, to 1.60 in the high water hazard category. CONCLUSIONS: There is
      little evidence for a relation between risk of congenital anomaly in proximate
      relative to distant zones and hazard potential of landfill sites as classified by
      the expert panel, but without external validation of the hazard potential scoring
      method interpretation is difficult. Potential misclassification of sites may have
      reduced our ability to detect any true dose-response effect.

PMID- 12409537
TI  - When reciprocity fails: effort-reward imbalance in relation to coronary heart
      disease and health functioning within the Whitehall II study.
AB  - BACKGROUND: A deleterious psychosocial work environment, as defined by high
      efforts expended in relation to few rewards reaped, is hypothesised to increase
      the risk of future poor health outcomes. AIMS: To test this hypothesis within a
      cohort of London based civil servants. METHODS: Effort-reward imbalance (ERI) was
      measured among 6895 male and 3413 female civil servants aged 35-55 during the
      first phase of the Whitehall II study (1985-88). Participants were followed until
      the end of phase 5 (1997-2000), with a mean length of follow up of 11 years.
      Baseline ERI was used to predict incident validated coronary heart disease (CHD)
      events during follow up and poor mental and physical functioning at phase 5.
      RESULTS: A high ratio of efforts in relation to rewards was related to an
      increased incidence of all CHD (hazard ratio (HR) = 1.36, 95% CI 1.12 to 1.65)
      and fatal CHD/non-fatal myocardial infarction (HR = 1.28, 95% CI 0.89 to 1.84)
      during follow up, as well as poor physical (odds ratio (OR) = 1.47, 95% CI 1.24
      to 1.74) and mental (OR = 2.24, 95% CI 1.89 to 2.65) functioning at phase 5, net
      of employment grade. A one item measure of high intrinsic effort also
      significantly increased the risk of these health outcomes, net of grade. ERI may
      be particularly deleterious with respect to CHD risk among those with low social
      support at work or in the lowest employment grades. DISCUSSION: Within the
      Whitehall II study, a ratio of high efforts to rewards predicted higher risk of
      CHD and poor physical and mental health functioning during follow up. Although
      the increased risk associated with ERI was relatively small, as ERI is common it
      could be of considerable public health importance.

PMID- 12409538
TI  - Fever and neutrophilic alveolitis caused by a vanadium based catalyst.
AB  - AIMS: To investigate a worker who experienced systemic and respiratory symptoms
      when exposed to a vanadium containing powder used as a catalyst in the production
      of maleic anhydride. METHODS: The investigation included inhalation challenge
      with the suspected compound combined with monitoring of lung function tests and
      post-challenge bronchoalveolar lavage. RESULTS: Exposure to the vanadium
      containing catalyst for 120 minutes resulted in a sustained decline in forced
      vital capacity and forced expiratory volume in one second, while the transfer
      factor for carbon monoxide did not change significantly. The subject developed
      fever and peripheral blood neutrophilia. Bronchoalveolar lavage performed 48
      hours after the end of challenge exposure showed a marked increase in neutrophils
      (60% of total cell count). CONCLUSIONS: Exposure to vanadium can cause a metal
      fume fever-like syndrome associated with neutrophilic alveolitis.

PMID- 12409539
TI  - Design of measurement strategies for workplace exposures.

PMID- 12409540
TI  - Digoxin--new perspective on an old drug.

PMID- 12409541
TI  - Long-term trends in the incidence of and survival with heart failure.
AB  - BACKGROUND: Heart failure is a major public health problem. Long-term trends in
      the incidence of heart failure and survival after its onset in the community have
      not been characterized. METHODS: We used statistical models to assess temporal
      trends in the incidence of heart failure and Cox proportional-hazards regression
      to evaluate survival after the onset of heart failure among subjects in the
      Framingham Heart Study. Cases of heart failure were classified according to the
      date of onset: 1950 through 1969 (223 cases), 1970 through 1979 (222), 1980
      through 1989 (307), and 1990 through 1999 (323). We also calculated 30-day, 1
      year, and 5-year age-adjusted mortality rates for each period. RESULTS: Heart
      failure occurred in 1075 subjects (51 percent of whom were women). As compared
      with the rate for the period from 1950 through 1969, the incidence of heart
      failure remained virtually unchanged among men in the three subsequent periods
      but declined by 31 to 40 percent among women (rate ratio for the period from 1990
      through 1999, 0.69; 95 percent confidence interval, 0.51 to 0.93). The 30-day, 1
      year, and 5-year age-adjusted mortality rates among men declined from 12 percent,
      30 percent, and 70 percent, respectively, in the period from 1950 through 1969 to
      11 percent, 28 percent, and 59 percent, respectively, in the period from 1990
      through 1999. The corresponding rates among women were 18 percent, 28 percent,
      and 57 percent for the period from 1950 through 1969 and 10 percent, 24 percent,
      and 45 percent for the period from 1990 through 1999. Overall, there was an
      improvement in the survival rate after the onset of heart failure of 12 percent
      per decade (P=0.01 for men and P=0.02 for women). CONCLUSIONS: Over the past 50
      years, the incidence of heart failure has declined among women but not among men,
      whereas survival after the onset of heart failure has improved in both sexes.
      Factors contributing to these trends need further clarification.

PMID- 12409543
TI  - Skin ulcers misdiagnosed as pyoderma gangrenosum.
AB  - BACKGROUND: Pyoderma gangrenosum is a diagnosis of exclusion, and the
      misdiagnosis of pyoderma gangrenosum can result in substantial complications in
      patients who have other causes of severe cutaneous ulceration. METHODS: We
      reviewed the charts of 240 patients with a diagnosis of pyoderma gangrenosum who
      were evaluated at our institution from 1975 through 2000, including 157
      consecutive patients treated for presumed pyoderma gangrenosum from 1984 through
      1992. We also reviewed the English-language literature. RESULTS: Ninety-five
      patients (49 from our institution and 46 described in the literature) had skin
      ulcers with a clinical resemblance to pyoderma gangrenosum. The final diagnoses
      were vascular occlusive or venous disease, vasculitis, cancer, primary infection,
      drug-induced or exogenous tissue injury, and other inflammatory disorders. Of the
      95 patients studied, 64 had been treated for pyoderma gangrenosum for a median of
      10 months (range, 3 to 180). These 64 included 15 of the 157 consecutive patients
      treated for pyoderma gangrenosum at our institution (10 percent). Of the ulcers
      in the 64 patients treated for pyoderma gangrenosum, it was clear that those in
      23 patients (36 percent) did not respond to treatment directed at pyoderma
      gangrenosum, those in 8 (12 percent) were exacerbated by such treatment, and
      those in 15 (23 percent) improved with such treatment. CONCLUSIONS: The
      misdiagnosis of pyoderma gangrenosum is not uncommon and exposes patients to
      risks associated with its treatment. A thorough evaluation is required in all
      patients suspected of having pyoderma gangrenosum in order to rule out
      alternative diagnoses.

PMID- 12409542
TI  - Sex-based differences in the effect of digoxin for the treatment of heart
      failure.
AB  - BACKGROUND: The Digitalis Investigation Group trial reported that treatment with
      digoxin did not decrease overall mortality among patients with heart failure and
      depressed left ventricular systolic function, although it did reduce
      hospitalizations slightly. Even though the epidemiologic features, causes, and
      prognosis of heart failure vary between men and women, sex-based differences in
      the effect of digoxin were not evaluated. METHODS: We conducted a post hoc
      subgroup analysis to assess whether there were sex-based differences in the
      effect of digoxin therapy among the 6800 patients in the Digitalis Investigation
      Group study. The presence of an interaction between sex and digoxin therapy with
      respect to the primary end point of death from any cause was evaluated with the
      use of Mantel-Haenszel tests of heterogeneity and a multivariable Cox
      proportional-hazards model, adjusted for demographic and clinical variables.
      RESULTS: There was an absolute difference of 5.8 percent (95 percent confidence
      interval, 0.5 to 11.1) between men and women in the effect of digoxin on the rate
      of death from any cause (P=0.034 for the interaction). Specifically, women who
      were randomly assigned to digoxin had a higher rate of death than women who were
      randomly assigned to placebo (33.1 percent vs. 28.9 percent; absolute difference,
      4.2 percent, 95 percent confidence interval, -0.5 to 8.8). In contrast, the rate
      of death was similar among men randomly assigned to digoxin and men randomly
      assigned to placebo (35.2 percent vs. 36.9 percent; absolute difference, -1.6
      percent; 95 percent confidence interval, -4.2 to 1.0). In the multivariable
      analysis, digoxin was associated with a significantly higher risk of death among
      women (adjusted hazard ratio for the comparison with placebo, 1.23; 95 percent
      confidence interval, 1.02 to 1.47), but it had no significant effect among men
      (adjusted hazard ratio, 0.93; 95 percent confidence interval, 0.85 to 1.02;
      P=0.014 for the interaction). CONCLUSIONS: The effect of digoxin therapy differs
      between men and women. Digoxin therapy is associated with an increased risk of
      death from any cause among women, but not men, with heart failure and depressed
      left ventricular systolic function.

PMID- 12409544
TI  - Images in clinical medicine. Atypical pyoderma gangrenosum in a splenectomy
      incision.

PMID- 12409545
TI  - Controlling tuberculosis in India.
AB  - BACKGROUND: Tuberculosis kills nearly 500,000 people in India each year. Until
      recently, less than half of patients with tuberculosis received an accurate
      diagnosis, and less than half of those received effective treatment. METHODS: We
      analyzed the effects of new policies introduced in 1993 that have resulted in
      increased resources, improved laboratory-based diagnosis, direct observation of
      treatment, and the use of standardized antituberculosis regimens and reporting
      methods. RESULTS: By September 2001, more than 200,000 health workers had been
      trained, and 436 million people (more than 40 percent of the entire population)
      had access to services. About 3.4 million patients had been evaluated for
      tuberculosis, and nearly 800,000 had received treatment, with a success rate
      greater than 80 percent. More than half of all those treated in the past 8 years
      were treated in the past 12 months. CONCLUSIONS: India's tuberculosis-control
      program has been successful in improving access to care, the quality of
      diagnosis, and the likelihood of successful treatment. We estimate that the
      improved program has prevented 200,000 deaths, with indirect savings of more than
      $400 million--more than eight times the cost of implementation. It will be a
      substantial challenge to sustain and expand the program, given the country's
      level of economic development, limited primary health care system, and large and
      mostly unregulated private health care system, as well as the dual threats of the
      human immunodeficiency virus and multidrug-resistant tuberculosis.

PMID- 12409546
TI  - Ventricular septal rupture after acute myocardial infarction.

PMID- 12409547
TI  - Case records of the Massachusetts General Hospital. Weekly clinicopathological
      exercises. Case 34-2002. A 55-year-old man with cognitive and sensorimotor
      findings and intracranial lesions.

PMID- 12409548
TI  - Heart failure--an epidemic of uncertain proportions.

PMID- 12409549
TI  - A milestone in tuberculosis control.

PMID- 12409550
TI  - An array of sunshine in multiple sclerosis.

PMID- 12409551
TI  - Oral contraceptives and the risk of breast cancer.

PMID- 12409552
TI  - Major birth defects after assisted reproduction.

PMID- 12409553
TI  - Low and very low birth weight after use of assisted reproductive technology.

PMID- 12409554
TI  - Male circumcision, penile human papillomavirus infection, and cervical cancer.

PMID- 12409555
TI  - Changes in the transmission of tuberculosis in New York.

PMID- 12409556
TI  - AIDS orphans.

PMID- 12409557
TI  - Fulminant hepatitis E in Japan.

PMID- 12409558
TI  - Testing medications in children.

PMID- 12409559
TI  - Radiology 2002--statistical concepts series.

PMID- 12409560
TI  - An introduction to biostatistics.
AB  - This introduction to biostatistics and measurement is the first in a series of
      articles designed to provide Radiology readers with a basic understanding of
      statistical concepts. Although most readers of the radiology literature know that
      application of study results to their practice requires an understanding of
      statistical issues, many may not be fully conversant with how to interpret
      statistics. The goal of this series is to enhance the ability of radiologists to
      evaluate the literature competently and critically, not make them into
      statisticians.

PMID- 12409561
TI  - Screening mammography: controversies and headlines.

PMID- 12409562
TI  - You do not know what you are doing unless you know what you are doing.

PMID- 12409563
TI  - Minimizing radiation-induced skin injury in interventional radiology procedures.
AB  - Skin injury is a deterministic effect of radiation. Once a threshold dose has
      been exceeded, the severity of the radiation effect at any point on the skin
      increases with increasing dose. Peak skin dose is defined as the highest dose
      delivered to any portion of the patient's skin. Reducing peak skin dose can
      reduce the likelihood and type of skin injury. Unfortunately, peak skin dose is
      difficult to measure in real time, and most currently available fluoroscopic
      systems do not provide the operator with sufficient information to minimize skin
      dose. Measures that reduce total radiation dose will reduce peak skin dose, as
      well as dose to the operator and assistants. These measures include minimizing
      fluoroscopy time, the number of images obtained, and dose by controlling
      technical factors. Specific techniques-dose spreading and collimation-reduce both
      peak skin dose and the size of skin area subjected to peak skin dose. For optimum
      effect, real-time knowledge of skin-dose distribution is invaluable. A trained
      operator using well-maintained state-of-the art equipment can minimize peak skin
      dose in all fluoroscopically guided procedures.

PMID- 12409564
TI  - Abdominal aortic aneurysms: cost-effectiveness of elective endovascular and open
      surgical repair.
AB  - PURPOSE: To evaluate the cost-effectiveness of elective endovascular and open
      surgical repair of infrarenal abdominal aortic aneurysms (AAAs) by taking into
      account short- and long-term outcomes. MATERIALS AND METHODS: A Markov decision
      model was developed to evaluate quality-adjusted life-years (QALYs) and lifetime
      costs of endovascular and open surgical repair. The incremental cost
      effectiveness ratio (CER) was calculated for endovascular repair relative to open
      surgery in a cohort of 70-year-old men with an AAA between 5 and 6 cm in
      diameter. Clinically effectiveness data were derived from the literature. Cost
      data were derived from Medicare reimbursement rates, the hospital database, and
      the literature. One- and multiple-way sensitivity analyses were performed on
      uncertain model parameters. Costs were converted to year 2000 U.S. dollars;
      future costs and outcomes were discounted at 3%. RESULTS: The incremental CER of
      endovascular repair was 9,905 dollars per QALY. QALYs and lifetime costs were
      higher for endovascular repair than for open surgery (6.74 vs 6.52 and 39,785
      dollars vs 37,606 dollars, respectively). In sensitivity analyses, the
      incremental CER was insensitive to immediate conversion rate and procedure
      mortality rate. The incremental CER was sensitive (ie, more than 75,000 dollars
      per QALY or endovascular repair was ruled out by dominance) to systemic-remote
      complications, long-term failures, and ruptures. CONCLUSION: The results suggest
      that endovascular repair is a cost-effective alternative compared with open
      surgery for the elective repair of AAA. The benefits and cost-effectiveness are
      highly dependent on uncertain outcomes, however, particularly long-term failure
      and rupture rates.

PMID- 12409565
TI  - Long-term outcome of patients with claudication after balloon angioplasty of the
      femoropopliteal arteries.
AB  - PURPOSE: To report the long-term outcome of patients with lifestyle-limiting
      claudication after percutaneous transluminal angioplasty (PTA) of the
      femoropopliteal arteries. MATERIALS AND METHODS: Between 1989 and 1992, 173
      consecutive claudicant patients (mean age, 65 years; age range, 41-90 years)
      underwent PTA in 218 limbs; all interventions included femoral and/or popliteal
      arterial segments, and additional iliac (n = 27) and infrapopliteal (n = 11)
      arterial lesions were also treated. Patients were followed up for 7-10 years.
      Altogether, 37 (17%) limbs were classified as Fontaine class 2A, and 181 (83%)
      were class 2B. Average length of the primary lesion was 5.2 cm. Reinterventions
      were analyzed. Patency rates and patient survival were assessed by means of life
      table analysis. Cox-Mantel tests and Cox proportional hazards models were used to
      define associated independent determinants. Development of chronic critical
      ischemia (CCI) and its determinants was assessed by using the Pearson chi(2) test
      and multiple logistic regression analysis. RESULTS: The primary and secondary
      patencies (+/- standard error of the estimate), respectively, were 46% +/- 3 and
      63% +/- 3 at 1 year, 25% +/- 3 and 41% +/- 4 at 5 years, and 14% +/- 3 and 22% +/
      4 at 10 years. One-third (71 of 218) of the limbs required repeat interventions,
      including surgical revascularization in 35 limbs. Fourteen (6.4%) limbs developed
      CCI, resulting in a 0.8% incidence per year. In multivariate analysis, poor
      postinterventional peripheral runoff was an indicator of increased risk of CCI
      development (P =.03). CONCLUSION: Although the long-term patency rates of PTA of
      the femoropopliteal arteries in claudicant patients were poor, the acceptable
      number of reinterventions and the low frequency of development of CCI imply the
      long-term benefits achievable with this treatment.

PMID- 12409566
TI  - Image-guided percutaneous drainage of tuberculous iliopsoas and spondylodiskitic
      abscesses: midterm results.
AB  - PURPOSE: To evaluate midterm results of percutaneous drainage (PD) with image
      guidance in 21 patients with tuberculous iliopsoas abscesses with or without
      spondylodiskitis. MATERIALS AND METHODS: Computed tomography (CT)-guided PD was
      performed in 21 patients with 26 tuberculous iliopsoas abscesses. Nineteen
      patients had bone involvement of two or more vertebrae. Eleven patients with
      spondylodiskitis had intradiskal abscesses. Five patients had bilateral psoas
      abscesses. Easily and safely accessible well-circumscribed abscesses larger than
      3 cm were selected for PD. Catheters were inserted into the abscess cavities with
      Seldinger technique in all cases. In conjunction with PD, all patients had
      antituberculous drug therapy and underwent clinical and imaging follow-up for at
      least 1 year. RESULTS: Percutaneous catheter placement was successful in all
      cases without procedural complications. On the basis of CT findings, complete
      evacuation of all abscesses was achieved initially. During follow-up, six (29%)
      of 21 patients had recurrences within 1 and 3 months after catheter removal. A
      total of 37 catheters were used; eight of the 37 catheters were inserted due to
      recurrences. Four patients needed two PD procedures, and two patients needed
      three due to recurrences. Four catheters were changed because of obstruction or
      dislocation. Drainage duration ranged from 5 to 36 days (mean, 14.9 days). The
      follow-up period was 12-52 months (mean, 24 months). None of the patients,
      including those with recurrence, required surgical drainage and debridement due
      to insufficient PD. CONCLUSION: Image-guided PD in conjunction with
      antituberculous drug therapy is an effective and safe procedure in the treatment
      of tuberculous iliopsoas abscesses with or without spondylodiskitis.

PMID- 12409567
TI  - Effectiveness of open versus antireflux stents for palliation of distal
      esophageal carcinoma and prevention of symptomatic gastroesophageal reflux.
AB  - PURPOSE: To compare the effectiveness of an antireflux stent with that of a
      standard open stent in preventing symptoms of gastroesophageal reflux in patients
      with inoperable distal esophageal cancer. MATERIALS AND METHODS: Fifty
      consecutive patients with inoperable distal esophageal tumors underwent placement
      of either a standard open or an antireflux stent across the cardia. Stents were
      allocated randomly before assessment of the stricture. All patients were followed
      up prospectively by the departmental research nurses. Technical and clinical
      success, reflux symptoms, complications, and reintervention rates were assessed.
      P values of observed differences were calculated by using the chi(2) and log-rank
      tests as appropriate. RESULTS: The technical success rate was 100%. Improvement
      in dysphagia was identical in both groups (three points on a five-point scale).
      Twenty-four (96%) of 25 patients with standard open stents had symptoms of
      esophageal reflux; 19 (76%) of 25 required treatment. Three (12%) of 25 patients
      with antireflux stents reported esophageal reflux; one (4%) of 25 required
      treatment. This difference was significant (P <.001). There was no significant
      difference in survival, complications, or reintervention rate. One case of late
      esophageal perforation occurred in each group. One patient died of aspiration
      within 24 hours after insertion of a standard open stent; no procedure-related
      deaths occurred with the antireflux stent. CONCLUSION: This antireflux stent is
      as safe and effective as the standard open stent in relieving malignant dysphagia
      and was successful in reducing symptomatic gastroesophageal reflux.

PMID- 12409568
TI  - Malignant liver tumors treated with MR imaging-guided laser-induced
      thermotherapy: experience with complications in 899 patients (2,520 lesions).
AB  - PURPOSE: To evaluate the complications from laser-induced thermotherapy (LITT) of
      malignant liver tumors and demonstrate that LITT is safe as an outpatient
      procedure. MATERIALS AND METHODS: During 8 years, 899 patients with malignant
      liver tumors were treated with magnetic resonance (MR) imaging-guided LITT. A
      total of 2,132 LITT procedures were performed to treat 2,520 lesions. To account
      for the technical evolution of LITT during this time and the change from
      performing the procedure on an inpatient basis to performing it on an outpatient
      basis, patients were assigned to four groups. Overall complication rates and
      major and minor complications in the inpatient versus outpatient groups were
      evaluated. Multidimensional contingency table analysis with the chi(2) test was
      performed. RESULTS: On the basis of a total of 2,132 LITT procedures performed,
      complications were divided into major and minor categories and detected at
      clinical or imaging studies. Major complications included three deaths (0.1%)
      within 30 days after LITT, pleural effusion requiring thoracentesis in 16 (0.8%)
      cases, hepatic abscess requiring drainage in 15 (0.7%) cases, bile duct injury in
      four (0.2%) cases, segmental infarction in three (0.1%) cases, and hemorrhage
      requiring transfusion in one (0.05%) case. Minor complications included
      postprocedural fever in 710 (33.3%), pleural effusion not requiring thoracentesis
      in 155 (7.3%), subcapsular hematoma in 69 (3.2%), subcutaneous hematoma in 24
      (1.1%), pneumothorax in seven (0.3%), and hemorrhage in two (0.1%) cases.
      Outpatient management did not significantly affect pleural effusion (P =.96) or
      subcapsular hematoma (P =.33) rate. CONCLUSION: MR imaging-guided LITT with local
      anesthesia is safe and yields an acceptably low rate of major complications.

PMID- 12409569
TI  - The small-bowel feces sign.

PMID- 12409570
TI  - CT colonography: multiobserver diagnostic performance.
AB  - PURPOSE: To prospectively evaluate multiobserver diagnostic performance and
      reader agreement for colorectal polyp detection in a well-characterized cohort of
      patients with increased number of polyps, compared with an average-risk patient,
      with colonoscopy as the reference standard. MATERIALS AND METHODS: A cohort of 70
      patients suspected of having polyps was examined with spiral computed tomographic
      (CT) colonography, with colonoscopy performed the same day. After air
      insufflation per rectum, supine and prone images were obtained with single
      detector row CT (5-mm collimation, 8-mm table increment, 2-mm reconstruction
      interval). Images were analyzed independently by four experienced abdominal
      radiologists using two-dimensional multiplanar reformation followed by selective
      use of three-dimensional endoscopic volume-rendered images. Data were analyzed
      both per polyp and per patient. RESULTS: Analysis per polyp demonstrated a pooled
      sensitivity of 0.68 for lesions 10 mm or larger (n = 40), with 75% agreement
      among the four readers. Analysis per patient demonstrated improved detection and
      agreement, with a pooled sensitivity of 0.88 for patients with polyps or cancers
      10 mm or larger (n = 28), with 94% agreement. When sensitivity and receiver
      operating characteristic analyses were analyzed per polyp size threshold, results
      among readers converged and peaked at polyp diameters of approximately 10 mm.
      CONCLUSION: In this patient cohort, diagnostic performance and interobserver
      agreement with single-detector row CT colonography was sufficient for detection
      of patients with lesions 10 mm or larger, with more variable results for smaller
      polyps.

PMID- 12409571
TI  - Colonic polyps: complementary role of computer-aided detection in CT
      colonography.
AB  - PURPOSE: To apply a computer-aided detection (CAD) algorithm to supine and prone
      multisection helical computed tomographic (CT) colonographic images to confirm if
      there is any added benefit provided by CAD over that of standard clinical
      interpretation. MATERIALS AND METHODS: CT colonography (with patients in both
      supine and prone positions) was performed with a multisection helical CT scanner
      in 40 asymptomatic high-risk patients. There were two consecutive series of
      patients, 20 of whom had at least one polyp 1.0 cm in size or larger and 20 of
      whom had normal colons at conventional colonoscopy performed the same day. The CT
      colonographic images were interpreted with an automated CAD algorithm and by two
      radiologists who were blinded to colonoscopy findings. RESULTS: For 25 polyps at
      least 1.0 cm in size ("large" polyps), sensitivity for detection by at least one
      radiologist was 48% (12 of 25). The sensitivity of CAD for detecting large polyps
      was also 48% (12 of 25), but the CAD algorithm detected four of 13 large polyps
      that were not detected by either radiologist (31%, 95% two-sided CI: 9, 61),
      increasing the potential sensitivity to 64% (16 of 25). For polyps identifiable
      retrospectively, sensitivity of CAD was 67% (12 of 18), and sensitivity of the
      combination of detection with the CAD algorithm or by at least one radiologist
      was 89% (16 of 18). There were an average of 11 false-positive detections per
      patient for CAD. CONCLUSION: In this series of patients in whom radiologists had
      difficulties detecting polyps (compared with sensitivities of 75%-90% reported in
      the literature), this CAD algorithm played a complementary role to conventional
      interpretation of CT colonographic images by detecting a number of large polyps
      missed by trained observers.

PMID- 12409572
TI  - Frequency of visualization and thickness of normal appendix at nonenhanced
      helical CT.
AB  - PURPOSE: To evaluate the frequency of visualization, thickness, and features of
      the normal appendix at nonenhanced helical computed tomography (CT). MATERIALS
      AND METHODS: Three radiologists blinded to patient surgical history
      retrospectively reviewed CT scans obtained for renal colic assessment in 187
      consecutive patients. No contrast material was administered. The frequency of
      visualization and the two-wall thickness of normal appendices were recorded.
      Interobserver agreement and effect of adequacy of intraperitoneal fat on
      identification of the appendix were assessed. RESULTS: The prevalence of
      appendectomy was 10.7% (20 of 187 patients). The means for the three reviewers'
      sensitivity, specificity, positive and negative predictive values, and accuracy
      of visualization of normal appendix were 79% (CI: 73%, 84%), 90% (CI: 78%, 96%),
      98% (CI: 97%, 99%), 34% (CI: 22%, 47%), and 80% (CI: 74%, 86%), respectively.
      There was no significant difference among the three reviewers (P >.05) according
      to conditional logistic regression and exact McNemar test results. For all
      reviewers, the frequency of appendix visualization was significantly lower in
      patients with less intraperitoneal fat (P =.01-.001, chi(2) test). The mean
      thickness of normal appendix if no intraluminal content was visualized was 6.6 mm
      +/- 1.0 (SD), and the mean thickness, excluding visualized intraluminal content,
      was 3.6 mm +/- 0.8. The nonweighted kappa value for interobserver agreement for
      normal appendix visualization was 0.69-0.75 among the three reviewers, which
      indicated good to excellent agreement. CONCLUSION: Most normal appendices are
      seen at nonenhanced helical CT. The thickness of normal appendix, when the
      content is not recognizable, overlaps the values currently used to diagnose
      appendicitis at CT.

PMID- 12409573
TI  - Gadolinium-enhanced MR imaging of the liver: optimizing imaging delay for hepatic
      arterial and portal venous phases--a prospective randomized study in patients
      with chronic liver damage.
AB  - PURPOSE: To investigate the optimal imaging delays for hepatic arterial and
      portal venous phases of gadolinium-enhanced dynamic spoiled gradient-recalled
      echo magnetic resonance (MR) imaging of the liver in patients with chronic liver
      damage. MATERIALS AND METHODS: MR images were obtained after intravenous bolus
      injection of gadopentetate dimeglumine in 100 patients with chronic liver damage.
      Test bolus imaging was performed to determine the aortic transit time. A 26
      second spoiled gradient-recalled-echo sequence was used. Patients were randomized
      into four groups so that the middle of k space was acquired at 5, 10, 15, and 20
      seconds for the first phase and 45, 50, 55, and 60 seconds for the second phase,
      respectively, from the time of arrival of contrast material in the abdominal
      aorta. Mean signal intensities of the liver, spleen, and abdominal aorta were
      measured, and images were reviewed prospectively by three radiologists in
      consensus. Analysis of variance, the Scheffe criterion for continuous data, and
      the Kruskal-Wallis test for categorical data were used for statistical
      evaluation. RESULTS: Intense splenic enhancement with the moire pattern without
      intense hepatic enhancement occurred at 10-15 seconds. Aortic and splenic
      enhancement significantly decreased from 45 to 50 seconds (P <.05). Spleen-to
      liver contrast-to-noise ratio began to decrease at 20 seconds and decreased
      constantly over time. Qualitative results correlated well with quantitative
      results. CONCLUSION: Biphasic imaging with k space centered at 10-15 and 50
      seconds or later after arrival of contrast material in the abdominal aorta may be
      the optimal technique to obtain ideal contrast enhancement. Empirically, delays
      of 28-34 and 68 seconds or later after initiating contrast material injection may
      be effective for biphasic imaging.

PMID- 12409574
TI  - CT tumor measurement for therapeutic response assessment: comparison of
      unidimensional, bidimensional, and volumetric techniques initial observations.
AB  - PURPOSE: To compare unidimensional, bidimensional, and volumetric techniques for
      evaluation of treatment response in patients with liver metastases from breast
      cancer in a phase III clinical trial. MATERIALS AND METHODS: Helical computed
      tomographic (CT) studies in 38 patients with liver metastases from breast cancer
      who were enrolled in a phase III clinical trial were evaluated before treatment
      and at 6 months after treatment. Two subspecialty radiologists measured all
      lesions on transverse CT scans with use of electronic calipers according to both
      unidimensional and bidimensional criteria. Volumetric measurements were made by
      tracing individual lesions. Measurements of individual lesions were summed to
      obtain patient response, which was categorized as complete response,
      disappearance of lesions; partial response, greater than 30% decrease in tumor
      diameter (unidimensional), greater than 50% reduction in tumor area
      (bidimensional), or greater than 65% reduction in tumor volume (volumetric);
      disease progression, greater than 20% increase in tumor diameter, greater than
      25% increase in tumor area, or greater than 73% increase in tumor volume: or
      stable disease (size response other than that of complete response, partial
      response, or disease progression). RESULTS: In 37 patients, there was concordant
      treatment response with use of unidimensional and bidimensional techniques.
      Volumetric measurement produced results different from those of the
      unidimensional and bidimensional techniques in 12 and 13 patients, respectively.
      In six patients with partial response per unidimensional and bidimensional
      criteria, the response based on the volumetric technique was stable disease. In
      two patients with stable disease per bidimensional and unidimensional criteria,
      the response was partial response by volumetric measurement. In four patients
      with disease progression per bidimensional and unidimensional criteria, the
      response was stable disease per volumetric criteria. CONCLUSION: Volumetric
      measurement of tumor burden gives different results for treatment response
      compared with that of the unidimensional or bidimensional technique in a
      considerable proportion of patients.

PMID- 12409575
TI  - Effect of race on biochemical disease-free outcome in patients with prostate
      cancer treated with definitive radiation therapy in an equal-access health care
      system: radiation oncology report of the Department of Defense Center for
      Prostate Disease Research.
AB  - PURPOSE: To report on the first collaboration of the Department of Defense Center
      for Prostate Disease Research concerned with the relationship between African
      American race and biochemical disease-free outcomes after definitive radiation
      therapy. MATERIALS AND METHODS: Information from the medical records of 1,806
      patients (1,349 white, 343 African American, 42 of "other" races, and 72 of
      "unknown" races) treated with definitive radiation therapy between 1973 and 2000
      was reviewed. Patients receiving adjuvant hormonal therapy or postoperative
      adjuvant or salvage radiation therapy were excluded. Biochemical failure was
      calculated in over 96% of cases by using ASTRO criteria; patients with fewer than
      three follow-up visits were considered to have biochemical failure with a
      prostate-specific antigen (PSA) value more than 10-fold the previous value or
      with any value greater than 50.0 ng/mL. Median radiation therapy doses were
      similar. The median follow-up was 58.4 months. Kaplan-Meier tests, Cox
      proportional hazards regression analysis, and log-rank tests were used for data
      analysis. RESULTS: There was no statistically significant difference in
      biochemical disease-free survival according to race when patients were stratified
      according to T stage. African American race conferred a negative prognosis for
      patients with lesions of Gleason biopsy score 7 (P =.004) but not for patients
      with lesions of Gleason score 2-4 (P =.14), 5-6 (P =.79), or 8-10 (P =.86).
      Similarly, African American race conferred a negative prognosis in patients with
      PSA values of 20.1-50.0 ng/mL (P =.01) at presentation but not in patients with
      PSA values less than or equal to 4.0 ng/mL (P =.84), 4.1-10.0 ng/mL (P =.71),
      10.1-20.0 ng/mL (P =.75), or above 50.0 ng/mL (P =.15) at presentation. At
      multivariate analysis, race was not a statistically significant predictor of
      outcome. CONCLUSION: In the equal-access health care system of the Department of
      Defense, African American race is not associated with a consistently negative
      prognosis in patients treated with definitive radiation therapy for prostate
      cancer. Race appears to confer a negative prognosis only in patients with
      advanced disease at presentation.

PMID- 12409576
TI  - Comprehensive MR imaging in the preoperative evaluation of living donor
      candidates for laparoscopic nephrectomy: initial experience.
AB  - PURPOSE: To evaluate the accuracy of magnetic resonance (MR) imaging in the
      preoperative evaluation of potential living renal donors who are candidates for
      laparoscopic nephrectomy. MATERIALS AND METHODS: Twenty-eight donor candidates
      who underwent subsequent laparoscopic nephrectomy were examined by using a torso
      phased-array coil at 1.5 T. Gadolinium-enhanced MR angiograms, MR venograms, and
      MR urograms were obtained in all patients by using an interpolated three
      dimensional T1-weighted spoiled gradient-echo sequence (3.4-6.8/1.2-2.3
      [repetition time msec/echo time msec], 25 degrees -40 degrees flip angle).
      Interpretation of the MR images was used to assess the arterial, venous, and
      ureteral anatomy, as well as parenchymal masses and scarring, and findings were
      compared with the surgical findings in all patients. Statistical evaluation was
      performed, with the surgical findings as the reference standard. RESULTS: At MR
      imaging, 31 of 32 renal arteries and one of three early-branching arteries were
      identified correctly. The correct venous anatomy was identified in 23 of 28
      patients, including a single left renal vein anterior to the aorta (n = 16),
      retroaortic left renal vein (n = 2), circumaortic left renal vein (n = 2), and
      single right renal vein (n = 3). A single collecting system in all harvested
      kidneys was identified correctly with MR urography. Overall, MR imaging correctly
      depicted vascular, ureteral, and parenchymal anatomy in 21 of 28 patients. Twenty
      seven of 28 patients underwent successful laparoscopic donor nephrectomy on the
      basis of the MR findings. One procedure was converted to open nephrectomy on the
      basis of complex venous anatomy not prospectively identified on the MR images.
      The sensitivity and positive predictive value of MR imaging in correctly
      determining the combined vascular, ureteral, and parenchymal anatomy in the
      harvested kidney were 75% (21 of 28) and 95% (21 of 22), respectively.
      CONCLUSION: Comprehensive gadolinium-enhanced MR imaging can depict the vascular
      anatomy, collecting system, and renal parenchyma preoperatively in patients who
      are candidates for laparoscopic living-donor nephrectomy.

PMID- 12409577
TI  - Female urinary genuine stress incontinence: anatomic considerations at MR imaging
      of the paravaginal fascia and urethra initial observations.
AB  - PURPOSE: To compare, on high-spatial-resolution magnetic resonance (MR) images,
      the presence and distribution of the paravaginal fascia in continent women and in
      those with genuine stress incontinence (GSI) to establish its role in the
      pathophysiology of GSI. MATERIALS AND METHODS: Eleven continent reference
      subjects and 10 GSI patients underwent MR imaging with a specifically designed
      endovaginal receiver coil. A urinary continence questionnaire and urogynecologic
      clinical examination had been completed. GSI was diagnosed with urodynamic tests.
      Paravaginal fascial tissue distribution was determined, and the paravaginal
      fascial volume (PFV) anteriorly associated with the urethra was measured.
      Retropubic urethral length (UL) in the supine position at rest was compared with
      its total length and expressed as a percentage ratio. Comparisons of urethral PFV
      and retropubic UL between reference subjects and the GSI patients were performed
      by means of two-sample t tests with unequal variances because data were
      parametric by means of the Shapiro-Francia W' test for normal data. RESULTS: The
      paravaginal fascia (connective tissue that contained venous plexus) was a
      consistent MR imaging feature in all women. Mean urethral PFV was 5.3 cm(3) +/-
      0.6 (SD) in reference subjects compared with 3.5 cm(3) +/- 2.0 in GSI patients (P
      =.017). The ratio of the retropubic UL to its total length was 82.6% +/- 7.4 in
      reference subjects compared with 57.4% +/- 9.8 in GSI patients (P <.001). There
      was a weak correlation between urethral PFV and retropubic UL (r = 0.46).
      CONCLUSION: There is a significant association between urethral PFV and
      continence status. GSI patients have a reduced urethral PFV, and greater than 40%
      of their urethral length lies below the pubis in the supine position at rest.
      However, the effects of age and hormonal status on urethral PFV remain to be
      evaluated.

PMID- 12409578
TI  - CT in detecting urinary tract calculi: influence on patient imaging and clinical
      outcomes.
AB  - PURPOSE: To determine changes in examination patterns and effectiveness of care
      since the introduction of unenhanced helical computed tomography (CT) for
      examination of patients presenting to the emergency department (ED) with symptoms
      of urinary tract calculi (UTC). MATERIALS AND METHODS: Hospital clinical and
      radiology information systems were used to retrospectively identify patients
      presenting with UTC symptoms from January to December 1997 (before introduction
      of unenhanced CT) and from January to December 1999 (after introduction of
      unenhanced CT). Chart abstraction was used to confirm the identification of
      patients with presenting symptoms suggestive of UTC and assess patient outcomes.
      Two hundred sixty-five patients presented before (1997) and 602 after (1999)
      unenhanced CT was introduced. Distributions of dichotomous variables were
      compared between the 1997 and 1999 groups by using logistic regression. Means
      were compared between the groups by using analysis of variance and mean total
      numbers of imaging studies by using Poisson regression. RESULTS: Total number of
      imaging studies increased by 26.7% per patient visit (P <.001). Rates of
      admission following the initial ED visit (13.7% in 1997 vs 13.4% in 1999), as
      well as percentage of patients who subsequently returned to the ED (12.0% in 1997
      vs 13.7% in 1999) or subsequently were admitted to the hospital (4.5% in 1997 vs
      5.3% in 1999) in the month following the initial ED visit, were similar between
      the two groups. Unsuspected unenhanced CT findings that could affect acute
      patient care were observed at 5.9% of examinations. CONCLUSION: Use of imaging
      for suspected UTC has increased markedly since the introduction of unenhanced CT,
      with little effect on acute care of patients in the ED.

PMID- 12409579
TI  - Tuberous sclerosis complex: renal imaging findings.
AB  - PURPOSE: To review the renal imaging findings and changes over time in a large
      series of young patients with tuberous sclerosis complex (TSC). MATERIALS AND
      METHODS: One hundred thirty-nine renal imaging studies (113 ultrasonographic
      scans, 15 computed tomographic scans, and 11 magnetic resonance images) were
      identified in 59 patients with TSC (mean age, 11.4 years; age range, 3 days to 36
      years). There were 31 male and 28 female patients. Angiomyolipomas and cysts were
      identified and characterized according to the following features: number,
      unilateral versus bilateral, largest diameter, and change over time. In patients
      whose initial examination results were normal, the age at onset of lesions was
      noted. The chi(2) test was used to determine whether cysts and angiomyolipomas
      occurred in different subpopulations. RESULTS: Angiomyolipomas were identified in
      47 (80%) patients and were too numerous to count in 36 (76%), focal in 38 (81%),
      and bilateral in 42 (89%). The mean largest diameter was 21 mm. Cysts were
      identified in 28 (47%) patients, 18 (64%) of whom had fewer than five cysts.
      Cysts were bilateral in 17 (61%) patients. The mean largest diameter was 20 mm.
      In patients with initially normal examination results, the mean age at
      presentation was 9.0 years for those with cysts and 9.2 years for those with
      angiomyolipomas. In 80 follow-up examinations, size and/or number increased in 32
      (40%) angiomyolipomas and 21 (26%) cysts. Cysts and angiomyolipomas did not occur
      in significantly different subpopulations (P =.13). CONCLUSION: Both
      angiomyolipomas and cysts occur commonly in pediatric patients with TSC and tend
      to increase in size and number with increasing age. Angiomyolipomas are more
      common than cysts and tend to be numerous.

PMID- 12409580
TI  - Evolution of a protocol for ketamine-induced sedation as an alternative to
      general anesthesia for interventional radiologic procedures in pediatric
      patients.
AB  - PURPOSE: To establish a protocol for credentialed pediatric radiology nurses,
      with radiologist supervision, to administer ketamine to induce sedation and
      analgesia during interventional radiologic procedures. MATERIALS AND METHODS:
      This study was conducted in two phases. The goal of the first phase was to
      develop a sedation protocol to replace that of using general anesthesia for
      specified pediatric interventional procedures. Ketamine was administered
      intravenously (with intermittent bolus or continuous infusion) or
      intramuscularly. Sedation induction times, adverse events, doses, and sedation
      and recovery durations were recorded. In phase 2, the results of phase 1 were
      reviewed and a formal ketamine protocol was developed. RESULTS: Neither sedation
      failures nor substantial adverse events occurred in phase 1. Mean duration of all
      sedations was 52 minutes, and median recovery room time was 0 minutes. In phase
      2, the results of phase 1 were reviewed and a sedation protocol was proposed to a
      hierarchy of hospital committees before final approval from the medical staff
      executive committee. Subsequently, standard order forms for radiology nurse
      administration of ketamine with radiologist supervision were prepared for
      exclusive use by the pediatric interventional radiology department. CONCLUSION:
      Ketamine-induced sedation may be a safe and effective alternative to general
      anesthesia for some interventional radiologic procedures in pediatric patients.
      Collaboration between anesthesia and radiology departments is important for
      development of a safe and successful ketamine sedation program. To the authors'
      knowledge, this is the first report describing the intravenous infusion of
      ketamine for sedation in pediatric patients and the only report describing the
      establishment of a protocol for ketamine administration by credentialed radiology
      nurses with radiologist supervision.

PMID- 12409582
TI  - Femur: MR imaging-guided radio-frequency ablation in a porcine model-feasibility
      study.
AB  - PURPOSE: To determine the feasibility of magnetic resonance (MR) imaging-guided
      and -monitored radio-frequency (RF) ablation of bone. MATERIALS AND METHODS:
      Seven femurs were treated in five pigs with use of a 0.2-T open MR imager. An 11
      gauge bone marrow needle was percutaneously inserted into the distal femur
      metaphysis with MR fluoroscopy (fast imaging with steady-state precession, or
      FISP, sequences) to introduce an RF electrode into the bone with further image
      guidance. Thermal ablation was performed for 10 minutes (90 degrees C +/- 2 [mean
      +/- SD]). MR follow-up was performed immediately after ablation and again at 7
      and 14 days after the procedure (with contrast material-enhanced T1-weighted, T2
      weighted, and fast short inversion time inversion-recovery, or STIR, sequences).
      The animals were sacrificed at day 14. The femurs were sliced, decalcified, and
      stained. Image analysis was performed to measure lesion diameter and contrast-to
      noise ratio (CNR) and to evaluate complications. RESULTS: Technical success was
      obtained in all animals. The lesion diameter perpendicular to the electrode was
      15.4 mm +/- 2.7. No significant complications were noted. The thermal lesions
      displayed low signal intensity with a sharp rim of high signal intensity. T2
      weighted images demonstrated the highest CNR and the lowest error in predicting
      the lesion size immediately after ablation (2.7 mm +/- 1.3). Contrast-enhanced T1
      weighted images demonstrated the highest accuracy at day 14 (1.0 mm +/- 1.0).
      CONCLUSION: RF ablation of bone with MR imaging as the sole imaging modality is
      feasible and allows monitoring of the ablation.

PMID- 12409581
TI  - Effective prophylactic protocol in delayed hypersensitivity to contrast media:
      report of a case involving lymphocyte transformation studies with different
      compounds.
AB  - A patient with maculopapular reactions to iopamidol needed to undergo angiography
      for a cerebral arteriovenous malformation. In vivo and in vitro tests were
      performed with ionic and nonionic contrast media, including iopamidol and
      iobitridol. All results were positive, demonstrating delayed hypersensitivity.
      The patient received 6-alpha-methylprednisolone and cyclosporine 1 week before
      and 2 weeks after four angiograms were obtained with the use of iobitridol, which
      was well tolerated.

PMID- 12409583
TI  - MR imaging of spatial extent of microvascular injury in reperfused ischemically
      injured rat myocardium: value of blood pool ultrasmall superparamagnetic
      particles of iron oxide.
AB  - PURPOSE: To (a) assess the value of a blood pool magnetic resonance (MR) imaging
      contrast agent (Clariscan) for characterizing microvascular injury in
      ischemically injured rat myocardium and (b) compare the extent of microvascular
      injury at Clariscan-enhanced MR imaging with infarction and areas at risk seen
      with histochemical staining. MATERIALS AND METHODS: Twenty rats underwent 45
      minutes of coronary artery occlusion and 3 hours of reperfusion. Sequential T1
      weighted spin-echo MR images were acquired in 10 rats to assess leakage of
      Clariscan into myocardium over time. Ten other rats underwent the same duration
      of occlusion and reperfusion (3 hours) so that the extent of microvascular injury
      in the entire heart could be measured and correlated with infarction and area at
      risk at necropsy. The Student t test and Bland-Altman method were used for data
      analysis. RESULTS: Clariscan improved visualization of regions with transmural
      and nontransmural microvascular injury. Accumulation of Clariscan was best
      reflected by the mean ratios of signal intensity in injured myocardium to that in
      normal myocardium measured before (0.98 +/- 0.01 [standard error of the mean])
      and after (1.34 +/- 0.04) injection. At 15 minutes after injection, the size of
      the enhanced region remained constant over the course of observation. The mean
      size of the hyperenhanced region (44% of the left ventricle +/- 2) was
      significantly (P <.001) larger than the mean size of true infarction at necropsy
      (29% +/- 3) but smaller than the mean size of the area at risk (50% +/- 2).
      CONCLUSION: Clariscan has potential for estimating the spatial extent of
      microvascular injury in ischemically injured myocardium and may be useful as a
      marker of microvascular injury after thrombolytic therapy.

PMID- 12409586
TI  - Case 52: gastric teratoma.

PMID- 12409584
TI  - Effect of transmyocardial laser revascularization on myocardial perfusion and
      left ventricular remodeling after myocardial infarction in rats.
AB  - PURPOSE: To monitor perfusion changes in remote myocardium caused by
      transmyocardial laser revascularization (TMLR) and to investigate the influence
      of TMLR on left ventricular morphology and function. MATERIALS AND METHODS: The
      coronary arteries were ligated in 32 Wistar rats. Eight weeks later, cine
      magnetic resonance (MR) imaging was performed in both the treatment (n = 12) and
      control group (n = 8). TMLR was then performed in the remote myocardium in the
      treated group. Twelve weeks after myocardial infarction, cine MR imaging,
      including dobutamine-induced (10 micro g per kilogram of body weight per minute
      via the tail vein) stress, was repeated and followed with hemodynamic
      measurements in both groups and with perfusion MR imaging (in-plane resolution,
      140 x 140 micro m) of the isolated heart at rest and during nitroglycerin-induced
      stress in the TMLR group (n = 10). RESULTS: Left ventricular dilatation and
      hypertrophy were enhanced in the TMLR group (change in end-diastolic volume at 8
      12 weeks: control group, 24.6 micro L +/- 16.7 and TMLR group, 81.7 micro L +/-
      15.7; change in left ventricular mass: control group, 54.5 mg +/- 19.2 and TMLR
      group, 124.1 mg +/- 30.7; P <.03 for both). Ejection fractions at rest were
      approximately equal (control group, 40% +/- 2; TMLR group, 38% +/- 2; P value not
      significant), but during dobutamine-induced stress, the ejection fraction was
      higher in the TMLR group (54.4% +/- 4.9; control group, 47.4% +/- 4.8; P <.05).
      TMLR-treated areas were better perfused than was untreated myocardium (difference
      in perfusion: TMLR-treated vs control region, 3.89 mL/min/g +/- 0.83 at rest vs
      2.29 mL/min/g +/- 1.06 during nitroglycerin-induced stress; P <.05 for both).
      Hemodynamic measurements revealed no differences between groups. CONCLUSION: High
      spatial-resolution perfusion MR imaging depicted a significant perfusion
      improvement after TMLR. Post-myocardial infarction remodeling of the left
      ventricle was found to be enhanced.

PMID- 12409587
TI  - Picture archiving and communication system: effect on reporting of incidental
      findings.
AB  - PURPOSE: To determine the effect of a picture archiving and communication system
      (PACS) on reporting of incidental findings outside the area of interest, with a
      focus on lumbar spinal magnetic resonance (MR) imaging. MATERIALS AND METHODS:
      Results of 2,500 lumbar spinal 1.5-T MR examinations were reviewed. These
      included 500 consecutive lumbar spinal MR reports for each of 5 years: 1 year
      prior to PACS introduction, 1 year during transition to PACS, and 3 consecutive
      years thereafter. Incidental findings cited in the reports were tabulated, and
      the frequency, organ system involved, and radiologist recommendations in each
      case were noted and compared, as were projected expenses based on the Medicare
      payment scale for recommended follow-up studies. Results of available follow-up
      studies were also reviewed. RESULTS: The number of incidental findings increased
      from 19 before PACS to 31 during transition and 53, 49, and 50 after PACS
      implementation, which resulted in a maximum increase of 179%. The increase was
      statistically significant during each post-PACS year. The most common incidental
      findings involved potential renal, pelvic, hepatic, pulmonary, and lymph node
      abnormalities. The total number of recommended follow-up studies increased from
      five before PACS to 15 during transition and 32, 22, and 18 after PACS
      implementation, with a maximum increase of as much as 540%. Recommended
      ultrasonographic studies increased the most from two in the pre-PACS year to 11
      during transition and 27, 17, and 14 in the 3 post-PACS years. Follow-up expense
      increased by a mean of 146% after PACS implementation from 4,221 dollars per
      1,000 studies in the pre-PACS year to 9,307 dollars, 13,426 dollars, 10,558
      dollars, and 8,252 dollars thereafter. Of the 202 incidental findings, four
      represented occult malignancy, which is an expense of 5,721 dollars per
      diagnosis. CONCLUSION: The introduction of PACS into radiology practice for
      lumbar spinal MR imaging appears to be associated with an increased number of
      reported incidental findings and recommended follow-up studies.

PMID- 12409588
TI  - Randomized controlled trial with low-dose spiral CT for lung cancer screening:
      feasibility study and preliminary results.
AB  - PURPOSE: To assess the feasibility of conducting a randomized controlled trial
      for lung cancer screening. MATERIALS AND METHODS: Subjects are being recruited
      into a randomized controlled trial to undergo either low-dose spiral computed
      tomography (CT) or observation. Subjects are from a high-risk group with known
      chronic obstructive pulmonary disease and sputum atypia and a moderate-risk group
      randomly selected from the general population of a Veterans Affairs Medical
      Center. All subjects must be 50-80 years of age with 30 or more pack-years of
      cigarette smoking and must not have undergone chest CT during the previous 3
      years. Baseline screening CT is performed with 50 mA, 120 kVp, 5-mm collimation,
      and a pitch of 2. CT scan interpretation and management of nodules is based on
      Society of Thoracic Radiology guidelines. The chi(2) test for categoric data was
      used for statistical analysis. RESULTS: To date, 304 eligible subjects have been
      contacted, and 239 (79%) have agreed to participate in the trial. One hundred
      nineteen (88%) of the 136 subjects in the high-risk group and 120 (71%) of the
      168 subjects in the moderate-risk group agreed to randomization (P <.001). To
      date, 190 subjects have been randomized. Of the first 92 subjects examined with
      CT, 22 (40%) of 55 in the high-risk group and eight (22%) of 37 in the moderate
      risk group had one to six noncalcified nodules that required follow-up (P =.07).
      In all but three subjects, nodules were smaller than 5 mm. Two of the three
      larger nodules were malignancies. CONCLUSION: Findings of this study indicate
      that a randomized controlled trial of CT to screen for lung cancer is feasible.

PMID- 12409589
TI  - Preoperative localization of small pulmonary lesions with a short hook wire and
      suture system: experience with 168 procedures.
AB  - PURPOSE: To evaluate use of a short hook wire and suture system for preoperative
      localization of pulmonary nodular lesions. MATERIALS AND METHODS: Percutaneous
      localization of 168 lesions was performed with computed tomographic (CT) guidance
      in 150 patients. Patients were classified into three groups: a 3-year early
      learning experience of treatment of 40 lesions mainly in one institution (group
      A1), a more recent 4-year experience of treatment of 88 lesions in the same
      institution (group A2), and the roughly synchronous recent 3-year experience of
      treatment of 40 lesions in a different hospital (group B). RESULTS: The hook wire
      was successfully placed without dislodgment in 146 patients, accounting for 164
      (97.6%) of 168 lesions. Group A2 showed a success rate of 100%. There was no
      difference in patients among the three groups in regard to size of lesions or
      their distance from the pleural surface. In patients in groups A2 and B, the
      proportion of nodules with ground-glass opacity and primary lung carcinoma at CT
      was significantly greater than that in patients in group A1. In 168 placements,
      nonsymptomatic pneumothorax cases were observed in 54 (32.1%), hemorrhages into
      the lung were observed in 25 (14.9%), and hemorrhage into the pleural space was
      observed in one (0.6%). No patient complained of notable pain during or after the
      procedure, and no serious complication was experienced. Unsuccessful placement
      was caused by too shallow a puncture with the introducer needle. CONCLUSION: This
      system with a flexible suture for preoperative localization has a high success
      rate.

PMID- 12409590
TI  - Computerized analysis of digitized mammograms of BRCA1 and BRCA2 gene mutation
      carriers.
AB  - PURPOSE: To evaluate, by using computer image analysis, the mammographic density
      patterns of women with germ-line mutations in BRCA1 and BRCA2 genes in comparison
      with those of women at low risk of developing breast cancer. MATERIALS AND
      METHODS: Mammograms from 30 carriers of BRCA1 and BRCA2 mutations and from 142
      low-risk women were collected retrospectively and digitized. In addition, 60 of
      the 142 low-risk women were randomly selected and age matched at 5-year intervals
      with the 30 mutation carriers. Mammographic features were extracted from the
      central regions of the breast images to characterize the mammographic density and
      heterogeneity of dense portions of the breast. These features were then merged
      into a single value related to the risk of breast cancer by using linear
      discriminant analysis. The applicability of these computer-extracted features and
      the output from linear discriminant analysis to differentiate between the
      carriers of BRCA1 and BRCA2 mutations and the low-risk women in the entire
      database and in an age-matched group were evaluated by using receiver operating
      characteristic analysis. RESULTS: Quantitative analysis of mammograms
      demonstrated that carriers of BRCA1 and BRCA2 mutations tended to have dense
      breast tissue, and their mammographic patterns tended to be low in contrast, with
      a coarse texture. Linear discriminant analysis resulted in values of the areas
      under the receiver operating characteristic curve of 0.91 and 0.92 in
      distinguishing between the BRCA1 and BRCA2 mutation carriers and the low-risk
      women in the entire database and the age-matched group, respectively. CONCLUSION:
      The computerized analysis of mammograms suggests that mammographic patterns in
      carriers of BRCA1 and BRCA2 mutations differ from those of women at low risk for
      breast cancer. Our computer-extracted features may be useful as radiographic
      markers for identifying women at high risk for breast cancer.

PMID- 12409591
TI  - Preoperative breast cancer staging: MR imaging of the axilla with ultrasmall
      superparamagnetic iron oxide enhancement.
AB  - PURPOSE: To evaluate magnetic resonance (MR) imaging with ultrasmall
      superparamagnetic iron oxide (USPIO) enhancement for preoperative axillary lymph
      node staging in patients with breast cancer by using histopathologic findings as
      the standard of reference. MATERIALS AND METHODS: MR imaging was performed with a
      1.5-T system within 24-36 hours after the start of intravenous slow-drip infusion
      of USPIO in 20 patients with breast cancer who were scheduled for surgery,
      followed by gadolinium-enhanced MR imaging. Lymph nodes were staged prospectively
      by using newly established criteria, and results were correlated with histologic
      findings. RESULTS: In two patients, preoperative findings led to a change in
      therapeutic approach, and neoadjuvant chemotherapy was given; both patients were
      excluded from statistical analysis. Results of axillary staging with USPIO
      enhanced MR imaging were true-positive in nine, true-negative in seven, false
      positive in zero, and false-negative in two of 18 patients (sensitivity, 82%;
      specificity, 100%; positive predictive value, 100%; second reader, kappa = 1.0).
      Four hundred five lymph nodes were detected with MR imaging. For first and second
      readers, respectively, lymph node-based sensitivity was 83% and 73% and
      specificity was 96% and 97% (kappa = 0.68). USPIO as the intravascular contrast
      agent could not replace gadolinium for assessment of the primary tumor; however,
      no clinically relevant interaction was seen. Thus, an integrated imaging approach
      was feasible in all patients. CONCLUSION: USPIO-enhanced MR imaging has the
      potential to become an adjunct to conventional MR imaging of the breast for
      preoperative assessment of axillary lymph nodes in patients with breast cancer.

PMID- 12409592
TI  - Acute anterior cruciate ligament stump entrapment in anterior cruciate ligament
      tears: MR imaging appearance.
AB  - PURPOSE: To describe the magnetic resonance (MR) imaging appearance of anterior
      cruciate ligament (ACL) stump entrapment in patients who presented with decreased
      knee extension after rupturing the ACL. MATERIALS AND METHODS: MR images in 15
      patients who had presented with a block to terminal knee extension after
      sustaining an ACL tear were retrospectively reviewed. The MR imaging appearances
      of entrapped ACL stumps were defined and correlated with arthroscopic and
      histologic findings. RESULTS: The entrapped ACL stumps had two distinct
      appearances. Type 1 stumps (n = 11) were characterized by a nodular mass located
      at the anterior aspect of the intercondylar notch, interposed between the lateral
      femoral condyle and tibia. Type 2 stumps (n = 4) were characterized by a
      tonguelike free end and angulation of the stump. Histologic evaluation of the
      resected specimens showed distorted ACL fibers intermixed with variable fibrosis
      and inflammation. CONCLUSION: Entrapment of an ACL stump can limit knee
      extension. The two observed appearances of entrapped ACL stumps likely represent
      two points along a spectrum of appearances, which possibly includes the cyclops
      lesion.

PMID- 12409593
TI  - Anterior cruciate ligament reconstruction with bioabsorbable polyglycolic acid
      interference screws: MR imaging follow-up.
AB  - PURPOSE: To examine at magnetic resonance (MR) imaging the degradation of an
      interference screw made of polyglycolic acid (67.5%) and trimethylene carbonate
      (32.5%) and compare the MR findings with the clinical evaluation results.
      MATERIALS AND METHODS: Clinical and MR imaging studies were performed
      concomitantly 6 months (in 20 patients), 1 year (in 10 patients), and 2 years (in
      eight patients) after surgery. Screw resorption rate, tibial tunnel appearance
      and contents, epiphyseal reaction, reconstructed ligament appearance, bone plug
      healing, joint effusion, and synovitis were evaluated. RESULTS: The screw was
      observed to be partially resorbed (by approximately one-third) at 6 months and
      totally resorbed at 1 year. Enhancement of the tunnel content, which can be
      linked to bone healing and screw replacement, was seen without a surrounding
      inflammatory reaction. Bone tunnel enlargement was observed and remained stable
      over time; this phenomenon has often been reported with metallic or polylactic
      acid interference screws and could be due to the position of the screw within the
      tunnel. The tissue that was seen at MR imaging to be replacing the screw was
      either fibrous or fatty and fibrous but never bone. CONCLUSION: Resorption of the
      screw does not appear to be related to clinical results.

PMID- 12409594
TI  - Improved image quality and detection of acute cerebral infarction with PROPELLER
      diffusion-weighted MR imaging.
AB  - PURPOSE: To compare periodically rotated overlapping parallel lines with enhanced
      reconstruction (PROPELLER) multishot fast spin-echo diffusion-weighted magnetic
      resonance (MR) imaging with single-shot echo-planar diffusion-weighted MR imaging
      for image quality and visualization of acute cerebral infarction. MATERIALS AND
      METHODS: Seventy subjects (35 men, 35 women; mean age, 55 years +/- 24 [SD]) who
      were suspected of having acute cerebral infarction (symptom duration, 2.8 days +/
      2.7) underwent PROPELLER and echo-planar MR imaging (b = 1,000 sec/mm(2)). Two
      neuroradiologists compared unlabeled images for presence of artifacts,
      visualization of infarction, and their preference of images. Interobserver
      agreement and image comparison were assessed by using the kappa statistic and the
      chi(2) test, respectively. RESULTS: PROPELLER MR imaging reduced susceptibility
      artifacts (n = 70 subjects), which limited visualization of temporal (echo
      planar, n = 64; PROPELLER, n = 0; P <.01, chi(2) test), frontal (echo-planar, n =
      58; PROPELLER, n = 1; P <.01), and parietal lobes (echo-planar, n = 5; PROPELLER,
      n = 0; P <.05) and cerebellum (echo-planar, n = 36; PROPELLER, n = 0; P <.01) and
      brainstem (echo-planar, n = 23; PROPELLER, n = 0; P <.01). Acute infarction (n =
      31 subjects) was better demonstrated at PROPELLER MR imaging (PROPELLER better, n
      = 18; echo-planar better, n = 1; PROPELLER and echo-planar equal, n = 12; P <.01,
      chi(2) test). PROPELLER MR imaging was preferred in all (n = 70) but one case in
      which the lesion lay within the intersection gap (PROPELLER preferred, n = 69;
      echo-planar preferred, n = 1; P <.01, chi(2) test). CONCLUSION: With a short
      increase in imaging time, PROPELLER MR imaging offers better image quality and
      detection of acute cerebral infarction than does echo-planar MR imaging.

PMID- 12409595
TI  - Adult primitive neuroectodermal tumor: proton MR spectroscopic findings with
      possible application for differential diagnosis.
AB  - PURPOSE: To assess the utility of proton magnetic resonance (MR) spectroscopy in
      the clinical categorization of primitive neuroectodermal tumors (PNETs) in
      adults. MATERIALS AND METHODS: In vivo proton MR spectroscopy was performed with
      an echo time of 136 msec in nine adults with PNET, and findings were
      retrospectively compared with spectroscopic findings of 22 meningiomas, 12 low
      grade astrocytomas, eight anaplastic astrocytomas, 23 glioblastomas, and 21
      metastases. Nine resonances were semiquantitatively evaluated. Statistical
      analysis was performed by using Kruskal-Wallis and Mann-Whitney U tests. The
      Hochberg correction was applied for multiple comparisons. Results were
      prospectively validated in 24 tumors of the six types included in the study.
      RESULTS: The resonances of choice for identifying PNET were alanine (P <.001) and
      glutamate and glutamine (P =.004), both decreased with respect to meningioma;
      choline increased with respect to low-grade (P <.001) and anaplastic astrocytoma
      (P =.055); and lipids at 1.30 ppm decreased and choline and other trimethyl-amine
      containing compounds increased with respect to glioblastoma (P <.001 and P =.004,
      respectively) and metastasis (P <.001 and P =.021, respectively). We developed an
      algorithm for bilateral differential diagnosis between PNET and other tumor
      types. The leave-one-out method was used to test the five possible differential
      situations in the retrospective data set, with the following results: PNET versus
      meningioma, 31/23/5/3 (number of total/correct/unclassifiable/incorrect
      procedures); PNET versus low-grade astrocytoma, 21/19/2/0; PNET versus anaplastic
      astrocytoma, 17/6/9/2; PNET versus glioblastoma, 32/28/2/2; and PNET versus
      metastasis, 30/27/1/2. In total, 131 consecutive procedures produced 103 (79%)
      correct classifications and nine (7%) misclassifications. Twenty-five (78%) of 32
      possible procedures in the prospective independent test set produced correct
      classifications and four (13%) produced incorrect classifications. CONCLUSION: In
      vivo proton MR spectroscopy provides useful information in clinical
      differentiation between PNETs and common brain tumors in adults.

PMID- 12409596
TI  - Noninvasive grading of untreated gliomas: a comparative study of MR imaging and 3
      (iodine 123)-L-alpha-methyltyrosine SPECT.
AB  - PURPOSE: To compare the accuracy of magnetic resonance (MR) imaging scores with
      that of 3-(iodine 123)-L-alpha-methyltyrosine ((123)I-IMT) single photon emission
      computed tomography (SPECT) in the noninvasive grading of untreated gliomas.
      MATERIALS AND METHODS: The study comprised 15 patients with low-grade gliomas
      (grades I-II, according to World Health Organization criteria) and 33 patients
      with high-grade gliomas (grades III-IV). The lesions were evaluated by using an
      MR imaging score based on nine criteria. The (123)I-IMT uptake was quantified as
      the ratio between the amino acid uptake in the tumor and that in the
      contralateral hemisphere. To test for potentially significant differences in
      diagnostic performance between contrast material-enhanced MR imaging and (123)I
      IMT SPECT, binormal receiver operating characteristic curves were fitted to the
      data and compared by using the area test. RESULTS: The accuracy of MR imaging in
      the noninvasive grading of untreated gliomas was higher than that of (123)I-IMT
      SPECT (88% vs 79%). However, the difference in diagnostic performance was not
      significant on the basis of findings at receiver operating characteristic
      analysis (P >.2). Neither MR imaging nor (123)I-IMT SPECT allowed differentiation
      between high-grade gliomas (grades III and IV). CONCLUSION: Although (123)I-IMT
      uptake is significantly higher in high-grade gliomas than in low-grade gliomas,
      the performance of (123)I-IMT SPECT adds little to the accuracy of determining
      tumor grade when MR imaging is performed.

PMID- 12409597
TI  - PET diagnostic accuracy: improvement with in-line PET-CT system: initial results.
AB  - The authors describe the initial application for tumor staging with an in-line
      system with a positron emission tomographic (PET) scanner and a multi-detector
      row helical computed tomographic (CT) scanner combined in one machine. Fifty
      three patients underwent imaging with four CT tube currents and PET emission and
      transmission data acquisition. Stepwise analysis of coregistered images revealed
      a significant (P <.05, McNemar test) improvement in lesion classification between
      PET images alone and coregistered images from the PET-CT examination.

PMID- 12409598
TI  - Randomly segmented central k-space ordering in high-spatial-resolution contrast
      enhanced MR angiography of the supraaortic arteries: initial experience.
AB  - Contrast material-enhanced three-dimensional (3D) magnetic resonance (MR)
      angiography of the supraaortic arteries with randomly segmented central k-space
      ordering (ie, contrast-enhanced timing-robust angiography [CENTRA]) was performed
      in 16 patients. CENTRA enabled reliable depiction of the aortic arch up to the
      circle of Willis at high spatial resolution (true voxel size, 0.81 x 0.81 x 1.0
      mm(3)). With CENTRA, the divergent demands of high spatial resolution, wide
      anatomic coverage, and arterial phase imaging have been reconciled. The random
      order of central k-space acquisition may minimize artifacts in contrast-enhanced
      3D MR angiography caused by unstable contrast material opacification at the
      initiation of sampling.

PMID- 12409599
TI  - Renal arteries: navigator-gated balanced fast field-echo projection MR
      angiography with aortic spin labeling: initial experience.
AB  - A cardiac-triggered free-breathing three-dimensional balanced fast field-echo
      projection magnetic resonance (MR) angiographic sequence with a two-dimensional
      pencil-beam aortic labeling pulse was developed for the renal arteries. For data
      acquisition during free breathing in eight healthy adults and seven consecutive
      patients with renal artery disease, real-time navigator technology was
      implemented. This technique allows high-spatial-resolution and high-contrast
      renal MR angiography and visualization of renal artery stenosis without exogenous
      contrast agent or breath hold. Initial promising results warrant larger clinical
      studies.

PMID- 12409600
TI  - MR colonography: development of optimized method with ex vivo and in vivo
      systems.
AB  - An ex vivo magnetic resonance (MR) colonographic system with a bovine colon with
      polyps of predetermined dimensions was developed for evaluation and optimization
      of different combinations of imaging sequences and intraluminal contrast agents.
      Findings were then applied during in vivo testing in human subjects. The results
      show that optimized contrast and lesion conspicuity and minimized motion
      artifacts can be obtained with true fast imaging with steady-state precession
      combined with water as an intraluminal contrast agent.

PMID- 12409601
TI  - Occlusive myocardial infarction enhanced or not enhanced with necrosis-avid
      contrast agents at MR imaging.

PMID- 12409602
TI  - Computer-aided diagnosis: blessing or curse?

PMID- 12409603
TI  - Imaging diagnosis of the snapping triceps syndrome.

PMID- 12409604
TI  - Diurnal variation in size of lymphangioleiomyomas?

PMID- 12409606
TI  - Prebiotic synthesis from CO atmospheres: implications for the origins of life.
AB  - Most models of the primitive atmosphere around the time life originated suggest
      that the atmosphere was dominated by carbon dioxide, largely based on the notion
      that the atmosphere was derived via volcanic outgassing, and that those gases
      were similar to those found in modern volcanic effluent. These models tend to
      downplay the possibility of a strongly reducing atmosphere, which had been
      thought to be important for prebiotic synthesis and thus the origin of life.
      However, there is no definitive geologic evidence for the oxidation state of the
      early atmosphere and bioorganic compounds are not efficiently synthesized from
      CO(2) atmospheres. In the present study, it was shown that a CO-CO(2)-N(2)-H(2)O
      atmosphere can give a variety of bioorganic compounds with yields comparable to
      those obtained from a strongly reducing atmosphere. Atmospheres containing carbon
      monoxide might therefore have been conducive to prebiotic synthesis and perhaps
      the origin of life. CO-dominant atmospheres could have existed if the production
      rate of CO from impacts of extraterrestrial materials were high or if the upper
      mantle had been more reduced than today.

PMID- 12409607
TI  - Molecular characterization of mouse gastric epithelial progenitor cells.
AB  - The adult mouse gastric epithelium undergoes continuous renewal in discrete
      anatomic units. Lineage tracing studies have previously disclosed the morphologic
      features of gastric epithelial lineage progenitors (GEPs), including those of the
      presumptive multipotent stem cell. However, their molecular features have not
      been defined. Here, we present the results of an analysis of genes and pathways
      expressed in these cells. One hundred forty-seven transcripts enriched in GEPs
      were identified using an approach that did not require physical disruption of the
      stem cell niche. Real-time quantitative RT-PCR studies of laser capture
      microdissected cells retrieved from this niche confirmed enriched expression of a
      selected set of genes from the GEP list. An algorithm that allows quantitative
      comparisons of the functional relatedness of automatically annotated expression
      profiles showed that the GEP profile is similar to a dataset of genes that
      defines mouse hematopoietic stem cells, and distinct from the profiles of two
      differentiated GEP descendant lineages (parietal and zymogenic cell). Overall,
      our analysis revealed that growth factor response pathways are prominent in GEPs,
      with insulin-like growth factor appearing to play a key role. A substantial
      fraction of GEP transcripts encode products required for mRNA processing and
      cytoplasmic localization, including numerous homologs of Drosophila genes (e.g.,
      Y14, staufen, mago nashi) needed for axis formation during oogenesis. mRNA
      targeting proteins may help these epithelial progenitors establish differential
      communications with neighboring cells in their niche.

PMID- 12409608
TI  - Finding genetic contributions to sporadic disease: a recessive locus at 12q24
      commonly contributes to patent ductus arteriosus.
AB  - The causes of many sporadic diseases are unexplained; the contribution of
      recessive loci with reduced penetrance is one possibility that has been difficult
      to explore. We describe an approach to this problem by first searching for
      diseases with higher prevalence in populations with high rates of consanguinity,
      then determining whether disease cases are more commonly the product of
      consanguinous union than controls in such populations, followed by analysis of
      genetic linkage in consanguinous cases. We demonstrate the utility of this
      approach by investigation of congenital heart disease in Iran. We found that
      patent ductus arteriosus (PDA), a common congenital heart disease, accounts for a
      higher fraction of congenital heart disease in Iran (15%) than in the United
      States (2-7%). Moreover, Iranian PDA cases demonstrated a marked increase of
      parental consanguinity (63%), compared with the general Iranian population (25%)
      or control cases with tetralogy of Fallot (30%). The recurrence of PDA among
      siblings was 5%. A genomewide analysis of linkage in 21 unrelated consanguinous
      PDA cases demonstrated a multipoint logarithm of odds score of 6.27 in favor of
      linkage of PDA to a 3-centimorgan interval of chromosome 12q24, with 53% of
      kindreds linked. These findings together establish a recessive component to PDA
      and implicate a single locus, PDA1, in one third or more of all PDA cases in
      Iran; they further suggest a role for this locus in PDA worldwide. Finally, these
      results suggest a general approach to the identification of recessive
      contributions to sporadic diseases.

PMID- 12409609
TI  - Confirmation by FRET in individual living cells of the absence of significant
      amyloid beta -mediated caspase 8 activation.
AB  - When cells are exposed to death-inducing molecules such as tumor necrosis factor
      alpha or Fas, caspase 8 is activated and cleaves an apoptotic facilitator, Bid,
      that is a member of the Bcl-2 family. After additional modification, the C
      terminal moiety of Bid is translocated to the mitochondria and induces the
      release of cytochrome c into the cytoplasm. In an attempt to directly observe the
      cleavage of Bid and the following events in living cells, we constructed a vector
      that encoded Bid fused with yellow fluorescent protein (YFP) and cyan fluorescent
      protein (CFP) (YFP-Bid-CFP). On expression of YFP-Bid-CFP in mammalian cells, we
      were able to observe the efficient transfer of energy from excited CFP to YFP
      within the YFP-Bid-CFP molecule and, importantly, the fusion protein YFP-Bid-CFP
      was fully functional in cells. When YFP-Bid-CFP was cleaved by caspase 8, on
      activation by anti-Fas Abs but not by Abeta or tunicamycin, no such transfer of
      energy was detected. To our knowledge, this is the first report of (i)
      visualization of the activation of Bid by proteolytic cleavage, with direct
      observation of the cleavage of YFP-Bid-CFP in the cytoplasm and subsequent
      translocation of the cleaved Bid to mitochondria and (ii) the absence of Abeta-
      or tunicamycin-mediated significant activation of caspase 8 in individual living
      cells.

PMID- 12409610
TI  - The catalytic cycle of beta -lactam synthetase observed by x-ray crystallographic
      snapshots.
AB  - The catalytic cycle of the ATP/Mg(2+)-dependent enzyme beta-lactam synthetase
      (beta-LS) from Streptomyces clavuligerus has been observed through a series of x
      ray crystallographic snapshots. Chemistry is initiated by the ordered binding of
      ATP/Mg(2+) and N(2)-(carboxyethyl)-l-arginine (CEA) to the apoenzyme. The apo and
      ATP/Mg(2+) structures described here, along with the previously described
      CEA.alpha,beta-methyleneadenosine 5'-triphosphate (CEA.AMP-CPP)/Mg(2+) structure,
      illuminate changes in active site geometry that favor adenylation. In addition,
      an acyladenylate intermediate has been trapped. The substrate analog N(2)
      (carboxymethyl)-l-arginine (CMA) was adenylated by ATP in the crystal and
      represents a close structural analog of the previously proposed CEA-adenylate
      intermediate. Finally, the structure of the ternary product complex
      deoxyguanidinoproclavaminic acid (DGPC).AMP/PP(i)/Mg(2+) has been determined. The
      CMA-AMP/PP(i)/Mg(2+) and DGPC.AMP/PP(i)/Mg(2+) structures reveal interactions in
      the active site that facilitate beta-lactam formation. All of the ATP-bound
      structures differ from the previously described CEA.AMP-CPP/Mg(2+) structure in
      that two Mg(2+) ions are found in the active sites. These Mg(2+) ions play
      critical roles in both the adenylation and beta-lactamization reactions.

PMID- 12409611
TI  - Glycoprotein gp110 of Epstein-Barr virus determines viral tropism and efficiency
      of infection.
AB  - The Epstein-Barr virus (EBV) genome has been detected in lymphomas and in tumors
      of epithelial or mesenchymal origin such as nasopharyngeal carcinoma or
      leiomyosarcoma. Thus, there is little doubt that EBV can infect cells of numerous
      lineages in vivo, in contrast to its in vitro infectious spectrum, which appears
      restricted predominantly to B lymphocytes. We show here that the EBV BALF4 gene
      product, the glycoprotein gp110, dramatically enhances the ability of EBV to
      infect human cells. gp110(high) viruses were up to 100 times more efficient than
      their gp110(low) counterparts in infecting lymphoid or epithelial cells. In
      addition, gp110(high) viruses infected the carcinoma cell line HeLa and the T
      cell lymphoma cell line Molt-4, both previously thought to be refractory to EBV
      infection. Analysis of several virus isolates showed that the amount of BALF4
      present within mature virions markedly differed among these strains. In some
      strains, gp110 was found expressed during lytic replication not only at the
      nuclear but also at the cellular membrane. Heterologous expression of gp110
      during the virus lytic phase neither altered virus concentration nor affected
      virus binding to cells. It appears that gp110 plays a crucial role after the
      virus has adhered to its cellular target. gp110 constitutes an important
      virulence factor that determines infection of non-B cells by EBV. Therefore, the
      use of gp110(high) viruses will help to determine the range of the target cells
      of EBV beyond B lymphocytes and provide a useful in vitro model to assess the
      oncogenic potential of EBV in these cells.

PMID- 12409612
TI  - Herpes viruses hedge their bets.
AB  - Static latency is the hallmark of all herpes viruses. The varicella zoster virus,
      for instance, causes varicella (chickenpox), and after a latent phase of between
      5 and 40 years, it can give rise to herpes zoster (shingles). This latency and
      the subsequent reactivation has intrigued and puzzled virologists. Although
      several factors have been suggested, it is unknown what triggers reactivation.
      However, latency can be explained with a simple evolutionary model. Here, we
      demonstrate that a simple, yet efficient, bet-hedging strategy might have evolved
      in a number of viruses, especially those belonging to the herpes virus family and
      most importantly in varicella zoster virus. We show that the evolution of latency
      can be explained by the population dynamics of infectious diseases in fluctuating
      host populations.

PMID- 12409613
TI  - A ligand for the aryl hydrocarbon receptor isolated from lung.
AB  - The aryl hydrocarbon receptor (AHR) is a ligand-inducible transcription factor
      that is best known because it mediates the actions of polycyclic and halogenated
      aromatic hydrocarbon environmental toxicants such as 3-methylcholanthrene and
      2,3,7,8-tetrachlorodibenzo-p-dioxin. We report here the successful identification
      of an endogenous ligand for this receptor; approximately 20 microg was isolated
      in pure form from 35 kg of porcine lung. Its structure was deduced as 2-(1'H
      indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester from extensive
      physical measurements and quantum mechanical calculations. In a reporter gene
      assay, this ligand activates the AHR with a potency five times greater than that
      of beta-naphthoflavone, a prototypical synthetic AHR ligand. 2-(1'H-indole-3'
      carbonyl)-thiazole-4-carboxylic acid methyl ester competes with 2,3,7,8
      [(3)H]tetrachlorodibenzo-p-dioxin for binding to human, murine, and fish AHRs,
      thus showing that AHR activation is caused by direct receptor binding, and that
      recognition of this endogenous ligand is conserved from early vertebrates (fish)
      to humans.

PMID- 12409614
TI  - Expression of human epileptic temporal lobe neurotransmitter receptors in Xenopus
      oocytes: An innovative approach to study epilepsy.
AB  - Poly(A(+)) RNA was extracted from the temporal lobe (TL) of medically intractable
      epileptic patients which underwent surgical TL resection. Injection of this mRNA
      into Xenopus oocytes led to the expression of ionotropic receptors for gamma
      aminobutyric acid (GABA), kainate (KAI) and alpha-amino-3-hydroxy-5-methyl-4
      isoxazolepropionic acid (AMPA). Membrane currents elicited by GABA inverted
      polarity at -15 mV, close to the oocyte's chloride equilibrium potential, were
      inhibited by bicuculline, and were potentiated by pentobarbital and
      flunitrazepam. These basic characteristics were also displayed by GABA currents
      elicited in oocytes injected with mRNAs isolated from human TL glioma (TLG) or
      from mouse TL. However, the GABA receptors expressed by the epileptic TL mRNA
      exhibited some unusual properties, consisting in a rapid current run-down after
      repetitive GABA applications and a large EC(50) (125 microM). AMPA alone evoked
      very small or nil currents, whereas KAI induced larger currents. Nevertheless,
      upon cyclothiazide treatment, AMPA elicited substantial currents that, like the
      KAI currents, were inhibited by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX).
      Furthermore, the glutamate receptor 5 (GluR5) agonist, ATPA, failed to evoke an
      obvious current although both RT-PCR and Western blot analyses showed GluR5
      expression in the epileptic TL. Oocytes injected with mouse TL or human TLG mRNAs
      generated KAI and AMPA currents similar to those evoked in oocytes injected with
      epileptic TL mRNA but, in contrast to these, the mouse TL and human TLG oocytes
      were also responsive to ATPA. Our findings are in accord with the concept that
      both a depression of GABA inhibition and a dysfunction of the KAI-receptor system
      maintain a high neuronal excitability that results in epileptic seizures.

PMID- 12409615
TI  - Effects of long-term treatment with the luteinizing hormone-releasing hormone
      (LHRH) agonist Decapeptyl and the LHRH antagonist Cetrorelix on the levels of
      pituitary LHRH receptors and their mRNA expression in rats.
AB  - The effects of depot formulations of the luteinizing hormone-releasing hormone
      (LHRH) agonist Decapeptyl (25 microg/day) for 30 days or LHRH antagonist
      Cetrorelix pamoate (100 microg/day) for 30 days and daily injections of 100
      microg of Decapeptyl for 10 days on the expression of mRNA for pituitary LHRH
      receptor (LHRH-R) and the levels of LHRH-R protein were evaluated in rats. Serum
      sex steroid concentrations and the weights of the reproductive organs were
      greatly reduced in all groups treated with analogs, demonstrating an efficient
      blockade of the pituitary-gonadal axis. Decapeptyl microcapsules elevated serum
      LH in female rats, but decreased it in male rats. LHRH-R mRNA expression in
      female pituitaries was reduced to 41% and 56-65% on days 10 and 30, respectively,
      whereas LHRH-R protein was 64% of control on day 10 and returned to pretreatment
      levels on day 30. Decapeptyl microcapsules reduced LHRH-R mRNA expression in male
      pituitaries to 58% on day 30 but not LHRH-R protein. Daily injections of
      Decapeptyl caused a desensitization of LH responses in female rats, while raising
      LHRH-R mRNA expression in female rats by 23% and LHRH-R protein levels by 119%.
      Cetrorelix pamoate reduced serum LH in female rats and diminished LHRH-R mRNA to
      30% and 26% and LHRH-R protein to 57% and 48% on days 10 and 30, respectively.
      Elevated LHRH-R protein levels of ovariectomized rats were reduced after 10-day
      treatment with Cetrorelix or 100 microg/day Decapeptyl. Thus, changes in the mRNA
      expression after treatment with Cetrorelix, but not always Decapeptyl, paralleled
      those of LHRH-R protein. The inhibitory effect of Cetrorelix on serum LH,
      pituitary LHRH-R mRNA, and LHRH-R protein was greater than that of Decapeptyl.

PMID- 12409616
TI  - A cell-free protein synthesis system for high-throughput proteomics.
AB  - We report a cell-free system for the high-throughput synthesis and screening of
      gene products. The system, based on the eukaryotic translation apparatus of wheat
      seeds, has significant advantages over other commonly used cell-free expression
      systems. To maximize the yield and throughput of the system, we optimized the
      mRNA UTRs, designed an expression vector for large-scale protein production, and
      developed a new strategy to construct PCR-generated DNAs for high-throughput
      production of many proteins in parallel. The resulting system achieves high-yield
      expression and can maintain productive translation for 14 days. Additionally, in
      the integration of a PCR-directed system for template creation, at least 50 genes
      can be translated in parallel, yielding between 0.1 and 2.3 mg of protein by one
      person within 2 days. Assessment of correct protein folding by the products of
      this high-throughput protein-expression system were performed by enzymatic assays
      of kinases and by NMR spectroscopic analysis. The cell-free system, reported
      here, bypasses many of the time-consuming cloning steps of conventional
      expression systems and lends itself to a robotic automation for the high
      throughput expression of proteins.

PMID- 12409617
TI  - Radiation damage to crystalline biological molecules: current view.

PMID- 12409618
TI  - Physical and chemical considerations of damage induced in protein crystals by
      synchrotron radiation: a radiation chemical perspective.
AB  - Radiation-induced degradation of protein or DNA samples by synchrotron radiation
      is an inherent problem in X-ray crystallography, especially at the 'brighter'
      light sources. This short review gives a radiation chemical perspective on some
      of the physical and chemical processes that need to be considered in
      understanding potential pathways leading to the gradual degradation of the
      samples. Under the conditions used for X-ray crystallography at a temperature of
      <100 K in the presence of cryoprotectant agents, the majority of radiation damage
      of the protein samples arises from direct ionization of the amino acid residues
      and their associated water molecules. Some of the chemical processes that may
      occur at these protein centres, such as bond scission, are discussed. Several
      approaches are discussed that may reduce radiation damage, using agents known
      from radiation chemistry to minimize radical-induced degradation of the sample.

PMID- 12409619
TI  - Too hot to handle? Synchrotron X-ray damage of lipid membranes and mesophases.
AB  - The call for brighter synchrotron X-radiation sources for use in structural
      biology research is barely audible as we enter the new millennium. Our brightest
      sources are already creating havoc when used at design specifications because of
      radiation damage. The time is long overdue to take stock of where we are and
      where we wish to go with regards to using existing sources and to designing new
      ones. The problem of radiation damage is particularly acute in studies involving
      kinetics and mechanisms where cryo-techniques are not always viable. Accordingly,
      we need to understand the very nature of radiation damage and to devise means of
      minimizing it. This is the thrust of the current report as applied to lipid
      membranes and mesophases. The experiments were performed at the most brilliant
      beamlines at CHESS, the APS and the ESRF. Two very different types of radiation
      damage are reported here. One involves a dramatic phase transformation and the
      other a disordering of lamellar stacking. How beam energy and dose rate affect
      damage is also discussed. The work highlights the free-radical-mediated nature of
      the damage process and the need for additional studies if the most efficient use
      is to be made of an important resource, synchrotron radiation.

PMID- 12409620
TI  - Evidence for the formation of disulfide radicals in protein crystals upon X-ray
      irradiation.
AB  - Irradiation of proteins with intense X-ray radiation produced by third-generation
      synchrotron sources generates specific structural and chemical alterations,
      including breakage of disulfide bonds and decarboxylation. In this paper,
      disulfide bond lengths in irradiated crystals of the enzyme Torpedo californica
      acetylcholinesterase are examined based on quantum simulations and on
      experimental data published previously. The experimental data suggest that one
      disulfide bond elongates by approximately 0.7 A upon X-ray irradiation as seen in
      a series of nine data sets collected on a single crystal. Simulation of the same
      bond suggests elongation by a similar value if a disulfide-radical anion is
      formed by trapping an electron. The absorption spectrum of a crystal irradiated
      under similar conditions shows a peak at approximately 400 nm, which in aqueous
      solution has been attributed to disulfide radicals. The results suggest that the
      formation of disulfide radicals in protein crystals owing to X-ray irradiation
      can be observed experimentally, both by structural means and by absorption
      spectroscopy.

PMID- 12409621
TI  - Investigation of possible free-radical scavengers and metrics for radiation
      damage in protein cryocrystallography.
AB  - The introduction of highly intense wiggler and undulator beamlines has
      reintroduced the problem of X-ray radiation damage in protein crystals even at
      cryogenic temperatures. Several metrics for monitoring radiation damage are
      considered and unit-cell volume expansion is systematically investigated using
      crystals of three different types, but it is found to be too variable to be a
      useful metric. Radical scavengers of secondary radiation damage are investigated
      as possible mitigating agents. Styrene is found to be ineffective. A method of
      spectroscopically measuring the radiation damage with a microspectrophotometer
      was used and, in conjunction with crystallographic data, provided tentative but
      suggestive evidence for the efficacy of ascorbate as a free-radical scavenging
      agent in cryocooled hen egg-white lysozyme crystals.

PMID- 12409622
TI  - Unit-cell volume change as a metric of radiation damage in crystals of
      macromolecules.
AB  - The use of third-generation synchrotron sources has led to renewed interest in
      the effect that ionizing radiation has on crystalline biological materials.
      Simple criteria have been sought to study the effects systematically. The unit
      cell volume of protein crystals shows a linear increase with absorbed dose and
      has therefore been proposed to be such a measure. This paper demonstrates that
      the increase is sample dependent, and thus it might not be a useful indicator
      when comparing different samples. For individual samples, however, the increase
      can be used to quantify ambient temperature and dose-rate effects. In this study,
      highly absorbing cubic crystals of holoferritin have been used to accurately
      determine how cell volume changes with absorbed dose. The experiments show that,
      for this protein, a dose-rate effect exists and that trapped radicals can be
      mobilized at ca 180 K.

PMID- 12409624
TI  - Investigation of radiation-dose-induced changes in organic light-atom crystals by
      accurate d-spacing measurements.
AB  - Changes in d-spacing have been measured for organic compounds as a function of
      temperature, wavelength and primary beam intensity using intense synchrotron
      radiation. The d-spacings of organic and protein crystals were found to increase
      irreversibly as a function of radiation dose. The activation energy of this
      thermally activated process was estimated. No evidence for a significant
      temperature increase of the sample due to exposure to intense X-ray beams could
      be found experimentally for flux densities up to 4 x 10(12) photons s-1 mm-2.

PMID- 12409623
TI  - Seeing the heat -- preliminary studies of cryocrystallography using infrared
      imaging.
AB  - As preparation for an extensive study that aims to image the cryocooling process
      of macromolecular crystals, the ability to thermally image solid objects and
      liquids at temperatures far below 273 K is demonstrated. In the case of a large
      lysozyme crystal (1.0 x 0.7 x 0.2 mm), qualitative measurements show the cooling
      process to take about 0.6 s with the cooling taking place in a wave starting from
      the face of the crystal nearest to the origin of the cryostream and ending at the
      point furthest away from the origin. Annealing of this lysozyme crystal, cooled
      under good cryoprotectant conditions, shows that cold striations form
      perpendicular to the cooling stream. These striations become more pronounced
      after successive annealing. Cryocooling of a non-cryoprotected crystal of glucose
      isomerase displayed an 'S-shaped' cold front wave traveling across the sample.
      These preliminary results are qualitative but show the power of infrared imaging
      as a new tool for fundamental and practical cryocrystallography studies.

PMID- 12409625
TI  - Experiments testing the abatement of radiation damage in D-xylose isomerase
      crystals with cryogenic helium.
AB  - Helium is a more efficient cryogen than nitrogen, and for macromolecular data
      collection at high-flux beamlines will deliver lower temperatures. An open-flow
      helium cryostat developed at the University of Toledo (the Pinkerton Device) has
      been used for macromolecular data collection. This device differs from standard
      commercial He cryostats by having a much narrower aperture providing a high
      velocity stream of He around the crystal that maximizes convective and conductive
      heat exchange between the crystal and the cryogen. This paper details a series of
      experiments conducted at the IMCA-CAT 17ID beamline using one crystal for each
      experimental condition to examine whether helium at 16 K provided better
      radiation-damage abatement compared with nitrogen at 100 K. These studies used
      matched high-quality crystals (0.94 A diffraction resolution) of D-xylose
      isomerase derived from the commercial material Gensweet SGI. Comparisons show
      that helium indeed abates the indicators of radiation damage, in this case
      resulting in longer crystal diffractive lifetimes. The overall trend suggests
      that crystals maintain order and that high-resolution data are less affected by
      increased radiation load when crystals are cooled with He rather than N(2). This
      is probably the result of a lower effective temperature at the crystal with
      concomitant reduction in free-radical diffusion. Other features, such as an
      apparent phase transition in macromolecular crystals at lower temperatures,
      require investigation to broaden the utility of He use.

PMID- 12409628
TI  - Blu-Ice and the Distributed Control System: software for data acquisition and
      instrument control at macromolecular crystallography beamlines.
AB  - The Blu-Ice and Distributed Control System (DCS) software packages were developed
      to provide unified control over the disparate hardware resources available at a
      macromolecular crystallography beamline. Blu-Ice is a user interface that
      provides scientific experimenters and beamline support staff with intuitive
      graphical tools for collecting diffraction data and configuring beamlines for
      experiments. Blu-Ice communicates with the hardware at a beamline via DCS, an
      instrument-control and data-acquisition package designed to integrate hardware
      resources in a highly heterogeneous networked computing environment. Together,
      Blu-Ice and DCS provide a flexible platform for increasing the ease of use, the
      level of automation and the remote accessibility of beamlines. Blu-Ice and DCS
      are currently installed on four Stanford Synchrotron Radiation Laboratory
      crystallographic beamlines and are being implemented at sister light sources.

PMID- 12409629
TI  - Effect of HMG-CoA reductase inhibitor on plasma cholesteryl ester transfer
      protein activity in primary hypercholesterolemia: comparison among CETP/TaqIB
      genotype subgroups.
AB  - We investigated the effects of HMG-CoA reductase inhibitors (statins) on the
      activity and concentration of plasma cholesterol ester transfer protein (CETP) in
      30 hypercholesterolemic patients. Patients were divided into three groups
      according to TaqIB polymorphism of the CETP gene. The activity (158 +/- 23%
      control, mean +/- SEM) and concentration (4.1 +/- 1.0 mg/l) of plasma CETP were
      significantly (p < 0.005) higher in the subjects with the B1B1 genotype than B2B2
      genotype (106 +/- 25% and 2.5 +/- 1.1 mg/l, respectively). Plasma CETP activity
      and concentration levels in the B1B2 group were intermediate between those of the
      B1B1 and B2B2 groups, and significantly (p < 0.05) low compared with the B1B1
      group.Both the activity and concentration of plasma CETP were positively
      correlated with the LDL-cholesterol concentration (r = 0.608, p < 0.0005 and r =
      0.552, p < 0.005, respectively). The administration of statins significantly
      reduced not only the activity (p < 0.01) but also the concentration (p < 0.05) of
      plasma CETP in hypercholesterolemic patients. Taken together, we confirmed that
      statins would be effective in increasing HDL levels in Japanese B1B1 carriers,
      because of a lower concentration of HDL cholesterol and higher level of plasma
      CETP compared to the other genotypes. The genetic variation in the CETP gene may
      be one important factor in designing better treatments.

PMID- 12409630
TI  - Association between abdominal wall fat index and carotid atherosclerosis in
      women.
AB  - We tried to investigate whether accumulation of visceral fat assessed by a simple
      but widely used ultrasonography was associated with common carotid
      atherosclerosis in women. The subjects were consecutively admitted in-patients
      whose body mass index was more than 22 kg/m2. Those with cardiorenal or
      nutritional disorders that would affect blood pressure, and lipid and glucose
      metabolism were excluded. An ultrasonographic evaluation with a 7.5 MHz linear
      type B-mode probe was performed by a specialist to determine the intima-media
      thickness (IMT) of the common carotid artery and maximum thickness of
      preperitoneal fat (Pmax) at the anterior surface of the liver and the minimum
      thickness of subcutaneous fat (Smin) of the abdomen. The Pmax/Smin ratio which
      was termed the abdominal wall fat index (AFI), was then calculated. The subjects
      were 241 women aged 69 +/- 12 (range, 26-104) years. Multiple regression analysis
      using the IMT as an object variable, adjusted by various risk factors as
      explanatory variables showed that AFI [odds ratio, 2.995; 95% confidence
      interval, 1.106-8.109] was a significant independent contributing factor along
      with known risk factors such as age, systolic blood pressure, total-cholesterol,
      and HDL-cholesterol.AFI was useful in evaluating disorders of metabolism,
      circulation and atherosclerosis.

PMID- 12409631
TI  - WBC count, atherosclerosis and coronary risk factors.
AB  - An association between total white blood cell (WBC) count and the risk of
      coronary heart disease (CHD) is well known. In the present study, we investigated
      the relationship between WBC counts and other clinical factors including coronary
      risk factors, and periodontal disease in 1,620 adults. Factors found to have a
      significant association with the WBC count by multivariate regression analysis
      were age (negative association), body mass index (negative association), serum
      triglycerides, high-density lipoprotein cholesterol (negative association), and
      periodontal levels in the smoking group.Whereas, in the non-smoking group,
      systolic blood pressure and diastolic blood pressure (negative association) were
      included and serum triglycerides were excluded.Non-smoking subjects who were free
      of periodontal disease had a mean WBC count of 4.69 +/- 1.0 x 109 cells/l. This
      value can be used as a reference for WBC counts in healthy subjects. Our data
      suggest that values significantly higher than this could be an important
      indicator of inflammation derived from cigarette smoking or periodontal disease.
      Further study is necessary to determine whether an improvement in the WBC count
      could prevent the occurrence of CHD.

PMID- 12409632
TI  - Extensive oligonucleotide microarray transcriptome analysis of the rat cerebral
      artery and arachnoid tissue.
AB  - Cerebral vessels have certain distinct anatomical and developmental
      characteristics which are well known, but their characteristic genetic expression
      profile remains as yet only poorly understood. We investigated gene expression in
      the rat cerebral artery in comparison with the rat descending aorta, two
      locations which have obviously different anatomical and developmental
      characteristics. Since the contamination of cerebral small arteries by arachnoid
      tissue is to a certain extent inevitable, we also performed a gene expression
      analysis of arachnoid tissue as a background. In an effort to obtain the
      necessary quality and quantity of total RNA, a novel freeze-fracture apparatus
      minimizing the time required for the entire procedure from tissue separation to
      RNA preparation was used. With the material obtained, a group of genes highly
      expressed in each tissue was detected by oligonucleotide microarray analysis. In
      the circle of Willis, peptide-19 (PEP-19), connexin-37 (CXN-37), growth arrest
      and DNA damage-inducible gene (GADD45), and the putative G protein coupled
      receptor RA1c, Notch-1, and jagged-1 were predominantly expressed. In arachnoid
      tissue, bone morphologic protein (BMP)-7, BMP-6, beta defensin-1, neuroendocrine
      protein 7B2, thiol-specific antioxidant protein, IL-18, beta-chain clathrin
      associated protein complex AP-1, and angiopoietin-2 were highly expressed. In the
      aorta, most of the abundantly expressed genes related to lipid metabolism. By
      means of oligonucleotide microarray analysis, the distinct gene expression
      profiles in the circle of Willis arachnoid tissue, and aorta were made evident.
      From these findings it is reasonable to conclude that a functional interaction
      exists between the circle of Willis and arachnoid tissue.

PMID- 12409633
TI  - The generation of monoclonal antibodies against human peroxisome proliferator
      activated receptors (PPARs).
AB  - Monoclonal antibodies (Mabs) are valuable reagents for the purification,
      characterization and immunolocalization of proteins. In this study, we raised
      Mabs against human peroxisome proliferator-activated receptors (PPARs) using
      baculovirus particles displaying surface glycoprotein gp64-fusion proteins as the
      immunizing agent. In this system, to display fusion proteins on the viral
      surface, the amino terminal sequences of human PPARd and PPARg2 are inserted in
      frame between the signal sequence and the mature domain of the gp64 nucleotide
      sequence.Mabs were raised by immunization with whole virus without a purification
      of the target antigens. The Mabs generated by this novel method were shown to
      recognize not only the gp64-PPARs fusion protein, but also mature, expressed
      proteins by a wide variety of techniques, including immunohistochemistry,
      immunoblotting, and electrophoretic mobility shift assays (EMSAs). Transfection
      of the transfer vector containing a nucleotide sequence encoding less than 30
      amino acids along with linearized baculovirus DNA allows for the production of a
      high affinity antibody against the corresponding mature form. This method is of
      potential utility in that it allows the production of valuable antibodies without
      the requirement of a protein purification step.

PMID- 12409634
TI  - The protective effects of tetrahydrocurcumin on oxidative stress in cholesterol
      fed rabbits.
AB  - Tetrahydrocurcumin (THC) is an antioxidative substance which is derived from
      curcumin by hydrogenation. Curcumin is the main component of turmeric and is
      responsible for the yellow color of curried foods.First, LDL derived from a
      normal human volunteer was incubated in the presence of an antioxidant with 10
      microM CuSO(4) at 37 degrees C for 2 hours.All antioxidants tested (THC,
      curcumin, probucol, and alpha-tocopherol) dose-dependently (1-10 microM)
      inhibited the oxidative modification of LDL. Probucol was the strongest, followed
      by THC, alpha-tocopherol, and curcumin.Next, in order to evaluate the
      antioxidative activity of THC in vivo, we fed rabbits diets containing 1%
      cholesterol with or without 0.5% THC and examined their effects on oxidative
      stress and atherosclerosis. Animals were divided into two groups: the control
      group rabbits (n = 12) were fed a normal chow diet and the experimental group (n
      = 12) was fed a diet containing 0.5% THC for one week.Then, 1% cholesterol was
      added to the diets and the animals were allowed to feed further for either 6 (n =
      4 for each group) or 12 weeks (n = 8 for each group). Although serum cholesterol
      levels rapidly increased after starting the high cholesterol diet, no difference
      was observed between the control and THC groups.TBARS formation in the absence of
      added copper ion was inhibited in the LDL separated from THC-treated animals
      compared with that from control animals.THC treatment tended to inhibit the area
      covered with atherosclerotic lesions compared with the control, although this was
      not significant (28.8 +/- 17.5% vs. 40.0 +/- 23.7%, p = 0.2). Formation of
      N(epsilon)-(hexanoyl) lysine, 4-hydroxynonenal and dityrosine in liver and kidney
      also had a tendency to be inhibited by THC treatment. Although free THC was not
      detected in serum and liver, THC was detected in samples treated with beta
      glucuronidase and sulfatase, suggesting that THC is present as a conjugate with
      glucuronic acid or sulfate. In conclusion, the present results suggest that
      curcuminoids, particularly THC, which are contained in turmeric, may be useful as
      a functional food factor.

PMID- 12409635
TI  - Effect of pravastatin-induced LDL-cholesterol reduction on coronary heart disease
      and cerebrovascular disease in Japanese: Hokuriku lipid coronary heart disease
      study-pravastatin atherosclerosis trial (Holicos-PAT).
AB  - The purpose of Holicos-PAT was to investigate the efficacy of serum lipid
      lowering by pravastatin against coronary heart disease (CHD) and cerebrovascular
      disease (CVD) in the Japanese population. Hypercholesterolemic men and women (n =
      2,232), aged 40-70 years, were followed up for 5 years, while they were receiving
      pravastatin (group P, n = 1,422) or only diet therapy (group C, n = 810). The
      primary endpoint was CHD (a composite of onset or worsening of angina pectoris,
      performing CABG or PTCA, non-fatal myocardial infarction, death from CHD
      including heart death or sudden death). The secondary endpoints were comprised of
      CVD, total mortality, variation of serum lipid and apoprotein levels, and a
      relationship between the LDL-C level and occurrence of CHD. For several reasons
      (proving to meet the exclusion criteria after registration, etc.), 1,290 cases of
      group P and 749 cases of group C were used as subjects for the primary analysis.
      The mean follow-up period was 4.5 years in group P and 4.2 years in group C for
      events of CHD. The mean LDL-C level (SD) in group P was 176 (29) mg/dl and
      decreased to 134 (29) mg/dl one year later. This effect continued during the
      follow-up period.CHD events occurred in 9.2/1000 patient-years for men and
      2.4/1000 patient-years for women without a history of CHD.CHD events occurred in
      55.3/1000 patient-years for men and 23.6/1000 patient-years for women with a
      history of CHD, which was 6 times higher in men and 10 times higher in women than
      in those without a history of CHD, respectively. The adjusted relative risk ratio
      of group P to group C for CHD events was 0.74 (95%CI: 0.47-1.19). In the patients
      with a history of CHD, the ratio was 0.55 (95%CI: 0.30-1.00). The effect was
      apparent in the patients with a history of CHD. The incidence of myocardial
      infarction in Japanese patients with hypercholesterolemia living in the Hokuriku
      district was apparently lower, than the worldwide incidence, indicative that
      pravastatin may have a tendency to inhibit the occurrence of events of
      arteriosclerotic disease.

PMID- 12409641
TI  - Different types of epithelial cadherin alterations play different roles in human
      carcinogenesis.
AB  - Epithelial cadherin (E-cadherin) gene and protein alterations are implicated in
      the existence of two clearly distinct types of tumors in the stomach (isolated
      cell and glandular carcinomas), breast (lobular and ductal carcinomas), and
      thyroid (papillary and follicular carcinomas), as well as in the occurrence of
      poorly differentiated foci in colorectal and prostate adenocarcinomas. A thorough
      correlation between clinicopathologic features and molecular data, and the study
      of early lesions from familial cases provide clues for the understanding of the
      role played by E-cadherin in these settings.

PMID- 12409642
TI  - Testing for HER-2/neu in breast cancer: is fluorescence in situ hybridization
      superior in predicting outcome?
AB  - Testing for alterations in HER-2/neu in breast cancer has become increasingly
      popular in recent years, particularly with the recent development of a humanized
      antiHER-2/neu monoclonal antibody, trastuzumab, which is currently being employed
      in conjunction with cytotoxic chemotherapy to treat metastatic breast cancer in
      patients whose tumors exhibit this HER-2/neu alteration. Controversy exists not
      only on the optimal method of laboratory testing for this HER-2/neu alteration
      (i.e., fluorescence in situ hybridization (FISH) versus immunohistochemistry
      (IHC) versus others), but also on the type of reagents used for a given method. A
      plethora of published studies on tissue-based HER-2/neu testing has recently
      appeared in many peer-reviewed journals; many have concluded that IHC could be
      used as a first-line screening test, with the recommendation of FISH to confirm
      indeterminate results. In contrast to these studies, a recent study by Pauletti
      et al. showed that HER-2/neu testing by IHC does not predict clinical outcome as
      accurately as does FISH. This commentary discusses the findings of this study,
      within a broader review of critical issues relating to HER-2/neu testing in
      breast cancer.

PMID- 12409643
TI  - Medulloblastomas with favorable versus unfavorable histology: how many small blue
      cell tumor types are there in the brain?
AB  - Prognostically favorable and unfavorable variants of medulloblastoma have
      recently been identified, corresponding to medulloblastoma with extensive
      nodularity and large cell/anaplastic medulloblastoma, respectively. In an effort
      to identify clinically relevant grading criteria for medulloblastoma in general,
      330 Pediatric Oncology Group (POG) cases were carefully reviewed for presence and
      extent of histologic anaplasia, nodularity, and desmoplasia. The resulting data
      was statistically analyzed using event-free and overall patient survival as
      endpoints. Significant anaplasia (moderate to severe) was identified in 24% of
      cases and was strongly associated with decreased survival times. Additionally,
      those with diffuse or extensive anaplasia fared worse than those with only focal
      anaplasia. Although the study confirmed the favorable prognosis for the rare
      cases of medulloblastoma with extensive nodularity, lesser degrees of nodularity
      or desmoplasia were not associated with a statistically significant survival
      advantage. Medulloblastoma grading based on anaplasia demonstrated a
      statistically stronger association with patient outcome than clinical staging.
      Therefore, histologic grading of medulloblastomas seems warranted as a routine
      diagnostic aid.

PMID- 12409644
TI  - Smooth muscle tumors of soft tissue.
AB  - This paper presents an overview of smooth muscle tumors occurring in deep soft
      tissue. Although the existence of leiomyomas of soft tissue has been questioned
      in the past, it appears that they do exist but are rare, and must be diagnosed
      using stringent histologic criteria that include no atypia and minimal or no
      mitotic activity. They segregate into two distinct clinicopathologic groups, one
      group occurring in patients of either sex in deep somatic soft tissue and the
      second occurring primarily in women in the pelvic retroperitoneum. The latter
      bear a histologic similarity to uterine leiomyomas. Leiomyosarcomas occur in
      retroperitoneum followed by deep somatic soft tissue and are diagnosed by the
      presence of nuclear atypia and essentially any level of mitotic activity.
      Leiomyosarcomas of deep somatic tissue commonly arise from small veins and their
      behavior can be predicted by a number of factors including age, grade, and
      "disruption" of tumor. Conversely, few factors have proved to be prognostically
      useful for leiomyosarcomas of the retroperitoneum, as nearly all prove fatal.
      Epstein Barr virus (EBV)-associated smooth muscle tumors are a recently emerging
      entity that occur in the setting of immunocompromise. Their behavior is closely
      tied to the immune status of the patient rather than to specific histologic
      features.

PMID- 12409645
TI  - Proliferative and neoplastic disorders in children with acquired immunodeficiency
      syndrome.
AB  - Acquired immunodeficiency syndrome (AIDS) is a multisystem disease and, besides
      infections, various proliferative and neoplastic disorders are seen in cytology,
      biopsy, and autopsy specimens from infected children. These lesions can be
      classified into four types: systemic lymphoproliferation, smooth muscle tumors,
      Kaposi sarcoma (KS), and human papilloma (HPV)-related genital lesions. In
      addition, isolated cases of multiple miscellaneous tumors have been reported.
      Proliferative and neoplastic disorders are categorized as lesions of undetermined
      pathogenesis; however, there are certain factors that are suggested to be related
      to their pathogenesis. The symptoms related to them may be atypical or difficult
      to appreciate, and proliferative and neoplastic disorders may clinically mimic an
      opportunistic infection. The type and site of proliferative and neoplastic
      disorder also tends to be atypical as compared with those seen in non HIV
      infected children. This is a brief but detailed review of these disorders in
      children with AIDS.

PMID- 12409647
TI  - Recent advances in breast cancer biology.
AB  - Developments in breast cancer biology over the last year have brought molecular
      medicine closer to the clinic. Within the past year, two major advances have
      taken place. First, microarray-based expression profiling has shown promise with
      the preliminary demonstration that clustering techniques can predict clinical
      outcome in lymphoma, pediatric leukemia, and breast cancer. Data in breast cancer
      have demonstrated the ability of microarray-based expression profiling to detect
      tumor cells in peripheral blood samples, to predict chemotherapy responses in
      fine-needle aspiration samples in neoadjuvant chemotherapy, and, most
      importantly, to predict disease-free survival and overall survival from profiles
      in breast cancer surgical specimens. Second, in breast cancer genetics, CHEK2 was
      identified as one of what are likely to be many low-penetrance breast cancer
      susceptibility genes. These studies demonstrate the transition of basic biologic
      research to clinical application.

PMID- 12409648
TI  - Radiation oncology: the year in review.
AB  - Radiotherapy plays an essential role in the treatment of patients with breast
      cancer. The literature in English dealing with radiation therapy in the
      management of breast cancer published between May 2001 and April 2002 was
      reviewed. A variety of articles were chosen by the authors to be presented in
      this review. The areas of particular interest include the role of boost therapy
      after whole-breast irradiation, the use of intraoperative irradiation after
      lumpectomy, the management of ductal carcinoma the effect of age on outcome of
      therapy, and side-effects of irradiation. Space does not allow a comprehensive
      review of all the published literature, but the articles chosen were thought to
      be of special interest to those involved in breast cancer management.

PMID- 12409649
TI  - Systemic therapy.
AB  - The systemic treatment of breast cancer is a moving target, reflected by the
      continuous update of treatment guidelines. Chemotherapy regimens, including the
      adjuvant role of taxanes and preoperative systemic therapy, continue to be
      optimized. A major challenge facing researchers and clinicians is how to improve
      the therapeutic index of present and future therapies, identify patients most
      likely to benefit from the proposed intervention, and avoid treating those who
      would be exposed to potential toxicities with minimal gain. Anti-estrogens are a
      prime example of a targeted therapy with a high therapeutic index. Data are now
      available on aromatase inhibitors in the adjuvant setting and pure antiestrogens
      in metastatic disease. The role of targeted antihuman epidermal growth factor
      receptor 2 therapy in the adjuvant setting is being actively investigated, but
      this is complicated by the inadequate standardization of human epidermal growth
      factor receptor 2 expression assays used in clinical practice. A long overdue
      revision of the breast cancer staging system becomes effective in January 2003,
      bringing it more in line with current standards of care and facilitating data
      collection for future outcome analysis of therapeutic interventions. These and
      other important developments since 2001 are examined in this review.

PMID- 12409650
TI  - Bisphosphonates in cancer therapy.
AB  - Bisphosphonates inhibit osteoclast-mediated bone resorption in metastatic bone
      disease. A wealth of preclinical data have begun to shed light on the complex
      mechanisms by which bisphosphonates inhibit bone resorption and interfere with
      the formation and growth of bone metastases. Nitrogen-containing bisphosphonates
      inhibit the mevalonate pathway, which results in the inhibition of osteoclast
      function and the induction of apoptosis in osteoclasts and tumor cells alike.
      There is now extensive evidence that bisphosphonates have cytostatic activity
      against tumor cell lines and inhibit tumor cell adhesion and invasion of the
      extracellular matrix. These data are supported by a growing body of evidence from
      animal models demonstrating that bisphosphonates can reduce skeletal tumor
      burden. However, it remains unclear whether this reduction reflects a direct
      antitumor effect or an indirect effect via osteoclast inhibition and alteration
      of the bone microenvironment. Further preclinical studies are needed to elucidate
      these biochemical mechanisms fully; ultimately, well-controlled clinical trials
      will be required to investigate whether the antitumor potential of
      bisphosphonates translates into a significant clinical benefit for patients with
      cancer.

PMID- 12409651
TI  - Mechanisms of resistance to imatinib mesylate in Bcr-Abl-positive leukemias.
AB  - The constitutive activity of the Bcr-Abl tyrosine kinase plays a critical role in
      the molecular pathogenesis of not only the chronic but also the accelerated and
      blastic phases of chronic myelogenous leukemia. Therefore, Bcr-Abl tyrosine
      kinase is a rational therapeutic target in all phases of chronic myelogenous
      leukemia. Although imatinib mesylate (STI571, Gleevec, Novartis, Basal,
      Switzerland) produces high rates of complete clinical and cytogenetic responses
      in the chronic phase, resistance is universal and clinical relapse develops
      rapidly in the advanced phases of chronic myelogenous leukemia. This resistance
      has been shown to be caused by specific ATP binding site mutations or
      amplification of Bcr-Abl gene, resulting in a Bcr-Abl tyrosine kinase that is
      resistant to further inhibition by imatinib. Alternative (Bcr-Abl-independent)
      mechanisms driving the growth and survival of the malignant clone may also be
      responsible for imatinib resistance. Novel tyrosine kinase inhibitors that also
      target Bcr-Abl tyrosine kinase, or agents that downregulate Bcr-Abl levels
      regardless of its wild-type or mutant status, may need to be developed clinically
      for the future therapy of imatinib-resistant chronic myelogenous leukemia.

PMID- 12409652
TI  - New drugs for patients with pancreatic cancer.
AB  - This past year has proved to be a relatively disappointing one for the
      development of agents that could improve the survival rates of patients with
      advanced pancreatic cancer. A well designed randomized trial of treatment of
      patients with gemcitabine with or without a farnesyl transferase inhibitor (tried
      because pancreatic cancers have a high incidence of K- abnormalities) showed no
      improvement in survival rates. A definitive randomized controlled trial with a
      histone deacetylase inhibitor also proved negative. There are some signs of hope
      in that in early nonrandomized studies there are some new agents that appear to
      have some activity against the disease. These agents include the thymidylate
      synthase inhibitor capecitabine (which is possibly activated at the tumor site),
      the antigastrin immunogen G17DT (which is an immunization designed to neutralize
      the pancreatic growth factor gastrin), and the topoisomerase I inhibitor 9
      nitrocamptothecin. In addition, the combination of the new agent oxaliplatin to
      high-dose 5FU plus leucovorin, which gave a median survival rate of 12.5 months,
      is also worthy of further study. Supportive care findings of interest for the
      patient with advanced pancreatic cancer of note include: the study in which
      eicosapentaenoic acid (fish oil) caused a modest weight gain (median of 1 kg),
      and the finding that ofloxacin plus ursodeoxycholic acid was not superior to
      ursodeoxycholic acid alone for the prevention or occlusion of biliary stents.

PMID- 12409653
TI  - Proteasome inhibitors as new anticancer drugs.
AB  - The targeted degradation of key regulatory proteins is an essential element of
      cell cycle control. The proteasome plays a central role in the degradation of
      such proteins and has therefore become an important therapeutic target for
      diseases involving cell proliferation, notably cancer. This review summarizes
      numerous studies demonstrating that proteasome inhibition induces apoptosis and
      sensitizes cancer cells to traditional tumoricidal agents both and The potent and
      selective proteasome inhibitor, PS-341, is particularly promising from a
      therapeutic perspective, and it is the only such inhibitor that has progressed to
      clinical trials. Preliminary data indicate that the drug is well tolerated by
      patients with cancer, and further trials are underway to assess the safety and
      efficacy of proteasome inhibition in hematologic and solid tumors, both as a
      monotherapy and in combination with other chemotherapeutics.

PMID- 12409654
TI  - Thalidomide and immunomodulatory drugs as cancer therapy.
AB  - The demonstration of increased angiogenesis in cancer pathogenesis prompted the
      use of thalidomide in both solid tumors and hematologic malignancies. Its broad
      spectrum of actions besides its antiangiogenic potential, specifically, its
      immunomodulatory properties, antiinflammatory actions, and direct effect on tumor
      cells and their microenvironment, provides an alternative strategy in the
      armamentarium against cancer. Thalidomide is being evaluated for treatment of
      hematologic cancers like multiple myeloma and myelodysplasia, and solid tumors
      like lung, breast, renal, and colon cancer. Thalidomide analogues, the
      immunomodulatory drugs have increased potency and have demonstrated efficacy and
      reduced toxicity in phase I and II clinical studies. This article reviews both
      laboratory-based and clinical studies with thalidomide and the immunomodulatory
      drugs and their application in different cancers.

PMID- 12409655
TI  - Emerging strategies in tumor vaccines.
AB  - Reports of novel developments in tumor vaccines that have appeared in the year
      ending May 1, 2002 are reviewed here. Antigenic moieties were revealed for tumors
      previously considered nonimmunogenic. The use of peptides spanning mutations
      detected exclusively in tumor tissue avoids the common concern for autoimmune
      responses. Carbohydrate biology is revealing novel antigenic moieties. The search
      for helper epitopes from tumor antigens has come into full swing. Humoral
      immunity is regaining terrain, particularly through the development of
      antiidiotypic antibodies. Major steps forward have been made in optimizing modes
      and routes of antigen delivery and in the use of immune adjuvants. In the clinic,
      phase I/II trials support the notion that tumor vaccines are safe. Because these
      trials are conducted in patients in whom tumor remission is not a realistic
      endpoint, patient responses were established by immune monitoring strategies to
      detect subtle changes in antitumor reactivity. Both clinical and laboratory data
      stress the vast potential of tumor vaccines for the treatment of cancer.

PMID- 12409656
TI  - Vascular endothelial growth factor as a target opportunity in hematological
      malignancies.
AB  - Vascular endothelial growth factor (VEGF) is a potent angiogenic peptide with
      diverse biologic effects. There are seven members of the VEGF family, VEGF-A
      through VEGF-E, placental growth factor and the newly described, tissue-specific
      endocrine gland-derived VEGF. VEGF expression is induced by a number of stimuli
      including hypoxia, activated oncogenes, and inflammatory cytokines while negative
      regulators include wild type von Hippel-Lindau and p53 tumor suppressor genes.
      VEGF activity is mediated through interactions with high affinity tyrosine kinase
      receptors. To date, three have been identified. Interaction with these receptors
      activates multiple signal pathways leading to the diverse biologic activity of
      VEGF. Evidence suggests that VEGF is also a survival factor for endothelial cells
      and perhaps tumor cells. The importance of angiogenic factors such as VEGF, while
      clearly established in solid tumors, has not been fully elucidated in human
      hematopoietic neoplasms. Evolving data generally that elevated levels of VEGF
      confer a poor prognosis to patients with these diseases. The central role of VEGF
      in angiogenesis coupled with the relatively restricted expression of its
      receptors, has led to the development of a number of agents to target this system
      that are currently under clinical investigation.

PMID- 12409658
TI  - Surgery for primary hyperparathyroidism: what is the best approach?

PMID- 12409657
TI  - Unilateral versus bilateral neck exploration for primary hyperparathyroidism: a
      prospective randomized controlled trial.
AB  - OBJECTIVE: To compare unilateral and bilateral neck exploration for primary
      hyperparathyroidism in a prospective randomized controlled trial. SUMMARY
      BACKGROUND DATA: Based on the assumption that unilateral neck exploration for a
      solitary parathyroid adenoma should reduce operating time and morbidity, a
      variety of minimally invasive procedures have challenged the idea that bilateral
      neck exploration is the gold standard for the surgical treatment of primary
      hyperparathyroidism. However, to date, no open prospective randomized trial has
      been published comparing unilateral and bilateral neck exploration. METHODS:
      Ninety-one patients with the preoperative diagnosis of primary
      hyperparathyroidism were randomized to unilateral or bilateral neck exploration.
      Preoperative scintigraphy and intraoperative parathyroid hormone measurement
      guided the unilateral exploration. Gross morphology and frozen section determined
      the extent of parathyroid tissue resection in the bilateral group. The primary
      end-point was the use of postoperative medication for hypocalcemic symptoms.
      RESULTS: Eighty-eight patients (97%) were cured. Histology and cure rate did not
      differ between the two groups. Patients in the bilateral group consumed more oral
      calcium, had lower serum calcium values on postoperative days 1 to 4, and had a
      higher incidence of early severe symptomatic hypocalcemia compared with patients
      in the unilateral group. In addition, for patients undergoing surgery for a
      solitary parathyroid adenoma, unilateral exploration was associated with a
      shorter operative time. The cost for the two procedures did not differ.
      CONCLUSIONS: Patients undergoing a unilateral procedure had a lower incidence of
      biochemical and severe symptomatic hypocalcemia in the early postoperative period
      compared with patients undergoing bilateral exploration. Unilateral neck
      exploration with intraoperative parathyroid hormone assessment is a valid
      surgical strategy in patients with primary hyperparathyroidism with distinct
      advantages, especially for patients with solitary parathyroid adenoma.

PMID- 12409659
TI  - Potential of surgery for curing type 2 diabetes mellitus.
AB  - OBJECTIVE: To review the effect of morbid obesity surgery on type 2 diabetes
      mellitus, and to analyze data that might explain the mechanisms of action of
      these surgeries and that could answer the question of whether surgery for morbid
      obesity can represent a cure for type 2 diabetes in nonobese patients as well.
      SUMMARY BACKGROUND DATA: Diabetes mellitus type 2 affects more than 150 million
      people worldwide. Although the incidence of complications of type 2 diabetes can
      be reduced with tight control of hyperglycemia, current therapies do not achieve
      a cure. Some operations for morbid obesity not only induce significant and
      lasting weight loss but also lead to improvements in or resolution of comorbid
      disease states, especially type 2 diabetes. METHODS: The authors reviewed data
      from the literature to address what is known about the effect of surgery for
      obesity on glucose metabolism and the endocrine changes that follow this surgery.
      RESULTS: Series with long-term follow-up show that gastric bypass and
      biliopancreatic diversion achieve durable normal levels of plasma glucose, plasma
      insulin, and glycosylated hemoglobin in 80% to 100% of severely obese diabetic
      patients, usually within days after surgery. Available data show a significant
      change in the pattern of secretion of gastrointestinal hormones. Case reports
      have also documented remission of type 2 diabetes in nonmorbidly obese
      individuals undergoing biliopancreatic diversion for other indications.
      CONCLUSIONS: Gastric bypass and biliopancreatic diversion seem to achieve control
      of diabetes as a primary and independent effect, not secondary to the treatment
      of overweight. Although controlled trials are needed to verify the effectiveness
      on nonobese individuals, gastric bypass surgery has the potential to change the
      current concepts of the pathophysiology of type 2 diabetes and, possibly, the
      management of this disease.

PMID- 12409660
TI  - New technique for liver resection using heat coagulative necrosis.
AB  - OBJECTIVE: To assess a new bloodless technique using radiofrequency energy for
      segmental liver resection of hepatic tumors. SUMMARY BACKGROUND DATA: Liver
      resection remains a formidable surgical procedure; safe performance requires a
      high level of training and skill. Intraoperative blood loss during liver
      resection remains a major concern because it is associated with a higher rate of
      postoperative complications and shorter long-term survival. METHODS: From January
      2000 to June 2001, 15 patients with various hepatic tumors were operated on using
      radiofrequency energy to remove the tumor in its entirety. Radiofrequency energy
      was applied along the margins of the tumor to create "zones of necrosis" before
      resection with a scalpel. RESULTS: No blood transfusions were required. The mean
      blood loss during resection was 30 +/- 10 mL. No mortality or morbidity was
      observed. The median postoperative stay was 8 days (range 5-9). No liver
      recurrence was detected in patients undergoing resection with this technique
      during follow-up periods ranging from 2 to 20 months. CONCLUSIONS: Segmental and
      wedge liver resection assisted by radiofrequency is safe. This novel technique
      offers a new method for transfusion-free resection.

PMID- 12409661
TI  - Applicability of intraoperative parathyroid hormone assay during thyroidectomy.
AB  - OBJECTIVE: To evaluate the applicability of intraoperative parathyroid hormone
      (quick PTH) assay to monitor parathyroid function and to identify clinically
      significant hypocalcemia compared with postoperative serum calcium monitoring.
      SUMMARY BACKGROUND DATA: Close monitoring of serum calcium levels is a standard
      of care to identify post-thyroidectomy hypocalcemia due to parathyroid
      insufficiency. METHODS: Quick PTH assay was performed before and after
      thyroidectomy for 100 patients at risk of postoperative hypocalcemia and 20
      control patients who underwent unilateral lobectomy. Postoperative serum calcium
      levels were closely monitored. RESULTS: Control patients had a normal but 38.9 +/
      5.9% (mean +/- SEM) decline in quick PTH after thyroidectomy. Eleven of 100 at
      risk patients (11%) developed postoperative hypocalcemia. Hypocalcemic patients
      had significantly lower quick PTH values after thyroidectomy compared with that
      of normocalcemic patients. Serum calcium was significantly lower in hypocalcemic
      patients the morning after operation but not early after the operation (within 6
      hours). A normal or less than 75% decline in quick PTH after thyroidectomy can
      accurately identify normocalcemic patients during surgery as compared to more
      than 24 hours by serum calcium monitoring. CONCLUSIONS: The quick PTH assay can
      monitor parathyroid function during thyroidectomy and identify patients at risk
      of clinically significant hypocalcemia much earlier than serum calcium
      monitoring. It may facilitate early discharge and the use of parathyroid
      autotransplantation during thyroidectomy.

PMID- 12409662
TI  - Various penetrance of familial medullary thyroid carcinoma in patients with RET
      protooncogene codon 790/791 germline mutations.
AB  - OBJECTIVE: To describe a genotype-phenotype correlation in MEN2 families with
      germline mutations of codons 790/791 and discuss options for the therapeutic
      management of gene carriers. SUMMARY BACKGROUND DATA: Heredity of MEN2 syndromes
      is caused by a heterozygous germline mutation in the protooncogene. Rare
      mutations of codons 790/791 associated with incomplete penetrant MEN2A/FMTC
      phenotype were reported in five families, contraindicating the prophylactic
      thyroidectomy for the genetically affected children. METHODS: Forty-five patients
      with a putative sporadic MTC were screened for germline mutations by direct DNA
      sequencing. Family members of identified index cases underwent genetic analysis.
      Gene carriers were examined clinically and biochemically, and all gene carriers
      underwent prophylactic thyroidectomy. RESULTS: Five index patients were
      identified, four of whom harbored mutations in codons 790/791 and one in codon
      634. In the kindreds, four L790F carriers and one Y791F carrier were detected.
      The thyroid gland histology of L790F carriers revealed medullary thyroid
      carcinoma in two patients (aged 29 and 50 years) and C-cell hyperplasia in two
      additional patients (aged 9 and 16 years). The Y791F carrier had a normal
      histology. CONCLUSIONS: Codon 790/791 mutations had diverse penetrance. Whereas
      prophylactic thyroidectomy in children is a justifiable approach for codon 790
      mutation carriers, the indication for thyroidectomy should depend on the clinical
      course of codon 791 carriers.

PMID- 12409663
TI  - Male gender is a predictor of morbidity and age a predictor of mortality for
      patients undergoing gastric bypass surgery.
AB  - PURPOSE: To determine preoperative risk factors predictive of adverse outcomes
      after gastric bypass surgery. SUMMARY BACKGROUND DATA: Gastric bypass results in
      sustained weight loss for seriously obese patients, but perioperative
      complications can be formidable. Preoperative risk assessment is important to
      establish the risk-benefit ratio for patients undergoing these operations.
      METHODS: Data for 10 risk factors predictive of adverse outcomes were collected
      on 1,067 consecutive patients undergoing gastric bypass surgery at the UCLA
      Medical Center from December 1993 until June 2000. Univariate analyses were
      performed for individual risk factors to determine their potential significance
      as predictors for complications. All 10 risk factors were entered into a logistic
      regression model to determine their significance as predictors for complications.
      Sensitivity analysis was performed. RESULTS: Univariate analysis revealed that
      male gender and weight were predictive of severe life-threatening adverse
      outcomes. Multistep logistic regression yielded only male gender as a risk
      factor. Male patients were heavier than female patients on entry to the study,
      accounting for weight as a potential risk factor. Patients older than 55 years
      had a threefold higher mortality from surgery than younger patients, although the
      complication rate, 5.8%, was the same in both groups. Sensitivity analysis
      demonstrated that the risk for severe life-threatening adverse outcomes in women
      increased from 4% for a 200-lb female patient to 7.5% for a 600-lb patient. The
      risk increased from 7% for a 200-lb male patient to 13% for a 600-lb patient.
      CONCLUSIONS: Large male patients are at greater risk for severe life-threatening
      complications than smaller and/or female patients. Risk factors thought to be
      predictive of adverse outcomes, such as a history of smoking or diabetes, proved
      not to be significant in this analysis. Older patients had the same complication
      rate but a threefold higher mortality, suggesting that they lack the reserve to
      recover from complications when they occur.

PMID- 12409664
TI  - Hospital and surgeon procedure volume as predictors of outcome following rectal
      cancer resection.
AB  - OBJECTIVE: To compare surgeon and hospital procedure volume as predictors of
      outcomes for patients with rectal cancer. SUMMARY BACKGROUND DATA: Although a
      "volume-outcome" relationship exists for several major cancer operations, the
      impact of procedure volume on outcomes following rectal cancer surgery remains
      uncertain, and it has not been determined whether hospital or surgeon volume is a
      more important predictor of outcomes. METHODS: A retrospective population-based
      cohort study utilizing the Surveillance, Epidemiology and End Results (SEER)
      Medicare linked database identified 2,815 rectal cancer patients aged 65 and
      older who had surgery for a primary tumor diagnosed in 1992-1996 in a SEER area.
      Hospital- and surgeon-specific procedure volume was ascertained based on the
      number of claims submitted over the 5-year study period. Outcome measures were
      mortality at 30 days and 2 years, overall survival, and the rate of
      abdominoperineal resections. Age, sex, race, comorbid illness, cancer stage, and
      socioeconomic status were used to adjust for differences in case mix. RESULTS:
      Neither hospital- nor surgeon-specific procedure volume was significantly
      associated with 30-day postoperative mortality or rates of rectal sphincter
      sparing operations. Although an association between hospital volume and mortality
      at 2 years was evident, this finding was no longer significant once surgeon
      specific volume was controlled for. In contrast, surgeon-specific volume was
      associated with 2-year mortality and remained an important predictor even after
      adjustment for hospital volume. Surgeon volume was also better than hospital
      procedure volume at predicting long-term survival. CONCLUSIONS: Surgeon-specific
      experience as measured by procedure volume can have a significant impact on
      survival for patients with rectal cancer.

PMID- 12409665
TI  - Role of mast cells and myofibroblasts in human peritoneal adhesion formation.
AB  - OBJECTIVE: To study fibroblasts and mast cells in human peritoneal adhesions and
      to evaluate whether their interaction plays a role in adhesion development.
      SUMMARY BACKGROUND DATA: Myofibroblasts play a critical role in wound
      repair/fibrosis. Mast cells influence the formation of peritoneal adhesions in a
      rat model, and they are modulators of fibroblast functions. METHODS: Peritoneal
      adhesion biopsies were processed for either histology (H&E, toluidine blue) or
      immunohistochemistry (tryptase, laminin, collagen type IV and VIII, and alpha
      SMA) or grown as explants for obtention of fibroblasts. The effects of mast cell
      (HMC-1) sonicate and selected mast cell mediators and cytokines on fibroblast
      proliferation ([ (3)H]thymidine) and collagen synthesis ([ (3)H]proline) and on
      fibroblast contractile activity (tridimensional collagen lattice) were evaluated.
      Mast cell mediators influencing fibroblast proliferation were partially
      characterized by enzymatic susceptibility and FPLC gel filtration column
      chromatography. RESULTS: Most of the fibroblasts in peritoneal adhesions were
      identified as alpha-SMA-positive myofibroblasts. Mast cell hyperplasia was
      observed and more than one third of the mast cells were degranulated. Few mast
      cells showed a faint staining for laminin or collagen type IV and VIII. Mast cell
      sonicate increased fibroblast proliferation and contractile activity while
      decreasing collagen synthesis. Mast cell sonicate proliferating activities were
      found to be proteinase-sensitive with a molecular weight of more than 158 kd, of
      approximately 40 kd, and of less than 10 kd. TGF-beta and tryptase enhanced
      collagen synthesis; TNF-alpha and chymase decreased it. None of the selected
      mediators increased fibroblast proliferation. CONCLUSIONS: Myofibroblasts are the
      main connective tissue cells present in human peritoneal adhesions, and mast
      cells play a direct role in peritoneal adhesion formation.

PMID- 12409666
TI  - Extended hepatic resection for hepatocellular carcinoma in patients with
      cirrhosis: is it justified?
AB  - OBJECTIVE: To evaluate the perioperative outcomes and long-term survival of
      extended hepatic resection for hepatocellular carcinoma (HCC) in patients with
      cirrhosis. SUMMARY BACKGROUND DATA: Hepatic resection is a well-established
      treatment for HCC in cirrhotic patients with preserved liver function and limited
      disease. However, the role of extended hepatic resection (more than four
      segments) for HCC in cirrhotic patients has not been elucidated. METHODS: Between
      1993 and 2000, 45 consecutive patients with histologically confirmed cirrhosis
      underwent right or left extended hepatectomy for HCC (group A). Perioperative
      outcomes and long-term survival of these patients were compared with 161 patients
      with HCC and cirrhosis who underwent hepatic resection of a lesser extent in the
      same period (group B). All clinicopathologic and follow-up data were collected
      prospectively. RESULTS: Group A patients had significantly higher intraoperative
      blood loss, longer operation time, and longer hospital stay than group B.
      However, the two groups were similar in overall morbidity and hospital mortality.
      There were no significant differences in the incidence of liver failure or other
      complications. The resection margin width was similar between the two groups.
      Despite significantly larger tumor size in group A compared with group B, long
      term survival was comparable between the two groups. CONCLUSIONS: Extended
      hepatic resection for HCC can be performed in selected cirrhotic patients with
      acceptable morbidity, mortality, and long-term survival that are comparable to
      those of lesser hepatic resection. Extended hepatectomy for large HCC extending
      from one lobe to the other or central HCC critically related to the hepatic veins
      is justifiable in cirrhotic patients with preserved liver function and adequate
      liver remnant.

PMID- 12409667
TI  - Long-term results of distal pancreatectomy for chronic pancreatitis in 90
      patients.
AB  - OBJECTIVE: To determine the indications for distal pancreatectomy for chronic
      pancreatitis and to evaluate the risks, functional loss, and outcome of the
      procedure. SUMMARY BACKGROUND DATA: Chronic pancreatitis is generally associated
      with continued pain, parenchymal and ductal hypertension. and progressive
      pancreatic dysfunction, and it is a cause of premature death in patients who
      receive conservative treatment. Good results have recently been reported by the
      authors and others for resection of the pancreatic head in this disease, but
      distal pancreatectomy is a less popular option attended by variable success
      rates. It remains a logical approach for patients with predominantly left-sided
      pancreatic disease, however. METHODS: A personal series of 90 patients undergoing
      distal pancreatectomy for chronic pancreatitis over the last 20 years has been
      reviewed, with a mean postoperative follow-up of 34 months (range 1-247).
      Pancreatic function was measured before and after operation in many patients.
      RESULTS: Forty-eight of 84 patients available for follow-up had a successful
      outcome in terms of zero or minimal, intermittent pain. There was one
      perioperative death, but complications developed in 29 patients, with six early
      reexplorations. Morbidity was unaffected by associated splenectomy or right-to
      left dissection. Late mortality rate over the follow-up period was 10%; most of
      these late deaths occurred because of failure to abstain from alcohol.
      Preoperative exocrine function was abnormal in two thirds of those tested and was
      unchanged at follow-up. Diabetic curves were seen in 10% of patients
      preoperatively, while there was an additional diabetic morbidity rate of 23%
      related to the procedure and late onset of diabetes (median duration 27 months)
      in another 23%. Diabetic onset was related to percentage parenchymal resection as
      well as splenectomy. Outcome was not clearly dependent on the etiology of
      pancreatitis or on disease characteristics as assessed by preoperative imaging.
      However, patients with pseudocyst disease alone did better than other groups.
      Twenty-one of 36 patients who failed to respond to distal pancreatectomy required
      further intervention, including completion pancreatectomy, neurolysis, and
      sphincteroplasty. Thirteen of these 21 patients achieved long-term pain relief
      after their second procedure. CONCLUSIONS: Distal pancreatectomy for chronic
      pancreatitis from any etiology can be performed with low mortality and a good
      outcome in terms of pain relief and return to work in approximately 60% of
      patients. Little effect is seen on exocrine function of the pancreas, but there
      is a diabetic risk of 46% over 2 years. Pseudocyst disease is associated with the
      best outcome, but other manifestations of this disease, including strictures,
      calcification, and limited concomitant disease in the head of the pancreas, can
      still be associated with a good outcome.

PMID- 12409668
TI  - Determinants of diagnostic performance of [F-18]fluorodeoxyglucose positron
      emission tomography for axillary staging in breast cancer.
AB  - OBJECTIVE: To prospectively investigate determinants of the accuracy of staging
      axillary lymph nodes in breast cancer using [F-18]fluorodeoxyglucose positron
      emission tomography (FDG PET). METHODS: Patients with primary operable breast
      cancer underwent FDG PET of the chest followed by sentinel node biopsy (SNB, n =
      47) and/or complete axillary lymph node dissection (ALND, n = 23). PET scans were
      independently interpreted by three observers in a blinded fashion with respect to
      the FDG avidity of the primary tumor and the axillary status. The results were
      compared to histopathological analyses of the axillary lymph nodes. Clinicians
      were blinded to the PET results. RESULTS: Axillary lymph node specimens and FDG
      PET scans were evaluated in 70 patients (59% cT1). Overall, 32 (46%) had lymph
      node metastases as established by SNB (18/47) or ALND (14/23), 20 of which were
      confined to a single node. The overall sensitivity of FDG PET was 25%, with a
      specificity of 97%. PET results were false-negative in all 18 positive SNBs and
      true-positive in 8/14 in the ALND group. The performance of FDG PET depended on
      the axillary tumor load and the FDG avidity of the primary tumor. Intense uptake
      in the primary tumor was found in only 57% of the patients, and this was
      independent of the size. There was excellent interobserver agreement of visual
      assessment of FDG uptake in primary tumor and axillary lymph nodes. CONCLUSIONS:
      The sensitivity of FDG PET to detect occult axillary metastases in operable
      breast cancer was low, and it was a function of axillary tumor load and FDG
      avidity of the primary tumor. Even though the clinical relevance of occult
      disease detected by SNB needs to be confirmed, it is suggested that FDG PET in
      these patients should be focused on exploiting its nearly perfect specificity and
      the potential prognostic relevance of variable FDG uptake.

PMID- 12409669
TI  - Novel approach to prevent the transition from the hyperdynamic phase to the
      hypodynamic phase of sepsis: role of adrenomedullin and adrenomedullin binding
      protein-1.
AB  - OBJECTIVE: To determine whether the combined administration of adrenomedullin and
      adrenomedullin binding protein-1 (AM/AMBP-1) has any modulatory effects on the
      cardiovascular response during the progression of sepsis. SUMMARY BACKGROUND
      DATA: Polymicrobial sepsis is characterized by an early, hyperdynamic phase
      followed by a late, hypodynamic phase. Recent studies have shown that AM, a newly
      reported potent vasodilator peptide, plays a major role in initiating the
      hyperdynamic response. Moreover, the reduced vascular responsiveness to AM
      appears to be responsible for the transition from the hyperdynamic phase to the
      hypodynamic phase of sepsis. Although the novel AMBP-1 augments AM-mediated
      action in vitro, it remains unknown whether AM/AMBP-1 maintains vascular
      responsiveness to AM at the late stage of sepsis. METHODS: Sepsis was induced by
      cecal ligation and puncture (CLP) in adult male rats. Human AMBP-1 (40 microg/kg
      body weight) was infused intravenously at the beginning of sepsis for 20 minutes
      and synthetic AM (12 microg/kg body weight) was continuously administrated for
      the entire study period using an Alzert micro-osmotic pump, beginning 3 hours
      before the induction of sepsis. At 20 hours after the onset of sepsis (i.e., the
      late stage), cardiac output, systemic oxygen delivery, stroke volume, total
      peripheral resistance, and organ blood flow in the liver, gut, kidneys, and heart
      were determined using radioactive microspheres. Plasma levels of transaminases
      (ALT, AST) and lactate were also measured. Additional studies were conducted to
      determine whether administration of AM alone or AMBP-1 alone alters the
      cardiovascular response at 20 hours after CLP. In additional rats, the necrotic
      cecum was excised at 20 hours after CLP following AM/AMBP-1 treatment, the
      peritoneal cavity irrigated with saline, and the midline incision closed in
      layers. Survival was then examined for a period of 10 days thereafter. RESULTS:
      Administration of AM/AMBP-1 prevented the decrease in the measured systemic and
      regional hemodynamic parameters at 20 hours after the onset of sepsis. Moreover,
      AM/AMBP-1 significantly attenuated hepatic damage and the elevation of plasma
      lactate, and prevented hemoconcentration. Treatment with AM/AMBP-1 reduced the
      overall 10-day mortality rate from 57% to 7%. Neither AM nor AMBP-1 alone was
      sufficient to maintain cardiovascular stability at 20 hours after CLP.
      CONCLUSIONS: Since AM/AMBP-1 delays or even prevents the transition from the
      hyperdynamic phase to the hypodynamic phase of sepsis, attenuates tissue injury,
      and decreases sepsis-induced morality, these agents should provide a novel
      approach for maintaining cardiovascular stability and preventing cell and organ
      damage during the progression of polymicrobial sepsis.

PMID- 12409670
TI  - Hypertonic saline resuscitation of hemorrhagic shock diminishes neutrophil
      rolling and adherence to endothelium and reduces in vivo vascular leakage.
AB  - OBJECTIVE: To evaluate the in vivo effects of hypertonic saline (HTS)
      resuscitation on the interactions of endothelial cells (ECs) and
      polymorphonuclear neutrophils (PMNs) and vascular permeability after hemorrhagic
      shock. SUMMARY BACKGROUND DATA: The PMN has been implicated in the pathogenesis
      of EC damage and organ injury following hemorrhagic shock. Compared to Ringer's
      lactate (RL), HTS resuscitation diminishes PMN and EC adhesion molecule
      expression and organ sequestration of PMNs. METHODS: In a murine model of
      hemorrhagic shock (50 mmHg for 45 minutes followed by resuscitation) using
      intravital microscopy on cremaster muscle, the authors studied PMN-EC
      interactions and vascular leakage (epifluorescence after 50 mg/kg fluorescent
      albumin) in three resuscitation groups: HTS (shed blood + 4 cc/kg 7.5% HTS, n =
      12), RL (shed blood + RL [2x shed blood volume], n = 12), and sham (no hemorrhage
      or resuscitation, n = 9). EC ICAM-1 expression was evaluated by
      immunohistochemistry. Data, presented as mean +/- SEM, were evaluated by analysis
      of variance with Bonferroni correction. RESULTS: There were no differences
      between groups in flow mechanics. Compared to RL, HTS animals (t = 90 minutes)
      displayed diminished PMN rolling and PMN adhesion to EC at time intervals beyond
      t = 0. There were no differences between the sham and HTS groups. Vascular
      leakage was 45% lower in HTS than in RL-resuscitated animals. Cremaster EC ICAM-1
      expression was similar in the two groups. CONCLUSIONS: Using HTS instead of RL to
      resuscitate hemorrhagic shock diminishes vascular permeability in vivo by
      altering PMN-EC interactions. HTS could serve as a novel means of
      immunomodulation in hemorrhagic shock victims, potentially reducing PMN-mediated
      tissue injury.

PMID- 12409671
TI  - From Cuthbertson to fast-track surgery: 70 years of progress in reducing stress
      in surgical patients.
AB  - OBJECTIVE: To evaluate the evolution of knowledge concerning the stress response
      in surgical patients and to determine the therapeutic benefit of stress reduction
      therapy. SUMMARY BACKGROUND DATA: The stress response in surgical patients is
      associated with tissue catabolism, organ failure, and prolonged recovery.
      Understanding the neural-hormonal basis for these events has stimulated efforts
      to attenuate these undesirable effects. A review of the results of these efforts
      is important for the application of stress reduction therapy and further
      improvement of surgical care. METHODS: Medline was searched from 1980 to the
      present using the terms "stress response," "neural-hormonal response," "fast
      track surgery," and "outcome in surgical patients." These papers were reviewed
      along with historical information relating to early descriptions of metabolic and
      stress responses in surgical patients. RESULTS: Improved understanding of the
      stress response in surgical patients has occurred over the past 70 years.
      Multiple examples of stress reduction associated with decreased morbidity and
      mortality are reported. CONCLUSIONS: Reduction of stress in surgical patients has
      improved outcome. The use of stress reduction techniques will continue to expand
      and contribute to the improvement of future surgical care.

PMID- 12409672
TI  - Interferon gamma modulates trauma-induced muscle wasting and immune dysfunction.
AB  - OBJECTIVE: To test the effect of burn injury in mice congenitally deficient in
      interferon gamma (IFN-gamma) and as well as in wild-type animals treated with IFN
      gamma neutralizing antibody. SUMMARY BACKGROUND DATA: The mechanisms underlying
      muscle wasting following burn trauma are incompletely characterized, although the
      hypercatabolic state is a consequence of increased proteasomal degradation.
      Concurrently, burn injury results in an immunocompromised state, and subsequent
      infections are the leading cause of morbidity and mortality in these patients.
      IFN-gamma, best conceptualized as a macrophage activating protein, modulates a
      variety of biologic pathways potentially relevant to muscle wasting and immune
      dysfunction. METHODS: Mice received either a 20% total body surface area burn or
      a control sham treatment. At days 1, 2, and 7 following treatment, skeletal
      muscle, peripheral blood, and spleen were harvested from both groups. Protein
      synthesis and degradation rates were measured. Lymphocyte subpopulation
      expression of major histocompatibility complex I (MHC I) molecules was assessed
      by flow cytometry, and proliferation capacity was measured using mixed lymphocyte
      reaction. RESULTS: IFN-gamma is critically involved in burn-induced weight loss;
      moreover, absence of IFN-gamma virtually abolished skeletal muscle
      hypercatabolism following burn injury. Lymphocyte proliferation and MHC I
      expression in the setting of burn trauma are also normalized in the absence of
      IFN-gamma. Both antigen presentation and proliferation functions are
      independently affected. CONCLUSIONS: IFN-gamma plays a fundamental role in
      mediating the hypercatabolic state of multiple cell types following burn trauma.

PMID- 12409673
TI  - Long-term venous complications after full-size and segmental pediatric liver
      transplantation.
AB  - OBJECTIVE: To assess the long-term incidence of venous complications, including
      portal vein and hepatic vein stenoses, in both whole cadaveric and reduced-size
      cadaveric and living related liver transplants in a pediatric population, and to
      assess the therapeutic modalities in the treatment of these lesions. SUMMARY
      BACKGROUND DATA: A shortage in appropriate-sized liver grafts for pediatric
      patients led to the use of segmental liver grafts, which became the predominant
      graft used in 325 of 600 (54%) transplants at the authors' institution. To assess
      the long-term impact of this strategy, the authors examined the incidence of late
      (>90 days) venous complications and the efficacy of all therapeutic
      interventions. METHODS: Six hundred pediatric liver transplants were performed in
      325 patients, with reduced-size or split (RSS; n = 207), living related (LRD; n =
      118), or full-size cadaveric grafts (FS; n = 275) from 1988 to 2000. All
      transplants identified with late portal vein or vena caval stenoses or thromboses
      from a cohort of 524 grafts with survival greater than 90 days were reviewed for
      demographics, symptoms, therapeutic intervention, recurrence, morbidity, and
      mortality. RESULTS: Fifty lesions were identified in 49 patients (38 portal vein
      and 12 hepatic vein-cava stenoses). Sex distribution was similar between portal
      vein and hepatic vein to cava, as was the mean patient age. Portal vein stenoses
      occurred in 32 LRD, 3 RSS, and 3 FS, while hepatic vein-cava stenoses occurred in
      2 LRD, 8 RSS, and 2 FS. In the 38 portal vein stenoses, 9 had prior perioperative
      portal vein and/or 5 hepatic artery thrombectomies. Portal vein stenoses were
      identified after bleeding (17/38), ascites (6/38), increased liver function tests
      (6/38), splenomegaly (5/38), or screening ultrasound (4/38). Portal vein stenosis
      was associated most often with cryopreserved vein for portal conduits. Excluding
      conduits, the incidence of late portal vein complications was reduced to 1%.
      Lesions became symptomatic at a mean of 50.8 +/- 184.2 months posttransplant. All
      patients underwent venous angioplasty with a 66% (25/38) success rate, while 7 of
      25 required further angioplasty and stenting. In the 13 unsuccessful
      angioplasties, 8 required surgical shunts for complete portal vein thrombosis.
      Recurrence occurred in 9 patients: all were amenable to stenting. Nine patients
      (24%) eventually died of sepsis (4) and surgical deaths at shunt or retransplant
      (5). Hepatic vein-cava stenoses occurred after a mean of 37.2 +/- 35.2 months,
      presenting with ascites (n = 10), increased liver function tests (n = 2), and
      splenomegaly (n = 2). All patients were diagnosed by venogram and managed by
      balloon dilatation alone (n = 6) or stented (n = 4), with an 80% (10/12) success,
      with two late recurrences amenable to repeat angioplasty or stenting. Long-term
      survival was 80% at 1 year. CONCLUSIONS: The use of segmental grafts without
      venous conduits is not associated with a significant rate of long-term venous
      complication. When late venous complications do occur, venous angioplasty and
      stenting are both a safe and effective management modality. If necessary, venous
      angioplasty may be repeated with the placement of a stent. When this is required,
      care must be taken to place the stent in a position where the metallic object
      will not interfere with future surgical manipulations should retransplantation be
      necessary.

PMID- 12409675
TI  - Biliary reconstruction and complications of right lobe live donor liver
      transplantation.
AB  - OBJECTIVE: To identify the possible reasons of failure of biliary reconstruction
      in right lobe live donor liver transplantation (LDLT) and to devise the best
      method of reconstruction and treatment strategy for the complications. SUMMARY
      BACKGROUND DATA: Right lobe LDLT was associated with a high biliary complication
      rate (15-64%) in the reported series. The causes of failure were not completely
      understood and the best treatment strategy has not been defined. METHODS: From
      1996 to 2001, 74 patients received right lobe LDLT. The operative procedures of
      the first 37 patients were critically reviewed to identify the possible reasons
      of leakage or stenosis from the anastomosis. The causes included right hepatic
      duct ischemia, double or triple hepaticojejunostomies, unrecognized branch of
      right hepatic duct, jejunal opening smaller than the size of right hepatic duct,
      and ductal plasty without division of newly created septum. The second 37
      patients had biliary reconstruction by a modified technique that preserved blood
      supply to the right hepatic duct and aimed at avoidance of risk factors. RESULTS:
      The overall complication rate decreased from 43% in the first 37 patients to 8%
      in the second 37 patients. There was no leakage from the anastomosis in the
      second group of patients. Percutaneous transhepatic biliary drainage (PTBD) for
      the biliary complications resulted in right portal vein and hepatic artery injury
      in four patients and accounted for mortality in three of them. To avoid
      complications from PTBD, three patients in the second group developing stenosis
      of hepaticojejunostomy had repeated hepaticojejunostomy without preoperative PTBD
      and recovered. CONCLUSIONS: With identification of risk factors and modification
      of the surgical technique, the complication rate of biliary reconstruction of
      right lobe LDLT could be reduced. Repeated hepaticojejunostomy without
      preoperative PTBD is the preferred approach once a complication develops.

PMID- 12409674
TI  - New insights into the interactions between T-cell costimulatory blockade and
      conventional immunosuppressive drugs.
AB  - OBJECTIVE: To determine the precise in vivo interaction between T-cell
      costimulatory blockade and conventional immunosuppression in transplantation.
      SUMMARY BACKGROUND DATA: Blocking B7 or CD154 T-cell costimulatory activation
      pathways prevents allograft rejection in small and large animal transplant models
      and is considered a promising strategy for clinical organ transplantation.
      METHODS: A fully MHC-mismatched vascularized mouse cardiac allograft model was
      used to test the interactions between anti-CD154 or CTLA4Ig monotherapy and
      conventional immunosuppressive drugs in promoting long-term graft acceptance. The
      frequency of alloreactive T cell was measured by ELISPOT. Chronic rejection was
      examined by histology. RESULTS: Cyclosporine, tacrolimus, and anti-IL-2R
      monoclonal antibody therapy abrogated the effect of a single-dose protocol of
      anti-CD154 therapy. In contrast, rapamycin acted synergistically with anti-CD154
      therapy in promoting long-term allograft survival. The addition of calcineurin
      inhibitors did not abolish this synergistic effect. Intense CD154-CD40 blockade
      by a multiple-dose schedule of anti-CD154 resulted in long-term graft survival
      and profound alloreactive T-cell unresponsiveness and overcame the opposite
      effects of calcineurin inhibitors. CTLA4Ig induced long-term graft survival, and
      the effect was not affected by the concomitant use of any immunosuppressive
      drugs. CONCLUSIONS: The widespread view that calcineurin inhibitors abrogate the
      effects of T-cell costimulatory blockade should be revisited. Sufficient
      costimulatory blockade and synergy induced by CD154 blockade and rapamycin
      promote allograft tolerance and prevent chronic rejection.

PMID- 12409676
TI  - Dose-dependent impairment of collagen deposition by topical granulocyte
      macrophage colony-stimulating factor in human experimental wounds.
AB  - OBJECTIVE: The authors studied the dose-dependent effect of topically
      administered granulocyte-macrophage colony-stimulating factor (GM-CSF) on the
      connective tissue response using an experimental repair model in surgical
      patients. SUMMARY BACKGROUND DATA: GM-CSF is primarily indicated in the treatment
      of immunosuppressed states. The effect of GM-CSF on the tissue repair response in
      humans is unclear. METHODS: Expanded polytetrafluoroethylene tubes were implanted
      subcutaneously and GM-CSF was applied locally at concentrations of 0.1 micro g/mL
      (total dose 0.4 micro g), 1.0 micro g/mL (4.0 micro g), 10 micro g/mL (40 micro
      g), or 75 micro g/mL (300 micro g) in one arm and saline alone (control) in the
      contralateral arm of 56 surgical patients. The content of collagen and total
      protein in the tubes was quantified as hydroxyproline and proline by high
      performance liquid chromatography 10 days after implantation. Cellularity and the
      number of procollagen I-positive fibroblasts were determined by histology and
      immunohistochemistry. The direct effects of GM-CSF on collagen production by and
      proliferation of wound fibroblasts cultured from granulation tissue were also
      measured. RESULTS: Local application of GM-CSF stimulated the inflammatory cell
      infiltration but reduced the number of fibroblasts in the granulation tissue. GM
      CSF treatment suppressed specifically and dose-dependently collagen deposition by
      up to 81%. A reduced collagen accumulation was also found in the control-treated
      arm at GM-CSF doses of 4 micro g or more, indicating a systemic depressive effect
      of GM-CSF on tissue repair. The selective downregulation of collagen production
      by GM-CSF was also found in wound fibroblasts in vitro. CONCLUSIONS: Inhibition
      of fibrogenesis with GM-CSF intervention may impair tissue repair processes
      during surgery.

PMID- 12409677
TI  - ESPAC-1 trial of adjuvant therapy for resectable adenocarcinoma of the pancreas.

PMID- 12409678
TI  - Patient evaluation and management with selective use of magnetic resonance
      cholangiography (MRC) and endoscopic retrograde cholangiopancreatography (ERCP)
      before laparoscopic cholecystectomy (LC).

PMID- 12409679
TI  - Optimizing outcomes in depression: focus on antidepressant compliance.
AB  - Major depressive disorder is a chronic and recurrent illness that is associated
      with significant morbidity and mortality. Patients frequently experience
      recurrent depressive episodes that are of longer duration and increased severity
      and which are less responsive to treatment than the index episode. Despite the
      highly prevalent nature of the illness, depression is frequently unrecognized and
      undertreated. Compliance with antidepressant medication is essential to
      consolidate treatment response and prevent relapse and recurrence. However,
      compliance with antidepressant medication is poor. Education of the patient and
      physician regarding the nature of depression and its treatment is essential for
      improving patient compliance. Although psychological mechanisms are a major
      factor affecting patient compliance, speed of onset of action and poor
      tolerability of antidepressant medication also have a considerable influence on
      patient compliance. The newer antidepressants, such as selective serotonin
      reuptake inhibitors, nonselective serotonin-norepinephrine reuptake inhibitors,
      and the selective norepinephrine reuptake inhibitors, are better tolerated than
      tricyclic antidepressants, possibly resulting in improved compliance and
      treatment outcome.

PMID- 12409680
TI  - Two items on the Hamilton Depression rating scale are effective predictors of
      remission: comparison of selective serotonin reuptake inhibitors with the
      combined serotonin/norepinephrine reuptake inhibitor, venlafaxine.
AB  - Recent studies have shown that the use of subscales derived from the Hamilton
      Depression (HAM-D) rating scale are just as reliable and enhance sensitivity for
      detecting response and remission after antidepressant treatment. The purpose of
      the present study was to determine if the responses on two items of the HAM-D
      scale, Depressed Mood (item 1) and Psychic Anxiety (item 10), were predictive of
      remission of depression in placebo-controlled studies following treatment with
      venlafaxine or selective serotonin reuptake inhibitors (SSRIs). Data from eight
      active- and placebo-controlled studies consisting of 2027 subjects who met the
      DSM-III-R/-IV criteria for major depressive disorder were analysed. Three
      treatment groups were compared: venlafaxine (n =843), SSRI (either fluoxetine,
      paroxetine or fluvoxamine, n=743) and placebo (n=441). Treatment duration was 6-8
      weeks. Patients who scored zero on the depressed mood and the psychic anxiety
      items of the HAM-D17 scale were designated as responders. These two scores were
      also combined to create an Absence of Depressive and Anxious Mood (ADAM) score.
      Between-group rate comparisons in outcome measures were carried out using
      Fisher's exact test and logistic regression models. Venlafaxine treatment
      improved depressed mood, psychic anxiety and ADAM scores after 2 weeks with
      greater efficacy than treatment with SSRIs or placebo. ADAM scores could also
      predict the odds ratio of a patient achieving a clinical remission (defined as
      total HAM-D17 score </= 7). The present results demonstrate that using just two
      items of the HAM-D17 can be very useful in assessing treatment response,
      differentiating between treatment groups and predicting remission rates.

PMID- 12409681
TI  - Relative sensitivity of the Montgomery-Asberg Depression Rating Scale, the
      Hamilton Depression rating scale and the Clinical Global Impressions rating scale
      in antidepressant clinical trials.
AB  - Although early antidepressant clinical trials simply relied on a clinician's
      judgment as to whether a depressed patient clinically improved or not, the
      Hamilton Depression (HAM-D) rating scale has become the 'gold standard' to assess
      the efficacy of new antidepressants. The alternative Montgomery-Asberg Depression
      Rating Scale (MADRS) has not achieved general acceptance. However, its ease of
      use warrants evaluation as to whether it is comparable to HAM-D in its
      sensitivity in detecting antidepressant-placebo differences in antidepressant
      clinical trials. A retrospective chart review was performed on the records of 208
      depressed adult patients that participated in eight randomized, placebo
      controlled, double-blind antidepressant clinical trials at the Northwest Clinical
      Research Center between 1996 and 2000. We compared the effect sizes of the HAM-D,
      MADRS and Clinical Impressions Rating Scale (CGI-S for severity and CGI-I for
      improvement) for patients assigned to placebo or an established antidepressant.
      The effect size (measured as the mean change in rating with antidepressants minus
      the mean change for placebo divided by the pooled SD of change, adjusted for age,
      gender and initial scores) was 0.49 with MADRS, 0.53 with HAM-D, 0.55 with CGI-S
      and 0.59 with CGI-I. The four rating scales had similar effect sizes regardless
      of the type of antidepressant evaluated. These data suggest that MADRS is as
      sensitive an instrument as HAM-D for detecting antidepressant efficacy in
      clinical trials. Thus, MADRS may be a desirable tool in large-scale, pivotal
      antidepressant clinical trials.

PMID- 12409682
TI  - Treatment of severely psychotic inpatients with schizophrenia: olanzapine versus
      other antipsychotic drugs.
AB  - Nine hundred and ten schizophrenic inpatients suffering from acute psychotic
      episodes were included in a naturalistic study. Patients were prescribed
      treatment with olanzapine (OLZ) or with typical antipsychotic (TYP) drugs.
      Patients receiving another atypical antipsychotic were excluded. Of the whole
      sample, 483 (53.4%) were treated with olanzapine and 421 (46.6%) with typical
      antipsychotics. Three specific subpopulations of greater severity were defined:
      patients with prominent psychotic symptoms, agitated patients, and patients
      initially treated with intramuscular (i.m.) medication because of their acute
      clinical condition. Severity of illness was assessed using the Clinical Global
      Impression (CGI) scale for severity, the Brief Psychiatric Rating Scale (BPRS)
      and the Nursing Observational Scale for Inpatient Evaluation. Baseline
      differences were adjusted per data analysis. The mean change from baseline to
      endpoint of overall symptomatology (total BPRS score) was significantly greater
      in the olanzapine group compared to the typical antipsychotic-treated group, both
      in the sample of patients with prominent positive symptoms (P < 0.001) and in the
      sample of agitated patients (P =0.015). Significant differences were also found
      in BPRS positive scores, BPRS negative scores and CGI scores in these two
      populations. Patients who had received previous i.m. drugs showed no
      statistically significant differences in symptomatic improvement between both
      treatments groups, except for a more favourable response of BPRS negative
      subscores in the olanzapine group (P =0.015). The results suggest that olanzapine
      may be considered as a first line treatment for severely psychotic inpatients
      with schizophrenia.

PMID- 12409683
TI  - A double-blind, placebo-controlled multicentre study of memantine in mild to
      moderate vascular dementia (MMM500).
AB  - The aim of the reported trial was to investigate the safety and efficacy of
      memantine in mild to moderate vascular dementia (VaD). This was a 28-week, double
      blind, parallel, randomized controlled trial of memantine 20 mg daily versus
      placebo which was conducted in 54 centres in the UK. Memantine is a
      uncompetitive, moderate affinity N-methyl-D-aspartate receptor antagonist.
      Patients with a diagnosis of probable VaD and Mini Mental State Examination total
      scores between 10 and 22 were eligible for inclusion. Primary efficacy parameters
      were the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) and
      the Clinical Global Impression of Change (CGI-C). A total of 579 patients were
      randomized and 548 patients with at least one post-baseline efficacy assessment
      qualified for the intent-to-treat analysis. At endpoint, memantine was shown to
      improve cognition relative to placebo in VaD: the change of ADAS-cog from
      baseline differed by a mean of -1.75 points (95% confidence intervals -3.023 to 
      0.49) and a median of 2 points between the two groups, while CGI-C ratings showed
      no significant differences between treatment groups. A total of 77% of all
      memantine-treated patients experienced adverse event, versus 75% of the placebo
      treated patients, dizziness being the most frequent adverse event (11% versus 8%,
      respectively). Memantine was well tolerated and safe.

PMID- 12409684
TI  - Ropinirole for antidepressant-induced sexual dysfunction.
AB  - Sexual dysfunction is a relatively common side-effect of antidepressants,
      occurring in approximately one-half of patients, and is associated with
      significant distress and treatment non-compliance. Dopaminergic agents have been
      reported to be helpful for the treatment of antidepressant-induced sexual
      dysfunction and, in this report, we examined the efficacy of the dopamine agonist
      ropinirole for this indication. Thirteen patients (three women, 10 men), aged
      42.6 +/- 7.7 years, who reported sexual dysfunction on a stable dose of
      antidepressant, were treated openly with ropinirole initiated at 0.25 mg/day and
      titrated up to 2-4 mg/day over 4 weeks, as tolerated. Ten of the 13 took
      ropinirole for at least 4 weeks, one discontinued due to an adverse event and two
      because of lack of response. Sexual dysfunction, as assessed by the Arizona
      Sexual Experience Scale scores, was reduced from 18.8 +/- 3.6 to 13.8 +/- 4.3
      after 4 weeks on ropinirole at a mean dose of 2.1 mg/day. Overall, seven of 13
      patients (54%) were rated as responders on the Clinical Global Impression of
      Improvement Scale. The addition of ropinirole may represent a potentially useful
      treatment strategy for antidepressant-induced sexual dysfunction.

PMID- 12409685
TI  - Somatization as a predictor of medication discontinuation due to adverse events.
AB  - Medication discontinuation due to intolerable side-effects remains a significant
      clinical problem in the treatment of depression. We were unable to locate studies
      which found predictors of medication cessation due to side-effects. We posited
      that an identifiable subgroup of medically healthy, depressed adults who
      discontinued medication because of adverse events would have higher pre-treatment
      somatic symptoms than patients who completed a course of treatment. The sample (n
      =940) was drawn from a series of double-blind, placebo-controlled studies of
      antidepressants (imipramine, phenelelzine, L-deprenyl, mianserin and
      desipramine). Within the medication group, side-effect dropouts had more somatic
      symptoms than study completers and those who discontinued treatment for
      miscellaneous reasons. Within the placebo-treated group, the small number of
      subject who discontinued treated because of side-effects precluded valid
      statistical analyses, but the findings were in the same direction as those in the
      medication group. Clearly, further research is required to determine whether
      these results, obtained from a series of university-based clinical trials with
      healthy subjects, are generalizable to patients with significant comorbid medical
      and/or psychiatric disorders, treated with newer antidepressants agents in a
      general clinical practice setting.

PMID- 12409686
TI  - Mirtazapine in social anxiety disorder: a pilot study.
AB  - Fourteen patients with social anxiety disorder (generalized type), according to
      DSM-IV criteria, were treated with mirtazapine 30 mg for 12 weeks. Twelve
      patients completed the study. Two patients (14.3%) dropped out due to side
      effects. Generally, mirtazapine was well tolerated. Five out of 12 patients
      (41.7%) were classified as responders, based on a Clinical Global Improvement
      score of 1 or 2 and a reduction of the Liebowitz Social Anxiety Scale (LSAS) of
      40%. The mean total score on the LSAS, as well as the anxiety and avoidance
      subscores, decreased significantly. This open pilot study suggests that further
      investigations are warranted to prove the efficacy of mirtazapine in generalized
      social anxiety disorder.

PMID- 12409687
TI  - Dysphoric mania induced by high-dose mirtazapine: a case for 'norepinephrine
      syndrome'?
AB  - The antidepressant mirtazapine antagonizes central presynaptic alpha2-adrenergic
      auto- and heteroreceptors resulting in increased central norepinephrine and
      serotonin activity. Histamine H2 receptors are also antagonized, as are
      postsynaptic serotonin 5-HT2 and 5-HT3 receptors, leading to serotonergic
      activity primarily via 5-HT1A receptors. Based on the case report of a patient
      who developed mania with higher than recommended dosage of mirtazapine, we review
      the literature on the atypical nature of manic symptoms with mirtazapine. Eight
      subjects, including those in our study, were identified as having developed
      mirtazapine-induced mania with atypical features, consisting of dysphoria,
      irritability, insomnia, psychomotor agitation and abnormal gait. Predisposing
      features may have included the presence of underlying brain dysfunction and
      certain selective serotonin reuptake inhibitor-mirtazapine combinations.
      Dysphoric mania with atypical features may be induced by mirtazapine, providing
      support for a common hypothesis such as 'central norepinephrine hyperactivity' as
      the basis for development of mania with mirtazapine.

PMID- 12409689
TI  - Magnetic resonance imaging of pediatric musculoskeletal trauma.
AB  - Musculoskeletal injury in children is common and can lead to lifelong disability.
      The unique ability of magnetic resonance imaging (MRI) to visualize the
      cartilaginous ends of growing bones, bone marrow, and supporting soft-tissue
      structures makes it ideally suited for evaluation of injury in these patients and
      the complicating growth disturbance. This article reviews the role of MRI in
      several common pediatric musculoskeletal injuries and their related growth
      disturbances. A review of normal musculoskeletal growth and enchondral
      ossification and the magnetic resonance signal characteristics of the growing
      skeleton is provided as necessary background. The discussion includes MRI
      features of physeal fractures and posttraumatic growth arrest, epiphyseal and
      osteochondral injuries, stress fractures, avulsion injuries, and musculoskeletal
      soft-tissue injuries.

PMID- 12409690
TI  - Magnetic resonance imaging of benign bone lesions: cysts and tumors.
AB  - A benign bone lesion may have a typical appearance on plain radiographs. This is
      the case with benign cortical defects and osteochondroma. With most other
      lesions, cross-sectional imaging is needed to complete the study of the tumor.
      The nidus of osteoid osteoma is well demonstrated on computed tomography, but
      magnetic resonance imaging also will show the nidus in most cases. Magnetic
      resonance imaging is considered the modality of choice for evaluation of other
      benign musculoskeletal lesions because it is highly sensitive to changes in the
      signal intensity of bone marrow and adjacent soft tissues. It provides useful
      information for diagnosis of the lesion as in primary or secondary aneurysmal
      bone cyst, chondroblastoma, osteoblastoma, fibrous dysplasia, and osteofibrous
      dysplasia, and it helps differentiate these lesions from osteomyelitis,
      Langerhans' cell histiocytosis, and stress fracture. Bone scanning is most useful
      for depicting multiple silent lesions as may be seen in multiple
      osteochondromatosis, nonossifying fibromas, and polyostotic fibrous dysplasia.

PMID- 12409691
TI  - Primary skeletal neoplasms: osteosarcoma and ewing sarcoma.
AB  - The care for children and adolescents with malignant bone tumors such as
      osteosarcoma and Ewing sarcoma will be improved by the magnetic resonance imager
      that can recognize the tumor early in its course and can stage it correctly for
      proper chemotherapy and local control. This can be accomplished by attention to
      the proper magnetic resonance imaging technique, recognition of the magnetic
      resonance appearance, and knowledge of the prognostic factors at diagnosis.
      Determination of response on follow-up static and dynamic contrast-enhanced
      magnetic resonance imaging and knowledge of optimal methods to determine
      recurrent tumor will improve the outcome for these children.

PMID- 12409692
TI  - Magnetic resonance imaging of congenital, inflammatory, and infectious soft
      tissue lesions in children.
AB  - Magnetic resonance imaging has the advantages of multiplanar capability and high
      degree of tissue differentiation. It is useful for assessing the extent of soft
      tissue abnormalities, such as vascular malformations, inflammatory and infectious
      processes, muscle disorders, and limb hypertrophy. Magnetic resonance imaging is
      sensitive to the presence of water and edema and is a good indicator for early
      diagnosis of inflammation and its level of activity. Fat-saturation techniques,
      including T2-weighted sequences and inversion recovery imaging, optimize
      diagnostic accuracy. T1-weighted images are good at defining the distribution and
      proportion of fat in the body, so they are useful in evaluating syndromes of the
      limbs, including vascular malformations, as well as lipoatrophy-lipodystrophy
      conditions. Magnetic resonance imaging provides guidance for efficient tissue
      biopsy. It allows comprehensive pretherapeutic assessment of soft-tissue vascular
      anomalies. It constitutes a good modality for following up the natural history of
      soft-tissue disorders during childhood.

PMID- 12409693
TI  - Magnetic resonance imaging of soft-tissue tumors in children.
AB  - Magnetic resonance imaging (MRI) has become an important diagnostic tool in the
      detection and characterization and local anatomic staging of soft-tissue tumors
      in children. This article outlines some of the procedural issues unique to the
      pediatric population.

PMID- 12409694
TI  - Magnetic resonance imaging of the pediatric knee.
AB  - Magnetic resonance imaging (MRI) is an excellent modality for imaging the
      pediatric knee because of its superb soft-tissue contrast, multiplanar
      capability, and lack of ionizing radiation. The knee is the most common joint
      imaged by MRI in the pediatric population. The majority of studies are performed
      on older children or adolescents with pain and/or known trauma. There are
      variations of injury and patterns of injury that are unique to children. The knee
      of a child also may be studied by MRI for other indications, including tumor,
      inflammatory disease, and developmental abnormalities. It is important to have a
      systematic approach to analysis of the knee MR images. Analysis should include
      individual attention to bones, articular cartilage, muscles and tendons, soft
      tissues, neurovascular bundle, joint space, fluid collections, ligaments, and
      menisci.

PMID- 12409695
TI  - Selective application of fundoplication during laparoscopic heller myotomy
      ensures favorable outcomes.
AB  - We propose that selective fundoplication during laparoscopic Heller myotomy
      achieves optimal outcomes. Fundoplication was applied selectively in 21 of 100
      patients undergoing laparoscopic Heller myotomy with hiatus hernia, patulous
      esophageal hiatus, or intraoperative perforation. Dysphagia and heartburn
      incidence and severity in patients undergoing myotomy with or without
      fundoplication were compared before and after myotomy. Median follow-up was 19
      months and was similar for both groups. Preoperative symptoms were similar for
      both groups of patients and showed significant improvement following myotomy with
      or without fundoplication. As well, there were no significant differences in
      postoperative dysphagia (26% vs. 14%), dysphagia score (1.1 +/- 1.4 vs. 0.8 +/-
      1.3), heartburn (21% vs. 27%), or heartburn score (0.9 +/- 1.5 vs. 1.4 +/- 1.6).
      Overall improvement was seen in 86% of patients undergoing myotomy with
      fundoplication and in 97% without fundoplication (P = 0.06). Selective
      application of fundoplication during laparoscopic Heller myotomy promotes optimal
      outcomes.

PMID- 12409696
TI  - Long-term gastrointestinal symptoms after laparoscopic nissen fundoplication.
AB  - Patients who have undergone fundoplication may be at risk for recurrent
      gastroesophageal reflux and may experience postoperative gastrointestinal
      symptoms. We investigated the long-term symptomatic outcome after laparoscopic
      Nissen fundoplication. Between 1993 and 1998 we treated 60 patients with
      laparoscopic fundoplication for gastroesophageal reflux disease. Signs of
      recurrence and gastrointestinal symptoms were assessed in 55 (92%) patients after
      a minimum follow-up of 1 year (median: 3.6 years). At follow-up, 52 patients
      (95%) were completely free of reflux symptoms. Mild gastrointestinal symptoms
      (flatulence, 60%; early satiety, 51%; meteorism, 42%; inability to vomit, 27%;
      dysphagia, 25%; diarrhea, 25%; epigastric pain, 24%; inability to belch, 22%)
      were found in a total of 51 patients (93%). Disturbing symptoms occurred in only
      9 patients (16%). Laparoscopic Nissen fundoplication results in excellent control
      of gastroesophageal reflux disease at long-term follow-up. Despite a high rate of
      gastrointestinal symptoms, patient satisfaction showed the operation to be
      effective and well tolerated.

PMID- 12409697
TI  - The learning curve in ambulatory laparoscopic cholecystectomy.
AB  - Whether laparoscopic cholecystectomy (LC) should be performed as an outpatient
      procedure is still under discussion. The aim of this study was to evaluate the
      influence of surgeon's experience in ambulatory management of LC. Three hundred
      eighty-one consecutive elective LCs were planned as outpatient procedures. An
      anesthetic protocol that includes free-opiates anesthesia, preemptive analgesia,
      and somatovisceral blockade was used. Percentages of ambulatory, overnight, and
      admitted patients were evaluated, and time series variation was also analyzed.
      Postoperative pain, nausea and vomiting incidence, postoperative recovery, and
      complications were examined. Two hundred ninety-one patients were strictly
      ambulatory (76.3%), 71 (18.6%) required overnight admission, and 19 (4.9%) were
      admitted. Percentage of ambulatory LC increased from 22% to 90% in 4 years of
      experience. Readmission rate was 0.01%. Free-opiates anesthetic techniques,
      preemptive analgesia, and somatovisceral blockade allowed us to obtain over 90%
      of ambulatory LC. The learning curve related to postoperative evaluation is
      crucial in obtaining those results.

PMID- 12409698
TI  - Gasless laparoscopic hepatic resection for cirrhotic patients with solid liver
      tumors.
AB  - Gasless laparoscopic hepatic resection with a 5-cm minilaparotomy was performed
      in 10 cirrhotic patients with small liver tumors. To maintain good visualization
      and working space during hepatic resections, we developed a simple retraction
      system. Mean operative time and blood loss were 291 minutes and 249 mL,
      respectively. No blood transfusion was required during the operations. No serious
      complications occurred such as gas embolism. Our laparoscopic procedures had
      various advantages. Blood, smoke, and water vapor could be aspirated by suction
      without disturbance of the visual field. There was no risk of gas embolism. It
      was possible to use conventional instruments through the ports or the wound made
      by a minilaparotomy. Hemostasis therefore could be performed easily. The
      procedure could be applicable to cirrhotic patients with some complications. This
      laparoscopic procedure is recommended for patients with small HCCs associated
      with liver cirrhosis who are not candidates for major hepatectomy.

PMID- 12409699
TI  - Splenic artery embolization using contour emboli before laparoscopic or
      laparoscopically assisted splenectomy.
AB  - The present study assessed preoperative splenic artery embolization using
      spherical embolic material, super absorbent polymer microspheres (SAP-MS), before
      laparoscopic or laparoscopically assisted splenectomy. Distal splenic artery
      embolization using 250 to 400 microm SAP-MS was performed in nine cases with ITP
      and in seven cases with the other diseases with splenomegaly. Laparoscopic or
      laparoscopically assisted splenectomies, including a hand-assisted procedure and
      the procedure involving left upper minilaparotomy, were done 2 to 4 hours after
      embolization. Conversion to traditional laparotomy was not required in any of the
      16 cases, while conversion to 12-cm laparotomy was required in one case with
      massive splenomegaly. Mean operating time was 161 minutes, and mean
      intraoperative blood loss was 290 mL. No major postoperative complications were
      identified, and only one patient reported postembolic pain before surgery.
      Preoperative splenic artery embolization using painless embolic material, SAP-MS,
      would be effective for easy and safe laparoscopic or laparoscopically assisted
      splenectomy.

PMID- 12409700
TI  - Early experience with laparoscopic ileal pouch-anal anastomosis for ulcerative
      colitis.
AB  - The purpose of this study was to describe our minimally invasive technique and
      outline perioperative and medium-term outcomes in patients undergoing
      laparoscopic ileal pouch-anal anastomosis (LIPAA) for ulcerative colitis. Data
      were obtained from a prospectively collected database of 13 LIPPA procedures
      performed for ulcerative colitis between May 1994 and November 2000. Medium-term
      quality-of-life follow-up was obtained by telephone interview. Eight males and
      five females had an LIPAA performed, all of whom had previously undergone total
      abdominal colectomy with ileostomy. Median operative time was 255 minutes (range,
      200-398 minutes) with one conversion (8%) due to adhesions. There were no deaths
      or intraoperative complications; however, six patients experienced seven
      postoperative complications within 30 days of final closure of defunctioning
      ileostomy (two leaks, two wound infections, one pulmonary embolus, and two
      reoperations for small bowel obstruction). Median length of stay was 7 days
      (range, 5-13 days). Median follow-up was 24 months (range, 6-66 months). The
      median number of day and night bowel movements was 6.0 (range, 3-10) and 1.0
      (range, 0-3), respectively, with five patients requiring medication to control
      frequency. None had incontinence of stool or retrograde ejaculation; however, one
      had occasional incontinence of gas, three had occasional nocturnal soiling, and
      one was impotent. Three patients (23%) had pouchitis, all treated successfully
      with oral antibiotics. All patients were satisfied with the outcome of their
      operation and all preferred their pouch to previous ileostomy. Patients reported
      their overall social, emotional, and physical well being to be satisfactory to
      excellent. Results of the SF-36, a generic quality-of-life survey, were similar
      to those from studies of patients following an open pelvic pouch procedure. The
      LIPAA is technically feasible in experienced centers. We believe that the
      technique is still evolving and that more time and experience is required to
      refine the procedure.

PMID- 12409701
TI  - Prevention of adhesions by bioresorbable tissue barrier following laparoscopic
      intraabdominal mesh insertion.
AB  - Intraabdominal adhesions represent a significant problem because of the morbidity
      associated with adhesive disease, including small bowel obstruction, difficulties
      in reoperative surgery, and possibly chronic pain. Coating solution of sodium
      hyaluronate (Sepracoat; Genzyme Production-Surgical Products, Cambridge, MA) was
      studied in New Zealand white rabbits to determine its potential role for
      prevention of postoperative adhesions following laparoscopic intraabdominal mesh
      insertion. A 2-cm polypropylene mesh was inserted laparoscopically to the left
      iliac fossa and fixed to anterior abdominal wall using a single prolen suture.
      Group 1 (n = 10) acted as the control group. Mesh was coated using 4% sodium
      hyaluronate in phosphate buffered saline (Sepracoat) in Group 2 (n = 10).
      Fourteen days later, all animals underwent diagnostic laparoscopy, and findings
      were recorded. All animals then were killed, the abdominal cavities were
      inspected, and adhesions were graded from 0 to 4. All meshes were removed and
      sent for histologic examination. The degrees of inflammation, fibrosis, and
      congestion were scored. No adhesions were seen on trocar sites on both groups.
      Eight of 10 animals in the control group and 5 of 10 animals in the study group
      had intraabdominal adhesions. The scoring of adhesions revealed that study group
      had only one (10%) significant adhesion, whereas the control group had eight
      (80%; < 0.001). Our study suggests that the Sepracoat reduces the incidence and
      severity of abdominal adhesions following laparoscopic mesh insertion and should
      be considered as a prophylactic agent, especially in those undergoing
      laparoscopic transabdominal mesh repair for hernia.

PMID- 12409702
TI  - The effect of the pneumoperitoneum on the peritoneal defense mechanisms in
      diabetic rats.
AB  - To investigate the effects of pneumoperitoneum on the peritoneal defense
      mechanism induced by streptozocin infusion during laparoscopic surgery in
      diabetic rats and to show the importance of regulation of diabetes for peritoneal
      defense mechanisms. One hundred twenty-six Sprague-Dawley male rats were
      allocated into six groups each consisting of 21 rats: group 1, nondiabetic sham
      laparotomy (control); group 2, nondiabetic pneumoperitoneum (control); group 3,
      uncontrolled diabetes plus sham laparotomy; group 4, controlled diabetes plus
      sham laparotomy; group 5, uncontrolled diabetes plus pneumoperitoneum; and group
      6, controlled diabetes plus pneumoperitoneum. Diabetes was constituted by
      intraperitoneal infusion of one dose of 60 mg/kg streptozotocin, and diabetes was
      regulated (in groups 4 and 6) by subcutaneous injection of 10 IU/kg insulin in
      the morning and evening after the blood glucose measurements since the fourth
      day. Peritoneal fluid samples were taken at the zero, second, and sixth hours
      after sham laparotomy for groups 1, 3, and 4 and after pneumoperitoneum for
      groups 2, 5, and 6 on the seventh day. Total peritoneal cell count, antibacterial
      activity of the peritoneal fluid, and types of phagocytic cells in the peritoneal
      fluid were assessed. Peritoneal cell count was found to be lower in uncontrolled
      diabetes due to high blood glucose levels (>200 mg/dL), which led to slow
      migration of phagocytic cells into the peritoneum. Pneumoperitoneum had augmented
      the effect on phagocytic cell migration to the peritoneum compared with the sham
      laparotomy in controlled diabetic rats. Uncontrolled and controlled diabetes have
      adverse effects on peritoneal defense mechanism killing functions by interfering
      with the antimicrobial activity of peritoneal fluid.

PMID- 12409703
TI  - Laparoscopic devine exclusion gastroenterostomy for the palliation of
      unresectable and obstructing gastric carcinoma.
AB  - The Devine exclusion gastroenterostomy is an effective procedure for the relief
      of gastric outlet obstruction in patients with unresectable carcinoma of the
      gastric antrum. We report on the successful laparoscopic application of this
      technique in two male patients aged 61 and 76 years with unresectable and
      obstructing antral gastric cancer. The operating time was 90 minutes for each
      patient, and the postoperative hospital stay was 3 and 4 days, respectively.
      There were no delays in gastric emptying and no recurrences of gastric outlet
      obstruction until the time of death, 3.5 and 9 months postoperatively,
      respectively. The laparoscopic approach to a Devine exclusion gastroenterostomy
      is a safe and effective minimally invasive approach to the palliation of
      unresectable obstructing gastric carcinoma.

PMID- 12409704
TI  - Laparoscopic percutaneous endoscopic gastrostomy removal in a patient with buried
      bumper syndrome: a new approach.
AB  - Buried bumper syndrome is an uncommon long-term complication of gastrostomy
      tubes. The overgrowth of the gastric mucosa over the internal bumper of the tube
      often is symptomatic and leads to mechanical failure of feed delivery and
      peritubal discharge. Whilst removal of the buried internal bumper has been
      accomplished endoscopically in some cases, it is traditionally removed at
      laparotomy. This is the first description, however, of a successful laparoscopic
      removal of a percutaneous endoscopic gastrostomy tube in a patient with a buried
      bumper syndrome. The patient made an uneventful recovery and was discharged home
      on the third postoperative day. The operative technique is described, and its
      merits are discussed.

PMID- 12409705
TI  - Acalculous gangrenous cholecystitis in a young adult: a gastrointestinal
      manifestation of polyarteritis nodosa.
AB  - The authors report a rare case of an acalculous gangrenous cholecystitis due to a
      form of vasculitis, polyarteritis nodosa (PAN). An 18-year-old man was admitted
      to the hospital with worsening symptoms of nausea, fever, intermittent abdominal
      pain, and high blood pressure that lasted for 4 days. After a sequential work-up,
      a diagnostic laparoscopy was performed and revealed a gangrenous cholecystitis
      with spontaneous perforation. Laparoscopic cholecystectomy was performed
      successfully. The patient had an uneventful recovery period and was discharged on
      the second postoperative day. The histopathologic examination showed gangrenous
      and perforated gallbladder, vasculitis, and clues of PAN. The purpose of this
      article is to describe a rare condition in a young patient that was diagnosed and
      treated with minimally invasive surgery.

PMID- 12409706
TI  - Esophageal intubation with duodenoscope in the presence of pharyngeal pouch by a
      guidewire and catheter-guided technique.
AB  - Esophageal perforation can occur during blind intubation with a side-viewing
      duodenoscope during endoscopic retrograde cholangiopancreatogram (ERCP) in
      patients with pharyngeal or esophageal anomalies. We describe a case of difficult
      intubation during an ERCP due to an asymptomatic and unsuspected pharyngeal pouch
      (Zenker's diverticulum). The side-viewing duodenoscope was withdrawn once
      resistance was encountered during intubation, and a forward-viewing gastroscope
      was inserted carefully under direct vision to evaluate the upper esophagus. After
      the diagnosis was made, intubation of the duodenoscope was performed by
      exchanging scopes over a guidewire. Subsequent ERCP with sphincterectomy and
      stone removal was uneventful. We caution that a side-viewing duodenoscope should
      be withdrawn once resistance is encountered during blind intubation during ERCP.
      Our technique minimizes patient discomfort and is rapid and easy to perform. In
      addition, no extra device such as an overtube is required.

PMID- 12409707
TI  - First histologic confirmation of the diagnosis made by the new wireless-capsule
      endoscopy.
AB  - Wireless-capsule endoscopy is a new painless technique for endoscopic imaging of
      the small bowel. A 63-year-old male with iron deficiency anemia and
      thrombocytosis and extensive negative workup was examined twice with the capsule
      and was found to have multiple bluish polypoid lesions with a villous-appearing
      texture. Some of these lesions actually were seen to be bleeding. This is the
      first time that we have obtained histologic evidence for lesions seen only on the
      video-capsule endoscopy. The lesion was reached by deep ileoscopy via
      colonoscopy. On histologic analysis, there was acute and chronic ileitis.

PMID- 12409708
TI  - Laparoscopic resection of an appendiceal mucocele.
AB  - A 78-year-old man was incidentally discovered to have an asymptomatic right lower
      quadrant abdominal mass during physical examination for influenza. CT scan of the
      abdomen revealed a cystic sausage-shaped lesion arising from the cecum.
      Diagnostic laparoscopy revealed an appendiceal mucocele. There was no ascites or
      metastatic peritoneal nodules. Laparoscopic excision of the unruptured
      appendiceal mucocele was achieved. Histopathologic examination of the mucocele
      showed epithelial dysplasia, a feature diagnostic of a mucinous cystadenoma. The
      patient was discharged on postoperative day one and recovered uneventfully. No
      analgesic was required after surgery. The patient remained well and symptom-free
      during the follow-up period. The laparoscopic approach allows diagnostic
      laparoscopy and appendectomy to be performed, and confers the advantages of
      minimal-access surgery, including the avoidance of a large incision, a better
      cosmetic outcome, and a short convalescent period.

PMID- 12409709
TI  - Laparoscopic accessory splenectomy with intraoperative gamma probe localization
      for recurrent idiopathic thrombocytopenic purpura.
AB  - Laparoscopic excision of retained splenic tissue has been described as a
      treatment of recurrent hematologic disease after formal splenectomy. It is
      associated with a shorter hospital stay, more rapid recovery, and lower or
      equivalent morbidity compared with open surgery. However, intraoperative
      identification of residual splenic tissue remains difficult, particularly when
      preoperative computed tomography or magnetic resonance imaging results are
      unremarkable. It has been suggested that the laparoscopic approach has a lower
      success rate due to the loss of tactile feedback. We report a case of successful
      laparoscopic excision of retained splenic tissue using technetium sulfur colloid
      injection and intraoperative gamma probe localization in a patient with recurrent
      idiopathic thrombocytopenic purpura, 12 years after open splenectomy. This
      represents the first report of this intraoperative adjunctive measure for the
      laparoscopic identification and excision of functional accessory splenic tissue.

PMID- 12409710
TI  - Laparoscopy is useful in the diagnosis and management of foramen of Morgagni
      hernia in children.
AB  - Foramen of Morgagni hernia is a rare form of congenital diaphragmatic hernia. We
      report the use of laparoscopy to diagnose and manage suspected foramen of
      Morgagni hernias in children. Cardiophrenic masses were seen on chest radiography
      in two asymptomatic children aged 1 and 3 years. Further radiologic workup was
      nondiagnostic. Laparoscopy was performed in both children, and the foramen of
      Morgagni hernias were immediately identified. Laparoscopic repair was performed
      on one of the children. Both children had uneventful postoperative courses, were
      discharged home early, and had no evidence of recurrence at the 6-month follow-up
      examination. Laparoscopy is a safe and effective technique to diagnose and
      potentially repair foramen of Morgagni hernias. We recommend the use of this
      modality as the primary diagnostic evaluation in infants and children with
      suspected foramen of Morgagni hernias.

PMID- 12409711
TI  - Laparoscopic excision of a lower posterior mediastinal paraspinal mass: technique
      and feasibility of the laparoscopic approach.
AB  - Paravertebral and paraspinal tumors in the posterior mediastinum are
      predominantly neurogenic in origin. The treatment comprises surgical extirpation.
      We report a case of a 40-year-old man with a 2-month history of pain epigastrium,
      radiating to the left scapula, and marked (10 kg) weight loss. Preoperative CT
      scan showed a paraspinal mass 8 cm in diameter at the level of the tenth thoracic
      vertebra. A CT scan-guided fine-needle aspiration cytologic analysis revealed the
      mass to be of neurogenic origin. Transabdominal laparoscopic excision of this
      lower posterior mediastinal neurogenic tumor was attempted and accomplished
      safely. The approach was through the left crural fibers, which were split to
      access the lower posterior mediastinum. Operating time was 122 minutes.
      Postoperatively, a left intercostal drain was inserted. The patient was
      discharged on the third postoperative day, after intercostal drain removal. Lower
      posterior mediastinal paraspinal tumors can be resected laparoscopically with
      careful preoperative investigation for tumor localization and a meticulous
      laparoscopic technique. A major advantage of transabdominal laparoscopic
      resection, as compared with open or thoracoscopic (VATS) excision, is that the
      patient recovers rapidly with minimal operative and anesthetic morbidity.

PMID- 12409714
TI  - Laparoscopic omental-cerebellar pedicled graft harvest.
AB  - The minimally invasive technique has altered our approach to many surgical
      diseases. Laparoscopic surgery is performed on a variety of abdominal organs. One
      such organ, the omentum, traditionally has been harvested via a laparotomy. The
      omental harvest now has been attempted successfully laparoscopically, although
      usually for reconstructive efforts. Here we describe the first case of a
      laparoscopic omental-cerebellar pedicled graft harvest.

PMID- 12409715
TI  - p16INK4a immunohistochemistry improves interobserver agreement in the diagnosis
      of cervical intraepithelial neoplasia.
AB  - It has been repeatedly shown that there is a substantial lack of interobserver
      reproducibility in the histologic diagnosis of cervical intraepithelial neoplasia
      (CIN), which might be improved by a more specific diagnostic biomarker. Cervical
      cancer and CIN, but not other cervical epithelia, express high levels of the
      cyclin-dependent kinase inhibitor p16, suggesting that staining for this marker
      could help to more precisely identify CIN in tissue sections and therefore reduce
      variation in interpretation of cervical lesions. To test this hypothesis, 194
      cervical cone biopsy samples were selected from a routine histopathology
      laboratory. Two consecutive sections from each biopsy were stained with
      hematoxylin and eosin and with a p16 -specific monoclonal antibody, respectively.
      Five experienced cervical pathologists examined the slides. The agreement in the
      diagnosis between pairs or groups of observers was calculated by kappa
      statistics. Significant discrepancies were observed in the diagnostic
      interpretation of hematoxylin and eosin-stained slides, particularly for low
      grade lesions (kappa value 0.60 [95% confidence interval 0.58-0.63]). There was
      significantly better agreement in the interpretation of p16 expression (kappa
      value 0.91 [95% confidence interval 0.84-0.99]). Expression of p16 was restricted
      to CIN 2/CIN 3, CIN 1 associated with high-risk human papillomavirus, or cervical
      cancer. p16 immunostaining allowed precise identification of even small CIN or
      cervical cancer lesions in biopsy sections and helped to reduce interobserver
      variation in the histopathologic interpretation of cervical biopsy specimens.
      Thus, p16 immunohistochemistry can reduce false-negative and false-positive
      biopsy interpretation and thereby significantly improve cervical (pre)-cancer
      diagnosis.

PMID- 12409716
TI  - Pathologic effects of neoadjuvant cyproterone acetate on nonneoplastic prostate,
      prostatic intraepithelial neoplasia, and adenocarcinoma: a detailed analysis of
      radical prostatectomy specimens from a randomized trial.
AB  - Neoadjuvant hormonal therapy (NHT; androgen ablation) is used prior to radical
      prostatectomy (RP) in an attempt to pathologically "downstage" prostatic
      adenocarcinoma and ultimately to improve disease-free survival. This study
      describes the pathologic effects of NHT with the antiandrogen cyproterone
      acetate, 300 mg/day for 12 weeks, on the RP specimens from men with clinically
      localized (stage T1 or T2) prostatic adenocarcinoma. There were 101 men in the
      pretreatment group (CPA) and 91 men in a control group who were treated with
      surgery alone. The prevalence and extent of morphologic effects were recorded for
      the nonneoplastic prostate, high-grade prostatic intraepithelial neoplasia, and
      invasive adenocarcinoma. The commonest effects on the nonneoplastic prostate were
      atrophy and basal cell hyperplasia and prominence. High-grade prostatic
      intraepithelial neoplasia was more commonly identified in the surgery alone group
      than the CPA group (p <0.01). In the CPA group, flat and low tufted patterns of
      high-grade prostatic intraepithelial neoplasia predominated. Following NHT, the
      adenocarcinoma showed characteristic morphologic alterations, including reduction
      in cytoplasmic quantity, cytoplasmic vacuolation, nuclear pyknosis, reduced gland
      diameter, and mucinous breakdown. In many cases there was prominence of
      collagenous stroma, obscuring malignant glands. Compared with the surgery alone
      group, the CPA group RP specimens had a significantly lower mean specimen weight
      (40.3 g vs 46.5 g, p = 0.025) and less tumor extent by several measures. Organ
      confined tumor (stage pT2, margin negative) was found in 41.6% of the CPA group
      compared with 19.8% of the surgery alone group (p = 0.0017). The overall rate of
      margin positivity was lower in the CPA group (27.7% vs 64.8%, p = 0.001). We
      consider that the difference in margin positivity is the result of tumor
      shrinkage with a decreased likelihood of sampling in routine sections. There was
      no significant difference in the rate of extraprostatic extension between the two
      groups. There was elevation of the Gleason score in the RP specimens versus
      baseline biopsy in 60% of the CPA group compared with 33% of the surgery alone
      group (p = 0.02). The higher rate of elevation in the CPA group largely resulted
      from an increase in primary or secondary Gleason score 5 tumor, a morphologic
      artifact introduced by NHT. Because of this, we recommend not giving a Gleason
      grade to RP specimens following NHT. Monotherapy with CPA has similar pathologic
      effects on benign and malignant prostate tissue as does dual agent androgen
      blockade. Prolonged follow-up of these patients is required to determine if NHT
      with CPA leads to improved disease-free survival.

PMID- 12409717
TI  - Prevalence and significance of inflammatory bowel disease-like morphologic
      features in collagenous and lymphocytic colitis.
AB  - Collagenous colitis (CC) and lymphocytic colitis (LC) are clinical syndromes
      characterized by the presence of chronic watery diarrhea, few or no endoscopic
      abnormalities and biopsies that typically show normal crypt architecture,
      increased mononuclear inflammation in the lamina propria, absence of neutrophils,
      and increased intraepithelial lymphocytes. Patients with CC also have a thickened
      subepithelial collagen layer. We have noted, anecdotally, that biopsy specimens
      from some patients with CC or LC contain certain histologic features, such as
      Paneth cell metaplasia (PM), that are normally seen in inflammatory bowel disease
      (IBD), or other types of healed colitis, and thus may cause diagnostic
      difficulty. Therefore, the purpose of this study was to evaluate the prevalence
      and significance of IBD-like morphologic features in colonic mucosal biopsies
      from patients with CC or LC. Five hundred thirty-one routinely processed
      hematoxylin and eosin-stained colonic mucosal biopsies from 150 patients with
      clinically, endoscopically, and histologically confirmed CC (79 patients,
      male/female ratio: 14/65, mean age: 60 yr) or LC (71 patients, male/female ratio:
      13/58, mean age: 55 yr) were evaluated in a blinded fashion for a variety of
      histologic features, including active crypt inflammation (cryptitis +/- crypt
      abscess), surface ulceration, Paneth cell metaplasia, crypt architectural
      irregularity, number of intraepithelial lymphocytes, and thickness of the
      subepithelial collagen layer (CC only). The results were compared between CC and
      LC and correlated with the clinical and endoscopic data. None of the patients had
      or developed IBD during the study period. Active crypt inflammation was a common
      finding in both groups, seen in 24 of 79 CC patients (30%) and 27 of 71 LC
      patients (38%). Surface ulceration was not seen in any of the LC biopsies but was
      present in 2 of 79 (2.5%) CC patients. Paneth cell metaplasia was frequent in
      both groups and significantly more common in CC compared with LC patients. Forty
      four percent of CC patients, but only 9 of 63 (14%) of LC patients had Paneth
      cell metaplasia (p <0.001). Crypt architectural irregularity, although rare, was
      present in 6 of 79 patients with CC (7.6%) and 3 of 71 (4.2%) patients with LC.
      In patients with CC, the presence of Paneth cell metaplasia was associated with
      more severe disease characterized by the presence of abdominal pain (p <0.001)
      and a higher frequency of bowel movements (>3 bowel movements/day) (p = 0.06).
      Also, active crypt inflammation correlated with antibiotic use at the time of
      clinical presentation (p = 0.04) and was present in the only two patients who had
      positive stool cultures (one each for and ). However, none of the other
      histologic findings correlated with any of the other clinical or endoscopic
      features, such as type of symptoms, stool consistency, type of medical treatment,
      associated autoimmune diseases or outcome (complete, partial, or no resolution)
      in either group of patients. Pathologists should be aware that some histologic
      features normally associated with IBD such as crypt irregularity and neutrophilic
      cryptitis and crypt abscesses are not uncommon in patients with CC or LC and that
      the presence of one or more of these features should not necessarily be
      interpreted as evidence against either of these diagnoses.

PMID- 12409718
TI  - Leydig cell tumors of the testis with unusual features: adipose differentiation,
      calcification with ossification, and spindle-shaped tumor cells.
AB  - We report 19 Leydig cell tumors (LCTs) of the testis with adipose differentiation
      (n = 12) and/or spindle cell growth (n = 8) in patients 28-70 years of age; three
      tumors with adipose differentiation showed psammomatous calcifications, two of
      which also had foci of ossification. In eight tumors fat-like cells apparently
      derived from lipid accumulation within neoplastic Leydig cells and appeared as
      focal to prominent clusters in a background of vacuolated, neoplastic Leydig
      cells. The fat-like cells were usually immunoreactive for Leydig cell markers
      (inhibin-alpha, calretinin, and melan-A) but were typically strongly positive for
      the adipose tissue marker, S-100 protein, supporting a hybrid cell phenotype.
      Four tumors had fat of stromal derivation. In two of these there were intermixed
      mature adipocytes, but in two others only lipoblastic cells were present. These
      four tumors lacked vacuolated, neoplastic Leydig cells, and the fat cells in the
      single case studied were negative for inhibin-alpha and melan-A but positive for
      S-100. Three of the 12 LCTs with adipose differentiation were clinically
      malignant, and each had several of the established malignant features. Eight
      tumors with spindle cells occurred in men 34-70 years of age. Two tumors had ill
      defined fascicles of spindle cells, and three showed prominent edematous to
      myxoid areas with spindle-shaped tumor cells. Two additional tumors had a fibroma
      like spindled component that blended with islands of more plump, polygonal to
      spindle-shaped Leydig cells. Finally, one tumor had foci resembling an
      unclassified sarcoma that merged with conventional LCT; the spindle cell
      component in this case did not react for Leydig cell markers in contrast to the
      spindle cells in five of the six other cases in which immunostains were
      performed. Spindle cell differentiation, by itself, did not appear to have
      prognostic significance. Of the six patients with available follow-up, two
      developed metastases, but their tumors had malignant features apart from spindle
      cells; the remaining four patients were disease free at a mean of 3.6 years.
      Awareness of these unusual patterns in LCTs may prevent misinterpretation of fat
      admixed with neoplastic Leydig cells as evidence of extratesticular growth (a
      criterion for malignant LCT) may help avoid misdiagnosis of a LCT as a testicular
      "tumor" of the adrenogenital syndrome (which may contain fat) and may prevent
      misdiagnosis of a LCT with spindle cells as a sarcoma or unclassified sex cord
      stromal tumor.

PMID- 12409719
TI  - Monophasic fibrous and poorly differentiated synovial sarcoma:
      immunohistochemical reassessment of 60 t(X;18)(SYT-SSX)-positive cases.
AB  - Diagnosing monophasic fibrous and poorly differentiated synovial sarcoma (SS) on
      morphology alone is often a source of problems for pathologists. SS bear the
      t(X;18)(p11.2,q11.2) translocation, which proved to be specific for this tumor
      type and is currently considered one of the most reliable diagnostic criteria. To
      evaluate the sensitivity of immunohistochemical techniques in diagnosing
      monophasic fibrous SS (MFSS) and poorly differentiated SS (PDSS), we examined 60
      t(X;18)(SYT-SSX)-positive cases (47 MFSS and 13 PDSS) for cytokeratin AE1/AE3,
      cytokeratin KL1, epithelial membrane antigen, E-cadherin, CD34, S-100 protein,
      alpha-smooth muscle actin, desmin, h-caldesmon, CD99, bcl2, and C-kit (CD117)
      antibodies. Of the four epithelial markers tested, epithelial membrane antigen
      proved to be the most sensitive, reacting with 100% of MFSS and 92% of PDSS,
      followed by cytokeratin AE1/AE3 (70% of MFSS, 46% of PDSS), cytokeratin KL1 (49%
      of MFSS, 38% of PDSS), and E-cadherin (47% of MFSS, 54% of PDSS). A staining for
      cytokeratin AE1/AE3 and/or E-cadherin was observed in 79% of MFSS and 69% of
      PDSS, and a staining for cytokeratin KL1 and/or E-cadherin was observed in 74% of
      MFSS and 62% of PDSS. S-100 protein was positive in 38% of MFSS and 23% of PDSS,
      and alpha-smooth muscle actin in 21% of MFSS and 8% of PDSS. Tumor cells were
      rarely positive for CD34 (6% of MFSS, 0% of PDSS) and desmin (2% of MFSS, 0% of
      PDSS). Most SS were strongly positive for bcl-2 (91% of MFSS, 92% of PDSS) and
      CD99 (91% of MFSS, 100% of PDSS). A weak and focal cytoplasmic reactivity for
      CD117 was observed in 11% of MFSS (only one case had a strong immunoreactivity)
      and 8% of PDSS. Staining with h-caldesmon was consistently negative. In
      conclusion, in keeping with literature data, our results show that reactivity for
      epithelial membrane antigen, cytokeratin AE1/AE3, and E-cadherin, in combination
      with CD34 negativity, are the most useful and sensitive markers for diagnosing
      monophasic fibrous and poorly differentiated t(X;18)-positive SS. They also
      support the fact that about one third of MFSS and one fourth of PDSS are positive
      for S-100 protein, a finding of diagnostic relevance when considering their
      distinction from other spindle to round cell sarcomas, especially malignant
      peripheral nerve sheath tumors.

PMID- 12409720
TI  - Histopathology of ulcerative colitis in initial rectal biopsy in children.
AB  - Definitive histologic diagnosis of ulcerative colitis relies upon mucosal
      architectural distortion and inflammation in the appropriate clinical setting.
      Although crypt branching, atrophy, and loss are usually present in first biopsies
      from adults with ulcerative colitis, it has been our impression that features of
      chronicity are often lacking in first biopsies from children. To test this
      hypothesis, initial rectal biopsies and follow-up biopsies and/or colonic
      resections from 53 children (age 15 months to 17 years) and 38 adults (age 21-76
      years) with ulcerative colitis were examined in a blinded fashion for villiform
      surface, crypt atrophy, branching crypts, lamina propria inflammation, crypt
      abscesses, cryptitis, and basal plasma cells. Mucosal architecture was classified
      as normal, focally abnormal, or diffusely abnormal. Medical records were reviewed
      for confirmatory evidence of ulcerative colitis and for duration of symptoms
      before biopsy. In 87 of 91 biopsies, the lamina propria contained a mixed
      inflammatory infiltrate. Crypt abscesses and cryptitis were common in both
      groups. Initial biopsies from children were less likely to show diffuse
      architectural abnormalities (17 of 53, 32.1%) compared with biopsies from adults
      (22 of 38, 57.9% p <0.05). Duration of symptoms before diagnosis was
      significantly shorter in children (mean 17.5 weeks) compared with adults (mean
      54.9 weeks). In summary, initial rectal biopsies from children with ulcerative
      colitis are less likely to show diagnostic mucosal architectural distortion than
      biopsies from adults. This difference may be related to a shorter duration of
      symptoms before biopsy.

PMID- 12409721
TI  - Vaginal melanoma: a clinicopathologic and immunohistochemical study of 26 cases.
AB  - Malignant melanomas of the vagina are rare tumors. In this study we present the
      clinicopathologic features and immunohistochemical analysis of 26 such cases seen
      in our institution over a period of 30 years. The patients' age ranged from 38 to
      90 years (mean 60 years); three patients were premenopausal. Ethnicity was known
      in 24 patients: 20 white, 2 hispanic, 1 black, and 1 Asian. The most common
      presenting symptom was vaginal bleeding, followed by vaginal mass. Grossly, the
      tumor was polypoid-nodular in the majority of cases. The neoplastic cells were
      epithelioid in 15 cases and spindled in three cases; eight cases had both cell
      types. Vascular-lymphatic invasion was seen in six cases and perineural invasion
      was seen in four cases. S-100 was strongly and diffusely positive in 25 of 26
      cases (96%). HMB-45 was strongly positive in 16 (62%), 3 (11%) were focally
      positive, 1 case showed a rare positive cell, and 6 (23%) were negative. With
      MART-1, 20 cases (77%) were strongly positive, 1 (4%) showed a rare weakly
      positive cell, and 5 (19%) were negative. Twenty-one cases (81%) expressed
      tyrosinase and 20 (77%) expressed microphthalmia transcription factor. Twenty
      cases were Chung's level IV, 3 were level III, and 2 were level II. The patients
      were treated as follows: anterior exenteration with or without lymph node
      dissection and with or without radiotherapy (RT) or chemotherapy (CT) (7 cases),
      wide local excision with or without lymph node dissection and RT/CT (10 cases),
      hysterectomy with vaginectomy with or without RT/CT (3 cases), vaginectomy with
      RT (1 case), RT (1 case), and RT and CT (1 case). One patient had palliative RT
      for the brain metastasis only. Follow-up was available in 23 patients ranging
      from 3 to 276 months (median 18 months). Local recurrence after primary treatment
      was seen in six patients and distant metastases in 11 patients. Fifteen patients
      died of the disease (3-83 months), 4 have no evidence of disease (5-24 months),
      and 4 are alive with disease (6-276 months). This study confirms the poor
      prognosis of patients with vaginal melanoma. S-100 remains the most sensitive
      marker for these tumors. HMB-45 is negative in 23% cases of vaginal melanoma.
      Tyrosinase and MART-1 are useful markers when S-100 is negative or only focally
      positive.

PMID- 12409722
TI  - T-cell/histiocyte-rich large B-cell lymphoma: a heterogeneous entity with
      derivation from germinal center B cells.
AB  - T-cell/histiocyte-rich large B-cell non-Hodgkin's lymphoma (THRLBCL) is an
      unusual morphologic variant of diffuse large B-cell lymphoma. We reviewed 30
      cases of THRLBCL to evaluate its heterogeneity based on morphologic,
      immunophenotypic, and genetic features. Cases were classified according to the
      appearance of the large neoplastic B cells into three morphologic variants: 1)
      lymphocytic and histiocytic (L&H-like) (resembling the L&H cells of nodular
      lymphocyte predominance Hodgkin's lymphoma (14 cases); 2) centroblast (or
      immunoblast)-like (10 cases), and 3) Reed-Sternberg cell-like (resembling the
      neoplastic cells of classic Hodgkin's lymphoma) (6 cases). We used a panel of
      immunohistochemical stains, including those with specificity for germinal center
      B cells: CD20, CD79a, CD30, CD15, epithelial membrane antigen, BCL-2, BCL-6, and
      CD10. The /JH polymerase chain reaction assay was further performed to
      investigate a relationship to follicular lymphoma. The results were correlated
      with Epstein-Barr virus status as determined by staining for latent membrane
      protein and EBER-1 in situ hybridization. All cases were of B-cell
      immunophenotype with strong surface CD20 reactivity in the neoplastic large
      lymphoid cells, although CD79a was more inconsistently and weakly expressed (10
      of 17). Nuclear positivity for the BCL-6 protein was detected in the tumor cells
      in 26 of 29 (90%) cases. However, differences in expression of other antigens
      were encountered in the histologic subtypes. Epithelial membrane antigen
      positivity, a feature often seen in nodular lymphocyte predominance Hodgkin's
      lymphoma, was observed in 11 of 30 (37%) cases and was most commonly seen in
      cases with L&H cell morphology (8 of 14; 57%). CD30 expression was observed in 9
      of 30 (30%) cases but was most frequent in cases with Reed-Sternberg-like
      morphology (3 of 6 [50%]). CD10 expression was infrequent overall (3 of 29; 10%),
      with 2 of 3 positive cases identified in the centroblastic group. The overall
      rarity of positivity for CD10, BCL-2 (3 of 22; 13%), and -2 JH rearrangement (1
      of 28; 4%) indicates a lack of connection to follicular lymphoma for all
      subtypes. The three cases that were negative for BCL-6 protein were LMP-1
      positive and EBER-1 positive by in situ hybridization, and 2 of 3 had neoplastic
      cells with Reed-Sternberg-like morphology. These results demonstrate that
      although a large proportion of THRLBCL represent tumors of germinal center B cell
      derivation, they exhibit a diversity of morphologic and immunophenotypic
      features. A subset of THRLBCL may be related to nodular lymphocyte predominance
      Hodgkin's lymphoma. A small percentage show features closely resembling classic
      Hodgkin's lymphoma and could be considered a variant of grey zone lymphoma.

PMID- 12409723
TI  - Sarcoma-like mural nodules in mucinous cystic tumors of the ovary revisited: a
      clinicopathologic analysis of 10 additional cases.
AB  - Ten mucinous cystic ovarian tumors that contained sarcoma-like mural nodules are
      described. The nodules were studied by conventional and immunohistochemical
      methods. The sarcoma-like mural nodules occurred predominantly in middle-aged
      women, were multiple and sharply demarcated from the adjacent mucinous tumor, had
      small size, and exhibited a heterogeneous cell population. Distinction of these
      lesions from true sarcomatous nodules and foci of anaplastic carcinoma is
      important because of the worse prognosis of the two latter tumors compared with
      the favorable behavior of the sarcoma-like mural nodules. Six of the eight
      patients with follow-up information were alive and clinically free of recurrence
      at a mean follow-up interval of 12 years. Two patients died of other causes
      (thyroid and breast carcinomas). The nature of the nodules is not clear. Sarcoma
      like mural nodules probably represent a reactive and self-limited phenomenon
      within a neoplasia. Their coexpression of vimentin and cytokeratins is consistent
      with an origin from submesothelial mesenchymal cells, which undergo partial
      transformation into epithelial cells.

PMID- 12409724
TI  - Calretinin, a more sensitive but less specific marker than alpha-inhibin for
      ovarian sex cord-stromal neoplasms: an immunohistochemical study of 215 cases.
AB  - Although inhibin has been shown to be a sensitive marker for ovarian sex cord
      stromal and fibrous neoplasms, it may be negative in some cases. Calretinin, a
      mesothelial marker, has shown promise as a marker for sex cord-stromal neoplasms.
      The aim of this study was to evaluate and compare calretinin and inhibin as
      immunohistochemical markers for sex cord-stromal and fibrous neoplasms. A total
      of 215 ovarian neoplasms were immunostained with commercially available
      antibodies to calretinin and inhibin. These tumors included 87 sex cord-stromal
      (39 granulosa cell, 13 Sertoli-Leydig, 4 Sertoli, 9 thecomas, 14 fibrothecomas,
      and 8 other stromal tumors), 37 fibrous (20 fibromas, 9 adenofibromas, and 8
      fibrosarcomas), 65 epithelial, 22 germ cell, and 4 miscellaneous neoplasms. The
      staining was evaluated on a 0-4 scale based on percentage of neoplastic cells
      labeling: 0 = none; 1+ = 1-25%; 2+ = 26-50%; 3+ = 51-75%; 4+ = 76-100%.
      Calretinin reactivity was detected in 100% of sex cord-stromal and 90% of fibrous
      neoplasms, including 32 that were inhibin negative (2 granulosa cell tumors, 1
      Sertoli-Leydig cell tumor, 1 thecoma, 3 fibrothecomas, 16 fibromas, 6
      adenofibromas, and 3 fibrosarcomas). All four calretinin-negative fibrous
      neoplasms were inhibin negative. Calretinin staining was also detected in 22% of
      epithelial neoplasms but none of the germ cell and miscellaneous neoplasms
      tested. Inhibin staining was detected in 92% of sex cord-stromal neoplasms, 22%
      of fibrous neoplasms, 2% of epithelial neoplasms, and none of the germ cell and
      miscellaneous neoplasms tested. Calretinin has a 97% sensitivity and 85%
      specificity for sex cord-stromal and fibrous neoplasms, whereas inhibin has a 71%
      sensitivity and 99% specificity. This study shows that both calretinin and
      inhibin are useful in the diagnosis of ovarian sex cord-stromal and fibrous
      neoplasms. Calretinin is a more sensitive but less specific immunohistochemical
      marker than inhibin. Calretinin is particularly useful in the diagnosis of sex
      cord-stromal and fibrous neoplasms that are inhibin negative. The high frequency
      of calretinin in fibrous neoplasms suggests that a subgroup of these neoplasms
      may be derived from specialized gonadal stromal cells, perhaps thecal cells.

PMID- 12409725
TI  - The terminal ileum is affected in patients with lymphocytic or collagenous
      colitis.
AB  - Lymphocytic colitis (LC) and collagenous colitis (CC) are diseases characterized
      by the presence of marked intraepithelial lymphocytosis. Both of these disorders
      affect primarily the colon. However, involvement of the distal small intestine
      has not been systematically studied. The purpose of this study was to evaluate
      the type and degree of intraepithelial lymphocytosis in the terminal ileum of
      patients with LC or CC. Terminal ileal mucosal biopsies from 22 patients with LC
      (male/female ratio 0.22, mean age 47 years) and 23 with CC (male/female ratio
      0.43, mean age 54 years) were evaluated for the number of intraepithelial
      lymphocytes (IEL) per 100 epithelial cells (EC) both in the villi and crypts. The
      results were compared with 30 patients with inflammatory bowel disease (16 with
      Crohn's disease [CD], 14 with ulcerative colitis [UC]) and 24 patients
      (male/female ratio 0.33, mean age 44 years) without colonic pathology as normal
      controls. None of the patients had celiac sprue. Paired terminal ileum and
      colonic mucosal biopsies from 6 patients with LC, 4 with CC, 5 with CD, 5 with
      UC, and 10 normal controls were also immunohistochemically stained with
      monoclonal antibodies to CD3, CD8, CD20, and a class II MHC antigen (LN3-HLA-DR).
      In the villi the IEL count/100 EC was 11.8 +/- 1.8 in LC and 10.3 +/- 1.9 in CC
      (p = 0.3). These values were both significantly higher than in CD (2.8 +/- 0.4, p
      <0.001), UC (3.1 +/- 0.4, p <0.001), or normal controls (2.2 +/- 0.2, p <0.001).
      In the crypts the IEL count was 3.8 +/- 0.5 in LC and 3.2 +/- 0.5 in CC (p =
      0.3). These values were also significantly higher than in CD (2.3 +/- 0.4, p =
      0.02), UC (2.1 +/- 0.3, p = 0.02), or normal controls (1.5 +/- 0.2, p <0.001).
      The presence of >5 IELs/100 EC in terminal ileum biopsies was highly specific for
      LC and CC (specificity 98%, sensitivity 73% and 56% for LC and CC, respectively).
      The IEL phenotype was similar in all groups of patients and in the ileum and
      colon of individual patients. Intraepithelial lymphocytes were CD3+, CD8+, CD20-,
      and LN3-HLA-DR-, indicative of a suppressor T-cell phenotype. Intraepithelial
      lymphocytosis occurs in the terminal ileum in patients with LC or CC and may be
      helpful in diagnosing these conditions and distinguishing LC or CC from CD or UC
      in diagnostically difficult cases. The results suggest that the terminal ileum
      may be involved by a similar pathogenic process as the colon in LC and CC.

PMID- 12409726
TI  - Amelanotic cellular blue nevus: a hypopigmented variant of the cellular blue
      nevus: clinicopathologic analysis of 20 cases.
AB  - Blue nevus and its variants typically present as pigmented lesions. Dermal
      melanin is responsible for coloration and is an expected histologic finding.
      Herein, we report 20 cases of an unusual amelanotic variant of cellular blue
      nevus. Our series showed clinical demographics similar to pigmented counterparts.
      Thus, there was a predilection for young individuals with a mean age of 24 years
      (range 6-74 years). Both sexes were affected, with a female-to-male ratio of
      approximately 2:1. The lower back, distal extremities, and scalp were the most
      common sites of occurrence. Importantly, the lack of pigmentation resulted in an
      atypical clinical appearance. A diagnosis of blue nevus by the attending
      physician was not considered in any of the reported lesions. All of the tumors
      extended deep into the reticular dermis or subcutaneous fat with a mean thickness
      of 5.5 mm (range 1.7-11 mm). Ulceration was present in two lesions. Mild
      cytologic atypia and pleomorphism were present in five cases. Mitotic activity
      (up to 3 mitoses/mm ) was observed in 11 lesions. A brisk lymphocytic host
      response was present in only one lesion. Tumor necrosis was not observed. Most,
      but not all, tumors showed reactivity for S-100 and HMB-45. Clinical follow-up
      (mean 32 months) was consistent with a benign course. Local recurrence was not
      observed after complete excision. None of the cases was associated with clinical
      evidence of lymph node or distant metastases. Recognition of amelanotic cellular
      blue nevus is important because the lack of expected pigmentation may result in
      clinical and pathologic diagnostic difficulty. In particular, amelanotic cellular
      blue nevus must be distinguished from malignant cellular blue nevus and other
      variants of melanoma.

PMID- 12409727
TI  - Evaluation of MIB-1-positive cell clusters as a diagnostic marker for cervical
      intraepithelial neoplasia.
AB  - The objects of the study were to evaluate MIB-1-positive cell clusters (MIB-C)
      for distinguishing normal, reactive, and cervical intraepithelial neoplasia (CIN)
      biopsies and to determine possible pitfalls. Seventy-seven consecutive cervical
      specimens routinely diagnosed (Dx_orig) as CIN 1 or 2, or no-CIN, were revised
      independently by two expert gynecopathologists. MIB-1 staining and oncogenic
      human papillomavirus (HPV) assessment (by polymerase chain reaction) were
      performed. Independent diagnoses (plus oncogenic HPV status, in case of
      disagreement between the experts) were used to obtain a final diagnosis
      (Dx_final) and compared with MIB-C. Four of the 27 (15%) Dx_final = normal were
      HPV positive. Agreement between the gynecopathologists was 72 of 77 (94%). There
      were 30 (39%) discrepancies between Dx_orig and Dx_final (23 = 30% downgrades and
      7 = 9% upgrades). All 23 downgrades were HPV negative and all seven upgrades were
      HPV positive. Overall agreement between Dx_orig and MIB-C was 73%, and with
      Dx_final 99%. Sensitivity, specificity, and positive and negative predictive
      values of MIB-C were very high without false negatives. Tangential cutting of MIB
      1-positive parabasal cells and inflammatory cells can erroneously be
      overdiagnosed as a MIB-C. One single false positive of the 48 non-CIN cases (an
      immature squamous metaplasia) showed a special, easily recognizable MIB-1
      pattern, different from CIN because the MIB-1 staining in the nuclei is not
      diffuse (as in CIN) but clumped. Moreover, positive nuclei are somewhat less
      densely packed than in CIN. When tangentially cut parabasal cells and
      inflammatory cells are carefully excluded, MIB-C is a strong diagnostic adjunct
      in distinguishing CIN from normal or benign cervical squamoepithelial lesions.

PMID- 12409728
TI  - Observer variation of encapsulated follicular lesions of the thyroid gland.
AB  - Although histologic definition of follicular thyroid lesions is readily
      available, application of the diagnostic criteria and personal experience may
      lead to disagreement among pathologists. To investigate interobserver variation
      in assessment of encapsulated follicular lesions, eight pathologists (four
      American and four Japanese) reviewed the same hematoxylin and eosin-stained slide
      of each of 21 cases of thyroid lesions showing encapsulation and follicular
      growth pattern. In 10% of the cases, there was complete agreement. At least seven
      pathologists agreed on the diagnosis in 29% of the cases, and at least six in 76%
      of the cases. American and Japanese pathologists agreed among themselves in 33%
      and 52% of cases, respectively. The frequency of diagnosis of adenomatous goiter
      among Japanese pathologists (31%) was considerably higher than that among
      American pathologists (6%). In contrast, the frequency of diagnosis (25%) of
      papillary carcinoma among American pathologists was considerably higher than that
      (4%) among Japanese pathologists. Our analysis revealed three main factors
      affecting observer variation: 1) interpretation of the significance of
      microfollicles intimately related to capillaries within the tumor capsule, 2)
      evaluation of what constituted the type of nuclear clearing indicative of
      papillary carcinoma, and 3) absence of clear morphologic criteria for separation
      of adenomatous goiter and follicular adenoma. To reduce observer variation of
      encapsulated follicular lesions, it will be necessary to provide more explicit
      criteria for diagnosis.

PMID- 12409729
TI  - Desmoplastic infantile ganglioglioma: a potentially malignant tumor?
AB  - Desmoplastic infantile ganglioglioma is a rare intracranial tumor of early
      childhood with a usually excellent prognosis despite malignant features both
      radiologically and histologically. We present the case of a desmoplastic
      infantile ganglioglioma with histologically highly anaplastic features and both
      intracerebral and pial metastases. After partial resection the tumor was rapidly
      progressive and new metastases appeared. A combination of vincristine and
      carboplatinum was used according to the Low Grade Glioma Protocol of the
      International Society of Pediatric Oncology, with a temporary good response. When
      histologically characterized by highly anaplastic features, it seems the biologic
      behavior of this tumor remains uncertain. The aggressive behavior and the
      responsiveness to chemotherapy in this case may challenge the belief in the
      benign nature of these rare tumors.

PMID- 12409730
TI  - Benign cystic mesothelioma of the liver.

PMID- 12409731
TI  - HIV-associated sensory neuropathies.

PMID- 12409732
TI  - Entrapment of recent thymic emigrants in lymphoid tissues from HIV-infected
      patients: association with HIV cellular viral load.
AB  - OBJECTIVE(S): Depletion of thymus derived naive T-cells is a feature of HIV
      infection. Here the impact of HIV infection on the compartmentalization of recent
      thymic emigrants of (RTE) and naive T-cells was examined. METHODS: Peripheral
      blood mononuclear cells (PBMC) and lymphoid tissue (LT) from 43 HIV-infected
      patients and 12 controls were examined for RTE distribution by measuring coding
      joint T-cell receptor excisional circles (cjTREC) by PCR and naive and memory T
      cell subsets and adhesion molecules (L-selection, LFA-1) by flow cytometry.
      RESULTS: In HIV-infected patients, the RTE as quantified by cjTRECs in CD4 LT
      cells were significantly higher than in PBMC. Their values, however, were less
      than in control subjects, in both the LT and PBMC compartments. This was
      associated with an increase in L-selectin and LFA-1 expression on LT derived T
      cells. In PBMC, a significant positive relationship between TREC and naive CD4
      cells and an inverse relationship between TREC and cellular viral load (CVL) was
      observed. Whereas in LT, there was a positive relationship between cjTREC and
      both naive CD4 cell percentage and CVL. CONCLUSIONS: Collectively, the data
      suggests that LT is a significant reservoir for RTE. The RTE appeared to be
      entrapped in LT from HIV-infected subjects. Such entrapment is probably a
      response to the high viral load in these tissues. These observations may
      partially explain the decline in RTE observed in the peripheral blood of HIV
      infected patients, and the delay in recovery of naive cells in blood after
      initiation of HAART.

PMID- 12409733
TI  - Rapid reconstitution of humoral immunity against cytomegalovirus but not HIV
      following highly active antiretroviral therapy.
AB  - OBJECTIVE: To determine the kinetics of reduction in human cytomegalovirus (HCMV)
      load and specific anti-glycoprotein B (gB) immune responses in patients with
      concurrent HCMV DNAaemia following the initiation of highly active antiretroviral
      therapy (HAART). DESIGN: Sequential analysis of eleven patients with HCMV
      DNAaemia who received HAART and eleven control patients with HCMV DNAaemia.
      METHODS: HCMV load was measured by quantitative competitive polymerase chain
      reaction and anti-gB, anti-HIV Env and Gag responses by an end-point dilution
      immunofluorescence assay using recombinant antigens expressed in insect cells.
      Estimates of the efficacy of the reconstituting immune system at controlling HCMV
      replication were based on previous dynamic models. RESULTS: In patients
      initiating HAART, HCMV DNA levels in blood declined rapidly, with a median half
      life of 5.2 days, consistent with an efficacy of the reconstituting immune system
      at inhibiting HCMV replication of 52.8-85% (median, 61%). Commensurate with this
      decrease, a significant increase in anti-gB titres was observed in the post-HAART
      period (corresponding to an average fourfold increase in titre by 1 month rising
      to an eightfold increase at month 3; = 0.01). No changes in titre were observed
      in the control group or for anti-HIV Gag antibody levels, while anti-HIV Env
      antibody levels decreased after HAART. CONCLUSIONS: In patients with HCMV
      DNAaemia, reconstitution of humoral immunity to HCMV gB occurs rapidly following
      the initiation of HAART. These changes contrast with the patterns observed for
      anti-HIV humoral immune responses.

PMID- 12409734
TI  - T-cell responses induced in normal volunteers immunized with a DNA-based vaccine
      containing HIV-1 env and rev.
AB  - OBJECTIVE: An effective HIV-1 vaccine will likely need to induce strong cell
      mediated immunity in humans. Therefore, we examined the ability of a DNA HIV-1
      vaccine to induce a T-cell response in HIV-1 seronegative humans. DESIGN:
      Individuals were enrolled in a phase I clinical trial of safety and immune
      responses to an env/rev-containing plasmid at doses of 100, 300 or 1000 microg.
      Peripheral blood mononuclear cells (PBMC) samples were analyzed by standard
      lymphocyte proliferation, cytotoxic T lymphocyte (CTL) and ELISPOT techniques.
      RESULTS: PBMCs from subjects immunized with doses as low as 300 microg
      proliferated in vitro to env (four of six) or (three of six) proteins.
      Importantly, when the dose of vaccine was increased to 1000 microg of DNA,
      lymphocytes secreted IFN-gamma in an ELISPOT assay following in vitro stimulation
      with env (three of six) or rev (four of six) proteins. CONCLUSION: We observed
      HIV-1 DNA plasmid vaccines induce CD4 T-helper cell responses in humans. We
      observed a discrepancy in the CD4 versus CD8 response suggesting the importance
      of analyzing both compartments in clinical evaluation. Furthermore, this report
      demonstrates the high level of immunogenicity of and its importance as a
      component of a prophylactic vaccine for HIV-1.

PMID- 12409735
TI  - Continuing intrathecal immunoactivation despite two years of effective
      antiretroviral therapy against HIV-1 infection.
AB  - OBJECTIVE: To study the effect of antiretroviral combination treatment on
      intrathecal immunoactivation in HIV-1 infection. METHOD: Lumbar punctures were
      performed at baseline, and after 4 months, 1 and 2 years on 30 neurologically
      asymptomatic, treatment-naive HIV-1-infected patients started on antiretroviral
      treatment with three or more drugs. Levels of neopterin, beta2-microglobulin and
      HIV-1 RNA were measured in cerebrospinal fluid (CSF) and blood. RESULTS: All
      patients continued the study until the 4-month follow-up, although seven
      discontinued before the 1-year control, and an additional five discontinued
      before the control after 2 years. Neopterin, beta2-microglobulin and HIV-1 RNA
      decreased significantly both in CSF and blood, but although 100% of the patients
      decreased their CSF concentrations of beta2-microglobulin and HIV-1 RNA to normal
      levels, only 55% had normal CSF neopterin concentrations after 2 years treatment.
      CONCLUSIONS: In addition to CSF viral load, antiretroviral combination therapy
      substantially decreases the intrathecal immunoactivation as reflected by CSF
      neopterin and beta2-microglobulin in neuroasymptomatic HIV-1-infected patients.
      However, almost half of the patients still have slightly increased CSF neopterin
      concentrations after 2 years of effective treatment, which might reflect an
      ongoing low-grade viral replication in brain tissue.

PMID- 12409736
TI  - Persistence of replication-competent HIV in both memory and naive CD4 T cell
      subsets in patients on prolonged and effective HAART.
AB  - OBJECTIVE: To investigate the phenotypic features of infected lymphocytes in
      patients on prolonged and effective highly active antiretroviral therapy (HAART).
      DESIGN: We examined highly purified subsets of memory and naive CD4 T lymphocytes
      for the presence of replication-competent virus. METHODS: In 11 highly selected
      HAART-treated patients, we isolated highly purified CD45RO CD45RA CD4 T cells
      using a magnetic bead-based procedure. In some patients, a subsequent cell
      separation according to CD62L expression was performed. We quantified total viral
      DNA in freshly isolated T-cell subsets. To verify whether the virus was
      replication-competent, HIV RNA was measured in supernatants following cell
      activation. RESULTS: HIV DNA was detectable in the CD45RO and CD45RA CD4 T-cell
      subsets in 100% and 90% of the patients tested, respectively. In central memory
      CD45ROCD62L, effector memory CD45RO+CD62L-, truly naive CD45RACD62L, and
      CD45RA+CD62L- CD4 T cells, HIV DNA was found in 100%, 55%, 88%, and 50% of the
      patients tested respectively. HIV DNA was significantly higher in the CD45RO
      fraction than in the CD45RA subset and in the CD45ROCD62L fraction than in the
      three other CD45RA/ROCD62L+/- subsets. Detectable HIV RNA was found in the
      culture supernatants of CD45RO and CD45RA CD4 T-cell subsets in 80% and 66% of
      the patients tested respectively, and in CD45ROCD62L, CD45RO+CD62L-, CD45RACD62L,
      and CD45RA+CD62L- CD4 T cells in 100%, 100%, 100% and 50% of the patients tested
      respectively. CONCLUSIONS: In patients on prolonged and effective HAART, the pool
      of infected CD4 T lymphocytes consists predominantly of memory cells but also
      contains naive cells.

PMID- 12409737
TI  - Metabolic activation of nucleoside and nucleotide reverse transcriptase
      inhibitors in dendritic and Langerhans cells.
AB  - BACKGROUND: Langerhans cells and interstitial dendritic cells are the earliest
      targets for HIV infection through sexual transmission of HIV. Metabolism of
      nucleoside analogues markedly differs in proliferating T lymphocytes and resting
      monocyte/macrophages, and thus their antiviral efficacy can substantially differ
      between both cell types. METHODS: The metabolism of radio-labelled zidovudine
      (ZDV), lamivudine (3TC) and tenofovir (PMPA) to their antivirally active
      metabolites was studied in primary cells, representative of early in vivo targets
      of HIV [i.e. monocyte-derived dendritic cells (MO-DC), MO-derived Langerhans
      cells (MO-LC), PHA/IL-2-activated T-blast cells] as well as in a laboratory T
      lymphocyte (CEM) cell line. RESULTS: Whereas lamivudine metabolism to its active
      triphosphate derivative (3TC-TP) did not markedly differ between T-cells and MO
      derived LC and DC, zidovudine was much better converted to ZDV-TP in T-cells than
      in MO-LC and MO-DC. In contrast, tenofovir was markedly more abundantly converted
      to its antivirally active diphosphate metabolite PMPApp in MO-DC and MO-LC than
      zidovudine and lamivudine. CONCLUSION: Our metabolic data suggest that tenofovir
      may be superior to zidovudine and lamivudine for inhibition of HIV replication in
      dendritic/Langerhans cells, the first-line cell types targeted by a primary HIV
      infection.

PMID- 12409738
TI  - Increased long-term mitochondrial toxicity in combinations of nucleoside analogue
      reverse-transcriptase inhibitors.
AB  - BACKGROUND: Some nucleoside analogue reverse transcriptase inhibitors (NRTI) may
      cause depletion of mitochondrial (mt) DNA in liver by inhibiting polymerase
      gamma. mtDNA depletion may contribute to lactic acidosis, steatohepatitis and
      liver failure. OBJECTIVE: To evaluate the long-term mitochondrial toxicity of
      NRTI combinations. METHODS: The HepG2 human hepatoma cell line was cultivated in
      the presence of zalcitabine (ddC), didanosine (ddI), stavudine (d4T), lamivudine
      (3TC), zidovudine (ZDV) and efavirenz at concentrations equivalent to steady
      state peak plasma levels (C ), and also in one-third and 10 times C. The NRTI
      were added to the medium alone or in combination. Control cells were incubated
      without any NRTI or with efavirenz. Cell growth, lactate production,
      intracellular lipid droplets, mtDNA and the mtDNA-encoded respiratory chain
      subunit COX II were monitored over a period of up to 30 days. RESULTS: Time- and
      dose-dependent mtDNA depletion was observed with ddC > ddI > d4T and mtDNA
      depletion preceded or coincided with a decline in COX II expression, a decrease
      in cell growth, increased lactate production and increased intracellular lipids.
      3TC and efavirenz did not affect any measurement. ZDV increased lactate
      moderately and cell growth was inhibited, despite normal mtDNA and COX II levels.
      The negative effects on some measurements were more pronounced in the 3TC-ZDV and
      ddC-d4T combinations, than in the single-NRTI incubations. The combination of ddI
      d4T was not more toxic than ddI alone. Mitochondrial damage by ZDV, d4T, ddI, and
      ddC did not reach steady-state by day 25. Using a Southern blot technique, mtDNA
      deletions were never observed. CONCLUSION: The data indicate additive or
      synergistic long-term mitochondrial toxicity in some NRTI combinations.

PMID- 12409739
TI  - A prospective study of adherence and viral load in a large multi-center cohort of
      HIV-infected women.
AB  - OBJECTIVES: To examine the relationship between antiretroviral adherence and
      viral load, and to determine the predictors of adherence over time in HIV
      infected women. DESIGN: Prospective observational study. METHODS: One-hundred
      sixty-one HIV-infected women who were taking antiretroviral therapy for a median
      of 3.0 years were recruited from the HIV Epidemiology Research Study, a
      multicenter cohort study of HIV infection in women. Antiretroviral adherence
      (percent of doses taken as prescribed) was measured over a 6-month period using
      MEMS caps. At baseline and follow-up, CD4 lymphocyte count and viral load were
      measured, and a standardized interview was administered to elicit medication
      history and drug use behaviors. To examine changes in adherence over time, the
      mean adherence to all antiretroviral agents was calculated for each monitored
      month. RESULTS: Adherence varied significantly over time (P < 0.001), ranging
      from a mean of 64% in month 1 to 45% in month 6. Nearly one-fourth of the
      participants had a 10% or greater decrease in adherence between consecutive
      months. Virologic failure occurred in 17% of women with adherence of > or = 88%,
      28% of those with 45-87% adherence, 43% of those with 13-44% adherence, and 71%
      of those with < or = 12% adherence. In multivariate analysis, factors predicting
      lower adherence included active drug use, alcohol use, more frequent
      antiretroviral dosing, shorter duration of antiretroviral use, younger age, and
      lower initial CD4 lymphocyte count. CONCLUSIONS: Antiretroviral adherence is not
      stable over time. Interventions aimed at monitoring and improving long-term
      adherence in women are urgently needed.

PMID- 12409740
TI  - Increased fat accumulation in the liver in HIV-infected patients with
      antiretroviral therapy-associated lipodystrophy.
AB  - OBJECTIVE: To determine liver fat content in patients with highly active
      antiretroviral therapy (HAART)-associated lipodystrophy. BACKGROUND:
      Lipodystrophy in several animal models is associated with fat accumulation in
      insulin-sensitive tissues, such as the liver. This causes hyperinsulinaemia,
      dyslipidaemia and other features of insulin resistance. DESIGN: A cross-sectional
      study. SUBJECTS AND METHODS: Three age- and weight-matched groups were compared:
      25 HIV-positive men with HAART-associated lipodystrophy (HAART+LD+), nine HIV
      positive men receiving HAART, but without lipodystrophy (HAART+LD-), and 35 HIV
      negative healthy men (HIV-). Liver fat content was measured using proton
      spectroscopy. Intra-abdominal and subcutaneous fat were determined using magnetic
      resonance imaging. RESULTS: Liver fat content was significantly higher in the
      HAART+LD+ (8 +/- 10%) than the HIV- (5 +/- 7%; P < 0.05) or the HAART+LD- (3 +/-
      5%; P < 0.01) group. Liver fat content correlated with serum fasting insulin in
      the HAART+LD+ (r = 0.47; P < 0.05) and HIV- groups (r = 0.65; < 0.001), but not
      with the amount of intra-abdominal fat. Within the HAART+LD+ group, serum insulin
      did not correlate with the amount of intra-abdominal fat. The HAART+LD+ group had
      a lower serum leptin concentration when compared to the two other groups.
      Features of insulin resistance, including hepatic fat accumulation, were not
      found in HAART+LD-group. CONCLUSIONS: The severity of the insulin resistance
      syndrome in patients with HAART-associated lipodystrophy is related to the extent
      of fat accumulation in the liver rather than in the intra-abdominal region. Fat
      accumulation in the liver may therefore play a causative role in the development
      of insulin resistance in these patients.

PMID- 12409741
TI  - A randomized, double-blind study of gemfibrozil for the treatment of protease
      inhibitor-associated hypertriglyceridaemia.
AB  - BACKGROUND: Hypertriglyceridaemia is common in patients with HIV, especially
      those taking protease inhibitors or with lipodystrophy, frequently observed at
      levels associated with accelerated cardiac disease. This study aimed to explore
      the efficacy and safety of gemfibrozil for hypertriglyceridemia in patients with
      HIV infection. METHODS: A 16-week, randomized, double-blind, comparative study of
      low saturated fat diet versus low saturated fat diet with gemfibrozil 600 mg
      twice daily in patients with triglycerides > or = 3mmol/l receiving protease
      inhibitor therapy. Following a 4-week period of dietary intervention alone,
      patients were randomized to gemfibrozil or matching placebo. The primary outcome
      was the difference in mean change in fasting triglycerides at week 16 between the
      two groups. RESULTS: 37 men were randomized (17 gemfibrozil, 20 placebo) with
      median fasting triglycerides 5.6 mmol/l. Mean changes in triglycerides from week
      4 to week 16 were -1.22 mmol/l and +0.35 mmol/l for the gemfibrozil and placebo
      groups respectively (between-group mean difference of 1.57 mmol/l; 95% confidence
      interval, -6.7 to 3.5; = 0.08). Only one patient treated had triglycerides return
      to a desirable range (< or = 2.00 mmol/l). No significant changes in the other
      metabolic parameters were observed. Gemfibrozil was well tolerated, did not
      appear to induce additional protease inhibitor toxicity, and did not induce
      changes in CD4 lymphocyte counts or HIV RNA load. CONCLUSIONS: Gemfibrozil is
      safe and demonstrated at most, modest efficacy for hypertriglyceridemia in HIV
      infected patients receiving protease inhibitors. Given the level of response,
      however, it is unclear whether these reductions will confer clinical benefit, at
      least in the presence of continued protease inhibitor use.

PMID- 12409742
TI  - Parents' disclosure of HIV to their children.
AB  - OBJECTIVE: Parents' disclosure of their HIV serostatus to all of their children
      is described over time and the impact of disclosure is examined for their
      adolescent children. DESIGN A representative cohort of parents living with HIV (n
      = 301) and their adolescent children (n = 395) was recruited and assessed
      repeatedly over 5 years. METHODS: Disclosures by parents living with HIV of their
      HIV status to their children were examined in three ways: (i) trends in
      disclosure over 5 years to all children; (ii) factors associated with parental
      disclosure; and (iii) the impact of disclosure on adolescent children (not
      younger children). RESULTS: Parents were more likely to disclose to older (75%)
      than to younger children (40%). Mothers were more likely to disclose earlier than
      fathers and they disclosed more often to their daughters than to their sons.
      Parents were more likely to disclose over time to children of all ages;
      disclosure did not vary according to parents' ethnicity, socio-economic status,
      self-esteem, or mental health symptoms. Disclosure was significantly more common
      among parents with poor health, more stressful life events, larger social
      networks, and those who perceived their children experiencing more HIV-related
      stigma. Over time, poor health status and a self-destructive coping style were
      associated with higher rates of disclosure. Parental disclosure was significantly
      associated with more problem behaviors and negative family life events among
      their adolescent children. CONCLUSION: Parental disclosure of HIV status is
      similar to disclosures by parents with other illnesses. Clinicians must assist
      patients to make individual decisions regarding disclosure.

PMID- 12409743
TI  - HIV dynamics and behaviour change as determinants of the impact of sexually
      transmitted disease treatment on HIV transmission in the context of the Rakai
      trial.
AB  - OBJECTIVE: To assess how the impact of sexually transmitted disease (STD)
      treatment on HIV incidence varies between stages of the HIV epidemic. METHODS: We
      simulated the spread of curable STD, herpes simplex virus type 2 and HIV in the
      dynamic transmission model. Parameters were quantified to represent a severe HIV
      epidemic as in Rakai, Uganda, using demographic, behavioural and epidemiological
      data from a recent STD treatment trial. RESULTS: The model fitted the HIV
      epidemic in Rakai if we assumed a considerable behavioural risk reduction,
      starting at the end of the Ugandan civil war in 1986. An improvement in STD
      treatment reduced HIV incidence in this population by 35% over 2 years if
      implemented in 1981, but only by 11 and 8% in 1988 or 1998. This trend resulted
      partly from the hypothesized behaviour change, which markedly reduced the
      prevalences of bacterial STD. In a simulated epidemic without behavioural change,
      the corresponding treatment impacts in 1988 and 1998 would be 19 and 15%.
      Enhanced herpetic ulceration in immunocompromised HIV patients contributed little
      to the reduced impact of treatment of bacterial STD over time. CONCLUSION: In HIV
      epidemics beyond the first decade, the impact of STD treatment programmes on HIV
      transmission may depend more on behavioural risk reduction than on the stage of
      the epidemic. Preceding behavioural change associated with restored civil
      stability may have contributed to the lack of impact of STD treatment on HIV in
      the Rakai trial. In advanced epidemics with less behaviour change, STD treatment
      may still be important for HIV prevention.

PMID- 12409744
TI  - Thymic volume predicts long-term immune reconstitution in HIV-infected children
      treated with highly active antiretroviral therapy.

PMID- 12409745
TI  - The boosting of didanosine by allopurinol permits a halving of the didanosine
      dosage.

PMID- 12409746
TI  - Utility of patch testing in patients with hypersensitivity syndromes associated
      with abacavir.

PMID- 12409747
TI  - Bilateral carotid stenosis in a young female HIV patient treated with highly
      active antiretroviral therapy.

PMID- 12409748
TI  - African-based CCR5 single-nucleotide polymorphism associated with HIV-1 disease
      progression.

PMID- 12409749
TI  - Interleukin 7 production by bone marrow-derived stromal cells in HIV-1-infected
      patients during highly active antiretroviral therapy.

PMID- 12409750
TI  - Nodal marginal zone lymphoma in AIDS patients: a casual association?

PMID- 12409751
TI  - The CD4 cell count 3 months after acute retroviral syndrome is associated with
      the presence of AIDS in the source individual.

PMID- 12409752
TI  - Trends in hepatitis C and HIV infection among inmates entering prisons in
      California, 1994 versus 1999.

PMID- 12409753
TI  - Notes from the XIV International AIDS Conference in Barcelona, Spain.

PMID- 12409754
TI  - A 10-year review of perioperative complications in pharyngeal flap surgery.
AB  - A 10-year retrospective study was undertaken to investigate perioperative
      complications in pharyngeal flap surgery in one institution using inferiorly and
      superiorly based flaps. In this fashion the current practice of surgical
      technique based on local findings and perioperative care, through regular
      monitoring by experienced nurses on the ward, was evaluated for adequacy. The
      charts of 275 patients who had 287 pharyngeal flap procedures were studied.
      Demographics, type and duration of operation, associated procedures, surgeon,
      anesthetist, duration of hospital stay, associated medical conditions, and
      perioperative complications such as bleeding, respiratory insufficiency, or flap
      dehiscence were evaluated. In this series a total complication rate of 6 percent
      was found, with 2.4 percent early (<6 weeks) and 3.8 percent late (>6 weeks)
      complications. Only two patients (0.7 percent) had postoperative bleeding
      requiring reoperation, and one patient (0.3 percent) needed reintubation. The
      most frequent complication was flap dehiscence in nine patients (3.1 percent),
      which occurred early in three and late in six. Pharyngeal flap surgery can be
      performed safely with very few complications provided the correct experience and
      infrastructure are present. Careful surgery, in conjunction with adequate
      anesthesia and postoperative monitoring, makes these procedures safe and
      rewarding.

PMID- 12409756
TI  - Velopharyngeal surgery: a prospective randomized study of pharyngeal flaps and
      sphincter pharyngoplasties.
AB  - Residual velopharyngeal insufficiency after palatal repair varies from 10 to 20
      percent in most centers. Secondary velopharyngeal surgery to correct residual
      velopharyngeal insufficiency in patients with cleft palate is a topic frequently
      discussed in the medical literature. Several authors have reported that varying
      the operative approach according to the findings of videonasopharyngoscopy and
      multiview videofluoroscopy significantly improved the success of velopharyngeal
      surgery. This article compares two surgical techniques for correcting residual
      velopharyngeal insufficiency, namely pharyngeal flap and sphincter
      pharyngoplasty. Both techniques were carefully planned according to the findings
      of videonasopharyngoscopy and multiview videofluoroscopy. Fifty patients with
      cleft palate and residual velopharyngeal insufficiency were randomly divided into
      two groups: 25 in group 1 and 25 in group 2. Patients in group 1 were operated on
      by using a customized pharyngeal flap according to the findings of
      videonasopharyngoscopy and multiview videofluoroscopy in each case. Those in
      group 2 received a sphincter pharyngoplasty also customized according to the
      findings of videonasopharyngoscopy and multiview videofluoroscopy. The median age
      of the patients in both groups was not significantly different (p > 0.5). The
      frequency of residual velopharyngeal insufficiency after the individualized
      velopharyngeal surgery was not significantly different between the patient groups
      (12 percent versus 16 percent; p > 0.05). It seems that customized pharyngeal
      flaps and sphincter pharyngoplasties performed according to the findings of
      videonasopharyngoscopy and multiview videofluoroscopy are safe and reliable
      procedures for treating residual velopharyngeal insufficiency in cleft palate
      patients.

PMID- 12409757
TI  - Pectoralis major myocutaneous flap for hypopharyngeal reconstruction.
AB  - The reconstruction of total or subtotal defects after surgical treatment for
      hypopharyngeal cancer is a challenging problem in head and neck surgery. The
      authors discuss reconstructive surgery performed in 37 patients affected by
      advanced hypopharyngeal cancer using the pectoralis major myocutaneous flap. In
      22 cases of total pharyngolaryngectomy, the reconstructive procedure originally
      proposed by the authors was based on the use of a pectoralis major myocutaneous
      flap directly sutured to the pharyngeal and esophageal stumps and the
      prevertebral fascia, which eventually represented the posterior wall of the
      neohypopharynx. In 15 cases of subtotal pharyngolaryngectomy, the posterior wall
      of the neohypopharynx consisted of a residual strip of pharyngeal mucosa. In each
      patient, removal of the tumor and reconstruction were performed during the same
      operation, with only a few complications. Neither flap necrosis nor strictures
      were encountered; five patients had pharyngeal fistula and one patient died
      because of massive pneumonia. Although the use of microvascular free flaps is a
      reliable procedure, the pectoralis major myocutaneous flap is still applicable
      for hypopharyngeal reconstruction, thanks to its feasibility and low complication
      rate. The other reconstructive options require surgical transgression of the
      abdomen and/or thorax in patients affected by malnutrition and other chronic
      systemic disorders.

PMID- 12409759
TI  - Computer-assisted secondary reconstruction of unilateral posttraumatic orbital
      deformity.
AB  - Until now, computer-assisted surgery has not been practiced as part of the
      surgical routine of posttraumatic orbital reconstruction. The purpose of this
      study was to investigate the use of a navigation system for computer-assisted
      preoperative planning with virtual reconstruction to obtain symmetry of the
      orbits and intraoperative control of virtual contours in comparison with the
      clinically achieved surgical results. A further objective of the computer
      assisted orbital analysis was to use an ideal measurement for the two-dimensional
      and three-dimensional changes following orbital reconstruction and to check the
      equality of the postoperative values for the affected orbits in comparison with
      those of the unaffected sides. Patients with unilateral posttraumatic orbital
      defects (n = 18) underwent computer-assisted surgery and preoperative planning
      using a spiral computed tomography database. Surgical procedures were preplanned
      with virtual correction by mirroring an individually defined three-dimensional
      segment from the unaffected side onto the deformed side, creating an ideal
      unilateral reconstruction. These computer-models were intraoperatively used as
      virtual templates to navigate the preplanned contours and the globe projection
      using the Stryker-Leibinger navigation system. Individual noninvasive
      registration with an overall inaccuracy of approximately 1 mm was achieved by
      using a maxillary occlusal splint with four markers. The mirroring of the
      unaffected side allowed an ideal virtual reconstruction. A mean decrease in
      enlarged orbital volume of 4.0 (SD +/- 1.9) cm was achieved, as was a mean
      increase in the sagittal globe projection of 5.88 (SD +/- 2.98) mm. With a paired
      Student test, the decrease between the preoperative and postoperative differences
      of the affected and unaffected sides was proved significant for orbital volume,
      globe projection, and computed tomography-based Hertel scale changes (p < 0.01).
      In 15 of 18 cases, simultaneous malar bone advancement resulted primarily in an
      additional increase in orbital volume before intraorbital augmentation with
      calvarial split-bone grafts could be performed. Intraorbital bony augmentation
      included one (n = 1), two (n = 7), three (n = 8), and all four (n = 2) orbital
      walls. Computer-assisted preoperative planning enables the surgeon to predict
      reconstructive surgical steps before the operation. Highly vulnerable structures
      such as the optic nerve can be detected and avoided intraoperatively, and
      virtually preplanned bone graft positions and/or orbital frame contours can be
      checked. Computer-assisted preoperative planning and surgery thus advance the
      difficult surgical field of orbital reconstruction, particularly through a
      greater exploitation of radiologic information without additional radiation to
      the patient.

PMID- 12409760
TI  - Neurovascular musculus obliquus internus abdominis flap free transfer for facial
      reanimation in a single stage.
AB  - A study of the anatomy and transplantation of the musculus obliquus internus
      abdominis with a neurovascular pedicle transfer for facial reanimation in one
      stage is presented. Eleven adult cadavers (22 face sides) were dissected to
      observe the shape, thickness, innervation, and blood supply of the musculus
      obliquus internus abdominis. The blood supply of this muscle primarily comes from
      the musculus obliquus internus abdominis branch of the deep circumflex iliac
      artery (diameter, 1.3 +/- 0.2 mm), but it can also come from the eleventh
      intercostal artery (diameter, 1.14 +/- 0.3 mm) and the infracostal artery
      (diameter, 1.5 +/- 0.2 mm). The branch of the deep circumflex iliac artery and
      its vena comitans, or the infracostal artery and its vena comitans, could be
      anastomosed for muscle transplantation. The innervation of the musculus obliquus
      internus abdominis comes from the tenth and eleventh intercostal nerves (length,
      12.7 +/- 1.5 cm) and the infracostal nerve (length, 12.9 +/- 1.3 cm). The
      eleventh intercostal nerve and the infracostal nerve were selected for
      anastomosis of muscle transplantation. From November of 1995 to November of 1999,
      14 patients with long established facial paralysis were treated with
      transplantation of a musculus obliquus internus abdominis flap in one stage and
      were followed for 10 months to 6 years. In 13 patients, the dynamic functions of
      the transplanted muscles were restored, the obliqueness of the mouth and philtrum
      while static was corrected, and the facial muscle activities while smiling were
      harmonized. The eyelids of the paralyzed side could be closed postoperatively,
      indicating that the function of the orbicularis oculi of the paralyzed side was
      restored. The single-stage transplantation of a free musculus obliquus internus
      abdominis flap with one vascular, multi-nerve pedicle is a new method for facial
      reanimation in the treatment of long established facial paralysis. Because of the
      simplicity of the procedure and the completeness of the functional reanimation of
      the paralyzed facial muscles, compared with the results of other free muscle flap
      transfers, it is an ideal procedure for facial reanimation.

PMID- 12409761
TI  - Reconstructive breast surgery: referring physician knowledge and learning needs.
AB  - Despite the positive impact that reconstructive breast surgery can have on a
      woman's quality of life, the percentage of eligible candidates that have this
      procedure remains surprisingly low. The authors hypothesized that this may be
      attributable to inadequate knowledge, inadequate information, and/or
      misinformation available to physicians caring for these patients. A needs
      assessment of primary care physicians, general surgeons, oncologists, and plastic
      surgeons was conducted to determine referring physicians' current level of
      knowledge of reconstructive breast surgery and to discover potential learning
      needs. This comprised a survey, focus groups, and individual interviews.
      Referring physicians rated their own knowledge of reconstructive breast surgery
      as low. Plastic surgeons rated their referring physicians' knowledge as even
      lower. Specific learning needs were identified, as large discrepancies between
      referring physicians' self-reported knowledge of individual breast reconstruction
      topics and their own opinion of their relevance were revealed. In addition,
      despite evidence to the contrary, more than one-third of referring physicians
      indicated a belief that a breast reconstruction delayed the detection of local
      cancer recurrence and adversely interfered with adjuvant oncologic therapy. This
      lack of knowledge and misinformation may be negatively affecting patient
      referrals to plastic surgeons, as more than one-third of referring physicians and
      90 percent of plastic surgeons believed that eligible candidates were not being
      offered referrals because of inadequate referring physician knowledge of this
      topic. Furthermore, patients older than 49 years were not being referred despite
      the fact that plastic surgeons would consider these patients as potential
      surgical candidates. Referring physician gender affected both referral patterns
      and perceived importance of reconstructive breast surgery. Finally, personal
      beliefs and past experiences played a role both in physicians' decisions to refer
      patients and in patients' decisions to have breast reconstructions. These
      deficiencies in information, knowledge, and learning needs should be addressed by
      educational interventions during residency training and through continuing
      education endeavors.

PMID- 12409763
TI  - Long-term results of MISTI gold breast implants: a retrospective study.
AB  - MISTI Gold breast implants (Bioplasty, St. Paul, Minn.) filled with
      polyvinylpyrrolidone-hydrogel were developed as a promising alternative to
      silicone-filled implants. Some studies have reported on the positive effects of
      the implant, such as improved radiolucency and biocompatibility of the gel;
      however, there are also reports that such implants increased in volume and were
      subject to capsular contracture in the human body, resulting in demands for their
      removal. The purpose of this retrospective study was to analyze the long-term
      results of a series of patients with MISTI Gold breast implants. Between 1991 and
      1993, the authors inserted 83 MISTI Gold implants in 61 patients with an average
      age of 46 years (range, 16 to 69). The authors were able to follow up 48 patients
      with 71 MISTI Gold implants. The average follow-up was 68 months (range, 10 to
      108 months). The retrospective study found that 59 percent of all MISTI Gold
      implants were removed after an average period of 4.14 years. The main reason for
      implant removal was an increase in volume of 38 percent, followed by capsular
      contracture in 14 percent of all 71 MISTI Gold implants. The average increase in
      volume of all removed MISTI Gold implants was 43 percent. Capsular contracture
      was graded as Baker I and II in 63 percent and as Baker III and IV in 37 percent.
      In conclusion, the authors believe that MISTI Gold implants do not fulfill the
      criteria of safe breast implants, and they agree with the December of 2000
      opinion of the Medical Devices Agency of the Department of Health in London that
      the hydrogel-filled breast implants should not be used until more information
      about the filler material and its metabolic fate is available.

PMID- 12409765
TI  - The sphenozygomatic suture as a key site for osteosynthesis of the
      orbitozygomatic complex in panfacial fractures: a biomechanical study in human
      cadavers based on clinical practice.
AB  - The aims of this study were to determine the forces required for fracturing the
      intact orbitozygomatic complex and to evaluate the strength of the
      orbitozygomatic complex-fixation, especially with regard to the sphenozygomatic
      suture as a fixation point. In severe midfacial and panfacial fractures, the
      sphenozygomatic suture is routinely used in the authors' practice as a key site
      for fixation of the orbitozygomatic complex, thus establishing a stable outer
      frame as a basis for subsequent reconstruction. However, this has never been
      formally described, nor has it been biomechanically tested. Eight human cadaver
      heads were subjected to forces applied in a standard fashion to the
      orbitozygomatic complex on both sides (n = 16) using a servohydraulic testing
      machine. The force required to break the intact orbitozygomatic complex was
      measured on both sides. Subsequently, fracture patterns were noted and each
      orbitozygomatic complex (n = 16) was assigned to one of four groups: four-point
      fixation (zygomatic arch, frontozygomatic suture, infraorbital rim,
      zygomaticomaxillary buttress) using a 1.3/2.0-mm titanium system (group 1) and a
      2.0-mm bioresorbable system (group 3); or three-point fixation (zygomatic arch,
      frontozygomatic suture, sphenozygomatic suture) using 1.3/2.0-mm titanium system
      (group 2) and a 2.0-mm bioresorbable system (group 4). Forces for failure of the
      constructs were measured. The force for failure of the intact orbitozygomatic
      complex was 1826 +/- 852 N. The mean force required for failure of the
      reconstructed orbitozygomatic complex was 504 +/- 178 N for group 1, 620 +/- 304
      N for group 2, 93 +/- 22 N for group 3, and 133 +/- 31 N for group 4. The
      titanium constructs provided 27.7 percent (four-point fixation) and 31.7 percent
      (three-point fixation) of the intact breaking strength of the orbitozygomatic
      complex, which was significantly higher (p < 0.05) compared with 5.4 percent
      (four-point fixation) and 7.7 percent (four-point fixation) for the bioresorbable
      system. Plate bending (91 percent) was the primary cause for failure in the
      titanium plating system, whereas plate and screw breakage (57 percent) was
      responsible for failure of the resorbable system. The fixation of the
      sphenozygomatic suture was a key site in the fixation of the orbitozygomatic
      complex, which could be demonstrated with superior results in the three-point
      fixation group compared with the four-point fixation group. The bioresorbable
      system showed the lowest values in this cadaver study. Further experimental and
      clinical studies might determine whether the bioresorbable materials are
      sufficient for the treatment of complex fractures of the orbitozygomatic complex.

PMID- 12409767
TI  - Correcting an anterior open-bite side effect during distraction with spring
      forces.

PMID- 12409768
TI  - A simplified bone distractor for induced osteogenesis.

PMID- 12409769
TI  - Alternatives to thumb replantation.
AB  - LEARNING OBJECTIVES: After studying this article, the participant should: 1. Have
      a variety of options for thumb reconstruction. 2. Know the advantages and
      disadvantages of the nonmicrosurgical and microsurgical techniques for thumb
      reconstruction. 3. Understand the decision making from the variety of thumb
      reconstruction techniques based on patient needs. 4. Have a basic understanding
      of the various thumb reconstruction techniques discussed. The traumatic
      amputation of the thumb is an absolute indication for attempted replantation. The
      profound disability of the hand resulting from absence of the thumb, with loss of
      pinch and grasp, obliges the surgeon to make every attempt to replant the
      amputated thumb and preserve hand function. However, not all attempts at
      replantation result in survival of the amputated portion, and unreconstructable
      damage to or complete loss of the amputated part may preclude attempted
      replantation. In such situations, the surgeon must have alternative methods of
      dealing with the sequelae of thumb loss. This article will discuss
      nonmicrosurgical and microsurgical techniques for thumb reconstruction.

PMID- 12409770
TI  - It's only a scalpel, not a magic wand!

PMID- 12409771
TI  - The deviated nose: optimizing results using a simplified classification and
      algorithmic approach.
AB  - The deviated nose presents a particular challenge to the rhinoplasty surgeon
      because, frequently, both a functional problem (airway obstruction) and an
      aesthetic problem must be addressed. An approach to the deviated nose is
      presented that relies on accurate preoperative planning and precise
      intraoperative execution of corrective measures to return the nasal dorsum to
      midline, restore dorsal aesthetic lines, and maintain airway patency. The
      principles of correction include wide exposure through the open approach, release
      of all deforming forces to the septum, straightening of the septum while
      maintaining an adequate dorsal and caudal strut, restoring long-term support,
      reducing the hypertrophied turbinates, and performing controlled stable
      percutaneous osteotomies. An operative algorithm is described that emphasizes
      simplicity and reproducibility, and case studies demonstrate the results that can
      be achieved with this approach.

PMID- 12409773
TI  - Rejuvenation of the midface by elevating the malar fat pad: review of technique,
      cases, and complications.
AB  - The midface is an area where definite and consistent improvement is still hard to
      achieve. Vertical suspension of the malar fat pad is an effective midface lift
      that complements facial rejuvenation to obtain an overall appearance of youth and
      beauty while maintaining the personal features of the patient. To substantiate
      its effectiveness, the authors evaluated the complications and long-term results
      of the malar fat pad elevation proper and in conjunction with other facial
      procedures. A retrospective review of the medical records of 458 consecutive
      patients who underwent malar fat pad elevation by the senior author (B.C.D.) from
      January of 1994 to January of 2000 was conducted. Because 14 patients had their
      malar fat pad re-elevated, the number of midface lifts totaled 472. Of these, 437
      had a combined superficial musculoaponeurotic system excision and tightening, 19
      had a combined limited superficial musculoaponeurotic system
      plication/imbrication, and 16 had elevation of the malar fat pad only. Elevating
      the malar fat pad appears to be a sound, straightforward, and effective means of
      rendering a youthful midface. It consistently reshapes the malar eminence,
      softens the nasolabial fold, and rejuvenates the lower eyelid. This technique
      provides lasting results, with an acceptable complication rate. Facial nerve
      injury, in particular, was infrequent and temporary. In addition, the prehairline
      scar happened to be quite inconspicuous, especially in patients older than 55
      years. This experience confirms that malar fat pad elevation is a safe and
      effective method to rejuvenate the central third of the face.

PMID- 12409775
TI  - The midface sling: a new technique to rejuvenate the midface.
AB  - In the early 1990s, the midface became the focus of facial rejuvenation, and
      various techniques effected elevation by plicating, or on, the midface. Recent
      analyses of facial aging demonstrate that selective ptosis of the midfacial
      tissues lateral to the nasolabial fold results in an infraorbital hollow and
      deepening of the nasolabial fold. Therefore, the authors propose that the
      midface, from the lower portion of the cheek mass, will result in superior
      midface positioning. Since 1996, the authors have elevated the midface in select
      patients by placing a sling of prosthetic (Gore-Tex) or autogenous (tendon or
      fascia) material through the cheek mass. The sling is secured medially to the
      infraorbital rim using a nonabsorbable periosteal suture or a mechanical anchor.
      As variable tension is applied laterally toward the superficial temporal fascia,
      the sling functions as a fulcrum to return the cheek mass to a more youthful
      anatomical position. Elevating the cheek mass in this fashion fills the
      infraorbital hollow and results in amelioration of deep nasolabial folds and
      jowling. With a mean follow-up of 18 months, 50 patients treated with the midface
      sling report satisfaction with the procedure. There have been no instances of
      nerve damage, infection, or hematoma in the midface. None of the slings have
      required removal and ectropion has not occurred. Because of postoperative
      asymmetry in one patient, additional elevation of the ipsilateral cheek mass was
      performed by increasing the tension on the lateral cheek portion of the midface
      sling. Mathematical models demonstrate the biomechanical superiority of lift
      through the use of multiple vectors as compared with linear pull techniques. In
      this fashion, the midface sling supports the cheek mass, providing rapid, simple,
      and secure elevation. Because of the limited subcutaneous dissection, there is a
      reduced risk of facial nerve damage and cutaneous vascular compromise. Unlike
      with other techniques, the lateral portion of the sling may be easily identified
      through a small incision in the temporal scalp, facilitating subsequent
      postoperative adjustment of the midface suspension. Furthermore, because the
      entire cheek mass is permanently supported with an inelastic sling, the results
      may last longer than those with techniques that rely on sutures to plicate or
      lift portions of the superficial musculoaponeurotic system.

PMID- 12409780
TI  - Cosmetic surgery reveals: resolution of the core paradox of cosmetic surgery by a
      shift in paradigm.

PMID- 12409778
TI  - Endoscopic forehead lift: review of technique, cases, and complications.
AB  - Endoscopy has provided a significant improvement in the surgical rejuvenation of
      the upper face. It offers a minimally invasive alternative that avoids many of
      the undesirable effects associated with the coronal approach. The standard
      minimal access forehead endoscopic procedure consists of a subperiosteal
      undermining through three small triangular prehairline incisions. To successfully
      elevate the eyebrows, it is essential to release the periosteum at the level of
      the supraorbital rims and ablate the brow depressor muscles of the glabella.
      Until the periosteum reattaches itself, elevation is maintained by a temporary
      suspension suture between staples at the incision sites and 5 cm posterior to the
      hairline. The transverse closure of the triangular skin incisions achieves some
      additional elevation. The biplanar approach adds a partial subcutaneous
      undermining of the forehead to the endoscopic technique and allows plication of
      the frontalis muscle and excision of excess forehead skin. It is offered to
      patients with very ptotic eyebrows, deep transverse wrinkles, or a high forehead.
      The prehairline incision is a disadvantage but is tolerated quite well in older
      patients. The medical records of 393 consecutive patients who underwent
      endoscopic forehead lift from 1994 to 2000 were reviewed. Because seven patients
      had the endoscopic forehead lift repeated, the number of forehead endoscopies
      totaled 400. The complication rate was quite acceptable and did not markedly
      increase when a forehead lift was performed in combination with other facial
      procedures. The endoscopic forehead lift consistently attenuated the transverse
      forehead wrinkles, reduced the glabellar frown lines, and raised the eyebrows. It
      provided an appearance that was less tired and angry in addition to opening the
      area around the eyes. Long-term follow-up has shown that the endoscopic forehead
      lift produces lasting and predictable results.

PMID- 12409781
TI  - Reading your own obituary.

PMID- 12409782
TI  - The game of the name: ASPRS revisited.

PMID- 12409783
TI  - Pharmacological treatment of obesity.

PMID- 12409784
TI  - The current status of tissue glues: part II. For adhesion of soft tissues.

PMID- 12409785
TI  - Human growth hormone and anti-aging.

PMID- 12409786
TI  - Reverse-flow island sural flap.

PMID- 12409787
TI  - Initial experience with the Brava nonsurgical system of breast enhancement.

PMID- 12409788
TI  - Litigation.

PMID- 12409789
TI  - Wound complications of infusion pain pump therapy.

PMID- 12409790
TI  - Ectopic tooth in a cleft lip and palate patient.

PMID- 12409791
TI  - Soft-tissue chondroma in the thumb.

PMID- 12409792
TI  - Paul of Aegina.

PMID- 12409793
TI  - Mohs' surgery to reduce the size of facial defects and necessity for complex
      repairs.

PMID- 12409794
TI  - The use of an extended groin flap for vaginal reconstruction.

PMID- 12409795
TI  - Reconstruction of the lower lip with a tongue flap.

PMID- 12409796
TI  - Necrosis of the toe resulting from protein-s deficiency.

PMID- 12409797
TI  - An unusual presentation of third crus of antihelix: correction by
      perichondrioplasty technique.

PMID- 12409798
TI  - "Second look" at auricular reconstruction with a postauricular island flap: "Flip
      flop flap".

PMID- 12409799
TI  - Multiple subcutaneous lipomas: do they need further diagnostic approach before
      excision?

PMID- 12409800
TI  - A "True" false-negative misadventure in free flap monitoring using laser Doppler
      flowmetry.

PMID- 12409801
TI  - Respect and equality for women.

PMID- 12409802
TI  - The drainage of large seromas: a quick, closed system.

PMID- 12409803
TI  - Hernia through an iliac crest bone-graft donor site.

PMID- 12409804
TI  - Collagen sheets as temporary wound cover in major open fractures before
      definitive flap cover.

PMID- 12409805
TI  - Consensus conference: Role of Physical Activity and Exercise Training in
      Neuromuscular Diseases. San Diego, California, USA. September 30-October 3, 2001.

PMID- 12409807
TI  - Performance and physiologic adaptations to resistance training.
AB  - Weight lifting, or resistance training, is a potent stimulus to the neuromuscular
      system. Depending on the specific program design, resistance training can enhance
      strength, power, or local muscular endurance. These improvements in performance
      are directly related to the physiologic adaptations elicited through prolonged
      resistance training. Optimal resistance training programs are individualized to
      meet specific training goals. When trained properly (i.e., similar intensity and
      volume), these functional and physiologic adaptations are similarly impressive
      among women and the aged as they are among young men. Yet, in contrast to
      relative measurements, sex and age differences exist in the absolute magnitude of
      adaptation. Of equal importance, perhaps most notably among the elderly, are the
      important health benefits that may also be derived from resistance training. For
      example, bone density, insulin sensitivity, and co-morbidities associated with
      obesity can be effectively managed with resistance exercise when it is conducted
      on a regular basis. The extent of the functional and health benefits to be
      accrued from resistance training depend on factors such as initial performance
      and health status, along with the specification of program design variables such
      as frequency, duration, intensity, volume, and rest intervals.

PMID- 12409808
TI  - Neural adaptations with chronic activity patterns in able-bodied humans.
AB  - The purpose of this article is to review the neural adaptations that occur in
      able-bodied humans with alterations in chronic patterns of physical activity. The
      adaptations are categorized as those related to cortical maps, motor command,
      descending drive, muscle activation, motor units, and sensory feedback. We
      focused on the adaptations that occur with such activities as strength training,
      limb immobilization, and limb unloading. For these types of interventions, the
      adaptations are widely distributed throughout the nervous system, but those
      changes that are observed with strength training are often not the converse of
      those found with reduced-use protocols.

PMID- 12409809
TI  - Membrane excitability and calcium homeostasis in exercising skeletal muscle.
AB  - Preservation of the membrane electrochemical gradients for Na, K, and Ca is vital
      to the maintenance of skeletal muscle structure and function. Muscle excitability
      may be depressed during contractile activity by changes in the gradients for Na
      and K, while muscle force may be reduced by an activity-induced increase in free
      intracellular Ca. Compensatory processes help to maintain ion electrochemical
      gradients in normal, active muscles, but compensatory mechanisms may be impaired
      in injured or diseased muscles, contributing to muscle pathology.

PMID- 12409810
TI  - Skeletal muscle plasticity: cellular and molecular responses to altered physical
      activity paradigms.
AB  - The goal of this article is to examine our current understanding of the chain of
      events known to be involved in the adaptive process whereby specific genes and
      their protein products undergo altered expression; specifically, skeletal muscle
      adaptation in response to altered loading states will be discussed, with a
      special focus on the regulation of the contractile protein, myosin heavy chain
      gene expression. This protein, which is both an important structural and
      regulatory protein comprising the contractile apparatus, can be expressed as
      different isoforms, thereby having an impact on the functional diversity of the
      muscle. Because the regulation of the myosin gene family is under the control of
      a complex set of processes including, but not limited to, activity, hormonal, and
      metabolic factors, this protein will serve as a cellular "marker" for studies of
      muscle plasticity in response to various mechanical perturbations in which the
      quantity and type of myosin isoform, along with other important cellular
      proteins, are altered in expression.

PMID- 12409811
TI  - Exercise-induced muscle damage in humans.
AB  - Exercise-induced muscle injury in humans frequently occurs after unaccustomed
      exercise, particularly if the exercise involves a large amount of eccentric
      (muscle lengthening) contractions. Direct measures of exercise-induced muscle
      damage include cellular and subcellular disturbances, particularly Z-line
      streaming. Several indirectly assessed markers of muscle damage after exercise
      include increases in T2 signal intensity via magnetic resonance imaging
      techniques, prolonged decreases in force production measured during both
      voluntary and electrically stimulated contractions (particularly at low
      stimulation frequencies), increases in inflammatory markers both within the
      injured muscle and in the blood, increased appearance of muscle proteins in the
      blood, and muscular soreness. Although the exact mechanisms to explain these
      changes have not been delineated, the initial injury is ascribed to mechanical
      disruption of the fiber, and subsequent damage is linked to inflammatory
      processes and to changes in excitation-contraction coupling within the muscle.
      Performance of one bout of eccentric exercise induces an adaptation such that the
      muscle is less vulnerable to a subsequent bout of eccentric exercise. Although
      several theories have been proposed to explain this "repeated bout effect,"
      including altered motor unit recruitment, an increase in sarcomeres in series, a
      blunted inflammatory response, and a reduction in stress-susceptible fibers,
      there is no general agreement as to its cause. In addition, there is controversy
      concerning the presence of sex differences in the response of muscle to damage
      inducing exercise. In contrast to the animal literature, which clearly shows that
      females experience less damage than males, research using human studies suggests
      that there is either no difference between men and women or that women are more
      prone to exercise-induced muscle damage than are men.

PMID- 12409812
TI  - Mechanisms of muscle injury gleaned from animal models.
AB  - Eccentric contractions of skeletal muscles produce injury and, ultimately, muscle
      strengthening. Current data suggest that the earliest events associated with
      injury are mechanical in nature and may be based primarily on the sarcomere
      strain experienced by the muscle. In this review, recent experimental data,
      primarily from rabbit dorsiflexor muscles, are used to provide general
      information regarding the factors that cause injury and means for preventing
      injury. Mechanical experiments reveal that excessive sarcomere strain is the
      primary cause of injury. We hypothesize that excessive strain permits
      extracellular or intracellular membrane disruption that may permit hydrolysis of
      structural proteins, leading to the myofibrillar disruption that is commonly
      observed. Inflammation that occurs after injury further degrades the tissue, but
      prevention of the inflammation leads to a long-term loss in muscle function.
      Simple preventative treatments such as increasing muscle oxidative capacity
      (getting into shape) or cyclic stress-relaxation of tissue (stretching out) have
      no measurable effect on the magnitude of muscle injury that occurs. Ultimately,
      an improved understanding of the damage mechanism may improve our ability to
      provide rehabilitative and strengthening prescriptions that have a rational
      scientific basis.

PMID- 12409814
TI  - Muscle fatigue in animal models of neuromuscular disease.
AB  - This review summarizes the literature regarding the fatigue properties of
      skeletal muscles in animal models of neuromuscular disease and the effect of
      exercise training on these properties in diseased muscles. Results of these
      studies are not consistent. Reasons for the variability may include the use of
      differing experimental conditions, varying stimulation protocols, different
      methods of muscle preparation, and a range of temperatures and ages. Despite the
      variability and small sample sizes, these studies of muscle fatigue have revealed
      definite trends. Whereas the slow oxidative soleus muscle from the diseased
      animals fatigued more slowly or at the same rate as controls, the extensor
      digitorum longus (a fast, glycolytic muscle) from the diseased animals fatigued
      more rapidly than controls. The diaphragm-a fast, oxidative, glycolytic muscle
      that is generally fatigue resistant-did not reveal significant changes in
      fatigability. Exercise training had a minimal impact on the fatigue properties of
      skeletal muscle from diseased animals. As molecular and biochemical mechanisms
      are further identified and defined, additional therapeutic interventions may
      become available for these disorders. It is hoped that this review will serve as
      a guide for investigators who use an animal model to evaluate interventions for
      neuromuscular diseases.

PMID- 12409815
TI  - Role of fatigue in limiting physical activities in humans with neuromuscular
      diseases.
AB  - New methods of examining both central and peripheral fatigue are now available. A
      broader understanding of the mechanisms of fatigue in healthy human subjects has
      begun to emerge. The mechanisms of fatigue in patients with various neuromuscular
      diseases are even more complex than in healthy persons. Examples of both central
      and peripheral fatigue in various neuromuscular diseases and other disorders are
      presented, including metabolic myopathy, chronic fatigue syndrome, postpolio
      syndrome, and amyotrophic lateral sclerosis.

PMID- 12409816
TI  - Physical activity, health impairments, and disability in neuromuscular disease.
AB  - Reduced physical activity is a consequence of progressive neuromuscular diseases,
      which negatively impacts quality of life and health outcomes. Reduced functional
      muscle mass is common to all neuromuscular diseases and results from both atrophy
      of disuse secondary to a sedentary lifestyle and muscle degeneration secondary to
      the disease itself. This review summarizes current concepts relating to the
      impact of reduced physical activity on health and fitness, potential determinants
      of physical activity levels in neuromuscular diseases, and new approaches to the
      quantitative measurement of physical activity in neuromuscular disease
      populations. The interrelationship of disease pathophysiology, impairment,
      functional limitation, disability, and societal limitation in the determination
      of physical activity in the community in neuromuscular diseases is discussed
      using Duchenne muscular dystrophy as an example. Future research pertaining to
      physical activity in neuromuscular disease will need to focus on the development
      of scientifically based recommendations concerning optimal exercise approaches
      with both disease-specific and general guidelines.

PMID- 12409817
TI  - Response to resistive strengthening exercise training in humans with
      neuromuscular disease.
AB  - The role of strengthening exercise to potentially improve weakness and the
      functional abilities of persons with neuromuscular diseases is controversial.
      There are questions about the ability of diseased skeletal muscle to respond to
      resistance exercise, particularly in light of concerns about weakness induced by
      exercise. Numerous studies show promising results of strength training, although
      methodologic issues limit conclusions. This article reviews current knowledge in
      this area and provides recommendations for future investigations.

PMID- 12409818
TI  - Adaptations in skeletal muscle disuse or decreased-use atrophy.
AB  - Those factors that seem to play some role in inducing adaptations of skeletal
      muscle in vivo are discussed. The role of myogenesis in maintaining and repairing
      muscle during atrophic and hypertrophic states is discussed, including pointing
      out that the modulation of myonuclear number is one means of adapting to varying
      chronic levels of neuromuscular activity. Finally, we point out the potential
      consequences of muscle atrophy on the control of movement and the susceptibility
      to fatigue.

PMID- 12409819
TI  - Response to aerobic exercise training in humans with neuromuscular disease.
AB  - There have been few studies examining the response of persons with neuromuscular
      disease and postpolio syndrome to cardiopulmonary testing and aerobic exercise
      training. In persons with neuromuscular disease that directly involves the
      cardiac and respiratory systems, deficits in performance may be primarily due to
      these limitations, along with loss of functional muscle tissue from the disease
      process. In the more slowly progressive disorders, deconditioning may play an
      important role in limiting aerobic exercise performance and may be amenable to
      training. Recommendations are provided for future exercise studies with these
      populations.

PMID- 12409820
TI  - Adaptations to exercise training and contraction-induced muscle injury in animal
      models of muscular dystrophy.
AB  - This article reviews the current status of exercise training and contraction
      induced muscle-injury investigations in animal models of muscular dystrophy. Most
      exercise-training studies have compared the adaptations of normal and dystrophic
      muscles with exercise. Adaptation of diseased muscle to exercise occurs at many
      levels, starting with the extracellular matrix, but also involves cytoskeletal
      architecture, muscle contractility, repair mechanisms, and gene regulation. The
      majority of exercise-injury investigations have attempted to determine the
      susceptibility of dystrophin-deficient muscles to contraction-induced injury.
      There is some evidence in animal models that diseased muscle can adapt and
      respond to mechanical stress. However, exercise-injury studies show that
      dystrophic muscles have an increased susceptibility to high mechanical forces.
      Most of the studies involving exercise training have shown that muscle
      adaptations in dystrophic animals were qualitatively similar to the adaptations
      observed in control muscle. Deleterious effects of the dystrophy usually occur
      only in older animals with advanced muscle fiber degeneration or after high
      resistive eccentric training. The main limitations in applying these conclusions
      to humans are the differences in phenotypic expression between humans and
      genetically homologous animal models and in the significant biomechanical
      differences between humans and these animal models.

PMID- 12409821
TI  - Molecular pathophysiology of myofiber injury in deficiencies of the dystrophin
      glycoprotein complex.
AB  - Duchenne muscular dystrophy is caused by mutations in the gene encoding
      dystrophin, a 427 kd protein normally found at the cytoplasmic face of the
      sarcolemma. In normal muscle, dystrophin is associated with a multimolecular
      glycoprotein complex. Primary mutations in the genes encoding members of this
      glycoprotein complex are also associated with muscular dystrophy. The dystrophin
      glycoprotein complex provides a physical linkage between the internal
      cytoskeleton of myofibers and the extracellular matrix, but the precise functions
      of the dystrophin-glycoprotein complex remain uncertain. In this review, five
      potential pathogenetic mechanisms implicated in the initiation of myofiber injury
      in dystrophin-glycoprotein complex deficiencies are discussed: (1) mechanical
      weakening of the sarcolemma, (2) inappropriate calcium influx, (3) aberrant cell
      signaling, (4) increased oxidative stress, and (5) recurrent muscle ischemia.
      Particular emphasis is placed on the multifunctional nature of the dystrophin
      glycoprotein complex and the fact that the above mechanisms are in no way
      mutually exclusive and may interact with one another to a significant degree.

PMID- 12409822
TI  - Oxidative stress and the pathogenesis of muscular dystrophies.
AB  - The muscular dystrophies represent a diverse group of diseases differing in
      underlying genetic basis, age of onset, mode of inheritance, and severity of
      progression, but they share certain common pathologic features. Most prominent
      among these features is the necrotic degeneration of muscle fibers. Although the
      genetic basis of many of the dystrophies has been known for over a decade and new
      disease genes continue to be discovered, the pathogenetic mechanisms leading to
      muscle cell death in the dystrophies remain a mystery. This review focuses on the
      oxidative stress theory, which states that the final common pathway of muscle
      cell death in these diseases involves oxidative damage.

PMID- 12409823
TI  - Role of physical activity and exercise training in neuromuscular diseases.
AB  - The objective of the State of the Science Roundtable conference was to provide a
      responsible assessment of the state of the science regarding exercise training
      and fatigue in humans and animals with neuromuscular diseases. The conference
      comprised a nonfederal, nonadvocate, 20-member panel that brought together
      exercise scientists, neuromuscular disease investigators, and clinicians during a
      21/2 day workshop. The literature was searched using MEDLINE, and an extensive
      bibliography of references was created. Experts in each area presented reviews
      based on this literature. Scientific evidence was given precedence over clinical
      anecdotal experience. After the presentations, the panel answered predefined
      questions and developed conclusions based on the scientific evidence presented in
      open forum and the scientific literature. The panel presented a draft statement
      during the conference and produced this revised statement after the conference.

PMID- 12409824
TI  - Development and use of a new staging system for severe acute pancreatitis based
      on a nationwide survey in Japan.
AB  - METHODOLOGY: In 1997, a cooperative nationwide survey of 192 patients diagnosed
      with severe acute pancreatitis in 1996 was carried out. RESULTS: Alcoholic
      pancreatitis was the major etiology (46%), and the male-to-female ratio was
      2.6:1. Overall, the mortality rate was 27%, which was similar to the rate (30%)
      in the first nationwide survey of 1,219 patients diagnosed between 1982 and 1986
      that was performed in 1987. A marked difference between the surveys was the early
      mortality rate within 2 weeks: 52% in the 1987 survey and 29% in the current
      survey. We devised a new stage classification system for acute pancreatitis.
      Stages 0 and 1 are equivalent to mild and moderate conditions, respectively, in
      the conventional classification, and stages 2 and higher correspond to severe
      acute pancreatitis. Severity scores of 2-8 are regarded as stage 2, scores of 9
      14, as stage 3, and scores of > or =15, as stage 4. The mortality rates were as
      follows: 0, stages 0 and 1 at hospitalization; approximately 10%, stage 2;
      approximately 30-40%, stage 3; and approximately 70-100%, stage 4. CONCLUSION: We
      found that stage at hospitalization reflected the prognosis of acute
      pancreatitis.

PMID- 12409825
TI  - Comparison of Ranson, APACHE II and APACHE III scoring systems in acute
      pancreatitis.
AB  - INTRODUCTION: Acute pancreatitis runs an unpredictable course. The early
      prediction of the severity of an acute attack has important implications for
      management and timely intervention. AIM: To assess the prognostic accuracy of
      Ranson and APACHE II and III scoring systems in predicting the severity of acute
      pancreatitis. METHODS: One hundred fifty-three patients with acute pancreatitis
      (67.3% gallstone-related, 9.2% alcoholic, 17% idiopathic, and 6.5% of
      miscellaneous causes) were studied prospectively. Data conforming to the scoring
      systems were recorded 24 (the APACHE scores) and 48 hours (the Ranson score)
      after admission. Analysis was performed by using receiver operating
      characteristic curves (ROC), area under a curve (AUC), and by comparing
      likelihood ratios of positive test (LRPT). RESULTS: One hundred nineteen cases of
      pancreatitis were classified as mild, and 34 were classified as severe. The
      mortality rate was 3.2%. All three scores correlated with length of stay and
      disease severity. AUC for Ranson was found to be significantly larger than AUC
      for APACHE II and APACHE III score (0.817, cut-off > or =3; 0.618, cut-off, > or
      =10; and 0,676, cut-off > or =42 respectively). The Ranson score achieved the
      highest sensitivity and the lowest false-negative rate, but the positive and
      negative predictive values and LRPT were of similar extent for all three scores.
      CONCLUSION: The APACHE III offers little, if any, advantage over the APACHE II
      score. Ranson criteria proved to be as powerful a prognostic model as the more
      complicated APACHE II and III scoring systems, but with the disadvantage of a 24
      hour delay.

PMID- 12409826
TI  - A prospective study of detection of pancreatic carcinoma by combined plasma K-ras
      mutations and serum CA19-9 analysis.
AB  - INTRODUCTION: Previous studies have demonstrated the possibility of detecting K
      mutations in the plasma of patients with pancreatic carcinoma. AIM: To
      investigate the diagnostic value of combined plasma K mutations with serum CA19-9
      in patients with pancreatic carcinoma. METHODOLOGY: The study included 58
      consecutive patients with suspected pancreatic masses and 21 healthy controls.
      DNA was extracted from plasma. Point mutation at codon 12 of K gene was analyzed
      by means of the enriched polymerase chain reaction-restriction fragment length
      polymorphism technique. RESULTS: No mutated K codon 12 was detected in the plasma
      DNA from the 21 healthy controls. Mutations of K codon 12 were found in plasma
      DNA samples from 29 (70.7%) of 41 patients with pancreatic carcinoma. Elevated
      CA19-9 was found in 30 (73.2%) of 41 pancreatic cancer patients. In total, 37 of
      41 (90.2%) patients with pancreatic carcinoma tested positive by either method.
      Mutated K was also found in 3 patients and elevated CA19-9 in 8 of the 17
      patients with other lesions in the pancreatic area. CONCLUSION: The results
      indicate that plasma K mutation analysis combined with serum CA19-9 determination
      could detect the majority of cases of pancreatic carcinoma.

PMID- 12409827
TI  - Expression of ERRP in normal and neoplastic pancreata and its relationship to
      clinicopathologic parameters in pancreatic adenocarcinoma.
AB  - INTRODUCTION AND AIMS: Epidermal growth factor (EGF) and its receptor (EGFR) play
      crucial roles in cellular signaling in many malignancies, including pancreatic
      neoplasia. Attenuation of EGFR signaling has been considered novel strategy for
      the management of human malignancies in several ongoing clinical trials. We
      recently isolated a novel negative regulator of EGFR, termed EGF receptor related
      protein (ERRP), whose expression appears to attenuate EGFR activation. In the
      current study, the expression of ERRP in normal and neoplastic pancreas was
      investigated and correlated with the clinicopathologic parameters in pancreatic
      ductal adenocarcinoma (DA). METHODOLOGY: Using rabbit polyclonal antibody that
      specifically interacts with ERRP, immunohistochemical staining was performed on
      45 benign pancreata and 106 cases of DA. The intensity and percentage of cells
      with cytoplasmic and membranous staining were scored as 0, 1, 2, or 3. A combined
      score was calculated as intensity x percent/3, and for comparative analysis, the
      data were arbitrarily divided into three groups: <20, 20-49, and > or =50. The
      expression of ERRP was correlated with patient age, gender, race, tumor size,
      stage, grade, and survival. RESULTS: ERRP was expressed in most benign ductal
      epithelium and islet cells, but not in normal acinar cells. In pancreatic ductal
      adenocarcinoma, ERRP expression frequency decreased progressively from well (WD)
      to moderate (MD) to poorly differentiated (PD) carcinoma (58%, 43%, and 15%
      respectively, < 0.001). ERRP expression was correlated with survival in DA
      showing decreased median survival with decreased ERRP score ( = 0.0035). Median
      survival of the lower intensity (0 or 1) group was less than that of the higher
      intensity (2 or 3) group (8 14 months, = 0.002). The higher expressing group (>
      or =50% of cells) had longer median survival (17 months) than the lower
      expressing (<50% of cells) group (10 months, = 0.003). Stepwise multiple
      regression analyses revealed that ERRP expression score and tumor grade are the
      significant predictors of survival in pancreatic ductal carcinomas ( < 0.03).
      CONCLUSION: ERRP is usually expressed in benign ductal epithelium, but not in
      ductal adenocarcinoma. Its expression decreases with decreasing tumor
      differentiation. Low levels of ERRP are associated with poor clinical outcome,
      suggesting that progressive loss of ERRP, a negative regulator of EGFR, may
      partly stimulate aggressive tumor cell growth in pancreatic adenocarcinoma.

PMID- 12409828
TI  - Analysis of duodenal drainage fluid after cholecystokinin (CCK) stimulation in
      healthy volunteers.
AB  - INTRODUCTION AND AIMS: Hormonal stimulatory agents are used to assess pancreatic
      function. Biologically derived secretin, the most widely used pancreatic
      secretagogue, is no longer available in the United States. Existing secretory
      tests using cholecystokinin alone are cumbersome, requiring a unique dual tube
      (gastric and duodenal) collection system and constant perfusion of a
      nonabsorbable marker to calculate enzyme output (in international units [IU]). A
      simpler, quantitative cholecystokinin stimulation test that measures enzyme
      concentrations (in international units per liter [IU/L]) instead of total output
      would obviate need for marker perfusion/collection. The aim of our experiment was
      to study the secretory patterns of pancreatic enzyme concentration in duodenal
      fluid after cholecystokinin stimulation in healthy volunteers. METHODOLOGY:
      Healthy subjects had a Dreiling tube inserted endoscopically into the ligament of
      Treitz. Gastric and duodenal aspiration ports were connected to low intermittent
      suction. A 20-minute baseline was obtained to clear the gastric and duodenal
      lumina of residual fluid. Cholecystokinin was infused at a constant rate of 40
      ng/kg per hour. Duodenal fluid was collected on ice for 80 minutes in four 20
      minute aliquots. Aspirated fluid was analyzed for enzyme concentration with an
      automated chemistry analyzer in the hospital biochemistry laboratory. RESULTS:
      Nineteen healthy volunteers were studied. The mean volume (+/-SEM) of duodenal
      fluid collected was 85 +/- 4.4 mL (range, 48 to 118 mL). Fluid analysis revealed
      a significant rise in mean lipase concentration (+/-SEM) from a baseline of
      595,680 +/- 11,930 IU/L to a peak of 1,778,847 +/- 171,204 IU/L (mean difference
      = 1,183,167 IU/L; 95% CI= 664,459 IU/L to 1,701,875 IU/L; < 0.001, Student test).
      Increases in amylase concentrations were markedly less pronounced and did not
      reach statistical significance. Mean peak lipase concentration occurred within 50
      minutes of acinar cell stimulation. All patients tolerated tube placement, and
      there were no episodes of acute pancreatitis or abdominal pain. CONCLUSIONS:
      Pancreatic lipase concentrations in duodenal fluid increase nearly threefold
      after cholecystokinin stimulation in healthy volunteers. This magnitude of enzyme
      secretory response may be a marker of pancreatic function and could potentially
      lead to a more clinically useful and simpler pancreatic function test. This
      physiologic study serves as the basis for our further investigations of
      cholecystokinin-stimulated lipase concentrations as a new test in the assessment
      of pancreatic insufficiency.

PMID- 12409829
TI  - The assessment of pancreatic exocrine function by bentiromide test in patients
      with chronic portal vein thrombosis.
AB  - INTRODUCTION: It has been noted in the literature that cavernous transformation
      of the portal vein (CTPV) can cause pancreatic duct atrophy, probably by enhanced
      collateral formation, but the clinical significance of this has not been
      established. AIMS: To evaluate whether CTPV affects the pancreatic exocrine
      functions. METHODOLOGY: Eighteen patients with CTPV were identified and
      prospectively studied. In these cases, despite a full clinical, biochemical,
      radiologic, and hematological evaluation, we found no etiologic factor for
      thrombosis in the portal vein (PV). All patients underwent a detailed evaluation
      for pancreatic morphology and pancreatic exocrine functions. In all cases,
      abdominal Doppler ultrasonography (US), abdominal spiral computed tomography
      (CT), and endoscopic retrograde cholangiopancreatography (ERCP) were performed
      for evaluation of pancreatic morphology. For the purpose of this study, serial
      biochemical tests, including measurement of serum amylase, pancreatic amylase,
      lipase, glucose, calcium, and lipids, were performed every 3 months. All 18
      patients also underwent a bentiromide test to determine whether there was any
      exocrine pancreatic insufficiency. The findings were compared with those for 20
      healthy control subjects and reference controls. RESULTS: For all 18 patients
      with idiopathic CTPV and all controls, ERCP was performed successfully. The
      pancreatic duct was determined to be smaller than in control subjects and in a
      reference control group ( < 0.05). In this group serum pancreatic amylase,
      alkaline phosphatase, and direct bilirubin levels were found to be higher than in
      controls, and statistically important differences between the two groups ( <
      0.05) were documented. In all 18 subjects the bentiromide test was well tolerated
      and was performed successfully. For 15 of them (83%), we found that urinary
      excretion of para-amino benzoic acid (PABA) was significantly less than in
      control subjects and the reference control group ( < 0.05). CONCLUSION:
      Pancreatic duct atrophy in patients with CTPV is clinically significant. When
      clinical signs are not manifest and routine biochemical tests are not useful for
      detecting exocrine pancreatic insufficiency, the bentiromide test is highly
      sensitive and specific for detecting probable pancreatic insufficiency in
      patients with CTPV.

PMID- 12409830
TI  - Treatment of unresectable, locally advanced pancreatic adenocarcinoma with
      combined radiochemotherapy with 5-fluorouracil and cisplatin.
AB  - INTRODUCTION: Adenocarcinoma of the pancreas remains one of the most difficult
      malignancies to treat. Its incidence has steadily increased over the past four
      decades, and its prognosis is still dismal. AIM To assess tumor control and the
      palliative benefit of 5-fluorouracil (5-FU), cisplatin (CDDP), and radiotherapy
      in patients with advanced pancreatic cancer. METHODOLOGY: Systemic chemotherapy
      consisted of 5-FU (600 mg/m ), given as a 22-hour infusion on days 1 to 5, and
      CDDP (100 mg/m ), given as a 90-minute infusion on day 2. Treatment courses were
      repeated identically on day 21. Radiotherapy was delivered using megavolt
      irradiation of 25-MV photons with a two- or four-field isocentric technique.
      RESULTS: Twenty-seven patients were treated with this radiochemotherapy (RCT).
      Twenty-one patients (78%) completed initial treatment. The median dose of
      radiation therapy delivered was 42.5 Gy. At the time of evaluation (1 month after
      the end of the RCT), no grade 4 (WHO) toxicity was observed; 12 patients had
      improved or stable body weight; pain was improved for 20 patients, with 11
      experiencing no pain; and analgesic consumption decreased for 18 patients, of
      whom 11 stopped intake. The clinical benefit response was 7/27 (26%). Median
      survival and time to progression were, respectively, 9 and 4.4 months.
      CONCLUSION: This RCT regimen had a good impact on clinical benefit in locally
      advanced pancreatic carcinoma, without severe side effects.

PMID- 12409831
TI  - Locoregional chemotherapy for patients with pancreatic cancer intra-arterial
      adjuvant chemotherapy after pancreatectomy with portal vein resection.
AB  - INTRODUCTION AND AIMS: The survival of pancreatic cancer patients with portal
      vein resection is extremely poor due to the high incidence of liver metastasis.
      The occurrence of liver metastasis is decreased by locoregional arterial infusion
      after pancreatic surgery. Chemosensitivity tests can provide the basis for
      individualized chemotherapy in each patient and predict the clinical response.
      Therefore, the current study was designed to clarify whether locoregional
      chemotherapy based on the results of chemosensitivity tests has the clinical
      effects of preventing liver metastasis and improving survival for patients with
      portal vein resection. METHODOLOGY: The resected specimens from 40 of 47 patients
      with resection of pancreatic cancer were assessed for chemosensitivity to various
      anticancer drugs. Fourteen patients underwent portal vein resection due to direct
      invasion, and nine of these patients received intra-arterial adjuvant
      chemotherapy on the basis of the results of MTT assay to prevent liver
      metastasis. The remaining five patients received no chemotherapy. RESULTS: None
      of the patients who received intra-arterial chemotherapy had liver metastasis,
      and this group of patients had improved survival. The mean survival of patients
      with intra-arterial chemotherapy was significantly longer than that of patients
      without chemotherapy (25.6 months with chemotherapy versus 9.4 months without
      chemotherapy). CONCLUSION: A pilot study of postoperative intra-arterial
      chemotherapy showed the reduction of liver metastasis and improvement of survival
      among pancreatic cancer patients with portal vein resection.

PMID- 12409832
TI  - Irsogladine malate up-regulates gap junctional intercellular communication
      between pancreatic cancer cells via PKA pathway.
AB  - INTRODUCTION: Gap junctions (GJs) are intercellular channels that aid
      communication between coupling cells and may play a critical role in cell
      differentiation and growth. Connexins (Cxs) are structural proteins of GJs.
      Though several reports have demonstrated that Cx expression decreases in various
      malignant tumors, a pancreatic cancer cell line, PANC-1, was reported to express
      Cx43 mRNA. It is known that irsogladine malate (IM) can up-regulate gap
      junctional intercellular communication (GJIC). We examined the effects of IM on
      GJ between pancreatic cancer cells (PC cells) and the mechanism of GJ up
      regulation. METHODOLOGY: GJIC between PC cells (PANC-1) was evaluated by dye
      transfer methods. The expression of Cx43 was estimated by Western blot analysis
      with immunoprecipitation sample and immunohistochemical analysis. Intracellular
      cAMP level was estimated by enzyme-linked immunoassay. RESULTS: IM increased cell
      coupling in a dose-dependent manner (0M-10 ). Western blot analysis of Cx43
      revealed that PANC-1 cells expressed Cx43 protein. Treatment with IM was found to
      move localization of Cx43 immunoreactive spots from the cytoplasm to boundary
      lesions with neighboring cells, but no major change was seen in the
      phosphorylation state of Cx43. Intracellular cAMP level was increased by IM. The
      PKA inhibitor H-89 and adenylyl cyclase inhibitor SQ22536 inhibited the effects
      of IM. CONCLUSION: These results suggest that IM up-regulates GJIC between PC
      cells via regulation of the PKA pathway. It also suggests a useful adjuvant of IM
      to pancreatic cancer therapy.

PMID- 12409833
TI  - Molecular cloning and characterization of chymopasin, a novel serine protease
      from rat pancreas.
AB  - INTRODUCTION: Pancreas secretes many enzymes for food digestion into the
      pancreatic juice. We cloned a novel serine protease, chymopasin, from rat
      pancreas. AIMS: To know the localization of this enzyme in the pancreas and to
      analyze the enzymatic characteristics. METHODOLOGY: We cloned chymopasin cDNA
      using 3' and 5' RACEs. Northern blot and in situ hybridization were used to study
      the expression of this enzyme. Recombinant chymopasin protein produced by was
      analyzed by Western blot using specific antibody, and its enzymatic
      characteristics were examined using commercially available synthetic substrates,
      fibrin and gelatin. RESULTS: The open reading frame of rat chymopasin consisted
      of 792 bp encoding 264 amino acid residues. The deduced amino acid sequence
      contained the essential catalytic triad characteristic of the serine protease
      family. There was no putative N-glycosylation site. The amino acid sequence of
      rat chymopasin showed 54.5% identity to rat chymotrypsin B. Northern blot
      analysis showed that the transcript was strongly expressed in the pancreas. In
      situ hybridization with digoxigenin-labeled cRNA probe showed that the positive
      signals were observed in the acinar cells, but not in the islet or duct cells.
      Chymopasin protein was detected in the pancreas homogenate and bile-pancreatic
      juice. Further, cerulein stimulated the secretion of rat chymopasin into bile
      pancreatic juice. CONCLUSION: These results suggested that rat chymopasin might
      be a digestive enzyme secreted from the acinar cells. From the enzyme assay using
      synthetic substrates, the purified recombinant chymopasin expressed in showed
      chymotrypsin-like activity. In addition, rat recombinant chymopasin showed
      fibrinolytic and gelatinolytic activities. These results suggested a role in the
      pathogenesis of pancreatic damage.

PMID- 12409834
TI  - Adenosine uptake inhibition ameliorates cerulein-induced acute pancreatitis in
      mice.
AB  - INTRODUCTION AND AIMS: Adenosine shows protective effects against cellular damage
      and dysfunction under several adverse conditions such as inflammation and
      ischemia. In the current study, we examined the effects of 3-[1-(6,7-diethoxy-2
      morpholinoquinazolin-4-yl)piperidin-4-yl]-1,6-dimethyl-2,4(1,3 )-quinazolinedione
      hydrochloride (KF24345), an adenosine uptake inhibitor, on cerulein-induced acute
      pancreatitis in mice to investigate whether inhibition of adenosine uptake could
      ameliorate the severity of acute pancreatitis. METHODOLOGY: Acute pancreatitis
      was induced in mice with six intraperitoneal injections of cerulein (50 microg/kg
      each) at hourly intervals. RESULTS: The cerulein injection increased activities
      of serum amylase and lipase and caused pathologic changes such as interstitial
      edema, polymorphonuclear cell infiltration, and acinar cell necrosis in the
      pancreas. KF24345 (10 mg/kg p.o.) ameliorated all these changes observed in mice
      with acute pancreatitis, and the suppressing effect of KF24345 on the elevation
      in serum amylase activity was abolished by the treatment with 8-(p
      sulfophenyl)theophylline, an adenosine receptor antagonist. In addition, 2
      (aminocarbonyl)- -(4-amino-2,6-dichlorophenyl)-4-[5,5-bis-(4-fluorophenyl)pentyl]
      1-piperazineacetamide (R75231) and dipyridamole, other adenosine uptake
      inhibitors, also decreased the elevated serum amylase activity. CONCLUSIONS:
      These are the first demonstrations that the adenosine uptake inhibitors
      ameliorate cerulein-induced acute pancreatitis in mice, and these data suggest
      that adenosine uptake inhibition could ameliorate the severity of acute
      pancreatitis in vivo.

PMID- 12409835
TI  - Effect of high dietary fat on insulin secretion in genetically diabetic Goto
      Kakizaki rats.
AB  - INTRODUCTION AND AIM: To clarify the effects of a high fat-diet on insulin
      secretion from genetically diabetic beta cells, Goto-Kakizaki rats and Wistar
      rats were subjected to oral glucose tolerance test (OGTT) after 12-week high-fat
      feeding. METHODOLOGY: We compared Wistar and Goto-Kakizaki (GK) rats fed a high
      fat diet (45% fat content) for 12 weeks, measuring insulin secretion and insulin
      release. RESULTS: Insulin secretion during oral glucose tolerance test (OGTT) was
      enhanced in high-fat diet-fed Wistar rats (WF) with normal glucose tolerance.
      Insulin secretion in high-fat diet-fed GK rats (GF) during OGTT also was enhanced
      together with deteriorated glucose tolerance. Basal insulin release from the
      isolated perfused pancreas at 3.3 m glucose in WF was comparable to that in
      normal chow-fed Wistar rats (WN), but basal insulin release in GF was remarkably
      higher than in normal chow-fed GK rats (GN). Stimulated insulin release induced
      by 16.7 m glucose was remarkably increased in WF compared with WN. Total insulin
      release at 16.7 m glucose in both GK rat groups was similar and minimal.
      CONCLUSION: These results indicate that normal pancreatic beta-cells have the
      ability to secrete sufficient insulin to compensate for the insulin resistance
      induced by a high-fat diet. In contrast, glucose metabolism in diabetic rats
      after high-fat diet deteriorated partly because of insufficient insulin secretion
      caused by genetic defects and lipotoxicity due to chronically high FFA levels.

PMID- 12409836
TI  - Central Orexin-A stimulates pancreatic exocrine secretion via the vagus.
AB  - INTRODUCTION: Digestive organs are controlled from the central nervous system,
      and the vagus nerve plays an important role. Orexins are recently purified
      neuropeptides localized in neurons within the lateral hypothalamus. AIM: To
      examine the effects of centrally injected Orexin-A and B on pancreatic exocrine
      secretion in conscious rats. METHODOLOGY: Rats were prepared with cannulae
      draining bile and pancreatic juice separately. The experiments were conducted
      without anesthesia on day 4 or 5 after the operation. RESULTS:
      Intracerebroventricular administration of Orexin-A (0.25, 0.5, and 1.0 nmol)
      significantly increased pancreatic fluid and protein output in a dose-dependent
      manner. A significant stimulatory effect of Orexin-B was not observed.
      Pretreatment with the ganglion blocker hexamethonium and with atropine completely
      abolished the stimulatory effect of central Orexin-A. Central Orexin-A
      significantly increased pancreatic secretion after pretreatment with omeprazole.
      Intravenous injection of Orexin-A had no effect. Centrally administered Orexin-A
      stimulated the vagal efferent nerve in anesthetized rats. CONCLUSIONS: Centrally
      administered Orexin-A stimulates pancreatic exocrine secretion through the vagal
      efferent nerve, and the stimulatory action is independent of gastric acid
      secretion.

PMID- 12409837
TI  - Stimulation of amylase release by Orexin is mediated by Orexin 2 receptor in
      AR42J cells.
AB  - INTRODUCTION AND AIMS: Orexins have been demonstrated to have mainly central
      physiological functions, including regulation of food and water intake, sleep,
      and arousal. However, little is known about their direct peripheral effects, if
      any. As a first step toward understanding the role of Orexin in non-neuronal
      tissues or cells, we initiated studies to examine expression of Orexin receptors
      (OXR) in an established pancreatic tumor cell line AR42J. Secondly, we wanted to
      determine whether Orexins, in various molecular forms, are active to stimulate
      any known pancreatic cell functions in AR42J cells. METHODOLOGY: Reverse
      transcription-PCR analysis was performed to identify the presence of specific
      Orexin receptor subtypes. Intracellular calcium mobilization and cAMP levels were
      measured following stimulation by Orexin A and B peptides, their respective C
      terminal decapeptide fragments, and hypocretin-2-gly (glycine-extended Orexin B).
      Release of alpha-amylase was measured in conditioned media after acute
      stimulation with the set of Orexin peptides for 30 minutes. Cell proliferation
      was determined by H-thymidine incorporation after 24 hours following treatment
      with Orexins under serum-free condition. RESULTS: RT-PCR and sequencing results
      showed that Orexin receptor subtype 2 (OX2R) was the main form expressed in AR42J
      cells. Orexins stimulated dose-dependent increases in intracellular calcium
      mobilization with EC50 0.05 nM for Orexin A and 0.1 nM for Orexin B but were
      unable to stimulate any significant cAMP accumulation or DNA synthesis even at
      micromolar concentrations. Both Orexin-A and -B, but not hypocretin-2-gly, also
      stimulated dose-dependent increases in amylase release in the AR42J cells. Orexin
      A and -B carboxyl-terminal decapeptides elicited significant but much lower
      calcium and amylase responses. CONCLUSION: Our data demonstrate that OX2R
      mediates Ca -dependent amylase release in AR42J cells, suggesting that Orexins
      may have secretory functions in pancreatic tumor cells.

PMID- 12409838
TI  - What is the risk of alcoholic pancreatitis in heavy drinkers?

PMID- 12409839
TI  - Acute gallstone pancreatitis.

PMID- 12409840
TI  - Acinar cell carcinoma of the pancreas in a morbidly obese patient.

PMID- 12409841
TI  - Do mast cells play any role in the pathogenesis of experimental pancreatic
      fibrosis in rats?

PMID- 12409842
TI  - Effects of selective endocrine or exocrine induction of AR42J on SNARE and Munc18
      protein expression.
AB  - INTRODUCTION AND AIM: We used the amphicrine AR42J as an excellent model to study
      the differentiation of the secretory machinery of pancreatic endocrine and
      exocrine cells. Dexamethasone treatment induced the AR42J to differentiate
      towards the exocrine phenotype capable of secreting amylase in response to
      cholecystokinin. In contrast, activin A plus hepatocyte growth factor treatment
      of a subclone of AR42J, AR42J-B13, induced this cell to differentiate
      morphologically and functionally toward an insulin-containing and insulin
      secreting endocrine phenotype. We took advantage of these unique properties of
      selective exocrine and endocrine induction of the AR42J to reveal which distinct
      combinations of exocytic SNARE complex proteins (syntaxin, SNAP-25 and VAMP) and
      associated Munc18 proteins were preferentially expressed to play a role in enzyme
      and insulin secretion. RESULTS AND CONCLUSION: To our surprise, both endocrine
      and exocrine induction of AR42J and AR42J-B13 caused very similar upregulation in
      the expression of the exocytic member isoforms of the syntaxin, SNAP-25, VAMP,
      and Munc18 families. We conclude that whereas the differentiation of the proximal
      components of the secretory machinery of the exocrine acinar and endocrine islet
      beta-cells is distinct, the differentiation of the distal components of
      exocytosis between these two cell types is very similar.

PMID- 12409845
TI  - A remarkable legacy of science: review of AHRQ-funded articles published in
      Medical Care during John Eisenberg's Directorship of AHRQ. Agency for Health care
      Research and Quality.

PMID- 12409843
TI  - The role of monocyte chemoattractant protein-1 in experimental chronic
      pancreatitis model induced by dibutyltin dichloride in rats.
AB  - INTRODUCTION: Recently, dibutyltin dichloride (DBTC) was reported to induce
      pancreatic fibrosis within 28 days in rats, but it is not clear that the induced
      condition should be considered chronic pancreatitis. AIM AND METHODOLOGY: The aim
      of this study was to clarify whether the pancreatic fibrosis induced by DBTC can
      be regarded as chronic pancreatitis. Furthermore, we examined the relation of
      monocyte chemoattractant protein-1 (MCP-1) to the development of pancreatic
      fibrosis in this model. DBTC solution was injected into the right jugular vein in
      rats, and biochemical and histologic changes were measured at days 1, 3, 7, 14,
      and 28. RESULTS: Microscopically, inflammatory cell infiltration was evident in
      the pancreas at days 1 and 3, mononuclear cell infiltration was observed at days
      7, 14, and 28, and pancreatic fibrosis was pronounced 7 days later. At day 28,
      interstitial fibrosis and atrophy of the gland and ductlike tubular complex had
      progressed. DBTC produced a significant decrease in the contents of pancreatic
      protein and amylase, whereas the pancreatic hydroxyproline content increased.
      Serum and pancreatic MCP-1 concentration significantly increased compared with
      the control group. Furthermore, the expression of PDGF mRNA in the pancreas
      increased following the MCP-1 elevation. CONCLUSIONS: These results suggest that
      this experimental model of pancreatic fibrosis induced by DBTC in rats was useful
      as a chronic pancreatitis model and that MCP-1 may play an important role in the
      development of pancreatic fibrosis.

PMID- 12409844
TI  - Resveratrol inhibits proliferation and induces apoptosis in human pancreatic
      cancer cells.
AB  - INTRODUCTION: Because of lack of early diagnosis and poor therapeutic
      responsiveness, median survival in patients with pancreatic cancer is <6 months,
      and survival beyond 5 years is rare. Thus, another dimension in chemotherapeutic
      agents for pancreatic cancer would be beneficial to control metastatic and
      unresectable disease. Resveratrol, a natural product from grapes, has been shown
      to be chemopreventive for carcinogen-induced skin cancer and also to inhibit
      proliferation of oral squamous, breast, colonic, and prostate cancer cells. AIM:
      To investigate the effect of resveratrol in pancreatic cancer. METHODOLOGY: To
      evaluate the potential role of resveratrol on pancreatic cancer cell
      proliferation, two human pancreatic cancer cell lines, PANC-1 and AsPC-1, were
      used. RESULTS: Resveratrol inhibited proliferation of both PANC-1 and AsPC-1 in a
      concentration- and time-dependent manner as measured by [ H]thymidine
      incorporation. Cell number of both PANC-1 and AsPC-1 was also significantly
      decreased following 48 and 72 hours of treatment with 100 micromol/L resveratrol.
      The growth inhibition induced by resveratrol was accompanied by apoptotic
      morphologic changes, characterized by cell rounding and cell membrane blebbing
      suggesting apoptosis. Propidium iodide staining of DNA, measured by flow
      cytometry, showed a dramatic increase in the fraction of sub-G0/G1 cells
      following resveratrol treatment in both PANC-1 and AsPC-1. The substantial
      apoptosis inducted by resveratrol on these two cell lines was confirmed by the
      terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end
      labeling assay. CONCLUSION: These findings suggest that the natural product
      resveratrol may have a potent antiproliferative effect on human pancreatic cancer
      with induction of apoptosis. Resveratrol is likely to be valuable for the
      management and prevention of human pancreatic cancer.

PMID- 12409846
TI  - John M. Eisenberg: telling the story.

PMID- 12409847
TI  - Commentary on John M. Eisenberg's "Physician utilization: the state of research
      about physicians' practice patterns".

PMID- 12409848
TI  - Physician utilization: the state of research about physicians' practice patterns.

PMID- 12409849
TI  - Structure, process, and outcomes in stroke rehabilitation.
AB  - BACKGROUND: The health services research framework of structure, process, and
      outcome is used commonly to examine quality of care, and it indicates that
      structure influences process, which in turn influences outcomes. However, little
      empirical work has been done to test this hypothesis, particularly for medical
      rehabilitation. OBJECTIVES: To determine if, among stroke patients, (1) structure
      of care was associated with process of care, and (2) structure of care was
      associated with outcomes after adjusting for process. RESEARCH DESIGN: Two-year,
      prospective study of 288 acute stroke patients in 11 VA medical centers, of whom
      128 were included in the current analysis. MEASURES: Structure of care: systemic
      organization, staffing expertise, and technological sophistication. Process of
      care: compliance with the AHCPR poststroke rehabilitation guidelines. PATIENT
      CHARACTERISTICS: baseline prior walking ability and Functional Independence
      Measure (FIM) motor subscale. OUTCOMES: the FIM motor subscale 6-months
      poststroke. RESULTS: The combination of systemic organization and staffing
      expertise, along with technological sophistication, were independent predictors
      of process of care (beta coefficients 0.21, P<0.05 and 0.37, P<0.001,
      respectively). When controlling simultaneously for patient characteristics,
      structure and process of care, structure of care did not have and process of care
      did have a statistically significant association (beta coefficient 0.18, P<0.01)
      with functional outcomes. CONCLUSIONS: Better process of care was associated with
      better 6-month functional outcomes, therefore improving process of care probably
      would improve stroke outcomes. However, our results indicate that improving key
      structure of care elements might facilitate improving process of care for stroke
      patients.

PMID- 12409850
TI  - The role of public insurance and the public delivery system in improving birth
      outcomes for low-income pregnant women.
AB  - BACKGROUND: Insurance expansions and service delivery system expansions are
      alternative policy instruments used to try to improve birth outcomes for low
      income women. OBJECTIVES: The objective of this research is to investigate the
      effect of expansions of public insurance on access and birth outcomes for
      pregnant women and the role of different delivery systems in these outcomes.
      MATERIALS AND METHODS: The experience in Florida during the years 1989-1994 is
      studied. Data are from linked birth certificates, hospital discharge data,
      Medicaid eligibility and claims files, and county health department records. Use
      of prenatal care and birthweight for low-income women is compared under different
      financing for prenatal care and for those using different delivery systems.
      Several approaches to control for self-selection are adopted, and similar results
      are obtained with each. RESULTS: Women enrolled in Medicaid have more prenatal
      care visits than the uninsured. Outcomes for those on Medicaid and the uninsured
      are significantly better if they receive care in the public health system than if
      they receive care in the private system-including private offices, clinics, and
      HMOs. Over time, the gap in outcomes between those in the public system and those
      receiving prenatal care from private physicians has diminished. CONCLUSIONS:
      Public insurance improves access to services, but the delivery system is a key
      factor in improving outcomes.

PMID- 12409851
TI  - Association between health insurance coverage of office visit and cancer
      screening among women.
AB  - BACKGROUND: Little is known regarding the nuances of insurance benefit design
      that may affect the receipt of clinical preventive services. OBJECTIVE: To
      evaluate whether differences in insurance coverage of physician office visits
      influences the receipt of cancer screening in women who have full coverage for
      the screening services. DESIGN: Cohort study of women enrolled in fee-for-service
      (FFS) or Preferred Provider Organization (PPO) health plans, where FFS plans have
      less generous office visit coverage, for the period 1995 to 1997. SETTINGS AND
      PARTICIPANTS: General Motors Corporation's employees and their dependents. MAIN
      OUTCOME MEASURES: Papanicolaou and mammography rates in women aged 21 to 64 years
      (n = 139,294) and 52 to 64 years (n = 56,554), respectively. RESULTS: Compared
      with FFS plans, enrollees in PPO plans were significantly more likely to obtain a
      Papanicolaou smear and mammogram (adjusted relative risk [RRa] = 1.22; 95% CI,
      1.21-1.24; and RRa, 1.17; 95% CI, 1.15-1.18, respectively). The association was
      more pronounced among hourly individuals (RRa, 1.27; 95% CI, 1.26-1.29 for
      Papanicolaou smears; RRa, 1.17; 95% CI, 1.16-1.19 for mammograms) than among
      salaried individuals (RRa, 1.10; 95% CI, 1.08-1.12 for Papanicolaou smears and
      RRa, 1.10; 95% CI, 1.06-1.12 for mammograms), corresponding to a greater
      differential in office visit coverage among the hourly group. CONCLUSIONS:
      Benefit structure appears to have an important effect on receipt of cancer
      screening in women. The findings highlight the need to ensure that future reforms
      of the health care system do not adversely affect the use of preventive services.

PMID- 12409852
TI  - Patient choice of breast cancer treatment: impact on health state preferences.
AB  - BACKGROUND: Multiple treatment options exist for many medical conditions. The
      extent to which physicians should involve the patient in the choice the treatment
      to be delivered is not well understood. OBJECTIVE: To test the impact of breast
      cancer treatment choice on patients' health state preferences. DESIGN AND
      SETTING: A cohort from 29 hospitals (primarily referral centers) in
      Massachusetts, Texas, Washington DC, and New York. Subjects were surveyed at 5
      months, 1 year, and 2 years following surgery and asked whether they had a choice
      in the type of treatment received. SUBJECTS: Women age 67 or older treated in
      1996 to 1997 for localized breast cancer (n = 683). MEASURES: Patient preferences
      for current health state, assessed with patient valuations using the visual
      analogue scale (VAS) from the EuroQol instrument and with general public
      valuations using the Health Utilities Index (HUI), and 1-year medical costs.
      RESULTS: For the adjusted analysis at 5 months, the adjusted mean VAS score was
      78.7 for women who reported a choice and 75.3 for women who reported no choice, a
      difference of 3.4 (P = 0.03). The difference in the HUI score was 3.6 (P= 0.10)
      and the difference in the 1-year medical costs was -4363 dollars (P = 0.01).
      There were no statistically significant differences at the 1-year and 2-year
      interviews. CONCLUSIONS: A woman's perception of choice of surgical treatment for
      breast cancer is associated with a short-term benefit on her preference of health
      state, suggesting choice helps with recovery, but does not provide long-term
      benefits.

PMID- 12409853
TI  - Change of subjective visual function in first-eye cataract patients when the rate
      of surgery increases in a population.
AB  - BACKGROUND: The increasing demand for cataract surgery has stimulated interest in
      outcome research and the potential public health impact of the intervention.
      OBJECTIVE: To determine the impact of an increased rate of first-eye cataract
      surgery on visual acuity (VA) and subjective visual ability/disability, before
      and after surgery, in a geographically defined population. RESEARCH DESIGN: A
      prospective, observational study. SUBJECTS: All patients who had first-eye
      cataract extraction at one clinic during two separate 1-year periods. Five
      hundred seventy-six patients had surgery in 1997, and 353 had surgery in 1992
      (17.2 and 10.6 per 1000 population 65 and older, respectively). MEASURES: Best
      corrected VAs were measured, and the patients answered self-administered
      questionnaires, before and after surgery. The questionnaires focused on the
      patients' subjective difficulties performing some common vision-dependent
      activities, such as reading, television-viewing, orientation, etc. RESULTS: In
      1997 compared with 1992 the VA of the eye to be operated was on average better
      (chi2 for trend; P<0.0001), and the subjective visual disability was less before
      surgery (mean disability index 6.9 vs. 7.5; P<0.0001). There was also a smaller
      percentage of mature cataracts (15% vs. 23%; P<0.0001). After surgery the VA of
      the operated eye was better in 1997 (chi2 for trend; P<0.001), but there was no
      difference in improvement of subjective visual ability, nor change in subjective
      visual disability, compared with 1992. The patients' expectations and actual
      postoperative improvement of their ability to cope with daily life were higher in
      1997 (chi2 for trend; P<0.0001 and P<0.001). CONCLUSIONS: A higher frequency of
      first-eye cataract surgery in a population was before surgery associated with an
      on average better VA of the eye to be operated, a less perceived visual
      disability regarding some common vision-dependent activities, a lower percentage
      of mature cataracts and thus earlier surgery. Consequently, a higher rate of
      surgery would likely be associated with a lesser amount of visual impairment
      because of cataract in the population.

PMID- 12409854
TI  - The value of patient-reported health status in predicting short-term outcomes
      after coronary artery bypass graft surgery.
AB  - BACKGROUND: Risk stratification for comparison of outcomes after coronary artery
      bypass grafting (CABG) typically includes only clinical measures of risk. Patient
      reported health status may be an important independent predictor of short-term
      health outcomes. OBJECTIVE: To determine whether patient-reported health status,
      as measured by the Physical and Mental Component Summary scores of the SF-36,
      predicts in-hospital mortality and prolonged length of stay after CABG, after
      controlling for other clinical predictors of those outcomes. RESEARCH DESIGN:
      Prospective cohort study conducted from September 1993 to November 1995.
      SUBJECTS: One thousand seven hundred seventy-eight adults who underwent isolated
      CABG for myocardial ischemia. MEASURES: In-hospital mortality and prolonged
      length of stay (> 14 days). RESULTS: There were 27 deaths and 223 patients with
      prolonged length of stay in the study sample. A 10-point decrease in the Physical
      Component Summary (PCS) score increased the odds of in-hospital mortality by 61%
      (OR, 1.61; 95% CI, 1.04-2.49), independent of established clinical risk factors.
      Similarly, a 10-point decrease in the PCS score increased the odds of prolonged
      length of stay by 33% (OR, 1.33; 95% CI, 1.13-1.57). A 10-point decrease in the
      Mental Component Summary score (MCS) decreased the odds of mortality by 36% (OR,
      0.64; 95% CI, 0.43-0.95). CONCLUSIONS: The PCS score is independently and
      significantly associated with in-hospital mortality and prolonged length of stay,
      after controlling for clinical risk factors. The MCS score is independently and
      significantly associated only with mortality, though the direction of the effect
      is unexpected. The result likely reflects a property of the scoring of the MCS
      and not a finding of clinical substance. Although caution must be taken when
      interpreting the summary scores, the SF-36 yields information not otherwise
      captured by clinical data and may be useful in risk stratification for in
      hospital mortality and prolonged length of stay after CABG.

PMID- 12409855
TI  - Premenstrual dysphoric disorder: is there an economic burden of illness?
AB  - OBJECTIVE: To quantify the economic burden associated with premenstrual dysphoric
      disorder (PMDD) by assessing health care service use and related expenditures,
      work loss, role limitation, and productivity. METHODS: Women ages 21 to 45,
      randomly selected from membership of a northern California HMO (n = 1,194),
      provided prospective daily symptom ratings and survey data on health care use and
      productivity for two menstrual cycles. Summary measures of 12-month utilization
      and expenditures based on HMO encounter data also were constructed. Based on
      daily symptom ratings, we classified women as having minimal (n = 186), moderate
      (n = 801), and severe (n = 151) premenstrual symptoms, or PMDD (n = 56) and
      compared health care use and expenditures, predicted values of productivity and
      work loss, and marginal effects of symptom severity on outcome measures. RESULTS:
      Women with PMDD had higher degrees of luteal phase (premenstrual) productivity
      impairment than those with minimal symptoms. Compared with the minimal and
      moderate symptom groups, women with PMDD continued to report lower productivity
      (P <0.01) in the 5 to 10 days after onset of menses (follicular phase). We found
      little evidence that women spent more time in bed, reduced time at work, or
      decreased activities at home or school as a result of premenstrual symptoms. As
      symptom severity increased, the likelihood of health care service use increased
      only for an emergency department, obstetrician/gynecologist, or alternative
      medicine provider visit. There were no significant differences in health care
      expenditures across the symptom groups. CONCLUSION: The economic burden
      associated with PMDD manifests itself primarily in reported productivity
      decrements rather than health care utilization or costs associated with time away
      from work.

PMID- 12409856
TI  - A qualitative study of patients' and physicians' views about practice-based
      functional health assessment.
AB  - BACKGROUND: Interest has increased in using patient-based measures of health
      status in everyday clinical practice. Patient reports of functioning and well
      being have been most commonly used in clinical-practice settings at the group
      level for research rather than at the individual-patient level for clinical
      decision-making. OBJECTIVES: Little is known about patients' and physicians'
      preferences for practice-based functional health assessment. Qualitative methods
      were used to discover patient and physician attitudes about the use of functional
      health assessment tools in everyday clinical practice. RESEARCH DESIGN: Six focus
      groups were conducted with 39 asthma patients who had been invited to participate
      in practice-based functional health assessment (FHA). Thirty in-depth,
      semistructured interviews were conducted with physicians in a single health
      maintenance organization to discover their attitudes about practice-based FHA.
      SETTING: A large group-model health maintenance organization in Southeastern
      Wisconsin that consists of 200,000 members and 315 providers across 22 locations.
      Patients were selected from the Asthma Clinic and physicians were selected among
      all MD providers. RESULTS: Patients identified numerous practical implementation
      problems with practice-based FHA, including the site of data collection, feedback
      on their responses, and who would have access to the data. Patients also
      identified several barriers and benefits of practice-based FHA. Before they would
      commit financial and human capital resources and time, clinicians wanted
      information about the effectiveness and value of practice-based FHA. CONCLUSIONS:
      Several barriers to practice-based FHA were identified by patients and
      physicians. The evidence-based barrier identified by physicians needs to be
      overcome with additional intervention studies that push the envelope on several
      fronts including: (1) the type of tool; (2) the type of patient; (3) the type of
      setting; and (4) the recipients of the information. Interpretation guides and
      assessment linkage steps need to be developed and tested.

PMID- 12409857
TI  - Loss of health insurance and the risk for a decline in self-reported health and
      physical functioning.
AB  - BACKGROUND: Millions of Americans are intermittently uninsured. The health
      consequences of this are not known. SETTING: National survey. PARTICIPANTS: Six
      thousand seventy-two participants in the Health and Retirement Study (HRS) age 51
      to 61 years old with private insurance in 1992. MEASUREMENTS: Loss of insurance
      coverage between 1992 and 1992 and development of a major decline in overall
      health or a new physical difficulty between 1994 and 1996. RESULTS: In 1994, 5768
      (95.0%) people continued to have private insurance, 229 (3.8%) reported having
      lost all insurance, and 75 (1.2%) converted to having only public insurance. Over
      the subsequent 2 years (1994-1996), the risk for a major decline in overall
      health was 15.6% for those who lost all insurance versus 7.2% for those with
      continuous private insurance (P <0.001). After adjusting for baseline
      sociodemographics, health behaviors, and health status, the adjusted relative
      risk for a major decline in health for those who lost coverage was 1.82 (95% CI,
      1.25-2.59) compared with those with continuous private insurance. Those who lost
      insurance also had a higher risk for developing a new mobility difficulty
      compared with those with continuous private insurance (28.5% vs. 20.4%,
      respectively; P= 0.02), but this was not significant in multivariate analysis
      (adjusted RR, 1.26; 95% CI, 0.90-1.68). CONCLUSIONS: Loss of insurance has
      adverse health consequences even within 2 years after becoming uninsured. Studies
      of insurance coverage should routinely measure the number of Americans uninsured
      at any time over the preceding 2 years as a more accurate measure of the
      population at risk from being uninsured.

PMID- 12409858
TI  - The mental health of adults born of unwanted pregnancies, their siblings, and
      matched controls: a 35-year follow-up study from Prague, Czech Republic.
AB  - This study tested the hypothesis that being born of an unwanted pregnancy is a
      risk factor for poor mental health in adulthood. Self-report and objective data
      were collected at ages 28 to 31 and 32 to 35 years in a cohort of nearly 200
      "unwanted" subjects born after their mothers had been twice denied an abortion
      for the same pregnancy. The same data were collected in a sociodemographically
      matched control cohort of "accepted" subjects whose mothers had not requested an
      abortion, and from siblings of both the unwanted subjects and the accepted
      control subjects. Logistic regression analyses conducted with several indicators
      of poor mental health in adulthood as dependent variables brought partial support
      for the hypothesis. Specifically, unwanted subjects became psychiatric patients
      (especially psychiatric inpatients) more frequently than their siblings and the
      accepted controls. Criminality, alcohol-related disorders, and heavy smoking were
      not associated with unwanted pregnancy.

PMID- 12409859
TI  - Depression, adult attachment, and recollections of parental caring during
      childhood.
AB  - The onset and course of depressive symptoms are influenced by a variety of
      interpersonal factors. Attachment theory provides a developmental framework for
      understanding the relationship between depressive symptoms and insecure
      attachment to one's parents and current romantic partner. The present study
      examined attachment theory for understanding depression and marital adjustment
      among 84 psychiatric inpatients diagnosed with major depressive disorder.
      Participants completed a diagnostic interview and self-report measures of
      depressive symptoms, adult attachment, marital adjustment, and recollections of
      childhood relationships with parents. Avoidant (but not anxious) adult attachment
      mediated the link between current depressive symptoms and patients' recollections
      of relationships with opposite-sex parents. Although nearly three fourths of the
      current sample of depressed psychiatric inpatients acknowledged the presence of
      marital problems, the negative correlation between depressive symptoms and
      marital adjustment did not reach statistical significance. Attachment theory may
      aid therapeutic approaches to depression within the context of marriage and other
      long-term romantic relationships.

PMID- 12409860
TI  - Social cognitive complexity and depression: cognitive complexity moderates the
      correlation between depression self-ratings and global self-evaluation.
AB  - The authors studied the psychometric characteristics of a standardized data
      collection method for assessing the complexity of an individual's cognitions
      about self and other people (social cognitive complexity). A total of 437 college
      undergraduates were assessed using this method and concurrently assessed for
      depression, self-deception, impression management, self-esteem, and
      positive/negative affectivity. It was found that a measure of overall social
      cognitive complexity was internally consistent and demonstrated concurrent and
      discriminant validity. In particular, a composite measure of the complexity of
      both positive and negative cognitions of self and other was associated with
      greater self-reported depression, after controlling for the other variables
      studied (, impression management). It was also found that social cognitive
      complexity moderated the degree of global self-evaluation in self-reported
      depression, such that global self-evaluation accounted for a considerably higher
      amount of the variance of depression in low-complex individuals than it did in
      high-complex individuals.

PMID- 12409861
TI  - Everyday memory and laboratory memory tests: general function predictors in
      schizophrenia and remitted depression.
AB  - This study was designed to compare neuropsychological memory measures
      ("laboratory memory tests") and an everyday memory measure in patients with
      schizophrenia, patients with major depression, and normal controls. Patients with
      schizophrenia ( N= 68) treated with typical (N = 33) or atypical ( N= 35)
      neuroleptics, patients with major depression (N = 30), and a control group (N =
      36) were evaluated with clinical measures (Positive and Negative Syndrome Scale
      and Hamilton Depression Rating Scale), laboratory memory tests (Digit-Span,
      Paired-Associates, Rey Complex Figure Test, and Digit-Symbol), everyday memory
      test (RMBT), and the Global Assessment of Functioning (GAF). The schizophrenia
      group had a significantly lower level of performance in everyday memory and
      general function but not in laboratory memory tests. Verbal and everyday memory
      measures were correlated with general function. The diagnosis rather than current
      symptoms (in remission) contributed to test variance and was correlated with
      performance on everyday memory and general function tests. Everyday memory and
      verbal memory were good predictors of general function in schizophrenic and
      depressive patients in the remitted phase. However, the advantages of these tests
      over laboratory memory tests need to be further investigated in larger and more
      representative samples.

PMID- 12409862
TI  - Daily charting of posttraumatic stress symptoms: a pilot study.
AB  - This pilot study describes a prospective life-charting method for posttraumatic
      stress (PTS) symptoms. This method summarizes daily symptoms, functional
      impairment, life events, substance use, and treatment. Findings include
      experience with 17 cases over periods lasting from 3 to 25 months, with a
      description of 4 case examples that are characteristic of the pilot sample.
      People with posttraumatic stress disorder (PTSD) can complete day charting of
      their symptoms over an extended period of time. Some people reported that day
      charting distressed them mildly as they analyzed daily thoughts or feelings that
      they ordinarily avoided or pushed from awareness. Nonetheless, most people
      reported that they learned and benefited from daily symptom charting. In addition
      to enhancing patient self-understanding (or "insight"), the method may prove
      useful in assessing treatments for PTSD. Finally, these preliminary findings have
      suggested hypotheses regarding the clinical phenomenology and course of PTSD. For
      example, PTS symptom cluster exacerbation, severity, and duration appear to be
      highly consistent within any given patient, but highly variable across patients.
      Daily charting of PTS symptoms over prolonged periods is feasible. This
      prospective PTSD symptom charting method may have therapeutic, clinical, and
      research potential for understanding individual and group patterns in PTSD over
      time.

PMID- 12409863
TI  - Affect regulation in women with borderline personality disorder traits.
AB  - Affect dysregulation is considered a defining feature of borderline personality
      disorder (BPD). In spite of this, there is a dearth of empirical research that
      examines affect regulation among persons with BPD. The present study examined the
      relationship between specific dimensions of affect regulation and borderline
      traits in a sample of 39 patients. Participants were administered the Personality
      Diagnostic Questionnaire-Revised to assess the degree of borderline traits and
      the Affect Intensity Measure and Affect Control Scale to assess dimensions of
      affect regulation, selected based on the biosocial theory of BPD. Results from
      hierarchical regression analyses indicated that level of affect intensity and
      affect control were significantly associated with number of BPD traits, even
      after controlling for level of depression. Findings for affect control remained
      significant even after controlling for affect intensity. These results,
      consistent with biosocial theory of BPD, suggest that persons with BPD experience
      emotions more intensely and have greater difficulty in controlling their
      affective responses.

PMID- 12409864
TI  - Religion, spirituality, and mental health.

PMID- 12409866
TI  - Dissociative identity disorder in Northern Ireland: a survey of attitudes and
      experience among clinical psychologists and psychiatrists.

PMID- 12409865
TI  - Obstetric complications and breast feeding in schizophrenia.

PMID- 12409867
TI  - The relationship between eating psychopathology and separation-individuation in
      young nonclinical women.

PMID- 12409868
TI  - Insight and neuropsychological functions in bipolar outpatients in remission.

PMID- 12409870
TI  - Relationships between anhedonia, depression, and schizophrenia.

PMID- 12409872
TI  - Diagnosis and prevention of neural tube defects.
AB  - PURPOSE OF REVIEW: Neural tube defects, including anencephaly, meningomyelocele
      and encephalocele, are among the most common birth defects that result in severe
      mortality and morbidity. Neural tube defects occur with an incidence of 1-5 per
      1000 births, showing marked geographic, ethnic and temporal variations. Although
      clear evidence exists on preventability of a large proportion of neural tube
      defects by periconceptional folic acid intake, only a low percentage of women are
      following the recommendations. RECENT FINDINGS: In the past few decades
      diagnostic modalities have undergone a change from blood screening tests, such as
      alpha-fetoprotein, to imaging methods. Ultrasound has become the standard tool
      for early diagnosis, whereas fetal magnetic resonance imaging has gained
      importance in evaluating distinct coexisting anomalies of the central nervous
      system. Since the United States authorized the addition of folic acid to grain
      products in 1996, many other countries are considering folic acid fortification
      of their grain products, or have started fortification. Hitherto there is no
      consensus either to the duration of supplementation or to the best dose. SUMMARY:
      Ultrasound and magnetic resonance imaging offer the possibility of early and
      accurate diagnosis of neural tube defects, and have therefore improved medical
      counseling and parents' decision making. Food fortification is the most practical
      way of ensuring sufficient folate supplementation and is warranted during the
      periconceptional period.

PMID- 12409873
TI  - Primary myelomeningocele closure and consequences.
AB  - PURPOSE OF REVIEW: Myelomeningocele, the most frequently occurring open neural
      tube defect, requires lifelong care of the patient by medical professionals and
      by relatives. A basic understanding of the neurosurgical measures that have to be
      taken in the newborn, the infant, the child and the adult is important also for
      physicians of other disciplines involved in the treatment of patients with
      myelomeningocele. RECENT FINDINGS: The most recent topic broadly discussed in
      this context is the role of foetal neurosurgery for closure of the neural tube
      defect. There is ongoing debate as to whether the beneficial postnatal effects of
      a prenatal operation in the unborn foetus outweighs the possible complications
      for the mother as well as the child. SUMMARY: As some of the problems associated
      with myelomeningocele occur only later in life, it will still take many years
      until the beneficial, as well as the adverse, effects of prenatal neurosurgical
      procedures can be evaluated.

PMID- 12409874
TI  - Neurogenic bladder dysfunction in patients with myelomeningocele.
AB  - PURPOSE OF REVIEW: The general management strategies in children with
      myelodysplasia are widely accepted, however diagnostic and therapeutic details
      still need to be discussed and clarified. RECENT FINDINGS: Ten articles are
      reviewed. Two articles are dealing with general clinical aspects; one underlines
      the need for urodynamics as a prerequisite for an adequate treatment strategy,
      the other recommends to evaluate adolescents and adults with myelodysplasia,
      because only the ultimate outcome allows a judgement of how effective our efforts
      are to achieve the goals. Increased excretion of glycosaminoglycan in
      myelodysplasia children above 5 years of age could become a marker for beginning
      bladder damage and deserves further interest. The question whether children with
      normal urodynamics after closing the spinal cord should be followed or not is
      clearly answered in a further article which also discusses the results of
      detethering in these patients. Four articles report on pharmacotherapy with new
      substances or new ways of application (intravesical oxybutynin, extended release
      oxybutynin formulation, intravesical resiniferatoxin). The results of collagen
      injections in children with neurogenic sphincter underactivity clearly
      demonstrate that the long-term results are disappointing. Last, but not least, a
      retrospective review on acute abdominal symptoms and signs in children with
      myelodysplasia clearly shows that these patients should be transferred to a
      centre because of complex reasons and treatment modalities. SUMMARY: Urodynamics 
      abnormal or normal - are a prerequisite for adequate treatment and follow-up in
      children with myelodysplasia. More studies should focus on adolescents and adults
      with myelodysplasia to judge the effectiveness of our diagnostic and therapeutic
      efforts. New ways of application and new developments in pharmacotherapy to relax
      the overactive detrusor may possibly further decrease the need for surgery in the
      future. With regards to sphincter underactivity, results with collagen injections
      in this group of patients are disappointing and provide no alternative to
      operative treatment options.

PMID- 12409875
TI  - Conservative management in neurogenic bladder dysfunction.
AB  - PURPOSE OF REVIEW: A few decades ago, urinary diversion, usually with an ileal
      conduit, was the ultimate outcome for most children with spina bifida. The
      revolutionary institution of clean intermittent catheterization has changed the
      algorithm totally. Furthermore many new drugs have been developed during the past
      decade and have decreased the need for surgery dramatically. In this article, we
      will focus on the most recent data on new modalities of therapy to help avoid
      urinary diversion or bladder augmentation. RECENT FINDINGS: In addition to clean
      intermittent catheterization and oxybutynin treatment, a new generation of
      anticholinergic medications, such as tolterodine, has been developed. For
      patients who drop out because of the side-effects of oral administration, new
      methods of administration are now available, including extended release and
      intravesical instillation. For those unresponsive, botulinum-A toxin and
      resiniferatoxin are two relatively new drugs in the field, administered as
      intravesical injection and instillation, respectively. Intravesical or
      transdermal electrical stimulation, sacral nerve stimulation and biofeedback
      therapy are under development, but as currently administered, are not yet
      completely successful. SUMMARY: Although life-saving in many respects, bladder
      augmentation introduces life-long risks of its own. Our goal in describing
      'conservative' management is to prevent this step. Many alternatives to surgery
      are available now and more effective strategies are under development.

PMID- 12409876
TI  - Renal function in meningomyelocele: risk factors, chronic renal failure, renal
      replacement therapy and transplantation.
AB  - PURPOSE OF REVIEW: This review is on renal function in patients with spina
      bifida. Risk factors for renal injury as well specific issues concerning the
      treatment of chronic renal failure, renal replacement therapy and kidney
      transplantation are discussed. Relevant work published earlier than 2000 is also
      considered because of a lack of recent literature. RECENT FINDINGS: Data from
      adult and paediatric surveys show renal damage to be the single most prevalent
      cause of morbidity and mortality; even in children, 30-40% exhibit evidence of
      renal damage. Additional factors such as chronic infection and stone formation
      will then render the kidney more vulnerable to progressive loss of renal mass and
      subsequent chronic renal failure. As in other patients with renal insufficiency,
      the control of hypertension, preferably with angiotensin-converting enzyme
      inhibitors, and adequate nutrition are mainstays of nephrological care. The
      modality of dialysis in these patients is complicated by ventriculoperitoneal
      shunts or urinary stomata in peritoneal dialysis, or difficult vascular access in
      haemodialysis. Renal transplantation is now considered the optimal treatment for
      end-stage renal disease in all age groups. Although more prone to complications,
      recent data on patients with meningomyelocele or severely abnormal lower urinary
      tracts demonstrate excellent patient and graft outcomes. SUMMARY: The common goal
      in caring for these patients must be the prevention of progressive renal damage.
      However, once kidney failure has occurred, good and safe techniques for renal
      replacement therapy are available to bridge the time to transplantation, which is
      undoubtedly the best treatment for these patients.

PMID- 12409877
TI  - Strategies in urological reconstruction in myelomeningocele.
AB  - PURPOSE OF REVIEW: This paper reviews recent advances in the strategies for
      urinary tract reconstruction in children with spina bifida. The aims of
      reconstruction are the preservation of renal function and achievement of urinary
      continence. Considerable controversy exists on the subjects of bladder
      augmentation, procedures to increase outlet resistance, and continent stomas. The
      authors put the most recently published information in perspective in the light
      of their own personal experience. RECENT FINDINGS: Thirty-seven papers covering
      the above-mentioned subjects published in the past 5 years (25 of them published
      since 2000) have been selected. Seven relevant older references are included.
      There is persistent interest in developing methods to enlarge the urinary bladder
      that avoid bringing the urine in contact with the intestinal mucosa. The
      artificial urinary sphincter and fascial slings are the most frequently reported
      methods to increase outlet resistance. The Mitrofanoff principle continues to be
      regarded as an effective method to construct a continent catheterizable channel,
      either with the appendix or reconfigured intestinal segments. The achievement of
      fecal continence has to be pursued in parallel with urinary continence.
      Incontinent diversions continue to be best for a small group of patients. The
      role of continent urinary diversion requires reassessment. SUMMARY: Progress in
      this area continues to be made. Periodic, critical and objective reviews on the
      subject should help the practitioner to arrive at sound decisions.

PMID- 12409879
TI  - Global perspectives and controversies in the epidemiology of male erectile
      dysfunction.
AB  - PURPOSE OF REVIEW: Erectile dysfunction is a neurovascular phenomenon that
      requires an intact psychological, neural, and vascular component. The advent of
      Food and Drug Administration approval of sildenafil citrate (Viagra) in 1998 has
      resulted in increased awareness and a large population of patients seeking
      treatment. Unfortunately, the estimated number of patients seeking medical
      therapy still persists at approximately 10%. The predominant reasons suggested
      here are the complexity of sexuality, taboos, cultural restrictions, lack of
      satisfactory treatment, and acceptance of the situation as a normal sequence of
      aging. This perspective discusses the global prevalence and the differences in
      prevalence on a worldwide basis. RECENT FINDINGS: Recent epidemiologic studies
      from Spain and Germany have suggested lower rates of erectile dysfunction. This,
      however, may actually reflect population or cultural differences in the
      perceptions and attitudes towards the condition. Aging, diabetes, coronary artery
      disease, and cigarette smoking as epidemiologic factors are reviewed extensively,
      including some of the controversies with the prevalence rates on a global scale.
      Chronic renal failure, pelvic surgery, and lifestyle determinants similarly
      suggest there may be subtle differences, requiring further education from the
      medical care provider in order to have patient acceptance on a relatively earlier
      scale. SUMMARY: Erectile dysfunction is a worldwide health issue that affects
      nearly half the men over the age of 40. As the world population ages, the number
      of patients affected by this disorder will certainly be increased. With the
      identification of risk factors, it may be possible to identify patients at risk
      of erectile dysfunction.

PMID- 12409880
TI  - Gene therapy for erectile dysfunction: where is it going?
AB  - PURPOSE OF REVIEW: This review will summarize the most recent preclinical data
      from the leading US laboratories regarding the application of gene therapy to the
      treatment of erectile dysfunction. The implications of these findings in the
      field of gene therapy in general, and more specifically to the treatment of non
      life threatening disorders such as erectile dysfunction, will be outlined. RECENT
      FINDINGS: The preclinical work of several laboratories has clearly documented
      'proof-of-concept' for the utility of gene therapy for the treatment of erectile
      dysfunction. A variety of vectors and several distinct molecular targets have
      been successfully leveraged. Such observations suggest that numerous potential
      strategies may exist for gene-based treatments of erectile dysfunction. SUMMARY:
      The apparent preclinical success of most, if not all, gene-based strategies for
      the treatment of erectile dysfunction is consistent with the multifactorial
      regulatory mechanisms governing the erectile process. The bottleneck in the gene
      therapy clinical development process therefore apparently will not lie in the
      ability to identify relevant molecular targets that are amenable to gene therapy
      for erectile dysfunction, but rather in the safety, specificity and longevity of
      those targets. That is, the next technical hurdle is to find the strategy(ies)
      that has the best safety profile, the greatest specificity for altering
      (increasing) intracavernous pressure 'on demand' and, furthermore, the most
      appropriate (longest?) half-life. While these criteria may correspond to
      intuition, finding molecular targets that clear these clinical hurdles may place
      restrictions on the molecular choices for gene transfer.

PMID- 12409881
TI  - Hormonal factors in female sexual dysfunction.
AB  - Female sexual dysfunction is a common, multifactorial medical condition, which
      can have a major impact on self-esteem, quality of life, mood and relationships.
      Hormonal imbalances may contribute to sexual dysfunction, in particular sexual
      arousal disorder. Androgens for the treatment of decreased libido, especially in
      postmenopausal women, have gained increased popularity despite preliminary and
      controversial results. The absence of precise definitions of androgen deficiency,
      unknown 'normal' ranges for androgens, and nuances in the sensitivity of the
      various assays have made research on androgens and libido in women difficult to
      interpret. This review presents the role of estrogen and androgens in sexual
      function and their potential roles as therapeutic agents for female sexual
      dysfunction.

PMID- 12409882
TI  - Ejaculatory duct obstruction.
AB  - PURPOSE OF REVIEW: We surveyed the growing literature on ejaculatory duct
      obstruction and provide suggestions regarding its diagnosis and management.
      RECENT FINDINGS: Ejaculatory duct obstruction is a rare cause of male
      infertility. With the advent of the high resolution transurethral ultrasound
      (TRUS) technology, there has been an increase in diagnosis of this disorder. As
      for the treatment, it appears that central cystic lesions and partial
      obstructions respond best to transurethral resection of the ejaculatory ducts
      (TURED). SUMMARY: Ejaculatory duct obstruction is a rare but surgically
      correctable cause of male infertility. Although there are no pathognomonic
      findings associated with ejaculatory duct obstruction, the diagnosis should be
      suspected in an infertile male with oligospermia or azoospermia with low
      ejaculate volume, normal secondary sex characteristics, testes, and hormonal
      profile, and dilated seminal vesicles, midline cyst, or calcifications on TRUS.
      In select cases, TURED has resulted in marked improvement in semen parameters,
      and pregnancies have been achieved. More studies are needed in the areas of
      diagnosis and long-term surgical outcome.

PMID- 12409883
TI  - Assessment of a blood pressure measurement training programme for lay observers.
AB  - This study assessed a training programme attended by 25 observers, intentionally
      chosen for their lay status, who were invited to participate in a prevalence of
      hypertension study. The results highlight the fact that the 14 trainee observers
      finally selected were comparable to professionals in terms of both the estimated
      validity of the blood pressure measurement [the mean difference (standard
      deviation) compared with the expert being -0.4 (1.8) mmHg for systolic blood
      pressure and 0.0 (1.8) mmHg for diastolic blood pressure] and estimated inter
      observer variability (100% of the observers complying with the criteria
      recommended for professional health-care workers), even though the training given
      to the former was in no way more comprehensive than or distinct from that
      recommended for professional health-care workers in community studies.

PMID- 12409884
TI  - Use of radial arterial tonometric continuous blood pressure measurement in
      cardiovascular reactivity studies.
AB  - BACKGROUND: Non-invasive continuous blood pressure monitoring has, for the past
      decade, been performed using the Finapres monitor. Radial tonometry is a new
      methodology for measuring non-invasive beat-to-beat blood pressure. This
      technique has been evaluated for other applications, but its use in
      cardiovascular reactivity testing has not yet been reported. DESIGN: A
      convenience sample was used to compare a radial tonometric device (Colin Pilot)
      with intermittent brachial blood pressure measurement (Critikon Dinamap) during
      reactivity testing. A second comparison was made between an Ohmeda Finapres and a
      Dinamap. METHODS: Twenty subject-testing sessions during a reactivity protocol
      were evaluated for blood pressure determination. Separate groups of subjects were
      used for Pilot versus Dinamap comparisons and Finapres versus Dinamap
      comparisons. Blood pressure signals from 15 subjects with Pilot and 15 subjects
      with Finapres data were evaluated for artifacts. Signals were also compared in a
      subject with Raynaud's phenomenon. RESULTS: Both devices tracked blood pressure
      well. The Finapres significantly overestimated systolic blood pressure ( P <
      0.001). The correlations between the Pilot and Dinamap were consistently higher
      than those between the Finapres and Dinamap. There were more artifacts (3.2%)
      with the Finapres than with the Pilot (0.2%). In the subject with Raynaud's
      phenomenon, the Finapres overestimated blood pressure by more than 40 mmHg and
      showed more than 75% of artifacts. On the other hand, the Pilot tracked blood
      pressure in the same subject without error. CONCLUSIONS: Radial tonometric
      continuous beat-to-beat blood pressure monitoring with the Colin Pilot was
      associated with a low artifact rating and high accuracy of blood pressure
      measurement during reactivity testing.

PMID- 12409885
TI  - A comparison of ambulatory blood pressure patterns across populations.
AB  - BACKGROUND: Black individuals are characterized by a blunted nocturnal decline
      (i.e. dipping) in blood pressure compared with whites. The resulting increase in
      cardiovascular load has been hypothesized to contribute to ethnic differences in
      hypertension and its sequelae. OBJECTIVE: To examine data from two different
      locations and determine factors related to ethnic differences in ambulatory blood
      pressure pattern. METHODS: Ambulatory blood pressure recordings were performed on
      300 youths from Memphis, Tennessee and 195 youths from Augusta, Georgia, USA.
      Stepwise regressions were performed to determine the factors associated with
      daytime and night-time blood pressure and the nocturnal decline in blood
      pressure. The factors examined were recording location, ethnicity, gender, age,
      height, weight and genetic predisposition. RESULTS: Significant factors in the
      model for the nocturnal decline in systolic blood pressure included location
      (R(2) = 0.031, P < 0.001), followed by ethnicity (R(2) change = 0.015, P < 0.006)
      and height (R(2) change = 0.009,P < 0.03). Significant factors in the model for
      the nocturnal decline in diastolic blood pressure included location ( R(2) =
      0.176, P < 0.001), followed by ethnicity ( R(2) change = 0.016, P < 0.002) and
      height (R(2) change = 0.02, P < 0.001). The nocturnal decline was greater in the
      Augusta subjects because of higher daytime systolic (P < 0.002) and diastolic (P
      < 0.001) blood pressure. Weight contributed significantly to the models for
      resting blood pressure and daytime blood pressure. Gender was the only variable
      that contributed to the model for resting systolic blood pressure. CONCLUSIONS:
      Both genetic and environmental factors contribute to individual differences in
      ambulatory blood pressure patterns. Much of the variance of ambulatory blood
      pressure levels and patterns remains, however, unexplained.

PMID- 12409886
TI  - White-coat effect in normotension and hypertension.
AB  - OBJECTIVES: The difference between clinic and daytime ambulatory blood pressure
      is referred to as the white-coat effect. In this study, we investigated (i) the
      magnitude of the white-coat effect in subjects with different daytime ambulatory
      blood pressure levels, and (ii) the association of the white-coat effect with
      left ventricular mass. METHODS: A total of 1581 subjects underwent clinic blood
      pressure readings, 24-h ambulatory blood pressure monitoring and left ventricular
      echocardiographic assessment. Their mean daytime systolic blood pressure varied
      from 88.0 to 208.9 mmHg and their mean daytime diastolic blood pressure from 40.3
      to 133.0 mmHg. RESULTS: A negative correlation was found between the systolic or
      diastolic white-coat effect and the systolic or diastolic daytime ambulatory
      blood pressure (r = -0.22, P < 0.000 and r = -0.50, P < 0.000, respectively).
      Left ventricular mass significantly correlated with ambulatory blood pressure (P
      < 0.001), but there was no association between left ventricular mass and clinic
      blood pressure or white-coat effect. Furthermore, the white-coat effect was
      reversed at the highest level of systolic or diastolic daytime ambulatory blood
      pressure (systolic over 170 mmHg or diastolic over 100 mmHg) when systolic or
      diastolic daytime ambulatory blood pressure was higher than systolic or diastolic
      clinic blood pressure (ambulatory blood pressure hypertension). CONCLUSIONS: The
      white-coat effect shows an inverse association with daytime ambulatory blood
      pressure level (systolic or diastolic), being significantly more prominent for
      levels below 140/80 mmHg for systolic/diastolic daytime ambulatory blood pressure
      and reversed with daytime ambulatory blood pressure levels above 170/100 mmHg.

PMID- 12409887
TI  - Comparison of arterial elasticity measured in left and right arms using the
      HDI/Pulsewave CR-2000 Research System.
AB  - BACKGROUND: Arterial elasticity is implicated as a risk factor for or a marker of
      cardiovascular disease. Current advances in non-invasive devices have now made it
      possible to measure arterial elasticity in an ambulatory setting. OBJECTIVE: The
      aim of this study was to determine whether there is a difference in blood
      pressure and arterial elasticity measured in the right and the left arms.
      METHODS: Simultaneous measurements were performed with two HDI/Pulsewave CR-2000
      Research CardioVascular Profiling Systems. The manufacturer recommends placing
      the blood pressure cuff on the left upper arm and the sensor on the skin
      overlying the right radial artery. We followed the manufacturer's recommendations
      and also placed both the cuff and the sensor on the same arm. Simultaneous
      measurements were made on both arms with both machines. The average of three
      measurements was used for each combination. Systolic and diastolic blood
      pressure, and large-artery and small-artery elasticity indices, were determined
      for each subject and used in the analysis. RESULTS: The subjects were 11 males
      and 9 females between 22 and 46 (33.5 +/- 7.4 years) years of age. There was no
      significant difference in the average difference for each test combination.
      CONCLUSION: Thus, when using the HDI/Pulsewave CR-2000 Research CardioVascular
      Profiling System, the blood pressure cuff and the sensor can be placed on either
      the same arm or opposite arms.

PMID- 12409888
TI  - Wrist blood pressure-measuring devices: a comparative study of accuracy with a
      standard auscultatory method using a mercury manometer.
AB  - BACKGROUND: In this study, we compared two wrist blood pressure-measuring
      devices, the Omron RX and the Nissei WS-310, against a mercury manometer. METHOD:
      A total of 152 subjects attending an out-patient hypertensive clinic were
      recruited from a randomized blood pressure survey, 87 patients (mean 44.4 +/-
      14.5 years of age) being selected according to the Association for the
      Advancement of Medical Instrumentation/British Hypertension Society standards.
      Device validation was assessed through the use of sequential same-arm readings
      compared with readings taken using a mercury sphygmomanometer by the two trained
      observers. RESULTS: There were no differences between the observers and the
      monitors for diastolic readings (2.8 +/- 4.8 mmHg for the Omron and 4.2 +/- 6.4
      mmHg for the Nissei) according to the Association for the Advancement of Medical
      Instrumentation standards. The largest standard deviations -- 8.3 mmHg for the
      Omron and 8.8 mmHg for the Nissei, respectively -- were seen for systolic
      readings recorded by the observers and the monitors. According to the British
      Hypertension Society standards, the Omron achieved an A grade for diastolic
      readings and a B grade for systolic readings within 5 and 10 mmHg. The Nissei
      monitor achieved an A grade for diastolic readings and a B grade for systolic
      readings within 5 and 10 mmHg. CONCLUSION: Patients found the wrist oscillometric
      devices that we tested to be comfortable and easy to use. These devices are
      appropriate for measuring diastolic blood pressure according to the standards,
      but the reliability of both devices decreased when measuring systolic blood
      pressure.

PMID- 12409889
TI  - Evaluation of the overall system precision of the Welch-Allyn transtelephonic
      home blood pressure monitor in adults with Parkinson's disease.
AB  - BACKGROUND: Non-invasive blood pressure (BP) devices should be independently
      evaluated before being used in special populations. The objective of this study
      was to assess the accuracy of the Welch-Allyn transtelephonic home blood pressure
      monitor in adults with Parkinson's disease to evaluate the device for use in a
      large clinical trial involving the safety and efficacy of a monoamine oxidase
      inhibitor. METHODS: BP measurements taken with the device were compared with the
      results obtained by two experienced observers using a mercury sphygmomanometer in
      patients with Parkinson's disease. The limits of agreement were then calculated
      for the device and compared with the results of the two observers. RESULTS: The
      agreement parameters between the two observers were -0.5 +/- 2.6 mmHg for
      systolic BP and 0.1 +/- 2.2 mmHg for diastolic BP. The agreement between the
      Welch-Allyn transtelephonic device and the observers was -2.6 +/- 4.5 mmHg and 
      1.9 +/- 3.2 mmHg for systolic and diastolic BP respectively. Nearly 90% of the
      readings were within 10 mmHg of the observers for both systolic and diastolic BP.
      Mild tremor had a moderate effect on the validity of the device. CONCLUSIONS: The
      Welch-Allyn transtelephonic device demonstrated acceptable precision in this
      cohort of patients with Parkinson's disease and is considered valid for use in a
      clinical trial involving these patients.

PMID- 12409890
TI  - The 'International Protocol': more insight or more arithmetic?

PMID- 12409891
TI  - Orthopaedic jargon.

PMID- 12409892
TI  - Physeal fractures, part I: histologic features of bone, cartilage, and bar
      formation in a small animal model.
AB  - Physeal fractures and the formation of physeal bars can pose significant problems
      in skeletal development for the injured, growing child. Regrettably, little
      experimental attention has been directed toward this clinical disturbance. The
      current study documents early histologic changes (days 2-6) and subsequent
      alterations (day 21) following a physeal fracture in the rat proximal tibia
      model. The fracture plane was usually contained within the physis but could
      involve many regions of the physis. In some instances, the fracture plane
      extended to the physeal epiphyseal border. When the fracture was contained within
      the physis, healing was uneventful. However, when the fracture extended through
      the physis to the epiphyseal physeal border, there was greater physeal
      disorganization and formation of vertical septa leading to physeal bars. Physeal
      bars appeared to form at sites of vertical fibrotic septa into which marrow
      cells, osteoclasts, and osteoblasts had migrated. Bar formation mediated by
      primary osteogenesis (rather than by endochondral bone formation) followed. This
      study examines the changes in the histologic features of the rat proximal tibial
      physis, epiphysis, and metaphysis after a physeal fracture and identifies key
      factors associated with physeal bar formation.

PMID- 12409893
TI  - Physeal fractures, part II: fate of interposed periosteum in a physeal fracture.
AB  - This study describes the histologic features of periosteum interposed into a
      physeal fracture of the rat proximal tibia. Periosteum was introduced into a
      physeal fracture in two groups of animals: those with an intact physis after
      fracture, and those with the medial half of the physis surgically ablated.
      Specimens of the proximal tibia underwent histologic analysis at 2, 4, 6, 10, and
      21 days after fracture to determine the histologic features of interposed
      periosteum in a physeal fracture. In animals with an intact physis, interposed
      periosteum underwent one of two fates: it was degraded by giant cells in the
      fracture plane, which allowed cellular infiltration, or if the periosteum was
      closely surrounded by physeal cartilage, the physis grew around it and appeared
      to force it toward the metaphysis. In animals whose physis received surgical
      ablation, physeal bar formation was always present, with poor organization of the
      remaining lateral growth plate. Histologic evidence from this study also
      underscores the fact that physeal bar formation occurs from the migration of
      osteoblasts and osteoclasts along vertical septa.

PMID- 12409894
TI  - Surgical management of posttraumatic distal radial growth arrest in adolescents.
AB  - Thirty adolescents underwent surgery for progressive deformity after
      posttraumatic distal radial growth arrest at the average age of 14.8 years.
      Patients underwent ulnar epiphysiodesis (n = 11), ulnar-shortening osteotomy (n =
      18), radial osteotomy (n = 7), and combined radial and ulnar epiphysiodesis (n =
      3) procedures. A modification of the Mayo Wrist Score (maximum 100) was used to
      assess functional outcome at an average follow-up of 21 months. Average wrist
      scores in 24 symptomatic patients improved from 82 to 98 after surgical
      treatment. All six asymptomatic patients maintained scores of 100. Of 18 patients
      who underwent ulnar shortening, average ulnar variance was corrected from 4.5-mm
      positive to neutral. Complications included one case of radial osteotomy
      displacement and two cases of continued ulnar overgrowth. Surgery for
      posttraumatic distal radial growth arrest can improve pain and loss of motion in
      symptomatic adolescents and prevent symptoms in asymptomatic patients with
      progressive deformity.

PMID- 12409895
TI  - Management of fractures in children with thermal injuries.
AB  - The purpose of this study is to analyze how fractures are managed in children
      with associated acute burns. A retrospective review of 20 years of experience at
      a major U.S. burn center was undertaken. A total of 28 fractures in 18 patients
      were identified during this time period. Variables studied included mechanism of
      the burn, fracture location, associated injuries, and type of fracture. The
      fractures were then analyzed according to management, healing times, and
      complication rates. Of the 24 available fractures, 22 went on to union in an
      appropriate amount of time. The average rate to union was 9.9 weeks and average
      follow-up was 32.5 months. There were five infectious complications, one loss of
      reduction, one knee instability, and one malunion requiring additional surgery.
      This study supports early definitive fracture treatment in the burned child. If
      internal fixation is chosen, it can be safely performed if performed within the
      first 48 hours after the burn. External fixation is also a viable alternative.
      High rates of union are possible.

PMID- 12409896
TI  - Sternal segment dislocation in children.
AB  - Three cases of sternal segment dislocation in children are described. The primary
      mechanisms were direct blow in a 4-year-old boy, indirect forces in a 3-year-old
      boy, and osteomyelitis in a 10-year-old boy. The two former cases were dislocated
      at the junction of the manubrium with the sternal body, and the latter case was
      at the junction of the first and second sternal segments. The dislocated segments
      were gradually rotated for approximately 2 weeks and were finally stabilized
      after rotation. While in the dislocated state, the patients were observed
      conservatively, although all the dislocated segments were remodeled. Surgical
      treatment of sternal segment dislocation is not inevitable.

PMID- 12409897
TI  - Long-term results after primary repairs of zone 2 flexor tendon lacerations in
      children younger than age 6 years.
AB  - In young children, methods of primary flexor tendon repair in the digital canal
      are controversial. The authors reviewed 12 children younger than age 6 years with
      zone 2 flexor tendon repairs. The mean follow-up period was 8 years. In all
      cases, the flexor digitorum profundus tendons were repaired according to the
      Kessler modified technique and the hands were immobilized by an above-elbow cast.
      As for postoperative complications, there were no fingers with tendon rupture and
      two fingers with tendon adhesion. One finger needed tenolysis. The total active
      motion (TAM) in the interphalangeal joints evaluated with the Strickland formula
      averaged 155 degrees, and the TAM percentage averaged 89% (range 74%-100%).
      Eleven patients had an excellent result and one had a good result. The percentage
      phalangeal length averaged 99% (range 96%-100%). Functional motion and nearly
      normal growth of the finger can be expected after primary zone 2 flexor tendon
      repairs in children younger than age 6 years.

PMID- 12409898
TI  - Operative treatment of clavicle fractures in children: a review of 21 years.
AB  - Between 1980 and 2000, 15 children (14 boys and 1 girl) underwent surgical
      treatment of a fractured clavicle at the authors' hospital. Eight patients were
      treated for midshaft fracture, two had medial fractures, and five had fractures
      to the lateral end, one of which occurred in combination with true disruption of
      the acromioclavicular joint. The indications for operative treatment of clavicle
      fractures are rare, in some cases debatable, and surgery is usually necessary
      only in older children. If surgically treated, the results are satisfactory
      without major complications. In the authors' experience intramedullary
      stabilization with elastic nails is the method of choice in most cases.

PMID- 12409899
TI  - Fractures in children younger than age 1 year: importance of collaboration with
      child protection services.
AB  - The medical records of all children less than 1 year of age presenting to the
      Accident and Emergency Department over a 5-year period (1995-1999) with a
      fracture were retrospectively reviewed for possible abuse. Seventy-four children
      presented with fractures during the study period, with a mean age at presentation
      of 5 months (range 2 weeks to 1 year). Of these children, 46 had skull fractures
      and 28 had long bone fractures. Children were classified into one of seven
      categories: definite abuse, likely abuse, suspicious, likely accident, definite
      accident, neglect, or unknown cause. A three-tier system of grading for possible
      abuse was then used to analyze variance. The first tier consisted of the initial
      assessment by staff clinicians, the second retrospectively by an orthopaedic
      registrar, and the third retrospectively by a designated doctor in child
      protection (consultant pediatrician), all using the same information from the
      case notes. The use of the three-tier system of grading demonstrated a variance
      in the diagnosis of nonaccidental injury. The possibility of abuse was
      underestimated at the time of the original injury in over a quarter of cases
      (28.4%) when compared with the assessment by the consultant pediatrician. In 34
      children (46%), there was no written documentation that nonaccidental injury was
      ever considered. While management depends on local guidelines and arrangements,
      the authors would advise that all children under 1 year of age with a fracture
      should be admitted to the hospital and referred to a pediatrician for child
      protection assessment.

PMID- 12409900
TI  - Olecranon apophysis fractures in children with osteogenesis imperfecta revisited.
AB  - The authors reviewed 17 fractures of the olecranon apophysis in 10 children with
      mild osteogenesis imperfecta (OI). Seven of the 10 patients sustained the same
      injury to the opposite extremity 1 to 70 months (mean 15.1) after their initial
      fracture. Four fractures were initially treated by cast immobilization alone. Two
      of these eventually required operative treatment because of refracture or late
      displacement. In all, 15 fractures were treated operatively. All had healed at
      the time the cast was removed; however, two refractured. At latest follow-up
      (mean 53 months), no patient reported pain or limited function. Children with OI
      may be prone to this injury. Cast immobilization with careful follow-up may be
      used for minimally displaced fractures, but operative treatment is recommended
      for displaced fractures. The high rate of bilateral injury (70%) suggests that
      children with OI who sustain this fracture should be counseled regarding the risk
      of injury to the opposite extremity.

PMID- 12409901
TI  - Roentgenographic measurement of angle between shaft and distal epiphyseal growth
      plate of radius.
AB  - To assess the accuracy of the use of the growth plate to shaft angle (GP-S) in
      the fractured distal radius, two prospective studies were performed. The first
      intraobserver study was made by three different observers who measured the GP-S
      angles of anteroposterior and lateral views of 62 wrist radiographs on two
      different occasions. The results showed a 95% concordance for a 5 degrees
      tolerance on anteroposterior views and 7 degrees on lateral views. The second, an
      interobserver study with six different observers, showed the same results. The
      results favored the use of the distal radius GP-S angle. It is an easy and
      accurate measurement that can be useful for the assessment of distal forearm
      deformities in children.

PMID- 12409902
TI  - Treatment of established and anticipated nonunion of the tibia in childhood.
AB  - Nonunion in long bone fractures is rare in the skeletally immature patient. The
      authors report the outcome of a series of patients treated for tibial bone loss
      and nonunion at average follow-up of 66 months. Nine children aged 18 months to
      17 years were treated. Three patients had established nonunion ranging from 7
      months to 6 years, three had bone loss (1-6 cm), and three had fractures in which
      nonunion was anticipated (one Gustilo IIIb and two Tscherne III). Treatment
      involved wound excision for open fractures, debridement of devascularized bone,
      and stabilization with monolateral fixators (two patients) and circular fixators
      (seven patients). Five patients had unifocal treatment and four had multifocal
      treatment (three bone transports). Treatment time ranged from 3 to 12 months and
      was not related to the complexity of treatment. Functional outcome was measured
      using the Short Musculoskeletal Functional Assessment, a validated outcome
      assessment tool. At the latest follow-up (average 66 months), the mean knee
      flexion was 134 degrees and mean ankle range was 12 degrees dorsiflexion, 31
      degrees plantar flexion. Physeal arrest was present in three children (limb
      length discrepancy 2-4 cm), but with no deformity. Functional outcome revealed a
      "Dysfunction Index" of 0% to 19% (average 7%) and a "Bother Index" of 0% to 16%
      (average 6%). Good function can be obtained following treatment of these severe
      injuries.

PMID- 12409903
TI  - Ultrasonography of the spine in neonates and young infants with a sacral skin
      dimple.
AB  - The relationship between a sacral skin dimple and an underlying intraspinal
      abnormality was assessed in 50 consecutive neonates and young infants who were
      referred to the authors' institution for ultrasonography of the spine because of
      the presence of a sacral skin dimple. There were 24 girls and 26 boys, with a
      mean age of 32 days (range 1-151). All the patients were neurologically normal.
      Of the 50 patients, 2 had a concomitant hairy patch. No patient with a sacral
      skin dimple demonstrated an intraspinal lesion by ultrasonography.
      Ultrasonography of the spine is not indicated as a routine study for a
      neurologically intact infant with an isolated sacral skin dimple.

PMID- 12409904
TI  - Reliability and necessity of dynamic computerized tomography in diagnosis of
      atlantoaxial rotatory subluxation.
AB  - Dynamic computerized tomography (DCT) has been accepted to be the standard
      diagnostic method of atlantoaxial rotatory subluxation (AARS) although its
      reliability and reproducibility has not been shown yet. The purpose of this study
      was to evaluate the intraobserver reproducibility and interobserver reliability
      of DCT. Standard DCT scans of 18 patients with acute torticollis and 12 normal
      subjects were examined two times in between a time interval of 1 month by three
      specialists and a last-year resident to define any existing AARS. The
      interobserver reliability kappa coefficient was -0.015 (poor) for the first
      examination and 0.327(fair) for the second one. The intraobserver reproducibility
      kappa coefficients were 0.135 (slight), -0.204 (poor), 1.00 (almost perfect), and
      0.474 (moderate) respectively. It was found that DCT has a poor reliability and
      reproducibility in diagnosing AARS in patients with acute torticollis. Therefore,
      its routine use is not cost effective in patients with acute torticollis where
      the deformity usually resolves by a simple cervical mobilization.

PMID- 12409905
TI  - Torticollis in children: can dynamic computed tomography help determine severity
      and treatment.
AB  - For children with torticollis, dynamic computed tomography scanning (DCTS) is the
      imaging modality of choice in diagnosing atlantoaxial rotatory subluxation
      (AARS). At present, there is no grouping system based on DCTS to determine
      severity and direct treatment. Fifty children with torticollis underwent DCTS in
      the workup for AARS. The relative rotation of C1 versus C2 was compared for left
      and right rotation views. Each DCTS was classified: stage 0, torticollis but
      normal DCTS; stage 1, limitation of motion (<15 degrees difference between C1 and
      C2, but C1 crosses midline of C2); and stage 2, fixed (C1 does not cross midline
      of C2). Duration of symptoms and treatment were compared. There were 27 girls and
      23 boys with a mean age of 8.2 years. There were 8 stage 0, 30 stage 1, and 12
      stage 2 DCTS. Average onset of symptoms to diagnosis was 6.7 days for stage 0,
      8.6 days for stage 1, and 20 days for stage 2. A significant trend was found
      between increasing intensity of treatment and stage. Using this grouping system,
      the authors found that patients with a higher stage had an increase in the mean
      duration of symptoms and intensity of treatment.

PMID- 12409906
TI  - Management of scoliosis and syringomyelia in children.
AB  - Scoliosis is often a characteristic of an underlying syrinx. Surgical treatment,
      in particular instrumentation, of scoliosis in a child with an unrecognized
      syrinx may be associated with an increased risk of neurologic complications. The
      effect of syrinx treatment on scoliosis is yet to be clearly determined. Since
      1976, nine children with scoliosis and a syrinx have been treated at a major
      pediatric referral center. Follow-up averaged 4 years 9 months. The average
      increase in curve size was 12 degrees (range 2 degrees -43 degrees ). The syrinx
      was treated operatively in five children. One child, who underwent foramen magnum
      decompression, required surgical stabilization of the spine. No neurologic
      complications were encountered. A compilation of reported cases in the literature
      was performed and analyzed. This analysis of 98 cases revealed that treatment of
      the syrinx resulted in no further progression of the scoliosis in 35 of 80 (48%)
      cases in which the curve history was reported. Surgical stabilization of the
      curve was required in 27 (31%) cases without neurologic complications.

PMID- 12409907
TI  - Scoliosis in velo-cardio-facial syndrome.
AB  - Velo-cardio-facial (VCF) syndrome caused by 22q11.2 deletion is a common genetic
      condition with variable features including congenital heart defects, facial
      anomalies, palatal anomalies, and cognitive problems. Besides the main
      characteristics, various other anomalies have been noted, including
      musculoskeletal problems. Scoliosis has been mentioned but not emphasized as a
      common feature. The authors evaluated 20 patients for scoliosis and connective
      tissue anomalies who were consecutively diagnosed with VCF syndrome and 22q11.2
      deletion at their clinics. The authors describe three children with VCF syndrome
      who had significant scoliosis and connective tissue findings. Two of these
      patients were initially referred to genetics for possible Marfan syndrome. The
      authors suggest that scoliosis should be considered a relatively common finding
      in patients with 22q11.2 deletion, and they should be monitored for this problem.
      In addition, 22q11.2 deletion should be among the diagnostic considerations in
      patients with unexplained scoliosis and developmental delay.

PMID- 12409908
TI  - Ethnic variance in the epidemiology of scoliosis in New Zealand.
AB  - A manual and computerized search of orthopaedic outpatient records over a 10-year
      period (1990-2000) identified 386 new patients younger than age 20 years with a
      diagnosis of scoliosis. Patients were grouped according to race and their numbers
      were compared with predicted values calculated from New Zealand census data. Of
      the various etiological categories, idiopathic scoliosis and scoliosis secondary
      to syringomyelia showed significant ethnic variance. For idiopathic scoliosis,
      higher numbers than predicted were observed in Europeans and lower numbers than
      predicted were observed in Polynesians. Conversely, for scoliosis secondary to
      syringomyelia, relatively higher numbers were observed in Polynesians and
      relatively lower numbers in Europeans and other ethnic groups. The demonstration
      in this study of a low incidence of idiopathic scoliosis and conversely a high
      incidence of syringomyelia in Polynesians has led the authors to reconsider the
      indications for magnetic resonance imaging when patients of this ethnic group are
      referred with scoliosis that initially appears to be idiopathic.

PMID- 12409909
TI  - Scoliosis screening revisited: findings from the District of Columbia.
AB  - The authors performed a retrospective review of scoliosis screening data
      collected by school health nurses annually from 1985 to 1996. The data collected
      included 20 variables for all in the sixth and eighth grades and follow-up data
      for a portion of the referred students in the District of Columbia's public
      schools. During the school years 1989 to 1990 and 1995 to 1996, 52,300 students
      were screened for scoliosis. Of those screened, only 1,218 (2%) were referred for
      further evaluation. Only 47% of these students reported for care. Only 223
      students (18%) provided any definitive information on the type of care or degree
      of curve. Findings indicate that many of the referred cases are never followed
      up. Thus, it is difficult to know the true prevalence of scoliosis or types of
      treatments provided in this population. Although the District of Columbia is
      modest in its referral rate, students referred are not being tracked for further
      diagnosis or treatment.

PMID- 12409910
TI  - Long-term follow-up of surgery for equinovarus foot deformity in children with
      cerebral palsy.
AB  - The factors associated with failed operative intervention in the treatment of
      equinovarus foot deformity in children with cerebral palsy (CP) were evaluated
      after long-term follow-up. One hundred eight children with CP who had surgery on
      the posterior tibialis tendon (split tendon transfer, intramuscular lengthening,
      or Z-lengthening) on 140 feet were reviewed at a mean age of 16.8 years with 7.3
      years of follow-up. The surgery was considered a failure when a 10 degrees or
      greater varus or valgus hindfoot deformity was present or if an additional
      operative intervention was required or planned. Involvement of CP, age at
      operation, and preoperative status of ambulation were significant factors in the
      outcome of the surgery. Hemiplegic patients demonstrated the best results,
      regardless of age or surgical procedure. Seventy-five percent of diplegic and
      quadriplegic patients who were younger than 8 years or who were not capable of
      community ambulation failed operative intervention, and surgery on the posterior
      tibialis tendon is not recommended in this group of patients.

PMID- 12409911
TI  - Kinematic and kinetic gait characteristics of normal children walking at a range
      of clinically relevant speeds.
AB  - Kinematic and kinetic data were obtained from 36 normal children who walked at
      five different clinically relevant speeds, which were mostly slower than normal
      speed. Speed groups were normalized for body height. Speed significantly affected
      most of the stride parameters, joint angles, joint moments, and the ground
      reaction force in all three planes of motion. The effects of speed were not
      always the same over the whole range of speeds studied. The clinical relevance of
      these findings is that when comparing pathologic gait characteristics with those
      of normal children, these should be derived from the same walking speed. This may
      help to differentiate between effects caused by speed and underlying pathology.

PMID- 12409912
TI  - Leg-length discrepancy and scoliosis in Marfan syndrome.
AB  - Leg-length discrepancy (LLD) greater than 2 cm is rare in the general population
      and is associated with a lumbar postural scoliosis; it has not been studied in
      the setting of Marfan syndrome. Thirteen LLDs of 2 cm or more were recorded from
      a group of 250 Marfan patients visiting a medical genetics clinic for complete
      care. Diagnosis was confirmed by standing anteroposterior pelvic radiograph
      and/or scanogram. Records and anteroposterior radiographs of the spine were
      reviewed to obtain Cobb angles for spinal curvatures. A mean discrepancy of 3.2
      +/- 1.0 cm and a Cobb angle of 37.0 degrees +/- 28.4 degrees were found. Twelve
      of 13 curves were convex toward the shorter leg, caudally. Twelve patients had
      scoliosis greater than 10 degrees. Five curves were severe and progressive,
      suggesting the need for spinal fusion and prior equalization of leg lengths. LLD
      correlated weakly with Cobb angle. LLD is more common in individuals with Marfan
      syndrome than in the general population and is associated with increased
      structural scoliosis.

PMID- 12409913
TI  - Dynamic pedobarograph in evaluation of varus and valgus foot deformities.
AB  - Objective documentation of dynamic varus and valgus deformities of the hindfoot
      is still a clinical dilemma. In a review of spastic foot deformities, clinical,
      radiographic, and foot pressure data were collected in 108 children with cerebral
      palsy. According to the clinical assessment, five categories of foot deformities
      were defined: severe varus, varus, neutral, valgus, and severe valgus. A coronal
      index of the pedobarograph was determined by comparing the pressure/time integral
      under the medial column to that under the lateral column of the foot. Coronal
      index is highly correlated with clinical assessment and offers better information
      than radiographic measurements in differentiating the clinical categories. The
      authors recommend the pedobarograph as the primary evaluation tool to measure the
      severity of deformity for patients with varus and valgus foot dysfunction. The
      severity of the deformity can be monitored with a single measurement, which has
      the best correlation with the clinical assessment. The clinical assessment is
      still the primary tool to determine general patterns, but it is difficult to
      apply an objective measurement. Radiographic study is most useful for the
      preoperative assessment when surgery is indicated.

PMID- 12409914
TI  - Peer reviewers.

PMID- 12409915
TI  - Debate: a healthy 12-year-old boy with an isolated mid-diaphyseal femur fracture
      should be treated with an antegrade, locked, intramedullary rod.

PMID- 12409916
TI  - "Intramuscular psoas lengthening improves dynamic hip function in children with
      cerebral palsy" by Novacheck et al.

PMID- 12409918
TI  - Evaluating emerging refractive technologies.

PMID- 12409920
TI  - Mixed astigmatism: theory and technique.

PMID- 12409919
TI  - Corneal topography in modern refractive surgery.

PMID- 12409921
TI  - InterWave aberrometry for custom ablation.

PMID- 12409922
TI  - Microkeratome update.

PMID- 12409923
TI  - Laser in situ keratomileusis after penetrating keratoplasty.

PMID- 12409924
TI  - Laser subepithelial keratomileusis: evolution of alcohol assisted flap surface
      ablation.

PMID- 12409925
TI  - Conductive keratoplasty and laser thermal keratoplasty.

PMID- 12409926
TI  - Presbyopic surgery.

PMID- 12409927
TI  - Phakic intraocular lens implantation.

PMID- 12409928
TI  - Clear lens replacement surgery.

PMID- 12409930
TI  - Maternal mortality: anesthetic implications.

PMID- 12409931
TI  - Epidural analgesia and the progress and outcome of labor and delivery.

PMID- 12409932
TI  - Combined spinal-epidural (CSE) for labor and delivery.

PMID- 12409933
TI  - Neonatal effects of labor analgesia.

PMID- 12409934
TI  - Neurologic complications of labor analgesia and anesthesia.

PMID- 12409935
TI  - Update on postdural puncture headache.

PMID- 12409936
TI  - Nonpharmacological means of pain relief for labor and delivery.

PMID- 12409937
TI  - Update on Pre-eclampsia.

PMID- 12409938
TI  - The drug-abusing parturient.

PMID- 12409940
TI  - Antihypertensive treatment in patients with type-2 diabetes mellitus: what
      guidance from recent controlled randomized trials?
AB  - BACKGROUND: Patients with type-2 diabetes have a high prevalence of hypertension
      and show an elevated incidence of cardiovascular events and nephropathy.
      OBJECTIVES: Recent randomized trials of antihypertensive therapy providing
      information about cardiovascular and renal risk in diabetes, blood pressure goals
      and best suitable drugs were reviewed. FINDINGS: Evidence that association of
      type-2 diabetes with hypertension markedly increases cardiovascular and renal
      risk is incontrovertible: even blood pressure values in the high-normal range
      represent a more relevant risk than in non-diabetics. More versus less intensive
      blood pressure lowering or active versus placebo treatment can significantly
      prevent cardiovascular and renal events, with a particularly consistent reduction
      of proteinuria and microalbuminuria. Although several of the trials showing
      significant reduction of cardiovascular or renal risk achieved diastolic blood
      pressure (DBP) between 75 and 82 mmHg, systolic blood pressure (SBP) 140 mmHg was
      never achieved in trials showing cardiovascular benefits and SBP 130 mmHg was
      only achieved in two trials in normotensive subjects showing proteinuria
      reduction. The recommendation given by all major guidelines to lower SBP 130 mmHg
      appears to be difficult to comply with. Evidence of the superiority or
      inferiority of different drug classes (angiotensin-converting enzyme inhibitors,
      calcium antagonists, diuretics and beta-blockers) is rather vague, especially for
      cardiovascular protection. As to angiotensin-receptor antagonists, losartan has
      shown significant cardiovascular protection over a beta-blocker, and irbesartan,
      although not showing cardiovascular benefits over a calcium antagonist, was
      significantly better in retarding renal dysfunction and failure. CONCLUSIONS: In
      most trials on hypertensive diabetics, the large majority of patients were on
      two, three and even four-drug therapy. Therefore, it appears reasonable that all
      effective and well tolerated antihypertensive agents can be used in association
      to achieve DBP 80 mmHg and, whenever possible, SBP 130 or 135 mmHg, with the
      regular inclusion of an angiotensin-receptor antagonist for its proven
      renoprotective action. Hopefully, better guidance will be provided by further
      trials.

PMID- 12409941
TI  - Non-invasive assessment of autonomic cardiovascular control in normal human
      pregnancy and pregnancy- associated hypertensive disorders: a review.
AB  - PURPOSE: Pre-eclampsia is a major complication of pregnancy. Although the
      disorder usually becomes apparent only in the third trimester of pregnancy,
      evidence is available that underlying pathophysiological abnormalities are
      already present early in pregnancy. The association between alterations in
      autonomic cardiovascular control and the development of hypertension in pregnancy
      has been investigated for some time. Non-invasive methods are especially of
      interest, since they have the advantage of minimal risk for the mother and the
      conceptus and enable repeated measurements during pregnancy. If non-invasive
      tests for autonomic cardiovascular control could demonstrate the increased
      sympathetic activity, as observed by microneurography than this method is a
      candidate for early identification of pre-eclampsia. Therefore, the literature on
      non-invasive testing of autonomic cardiovascular control in normal pregnancies
      and pre-eclampsia was summarized. DATA IDENTIFICATION AND SELECTION: Medline was
      searched and 36 articles on autonomic cardiovascular control in human pregnancy
      by non-invasive test methods were reviewed. For each test method, data of
      different studies were summarized to evaluate if the method could discriminate
      between healthy pregnancy and pre-eclampsia. CONCLUSION: Although small
      differences have been observed between normal pregnancy and pre-eclampsia in
      individual studies using non-invasive methods, the consistency in the available
      data is insufficient to discriminate between normal pregnancy and pre-eclampsia.
      The failure to demonstrate the increased sympathetic activity, as observed by
      direct microneurography, might be due to methodological factors of the non
      invasive studies. Alternatively, sympathetic activity to resistance vessels in
      skeletal muscle may not be a proper reflection of autonomic cardiovascular
      control in pregnancy. Well-designed longitudinal research could be useful to test
      these suppositions.

PMID- 12409942
TI  - High salt intake early in life: does it increase the risk of hypertension?

PMID- 12409943
TI  - Heart rate variability and pregnancy.

PMID- 12409944
TI  - Cardiovascular risk evaluation: an inexact science.

PMID- 12409945
TI  - Night-time blood pressure: dipping into the future?

PMID- 12409946
TI  - From linkage to genes in human hypertension.

PMID- 12409947
TI  - Gender and vascular smooth muscle cells: a direct influence on Ca2+ handling?

PMID- 12409948
TI  - Reactive oxygen species: the missing link between magnesium deficiency and
      hypertension?

PMID- 12409949
TI  - Aminopeptidase A, pregnancy and hypertension.

PMID- 12409950
TI  - Endothelium-derived contracting factor: a new way of looking at endothelial
      function in obesity.

PMID- 12409951
TI  - Mineralocorticoid-induced hypertension in obese Zucker rats.

PMID- 12409952
TI  - Left ventricular hypertrophy, cardiac imaging and cardiac electric activity.

PMID- 12409953
TI  - Hypertension magnitude and management in the elderly population of Spain.
AB  - OBJECTIVE: The present study assessed the prevalence, awareness, treatment and
      control of hypertension among the elderly population of Spain. DESIGN: Based on a
      nationally representative sample of 4009 individuals aged 60 years, two sets of
      six blood pressure measurements were obtained by trained observers at each
      subject's home, using standardized methods. In each set, three mercury-based
      measurements were alternated with three automated measurements. RESULTS: The mean
      systolic blood pressure (SBP)/diastolic blood pressure (DBP) was 143/79 mmHg, and
      the pulse pressure was 64 mmHg. The prevalence rate of hypertension (SBP 140
      mmHg, DBP 90 mmHg, or current drug treatment) was 68.3%. No result obtained was
      sensitive to a particular measurement device. Of the hypertensives, 65% were
      aware of their condition, 55.3% were treated and 16.3% were controlled. Among
      treated hypertensives, SBP control (32.2%) was much lower than DBP control
      (82.3%). Control was lower in men than in women, in older than in younger
      subjects, and in those with lowest than in those with higher educational levels.
      About 57% of uncontrolled treated hypertensives were on monotherapy. Weight loss
      was among the least heeded items of advice (39% among overweight hypertensives).
      CONCLUSIONS: Hypertension is a major public health problem in elderly Spaniards.
      Most hypertensives had their hypertension uncontrolled. Greater emphasis should
      be laid on the most disadvantaged (the older, men, and those with lowest
      education) in terms of hypertension management, and on reinforcing weight loss
      and combining drugs for enhanced hypertension control.

PMID- 12409954
TI  - Arterial stiffness in postmenopausal women: determinants of pulse wave velocity.
AB  - OBJECTIVE To investigate the degree and potential cardiovascular determinants of
      arterial stiffness, assessed by aortic pulse wave velocity (PWV) measurements,
      and to relate arterial stiffness to absolute 10-12-year risks of stroke, coronary
      heart disease and death, as estimated by available risk functions, in
      postmenopausal women. METHOD We performed a cross-sectional study among 385
      postmenopausal women, aged 50-74 years, sampled from the general population.
      Arterial stiffness was assessed non-invasively by measurement of aortic PWV using
      applanation tonometry. Information on health was obtained by medical history,
      registration of current medication, and physical examination. Height, weight,
      waist and hip circumferences, fasting glucose, total and high-density lipoprotein
      (HDL) cholesterol, triglycerides, resting blood pressure, and heart rate were
      measured. Three risk scores were used to estimate, for each individual, the
      absolute risk of stroke, coronary heart disease, and death within 10-12 years as
      a function of their cardiovascular risk factor profile. The relationship between
      PWV and these risk scores was subsequently determined. RESULTS Significant
      positive relationships with PWV were found for body mass index, fasting glucose,
      diabetes mellitus, and triglycerides in analyses adjusted for age, mean arterial
      blood pressure, and heart rate. Height and HDL cholesterol were inversely related
      to PWV. The risks of stroke, coronary heart disease, and death increased with
      increasing PWV in a linear graded manner. CONCLUSIONS This cross-sectional study
      among postmenopausal women provides evidence that most of the established
      cardiovascular risk factors are determinants of aortic PWV. Increased PWV marks
      an increased risk of stroke, coronary heart disease, and death within 10-12
      years.

PMID- 12409955
TI  - Coronary and cardiovascular risk estimation in uncomplicated mild hypertension. A
      comparison of risk assessment methods.
AB  - OBJECTIVE: To compare the accuracy of five risk assessment methods in identifying
      patients with uncomplicated mild hypertension at high coronary heart disease
      (CHD) and cardiovascular disease (CVD) risk.DESIGN Comparison of risk estimates
      using each risk assessment method with CHD risk 15% and CVD risk 20% over 10
      years calculated using the Framingham risk functions. SETTING: British
      population. SUBJECTS: People aged 35-64 years with uncomplicated mild systolic
      hypertension (systolic blood pressure (SBP) 140-159 mmHg, = 202) from the 1995
      Scottish Health Survey. MAIN OUTCOME MEASURES: Sensitivity, specificity, positive
      and negative predictive values. RESULTS: Compared with CHD risk 15% over 10
      years, the Sheffield table and Joint British Societies (JBS) Chart had good
      sensitivity and specificity ( 90%). The New Zealand (NZ) Chart had sensitivity
      83% and specificity 89%. Compared with CVD risk 20% over 10 years the Sheffield
      table had sensitivity 81%, the JBS Chart had sensitivity 63%, and the NZ Chart
      had sensitivity 75%. All had good specificity ( 90%). For CHD risk and CVD risk
      the World Health Organization/International Society of Hypertension (WHO-ISH) and
      United States Joint National Committee VI (JNC-VI) methods had high sensitivity
      at the cost of very poor specificity ( 50%). CONCLUSION: In patients with
      uncomplicated mild hypertension, the Sheffield table and JBS Chart both
      identified CHD risk 15% over 10 years with acceptable accuracy, while the NZ
      Chart was less accurate. Compared with CVD risk 20% over 10 years, these three
      risk assessment methods were all less accurate, but the Sheffield table retained
      the highest sensitivity ( 0.05 versus JBS Chart, = NS versus NZ Chart). The WHO
      ISH and JNC-VI methods had unacceptably low specificities compared with both
      measures of risk and failed to differentiate between those at high and low risk.

PMID- 12409956
TI  - Prognostic significance of the nocturnal decline in blood pressure in individuals
      with and without high 24-h blood pressure: the Ohasama study.
AB  - OBJECTIVE: To examine the relationship between the normal nocturnal decline in
      blood pressure and the risk of cardiovascular mortality in individuals with and
      without high 24-h blood pressure values. METHODS: We obtained 24-h ambulatory
      blood pressure readings from 1542 residents of Ohasama, Japan, who were aged 40
      years or more and were representative of the Japanese general population. We then
      followed up their survival for a mean of 9.2 years. The relationship was analysed
      using a Cox proportional hazards model adjusted for possible confounding factors.
      RESULTS: There was a linear relationship between the nocturnal decline in blood
      pressure and cardiovascular mortality. On average, each 5% decrease in the
      decline in nocturnal systolic/diastolic blood pressure was associated with an
      approximately 20% greater risk of cardiovascular mortality. There were no
      significant interactions for the risk between 24-h systolic/diastolic blood
      pressure values and continuous values for the nocturnal decline in blood pressure
      ( for interaction 0.6). Even when 24-h blood pressure values were within the
      normal range ( 135/80 mmHg, average 118/69 mmHg), diminished nocturnal decreases
      in systolic/diastolic blood pressure were associated with an increased risk of
      cardiovascular mortality. CONCLUSIONS: This is the first study to demonstrate
      that a diminished nocturnal decline in blood pressure is a risk factor for
      cardiovascular mortality, independent of the overall blood pressure load during a
      24-h period, in the general population.

PMID- 12409957
TI  - Estimation of 24-h urinary sodium excretion using lean body mass and overnight
      urine collected by a pipe-sampling method.
AB  - BACKGROUND Although salt intake can be estimated from 24-h urinary sodium
      excretion (Na24 ), for a long time there has been no precise and easy method for
      its measurement. OBJECTIVE: To investigate the possibility of estimating Na24
      using pipe-sampling of overnight urine and lean body mass. PARTICIPANTS AND
      METHODS: Body height, body weight and body fat determined by bioelectrical
      impedance (lean body mass = body weight body fat) was measured in 351 healthy
      individuals (126 men, 225 women). Twenty-four-hour urine was collected and
      creatinine and sodium were measured. To predict 24-h urinary creatinine excretion
      (Cr24 ), the relationship between Cr24 and lean body mass was investigated. Both
      24-h urine and overnight urine specimens were collected in 149 individuals (71
      men, 78 women) using a sampling pipe (semi-automatic proportional urine sampling
      device; height 16 cm, width 1.5 cm). Multiple regression analysis was used to
      estimate Na24. RESULTS: The prediction of Cr24 (Pr.UCr24 ) was derived from lean
      body mass. Using Pr.UCr24 and the overnight urinary Na/Cr excretion ratio (Na n
      /Cr n ), Na24 was estimated as 0.634 (Na n /Cr n ) Pr.UCr 24 + 104.7 mmol/day for
      men and 0.682 (Na n /Cr n ) Pr.UCr 24 + 62.6 mmol/day for women. The correlation
      coefficient (r) between true Na24 and Na24 estimated by these formulae was r =
      0.78 ( P<0.001; mean difference SD-0.03 39.0 mmol/day). CONCLUSIONS: A new pipe
      sampling method using overnight urine and lean body mass was easy and reliable
      for the estimation of Na 24. Furthermore, this method is convenient and may
      enable counselling on salt intake.

PMID- 12409958
TI  - Association of the D8S282 marker near the lipoprotein lipase gene locus with
      systolic blood pressure in healthy Chinese subjects.
AB  - OBJECTIVE: To investigate the association between the marker D8S282 near the
      lipoprotein lipase (LPL) gene locus, and blood pressure, anthropometric and
      biochemical parameters in 229 healthy Chinese subjects. METHOD Genotyping was
      performed using an automated DNA sequencer and the Base ImageIR software. Eight
      different alleles were identified (272-286 bp) resulting in 15 genotypes in our
      population. We investigated the association between the common (28.8%) 278 bp
      allele and the anthropometric and biochemical parameters. RESULTS: In a tertile
      analysis, the frequency of the 278 bp allele increased linearly ( P = 0.003) with
      increasing systolic blood pressure (SBP). The relationship was most evident in
      the females ( n = 141); SBP was higher in homozygotes for the 278 bp allele (117
      +/- 10 mmHg, = 12) than those without this allele (109 +/- 9 mmHg, = 77, 0.05)
      and was gene-dose dependent, and this difference was more significant after
      adjusting for age (P = 0.004). No relationship between the locus and the
      anthropometric or biochemical parameters investigated was observed. CONCLUSION:
      The D8S282 marker near the LPL gene locus contributes to the variance of SBP in
      healthy Hong Kong Chinese subjects, particularly in females.

PMID- 12409959
TI  - Chronic administration of a tyrosine kinase inhibitor restores functional and
      morphological changes of the basilar artery during chronic hypertension.
AB  - OBJECTIVE: Activation of tyrosine kinase appears to play an important role in
      pathogenesis of cardiovascular disease during chronic hypertension. In the
      present study, we tested the hypothesis that long-term treatment with an
      inhibitor of tyrosine kinase would have beneficial effects on hypertension
      induced morphological and functional changes of the cerebral artery. METHODS:
      Male spontaneously hypertensive rats (SHR; 4 months old) were fed normal rat
      chow, or that containing an inhibitor of tyrosine kinase, genistein (1 mg/kg
      chow). Normotensive Wistar-Kyoto (WKY) rats were also fed either of the chows.
      After feeding the rats for 2 months, we measured wall thickness, diameter of the
      basilar artery and its dilator responses to acetylcholine (ACh); Y-26763, an
      opener of ATP-sensitive potassium channels; and Y-27632, an inhibitor of Rho
      associated kinase. RESULTS: Treatment with genistein did not cause significant
      changes in physiological variables, including mean arterial pressure in either
      strain. In control SHR, the wall thickness of the basilar artery was greater than
      that of WKY rats. Genistein treatment reduced the wall thickness significantly in
      SHR. Vasodilator responses induced by ACh and Y-26763 were markedly attenuated in
      SHR compared to WKY rats, and treatment of SHR with genistein significantly
      improved the vasodilatation. Dilatation of the artery in response to Y-27632 was
      enhanced in SHR compared to WKY rats and treatment of SHR with genistein did not
      affect the enhanced vasodilator responses to Y-27632. CONCLUSIONS: Chronic
      treatment with genistein may be a novel approach to prevent cerebrovascular
      disorders.

PMID- 12409960
TI  - Gender-dependent difference in cell calcium handling in VSMC isolated from SHR:
      the effect of angiotensin II.
AB  - OBJECTIVE: To investigate gender-dependent difference in the free cytosolic
      calcium concentration ([Ca2+ ]i ) response to angiotensin II (Ang II) in vascular
      smooth muscle cells (VSMC) isolated from spontaneously hypertensive rats (SHR).
      To further evaluate this gender-dependent difference by studying the role of
      thapsigargin-sensitive intracellular calcium stores and calcium influx in VSMC
      isolated from male and female SHR. DESIGN AND METHODS: Confluent primary cultures
      of VSMC isolated from male (n = 14) and female (n = 14) SHR aged 10 weeks were
      used in this study. [Ca2+ ]i was measured by image analysis of single myocytes
      loaded with Fura-2. [Ca2+ ]i response of VSMC to Ang II was measured in the
      presence and absence of extracellular Ca2+, to evaluate the influence of Ca2+
      influx. To characterize inositol triphosphate (IP3 )-sensitive sarcoplasmic
      reticulum calcium stores, thapsigargin-sensitive calcium stores were measured in
      VSMC isolated from SHR of both genders. RESULTS: VSMC isolated from male SHR were
      characterized by an augmented [Ca2+ ]i response to angiotensin II in comparison
      with VSMC isolated from female SHR. Surprisingly, the thapsigargin-stimulated
      [Ca2+ ]i rise was found to be significantly greater in VSMC isolated from female
      SHR compared with VSMC isolated from male SHR. On the other hand, the gender
      dependent difference in [Ca2+ ]i response to angiotensin II was abolished in the
      absence of extracellular calcium. CONCLUSIONS: We demonstrated in VSMC isolated
      from SHR of both genders that a greater [Ca2+ ]i response to angiotensin II in
      male than female VSMC is dependent on Ca2+ influx.

PMID- 12409961
TI  - Effects of low dietary magnesium intake on development of hypertension in stroke
      prone spontaneously hypertensive rats: role of reactive oxygen species.
AB  - OBJECTIVES: To investigate whether low dietary Mg2+ intake influences the
      development of hypertension in stroke-prone spontaneously hypertensive rats
      (spSHRs) and whether these effects are associated with vascular functional and
      structural changes, and to assess the role of reactive oxygen species and the
      activation of vascular mitogen-activated protein (MAP) kinases in these
      processes. METHODS: Six-week-old male spSHRs (n = 18) were divided into three
      groups: control (normal chow, 0.21% Mg2+ ), low Mg2+ group (Mg2+ -free diet), and
      high Mg2+ group (Mg2+ -rich diet, 0.75%). Systolic blood pressure (SBP) was
      assessed weekly for 16 weeks. In a second series of experiments, 6-week-old
      spSHRs (n = 18) were divided into three groups and studied weekly for 7 weeks:
      control group, low Mg2+ group, and low Mg2+ group receiving the superoxide
      dismutase mimetic, tempol (1 mmol/l). RESULTS: The low Mg2+ diet caused an
      initial decrease in SBP followed, 5 weeks later, by an exacerbated development of
      hypertension. This was associated with a transient reduction in the plasma
      concentrations of substances associated with the thiobarbituric acid reaction
      (markers of oxidative stress), which increased rapidly 2 weeks later. In the low
      Mg2+ group, acetylcholine-induced vasodilatation was decreased compared with that
      in controls ( P<0.05). The media : lumen ratio was greater in rats receiving a
      low Mg2+ diet than in those fed a high Mg2+ diet ( P<0.05). Mg2+ depletion was
      associated with increased vascular superoxide anion compared with that in Mg2+ 
      supplemented rats (1.2 0.24 compared with 0.65 0.1 nmol/min per mg).
      Phosphorylation of MAP kinases was increased two- to threefold in Mg2+ -deficient
      rats. Tempol prevented the progression of hypertension and normalized the
      vascular changes in rats fed a low Mg2+ diet. CONCLUSIONS: Chronic Mg2+
      deficiency leads to development of severe hypertension, endothelial dysfunction
      and vascular remodelling. These processes are associated with oxidative stress
      and upregulation of redox-dependent MAP kinases. Tempol normalized vascular
      changes and attenuated the development of hypertension. Our findings suggest that
      reactive oxygen species play an important part in vascular processes that are
      associated with progression of hypertension in Mg2+ -deficient spSHRs.

PMID- 12409962
TI  - Possible involvement of aminopeptidase A in hypertension in spontaneously
      hypertensive rats (SHRs) and change of refractoriness in response to angiotensin
      II in pregnant SHRs.
AB  - BACKGROUND: Hypertension complicated with pregnancy is a major cause of maternal
      and fetal mortality, but its pathophysiology is unclear. OBJECTIVE: To
      investigate the pressor response to angiotensin II (Ang II) and the involvement
      of the Ang II degrading protease, aminopeptidase A, in spontaneously hypertensive
      rats (SHRs). DESIGN: Pregnant SHRs and Wistar-Kyoto (WKY) rats were studied.
      Angiotensin II (200 ng/kg per min) or saline was infused by osmotic pump from day
      of 15 gestation, and caesarean section was performed at day 20 of gestation.
      Blood pressure during pregnancy, weight of placentas and pups at caesarean
      section, and aminopeptidase A activity in placenta and renal cortex were
      measured. RESULTS: Ang II treatment induced increases in blood pressure that were
      greater in non-pregnant WKY rats than those in pregnant WKY rats, pregnant SHRs,
      and non-pregnant SHRs. Renal aminopeptidase A activity in SHRs was significantly
      lower than that in WKY rats. Renal aminopeptidase A activity in pregnant SHRs was
      significantly greater than that in non-pregnant SHRs, but there was no
      significant increase in pregnant WKY rats. Placental aminopeptidase A activity in
      SHRs was greater than that in WKY rats. Placental aminopeptidase A activity in
      WKY rats was increased by Ang II, but was not increased in SHRs. Weights of
      placentas and pups were significantly lower in SHRs than in WKY rats.
      CONCLUSIONS: Renal aminopeptidase A may be involved in the development of
      hypertension and the regulation of blood pressure in SHRs. Placental
      aminopeptidase A may be upregulated in response to fetal stress in pregnant SHRs.

PMID- 12409963
TI  - Obesity increases prostanoid-mediated vasoconstriction and vascular thromboxane
      receptor gene expression.
AB  - OBJECTIVES: Vasoconstrictor prostanoids have been implicated in abnormal
      vasomotion in atherosclerosis and hypertension. METHOD: Using lean and diet
      induced obese mice, we investigated whether obesity affects vascular function or
      expression of genes involved in prostanoid action. RESULTS: In lean C57BL/6J
      mice, at high concentrations acetylcholine caused endothelium-dependent
      contractions in the carotid artery but not in the aorta. Endothelium-dependent
      contractions to acetylcholine were blocked by the non-selective cyclooxygenase
      (COX) inhibitors indomethacin and meclofenamate, or a prostaglandin
      H2/thromboxane A2 receptor antagonist, but not by inhibitors of COX-2,
      thromboxane synthase or cytochrome P450 monooxygenase. Obesity increased
      endothelium-dependent contractions to acetylcholine in the carotid artery, and
      prostanoid-mediated vasoconstriction was now present in the aorta. Similarly,
      contractions to endothelin-1 were largely blocked by meclofenamate and were
      increased in the aorta of obese mice. Real-time quantitative polymerase chain
      reaction analysis of the thromboxane receptor gene in the carotid artery revealed
      a robust upregulation in obese animals (18-fold, 0.05); in comparison, obesity
      had a less pronounced effect on thromboxane synthase (2.1-fold increase, 0.05),
      or preproendothelin-1 gene expression (4.2-fold increase, 0.05). CONCLUSIONS:
      These data demonstrate that obesity augments prostanoid-dependent
      vasoconstriction and markedly increases vascular thromboxane receptor gene
      expression. These changes are likely to promote the development of vascular
      disease, hypertension and thrombosis associated with obesity.

PMID- 12409964
TI  - Increased sensitivity of the obese Zucker rat to deoxycorticosterone-salt-induced
      hypertension.
AB  - OBJECTIVE: The objective of this study was to test the hypothesis that obesity
      increases the sensitivity of rats to experimentally induced hypertension. DESIGN
      AND METHODS: To induce hypertension, unilaterally nephrectomized lean and obese
      Zucker rats were injected with 25 mg/kg of deoxycorticosterone acetate (DOCA)
      twice weekly for 5 weeks and given water containing 1% NaCl to drink.
      Unilaterally nephrectomized control rats were injected with vehicle and drank tap
      water. Systolic blood pressure (SBP) was measured by the tail cuff method. Renal
      histology and urinary albumin excretion were used to assess the effects of the
      experimental treatment on the kidney. RESULTS: Obese rats exhibited a significant
      rise in SBP at 4 days after the start of DOCA-salt treatment. In contrast, SBP of
      DOCA-treated lean rats was not significantly elevated from pretreatment
      measurements until day 22. Moreover, SBP was significantly higher during the
      plateau phase of blood pressure development in obese DOCA-salt treated rats (196
      mmHg) than in correspondingly treated lean rats (150 mmHg). Both obesity and DOCA
      salt treatment promoted glomerulosclerosis and mild tubulointerstitial damage in
      the kidney with DOCA-salt treatment exacerbating the effect of obesity. Urinary
      albumin excretion was significantly greater in obese control rats compared with
      lean controls and in DOCA-treated obese rats relative to vehicle-treated obese
      rats. CONCLUSION: Results of this study indicate that obese Zucker rats are more
      sensitive to mineralocorticoid-induced hypertension than lean rats. This study
      provides experimental evidence supporting the epidemiological findings that
      obesity is a risk factor for the development of hypertension.

PMID- 12409965
TI  - Orlistat improves blood pressure control in obese subjects with treated but
      inadequately controlled hypertension.
AB  - OBJECTIVE: To investigate the hypothesis that weight reduction with orlistat plus
      mild caloric restriction leads to better blood pressure control than diet alone
      in obese individuals with inadequately controlled hypertension. DESIGN This was a
      1-year, prospective, randomized, double-blind, placebo-controlled, multicenter
      trial of orlistat plus diet versus placebo plus diet in obese hypertensives.
      INTERVENTIONS: Participants were randomized to receive either orlistat or
      placebo; all received a 600 kcal deficient diet with no more than 30% of calories
      from fat. Weight and blood pressure, lipid levels and fasting glucose and insulin
      levels were followed. MAIN OUTCOME MEASURES: Patients on orlistat experienced
      greater weight loss (-5.4 +/- 6.4 versus -2.7 +/- 6.4 kg, P< 0.001) and greater
      reduction in body mass index (-1.9 +/- 2.3 versus -0.9 +/- 2.2 kg/m2, P<0.001).
      Target weight loss, defined as > or= 5% body weight (BW), was obtained in more
      orlistat-treated patients than in the placebo group (46 versus 23%, P<0.001).
      Diastolic BP decreased more in orlistat-treated patients than in the placebo
      group (-11.4 +/- 8.3 versus -9.2 +/- 8.4 mmHg, P = 0.002). A greater percentage
      of orlistat-treated patients reached goal diastolic blood pressure (BP), defined
      as final diastolic BP< 90 mmHg or a reduction of at least 10 mmHg (67 versus 53%,
      P< 0.001). The orlistat-treated group had significantly greater reductions in
      total cholesterol ( P<0.001), low-density lipoprotein cholesterol (P = 0.001) and
      non-high-density lipoprotein cholesterol (P< 0.005) and target 30% cardiovascular
      risk reduction was obtained in more orlistat-treated patients (36.1 versus 24.0%,
      P< 0.04). CONCLUSION: A weight-loss program with orlistat is more effective than
      diet alone to lower blood pressure and results in greater cardiovascular risk
      reduction.

PMID- 12409966
TI  - The protective effects of taurine against renal damage by salt loading in Dahl
      salt-sensitive rats.
AB  - OBJECTIVES: We evaluated whether taurine prevents renal damage which is
      accompanied with enhanced expression of lectin-like oxidized low-density
      lipoprotein (OxLDL) receptor-1 (LOX-1) mRNA, in salt-loaded Dahl salt-sensitive
      (DS) rats. METHODS: Male, 4-week-old DS rats were fed on either a high-salt (8%
      NaCl) or normal-salt (0.66% NaCl) diet for 4 weeks. Some DS rats with high-salt
      diet were given drinking water containing 1% taurine. We evaluated blood
      pressure, renal function, renal LOX-1 expression and parameters for oxidative
      stress. RESULTS: In salt-loaded DS rats, there was a significant increase in
      heart weight and urinary protein, accompanied with enhanced LOX-1 expression in
      kidney. All of these were reduced by concomitant supplementation of taurine,
      although both antihypertensive and antihyperlipidemic effects of taurine were
      only slight in salt-loaded DS rats. On the other hand, salt-induced increment in
      urinary 8-hydroxy-deoxyguanosine, a parameter of oxidative damage, was completely
      normalized by taurine supplementation. CONCLUSIONS: The protective effects of
      taurine supplementation against renal damage induced by salt loading in DS rats
      may be attributed to the suppression of LOX-1, probably through its antioxidant
      effects.

PMID- 12409967
TI  - Acute intrarenal administration of cortisol has no effect on renal blood flow in
      hypertensive individuals.
AB  - BACKGROUND: Cortisol is known to increase blood pressure. One possible mechanism
      is the reported increase in renal vascular resistance (RVR). It is unknown
      whether this is due to a direct effect of cortisol on the kidneys. OBJECTIVE: To
      study the effect of infusion of cortisol directly into the renal artery on renal
      blood flow (RBF) and on renal 11beta-hydroxysteroid dehydrogenase (11beta-HSD)
      mediated conversion of cortisol to cortisone in patients with primary
      hypertension. DESIGN AND METHODS: Twenty-seven patients with primary hypertension
      participated in this study. Fifteen received placebo and 12 received
      glycyrrhetinic acid (GRA; 500 mg) orally 2.5 h before the study. After a 10 min
      infusion of 5% glucose, cortisol was infused in stepwise increasing doses (0.625,
      1.25 and 2.5 microg/kg per min), for 10 min each dose. At the end of each
      infusion step, RBF was measured using the xenon-133 washout technique. Plasma
      samples from the femoral artery and renal vein were taken for measurement of
      cortisol and cortisone. Urine was collected for measurement of steroid
      concentrations for 6 h on the day before the infusion and for 6 h after the
      infusion. RESULTS: After placebo or GRA, cortisol infusion did not change RVR,
      RBF or blood pressure. RVR values were 0.72 (0.45-0.89) mmHg/ml per min per 100
      ml tissue [median (first and third quartiles)] and 0.71 (0.64-0.91) mmHg/ml per
      min per 100 ml tissue during infusion of 5% glucose and infusion of the highest
      dose of cortisol, respectively ( P= NS). Cortisol infusion increased the venous
      arterial difference in plasma cortisone concentration across the kidney from 76
      (40-115) nmol/l to 138 (100-186) nmol/l (P< 0.05) and increased the cortisol :
      cortisone ratios in the renal vein and in urine (both P< 0.05). As compared with
      placebo, administration of GRA increased the cortisol : cortisone ratios in
      peripheral and renal veins and in the urine. CONCLUSION: Acute infusion of
      cortisol in high doses directly into the renal artery in patients with primary
      hypertension did not affect RBF or RVR. Infusion of cortisol resulted in
      increased cortisol-cortisone conversion by renal 11beta-HSD2, but the concurrent
      increase in renal and urinary cortisol : cortisone ratio suggests a relative
      insufficiency of renal 11beta-HSD2 activity as a result of enzyme saturation.
      This may enhance mineralocorticoid receptor stimulation by cortisol.

PMID- 12409968
TI  - Magnetocardiographic indices of left ventricular hypertrophy.
AB  - OBJECTIVE: We tested the hypothesis that multichannel magnetocardiographic (MCG)
      mapping can detect and quantify the degree of left ventricular hypertrophy (LVH).
      DESIGN: A cross-sectional study. SETTING: Helsinki University Central Hospital, a
      tertiary referral center. PARTICIPANTS: Forty-two patients with pressure overload
      induced LVH by gender-specific echocardiographic criteria (LVH group), and 12
      healthy middle-aged controls. MAIN OUTCOME MEASURES: MCG QRS-T area integrals and
      QRS-T angle in magnetic field maps in relation to echocardiographic LVH as well
      as left ventricular (LV) mass and structure. Conventional 12-lead
      electrocardiographic (ECG) LVH indices (Sokolow-Lyon voltage, Cornell voltage,
      Cornell voltage duration product) were assessed for comparison. RESULTS: MCG QRS-
      and T-wave integrals provided complementary information of echocardiographic LV
      mass. Their combination, the QRS-T integral, and the QRS-T angle were increased
      in patients with LVH and, in those patients, correlated significantly with LV
      mass indexed to body surface area (r = 0.455;P = 0.002 and r= 0.379; P= 0.013,
      respectively). A QRS-T integral 16000 fT.s had identical sensitivity of 62% at
      92% specificity as the gender-adjusted Cornell voltage duration product of 240
      micro V.s for the detection of LVH. CONCLUSIONS: The MCG method can detect
      patients with LVH and also quantify the degree of LVH in patients with increased
      LV mass.

PMID- 12409969
TI  - Comparative effects of candesartan and enalapril on left ventricular hypertrophy
      in patients with essential hypertension: the candesartan assessment in the
      treatment of cardiac hypertrophy (CATCH) study.
AB  - BACKGROUND: A limited number of studies have evaluated the effect of angiotensin
      II receptor antagonists (AIIAs) on left ventricular hypertrophy (LVH) in
      comparison with other antihypertensive drugs, and no large study has compared
      AIIAs with angiotensin-converting enzyme inhibitors (ACEIs). METHODS AND RESULTS:
      The CATCH (Candesartan Assessment in the Treatment of Cardiac Hypertrophy) study
      was a multicenter prospective randomized double-blind trial comparing the effects
      of candesartan cilexetil (8-16 mg once daily) and enalapril (10-20 mg once daily)
      with possible addition of hydrochlorothiazide (12.5-25 mg once daily) on
      echocardiographic left ventricular mass index (LVMI), in 239 hypertensives with
      LVH (LVMI 120 g/m2 in men and 100 g/m2 in women). Two-dimensionally guided M-mode
      echocardiograms were carried out at screening (recruiting scan), randomization
      (baseline scan) and after 24 and 48 weeks of treatment. Baseline and treatment
      echocardiograms were read at two central labs without knowledge of the scan time
      sequence. In intention-to-treat (ITT) analyses (196 patients), systolic and
      diastolic blood pressures (SBP, DBP) were significantly and equally reduced by
      the two treatments. Candesartan and enalapril reduced LVMI to the same extent,
      i.e. by 15.0 and 13.1 g/m2 (-10.9 and -8.4%; P<0.001 for both). The proportion of
      patients achieving normalization of LVMI was non-significantly higher with
      candesartan (36.3 versus 28.6%). Similar results were obtained in per-protocol
      (PP) analyses. Cough incidence was lower with candesartan ( P<0.03). CONCLUSIONS:
      CATCH is the first large study comparing the effects of an AIIA and an ACEI on
      LVMI. Candesartan cilexetil was found to be equally effective as enalapril in
      reducing SBP, DBP and LVMI in hypertensives with LVH, according to both ITT and
      PP analyses.

PMID- 12409970
TI  - Benefit and harm of low-dose aspirin in well-treated hypertensives at different
      baseline cardiovascular risk.
AB  - BACKGROUND: The effects of aspirin in subjects without cardiovascular disease are
      controversial. In the intensively treated patients of the Hypertension Optimal
      Treatment (HOT) Study, randomization to low-dose aspirin (75 mg daily) versus
      placebo significantly reduced cardiovascular events (-15%) and myocardial
      infarction (-36%), but increased major bleedings (+65%). The present analyses of
      HOT Study data aim at identifying subgroups of hypertensives with different
      benefit-to-harm ratios from aspirin, in order to provide recommendations about
      the use of aspirin in hypertension. METHODS: The 18 790 hypertensive patients
      (aspirin 9399, placebo 9391; average treatment duration 3.8 years) were
      stratified for global cardiovascular risk and for individual risk factors.
      Subgroup-treatment interaction analyses (end points: cardiovascular events,
      myocardial infarction, major bleedings) were performed by a Cox proportional
      hazard model. Relative and absolute benefits and harms were calculated. RESULTS:
      Interaction analyses indicated that of all subgroups, only patients with serum
      creatinine > 1.3 mg/dl had a significantly greater reduction of cardiovascular
      events and myocardial infarction (-13 and -7/1000 patient-years), while risk of
      bleeding was not significantly different between subgroups. In addition to
      patients with higher creatinine, a favourable balance between benefit and harm of
      aspirin was found in subgroups of patients at higher global baseline risk and
      baseline systolic pressure > or = 180 or diastolic pressure > or = 107 mmHg.
      CONCLUSIONS: Low-dose aspirin should be recommended to well-treated hypertensive
      patients with even moderate increase in serum creatinine. Aspirin may also be
      recommended in well-treated hypertensives at higher global cardiovascular risk or
      higher initial blood pressures.

PMID- 12409971
TI  - Clinical value of diastolic dysfunction in hypertension.

PMID- 12409972
TI  - Do we understand the electrophysiologic mechanisms responsible for drug-induced
      cardiac arrhythmias?

PMID- 12409973
TI  - Refractory patterns and susceptibility to drug-induced polymorphic ventricular
      tachycardias in dogs with chronic atrioventricular block: relation to the type of
      anesthesia.
AB  - Controversy exists as to the homogeneity of repolarization throughout the canine
      ventricular wall in vivo. The type of anesthesia has been shown to affect
      regional differences in monophasic action potential duration and the inducibility
      of polymorphic ventricular tachycardias (PVTs) in normal canine hearts. This
      study was conducted to determine refractory patterns and arrhythmia
      susceptibility in relation to halothane or pentobarbital anesthesia in dogs with
      chronic atrioventricular block and biventricular hypertrophy. In 12 dogs with
      chronic atrioventricular block, 60 needle electrodes (12 mm long, four bipolar
      electrodes, interelectrode distance of 2 mm) were inserted into the left and
      right ventricle. Six dogs were anesthetized with pentobarbital and six with
      halothane. Effective refractory periods (ERPs) were determined along 14 randomly
      selected needles at baseline and after application of almokalant (0.34 mmol/kg)
      (basic cycle length 1,000 ms, extrastimulus technique). At baseline and on
      almokalant, ERPs were uniform, independent of the type of anesthesia. With
      halothane anesthesia, ERPs were significantly longer under both conditions.
      Almokalant induced not only a prolongation of ERP in both groups but also a
      significant increase in transmural dispersion of ERP and in maximum dispersion of
      ERP. However, local refractory gradients were not specific to any muscle layer
      and did not seem to be related to the occurrence of PVTs. Almokalant did not
      induce arrhythmias in any dog in the pentobarbital group, but in four of six
      animals in the halothane group, apparently due to the more marked prolongation in
      ERP. Independent of the type of anesthesia, hypertrophied hearts of dogs with
      chronic atrioventricular block exhibit uniform refractory patterns. Longer ERPs
      with a comparable degree of dispersion on halothane are associated with a high
      incidence of drug-induced PVTs, whereas shorter ERPs on pentobarbital seem to
      prevent arrhythmia induction.

PMID- 12409974
TI  - Calyculin A and outward K+ channel currents in rat tail artery smooth muscle
      cells.
AB  - Protein dephosphorylation mediated by phosphatases represents an important
      mechanism for modulating the functions of the targeted proteins. Calyculin A has
      been extensively used as a specific inhibitor of protein phosphatases. However,
      the effect of calyculin A on K channel currents in vascular smooth muscle cells
      (SMCs) and the underlying mechanisms had been unknown. It was found in the
      current study that calyculin A inhibited the whole-cell outward K channel
      currents in rat tail artery SMCs in a concentration-dependent (median inhibitory
      concentration, 12.6 n ) and reversible fashion. The extracellular applied
      calyculin A induced a biphasic change in K current amplitude with an initial
      transient increase followed by a long-lasting inhibition (n = 6). The
      intracellularly applied calyculin A (100 nM ) caused a lesser inhibition (33 +/-
      1%) of K channel currents than that caused by the extracellularly applied
      calyculin A (55.3 +/- 8% inhibition) and did not result in an initial increase in
      K channel currents. The inhibitory effect of the intracellularly applied
      calyculin A on K channel currents was reversed to a stimulatory effect after ATP
      was omitted from the intracellular solution. The K currents inhibited by
      calyculin A were conducted by the iberiotoxin-sensitive K channels in SMCs.
      Moreover, okadaic acid (0.03-3 microM ) did not cause any significant change in
      K(Ca) channel currents. In conclusion, calyculin A inhibited K(Ca) channel
      currents in vascular SMCs. This effect of calyculin A, however, was not mediated
      by the inhibition of protein phosphatases.

PMID- 12409975
TI  - Protein tyrosine kinases and L-type Ca2+ currents in cells that have survived in
      epicardial border zone of canine infarcted heart.
AB  - Previously a reduction was shown in the density of the L-type Ca currents in
      cells that have survived in the epicardial border zone of the 5-day infarcted
      canine heart (IZ). A hyporesponsiveness of I(CaL) to beta-adrenergic stimulation
      in IZs versus cells from the noninfarcted heart (NZs) was also shown. To
      determine the role of protein tyrosine kinase (PTK) activity in this altered
      adrenergic response as well as in the reduced basal current function in IZs, the
      effects of genistein and T23, specific inhibitors of PTK, on basal I(CaL) in the
      absence and presence of isoproterenol (5 nM ) were studied using whole-cell patch
      clamp techniques. Genistein reduction of I(CaL) was similar in NZs and IZs and
      was not mimicked by daidzein, an inactive analogue of genistein. Submaximal
      isoproterenol produced a small response in both cell types that was potentiated
      in the presence of genistein. T23 also reduced I(CaL) in both NZs and IZs;
      however, submaximal isoproterenol was not potentiated in its presence. In sum,
      basal I(CaL) is sensitive to genistein and T23, suggesting that persistent PTK
      activity contributes to I(CaL) in both NZs and IZs. With genistein but not with
      T23, there is an enhanced sensitivity of I(CaL) to isoproterenol in both NZs and
      IZs but peak I(CaL) is not fully restored in IZs. Thus, dysregulation of PTK
      activity cannot account for the reduced basal Ca currents or hyporesponsiveness
      of I(CaL) to isoproterenol in the cells that have survived in the infarcted
      heart.

PMID- 12409976
TI  - Stress susceptibility as a determinant of the response to adrenergic stimuli in
      mesenteric resistance arteries of the rat.
AB  - Characterized by the behavioral response to apomorphine, two outbred lines of
      Wistar rats can be recognized with constitutionally determined high (apomorphine
      susceptible, APO-SUS) or low (apomorphine unsusceptible, APO-UNSUS) adrenal
      responses to similar environmental stress. Within the accumbens nucleus, the APO
      SUS and APO-UNSUS rats differ in alpha -adrenergic receptor responsiveness. This
      study explored whether these differences in adrenergic receptor sensitivity also
      exist in mesenteric resistance arteries. A Mulvany myograph was used to study the
      vasomotor responses of isolated mesenteric resistance arteries to adrenergic
      receptor stimulation. Phenylephrine (alpha1-agonist)-induced vasoconstriction did
      not differ between the two lines (pEC : 5.8 +/- 0.05 microM versus 5.8 +/- 0.04
      microM and Emax: 36 +/- 2 kPa versus 33 +/- 1 kPa for APO-SUS, n = 9, and APO
      UNSUS, n = 11, respectively, p > 0.1). After precontraction with phenylephrine,
      salbutamol (beta -agonist)-induced relaxation was less in APO-SUS rats (pEC50 4.9
      +/- 0.06 versus 5.3 +/- 0.06M for APO-SUS, n = 9, and APO-UNSUS, n = 7,
      respectively, p < 0.001). Likewise, clonidine (alpha2-agonist)-induced relaxation
      was reduced in APO-SUS rats (pEC50: 6.7 +/- 0.07 versus 7.0 +/- 0.04, for APO
      SUS, n = 9, and APO-UNSUS, n = 8, respectively; p < 0.01). In conclusion,
      constitutionally determined high susceptibility to stress is accompanied by an
      impaired vasorelaxation to adrenergic stimuli whereas vasoconstriction is
      unaffected. An unopposed vasoconstrictor action of norepinephrine may place the
      APO-SUS rats at increased risk for the development of hypertension, insulin
      resistance, and atherosclerosis.

PMID- 12409977
TI  - Nicorandil and leukocyte activation.
AB  - Nicorandil, a hybrid compound of an ATP-sensitive potassium (KATP ) channel
      opener and a nitric oxide donor, has been reported to preserve microvascular
      integrity in patients with reperfused myocardial infarction. The aim of the
      current study was to test the hypothesis that nicorandil suppresses activation of
      polymorphonuclear leukocytes (PMNLs), resulting in reduction of PMNL migration
      into tissue upon ischemia/reperfusion. Nicorandil, along with the mitochondrial
      KATP channel opener diazoxide and the nitric oxide donors nitroglycerin and
      isosorbide dinitrate, suppressed pseudopod projection in human PMNLs treated with
      10(-9)-formyl-methionyl-leucyl-phenylalanine (FMLP) and subjected to shear stress
      (5 dyn/cm(2)) with a cone-and-plate shear device. Suppression by nicorandil and
      diazoxide was reversed by KATP channel blockers, 5 hydroxydecanoate and
      glibenclamide. FMLP-induced increase of [Ca2+] in PMNLs was suppressed by
      nicorandil and diazoxide, and 5 hydroxy-decanoate and glibenclamide reversed this
      suppression. Results of reverse transcription polymerase chain reaction with rat
      PMNL mRNA indicated the presence of mRNAs of Kir6.2 and Kir6.1 but not mRNAs of
      sulfonylurea receptor 1 or 2. Isosorbide dinitrate, diazoxide, and nicorandil
      reduced leukocyte migration and microvascular obstruction in reperfused ischemic
      tissue of rat mesenteric microcirculation. In conclusion, nicorandil attenuates
      ischemia/reperfusion-induced PMNL activation via donation of nitric oxide and K
      channel-related cascade.

PMID- 12409978
TI  - Angiotensin-(1-7) inhibits angiotensin II-induced signal transduction.
AB  - The inhibitory effects of angiotensin-(1-7) on angiotensin II-induced
      vasoconstriction, growth of vascular smooth muscle cells, stimulation of protein
      kinase C, extracellular signal-regulated kinases (ERK), and angiotensin subtype 1
      receptor (AT1) and subtype 2 receptor (AT2) mRNA expression were investigated.
      The hemodynamic effects of angiotensin-(1-7) were measured in Wistar rats.
      Vasoconstriction was measured using aortic rings. DNA synthesis or protein
      synthesis was measured in cultured vascular smooth muscle cells using [3H]
      thymidine or [3H] leucine incorporation, respectively. Angiotensin II stimulated
      protein kinase C and ERK1/2 were measured by Western blot analysis using
      phosphospecific protein kinase C and ERK1/2 antibodies. AT1 and AT2 receptor mRNA
      expression was measured using reverse-transcription polymerase chain reaction.
      Infusion of angiotensin II significantly increased whereas infusion of
      angiotensin-(1-7) had no effects on mean arterial blood pressure in Wistar rats.
      Angiotensin-(1-7) dose-dependently showed partial antagonism on angiotensin II
      induced contraction of aortic rings. Angiotensin-(1-7) showed partial antagonism
      on angiotensin II-induced DNA synthesis and protein synthesis. Angiotensin-(1-7)
      showed partial antagonism on angiotensin II-induced activation of protein kinase
      C and ERK1/2. The administration of angiotensin-(1-7) showed partial antagonism
      on angiotensin II-induced downregulation of AT1 receptor mRNA expression, whereas
      AT2 receptor mRNA expression was unchanged. Angiotensin-(1-7) showed partial
      antagonism on angiotensin II-induced intracellular signal transduction and may
      play a crucial role in the adaptation process of AT1 receptors to sustained
      stimulation of angiotensin II.

PMID- 12409979
TI  - Nitric oxide formation and corresponding relaxation of porcine coronary arteries
      induced by plant phenols: essential structural features.
AB  - The high intake of polyphenols is thought to contribute to the beneficial
      cardiovascular effects of plant-centered diets. A putative mechanism underlying
      the cardioprotective activity is thought to be a plant phenol-induced increase of
      nitric oxide formation by the constitutive endothelial nitric oxide synthase.
      Twenty-eight phenols of different classes commonly occurring in plant foods were
      examined for their capability of enhancing the endothelial nitric oxide release
      of isolated porcine coronary arteries by direct real-time measurement of the
      luminal surface nitric oxide concentration with an amperometric microsensor.
      Additionally, the relaxing activity of the phenols was measured on porcine
      coronary rings. Quercetin, myricetin, leucocyanidol, and oligomeric
      proanthocyanidins induced the highest increases in nitric oxide release
      (delta[NO] > 8.5 nM ); caffeic acid, fisetin, hyperosid, and isoquercitrin were
      moderately active (5 nM < delta[NO] < 8.5 nM ); the other phenolic compounds
      caused only marginal increases of the nitric oxide levels (delta[NO] < 5 nM). The
      nitric oxide-stimulating activity of the phenols was uniformly positively
      correlated with their vasorelaxing activity. However, endothelium-dependent
      vasorelaxations were limited to phenols inducing nitric oxide elevations > 5 nM
      (= Km value of the soluble guanylate cyclase). Analysis of structure-activity
      relations revealed that a high nitric oxide activity was confined to a flavan
      moiety with free hydroxyl-residues at C3, C3', C4', C5, and C7 and a hydroxyl-,
      oxo-, or phenolic substituent at C4, whereas the caffeic acid scaffolding emerged
      as the minimally essential motif for the nitric oxide-dependent vasorelaxation.

PMID- 12409980
TI  - Sevoflurane and bradykinin-induced calcium mobilization in pulmonary arterial
      valvular endothelial cells in situ: sevoflurane stimulates plasmalemmal calcium
      influx into endothelial cells.
AB  - Kinins locally synthesized in the cardiovascular tissue are believed to
      contribute to the regulation of cardiovascular homeostasis by stimulating the
      endothelial cells to release nitric oxide, prostacyclin, or a hyperpolarizing
      factor via autocrine-paracrine mechanisms. This study was designed to investigate
      the action of sevoflurane on bradykinin-induced Ca2+ mobilization in endothelial
      cells in situ. Utilizing fura-2-loaded rat pulmonary arterial valve leaflets, the
      effects of sevoflurane were examined on bradykinin-induced increases in
      intracellular Ca2+ concentration ([Ca2+]i) in endothelial cells in situ. In the
      presence of extracellular Ca2+ (1.5 mM), bradykinin (3-30 microM) produced an
      initial phasic and a subsequent tonic increase in [Ca2+]i in a concentration
      dependent manner. However, it produced only the phasic increase in [Ca2+]i in the
      absence of extracellular Ca2+. Sevoflurane (5%, 0.67 mM) inhibited both the
      phasic and tonic responses to bradykinin. In these experiments, sevoflurane (3
      5%) generated sustained increases (approximately 20-40% of the bradykinin-induced
      maximal increase in [Ca2+]i) in the resting [Ca2+]i level. Sevoflurane still
      increased [Ca2+]i after depletion of the intracellular Ca stores with ionomycin
      (0.1 microM ). However, the sevoflurane-induced increase in [Ca2+]i was
      eliminated by removal of the extracellular Ca and attenuated by NiCl (1-3 mM). In
      conclusion, in the pulmonary arterial valvular endothelial cells, sevoflurane
      inhibits both bradykinin-induced Ca2+ release from the intracellular stores and
      bradykinin-induced plasmalemmal Ca2+ influx. In addition, sevoflurane appears to
      stimulate the plasmalemmal Ca2+ influx and thereby increase the endothelial
      [Ca2+]i level. Sevoflurane might influence the pulmonary vascular tone through
      its direct action on the pulmonary arterial valvular endothelial cells.

PMID- 12409981
TI  - Left but not right cardiac hypertrophy in atrial natriuretic peptide receptor
      deficient mice is prevented by angiotensin type 1 receptor antagonist losartan.
AB  - Mice with a genetic deletion of the atrial natriuretic peptide (ANP) receptor,
      guanylyl cyclase A (GC-A -/-), have chronic arterial hypertension and cardiac
      hypertrophy from the first day of life. To characterize the role of the
      angiotensin II and endothelin systems in the development of this cardiovascular
      phenotype, the effects of chronic treatment with either the angiotensin type I
      (AT1) receptor antagonist losartan or the endothelin A receptor antagonist
      BSF208075 were tested. Losartan almost completely reversed systemic arterial
      hypertension and left ventricular hypertrophy of GC-A -/- mice. This was
      accompanied by a marked regression of the left ventricular mRNA expression of
      cardiac hypertrophy markers such as ANP and brain natriuretic peptide and a
      significant reduction of left ventricular and pulmonary interstitial collagen
      accumulation. BSF208075 had no effect on any of these cardiovascular parameters.
      Intriguingly, GC-A -/- mice also showed a very marked right ventricular
      hypertrophy, which was not reversed by losartan or BSF208075 treatment. Analyses
      of components of the renin-angiotensin system (RAS) revealed an inhibition of
      renal and systemic RAS contrasting with increased local left ventricular
      angiotensin II levels in GC-A -/- mice. Collectively, the results suggest that
      RAS plays a more important role than the endothelin system in the pathogenesis of
      arterial hypertension as well as left ventricular hypertrophy and fibrosis in GC
      A gene-disrupted mice.

PMID- 12409982
TI  - Anti-arrhythmic efficacy of nifekalant hydrochloride, a pure class III anti
      arrhythmic agent, in patients with healed myocardial infarction and inducible
      sustained ventricular tachycardia.
AB  - In recent clinical trials, class III anti-arrhythmic drugs were found to reduce
      arrhythmic deaths in patients after myocardial infarction. The purpose of this
      study was to assess the electrophysiologic properties and anti-arrhythmic
      efficacy for inducible sustained ventricular tachycardias (VTs) of the pure class
      III agent nifekalant hydrochloride (MS-551) in comparison with those of
      procainamide. Programmed ventricular stimulation of up to three extra stimuli was
      performed for induction of VTs. Effective refractory period (ERP) of the ischemic
      zone and normal zone was also measured before and after nifekalant. Nifekalant
      and procainamide suppressed sustained VT induction in four of 15 patients and in
      six of 15 patients, respectively (p = NS). Sinus cycle length, PR interval, and
      QRS duration were not changed, but QT and QTc intervals were significantly
      increased with nifekalant (p < 0.01). Ventricular ERP also increased, whereas
      there were no significant differences in the increase of ERP between the ischemic
      and normal zones. The suppression of VT induction did not correlate with the
      changes in QT, QTc, and ERP after nifekalant administration. There were no
      significant differences in induced VT cycle length at baseline study between
      responders and nonresponders to nifekalant. Reverse use dependence was not
      apparent on review of electrophysiologic parameters. Neither proarrhythmic events
      nor hemodynamic disturbances occurred after nifekalant administration. It was
      concluded that nifekalant could be used safely and showed comparable
      effectiveness to procainamide for the suppression of VT induction.

PMID- 12409983
TI  - Morphine-potentiated agonist-induced platelet aggregation through alpha2
      adrenoceptors in human platelets.
AB  - Morphine dose-dependently (0.6, 1, and 5 microM) potentiated platelet aggregation
      and ATP release stimulated by agonists (i.e., collagen and U46619) in washed
      human platelets. Furthermore, morphine (1 and 5 microM) markedly potentiated
      collagen (1 microg/ml) evoked an increase of intracellular Ca2+ mobilization in
      fura 2-AM loading human platelets. Morphine (1 and 5 microM) did not influence
      the binding of fluorescein isothiocyanate-triflavin to platelet glycoprotein
      IIb/IIIa complex. Yohimbine (0.1 microM), a specific alpha2-adrenoceptor
      antagonist, markedly abolished the potentiation of morphine in platelet
      aggregation stimulated by collagen. Moreover, morphine (0.6-5 microM) markedly
      inhibited prostaglandin E1 (10 microM)-induced cAMP formation in human platelets,
      and yohimbine (0.1 microM) significantly reversed the inhibition of cAMP by
      morphine (0.6 and 1 microM) in this study. Morphine (1 and 5 microM)
      significantly potentiated thromboxane B2 formation stimulated by collagen in
      human platelets, and yohimbine also reversed this effect of morphine in this
      study. In addition, morphine (1 and 5 microM) did not significantly affect
      nitrate production in human platelets. Morphine may exert its potentiation in
      platelet aggregation by binding to alpha2-adrenoceptors in human platelets, which
      leads to reduced cAMP formation and subsequently to increased intracellular Ca2+
      mobilization; this, in turn, is followed by increased thromboxane A formation and
      finally potentiates platelet aggregation and ATP release.

PMID- 12409984
TI  - Anti-anginal effect of fasudil, a Rho-kinase inhibitor, in patients with stable
      effort angina: a multicenter study.
AB  - Rho-kinase plays an important role in calcium sensitization for vascular smooth
      muscle (VSMC) contraction and may be involved in the inappropriate coronary
      vasoconstriction during exercise-induced myocardial ischemia. In this multicenter
      phase II study, the anti-anginal effect of fasudil, which is metabolized to a
      specific Rho-kinase inhibitor hydroxyfasudil after oral administration, was
      examined in patients with stable effort angina. In the phase IIa trial, after a 2
      week washout period of anti-anginal drugs, 45 patients received increasing doses
      of fasudil (5, 10, and 20 mg TID for every 2 weeks). The fasudil treatment
      significantly prolonged the maximum exercise time and the time to the onset of 1
      mm ST segment depression on treadmill exercise test (both p < 0.01), whereas
      blood pressure and heart rate during exercise were unchanged before and after the
      treatment. Higher doses of fasudil (20 and 40 mg TID) were subsequently tested in
      22 patients in the same manner with similar positive results. In the phase IIb
      trial, after a 2-week washout period of anti-anginal drugs, 125 patients were
      assigned, in a double-blind manner, to a 4-week oral treatment with a different
      dose of fasudil (5, 10, 20, or 40 mg TID) and treadmill exercise test was
      performed before and after the treatment. Again, both maximum exercise time and
      time to the onset of 1-mm ST segment depression were prolonged in all groups. A
      significant dose-response relation was noted across the treatment groups for the
      exercise tolerance index that was determined by the combined effect of exercise
      time and ST segment depression (p = 0.006). Fasudil was well tolerated in both
      trials without any serious adverse reactions. These results suggest the efficacy
      and adequate safety profile of fasudil, the first drug in a novel class of
      vasodilators, for the treatment of stable effort angina.

PMID- 12409985
TI  - Cardioprotection with grapes.
AB  - Epidemiologic studies suggest that mild-to-moderate wine consumption is
      associated with a reduced incidence of mortality and morbidity from coronary
      heart disease. Because wines are produced from grapes, this study was done to
      determine whether the grapes were equally cardioprotective. Sprague-Dawley male
      rats were given (orally) standardized grape extract (SGE) (obtained from the
      California Table Grape Commission, Fresno, CA, U.S.A.) (50, 100, or 200 mg/kg
      body weight per day) for 3 weeks. Time-matched control experiments were performed
      by feeding the animals 45 microg/100 g of glucose plus 45 microg/100 g of
      fructose per day for 3 weeks. After 21 days, rats were killed and the hearts
      excised and perfused via working mode. Hearts were made ischemic for 30 min
      followed by 2 h of reperfusion. At 100 mg/kg and at 200 mg/kg, grapes provided
      significant cardioprotection as evidenced by improved postischemic ventricular
      recovery (aortic flow, developed pressure, the maximum first derivative of the
      developed pressure) and reduced amount of myocardial infarction. There were no
      differences in results between the two groups (100 mg/kg versus 200 mg/kg). No
      cardioprotection was apparent when rats were given grape samples at a dose of 50
      mg/100 g/d. SGE reduced the malonaldehyde content of the heart, indicating
      reduction of oxidative stress during ischemia and reperfusion. In vitro studies
      demonstrated that the SGE could directly scavenge superoxide and hydroxyl
      radicals that are formed in the ischemic reperfused myocardium. The results
      demonstrate that the hearts of the rats fed SGE are resistant to myocardial
      ischemia reperfusion injury, suggesting a cardioprotective role of grapes.

PMID- 12409986
TI  - Anti-arrhythmic peptide N-3-(4-hydroxyphenyl)propionyl Pro-Hyp-Gly-Ala-Gly-OH
      reduces dispersion of action potential duration during ischemia/reperfusion in
      rabbit hearts.
AB  - During ischemia, cardiac gap junctions close and neighboring cells uncouple. This
      leads to slow conduction, increased dispersion of APD90 (duration from action
      potential beginning to 90% of repolarization), nonuniform anisotropy, and
      unidirectional conduction block, all of which favor the induction of reentry
      arrhythmias. It has been suggested that anti-arrhythmic peptides increase gap
      junction conductance during states of reduced coupling. The aim of this study was
      to test the effect of the anti-arrhythmic peptide N-3-(4-hydroxyphenyl)propionyl
      Pro-Hyp-Gly-Ala-Gly-OH (HP-5) (10(-10) ) on dispersion of epicardial APD90 during
      both normokalemic and hypokalemic ischemia/reperfusion in isolated perfused
      rabbit hearts. HP-5 did not affect average APD90, heart rate, left ventricular
      contractility (LVP dP/dtmax), or mean coronary flow. HP-5 significantly reduced
      the epicardial APD dispersion during hypokalemic ischemia (HP-5 treated: 24.1 +/-
      3.4 ms, untreated: 33.9 +/- 3.1 ms, p < 0.05 versus untreated) and during
      normokalemic reperfusion but not during normokalemic ischemia or control
      conditions. In addition, among untreated hearts subjected to hypokalemic
      ischemia/reperfusion, seven of 10 developed ventricular fibrillation, whereas
      only three of nine hearts perfused with HP-5 developed ventricular fibrillation.
      These results show that HP-5 is able to reduce APD90 dispersion during
      hypokalemic ischemia in rabbit hearts.

PMID- 12409987
TI  - Differential renal response to Nomega-nitro-L-arginine methyl ester and L
      arginine in rats with hypertensive or diabetic nephropathy.
AB  - The present experiments were designed to assess the renal functional response to
      alterations in nitric oxide formation in animals with different forms of
      nephropathy. To address this issue, the effects of Nomega-nitro-L-arginine methyl
      ester (L-NAME) or L-arginine were assessed in animal models exhibiting arterial
      hypertension due to chronic nitric oxide inhibition (L-NAME, 50 mg/l in drinking
      water for 12 weeks) or diabetes mellitus (streptozotocin, 60 mg/kg IP). Vehicle
      treated, age-matched animals served as controls. Following 12 weeks of
      pretreatment, mean arterial pressure (MAP), renal hemodynamics, urinary albumin,
      and electrolyte excretion were determined in standard clearance experiments prior
      to and following infusion of L-NAME (50 microg/kg/min), l-arginine (5 mg/kg/min),
      or saline vehicle. In control animals, L-NAME resulted in an increase in MAP and
      renal vascular resistance and a decline in glomerular filtration rate and renal
      plasma flow, as expected. L-arginine had no effect on renal hemodynamics. In
      nitric oxide-depleted hypertensive animals, L-NAME had no additional effect on
      MAP or renal hemodynamics. Infusion of L-arginine reduced elevated MAP but did
      not reverse changes in renal hemodynamics. Diabetic rats demonstrated glomerular
      hyperfiltration and proteinuria. No significant changes in MAP or renal
      hemodynamics were observed following infusion of L-NAME or L-arginine,
      respectively. However, L-NAME increased urinary albumin excretion in the absence
      of hemodynamic changes. The effects of nitric oxide on vascular tone were shown
      to be dependent on the vascular bed and the underlying disease. Variations in
      local nitric oxide formation and susceptibility may account for the differential
      response of the systemic and renal vasculature and contribute to the degree of
      renal functional impairment observed in different systemic diseases.

PMID- 12409988
TI  - Combination of low-dose valsartan and enalapril improves endothelial dysfunction
      and coronary reserve in Nomega-nitro-L-arginine methyl ester-treated
      spontaneously hypertensive rats.
AB  - Combination of nonhypotensive doses of valsartan and enalapril markedly improved
      survival (+87%) compared with untreated animals (37%) in spontaneously
      hypertensive rats (SHRs) with endothelial dysfunction. However, the combination
      had no effect on kidney function, and proteinuria persisted over the 12 weeks of
      the study. It was hypothesized that the greater survival was due to improvement
      in endothelial function or coronary vasculature despite blockade of nitric oxide
      synthase and high blood pressure. Therefore, endothelial function was evaluated
      in isolated aortic ring and maximal coronary blood flow was studied in isolated
      perfused SHR hearts (20-24 weeks) treated with -nitro-l-arginine methyl ester (L
      NAME) (50 mg/l) for 4 weeks. The animals received vehicle, valsartan 5 mg/kg/d,
      enalapril 1 mg/kg/d, valsartan 50 mg/kg/d, or the combination valsartan 5 mg/kg/d
      with enalapril 1 mg/kg/d in drinking water. Normotensive Wistar-Kyoto (WKY) rats
      were used as control. Blood pressure was measured by telemetry. Histopathology
      was performed on heart, kidney (hematoxylin-eosin), and aorta (Masson trichrome).
      L-NAME elevated blood pressure by 50 mm Hg after vehicle (199 +/- 5 mm Hg).
      Valsartan 50 mg/kg/d completely abolished this increase (150 +/- 4 mm Hg) whereas
      the valsartan-enalapril combination synergistically decreased blood pressure (-37
      mm Hg at 162 +/- 7 mm Hg) compared with monotherapy (valsartan 5 mg/kg/d -10 mm
      Hg; enalapril 1 mg/kg/d -15 mm Hg). All treatments improved the histopathology,
      most markedly in those receiving the valsartan-enalapril combination. The
      severity mean grades for lesions were 2.1, 1.9, 1.7, 1.1, and 0.9 in vehicle
      treated SHRs, enalapril 1 mg/kg/d, valsartan 5 mg/kg/d, valsartan 5 or 50
      mg/kg/d, and the valsartan-enalapril combination, respectively, compared with
      0.02 in WKY rats. Acetylcholine-induced relaxation was significantly greater in
      treated SHRs than after vehicle (-40% at 0.1 mmol acetylcholine) but the
      combination induced the maximal relaxation (-85%). The ratio of maximal tension
      induced by serotonin in rings with and without endothelium was 1.4 and 1.3 in
      vehicle and valsartan 5 mg/kg/d-treated rats whereas it did not differ from 1 in
      WKY rats and all other treated groups. The cardiac hypertrophy (+27%) was
      prevented by valsartan 50 mg/kg/d and the valsartan-enalapril combination.
      Coronary reserve was significantly increased by valsartan 50 mg/kg/d (+85% at 7.8
      +/- 0.7 ml/min/g) and the valsartan-enalapril combination (+42% at 6.0 +/- 0.4
      ml/min/g) compared with 4.2 +/- 0.5 (vehicle). This was not different of 8.8 +/-
      0.5 (WKYs). Despite the maintenance of a high blood pressure, low-dose valsartan
      enalapril significantly improved endothelial function and histopathology and
      increased coronary reserve in SHRs chronically receiving L-NAME.

PMID- 12409989
TI  - Pharmacokinetics of multiple doses of valsartan in patients with heart failure.
AB  - Angiotensin II has adverse actions in heart failure including vasoconstriction,
      aldosterone secretion, and activation of the sympathetic nervous system.
      Valsartan, a potent specific angiotensin II type 1 receptor blocker, may produce
      beneficial effects in heart failure. The purpose of this study was to evaluate
      the steady-state pharmacokinetics of valsartan 40, 80, and 160 mg each given
      every 12 h for 7 days in heart failure patients. Eighteen patients with chronic
      stable heart failure and left ventricular ejection fractions <or= 40% received
      each dosing regimen starting with the 40-mg dose. On day 7 of each dosing period,
      serial blood samples were obtained over 12 h for pharmacokinetic assessment.
      Results showed that the mean area under the concentration-time curve (AUC) and
      maximum concentration (Cmax) increased in a linear and nearly proportional manner
      with valsartan dose. A dose-proportionality assessment, based on a statistical
      power model, showed that doubling the dose increased the AUC and Cmax 1.8 times.
      The pharmacokinetics of valsartan are predictable in heart failure patients
      within the dose range of 40-160 mg BID. Age did not appear to have influenced the
      valsartan clearance in heart failure patients. The pharmacokinetic values were
      higher in heart failure patients than in healthy volunteers. All doses were
      generally safe and well tolerated.(max) (max)

PMID- 12409990
TI  - Cocaine-induced anxiety: alleviation by diazepam, but not buspirone,
      dimenhydrinate or diphenhydramine.
AB  - Clinical reports and animal experiments indicate that both cocaine administration
      and cocaine withdrawal increase anxiety. We investigated the ability of a number
      of putative anxiolytic agents to alleviate these anxiety states using the
      elevated plus-maze. Rats in the cocaine condition received either saline or
      cocaine (20 mg/kg) 40 min prior to testing; those in the withdrawal condition
      were tested 48 h following a chronic treatment regime (saline or cocaine 20 mg/kg
      per day for 14 days). Prior to testing, animals received a benzodiazepine (1.0 or
      2.0 mg/kg diazepam), a serotonergic agonist (0.5 or 1.0 mg/kg buspirone), an
      antihistamine (50 mg/kg dimenhydrinate or 27 mg/kg diphenhydramine) or a saline
      injection. All drugs were administered intraperitoneally. Cocaine administration
      and cocaine withdrawal reduced the percentage time spent on and the number of
      entries into the open arms. Diazepam dose-dependently alleviated cocaine
      withdrawal-induced anxiety and non-significantly attenuated cocaine-induced
      anxiety. Buspirone, dimenhydrinate and diphenhydramine did not consistently
      alleviate the anxiety caused by either cocaine pre-treatment regime; in the
      saline conditions, however, each of these treatments was anxiogenic. In summary,
      benzodiazepines alleviated cocaine-induced anxiety, while future research on the
      ability of serotonergic and antihistaminergic drugs to alleviate these anxiety
      states is warranted.

PMID- 12409991
TI  - Further evidence for the predictive validity of the unstable elevated exposed
      plus-maze, a behavioural model of extreme anxiety in rats: differential effects
      of fluoxetine and chlordiazepoxide.
AB  - The unstable elevated exposed plus-maze (UEEPM) is a novel model of extreme
      anxiety which elicits unconditioned flight/escape behaviour in rats. The current
      studies aimed to investigate further the predictive validity of the paradigm, by
      examining the effects on UEEPM behaviour of both clinically effective (chronic
      fluoxetine) and ineffective (acute fluoxetine and chlordiazepoxide) treatments
      for panic disorder. In the first experiment, male Brown Norway rats received a
      single injection of fluoxetine (1.0-10.0 mg/kg p.o.) or chlordiazepoxide (CDP,
      1.0-10.0 mg/kg i.p.) 30 min prior to UEEPM exposure. In the second experiment, in
      order to assess the effects of chronic dosing or handling on baseline UEEPM
      behaviour, subjects received either 21 days vehicle injection (p.o.) or handling,
      before being exposed to the test. Finally, rats received 21 days fluoxetine (1.0
      10.0 mg/kg) in their food, before being tested in the UEEPM. Acute CDP and
      fluoxetine had no effect on UEEPM behaviour. Chronic handling and vehicle
      administration (p.o.) significantly reduced escape in the UEEPM, hence preventing
      the effects of chronic fluoxetine administration from being investigated by p.o.
      dosing. Chronic fluoxetine in subjects' food (10.0 mg/kg) significantly
      attenuated animals' propensity to escape from the UEEPM. The results further
      support the pharmacological similarity between symptoms of panic in humans and
      escape in the UEEPM and suggest that the UEEPM may represent a paradigm to
      facilitate investigation into the neurochemical basis of extreme anxiety
      disorders.

PMID- 12409992
TI  - A potential antidepressant activity of SA4503, a selective sigma 1 receptor
      agonist.
AB  - The aim of the present study was to examine SA4503 [1-(3,4-dimethoxyphenethyl)-4
      (3-phenylpropyl)piperazine dihydrochloride], a novel selective receptor agonist,
      in respect of its potential antidepressant action. To this end we used a forced
      swimming test in rats to study SA4503 alone, as well as its interaction with
      imipramine, a classic tricyclic antidepressant. SA4503 decreased the immobility
      time in the forced swimming test in rats (although only at one of the three doses
      used); at the same time it did not change the locomotor activity recorded under
      the same experimental conditions. Moreover, SA4503 showed a synergistic effect
      with imipramine in the forced swimming test (both those compounds given jointly
      decreased the immobility time, but were ineffective when administered
      separately). It had previously been shown that repeated administration of
      antidepressants with different pharmacological profiles enhanced the action of D
      amphetamine, quinpirole and other dopamine stimulants. SA4503 administered
      repeatedly increased the locomotor hyperactivity induced by D-amphetamine and
      quinpirole (a dopamine D /D receptor agonist), but not by (+/-)-7-hydroxy
      dipropyloamino-tetralin hydrobromide [(+/-)-7-OH-DPAT; a dopamine D receptor
      agonist]. The results presented in this paper support the suggestion that SA4503
      may have potential antidepressive properties.

PMID- 12409993
TI  - Acute and chronic effects of the neuroactive steroid pregnanolone on schedule
      controlled responding in rhesus monkeys.
AB  - This study used schedule-controlled responding to examine the acute and chronic
      effects of the neuroactive steroid and positive -aminobutyric acid A (GABA )
      modulator pregnanolone. Pregnanolone, the positive GABA modulator triazolam, the
      GABA chloride channel site antagonist pentylenetetrazol (PTZ) and the -methyl-d
      aspartate (NMDA) antagonist ketamine were administered to monkeys ( = 4)
      responding under a multiple fixed ratio (FR/FR) schedule of food presentation and
      stimulus shock termination (SST), before, during and after daily treatment with
      pregnanolone (3.2 mg/kg subcutaneously). Pregnanolone decreased responding in a
      dose- and time-related manner, with a duration of action of <2 h. Mutual
      antagonism occurred between pregnanolone and PTZ in the food component, and PTZ
      antagonized pregnanolone in the SST component. Daily treatment with pregnanolone
      increased the sensitivity to PTZ 24 h but not 2 h after daily pregnanolone
      administration, and daily pregnanolone treatment did not alter the sensitivity to
      pregnanolone, triazolam or ketamine. Baseline responding in the food component
      was decreased in some monkeys 24 h after daily pregnanolone administration and in
      all monkeys 48 h after discontinuation of daily pregnanolone treatment. These
      results suggest that positive GABA modulation is one mechanism by which
      pregnanolone decreases FR responding, and that dependence resulting from daily
      pregnanolone treatment is not necessarily accompanied by tolerance to
      pregnanolone. Failure of pregnanolone to confer tolerance under these conditions
      might suggest that neuroadaptations at the GABA receptor complex vary according
      to the site at which positive GABA modulation occurs.

PMID- 12409994
TI  - Delta opioid antagonist effects of buprenorphine in rhesus monkeys.
AB  - Buprenorphine is an opioid with high affinity for delta, mu and kappa opioid
      receptors. The delta receptor-mediated effects of buprenorphine have not been
      studied. Thus, the present study examined the delta receptor-mediated effects of
      buprenorphine in rhesus monkeys. assays of receptor binding and agonist
      stimulated GTP S binding confirmed that buprenorphine had high affinity for, and
      low efficacy at, delta receptors. In an assay of schedule-controlled responding
      for food presentation in four monkeys, buprenorphine produced little effect
      alone, but it antagonized the effects of the delta agonist SNC80, the mu agonist
      morphine and the kappa agonist U50,488. Buprenorphine was approximately 30-fold
      less potent as a delta antagonist than as a mu or kappa antagonist. In three
      monkeys trained to discriminate SNC80 from saline, buprenorphine alone produced
      only saline-appropriate responding, and buprenorphine pretreatment antagonized
      the discriminative stimulus effects of SNC80. In a fourth monkey, buprenorphine
      produced a partial substitution for SNC80 that could be blocked by the delta
      selective antagonist naltrindole but not by the mu-selective antagonist
      quadazocine. These results indicate that, in rhesus monkeys, buprenorphine has
      very low efficacy at delta receptors, and that buprenorphine produces delta
      receptor-mediated effects with lower potency than it produces mu or kappa
      receptor-mediated effects.

PMID- 12409995
TI  - Evaluation of the discriminative stimulus effects of the low-affinity N-methyl-D
      aspartate channel blockers AR-R 13950AA and AR-R 16283AA in rats and rhesus
      monkeys.
AB  - Low-affinity channel-blocking -methyl-D-aspartate (NMDA) antagonists have been of
      interest for clinical development because they are purported to produce few
      phencyclidine (PCP)-like side-effects, particularly at therapeutic doses. In the
      current study, two low-affinity NMDA channel blockers, AR-R 13950AA and AR-R
      16283AA, were evaluated for NMDA antagonist-associated behavioral effects. The
      drugs were tested in rats and rhesus monkeys trained to discriminate PCP from
      saline, using a standard two-lever drug discrimination paradigm, under a fixed
      ratio (FR) schedule of food reinforcement. Both drugs were also tested in rats
      trained to discriminate NPC 17742, a competitive NMDA antagonist, from saline in
      a similar experimental procedure. In rats, both AR-R 13950AA and AR-R 16283AA
      resulted in intermediate levels of PCP-lever selection (up to 60%). Testing in
      NPC 17742-trained rats produced at most 30% NPC 17742-lever responding. In rhesus
      monkeys, AR-R 13950AA produced virtually no PCP-lever responding at any dose,
      while AR-R 16283AA produced a dose-dependent substitution for PCP in all four
      subjects. The results with AR-R 16283AA in monkeys suggest that, at doses above
      therapeutic levels, it may produce PCP-like intoxication in humans. Overall, the
      results suggest that, while there is some overlap of the discriminative stimulus
      effects produced by the AR-R compounds with those of PCP, there are also
      important differences.

PMID- 12409996
TI  - The selective glycine antagonist gavestinel lacks phencyclidine-like behavioral
      effects.
AB  - Gavestinel [GV150526A; ( E)-3[(phenylcarbamoil)ethenyl]-4,6-dichloroindole-2
      carboxylic acid sodium salt] is a selective antagonist at the strychnine
      insensitive glycine site of the -methyl-D-aspartate (NMDA) receptor. It was
      tested for its ability to substitute for phencyclidine (PCP) in rats and rhesus
      monkeys trained to discriminate PCP from saline, under a two-lever fixed-ratio
      (FR) food reinforcement schedule, and for its ability to maintain responding in
      rhesus monkeys trained to self-administer PCP under a FR reinforcement schedule.
      No PCP-lever responding was observed after gavestinel (1-56 mg/kg i.p.)
      administration to rats discriminating PCP (2.0 mg/kg i.p.) from saline. The
      highest dose of gavestinel (100 mg/kg i.p.) tested eliminated responding.
      Likewise, no PCP-lever responding was observed after gavestinel (1-30 mg/kg s.c.)
      administration to rhesus monkeys discriminating PCP (0.08 or 0.1 mg/kg i.m.) from
      saline; the highest dose of gavestinel (30 mg/kg s.c.) tested reduced response
      rates to approximately 50% of those observed after its vehicle ( -cyclodextrin in
      0.9% saline). Gavestinel (0.1-1 mg/kg per i.v. infusion) was not self
      administered by rhesus monkeys that reliably self-administered PCP (0.0056 or
      0.01 mg/kg per i.v. infusion). Infusion rates at the highest dose were typically
      lower than those for vehicle or saline, suggesting behavioral activity. Together,
      these results suggest that at behaviorally active doses gavestinel is not PCP
      like and is likely to have low abuse liability.

PMID- 12409997
TI  - Pretreatment with corticosterone attenuates the nucleus accumbens dopamine
      response but not the stimulant response to cocaine in rats.
AB  - It has been suggested that stress, via corticosterone secretion, can modulate
      some of the behavioural responses to cocaine. In particular, we have demonstrated
      that daily exposure to electric footshock stress or daily pretreatment with
      corticosterone shifts the ascending limb of the dose-response curve for the
      acquisition of cocaine self-administration upwards and to the left. It has been
      suggested that this corticosterone-induced increase in sensitivity to low doses
      of cocaine is associated with an enhancement of dopaminergic neurotransmission.
      The present study was designed to test this hypothesis. Adult male rats were
      pretreated with corticosterone (2.0 mg/kg intraperitoneally) 15 min prior to an
      injection of cocaine (5.0, 10.0 or 20.0 mg/kg intraperitoneally), and motor
      activity and extracellular dopamine concentrations in the nucleus accumbens were
      monitored. Cocaine administration resulted in dose-related increases in motor
      activity that were unaffected by pretreatment with corticosterone. However,
      rather than augmenting cocaine-induced increases in dopamine in the nucleus
      accumbens, corticosterone pretreatment actually caused attenuation at the two
      highest doses of cocaine tested. These data suggest dissociation between
      locomotor activation and nucleus accumbens dopamine responses to cocaine, and
      indicate that other brain regions and/or mechanisms may be involved in the
      changes in sensitivity to cocaine induced by corticosterone.

PMID- 12410000
TI  - Vitamins, fever and birth defects- consistent interaction or persistent bias?

PMID- 12410001
TI  - Modeling infection transmission- the pursuit of complexities that matter.

PMID- 12410002
TI  - Maternal periconceptional vitamins: interactions with selected factors and
      congenital anomalies?
AB  - BACKGROUND: The mechanisms by which folic acid may contribute to reductions in
      risk of several congenital anomalies are unknown. The data gap includes a lack of
      information on possible effect modification between maternal folic acid use and
      other maternal exposures. We hypothesized that effects of congenital anomalies
      associated with maternal fever, cigarette smoking or alcohol use would be
      modified by intake of vitamins. METHODS: We explored case-control data that
      showed risk reductions among infants and fetuses whose mothers consumed vitamins.
      Data were from California deliveries of infants and fetuses in the period 1987
      1989. Maternal telephone interviews were completed for 207 (87%) conotruncal
      cases, 489 (85%) orofacial cleft cases, 265 (84%) neural tube defect cases, 165
      (82%) limb anomaly cases, and 734 controls (nonmalformed infants). RESULTS:
      Considering women who reported vitamin use and no periconceptional fever as
      referents, for each anomaly group we observed elevated effects for the
      combinations of maternal vitamin use/fever, no use/no fever and no use/fever.
      Effects were most elevated for the combination of no vitamin use and fever.
      Adjusted for maternal body mass index, education and race/ethnicity, odds ratios
      were 2.4 (95% confidence inter-val = 1.0-5.9) for conotruncal defects, 2.9 (1.4
      5.8) for cleft lip with or without cleft palate, 1.3 (0.4-3.9) for cleft palate,
      3.1 (1.4-6.8) for neural tube defects, and 2.6 (1.0-6.4) for limb-deficiency
      defects. These interactions were further investigated relative to maternal use of
      fever-reducing medications. Effects tended to be highest among those women who
      did not use vitamins, had fevers, and did not use fever-reducing medications.
      Compared with women who used vitamins and did not smoke periconceptionally,
      anomaly risks tended to be highest among women who did not use vitamins and
      smoked. No specific pattern emerged involving alcohol intake. CONCLUSIONS: These
      data further suggest that the underlying mechanisms of folic acid associated with
      congenital anomalies may be complex.

PMID- 12410003
TI  - The theoretical population-level impact of a prophylactic human papilloma virus
      vaccine.
AB  - BACKGROUND: The ongoing development of a vaccine against human papillomavirus
      (HPV) raises important questions about the impact of various vaccination
      strategies. METHODS: Two mathematical models are developed to explore the
      population-level impact of an HPV vaccine. The first model focuses on the
      infection process and the second on the disease process (specifically, cervical
      carcinoma and cancer). RESULTS: Both population characteristics (, sexual mixing
      and rates of sex partner change) and vaccine characteristics affect the steady
      state prevalence of HPV that would be expected if a vaccine program is
      implemented. Under a particular set of assumptions, we find that vaccinating both
      men and women against a specific HPV type would result in a 44% decrease in
      prevalence of that type whereas vaccinating only women would result in a 30%
      reduction. We also find that if a vaccine gives protection against some, but not
      all, high risk types of HPV, the reduction in disease may be less than the
      reduction in HPV because the remaining high risk HPV types may replace the
      disease caused by the eliminated types. CONCLUSIONS: A multivalent vaccine
      containing the majority of disease-causing HPV types would greatly reduce the
      need for colposcopy, biopsy and treatment. However, it is unlikely that Pap
      screening programs would become redundant unless the vaccine is highly effective
      and coverage is widespread. In contrast to less common infections that are
      primarily restricted to core groups, targeting the vaccine towards the most
      sexually active individuals is less effective for a common sexually transmitted
      infection such as HPV.

PMID- 12410004
TI  - Obtaining sensitive data through the Web: an example of design and methods.
AB  - Several studies have suggested that the quality of coital data from diaries is
      superior to that collected by retrospective questionnaires. By collecting data
      over short intervals of time, diaries can present a more comprehensive picture of
      exposure, while minimizing the potential for recall bias. Despite these
      advantages, paper diaries have limited use because of their expense and
      difficulty of implementation. Web-based data collection offers the opportunity to
      make improvements to the quality of epidemiologic exposure measurement by
      providing privacy and convenience to study participants while reducing costs
      associated with questionnaire administration and allowing for real-time data
      processing. We adapted coital diaries for Web-based data collection in a study of
      transmission rates of genital human papillomavirus infection among young adults.
      University women complete an online sexual behavior questionnaire ("diary") every
      2 weeks over a 3-year follow-up period; men complete a single online sexual
      behavior questionnaire ("journal"). In this paper we describe the design,
      methodology and implementation issues that emerge in conducting a Web-based
      epidemiologic study. We also discuss compliance, as well as methods for assuring
      appropriate security, confidentiality and privacy.

PMID- 12410005
TI  - Perceptions of racial discrimination and the risk of preterm birth.
AB  - BACKGROUND: Because racial discrimination might contribute to their excess of
      preterm births, we assessed experiences of racism in relation to preterm birth
      among African-American women. METHODS: We used data from the Black Women's Health
      Study, a follow-up study of African-American women begun in 1995. Data on
      subsequent singleton births were obtained using follow-up questionnaires in 1997
      and 1999; nine questions about experiences of racism were asked in 1997. We
      compared mothers of 422 babies born 3 or more weeks early (because of premature
      labor for unknown reasons or rupture of membranes) with mothers of 4544 babies of
      longer gestation. We used generalized estimating equation models to estimate odds
      ratios (ORs) for preterm birth, controlling potential confounders. RESULTS: The
      adjusted ORs for preterm birth were 1.3 (95% confidence interval [CI] = 1.1-1.6)
      for women who reported unfair treatment on the job and 1.4 (1.0-1.9) for women
      who reported that people acted afraid of them at least once a week. Overall ORs
      for the seven other racism questions were close to 1.0. Among 491 women with
      </=12 years of education, ORs were 2.0 or greater for four racism variables.
      CONCLUSIONS: These data provide some evidence for an increase in preterm birth
      among women who report experiences of racism, particularly women with lower
      levels of education.

PMID- 12410006
TI  - Vigorous leisure activity and pregnancy outcome.
AB  - BACKGROUND: Preterm birth is the leading cause of perinatal mortality in North
      America and Europe and a major predictor of neonatal and infant morbidity.
      Postterm birth is associated with increased infant mortality and morbidity, as
      well as increased frequency of surgical or induced labor. Because vigorous
      leisure activity may affect timing of delivery, this study examined association
      between vigorous leisure activity and birth outcomes. METHODS: Women (N = 1,699)
      with a singleton pregnancy were recruited at 24-29 weeks' gestation from prenatal
      clinics in central North Carolina between 1995 and 1998. The type and duration of
      any regular vigorous leisure activity was assessed in a telephone interview
      covering the 3-month period before pregnancy and during the first and second
      trimesters of pregnancy. RESULTS: The prevalence of vigorous leisure activity was
      22% before pregnancy, 14% during the first trimester, and 8% during the second
      trimester. Vigorous leisure activity before pregnancy was unrelated to preterm
      (<37 weeks) as compared with term delivery (37 to <42 weeks). The risk of preterm
      birth was somewhat reduced with vigorous leisure activity during the first
      trimester (odds ratio = 0.80; 95% confidence interval = 0.48-1.35) and more so
      during the second trimester (odds ratio = 0.52; 95% confidence interval = 0.24
      1.11). Vigorous leisure activity before pregnancy or during the first or second
      trimester was not associated with postterm delivery (>/=42 weeks). CONCLUSIONS:
      Vigorous leisure activity during the first trimester, and even more so in the
      second trimester, was associated with a reduced risk of preterm birth. There was
      no association with postterm birth. To address the etiologic role of activity on
      pregnancy outcome and to overcome self-selection, a randomized clinical trial
      would be needed.

PMID- 12410007
TI  - Paternal age and preeclampsia.
AB  - BACKGROUND: Paternal aging is associated with premeiotic damage to spermatogonia,
      a mechanism by which new point mutations are introduced into the gene pool. We
      hypothesized that paternal age might contribute to preeclampsia. METHODS: We
      studied the incidence of preeclampsia in 81,213 deliveries surveyed in 1964-1976
      in the Jerusalem Perinatal Study. We controlled for maternal age, parity and
      other risk factors using logistic regression. RESULTS: Preeclampsia was reported
      in 1303 deliveries (1.6%). Compared with fathers age 25-34 years, the odds ratios
      (ORs) for preeclampsia were 1.24 (95% confidence interval = 1.05-1.46) for age 35
      44 and 1.80 (1.40-2.31) for age 45+. For fathers age <25, the OR was 1.25 (1.04
      1.51). Although weaker than maternal age effects, paternal effects were
      consistent within subgroups of other variables. CONCLUSIONS: These findings
      support the hypothesis that a modest proportion of preeclampsia might be
      explained by new mutations acquired from fathers and add to a growing body of
      evidence for paternal age effects in birth defects, neuropsychiatric disease and
      neoplasia.

PMID- 12410008
TI  - Influence of medical conditions and lifestyle factors on the menstrual cycle.
AB  - BACKGROUND: Few studies have described medical and lifestyle factors associated
      with various menstrual cycle characteristics. METHODS: We analyzed cross
      sectional data collected from 3941 premenopausal women from Iowa or North
      Carolina participating in the Agricultural Health Study between 1994 and 1996.
      Eligible women were age 21-40, not taking oral contraceptives, and not currently
      pregnant or breast feeding. We examined four menstrual cycle patterns: short
      cycles (24 days or less), long cycles (36 days or more), irregular cycles, and
      intermenstrual bleeding. RESULTS: Long and irregular cycles were less common with
      advancing age and more common with menarche after age 14, with depression, and
      with increasing body mass index. The adjusted odds of long cycles increased with
      increasing body mass index, reaching 5.4 (95% confidence interval [CI] = 2.1
      13.7) among women with body mass indexes of 35 or higher compared with the
      reference category (body mass index of 22-23). Smoking was associated with short
      cycles. Long cycles, irregular cycles, and intermenstrual bleeding were
      associated with a history of infertility. Having long cycles was associated with
      a doubling in the adjusted odds of having a fetal loss among women who had been
      pregnant within the last 5 years (odds ratio = 2.3; 95% CI = 0.9-5.7).
      CONCLUSIONS: Menstrual patterns are influenced by a number of host and
      environmental characteristics. Factors that perturb menstruation may increase a
      woman's risk of other reproductive disorders.

PMID- 12410009
TI  - Ovarian hormones in premenopausal women: variation by demographic, reproductive
      and menstrual cycle characteristics.
AB  - BACKGROUND: Ovarian function influences many areas of concern in women's health,
      including breast cancer and other chronic diseases. However, ovarian function has
      been little studied in healthy, premenopausal women, partly because of cyclical
      variation. METHODS: We measured biomarkers of ovarian function (daily urinary
      metabolites of estrogen and progesterone) among 411 women age 18-39 years, who
      were Kaiser Permanente members in Northern California in 1990-1991. We have
      summarized the hormone metabolite levels of about 1,500 cycles and examined their
      associations with demographic and menstrual cycle characteristics. RESULTS:
      Cycles with a short follicular phase showed elevations of 10-13% in both baseline
      (days 1-5) and average follicular-phase estrogen metabolite levels, as well as
      some elevations in progesterone metabolites. Progesterone metabolite levels were
      directly related to the length of the luteal phase. Compared with whites,
      Hispanics had estrogen metabolite levels that were 7-13% higher in the follicular
      and luteal phases, whereas nonwhite, non-Hispanic women (primarily Asians) had
      slightly lower levels. Generally, women with a prior pregnancy or those with a
      later age at menarche had lower estrogen metabolite levels, whereas women with
      prior induced abortions had higher levels. Luteal-phase progesterone metabolite
      levels tended to be lower among women who were overweight, were less educated,
      were older at their first livebirth, or had an induced abortion. CONCLUSIONS:
      Some menstrual cycle characteristics provide a crude surrogate of the hormonal
      milieu, particularly luteal-phase length and progesterone levels. Hormone levels
      varied by reproductive characteristics, potentially explaining their relevance to
      breast cancer risk.

PMID- 12410010
TI  - Smoothing in survival models: an application to workers exposed to metalworking
      fluids.
AB  - BACKGROUND In occupational epidemiology it is typically assumed that the relation
      between exposure, possibly transformed, and the risk of an adverse health outcome
      is linear in the parameters. Alternatively, exposure is transformed into a
      categorical variable. METHODS We used nonparametric regression to examine the
      linearity assumption for prostate and brain cancer mortality in a cohort of
      46,400 autoworkers exposed to metalworking fluids. Using a nested case-control
      sample, we fit Cox proportional hazards models with penalized splines, in which
      we allowed the risk to be a smooth function of exposure to each of three types of
      metalworking fluids. Two dose metrics in addition to cumulative exposure were
      considered. RESULTS The shape of the dose-response curve for soluble metalworking
      fluids and each cancer was approximately piecewise linear, with a small increase
      in risk at lower exposures followed by a larger increase at exposures above a
      critical point. CONCLUSIONS This example illustrates that the penalized spline
      methodology can be easily applied to cohort studies to estimate smooth exposure
      response curves.

PMID- 12410011
TI  - Cohort mortality study of German cockpit crew, 1960-1997.
AB  - BACKGROUND: Cockpit crew in civil aviation are exposed to several potential
      health hazards, among them cosmic ionizing radiation. To assess the influence of
      occupational and other factors on mortality we conducted a cohort study among
      cockpit crew. METHODS: All pilots and other cockpit personnel of two German
      airlines were traced through registries and other sources for the period 1960
      1997. Standardized mortality ratios, with German population rates as the
      reference, were calculated. We estimated the individual radiation dose based on
      individual job histories and assessed dose-response trends in stratified and
      regression analyses. RESULTS: We compiled a cohort of 6061 male cockpit
      personnel, yielding 105,037 person-years of observation. The maximum estimated
      individual radiation dose was 80.5 mSv. Among 255 deaths overall (standardized
      mortality ratio [SMR] = 0.48; 95% confidence interval [CI] = 0.42-0.54) there
      were 76 cancer deaths (SMR = 0.56; CI = 0.43 - 0.74). Most cancer and
      cardiovascular SMRs were reduced. A slight increase was seen for brain cancer
      (SMR = 1.68; CI = 0.66-3.62). Employment duration was associated with the all
      cancer mortality in Poisson regression analyses. No other dose-response relation
      was found. CONCLUSIONS: German cockpit crew have a low overall and cancer
      mortality. The role of occupational causes, and particularly cosmic radiation,
      appears limited.

PMID- 12410012
TI  - Dietary folate and the risk of nonfatal myocardial infarction.
AB  - BACKGROUND: Elevated homocysteine levels have been associated with a higher risk
      of cardiovascular disease. Because folate intake can reduce homocysteine levels,
      we investigated the association between dietary folate intake and nonfatal
      myocardial infarction. METHODS: We conducted a case-control study in three
      tertiary hospitals of Pamplona, Spain, between 1999 and 2001. Study physicians
      enrolled 171 patients less than 80 years of age with a first nonfatal myocardial
      infarction and 171 control patients matched by age, sex, hospital and calendar
      month. We excluded patients with any prior major cardiovascular disease.
      Participants were interviewed about medical factors and life-style and completed
      a food frequency questionnaire previously validated in Spain. We calculated
      energy-adjusted intakes of folate and estimated relative risks (RRs) of
      myocardial infarction and 95% confidence intervals (CIs) using conditional
      logistic regression. Relative risks were adjusted for conventional risk factors.
      RESULTS: Only 6% of participants were taking vitamin supplements. The main
      sources of folate were green leafy vegetables, green beans, oranges, peppers and
      lettuces. The estimated matched RR of myocardial infarction for the top three
      quartiles of folate intake (, above 340 microg/day) was 0.57 (CI = 0.35-0.94),
      compared with the lowest quartile of intake. The multivariate adjusted RR was
      0.51 (CI = 0.24-1.06). There was no apparent dose effect above this threshold.
      CONCLUSIONS: Our results in a Mediterranean population with natural plant foods
      as the main source of folate provide further evidence to support the hypothesis
      that dietary folate intake may be an independent protective factor for myocardial
      infarction. The magnitude of the effect, its biological plausibility, and the
      consistency across studies offer support for a causal association.

PMID- 12410013
TI  - Contextual factors and the black-white disparity in heterosexual HIV
      transmission.
AB  - ABSTRACT African-Americans have the highest rates of human immunodeficiency virus
      (HIV) transmission, including heterosexual transmission, in the United States.
      Although numerous factors probably contribute to the extreme racial disparity,
      reasons for its persistence remain poorly explained. Mathematical modeling
      demonstrates that concurrent sexual partnerships speed transmission of HIV
      through sexual networks more effectively than does serial monogamy, for the same
      total number of sexual partners. This paper examines the evidence that the social
      and economic environment for many African-Americans discourages long-term
      monogamy and promotes concurrent sexual partnerships, which may, in turn, fuel
      the HIV epidemic in this population.

PMID- 12410014
TI  - Estimating the influence of rescreening interval on the benefits associated with
      cancer screening: approaches and limitations.
AB  - ABSTRACT Randomized controlled trials that seek to measure the ability of a
      screening test to lower cancer mortality generally do not provide data that bear
      on the relative efficacy of different screening intervals. Guidance regarding the
      choice of a screening interval that achieves a high level of case-finding,
      without being excessively costly, can be obtained from one or more of several
      study designs that examine the subsequent occurrence of cancer in persons who
      have had a negative screening test. However, each of these can potentially
      provide a misleading result, and so their limitations must be considered before
      using the data they generate to develop a rational rescreening policy.

PMID- 12410015
TI  - Organic solvents and the risk of multiple sclerosis.
AB  - BACKGROUND: Epidemiologic studies suggest that environmental factors may be part
      of the yet unknown causation of multiple sclerosis (MS). Several case-control
      studies have shown a history of elevated exposure to organic solvents among
      cases. METHODS: Three cohorts of 11,542 painters, 36,899 construction workers and
      9,314 food-processing workers were identified by the 1970 census in Norway. The
      cohorts were followed until the end of 1986 for registration of disability
      pensions. RESULTS: A total of nine painters, 12 construction workers and six food
      workers had received a disability pension because of MS. The relative risk for
      painters compared with workers not exposed to organic solvents was 2.0 (95%
      confidence inter-val = 0.9-4.5) for MS. CONCLUSIONS: These results are compatible
      with the hypothesis of organic solvents being a possible risk factor for MS.

PMID- 12410017
TI  - Swimming and birth weight.
AB  - BACKGROUND: Swimmers can be exposed to high levels of trihalomethanes, byproducts
      of chlorination disinfection. There are no published studies on the relation
      between swimming and birth weight. We explored this relation in a large birth
      cohort, the Avon (England) Longitudinal Study of Parents and Children (ALSPAC),
      in 1991-1992. METHODS: Information on the amount of swimming per week during the
      first 18-20 weeks of pregnancy was available for 11,462 pregnant women. Fifty
      nine percent never swam, 31% swam up to 1 hour per week, and 10% swam for longer.
      We used linear regression to explore the relation between birth weight and the
      amount of swimming, with adjustment for gestational age, maternal age, parity,
      maternal education level, ethnicity, housing tenure, drug use, smoking and
      alcohol consumption. RESULTS: We found little effect of the amount of swimming on
      birth weight. More highly educated women were more likely to swim compared with
      less educated women, whereas smokers were less likely to swim compared with
      nonsmokers. CONCLUSIONS: There appears to be no relation between the duration of
      swimming and birth weight.

PMID- 12410016
TI  - Does vehicle color influence the risk of being passively involved in a collision?
AB  - BACKGROUND: Bright- or light-colored vehicles are sometimes regarded as safer
      because they are presumably more visible. We examined the effect of vehicle color
      on the risk of being passively involved in a collision. METHODS: This paired case
      control study used data from the Spanish database of traffic crashes. We selected
      those collisions from 1993 to 1999 in which only one of the drivers committed an
      infraction. The violators constituted the control group; the other drivers formed
      the case group. Information about the color of the vehicle and other confounding
      variables was also collected. RESULTS: When white was compared with the remaining
      colors, a protective estimate was obtained (adjusted odds ratio [aOR] = 0.97; 95%
      confidence interval = 0.94-1.00). The results were similar for light colors
      (white plus yellow) compared with all remaining colors (aOR = 0.96; 0.94-0.99).
      The protective effect of light colors was specifically observed for open roads
      and under daylight conditions. It was stronger in conditions other than good
      weather (aOR = 0.91; 0.86-0.99) than in good weather conditions. CONCLUSIONS:
      Light colors (white and yellow) were associated with a slightly lower risk of
      being passively involved in a collision, although only under certain
      environmental conditions.

PMID- 12410018
TI  - Organochlorine exposure and age at natural menopause.
AB  - BACKGROUND: The effect of potential endocrine-modulating organochlorines on
      menopause has not been extensively examined. METHODS: We evaluated the
      associations of plasma polychlorinated biphenyls (PCBs) and 1,1-dichloro-2,2-bis(
      -chlorophenyl)ethylene (DDE) with age at natural menopause. We analyzed data from
      1407 women in a population-based, case-control study of breast cancer that was
      carried out in 1993-1996 in North Carolina. RESULTS: The adjusted hazard ratio
      estimating the rate of onset of natural menopause was 1.4 (95% confidence
      interval = 0.9-2.1) for the top decile of DDE compared with values below the
      median. This association is similar in magnitude to the association between
      smoking and menopause (hazard ratio = 1.4 [1.1-1.9]). No association was seen
      with PCBs. CONCLUSIONS: The suggested effect of DDE on timing of natural
      menopause encourages further research to corroborate these findings and evaluate
      potential mechanisms. Prospective studies, in which exposure measurements are
      taken before menopause, would be particularly useful.

PMID- 12410019
TI  - Confidence intervals for seasonal relative risk with null boundary values.
AB  - In evaluating the relative risk of seasonality, the null value is a boundary
      value. In this case, tests for the null hypothesis exist, but standard methods
      for confidence intervals are not appropriate. We provide a method for
      constructing confidence intervals under the circular normal model. The proposed
      confidence intervals are valid for all values of the underlying seasonal risk if
      the model is correct and for the null boundary value of the seasonal risk,
      regardless of model assumptions and sample size. We apply our method to seasonal
      suicide data from a recent report.

PMID- 12410021
TI  - Different convergence parameters applied to the S-PLUS GAM function.

PMID- 12410020
TI  - Does bleach disinfection of syringes protect against hepatitis C infection among
      young adult injection drug users?
AB  - BACKGROUND: Hepatitis C virus (HCV) has emerged as a major public health problem
      among injection drug users. In this analysis we examine whether disinfection of
      syringes with bleach has a potentially protective effect on anti-HCV
      seroconversion. METHODS: We conducted a nested case-control study comparing 78
      anti-HCV seroconverters with 390 persistently anti-HCV seronegative injection
      drug users. These data come from the Second Collaborative Injection Drug Users
      Study, a prospective cohort study that recruited injection drug users from five
      U.S. cities between 1997 and 1999. We used conditional logistic regression to
      determine the effect of bleach disinfection of syringes on anti-HCV
      seroconversion. RESULTS: Participants who reported using bleach all the time had
      an odds ratio (OR) for anti-HCV seroconversion of 0.35 (95% confidence interval =
      0.08-1.62), whereas those reporting bleach use only some of the time had an odds
      ratio of 0.76 (0.21-2.70), when compared with those reporting no bleach use.
      CONCLUSIONS: These results suggest that bleach disinfection of syringes, although
      not a substitute for use of sterile needles or cessation of injection, may help
      to prevent HCV infection among injection drug users.

PMID- 12410022
TI  - Studies of particulate air pollution and mortality: when do authors comment on
      the policy implications?

PMID- 12410023
TI  - Active and passive smoking in breast cancer.

PMID- 12410024
TI  - Active and passive smoking in breast cancer.

PMID- 12410025
TI  - Can a negative time trend of sperm density be explained by changes in
      reproductive pattern?

PMID- 12410026
TI  - Low acceptance of an internet-based online questionnaire by young adults.

PMID- 12410027
TI  - Central discoid corneal dystrophy.
AB  - PURPOSE: To present a small kindred with a unique dominantly inherited corneal
      stromal dystrophy. METHODS: A 31-year-old man was noted to have bilateral,
      symmetric, central discoid corneal stromal opacification. We performed bilateral
      penetrating keratoplasties for decreased visual acuity, glare, and photophobia.
      RESULTS: Light microscopy revealed multiple extracellular vacuoles, concentrated
      in the anterior one-half of the central corneal stroma. Material within the
      vacuoles demonstrated intense reactivity with alcian blue and colloidal iron
      stains, consistent with glycosaminoglycan deposition. Transmission electron
      microscopy demonstrated nonmembrane-bound vacuoles in the stroma that contained a
      faintly osmiophilic matrix and black circular profiles. Immunohistochemical
      analysis of the vacuolar deposits revealed that chondroitin sulfate was the
      primary glycosaminoglycan present. A clinical and serologic evaluation revealed
      no evidence of a systemic storage disorder. Genetic analysis did not reveal a
      mutation in the coding region of the CHST6 gene. CONCLUSIONS: Given these unique
      clinical and histopathologic findings as well as nearly identical clinical
      findings in the patient's father and one of four brothers, the authors believe
      that this represents a previously unreported, dominantly inherited corneal
      stromal dystrophy.

PMID- 12410028
TI  - Use of a portable topography machine for screening donor tissue for prior
      refractive surgery.
AB  - PURPOSE: We investigated whether a portable, hand-held topography unit could be
      used to measure corneal topography either at the donor site or in the laboratory
      and whether the technology could be used to screen donor eye tissue for prior
      refractive surgery. METHODS: The corneal topography of 22 eyes of 12 normal
      donors was measured with the Keratron Scout portable topography machine before
      and after whole-eye enucleation. Field and laboratory measurements of central
      curvature, astigmatism, and the difference between the corneal curvature at the 7
      mm and the 3-mm zone were compared. The 7-mm and 3-mm zone curvature differences
      were also used to screen for eyes that had undergone refractive surgery. RESULTS:
      The mean central curvature of the normal eyes in the field [43.28 +/- 1.58
      diopter (D)] was not significantly different from the mean curvature in the
      laboratory (43.52 +/- 1.72 D; p= 0.20). Field and laboratory astigmatism was 2.02
      +/- 1.13 D and 1.64 +/- 1.38 D, respectively (p = 0.26, not significant). The
      eyes had a normal prolate shape, with the corneal power less in the periphery
      than in the center (mean difference between the 7-mm and 3-mm zone of -1.48 +/-
      0.83 D in the field and -1.77 +/- 0.73 D in the lab; = 0.069). Field and
      laboratory measurements of corneal shape correlated well with each other. Eight
      of eight eyes with refractive surgery for myopia and one of two eyes with
      hexagonal keratotomy for hyperopia were outside 2 SD of the normal range.
      CONCLUSION: The Scout can be used to measure corneal topography at the donor site
      and in the eye bank laboratory with comparable results. Regional power
      differences between the corneal periphery and center could be used as a method
      for screening donor eyes for prior refractive surgery.

PMID- 12410029
TI  - Intraocular lens power calculations after laser in situ keratomileusis.
AB  - PURPOSE: To compare the accuracy of several techniques for calculating
      intraocular lens (IOL) power after laser in situ keratomileusis (LASIK). METHODS:
      Retrospective review of 10 eyes from nine patients undergoing phacoemulsification
      after LASIK. Corneal power (K) was measured by manual keratometry (MK),
      refractive history (RH), contact lens overrefraction (CTL), videokeratography
      (VK), and an average of the refractive history and contact lens methods (AVG 2).
      Results were compared with the back-calculated K value generated by the Holladay
      IOL Consultant program. Age-matched patients undergoing phacoemulsification
      without previous refractive surgery served as controls. RESULTS: Mean spherical
      equivalent postoperative refraction was +0.21 diopter (D) (SD, 1.54; range, -2.25
      to +2.25 D) for patients undergoing cataract extraction after LASIK versus -0.56
      D (SD, 0.66; range, -2.375 to +0.5 D; p= 0.16) for controls. Thirty percent of
      cases versus 90% of controls were within 1 D ( p= 0.002) of emmetropia. Forty
      percent of cases versus no controls were more than 1 D hyperopic ( p= 0.08). The
      mean differences for each method compared with the back-calculated K values were
      MK, +0.82 D; VK, +1.24 D; RH, -0.76 D; CTL, +0.91 D; AVG 2, +0.08 D. The mean
      absolute deviations from the back-calculated K values were MK, 1.91 D; VK, 2.01
      D; RH, 1.68 D; CTL, 1.62 D; AVG 2, 1.42 D. CONCLUSION: Significant refractive
      errors occurred with each of the methods investigated for determining IOL power
      after LASIK. RH, CL, or AVG 2 provided the most accurate results.

PMID- 12410030
TI  - Corneal topography after ocular rubbing.
AB  - PURPOSE: To examine the immediate effect of ocular rubbing on corneal topography.
      METHODS: Corneal topography and analysis were performed before, immediately
      after, and 5 minutes after eyelid rubbing in 29 volunteers without ocular
      disease. RESULTS: The surface regularity index increased from a baseline of 0.24
      to 0.91 ( p< 0.0001) immediately after rubbing and returned to baseline after 5
      minutes. The surface asymmetry index increased from 0.27 to 0.89 ( p= 0.0018)
      immediately after rubbing. There was a small amount of astigmatism induced
      immediately by rubbing (0.5 diopter) ( p= 0.01). CONCLUSIONS: Ocular rubbing
      should be avoided prior to standard corneal topography. The increased surface
      regularity index may reflect the alterations of the tear film and/or the molding
      of the corneal surface.

PMID- 12410031
TI  - Preexisting and postoperative glaucoma in repeated corneal transplantation.
AB  - PURPOSE: To evaluate the incidence, risk factors, management, and visual outcome
      of postoperative glaucoma in comparison with preexisting glaucoma in repeated
      corneal transplantation. METHODS: The charts of all the patients who underwent
      repeated corneal transplantation between 1985 and 1998 were reviewed for the
      occurrence of preexisting and postoperative glaucoma. Eighty patients underwent
      122 repeated corneal transplantations, of which six underwent surgery in both
      eyes. The mean follow-up period from the primary keratoplasty was 89.5 months and
      the minimal follow-up period was at least 6 months after the last
      transplantation. RESULTS: Postoperative glaucoma affected 29 eyes (34%) in 28
      patients (35%) with repeated corneal transplantation. Herpetic scar as an
      indication for transplantation and a history of previous immune graft rejection
      were more common in patients who developed postoperative glaucoma compared with
      the entire regrafted group ( p= 0.016 and p< 0.001, respectively). The incidence
      of glaucoma usually increased with the increased number of keratoplasties. The
      following types of glaucoma were disclosed: closed angle (59%), corticosteroid
      induced (21%), open angle (11%), angle recession (3%), aqueous misdirection (3%),
      and unknown cause (3%). Surgical intervention was required in 62%. Glaucoma was
      controlled in nine eyes (31%) and resolved following regrafting or
      discontinuation of corticosteroids in four eyes (14%), of which five (17%) had
      clear regrafts. Better intraocular pressure control was achieved in those cases
      that did not require surgical intervention ( p= 0.019). In 15 eyes (52%),
      regrafts failed due to uncontrolled glaucoma and/or other causes. At the end of
      the follow-up period, visual acuity was 20/30 to 20/200 in 17%, counting fingers
      from less than 20 ft in 31%, hand movement/light perception in 35%, and no light
      perception in 17%. Six of the 86 eyes (7%) in six patients (7.5%) had preexisting
      glaucoma. Graft clarity and glaucoma control in patients with preexisting
      glaucoma were similar to those of postkeratoplasty glaucoma (50% had controlled
      glaucoma and 33% had clear regraft). CONCLUSIONS: Glaucoma, either preexisting or
      postoperative, is one of the most devastating complications of repeated corneal
      transplantation and the cause for regraft failure and visual loss even when
      intensively treated. Close monitoring and early targeted therapy are warranted to
      increase the survival of repeated corneal transplants in eyes affected by
      glaucoma.

PMID- 12410032
TI  - Intraoperative daunorubicin versus conjunctival autograft in primary pterygium
      surgery.
AB  - PURPOSE: To evaluate the safety and efficacy of intraoperative daunorubicin
      during a bare sclera procedure in primary pterygium surgery and to compare with
      conjunctival autograft. METHODS: The data for 84 patients who underwent pterygium
      surgery at Safdarjung Hospital and Guru Nanak Eye Center were analyzed
      retrospectively. The patients were divided into two groups: group A, those who
      underwent bare sclera excision along with conjunctival autograft, and group B,
      those who underwent bare sclera excision with intraoperative daunorubicin (0.02%)
      for 3 minutes. We evaluated pterygium recurrence and postoperative complications
      for both groups. Recurrence of pterygium was defined as growth of 2 mm of
      fibrovascular tissue over the corneoscleral limbus into the clear cornea in the
      area of previous pterygium excision. RESULTS: Follow-up ranged from 18 to 37
      months (mean, 27). Recurrence rates of 8.33% (three of 36) and 7.14% (three of
      42) were found in groups A and B, respectively. When compared statistically, the
      difference was not significant. All the recurrences occurred in patients younger
      than 30 years of age. Pyogenic granuloma, graft edema, loose graft, and dellen
      formation were seen, respectively, in 5.5% (two of 36), 2.77% (one of 36), 2.77%
      (one of 36), and 2.77% (one of 36) patients in group A. Nine of 42 (21.42%)
      patients in group B had chemosis of the conjunctiva and two of 42 (4.76%) had
      delayed epithelization. CONCLUSION: We conclude that intraoperative daunorubicin
      (0.02%) and conjunctival autograft are both equally effective adjuncts to
      pterygium surgery.

PMID- 12410033
TI  - Fluorescein-potentiated argon laser therapy improves symptoms and appearance of
      corneal neovascularization.
AB  - PURPOSE: To evaluate patients' self-assessment of their symptoms and cosmetic
      appearance after fluorescein-potentiated argon laser treatment (FPAL) for corneal
      inflammation associated with neovascularization. To describe the objective
      effects of FPAL therapy on established corneal neovascularization with secondary
      corneal edema and lipid keratopathy. METHODS: Fifteen patients with corneal
      neovascularization resulting from various infectious and traumatic etiologies
      were enrolled in an open, nonrandomized pilot study. Treatment consisted of
      repeated sessions of intravenous fluorescein, a photosensitizer, combined with
      blue-green argon laser applications to abnormal corneal vessels. Patients
      completed a written survey to grade their symptoms and cosmetic appearance prior
      to treatment and at the end of the follow-up period. Objective changes in signs
      after FPAL treatment were described by two nonmasked ophthalmologists after slit
      lamp examinations and review of serial corneal photographs. RESULTS: Clinical
      symptoms of blurred vision (p <or= 0.003), photophobia (p <or= 0.03), and
      cosmetic appearance ( p <or= 0.02) were found to be significantly improved by the
      patient's subjective assessment survey. There was a trend toward pain reduction
      (p <or= 0.06) but no apparent reduction in tearing or foreign body sensation (p
      <or= ns). Objective signs of corneal edema, neovascularization, and lipid
      keratopathy appeared to be reduced after FPAL therapy. CONCLUSION: FPAL therapy
      for corneal neovascularization, edema, and lipid keratopathy resulted in a
      significant reduction in symptoms and improved quality of life for 14 of 15 (93%)
      patients. A controlled clinical trial to confirm the reported improvement in
      signs observed in this pilot study should be considered.

PMID- 12410034
TI  - Familial, band-shaped, spheroidal keratopathy histopathology in ethnic Chinese
      siblings.
AB  - PURPOSE: To describe the histopathology of familial, band-shaped, spheroidal
      keratopathy in ethnic Chinese siblings. New histopathologic findings are
      presented that may shed light on the etiology of this rare and unique condition.
      METHODS: Three ethnic Chinese siblings in Urumqi, People's Republic of China,
      were examined. One brother and sister had spheroidal, amber-colored droplets in
      the superficial, central corneal stroma. Each had a diffuse gray haze and
      thickening of the peripheral corneal stroma. A histopathologic study of
      penetrating keratoplasty specimens was performed. Another sister had only
      thickening and haze of the corneal stroma. RESULTS: Typical spheroidal deposits
      in the superficial stroma were demonstrated. One cornea had vascularization and
      amyloid deposition. One cornea had loss of endothelial cells and a thickened
      Descemet's membrane. CONCLUSION: Neovascularization and amyloid deposition are
      likely secondary phenomena in this familial disease. A new clinical finding is
      the hazy, thickened stroma. New pathologic findings are the loss of endothelial
      cells and the marked thickening of Descemet's membrane. An endothelial cell
      dystrophy may accompany familial, band-shaped, spheroidal keratopathy.

PMID- 12410035
TI  - Ketotifen fumarate treatment of superior limbic keratoconjunctivitis.
AB  - PURPOSE: To report the effect of topically applied ketotifen fumarate in the
      treatment of superior limbic keratoconjunctivitis (SLK). METHODS: Five patients
      with clinical findings of bilateral SLK with no relief of symptoms with standard
      reported modalities of treatment were treated with topical ketotifen fumarate
      twice daily in both eyes. All patients were evaluated 2 to 4 weeks after
      initiation of treatment of symptomatic and clinical improvement and at regular
      intervals thereafter. RESULTS: Topical ketotifen provided immediate relief of
      ocular symptoms in all patients. In one patient, the response was long lasting,
      whereas in the other four, it was temporary, lasting 1 to 3 months. The objective
      signs, however, did not necessarily correlate with the subjective improvement.
      CONCLUSIONS: Ketotifen fumarate can be effective at least in the short to medium
      term in the management of SLK. Although the mechanism of action of ketotifen
      remains unclear, this preliminary experience further supports the use of agents
      with mast cell-stabilizing activity in the treatment of SLK.

PMID- 12410036
TI  - Treatment of recurrent corneal erosions using autologous serum.
AB  - PURPOSE: To study the effect of autologous serum in the treatment of recurrent
      corneal erosions. METHODS: Eleven eyes of 11 consecutive patients with acute
      macroform corneal erosions who had suffered several relapses despite receiving
      different types of treatment were analyzed from November 2000 to February 2002.
      All patients were treated with autologous serum for 3 months. RESULTS: Mean
      follow-up time was 9.4 +/- 3.7 months (range, 4-16). No side effects were noted
      in any of the treated patients. Treatments prior to the use of autologous serum
      had failed to avoid recurrences in all the patients, with the mean recurrence
      rate being 2.2 recurrences per month of follow-up. After the onset of serum
      treatment, only a single recurrence was recorded in three of the patients (0.028
      recurrences per month of follow-up). CONCLUSION: The use of autologous serum for
      the treatment of patients with recurrent corneal erosion is effective and safe in
      reducing the number of recurrences experienced by patients.

PMID- 12410037
TI  - Factors associated with the need for penetrating keratoplasty in keratoconus.
AB  - PURPOSE: This study was designed to identify factors that may help to determine
      the likelihood of a patient with keratoconus undergoing a penetrating
      keratoplasty (PK) after referral to a cornea service. METHODS: A retrospective
      chart review of 109 patients from a corneal referral practice was undertaken to
      identify clinical characteristics at presentation that were predictive of
      subsequent PK. RESULTS: Overall, during an average follow-up of 10.9 years, 39
      (35.8%) did not have a PK for keratoconus in either eye, 34 (31.2%) had a PK in
      one eye, and 36 (33.0%) had a PK in both eyes. The presence of corneal scarring
      and steep keratometry values were significant risk factors for subsequent PK.
      CONCLUSION: In a corneal referral practice, 64.2% of patients go on to PK in one
      or both eyes during long-term follow-up. The presence of scarring and high
      keratometry values at initial presentation may help to predict the likelihood of
      requiring a PK and may aid in patient counseling.

PMID- 12410038
TI  - An immunohistochemical analysis and comparison of posterior polymorphous
      dystrophy with congenital hereditary endothelial dystrophy.
AB  - PURPOSE: To evaluate the immunohistochemical profiles of the abnormal endothelial
      cells of posterior polymorphous dystrophy (PPMD) and congenital hereditary
      endothelial dystrophy (CHED). METHODS: Formalin-fixed, paraffin-embedded sections
      of seven corneas with the diagnosis of PPMD (seven patients), six corneas with
      the diagnosis of CHED (four patients), and five control corneas were stained with
      hematoxylin-eosin. Adjacent histologic sections were stained with monoclonal
      antibodies that react with pancytokeratin, AE1/AE3, cytokeratin (CK) 7, CK 20,
      CAM 5.2, and epithelial membrane antigen. The immunoreactivity of the corneal
      endothelium was assessed by light microscopy. RESULTS: The endothelial cells
      stained positive for pancytokeratin and CK 7 in seven of seven corneas of
      patients with PPMD and five of six corneas of patients with CHED; variable
      positivity was seen to AE1, AE3, and CAM 5.2. The endothelium was uniformly
      negative to staining by CK 20. The epithelium stained positive with
      pancytokeratin, AE1, and AE3. All control corneas were negative for
      pancytokeratin, CK 7, and CK 20. CONCLUSION: The abnormal endothelium in both
      PPMD and CHED expresses similar CKs, including CK 7, which is not present in
      normal endothelium or surface epithelium. This may indicate a shared
      developmental abnormality in these conditions, as previously suggested by
      ultrastructural studies and genetic mapping.

PMID- 12410039
TI  - Tectonic grafts for corneal thinning and perforations.
AB  - PURPOSE: To evaluate the success of tectonic grafts in cases of corneal thinning
      and perforations. METHODS: We performed 42 tectonic grafts in 41 eyes of 40
      patients. Three types of tectonic grafts were used in our treatment protocol.
      These were (a) full-thickness grafts, (b) mushroom grafts, and (c) lamellar
      grafts. The parameters evaluated were indications, visual acuity, location, size
      and type of graft, postoperative outcome, and complications, if any. RESULTS: The
      most common indication for tectonic grafts was corneal thinning and perforation
      subsequent to infection (12 eyes) followed by those due to immunologic causes
      (six eyes) and trauma (six eyes). Twenty-four full-thickness tectonic grafts,
      nine mushroom grafts, and nine lamellar patch grafts were performed. Anatomical
      success was achieved in 35 of 41 (85.4%) eyes. Visual acuity of 6/24 or better
      was obtained in 29 of 41 (70.73%) eyes. The mean of best-corrected visual acuity
      (expressed in decimal) improved from 0.2 +/- 0.26 to 0.34 +/- 0.26 at an average
      follow-up of 10.83 +/- 6.27 months. The major complications were peripheral
      anterior synechiae in four eyes (9.76%) and graft melting in five eyes (12.2%).
      CONCLUSIONS: Tectonic graft is a useful therapeutic option in selected cases of
      corneal thinning and perforations because it effectively restores the integrity
      of the eye and allows acceptable visual rehabilitation.

PMID- 12410040
TI  - The postmortem sociomedical interview: uncertainty in confirming infectious
      disease risks of young tattooed donors.
AB  - PURPOSE: To assess the reproducibility of relatives' replies to questions asked
      at the time of corneal donation and again 2 months later concerning infectious
      disease risk factors and to identify characteristics associated with inconsistent
      responses. METHODS: A reinterview study involving individuals who answered
      questions regarding an eye donor's sociomedical history within 1 day of the
      decedent's death and who consented to be recontacted 6 to 12 weeks later. The
      main outcome measures were frequency of answering differently on the same
      questions of infectious disease risk factors and the donors' and relatives'
      characteristics that predicted inconsistency. RESULTS: Of 368 individuals who
      agreed to a reinterview, 263 (71.5%) completed and returned the survey
      questionnaire. Thirty-eight (14.4%) respondents answered differently on at least
      one question concerning infectious disease risk factors. The family of donors
      with a trauma-related death was 2.9 [95% confidence interval (CI), 1.0-8.3] times
      more likely to give inconsistent responses. Different responses to behavioral
      questions occurred 22 (95% CI, 1.6-315) times more often by relatives of donors
      who were both younger than 40 years old and had a tattoo. CONCLUSION: The
      postmortem sociomedical interview cannot assure complete knowledge of the risk of
      potentially transmissible disease of all donors. Relatives of young, tattooed
      donors tend to give inconsistent responses about infectious disease risk factors.

PMID- 12410041
TI  - Corneal topographic changes after retinal detachment surgery.
AB  - PURPOSE: To evaluate the changes in corneal topography after scleral buckling
      surgery for retinal detachment. METHODS: Twenty-one eyes of 21 patients with the
      diagnosis of retinal detachment were included in this prospective study. Scleral
      buckling surgery was performed on all patients. The corneal topography of each
      was measured before surgery and at 1 week and 1 and 6 months after surgery by
      computer-assisted videokeratoscopy using the EyeSys 2000 Corneal Analysis System.
      Changes in corneal videokeratographies were analyzed using the Holladay
      Diagnostic Summary (HDS) software package. RESULTS: A statistically significant
      central corneal steepening (average, 1.8 diopter) was noted 1 week after surgery.
      The total and irregular astigmatic components both revealed a significant but
      transient increase in the first postoperative month. All these topographic
      changes persisted for as long as 6 months but returned to preoperative values
      afterward. CONCLUSION: Scleral buckling was found to induce transient changes in
      corneal topography producing both myopia and corneal astigmatism.
      Videokeratography is helpful for documenting such corneal changes after scleral
      buckling surgery for retinal detachment.

PMID- 12410043
TI  - Ocular surface inflammation induced by Propionibacterium acnes.
AB  - PURPOSE: In the eye, is commonly isolated in the lid, conjunctiva, and meibomian
      gland secretion. Well known as a causative bacterium of granulomatous
      endophthalmitis and a potent inflammatory stimulus, reportedly induces a delayed
      type hypersensitivity (DTH) response and forms granulomas in the liver and lung
      in animal models. In this study, we examined whether can induce a DTH response in
      the cornea. METHODS: Six- to 8-week-old female Lewis rats were immunized with
      heat-killed suspension of and assessed as to DTH response via ear challenge at 2
      weeks after immunization. At 3 weeks after immunization, suspension was injected
      in the rat corneal stroma, which was then observed biomicroscopically at 6, 24,
      and 48 hours after injection. Phenol-killed suspension was also used for the
      comparison. Histological examination was also performed on the corneal tissues,
      using hematoxylin and eosin staining as well as immunohistochemical staining
      against CD4 and CD8 T cells. RESULTS: Rats immunized with suspension showed
      significantly higher ear swelling values at both the 24- and 48-hour measurements
      than did the naive controls (p < 0.005). Massive cellular infiltration with
      stromal edema was observed biomicroscopically at 48 hours after injection of
      suspension in the corneal stroma. Histological study showed that the cell
      infiltration pattern was similar to that of DTH in the skin, i.e., neutrophils
      infiltrated at 6 hours, followed by mononuclear cells that, including macrophages
      and lymphocytes, increased and mixed with neutrophils, accompanied by stromal
      edema at 48 hours. Immunohistochemical study revealed that CD4 T-cell
      infiltration in the corneal stroma appeared to predominate over CD8 T-cell
      infiltration. CONCLUSIONS: These results indicate that can induce a DTH response
      in the cornea and may be a causative bacterium of ocular surface inflammation.

PMID- 12410042
TI  - Effectiveness of mupirocin and polymyxin B in experimental Staphylococcus aureus,
      Pseudomonas aeruginosa, and Serratia marcescens keratitis.
AB  - PURPOSE: The purpose of this study was to determine the effectiveness of
      mupirocin and polymyxin B, alone and in combination, in vitro and in vivo using
      rabbit models of, and keratitis. METHODS: Rabbit eyes were intrastromally
      injected with 1,000 colony-forming units (CFUs) of or or 100 CFUs of Rabbits were
      then treated with 2.7 mg/mL mupirocin, 10,000 U/mL polymyxin B, a
      mupirocin:polymyxin B combination, or 0.3% ciprofloxacin. Vehicle and untreated
      controls were also included. Treatment schedules depended on the strain injected.
      The number of CFUs was determined for all eyes after treatment. RESULTS: The
      mupirocin:polymyxin B combination was effective for all three genera both in
      vitro and in vivo. For keratitis, the mupirocin:polymyxin B combination was more
      effective than either drug alone and significantly reduced the log number of
      bacteria in the cornea by more than 3 logs compared with the vehicle or untreated
      controls (p <or= 0.0016). For, the mupirocin:polymyxin B combination treatment
      significantly reduced the number of CFUs per cornea relative to the individual
      drugs, vehicle, or untreated controls (p <or= 0.016). For, the
      mupirocin:polymyxin B combination therapy significantly reduced the number of
      bacteria in rabbit corneas relative to the individual drugs, vehicle, or
      untreated groups (p <or= 0.0001). Therapy with the mupirocin:polymyxin B
      combination was equivalent to ciprofloxacin therapy (p = 0.80). CONCLUSION: The
      mupirocin:polymyxin B combination was effective in treating experimental, and
      keratitis.

PMID- 12410044
TI  - Characterization of human ocular mucin secretion mediated by 15(S)-HETE.
AB  - PURPOSE: The eicosanoid 15-(S)-hydroxy-5,8,11,13-eicosatetraenoic acid [15(S)
      HETE] is reported to stimulate mucin production in both airway and ocular surface
      epithelia. The current study was undertaken to evaluate the effects of 15(S)-HETE
      on secretion of specific ocular mucins by human conjunctiva. METHODS: Segments of
      human bulbar conjunctival tissue were incubated with 15(S)-HETE (1-1000 nM) for
      30 minutes at 37 degrees C. Secretion of human ocular mucins MUC1, MUC2, MUC4,
      and MUC5AC into the incubation media was measured by dot-blot immunoassay using
      antibodies directed to unique mucin polypeptide epitopes. Sodium dodecyl sulfate
      polyacrylamide gel electrophoresis and Western blotting were used to verify the
      specificity of anti-mucin antibody binding and to investigate the presence of
      MUC1 mucin in human tears. RESULTS: 15(S)-HETE (10(-8)-10(-6) M) stimulated
      secretion of conjunctival mucins in a concentration-dependent manner. Significant
      increases in total mucin secretion were observed at 10(-7) M 15(S)-HETE with a
      maximum response (>50% increase above controls) at 10(-6) M. Results of
      immunoassays showed that 15(S)-HETE differentially stimulates secretion of MUC1
      mucin with no detectable effects on MUC2, MUC4, or MUC5AC release. Western
      analysis of tear samples from human volunteers indicated that MUC1 is a component
      of the preocular tear film. CONCLUSIONS: The results demonstrate that 15(S)-HETE
      is a selective secretogogue for MUC1 in isolated human conjunctival tissue.
      Although the biochemical mechanism(s) and cellular origins of MUC1 secretion
      remain to be established, the ubiquitous expression of MUC1 in corneal and
      conjunctival epithelia and its presence in human tears suggest that secreted MUC1
      may contribute to the mucin layer that coats and protects the ocular surface.

PMID- 12410045
TI  - Epicorneal aspergilloma after penetrating keratoplasty.
AB  - PURPOSE: To report an epicorneal aspergilloma in a postkeratoplasty patient with
      a bandage soft contact lens. METHODS: Case report of a 77-year-old
      postkeratoplasty patient who presented with an epicorneal mass under a bandage
      soft contact lens placed for a nonhealing epithelial defect. On removal of the
      contact lens, a 4 x 4-mm placoid mass fell free from the corneal surface and was
      sent for culture and histopathology. RESULTS: Gram stain demonstrated septated
      branching hyphae, and cultures confirmed the diagnosis of Histopathologic
      sections of the epicorneal mass revealed a full-thickness aspergilloma.
      CONCLUSION: Contact lens removal and aggressive antimycotic treatment resulted in
      epithelial healing and resolution of the keratomycosis. The patient remained
      stable for 6 months followed by a successful repeat penetrating keratoplasty.

PMID- 12410046
TI  - Excimer laser phototherapeutic keratectomy retreatment of anterior basement
      membrane dystrophy and Salzmann's nodular degeneration with topical mitomycin C.
AB  - PURPOSE: To report a case of excimer laser phototherapeutic keratectomy
      retreatment of anterior basement membrane (ABM) dystrophy and Salzmann's nodular
      degeneration with a single intraoperative application of topical mitomycin C
      (0.02%). METHODS: Case report. RESULTS: A 91-year-old woman underwent excimer
      laser phototherapeutic keratectomy (PTK) in the left eye for ABM dystrophy and
      Salzmann's nodular degeneration causing decreased visual acuity (VA), ocular
      irritation, and recurrent erosions. Slit-lamp examination of both eyes revealed
      diffuse ABM dystrophy changes with mild to moderate subepithelial and anterior
      stromal haze and scarring involving the visual axis. The PTK treatment was
      preceded by a superficial keratectomy with a blade. The excimer laser was set for
      a 6-mm circular ablation zone with a treatment depth of 5 microm. The cornea
      remained clear for several months. Six months after surgery, the patient
      presented with difficulty reading and VA of 20/70. Slit-lamp examination of the
      left eye revealed recurrent Salzmann-type nodular degeneration inferior to the
      visual axis. A treatment course of topical steroids was not successful. She
      underwent another superficial keratectomy with a blade and PTK treatment (same
      laser parameters as the first procedure) with a 2-minute application of 0.02%
      mitomycin C on a cellulose sponge. The surgery proceeded without complications.
      On postoperative day 7, she presented with a healed epithelium and faint anterior
      stromal haze. Best-corrected visual acuity was 20/50, which is her best-expected
      VA. Six months after the procedure, the cornea revealed no signs of recurrence.
      CONCLUSION: The use of topical mitomycin C in conjunction with PTK may prevent
      recurrence of Salzmann's nodular degeneration.

PMID- 12410047
TI  - Conjunctival sporotrichosis in the absence of antecedent trauma.
AB  - PURPOSE: To describe a patient with conjunctivitis. METHODS: Case report and
      review of the literature. RESULTS: A 34-year-old cattle farmer with no history of
      trauma developed gradual onset of an inflamed bulbar conjunctival mass associated
      with ipsilateral preauricular lymphadenopathy. Excisional biopsy of the
      conjunctival mass and subsequent histopathologic examination revealed suppurative
      granulomatous inflammation and small budding yeasts. Electron microscopy
      confirmed the presence of small intracellular and extracellular yeast organisms.
      Cultures grew the dimorphic fungi Treatment with oral itraconazole and topical
      fluconazole resulted in complete resolution of the infection. CONCLUSION:
      characteristically infects the skin and regional lymphatics after penetrating
      trauma, but atraumatic infection of pulmonary mucosal surfaces can occur upon
      inhalation of the fungal spores. Our case report suggests that atraumatic
      exposure to may be sufficient to establish conjunctival infection.

PMID- 12410048
TI  - Histopathology of corneal changes in lecithin-cholesterol acyltransferase
      deficiency.
AB  - PURPOSE: Lecithin-cholesterol acyltransferase (LCAT) deficiency is a rare entity.
      This dyslipoproteinemia may lead to corneal opacity, renal failure, and
      arteriosclerosis. METHODS: Presentation of a 66-year-old man with bilateral
      corneal opacification due to LCAT deficiency caused by a single-nucleotide
      exchange in codon 123 of gene. An extracapsular cataract extraction combined with
      full-thickness corneal transplantation was performed. The corneal specimen was
      analyzed by light and transmission electron microscopy. RESULTS: All stromal
      layers showed extracellular vacuoles with acid mucopolysaccharide contents
      measuring up to 2.5 microm. Amyloid deposits measuring up to 12 microm in
      diameter were detected in the stroma and especially predescemetally. CONCLUSION:
      To our knowledge, this is the first histologic description of secondary
      amyloidosis in a full-thickness corneal specimen with LCAT deficiency. The
      disease is associated with anemia, proteinuria, a lack of plasma high-density
      lipoprotein, and the presence of target cells. Bilateral corneal opacification is
      a characteristic of the disease and may allow early detection of homozygous LCAT
      deficiency by the ophthalmologist.

PMID- 12410049
TI  - The use of postoperative topical mitomycin C in the treatment of recurrent
      conjunctival papilloma.
AB  - PURPOSE: To describe the use of postoperative topical mitomycin C (MMC) in the
      treatment of recurrent conjunctival papilloma. METHODS: Case report. RESULTS: We
      report a 26-year-old man with recurrent conjunctival papilloma despite repeated
      surgical excision, cauterization, and cryotherapy. He was then treated with
      excision by cryotherapy, followed by a 2-week course of topical MMC eyedrops
      prescribed at postoperative day 7 (0.02 mg/mL, four times daily). No recurrence
      was observed 24 months postoperatively, and no complication was observed during
      the follow-up period. CONCLUSION: Postoperative topical MMC may be a useful
      adjunct in the management of recurrent conjunctival papilloma.

PMID- 12410050
TI  - Comment on transplantation of Descemet's membrane carrying viable endothelium
      through a small scleral incision.

PMID- 12410051
TI  - Comment on intraoperative use of mitomycin C in excision of ocular surface
      neoplasia with or without limbal autograft transplantation.

PMID- 12410052
TI  - Interactions between lithium and non-steroidal antiinflammatory drugs.

PMID- 12410053
TI  - Multifocal myoclonus associated with mefloquine chemoprophylaxis.

PMID- 12410054
TI  - Cerebral hemodynamic responses to betel chewing: a Doppler study.
AB  - We sought to evaluate cerebral hemodynamic responses to betel chewing. Thirty
      healthy male volunteers (mean age = 35 years), ten new chewers, ten occasional
      chewers, and ten chronic chewers were included in this study. We used carotid
      duplex sonography and transcranial Doppler to measure the flow velocities and
      flow volume (FV) of the common carotid (CCA), internal carotid (ICA), external
      carotid (ECA) arteries, and the flow velocity of middle cerebral artery (MCA).
      Blood pressure (BP) and heart rate (HR) were recorded simultaneously. All
      subjects were asked to chew fruit-flavored chewing gum for 10 minutes. Blood
      flows of the above vessels were measured four times at baseline and at the 2nd,
      6th, and 12th minute after chewing. A repeated study was followed in the same
      subject but substituted with betel nut. Chronic chewers had delayed onset time
      and shortened vanishing time of facial-flushing sensation. Systolic and diastolic
      BPs were mildly elevated during gum chewing (p = 0.008 and 0.015, respectively),
      whereas diastolic BP was dropped during betel chewing (p = 0.008). Heart rate
      increased prominently during betel chewing (p < 0.0001), especially in new and
      occasional chewers. The peak systolic, end diastolic velocities, and FV in ECA
      and CCA increased significantly during betel chewing (p < 0.0001). The blood
      flows in the ICA and MCA had no significant changes during gum or betel chewing.
      Betel chewing has a central sympathetic effect resulting in accelerated HR,
      increased blood flows in ECA and CCA, but has a peripheral cholinergic effect
      resulting in a drop of diastolic BP. Intracranial cerebral hemodynamics is not
      affected during betel chewing. The inotropic and chronotropic effect to the heart
      from betel chewing is probably an unfavorable risk for patients with ischemic
      heart disease.

PMID- 12410055
TI  - Reversible coma caused by risperidone-ritonavir interaction.
AB  - Medications that act on the central nervous system are frequently used in people
      infected with human immunodeficiency virus (HIV). Actually, drug interactions are
      an important factor in the treatment of patients with (HIV) infection and because
      of the complexity of the current drug regimens, clinicians should be trained in
      order to recognize and manage drug interactions. Herein, we present an HIV
      infected male admitted for manic behavior and treated with risperidone who
      developed a profound coma secondary to increased levels of risperidone because of
      a possible drug interaction with ritonavir and indinavir. Subsequently, we
      discuss this interaction, rarely described in the literature. Risperidone is a
      cytochrome P450 (CYP2D6) enzyme substrate and weak inhibitor and a CYP3A4
      substrate. Possible interactions with CYP2D6 inhibitors (amiodarone, fluoxetine
      or ritonavir) and CYP3A4 inhibitors (indinavir and ritonavir) can increase its
      serum concentrations and produce significant adverse effects. In conclusion, this
      drug combination should be administered with caution and routinely examined for
      signs and symptoms of risperidone toxicity. Dosages should be reduced as needed.
      Finally, we think that in patients taking multiple medications, plasma levels of
      risperidone should be monitored especially if drug interactions are possible.

PMID- 12410056
TI  - Comparison of intravenous immunoglobulin preparations on microglial function in
      vitro: more potent immunomodulatory capacity of an IgM/IgA-enriched preparation.
AB  - Intravenous immunoglobulins (IVIg) have been used successfully as an
      immunomodulating treatment for patients with inflammatory diseases of the central
      nervous system (CNS) including multiple sclerosis (MS). It was shown previously
      that IVIg could modulate the functions of microglia, the main immune cell in the
      CNS. We have compared five commercially available IVIg preparations on their
      capacity to modulate tumor necrosis factor (TNF)-alpha secretion and nitric oxide
      production in cultured microglia. All preparations induced a dose-dependent
      stimulation of TNF-alpha secretion as measured by ELISA. There were some small
      differences between preparations consisting of IgG, while the preparation
      enriched for IgM and IgA induced a considerably higher TNF-alpha production at 1
      mg/mL and 10 mg/mL. Similar results were seen for nitric oxide production as
      measured indirectly by the Griess reaction. These results indicate that IgM/IgA
      enriched IVIg may be a more potent immunomodulator than pure IgG preparations on
      inflammatory reactions in the CNS.

PMID- 12410057
TI  - Beneficial effects of botulinum toxin type a for patients with painful tic
      convulsif.
AB  - Botulinum toxin is a well-known therapy for patients with diverse movement
      disorders. Its application has been extended to other disorders. Here, we
      document the case of a 70-year-old man with hemifacial spasm associated to
      trigeminal neuralgia secondary to an ectatic basilar artery. He was treated with
      botulinum toxin type A, 2.5 mouse units over five sites at the orbicularis oculi
      and one over the buccinator muscle. After botulinum toxin injections, relief was
      gained not only from twitching but also from pain. When the effects of the toxin
      vanished, spasms and pain recurred. Further infiltrations were given every 12
      weeks following the same response pattern. This observation further validates the
      increasing role of botulinum toxin in pain management.

PMID- 12410058
TI  - Olanzapine for Huntington's disease: an open label study.
AB  - The aim of this prospective open label study was to assess the efficacy of
      olanzapine for motor symptoms in Huntington's disease (HD). Olanzapine was
      administrated to nine patients with genetically confirmed HD in increasing doses
      until satisfactory clinical effect or the appearance of side effects. The
      patients were evaluated at baseline and after 14 days of treatment using the
      motor scale of the Unified HD Rating Scale (UHDRS). The patients improved
      significantly in most subscores of the UHDRS, including fine motor tasks,
      although some patients needed a rather high dose (30 mg per day). No adverse
      effects were reported by the patents spontaneously or were observed directly by
      the investigator. High-dose olanzapine seems to be useful in choreatic HD
      patients. A double blind, placebo-controlled trial appears warranted to
      definitively establish the symptomatic value of olanzapine in HD.

PMID- 12410059
TI  - Colchicine-induced acute myopathy in a patient with concomitant use of
      simvastatin.
AB  - Colchicine and 3-hydroxy-3-methy-glutaryl coenzyme A (HMG-CoA) reductase
      inhibitors are well known to cause myopathy. Myotoxicity is dose-dependent in
      both drugs; therefore, the onset of symptoms usually takes months or years. We
      report the case of a patient with chronic renal failure who had been taking
      simvastatin for 2 years and developed acute weakness 2 weeks after the start of
      treatment with colchicines for recurrent gout. The electromyography and elevated
      muscle enzymes indicated that his symptoms were caused by myopathy. When this
      patient stopped taking both drugs, his weakness resolved rapidly. Acute myopathy
      induced by combination therapy with colchicines and simvastatin is rare. In
      patients with chronic renal failure, co-administration of colchicine with
      simvastatin may accelerate the onset of myopathy because CYP3A4 (part of
      cytochrome P450) is crucial in the breakdown of both drugs. When adding
      colchicine to a medication regimen that includes a HMG-CoA reductase inhibitor
      for patients with renal insufficiency, drugs that are metabolized outside the
      CYP3A4 system (e.g., fluvastatin and pravastatin) should be selected instead.

PMID- 12410060
TI  - Severe weight gain induced by combination treatment with risperidone and
      paroxetine.
AB  - Successful combination therapy with atypical antipsychotics and selective
      serotonin reuptake inhibitors has been reported for several psychiatric
      conditions. However, great attention should be paid to the possible adverse
      effects. In this retrospective chart review, we focused on the drug-drug
      interaction of paroxetine and risperidone. Retrospectively, we identified two
      patients treated with a combination of risperidone and paroxetine therapy, and
      analyzed their medical records. During a 3-month period of monotherapy with
      risperidone, the changes in body weight were +/- 0.0 kg in Patient 1 and -2.0 kg
      in Patient 2. In contrast, during combination therapy with paroxetine and
      risperidone, the body-weight changes were +14.0 kg in Patient 1 (after 4 months)
      and +13.5 kg in Patient 2 (after 5 months). In addition, diabetes mellitus was
      observed in Patient 2. Regarding the mechanism of severe weight gain in these two
      patients, we speculate a drug-drug interaction involving inhibition of the
      cytochrome P450 enzyme 2D6 (CYP4502D6) by paroxetine.

PMID- 12410061
TI  - Adjuvant galantamine administration improves negative symptoms in a patient with
      treatment-refractory schizophrenia.
AB  - Because of the demonstration of a selective alpha nicotinic receptor abnormality
      in patients with schizophrenia, galantamine was added to the stable regimen of
      atypical and other antipsychotic medications in a 43-year-old man manifesting
      severe and persistent positive and negative symptoms, as well as mood disturbance
      and cognitive dysfunction. Galantamine is an inhibitor of acetylcholinesterase
      and a positive allosteric modulator of nicotinic cholinergic receptors (with a
      FDA-approved indication for the treatment of patients with mild to moderate
      Alzheimer disease (AD) under the trade name Reminyl). Galantamine HBr was
      initiated at a dose of 4 mg po BID, which was maintained for the first week of
      adjuvant therapy, and eventually was increased to 12 mg po BID during the final
      weeks of his 2-month trial. Remarkably, within 1 week of its initiation, there
      was a dramatic and clinically significant decrease of negative symptoms, as
      reflected in formal ratings on the Scale for the Assessment of Negative Symptoms.
      Moreover, within a few days of galantamine discontinuation, negative symptoms
      worsened, returning to the baseline level of severity. In addition to targeting
      memory dysfunction in AD, acetylcholinesterase inhibitors may have an expanded
      range of targets and clinical indications, including behavioral and psychotic
      symptoms. Galantamine is distinguished from other acetylcholinesterase inhibitors
      by its positive allosteric modulatory properties, improving the efficiency of
      transduction of the acetylcholine signal at nicotinic receptors. This latter
      property may have contributed to the observed improvement in negative symptoms
      observed in this patient. Importantly, positive symptoms were unchanged during
      this 2-month trial.(7)

PMID- 12410062
TI  - A patient with Cotard syndrome who showed an improvement in single photon
      emission computed tomography findings after successful treatment with
      antidepressants.
AB  - We report the case of a presenile woman with Cotard syndrome, in the context of
      major depression, who showed an improvement in bilateral frontal hypoperfusion in
      a SPECT study using 99mTc-HMPAO after undergoing successful treatment with
      antidepressant therapy. We also retrospectively evaluated her clinical course
      based on the clinical stages. The symptoms of Cotard syndrome have been reported
      to change dramatically according to the stages. This peculiarity made it
      difficult for us to rapidly diagnose Cotard syndrome in the context of major
      depression, and not dementia, and thereby adequately treat the patient in our
      case. Differences in the reduced blood flow regions and a time lag from
      psychiatric remission were observed before the improvement in the SPECT findings
      when comparing our case with a previously reported case of Cotard syndrome. These
      differences suggest that the mechanism of Cotard syndrome is still not well
      understood at the present time.

PMID- 12410063
TI  - Antiepileptic-antipsychotic drug interactions: a critical review of the evidence.
AB  - The potential for drug-drug interactions in psychiatry and patients with epilepsy
      is very high. Moreover, antiepileptic drugs are widely used outside epilepsy as
      psychotropic agents and their spectrum of activity on behavior is of considerable
      interest to psychopharmacology. In both neurologic and psychiatric practice,
      pharmacotherapy combinations are commonly used to treat comorbid psychiatric and
      neurologic disorders, to reduce or control the adverse effects of a medication or
      to increase its efficacy. This paper focuses on the metabolic pharmacokinetic
      interactions between two classes of psychotropic drugs: antiepileptic and
      antipsychotic drugs. The degree of documentation varies for many interactions
      from clinical case-report experiences to well established research outcomes. The
      evidence and the clinical significance of these interactions are reviewed. In
      general, it is better to use as few drugs as possible, as multicolored
      politherapies increase the possible adverse effects of drug interactions and
      reduce patient compliance.

PMID- 12410064
TI  - Pergolide-induced pleuropulmonary fibrosis.
AB  - Pleuropulmonary fibrosis is a rare, but well-recognized adverse effect of ergot
      alkaloids. We report on four patients who developed pleural and/or pulmonary
      fibrosis during treatment with pergolide and give characteristics of 87 cases
      with one or more symptoms of serosal fibrosis. Retroperitoneal and
      pleuropulmonary fibrosis are serious conditions, which are often irreversible
      after drug withdrawal. Increased awareness may help to diagnose these
      complications at an earlier stage and to minimize any permanent damage to the
      patient.

PMID- 12410065
TI  - Paroxetine in the treatment of adolescent major depression.

PMID- 12410066
TI  - Paroxetine in the treatment of adolescent major depression.

PMID- 12410067
TI  - Zero tolerance and searching for premeditated school shooters.

PMID- 12410068
TI  - Weight gain associated with atypical antipsychotics.

PMID- 12410069
TI  - Two cases of ADHD following GABHS infection: a PANDAS subgroup?

PMID- 12410070
TI  - Oppositional defiant disorder and conduct disorder: a review of the past 10
      years, part II.
AB  - OBJECTIVE: To review empirical findings on oppositional defiant disorder (ODD)
      and conduct disorder (CD). METHOD: Selected summaries of the literature over the
      past decade are presented. RESULTS: Research on ODD and CD during the past decade
      has addressed the complexity involved in identifying the primary risk factors and
      developmental pathways to disruptive behavior disorders (DBD). In some domains,
      research is entering an entirely new phase because of the availability of new
      technologies. In others, larger data sets and more complicated methodological and
      statistical techniques are testing increasingly complex models. Yet questions
      remain regarding the most useful subtyping systems, the identification of the
      most significant risk factors, and the relationships between risk factors from
      multiple domains. CONCLUSIONS: Convincing evidence of causal linkages remains
      elusive. Research has questioned the notion that CD is intractable, especially
      when multiple domains of risk and impairment are the targets of intervention. It
      is apparent that there is not one single causative factor; thus it is not likely
      that one single modality will suffice to treat CD. Future steps will involve the
      restructuring of diagnostic criteria to capture adequate subtypes and indicators,
      clarification of the neurological underpinnings of the disorder, and refinement
      in the models available to explain the varied pathways to DBD.

PMID- 12410071
TI  - Cigarette smoking and psychiatric comorbidity in children and adolescents.
AB  - OBJECTIVE: To review the current state of knowledge of psychiatric comorbidity in
      adolescent cigarette smokers. METHOD: assisted literature search was conducted
      and seminal articles were cross-referenced for comprehensiveness of the search.
      For each disorder, a synopsis of knowledge in adults is provided and compared
      with the knowledge in adolescents. RESULTS: Psychiatric comorbidity is common in
      adolescent cigarette smokers, especially disruptive behavior disorders (such as
      oppositional defiant disorder, conduct disorder, and attention
      deficit/hyperactivity disorder), major depressive disorders, and drug and alcohol
      use disorders. Anxiety disorders are modestly associated with cigarette smoking.
      Both early onset (<13 years) cigarette smoking and conduct problems seem to be
      robust markers of increased psychopathology, including substance abuse, later in
      life. In spite of the high comorbidity, very few adolescents have nicotine
      dependence diagnosed or receive smoking cessation treatment in child and
      adolescent psychiatric treatment settings. CONCLUSIONS: There is increasing
      evidence for high rates of psychiatric comorbidity in adolescent cigarette
      smokers. Cigarette smoking in adolescence appears to be a strong marker of future
      psychopathology. Child and adolescent psychiatry treatment programs may be a good
      setting for prevention efforts and treatment, which should focus on both nicotine
      dependence and psychiatric disorders.

PMID- 12410072
TI  - Efficacy of a new pattern of delivery of methylphenidate for the treatment of
      ADHD: effects on activity level in the classroom and on the playground.
AB  - OBJECTIVES: To evaluate the pharmacodynamic effects of an experimental (EXP)
      delivery of methylphenidate (MPH) in children with attention
      deficit/hyperactivity disorder and to investigate the situational nature of
      effects in laboratory classroom and playground settings. METHOD: A "sipping"
      study methodology was used to deliver a bolus followed by small but increasing
      MPH doses as the EXP regimen. A randomized, double-blind crossover design was
      used to compare the EXP regimen to a thrice-daily (TID) regimen and a placebo
      (PLA) regimen. Measures of efficacy were obtained from a Motionlogger actigraph
      to quantify activity and from the Swanson, Kotkin, Agler, M-Flynn, and Pelham
      (SKAMP) rating scale to quantify two domains of behavior (attention and
      deportment). RESULTS: Compared with PLA, both EXP and TID delivery of MPH
      produced large, significant reductions in activity and inappropriate behavior in
      the classroom, but the two MPH regimens did not differ in onset or duration of
      effects across the day. The MPH effects were situationally dependent and were
      smaller for the playground than for the classroom settings. CONCLUSIONS: The
      findings of this "proof of concept" study support the efficacy of a continuous,
      ascending delivery of MPH. The situational effects of MPH provide support for the
      theory of selective effects of stimulants, dependent on the demands of the
      environment.

PMID- 12410073
TI  - A randomized, double-blind, placebo-controlled trial of porcine versus synthetic
      secretin for reducing symptoms of autism.
AB  - OBJECTIVE: To compare the effects of a single dose of biologic and synthetic
      porcine secretin to placebo on a variety of autism symptoms. METHOD: Eighty-five
      children with autism without other medical conditions and not taking other
      psychotropic medications participated (ages between 3 and 12 years, mean IQ =
      55). Children were grouped into trios matched by age and communication level and
      then randomly assigned to one of three treatment groups: biologic secretin (2
      CU/kg), synthetic secretin (0.4 microg/kg), and placebo. Measures collected 1
      week before and 4 weeks after infusion included autism symptoms, language skills,
      and problem behaviors, gathered from parents, teachers, and investigators, who
      were all blind to treatment. Two-factor, repeated-measures analyses of variance
      (3 treatment levels by 2 repeated measures, pre- and postinfusion) were used to
      examine efficacy. RESULTS: Direct observation measures did not show change over
      time related to secretin. Parent reports showed an overall reduction of symptom
      severity for all treatment groups, including the placebo group. One teacher
      report measure showed decreases in autism symptoms in the placebo and synthetic
      secretin groups. CONCLUSIONS: No evidence that either biologic or synthetic
      secretin provided amelioration of symptoms beyond placebo was observed. This held
      true when children with and without gastrointestinal problems were examined
      separately.

PMID- 12410074
TI  - Commentary: the primacy of the scientific method.

PMID- 12410075
TI  - The social-emotional development of "late-talking" toddlers.
AB  - OBJECTIVE: To examine the social-emotional problems and competencies of toddlers
      who evidenced lags in expressive language without concomitant receptive language
      delays. METHOD: Maternal report and observation of 14 "late-talking" toddlers was
      compared with that of 14 control toddlers. Participants were selected on the
      basis of maternal report of vocabulary production with the MacArthur
      Communicative Development Inventory Short Forms and by direct assessment with the
      Mullen Scales of Early Learning. Social-emotional functioning was assessed with
      the Infant-Toddler Social and Emotional Assessment, the Child Behavior Checklist
      1.5-5, and the Vineland Adaptive Behavior Scales-Expanded Form. Toddler affect
      was observed using the Parent-Child Early Relational Assessment. The Parenting
      Stress Index Short Form was used to assess maternal stress. RESULTS: Late talkers
      were rated higher in depression/withdrawal and lower in social relatedness,
      pretend play/imitation, and compliance on the Infant-Toddler Social and Emotional
      Assessment and more withdrawn on the Child Behavior Checklist than controls.
      Observation indicated late talkers were more serious, more depressed/withdrawn,
      and less interested in play. Late talkers were reported to be lower in
      socialization on the Vineland. Mothers of late talkers endorsed higher parent
      child dysfunction on the Parenting Stress Index. No differences were found for
      externalizing behaviors or peer relationships. CONCLUSIONS: Early lags in
      expressive language are associated with poor social-emotional adjustment.
      Intervention may ameliorate difficulty in linguistic and social-emotional
      functioning.

PMID- 12410076
TI  - Affect regulation and addictive aspects of repetitive self-injury in hospitalized
      adolescents.
AB  - OBJECTIVE: The incidence of self-injurious behavior (SIB) in adolescent
      psychiatric inpatients has been reported to be as high as 61%, yet few data exist
      on the characteristics and functional role of SIB in this population. Because of
      the repetitive nature of SIB and its potential to increase in severity, features
      of SIB and its specific reinforcing effects were examined. METHOD: Participants
      were 42 self-injuring adolescents admitted to a hospital over a 4 month period.
      Data sources consisted of self-report questionnaires and medical chart review.
      RESULTS: Mean age was 15.7 +/- 1.5 years. Reported urges to self-injure were
      almost daily in 78.6% of the adolescents ( n= 33), with acts occurring more than
      once a week in 83.3% (n = 35). The two primary reasons endorsed for engaging in
      self-injury were "to cope with feelings of depression" (83.3%, n= 35) and "to
      release unbearable tension" (73.8%, n= 31). Of the sample, 97.6% ( n= 41)
      endorsed three or more addictive symptoms. CONCLUSIONS: SIB in hospitalized
      adolescents serves primarily to regulate dysphoric affect and displays many
      addictive features. Those with clinically elevated levels of internalized anger
      appear at risk for more addictive features of this behavior.

PMID- 12410077
TI  - A follow-up study of adolescent attempted suicide in Israel.
AB  - OBJECTIVES: (1) To compare the outcome of adolescent subjects who have made a
      suicide attempt with the outcome of matched controls, using their psychological
      and psychometric screening tests for military service at age 16.5 years. Their
      subsequent performance during military service between ages 18 and 21 was also
      evaluated. (2) To compare the prognosis of those attempters who received
      intensive psychiatric inpatient evaluation in a general hospital with the
      prognosis of those who received emergency room treatment only. METHOD: The
      computerized military records of 216 adolescents, who had been treated between
      1987 and 1988 for attempted suicide in a general hospital emergency room, prior
      to their induction into the army, were evaluated. They were rated on the
      following tests: cognitive/educational performance and psychosocial adaptation,
      psychiatric and psychological health diagnoses, and performance during their
      military service between 1989 and 1992. RESULTS: Although the female attempters
      had slightly more problems in the military than the controls, their overall
      prognosis was surprisingly good. The male suicide attempters did very poorly in
      their subsequent military service. There was no long-term advantage in having had
      a psychiatric evaluation performed in a hospital over a brief emergency room
      evaluation. Most differences between attempters and controls were in service
      performance, rather than in cognitive and psychometric tests. CONCLUSIONS: There
      may be marked differences between the sexes in the significance of attempted
      suicide and in the indications for intervention. The policy of mandatory general
      hospitalization for suicide attempters may need reevaluation.

PMID- 12410078
TI  - Discriminative validity of a parent version of the Young Mania Rating Scale.
AB  - OBJECTIVE: To examine the usefulness of a parent report version of the Young
      Mania Rating Scale (P-YMRS) in distinguishing bipolar disorder from other mental
      health conditions in children and adolescents. METHOD: Parents of 117 youths aged
      5 to 17 years presenting to an outpatient research center completed an adapted
      Young Mania Rating Scale (P-YMRS). Eligible subjects underwent a diagnostic
      evaluation including a semistructured instrument (Schedule for Affective
      Disorders and Schizophrenia for School-Age Children) and also a clinical
      evaluation by a child and adolescent psychiatrist in more than 75% of the
      subjects. RESULTS: Factor analyses of the P-YMRS suggested one dimension, with a
      total score showing acceptable internal consistency (alpha =.75). Logistic
      regressions discriminated bipolar mood disorder versus unipolar disorder, versus
      disruptive behavior disorder, and versus any other diagnosis. Classification
      rates exceeded 78%, and receiver operating characteristics analyses showed good
      diagnostic efficiency, with areas under the curve greater than 0.82. CONCLUSIONS:
      The P-YMRS may be used to derive clinically meaningful information about mood
      disorders in youths.

PMID- 12410079
TI  - DSM-IV-defined anxiety disorder symptoms in South African children.
AB  - OBJECTIVE: To examine -defined anxiety disorder symptoms in a large sample of
      normal South African schoolchildren. METHOD: Children completed two self-report
      questionnaires: the Spence Children's Anxiety Scale (SCAS) and the 41-item
      version of the Screen for Child Anxiety Related Emotional Disorders (SCARED).
      RESULTS: Psychometric properties of the SCAS and the SCARED were moderate
      (convergent validity) to sufficient (reliability). Factor analyses yielded
      evidence for the presence of a number of hypothesized anxiety categories (i.e.,
      social phobia, panic disorder, fears, and generalized anxiety disorder).
      Furthermore, anxiety levels of South African children were higher than those of
      Western (i.e., Dutch) children. Differences were found with regard to the content
      of prevalent anxiety symptoms among South African and Western children.
      CONCLUSION: Although psychometric properties of the SCAS and the SCARED in South
      African children somewhat deviated from those obtained in Western countries, both
      scales seem to be useful for assessing childhood anxiety symptoms in this
      country.

PMID- 12410080
TI  - Screening young people for autism with the developmental behavior checklist.
AB  - OBJECTIVE: To determine whether a subset of items from the Developmental Behavior
      Checklist (DBC) could be selected to construct a reliable autism screening tool.
      METHOD: A 29-item scale-the Developmental Behavior Checklist-Autism Screening
      Algorithm (DBC-ASA)-was developed by using items from the DBC and evaluated in a
      sample comprising 180 children who met criteria for autism and 180 controls
      matched for age, sex, and IQ range. RESULTS: This study found that the DBC-ASA
      has good validity in discriminating young people (4-18 years) with autism and IQ
      ranging from normal to severe intellectual disability from others using a cutoff
      score of 17. CONCLUSION: The DBC-ASA is an effective autism screening
      questionnaire for at-risk young people, including those with intellectual
      disability.

PMID- 12410082
TI  - Genetics of childhood disorders: XLIV. autism, part 3: psychopharmacology of
      autism.

PMID- 12410081
TI  - Case study: disgust and a specific phobia of buttons.
AB  - The role of disgust in childhood phobias has received limited attention in the
      psychiatric literature. Available studies suggest that attention to the emotion
      of disgust is optimal for reduction of phobic symptoms given that the interaction
      between fear and disgust has been found to maintain and even exacerbate phobias.
      Disgust was targeted via imagery exposures as part of an exposure-based cognitive
      behavioral intervention for a 9-year-old Hispanic American boy who presented with
      a specific phobia of buttons. Posttreatment, 6-month, and 12-month follow-up
      assessment results demonstrated maintenance of treatment gains. The role of
      disgust in treating specific phobias in children is discussed.

PMID- 12410083
TI  - New possibilities to achieve increased understanding of disease mechanisms in
      idiopathic inflammatory myopathies.
AB  - The development of new technologies within molecular biology and the mapping of
      the genome bring us closer to understanding the molecular basis of chronic
      inflammatory diseases, including the idiopathic inflammatory myopathies. This
      accomplishment appears particularly promising for the myopathies, because the
      muscle is an organ that is easily available for tissue studies and is thus
      particularly suitable for studies of molecular expression on both the gene and
      protein levels. The information gained from such studies will depend on the
      clinical characterization of the studied patients, which is another challenge
      concerning the inflammatory myopathies. In conjunction with the development of
      new technologies this area of clinical research is making progress through an
      international effort. As a result, new tools to assess disease activity and
      damage for inflammatory myopathies have been recently suggested. A combined
      effort to perform longitudinal studies on repeated muscle biopsies from patients
      who are well defined clinically, as well as genetically, is likely to bring us
      increased knowledge on disease mechanisms that could lead to the development of
      new therapies and an improved outcome for patients with chronic inflammatory
      myopathies.

PMID- 12410084
TI  - Lipid-lowering agents and myopathy.
AB  - Each of the lipid-lowering agents available today can cause myopathy. The
      severity of the muscle disorder may vary from trivial myalgias or elevations of
      creatine kinase in asymptomatic individuals to rhabdomyolysis with myoglobinuria,
      renal failure, and death. Fortunately, significant myopathy occurs at a low rate.
      However, the large number of individuals taking these medications renders it a
      significant problem. Although the pathophysiology of the myopathy remains
      speculative, its occurrence appears to be dose related. Consequently, the total
      dosage of lipid-lowering drug consumed, the concomitant use of other medications
      that affect their blood levels, and the individual's specific drug-metabolizing
      enzyme profile may contribute to this toxicity.

PMID- 12410085
TI  - Recent advances in the understanding of skeletal muscle fatigue.
AB  - Prolonged or repeated contractions of skeletal muscles lead to impaired muscle
      function, fatigue develops. Fatigue may be caused by factors within the muscle
      cells (peripheral fatigue) and diminished activation from the central nervous
      system (central fatigue). The relative importance of peripheral central fatigue
      depends on the type of physical activity. Central fatigue may be more prominent
      in elderly subjects. Increased concentration of inorganic phosphate seems to be
      of major importance for acute peripheral fatigue. There is frequently a long
      lasting depression of force production after fatiguing muscle activity,
      especially at low stimulation frequencies. This low-frequency fatigue seems to be
      due to "structural" changes in proteins involved in intracellular Ca handling.
      Contractions in which the muscle is stretched (eccentric contractions) cause
      muscle weakness and damage. The initial defect induced by eccentric contractions
      is overstretched sarcomeres, but these appear to cause localized membrane tears
      that subsequently contribute to muscle weakness and damage.

PMID- 12410086
TI  - Inclusion body myositis.
AB  - Inclusion body myositis (IBM) is an inflammatory myopathy with distinctive
      clinicopathologic features. The etiology of IBM remains elusive. The immune
      mediated basis for this disease has been challenged by evidence implicating a
      number of divergent etiologic factors. These factors include mitochondrial
      deletions, nitric oxide induced oxidative stress, myonuclear breakdown, and
      abnormal accumulation within muscle fibers of brain-specific Alzheimer type
      proteins. The treatment of IBM with conventional immunosuppressive agents has
      been disappointing. Therapeutic approaches currently under study or consideration
      are beta-interferon and synthetic anabolic hormones.

PMID- 12410087
TI  - Clinical outcomes in juvenile dermatomyositis.
AB  - Juvenile dermatomyositis is a chronic inflammatory illness of unknown etiology
      that affects primarily muscle and skin. It has an incidence of 2-3 per 1,000,000,
      per year. The disease can affect other organ systems, including the
      gastrointestinal tract, lungs, and heart. In addition, calcinosis is seen in one
      third of patients. The mainstay of therapy is corticosteroids; some children
      require additional immunosuppressive agents because of corticosteroid resistance
      or intolerance. Functional outcomes have become good with modern treatments, but
      the disease remains chronic in a large number of children and sequelae are often
      seen.

PMID- 12410089
TI  - Pulmonary hypertension in systemic sclerosis: bete noire no more?

PMID- 12410088
TI  - Cardiac involvement in myositis.
AB  - After careful examination, cardiac involvement can be found in certain patients
      with inflammatory muscle disease. The clinical significance is not always clear,
      although in some patients profound disturbances can become manifest. Currently,
      no laboratory assay can be relied on to detect cardiac disease with 100%
      accuracy. Cardiac troponin I is, however, the best test currently available.

PMID- 12410090
TI  - Murine animal models of systemic sclerosis.
AB  - Animal models of systemic connective tissue diseases have provided valuable
      insights into the causative mechanisms and the pathogenesis of these diseases,
      and have provided the means to test potentially useful therapeutic interventions.
      Although numerous animal models for systemic sclerosis (SSc) have been described,
      the most extensively studied are murine. One advantage of murine animal models is
      the large body of genetic information available for the mouse that is not
      available for other species. No animal model described to date reproduces
      precisely all manifestations of SSc. However, all animal models display tissue
      fibrotic changes similar to those present in SSc. The prudent interpretation of
      the results obtained from the study of animal models has provided substantial and
      valuable information about the pathogenesis of the human disease.

PMID- 12410091
TI  - Pathogenesis of fibrosis: role of TGF-beta and CTGF.
AB  - Transforming growth factor (TGF)-beta regulates diverse biologic activities
      including cell growth, cell death or apoptosis, cell differentiation, and
      extracellular matrix (ECM) synthesis. TGF-beta is believed to be a key mediator
      of tissue fibrosis as a consequence of ECM accumulation in pathologic states such
      as systemic sclerosis. TGF-beta is known to induce the expression of ECM proteins
      in mesenchymal cells, and to stimulate the production of protease inhibitors that
      prevent enzymatic breakdown of the ECM. Connective tissue growth factor (CTGF),
      which is induced by TGF-beta, has been reported to mediate stimulatory actions of
      TGF-beta ECM synthesis. This review focuses on the possible role of TGF-beta and
      CTGF in the pathogenesis of fibrosis.

PMID- 12410092
TI  - Targeting mediators of vascular injury in scleroderma.
AB  - Increasing evidence suggests that the vasculopathy of scleroderma is mediated by
      a number of soluble factors and involves a complex interaction between
      endothelial cells, smooth muscle cells, extracellular matrix, intravascular
      coagulation factors, and circulating cells. Novel therapeutic approaches beyond
      vasodilator therapy are being developed by recognizing important molecular
      pathways involved in scleroderma vascular disease. The success of this strategy
      is most evident in pulmonary hypertension, an often fatal complication of
      scleroderma. In this article, the authors explore therapies for scleroderma that
      target endothelial cells, smooth muscle cells, reactive oxygen species, and
      circulating blood cells. The authors highlight clinical trials that have
      investigated the role of prostacyclin (and its analogues) and bosentan in
      managing scleroderma-related pulmonary hypertension. Finally, the authors look at
      the potential role of biomarkers as surrogate indicators of active vascular
      disease in scleroderma.

PMID- 12410093
TI  - The role of infectious agents in the pathogenesis of systemic sclerosis.
AB  - Over the past few years, increasing evidence has accumulated to implicate
      infectious agents in the etiology of systemic sclerosis (SSc) and Raynaud
      phenomenon. Infection rates in patients with SSc compared with those in control
      populations do not provide clear support for any specific pathogen. However,
      increased antibody titers, a preponderance of specific strains in patients with
      SSc, and evidence of molecular mimicry inducing autoimmune responses suggest
      mechanisms by which infectious agents may contribute to the development and
      progression of SSc. Here we review studies examining the potential involvement
      of, cytomegalovirus, and parvovirus B19 in SSc pathogenesis.

PMID- 12410094
TI  - Scleroderma in children.
AB  - Juvenile systemic scleroderma (jSSc) is a rare childhood disease. In the review
      period covered within this article, there were few reports devoted exclusively to
      it. In the past year, there was no breakthrough regarding pathogenesis,
      classification, or treatment. In the pediatric field, the proposed classification
      system for jSSc shows significant progress toward a definition of the pediatric
      population. It should allow better evaluation of this patient group. In adult
      systemic scleroderma, European efforts to establish indices for disease activity
      have been published. They should help to assess the disease activity in a
      standardized way and therefore enable earlier adequate treatment for patients.
      Biologic markers and new assessment methods for particular organ involvement help
      to determine disease activity/severity as well. There is still no effective
      disease-modifying treatment for systemic scleroderma and jSSc. The summarized
      data of the phase I/II autologous stem cell transplantation trial have been
      published. The first guidelines for autologous stem cell transplantation for jSSc
      are proposed. In organ-specific treatment, the introduction of bosentan, a dual
      endothelin receptor antagonist, to control pulmonary hypertension is a real gain
      in the therapeutic options. New methods to assess prognosis are evolving and need
      to be validated in a larger patient population.

PMID- 12410095
TI  - Scleroderma overlap syndromes.
AB  - Scleroderma is a connective tissue disease that causes fibrosis and vascular
      abnormalities, but that also has an autoimmune component. Many patients with
      scleroderma have a positive antinuclear antibody, and there can be family
      histories of other connective tissue diseases such as systemic lupus
      erythematosus (SLE) and rheumatoid arthritis. Some patients have features of
      scleroderma and other autoimmune conditions. This article will review recent
      literature to help in the understanding of scleroderma with overlap features.
      Recent reports of scleroderma overlap with rheumatoid arthritis suggest distinct
      features of diffuse scleroderma with positive Scl-70, pulmonary fibrosis, and
      later seropositive erosive rheumatoid arthritis. SLE rarely occurs with
      scleroderma. Sjogren syndrome symptoms are common in scleroderma. In primary
      Sjogren syndrome, anticentromere antibody positive patients have more Raynaud
      phenomenon. Antibodies that occur in scleroderma that are thought to be specific
      are present in other connective tissue diseases. For instance, Scl-70 antibody is
      reported in as many as 35% of patients with scleroderma but can be present in 25%
      of patients with SLE. Myositis or myopathy can be features of scleroderma.
      Scleroderma overlap with polymyositis is frequently anti-PM Scl antibody
      positive, whereas anti-Jo-1 does not normally occur in the overlap of scleroderma
      and polymyositis but is usually exclusively positive in polymyositis with
      arthritis and alveolitis. A better prognosis is found with PM Scl antibody in
      myositis. Vasculitis is not a typical feature of scleroderma, but has been
      reported. Eosinophilic fasciitis is rare, and the onset could be associated with
      simvastatin.

PMID- 12410096
TI  - Stem cell therapy in scleroderma.
AB  - Scleroderma has a high mortality rate, especially in patients with early diffuse
      disease and poor prognostic features (such as high skin scores and internal organ
      involvement). In addition, there is no proven therapy for this disease. Finally,
      scleroderma has an autoimmune-related pathogenesis, particularly in early
      illness. In this setting, stem cell therapy is a reasonable potential choice. The
      rationale behind high-dose immunosuppressive therapy and stem cell
      transplantation in scleroderma, the regimens used, and the recent data from pilot
      studies are reviewed. The encouraging data, proper patient selection criteria,
      and appropriate therapy regimen make controlled studies appropriate, and such
      studies are currently under way in Europe and are soon to begin in the United
      States.

PMID- 12410097
TI  - Cytokine directed therapy in scleroderma: rationale, current status, and the
      future.
AB  - The hallmark of scleroderma is cutaneous and visceral fibrosis characterized and
      by increased biosynthesis of multiple matrix proteins by interstitial
      fibroblasts. Studies over recent years have delineated pathways involved in
      promoting matrix synthesis and elucidated the molecular pathways of regulation.
      Central to the regulation of fibrosis are extracellular mediators, called
      cytokines, which are elaborated by a variety of cells, including those in the
      immune system, vascular cells, and fibroblasts themselves. The concept that
      inhibiting or promoting the action of these naturally occurring profibrotic or
      antifibrotic molecules, respectively, is a rational therapeutic approach to
      treating scleroderma and other fibrotic diseases finds support in animal studies
      and anticytokine therapy conducted in relation to rheumatoid arthritis and other
      disorders. This review looks at cytokines known or thought to play a role in
      scleroderma and/or other fibrotic states and at potential therapy directed at
      these mediators. Potential targets for therapy include transforming growth factor
      beta (TGF-beta), connective tissue growth factor (CTGF), IL-4, IL-13, MCP-1, and
      endothelin, among others.

PMID- 12410098
TI  - Phototherapy for scleroderma: biologic rationale, results, and promise.
AB  - Scleroderma is a chronic disease of connective tissue characterized by deposition
      of large amounts of collagen. Localized scleroderma affects only the skin,
      whereas systemic disease, systemic sclerosis, may affect the lungs,
      gastrointestinal tract, kidneys, and heart in addition to the skin. Although the
      various forms of localized scleroderma are not life threatening, they result in
      considerable morbidity owing to joint contracture, loss of flexibility, and
      disfigurement. Although many different treatments have been attempted, until now
      none has proven to be effective. Accumulating evidence indicates that UVA
      irradiation offers a genuine opportunity to ameliorate localized scleroderma and
      the cutaneous manifestations of systemic sclerosis.

PMID- 12410099
TI  - [c-kit: an irresistible ascension from diagnostic marker to therapeutic].

PMID- 12410100
TI  - [Thymoma with epithelial micronodules and lymphoid hyperplasia: six cases of a
      rare and equivocal subtype].
AB  - Thymomas with the characteristic pattern of small epithelial nodules separated by
      an abundant lymphoid tissue have been recently described with divergent
      interpretations. These thymomas are not specified in currently used
      classification systems. We present six such thymomas, including three that
      represented 1.38% of a series of 217 consecutive cases. These thymomas were
      totally encapsulated (Masaoka stage I, n=1) or minimally invasive (stage II,
      n=5). The epithelial cells of the nodules were oval and bland-appearing. In one
      case, these cells formed rosettes. Cysts, that were present in four cases, showed
      a strong linear expression of EMA and were associated with foci of glandular
      differentiation. The lymphoid tissue was composed of large immature (CD1a and
      CD99-positive) T-cell areas (with epithelial cells restricted to small foci of
      residual thymus) and of B-cell (CD20-positive) areas with germinal centers.
      Mature T-cells were also present. Furthermore, one case, associated with
      myasthenia gravis, had an important WHO type B2 (cortical) component. Such a
      combined case has not been previously reported. Our study demonstrates that so
      called micronodular thymomas are rare, usually have clinical and pathological
      features of WHO type A (medullary) thymomas, and that the lymphoid component is
      hyperplastic corresponding to both immature T-cell lymphoid tissue and B-cell
      lymphoid hyperplasia with germinal centers.

PMID- 12410101
TI  - [Pigmented lesions of the vulva: histological features].
AB  - The vulva is an anatomical and histological combination of cutaneous and mucous
      components. It is the site of various pigmented lesions, in 10 to 12% of white
      women, often of unknown etiology. The clinical features are polymorph, non
      specific, thus requiring a biopsy. Histological analysis helps to rule out the
      diagnosis of melanoma, which frequently leads to mutilating surgical treatment
      and which has an unfavorable prognosis. We present a review of the anatomical and
      histological characteristics of the normal vulva and of the process of
      melanogenesis. In addition, the histological criteria that enable the etiological
      diagnosis of vulvar pigmented lesions are presented. Some of these lesions are
      tumoral, melanocytic or non-melanocytic, isolated or related to a general
      pathology; others, non-tumoral, related to inflammatory, immunological, hormonal,
      or paraneoplasic mechanisms, can be manifestations of systemic diseases. Biopsy
      specimen analysis and anatomo-clinical correlation are essential for the
      appropriate diagnosis and the treatment of these lesions.

PMID- 12410102
TI  - [Brain biopsy in systemic diseases].
AB  - In systemic diseases, brain biopsy is an exceptional diagnostic procedure which
      must be restricted to those rare forms involving only the central nervous system,
      at least clinically, and when a treatable disease is suspected the treatment of
      which requires a precise histological diagnosis. According to the clinical
      presentation and radiological appearance, an open biopsy or a stereotactic biopsy
      under radiological control will be proposed. In this paper, will be reviewed the
      indications and neuropathological findings in systemic amyloidoses extending to
      the central nervous system, cerebral angiitis, sarcoidosis, Whipple's disease,
      Langerhans'cell as well as non-Langerhans'cell systemic histiocytoses and
      paraneoplastic encephalomyelitis.

PMID- 12410103
TI  - [Fibromatosis of the breast: clinical and pathology analysis of two cases].
AB  - Fibromatosis of the breast is an uncommon benign disease that mimics carcinoma
      clinically as well as radiographically. Its microscopic diagnosis among spindle
      cell tumors is fundamental, especially on frozen sections. We report two cases of
      mammary fibromatosis observed in young woman (26 and 31 years old). The two were
      clinically and mammographically suspect. Diagnosis was made on frozen sections
      and confirmed on paraffin embedded specimen. The lesions are characterized by
      spindle cell proliferation of variable cellularity and collagenization. Few
      mitotic figures were present in one case. Several lesions must be considered in
      the differential diagnosis of mammary fibromatosis. Wide local excision is
      recommended for initial therapy, but local recurrence is frequent. In our cases,
      In spite of apparently complete excision, one patient relapsed.

PMID- 12410104
TI  - [Embryonal botryoid rhabdomyosarcoma of the bladder].
AB  - A 10-year-old black child presented with bloody urine and urine retention due to
      a bladder tumor. Cystoprostetatectomy led to the diagnosis of embryonal botryoid
      rhabdomyosarcoma. At gross examination, tumor presented a grape-shaped form.
      Microscopically, the specimen presented undifferentiated cells in a myxoid stroma
      and subepithelial cambium. The tumor was desmin and MyoD positive. The child died
      before chemotherapy could be completed.

PMID- 12410105
TI  - [Multifocal nodular oncocytic hyperplasia of the parotid: case report].
AB  - Multifocal nodular oncocytic hyperplasia of salivary glands is a tumor-like
      lesion that occurs predominantly in the parotid gland. The differential diagnosis
      of the clear cell variant includes many malignant salivary gland tumors. We
      report the case of a 66-year-old woman who was referred for a left total
      parotidectomy allowing the final diagnosis of clear cell multifocal nodular
      oncocytic hyperplasia. The differential diagnoses and histopathogenesis of this
      rare entity are discussed.

PMID- 12410106
TI  - [Lipomatous pleomorphic adenoma of the parotid].
AB  - Lipomatous tumors rarely occur in the salivary glands. We report an unusual case
      of lipomatous pleomorphic adenoma in a 47-year-old man. The patient had no
      significant medical history and presented with a well circumscribed nodule
      measuring 3 cm in the right parotid. Histologically, the tumour was predominantly
      composed of sheets of mature fat cells. Rare myoepithelial cells and exceptional
      tubules were intermingled with the mature adipose tissue. One year after surgery
      the patient was alive without recurrence. In conclusion, it is a rare neoplasm
      who needs to be recognized and discussed with true fatty tumors and lipomatosis.

PMID- 12410107
TI  - [Intravascular large B-cell lymphoma revealed by proteinuria: a case report].
AB  - We report the case of an intravascular large B-cell lymphoma in a 49-year-old
      woman, which was revealed by proteinuria. This type of lymphoma is very rare and
      corresponds to the proliferation of malignant lymphoid cells within the lumina of
      small vessels, resulting in ischemic lesions involving mainly brain and skin.
      Renal involvement is quite rare and remains asymptomatic, being discovered at
      autopsy. In this case, the renal biopsy demonstrated the presence of large
      malignant B cells in the glomerular lumina, associated with minimal glomerular
      damage. The mechanisms of the proteinuria occurring during intravascular lymphoma
      remain to elucidate.

PMID- 12410108
TI  - [Pancreatic vascular tumours of childhood: a heterogeneous nosologic spectrum].
AB  - Infantile pancreatic vascular tumors are very unusual and are described with an
      old and imprecise terminology. We report two new cases in 2 and 4 months old
      children, the first one associated with Kasabach-Merritt syndrome, the second
      revealed by cholestasis. The histology diagnosis was kaposiform
      hemangioendothelioma and juvenile capillary hemangioma respectively. Outcome was
      favourable after selective embolization for one and biliary derivation for the
      other. These case reports show that infantile vascular pancreatic tumors form a
      heterogeneous group. Most of them would be in fact kaposiform
      hemangioendothelioma with a benign behavior, in contrast with aggressive growth
      for retroperitoneal localizations.

PMID- 12410109
TI  - [Microcystic mammary tumor].

PMID- 12410110
TI  - [A painful swelling of the nipple].

PMID- 12410111
TI  - [An unusual subcutaneous tumor].

PMID- 12410113
TI  - [Villous adenoma of the urinary bladder: an usual tumor in an unusual location].

PMID- 12410112
TI  - [An uncommon tumor of the lung].

PMID- 12410114
TI  - [Cellular angiofibroma, angiomyofibroblastoma and aggressive angiomyxoma: members
      of a spectrum of genital stromal tumours?].

PMID- 12410115
TI  - [Pediatric rhabdomyosarcoma of the infratemporal fossa].
AB  - OBJECTIVE: Prognosis of rhabdomyosarcoma of the infratemporal fossa is generally
      poor. We report our experience. MATERIAL AND METHODS: Twenty-three children with
      rhabdomyosarcoma of the infratemporal fossa were treated at the Gustave Roussy
      and Curie Institutes between 1984 and 1999. Seventeen children received
      radiotherapy (group 1), four children were treated surgically with or without
      postoperative radiotherapy (group 2), and two children received no further
      treatment after chemotherapy (group 3). RESULTS: In group 1, there were 10 local
      recurrences and one metastatic failure; all 11 children died from their disease.
      Nodal recurrence was salvaged successfully in one other with chemotherapy and
      surgery. In group 2, three children were disease free at 3 years and one died of
      local recurrence. In group 3, one child experienced a local recurrence
      successfully salvaged with radiotherapy. This child was disease free at 3 years.
      The other child developed local recurrence and died. DISCUSSION: Overall survival
      rate in our patients was 50%. Local control remained the main prognostic factor
      for survival. Surgery has already been shown to improve local control in other
      localizations of rhabdomyosarcoma. If residual tumor tissue remains after neo
      adjuvant chemotherapy, surgery should be considered in a multidisciplinary
      discussion of therapeutic options. Indications for postoperative radiotherapy
      depend on age and histological features of the surgical specimen.

PMID- 12410116
TI  - [Relapsing polychondritis revealed by ENT symptoms: clinical characteristics in
      three patients].
AB  - Relapsing polychondritis (RP) is a recurrent, chronic and rare disease of unknown
      etiology, considered as a systemic vasculitis. RP is characterized by
      inflammation of cartilaginous structures of the ears, nose, respiratory tract and
      joints. RP is likely initiated by ENT symptoms. Etiology is unknown but the
      association with HLA-DR4 and the occurrence of antibodies to type-II collagen
      suggest that an immunologic mechanism is involved in its pathogenesis. Diagnosis
      is difficult requiring identification of elastic cartilaginous injuries. Delay
      before diagnosis is usually important after the first attack. Neither serum
      investigation nor histological confirmation are necessary to establish the RP
      diagnosis, and ENT symptoms are generally sufficient to achieve the diagnosis.
      Prognosis is linked to laryngeal, tracheal and cardiovascular involvements. An
      association with myelodysplasia is acknowledged. Based on these three cases and
      data in the literature, we review classical diagnostic criteria (McAdam),
      prognosis and therapeutic outcome.

PMID- 12410117
TI  - [Treatment of Bell's palsy with acyclovir and methylprednisolone].
AB  - OBJECTIVE: An open therapeutic trial was conducted in patients with Bell's palsy.
      Results were compared with data in the literature. MATERIALS AND METHODS: Between
      1997 and 2000, 76 patients with Bell's palsy were treated with intravenous
      methylprednisolone (2 mg/kg/day) and acyclovir (5-10 mg/kg/8 hours) for 7 days.
      Treatment was initiated in all patients before the 14th day of illness. Severity
      of the palsy was scored on the first day of treatment and again one year later
      using the House and Brackman scale. RESULTS: Grade II or III palsy were observed
      in 38% of the patients at initial presentation, grades IV to VI in 62%. After
      treatment, 92% of the patients had reverted to grades I and II (good outcome) and
      only 8% had sequelae at 1-year follow-up. All patients with initial grade I or II
      recovered completely. For patients with grade IV, V, or VI complete recovery at 1
      year was observed in 94, 86 and 50% respectively. CONCLUSION: Data in the
      literature suggest that corticosteroids should improve recovery in Bell's plasy.
      In our study, adjunction of acyclovir did not demonstrate any clear improvement
      in the cure rate. Benefit could depend on early prescription.

PMID- 12410118
TI  - [Bilateral vestibular areflexia: quantification is required].
AB  - Bilateral vestibular loss, that should be more precisely qualified as "horizontal
      semicircular canal bilateral loss", is a concept usually defined by the following
      characteristics: - no response to caloric tests, - no response to pendular test
      with a 20-second period, - increasing gain of the cervico-ocular reflex. We
      present five cases. We increased the stimulation frequency to a level higher than
      usually, employed and observed that: - at a given frequency threshold a certain
      amount of reactivity may be observed, - above that threshold the reactivity
      increases in proportion with stimulation frequency. The apparent vestibular loss
      is actually related to stimulation frequency. This phenomenon could be explained
      by considering the physiology of phasic and tonic cells.

PMID- 12410119
TI  - [Otosclerosis surgical techniques and results in 150 patients].
AB  - OBJECTIVES: To analyze outcome after otosclerosis surgery with stamedeotomy with
      blood clot sealing. PATIENTS AND METHODS: Otosclerosis surgery was performed in
      150 adult patients between 1997 and 1999 by five surgical teams (70% of the
      procedures were performed by senior surgeons) and followed for 18 months.
      Stapedotomy was carried out under general anesthesia with an intrameatal approach
      in 96% of the cases. Stapedotomy (n=120, 80%) was performed with a drill in 141
      cases and by laser in 9 (6%). Ninety percent of the Teflon prostheses had a 0.4
      mm diameter and a 4.5 mm length. The footplate opening was sealed with blood
      clots. Venous interposition (n=30, 20%) was performed in the event of partial or
      total stapedectomy which occurred in spite of an initial stapedotomy attempt.
      RESULTS: The preoperative air-bone gap (ABG) was 32 +/- 10.3 dB. The gain in air
      conduction was 25 +/- 11.7 dB with 75% of the patients having more than 15 dB
      gain. The ABG was 10 +/- 5.4 dB with 73% of the patients having less than 5 dB
      gain. The interaural difference was 0.5 +/- 14.1 dB and the bone conduction (BC)
      variation was 1 +/- 7.5 dB. Functional failures were related to significant
      intralabyrinthine bleeding and revision procedure. The following factors had not
      effect on outcome: i) stapedotomy versus partial or total stapedectomy, footplate
      opening sealed by clots or vein, ii) diameter of the stapedotomy and/or the
      prosthesis, iii) surgical procedure performed by a junior surgeon. CONCLUSION:
      Sealing the stapedotomy opening with blood clots appears to provide reliable and
      reproducible functional outcome that remains stable over time. In this study,
      changing from partial to total stapedectomy with vein interposition did not
      modify the functional outcome.

PMID- 12410120
TI  - [Analysis of nasal and exhaled nitric oxide concentration in nasal polyposis].
AB  - Nitric oxide (NO) is implicated in the pathophysiology of inflammatory airway
      diseases. It has been identified as a potential marker of airway inflammation.
      OBJECTIVE: The purpose of the study was to assess the concentrations of nasal NO
      in upper and lower airways in nasal polyposis patients. PATIENTS: 18 nasal
      polyposis patients (14 men, 4 women) and 21 control subjects (7 men, 14 women),
      all non asthmatic non smokers, without respiratory infections were prospectively
      studied. METHODS: They included nasal obstruction scoring, nasal endoscopic
      grading, allergy testing, nasal cytology, flow-volume spirometry and measurement
      of nasal (NNO) and exhaled NO (ENO) concentrations. NO was measured by a
      chemiluminescence NO Analyser (Sievers 280). NNO was analysed by aspiration with
      a constant flow of 3 l/mn. ENO was analysed during a slow expiration (50 ml/s)
      against a constant resistance of 10 cm H2O. RESULTS: NNO was significantly
      (p<0,001) decreased in NP group (596.4 +/- 102.06 ppb) compared to control group
      (2 251.6 +/- 288.6 ppb). ENO was significantly (p<0.05) increased in NP group
      (45.4 +/- 14.1 ppb) compared to control group (11.2 +/- 1.16 ppb). NNO and ENO
      were not significantly different between atopic and non-atopic NP patients. NNO
      concentrations was inversely correlated with the values of nasal endoscopic
      grading. No correlation was found between NNO concentrations and respectively
      nasal obstruction scoring and eosinophil count in nasal mucosa. CONCLUSION:
      Further studies are necessary to understand the pathophysiology of decreasing NNO
      and increasing ENO in nasal polyposis. In particular, ENO could be consider as a
      biologic marker of lower airway inflammation in nasal polyposis.

PMID- 12410121
TI  - [Function of the laryngeal muscles in the control of the fundamental frequency of
      voice].
AB  - The control of the laryngeal fundamental frequency by the laryngeal muscles is
      not yet clear and the subject of many controversies. We report here a review of
      the literature of many experimental studies on human and animals, to explain
      different theories about the function of these muscles.

PMID- 12410123
TI  - [The European School of Surgery].

PMID- 12410122
TI  - [Chondromas and low-grade chondrosarcomas of the larynx: a case report].
AB  - OBJECTIVE: We report a case of cricoid chondroma, underlining the difficulty in
      establishing a precise differential diagnosis between chondroma and low-grade
      chondrosarcoma of the larynx. MATERIAL AND METHODS: A 48-year-old woman developed
      inspiratory dyspnea. The final diagnosis was cricoid chondroma. We reviewed our
      case and data in the literature on these cartilaginous tumors. RESULTS: The
      patient was treated with conservative surgery. At 18 months follow-up, no
      recurrence has been detected. DISCUSSION: These tumors are rarely found in an ENT
      location and have similar histological features. According to many authors, the
      clinical course alone enables a distinction between chondroma and low-grade
      chondrosarcoma. Surgical treatment is indicated and provides good phonatory
      function in the vast majority of the cases.

PMID- 12410124
TI  - [Inguinal hernia: what is the optimal size of prosthetic patch?].
AB  - The use of prosthetic material for hernia repair is steadily increasing although
      some surgeons consider this excessive. This shift in surgical practice seems
      inevitable given the advantages of mesh prosthetic repair, but one may wonder
      about the amount of prosthetic material left in place which varies widely from
      one technique to another. While it may be impossible to determine the ideal size
      of a mesh, it is nevertheless useful to evaluate the relative advantages and
      drawbacks of techniques using meshes of different sizes. This study provides some
      elements of reflection based on anatomical, technical, and clinical data. The myo
      pectineal orifice of Fruchaud is divided in two parts by the ilio-pubic tract.
      While the lower part is occupied by the femoral nerve and vessels and the lacunar
      ligament, the upper part contains the zone of weakness through which most groin
      hernias protrude. This area is small in size and can be covered by a mesh 8-9 cm
      long and 5-6 cm wide. There is no difference in the rate of recurrence of repairs
      using a wide preperitoneal mesh and those using a smaller onlay mesh. The
      theoretical advantage of a wide preperitoneal mesh is to prevent the possible
      occurrence of a femoral hernia. Given the rarity of femoral hernia, this
      advantage must be balanced against the drawbacks of this technique which include
      the need for general anesthesia, a higher incidence of early postoperative
      complications, and particularly a higher risk of late complications due to
      adhesion of the mesh to bladder and iliac vessels. Small onlay mesh prostheses
      are preferrable in most cases; the use of a wide preperitoneal mesh should be
      reserved for those cases of inguinal hernia at high risk of recurrence,
      particularly if bilateral.

PMID- 12410125
TI  - [Management of familial polyposis coli].
AB  - Familial Multiple Polyposis Coli is an autosomal dominant hereditary illness
      characterized by the appearance in childhood of hundreds of colorectal polyps
      which inexorably undergo malignant transformation. It is accompanied by
      extracolonic manifestations some of which may also be life-threatening. Total
      colectomy should not be postponed beyond age 20 except in rare cases of an
      attenuated form of the disease (AAPC). Subtotal Colectomy with ileorectal
      anastomosis is a well-tolerated procedure with quite acceptable functional
      results, but the need for eventual proctectomy is about 30% at 20 years and the
      risk of rectal cancer is about 10% at 20 years even with close endoscopic
      surveillance. Total colectomy with ileal pouch-anal anastomosis is therefore the
      intervention of choice since it eliminates the risk of late rectal carcinoma
      albeit with more serious morbidity and less good functional results. Desmoid
      tumors are the leading cause of death in patients who have undergone total
      colectomy. NSAID's, tamoxifen, and chemotherapy are used preventively and
      therapeutically; surgical excision is sometimes required. Duodenal adenomas are
      present in almost 100% of these patients post-colectomy and the risk of duodenal
      cancer is 200 times higher than in the general population. Endoscopic
      surveillance of the duodenum is essential and prophylactic duodenal resection
      should be considered when duodenal polyposis is extensive.

PMID- 12410126
TI  - [At last, an effective therapy for non-differentiated GI sarcomas (gastro
      intestinal stromal tumor)].
AB  - Gastrointestinal stromal tumors (GISTs) are non differentiated sarcoma of the
      gastrointestinal tract and have for a long time been confused with well
      differentiated tumors and classified as leiomyosarcoma. These tumors are
      characterized immunohistochemically by CD 117 staining. This marker represents
      the expression of c-kit which is a receptor for growth factor with enzymatic
      activity (tyrosine kinase). Recent studies have found that an inhibitor of
      specific tyrosine kinase is effective in the treatment of GIST with an estimated
      response rate of more than 60%. This new drug could significantly improve the
      prognosis of these aggressive chemoresistant tumors.

PMID- 12410127
TI  - [Continent colostomy or pseudo-continent colostomy].

PMID- 12410128
TI  - [Laparoscopic ovarian cystectomy].

PMID- 12410129
TI  - [Surgical treatment of chronic pilonidal sinus by controlled scarification].

PMID- 12410130
TI  - [A rare cause of peritonitis in a child].

PMID- 12410131
TI  - [Severe dysplasia in Barrett's esophagus].

PMID- 12410132
TI  - [Congress of the American Society of Clinical Oncology].

PMID- 12410133
TI  - [Mood of the moment: the anesthesia].

PMID- 12410134
TI  - [From the epidemic of obesity to that of gastroplasty].

PMID- 12410135
TI  - [Surgery of morbid obesity in the adult: clinical efficacy of different surgical
      procedures].
AB  - Obesity is defined as morbid when the Body Mass Index (BMI) exceeds 40 kg/m(2).
      The initial approach should be a multidisciplinary medical assessment. The three
      principal surgical interventions practiced in France are: placement of an
      adjustable gastroplasty ring, vertical banded gastroplasty, and Roux-en-Y gastric
      bypass (short circuit). The indications for surgical therapy are those defined by
      recent consensus conferences: Morbid Obesity (BMI 40), Major Obesity (BMI 35)
      with associated factors of co-morbidity, or stable or worsening obesity of five
      years duration resistant to multidisciplinary medical management for a least a
      year. Studies of these three surgical techniques with at least one year of follow
      up shows significant average weight loss on the order of 20-50 kg. Studies of
      adjustable ring gastroplasty show an average loss of 45% of excess weight at one
      year; maintenance of weight loss beyond one year is not yet well documented. Long
      term results of vertical banded gastroplasty and gastric bypass are better
      defined. Initial weight loss for vertical banded gastroplasty is about 61%; some
      patients maintain this weight loss and others tend to regain some of their excess
      weight. For gastric bypass, the initial weight loss is about 68% of excess weight
      and there is a greater tendency to maintain this weight loss. Comparative
      studies, mostly from North America and of variable methodologic quality, conclude
      that weight loss with gastric bypass is superior to that with vertical banded
      gastroplasty. The indications for the respective techniques vary according to the
      severity of the obesity (BMI), and to the patient's eating habits. Gastric bypass
      which has the best short and long term results may be best reserved for patients
      with the most severe obesity or co-morbid conditions.

PMID- 12410136
TI  - [Diagnostic and therapeutic strategy for an incidental finding of an adrenal
      mass].
AB  - The incidental finding of an unsuspected adrenal mass ranges from 0.5% to 5% in
      abdominal CT series. The optimal diagnostic approach to such masses is to
      diagnose malignant or secretory tumors requiring excision and to otherwise avoid
      unnecessary surgery. Physical examination generally contributes little. A
      standard biochemical evaluation should include the measurement of 24 hour urinary
      catecholamines and metanephrine, urinary free cortisol and plasma cortisol levels
      at 8 a.m. and 8 p.m. combined with an overnight low-dose dexamethasone
      suppression test, serum potassium assay, and determination of upright plasma
      aldosterone to plasma renin activity. These tests will serve to screen for
      pheochromocytoma, subclinical Cushing's syndrome, and primary hyperaldosteronism
      respectively. Imaging characteristics suggestive of malignancy include: size
      greater than 4 cm., heterogeneous lesion and/or density greater than 20
      Hounsfield Units on CT scan, slow enhancement with delayed washout after
      intravenous contrast injection on CT scan, and slightly decreased signal
      intensity in out of phase (fat suppressed) MR acquisition. Fine-needle aspiration
      biopsy should be performed only if metastatic disease is suspected. Adrenal
      scintigraphy with iodocholesterol may be useful where adenoma with subclinical
      Cushing's syndrome or solid tumor is suspected. In summary, the following
      strategy is recommended for the management of adrenal  incidentalomas : mass
      lesions larger than 4 cm. and hormone-secreting tumors should be removed. All non
      secreting adrenal  incidentalomas  smaller than 4 cm. in diameter should be
      followed by serial imaging at regular intervals (6, 12, and 36 months) and by
      endocrine reevaluation at one year.

PMID- 12410137
TI  - [Surgical treatment of morbid obesity by gastrojejunal bypass using laparoscopic
      roux-en-Y (gastric short circuit)].

PMID- 12410138
TI  - [Prosthetic extraperitoneal hernia repair by a pararectal approach using a non
      wrinkling prosthetic patch].

PMID- 12410139
TI  - [Inguinal hernias: local anesthetic technique].

PMID- 12410140
TI  - [A strangled Spigelian hernia].

PMID- 12410141
TI  - [A T3 cancer of the mid-rectum].

PMID- 12410143
TI  - [Requested comment: the viewpoint of a noncardiac surgeon].

PMID- 12410142
TI  - [Extracorporeal circulation: an extraordinary tool that is not just for cardiac
      surgeons].
AB  - Extracorporeal circulation (ECC) is not only used for open heart surgery. There
      are also other surgical and medical applications. ECC can be used for encephalic
      arteries surgery to induce hypothermia and maximally protect the brain. Femoro
      femoral ECC may be needful for urgent traumatologic surgery of the supra-aortic
      trunci. Intracranial aneurysm repair can occasionally necessitate deep
      hypothermia and circulatory arrest with ECC. Renal cell carcinomas may
      metastasize to the right atrium and surgery with ECC is mandatory for complete
      excision. Some reports in the literature mention use of ECC for hepatic surgery
      of intra-hepatic aneurysms. With acute peripheral ischemia, metabolites in the
      affected limb can be washed out with good results. Medical indications for ECC
      are numerous with pulmonary assistance as one of the foremost when mechanical
      ventilation failed. Homogeneous and rapid rewarming of hypothermic patients can
      be achieved with ECC. Finally, some groups have reported the use of ECC to
      administer chemotherapy in limb melanoma.

PMID- 12410144
TI  - [Desmoids tumors].
AB  - Desmoid tumor can be defined as a pseudoencapsulated infiltrative growth of well
      differentiated collagenous fibroblasts and fibrocytes arising either in fascia or
      musculoaponeurotic structures. The etiology of desmoid tumors is poorly defined.
      The most commonly implicated etiologic factors are trauma, hormonal disturbances,
      and genetic or hereditary factors. Desmoid tumors of the anterior abdominal wall
      are much less common than extra-abdominal desmoids; they may occur at any age but
      are most common in the third and fourth decades. Although both sexes may be
      affected, abdominal desmoids predominate in females, particularly in females of
      childbearing age. Extra-abdominal desmoids, which most commonly occur on the
      back, chest wall, head and neck, or lower extremity, have a male predominance.
      Most patients complain of a painless mass of several months or years' duration.
      The primary consideration in surgical treatment of desmoid tumors should be the
      prevention of local recurrence. In most instances, this can be achieved by wide
      local excision or muscle group resection. There is no clear evidence that
      irradiation or chemotherapy are effective in controlling desmoid tumors.

PMID- 12410147
TI  - [Molecular pathology of colon cancer: an example of new diagnostic strategies].

PMID- 12410148
TI  - [Pathology of myxoid bone tumors of the skull base].
AB  - Myxoid bone tumors of the skull encompass chordomas and chondrosarcomas. Their
      accurate diagnosis is usually a challenge and it is of utmost importance to
      identify chordomas because of the poorer prognosis. Even if the topography of the
      tumor is suggestive (median versus lateral), modern imaging is not specific
      enough and the diagnosis is based on histological features. We report nine cases
      of myxoid bone tumors of the skull including four chordomas, one chondroid
      chordoma and four chondrosarcomas. Smears are useful for rapid intraoperative
      diagnosis. Chondrosarcomas show cords of small round cells in a myxoid background
      while chordomas are made of multilayered sheets of larger, often vacuolated
      cells. Histology shows areas of cartilaginous matrix associated with myxoid areas
      in chondrosarcomas and in chondroid chordomas. Immunohistochemistry is
      determinant showing the expression of epithelial markers and Tau protein in
      chordomas only.

PMID- 12410149
TI  - [Detection of HHV8 latent nuclear antigen by immunohistochemistry. A new tool for
      differentiating Kaposi's sarcoma from its mimics].
AB  - The purpose of this work was to study the value of HHV8 latent nuclear antigen 1
      detection by immunohistochemistry in Kaposi sarcoma and its mimics. MATERIALS AND
      METHODS: : We used the mAB LNA53 against the latent nuclear antigen 1 of HHV8 to
      study its expression by immunohistochemistry in paraffin embedded biopsy of
      Kaposi and its mimics. We also performed in vitro PCR for HHV8 DNA, extracted
      from the same paraffin embedded biopsies. We studied characteristic lesions of 26
      Kaposi sarcoma; 20 cutaneous lesions raising problems of differential diagnosis.
      We also studied 11 biopsies of skin, mucosa, or lymph nodes of patients infected
      by HHV8 but without Kaposi sarcoma, and 22 lesions initially classified by
      histological analysis as  uncertain Kaposi sarcoma . RESULTS: : In all cases of
      Kaposi, HHV8 was detected in the majority of tumor cells, with no expression in
      other adjacent cells. In these biopsies HHV8 DNA, was identified by in vitro PCR.
      None of the 20 Kaposi sarcoma mimics and the 11 lesions of patients infected by
      HHV8 but without any Kaposi sarcoma, were HHV8+ on immunohistochemistry sections
      or by PCR. From the 22 cases of uncertain Kaposi sarcoma, only the 14 lesions
      HHV8 PCR+ and with a clinical evolution in accordance with a Kaposi sarcoma, were
      HHV8+ on immunohistochemistry. In contrast, the 8 cases negative for HHV8 on
      immunohistochemistry were also PCR- and had a self-healing evolution in
      accordance with the diagnostic of pyogenic granuloma. CONCLUSION: : Detection of
      the latent nuclear antigen 1 of HHV8 by immunohistochemistry is a specific and
      sensitive diagnostic tool for differentiating Kaposi sarcoma from its mimics.

PMID- 12410150
TI  - [Genetic pathways in colorectal cancer: interest for the pathologist].
AB  - Molecular biology studies have led to the identification of two different types
      of colorectal carcinomas. The first group, called LOH (for loss of
      heterozygosity), represents 80% of colorectal cancers and is characterised by
      aneuploidy, allelic losses and a location in the distal colon. The second group
      displays phenotypic microsatellite instability (MSI-positive tumours), has a near
      diploid karyotype and a relatively low frequency of allelic losses. It accounts
      for 15% of all colorectal cancers and for about 30% of right-sided cancers. Four
      different pathways have been identified as responsible for tumour progression:
      the WNT/Wingless, the K-ras, the Transforming growth factor (TGF) and the P53
      pathways. The involvement of these pathways depends on the tumour type. In LOH
      positive tumours, the WNT/Wingless pathway is activated through an APC mutation,
      whereas MSI+ tumours do so through a catenin stabilising mutation. The TGFb
      growth inhibitory pathway is altered either by mutations in the signal
      transduction molecules SMAD2 and SMAD4 in LOH positive tumours or by mutations of
      TGFbRII in MSI+ tumours. In the p53 pathway, mutations in BAX may contribute to
      the adenoma-carcinoma transition just as p53 mutations may do in LOH positive
      tumours. Until now, cancer phenotype determination has had no clinical
      implications. However, the predictive value of the MSI status was recently
      stressed as a predictive factor for response to chemotherapy.
      Immunohistochemistry could represent a complementary strategy to molecular
      biology in assessing MSI status. This simple test would allow to screen all
      colorectal carcinomas for MSI status, which would provide valuable management
      information in addition to the histological assessment for tumour stage and
      grade.

PMID- 12410151
TI  - [Cytopathologist's role in detecting and identifying pathogens].
AB  - This review highlights the contribution of the cytopathologist in the diagnosis
      of infectious diseases, with emphasis on the detection and identification of
      microorganisms in various cytologic specimens. Morphological analysis of the main
      bacteria, parasites and mycoses observed in cytologic specimens, as well as the
      cytopathogenic effects of the viruses are discussed. The differential diagnosis
      (contaminants and exogenous or endogenous foreign bodies) is discussed. Finally,
      the main pathogens noted in each specimen are briefly reviewed.

PMID- 12410153
TI  - [Peripheral ameloblastic fibrosarcoma].
AB  - We describe the clinicopathological features of a peripheral ameloblastic
      fibrosarcoma (PAFS) diagnosed in a 89-years-old man with a past history of
      recurrent peripheral ameloblastoma. Like other peripheral odontogenic tumors,
      PAFS shows histological features comparable to those of the central intraosseous
      form, with (fibro)sarcomatous proliferation associated to benign-appearing
      ameloblastomatous areas. The differential diagnosis must be made with a low-grade
      spindle ameloblastic carcinoma and with a collision tumor (a non odontogenic
      sarcoma associated with a recurrent ameloblastoma). Almost any odontogenic tumor
      has been observed in the peripheral soft tissues, but our case seems to be, to
      our best knowledge, the first case of PAFS reported in the literature. This fact
      can only reflect the rarity of its central counterpart. A particular feature is
      the old age of our patient (ameloblastic fibrosarcoma usually occurs in
      adolescent or young adult). Another particular feature is that this PAFS appeared
      in the contiguity of a recurrent peripheral ameloblastoma. As proposed by many
      authors, this finding suggests that peripheral odontogenic tumors should require
      a long-term follow-up and, maybe, a more aggressive initial surgical management.

PMID- 12410152
TI  - [Carcinosarcoma of the scalp].
AB  - A 41-year-old patient had a large and quick growing tumor of the scalp, known
      during many years. The histopathologic and immunohistochemical evaluations lead
      to the diagnosis of a cutaneous carcinosarcoma or sarcomatoid carcinoma. In spite
      of the surgical treatment, the evolution was rapidly fatal with widespread
      metastasis. From data of the literature, we discuss the diagnosis and
      histogenesis of this rare cutaneous tumor.

PMID- 12410154
TI  - [Signet ring cell carcinoma of the pancreas: a case report].
AB  - We report a case of signet ring cell carcinoma of the pancreas. This rare variant
      of ductal adenocarcinoma is composed exclusively of signet ring neoplastic cells
      in a mucinous stroma. Altogether, clinical, radiological and immunohistochemical
      data supported the pancreatic origin of the tumor.

PMID- 12410155
TI  - [Multifocal serous cystadenoma of the pancreas synchronous with ampullary
      adenocarcinoma].
AB  - Pancreatic cysts are common, but cystic tumors are uncommon. We report a rare
      case of serous cystadenoma of the pancreas synchronous with ampullary
      adenocarcinoma which supports a common etiopathogeny of these tumors. We discuss
      the differential diagnosis with mucinous cystadenoma which is potentially
      malignant and recall the microscopic and radiologic features.

PMID- 12410156
TI  - [Begnin naevus cell inclusions in two patients treated for cancer].
AB  - In 1897, Reis was the first to describe benign nevus inclusions in the lymph node
      of patients undergoing surgery for genital neoplasia. These inclusions are very
      rarely encountered and can be misleading in the absence of careful analysis. We
      report on two cases of nevus cell inclusions in axillary and inguinal lymph nodes
      dissected in the context of breast cancer and thigh sarcoma respectively.
      Cautious morphological analysis should be compared with histochemistry and
      immunohistochemistry data to avoid erroneous diagnosis of metastasis. We also
      should bare in mind the possible occurrance of primitive lymph node melanoma.

PMID- 12410157
TI  - [A palate tumor revealed by pain].
AB  - A 41-year-old female presented in April 1996 with a tumor of the hard palate
      revealed by increasing left palate pain. Adenoid cystic carcinoma was suspected
      on clinical and imaging data. Two limited surgical procedures showed a tumor
      histologically made of small lobules of granular cells, PAS positive and
      expressing S100 protein, infiltrating some medullary spaces of the palatine bone,
      consistent with a granular-cell tumour. Pain recurred in the territory of the
      maxillary branch of the left trigeminal nerve (V2). Imaging showed a tumor of the
      origin of V2-extending through the foramen rotondum. Two radical interventions in
      September and in October 2000 showed an infiltrating tumor of the V2 and palatine
      mucosa, with the same histology. There was no immuno-staining for p53, and less
      than 5% of nuclei expressed Ki67. Malignant Abrikossof tumors are exceptional,
      morphologically difficult to differentiate from benign ones, only metastasis
      proving malignancy. Tumor size above 5 cm, recurrence and infiltrative character
      are considered pejorative. The value of p53 and Ki67 expression remains
      controversial. We discuss our observation according to these criteria.

PMID- 12410158
TI  - [Postmenopausal frontal fibrosing alopecia. Report of 3 cases].
AB  - Postmenopausal frontal fibrosing alopecia is a rare aspect of scarring alopecia
      concerning elderly women. It appears as a receding anterior hair line localised
      in the frontal and temporal regions. It is a particular pathologic and clinical
      form of lichen planopilaris. The histologic aspect is that of a lichenoid
      inflammatory infiltrate affecting the dermal follicular junction, accompanied by
      a fibrous scarring aspect, the latter contributing to the diagnosis and
      individualization of this entity. Discoid lupus erythematous is the main
      histologic differential diagnosis. Postmenopausal period is the only associated
      condition found in affected women. Evolution is unpredictable and does not seem
      to be modified by treatment.

PMID- 12410159
TI  - [A small lesion of the hepatic capsule].

PMID- 12410160
TI  - [Polyp of the external auditory canal].

PMID- 12410161
TI  - [Mastoid tumor simulating meningitis].

PMID- 12410162
TI  - [Intrasinusal bone marrow lymphoid infiltration].

PMID- 12410163
TI  - [A recurrent lesion of the lip].

PMID- 12410164
TI  - The immunopathogenesis of membranous nephropathy.
AB  - Membranous nephropathy is an important disease: it is one of the leading primary
      causes of the nephrotic syndrome in adults, and, in up to a third of patients,
      causes progressive renal impairment resulting in end stage renal failure. Ever
      since histological techniques demonstrated the presence of glomerular
      immunoglobulin deposits in this disease the immune system has been implicated in
      pathogenesis. Initial ideas focussed on the deposition of circulating immune
      complexes, but the development of an animal model (Heymann nephritis) suggested
      the alternative mechanism of antibody reacting with an intrinsic glomerular
      antigen. However, attempts to find evidence for this Heymann type mechanism in
      the human disease have, in general, been unsuccessful. This article briefly
      reviews the development of ideas about the pathogenesis of membranous
      nephropathy, and proposes the hypothesis that the disease is caused by formation
      of low affinity non-complement fixing IgG4-containing immune complexes.

PMID- 12410165
TI  - Acute renal failure. Extracorporeal treatment strategies.
AB  - The mortality for acute renal failure remains to be high (around 50-70%) despite
      manifold improvements in terms of techniques and equipment for renal replacement
      therapies as well as patient monitoring and intensive care support. At present,
      it is not clear if the method chosen for renal replacement therapy, i.e.
      intermittent hemodialysis or continuous hemofiltration, might impact
      significantly on the outcome of these patients. Whilst earlier retrospective
      studies suggested that CVVH might result in better survival and renal recovery in
      acute patients, recent prospective studies were unable to confirm these findings.
      These studies were, however, not evenly randomised in terms of severity of
      illness or too small to produce conclusive results. In clinical routine CVVH is
      typically chosen for treating patients with hemodynamic instability and volume
      overload. If one decides to perform CVVH, however, a filtrate volume of at least
      35 ml/kg body weight and hour should be used as this was shown to be associated
      with better survival as compared to smaller filtrate volumes. A second
      controversy exists to date whether the choice of the dialyzer membrane might be
      of significant relevance for the outcome of patients with acute renal failure.
      Earlier studies indicated that the use of biocompatible membranes in these
      patients may result in improved patient survival and renal recovery. More
      recently, however, these results could not be confirmed by larger randomized,
      prospective clinical studies. Thus, the choice of the dialyzer membrane should be
      based on individual assessment rather than treatment bias.

PMID- 12410166
TI  - Current management options in Behcet's disease.
AB  - Behcet's disease (BD) is a multi-system inflammatory disorder, which causes
      recurrent oral and genital ulceration, intraocular inflammation and skin lesions.
      Less commonly, locomotor, vascular, neurological and gastro-intestinal
      manifestations may occur. The pathophysiology of Behcet's disease is not well
      understood, but may involve a generalised vascular dysfunction. Although rare in
      Western Europe, BD can cause significant morbidity and mortality to affected
      individuals. In this article, we review the clinical features and discuss current
      management options.

PMID- 12410167
TI  - [Diabetic nephropathy. A historical, clinical and diagnostic framework].
AB  - Diabetic nephropathy is the major chronic complication of diabetes mellitus for
      mortality and morbidity. It is a condition of renal damage appearing in the
      course of diabetes mellitus, with a clinical expression characterized by urinary
      signs and arterial hypertension. This condition is functionally distinguished by
      a progressive decrease of the glomerular filtration rate, and in the Western
      world it is currently the major determinant of end stage renal disease. In the
      last twenty years the incidence of renal failure in the course of diabetes
      mellitus has grown continuously, particularly in type 2 diabetic patients. The
      majority of patients with diabetic nephropathy reach end-stage renal failure
      within ten years from the first evidence of proteinuria, and, in the United
      States, about 30% of the chronically dyalitic patients have diabetic nephropathy.
      The identification and the control of the renal disease over time are based on
      the measurement of proteinuria. Although the most useful and reliable dosage
      methods for proteinuria are still debated, it appears clear today that a spot
      measurement of albuminuria is not a reliable indication for the diagnosis of
      diabetic renal disease. The measurement of albuminuria as well as of creatinuria
      several times a year in the diabetic subject is therefore recommended,
      considering also that the test needs repetition both when positive and negative.
      Despite of the relevant results achieved in the last few years by clinical
      research both in the diagnostic and in the therapeutic fields, the role of
      prophylactic measures still remains essential in diabetics at higher risk of
      nephropathy.

PMID- 12410168
TI  - Statins and omega-3 fatty acids in the treatment of dyslipidemia and coronary
      heart disease.
AB  - Dyslipidemia including hypercholesterolemia and hypertriglyceridemia often
      associated with low levels of HDL-cholesterol is a common and important cluster
      of risk factors for coronary heart disease. Dyslipidemia is also commonly
      associated with hypertension, hyperinsulinemia and central obesity in the
      metabolic syndrome. Lifestyle adjustments including increased physical activity
      and dietary modifications leading to weight reduction are important first steps
      in the prevention of coronary heart disease in patients with such abnormalities
      in lipid metabolism. When these adjustments are insufficient to achieve desirable
      results, the combined treatment with statins and omega-3 fatty acids is an
      efficient treatment alternative. Both statins and omega-3 fatty acids have
      documented their effects against coronary heart disease (CHD) both in primary and
      secondary prevention trials. The mechanisms involved are only partly explained,
      however, the synergistic effects of statins and omega-3 fatty acids significantly
      reduce the risk for CHD in patients with dyslipidemia.

PMID- 12410169
TI  - [Testis cancer markers. Clinical use].
AB  - Testis tumour is relatively rare and more frequent between 15-35 years of age.
      The 90% of this tumour derivates from germinal cells, the remaining cases
      originate from stromal cells or are secondary lesions from other neoplasms. The
      present clinical use of serum markers, especially alfa-fetoprotein (AFP), human
      chorionic gonadotrophin protein (HCG) and serum lactate dehydrogenase (LDH) is
      examined.

PMID- 12410170
TI  - Current issues in the prevention of rheumatic fever.
AB  - Variation in strain virulence helps to account for the wide spectrum of group A
      streptococcal diseases and for their striking epidemiological variation. Recent
      studies of the genetic control of the expression of the virulence factors of
      group A streptococci (GAS) are beginning to illuminate such variation. Although
      still obscure, the pathogenesis of acute rheumatic fever (RF) requires primary
      infection of the throat by highly virulent GAS strains. Those that have clearly
      caused RF contain large hyaluronate capsules and extended M-protein molecules.
      The M molecule contains some epitopes cross-reactive with host tissues, and also
      has superantigenic properties like the secreted GAS erythrogenic toxins. In
      settings where ARF has become rare, GAS pharyngitis continues to be quite common
      but is most often caused by relatively attenuated strains. These, however, may
      colonize the throat avidly, and often stubbornly. GAS "skin strains" that cause
      pyoderma (impetigo) are molecularly distinct from "throat strains". Although they
      may secondarily colonize and infect the throat, the pyoderma strains are
      generally less virulent and are not rheumatogenic. Some skin strains, however,
      may cause acute glomerulonephritis. The diagnosis, treatment and prevention of
      GAS pharyngitis is reviewed in relation to the varying prevalence of RF in
      different geographical and social settings.

PMID- 12410171
TI  - Carcinoid tumour.
AB  - Carcinoid tumours are relatively rare neoplasms that often present as diagnostic
      dilemmas due to obscure or non-specific symptomatology. The ability of carcinoid
      tumours to cause clinical symptoms by secretion of hormones or biogenic amines is
      best recognised in the form of the carcinoid syndrome. Although generally slow
      growing, a significant proportion demonstrates aggressive tumour growth and may
      be difficult to manage. Ten percent of carcinoids are part of the spectrum of
      multiple endocrine neoplasia type 1, which should be considered in the
      investigation and management of these patients. A further 10% of carcinoid
      tumours are associated with other noncarcinoid tumours of various histological
      types. This review discusses recent improvements in biochemical diagnosis with
      the introduction of plasma chromogranin A, and puts into context the use of the
      imaging modalities, including Indium-111 Octreotide scintigraphy, and newer
      developing techniques, such as positron emission tomography. The therapeutic
      options are reviewed, including the use of somatostatin analogues as the
      treatment of choice in the control of hormone-mediated symptoms, the role of
      surgery, the use of chemotherapy, biotherapy using interferon, and the exciting
      new field of receptor-targeted therapy. In addition, the challenging
      interventional management of liver metastases is discussed, including the role of
      hepatic-artery embolisation and chemo-embolisation, radiofrequency ablation and
      the place of orthotopic liver transplantation in selected patients. We conclude
      that with the increasing number of investigative procedures and therapeutic
      options available to diagnose and treat carcinoid tumours, a multidisciplinary
      approach is needed. Furthermore, additional scientific research and controlled
      clinical trials are needed to determine the efficacy of the many treatment
      options, which for these rare tumours can only be achieved by collaboration.

PMID- 12410172
TI  - Role of food hypersensitivity in irritable bowel syndrome.
AB  - A significant proportion of IBS patients attribute their symptoms to adverse food
      reactions. Dietary elimination and re-challenge studies support the role of diet
      in the pathogenesis of IBS. The aetiopathogenesis of IBS is thought to be
      multifactorial involving an interaction between diet, infection, antibiotics and
      psychosocial factors. Serum IgE and IgG4 antibodies are elevated in food
      hypersensitivity induced atopic conditions and a similar mechanism has been
      postulated in IBS. Increased number of mast cells is present in the ileocaecal
      region of IBS patients. Once sensitized, they are capable of inducing secretory
      and sensorimotor abnormalities of the gut. The management of IBS is usually aimed
      at controlling symptoms, however, evaluation of food hypersensitivity may provide
      a useful adjunct in those with severe symptoms or a clear history of adverse food
      reaction. There are no well-established tests available but skin prick tests and
      food specific serum IgG4 and IgE antibodies may help in identifying the offending
      foods. Other options, which may be explored in individual cases, include
      sequential dietary exclusion, use of hypoallergenic diets, disodium cromoglycate
      and novel techniques such as colonoscopic allergen provocation test.
      Pathophysiology of hypersensitivity induced IBS has been discussed in the light
      of current data and a management algorithm has been proposed for managing food
      hypersensitivity in IBS.

PMID- 12410173
TI  - The prevalence of pathological gambling in Romanian teenagers.
AB  - BACKGROUND: The liberalization of teenagers' way of life strikingly increased in
      Romania after 1989; this includes gambling. The goal of our study is to analyze
      the different aspects of gambling in some teenager communities in Romania.
      METHODS: The study included 500 school-teenagers from 3 different Romanian
      districts (Cluj, Salaj and Bacau). Of these 217 (43.40%) were males and 283
      (56.60%) females. Median age was 16 years old (range 14-19). A structural
      questionnaire was applied to the teenagers consisting in "The 20 questions of the
      American Anonymous Gambling Association". Other 20 questions about their age,
      gender, family, income, school, toxic abuse, gambling preferences, the frequency
      and the amount of money they use in gambling were also proposed. RESULTS: The
      results of the study were as it follows: 34 (6.8%) of the tested teenagers were
      pathological gamblers, 28 (82.36%) males and 6 (17.64%) females, with a ratio F:M
      of 1:4.6. The average age of starting gambling was 13.25 1.51 years old. The
      majority (82.35%) prefers group gambling and only 17.64% prefer individual
      gambling. Of these, 47.5% of them gamble very often (almost every day) and 38.2%
      gamble often (once a week). The most frequent gambling was: pool (55.88%), poker
      (35.29%), bingo (32.35%), and basketball on a bet (5.88%), black-jack, roulette
      and craps (2.94% each). Gambling was the reason for school absenteeism and modest
      results at school in 64.70% and 52.94% of all the teenagers respectively.
      CONCLUSIONS: The results of the study revealed very concerning aspects of the
      increased incidence of gambling among Romanian teenagers, compared to the UK (6%
      of them are gambling).

PMID- 12410174
TI  - [RDW: new screening test for coeliac disease? ].
AB  - BACKGROUND: Notwithstanding the presence of numerous examinations for screening
      coeliac disease, it may still escape timely diagnosis. For this reason we carried
      out an investigation to see whether simple haematochemical anomalies (as revealed
      in what are now routine examinations carried out during hospitalisation) might
      make diagnosis quicker or at least trigger the suspicion of coeliac disease.
      METHODS: Retrospectively, of 21 adult patients admitted to our hospital for the
      first time and who were diagnosed with coeliac disease, we considered
      haemoglobin, iron, calcium, potassium, albumin and RDW (part of the normal blood
      count). RESULTS: We found that elevated RDW was the most frequent anomaly (67% of
      patients) of the six haematochemical parameters observed. In addition, it became
      normal in most patients after a gluten-free diet. CONCLUSIONS: Elevated RDW was
      more frequent than sideropenic anaemia in patients with coeliac disease. In
      addition, RDW indicates a response to diet therapy because it became normal after
      a gluten-free diet.

PMID- 12410175
TI  - Head and neck cancer: the complexities of care.

PMID- 12410176
TI  - Molecular genetics of head and neck cancer.
AB  - BACKGROUND: Head and neck cancers have multiple genetic abnormalities that
      influence tumor behavior and may be useful in developing new treatments. METHODS:
      Genetic alterations implicated in head and neck cancer oncogenesis and behavior
      are reviewed, and molecular techniques for detection and treatment are evaluated.
      RESULTS: The large number of genetic changes present in head and neck cancer
      cells precludes meaningful use of simple molecular tests and treatments.
      Detection of abnormalities in multiple genes provides better prognostic
      information than the detection and assessment of single mutations. Screening
      tests that rely on amplification of genetic material present in bodily fluids are
      hindered by the genomic complexity of head and neck cancer. Introduction of
      genetic material into head and neck cancer cells for gene therapy has shown some
      efficacy. CONCLUSIONS: Head and neck cancers comprise a complex genetic disease.
      Although much has been learned about the molecular genetics of head and neck
      cancers, continued study of multiple genes is critical for further progress. Gene
      therapy, although promising, must also overcome this complexity.

PMID- 12410177
TI  - Transoral laser microsurgery in carcinomas of the oral cavity, pharynx, and
      larynx.
AB  - BACKGROUND: Since the introduction of laser technology in the 1960s, use of the
      technique in treating laryngeal diseases has demonstrated several advantages over
      conventional resections in selected cases. METHODS: The authors review the
      published data on oncologic laser surgery for the treatment of head and neck
      carcinomas, and they also describe their own clinical experience with transoral
      laser surgery for the treatment of carcinomas of the oral cavity, pharynx, and
      larynx. RESULTS: Laser surgery has achieved a key position in minimally invasive
      treatment concepts in the ears, nose, and throat area, especially for the
      treatment of malignancies of the upper aerodigestive tract. The CO2 laser is the
      approach most commonly used. CONCLUSIONS: New and improved applications of laser
      therapy in the treatment of cancer are being explored. As more surgeons become
      experienced in the use of lasers and as our knowledge of the capabilities and
      advantages of this tool expands, lasers may play a larger role in the management
      of head and neck cancers.

PMID- 12410178
TI  - Treatment of locally advanced head and neck cancer: historical and critical
      review.
AB  - BACKGROUND: Advanced squamous cell cancers of the head and neck have
      traditionally been associated with high rates of morbidity and mortality.
      Advances in management have improved outcomes for most of these patients.
      METHODS: The author reviews the historical progress in management of these
      difficult tumors and adds his own wide experience to describe and evaluate newer
      approaches to management. RESULTS: Over the last 10 years, overall survival rates
      for patients with head and neck cancers have improved as has quality of life. New
      standards of care have been defined for patients with nasopharyngeal cancer and
      for those with advanced unresectable disease. Organ preservation is more commonly
      achieved. CONCLUSIONS: Newer targeted therapies are likely to add to the progress
      that has already been achieved in the multimodality management of patients with
      head and neck cancers.

PMID- 12410179
TI  - Evaluation and management of oropharyngeal Dysphagia in head and neck cancer.
AB  - BACKGROUND: Dysphagia is a common symptom of head and neck cancer or sequelae of
      its management. Swallowing disorders related to head and neck cancer are often
      predictable, depending on the structures or treatment modality involved.
      Dysphagia can profoundly affect posttreatment recovery as it may contribute to
      aspiration pneumonia, dehydration, malnutrition, poor wound healing, and reduced
      tolerance to medical treatments. METHODS: The author reviewed the normal anatomy
      and physiology of swallowing and contrasted it with the commonly identified
      swallowing deficits related to head and neck cancer management. Evaluation
      methods and treatment strategies that can be used to successfully manage the
      physical and psychosocial effects of dysphagia are also reviewed. RESULTS:
      Evaluation of dysphagia by the speech pathologist can be achieved with
      instrumental and noninstrumental methods. Once accurate identification of the
      deficits is completed, a range of treatment strategies can be applied that may
      return patients to safe oral intake, improve nutritional status, and enhance
      quality of life. CONCLUSIONS: To improve safety of oral intake, normalize
      nutritional status, reduce complications of cancer treatment and enhance quality
      of life, accurate identification of swallowing disorders and efficient management
      of dysphagia symptoms must be achieved in an interdisciplinary team environment.

PMID- 12410180
TI  - Ethical considerations in the treatment of head and neck cancer.
AB  - BACKGROUND: The second half of the 20th century saw not only important
      developments in medical science and technology, but also a rapid growth in the
      application of biomedical ethics in medical decision making. Withdrawal of
      treatment, allowing to die, informed consent, and patient autonomy are concerns
      that now comprise a part of the overall medical treatment, particularly in
      patients with head and neck cancers. METHODS: The author discusses ethical issues
      relating to disfigurement/dysfunction in head and neck cancer patients and
      examines the aspects of "principlism": autonomy, nonmaleficence, beneficence, and
      justice. Two case reports are presented to illustrate the ethical challenges that
      may confront physicians who treat head and neck cancer patients. RESULTS: Head
      and neck oncology generates unique problems relating to disfigurement and
      dysfunction. An algorithm that considers the patient's medical good and greater
      good, as well as the goods of others, can assist in arriving at appropriate
      ethical decisions. CONCLUSIONS: Bioethical decision making requires the
      integration of virtues with principles, followed by the application of these
      standards to each patient.

PMID- 12410181
TI  - Once-daily aminoglycosides in patients with neutropenic fever.

PMID- 12410182
TI  - Retroperitoneal fibrosis (Ormond's disease): clinical pathologic study of eight
      cases.

PMID- 12410183
TI  - Promoting the use of evidence-based medicine in pediatrics.

PMID- 12410184
TI  - Titration of growth hormone dose using insulin-like growth factor-1 measurements:
      is it feasible in children?

PMID- 12410185
TI  - Increased asthma symptoms and healthcare utilization during the fall and winter
      seasons in children with asthma living in the inner city: opportunity for school
      based intervention.

PMID- 12410186
TI  - Is insulin-like growth factor-1 monitoring useful in assessing the response to
      growth hormone of growth hormone-deficient children?
AB  - OBJECTIVE: To assess the relationship between insulin-like growth factor-1 (IGF
      1), the growth hormone (GH) dose utilized to treat GH-deficient children and the
      changes noticed in height-standard deviation score (H-SDS) and height velocity
      (HV). STUDY DESIGN: We studied 24 prepubertal GH-deficient patients with a mean
      age of 10.5 +/- 1.8 years and a mean bone age (BA) of 8.4 +/- 2.1 years. H-SDS
      for chronologic age (CA) and BA before therapy were -2.6 +/- 0.8 and -1.2 +/-
      0.8, whereas height velocity (HV)-SDS was -1.1 +/- 1.5. Serum IGF-1 and insulin
      like growth factor binding protein-3 (IGFBP-3) levels were measured before, after
      6 and 12 months of GH, and correlated with the GH dose used. Based on the
      increment of IGF-1 used during treatment, patients were divided into 2 groups: G1
      (>1 SDS) and G2 (<1 SDS). HV-SDS and interval height increases were analyzed.
      RESULTS: HV-SDS, as well as H-SDS for CA and BA during the first year of
      treatment, were significantly greater than before therapy. IGF-1 SDS increased
      significantly during the first 6 months of therapy (P <.0003), but increased no
      further at 12 months despite the use of a higher GH dose (0.1 vs 0.14 IU/kg/day),
      whereas IGFBP-3 SDS increased at both 6 and 12 months. There was no correlation
      between the GH dose used and IGF-1 and IGFBP-3 levels. When patients were divided
      according to their IGF-1 increment during therapy, a significant increase in H
      SDS for BA and in HV-SDS was noted only in group 2. CONCLUSIONS: The increment in
      IGF-1 SDS during therapy did not correlate with the interval height increase. IGF
      1 measurement may be helpful in monitoring compliance and safety, but seems to be
      less useful in adjusting the GH dose needed to treat prepubertal GH-deficient
      children.

PMID- 12410187
TI  - Infants of diabetic mothers are at increased risk for the oculo-auriculo
      vertebral sequence: A case-based and case-control approach.
AB  - OBJECTIVES: To determine if infants of diabetic mothers (IDM) are at increased
      risk for dysplastic ears and the oculoauriculo-vertebral spectrum (OAVS). STUDY
      DESIGN: Cases of IDM with dysplastic external ears seen at Cedars-Sinai Medical
      Center were combined with case series in medical literature describing similar
      patients. Data from a large congenital birth defects registry in Spain were
      analyzed, and odds ratios (OR) for infants born to either a gestational or
      preconceptionally diabetic mother to have one of the studied malformations were
      calculated with 95% confidence intervals. RESULTS: Among the 30 patients in the
      case series, 50.0% (15) had hemifacial microsomia; 46.7% (14) had hearing loss;
      33.3% (10) had facial nerve palsy; 33.3% (10) had vertebral anomalies; 36.7% (11)
      had cardiovascular defects, of which 45% (5) were conotruncal defects; 26.7% (8)
      had renal anomalies; 13.3% (4) had limb defects (all radial ray hypoplasia); 10%
      (3) had DiGeorge sequence; 6.7% (2) had laterality defects; and 6.7% (2) had
      imperforate anus. Within the cases from the birth defects registry, the odds
      ratio for OAVS in infants of mothers with gestational diabetes mellitus was 2.28
      (95% CI, 1.03-4.82, P =.03), and the OR for ear anomalies in these infants was
      1.21 (95% CI, 0.94-1.56, P =.13). When infants of mothers with preconceptionally
      diagnosed type 1 or 2 diabetes were considered, the OR for OAVS was 1.50 (95% CI,
      0.08-9.99, P =.49), and the OR for dysplastic ears was 0.94 (95% CI, 0.48-1.81, P
      =.85). CONCLUSIONS: Our data indicate that OAVS occurs with a higher incidence in
      IDM than in the general population. Associated problems include hearing loss,
      athymia, and cardiac, renal, and limb malformations. Therefore, we recommend that
      an IDM with features consistent with OAVS undergo a workup including hearing
      evaluation, skeletal survey, echocardiogram, renal ultrasonogram, and
      immunodeficiency workup if clinically indicated. Furthermore, noting that most of
      these defects occur in structures of neural crest origin, we hypothesize that
      poorly controlled maternal diabetes interferes with cephalic neural crest cell
      migration.

PMID- 12410188
TI  - Home sodium monitoring in patients with diabetes insipidus.
AB  - OBJECTIVE: To determine whether home care givers can accurately measure plasma
      sodium in children with diabetes insipidus (DI) by using an I-STAT portable
      clinical analyzer (PCA) and to collect preliminary data on home PCA use. STUDY
      DESIGN: Care givers of 4 children with DI and impaired thirst or inability to
      access water freely were instructed in PCA use. During an initial preclinical
      phase, the accuracy of sodium concentration measured by care givers was assessed
      by comparison to simultaneous analysis in a clinical laboratory. Participants
      were subsequently randomly assigned to daily home PCA monitoring or routine care.
      All participants crossed over from their original randomized group assignment to
      the alternate group. RESULTS: After a single education session, all care givers
      were able to perform PCA testing. There was good correlation between PCA and
      laboratory sodium (r = 0.92). On the basis of Error Grid Analysis, use of the PCA
      sodium would have resulted in treatment decisions identical to those made based
      on the laboratory sodium value in 62 of 66 instances. Four minor differences in
      treatment would have occurred. There was no statistically significant difference
      in clinical outcome during daily monitoring versus routine care. CONCLUSIONS:
      Results obtained by care givers using the PCA are sufficiently reliable for
      assessment of fluid status and making treatment decisions.

PMID- 12410189
TI  - Nocturnal hypoglycemia detected with the Continuous Glucose Monitoring System in
      pediatric patients with type 1 diabetes.
AB  - OBJECTIVE: To use the Continuous Glucose Monitoring System (CGMS, MiniMed,
      Sylmar, Calif) to determine if bedtime blood glucose levels were associated with
      the occurrence of nocturnal hypoglycemia. STUDY DESIGN: Patients (n = 47, 18
      boys, mean age 11.8 +/- 4.6 years) with type 1 diabetes used CGMS for 167 nights.
      Data were analyzed for glucose </=40 or </=50 mg/dL, comparing bedtime blood
      glucose levels of </=100 or >100 mg/dL and </=150 or >150 mg/dL. RESULTS: A
      glucose value of </=40 mg/dL occurred on 27% of nights and </=50 mg/dL on 35% of
      nights. There was a 2-fold increase (45% vs 22%, P =.015) in the incidence of
      hypoglycemia with a bedtime glucose </=100 mg/dL and a 1.7-fold increase (46% vs
      26%, P =.01) with a value of </=150 mg/dL; most episodes occurred between 9 PM
      and 1 AM. There was no difference in hypoglycemia duration (86.4 minutes for
      glucose </=100 mg/dL vs 84.5 minutes for >100 mg/dL, P = NS), and no bedtime
      glucose value between 110 and 300 mg/dL decreased the incidence of nocturnal
      hypoglycemia to </=10%. The incidence of nocturnal hypoglycemia was similar for
      patients using insulin pump and injection therapy, and there was no correlation
      between hemoglobin A1c and incidence or duration of hypoglycemia. CONCLUSIONS:
      Nocturnal hypoglycemia is frequent, of long duration, associated with bedtime
      glucose values </=100 to 150 mg/dL, and predominately in the early part of the
      night. CGMS is a useful tool to diagnose asymptomatic nocturnal hypoglycemia.

PMID- 12410190
TI  - Understanding the seasonal pattern of childhood asthma: results from the National
      Cooperative Inner-City Asthma Study (NCICAS).
AB  - OBJECTIVE: To contrast the seasonal patterns of asthma symptoms and utilization
      and determine the impact of allergen sensitivity, environmental tobacco smoke
      (ETS) exposure, and air pollution on the seasonal patterns of asthma. STUDY
      DESIGN: Participants in the National Cooperative Inner-City Asthma Study (NCICAS)
      were tracked for approximately 4 years after allergen skin testing and
      determination of exposure to ETS. Air pollution data were obtained from EPA
      monitoring sites in NCICAS cities. RESULTS: Asthma symptoms (wheeze) and health
      care utilization (unscheduled visits and hospitalization) had similar seasonal
      patterns, with low points during the summer months of June through August and a
      distinct autumn peak beginning in September. Seasonal patterns were similar among
      children with no allergen skin test reactivity, those reactive only to indoor
      allergens, and those reactive to outdoor allergens. ETS exposure, whether defined
      by self-report or urinary cotinine/creatinine ratio, was not related to the
      observed seasonal patterns. Among the pollutants evaluated, only the seasonal
      pattern of SO(2) coincided with that of asthma morbidity. CONCLUSIONS: Atopy,
      ETS, and most air pollutants do not appear to contribute to the distinct asthma
      seasonal pattern. On a population level, changes in symptoms are mirrored by
      changes in utilization.

PMID- 12410191
TI  - Relationship of nutritional status to health and societal participation in
      children with cerebral palsy.
AB  - OBJECTIVES: To describe nutritional status in a population-based sample of
      children with moderate or severe cerebral palsy (CP) and to explore the
      relationships between nutritional status and health and functional outcomes.
      STUDY DESIGN: A population-based strategy was used to enroll children with CP at
      6 geographic sites. Research assistants performed anthropometric assessment,
      determined severity of motor impairment, and interviewed caregivers with the
      Child Health Questionnaire and a questionnaire designed specifically for this
      study. Anthropometric measures were converted to Z scores and the relationship
      between health and nutritional status was assessed using regression models.
      RESULTS: Among the 235 participants, indicators of malnutrition were common. Poor
      nutritional status correlated with increased health care utilization
      (hospitalizations, doctor visits) and decreased participation in usual activities
      by the child and parent. CONCLUSIONS: Malnutrition is common in children with
      moderate or severe CP and associated with poorer health status and limitations in
      societal participation. Further studies are needed to determine the nature of
      these associations and how to manage nutrition in children with CP to optimize
      growth and health outcomes.

PMID- 12410192
TI  - Bisphosphonates to treat osteopenia in children with quadriplegic cerebral palsy:
      a randomized, placebo-controlled clinical trial.
AB  - OBJECTIVE: To evaluate in a double-blind, placebo-controlled clinical trial the
      safety and efficacy of intravenous pamidronate to treat osteopenia in
      nonambulatory children with cerebral palsy. STUDY DESIGN: Six pairs of subjects
      generally matched within each pair for age, sex, and race completed the protocol.
      One member of each pair randomly received plain saline placebo, the other
      pamidronate. Drug/placebo was administered intravenously daily for 3 consecutive
      days, and this 3-day dosing session was repeated at 3-month intervals for one
      year. Evaluations were continued for 6 months after the year of treatment. Bone
      mineral density (BMD) was measured in the distal femur, a site specifically
      developed for use in this contracted population, and the lumbar spine. RESULTS:
      In the metaphyseal region of the distal femur, BMD increased 89% +/- 21% (mean +/
      SEM) over the 18-month study period in the pamidronate group compared with 9% +/
      6% in the control group. Age-normalized z scores increased from -4.0 +/- 0.6 to 
      1.8 +/- 1.0 in the pamidronate group and did not significantly change in the
      control group (-4.2 +/- 0.3 to -4.0 +/- 0.3). The first dosing with pamidronate
      caused a transient drop in serum calcium that was asymptomatic and not treated.
      No other potentially adverse effects were noted. CONCLUSIONS: In this small
      controlled clinical trial, pamidronate was found to be a safe and very effective
      agent to increase BMD in nonambulatory children with cerebral palsy.

PMID- 12410193
TI  - Development of airway function in infancy after preterm delivery.
AB  - OBJECTIVE: To assess airway function at 1 year and compare this with similar
      measurements made shortly after birth in preterm infants without clinical
      neonatal respiratory disease. STUDY DESIGN: Infants born at </=36 weeks'
      gestational age were eligible if they required no neonatal ventilatory support
      and were otherwise healthy. Paired measurements of maximal expiratory flow at
      functional residual capacity (V'(maxFRC)) were obtained ~3 weeks after birth in
      24 preterm infants (gestational age [mean +/- SD], 33.2 +/- 2.2 weeks) and
      repeated at a corrected postnatal age (mean +/- SD) of 57.0 +/- 12.2 weeks.
      V'(maxFRC) values were expressed as Z scores by means of sex-specific prediction
      equations. RESULTS: V'(maxFRC) was within normal range for all infants shortly
      after birth (mean +/- SD Z score: -0.06 +/- 0.92). By 1 year, Z scores had
      reduced significantly [mean (95% CI) 2nd-1st test: -1.94 (-2.27, -1.60)].
      V'(maxFRC )Z scores at 3 weeks were highly correlated with those at 1 year of age
      (Spearman correlation coefficient 0.64). CONCLUSIONS: Airway function during the
      first year shows considerable tracking. Even in the absence of neonatal
      respiratory disease, preterm delivery is associated with altered airway
      development during early infancy.

PMID- 12410194
TI  - A breast-feeding assessment score to evaluate the risk for cessation of breast
      feeding by 7 to 10 days of age.
AB  - OBJECTIVES: To develop a succinct and comprehensive breast-feeding assessment
      score (BAS) to accurately identify infants at risk for early cessation of breast
      feeding before initial hospital discharge. STUDY DESIGN: Mothers who intended to
      breast-feed their infants were solicited from 9 suburban hospitals. Two detailed
      data forms covering 107 items were completed before hospital discharge. A third
      form was completed at 7 to 10 days of age after telephone contact with the
      mother. RESULTS: Cessation of breast-feeding occurred in 113 of 1075 infants
      (10.5%). A multiple logistic regression analysis revealed 8 variables that were
      significant (P <.05) in predicting breast feeding cessation. A BAS was developed
      based on the odds ratios and relative risks of breast-feeding cessation for these
      8 variables. CONCLUSIONS: The BAS was easily and quickly performed before
      hospital discharge for near term and term infants, which accurately predicted the
      risk of breast-feeding cessation within 7 to 10 days of age in the population
      studied.

PMID- 12410195
TI  - An observer-blinded study of 1% permethrin creme rinse with and without
      adjunctive combing in patients with head lice.
AB  - OBJECTIVES: To determine if NIX (Warner Lambert Healthcare, Morris Plains, NJ) 1%
      Permethrin Creme Rinse Lice Treatment (1% PLT) without combing will effectively
      treat >/=95% of patients on day 2 or on day 15; to determine whether combing
      influences efficacy. STUDY DESIGN: A randomized, observer-blinded study enrolled
      95 infested adults and children. All patients were treated with 1% PLT on day 1
      and, if still infested, on day 8. One third of households were randomized to the
      combing group and two thirds to the no-combing group. Efficacy was assessed by:
      (1) visual inspection on days 1, 2, 8, 9, and 15 and, (2) shampooing/straining on
      days 2, 9, and 15. The target efficacy was 95%. RESULTS: In the no-combing group,
      the lice-free rate was 83.1% on day 2 (95% CI, 71.0-91.6), 45.8% on day 8 (before
      second treatment) (95% CI, 32.7-59.2), 77.6% on day 9 (95% CI, 64.7-87.5), and
      78.3% on day 15 (95% CI, 65.8-87.9). Adjunctive combing did not improve efficacy
      on any day. CONCLUSIONS: In this population, 1% PLT was significantly less than
      95% effective and suggests resistance to 1% PLT. The failure of nit removal
      combing by nonprofessional caregivers to improve efficacy demonstrates the
      unreliability of combing as adjunctive treatment in this setting.

PMID- 12410196
TI  - Limited accuracy and reliability of infrared axillary and aural thermometers in a
      pediatric outpatient population.
AB  - OBJECTIVE: To evaluate the accuracy and reliability of infrared axillary and
      aural thermometers in the outpatient setting. STUDY DESIGN: A prospective
      observational study of infrared axillary, aural, and digital rectal temperature
      values from 198 children, aged 3 to 36 months (mean, 1.3 years). RESULTS:
      Sensitivity and specificity of the axillary thermometer for rectal fever were
      63.5% and 92.6%, respectively (diagnostic accuracy, 83.3%); those for the aural
      thermometer were 68.3% and 94.8%, respectively (diagnostic accuracy, 86.4%). For
      all patients, the mean biases of the axillary and aural temperatures were -0.33
      degrees F and -0.24 degrees F, respectively. The biases of both thermometers'
      measurements were significantly correlated with rectal temperature (P <.02);
      thus, as rectal temperature increased, the accuracy of the compared axillary and
      aural temperature decreased. Underestimation of rectal temperature was greatest
      among febrile 1- to 3-year-old children (axillary bias, -1.20; aural bias, 
      0.36). Age was correlated with an axillary temperature bias (P <.01). CONCLUSION:
      Axillary and aural infrared thermometers were comparable, albeit significantly
      different than rectal temperature measurements, particularly as the child's age
      and rectal temperature increased. These thermometers may be useful as noninvasive
      screening methods in outpatient settings for children who are at least 3 months
      old, but rectal values should be used for clinical accuracy.

PMID- 12410197
TI  - Efficacy of zinc-fortified oral rehydration solution in 6- to 35-month-old
      children with acute diarrhea.
AB  - OBJECTIVE: To determine the efficacy of zinc-fortified oral rehydration salts
      solution (ORS) in comparison to ORS without zinc in 6- to 35-month-old urban
      children with acute diarrhea not sick enough to be hospitalized. DESIGN: Double
      blind, randomized, controlled trial. METHODS: Children (n = 1219) with acute
      diarrhea were randomly assigned to one of 3 groups. The first group received a
      zinc syrup (15 mg zinc to 6- to 11-month-old children and 30 mg to 12- to 35
      month-old children), the second group received zinc premixed with ORS (40 mg/L),
      and the control children received ORS only. Households were visited twice weekly
      until recovery. RESULTS: The total number of stools was lower in the zinc-ORS
      group (rate ratio, 0.83; 95% CI, 0.71-0.96), as was the proportion of children
      with watery stools (odds ratio, 0.61; 95% CI, 0.39-0.95), compared with the
      control group; there was no significant effect on diarrheal duration. ORS intake
      and proportion of children with vomiting were not significantly different between
      the zinc-ORS and control groups. The zinc syrup group had lower diarrheal
      duration (relative hazards, 0.89; 95% CI, 0.80-0.99) and total stools (rate
      ratio, 0.73; 95% CI, 0.70-0.77) than control children. CONCLUSIONS: Zinc-ORS was
      moderately efficacious in reducing the severity of acute diarrhea without
      increasing vomiting or reducing ORS intake.

PMID- 12410198
TI  - Grading of hemorrhage in children with idiopathic thrombocytopenic purpura.
AB  - OBJECTIVE: To develop an instrument to allow semiquantitative assessment of
      hemorrhage in children with idiopathic thrombocytopenic purpura (ITP). STUDY
      DESIGN: Bleeding severity was graded on a scale of 0 to 4 in 4 different sites
      (overall, oral, epistaxis, and skin) on the basis of history during the previous
      24 hours and physical examination. RESULTS: Children with ITP (n = 54) were
      assessed on 109 different occasions by multiple observers, including 81
      measurements by one of the authors. Grade of bleeding correlated inversely with
      platelet count. Grade 3 or 4 hemorrhage was infrequently encountered except
      involving the skin, where assessment was difficult. Grade 4 mucosal or internal
      hemorrhage was noted in 7 patients; none had life-threatening or fatal bleeding.
      Interrater agreement in grading of overall and mouth bleeding and epistaxis was
      acceptable. CONCLUSIONS: We conclude that scoring of hemorrhage is possible in
      children with ITP and that the grade of hemorrhage may represent a clinically
      meaningful end point in future studies.

PMID- 12410199
TI  - The metabolic response to intravenous medium-chain triglycerides in infants after
      surgery.
AB  - OBJECTIVE: The aim of this study was to determine if administration of mixed
      medium-chain triglycerides (MCT)/long chain triglycerides (LCT) fat emulsion
      would increase net fat oxidation and if carbohydrate intake would influence net
      fat oxidation. STUDY DESIGN: Stable infants receiving total parenteral nutrition
      were studied after surgery. Respiratory gas exchange was measured by indirect
      calorimetry and urinary nitrogen excretion by the micro-Kjeldahl method.
      Intravenous fat (4 g/kg/day) was given as either pure LCT fat emulsion or 50/50
      MCT/LCT fat emulsion. Carbohydrate intake was either "high" (15 g/kg/day) or
      "low" (10 g/kg/day). Four groups of patients were studied: group 1 = LCT and high
      carbohydrate; group 2 = LCT and low-carbohydrate; group 3 = MCT/LCT and high
      carbohydrate; group 4 = MCT/LCT and low-carbohydrate. RESULTS: At a carbohydrate
      intake of 15 g/kg/day, the calories available from glucose exceeded the measured
      resting energy expenditure (REE), and no differences were seen in either energy
      expenditure or net fat oxidation between patients receiving LCT and MCT/LCT fat
      emulsions. However, at a carbohydrate intake of 10 g/kg/day, when glucose
      calories were less than REE, net fat oxidation was significantly higher in
      patients receiving MCT/LCT (median, 1.94; range, 1.05-2.24 g/kg/day) compared
      with patients receiving LCT (median, 0.60; range, -0.09 to 1.35; P =.03).
      CONCLUSION: Providing that carbohydrate calories do not exceed REE, partial
      replacement of LCT by MCT in intravenous fat emulsions can increase net fat
      oxidation in infants after surgery.

PMID- 12410200
TI  - Clinical and molecular features of congenital disorder of glycosylation in
      patients with type 1 sialotransferrin pattern and diverse ethnic origins.
AB  - OBJECTIVE: To increase awareness of congenital disorders of glycosylation (CDG),
      we report the features of patients with a variety of clinical presentations
      ranging from mild hypotonia and strabismus to severe neurologic impairment. STUDY
      DESIGN: Nine North American patients with CDG type I and different ethnic origins
      were studied. RESULTS: All patients had transferrin isoelectric focusing studies
      with a type 1 sialotransferrin pattern. Molecular analysis showed the previously
      described R141H, V231M, and T237M PMM2 mutations in four patients as well as 3
      rare mutations (DeltaC389, L104V, and IVS1 -1 G-->A) in the PMM2 gene in two
      Asian patients. CONCLUSIONS: The clinical features of these patients with diverse
      ethnic backgrounds confirm the variable course of CDG type I. Screening for CDG
      should be considered in children with relatively mild neurologic impairment,
      especially if they have suggestive findings such as cerebellar hypoplasia and
      abnormal fat distribution.

PMID- 12410201
TI  - Macronutrient intake in anorexia nervosa: The National Heart, Lung, and Blood
      Institute Growth and Health Study.
AB  - OBJECTIVE: To compare the macronutrient intake of females with or without a
      history of anorexia nervosa (AN) at three times: two years and one year before
      the onset of AN, and during the first year of the illness. STUDY DESIGN:
      Prospective cohort study with 3-day food intake records collected over 10 years.
      Subjects were 154 white females (aged 9 or 10 years at study entry), of whom 14
      had AN and 140 were healthy females matched for age at study entry and parental
      education. RESULTS: Compared with the healthy girls, girls with AN reported
      significantly lower total energy intake and fat intake during the first year of
      the illness; the lower total energy intake was evident already at the 1-year (but
      not the 2-year) pre-onset assessment. CONCLUSIONS: To identify AN early on,
      health practitioners caring for adolescent girls should inquire about food intake
      and reluctance to eat certain foods, especially those containing fat.

PMID- 12410202
TI  - Early brain atrophy in persistent hyperinsulinemic hypoglycemia of infancy.
AB  - We present two siblings with persistent hyperinsulinemic hypoglycemia of infancy,
      accelerated intrauterine growth and early neonatal brain atrophy. Fetal plasma
      glucose and insulin levels in the second sibling revealed normoglycemia despite
      hyperinsulinemia. The absence of intrauterine hypoglycemia suggests that the
      brain damage is not secondary to hypoglycemia and other etiologies must be
      considered.

PMID- 12410203
TI  - Choroid plexus arteriovenous malformation presenting with intraventricular
      hemorrhage.
AB  - Intraventricular hemorrhage (IVH) uncommonly occurs in an otherwise healthy term
      neonate. We report a case of IVH in a term infant that was the result of an
      angiographically demonstrated arteriovenous malformation (AVM) despite the infant
      having a cranial ultrasonogram and magnetic resonance angiogram, which did not
      demonstrate the AVM.

PMID- 12410204
TI  - Application of the fetal alcohol syndrome facial photographic screening tool in a
      foster care population.
AB  - We determined the prevalence of fetal alcohol syndrome (FAS) in a foster care
      population and evaluated the performance of the FAS Facial Photographic Screening
      Tool. All children enrolled in a Washington State Foster Care Passport Program
      were screened for three conditions: (1) the FAS facial phenotype from a
      photograph, (2) evidence of brain damage with prenatal alcohol exposure from
      their Health and Education passport, and/or (3) other syndromes identifiable from
      a facial photograph. Screen-positives received diagnostic evaluations at a FAS
      Diagnostic and Prevention Network clinic. The prevalence of FAS in this foster
      care population was 10 to 15/1000, or 10 to 15 times greater than in the general
      population. The screening tool performed with 100% sensitivity, 99.8%
      specificity, 85.7% predictive value positive, and 100% predictive value negative.
      We conclude that the foster care population is a high-risk population for FAS.
      The screening tool performed with very high accuracy and could be used to track
      FAS prevalence over time in foster care to accurately assess the effectiveness of
      primary prevention efforts.

PMID- 12410205
TI  - The interval between menarche and age of first sexual intercourse as a risk
      factor for subsequent HPV infection in adolescent and young adult women.
AB  - We sought to determine whether the interval between menarche and age of first
      sexual intercourse is associated with subsequent human papilloma virus (HPV)
      infection and if so, whether the association is independent of the age of first
      sexual intercourse. Female university students completed a survey and were
      screened for cervicovaginal HPV infection. HPV-positive subjects were matched to
      HPV-negative subjects (n = 504). Mean subject age was 20.4 +/- 2.1 years, age of
      first sexual intercourse 16.7 +/- 1.8 years, and interval 4.4 +/- 2.0 years. The
      interval was associated with HPV infection, but the association became
      nonsignificant in univariate stratified analyses and multivariate models
      estimating the association between the interval and HPV infection. A short
      interval is associated with HPV infection, but the association is not independent
      of age of first sexual intercourse. Age of first sexual intercourse should be
      considered an important and identifiable risk factor for subsequent HPV infection
      in research and clinical settings.

PMID- 12410206
TI  - The diagnostic evaluation of children with cyclic vomiting: a cost-effectiveness
      assessment.
AB  - Because patients with cyclic vomiting often (82%) have a family history of
      migraines and often (60%) respond to antimigraine therapy, we investigated
      whether an initial therapeutic trial could precede diagnostic testing. We used a
      decision analysis program to compare the cost and benefit of three initial
      treatment strategies. The costs of the three strategies were extensive diagnostic
      evaluation, $3020; empiric treatment alone, $1830, and upper GI series with small
      bowel follow-through (UGI-SBFT) plus empiric treatment, $1600, respectively. When
      compared with the extensive evaluation strategy, initial antimigraine treatment
      avoided 65% of the esophagogastroduodenoscopys. On the basis of this decision
      analysis, a UGI-SBFT plus empiric migraine therapy was the most cost-effective
      initial strategy to treat cyclic vomiting syndrome. The cost of complications of
      a missed malrotation with volvulus was higher than that of adding a UGI-SBFT to
      each evaluation.

PMID- 12410207
TI  - Cardiolipin deficiency in X-linked cardioskeletal myopathy and neutropenia (Barth
      syndrome, MIM 302060): a study in cultured skin fibroblasts.
AB  - We determined cardiolipin concentrations in cultured skin fibroblasts of 5
      patients with X-linked cardioskeletal myopathy and neutropenia (Barth syndrome,
      MIM 302060) and in two groups of control patients. High-performance liquid
      chromatography-electrospray mass spectrometry was used to quantify total
      cardiolipin and subclasses of cardiolipin molecular species in cultured skin
      fibroblasts. Total cardiolipin and cardiolipin subclasses were decreased in
      patients with Barth syndrome as compared with normal control patients and disease
      control patients. Patients with Barth syndrome have a specific decrease of
      various cardiolipin molecular species, foremost tetralineoyl-cardiolipin.
      Therefore the analysis of cardiolipin in fibroblasts offers a specific
      biochemical approach to detect this disorder.

PMID- 12410208
TI  - Lethal neonatal and severe late infantile forms of carnitine palmitoyltransferase
      II deficiency associated with compound heterozygosity for different protein
      truncation mutations.
AB  - We describe a lethal neonatal form of carnitine palmitoyltransferase II (CPT II)
      deficiency with compound heterozygosity for 2 truncation mutations (Q413fs and
      109AGC --> GCAGC). A new phenotype for a severe late infantile form of CPT II
      deficiency with hypoglycemia is associated with compound heterozygosity for the
      severe Q413fs mutation and a mild point mutation (P50H).

PMID- 12410209
TI  - Umbilical venous line displacement as a consequence of abdominal girth variation.

PMID- 12410210
TI  - Aplastic anemia in Nijmegen breakage syndrome.

PMID- 12410211
TI  - Stroke prevention trial in sickle cell anemia: comments on effects of chronic
      transfusion on pain.

PMID- 12410213
TI  - Study of an outbreak of Enterobacter cloacae sepsis in a neonatal intensive care
      unit: the application of epidemiologic chromosome profiling by pulsed-field gel
      electrophoresis.
AB  - OBJECTIVE: From October 1996 to March 1997, a cluster of 11 cases of neonatal
      sepsis caused by Enterobacter cloacae with similar antimicrobial susceptibility
      patterns occurred in a neonatal intensive care unit. This outbreak prompted an
      investigation. METHOD: Twelve isolates obtained from 6 neonatal patients who
      developed E cloacae sepsis during the outbreak were analyzed. Four E cloacae
      isolates from 2 preterm neonates without E cloacae infection on the same ward,
      and 1 isolate from the hands of a nurse, were also examined. No E cloacae were
      isolated from the environment. Bacterial DNA digested with XbaI or NotI was
      analyzed with pulsed-field gel electrophoresis. RESULT: Three distinct banding
      patterns were identified by pulsed-field gel electrophoresis. Of the 6 preterm
      infants with sepsis, strain I was identified in 1, strain II in 2, a mixed
      infection of strains I and II in 2, and strain III was found in only 1 infant. An
      isolate from the hands of a nurse was identified as strain II, as were the 4
      isolates from the 2 preterm neonates without E cloacae infection. Thus, this
      outbreak of sepsis was caused by 2 genotypes of E cloacae. CONCLUSION: This study
      demonstrates that pulsed-field gel electrophoresis with restriction enzyme
      digestion is a valuable tool for genetic characterization of multidrug-resistant
      E cloacae strains during outbreaks.

PMID- 12410214
TI  - Underlying characteristics of patients harboring highly resistant Acinetobacter
      baumannii.
AB  - BACKGROUND: Highly resistant (HR) Acinetobacter baumannii (AB) are frequently
      hospital-acquired and may be important causes of severe nosocomial infections.
      OBJECTIVE: Determine risk factors associated with such colonization/infection.
      METHOD: Retrospective review in 2000 of all AB isolates from sterile (blood,
      cerebrospinal fluid [CSF]) and nonsterile (respiratory, urine, and miscellaneous)
      sites. HR was defined as resistance to amikacin and/or imipenem and/or ampicillin
      sulbactam. Isolates were analyzed as representing infection or colonization. A
      database including prior hospitalization, prior antibiotic use, nursing home
      residency, and procedures undergone was compiled. RESULTS: One hundred twenty-two
      cases of AB were identified. Eighty-four met the definition of HR; 6 (4.9%) were
      completely resistant to all antibiotics. Four (4.7%) isolates were from sterile
      body sites (3 blood, 1 CSF); 43 (51.2%) were from respiratory sites; 20 (23.8%)
      were from urinary sites; and 17 (20.2%) were from "other" sites. Only 4 (20%) of
      the urinary, 6 (35.2%) of the miscellaneous, and 23 (53.4%) of the respiratory
      isolates were deemed true pathogens; all blood/CSF isolates were considered
      pathogens. Associated risk factors included prior antibiotic usage (71%); prior
      hospitalization (24%); prior nursing home residency (34%); ventilator use (77%);
      tracheostomy placement (56%); and Foley catheterization (85%). Twenty-seven (63%)
      of 43 respiratory, 8 (40%) of 20 urinary, and 6 (35%) of 17 "other" body isolates
      were treated. Outcome was not statistically significant in treated versus
      untreated patients. All patients with CSF/blood isolates underwent successful
      microbiologic eradication with 50% survival. The overall mortality rate was 10%.
      CONCLUSION: Antibiotics, Foley catheters, and tracheostomy/ventilator usage were
      strongly associated with AB isolation. Prior hospitalization and nursing home
      residency were less common risk factors. Outcome was not different in treated
      versus untreated patients, indicating colonization is a marker of severe illness
      but is not necessarily causal.

PMID- 12410215
TI  - Enteral vancomycin to control methicillin-resistant Staphylococcus aureus
      outbreak in mechanically ventilated patients.
AB  - BACKGROUND: Screening for and treating gut carriage of methicillin-resistant
      Staphylococcus aureus (MRSA) may control transmission and subsequent endemicity
      of MRSA. OBJECTIVE: Enteral vancomycin was evaluated as a measure to control an
      outbreak of MRSA infection in the intensive care unit (ICU). METHODS: During the
      8-month study of sequential design, 176 patients were admitted, 65 (37%) of whom
      required a minimum of 3 days of ventilation. Forty-four patients were studied in
      the first 5 months, during which traditional measures were reinforced (control
      group). During the following 3 months, 13 of 21 patients developed MRSA carriage
      and received 2 g/day of enteral vancomycin, with high standards of hygiene
      maintained (treatment group). RESULTS: Thirty-three MRSA infections occurred in
      22 patients (50%) in the control group, whereas 2 patients (9.5%) had 2 MRSA
      infections in the treatment group (P <.05 for carriage, infection rates, and
      episodes). Of the 33 MRSA infections in the control group, 27 were due to MRSA
      acquired in the ICU, whereas the 2 infections in the treatment group were primary
      endogenous (ie, caused by MRSA present in the patient's admission flora). The
      probability of developing an MRSA infection was reduced in patients receiving
      enteral vancomycin compared with patients in the control group (odds ratio, 0.37;
      95% CI, 0.24-0.58). Enteral vancomycin significantly reduced the level of MRSA
      carriage; the mean carriage index was 1.01 in the control group versus 0.58 in
      the test group (P <.05). Neither vancomycin-resistant enterococci nor vancomycin
      intermediate Staphylococcus aureus were isolated from either surveillance or
      diagnostic samples. CONCLUSIONS: The eradication of MRSA gut carriage by enteral
      vancomycin in a small subset of ICU patients was effective in the control of an
      MRSA outbreak.

PMID- 12410216
TI  - Epidemiology of vancomycin-resistant Enterococcus faecium under a selective
      isolation policy at an urban county hospital.
AB  - BACKGROUND: We report our experience in a county hospital with the use of
      selective contact isolation for patients with vancomycin-resistant Enterococcus
      faecium (VREF). About 12% of patients with VREF are isolated for reasons such as
      draining wounds and uncontrolled diarrhea. METHODS: Passive surveillance
      identified all inpatients (181) from 1995 to 1999 with cultures positive for
      VREF. Data were collected via electronic databases and from prospectively
      maintained infection control records. Isolates were typed with use of pulsed
      field gel electrophoresis. RESULTS: Nearly all patients (175/181) with VREF had
      been admitted at least 48 hours or had a history of previous hospitalization.
      Most patients (69%) had urine cultures positive for VREF without blood cultures
      positive for the organism. Only 12 of 127 (9.%) patients with complete data had
      VREF infection on the basis of receiving treatment and/or having more than 1
      blood culture positive for VREF. After VREF became endemic, statistically
      significant increased prevalence was not detected via surveillance of clinical
      cultures nor sequential point-prevalence studies. Two major genotypes carrying
      vanB resistance genes were identified and persisted throughout the period
      studied. VREF persisted in individual patients up to 46 months. CONCLUSIONS: The
      number of VREF infections in this facility has been low, despite appreciable
      colonization, for an extended period during which selective isolation was used.

PMID- 12410217
TI  - Direct costs associated with a nosocomial outbreak of adenoviral conjunctivitis
      infection in a long-term care institution.
AB  - BACKGROUND: In October 2000, 41 people were infected during an outbreak of
      adenoviral keratoconjunctivitis. Such nosocomial outbreaks are frequently
      reported in long-term care institutions, even though simple measures to prevent
      or limit such occurrences are well documented. This study describes the
      significant direct costs incurred as a result of this nosocomial outbreak that
      involved patients and staff. METHODS: The costs measured in this study were
      grouped into the following 4 categories: medical, investigative, preventive, and
      lost productivity. Information about costs incurred by the hospital was gathered
      from a number of sources. RESULTS: The outbreak cost the hospital US $29,527
      ($1085 for medical costs, $8210 for investigative costs, $3048 for preventive
      measures, and $17,184 for lost productivity). CONCLUSION: This study demonstrates
      the substantial expense incurred by 1 hospital as a result of an outbreak of a
      preventable disease. The measures necessary to prevent such a costly outbreak are
      simple and, therefore, cost-effective.

PMID- 12410218
TI  - Analysis of antimicrobial resistance among gram-negative bacilli and
      antimicrobial use in intensive care unit patients for 5 years in a Veterans
      Affairs medical center.
AB  - BACKGROUND: Gram-negative bacilli antimicrobial resistance remains a significant
      problem for patients in the intensive care unit (ICU). Patterns of antimicrobial
      use may be a contributing factor. METHODS: Gram-negative bacilli from ICU
      patients of a Veterans Affairs (VA) medical center were tested to determine in
      vitro antimicrobial susceptibility (205 isolates in 1995 and 209 in 1999).
      Antimicrobial use was calculated from 1995 through 1999. RESULTS: For Pseudomonas
      aeruginosa, significant declines in susceptibility to ciprofloxacin (medical ICU
      [MICU] individually and all units) and aztreonam (all units) were noted. For gram
      negative bacilli that was non-P aeruginosa, significant increases in
      susceptibility to ceftazidime (MICU, surgical ICU, and all units), gentamicin
      (all units), and ticarcillin/clavulanate (MICU) were noted. The most notable
      trends in antimicrobial usage were sharp increases in fluoroquinolone use in the
      MICU and surgical ICU and substantial decreases in the use of third-generation
      cephalosporins, monobactams, and aminoglycosides. In each instance of significant
      change in the susceptibility of a group of organisms to an antibiotic, there was
      a corresponding inverse change in the use of the antibiotic and/or its
      antimicrobial category (except for aztreonam). CONCLUSIONS: Significant changes
      in antimicrobial use may affect certain gram-negative bacilli antimicrobial
      susceptibilities in ICUs.

PMID- 12410219
TI  - Postdischarge surveillance of surgical site infections: a multi-method approach
      to data collection.
AB  - BACKGROUND: Surveillance of surgical site infections (SSIs) is an important
      clinical indicator of quality patient care, yet an increasing number of SSIs
      manifest after discharge and are not detected through standard surveillance
      methods. AIM: This study evaluated a multimethod approach to postdischarge
      surveillance of SSIs with use of a cesarean section procedure as a case study.
      METHOD: A postdischarge questionnaire was sent on day 30 to women (n = 277) who
      had undergone cesarean section. A follow-up telephone interview was conducted if
      the questionnaire had not been returned within 2 weeks, a diagnosis of infection
      could not be clearly determined from the responses given, or to confirm the
      diagnosis of infection. If follow-up could not be made, a chart audit was
      undertaken. RESULTS: A total response rate of 89% (247/277) was obtained. Twenty
      one women with SSI were identified through questionnaire responses. Additional
      strategies of telephone follow-up and chart review of patients with possible
      infection and of nonresponders identified more postdischarge infections (33%,
      14/42). The overall infection rate was 17% (42/247) compared with 2.8% (7/247) at
      discharge. CONCLUSION: Postdischarge surveillance approaches need to achieve the
      best possible response rate, reflect follow-up health care delivery patterns, be
      cost-effective, gather data from both patients and treating physicians, and use
      standard definitions to facilitate benchmarking with other health care facilities
      and surveillance systems. The inclusion of contacting nonresponders in any method
      of postdischarge surveillance is recommended to determine the most accurate
      infection rate.

PMID- 12410220
TI  - Pseudomonas aeruginosa infections in a neonatal intensive care unit.
AB  - This report describes a cluster of nosocomial infections with Pseudomonas
      aeruginosa in a neonatal intensive care nursery. All 5 cases of P aeruginosa
      infection were clustered in September 1999. Aggressive infection control measures
      were instituted, including installation of a user-friendly handwashing soap and
      environmental cleaning. On the basis of the finding of persistent dirty
      equipment, a new full-time position was created that was dedicated to equipment
      cleaning. These measures were effective in eliminating the cluster. The nursery
      has remained free of P aeruginosa infection for more than 2 years, attesting to
      the success of our program.

PMID- 12410221
TI  - Compliance with methicillin-resistant Staphylococcus aureus precautions in a
      teaching hospital.
AB  - BACKGROUND: Nosocomial transmission of methicillin-resistant Staphylococcus
      aureus (MRSA) occurs primarily through the contaminated hands of health care
      workers who do not follow appropriate precautionary measures. This study
      investigates various factors associated with compliance with MRSA precautions
      during routine patient care. METHODS: This observational study took place at a
      teaching hospital in Montreal, Canada. Nurses (184), physicians (41),
      occupational therapists and physical therapists (19), orderlies (102),
      housekeeping personnel (28), other health care workers (65), and visitors (49)
      were anonymously observed. Compliance with MRSA precautions was measured
      according to appropriate use of gowns and gloves as well as hand hygiene.
      RESULTS: In 488 observations, the average compliance was 28%. In multivariate
      analysis, in comparison with nurses, compliance was lower among physicians (odds
      ratio [OR], 0.35; 95% confidence interval [CI], 0.14 to 0.86), orderlies (OR,
      0.37; CI, 0.2-0.69), visitors (OR, 0.2; CI, 0.08-0.49), housekeeping personnel
      (OR, 0.06; CI, 0.01-0.47), and other types of health care workers (OR, 0.39; CI,
      0.18-0.85), but was higher among occupational and physical therapists (OR, 11.7;
      CI, 2.55-53.8). CONCLUSIONS: Compliance with MRSA precautions is low. The only
      significant predictor of MRSA compliance was the professional category of the
      health care worker.

PMID- 12410222
TI  - Process improvement plan for the reduction of sternal surgical site infections
      among patients undergoing coronary artery bypass graft surgery.
AB  - In an attempt to reduce sternal infections caused by Staphylococcus aureus, a
      protocol was introduced that included the administration of intranasal mupirocin
      calcium 2% before surgery to patients undergoing cardiothoracic surgery.
      Surveillance data indicated a 55% reduction in the rate of deep sternal wound
      infections caused by S aureus and superficial sternal wound infections have
      declined from 25 to 6 since the adoption of the protocol. At the study
      institution, this protocol is now an ongoing process to reduce the incidence of
      sternal infections caused by S aureus among cardiothoracic patients.

PMID- 12410225
TI  - Deciphering tsetse's secret partner.

PMID- 12410226
TI  - Replication timing and metazoan evolution.

PMID- 12410227
TI  - Shining a light on photolyases.

PMID- 12410228
TI  - Pathways of neuronal migration.

PMID- 12410229
TI  - Chromosomal gradient of histone acetylation established by Sas2p and Sir2p
      functions as a shield against gene silencing.
AB  - Genes located in chromosomal regions near telomeres are transcriptionally silent,
      whereas those located in regions away from telomeres are not. Here we show that
      there is a gradient of acetylation of histone H4 at lysine 16 (H4-Lys16) along a
      yeast chromosome; this gradient ranges from a hypoacetylated state in regions
      near the telomere to a hyperacetylated state in more distant regions. The
      hyperacetylation is regulated by Sas2p, a member of the MYST-type family of
      histone acetylases, whereas hypoacetylation is under the control of Sir2p, a
      histone deacetylase. Loss of hyperacetylation is accompanied by an increase in
      localization of the telomere protein Sir3p and the inactivation of gene
      expression in telomere-distal regions. Thus, the Sas2p and Sir2p function in
      concert to regulate transcription in yeast, by acetylating and deacetylating H4
      Lys16 in a mechanism that may be common to all eukaryotes.

PMID- 12410230
TI  - Regional loss of imprinting and growth deficiency in mice with a targeted
      deletion of KvDMR1.
AB  - Genomic imprinting is an epigenetic modification that results in expression from
      only one of the two parental copies of a gene. Differences in methylation between
      the two parental chromosomes are often observed at or near imprinted genes.
      Beckwith-Wiedemann syndrome (BWS), which predisposes to cancer and excessive
      growth, results from a disruption of imprinted gene expression in chromosome band
      11p15.5. One third of individuals with BWS lose maternal-specific methylation at
      KvDMR1, a putative imprinting control region within intron 10 of the KCNQ1 gene,
      and it has been proposed that this epimutation results in aberrant imprinting
      and, consequently, BWS1, 2. Here we show that paternal inheritance of a deletion
      of KvDMR1 results in the de-repression in cis of six genes, including Cdkn1c,
      which encodes cyclin-dependent kinase inhibitor 1C. Furthermore, fetuses and
      adult mice that inherited the deletion from their fathers were 20-25% smaller
      than their wildtype littermates. By contrast, maternal inheritance of this
      deletion had no effect on imprinted gene expression or growth. Thus, the
      unmethylated paternal KvDMR1 allele regulates imprinted expression by silencing
      genes on the paternal chromosome. These findings support the hypothesis that loss
      of methylation in BWS patients activates the repressive function of KvDMR1 on the
      maternal chromosome, resulting in abnormal silencing of CDKN1C and the
      development of BWS.

PMID- 12410231
TI  - Predicting three-dimensional genome structure from transcriptional activity.

PMID- 12410232
TI  - Medical applications of haplotype-based SNP maps: learning to walk before we run.

PMID- 12410233
TI  - Detection of regulatory variation in mouse genes.
AB  - Functional polymorphism in genes can be classified as coding variation, altering
      the amino-acid sequence of the encoded protein, or regulatory variation,
      affecting the level or pattern of expression of the gene. Coding variation can be
      recognized directly from DNA sequence, and consequently its frequency and
      characteristics have been extensively described. By contrast, virtually nothing
      is known about the extent to which gene regulation varies in populations. Yet it
      is likely that regulatory variants are important in modulating gene function:
      alterations in gene regulation have been proposed to influence disease
      susceptibility and to have been the primary substrate for the evolution of
      species. Here, we report a systematic study to assess the extent of cis-acting
      regulatory variation in 69 genes across four inbred mouse strains. We find that
      at least four of these genes show allelic differences in expression level of 1.5
      fold or greater, and that some of these differences are tissue specific. The
      results show that the impact of regulatory variants can be detected at a
      significant frequency in a genomic survey and suggest that such variation may
      have important consequences for organismal phenotype and evolution. The results
      indicate that larger-scale surveys in both mouse and human could identify a
      substantial number of genes with common regulatory variation.

PMID- 12410236
TI  - Bubble babies and bathwater.

PMID- 12410237
TI  - FDA appointee faces angry, demoralized staff.

PMID- 12410238
TI  - Biotechs hold their own in shifting industry.

PMID- 12410239
TI  - Angiogenesis inhibitors suffer new setback.

PMID- 12410240
TI  - US panel advises resumption of gene trials.

PMID- 12410241
TI  - Poor crop management plagues Bt cotton experiment in India.

PMID- 12410243
TI  - From precautionary principle to risk-risk analysis.

PMID- 12410244
TI  - The dialogue between precaution and risk.

PMID- 12410245
TI  - Is your biotech giving away the store?

PMID- 12410246
TI  - A turning point in Johannesburg?

PMID- 12410247
TI  - Labeling should be mandatory.

PMID- 12410248
TI  - An open-source oligomicroarray standard for human and mouse.

PMID- 12410249
TI  - Value drivers in licensing deals.

PMID- 12410250
TI  - Neural stem cells, scaffolds, and chaperones.

PMID- 12410251
TI  - Shewanella--the environmentally versatile genome.

PMID- 12410252
TI  - Pumping out the arsenic.

PMID- 12410253
TI  - Celebrating diversity and mimicking maturation.

PMID- 12410254
TI  - A parasite genome sheds light on an old enemy.

PMID- 12410257
TI  - Intellectual property protection for plant innovation: unresolved issues after
      J.E.M. v. Pioneer.

PMID- 12410261
TI  - White coats "off the peg".

PMID- 12410262
TI  - Job insecurity.

PMID- 12410263
TI  - From scepticism to acceptance.

PMID- 12410264
TI  - A clash of two cultures.

PMID- 12410265
TI  - Breaking down the barriers.

PMID- 12410266
TI  - Suspicions intensify over elusive European Academy of Sciences.

PMID- 12410267
TI  - Tribes query motives of knowledge databases.

PMID- 12410268
TI  - Low stocks prompt calls for North Atlantic fishing ban.

PMID- 12410269
TI  - Mosquito researchers deny plotting secret biowarfare test.

PMID- 12410270
TI  - Penicillin paper restores Fleming's healthy reputation.

PMID- 12410271
TI  - Biologists join drive to turn down the lights.

PMID- 12410272
TI  - Japan plans web of English journals.

PMID- 12410273
TI  - MIT gets plugged in for global data archive.

PMID- 12410274
TI  - Developing nations take initiative on greenhouse gases.

PMID- 12410276
TI  - Neuroscience: addicted.

PMID- 12410277
TI  - Japanese universities: independence days.

PMID- 12410278
TI  - A list of published papers is no measure of value.

PMID- 12410279
TI  - Realistic attitude takes postdocs a long way.

PMID- 12410280
TI  - Patents limit medical potential of sequencing.

PMID- 12410281
TI  - Culture gap: physics still seeks its unifying theory.

PMID- 12410282
TI  - Culture gap: in biology, what works, continues.

PMID- 12410283
TI  - Science, conservation and fox-hunting.

PMID- 12410289
TI  - Burnt into memory.

PMID- 12410290
TI  - Animal behaviour: when it pays to waggle.

PMID- 12410291
TI  - Astronomy: relic of the dawn of time.

PMID- 12410293
TI  - Chemistry: only skin-deep.

PMID- 12410292
TI  - Materials science: nanomaterial advantage.

PMID- 12410294
TI  - Molecular biology: RNA gets a grip on translation.

PMID- 12410295
TI  - Environment: trash trends.

PMID- 12410296
TI  - Neurobiology: social eating for stress.

PMID- 12410298
TI  - Herbicides: feminization of male frogs in the wild.

PMID- 12410299
TI  - Brain development: memory enhancement in early childhood.

PMID- 12410300
TI  - Chemical mimicry: male ants disguised by the queen's bouquet.

PMID- 12410301
TI  - Palaeoclimatology: tropical temperatures in greenhouse episodes.

PMID- 12410304
TI  - A stellar relic from the early Milky Way.
AB  - The chemical composition of the most metal-deficient stars largely reflects the
      composition of the gas from which they formed. These old stars provide crucial
      clues to the star formation history and the synthesis of chemical elements in the
      early Universe. They are the local relics of epochs otherwise observable only at
      very high redshifts; if totally metal-free ('population III') stars could be
      found, this would allow the direct study of the pristine gas from the Big Bang.
      Earlier searches for such stars found none with an iron abundance less than
      1/10,000 that of the Sun, leading to the suggestion that low-mass stars could
      form from clouds above a critical iron abundance. Here we report the discovery of
      a low-mass star with an iron abundance as low as 1/200,000 of the solar value.
      This discovery suggests that population III stars could still exist--that is,
      that the first generation of stars also contained long-lived low-mass objects.
      The previous failure to find them may be an observational selection effect.

PMID- 12410303
TI  - Social feeding in Caenorhabditis elegans is induced by neurons that detect
      aversive stimuli.
AB  - Natural Caenorhabditis elegans isolates exhibit either social or solitary feeding
      on bacteria. We show here that social feeding is induced by nociceptive neurons
      that detect adverse or stressful conditions. Ablation of the nociceptive neurons
      ASH and ADL transforms social animals into solitary feeders. Social feeding is
      probably due to the sensation of noxious chemicals by ASH and ADL neurons; it
      requires the genes ocr-2 and osm-9, which encode TRP-related transduction
      channels, and odr-4 and odr-8, which are required to localize sensory
      chemoreceptors to cilia. Other sensory neurons may suppress social feeding, as
      social feeding in ocr-2 and odr-4 mutants is restored by mutations in osm-3, a
      gene required for the development of 26 ciliated sensory neurons. Our data
      suggest a model for regulation of social feeding by opposing sensory inputs:
      aversive inputs to nociceptive neurons promote social feeding, whereas
      antagonistic inputs from neurons that express osm-3 inhibit aggregation.

PMID- 12410305
TI  - Measurement of the conductance of a hydrogen molecule.
AB  - Recent years have shown steady progress towards molecular electronics, in which
      molecules form basic components such as switches, diodes and electronic mixers.
      Often, a scanning tunnelling microscope is used to address an individual
      molecule, although this arrangement does not provide long-term stability.
      Therefore, metal-molecule-metal links using break-junction devices have also been
      explored; however, it is difficult to establish unambiguously that a single
      molecule forms the contact. Here we show that a single hydrogen molecule can form
      a stable bridge between platinum electrodes. In contrast to results for organic
      molecules, the bridge has a nearly perfect conductance of one quantum unit,
      carried by a single channel. The hydrogen bridge represents a simple test system
      in which to understand fundamental transport properties of single-molecule
      devices.

PMID- 12410306
TI  - High tensile ductility in a nanostructured metal.
AB  - Nanocrystalline metals--with grain sizes of less than 100 nm--have strengths
      exceeding those of coarse-grained and even alloyed metals, and are thus expected
      to have many applications. For example, pure nanocrystalline Cu (refs 1-7) has a
      yield strength in excess of 400 MPa, which is six times higher than that of
      coarse-grained Cu. But nanocrystalline materials often exhibit low tensile
      ductility at room temperature, which limits their practical utility. The
      elongation to failure is typically less than a few per cent; the regime of
      uniform deformation is even smaller. Here we describe a thermomechanical
      treatment of Cu that results in a bimodal grain size distribution, with
      micrometre-sized grains embedded inside a matrix of nanocrystalline and ultrafine
      (<300 nm) grains. The matrix grains impart high strength, as expected from an
      extrapolation of the Hall-Petch relationship. Meanwhile, the inhomogeneous
      microstructure induces strain hardening mechanisms that stabilize the tensile
      deformation, leading to a high tensile ductility--65% elongation to failure, and
      30% uniform elongation. We expect that these results will have implications in
      the development of tough nanostructured metals for forming operations and high
      performance structural applications including microelectromechanical and
      biomedical systems.

PMID- 12410307
TI  - Variable effects of nitrogen additions on the stability and turnover of soil
      carbon.
AB  - Soils contain the largest near-surface reservoir of terrestrial carbon and so
      knowledge of the factors controlling soil carbon storage and turnover is
      essential for understanding the changing global carbon cycle. The influence of
      climate on decomposition of soil carbon has been well documented, but there
      remains considerable uncertainty in the potential response of soil carbon
      dynamics to the rapid global increase in reactive nitrogen (coming largely from
      agricultural fertilizers and fossil fuel combustion). Here, using 14C, 13C and
      compound-specific analyses of soil carbon from long-term nitrogen fertilization
      plots, we show that nitrogen additions significantly accelerate decomposition of
      light soil carbon fractions (with decadal turnover times) while further
      stabilizing soil carbon compounds in heavier, mineral-associated fractions (with
      multidecadal to century lifetimes). Despite these changes in the dynamics of
      different soil pools, we observed no significant changes in bulk soil carbon,
      highlighting a limitation inherent to the still widely used single-pool approach
      to investigating soil carbon responses to changing environmental conditions. It
      remains to be seen if the effects observed here-caused by relatively high, short
      term fertilizer additions-are similar to those arising from lower, long-term
      additions of nitrogen to natural ecosystems from atmospheric deposition, but our
      results suggest nonetheless that current models of terrestrial carbon cycling do
      not contain the mechanisms needed to capture the complex relationship between
      nitrogen availability and soil carbon storage.

PMID- 12410308
TI  - Quantifying nitrogen-fixation in feather moss carpets of boreal forests.
AB  - Biological nitrogen (N) fixation is the primary source of N within natural
      ecosystems, yet the origin of boreal forest N has remained elusive. The boreal
      forests of Eurasia and North America lack any significant, widespread symbiotic N
      fixing plants. With the exception of scattered stands of alder in early primary
      successional forests, N-fixation in boreal forests is considered to be extremely
      limited. Nitrogen-fixation in northern European boreal forests has been estimated
      at only 0.5 kg N ha(-1) yr(-1); however, organic N is accumulated in these
      ecosystems at a rate of 3 kg N ha(-1) yr(-1) (ref. 8). Our limited understanding
      of the origin of boreal N is unacceptable given the extent of the boreal forest
      region, but predictable given our imperfect knowledge of N-fixation. Herein we
      report on a N-fixing symbiosis between a cyanobacterium (Nostoc sp.) and the
      ubiquitous feather moss, Pleurozium schreberi (Bird) Mitt. that alone fixes
      between 1.5 and 2.0 kg N ha(-1) yr(-1) in mid- to late-successional forests of
      northern Scandinavia and Finland. Previous efforts have probably underestimated N
      fixation potential in boreal forests.

PMID- 12410309
TI  - Honeybee colonies achieve fitness through dancing.
AB  - The honeybee dance language, in which foragers perform dances containing
      information about the distance and direction to food sources, is the
      quintessential example of symbolic communication in non-primates. The dance
      language has been the subject of controversy, and of extensive research into the
      mechanisms of acquiring, decoding and evaluating the information in the dance.
      The dance language has been hypothesized, but not shown, to increase colony food
      collection. Here we show that colonies with disoriented dances (lacking direction
      information) recruit less effectively to syrup feeders than do colonies with
      oriented dances. For colonies foraging at natural sources, the direction
      information sometimes increases food collected, but at other times it makes no
      difference. The food-location information in the dance is presumably important
      when food sources are hard to find, variable in richness and ephemeral.
      Recruitment based simply on arousal of foragers and communication of floral
      odour, as occurs in honeybees, bumble bees and some stingless bees, can be
      equally effective under other circumstances. Clarifying the condition-dependent
      payoffs of the dance language provides new insight into its function in honeybee
      ecology.

PMID- 12410310
TI  - Scotopic colour vision in nocturnal hawkmoths.
AB  - Humans are colour-blind at night, and it has been assumed that this is true of
      all animals. But colour vision is as useful for discriminating objects at night
      as it is during the day. Here we show, through behavioural experiments, that the
      nocturnal hawkmoth Deilephila elpenor uses colour vision to discriminate coloured
      stimuli at intensities corresponding to dim starlight (0.0001 cd x m(-2)). It can
      do this even if the illumination colour changes, thereby showing colour constancy
      a property of true colour vision systems. In identical conditions humans are
      completely colour-blind. Our calculations show that the possession of three
      photoreceptor classes reduces the absolute sensitivity of the eye, which
      indicates that colour vision has a high ecological relevance in nocturnal moths.
      In addition, the photoreceptors of a single ommatidium absorb too few photons for
      reliable discrimination, indicating that spatial and/or temporal summation must
      occur for colour vision to be possible. Taken together, our results show that
      colour vision occurs at nocturnal intensities in a biologically relevant context.

PMID- 12410311
TI  - Antagonistic pathways in neurons exposed to body fluid regulate social feeding in
      Caenorhabditis elegans.
AB  - Wild isolates of Caenorhabditis elegans can feed either alone or in groups. This
      natural variation in behaviour is associated with a single residue difference in
      NPR-1, a predicted G-protein-coupled neuropeptide receptor related to
      Neuropeptide Y receptors. Here we show that the NPR-1 isoform associated with
      solitary feeding acts in neurons exposed to the body fluid to inhibit social
      feeding. Furthermore, suppressing the activity of these neurons, called AQR, PQR
      and URX, using an activated K(+) channel, inhibits social feeding. NPR-1 activity
      in AQR, PQR and URX neurons seems to suppress social feeding by antagonizing
      signalling through a cyclic GMP-gated ion channel encoded by tax-2 and tax-4. We
      show that mutations in tax-2 or tax-4 disrupt social feeding, and that tax-4 is
      required in several neurons for social feeding, including one or more of AQR, PQR
      and URX. The AQR, PQR and URX neurons are unusual in C. elegans because they are
      directly exposed to the pseudocoelomic body fluid. Our data suggest a model in
      which these neurons integrate antagonistic signals to control the choice between
      social and solitary feeding behaviour.

PMID- 12410312
TI  - Progenitor cell maintenance requires numb and numblike during mouse neurogenesis.
AB  - Neurons in most regions of the mammalian nervous system are generated over an
      extended period of time during development. Maintaining sufficient numbers of
      progenitors over the course of neurogenesis is essential to ensure that neural
      cells are produced in correct numbers and diverse types. The underlying molecular
      mechanisms, like those governing stem-cell self-renewal in general, remain poorly
      understood. We report here that mouse numb and numblike (Nbl), two highly
      conserved homologues of Drosophila numb, play redundant but critical roles in
      maintaining neural progenitor cells during embryogenesis, by allowing their
      progenies to choose progenitor over neuronal fates. In Nbl mutant embryos also
      conditionally mutant for mouse numb in the nervous system, early neurons emerge
      in the expected spatial and temporal pattern, but at the expense of progenitor
      cells, leading to a nearly complete depletion of dividing cells shortly after the
      onset of neurogenesis. Our findings show that a shared molecular mechanism, with
      mouse Numb and Nbl as key components, governs the self-renewal of all neural
      progenitor cells, regardless of their lineage or regional identities.

PMID- 12410313
TI  - N-CoR controls differentiation of neural stem cells into astrocytes.
AB  - Understanding the gene programmes that regulate maintenance and differentiation
      of neural stem cells is a central question in stem cell biology. Virtually all
      neural stem cells maintain an undifferentiated state and the capacity to self
      renew in response to fibroblast growth factor-2 (FGF2). Here we report that a
      repressor of transcription, the nuclear receptor co-repressor (N-CoR), is a
      principal regulator in neural stem cells, as FGF2-treated embryonic cortical
      progenitors from N-CoR gene-disrupted mice display impaired self-renewal and
      spontaneous differentiation into astroglia-like cells. Stimulation of wild-type
      neural stem cells with ciliary neurotrophic factor (CNTF), a differentiation
      inducing cytokine, results in phosphatidylinositol-3-OH kinase/Akt1 kinase
      dependent phosphorylation of N-CoR, and causes a temporally correlated
      redistribution of N-CoR to the cytoplasm. We find that this is a critical
      strategy for cytokine-induced astroglia differentiation and lineage
      characteristic gene expression. Recruitment of protein phosphatase-1 to a
      specific binding site on N-CoR exerts a reciprocal effect on the cellular
      localization of N-CoR. We propose that repression by N-CoR, modulated by opposing
      enzymatic activities, is a critical mechanism in neural stem cells that underlies
      the inhibition of glial differentiation.

PMID- 12410314
TI  - Specific aspartyl and calpain proteases are required for neurodegeneration in C.
      elegans.
AB  - Necrotic cell death underlies the pathology of numerous human neurodegenerative
      conditions. In the nematode Caenorhabditis elegans, gain-of-function mutations in
      specific ion channel genes such as the degenerin genes deg-1 and mec-4, the
      acetylcholine receptor channel subunit gene deg-3 and the G(s) protein alpha
      subunit gene gsa-1 evoke an analogous pattern of degenerative (necrotic-like)
      cell death in neurons that express the mutant proteins. An increase in
      concentrations of cytoplasmic calcium in dying cells, elicited either by
      extracellular calcium influx or by release of endoplasmic reticulum stores, is
      thought to comprise a major death-signalling event. But the biochemical
      mechanisms by which calcium triggers cellular demise remain largely unknown. Here
      we report that neuronal degeneration inflicted by various genetic lesions in C.
      elegans requires the activity of the calcium-regulated CLP-1 and TRA-3 calpain
      proteases and aspartyl proteases ASP-3 and ASP-4. Our findings show that two
      distinct classes of proteases are involved in necrotic cell death and suggest
      that perturbation of intracellular concentrations of calcium may initiate
      neuronal degeneration by deregulating proteolysis. Similar proteases may mediate
      necrotic cell death in humans.

PMID- 12410315
TI  - Induction of somatic hypermutation in immunoglobulin genes is dependent on DNA
      polymerase iota.
AB  - Somatic hypermutation of immunoglobulin genes is a unique, targeted, adaptive
      process. While B cells are engaged in germinal centres in T-dependent responses,
      single base substitutions are introduced in the expressed Vh/Vl genes to allow
      the selection of mutants with a higher affinity for the immunizing antigen.
      Almost every possible DNA transaction has been proposed to explain this process,
      but each of these models includes an error-prone DNA synthesis step that
      introduces the mutations. The Y family of DNA polymerases--pol eta, pol iota, pol
      kappa and rev1--are specialized for copying DNA lesions and have high rates of
      error when copying a normal DNA template. By performing gene inactivation in a
      Burkitt's lymphoma cell line inducible for hypermutation, we show here that
      somatic hypermutation is dependent on DNA polymerase iota.

PMID- 12410316
TI  - Dual regulation of voltage-gated calcium channels by PtdIns(4,5)P2.
AB  - Voltage-gated calcium channels (VGCCs) conduct calcium into cells after membrane
      depolarization and are vital for diverse biological events. They are regulated by
      various signalling pathways, which has profound functional consequences. The
      activity of VGCCs decreases with time in whole-cell and inside-out patch-clamp
      recordings. This rundown reflects persistent intrinsic modulation of VGCCs in
      intact cells. Although several mechanisms have been reported to contribute to
      rundown of L-type channels, the mechanism of rundown of other types of VGCC is
      poorly understood. Here we show that phosphatidylinositol-4,5-bisphosphate
      (PtdIns(4,5)P2), an essential regulator of ion channels and transporters, is
      crucial for maintaining the activity of P/Q- and N-type channels. Activation of
      membrane receptors that stimulate hydrolysis of PtdIns(4,5)P2 causes channel
      inhibition in oocytes and neurons. PtdIns(4,5)P2 also inhibits P/Q-type channels
      by altering the voltage dependence of channel activation and making the channels
      more difficult to open. This inhibition is alleviated by phosphorylation by
      protein kinase A. The dual actions of PtdIns(4,5)P2 and the crosstalk between
      PtdIns(4,5)P2 and protein kinase A set up a dynamic mechanism through which the
      activity of VGCCs can be finely tuned by various neurotransmitters, hormones and
      trophic factors.

PMID- 12410317
TI  - Thiamine derivatives bind messenger RNAs directly to regulate bacterial gene
      expression.
AB  - Although proteins fulfil most of the requirements that biology has for structural
      and functional components such as enzymes and receptors, RNA can also serve in
      these capacities. For example, RNA has sufficient structural plasticity to form
      ribozyme and receptor elements that exhibit considerable enzymatic power and
      binding specificity. Moreover, these activities can be combined to create
      allosteric ribozymes that are modulated by effector molecules. It has also been
      proposed that certain messenger RNAs might use allosteric mechanisms to mediate
      regulatory responses depending on specific metabolites. We report here that mRNAs
      encoding enzymes involved in thiamine (vitamin B(1)) biosynthesis in Escherichia
      coli can bind thiamine or its pyrophosphate derivative without the need for
      protein cofactors. The mRNA-effector complex adopts a distinct structure that
      sequesters the ribosome-binding site and leads to a reduction in gene expression.
      This metabolite-sensing regulatory system provides an example of a 'riboswitch'
      whose evolutionary origin might pre-date the emergence of proteins.

PMID- 12410319
TI  - Relationship between local structure and phase transitions of a disordered solid
      solution.
AB  - The Pb(Zr,Ti)O3 (PZT) disordered solid solution is widely used in piezoelectric
      applications owing to its excellent electromechanical properties. Six different
      structural phases have been observed for PZT at ambient pressure, each with
      different lattice parameters and average electric polarization. It is of
      significant interest to understand the microscopic origin of the complicated
      phase diagram and local structure of PZT. Here, using density functional theory
      calculations, we show that the distortions of the material away from the parent
      perovskite structure can be predicted from the local arrangement of the Zr and Ti
      cations. We use the chemical rules obtained from density functional theory to
      create a phenomenological model to simulate PZT structures. We demonstrate how
      changes in the Zr/Ti composition give rise to phase transitions in PZT through
      changes in the populations of various local Pb atom environments.

PMID- 12410320
TI  - Asthma in Hutterites.

PMID- 12410321
TI  - Doctors, medical societies and the pharmaceutical industry.

PMID- 12410322
TI  - The relationship among inspiratory muscle strength, the perception of dyspnea and
      inhaled beta2-agonist use in patients with asthma.
AB  - BACKGROUND: It is well documented that the perception of dyspnea (POD),
      subjectively reported by patients, is related to the activity and strength of the
      inspiratory muscles, and influences the use of 'as needed' beta2-agonists. STUDY
      OBJECTIVE: To investigate the relationship among the increase in inspiratory
      muscle strength after specific inspiratory muscle training, beta2-agonist
      consumption and the POD in patients with persistent, mild to moderate asthma.
      METHODS: Inspiratory muscle strength, daily beta2-agonist consumption and the POD
      were measured in 30 patients with mild to moderate asthma. Patients were then
      randomly assigned to two groups: one group received specific inspiratory muscle
      training until an increase of more than 20 cm H2O was reached, and one group was
      a control group and received sham training. Inspiratory muscle strength, the POD
      and daily beta2-agonist consumption were assessed during and after the training
      period. RESULTS: There was no good correlation between the baseline maximal
      inspiratory pressure and the POD, or between the baseline maximal inspiratory
      pressure and the mean daily beta2-agonist consumption. However, there was a
      significant correlation between the POD and the mean daily beta2-agonist
      consumption. The increase in inspiratory muscle strength after the inspiratory
      muscle training was closely correlated with the decrease in the POD (P<0.001) and
      the decrease in beta2-agonist consumption (P<0.001). CONCLUSIONS: The present
      study shows that, in patients with mild to moderate, persistent asthma, there is
      a correlation between the POD and the mean daily beta2-agonist consumption. When
      the inspiratory muscles are strengthened, there is a significant decrease in the
      POD and in beta2-agonist consumption.

PMID- 12410323
TI  - Respiratory symptoms and asthma in two farming populations: a comparison of
      Hutterite and non-Hutterite children.
AB  - OBJECTIVE: To determine the prevalence of asthma and respiratory symptoms in a
      farming population of Hutterite and non-Hutterite children. PARTICIPANTS AND
      SETTING: A population of 830 school-age, farm-dwelling children in rural
      Saskatchewan that included 83 children residing in Hutterite farming colonies.
      METHODS: A cross-sectional survey questionnaire was sent to parents of children
      attending grades 1 to 5 in schools within a grain-growing and mixed-farming
      region of central Saskatchewan. The questionnaire was used to identify
      respiratory symptoms, environmental and host characteristics, and reported doctor
      diagnosed asthma. RESULTS: The prevalence of asthma in Hutterite children was
      2.4% compared with 9.2% in non-Hutterite children. While Hutterite children did
      not differ from their farming counterparts with regard to the frequency of
      reported respiratory allergies, they were less likely to be exposed to cigarette
      smoke and to participate in farm-related activities. In the multivariate
      analysis, being Hutterite continued to be protective for asthma (odds ratio 0.21;
      95% CI 0.05 to 0.89). CONCLUSION: The observed lower rate of asthma in Hutterite
      children than in non-Hutterite children may be related to both genetic factors
      and differences in farming and household factors between the two groups. Key
      Words: Asthma; Children; Farming; Hutterite

PMID- 12410324
TI  - Incidence of pulmonary disease caused by mycobacteria other than tuberculosis in
      British Columbia.
AB  - CONTEXT: The incidence of pulmonary disease due to mycobacteria other than
      tuberculosis (TB) in Canada has not been documented. OBJECTIVE: To determine the
      incidence of pulmonary disease due to mycobacteria in the nonimmunocompromised
      population of British Columbia. DESIGN: A retrospective cohort study of 110 cases
      of mycobacteria infection other than TB identified from 1991 to 1995. SETTING:
      British Columbia Centre for Disease Control, Division of TB Control. RESULTS: The
      overall incidence rate of infection with mycobacteria other than TB was 0.63 10
      5/year. This incidence rate was significantly higher among women (relative risk
      [RR]=2, P=0.0006) and in those aged 55 years or older (RR=8, P<0.00001). In
      contrast with TB, patients were more frequently born in Canada (P<0.00001) or in
      industrialized countries other than Canada (P<0.00001), and were less likely to
      be Aboriginal (P=0.0007) or foreign born from Asia (P<0.0001). The most common
      organism isolated in British Columbia was Mycobacterium avium-intracellulare
      (82.7%). Overall, 78 (71%) cases had underlying lung disease. Drug intolerance
      was very common (42%). After treatment, 55% and 41% of the patients were rendered
      smear negative or culture negative, respectively. Radiological improvement was
      noted in 55% of patients, and 60% of patients responded symptomatically to
      treatment. CONCLUSIONS: The overall incidence of pulmonary disease is low. It is
      a disease predominantly of women 55 years and older, and targets completely
      different ethnic groups than TB, suggesting a protective effect of infection with
      Mycobacterium tuberculosis. M avium-intracellulare was the most common pathogen
      isolated. Further investigation is required into the natural history of so-called
      'colonizers'. Considerable morbidity may be prevented with earlier intervention.

PMID- 12410325
TI  - Fibrothorax and severe lung restriction secondary to lupus pleuritis and its
      successful treatment by pleurectomy.
AB  - Pleural disease is a common pulmonary manifestation of systemic lupus
      erythematosus (SLE) that usually responds to corticosteroids and other
      immunosuppressive agents. In the present report, a new approach, pleural
      decortication, was used in a patient with medically refractory chronic pleuritis
      secondary to severe SLE. A 26-year-old woman with known SLE developed progressive
      dyspnea and pleuritic chest pain over several months. The other systemic
      manifestations of her lupus were controlled with cyclophosphamide and prednisone.
      A computed tomography scan revealed a persistent, small, loculated right pleural
      effusion; pleural thickening; and atelectasis of the right middle and lower
      lobes. Pulmonary function tests showed a severe restrictive defect. The patient
      was disabled by her severe dyspnea despite maximal medical therapy, and,
      therefore, surgery was considered. A right thoracotomy revealed entrapment of the
      right lung by dense visceral pleura. Decortication was performed. On pathology,
      pleuritis with vascular pleural adhesions was found. No lupus pneumonitis was
      noted. Postoperatively, a significant clinical improvement in dyspnea was evident
      within several weeks. On a 6 min walk test, the patient achieved 384 m with a
      Borg dyspnea scale rating of 2 compared with 220 m and a Borg dyspnea scale
      rating of 4 preoperatively. Her forced vital capacity improved from 24% predicted
      to 47% predicted, and her total lung capacity improved from 35% predicted to 54%
      predicted. Medical therapy of systemic lupus erythematosus has been proven to be
      effective in controlling pleuritis in most cases. However, in the event of
      refractory pleuritis or pleural thickening, decortication may be a viable
      alternative.

PMID- 12410326
TI  - Long term survival in a patient with pulmonary lymphangioleiomyomatosis.
AB  - A patient with pulmonary lymphangioleiomyomatosis was diagnosed more than 22
      years after the onset of symptoms by a thoracoscopic lung biopsy, after a high
      resolution computerized tomogram of the chest was highly suggestive of the
      disease. After nearly 30 years since the onset of her symptoms, the patient leads
      a relatively normal life with only mildly abnormal lung function and has minimal
      reduction in her exercise tolerance. There have been few reports of patients
      surviving for such a long time after the onset of this disease; the literature
      suggests that most patients die within 15 years of symptom onset.

PMID- 12410327
TI  - Microscopic pulmonary tumour embolism: an unusual presentation of thymic
      carcinoma.
AB  - The present report describes the first reported case of microscopic pulmonary
      tumour embolism (MPTE) from thymic carcinoma. The carcinoma was discovered during
      an autopsy in a 55-year-old man who had undergone surgery for a pilonidal sinus
      two weeks before presentation. Pulmonary thromboembolism was suspected. This case
      was unusual because MPTE has never before been associated with thymic carcinoma,
      MPTE was the first clinical indication of an occult malignancy, and the clinical
      presentation was that of sudden onset of dyspnea associated with acute cor
      pulmonale. The cause of death was determined to be hypoxia secondary to extrinsic
      compression of the right pulmonary artery and extensive tumour emboli in the
      small arteries, arterioles and venules of the pulmonary parenchyma. A review of
      the clinical presentation and diagnosis of MPTE is included.

PMID- 12410328
TI  - Illusions in action: consequences of inconsistent processing of spatial
      attributes.
AB  - Many authors have performed experiments in which subjects grasp objects in
      illusory surroundings. The vast majority of these studies report that illusions
      affect the maximum grip aperture less than they affect the perceived size. This
      observation has frequently been regarded as experimental evidence for separate
      visual systems for perception and action. In order to make this conclusion, one
      assumes that the grip aperture is based on a visual estimate of the object's
      size. We believe that it is not, and that this is why size illusions fail to
      influence grip aperture. Illusions generally do not affect all aspects of space
      perception in a consistent way, but mainly affect the perception of specific
      spatial attributes. This applies not only to object size, but also to other
      spatial attributes such as position, orientation, displacement, speed, and
      direction of motion. Whether an illusion influences the execution of a task will
      therefore depend on which spatial attributes are used rather than on whether the
      task is perceptual or motor. To evaluate whether illusions affect actions when
      they influence the relevant spatial attributes we review experimental results on
      various tasks with inconsistent spatial processing in mind. Doing so shows that
      many actions are susceptible to visual illusions. We argue that the frequently
      reported differential effect of illusions on perceptual judgements and goal
      directed action is caused by failures to ensure that the same spatial attributes
      are used in the two tasks. Illusions only affect those aspects of a task that are
      based on the spatial attributes that are affected by the illusion.

PMID- 12410329
TI  - Contour integration in striate cortex. Classic cell responses or cooperative
      selection?
AB  - Psychophysics has established various rules of contour integration in gestalt
      perception. We tested the rule of good continuation by stimulating behaving
      monkeys with simple figures composed of Gabor patches, while recording from upper
      layer cells in visual cortex (V1). By decomposing these figures into their
      components and stimulating receptive field centers and surrounds separately with
      this stimulus set, we tested center-surround interaction for linearity. In pure
      fixation tasks, the interaction was negative for the early strong evoked
      response, i.e., in this phase figural context rather inhibited the cells.
      However, in the following tonic response phase, a subgroup of neurons showed
      positive interaction during the whole stimulus presentation period of at least
      1,000 ms. Attention to the figure in discrimination tasks only slightly improved
      this positive interaction between 150 and 300 ms. We interpret these results as
      selective cooperation and mutual facilitation of cortical V1 cells, thereby
      supporting the saliency of borders and contours in perception of visual scenes.

PMID- 12410330
TI  - Spatial and temporal constraints on performance in children with movement co
      ordination problems.
AB  - Eight 10-year-old children manifesting movement co-ordination problems (MCP), as
      assessed by the Movement Assessment Battery for Children (MABC), and a matched
      control group of eight children of a similar age without such problems, were
      required to carry out a laboratory ball-catching task. The task was constrained
      in such a way as to allow separate kinematic analyses of reaching (Experiment 1)
      and grasping (Experiment 2) subactions. Significant differences between the
      groups, in favour of the control group, were found with respect to both spatial
      and temporal performance in intercepting the moving ball. The MCP children were
      shown to initiate reaching movements later and to initiate grasping movement of
      the fingers earlier in time than the controls. MCP children also made more
      spatial errors. These findings are discussed in the context of the distinction
      made in the neuropsychological literature between proximal and distal motor
      control systems and the visual perceptual system.

PMID- 12410331
TI  - Interaction of discrete and rhythmic movements over a wide range of periods.
AB  - This study investigates a complex task in which rhythmic and discrete components
      have to be combined in single-joint elbow rotations. While previous studies of
      similar tasks already reported that the initiation of the discrete movement is
      constrained to a particular phase window of the ongoing rhythmic movement,
      interpretations have remained contradictory due to differences in paradigms,
      oscillation frequencies, and data analysis techniques. The present study aims to
      clarify these findings and further elucidate the bidirectional nature of the
      interaction between discrete and rhythmic components. Participants performed
      single-degree-of-freedom elbow oscillatory movements at five prescribed periods
      (400, 500, 600, 800, 1,000 ms). They rapidly switched the midpoint of oscillation
      to a second target after an auditory signal that occurred at a random phase of
      the oscillation, without stopping the oscillation. Results confirmed that the
      phase of the discrete movement initiation is highly constrained with respect to
      the oscillation period. Further, the duration, peak velocity, and the overshoot
      of the discrete movement varied systematically with the period of the rhythmic
      movement. Effects of the discrete-onto-rhythmic component were seen in a phase
      resetting of the oscillation and a systematic acceleration after the discrete
      movement, which also varied as a function of the oscillation period. These
      results are interpreted in terms of an inhibitory bidirectional coupling between
      discrete and rhythmic movement. The interaction between discrete and rhythmic
      movement elements is discussed in comparison to sequential and gating processes
      suggested previously.

PMID- 12410332
TI  - Sartorius muscle afferents influence the amplitude and timing of flexor activity
      in walking decerebrate cats.
AB  - Recent investigations have demonstrated that afferent signals from hindlimb
      flexor muscles can strongly influence flexor burst activity during walking and
      during fictive locomotion in decerebrate cats. We have reported previously that
      modifying afferent feedback from the sartorius (Sart) muscles by assisting or
      resisting hip flexion has a marked effect on the magnitude and duration of
      activity in iliopsoas (IP) as well as the sartorius muscles. The objective of the
      present investigation was to identify the afferents responsible for these effects
      by examining, in walking decerebrate cats, the influence of electrically
      stimulating sartorius afferents on burst activity in the IP and tibialis anterior
      (TA) muscles. Stimulation of the sartorius nerve at group I strength resulted in
      an increase in the duration of IP and TA bursts and an increase in the magnitude
      of IP bursts. The effect on burst durations was only observed at stimulus
      strengths of 1.6 T and higher. At lower stimulus strengths, there was a strong
      excitatory effect on IP bursts but no effect on TA bursts. Stimulation of the
      sartorius nerve at group II strength yielded variable results. When group II
      stimulation was delivered repeatedly during a walking sequence, the initial
      response was usually a strong inhibition of burst activity in IP and TA followed
      by a progressive reduction in inhibition and the emergence in IP of an excitatory
      response. This observation, together with findings of previous studies, suggests
      the existence of parallel excitatory and inhibitory pathways from sartorius group
      II afferents to flexor motoneurons. Taken together, these results support an
      earlier speculation that feedback from large afferents from the sartorius muscles
      has a strong influence on the generation of flexor burst activity in walking
      cats.

PMID- 12410333
TI  - Spread of electrical activity at cortical level after repetitive magnetic
      stimulation in normal subjects.
AB  - In normal subjects, focal repetitive transcranial magnetic stimulation (rTMS) of
      the hand motor area evokes muscle potentials (MEPs) from muscles in the hand
      (target muscles) and the arm (non-target muscles). In this study we investigated
      the mechanisms underlying the spread of MEPs induced by focal rTMS in non-target
      muscles. rTMS was delivered with a Magstim stimulator and a figure-of-eight coil
      placed over the first dorsal interosseus (FDI) motor area of the left hemisphere.
      Trains of 10 stimuli were given at a suprathreshold intensity (120% of motor
      threshold) and at frequencies of 5, 10 and 20 Hz at rest. Electromyographic (EMG)
      activity was recorded simultaneously from the FDI (target muscle) and the
      contralateral biceps muscle and from the FDI muscle ipsilateral to the side of
      stimulation (non-target muscle). rTMS delivered in trains to the FDI motor area
      of the left hemisphere elicited MEPs in the contralateral FDI (target muscle)
      that gradually increased in amplitude over the course of the train. Focal rTMS
      trains also induced MEPs in the contralateral biceps (non-target muscle) but did
      so only after the second or third stimulus; like target-muscle MEPs, in non
      target muscle MEPs progressively increased in amplitude during the train. At no
      frequency did rTMS elicit MEPs in the FDI muscle ipsilateral to the site of
      stimulation. rTMS left the latency of EMG responses in the FDI and biceps muscles
      unchanged during the trains of stimuli. The latency of biceps MEPs was longer
      after rTMS than after a single TMS pulse. In conditioning-test experiments
      designed to investigate the cortical origin of the spread, a single TMS pulse
      delivered over the left hemisphere at an interstimulus interval (ISI) of 50, 100
      and 150 ms reduced the amplitude of the test MEP evoked by a single TMS pulse
      delivered over the right hemisphere; and a conditioning rTMS train delivered over
      the left hemisphere increased the amplitude of the test MEP evoked by a single
      TMS pulse over the right hemisphere. A conditioning rTMS train delivered over the
      left hemisphere and paired magnetic shocks (test stimulus) at 3 and 13 ms ISIs
      over the right hemisphere reduced MEP inhibition at the 3-ms ISI but left the MEP
      facilitation at 13 ms unchanged. Using a control MEP size matched with that
      observed after a conditioning contralateral rTMS, we found that paired-pulse
      inhibition remained unchanged. Yet a single TMS conditioning pulse sufficiently
      strong to evoke a MEP in the contralateral FDI and biceps muscles simultaneously
      (as rTMS did) left paired-pulse inhibition unchanged. We conclude that the spread
      of EMG activity to non-target muscles depends on cortical mechanisms, mainly
      including changes in the excitability of the interneurones mediating
      intracortical inhibition.

PMID- 12410334
TI  - Inhibition of cyclooxygenase 2 by nimesulide improves cognitive outcome more than
      motor outcome following diffuse traumatic brain injury in rats.
AB  - Prostanoid synthesis is regulated by the enzyme cyclo-oxygenase (COX) that is
      present in at least two isoforms: COX-1, the constitutive form, and COX-2, the
      inducible form. Expression of COX-2 has recently been shown to be an important
      determinant of the cytotoxicity connected with inflammation following ischemic
      injury to the brain. The present study examines the temporal and spatial profiles
      of COX-2 expression following diffuse traumatic brain injury (TBI) in rats, and
      the effects of the COX-2 inhibitor nimesulide on cognitive and motor outcomes.
      Adult, male Sprague-Dawley rats were injured using the 2-meter impact
      acceleration model of diffuse TBI. At preselected time points after injury,
      animals were killed and the expression of COX-2 was measured in the hippocampus
      and parietal cortex by immunohistochemistry and Western blotting techniques.
      Effects of nimesulide (6 mg/kg daily over ten days) on cognitive and motor
      outcome was assessed in a separate group of animals using the Barnes circular
      maze and rotarod test, respectively. A highly significant up-regulation of COX-2
      expression was found in the hippocampus as early as 3 h post-trauma and
      persisting for at least 12 days after TBI. In contrast, a slight but significant
      upregulation of COX-2 expression occurred in the cortex only at 3 days after
      trauma. Administration of the COX-2 inhibitor nimesulide resulted in a
      significant and substantial improvement in cognitive function compared to vehicle
      treated controls, while motor deficits after injury was only improved at 24 h
      after injury. We conclude that COX-2 is involved in the development of functional
      deficits following diffuse TBI, particularly cognitive deficits, and that these
      can be improved by administration of COX-2 inhibitors.

PMID- 12410335
TI  - Pharmacological interventions in the newborn piglet in the first 24 h after
      hypoxia-ischemia. A hemodynamic and electrophysiological perspective.
AB  - The purpose of this study was to investigate whether combined inhibition of
      neuronal and inducible nitric oxide synthase (NOS) by 2-iminobiotin, free radical
      scavenging by allopurinol, and non-protein-bound iron chelation with deferoxamine
      improved cerebral oxygenation, electrocortical brain activity, and brain energy
      status during the first 24 h after hypoxia-ischemia (HI) in the newborn piglet.
      Forty-three newborn piglets were subjected to 1 h of severe HI by occluding both
      carotid arteries and phosphorous magnetic resonance spectroscopy ((31)P-MRS)
      guided hypoxia, whereas five served as sham-operated controls. Upon reperfusion,
      piglets received vehicle (n=12), 2-iminobiotin (n=11), allopurinol (n=10), or
      deferoxamine (n=10). Cerebral oxygenation was recorded with near-infrared
      spectrophotometry (NIRS), electrocortical brain activity was assessed with
      amplitude-integrated EEG (aEEG), and cerebral energy status with (31)P-MRS. The
      oxygenated hemoglobin (HbO(2)) and total hemoglobin (tHb) were significantly
      increased in vehicle-treated piglets compared with 2-iminobiotin-treated and
      deferoxamine-treated piglets. No change in deoxygenated Hb (HHb) was demonstrated
      over time. The aEEG was significantly preserved in 2-iminobiotin- and
      deferoxamine-treated piglets compared with vehicle-treated piglets. Allopurinol
      treatment was not as effective as 2-iminobiotin treatment after HI.
      Phosphocreatine/inorganic phosphate ratios (PCr/P(i)) were significantly
      decreased for vehicle-treated piglets at 24 h post-HI, whereas 2-iminobiotin,
      allopurinol, and deferoxamine prevented the development of secondary energy
      failure. We speculate that the beneficial effects, especially of 2-iminobiotin,
      but also of deferoxamine, are due to reduced peroxynitrite-mediated oxidation.

PMID- 12410336
TI  - Deployment of fingertip forces in tactile exploration.
AB  - The purpose of this study was to examine how contact forces normal to the skin
      surface and shear forces tangential to the skin surface are deployed during
      tactile exploration of a smooth surface in search of a tactile target. Six naive
      subjects participated in two experiments. In the first experiment, the subjects
      were asked to explore a series of unseen smooth plastic surfaces by using the
      index finger to search for either a raised or recessed target. The raised targets
      were squares with a height of 280 micro m above the background surface and that
      varied in side lengths from 0.2 mm to 8.0 mm. A second series of smooth plastic
      surfaces consisted of small recessed squares (side lengths: 2.0, 3.0, 4.0 and 8.0
      mm) that were etched to a depth of 620 micro m. Although made of an identical
      material, the plastic substrate had a lower coefficient of friction against the
      skin because only the recessed square had been subjected to the electrolytic
      etching process. The surfaces were mounted on a six-axes force and torque sensor
      connected to a laboratory computer. From the three axes of linear force, the
      computer was able to calculate the instantaneous position of the index finger and
      the instantaneous tangential force throughout the exploratory period. When
      exploring for the raised squares, the subjects maintained a relatively constant,
      average normal force of about 0.49 N with an average exploration speed of 8.6
      cm/s. In contrast, all subjects used a significantly higher average normal force
      (0.64 N) and slightly slower mean exploration speed (7.67 cm/s) when searching
      for the small recessed squares. This appeared to be an attempt to maximize the
      amount of skin penetrating the recessed squares to improve the probability of
      target detection. In a second experiment, subjects were requested to search for
      an identical set of raised squares but with the fingertip having been coated with
      sucrose to impede the scanning movement by increasing the friction. Overall, the
      subjects maintained the same constant normal force that they used on the uncoated
      surface. However, they increased the tangential force significantly. The
      similarity of the search strategy employed by all subjects supports the
      hypothesis that shear forces on the skin provide a significant stimulus to
      mechanoreceptors in the skin during tactile exploration. Taken together, these
      data suggest that, in active tactile exploration with the fingertip, the
      tangential finger speed, the normal contact force, and the tangential shear force
      are adjusted optimally depending on the surface friction and whether the target
      is a raised asperity or a recessed indentation.

PMID- 12410337
TI  - Glutamate excess and free radical formation during and following kainic acid
      induced status epilepticus.
AB  - Kainic acid (KA) induces seizures and degeneration in CA1 of the ventral
      hippocampus, though its mechanism of action is unknown. We used KA to induce
      seizures in freely moving rats prepared for in vivo microdialysis with probe
      placement, and then measured extracellular glutamate with an online fluorometric
      detector. Generation of free radicals was monitored by electron paramagnetic
      resonance (EPR) spectroscopy coupled with perfusion of the spin-trapping agent,
      alpha-(4-pyridyl- N-oxide)- N- tert-butylnitrone (POBN). Regional antioxidant
      efficacy was measured by observing the eliminating ratio of nitroxide radicals,
      using 3-carbamoyl-2, 2, 5, 5-tetramethylpyrrolidine-1-oxyl (carbamoyl-PROXYL)
      applied exogenously from the probe. Increased levels of extracellular glutamate
      observed at the initiation of KA-induced seizures appear to be associated with
      generation of lipid free radicals and with a decrease in residual antioxidant
      effects. These data suggest that collapse of the redox state in the hippocampus,
      the region most vulnerable to injury from seizure activity, may be critical in
      the regional injury induced by seizures. Further, we propose that the functional
      failure of glutamate transporters due to oxidative stress results in high levels
      of extracellular glutamate during sustained generalized seizures induced with KA.

PMID- 12410338
TI  - Pervasive synchronization of local neural networks in the secondary somatosensory
      cortex of cats during focal cutaneous stimulation.
AB  - Extracellular discharges were recorded from 205 neurons in the secondary
      somatosensory (SII) cortex of isoflurane-anesthetized cats. Cross-correlation
      analysis was used to characterize the temporal coordination of SII neurons
      recorded during cutaneous stimulation with a focal air jet that moved back-and
      forth across the distal forelimb. Over two-thirds of the recorded neuron pairs (
      n=357) displayed significant levels of synchronized activity during one or both
      directions of air-jet movement. The probability of detecting correlated activity
      varied according to the distance separating the neurons. Whereas synchronized
      responses were observed in 82.3% of the pairs in which the neurons were separated
      by 200-300 micro m, the incidence of synchronization declined to 52.3% for
      neurons that were separated by 600-800 micro m. The distance between neurons also
      had a significant effect on the temporal precision of correlated activity. For
      neurons that were separated by 200-300 micro m, synchronized responses in the
      cross-correlograms (CCGs) were characterized by narrow (0.5-1.0 ms) peaks at time
      zero. For SII neurons that were more widely separated, the peak half-widths were
      substantially broader and more likely to be displaced from time zero. Analysis of
      directional sensitivity indicated that only 14.2% of the correlated neurons
      displayed a directional preference for synchronized activity. By comparison,
      63.4% of the neurons displayed a directional preference in their discharge rate.
      These results indicate that stimulus-induced synchronization is a prominent
      feature among local populations of SII neurons, but synchronization does not
      appear to play a critical role in coding the direction of stimulus movement. A
      comparison of these results with those obtained from similar experiments
      conducted in primary somatosensory (SI) cortex indicates that neuronal
      synchronization is more likely in SII cortex. This finding is discussed with
      respect to the known functional differences between the SI and SII cortical
      areas.

PMID- 12410339
TI  - Hierarchical somesthetic processing of tongue inputs in the postcentral
      somatosensory cortex of conscious macaque monkeys.
AB  - The representation of the oral structures in the lateralmost part of the
      postcentral somatosensory cortex in conscious macaque monkeys was studied by
      recording the activities of single neurons. A total of 104 penetrations were made
      in the oral regions of six hemispheres in four animals and 2,292 neurons were
      isolated. The characteristics of the receptive fields (RF) of 1,598 neurons were
      identified. Of them, 513 neurons (area 3b, 196; area 1, 104; area 2, 213) along
      44 penetrations responded to mechanical stimulation of the tongue (tongue
      neurons). The relative incidence of tongue neurons that had bilateral RFs
      increased gradually (bilateral integration) on moving caudally from area 3b to
      area 2. There was also a tendency for the RFs on the tongue to expand in the
      anteroposterior axis of the tongue (anteroposterior integration). Furthermore,
      the relative incidence of tongue neurons with composite RFs covering both the
      tongue and other surrounding oral structures was significantly higher in area 2
      than in areas 3b and 1 (interstructural integration). As a result of the
      bilateral, anteroposterior and interstructural integration, the extent of the RFs
      of tongue neurons increased progressively from area 3b to area 2. We therefore
      concluded that hierarchical somatosensory processing, which has been established
      in the postcentral somatosensory cortex representing other body parts, is also
      present in the oral representation. We speculate that the hierarchical scheme in
      the oral representation might be a prerequisite neural process for the oral
      stereognosis that eventually takes place in the association cortices.

PMID- 12410340
TI  - The lobulus petrosus of the paraflocculus relays cortical visual inputs to the
      posterior interposed and lateral cerebellar nuclei: an anterograde and retrograde
      tracing study in the monkey.
AB  - The afferent and efferent projections of the lobulus petrosus (LP) of the
      paraflocculus were examined by retrograde tracing with cholera toxin subunit B
      (CTB) and anterograde tracing with CTB or biotinylated dextran (BD) in the
      macaque. Following injections of the tracers into the LP, labeled neurons were
      seen mainly in the lateral, dorsal, paramedian and dorsolateral parts of the
      contralateral pontine nuclei (Pn) and in the ventromedial part of the principal
      olivary nucleus and the lateral pole of the medial accessory olivary nucleus at
      the rostral levels. Labeled terminals were seen ipsilaterally in the
      ventrolateral part of the posterior interposed nucleus and the basal interstitial
      nucleus of the cerebellum at their rostral levels, and in the ventromedial part
      of the lateral cerebellar nucleus. To reveal the connections between the LP
      projecting pontine neurons and the corticopontine axons, BD was injected into the
      left prearcuate region or extrastriate visual areas, and CTB into the right LP.
      Labeled terminals from the prearcuate region were seen mainly in the left dorsal,
      medial and paramedian Pn, whereas those from the extrastriate visual areas were
      seen in the lateral and dorsolateral Pn. The distribution of the LP-projecting
      neurons overlapped that of the terminals from the extrastriate visual areas but
      did not overlap that of the terminals from the prearcuate region. The present
      study demonstrates that the LP of the monkey receives cortical visual inputs and
      projects to the posterior interposed and lateral cerebellar nuclei, suggesting
      that the LP may be involved in the control of voluntary eye movements.

PMID- 12410341
TI  - Medial prefrontal cortex early lesion effects on classical conditioned
      bradycardia.
AB  - The effects of medial prefrontal cortex early lesion (mPFl) on classical
      conditioned bradycardia (CB) were studied in adult rabbits. In lesioned rabbits,
      baseline HR, orienting and conditioned HR responses were similar to controls.
      Since mPFl alone does not affect CB, while it is known to prevent the HR
      increments produced by a concomitant early cerebellar vermal ablation, medial
      prefrontal cortex must be involved in the reorganization of the CB control
      mechanisms following early cerebellar vermal ablation.

PMID- 12410342
TI  - The functional role of interhemispheric synchronization in the control of
      bimanual timing tasks.
AB  - The aim of the present study was to investigate whether synchronized activity
      between the right and left primary sensorimotor cortices has a functional role in
      the organization of bimanual in-phase and anti-phase movement patterns, performed
      at different cycling frequencies. To this end we evaluated the cortical dynamics
      by means of task-related EEG. Both behavioral performance and coupling between
      the primary sensorimotor cortices in the beta frequency band were reduced with
      increasing movement speed, and this effect was far more powerful in the anti
      phase than in-phase mode. Thus, a progressive degradation of interhemispheric
      connectivity with cycling rate was associated with a deteriorating behavioral
      output. Overall, these results support a significant role for interhemispheric
      synchronization in the control of bimanual movements.

PMID- 12410343
TI  - Cell adhesion receptors - signaling capacity and exploitation by bacterial
      pathogens.
AB  - Cell adhesion receptors play an essential role in multicellular organisms by
      mediating the direct association of cells with each other and with proteins of
      the extracellular matrix. Members of different protein families such as
      integrins, cadherins, immunoglobulin superfamily cell adhesion molecules
      (IgCAMs), selectins, and syndecans not only support the structural integrity of
      cells and tissues, but also contribute to the transduction of signals.
      Interestingly, several of these molecules are exploited by bacterial pathogens to
      establish tight contact with eukaryotic cells. Using the example of integrins,
      cadherins, and IgCAMs, this review illustrates the signaling capacity of cell
      adhesion receptors and highlights a number of bacterial adhesins that are known
      to engage these receptors. Where applicable, the role of the receptor-adhesin
      interaction in the course of the infection is discussed.

PMID- 12410344
TI  - Emerging and re-emerging infectious diseases.
AB  - In human history, numerous infectious diseases have emerged and re-emerged. Aside
      from many others, the so-called 'exotic' agents in particular are a threat to our
      public health systems due to limited experience in case management and lack of
      appropriate resources. Many of these agents are zoonotic in origin and
      transmitted from animals to man either directly or via vectors. The reservoirs
      are often infected subclinically or asymptomatically and the distribution of the
      diseases basically reflects the range and the population dynamics of their
      reservoir hosts. As examples, emergence/re-emergence is discussed here for
      diseases caused by filoviruses, hantaviruses, paramyxoviruses, flaviviruses and
      Yersinia pestis. In addition, bioterrorism is addressed as one factor which has
      now to be considered in infectious disease emergence/re-emergence. Preparedness
      for known and unknown infectious diseases will be a top priority for our public
      health systems in the beginning of the millennium.

PMID- 12410345
TI  - History and prospects for viral disease eradication.
AB  - Edward Jenner first articulated the concept of eradication when he first
      inoculated the vaccinia. Before considering a disease for eradication some
      factors should be considered, such as the biological characteristics of the
      infectious agent: does the infectious agent infects only humans? Does it have a
      non-human reservoir and induce long-life immunity after infection? Is there a
      tool or intervention that effectively interrupts the chain of transmission from
      one individual to another? The first disease to be eradicated was smallpox. This
      extraordinary initiative set the example for any future disease eradication
      program. The eradication of polio from the Americas was launched in May 1985 and
      the Region of the Americas was certified polio-free in September 1994. At this
      same year, the Pan American Health Organization (PAHO) launched an initiative to
      eradicate measles from the Americas. Only 1,500 cases have been reported during
      the year 2000, and transmission was interrupted in most countries of the Region.
      Tremendous progress has been achieved in disease eradication efforts, which
      resulted in the global eradication of smallpox, the eradication of poliomyelitis
      from the Americas and its nearly global eradication, and the nearly complete
      eradication of measles from the Americas. The biotechnology revolution is
      providing us with many new vaccines and we have to continue the search for those
      diseases that could eventually be eradicated. Eradication of a disease brings the
      greatest health benefit, which is the absence of the health threat. It is also
      the quintessential example of health equity, as all mankind reaps the benefits,
      bringing eternal cost savings. As Louis Pasteur pointed out, "it is within the
      power of man to eradicate infection from the earth".

PMID- 12410346
TI  - Measles virus: immunomodulation and cell tropism as pathogenicity determinants.
AB  - As important determinants of measles virus (MV) pathogenicity, the MV
      glycoproteins play a key role in conferring the cellular tropism of this virus,
      but also in modulating the activity of immunocompetent cells. Whereas all MV
      strains are able to use CD150 (SLAM) for binding and entry into target cells,
      only certain, mainly vaccine, strains, can use both CD46 and CD150. Both
      molecules are down-regulated from the cell surface and this is brought about by
      both infection and contact with the MV H protein of strains that are able to
      interact with these molecules. Whereas down-regulation of CD46 could be linked to
      enhanced sensitivity to complement-mediated lysis, and may thus represent an
      attenuation marker for vaccine strains, pathogenetic consequences of CD150 down
      regulation are unknown as yet. Although the role of CD150 is not entirely clear,
      viruses containing a wild-type strain-derived H protein revealed a particular
      tropism for human dendritic cells in vitro, and replicated well in secondary
      lymphatic tissues of cotton rats where they were also able to cause
      immunosuppression, as documented by an impaired proliferative response of
      lymphocytes ex vivo. Most likely, inhibition of T cell expansion by these cells
      is brought about by another activity of the MV glycoprotein complex, namely by
      disrupting a pathway important for S-phase entry of T cells, by a mere surface
      contact.

PMID- 12410347
TI  - Can varicella be eliminated by vaccination? Potential clinical and economic
      effects of universal childhood varicella immunisation in Germany.
AB  - Varicella is a potentially serious infection not only in immunocompromised
      individuals but also in otherwise healthy adults and children. Vaccination plays
      an important role in preventing the disease and its sequelae. A universal
      vaccination in childhood is expected to reduce substantially the number of
      uncomplicated cases of varicella and decrease the number of complicated cases
      requiring hospitalisation. To generate data as basis for decisions of the health
      authorities concerning prevention of varicella, epidemiological and health
      economic data were collected in two studies. Using an age-structured decision
      analytic model the benefits, costs and cost effectiveness of a varicella
      immunisation program for a period of 30 years were assessed. It was shown that
      after the first year of life seroprevalence rates increased steadily and reached
      62% among the 4- to 5-year olds and 94% among the 10- to 11-year olds,
      respectively; 90% of varicella patients were younger than 12 years. A severe
      course was assessed for 16.3% of the cases. Overall incidence of complications
      was estimated to be 5.7%. A routine varicella vaccination program targeting
      healthy children could prevent 82.7% of varicella cases and over 4,700 major
      complications per year provided the coverage level was 85%. Under these
      conditions the elimination of varicella is predicted to be achievable within 18
      years. It is expected that a combined measles, mumps, rubella and varicella
      vaccine could provide the required coverage. Average yearly discounted net cost
      savings of universal childhood vaccination are 51 million Euro with a benefit
      cost ratio of 4.12. Childhood vaccination with catch-up of adolescents provides
      additional clinical benefits. The break-even point indicating first net savings
      could be achieved already 3 years after the implementation of the vaccination
      program. In summary, routine childhood varicella vaccination appears to be a
      highly efficient strategy to significantly reduce the sizeable burden of
      varicella and would lead to net savings from both the societal but also the payer
      perspective.

PMID- 12410348
TI  - Treatment with an anti-CD18 monoclonal antibody in rabbits inhibits pneumococcal
      induced leukocyte recruitment in the skin, but not in the meninges.
AB  - Inflammatory recruitment of leukocytes into the cerebrospinal fluid (CSF) during
      bacterial meningitis has been shown to contribute to the neurological damage
      commonly associated with this disease. In this study we tested whether inhibition
      of firm leukocyte adhesion to vascular endothelium could reduce leukocyte
      recruitment into the subarachnoid space (SAS) and into the skin in rabbits
      challenged with pneumococcal cell wall (PCW) antigen. PCW was given either as an
      intracisternal or an intradermal (i.d.) injection. Intravenous (i.v.) treatment
      with a monoclonal antibody (mAb), IB4, against the leukocytic adhesion molecule
      CD18 has previously been documented to attenuate leukocyte CSF accumulation in
      experimental bacterial meningitis. In the present study, i.v. treatment with anti
      CD18 mAbs (IB4) only tended to inhibit CSF leukocyte influx in animals with PCW
      induced meningitis. However, if the antigen was injected i.d., treatment i.v.
      with the same mAb (IB4) dramatically reduced leukocyte accumulation in the skin.
      Our findings indicate that the mechanisms responsible for PCW-induced
      inflammatory accumulation of leukocytes in skin and meninges are different.

PMID- 12410349
TI  - Evaluation of different detection methods of biofilm formation in Staphylococcus
      aureus.
AB  - The icaADBC gene locus of Staphylococcus aureus and its polysaccharide
      intercellular adhesin (PIA/PNSG) were recently identified, but biofilm formation
      has rarely been detected in vitro. In this study we evaluated a tissue culture
      plate (TCP) assay and a tube test, as well as Congo red agar, using the two basic
      media trypticase soy broth (TSB) and brain heart infusion (BHI) broth with
      different sugar supplements for detection of biofilm formation in 128 ica
      positive S. aureus isolates. Of the S. aureus strains, 57.1% displayed a biofilm
      positive phenotype under optimized conditions in the TCP test. The tube test
      correlated well with the TCP test for strongly biofilm-producing strains, whereas
      weak producers were not safely discriminated from biofilm-negative strains.
      Screening on Congo red agar displayed a strong correlation with the TCP and the
      tube test for only 3.8%, and is therefore not recommended for investigation of
      biofilm formation in S. aureus.

PMID- 12410350
TI  - Minimal attachment killing (MAK): a versatile method for susceptibility testing
      of attached biofilm-positive and -negative Staphylococcus epidermidis.
AB  - Due to its ability to attach to polymeric surfaces Staphylococcus epidermidis is
      a common pathogen in chronic, medical device-associated infections. Attached S.
      epidermidis displays reduced susceptibility against a variety of antimicrobial
      substances, and little correlation between standard susceptibility test results
      and clinical outcome of antibiotic treatment is observed. In this study we
      established a new, versatile, and easy method of antimicrobial susceptibility
      testing for attached Staphylococcus epidermidis, suitable for both biofilm
      negative and biofilm-positive attached bacteria using readily available
      equipment. For three biofilm-positive wild-type strains and their biofilm
      negative mutants minimal attachment killing concentrations (MAK) of penicillin,
      oxacillin, vancomycin, and gentamicin were determined. Depending on strain and
      investigated antibiotics, a heterogeneous MAK (MAK(hetero)) could be
      differentiated from a homogeneous resistance (MAK(homo)), favoring a model of few
      persisters within attached cells under antibiotic treatment. For the biofilm
      negative mutants, a lower MAK(homo) was detected than for the corresponding wild
      types for some of the tested antibiotics, which probably resulted from higher
      bacterial inocula of wild-type strains, whereas the MAK(hetero) were comparable
      for mutants and wild types for most of the tested antibiotics and strains. These
      data indicate that biofilm formation is not a necessary prerequisite for
      persistence of attached S. epidermidis cells under antibiotic treatment, which
      could explain therapeutic failure in foreign body-associated infections due to
      biofilm-negative S. epidermidis isolates. The highly individual resistance
      phenotypes of the investigated strains with different antibiotics suggests that
      MAK determination could help to predict the therapeutic outcome of foreign body
      associated infections with both biofilm-positive and biofilm-negative S.
      epidermidis.

PMID- 12410351
TI  - Acute cytomegalovirus infections in blood donors are indicated by increased serum
      neopterin concentrations.
AB  - In Austria serum neopterin measurement was introduced as an additional unspecific
      screening marker for the detection of routinely unscreened viral infections in
      blood donations in 1994. This study was performed to test for associations
      between serum neopterin concentrations in blood donations and cytomegalovirus
      infections of the donors. All consecutive blood donations from volunteer blood
      donors collected during 1 year were incorporated into the study. Serum neopterin
      concentrations were measured by enzyme-linked immunosorbent assay (ELISA), and
      each donation of donors with CMV seronegativity or unknown CMV status was also
      screened for CMV antibodies by CMV IgG/IgM antibody ELISA. Data of donors who had
      two or more donations within this period were retrospectively analyzed for CMV
      seroconversions. CMV seroconversion was defined as a change in the donor's CMV
      status from antibody negative to positive. Frozen, stored plasma samples of the
      matching donors were tested for CMV IgM antibodies to confirm seroconversion. CMV
      seroconversions were classified by antibody patterns. In total, 56,068
      consecutive blood donations were given by 44,427 volunteer donors. Among these,
      9,105 had more than one donation during the observation period, and 4,329 (47.5%)
      out of these repeated donors were initially CMV antibody negative, of whom 36
      were recruited as candidates for CMV seroconversion; 20 conversions were
      confirmed. All early infections ( n=8) were associated with neopterin
      concentrations of more than 13 nmol/l (98th percentile of all donations = 12.1
      nmol/l) and all donations were excluded from transfusion solely on the basis of
      their elevated neopterin level. In addition, 17% of late and carrier states (
      n=12) showed elevated neopterin concentrations. Acute CMV infections among blood
      donors presented with elevated serum neopterin concentrations even before CMV
      IgG/IgM antibodies were detectable.

PMID- 12410353
TI  - Interventional management of abdominal sepsis: when and how.
AB  - BACKGROUND: To decide "how and when to treat intra-abdominal infection" is one of
      the most important challenges for surgeons interested in abdominal sepsis. The
      minimally invasive approach to intra-abdominal infection, both diagnostic and
      therapeutic, has gained great popularity in recent years: the cause of infection
      is assessed as soon as possible by means of sophisticated radiography and
      minimally invasive surgery, patients with intra-abdominal infection are treated
      with the least surgical injury in order not to aggravate the systemic response
      ("second hit"), and clinicians rely on clinical scoring combined with new imaging
      techniques to decide for reintervention. In some patients with severe intra
      abdominal infection damage control followed by a few planned relaparotomies seems
      necessary to provide a solid basis for the patient to start recovering. Paying
      close attention in these patients to maximal support vital systems and preventing
      local complications seems crucial for their eventual prognosis. DISCUSSION: In
      this context we discuss important surgical topics such as primary resection and
      anastomosis in perforated diverticulitis, planned relaparotomy vs. relaparotomy
      "on demand," intra-abdominal hypertension, and primary and delayed abdominal wall
      closure techniques after operation for severe intra-abdominal infection.

PMID- 12410352
TI  - Qualitative detection of Legionella species in bronchoalveolar lavages and
      induced sputa by automated DNA extraction and real-time polymerase chain
      reaction.
AB  - Molecular assays for qualitative detection of Legionella spp. in clinical
      specimens were evaluated. DNA extraction was done either with a fully automated
      DNA extraction protocol on the MagNA Pure LC System or with manual DNA
      extraction. Amplification and detection were done by real-time polymerase chain
      reaction (PCR) on the LightCycler (LC) instrument. Oligonucleotides were derived
      from the 16S rRNA gene of Legionella spp. The assays included a specially
      designed DNA fragment as Legionella-specific internal control. For both molecular
      assays, the detection limit was determined to be 5 CFU per LC PCR run. Sixty-one
      clinical specimens were tested with the molecular assays. Results were compared
      to culture. Five samples were found to be positive with the molecular assays.
      Three of them were positive in culture. No inhibition was found throughout the
      whole study. In conclusion, the molecular assays described may lead to safe and
      early diagnosis of Legionnaires' disease. They proved to be suitable for the
      routine molecular diagnostics laboratory.

PMID- 12410354
TI  - Primary hyperparathyroidism, C-cell hyperplasia and papillary thyroid carcinoma
      in a patient with RET germline polymorphism S836S.
AB  - BACKGROUND: In most examined populations the RET germline polymorphism S836S is
      found in about 3.6% of the normal population but in about 9% of patients
      suffering from sporadic C-cell hyperplasia or medullary thyroid carcinoma. The
      polymorphism S836S is thought to be involved in the development of sporadic
      medullary thyroid carcinoma. CASE PRESENTATION: We report a 48-year-old woman
      suffering from primary hyperparathyroidism (parathormone 121-166 pg/ml, normal
      <72), bilateral diffuse and nodular C-cell hyperplasia (calcitonin after
      pentagastrin administration 156 pg/ml, normal <4.6), and papillary thyroid
      carcinoma. Two commercial analyses of RET did not reveal any germline mutation
      within the known hot spots. However, sequencing revealed the presence of the RET
      polymorphism S836S. Following total thyroidectomy and removal of two hyperplastic
      parathyroid glands parathormone decreased to 51 pg/ml and calcitonin was no
      longer detected. CONCLUSIONS: The pathogenetic importance of the RET polymorphism
      S836S is still obscure. However, according to the published overrepresentation of
      the RET polymorphism S836S in patients suffering from apparent sporadic medullary
      thyroid carcinoma, it is conceivable that it also plays a role in multiglandular
      endocrine disease.

PMID- 12410355
TI  - Total parathyroidectomy without autotransplantation as a standard procedure in
      the treatment of secondary hyperparathyroidism.
AB  - BACKGROUND: Total parathyroidectomy with autografting of parathyroid tissue and
      subtotal resection of the parathyroid glands are currently considered as standard
      surgical procedures for the treatment of severe secondary hyperparathyroidism.
      However, a considerable recurrence rate following these procedures ranges from 5%
      to 80%. We present a retrospective analysis of the results of parathyroidectomy
      with autotransplantation to the forearm versus parathyroidectomy alone. PATIENTS
      AND METHODS: We analyzed the clinical course of 11 consecutive patients who had
      undergone parathyroidectomy between 1995 and 1999, and who were not
      simultaneously autografted. Controls were 11 patients in whom autotransplantation
      of parathyroid tissue into the forearm had been routinely performed between 1993
      and 1996 at our institution. Clinical symptoms and recurrence of
      hyperparathyroidism were assessed for comparison of the alternative treatment
      modalities. Recurrence of disease was defined by elevated parathormone (PTH)
      levels (>7.6 pmol/l) with clinical symptoms and/or need for reoperation. RESULTS:
      No recurrence of hyperparathyroidism was observed in patients without
      autotransplantation after a mean follow-up of 23 months (range 1-49). Measurement
      of intact serum PTH revealed residual PTH secretion even after removal of four
      glands (mean 2.02 pmol/l). Clinical symptoms improved substantially after
      surgery. In the historical control group 3 of the 11 autotransplanted patients
      (27%) required resection of transplanted tissue. Additionally, two patients (18%)
      presented with increased PTH secretion and clinical symptoms of recurrent
      hyperparathyroidism during follow-up. Thus, a total of five patients (45%)
      experienced relapsing hyperparathyroidism caused by the implanted tissue.
      CONCLUSIONS: Total parathyroidectomy without autotransplantation is a safe
      procedure with a low rate of recurrent hyperparathyroidism when compared to
      parathyroidectomy with autotransplantation to the forearm in a historical
      control. These preliminary results mandates further investigations including a
      randomized trial.

PMID- 12410356
TI  - Celiac axis stenosis in pancreatic head resection for chronic pancreatitis.
AB  - BACKGROUND AND AIMS: To determine the outcome of pancreatic head resection for
      chronic pancreatitis in the presence of celiac axis stenosis or occlusion we
      analyzed the blood supply of the upper abdominal organs in 11 patients before and
      after surgery. PATIENTS AND METHODS: Between March 1994 and April 2000 we
      performed 145 pancreatic head resections for chronic pancreatitis. Preoperatively
      11 patients showed celiac axis stenosis at angiography. All 11 patients underwent
      duplex ultrasonography postoperatively and 8 had magnetic resonance angiography
      during follow-up. RESULTS: In two cases division of the median arcuate ligament
      was performed to reestablish hepatic artery blood flow. No further
      revascularization procedures of the celiac axis were necessary. Postoperative
      duplex ultrasonography and magnetic resonance angiography showed normal blood
      flow in five patients. Four patients still had an occlusion or a significant
      celiac axis stenosis, and two had a stenosis only during expiration. At follow-up
      nine patients were completely free of abdominal pain (82%), and all had gained
      weight postoperatively, ranging from 5 to 16 kg. CONCLUSIONS: Our data suggest
      that celiac axis stenosis infrequently causes complications in pancreatic head
      resection for chronic pancreatitis and therefore does not represent a
      contraindication for this procedure. Nevertheless the hepatopedal blood flow must
      be confirmed by palpation or duplex ultrasonography after pancreatic head
      resection in these patients.

PMID- 12410357
TI  - Carotid endarterectomy contralateral to carotid artery occlusion: analysis from a
      randomized study.
AB  - BACKGROUND AND AIMS: Many studies have reported the benefits of carotid
      endarterectomy (CEA) contralateral to an occluded internal carotid artery (ICA),
      with varying results. This study analyzed perioperative and late outcomes in a
      recent trial in which patients were randomized to carotid eversion endarterectomy
      (CEE) or traditional CEA with patching (CEAP). PATIENTS AND METHODS: In 336
      primary CEAs (310 patients) 68 were contralateral to an occluded ICA (group I).
      The remaining 268 CEAs served as control group (group II). All patients underwent
      clinical follow-up and duplex ultrasonography at 1, 6, and 12 months and every
      year thereafter. Endpoints of the study were early and late neurological events,
      and deaths. RESULTS: Group I had a significantly higher incidence of
      perioperative electroencephalic changes and need for shunting. The perioperative
      stroke rate in group I was almost three times as high as in group II, but the
      difference was not significant. Similarly, the perioperative minor neurological
      event and death rates, as with the cumulative stroke-free and survival rates at
      1, 3, and 5 years, were comparable in the two groups. CONCLUSIONS: CEA
      contralateral to an occluded ICA can be implemented with perioperative stroke and
      mortality rates and late stroke-free and survival rates comparable to CEA with no
      contralateral ICA occlusion.

PMID- 12410358
TI  - Mode of tumor spread and surgical strategy in gallbladder carcinoma.
AB  - BACKGROUND AND AIMS: The mode and degree of tumor spread in gallbladder carcinoma
      is poorly documented. The present study classifies the patterns of dissemination
      of this tumor with a focus on surgical strategy. PATIENTS AND METHODS: Surgical
      specimens from 112 patients who underwent curative resection were reviewed. There
      were stage I, II, III, and IV in 9, 11, 14, and 78 patients, respectively.
      RESULTS: Six types of spread were identified. In the hepatic bed type ( n=20) a
      large mass in the fundus and body penetrated into the liver through the
      gallbladder bed with or without contiguous spread to the gastrointestinal tract.
      The extent of hepatectomy was individualized from wedge resection to extended
      right hepatectomy based on the clinical findings. In the hepatic hilum type (
      n=26) a relatively small tumor in the neck infiltrated the hepatic hilum causing
      obstructive jaundice. Extended right hepatectomy plus bile duct resection with or
      without portal vein resection was necessary for curative resection because the
      tumor had extended into the right portal pedicle, and postoperative hepatic
      failure was common. In the bed and hilum type ( n=18) a huge mass occupying the
      entire gallbladder involved both the gallbladder bed and the hepatic hilum.
      Extended right hepatectomy with combined resection of contiguous spread was
      necessary for curative resection. In the lymph node type ( n=15) enlarged
      metastatic lymph nodes were the most prominent feature, and the primary tumor
      remains limited to the gallbladder in most cases. Extended lymphadenectomy with
      combined individualized resection was performed. In the cystic duct type ( n=9) a
      small mass arising from the cystic duct involved the common bile duct. This type
      presented at an earlier stage than the first four types. In the localized type (
      n=24) tumor spread is localized to the gallbladder and presented at the earliest
      stage of any type. Simple cholecystectomy with or without wedge hepatic resection
      and regional lymphadenectomy resulted in a satisfactory outcome. Prognosis
      depends on the stage rather than on the mode of tumor spread. Even in the
      advanced types favorable results may be obtained in selected patients undergoing
      radical resection for M0 tumors without portal vein invasion. Success also was
      achieved in the rare patients with para-aortic lymph node metastases that were
      not infiltrative. CONCLUSIONS: These six types of gallbladder cancer can be
      diagnosed preoperatively by clinical and radiological examination. This
      information should assist the surgeon in the choice of operation and predict
      outcome.

PMID- 12410359
TI  - Experience with different methods of treatment of nonparasitic liver cysts.
AB  - BACKGROUND AND AIMS: In a search for the optimal management of nonparasitic liver
      cysts, a study was made of the effectiveness of different methods. PATIENTS AND
      METHODS: Between 1 January 1982 and 15 December 2001 we treated 132 patients with
      nonparasitic liver cysts. In 72 patients 31 cysts were treated with enucleation,
      60 with deroofing, and 24 with stitching by laparotomy; two liver resections were
      also performed. In a further 34 patients 36 cysts were treated with deroofing by
      minimally invasive surgery. In an additional 26 patients 32 cysts were treated
      with various interventional radiological methods. RESULTS: There was no
      mortality. The morbidity rate after laparotomy was significant (22.2%). The rate
      of recurrence after enucleation and deroofing was 6.5% and 13.8%, respectively,
      but there were no recurrences after stitching and liver resection. The recurrence
      rate following laparoscopic deroofing was 19.4%, and that following
      interventional radiological procedures was 50%. CONCLUSIONS: Treatment is
      required only if cysts are highly symptomatic or if growth is detected.
      Interventional radiological methods do not prove more favorable than surgery.
      Laparoscopic fenestration is preferred because of its low morbidity and the short
      period of hospitalization. Traditional surgical methods should be reserved merely
      for cases in which laparoscopic deroofing is not feasible.

PMID- 12410360
TI  - Wortmannin inhibits growth of human non-small-cell lung cancer in vitro and in
      vivo.
AB  - BACKGROUND AND AIMS: Recently we demonstrated that phosphatidylinositol 3-kinase
      (PI3K) is overexpressed in human lung cancer. This study evaluated whether the
      PI3K inhibiting agent wortmannin affects proliferation of human lung cancer cells
      in vitro and in vivo. METHODS: Effects of exposure of human non-small-cell lung
      cancer (NSCLC) cells (KNS-62, Colo-699) to wortmannin were investigated in vitro
      by proliferation, cytotoxicity, and DNA fragmentation assays. In vivo we examined
      the effects of blocking PI3K by wortmannin prior to xenotransplantation of human
      NSCLC cells into SCID-bg mice and the effect of systemic wortmannin
      administration following intrapulmonary xenotransplantation of human NSCLC.
      RESULTS: Exposure of KNS-62 and Colo-699 lung cancer cells to wortmannin
      inhibited proliferation in correlation to concentration in vitro. In vivo the
      blocking of PI3K by wortmannin prior to xenotransplantation caused a significant
      delay in the growth of subcutaneously induced tumors. Systemic wortmannin
      administration increased mean survival after intrapulmonary xenotransplantation
      of human NSCLC significantly by 38% and 47%. CONCLUSIONS: These data suggest
      inhibition of PI3K activity as a potential target for treatment of human NSCLC.
      Systemic toxicity of wortmannin requires development of improved PI3K inhibitors
      with favorable pharmacological properties.

PMID- 12410361
TI  - Thymidine phosphorylase and dihydropyrimidine dehydrogenase activity in
      colorectal carcinoma and patients prognosis.
AB  - BACKGROUND AND AIMS: 5-Fluorouracil (5-FU) is a widely used for colorectal
      carcinoma. However, the therapeutic effect of 5-FU differs among patients. This
      difference may be based on the difference in sensitivity of carcinoma cells to 5
      FU. The activities of thymidine phosphorylase (TP) and dihydropyrimidine
      dehydrogenase (DPD) are reported to be correlated with cancer cell sensitivity
      against 5-FU in vitro. We evaluated whether TP and DPD are useful markers of
      tumor sensitivity for 5-FU in colorectal carcinomas. PATIENTS AND METHODS: We
      analyzed the TP and DPD in 189 patients with colorectal carcinoma using an enzyme
      linked immunosorbent assay in relation to patients prognosis. RESULTS: The
      tumors' mean TP activity was significantly higher than that of noncancerous
      tissues (100 vs. 47 U/mg protein), but the tumors' mean DPD activity was
      significantly lower than that of noncancerous tissues (58 vs. 84 U/mg protein).
      Tumor TP, DPD, and TP/DPD values were not correlated with tumor location or
      histological types of tumors. Even tumor TP and TP/DPD values in Dukes' stage A
      tumors were lower than those of other stages; DPD values were not correlated with
      tumor stages. In 100 patients who underwent intravenous adjuvant 5-FU
      chemotherapy, prognosis was not correlated with tumor-TP, DPD, or TP/DPD values.
      Moreover, in 20 patients with synchronous liver metastasis who underwent
      postoperative 5-FU therapy through the hepatic artery, the survival times of
      patients was not correlated with tumor-TP, DPD, or TP/DPD values. CONCLUSIONS:
      These findings indicate that it is questionable to decide the indication of 5-FU
      chemotherapy according to tumor TP or DPD status in patients with colorectal
      cancer.

PMID- 12410362
TI  - Incisional hernia treatment with progressive pneumoperitoneum and retromuscular
      prosthetic hernioplasty.
AB  - BACKGROUND AND AIM: Major incisional hernias of the abdominal wall often pose a
      serious surgical problem. The choice between simple suture repair and mesh repair
      remains uncertain. METHODS: Seventy-seven patients underwent surgery to repair
      large abdominal incisional hernias, i.e., with parietal defects of 10 cm or more,
      by retromuscular prosthetic hernioplasty between 1996 and 1999. All patients were
      treated preoperatively by progressive pneumoperitoneum and were followed up for 2
      5 years (mean 38.3 months). RESULTS: Almost all patients tolerated the
      pneumoperitoneum; no postoperative death occurred. Six patients developed a
      subcutaneous infection but none of them required removal of the mesh. Two
      patients (2.6%) had recurrent incisional hernia. CONCLUSIONS: This study shows
      that pneumoperitoneum is useful in preparing patients for incisional
      hernioplasty. Retromuscular mesh repair represents an appropriate surgical
      procedure, particularly in view of its low rate of recurrence.

PMID- 12410363
TI  - Intratumoral blood flow characteristics and prognostic factors in patients with
      endometrial carcinoma.
AB  - Purposes of the study were to evaluate the correlation between intratumoral blood
      flow and stage, histologic grade, depth of myometrial invasion and lymph node
      metastasis in endometrial carcinoma and to assess if vascular/lymphatic spaces
      invasion is predictable by Doppler ultrasound. Fifty-three patients with
      endometrial carcinoma were enrolled before surgical treatment. Transvaginal Color
      Doppler Ultrasound was performed to detect the areas of increased vascularity
      (>/=3) and to record the lowest resistance index (RI) from the blood flow signals
      within the tumour. Formalin fixed, paraffin embedded pathology slides were
      reviewed by a senior pathologist to evaluate histologic grading, depth of
      myometrial invasion, presence of lymph node metastasis and vascular/lymphatic
      spaces invasion. The number of patients with positive lymph node metastasis was
      too small to perform any statistical evaluation. Significantly lower RI was noted
      in tumours of advanced stage (>FIGO Stage I), tumours with higher histologic
      grade (Grade 3) and with presence of vascular invasion. No correlation was found
      for myometrial invasion (>50%). A high number of vascular areas was positively
      correlated with all the prognostic signs. Assessment of tumour changes in
      vascularity using colour Doppler ultrasound provides useful information for the
      preoperative prediction regarding stage and histologic grade. The good
      correlation between Doppler ultrasound results and histological finding of
      vascular/lymphatic spaces invasion is another point in favour of routine colour
      Doppler studies in patients with endometrial carcinoma. We believe this technique
      is useful both for preoperative staging and that recording of tumour recurrence
      pattern may lead to early selection of those patients that need additional
      therapy.

PMID- 12410364
TI  - Adnexal torsion after gonadotrophin ovulation induction for IVF or ICSI and its
      conservative treatment.
AB  - This study was designed to find out the incidence of ovarian torsion in the
      patients who were in ovulation induction treatment for either In vitro
      fertilization (IVF) or Intracytoplasmic sperm injection (ICSI). Also operative
      laparoscopic conservative treatment (detorsion or unwinding the twisted adnex)
      was tried to perform to all the patients. Among 10,583 cycles 9 ovarian torsion
      cases had been diagnosed laparoscopically between January 1994 and October 1998.
      104 ovarian hyperstimulation syndrome (OHSS) patients were evaluated during that
      time. From 104 hyperstimulated cases three had torsion of the adnex and two of
      them were pregnant. Five of the patients were clinically and one was chemically
      pregnant. First, laparoscopy was done to all the patients and 8 of them could be
      detorsioned, in one case unwinding performed by laparotomy because of the large
      size of the ovary. No complications were observed after conservative surgery.
      These results demonstrate that, in the IVF or ICSI clinics ovarian torsion has to
      be regarded as one of the major complications especially if the patients are
      hyperstimulated or pregnant or both. Immediate manipulation is needed
      conservatively, preserving the ovaries which were very important for those
      infertile patients.

PMID- 12410365
TI  - Sex hormones, hemostasis and early pregnancy loss.
AB  - AIMS: This study was designed to determine the association between coagulation
      factors and spontaneous abortion adjusting for sex steroids and to examine the
      influence of sex hormones on coagulation factors early in pregnancy. METHODS:
      Pregnant women presenting to the emergency department at the Hospital of the
      University of Pennsylvania were recruited and followed through 22 weeks
      gestation. Cases were women who experienced a spontaneous abortion (n=29) and
      controls were women who maintained their pregnancy to 22 weeks gestation (n=89).
      Participants completed a baseline questionnaire to assess demographic,
      reproductive, and drug use information. Blood samples measured estradiol,
      progesterone, fibrinogen, and factor VII antigen. RESULTS: Cases of spontaneous
      abortion had significantly lower levels of estradiol, progesterone, fibrinogen
      and factor VII antigen compared to controls. The relationship between low levels
      of fibrinogen and factor VII antigen was diminished adjusting for the sex
      steroids. Regression analyses found low progesterone was the primary prospective
      marker for early pregnancy loss among our study population. CONCLUSIONS: The
      relationship between coagulation factors and spontaneous abortion was reduced
      after adjustment for progesterone suggesting that progesterone mediates the
      relationship between low levels of coagulation factors and spontaneous abortion.
      Progesterone seems to be the primary marker for a spontaneous abortion among
      women seeking emergent care.

PMID- 12410366
TI  - Pregnancy following placental abruption.
AB  - The aim of the present study by a retrospective chart review was to examine the
      recurrence rate after placental abruption. Between 1985 and 1998, 81 patients had
      a placental abruption. We had 2-year follow-up information about 31 patients and
      27 of them had a total of 34 subsequent pregnancies. Recurrent placental
      abruption was observed in 6 pregnancies in 6 patients (6/27, 22.2%). Of the 6
      recurrent placental abruptions, the gestational age was 1-3 weeks earlier than
      that of previous abruption in 4 patients. One patient delivered a healthy baby
      after her first abruption and then experienced a second abruption. We conclude
      that careful management is needed after 30 weeks in pregnant women with a
      previous history of placental abruption.

PMID- 12410367
TI  - Risk factors for pelvic surgery.
AB  - One hundred and eighty four women who had corrective surgery for stress
      incontinence, genital prolapse or both were compared with two hundred and ninety
      women who had no surgery for these conditions. Patients and controls did not
      differ in terms of age, height, weight or body mass index. Younger age at first
      delivery (20.1+/-4.1 vs 22.8+/-4.9, p<0.000) and a smoking history (33.2% vs 23%,
      p<0.015) were found as risk factors for the study group. Women who underwent
      surgery had greater gravidity (4.85+/-2.9 vs 3.87+/-2.5, p<0.001), greater parity
      (3.03+/-1.9 vs 2.19+/-1.3, p<0.000), were less often nulliparous (2.2% vs 7.9%,
      p<0.008), less likely to have had a cesarean delivery (1.1% vs 9%, p<0.001) and
      more likely to have had a vaginal delivery (97.3% vs 85.9%, p<0.000) than the
      control group. The study group have had larger neonates on average (3800+/-416 vs
      3373+/-637 gm's, p<0.000) and had greater use of forceps or vacuum extractor for
      at least one delivery (17.9% vs 7.6%, p<0.001). Highly significant relationship
      was found between the risk of having corrective surgery and the number of
      children born vaginally. Women who had 4 or more vaginal deliveries had 11.7
      times more risk of urinary incontinence or genital prolapse.

PMID- 12410368
TI  - A preliminary study of fetal ductus venosus blood flow during the first stage of
      labor.
AB  - OBJECTIVE: The measurement of fetal ductus venosus blood flow during labor by
      means of color Doppler sonography. METHODS: 26 women between 37 and 41 weeks of
      gestation were included in the study. At various stages of cervical dilation (<2
      cm, 2-4 cm, 6- 8 cm, and fully dilated) blood flow velocity waveforms of the
      fetal ductus venosus during and between contractions were studied in fetuses with
      a negative non-stress test. The Pulsatility index for veins (PIV) and the Peak
      velocity index for veins (PVIV), respectively were calculated off-line. The
      mean+/-standard deviation between and during contractions were determined for
      descriptive analysis. RESULTS: Waveforms were visualized during 139 contractions
      and 159 episodes of uterine relaxation in 24 of 26 fetuses (92.3%) in normal
      labor. Three and more waveforms were recorded, in 59.0% during contractions
      (82/139) and in 57.9% between contractions (92/159), respectively. The mean PIV
      and PVIV values during contractions were 1.68+/-1.02 and 1.46+/-0.72,
      respectively. Between contractions the values were 0.49+/-0.21 for the PIV and
      0.44+/-0.18 for the PVIV, respectively. CONCLUSION: Ductus venosus blood flow can
      be visualized in labor. Further studies are needed to establish normal values.

PMID- 12410369
TI  - Using acupuncture to treat premenstrual syndrome.
AB  - More than 60% of the women in both groups suffered from premenstrual syndrome
      (PMS) symptoms, such as anxiety, mastalgia, insomnia, nausea and gastrointestinal
      disorders, whereas a smaller number of women suffered from phobic disorders,
      premenstrual headaches and migraines. There were three women from the first group
      and seven women from the second group who continued the medication treatment with
      progestins, whereas one woman from the first group and nine women from the second
      group continued to take fluoxetine. In the first group, nine women stopped having
      PMS symptoms after two AP treatments, eight women stopped having them after three
      treatments and one woman stopped having them after four treatments. In four women
      from the first group and 16 women from the second group, PMS symptoms appeared
      during the following period (cycle) or continued even after four treatments, so
      the medication was continued. In the first group, one woman had a smaller
      subcutaneous hematoma after the AP acupoint Ren 6. There was a statistical and
      relevant reduction in PMS symptoms with the AP treatments in the first group
      (P<0.001), whereas their reduction was irrelevant in the placebo AP group
      (P>0.05). The success rate of AP in treating PMS symptoms was 77.8%, whereas it
      was 5.9%. in the placebo group. The positive influence of AP in treating PMS
      symptoms can be ascribed to its effects on the serotoninergic and opioidergic
      neurotransmission that modulates various psychosomatic functions. The initial
      positive results of PMS symptoms with a holistic approach are encouraging and AP
      should be suggested to the patients as a method of treatment.

PMID- 12410370
TI  - Frequency of, indications for and clinical epidemiological characteristics of
      first time cesarean section, compared with repeated cesarean section.
AB  - The aim of this study was to determine the frequency of, indications for and
      clinical epidemiological characteristics in patients having their first cesarean
      section (FCS) and then to compare the data with that found in patients with
      repeated cesarean section (RCS). PATIENTS AND METHODS: A cross-sectional study
      was carried out. 493 pregnant patients who gave birth by cesarean section or
      vaginal delivery were seen. Some of the variables analyzed were: age, prenatal
      care consultations, gyneco-obstetric antecedents, cesarean section indication and
      neonate weight. Statistical analysis included ANOVA, chi(2) and OR, with a 95%
      CI. Significance was p<0.05. RESULTS: 66% of the patients had vaginal births (VB)
      and 33.4% had cesarean sections, with a FCS frequency of 61%. The three most
      frequent indications for FCS were dystocias and cephalopelvic disproportion
      (45%), fetal distress (12.8%), and pelvic presentation (9.9%). Meanwhile, those
      for RCS were previous cesarean section (51%), dystocias (20%) and pelvic
      presentation (6.2%). The variables significantly associated with FCS were: first
      pregnancy, antecedent of labor room induction and a neonate weight above 3500 g.
      The remaining variables were not associated with FCS. Percentages of nulliparity,
      secondgravidity and multigravidity were greater in RCS patients. CONCLUSION: The
      frequency of FCS is still high in Mexico. Adequate following of programs to
      diminish the percentage of FCS and increase the number of VB, would significantly
      reduce the prevalence of cesarean section.

PMID- 12410371
TI  - Distribution of ABO and Rh blood groups in patients with HELLP syndrome.
AB  - The aim of this retrospective study was to evaluate the relationship between
      HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome and the
      maternal blood groups. Five hundred and forty-seven women with severe
      preeclampsia were included and divided into eight groups according to their blood
      groups: A Rh-positive (n=203), A Rh-negative (n=38), B Rh-positive (n=83), B Rh
      negative (n=10), 0 Rh-positive (n=148), 0 Rh-negative (n=21), AB Rh-positive
      (n=39), and AB Rh-negative (n=5). The groups were controlled by analysis of
      variance and found to be homogeneous with respect to parity, gestational age,
      blood pressure, hemoglobin, hematocrit, platelet values, prothrombin time,
      partial thromboplastin time, fibrinogen, creatinine, alanine aminotransferase,
      aspartate aminotransferase, bilirubin, uric acid, and proteinuria. Incidence of
      HELLP syndrome was 24% in the overall study population whereas 48% of the
      patients with the blood group O Rh-negative had HELLP syndrome associated with an
      increase in risk by a factor of 3.1. To our knowledge this is the first report of
      such an association.

PMID- 12410372
TI  - Fecundity of infertile women with minimal or mild endometriosis. A clinical
      study.
AB  - Despite significant developments in medical and surgical approaches for treating
      endometriosis, the optimal therapy has yet to be established. The relationship
      between prevalence of fecundity and stage of endometriosis according to their
      management was studied. Of 151 consecutive women with laparoscopy-proved
      endometriosis stage-1 and 2, operative laparoscopy was performed in 49, medical
      treatment in 59 and expectant management in 43 cases. During a 24-month period
      the cumulative pregnancy rates were found to be 36.7%, 30.5% and 20.9%
      respectively. Survival analysis showed that the probability of carrying the
      pregnancy beyond 20 weeks were 30.6%, 25.4% and 16.2% respectively. Diagnosis and
      treatment of early endometriosis is beneficial for the infertile women.
      Laparoscopic surgery seems to be the milestone of treatment in these cases,
      increasing the fecundity and involving minimal risk.

PMID- 12410373
TI  - Plexiform neurofibroma during and after pregnancy.
AB  - Neurofibromatosis is a genetic disease that affects multiple organ systems, and
      has a wide range of clinical features. Neurofibromatosis in pregnancy is
      encountered with a frequency of 1:2434 to 1:18,500 deliveries. Plexiform
      neurofibromas are rare subcutaneous nodules or amorphous overgrowth of
      subcutaneous tissues, which may affect the underlying bone, and produce
      deformities. We present a patient with a giant plexiform neurofibroma of the
      thigh which got larger in pregnancy, and shrunk a bit in the postpartum period.

PMID- 12410374
TI  - Angiosarcoma of the breast associated with Kasabach-Merritt syndrome.
AB  - We report a 55-year-old white woman with an angiosarcoma of the left breast,
      anemia and thromobocytopenia due to a consumptive coagulopathy (Kasabach-Merritt
      syndrome).

PMID- 12410375
TI  - Successful pregnancy in a patient having high basal serum levels of sex steroid
      hormones.
AB  - A 25-year-old infertile woman who had higher basal levels of serum progesterone
      (P) and estradiol (E(2)) was examined. Ultrasonography and gonadotropin-releasing
      hormone test suggested polycystic ovarian syndrome. The high serum E(2) and P
      concentration increased even more along follicle growth and after ovulation,
      respectively. Although the source of the higher levels of steroids was unclear,
      she became pregnant with artificial insemination of husband's sperm and luteal
      support with human chorionic gonadotropin administration, and delivered a healthy
      newborn. Through the present study, we can conclude that the high basal level of
      P in follicular phase may not always impair reproduction, although several
      reports stress that it adversely affects oocyte maturation and fertilization, and
      is harmful to endometrial receptivity.

PMID- 12410376
TI  - Uterine cervical adenofibroma associated with Turner's syndrome in a young woman.
AB  - A 32-year-old woman with Turner's syndrome complained of abnormal genital
      bleeding, which was diagnosed as a delivered myoma. Vaginal myomectomy was
      performed, and the tumor was histopathologically diagnosed as an adenofibroma of
      the uterine corpus. As these are extremely rare, we report this case with a
      review of some of the literature.

PMID- 12410377
TI  - Successful prenatal treatment of congenital heart block with ritodrine
      administered transplacentally.
AB  - Congenital heart block (CHB) is rather rare, and a poorer prognosis has been
      documented in fetuses with a ventricular rate <55 beats per minutes (bpm), in
      which therapeutic interventions during pregnancy have been warranted. We present
      a case of CHB associated with maternal anti-SSA/Ro antibody, diagnosed at 28
      weeks' gestation. Fetal echocardiography revealed atrioventricular dissociation,
      with an atrial rate of 170 bpm and a ventricular rate of 54 bpm. To increase the
      fetal heart rate, maternal intravenous ritodrine infusion was undertaken, fetal
      ventricular rate was rapidly increased to 65 bpm. The pregnancy successfully
      continued until term, and a female infant weighing 2919 g was delivered by
      cesarean section with Apgar scores of 8 and 8 and 1 and 5 min. The infant is now
      12 months of age and growing normally on oral terbutaline without pacing. In a
      case of fetal heart block, maternal administration of ritodrine may be a
      therapeutic intervention to improve the fetal and neonatal prognosis.

PMID- 12410378
TI  - Hypertension in a pregnancy with renal anemia after recombinant human
      erythropoietin (rhEPO) therapy.
AB  - Management of renal anemia in pregnancy remains a major issue. We report the use
      of human recombinant erythropoietin (rhEPO) combined with parenteral iron sucrose
      in a pregnancy with chronic glomerulonephritis, progressive anemia and initially
      normal blood pressure. Therapy from 32 weeks gestation increased the hematocrit
      by 0.4% daily and the hemoglobin from 8.6 to 10.3 g/dL within 2 weeks. Despite
      the improvement of anemia, Cesarean section had to be performed at 34 weeks due
      to acute hypertension, preeclampsia and worsening renal function. Blood pressure
      remained elevated postpartum. Because of symptomatic postpartum anemia with a
      hemoglobin of 7.5 g/dL on the 5th postoperative day rhEPO in combination with
      parenteral iron sucrose was readministered over 3 following days. Blood pressure
      reached a maximum of 210/130 mm Hg 3 weeks later. Possible causes include
      advancing preeclampsia and renal disease, but also rhEPO (due to its intrinsic
      vascular effects and/or the rapid response of the hematocrit), and a combination
      of both.

PMID- 12410379
TI  - Glycogen synthase kinase-3 is associated with neuronal and glial
      hyperphosphorylated tau deposits in Alzheimer's disease, Pick's disease,
      progressive supranuclear palsy and corticobasal degeneration.
AB  - Tau phosphorylation was examined in Alzheimer's disease (AD), Pick's disease
      (PiD), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD)
      using phospho-specific tau antibodies recognizing the phosphorylated form of
      Ser202, Ser214 and Ser 396, and antibodies to non-phosphorylated glycogen
      synthase kinase-3alpha/beta (GSK-3alpha/beta), which regulates phosphorylation at
      these specific sites on tau and phosphorylated GSK-3betaSer9 (GSK-3beta-P); this
      antibody is directed to the inactive form of GSK-3beta. Phospho-specific tau
      antibodies recognized disease-specific band patterns on Western blots of sarcosyl
      insoluble fractions: four bands of 73, 68, 64 and 60 kDa in AD, two bands of 68
      and 64 kDa in PSP and CBD, and two bands of 64 and 60 kDa in PiD. Moreover, anti
      phospho-tau Ser202, Ser214 and Ser369 decorated neurons with neurofibrillary
      tangles, dystrophic neurites of senile plaques, neuropil threads, Pick bodies,
      astrocytes and oligodendrocytes with coiled bodies. No differences in the
      expression of GSK-3alpha/beta were seen between neurons with and without
      neurofibrillary tangles. GSK-3alpha/beta was enriched in sarcosyl-insoluble
      fractions, suggesting association of this kinase with tau hyperphosphorylation.
      In addition, strong expression of the phosphorylated form of GSK-3beta was found
      in a subpopulation of neurons with neurofibrillary tangles, and in dystrophic
      neurites of senile plaques, neuropil threads, Pick bodies, tau-containing
      astrocytes and coiled bodies in AD, PiD, PSP and CBD. This was not due to cross
      reactivity between GSK-3 and phospho-tau. Specific bands differing from those of
      phospho-tau were seen on Western blots of sarcosyl-insoluble fractions processed
      for GSK-3alpha/beta and GSK-3beta-P. Double-labeling immunohistochemistry
      discloses that GSK-3beta-P co-localizes with abnormal tau in about 50% of neurons
      with neurofibrillary tangles, and in neuronal processes, astrocytes and
      oligodendrocytes in various tauopathies. The present results support a pivotal
      role for GSK-3 in tau phosphorylation in neurons and glial cells. Moreover, the
      elevated number of tau-containing cells stained with anti-GSK-3beta-P antibodies
      suggests a partial inactivation of the kinase, or sequestration of the
      phosphorylated form, which may contribute to the regulation of the cascade of tau
      hyperphosphorylation in tauopathies, and to protect tau-containing cells from
      apoptosis.

PMID- 12410380
TI  - Increased expression of the putative axon growth-repulsive extracellular matrix
      molecule, keratan sulphate proteoglycan, following traumatic injury of the adult
      rat spinal cord.
AB  - Keratan sulphate proteoglycan (KSPG) is a developmentally regulated barrier
      molecule, directing axonal growth during central nervous system (CNS) formation.
      The possible re-expression and functional significance of KSPG in preventing axon
      regeneration following spinal cord injury (SCI) is poorly understood. In the
      present investigation, the spatio-temporal expression of KSPG was studied
      following experimental SCI. There was no indication of sparing of axons at the
      lesion epicentre following severe compression injury. By 7 days post operation
      (p.o.) a diffuse increase of KSPG immunoreactivity (KSPG-IR) was observed in the
      parenchyma surrounding the lesion. This was followed by a delayed (21-28 days
      p.o.) and largely heterogeneous increase of KSPG-IR in the lesion epicentre,
      which revealed both cellular and extracellular matrix-like distribution patterns.
      Although no re-growth of anterogradely labelled corticospinal axons was observed,
      many 200-kDa neurofilament (NF)-positive axons could be detected growing into the
      connective tissue scar. This phase of spontaneous axonal re-growth was closely
      associated with a framework of glial cells (including Schwann cells from damaged
      local spinal nerve roots) that had migrated into the lesion site. The spontaneous
      nerve fibre re-growth could be detected in both KSPG-rich and KSPG-poor
      territories. The present data suggest that the lesion-induced up-regulation of
      KSPG-IR may have contributed to the lack of corticospinal axon re-growth.
      However, the lack of any direct spatio-temporal correlation between the
      distribution of raised KSPG-IR and spontaneous NF-positive axonal regeneration
      suggests that at least some populations of axons can resist the putative
      inhibitory effects of this extracellular matrix molecule.

PMID- 12410381
TI  - A comparative study on the expression of cyclooxygenase and 5-lipoxygenase during
      cerebral ischemia in humans.
AB  - Prostaglandins and leukotrienes (eicosanoids), metabolites of the arachidonic
      acid pathway, are subjected to altered synthesis or relocation after an ischemic
      insult. Although cyclooxygenase (COX) expression has been reported in human
      cerebral ischemia, no information is available on the expression of 5
      lipoxygenase (5-LO) and its topographical correlation to COX induction. The
      objective of this study was to elucidate the comparative distribution of
      eicosanoids in ischemic tissues. COX and 5- LO, key enzymes for the synthesis of
      prostaglandins and leukotrienes, respectively, were examined in autopsied brains.
      COX1 was expressed intensely in the microglia but weakly in the neurons in
      control brains. These COX1-immunoreactive microglia showed a more activated form
      following ischemic damage and hypoxemia. In contrast, COX2 was absent in the
      control brains, and was induced robustly in the neuronal cell bodies and
      dendrites during the acute stages of focal ischemic damage, and then subsided at
      the subacute stages. These COX2-immunoreactive neurons accumulated in the peri
      infarct regions, but were absent from the distant regions. In focal ischemic
      damage and Binswanger's disease, COX2 was up-regulated in the microglia. Neuronal
      immunostaining for 5-LO was up-regulated occasionally during hypoxemia and focal
      ischemic damage. Glial cells immunoreactive for 5-LO appeared in the foci of the
      ischemic damage, with small blood vessels being infiltrated by 5-LO
      immunoreactive mononuclear leukocytes. These findings indicate that the isozymes
      of COX are differentially regulated depending on the cellular source and the
      types of ischemic damage, and that vascular 5-LO may accelerate the migration of
      leukocytes and augment the blood-brain barrier permeability. The possibility of
      increased substrate availability for the other should be noticed in specific
      inhibition of either COX or 5-LO since these two enzymes are accumulated in
      parallel in ischemic tissues.

PMID- 12410382
TI  - The microvasculature of the human cerebellar meninges.
AB  - The vascular architecture of the human cerebellar meninges was investigated. The
      surface meninges were poor in vasculature. In the sulci, the meninges were highly
      vascular but had few capillaries. The venous blood vessels gave long side
      branches at right angles to the parent vessels in a cruciform pattern, running
      horizontally along the cerebellar sulci. They were situated at the origin of the
      secondary or tertiary sulci. Anastomoses between these horizontal branches gave a
      crosshatched appearance. Short branches often extended to the bases of the sulci,
      terminating in T-shaped bifurcations with numerous tiny branches, like the roots
      of a tree. The arteries ran perpendicular to venous branches which were parallel
      to each other exclusively along the sagittal plane. These arteries bifurcated to
      straddle the horizontally running veins at the origin of the secondary or
      tertiary sulci. They gave off many small branches like teeth of a fork from each
      artery in the secondary or tertiary sulci after they bifurcated to straddle the
      venous branches and penetrated the cerebellar cortex at the bases of sulci. These
      fork-like ramifications in the bases of the sulci were most likely responsible
      for the ready development of pronounced ischemic state. They might also play an
      important role in the occurrence of ischemic damage at the bases of sulci in
      cases of severe generalized ischemia.

PMID- 12410383
TI  - Miyoshi myopathy patients with novel 5' splicing donor site mutations showed
      different dysferlin immunostaining at the sarcolemma.
AB  - We analyzed five clinically defined cases of Miyoshi myopathy both genetically
      and immunologically. Western blot of muscle specimens confirmed that all of these
      patients had dysferlin deficiency. Immunohistochemistry revealed that two of the
      five patients showed positive dysferlin immunostaining. Subsequent mutation
      analysis of the dysferlin gene in these two patients revealed that both had novel
      5' splicing donor site mutations. One patient with a homozygous G to C
      substitution at nucleotide 1036+1 exon 6 splicing donor site showed patchy
      sarcolemmal dysferlin immunostaining. The second patient with both a heterozygous
      G to A substitution at nucleotide 1310+1 exon 10 splicing donor site and a
      heterozygous C to G substitution at nucleotide 1939 (which induces Tyr 522 Stop
      of exon 18) showed both patchy sarcolemmal and diffuse cytoplasmic dysferlin
      immunostaining. In contrast to Becker muscular dystrophy, the clinical course and
      severity of dysferlin staining positive patients was not clearly different from
      negative patients. These results suggest that a splicing mutation of the
      dysferlin gene may have the potential to cause decreased dysferlin expression but
      may not be related to the milder clinical phenotype.

PMID- 12410384
TI  - Pre-embedding immunogold labeling of TUNEL stain enables evaluation of DNA strand
      breaks and ultrastructural alterations in individual cells of neuronal tissue.
AB  - In the brain apoptosis may occur as a physiological phenomenon during periods of
      programmed cell death as well as under pathological conditions such as ischemia,
      trauma, tumor, and degenerative diseases. While the definition of apoptotic cell
      death was originally based on ultrastructural alterations, the detection of DNA
      double-strand breaks has become an important feature in studies of apoptosis.
      Currently, the terminal transferase-mediated dUTP nick-end labeling (TUNEL)
      procedure is widely used for detection of apoptotic cell death. However, there is
      a growing body of evidence to suggest that the TUNEL staining does not label
      apoptotic alterations exclusively. Therefore, a new staining procedure was
      developed combining TUNEL methodology with pre-embedding nanogold labeling to
      detect DNA double-strand breaks in individual cells by electron microscopy and
      assess the accompanying ultrastructural alterations. In vitro DNAse-treated
      vibratome sections (thickness, 20 micro m) from normal adult rat brains were used
      to develop the staining procedure consisting of the following steps: (i) TUNEL
      staining of free-floating vibratome sections using fluorescein isothiocyanate
      (FITC)-labeled UTP, (ii) conversion of the fluorescence signal into an electron
      dense signal using an anti-FITC antibody coupled with ultrasmall (diameter, 0.8
      nm) gold particles followed by silver enhancement, and (iii) osmification,
      embedding in Spurr resin and cutting of ultrathin sections. Early postnatal brain
      tissue was used to study physiologically occurring apoptotic cell death. Under
      these conditions different patterns of gold staining were observed probably
      representing different states of cellular decay along the apoptotic avenue.
      Severe focal brain ischemia was studied as a pathological situation in which
      intense TUNEL staining occurs. Under these conditions TUNEL labeling of cells was
      regularly observed in conjunction with ultrastructural alterations indicative of
      necrosis. These results suggest that under pathological conditions apoptosis and
      necrosis are not mutually exclusive mechanisms but rather may occur concurrently
      along a continuum in which cell death occurs.

PMID- 12410385
TI  - NACP/alpha-synuclein, NAC, and beta-amyloid pathology of familial Alzheimer's
      disease with the E184D presenilin-1 mutation: a clinicopathological study of two
      autopsy cases.
AB  - Approximately 60% of familial and sporadic Alzheimer's disease (AD) cases
      manifest Lewy bodies (LBs), of which a major component is alpha-synuclein.
      Although the pathogenic role of alpha-synuclein in AD remains unclear, LB
      formation might be associated with pathological beta-amyloid (Abeta)
      overproduction. Here, we present the clinical and pathological characteristics of
      two affected family members from a pedigree with the E184D mutation of presenilin
      1. One case presented with typical clinical features of AD, but the other case
      also developed clinical characteristics of dementia with Lewy bodies (DLB),
      including visual hallucinations, delusions, and parkinsonism. In both cases,
      neuropathological examination revealed numerous neurofibrillary tangles and
      severe Abeta deposition in senile plaques and amyloid angiopathy, in which
      Abeta42 rather than Abeta40 was predominant. Furthermore, remarkable alpha
      synuclein pathology, including LBs and the accumulation of the non-Abeta
      component of AD amyloid (NAC) in plaques and astrocytes, was detected only in the
      case that presented with the symptoms of DLB. These findings suggest that (1) LB
      pathology can influence the clinical features of familial AD, (2) the E184D
      mutation of presenilin-1 may be associated with the LB formation through Abeta
      overproduction, although the process of LB formation is strongly affected by
      other unknown mechanisms, (3) in neurodegenerative disorders with LBs, there is a
      common pathophysiological background inducing NAC accumulation in neuritic
      plaques and astrocytes, and (4) the NAC accumulation in neuritic plaques is
      modulated by the abnormally aggregated tau protein.

PMID- 12410386
TI  - Bilateral periventricular nodular heterotopia due to filamin 1 gene mutation:
      widespread glomeruloid microvascular anomaly and dysplastic cytoarchitecture in
      the cerebral cortex.
AB  - Bilateral periventricular nodular heterotopia (BPNH) is a neuronal migration
      disorder that is characterized by subependymal nodules of gray matter. Recently,
      a causative gene for BPNH, filamin 1, has been identified, and possible roles of
      the translated protein in cell migration and blood vessel development have been
      proposed. We report here the histopathological features of an autopsy case of
      BPNH with widespread glomeruloid microvascular anomaly and dysplastic
      cytoarchitecture in the cerebral cortex, in whom we found a novel exon 11
      (Val528Met) filamin 1 mutation. Within the periventricular nodules, well
      differentiated pyramidal neurons were randomly oriented. A small proportion of
      neurons were immunolabeled with antibodies raised against calbindin D-28k,
      parvalbumin, or calretinin. We used a carbocyanine dye (DiI) tracing technique to
      investigate the extent of fiber projections within and outside the nodules. The
      labeled fibers formed bundles that extended into the surrounding white matter.
      Connections between adjacent nodules were evident. Connections between the
      nodules and the cerebral cortex were also seen, with a small number of labeled
      fibers reaching the cortex. In the cerebral cortex, small closely packed vessels
      ran in a parallel fashion throughout all of the layers. Immunohistochemically,
      the inner rim of individual vessel lumina was labeled by an antibody against
      factor VIII, and the vessel walls were labeled by antibodies against actin and
      laminin. Astrocyte processes, labeled with an antibody to glial fibrillary acidic
      protein, invaded these vascular channels. Ultrastructurally, a network of basal
      lamina-like materials lined with endothelial cells was evident. The
      cytoarchitecture of the cerebral cortex was disturbed, in that the columnar
      neuronal arrangement was distorted around the malformed vessels. This case
      appears to represent an example of BPNH manifesting widespread developmental
      anomalies within the blood vessels and the cortical cytoarchitecture in the
      cerebrum.

PMID- 12410387
TI  - Anti-tau phospho-specific Ser262 antibody recognizes a variety of abnormal hyper
      phosphorylated tau deposits in tauopathies including Pick bodies and argyrophilic
      grains.
AB  - The rabbit polyclonal anti-tau phospho-specific Ser262 antibody (577814
      Calbiochem) recognizes disease-specific band patterns on Western blots of
      sarkosyl-insoluble fractions in Alzheimer's disease (AD), progressive
      supranuclear palsy (PSP), corticobasal degeneration (CBD), argyrophilic grain
      disease (AGD) and Pick's disease (PiD): four bands of 74/72, 68, 64 and 60 kDa in
      AD, two bands of 68 and 64 kDa in PSP, CBD and AGD, and two bands of 64 and 60
      kDa in PiD. Moreover, anti-tau phospho-specific Ser262 decorates neurons with
      neurofibrillary tangles, neurons with pre-tangles, dystrophic neurites of senile
      plaques, neuropil threads, Pick bodies, argyrophilic grains, and coiled bodies.
      Achromatic neurons in CBD, ballooned neurons in AGD, tufted astrocytes in PSP,
      astrocytic plaques in CBD and tau-containing astrocytes in AGD are not
      immunostained with the anti-tau phospho-specific Ser262 antibody. The lack of
      phospho-specific Ser262 immunoreactivity in tau-containing inclusions in
      astrocytes suggests different kinase equipment and activation in comparing
      neurons and astrocytes in tauopathies. Pick bodies in PiD and grains in AGD are
      weakly, or not all, immunostained in tissue samples with long post-mortem delays,
      although Ser262 is preserved in brain homogenates corresponding to the same time
      points processed for Western blot. This indicates postmortem modifications of tau
      in Pick bodies and argyrophilic grains, but not in other tau-containing
      inclusions, including paired helical filaments and coiled bodies, and suggests
      differences in tau conformation, particularly that involving phospho-tau Ser262
      among tauopathies. However, it is important to note that phosphorylation of tau
      at Ser262 does occur in Pick bodies and argyrophilic grains, and this may have
      important consequences in reducing the capacity of binding phospho-tau to
      microtubules in these inclusions.

PMID- 12410388
TI  - The spatial patterns of prion protein deposits in cases of variant Creutzfeldt
      Jakob disease.
AB  - The spatial patterns of the prion protein (PrP) deposits were studied in
      immunostained sections of areas of the cerebral cortex, hippocampus, dentate
      gyrus, and the molecular layer of the cerebellum in 11 cases of variant
      Creutzfeldt-Jakob disease (vCJD). Clustering of PrP deposits, with a regular
      distribution of the clusters parallel to the tissue boundary, was the most common
      spatial pattern observed. Two morphological types of PrP deposit were recognised,
      those consisting of a condensed core (florid deposits) and those deposits lacking
      a condensed core (non-florid deposits). The florid and non-florid PrP deposits
      exhibited a different profile of spatial patterns. First, the florid deposits
      exhibited a regularly distributed pattern of clusters more frequently than the
      non-florid deposits. Second, the florid deposits formed larger clusters (greater
      than 1,600 micro m in diameter) less frequently than the non-florid deposits. In
      the areas of the cerebral cortex that exhibited a regular distribution of PrP
      deposit clusters, the cluster size of the deposits approximated that of the
      groups of cells of the cortico-cortical pathway origin in only 12% of analyses.
      No significant differences in the frequency of the different types of spatial
      pattern were observed in different brain regions, or in the cerebral cortex
      between the upper and lower laminae. It was concluded that the spatial patterns
      of the PrP deposits in the cerebral cortex in vCJD are unlikely to reflect the
      degeneration of the cortico-cortical pathways as has been reported in sporadic
      CJD (sCJD). In addition, different factors could be involved in the development
      of the deposits with and without a condensed core.

PMID- 12410389
TI  - Skeletal muscle abnormalities in two patients with dystonia.
AB  - We report two patients with dystonia aged 53 and 27 years. One patient was
      diagnosed as a sporadic case of primary dystonia. The other patient was diagnosed
      as having secondary dystonia following head injury. Skeletal muscle specimens
      were obtained by open biopsy from the two patients. The muscle biopsy specimens
      showed lobulated fibers, ring fibers, and type 1 fiber atrophy. Dystonia
      comprises involuntary movement and causes abnormal muscle tone. We considered
      that the abnormal muscle tone caused by dystonia might be involved in the
      pathogenesis of these histochemical changes in skeletal muscle.

PMID- 12410390
TI  - Spontaneous human herpes virus type 1 infection in a chinchilla (Chinchilla
      lanigera f. dom.).
AB  - A 1-year-old male chinchilla with a 2-week history of conjunctivitis suffered
      subsequently from neurological signs comprising seizures, disorientation,
      recumbency and apathy. After 3 weeks of progressive central nervous disease the
      animal was killed in view of the poor prognosis. A non-suppurative meningitis and
      polioencephalitis with neuronal necrosis and intranuclear inclusion bodies were
      observed at necropsy and by light microscopy. The brain stem and cerebral
      cortices were most severely affected. Both eyes displayed ulcerative keratitis,
      uveitis, retinitis and retinal degeneration, and optical neuritis. Additionally,
      a purulent rhinitis with focal erosions, epithelial degeneration and intranuclear
      inclusion bodies was present. Ultrastructurally, herpes virus particles were
      detected in neurons of the brain. Immunohistochemistry with antisera specific for
      human herpes virus types 1 and 2 resulted in viral antigen labeling in neurons,
      glial cells and in neuronal processes. Viral antigen was found in the
      rhinencephalon, cerebral cortices, hippocampus, numerous nuclei of the brain
      stem, single foci in the cerebellum, and in a solitary erosive lesion of the
      right nasal vestibulum. Viral antigen was not detected in the eyes. The virus was
      isolated from the CNS, and nucleic acid sequence analysis of the glycoprotein B
      and the DNA polymerase revealed a sequence homology with human herpes virus type
      1 of 99% and 100%, respectively. The clinical signs, the distribution of the
      lesions and the viral antigen suggest a primary ocular infection with subsequent
      spread to the CNS. Chinchillas are susceptible to human herpes virus 1 and may
      play a role as a temporary reservoir for human infections.

PMID- 12410391
TI  - Advanced glycation end products (AGE) and the receptor for AGE are present in
      gastrointestinal tract of familial amyloidotic polyneuropathy patients but do not
      induce NF-kappaB activation.
AB  - Familial amyloidotic polyneuropathy (FAP), Portuguese type, is a hereditary
      amyloidosis caused by mutated transthyretin (ATTR) in which an exchange of valine
      for methionine at position 30 has taken place (ATTR Val30Met). Gastrointestinal
      complications, such as nausea, diarrhoea and malabsorption, have a significant
      impact on survival since the cause of death in the majority of cases is a
      consequence of extreme malnutrition due to dysmotility of the gastrointestinal
      tract. Recently, a role of the receptor for advanced glycation end products
      (RAGE) has been implicated in amyloid toxicity. Transthyretin (TTR) amyloid
      fibrils have been shown to have affinity for RAGE and subsequently induce NF
      kappaB activation and apoptosis. Since gastrointestinal dysfunction plays an
      important role in FAP, we wanted to investigate if amyloid toxicity in the
      gastrointestinal tract is related to RAGE, NF-kappaB activation and apoptosis.
      Gastrointestinal tract autopsy samples were studied for the distribution of
      amyloid, RAGE, advanced glycation end products (AGE) and NF-kappaB. Furthermore,
      we examined the immunoreactivity of an apoptotic marker to investigate if an
      apoptotic pathway contributes to amyloid toxicity. The distribution of RAGE and
      AGE strongly correlated to that of amyloid deposits. Sequential
      immunofluorescence staining revealed a clear relationship between TTR, AGE and
      RAGE. No correlation between NF-kappaB, apoptotic marker and amyloid deposits was
      found. We conclude that RAGE-AGE or RAGE-TTR interaction might play important
      roles for gastrointestinal dysfunction and amyloid toxicity, although not through
      NF-kappaB activation and apoptosis.

PMID- 12410392
TI  - Distribution of extracellular matrix tenascin-X in sciatic nerves.
AB  - Tenascin-X (TNX) is an extracellular matrix protein that is highly expressed in
      the peripheral nervous system as well as muscular tissues, especially the heart
      and skeletal muscle. However, the expression manner and the physiological role of
      TNX in the peripheral nervous system have not been fully investigated. In this
      study, we elucidated its distribution in adult mouse sciatic nerves by
      immunohistochemical staining. TNX was found to be localized in the perineurium
      and the endoneurium of sciatic nerve fibers. To examine the physiological role of
      TNX, we investigated sciatic nerves of TNX-deficient mice that are viable and
      fertile and have no obvious deficits in general performance. The thickness of
      myelin sheaths and the size of the individual axons in these mice appeared
      normal. The ultrastructure of the sciatic nerves of TNX-deficient mice were
      similar to those of wild-type mice. Thus, the lack of a discernible phenotype in
      the sciatic nerves of TNX-deficient mice suggests that TNX has either a redundant
      or a very subtle function in the macromolecular organization in the peripheral
      nerve.

PMID- 12410393
TI  - Pick's disease: alpha- and beta-synuclein-immunoreactive Pick bodies in the
      dentate gyrus.
AB  - Recent studies have shown that neurofibrillary tangles frequently coexist with
      alpha-synuclein (alpha-S)-positive fibrillary inclusions in the limbic system in
      Alzheimer's disease. To elucidate whether alpha-, beta- and gamma-S
      immunoreactivity is present in Pick bodies (PBs), we examined
      immunohistochemically and immunoelectron microscopically the brains from three
      patients with Pick's disease. Numerous PBs were distributed widely, and were
      occasionally immunoreactive for alpha-S and beta-S, but not for gamma-S in all
      three cases. However, these immunoreactive PBs were almost all restricted to the
      dentate gyrus. Despite the co-localization of phosphorylated tau and alpha-S or
      beta-S (as evidenced by double-labeling immunohistochemistry), immunoelectron
      microscopy revealed that alpha-S and beta-S immunoreactivity occurs in granular
      and vesicular structures, but not in filamentous structures. These findings
      suggest that alpha-S and beta-S are up-regulated in the neuronal perikarya but
      they are not incorporated into the constituent filaments of PBs, and that the
      preferential distribution of alpha-S- and beta-S-positive PBs in the dentate
      gyrus may represent the cellular response to PB formation in this particular
      system.

PMID- 12410394
TI  - Long-lasting neuronal apoptotic cell death in regions with severe ischemia after
      photothrombotic ring stroke in rats.
AB  - Apoptotic and necrotic cell death may act in concert in focal cerebral ischemia.
      This study explored the temporal and spatial pattern of apoptosis and necrosis in
      a novel photothrombotic ring stroke model with or without spontaneous
      reperfusion. Adult male Wistar rats were subjected to a ring-shaped laser
      irradiation beam simultaneously with intravenous erythrosin B infusion. The
      presence and attributes of apoptosis and necrosis in the anatomically well
      defined cortical region at risk and ring-lesion region were verified under light
      microscopy with TUNEL, Hoechst 33342, and hematoxylin and eosin staining. Cells
      exhibiting apoptotic morphology with chromatin condensation and apoptotic bodies
      and necrotic ghost appearance were observed. The occurrence of apoptosis and
      necrosis in the ischemic regions was confirmed by electron microscopy and gel
      electrophoresis, in which DNA isolated from the lesion area revealed both a
      ladder and a smear. Double staining with TUNEL and the cell markers NeuN, glial
      fibrillary acidic protein, and ED-1 revealed that the majority of apoptotic cells
      were of neuronal origin. Cells exhibiting pyknosis/eosinophilia, apoptosis, or
      ghost appearance were quantified by stereological means. In subregions with
      severe ischemia, the peak appearance of apoptotic cells started earlier, i.e., at
      24 h, than the peak of necrotic cells, and the high concentration of the
      apoptotic cells remained as long as that of necrotic cells, i.e., until 72 h post
      ischemia. The ratio of apoptotic to necrotic cells was approximately 1:2.
      Therefore, apoptosis may be an important contributor to neuronal cell death in
      brain regions with severely reduced blood flow after thrombo-embolic stroke.

PMID- 12410395
TI  - Inverse association of Pin1 and tau accumulation in Alzheimer's disease
      hippocampus.
AB  - Neurofibrillary degeneration, one of the pathological hallmarks of Alzheimer's
      disease, is not ubiquitous to all brain regions or neurons. While a high degree
      of vulnerability has been documented for entorhinal cortex, hippocampal and
      neocortical pyramidal neurons other brain structures are largely spared. Even
      within highly vulnerable regions such as hippocampus neurons are affected to a
      variable extent. The molecular basis for this selective susceptibility remains
      unknown. Neurofibrillary degeneration involves hyperphosphorylation of tau which
      critically impairs its binding capacity to microtubule and, therefore, is
      believed to disrupt the axonal cytoskeleton. Recently, Lu et al. [Nature (1999)
      399:784] described the ability of the peptidyl-prolyl cis-trans isomerase Pin1 to
      recover microtubule-binding affinity and microtubule stabilisation of
      phosphorylated tau. In the present study, we analysed the potential involvement
      of Pin1 in selective vulnerability of hippocampal neurons to neurofibrillary
      degeneration in Alzheimer's disease. Pin1 immunoreactivity appeared as
      cytoplasmic granules affecting hippocampal subfields to a different extent
      (CA2>subiculum>CA1>CA3/CA4). Since the main markers of granulovacuolar
      degeneration do not co-label Pin1-immunoreactive granules, we propose that these
      granules may represent a new lesion in Alzheimer's disease. Neurons containing
      Pin1 granules were devoid of neurofibrillary tangles. Granular accumulation of
      Pin1 may correspond to an absence of neurofibrillary lesions in these cells and
      might be associated with other mechanisms of neuronal degeneration.

PMID- 12410396
TI  - The reciprocal change of neurotrophin-4 and glial cell line-derived neurotrophic
      factor protein in the muscles, spinal cord and cerebellum of the dy mouse.
AB  - Laminin alpha2 (merosin)-deficient congenital muscular dystrophy (CMD) patients
      show progressive muscle fiber necrosis and ineffective muscle regeneration,
      probably due to a lower formation of multinucleated myotubes due to an adhesion
      defect of myoblasts to each other. Some recent studies found that CMD patients
      have a white matter disorder and cerebellum atrophy. In the spinal cord of dy
      mice, a model of CMD, inducible nitric oxide synthase (iNOS) was markedly
      expressed. Using Western blotting and immunohistochemical analyses, we
      investigated the levels of neurotrophin-4 (NT-4), brain-derived neurotrophic
      factor, glial cell line-derived neurotrophic factor (GDNF) and ciliary
      neurotrophic factor (CNTF) in the central nervous system and skeletal muscles of
      dy mice. In the dy mice, the microtubule-associated protein-2 (MAP-2) protein
      level was markedly decreased in the Purkinje and granule cells of the cerebellum,
      and in lumbar motoneurons of the spinal cord. The motoneurons and axons of dy
      mice possessed lower expressions of phosphorylated tau. The amount of NT-4 was
      markedly lower in the cerebellum, spinal cord and hindlimb muscles of dy mice. In
      dy mice, GDNF was markedly enhanced in the Purkinje and granule cells of the
      cerebellum, in many lumbar motoneurons, and in the regenerating atrophied fibers.
      The CNTF protein level did not differ in the hindlimb muscles between the normal
      and dy mice. Therefore, GDNF could act to inhibit the death of Purkinje and
      granular neurons, and motoneurons, and to promote the remodeling of the
      neuromuscular junction of atrophied muscle fibers of dy mice. Furthermore, dy
      mice include neurogenic abnormalities in the cerebellum and spinal cord along
      with myogenic disorder of muscle fibers.

PMID- 12410397
TI  - Cytoskeletal derangements in hereditary myopathy with a desmin L345P mutation.
AB  - Patients with abnormal accumulations of desmin have been described in myopathies
      with or without cardiac involvement. Desmin deposits were sometimes associated
      with abnormal aggregates of other cytoskeletal proteins. In the present study we
      present how the cytoskeletal organisation of desmin, nestin, synemin, paranemin,
      plectin and alphaB-crystallin is altered in skeletal muscles from a patient with
      a L345P mutation in the desmin gene. In general, accumulations of desmin together
      with synemin, nestin, plectin and alphaB-crystallin were present between
      myofibrils and beneath the sarcolemma. However, as the biopsy samples were very
      myopathic, large variability in fibre size and fibre maturation was seen, thus
      the myofibrillar content and the cytoskeletal organisation varied considerably.
      In cultured satellite cells from the patient, desmin aggregates were not observed
      in initial passages, but occurred over time in culture in the form of
      perinuclear, peripheral or cytoplasmic deposits. Nestin colocalised to the
      abnormal desmin deposits to a larger extent than did vimentin. alphaB-Crystallin
      was only present in cells with a disrupted desmin network. Plectin was altered in
      a subset of cells with a disrupted desmin network, whereas synemin and paranemin
      were not detected. We conclude that the L345P desmin mutation has a profound
      influence on the cytoskeletal organisation both in vivo and in vitro, which
      reflects the pathogenesis of the desmin myopathy.

PMID- 12410398
TI  - Paranodal demyelination by gradual nerve stretch can be repaired by elongation of
      internodes.
AB  - Nerve elongation resulting from leg-lengthening surgery can be injurious. We
      investigated peripheral nerve injury and recovery after gradual elongation of the
      rat sciatic nerve by progressive stretching. Indirect nerve elongation was
      produced by leg lengthening by 15 mm, at a rate of 3 mm/day (group I) or 5 mm/day
      (group II). The elongated length was then maintained. At 0 weeks, representing
      the 7th day after starting leg lengthening, and at weeks 2, 4, and 6, transverse
      semithin sections of sciatic nerve were examined. At the same time a teased fiber
      study was performed. As a result of nerve elongation axon diameter was decreased,
      although it later recovered. Axon diameter recovered more slowly in group II than
      I. Myelin thickness did not change compared with controls. In the teased fiber
      study, internodal length was increased by about 10% after nerve elongation in
      each group. Almost all nerve fibers showed demyelination at 0 weeks; myelination
      recovered with time, more slowly in group II than I. More obvious demyelination,
      axonal degeneration, and remyelination were observed in group II. We conclude
      that mild demyelination was repaired by elongation of internodes, while more
      severe demyelination was repaired by intercalation of segments.

PMID- 12410399
TI  - Adoptive transfer-experimental allergic neuritis in newborn Lewis rats results in
      inflammatory infiltrates, mast cell activation, and increased Ia expression with
      only minor nerve fiber degeneration.
AB  - Experimental allergic neuritis (EAN) induced in the Lewis rat by the adoptive
      transfer of a P2-specific T cell line (AT-EAN) is considered an animal model of
      Guillain-Barre syndrome. It is not yet known whether AT-EAN is inducible at early
      stages in the development of the peripheral nervous system (PNS) or whether
      disease activity is modified because of immaturity of either the nervous system
      or the immune system. We therefore compared the susceptibility of neo-natal and
      adult Lewis rats to AT-EAN induced by the adoptive transfer (intraperitoneally)
      of 10(6) activated P2-specific T cells. P2 antigen was already present in 7 day
      old Lewis rats and P2-specific T cell transfer into 3-day-old rats induced
      clinical disease associated with an inflammatory response (sciatic nerves and
      spinal ganglia). In injected newborn rats we observed local activation of mast
      cells, infiltration of the PNS by inflammatory cells, and induction of Ia antigen
      expression in Schwann cells. Unlike in adults, segmental or paranodal
      demyelination despite occasional nerve fiber degeneration did not occur. However,
      the difference between newborn and adult rats could not be ascertained
      statistically because of the relative rarity of the lesions, their focal
      character, the admixture of fiber demyelination and degeneration, and most
      importantly, size differences of the myelinated fibers, which result in a large
      developmental decrease in fiber density in adults compared to newborns.

PMID- 12410400
TI  - Expression of the cytokine leukemia inhibitory factor and pro-apoptotic insulin
      like growth factor binding protein-3 in Alzheimer's disease.
AB  - Amyloid-beta (Abeta) deposition in cerebral blood vessel walls is one of the key
      features of Alzheimer's disease (AD). Abeta(1-40) carrying the "Dutch" mutation
      (DAbeta(1-40)) induces rapid degeneration of cultured human brain pericytes
      (HBP). To study the mechanisms of this Abeta-induced toxicity, a comparative cDNA
      expression array was performed to detect differential gene expression of Abeta
      treated versus untreated HBP. Messenger RNA expression of leukemia inhibitory
      factor (LIF) and insulin-like growth factor binding protein 3 (IGFBP-3) was
      increased in DAbeta(1-40)-treated HBP, whereas early growth response factor-1
      (Egr-1) expression was decreased. Corresponding protein expression was
      investigated in AD and control brains. In all AD cases examined, LIF expression
      was observed in senile plaques and cerebral amyloid angiopathy, whereas IGFBP-3
      expression in these lesions was only observed in a subset of cases. LIF and IGFBP
      3 were also expressed in neurofibrillary tangles, as well as in neurons in AD and
      control brains. Egr-1 was predominantly expressed in astrocytes. Given its known
      involvement in both neuronal and immune responses to injury, the cytokine LIF may
      be a mediator of the inflammatory reaction seen in AD. IGFBP-3 is known to
      inhibit cell proliferation and induce apoptosis and may therefore contribute to
      neuronal degeneration in AD.

PMID- 12410401
TI  - Association of Lewy bodies and glial cytoplasmic inclusions in the brain of
      Parkinson's disease.
AB  - We report the histopathological and immunohistochemical findings from the brain
      of an elderly patient diagnosed with Parkinson's disease (PD). Neuropathological
      examination revealed moderate neuronal cell loss and astrocytosis in the
      substantia nigra. Lewy bodies were found in many sites characteristic for PD,
      including the substantia nigra, locus coeruleus, hypothalamus, substantia
      innominata, pontine raphe nucleus, and dorsal motor vagal nucleus, cingulate and
      insular cortices. Furthermore, argyrophilic glial intracytoplasmic inclusions
      were found predominantly in the ventral pons, cerebellar white matter, precentral
      and frontal white matter, internal and external capsule, claustrum, and putamen.
      Inclusions were triangular in shape, and immunopositive for ubiquitin and alpha
      synuclein. In view of these histopathological and immunohistochemical findings
      and patterns of distribution, the inclusions were suggested to be glial
      cytoplasmic inclusions (GCIs) in multiple system atrophy (MSA). These findings
      suggested that our case might have experienced two pathological processes; PD and
      the early stage of MSA (striatonigral degeneration) that had not progressed to
      striatal involvement. Alternatively a common pathological background including
      abnormal processing of alpha-synuclein could contribute to widespread
      accumulation of Lewy bodies and GCIs in a single condition accompanied by nigral
      degeneration.

PMID- 12410402
TI  - A spinal intradural enterogenous cyst with well-differentiated muscularis
      propria.
AB  - We report a case of a newborn presenting with severe compression of the spinal
      cord due to a large, solitary mass extending from C4 to T2. Neurosurgical
      exploration revealed a large intradural, extramedullary cystic lesion,
      compressing the spinal cord. Slowly progressive respiratory failure due to severe
      myelopathy led to the death of the child 19 days postpartum. At autopsy, a well
      differentiated enterogenous cyst was found, the cyst wall containing gastric and
      esophageal type mucosa, and a bona fide muscularis propria. The gastrointestinal
      tract was completely normal. The possible developmental history of intradural
      enterogenous cysts is discussed.

PMID- 12410403
TI  - [Target pressure evidences].

PMID- 12410404
TI  - [Diffuse lamellar keratitis: prophylactic treatment with ketorolac tromethamine
      0.5% in an animal model].
AB  - PURPOSE: The objective of this study is to evaluate the use of a topical non
      steroidal anti-inflammatory drug in the treatment of induced diffuse lamellar
      keratitis (DLK) in an animal model. MATERIALS AND METHODS: A corneal flap was
      created in 40 eyes of 20 Dutch-belted rabbits using the ASC microkeratome. The
      interface was inoculated with either Pseudomonas Aeruginosa Lipopolysaccharide
      (LPS) endotoxin or Ultra Palmolive liquid dish washer. The rabbits were divided
      in two groups: Group I (n=20) treated with ketorolac tromethamine ophthalmic
      solution 0.5% 4 times a day and the group II (n=20) used as control. The rabbits
      were examined at the slit lamp at day 1, 3, 5 and 7 postoperatively. DLK was
      graded from I-IV. RESULTS: At the end of the study 31 eyes were available for
      evaluation. 28 eyes (90%) developed DLK: 86% of the treated group and 94% of the
      control group during the follow-up. The treated group showed a lower rate of DLK
      as well as a lower severity. However, no statistically significant difference was
      found when comparing both groups (P>0.05). CONCLUSION: Pseudomonas aeruginosa LPS
      endotoxin and Palmolive Ultra can induce DLK in rabbit eyes. The postoperative
      prophylactic treatment with a topical non-steroidal anti-inflammatory drug showed
      a tendency towards a lower DLK rate as well as the severity of the disease.

PMID- 12410405
TI  - [Variables related to the first presbyopia correction].
AB  - PURPOSE: We carried out a prospective study based on variables related to the age
      of appearance of presbyopia (AAP): refraction defect, sex, iris color, profession
      and pupil diameter. METHOD: Our sample population was made up of 179 persons who
      present consecutively for the first optical correction of presbyopia as sole
      reason, having a refractive defect equal to 1 diopter or less. RESULTS: In our
      series the AAP was not influenced by the small refraction defect, neither by sex
      or iris color. Different professions showed a significant AAP difference later in
      life (farmers, x = 51.76 D.E. 5.47 years) or earlier (services workers, x = 46.15
      D.E. 3.55 years) (p<0.000003, ANOVA), than other professions such as housewife
      (48.42 D.E. 4.71 years) and construction workers (47.54 D.E. 3.93 years). We
      found significant differences in AAP among subjects with intense miosis (<2,5 mm,
      x = 51 D.E. 5.39 years) and without miosis (3 to 7 mm, x = 47.47 D.E. 4.71 years)
      (p<0.02 t Student). CONCLUSIONS: The variables which determine a significant
      delay in the AAP are: profession (farmer and housewife) and miosis, a 1 mm
      pupilar diameter reduction, in near vision, could contribute to a delay of 1.53
      years in AAP.

PMID- 12410406
TI  - [Benign hair-follicle derived eyelids tumors in adults].
AB  - PURPOSE: Benign eyelid neoplasms derived from hair follicles are frequently
      misdiagnosed, including pilomatricoma, trichoepithelioma, trichilemmoma,
      trichoblastoma and inverted follicular keratosis. METHODS: We reviewed 17 tumors
      seen in the last 9 years, between 1992 and 2002. Excisional biopsy constituted
      the treatment in all cases. RESULTS: The mean age was 44.5 years (range 13-80
      years). Ten were women and 7 men. Pilomatricoma and trichoepithelioma accounted
      for 76.5% of all neoplasms. All trichoepitheliomas were found as solitary tumors
      and no patient had a history of familial trichoepithelioma. The remaining
      neoplasms (23.5%) were trichilemmomas, trichoblastoma and inverted follicular
      keratosis. No patient recurred locally and there were no malignant
      transformations after a mean follow-up of 3.1 years. The most frequent hair
      follicle neoplasms in our series was pilomatricoma (9 cases). CONCLUSIONS: Benign
      hair follicle neoplasms are rare in the eyelid. Most can simulate a basal cell
      carcinoma when evaluation is based on clinical evidence alone, and only the
      pilomatricoma may resemble a benign neoplasm. Thereby they must be excised with
      free surgical margins. All excised eyelid lesions should be sumitted for
      histopathologic examination because it is not possible to obtain 100% accuracy in
      diagnosing eyelid tumors.

PMID- 12410407
TI  - [Amino acid concentrations in the vitreous body in control subjects].
AB  - PURPOSE: Concentrations of amino acids in the vitreous body of a control group
      were determined. MATERIAL AND METHODS: Patients who neither had undergone prior
      vitreous or intraocular surgery nor had a history of intraocular ischemia such as
      retinal vascular occlusion, diabetic retinopathy glaucoma history were studied.
      Undiluted vitreous samples were obtained from 64 patients with retinal
      detachment, preretinal macular membranes and macular holes, who underwent pars
      plana vitrectomy. Free amino acids were determined using high-performance liquid
      chromatography. Patients were divided into three groups: A (<50 years old), B (50
      65 years old) and C (>65 years old). RESULTS: Glutamine+histidine had the higher
      concentration with 851.1 D.E. 74.2 mcmol/L, and the vitreous concentration of
      glutamate was 3.8 D.E. 5.1 mcmol/L and aspartate 3.7 D.E. 4.1 mcmol/L. No
      statistically significant differences were found in the vitreous concentrations
      of amino acids between different age groups and no statistically significant
      differences were found between the 3 pathological groups analysed (retinal
      detachment, macular hole and epiretinal membrane). CONCLUSIONS: These results
      show that the concentration of acid amino acids in the vitreous body of a control
      group was not high and that in mature eyes the concentration of amino acids was
      maintained at a fairly constant level.

PMID- 12410408
TI  - [Transpupillary thermotherapy in occult subretinal neovascularization in age
      related macular degeneration. Preliminary results].
AB  - PURPOSE: To determine the efficacy of transpupillary thermotherapy (TTT) to treat
      choroidal neovascularization (CNV) in patients with age-related macular
      degeneration (ARMD). PATIENTS AND METHODS: Eight patients (ten eyes) with occult
      CNV were treated by TTT. A 810 nm diode laser was used to perform TTT. The diode
      laser was delivered through a panfunduscopic contact lens. RESULTS: Three eyes
      showed a visual acuity improvement and a decrease in exudation on fluorescein
      angiography. Four eyes remained stable. Nevertheless, lesions worsened after
      treatment in three cases. One of these cases suffered an overtreatment.
      CONCLUSIONS: TTT may be a useful therapy in some cases of CNV in patients with
      age-related macular degeneration. Randomized and multicentric studies are
      necessary to stablish precise indications of this therapy.

PMID- 12410409
TI  - [Innervation of the lachrymal gland in patients with primary Sjogren's syndrome.
      An immunohistopathological study].
AB  - PURPOSE: Histopathological parameters of the main lachrymal gland from patients
      with primary Sjogren's syndrome (SS1) were investigated, and the relation between
      morphological and immunohistochemical changes in the innervation of lachrymal
      gland in patients with SS1, as well as the immunopathological differences between
      SS1, non-autoimmune keratoconjunctivitis sicca (KCS) and controls were analysed.
      METHODS: Lachrymal glands from patients with SS1, KCS and control subjects were
      biopsied and examined using standard transmission electron microscopic techniques
      and an immunohistochemical method (vasoactive intestinal polypeptide-VIP).
      RESULTS: Moderate numbers of myelinated and non-myelinated nerve fibres were
      found in the connective tissue around lachrymal glands in patients with SS1. Non
      myelinated nerve fibres made contact with glandular epithelium, myoepithelial
      cells, vascular endothelium, plasma cells and fibroblasts. Patients with non
      immunological KCS had similar characteristics as SS1 in number and activity,
      showing a normal morphological pattern. Control subjects showed a higher number
      of active nerve fibres. CONCLUSION: Main lachrymal gland from patients with SS1
      were therefore definitively innervated with moderate activity and normal
      structures. The ultrastructural study demonstrated there were no statistical
      differences with respect to patients with non-autoimmune KCS. Immunohistochemical
      studies showed a similar VIP activity in lachrymal gland between patients with
      SS1 and KCS, but there was a significant decrease in the innervation activity
      with regard to control subjects. All this implies that the autoimmunological
      factor in patients with SS1 does not significantly affect the lachrymal gland
      innervation.

PMID- 12410410
TI  - [A case of punctate inner choroidopathy: differential diagnosis].
AB  - CASE REPORT: We present the case of a 27-year old woman suffering from a
      chorioretinal inflammatory disease that was diagnosed as punctate inner
      choroidopathy (PIC) after a complete ophthalmic evaluation. DISCUSSION: PIC must
      be taken into consideration when evaluating a patient with a white dot syndrome.

PMID- 12410411
TI  - [Renal-coloboma syndrome].
AB  - CASE REPORT: We describe a woman with optic disc pit and bilateral renal
      hypoplasia as a papillorenal syndrome. DNA analysis for PAX2 mutations revealed a
      heterozygous mutation (nucleotide 619 in exon 9). A first uncle and a cousin had
      the same PAX2 mutation. DISCUSSION: The association of optic nerve colobomas and
      renal anomalies comprises a autosomal dominant syndrome for mutations in the PAX2
      gene. Ophthalmic and renal diseases are highly variable; the ophthalmologist must
      check for a renal problem when a coloboma is detected.

PMID- 12410412
TI  - [First documents about the visual pathways].

PMID- 12410413
TI  - [The insect's eyes].

PMID- 12410414
TI  - [Sympathetic ophthalmia and intraocular silicone oil].

PMID- 12410415
TI  - [Ocular toxocariosis: the reality of a little known problem].

PMID- 12410416
TI  - [Macrotrabeculectomy].

PMID- 12410417
TI  - [Paralytic ectropion correction with porous polyethylene spacer by subciliar
      external approach].
AB  - PURPOSE: To evaluate the efficacy of porous polyethylene spacer in paralytic
      ectropion. METHODS: Nine eyes of 8 patients (5 male and 3 female, medium age 55.6
      S.D. 11.2 years) with paralytic ectropion were operated. All of them presented a
      scleral show of more than 3 mm, exposure queratopathy and epiphora grade III-IV
      in Munk scale. A tarsal strip procedure, internal cathoplasty and porous
      polyethylene spacer sutured to the inferior border of the tarsal plate and over
      the palpebral retractors by subciliar external approach were performed. RESULTS:
      The mean followup time was 9.8 S.D. 4.3 months. The scleral show, exposure
      queratopathy and epiphora improved in all patients. There were two extrusions of
      the synthetic material, with removal of the implant in one of them. In these two
      cases a long lasting facial palsy with miocutaneous atrophy was the cause of the
      ectropion. CONCLUSIONS: Porous polyethylene speacer is a good alternative for
      paralytic ectropion treatment. This technique decreases the risk of infectious
      disease transmission as in homologous grafts and the need of a second surgical
      procedure as in autologous grafts.

PMID- 12410418
TI  - [Variability of electrophysiological readings in mature cataracts].
AB  - PURPOSE: To find out whether the opacity of the lens in well-developed cataracts
      might be so dense as to influence the electrophysiological readings in any way,
      modifying these to such an extent that they might become pathological. METHOD: A
      prospective study was carried out on 24 eyes from 21 patients with advanced
      cataracts (visual acuity from light perception and counting fingers making it
      impossible to see the retina). During the study, the eyes were subjected to an
      electrophysiological exploration: electroretinogram (ERG) and visual evoked
      potentials (VEP), both before and after surgery, analysing the possible changes
      in the recordings attribuitable to the opacity of the lens. RESULTS: No
      significant differences were observed in the electrophysiological readings before
      surgery with respect to postoperative readings, either in terms of latencies or
      in the amplitude of readings, in either the ERG or in the VEP in all the explored
      eyes. Although an increase in the amplitude and a slight wave reduction in
      latencies were indeed observed in the ERG following surgery, these values were
      not significant. CONCLUSIONS: The opacity of the lens itself does not
      significantly change the values of the electrophysiological readings, so that
      electrophysiological exploration in well-developed cataracts is considered to be
      most accurate test for predicting visual function in these patients.

PMID- 12410419
TI  - [Respiratory effects of chronic therapy with latanoprost in patients with chronic
      obstructive pulmonary disease (COPD)].
AB  - PURPOSE: To study the respiratory effects of chronic therapy with latanoprost in
      Chronic Obstructive Pulmonary Disease (COPD) patients. METHODS: We prospectively
      performed a spirometry in 19 COPD patients treated with latanoprost for more than
      3 months, and the same masked-examiner repeated the test, under the same
      conditions, one week after latanoprost wash-out. RESULTS: We found that
      latanoprost withdrawal increased forced espiratory volume (FEV1) (litre) from 1.5
      S.D. 0.5 to 1.6 S.D. 0.5 and FEV1/FVC (forced vital capacity) index from 64.4
      S.D. 8.6% to 66.5 S.D. 7.7% (both comparisons p=0.02, Wilcoxon signed-rank test).
      CONCLUSION: Chronic therapy with latanoprost seems to induce a mild, though
      statistically significant, bronchoconstriction in COPD patients.

PMID- 12410420
TI  - [Photocoagulation guided by fundus camera (new photocoagulation method of the
      retina with a non-contact and wide field system)].
AB  - PURPOSE: To design a device that integrates a laser photocoagulator in a fundus
      camera so that the functions of both are incorporated for their simultaneous use.
      This system would allow the visualizacion of the fundus during photocoagulation,
      with a no-contact, no hand-helped lens technique. MATERIAL AND METHODS: To test
      the device we used a fundus camera Fx500 (Kowa) and a diode laser Oculight SLx
      (Iris Medical). We analysed the physical and power laser parameters, performing a
      comprehensive control of the device's safety. In order to measure the error in
      the precision of the laser, we designed a micrometric test to evaluate the
      directionality of the beam and the focusing system. Finally, we test the size,
      time of exposure and intensity necessary to obtain an effective impact. RESULTS:
      With our system, transpupilar photocoagulation fullfils the main safety
      requirements on laser radiation and illumination in retinoscopy. After diverse
      adjustments, the laser impacts were placed in the desired retinal areas. The
      lesions generated in the pig eyes were quite similar to those obtained by
      conventional techniques and they were time and intensity dependent. CONCLUSIONS:
      Photocoagulation with our sytem is very simple and potentially safe and
      effective. It may facilitate the photocoagulation process inasmuch as it is more
      comfortable and user-friendly.

PMID- 12410421
TI  - [Choroidal melanoma treated with 810 nm diode laser and indocyanine green. A case
      report].
AB  - CASE REPORT: A 35 year-old female with a pigmented choroidal tumor in the
      inferotemporal quadrant, of 3.31 x 7.64 x 5.46 mm. The patient received an
      intravenous injection of 25 mg of indocyanine green previous to photocoagulation
      of the lesion with an 810 nm diode laser. After one year follow-up the tumor
      showed involution demonstrated by clinical and ultrasonographic evaluation.
      DISCUSSION: Indocyanine green allows maximal absortion of light energy delivered
      by diode laser, enhancing its action by making the deepest tissues vulnerable to
      photocoagulation and reducing time of exposure and number of sessions.

PMID- 12410422
TI  - [Anophthalmia as an isolated congenital defect].
AB  - CASE REPORT: We present the case of a newborn male whose only anomaly was an
      anophthalmia in his left eye. Complementary explorations were carried out to
      discard associated systemic pathologies. DISCUSSION: Anophthalmia/microphthalmia
      is the most frequent congenital eye malformation in the newborn. Its prevalence
      in Spain for the past twenty years was 21.34/100,000 newborn. The most usual
      presentation is as part of syndromes, appearing only exceptionally in an isolated
      way. It is important for the ophthalmologist to be aware of this pathology since
      the early treatment, because the corresponding orbital prosthesis may help to
      avoid, at least in part, dysmorphogenesis and derived aesthetic problems.

PMID- 12410423
TI  - [Intraoperatory rupture of the vein in an arteriovenous crossing sheathotomy].
AB  - CASE REPORT: We present a 43 year-old man with hypertension, diabetes and
      hypercholesterolemia who suffered an inferior temporal branch retinal vein
      occlusion in his right eye (visual acuity: counting fingers). An arteriovenous
      adventitial sheathotomy was made but the vein was perforated during surgery. The
      eye fundus and his final visual acuity improved (20/40) in spite of the
      complication. DISCUSSION: We comment the published experiences with this surgery
      and its complications.

PMID- 12410424
TI  - [Historical background of studies on eye morphogenesis (III)].

PMID- 12410426
TI  - [The neurasthenia as eternal revenant].

PMID- 12410428
TI  - [The diagnosis of brain death: medical and legal aspects with special reference
      to the German Transplantation Law (TPG)].
AB  - The diagnosis of brain death following total and irreversible cessation of all
      cerebral functions is based on anthropological assumptions and conventions as
      well as on the exact medical diagnosis of total loss of brain function. The
      question whether individual life ends after cerebral function is irreversibly
      lost cannot be answered by medical definition alone. Clear and unrefutable legal
      definitions of death and the cessation of the rights of the individual must be
      provided before organs may be harvested from brain dead individuals. Acceptance
      of these definitions by the general population is of paramount importance for the
      practice of organ donation. In the first part of this article, the legal
      definition of death and the provisions of the German transplantation law are
      critically reviewed. The legal statements deal with the question of the
      definition of death and how death can be detected. The provisions of the German
      transplantation law are referenced with special attention to the provision of
      prior consent to the removal of organs following after the diagnosis of brain
      death. The provisions of the German constitution with respect to the preservation
      of the personal rights of the individual are discussed in the light of organ
      harvesting. The second part deals with the medical procedure of determining brain
      death in adults. The medical statements pertain to the diagnostic steps to be
      taken in the diagnosis and determination of brain death. The prerequisites for
      entering the diagnostic procedure to determine brain death are described. The
      clinical signs of total and irreversible cessation of brain function are listed,
      and the technical examinations to corroborate the clinical signs of brain death
      as accepted in Germany are delineated. In the perspective of the authors,
      individuals having suffered brain death still possess the protection of their
      personal human rights according to the German constitution since it cannot be
      conclusively demonstrated that total loss of brain function alone constitutes the
      cessation of life in the sense of the German constitution.

PMID- 12410427
TI  - [On the history of the concept neurasthenia and its modern variants chronic
      fatigue-syndrome, fibromyalgia and multiple chemical sensitivities].
AB  - This article deals with the history of the terminological and nosological
      development of the concept neurasthenia introduced in 1869 by George Miller Beard
      and in particular with its reappearance in western medicine in the 1980 s.
      Beginning with its predecessors in antiquity and continuing with hypochondria,
      which became a fashionable disease in the 18 th century, the concept neurasthenia
      reached a high point and world-wide medical acceptance at the end of the 19
      th/beginning of the 20 th century. However, between the 1930 s and 1960 s it
      declined in popularity and gradually disappeared until finally it only had a
      rudimentary nosological role in the term "pseudoneurasthenia". In the countries
      of the Far East, on the contrary, the concept of neurasthenia has been in
      continual use since its importation in the first decades of the last century. In
      the 1980 s, when an interest in the symptoms of chronic fatigue was reawakened in
      western medicine, the concept neurasthenia reappeared, this time to define the
      particular form of a neurotic disorder. Parallel to these developments increasing
      importance was attached to clinical descriptions of illnesses which on account of
      their similarity to the symptoms of neurasthenia could be termed modern variants
      of the concept neurasthenia. These are "Chronic-Fatigue-Syndrome", "Fibromyalgia"
      and "Multiple Chemical Sensitivities" which have more or less adopted the organic
      inheritance of Beard's former concept of neurasthenia, despite the fact that so
      far the question of organicity could not be decisively answered in a single case.
      In order to clarify possible influences on the development of the concept
      neurasthenia and its variants, the theories and ideas of E. Shorter, medical
      historian at the University of Toronto, are discussed in the final part of the
      article, whereby the particular cultural background in each case has a decisive
      influence on the manifestation of the psychosomatic symptoms.

PMID- 12410429
TI  - [Temporal perception and organisation, neuronal synchronisation and
      schizophrenia].
AB  - Basic perceptual or motor skills involving the central nervous system as well as
      the subjective present require the orderly temporal organization of internal and
      external information. Current research in schizophrenia increasingly centers on
      the accompanying neurocognitive deficits with frequent reports of altered
      temporal processes. There has been, however, less explicit research on the basic
      phenomenon of temporal order. Using concrete operationalized neuropsychological
      procedures the present study addressed the question whether chronic schizophrenic
      patients (28 medicated as well as 7 unmedicated) differ in their ability to
      correctly judge the temporal order of visual or acoustic stimuli when compared
      with a healthy control group (n = 26). Within this context we found a significant
      impairment in basal temporal perception among patients. Moderating variables such
      as medication, attention deficits or the effects of motivation as an essential
      explanatory factor for this finding could be excluded by statistical analysis.
      Instead, our findings point to a fundamental disturbance in the temporal
      coordination of neuronal network functions in association with schizophrenic
      psychoses. Within this context neurophysiological, neurochemical, neuroanatomical
      and neuropsychological overlapping of schizophrenia and temporal perception are
      being presented along with a discussion of the hypothesis that disturbances in
      neuronal synchronization and in timing processes at different levels are of
      essence and a possible underlying substrate in the schizophrenic spectrum.

PMID- 12410430
TI  - [Attitudes of psychiatrists toward physician-assisted suicide].
AB  - BACKGROUND: Physician-assisted suicide (PAS) is an important subject of the
      public debate. So far, legal regulations exist in the Netherlands, Belgium and in
      Oregon (USA). This review reports results of nine empirical studies from Japan,
      the Netherlands, the United Kingdom and the U. S. which examine attitudes of
      psychiatrists toward PAS. RESULTS: The approval of PAS by psychiatrists varies
      between the four countries (40 - 69 %). Comparisons with the attitudes of other
      physicians show a greater agreement among the psychiatrists. A psychiatric
      examination in order to evaluate competence even in patients with severe somatic
      illness was advocated by the majority of psychiatrists. CONCLUSION:
      Psychiatrists' attitudes toward PAS vary and are compared with other medical
      specialties, as well as in different legal and cultural contexts. Therefore, and
      because of missing empirical studies, results can not be transferred into the
      context of German speaking countries easily. So far, no acknowledged criteria for
      the assessment of competence exist. Further empirical research is needed on
      German psychiatrists' attitudes towards PAS and on competence assessment at the
      end of life. It remains an open question how legal changes and future
      developments of palliative care will influence attitudes toward PAS.

PMID- 12410432
TI  - [Wilhelm Griesingers "Magna Charta" of psychiatry. Its reception and impact on
      modern psychiatry].
AB  - The work of Wilhelm Griesinger, really a magna charta of psychiatry, is usually
      reduced to just one sentence: "Geisteskrankheiten sind Gehirnkrankheiten",
      roughly: "mental illnesses are brain disorders". However, this is neither
      explicitly stated in Griesingers work nor does it adequately summarise his
      conception. This misinterpretation will be questioned by a careful analysis of
      the literature, and, in addition to that, the dimensions of Griesingers
      psychiatry including its delayed impact on the development of modern psychiatry
      will be described.

PMID- 12410431
TI  - [Exogenous psychosis induced by cobalamin-deficiency].
AB  - The case of a 69 years old female patient is reported, who developed paranoid
      behaviour due to cobalamin-deficiency without megaloblastosis based on a chronic
      gastric atrophy. The psychosis showed complete remission after vitamin B 12
      supplementation. The discussion leads to the question, whether or not chronic use
      of tricyclic antidepressants may be one cause of atrophic gastritis. Furthermore,
      differentialdiagnostic reflections consider the role of cobalamine and folate in
      the synthesis of monoamine neurotransmitters in the brain.

PMID- 12410433
TI  - [Sex specific trends of sudden cardiac death and acute myocardial infarction:
      results of the population-based KORA/MONICA-Augsburg register 1985 to 1998].
AB  - BACKGROUND AND AIM: Myocardial infarction (MI) is the main single cause of death
      in adult populations. For the MONICA Augsburg population, MI-morbidity,
      mortality, and 28-day case fatality and their determinants were assessed by
      gender, and suggestions for an intensified acute care program were presented.
      PATIENTS AND METHODS: From 1985 to 1998, 13 499 25- to 74-year-old MI cases (9537
      men, 3962 women) were registered; 7873 cases (5300 men, 2573 women) died within
      28 days. Cardiac deaths were identified by regional health departments; causes of
      death were validated by the last treating physician and the coroner (response >
      90 %). Hospitalized patients were interviewed about history and circumstances of
      the acute event; treatment data were abstracted from hospital charts. The
      prehospital phase, the first and the 2nd to 28thday after hospitalization were
      analyzed separately. RESULTS: MI-morbidity per 100 000 population declined from
      560 to 397 MI cases in men and from 161 to 145 in women; mortality decreased from
      317 to 232 in men and from 101 to 96 in women. The decline in men was due to
      decreasing incident and recurrent MI whereas in women it was only due to a
      reduction of recurrent MI. One third died before hospitalization, mainly at home.
      Case fatality (CF) on the first day in hospital increased. In 24 hour survivors,
      evidence based treatment increased considerably, and was accompanied by
      decreasing 28-day-CF from 13.0 % to 8.4 % in men, and from 12.5 % to 10.7 % in
      women. CONCLUSION: Aggressive risk factor management and education of patients
      with cardiovascular risk factors concerning acute symptoms and the use of the
      emergency system will consequently improve pre-hospital and 28-day survival of
      the population.

PMID- 12410434
TI  - [Endometriosis of the transverse colon--a rare localization].
AB  - HISTORY: A 65-year-old woman with no complaints came to our hospital for a
      colonoscopy because of a family history of a colorectal carcinoma. Because of
      postmenopausal complaints she had been undergoing estrogen therapy for the past
      five years. INVESTIGATIONS: Colonoscopy revealed a 2 x 2 cm polyp like structure
      with central tissue proliferation in the transverse colon. Neither
      chromoendoscopy with indigocarmine nor multiple biopsies indicated an adenomatous
      glandular proliferation. Miniendosonography revealed the image of a tumour
      located in the muscularis propria. DIAGNOSIS AND CLINICAL COURSE: As a malign
      process could not definitely be excluded, a colon segment resection was carried
      out by laparoscopy. In the operative specimen there was a 2 x 2 cm large tumour
      growing under the mucosa. Histologically it was an intramural manifestation of an
      extragenital endometriosis in the area of the muscularis propria with resulting
      nodular proliferation of the local muscle system. The ectopic endometrial glands
      in the area of the endometriosis revealed a complex hyperplasia without atypical
      features, an image suggesting oestrogen stimulation. CONCLUSION: In many cases
      the diagnosis of an intestinal endometriosis can not be made through a non
      invasive diagnostic method such as colonoscopy with biopsy because of the
      intramural localisation in the muscularis propria. In order to safely rule out a
      malignant lesion, in unclear cases a resection should be aimed at.

PMID- 12410435
TI  - [Pancreatic cancer--Case report].

PMID- 12410436
TI  - [Pancreatic cancer--diagnostic].

PMID- 12410437
TI  - [Pancreatic cancer--treatment].

PMID- 12410441
TI  - [Antibacterial products in the home: chance or hazard?].

PMID- 12410440
TI  - [Montelukast].

PMID- 12410442
TI  - [Is anticoagulation with heparins in phenprocoumon treated patients safe during
      operations?].

PMID- 12410444
TI  - [Induction of remission with infliximab in therapy-refractory Wegener's
      granulomatosis--Follow-up of six patients].

PMID- 12410443
TI  - [Deficits in quality care by physicians].

PMID- 12410445
TI  - [Orthopedic surgery of the knee joint. Proceedings of the German Orthopedics
      Congress. Berlin, 2001].

PMID- 12410446
TI  - [MRI vs. arthroscopy in the diagnosis of cartilage lesions in the knee. Can MRI
      take place of arthroscopy?].
AB  - INTRODUCTION: The accuracy of magnet resonance imaging in diagnosing cartilage
      lesions is discussed controversially. The sensitivity of this examination ranges
      from 15 % to 96 %. Clinical evidence demonstrates that cartilage lesions,
      diagnosed by MRI, were not confirmed in arthroscopy. The purpose of this
      prospective study was to analyse the practicability of replacing arthroscopy by
      MRI in diagnosis of cartilage lesions. PATIENTS AND METHODS: 195 patients with
      acute or chronic knee pain were examined by reason of a pathological clinic
      result by MRI preoperatively. In group A (n = 86), a standard program was
      performed in the radiological department of German Army Hospital (sagittal STIR
      TSE und PD TSE, coronary und transversal T2 FFE [TR = 660 ms, TE = 18 ms, FA = 30
      degrees, 512er-Matrix]), in 21 patients (subgroup AK) a cartilage specific
      sequence (fs T1 W FFE) without gadolinium was added. Patients in group B (n = 88)
      were examined in a private outpatient clinic (sagittal T1 SE, T2 SE and T2 FLASH
      [TR = 608 ms, TE = 18 ms, FA = 20 degrees, 256er-Matrix]) with the use of
      gadolinium. A clear clinical diagnosis had to be performed before MRI
      examination. RESULTS: 156 lesions of the cartilage were detected
      arthroscopically. The sensitivity of the examination was in group A 33 %; group B
      53 %; group AK 38 %, specificity in group A 99 %; group B 98 % and group AK 98 %.
      The positive and negative predictive values were in group A 75 %/98 %; group B 48
      %/98 % and in group AK 50 %/97 %. CONCLUSION: MRI was not able to detect reliable
      cartilage lesions. Until now, arthroscopy is the golden standard to detect
      cartilage lesions.

PMID- 12410447
TI  - [Arthroscopic management of tibial plateau fractures].
AB  - Since the mid 1980 s the arthroscopically and radiologically controlled
      management of tibial plateau fractures is an established part of arthroscopic
      surgery of the knee. The aim of this study is to analyse the results of this
      method in our patient population. Between January 1, 1994 and December 31, 1998
      59 patients were operated under arthroscopic and radiologic control. Of the 59
      tibial plateau fractures there were concomitant ligamentous injuries in 21 cases.
      In 34 cases an additional arthroscopic procedure was performed (partial
      meniscectomy 19 times, a meniscal repair 7 times. An arthroscopic procedure was
      necessary because of chondral lesions 14 times, and in 10 cases a rupture of the
      ACL was found, which was treated by resection). None of the 8 patients with
      lateral wedge fracture had a concomitant intraarticular lesion. The
      intraoperative use of Endobon provided good mechanical stability, but it is not
      always necessary. The negative aspect of Endobon, however, is the high cost. The
      number of complications in our series was low (3 intra- and 6 postoperative
      complications). The average follow-up interval was 48 months. According to the
      Lysholm-Score, 41 patients investigated obtained an average of 84 points. Because
      of its good results this procedure can be recommended when conducted by an
      experienced arthroscopic surgeon. However, the range of indications is limited to
      special tibial plateau fractures. In case of intraoperative problems or
      complications we recommend an early change to conventional methods of internal
      fixation of tibial plateau fractures.

PMID- 12410449
TI  - [Anterior cruciate ligament reconstruction - graft options and fixation
      techniques].
AB  - With the introduction of arthroscopy most of the surgeon have changed their
      technique in ACL-reconstruction from open to arthroscopically performed
      techniques. Several new techniques have been developed in the past, including new
      fixation devices and different grafts. The cruciate ligament reconstruction
      comprises a composition of both, the graft and the fixation to the bone. Well
      accepted autografts are the patellar midthird, the semitendinosus/gracilis or the
      quadriceps tendon. In special cases allografts are alternatives. The fixation can
      cause failure due to overstrain or creep during the postoperative period of
      healing. Considering their biomechanical properties, cruciate ligament
      reconstruction should aim for a graft behavior comparable with the native
      cruciate ligament. Results gained from basic science and clinical studies are
      reviewed in the following article.

PMID- 12410448
TI  - [Midterm results after treatment of injuries of the distal extensor mechanism
      with the MPT-fixateur. A critical analysis].
AB  - Between 1994 and 2000 at our institution 37 patients (8 women, 29 men) with
      fractures of the lower patellar pole and a proximal avulsion fracture of the
      patellar ligament underwent a primary surgical repair and patello-tibial fixateur
      for external protection. All patients underwent immediately after the
      reconstruction a functional rehabilitation program without any movement
      limitation and under early full weight bearing. Postoperative follow-up after an
      average of 58.5 months (range 14 to 102 months) was possible in 26 patients.
      Physical examination, roentgenographic evaluation and isokinetic testing were
      performed. The clinical evaluation was carried out according to the strict
      criteria of the IKDC-score. The radiological measurement of the patella height
      was carried out using the index of Blackburne & Peel; the femoropatellar
      changings were registered according to the score of Sperner. The clinical
      evaluation showed in 8 patients a normal, in 10 patients a nearly normal, in 7
      patients an abnormal and only in 1 patient a severe abnormal result. The average
      muscle strength deficit in comparison to the contralateral knee joint was between
      10 % and 20 %. All patients showed clinically and radiologically a sufficient
      distal knee extensor mechanism. The patella height ratio was in the average 0.82
      on the injured and 0.79 on the non-injured side. In 17 cases we didn't saw any
      femoropatellar arthrosis. Eight patients showed a moderate femoropatellar
      arthrosis. There was no case with severe femoropatellar arthrosis. By good follow
      up results in general we could demonstrate the value of the MPT-fixateur as a
      dynamic protection method after reconstructive operations of the distal knee
      extensor mechanism.

PMID- 12410450
TI  - [Primary- and revision-reconstruction of the anterior cruciate ligament with
      allografts: a retrospective study including 325 patients].
AB  - At our institution we have used fresh-frozen allografts for the reconstruction of
      the anterior and posterior cruciate ligament since 1993. METHOD: In this
      retrospective study we evaluated the clinical outcome of 325 fresh-frozen
      allografts (bone-patellar-tendon-bone allografts and Achilles-bone-tendon
      allografts) for primary and revision ACL-reconstruction. Patients (average age 38
      years) were operated between 5/1993 and 2/1998 and mean follow-up was 38 (range
      24 to 71) months. Clinical evaluation consisted of a case history, an
      examination, IKDC, Cincinnati knee score (CKS), KT-1000 testing and standardized
      X-rays. RESULTS: Overall subjective rating according to the CKS was more than 82
      points for both groups. Objective results according to the IKDC were normal or
      nearly normal in 75.6 % of primary- and 67.0 % of revision-ACL reconstructions.
      The stability measured with the KT-1000 showed an average maximum side to side
      difference of 2.1 mm for primary ACL reconstruction and 2.3 mm for revisioners.
      The total failure-rate (= rerupture-rate + laxity-failures) was 13.7 % for
      primary and 15.0 % for revision ACL reconstructions. CONCLUSION: Given the
      increased failure-rate, autograft tissue remains our graft of first choice for
      primary ACL-reconstruction. We advise to reserve allografts for revision
      procedures where suitable autogenous tissues have been previously compromised,
      where a contraindication for autogenous tissue harvest exists or for multiple
      ligament surgery. No specific complications were observed with the use of
      allograft tissue.

PMID- 12410451
TI  - [Revision of the anterior cruciate ligament in TransFix(R)- and OATS(R)
      technique].
AB  - Transplant failure after anterior cruciate ligament-plastic is a typical
      complication. In larger collectives, revisions amount to about 8-12 % of the
      reconstructive operations of the anterior cruciate ligament. The number of
      revisions is also growing in our clinic and makes at present 11 %. There are
      different reasons of transplant failure. Many mistakes occur as a result of
      technical pitfalls during the preparation. A new "adequate trauma" is rarely the
      cause of a rerupture. In this paper a new concept of revision in failed anterior
      cruciate ligament reconstructions will be presented, which can be frequently
      performed as one-step technique even in bone tunnel enlargement or sclerosis of
      the tunnel. Our results in 21 cases will be discussed with the literature. In our
      opinion the TransFix(R) technique, if necessary in conjunction with the OATS(R)
      technical equipment, is a reproducable alternative for one step revision surgery
      and should be recommended.

PMID- 12410453
TI  - [Gait anlysis in patients with osteoarthritis of the knee before and after total
      knee replacement].
AB  - AIM: The reduction in quadriceps femoris muscle activation is considered to be
      one of the major mechanisms involved in pathological motion patterns in patients
      with osteoarthritis (OA) of the knee. These activation deficits are, at least in
      part, reversible after total knee arthroplasty (TKA). The purpose of this study
      was to investigate the effects of TKA on motion patterns in patients with OA of
      the knee. METHOD: 50 patients with knee OA were investigated prior and at 33 +/-
      8 months after unilateral TKA. The control group comprised 17 healthy volunteers
      matched to the study group with respect to age. The gait analysis was performed
      with an optoelectronic motion analysis system (Elite(R), Italian). RESULTS: Step
      length, step duration and velocity increased after surgery (p < 0.05), but
      remained lower than the values of the controls (p < 0.05). Extension angles in
      stand and swing phase remained unchanged and significantly lower when compared to
      control values (p = 0.01, p = 0.04). Flexion angles in swing (p = 0.02) and stand
      phase (p = 0.01) increased on the operated side and were significantly higher
      than the flexion angle in the control group (p = 0.02, p = 0.03). Reextension in
      stand phase, which was investigated for quantification of functional range of
      motion, increased bilaterally after surgery (p < 0.01), but remained lower than
      the reextension of the controls (p </= 0.01). CONCLUSION: Although a significant
      improvement of pathological motion patterns in patients with OA of the knee after
      unilateral TKA occurred, a deficit persisted 33 +/- 8 months after surgery. The
      improvement of functional range of motion in stand phase was only caused by
      increased flexion. No influence was found with gait analysis on extension after
      TKA.

PMID- 12410452
TI  - [Results after anterior cruciate ligament revision surgery].
AB  - Revision surgery after failed anterior cruciate ligament reconstructions has
      increased tremendously. Reasons for revisions are persistent loss of motion,
      recurrent joint laxity, a painful knee or joint infections. In a retrospective
      study with a mean follow-up of 35.2 months 82 patients were examined after
      revision surgery. Time interval between primary and revision surgery, causes of
      revisions and treatment modalities were evaluated and compared to subjective,
      clinical and radiological parameters. In all cases a clinical improvement could
      be achieved. But results after revision operations are inferior to first
      reconstructions. The mean Tegner score improved after revision surgery from 2.4
      to 4.6 points. The mean Lysholm score increased after secondary surgery from 54
      to 76 points. The overall IKDC results of follow-up showed category A - 35.4 %, B
      - 39 %, C - 13.4 % and D - 12.2 % of the patients. A distinction between patients
      with preoperative isolated loss of motion and patients with isolated joint laxity
      seems useful. Revision operations with an improvement of joint mobility showed a
      higher subjective satisfaction, a lower rate of joint instability and better
      overall IKDC result compared to those with a high grade of preoperative joint
      laxity. Better results could be also achieved for early revision compared to late
      revisions and also for autologous grafts compared to alloplastic revision plasty.
      Transplant retaining procedures are only possible in selected cases and showed no
      clinical benefit compared to second revision of cruciate replacements. As a
      result of this study we conclude that early revision operation and the use of an
      autologous graft can be recommended but the surgeon has to be prepared to
      encounter many demanding technical problems.

PMID- 12410454
TI  - [Kinematic changes after bicondylar resurfacing knee arthroplasty].
AB  - AIM: Knee joint motion appears as a hinge movement around the flexion - extension
      axis. But corresponding to the rolling-sliding-mechanism and alternative models
      of knee joint kinematics an instant center pathway must be expected. Objective of
      the study was the comparison of this pathway when assessed in the sagittal plane
      in patients with preoperative varus or valgus deformity. METHOD: A total of 40
      patients either with varus or valgus deformity (20 in each group) were examined
      before and 6 months after implantation of PFC(R)-SIGMA prostheses. Apart from the
      influence of knee joint deformity (35 degrees varus to 24 degrees valgus), a so
      called soft tissue ratio was investigated. Therefore the relation of thigh and
      femur as well as lower limb and tibia diameters was calculated and combined in
      one value. The examination by means of photogrammetry consisted of a standardized
      chair with passive knee joint movement (90 degrees to 0 degrees flexion)
      supported by an electric motor. The position of defined skin markers was assessed
      by digital camara with online transmission to PC. The instant center pathway was
      then evaluated applying the Reuleaux-technique based on the changes of skin
      marker positions. RESULTS: Results showed a dependence of the course and
      dimension of the instant center pathway on the extent of soft tissue ratio as
      well as knee joint deformity. Small values of the ratio (W = 2.9) were
      represented by round or oval courses of the pathway whereas increasing ratios (W
      = 4.0) led to triangular and slightly increased dimensions of the courses. Varus
      deformitywas primarily combined with an increase of the pathways dimension and in
      contrast, valgus deformity showed decreased pathways. In each case, dimension
      normalized after prostheses implantation. CONCLUSION: The instant center pathway
      of knee joint motion showed for both patient groups characteristic phenomen. They
      were clearly combined with constitutional and clinical features of each patient.

PMID- 12410455
TI  - [Bone defects in revision total knee arthroplasty: classification and
      management].
AB  - The goal of bone reconstruction in revision total knee arthroplasty is to provide
      a stable support for the implant and to re-establish the correct joint line.
      Therefore, a useful, therapy-based classification of the defects is necessary.
      According to Stockley et al. (1992), the defects are classified into contained
      and uncontained defects. Uncontained defects can be reconstructed using
      structural allografts or metal wedges. In contained defects, cancellous allograft
      can be used. For aseptic loosening of total knee arthroplasty, the defect
      classification according to Engh and Parks (1994) can be helpful because of its
      recommendations for reconstruction. In case of the more common first or second
      graded defects, reconstruction is performed using modular revision components or
      allografts. For the rare third graded defects, bulk allografts or modular tumour
      endoprostheses are recommended. On the basis of more than 150 revision total knee
      arthroplasties performed in our hospital the classification of bone defects and
      their clinical consequences are presented in this review.

PMID- 12410456
TI  - [The influence of the drain suction in knee arthroplasty].
AB  - PROBLEM: In a prospective randomised clinical study, we investigated the impact
      of drain-suction on the post-operative blood loss and on both clinical and
      laboratory parameters after knee replacement operations. PATIENTS AND METHOD: In
      this study, 116 patients with unilateral implantation of knee replacements were
      evaluated. The patients' average age was 71.2 years. The operation was carried
      out mostly without tourniquet application. All patients received two wound
      drains, 57 with and 59 without suction. The postoperative blood loss as well as
      clinical and laboratory parameters were assessed. RESULTS: The average peri
      operative blood loss amounted to 338 ml. The post-operative blood loss in the
      group without drain suction was 436 ml and 528 ml in the group with suction. No
      significant differences could be found concerning the hemoglobin values pre
      operatively and on the first and seventh post-operative day, the drainage
      quantity 12, 24, 36, and 48 hours post-operatively, the wound healing and the
      CRP. Six patients in the group without and five patients in the group with drain
      suction had to receive blood transfusions. DISCUSSION: The application of suction
      on the drainage system had no significant impact on the post-operative blood loss
      and the postoperative course. In nine out of ten cases no homologous blood was
      needed.

PMID- 12410457
TI  - [Is meniscal repair an adequate procedure to prevent early osteoarthritis in
      athletes with chronic anterior knee instabilitity?].
AB  - We retrospectively evaluated the clinical outcome of arthroscopic assisted
      meniscal suture repair in athletes on different competitive sports levels with
      stable joint function and persisting anterior knee instability. Return to former
      sports levels and early osteoarthrotic changes were especially focussed.
      Examination included 50 athletes (32 men, 18 women) who underwent meniscal repair
      in inside-out technique during the period of 1989 to 1998. 23 patients had
      isolated full-thickness meniscal tears, 27 an associated rupture of the anterior
      cruciate ligament which was reconstructed in 13 cases with a patellar-tendon
      autograft. 3 study groups were formed referring to the athletes preoperative
      sports level evaluated with Tegner's score. Reexamination included Lysholm score,
      IKDC score and Fairbank's score. With a mean age of 32.1 years (range 13-53
      years) and an average follow-up of 6.3 years 72 % of the patients (n = 36) showed
      a stable joint function on reexamination. With no persisting anterior knee
      instability 86 % of the professional athletes returned to former full sports
      activities on competitive levels. Non competitive athletes returned in all cases
      (100 %) to their former level. Fairbank's score increased by 0.1 observing
      minimal osteoarthitic signs. However, persisting anterior knee instability showed
      on reexamination poor results. Only one third of all athletes were able to return
      to former activity levels. Osteoarthritic changes were observed in all patients.
      Professional athletes had the most severe osteoarthritic changes with a
      significant (p = 0.03) increase of 0.8 in Fairbank's score. The results
      demonstrate that complete recovery on sports activities after meniscal repair is
      not possible without reconstruction of the anterior cruciate ligament. Isolated
      meniscal repair shows poor results in persisting anterior knee instability and
      does not prevent increasing osteoarthritic changes in athletes.

PMID- 12410458
TI  - [Cross-linked hyaluronic acid in the treatment of osteoarthritis of the knee-
      results of a prospective randomized trial].
AB  - PURPOSE: The objective of this trial was to compare the effectiveness of
      intraarticular injection of highly cross-linked hyaluronic acid (HA) with
      intraarticular injection of gaseous oxygen (O 2 ) in patients with clinical
      symptoms of cartilage damage in the knee. METHODS: Based on arthroscopically
      verified diagnosis, 111 patients were randomised and treated prospectively either
      with HA or O 2. The treatment was completed with an exercise program. The follow
      up was one year. 109 patients (56 x HA, 53 x O 2 ) were statistically calculated
      with the Wilcoxon-test according to the results of the Lysholm-score, the Tegner
      activity-index, the Womac-score for pain, stiffness, function and the VAS for
      pain in rest and under strain. RESULTS: Both treatments were able to attain a
      statistically significant reduction of pain (VAS in rest and under strain, Womac
      part A), a reduction of joint stiffness (Womac part B) and improvement of joint
      function (Womac part C, Lysholm-score) during the follow up of one year. The
      Tegner-activity-index showed no significant change under both treatments. The
      comparison of both treatments showed differences in VAS under strain (p = 0.001),
      the Lysholm-score (p = 0.003), Womac part A (p = 0.003) and part C (p = 0.001).
      As a result HA showed significant better improvements with the VAS and Lysholm
      score and oxygen showed significant better changes in the Womac-score part A and
      C. The results with cartilage damage 2 degrees were the same as in the total (VAS
      strain: p = 0.029 for O 2, Lysholm-score: p = 0.003 for HA, WOMAC part A: p =
      0.009 for HA, Womac part C: p = 0.006 for O 2 ). The results with cartilage
      damage 3 degrees showed significant differences in reduction of joint stiffness
      (Womac part B: p = 0.012) for O 2. For cartilage damage 4 degrees HA showed
      significant reduction of pain (VAS rest: p = 0.001, VAS strain: p = 0.003) and O
      2 significant reduction of pain and function (Womac part A: p = 0.004, part C: p
      = 0.002). CONCLUSION: Both methods are suitable to improve significantly the
      discomfort due one year to osteoarthritis. The pain relief by HA and the
      improvement of joint function by O 2 treatment have been shown for higher degrees
      of cartilage damage.

PMID- 12410459
TI  - [Significance of lateral release in the therapy of patellar chondromalacia].
AB  - A retrospective study was performed in 26 patients who underwent an operation for
      femoro-patellar pain due to a patellar chondromalacia with or without minor
      patellar dislocation/lateral pressure syndrome. The average age of the patients
      was 28.5 (15-39) years. 22 of the 26 patients revealed minor chondral damages of
      the stages 1 and 2 according to Outerbridge. In 12 patients ("lavage" group), an
      arthroscopic joint debridement only was carried out, while an additional open,
      lateral retinaculum release was made in 14 patients ("lateral release" group).
      The patella's distance of dislocation according to Hepp was reduced on an average
      of 3.0 (0-7) mm (p = 0.0019). The results of Bentley's score obtained during the
      follow-up interval on an average of 30.1 (9 to 60) months were almost identical
      for both groups. "Good" and "very good" results were achieved in the "lavage"
      group (83.3 %) and "lateral release" group (78.6 % of the patients). Lateral
      release should be used in cases of patellar decentration between 5 and 10 mm and
      adequate pain symptoms. The post-operative distance of dislocation should be less
      than 5 mm. Under such conditions and with minor chondral damage, a combined
      approach by using an arthroscopic joint debridement and open lateral release is
      promising to treat a patellar dislocation/lateral pressure syndrome.

PMID- 12410460
TI  - [Recurrence of Baker's cysts with regard to operation procedure and
      intraarticular pathology].
AB  - During the period from January 1990 to December 1998 65 patients were operated
      upon for a Baker's cyst. 41 patients (43 operations) were subjected to a clinical
      and sonographical follow-up examination and interrogation. In 11 cases, the cysts
      were merely removed, while an open synovectomy was carried out four times
      (rheumatics) in addition to the removal of the cysts, and arthroscopy with
      exstirpation was performed in 28 cases. The total recurrence rate was 14 %
      (6/43). Any significant differences between the groups were not found (p =
      0.291). The overall complication rate was 18.6 %. In case of recurrence, the
      clinical results were significantly worse (p = 0.036). Apart from technical
      aspects of operation, the not quantifiable correlation between grade of
      chondromalacia and the formation of effusions following joint degeneration has to
      be discussed as a cause for recurrences. If both interventions are carried out in
      one course, there is no increased operative risk. Especially in cases with
      intraarticular pathological symptoms arthroscopy should precede each cyst
      exstirpation. With regard to the frequency of recurrence, the patients'
      expectation should be preoperatively objectified.

PMID- 12410461
TI  - [The importance of vascular injuries in sport accidents--a rare but serious
      complication].
AB  - There are about 1.5 million sports injuries in Germany every year, but
      concomitant vascular injuries are rarely encountered. Only single cases have been
      reported in the literature. The records of 216 patients with vascular injuries
      who were admitted to the university hospital in Jena between 1987 and 1996 were
      retrospectively reviewed. Six patients sustained a vascular injury during the
      accident in different kinds of sport. Vascular repair was successfully performed
      in three cases. Organ resection was necessary in two cases and one patient was
      treated conservatively. Most vascular lesions are related to blunt trauma which
      might create delayed symptoms of ischemia. Therefore measurement of limb
      pressures, Doppler scan, duplex ultrasonography and angiography are adjuncts in
      patients evaluation. In case of bleeding or complete ischemia the prompt arterial
      reconstruction is indicated and subsequently minimizes the risk of reperfusion
      injury.

PMID- 12410462
TI  - [The significance of oxidative mechanisms in diseases of the retina].
AB  - The eye is at high risk to be damaged by oxidative mechanisms. One major reason
      is the exposure to light throughout life. Anterior segment structures are mostly
      exposed to UV light. Visible blue light is believed to be a significant damaging
      mechanism for the retina. The biochemical composition of the posterior segment
      structures (unsaturated fatty acids) is an important factor making the eye more
      susceptible than other organs. Damaging mechanisms such as xanthin oxidase
      mechanisms are responsible for damage occurring in ischaemic diseases. These
      mechanisms are well known from diseases of other organs. Ischaemic processes are
      no longer believed to be the primary damaging mechanisms in diabetic retinopathy.
      Here, advanced glycation end products (AGE's) and related products may induce
      oxidative reactions and the expression of growth factors. In age-related macular
      degeneration photodynamic processes occurring already in childhood are believed
      to be a major factor contributing to the pathogenesis of the disease process. In
      addition, the expression of growth factors and new vessel growth can be initiated
      via inflammatory reactions or oxidative metabolites. In this manuscript we give
      an overview on oxidative mechanisms involved in the pathogenesis of retinal
      diseases. Different therapeutical and preventive approaches such as the results
      of the ARED-Study and possible side effects are discussed.

PMID- 12410463
TI  - [When is congenital hypertrophy of the retinal pigment epithelium (CHRPE)
      associated with the Gardner's syndrome? An overview with clinical examples].
AB  - Congenital hypertrophy of the retinal pigment epithelium (CHRPE) can be
      associated with Gardner's syndrome (GS). During childhood multiple adenomatose
      polyps develop in the colon ascendens (familiar-autosomal Polyposis coli [FAP]),
      and always become malignant until the age of 35. The tumour-suppressive FAP-gen
      was identified at the long arm of chromosome 5 (5q21). Ophthalmic funduscopy is
      very important. Patients with more than 3 CHRPE in one eye or a bilateral CHRPE,
      as well as patients with a positive family history and one unilateral solid CHRPE
      require further gastroenterological evaluation.

PMID- 12410464
TI  - [Do blind persons have a better sense of smell than normal sighted people?].
AB  - Functional disorders of sense organs may intensify the remaining senses. It is
      presumed that blind persons do not only hear better and have an intensified
      tactile sense but also have a stronger sense of smell. Better hearing ability was
      demonstrated by auditory evoked potentials. We investigated the sense of smell of
      blind persons by subjective tests (Sniffin' sticks: threshold, discrimination and
      identification) and for the first time also by objective tests (olfactory evoked
      potentials and trigeminal evoked potentials) and compared the results with the
      smelling ability of normal sighted persons by pair matching. Moreover, the
      investigated persons judged their performance via a questionnaire. The subjective
      test showed neither differences in the peripheral function nor in the central
      function between both groups. The amplitudes and latencies of the evoked
      potentials of vanillin, carbon dioxide and hydrogen sulfide were also not
      different. Blind persons tried unasked to identify the smell given in the
      discrimination test and thought themselves to be better in smelling. For the
      first time the smelling ability of blind people was compared with normal sighted
      people by objective test methods. Neither with subjective nor with objective
      methods differences were found.

PMID- 12410465
TI  - [Aberrometry due dilated pupils--Which mydriatic should be used?].
AB  - BACKGROUND: For a wavefront-based LASIK procedure aberrometric measurements are
      necessary via a dilated pupil. The more dilated the pupil is the more aberrations
      can be identified. There are different mydriatic eyedrops used to dilate the
      pupil. It is unclear so far which mydriatic is best for measuring aberrations
      before LASIK. METHODS: We performed aberrometry measurements on 50 eyes under the
      following different conditions: physiological mydriasis under mesopic
      environment, tropicamide-induced dilation, phenylephrine-induced dilation, and
      cyclopentolate-induced dilation. The wavefront measurements were compared with
      the respective subjective refraction (sr). RESULTS: The refractive myopic error
      measured by aberrometry was less than after subjective refraction depending on
      the mydriatic used. Phenylephrine-induced mydriasis resulted in 0.19 D less
      myopia, tropicamide induced 0.35 D less myopia, and cyclopentolate 0.42 D less on
      the average. The aberrometry measurements under mesopic conditions led to 0.24 D
      less myopia than measured subjectively. CONCLUSION: Using cyclopentolate eyedrops
      wavefront analysis results in a considerable difference in the preoperative
      refractive error compared to the standard subjective refraction. Regarding the
      average differences in refraction the aberrometry measurements after
      neosynephrine-induced dilation of the pupil usually resemble the subjective
      refractive error. For practical reasons we would like to recommend aberrometry
      measurements under mesopic conditions without applying mydriatics provided the
      pupillary diameter is at least 6 mm.

PMID- 12410466
TI  - [Visual acuity measured via the Freiburg visual acuity test (FVT), Bailey Lovie
      chart and Landolt Ring chart].
AB  - INTRODUCTION: If different ways for correcting refractive errors of the human eye
      have to be compared, accurate and reproducible measurement procedures are
      necessary. METHODS: Binocular visual acuity of 130 students without pathologies
      was measured with the Freiburg Visual Acuity Test, the Bailey-Lovie chart and a
      Landolt ring chart (4 orientations). The reproducibility of the FVT was
      determined by repeated measurements. RESULTS: The average visual acuity was 1.93
      +/- 0.03 (= 20/10.4) with the FVT, 1.82 +/- 0.03 (= 20/11) with the Landolt ring
      chart, and 1.48 +/- 0.02 (= 20/13.5) with the Bailey-Lovie chart. 50 % of all
      repeated measurements with the FVT were within an interval of +/- 0.035 logMAR
      from the mean value. 95 % were within +/- 0.1 logMAR. Results of earlier studies
      are discussed. CONCLUSION: On average, visual acuity values found with the
      Freiburg Visual Acuity Test were slightly larger as compared to the Landolt ring
      chart (difference = 0.025 logMAR). Taking the maximal difference of 0.05 logMAR
      tolerated by the international standard DIN EN ISO 8597 into account, both tests
      are equivalent. The results found with the Bailey-Lovie chart were substantially
      lower as compared to the Landolt ring chart (difference = 0.09 logMAR). The
      Freiburg Visual Acuity Test has a high reproducibility and measures visual acuity
      on a continuous scale that is not limited to the traditional visual acuity steps.
      Thus, it can be recommended as a reference procedure for comparative visual
      acuity studies.

PMID- 12410467
TI  - [Complications of a voluminous congenital ciliary body cyst].
AB  - BACKGROUND: Multiple cysts of iris and ciliary body may cause many complications
      such as acute or chronic angle closure glaucoma. PATIENT: We present a boy with
      multiple congenital cysts of the iris pigment epithelium and a voluminous cyst of
      the unpigmented ciliary body epithelium of the right eye. This resulted in
      lenticular astigmatism, concomitant strabismus divergens and subsequently to
      anisometropia. The voluminous cyst (8 x 12 mm in diameter) was folded around the
      lens, reached the optic axis and resulted in displacement of the lens and contact
      between the iris and the corneal endothelium from 6.30 to 11. After puncture and
      partial resection of the cyst at the age of 8 months the boy developed a
      subcapsular multivesicular cataractic clouding of the temporal lens and a
      progredient myopia (up to - 14.0/- 2.0/0 degrees ); in contrast the left eye was
      hyperopic (+ 3.5/- 3.75/0 degrees ). The lens was subluxated superonasally due to
      congenital damage of the zonular fibres. Because development of visual acuity
      seemed limited by these determinants (20/200 at the right eye), cataract surgery
      with posterior capsulorhexis, anterior vitrectomy, and implantation of a capsular
      tension ring and posterior chamber intraocular lens was performed at the age of
      nearly five. Actually, there is an orthotropia, best corrected visual acuity in
      the distance of 20/32 in the right and 20/20 in the left eye; binocular vision is
      somewhat restricted. CONCLUSION: Usually congenital cysts are clinically not very
      relevant; occasionally surgical intervention is required to ensure adequate
      development of visual acuity.

PMID- 12410468
TI  - [Horner's syndrome in dissection of the carotid artery after chiropractic
      manipulation].
AB  - CASE REPORT: We report on a 37-year old patient with sudden onset of pain of the
      right scalp and an ipsilateral small pupil, presenting five weeks after
      chiropractic manipulation of the neck. METHODS/RESULTS: Pharmacologic pupil
      testing showed a postganglionic Horner's syndrome on the right side. Magnetic
      resonance angiography confirmed the diagnosis of a dissection of the right
      internal carotid artery at a subacute stage. CONCLUSION: There appears to be a
      causal relationship between carotid artery dissection and the chiropractic
      manipulation of the cervical spine. Ophthalmological signs played the key role in
      detecting this complication.

PMID- 12410469
TI  - [Pterygoid corneal dystrophy].
AB  - BACKGROUND: Pterygia are characterised by progressive growth of fibrovascular
      tissue over the nasal limbus towards the corneal center with the loss of Bowman's
      layer. We report on three patients with bilateral symmetrical affection of the
      nasal and temporal limbus in one family. PATIENTS: A 81-year-old female, her 61
      year-old son and her 37-year-old grandson presented with a familiar form of
      pterygium-like corneal changes. Remarkable was the bilateral symmetrical
      affection with involvement of the nasal and temporal limbus. Both male patients
      had multiple excisions (including lamellar keratoplasty) but suffered from
      persistent recurrences, which led to sustained reduction of the visual acuity.
      Histological examination revealed typical elastoid degeneration of collagen
      fibres. CONCLUSION: We assume autosomal dominant heredity with varying expression
      for this "pterygoid corneal dystrophy". It does not seem to differ histologically
      from normal pterygia, but recurrences appear to be more frequent and more
      aggressive.

PMID- 12410470
TI  - [II: Difference plots or scattergram--when to use which?].
AB  - Sometimes the statistical comparison of diagnostic measurement methods or
      subsequent measurement series in the same individuals is based on bivariate
      scattergrams; correlation coefficients and linear regression lines are provided
      in addition. However, this strategy for data representation must be considered
      inappropriate, as soon as the measurement series under consideration show the
      same physical index (e.g. repeated measurement of the intraocular pressure [mm
      Hg] 2 and 4 weeks after glaucoma surgery). Such data can be handled by
      computation of the intraindividual difference of an individual's measurement. The
      resulting series of intraindividual deviations can then be analysed using
      standard strategies: description can be based on the intraindividual differences'
      median and quartiles, graphical representation on the differences' distribution's
      box whisker plot. This procedure is particularly attractive for data arising from
      ophthalmological studies, when two eyes of one patient are to be compared. The
      statistical comparison of diagnostic methods can further be based on the
      Bland/Altman diagram, which not only illustrates the distribution of differences,
      but also motivates a dependence between the order of deviations and the absolute
      order of the measurement values. Whereas a box plot of intraindividual
      differences and a Bland/Altman diagram illustrate the concordance of two
      measurement series, the correlation scattergram rather visualizes their
      reproducibility.

PMID- 12410472
TI  - Risk factors for development of vancomycin-resistant enterococcal bloodstream
      infection in patients with cancer who are colonized with vancomycin-resistant
      enterococci.
AB  - Vancomycin-resistant Enterococcus faecium (VRE) is a common nosocomial isolate,
      especially among patients with cancer. VRE infections have substantial
      attributable mortality among patients with cancer. The purpose of this study was
      to identify risk factors for developing bloodstream infection with VRE in
      patients with cancer who are colonized with VRE. VRE colonization was
      prospectively identified in 197 patients with cancer during 4-year period, of
      whom 179 (91%) had complete records for evaluation. Of these 179 patients, 24
      (13.4%) developed hospital-acquired VRE bloodstream infections. Risk factors for
      VRE bloodstream infection included vancomycin use (relative risk [RR], 1.98; 95%
      confidence interval [CI], 1.25-3.14), diabetes mellitus (RR, 3.91; 95% CI, 1.20
      12.77), gastrointestinal procedures (RR, 4.56; 95% CI, 1.05-19.7), and acute
      renal failure (RR, 3.10; 95% CI, 1.07-8.93). Strategies for preventing VRE
      bloodstream infection in VRE-colonized patients with cancer should include
      limiting vancomycin use and, perhaps, gastrointestinal procedures.

PMID- 12410473
TI  - Efficacy of atovaquone/proguanil for malaria prophylaxis in children and its
      effect on the immunogenicity of live oral typhoid and cholera vaccines.
AB  - A double-blind, placebo-controlled study was conducted to measure the impact of
      malaria prophylaxis with atovaquone/proguanil (A-P) on the immunogenicity of
      vaccines against typhoid fever and cholera, Salmonella serotype Typhi Ty21a and
      Vibrio cholerae CVD103-HgR, respectively. A total of 330 Gabonese schoolchildren
      were assigned to receive either A-P or placebo for 12 weeks. Vaccination occurred
      3 weeks after the start of prophylaxis, and immunogenicity was assessed 4 weeks
      after vaccination. The protective efficacy of A-P against Plasmodium falciparum
      malaria was of 97% (95% confidence interval, 79%-100%). The 2 treatment groups
      did not differ significantly with regard to changes in antibody titers after
      vaccination (P=.96 for anti-S. Typhi IgG antibodies, P=.07 for anti-S. Typhi IgA
      antibodies, and P=.64 for vibriocidal antibodies). The A-P combination was highly
      effective for malaria prophylaxis, without interfering with the in vivo
      immunogenicity of CVD103-HgR and Ty21a vaccines, and it could therefore be
      simultaneously administered with these vaccines.

PMID- 12410474
TI  - Lactobacillus bacteremia during a rapid increase in probiotic use of
      Lactobacillus rhamnosus GG in Finland.
AB  - Lactobacilli supposedly have low pathogenicity; they are seldom detected in blood
      culture. Lactobacillus rhamnosus GG, which originates indigenously in the human
      intestine, became available for use as a probiotic in 1990 in Finland. We
      evaluated the possible effects of the increased probiotic use of L. rhamnosus GG
      on the occurrence of bacteremia due to lactobacilli. Lactobacilli were isolated
      in 0.02% of all blood cultures and 0.2% of all blood cultures with positive
      results in Helsinki University Central Hospital and in Finland as a whole, and no
      trends were seen that suggested an increase in Lactobacillus bacteremia. The
      average incidence was 0.3 cases/100,000 inhabitants/year in 1995-2000 in Finland.
      Identification to the species level was done for 66 cases of Lactobacillus
      bacteremia, and 48 isolates were confirmed to be Lactobacillus strains. Twenty
      six of these strains were L. rhamnosus, and 11 isolates were identical to L.
      rhamnosus GG. The results indicate that increased probiotic use of L. rhamnosus
      GG has not led to an increase in Lactobacillus bacteremia.

PMID- 12410475
TI  - The role of bacterial virulence and host factors in patients with Escherichia
      coli bacteremia who have acute cholangitis or upper urinary tract infection.
AB  - We studied the pathogenic role of host and Escherichia coli virulence factors in
      the development of E. coli bacteremia in patients with acute cholangitis (AC) or
      upper urinary tract infection (UTI). Isolates recovered from 75 adult patients
      consecutively admitted to the hospital with E. coli bacteremia caused by AC
      (n=24) or upper UTI (n=51) were evaluated, as were 30 fecal strains isolated from
      healthy control individuals. Virulence genes of E. coli were detected by
      polymerase chain reaction analysis, including papG genes (classes I-III),
      sfa/foc, fimH, afa, hlyA, cnf1, and iutA. Our results show that biliary tract
      obstruction and urinary tract obstruction are important host factors for the
      development of E. coli bacteremia in patients with AC and upper UTI,
      respectively. With regard to E. coli virulence factors, the papG class II gene
      might play a more important role in the development of E. coli bacteremia in
      patients with upper UTI than in those with AC.

PMID- 12410476
TI  - Mycoplasma genitalium infections in asymptomatic men and men with urethritis
      attending a sexually transmitted diseases clinic in New Orleans.
AB  - We report the results of a study of Mycoplasma genitalium (detected with a
      modified polymerase chain reaction [PCR] assay) in men with urethritis and in
      asymptomatic control subjects at a sexually transmitted diseases clinic in New
      Orleans. Data for 97 men with urethritis and 184 asymptomatic men were available
      for analysis. M. genitalium infection rates in symptomatic and asymptomatic men
      who were negative for Chlamydia trachomatis and Neisseria gonorrhoeae were 25%
      and 7%, respectively (P=.006). M. genitalium coinfection rates among men with
      chlamydial and gonococcal urethritis were 35% and 14%, respectively. Men with M.
      genitalium urethritis resembled those with C. trachomatis in that both groups
      were younger and more likely to experience milder urethral symptoms. Among men
      with urethritis, the sensitivities of PCR of urine and swab specimens for the
      detection of M. genitalium were 87% and 91%, respectively. M. genitalium is
      associated with nongonococcal urethritis in this population.

PMID- 12410477
TI  - Antimicrobial use and serotype distribution of nasopharyngeal Streptococcus
      pneumoniae isolates recovered from Greek children younger than 2 years old.
AB  - The serotype distribution of 781 nasopharyngeal pneumococcal isolates recovered
      from 2448 unselected children aged 2-23 months was studied. Only 3.9% of the
      children for whom cultures were performed attended day care centers. The
      proportions of pneumococcal isolates that belonged to serotypes related to the 7
      , 9- and 11-valent conjugate pneumococcal vaccine were 65%, 66%, and 70%,
      respectively. The pneumococcal carriage rate among untreated children was 34%;
      the rates among children treated with antibiotics during the periods 1-30 or 31
      60 days before the time of nasopharyngeal sampling were 25% and 36%,
      respectively. There was a significant positive association between antimicrobial
      use and carriage of antibiotic-resistant pneumococci, which belonged mainly to
      vaccine-related serotypes. The proportion of isolates that belonged to vaccine
      related serotypes in untreated carriers was 72%; however, the proportions in
      carriers treated 1-30 days or 31-60 days before sampling were 66% and 56%,
      respectively. In the nasopharynx, antimicrobial use selects for antibiotic
      resistant pneumococci, mainly of vaccine-related serotypes, whereas it may
      promote an increase in the frequency of colonization with nonvaccine serotypes.

PMID- 12410478
TI  - Crack cocaine use and other risk factors for tuberculin positivity in drug users.
AB  - Two-step tuberculin testing and standardized interviews of 793 current and former
      drug users were performed to determine the risk factors for tuberculin
      positivity. The prevalence of tuberculin positivity was 25%. Factors
      independently associated with tuberculin positivity among participants
      seronegative for human immunodeficiency virus (HIV) included crack cocaine use
      (adjusted odds ratio [OR], 1.6; 95% confidence interval [CI], 1.0-2.5),
      employment as a home health aide (adjusted OR, 2.1; 95% CI, 1.0-4.1), birth in
      Puerto Rico (adjusted OR, 2.2; 95% CI, 1.3-3.6), foreign birthplace (adjusted OR,
      4.7; 95% CI, 1.6-13.6), African American race (adjusted OR, 2.5; 95% CI, 1.2
      5.0), reported tuberculosis exposure (adjusted OR, 2.3; 95% CI, 1.2-4.4), and
      older age (adjusted OR, 2.9; 95% CI, 1.2-6.7). Additional risk factors among HIV
      infected participants included alcoholism (adjusted OR, 2.4; 95% CI, 1.0-5.8) and
      high CD4(+) lymphocyte count. Identification of and administration of appropriate
      chemoprophylaxis to drug users with these risk factors should be given high
      priority.

PMID- 12410479
TI  - Recommendations for prevention of and therapy for exposure to B virus
      (cercopithecine herpesvirus 1).
AB  - B virus (Cercopithecine herpesvirus 1) is a zoonotic agent that can cause fatal
      encephalomyelitis in humans. The virus naturally infects macaque monkeys,
      resulting in disease that is similar to herpes simplex virus infection in humans.
      Although B virus infection generally is asymptomatic or mild in macaques, it can
      be fatal in humans. Previously reported cases of B virus disease in humans
      usually have been attributed to animal bites, scratches, or percutaneous
      inoculation with infected materials; however, the first fatal case of B virus
      infection due to mucosal splash exposure was reported in 1998. This case prompted
      the Centers for Disease Control and Prevention (Atlanta, Georgia) to convene a
      working group in 1999 to reconsider the prior recommendations for prevention and
      treatment of B virus exposure. The present report updates previous
      recommendations for the prevention, evaluation, and treatment of B virus
      infection in humans and considers the role of newer antiviral agents in
      postexposure prophylaxis.

PMID- 12410480
TI  - Nursing home-acquired pneumonia.
AB  - Pneumonia is the most serious of the common infections that occur in nursing
      homes, with a high case-fatality rate and considerable mortality among survivors.
      Risk factors for nursing home-acquired pneumonia (NHAP) have been defined, and
      prediction models for death due to NHAP have been developed. The bacterial
      etiology of NHAP has been debated, but "typical" bacterial pathogens
      (Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis) are
      most important. Clinical presentation of NHAP is said to be "atypical," but this
      may be confounded by dementia in the nursing home resident. A recent guideline
      has made recommendations regarding the minimal diagnostic workup when a resident
      has a suspected case of pneumonia. Until recently, most guidelines for the
      treatment of pneumonia did not specifically address NHAP; there is some evidence
      that use of a quinolone alone may be an acceptable first choice of therapy for
      most cases. Pneumococcal and influenza vaccination have been the primary
      prevention measures. However, additional methods to prevent NHAP should be
      evaluated, including improving the oral hygiene of residents and instituting
      pharmacological interventions.

PMID- 12410481
TI  - Antimicrobial-resistant, Gram-positive bacteria among patients undergoing chronic
      hemodialysis.
AB  - Numerous antimicrobial-resistant pathogens (ARPs) have emerged among patients who
      undergo chronic hemodialysis (CHD), including vancomycin-resistant enterococci,
      vancomycin-resistant coagulase-negative staphylococci, Staphylococcus aureus with
      reduced susceptibility to vancomycin, and linezolid-resistant S. aureus. In June
      2002, the first isolate of vancomycin-resistant S. aureus (minimum inhibitory
      concentration of vancomycin, > or =32 microg/mL) was isolated in the United
      States from a patient who required CHD. Frequent administration of antibiotics
      and repeated exposure to settings conducive to cross-transmission contribute to a
      patient population at considerable risk of harboring ARPs. Dissemination of ARPs
      among patients who are undergoing CHD is facilitated by the requirement for
      regular hemodialysis in a closed setting in which health care workers provide
      concurrent care to multiple patients. Frequent hospitalizations in this patient
      population further contribute to acquisition of ARPs and to the spread of ARPs to
      other hospitalized patients. The epidemiology of antimicrobial-resistant, gram
      positive pathogens in patients undergoing CHD is reviewed, and recommendations
      for limiting further dissemination are provided.

PMID- 12410482
TI  - Switching effective antiretroviral therapy: a review.
AB  - One approach to target the long-term metabolic toxicity and disfiguring body
      shape changes associated with antiretroviral therapy is to switch one component
      of a regimen to an alternative drug, usually from a different class of
      antiretrovirals. Most commonly, substitutions have involved protease inhibitors,
      but the thymidine analogue nucleosides, especially stavudine, have been
      investigated more recently. Certain trends from these studies have emerged.
      First, if the patient has had sustained viral suppression, switching therapy is
      generally virologically safe. Second, metabolic disturbances, such as insulin
      resistance and dyslipidemia, appear to be at least partially reversible.
      Substitution of other agents for protease inhibitors has not been associated with
      reversal or improvement in fat redistribution. Studies in which thymidine
      analogue reverse-transcriptase inhibitors have been switched have reported modest
      improvements in peripheral lipoatrophy. Larger, controlled, long-term studies and
      a more standardized approach to definition of metabolic and morphological
      abnormalities are needed.

PMID- 12410483
TI  - A cohort study of nevirapine tolerance in clinical practice: French Aquitaine
      Cohort, 1997-1999.
AB  - We performed a retrospective study to evaluate, under routine circumstances, the
      tolerance and immunovirological changes associated with antiretroviral regimens
      that contain nevirapine in 137 patients (88% were antiretroviral experienced).
      During a mean follow-up of 11 months, 33% of patients reported side effects
      attributed to nevirapine, and 21% discontinued treatment because of poor
      tolerance. Administration of antihistamines or corticosteroids at the initiation
      of treatment was not protective against adverse events (relative risk, 0.82; 95%
      confidence interval, 0.49-1.38). The proportion of patients with hepatitis C
      virus (HCV) and/or hepatitis B virus (HBV) coinfection who had alanine
      aminotransferase levels of >100 IU/L increased from 19.4% at baseline to 42.9% at
      month 12 of follow-up (P=.02). We noticed a significant increase of the
      proportion of patients with total cholesterol levels of >5.5 mM (P=.02). We have
      shown that there is a high level of discontinuation of nevirapine therapy in
      clinical practice and that side effects were not prevented by administration of
      antihistamines or corticosteroids. Coinfection with HCV or HBV increased the risk
      of hepatotoxicity, which lead to the cautious use of nevirapine for such
      patients.

PMID- 12410484
TI  - Comorbid conditions, treatment, and health maintenance in older persons with
      human immunodeficiency virus infection in New York City.
AB  - We retrospectively examined comorbid conditions and health maintenance in 198
      patients aged > or =55 years who attended 3 New York City human immunodeficiency
      virus (HIV) clinics between 1 January 1990 and 30 June 1998. Annual influenza and
      pneumococcal vaccinations within 5 years were given in 82% and 86% of patients,
      respectively. Among 57 women, 79% had a Papanicolaou smear within 1 year, and 53%
      had a mammogram within 2 years. Of 165 patients who received care after 1 July
      1996, 147 (89%) had comorbid conditions (mean number of conditions, 2.4), and 133
      (81%) received HIV-unrelated medications (mean number of medications, 2.7).
      Receipt of highly active antiretroviral therapy, its discontinuation because of
      toxicity, and having an undetectable HIV load were not related to comorbid
      conditions or use of concurrent medications. Comorbid conditions and use of
      concurrent HIV-unrelated medications need not adversely affect treatment of HIV
      infected older individuals, but increased attention to health maintenance may be
      necessary.

PMID- 12410485
TI  - Lipodystrophy in a cohort of human immunodeficiency virus-infected Asian
      patients: prevalence, associated factors, and psychological impact.
AB  - We investigated the prevalence of and factors associated with lipodystrophy in a
      cohort of human immunodeficiency virus (HIV)-infected patients in Singapore. A
      standardized questionnaire was administered to 410 consecutive patients (mainly
      Chinese men), and blood samples were obtained for metabolic measurements for
      fasting patients. Peripheral fat loss was reported by 46% of subjects, central
      fat gain was reported by 32%, and 8% of patients overall had a mixed clinical
      presentation. Levels of total cholesterol, triglycerides, glucose, and lactate
      were elevated in 19%, 38%, 12%, and 16% of patients, respectively. A mixture of
      drug-related and non-drug-related factors was associated with these changes. The
      body-shape changes affected the mood of 36% of patients and the work and/or
      social activity of 23% of patients, but only <1% of affected subjects reported a
      desire to stop receipt of antiretroviral therapy because of these changes. We
      conclude that the prevalence of and factors associated with body-shape changes
      and metabolic abnormalities in HIV-infected Asian patients are similar to those
      reported for Western cohorts, but the changes did not appear to have a major
      psychosocial impact on this patient population.

PMID- 12410486
TI  - Fatal immune restoration disease in human immunodeficiency virus type 1-infected
      patients with progressive multifocal leukoencephalopathy: impact of
      antiretroviral therapy-associated immune reconstitution.
AB  - Immune reconstitution resulting from use of highly active antiretroviral therapy
      in patients infected with human immunodeficiency virus type 1 (HIV-1) has been
      associated with a significant decrease in infectious morbidity and with improved
      survival. Occasionally, patients with quiescent disease due to human
      cytomegalovirus or nontuberculous mycobacteria may experience paradoxical
      worsening due to "dysregulated" restitution of the immune system (that is, immune
      restoration disease [IRD]). Acquired immunodeficiency syndrome-related
      progressive multifocal leukoencephalopathy (PML) is uncommon and often improves
      with immune recovery. We describe 2 HIV-1-infected patients with PML that
      presented with paradoxical worsening after the patients had commenced active
      antiretroviral therapy. After they had a transient response to high-dose
      corticosteroid therapy, both patients died of progressive neurological
      deterioration. IRD in these patients with PML was unexpected and occurred soon
      after they had started receiving active antiretroviral therapy, during the period
      of improved antigen-specific T-helper cell function. Predictors of patients'
      proclivity for these adverse events are uncertain. Evaluation of targeted
      immunomodulatory therapy directed towards disease-specific IRD is critical and
      may play an important role in improved survival for patients who are at risk.

PMID- 12410487
TI  - Effects of recombinant human growth hormone on fat distribution in patients with
      human immunodeficiency virus-associated wasting.
AB  - In light of current interest in recombinant human growth hormone (GH) as a
      treatment for fat distribution abnormalities, we retrospectively evaluated
      regional changes in fat and lean body mass in a subset of subjects who
      participated in randomized, double-blind, placebo-controlled trials of GH for
      treatment of wasting. Treatment with a pharmacologic dose of GH (0.1 mg/kg/day)
      resulted in significant and sustained increases in lean body mass and losses of
      fat in both the trunk and appendicular regions.

PMID- 12410488
TI  - Trends of multiple-drug resistance among Salmonella serotype Typhi isolates
      during a 14-year period in Egypt.
AB  - A total of 853 isolates of Salmonella serotype Typhi recovered from patients with
      typhoid fever who were admitted to a major infectious disease hospital in Cairo,
      Egypt, from 1987 through 2000 underwent antibiotic susceptibility testing to
      determine multiple-drug resistance. The observed resurgence of chloramphenicol
      susceptibility (P=.002) may suggest reuse of this drug for the treatment of
      typhoid fever in Egypt.

PMID- 12410489
TI  - Risk factors associated with the development of infection with linezolid- and
      vancomycin-resistant Enterococcus faecium.
AB  - This retrospective cohort study revealed that linezolid resistance in vancomycin
      resistant Enterococcus faecium was dependent on prior linezolid exposure and
      duration of linezolid therapy. These strains of E. faecium were resistant to the
      entire class of oxazolidinones.

PMID- 12410490
TI  - The safety of voriconazole.

PMID- 12410491
TI  - Assessment of procalcitonin levels in emergency department patients.

PMID- 12410493
TI  - Straightening of the hair is not pathognomonic for HIV infection.

PMID- 12410494
TI  - Simvastatin-nelfinavir interaction implicated in rhabdomyolysis and death.
AB  - We report the first death associated with rhabdomyolysis in a patient treated
      with a statin and a protease inhibitor, which produced a significant drug-drug
      interaction.

PMID- 12410495
TI  - A Belgian traveler who acquired yellow fever in the Gambia.
AB  - A 47-year-old Belgian woman acquired yellow fever during a 1-week vacation in The
      Gambia; she had never been vaccinated against yellow fever. She died of massive
      gastrointestinal bleeding 7 days after the onset of the first symptoms. This
      dramatic case demonstrates that it is important for persons to be vaccinated
      against yellow fever before they travel to countries where yellow fever is
      endemic, even if the country, like The Gambia, does not require travelers to be
      vaccinated.

PMID- 12410496
TI  - Molecular diagnosis of endocarditis due to Lactobacillus casei subsp. rhamnosus.
AB  - We report a case of endocarditis due to Lactobacillus casei subsp. rhamnosus. The
      bacterium isolated from blood cultures and from valve tissue specimens was
      identified using both phenotypical analysis and DNA sequence analysis, which
      revealed that the rod profiles of the pathogens recovered from blood cultures and
      valve tissue specimens were the same.

PMID- 12410498
TI  - The third strike.

PMID- 12410497
TI  - Prospective randomized study of N-acetylcysteine, fenoldopam, and saline for
      prevention of radiocontrast-induced nephropathy.
AB  - The objective of this study was to compare the efficacy of N-acetylcysteine
      (NAC), fenoldopam, and saline in preventing radiocontrast-induced nephropathy
      (RCIN) in high-risk patients undergoing cardiovascular procedures. We
      prospectively enrolled 123 patients who were scheduled for cardiovascular
      procedures and had a baseline creatinine > 1.6 mg/dl or creatinine clearance of <
      60 ml/min. Patients were randomly assigned to receive either saline (0.45% normal
      saline at 1 cc/kg) for 12 hr before and 12 hr after the procedure, or fenoldopam
      (0.1 microg/kg/min) plus saline for 4 hr prior and 4 hr after the procedure, or
      NAC orally (600 mg) plus saline every 12 hr for 24 hr prior and 24 hr after the
      procedure. All the patients received low-osmolality nonionic contrast. RCIN was
      defined as an increase in creatinine level > 0.5 mg/dl after 48 hr. The incidence
      of RCIN was 17.7% in the NAC group, 15.3% in the saline group, and 15.7% in the
      fenoldopam group (P = 0.919). Of the 20 patients who developed RCIN, 2 required
      dialysis. Serum creatinine decreased after 48 hr (vs. baseline) in 38% patients
      in the NAC group, 18% in the fenoldopam group, and 15% in the saline group. In
      patients with chronic renal insufficiency, NAC or fenoldopam offered no
      additional benefit over hydration with saline in preventing RCIN.

PMID- 12410499
TI  - Balloon-based radiation therapy for treatment of in-stent restenosis in human
      coronary arteries: results from the BRITE I study.
AB  - Catheter-based intracoronary radiation therapy demonstrated reduction of the
      recurrence rate of in-stent restenosis by 35%-50% when compared to conventional
      therapy. The objectives of this study were to determine the safety and
      feasibility of a new balloon-shaped source design and a higher applied dose to
      reduce the restenosis rates. Thirty-two patients with in-stent restenosis who met
      study eligibility criteria were successfully treated with standard PCI
      techniques. Following a successful intervention, a P-32 beta-balloon source was
      positioned to cover the angioplasty site and a dose of a 20 Gy at 1 mm from the
      surface of the source was administered. The primary endpoint was a composite of
      major adverse cardiac events (any death, MI, emergent CABG, or repeat target
      vessel revascularization) during 6 months of follow-up. At 6 months, only one
      patient underwent repeat PTCA to the target vessel (3%). There were no instances
      of death, emergency surgery, late thrombosis, total occlusions, or MI. Binary
      restenosis measured by QCA at the stented segment was 0% and for the whole
      analysis vessel was 7.5%. Beta-radiation delivered with a balloon P-32 source
      design for patients with in-stent restenosis results in lower than expected rate
      of angiographic and clinical restenosis and the absence of late complications.

PMID- 12410500
TI  - Is radioangioplasty next?

PMID- 12410501
TI  - Comparison of costs and safety of a suture-mediated closure device with
      conventional manual compression after coronary artery interventions.
AB  - The aim of this study was to assess costs and safety of immediate femoral sheath
      removal and closure with a suture-mediated closure device (Perclose, Menlo Park,
      CA) in patients undergoing elective (PCI). A total of 193 patients was
      prospectively randomized to immediate arterial sheath removal and access site
      closure with a suture-mediated closure device (SMC; n = 96) or sheath removal 4
      hr after PCI followed by manual compression (MC; n = 97). In the SMC group,
      patients were ambulated 4 hr after elective PCI if hemostasis was achieved. In
      the MC group, patients were ambulated the day after the procedure. In addition to
      safety, total direct costs including physician and nursing time, infrastructure,
      and the device were assessed in both groups. Total direct costs were
      significantly (all P < 0.001) lower in the SMC group. Successful hemostasis
      without major complication was achieved in all patients. The time to achieve
      hemostasis was significantly shorter in the SMC group (7.1 +/- 3.4 vs. 22.9 +/-
      14.0 min; P < 0.01) and 85% of SMC patients were ambulated on the day of
      intervention. Suture-mediated closure allows a reduction in hospitalization time,
      leading to significant cost savings due to decreased personnel and
      infrastructural demands. In addition, the use of SMC is safe and convenient to
      the patients.

PMID- 12410502
TI  - Can the use of suture-mediated closure devices save the American health care
      system?

PMID- 12410503
TI  - Resolution of refractory no-reflow with intracoronary epinephrine.
AB  - Refractory no-reflow is associated with adverse outcomes in patients undergoing
      percutaneous coronary intervention. Charts were reviewed to identify 29
      consecutive patients in whom intracoronary epinephrine was administered for
      refractory no-reflow. The effects of intracoronary epinephrine on coronary flow
      (TIMI grade), cardiac rhythm, and systolic blood pressure in the cardiac
      catheterization laboratory were assessed. Administration of intracoronary
      epinephrine (mean dose, 139 +/- 189 microg) resulted in significant improvement
      in coronary flow. After administration, TIMI 3 flow was established in 69% of
      patients. Overall, TIMI flow significantly increased (mean TIMI flow form 1.0 +/-
      1.0 to 2.66 +/- 0.55; P = 0.0001). Intracoronary epinephrine resulted in
      significant but tolerable increase in heart rate (72 +/- 19 to 86 +/- 26
      beats/min; P = 0.009), but no cases of acute dysrhythmia. These findings indicate
      that intracoronary epinephrine may exert salutary effects in patients suffering
      refractory no-reflow following elective or acute coronary interventions.

PMID- 12410504
TI  - Epinephrine: a new pharmacologic treatment for no-reflow?

PMID- 12410505
TI  - Comparison of early results of percutaneous metallic mitral commissurotome with
      Inoue balloon technique in patients with high mitral echocardiographic scores.
AB  - We compared the safety, efficacy, and cost of the newly introduced percutaneous
      metallic commissurotome (PMC) with the results of Inoue balloon mitral
      valvuloplasty (BMV) in 80 patients with mitral stenosis (MS). The mean increase
      in mitral valve area (MVA) was 0.95 +/- 0.19 to 1.7 +/- 0.35 cm(2) for PMC and
      0.97 +/- 0.15 to 1.81 +/- 0.36 cm(2) for BMV (P = NS). The Wilkins
      echocardiographic scores before dilatation did not correlate with any difference
      in MVA after dilatation. Bilateral commissural splitting was significantly more
      common with PMC than with BMV (30/39 patients, 76.9%, vs. 21/40 patients, 52.5%;
      P = 0.02). Postprocedural severe mitral regurgitation occurred in 1/39 (2.6%) in
      the PMC group and in 4/41 (9.8%) in the BMV group. Because the PMC device is
      resterilizable, we estimated the cost to be one-fourth the cost of BMV with the
      Inoue balloon. The estimated device cost ratio of PMC to BMV for each patient was
      1 to 4.25. The early results of PMC on the MVA are comparable to BMV. However,
      PMC had better results not only in patients with high echocardiographic scores,
      but the PMC device splits commissural calcification better than BMV.

PMID- 12410506
TI  - Percutaneous mitral balloon valvuloplasty in pregnant women with mitral stenosis.
AB  - Forty-four consecutive pregnant patients with mitral stenosis were submitted to
      percutaneous mitral valvuloplasty (PMV) over a period of 12 years. The mean age
      was 28 +/- 6 years and the mean gestational age was 23 +/- 6 weeks. The mean
      mitral valve area had a significant increase from 1.17 +/- 0.26 to 2.06 +/- 0.41
      cm(2) (P = 0.0000). The mean mitral valve gradient decreased from 16.22 +/- 5.55
      to 7.94 +/- 3.75 mm Hg (P = 0.0001). The procedure was performed successfully in
      95% of the patients and there were no major complications. Concerning labor and
      delivery, we evaluated 37 patients. Thirty patients (81%) reached term and
      delivered normal infants. Seven patients (18.9%) delivered prematurely, resulting
      in two fetal death; one patient delivered a stillborn. We concluded that PMV is a
      safe procedure for the treatment of mitral stenosis in pregnant patients,
      providing significant symptomatic relief and better clinical conditions for labor
      and delivery.

PMID- 12410507
TI  - Percutaneous mitral valvuloplasty by the Inoue balloon technique is the ideal
      procedure for treatment of significant mitral stenosis in pregnant women.

PMID- 12410508
TI  - Combined cutting balloon angioplasty and intracoronary beta radiation for
      treatment of in-stent restenosis: clinical outcomes and effect of pullback
      radiation for long lesions.
AB  - Intracoronary beta (beta) radiation decreases the incidence of target lesion
      revascularization after percutaneous intervention (PCI) for in-stent restenosis
      (ISR). Cutting balloon (CB) angioplasty may also be superior to other
      percutaneous techniques for the treatment of ISR. We sought to study the outcomes
      of patients with ISR who underwent both CB angioplasty and intracoronay beta
      radiation and compare them to patients with ISR who underwent other PCI
      techniques without concomitant radiation. We also sought to evaluate the safety
      and efficacy of pullback intracoronary beta radiation for the treatment of long
      ISR lesions. Between January 2001 and November 2001, 102 patients (mean age = 55
      +/- 13 years) with ISR underwent both CB angioplasty and intracoronay beta
      radiation. beta radiation was delivered using the Beta Cath (Novoste) 30 mm
      system, and pullback radiation was performed in 41 patients. A comparison group
      included a total of 393 patients with ISR who underwent other PCI techniques
      without concomitant intracoronary radiation therapy. Follow-up was obtained in 99
      patients (97%) in the CB angioplasty with intracoronary radiation group and 377
      patients (96%) in the comparison group. At follow-up, both target vessel
      revascularization (TVR) and major adverse cardiovascular events (MACE) occurred
      significantly less in the CB angioplasty with intracoronary radiation group than
      in the comparison group (7% vs. 18% for TVR, and 14% vs. 24% for MACE; P < 0.05
      for both). In the pullback radiation group, TVR was performed in five patients
      (12%), and MACE occurred in eight patients (20%). A combination of CB angioplasty
      and intracoronay beta radiation for ISR seems to yield low rates of subsequent
      target vessel revascularization and adverse cardiac events. In addition, pullback
      beta radiation using the Beta Cath (Novoste) 30 mm system is safe and can be used
      to treat long ISR lesions effectively. Further randomized trials are needed to
      confirm these findings.

PMID- 12410509
TI  - Through a glass, darkly.

PMID- 12410510
TI  - Export aspiration catheter thrombosuction before actual angioplasty in primary
      coronary intervention for acute myocardial infarction.
AB  - Primary percutaneous coronary intervention (PCI) for acute myocardial infarction
      (AMI) in lesions with a large thrombus load increases the procedural complication
      rate. We describe a thrombus reduction technique in this setting using the Export
      aspiration catheter (EAC) for primary thrombosuction before actual angioplasty.
      The EAC is a component of the GuardWire Plus system (PercuSurge, Sunnyvale, CA),
      which was originally developed for emboli containment in saphenous vein graft and
      peripheral vessel interventions. Primary EAC thrombosuction was performed
      successfully in 12 patients undergoing primary PCI, and gross thrombi were
      obtained from 9 patients (75%). After definitive treatment with balloon
      angioplasty and/or stenting, TIMI 3 flow was restored in all target vessels.
      There was no angiographic evidence of distal branch loss or vessel injury. No
      major procedural or in-hospital complication occurred in any patients. This
      primary EAC thrombosuction technique may offer a new, potentially effective
      method for thrombus burden reduction in treating AMI patients.

PMID- 12410511
TI  - Focus on the infarct-related artery: a thrombus runs through it.

PMID- 12410512
TI  - Plasma lidocaine concentrations after local anesthesia of the groin for cardiac
      catheterization.
AB  - This study aimed to investigate serum lidocaine concentrations after subcutaneous
      infiltration of the groin for cardiac catheterization. One hundred twenty-six
      patients for planned heart catheterization received five different dosages (5-25
      ml) of lidocaine 2% for local anesthesia of the groin in a randomized manner. All
      of them received an arterial sheath and 13 received both an arterial sheath and a
      venous sheath for right heart catheterization. Blood samples were taken before as
      well as 15, 30, and 120 min after subcutaneous application of the drug. Although
      in 33 patients with an arterial sheath (no venous sheath) excessive doses of
      lidocaine 2% (20-25 ml) were used, neither symptoms of intoxication nor toxic
      plasma levels were observed. However, in patients receiving an additional venous
      sheath, toxic plasma levels were obtained in a third of the cases. One of them
      showed symptoms of intoxication.

PMID- 12410513
TI  - A randomized prospective trial of ioxaglate 320 (Hexabrix) vs. iodixanol 320
      (Visipaque) in patients undergoing percutaneous coronary intervention.
AB  - We performed a randomized, prospective, double blind trial comparing the use of
      the ionic dimer contrast agent ioxaglate 320 (Hexabrix) with the nonionic dimer
      contrast agent iodixanol 320 (Visipaque) in 618 patients undergoing percutaneous
      coronary intervention (PCI) for stable or unstable coronary artery syndromes. The
      aim was to determine whether the different anticoagulant and antiplatelet
      properties of these two contrast agents resulted in a significant difference in
      the incidence of a combined endpoint comprising the major complications of PCI.
      Procedural success rates were marginally higher in the Visipaque group compared
      to the Hexabrix group, although this did not reach statistical significance
      (96.7% vs. 93.9%; P = 0.09). There was a borderline statistically significant
      higher requirement for bailout stenting in the Visipaque group compared to the
      Hexabrix group (6.8% vs. 3.2%; P = 0.05), although this was not a predefined
      endpoint. The incidence of the combined primary endpoint of failed catheter
      laboratory outcome/requirement for bailout stenting/requirement for
      abciximab/myocardial infarction/death before hospital discharge was higher in the
      Visipaque group compared to the Hexabrix group (17.9% vs. 14.8%), although this
      did not reach statistical significance (P = 0.29). When subgroup analysis was
      performed, the incidence of the combined endpoint in patients with stable
      coronary artery disease randomized to receive either Visipaque or Hexabrix was
      identical (13.7%). In patients with an acute coronary syndrome, there was a trend
      toward a reduced incidence of the combined endpoint in the Hexabrix compared to
      the Visipaque group, although this did not reach statistical significance (17.2%
      vs. 24.8%; P = 0.17). More adverse reactions occurred in the Hexabrix group
      compared to the Visipaque group (8.7% vs. 4.9%; P = 0.06). We conclude that there
      is no clear advantage with the use of an ionic contrast agent in a large
      population of patients undergoing PCI for both stable and unstable coronary
      artery disease. Although the study was underpowered to detect significant
      differences with the use of either agent when patients with either stable or
      unstable coronary disease were studied, it is highly unlikely that the ionicity
      of the contrast agent confers any advantage for patients with stable coronary
      disease. There remains a possibility that ionic agents do have advantages for
      patients with unstable coronary artery disease undergoing PCI, although a larger
      study than ours would be required to confirm or refute this.

PMID- 12410514
TI  - Transjugular approach to balloon mitral valvuloplasty helps overcome impediments
      caused by anatomical alterations.
AB  - Ten patients who had anatomic alterations that cause impediments to successful
      completion of conventional transfemoral balloon mitral valvuloplasty (BMV)
      underwent transjugular BMV. They included six patients in whom conventional BMV
      could not be completed due to cardiac anatomic distortion; two patients with
      dextrocardia (one with visceroatrial situs solitus and the other with situs
      inversus); two patients with venous abnormalities (one with azygous continuation
      of the inferior vena cava and the other with bilateral iliac/femoral vein
      occlusion). Transjugular BMV was successful in all 10 patients (mean mitral valve
      area increasing from 0.68 +/- 0.17 to 1.92 +/- 0.40 cm(2); range, 1.56-2.76
      cm(2)); it was quick (mean total fluoroscopy time, 10.5 +/- 2.7 min; range, 7.3
      15.2 min); and it was safe (no major or minor complications except one patient
      who developed severe mitral regurgitation that only required medical therapy).
      The jugular approach to BMV overcomes many of the technical problems caused by
      anatomic changes that are encountered in transfemoral BMV and complements the
      latter approach.

PMID- 12410515
TI  - Beyond peripheral arteries in Buerger's disease: angiographic considerations in
      thromboangiitis obliterans.
AB  - Thromboangiitis obliterans is an inflammatory peripheral vascular disease that is
      strongly associated with smoking. It predominantly affects distal small- and
      medium-sized blood vessels of both the upper and lower extremities. We present
      histological evidence of this disease process affecting the internal mammary
      arteries. This can be of paramount clinical significance for patients with
      Buerger's disease who present with obstructive coronary artery disease and
      require coronary artery bypass grafting surgery (CABG). Internal mammary arteries
      involved with thromboangiitis obliterans cannot be utilized as arterial conduits
      during CABG and other alternatives have to be used. Therefore, we recommend
      preoperative angiography of both internal mammary arteries in patients with
      Buerger's disease requiring CABG to prevent extensive intraoperative dissection
      of diseased internal mammary arteries.

PMID- 12410516
TI  - Coronary artery saddle embolus and myocardial infarction in a patient with
      prosthetic mitral valve.
AB  - Coronary embolism is a rare cause of transmural myocardial infarction. A 58-year
      old female with mechanical mitral valve prosthesis and chronic atrial
      fibrillation who presented with anterolateral myocardial infraction is described.
      The etiologies, diagnosis, treatment dilemma and various management options are
      discussed.

PMID- 12410517
TI  - Coronary artery fistula embolization in an infant with pulmonary atresia intact
      ventricular septum: a case report.
AB  - This report presents a case of pulmonary atresia/intact ventricular septum with
      right ventricular-dependent coronary circulation. At 7 months of age, the infant
      underwent coil embolization of the connection between the right ventricle and the
      coronary circulation. The child is currently well following surgical
      decompression of the right ventricle.

PMID- 12410518
TI  - Stents: what's available to the pediatric interventional cardiologist?

PMID- 12410519
TI  - Photodynamic therapy: applications in atherosclerotic vascular disease with
      motexafin lutetium.
AB  - Photodynamic therapy (PDT) has been approved as a tissue-specific light-activated
      cytotoxic therapy for many diseases. The ability of PDT to destroy target tissues
      selectively is especially appealing for atherosclerotic plaque. Biotechnology has
      developed a new generation of selective photosensitizers and catheter-based
      technological advances in light delivery have allowed the introduction of PDT
      into the vasculature. The largest experience to date is with motexafin lutetium
      (MLu, Antrin), an expanded porphyrin (texaphyrin) that accumulates in plaque. The
      combination of the motexafin lutetium and endovascular illumination, or Antrin
      phototherapy, has been shown to reduce plaque in animal models. Antrin
      phototherapy generates cytotoxic singlet oxygen that has been shown to induce
      apoptosis in macrophages and smooth muscle cells. The safety, tolerability, and
      preliminary efficacy of Antrin phototherapy has been assessed in a phase 1 dose
      ranging clinical trial in subjects with peripheral artery disease and is
      currently being examined in a phase 1 study in subjects with lesions of the
      native coronary arteries undergoing stent implantation. The preliminary results
      suggest that Antrin phototherapy is safe, well tolerated, and nontraumatic.

PMID- 12410520
TI  - Treatment of pulmonary hypertension: a promising new age.

PMID- 12410521
TI  - Transcatheter patch occlusion of experimental atrial septal defects.
AB  - The effectiveness and safety of transcatheter patch atrial septal defect (ASD)
      occlusion were studied in 20 piglets. Experimental atrial septal defects were
      created by foramen ovale dilation. ASDs were corrected by polyurethane patches of
      two types (flat and sleeve). Specially made balloon catheters supported the
      patches for periods varying from 1 to 6 days; after this period, the supporting
      catheters were withdrawn and the patches were released. All transcatheter patches
      were safely embedded in the atrial septum 48 hr or more after implantation. All
      defects were fully occluded. One patch became infected. The transcatheter patch
      experimental ASD occlusion method was found effective and safe, potentially
      applicable in the occlusion of human ASDs.

PMID- 12410522
TI  - Frameless patch occlusion of atrial septal defects: frameless--less secure.

PMID- 12410524
TI  - Non invasive assessment of mechanical valve obstruction.

PMID- 12410526
TI  - Facilitating viral recombination.

PMID- 12410527
TI  - Paramyxovirus strategies for evading the interferon response.
AB  - Two genera, the Respirovirus (Sendai virus (SeV) and human parainfluenza virus
      (hPIV3) and the Rubulavirus (simian virus (SV) 5, SV41, mumps virus and hPIV2),
      of the three in the subfamily Paramyxovirinae inhibit interferon (IFN) signalling
      to circumvent the IFN response. The viral protein responsible for the inhibition
      is the C protein for respirovirus SeV and the V protein for the rubulaviruses,
      both of which are multifunctional accessory proteins expressed from the P gene.
      SeV suppresses IFN-stimulated tyrosine phosphorylation of signal transducers and
      activators of transcription (STATs) at an early phase of infection and further
      inhibits the downstream signalling without degrading any of the signalling
      components in most cell lines. On the contrary, the Rubulavirus V protein targets
      Stat1 or Stat2 for degradation. Proteasome-mediated degradation appears to be
      involved in most cases. Studies on the molecular mechanisms by which
      paramyxoviruses evade the IFN response will offer important information for
      modulating the JAK-STAT pathway, designing novel antiviral drugs and recombinant
      live vaccines, and improving paramyxovirus expression vectors for gene therapy.

PMID- 12410528
TI  - Potential roles of cellular proteins in HIV-1.
AB  - Human immunodeficiency virus type-1 particles contain host proteins, both on
      their surface and interior. This review summarises the cellular proteins found in
      these virions and covers some of their potential roles in the viral life cycle
      and pathogenesis. For most proteins studied, their role and function are either
      unknown or in the hypothesis stage. This reflects the relatively recent emphasis
      given to these proteins by the HIV-1 field as well as the incomplete
      understanding of their function in the cell. The study of cellular proteins in
      HIV-1 promises to help us better understand the interaction of this virus with
      the cell, the immune system, and the whole human host as well as to shed light on
      the nature of AIDS and suggest more targets for therapeutic intervention.
      Finally, many of the cell systems themselves are still poorly understood. The
      extensive study of HIV-1 has already brought increased attention to the fields of
      immunology and vaccine science and, in the same way, might assist our
      understanding of the cellular pathways themselves.

PMID- 12410529
TI  - Molecular diagnosis of influenza.
AB  - The past decade has seen tremendous developments in molecular diagnostic
      techniques. In particular, the development of PCR technology has enabled rapid
      and sensitive viral diagnostic tests to influence patient management. Molecular
      methods used directly on clinical material have an important role to play in the
      diagnosis and surveillance of influenza viruses. Molecular diagnostic tests that
      allow timely and accurate detection of influenza are already implemented in many
      laboratories. The combination of automated purification of nucleic acids with
      real-time PCR should enable even more rapid identification of viral pathogens
      such as influenza viruses in clinical material. The recent development of DNA
      microarrays to identify either multiple gene targets from a single pathogen, or
      multiple pathogens in a single sample has the capacity to transform influenza
      diagnosis. While molecular methods will not replace cell culture for the
      provision of virus isolates for antigenic characterisation, they remain
      invaluable in assisting our understanding of the epidemiology of influenza
      viruses.

PMID- 12410530
TI  - HIV viral load: the myth of the undetectable?
AB  - There is a wealth of data supporting the use of viral load measurements to
      monitor therapy. Indeed, clinical drug trial endpoints routinely include the
      proportion of patients with a plasma viral load reduction of greater than 0.5
      log(10), or greater than 1 log(10). Since a higher viral load reflects increased
      amounts of virus replication, it would seem desirable to reduce this replication
      as far as possible, so that the goal of therapy has become one of viral
      undetectability in plasma. However, virological suppression to undetectable
      levels is not an absolute determinant of outcome because recent observational
      cohort data suggest that any significant reduction of viral load is associated
      with clinical benefit. There are also technical problems when attempting to
      measure undetectability, with lower limits of detection of 400 or 50 RNA
      copies/ml of plasma being driven more by the performance of commercial assays
      than by any inherent cut-off value with proven prognostic significance.
      Furthermore, the obsession with undetectability has created the concept of the
      'viral blip', or 'intermittent viraemia' commonly defined as a single viral load
      measurement of between 50 and 400 copies/ml, preceded and followed by consistent
      measurements of less than 50 copies/ml, in a patient receiving therapy. Such
      blips should be considered in the context of frequent transient changes in viral
      load which occur below the lower limit of detection by existing laboratory
      assays. In my view, there remains a misunderstanding about the importance
      ascribed to these relatively minor changes in lower detection limits, when
      considered against the background of virus within the body as a whole. I also
      consider other possible uses of HIV-1 quantification in clinical practice, such
      as identifying the inherent potency of antiviral regimens.

PMID- 12410531
TI  - Pharyngoesophageal reconstruction with lateral thigh free flap.
AB  - BACKGROUND: We evaluated the use of a lateral thigh free flap in
      pharyngoesophageal reconstruction, which is often overlooked and less widely used
      despite its distinct advantages. METHODS: This study reviewed the patient's
      medical records, including the patient's age, gender, histopathologic diagnosis,
      surgical defects, flap size, flap survival, donor and recipient site
      complications, and swallowing function and voice rehabilitation. RESULTS: Twelve
      lateral thigh free flaps were used to primarily reconstruct the pharyngoesophagus
      in 11 patients after tumor resection from July 1997 to May 1999. Eleven of the 12
      flaps (91.7%) were transferred successfully. In one patient, the flap failure
      occurred as a result of venous thrombosis, and therefore another lateral thigh
      free flap from the opposite thigh was used 3 days later. The swallowing function
      was restored in all patients. Prosthetic voice rehabilitation was successfully
      achieved in all five patients, who primarily underwent tracheoesophageal
      punctures. No frank fistula or stricture developed. Significant donor site
      morbidity was not noted. CONCLUSIONS: The lateral thigh free flap is useful and
      reliable in selected cases of pharyngoesophageal reconstruction and versatile in
      flap design with favorable functional outcomes of swallowing and voice
      rehabilitation with minimal donor site morbidity.

PMID- 12410532
TI  - Merkel cell carcinoma of the head and neck: a retrospective case series.
AB  - BACKGROUND: Eighty-five percent of all Merkel cell carcinomas appear on sun
      exposed areas, with 50% to 55% occurring on the head and neck. METHODS: A chart
      review was performed on 22 patients treated for Merkel cell carcinoma of the head
      and neck between 1981 and 1998. RESULTS: Fifteen patients were men (68%). The
      average age at operation was 69.9 years (range, 24-84 years). The average
      duration of follow-up was 3.6 years (range, 3 days-8.6 years). Overall survival
      at 1, 2, and 3 years postoperatively was 78%, 68%, and 68%, respectively. The
      only independent predictor of survival was the type of surgical therapy. All
      patients who underwent wide local excision (WLE) of the primary tumor with
      dissection of the lymphatic drainage basin were alive at 2 years as opposed to
      68% who had WLE alone and 33% who had Mohs surgery. CONCLUSIONS: WLE and
      dissection of the lymphatic drainage basin provided the best overall survival.

PMID- 12410533
TI  - Nasopharyngeal carcinoma in situ (NPCIS)--pathologic and clinical perspectives.
AB  - BACKGROUND: Dysplasia or carcinoma in situ lesions (NPCIS) of the nasopharynx
      have rarely been reported. The prevalence, biologic behavior, and the
      transformation period of the pure preinvasive lesions have not been fully
      explained. METHODS: All cases of NPCIS were retrospectively reviewed during the
      period between 1990 and 2000. The clinical features of all cases were studied.
      The biopsy samples were examined using light microscopy and in situ hybridization
      (ISH) for EBV-encoded RNA (EBER). The sera taken before and after the
      transformation were analyzed for anti-viral capsid antigen (VCA) EBV titers and
      circulating cell-free EBV DNA concentration. RESULTS: Three cases of NPCIS were
      identified. Two of the three cases subsequently developed into invasive NPC after
      initial presentation. The interval of transformation varied from 40 to 48 months.
      In all three cases, the specimens showed abnormal findings on light microscopy
      and positive staining for EBER. Elevated anti-VCA titers were present in two of
      the preinvasive lesions. No cell-free EBV DNA was detected in the sera of these
      patients during the preinvasive phase of the disease. CONCLUSIONS: Preinvasive
      NPC is a rare but distinct entity. Its transformation period can be as long as 4
      to 5 years. Elevated anti-VCA titers, in the presence of abnormal cells on light
      microscopy, should alert the pathologist to perform ISH EBER studies to diagnose
      this rare condition.

PMID- 12410534
TI  - First bite syndrome: a complication of surgery involving the parapharyngeal
      space.
AB  - INTRODUCTION: First bite syndrome (FBS) is the development of pain in the parotid
      region after the first bite of each meal and can be seen after surgery of the
      parapharyngeal space. The cause is not clear but has been proposed to involve a
      loss of sympathetic nerve function to the parotid, causing a denervation
      supersensitivity of salivary gland myoepithelial cells. The purpose of this study
      was to review the records of 12 patients with FBS to determine any common
      features of the operations performed that would support this theory of parotid
      "sympathectomy" as an etiologic factor of FBS. METHODS: Retrospective review of
      12 patients with FBS managed at two tertiary care centers. RESULTS: Twelve
      patients were diagnosed with FBS after surgery involving the parapharyngeal
      space. All patients had most of their parotid gland preserved. Six patients
      exhibited a postoperative Horner's syndrome, suggesting sympathetic chain
      interruption. The six patients without Horner's syndrome were found to have
      undergone external carotid artery ligation inferior to the parotid gland,
      suggesting an interruption of sympathetic innervation to the parotid gland
      itself. CONCLUSIONS: Preservation of parotid gland tissue and a loss of its
      sympathetic nerve supply, whether by disruption of the cervical sympathetic chain
      as evidenced by a Horner's syndrome or more selective denervation by ligation of
      the external carotid artery with its accompanying sympathetic nerve plexus, were
      common features of all patients. This series supports the concept of parotid
      "sympathectomy" as an etiologic factor in FBS.

PMID- 12410535
TI  - Correlation of biochemical parameters with single parathyroid adenoma weight and
      volume.
AB  - OBJECTIVE: To determine the relationship of the biochemical parameters serum
      phosphate, serum calcium, and serum parathyroid hormone levels with respect to
      parathyroid adenoma weight and volume in primary hyperparathyroidism. STUDY
      DESIGN: Retrospective review of 63 cases of primary hyperparathyroidism from 1992
      to 1998. METHODS: Single parathyroid adenomas were identified from surgical
      pathology reports. Preoperative calcium, phosphate, and parathyroid hormone
      levels were collected from charts. The volume of the adenoma was calculated using
      a mathematical equation for the volume of an ellipsoid object. The data were
      analyzed using a multiple analysis of variance, and a correlation coefficient was
      calculated. The level of significance was set at p < or = .05. RESULTS: With
      respect to adenoma volume, there was a significant correlation with serum calcium
      and parathormone levels (p = .0001 and p = .0001, respectively). There was no
      significant correlation between serum phosphate and adenoma volume. With respect
      to adenoma weight, there was a significant correlation with serum calcium and
      parathormone levels (p = .0001 and p = .0001, respectively). There was no
      significant correlation between serum phosphate and adenoma weight. CONCLUSIONS:
      Preoperative serum calcium and parathormone levels may be able to predict adenoma
      weight and volume in primary hyperparathyroidism for a single adenoma.

PMID- 12410536
TI  - Elevated serum vascular endothelial growth factor and decreased survival in
      advanced laryngeal carcinoma.
AB  - PURPOSE: The purpose of this study was to determine whether serum vascular
      endothelial growth factor (s-VEGF) levels at the time of diagnosis correlate with
      any known tumor variables and overall survival in patients with advanced
      laryngeal squamous cell carcinoma. Comparisons with a cohort of normal healthy
      controls were also performed to determine the potential usefulness of s-VEGF as a
      screening tool. EXPERIMENTAL DESIGN: Serum from patients enrolled in the VA
      Laryngeal Cooperative Study #258 (n = 183), as well as normal healthy controls (n
      = 40) was used in this analysis. Quantitative enzyme-linked immunosorbent assays
      (ELISA) for VEGF were performed in duplicate on each serum sample. Demographic
      and survival data were available for each patient enrolled in the study.
      Univariate analyses, multivariate Cox regression analyses, and Kaplan-Meier
      survival analysis were used. RESULTS: The mean serum concentration of s-VEGF for
      the healthy control group was 47.83 +/- 0.13 pg/mL. For all patients enrolled in
      the VA Cooperative Study, regardless of treatment group, the mean s-VEGF level
      was 317.22 +/- 25.46 pg/mL. The patients randomly assigned to the surgical arm (n
      = 97) had a mean value of 315.44 +/- 30.44 pg/mL. Those randomly assigned to the
      induction chemotherapy arm (n = 86) had a mean s-VEGF level of 319.22 +/- 42.11
      pg/mL. Serum VEGF levels were significantly elevated in patients with laryngeal
      carcinoma compared with healthy controls (p < .001). The serum VEGF levels in
      each arm of the trial were also elevated versus the healthy controls (p < .001,
      surgery arm plus radiotherapy; p < .001, chemotherapy plus radiotherapy). In a
      univariate analysis, elevated s-VEGF correlated with poor Karnofsky performance
      status for all patients with advanced laryngeal carcinoma (p < .008). High s-VEGF
      levels also correlated with a poor performance score in patients on the
      chemotherapy arm of the VA Laryngeal Trial (p < .004). Elevated s-VEGF levels in
      the surgical plus radiotherapy arm correlated with node-positive disease (p =
      .047) and supraglottic location of the tumor (p = .022). In a multivariate
      analysis using all known tumor variables and s-VEGF levels, elevated s-VEGF
      levels and infiltrating growth pattern correlated with decreased survival for all
      evaluated patients with advanced laryngeal carcinoma (p = .065, and p = .018,
      respectively). CONCLUSIONS: Serum VEGF levels are significantly elevated in
      patients with advanced laryngeal carcinoma versus healthy controls. Elevated
      pretreatment s-VEGF levels tended to indicate a more aggressive disease state and
      a poorer overall survival in advanced laryngeal carcinoma.

PMID- 12410537
TI  - Planned neck dissection after definitive radiotherapy for squamous cell carcinoma
      of the head and neck.
AB  - BACKGROUND: To define the role of planned neck dissection after definitive
      radiotherapy for patients with node-positive squamous cell carcinoma of the head
      and neck. METHODS: Review of the pertinent literature. RESULTS: Radiotherapy
      alone produces a relatively high likelihood of regional control for patients with
      early-stage neck disease. Patients with more advanced neck disease have a higher
      probability of regional control if a planned neck dissection follows
      radiotherapy. However, for patients who have a complete response to radiotherapy,
      the likelihood of an isolated recurrence in the neck is low. Radiographic
      evaluation of the response to radiotherapy may better define the subset of
      patients who are likely to benefit from a neck dissection. CONCLUSIONS: Neck
      dissection after definitive radiotherapy improves regional control for patients
      with advanced neck disease. Patients who have a complete clinical and
      radiographic regional response to radiotherapy have a low probability of an
      isolated recurrence in the neck. It is advisable to proceed with a neck
      dissection for patients who have an equivocal response to radiotherapy, because
      the likelihood of salvage of an isolated recurrence in the neck is remote.

PMID- 12410538
TI  - Digital necrosis associated with squamous cell carcinoma of the tonsil.
AB  - BACKGROUND: Digital necrosis is an uncommon paraneoplastic syndrome. Fewer than
      50 cases have been sporadically reported through the literature over the last 30
      years. CASE REPORT: We describe the unfortunate case of a 62-year-old woman with
      a locally advanced squamous cell carcinoma of the tonsil. She was admitted to the
      hospital for symptomatic hypercalcemia and was found to have metastatic disease.
      She subsequently had digital necrosis develop. Despite numerous attempts to
      control the rapidly progressive ischemia, little objective evidence of response
      was noted. Her primary disease did not respond to palliative radiation, and her
      general condition rapidly deteriorated. CONCLUSIONS: A review of the literature
      provided some insight into the possible etiology of this unique complication of
      malignancy. Unfortunately, the treatment options suggested were of limited value,
      because there was no discernible benefit with any directed treatment. A brief
      summary and discussion of the literature follows.

PMID- 12410539
TI  - Onions--a global benefit to health.
AB  - Onion (Allium cepa L.) is botanically included in the Liliaceae and species are
      found across a wide range of latitudes and altitudes in Europe, Asia, N. America
      and Africa. World onion production has increased by at least 25% over the past 10
      years with current production being around 44 million tonnes making it the second
      most important horticultural crop after tomatoes. Because of their storage
      characteristics and durability for shipping, onions have always been traded more
      widely than most vegetables. Onions are versatile and are often used as an
      ingredient in many dishes and are accepted by almost all traditions and cultures.
      Onion consumption is increasing significantly, particularly in the USA and this
      is partly because of heavy promotion that links flavour and health. Onions are
      rich in two chemical groups that have perceived benefits to human health. These
      are the flavonoids and the alk(en)yl cysteine sulphoxides (ACSOs). Two flavonoid
      subgroups are found in onion, the anthocyanins, which impart a red/purple colour
      to some varieties and flavanols such as quercetin and its derivatives responsible
      for the yellow and brown skins of many other varieties. The ACSOs are the flavour
      precursors, which, when cleaved by the enzyme alliinase, generate the
      characteristic odour and taste of onion. The downstream products are a complex
      mixture of compounds which include thiosulphinates, thiosulphonates, mono-, di-
      and tri-sulphides. Compounds from onion have been reported to have a range of
      health benefits which include anticarcinogenic properties, antiplatelet activity,
      antithrombotic activity, antiasthmatic and antibiotic effects. Here we review the
      agronomy of the onion crop, the biochemistry of the health compounds and report
      on recent clinical data obtained using extracts from this species. Where
      appropriate we have compared the data with that obtained from garlic (Allium
      sativum L.) for which more information is widely available.

PMID- 12410540
TI  - Effects of tanshinone I isolated from Salvia miltiorrhiza bunge on arachidonic
      acid metabolism and in vivo inflammatory responses.
AB  - Arachidonic acid (AA) mainly released from the cell membrane by phospholipase
      A(2) (PLA(2)) is converted to eicosanoids by the action of cyclooxygenase (COX)
      and lipoxygenase (LO). In order to find the specific inhibitors of AA metabolism
      especially PLA(2) and COX-2, 300 plant extracts were evaluated for their
      inhibitory activity on PGD(2) production from cytokine-induced mouse bone marrow
      derived mast cells in vitro. From this screening procedure, the methanol extract
      of Salvia miltiorrhiza was found to inhibit PGD(2) production and the ethyl
      acetate subfraction gave the strongest inhibition of five subfractions tested.
      From this ethyl acetate subfraction, an activity-guided isolation finally gave
      tanshinone I as an active principle. This investigation deals with the effects of
      tanshinone I on AA metabolism from lipopolysaccharide (LPS)-induced RAW 264.7
      cells and in vivo antiinflammatory activity. Tanshinone I inhibited PGE(2)
      formation from LPS-induced RAW macrophages (IC(50) = 38 microM). However, this
      compound did not affect COX-2 activity or COX-2 expression. Tanshinone I was
      found to be an inhibitor of type IIA human recombinant sPLA(2)(IC(50) = 11
      microM) and rabbit recombinant cPLA(2) (IC(50) = 82 microM). In addition,
      tanshinone I showed in vivo antiinflammatory activity in rat carrageenan-induced
      paw oedema and adjuvant-induced arthritis.

PMID- 12410541
TI  - Anxiolytic and antiemetic activity of Zingiber officinale.
AB  - The benzene fraction (BF) of a petroleum ether extract of dried rhizomes of
      ginger, which contained anticonvulsant principle(s), was screened for anxiolytic
      and antiemetic activity. Motor coordination was not affected by BF per se, but
      diazepam-induced motor incoordination was potentiated. Animals treated with BF
      showed decreased occupancy in the closed arm of the elevated plus maze suggesting
      the presence of anxiolytic principles in the BF. BF also blocked lithium sulphate
      induced conditioned place aversion indicating antiemetic activity. These findings
      suggest that the fraction (BF) possesses anticonvulsant, anxiolytic and
      antiemetic activity.

PMID- 12410542
TI  - Effects of Gentiana lutea ssp. symphyandra on the central nervous system in mice.
AB  - A methanolic extact of Gentiana lutea ssp. symphyandra roots has been
      investigated for its possible effects on the central nervous system of mice. At
      doses of 250 and 500 mg/kg (i.p.), the methanol extract of Gentiana roots caused
      a significant increase in the swimming endurance test and exhibited slight
      analgesic activity, but no lethality in mice suggesting some activity on the
      central nervous system. However, there was no indication of sedation or muscular
      fatigue at the doses employed. HPLC analysis showed that three secoiridoid
      compounds, gentiopicroside, swertiamarine and sweroside were present and may have
      been responsible for the CNS effects of the methanol extract of Gentiana lutea
      ssp. symphyandra roots.

PMID- 12410543
TI  - Effect of silybin and its congeners on human liver microsomal cytochrome P450
      activities.
AB  - Silybin and related flavonolignans form a major part of the Silybum marianum
      extract, silymarin, which has been used to treat liver diseases for hundreds of
      years. Although regarded as safe, many of the extract constituents remain thus
      far untested for their possible effects on liver biotransformation enzymes.
      Cytochromes P450 (CYP) are very important in this regard. We tested the effect of
      four flavonolignans: silybin, its hemisynthetic derivative dehydrosilybin,
      silydianin, and silycristin on three specific CYP activities: bufuralol 1'
      hydroxylation (CYP2D6), p-nitrophenol hydroxylation (CYP2E1), and nifedipine
      oxidation (CYP3A4). All flavonolignans displayed dose-dependent inhibition of
      these activities with IC(50) values in the micromolar range. The inhibition was
      competitive or mixed as revealed by double reciprocal plots of kinetic
      experiments. However, the inhibition is not considered to be relevant for therapy
      because physiological concentrations of the individual flavonolignans do not
      exceed 0.5 microM. The data support the use of the extract as a dietary
      supplement.

PMID- 12410544
TI  - Antistress effects of bacosides of Bacopa monnieri: modulation of Hsp70
      expression, superoxide dismutase and cytochrome P450 activity in rat brain.
AB  - The antistress effect of bacosides of Brahmi (Bacopa monnieri, BBM), dissolved in
      distilled water, was -studied in adult male Sprague Dawley rats by administering
      oral doses of 20 and 40 mg/kg for 7 consecutive days. In half of the animals
      treated with 20 or 40 mg/kg of BBM, stress was given 2 h after the last dose.
      Stress was also administered to the animals treated with distilled water alone.
      BBM, at both doses, did not induce a significant change in the expression of
      Hsp70 in any brain region studied while stress alone produced a significant
      increase in the Hsp70 expression in all the brain regions. A significant decrease
      in the activity of superoxide dismutase (SOD) was evident in the hippocampus with
      the lower dose of BBM and in animals given stress alone, while an increase in the
      activity of SOD was observed in the brain regions with the higher dose of BBM. An
      increase in the activity of cytochrome P450 (P450) dependent 7-pentoxyresorufin-o
      dealkylase (PROD) and 7-ethoxyresorufin-o-deethylase (EROD) was observed in all
      the brain regions after exposure to stress alone and with both doses of BBM
      although the magnitude of induction of P450 expression was less with a higher
      dose of BBM. Interestingly, stress when given to the animals pretreated with BBM
      for 7 days resulted in a decrease in Hsp70 expression in all the brain regions
      with a significant decrease occurring only in the hippocampus. Likewise the
      activity of SOD was found to be further reduced in all the brain regions in the
      animals treated with the lower dose of BBM followed by stress. However, when
      stress was given to the animals pretreated with the higher dose of BBM, a
      significant increase in the enzyme activity was observed in the cerebral cortex
      and in the rest of the brain while the activity of SOD was reduced to a much
      greater extent in the cerebellum and in the hippocampus. Likewise, the activity
      of P450 enzymes was found to be restored to almost control levels in the animals
      given stress and pretreated with the higher dose of BBM, while a lesser degree of
      induction, compared with animals treated with BBM or stress alone, was observed
      in the animals pretreated with the lower dose of BBM and given stress. The data
      indicate that BBM has potential to modulate the activities of Hsp70, P450 and SOD
      thereby possibly allowing the brain to be prepared to act under adverse
      conditions such as stress.

PMID- 12410545
TI  - Antimalarial activity of extracts and alkaloids isolated from six plants used in
      traditional medicine in Mali and Sao Tome.
AB  - Methanol and chloroform extracts were prepared from various parts of four plants
      collected in Mali: Guiera senegalensis (Gmel.) Combretaceae, Feretia apodanthera
      (Del.) Rubiaceae, Combretum micranthum (Don.) Combretaceae, Securidaca
      longepedunculata (Fres.) Polygalaceae and two plants -collected in Sao Tome:
      Pycnanthus angolensis (Welw.) Myristicaceae and Morinda citrifolia (Benth.)
      Rubiaceae were assessed for their in vitro antimalarial activity and their
      cytotoxic effects on human monocytes (THP1 cells) by flow cytometry. The methanol
      extract of leaves of Feretia apodanthera and the chloroform extract of roots of
      Guiera senegalensis exhibited a pronounced antimalarial activity. Two alkaloids
      isolated from the active extract of Guiera senegalensis, harman and
      tetrahydroharman, showed antimalarial activity (IC(50) lower than 4 microg/mL)
      and displayed low toxicity against THP1. Moreover, the decrease of THP1 cells in
      S phase of the cell cycle, after treatment with harman and tetrahydroharman, was
      probably due to an inhibition of total protein synthesis.

PMID- 12410546
TI  - Effect of valepotriates (valerian extract) in generalized anxiety disorder: a
      randomized placebo-controlled pilot study.
AB  - The aim of the present study was to carry out a controlled pilot study on the
      putative anxiolytic effect of valepotriates. Thirty-six outpatients with
      generalized anxiety disorder (DSM III-R), after a 2-week wash-out, were
      randomized to one of the following three treatments for 4 weeks (n = 12 per
      group): valepotriates (mean daily dose: 81.3 mg), diazepam (mean daily dose: 6.5
      mg), or placebo. A parallel, double-blind, flexible-dose, placebo-controlled
      design was employed. No significant difference was observed among the three
      groups at baseline or in the change from baseline on the Hamilton anxiety scale
      (HAM-A) or in the trait part of the state-trait anxiety inventory (STAI-trait).
      Moreover, the three groups presented a significant reduction in the total HAM-A
      scores. On the other hand, only the diazepam and valepotriates groups showed a
      significant reduction in the psychic factor of HAM-A. The diazepam group also
      presented a significant reduction of the STAI-trait. Although the principal
      analysis (HAM-A between group comparison) found negative results (probably due to
      the small sample size in each group), the preliminary data obtained in the
      present study suggest that the valepotriates may have a potential anxiolytic
      effect on the psychic symptoms of anxiety. However, since the number of subjects
      per group was very small, the present results must be viewed as preliminary.
      Thus, further studies addressing this issue are warranted.

PMID- 12410547
TI  - Antimutagenic effects of black tea (World Blend) and its two active polyphenols
      theaflavins and thearubigins in Salmonella assays.
AB  - Almost two thirds of the world population consume tea everyday. Tea is processed
      differently in different parts of the world to give green (20%), black (78%) or
      oolong tea (2%). The antimutagenic and anticarcinogenic activities of green tea
      were extensively investigated compared with those of black tea. Considering the
      potent antimutagenic effects of green tea we recognized the need to evaluate the
      antimutagenic effects of black tea (World Blend Tea, Southern Tea Co., Marietta,
      GA) in Salmonella strains TA97a, TA98, TA100 and TA102 in preincubation tests,
      both with and without S9 activation. Attempts have also been made to compare the
      results of the tea extracts with their two active polyphenols theaflavins and
      thearubigins. Antimutagenicity assays were carried out in bacterial plates
      treated with different concentrations (1%, 2.5%, 5%, 10% and 20%) of tea extracts
      against known bacterial mutagens sodium azide, 4-nitro-o-phenylenediamine, cumine
      hydroperoxide, 2-aminofluorene and danthron. A significant decrease in the number
      of revertant colonies was observed in the plates treated with 1% to 20% of tea
      extract plus positive mutagen when compared with positive mutagen only. Both the
      active polyphenols theaflavins and thearubigins extracted from the black tea
      (World blend) also showed significant antimutagenic effects against known
      positive compounds in these strains. In the experiments with S9 activation, the
      antimutagenic effects were significantly higher. These results indicate that
      black tea and its two polyphenols have significant antimutagenic effects in Ames
      Salmonella assays.

PMID- 12410548
TI  - Hypoglycaemic activity of Scopariadulcis L. extract in alloxan induced
      hyperglycaemic rats.
AB  - Scoparia dulcis L. commonly known as 'Sweet Broomweed' is widely used in Indian
      folk medicine for the treatment of diabetes mellitus. Oral administration of
      0.15, 0.30 and 0.45 g/kg body weight of the aqueous extract of the Scoparia
      dulcis leaves (SLEt) for 45 days resulted in a significant reduction in blood
      glucose, glycosylated haemoglobin and an increase in total haemoglobin but in the
      case of 0.45 g/kg body weight the effect was highly significant. The aqueous
      extract also prevented a decrease in the body weight. An oral glucose tolerance
      test was also performed in experimental diabetic rats, in which there was a
      significant improvement in glucose tolerance in animals treated with SLEt and the
      effect was comparable to that of glibenclamide.

PMID- 12410549
TI  - Relaxant activity of raspberry (Rubus idaeus) leaf extract in guinea-pig ileum in
      vitro.
AB  - Tea made from the leaves of Rubus idaeus L. (raspberry) has been used for
      centuries as a folk medicine to treat wounds, diarrhoea, colic pain and as a
      uterine relaxant. Extracts of dried raspberry leaves prepared with different
      solvents, (n-hexane, ethyl acetate, chloroform and methanol) were tested in vitro
      for relaxant activity on transmurally stimulated guinea-pig ileum. The methanol
      (MeOH) extract exhibited the largest response and also indicated that the active
      compounds are of a relatively polar nature. Hence the bulk of the leaves were
      extracted with methanol and the dried extract fractionated on a silica gel
      column, eluting with chloroform, mixtures of chloroform and methanol and finally
      methanol. Each fraction was examined by thin layer chromatography and tested for
      relaxant activity in an in vitro transmurally stimulated guinea-pig ileum
      preparation. The fractions eluted with chloroform (CHCl(3)) lacked relaxant
      activity. Samples eluted with CHCl(3)/MeOH (95:5) had moderate relaxant activity,
      while a second distinctive peak of activity eluted with a more polar solvent
      mixture (CHCl(3)/MeOH 50:50) provided strong dose dependent responses. Evidence
      was obtained that there are at least two components of raspberry leaf extract
      which exhibit relaxant activity in an in vitro gastrointestinal preparation.

PMID- 12410550
TI  - Studies on the antiinflammatory activity of Betula alnoides bark.
AB  - The antiinflammatory activity of Betula alnoides extract was evaluated in acute
      and subacute inflammation models. The extract was also evaluated for
      antiinflammatory activity in sheep RBC induced sensitivity and in membrane
      stabilization models. Except for the sheep RBC induced sensitivity model, the
      extract showed significant antiinflammatory activity.

PMID- 12410551
TI  - Screening of eight alkaloids and ten flavonoids isolated from four species of the
      genus Boronia (Rutaceae) for antimicrobial activities against seventeen clinical
      microbial strains.
AB  - Eight alkaloids and ten flavonoids isolated from four species of Boronia of the
      Rutaceae were screened against 17 clinical microbial strains. Of the test
      compounds, three acridone and one quinolone alkaloids and eight flavonoids were
      reported as novel natural products. Screening was carried out by the standard
      disc diffusion method. Of the tested compounds, six alkaloids and seven
      flavonoids including the novel products were active against six clinical strains.
      The active compounds showed mild to moderate activities against Bacillus
      subtilis, Staphylococcus aureus, Sarcina lutea, exterotoxigenic Escherichia coli,
      Salmonella typhi and Klebsiella sp. Of the active flavonoids, some exhibited
      fairly significant activity towards Staphylococcus aureus, Sarcina lutea,
      Salmonella typhi and Klebsiella sp. The flavonoids were observed to have higher
      spectrum and magnitude of activity than those of the alkaloids. A standard
      ampicillin disc was used to compare the results.

PMID- 12410552
TI  - Effect of Artemisia santonicum L. on blood glucose in normal and alloxan-induced
      diabetic rabbits.
AB  - The hypoglycaemic effect of panicles of Artemisia santonicum L. in normal and
      alloxan-induced diabetic rabbits was investigated. Blood glucose levels were
      determined after oral administration of an aqueous extract of Artemisia
      santonicum L. In normal and diabetic rabbits, 2 mL/kg (0.42 g/kg) aqueous extract
      significantly (p < 0.01) reduced blood glucose levels 6 h after administration,
      which was consistent and time-dependent.

PMID- 12410553
TI  - Effects of black radish root (Raphanus sativus L. var niger) on the colon mucosa
      in rats fed a fat rich diet.
AB  - The effect of black radish root (Raphanus sativus L. var niger) was studied on
      the structure and redox state of the colon mucosa in fat-rich diet fed rats. The
      epithelial lining disrupted, the number of enterocytes and the goblet cells
      reduced and inflammatory cells were observed in rats fed with a fat-rich diet.
      After treatment with granules from black radish root all of the histopathological
      changes and parameters of the redox state caused by the fat-rich diet were
      improved. The structure of the epithelial cells was similar to the controls, the
      number of goblet cells increased and no inflammation was observed.

PMID- 12410554
TI  - Studies on essential oils: part 10; antibacterial activity of volatile oils of
      some spices.
AB  - The essential oils extracted from the seeds of seven spices, Anethum graveolens,
      Carum capticum, Coriandrum sativum, Cuminum cyminum, Foeniculum vulgare,
      Pimpinella anisum and Seseli indicum have been studied for antibacterial activity
      against eight pathogenic bacteria, causing infections in the human body. It has
      been found that the oil of C. capticum is very effective against all tested
      bacteria. The oil of C. cyminum and A. graveolens also gave similar results.
      These oils are equally or more effective when compared with standard antibiotics,
      at a very low concentration.

PMID- 12410555
TI  - Antitubercular constituents from the hexane fraction of Morinda citrifolia Linn.
      (Rubiaceae).
AB  - A crude ethanol extract and hexane fraction from Morinda citrifolia Linn.
      (Rubiaceae) show antitubercular activity. The major constituents of the hexane
      fraction are E-phytol, cycloartenol, stigmasterol, beta-sitosterol, campesta
      5,7,22-trien-3beta-ol and the ketosteroids stigmasta-4-en-3-one and stigmasta-4
      22-dien-3-one. E-Phytol, a mixture of the two ketosteroids, and the
      epidioxysterol derived from campesta-5,7,22-trien-3beta-ol all show pronounced
      antitubercular activity.

PMID- 12410556
TI  - Evaluation of antipyretic potential of Leucas lavandulaefolia (Labiatae) aerial
      part extract.
AB  - Methanol extract of Leucas lavandulaefolia (LLFE) was subjected to antipyretic
      evaluation with yeast-induced pyrexia in rats. A yeast suspension (10 mL/kg,
      s.c.) increased the rectal temperature 19 h after administration. The extract at
      doses of 100, 200, 400 mg/kg (i.p.) produced significant dose dependent lowering
      of body temperature in yeast-provoked elevation of body temperature in rats. The
      antipyretic effect produced was comparable to that of a standard antipyretic
      drug, paracetamol.

PMID- 12410557
TI  - Potential antiamoebic property of the roots of Piper longum Linn.
AB  - In an earlier study we reported the effect of ethanol extracts of Piper longum
      fruit against caecal amoebiasis in rats. A follow-up study to determine whether
      the roots possess similar antiamoebic activity was carried out. The ethanolic
      extract of roots was amoebicidal at 1,000 microg/mL in vitro and cured 88% of
      caecal amoebiasis cases, suggesting that both the root and fruit of P. longum
      possess antiamoebic activity to approximately the same extent.

PMID- 12410558
TI  - Antimicrobial potential of two different Hypericum species available in India.
AB  - The antimicrobial activity of extracts of the leaves and stems of two different
      varieties of Hypericum was evaluated by the disc diffusion method. Petroleum
      ether, acetone, chloroform and methanol extracts of Hypericum mysorense and
      Hypericum patulum stems and leaves were investigated for their antimicrobial
      activity against six different strains of bacteria and fungi by the zone of
      inhibition method (ZIM). The results showed that both the stem and leaf extracts
      of both species have a very broad spectrum of antibacterial activity. The
      petroleum ether and acetone extract of the leaves and stems of H. mysorense did
      not show antifungal effects against any of the six fungal organisms tested but
      other extracts showed a potential antifungal effect which was comparable to that
      of griseofulvin, the standard antifungal agent. Thus these results demonstrate
      that the leaf and stem extracts of both the Hypericum species have a very broad
      spectrum of activity and suggest that they may be useful in the treatment of
      various microbial infections.

PMID- 12410559
TI  - Psychopharmacological profiles of Leucas Lavandulaefolia Rees.
AB  - Methanol extract of Leucas lavandulaefolia (LLFE) was evaluated for different
      psychopharmacological profiles with various animal models in rats and mice. The
      extract showed a potential reduction in spontaneous activity and caused a
      significant decrease in exploratory behavioural pattern by the head dip and Y
      maze test. It also showed a significant reduction in muscle relaxant activity by
      rotarod, 30 degrees inclined screen and traction tests. The extract showed a
      remarkable potentiation of pentobarbitone induced sleeping time in mice.

PMID- 12410560
TI  - Anti-stress and anti-fatigue effect of fermented rice bran.
AB  - The anti-stress and anti-fatigue effects of a hot water extract of fermented rice
      bran (FRB) were investigated with Saccharomyces cerevisae IFO 2346 on rats or
      mice. Oral administration (1 g/kg/day) of a hot water extract of FRB inhibited
      major changes in weight of the adrenal, thymus, spleen and thyroid, showing the
      anti-stress effect. A hot water extract of FRB also inhibited the increase of GPT
      and LDH activity, cholesterol and serum glucose levels. Administration (1
      g/kg/day) for 2 weeks significantly prolonged the swimming time, resulting in an
      increase of the anti-fatigue effect. From these results, it can be considered
      that FRB has an anti-stress and anti-fatigue effect.

PMID- 12410562
TI  - Thymic model for examining BRCA2 expression and function.
AB  - Mutations in the human BRCA2 breast cancer susceptibility gene are associated
      with increased risks of breast, ovarian, and other cancers. BRCA2 has been
      hypothesized to function in processes of DNA damage/breakage repair, cell
      proliferation, and apoptosis. These processes continually occur in the thymus
      during thymocyte development, and BRCA2 mRNA is highly expressed in thymus
      relative to most other organs. We therefore used the thymus as a model system to
      study BRCA2 expression and function. Quantitative reverse transcription
      polymerase chain reaction experiments showed that highly activated immature
      CD4(+) CD8(+) double-positive human thymocytes that exhibited high levels of
      proliferation and apoptosis had increased BRCA2 mRNA levels relative to other
      thymocyte subsets. BRCA2 mRNA levels were upregulated in thymocytes treated with
      the DNA-damaging agent etoposide. Only modest increases were associated with
      proliferation in human peripheral lymphocytes in response to concanavalin A
      (ConA) mitogen. Mice homozygous for a targeted mutation in Brca2 exon 27
      (Brca2(Delta27/Delta27)) showed normal thymic architecture but had 18% decreased
      thymocyte cellularity compared with wild-type mice. Thymocytes from these
      Brca2(Delta27/Delta27) mice displayed decreased apoptosis in response to
      etoposide-induced DNA damage compared with wild-type thymocytes. These studies
      suggest that BRCA2 mRNA levels are modulated during DNA damage and may be
      important during apoptosis.

PMID- 12410563
TI  - Induction of marked apoptosis in mammalian cancer cell lines by antisense DNA
      treatment to abolish expression of DENN (differentially expressed in normal and
      neoplastic cells).
AB  - We previously reported the isolation of the novel human DENN gene, which is
      differentially expressed in normal and neoplastic cells. DENN is identical to
      MADD (mitogen-activated protein kinase-activating death domain), which interacts
      with tumor necrosis factor receptor 1 through their death domains. DENN is also
      homologous to Rab3 GEP, a rat Rab3 GDP/GTP exchange protein. Real-time reverse
      transcription-polymerase chain reaction analysis showed that DENN expression in
      cancer cell lines was 26-50 times that in normal cells. The Jurkat human
      leukemia, PLC/PRF/5 human hepatoma, and NS-1 mouse myeloma cell lines as well as
      the MRC-5 human fetal lung and Vero monkey kidney cell lines were treated
      successfully with four separate DENN-targeted antisense oligodeoxynucleotides
      (ODNs) to abrogate DENN expression. Quantitative assessment of cell viability and
      apoptosis by flow cytometry via fluorescein diacetate and propidium iodide
      membrane-integrity tests, terminal deoxynucleotidyl transferase-mediated
      deoxyuridine 5-triphosphate-biotin nick end-labeling, and annexin V assays showed
      that antisense silencing of DENN resulted in markedly more pronounced cell death
      in cancer cells compared with nonmalignant cells. Antisense-treated cell lines
      exhibited extensive loss of DNA content, forming distinct sub-G(1) peaks, while
      cell proliferation diminished significantly. Ultrastructural features of
      programmed cell death in cells subjected to antisense ODNs were authenticated by
      electron microscopy. In contrast, transfection of cell lines with a plasmid
      construct to achieve DENN overexpression augmented cellular proliferation and
      could reverse the apoptotic effect of antisense and staurosporine treatment. Our
      findings suggest that DENN is intimately involved in anti-apoptotic and cell
      survival processes.

PMID- 12410564
TI  - Contributions of mitogen-activated protein kinase and nuclear factor kappa B to N
      (4-hydroxyphenyl)retinamide-induced apoptosis in prostate cancer cells.
AB  - The synthetic retinoid N-(4-hydroxyphenyl)retinamide (4-HPR) has been shown to
      induce apoptosis in various types of tumors, including prostate cancer. We sought
      to examine the key mechanisms affecting the resistance to 4-HPR-induced apoptosis
      in three human prostate cancer cell lines, PC-3, DU145, and LNCaP. Concentrations
      of more than 40 microM 4-HPR produced apoptosis to almost the same extent in all
      cell lines; however, only the LNCaP line remained highly sensitive to
      concentrations less than 10 microM. These differing sensitivities at low
      concentrations correlated well with the level of constitutive activation of
      nuclear factor kappa B (NFkappaB) in the individual cell lines. We found that
      NFkappaB activation inhibited c-jun NH(2)-terminal kinase and caspase 3
      activation induced by 4-HPR and that NFkappaB inhibition by the I kappa B alpha
      phosphorylation inhibitor compound Bay 117082 resulted in increasing
      sensitization of both PC-3 and DU145 lines to apoptosis induced by 4-HPR at low
      concentrations. Furthermore, we found that inhibition of extracellular signal
      regulated kinase (ERK) enhanced the suppression of NFkappaB by 4-HPR and also
      resulted in sensitization to apoptosis in the DU145 cell line, in which ERK is
      activated constitutively. It thus appears that mitogen-activated protein kinase
      associated with the activity of NFkappaB plays an important role in the degree of
      resistance to 4-HPR-induced apoptosis in human prostate cancer cells.

PMID- 12410565
TI  - Nerve growth factor and enhancement of proliferation, invasion, and
      tumorigenicity of pancreatic cancer cells.
AB  - Nerve growth factor (NGF) exerts both stimulatory and inhibitory effects on
      neuronal and certain non-neuronal tumors. In pancreatic cancer NGF is
      overexpressed, and this overexpression is associated with increased perineural
      invasion. NGF has the potential to stimulate the growth of some pancreatic cancer
      cell lines, and this effect is mediated by the phosphorylation of tyrosine kinase
      receptor A and mitogen-activated protein kinase activation; it is dependent on
      the expression levels of tyrosine kinase receptor A and p75 receptors. To
      determine whether cancer cell-derived NGF can participate in the regulation of
      pancreatic cancer cell proliferation, PANC-1 human pancreatic cancer cells were
      stably transfected with a full-length human beta-NGF expression vector. In vitro
      and in vivo growth characteristics were analyzed by proliferation assays and
      invasion assays and in a nude mouse tumor model. Stable transfection of NGF in
      PANC-1 cells resulted in enhanced anchorage-dependent growth, with a decrease in
      doubling times of up to 50%, and in an approximately twofold increase in
      anchorage-independent cell growth and cell invasion. Furthermore, stably
      transfected PANC-1 cells showed enhanced tumorigenicity in nude mice. These
      results suggest that NGF has the capacity to act in a paracrine and/or an
      autocrine manner in pancreatic cancer and that it enhances cancer cell growth and
      invasion in vivo, thereby contributing to the aggressiveness and poor prognosis
      of this disease.

PMID- 12410566
TI  - Multiple human chromosomes carrying tumor-suppressor functions for the mouse
      melanoma cell line B16-F10, identified by microcell-mediated chromosome transfer.
AB  - Many tumor-suppressor genes are involved in the development and progression of
      cellular malignancy. To understand the functional role of tumor-suppressor genes
      in melanoma and to identify the human chromosome that carries these genes, we
      transferred individually each normal human chromosome, except for the Y
      chromosome, into the mouse melanoma cell line B16-F10, by microcell fusion. We
      examined the tumorigenicity of hybrid cells in nude mice and their in vitro
      growth properties. The introduction of human chromosomes 1 and 2 elicited a
      remarkable change in cell morphologic features, and cellular senescence was
      induced at seven to 10 population doublings. The growth rates of tumors derived
      from microcell hybrid clones containing introduced human chromosome 5, 7, 9, 10,
      11, 13, 14, 15, 16, 19, 20, 21, 22, or X were significantly slower than that of
      the parental B16-F10 cells, whereas the introduction of other human chromosomes
      had no effect on the tumorigenicity of these cells. The majority of microcell
      hybrid clones that exhibited suppressed tumorigenicity also showed a moderate
      reduction in doubling time compared with B16-F10 cells. Microcell hybrid clones
      with an introduced human chromosome 5 showed complete suppression of in vitro
      transformed phenotypes, including cell growth, saturation density, and colony
      forming efficiency in soft agar. Thus, these results indicated the presence of
      many cell senescence-related genes and putative tumor-suppressor genes for the
      mouse melanoma cell line B16-F10 and showed in vitro that many tumor-suppressor
      genes control the phenotypes of transformed cells in the multistep process of
      neoplastic development.

PMID- 12410568
TI  - Health status and health-related quality of life associated with hemophilia.
AB  - The hemophilias are a group of disorders associated with a chronic burden of
      morbidity and early mortality. Improvements in these adverse features have been
      achieved by the use of clotting factor concentrates within comprehensive centers
      of specialized care providing home infusion programs. Offsetting effects from
      transfusion-transmitted hepatitis and HIV infection are in recent decline. The
      net impact of these changes merits assessment. To test the a priori hypotheses
      that increasing severity of factor VIII deficiency would be associated with an
      increasing burden or morbidity and that hepatitis and HIV positivity would impair
      health status further, a cross-sectional study of a population-based cohort was
      undertaken in a regional hemophilia program in Ontario, Canada. A survey was made
      of mild, moderate, and severe hemophiliacs over 13 years of age who self-reported
      their health status using a standard 15-item questionnaire. The responses were
      converted to levels in the Health Utilities Index Mark 2 (HUI2) and Mark 3 (HUI3)
      health status classification systems to form multi-element vectors from which
      single-attribute morbidity and overall health-related quality of life utility
      scores were determined. The burden of morbidity was greater in hemophiliacs than
      in the general population and correlated with the category of disease (mild <
      moderate < severe). Hepatitis and HIV positivity conferred additional burdens of
      morbidity, which were mainly in the attributes of mobility (HUI2), ambulation
      (HUI3), and pain (HUI2/3), all of these differences reaching levels of
      statistical significance. Despite demonstrable improvements in the safety,
      effectiveness, and utilization of clotting factor concentrates, hemophiliacs
      continue to experience an important burden of morbidity. Measurement of this
      burden, as reported here, provides a basis for future economic evaluation of the
      costs and consequences of health care interventions provided to this population.

PMID- 12410567
TI  - Amifostine does not prevent activation of TGFbeta1 but induces smad 7 activation
      in megakaryocytes irradiated in vivo.
AB  - Experiments were undertaken to assess the role of amifostine in the activation of
      latent TGFbeta1 and in the smad proteins cascade (smad 2/3, smad4, smad7),
      focusing on megakaryocytes, in the bone marrow irradiated in vivo. Non-irradiated
      megakaryocytes were negative for active TGFbeta1. Immunopositivity to active
      TGFbeta1 was detected in megakaryocytes 10 days after irradiation in amifostine-
      treated and untreated marrows. Smad 2/3 and smad 4 were strongly positive in the
      nucleus of megakaryocytes 10 days after irradiation. At the same time, a
      predominant hypocellular bone marrow with foci of hematopoiesis was observed with
      few megakaryocytes. An increase in the number of reticulin fibers was also seen.
      In amifostine-treated marrows, smad 2/3 and smad4 were not detected in the
      nucleus but were positive in the cytoplasm of megakaryocytes 10 days after
      irradiation. Coincidentally, bone marrows were cellular with megakaryocytes.
      Smad7 immunoexpression was detected in the cytoplasm of megakaryocytes in the non
      irradiated, amifostine-treated and in the irradiated, amifostine-treated marrows.
      Data indicate that amifostine does not prevent latent TGFbeta1 activation in
      irradiated megakaryocytes. While TGFbeta1 signal transduction occurs in
      megakaryocytes in untreated bone marrows, it is inhibited in megakaryocytes in
      amifostine-treated marrows due to the induction of smad 7 activation. This is the
      first report showing smad 7 activation by amifostine. Our results also suggest a
      role for TGFbeta1 as an inhibitor of megakaryocytes in vivo.

PMID- 12410569
TI  - Hydroxyurea (HU) for prevention of recurrent stroke in sickle cell anemia (SCA).
AB  - Cerebrovascular accident (CVA) is a major cause of morbidity and death in sickle
      cell anemia (SCA). Transfusion of packed erythrocytes is widely used to prevent
      this complication. However, chronic transfusion may lead to iron overload,
      alloimmunization, or infections. Cost and compliance may compromise transfusion
      therapy. A possible alternative, the prophylactic use of hydroxyurea (HU), has
      not been tried to determine whether it may prevent recurrent stroke. We used HU
      in five children with SCA who had suffered stroke, in three of them after a first
      episode and in the other two after a second CVA. Four had infarctive stroke and
      one a transient ischemic attack (TIA). Four patients took HU at a dose of 40
      mg/kg/d, one patient at 30 mg/kg/d. None of the patients had recurrent stroke
      during 42-112 months of observation. None experienced pain crises. In all, HbF
      increased significantly and was maintained above 14.7% during treatment. The
      total Hb concentration increased 19.5 g/L (median) above the value before
      treatment. HU was well tolerated. None of the five children had leukopenia or
      thrombocytopenia during therapy. HU appears to prevent recurrence of stroke in
      SCA without risk of major toxicity.

PMID- 12410570
TI  - Danazol for the treatment of thrombocytopenia in patients with myelodysplastic
      syndrome.
AB  - Thrombocytopenia is a poor prognostic indicator in the myelodysplastic syndromes
      (MDS). Treatment options for patients with symptomatic thrombocytopenia are
      limited. Danazol, an attenuated androgen, may have some efficacy in increasing
      the platelet count of patients with MDS. We retrospectively reviewed 33 patients
      with primary MDS who were treated with danazol for 6 or more weeks. After 6 weeks
      on danazol, the mean platelet count increased from 42 x 10(9)/L to 60 x 10(9)/L
      (P < 0.015), and 25 out of 33 patients (76%) had an increase in their platelet
      counts. Following 12 weeks of treatment, the mean platelet count increased to 67
      x 10(9)/L (P < 0.005), and 21 out of 29 patients (72%) had an increase in their
      platelet counts. Seven out of nine patients no longer required platelet
      transfusions because bleeding stopped after 6 weeks on danazol. Mean duration of
      response was 10 months (range 2-68 months). Responses were seen in all French
      American-British (FAB) subtypes and in all International Prognostic Scoring
      System (IPSS) scores. Therapy was well tolerated. Danazol may be effective in MDS
      patients who are thrombocytopenic.

PMID- 12410571
TI  - Resistance of bcr-abl-positive acute lymphoblastic leukemia to daunorubicin is
      not mediated by mdr1 gene expression.
AB  - In vitro resistance to anthracyclines is thought to be a poor prognosis in
      achieving long-term remission in patients with acute lymphoblastic leukemia
      (ALL). Expression of a multidrug resistance gene (mdr1) that codes for 170 Kd
      transmembrane glycoprotein is responsible for conferring resistance to malignant
      cells to anthracyclines. The t(9:22) translocation, resulting in bcr-abl fusion
      gene, is commonly found in B-lineage ALL and is known to be a poor prognostic
      factor for long-term remission. To investigate whether resistance to
      anthracyclines contributes to poor prognosis in bcr-abl-positive ALL, we studied
      daunorubicin sensitivity by an in vitro colorimetric methyl tetrazolium (MTT)
      assay in B-lineage ALL patients who were bcr-abl-positive and compared them with
      the B-lineage, age-matched bcr-abl-negative group. We also looked for and
      compared the presence of mdr1 gene expression in these two groups of patients by
      RT-PCR. Of the 46 patients included in the study, 16 (34.7%) were positive for
      the bcr-abl fusion gene. mdr1 gene expression was seen in 14 of these 46 patients
      (30.4%). However, the expression of the mdr1 gene was relatively lower in the bcr
      abl-positive group (3 out of 16, 18.7%) compared to the bcr-abl-negative group
      (11 out of 30, 36.6%). The median LD(50) of daunorubicin (concentration lethal to
      50% of the leukemic blasts) differed significantly between bcr-abl-positive and 
      negative patients (P = 0.018). This in vitro study suggests that bcr-abl-positive
      ALL is relatively resistant to daunorubicin, but this resistance is not mediated
      through mdr1 gene expression.

PMID- 12410572
TI  - In vitro production of anti-RBC antibodies and cytokines in chronic lymphocytic
      leukemia.
AB  - B-chronic lymphocytic leukemia (B-CLL) patients have a high prevalence of
      autoimmune phenomena, mainly autoimmune hemolytic anemia (AIHA). Immunoregulatory
      cytokines play a role in the regulation of both autoimmunity and leukemic B-cell
      growth. Mitogen-stimulated direct antiglobulin test (MS-DAT) is a recently
      described test able to disclose latent anti-RBC autoimmunity in AIHA. We
      investigated the prevalence of anti-RBC autoimmunity by MS-DAT and the pattern of
      cytokine production by PHA-stimulated whole blood cultures from 69 B-CLL patients
      and 53 controls. Results showed that anti-RBC IgG values in unstimulated, PHA-,
      PMA-, and PWM-stimulated cultures were significantly higher in B-CLL patients
      compared with controls. In B-CLL, the prevalence of anti-RBC autoimmunity was
      28.9% by MS-DAT, compared with 4.3% by the standard DAT. Production of IFN-gamma,
      IL-2, IL-13, TNF-alpha, sCD23, and sCD30 was significantly increased in all B-CLL
      patients compared with controls, whereas there was no difference in IL-4, IL-6,
      IL-10, and TGF-beta production. Multivariate analysis showed that IL-4 was
      significantly increased in MS-DAT-positive compared with -negative patients.
      Patients with autoantibody positivity displayed greater IFN-gamma production than
      negative patients. These data are in line with the hypothesis that autoimmune
      phenomena in B-CLL are associated with an imbalance towards a Th-2-like profile.
      The elevated prevalence of anti-RBC autoimmunity found by MS-DAT suggests that an
      underestimated latent autoimmunity exists in B-CLL.

PMID- 12410573
TI  - Clinical course of thrombocytopenia in patients treated with imatinib mesylate
      for accelerated phase chronic myelogenous leukemia.
AB  - We studied 28 patients with accelerated phase chronic myelogenous leukemia (CML)
      who were enrolled on the Novartis expanded access study 114. Diagnosis of
      accelerated phase CML was based on karyotypic evolution (n = 9) and hematologic
      criteria (n = 18). All patients were begun on 600 mg/day of imatinib mesylate.
      Dose reductions to 400 mg/day and then 300 mg/day were prescribed for an absolute
      neutrophil count (ANC) of <0.5/microl or a platelet count of <20,000/microl.
      Twenty-seven of the 28 patients continued treatment for a median of 34 weeks.
      Eleven patients developed thrombocytopenia following an average of 8.4 +/- 1.4
      weeks of therapy. The onset of thrombocytopenia was associated with disease
      progression in one patient and a decline in bone marrow megakaryocytes in the
      other 10. Nine patients recovered to a platelet count of >20,000/microl after an
      average of 19.7 +/- 1.8 weeks. Patients who developed thrombocytopenia had a
      longer duration of disease (9.39 vs. 4.35 years; P < 0.01) and were more likely
      to be diagnosed with accelerated phase CML by hematologic criteria. Hematologic
      responses in patients with and without thrombocytopenia were comparable; however,
      31.3% of patients without thrombocytopenia had a complete cytogenetic response
      compared to none of those with thrombocytopenia. Grade III-IV thrombocytopenia is
      common in accelerated phase CML and may be a marker for the inability to achieve
      cytogenetic response using single agent imatinib mesylate.

PMID- 12410574
TI  - Myelodysplastic features in visceral leishmaniasis.
AB  - We have detected trilineage myelodysplasia in two children recently diagnosed to
      have visceral leishmaniasis (V.L.), which led us to investigate retrospectively
      available peripheral blood and bone marrow aspirate smears of 5 children
      previously diagnosed as V.L. We saw that they also had trilineage myelodysplasia.
      We postulate that elevated levels of tumor necrosis factor-alpha (TNFalpha) may
      cause trilineage myelodysplasia in the patients with V.L. This nonclonal
      myelodysplasia may be responsible for pancytopenia along with hypersplenism,
      hemolysis and reticuloendothelial hyperplasia causing abnormal retention of iron
      in V.L.

PMID- 12410575
TI  - Sustained molecular remission in a patient with CML in blastic crisis receiving
      dose-reduced hematopoietic stem-cell transplantation followed by early withdrawal
      of cyclosporine and prophylactic use of interferon-alpha.
AB  - A 54-year-old man with chronic myelocytic leukemia in blastic phase received
      reduced-intensity transplantation (RIST) from an HLA-identical unrelated donor.
      The preparative regimen consisted of busulfan, fludarabine, and anti-thymocyte
      globulin. Graft-versus-host disease (GVHD) prophylaxis was cyclosporine alone.
      Because he had a high risk of relapse, we discontinued cyclosporine on day 37,
      but he did not develop any signs of acute GVHD. To induce GVHD and augment a
      graft-versus-leukemia effect, we initiated interferon-alpha therapy on day 80 to
      a maximum dosage of three million units five times a week. He achieved molecular
      remission on day 94 followed by the development of extensive chronic GVHD the
      severity of which paralleled to the dose of interferon-alpha GVHD gradually
      subsided after discontinuation of interferon-alpha and the patient remains in
      molecular remission 18 months after transplantation. This case suggests that
      early withdrawal of cyclosporine and the prophylactic use of interferon-alpha are
      promising in RIST for high-risk leukemia.

PMID- 12410576
TI  - Diagnosis of lupus anticoagulant in the lupus anticoagulant-hypoprothrombinemia
      syndrome: report of two cases and review of the literature.
AB  - We report a severe hemorrhagic disorder in two pediatric patients with lupus
      anticoagulant (LA) associated to acquired factor II (prothrombin) deficiency. In
      both patients, hemorrhagic symptoms resolved after corticosteroid therapy. Serial
      coagulation studies showed that Staclot LA assay was more sensitive than
      DVVconfirm and Staclot PNP tests to confirm the presence of LA when associated
      with severe factor II deficiency. Both patients had non-neutralizing anti
      prothrombin antibodies and their titers inversely correlated with factor II
      activity (r = -1.0, P < 0.0001). Associated findings in these patients included
      positive immunologic tests for systemic lupus erythematosus, a positive anti
      cardiolipin antibody, and anti-beta(2) GPI antibodies in one case. Our findings
      point out the difficulty in diagnosing LA associated with acquired factor II
      deficiency and suggest that, in confirmation of its phospholipid dependency, the
      inclusion of a source of normal human plasma in the test sequence to correct for
      any factor deficiency and a confirmatory step utilizing hexagonal (II) phase
      phospholipids may be crucial to the diagnosis of LA in some patients with LA
      hypoprothrombinemia syndrome.

PMID- 12410577
TI  - Pregnancy and successful labor in the course of chronic lymphocytic leukemia.
AB  - Pregnancy and leukemia are difficult to manage. Protecting the mother from
      hemorrhage and infection and the fetus from developmental failure are the main
      aims. Chronic lymphocytic leukemia (CLL) has been seen very rarely with
      pregnancy. In this article, the successful labor of a 43-year-old woman with CLL
      is reported. She was not a candidate for chemotherapy at that time. She was
      without symptoms when she got pregnant. In the 30th gestational week she was
      found to have urinary tract infection and preterm labor and she was stabilized.
      Gestational diabetes and preeclampsia were also determined after that period and
      managed. The patient was delivered by cesarean section in the 39th gestational
      week. Cord blood was collected and preserved. No postpartum complication was seen
      in either the patient or the infant. This is one of the rare cases presenting CLL
      with pregnancy in the literature.

PMID- 12410578
TI  - CD4-CD8- T-cell polymyositis in a patient with chronic active Epstein-Barr virus
      infection.
AB  - We describe a 17-year-old woman with chronic active Epstein-Barr virus infection
      (CAEBV), who developed EBV+CD4-CD8- T-cell polymyositis. At 14 years of age,
      CAEBV was diagnosed with fever, cytopenia, liver dysfunction, and
      hepatosplenomegaly. Despite the transient remission of interferon-alpha therapy,
      migratory lesions emerged in back and extremities. MRI indicated polymyositis.
      Biopsy specimens revealed intramuscular infiltration of CD3+, CD4-, CD8-, CD56-,
      and EBV-encoded RNA 1+ cells. Circulating CD4-CD8-Vdelta2/Vgamma9 cells
      increased. gammadeltaT-cells contained 20-200 times higher EBV-DNA (2 x 10(4)
      copies/microgDNA) than alphabetaT-cells or NK-cells. The ominous polymyositis
      might denote the musculotropic invasion of EBV+gammadeltaT-cell
      lymphoproliferative disease as a consequence of CAEBV.

PMID- 12410579
TI  - Myxedema ascites in the posttransplant setting: case report.
AB  - Ascites is a rare but important complication of hypothyroidism. Because of the
      rarity of the disease and the inconsistency of symptoms associated with
      hypothyroidism, patients often go undiagnosed for months. Institution of thyroid
      replacement hormone results in rapid and complete resolution of ascites. Here we
      present a case of myxedema ascites that presented in a 52-year-old man 4 months
      after allogeneic bone marrow transplant (BMT). Diagnoses initially considered in
      the differential included the common post-BMT complications, namely, hepatic veno
      occlusive disease, graft vs. host disease, and infection. However, posttransplant
      patients are also at risk for illnesses unrelated to their underlying diagnosis
      or transplant procedure, including hypothyroidism. This case illustrates the
      importance of considering a broad differential diagnosis in posttransplant
      patients, especially those in whom the clinical course is atypical.

PMID- 12410581
TI  - Disseminated histoplasmosis.

PMID- 12410580
TI  - Treatment of a patient with end-stage renal disease with Rituximab:
      pharmacokinetic evaluation suggests Rituximab is not eliminated by hemodialysis.
AB  - The purpose of this study was to determine if therapeutic levels of Rituximab
      could be achieved in a patient with renal failure being dialyzed and if Rituximab
      is removed by hemodialysis. A 54-year-old man with low-grade lymphoma and renal
      failure on hemodialysis received 8 weekly treatments of Rituximab at 375 mg/M(2).
      Serum Rituximab levels were obtained before and after each treatment, before and
      after dialysis following each treatment, as well as in the dialysate fluid. The
      serum levels of Rituximab increased gradually with each treatment and were
      comparable to levels in patients with normal renal function. The postdialysis
      levels were higher than the predialysis levels as a consequence of hemo
      concentration after dialysis. Rituximab was not detected in the dialysate fluid.
      The patient developed life-threatening hyperkalemia after the fourth treatment,
      which we believe occurred secondary to tumor lysis. Therapeutic levels of
      Rituximab may be maintained in patients undergoing dialysis. Rituximab is not
      eliminated by hemodialysis.

PMID- 12410582
TI  - Unusually indolent T-cell prolymphocytic leukemia associated with a complex
      karyotype: is this T-cell chronic lymphocytic leukemia?
AB  - T-cell prolymphocytic leukemia (T-PLL) is typically associated with an aggressive
      clinical course, with a median survival of less than 1 year. We report a case of
      T-PLL that displays multiple cytogenetic abnormalities, with the most complex
      subclone having the following karyotype: 47, Y, -X, +8, inv (10) (p12q26), del
      (11) (p13p15) +marker. However, despite this genetic complexity, the leukemia has
      behaved in a remarkably indolent manner, with the patient remaining asymptomatic,
      without therapeutic intervention, for more than 7 years. The unusually benign
      behavior of this disease calls into question the validity of grouping such cases
      under the umbrella of T-PLL and warrants a reconsideration of T-cell chronic
      lymphocytic leukemia (no longer recognized as a distinct disease) as a bona fide
      diagnostic entity.

PMID- 12410583
TI  - Occurrence of multiple myeloma in both donor and recipient after bone marrow
      transplantation.
AB  - The transplantation of malignant cells during allogeneic transplant is a rare
      occurrence. 27 months after donating progenitor cells, a diagnosis of multiple
      myeloma was made in a 6/6 HLA-phenotypically matched unrelated donor. The 42-year
      old recipient transplanted for chronic phase chronic myeloid leukemia developed
      IgA myeloma 40 months after transplantation. Serum electrophoresis and bone
      marrow investigations established the diagnosis of IgA K multiple myeloma in
      both. This case illustrates the natural history and biology of multiple myeloma.

PMID- 12410584
TI  - Effect of ABO blood group on the collagen-binding assay for von Willebrand
      factor.
AB  - von Willebrand disease (VWD) is the most common congenital bleeding disorder and
      is caused by a quantitative or qualitative abnormality of von Willebrand factor
      (VWF). Ristocetin cofactor (RCoF) assay is used to evaluate VWF activity, but it
      does not assess collagen-binding activity. Normal values of RCoF and VWF antigen
      vary with ABO blood group type. The collagen-binding assay (CBA) measures VWF
      activity; however, its relationship with ABO blood group has not been completely
      explored. We performed CBA on plasma samples from 131 healthy volunteers to
      determine if CBA values correlated with blood type. Individuals with blood group
      O had a mean CBA value of 94 +/- 28%, which was significantly different from the
      mean of 117 +/- 33% in persons with non-O blood groups (P = 0.0001). Thus, CBA
      values appear to correlate with ABO blood type in a manner similar to RCoF.

PMID- 12410585
TI  - Severe congenital Factor VII deficiency associated with the 13q deletion
      syndrome.
AB  - The first reported case of clinically significant congenital Factor VII
      deficiency in association with the 13q deletion syndrome is presented. It
      illustrates the importance of knowledge of the specific genes involved in gross
      deletion syndromes and adds to the current clinical experience of this rare
      disease.

PMID- 12410586
TI  - Angiotropic large cell lymphoma presenting as fever of unknown origin.

PMID- 12410587
TI  - Prevalence and distribution of the prothrombin G20210A mutation.

PMID- 12410588
TI  - Persistent thrombocytopenia during remission in acute leukemia does not preclude
      long-term disease-free survival.

PMID- 12410589
TI  - Tumor lysis syndrome induced by hydroxyurea therapy for leukemic transformation
      of polycythemia vera.

PMID- 12410590
TI  - Ureteric obstruction by retroperitoneal lymphoplasmacytic lymphoma.

PMID- 12410591
TI  - Chronic pure red cell aplasia associated with parvovirus B19 infection in an
      immunocompetent patient.

PMID- 12410592
TI  - Distribution and gene expression of cytoskeletal proteins in two-cell rat embryos
      and developmental arrest.
AB  - Previous observations in rat two-cell embryos suggested that distribution of
      microfilaments and microtubules are involved in developmental arrest. Therefore,
      we examined the distribution of cytoskeletal proteins, actin binding proteins,
      and microtubule-associated proteins in rat two-cell embryos. We also examined
      gene expression of beta-actin, alpha-tubulin, and cytoskeletal proteins that
      showed changes in their distributions. Distribution of cytoskeletal proteins was
      examined by immunocytochemistry. Although distributions of alpha-actinin, MAP1A,
      MAP1B/MAP5, and MAP2 were disturbed in arrested embryos, these abnormal
      distributions occurred following the initiations of developmental arrest and
      marked damage of microfilaments and microtubules. Gene expression of cytoskeletal
      proteins was examined by RT-PCR. Beta-actin and alpha-actinin mRNA was detected
      in normal late two-cell stage but not in arrested embryos. The difference
      occurred after zygotic gene activation. Expression of alpha-tubulin was detected
      in neither normal late two-cell stage nor arrested embryos. No MAP1A, MAP1B/MAP5,
      or MAP2 expression was detected in embryos during the two-cell stage. In
      conclusion, both distributions of microfilaments and microtubules are closely
      involved in rat developmental arrest, but other distributions of cytoskeletal
      proteins, actin binding proteins, and microtubule-associated proteins do not
      appear to have major roles in two-cell arrest. Furthermore, mRNA expression
      patterns are different between microfilaments and microtubules. Both distribution
      and mRNA transcription of microfilaments are involved in rat developmental
      arrest, whereas only distribution of maternal microtubules is disturbed in
      arrested embryos.

PMID- 12410593
TI  - Tropomyosin isoforms present in the sea anemone, Anthopleura japonica (Anthozoa,
      Cnidaria).
AB  - Five isoforms of tropomyosin, designated as TMa, TMb, TMc, TMd, and TMe, were
      detected in the sea anemone, Anthopleura japonica. The apparent molecular weights
      of these isoforms were estimated to be approximately 30 kD to 37.5 kD, and their
      pI values were approximately 4.55 (TMa and TMb) and 4.65 (TMc, TMd, and TMe).
      Although sea anemone tropomyosin isoforms have the ability to bind to rabbit
      skeletal muscle actin, they preferably bind to actin at higher concentrations of
      Mg(2+) (10-20 mM) and slightly lower pH (6.2-7.2) than those used in conventional
      conditions. Antigenic properties of sea anemone tropomyosin seemed to be
      considerably specific to each isoform. Distribution of tropomyosin isoforms in
      the sea anemone body was somewhat portion-specific. TMa, TMb, and TMe were
      detected similarly in the extracts from tentacle, oral disc, column, mouth, and
      pedal disc. Although TMc and TMd were detected abundantly in the tentacle extract
      and moderately in the column and mouth extracts, these components were not
      contained in the pedal disc extract and detected only faintly in the oral disc
      extract.

PMID- 12410594
TI  - Oxidative, heat and anthelminthic stress responses in four species of
      Trichinella: comparative study.
AB  - The aim of this study was to compare levels of stress proteins in four
      Trichinella species when exposed to different stressors. Heat shock protein (HSP)
      60, 70 and 90 responses were evaluated in infective larvae (L(1)) of four classic
      Trichinella species following exposure to oxidative, anthelminthic and thermal
      stress. Larvae of T. nativa, T nelsoni, T. pseudospiralis and T. spiralis were
      exposed to peroxide shock (0.2%, 1%, or 2% H(2)O(2)for 2h), high temperatures (40
      degrees C or 45 degrees C for 2h), or 0.1 microg/ml of the benzimidazole
      anthelminthics: mebendazole (MBZ), albendazole (ALB) or thiabendazole (TBZ) for
      4h. Following exposures, the L(1) were tested for induced morphological changes.
      Those observed were: (i) no change (in all species exposed to 40 degrees C) (ii)
      aberrant forms (in all species exposed to anthelminthics, in T. nativa, T.
      nelsoni and T. spiralis exposed to 45 degrees C, and in T. spiralis and T.
      nelsoni exposed to 0.2% H(2)O(2)) and (iii) severe degradation or death (in T.
      nativa and T. pseudospiralis exposed to 0.2% H(2)O(2), and in all species at 1%
      and 2% H(2)O(2)). In Western blot analyses, L(1) proteins were probed with
      monoclonal antibodies (mAbs) specific for the three HSPs. Greater changes in HSP
      levels occurred following H(2)O(2) exposure than with other stresses in all
      Trichinella species, while accumulation of a 50 kDa HSP was only observed in T.
      spiralis and T. pseudospiralis. Anthelminthic stress only caused decreased HSP
      levels in T. nativa. Thermal stress caused no significant changes in the HSP
      response of any species. It is suggested that other stress proteins (e.g.,
      glucose-regulated proteins) may be involved in adaptation to thermal stress.

PMID- 12410595
TI  - Dynamics of vitellogenin mRNA expression and changes in hemolymph vitellogenin
      levels during ovarian maturation in the giant freshwater prawn Macrobrachium
      rosenbergii.
AB  - The dynamics of vitellogenin mRNA expression during ovarian maturation in
      Macrobrachium rosenbergii were examined by measuring hemolymph vitellogenin (Vg)
      levels and Vg mRNA expression in the hepatopancreas and ovary at differing
      reproductive stages in both intact and eyestalk ablated animals. Vg mRNA was
      quantified using real-time RT-PCR and hemolymph Vg was measured by enzyme
      immunoassay. In intact animals, Vg mRNA levels in the hepatopancreas and
      hemolymph Vg levels showed a gradual increase during the molt cycle concomitant
      with increasing gonadosomatic index (GSI), with Vg levels decreasing prior to
      ecdysis although GSI continued to increase. Eyestalk ablation was seen to
      accelerate Vg synthesis as well as ovarian maturation, although it did not alter
      the overall pattern of Vg expression. Vg mRNA expression was negligible in the
      ovary of both intact and eyestalk ablated animals, confirming that the
      hepatopancreas is the principal site of Vg synthesis in M. rosenbergii with the
      ovary being only a minor contributor. This study has shown that Vg synthesis is
      correlated to ovarian maturation and the molt cycle in M. rosenbergii.

PMID- 12410596
TI  - Studies on lipid metabolism in trout (Oncorhynchus mykiss) branchial cultures.
AB  - Cultured branchial cell epithelia from freshwater rainbow trout were incubated
      with ((32)P)phosphate and ((14)C)acetate as lipid precursors under both
      symmetrical (L15 media apical/L15 media basolateral) and asymmetrical (freshwater
      apical/L15 media basolateral) culture conditions. Epithelia composed of pavement
      cells alone, or containing both pavement cells and chloride cells, were examined.
      Lipids (labeled with (32)P and (14)C) were isolated and assayed by thinlayer
      chromatography, and fatty acids (labeled with (14)C) were isolated and assayed by
      paper chromatography. The main goal was to see whether the loss of a major
      incorporation into ((32)P)phosphatidylethanolamine [((32)P)PE], previously seen
      in eel gills in vivo when the fish were transferred from an osmotic steady state
      to more dilute media, was the result of a hormonal regulation, i.e., did it only
      apply to gill tissue in vivo or could it also be seen in the absence of hormonal
      modulation after incorporation of ((32)P)phosphate in vitro? We likewise wished
      to see whether a major incorporation into ((32)P)PE was dependent upon the
      presence of chloride cells. Results show that it is possible to obtain a
      ((32)P)PE dominated incorporation pattern, even in the pavement cells alone,
      provided that ((32)P)phosphate is added specifically to freshwater on the apical
      side of epithelia bathed asymmetrically (freshwater/L15). This is identical to
      the pattern seen in vivo in trout adapted to freshwater. However, this pattern is
      not seen under symmetrical conditions (L15/L15) or when ((32)P)phosphate is added
      to the basolateral media. The shift from symmetrical (L15/L15) to asymmetrical
      (freshwater/L15) culture conditions thus leads to the establishment of a major
      incorporation into ((32)P)PE and not to the equivalent loss as seen in vivo in
      more dilute apical media. We conclude that hormonal control is not needed to
      change the pattern of short-term lipid formation but, nevertheless, the responses
      are not altogether the same in vitro and in vivo. Furthermore, cultured trout
      gill epithelia, in contrast to gills in vivo, do not exhibit a marked
      incorporation of ((14)C)acetate into palmitoleic acid.

PMID- 12410597
TI  - Early estrogen exposure induces abnormal development of Fundulus heteroclitus.
AB  - Many chemicals released into the environment exhibit estrogenic activity, having
      the potential to disrupt development and the functioning of the endocrine system.
      In order to establish a model system to study the effects of such environmental
      chemicals on aquatic animals, we examined the effects of a natural estrogen, 17
      beta-estradiol (E(2)), on early development of Fundulus heteroclitus. Embryos of
      F. heteroclitus were reared in seawater containing 10(-10), 10(-8), and 10(-6) M
      E(2) throughout the experiment. Hatching and survival rates decreased in a dose
      dependent manner, and fry treated with 10(-6) M E(2) and 10(-8) M E(2) were dead
      by two weeks and 12 weeks after hatching, respectively. More than 85% of fry
      treated with 10(-8) M E(2) showed malformations: i.e., eye extrusion, crooked
      vertebral column, faded lateral-stripe pattern eight weeks after hatching. Body
      weight and head and body lengths were significantly reduced in E(2)-treated fry
      when compared to controls. Ossification was not completed in vertebrae, cranial
      bones, and other bones in fry treated with 10(-8) M E(2) even 12 weeks after
      hatching. Sex ratio of control fry was 57% male and 43% female, whereas fry
      treated with 10(-8) M E(2) were 100% female eight weeks after hatching. The
      present results demonstrate that exogenous estrogen induced death of embryos and
      fry, malformations, sex reversal, and incomplete ossification of vertebrae and
      cranial bones, which would result in shorter body and head lengths and in
      malformed vertebrae leading to a hunchback condition.

PMID- 12410598
TI  - Variation in plasma lipids during the reproductive cycle of male and female
      desert tortoises, Gopherus agassizii.
AB  - Plasma triacylglycerol, phospholipid, cholesterol, cholesterol esters, fatty
      acids, and total lipids were measured in 30 female and 20 male desert tortoises
      (Gopherus agassizii) during the annual reproductive cycle in the eastern Mojave
      desert, Nevada. Blood samples were collected at monthly intervals from April to
      October. All lipid fractions, with the exception of free fatty acids, were
      significantly higher in female plasma than in male plasma in all months of the
      year. In contrast, free fatty acids were higher in male plasma than in female
      plasma in all months. The seasonal pattern in estradiol secretion mirrored that
      of triacylglycerol, phospholipid, cholesterol, and total lipid, all of which
      showed a significant correlation with the hormone. Estradiol and the
      vitellogenesis-associated lipids were all significantly higher in August,
      September, October, and April than in June. The seasonal variation in cholesterol
      ester levels in females did not correlate with any of the reproductive events and
      did not appear to be involved in yolk precursor formation. Total lipid in males
      showed a negative correlation with testosterone and spermatogenesis. Individual
      fatty acids in the June and August samples (at the highest and lowest estradiol
      levels) were compared in male and female plasma. The percent of C18:3n3, C18:2n6,
      C18:1n9, C20:5n3, and C22:5 were significantly higher in the June female plasma
      sample than in the August sample. Docosahexanoic (C22:6n3) acid was barely
      detectable in female plasma in either month.

PMID- 12410599
TI  - Expression of the gene of interest fused to the EGFP-expressing gene in
      transgenic mice derived from selected transgenic embryos.
AB  - The present paper describes the expression of a target fusion gene, WAP/hGH fused
      to the EGFP-expressing gene in transgenic mice derived from the transfer of
      transgenic embryos selected because of their expression of enhanced green
      fluorescent protein (EGFP). The 6.7-kb fusion gene was microinjected as a single
      cassette gene construct into the pronuclei of mouse zygotes. The surviving
      embryos were cultured and were classified according to the EGFP expression
      patterns at the morula or blastocyst stage. After the transfer of embryos with
      uniform-expression or mosaic-expression of EGFP, transgenesis occurred in 85.7%
      to 86% or 44.1% to 44% of the pups, respectively. No transgenic pups were derived
      from EGFP negative embryos. In the transgenic females, EGFP was ubiquitously
      expressed under the control of the CAG promoter, and hGH was expressed under the
      control of the WAP promoter in an appropriate fashion: hGH was secreted into the
      milk of lactating transgenic females. The presence or absence of the expression
      of EGFP coincided with that of the hGH gene in the transgenic mice. The present
      cassette gene construct is a useful example for circumventing the routine
      analyses of DNA and RNA required for the generation and maintenance of transgenic
      lines.

PMID- 12410600
TI  - Factors affecting the efficiency of somatic cell nuclear transplantation in the
      fish embryo.
AB  - Procedures to improve somatic cell nuclear transplantation in fish were
      evaluated. We reported effects of nonirradiated recipient eggs, inactivated
      recipient eggs, different combinations between recipient eggs and donor cells,
      duration of serum starvation, generation number, and passage number of donor
      cells on developmental rates of nuclear transplant (NT) embryos. Exposure to
      25,000 R of gamma-rays inactivated recipient eggs. Single nucleus of cultured,
      synchronized somatic cell from gynogenetic bighead carp (Aristichthys nobilis)
      was transplanted into nonirradiated or genetically inactivated unfertilized egg
      of gibel carp (Carassius auratus gibelio). There was no significant difference in
      developmental rate between nonirradiated and inactivated recipient eggs (27.27%
      vs. 25.71%, respectively). Chromosome count showed that 70.59% of NT embryos
      contained 48 chromosomes. It showed that most NT embryos came from donor nuclei
      of bighead carp, which was supported by microsatellite analysis of NT embryos.
      But 23.53% of NT embryos contained more than 48 chromosomes. It was presumed that
      those superfluous chromosomes came from nonirradiated recipient eggs. Besides,
      5.88% of NT embryos were chimeras. Eggs of blunt-snout bream (Megalobrama
      amblycephala) and gibel carp were better recipient eggs than those of loach
      (Misgurnus anguillicaudatus) (25% and 18.03% vs. 8.43%). Among different duration
      of serum starvation, developmental rate of NT embryos from somatic nuclei of
      three-day serum starvation was the highest, reaching 25.71% compared to 14.14%
      (control), 20% (five-day), and 21.95% (seven-day). Cultured donor cells of less
      passage facilitated reprogramming of NT embryos than those of more passage.
      Recloning might improve the developmental rate of NT embryos from the
      differentiated donor nuclei. Developmental rate of fourth generation was the
      highest (54.83%) and the lowest for first generation (14.14%) compared to second
      generation (38.96%) and third generation (53.01%).

PMID- 12410601
TI  - Purification and identification of a second form of vitellogenin from ascites of
      medaka (Oryzias latipes) treated with estrogen.
AB  - Estrogen treatment of medaka leads to accumulation of ascites, in which
      vitellogenin (Vg) and choriogenins (precursors to vitelline envelope) are
      abundant. Besides those female-specific proteins, we detected a new component in
      ascites that cross-reacts with antiserum against egg yolk proteins. We
      tentatively named it egg yolk-related protein (YRP). YRP was purified from
      ascites by hydroxylapatite chromatography followed by gel filtration. Purified
      YRP had a molecular mass of 460 kDa in intact state while 570 kDa for Vg. The
      molecular weight of purified YRP on SDS-PAGE under both reducing and nonreducing
      conditions was 130 kDa. YRP was confirmed to be a lipoglycophosphoprotein by
      staining with Sudan black, periodic acid-Schiff (PAS) and methyl green. Amino
      acid composition of YRP resembled that of Vg except for a relatively low content
      of serine. A specific antiserum against YRP was raised in a rabbit. Antiserum
      against YRP specifically immunostained its antigen but not Vg or choriogenins.
      YRP was detected as a female-specific protein in serum of breeding medaka. The
      antiserum also cross-reacted with a band at 29 kDa in egg extracts, which is not
      immunoreactive to antiserum against Vg. These data show that YRP is a precursor
      to some egg yolk proteins with differing antigenicity from Vg (Hamazaki et al.
      '87). We thus conclude that YRP is a second form of medaka Vg and rename YRP as
      Vg 2 while formerly reported Vg as Vg 1.

PMID- 12410602
TI  - Juvenoid hormone methyl farnesoate is a sex determinant in the crustacean Daphnia
      magna.
AB  - Daphnids (Daphnia magna) utilize cyclic parthenogenesis as a reproductive
      strategy. During periods of abundant resources, these organisms reproduce
      asexually. In response to environmental cues that signal the onset of
      environmental adversity, daphnids produce males and reproduce sexually. The
      environmental cues that stimulate the sexual reproductive phase are well known;
      however, the endocrine signals that transduce these environmental cues remain
      unknown. The present study was undertaken to test the hypothesis that the
      crustacean juvenoid hormone, methyl farnesoate, is a male sex determinant in this
      species. Continuous exposure to aqueous concentrations of methyl farnesoate
      greater than approximately 30 nM stimulated a concentration-dependent production
      of male-containing broods of organisms. Short-term exposures to methyl farnesoate
      during periods of egg and embryo maturation revealed that male sex determination
      occurred during a specific 12-hour period of ovarian egg development. Exposure of
      eggs to 400 nM methyl farnesoate during this sensitive developmental period
      resulted in the production of all-male broods of offspring, while exposure to
      concentrations as low as 52 nM produced mixed broods of males and females. This
      active concentration range of methyl farnesoate is consistent with levels
      measured in the hemolymph of some decapod crustaceans. These results demonstrate
      that methyl farnesoate is capable of programming daphnid embryos to develop into
      males and is likely the endocrine factor responsible for initiating the sexual
      reproductive phase in these organisms.

PMID- 12410603
TI  - Specific binding of the endocytosis tracer horseradish peroxidase to intestinal
      fatty acid-binding protein (I-FABP) in apical membranes of carp enterocytes.
AB  - In a previous study we had demonstrated that a 15-kDa protein present in carp
      intestinal brush-border membrane vesicles (BBMV) was able to bind the endocytosis
      tracer horseradish peroxidase (HRP) with high specificity. Here we show that this
      protein corresponds to a peripheral membrane protein, identified by partial amino
      acid sequence analysis as the intestinal fatty acid-binding protein (I-FABP), a
      member of the small cytosolic fatty acid binding protein family (FABPs). The
      presence of I-FABP and its HRP-binding activity was demonstrated both in the
      cytosolic and membrane-associated fractions of intestinal mucosa by Western and
      ligand blot analyses, respectively. Also, both fractions displayed significant
      capacity to bind [(3)H]palmitic acid, a known ligand for I-FABP.
      Immunohistochemical analysis showed that I-FABP localizes both in the cytosol and
      in the brush-border membranes of epithelial cells. Taken together the unusual
      extra-cellular localization of I-FABP as well as its ability to interact with HRP
      suggests a novel function for this protein in the intestinal mucosa.

PMID- 12410604
TI  - Effects of prenyl pyrophosphates on the binding of S-Ras proteins with KSR.
AB  - BALB/3T3 cells were transformed by transfection with DNA encoding the mutated
      ras(Q(61)K) from shrimp Penaeus japonicus (Huang et al., 2001. J. Exp. Zool.
      289:441-448). On a Western blot, the kinase suppressor of Ras (KSR) in the
      membrane fraction was expressed at slightly reduced level as compared to that of
      the untransformed cells. To understand this in more detail, the interaction of
      the bacterially expressed shrimp Ras (S-Ras) with KSR was investigated using KSR
      purified from mice brains. SDS-polyacrylamide gel electrophoresis and Western
      blot analysis revealed that the monomers of the purified KSR have a relative
      molecular mass of 60,000. Purified KSR was found to bind with digoxigenylated S
      ras-encoding fusion protein (Dig-S-Ras) with high affinity in the absence of ATP,
      and the binding activity of KSR was sustained upon phosphorylation of Dig-S-Ras
      with mitogen-activated protein kinase (MAPK). The association of purified KSR
      with S-Ras was confirmed. Differences between the effects of farnesyl
      pyrophosphate and geranylgeranyl pyrophosphate on the binding of S-Ras with the
      purified KSR were assessed. Densitometer analysis revealed that at nanogram
      concentration, farnesyl pyrophosphate inhibited the binding of S-Ras with KSR
      competently, but geranylgeranyl pyrophosphate did not. The present study provides
      the evidence that decrease of the concentration of farnesyl pyrophosphate to sub
      microgram levels lower the affinity of Ras proteins with KSR in the signaling
      pathway.

PMID- 12410605
TI  - Mechanical properties of the dorsal fin muscle of seahorse (Hippocampus) and
      pipefish (Syngnathus).
AB  - The dorsal and pectoral fins are the primary locomotor organs in seahorses
      (Hippocampus) and pipefish (Syngnathus). The small dorsal fins beat at high
      oscillatory frequencies against the viscous medium of water. Both species are
      able to oscillate their fins at frequencies likely exceeding the point of flicker
      fusion for their predators, thus enhancing their ability to remain cryptic. High
      speed video demonstrated that seahorse dorsal fins beat at 30-42 Hz, while
      pipefish dorsal fins oscillate at 13-26 Hz. In both species, the movement of the
      fin is a sinusoidal wave that travels down the fin from anterior to posterior.
      Mechanical properties of seahorse and pipefish dorsal fin muscles were tested in
      vitro by the work loop method. Maximum isometric stress was 176.1 kN/m(2) in
      seahorse and 111.5 kN/m(2) in pipefish. Work and power output were examined at a
      series of frequencies encompassing the range observed in vivo, and at a number of
      strains (percent length change during a contractile cycle) within each frequency.
      At a given strain, work per cycle declined with increasing frequency, while power
      output rose to a maximum at an intermediate frequency and then declined.
      Frequency and strain interacted in a complex fashion; optimal strain was
      inversely related to cycle frequency over most of the frequency range tested.
      Seahorse dorsal fin muscle was able to generate positive work at higher cycling
      frequencies than pipefish. Both species produced positive work at higher
      frequencies than have been reported for axial and fin muscles from other fish.

PMID- 12410606
TI  - Experimentally induced anhydrobiosis in the tardigrade Richtersius coronifer:
      phenotypic factors affecting survival.
AB  - The ability of some animal taxa (e.g., nematodes, rotifers, and tardigrades) to
      enter an ametabolic (cryptobiotic) state is well known. Nevertheless, the
      phenotypic factors affecting successful anhydrobiosis have rarely been
      investigated. We report a laboratory study on the effects of body size,
      reproductive condition, and energetic condition on anhydrobiotic survival in a
      population of the eutardigrade Richtersius coronifer. Body size and energetic
      condition interacted in affecting the probability of survival, while reproductive
      condition had no effect. Large tardigrades had a lower probability of survival
      than medium-sized tardigrades and showed a positive response in survival to
      energetic condition. This suggests that energy constrained the possibility for
      large tardigrades to enter and to leave anhydrobiosis. As a possible alternative
      explanation for low survival in the largest specimens we discuss the expression
      of senescence. In line with the view that processes related to anhydrobiosis are
      connected with energetic costs we documented a decrease in the size of storage
      cells over a period of anhydrobiosis, showing for the first time that energy is
      consumed in the process of anhydrobiosis in tardigrades.

PMID- 12410608
TI  - Changes in sex steroid levels in yolks of the leghorn chicken, Gallus domesticus,
      during embryonic development.
AB  - Yolk steroid hormones have been documented to have growth and behavior effects on
      hatchlings in several avian species. The purpose of these investigations was to
      determine initial levels of androstenedione (A), dihydrotestosterone (DHT),
      estradiol (E(2)), and testosterone (T), and document any changes in those
      hormones during the course of embryonic development in the Leghorn chicken,
      Gallus domesticus. Eggs were collected, labeled for hen of origin and egg
      sequence, incubated at 37.8 degrees C, and sacrificed at predetermined times
      during development. The embryos were staged, the yolk material collected,
      homogenized and hormones extracted. A, DHT, E(2), and T were separated via column
      chromatography and hormone levels determined using radioimmunoassays (RIAs).
      Results indicate a significant decrease in A and T during embryonic development,
      similar to that reported by our laboratory for the alligator, with A levels being
      significantly greater initially than levels of all other hormones. Changes in DHT
      mirrored changes in T levels. Chicken E(2) yolk content dynamics differ from
      those we have measured in both the turtle and the alligator. After an initial
      decline, E(2) in the yolks of chicken eggs undergoes a significant increase at
      the end of development, between embryonic stages 40 and 45 (days 14 and 20 of
      development). As the increase is much larger than could be accounted for by
      hormones present in the yolk material, this may represent early embryonic
      production of steroid hormones by the developing gonads.

PMID- 12410607
TI  - Effects of altered photoperiod and temperature, serotonin-affecting drugs, and
      melatonin on brain tyrosine hydroxylase activity in female catfish,
      Heteropneustes fossilis: a study correlating ovarian activity changes.
AB  - Exposure of female catfish, Heteropneustes fossilis to 30-day regimes of long
      photoperiod (16L), elevated temperature (28 +/- 2 degrees C), or a combination of
      both stimulated brain tyrosine hydroxylase (TH) activity significantly over that
      of control fish held in natural conditions in gonad resting (10.5L:13.5D, 10 +/-
      2 degrees C) and preparatory (12.5L:11.5D,18 +/- 2 degrees C) phases. The
      response was high in the combination group in both phases. The increase in TH
      activity was higher in forebrain regions (telencephalon and hypothalamus) than
      medulla oblongata. Exposure of the fish to short photoperiod (8L:16D) and total
      darkness decreased the enzyme activity significantly in both resting and
      preparatory phases regardless of the temperature. The inhibition was high in fish
      held under total darkness. Gonadosomatic index (GSI) was significantly elevated
      in long photoperiod and high temperature groups, alone or in combination, and
      decreased significantly in short photoperiod (only in preparatory phase) and
      total darkness groups. Administration of the serotonin precursor 5
      hydroxytryptophan (5-HTP; 5mg/100g body weight [BW], three daily intraperitoneal
      [i.p.] injections prior to sacrificing) stimulated TH activity in fish held under
      long and normal photoperiods in both phases. Three daily injections of the
      serotonin blocker parachlorophenylalanine (p-CPA; 10mg/100g BW) and melatonin (75
      microg/100g BW) prior to sacrificing inhibited brain TH activity significantly in
      both phases. GSI was significantly stimulated by 5-HTP, and inhibited by both p
      CPA and melatonin injections. Changes in TH activity and GSI can be correlated
      and explained on the basis of previous reports on changes in catecholamine
      activity that modulates gonadotropin secretion in the catfish. Further, the
      photoperiod and temperature-induced changes in TH activity may be modulated by
      alterations in serotonergic activity.

PMID- 12410609
TI  - Ejaculate of sneaker males is pheromonally inconspicuous in the black goby,
      Gobius niger (Teleostei, Gobiidae).
AB  - The black goby, Gobius niger, shows alternative male mating tactics, i.e.,
      parental and sneaker males. Males release a sexual pheromone that attracts
      females and stimulates aggressive displays in males. This pheromone is produced
      by the mesorchial gland, a structure well developed in parental males but
      markedly undeveloped in sneakers. We measured the behavioral response of parental
      males to the ejaculates of males performing different reproductive tactics.
      Parental males reacted to the ejaculate of other parental males, with stereotypic
      aggressive behaviors, but not to the ejaculate of sneakers; consequently sneaker
      male ejaculate appears to be pheromonally inconspicuous.

PMID- 12410610
TI  - Effect on growth and reproduction of hormone immersed and masculinized fighting
      fish Betta splendens.
AB  - To produce all-male progenies in the fighting fish, Betta splendens, six groups
      of fry were subjected to discrete immersion treatment at different 17alpha
      methyltestosterone (MT) doses (viz. 100, 200, 500, 700, 900, and 1,000 microg/l)
      for a constant duration (3 hr/day) and frequency (second, fifth, and eighth day
      after hatching). The treatment at 900 microg/l led to 98% masculinization and 71%
      survival at sexual maturity. Treated groups, which showed significant deviation
      from the 1:1 sex ratio, were classified into two different series: S1 and S2. The
      groups that showed nearly cent-percent masculinization were classified as S1, and
      the other groups were classified as S2. The S1 males showed remarkably slower
      growth and attained 3.5 cm total length compared to 6.0 cm attained by a normal
      male. The S2 males attained 5.4 cm total length. Apart from these morphological
      defects, both S1 and S2 males suffered functional (decreased sperm count and
      sperm motility) and behavioral defects (incomplete embracing during mating) in
      their reproductive ability, leading to approximately 50% and 30% reduction in
      fecundity per mating, respectively. The cumulative fecundity loss suffered by the
      S1 male during its active reproductive phase is discussed. When normal and sex
      reversed males were presented, a female preferred the former. Progeny testing of
      the sex-reversed males showed the occurrence of 12.75% males, indicating the
      possible role of autosomal genes in the sex determination mechanism of this
      species. Discrete immersion treatment at optimal/super-optimal doses ensured not
      only a higher percentage of masculinization, but also a higher frequency of
      homogametic males (XX).

PMID- 12410611
TI  - Identification of the 48-kDa G11 protein from guinea pig testes as sperad.
AB  - A protein found specifically in the membrane of spermatozoa called G11 has been
      implicated in sperm-egg binding and fusion. This study describes purification and
      identification of the G11 antigen. The G11 protein was purified using anion
      exchange chromatography, immunoaffinity chromatography and preparative SDS-PAGE
      and was subjected to amino acid microsequencing by tandem mass spectrometry.
      Internal amino acid sequence data derived from the 48-kDa G11 protein revealed
      that G11 is the recently discovered guinea pig sperm protein, sperad. Sperad is a
      transmembrane protein present in the periacrosomal plasma membrane of guinea pig
      sperm. The cytoplasmic domain of sperad was amplified from a guinea pig testes
      cDNA expression library by polymerase chain reaction and cloned into a
      prokaryotic gene expression vector, pGEX-2T. The recombinant glutathione S
      transferase fusion protein was immunoblotted with monoclonal antibody G11. The
      results obtained from this study confirmed the monoclonal antibody G11 epitope
      location on the cytoplasmic domain of sperad.

PMID- 12410612
TI  - Production of germline chimera in loach (Misgurnus anguillicaudatus) and proposal
      of new method for preservation of endangered fish species.
AB  - As part of the technique for preservation of endangered fish species, germline
      chimeras using the loach (Misgurnus anguillicaudatus) model were generated by
      embryonic cell manipulation. Transplanting cells from early-stage embryos of a
      wild-type strain to the blastoderm of an orange-type strain generated chimeras.
      Within three days, many of the resulting individuals exhibited a dark pigment on
      several parts of their body, characteristic of the donor but not of the orange
      strain. At one year of age, four chimeras (one female and three males) were pair
      mated with the orange type, and F(1) was obtained. One of the four F(0) chimeras
      produced progeny similar to the wild type at a frequency of 0.24% (2/841). The
      results suggest that this method is a promising technique for the preservation of
      endangered fish species.

PMID- 12410613
TI  - Egg coats of the rock shrimp Rhynchocinetes typus: ultrastructural
      characterization and their function during fertilization.
AB  - The aim of the present work was to characterize structurally and
      ultrastructurally the egg coats of the rock shrimp, Rhynchocinetes typus, and to
      describe their functional roles during fertilization. Oocytes fixed directly from
      the ovary, have a total diameter of 549 microm and are covered by a 10- microm
      thick transparent envelope. Electron microscope sections (dehydrated) of the egg
      envelope revealed an electron-dense external coat of 0.4 microm covered by
      filamentous processes, and a granular inner coat of 4- microm thickness. Oocytes
      placed for 5 min in seawater had a significantly larger diameter (573 microm),
      because of the increase in the thickness of the egg coats (32 microm) and the
      formation of a 16- microm perivitelline space. The diameter of the egg proper was
      reduced by the same extent as the size of the perivitelline space. All these
      changes were associated to the loss of the egg fertilizability. SDS-PAGE of
      isolated and solubilized egg coats with 20% beta-mercaptoethanol or 25 mM
      dithiothreitol (DTT) showed bands between 58 and 105 kDa and between 44 and 103
      kDa, respectively. During normal fertilization, the sperm undergoes a drastic
      change in shape after first contact with the egg. We observed a similar change
      when solubilized egg coats were placed with vas deferens sperms. When the
      solubilized egg coat proteins were ultrafiltrated with a membrane of 10,000 MWCO
      (pore size) and then assayed for their effect on fertilization, an inhibitory
      effect of 30%, 41%, and 59% was found when oocytes were incubated with
      spermatozoa pre-treated with 30, 60, and 120 microg/ml of proteins solubilized
      with beta-mercaptoethanol. A similar inhibitory effect was found when egg coat
      proteins solubilized with 25 mM DTT were used. Our results suggest that, in the
      shrimp, the egg coats play an active role during the morphological changes of the
      sperm during their passage through them.

PMID- 12410614
TI  - In vitro analysis of the origin, migratory behavior, and maturation of cortical
      pyramidal cells.
AB  - During development neurons migrate from their site of origin to their final
      destinations under a variety of mechanisms. Although evidence has been
      accumulating that the cells from cortical ventricular zone (VZ) migrate radially
      and produce pyramidal cells, evidence that directly links the origin and the
      terminal phenotype of radially migrating cells has been limited. Further, the
      relation between the migratory behavior of these cells and their mature
      morphology remains obscure. To address these issues, we developed an in vitro
      preparation that enables visualization of cells derived from the cortical VZ. VZ
      cells of a rat cortex at embryonic days 18 to 19 were labeled by injecting green
      fluorescent protein (GFP)-encoding plasmid into the lateral ventricle, followed
      by electroporation. The cortex was then sliced and cultured organotypically.
      After 1 day, GFP(+) cells exhibited neural progenitor and radial glial cell
      natures. Over the next few days, many GFP(+) cells migrated toward the pial
      surface, extending leading processes toward the pial surface and leaving a thin
      trailing process that almost reached the VZ. The leading processes of these
      neurons were positive for microtubule-associated protein 2, and some transformed
      into dendritic arbor-like structures by day 5 or 6, and their trailing processes
      exhibited morphologic features indicative of prospective axons. Time-lapse
      analysis confirmed extension of the trailing processes. Expression of molecular
      markers and morphologic analysis demonstrated that the vast majority of the
      migrated GFP(+) cells differentiated into excitatory neurons with pyramidal cell
      like morphology. These results strongly suggested that cells derived from the
      cortical VZ generate neurons that migrate radially. These neurons appeared to
      extend prospective dendrites in front and leave prospective axons behind,
      subsequently differentiating into pyramidal cells.

PMID- 12410615
TI  - Origin of the dopaminergic innervation of the central extended amygdala and
      accumbens shell: a combined retrograde tracing and immunohistochemical study in
      the rat.
AB  - The origin of the dopaminergic innervation of the central extended amygdala (EAc;
      i.e., the lateral bed nucleus of the stria terminalis [BSTl]-central amygdaloid
      nucleus [Ce] continuum) and accumbens shell (AcSh) was studied in the rat by
      combining retrograde transport of Fluoro-Gold (FG) with tyrosine hydroxylase (TH)
      immunofluorescence. Perikaryal profiles (PP) immunoreactive to FG and to both FG
      and TH were counted in A8-A14 dopaminergic districts. Our results suggest that
      dopaminergic inputs to the EAc and AcSh arise from the ventral tegmental area
      A10, substantia nigra, pars compacta-A9, and retrorubral nucleus-A8 groups as
      well as from the dorsal raphe nucleus and periaqueductal gray substance, housing
      the dorsocaudal part of A10 group (A10dc). Quantitative estimates reveal that the
      A10dc group contains approximately half of the total number of FG/TH double
      labeled PP projecting to Ce and BSTl. By using an anti-dopamine serum, DR/PAG
      projections to Ce were confirmed to be in part dopaminergic. In contrast, modest
      numbers of FG/TH double-labeled PP were seen in the A10dc group after injections
      in the sublenticular extended amygdala, interstitial nucleus of the posterior
      limb of the anterior commissure or AcSh. Ventral mesencephalic projections to the
      EAc display a crude mediolateral topographic organization, whereas those to the
      AcSh are topographically organized along a mediolateral and an inverted
      dorsoventral dimension. The diencephalic dopaminergic groups do not innervate the
      EAc or AcSh, except for the periventricular gray-A11 which sends light
      dopaminergic projections to Ce and BSTl. Overall, the present results provide
      additional details on the organization of the mesolimbic dopaminergic system that
      critically controls behavioral responsiveness to salient environmental stimuli.

PMID- 12410617
TI  - Tyrosine hydroxylase-immunoreactive interneurons in the olfactory bulb of the
      frogs Rana pipiens and Xenopus laevis.
AB  - We studied tyrosine hydroxylase (TH)-immunoreactive neurons and neuropil in the
      olfactory bulb of the leopard frog, Rana pipiens, and in the clawed frog, Xenopus
      laevis. In both frogs, TH processes in the main olfactory bulb showed a
      trilaminar organization, with a densely stained external glomerular layer (GL), a
      moderately stained middle mitral cell layer (MCL), and internally a weakly
      stained internal plexiform layer (IPL) and granule cell layer (GRL). TH-positive
      cells in the MCL and IPL could be divided into two types. Type 1 cells had one or
      two thick dendrites that arborized within glomeruli in the GL and often had a
      thin "axon-like" process that exited the cell on the internal surface, with a
      recurrent collateral that ascended into the GL. Type 2 cells had beaded dendrites
      arborizing in the MCL and no discernible axons. Both type 1 and type 2 cells were
      numerous in the MCL and IPL of Rana, whereas only type 2 cells were common in the
      MCL and IPL of Xenopus. In the GL, labeled cells were numerous in Xenopus but
      rare in Rana. Mitral cells were stained retrogradely by tracer injection into the
      lateral olfactory tract and by local injection into the bulb. In no case was
      double labeling for TH observed, suggesting that TH-positive cells in frog
      olfactory bulb are likely to be interneurons. Double labeling with an anti-gamma
      aminobutyric acid (GABA) antibody showed that the TH-positive cells formed a
      population separate from the GABA-containing interneurons.

PMID- 12410616
TI  - Patterns of dye coupling in lumbar motor nuclei of the rat.
AB  - Gap junctions exist on motoneurons of the spinal nucleus of the bulbocavernosus
      (SNB) and the dorsolateral nucleus (DLN), both sexually dimorphic motor nuclei in
      the lumbar spinal cord of the rat. In addition, messenger RNA for gap junction
      proteins is expressed in motoneurons of the retrodorsolateral nucleus (RDLN), a
      nondimorphic spinal motor nucleus that innervates a muscle of the foot. Gap
      junctions on SNB and DLN motoneurons are androgen sensitive; the number and size
      of gap junctions decrease following castration, a change that can be reversed
      with exogenous testosterone replacement. In contrast, RDLN gap junction mRNA
      levels remain constant throughout hormone manipulation. In this study, dye
      coupling was used to examine patterns of gap junction-mediated connectivity in
      these three lumbar spinal motor nuclei. Injection of dye into single motoneurons
      resulted in spatially extensive labeling of neighboring cells in all three
      nuclei; significantly more coupling was observed in the sexually dimorphic nuclei
      than in the RDLN. Dye-coupled clusters of cells included motoneurons and
      interneurons; coupling was bilateral in the SNB. Treatment with oleamide, a gap
      junction blocker, completely attenuated labeling. In all nuclei, androgen
      manipulation did not alter the number, identity, or distribution of coupled
      cells. Thus, sexually dimorphic nuclei in the spinal cord exhibit greater dye
      coupling than do nondimorphic populations, and the patterns of connectivity are
      insensitive to androgen despite modification of their number and size.

PMID- 12410618
TI  - Gene organization and expression of a neuropeptide Y homolog from the land
      planarian Arthurdendyus triangulatus.
AB  - Neuropeptide Y is one of the most widespread regulatory peptides within the
      vertebrate nervous system and shares the C-terminal motif [FY]-x(3)-[LIVM]-x(2)-Y
      x(3)-[LIVMFY]-x-R-x-R-[YF] with pancreatic polypeptide, peptide YY, and fish
      pancreatic peptide Y. All four peptides are believed to have arisen from a single
      ancestral gene through successive gene duplication events in vertebrates. The
      origin of this peptide family may date back further still; similarly sized
      peptide transmitters with an identical C-terminal motif have been identified in
      molluscs and flatworms and designated neuropeptide F (NPF). Cloning of the npf
      gene from the parasitic flatworm Moniezia expansa identified some unusual
      features within the peptide precursor organization but, at the same time,
      provided support for an evolutionary relationship of npf and npy genes through
      the presence of a single intron at a conserved position. To extend the analysis
      of the evolutionary relationships between invertebrate NPF and vertebrate NPY
      family peptides, the NPF precursor from the turbellarian Arthurdendyus
      triangulatus was characterized. Sequence analysis revealed the npf transcript to
      be 362 base pairs in length encoding a single open reading frame of 81 amino
      acids. The precursor comprises a signal peptide followed by the mature peptide of
      36 amino acids in length, terminating in the typical invertebrate GRPRF motif,
      followed by a carboxyterminal glycyl extension. The NPF precursor of A.
      triangulatus shows significant similarities to the vertebrate NPY peptides.
      Indeed, the N-terminus of A. triangulatus prepro-NPF corresponds more closely to
      that of the vertebrate peptide homologs than to that of other invertebrate NPFs
      isolated to date. Immunocytochemical localization studies have demonstrated NPF
      immunoreactivity throughout the nervous system of A. triangulatus, particularly
      in association with muscular structures. The data support an early evolutionary
      origin for this peptide transmitter family within the nervous system of basal
      bilaterians.

PMID- 12410619
TI  - Distribution of thyrotropin-releasing hormone immunoreactivity in the brain of
      the dogfish Scyliorhinus canicula.
AB  - To improve knowledge of the peptidergic systems of elasmobranch brains, the
      distribution of thyrotropin-releasing hormone-immunoreactive (TRHir) neurons and
      fibers was studied in the brain of the small-spotted dogfish (Scyliorhinus
      canicula L.). In the olfactory bulbs, small granule neurons richly innervated the
      olfactory glomeruli. In the telencephalic hemispheres, small TRHir neurons were
      observed in the superficial dorsal pallium, whereas TRHir fibers were widely
      distributed in pallial and subpallial regions. In the preoptic region, TRHir
      neurons formed a caudal ventrolateral group in the preoptic nucleus. In the
      hypothalamus, the most conspicuous TRHir populations were associated with the
      lateral hypothalamic recess, but small TRHir populations were found in the
      posterior tubercle and ventral wall of the posterior recess. The preoptic region
      and hypothalamus exhibited rich innervation by TRHir fibers. TRHir fibers were
      observed coursing to the neurohypophysis and the neuroepithelium of the saccus
      vasculosus, but not to the neurohemal region of the median eminence. Some
      stellate-like TRHir cells were observed in a few cell cords of the
      neurointermediate lobe of the hypophysis. The thalamus, pretectum, and midbrain
      lacked TRHir neurons. Further TRHir neuronal populations were observed in the
      central gray and superior raphe nucleus of the isthmus, and a few TRHir cells
      were located in the nucleus of the trigeminal descending tract at the level of
      the rostral spinal cord. In the brainstem, the central gray, interpeduncular
      nucleus, secondary visceral region of the isthmus, rhombencephalic raphe,
      inferior olive, vagal lobe, and Cajal's commissural nucleus were all richly TRHir
      innervated. Comparison of the distribution of TRHir neurons observed in the
      dogfish brain with that observed in teleosts and tetrapods reveals strong
      resemblance but also interesting differences, indicating the presence of both a
      conserved basic vertebrate pattern and a number of derived characters.

PMID- 12410620
TI  - Axonal sprouting of a brainstem-spinal pathway after estrogen administration in
      the adult female rhesus monkey.
AB  - The nucleus retroambiguus (NRA) is located in the caudal medulla oblongata and
      contains premotor neurons that project to motoneuronal cell groups in the
      brainstem and spinal cord. NRA projections to the lumbosacral cord are species
      specific and might be involved in mating behavior. In the female cat, this
      behavior is estrogen dependent, and estrogen induces axonal sprouting in the NRA
      lumbosacral pathway. Because female receptive behavior in primates is not fully
      dependent on estrogen, the question arises as to whether the capacity of estrogen
      induced sprouting is preserved in primates. The effect of estrogen was studied on
      the NRA-lumbosacral projection with the use of wheat germ agglutinin conjugated
      to horseradish peroxidase as a tracer in six adult ovariectomized rhesus monkeys
      with or without estrogen priming (three controls and three treated with 20
      microg/day of estradiol benzoate subcutaneously for 14 days). Light microscopy
      showed that the density of arborizing labeled NRA axons in the lumbosacral cord
      was greater in estrogen-treated than in control animals. Ultrastructurally,
      labeled NRA terminal profiles were quantified in motoneuron pools that supply
      muscles of the abdominal wall, axial, and pelvic floor. After estrogen treatment,
      the average number of labeled terminal profiles per area of the abdominal wall,
      axial, and pelvic floor motoneuron pool increased 1.5-, 3.3-, and 2.8-fold,
      respectively. In the estrogen-treated cases, 8.9% of labeled terminal profiles
      showed characteristics of growth cones. In controls, such profiles were rarely
      observed. The results showed that estrogen induces axonal sprouting in a
      brainstem-spinal pathway in the adult female rhesus monkey. These findings
      supported the concept that the NRA-lumbosacral pathway may be involved in sexual
      behavior. Moreover, they demonstrated that a long descending brainstem-spinal
      tract in adult nonhuman primates retains the capacity for axonal sprouting.

PMID- 12410622
TI  - The interaction of cigarette smoking and antioxidants. Part I: diet and
      carotenoids.
AB  - It is logical that the requirement for antioxidant nutrients depends on a
      person's exposure to endogenous and exogenous reactive oxygen species. Since
      cigarette smoking results in an increased cumulative exposure to reactive oxygen
      species from both sources, it would seem cigarette smokers would have an
      increased requirement for antioxidant nutrients. Logic dictates that a diet high
      in antioxidant-rich foods such as fruits, vegetables, and spices would be both
      protective and a prudent preventive strategy for smokers. This review examines
      available evidence of fruit and vegetable intake, and supplementation of
      antioxidant compounds by smokers in an attempt to make more appropriate
      nutritional recommendations to this population.

PMID- 12410621
TI  - The FDA, medical foods, and patents.

PMID- 12410623
TI  - Intravenous nutrient therapy: the "Myers' cocktail".
AB  - Building on the work of the late John Myers, MD, the author has used an
      intravenous vitamin-and-mineral formula for the treatment of a wide range of
      clinical conditions. The modified "Myers' cocktail," which consists of magnesium,
      calcium, B vitamins, and vitamin C, has been found to be effective against acute
      asthma attacks, migraines, fatigue (including chronic fatigue syndrome),
      fibromyalgia, acute muscle spasm, upper respiratory tract infections, chronic
      sinusitis, seasonal allergic rhinitis, cardiovascular disease, and other
      disorders. This paper presents a rationale for the therapeutic use of intravenous
      nutrients, reviews the relevant published clinical research, describes the
      author's clinical experiences, and discusses potential side effects and
      precautions.

PMID- 12410624
TI  - Nutritional support for chronic myelogenous and other leukemias: a review of the
      scientific literature.
AB  - Chronic myelogenous leukemia (CML) is a slowly progressive disease characterized
      by the overproduction of granulocytes (neutrophils, eosinophils, and basophils).
      A blood smear shows moderate elevations in white blood cell counts that may
      persist for years and be benign. Platelets are increased in number, although
      their function is impaired, resulting in symptoms of easy bleeding (purpura,
      swollen gums). Conventional medical treatment is a marrow transplant and
      alkylating agents, which are usually prescribed only during crisis. Several
      nutrients and botanicals have been studied for use in CML, including vitamin A
      and all-trans retinoic acid (Retin-A), vitamin D3, vitamin E, vitamin B12,
      indirubin (found in herbs including Indigofera tinctoria and Isatis tinctoria),
      and Curcuma longa. This article briefly reviews the scientific literature on the
      therapeutic use of these nutrients for CML.

PMID- 12410626
TI  - Medium chain triglycerides. Monograph.

PMID- 12410625
TI  - The treatment of small intestinal bacterial overgrowth with enteric-coated
      peppermint oil: a case report.
AB  - Recent investigations have shown that bacterial overgrowth of the small intestine
      is associated with a number of functional somatic disorders, including irritable
      bowel syndrome (IBS), fibromyalgia, and chronic fatigue syndrome. A number of
      controlled studies have shown that enteric-coated peppermint oil (ECPO) is of
      benefit in the treatment of IBS. However, despite evidence of strong
      antimicrobial activity, ECPO has not been specifically investigated for an effect
      on small intestinal bacterial overgrowth (SIBO). A case report of a patient with
      SIBO who showed marked subjective improvement in IBS-like symptoms and
      significant reductions in hydrogen production after treatment with ECPO is
      presented. While further investigation is necessary, the results in this case
      suggest one of the mechanisms by which ECPO improves IBS symptoms is
      antimicrobial activity in the small intestine.

PMID- 12410627
TI  - Rhodiola rosea. Monograph.

PMID- 12410629
TI  - September 11, 2001: then and now.
AB  - This article, written by a historian, uses the sequential questioning technique
      to present a selected historical and statistical overview of the tragic events of
      September 11, 2001, including: the hijackings; the suicide attacks in New York,
      Washington, D C, and Pennsylvania; background on Osama bin Laden and al-Qaeda;
      rescue and recovery efforts; and a brief discussion of how the horrors of the day
      continue to affect the American people a year later. Especially sobering are the
      dollar costs of the attacks and the projected expenses of U.S. efforts to control
      the spread of international terrorism (estimated at $640 billion, just through
      fiscal year 2003). Throughout, the article draws on the experiences of the
      victims, the rescuers, and the survivors.

PMID- 12410630
TI  - Ready or not, disasters happen.
AB  - The New York State Nurses Association was--as was the entire country--plunged
      into disaster response mode by 9:30 am on the morning of Tuesday, September 11,
      2001. Although the association had engaged in limited disaster planning prior to
      this event, that planning was in terms of an internal disaster such as a fire in
      our headquarters building. There was no plan for responding to a community
      catastrophe of the magnitude being experienced. The association faced unique
      challenges--including the fact that our New York City offices are located near
      ground zero--but was fortunate in having expert resource persons on staff and
      available to organize a response. Since September, the association has applied
      the lessons learned from this experience and developed a comprehensive disaster
      plan for the future. The purpose of this article is to share those lessons
      learned with the community of nursing associations in the hope that others can
      use the information to build effective disaster plans of their own.

PMID- 12410631
TI  - The American Psychiatric Nurses Association responds to the September 11 tragedy.
AB  - This article describes how the American Psychiatric Nurses Association (APNA)
      responded to the September 11 tragedy, as an organization. Also included are
      anecdotes from APNA members who participated individually in the aftermath of
      this tragedy. Because such a traumatic event can result in psychiatric disorders,
      a brief synopsis of these disorders is included. The economic effects of
      emotional difficulties for our nation are explored, especially those related to
      the most serious disorder resulting from such a traumatic event, Post Traumatic
      Stress Disorder. Strategies that APNA is focusing on for the future, as a result
      of this tragedy, are presented.

PMID- 12410632
TI  - Ethical grounding for entry into practice: respect, collaboration, and
      accountability.

PMID- 12410633
TI  - Images on the web: findable, usable, but what's legit?
AB  - The Internet engages us, not only because it takes us to unexpected places with
      content to explore, but also because the trip is complete with images and sounds.
      So in this multimedia wonderland, how can one find images and, as importantly,
      use them responsibly?

PMID- 12410634
TI  - Nursing classifications: Home Health Care Classification System (HHCC): an
      overview.
AB  - This paper provides an overview of the Home Health Care Classification (HHCC)
      System focusing on its two interrelated taxonomies: HHCC of Nursing Diagnoses and
      HHCC of Nursing Interventions both of which are classified by 20 Care Components.
      It highlights the major events that influenced its development, current status,
      and future uses. The two HHCC taxonomies and their 20 Care Components are used as
      a standardized framework to code, index, and classify home health clinical
      nursing practice. Further, they are used to document, electronically track,
      evaluate outcomes and analyze home health care over time, across settings,
      population groups, and geographic locations.

PMID- 12410635
TI  - Public health nursing practice: aftermath of September 11, 2001.
AB  - America's experience on September 11, 2001, forms the backdrop of this review of
      the public health nursing role in bioterrorism preparedness. The risks and
      challenges to the public health infrastructure are reviewed in order to place
      bioterrorism preparedness in a public health context. A review of the literature
      provides background material on the extent to which public health has evolved in
      planning for a bioterrorism event. The skills and competencies that will prepare
      public health nurses in their planning for and response to threats of
      bioterrorism are addressed. Anthrax is used as an example to illustrate how
      public health nursing can assist in a bioterrorism response.

PMID- 12410636
TI  - When terror is routine: how Israeli nurses cope with multi-casualty terror.
AB  - The wave of terror that has befallen the Israeli civilian population over the
      past two years, striking deep into the heart of towns and cities all over the
      country, presents a unique challenge for the health care system in general and
      nursing in particular. This article has a two-fold purpose: (a) to describe
      discussions that took place with four focus groups consisting of emergency room
      nurses who had recently cared for victims of terror, and (b) to delineate
      recommendations for policy enhancement based upon these discussions. Qualitative
      analysis of the data collected from focus group discussions revealed four stages
      of personal and professional involvement, each one eliciting a specific response
      from the nurses: call up to report for duty, waiting for casualties to arrive,
      caring for the victims, and closure of the event. Nurses identified numerous
      hardships and great anxiety along with a strong sense of professional
      fulfillment. Recommendations for policy include: incorporating stress management
      and debriefing skills in post-basic ER training, designing workshops and drills
      in trauma care for non-ER nurses who float into the ER in the wake of a multi
      casualty act of terror, and developing leadership seminars for head nurses in the
      ER departments.

PMID- 12410637
TI  - Novel mesenchymal and haematopoietic cell isoforms of the SHP-2 docking receptor,
      PZR: identification, molecular cloning and effects on cell migration.
AB  - SHP-2 (Src homology phosphatase type-2) is essential for haematopoietic skeletal
      and vascular development. Thus the identification of its binding partners is
      critically important. In the present study, we describe a unique monoclonal
      antibody, WM78, which interacts with PZR, a SHP-2 binding partner. Furthermore,
      we identify two novel isoforms of PZR, PZRa and PZRb, derived by differential
      splicing from a single gene transcription unit on human chromosome 1q24. All are
      type 1 transmembrane glycoproteins with identical extracellular and transmembrane
      domains, but differ in their cytoplasmic tails. The PZR intracellular domain
      contains two SHP-2 binding immunoreceptor tyrosine-based inhibitory motifs
      (VIY(246)AQL and VVY(263)ADI) which are not present in PZRa and PZRb. Using the
      WM78 monoclonal antibody, which recognizes the common extracellular domain of the
      PZR isoforms, we demonstrate that the PZR molecules are expressed on mesenchymal
      and haematopoietic cells, being present on the majority of CD34(+)CD38(+) and
      early clonogenic progenitors, and at lower levels on CD34(+)CD38(-) cells and the
      hierarchically more primitive pre-colony forming units. Interestingly, we show by
      reverse transcriptase-PCR that the PZR isoforms are differentially expressed in
      haematopoietic, endothelial and mesenchymal cells. Both PZR and PZRb are present
      in CD133(+) precursors and endothelial cells, PZRb predominates in mesenchymal
      and committed myelomonocytic progenitor cells, and all three isoforms occur in
      erythroid precursor cell lines. Importantly, using SHP-2 mutant (Delta 46-110)
      and SHP-2 rescue of embryonic fibroblasts stably expressing the PZR isoforms, we
      demonstrate for the first time that PZR, but not PZRa or PZRb, facilitates
      fibronectin- dependent migration of cells expressing a competent SHP-2 molecule.
      These observations will be instrumental in determining the mechanisms whereby PZR
      isoforms regulate cell motility.

PMID- 12410639
TI  - Control of glucose phosphorylation in L6 myotubes by compartmentalization,
      hexokinase, and glucose transport.
AB  - In muscle, insulin enhances influx of glucose and its conversion to glucose 6
      phosphate (G6P) by hexokinase (HK). While effects of insulin on glucose transport
      have been demonstrated, its effect on the activity of HK of cells has not. In L6
      myotubes treated for 24 h with insulin there was increased expression of the HK
      isoform, HKII, and increased glucose phosphorylation without a concomitant
      increase in glucose transport, indirectly suggesting that phosphorylation of
      glucose was a target of insulin action [Osawa, Printz, Whitesell and Granner
      (1995) Diabetes 44, 1426-1432]. In the present work the same treatment led to a 2
      fold rise in G6P, suggesting that transport and/or HK were important targets of
      insulin action. We used a method to identify the site of rate control involving
      the specificity of phosphorylation towards 2-deoxy-[1-14C]glucose and D-[2
      3H]glucose. Glucose transport does not greatly discriminate between these two
      tracers while HK shows increased specificity for glucose. Specificity of the
      glucose phosphorylation of the cells increased with addition of insulin and when
      extracellular glucose was raised. Specificity was reduced at low glucose
      concentrations or when the inhibitor of transport, cytochalasin B, was added. We
      conclude that transport and HK share nearly equal control over glucose
      phosphorylation in these cells. A computer program was used to test models for
      compatibility with the different types of experiments. The predicted
      intracellular glucose and transport rates associated with phosphorylation
      activity were lower than their measured values for the whole cell. In the most
      likely model, 15+/-4% of the glucose transporters serve a proportionate volume of
      the cytoplasm. Insulin activation of glucose phosphorylation might then result
      from stimulation of these transporters together with HK recruitment or relief
      from inhibition by G6P.

PMID- 12410640
TI  - Distribution of haemophilia in the French Basque country.
AB  - Because peculiar profiles for some genetic haematological diseases have been
      described among Basques, we aimed to investigate the distribution of haemophilia
      among this specific population. Hence, we retrospectively assessed all the cases
      of factor (F) VIII and FIX deficiencies seen in the French Basque country during
      a 16-year period. Data on 41 patients with haemophilia (FVIII or FIX = 25%) were
      compiled. Incidence and prevalence for the whole population ranged within the
      classical limits (but with an unusually high A : B ratio) and tended to be
      slightly lower in autochthonous Basques (P = n.s.). Our data did not support
      significant differences in the distribution of this disease among French Basques.

PMID- 12410638
TI  - Glucagon-like peptide-1 mobilizes intracellular Ca2+ and stimulates mitochondrial
      ATP synthesis in pancreatic MIN6 beta-cells.
AB  - Glucagon-like peptide-1 (GLP-1) is a potent regulator of glucose-stimulated
      insulin secretion whose mechanisms of action are only partly understood. In the
      present paper, we show that at low (3 mM) glucose concentrations, GLP-1 increases
      the free intramitochondrial concentrations of both Ca(2+) ([Ca(2+)](m)), and ATP
      ([ATP](m)) in clonal MIN6 beta-cells. Suggesting that cAMP-mediated release of
      Ca(2+) from intracellular stores is responsible for these effects, increases in
      [ATP](m) that were induced by GLP-1 were completely blocked by the Rp isomer of
      adenosine-3',5'-cyclic monophosphothioate (Rp-cAMPS), or by chelation of
      intracellular Ca(2+). Furthermore, inhibition of Ins(1,4,5) P (3) (IP(3))
      receptors with xestospongin C, or application of ryanodine, partially inhibited
      GLP-1-induced [ATP](m) increases, and the simultaneous blockade of both IP(3) and
      ryanodine receptors (RyR) completely eliminated the rise in [ATP](m). GLP-1
      appeared to prompt Ca(2+)-induced Ca(2+) release through IP(3) receptors via a
      protein kinase A (PKA)-mediated phosphorylation event, since ryanodine
      insensitive [ATP](m) increases were abrogated with the PKA inhibitor, H89. In
      contrast, the effects of GLP-1 on RyR-mediated [ATP](m) increases were apparently
      mediated by the cAMP-regulated guanine nucleotide exchange factor cAMP-GEFII,
      since xestospongin C-insensitive [ATP](m) increases were blocked by a dominant
      negative form of cAMP-GEFII (G114E,G422D). Taken together, these results
      demonstrate that GLP-1 potentiates glucose-stimulated insulin release in part via
      the mobilization of intracellular Ca(2+), and the stimulation of mitochondrial
      ATP synthesis.

PMID- 12410641
TI  - Inherited coagulation disorders in southern Iran.
AB  - A comprehensive survey concerning the Shiraz Hemophilia Society and the
      associated haemophilia treatment centre was undertaken in April 2002 to collect
      data on demographics, signs and symptoms in the southern Iranian population with
      haemophilia and allied disorders. The total number of patients with coagulation
      disorders was 367. Haemophilia A (factor [F] VIII deficiency) was found in 271,
      39 had haemophilia B (FIX deficiency) and 24 had von Willebrand disease. The rare
      coagulation disorders (n = 33) included 11 patients with FX deficiency; 10 with
      FVII; six with FXIII; two with afibrinogenaemia; two with FXI; one with combined
      FVIII and FV; and one with combined FVII, FVIII and FIX deficiency. The
      prevalence was 6.64 per 100,000 inhabitants. The most common symptoms were
      haemarthrosis, haematomas and epistaxis. None of the patients were human
      immunodeficiency virus positive but 47 (15%) were hepatitis C virus positive and
      two (0.7%) were hepatitis B positive, so that the rate of transfusion-transmitted
      infections was lower compared with other populations.

PMID- 12410642
TI  - Prophylactic versus on-demand treatment strategies for severe haemophilia: a
      comparison of costs and long-term outcome.
AB  - A multicentre study was performed to compare clotting factor use and outcome
      between on-demand and prophylactic treatment strategies for patients with severe
      haemophilia. Data on treatment and outcome of 49 Dutch patients with severe
      haemophilia, born 1970-80, primarily treated with prophylaxis, were compared with
      those of 106 French patients, who were primarily treated on demand. Dutch
      patients received intermediate dose prophylaxis, for a median duration of 12.7
      years. Patients primarily treated with prophylaxis had fewer joint bleeds per
      year (median 2.8 vs. 11.5), a higher proportion of patients without joint bleeds
      (29% vs. 9%), lower clinical scores (median 2.0 vs. 8.0), and less arthropathy as
      measured by the Pettersson score (median 7 points vs. 16 points). Mean annual
      clotting factor use was equal at 1,488 +/- 783 IU kg-1 year-1 (mean +/- standard
      deviation) for patients primarily treated with prophylaxis and 1,612 +/- 1,442 IU
      kg-1 year-1 for patients primarily treated on demand. These findings suggest
      that, compared with a primarily on-demand treatment strategy, a primarily
      prophylactic treatment strategy leads to better outcome at equal treatment costs
      in young adults with severe haemophilia.

PMID- 12410643
TI  - Prophylactic treatment for severe haemophilia: comparison of an intermediate-dose
      to a high-dose regimen.
AB  - A multicentre study was performed in Sweden and the Netherlands, comparing
      effects of two prophylactic regimens in 128 patients with severe haemophilia,
      born 1970-90. 42 Swedish patients (high-dose prophylaxis), were compared with 86
      Dutch patients (intermediate-dose prophylaxis). Patients were evaluated at the
      date of their last radiological score according to Pettersson. Annual clotting
      factor consumption and bleeding frequency were registered for a period of three
      years before evaluation. Patients in the high-dose group were younger at
      evaluation (median 15.2 vs. 17.9 years), started prophylaxis earlier (median 2
      vs. 5 years), and used 2.19 times more clotting factor kg-1 year-1. Patients
      treated with high-dose prophylaxis had fewer joint bleeds (median 0.3 year-1 vs.
      3.3 year-1) and the proportion of patients without arthropathy as measured by the
      Pettersson score was higher (69% vs. 32%), however, the age-adjusted difference
      in scores (median 0 points vs. 4 points) was small and at present not
      statistically significant. Clinical scores and quality of life were similar.
      These findings suggest that, compared with intermediate-dose prophylaxis, high
      dose prophylaxis significantly increases treatment costs and reduces joint bleeds
      over a period of 3 years, but only slightly reduces arthropathy after 17 years of
      follow-up.

PMID- 12410645
TI  - Paradoxical hyperfibrinolysis is associated with a more intensely haemorrhagic
      phenotype in severe congenital haemophilia.
AB  - To elucidate potential causes for differing bleeding phenotypes of haemophilic
      patients of identical degree of coagulation factor deficiency, we investigated 21
      male patients with severe haemophilia. Median annual coagulation factor demand
      and the extent of haemophilic arthropathy were used to discriminate between
      intensely and less intensely haemorrhagic phenotypes. Haemophiliacs with a median
      annual coagulation factor demand of 800 IU per kg bodyweight or more and with
      three or more joints affected by haemophilic arthropathy represented the
      intensely haemorrhagic phenotype group; all other patients comprised the less
      intense group. The discriminator values represent the respective medians of the
      overall group. The results of activated partial thromboplastin time, endogenous
      thrombin potential, pro- and anticoagulant factor analysis did not differ between
      the two groups. Median tissue-type plasminogen activator concentration (TPA) was
      elevated significantly in haemophiliacs with an intensely haemorrhagic phenotype,
      as was the activity of the thrombin-activatable fibrinolysis inhibitor. Median
      activity of the plasminogen activator inhibitor 1 (PAI 1) and the concentration
      of TPA-PAI 1 complexes were increased to approximately double those in nonsevere
      haemophiliacs. Coexistent congenital thrombophilia was found significantly more
      often in the less intensely haemorrhagic group. Thus, increased stimulation of
      the fibrinolytic system was associated with a more intensely haemorrhagic
      phenotype in our patients. We hypothesize that ineffective haemophilic
      haemostasis in response to trauma evokes a protracted stimulation of the entire
      haemostatic system, including costimulation of fibrinolysis. The absence of
      coexistent congenital thrombophilia predisposes to excess stimulation of
      fibrinolysis, which cannot be downregulated effectively due to the dysfunctional
      intrinsic pathway. The association of a more intensely haemorrhagic phenotype
      with a paradoxical hyperstimulation of the fibrinolytic system resembles a
      vicious circle, where bleeding seems to cause predisposition to more bleeding.

PMID- 12410644
TI  - Clinical efficacy of highly purified, doubly virus-inactivated factor VIII/von
      Willebrand factor concentrate (Fanhdi) in the treatment of von Willebrand
      disease: a retrospective clinical study.
AB  - The goal of therapy in patients with von Willebrand disease (vWD) is to correct
      the dual defect of primary haemostasis and intrinsic coagulation reflected by low
      levels of von Willebrand factor (vWF) and factor VIII coagulant activity
      (FVIII:C). Factor VIII/von Willebrand factor (FVIII/vWF) concentrates are
      currently the treatment of choice in vWD patients unresponsive to desmopressin
      (DDAVP). However, only few studies on their clinical use are available so far.
      The main objective of this study was to retrospectively evaluate the clinical
      efficacy of a highly purified, doubly virus-inactivated FVIII/vWF concentrate
      with a high content of FVIII/vWF (Fanhdi). Twenty-two patients with congenital
      vWD have been treated from 1999 to 2001 at eight specialized centres belonging to
      the Italian Association of Hemophilia Centers (AICE). Ten males and 12 females,
      median age 28.5 years, range 5-70 years) had type 3 vWD (six cases), DDAVP
      unresponsive type 1 (nine cases) and type 2B (seven cases). The study drug was
      given to stop or prevent 12 bleeding episodes or to prevent excessive bleeding
      during 14 surgical or invasive procedures. Overall, replacement therapy with the
      concentrate showed an excellent to good clinical efficacy in 92% of bleeding
      episodes and in 93% of surgical procedures. No adverse events occurred during
      1,601 infusions, accounting for a total of 304,500 IU of FVIII:C administered.
      These results confirm the efficacy and safety of this concentrate in the
      management of bleeding episodes and in the prevention of excessive bleeding
      during major and minor surgery.

PMID- 12410646
TI  - First-time development of FVIII inhibitor in haemophilia patients during the
      postoperative period.
AB  - Development of inhibitor to FVIII in haemophilia patients is well-known and is
      not uncommon. However, their development for the first time during the
      postoperative period has hardly been reported. In a developing country such as
      India, where resources are limited, development of such an eventuality may prove
      disastrous. However, as many of our patients are sparingly treated, therefore,
      even if they test negative for the inhibitor preoperatively, they may get the
      requisite FVIII antigenic stimulation during the preoperative and immediate
      postoperative period, leading to the development of inhibitors during this
      critical time of wound healing. We describe here six patients who developed such
      an inhibitor, from a group of 35 patients with haemophilia A who underwent
      various surgical procedures (19%). We stress that such an eventuality may not
      remain rare in developing countries as more patients of severe haemophilia
      undergo surgery and are therefore challenged for the first time in their life
      with large amounts of FVIII concentrate during their preoperative period.

PMID- 12410647
TI  - Overall haemostatic potential can be used for estimation of thrombin-activatable
      fibrinolysis inhibitor-dependent fibrinolysis in vivo and for possible follow-up
      of recombinant factor VIIa treatment in patients with inhibitors to factor VIII.
AB  - Thrombin generation induced by recombinant factor VIIa (rFVIIa) in patients with
      haemophilia and/or inhibitors to factor VIII/IX could enhance generation of
      thrombin-activatable fibrinolysis inhibitor (TAFI), a recently described link
      between coagulation and fibrinolysis. TAFI is unstable and it is not easy to
      measure its active form in vivo. Overall haemostatic potential (OHP) is a novel
      method for haemostasis estimation, based on determination of the fibrin
      aggregation curve in which tiny amounts of thrombin are used for activation of
      clotting. We measured OHP in six patients with inhibitors to factor VIII before
      injection of rFVIIa and 10 and 120 min thereafter. Overall fibrinolytic potential
      (OFP) and clot lysis time (CLT) analysed by this method could be used for
      indirect estimation of TAFI generation. We found no change in pro-TAFI and total
      TAFI antigen before and after treatment with rFVIIa. OHP was almost undetectable
      before treatment but increased into the range of normal pooled plasma 10 and 120
      min after rFVIIa treatment, as did CLT. However, after addition of potato tuber
      carboxypeptidase inhibitor, a specific inhibitor of TAFI, the shortening of CLT
      was lower than that in NPP. OFP was increased in patient plasma both 10 and 120
      min after treatment compared with NPP. There was a strong positive correlation
      between pro-TAFI concentration and shortening of CLT after PTCI addition and a
      negative correlation between pro-TAFI concentration and OFP 10 min after rFVIIa
      injection. Thus, rFVIIa normalizes OHP and CLT 10 min after injection. While this
      improvement slightly decreases, but still exists after 2 hours, it suggests
      efficacy in bleeding prevention using a protocol based on rFVIIa administration
      every 2 hours.

PMID- 12410648
TI  - DDAVP nasal spray for treatment of menorrhagia in women with inherited bleeding
      disorders: a randomized placebo-controlled crossover study.
AB  - To assess DDAVP (1-deamino-8-d-arginine vasopressin; desmopressin) nasal spray in
      the management of menorrhagia in patients with inherited bleeding disorders, 39
      women (aged 18-50 years) with menorrhagia were recruited and were randomized to
      start 2 months' therapy with placebo or DDAVP (300 micro g) spray in a double
      blind crossover study. Twenty-eight and 24 completed first and second period of
      treatment, respectively. Menstrual loss was assessed using the pictorial blood
      assessment chart (PBAC) during each treatment period. The main outcome measure
      was comparison of PBAC scores following DDAVP and placebo treatments. The safety
      of DDAVP spray was also assessed by monitoring side-effects. Overall, PBAC scores
      were significantly lower in the second treatment period than the first (P =
      0.01). After adjusting for this differences, mean PBAC scores were slightly lower
      (mean difference 8; 95% confidence interval of - 15.5 to 31.6) in women receiving
      DDAVP than when receiving placebo, although this difference was not statistically
      significant (P = 0.51). In conclusion, although there was an indication that
      menstrual bleeding was less heavy when women received DDAVP than when receiving
      placebo, the small sample size meant that this difference was not significant.

PMID- 12410649
TI  - Interferon and ribavirin in HIV-negative haemophiliacs with chronic hepatitis C
      who were nonresponders to a previous interferon treatment.
AB  - Between January 1999 and December 2001, 33 HIV-negative haemophiliacs with
      interferon-nonresponsive chronic hepatitis C were treated with interferon (IFN)
      alpha2b (5 MU three times weekly) and ribavirin (1-1.2 g daily) for 12 months.
      Four patients (12.1%) dropped out of the study due to adverse effects. At the end
      of therapy, normalization of ALT occurred in 14/33 treated patients (42.4%) and
      HCV-RNA was cleared in 12 (36.4%). Eleven patients (33.3%) became sustained
      responders. Genotype 1 was the only factor associated with a poor response to
      therapy (P < 0.001). Our study shows that IFN and ribavirin combination therapy
      is effective in HIV-negative chronically HCV-infected haemophiliacs who do not
      respond to a previous IFN treatment.

PMID- 12410650
TI  - Viral pharmacovigilance study of haemophiliacs receiving porcine factor VIII.
AB  - Porcine factor VIII (FVIII; Hyate:C; Speywood Biopharm Ltd, UK) has been used
      since 1980 for the treatment both of patients with acquired haemophilia and those
      with congenital haemophilia and inhibitory antibodies. Each batch is extensively
      screened using cell-culture techniques to confirm the absence of viruses. The
      production process does not incorporate specific virucidal treatment steps, such
      as heat treatment or the addition of a solvent/detergent mixture. Low levels of
      porcine parvovirus were detected in some batches of the product in late 1996 and
      supply was suspended. In this retrospective study, sera from 81 recipients of
      porcine FVIII and 125 other volunteers were screened for evidence of antibodies
      against a range of porcine viruses: porcine parvovirus (PPV),
      encephalomyocarditis virus (EMCV), and porcine respiratory and reproductive
      syndrome virus (PRRSV). The 125 volunteer controls included subjects from six
      categories: healthy control subjects, pig abattoir personnel, personnel involved
      in the manufacture of porcine FVIII, recipients of porcine heparin, recipients of
      porcine insulin, and haemophiliacs treated only with human FVIII. No antibodies
      to PPV or PRRSV were detected in any subject. Four patients and two volunteers
      were found to have antibodies to EMCV, but this incidence is similar to that
      observed in the general population. In conclusion, there was no evidence of
      transmission of PPR or other marker porcine virus associated with the use of
      porcine FVIII concentrate (Hyate: C).

PMID- 12410651
TI  - Clinical and radiographic scores in haemophilic arthropathies: how well do these
      correlate to subjective pain status and daily activities?
AB  - Haemophilic patients who reached adulthood before the establishment of
      prophylactic treatment frequently show multiple and substantial arthropathies.
      The aim of this study was to determine to what extent haemophiliac's subjective
      impairment due to arthropathies correlates with objective clinical and
      radiographic parameters. By means of a questionnaire and a visual analogue scale,
      we consulted 79 haemophiliacs concerning their joint-pain status, how these were
      treated and to what extent their daily activities had been affected. Using a
      scoring system suggested by the Advisory Committee of the World Federation of
      Haemophilia, clinical evaluation was performed. Radiographs of 60 patients were
      assessed by means of the Petterson scale. The results were statistically
      compared. We found a significant correlation between pain intensity and clinical
      pathology as well as between pain intensity and radiographic joint damage for
      both knees and for the right ankle. The number of painful joints correlated well
      with the number of clinically/radiographically affected joints. The more
      pronounced the objective damage to joints, the more frequently patients claimed
      to have constant pain, depressive episodes and a dependency on pain-relieving
      medication. The more pronounced the objectively assessed damage to the knee and
      ankle joint, the higher the likelihood that the patient suffers from severe joint
      pain and reduction of activity. Treatment of painful symptoms from arthropathies
      is often insufficient. Scores and questionnaires may help to define the
      haemophiliacs pain status more clearly, thereby offering a possibility of
      assessment and long-term observation.

PMID- 12410652
TI  - Orthopaedic surgery in severe bleeding disorders: a low-volume, high-cost
      procedure.
AB  - As more and more nations are scrutinizing their health care costs, attention has
      been focused on high-cost low-density disease. Assessment of actual total cost of
      care for haemophilia and its positive outcome becomes essential to justify
      support for these patients. In this study, we assessed hospital cost and
      diagnosis-related group (DRG) reimbursement for patients undergoing elective
      orthopaedic surgical procedures from May 1999 to December 1999. Hospital cost was
      assessed by a prospective microcost-analysis method. To identify real hospital
      costs, we performed registration of preoperative phase, operative phase and 1
      year follow-up costs. Hospital cost included personnel costs and costs for
      clinical and laboratory procedures, blood products, prosthetic implants,
      coagulation factor concentrates and drugs. These data were compared with hospital
      DRG reimbursement. We included nine consecutive patients, with a mean age 38
      years (19-54 years) who had had 10 major orthopaedic surgical procedures
      performed during the study period. Six patients had haemophilia A, two had
      haemophilia B and one had factor VII deficiency. Data analysis showed a mean cost
      of US$ 54,201 (range US$ 25,795-105,479; 1US$ = 8.5 NOK). The average actual
      hospital revenue (50% DRG reimbursement + income related to length of stay) was
      $4,730 (range $ 1,308-13,601). Our study confirms that orthopaedic surgery in
      patients with severe bleeding disorders puts the hospital to a considerable
      expense. Activity-based financing, as used in Norway, does not provide a proper
      reimbursement for this part of the haemophilia care.

PMID- 12410653
TI  - Chemical synoviorthesis with rifampicine and hyaluronic acid in haemophilic
      children.

PMID- 12410654
TI  - Unresolved issues in prophylaxis.

PMID- 12410655
TI  - Sequential treatment with bolus and continuous infusion of recombinant factor
      VIIa for hip arthroplasty in a patient with haemophilia A and inhibitor.
AB  - We describe a total arthroplasty of the hip in a 40-year-old male patient with
      haemophilia A and a high-titre inhibitor to factor VIII, treated with rFVIIa. The
      patient received sequential therapy first as bolus in the early postoperative
      phase in order to obtain appropriate haemostasis and then as continuous infusion
      with lower doses to avoid frequent episodes of bleeding without a higher
      consumption of product. After an initial dose of 150 micro g kg-1 for the first
      five days after surgery, we used bolus doses of 120-90 micro g kg-1 every 2.5-3
      h, achieving plasma FVII:C levels above 40 U mL-1. We then continued with
      continuous infusion at decreasing doses 15-7 micro g kg-1 h-1 for 12 days (FVII:C
      19-7 U mL-1). There were no bleeding complications nor signs of clotting
      activity. The rehabilitation programme was continued without prophylactic
      treatment. The total consumption of rFVIIa was 6.3 mg kg-1, implying a saving of
      at least 30% of the product with respect to previous publications.

PMID- 12410656
TI  - Successful percutaneous transluminal coronary angioplasty for acute myocardial
      infarction in von Willebrand's disease.
AB  - An elderly woman with mild von Willebrand's disease presented with acute
      myocardial infarction. Percutaneous transluminal coronary angioplasty, to
      mechanically disrupt the thrombus without anticoagulation, was successfully
      undertaken. Haemostatic cover was also avoided.

PMID- 12410657
TI  - A duplex issue: (i) time to re-appraise the diagnosis and classification of von
      Willebrand disorder, and (ii) clarification of the roles of von Willebrand factor
      collagen binding and ristocetin cofactor activity assays.

PMID- 12410658
TI  - Factor-sparing use of the COX-2 inhibitor rofecoxib in haemophilic arthropathy.

PMID- 12410664
TI  - Concordance between undergraduate dental students and their lecturers in their
      attitudes towards difficult patients.
AB  - The 'difficult' patient syndrome is caused by an imbalance in the dentist-patient
      relationship which may be influenced by human, cultural and psychosocial factors.
      The aim of this study was to compare the concordance between undergraduate dental
      students and lecturers in the degree of difficulty assigned to vignettes
      describing 'difficult' patients and to describe the extent to which ratings are
      influenced by gender, place of study and experience of specific 'difficult'
      patients. A questionnaire with 21 patient-stereotypes identified as difficult
      from the specialized literature was prepared. Both students and lecturers had to
      determine the degree of difficulty of each stereotype on a Likert-like scale. The
      students selected were in the final 2 years before graduation in Santiago de
      Compostela (Spain) and Porto (Portugal) Dental Schools. Lecturers were selected
      by simple random sampling method. Both lecturers and undergraduate students found
      more difficulty in those patients classified as aggressive, manipulative help
      rejecters or patients with invasive companions. On the other hand, drug abusers
      and HIV-positive patients were ranked as presenting low levels of difficulty. Our
      results seem to point to the need of improving undergraduate teaching and
      learning of specific procedures for the management of aggressive or stubborn
      patients and those with invasive companions.

PMID- 12410665
TI  - Information and communication technology among undergraduate dental students in
      Finland.
AB  - Use of information and communication technology (ICT) is rapidly increasing in
      medical and dental education. The aim of the present study was to determine the
      knowledge, skills and opinions of dental undergraduate students regarding ICT and
      to analyze possible shifts in the acquisition of these resources. For these
      purposes a survey of all undergraduate dental students at the University of Oulu,
      Finland, was conducted during the spring term 2000. All the students in the 5
      years of study (n = 140) were asked to answer a questionnaire presented during a
      lecture or demonstration. An overall response rate of 95% was achieved. The
      frequencies and percentage distributions of the items were analyzed separately
      for each year (1-5). All the students in the faculty are provided with personal e
      mail addresses at the beginning of their studies and special emphasis has been
      laid on the utilization of their ICT knowledge and skills. An overwhelming
      majority of the students, more than 95%, judged themselves to have good or
      satisfactory skills in word processing, but only a slight majority considered
      that they could manage some advanced operating system functions. Use of ICT
      services was high, as about 60% of the students used e-mail and one-third WWW
      services daily. Literature retrieval was widely employed, so that almost 80% of
      the students had used literature databases (including Ovid Medline and
      collections of electronic full-text articles), which were introduced and provided
      by the Medical Library when the students were in their second year. More than 50%
      had received educational material in electronic form often or sometimes, and
      almost 80% had communicated by e-mail with a faculty teacher. A clear trend (P <
      0.05) was found for the younger students to use ICT services in general and for
      educational purposes more often than the older ones. In conclusion, e-mail and
      WWW have been widely adopted for both private and educational purposes by dental
      students in Finland and are employed together with WWW-based medical and dental
      publication databases. The younger students have more interest in ICT and better
      skills, which presents a challenge for dental education in the future.

PMID- 12410666
TI  - Comparison of dental licensure, specialization and continuing education in five
      countries.
AB  - Dental practice and education are becoming more globalized. Greater practitioner
      and patient mobility, the free flow of information, increasingly global standards
      of care and new legal and economic frameworks (such as European Union [EU]
      legislation) are forcing a review of dental licensure, specialization and
      continuing education systems. The objective of this study was to compare these
      systems in Canada, France, Germany, the UK and the US. Representatives from the
      five countries completed a 29-item questionnaire, and the information was
      collated and summarized qualitatively. Statutory bodies are responsible for
      licensing and re-licensing in all countries. In the two North American countries,
      this responsibility rests with individual states, and in Europe, with the
      countries themselves, mainly governed by the legal framework of the EU. In some
      countries, re-licensure requires completion of continuing education credits.
      Approaches to dental specialization tend to differ widely with regard to
      definition of specialities, course and duration of training, training facilities,
      and accreditation of training programmes. In most countries, continuing education
      is provided by a number of different entities, such as universities, dental
      associations, companies, institutes and private individuals. Accreditation and
      recognition of continuing education is primarily process-driven, not outcome
      orientated. Working towards a global infrastructure for dental licensing,
      specialization and continuing education depends on a thorough understanding of
      the international commonalities and differences identified in this article.

PMID- 12410667
TI  - Orthodontic undergraduate education: assessment in a modern curriculum.
AB  - This paper describes the problems of assessment for students on an undergraduate
      orthodontic course which is using problem-based learning to encourage active self
      learning, deep learning and give students the skills to become effective lifelong
      learners in the future. Traditional assessment does little to encourage a range
      of behaviours and skills which are encouraged through problem-based learning but
      which must be rewarded, in the minds of the students, by the chosen method of
      assessment. This is because learner behaviour is driven by assessment. Details of
      the range of assessment methods available and those chosen on the orthodontic
      undergraduate course at the University of Manchester Dental School are reported
      and discussed.

PMID- 12410668
TI  - Learning root debridement with curettes and power-driven instruments in vitro:
      the role of operator motivation and self-assessment.
AB  - The influence of systematic dummy-head training with Periopolishe (PP, group A)
      and Gracey instruments (GRA, group B) on the effectiveness of root debridement
      was evaluated by Ruhling et al., 2002 (9). Their results indicate that
      independent of the instrument used, untrained operators were only able to debride
      root surfaces at low levels of effectiveness. It was possible to increase
      effectiveness to a high level through systematic training in both groups. The aim
      of the present study was to assess the role of operator motivation and self
      assessment on scaling effectiveness. Before baseline, operators were asked to
      answer a questionnaire rating the expectation of the instrument performance. Four
      groups of inexperienced operators (n = 11 each) received 10 weeks dummy-head
      training. In groups A (GRA) and B (PP), training was combined with a motivational
      programme. Groups C (GRA) and D (PP) received the same training, but no
      additional motivational programme. In a dummy-head, 10 test teeth were debrided
      and operators were asked to estimate their effectiveness of debridement at each
      test day. Effectiveness was calculated as percentage of debrided root area on 10
      test teeth at different time points with an image analysis programme (NIH Image)
      and ANOVA. Two groups were compared using the Mann-Whitney U-test (unpaired) and
      the Wilcoxon signed ranks test (paired). Motivated groups (A and B) reached about
      25% higher debridement results (p < 0.001) and were able to estimate their
      effectiveness more precisely compared to groups C and D. In the low motivation
      groups (C and D), overestimation of more than 20% was evident (p < 0.001). The
      questionnaires revealed underestimation of the GRA instruments and overestimation
      of PP instruments. Operator motivation and self-assessment greatly influence
      learning of effective root debridement.

PMID- 12410669
TI  - Undergraduate education in endodontology at two European dental schools. A
      comparison between the Faculty of Odontology, Malmo University, Malmo, Sweden and
      Faculty of Odontology, Paris 5 University (Rene Descartes), France.
AB  - The aim of this study was to compare the courses in endodontics and to assess the
      treatment quality in the student clinics in two dental schools, in Malmo, Sweden
      and Paris, France. A further aim was to improve the curriculum development in
      Paris 5 and Malmo by testing student exchange programmes. The comparison was
      based on the guidelines for undergraduate education set up by the European
      Society of Endodontology (ESE) [Int. Endod. J. 25 (1992) 169] and on the criteria
      formulated by Qualtrough and Dummer [Int. Endod. J. 30 (1997) 234]. The latter
      criteria covered the following aspects: educational methods, the timing of
      endodontic teaching, pre-clinical practical exercises, student assessment,
      recommended literature, clinical/practical procedures, the education of the staff
      and number of students per teacher. The quality guidelines for endodontic
      treatment set up by the ESE [Int. Endod. J. 27 (1994) 115] were used for the
      assessment of the quality of the treatment. The following aspects were covered:
      history, diagnosis and treatment planning, records, infection control, root-canal
      treatment, assessment of endodontic treatment. The undergraduate education in
      endodontics was fundamentally similar in Paris 5 and Malmo. The main differences
      observed were related to: Educational methods: In Malmo, problem-based learning
      and in Paris 5, traditional. Assessment of student performance. In Malmo, self
      assessment and in Paris 5, credits for clinical/practical procedures.
      Clinical/practical procedures relating to infection control. Aseptic treatment
      regimens were more meticulously performed in Malmo than in Paris 5. Assessment
      (follow-up) of all endodontic treatments was a routine only in Malmo.

PMID- 12410671
TI  - The art of repair in surgical hair restoration--part II: the tactics of repair.
AB  - BACKGROUND: As patient awareness of new hair transplantation techniques grows,
      the repair of improperly planned or poorly executed procedures becomes an
      increasingly important part of surgical hair restoration. OBJECTIVE: Part II of
      this series is written to serve as a practical guide for surgeons who perform
      repairs in their daily practices. It focuses on specific repair techniques.
      METHODS: The repairs are performed by excision with reimplantation and/or by
      camouflage. Follicular unit transplantation is used for the restorative aspects
      of the procedure. RESULTS: Using punch or linear excision techniques allows the
      surgeon to relocate poorly planted grafts to areas that are more appropriate. The
      key elements of camouflage include creating a deep zone of follicular units,
      angling grafts in their natural direction, and using forward and side weighting
      of grafts to increase the appearance of fullness. In special situations, removal
      of grafts without reimplantation can be accomplished using lasers or
      electrolysis. CONCLUSION: Meticulous surgical techniques and optimal utilization
      of a limited hair supply will enable the surgeon to achieve the best possible
      cosmetic results for patients requiring repairs.

PMID- 12410672
TI  - The potential role of minoxidil in the hair transplantation setting.
AB  - BACKGROUND: Over the last decade surgical management of hair loss has become an
      increasingly popular and satisfying procedure for both men and women, as
      innovations in donor harvesting, graft size, and hairline design have resulted in
      consistently natural-appearing hair restoration. OBJECTIVE: In addition, a better
      understanding of the regulation of the hair-growth cycle has led to advances in
      the pharmacologic treatment of androgenetic alopecia. METHODS: Currently there
      are two U.S. Food and Drug Administration (FDA)-approved agents that promote hair
      regrowth: over-the-counter topical minoxidil solution for men and women and
      prescription oral finasteride tablets for men. In October 2001, a group of 11
      international experts on hair loss and hair transplantation convened to review
      the physiology and effects of pharmacologic treatments of hair loss and to
      discuss the value of administering topical minoxidil therapy as an adjunct to
      hair transplantation. RESULTS: This article presents the key findings and
      consensus points among the participants, including their current use of
      pharmacologic treatments, strategies for optimal results both pre- and
      postsurgery, and the importance of realistic patient expectations and compliance.
      CONCLUSIONS: Based on the surgeons' clinical experience, the use of approved hair
      regrowth agents in hair transplant patients with viable but suboptimally
      functioning follicles in the region to be transplanted can increase hair density,
      speed regrowth in transplanted follicles, and complement the surgical result by
      slowing down or stopping further hair loss.

PMID- 12410673
TI  - A new ePTFE soft tissue implant for natural-looking augmentation of lips and
      wrinkles.
AB  - BACKGROUND: Expanded polytetrafluoroethylene (ePTFE) implants have been used for
      augmentation of thinning lips and wrinkles due to aging for more than 10 years.
      The aesthetic results have often been excellent, but complications such as
      infection, extrusion, migration, shrinkage, and hardening have occurred in some
      patients. OBJECTIVE: To assess short-term results and complications in patients
      undergoing augmentation of the lips, nasolabial folds, and marionette lines with
      a newly designed ePTFE implant. METHODS: Thirty patients received 60 Advanta
      ePTFE implants for augmentation of the lips, nasolabial folds, or marionette
      lines. RESULTS: All patients received a natural-looking augmentation following 3
      4 days of noticeable swelling. The only significant complications involved two
      upper lip implants that were removed for suspected infection. CONCLUSION: In a
      preliminary series, Advanta ePTFE implants provided effective, natural-looking
      augmentation of the lips and nasolabial folds with minimal complications.

PMID- 12410674
TI  - Superpulsed CO2 laser treatment of basal cell carcinoma with intraoperatory
      histopathologic and cytologic examination.
AB  - BACKGROUND: CO2 laser is currently one of the most versatile and useful laser
      devices in dermatologic practice in the fields of both cosmetology and oncology.
      The CO2 laser in a superpulsed mode enables the operator to effect precise and
      adequate vaporization of the affected area, with the possibility to appreciate
      visually the depth achieved, and, when necessary, to perform histologic and
      cytologic examination of the surrounding skin. OBJECTIVE: To show superpulsed CO2
      laser treatment of basal cell carcinoma. METHODS: One hundred forty patients
      presenting single, multiple, superficial, or nodular basal cell carcinoma (BCC)
      have been treated with the superpulsed CO2 laser. Before the laser treatment the
      lesion was subjected to cytologic examination by scraping; this examination was
      then repeated when the papillary dermis was clinically detectable, and again when
      the operator considered the BCC completely vaporized. In selected subjects,
      histopathologic examination was done three times (biopsies were obtained at the
      same time as the samples for the cytologic examination). RESULTS: Recovery time
      was fast, with good healing outcomes. After 3 years follow-up no recurrences were
      seen. The cytologic and histopathologic examinations showed BCC in the specimens
      obtained prior to and during laser therapy, but not in those obtained after laser
      therapy. CONCLUSION: This technique causes minimal thermal cellular damage and no
      severe morphologic cellular alterations. Thus it permits an intraoperatory
      cytologic and histopathologic examination. Finally, this technique enables the
      operator to recognize the different skin levels removed by vaporization and to
      stop the vaporization as soon as unaffected dermis has been reached, as shown by
      intraoperatory cytologic and histopathologic examination.

PMID- 12410675
TI  - Successful surgical treatment of verrucous hemangioma: a combined approach.
AB  - BACKGROUND: Verrucous hemangioma, also known as angiokeratoma circumscriptum
      naeviforme, is a rare congenital vascular abnormality. Episodes of bleeding and
      infection following trauma or scratching are frequent. Superficial ablative
      therapies using laser, cryotherapy, and electrocautery are always followed by
      recurrence. OBJECTIVE: To report the clinical and histopathologic characteristics
      and treatment results of verrucous hemangioma. METHODS: This study included 23
      patients with verrucous hemangioma treated by en toto surgical excision in
      combination with laser therapy. Palpation, inspection, computed tomography (CT),
      or magnetic resonance imaging (MRI) was performed to delineate surgical margins.
      RESULTS: The clinical presentation of verrucous hemangioma ranged from a small
      solitary verrucous plaque or cluster of lesions with unilateral limb involvement
      to Klippel-Trenaunay syndrome with bone hypertrophy. Histologically all specimens
      revealed the existence of hemangioma-like components in the subcutaneous tissue
      and dilated subepidermal blood cysts. The 14 patients presenting with small,
      localized lesions were cured by one session of surgery without recurrence, while
      the 9 patients with wider and more extensive lesions required combination therapy
      in several stages for optimal results. CONCLUSION: Surgical excision in
      combination with laser therapy is the preferred treatment for verrucous
      hemangioma because the crucial pathologic change is concentrated in the
      subcutaneous tissue. The use of clinical inspection, palpation, and imaging
      studies before surgery is helpful in delineating the underlying mass.

PMID- 12410676
TI  - Eyebrow reconstruction with the subcutaneous island pedicle flap.
AB  - BACKGROUND: Surgical defects of the eyebrow region routinely present a cosmetic
      challenge to the reconstructive surgeon. OBJECTIVE: To present the use of a
      commonly employed reconstructive technique for an uncommon location. METHODS:
      Defects and repairs are demonstrated to illustrate techniques and document
      outcomes. The biomechanical influences on flap choice are explored. RESULTS: The
      subcutaneous island pedicle flap yielded excellent functional and cosmetic
      results when medium or larger defects were confronted in the eyebrow region. A
      centrally based pedicle enhanced cosmetic outcome, while rendering an
      uncompromised vascular supply. CONCLUSION: The subcutaneous island pedicle flap
      provides a competitive repair alternative when reconstructing substantial defects
      of the eyebrow region.

PMID- 12410677
TI  - Nonablative remodeling: a 14-month clinical ultrasound imaging and profilometric
      evaluation of a 1540 nm Er:Glass laser.
AB  - BACKGROUND: Nonablative remodeling has been recently proposed as a new antiaging
      treatment with no downtime. OBJECTIVE: To evaluate the efficacy and safety of
      nonablative skin remodeling with a 1540 nm Er:glass laser and contact cooling on
      perioral and periorbital rhytides at 14 months follow-up. METHODS: Forty-two
      female patients (mean age 47 years), Fitzpatrick skin types I-IV were treated
      five times at 6-week intervals and checked 6 months after the last treatment.
      Patients were evaluated using clinical data, patient satisfaction (scale 1-4),
      digital pictures, ultrasound imaging, and profilometry data from silicone
      imprints in order to quantify the degree of improvement. RESULTS: All subjects
      reported an improvement in the quality and visual aspect of their skin at 6
      months (mean patient satisfaction 3.06/4) and at 14 months after enrollment (mean
      patient satisfaction 2.90/4). This was confirmed by a 43.41% reduction of
      anisotropy (P < 0.001) 6 weeks after the fourth treatment, reaching 44.85%
      reduction 6 months after the fifth treatment (P <.001). Ultrasound imaging
      demonstrated a 17% increase in dermal thickness (P <.001) at 6 months and 11% 6
      months after the last treatment (P <.05). A lack of immediate or late adverse
      effects was noted at all stages of the procedure. CONCLUSION: This study
      demonstrated that irradiation with a 1540 nm Er:glass laser emitting in a pulsed
      mode and coupled with an efficient cooling system increased dermal thickness,
      reduced the anisotropy of the skin, and improved clinical aspects. The lack of
      adverse effects within the 14 months confirmed that this procedure was safe.
      Overall the stability of the results many months after the treatment was
      remarkable.

PMID- 12410678
TI  - Evaluation of a long-pulsed Nd:YAG laser at different parameters: an analysis of
      both fluence and pulse duration.
AB  - BACKGROUND: Effective hair removal continues to pose a challenge to the
      physician. The use of lasers represents a significant advance in epilation, but
      still requires further refinement. The long-pulsed Nd:YAG laser may offer
      advantages over other systems because of its significant depth of penetration and
      minimal absorption by epidermal melanin, but ideal parameters need to be
      determined. OBJECTIVE: To evaluate the efficacy of a long-pulsed Nd:YAG laser
      system and determine the optimal parameters for hair removal. METHODS: Twenty-two
      subjects were treated with a cryogen spray-cooled long-pulsed Nd:YAG laser. Four
      adjacent sites were assigned to each subject, where the following sets of
      parameters were utilized: 50 J/cm2 with a 25-msec pulse duration, 60 J/cm2 with a
      50-msec pulse duration, 80 J/cm2 with a 50-msec pulse duration, and control. Hair
      counts were obtained immediately, 1 week, 1 month, and 3 months after treatment,
      and multivariate regression analysis was used to determine the significance of
      hair reduction. Acute reactions and adverse events were also evaluated. RESULTS:
      Treatment at all three sets of parameters resulted in significant mean hair
      reductions immediately, at 1 week, and at 1 month (P <.001). At 3 months, the
      higher settings of 60 J/cm2 and 50 msec and 80 J/cm2 and 50 msec were
      statistically significant for reduced mean hair counts (P =.014, P =.042,
      respectively), while the lowest setting at 50 J/cm2 and 25 msec was not
      significant (P =.079). Patient and physician assessments suggested optimal hair
      reduction at the highest fluence (80 J/cm2) and longest pulse duration (50 msec).
      The most common acute reactions were pain during treatment, erythema, and
      perifollicular edema, all of which were more severe with higher fluences.
      CONCLUSION: The long-pulsed Nd:YAG laser is a safe and effective method of hair
      removal. Increased fluence (60-80 J/cm2) and longer pulse duration (50 msec)
      settings were generally correlated with reduced hair counts and improved clinical
      outcome.

PMID- 12410679
TI  - Quantitative venous severity scoring using the venous arterial flow index by
      duplex sonography.
AB  - BACKGROUND: Volume flow, as the product of the mean blood flow velocity by the
      cross sectional area, means an interesting hemodynamic pattern that can be
      calculated by duplex. OBJECTIVE: To quantify the severity of venous insufficiency
      using the correlation between the volume flow in the common femoral vein (VFV)
      and artery (VFA), called the venous arterial flow index (VAFI). METHODS: A total
      of 163 consecutive patients were included: 46 patients with postthrombotic
      syndrome (PTS, group 1), 38 patients with complete varicosity of the greater
      saphenous vein (group 2), 40 patients with only segmental or truncal varicosity
      (group 3), and 39 patients with competent veins (group 4). Under standardized
      conditions, duplex sonography was performed to calculate volume flow in the
      common femoral vein and artery as a product of mean blood flow velocity (vm) and
      precise diameter (d = 2pir) of the vessel due to the formula VF = vmxpir2
      (L/min). Division of the venous and arterial volume flow data calculated the
      VAFI. RESULTS: Significant differentiation of VFV (P <.001) and VAFI (P <.0001)
      between varicose veins and healthy limbs were found. In PTS the mean VFV was 0.50
      L/min and the mean VAFI was 1.465. In the complete varicosity group, mean VFV was
      0.46 L/min and mean VAFI was 1.48. In group 3, the mean VFV was 0.41 L/min and
      the mean VAFI was 1.31. In healthy persons, mean VFV was 0.36 L/min and mean VAFI
      was 0.87. CONCLUSION: The VAFI can be used to quantify the hemodynamic severity
      in venous insufficiency.

PMID- 12410680
TI  - Selective nonablative treatment of acne scarring with 585 nm flashlamp pulsed dye
      laser.
AB  - BACKGROUND: Selective nonablative wrinkle reduction with low-fluence pulsed dye
      laser has been shown to provide cosmetic benefits by stimulating the production
      of dermal collagen. The clinical efficacy for improving the appearance of acne
      scarring using selective nonablative laser treatments has yet to be established.
      OBJECTIVE: To evaluate the improvement in the appearance and topography of acne
      scarring following application of a 585 nm pulsed dye laser with a temporal
      profile and pulse duration designed specifically to target healthy
      microvasculature in the dermis. METHODS: Ten patients (mean age 34.8 years) with
      Fitzpatrick skin types I-IV and shallow to moderately deep, saucerized facial
      acne scars were enrolled in a prospective trial to receive a single laser
      treatment of both cheeks. Patients were evaluated at 30, 60, 90, and 120 days to
      assess the degree of clinical improvement. The evaluation process included
      assessment of pre- and posttreatment photography by two independent observers,
      patient assessment surveys, and surface profilometry using silicone imprints in
      order to quantify the degree of clinical improvement. RESULTS: All 10 patients
      reported visible cosmetic improvement in the treated areas while surface
      profilometry showed that, on average, the depth of the acne scars was reduced by
      47.8%. No adverse effects of this treatment were reported. CONCLUSION: The
      treatment of acne scars utilizing a 585 nm pulsed dye laser with a temporal
      profile and pulse duration designed specifically to target healthy
      microvasculature in the dermis may be a safe and effective noninvasive
      alternative for a natural result.

PMID- 12410681
TI  - Techno pearls for digital image management.
AB  - BACKGROUND: The past decade has provided a paradigm shift in image management.
      Technological advances have enabled affordable, high-quality digital clinical
      photography. In addition, this technology has enabled doctors to easily compose
      and present multimedia lectures with programs such as Microsoft PowerPoint. Since
      most practitioners already possess large numbers of conventional slides and
      photographs, digitization is required to convert these to a usable format.
      Depending on the type of image and resolution, it can take anywhere from 30
      seconds to several minutes to scan each slide. This drawback delays or prevents
      many practitioners from switching to digital technology. OBJECTIVE: Using a
      digital camera and the XP version of Windows, some common tasks associated with
      digital images and PowerPoint presentations may be simplified and facilitated.
      METHODS: Using common digital cameras and computer image editing software,
      slides, photographs, radiographs, and textbook images may be digitized in seconds
      with adequate quality for most common clinical and educational applications. In
      addition, the use of new dual monitor functionality is discussed. This new
      technology comes standard with Windows XP and allows the use of two monitors
      simultaneously, allowing the user to view thumbnail images on one monitor and the
      PowerPoint presentation on the other monitor. Images may be dragged and dropped
      into the presentation, thereby avoiding repetitive menu commands. RESULTS: The
      author shows several techniques and shortcuts to assist the clinical practitioner
      in digitizing slides and facilitating the management of these images in
      PowerPoint presentations. CONCLUSION: A digital camera can be used to adequately
      digitize most slide pictures, and these images can be managed in a more simple
      and direct manner utilizing the Windows XP operating system that is shipping with
      most new computers.

PMID- 12410682
TI  - Squamous cell carcinoma in chronic lymphedema: case report and review of the
      literature.
AB  - BACKGROUND: Squamous cell carcinoma (SCC) arising in chronic lymphedema is rare;
      only nine cases have been reported. OBJECTIVE: To present the evolution of SCC in
      chronic lymphedema. METHODS: Case report and literature review. RESULTS: The
      tumor was treated by wide excision and covered by a skin graft. CONCLUSION: In
      most of the other reported SCC cases in lymphedema, there are additional factors
      for carcinogenesis. There is no additional carcinogenic factor except for chronic
      lymphedema in our case. This strongly supports that lymphedema itself is one of
      the carcinogenic factors for not only angiosarcoma but also SCC.

PMID- 12410683
TI  - Intralesional corticosteroid treatment of multiple eruptive keratoacanthomas:
      case report and review of a controversial therapy.
AB  - BACKGROUND: Use of intralesional corticosteroids in the management of
      keratoacanthomas has been reported in older literature. Yet this therapy is no
      longer a commonly considered treatment option. OBJECTIVE: To report management of
      a therapeutically challenging patient with multiple eruptive keratoacanthomas
      with intralesional corticosteriod treatment to revive awareness of this treatment
      option. METHODS: A 55-year-old female with frequent episodes of multiple eruptive
      keratoacanthomas was treated with intralesional corticosteroids and methotrexate.
      RESULTS: Intralesional corticosteroids successfully treated eruptive
      keratoacanthomas with complete regression and minimal scarring within 2-4 weeks.
      CONCLUSION: Despite its limitations, intralesional corticosteroids may have a
      role in the treatment of select keratoacanthomas.

PMID- 12410684
TI  - Infantile digital fibroma treated with mohs micrographic surgery.
AB  - BACKGROUND: Infantile digital fibroma (IDF) is a rare benign fibrous tumor of
      childhood that frequently recurs despite local excision. Conservative,
      nonsurgical management may result in regression and/or joint deformity.
      OBJECTIVE: To describe the histologic features of IDF and discuss a case excised
      using Mohs micrographic surgery (MMS). METHODS: Case report and review of the
      clinical, histologic, and ultrastructural features. RESULTS: Characteristic
      inclusion bodies of actin were identified with hematoxylin and eosin, Masson's
      trichrome, and rapid actin immunostain. The tumor was debulked and the majority
      was removed after one stage of MMS, except where the deep margin approached the
      joint space. The defect healed by secondary intention. At 2 years the patient had
      no recurrence or functional joint deformity. CONCLUSION: MMS is a surgical
      treatment option for IDF.

PMID- 12410685
TI  - Tattoo-associated dermatoses: a case report and review of the literature.
AB  - BACKGROUND: Tattoos are increasingly popular in today's society, especially with
      the advent of laser tattoo removal. As a result, observed reactions within
      tattoos are likely to become more abundant. Three main classes of tattoo
      associated dermopathies can be distinguished in the English literature:
      allergic/granulomatous/lichenoid, inoculation/infection, and coincidental
      lesions. Injury to the dermis, such as during placement of a tattoo, can also
      flare a Koebner response in patients with active susceptible disease. OBJECTIVE:
      This case report and review of the English literature provides a quick reference
      to tattoo reactions, techniques available for removal of tattoos, and disorders
      other than tattoos known to exhibit the Koebner response. METHODS: The English
      literature was reviewed via MEDLINE citations from 1966 to December 2001 to
      delineate articles involving tattoo reactions and Koebner reactions significant
      to dermatology. CONCLUSION: Numerous conditions have been documented in
      association with tattoos and the process of tattoo application. Awareness and
      identification of dermatoses associated with tattoos, tattoo removal options, and
      conditions associated with the Koebner response are important to both the
      dermatologist and dermatologic surgeon.

PMID- 12410686
TI  - Pitfall in pigmentation: pseudopods in the nail plate.
AB  - BACKGROUND: We present here a patient with an unusual type of nail plate
      pigmentation featuring pseudopod formation. OBJECTIVE: To identify additional
      dermoscopic criteria. METHODS: Dermoscopy of the nail with control biopsy.
      RESULTS: Pseudopods of the nail resulted from erythrocytes entrapped between the
      layers of the nail plate. CONCLUSION: Pseudopod formation of the nail may
      represent a diagnostic criterion to distinguish hemorrhage and melanoma of the
      nail apparatus.

PMID- 12410690
TI  - Notice of dual publication.

PMID- 12410688
TI  - Laser and sclerotherapy treatment of leg veins: my perspective on treatment
      outcomes.

PMID- 12410692
TI  - Dermatological aspects of angiogenesis.
AB  - Neovascularization is vital for the growth of tumours, providing a lifeline for
      sustenance and waste disposal. Tumour vessels can grow by sprouting,
      intussusception or by incorporating bone marrow-derived endothelial precursor
      cells into growing vessels. Recent advances in vascular biology have identified
      some key factors that control vascular growth, and have led to the hypothesis
      that in normal tissues vascular quiescence is maintained by the dominant
      influence of endogenous angiogenesis inhibitors over angiogenic stimuli. In
      contrast, increased secretion of angiogenic factors and the down-regulation of
      endogenous angiogenesis inhibitors induce tumour angiogenesis. Vascular
      quiescence in the skin seems to be primarily maintained by a balance between the
      endogenous angiogenesis inhibitors thrombospondin 1 and thrombospondin 2 and the
      potent proangiogenic factor vascular endothelial growth factor A. Inhibiting
      tumour growth by controlling angiogenesis is an intriguing approach with great
      potential for the treatment of vascular tumours such as haemangioma, Kaposi's
      sarcoma and solid cutaneous tumours such as squamous cell carcinoma, melanoma and
      basal cell carcinoma. In this review, the role of angiogenesis and more recent
      topics such as lymphangiogenesis in cutaneous tumour growth, invasion and
      metastasis will be discussed.

PMID- 12410693
TI  - Expression of lamins depends on epidermal differentiation and transformation.
AB  - BACKGROUND: It has been suggested that A- and B-type lamins, proteins of the
      nuclear lamina, play important roles in the morphogenesis of the nucleus and
      cellular differentiation. OBJECTIVE: To investigate the expression of these
      nuclear proteins in normal skin and some keratinocytic tumours of the skin.
      METHODS: We examined by means of immunohistochemistry the expression of lamins in
      normal skin and some keratinocytic tumours of the skin, such as squamous cell
      carcinoma (SCC), basal cell carcinoma (BCC), Bowen's disease, solar keratosis,
      keratoacanthoma and seborrhoeic keratosis. RESULTS: In normal skin, A-type lamin
      was expressed in all epidermal cells, but the expression level of B-type lamins
      diminished from basal cells to granular cells. In keratinocytic tumours, the
      expression of A-type lamin was reduced, especially in BCCs, Bowen's disease and
      poorly differentiated SCCs. B-type lamins were reduced and exhibited
      heterogeneous expression patterns in most well-differentiated SCCs and
      keratoacanthomas. Antibodies against B-type lamins stained only peripheral cells
      of the lobules in keratoacanthomas, while no regular staining patterns were seen
      in well-differentiated SCCs. CONCLUSIONS: Lamin expression depends on the
      differentiation and transformation of the human skin. This finding should be
      useful for the diagnosis of keratinocytic tumours.

PMID- 12410694
TI  - Molecular basis of the alteration in skin collagen metabolism in response to in
      vivo dexamethasone treatment: effects on the synthesis of collagen type I and
      III, collagenase, and tissue inhibitors of metalloproteinases.
AB  - BACKGROUND: Glucocorticoids are widely used for the treatment of various
      diseases, despite known side-effects such as skin atrophy. Many studies have
      shown that the status of collagen fibres in the skin is affected by
      glucocorticoid treatment. However, the molecular mechanism underlying the
      alteration of collagen metabolism in the skin by glucocorticoid treatment remains
      unknown. OBJECTIVES: To characterize the molecular mechanisms related to the
      deterioration of the dermis in response to glucocorticoids, the status of two
      major types of collagen, collagenase, and tissue inhibitors of metalloproteinases
      (TIMPs) in the dorsal skin of rats was studied at the protein and mRNA levels.
      METHODS: Samples of rat dorsal skin were obtained after daily (1 mg kg-1)
      subcutaneous injections of dexamethasone (DEX) for 8 days. mRNA levels of two
      types of collagen and of TIMPs were measured by a lysate RNase protection assay.
      mRNA levels of collagenase were measured by a quantitative polymerase chain
      reaction. Protein levels of collagen and collagenase were measured by an
      immunoblot analysis. RESULTS: Levels of type I tropocollagen and type III
      tropocollagen were drastically reduced in response to DEX. The effects of DEX
      treatment were more severe on type III than type I collagen: it also produced a
      significant decrease in fibril collagen of type III collagen. DEX treatment was
      found to decrease both active and latent forms of collagenase as well as its mRNA
      levels. Among TIMPs, mRNA levels of TIMP-1 and TIMP-2 were decreased in response
      to DEX treatment, whereas those of TIMP-3 were not affected. CONCLUSIONS: These
      results suggest that DEX treatment strongly interferes with both the synthesis
      and degradation of type I collagen and, more drastically, type III collagen, the
      molecule that is known to play a major role in the initiation of wound healing.
      The present study may provide a molecular basis for the deterioration of skin
      function, impaired wound healing, and skin atrophy caused by glucocorticoid
      treatment.

PMID- 12410695
TI  - Modelling the remission of individual acne lesions in vitro.
AB  - BACKGROUND: Acne lesions spontaneously remit, but the mechanism of this remission
      has not been elaborated. It is known, however, that the remission is associated
      with a de-differentiation of sebocytes, causing a cessation of sebum secretion
      specific to that particular pilosebaceous unit. We have previously described the
      cytokines that will promote in vitro the lesions of acne. OBJECTIVES: To show
      that those same cytokines may also promote a de-differentiation of sebocytes
      analogous to that seen during remission of some lesions. METHODS: Human chest
      sebaceous glands were maintained in vitro as whole organs. We then chronicled the
      effects of the appropriate cytokines and growth factors on the glandular rates of
      (i) lipogenesis and (ii) DNA synthesis, as well as on (iii) glandular morphology,
      (iv) the expression patterns of the proliferation marker Ki-67, (v) keratinocyte
      specific markers, and (vi) the sebocyte marker epithelial membrane antigen.
      RESULTS: We have shown that the same cytokines that promote comedogenesis
      (interleukin-1alpha), expression of infundibular intercellular adhesion molecule
      1 and human leucocyte-associated antigen-DR (tumour necrosis factor-alpha and
      interferon-gamma), and infundibular disruption (epidermal growth
      factor/transforming growth factor-alpha) in human infundibula in vitro, will also
      inhibit sebaceous lipogenesis in vitro and will also induce, histologically, a de
      differentiation of human sebocytes into a keratinocyte-like phenotype.
      CONCLUSIONS: These results confirm our hypothesis that the cytokines that induce
      the infundibular changes in acne may also inhibit the secretion of lipid from the
      sebaceous gland and thus, on diffusing down to the gland, contribute to the
      remission of the individual lesions. These findings help to explain the known
      natural history of the disease.

PMID- 12410697
TI  - Differential expression of collagen integrin receptor on fetal vs. adult skin
      fibroblasts: implication in wound contraction during healing.
AB  - BACKGROUND: Fetal skin wound healing is characterized by an absence of
      contraction and scar formation, two important observations associated with adult
      healing often leading to pathological problems. OBJECTIVES: We have studied the
      capacity of adult and fetal human skin fibroblasts to contract collagen gels,
      collagen being the major structural component of dermal matrix. METHODS: In
      parallel with collagen gel contraction studies, we have used fluorescence
      activated cell sorter analysis to study the levels of collagen receptors
      expressed at the surface of fibroblasts derived from fetal or adult skin samples.
      RESULTS: Strong differences were detected between freshly isolated fetal and
      adult fibroblasts. Fetal fibroblasts had a very low capacity to contract collagen
      gel, whereas adult cells significantly contracted gels in the same conditions.
      The expression of alpha1, alpha2 and alpha3 integrin subunits was also
      significantly different depending of the donor age: alpha1 and alpha3 integrin
      subunit expression was lower in fetal cells compared with adult cells, whereas
      alpha2 integrin subunit expression was higher. When grown in monolayers, adult
      cells showed rapid changes in their contractile capacity and integrin expression
      while fetal cells were only affected after several passages. CONCLUSIONS: These
      observations indicate that intrinsic differences between fetal and adult
      fibroblasts can strongly influence the quality of wound repair.

PMID- 12410696
TI  - Confocal laser scanning microscopic observation of glycocalyx production by
      Staphylococcus aureus in mouse skin: does S. aureus generally produce a biofilm
      on damaged skin?
AB  - BACKGROUND: Bacteria that adhere to damaged tissues encase themselves in a
      hydrated matrix of polysaccharides, forming a slimy layer known as a biofilm.
      This is the first report of detection of glycocalyx production by Staphylococcus
      aureus using confocal laser scanning microscopy (CLSM) on damaged skin tissues.
      OBJECTIVES: To analyse glycocalyx production by S. aureus cells on damaged skin
      tissues and the influence of polymorphonuclear leucocytes (PMNs) and various
      antimicrobial agents on its production using CLSM in cyclophosphamide (Cy)
      treated (neutropenic) or non-Cy-treated (normal) mice. METHODS: S. aureus cells
      were inoculated on damaged skin tissues in neutropenic or normal mice with or
      without topical application of antimicrobial agents. S. aureus cells were stained
      with safranine, and positive staining with fluorescein isothiocyanate-conjugated
      concanavalin A was considered to indicate the presence of glycocalyx. RESULTS:
      All S. aureus cells tested on damaged skin tissues formed microcolonies encircled
      by glycocalyx. The colony counts of S. aureus cells on croton oil dermatitis in
      normal mice treated with 2% fusidic acid ointment were about 100 times lower than
      those in neutropenic mice (control). CONCLUSIONS: As S. aureus cells can
      generally produce a biofilm on damaged skin tissues, antimicrobial agents may not
      eradicate S. aureus cells without the help of PMNs. S. aureus glycocalyx may play
      a crucial role in colonization and adherence to damaged skin tissues.

PMID- 12410698
TI  - Long-term follow-up of leucoderma patients treated with transplants of autologous
      cultured melanocytes, ultrathin epidermal sheets and basal cell layer suspension.
AB  - BACKGROUND: In vitiligo and piebaldism the lack of melanin in the epidermis is
      due to the fact that melanocytes are missing. The patients suffer psychologically
      and the white areas have lost the part of the skin barrier protection normally
      provided by the melanocytes. Medical treatments are ineffective in many of the
      patients, and surgical methods have therefore been developed. OBJECTIVES: It is
      important to investigate the long-term results and factors that might influence
      the outcome of melanocyte transplantations in order to form a basis for guidance
      in the selection of patients who will benefit most from the treatments. METHODS:
      A follow-up of 132 patients who had been treated by transplantation on 176
      occasions in total, 1-7 years previously, was carried out by questionnaires and
      clinical examinations. We investigated the responses in five types of leucoderma
      to three different transplantation methods: autologous cultured melanocytes,
      ultrathin epidermal sheets and basal layer cell suspension. RESULTS: Stable types
      of leucoderma, i.e. segmental vitiligo and piebaldism, responded in most cases
      with 100% repigmentation, regardless of the surgical method used. For these types
      of leucoderma surgery seems to be the method of choice. The largest group,
      vitiligo vulgaris, was thoroughly scrutinized and three statistical models were
      used to analyse the data. The ultrathin epidermal sheet method gave somewhat
      better overall results, but was the method that gave the worst outcome in knee
      and elbow areas, emphasizing the importance of the right choice of method
      depending on the anatomical location to be treated. Irrespective of the method,
      fingers and elbows were the most difficult areas to repigment. The trunk and the
      arms and legs (not including elbows and knees) responded best. Patients with
      increasing and/or extensive vitiligo vulgaris more often showed incomplete
      repigmentation. They also had a lower chance of retaining their repigmentation
      compared with those with less extensive vitiligo. Patients in whom untreated
      white lesions had increased in recent years tended to respond less well to
      transplantation compared with patients with unchanged or decreased lesions.
      Within the vitiligo vulgaris group, patients with short disease duration or with
      small total vitiligo area responded best to transplantation. The subgroup of
      vitiligo vulgaris patients with hypothyroidism tend to respond less well to the
      transplantation and they were generally older at vitiligo onset. This information
      is of great importance for the selection of patients and when informing about the
      chances of improvement after transplantation. Slight hyperpigmentation was
      common, especially when ultrathin epidermal sheets had been used. No scars or
      indurations were seen in treated areas. CONCLUSIONS: Transplantations are the
      methods of choice in stable types of leucoderma. Progressive, widespread vitiligo
      vulgaris should never be selected for transplantation.

PMID- 12410699
TI  - Clinical and histopathological spectrum of cutaneous vasculitis in rheumatoid
      arthritis.
AB  - BACKGROUND: Cutaneous manifestations are the most frequent, and often the initial
      feature of extra-articular involvement in patients with rheumatoid vasculitis.
      OBJECTIVES: The purpose of the study was to evaluate the clinical and
      histological spectrum of cutaneous vasculitis and the associated systemic
      involvement in patients with rheumatoid vasculitis. METHODS: Among 525 patients
      with rheumatoid arthritis, 20 tissue specimens with histologically proven
      cutaneous necrotizing vasculitis from 11 patients were investigated by studying
      the types and levels of affected vessels and related clinical features. RESULTS:
      Small-vessel vasculitis identified as dermal necrotizing venulitis was found in
      10 patients, clinically characterized by palpable purpura, maculopapular
      erythema, erythema elevatum diutinum and haemorrhagic blisters. Arteritis
      histologically resembling cutaneous polyarteritis nodosa, clinically
      characterized by subcutaneous nodules, livedo reticularis, atrophie blanche and
      deep ulcers was identified in four patients all with systemic complications.
      Coexistence of venulitis and arteritis was identified in three patients.
      Different cutaneous vasculitic manifestations often coexisted and recurred in the
      same patient. Three patients with systemic complications of mononeuritis
      multiplex (two of three), interstitial pulmonary fibrosis (two of three) and
      abdominal microaneurysms (one of three) died within 1 year of onset of the
      cutaneous vasculitis. Immunofluorescence demonstrated vessel wall deposition of
      IgM and/or complement in six of the seven patients examined. CONCLUSIONS:
      Features of cutaneous rheumatoid vasculitis overlapping both the characteristics
      of cutaneous necrotizing venulitis and cutaneous polyarteritis nodosa together
      with coexistence of these different type of vasculitis in the same or different
      lesional skin account for the associated diverse cutaneous vasculitic
      manifestations. Although dermal venulitis (leucocytoclastic vasculitis) was the
      most common presentation, the presence of leucocytoclastic vasculitis in
      rheumatoid patients did not necessarily indicate a favourable prognosis.
      Associations with mononeuritis multiplex and bowel involvement had a fatal
      prognosis, while patients with superficial dermal venulitis without other extra
      articular involvement may follow a favourable prognosis.

PMID- 12410700
TI  - Comparison of different activity parameters in atopic dermatitis: correlation
      with clinical scores.
AB  - BACKGROUND: Several laboratory markers have been described to correlate
      positively with disease activity of atopic dermatitis (AD). These include soluble
      adhesion molecules and eosinophil granular proteins. Although the correlation of
      these parameters with the severity and extent of skin involvement has been
      repeatedly studied in the past, no systematic investigation has been performed
      over a lengthy period of time. In addition, no subjective disease parameters
      recorded by the patient have been included in studies dealing with disease
      activity. OBJECTIVES: To assess the validity of different objective and
      subjective parameters [soluble E-selectin (sE-selectin), soluble vascular cell
      adhesion molecule-1 (sVCAM-1), eosinophil cationic protein (ECP), urinary nitrate
      excretion (reflecting endogenous nitric oxide formation) and the patients'
      impressions of pruritus, sleeplessness and skin status] as markers of AD disease
      activity. METHODS: Twenty patients were examined for 1 year and their skin status
      was evaluated by an established score (SCORAD). sE-selectin, sVCAM-1 and ECP were
      analysed by commercial test kits. Urinary nitrate concentration was measured by
      gas chromatography-mass spectrometry. The subjective parameters, pruritus,
      sleeplessness and impression of skin status, were recorded by the patients on a
      visual analogue scale. RESULTS: In this long-term trial, only sE-selectin and the
      subjective parameters showed a statistically significant correlation with the
      SCORAD score. CONCLUSIONS: Our data indicate that basic clinical scoring remains
      a most effective and relevant method of recording skin disease activity in AD.

PMID- 12410701
TI  - Reliance on erythema scores may mask severe atopic dermatitis in black children
      compared with their white counterparts.
AB  - BACKGROUND: The prevalence of atopic dermatitis (AD) has been shown to be higher
      in London-born black Caribbean children than in their white counterparts, but
      little is known about the severity of the disease. OBJECTIVES: To carry out a
      longitudinal survey to investigate potential risk factors for AD severity in
      children. We report our findings in relation to differences in disease severity
      between white and black children and the effect of inclusion and exclusion of
      erythema scores on this comparison. METHODS: The recruited children were
      identified by their general practitioners (GPs) as having presented with AD, and
      the U.K. diagnostic criteria for AD were used to verify the diagnosis. Interview
      and clinical examination of children took place up to four times, 6 months apart.
      Each time, the same observer assessed AD severity using the SCORAD (SCORe Atopic
      Dermatitis) index. Potential risk factors and confounders were evaluated with a
      five-page questionnaire. Non-parametric tests were used for statistical analysis
      and the study participant remained the unit of the analysis. RESULTS: In total,
      137 children (82 urban and 55 rural) were recruited, and each seen up to four
      times. This gave 380 observations (69% of an expected 548). The urban population
      contained 42 (51%) white children, 26 (32%) black children and 14 (17%) from
      other races. The rural population was entirely white. The 14 children from other
      races were completely excluded from the statistical analysis. The black children
      were all born in the U.K. On crude analysis, children with black skin showed a
      non-significantly lower risk of severe disease when compared with white children
      (odds ratio, OR 0.84; 95% confidence interval, CI 0.4-1.76; P = 0.65), while a
      highly significantly increased risk was found after adjusting for erythema score
      (OR 5.93; 95% CI 1.94-18.12; P = 0.002). The difference remained significant even
      after controlling for other potential confounders. CONCLUSIONS: Black children
      with AD are about six times more at risk of having severe AD than their white
      counterparts. GPs and dermatologists should note that erythema can be a
      misleading indicator of severity in black children. Difficulties of assessment
      due to skin pigmentation might mean that severe cases are not being detected and
      appropriately treated.

PMID- 12410702
TI  - Evaluation of a 1-h exposure time to mechlorethamine in patients undergoing
      topical treatment.
AB  - BACKGROUND: Mechlorethamine is frequently used in the treatment of cutaneous
      lymphoma, but its application is limited in 30-80% of cases because of cutaneous
      intolerance. Reducing the concentration to avoid this side-effect has been only
      modestly successful. OBJECTIVES: To investigate whether a shorter application
      period could reduce the frequency of intolerance. METHODS: In an open prospective
      study in 39 patients with cutaneous T-cell lymphoma or parapsoriasis,
      mechlorethamine was applied according to the usual practices of the participating
      physicians (number of weekly applications, treatment confined to lesions or
      performed over the entire body) and then washed off after 1 h in all cases.
      RESULTS: Cutaneous intolerance was observed in 19 of 39 patients (49%). Six of
      these patients showed allergic contact dermatitis to mechlorethamine after a mean
      period of 9.3 weeks, while the other 13 developed irritant contact dermatitis
      after a longer period. Cutaneous intolerance did not differ significantly
      according to the number of applications per week or the extent of body area
      treated. The therapeutic response rate was 69%, and no difference in therapeutic
      efficacy was noted between daily and intermittent applications. CONCLUSIONS:
      Comparison with published studies showed no significant difference in the number
      of cases of cutaneous intolerance after short-term application, although their
      occurrence was delayed. Therapeutic response was decreased appreciably by short
      term application as compared with results in the literature.

PMID- 12410703
TI  - Evidence that superficial basal cell carcinoma is monoclonal from analysis of the
      Ptch1 gene locus.
AB  - BACKGROUND: Superficial basal cell carcinoma (BCC) arises as an apparently
      multifocal proliferation of tumour nests attached to the epidermis, which is at
      odds with a monoclonal origin. Computer-assisted reconstruction shows that these
      nests join in three dimensions, but it remains unknown whether this tumour is
      monoclonal. An early event in BCC formation, loss of heterozygosity (LOH) at the
      Patched 1 (Ptch1) locus, can be used as a tool to address whether this tumour is
      monoclonal. OBJECTIVES: To determine whether superficial BCC is monoclonal by
      analysing individually microdissected superficial BCC nests and looking for the
      same pattern of LOH in each. METHODS: Six cases of superficial BCC were analysed
      for LOH at the Ptch1 gene locus using the D9S287 microsatellite marker. Identical
      allelic patterns were sought in each nest from a given tumour. These patterns
      were no allelic loss, loss of the shorter allele or loss of the longer allele,
      each with a respective probability of occurrence, as estimated from published
      findings. RESULTS: All cases were informative. Four cases showed no LOH in each
      nest and two showed loss of the same allele. If these nests arose independently,
      then the probability of this result was between 4 x 10-11 and 2 x 10-14. The lack
      of LOH, seen in four cases, could be due to monoclonal expansion of a cell
      retaining both D9S287 alleles, or due to a polyclonal proliferation. Therefore, a
      separate analysis excluding these cases was done, giving a probability of between
      2.2 x 10-4 and 1.0 x 10-7. CONCLUSIONS: These probabilities were so extreme that
      it was unlikely that the nests arose independently, thus providing the first
      molecular evidence that superficial BCC is monoclonal.

PMID- 12410704
TI  - An immunohistochemical and ultrastructural study of syringocystadenoma
      papilliferum.
AB  - BACKGROUND: Syringocystadenoma papilliferum is a benign hamartomatous tumour of
      the skin. The histogenesis of this tumour is still controversial. There have been
      few reports regarding immunohistochemical investigations using only a limited
      range of antibodies and ultrastructural studies on this rare tumour. OBJECTIVES:
      To elucidate the immunohistochemical and ultrastructural properties of this
      tumour. METHODS: We investigated the immunohistological patterns of 12 different
      anticytokeratin (CK) antibodies and several other markers in five cases of this
      tumour, comparing them with the patterns in adult sweat glands. One of these
      cases was also evaluated ultrastructurally. RESULTS: The luminal columnar cells
      of the tumour were mostly positive for CK7 and more than 70% were positive for
      CK19. These cells showed the heterogeneous expression of CK1/5/10/14, CK14 and
      CK5/8. These patterns were also observed in the luminal cells in the secretory or
      the ductal portion of the adult sweat glands. The basal cuboidal cells of the
      tumour almost constantly expressed CK1/5/10/14, CK5/8, CK14 and CK7 (except for
      one case), similar to the patterns of basal cells in the transitional portion and
      myoepithelial cells in the sweat glands. However, the basal tumour cells
      expressed CK19 and vimentin heterogeneously, and alpha-smooth muscle actin
      focally (three cases). Ultrastructurally, the constituent epithelial cells were
      mainly divided into three types: luminal cells, basal cells and clear cells. The
      luminal tumour cells bore features of the secretory or ductal luminal cells of
      sweat glands, although they were somewhat immature in appearance. The basal
      tumour cells were fundamentally basaloid in nature. The clear cells were
      undifferentiated or primitive in appearance, suggesting stem or progenitor cell
      properties. Transitional forms between the clear cells and the other two cell
      types were also identified. CONCLUSIONS: The tumour epithelium was composed of
      several cell types demonstrating various developmental stages from the primitive
      clear cells to the basal cells demonstrating a tendency to differentiate toward
      basal cells in the apocrine transitional portion or myoepithelial lineage, or
      luminal cells toward the ductal or secretory epithelium. These results support
      the classical concept that syringocystadenoma papilliferum is a hamartomatous
      tumour that arises from pluripotent cells.

PMID- 12410705
TI  - Cosmetic camouflage advice improves quality of life.
AB  - BACKGROUND: The subjective benefit of attendance at cosmetic clinics has not
      previously been reported. OBJECTIVES: To assess the effect on perceived quality
      of life (QoL) of cosmetic camouflage advice. METHODS: In a three-centre study,
      135 individuals were invited to complete a dermatology-specific QoL measure, the
      Dermatology Life Quality Index (DLQI), before and 1 month after their first visit
      to a cosmetic camouflage clinic. RESULTS: Eighty-two completed DLQI
      questionnaires were returned before the camouflage clinic appointment, and 56
      corresponding questionnaires were returned 1 month after. The mean age of
      responders was 50 years, and the mean duration of their skin conditions was 15
      years. The main conditions seen were pigmentary disorders (29%), scars (22%) and
      vascular disorders (13%). There was a significant difference in mean DLQI scores
      before and after the clinic visit (9.1 vs. 5.8, P = 0.0001). CONCLUSIONS: When
      assessed at 1 month, attendance at a cosmetic camouflage clinic appears to
      improve QoL significantly.

PMID- 12410706
TI  - Non-melanoma skin cancer risk in the Queensland renal transplant population.
AB  - BACKGROUND: Non-melanoma skin cancer (NMSC) is an important complication of solid
      organ transplantation, especially in areas of high ultraviolet light exposure.
      Registry data may underestimate the scale of the problem. OBJECTIVES: A single
      observer study of a Queensland renal transplant population was conducted between
      July 1999 and April 2000 utilizing both cross-sectional and retrospective data.
      The aims were to determine accurately the risk of NMSC following renal
      transplantation and compare this with currently available registry data. PATIENTS
      AND METHODS: A structured interview and full skin examination was completed by
      398 renal transplant recipients. Case notes and histology reports were examined
      for details of previous skin tumours. Independently collected data on 341
      subjects from the Australia and New Zealand Dialysis and Transplantation Registry
      (ANZDATA) were also examined. RESULTS: One hundred and eighty-seven of 361
      (51.8%) transplant recipients of Fitzpatrick skin types I-IV had developed 3979
      histologically diagnosed NMSCs since first transplantation. The ratio of SCC/BCC
      was reversed from 1 : 3.7 before transplantation to 2 : 1 after transplantation.
      NMSC increased with duration of immunosuppression; 29.1%, 52.2%, 72.4% and 82.1%
      of those immunosuppressed for < 5, 5-10, 10-20 and > 20 years, respectively, had
      developed at least one tumour. The ANZDATA registry under-recorded the numbers of
      patients with NMSC by 28.4% and gave no indication of tumour numbers.
      CONCLUSIONS: NMSC is a greater clinical problem in renal transplant recipients
      living in subtropical Queensland, Australia, than is shown by currently available
      registry data. This has implications for the development of prevention and
      surveillance strategies.

PMID- 12410707
TI  - Taking treatment to the patient: development of a home TL-01 ultraviolet B
      phototherapy service.
AB  - BACKGROUND: While most patients requiring phototherapy can attend for hospital
      based out-patient ultraviolet (UV) B therapy, a significant number cannot attend
      because of geographical, work, economic and other reasons. OBJECTIVES: To
      determine whether there was a need for home phototherapy in the Tayside area and,
      if so, to establish protocols and then to assess if such a service would be
      workable. METHODS: Patients referred from dermatology out-patient clinics in
      Tayside for narrow-band UVB (TL-01) phototherapy completed a pilot questionnaire
      that was followed by a two-phase project. In phase 1, patients with psoriasis
      were trained to use the home phototherapy equipment (HoPE) within the hospital
      department under nursing supervision while a teaching package and protocols were
      developed. In phase 2, home phototherapy was made available for patient use in
      the community, supported by a specialist home phototherapy nurse. Waldmann UV100
      home therapy units were used, with accurate dosimetry. Detailed treatment records
      were kept and questionnaires were used to assess acceptability and costs of
      therapy. RESULTS: Fifty-two pilot questionnaires were completed. Forty-two per
      cent of respondents found hospital phototherapy inconvenient and 75% felt
      phototherapy at home would be helpful. In phase 1, seven of 10 patients trained
      to use the HoPE completed therapy with the HoPE unit alone, reaching minimal
      residual activity (MRA) or clearance in a median of 18 exposures (median dose
      10.38 J cm-2). In phase 2, 32 courses of home phototherapy were given to 30
      patients. Of 23 with psoriasis, 18 reached clearance or MRA in a median of 22.5
      exposures (median dose 9.84 J cm-2). Although self-reported erythema rates
      appeared higher than expected, all post-treatment questionnaire respondents would
      choose home phototherapy over hospital therapy if required in the future.
      CONCLUSIONS: UVB (TL-01) home phototherapy is a useful practical development that
      has fulfilled a need in our catchment area. Where appropriate training and
      support teams are available it appears to be similar in effectiveness to hospital
      therapy, to be safe and to be cost-effective for patients.

PMID- 12410708
TI  - Response of psoriasis to sunbed treatment: comparison of conventional ultraviolet
      A lamps with new higher ultraviolet B-emitting lamps.
AB  - BACKGROUND: Sunbeds fitted with conventional ultraviolet (UV) A lamps that have
      about 0.7% UVB emission are widely used by patients with psoriasis even though
      they are minimally effective. A new fluorescent sunbed lamp has been developed
      that emits a higher proportion of UVB (4.6%) than conventional lamps and also
      requires shorter exposure times to achieve equivalent erythema. OBJECTIVES: To
      perform a randomized, within-patient comparison of conventional sunbed lamps
      (Cleo Performance) with the new lamps (Cleo Natural) in the treatment of
      psoriasis. METHODS: A sunbed and canopy unit were modified to allow exposure to
      Cleo Performance lamps on one side of the body (front and back) and Cleo Natural
      lamps to the other side of the body. Two studies were done. In study 1, equal
      erythemal doses were given from the two lamp types. In study 2, equal exposure
      times were given. We treated 34 patients with psoriasis, giving 12 exposures over
      a period of 4 weeks. Assessment was made using a modified Psoriasis Area and
      Severity Index (PASI) score, individual plaque assessment and patient
      questionnaire. RESULTS: Fourteen patients completed each study. In study 1, there
      was no significant difference in median improvement in half-body PASI score for
      the two lamp types. In study 2, there was a significant difference in PASI score
      improvement between the two lamps (median Cleo Performance change minus median
      Cleo Natural change was - 2.20; 95% confidence interval - 3.75 to - 0.65; P =
      0.006). CONCLUSIONS: That no difference in response was found when equal
      erythemal doses were given suggests that the spectral emission of the Cleo
      Natural lamp is of no greater advantage for clearance of psoriasis than
      conventional lamps. However, the Cleo Natural lamps are more erythemally
      powerful, and exposure times similar to those used in conventional sunbeds result
      in a significant improvement of psoriasis. The risk of non-melanoma skin cancer
      from different patterns of exposure to Cleo Natural lamps can be estimated using
      established numerical models.

PMID- 12410709
TI  - A randomized, observer-blinded trial of twice vs. three times weekly narrowband
      ultraviolet B phototherapy for chronic plaque psoriasis.
AB  - BACKGROUND: The optimum treatment frequency for narrowband (TL-01) ultraviolet B
      (NB-UVB) in psoriasis is not yet known. We have previously found three times
      weekly to be preferable to five times weekly treatment in our population.
      OBJECTIVES: To compare twice weekly with three times weekly NB-UVB phototherapy
      in chronic plaque psoriasis. METHODS: In an observer-blinded, randomized
      comparison, patients with chronic plaque psoriasis referred from dermatology out
      patient clinics in Tayside for NB-UVB phototherapy received either twice weekly
      (Monday and Friday) or three times weekly (Monday, Wednesday and Friday) whole
      body NB-UVB phototherapy following our standard departmental treatment protocol.
      Treatment was continued to clearance or until the fourth treatment after minimal
      residual activity (MRA) was first documented. Number of days in treatment, number
      of treatments, total dose and time to relapse were recorded. RESULTS: In total,
      113 patients were recruited, skin phototypes I-III: 58 in the twice weekly and 55
      in the three times weekly group. Forty patients in the twice weekly group reached
      clearance/MRA, as did 44 in the three times weekly group. It took 1.5 (95%
      confidence interval 1.3-1.7) times longer to reach clearance/MRA with twice
      weekly therapy, a geometric mean of 88 vs. 58 days (P < 0.0001). Small
      differences in numbers of treatments and total dose to reach clearance tended to
      favour three times weekly therapy, but these were not significant. CONCLUSIONS:
      Three times weekly NB-UVB clears psoriasis significantly faster than twice weekly
      treatment, and therefore is preferable for most patients.

PMID- 12410710
TI  - Narrowband (TL-01) ultraviolet B phototherapy for pruritus in polycythaemia vera.
AB  - BACKGROUND: There are several reports of the efficacy of broadband ultraviolet
      (UV) phototherapy in the treatment of pruritus associated with polycythaemia
      vera. OBJECTIVES: To evaluate whether narrowband (TL-01) UVB phototherapy is also
      effective in treating this condition. METHODS: Ten patients with pruritus
      associated with polycythaemia vera were treated with narrowband (TL-01) UVB
      phototherapy. The first irradiation dose was 2/3 of the minimal erythema dose;
      the treatment schedule consisted of three irradiation sessions per week, with
      dose increments of 10% each session for skin types I and II, and 15% for skin
      types III and IV. RESULTS: Patients reported a marked relief of symptoms after an
      average of six treatments (median cumulative dose 1851.52 mJ cm-2, range 1180.4
      2468.4). A complete remission of the pruritus occurred within 2-10 weeks of
      treatment (median cumulative dose 5371.46 mJ cm-2, range 3271.2-7336.3) in eight
      of 10 patients. Two patients had only a partial and temporary relief of pruritus
      after two cycles of treatment and a cumulative dose of 3271.2 mJ cm-2.
      CONCLUSIONS: Narrowband UVB phototherapy is effective for treatment of pruritus
      associated with polycythaemia vera, and has the advantage of being less
      erythemogenic than broadband UVB.

PMID- 12410711
TI  - There is no clear association between low serum ferritin and chronic diffuse
      telogen hair loss.
AB  - BACKGROUND: Low iron stores are considered a possible cause of chronic diffuse
      telogen hair loss in women. Estimation of serum ferritin is recommended as part
      of the initial assessment when women present with chronic diffuse telogen hair
      loss, and iron supplementation therapy is commonly recommended for those found to
      have low iron stores. OBJECTIVES: To evaluate the relationship between low serum
      ferritin (</=20 micro g L-1) and chronic diffuse telogen hair loss in women.
      METHODS: Between 1997 and 1999, 194 consecutive women who presented to a
      specialist hair clinic were assessed for diffuse telogen hair loss of greater
      than 6 months duration. All underwent biochemical investigations that included
      serum ferritin and had two 4-mm punch biopsies taken from the vertex of the
      scalp. One biopsy was sectioned horizontally and the other vertically. RESULTS:
      Twelve women were found to have a serum ferritin of 20 micro g L-1 or less
      (6.2%). Androgenetic alopecia was found on scalp biopsy in seven of these 12
      women, while the other five women had normal histology. The five women with low
      iron stores and normal histology were treated with iron supplementation alone.
      This was continued until the serum ferritin was > 20 micro g L-1. Cessation or
      reversal of hair loss was not seen in any of these women. CONCLUSIONS: No direct
      relationship between low serum ferritin and hair loss can be established. The
      usefulness of serum ferritin in the routine investigation of women with chronic
      diffuse telogen hair loss is unclear, as is the role of iron supplementation
      therapy in the management of hair loss.

PMID- 12410712
TI  - Fatal bacteria granuloma after trauma: a new entity.
AB  - In the past 20 years, more than 20 cases of a type of granulomatous disease have
      been noticed by dermatologists in different areas of China. The patients had
      these features in common: (i) the lesions followed a slight trauma to the face;
      (ii) they were spreading dark-red plaques without pus or ulceration; (iii) new
      lesions appeared near to or far from the original lesion; (iv) histopathology
      showed histiocytic granuloma; (v) the patients had severe headache and clouding
      of consciousness during the later stages of the disease; (vi) all patients died
      within 1.5-4 years; (vii) treatment with prednisone led to some healing of the
      lesions but accelerated death; and (viii) all patients were from rural areas. We
      examined the tissues from two similar patients by electron microscopy and
      identified two kinds of bacteria as a possible cause of the disease. One was an
      anaerobic actinomycete, the other was Staphylococcus capitis. The anaerobic
      actinomycete was sensitive to lincomycin (a forerunner of clindamycin). After a 5
      month therapy with lincomycin, one patient survived. We infer that the cause of
      death is the unknown anaerobic actinomycete. Because the disease is very severe,
      we suggest the name 'fatal bacteria granuloma after trauma' to draw attention.

PMID- 12410713
TI  - Localized heat urticaria in a patient is associated with a wealing response to
      heated autologous serum.
AB  - We report a case of localized heat urticaria in a 71-year-old woman who developed
      weals and loss of consciousness after taking a bath. Exposing her skin to heat at
      40 degrees C or immersing her hands in water at 40 degrees C produced urticarial
      lesions and increased her plasma histamine level. Desensitization with hot water
      improved her symptoms and normalized her plasma histamine level after heat
      challenge. An intracutaneous injection of her serum produced no reaction, while
      an injection of her serum that had been heated at 40 degrees C for 15 min induced
      a weal flare response. Further examination revealed that the weal-inducing
      activity of her heated serum remained for at least for 6 h and that treatment of
      her serum at 60 degrees C for 2 h did not abrogate its weal-inducing activity.
      These findings indicate that certain materials in her serum that are activated by
      heat are responsible for the development of her anaphylactic and urticarial
      reactions and that these reactions may be mediated by histamine.

PMID- 12410714
TI  - A case of primary cutaneous CD30+ T-cell lymphoproliferative disorder with
      features of granulomatous slack skin disease.
AB  - We present a patient with primary CD30+ cutaneous T-cell lymphoma whose
      histological and clinical features overlapped with those of granulomatous slack
      skin disease (GSSD). A 26-year-old woman had infiltrative erythema on the
      abdominal wall and an incurable ulcerative lesion on the left knee. Her skin
      progressively became atrophic and pendulous, showing a hyperpigmented appearance
      over almost the whole body. Histopathologically, a dense lymphoid cell infiltrate
      accompanying numerous macrophages and multinucleated giant cells (MGC) extended
      into the subcutaneous tissue. Most lymphoid cells were small and positive for T
      cell markers. Some relatively large atypical cells were scattered in the lesion,
      most of which (60%) were positive for CD30. T-cell receptor-beta gene
      rearrangement was confirmed in the abdominal lesion. MGC infiltrated more
      dominantly into a deeeper layer of the skin with the elastic fibres there almost
      completely disappearing. Immunoreactivity for CD30 of MGC was negative and
      overexpression of elastolytic metalloproteinases was observed. The association
      between primary cutaneous CD30+ lym- phoproliferative disorders and GSSD has not
      previously been reported. Overexpression of elastolytic metalloproteinases in MGC
      contributes to the disappearance of the elastic fibres and enhances the severity
      of the clinical course.

PMID- 12410715
TI  - Granular parakeratosis: four paediatric cases.
AB  - Axillary granular parakeratosis (GP) was first described in 1991 as a peculiar
      eruption presenting with erythematous hyperpigmented and hyperkeratotic papules
      and plaques of the cutaneous folds frequently associated with pruritus.
      Histopathology shows a characteristic picture with a conspicuous granular
      appearance of the parakeratotic horny layer. Until now, only 24 adults, mainly
      women aged over 40 years, have been reported with GP. We demonstrate that this
      condition can also occur in young children. Four children aged between 10 and 24
      months had asymptomatic hyperpigmented scaling papules 2-3 mm in diameter located
      on the groin, lower back, buttocks and flanks. In all cases the mothers reported
      the habit of frequent washing followed by application of many topical products.
      Biopsy revealed the same features in all four patients: the epidermis showed a
      thickened horny layer with a unique compact parakeratosis with maintenance of the
      stratum granulosum and marked retention of keratohyaline granules throughout the
      stratum corneum.

PMID- 12410716
TI  - Acquired digital arteriovenous malformation: a report of three cases and study
      with epiluminescence microscopy.
AB  - Acquired digital arteriovenous malformation is an abnormal connection between the
      arteriole and venule in the finger, fed by the digital vessels. Lesions are
      characterized by small, slightly raised dark-red macules on the distal part of
      the fingers. In the past, similar cases had been described using the terms
      'cutaneous keratotic haemangioma' and 'periungual and subungual arteriovenous
      tumours'. In this article, we would like to discuss three additional cases that
      were studied using epiluminescence microscopy. Pathological findings and the
      possible pathogenesis are also presented.

PMID- 12410717
TI  - IgG/IgA pemphigus with IgG and IgA antidesmoglein 1 antibodies detected by enzyme
      linked immunosorbent assay.
AB  - Pemphigus is an autoimmune mucocutaneous bullous disease characterized by
      autoantibodies against the cell surfaces of epidermal keratinocytes. Six cases
      with deposition of both IgG and IgA on keratinocyte cell surfaces have been
      reported in the recent literature. We provisionally termed these cases IgG/IgA
      pemphigus. We describe a 42-year-old Japanese woman with clinical and
      histopathological features resembling herpetiform pemphigus who demonstrated in
      vivo bound and circulating anticell surface autoantibodies of both IgG and IgA
      classes on immunofluorescence examination. Enzyme-linked immunosorbent assay
      using baculovirus-expressed recombinant desmoglein (Dsg) 1 and Dsg 3 showed that
      both IgG and IgA antibodies reacted with Dsg1. The reactivity was completely
      adsorbed with preincubation of serum with Dsg1 baculoprotein, further confirming
      the exclusive reactivity of both IgG and IgA antibodies with Dsg1. This is the
      second case of IgG/IgA pemphigus in which the human target antigens for both IgG
      and IgA antibodies have been unequivocally identified. This study provides
      further evidence that IgG/IgA pemphigus is a distinct disease entity.

PMID- 12410718
TI  - Successful treatment of facial plane warts with imiquimod.

PMID- 12410719
TI  - Terra firme-forme dermatosis of the scalp.

PMID- 12410720
TI  - Seborrhoeic wart or basal cell papilloma: what's in a name?

PMID- 12410723
TI  - Linear cutaneous leishmaniasis occurring on a leg affected by tuberculoid
      leprosy.

PMID- 12410722
TI  - A case of cutaneous-type adult T-cell leukaemia/lymphoma showing granuloma
      formation under a parapsoriatic eruption.

PMID- 12410724
TI  - Recalcitrant ulcers in necrobiosis lipoidica diabeticorum healed by topical
      granulocyte-macrophage colony-stimulating factor.

PMID- 12410725
TI  - Multiple fixed drug eruptions due to cetirizine.

PMID- 12410726
TI  - Perforating granuloma annulare presenting on the ears.

PMID- 12410727
TI  - Phakomatosis pigmentovascularis type IIa with generalized vitiligo.

PMID- 12410729
TI  - Is topical tacrolimus effective in alopecia areata universalis?

PMID- 12410728
TI  - Merkel cell carcinoma, Kaposi's sarcoma, basal cell carcinoma and
      keratoacanthoma: multiple association in a patient with chronic lymphatic
      leukaemia.

PMID- 12410730
TI  - Erythematosus actinic lichen planus: a new clinical form associated with oral
      erosive lichen planus and chronic active hepatitis B.

PMID- 12410731
TI  - Chronic erosive herpes simplex virus infection of the penis in a human
      immunodeficiency virus-positive man, treated with imiquimod and famciclovir.

PMID- 12410732
TI  - Hypersensitivity to mosquito bites in association with chronic Epstein-Barr virus
      infection and natural killer (NK) leukaemia/lymphoma with expansion of NK cells
      expressing a low level of CD56.

PMID- 12410733
TI  - Angiopericytomatosis and subcutaneus thrombophlebitis in multiple myeloma.

PMID- 12410734
TI  - A case of IgA pemphigus successfully treated with acitretin.

PMID- 12410735
TI  - Possible causal role of lisinopril in a case of Kaposi's sarcoma.

PMID- 12410736
TI  - Absent lentigines in psoriatic plaques.

PMID- 12410737
TI  - The urological complications of renal transplantation: a series of 1535 patients.
AB  - OBJECTIVE: To determine the incidence of urological complications of renal
      transplantation at one institution, and relate this to donor and recipient
      factors. PATIENTS AND METHODS: A consecutive series of 1535 renal transplants
      were audited, and a database of donor and recipient characteristics created for
      risk-factor analysis. An unstented Leadbetter-Politano anastomosis was the
      preferred method of ureteric reimplantation. RESULTS: There were 45 urinary
      leaks, 54 primary ureteric obstructions, nine cases of ureteric calculi, three
      bladder stones and 19 cases of bladder outlet obstruction at some time after
      transplantation. The overall incidence of urological complications was 9.2%, with
      that for urinary leak or primary ureteric obstruction being 6.5%. One graft was
      lost because of complications, and there were three deaths associated directly or
      indirectly with urological complications. There was no association with recipient
      age, cadaveric vs living-donor transplants, or cold ischaemic times before organ
      reimplantation, although the donor age was slightly higher in cases of urinary
      leak. There was no association with kidneys imported via the UK national organ
      sharing scheme vs the use of local kidneys. The management of these complications
      is discussed. CONCLUSION: The incidence of urological complications in this
      series has remained essentially unchanged for 20 years. The causes of these
      complications and techniques for their prevention are discussed.

PMID- 12410738
TI  - Magnesium status of patients with renal stones and its effect on urinary citrate
      excretion.
AB  - OBJECTIVES: To assess the magnesium status and its effect on urinary citrate
      excretion in patients with renal stones, as they have a low muscular magnesium
      content. PATIENTS, SUBJECTS AND METHODS: Using a magnesium-tolerance test (0.1
      mmol/L MgSO4/kg body weight, delivered intravenously), the magnesium status was
      assessed in 17 patients with renal stones from rural North-east Thailand, and in
      three groups of normal subjects from different environments (i.e. 17 from rural
      Central Thailand, 16 from urban and 14 from rural North-east Thailand).
      Participants with magnesium deficiency (magnesium retention > 50%) were
      supplemented with 300 mg chelated magnesium daily for 1 month and reassessed.
      Their urinary citrate excretion was also measured before and after
      supplementation. RESULTS: Nine of the patients with renal stones were magnesium
      deficient, as were six normal subjects from the same area, whereas only one and
      two of the rural Central and urban North-east Thais had magnesium deficiency. The
      magnesium status of the 13 deficient subjects significantly improved (P = 0.003)
      after supplementation with chelated magnesium. The supplement also caused a
      significant increase in mean (sd) urinary citrate excretion, from 237.7 (173.1)
      to 361.3 (284.1) mg/day (P= 0.012). CONCLUSIONS: These results indicate that
      magnesium deficiency is common among patients with renal stones in rural North
      east Thailand, and that the probable cause is environmental. The increase in
      urinary citrate excretion after magnesium supplementation suggests that magnesium
      is important in renal stone formation, through its effect on citrate metabolism.

PMID- 12410739
TI  - Flexible ureteroscopes: a user's guide.
AB  - OBJECTIVE: To compare, quantitatively and qualitatively, four small-diameter
      flexible ureteroscopes. MATERIALS AND METHODS: Four flexible ureteroscopes from
      different manufacturers, i.e. the DUR-8 (ACMI, Southborough, MA, USA), Olympus
      UPF-3 (Keymed, Southend-on-Sea, UK), Storz 11274AA (Karl Storz GmbH, Tuttlingen,
      Germany) and the Wolf 9 F (Henke Sass Wolf GmbH, Tuttlingen, Germany), were
      assessed quantitatively by measuring the active tip deflection and irrigation
      flow rate with laser fibres (200 micro m, 365 micro m), an electrohydraulic
      lithotripter (1.9 F) and grasping forceps (3 F) in position. They were then
      assessed subjectively by two endourologists who scored them, using a visual
      analogue scale (maximum 10), for insertion, deflection mechanism,
      manoeuvrability, rigidity, image quality and overall satisfaction. RESULTS: All
      the endoscopes are < 9 F at the tip, although the length of the smallest diameter
      (bevelled tip vs section of shaft) was variable. Tip deflection was 87-100% of
      the manufacturers' specifications and decreased by similar percentages with
      instruments in the working channel. The irrigation flow rate was comparable for
      instruments with a 3.6 F working channel (72-88 mL/min with an empty working
      channel), although much greater for the Wolf, which has a 4 F channel (116
      mL/min). Direction and image size were nearly identical, as was the field of
      view, apart from the Wolf (60 degrees vs 90 degrees ). There was agreement in the
      user assessment for three instruments, with overall satisfaction scores being
      Storz (4), ACMI (7.5) and Olympus (8.6), but disagreement in scores for Wolf (1.9
      vs 5.3). CONCLUSIONS: Whilst there were considerable similarities in the
      objective assessment among the instruments, the user assessment showed
      qualitative variability. Thus it is important to try the different instruments
      before selecting one. Additional variables to consider include durability, cost
      and service/warranty, which vary considerably among instruments.

PMID- 12410740
TI  - Nocturia in the Dutch adult population.
AB  - OBJECTIVE: To estimate the prevalence of nocturia in the Dutch adult population,
      its association with sociodemographic and health characteristics, and to assess
      problems experienced by persons with nocturia. SUBJECTS AND METHODS: In spring
      2001 a telephone survey was conducted among a representative sample of 4721 Dutch
      respondents (response 53%). Using questions from the Bristol Lower Urinary Tract
      Symptoms questionnaire respondents were asked about having nocturia and the
      problems they experienced. In addition, questions were asked about
      sociodemographic and health characteristics. RESULTS: The prevalence of nocturia
      (a mean of twice or more/night) among Dutch men and women over 18 years old was
      13%, standardized for age and sex. Women had nocturia more often than men (16% vs
      9%) and the prevalence was positively associated with age, poor health status and
      use of medication. CONCLUSION: The prevalence of nocturia in Dutch men and women
      differs more than reported in earlier studies. The prevalence in the Netherlands
      seems slightly higher than in other Western countries, but Dutch persons with
      nocturia report fewer problems. Nocturia does not occur in isolation and is
      associated with sleep disturbances. It is worthwhile for general practitioners to
      routinely check whether patients who contact them for lower urinary tract
      symptoms or sleeping disorders have nocturia.

PMID- 12410741
TI  - Benign prostatic hyperplasia: the opposite effects of alcohol and coffee intake.
AB  - OBJECTIVE: To assess several lifestyle factors influencing benign prostatic
      enlargement and therefore the severity of benign prostatic hyperplasia (BPH).
      SUBJECTS AND METHODS: In age-stratified cohorts from population-based random
      samples of 882 men (aged 65, 70, 75 and 80 years) each participant completed a
      standardized questionnaire, including weight, height, socio-economic status, use
      of cigarettes, alcohol and coffee consumption. The questionnaire also elicited
      detailed information on the medical history of prostatic and (over the past
      month) lower urinary tract symptoms, applying all questions from the American
      Urology Association instrument. The lifestyle variables were evaluated for
      confounding by multiple logistic regression, controlling for age, relative weight
      and professional education, with those classified as having BPH analysed as the
      dependent variable. RESULTS: The prevalence of surgery for BPH increased with age
      from 15% at 65 years to 41% at 80 years. There was a strong inverse association
      between alcohol intake and men treated surgically for BPH or in 'watchful
      waiting' for surgical intervention, but a positive correlation with coffee
      consumption, and although not significantly, with the number of cigarettes
      smoked. Nevertheless, those who had never smoked have a slightly greater risk of
      BPH than current smokers. The body mass index and professional education were not
      associated with the risk of BPH. CONCLUSIONS: Given the opposite effects of
      coffee and moderate alcohol consumption, together with the increased risk for
      clinical BPH in men with coronary heart disease, coffee constituents, which
      increase the serum concentration of low-density lipoprotein cholesterol, may be
      involved in the pathophysiology of BPH. Further epidemiological studies are
      needed to evaluate whether avoiding coffee intake reduces the risk of BPH.

PMID- 12410742
TI  - Lower urinary tract symptoms: social influence is more important than symptoms in
      seeking medical care.
AB  - OBJECTIVE: To determine associations among lower urinary tract symptoms (LUTS),
      symptom severity, subjective beliefs and social influences when seeking primary
      medical care in men aged > or = 50 years. SUBJECTS AND METHODS: A population
      based survey was conducted among 5052 men aged > or = 50 years, using patient
      registers of 22 general practitioners (GPs) in the Netherlands from November 1999
      to May 2000. The questionnaire contained items concerning age, educational level,
      International Prostate Symptom Score (IPSS), bothersome score (BS), and questions
      from the Health Belief Model on attitude and social influences. The study
      population comprised men with an IPSS openface> 7. The odds ratios (ORs)
      corrected for the IPSS were calculated. RESULTS: In all, 3544 questionnaires
      (70.2%) were returned. Two groups of men with an IPSS openface> 7 were compared:
      those who consulted their GP in the previous 2 years because of voiding problems
      (268 cases) and the controls (272) who did not visit a GP for these symptoms.
      Cases more often thought a physician could improve their condition (OR 2.85),
      appeared to be more often advised by others to seek medical care (OR 6.36) and
      thought more often that this advice influenced their decision (OR 13.95). They
      also had more frequently received information from the media (OR 2.66) which
      affected their attendance (OR 12.52). In a multiple regression analysis, advice
      from others or information from the media were stronger predictors of seeking
      care than the influence of symptoms on daily life, the IPSS or the BS.
      CONCLUSION: Social influences, i.e. advice from others or the media, were more
      important factors in the decision to seek medical care than symptom severity.

PMID- 12410743
TI  - Sacral neuromodulation in functional urinary retention: an effective way to
      restore voiding.
AB  - OBJECTIVE: To determine the long-term efficacy and complications of sacral nerve
      stimulation as an alternative therapy for functional unobstructive urinary
      retention, often considered to be psychogenic and effectively treated by clean
      intermittent catheterization, but for which pelvic floor dysfunction has been
      recognized as a possible cause. PATIENTS AND METHODS: Twenty patients (17 women
      and three men, mean age 48 years) with idiopathic, unobstructive functional
      urinary retention and in whom other forms of therapy had failed, had a pulse
      generator implanted (Medtronic, Minneapolis, MN, USA) and a sacral nerve implant.
      Their mean duration of symptoms was 68 months; 13 patients had chronic pelvic and
      perineal pain associated with their obstructive voiding symptoms. All patients
      were managed with clean intermittent catheterization and pharmacological therapy
      (alpha-blockers) before the procedure. All patients had a percutaneous nerve
      evaluation before the permanent implant, which showed> 50% improvement in their
      symptoms. All patients were evaluated at 1, 6 12, 18 and 24 months, then yearly
      thereafter. The results were assessed both subjectively by patient's symptoms and
      objectively by checking the postvoid residual volume (PVR) and voided volume.
      RESULTS: Eighteen patients were able to void spontaneously with a mean increase
      in voided volume from 48 to 198 mL, and a significant decrease in PVR from 315 to
      60 mL. Eighteen of the patients had a > or = 50% improvement in their symptoms
      and said they would recommend the therapy to a friend or relative. Complications
      occurred in six patients. CONCLUSION: Sacral nerve stimulation is an effective
      and durable new approach to functional urinary retention, with few associated
      complications. Test stimulation provides a valuable tool for selecting patients.

PMID- 12410744
TI  - Urinary catheter 'deflation cuff' formation: clinical audit and quantitative in
      vitro analysis.
AB  - OBJECTIVE: To investigate reports from district nursing staff of difficulty in
      removing long-term urinary catheters (LTCs) because of the formation of a 'cuff'
      on deflating the self-retaining balloon. PATIENTS AND METHODS: Problems
      experienced by district nurses when removing urethral and suprapubic LTCs were
      audited, noting the type of problem, the catheter and any action taken.
      Quantitative in vitro studies were conducted on the deflated self-retaining
      balloons after incubating a similar range of catheters in saline at 37 degrees C
      for 6 weeks, using suprapubic profilometry to assess the resistance to withdrawal
      (retention force). RESULTS: Questionnaires were returned on 154 patients with
      LTCs; 56% had urethral and 44% suprapubic catheters. The catheters were hydrogel
      coated (83%), all-silicone (13%) and PTFE-coated (3%). Twenty-two (14%) of the
      sample reported problems with catheter removal in the previous year, including 15
      (68%) with all-silicone catheters and 15 (68%) with suprapubic catheters; cuff
      formation was noted in 60%. In the laboratory, 10 of the balloons formed a 'cuff'
      on deflation, but there was great variability in the effect this had on the
      retention force, with values of 0.5-3 N for different catheters. CONCLUSIONS:
      Most problems with catheter removal involved all-silicone and suprapubic
      catheters. Suprapubic profilometry confirmed increased resistance to withdrawal
      by formation of a 'cuff' on deflation of the balloon of all-silicone catheters.
      These results suggest that the first choice of catheter material for long-term
      urethral and suprapubic use should be hydrogel-coated latex.

PMID- 12410745
TI  - Changes in molecular forms of prostate-specific antigen during treatment with
      finasteride.
AB  - OBJECTIVE: To study the influence of finasteride treatment on the molecular forms
      of prostate-specific antigen (PSA) in patients with benign prostatic hyperplasia
      (BPH). PATIENTS AND METHODS: Total PSA, free PSA and PSA complexed to alpha1
      antichymotrypsin (PSA-alpha1ACT) were measured in plasma and serum from 40 men
      with BPH and a total PSA of < 20 ng/mL, using in-house and commercial
      immunoassays, before and during treatment with finasteride (30 men) or placebo
      (10 men). RESULTS: The baseline values were not significantly different between
      the groups, with mean (sd) total plasma PSA levels of 3.6 (4.3) and 4.8 (5.9)
      ng/mL in the finasteride and placebo groups, respectively. Finasteride, but not
      placebo, induced a significant reduction in total PSA, free PSA and PSA-alpha1ACT
      levels in plasma and serum (P < 0.001). However, complexed-to-total (c/t) and
      free-to-total (f/t) PSA ratios remained constant in both groups, both in plasma
      and serum, during the follow-up. CONCLUSION: The decrease in total PSA after
      finasteride treatment results from a proportional reduction in its two major
      molecular forms, free PSA and PSA-alpha1ACT, which explains why the c/t and
      f/tPSA ratios do not change significantly despite treatment. This suggests that
      routine analysis of molecular forms of PSA could improve the utility of the
      change in total PSA associated with finasteride for the early diagnosis of
      prostate cancer. It also suggests that any subsequent change in both ratios,
      particularly an increase in c/tPSA or a decrease in f/tPSA ratio, could be
      considered an early sign of neoplastic degeneration rather than a therapeutic
      consequence.

PMID- 12410746
TI  - Prostatitis-like symptoms: one year later.
AB  - OBJECTIVES: To re-survey (after 1 year) men identified in 1999 as having perineal
      and/or ejaculatory pain/discomfort severe enough to suggest a clinical diagnosis
      of chronic prostatitis (using the National Institutes of Health-Chronic
      Prostatitis Symptom Index, NIH-CPSI), and to compare them with an age-matched
      population of men who had no prostatitis-like symptoms in the initial survey, to
      determine the effect of time on specific symptoms associated with the diagnosis
      of chronic prostatitis. SUBJECTS AND METHODS: A comprehensive questionnaire
      incorporating the pain and voiding domains of the NIH-CPSI, and data on
      demographics, medical history, socio-economic status, health-seeking behaviour
      and a quality of life assessment, was sent to 67 men who had reported prostatitis
      like symptoms in the 1999 survey, and to 202 age-matched controls (1 : 3) who
      reported no prostatitis-like symptoms in the same survey. RESULTS: Forty men
      (60%) with previous prostatitis-like symptoms, i.e. a mean (sd) 1999 NIH-CPSI
      pain score of 8.8 (0.4), and 119 (59%) of the control population completed and
      returned the survey. There was no difference in the 1999 demographics (P = 0.82)
      or NIH-CPSI pain score (P = 0.49) between patients who returned the recent
      questionnaire and those who could not be located or declined to complete the
      survey. Fifteen men (38%) identified with prostatitis in 1999 did not report
      similar symptoms in 2000. The initial mean NIH-CPSI pain score (0-21) for the men
      who had resolution of their prostatitis-like symptoms was 7.5 (0.6); 1 year later
      it was 0.73 (0.3). Their mean age was 51.1 (3.9) years and mean duration of
      symptoms 1.1 (0.3) years. Those with persistent symptoms had an initial NIH-CPSI
      pain score of 9.6 (0.5); 1 year later it was 8.68 (0.4), at mean age of 51.4
      (2.5) years and duration of symptoms 2.2 (0.3) years. Four men (3%) in the
      control group who had no symptoms in 1999 reported prostatitis-like symptoms in
      2000; these men had a mean age of 52.5 (5.9) and NIH-CPSI pain score of 7.0
      (0.9). CONCLUSION: About a third of men reporting prostatitis-like symptoms in
      the general population had resolution of their symptoms (usually those with a
      shorter duration and less severe symptoms) 1 year later. The severity of symptoms
      of men with persistent chronic prostatitis remained relatively unchanged over the
      year.

PMID- 12410747
TI  - Hormonal treatment for male-pattern hair loss: implications for cancer of the
      prostate?

PMID- 12410748
TI  - Survival prospects after screen-detection of prostate cancer.
AB  - OBJECTIVE: To ascertain more realistic survival values for screen-detected
      prostate cancer than those in current use which are derived from conventionally
      presenting, usually symptomatic, populations. MATERIALS AND METHODS: Survival
      data for conventionally detected cases were derived from the Surveillance,
      Epidemiology and End Results database for men diagnosed in the years 1983-1988.
      The incidence of screen-detected prostate cancer by age and grade was taken from
      published data. RESULTS: For a cohort of men, initially 55 years old, screen
      detected cases were estimated to outnumber by 2-3-fold, depending on age, those
      detected by conventional means. By assuming various survival characteristics for
      the screen-detected cases the mean lead time was estimated to be 9 years. Because
      screen-detected cases usually have clinically localized disease they are commonly
      advised on survival times derived from conventionally detected cases. Applying
      these survival times over-predicts the number of deaths by factors of at least
      3.4, 1.9 and 1.5 at 65, 75 and 85 years old, respectively. CONCLUSIONS: Screening
      detects prostate cancer a mean of 9 years before clinical presentation. The
      prognosis of screen-detected prostate cancer is considerably better than that of
      conventionally presenting localized disease. The advice given to patients with
      early prostate cancer should take account of this.

PMID- 12410749
TI  - Gleason score on biopsy: is it reliable for predicting the final grade on
      pathology?
AB  - OBJECTIVE: To assess the correlation of the Gleason score on biopsy and the final
      pathology after radical prostatectomy (RP) for prostate adenocarcinoma. PATIENTS
      AND METHODS: In a retrospective analysis within a tertiary-care centre, the
      charts of 537 patients who had undergone radical prostatectomy from April 1989 to
      November 2000 were reviewed. The RPs were undertaken in one institution; 167
      biopsies were taken and interpreted in the referring centres, and 355 were taken
      and interpreted in the authors' institution by up to 15 pathologists. All the
      final pathology specimens were interpreted by the same group of pathologists. The
      main outcome measures were: the pathological report of the biopsy including the
      primary and secondary Gleason grade; the final pathological grade (primary and
      secondary); the margin status; and the identification of the pathologist for the
      biopsy and final pathology. RESULTS: In all, 390 patients had inclusion criteria
      (the Gleason grade before and after RP) available. For the individual scores
      38.2% of tumours were undergraded, 32.6% overgraded and only 29.2% had identical
      grading in preoperative biopsies and final specimens. When grouped into more
      meaningful categories (Gleason 2-4, 5-6, 7 and 8-10) the correlation improved,
      with 48.5% of patients remaining in the same group after RP. For 39 patients the
      same pathologist assessed the biopsy and final specimen; in these cases
      individual scores were identical in 49% and group scores were identical in 64%.
      CONCLUSION: Gleason grading of the prostate biopsy remains a poor predictor of
      pathological outcome. Assessment by the same pathologist reduces the discrepancy
      but over half the patients are under- or overgraded on final pathology.
      Clinicians should be aware of these limitations when using the biopsy Gleason
      grade in decision making.

PMID- 12410751
TI  - Antimicrobial prophylaxis for transrectal prostatic biopsy: a prospective study
      of ciprofloxacin vs piperacillin/tazobactam.
AB  - OBJECTIVE: To compare the efficacy of short-term parenteral prophylaxis with
      piperacillin/tazobactam (P/T) with long-term oral prophylaxis with ciprofloxacin
      in preventing infective complications after transrectal prostatic biopsy (TPB).
      PATIENTS AND METHODS: Patients scheduled for TPB were randomized to receive P/T
      (2250 mg intramuscular) twice daily for 2 days (Group 1), or ciprofloxacin (500
      mg orally) twice daily for 7 days (Group 2), beginning on the evening before the
      procedure in both groups. All patients received a 100-mL phosphate enema 3 h
      before TPB. Evaluation included self-recording of body temperature in the 3 days
      after TPB, and culture of mid-stream urine (MSU) samples taken before and 3 and
      15 days after TPB. Patients with indwelling urethral catheters or taking
      antibiotics or immunosuppressive drugs were excluded, as were patients with
      positive MSU cultures before TPB. RESULTS: Of the 138 evaluable patients, 72
      received parenteral P/T and 66 oral ciprofloxacin. Bacteriuria (> 105 c.f.u./mL)
      after TPB occurred in two of 72 (2.8%) patients in Group 1 and in three of 66
      (4.5%) patients in Group 2; this difference was not statistically significant (P
      > 0.1). However, of the five patients with bacteriuria, two were symptomatic and
      both were in Group 2. Pyrexia occurred in only one patient in Group 2 with
      symptomatic urinary tract infection, and required hospitalization. No other
      patient reported a body temperature openface> 37.5 degrees C or drug-related side
      effects. CONCLUSIONS: This prospective study showed that short-term prophylaxis
      with P/T was associated with a low rate of asymptomatic bacteriuria, requiring no
      further treatment, whereas although the rate was similar on long-term prophylaxis
      with ciprofloxacin patients required further treatment, with one needing
      hospitalization. We recommend short-term prophylaxis with P/T despite its
      disadvantages of cost and parenteral administration.

PMID- 12410752
TI  - Penile scintigraphy with 99mTc-human immunoglobulin G: a novel method for
      distinguishing the unstable and stable phases of Peyronie's disease.
AB  - OBJECTIVE: To investigate the value of penile scintigraphy using 99mTc-human
      immunoglobulin G (IgG) to differentiate the unstable (acute) and stable (chronic)
      phases of Peyronie's disease (PD). PATIENTS AND METHODS: Thirty-two consecutive
      patients (25 with PD and seven without) were evaluated using a detailed sexual
      history, serum chemistry panel, colour Doppler ultrasonography during
      simultaneous intracavernosal injection of 50 mg papaverine and stimulation, and
      99mTc-IgG scanning. When indicated, nocturnal penile tumescence monitoring,
      dynamic infusion cavernosometry, cavernosonography and cavernosal artery systolic
      occlusion pressure were measured. After administering 370 MBq of 99mTc-IgG,
      images were taken at 30 min, 1, 2, 3 and 4 h. The scans were considered positive
      if there was any focal accumulation of radiopharmaceutical consistent with PD
      plaque formation. RESULTS: Eleven of the 25 patients with PD (mean age 56 years,
      sd 8) were in the unstable phase, the remaining 14 being in the stable phase.
      There was a localized increase in 99mTc-IgG activity in 10 patients who had
      unstable PD. There was complete resolution of increased activity in two patients
      at 12 and 13 months of follow-up. Of the 14 patients in the stable phase, 12 (at
      > 1 year) showed neither increased nor decreased 99mTc-IgG activity. In the
      remaining two patients there was increased activity on the plaque side. There was
      no local increase in activity in the control group. CONCLUSION: Inflammatory
      reactions can develop at various intervals during the unstable phase of PD.
      Medical methods should be used during the unstable phase and surgery delayed
      until the stable phase of the disease begins. An objective method of
      differentiating between the phases is therefore important. Penile 99mTc-IgG
      imaging is a new diagnostic approach for confirming the unstable phase of PD.

PMID- 12410753
TI  - Adult paratesticular tumours.

PMID- 12410754
TI  - Alfuzosin in the treatment of high leak-point pressure in children with
      neurogenic bladder.
AB  - OBJECTIVE: To decrease the detrusor leak-point pressure (LPP) of > 40 cmH2O in
      children with a neurogenic bladder, using the alpha1-adrenergic blocking agent
      alfuzosin. PATIENTS AND METHODS: Videocystometry was used to measure the detrusor
      LPP and several other variables before and 3 weeks after the oral administration
      of alfuzosin (2.5-7.5 mg/day) in 17 children (mean age 6.3 years) with an upper
      motor neurone lesion. RESULTS: The mean (sd) detrusor LPP decreased from 68 (37)
      to 46 (31) cmH2O (P < 0.01), reflex volume (defined as the volume at the first
      uninhibited bladder contraction of > 15 cmH2O) increased from 78 (69) to 112
      (118) mL (+ 44%), bladder compliance increased from 9.3 (6.1) to 19.6 (14.6)
      mL/cmH2O (+ 111%), maximal vesical pressure decreased from 84 (40) to 70 (47)
      cmH2O (- 17%), and the mean number of uninhibited bladder contractions decreased
      from 6.3 to 3.5 (- 44%). The therapy was well tolerated; side-effects were rare
      and not severe. Intermittent catheterization could be avoided in six children.
      CONCLUSION: Alfuzosin decreases the detrusor LPP in children with a neurogenic
      bladder caused by an upper motor neurone lesion, significantly and
      therapeutically, and should be considered as an alternative or addition to
      intermittent catheterization and anticholinergic drugs in selected patients.

PMID- 12410755
TI  - Vesico-ureteric reflux in the young infant with follow-up direct radionuclide
      cystograms: the medical and surgical outcome at 5 years old.
AB  - OBJECTIVE: To compare the 5-year outcome of 82 infants with vesico-ureteric
      reflux (VUR) against the initial (< 1 year) and follow-up results of the direct
      radionuclide cystogram (DRC). PATIENTS AND METHODS: An initial DRC was taken at a
      mean age of 0.6 years and the follow-up study at 1.7 years. VUR was graded using
      'one-third bladder volume' grades (BVG) of 'low', 'moderate', 'high' and 'void',
      with 'low' considered the most severe. Renal scintigraphy was used to assess
      renal scarring in 80 of the 82 patients. The outcome at a minimum age of 5 years
      was defined as resolved reflux, those with corrective surgery or those still
      being medically followed. RESULTS: Those being followed comprised 29%, corrective
      reflux surgery 17% and resolved 54% of the patients. Children with VUR grades of
      'high' or 'moderate' (as the worst grade either side) were more likely to have
      resolution than those with 'low' (by four and two times, respectively). Reflux at
      'low' bladder volume was 2.6 times more likely to be associated with renal
      scarring than the other grades combined. 'Low' reflux was present in nine of 14
      children needing surgery. There was a linear relationship between VUR grade and
      the scintigraphic findings. CONCLUSION: The severity of VUR can be assessed from
      the bladder-volume graded DRC. Continuing VUR at 'low' BVG is associated with
      increased renal scarring, resistance to natural resolution and corrective reflux
      surgery.

PMID- 12410757
TI  - An experimental study of self-expanding ureteric metallic stents: macroscopic and
      microscopic changes in the canine ureter.
AB  - OBJECTIVE: To evaluate the efficacy and safety of self-expanding metallic stents
      after insertion into the canine ureter. MATERIALS AND METHODS: Actively expanding
      metallic (Nitinol) stents (diameter 8-10 mm, length 4-6 cm) were placed in eight
      mongrel dogs (18-34 kg). Under general anaesthesia, a midline abdominal incision
      was made and a stent inserted directly into the ureter through a small incision;
      each animal was stented on one side. The dogs were assessed after 6 or 19 days or
      2, 5 (two), 6 (two) and 7 months. Ureteric specimens were evaluated both
      macroscopically and microscopically. RESULTS: Macroscopically there was no
      leakage of urine in any of the animals. On day 6 the inserted stent was patent
      despite blood clots in the mesh. The lumen was smooth and shiny in three dogs
      examined at 5, 6 and 7 months. One of the two dogs assessed at both 5 and 6
      months had hydronephrosis associated with papillary hyper-epithelialization
      inside the stent, while the other animals had no dilatation of the renal pelvis.
      Microscopically there was loss of epithelium and bleeding of the ureteric wall at
      6 days. Epithelial regeneration started after 19 days and was complete in the
      lumen at 2 months, with the stent incorporated into the wall of the ureter.
      Epithelialization was maintained up to 7 months, after which the problem of
      urothelial hyperplasia persisted, but an adequate lumen was maintained by
      epithelial regeneration. This epithelium was smooth and shiny, and composed of
      thin layers of cells. CONCLUSION: Self-expanding metallic stents may be effective
      if hyperplastic epithelialization does not occur, as the stent was epithelialized
      within 2 months and the regenerated epithelium maintained for up to 7 months.
      Metallic stents may be useful for treating patients with renal failure caused by
      ureteric stenosis from malignant tumours.

PMID- 12410756
TI  - Vasopressin and hypercalciuria in enuresis: a reappraisal.
AB  - OBJECTIVE: To test the hypotheses that vasopressin deficiency or hypercalciuria
      are important in polyuric and non-polyuric bedwetting, as nocturnal polyuria is a
      pathogenetic factor in enuresis responsive to antidiuretic therapy with
      desmopressin. SUBJECTS AND METHODS: Vasopressin deficiency has been implicated as
      a cause of nocturnal polyuria, but measurements of vasopressin in plasma have
      given contradictory results, because the hormone is released in pulses. Urinary
      levels reflect the secretion over longer periods. Hypercalciuria has also been
      proposed as a pathogenetic factor. Twenty-eight enuretic children who responded
      to desmopressin therapy with or without added anticholinergic agents (diuresis
      dependent enuresis, DE), 15 children with therapy-resistant enuresis (not
      diuresis-dependent, NDE) and 51 continent controls were assessed. Urinary
      vasopressin, calcium and osmolality were measured in the morning after a 12-h
      thirst provocation. Urine production was recorded for 2 days. RESULTS: Because
      most data were not normally distributed, the values are expressed as the median
      (range). There were no differences in urine osmolality; i.e. con-trols 919 (636
      1232), DE 849 (462-1149), NDE 968 (664-1191) mOsml/kg); vasopressin, controls 34
      (8-983), DE 26 (9-295), NDE 50 (9-116) pmol/L; or calcium excretion (expressed as
      the calcium/creatinine ratio), controls 0.16 (0.01-0.71), DE 0.14 (0.04-0.67),
      and NDE 0.23 (0.03-0.69). The DE group produced more urine, at 18.4 (9.2-52.5)
      mL/kg/day, than the other groups, i.e. control 12.7 (8.3-42.8) and NDE 12.1 (6.3
      36.8) mL/kg/day (P = 0.008). CONCLUSION: All enuretic children with nocturnal
      polyuria do not have vasopressin deficiency. The urinary calcium excretion does
      not differ between enuretic and dry children.

PMID- 12410758
TI  - Progesterone: a novel adjunct to intravesical chemotherapy.
AB  - OBJECTIVE: To investigate the effect of progesterone on multidrug-resistant
      urothelial cell lines, as the failure of intravesical chemotherapeutic drugs is
      often caused by multidrug resistance (MDR), mediated by the drug efflux pump P
      glycoprotein (PGP), the function of which can be down-regulated by various
      compounds including steroid hormones. MATERIALS AND METHODS: Two urothelial cell
      lines (RT112S and MGH-U1S) and their MDR sublines (RT112R, to cisplatin; and MGH
      U1R, a cell line expressing PGP) were used to assess the cytotoxic effects of
      progesterone, epirubicin and their combination. Cytotoxicity was assessed using a
      tetrazolium-based assay and in situ confocal microscopy. RESULTS: Cell lines
      sensitive to epirubicin (MGH-U1S, RT112S and RT112R) required a much lower dose
      of epirubicin to kill half the cells than did the MDR cell line. Progesterone was
      intrinsically cytotoxic to all cell lines with little difference among them.
      Combined therapy had no cumulative effect on epirubicin-sensitive cell lines, but
      reversed MDR in the MGHU1R cell line, both assessed by confocal microscopy and by
      the tetrazolium assay. CONCLUSIONS: Progesterone can reverse MDR in urothelial
      cells in vitro. This, combined with its effects on cell differentiation and
      apoptosis, together with its safety and tolerability compared to other MDR
      agents, suggests it may be a valuable adjunct to intravesical chemotherapy.

PMID- 12410759
TI  - Contralateral response in renal pelvic pressure and diuresis during increasing
      ipsilateral pelvic pressure and flow: a study of the normal and denervated upper
      urinary tract in pigs.
AB  - OBJECTIVE: To examine, in young pigs, changes in baseline pelvic pressure and
      diuresis in the contralateral kidney during conditions of increasing pelvic
      pressure and perfusion with isotonic saline in the ipsilateral renal pelvis; the
      role of a reno-renal nervous mechanism was examined by denervating the kidneys,
      and the effect of bladder filling on these variables assessed. MATERIALS AND
      METHODS: Female pigs (37-40 kg) were assessed under general anaesthesia.
      Transparenchymally, one 6 F and two 6 F catheters were introduced into the right
      and left renal pelvis, respectively. Through a bladder incision an 8 F catheter
      was introduced 10 cm into the right ureter to collect urine and the orifice
      closed around the catheter. For bladder drainage and to measure bladder pressure
      a 10 F catheter was placed in the bladder and both the 8 F and 10 F catheters
      lead out through the urethra. In group A, five animals served as controls, with
      group B comprising eight with intact nerves and group C eight with denervated
      kidneys. In group B and C the left renal pelvis was perfused with isotonic saline
      at 2, 4, 6, 8, 10, 12 and 16 mL/min while the bilateral pelvic pressure and right
      renal diuresis were recorded; the bladder was kept empty and 0.5 h later the left
      pelvis was perfused with 10 mL/min while the bladder catheter was closed.
      Perfusion continued until micturition occurred. The bilateral pelvic pressure,
      bladder pressure and right renal diuresis were recorded. In group C the kidneys
      were surgically denervated, dividing all adhesions and all connective tissue
      around the pelvis and the vascular pedicle. The renal artery was freed to the
      aortic level. RESULTS: During the pressure-perfusion study the mean (sd) right
      pelvic pressure was 7.4 (0.2) mmHg in group B and 8.6 (0.2) mmHg in group C. The
      diuresis from the right kidney in both groups was similar and the same as that in
      group A. The perfusion rate and pressure on the left side had no influence on
      pelvic pressure and diuresis on the right side. During perfusion with a full
      bladder the right pelvic pressure was 8.6 mmHg in group B and 9.5 mmHg in group
      C. Diuresis in group B was approximately 0.6 mL/min and a little higher in group
      C, at approximately 1 mL/min, but identical to that in group A. CONCLUSION: These
      results indicate that a reno-renal reflex mechanism has no apparent role in young
      pigs during pressure-perfusion measurements with an empty or full bladder.

PMID- 12410760
TI  - Correlation between major histocompatibility complex class I molecules and CD8+ T
      lymphocytes in prostate, and quantification of CD8 and interferon-gamma mRNA in
      prostate tissue specimens.
AB  - OBJECTIVE: To investigate the immunology of host-tumour interaction, critical for
      the development of immunotherapy against cancers, by assessing the major
      histocompatibility complex (MHC) class I expression in both benign and malignant
      prostate disease, and the relationship between their expression and degree of
      tumour-infiltrating lymphocytes. MATERIALS AND METHODS: Direct serial analysis of
      gene expression in tumours is an extremely sensitive and powerful tool for
      monitoring immunological changes in the immunotherapy of solid tumours. Most
      previous monitoring protocols rely mainly on the analysis of patient's peripheral
      blood but in the present study the direct molecular analysis of small tissue
      samples was used, and its accuracy compared with that of conventional
      immunohistochemical analysis. Twenty-four formalin-fixed, paraffin-embedded
      prostate samples (11 benign and 13 carcinoma) were used for the
      immunohistochemical analysis of CD8+ T lymphocytes and MHC class I expression.
      CD8+ T lymphocytes were counted using an ocular grid and MHC class I measured
      using digital image-analysis software. Twenty-seven frozen prostate tissue
      samples (12 benign and 15 carcinoma) were used for direct gene measurements of
      CD8 and interferon-gamma using a quantitative real-time polymerase chain
      reaction. RESULTS: There were significantly fewer CD8+ T lymphocytes in prostate
      carcinoma nests than in benign prostate. There was a significant correlation
      between the number of CD8+ T lymphocytes and MHC class I expression in the
      prostate. There was a strong correlation between the immunohistochemical
      estimates of CD8+ T lymphocytes and CD8 gene by polymerase chain reaction, but no
      significant difference between benign prostate and prostate carcinoma tissue in
      gene measurements. CONCLUSION: Down-regulation of MHC class I expression by
      prostate cancer cells is associated with fewer CD8+ T lymphocytes and hence might
      be important in cancer growth. In addition, the measurement of gene expression in
      small tissue samples might be useful for monitoring the efficacy of treatment
      throughout cancer therapy.

PMID- 12410761
TI  - Total sex-reassignment surgery in female-to-male transsexuals: a one-stage
      technique.

PMID- 12410762
TI  - Isolated renal haemangioma in children: presentation and management.

PMID- 12410763
TI  - Seminal vesiculectomy to resolve defecation-induced orgasm.

PMID- 12410765
TI  - A systematic review of tension-free urethropexy for stress urinary incontinence:
      intravaginal slingplasty and the tension-free vaginal tape procedure.

PMID- 12410767
TI  - The testis--what did he witness?

PMID- 12410768
TI  - Right acute hemiscrotum caused by insertion of an inflamed appendix.

PMID- 12410769
TI  - A novel retractor for hypospadias repair.

PMID- 12410776
TI  - Addiction and the family: is it time for services to take notice of the evidence?

PMID- 12410777
TI  - ERIT-Italia, the Italian Federation for Professionals Working in the Field of
      Drug Abuse.
AB  - What is ERIT-Italia? In what cultural context was it founded and in what state
      were the services for drug dependency at that time? What has it produced in
      recent years? Can a professional association successfully work alongside
      administrations and governments to contribute to the development of effective
      treatment for drug addiction? It is these questions which are addressed in this
      description of the major Italian professional body concerned with drug misuse.

PMID- 12410778
TI  - Dysregulation of the hypothalamic-pituitary-thyroid axis in alcoholism.
AB  - Thyroid dysfunction is a prominent finding in alcoholism. Subclinical and
      clinical hypothyroidism have been associated with clinical depression and
      cognitive impairment and may increase the relapse risk among alcoholics. In spite
      of these important clinical associations, there is no consensus on thyroid
      dysfunction in alcoholism in the literature. In this paper, we present a review
      of the literature and develop a hypothesis that may explain dysfunction of the
      hypothalamic-pituitary-thyroid axis in alcoholism. Based on a Medline research of
      the years 1980-2001 we found 33 empirical studies that assessed thyroid function
      in alcoholism. The most consistent findings were a reduction in total thyroxine
      and total and free triiodothyronine concentrations during early abstinence. About
      one-third of all alcoholics also displayed a blunted thyroid stimulation hormone
      (TSH) response in the thyrotrophin-releasing hormone test (TRH-test). Blunting
      was observed frequently during detoxification, but was also present in some
      alcoholics after several weeks of abstinence. We suggest that a reduction in
      peripheral thyroid hormones may be caused by a direct toxic effect of alcohol on
      the thyroid gland, which induces a central compensatory activation of the
      hypothalamic-pituitary axis with an increased TRH release. The TRH release
      induces a downregulation of pituitary TRH receptors, which manifest as a blunted
      TSH response to the TRH test. We discuss further additional effects of alcohol on
      thyroid-hormone metabolizing deiodinases and on monoaminergic systems, which may
      interact directly with mood states among abstinent alcoholics.

PMID- 12410779
TI  - Suicide among heroin users: rates, risk factors and methods.
AB  - The current paper examines critically the literature on suicide rates, suicide
      risk factors and methods employed for suicide among heroin users, and compares
      these to those of the general population. Heroin users have a death rate 13 times
      that of their peers, and deaths among heroin users attributed to suicide range
      from 3-35%. Overall, heroin users are 14 times more likely than peers to die from
      suicide. The prevalence of attempted suicide is also many orders of magnitude
      greater than that of community samples. The major general population risk factors
      for suicide also apply to heroin users (gender, psychopathology, family
      dysfunction and social isolation). Heroin users, however, have extremely wide
      exposure to these factors. They also carry additional risks specifically
      associated with heroin and other drug use. Drugs as a method of suicide play a
      larger role in suicide among heroin users than in the general population. Heroin,
      however, appears to play a relatively small role in suicide among this group.
      Overall, suicide is a major clinical issue among heroin users. It is concluded
      that suicide is a major problem that treatment agencies face, and which requires
      targeted intervention if the rates of suicide among this group are to decline.

PMID- 12410781
TI  - Community pharmacy services for drug misusers in Scotland: what difference does 5
      years make?
AB  - AIMS: To assess current levels of participation of community pharmacists in
      needle exchange provision, assess participation in dispensing any drugs for drug
      misuse, explore methadone dispensing practice, assess involvement in health
      promotion for drug misusers, assess levels of training in drug misuse and compare
      all of the above with data from 5 years previously. DESIGN: A cross-sectional
      postal questionnaire. SETTING: All community pharmacies in Scotland (n = 1162).
      PARTICIPANTS: A total of 969 pharmacists managing community pharmacies on a day
      to-day basis (response rate 83.4%). MEASUREMENTS: Descriptive data were collected
      on demography, drug misuse services provided and training. Data were combined
      with a dataset from an identical survey conducted 5 years previously for
      statistical comparison. RESULTS: Levels of needle exchange provision has not
      changed significantly (9.7% in 2000 compared to 8.6% in 1995). Of all
      respondents, 71.5% now dispense drug for the management of drug misuse, 68.9%
      dispense methadone and 56.7% provide a supervised methadone consumption service.
      The number of methadone clients receiving methadone through pharmacies has
      increased from 3387 in 1995 to 8792 in 2000 and the mean number of clients
      dispensed methadone per pharmacy has increased from 7.3 in 1995 to 13.2 in 2000;
      65.1% of all methadone clients now consume their methadone under pharmacist
      supervision. The proportion of pharmacists dispensing methadone who provide a
      supervised consumption service has increased significantly from 37% to 82.8%.
      Considerable changes in pharmacy practice are evident with significant increases
      in the number of pharmacists who always lay down ground rules, ask for
      identification on first visits, make up prescriptions in advance and provide
      verbal advice and leaflets on the management of drug misuse. Training in drug
      misuse doubled from 31.8% to 66.8%. CONCLUSIONS: Community pharmacy involvement
      with drug misusers has increased dramatically in the last 5 years. However, this
      increase is largely in methadone dispensing and supervision. Pharmacists appear
      to be more proactive in providing advice and information, perhaps as a result of
      greater training.

PMID- 12410780
TI  - A randomized controlled trial of buprenorphine in the management of short-term
      ambulatory heroin withdrawal.
AB  - AIM: To determine whether buprenorphine is more effective than clonidine and
      other symptomatic medications in managing ambulatory heroin withdrawal. DESIGN:
      Open label, prospective randomized controlled trial examining withdrawal and 4
      week postwithdrawal outcomes on intention-to-treat. SETTING: Two specialist, out
      patient drug treatment centres in inner city Melbourne and Sydney, Australia.
      PARTICIPANTS: One hundred and fourteen dependent heroin users were recruited.
      Participants were 18 years or over, and with no significant other drug
      dependence, medical or psychiatric conditions or recent methadone treatment. One
      hundred and one (89%) participants completed a day 8 research interview examining
      withdrawal outcomes, and 92 (81%) completed day 35 research interview examining
      postwithdrawal outcomes. INTERVENTIONS: Participants randomized to control (n =
      56) (up to 8 days of clonidine and other symptomatic medications) or experimental
      (n = 58) (up to 5 days of buprenorphine) withdrawal groups. Following the 8-day
      withdrawal episode, participants could self-select from range of postwithdrawal
      options (naltrexone, substitution maintenance, or counselling). MEASUREMENTS:
      Retention in withdrawal; heroin use during withdrawal; and retention in drug
      treatment 4 weeks after withdrawal. SECONDARY OUTCOMES: Withdrawal severity;
      adverse events, and heroin use in the postwithdrawal period. FINDINGS: The
      experimental group had better treatment retention at day 8 (86% versus 57%, P =
      0.001, 95% CI for numbers needed to treat (NNT) = 3-8) and day 35 (62% versus
      39%, P = 0.02, 95% CI for NNT = 4-18); used heroin on fewer days during the
      withdrawal programme (2.6 +/- 2.5 versus 4.5 +/- 2.3, P < 0.001, 95% CI = 1-2.5
      days) and in the postwithdrawal period (9.0 +/- 8.2 versus 14.6 +/- 10, P < 0.01,
      95% CI = 1.8-9.4); and reported less withdrawal severity. No severe adverse
      events reported. CONCLUSIONS: Buprenorphine is effective for short-term
      ambulatory heroin withdrawal, with greater retention, less heroin use and less
      withdrawal discomfort during withdrawal; and increased postwithdrawal treatment
      retention than symptomatic medications.

PMID- 12410782
TI  - Alcohol-related human losses in Russia in the 1980s and 1990s.
AB  - AIMS: The estimation of alcohol-related human losses in Russia in the 1980s and
      1990s. DESIGN: The estimation was made by comparing changes in the total number
      of deaths and in specific categories, and alcohol consumption in Russia during
      this time. SETTING: The anti-alcohol campaign, launched in 1985, and the market
      reforms launched in 1992 were associated with large and rapid changes of alcohol
      consumption in Russia. FINDINGS: In the early 1980s, the aggregate number of
      direct and indirect alcohol-related life losses was more than 500,000 per annum,
      or 32% of total deaths. Half of the alcohol-related human losses in Russia over
      the period studied were due to accidents, poisoning and violence. Following the
      anti-alcohol campaign and reduction in annual per capita alcohol consumption from
      14.2 (1984) to 10.5 l (1986), mortality decreased from 1161.6 to 1054.0 per
      100,000 of the population. It is estimated that from 1986 to 1991 the lives of
      1.22 million people were spared; that is, 11.4% of the number of deaths expected
      without the anti-alcohol campaign. All categories of deaths were reduced with the
      exception of neoplasms, infectious and parasitic diseases. In the period of the
      so-called market reforms both alcohol consumption and mortality increased
      sharply. The total number of alcohol-related deaths for 1994 was 751,000 in the
      population, or 33% of all deaths (direct and indirect losses). In 1995 alcohol
      consumption started to decrease. A decrease in mortality was registered despite
      the sharp deterioration of the quality of life in the country. However, a new
      growth of total mortality, fatal alcohol poisonings and number of alcohol
      psychoses began in 1999-2000. CONCLUSION: The results of this study show the
      enormous scale of alcohol-related mortality in Russia. It has been revealed that
      alcohol-related deaths are at the top of the hierarchy of all premature deaths in
      the country. Decreasing alcohol consumption is an important means of decreasing
      total mortality in Russia.

PMID- 12410783
TI  - Trajectories of drinking from 18 to 26 years: identification and prediction.
AB  - OBJECTIVE: To identify developmental trajectories of drinking between the ages of
      18 and 26 years and to identify variables, amenable to policy influence, which
      predict these trajectories. DESIGN: Longitudinal data were analysed using latent
      class mixture modelling. SETTING: Participants were interviewed in a central
      location. PARTICIPANTS: Provincial city birth cohort, cross-national studies
      suggest findings are generalizable to other similar market economies.
      MEASUREMENTS: The frequency of drinking over the past year and the typical
      quantity consumed per drinking occasion were computed from five location-specific
      questions. Measures used to predict membership of trajectory groups were ease of
      access to alcohol, drinking on licensed premises, response to alcohol
      advertising, educational achievement, parental consumption, age of onset of
      regular drinking and living arrangements. RESULTS: Three trajectories of
      quantities consumed showed reduced consumption after age 21 but one trajectory
      showed marked increases. Three trajectories of frequency of drinking increased or
      remained stable over time. Access to licensed premises at age 18 had the most
      significant impact on membership of the trajectory groups and educational
      achievement had a significant impact on membership of the heavier quantity
      trajectory groups. Parental alcohol consumption, access to alcohol at 15 years,
      liking for alcohol advertising, living arrangement and age of onset of regular
      drinking also influenced trajectory membership. CONCLUSIONS: Quantity and
      frequency of drinking in adolescence and early adulthood had different
      trajectories. Membership of heavier drinking groups was affected by environmental
      influences which are subject to policy change, particularly that of earlier
      access to licensed premises. In a small group high-quantity consumption did not
      decrease at age 26.

PMID- 12410784
TI  - Children in fatal crashes: driver blood alcohol concentration and demographics of
      child passengers and their drivers.
AB  - AIMS: This study examines whether differences in two risk factors for crash
      related injury for children-riding with a drinking driver and failure to use
      restraints-are related to various driver characteristics such as age, gender,
      ethnicity and drinking. DESIGN, PARTICIPANTS, MEASUREMENTS: Data on driver blood
      alcohol concentration (BAC), use of restraints and certain demographics were
      drawn from the Fatality Analysis Reporting System. Ethnicity data came from the
      Multiple Cause of Death File and socioeconomic information from the US Census.
      The use of restraints by child passengers and the drinking of alcohol by adult
      drivers are examined as a function of age, gender and membership of five
      racial/ethnic groups: White American, Black American, Native American,
      Asian/Pacific Islander American and Hispanic American. This study covers 160,770
      drivers and 12,266 children younger than 16 years killed in motor vehicle crashes
      from January 1,1990 to December 31,1996. FINDINGS: As might be expected, analyses
      of fatally injured drivers showed that, compared with men, women were more likely
      to be accompanied by children at the time of their crash, but those children were
      more likely to be restrained than if travelling with men. Drivers who had been
      drinking at the time of their crash were less likely to be transporting children
      and those children were less likely to be restrained. Analyses of killed children
      indicated that some ethnic groups, compared with White drivers, were more likely
      to be BAC-positive and children were less likely to be restrained. CONCLUSIONS:
      These findings underscore the continuing need to understand cultural factors in
      traffic safety and develop and disseminate culturally appropriate education
      programs.

PMID- 12410785
TI  - Community-based alcohol counselling: a randomized clinical trial.
AB  - AIMS: To examine the effectiveness of a brief intervention (BI) and cognitive
      behaviour therapy (CBT) for alcohol abuse. DESIGN: A randomized trial with
      clients randomized within counsellors. SETTING: Community-based drug and alcohol
      counselling in Australia. PARTICIPANTS: Of all new clients attending counselling.
      869 (82%) completed a computerized assessment at their first consultation. Four
      hundred and twenty-one (48%) were defined as eligible, of whom 295 (70%)
      consented and were allocated randomly to an intervention. Of these, 13 3 (45%)
      were followed-up at 6 months post-test. INTERVENTIONS: BI comprised the elements
      identified by the acronym FRAMES:feedback, responsibility, advice, menu, empathy,
      self-efficacy. Face-to-face counselling time was not to exceed 90 minutes. CBT
      comprised six consecutive weekly sessions: introduction: cravings and urges;
      managing crises; saying 'no' and solving problems: emergencies and lapses: and
      maintenance. Total face-to-face counselling time was 270 minutes (six 45-minute
      sessions). MEASUREMENTS: Treatment outcomes are measured in terms of counsellor
      compliance, client satisfaction, weekly and binge consumption, alcohol-related
      problems, the AUDIT questionnaire and cost-effectiveness. FINDINGS: When analysed
      on an intention-to-treat basis and for those followed-up. treatment outcomes
      between BI and CBT were not statistically significantly different at pre- or post
      test, whether considered as continuous or categorical variables. BI was
      statistically significantly more cost-effective than CBT and there was no
      difference between them in clients' reported levels of satisfaction. CONCLUSION:
      For low-dependence alcohol abuse in community settings, BI may be the treatment
      of choice.

PMID- 12410786
TI  - Alcohol urges in alcohol-dependent drinkers: further validation of the Alcohol
      Urge Questionnaire in an untreated community clinical population.
AB  - BACKGROUND: Alcohol craving is a key element of the alcohol dependence syndrome.
      However, there is a lack of consensus about the precise nature of craving and the
      most appropriate method of measurement. Alcohol urges measured by the Alcohol
      Urge Questionnaire showed a unidimensional structure and evidence of validity and
      reliability in a US clinical population. The main aim of this study was to
      establish the validity of the AUQ in an untreated UK clinical population, and its
      relationships to drinking and personality factors. SUBJECTS: All subjects (n =
      80) were alcohol-dependent (DSM-IV) and presenting for pre-treatment assessment
      at a community alcohol team in South-west -London. METHOD: All subjects completed
      the AUQ, Severity of Alcohol Dependence -Questionnaire (SADQ), Spielberger's
      State Trait Anxiety Inventory (STAI) and Eysenck Personality Questionnaire (EPQ)
      and provided a breath specimen for alcohol analysis (BAL). RESULTS: Principal
      components analysis of AUQ revealed one factor which accounted for 69% of
      variance with high interitem correlations, and an alpha reliability of 0.93. AUQ
      was significantly correlated with SADQ, BAC, state and trait anxiety and
      negatively correlated with time since last drink. There were no significant
      correlations between AUQ and any of the EPQ subscales. SADQ was correlated with
      neuroticism, but not other EPQ subscales. A regression analysis showed that only
      SADQ, time since last drink and BAL were significant predictors of alcohol urges.
      CONCLUSIONS: This study confirmed the AUQ factor structure and provided further
      evidence for the validity of AUQ. The relationship between BAL and urges deserves
      further research. The results did not support the contention that -anxiety and
      personality factors predict urges when drinking-related variables, which also
      predict urges, are controlled for. The AUQ is a useful measure for clinical and
      experimental alcohol craving research.

PMID- 12410787
TI  - Four cases of erectile dysfunction in substance abusers treated with sildenafil.
AB  - This case report describes four cases of substance abusers with sexual
      dysfunction, three of them with erectile dysfunction, and the fourth with
      erectile dysfunction and ejaculatia praecox. They were treated with sildenafil
      and their condition improved. There is a need to examine more fully the problem
      of sexual dysfunction in patients reporting for the treatment of addictions,
      given that it appears that their problem can be treated.

PMID- 12410790
TI  - Challenging the traditional treatment divisions in Poland.

PMID- 12410791
TI  - The Nobel Prize in Physiology or Medicine for 2002.

PMID- 12410792
TI  - In vitro production and characterization of partly assembled human CD3 complexes.
AB  - Pairwise assembly of human CD3 chains takes place in the endoplasmic reticulum of
      T cells. Subsequently, the CD3 heterodimers form complexes with Ti alpha and Tiss
      chains forming hexameric Ti alpha beta CD3 gamma epsilon delta epsilon complexes.
      Finally, association with the zeta 2 homodimer occurs in Golgi apparatus before
      the fully assembled T-cell receptor is transported to the cell surface. To study
      the structural properties of the human CD3 chains, we have developed new methods
      to produce and fold the extracellular domains of CD3 gamma, CD3 delta and CD3
      epsilon. Proteins were expressed in Escherichia coli as denatured chains and de
      novo folded in vitro. CD3 gamma and CD3 epsilon folded as soluble monomers,
      whereas CD3 delta did not yield any soluble proteins. When folding the chains
      pairwise, soluble CD3 gamma epsilon and CD3 delta epsilon heterodimers could be
      isolated, whereas CD3 gamma delta heterodimers were not produced. Using
      antibodies as structural probes, we identified two different types of antigenic
      epitopes that were dependent on heterodimerization. Our data indicate that CD3
      epsilon undergoes a conformational change after dimerization with CD3 gamma or
      CD3 delta. Furthermore, we demonstrated that the CD3 gamma epsilon heterodimer
      could be purified using immunoaffinity chromatography.

PMID- 12410793
TI  - Specific acquired resistance in mice immunized with killed mycobacteria.
AB  - Past attempts to raise resistance against Mycobacterium tuberculosis using
      various preparations of killed mycobacteria have questioned the specificity of
      the generated immune response. In the present study, we have focused on the
      protective efficacy of experimental vaccines based on killed mycobacteria. We
      demonstrate that killed mycobacteria can confer high levels of protection, which
      can be adoptively transferred to recipient T-cell-deficient mice. Moreover,
      protective antigens can be found in the cell wall, membrane and cytosol of the
      mycobacterial cell, and hence emphasize the importance of searching for
      protective antigens in various compartments of the mycobacterial cell.

PMID- 12410794
TI  - DNA immunization of mice against the VP1 capsid protein of coxsackievirus B4.
AB  - The protective activity of a DNA plasmid encoding the immunodominant capsid
      protein VP1 of coxsackievirus B4 (CBV-4) was studied in BALB/c mice. The plasmid
      pCI-B4-1-c - which gave the highest expression level of VP1 in cultured monkey
      and human cells - was chosen for immunization. Two injections of pCI-B4-1-c (1
      month apart) into the regenerating mouse muscle tissue induced a specific
      antibody response to CBV-4, as shown by immunoenzyme and neutralization assays.
      Upon challenge with live CBV-4, the mortality rate of mice vaccinated with the
      recombinant plasmid was significantly reduced (21% versus >58%) as compared with
      that of mice that had been either nontreated or injected with a control plasmid
      devoid of the insert. The VP1-based vaccine, however, did not provide complete
      protection as - after virus challenge - moderate viraemia occurred together with
      modest plasma elevations of pathogenesis-related enzymes (amylase and creatine
      kinase). Yet, immunofluorescence of the small intestine and heart did confirm the
      protective effect of the VP1-encoding vaccine. In order to obtain a more complete
      protection against CBV-4, it may be beneficial to immunize mice with combinations
      of separate DNA plasmids encoding not only VP1 but also the VP2 and VP3 capsid
      proteins.

PMID- 12410795
TI  - Subcellular redistribution and surface exposure of the Ro52, Ro60 and La48
      autoantigens during apoptosis in human ductal epithelial cells: a possible
      mechanism in the pathogenesis of Sjogren's syndrome.
AB  - The Ro52, Ro60 and La48 autoantigens are associated with Sjogren's syndrome (SS)
      and systemic lupus erythematosus (SLE). The mechanisms behind tolerance breakdown
      of these self-peptides remain unclear; however, apoptosis has been proposed to
      cause their presentation to the immune system. We have examined the localization
      of transiently expressed enhanced green fluorescent protein (EGFP)-tagged Ro52,
      Ro60 and La48 autoantigens in a human salivary gland (HSG) cell line by laser
      confocal microscopy under normal growth conditions and during apoptosis. Surface
      exposure of Ro52, Ro60 and La48 was demonstrated on nonfixed apoptotic cells with
      monoclonal antibodies (MoAbs) or with primary SS patient antisera. Laser scanning
      cytometry determined the apoptotic frequency. EGFP alone was studied as control.
      We found that Ro52 mainly is cytoplasmic, Ro60 both nuclear and cytoplasmic,
      while La48 only resides in the nucleus under normal conditions. During early
      apoptosis, La48 is dramatically redistributed to the cytoplasm, while the
      localization of Ro52 and Ro60 is maintained. All three autoantigens filled
      apoptotic blebs and covered TUNEL (terminal-deoxynucleotidyl-transferase-mediated
      dUTP-digoxigenin nick end labelling)-positive apoptotic bodies. Identical results
      were obtained in COS-7 cells. We have developed a transfection system to study
      the intracellular localization of the three autoantigens Ro52, Ro60 and La48,
      without antibody detection. During apoptosis, there is an intracellular
      redistribution of endogenous and EGFP-tagged Ro52, Ro60 and La48, leading to
      surface exposure. These findings may indicate a role for apoptosis in the
      induction and facilitation of humoral responses to Ro52, Ro60 and La48 in the
      autoimmune exocrinopathy of SS.

PMID- 12410796
TI  - Phagocyte activation by Trp-Lys-Tyr-Met-Val-Met, acting through FPRL1/LXA4R, is
      not affected by lipoxin A4.
AB  - Lipoxin A4 (LXA4) has been shown to bind to the leucocyte formyl peptide receptor
      (FPR) homologue, FPRL1, without triggering the biological activities induced by
      other FPRL1 agonists. We investigated the direct effect of LXA4 as well as the
      effect on agonist-induced biological responses using transfected HL-60 cells
      expressing FPR, FPRL1 or FPRL2. LXA4 neither induced an intracellular rise in
      calcium in these transfectants nor affected the response induced by the peptide
      Trp-Lys-Tyr-Met-Val-Met (WKYMVM), an agonist that activates cells through FPRL1
      and -2. Both agonists induced Erk-2 activation; however, the eicosanoid-induced
      activity was independent of FPRL1 and FPRL2. Moreover, LXA4 was unable to trigger
      neutrophil upregulation of complement receptor 3 and respiratory burst, and it
      had no effect on the responses induced by triggering with WKYMVM. We conclude
      that LXA4 is unable to affect the WKYMVM-induced signalling through FPRL1 and
      suggest that it acts through a receptor different from FPRL1.

PMID- 12410797
TI  - Immunization with peptides from 60 kDa Ro in diverse mouse strains.
AB  - Antibodies binding the Ro (or SSA) and La (or SBB) proteins are commonly found in
      a high proportion of sera from patients with systemic lupus erythematosus or
      Sjogren's syndrome. The mechanism by which these autoantibodies arise is not
      known. Others and we have shown that immunization of nonautoimmune-prone mice
      with short peptides from the Ro ribonucleoprotein particle can induce
      autoimmunity to 60 kDa Ro and 52 kDa Ro as well as to the 48 kDa La protein after
      epitope spreading. We have explored the differences in the epitope spreading
      after 60 kDa Ro peptide immunization in several strains of mice. There is intra-
      and intermolecular diversification of the immune response after immunization of
      DBA/2J animals with a monomer peptide representing the residues 480-494 of the 60
      kDa Ro protein, but this peptide does not induce epitope spreading when used as
      the immunogen in either C57Bl/6J or PL/J mice. Similar to previously studied
      BALB/c mice, DBA/2J mice have antibodies binding many epitopes of 60 kDa Ro, and
      some sera bind 52 kDa Ro as well as La. These mice have antinuclear antibody in
      their sera. These data demonstrate that Ro peptide immunization results in
      different outcomes depending upon the strain of mouse used. Furthermore, these
      data suggest that genetic variation is important with regard to responding
      towards short peptide immunization by epitope spreading.

PMID- 12410798
TI  - CD14-mediated induction of interleukin-8 and monocyte chemoattractant protein-1
      by a heat-resistant constituent of Porphyromonas gingivalis in endothelial cells.
AB  - Viable and inactivated Porphyromonas gingivalis dose-dependently induced
      interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) secretion in
      human umbilical vein endothelial cells (HUVECs). The inactivated P. gingivalis,
      in comparison with viable bacteria, tended to enhance the production of both
      chemokines more strongly. The production of MCP-1 protein began increasing
      immediately after stimulation by P. gingivalis, and there was a nearly linear
      increase from 0 to 8 h of incubation, whereas IL-8 production showed a linear
      increase between 4 and 12 h of incubation. The IL-8 and MCP-1 mRNA expressions in
      HUVECs as determined by reverse transcriptase-polymerase chain reaction (RT-PCR)
      or Quantikine mRNA colorimetric quantification kits were found to be enhanced by
      P. gingivalis. Furthermore, the time courses of IL-8 and MCP-1 mRNA expressions
      were in accordance with those of protein production. Addition of polymyxin B or
      boiling did not weaken the stimulatory effect of P. gingivalis, which inhibited
      the effect of Escherichia coli lipopolysaccharide (E. coli LPS) and tumour
      necrosis factor-alpha (TNF-alpha), respectively. In contrast, the induction of IL
      8 and MCP-1 by P. gingivalis was significantly reduced by anti-CD14 antibody. Our
      results suggest that some heat-stable component of P. gingivalis, including LPS,
      may be responsible for the induction of IL-8 and MCP-1 in HUVECs by a CD14
      dependent mechanism. These effects might be involved in the accumulation and
      activation of neutrophils and monocytes at an early stage of the periodontal
      pathogenesis.

PMID- 12410799
TI  - Treatment of an immortalized APC cell line with both cytokines and LPS ensures
      effective T-cell activation in vitro.
AB  - Antigen-presenting cells (APCs) are crucial for the generation of a functional
      immune response to pathogens. Furthermore, there is abundant evidence for their
      importance in primary T-cell activation, B-cell maturation and maintenance of an
      ongoing immune response. In the present study, we have analysed phenotypic
      characteristics and functionality of a p53-deficient APC cell line (JawsII)
      derived from mouse bone marrow culture. We show that unstimulated JawsII cells
      express low surface levels of major histocompatibility complex (MHC) and
      costimulatory molecules, both of which can be upregulated upon treatment with
      cytokines in vitro. Cytokine stimulation also leads to an enhanced T-cell
      activation capacity but has only little effect on cytokine release by the JawsII
      cells themselves. On the contrary, stimulation of the JawsII cells with
      lipopolysaccharide (LPS) leads to the production and secretion of high amounts of
      interleukin-1 (IL-1), IL-6 and tumour necrosis factor-alpha (TNF-alpha) but no
      increase in the surface levels of MHC and costimulatory molecules, and has only
      little effect on the T-cell activation capacity. Our data suggest that the
      effects observed upon treatment with cytokines or LPSs are complementary, and
      that both stimuli are needed for mediating a strong and efficient JawsII cell
      dependent T-cell activation.

PMID- 12410800
TI  - Transcriptional regulation of serum amyloid A1 gene expression in human aortic
      smooth muscle cells involves CCAAT/enhancer binding proteins (C/EBP) and is
      distinct from HepG2 cells.
AB  - Regulation of acute-phase serum amyloid A (A-SAA) synthesis by proinflammatory
      cytokines and steroid hormones in human aortic smooth muscle cells (HASMCs) is
      distinct from that in HepG2 cells. To study the cis- and trans-activating
      promoter element involved in the SAA1 gene expression by HASMCs and HepG2 cells,
      we constructed plasmid vectors for luciferase reporter gene assay with varying
      lengths of SAA1 upstream regulatory region (up to 1431 bp), and examined their
      response to proinflammatory cytokines and/or steroid hormones. The corresponding
      vectors with the SAA4 upstream regulatory region served as controls. The presence
      of proposed transcriptional regulatory factors binding to these regions was
      confirmed immunohistochemically. The sequences of 1478 and 1836 bp of the SAA1
      and SAA4 5'-flanking regions were determined, respectively. SAA1 promoter
      transcription in cultured HASMCs was upregulated not by proinflammatory
      cytokines, but rather by glucocorticoids. This differed from HepG2 cells, in
      which SAA1 promoter transcription was upregulated synergistically by
      proinflammatory cytokines and glucocorticoids. The promoter activity of a series
      of truncated SAA1 promoter constructs measured using the reporter gene assay
      showed that the 5'-region from -252 to -175, containing a consensus site for
      CCAAT/enhancer binding proteins alpha,beta (C/EBPalpha,beta), was essential for
      SAA1 induction in HASMCs. In HepG2 cells, the 5'-region from -119 to -79,
      containing a nuclear factor kappa-B (NFkappaB) consensus sequence, was essential
      for the induction. The functional significance of the C/EBP site as indicated by
      the immunohistochemical result was that in HASMCs anti-C/EBPbeta reactivity was
      shifted from the cytoplasm to the nuclei. We have, therefore, demonstrated that
      the region containing the C/EBPalpha,beta consensus binding site between the
      bases -252 and -175 is important for the glucocorticoid-induced SAA1 gene
      expression in HASMCs but not in HepG2 cells.

PMID- 12410802
TI  - Circulating, interferon-producing plasmacytoid dendritic cells decline during
      human ageing.
AB  - Increased frequency and severity of infections in the elderly have been taken as
      indicative of declining immune function. Dendritic cells (DCs), the most
      important antigen-presenting cells, play a central role in initiating and
      modulating immune responses. One type, DC2, arises from precursor plasmacytoid
      DCs (pDCs), a rare population of circulating blood cells, whose hallmark function
      is rapid and copious production of interferon-alpha (IFN-alpha) upon microbial
      challenge. We found significant decreases of the circulating pDCs during ageing
      in healthy adult humans, as defined both by flow cytometry and IFN-alpha
      generation. Mean pDC/mm3 in peripheral blood declined from 7.8 for the youngest
      age group (18-39 years) to 4.2 for the oldest (60-91 years; P = 0.017). IFN-alpha
      generation declined similarly, from 3537 to 1201 IU/ml, respectively (P = 0.006).
      There was also a slight decline over the age range in the amount of IFN generated
      per pDC (slope = -0.0087; P = 0.046). CD4+ T cells decreased by approximately 20%
      over the same age range (P = 0.001), while there was no change in the total
      lymphocyte or monocyte counts.

PMID- 12410801
TI  - Evidence of clonotypic pattern of T-cell repertoire in synovial fluid of children
      with juvenile rheumatoid arthritis at the onset of the disease.
AB  - Rheumatoid arthritis (RA) and juvenile rheumatoid arthritis (JRA) are
      characterized by chronic inflammation, synovial cell proliferation and
      progressive joint damage. It has been speculated that T cells play an important
      role in the pathogenesis of RA and JRA in the early stage of the disease.
      Previous studies have demonstrated discrepant results regarding the significance
      of T-cell clonality in RA or JRA lesions. It can be postulated that the
      heterogeneity of these data may be linked to the stage of the disease, as the
      relative importance of selective immunological events is different during the
      time from onset to established disease. To avoid this problem, we conducted the
      present study in nine children affected by JRA at the onset of the disease and
      before treatment. We analysed the T-cell receptor beta chain variable (TCRBV) of
      CD4+ and CD8+ lymphocytes in peripheral blood (PBL) and synovial fluid (SFL), by
      a panel of monoclonal antibodies (MoAbs). Furthermore, to assess the clonotypic
      pattern of T-cell repertoire, the CDR3 length distribution was evaluated by
      spectratyping analysis. Our results showed no significant expansion of distinct
      TCRBV subset in either synovial or peripheral compartments. Conversely, when we
      studied the CDR3 length distribution, an oligoclonal pattern was found in the SFL
      of six patients, suggesting the presence of a clonotypic restriction of T cells
      in SFL, which is not detectable in PBL. These findings are consistent with an
      antigen driven T-cell expansion sequestered at the inflammatory site.

PMID- 12410803
TI  - Macrophages from high-risk HLA-DQB1*0201/*0302 type 1 diabetes mellitus patients
      are hypersensitive to lipopolysaccharide stimulation.
AB  - Levels of nonantigen-induced pro-inflammatory cytokines and prostaglandin in
      macrophages isolated from human leucocyte antigen (HLA)-matched type 1 diabetes
      mellitus patients, first-degree relatives and healthy controls were determined.
      We hypothesize that monocytes isolated from patients are sensitized or
      preactivated and therefore, have an altered response to in vitro stimulus
      compared with control groups as measured by levels of pro- and anti-inflammatory
      mediators. In this study, peripheral blood monocytes were differentiated to
      macrophages with macrophage-colony stimulating factor (M-CSF) to determine
      lipopolysaccharide (LPS)-stimulated tumour necrosis factor (TNF)-alpha,
      interleukin (IL)-1beta, IL-6, IL-12 and prostaglandin E-2 (PGE-2) secretion from
      hetero- or homozygous HLA DQB1*0201 and *0302 type 1 diabetes mellitus patients,
      first-degree relatives and homozygous HLA DQB1*0602 healthy controls. LPS
      stimulated secretion of TNF-alpha, IL-1beta and IL-6 was immediate and markedly
      higher in the HLA-DQB1*0201/*0302 type 1 diabetes patients compared with all
      other groups including HLA-matched healthy first-degree relatives. In
      DQB1*0201/*0302 diabetes patients PGE-2 secretion was delayed but increased by
      LPS stimulation compared with HLA-matched healthy relatives. IL-12 was not
      detected at any condition. These data suggest that macrophages from
      DQB1*0201/*0302 type 1 diabetes patients are sensitized to secrete both cytokines
      and PGE-2 following nonantigenic stimulation. Sensitized macrophages may be
      important to high-risk DQB1*0201/*0302-associated type 1 diabetes.

PMID- 12410804
TI  - Transforming growth factor-beta (TGF-beta) and tissue transglutaminase expression
      in the small intestine in children with coeliac disease.
AB  - The production of cytokines from T cells and macrophages is of potential
      importance for the histological changes apparent in coeliac disease (CoD). Small
      intestinal biopsy specimens from children with CoD and disease control subjects
      were investigated for their content of cytokines and tissue transglutaminase
      (tTG). The transforming growth factor-beta1 (TGF-beta1) expression was increased
      in the lamina propria of children with villous atrophy. In contrast, TGF-beta3
      was expressed at a higher level in the epithelium and the lamina propria of the
      disease control subjects. The tTG expression was increased in the small intestine
      of CoD patients as compared with that in subjects. Interleukin-4 (IL-4) was
      detected in the lamina propria of both CoD patients and controls, and some of the
      investigated biopsy specimens also showed IL-4 expression in the epithelium. We
      conclude that children with active CoD could have an altered expression of TGF
      beta and tTG in the small intestine and that a disturbed regulation of TGF-beta
      may be of importance in the immune pathogenesis of CoD.

PMID- 12410805
TI  - Analysis of complement-bound HCV complexes using a novel immuno-capture RT-PCR
      method.
AB  - Recently, more and more evidence has supported the hypothesis that liver cell
      injury was immune-mediated in patients with hepatitis C virus (HCV) infection,
      and that circulating immune complexes (CICs) might play a role in the
      pathogenesis of chronic hepatitis C (HC). In the present study, we have combined
      immuno-capture and reverse transcriptase-polymerase chain reaction (RT-PCR), and
      developed a quick method of high specificity for the detection of complement
      bound HCV-CIC. We found that there were higher frequencies of HCV-C1q CIC than
      that of HCV-factor B, and there was a deviation of complement from immunoglobulin
      (Ig) in HCV-CIC. These findings suggest that immuno-capture RT-PCR (iRT-PCR) for
      the detection of HCV-bound CIC is a valuable method for the analysis of the
      composition of the immune complexes, and for the understanding of host immune
      response and immune pathogenesis in HCV-infected individuals.

PMID- 12410806
TI  - Characterization of Arabidopsis thaliana AtFKBP42 that is membrane-bound and
      interacts with Hsp90.
AB  - The twisted dwarf1 (twd1) mutant from Arabidopsis thaliana was identified in a
      screen for plant architecture mutants. The TWD1 gene encodes a 42 kDa FK506
      binding protein (AtFKBP42) that possesses similarity to multidomain PPIases such
      as mammalian FKBP51 and FKBP52, which are known to be components of mammalian
      steroid hormone receptor complexes. We report here for the first time the
      stoichiometry and dissociation constant of a protein complex from Arabidopsis
      that consists of AtHsp90 and AtFKBP42. Recombinant AtFKBP42 prevents aggregation
      of citrate synthase in almost equimolar concentrations, and can be cross-linked
      to calmodulin. In comparison to one active and one inactive FKBP domain in
      FKBP52, AtFKBP42 lacks the PPIase active FKBP domain. While FKBP52 is found in
      the cytosol and translocates to the nucleus, AtFKBP42 was predicted to be
      membrane-localized, as shown by electron microscopy.

PMID- 12410807
TI  - The role of double-strand break-induced allelic homologous recombination in
      somatic plant cells.
AB  - During meiosis, homologous recombination occurs between allelic sequences. To
      evaluate the biological significance of such a pathway in somatic cells, we used
      transgenic tobacco plants with a restriction site for the rare cutting
      endonuclease I-SceI within a negative selectable marker gene. These plants were
      crossed with two tobacco lines containing, in allelic position, either a deletion
      or an insertion within the marker gene that rendered both marker gene and
      restriction site inactive. After the double-strand break induction, we selected
      for repair events resulting in a loss of marker gene function. This loss was
      mostly due to deletions. We were also able to detect double strand break-induced
      allelic recombination in which the break was repaired by a faithful copying
      process from the homologue carrying the shortened transgene. The estimated
      frequency indicates that homologous recombination in somatic cells between
      allelic sites appears to occur at the same order of magnitude as between ectopic
      sites, and is thus far too infrequent to act as major repair pathway. As somatic
      changes can be transferred to the germ line, the prevalence of intrachromatid
      rearrangements over allelic recombination might be an indirect prerequisite for
      the enhanced genome plasticity postulated for plants.

PMID- 12410808
TI  - Expression of the Arabidopsis histone H2A-1 gene correlates with susceptibility
      to Agrobacterium transformation.
AB  - Transformation of plant cells by Agrobacterium tumefaciens involves both
      bacterial virulence proteins and host proteins. We have previously shown that the
      Arabidopsis thaliana gene H2A-1 (RAT5), which encodes histone H2A-1, is involved
      in T-DNA integration into the plant genome. Mutation of RAT5 results in a
      severely decreased frequency of transformation, whereas overexpression of RAT5
      enhances the transformation frequency (Mysore et al., 2000b). We show here that
      the expression pattern of RAT5 correlates with plant root cells most susceptible
      to transformation. As opposed to a cyclin-GUS fusion gene whose expression is
      limited to meristematic tissues, the H2A-1 gene is expressed in many non-dividing
      cells. Under normal circumstances, the H2A-1 gene is expressed in the elongation
      zone of the root, the region that is most susceptible to Agrobacterium
      transformation. In addition, when roots are incubated on medium containing
      phytohormones, a concomitant shift in H2A-1 expression and transformation
      susceptibility to the root base is observed. Inoculation of root segments with a
      transfer-competent, but not a transformation-deficient Agrobacterium strain
      induces H2A-1 expression. Furthermore, pre-treatment of Arabidopsis root segments
      with phytohormones both induces H2A-1 expression and increases the frequency of
      Agrobacterium transformation. Our results suggest that the expression of the H2A
      1 gene is both a marker for, and a predictor of, plant cells most susceptible to
      Agrobacterium transformation.

PMID- 12410809
TI  - Comprehensive transcript profiling of Pto- and Prf-mediated host defense
      responses to infection by Pseudomonas syringae pv. tomato.
AB  - The disease resistance gene Pto encodes a serine/threonine protein kinase that
      confers resistance in tomato to Pseudomonas syringae pv. tomato strains that
      express the effector protein AvrPto. Pto-mediated resistance to bacterial speck
      disease also requires Prf, a protein with leucine-rich repeats and a putative
      nucleotide-binding site, although the role of Prf in the defense pathway is not
      known. We used GeneCalling, an open-architecture, mRNA-profiling technology, to
      identify genes that are either induced or suppressed in leaves 4 h after
      bacterial infection in the Pto- and Prf-mediated tomato-Pseudomonas(avrPto)
      interaction. Over 135 000 individual cDNA fragments representing an estimated 90%
      of the transcripts expressed in tomato leaves were examined and 432
      differentially expressed genes were identified. The genes encode over 25 classes
      of proteins including 11 types of transcription factors and many signal
      transduction components. Differential expression of 91% of the genes required
      both Pto and Prf. Interestingly, differential expression of 32 genes did not
      require Pto but was dependent on Prf. Thus, our data support a role for Prf early
      in the Pto pathway and indicate that Prf can also function as an independent host
      recognition determinant of bacterial infection. Comprehensive expression
      profiling of the Pto-mediated defense response allows the development of many new
      hypotheses about the molecular basis of resistance to bacterial speck disease.

PMID- 12410810
TI  - ABI5 acts downstream of ABI3 to execute an ABA-dependent growth arrest during
      germination.
AB  - The development of a germinating embryo into an autotrophic seedling is arrested
      under conditions of water deficit. This ABA-mediated developmental checkpoint
      requires the bZIP transcription factor ABI5. Here, we used abi3-1, which is also
      unable to execute this checkpoint, to investigate the relative role of ABI3 and
      ABI5 in this process. In wild-type Arabidopsis plants, ABI3 expression and
      activity parallel those described for ABI5 following stratification. During this
      process, transcript levels of late embryogenesis genes such as AtEm1 and AtEm6
      are also re-induced, which might be responsible for the acquired osmotic
      tolerance in germinated embryos whose growth is arrested. ABI5 expression is
      greatly reduced in abi3-1 mutants, which has low AtEm1 or AtEm6 expression. Cross
      complementation experiments showed that 35S-ABI5 could complement abi3-1, whereas
      35S-ABI3 cannot complement abi5-4. These results indicate that ABI5 acts
      downstream of ABI3 to reactivate late embryogenesis programmes and to arrest
      growth of germinating embryos. Although ABI5 is consistently located in the
      nucleus, chromosomal immunoprecipitation (ChIP) experiments revealed that ABA
      increases ABI5 occupancy on the AtEm6 promoter.

PMID- 12410811
TI  - Double antisense plants lacking ascorbate peroxidase and catalase are less
      sensitive to oxidative stress than single antisense plants lacking ascorbate
      peroxidase or catalase.
AB  - The plant genome is a highly redundant and dynamic genome. Here, we show that
      double antisense plants lacking the two major hydrogen peroxide-detoxifying
      enzymes, ascorbate peroxidase (APX) and catalase (CAT), activate an
      alternative/redundant defense mechanism that compensates for the lack of APX and
      CAT. A similar mechanism was not activated in single antisense plants that lacked
      APX or CAT, paradoxically rendering these plants more sensitive to oxidative
      stress compared to double antisense plants. The reduced susceptibility of double
      antisense plants to oxidative stress correlated with suppressed photosynthetic
      activity, the induction of metabolic genes belonging to the pentose phosphate
      pathway, the induction of monodehydroascorbate reductase, and the induction of
      IMMUTANS, a chloroplastic homologue of mitochondrial alternative oxidase. Our
      results suggest that a co-ordinated induction of metabolic and defense genes,
      coupled with the suppression of photosynthetic activity, can compensate for the
      lack of APX and CAT. In addition, our findings demonstrate that the plant genome
      has a high degree of plasticity and will respond differently to different
      stressful conditions, namely, lack of APX, lack of CAT, or lack of both APX and
      CAT.

PMID- 12410812
TI  - The Nod factor-elicited annexin MtAnn1 is preferentially localised at the nuclear
      periphery in symbiotically activated root tissues of Medicago truncatula.
AB  - The Medicago truncatula MtAnn1 gene, encoding a putative annexin, is
      transcriptionally activated in root tissues in response to rhizobial Nod factors.
      To gain further insight into MtAnn1 function during the early stages of
      nodulation, we have examined in detail both spatio-temporal gene expression
      patterns and MtAnn1 activity and localisation in root tissues. Analysis of
      transgenic Medicago plants expressing a pMtAnn1-GUS fusion has revealed a novel
      pattern of transcription in both outer and inner cell layers of the root
      following either Nod factor-treatment or rhizobial inoculation. The highest gene
      expression levels were observed in the endodermis and outer cortex. These
      transgenic plants also revealed that MtAnn1 expression is associated with lateral
      root development and cell differentiation in the root apex independent of
      nodulation. By purifying recombinant MtAnn1 we were able to demonstrate that this
      plant annexin indeed possesses the calcium-dependent binding to acidic
      phospholipids typical of the annexin family. Antisera against recombinant MtAnn1
      were then used to show that tissue-specific localisation of the MtAnn1 protein in
      Medicago roots matches the pMtAnn1-GUS expression pattern. Finally, both
      immunolabelling and in vivo studies using MtAnn1-GFP reporter fusions have
      revealed that MtAnn1 is cytosolic and in particular localises to the nuclear
      periphery in cortical cells activated during the early stages of nodulation. In
      the light of our findings, we discuss the possible role of this annexin in root
      tissues responding to symbiotic rhizobial signals.

PMID- 12410813
TI  - Mutations at CRE1 impair cytokinin-induced repression of phosphate starvation
      responses in Arabidopsis.
AB  - Plants display a number of responses to low phosphate availability, involving
      biochemical and developmental changes. Recently we have shown that many of these
      responses can be repressed in roots by exogenous addition of cytokinins. In order
      to understand the genetic basis to this effect of cytokinins, and its relation
      with the better known roles of cytokinins in the control of cell-cycle and
      differentiation, we have undertaken mutant screening and characterization using a
      transgenic line of Arabidopsis thaliana harbouring a reporter gene specifically
      responsive to Pi starvation (AtIPS1::GUS). One type of mutant identified
      displayed reduced sensitivity of AtIPS1::GUS to cytokinin repression. Several
      other Pi starvation response genes showed reduced cytokinin sensitivity in these
      lines. These mutants also showed reduced cytokinin repression of the anthocyanin
      accumulation induced by Pi starvation in the aerial part of the plants. Mapping
      and molecular characterization of these mutants showed that they were allelic of
      CRE1/WOL, a locus known to encode a cytokinin receptor. CRE1 is downregulated by
      Pi starvation and induced by cytokinins, both in the wild-type and in the cre1
      mutants, in which cre1 mRNA levels are higher. These results reveal the existence
      of a positive feed-back loop, in addition to the already established negative
      feedback loop, in cytokinin signalling and indicate that the negative regulation
      of Pi starvation responses by cytokinins involves a two-component signalling
      circuitry, as it is the case of other types of cytokinin response.

PMID- 12410814
TI  - Expression of a Phytophthora sojae necrosis-inducing protein occurs during
      transition from biotrophy to necrotrophy.
AB  - Phytophthora sojae is an oomycete that causes stem and root rot on soybean
      plants. To discover pathogen factors that produce disease symptoms or activate
      plant defense responses, we identified putative secretory proteins from expressed
      sequence tags (ESTs) and tested selected candidates using a heterologous
      expression assay. From an analysis of 3035 ESTs originating from mycelium,
      zoospore, and infected soybean tissues, we identified 176 putative secreted
      proteins. A total of 16 different cDNAs predicted to encode secreted proteins
      ranging in size from 6 to 26 kDa were selected for expression analysis in
      Nicotiana benthamiana using an Agrobacterium tumefaciens binary potato virus X
      (PVX) vector. This resulted in the identification of a 25.6-kDa necrosis-inducing
      protein that is similar in sequence to other proteins from eukaryotic and
      prokaryotic species. The genomic region encoding the P. sojae necrosis-inducing
      protein was isolated and the expression pattern of the corresponding gene
      determined by RNA blot hybridization and by RT-PCR. The activity of this P. sojae
      protein was compared to proteins of similar sequence from Fusarium oxysporum,
      Bacillus halodurans, and Streptomyces coelicolor by PVX-based expression in N.
      benthamiana and by transient expression via particle bombardment in soybean
      tissues. The P. sojae protein was a powerful inducer of necrosis and cell death
      in both assays, whereas related proteins from other species varied in their
      activity. This study suggests that the P. sojae necrosis-inducing protein
      facilitates the colonization of host tissues during the necrotrophic phase of
      growth.

PMID- 12410816
TI  - NAN fusions: a synthetic sialidase reporter gene as a sensitive and versatile
      partner for GUS.
AB  - GUS continues to be the reporter of choice for many gene fusion applications, due
      to the unparalleled sensitivity of the encoded enzyme and the ease with which it
      can be quantified in cell-free extracts and visualized histochemically in cells
      and tissues. A compatible and functionally equivalent reporter gene would
      facilitate dual promoter studies and internal standardization of expression
      analyses in the same plant. A search for a candidate enzyme activity not found in
      plants, which might form the basis of a novel GUS-compatible reporter system, led
      us to investigate nanH, a Clostridium perfringens gene which encodes the so
      called 'small' cytoplasmic sialidase. Expression of the native, AT-rich nanH gene
      in transgenic plants did not, however, result in detectable sialidase activity.
      For this reason, a codon-optimized derivative, NAN, was synthesized which
      possesses a GC content similar to that found in highly expressed plant genes. NAN
      enzyme activity was expressed at high levels in both stably and transiently
      transformed cells, possessed kinetic and stability properties similar to those of
      GUS, and showed optimal activity in GUS buffer. Moreover, NAN and GUS activity
      could be visualized simultaneously in polyacrylamide gels using the corresponding
      methylumbelliferone-based substrates, and in whole seedlings and tissue sections
      using the histochemical substrates 5-bromo-4-chloro-3-indolyl alpha-d-N
      acetylneuraminic acid (X-NeuNAc) and 5-bromo-6-chloro-3-indolyl beta-d
      glucuronide (X-GlucM), respectively.

PMID- 12410815
TI  - NPP1, a Phytophthora-associated trigger of plant defense in parsley and
      Arabidopsis.
AB  - Activation of non-cultivar-specific plant defense against attempted microbial
      infection is mediated through the recognition of pathogen-derived elicitors.
      Previously, we have identified a peptide fragment (Pep-13) within a 42-kDa cell
      wall transglutaminase from various Phytophthora species that triggers a
      multifacetted defense response in parsley cells. Many of these oomycete species
      have now been shown to possess another cell wall protein (24 kDa), that evoked
      the same pattern of responses in parsley as Pep-13. Unlike Pep-13, necrosis
      inducing Phytophthora protein 1 (NPP1) purified from P. parasitica also induced
      hypersensitive cell death-like lesions in parsley. NPP1 structural homologs were
      found in oomycetes, fungi, and bacteria, but not in plants. Structure-activity
      relationship studies revealed the intact protein as well as two cysteine residues
      to be essential for elicitor activity. NPP1-mediated activation of pathogen
      defense in parsley does not employ the Pep-13 receptor. However, early induced
      cellular responses implicated in elicitor signal transmission (increased levels
      of cytoplasmic calcium, production of reactive oxygen species, MAP kinase
      activation) were stimulated by either elicitor, suggesting the existence of
      converging signaling pathways in parsley. Infiltration of NPP1 into leaves of
      Arabidopsis thaliana Col-0 plants resulted in transcript accumulation of
      pathogenesis-related (PR) genes, production of ROS and ethylene, callose
      apposition, and HR-like cell death. NPP1-mediated induction of the PR1 gene is
      salicylic acid-dependent, and, unlike the P. syringae pv. tomato DC3000(avrRpm1)
      induced PR1 gene expression, requires both functional NDR1 and PAD4. In summary,
      Arabidopsis plants infiltrated with NPP1 constitute an experimental system that
      is amenable to forward genetic approaches aiming at the dissection of signaling
      pathways implicated in the activation of non-cultivar-specific plant defense.

PMID- 12410817
TI  - Construction of a specialized cDNA library from plant cells isolated by laser
      capture microdissection: toward comprehensive analysis of the genes expressed in
      the rice phloem.
AB  - Laser capture microdissection (LCM) is a powerful system which allows the
      isolation of selectively targeted cells from a tissue section for the analysis of
      gene-expression profiles of individual cells. The technique has been successfully
      used for the isolation of specific mammalian cells, mainly cancer cells. However,
      LCM has never been reported to be applied to the gene expression analysis of
      plant cells. We used a modified LCM system and successfully applied it to target
      and isolate phloem cells of rice leaf tissue whose morphology is apparently
      different from the surrounding cells. Total RNA was extracted from microdissected
      (approximately 150) phloem cells and the isolated RNA was used for the
      construction of a cDNA library following the T7 RNA polymerase amplification.
      Sequence analysis of 413 randomly chosen clones from the library revealed that
      there was a high level of redundancy in the population and the clones could be
      subclassified into 124 different groups that contained related sequences.
      Approximately 37% of both the redundant population and the non-redundant
      subgroups had novel components while approximately 63% were either homologues to
      the known genes reported to be localized in phloem of different plant species, or
      were homologues to other known genes. In situ hybridization revealed that
      putative amino acid permease, one of the non-redundant clones, was specifically
      expressed in the phloem. The results proved the effectiveness of construction of
      a specialized cDNA library from the specific plant cells.

PMID- 12410818
TI  - On-line measurements of K+ activity in the tensile water of the xylem conduit of
      higher plants.
AB  - In higher plants the xylem is the main pathway for anti-gravitational, long
      distance transport of nutrients and water from the root through the shoot to the
      upper leaves. In the xylem conduit water is in a metastable state if tension
      larger than 0.1 MPa (i.e. negative pressure) is developed. While diurnal changes
      in negative pressure of individual xylem vessels can quite accurately be recorded
      by the minimal-invasive xylem pressure probe technique and water flow by non
      invasive NMR techniques, the problem of continuous monitoring of solute flow
      remains a hitherto unresolved challenge. As shown here, integration of a K+
      selective and a potential measuring microelectrode into the xylem pressure probe
      allowed on-line measurements of the K+ activity in individual xylem vessels of
      maize roots together with pressure and trans-root potential, the potential
      difference between the xylem and the external medium (i.e. the overall driving
      force of ions through the root tissue). When light irradiation was increased from
      10 micro mol m(-2) s(-1) to 300 micro mol m(-2) s(-1) and negative pressure
      developed in the vessel, xylem K+ activity dropped from 3.6 +/- 2.6 mm to 0.9 +/-
      0.7 mm (n = 16), whereas the trans-root potential depolarized from -2 +/- 11 mV
      to + 12 +/- 11 mV (n = 11), i.e. by + 14 +/- 7 mV. The effect of light on all
      three parameters was reversible. Exposure of the root to various K+ activities in
      the bath ranging from 0.1 to 43 mm revealed that the K+ activity of the xylem sap
      was shielded against short-term fluctuations in K+ supply to a large extent. In
      contrast, control experiments in which the root was cut 1 cm below the probe
      insertion point, allowing direct entry of external K+ into the xylem vessels,
      demonstrated that the xylem equilibrated rapidly with external K+. This was taken
      simultaneously as a proof for the correct reading of the probe.

PMID- 12410819
TI  - Conjugative transposons: the tip of the iceberg.
AB  - Elements that excise and integrate, such as prophages, and transfer by
      conjugation, such as plasmids, have been found in various bacteria. These
      elements appear to have a diversified set of characteristics including cell-to
      cell contact using pili or cell aggregation, transfer of single-stranded or
      double-stranded DNA, low or high specificity of integration and serine or
      tyrosine recombinases. This has led to a highly heterogeneous nomenclature,
      including conjugative transposons, integrative 'plasmids', genomic islands and
      numerous unclassified elements. However, all these elements excise by site
      specific recombination, transfer the resulting circular form by conjugation and
      integrate by recombination between a specific site of this circular form and a
      site in the genome of their host. Whereas replication of the circular form
      probably occurs during conjugation, this replication is not involved in the
      maintenance of the element. In this review, we show that these elements share
      very similar characteristics and, therefore, we propose to classify them as
      integrative and conjugative elements (ICEs). These elements evolve by acquisition
      or exchanges of modules with various transferable elements including at least
      ICEs and plasmids. The ICEs are probably widespread among the bacteria.

PMID- 12410820
TI  - The rpf gene of Micrococcus luteus encodes an essential secreted growth factor.
AB  - Micrococcus luteus secretes a small protein called Rpf, which has autocrine and
      paracrine signalling functions and is required for the resuscitation of dormant
      cells. Originally isolated from the supernatant of actively growing cultures, Rpf
      was also detected on the surface of actively growing bacteria. Most molecules may
      be sequestered non-productively at the cell surface, as a truncated form of the
      protein, encompassing only the 'Rpf domain' is fully active. The C-terminal LysM
      module, which probably mediates binding to the cell envelope, is not required for
      biological activity. Rpf was essential for growth of M. luteus. Washed cells,
      inoculated at low density into a minimal medium, could not grow in its absence.
      Moreover, the incorporation of anti-Rpf antibodies into the culture medium at the
      time of inoculation also prevented bacterial growth. We were unable to inactivate
      rpf using a disrupted form of the gene, in which most of the coding sequence was
      replaced with a selectable thiostrepton resistance marker. Gene disruption was
      possible in the presence of a second, functional, plasmid-located copy of rpf,
      but not in the presence of a rpf derivative whose protein product lacked the
      secretory signal sequence. As far as we are aware, Rpf is the first example of a
      truly secreted protein that is essential for bacterial growth. If the Rpf-like
      proteins elaborated by Mycobacterium tuberculosis and other mycobacteria prove
      similarly essential, interference with their proper functioning may offer novel
      opportunities for protecting against, and treating, tuberculosis and other
      mycobacterial disease.

PMID- 12410821
TI  - A family of autocrine growth factors in Mycobacterium tuberculosis.
AB  - Mycobacterium tuberculosis and its close relative, Mycobacterium bovis (BCG)
      contain five genes whose predicted products resemble Rpf from Micrococcus luteus.
      Rpf is a secreted growth factor, active at picomolar concentrations, which is
      required for the growth of vegetative cells in minimal media at very low inoculum
      densities, as well as the resuscitation of dormant cells. We show here that the
      five cognate proteins from M. tuberculosis have very similar characteristics and
      properties to those of Rpf. They too stimulate bacterial growth at picomolar (and
      in some cases, subpicomolar) concentrations. Several lines of evidence indicate
      that they exert their activity from an extra-cytoplasmic location, suggesting
      that they are also involved in intercellular signalling. The five M. tuberculosis
      proteins show cross-species activity against M. luteus, Mycobacterium smegmatis
      and M. bovis (BCG). Actively growing cells of M. bovis (BCG) do not respond to
      these proteins, whereas bacteria exposed to a prolonged stationary phase do.
      Affinity-purified antibodies inhibit bacterial growth in vitro, suggesting that
      sequestration of these proteins at the cell surface might provide a means to
      limit or even prevent bacterial multiplication in vivo. The Rpf family of
      bacterial growth factors may therefore provide novel opportunities for preventing
      and controlling mycobacterial infections.

PMID- 12410822
TI  - A high-molecular-weight outer membrane protein of Xanthomonas oryzae pv. oryzae
      exhibits similarity to non-fimbrial adhesins of animal pathogenic bacteria and is
      required for optimum virulence.
AB  - Transposon insertions in a novel 3.798 kb open reading frame (ORF) of the rice
      pathogen, Xanthomonas oryzae pv. oryzae (Xoo) cause virulence deficiency and
      altered colony/lawn morphology. This ORF encodes a protein, XadA, of 1,265 amino
      acids that exhibits significant similarity to non-fimbrial adhesins of animal
      pathogenic bacteria such as Yersinia YadA and Moraxella UspA1. An interesting
      feature is that the YadA similarity region is repeated six times within the XadA
      sequence and encompasses almost the entire length of the protein. Anti-XadA
      antibodies identified a 110 kDa outer membrane protein that was sensitive to
      protease treatment of whole cells. XadA expression is induced in minimal medium.
      Homology modelling suggests that XadA adopts a beta-helix conformation-like
      pertactin, a non-fimbrial adhesin of Bordetella pertussis. This work is the first
      characterization of a non-fimbrial adhesin-like molecule in a plant pathogenic
      bacterium. It extends our knowledge about the repertoire of homologous virulence
      factors that are deployed by animal and plant pathogenic bacteria to include
      functions potentially involved in adhesion.

PMID- 12410823
TI  - An Inv/Mxi-Spa-like type III protein secretion system in Burkholderia
      pseudomallei modulates intracellular behaviour of the pathogen.
AB  - Burkholderia pseudomallei is the causative agent of melioidosis, a serious
      infectious disease of humans and animals that is endemic in subtropical areas. B.
      pseudomallei is a facultative intracellular pathogen that may invade and survive
      within eukaryotic cells for prolonged periods. After internalization, the
      bacteria escape from endocytic vacuoles into the cytoplasm of infected cells and
      form membrane protrusions by inducing actin polymerization at one pole. It is
      believed that survival within phagocytic cells and cell-to-cell spread via actin
      protrusions is required for full virulence. We have studied the role of a
      putative type III protein secretion apparatus (Bsa) in the interaction between B.
      pseudomallei and host cells. The Bsa system is very similar to the Inv/Mxi-Spa
      type III secretion systems of Salmonella and Shigella. Moreover, B. pseudomallei
      encodes proteins that are very similar to Salmonella and Shigella Inv/Mxi-Spa
      secreted proteins required for invasion, escape from endocytic vacuoles,
      intercellular spread and pathogenesis. Antibodies to putative Bsa-secreted
      proteins were detected in convalescent serum from a melioidosis patient,
      suggesting that the system is functionally expressed in vivo. B. pseudomallei
      mutant strains lacking components of the Bsa secretion and translocation
      apparatus were constructed. The mutant strains exhibited reduced replication in
      J774.2 murine macrophage-like cells, an inability to escape from endocytic
      vacuoles and a complete absence of formation of membrane protrusions and actin
      tails. These findings indicate that the Bsa type III secretion system plays an
      essential role in modulating the intracellular behaviour of B. pseudomallei.

PMID- 12410824
TI  - A novel class of microbial phosphocholine-specific phospholipases C.
AB  - In this report we describe the 1,500-fold purification and characterization of
      the haemolytic phospholipase C (PLC) of Pseudomonas aeruginosa, the paradigm
      member of a novel PLC/phosphatase superfamily. Members include proteins from
      Mycobacterium tuberculosis, Bordetella spp., Francisella tularensis and
      Burkholderia pseudomallei. Purification involved overexpression of the plcHR1,2
      operon, ion exchange chromatography and native preparative polyacrylamide gel
      electrophoresis. Matrix-assisted laser desorption ionization time-of-flight
      (MALDI-TOF) mass spectrometry confirmed the presence of two proteins in the
      purified sample with sizes of 17,117.2 Da (PlcR2) and 78,417 Da (PlcH).
      Additionally, liquid chromatography electrospray mass spectrometry (LCMS)
      revealed that PlcH and PlcR2 are at a stoichiometry of 1 : 1. Western blot
      analysis demonstrated that the enzyme purifies as a heterodimeric complex,
      PlcHR2. PlcHR2 is only active on choline-containing phospholipids. It is equally
      active on phosphatidylcholine (PC) and sphingomyelin (SM) and is able to
      hydrolyse plasmenylcholine phospholipids (plasmalogens). Neither PlcHR2 nor the
      M. tuberculosis homologues are inhibited by D609 a widely used, competitive
      inhibitor of the Bacillus cereus PLC. PlcH, PlcR2, and the PlcHR2 complex bind
      calcium. While calcium has no detectable effect on enzymatic activity, it
      inhibits the haemolytic activity of PlcHR2. In addition to being required for the
      secretion of PlcH, the chaperone PlcR2 affects both the enzymatic and haemolytic
      properties of PlcH. Inclusive in these data is the conclusion that the members of
      this PC-PLC and phosphatase family possess a novel mechanism for the recognition
      and hydrolysis of their respective substrates.

PMID- 12410825
TI  - A novel assembly process of the multicomponent xenobiotic efflux pump in
      Pseudomonas aeruginosa.
AB  - The nfxC-type cells of Pseudomonas aeruginosa show resistance to a wide range of
      structurally and functionally diverse antibiotics, which is a phenomenon that is
      mainly attributable to the expression of the MexEF-OprN xenobiotic transporter.
      The MexF, MexE and OprN subunits of this transporter are located on the inner
      membrane, the periplasm and the outer membrane, respectively, and are assumed to
      function as an energy-dependent transporter, a bridge connecting the inner and
      outer membranes and outer membrane channel respectively. The nfxC-type cells
      showed a single protein band of MexF and OprN, whereas MexE appeared as three
      distinct bands in an SDS-polyacrylamide gel electrophoretogram. The mutant cells
      lacking MexF produced undetectable OprN and only a full-size of MexE even though
      the cells had unimpaired oprN and mexE. Expression of the plasmid-borne MexF in
      this mutant fully restored OprN and three MexE bands. Another class of mutants
      producing a full amount of MexF yielded undetectable OprN and two MexE bands
      lacking the smallest protein species suggesting that the presence of the smallest
      MexE subunit is required for stabilization of OprN. To identify which part of
      MexE was needed for stabilization and assembly of OprN, the carboxyl-terminal
      truncated MexE tagged with polyhistidine was constructed and protein bands were
      visualized in the presence of MexF with an antibody raised against polyhistidine
      or MexE. The results revealed that the proteolytic processing of MexE would occur
      at carboxyl terminal amino acids between 11 and 16, thereby suggesting that the
      presence of the C-terminal truncated MexE is essential for stabilization and the
      proper assembly of OprN. Nucleotide sequencing of mutant mexFs, which produce a
      wild-type level of MexF but are unable to support the production of the smallest
      MexE, thereby destabilizing OprN, revealed that all the mutations were located
      within two large periplasmic domains of MexF between transmembrane segments 1-2
      and 7-8. Taking these findings together, we concluded that two large periplasmic
      domains of MexF interact with MexE thereby promoting programmed processing of
      MexE, and this complex eventually assists the correct assembly and sorting of
      OprN.

PMID- 12410826
TI  - The Salmonella enterica sv. Typhimurium smvA, yddG and ompD (porin) genes are
      required for the efficient efflux of methyl viologen.
AB  - In Gram-negative bacteria, a subset of inner membrane proteins in the major
      facilitator superfamily (MFS) acts as efflux pumps to decrease the intracellular
      concentrations of multiple toxic substrates and confers multidrug resistance. The
      Salmonella enterica sv. Typhimurium smvA gene encodes a product predicted to be
      an MFS protein most similar to QacA of Staphylococcus aureus. Like mutations in
      qacA, mutations in smvA confer increased sensitivity to methyl viologen (MV).
      Mutations in the adjacent ompD (porin) and yddG (drug/metabolite transporter)
      genes also confer increased sensitivity to MV, and mutations in smvA are
      epistatic to mutations in ompD or yddG for this phenotype. YddG and OmpD probably
      comprise a second efflux pump in which the OmpD porin acts as an outer membrane
      channel (OMC) protein for the efflux of MV and functions independently of the
      SmvA pump. In support of this idea, the pump dependent on YddG and OmpD has a
      different substrate specificity from the pump dependent on SmvA. Mutations in
      tolC, which encodes an OMC protein, confer increased resistance to MV. TolC
      apparently facilitates the import of MV, and a subset of OMC proteins including
      the OmpD porin and TolC may facilitate both import and export of distinct subsets
      of toxic substrates.

PMID- 12410827
TI  - Knotting dynamics during DNA replication.
AB  - The topology of plasmid DNA changes continuously as replication progresses. But
      the dynamics of the process remains to be fully understood. Knotted bubbles form
      when topo IV knots the daughter duplexes behind the fork in response to their
      degree of intertwining. Here, we show that knotted bubbles can form during
      unimpaired DNA replication, but they become more evident in partially replicated
      intermediates containing a stalled fork. To learn more about the dynamics of knot
      formation as replication advances, we used two-dimensional agarose gel
      electrophoresis to identify knotted bubbles in partially replicated molecules in
      which the replication fork stalled at different stages of the process. The number
      and complexity of knotted bubbles rose as a function of bubble size, suggesting
      that knotting is affected by both precatenane density and bubble size.

PMID- 12410828
TI  - Loss of RD1 contributed to the attenuation of the live tuberculosis vaccines
      Mycobacterium bovis BCG and Mycobacterium microti.
AB  - Although large human populations have been safely immunized against tuberculosis
      with two live vaccines, Mycobacterium bovis BCG or Mycobacterium microti, the
      vole bacillus, the molecular basis for the avirulence of these vaccine strains
      remains unknown. Comparative genomics has identified a series of chromosomal
      deletions common to both virulent and avirulent species but only a single locus,
      RD1, that has been deleted from M. bovis BCG and M. microti. Restoration of RD1,
      by gene knock-in, resulted in a marked change in colonial morphology towards that
      of virulent tubercle bacilli. Three RD1-encoded proteins were localized in the
      cell wall, and two of them, the immunodominant T-cell antigens ESAT-6 and CFP-10,
      were also found in culture supernatants. The BCG::RD1 and M. microti::RD1 knock
      ins grew more vigorously than controls in immunodeficient mice, inducing
      extensive splenomegaly and granuloma formation. Increased persistence and partial
      reversal of attenuation were observed when immunocompetent mice were infected
      with the BCG::RD1 knock-in, whereas BCG controls were cleared. Knocking-in five
      other RD loci did not affect the virulence of BCG. This study describes a genetic
      lesion that contributes to safety and opens new avenues for vaccine development.

PMID- 12410829
TI  - Characterization of interaction sites in the Saccharomyces cerevisiae ribosomal
      stalk components.
AB  - The interactions among the yeast stalk components (P0, P1alpha, P1beta, P2alpha
      and P2beta) and with EF-2 have been explored using immunoprecipitation, affinity
      chromatography and the two-hybrid system. No stable association was detected
      between acidic proteins of the same type. In contrast, P1alpha and P1beta were
      found to interact with P2beta and P2alpha respectively. An interaction of P0 with
      P1 proteins, but not with P2 proteins, was also detected. This interaction is
      strongly increased with the P0 carboxyl end, which is able to form a pentameric
      complex with the four acidic proteins. The P1/P2 binding site has been located
      between residues 212 and 262 using different C-terminal P0 fragments.
      Immunoprecipitation shows the association of EF-2 with protein P0. However, the
      interaction is stronger with the P1/P2 proteins than with P0 in the two-hybrid
      assay. This interaction improves using the 100-amino-acid-long C-end of P0 and is
      even higher with the last 50 amino acids. The data indicate a specific
      association of P1alpha with P2beta and of P1beta with P2alpha rather than the
      dimerization of the acidic proteins found in prokaryotes. In addition, they
      suggest that stalk assembly begins by the interaction of the P1 proteins with P0.
      Moreover, as functional interactions of the complete P0 were found to increase
      using protein fragments, the data suggest that some active sites are exposed in
      the ribosome as a result of conformational changes that take place during stalk
      assembly and function.

PMID- 12410830
TI  - The Haemophilus influenzae Hia autotransporter harbours two adhesive pockets that
      reside in the passenger domain and recognize the same host cell receptor.
AB  - Haemophilus influenzae is a human-specific pathogen and a major source of
      morbidity worldwide. Infection with this organism begins with colonization of the
      nasopharynx, a process that probably depends on adherence to respiratory
      epithelium. The Hia autotransporter protein is the major adhesin ex-pressed by a
      subset of non-typeable H. influenzae strains and promotes high-level adherence to
      a variety of human epithelial cell lines. In the current study, we discovered
      that the Hia passenger domain contains two distinct binding pockets, including
      one at the C-terminal end and a second at the N-terminal end. Competition assays
      revealed that the two binding pockets interact with the same host cell receptor
      structure, although with differing affinities. Additional experiments
      demonstrated that both binding domains are required for full-level bacterial
      adherence. These observations are reminiscent of eukaryotic cell adhesion
      molecules and highlight the first example of a bacterial adhesin with two domains
      that participate in a bivalent interaction with identical host cell receptors.
      Such an interaction increases avidity, thus stabilizing bacterial adherence to
      the epithelial surface, despite physical forces such as coughing, sneezing and
      mucociliary clearance.

PMID- 12410831
TI  - The glycosylphosphatidylinositol (GPI) signal sequence of human placental
      alkaline phosphatase is not recognized by human Gpi8p in the context of the yeast
      GPI anchoring machinery.
AB  - Biosynthesis of glycosylphosphatidylinositol (GPI)-anchored proteins involves the
      action of a GPI trans-amidase, which replaces the C-terminal GPI signal sequence
      (GPI-SS) of the primary translation product with a preformed GPI lipid. The
      transamidation depends on a complex of four proteins, Gaa1p, Gpi8p, Gpi16p and
      Gpi17p. Although the GPI anchoring pathway is conserved throughout the eukaryotic
      kingdom, it has been reported recently that the GPI-SS of human placental
      alkaline phosphatase (hPLAP) is not recognized by the yeast transamidase, but is
      recognized in yeast that contain the human Gpi8p homologue. This finding suggests
      that Gpi8p is intimately involved in the recognition of GPI precursor proteins
      and may also be responsible for the subtle taxon-specific differences in
      transamidase specificity that sometimes prevent the efficient GPI anchoring of
      heterologously expressed GPI proteins. Here, we confirm that the GPI signal
      sequence of hPLAP is indeed not recognized by the yeast GPI-anchoring machinery.
      However, in our hands, GPI attachment cannot be restored by the co-expression of
      human Gpi8p in yeast cells under any circumstances.

PMID- 12410832
TI  - Competence for natural transformation in Neisseria gonorrhoeae: components of DNA
      binding and uptake linked to type IV pilus expression.
AB  - The mechanisms by which DNA is taken up into the bacterial cell during natural
      genetic transformation are poorly understood. Although related components
      essential to the uptake of DNA during transformation have been defined in Gram
      negative species, it remains unclear whether DNA binding and uptake are
      dissociable events. Therefore, DNA uptake has been the earliest definable step in
      any Gram-negative transformation pathway. In the human pathogen Neisseria
      gonorrhoeae, sequence-specific DNA uptake requires an intact type IV pili (Tfp)
      biogenesis machinery along with three molecules that are dispensable for Tfp
      expression: ComP (a pilin subunit-like molecule), PilT (a cytoplasmic protein
      involved in pilus retraction) and ComE (a periplasmic protein with intrinsic DNA
      binding activity). By conditionally altering the levels of ComP and PilT
      expression, we show here that DNA binding and uptake are resolvable events.
      Consequently, we are able to demonstrate that PilT is largely dispensable for
      functional DNA binding and, therefore, contributes specifically to uptake.
      Furthermore, sequence specificity in this system is imposed at the level of DNA
      binding, a process that is influenced by both ComP and PilE. However, sequence
      specific DNA binding is not attributable to an intrinsic property of the Tfp
      subunit protein. Finally, we demonstrate the existence of a robust, non-specific
      DNA-binding activity associated with the expression of both Tfp and PilT, which
      is unrelated to transformation but obscures the observation of specific binding
      events.

PMID- 12410833
TI  - Selection of plasmid molecules for conjugative transfer and replacement strand
      synthesis in the donor.
AB  - Plasmid selection and strand replacement synthesis in donor cells during
      conjugative transfer was examined by a procedure involving electroporation of
      test plasmid DNA, containing a base pair mismatch, into donor cells prior to
      mating. Multiple copies of the plasmid were transferred from a donor cell that
      allowed vegetative replication of the plasmid. Under conditions non-permissive
      for vegetative replication, there were further rounds of transfer after a lag
      period. Strand replacement in the donor did not depend solely on the initiation
      mechanism for vegetative replication, indicating a conjugation-specific mechanism
      was also available. The lag period between first and second rounds of transfer
      argues against the transfer of multiple copies into recipients by the spooling of
      copies generated on a master molecule by rolling-circle replication.

PMID- 12410834
TI  - Molecular and functional analysis of the type III secretion signal of the
      Salmonella enterica InvJ protein.
AB  - Central to the pathogenicity of Salmonella enterica is the function of a type III
      secretion system (TTSS) encoded within a pathogenicity island at centisome 63
      (SPI-1). An essential component of this system is a supramolecular structure
      termed the needle complex. Proteins to be delivered into host cells possess
      specific signals that route them to the type III secretion pathway. In addition,
      some bacterial proteins have signals that deliver them to the secretion complex
      to either become their structural components or exert their function at that
      location. One of these proteins is InvJ, which controls the length of the needle
      substructure of the needle complex. In this study, we have analysed the signal
      that targets InvJ to the TTSS. We found that amino acid residues 4 to 7 of InvJ
      are necessary and sufficient to mediate secretion of InvJ or a reporter protein
      in a TTSS-dependent manner. InvJ secretion was found to be essential for its
      function in needle length determination, effector protein secretion and bacterial
      invasion of epithelial cells. Frameshift mutagenesis analysis indicated that the
      InvJ type III secretion signal sequence tolerates significant alterations in its
      amino acid sequence without affecting InvJ secretion. Introduction of silent
      mutations in the secretion signal coding sequence that result in drastically
      different predicted mRNA folds had no effect on InvJ secretion or expression.

PMID- 12410835
TI  - Regulation of the yeast Rlm1 transcription factor by the Mpk1 cell wall integrity
      MAP kinase.
AB  - The Mpk1 MAP kinase of the Saccharomyces cerevisiae cell wall integrity
      signalling pathway phosphorylates and activates the Rlm1 transcription factor in
      response to cell wall stress. Rlm1 is related to mammalian MEF2 isoforms, and
      shares a similar DNA-binding specificity. Signalling through Rlm1 regulates the
      expression of at least 25 genes, most of which have been implicated in cell wall
      biogenesis. We report here the transcriptional induction by agents of cell wall
      stress of a set of lacZ reporter plasmids derived from several Rlm1-responsive
      genes. Analysis of substitution mutations at putative Mpk1 phosphorylation sites
      within Rlm1 revealed that Ser427 and Thr439 are important for its stress-induced
      transcriptional activation of these reporter plasmids. Assessment of Rlm1
      activation potency when fused to a heterologous DNA-binding domain showed that
      the identified seryl and threonyl residues are necessary for the Rlm1
      transcriptional activation function independently of its DNA binding. We also
      demonstrate that a MAP kinase docking site, shown recently to mediate activation
      of MEF2A and MEF2C, is conserved in Rlm1 and is required for its ability to
      mediate transcriptional activation in response to agents that induce cell wall
      stress. Finally, intracellular localization analyses show that Rlm1 resides in
      the nucleus regardless of its activation and phosphorylation status. Together
      these observations support the inference that Mpk1 regulates the Rlm1
      transcriptional activation function by phosphorylation of Ser427 and Thr439.

PMID- 12410836
TI  - DNA damage induction of recA in Mycobacterium tuberculosis independently of RecA
      and LexA.
AB  - The ubiquitous and highly conserved RecA protein is generally expressed from a
      single promoter, which is regulated by LexA in conjunction with RecA. We show
      here using transcriptional fusions to a reporter gene that the Mycobacterium
      tuberculosis recA gene is expressed from two promoters. Although one promoter is
      clearly regulated in the classical way, the other remains DNA damage inducible in
      the absence of RecA or when LexA binding is prevented. These observations
      demonstrate convincingly for the first time that there is a novel mechanism of
      DNA damage induction in M. tuberculosis that is independent of LexA and RecA.

PMID- 12410837
TI  - Requirement of spermidine for developmental transitions in Aspergillus nidulans.
AB  - Deletion of the spermidine synthase gene in the fungus Aspergillus nidulans
      results in a strain, deltaspdA, which requires spermidine for growth and
      accumulates putrescine as the sole polyamine. Vegetative growth but not
      sporulation or sterigmatocystin production is observed when deltaspdA is grown on
      media supplemented with 0.05-0.10 mM exogenous spermidine. Supplementation of
      deltaspdA with >/= 0.10 mM spermidine restores sterigmatocystin production and
      >/= 0.50 mM spermidine produces a phenotype with denser asexual spore production
      and decreased radial hyphal growth compared with the wild type. DeltaspdA spores
      germinate in unsupplemented media but germ tube growth ceases after 8 h upon
      which time the spores swell to approximately three times their normal diameter.
      Hyphal growth is resumed upon addition of 1.0 mM spermidine. Suppression of a G
      protein signalling pathway could not force asexual sporulation and
      sterigmatocystin production in deltaspdA strains grown in media lacking
      spermidine but could force both processes in deltaspdA strains supplemented with
      0.05 mM spermidine. These results show that increasing levels of spermidine are
      required for the transitions from (i) germ tube to hyphal growth and (ii) hyphal
      growth to tissue differentiation and secondary metabolism. Suppression of G
      protein signalling can over-ride the spermidine requirement for the latter but
      not the former transition.

PMID- 12410838
TI  - Regulation and mode of action of the second small RNA activator of RpoS
      translation, RprA.
AB  - Translation of the stationary phase sigma factor RpoS is stimulated by at least
      two small RNAs, DsrA and RprA. DsrA disrupts an inhibitory secondary structure in
      the rpoS leader mRNA by pairing with the upstream RNA. Mutations in rprA and
      compensating mutations in the rpoS leader demonstrate that RprA interacts with
      the same region of the RpoS leader as DsrA. This is the first example of two
      different small RNAs regulating a common target. Regulation of these RNAs
      differs. DsrA synthesis is increased at low temperature. We find that RprA
      synthesis is regulated by the RcsC/RcsB phosphorelay system, previously found to
      regulate capsule synthesis and promoters of ftsZ and osmC. An rcsB null mutation
      abolishes the basal level, whereas mutations in rcsC that activate capsule
      synthesis also activate expression of the rprA promoter. An essential site with
      similarity to other RcsB-regulated promoters was defined in the rprA promoter.
      Activation of the RcsC/RcsB system leads to increased RpoS synthesis, in an RprA
      dependent fashion. This work suggests a new signal for RpoS translation and
      extends the global regulation effected by the RcsC/RcsB system to coregulation of
      RpoS with capsule and FtsZ.

PMID- 12410839
TI  - The UV-B stimulon of the terrestrial cyanobacterium Nostoc commune comprises
      early shock proteins and late acclimation proteins.
AB  - The UV-B and desiccation-tolerant terrestrial cyanobacterium Nostoc commune was
      grown under defined UV irradiation. Proteome changes were monitored in the
      membrane and the cytosolic and the extracellular fractions. Tools were developed
      to separate stress-triggered from growth stage-dependent changes. UV-B changed
      the relative cellular concentration of 493 out of 1,350 protein spots at least by
      a factor of three, rendering the UV-B stimulon of N. commune the most complex one
      described so far. It comprises two different parts: an early shock response
      influencing 214 proteins and a late acclimation response involving 279 proteins.
      The shock response comprised many membrane or membrane-associated proteins,
      whereas the acclimation response mainly changed cytosolic proteins. Most of the
      shock-induced changes were transient and did not overlap with the acclimation
      response. In the extracellular fraction, UV irradiation induced superoxide
      dismutase and the water stress protein. In total, 27 intracellular, UV-B-induced
      proteins were partially sequenced by electrospray ionization tandem mass
      spectrometry. Three functional classes were identified: proteins involved in
      lipid metabolism, in carbohydrate metabolism and in regulatory pathways. About
      50% of the sequenced proteins were homologous to cyanobacterial database entries
      with un-known function. Interestingly, all of these proteins belong to the UV-B
      acclimation response. We conclude that the UV-B shock response and the UV-B
      acclimation response represent two completely different and remarkably complex
      strategies of N. commune to protect itself against UV-B radiation in its natural
      environment.

PMID- 12410840
TI  - Rst1 and Rst2 are required for the a/alpha diploid cell type in yeast.
AB  - In the budding yeast Saccharomyces cerevisiae, the preservation of the mating
      competent haploid (a or alpha) and the mating incompetent diploid (a/alpha) is
      necessary to prevent aneuploidy. Once haploid cells respond to pheromone, the
      mating-specific signal transduction pathway is activated, and the MAP kinase Fus3
      phosphorylates two specific repressor proteins Rst1 and Rst2 (also known as Dig1
      and Dig2) to promote Ste12-dependent transcription of mating-specific genes. In
      contrast, diploid cells cannot mate because genes that encode components of the
      mating pathway are repressed through the combined action of the Mata1-Matalpha2
      and Matalpha2-Mcm1 repressors. Surprisingly, repression of Ste12 by Rst1 and Rst2
      is essential for diploid sterility. Homozygous deletion of both RST1 and RST2
      (rst-) causes a/alpha diploid cells constitutively to express a-specific genes
      and mate preferentially as a-cells. This phenotype is sensitive to Ste12 dosage,
      as removal of one copy of STE12 completely reduces the ectopic activation of a
      specific genes. The Matalpha2-Mcm1 complex, which normally represses a-specific
      genes, is defective in rst- diploids because Matalpha2 is destabilized in rst-
      diploids, possibly as a consequence of its relocalization from the nucleus to the
      cytoplasm. This study finds that Rst1 and Rst2 are necessary for the a/alpha
      diploid cell type. Rst1 and Rst2 are required in order to prevent the
      amplification of a robust Ste12 transcriptional programme that appears to over
      ride Matalpha2-dependent repression of haploid and a-specific genes.

PMID- 12410841
TI  - The N-terminus of enteropathogenic Escherichia coli (EPEC) Tir mediates transport
      across bacterial and eukaryotic cell membranes.
AB  - Enteropathogenic Escherichia coli (EPEC) uses a type III secretion system to
      translocate into host cells several effector molecules that are required for
      virulence. One of these, the translocated intimin receptor, Tir, inserts into the
      host cell cytoplasmic membrane, where it functions as the receptor for intimin,
      an outer membrane adhesin expressed by EPEC. A chaperone for Tir, called CesT, is
      required for stability of Tir in the EPEC cytoplasm. In this study, the cyaA gene
      reporter system was used to identify domains in Tir that mediate secretion into
      the culture supernatant and translocation into host cells. A Tir-CyaA fusion
      containing the first 15 N-terminal residues of Tir was secreted and translocated
      into HeLa cells by a deltatirdeltacesT mutant; however, maximal secretion and
      translocation was observed with the first 26 N-terminal residues of Tir. Fusions
      containing progressively larger N-terminal sequences of Tir were also efficiently
      secreted and translocated into HeLa cells by the deltatirdeltacesT strain.
      However, in a deltatir mutant that expresses CesT, Tir26-CyaA and an additional
      fusion containing the first 69 N-terminal residues of Tir were not secreted or
      translocated, but fusions containing larger N-terminal Tir sequences were
      secreted and translocated by the deltatir mutant. Wild-type EPEC secreted and
      translocated the Tir15-CyaA fusion, whereas longer fusions, such as Tir26-CyaA
      and Tir69-CyaA, were translocated to higher levels, similar to what was observed
      with the deltatirdeltacesT mutant. A Tir-CyaA fusion containing the CesT binding
      domain was translocated into HeLa cells more rapidly in the presence of CesT
      compared with translocation in the absence of CesT. Collectively, these results
      suggest that an N-terminal domain of 26 amino acids functions as a CesT
      independent signal that is capable of delivering Tir into both the culture
      supernatant and the cytosol of host cells. Furthermore, in addition to its role
      in the stability of Tir, CesT may function in translocation by mediating rapid
      delivery of Tir into host cells.

PMID- 12410842
TI  - Thioredoxins are required for protection against a reductive stress in the yeast
      Saccharomyces cerevisiae.
AB  - Thioredoxins are small, highly conserved oxidoreductases that are required to
      maintain the redox homeostasis of the cell. They have been best characterized for
      their role as antioxidants in protection against reactive oxygen species. We show
      here that thioredoxins (TRX1, TRX2) and thioredoxin reductase (TRR1) are also
      required for protection against a reductive stress induced by exposure to
      dithiothreitol (DTT). This sensitivity to reducing conditions is not a general
      property of mutants affected in redox control, as mutants lacking components of
      the glutathione/glutaredoxin system are unaffected. Furthermore, TRX2 gene
      expression is induced in response to DTT treatment, indicating that thioredoxins
      form part of the cellular response to a reductive challenge. Our data indicate
      that the sensitivity of thioredoxin mutants to reducing stress appears to be a
      consequence of elevated glutathione levels, which is present predominantly in the
      reduced form (GSH). The elevated GSH levels also result in a constitutively high
      unfolded protein response (UPR), indicative of an accumulation of unfolded
      proteins in the endoplasmic reticulum (ER). However, there does not appear to be
      a general defect in ER function in thioredoxin mutants, as oxidative protein
      folding of the model protein carboxypeptidase Y occurs with similar kinetics to
      the wild-type strain, and trx1 trx2 mutants are unaffected in sensitivity to the
      glycosylation inhibitor tunicamycin. Furthermore, trr1 mutants are resistant to
      tunicamycin, consistent with their high UPR. The high UPR seen in trr1 mutants
      can be abrogated by the GSH-specific reagent 1-chloro-2,4-dinitrobenzene. In
      summary, thioredoxins are required to maintain redox homeostasis in response to
      both oxidative and reductive stress conditions.

PMID- 12410843
TI  - Mutants in flaI and flaJ of the archaeon Methanococcus voltae are deficient in
      flagellum assembly.
AB  - The fla gene locus of Methanococcus voltae encodes the major structural
      components of the flagellum as well as other flagellar-related proteins. The
      flaHIJ genes have been found in all flagellated archaea, suggesting a central
      role in flagella biogenesis. FlaI shares similarity with the type II and type IV
      secretion NTPases (such as PilB, VirB11 and TadA), and FlaJ exhibits similarity
      to putative bacterial integral membrane proteins involved in type IV pilus
      biogenesis such as TadB. In this study, reverse transcription polymerase chain
      reaction (RT-PCR) and Northern blotting data revealed that flaHIJ are co
      transcribed with the upstream structural flagellin genes, thus demonstrating the
      expression of the entire fla gene cluster in vivo. Non-polar mutants in flaI and
      flaJ of M. voltae were isolated using insertional inactivation via a novel
      mutagenic vector. These mutants were non-motile and non-flagellated by
      microscopy, demonstrating the involvement of FlaI and FlaJ in flagella
      biogenesis. Interestingly, all the mutants maintained the ability to produce and
      localize flagellins to the cytoplasmic membrane. Amino-terminal sequencing of
      flagellins produced by the flaJ mutant strain revealed that the flagellins did
      not have their cognate leader peptides, thus indicating that preflagellin
      processing had occurred in vivo. This result was confirmed using an in vitro
      processing assay. The fla- phenotype and protein secretion characteristics of the
      flaI and flaJ mutants therefore implicate these respective genes in archaeal
      flagellin secretion and assembly. These findings further support a model
      describing the archaeal flagellum as a novel prokaryotic motility structure.

PMID- 12410844
TI  - On the mechanism of substrate specificity by resistance nodulation division (RND)
      type multidrug resistance pumps: the large periplasmic loops of MexD from
      Pseudomonas aeruginosa are involved in substrate recognition.
AB  - Tripartite efflux systems of Gram-negative bacteria that contain an inner
      membrane transporter belonging to the resistance nodulation division (RND)
      superfamily can extrude a large variety of structurally diverse compounds. To
      gain an insight into the molecular mechanisms of substrate recognition by these
      multidrug resistance (MDR) transporters, we isolated spontaneous mutations that
      altered the substrate specificity of the MexCD-OprJ pump from Pseudomonas
      aeruginosa. These mutations enabled the pump to extrude the normally non
      transported beta-lactam antibiotic carbenicillin. All amino acid substitutions
      were mapped to the large periplasmic loops (LPLs) of the RND proper, MexD. Q34K,
      E89K, A292V and P328L were found in the first LPL, located between transmembrane
      domains (TMD) 1 and 2, whereas F608S and N673K were contained in the second LPL,
      located between TMD7 and TMD8. These mutations also had a substantial impact on
      the MexCD-OprJ-mediated transport of numerous other substrates. Subsequent
      replacement of amino acid residues identified above by cysteines rendered MexCD
      OprJ susceptible to inhibition by a thiol-reactive agent, MIANS. Interestingly,
      MIANS inhibited the transport of some (pyronin, EtBr) but not other (ANS, Leu
      Nap) substrates of the pump. Our results suggest that the precise structure of
      the periplasmic loops of MexD determines the rate of transport of individual
      substrates. These results are consistent with the hypothesis that, in the case of
      RND transporters, the LPLs are directly implicated in substrate recognition and
      contain multiple sites of interaction for various structurally diverse compounds.

PMID- 12410847
TI  - Role of endothelin-1 and thromboxane A2 in renal vasoconstriction induced by
      angiotensin II in diabetes and hypertension.
AB  - BACKGROUND: Interactions among angiotensin II (Ang II), endothelin-1 (ET-1) and
      thromboxane A2 (TXA2) may play an important role in the regulation of renal
      function. The present study investigated the participation of TXA2 and ET-1 in
      the increase in renal vascular resistances (RVR) induced by Ang II, as well as
      the consequences of diabetes, hypertension, and the combination of both on this
      response. METHODS: Isolated kidneys from male normoglycemic or streptozotocin
      induced diabetic Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats
      (SHR) were used. The increase in perfusion pressure (PP) produced by Ang II was
      studied in the absence or presence of the TXA2 receptor antagonist, ifetroban, or
      the ETA/ETB receptor antagonist, PD145065. RESULTS: Systolic arterial pressure
      (SAP) was higher in SHR than in WKY, but diabetic rats (D) from each strain
      showed lower SAP values than their respective non-diabetic rats. Basal renal PP
      was higher in WKY and SHR than in WKY-D and SHR-D. Increases in renal PP produced
      by Ang II were comparable in the kidneys from all groups. Either ifetroban or
      PD145065 reduced the maximal Ang II response in all animals. The maximal
      inhibitory effect of ifetroban was higher (P<0.05) in WKY than in the other
      groups. However, the maximal inhibitory effect of PD145065 was lower in SHR than
      in the other groups. CONCLUSION: This study supports a role for ET-1 and TXA2 as
      mediators of the increase in renal vascular resistance produced by Ang II. These
      results indicate that the participation of ET-1 in the renal vasoconstriction
      produced by Ang II was reduced under hypertensive conditions, and that of TXA2
      was reduced by both diabetes and hypertension.

PMID- 12410848
TI  - Angiotensin II and growth factors in the pathogenesis of diabetic nephropathy.
AB  - The renin-angiotensin system (RAS) and growth factors mediate structural and
      functional changes during the course of diabetic nephropathy (DN). Studies in
      humans and experimental models with DN suggest their involvement in the
      development and progression of DN. Activation of renal tissue RAS and increased
      expression of growth factors have been demonstrated at early stages of the
      disease. Angiotensin II and growth factors alter renal hemodynamics and exert
      trophic changes in renal cells that eventually result in fibrosis through direct
      mechanisms or through the release of other mediators. Their effects are likely
      modulated by metabolic changes including high glucose and free fatty acids. While
      blockade of the RAS ameliorates DN in humans, such evidence for blockade of
      growth factors is still lacking. It is likely that susceptibility to the
      development of DN and therapeutic efficacy are modulated by genetic polymorphisms
      in components of the RAS and growth factors including their receptors and other
      target molecules. Approaches to understand the intricate relationship between
      these systems and the mechanism(s) by which they alter capillary permeability and
      result in structural changes are areas of fruitful investigation.

PMID- 12410849
TI  - Angiotensin II regulates the synthesis of proinflammatory cytokines and
      chemokines in the kidney.
AB  - BACKGROUND: Emerging evidence suggests that angiotensin II (Ang II) is not only a
      vasoactive peptide, but also a true cytokine that regulates cell growth,
      inflammation and fibrosis. Many studies have demonstrated that this peptide plays
      an active role in the progression of renal injury. Some of Ang II-induced effects
      are mediated by the production of a large array of growth factors. The aim of
      this study was to investigate whether Ang II could regulate the expression of
      cytokines and chemokines in the kidney and its correlation with the Ang II
      induced renal damage. METHODS: The model of Ang II-induced renal damage was done
      by systemic Ang II infusion into normal rats (50 ng/kg/min; subcutaneous osmotic
      minipumps). In addition, the implication of Ang II was investigated in a model of
      immune complex nephritis in rats treated with the angiotensin converting enzyme
      (ACE) inhibitor quinapril. The mRNA expression was analyzed by RT-PCR and/or
      Northern blot, and protein levels by Western blot and/or immunohistochemistry.
      RESULTS: Rats infused with Ang II for 3 days caused elevated renal expression of
      tumor necrosis factor-alpha (TNF-alpha; gene and protein levels). TNF-alpha
      positive cells were observed in glomeruli (mainly in endothelial cells), tubules
      and vessels. In rats with immune complex nephritis, the renal overexpression of
      TNF-alpha was diminished by the ACE inhibitor quinapril. Systemic infusion of Ang
      II also increased renal synthesis of cytokines (interleukin-6, IL-6) and
      chemokines (monocyte chemoattractant protein-1; MCP-1) that were associated with
      elevated tissue levels of activated nuclear factor-kappaB (NF-kappaB) and the
      presence of inflammatory cell infiltration. CONCLUSIONS: Ang II in vivo increases
      TNF-alpha production in the kidney. Ang II also up-regulates other
      proinflammatory mediators, including IL-6, MCP-1 and NF-kappaB, coincidentally
      associated to the presence of glomerular and interstitial inflammatory cells in
      the kidney. All these data further strengthen the idea that Ang II plays an
      active role in the inflammatory response in renal diseases.

PMID- 12410850
TI  - Comparative effects of ACE inhibition and angiotensin II receptor blockade in the
      prevention of renal damage.
AB  - Angiotensin II (Ang II) regulates a number of genes associated with progression
      of renal disease. The regulation of gene expression by Ang II occurs through
      specific receptors that are linked to changes in the activity of transcription
      factors within the nucleus of target cells. In particular, members of the nuclear
      factor-kappaB family of transcription factors are activated, which in turn fuels
      at least two autocrine reinforcing loops that amplify Ang II and tumor necrosis
      factor-alpha formation. Angiotensin converting enzymes (ACE) inhibitors and
      angiotensin antagonists (AIIAs) differ both pharmacokinetically and
      pharmacodynamically in patients with end-stage renal disease (ESRD). Several ACE
      inhibitors (such as captopril, enalapril and lisinopril) are dialyzable, whereas
      all of the AIIAs studied are not. Dose titration may be necessary when
      administering ACE inhibitors to patients with renal failure (ESRD), but is rarely
      a consideration when AIIAs are used.

PMID- 12410851
TI  - Effects of antihypertensive drugs in experimental type 2 diabetes-related
      nephropathy.
AB  - BACKGROUND: It has been extensively reported that antihypertensive drugs reduce
      proteinuria and glomerulosclerosis (GS) in many experimental nephropathies and in
      humans. However, the role of calcium channel blockers (CCBs) in the prevention of
      proteinuria and GS remains controversial and in most cases only dihidropyridine
      CCBs are studied. Few studies have reported whether the time at which drug
      administration is initiated plays a role in the reduction of proteinuria and GS.
      METHODS: Fifty-six male Obese Zucker rats (OZR) were used as a model of
      spontaneous type 2 diabetes-related nephropathy. Biochemical and histological
      analysis were performed to compare the efficacy of a non-dihydropyridine-CCB
      diltiazem [DZM; 100 mg/kg body weight (BW)/day], an ACEI quinapril (10 mg/kg
      BW/day), or both in diminishing proteinuria and GS, and to determine their role
      in effective prevention and treatment. RESULTS: Only quinapril was able to
      diminish proteinuria. As far as histological lesions, both treatments were
      effective, although only quinapril prevented GS. The combination of quinapril
      plus DZM did not demonstrate any beneficial effects. Surprisingly, quinapril
      ameliorated the damage of podocytes whereas DZM did not, thus leading to doubt
      concerning the efficiency of DZM in long-term studies. Nonetheless, the
      combination of quinapril plus DZM demonstrated a greater reduction in podocyte
      damage than treatment with DZM alone, which shows an interesting association in
      the prevention of longer-term glomerular damage. Few differences were found
      between prevention and treatment. CONCLUSIONS: Quinapril, but not DZM, was able
      to diminish proteinuria in OZR. Both treatments were effective in diminishing GS,
      although only quinapril totally prevented it. The combination of both drugs
      prevented long-term glomerular damage, which is intriguing.

PMID- 12410852
TI  - Role of calcium channel blockers in the future, in view of the INSIGHT Study.
AB  - The data from The International Nifedipine Intervention as a Goal in Hypertension
      Treatment (INSIGHT) Study indicate that effectively reducing blood pressure can
      decrease the incidence of cardiovascular events in high risk patients with
      concomitant pathology, including diabetes and hypercholesterolemia, as well as in
      smokers and those with poor family history. Old and new antihypertensive drugs
      were similar in preventing cardiovascular mortality as major events. The
      glomerular filtration rate of patients on co-amilozide went down compared to
      those on nifedipine. Metabolic parameters, as expected, were not disturbed during
      treatment with calcium channel blockers, in contrast to the high-dose diuretic
      treated population. Ankle edema induced by nifedipine was very disturbing. It can
      be concluded that overall calcium channel blockers are neither better nor worse
      than conventional therapy, allowing for possible small differences in stroke
      (advantage to calcium channel blockers) and myocardial infarction (advantage to
      diuretics). Thus, calcium channel blockers should be included in the future among
      the first choice drugs.

PMID- 12410853
TI  - Angiotensin II type 1 receptor blockade to control blood pressure in
      postmenopausal women: influence of hormone replacement therapy.
AB  - BACKGROUND: Hypertension is twice as common in postmenopausal than in
      premenopausal women. This study evaluated the effectiveness of a blockade of the
      renin-angiotensin-aldosterone system (RAAS) with candesartan cilexetil (CC) to
      control blood pressure (BP) in hypertensive menopausal women, and the influence
      of hormone replacement therapy (HRT). METHODS: This was designed as a
      prospective, open-label and non-comparative study. Included were 618 hypertensive
      menopausal women grade I/II according to the Sixth Report of the Joint National
      Committee (VI-JNC), with an average age 52+/-4.7 years (95% CI 52.3-53.0) and
      with a last menstrual period (LMP) at least one year before. BP was determined by
      measurement in four visits during six months of follow-up, according to the
      recommendations of the OMS/SIH. Optimal control of BP was considered as BP
      <140/90 mm Hg. RESULTS: A statistically significant decrease in systolic (SBP;
      19.9+/-11.2) and diastolic (DBP; 11.5+/-7.3) blood pressure mm Hg values was
      observed (P<0.01). The control of BP increased significantly over time to 61.2%
      (P<0.01). In multivariate analysis, only age was associated with control of BP
      (beta= -0.062; P=0.004). Of the women not controlled in the second visit, 12.5 mg
      of hydrochlorothiazide (HCTZ) were added to 31.5% (N=122), with 80% more BP
      control achieved in visit 3 than in the non-supplement group (OR=1.8; 95% CI 1.04
      3.05; P<0.03). One hundred and three (16.7%) patients were receiving HRT for
      2.01+/-2.23 years (95% CI 1.55-2.46). HRT did not affect the control of BP. No
      severe adverse reactions were reported. CONCLUSIONS: Candesartan cilexetil
      significantly reduced SBP and DBP and increased control (61.2%) of BP in
      hypertensive menopausal women. Only age had an inverse association with control
      of BP. In this study, HRT did not affect the control of BP.

PMID- 12410854
TI  - Renal damage associated with proteinuria.
AB  - Experimental studies have demonstrated that proteins filtered by the glomerulus
      induce a proliferation of proximal tubular cells accompanied by an increased
      synthesis of many vasoactive and proinflammatory substances. The appearance of
      interstitial cellular infiltrates, a well-known finding in proteinuric diseases,
      precedes progressive tubulointerstitial fibrosis. Activation of the transcription
      factor kappaB (NF-kappaB) plays a pivotal role in the renal damage induced by
      proteinuria. In this scenario, any therapeutic intervention that reduces
      proteinuria should be beneficial for the kidney. Drugs that block the renin
      angiotensin system [angiotensin converting enzyme (ACE) inhibitors and
      angiotensin II receptor antagonists (ARA)] have repeatedly shown striking
      antiproteinuric and renoprotective properties, both in experimental and clinical
      studies. Studies in patients with type 1 and type 2 diabetic nephropathy as well
      as in non-diabetic nephropathies have confirmed that the renoprotection obtained
      with ACEI/ARA is closely related with their antiproteinuric effect and is largely
      independent of blood pressure changes. However, resistance to the antiproteinuric
      effect of ACEI/ARA is a common clinical observation. Several therapeutic measures
      (that is, adequate blood pressure control, early introduction of ACEI/ARA,
      dietary protein restriction, low salt diets, weight loss in overweight patients,
      addition of a diuretic, increasing ACEI/ARA dose titrated against proteinuria
      levels, combined therapy ACEI plus ARA, addition of drugs with antiproteinuric
      effect such as non-dihydropiridine calcium channel blockers or NSAIDs) may
      increase the proteinuria reduction induced by ACEI and ARA.

PMID- 12410856
TI  - Role of combination therapy with ACE inhibitors and calcium channel blockers in
      renal protection.
AB  - Over recent years, a target blood pressure of 125/75 mm Hg has been sought in
      order to reduce the rate of chronic renal disease (CKD) progression and
      cardiovascular mortality. Some antihypertensive agents, such as angiotensin
      converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists and
      calcium channel blockers also may be capable of reducing CKD progression because
      they halt some of the pathogenetic mechanisms involved in renal damage. The
      possibility that combination treatments with ACE inhibitors and calcium-channel
      blockers may confer additive or even synergistic renoprotective effects other
      than blood pressure control is not only fascinating, but also particularly
      important because multidrug antihypertensive regimens are required to obtain
      adequate blood pressure in the majority of patients with CKD. This combination
      may provide better blood pressure control, appears to be better tolerated with
      fewer side effects than either drug alone, and may exert a greater renoprotective
      effect in patients at risk for renal failure than either an ACE inhibitors or a
      calcium channel blocker. However, the current available data are too few to
      confirm this hypothesis. Cardiovascular disease accounts for more than 50% of the
      deaths of hemodialysis patients. Thus, care must be taken to prevent and treat
      the cardiovascular risk factors optimally from the early phase of CKD, and for
      this reason effective antihypertensive therapy is the most important treatment,
      not only in order to delay CKD progression, but also to reduce the burden of
      cardiovascular disease. In this perspective combination therapy with ACE
      inhibitors and calcium channel blockers can give further advantages.

PMID- 12410855
TI  - Effects of dual blockade of the renin-angiotensin system in primary proteinuric
      nephropathies.
AB  - BACKGROUND: Blockade of the renin-angiotensin system (RAS) with angiotensin
      converting enzyme (ACE) inhibitors or with angiotensin II type 1 (AT1) receptor
      blockers has been shown to reduce proteinuria and to slow down the progression of
      renal disease in diabetic and non-diabetic primary proteinuric nephropathies.
      Additionally, this beneficial effect is not dependent on blood pressure control.
      METHODS: To assess and compare the effects of lisinopril (up to 40 mg/day),
      candesartan (up to 32 mg/day) and combination therapy (lisinopril up to 20 mg/day
      plus candesartan up to 16 mg/day) on urinary protein excretion, 45 patients with
      primary proteinuric nephropathies (urinary protein/creatinine ratio 3.8+/-2.4
      g/g) and normal or slightly reduced renal function (CCr 95+/-33 mL/min) were
      enrolled in a six month multicenter, prospective, open, randomized, active
      controlled and parallel-group trial with 1:1:1 allocation. Blood pressure goal
      was set at or below 125/75 mm Hg for all patients, with additional
      antihypertensive medication prescribed if required. RESULTS: Renal function,
      estimated by creatinine clearance, remained stable throughout the study.
      Hyperkalemia (K>5.5 mmol/L) was detected in 3.1% of all measurements in follow
      up, and was more frequent in patients treated with lisinopril alone or lisinopril
      plus candesartan (P<0.001) than in those on candesartan alone. No other relevant
      adverse event was recorded. The blood pressure goal (<125/75 mm Hg) was achieved
      by week 4 in all treatment groups (P<0.005 when compared to baseline), and
      afterwards the mean systolic and diastolic blood pressure remained below these
      values until the end of the trial with no statistically significant differences
      between groups. Urinary protein/creatinine ratio (percentage reduction 95%
      confidence intervals CI) decreased in patients treated with lisinopril alone to 
      33% (CI -12-56) to -31% (CI 0-68) and to -50% (CI -9-90), in patients treated
      with candesartan to -28% (CI -12-45), to -41% (CI -30-52) and to -48% (CI -32
      63), in patients treated with the combination of both to -60% (CI -44-77) to -54%
      (CI -38-69) and to -70% (CI -57-83) at two, three, and six months, respectively.
      All comparisons with baseline achieved statistical significance and treatment
      with combination therapy was statistically more effective in proteinuria
      reduction than treatment with candesartan alone at two and six months (P=0.004
      and P=0.023, respectively) and than treatment with lisinopril only at two months
      (P=0.03). CONCLUSION: Dual blockade of the renin-angiotensin system with ACE
      inhibitors and AT1 receptor blockers produces a beneficial antiproteinuric effect
      that could not be explained only by the systemic blood pressure reduction. All
      treatments were well tolerated.

PMID- 12410857
TI  - Angiotensin blockade in type 2 diabetic renal disease.
AB  - The available evidence on renal protection in type 2 diabetes mellitus favors the
      administration of an angiotensin receptor blocker (ARB) more than that of an
      angiotensin converting enzyme inhibitor (ACEi). This evidence is based on recent
      studies showing that losartan and irbesartan can prevent the development of overt
      diabetic nephropathy in microalbuminuric type 2 diabetic patients as well as slow
      the velocity of progression to end-stage renal disease in patients with overt
      type 2 diabetic nephropathy. These studies do not deny the possibility that ACEi
      are equally effective, but studies of an adequate magnitude are lacking. These
      findings on ARB administration do not preclude the importance of strict control
      of blood pressure and proteinuria and/or albuminuria to avoid or retard renal
      damage in type 2 diabetic patients.

PMID- 12410858
TI  - Losartan in patients with type 2 diabetes and proteinuria: observations from the
      RENAAL Study.
AB  - BACKGROUND: Recently, the Reduction of Endpoints in NIDDM with the Angiotensin II
      Antagonist Losartan (RENAAL) Study demonstrated the benefit of losartan in
      reducing renal outcomes in patients with type 2 diabetes and proteinuria.
      Additional questions concerning the reduction of proteinuria and its relationship
      to end-stage renal disease (ESRD) as well as cardio-renal outcomes and the safety
      and tolerability of losartan remain to be addressed. METHODS: Three analyses were
      performed: (a) the impact of losartan on the relationship between the reduction
      of proteinuria and ESRD; (b) a time-to-event analysis of the cardio-renal
      composite endpoint of ESRD, myocardial infarction, stroke or all-cause death; and
      (c) additional analyses of adverse events, particularly in patients with serum
      creatinine >or=2.0 mg/dL. RESULTS: After adjusting the values for proteinuria
      over the entire study, the reduction of proteinuria accounted for approximately
      half of the treatment effect of losartan on the risk reduction for ESRD. In
      addition, losartan was associated with a 21% risk reduction for the composite
      cardio-renal outcome (P=0.003). The addition of losartan to a conventional
      antihypertensive regimen did not increase the overall incidence of adverse
      events, regardless of severity of renal impairment. CONCLUSIONS: Losartan
      significantly reduced the risk of cardiorenal outcomes and was well tolerated by
      patients, including those with serum creatinine levels >or=2.0 g/dL. In addition,
      although this study shows that the reduction of proteinuria does not completely
      explain the impact of intervention on outcomes such as ESRD, reduction of
      proteinuria must remain an important consideration when treating patients with
      type 2 diabetes and nephropathy. However, the reduction of outcomes such as ESRD
      should remain the goal of therapy when evaluating renal protection in this
      patient population.

PMID- 12410859
TI  - Losartan reduces the burden and cost of ESRD: public health implications from the
      RENAAL study for the European Union.
AB  - Type 2 diabetes is the leading cause of end-stage renal disease (ESRD) in most
      industrialized countries in Europe. The RENAAL (Reduction of Endpoints in NIDDM
      with the Angiotensin II Antagonist Losartan) Study evaluated the renal protective
      effects of losartan versus placebo on a background of non-ACE-I/non-AIIA
      conventional antihypertensive therapy in 1513 patients with type 2 diabetes and
      nephropathy. Losartan reduced the incidence of doubling of serum creatinine, end
      stage renal disease (ESRD), or death by 16% (P=0.022) and reduced the risk of
      progression to ESRD, defined as the initiation of dialysis or transplantation, by
      29% (P=0.002). We set out to estimate the potential effect of losartan on the
      burden and costs associated with ESRD over 3.5 years in the European Union (EU).
      The risk reduction in new cases of ESRD was calculated by combining type 2
      diabetes population estimates for the EU with the percent absolute risk reduction
      of ESRD in patients treated with losartan as observed in RENAAL. The number of
      days each patient experienced ESRD was defined as the length of time from onset
      of ESRD until the minimum of death or 3.5 years. ESRD-free person-years avoided
      with losartan treatment were calculated by combining the population estimate with
      the ESRD days avoided divided by number of days in a year. ESRD costs from
      Germany were used to approximate the potential cost savings from reduced time
      with ESRD and fewer ESRD cases on a EU wide basis. There are approximately
      700,000 diagnosed type 2 diabetes patients with proteinuria (urine
      albumin/creatinine >or=300 mg/g) in the EU. The addition of losartan to the
      treatment regimen of these patients is expected to lead to a reduction of 44,100
      cases of ESRD, 64,400 fewer person-years with ESRD, and reduce ESRD-related costs
      by euro 2.6 billion over 3.5 years based on RENAAL data. Treatment with losartan
      not only reduced the incidence of ESRD, but also can result in substantial cost
      savings in the European Union.

PMID- 12410860
TI  - Cardiovascular calcification in patients with end-stage renal disease: a century
      old phenomenon.
AB  - The mortality risk from cardiovascular disease is increased in patients with end
      stage renal disease (ESRD). This is due to both traditional and dialysis-specific
      factors. Recently, a number of the dialysis-specific risk factors have been
      implicated in the pathogenesis of cardiovascular calcification. These include:
      hyperphosphatemia, high calcium-phosphate (Ca x P) product, elevated parathyroid
      hormone levels, duration of dialysis, and treatment with calcium-containing
      phosphate binders and vitamin D analogs. The recent availability of electron beam
      computed tomography (EBCT) has triggered increased awareness of the occurrence of
      cardiovascular calcification in ESRD patients. Given the development of transient
      hypercalcemia with calcium-containing binders, a link between calcium load from
      use of calcium-containing phosphate binders and development coronary
      calcification has been proposed. However, a causal relationship between use of
      these agents and cardiovascular calcification has not been established. Moreover,
      this phenomenon had been recognized over a century ago, long before these
      phosphate binders became available. Although its pathogenesis is likely to be
      multifactorial, available data strongly implicate elevated serum phosphorus as
      the primary culprit. Furthermore, the risk of calcification may be aggravated by
      vitamin D therapy, particularly in patients with severe secondary
      hyperparathyroidism. Therefore, achieving vigorous control of serum phosphorus,
      Ca x P product and parathyroid hormone level might decrease cardiovascular
      calcification and improve survival of patients on maintenance hemodialysis. Since
      calcium acetate is the most cost-effective phosphate binder available, we
      recommend that it should remain the first line treatment of hyperphosphatemia in
      patients with ESRD.

PMID- 12410862
TI  - Variant Creutzfeldt-Jakob disease: an unfolding epidemic of misfolded proteins.
AB  - Variant Creutzfeldt-Jakob disease (vCJD) is an emerging infectious disease
      believed to be the human manifestation of bovine spongiform encephalopathy (BSE).
      Variant CJD belongs to a family of human and animal diseases called transmissible
      spongiform encephalopathies (TSE). The pathogenesis of TSE is not fully
      understood, but a modified form of a normal cellular protein plays a central
      role. Current measures to control vCJD aim to prevent transmission of the
      infectious agent from animals to humans through food or pharmaceutical products
      and to prevent transmission from person to person via medical interventions. The
      anticipated development of preclinical diagnostic tests and treatments for vCJD
      will create new control options and difficult choices.

PMID- 12410861
TI  - Influence of the new immunosuppressive combinations on arterial hypertension
      after renal transplantation.
AB  - Arterial hypertension is highly prevalent after renal transplantation and may
      contribute to the risk of cardiovascular disease. Also, arterial hypertension has
      been reported to be an independent risk factor for graft failure.
      Immunosuppressive drugs such as corticosteroids, cyclosporine and tacrolimus may
      be important contributing factors to post-transplant hypertension. Recent data
      from multicenter trials and from conversion studies (cyclosporine to tacrolimus)
      suggest that renal transplant patients under tacrolimus-based therapy showed less
      arterial hypertension compared with cyclosporine treated patients. New
      immunosuppressive drugs, including mycophenolate mofetil and rapamycin, are not
      nephrotoxic and they do not have any hypertensive effect. New immunosuppressive
      combinations including mycophenolate mofetil in a triple therapy regimen
      (associated with corticosteroids and cyclosporine) can reduce blood pressure so
      that corticosteroids can be stopped or cyclosporine reduced or even eliminated.
      Non-nephrotoxic regimens using rapamycin (sirolimus) as basic immunosuppression,
      associated with azathioprine or mycophenolate mofetil, could reduce the incidence
      of post-transplant arterial hypertension. Also, in renal transplant patients
      initially immunosuppressed with rapamycin, cyclosporine and corticosteroids,
      after the elimination of CSA, a lower blood pressure is achieved. In summary, new
      protocols with mycophenolate mofetil and/or rapamycin may permit several
      combinations that offer important alternatives to classical immunosuppressive
      regimens to reduce the incidence and clinical impact of arterial hypertension
      after renal transplantation.

PMID- 12410863
TI  - Scientific rationale and benefits of nucleotide supplementation of infant
      formula.
AB  - The present review examines the role of dietary nucleotides in infants, and the
      scientific rationale and benefits of nucleotide supplementation of infant
      formula. The immunoprotective benefits of human milk, the biology of human milk
      nucleotides, and the immunological and gastrointestinal effects of dietary
      nucleotides in animal studies and in vitro experiments are examined. Clinical
      studies are reviewed, especially those examining the efficacy of nucleotide
      supplemented infant formula in enhancing immunity and reducing the risk of
      sepsis. The presence of human milk cells, and a variety of immunoactive and
      trophic components of human milk, can explain the reduced incidence of sepsis in
      breastfed term and preterm infants. Nucleotides, believed to play an
      immunomodulatory role, are found in lower concentrations in infant formula.
      Animal studies have shown that dietary nucleotides enhance a number of immune
      responses and the growth, differentiation and repair of the gut. Several clinical
      studies have reported beneficial effects of nucleotide supplementation on gut
      microflora, diarrhoea and immune function, and one study has reported better
      catch-up growth in term infants with severe intrauterine growth retardation. More
      basic research studying the metabolism of nucleotides in neonates is encouraged.
      Additional randomized controlled trials are necessary to demonstrate the clinical
      benefits of nucleotide supplementation of infant formula, as it cannot be
      presumed that nucleotides produce the same benefits for the infant as human milk.
      Studies are especially necessary in high-risk neonatal situations, such as
      extreme prematurity, significant suboptimal nutrient intake before and after
      birth, and recovery from gut injury.

PMID- 12410864
TI  - Palivizumab prophylaxis of respiratory syncytial virus infection in high-risk
      infants.
AB  - Palivizumab prophylaxis significantly reduces hospitalization for respiratory
      syncytial virus (RSV) disease in preterm infants. However, palivizumab is very
      expensive. Data from a New Zealand cost-effectiveness analysis were considered by
      representatives of the Infectious Diseases and Immunisation, Fetus and Newborn,
      and Respiratory Committees of the Paediatric Society of New Zealand. Prophylaxis
      in all high-risk groups was associated with net cost. The consensus panel
      recommends that the priority for palivizumab be given to babies discharged on
      home oxygen with chronic lung disease, followed by babies born at 28 weeks or
      less gestation.

PMID- 12410865
TI  - Paediatric flexible bronchoscopy.
AB  - Flexible bronchoscopy is an emerging diagnostic, therapeutic and supportive
      procedure used in paediatric respiratory medicine. Despite the improvements in
      instruments and anaesthetic support for this procedure, supervised training,
      strict quality-control measures and ongoing research are essential to ensure
      standards of safe practice and judicial use of the procedure.

PMID- 12410866
TI  - Hypocarbia in the ventilated preterm infant and its effect on intraventricular
      haemorrhage and bronchopulmonary dysplasia.
AB  - OBJECTIVE: To examine the relationship between PaCO2 levels in ventilated very
      preterm infants and (i) the incidence of severe intraventricular haemorrhage
      (IVH) and periventricular leukomalacia (PVL); and (ii) bronchopulmonary dysplasia
      (BPD). METHODS: A retrospective cohort analysis of preterm infants comparing
      PaCO2 levels with the incidence of severe IVH/PVL and BPD was carried out on
      patients born at less than 29 weeks gestation from 1992 to 1994 and admitted to
      the tertiary neonatal intensive care unit at the King Edward Memorial Hospital
      (314 infants). During the first 96 h, PaCO2 levels were examined including lowest
      and highest PaCO2 levels, mean PaCO2 levels and duration of hypocarbia both pre-
      and post-surfactant administration. RESULTS: Of the 314 infants, there were 40
      early neonatal deaths (less than 48 h) who were not included in the analysis. Of
      the 274 surviving infants, 72 (26%) infants had severe IVH. Infants whose PaCO2
      fell below 30 mmHg at any stage in the first 48 h of life had an increased risk
      of severe IVH or PVL (odds ratio 2.38; 95% CI 1.27-4.49; P = 0.007). Of the 265
      survivors to 36 weeks corrected gestational age, 134 (51%) had BPD. Infants with
      at least three PaCO2 values less than 30 mmHg in the first 24 h of life had an
      increased risk of BPD (odds ratio 2.21; 95% CI 1.05-4.57; P = 0.036).
      CONCLUSIONS: The risk of severe IVH/PVL was significantly increased by
      hypocarbia. There was also an association between hypocarbia and BPD,
      particularly when hypocarbia was prolonged. These findings suggest that avoidance
      of hypocarbia may reduce the incidence of severe IVH/PVL and BPD in preterm
      infants.

PMID- 12410867
TI  - Effectiveness of an individualized multidisciplinary programme for managing
      unsettled infants.
AB  - OBJECTIVE: To ascertain the effectiveness of an individualized multidisciplinary
      residential programme for managing young unsettled infants and whether changes in
      unsettled behaviour were maintained. METHODS: One hundred and nine clients of a
      Tresillian residential unit with singleton infants aged less than 20 weeks were
      studied before, during and after intervention. Mothers completed a 24 h infant
      activity record prior to admission, during the stay and 1 month after discharge.
      Intervention consisted of settling techniques, parent education, support and
      counselling. RESULTS: By day 4 of admission, the mean duration of unsettled
      (fussing, crying) behaviour had decreased significantly and mean sleeping time
      and awake/content times both increased significantly (P < 0.001). These changes
      were maintained 1 month after discharge. Changes in behaviour were particularly
      marked for very unsettled infants. CONCLUSIONS: In the absence of formal
      controls, the individualized programme appears effective in managing the
      behaviour of unsettled infants.

PMID- 12410868
TI  - House dust mite allergen levels in carpeted sleeping accommodation are higher in
      private houses than public places.
AB  - OBJECTIVE: To compare mite allergen levels in carpeted sleeping accommodation in
      private dwellings and public places. METHODS: The concentration of
      Dermatophagoides pteronyssinus Group 1 allergen in house dust was measured in mat
      tresses and bedroom floors in 12 homes, 5 hotels, 11 child care centres and a
      university hall of residence. Indoor temperature and relative humidity were also
      measured. A questionnaire clarified details regarding the age of the building,
      age of the carpet, method and frequency of cleaning, frequency of room use and
      use of air-conditioning. RESULTS: Median allergen levels in mattresses and
      carpets in private homes (21.1 and 20.6 micro g/g dust, respectively) were
      significantly higher than in public places (2.5 and 3.1 micro g/g, respectively;
      P < 0.0001). Mean relative humidity was significantly higher in private houses
      (68.5%; 95% CI 67.2-69.3%) than in public places (56.4%; 95% CI 52.7-60.1%; P <
      0.0001). CONCLUSIONS: Carpeted sleeping accommodation in public places has lower
      house dust mite allergen levels than private houses. Lower levels of relative
      humidity may be an important component of the explanation.

PMID- 12410869
TI  - Milk formulas in acute gastroenteritis and malnutrition: a randomized trial.
AB  - OBJECTIVE: To compare three low-lactose milk formulas differing in osmolality and
      degree of protein hydrolysis in the treatment of diarrhoea and malnutrition in
      subjects with high rates of lactose intolerance, osmotic diarrhoea and a
      tropical/environmental enteropathy. METHODS: A randomized double-blind trial of
      180 Aboriginal children under 3 years of age admitted with acute diarrhoea and/or
      malnutrition was carried out. The intervention milk formulas were: (i) De-Lact, a
      low-osmolality lactose-free formula; (ii) O-Lac, a lactose-free formula; and
      (iii) Alfare, a partially hydrolysed formula. Outcome measures were diarrhoeal
      severity, weight gain, formula palatability and changes in intestinal
      permeability (L/R ratios). RESULTS: The duration of diarrhoea in days (mean; 95%
      confidence interval) was significantly longer on Alfare (8.5; 7.0-10.0) compared
      to De-Lact (6.1; 5.0-7.2) and O-Lac (6.9; 5.6-8.1; P = 0.04). There were no
      differences in mean intake between formulas, but palatability of Alfare was
      significantly worse (P < 0.01) than the other formulas. Over the trial 5 days,
      improvement in L/R ratios was significantly greater (P = 0.05) for De-Lact (18.6;
      10.6-26.6) than for Alfare (8.5; 2.1-14.9). Weight gain was not significantly
      different between the three formulas, except in a malnourished subgroup who had
      better weight gain on De-Lact (P = 0.05). CONCLUSIONS: In these Aboriginal
      children with diarrhoea and growth failure, a low osmolality milk was associated
      with better outcomes and a partially hydrolysed formula with less improvement in
      mucosal recovery, suggesting that cow's milk protein intolerance is not
      contributing to greater diarrhoeal severity or enteropathy in Aboriginal
      children.

PMID- 12410870
TI  - Persistent cough in children and the overuse of medications.
AB  - OBJECTIVE: Children referred for persistent cough were evaluated for the
      referring and final diagnosis, and the extent of the use of medications prior to
      referral and the side effects encountered. METHODS: Data on children seen by
      respiratory paediatricians for persistent cough (> or =4 weeks) in a tertiary
      respiratory setting were collected prospectively over 12 months. RESULTS: Of the
      49 children, 61.2% were diagnosed with asthma at referral, with similar referral
      rates from general practitioners and paediatricians. Children with isolated cough
      were just as likely to have been diagnosed with asthma as children with cough and
      wheeze. Medication use (asthma, gastro-oesophageal reflux and antibiotics) prior
      to referral was high, asthma medications were most common, and of these 12.9% had
      significant steroid side effects. The most common abnormality found (46.9%) was a
      bronchoscopically defined airway lesion, and in 56.5% of these children, another
      diagnosis (aspiration, achalasia, gastro-oesophageal reflux) existed. No children
      had a sole final diagnosis of asthma and pre-referral medications were weaned in
      all children. CONCLUSION: Over diagnosis of asthma and the overuse of asthma
      treatments with significant side effects is common in children with persistent
      cough referred to a tertiary respiratory clinic. Children with persistent cough
      deserve careful evaluation to minimize the use of unnecessary medications and, if
      medications are used, assessment of response to treatment is important.

PMID- 12410872
TI  - Infant-furniture-related injuries among preschool children in New Zealand, 1987
      1996.
AB  - OBJECTIVE: To describe the epidemiology of infant-furniture-related fatalities
      and hospitalizations in New Zealand, for children aged 0-4 years. METHODS: Infant
      furniture-related deaths and hospitalizations were selected from the New Zealand
      Health Information Service databases for the 10-year period 1987-1996.
      Intentional injuries were excluded. RESULTS: Forty-three fatalities were
      identified. Twenty-two fatalities (51%) occurred in cots, while 13 (30%) occurred
      in beds. Other products involved were prams, push chairs, high chairs, car seats,
      portable cots and walkers. A total of 1679 infants were hospitalized through
      infant-furniture-related injuries. Increasing trends in hospitalizations for baby
      walkers, beds and bunks were observed. CONCLUSIONS: On average, four infants die
      each year from injuries related to infant furniture, and hospitalizations from
      injuries associated with infant furniture use are increasing. Mandatory standards
      are one measure to reduce these numbers, but education is also necessary.

PMID- 12410871
TI  - Controlling seizures in the prehospital setting: diazepam or midazolam?
AB  - OBJECTIVE: To determine which is the most effective and safe treatment for
      controlling seizures in children out-of-hospital: diazepam or midazolam. METHODS:
      A retrospective review of the medical records of children presenting to the
      Emergency Department of the Children's Hospital at Westmead (CHW-ED) with
      seizures requiring treatment in the field by paramedics was carried out over a 4
      year period (April 1996 to March 2000). In New South Wales, children with
      seizures in the prehospital setting received 0.5 mg/kg per rectum (p.r.) or 0.1
      mg/kg i.v. diazepam until March 1998 and from March 1997 onwards they received
      0.15 mg/kg i.m. or 0.1 mg/kg i.v. midazolam. The main outcome measured was
      cessation of seizure in the prehospital setting. Secondary outcomes were time
      taken to initiate treatment and the frequency of cardiorespiratory compromise.
      RESULTS: Over the 4-year period, 2566 children presented to CHW-ED with a
      seizure; 107 children were eligible for entry into the present study. Of these
      107 patients, 62 received diazepam and 45 received midazolam. Thirty-one (50.0%)
      in the diazepam group and 15 (33.3%) in the midazolam group were febrile
      seizures. Both groups were similar in terms of demographics and seizure type. A
      comparison of diazepam with midazolam showed that both drugs were effective in
      stopping seizures within 5 min of drug administration (37.1% cf. 51.1%). Fewer
      patients in the midazolam group suffered apnoea (20.0% cf. 29.0%; P < 0.05).
      CONCLUSION: Midazolam controls seizures as effectively as diazepam in the
      prehospital setting. Furthermore, midazolam potentially reduces respiratory
      depression and time to treatment.

PMID- 12410873
TI  - Regional and urban Victorian diabetic youth: clinical and quality-of-life
      outcomes.
AB  - OBJECTIVES: To compare groups of urban and regional Victorian diabetic children
      and assess their quality of life, diabetes knowledge, access to services and
      metabolic control. METHODS: Forty-seven children from three regional Victorian
      communities (Horsham, Warrnambool and Sale; n = 16, 18 and 13, respectively) were
      compared with 120 age-, sex- and duration of diabetes-matched children attending
      the Royal Children's Hospital (RCH) diabetes clinic in Melbourne. Quality of
      life, diabetes knowledge, use of services, and metabolic control were assessed
      using the child health questionnaire (CHQ PF-50/CF-80); a diabetes-knowledge
      questionnaire; access to a diabetes nurse educator (DNE), dietitian and
      complication screening; and indices of mean HbA1C (values are taken every 3
      months in the 'yearly HbA1C'), respectively. RESULTS: Comparisons of CHQ data
      showed that regional diabetic youth scored significantly lower on most subscales.
      The greatest deficits were seen in areas of mental health, self-esteem, parent
      impact (emotional) and family cohesion. Diabetes knowledge and median yearly
      HbA1C for patients were not significantly different between the regional and
      urban centres (8.1%, 8.9%, 8.4% and 8.6% at RCH, Horsham, Warrnambool and Sale,
      respectively). Patients in regional centres had reportedly less access to team
      based diabetes care. CONCLUSIONS: Regional youth in Victoria, with similar levels
      of metabolic control and diabetes knowledge as their urban counterparts, have a
      markedly lower quality of life, implying a negative synergy between diabetes and
      the demands of regional lifestyles.

PMID- 12410874
TI  - Developmental outcome of preterm infants after surfactant therapy: systematic
      review of randomized controlled trials.
AB  - OBJECTIVES: To review neuro-developmental outcome at 1 and 2 years of age
      following randomized controlled trials (RCT) of neonatal surfactant therapy.
      METHODS: A systematic review of the MEDLINE, Embase and Cochrane Controlled Trial
      Register databases, searching for RCT of surfactant replacement therapy with
      follow-up outcomes, was carried out. The main outcome measures were severe and
      mild disability at 1 and 2 years plus composite adverse outcome of death and/or
      severe disability. RESULTS: A meta-analysis using odds ratios was carried out on
      13 RCT. There were a total of 2218 treated and 2090 control infants who underwent
      follow up at 1 year of age. There were 303 treated and 292 control infants with
      follow up at between 18 months and 2 years of age. Surfactant therapy was
      associated with a lower rate of mild disability at 1 year (OR 0.79; 95% CI 0.66
      0.95). There was a reduction in the combined adverse outcome (death or severe
      disability rate) at 1 year (OR 0.8; 95% CI 0.72-0.89). Neither the 1 year nor the
      2 year follow-up examination showed a statistical difference in the severe
      disability rate between the control and treated group. CONCLUSION: Surfactant
      therapy increases survival without an increase in subsequent morbidity at 1 and 2
      years of age.

PMID- 12410875
TI  - Marked increase in serum transferrin receptor among Thai children with Hb-E-beta
      thalassaemia.
AB  - OBJECTIVE: To determine the serum transferrin receptor (sTfR) level in patients
      with Hb-E-beta-thalassaemia attending a paediatric haematology clinic. METHODS:
      Sixty-four patients with Hb-E-beta-thalassaemia aged 2.9-10.8 years were
      attending a paediatric haematology clinic at King Chulalongkorn Memorial
      Hospital, Bangkok, Thailand. Circulating transferrin receptor was measured, as
      was the complete blood count and percentage of reticulocytes. A transfusion
      regimen recommended by the Thalassaemia International Federation was used
      whenever parents agreed to the treatment. RESULTS: In patients with Hb-E-beta
      thalassaemia, the concentration of sTfR varied from 1.88 to 28.44 mg/L (mean +/-
      SD 13.99 +/- 5.37), while in the control group, it varied from 0.95 to 2.56 mg/L
      (mean +/- SD 1.58 +/- 0.41; n = 31). The sTfR level correlated inversely to a
      single measurement of haemoglobin in the same specimen (r = - 0.433; P = 0.00)
      and was elevated compared to the control group (P = 0.00; alpha < 0.05). In
      addition, the sTfR level correlated inversely to mean pre-transfusion haemoglobin
      (r = - 0.36; P = 0.003). CONCLUSIONS: The level of sTfR is elevated in children
      with Hb-E-beta-thalassaemia. The sTfR level can be used as an adjunct real-time
      assessment of erythropoietic activity, comparable with mean pre-transfusion
      haemoglobin. Measurement of sTfR is easy using most automated chemical analyzers,
      and material can be obtained from routine specimen collections. Further studies
      should be carried out in a larger population to verify the benefits of this test
      to patients.

PMID- 12410876
TI  - Child and parent satisfaction with the use of spacer devices in acute asthma.
AB  - OBJECTIVE: To evaluate child and parent satisfaction with the use of spacers in
      acute asthma. METHODS: All parents of children presenting to the emergency
      department of Sydney Children's Hospital over a 3-month period with mild to
      moderately severe acute asthma who were treated with bronchodilators by spacer
      device were asked to complete an anonymous questionnaire. Children aged 8 years
      and older completed a separate questionnaire independently. RESULTS: One hundred
      and eleven of 158 parents (70%) responded. The majority (84%) found it 'easy' or
      'very easy' to use the spacer and 85% reported that they intended to use the
      spacer at home. Of those parents who had previously used a nebulizer (n = 73),
      84% said that the spacer was easier to use, 77% said that the spacer was better
      tolerated by their child and 84% said that overall they preferred the spacer.
      Seventeen of 31 children aged 8-14 years treated with a spacer (55%) responded to
      the satisfaction survey. All respondents found it 'easy' or 'OK' to use the
      spacer and the majority (82%) 'liked it' or thought 'it was OK'. The majority of
      children (82%) said that they preferred using spacers because it was quicker
      (29%) or easier to use (53%). CONCLUSION: The use of spacer devices in mild to
      moderately severe acute asthma is highly acceptable for children and parents; the
      majority prefer this mode of drug delivery to nebulization.

PMID- 12410877
TI  - What is the value of a human baby?

PMID- 12410878
TI  - Fever in a teenage traveller.

PMID- 12410879
TI  - Neonatal ascites and hyponatraemia following umbilical venous catheterization.
AB  - The complications associated with umbilical venous catheterization in neonates
      range from pericardial effusion, portal hypertension, and peritoneal perforation
      with ascites, to Wharton's jelly embolism. The case of a term neonate who
      developed ascites and severe hyponatraemia (serum sodium 119 mmol/L) most
      probably following peritoneal perforation by an umbilical venous catheter is
      reported. The presenting feature was convulsions associated with dilutional
      hyponatraemia, probably following absorption of a large quantity of ascitic fluid
      across the peritoneum. Conservative management was associated with gradual
      recovery over 24 h. The case highlights that, irrespective of the route,
      excessive administration of salt-free fluids can lead to dilutional hyponatraemia
      with adverse consequences. The present case illustrates the importance of
      confirming intravascular positioning of umbilical catheters by ensuring free flow
      of blood on aspiration, to prevent/detect inadvertent peritoneal perforation.
      Ideally, echocardiographic confirmation of optimal intravascular placement of
      such catheters is preferred as radiographic confirmation is reported to be
      unreliable.

PMID- 12410880
TI  - Low molecular weight heparin for neonatal thrombosis.
AB  - The clinical course of a term neonate (birthweight 3.14 kg) who developed
      thrombosis of the left common and internal iliac veins on day 21 following
      recovery from Streptococcus mitis septicemia, with shock diagnosed on day 13, is
      reported. Subcutaneous low molecular weight heparin (LMWH) was commenced (1.5
      mg/kg 12 hourly for 10 days) after 13 h of standard heparin infusion, due to
      difficulties in securing a peripheral venous access. The inflammation of the left
      leg was completely resolved by day 5 of LMWH therapy. Prothrombin time, activated
      prothrombin time and fibrinogen levels were within normal limits during LMWH
      therapy. Treatment-related side effects, such as thrombocytopenia and bleeding
      tendency were not noted. Doppler studies 6 weeks after discharge home on day 33
      revealed complete resolution of the thrombus. Apart from septicaemia and shock,
      the presence of an indwelling central venous catheter and a history of untreated
      maternal diabetes were additional risk factors for thrombosis. Because it is as
      effective as standard heparin, LMWH may be a therapeutic option for thrombosis in
      high-risk neonates, particularly given its ease of administration by the
      subcutaneous route, predictable pharmacokinetics and reduced incidence of adverse
      effects such as bleeding complications.

PMID- 12410881
TI  - Paediatric narcolepsy: complexities of diagnosis.
AB  - Narcolepsy is a sleep disorder that is characterized by excessive daytime
      sleepiness and the inappropriate intrusion of aspects of rapid eye movement sleep
      into wakefulness. While the disorder emerges from an interplay of genetic and
      environmental factors, recent findings suggest that abnormalities in the
      neurotransmission of hypocretin may be implicated in its pathogenesis. Although
      narcolepsy has typically been associated with adulthood, there is a growing
      evidence base for the emergence of the disorder in childhood. We report suspected
      narcolepsy in early infancy, highlighting both the complexities of presentation
      and subsequent diagnosis associated with paediatric narcolepsy, and the
      significant psychosocial difficulties experienced by children and families
      managing this disorder.

PMID- 12410882
TI  - Ethnicity and asthma symptoms associated with ingestion of fruits.

PMID- 12410883
TI  - Are these really sids deaths? Not by definition.

PMID- 12410884
TI  - Growth and adrenal suppression due to moderate- to high-dose inhaled fluticasone.

PMID- 12410892
TI  - Multifocal glasses impair edge-contrast sensitivity and depth perception and
      increase the risk of falls in older people.
AB  - OBJECTIVES: To determine the extent to which multifocal glasses impair contrast
      sensitivity and depth perception at critical distances required for detecting
      hazards in the environment and whether multifocal glasses use increases the risk
      of falls in older people. DESIGN: One-year prospective cohort study. SETTING:
      Falls Laboratory, Prince of Wales Medical Research Institute. PARTICIPANTS: One
      hundred fifty-six community-dwelling people aged 63-90. MEASUREMENTS: Contrast
      sensitivity, depth perception, accidental falls. RESULTS: Eighty-seven subjects
      (55.8%) were regular wearers of multifocal (bifocal, trifocal, or progressive
      lens) glasses. These subjects performed significantly worse in the distant depth
      perception and distant edge-contrast sensitivity tests in conditions that forced
      them to view test stimuli through the lower segments of their glasses. Multifocal
      glasses wearers were more than twice as likely to fall in the follow-up period
      than nonmultifocal glasses wearers (odds ratio (OR) = 2.29, 95% confidence
      interval (CI) = 1.06-4.92), when adjusting for age, poor vision, reduced lower
      limb sensation and strength, slow reaction time, and increased postural sway.
      Multifocal glasses wearers were also more likely to fall because of a trip (OR =
      2.79, 95% CI = 1.08-7.22), when outside their homes (OR = 2.55, 95% CI = 1.14
      5.70), and when walking up or down stairs (P <.01). The population attributable
      risks of regular multifocal glasses use were 35.2% for any falls, 40.9% for falls
      due to a trip, and 40.9% for falls outside the home. CONCLUSIONS: The study
      findings indicate that multifocal glasses impair depth perception and edge
      contrast sensitivity at critical distances for detecting obstacles in the
      environment. Older people may benefit from wearing nonmultifocal glasses when
      negotiating stairs and in unfamiliar settings outside the home.

PMID- 12410893
TI  - Factors associated with falls in older patients with diffuse polyneuropathy.
AB  - OBJECTIVES: To identify clinical factors associated with falls by older persons
      with polyneuropathy (PN). DESIGN: A cross-sectional study of 82 subjects aged 50
      to 85 with clinical and electrodiagnostic evidence of PN. SETTING:
      Electrodiagnostic and biomechanical research laboratories. PARTICIPANTS: Patients
      referred to the electrodiagnostic laboratory. MEASUREMENTS: History and physical
      examination, including semiquantitative methods of peripheral nerve function, and
      clinical balance testing. Falls were defined by retrospective self-report over a
      2-year period. RESULTS: Forty (48.8%), 28 (34.1%), and 18 (22.0%) subjects
      reported a history of at least one fall, multiple falls, and injurious falls,
      respectively. Factors associated with single and multiple falls were similar, so
      only results for multiple and injurious falls are reported. Bivariate analysis
      showed that an increased body mass index (BMI) and more severe PN (as determined
      by the Michigan Diabetes Neuropathy Score) were associated with both fall
      categories. Men reporting falls also demonstrated a decreased unipedal stance
      time. Age, sex, nerve conduction study parameters, Romberg testing, medications,
      and comorbidities were not consistently associated with either fall category.
      Logistic regression demonstrated that multiple and injurious falls were
      associated with an increased BMI and more severe PN, controlling for age, sex,
      medications, and comorbidities (pseudo R2 = 0.458 and 0.484, respectively).
      CONCLUSIONS: Although previous work has demonstrated that all older persons with
      PN are at increased risk for falls, patients with increased BMI and more severe
      PN are at particularly high risk and should be targeted for intervention.

PMID- 12410894
TI  - Physical activity as a determinant of change in mobility performance: the
      Longitudinal Aging Study Amsterdam.
AB  - OBJECTIVES: This study examined the association of (change in) physical activity
      and decline in mobility performance in older men and women. DESIGN: A 3-year
      prospective study using data of the Longitudinal Aging Study. SETTING:
      Netherlands. PARTICIPANTS: Two thousand one hundred nine men and women aged 55 to
      85. MEASUREMENTS: Total physical activity (expressed as hours per day and
      kilocalories per day) and sports participation were measured using a validated,
      interviewer-administered questionnaire. Mobility performance was assessed using
      two timed tests: 6-meter walk and repeated chair stands. RESULTS: Mobility
      performance declined for 45.6% of the sample. At baseline, the mean time +/-
      standard deviation spent on total physical activity was 3.0 +/- 2.1 h/d or 719 +/
      543 kcal/d, and 56.6% of the sample participated in sports. Sports participation
      and a higher level of total physical activity, walking, or household activity
      were associated with a smaller mobility decline. After 3 years, total physical
      activity declined, and only 53.4% of those reporting sports at baseline continued
      doing so. Continuation of physical activity over time was associated with the
      smallest decline in mobility. The observed associations were similar for those
      with and without chronic disease (P> 0.3). The conclusions did not change after
      adjustment for potential confounders, including demographic and lifestyle
      variables, depression, and cognitive status. CONCLUSIONS: Physical activity, and
      especially a regularly active lifestyle, may slow the decline in mobility
      performance. A beneficial effect was observed for sports and nonsports
      activities, independent of the presence of chronic disease.

PMID- 12410895
TI  - Age-related differences in lower extremity power after support surface
      perturbations.
AB  - OBJECTIVES: The purpose of this study was to examine a comprehensive measure
      relating to the ability to generate, absorb, and transfer mechanical energy
      introduced by a perturbation. It was hypothesized that this measure would reveal
      age-related differences leading to different balance recovery responses (i.e.,
      feet-in-place and compensatory step). DESIGN: Cross-sectional, descriptive study.
      SETTING: The Motor Control Laboratory at the University of Oregon. PARTICIPANTS:
      Eighteen younger (aged 18-35) and 21 older (aged 65-85) women received forward
      and backward support surface translations of varying amplitudes and velocities.
      MEASUREMENTS: Lower extremity peak positive joint power and peak negative muscle
      power were examined at the largest perturbation in which a feet-in-place response
      was used and the subsequent perturbation where a step occurred. Peak positive
      joint power depicts the maximum rate of passive transfer of energy into a segment
      and is indicative of the maximum destabilization of that segment. Peak negative
      muscle power is the maximum rate of energy absorption by muscle, which reduces
      the effect of the perturbation on the segment. RESULTS: After a backward
      perturbation, there was a significant main effect of age for muscle power and a
      significant main effect of response type for joint power. For the forward
      condition, there was a significant main effect of response type for muscle power
      only. CONCLUSIONS: The mechanical reason for the emergence of the compensatory
      step after support-surface perturbations is clear; the feet-in-place response is
      energetically more demanding than the compensatory step. The energy analysis
      suggests a mechanical basis as one reason for older adults' reliance on the
      compensatory step: older adult muscles absorb less energy. The results of this
      study also highlight the importance of the proximal knee and hip musculature
      versus the distal ankle musculature.

PMID- 12410896
TI  - Response of elevated methylmalonic acid to three dose levels of oral cobalamin in
      older adults.
AB  - OBJECTIVES: Because the effects of lower-dose oral cobalamin (Cbl) supplements on
      older people with cobalamin deficiency are not known, we determined whether oral
      Cbl supplements at three different dose levels would normalize elevated serum
      methylmalonic acid (MMA) and total homocysteine (tHcy) concentrations. DESIGN:
      Sequential nonrandomized intervention study of three dose levels. SETTINGS: Two
      university-based senior care clinics. PARTICIPANTS: Twenty-three older adults
      (aged >/=65) with serum Cbl levels of 221 pmol/L (300 pg/mL) or lower and serum
      MMA greater than 271 nmol/L who had been enrolled in a previous screening study
      for Cbl deficiency (mean age 79 +/- 9; 17 male, 6 female; 17 white, 6 other).
      INTERVENTION: Sequential daily treatment with 25 microg oral cobalamin, followed
      by 100 microg and 1,000 microg cobalamin each for a 6-week period. MEASUREMENTS:
      Serum MMA, tHcy, and other metabolites at baseline and after each 6-week dosing
      interval. RESULTS: Treatment with 25 microg and 100 microg lowered but did not
      normalize MMA levels in most subjects. A dose of 1,000 microg/day proved to be
      the most effective in lowering MMA levels to within normal limits. Serum tHcy was
      normalized in six of 11 subjects who had elevated tHcy pretreatment with oral Cbl
      alone and in one subject in combination with a multivitamin. CONCLUSIONS: Most
      Cbl-deficient older people require more than 100 microg of oral Cbl to normalize
      serum MMA, which is a larger dose than is available in most standard
      multivitamins and Cbl supplements.

PMID- 12410897
TI  - Is there a relationship between fat-free soft tissue mass and low cognitive
      function? Results from a study of 7,105 women.
AB  - OBJECTIVES: To test the hypothesis that low fat-free soft tissue mass and
      cognitive impairment are independently associated. DESIGN: Cross-sectional study.
      SETTING: Five geographic areas of France. PARTICIPANTS: Seven thousand one
      hundred five community-dwelling women aged 75 and older recruited from electoral
      rolls between 1992 and 1994. MEASUREMENTS: Fat-free soft tissue mass, body fat
      mass, and bone mineral density were measured using dual-energy x-ray
      absorptiometry. Study participants were assessed for cognitive impairment using
      the Short Portable Mental Status Questionnaire and divided into two groups
      according to their scores. Logistic regression models were used to calculate
      multivariate-adjusted differences in body composition between two groups of
      subjects according to their cognitive function. RESULTS: After adjustment for
      confounders, compared with women in the highest quartile of fat-free soft tissue
      mass, women in the lowest quartile had an odds ratio of 1.43 (95% confidence
      interval (CI) = 1.07-1.91) for cognitive impairment. Low fat mass was also
      associated with lower cognitive function, with an odds ratio of 1.35 (95% CI =
      1.01-1.79) for the lower quartile of fat mass compared with the highest quartile.
      There was no association between cognitive impairment and bone mineral density.
      CONCLUSIONS: This finding supports the hypothesis that low muscle mass is
      associated with cognitive impairment in older women. These two components
      represent major causes of frailty and functional decline in older people and
      could have some common mechanisms. Nevertheless, these results do not predict the
      causal variable.

PMID- 12410898
TI  - Percentage of body fat and body mass index are associated with mobility
      limitations in people aged 70 and older from NHANES III.
AB  - OBJECTIVES: To assess the association between functional limitations and body
      composition indices, including percentage of body fat, muscle mass, and body mass
      index (BMI). DESIGN: A cross-sectional, population-representative sample.
      SETTING: All noninstitutionalized people living in the United States (National
      Health and Nutrition Examination Survey). Data were collected between 1988 and
      1994. PARTICIPANTS: One thousand five hundred twenty-six women and 1,391 men aged
      70 and older. MEASUREMENTS: Independent variables included BMI, muscle mass, and
      percentage of body fat; the latter two were assessed using predictive equations.
      The dependent variable, functional limitations, was defined as difficulty in
      performing at least three of five functional living tasks, such as carrying a 10
      pound bag of groceries. RESULTS: Women in the highest quintile for percentage of
      body fat and women with a BMI of 30 or greater were two times more likely to
      report functional limitations than women in the comparison groups. Similar, but
      weaker, relationships were found among men; men in the highest quintile for body
      fat and men with a BMI of 35 or greater were 1.5 times more likely to report
      limitations. Low muscle mass (sarcopenia) and sarcopenia in combination with high
      percentage of body fat (sarcopenic obesity) were not associated with a greater
      likelihood of reporting functional limitations. CONCLUSIONS: Prevention of
      excessive accumulation of body fat and maintenance of a BMI in the normal range
      may reduce the likelihood of functional limitations in old age.

PMID- 12410899
TI  - The relationship between weight loss and all-cause mortality in older men and
      women with and without diabetes mellitus: the Rancho Bernardo study.
AB  - OBJECTIVES: To examine the relationship between measured weight change over an
      approximate 10-year time period on all-cause mortality over the following 12
      years in 1,801 community-dwelling men and women (mean age 71 at the beginning of
      mortality follow-up) with and without diabetes mellitus. DESIGN: A longitudinal
      cohort study. SETTING: A geographically defined community in southern California.
      PARTICIPANTS: One thousand eight hundred one older men and women with and without
      diabetes mellitus. MEASUREMENTS: Weight, body mass index (BMI), blood pressure,
      and fasting plasma glucose were measured in 1972-74 (Visit 1) when participants
      were aged 40 to 79 and again in 1984-87 (Visit 2). Lifetime weight history and
      dieting for weight control were ascertained in 1985 using a mailed questionnaire.
      Vital status was determined for the next 12 years, from Visit 2 (1984-87) through
      1996. The Cox proportional hazards model was used to assess the age- and multiply
      adjusted effect of weight change on mortality. RESULTS: At Visit 1, diabetic men
      (n = 140) and women (n = 90) were more overweight than nondiabetic men (n = 633)
      and women (n = 938). Weight gain between Visits 1 and 2 was not a significant
      predictor of mortality in this cohort. Men and women losing 10 or more pounds
      between visits had higher age-adjusted death rates during the following 12 years
      than those with stable weight or weight gain. Weight loss was associated with an
      increased hazard ratio (HR) for all-cause mortality in nondiabetic men (HR =
      1.38, 95% confidence interval (CI) = 1.06-1.80) and women (HR = 1.76, 95% CI =
      1.33-2.34) and diabetic men (HR = 3.66, 95% CI = 2.15-6.24) and women (HR = 1.65,
      95% CI = 0.70-3.87) after adjustment for age, smoking, and sedentary lifestyle.
      Significant associations persisted in analyses excluding cigarette smokers and
      those with depressed mood and low baseline BMI. After excluding those who died
      within 5 years of the weight loss, the increased HR was statistically significant
      in men and women with and without diabetes mellitus. Stratified analyses
      comparing those who reported dieting for weight control with those not dieting
      showed similar trends, with a higher mortality risk for weight loss in those who
      lost weight without dieting. CONCLUSION: In this population of older individuals,
      weight loss predicted increased all-cause mortality risk not explained by
      covariates.

PMID- 12410900
TI  - Description of the National Pressure Ulcer Long-Term Care Study.
AB  - OBJECTIVES: To describe and provide baseline data from The National Pressure
      Ulcer Long-Term Care Study (NPULS). DESIGN: Retrospective cohort study of
      detailed resident characteristics, treatments, and outcomes using convenience
      sampling. SETTING: One hundred nine long-term care facilities throughout the
      United States. PARTICIPANTS: Two thousand four hundred twenty adult residents
      aged 18 and older, with a length of stay of 14 days or longer and who were at
      risk of developing a pressure ulcer, as defined by a Braden Scale for Predicting
      Pressure Sore Risk MEASUREMENTS: More than 500 characteristics were obtained for
      each resident over a 12-week period. This paper describes the NPULS database with
      respect to the resident (sex, age, diagnoses, severity of illness scores, Braden
      Scale score, activities of daily living, cognitive ability, mobility, bowel or
      bladder incontinence, laboratory values, nutritional assessment, and pressure
      ulcer assessment documentation), treatment (nutritional interventions, pressure
      relieving devices, incontinence interventions, protective devices, turning
      schedules, and pressure ulcer treatments), and outcome variables (pressure ulcer
      development and healing, pressure ulcer and systemic infection, changes in
      nutritional status, and discharge disposition) associated with pressure ulcers.
      Descriptive statistics and bivariate associations were used for preliminary
      analyses of resident, treatment, and outcome characteristics. RESULTS: The
      average age +/- standard deviation was 79.7 +/- 14.2; 70% of the residents were
      female. Fifty-three percent of residents (n = 1,293) were at risk of developing a
      pressure ulcer but never developed one during the study (Group 1), 19% developed
      a new pressure ulcer during the study (n = 457) (Group 2), 22% had an existing
      pressure ulcer (n = 534) (Group 3), and 6% had an existing pressure ulcer and
      developed a new ulcer during the study (n = 136) (Group 4). Residents who
      developed a new pressure ulcer (Group 2) were more likely to be female, older,
      cognitively impaired, and immobile than residents who had an existing pressure
      ulcer (Group 3). CONCLUSIONS: This baseline study describes the NPULS database
      with respect to the resident, treatment, and outcome variables associated with
      pressure ulcers. Future studies will focus on multivariate analyses for risk
      factor prediction of pressure ulcer development and pressure ulcer healing.
      Research-based pressure ulcer prevention and treatment protocols can then be
      developed.

PMID- 12410901
TI  - Mood symptoms and cognitive performance in women estrogen users and nonusers and
      men.
AB  - OBJECTIVES: Previous studies have suggested sex differences in mood and cognition
      and that estrogen effects may partially explain such differences. In this study,
      we explore sex differences for a range of mood symptoms and for
      neuropsychological performance in men and postmenopausal women and assess the
      potential influence of estrogen on these measures. DESIGN: Cross-sectional study
      of men and women examining mood, neuropsychological test data, and estrogen
      replacement therapy (ERT) use. SETTING: Outpatient study at an urban teaching
      hospital with subjects recruited from the community. PARTICIPANTS: All subjects
      (N = 96) were between the ages of 57 and 75 and included 31 women using ERT, 16
      non-ERT users, and 49 men. Subjects did not have major depression and were
      nondemented. MEASUREMENT: The three groups were compared according to profile of
      mood states and neuropsychological performance, and statistical analyses were
      controlled for socioeconomic status, age, and education level. RESULTS: Female
      ERT users were less depressed and less angry and performed better on measures of
      verbal fluency and working memory than the other subject groups. CONCLUSION:
      Postmenopausal estrogen use is associated with better mood and cognitive
      performance on tasks of fluency and working memory. These results suggest that
      estrogen should be examined as a potentially critical variable influencing late
      life sex differences in mood and cognition.

PMID- 12410902
TI  - Quality of care of nursing home residents hospitalized with heart failure.
AB  - OBJECTIVES: To determine whether the quality of heart failure (HF) care of
      hospitalized nursing home (NH) residents is different from that of patients
      admitted from other locations. DESIGN: Retrospective chart review. SETTING:
      Nursing home residents discharged from hospitals. PARTICIPANTS: Medicare
      beneficiaries aged 65 and older. MEASUREMENTS: Subjects were discharged with a
      primary discharge diagnosis of HF in Alabama in 1994. They were categorized as
      having been admitted from a NH or other locations. Bivariate logistic regression
      analysis was used to estimate crude odds ratios (ORs) and 95% confidence
      intervals (CIs) for left ventricular function (LVF) evaluation and angiotensin
      converting enzyme (ACE) inhibitor use for NH residents relative to nonresidents.
      Multivariate generalized linear models were developed to determine independence
      of associations. RESULTS: Subjects (N = 1,067 years) had a mean age +/- standard
      deviation of 79 +/- 7.4, 60% were female, and 18% were African Americans. Fewer
      NH residents (n = 95) received LVF evaluation (39% vs 60%, P <.001) and ACE
      inhibitors (50% vs 72%, P =.111). NH residents had lower odds for LVF evaluation
      (OR = 0.42, 95% CI = 0.27-0.64). The odds for ACE inhibitor use, although of
      similar magnitude, did not reach statistical significance (OR = 0.40, 95% CI =
      0.12-1.28). After adjustment of patient and care characteristics, admission from
      a NH was significantly associated with lower LVF evaluation (adjusted OR = 0.64,
      95% CI = 0.49-0.82) but not with ACE inhibitor use (adjusted OR = 0.59, 95% CI =
      0.16-2.14). CONCLUSIONS: Quality of HF care received by hospitalized NH residents
      was lower than that received by others. Further studies are needed to determine
      reasons for the lack of appropriate evaluation and treatment of NH patients with
      HF who are admitted to hospitals.

PMID- 12410903
TI  - Do older adults expect to age successfully? The association between expectations
      regarding aging and beliefs regarding healthcare seeking among older adults.
AB  - OBJECTIVES: To measure expectations regarding aging among community-residing
      older adults, identify characteristics associated with having low expectations
      regarding aging, and examine whether expectations regarding aging are associated
      with healthcare-seeking beliefs for age-associated conditions. DESIGN: Self
      administered mail survey. SETTING: Greater Los Angeles. PARTICIPANTS: Four
      hundred twenty-nine of 588 (73%) randomly selected community-residing adults aged
      65 to 100 (mean age 76) cared for by 20 primary care physicians; 54% were women,
      and 76% were white. MEASUREMENTS: The Expectations Regarding Aging Survey, a
      validated survey measuring expectations regarding aging; 13 items measuring care
      seeking beliefs; and validated measures of health status. RESULTS: More than 50%
      of participants felt it was an expected part of aging to become depressed, to
      become more dependent, to have more aches and pains, to have less ability to have
      sex, and to have less energy. After adjusting for sociodemographic and health
      characteristics using multivariate regression, older age was independently
      associated with lower expectations regarding aging (P <.001), as was having lower
      physical and mental health-related quality of life. Having lower expectations
      regarding aging was independently associated with placing less importance on
      seeking health care (P =.049). CONCLUSIONS: Most older adults in this sample did
      not expect to achieve the model of successful aging in which high cognitive and
      physical functioning is maintained. Older age was independently associated with
      lower expectations regarding aging. Furthermore, having low expectations
      regarding aging was independently associated with not believing it important to
      seek health care.

PMID- 12410904
TI  - Outcome of West Nile fever in older adults.
AB  - OBJECTIVES: To determine the effect of clinical presentation and cognitive
      changes on the postdischarge outcome in older adult patients with West Nile fever
      (WNF). DESIGN: Retrospective, cohort analysis. SETTING: Meir Hospital located in
      the center of Israel in the Sharon region. PARTICIPANTS: Thirty-two patients aged
      65 and older hospitalized during a WNF outbreak. MEASUREMENTS: All patients'
      charts were analyzed retrospectively with special emphasis on their cognitive and
      functional state. A follow-up examination of patients with functional decline at
      discharge was performed after 3 months. RESULTS: A change in consciousness,
      rather than in cognition, predicted the outcome. The death rate was 22% (7/32);
      all fatal cases were aged 78 and older. Similarly, the functional decline and
      residual damage appeared only in the older age group (>or=75). Eighty-eight
      percent of the survivors returned to their premorbid function. In contrast to
      other viral infections, chronic conditions in the subjects had no effect on the
      outcome. CONCLUSIONS: In older adults, WNF carries a high death rate, but the
      outcome is favorable for the survivors.

PMID- 12410905
TI  - Outcomes of pain in frail older adults with dementia.
AB  - OBJECTIVES: To describe the outcomes of pain in cognitively impaired older adults
      in a Program of All-inclusive Care for older people (PACE) setting and to
      determine whether pain and psychotropic drug use, behavioral disturbances,
      hospital, nursing facility, and emergency department use, or mortality increases
      with the level of pain reported. DESIGN: Retrospective review of an observational
      cohort of patients with dementia. SETTING: A first-generation PACE program
      located in Portland, Oregon. Patients with the diagnosis of dementia had been
      assessed for pain in a prior study. PARTICIPANTS: One hundred fifty-four
      cognitively impaired subjects. MEASUREMENTS: Standardized pain assessments were
      administered to cognitively impaired subjects between June and October 1998.
      After the pain assessment, information about mortality and healthcare use,
      including use of medication, was collected and analyzed. Subjects who reported
      moderate to severe pain were compared with demented subjects who reported no or
      mild pain. RESULTS: There were no differences in patient characteristics (age,
      sex, functional limitations, disruptive behaviors, and incontinence), medications
      (pain and psychotropic), use (hospital, nursing home, or emergency department
      visit), or mortality by level of pain alone or by levels of pain and dementia
      together. CONCLUSIONS: The study did not demonstrate that a single point-in-time
      measurement of pain in demented persons was associated with an increased rate of
      behavioral problems, narcotic use, or hospital or emergency department use over
      the following year. Prospective studies are needed that measure pain over time to
      determine more accurately the relationship between pain and negative outcomes in
      dementia.

PMID- 12410906
TI  - Use of lipid-lowering drugs in older adults with and without dementia: a
      community-based epidemiological study.
AB  - OBJECTIVES: To compare the use of lipid-lowering drugs in community-dwelling
      older adults with and without dementia. DESIGN: Comparison of lipid-lowering drug
      use by demented cases and nondemented controls based on secondary analysis of
      data from a longitudinal epidemiologic study. SETTING: Longitudinal study of a
      largely rural, low- socioeconomic-status, community-based cohort of older persons
      residing in the mid-Monongahela Valley of South-west Pennsylvania (the
      Monongahela Valley Independent Elders Survey). PARTICIPANTS: Eight hundred forty
      five individuals of mean +/- standard deviation (SD) age of 80.5 +/- 4.6,
      participating in the fifth biennial wave of data collection. MEASUREMENTS:
      Demographics; medical history; medication regimen (including examination of
      prescription bottle labels); self-report of most recent visit to primary care
      physician (PCP); and standardized clinical assessment to determine presence of
      dementia, including Clinical Dementia Rating (CDR). RESULTS: One hundred seventy
      participants (20.1% of total subject cohort) had dementia, with a CDR of 0.5 or
      greater. Mean ages of demented and nondemented individuals were 83.5 +/- 5.1 and
      79.8 +/- 4.2, respectively. Similar proportions, 87.7% and 89.5%, of these groups
      reported PCP visits in the previous year. Of the total sample, 9.4% (3.5% of the
      demented and 10.8% of the nondemented) were taking lipid-lowering drugs. After
      adjustment for age, sex, education, visit with PCP within the past year, and
      potential confounding clinical and lifestyle variables (self-reported heart
      disease, stroke or transient ischemic attacks, hypertension, smoking, and alcohol
      consumption), dementia was associated with a lower likelihood of taking a lipid
      lowering drug (odds ratio = 0.39, 95% confidence interval = 0.16-0.95). In post
      hoc subgroup analyses, similar results were found when restricting lipid-lowering
      drugs to statins alone but were not statistically significant. Drug use was not
      associated with severity of dementia (CDR = 0.5 vs CDR >or= 1). CONCLUSIONS:
      Demented individuals were less likely than their nondemented counterparts to be
      taking lipid-lowering drugs. This finding could reflect different prescribing
      patterns by physicians for demented and nondemented patients or a possible
      protective effect of these drugs against dementia.

PMID- 12410907
TI  - Use of artificial networks in clinical trials: a pilot study to predict
      responsiveness to donepezil in Alzheimer's disease.
AB  - OBJECTIVES: To evaluate the accuracy of artificial neural networks compared with
      discriminant analysis in classifying positive and negative response to the
      cholinesterase inhibitor donepezil in a group of Alzheimer's disease (AD)
      patients. DESIGN: Convenience sample. SETTING: Patients with mild to moderate AD
      consecutively admitted to a geriatric day hospital and treated with donepezil 5
      mg/day. PARTICIPANTS: Sixty-one older patients of both sexes with AD.
      MEASUREMENTS: Accuracy in detecting subjects sensitive (responders) or not
      (nonresponders) to 3-month therapy with ANNs. The criterion standard for
      evaluation of efficacy was the scores of Alzheimer's Disease Assessment Scale
      Cognitive portion and Clinician's Interview Based Impression of Change-plus
      scales. RESULTS: ANNs were more effective in discriminating between responders
      and nonresponders than other advanced statistical methods, particularly linear
      discriminant analysis. The total accuracy in predicting the outcome was 92.59%.
      CONCLUSIONS: ANNs appear to be a useful tool in detecting patient responsiveness
      to pharmacological treatment in AD.

PMID- 12410908
TI  - Management of nonmalignant pain in home-dwelling older people: a population-based
      survey.
AB  - OBJECTIVES: To investigate use of prescribed analgesic drugs in relation to
      experience of joint or back pain in a home-dwelling older population, to study
      changes in the use of analgesic drugs over 10 years, and to investigate
      concomitant use of protective gastrointestinal drugs with prescribed analgesic
      drugs in 1999. DESIGN: Cross-sectional mailed surveys 10 years apart. SETTING:
      Helsinki, Finland. PARTICIPANTS: Random samples of older birth cohorts born in
      1904, 1909, and 1914 in 1989 (n = 644) (n=644)-->, and of three separate cohorts
      born in 1914, 1919, and 1924 in 1999 (n = 3,000). MEASUREMENTS: Use of various
      types of analgesic and protective gastrointestinal drugs, prescribed and over the
      counter. Experience of joint and back pain that interferes with daily
      functioning. RESULTS: The response rate of home-dwelling older people was 83% in
      1989 and 81% in 1999. Although the use of analgesic drugs as self-treatment
      increased from 28.5% to 41.4% during the 10 years, in 1999, only 35.5% to 38.2%
      of those suffering joint or back pain that impaired daily functioning had been
      prescribed an analgesic drug for regular use. Of those using prescribed
      medication, 57.5% were on nonsteroidal antiinflammatory drugs (NSAIDs), 20.9%
      acetaminophen, and 18.5% weak opiates. Only one-fifth of those individuals taking
      NSAIDs were on a concomitant gastroprotective drug. CONCLUSIONS: Pain is markedly
      undertreated in community-dwelling older people, which may have serious
      implications for their well-being and functioning. Although we noted a tendency
      for safety in the use of prescribed analgesic drugs, a significant effort must
      sill be made to implement evidence-based practice. Self-treatment of pain has
      increased in 1 decade, which may reduce the overall safety of analgesic drug use
      among older people.

PMID- 12410909
TI  - Diurnal, week-to-week, and long-term variation in urine deoxypyridinoline cross
      link excretion in healthy older women.
AB  - OBJECTIVES: To establish a reference range for morning and afternoon excretion of
      urinary deoxypyridinoline (DPD) in apparently healthy older women selected from a
      volunteer database. To assess the extent of diurnal variation and short and long
      term within-subject longitudinal variation. DESIGN: Prospective, observational,
      cohort study. SETTING: Clinical Age Research Unit, King's College School of
      Medicine, London, United Kingdom. PARTICIPANTS: Forty-two women aged 68 to 89
      (median age 75) selected from a volunteer database. METHODS: Subjects completed
      an osteoporosis risk factor questionnaire and a physical examination and had a
      measurement of the broadband ultrasound attenuation and speed of sound of their
      right heel. Subjects provided six urine samples: morning and afternoon at
      baseline and 1 week and 60 weeks later for measurement of DPD. RESULTS: The mean
      baseline values for DPD of morning and afternoon samples were 7.2 nM/mM and 6.0
      nM/mM creatinine, respectively. The majority of subjects showed diurnal
      variation, with mean afternoon values 15% lower than morning values (P <.0001 for
      afternoon vs morning values). The mean difference in DPD after 60 weeks was 1.67
      nM/mM for morning and 1.34 nM/mM for afternoon creatinine. This difference was
      not significant. Some individuals displayed marked changes in DPD excretion with
      no change in health status or treatment. DPD excretion in a nonfasting afternoon
      sample showed similar characteristics to morning void samples in terms of
      scatter, week-to-week variation, and long-term reproducibility. CONCLUSIONS: The
      study was set up to provide background data to assist the development of a
      clinical osteoporosis service for older women. Further studies are needed to
      determine whether these measurements predict fracture risk and respond to
      treatment changes in this age group.

PMID- 12410910
TI  - Optimizing coding and reimbursement to improve management of Alzheimer's disease
      and related dementias.
AB  - The objectives of this study were to review the diagnostic, International
      Classification of Disease, 9th Revision, Clinical Modification (ICD-9-CM),
      diagnosis related groups (DRGs), and common procedural terminology (CPT) coding
      and reimbursement issues (including Medicare Part B reimbursement for physicians)
      encountered in caring for patients with Alzheimer's disease and related dementias
      (ADRD); to review the implications of these policies for the long-term clinical
      management of the patient with ADRD; and to provide recommendations for promoting
      appropriate recognition and reimbursement for clinical services provided to ADRD
      patients. Relevant English-language articles identified from MEDLINE about ADRD
      prevalence estimates; disease morbidity and mortality; diagnostic coding
      practices for ADRD; and Medicare, Medicaid, and managed care organization data on
      diagnostic coding and reimbursement were reviewed. Alzheimer's disease (AD) is
      grossly undercoded. Few AD cases are recognized at an early stage. Only 13% of a
      group of patients receiving the AD therapy donepezil had AD as the primary
      diagnosis, and AD is rarely included as a primary or secondary DRG diagnosis when
      the condition precipitating admission to the hospital is caused by AD. In
      addition, AD is often not mentioned on death certificates, although it may be the
      proximate cause of death. There is only one ICD-9-CM code for AD-331.0-and no
      clinical modification codes, despite numerous complications that can be directly
      attributed to AD. Medicare carriers consider ICD-9 codes for senile dementia (290
      series) to be mental health codes and pay them at a lower rate than medical
      codes. DRG coding is biased against recognition of ADRD as an acute, admitting
      diagnosis. The CPT code system is an impediment to quality of care for ADRD
      patients because the complex, time-intensive services ADRD patients require are
      not adequately, if at all, reimbursed. Also, physicians treating significant
      numbers of AD patients are at greater risk of audit if they submit a high
      frequency of complex codes. AD is grossly undercoded in acute hospital and
      outpatient care settings because of failure to diagnose, limitations of the
      coding system, and reimbursement issues. Such undercoding leads to a lack of
      recognition of the effect of AD and its complications on clinical care and
      impedes the development of better care management. We recommend continuing
      physician education on the importance of early diagnosis and care management of
      AD and its documentation through appropriate coding, expansion of the current ICD
      9-CM codes for AD, more appropriate use of DRG coding for ADRD, recognition of
      the need for time-intensive services by ADRD patients that result in a higher
      frequency of use of complex CPT codes, and reimbursement for CPT codes that cover
      ADRD care management services.

PMID- 12410911
TI  - Psychiatric aspects of mental competency in the aging.

PMID- 12410912
TI  - Back to the future of mental capacity assessment.

PMID- 12410916
TI  - Guidelines, evidence-based medicine, and Glidepaths: talking the talk.

PMID- 12410913
TI  - The development of outpatient Clinical Glidepaths.
AB  - For clinicians who are struggling with the complexities of medical decision
      making, practice guidelines and evidence-based medicine (EBM) have become
      increasingly popular and have potential to positively influence the practice of
      medicine. Nevertheless, they have their limitations. Guidelines are often rigid,
      based solely on age, and usually do not take into account a patient's
      comorbidities, life expectancy, and nonmedical preferences. EBM studies may not
      always include particular patient populations commonly seen by the geriatric
      clinician (e.g., studies on lipid-lowering agents or antihypertensive drug
      usually exclude the very old or patients who are frail, demented, or at the end
      of life). These limitations have made it difficult for geriatric clinicians to
      use these guidelines because of the need to individualize evaluation and
      treatment approaches and take into account the varied preferences of their older
      patients. The purpose of this paper is to present an alternative model of care
      for geriatric clinicians called The Clinical Glidepaths. The Clinical Glidepaths
      are outpatient tools intended to assist geriatric clinicians in their decision
      making process. They are based on the following principles. (1) Clinicians need
      guidance concerning many different types of patients, not rigid guidelines based
      solely on age. (2) EBM should be used but has some limitations of which to be
      aware. (3) Clinical experience, which emphasizes individual outcomes instead of
      populations, is an important component of medical decisions. (4) There needs to
      be room for patient preferences in medical decision-making. (5) An approach to
      patients based on probable life expectancy and function, instead of age, will be
      more applicable and useful. (6) Making a useful tool will focus on common
      problems seen in every day geriatric practices.

PMID- 12410918
TI  - Is percutaneous endoscopic gastrostomy really better?

PMID- 12410919
TI  - Retrospective comparison of postoperative complications after cardiovascular
      surgery in patients aged 80 and older.

PMID- 12410920
TI  - Anterior cervical osteophytes: a rare cause of dysphagia and upper airway
      obstruction in older patients.

PMID- 12410921
TI  - Non-Hodgkin's lymphoma in older people: age is not always an adverse prognostic
      factor.

PMID- 12410922
TI  - Burns in older people--outcomes and risk factors.

PMID- 12410923
TI  - The job market in geriatrics: a cause for concern.

PMID- 12410924
TI  - How well are community-living people treated for osteoporosis after hip fracture?

PMID- 12410925
TI  - Early normalization of low vitamin B12 levels by oral cobalamin therapy in three
      older patients with pernicious anemia.

PMID- 12410926
TI  - Randomized trial of trigger point injection for renal colic.
AB  - BACKGROUND: Many drugs have been utilized for the treatment of renal colic, but
      to date no drugs that relieve pain quickly and completely have been developed.
      Thus, we conducted a prospective trial to evaluate the effects of trigger point
      injection on renal colic. In this study, we used a local injection of lidocaine
      to the trigger point of patients experiencing renal colic, and evaluated the
      efficacy in patients using the visual analog scale. METHODS: Sixty patients with
      renal colic were enrolled in this study and divided into two groups by a simple
      randomization: (i) the butylscopolamine group (n = 30, intravenous injection of
      butylscopolamine bromide and sulpyrine); and (ii) the lidocaine group (n = 30,
      local anesthesia to the trigger point with lidocaine). RESULTS: Renal colic had
      disappeared completely at the end of the trigger point injection in 15/30
      patients and the average time required to produce a 50% improvement in symptoms
      was 9 min in all patients in the group. In the lidocaine group, only one patient
      needed an additional anodyne treatment after 60 min and none of the 29 patients
      whose pain disappeared within 60 min needed further anodyne treatment within 24
      h. These results were all significantly superior to those of the conventional
      treatment. No side-effects and complications were observed. CONCLUSION: Trigger
      point injection, in our experience, is an easy, safe and effective method for the
      amelioration of renal colic. It was significantly superior to the combination of
      intravenous butylscopolamine and sulpyrine.

PMID- 12410927
TI  - Hand-assisted retroperitoneoscopic radical nephrectomy: initial experience.
AB  - OBJECTIVES: To report our initial experience of hand-assisted
      retroperitoneoscopic radical nephrectomy for stage T1 renal tumors. METHODS: The
      clinical data on 22 consecutive patients who had undergone hand-assisted
      retroperitoneoscopic radical nephrectomy and 22 who had undergone open radical
      nephrectomy were reviewed. The operation was performed with a hand placed
      retroperitoneally through a pararectal longitudal 7-7.5 cm incision using a LAP
      DISC. RESULTS: The total operating time was between 2.3 and 5.8 h (mean: 3.4 h).
      The estimated blood loss was between 15 and 650 mL (mean: 170 mL). The
      complication rate was 9% (2/22). No conversions to open procedure occurred. In
      comparison to open radical nephrectomy, the operating time was similar (3.4 vs
      3.9 h) whereas the estimated blood loss was significantly less in this procedure
      (170 vs 495 mL). During the convalescence period the patients revealed
      significantly less postoperative pain, shorter intervals to resuming oral intake
      and more rapid return to normal activities compared to the open radical
      nephrectomy patients. CONCLUSION: Hand-assisted retroperitoneoscopic radical
      nephrectomy is an effective and safe procedure for T1 renal tumors.

PMID- 12410928
TI  - Symptom-specific quality of life in patients with benign prostatic hyperplasia.
AB  - BACKGROUND: We investigated which factors are most bothersome to preoperative
      patients with benign prostatic hyperplasia (BPH). METHODS: A total of 423 newly
      diagnosed patients and 388 preoperative patients with symptomatic BPH were
      evaluated. International prostate symptom score (IPSS) and IPSS quality-of-life
      (QOL) assessment score were used for assessment of symptoms and symptom-specific
      QOL of the patients with BPH. Uroflow variables were measured in all patients.
      Other objective variables such as prostate volume, transition zone volume,
      Schaefer's obstruction grade, and detrusor pressure at maximal urinary flow were
      evaluated in 209 preoperative patients. We analyzed the relationships between
      symptom-specific QOL and other variables. Statistical analyses were performed
      using Spearman's correlation coefficient and a stepwise linear regression model.
      RESULTS: Symptom-specific QOL scores had moderate to good correlation with IPSS
      (P < 0.0001; r = 0.525-0.560). Filling symptom subscore had a slightly greater
      impact on symptom-specific QOL than voiding subscore in both groups of patients.
      Weak stream, feeling of incomplete emptying, and nocturia significantly decreased
      symptom-specific QOL in both groups of patients. While newly diagnosed patients
      suffered from frequency as well, urgency had the strongest impact on symptom
      specific QOL of preoperative patients. Objectively measurable variables had no
      association with symptom-specific QOL. CONCLUSION: Japanese patients with BPH
      generally suffer from weak stream, feeling of incomplete emptying, and nocturia
      in all disease phases. Frequency is problematic for newly diagnosed patients and
      urgency is problematic for preoperative patients as well. Symptom-specific QOL of
      BPH patients cannot be estimated by physically measurable variables.

PMID- 12410929
TI  - Increased transforming growth factor-beta1 and tubulointerstitial fibrosis in
      rats with congenital hydronephrosis.
AB  - OBJECTIVES: Most of our knowledge concerning renal obstruction has been derived
      from experimental animal models, and it is not yet well defined in spontaneous
      hydronephrosis. The aim of our study is to evaluate the roles of transforming
      growth factor-beta1 (TGF-beta1) and apoptosis in congenital hydronephrotic
      kidneys in comparison with experimental models. METHODS: We made histological
      studies on kidneys from 6-week-old Wistar-Imamichi rats with congenital
      unilateral hydronephrosis as well as surgical models of complete or partial
      unilateral ureteral obstruction. The severity of hydronephrotic kidneys was
      evaluated on routine hematoxylin and eosin (H&E) stained sections, and the
      tubulointerstitial fibrosis analyzed morphometrically on Masson's trichrome
      stained sections. Renal tubular atrophy was assessed on periodic acid Schiff
      (PAS) stained sections, and tubular cell apoptosis assessed with TUNEL technique.
      The renal TGF-beta1 level was determined by a sandwich enzyme-linked
      immunosorbent assay (ELISA). RESULTS: We observed a significant loss of kidney
      weight with profound compensatory growth of the contralateral kidney in rats with
      congenital hydronephrosis. Most of the hydronephrotic kidneys were markedly
      enlarged with dilatation of the collecting system, renal parenchymal thinning,
      tubular atrophy, interstitial infiltration and fibrosis. The renal TGF-beta1
      level was markedly elevated in hydronephrotic kidneys as compared with normal
      controls (326.01 +/- 30.64 pg/mg protein vs 227.81 +/- 11.07 pg/mg protein, P <
      0.01). The tubular apoptotic score in hydronephrotic kidneys was also
      significantly higher than normal controls (2.17 +/- 0.50/HPF [high power field]vs
      0.14 +/- 0.04/HPF, P < 0.01). The increased TGF-beta1 and apoptotic status
      paralleled the histological changes of tubulointerstitial fibrosis and tubular
      atrophy. Similar findings were also obtained in experimental obstructive models.
      CONCLUSION: In comparison with surgical models of partial and complete ureteral
      obstruction, our data provide solid morphological and molecular evidences of
      renal obstruction in rats with congenital hydronephrosis.

PMID- 12410930
TI  - Calcium oxalate monohydrate crystal binding substance produced from Madin-Darby
      canine kidney cells.
AB  - BACKGROUND: The interaction between kidney urothelium and crystals is a critical
      event in the growth of renal calculi. When studying calcium oxalate monohydrate
      (COM) crystal binding to Madin-Darby canine kidney (MDCK) cells in culture, we
      observed that crystals also attached to areas on the coverslips devoid of cells.
      This phenomenon could be the result of substances produced by the cells that
      adhere to the glass and subsequently bind COM crystals. We investigated the
      characteristics of this COM binding substance. METHODS: Media was collected from
      cultures of MDCK cells (conditioned media) and proteins were separated by high
      performance liquid chromatography. The molecular weights and purity of isolated
      proteins were determined by polyacrylamide gel electrophoresis. The conditioned
      media and each separated fraction were applied to glass and to MDCK cells and COM
      binding ability determined using 14C-labeled crystals. The binding of radio
      labelled calcium oxalate dihydrate, brushite, uric acid, and apatite to
      coverslips were also studied. RESULTS: Fourteen times more COM bound to
      coverslips incubated with conditioned media than those with control media. The
      molecular weight of the protein bound to the glass was determined to be 200 kDa.
      The COM crystals binding to this protein was 1.5 micro g/ng. Other crystals bound
      to a lesser extent. The incubation of cells with this protein inhibited COM
      binding by 39%. CONCLUSION: The MDCK cells produce a 200-kDa protein that has a
      high binding affinity for COM crystals. This protein binds to glass and is
      responsible for crystal binding to areas devoid of cells. This protein also has
      an inhibitory effect on COM binding to MDCK cells in culture.

PMID- 12410931
TI  - Angiogenesis in renal cell carcinoma: Evaluation of microvessel density, vascular
      endothelial growth factor and matrix metalloproteinases.
AB  - BACKGROUND: Angiogenesis, the growth of new blood vessels, has a critical role in
      tumor growth and metastasis. The purpose of this study was to investigate the
      involvement of angiogenesis and angiogenic factors in the pathogenesis of renal
      cell carcinoma (RCC). METHODS: Formalin-fixed and paraffin-embedded tissue blocks
      from 70 patients with RCC were studied. The situations of tumor angiogenesis were
      evaluated by assessing microvessel density (MVD) through CD31 immunostaining. The
      expression of vascular endothelial growth factor (VEGF), matrix metalloproteinase
      2 (MMP-2) and metalloproteinase-9 (MMP-9) was detected immunohistochemically.
      RESULTS: The value of MVD ranged from 12.0 to 93.0 with a median of 39.91 in RCC.
      Of the 70 RCCs, the expression of VEGF was detected in 52 (74.3%), MMP-2 in 29
      (41.4%) and MMP-9 in 19 (27.1%) cases. Statistical analysis revealed significant
      associations of the tumor stage with MVD, and the expression of VEGF and MMP-2 in
      RCC. Additionally, MVD was closely related to the expression of VEGF but was not
      related to the expression of MMP-2 and MMP-9 in RCC. CONCLUSION: The degree of
      angiogenesis may be closely related to the tumor progression of RCC. The
      expression of VEGF may be responsible for angiogenesis in RCC, and both VEGF and
      MMP-2 expression may function as tumor associated angiogenic factors in RCC.

PMID- 12410932
TI  - Transitional cell carcinoma of the ureteral stump eight years after nephrectomy
      for benign disease.
AB  - A case of primary carcinoma of the ureteral stump is reported. A 68-year-old man
      presented with asymptomatic gross hematuria. He had undergone a right nephrectomy
      for a benign disease previously. Cystoscopy and left ureteroscopy showed no
      abnormalities. A computed tomography showed a solid mass on the region of the
      right ureteral stump. He underwent a right ureterectomy and bladder cuff
      resection. A pathological examination showed transitional cell carcinoma.

PMID- 12410933
TI  - Giant bladder diverticulum due to previous bullet injury: findings of gadolinium
      enhanced magnetic resonance imaging.
AB  - Non-obstructive acquired giant bladder diverticulum is rare. An 84-year-old man
      presented with difficulty in urination. Radiological examinations including
      pelvic magnetic resonance imaging, urethrocystography and urethrocystoscopy
      demonstrated a giant bladder diverticulum with normal infravesical urinary tract.
      The patient had a past history of gunshot bladder injury and underwent surgical
      removal of the bullet. The giant bladder diverticulum was thought to be
      associated with the injury or the operation.

PMID- 12410935
TI  - Traumatic rhabdomyolysis resulting from continuous compression in the exaggerated
      lithotomy position for radical perineal prostatectomy.
AB  - This report demonstrates a case of rhabdomyolysis as a result of the exaggerated
      lithotomy position during radical perineal prostatectomy. The pathogenesis,
      diagnosis, management, and preventive measures of rhabdomyolysis are also
      reviewed.

PMID- 12410936
TI  - Erosion of a penile prosthesis due to an indwelling urethral catheter as a late
      complication.
AB  - A case of erosion of a penile prosthesis caused by indwelling of a catheter in
      the urethra is reported. A 73-year-old man had maintained sexual intercourse with
      penile prostheses (Jonas prosthesis, 19 cm) for 11 years without any
      complications until he developed cerebral infarction. One month after starting an
      indwelling urethral catheter in a neurosurgery clinic, the left-side penile
      prosthesis eroded from the area of the fossa navicularis, and was immediately
      removed. This type of complication is not unusual in patients with a neurogenic
      bladder. However, it is not well recognized in patients who suddenly develop a
      neurogenic bladder following a long-term uneventful period after the implantation
      of penile prostheses. Therefore, urologists should inform patients who receive
      this type of treatment that erosion of the prosthesis may develop when they need
      an indwelling urethral catheter as a late complication.

PMID- 12410937
TI  - Intra-abdominal testis with loop-like epididymis and intra-canalicular vas and
      vessels.
AB  - A case of intra-abdominal testis with loop-like epididymis and intra-canalicular
      vas and vessels is presented. A 3-year-old male with left impalpable testis since
      birth was admitted to our department. Physical examination and ultrasonography
      were inconclusive. Laparoscopy revealed a small left abdominal testis with
      surrounding adhesions close to the left-obliterated umbilical artery. The vas
      deferens and spermatic vessels were entering into the internal inguinal ring. The
      processus vaginalis was patent. At inguinal exploration the testis was atrophic
      and the epididymis was loop-like, joining the vas deferens in the inguinal canal.
      The spermatic vessels continued to the atrophic testis in a loop-like manner. The
      testis, epididymis and the vas deferens were removed. Histopathological
      examination of the testis revealed Sertoli cells only. If inguinal exploration
      had been performed without laparoscopy, the presence of the vas deferens and
      spermatic vessels in the inguinal canal with the absence of the testis could have
      been misdiagnosed as vanishing testis. Abdominal testis would thus have been
      missed, with increased risk of complications, particularly malignancy.

PMID- 12410938
TI  - The relationship of protein conservation and sequence length.
AB  - BACKGROUND: In general, the length of a protein sequence is determined by its
      function and the wide variance in the lengths of an organism's proteins reflects
      the diversity of specific functional roles for these proteins. However,
      additional evolutionary forces that affect the length of a protein may be
      revealed by studying the length distributions of proteins evolving under weaker
      functional constraints. RESULTS: We performed sequence comparisons to distinguish
      highly conserved and poorly conserved proteins from the bacterium Escherichia
      coli, the archaeon Archaeoglobus fulgidus, and the eukaryotes Saccharomyces
      cerevisiae, Drosophila melanogaster, and Homo sapiens. For all organisms studied,
      the conserved and nonconserved proteins have strikingly different length
      distributions. The conserved proteins are, on average, longer than the poorly
      conserved ones, and the length distributions for the poorly conserved proteins
      have a relatively narrow peak, in contrast to the conserved proteins whose
      lengths spread over a wider range of values. For the two prokaryotes studied, the
      poorly conserved proteins approximate the minimal length distribution expected
      for a diverse range of structural folds. CONCLUSIONS: There is a relationship
      between protein conservation and sequence length. For all the organisms studied,
      there seems to be a significant evolutionary trend favoring shorter proteins in
      the absence of other, more specific functional constraints.

PMID- 12410939
TI  - Are the results of dental research accessible to Canadian dentists?
AB  - The aim of this joint CDA-IMHA study was to investigate what Canadian dentists
      think about the utility of dental research. A questionnaire was sent to all
      dentists in Canada with the December 2001 JCDA. By April 1, 2002, 2,788
      questionnaires, representing a response rate of approximately 16%, had been
      returned. In this second article in a 3-part series, we address the theme of
      research accessibility. The study results show that while 75% of respondents
      think that research results are easily accessible, 90% would like them to be more
      accessible. For clinical dentists, the most important source of information about
      research is generalist dental journals ( JCDA in particular), while
      teachers/researchers prefer specialist journals. In addition, clinical dentists
      prefer to learn about research through clinical practice guidelines rather than
      conventional scientific reports.

PMID- 12410940
TI  - Parental factors associated with regular use of dental services by second-year
      secondary school students in Quebec.
AB  - The aim of this study was to identify the parental factors associated with
      regular use of dental services by second year secondary school students in
      Quebec. Data were collected in 1996-97, as part of a provincial survey on the
      dental health of Quebec students. A stratified probabilistic sample of 1,351
      students, representative at the provincial level, was obtained. Data about
      frequency of use of dental services, parents' socio-economic characteristics,
      dental insurance (private and public) and parents' utilization of dental services
      were selected for this study. Half of the students used dental services regularly
      (i.e., once every 6 months). Multivariate analysis showed that the strongest
      parental factors associated with regular use were (in decreasing order of
      importance) the date of the mother's most recent dental visit, dental insurance,
      household income and the date of the father's most recent dental visit. After
      adjustment for the parents' socio-economic characteristics and the availability
      of dental insurance, students with one parent (particularly the mother) who had
      visited the dentist within the previous year had better odds of using dental
      services every 6 months, as recommended by professional standards.

PMID- 12410941
TI  - Furcation therapy with bioabsorbable collagen membrane: a clinical trial.
AB  - This study compared the effectiveness of 2 barrier membranes, expanded
      polytetrafluoroethylene (e-PTFE) and collagen, in treating Class II furcation
      defects of mandibular molars in humans. Seventeen nonsmoking subjects with no
      history of systemic disease each presenting with Class II furcation defects in 2
      mandibular molars were selected and underwent initial therapy. At the time of the
      surgery and at 8-month follow-up, soft-tissue measurements consisting of the
      gingival index, vertical and horizontal probing depth, recession and clinical
      attachment level were obtained at the midfurcation level. At the time of membrane
      placement and at 12-month re-entry, horizontal midfurcation probing depth and
      hard-tissue measurement of vertical fill (from the crown to the depth of the
      pocket) were also obtained. According to the surgical protocol, both membranes
      were completely covered with a coronally positioned flap, and in all cases
      healing was uneventful. Data were analyzed first by comparing baseline
      measurements (at surgery) with measurements at 8-month follow-up and 12-month re
      entry for both e-PTFE and collagen membranes according to repeated-measures
      analysis of variance. The changes from surgery to follow-up and re-entry were
      then compared between the 2 treatment modalities with paired Wilcoxon rank-sum
      tests. No statistically significant differences were found between e-PTFE and
      collagen membranes with respect to gingival index, reduction in probing depth,
      gain in clinical attachment or filling of the horizontal defect. However, the
      improvement in vertical fill at 12-month re-entry was more substantial for the
      teeth treated with collagen membrane than those treated with e-PTFE (p < 0.05).
      Within the limits of this study, it appears that collagen is a beneficial
      material for regenerative therapy of Class II furcation defects in humans,
      yielding results that are similar to or better than (vertical fill) those for e
      PTFE membrane.

PMID- 12410942
TI  - Advances in the diagnosis of oral premalignant and malignant lesions.
AB  - The diagnosis and treatment of oral premalignant lesions and squamous cell
      carcinoma are currently based on histopathologic features, site of involvement
      and stage of disease. Recent advances in techniques for detecting lesions and
      predicting their progression or recurrence are reviewed here. Adjuncts for
      detection of lesions and selection of biopsy sites include vital tissue staining
      (with toluidine blue) and exfoliative cytology. Advances in diagnosis and staging
      at the molecular level are expected to affect choice of treatment and patient
      outcomes. Oral health care providers should be aware of these advances in the
      evaluation and diagnosis of oral premalignant lesions and squamous cell
      carcinoma.

PMID- 12410943
TI  - Local anesthetic cartridges and latex allergy: a literature review.
AB  - PURPOSE: To assess the validity of recommendations to avoid using cartridges for
      dental local anesthetic in patients with latex allergies. METHODS: A MEDLINE
      search was conducted for the period 1966 to 2001, and relevant publications were
      reviewed for evidence of allergic reactions precipitated by latex in medication
      vials or cartridges for dental local anesthetic. RESULTS: Twelve publications met
      the selection criteria and are summarized here: 4 case reports, 5 experimental
      studies, 1 clinical update and 2 letters to the editor. CONCLUSION: The medical
      literature provides some evidence that latex allergen can be released into
      pharmaceutical solutions contained within vials, by either penetration through or
      direct contact with natural latex stoppers. However, there are no reports of
      studies or cases in which a documented allergy was due to the latex component of
      cartridges for dental local anesthetic.

PMID- 12410944
TI  - Sampling survey on low-birth weight in China in 1998.
AB  - OBJECTIVE: To study the weight of live births and incidence of low-birth weight
      (LBW) in China. METHODS: A national survey on the weight of live births with
      gestational ages of 28 weeks or over in 16 cities and 28 counties of 11 provinces
      in China was carried with stratified sampling during July to October, 1998.
      RESULTS: Totally 22 350 live newborns, 11 584 males and 10 766 females, with
      gestational ages of 28 weeks or more in sampling sites were measured at their
      birth. Rates of multiple births and preterm birth (< 37 weeks of gestation) were
      1.8% and 3.5%, respectively. LBW rates were 4.20% and 6.26% for urban and rural
      areas, respectively, with a national weighted-average of 5.87%. Full term births
      (>/= 37 weeks of gestation) accounted for 61.2% and 71.6% of the babies with LBW
      in national and rural areas, respectively. Their average birth weight was 3 301 g
      and 3 225 g in urban and rural areas, respectively, with statistically
      significant difference, and 3 280 g and 3 173 g for boys and girls, respectively,
      approaching to the values recommended by the World Health Organization (WHO).
      Live birth weight in the coastal, inland, and remote areas appeared a trend of
      gradual decrease. Early neonatal mortality of babies with LBW was 50.0 per
      thousand and 179.4 per thousand in urban and rural areas, respectively, with a
      national average of 151.5 per thousand, significant higher than those with normal
      birth weight. CONCLUSIONS: The average birth weight and LBW rate in live births
      of China were close to those in the developed countries, and there was
      significant difference in them between varied regions. The majority of LBW in
      China was attributed to intrauterine growth retardation (IUGR). Early neonatal
      mortality in babies with LBW was significantly higher than that with normal birth
      weight. Further intervention measures should be implemented.

PMID- 12410945
TI  - A national sampling survey on birth weight in 1998 in China: mean value and
      standard deviation.
AB  - OBJECTIVE: To understand the distribution of live birth weight in China. METHODS:
      A national survey on live birth weight was performed during July-October, 1998 in
      China, with stratified sampling. Totally, 22 350 live newborns (11 584 males and
      10 766 females) with 28 weeks or more of gestation were measured for their birth
      weight in the sampling sites during 1998. RESULTS: The ratio of male to female
      newborns measured was 1.08. The rates of multiple birth and preterm birth (< 37
      weeks of gestation) were 1.8% and 3.5%, respectively. Live birth weight was
      higher in the urban areas (3 301 g) than that in the rural area (3 225 g) (t =
      9.4. P < 0.001), the highest in the coastal areas (3 262 g), middle in the inland
      areas (3 254 g) and the lowest in the remote areas (3 115 g) (F = 177.9, P <
      0.001), with a decreasing trend. Live birth weight in the first-class rural areas
      approximated to that in the urban areas, and that in the second-class, third
      class and fourth-class rural areas decreased significantly. The average live
      birth weight in the fourth-class rural areas was 200 g lower than that in the
      urban areas. CONCLUSIONS: Generally, the average live birth weight in China was
      closed to that in the developed countries. But, a big difference in the average
      live birth weight between regions with varied economic development and health
      care condition was observed. An intervention measure should be implemented in the
      poverty-stricken rural areas to increase their average live birth weight.

PMID- 12410946
TI  - A case-control study on risk factors for low birth weight in China.
AB  - OBJECTIVE: To identify the risk factors for low birth weight (LBW) in Chinese
      newborns with varied characteristics. METHODS: A 1:1 matched case-control study,
      with 999 babies of LBW was performed in 44 counties of 11 provinces in China
      during July to October, 1998 for identifying their risk factors using simple and
      multivariate logistic regression models. RESULTS: The determinants of LBW in
      China included factors, such as multiparity (OR = 106.9), preterm birth (OR =
      18.7), abnormal maternal health status (OR = 2.61) and maternal malnutrition (OR
      = 3.42), maternal medical conditions during pregnancy (OR = 1.93), maternal
      schooling (OR = 1.43), et al. Distribution of the risk factors for LBW was
      significantly different between coastal, inland and remote areas. LBW was mainly
      attributed to intrauterine growth retardation (IUGR) (71.6%) in the rural areas,
      and to multiparity and preterm birth, in addition to IUGR, in the urban areas.
      There was different in the risk factors for LBW with preterm births and IUGR.
      CONCLUSIONS: It is an effective way to reduce incidence of low birth weight in
      China that all measures for prevention and control should be relevant to its risk
      factors.

PMID- 12410947
TI  - Prevalence of subclinical vitamin A deficiency and its affecting factors in 8 669
      children of China.
AB  - OBJECTIVE: The survey will reveal current status of subclinical vitamin A
      deficiency (SVAD) and explore its affecting factors in children of China.
      METHODS: Totally 8 669 children aged under 6 years were randomly selected from 14
      provinces for clinical examination, health and dietary questionnaire and serum
      level of vitamin A measurement with fluorescence method. The cut-off value for
      SVAD was defined as </= 0.70 micro mol/L. RESULTS: Prevalence of SVAD was 11.7%
      and that of suspected SVAD 39.2% in all subjects, which decreased with the
      increase of gross domestic product, average annual family income, mother's
      schooling and children's age. Prevalence of SVAD and suspected SVAD higher in
      rural areas (15.0%) than in urban areas (5.2%), and higher in children with a
      minority mother (22.6%) than in those with a Han nationality mother (8.7%).
      Prevalence of SVAD and suspected SVAD was higher in children whose blood samples
      were collected within one week in-taking vitamin A-rich food (12.6%-22.6%) than
      those in-taking vitamin A daily (4.1%-10.0%), and higher in children suffering
      from respiratory infection, fever and diarrhea two weeks before their blood
      collection (15.2%-20.3%) than in those without those diseases (10.1%-11.1%).
      Logistic regression analysis showed that poor family economic status, living in
      rural areas, children with a minority mother, younger age, no-dairy milk products
      intake, and respiratory infection and fever all were risk factors for SVAD.
      CONCLUSIONS: More than half of children under six years old in China (50.9%) had
      vitamin A nutrition problem. Varied factors played roles to different extent in
      SVAD in children.

PMID- 12410948
TI  - Prevalence of cerebral palsy in children aged 1 - 6 in Guangxi, China.
AB  - OBJECTIVE: To study the prevalence of cerebral palsy (here in after referred to
      CP) in children aged 1 - 6 in Guangxi, China, and its epidemiologic
      characteristics and relevant risk factors. METHODS: Investigations on the
      prevalence and etiology of CP in children at ages of 1 - 6 were conducted in
      Nanning, Hengxian and Qinzhou of Guangxi from June to December in 1998, with a
      cluster sampling. RESULTS: Totally, 150 806 children aged 1 - 6 were investigated
      in Nanning, Hengxian and Qinzhou of Guangxi, with 89 418 boys and 61 388 girls.
      Among them, 193 children were diagnosed as CP, with a prevalence rate of 1.28 per
      thousand, higher in boys (136 cases, 1.52 per thousand ) than in girls (57 cases,
      0.93 per thousand ), with statistical significance (chi(2) = 9.536 7, P = 0.02).
      Logistic regression analysis showed that risk factors for CP were children who
      could not cry after birth (neonatal asphyxia), Apgar score less than eight,
      delivery at lower level of maternity hospital, number of mother's gravidity, no
      prenatal checks for mothers, and taking antipyretics and preserved food with salt
      during pregnancy. CONCLUSIONS: Prevalence of CP in children of Guangxi was at a
      lower level in comparison with that in other areas at home and abroad, which,
      maybe, was related with the lower neonatal survival and higher infant mortality.

PMID- 12410949
TI  - Studies on survival and outgrowth of processes of cultured rat hippocampus
      neurons in containing selenium and free serum medium.
AB  - OBJECTIVE: To study the effect of selenium on cultured newborn rat's hippocampus
      neurons survival and outgrowth development. METHODS: Using the technique of
      primary culture of hippocampal neurons of newborn rat. The different dose of Se
      (62.5 microgram/L, 125.0 microgram/L, 182.5 microgram/L) were added into the
      medium at same time. We not only investigated the number of survival of neurons
      on 1 - 14 d and 1d to 10 d in with and without serum containing-Se medium, but
      also observed the length outgrowth of the neurite at 16 h, 24 h, 36 h, 48 h
      during culture. RESULTS: Selenium could obviously enhance the outgrowth of early
      processed in 10% fetal serum medium and average length of neurite outgrowth is 15
      - 20 micrometer more longer than control groups (P < 0.01) and selenium could
      also increase the livability of neurons and prolong survival time of cultured
      neurons in serum-free medium. CONCLUSIONS: Selenium may play a very important
      role for early processed growth and development of hippocampal neurons.

PMID- 12410950
TI  - The effects of an instant haw beverage on lipid levels, antioxidant enzyme and
      immune function in hyperlipidemia patients.
AB  - OBJECTIVE: To determine the effectiveness of an instant haw beverage in
      regulating lipid disturbance, enhancing antioxidant enzyme activity and immune
      function. METHODS: Data was collected from 60 hyperlipidemic subjects. In this
      crossover design, each subject randomly received either the instant haw beverage
      (100 ml corresponding to 3 g of haw powder or 30 g of fresh haw fruit plus the
      carrier-guar gum plus some starch) or placebo (guar gum 1.5 g plus some starch as
      the carrier of the beverage) twice daily. Each supplementation lasted 31 days
      with a 28-day washout period between treatments. RESULTS: The instant haw
      beverage significantly reduced total serum cholesterol (9.6%), triglyceride
      (12.1%), LDLC (18%) while significantly increased SOD activities (7.5%). The
      placebo was shown to have positive results in some of the lipid profiles, though
      the effects of the instant haw beverage demonstrated greater significance. Serum
      triglyceride levels were significantly decreased and SOD activity significantly
      increased only as subjects were supplemented with the instant haw beverage while
      no significant changes were seen with placebo. CONCLUSION: Supplementation with
      the instant haw beverage positively affects blood lipid profile, antioxidant
      status and immune function in individuals with hyperlipidemia.

PMID- 12410951
TI  - The study of thyroid diseases in a community not using iodized salt.
AB  - OBJECTIVE: To investigate the prevalence of thyroid diseases in a community which
      did not use iodized salt. METHODS: The survey was conducted in Panshan, Liaoning
      Province. 1 103 inhabitants aged 14 years or more attended the examinations,
      which included questionnaire, physical examination and serum analysis. Iodine in
      the urine and thyroid B ultrasound examination were also conducted. RESULTS: The
      prevalence of overt hyperthyroidism and hypothyroidism was 16.3 per thousand and
      2.7 per thousand, respectively. Subclinical hyperthyroidism and hypothyroidism
      were detected in 37.2 per thousand and 9.1 per thousand of the subjects,
      respectively. Serum autoantibodies to thyroid were detected in 10.9% of the
      entire population. The prevalence of goiter was 20.7% (diffuse goiter 16.8% and
      nodular goiter 3.9%). CONCLUSION: In the iodine deficient areas, perhaps
      autoimmununization is not only related to the development of goiter but is also
      the main cause of subclinical hyperthyroidism and hypothyroidism.

PMID- 12410952
TI  - The relationship between nonresponse to hepatitis B vaccine and HLA
      genotype/haplotype.
AB  - OBJECTIVE: To study the relationship between the nonresponse to hepatitis B
      vaccine and HLA genotype/heplotype in Chinese population and provide the evidence
      for explaining the genetic mechanism of this nonresponse. METHODS: Our research
      focused on the relationship between nonresponse to Hepatitis B vaccine and HLA
      DRB1, DRB3, DRB4, DRB5 and DQB1 genotype/haplotype in Chinese population,
      collected from a community in Guangxi Zhuang Autonomous Region. The group
      specific amplification was employed to characterize 107 individuals' genotype and
      haplotype of HLA clusters. Different models statistics such as relative risk
      test, correlation test and linkage disequilibrium analysis were used to analyze
      the data. RESULTS: The results showed that there is a linkage disequilibrium
      between nonresponse to Hepatitis B vaccine and HLA haplotype DR4, 1122 (DRB1 *
      0401- 22, 1122)-DR53 (DRB4 * 0101101, 0102/3)-DQB4 (DQB1 * 04). CONCLUSION: In
      Chinese population, nonresponse to hepatitis B vaccine is highly associated with
      special HLA haplotye.

PMID- 12410953
TI  - Effect of superior fiber complex on insulin sensitivity index and blood lipids in
      non-insulin dependent diabetes mellitus rats.
AB  - OBJECTIVE: To explore the factors affected insulin sensitivity index (ISI) and
      the effects of superior fiber complex (SFC) on ISI and blood lipids in non
      insulin dependent diabetes mellitus (NIDDM) rats. METHODS: Twenty-six male Wistar
      rats were injected with low dose of streptozotocin and fed a diet with high
      calorie and high fat for ten weeks and glucose tolerance (GTT), fasting insulin
      (FINS), total cholesterol (TC) and triglyceride (TG) were measured while area
      under curve (AUC) and insulin sensitivity index (ISI) were also calculated. The
      results were compared with those from 7 normal control rats. Multi-factor
      regression analysis was used to analyze those factors affected ISI. In the same
      experiment, 13 rats with diabetes mellitus were treated with Superior Fiber
      Complex (SFC) for 8 weeks and the results were compared with the pre-treated
      data. RESULTS: Compared with the control group, AUC in the diabetic group was
      larger, and FINS, TC and TG were higher; but ISI was lower. Therefore, The TG and
      AUC was the major factor affected ISI. TC and TG were lowered and AUC was reduced
      and ISI increased. CONCLUSION: High TG and impaired glucose tolerance (IGT) are
      main risk factors of ISI in the rat model, and SFC could increase ISI, decrease
      high blood lipids and prevent IGT.

PMID- 12410954
TI  - A case-control study on risk factors of helicobacter pylori infection in out
      patients with stomach diseases.
AB  - OBJECTIVE: To investigate the risk factors of Helicobacter Pylori (Hp) infection.
      METHODS: All cases and controls came from 561 cases of out-patients with stomach
      diseases seeking gastroscopy in the Zhejiang Province First Hospital between
      April and July in 2000. The tissue samples of patients were stained for Hp by the
      improved Warthin-Starry technique and by methylene blue stain for routine
      histopathology. We classified patients as cases or controls based on the
      detection of Hp or not. Before gastroscopy, a questionnaire on lifestyle and
      health condition of was administered to patients by the interviewers. RESULTS:
      The overall prevalence of Hp infection was 50.21% and the risk factors of Hp
      infection were significantly different between males and females. As for males,
      the duration of daily heavy physical activities, numbers of siblings in the
      household, family history of oliver disease, preference of spicy food and smoking
      were the risk factors for Hp infection. However, preference of beans and bean
      products, drinking well water, drinking tea, eating regularly and good education
      appears to decrease the prevalence of infection. As for females, consumption of
      caffeine contained beverages seemed to increase risk for infection. By analyzing
      with unconditional Logistic Regression Model in male and female groups combined,
      it brought to light that intake of egg and peppery food were the risk factors of
      infection, and intake of beans and drinking tea were the protective factors.
      CONCLUSION: Consumption of beans and drinking tea must be advocated and the
      consumption of spicy food should be discouraged.

PMID- 12410955
TI  - A study on the relationship between genetic and environmental factors of type 2
      diabetes mellitus in humans.
AB  - OBJECTIVE: To study the relationship between the inheritable factor and
      environmental factors of type 2 diabetes mellitus in humans. METHODS: A case
      control study based on 154 type 2 diabetes mellitus and 130 healthy controls was
      carried out in Jiangsu Province in 1997. RESULTS: The age, family history of
      diabetes mellitus, hypertension history, high waist/hip ratio (WHR), high
      systolic blood pressure, huge fetus history, and the genotype of beta(3)
      adrenergic receptor (beta(3)-AR) were the risk factors of type 2 diabetes
      mellitus; while occupational physical activity was protective factor of type 2
      diabetes mellitus. The risk for diabetes mellitus distinctly increased while
      genetic factor and obesity, beta(3)-AR mutation were coexisting. CONCLUSION: Type
      2 diabetes mellitus is caused by the effect of both genetic and environmental
      factors.

PMID- 12410956
TI  - Dynamic analyses on physical growth and development status in Chinese students.
AB  - OBJECTIVES: To analyze the increments of physical growth and development in
      adolescents and young students in China during the years of 1979-2000 and to lay
      a scientific basis to make a plan for promoting their healthy growth and
      development in the new century. METHODS: Students aged seven to 17 years of Han
      ethnic were randomly selected from 16 proviness and municipalities during the
      past 21 years, and increments of their height, body weight, chest circumference
      and Weierweike index were measured. RESULTS: Significant increments of physical
      growth and development were found in adolescents and young students of China
      during 1979-2000, showing a clearly secular trend in changes of growth and
      development with the advanced growth spurt the most prominent. The average
      increments were 6.2 cm, 4.8 cm, 7.5 cm and 6.1 cm for height, 8.2 kg, 5.1 kg, 5.4
      kg and 3.8 kg for body weight, and 4.8 cm, 3.2 cm, 2.2 cm and 2.0 cm for chest
      circumference, respectively, for the urban boys, urban girls, rural boys and
      rural girls. The increment of height was more in the rural students than in the
      urban ones, but, the increments of body weight and chest circumference in the
      rural youth lagged behind the urban ones. It was showed significant improvement
      in Weierweike Index in the urban students and an increasing trend of "bean
      sprout" statue in the rural students. CONCLUSION: It is suggested much more
      should be input for the rural students in the future. For their nutritional
      intake, disease prevention and treatment, strengthening physical exercises,
      reducing study burden and rational daily life system.

PMID- 12410957
TI  - Dynamic analysis on the detecting rate of iron-deficient anemia of Chinese
      students.
AB  - OBJECTIVE: To analyze the detecting rate of iron-deficient anemia and the compose
      ratio of different degree of anemia in Chinese students. METHOD: By using the WHO
      screening standard, and using the row data of 1995 and 2000 National Survey
      sample, to screen the prevalence of anemia in the primary and secondary school
      students, and compare the detecting rates among different populations. RESULTS:
      The detecting rates of iron-deficient anemia have been decreased in a large scale
      in the Chinese students. Situations are better in the young ages than in the
      relative old ages. The detecting rates has decreased 7.6% and 5.7% in the urban
      boys aged 7 and 9 years old, respectively, in recent 5 years, which are more
      evident than the urban girls. In rural boys and girls, the detecting rates of
      iron-deficiency anemia of all the age groups have decreasing 3%-7%, which are
      more significant than in the urban ones. The composing ratio of the middle- and
      serious-degree anemia has already lower than 2%-3%, whereas the ratios of the
      marginal anemia have risen significantly in the recent 5 years. In totally, the
      ratios have risen 7.2%, 1.3%, 7.0% and 6.0% in the urban boys, urban girls, rural
      boys and rural girls, respectively. This phenomenon shows that the problem of the
      iron-deficiency anemia of the Chinese students will be easily to be overcome in
      the future. CONCLUSIONS: According to the situation, three measures are suggested
      by the authors: Focus on increasing the iron storage of the students by
      scientific arrangement of food intake. Put the students who are during the peak
      adolescent growth as the key population. Put the widespread of knowledge of
      anemia-prevention as the contents in the school nutrition education.

PMID- 12410958
TI  - Dynamic observations of their body constitution status in Zhuang students of
      Guangxi from 1985 to 2000.
AB  - OBJECTIVE: To study the rules of changes in body constitution of Zhuang students
      in Guangxi and factors influencing it. METHOD: Data on body constitution of
      Zhuang students aged seven to 22 in the year of 2000 were compared with those in
      1985. RESULTS: The average height of Zhuang students increased by 3.80 cm and
      2.45 cm for boys and girls in urban areas, respectively from 1985 to 2000 in
      Guangxi, and by 1.40 cm and 1.32 cm in rural areas, respectively. The average
      weight increased by 3.58 and 1.90 kg for boys and girls in urban areas,
      respectively, and by 0.65 kg and 0.02 kg in rural areas, respectively. The
      average chest circumference increased by 2.09 and 1.28 cm for boys and girls in
      urban areas, respectively, but in the rural areas, that for boys increased by
      0.08 cm and for girls decreased by 0.01 cm. The average systolic blood pressure
      (BP) decreased by 4.33 mm Hg and 5.06 mm Hg (0.58 kPa and 0.67 kPa) for boys and
      girls in urban areas, respectively, and by 5.04 mm Hg and 7.03 mm Hg (0.67 kPa
      and 0.94 kPa) in rural areas, respectively. The average diastolic BP increased by
      12.04 mm Hg and 10.84 mm Hg (1.60 kPa and 1.44 kPa) for boys and girls in urban
      areas, respectively, and by 8.72 mm Hg and 6.54 mm Hg (1.16 kPa and 0.87 kPa) in
      rural areas, respectively. The average vital capacity increased by 195.15 ml and
      109.75 ml, and 23.54 ml and 13.44 ml for urban boys and girls, and rural boys and
      girls, respectively. The average record of 50 m x 8 run to and for decreased by
      5.00 s and 8.79 s for urban boys and girls, respectively, and by 5.27 s and 7.21
      s for rural boys and girls, respectively. The average record of 1 000 m run
      decreased by 19.85 s and 23.88 s for urban and rural boys, respectively, and that
      of 800 m run decreased by 23.19 s and 6.25 s for urban and rural girls,
      respectively. CONCLUSIONS: The results mentioned above suggested that provision
      of reasonable nutrition and active physical training for the Zhuang students are
      basic measures to improve their body constitution and promote their levels of
      growth and development.

PMID- 12410959
TI  - Effect of ethylnitrosourea on HPRT gene in human promyelocytic leukemia cells.
AB  - OBJECTIVE: To explore the molecular spectra and mechanism of human hypoxanthine
      guanine phosphoribosyl transferase (HPRT) gene mutation induced by
      ethyluitrosourea (ENU). METHODS: Single cell cloning culture, two-way screening,
      multiple PCR amplification and electrophoresis technique were used. RESULTS: With
      dose of ENU increasing, cell plating efficiency reduced (in the group with 100
      200 micro g/ml doses, P < 0.01) and mutation frequency increased (in the group
      with 12.5-200.0 micro g/ml doses, P < 0.05) significantly. There was no all exons
      deletion in spontaneous mutations, and only 7.7% of them were detected as single
      exon deletion. But, deletion was found in 79.7% of ENU-induced mutations (62.5%
      89.4%, P < 0.01), and deletion mutations in all nine exons of HPRT gene. Most of
      ENU-induced mutations were chain deletion with multiple exons (88.1%).
      CONCLUSIONS: The spectra in spontaneous mutations differed completely from ENU
      induced ones. ENU was liable to cause bigger changes in genetic structure, which
      suggested a stronger ENU's mutagenesis.

PMID- 12410960
TI  - An experimental study of therapeutic effect of ACEI on chemical-induced ARDS in
      rats.
AB  - OBJECTIVE: To investigate the role of angiotensin converting enzyme inhibitor
      (ACEI) in the treatment of acute respiratory distress syndrome (ARDS). METHODS:
      Changes in physiological and biochemical indexes, and circulating endothelial
      cells (CEC) were observed in rats of oleic acid-induced ARDS with ACEI-Captopril
      (Cap) therapy and controls, respectively. RESULTS: Under the normal systemic
      blood pressure, Captopril therapy showed good effect on ARDS in rats. Two hours
      after administration of Captopril, their pulmonary arterial pressure reduced to
      (14.43 +/- 1.51) mm Hg (1 mm Hg = 0.133 kPa), approximating to normal level, from
      (23.50 +/- 5.79) mm Hg. The number of CEC, which reflected injuries in pulmonary
      capillaries, decreased to (4.25 +/- 0.20)/0.9 micro l from (6.88 +/- 1.90)/0.9
      micro l. Value of oxygen pressure in arterial blood (PaO(2)) increased to (70.48
      +/- 9.54) mm Hg from (35.08 +/- 4.59) mm Hg. In the mean time, ratio of wet to
      dry lung weight was returned to nearly normal. So, it indicated that high-dose of
      oleic acid could only induce mild lung injury, and the development of ARDS was
      obviously inhibited by ACEI. CONCLUSIONS: ACEI may effectively depress pulmonary
      arterial hypertension, block the development of ARDS, and have certain good
      protective effect on pulmonary capillary endothelia.

PMID- 12410961
TI  - Effects of zinc on bone development in mouse embryo in vitro.
AB  - OBJECTIVE: This study was designed to explore the effects of zinc on bone
      development. METHODS: Forelimbs of mice with 16 d gestation were cultured by a
      rotating device. RESULTS: Contents of OC and (45)Ca and activities of AKP in the
      bone tissues cultured at zinc-deficiency media and at media with 120 micro mol/L
      of Zn(2+) decreased significantly. Synthesis of OC, absorption of calcium and
      activities of AKP in the bone tissues cultures at media with 45 and 70 micro
      mol/L of Zn(2+) increased significantly. Radiograph of bone tissues showed that
      length of long bone cultured at zinc-deficiency media and at media with 120 micro
      mol/L of Zn(2+) shortened and their density reduced, and those cultured at media
      with 45 and 70 micro mol/L of zinc increased, as compared with self-control bone.
      Histological analysis showed the death of bone cells and loss of stroma in the
      bone tissues cultured at media with 120 micro mol/L of Zn(2+), and active
      proliferation and differentiation of bone cells, and secretion and synthesis of
      osteoid increased in the bone tissues cultured at media with 45 and 70 micro
      mol/L of zinc. CONCLUSIONS: Adequate supplementation of zinc could promote
      formation and development of bone tissues and deficiency or excess of zinc could
      alter their growth and development and normal metabolism.

PMID- 12410962
TI  - Study on the distribution of nodularin in tissues and cell level in mice.
AB  - OBJECTIVES: To study the tissue distribution of nodularin in mice and the
      cellular location of nodularin in the target organs. METHODS: The nodularin was
      labeled with radioactive isotope (125)I and then was given to mice via oral,
      intraperitoneal and intravenous administration. The distribution of nodularin in
      target organs and the cellular location of nodularin were studied by radioisotope
      and autoradiography techniques. RESULTS: The radioisotope study results showed
      that nodularin was mainly distributed in the kidney and liver in mice. Further
      autoradiography study indicated that nodularin was distributed in the renal cell
      nuclei and liver cell nuclei. CONCLUSION: The kidney and liver are the two main
      target organs for nodularin in mice.

PMID- 12410963
TI  - GIS prediction model of malaria transmission in Jiangsu province.
AB  - OBJECTIVES: To perform GIS spatial analysis on malaria transmission patterns in
      Jiangsu after setting up a malaria database and developing GIS model of malaria
      transmission in Jiangsu province. METHODS: The epidemiological GIS database of
      malaria in Jiangsu province was established using ArcView 3.0a software. The
      climate data covering Jiangsu province and its peripheral area were extracted
      from the FAOCLIM database, the total growing degree days (TGDD) for Plasmodium
      vivax were calculated, and spatial distribution for TGDD was analyzed by ArcVeiw
      3.0a. RESULTS: The predicted malaria distribution map based on TGDD was created,
      which showed that the transmission of malaria decreased gradually from west to
      east, which can be divided into three belts according to the degree of
      transmission. The 14-year mean morbidity distribution map of malaria in Jiangsu
      showed that the middle and west parts of Jiangsu is the most serious endemic
      area. The morbidity in the areas along the Taihu valley, such as Suzhou, Wuxi and
      Changzhou, as well as Nantong and a few of northern counties are the lowest. The
      morbidity of other places is at the middle level. The 14-year mean morbidity
      distribution map of malaria is correlated with predicted malaria distribution map
      for TGDD. CONCLUSION: It is possible to monitor the malaria transmission by GIS
      predicted model based on TGDD.

PMID- 12410964
TI  - Using PCR/RFLP to detect spotted fever group rickettsia in ticks and rodents
      collected in Ninghua, Fujian province.
AB  - OBJECTIVE: To study the existence of natural foci of Spotted Fever in Ninghua,
      Fujian province. METHODS: Using DNA polymerase chain reaction and restriction
      endonuclease fragment length polymorphism analysis (PCR/RFLP) to detect spotted
      fever group rickettsiae (SFGR) in ticks and rodents. RESULTS: It was found that
      H. wellingtoni, H. yeni, and Dermacentor auratus were infected with Rickettsia
      sibirica; the DNA fragments were cloned, the PCR products from isolated strain NH
      97 were antigenically and genotypically identical to Rickettsia sibirica. Rattus
      flavipectus were found infected with R. conorii. One of the sequeuce analysis
      showed that the DNA sequence was different from other SFGR and close to R.
      japanic. CONCLUSION: Natural foci of R. sibirica, R. sibrica, R. japanic and
      R.conorii are found in Ninghua, Fujian province of China.

PMID- 12410965
TI  - Development and psychometric tests of a Chinese version of the SF-36 Health
      Survey Scales.
AB  - OBJECTIVE: To develop and evaluate scaling and scoring assumptions, and the
      reliability and the validity of a Chinese version of the SF-36 scales. METHODS: A
      multi-stage mixed sampling procedure was used to select a representative sample
      of the general population. The sample size was 1 000 households. All family
      members of a selected household, aged 18 and older, completed a survey by self
      administration. Formal psychometric methods for testing assumptions underlying
      item scoring and scale construction were used according to the standard procedure
      of the IQOLA Project. RESULTS: Of the 1 985 collected questionnaires, 1 972 were
      qualified. Of them, 1 688 (85.6%) were respondents. 1 316 respondents answered
      all 36 items, while the remaining (372 respondents) answered with one or several
      missing responses. Among the non-respondents, 65.5% were illiteracy or quasi
      illiteracy. The assumption of equal intervals was violated for the VT and MH
      scales. The recoded item values were used to calculate scale scores. The
      clustering and ordering of the item means were approximately the same as that of
      the source version and other two Chinese versions. The items in each scale had
      similar standard deviations except those in the PF, BP, SF scales. The
      correlations between an item and its hypothesized scale were identical for all
      except the SF and VT scales. The scaling success rates of convergent validity
      were 0% for the SF scale, 75% for the VT scale, and 100% for the other six
      scales. The scaling success rates of discriminat validity ranged from 87.5% to
      100% for all scales except for the SF scale. The Cronbach' alpha coefficients of
      internal consistency reliability ranged from 0.72 to 0.88, which were
      satisfactory for group comparison except 0.39 for the SF scale and 0.66 for the
      VT scale. The two-weeks test-retest reliability coefficient ranged from 0.66 to
      0.94. Factor analysis identified two principal components: a "physical" factor
      and a "mental" factor. Taken together, these two factors could be used to explain
      56.3% of the total variance. CONCLUSION: The Chinese version of the SF-36 Health
      Survey Scale has achieved conceptual equivalence and satisfied the psychometric
      scaling assumptions well enough to warrant wide use in China. Known-groups
      validity will give more meaningful evidences of the validity of the Chinese SF-36
      scales.

PMID- 12410966
TI  - Effect of ambient conditions on the antibacterial activity of antibacterial agent
      based on sodium titanium phosphate.
AB  - OBJECTIVE: To investigate the effects of ambient conditions on the antibacterial
      activity of inorganic antibacterial agent based on sodium titanium phosphate.
      METHODS: The number of live E. Coli ATCC 44113 was counted after the suspension
      was shaken and incubated in flask with antibacterial agent under ambient
      conditions. RESULT: The number of live bacteria increased when the concentration
      of bacteria increased in the range of 1.2 x 10(2) to 1.2 x 10(8) cfu/ml. The
      antibacterial activity increased with the increase of ambient temperature in the
      range of 16 approximately 46 degrees C, showing good antibacterial activity at
      human body temperature. With the increase of the concentrations of co-existing
      NaCl and protein, the antibacterial activity was found to decrease at first and
      level off at 0.01 g/ml and 0.0005 g/ml respectively. CONCLUSION: The
      antibacterial agent has to be used together with organic antibacterial agent in
      order to achieve good antibacterial effect when the ambient bacterial
      concentration is high. The antibacterial agent is promising to be used in the
      preparation of antibacterial cloth because it is highly effective at body
      temperature and expected to remain antibacterial in perspiration.

PMID- 12410967
TI  - [A preliminary study on development of human visual system in fetus by DiI
      tracing].
AB  - OBJECTIVE: To reveal the morphological features and dynamic processes of the
      development of inter-connections in the retina, lateral geniculate nucleus (LGN),
      superior colliculus (SC) and visual cortex (VC) in human fetal life by using a
      fluorescent tracer, 1, 1'-dioctadecyl-3, 3, 3', 3'-tetramethylin-docarbocyanine
      perchlorate (DiI). METHODS: DiI was embedded into the optic tract, brachium of
      superior colliculus and subplate of visual cortex in fixed postmortem human
      tissues of 7 fetuses. The tissue was incubated at 37 degrees C for 4 to 10 weeks
      (ws). After DiI had satisfactorily diffused via axons of the visual system, the
      tissue was sectioned, mounted and observed under a confocal laser scanning
      microscope. RESULTS: In 12 week-fetus, retinogeniculate axon has already reached
      LGN, but there was no cellular lamination. After embedment, axons from retina
      arrived at SC, and the fibers were distributed along the dorsal part of the SC.
      At 12 and 22 ws, there were subplates under visual cortex. CONCLUSION: The
      retinogeniculate axon reaches LGN before 12 ws and forms cellular lamination
      after 12 ws. The axon from retina reaches SC before 12 ws. The subplate under
      visual cortex forms before 12 ws and disappears after 22 ws. DiI can be easily
      and effectively used to label the axon of visual system of human fetus to study
      the prenatal development of human visual pathway.

PMID- 12410968
TI  - [Liposome-mediated gene transfer into retina].
AB  - OBJECTIVE: To evaluate the efficiency of liposome mediated gene transfer to
      retina, the time of gene expression in retinal cells, retinal damage caused by
      liposome and the possibility of using liposome mediated gene transfer to retina
      for treating fundus diseases. METHODS: The ratio of cationic liposome to green
      fluorescein protein (GFP) expression plasmid for high efficacy of transfection
      was tested in vitro. Then optimal liposome-plasmid mixture was injected into the
      subretinal space of Sprague-Dawley (SD) or Royal college of surgeon (RCS) rats.
      The GFP expression was observed by using fluorescence microscopy, and
      morphological changes were examined by using paraffin embedded sections, HE
      staining and transmission electron microscopy. RESULTS: The GFP expression in
      retinal cells was observed lasting more than 4 weeks. However, upon 4 weeks of
      transfection the swelling and degeneration in outer segment of photoreceptors
      could be observed. The aggravated degeneration with disappearance of outer
      segments, only one layer of photoreceptor nucleus surviving, apoptotic inner
      granular layer cells and neovascularization were observed 8 weeks after
      transfection. But no inflammatory cells were observed. Three of 5 RCS rats that
      received plasmid pCNTF (ciliary neurotrophic factor) delivery at 4 weeks old
      showed more surviving nuclei of photoreceptors after 3 to 5 weeks of
      transfection. CONCLUSION: Liposome is able to deliver genes to retinal cells with
      efficacy, and the expression of therapeutic gene such as CNTF in retinal cells
      can rescue photoreceptors from degeneration. But liposome used here is to some
      extent harmful to photoreceptors.

PMID- 12410969
TI  - [Pathological research in experimental diabetes in rat].
AB  - OBJECTIVE: To study dynamically the pathological changes of diabetic retinopathy
      (DR). METHODS: The techniques of light microscopy, immunohistochemical staining,
      electron microscopy and histochemical electron microscopy were used to
      quantitatively analyze the Type IV collagen, laminin and their anionic sites in
      the rat retinal capillary basement membrane (RBM). RESULTS: RBM became gradually
      thickened and was accompanied with an increased staining reaction for type IV
      collagen and laminin and decrease of anionic sites in number. CONCLUSION: The
      increase in thickness, in type IV collagen and laminin and the decrease of the
      anionic sites in the RBM may be the pathological changes of the exudative lesion
      in DR.

PMID- 12410970
TI  - [VEGF expression in dog retina after chorioretinal venous anastomosis].
AB  - OBJECTIVE: To identify changes in vascular endothelial growth factor (VEGF)
      expression in the dog retina after laser-induced chorioretinal venous anastomosis
      (CRVA), in order to find out the relationship between CRVA treatment and the
      related neovascular complications. METHODS: Immediately after branch retinal vein
      occlusion (BRVO) model was made in 5 eyes of 5 normal dogs, CRVA treatment was
      done over a small tributary vein in the drainage distribution of the occluded
      vein. In each eye, there were 2 - 3 treatment sites. Four to six weeks later, a
      repeated treatment was given if the first treatment failed to show the
      anastomosis. The treatment sites with successful CRVA were divided into two
      groups: the small laser spot group, which received one treatment and the big
      laser spot group, which received more than one treatment. The expression of VEGF
      was investigated immunohistochemically in the treatment sites with successful
      anastomoses and in the 5 normal fellow eyes (control). RESULTS: There were
      totally 10 successful anastomoses in the 5 experimental eyes, among which, five
      received one treatment and the other 5 received more than one treatment. On
      fundus examination, the small laser spots were round and small, and the big laser
      spots were large with local proliferation. VEGF immunoreactivity was absent/weak
      in the normal dog retina, and remained unchanged in the small laser spot group,
      but somewhat increased in the big laser spot group. No neovascular complications
      occurred. All immunostaining experiments were accompanied by proper controls and
      none of the negative controls showed any immunoreactivity. CONCLUSIONS: Proper
      laser treatment can induce CRVA quite safely in nonischemic dog retina, which
      does not cause changes in the expression of VEGF, but severe laser damage in the
      treatment site can cause increased VEGF expression which may be related to
      neovascular complications.

PMID- 12410971
TI  - [An experimental study of therapeutic effect of basic fibroblast growth factor on
      experimental retinal ischemia/reperfusion injury].
AB  - OBJECTIVE: To evaluate the therapeutic effect of basic fibroblast growth factor
      (bFGF) injected into the vitreous cavity on experimental retinal
      ischemia/reperfusion injury. METHOD: The Wistar rat model of experimental retinal
      ischemia/reperfusion injury was made by increasing the intraocular pressure. The
      rats were divided into normal, ischemia and treatment groups randomly. At the
      beginning of reperfusion, normal saline was injected into the vitreous cavity in
      ischemia group and 2 micro g of bFGF was injected into the treatment group. The
      histological and ultrastructural changes in retina of different time after
      reperfusion were observed. The retinal ganglion cell number was counted by using
      microscope. The thickness of inner layer of retina was measured by using Image
      Diagnosis System. RESULT: In the early period of retinal ischemia/reperfusion
      injury, the edematous status of retina of treatment group was lighter than that
      of the ischemia group. The retinal inner layer thickness and the RGC number of
      treatment group were greater than that of the ischemia group during all the post
      reperfusion stages. At 168 hours after reperfusion, the thickness of the retinal
      nerve fiber layer and the RGC numbers of ischemia groups were obviously lower
      than that of the normal groups. But the differences of thickness of the nerve
      fiber layer and RGC number between the treatment and normal group were of no
      statistical importance. The nuclear membranes of RGCs were edematous and the
      mitochondrial cristae were unclear at 24th hour after reperfusion, the apoptotic
      body can be found, and the microtubules in nerve fibers became unclear and even
      disappeared in the ischemic group. While in the treatment group, the nucleus was
      clear, only part of the nuclear membrane was edematous, the cell organs were
      abundant and the structures of mitochondria and microtubules were clear.
      CONCLUSION: Injection of bFGF into the vitreous cavity has the therapeutic effect
      on experimental retinal ischemia/reperfusion injury.

PMID- 12410973
TI  - [Experimental study on the treatment of corneal melting after alkali burn with GM
      6001].
AB  - OBJECTIVE: To eva1uate the effect of synthetic inhibitors of matrix
      metalloproteinases (GM 6001) on the prevention of melting of rabbit corneas after
      alkali burn. METHODS: Severe and moderate rabbit alkali burns were made by
      different concentrations of NaOH. Corneas with severe or moderate alkali injuries
      were topically treated with 400 mg/L or 200 mg/L GM 6001 for 30 days. Vehicle was
      used as control. All corneas were evaluated for melting, opacity and other
      pathological changes. RESULTS: After severe alkali burns, all of the 8 corneas of
      the control group melted in 13 +/- 5 days, and 2 corneas perforated. Only did 2
      corneas melt in 19 +/- 4 days after burn and not perforate in 400 mg/L GM 6001
      group. The rates of corneal melting and perforation in 400 mg/L GM 6001 group
      were lower than that of the control (P < 0.05), and the initial time of melting
      was later than that of the control (P < 0.0l). After moderate alkali burn, all of
      the 6 corneas of control melted in 14 +/- 6 days, and 1 cornea perforated. Only
      did 2 of 200 mg/L GM 6001 treated corneas melt in 19 +/- 4 days without
      perforation after burn. The rate of corneal melting and the degree of corneal
      opacity were lower in 200 mg/L GM 6001 treated than that of the control, the
      difference being significant (P < 0.0l). Histologic section of GM 6001 treated
      corneas revealed much less collagen fiber destruction and inflammatory cell
      infiltration than that of the control. CONCLUSION: GM 6001 not only can prevent
      and delay the corneal melting after alkali burn, but also can reduce the
      destruction of corneal collagen fibers and infiltration of inflammatory cells in
      the corneal tissue.

PMID- 12410972
TI  - [Relative quantitative analysis of corneal immunogenicity].
AB  - OBJECTIVE: To quantitate the relative immunogenicity of three major corneal cell
      layers (epithelium, stroma, and endothelium) among the whole corneal
      immunogenicity respectively. METHODS: Cellular immunity: Three porcine major
      corneal cell layers were heterotopically allografted to subcutaneous layer of 40
      BALB-c mice respectively. Twelve days later, the peripheral white blood cells of
      recipients were double directly stained with anti-mouse IgG-fluorescein conjugate
      mAb and analyzed by flow cytometry. Humoral immunity: The suspension of porcine
      cornea or corneal epithelium was used as antigen to produce anti-porcine immune
      sera in C57BL-6 mice. With the anti-porcine immune sera, enzyme linked
      immunosorbent assay was performed. RESULTS: On cellular immunity detection, the
      immunogenicities of intact endothelium, epithelium and stroma, equal in
      thickness, were 70.75%, 27.63%, and 1.62% respectively. On humoral immunity
      detection, the immunogenicities were 62.11%, 31.77% and 6.12% in the three
      respective layers of equal thickness. CONCLUSION: These findings indicate that
      the immunogenicity of corneal stroma is the lowest among the three corneal cell
      layers of equal thickness. The preliminary results provide the experimental basis
      for clinical application of xenogenic graft of corneal stroma.

PMID- 12410974
TI  - [Characteristics of optical coherence tomography for exudative age-related
      macular degeneration].
AB  - OBJECTIVE: To observe the characteristics of optical coherence tomography (OCT)
      for exudative age-related macular degeneration (AMD). METHODS: Thirty-eight
      patients (42 eyes) diagnosed as exudative AMD by color fundus photography, fundus
      fluorescein angiography (FFA) and indocyanine green angiography (ICGA) were
      examined by OCT. The results of OCT were analyzed and compared with that of FFA
      and ICGA. RESULTS: The characteristics of OCT for exudative AMD: fibrotic
      choroidal neovascularization (34 eyes), serous detachment of neurosensory
      epithelium (38 eyes), detachment of the nerve fiber layer (8 eyes), and
      hemorrhagic and serous detachment of retinal pigment epithelium (11 eyes and 9
      eyes, respectively). CONCLUSION: The major characteristic of OCT of exudative AMD
      is fibrotic choroidal neovascularization combined with serous and hemorrhagic
      detachment of neurosensory epithelium or retinal pigment epithelium, which would
      be helpful for diagnosing and evaluating exudative AMD.

PMID- 12410975
TI  - [Incidence of vitreoretinal pathologic conditions in myopic eyes after laser in
      situ keratomileusis].
AB  - OBJECTIVE: To determine the incidence of vitreoretinal pathologic conditions in
      myopic eyes after laser in situ keratomileusis. METHODS: Vitreoretinal pathologic
      conditions of 1981 consecutive eyes (995 patients) having undergone laser
      assisted in situ keratomileusis for the correction of myopia were studied.
      Preoperative and postoperative basic examinations included visual acuity,
      manifest and cycloplegic refraction, slit-lamp microscope examination,
      applanation tonometry and a fundus examination after pupil dilatation by indirect
      ophthalmoscopy and biomicroscopy with spherical lens of + 90 diopters. Before
      laser in situ keratomileusis, preventive treatment was carried out for
      predisposing lesion of retinal detachment in 8 eyes: 6 eyes for lattice
      degeneration and 2 eyes for atrophic holes. Postoperative examinations were
      conducted at 1, 3 and 12 months and once a year thereafter. All eyes were
      followed up for >/= 12 months. RESULTS: Eyes were followed for a mean of (18.40
      +/- 4.50) months (range 12 - 28) after the surgery. Sixteen eyes of 13 patients
      (0.81%) developed vitreoretinopathy after LASIK, including 6 eyes with lattice
      degeneration (0.30%) in which one of them had previous laser treatment, 2 with
      posterior vitreous detachment (0.10%), 2 with macular hemorrhage (0.10%), 4 with
      rhegmatogenous retinal detachment (0.20%), and 2 with retinal tear without
      retinal detachment (0.10%) in which one of them had previous laser treatment for
      lattice degeneration. Five patients were males (5 eyes involved). Others were
      females. Mean age of the group with vitreoretinal pathologic conditions was 31.80
      +/- 5.85 years (range 22 to 43). The interval between refractive surgery and
      development of vitreoretinal complication was (10.38 +/- 6.20) months (range 1 to
      24). The eyes that developed vitreoretinopathy had myopia -4.75 to -15.00
      diopters (mean -9.45 +/- 2.61 D) before LASIK. The comparison of incidences of
      vitreoretinopathy after LASIK between the group of >/= -6.00 D and < -6.00 D
      before surgery showed significant difference (P < 0.01, chi(2) = 60.78). The
      comparison of incidences of vitreoretinopathy after LASIK had also significant
      difference (P < 0.01, chi(2) = 138.64) between the eyes with pre-LASIK lattice
      degeneration and dry hole and eyes without such lesions. The cases of lattice
      degeneration and retinal tear were treated with laser retinopexy. All cases of
      rhegmatogenous retinal detachment were managed with cryoretinopexy and scleral
      buckling. Retinal reattachment was attained in all eyes and good visual acuities
      were recovered. CONCLUSION: No direct cause-effect relationship between LASIK and
      vitreoretinopathy can be proven from this study. Although the incidence of
      vitreoretinal pathologic conditions in myopic eyes after laser in situ
      keratomileusis is low, it is necessary to strictly filter candidates.
      Preoperatively and postoperatively, pay attention to the lattice degeneration and
      other retina lesions, and long-term follow-up is important.

PMID- 12410976
TI  - [Clinical features of 48 cases with retinal angioma].
AB  - OBJECTIVE: To summarize the clinical features of 48 cases with retinal angioma.
      METHODS: The 48 cases were retrospectively summarized. The clinical features
      included sex distribution, age at first visit, chief complains, visual acuity,
      and the size, number and site of retinal angioma identified by fundus fluorescein
      angiography (FFA) and fundus examination. RESULTS: There were 24 males and 24
      females. The mean age at onset was 27 years. Thirteen cases (27%) had bilateral
      retinal angiomas. Multiple angiomas were found in 22 eyes (36%). Seventeen cases
      (35%) were identified as von Hippel Lindau (VHL) disease. The location of angioma
      was in the temporal retina in all the cases with only one angioma. All the
      symptomatic tumors were larger than 1 disc diameter (DD). The common symptoms of
      patients with retinal angioma were visual loss in 77% cases, floaters in 15%
      cases and distortion in 8% cases. CONCLUSION: Retinal angioma is an uncommon
      disease prone to be involved in both eyes and to primarily damage the vision of
      young and middle-aged adults.

PMID- 12410977
TI  - [A clinical observation of low and negative power intraocular lens implantation].
AB  - OBJECTIVE: To evaluate the clinical effects of the low power and negative power
      acrylic foldable intraocular lens (Acrysof IOL) implantation. METHODS: Forty
      patients (56 eyes) received phacoemulsification and above mentioned Acrysof IOL
      implantation. Intraoperative and postoperative complications, visual acuity and
      refractive error were observed. RESULTS: No intraoperative complications
      occurred. During 3 months of follow-up, the corrected visual acuity was less than
      0.1 in 2 eyes, 0.1 - 0.4 in 12 eyes, 0.5 - 0.9 in 36 eyes, and 1.0 - 1.5 in 6
      eyes. Posterior capsular opacification was found in 4 eyes (7.2%). Capsular
      distension was found in 1 eye (1.8%). No retinal detachment was seen. CONCLUSION:
      It is safe and effective for highly myopic patients with cataract to implant a
      low or negative power Acrysof IOL after phacoemulsification.

PMID- 12410978
TI  - [Evaluation of visual function following neodymium: YAG laser posterior
      capsulotomy].
AB  - OBJECTIVE: To probe into the clinical application of contrast sensitivity and
      glare sensitivity in evaluating visual function of posterior capsular
      opacification (PCO) and also investigate the visual function criterion in
      performing neodymium:yttrium aluminum garnet (Nd:YAG) laser posterior
      capsulotomy. METHODS: Measurements of visual acuity, contrast sensitivity and
      glare sensitivity were obtained from 73 pseudophakic eyes (67 cases) before and
      after Nd:YAG laser posterior capsulotomy and the results were analysed. The
      method of Nd:YAG laser surgery was posterior capsular circular resection. The
      diameter of capsular chip was 5 mm. The average energy of single pulse was (2.93
      +/- 0.63) mJ and the mean total energy was (57.47 +/- 36.05) mJ. The average
      follow-up was (14 +/- 6) months. RESULTS: Visual acuity, contrast sensitivity
      curve and glare sensitivity curve improved in all cases postoperatively.
      Comparing the parameters of pre-laser and post-laser measurement, there was very
      significant difference (P < 0.01). The only postoperative complication was the
      laser spot in intraocular lens (IOL, 5 eyes, 6.8%). No retinal detachment,
      cystoid macular edema and dislocation of IOL were observed in this series.
      CONCLUSION: Contrast sensitivity and glare sensitivity can represent the visual
      function of PCO sensitively and completely. They can be regarded as evaluation
      criterion of surgical timing and effect of Nd:YAG laser posterior capsulotomy.

PMID- 12410979
TI  - [Citation analysis of originals in Chinese Journal of Ophthalmology].
AB  - OBJECTIVE: To evaluate the academic level and the popularity of Chinese Journal
      of Ophthalmology. METHOD: According to the information of Chinese science and
      technology papers and citation database (CSTPC), I statistically analyzed the
      amount and distribution of the originals in Chinese Journal of Ophthalmology
      cited by the journals included by CSTPC. RESULT: The originals of Chinese Journal
      of Ophthalmology were high-qualified and influential, and their authors were all
      over the country. CONCLUSION: With the unique style and character, Chinese
      Journal of Ophthalmology is the main medical core periodical and one of the most
      important information resources in the field of ophthalmology in China.

PMID- 12410980
TI  - [Study on the near, middle and long distance stereopsis of normal and children
      with intermittent exotropia].
AB  - OBJECTIVE: To study the pre- and post-operative changes of stereopsis at
      different distances in normal and children with divergence in excess type of
      intermittent exotropia. METHODS: TNO and new stereo tests (NST) and the middle
      and long distance stereotest were used for the evaluation of stereoacuity at 40
      cm - 5 m in 844 normal and 35 children aged 4 - 12 years with divergence excess
      type of intermittent exotropia undergoing operative correction of strabismus.
      RESULT: (1) Normal subjects: The TNO test showed that the near distance
      stereoacuity </= 60" was in 98% subjects aged 4 - 8 years. The stereoacuity was
      increased with the increase of age, the correlation being linear. The
      stereoacuity in children aged 10 - 11 years was the lowest. In the comparison of
      stereoacuity between children aged 4 - 8 years and 9 - 12 years, the difference
      in distribution was very significant (P < 0.01). The NST test showed that the
      near stereoacuity >/= 40" was in 97% subjects. The mean stereoacuity was 40" -
      42" in children various in age. The middle and far distance stereoacuity was the
      greatest in children aged 4 years, along with the increase of age, it was
      gradually declined and at 9 - 10 years it was the lowest. (2) Divergence excess
      type of intermittent extropia: There was no significant difference between the
      pre- and post-operative near stereoacuity examined by TNO and NST (P > 0.05) The
      pre-operative middle and long distance stereoacuities were greater than that in
      the normal children, the difference being significant (P < 0.05). The post
      operative middle distance stereoacuity was improved and approximately normal in
      comparison with that before the surgery, and the far distance stereoacuity was
      improved mildly. CONCLUSIONS: (1) In the normal group, the development of
      stereopsis at different distances begins at 4 years, keeping on developing with
      the increase of age, and the stereoacuity is elevated after 8 years and in 9 - 11
      years well developed. (2) In the group of divergence excess type of intermittent
      exotropia, the pre-operative near stereoacuity is well, but the middle and far
      distance stereoacuities are poor and the middle stereoacuity improves
      significantly after the surgery. The recovery of middle distance stereoacuity
      seems to be an objective criterion of the operative therapeutic effect.

PMID- 12410981
TI  - [Botulinum toxin A in treatment of the sixth cranial nerve palsy].
AB  - OBJECTIVE: To study the methods and the effects of botulinum toxin A (BTXA) in
      the treatment of paralytic esotropia (PE) due to the sixth cranial nerve palsy.
      METHODS: BTXA was injected into the extra-ocular muscles of 89 patients with PE.
      The number of injections was 1 to 5, in average 1.5. Of them, 27 patients
      received injections combining with surgeries at the same time, and 16 received
      surgeries after injections for 3 to 28 months. The procedures include recession
      resection (or combining with myectomy), Jenson procedure, or vertical muscle
      transposition. RESULTS: Of the patients having received injections alone, 35
      restored orthotropia and binocular single vision after 1 to 4 injections. Eleven
      patients restored to orthotropia after the injection and surgery at the second
      stage, and the mean correction of the strabismus degree was 42.7( triangle up )
      +/- 32.2( triangle up ). Fourteen cases in the simultaneous surgical and
      injection group restored orthotropia after the surgery, and the mean correction
      of the strabismus degree was 90.0( triangle up ) +/- 40.1( triangle up ). Of
      them, 14 restored binocular single fusion and their range of visual fixation
      expanded to 20 degrees - 70 degrees. CONCLUSIONS: BTXA injected into extra-ocular
      muscles is an ideal therapy for the treatment of PE. Injection of BTXA during the
      first 6 months after the onset as a preoperative therapy may alleviate medial
      rectus restriction and promote the recovery of the lateral rectus functions. Some
      patients may restore orthotropia by injection alone. Patients under-corrected at
      six months after onset can be treated with surgery. Injection combined with
      surgery at the same time may preserve the function of medial rectus, avoid
      performing operation on more than two rectus, prevent the risk of anterior
      segment ischemia in surgery of multiple muscles and expand the field of binocular
      single vision as large as possible.

PMID- 12410982
TI  - [A clinical observation on variation of crossed disparity and uncrossed disparity
      in intermittent exotropia].
AB  - OBJECTIVE: To understand the clinical variety of crossed disparity and uncrossed
      disparity in intermittent exotropia. METHODS: Zero disparity stereo-acuity,
      crossed disparity and uncrossed disparity stereo-acuity of 55 cases with
      intermittent exotropia were examined with stereogram designed by Yan Shaoming
      before surgery. RESULTS: In group 1 consisting of 25 cases, the zero disparity
      stereo-acuity of normal persons was 48%, the values of crossed disparity and
      uncrossed disparity stereoacuity were not in the normal range, and the crossed
      disparity was larger than the uncrossed disparity stereo-acuity (t = 843.5, P <
      0.000 1). In group 2 including 26 cases, the zero disparity stereo-acuity of
      normal person was 30.8%, the value of crossed disparity was abnormal, and the
      uncrossed disparity was not found. In group 3 consisting of 4 cases, only the
      abnormal zero disparity stereo-acuity was found. In the 55 cases, there was no
      coexistence of zero disparity and uncrossed disparity, no existence of only
      crossed disparity or only uncrossed disparity, and no coexistence of crossed and
      uncrossed disparity. CONCLUSIONS: (1) In the cases with intermittent exotropia,
      the zero disparity stereoacuity, the crossed disparity and uncrossed disparity
      stereoacuities are abnormal. (2) The sequential damage of stereopsis in
      intermittent exotropia is uncrossed disparity, crossed disparity and zero
      disparity. (3) It is proved in the clinic that the binocular temporal retinae
      correspond to the crossed disparity and the binocular nasal retinae correspond to
      the uncrossed disparity.

PMID- 12410983
TI  - [Extraocular muscle surgery for thyroid associated ophthalmopathy].
AB  - OBJECTIVE: To identify the indication, method and therapeutic results of
      extraocular muscle surgery for thyroid associated ophthalmopathy (TAO). METHODS:
      The results of extraocular muscle surgery in 11 patients with TAO were analyzed.
      The main purpose of the surgery was to release the restriction induced by
      fibrotic extra-ocular muscles. Recession was used in most of the patients.
      RESULTS: Different degrees of realignments were gained, and restricted ocular
      movements were improved in 11 patients postoperatively. Nine (9/11) patients
      restored binocular vision in functional positions of gaze. Better alignment was
      gained in 2-month-follow-up. CONCLUSIONS: Diplopia and restricted ocular
      movements are the main indications of extra-ocular muscle surgery in TAO. Timing
      of surgery is crucial, and it is better to be carried out when the disease has
      been stationary for 4 - 6 months. Under local anesthesia, the doctor can adjust
      the position of muscle to insure an excellent result. The extra-ocular muscular
      surgery for TAO is a good functional rehabilitative measure.

PMID- 12410984
TI  - [Surgical treatment of diplopia in patients with Graves' ophthalmopathy].
AB  - OBJECTIVES: To investigate the timing and effect of surgical treatment of
      diplopia caused by hypertrophic inferior rectus in patients with Graves'
      ophthalmopathy and pathologic changes of inferior recti. METHODS: Eleven diplopic
      patients with restrictive superior motion and enlarged inferior recti confirmed
      by CT scan were collected, and the inferior recti were recessed. Specimens of
      inferior recti obtained during operation were stained by HE, PAS and observed by
      light microscope. RESULTS: There was no diplopia after operation when patients
      looked down and horizontally in eleven cases. Eye position was normal. HE and PAS
      stain showed stiffness of muscular fiber, small muscular cell with degeneration,
      obvious proliferation of fibrous tissue in endomysium, perimysium and epimysium,
      which enlarged extraocular muscle. CONCLUSION: Poor function of inferior recti
      due to enormous proliferation of fibrous tissue and degeneration of muscular
      fiber results in the occurrence of diplopia. Recession of inferior recti can
      eliminate patients' diplopia.

PMID- 12410985
TI  - [Electron microscopic analysis of expression of NMDA-R1 in the developmental
      process of visual cortex in strabismic amblyopic cat].
AB  - OBJECTIVE: To investigate the expression and distribution of N-methyl-D-aspartate
      receptor subunit 1 (NMDA-R1) in neuronal ultrastructure in visual cortex of
      strabismic amblyopic cat during development. METHODS: Eleven kittens were used
      for this study. Esotropia in six kittens had been made monocularly by tenotomy at
      two weeks of age. Two pairs of normal and strabismic kittens were sacrificed in
      three weeks of age, one week after tenotomy. Another two pairs of normal and
      strabismic kittens were sacrificed in five weeks of age, three weeks after
      tenotomy. One normal and two strabismic amblyopic cats were sacrificed after 6
      months of age. Animals were deeply anaesthetized and perfused transcardially with
      4% paraformaldehyde. Cryostat sections of frontal central area P5-P0 were cut to
      25 micro m thickness. The mouse anti-NMDA-R1 monoclonal antibody (mAb54.1,
      PharMingen) was used. After stained, a light microscope was used to select
      regions of layer II-III, layer IV and layer V-VI of visual cortex area 17 for re
      embedding. HITACHI H-7000 transmission electron microscope at magnifications
      ranging from 30 000 - 300 000 X was used for observation. RESULTS: Three hundred
      and twenty-eight neurons of strait cortex were observed. NMDA-R1 receptor was
      located at the nuclei, Nissl body, cytoplasm, plasma membrane and the
      postsynaptic element of axons and dendrites. The ultrastructural morphology,
      including the mitochondrion, smooth endoplasmic reticulum, rough endoplasmic
      reticulum, and the Golgi apparatus, was not significantly different in the
      comparison between the cells in visual cortex of normal and strabismic groups. In
      the entire normal group, the percentage density of NMDA-R1 labeled cells was
      higher than that of strabismic groups (chi(2) = 4.280, 4.41, 4.89; P < 0.05). One
      thousand and three hundred and twenty NMDA-R1 immunopositive synapses were
      counted. The NMDA-R1 immunopositive synapses were dominated in layer II-III of
      visual cortex and increased during the development of normal kittens (F = 3.28, P
      < 0.05). There was no significant difference of NMDA-R1 immunopositive synapse
      distribution between the normal and strabismic kitten at 3 weeks (one week after
      operation) of age (F = 0.17, P > 0.05). The reduction of NMDA-R1 immunopositive
      synapse of plasma membrane in visual cortex of strabismic kitten was started at 5
      weeks (threes weeks after surgery) of age. It was decreased significantly in
      strabismic amblyopic cat compared with that of the normal cat (F = 26.94, 47.01;
      P < 0.001). The ratios of nuclear membrane invagination of cells in visual cortex
      of normal and strabismic cat were higher than those of normal and squint kittens
      (chi(2) = 36.24, P < 0.01), but the ratio was not significantly different between
      the normal and strabismic group. CONCLUSION: (1) In the normal developmental
      process of cat, the plasticity of the neuronal synapsis in II and III layer of
      visual cortex is relatively great. (2) In the strabismus amblyopia occurring in
      the plastic critical period of visual development, no pathological changes of
      neuronal organelle in the visual cortex are found, but there are changes at
      molecular level in the neuronal synapsis.

PMID- 12410986
TI  - [Histochemical studies on the change of nitric oxide synthetase in lateral
      geniculate nucleus of monocular deprived kittens].
AB  - OBJECTIVE: To observe the change of nitric oxide synthetase (NOS) in lateral
      geniculate nucleus of normal and monocular deprived kittens and to discuss the
      role of nitric oxide in the etiopathology of amblyopia. METHODS: The distribution
      of nitric oxide synthetase in lateral geniculate nucleus (LGN) of normal and
      monocular deprived kittens had been studied by using nicotinamide adenine
      dinucleotide phosphate (NADPH)-diaphorase histochemical method (NDP). RESULTS: In
      normal kittens, NOS positive cells were not seen in any lamina of LGN, but NOS
      positive fibers were discovered. In monocular deprived kittens, NOS positive
      fibers were seen in every layers of LGN, in the nondeprived laminae of LGN there
      was strip-shaped distribution of NOS positive cells, and in the deprived laminae
      the NOS positive cells were occasionally seen. CONCLUSION: NOS might act as a new
      class of neurotransmitter and be involved in the formation of emblyopia.

PMID- 12410987
TI  - [A clinical analysis of high myopia with primary open-angle glaucoma].
AB  - OBJECTIVE: To approach the bases of early diagnosis of high myopia (HM) combined
      with primary open-angle glaucoma (POAG). METHODS: (1) There were 3 groups of
      POAG: group A with HM (40 eyes of 21 cases), group B with medium myopia (40 eyes
      of 21 cases) and group C with low myopia (42 eyes of 21 cases). Their visual
      field defect, retinal nerve fiber layer defect (RNFLD), the maximum intraocular
      pressure and corrected visual acuity were compared. (2) The stereo-photos of the
      HM-POAG were observed directly, and their clinical characteristics were analyzed.
      RESULTS: (1) On the initial visit, the patients of group A obviously suffered
      more serious visual field defects and RNFLD, and the corrected visual acuity was
      lower than that of the two other groups. (2) The specific fundus changes at the
      papilla and its surrounding retina of the HM patients interfered with the early
      detection of glaucoma. The dilatation of pupil to examine the fundus and the use
      of stereo-photos were the main measures to elevate the detectable rate of
      glaucoma. CONCLUSION: Recognizing the early clinical characteristics of HM itself
      combined with that of POAG may help us to improve the proficiency of HM-POAG
      early detection.

PMID- 12410988
TI  - [Clinical analysis of 271 cases of orbital inflammatory pseudotumors].
AB  - OBJECTIVE: To analyze and summarize the clinical signs, the diagnostic and
      differential diagnostic value of imaging examination in orbital inflammatory
      pseudo-tumors and the comparison of the therapeutic effect of various treatments.
      METHOD: Retrospectively, 271 cases (303 eyes) of orbital inflammatory
      pseudotumors were analyzed. RESULTS: Ultrasonography and CT had their diverse
      manifestations according to the different characterizations of the histopathology
      of tumors. B-ultrasonography showed a tumor with low reflection and strong sound
      transmission in diffuse lymphocytic infiltrative pseudotumor. A tumor with fibro
      proliferative lesion had low reflection, weak sound transmission and irregular
      border. CT showed lesions touching closely with the globe. Steroid and
      radiotherapy were effective for diffuse lymphocytic infiltrative pseudotumors.
      The various therapies were not effective for fibro-proliferative lesions.
      CONCLUSION: Imaging examinations are valuable for the diagnosis, differential
      diagnosis, the evaluation of histopathology types and the choice of treatment for
      orbital inflammatory pseudotumors.

PMID- 12410989
TI  - [Preliminary results of foldable intraocular lens implantation in children with
      cataract].
AB  - OBJECTIVE: To evaluate the result of phacoemulsification and foldable intraocular
      lens implantation (IOL) through a small incision in children with cataract.
      METHODS: Phacoemulsification with anterior vitrectomy and foldable IOL
      implantation in the capsular bag was performed in 37 eyes of 28 children aged 3 -
      15 years (mean 7 years), including 27 eyes of congenital cataract and 10 eyes of
      traumatic cataract. The visual acuity, corneal curvature and possible
      complication were followed up for 10 months (range, 3 - 15 months). RESULT: The
      best corrected visual acuity (BCVA) of congenital cataract were all >/= 0.1, and
      59.3% >/= 0.5. All the BCVA of cases with traumatic cataract >/= 0.3, and 80% >/=
      0.5. The surgically induced astigmatism (SIA) was (1.18 +/- 0.65) D, (0.67 +/-
      0.59) D and (0.60 +/- 0.39) D in one week, one month, and three months
      respectively after the operation, and it was stable in the postoperative one
      month. Secondary cataract occurred in 5 cases (13.5%), and no other complications
      were found. CONCLUSIONS: Phacoemulsification and foldable IOL implantation
      through a small incision in children with cataract can reduce early post
      operative astigmatism and shorten the period of visual rehabilitation. It is a
      safe procedure with milder inflammatory reaction and less complication.

PMID- 12410990
TI  - [Photodynamic therapy of pigmented choroidal melanomas in rabbits].
AB  - OBJECTIVE: To evaluate the effect of photo-dynamic therapy in the destruction of
      experimental pigmented choroidal melanoma using a liposomal preparation of
      benzoporphyrin derivative (BPD), verteporfin. METHODS: Pigmented choroidal tumors
      were established in 44 New Zealand albino rabbit eyes. Animals were treated with
      daily injections of cyclosporine. Funduscopic examinations and ultrasonography
      were used to follow the tumor growth. When the tumor exceeded 2 mm in thickness
      (tumor height ranged from 2.0 - 4.6 mm), the rabbits were divided into three
      groups. In the 10 rabbits in the control group, 6 were treated with laser 120 -
      150 J/cm(2) for tumors with the height range of 2.1 - 3.0 mm without photo
      dynamic therapy, and 4 were not treated at all. The benzoporphyrin derivative was
      injected intravenously (1 mg/kg) for the rabbits in treatment group I (14
      rabbits) and II (20 rabbits), and 692 nm argon-pumped dye laser at different
      light doses 60 - 150 J/cm(2) was used to irradiate the tumors. After the
      treatment for 4 - 6 weeks, the rabbits were sacrificed and the therapeutic
      results were observed. RESULTS: In treatment group I, the irradiation dose was 60
      - 80 J/cm(2) and the tumor height was < 3 mm, in comparison with that of the
      control group the difference being very significant (P < 0.001). In the treatment
      group II, the thickness of the tumor was 3.0 - 4.6 mm and the irradiation dose
      was > 80 J/cm(2) (P < 0.001, companed with the control group). In contrast, the
      tumor grew continuously in all the animals in the control group and filled most
      of the vitreous cavity by 2 - 3 weeks. CONCLUSION: These data suggest that
      photodynamic therapy have a role in the management of pigmented choroidal
      melanomas.

PMID- 12410991
TI  - [Pressure influence on mRNA and protein expression of inducible nitric oxide
      synthase in purified retinal ganglion cells of rats].
AB  - OBJECTIVE: To study the inducible nitric oxide synthase (iNOS) mRNA and protein
      expression in rat purified retinal ganglion cells (RGCs) that cultured under
      different pressures. METHODS: (1) To culture RGCs that from Sprague Dawley (SD)
      neonatal rats (postnatal 1 - 5 days) on two planes in assimilative culture
      solution, RGCs were purified by Thy1.1 with sheep anti rat FITC monoclonal
      antibody. (2) RGCs were cultured under pressures of 0, 20, 40, 60 and 80 mm Hg,
      respectively. The changes of iNOS mRNA and protein in RGCs under different
      pressures were demonstrated qualitatively and quantitatively by in situ
      hybridization, RT-PCR and Western blot. RESULTS: After cultured for 12 and 24
      hours in vitro, the purification rate of RGCs in the experiment reached 98%. The
      expression of iNOS mRNA and protein in RGCs became higher and higher as the
      pressure was increased. There were no iNOS mRNA and protein expression in the
      control group (0 mm Hg) and weak expression in 20 mm Hg group (P < 0.05). 40, 60
      and 80 mm Hg groups had a very significant difference from the control group,
      respectively (P < 0.01). CONCLUSION: Pressure can evoke the expression of nitric
      oxide synthase mRNA and protein in purified retinal ganglion cells in vitro, thus
      the nitric oxide can be one of the causes of RGC damage, that may induce or
      aggravate glaucoma.

PMID- 12410992
TI  - [Effect of infrasound on ultrastructure and permeability of rat's blood-retinal
      barrier].
AB  - OBJECTIVE: To investigate the possible effect of infrasound on the ultra
      structure and permeability of rat's blood-retinal barrier (BRB). METHODS: Ultra
      structural changes of BRB were observed through the injection of lanthanum
      nitrate (La), which was used as a tracer to demonstrate the breakdown of the BRB,
      into blood vessels. Fifteen mature male rats divided into 5 groups were exposed
      to infrasound at a 8 Hz frequency, 130 dB sound pressure level in a pressure
      chamber especially designed for the experiment for 0, 1, 7, 14, 21 days,
      respectively. RESULTS: Under the action of infrasound, along with the
      prolongation of exposure, the damage of BRB was severer and severer. On the 1st
      day, there was no significant change in La leakage. On the 7th day, La diffused
      in the interphotoreceptor space at nuclear level. On the 14th day, La granules
      could be seen in the space of nervous cells. Finally, on the 21st day, La was
      found between synapses, synapses and nerve cells, as well as between the nerve
      cells and supporting cells, then sometimes reached vitreous body. Under the
      electron microscope, there were no significant morphological changes, but changes
      related to metabolism, such as edematous mitochondria, dilated rough endoplasmic
      reticula, precipitation of glycogen grandules, widening of perinuclear space,
      etc. CONCLUSIONS: The results thus suggest that the exposure to infrasound cause
      the breakdown of rat's blood-retinal barrier and visual impairment.

PMID- 12410993
TI  - [Prolongation of corneal allograft survival in mice with a cyclosporine drug
      delivery system implant].
AB  - OBJECTIVE: To study the immunosuppressive effect and mechanism of cyclospoirne A
      (CsA) in a drug delivery system (DDS) implanted in the anterior chamber of
      corneal allograft in a mouse model. METHODS: Female BALB-c mice were the
      recipients of corneal allografts from C57BL-6 donor mice. A total of 90
      allografts were implanted in penetrating keratoplasty. Cyclosporine A was
      incorporated into a polyactide-coglycolide-co-caprolactone (PGLC) polymer and
      small pellets of CsA PGLC were placed into the anterior chamber of recipient
      mouse eyes at the time of transplantation. Control recipients did not receive any
      implants or received implants containing no drug. The clinical condition of the
      grafts was observed by slit-lamp microscope every three days and the tempo and
      the time of rejection of the grafts were recorded. Some grafts were removed at
      weekly intervals for histopathological and immunohistopathological analysis.
      RESULTS: The corneal allografts of the mice with CsA PGLC implanted (group A)
      prolonged their survival time significantly with a median of 35 +/- 3 days. In
      contrast, the median survival time of corneal allografts in eyes of recipients
      receiving implants containing no drug (group B) and eyes receiving allografts but
      no implant (group C) was 14 +/- 3 days. The differences between A and B and
      between A and C group were statistically very significant (P < 0.001). The
      corneal donor of the eyes treated with the CsA PGLC implant remained clear until
      the implant pallet began to shrink in size and graft rejection began. The grafts
      which came under an immune attack progressively were vascularized and thickened,
      and became opaque. In the control animals, the development of the immune response
      overlapped with the acute inflammatory reaction, which occurred in the mouse eye
      following corneal transplantation. Histopathologically and
      immunohistopathologically, the grafts, ciliary body and iris which were subjected
      to an immune response contained a dense infiltrate of neutrophils, CD(4)(+) and
      CD(8)(+) T lymphocytes, and many CD(11B)(+) inflammatory cells including
      macrophages and Langerhans cells in the control rejection mice. This cellular
      infiltrate was decreased in the recipients, and delayed in ciliary body and iris
      whose corneas were transplanted with the CsA PGLC implant in the anterior
      chamber. CONCLUSION: Intraocular CsA in a sustained release system as a means
      significantly prolongs corneal allograft survival in mouse model and protests
      corneal allografts from acute, immune-mediated rejection.

PMID- 12410994
TI  - The clinical value of rearrangement of IgH gene and bcl-2/J(H) fuse gene in the
      diagnosis of orbital lymphoproliferative disorders.
AB  - OBJECTIVE: To determine whether polymerase chain reaction (PCR) for the assay of
      B-cell gene rearrangement in patients with orbital lymphoproliferative disorders
      could be useful in the diagnosis of lymphoma, especially in differentiating a
      benign lesion from a malignant one. METHODS: In addition to clinical,
      pathological and immunohistochemical evaluations, 48 cases of orbital
      lymphoproliferative disorders were examined for immunoglobulin heavy chain (IgH)
      gene rearrangement and bcl-2/J(H) fuse gene rearrangement by means of PCR to
      amplify the third frame work region (FR3) and bcl-2/J(H) fuse gene with formalin
      fixed and paraffin-embedded tissues. RESULTS: The PCR using primer FR3A showed
      that 22 cases had discrete single products, which were within the molecular
      weight range of 100 to 120 bp, and were therefore interpreted as monoclonal. The
      positive rates of FR3 region of IgH gene rearrangement in patients with malignant
      lymphoma, benign reactive lymphoid hyperplasia and lymphocytic inflammatory
      pseudotumor were 75.0% (15/20), 40.0% (4/10) and 16.7% (3/18) respectively. The
      four patients with simultaneously bilateral ocular adnexal lymphoid neoplasm
      exhibited identical clonal IgH gene rearrangement patterns. A faint smear pattern
      or no band at all was demonstrated in the remaining 26 cases, representing
      polyclonal populations of lymphoid cells. The PCR using bcl-2 primer showed that
      6 cases had discrete single products that were within the molecular weight range
      of 100 to 300 bp, and were interpreted as having bcl-2/J(H) fuse gene. They were
      2 cases of follicular B-cell lymphomas, 1 case of diffuse mixed large and small
      cell B-lymphoma and 3 cases of diffuse small cell B-lymphoma. A faint smear
      pattern or no band at all was demonstrated in the remaining 17 cases of
      lymphomas, lymphocytic inflammatory pseudotumor and benign reactive lymphoid
      hyperplasia. The positive rates of bcl-2/J(H) fuse gene rearrangement in patients
      with malignant lymphoma, benign reactive lymphoid hyperplasia and lymphocytic
      inflammatory pseudotumor were 30.0% (6/20), 0% (0/10), and 0% (0/18),
      respectively. CONCLUSIONS: Molecular genetic analysis by PCR using the FR3A
      primer is helpful in the diagnosis of orbital lymphoproliferative disorders,
      especially those in which the diagnosis can not be made by routine
      histopathological finding and immunohistochemistry evaluation. However, the rate
      of bcl-2/J(H) fuse gene rearrangement is too low to be suitable for clinical
      diagnosis of orbital lymphoproliferative disorders.

PMID- 12410995
TI  - The clinical study of lateral orbitotomy.
AB  - OBJECTIVE: To observe the effect of lateral orbitotomy. METHODS: Lateral
      orbitotomy for orbital tumors within muscle cone and area of lacrimal gland was
      performed for 70 cases by standard lateral orbitotomy, modified lateral
      orbitotomy and lateral orbitotomy combined with medial orbitotomy from July 1999
      to April 2001 in Armed Police General Hospital. RESULTS: The indications of
      standard lateral orbitotomy were suitable for the orbital tumor below the optic
      nerve (38 cases), and modified lateral orbitotomy (involving supra or infra
      orbital edge) for the orbital tumors above the optic nerve (28 cases), as well as
      lateral orbitotomy combined with medial orbitotomy for the orbital tumors
      surrounding the optic nerve (4 cases). There were total removal of orbital tumors
      in 63 cases, partial removal 4 cases, decompression 3 cases of Graves' diseases.
      CONCLUSION: The indications of lateral orbitotomy depend on the category,
      location and extent of orbital tumors. Lateral orbitotomy involving supra or
      infra orbital edge enlarges the operative field, and improves the successful rate
      of orbital removal.

PMID- 12410996
TI  - Histopathologic classification of 3 476 orbital diseases.
AB  - OBJECTIVE: To investigate the histopathologic classification and distribution of
      orbital diseases. METHODS: The authors analyzed 3 476 orbital diseases examined
      in 1976 - 2000 in the pathology laboratory. RESULTS: Benign orbital diseases were
      81.90%. The 10 leading benign orbital diseases were cavernous hemangioma (515),
      vascular leiomyoma (364), inflammatory pseudotumor (347), dermoid (230),
      schwannoma (183), meningioma (150), benign mixed tumor of the lacrimal gland
      (147), mucocele (141), varix (132) and neurofibroma (76). Malignant orbital
      tumors were 18.10%. The numbers of malignant tnmors were malignant lacrimal gland
      epithelial tumors (129, 20.51%), rhabdomyosarcoma (75), non-Hodgkin's disease
      (65), secondary to nasosinus carcinoma (51), metastatic tumor (50), chloroma
      (32), extraocular extension of retinoblastoma (26) and extraocular extension of
      choroid malanoma (23). CONCLUSIONS: The vascular tumors and malformations are
      commonly seen in orbital diseases. The primary malignant tumor in the orbit is
      the malignant lacrimal gland epithelial tumors.

PMID- 12410997
TI  - The outcome of orbital decompression for thyroid associated ophthalmopathy.
AB  - OBJECTIVE: To evaluate the therapeutic results of orbital decompression for
      severe thyroid orbitopathy. METHODS: The records of 27 patients (30 eyes) having
      undergone orbital decompression of one wall, two walls and three walls for severe
      thyroid orbitopathy were analyzed for changes in visual acuity, visual field or
      pattern visual evoked potential, movement and reduction in proptosis. The
      indications were corneal exposure, severe proptosis and optic neuropathy.
      RESULTS: After surgery, the patients were followed up for a mean of 13.7 months.
      The visual acuity improved obviously in 19 eyes (63.3%), visual acuity was
      improved slightly in 4 eyes (13.3%), visual acuity kept in 0.2 - 0.8 (no change)
      in 4 cases (13.3%), visual acuity deteriorated obviously and not recovered in 3
      eyes (10.0%). Proptosis was decreased by a mean of 3.6 mm (range 1 - 7 mm), the
      decrease >/= 2.0 mm being in 93.3% eyes. CONCLUSION: Orbital decompression is
      effective in improving vision in most patients with severe thyroid associated
      ophthalmopathy, and the proptosis can be effectively improved.

PMID- 12410998
TI  - Imaging diagnosis of enlarged superior ophthalmic vein.
AB  - OBJECTIVE: To evaluate the diagnostic value of CT, MRI and Doppler ultrasound in
      dilatation of superior ophthalmic vein (SOV) and its etiologies. METHODS: One
      hundred and sixteen cases of enlarged SOV were analyzed with regard to imaging
      techniques. RESULTS: SOV enlargement was noted to occur in carotid-cavernous
      fistula (92 cases), ophthalmic Graves' disease (14), Tolosa-Hunt syndrome (2),
      inflammation at the apex of the orbit (2), ocular vascular deformity (2), orbital
      pseudotumor (1), orbital hematoma (1), cavernous sinus tumor (1) and thrombosis
      of cavernous sinus (1). The dilated vein appeared as signal void tubular shadows
      on both T(1) and T(2) weighted images. The diameter of the enlarged vein was 3.5 
      7.0 mm. Extraocular muscle enlargement, orbital lesions, enlarged cavernous
      sinus, etc were also revealed by MRI, CT and B-ultrasound scan. CONCLUSIONS: The
      dilated SOV may be well demonstrated by MRI, CT and ultrasound scanning. The
      etiological diagnosis of enlarged SOV can be made in combination with the
      associated findings. The authors suggest that some carotid-cavernous fistula
      cases be occluded by retrograde embolization via the SOV route.

PMID- 12410999
TI  - Etiological analysis on the ocular fungal infection.
AB  - OBJECTIVE: To review the distribution and shifting trends of fungal culture
      specimens in Beijing Institute of Ophthalmology. METHODS: Retrospective analyses
      of the fungal culture positive rate, the distribution and change of isolates were
      performed on 2 609 specimens during a 12-year period (1989 - 2000). RESULTS: The
      number of positive cultures was 775 (707 from the cornea, 91.23%; 22 from the
      conjunctiva, 2.84%; 15 from anterior chamber, 1.94%; 9 from the vitreous body,
      1.16%; 3 from lacrimal sac, 0.39% and 19 from other parts of eye, 2.45%). The
      average culture-positive rate was 29.70%. The average ratio of the positive
      cultures between the first half (from January to June) and the second half (from
      July to December) of the years was 1:2.1. The main genus cultured was Fusarium
      (58.71%), next was Aspergillus (16.8%). The percentage of Fusarium was increased
      (53.63% from 1989 through 1994 to 60.23% from 1995 through 2000), and the
      percentage Aspergillus was decreased (22.35% from 1989 through 1994 to 15.10%
      from 1995 through 2000). CONCLUSIONS: The Fusaruim is the predominant pathogens
      of ocular fungal infection in the northern part of China, its frequency was
      increased during this 12-year period, and meanwhile the frequency of the
      Aspergillus was decreased. It is very important to comprehend the distribution
      and shifting trends of pathogenic fungi continuously for diagnosis, prevention
      and treatment of fungal infectious ocular disease.

PMID- 12411000
TI  - Late postoperative complication of the foldable lens implantation: opacification
      of the intraocular lenses.
AB  - OBJECTIVE: To analyze the cause of the late postoperative opacification of the
      lens optic of implanted intraocular lens (IOL). METHODS: Twenty-two foldable
      hydrophilic acrylic lenses with opacification of their optics in 19 patients were
      taken out of the eye by surgery and examined by gross examination and microscopy.
      The lenses were stained with alizarin red and von Kossa method (special stains
      for calcium). Some were submitted for energy dispersive X-ray spectroscopy and
      scanning electron microscopy. The same kind of transparent IOLs were examined as
      the control group. RESULTS: Granular deposits of variable sizes were revealed on
      the surface and within the lens optics. The deposits that were stained positive
      with alizarin red and von Kossa method showed the presence of calcium. Energy
      dispersive X-ray spectroscopy demonstrated the calcium and the phosphate present
      in the deposits. The distribution of the granules was dense in the central part
      of the optic and sparse at its periphery. There were negative findings in the
      haptics of the lenses taken out and the control lenses. CONCLUSION: The cause of
      the opacification of the foldable lens optics is the deposits that consist of
      calcium and phosphate occurring inside and on the surface of the optics.

PMID- 12411001
TI  - Treatment of corneal epithelial in-growth after excimer laser in situ
      keratomileusis.
AB  - OBJECTIVE: To evaluate efficacy of photo therapeutic keratectomy (PTK) on corneal
      epithelial growth under the lamellar flap after excimer laser in situ
      keratomileusis (LASIK). METHODS: In the 6 eyes with epithelial in-growth, the
      corneal cap was lifted, and the in-growing epithelium was removed from the
      interface. Five to 10 pulses of PTK being 7 mm in diameter were placed over the
      undersurface of the flap and the stromal bed, irrigation between the interface
      and replacing corneal flap were performed, and 50 to 75 pulses PTK being 3 mm in
      diameter were utilized to smooth the flap edge. The follow-up period ranged from
      5 to 12 months. RESULTS: In the follow-up, no epithelial implantation reoccurred
      in these 6 eyes. The uncorrected visual acuity achieved their best preoperative
      corrected visual acuity. CONCLUSION: The results indicate that PTK can prevent
      recurrent epithelial in-growth after LASIK.

PMID- 12411002
TI  - An experimental study of anti-angiogenesis with recombinant human kringle 5.
AB  - OBJECTIVE: To investigate the anti-angiogenesis effects of recombinant human
      kringle 5 (rhk5) eye drops on corneal neovascularization (CNV) in rabbits induced
      by alkali burn. METHODS: Forty New Zealand albino rabbits were burned on the
      central corneas of their right eyes by 1 mol/L NaOH for 60s. Animals were
      randomly divided into 4 groups, 10 rabbits each group. Then rhk5 eye drops with
      different concentrations were applied four times daily for four weeks on each
      group: 5 mg/L in group 1, 10 mg/L in group 2, 20 mg/L in group 3 and carrier
      solution in group 4 (controls). The occurrence and development of CNV was
      observed every other day by slit-lamp microscope, and the area of CNV was
      calculated. Then the rabbits were killed on the 28th day (d), and the corneas
      were taken for histopathological examinations. Pearson's analysis was used to
      analyze the correlation between the number of inflammatory cells and the area of
      CNV. RESULTS: The occurrence of CNV in group 1 was (3.4 +/- 0.5) d, group 2 (6.8
      +/- 0.4) d, group 3 (6.7 +/- 0.7) d and group 4 (3.7 +/- 0.5) d. Significant
      difference (P < 0.05) in the occurrence time of CNV was found between group 2 and
      the control. Compared with the control group, the CNV occurrence was
      significantly delayed in the group treated by 10 mg/L rhk5. No significant
      difference was found between control group and group 1, and between group 2 and
      group 3. The CNV areas of group 2 and group 3 were also smaller than the control
      group (P < 0.05). The area of CNV had close relationship with the retrocorneal
      membrane and with the number of inflammatory cells (P < 0.05). CONCLUSION:
      Topical application of recombinant human rhk5 has prominent effectiveness on the
      inhibition of angiogenesis induced by alkali burn.

PMID- 12411003
TI  - The expression of protein betaig-h3 inducible by transforming growth factor-beta
      in keratoconus and normal cornea.
AB  - OBJECTIVE: To observe the expression of a protein inducible by transforming
      growth factor-beta (betaig-h3) in normal cornea and keratoconus and discuss the
      effects of extracellular matrix on keratoconus. METHODS: In situ hybridization
      method was used to detect the expression of betaig-h3 in the cornea. The cDNA
      library was screened with human betaig-h3 cDNA probe to orient betaig-h3 mRNA in
      cells. The level of betaig-h3 was detected in normal cornea and keratoconus.
      RESULTS: betaig-h3 mainly expressed in the stroma in normal cornea and
      keratoconus. The positive expression decreased along with the increase of
      severity of the keratoconus. The negative expression was seen in severe lesions
      of keratoconus. The strong positive expression was seen at the interface area
      between the normal and the lesion of keratoconus. CONCLUSION: The decreasing of
      the level of betaig-h3 causes the diminution of corneal steadiness that is
      related to the formation of keratoconus.

PMID- 12411004
TI  - Experimental study on the effect of cyclosporine A drug delivery system implanted
      in anterior chamber on high-risk corneal graft rejection.
AB  - OBJECTIVE: To evaluate the efficacy and feasibility of cyclosporine A (CsA) drug
      delivery system (DDS) for prevention of high-risk corneal graft rejection in
      rats. METHODS: (1) Corneal vascularization was induced in 60 Wistar rats (60
      eyes) by passing 8-0 silk suture in corneal stroma. (2) Wistar rats with corneal
      vascularization received corneal grafts from Sprague-Dawley rats to develop the
      high-risk keratoplasty models. (3) Forty animal models (40 eyes) were divided
      into 4 groups: receiving no therapy, 1% CsA eye drop, CsA DDS implanted
      subconjunctively, or CsA DDS implanted in anterior chamber. During the 1-month
      follow-up, survival times (the occurrence time of graft rejection) of these
      animal models were recorded, and CsA concentration in aqueous humor was regularly
      detected. (4) Other 8 normal Wistar rats (16 eyes) were divided into 2 groups
      with CsA DDS implanted subconjunctively or in anterior chamber. Histopathological
      examination on local ocular tissues was performed at 2 and 4 weeks after DDS
      implantation. RESULTS: Corneal vascularization was successfully induced in 51
      Wistar rats (51 eyes), but failed in the other 9 rats because of complications in
      or after operation. 40 high-risk keratoplasty animal models (40 eyes) were all
      successful which exhibited typical rejection processes. The mean survival time of
      4 trial groups was (8.20 +/- 1.48) days, (10.60 +/- 1.90) days, (11.40 +/- 2.50)
      days and (17.00 +/- 6.05) days respectively. The mean CsA concentration in
      aqueous humor of 4 trial groups was 0 micro g/L, (47.90 +/- 3.48) micro g/L,
      (56.50 +/- 6.24) micro g/L, (121.70 +/- 16.79) micro g/L respectively. The mean
      CsA concentration in aqueous humor of CsA DDS subconjunctively implanted group
      was (58.96 +/- 3.66) micro g/L, (59.74 +/- 6.50) micro g/L, (50.66 +/- 4.13)
      micro g/L at 1, 2 and 4 weeks postoperatively, and the mean CsA concentration of
      CsA DDS intrachamberly implanted group was (133.10 +/- 18.30) micro g/L, (124.56
      +/- 9.65) micro g/L, (107.45 +/- 11.48) micro g/L at the corresponding time.
      After CsA DDS implantation, chronic inflammation occurred in local ocular
      tissues, and the inflammation reduced gradually. CONCLUSIONS: The CsA DDS,
      especially CsA DDS implanted in anterior chamber, can significantly improve CsA
      concentration in aqueous humor and maintain a high concentration for a long
      period of time, which has strong effects on prevention of high-risk corneal graft
      rejection with only little toxicity. It is a safe and effective method for CsA
      application.

PMID- 12411005
TI  - Effect of genistein on proliferation of rabbit lens epithelial cell.
AB  - OBJECTIVE: To assess the effects of genistein (inhibitor of receptor protein
      tyrosine kinase) on the proliferation of rabbit lens epithelial cells (RLEC) and
      the activity of cell membrane receptor protein-tyrosine kinase (RTPK) of RLEC and
      approach the mechanism of genistein in prevention and treatment of after
      cataract. METHODS: RLECs were cultured in vitro with the addition of 0 (control),
      5, 10 and 15 mg/L genistein. The proliferation rates of the cells were measured
      by tritiated thymidine ((3)H-TdR) incorporation, and Casnetllie modified method
      was used to measure RTPK activities on the cell membrane after the action of
      various concentrations of genistein maintaining for 24 hours. RESULTS: The rates
      of (3)H-TdR incorporation in the cultures with 5, 10 and 15 mg/L genistein for 3
      days were 630 +/- 137, 489 +/- 166 and 314 +/- 98, respectively. The rates were
      all different from the rate of the control significantly (P < 0.05), and the
      inhibition rate of cell proliferation was elevated along with the increase of the
      genistein concentration. After the maintenance of the action of genistein for 24
      hours, the activity of RTPK was significantly lowered in the RLECs. The activity
      in the culture with 10 and 15 mg/L was significantly different from that in the
      control (P < 0.05). CONCLUSION: In vitro, genistein may inhibit the proliferation
      of RLECs via the inhibition of the activity of the cell membrane RTPK.

PMID- 12411006
TI  - Effect of transforming growth factor-beta(2) on extracellular matrix synthesis in
      bovine trabecular meshwork cells.
AB  - OBJECTIVE: To investigate the effect of transforming growth factor-beta(2) (TGF
      beta(2)) in human aqueous humor on extracellular matrix synthesis in cultured
      bovine trabecular meshwork cells. METHODS: Cultured 3-5 passage bovine trabecular
      meshwork cells were divided into control group and experimental group. After
      treated with 0 ng/L (control), 0.32 x 10(3) ng/L, 1.00 x 10(3) ng/L, 3.20 x 10(3)
      ng/L TGF-beta(2) for 48 h, collagen, fibronectin and hyaluronic acid synthesis in
      bovine trabecular meshwork cells were examined respectively by (3)H-proline
      incorportion and liquid scintillation technique, enzyme linked immunosorbent
      assay (ELISA) and radioimmunoassay (RIA). RESULTS: In comparison with the control
      group, TGF-beta(2) significantly promoted the synthesis of collagen at 0.32 x
      10(3) ng/L (P < 0.05), 1.00 x 10(3) ng/L (P < 0.01), 3.20 x 10(3) ng/L (P <
      0.01), (3)H-proline incorporation increased in a concentration-dependent manner;
      and 1.00 x 10(3) ng/L (P < 0.05), 3.20 x 10(3) ng/L (P < 0.01) TGF-beta(2)
      significantly promoted the synthesis of fibronectin in cultured bovine trabecular
      meshwork cells. 1.00 x 10(3) ng/L (P < 0.01) and 3.20 x 10(3) ng/L (P < 0.01) TGF
      beta(2) significantly inhibited the synthesis of hyaluronic acid in the cultured
      cells. CONCLUSION: The data suggest that TGF-beta(2) play important roles in
      extracellular matrix age-related changes of normal trabecular meshwork and
      abnormal deposition of the extracellular matrix in the trabecular meshwork,
      especially the juxtacanalicular tissue of primary open-angle glaucoma patients.

PMID- 12411007
TI  - Mechanism and treatments of regression and haze after photorefractive
      keratectomy.
AB  - OBJECTIVES: To investigate the effects of apoptosis-induced corneal wound healing
      response on regression and haze after photorefractive keratectomy as well as the
      influence of zinc on the cornea having undergone PRK. METHODS: Ninety rabbits
      divided into three groups underwent bilateral 193 nm excimer laser
      photorefractive keratectomy. The eyes were treated perioperatively with 0.1%
      flumetholon, 0.04% mitomycin C (MMC) or 0.5% zinc sulfate, and 0.9% NaCl solution
      as control. Comparative studies on haze, corneal thickness, histopathology and
      apoptosis were made periodically after operation. RESULTS: (1) Apoptosis was
      detected remarkably in anterior keratocytes at 4 hours, 2 weeks, 1 month after
      PRK. The level of keratocyte apoptosis in ZnSO(4) group was the least among all
      the groups (P < 0.01). (2) Corneal thickness and the number of keratocytes were
      increased after operation. The level of proliferation and haze was the highest in
      the control group and lowest in both MMC group and ZnSO(4) group (P < 0.01). (3)
      Corneal epithelial cells were proliferated after operation. The epithelial
      thickness was the least in ZnSO(4) group (P < 0.01). There were no statistical
      differences among others (P > 0.05). CONCLUSIONS: Regression and haze after PRK
      may result from the corneal wound healing response, which probably is initiated
      by keratocyte apoptosis. Zinc can inhibit apoptosis, glucocorticoids and MMC can
      prevent the over-proliferation, all of them can reduce regression and haze after
      PRK, while topical zinc application may become a kind of safe and effective way
      in the future.

PMID- 12411008
TI  - [Study of relationship between T helper cell type-1 and type-2 cytokines and
      intrahepatic cholestasis of pregnancy].
AB  - OBJECTIVE: To investigate the effect of T helper cell type-1 (TH(1)) cytokines
      [interferon-gamma (IFN-gamma), tumor necrosis factor-a (TNF-alpha)] and T helper
      cell type-2 (TH(2)) cytokines [interleukin-4 (IL-4)] on pathogenesis of
      intrahepatic cholestasis of pregnancy (ICP). METHODS: The peripheral blood
      mononuclear cells (PBMC) from 20 cases of ICP patients (study group) and 20 cases
      of normal pregnant women (control group) were cultured with photohemglutinin
      stimulation. TNF-alpha, IFN-gamma and IL-4 were determined in the supernatant by
      enzyme- linked-immunoassay. RESULTS: (1) In supernatants of cultured PHA induced
      PBMC, the levels of IFN-gamma and TNF-alpha of study group were (639 +/- 156)
      ng/L and (1 021 +/- 231) ng/L, which were significantly higher than those of
      control group, (464 +/- 147) ng/L and (728 +/- 175) ng/L (P < 0.001); the IL-4
      level of study group was (22 +/- 4) ng/L, which was lower than that of control
      group, (27 +/- 6) ng/L (P < 0.05); (2) In supernatants, the ratio of TNF-alpha/IL
      4 of study group was 48 +/- 11, which was significantly higher than that of
      control group (30 +/- 8), the ratio of IFN-gamma/IL-4 of study group was 30 +/-
      8, which was also higher than that of control group (19 +/- 6, P < 0.001); (3)
      There were significant positive correlations between total bile acid and
      concentrations of the TH(1) cytokines, the correlation coefficients(r) were 0.458
      and 0.692, respectively (P < 0.01). CONCLUSIONS: A shift in the balance of
      cytokine profiles away from TH(1)-type reactivity to TH(2)-type reactivity occurs
      in ICP. The enhanced cell-mediated immune reaction disturbs the immune tolerance
      balance between mother and fetus; The enhanced TH(1)-type immune response of ICP
      may contribute to the damage of hepatic cells and the occurrence of cholestasis.

PMID- 12411009
TI  - [Relationship between human leukocyte antigen-DRB1 allele gene polymorphism and
      intrahepatic cholestasis of pregnancy].
AB  - OBJECTIVE: To study the relationship between human leukocyte antigen-DRB1 (HLA
      DRB1) allele genes polymorphism and intrahepatic cholestasis of pregnancy (ICP).
      METHODS: Forty-two patients with ICP were tested for HLA-DRB1 allele genes
      polymorphism with the polymerase chain reaction technique and sequence specific
      oligonucleotide (PCR-SSO) probes hybridization, 56 normal pregnant women as
      control group were also tested. In addition, the phenotype frequencies of HLA
      DRB1 alleles were compared with it's clinical character in patients with ICP.
      RESULTS: The higher frequencies were observed for alleles DR9, DR12 and DR4 in
      both groups. DR6 alleles were detected in 14 cases out of 42 patients. Patients
      with ICP had a significantly higher frequency of the allele DR6 when compared to
      control group (16.7% vs 3.6%), with a relative risk (RR) as 6.5 (P < 0.01). No
      significant differences were observed between the frequencies of other detected
      HLA-DRB1 alleles in both groups. There was no association between HLA-DR6 allele
      and the level of liver function and cholylglycine in ICP. CONCLUSION: The study
      showed that HLA-DR6 gene might be one of the susceptibility genes to ICP.

PMID- 12411010
TI  - [Maternal-fetal mixed lymphocyte culture in intrahepatic cholestasis of
      pregnancy].
AB  - OBJECTIVE: To determine the maternal-fetal histocompatibility in intrahepatic
      cholestasis of pregnancy (ICP) by means of a morphologic method for mixed
      lymphocyte culture. METHODS: Twenty-two pregnant women with ICP and 21 normal
      pregnant women were enrolled in the present study. Mixed lymphocyte culture was
      conducted using lymphocytes obtained from maternal peripheral blood and cord
      blood of their fetuses. The transformational rates of lymphocytes were calculated
      and compared between normal and ICP-complicated pregnancies. RESULTS: The
      transformational rate in ICP was (24 +/- 5)%, while that in normal pregnant women
      was (36 +/- 9)%, the difference was significant between two groups (P < 0.001).
      The presence of pregnancy-induced hypertension did not affect the
      transformational rates in ICP group (P > 0.05). The transformational rate of
      lymphocyte in ICP did not correlate with cholylglycine level in serum
      significantly (P > 0.05). CONCLUSION: Decreased maternal-fetal lymphocyte
      reaction is demonstrated in ICP and it may play an etiological role.

PMID- 12411011
TI  - [A report of fourteen cases with hemolysis, elevated liver enzymes and low
      platelet count syndrome].
AB  - OBJECTIVE: To summarize the incidence, diagnosis, treatment and prognosis of
      patients with hemolysis, elevated liver enzymes and low platelet count (HELLP)
      syndrome. METHODS: The clinical data of fourteen cases with HELLP syndrome
      complicated by severe pregnancy-induced hypertension were analyzed
      retrospectively during the past seven years. RESULTS: The incidence of HELLP
      syndrome was 8% in the patients with severe pregnancy-induced hypertension.
      According to the diagnosis criteria used by Tennessee University, there were
      eight cases with complete HELLP syndrome and six cases with partial HELLP
      syndrome. The major therapeutic way were intensive maternal and fetal monitoring,
      active management of preeclampsia and eclampsia, administration of
      corticosteroids and termination the pregnancy as fast as possible. The major
      complications were DIC, placental abruption, pneumonedema and acute renal
      failure. The maternal and perinatal mortality were 7% and 29%, respectively.
      CONCLUSIONS: HELLP syndrome was a serious life-threatening complication of severe
      pregnancy-induced hypertension. In order to decrease the maternal and perinatal
      mortality rate, HELLP syndrome should be diagnosed and treated as fast as
      possible.

PMID- 12411012
TI  - [Examining consecutively serum leptin levels in normal pregnant and pregnancy
      induced hypertension women].
AB  - OBJECTIVE: To detect successsively serum leptin levels in normal, pregnancy
      induced hypertension (PIH) pregnant women. METHODS: Levels of serum leptin were
      measured in the 16-20, 24-28, 32-36 weeks of gestation, at the delivery time in
      50 healthy, 14 PIH pregnant women and their newborns and in 40 healthy non
      pregnant women by Immuno-radioassay method. Serum leptin levels were correlated
      with body weight, body mass index (BMI), blood pressure and placental weight.
      RESULTS: (1) The serum leptin levels were increased gradually during the normal
      (14.1 +/- 2.2)-(25.4 +/- 2.7) micro g/L and the PIH pregnancy [(13.4 +/- 3.0)
      (21.4 +/- 3.7)] micro g/L, especially in the PIH women. It was found that leptin
      concentrations rose markedly from 28 to 36 weeks of gestation, but increased
      slightly before the 28 weeks of gestation and after the 36 weeks of gestation in
      normals, and in contrast to the normal pregnancy, consistently higher until to
      the delivery time in the PIH. (2) The positive correlations were significant
      between the levels of serum leptin with their body weight and BMI in the normal
      pregnant and non-pregnant women (r = 0.478-0.639, P < 0.05 or P < 0.01), but not
      significant in the PIH pregnant (r = 0.035-0.379, P > 0.05). (3) The positive
      correlations were significant between the serum leptin concentrations and the
      systolic blood pressure, diastolic blood pressure and mean artery pressure in the
      PIH women after 20 weeks of gestation (r = 0.639-0.852, P < 0.05), but not
      significant in the normal pregnant, the PIH before 20 weeks of gestation and the
      non-pregnant women (r = 0.113-0.498, P > 0.05). (4) Before the delivery time, the
      positive correlation between the serum leptin concentrations of the pregnant
      women and that of the newborns was not significant, and also not significant
      between the puerperas' serum leptin levels and the placental weight in the normal
      pregnant (r = 0.132, 0.097, P > 0.05). But it was interesting that significant
      positive correlation was found between the puerperas' serum leptin concentrations
      and the cord serum leptin levels (r = 0.792, P < 0.01) and significant negative
      correlation was detected between the puerperas' serum leptin levels and the
      placental weight in the PIH women (r = -0.819, P < 0.01). (5) The leptin levels
      of cord blood were positively correlated with the body weight and BMI of newborns
      in both of the normal and PIH pregnancy (r = 0.520-0.655, P < 0.05 or P < 0.01).
      CONCLUSION: The characteristic change of serum leptin levels and correlations
      between the serum leptin concentrations and the related pregnant signs was
      different in normal and PIH pregnancy.

PMID- 12411013
TI  - [Analysis of 55 cases of transvaginal multifetal pregnancy reduction].
AB  - OBJECTIVE: To report the outcomes of transvaginal ultrasound-guided multifetal
      pregnancy reduction (MFPR) in early high-order multiple gestation. METHODS: Fifty
      five cases of high-order multiple pregnancy including 1 septuplet, 7 quintuplets,
      16 quadruplets and 31 triplets resulted from either superovulation/intrauterine
      insemination or in vitro fertilization-embryo transfer, were treated by
      transvaginal ultrasound guided MFPR at 49 - 79 days of gestational age. Their
      outcomes and complications were reported. RESULTS: Multifetal reduction were
      successfully done in 53 cases (96%). Miscarriage occurred in 8 patients (15%).
      Twenty-one cases (47%) were premature delivery and 24 patients underwent term
      delivery resulting in 87 infants. Five preterm infants died of neonatal
      respiratory distress syndrome. Among them none has malformation. Of the 82 live
      infants, 1 had hexadactyly and another arterial septum defect occurred. No organ
      injury, massive hemorrhage and infection occurred after MFPR. CONCLUSIONS: MFPR
      during early pregnancy is a safe, effective, simple operation for the purpose of
      reducing perinatal and maternal complication.

PMID- 12411014
TI  - [Investigation of the hemodynamic changes during uterine arterial embolization in
      the treatment of adenomyosis].
AB  - OBJECTIVE: To investigate the hemodynamic changes before and after uterine
      arterial embolization (UAE) in the treatment of adenomyosis. METHODS: UAE was
      performed in 30 patients with adenomyosis diagnosed by clinical manifestation,
      magnetic resonance and/or color Doppler flow imaging (CDFI). The mean flow
      velocity (Vm), resistance index (RI) and pulsatility index (PI) of bilateral
      uterine arteries were measured by CDFI 1 week before, 1 week, 1 month and 3
      months after UAE. Mean time of the blood flow in normal myometrium and
      adenomyosis lesions were observed by color Doppler energy. RESULTS: Vm, PI and RI
      were markedly reduced after UAE, especially on the 7th day after UAE (P < 0.01).
      Concomitantly the blood flow volume (BFV) in normal myometrium was also decreased
      and recovered to normal again 1 month and 3 months after treatment (P < 0.05,
      compared to the 7th day after UAE) but the BFV inside the adenomyosis lesion kept
      lower state after UAE. CONCLUSIONS: The most obvious hemodynamic changes of
      uterine arteries occurred 1 week after UAE. The blood supply of normal myometrium
      recovered to normal after 30 days. But those of lesions were irreversible until 3
      months after UAE.

PMID- 12411015
TI  - [Study on the expression of vascular endothelial growth factor in patients with
      adenomyosis of the uterus].
AB  - OBJECTIVE: To investigate the role of angiogenesis and expression of vascular
      endothelial growth factor (VEGF) in the pathophysiology of adenomyosis of the
      uterus. METHODS: The study included 32 patients with histologically proven
      adenomyosis and 30 patients with asymptomatic leiomyoma of the uterus.
      Immunohistochemical staining was used to detect VEGF expression in different
      parts of the uterus. A computerized morphometric study on the VEGF expression was
      performed. RESULTS: The VEGF H-Score of glandular cells in the endometrium of
      adenomyosis uterus [proliferative phase (9.6 +/- 1.4), secretory phase (11.7 +/-
      1.6)] was much higher than that of leiomyoma uterus [proliferative phase (8.3 +/-
      1.7), secretory phase (10.2 +/- 1.5)] (P < 0.05), and increased in the secretory
      phase (P < 0.05). Compared with eutopic endometrium, the VEGF H-Score in ectopic
      endometrium [proliferative phase (11.9 +/- 1.8), secretory phase (13.0 +/- 1.7)]
      increased significantly (P < 0.05), but showed no cyclic change (P > 0.05). The
      VEGF H-Score of myometrium around the ectopic lesions [proliferative phase (9.5
      +/- 1.3), secretory phase (8.7 +/- 1.3)] was higher than that of normal
      myometrium [proliferative phase (4.8 +/- 1.9), secretory phase (4.5 +/- 1.4)] (P
      < 0.01). CONCLUSION: The angiogenesis activity of the endometrium and myometrium
      of adenomyosis uterus was markedly increased.

PMID- 12411016
TI  - [Expression of lethal gene mRNA on placenta villi in patients with spontaneous
      abortion].
AB  - OBJECTIVE: To study the role of lethal gene: including retinoic X receptor
      (RXR)alpha, N-myc and transcript enhancer factor (TEF)-1 in human spontaneous
      abortion. METHODS: The levels of RXRalpha, N-myc and TEF-1 mRNA expression on
      placenta villi from 38 spontaneous abortion women and 33 normal early pregnant
      women were examined by reverse transcription, polymerase chain reaction. RESULTS:
      (1) The levels of RXRalpha mRNA on placenta villi from the abortion group were
      significantly decreased as compared with those from normal group (0.4 +/- 0.3
      versus 0.6 +/- 0.3, P < 0.05); There were no significant differences in the
      levels of N-myc mRNA expression between the abortion group and normal group (2.1
      +/- 1.2 versus 2.2 +/- 0.9, P > 0.05). The levels of TEF-1 mRNA on placenta from
      abortion group were significantly lower than those from normal group (1.6 +/-
      1.1, 2.3 +/- 1.2, P < 0.05); (2) The levels of RXR alpha mRNA, TEF-1 mRNA in
      recurrent abortion group were significantly lower than those from non-recurrent
      group (0.3 +/- 0.2 versus 0.6 +/- 0.4, P < 0.05, 1.0 +/- 1.1 versus 1.9 +/- 1.2,
      P < 0.05). CONCLUSION: It was suggested that the lower expression of RXR alpha
      mRNA, TEF-1 mRNA may play an important role in the pathogenesis of spontaneous
      abortion especially in recurrent abortion.

PMID- 12411017
TI  - [Factors affecting disease recurrence and the role of secondary therapies in the
      management for patients with recurrent ovarian carcinoma].
AB  - OBJECTIVE: To identify variants affecting disease recurrence and clarify the role
      of re-debulking surgery and second-line chemotherapy in the management of
      recurrent advanced epithelial ovarian cancer (AEOC). METHODS: One hundred and
      sixty-seven patients with recurrent AEOC treated in our hospital between Jan.
      1986 and Dec. 1997 were retrospectively reviewed. Survival was calculated by
      Kaplan-Meier method with difference in survival estimated by Log-rank test.
      Independent prognostic factors were identified by the COX stepwise regression
      model, and variants associated with disease recurrence were found by logistic
      stepwise regression methods. RESULTS: The median age was 51 (range 26-71) years.
      Sixty patients underwent re-debulking surgery, 23 of them with residual disease
      </= 1 cm. There was a significant difference in survival between optimal and sub
      optimal groups, with an estimated median survival of 20 and 10 months,
      respectively (chi(2) = 9.42, P = 0.021). When patients with sub-optimal surgical
      results were compared with those who had chemotherapy alone, there was a
      significant difference in median survival, 10 vs. 13 months (chi(2) = 4.38, P =
      0.036 4). Age of the patients, refractory ascites, second-line chemotherapy, and
      residual disease after primary surgery were independent prognostic factors of
      survival identified by COX regression analysis. Logistic stepwise regression
      analysis revealed that age, platinum-based chemotherapy, neoadjuvant
      chemotherapy, and the size of residual disease after primary surgical
      cytoreduction were factors affecting progression-free interval. CONCLUSIONS: The
      age at diagnosis, residual disease, first-line chemotherapy, and neoadjuvant
      chemotherapy are factors affecting disease recurrence. Patients received second
      line chemotherapy and with residual disease </= 1 cm after secondary surgery
      experience a better prognosis than those without receiving second-line
      chemotherapy or with residual disease > 1 cm after secondary cytoreduction.

PMID- 12411018
TI  - [Value of hysteroscopy and dilatation and curettage in diagnosis of endometrial
      carcinoma].
AB  - OBJECTIVE: To discuss the value of hysteroscopy and fractional dilatation and
      curettage (D&C) in endometrial carcinoma diagnosis. METHODS: Assort 156
      endometrium carcinoma patients of our hospital to two groups, examined by D&C
      (group A, 93 patients) or hysteroscopy (group B, 63 patients). Compared the
      diagnosis's veracity of the two methods. RESULTS: In group A 34% (31/92) of
      patients' clinical stage was earlier than their surgical stage, 15% (14/92) of
      patients' clinical stage was later than their surgical stage, 75% (68/91) of
      involvement of cervical canal was estimated precisely, while the positive
      peritoneal cytology rate was 32% (23/71). In group B the rates were 43% (27/63),
      3% (2/63), 90% (56/62) and 35% (18/51), respectively. There is no statistic
      difference between the two groups of the positive peritoneal cytology rate and
      the earlier clinical stage than surgical stage (P > 0.05), but there is statistic
      difference between the two groups in estimating the involvement of cervical canal
      and the earlier surgical stage than clinical stage (P < 0.05). CONCLUSION: The
      hysteroscopy can discover the involvement of cervical mucosa more accurately in
      the endometrial carcinoma patients, but not improve the positive peritoneal
      cytology rate.

PMID- 12411019
TI  - [Preliminary results of intraoperative radiation therapy for cervical carcinoma
      IIb].
AB  - OBJECTIVE: To assess the effects of intraoperative radiation therapy (IORT) for
      cervical carcinoma IIb. METHODS: One hundred and eighty-two patients with
      cervical carcinoma (stage IIb) underwent radiation therapy. Of them, 97 patients
      received IORT. They received external beam radiotherapy with 6 MV X ray 20 Gy/10
      fractions to pelvic field and afterloading radiotherapy with 10-14 Gy/2 fractions
      on point A before operation. After having rest of 1 week, patients completed
      total hysterectomy and bilateral adnexectomy + intraoperative radiotherapy with
      12 MeV electron beam 18-20 Gy to pelvic field (the applicator for special use in
      IORT of pelvic field was designed and made by us. We have the patent of China for
      the special applicator.) The single radiotherapy group completed external beam 30
      Gy to pelvic field and 20 Gy to pelvic where shelter in the center and
      afterloading radiotherapy 35-40 Gy/5-6 fractions on point A. RESULTS: The 5-year
      survival rate in the IORT group was 95%, and that in the single radiotherapy
      group 88%. The difference between two groups is not statistically significant
      (chi(2) = 1.946, P > 0.05). However, there were quite improvements of survival
      rate and survival quality for cervical adenocarcinoma. Their 5-year survival
      rates were 91% and 33% (P < 0.01), respectively in IORT group and single
      radiotherapy group. The incidence of the complications in the IORT group which
      are radioactive proctitis, bone marrow depression, and reaction of digestive
      system are lower than those in single radiotherapy group. CONCLUSIONS: IORT
      provided a new therapy method for cervical carcinoma IIb especially for cervical
      adenocarcinoma. There are positive significance for reducing the range of the
      operation, decreasing complications of radiotherapy, and improving survival
      quality.

PMID- 12411020
TI  - [Experimental therapy with angiogenesis inhibitor TNP-470 on human ovarian cancer
      transplanted subcutaniously in nude mice].
AB  - OBJECTIVE: To study the effect of an angiogenesis inhibitor TNP-470 (TNP) used
      alone and in combination with cytoxan (CTX) in the treatment of human ovarian
      cancer transplanted s.c. in nude mice. METHODS: Human ovarian cancer transplanted
      s.c. in nude mice model was established, then divided into 5 groups: control
      group, vehicle group, TNP group, CTX group and TNP + CTX group, different
      treatments were served from day 8 after transplantation and all mice were
      sacrificed after 28 days. The weights of the mice and the volumes of the tumors
      were measured respectively during the therapy time. Moreover, microscopy was done
      after H&E staining. RESULTS: The growth inhibiting rates in the TNP and CTX group
      were 26.1% and 33.9% respectively; After combined, the rate was increased to
      70.5%. There were no obvious decrease in the weight of all treated mice.
      CONCLUSIONS: Treatment with TNP is an potentially useful method of antitumor
      therapy in ovarian cancer, although the inhibition effects were not obvious in
      small doses. Moreover, TNP could enhance the effectiveness of antitumor drug.

PMID- 12411021
TI  - [Value of long-distance fetal heart rate monitoring on the pre-partum health care
      of the pregnant woman with umbilical cord loops].
AB  - OBJECTIVE: To explore the value of the long-distance fetal heart rate (FHR)
      monitoring on the pre-partum health care of self-monitoring at home for pregnant
      woman with the umbilical cord loops. METHODS: The umbilical cord loops was
      diagnosed by ultrasonography. In the study group, 896 pregnant women with the
      umbilical cord loops accepted long-distance FHR monitoring and the count of fetal
      movement (FM) as family-self monitoring methods, while in the control group, 1
      914 pregnant women with the umbilical cord loops used the count of FM only as
      family-self monitoring method. Abnormal non-stress test (NST), variable
      deceleration, fetal distress, neonate asphyxia, fetal death, stillbirth,
      operative delivery rate were analyzed between the study and control group
      retrospectively. RESULTS: The incidence of NST reactive pattern and non- reactive
      pattern and the variable deceleration in long-distance FHR monitoring of the
      study group were significantly higher than those in routine FHR monitoring. The
      incidence of fetal distress in the study group (35.0%) was significantly higher
      than that in the control group (30.9%), while the incidence of neonatal asphyxia
      in the study group (3.5%) was significantly lower than that in the control group
      (5.6%). The incidence of outside hospital fetal death in the study group (0.1%)
      was significantly lower than that in the control group (0.8%). There were no
      significant differences of cesarean section rate, forceps or vacuum extractor
      delivery between the two groups (P > 0.05). CONCLUSIONS: This study suggested
      that the high variable rate in the long-distance FHR monitoring curve was related
      to the incidence of the fetal distress. It didn't increase the cesarean section
      rate and vaginal operative delivery rate, but decreased the neonatal asphyxia and
      outside hospital fetal death rate. The long-distance FHR monitoring combined with
      the count of FM may be a better family-self monitoring method for the pregnant
      women with the umbilical cord loops.

PMID- 12411022
TI  - [Clinical value of remote fetal monitoring network in high-risk pregnancy].
AB  - OBJECTIVE: To investigate the clinical value of remote fetal monitoring network
      in high-risk pregnancy. METHODS: Non-stress test (NST) was carried on in 116 high
      risk gravida by remote fetal monitoring network (study group). One hundred high
      risk pregnant women served as control group, were monitored by fetal movement
      counting daily and regular NST check-up in hospital. Results of fetal monitoring,
      neonatal prognosis and cesarean section were analyzed between the study and
      control group. RESULTS: NST was applied more frequently in the study group (9.2
      +/- 4.9) times than in control group (2.6 +/- 1.3) times (P < 0.001). But the
      costs were similar. The incidences of neonatal asphyxia (10.3%) and preterm birth
      (12.6%) in the study group were lower than those in the control group (20.8% and
      24.5%) (P < 0.05). In the study group, there was significant difference in the
      rate of poor neonatal prognosis between normal and abnormal NST groups (64.8% and
      17.7%) (P < 0.05). There was no significant difference in the rates of cesarean
      section (75.9% and 75.0%, respectively) and poor neonatal prognosis of cesarean
      section with abnormal NST (71.7% and 60.6%, respectively) between the study and
      control groups (P > 0.05). CONCLUSIONS: Remote fetal monitoring network can be
      used to improve the quality of fetal monitoring, especially in primary hospital.
      It decreased the rate of neonatal asphyxia and preterm delivery but didn't
      increase the cesarean section rate. It offers a reliable and economic method of
      self-monitoring for high-risk pregnant women.

PMID- 12411023
TI  - [Clinical application of the expert type terminal of remote electronic fetal
      heart rate home monitoring system].
AB  - OBJECTIVE: To investigate the clinical value of the expert type terminal of long
      distance electronic fetal heart rate home monitoring system in the application to
      self-monitoring of pregnant woman at home in peripartum. METHODS: All the
      pregnant women (n = 284) were divided into two groups. Research group (n = 134)
      contained 73 high risk gravida. There were 78 high-risk gravida in control group
      (n = 150). In the research group, self-monitoring at home in 134 women was taken
      by the expert type terminal of long-distance electronic fetal heart rate
      monitoring system through telephone and fetal movement counting. The women were
      requested to auscultate and transfer fetal heart rate (FHR) to electronic FHR
      monitoring center in hospital. Non-stress test (NST) was made 1 approximately 2
      times every week when fetal movement was active. When women felt any abnormality
      of baby, she should immediately test NST and then the photograph of NST was send
      to FHR monitoring center by telephone. Doctor would make a diagnosis and
      management in time according to the photograph of NST. In the control group, the
      way of fetal monitoring was fetal movement counting and regular NST test in the
      outpatient clinic. RESULTS: The incidence of abnormal NST was significantly
      higher in the research group than that in the control group (respectively 22.0%
      vs 13.5%, P < 0.05). The neonatal asphyxia was significantly lower in the
      research group than that in the control group (respectively 1.5% vs 4.0%, P <
      0.05). The incidence of abnormal NST was not different between the high-risk
      women and non-high-risk women in the research group (respectively 22.3% vs 21.6%,
      P > 0.05). CONCLUSIONS: The expert type terminal of long-distance electronic FHR
      monitoring system through telephone is a new way of the FHR self-monitoring at
      home. The application of this method could ease mental press of the women,
      decrease significantly perinatal mortality, decrease incidence of neonatal
      asphyxia, and improve quality of obstetrics. Whatever there are high risk factors
      in any pregnant women, the system should be applied to all late pregnant women.

PMID- 12411024
TI  - [Management of abnormal fetal heart rate in the second stage of labor].
AB  - OBJECTIVE: We investigated the correlations between abnormal fetal heart rate
      (FHR) during the second stage of labor and delivery types and intrapartum
      maternal complications and fetal outcome. METHODS: The data of 232 nulliparas
      with single vertex in the second stage of labor (111 cases with normal FHR, 121
      cases with abnormal FHR) were analyzed retrospectively. RESULTS: The incidence of
      abnormal FHR in the second stage of labor was 52.2% (121/232). The patterns of
      abnormal FHR included: 81 (66.9%) cases with moderate and/or severe variable
      deceleration (VD), 27 (22.3%) cases with scattered late deceleration (LD), only
      one with continuous LD, 4 (3.3%) cases prolonged deceleration (PD), 2 (1.7%)
      cases with VD and LD, 3 (2.5%) cases with VD and PD, 4 (3.3%) cases with
      diminished baseline variability. There were 13 (11.7%) among the cases with
      normal FHR and 35 (28.9%) among the cases with abnormal FHR underwent assistant
      delivery operations (forceps or/and vaccum), respectively (P < 0.05). Furthermore
      29 of 35 (82.9%) cases underwent assistant operations for vagina delivery due to
      abnormal FHR, the others underwent assistant operations for vagina delivery due
      to weak expulsive force or malpositioning of fetal head. There was one case of
      complicated vaginal laceration in the group with abnormal FHR. There was no
      difference of newborns with low Apgar score between two groups. CONCLUSIONS:
      There was a very high incidence of abnormal FHR during the second stage of labor,
      however, the most cases were response to parasympathetic stimulation due to
      umbilical cord or fetal head compression by mothers over push and descent of
      fetal head, or temporal diminishing of uterine placenta blood flow. It suggests
      that it is unnecessary to interfere immediately, unless truly fetal distress.

PMID- 12411025
TI  - [Analysis about clinical data of intrauterine infection of hepatitis B virus].
AB  - OBJECTIVE: To investigate a practical diagnostic method in clinic for fetuses
      infecting with hepatitis B (HBV) and study the mutual effects between fetal
      infection and clinical factors. METHODS: Venous blood was drawn from 144 cases of
      HBV carrier mothers and their neonates. HBV DNA was detected by polymerase chain
      reaction (PCR) and hybridization, HBV M was detected by enzyme linked
      immunoadsorbent assay (ELISA), and aspartate aminotransferase/alanine
      aminotransferase (AST/ALT) was detected by IFCC. Umbilical blood and femoral
      blood was taken from 40 of 144 neonates for HBV DNA detection. Clinical data,
      neonatal AST and ALT level were compared between fetal infection group and
      control group. RESULTS: (1) The fetal infectious rate was 22.9% (33/144).
      Comparing with peripheral venous blood sample, the sensitivity and positive
      predictive value of HBV DNA detected in cords was 100.0%, 80.0% respectively.
      Following up the infants, HBV DNA was found persistently positive in 7 of 28
      intrauterine infectious infants 6 approximately 9 months after birth. HBsAg was
      found changing to be negative 1 month later in the infants with HBsAg positive at
      birth. (2) The fetal infectious rate in mothers with HBeAg (+) or HBV DNA (+) was
      70.5%, 61.1% respectively which was significantly higher than that in mothers
      with HBeAg (-) or HBV DNA (-). P < 0.01. There was no significantly difference in
      mothers' age, gestational age, delivery way, birth weight (BW), body length (BL),
      Apgar score between fetal infectious group and control group. (3) The mean value
      of AST, ALT in fetal infectious group was (61.2 +/- 31.3) IU, (24.7 +/- 14.9) IU
      respectively, which was significantly higher than that in control group [(55.2 +/
      37.1) IU, (19.0 +/- 10.1) IU]. P < 0.01. CONCLUSIONS: (1) Detection of HBV DNA
      in cord blood is a sensitive index for diagnosing fetal infection, however
      detection of peripheral venous blood is with the significance of making correct
      diagnosis. (2) HBsAg or HBV DNA positive in mothers is one of the risk factors of
      intrauterine infection. There is no relationship among fetal infection and
      mothers' age, gestational age, delivery way, neonates' sex, BW, BL. (3) The liver
      function of neonates infected with HBV intrauterinely maybe impaired to some
      extent.

PMID- 12411026
TI  - [Study on the trend of changes in fetal macrosomia in Yantai during the past 30
      years].
AB  - OBJECTIVE: To investigate the changing trend of incidence and the relevant
      factors in fetal macrosomia. METHODS: 84 883 newborns during Jan. 1, 1970 to Dec.
      31, 1999 were used to analyze the incidence of fetal macrosomia, the average
      birth weight, the percentage of superior fetal macrosomia, the distribution of
      gestational age, the rate of cesarean section and the vaginal delivery, the
      relevant factors of fetal macrosomia. RESULTS: All the cases were divided into 3
      groups, one group from 1970 to 1979, the second one from 1980 to 1989, the third
      one from 1990 to 1999. The incidence of fetal macrosomia for three groups were
      2.6%, 6.9% and 13.2% (P < 0.01). The rate of cesarean section were 2.3%, 28.9%,
      45.3% (P < 0.01). The percentage of superior fecal macrosomia were 9.4%, 11.2%,
      16.2% (P < 0.01). The incidence of complications of vaginal delivery such as
      should dystocia, were 4.3%, 5.0%, 1.7%, respectively, wheres these complications
      were not found in cesarean section. The average birth weight of fetal macrosomia
      were (4 220 +/- 250) g, (4 223 +/- 146) g, (4 253 +/- 250) g in 3 groups. There
      were signifigant differences maternal height, weight, abdominal perimeter and GDM
      mac. CONCLUSIONS: The incidence of fetal macrosomia, the average birth weight,
      the percentage of superior fetal macrosomia and the rate of cesarean section
      gradually rose in Yantai in the past 30 years. The occurrence of fetal macrosomia
      may associate with many factors of pregnant women, such as weight, nutrition,
      diabetes, gestational age and fetal sex. Cesarean section is a relatively safer
      choice for macrosomia delivery.

PMID- 12411027
TI  - [Expression of macrophage colony-stimulating factor in human luteinized granulosa
      cells].
AB  - OBJECTIVE: To detect and localize the expression of macrophage colony-stimulating
      factor (M-CSF) in human luteinized granulosa cells and investigate the effects of
      follicle stimulating hormone (FSH) on M-CSF production by human luteinized
      granulosa cells in vitro. METHODS: Human luteinized granulosa cells were isolated
      from follicular fluid of superovulated infertile patients undergoing
      intracytoplasmatic sperm injection. Some of the luteinized granulosa cells were
      used for detecting M-CSF by immunocytochemical staining (ABC method). Most of
      them were cultured with HAM's F-10 medium alone or plus various concentrations of
      FSH (2, 5, 15, 25 IU/ml). The media were collected after 72 hours and their M-CSF
      contents were measured by a solid phase enzyme-linked immunosorbant assay.
      RESULTS: About 80% of the luteinized granulosa cells were positively stained for
      M-CSF antibody. The immunoreactive signals of M-CSF were specially located in the
      cytoplasma of the luteinized granulosa cells. No immunoreactivity of M-CSF was
      observed in vaginal squamous epithelial cells through contaminations during
      transvaginal oocyte retrieval. The concentration of M-CSF in cultured luteinized
      granulosa cells medium without FSH stimulation was low. However, addition of 2,
      5, 15, 25 IU/ml concentrations of FSH caused significant dose-dependent increases
      of M-CSF production after 72 hours culture by luteinized granulosa cells (P <
      0.01). CONCLUSIONS: Human luteinized granulosa cells can synthesize and secrete M
      CSF. FSH can directly stimulate M-CSF secretion by human luteinized granulosa
      cells. The mechanism of FSH regulating follicular development may partially via M
      CSF/receptor pathway.

PMID- 12411028
TI  - [In vitro study on hormonal regulation of human endometrial stroma cell
      decidualization].
AB  - OBJECTIVE: To investigate the roles of luteinizing hormone releasing-hormone
      (LHRH), follicle stimulating hormone (FSH), human chorionic gonadotropin (hCG)
      and ovary steroids in regulation of human endometrial stroma cell (ESC)
      decidualization. METHODS: Stroma cells derived from human endometrium during the
      proliferative phase were cultured in vitro and treated with physiological doses
      of estradiol (E(2)), testosterone (T), progesterone (P) or LHRH, FSH and hCG.
      Their morphologic changes and prolactin (PRL) production in the media were
      examined and compared. RESULTS: Addition of E(2) or T or P stimulated ESC
      proliferation, resulting in increase of the saturation density. The fibroblast-
      morphologic changes to polygonal shape and began to express PRL simultaneously
      after treatment of P or T. P in presence of E(2) or T significantly enhanced PRL
      production (P < 0.01), suggesting a synergistic action between them in
      stimulating ESC decidualization. LHRH, FSH or hCG also induced morphologic
      changes and PRL production by ESC in the presence of E(2) + P. Among them the
      impact of hCG is most remarkable, especially in this culture system. CONCLUSIONS:
      E(2), T and P play an important role in proliferation and differentiation of the
      ESC. LHRH, FSH, hCG also directly exert an effect on ESC decidualization.

PMID- 12411029
TI  - [Effect of interleukin-1beta on aromatase activity in human osteoblast-like
      cells].
AB  - OBJECTIVE: To study the stimulation of interleukin (IL)-1beta and interleukin-1
      receptor antagonist (IL-1ra) on aromatase activity in human osteoblast cells.
      METHODS: In the present study, the effect of IL-1beta and IL-1ra on aromatase
      (Arom) activity and mRNA expression in human osteoblast-like cells was
      investigated by [(3)H] water released upon the conversion of [1beta-(3)H]
      androstenedione to estrone and the reverse-transcription polymerase cain reaction
      (RT-PCR) method. The experimental group is divided into four group: G1 (IL-1beta
      1 microgram/L), G2 (10 microgram/L), G3 (IL-1beta 10 microgram/L + IL-1ra 500
      microgram/L) and G4 (IL-1ra 500 microgram,/L). RESULTS: The activity of G1 and G2
      resulted in (4 211 +/- 348) pmol/10(6) cell.h(-1) and (4 958 +/- 231) pmol/10(6)
      cell.h(-1), respectively. IL-1ra neutralized the increased arom activity to
      control level in G3 (3 652 +/- 203) pmol/10(6) cell.h(-1). Arom mRNA expression
      was increased with the dose increasing of IL-1beta. CONCLUSION: These findings
      suggest that IL-1beta stimulates arom activity through the IL-1 receptor and
      addition of IL-1beta increased arom activity in a dose-dependent manner.

PMID- 12411030
TI  - [Study on chemotherapy-induced disorders of glucose metabolism in patients with
      malignant ovarian tumor].
AB  - OBJECTIVE: To determine the effect of chemotherapy on glucose metabolism in
      patients with malignant ovarian tumor. METHODS: The blood glucose assay and
      associated clinical materials of 375 cases with malignant ovarian tumor who
      received chemotherapy from January 1997 to December 2001 were analyzed
      retrospectively. RESULTS: Thirty-two cases (8.5%) had elevated fasting blood
      glucose after chemotherapy. Among them, 14 cases (3.7%) were diagnosed as
      diabetes mellitus, 9 cases (2.4%) were diagnosed as impaired glucose tolerance.
      Paclitaxel based chemotherapy seemed to have more opportunity to induce disorders
      of glucose metabolism than that in cisplatin based chemotherapy (P < 0.05), and
      this happened most frequently in 1 approximately 3 courses. CONCLUSION:
      Chemotherapy may induce disorders of glucose metabolism, which most frequently
      occurred in 1 approximately 3 courses, including impaired glucose tolerance or
      diabetes mellitus,especially in patients received paclitaxel chemotherapy.

PMID- 12411031
TI  - Value of four-chamber view of the fetal echocardiography for the prenatal
      diagnosis of congenital heart dise.
AB  - OBJECTIVE: To investigate the value of four-chamber view for the prenatal
      diagnosis of congenital heart disease. METHODS: A total of 780 fetal hearts were
      examined by the four-chamber view between 16 and 36 weeks of gestation, and the
      clinical data were analyzed and the newborns were followed. RESULTS: Among the
      780 fetus, the four-chamber view was obtained in 94.6% of the fetus and three of
      them were found abnormal and heart malformations were diagnosed. One was Ebstein
      syndrome, the second was seriously ventricular septal defect and the third was
      single ventricle and single atrium. The first and the third case were confirmed
      after birth by echocardiography and autopsy, and the second case was single
      ventricle and single atrium diagnosed by echocardiography of the newborn. The
      other 777 newborns were followed to six weeks after birth. Three more heart
      malformations were diagnosed. One is ventricular septal defect, one is atrial
      septal defect and the third is pulmonary artery stenosis with atrial septal
      defect. The sensitivity of the four-chamber view for the prenatal diagnosis of
      the congenital heart disease is 50% and the specificity is 100%. CONCLUSIONS: The
      four-chamber view of fetal heart shows the majority structures of the fetal heart
      and the successive rate of detection is high. It has a higher sensitivity and a
      very high specificity for the identification of congenital heart disease. We
      advocate the four-chamber view of fetal heart as a basic obstetric scanning.

PMID- 12411032
TI  - Influence of abnormal cervical pap smear undertaken during pregnancy to the
      outcome of the pregnancy.
AB  - OBJECTIVE: To investigate the influence of abnormal cervical pap smear undertaken
      in pregnancy to the outcome of the pregnancy. METHODS: A total of 1 069 primipara
      deliveried in Beijing Chaoyang hospital from Jan 1999 to May 2001 were reviewed,
      furthermore we compared the group of normal pap smear (group A) with the group of
      abnormal pap smear (group B), and analysed the difference of the complications
      during pregnancy, methods of delivery, the first stage of labor, fetal distress
      and the outcome of the cervical pap smear postpartum. RESULTS: The incidence of
      premature rupture of the membranes and fetal distress in group B, which were
      39.39% and 30.30%, respectively, were significantly higher than that of group A,
      which were 5.21% and 15.25%, respectively (P < 0.01). There was no statistical
      difference in premature delivery, the ratio of cesarean section and the first
      stage of labor which were 3.38% and 3.03%, 44.11% and 30.30%, 7.3 h and 7.7 h,
      respectively (P > 0.05). The regression rate for patients with abnormal cervical
      pap smear postpartum was 62%. CONCLUSIONS: The outcomes of the pregnancy such as
      premature rupture of the membranes and fetal distress were affected by the
      abnormal cervical pap smear undertaken during pregnancy. It is important to
      undergo routine cervical pap smear examination during pregnancy.

PMID- 12411033
TI  - A study of rubella virus infection during pregnancy.
AB  - OBJECTIVE: To investigate the status of rubella virus (RV) infection in pregnant
      women and evaluate the effect on fetus of RV infection during pregnancy. METHODS:
      Enzyme linked immunosorbent assay (ELISA) was used to detect the RV specific IgG
      and IgM antibodies in 1 471 serum samples of pregnant women, and reverse
      transcription polymerase chain reaction (RT-PCR) was employed to detect RV RNA in
      placental and fetal tissues obtained after termination of pregnancy, tissue
      samples of 3 dead fetus or artificial labor fetus were also made into tissue
      slices and observed by electron microscope. RESULTS: RV IgG was detected positive
      in 76.1% of cases (1 119/1 471) and 7.4% of cases (109/1 471) were RV IgM
      positive, 14.1% (208/1 471) of cases were found to be double-negative of RV IgG
      and IgM while 2.4% of cases (35/1 471) were RV double-positive of IgG and IgM.
      Among seven follow-up pregnant women, two cases developed fetal death and one
      woman received labor induction voluntarily. Rubella virus particles were detected
      in myocardial cells of 1 induced fetus. In addition, RV particles were also
      detected in placenta, myocardium, liver and brain in 2 dead fetus. CONCLUSIONS: A
      part of the population under study was susceptive to RV and about 7.0% was
      infected by RV during pregnancy. Among these infected women, intrauterine
      infection may have occurred and caused varied degree of hurt to fetus or resulted
      in serious congenital rubella syndrome (CRS). These findings suggest that RV IgG
      and IgM should be monitored repeatedly during pregnancy in order to prevent the
      development of CRS and assure aristogenesis.

PMID- 12411034
TI  - Study on the relationship between opioid receptors and fetal distress.
AB  - OBJECTIVE: To evaluate the role of opioid receptors in the fatal distress.
      METHODS: Pregnant near-term rabbits were given an intravenous dose of normal
      saline solution or the opiate antagonist beta-FNA and ICI and then asphyxiated.
      The rabbit fetus were delivered by cesarean section and evaluated for
      respiration, heart beat, color, muscle tone, and response to stimulation at 1, 5,
      10, 15, and 30 minutes of age. RESULTS: The FNA-treated pups (6.8 +/- 1.7) and
      the ICI-treated pups (4.9 +/- 0.7) had significantly better scores than the
      saline-treated pups (2.5 +/- 1.1) and the fetal distress group (2.1 +/- 1.0, P <
      0.01 and P < 0.05); there was no statistical difference between the saline group
      and the non treated pups (P > 0.05). The Apgar scores in ICI group, saline group,
      and fetal distress group were significantly decreased than that in control group
      (P < 0.01 and P < 0.05); Scores of all five subjects could be raised markedly in
      FNA group, there was no significant difference in the FNA-treated pups and the
      control group (P > 0.05). CONCLUSIONS: These results suggested that both mu- and
      delta- receptors participated in conducting the endogenous opioid peptides
      effect, it was associated with the pathophysiological changes in fetal distress;
      mu- receptor was much more important between the two.

PMID- 12411035
TI  - Clinical study on labor pain relief using the combined spinal-epidural analgesia
      and inhaling nitrous oxide.
AB  - OBJECTIVE: To study the pain relief effectiveness of the combined spinal-epidural
      analgesia (CSEA) and the inhalation of nitrous oxide, and the influences on the
      mothers and infants. METHODS: The 300 cases of pregnant women were randomly
      divided into 3 groups: CSEA group, nitrous oxide group and control group. The
      nitrous oxide group was that pregnant women inhaled nitrous oxide premixed with
      oxygen (50%:50%), the pregnant women of the CSEA group were injected fentanyl and
      bupivacaine in the subarachnoid and epidural space, analgesic was not used in the
      control group. The degree of labor pain, duration of the labor, way of delivery,
      bleeding volume, rate of anoxia of newborn, blood gas analysis to maternal radius
      artery and fetal umbilical blood among 3 groups were observed. RESULTS: The
      effect for analgesia labor of the CSEA group was much better than that of the
      nitrous oxide group (P < 0.01). In the first stage of labor and total stage of
      labor, the CSEA group was shorter than the others (P < 0.05), but there was no
      difference between the nitrous oxide group and the control group (P > 0.05). In
      the second stage of labor, the 3 groups were alike to each other. The bleeding
      volume of caesarean section (373 +/- 77) ml in the nitrous oxide group was much
      more than the other 2 groups, there was no difference between the CSEA group (259
      +/- 78) ml and the control group (239 +/- 89) ml. The rate of obstetric forceps
      of CSEA group was higher than the control group (P < 0.01), and the rate of
      caesarean section of the nitrous oxide group was much higher than the CSEA group.
      The blood gas analysis to maternal radius artery and fetal umbilical blood and
      the rate of anoxia of newborn of 3 groups revealed no significant difference.
      CONCLUSIONS: The effectiveness of the combined spinal-epidural analgesia CSEA for
      analgesia labor is confirmed and has rarely side-effect, and it can be the first
      choice, and the inhalation of nitrous oxide can safely provide effective labor
      analgesia, too.

PMID- 12411036
TI  - Clinical analysis of 4 cases of juvenile granulosa cell tumor of the ovary.
AB  - OBJECTIVE: To review the diagnosis, treatment and prognosis of juvenile granulosa
      cell tumor of the ovary (JGCT). METHODS: To review four patients with JGCT
      treated in Peking Union Medical College Hospital from 1983 to 2002. RESULTS: JGCT
      is rare and most of the patients are adolescent or children. Solid pelvic mass
      with ascites and pleural effusion were mainly clinical feature. The levels of
      estrogen of the four patients were normal. Diagnoses were made by pathology. All
      4 patients were at stage I and treated with surgery and combined chemotherapy.
      Two patients with high mitotic index progressed and died after 10 and 14 months,
      and the others without high mitotic index obtained a complete remission for 25
      and 32 months. CONCLUSIONS: The diagnosis of JGCT is made by pathology
      definitely. The prognosis is poor when patient has high mitotic index.
      Cytoreductive surgery is the treatment of choice and combination chemotherapy may
      be helpful to improve the prognosis of JGCT.

PMID- 12411037
TI  - Tissue array technique for p53 expression in human ovarian neoplasms.
AB  - OBJECTIVE: To investigate the expression of p53 in human ovarian neoplasms by
      tissue array technique. METHODS: The expression of p53 protein in various ovarian
      tissues was studied by tissue array and immunohistochemistry. RESULTS: The
      expression rate of p53 was 33% in ovarian cancers. There were no expressions in
      normal ovarian tissues, benign ovarian neoplasms and borderline ovarian neoplasms
      (P < 0.005). p53 expression was not associated with age of patients and grade of
      differentiation (P > 0.05) while p53 expression was associated with tissue types
      (P < 0.05). CONCLUSION: The expression rates of p53 in ovarian cancers were
      obviously increased.

PMID- 12411038
TI  - Cyclooxyenase-2 expression in endometrium carcinoma.
AB  - OBJECTIVE: To investigate the expression of cyclooxyenase-2 (COX-2) in
      carcinogensis and development of endometrium carcinoma. METHODS: Immunostainings,
      westernblotting and quantitve reverse transcription-polymerase chain reaction (RT
      PCR) assay were utilized to measure levels of protein and mRNA expression of COX
      2 in following five study groups: 25 cases with proliferative phase, 25 cases
      with secretory phase, 25 cases with endometritis, 23 cases with atypical
      proliferative phase and 34 cases with endometrium carcinoma. RESULTS: COX-2
      expression of both RNA and protein in patients with endometrial carcinoma was
      higher significantly than patients with proliferative phase, secretary phase,
      endometritis, atypical proliferate phase. Immunostaining score was 5.46 +/- 0.12
      vs 3.20 +/- 0.18, 4.78 +/- 0.12, 6.10 +/- 0.25, 8.70 +/- 0.93, average absorbent
      value was 0.75 +/- 0.23 vs 0.41 +/- 0.45, 0.56 +/- 0.31, 1.10 +/- 0.56, 1.46 +/-
      0.41; concentration of mRNA [(93 +/- 8) vs (65 +/- 11), (79 +/- 6), (299 +/- 11),
      (493 +/- 30) fpg/ micro g respectively]. Successively the expression of COX-2 in
      atypical proliferation group was higher than normal endometrial and endometritis
      group. The expression in proliferative phase group was higher significantly than
      secretory phase group (P < 0.05). CONCLUSION: COX-2 may play an important role in
      the development of endometrial carcinoma.

PMID- 12411039
TI  - Decreasing bleeding effect of transamin on the induced abortion.
AB  - OBJECTIVE: To confirm the decreasing bleeding effect of transamin on the induced
      abortion for the early pregnancy with more than two months. METHODS: A total of
      120 women are divided into two groups (60 pairs) based on the pelvic examination
      and the size of embryo measured by B ultrasound. Those women in the treated group
      (n = 60) were administed Transamin 1 g/20 ml (iv for 5 minutes) 30 minutes before
      operation; control group (n = 60) were given 5% glucose and saline 20 ml (iv for
      5 minutes) 30 minutes before operation. RESULTS: There wasn't any singnificant
      difference (P > 0.05) between the two groups in the patient's age, pregnancy age,
      parities, the cavity volume of uterine, hemoglobin and blood platelet count. The
      bleeding volume was (51.6 +/- 17.2) ml for the treated group and (63.3 +/- 17.1)
      ml for the control group (P < 0.05). CONCLUSIONS: Transamin has effective
      hemostasis during the induced abortion for the early pregnancy with > 2 months.
      It could decrease the volume of bleeding during the operation and benefit for
      patients recovering.

PMID- 12411040
TI  - [The relationship between donor TNFalpha - 308 (G/A) genotype and recipient acute
      GVHD in allo-BMT].
AB  - OBJECTIVE: To study the relationship between donor TNFalpha - 308 (G/A) genotype
      and recipient acute graft versus host disease (aGVHD). METHODS: TNFalpha - 308
      (G/A) and TNFalpha - 308 (G/G) genotypes were analyzed by DHPLC and DNA sequence
      in twenty-one degree III/IV (III/IV) aGVHD patients, and twenty-eight degree 0/I
      (0/I) aGVHD patients. Serum TNFalpha levels were determined by ELISA. RESULTS:
      The frequency of TNFalpha - 308 (G/A) genotype was significantly higher in III/IV
      aGVHD patients than in 0/I aGVHD patients (8/21 vs 1/28) (P < 0.05); and so did
      for higher serum TNFalpha levels (P < 0.05). TNFalpha levels were higher in
      III/IV aGVHD patients than in 0/I aGVHD patients in TNFalpha - 308 (G/G) patients
      (P < 0.01). CONCLUSION: TNFalpha - 308 (G/A) is positively related to serum
      TNFalpha levels and most likely contributes to high risk for III/IV aGVHD.

PMID- 12411041
TI  - [Expression of Mdr1 gene in a murine bone marrow transplantation model].
AB  - OBJECTIVE: To investigate the expression of mdr1 gene in hematopoietic cells of a
      murine bone marrow transplantation model and to explore the feasibility of
      transferring mdr1 gene into hematopoietic cells to pro-vent myelosuppression from
      chemotherapy. METHODS: mdr1 gene was transferred into hematopoietic cells of
      murine bone marrow by retrovirus vector. The expression and function of mdr1 gene
      in vivo was tested in a murine bone marrow transplantation model. RESULTS: (1)
      mdr1 gene was successfully transferred into murine MNC, the transduction rate was
      35%. (2) mdr1 gene transferred murine bone marrow transplantation model was
      established successfully by scheduled-bone marrow transplantation method. (3) In
      1 approximately 5 months period, stable and effective expression of mdr1 gene
      could be detected in hematopoietic cells of the recipient mouse, the percentage
      of mdr1 gene expression cells in recipient's hematopoietic cells decreased
      monthly to 8.0%, 8.0%, 7.5%, 4.0% and 3.0%. (4) mdr1 expression hematopoietic
      cells had efficient resistance to chemotherapy. CONCLUSION: It is an effective
      approach to transfer mdr1 gene into hematopoietic cells for preventing
      myelosuppression in chemotherapy.

PMID- 12411042
TI  - [Allogeneic peripheral blood stem cell transplantation in the treatment of
      hematologic malignancies].
AB  - OBJECTIVE: To investigate the application of allogeneic peripheral blood stem
      cell transplantation (allo-PBSCT) in the treatment of hematologic malignancies.
      METHODS: Between October 1995 and August 2001, fifty-one patients with
      hematologic malignancies (median age 34 years, range 5.5 approximately 52 years)
      received allo-PBSCT from HLA-identical (50) or 1-antigen mismatched sibling
      donors with conditioning regimens of TBI + CY or modified BU/CY2. Thirty-one
      patients were acute leukemia (AL) (15 in CR(1), 7 in CR(2) or greater, 10 in
      relapse including 2 relapse after allo-BMT and the other one never achieved
      remission); 12 chronic myeloid leukemia (CML) (CP 5, AP 2, BC 4 and relapse after
      allo-BMT 1); 7 MDS (RAEB 1, RAEB-T 1, AL secondary to MDS 5); Burkitt's lymphoma
      1. A combination of cyclosporine and methotrexate was administered for GVHD
      prophylaxis. RESULT: All patients were engrafted. The median time (range) to
      neutrophil >/= 0.5 x 10(9)/L and platelet >/= 20 x 10(9)/L was 14 (10
      approximately 20) and 11 (7 approximately 45) days post-transplant, respectively.
      Grade II approximately IV acute GVHD occurred in 20/51 (39%) and grade III
      approximately IV aGVHD in 2 patients. Clinical chronic GVHD was diagnosed in 23
      of 44 (52%) evaluable patients. Fourteen patients died: 8 died of transplant
      related complications, 6 of relapse. Thirty-seven patients are alive with a
      median follow-up of 399 (75 approximately 2 176) days, and among them 34 are in
      continuous complete remission, the other 3 relapsed. The 2-year probability of
      overall survival, disease-free survival (DFS) and relapse is 64%, 61% and 24%,
      respectively. CONCLUSION: Allogeneic PBSCT is safe for both donors and
      recipients, and results in a rapid and stable engraftment without increase in
      incidence or severity of acute GVHD.

PMID- 12411043
TI  - [Promotion of post BMT hematopoiesis reconstitution by cotransplantation of IL-3
      transfected marrow stromal cells in mice].
AB  - OBJECTIVE: To explore whether bone marrow stromal cell line QXMSC1 (H-2(d))
      engineered to secrete IL-3 (QXMSC1 IL-3) can improve the hematopoiesis post
      allogeneic bone marrow transplantation (BMT) in mice. METHODS: The stromal cell
      line QXMSC1 IL-3 was established by transfecting QXMSC1 (H-2(d)) cell with a
      recombined retrovirus vector PL3SN containing mice IL-3 gene cDNA. Lethally
      irradiated mice C57BL/6 (H-2(b)) were transplanted with T cell depleted
      allogeneic bone marrow (BALB/c, H-2(d), 1 x 10(7)/mice) and QXMSC1 IL-3 cells (5
      x 10(5)/mice). The numbers of RBC and WBC in peripheral blood were counted 20 and
      40 days after bone marrow transplantation. The marrow nucleated cells, CFU-S, CFU
      GM, CFU-E and CFU-GEMM yields were measured in recipient mice. RESULT: QXMSC1 IL
      3 cells could stably secrete IL-3 and increase the peripheral RBC and WBC counts
      as well as the number of marrow nucleated cells and CFU-GM, CFU-E, CFU-GEMM
      yields. CONCLUSION: Cotransplantation of QXMSC1 IL-3 cells with T cell depleted
      marrow grafts improve hematopoiesis post allogeneic BMT in mice.

PMID- 12411044
TI  - [Effect of Ly49A transfected mouse spleen cells on graft versus host disease and
      graft versus leukemia after haploidentical allogeneic bone marrow transplantation
      in mice].
AB  - OBJECTIVE: To observe the effect of Ly49A transfected mouse spleen cells on graft
      versus host disease (GVHD) and graft versus leukemia (GVL) effect after
      haploidentical allogeneic bone marrow transplantation in mice. METHODS: Ly49A
      gene was transfected into spleen cells of C57BL/6 mice by retrovirus and the
      expression rate of Ly49A receptor was evaluated by flow cytometry. The murine
      model of haploidentical allogeneic acute GVHD was established by using C57BL/6(H 
      2b) mouse as donor, and (BALB/c x C57BL/6) F1(H - 2d/b) (CB(6)F(1)) mouse as the
      recipient which was injected EL9611 cells before transplantation. After
      irradiation (TBI, (60)Co 10.5 Gy), the recipient received mixed graft of spleen
      cells and bone marrow cells to establish a GVHD model. The effects of Ly49A
      transfected spleen cells on GVHD and GVL post haploidentical allogeneic bone
      marrow transplantation were detected with this model. RESULTS: The expression
      rate of Ly49A receptor was (42.20 +/- 4.87)%, (18.67 +/- 2.48)% and (18.73 +/-
      3.82)% for pLXSN-Ly49A, pLXSN transfected and untransfected spleen cells
      respectively. Among haploidentical allo-BMT (C57BL/6(H - 2b)-->CB6F1(H - 2d/b))
      groups, the survival time was (7.80 +/- 3.36) days for irradiation group; (21.70
      +/- 2.87) days for cyclophosphomide therapy group; (29.40 +/- 6.43) days for
      mixed bone marrow cells and spleen cells transplantation group; (29.10 +/- 7.39)
      days for mixed bone marrow cells and pLXSN transfected spleen cells
      transplantation group and (45.00 +/- 12.38) days for mixed bone marrow cells and
      Ly49A transfected spleen cells transplantation group, which was much longer than
      that of any other groups (P = 0.000). CONCLUSION: The Ly49A transfected spleen
      cell transplantation could alleviate GVHD and retain GVL effect in the acute GVHD
      model post haploidentical allo-BMT.

PMID- 12411045
TI  - [Study of in vitro expansion and differentiation into neuron-like cells of human
      umbilical cord blood mesenchymal stem cells].
AB  - OBJECTIVE: To explore the isolation, purification and expansion of human
      umbilical cord blood mesenchymal stem cells (MSCs) into neuron-like cells in
      vitro. METHODS: Human cord blood samples were obtained sterilely with 20 U/ml
      preservative-free heparin. MSCs were isolated by lymphocyte separation medium
      (density 1.077 g/ml), and purified and expanded with Mesencult trade mark medium.
      The surface antigen expression of MSCs was detected by flow cytometry. The
      passage 2, 5 and 8 of the expanded MSCs were induced to differentiate to neuron
      like cells. Specific markers and structures were detected by immunohistochemistry
      and histochemistry methods. RESULTS: The number of MSCs increased two- to three
      fold with each expanded passage. 6.6 x 10(5) primary MSCs were expanded ten
      passages to reach a number of 9.9 x 10(8), and was increased about 1.5 x 10(3)
      fold. Flow cytometry showed that MSCs did not express antigens CD(34), CD(11a)
      and CD(11b), but expressed strongly CD(29) and weakly CD(71), which was identical
      to human bone marrow-derived MSCs. 70% cells exhibited typical neuron-like
      phenotype after induction. Immunohistochemistry staining showed that all of the
      induced different-passage MSCs expressed neurofilament (NF) and neuron-specific
      enolase (NSE). Special Nissl body was found by histochemistry. CONCLUSION: MSCs
      in human umbilical cord blood can expand in vitro and differentiate into non
      mesenchymal cells.

PMID- 12411046
TI  - [Effect of CD(40) on the in vitro biological behavior of malignant B
      lymphocytes].
AB  - OBJECTIVE: To explore the effect of recombinant human soluble CD(40) ligand
      (rhsCD(40)L) and CD(40)L cDNA transfected cell (CD(40)L-TC) on the behavior of
      malignant B lymphocytes, and investigate the possibility of using rhsCD(40)L as a
      new bio-factor in tumor immunotherapy. METHOD: rhsCD(40)L and CD(40)L-TC were
      obtained by gene recombinant techniques. Multiple myeloma cell lines, XG2, XG7,
      U266 and 8226, B-lymphoma cell lines, Raji and Daudi were selected to detect
      responses to rhsCD(40)L and CD(40)L-TC stimulation. Cell growth curve, cell
      cycle, early apoptosis as well as membrane surface molecules on these cell lines
      were analyzed. RESULTS: (1) The expression levels of CD(40) molecule on malignant
      B lymphocytes showed heterogeneity. High level of CD(40) on XG2, moderate on
      8266, Raji, and Daudi, and no expression on U266 and XG7 were detected. The
      rhsCD(40)L stimulation gave rise to a typical homo-type cell aggregation of XG2
      and Daudi. Meanwhile, at least 10 to 20 of CD(40)(+) XG2 or CD(40)(+) Daudi cells
      were found adherent to one pre-treat ed CD(40)L-TC. (2) Co-incubation with
      rhsCD(40)L (5 micro g/ml), or CD(40)L-TC (tumor cell: CD(40) = 5:1) resulted in a
      significant inhibition of in vitro cell growth of XG2, Raji and Daudi, with G(1)
      phase arrest for XG2 and G(2)-phase for Raji and Daudi. These two kinds of CD(40)
      stimulators induced XG2, Raji and Daudi cells to apoptosis in vitro. The
      apoptotic rate for XG2 was 23.3% (rhsCD(40)L) and 18.8% (CD(40)L-TC), for Daudi
      14.2% and 15.9%, and for Raji 11.6% and 8.9% respectively. (3) Phenotype analysis
      showed that CD(95) expression levels were significantly up-regulated on XG2, Raji
      and Daudi after stimulation with rhsCD(40)L or CD(40)L-TC, and CD(80) and CD(18)
      expression levels on Raji were respectively enhanced and decreased. CONCLUSION:
      The abilities to directly inhibit XG2, Daudi and Raji cell proliferation, to
      induce themapoptosis, as well as to up-regulate immune co-stimulator molecule
      CD(80) expression on Raji cells would make rhsCD(40)L a potential bio-factor for
      tumor immuno-therapy.

PMID- 12411047
TI  - [Clinical and cytogenetic studies of hematological malignancies with isolated
      trisomy 11].
AB  - OBJECTIVE: To evaluate the association between isolated trisomy 11 and the
      clinical, hematological, immunological, prognostic aspects in hematological
      malignancies. METHODS: Bone marrow cell cytogenetic analysis was performed by
      direct method and/or 24 h culture method. RHG banding was used for karyotype
      analysis. Immunophenotype analysis was carried out by flow cytometry. Ten
      patients with acute myeloid leukemia (AML) were treated with HA regimen
      chemotherapy and followed up. RESULTS: The isolated trisomy 11 was found in 11 of
      1 * ! 763 hematological malignancies cases (0.6%). The diagnoses included 10 AML
      (6 M(2), 2 M(5), 1 M(1), 1 M(4)), and 1 myelodysplastic syndromes. Ten of them
      have no hepatosplenomegaly. The immunophenotypical analysis of leukemia cells
      showed positive for CD(13), CD(33) and CD(34) in 5 cases. Follow-up data were
      available in 10 cases. The complete remission rate was 40% with a median survival
      of 10 months. CONCLUSION: The isolated trisomy 11 was mainly seen in AML,
      especially in M(2) subtype. Their prognosis was poor.

PMID- 12411048
TI  - The role of B7 molecules in T cell anergy.
AB  - OBJECTIVE: To explore the role and mechanism of B7 molecules in T cell anergy.
      METHODS: Anti-B7-1 (CD(80)) and anti-B7-2 (CD(86)) monoclonal antibodies were
      used to induce T cell anergy. T cell proliferation were assayed by mixed
      lymphocyte reaction (MLR) with (3)H-TdR incorporation, and cytokine mRNA
      transcripts were analyzed with reverse transcriptase-polymerase chain reaction
      (RT-PCR). B7-transfected-CHO cells were used as artificial antigen presentation
      cells (APCs) in MLR to exclude the effects of other costimulatory molecules.
      RESULTS: MLR results showed that the proliferation of T cells was inhibited to
      various extents by anti-CD(80) or anti-CD(86) monoclonal antibody, the effect of
      anti-CD(86) antibody was greater than that of anti-CD(80) antibody, and the
      proliferation was totally blocked when the two were used together. The results of
      RT-PCR demonstrated that IL-2 and IFN-gamma mRNA transcripts decreased whereas IL
      4 mRNA transcripts increased in T cell after treatment with anti-B7 antibo-dies
      for 24 hours. In MLR with artificial APC, signal one (DR7) alone could stimulate
      T cell proliferation at a certain threshold intensity. Costimulator B7-1 molecule
      could help signal one in T cell proliferation. This effect was blocked by anti
      CD(80). CONCLUSION: B7 molecules play an important role in T cell immune
      response. Blockade of B7 family resulted in T cell anergy. The role of CD(86) may
      be more important than that of CD(80). The conversion of cytokine profile from
      Th1's to Th2's reflected that anergetic T cells were differentiated into Th2
      cells by anti-B7 suggesting that anergetic blockade of costimulator molecules may
      be one of the mechanisms of T cell.

PMID- 12411049
TI  - Expression of B7 costimulator in eight human malignant hematological cell lines
      and its significance.
AB  - OBJECTIVE: To explore the expression of B7 co-stimulator in human malignant
      hematological cell lines and its significance. METHODS: Amplified and purified
      plasmid DNA was transfected by liposome and detection of B7 gene expression by
      flow cytometry and RT-PCR. RESULT: Eight human malignant hematological cell lines
      U937, K562, CEM, Daudi, GM, PEER, Jurkat, Raji express high level of HLA
      molecules, low or undetectable level of B7-1 gene, and high level of B7-2 gene.
      Expression level of B7-1 gene was enhanced after B7-1 transfection. T cell
      expressed high level of IL-2 mRNA after B7-1 transfection. CONCLUSION: Multiple
      human malignant hematological cell lines express low or undetectable level of B7
      1 gene, suggesting that B7-1 plays a critical role in tumor immunity.

PMID- 12411050
TI  - BU-CTX(2) as conditioning regimen for allogeneic hematopoietic stem cell
      transplantation in sixty patients with leukemia.
AB  - OBJECTIVE: To evaluate the long-term outcome of 60 leukemia patients undergoing
      allogeneic hematopoietic stem cell transplantation (allo-HSCT) prepared with
      busulphan-cyclophosphamide (BU-CTX(2)) conditioning regimen. METHODS: From April
      1994 to August 2000, 60 leukemia patients (35 male, 25 female; median age 32
      years old), including 20 acute myeloid leukemia (AML, CR(1) n = 19, CR(2) n = 1),
      15 acute lymphocytic leukemia (ALL, CR(1) n = 8, CR(2) n = 6, CR(3) n = 1), and
      25 chronic myeloid leukemia (CML, CP(1) n = 24, CP(2) n = 1) received allogeneic
      hematopoietic stem cells from HLA-identical siblings (n = 53), 1-locus mismatched
      siblings (n = 4), or HLA-identical unrelated donor (n = 3). BU-CTX(2) was used as
      conditioning regimen. All patients received cyclosporine A and either
      methotrexate (n = 54) or methylprednisolone (n = 6) for graft-versus-host disease
      (GVHD) prophylaxis. RESULTS: All 60 patients got sustained engraftment. Acute
      GVHD (aGVHD) occurred in 22 patients (36.7%), while the incidence of aGVHD was
      48.0% for the CML, 30.0% for the AML and 26.7% for the ALL patients. Thirty-eight
      patients are still alive in complete remission with a median follow-up of 30 (12
      approximately 84) months and 22 died. The main causes of death were aGVHD in 3,
      CMV-IP in 7, and relapse in 11 patients. The remaining one died of pulmonary
      infection. Among 11 patients who died of relapse, 8 were ALL relapsed in the
      early posttransplant stage. All 4 long-term survivors of ALL developed chronic
      GVHD. The probability of DFS at 3 year for CML, AML and ALL patients was 80.0%,
      70.0% and 26.7%, respectively. CONCLUSION: BU-CTX(2) is an effective conditioning
      regimen for patients with AML and CML, resulting in a low relapse and high long
      term survival rate. However, it is not effective enough for patients with ALL,
      because of a higher incidence of relapse.

PMID- 12411051
TI  - Study on the expression of IkappaB-alpha protein in TNF-alpha induced apoptosis
      of U937 cells.
AB  - OBJECTIVE: To investigate the TNF-alpha induced apoptosis of U937 cells, the
      expression, degradation and subcellular localization of IkappaB-alpha, and its
      degradation mechanism. METHOD: Changes and subcellular loca-lization of IkappaB
      alpha were observed by fluorescence microscopy, expression and degradation of
      IkappaB-alpha protein with N-tosyl-L-phenylalanylchloromethyl ketone (TPCK
      protease inhibitor) blocking test and apoptosis of U937 cell by flow cytometry.
      RESULTS: (1) immunolfluorescence assay showed that IkappaB-alpha localized in
      cytoplasm only. (2) The level of IkappaB-alpha protein was downregulated after
      TNF-alpha stimulation, flow cytometry also confirmed the downregulation. (3) The
      downregulation of IkappaB-alpha protein levels in TNF-alpha induced apoptosis was
      partially inhibited by TPCK. (4) The apoptosis rate of U937 cells induced by TNF
      alpha was (60.73 +/- 1.61)%. CONCLUSION: (1) Degradation of IkappaB-alpha protein
      during TNF-alpha induced apoptosis of U937 cells suggested the activation of NF
      kappaB. (2) TPCK sensitive protease plays an important role in the degradation of
      IkappaB-alpha protein. (3) TPCK sensitive protease also involved in the apoptosis
      of U937 cells induced by TNF-alpha.

PMID- 12411052
TI  - WT1 downregulation during K562 cell differentiation and apoptosis induced by
      bufalin.
AB  - OBJECTIVE: To study the change of WT1 gene expression during human leukemic K562
      cell differentiation and apoptosis induced by bufalin. METHODS: Cell viability
      was determined by trypan blue exclusion, cell differentiation and apoptosis by
      nitro blue tetrazolium (NBT) reduction test, morphology and flow cytometry,
      expression of WT1 protein by Western blot analysis, and expression of WT1 mRNA by
      reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS: (1) The cell
      proliferation was inhibited by bufalin and the IC(50) at 24, 48, 72 h were 0.026,
      0.032 and 0.006 micro mol/L, respectively. (2) Bufalin induced K562 cell
      differentiation towards macrophage/monocyte within concentration from 0.01 to
      0.05 micro mol/L and apoptosis at higher than 0.026 micro mol/L. (3) The
      expression of WT1 protein and mRNA were downregulated by bufalin in the initial
      stage of differentiation and apoptosis induced by bufalin. CONCLUSION: K562 cell
      differentiation and apoptosis induced by bufalin might relate to the
      downregulation of WT1 expression.

PMID- 12411053
TI  - Effects of As(2)O(3) on BCR-ABL protein level and signal transduction in CML
      cells.
AB  - OBJECTIVE: To explore the effects of As(2)O(3) on BCR-ABL protein level and
      signal transduction in chronic myeloid leukemia (CML) cells. METHODS:
      Immunoprecipitation, protein tyrosine kinase (PTK) activity assay, real-time
      Taqman quantitative PCR and Western blot were used. RESULTS: As(2)O(3)
      downregulated BCR-ABL protein and STAT1 protein of CML mononuclear cells in the
      concentrations of 1.0 approximately 2.0 micro mol/L and 0.5 approximately 2.0
      micro mol/L after 48 h exposure, respectively. However, p27 protein level was not
      affected. The PTK activity of BCR-ABL protein was also mildly decreased in CML
      monouclear cells at 60 h. The bcr-abl mRNA level remained unchanged. CONCLUSION:
      As(2)O(3) downregulats BCR-ABL protein, STAT1 protein, BCR-ABL signal
      transduction and PTK activity in CML cells.

PMID- 12411054
TI  - Quantification of bcr/abl mRNA expression level in leukemia cells by FQ-RT-PCR.
AB  - OBJECTIVE: To establish a fluorogenic probe quantitative RT-PCR (FQ-RT-PCR)
      method for detection of bcr/abl mRNA fusion gene expression level in leukemia
      cells, and provide a useful tool for leukaemia diagnosis and minimal residual
      disease inspectation. METHOD: The conventional RT-PCR was used to amplify bcr/abl
      gene from cultured K562 cells, the quantitative standard template was constructed
      with A-T clone method. The fluo-rogenic quantitative RT-PCR method by using
      Applied Biosystems 7700 Sequence Detector for detecting the expression of bcr/abl
      fusion gene was successfully. The sensitivity, stability and repetitiveness of
      this method was determined. The peripheral blood samples from 14 CML patients,
      one of whom before and one month after bone marrow transplantation (BMT) and 4
      cases of ALL in the early stages were detected. RESULTS: The sensitivity of FQ-RT
      PCR for detecting bcr/abl fusion gene was about 10(-5) micro g RNA from K562 cell
      and 10 copies recombined plasmid. The repetition CT value (cycle threshold) and
      the coefficient variation (CV) among tubes and batches were 2.0% and 3.7%,
      respectively. The median bcr/abl fusion gene expression level of 14 CML patients
      was 5.15 x 10(4) copies/ micro g RNA. The products analyzed by electrophoresis
      showed that 11 cases were b2a2 and 3 cases b3a2. 1.2 x 10(5) copies/ micro g RNA
      in one CML patient before BMT was changed to 2.3 x 10(3) copies/ micro g RNA one
      month after BMT. B2a2 was observed in one of the four (25.0%) patients with ALL,
      and its level of expression was 8.2 x 10(5) copies/ micro g RNA. CONCLUSION: The
      established FQ-RT-PCR method is sensitive, specific, reliable, accurate and good
      at repetitiveness. The results expressed in copies were easy for evaluation and
      comparation. Two different bcr/abl fusion gene form - b2a2, b3a2 can be detected
      by the method. It can be widely applied to diagnosis and detection of minimal
      residual disease for CML and some ALL patients.

PMID- 12411055
TI  - Studies of WT1 gene expression in leukemia patients.
AB  - OBJECTIVE: To explore the expression of WT1 gene in leukemia patients and its
      clinical implications. METHODS: Expression of WT1 mRNA was detected in two
      leukemia cell lines (K562 and HL-60), 49 acute leukemia (AL) patients, 33 chronic
      myeloid leukemia (CML) patients and 25 healthy subjects by reverse trans-criptase
      nested polymerase chain reaction (RT-Nested PCR). RESULTS: WT1 gene was expressed
      in all subtype of AL including K562 and HL-60 cell lines, 21/29 newly diagnosed
      and relapsed AL patients, 1/20 complete remission (CR) AL patients, 15/18 CML
      blastic crisis patients, 1/5 CML patients in accelerated phase, and 1/10 CML
      patients in chronic phase. WT1 gene was undetectable in 25 healthy subjects. The
      expression level of WT1 gene was related to the prognosis of AL, patients with
      relative level >/= 1.0 had lower CR rates and disease-free survival. For CML
      patients, WT1 gene expression was associated with the clinical phase, it
      increased with disease progressed. CONCLUSION: WT1 gene expression is associated
      with pathogenesis of leukemia. It is a prognostic factor and a marker for the
      detection of minimal residual disease in AL and may used as an indicator for
      diagnosing CML blastic crisis.

PMID- 12411056
TI  - Tumor antigen peptides from HL-60 cells induce specific immune response.
AB  - OBJECTIVE: To prepare tumor antigen peptides from HL-60 cells and to induce
      specific immune response. METHODS: HL-60 antigen peptides were obtained using
      techniques including freezing and thawing, heat precipitation and acid
      precipitation. The stimulating effect of the in vitro Hsp70 binding HL-60
      peptides on PBMC and the proliferation of stimulated PBMC were observed by T cell
      activation test. The cytotoxicity of proliferated PBMC is detected by incubating
      HL-60 cells or K562 cells with PBMC respectively. RESULTS: The obtained tumor
      antigen peptides were a peptides mixture. The mixed peptides could activate PBMC
      and cause PBMC proliferation in vitro after presented by Hsp70. The proliferated
      PBMC showed specific cytotoxicity to HL-60 cells but not to K562 cells.
      CONCLUSION: The method for preparing of human leukemia tumor antigen peptides
      used in this paper is simple and easy; the obtained antigen peptides can induce
      specific immune response in vitro.

PMID- 12411057
TI  - The mechanism of STI571 inducing apoptosis of K562 cells.
AB  - OBJECTIVE: To investigate the mechanism of STI571 inducing apoptosis of K562
      cells which express P210(BCR/ABL). METHODS: Apoptosis was analyzed by Annexin
      V/PI, DioC6 [3] staining, DCFH-DA staining, DNA-PI staining and DNA ladder.
      Western blot was used to analyse mitochondrial and cytosolic cyto C, Bcl-X(L),
      caspase-3, actin protein and the level of tyrosine phosphorylation. RESULTS:
      After exposure to STI571, K562 cells were induced to apoptosis. Tyrosine
      phosphorylation level of P210(BCR/ABL) and Bcl-X(L) was decreased. Caspase-3 was
      activated and there was an cytosolic accumulation of cyto C. CONCLUSION: STI571
      could rapidly decrease the tyrosine phosphorylation level of P210(BCR/ABL). The
      signal pathway mediated by the cytosolic translocation of mitochondrial cyto C
      was one of the mechanisms that STI571 inducing apoptosis. STI571 was an effective
      gene targeting therapeutic agent.

PMID- 12411058
TI  - Expression and clinical implications of the soluble drug resistance-related
      calcium-binding protein (sorcin) gene in leukemia patients.
AB  - OBJECTIVE: To study the relationship between the expression of soluble drug
      resistance-related calcium-binding protein (sorcin) gene and the clinical
      multidrug resistance in acute leukemia (AL). METHODS: A semi-quantitative reverse
      transcriptase-polymerase chain reaction (RT-PCR) was used to investigate the
      transcription levels of the human sorcin gene in 95 AL patients and 27 controls.
      RESULTS: Sorcin gene expression was significantly higher in AL patients than in
      normal contrls (P < 0.001), and higher in relapsed/refractory acute myeloid
      leukemia (AML) patients than in those newly diagnosed or in complete remission.
      Sorcin gene overexpression was significantly lower in non-resistant patients than
      in resistant ones (P < 0.001). CR rates of these two groups were 20.0% and 80.0%,
      respectively. Sorcin gene expression was higher in AML-M(5) patients than M(2),
      M(3), M(4) patients. CONCLUSION: Sorcin gene overexpression is significantly
      associated with clinical multidrug resistance and prognosis, it is one of the
      indicators for predicting prognosis of AL patients.

PMID- 12411059
TI  - Study on the relationship between NB4 cell apoptosis induced by tanshinone IIA
      and the cell mitochondrial transmembrane potential.
AB  - OBJECTIVE: To explore the relationship between NB4 cell apoptosis induced by
      tanshinone IIA (TanIIA) and the cell mitochondrial transmembrane potential
      (DeltaPsim). METHODS: NB4 cells were treated with TanIIA, As(2)O(3), TanIIA plus
      1.0 micro g/ml CsA and As(2)O(3) plus 1.0 micro g/ml CsA, respectively.
      Morphological changes were observed under light microscope and transmission
      electron microscope. The percentages of sub-G(1) cells and DeltaPsim of cells
      doublely stained with PI and Rh123 were assayed by flow cytometry. RESULTS: The
      percentages of sub-G(1) cells after treatment with 1.0 micro g/ml and 2.0 micro
      g/ml TanIIA had no significant difference but was higher than that of 0.5 micro
      g/ml. After treatment with TanIIA, NB4 cells appeared the classical apoptotic
      morphology. The percentages of sub-G(1) cells were increased, while the DeltaPsim
      reduced (P < 0.01) and there was a linear correlation between them. The increment
      of sub-G(1) cell percentages and decrement of DeltaPsim induced by TanIIA were
      partly inhibited by CsA (P < 0.01). CONCLUSIONS: TanIIA can induce NB4 cells
      apoptosis through opening the mitochondrial permeability transition pore and
      reducing DeltaPSgr;m, and this effect could be inhibited by CsA.

PMID- 12411060
TI  - Effects of novel human chemokine-like factor 1 (CKLF1) on bone marrow
      hematopoietic stem cell/progenitor cell in vitro.
AB  - OBJECTIVE: To explore the effects of a novel human chemokine-like factor 1
      (CKLF1) on stem cell/progenitor cells. METHODS: Human bone marrow mononuclear
      cells were separated by Ficoll (1.077 g/ml), and cultured in suspension and
      semisolid colony culture. The effects of CKLF1 on CFU-GM and CFU-Mix were
      observed. RESULTS: The number of CFU-GM was significantly increased in 10 groups
      by addition of CKLF1 plasmid supernatant. The mean value was 234.81 +/- 98.71/1 x
      10(5) cells, 2.42 fold of control group (P < 0.05). The mean value of CFU-Mix in
      groups of negative control, CKLF1, PHA, GM-CSF and G-CSF were 82.00 +/- 20.25,
      105.76 +/- 36.70, 146.63 +/- 27.09, 143.33 +/- 60.23 per 1 x 10(5) cells,
      respectively, no statistical differences were seen between control and CKLF1
      groups. The CD(34)(+) cells were detected by FACS. The average percentage in the
      groups of normal control, CKLF1, PHA and GM-CSF were (0.75 +/- 0.62)%, (1.32 +/-
      0.87)%, (0.15 +/- 0.02)%, and (0.29 +/- 0.23)%, respectively. Compared with
      control, no significant differences were seen between each group (P > 0.05).
      CONCLUSION: Novel chemokine-like factor 1 can increase the proliferation of CFU
      GM, which indicated that CKLF1 could increase the proliferation of human bone
      marrow hematopoietic progenitor cells and colony formation.

PMID- 12411061
TI  - Clinical and experimental study of two cases of myelodysplastic syndrome with
      t(3; 5) (q25; q34) translocation.
AB  - OBJECTIVE: To report two myelodysplatic syndromes (MDS) patients with t(3; 5)
      (q25; q34). METHODS: Chromosome specimens were prepared by short-term culture of
      bone marrow cells. Karyotype analysis was performed by R banding technique,
      chromosome painting (fluorescence in situ hybridization, FISH) by using whole
      chromosome 3 and 5 probes in case 1. RESULTS: The clinical and hematological
      findings were compatible with diagnosis of MDS. Karyotype analysis showed that
      both patients had identical t(3; 5) (q25; q34) translocation. A reciprocal
      translocation between chromosomes 3q and 5q was proved by FISH in one patient.
      CONCLUSIONS: t(3; 5) translocation is a rare chromosome abnormality specifically
      associated with MDS and frequently displays trilineage dysplasia. Chromosome
      painting technique is a reliable tool for detecting this translocation.

PMID- 12411062
TI  - A preliminary study on the early diagnosis of myelodysplastic syndromes.
AB  - OBJECTIVE: To evaluate the four techniques for clonal analysis in the early
      diagnosis of myelodysplastic syndromes (MDS). METHODS: Four techniques for clonal
      analysis were performed in bone marrow samples from fifty patients with suspected
      MDS: (1) Conventional cytogenetics (CC) for clonal chromosomal abnormalities; (2)
      BrdU-sister chromatid differentiation (BrdU-SCD) for cell cycle analysis; (3)
      Fluorescence in situ hybridization (FISH) for trisomy 8; (4) PCR-SSCP for N-ras
      mutation. RESULTS: The diagnosis of forty-five patients was compatible with FAB
      criteria of MDS, the other five patients didn't fully meet the FAB criteria. They
      had either only one lineage dyspoiesis or no any obvious dysplastic features and
      two of them were diagnosed as suspicious refractory anemia (RA), one as anemia
      with hypercellular bone marrow and two as chronic aplastic anemia. The results of
      the four techniques performed in them showed that four patients had clonal
      karyotype abnormalities, two had prolonged cell cycle, three had trisomy 8 of
      different proportions, and one had N-ras mutation. Thus, they were all diagnosed
      as RA. CONCLUSION: The untypical MDS patients can be diagnosed early by
      examination with combining several clonal analysis techniques.

PMID- 12411063
TI  - The relationship between myelodysplastic syndromes and autoimmune disorders.
AB  - OBJECTIVE: To explore the relationship between the myelodysplastic syndromes
      (MDS) and autoimmune disorders (AID). METHODS: The clinical data of 117 MDS
      patients were reviewed. RESULTS: Nineteen (16.2%) of 117 MDS patients had AIDs.
      The commonest AID associated with MDS was rheumatoid arthritis (31.6%) and
      ulcerative colitis (26.3%). Compared with that in MDS patients without autoimmune
      disorders, the leukemic transformation rate was not increased in the MDS/AID but
      the median survival time was shorter in MDS/AID patients. CONCLUSION: MDS
      patients associated with autoimmune disorders may be an unfavorable factor for
      their prognosis.

PMID- 12411064
TI  - Complications and conversions in myeloproliferative disorders: an analysis of 356
      cases.
AB  - OBJECTIVE: To investigate the complications and conversions in myeloproliferative
      disorders (MPD). METHODS: Three hundred and fifty six patients with MPD were
      reviewed, including 78 with etiologic thrombocythemia (ET), 93 with primary
      myelofibrosis (MF), 185 with polythythemia vera (PV). The clinical observation,
      follow-up, analysis with SPSS statistic software were performed. RESULTS: Out of
      the 356 cases, 101 (28.5%) developed thromboembolic events, 81 (22.8%)
      hemorrhage, 60 (16.9%) hypertension, 20 (5.6%) coronary heart disease, 3 (0.8%)
      hemolysis and 1 (0.3%) gastrointestinal ulcer, 2 (0.6%) calculus and 1 (0.3%)
      bone marrow necrosis. Twenty four patients (6.7%) developed MF (9 in ET, 15 in
      PV), 2 (0.6%) erythrocytosis (1 in ET, 1 in MF), 3 (0.8%) thrombocythemia (all in
      PV), 5 (1.4%) acute leukemia (2 in ET, 3 in MF) and 1 (0.3%) multiple myeloma (in
      ET). Eleven cases (3.1%) died, 5 (1.4%) from acute leukemia, 2 (0.6%) fatal
      hemorrhages, 1 (0.3%) each myocardial infarction and infectious shock, 2 (0.6%)
      unknown causes. CONCLUSION: Embolism and bleeding were the main complications in
      MPD. Conversions among ET, MF and PV hematological malignancies could occur.

PMID- 12411065
TI  - [Meta-analysis on the relationship between children's intelligence and factors as
      iodine deficiency, supplement iodine and excessive iodine].
AB  - OBJECTIVE: To estimate the role and extent of iodine deficiency, iodine
      supplement and iodine excess on mental development of children. METHODS: Meta
      analysis was applied to study 128 independent items from 63 published and non
      published papers and reports. The standards of references collected included: age
      of sample declared by references was 5 - 15; belong to comparison study; children
      lived in iodine deficiency disorders (IDD) and iodine excess areas; no difference
      of social economic and culture development level between the study group and the
      control group. RESULTS: Sixty-seven percent and 79% of the reports mainly
      involved severe IDD areas respectively. Hunter test of each studies, i.e. iodine
      deficiency, iodine supplement and excessive iodine group had not discovered
      statistic difference at the level of alpha = 0.05. The weighted average ES of
      damage affecting on children's intelligence by iodine deficiency achieved 0.69,
      which was equivalent to a marked drop in 10.4 IQ points [95% confidence interval
      (CI): 9.9 - 10.9] when comparing with the children living under non-IDD. The
      weighted average ES of protective effect on children's intelligence by iodine
      supplement reached 0.81, which meant that the IQ of children born after
      correction of iodine deficiency increased 12.2 points (95% CI: 11.5 - 12.9) in
      comparison with those born at least one year before the correction of iodine
      deficiency. Most of the references about the relationship between iodine excess
      and intelligence were gathered from proceedings, while the others were from
      journals. They location were in some areas of Shandong, Hebei, Shanxi and Inner
      Mongolia. The mean ES of the role of iodine excess on intelligence was 0.21,
      which was corresponding to 3.2 IQ points (95% CI: 2.5 - 4.0). CONCLUSION: 1)
      Iodine deficiency played a role of intermediate strength compared with other
      causes in delaying brain development making children to be at least 10 IQ points
      loss in IDD areas. 2) Effective iodine supplement plays a remarkable
      strengthening role in promoting brain development and can cause 12 IQ points
      increase for children who were born after the correction of iodine status. 3)
      Iodine excess has not shown significant important role in children's
      intelligence.

PMID- 12411066
TI  - [Study on the neonate umbilical cord blood thyroid stimulating hormone level in
      the universal iodized salt areas and its application].
AB  - OBJECTIVE: To investigate the neonatal umbilical cord blood thyroid stimulating
      hormone (TSH) level in the universal iodized salt areas and put forward the cut
      point, then analyze its application. METHODS: Seven provinces were selected where
      the pregnant women having satisfied urinary iodine levels, then the urinary
      samples of pregnant women and the neonates cord blood were collected for urine
      iodine and TSH tests, and the relative factors were also recorded. RESULTS: Total
      1 524 urine and cord blood samples were collected from pregnant women and their
      new borns respectively. The median urinary iodine of pregnant women was 246.0
      micro g/L, and the median TSH was 3.58 mU/L. The TSH level among seven areas and
      the neonatal delivery type varied significantly. CONCLUSIONS: The neonatal cord
      blood TSH was influenced by several factors and could not be controlled, thus not
      be suitable as a iodine deficiency disorders surveillance indicator.

PMID- 12411067
TI  - [Effects of three different iodine interventions on the speed of normalization of
      enlarged thyroid gland due to iodine deficiency].
AB  - OBJECTIVE: To compare the effects of three different iodine interventions on the
      speed of normalization of enlarged thyroid gland. METHODS: Schoolchildren aged 8 
      10 years were randomized divided into one of three groups: group A was given
      iodized salt by researchers with an iodine concentration of 25 mg/kg; group B
      used iodized salt purchased from the market; and group C was similar to group B
      with additional intake of iodized oil capsules containing 400 mg iodine at the
      beginning of the study. Salt iodine content was measured bimonthly for 18 months
      and indicators of iodine deficiency were measured at baseline and 6, 9, 12 and 18
      months thereafter. RESULTS: The prevalence of goiter measured by ultrasound,
      based on the World Health Organization (WHO) body surface area reference > 97(th)
      percentile, was 18% at baseline and declined to less than 5% by 12 month in
      groups A and C respectively, and to 9% after 18 months in group B. Rates of
      goiter were similar by palpation or by ultrasound. The median urinary iodine was
      94 micro g/L at baseline and increased in all groups to > 200 micro g/L at the 6
      month follow-up. CONCLUSIONS: In this sample of schoolchildren with initially low
      or moderate level of iodine deficiency, the group receiving salt with 25 mg/kg
      (group A) recovered from iodine deficient on all indicators after 18 months of
      study. However when the iodine content of salt was floating, as seen in group B,
      the sizes of thyroid did not yet achieve normal status by 18 months.

PMID- 12411068
TI  - [Distribution of noniodized salt and related affecting factors in Xinjiang].
AB  - OBJECTIVE: To find out the distribution of noniodized salt and related affecting
      factors in Xinjiang. METHOD: Using NTTST's iodized salt inspection Plan. RESULTS:
      A total number of 17 973 house holds being surveyed in which 69.4% of those used
      iodized salt and 30.5% used noniodizd salt. In northern Xinjiang, 7 672
      households being surveyed in which 83.9% used iodized salt while in eastern
      Xinjiang 1 200 house holds being surveyed in which 62.2% used iodized salt. In
      southern Xinjiang, 9 101 house holds being surveyed in which 58.2% used iodized
      salt. Data showed a statistically significant difference (chi(2) = 1 329.87, P <
      0.01). The noniodized salt comes from shop-on-wheels (57.4%) and rock salt
      (23.0%). The source of iodine was different in different areas. In eastern and
      southern Xinjiang it came from shop-on-wheels, while in northern Xinjiang came
      from retail sites. Factors related to the use of iodized salt were awareness
      about iodine deficiency disorders (IDD) and income. CONCLUSION: Programs on
      fighting against iodine deficiency in Xinjiang needs more attention, especially
      in the following aspects as publicity on IDD, administration of salt market and
      supervision system.

PMID- 12411069
TI  - [Application of Monte Carlo sampling method in iodized salt monitoring].
AB  - OBJECTIVE: To explore a sampling method which could reflect iodine deficiency
      disorders (IDD) status at provincial level and discover risk areas with non
      iodized salt problem. METHOD: Baseline data of Iodized salt from Gansu and Fujian
      provinces were analyzed with Monte Carlo method both at county and prefecture
      levels respectively. True positive rate and false positive rate were also
      calculated. RESULTS: With data from 7 - 8 villages or 4 - 5 townships counties at
      risk could be discovered. The true positive rate was around 80% and false
      positive rate was around 20%. At prefecture level, when randomly selecting and
      checking 3 counties, the samples would satisfy the discovery of all the risk
      areas with non-iodized salt problem. CONCLUSIONS: We suggested that the sampling
      method of iodized salt investigation in national IDD surveillance as follows: to
      randomly choose 3 counties at each prefecture, 4 townships at each county, 2
      villages at each township and 10 salt samples by household survey. The coverage
      rate of iodized salt in a province could be calculated by post-weighted method
      with population number.

PMID- 12411070
TI  - [The contribution of pubertal maturation timing to adolescent smoking behavior].
AB  - OBJECTIVE: To study the contribution of puberty maturation to smoking behavior in
      Chinese adolescents. METHODS: A cross-sectional survey was carried out. One
      thousand four hundred and fifty-three senior middle school students aged from 15 
      18 years were recruited in Shanghai in 2000. A standardized self-administrated
      questionnaire was designed to obtain information on smoking, age at first
      nocturnal ejaculation in boys, age at menarche in girls and variables that might
      be associated with smoking in adolescents. RESULTS: In boys, the prevalence of
      experimental smoking was highest among later maturers (28.6%), followed by the
      earlier (21.3%) and the average (21.7%), and the prevalence of current smoking
      was highest among earlier maturers (16.4%), followed by the later (7.1%) and then
      the average (4.8%). In girls, the prevalence of ever smoked among earlier,
      average and later maturers were as follows: 24.2%, 12.0%, 6.3% respectively. When
      psychosocial variables which might be associated with smoking were under control,
      early maturation was a significant risk factor for current smoking in boys (OR =
      3.68, 95% CI: 1.23 - 10.99), and might be a risk factor for ever smoked in girls
      (OR = 2.23, 95% CI: 0.89 - 5.60). Whereas late maturation might have been a risk
      factor for boys to experiment smoking (OR = 1.48, 95% CI: 0.72 - 3.06), while in
      girls it might be protective (OR = 0.64, 95% CI: 0.22 - 1.86). CONCLUSION:
      Earlier or later matured boys and earlier matured girls were at higher risk of
      smoking. Pubertal changes and timing need to be considered in smoking prevention.

PMID- 12411071
TI  - [Knowledge on hypertension and the effect of management on hypertension in
      patients attending hospital clinics].
AB  - OBJECTIVE: To estimate the current knowledge on hypertension and the effect of
      management on hypertension in patients attending hospital clinics. METHODS: A
      cross-sectional survey was used in the outpatients over the age of 35 years in 18
      general hospitals (provincial, district and community) which represented the
      different levels of medical care in 8 major cities covering Northern and Southern
      China including an interview with two blood pressure measurements and one
      questionnaire in one clinical visit. RESULTS: A total of 9 703 subjects
      participated in this project, who were similarly distributed by gender and age in
      the hospitals at different levels. Of all the 9 703 subjects, 4 510 (46.5%) were
      found to be hypertensive. 6.4%, 12.1%, 25.5%, 41.1% and 14.6% of all the
      participants were categorized into knowledge on hypertension grade 0, 1, 2, 3, 4
      respectively. The classification was based on the number of correct answers to
      four questions about knowledge of hypertension. The higher the grade of
      hypertension knowledge the more response to higher rate of awareness, treatment,
      and control in this hypertensive population was noticed. There was significantly
      positive correlation between the grade of hypertension knowledge and treatment
      compliance. The major cause of poor treatment compliance was due to lack of
      hypertension knowledge. CONCLUSION: There was poor knowledge on hypertension in
      the investigated participants, which would influence on the management of
      hypertension. Data suggested that health education on the knowledge of
      hypertension in the population needs to be improved.

PMID- 12411072
TI  - [A population-based case-control study on the risk factors of urinary calculi].
AB  - OBJECTIVE: To determine the risk factors of urinary calculi in Shenzhen for
      proper interventions. METHODS: A population-based case-control study including
      334 urinary calculi cases and 721 controls was carried out. A total number of 34
      factors were analyzed using unconditional logistic regression. RESULTS: Seventeen
      factors were associated with urolithiasis based on the logistic regression
      analysis. Ten factors entered the last model of the logistic multivariate
      regression. The more protein consumption (OR = 2.14, 95% CI: 1.71 - 2.69),
      positive history of first relatives with urolithiasis (OR = 2.61, 95% CI: 1.70 -
      4.01), longer outdoor exposure (OR = 1.39, 95% CI: 1.16 - 1.66) and chronic
      inflammation of urinary system (OR = 4.09, 95% CI: 1.38 - 12.14) were risk
      factors of urinary calculi. Higher education background (OR = 0.46, 95% CI: 0.29 
      0.73), drinking more water (OR = 0.59, 95% CI: 0.48 - 0.72), drinking more juice
      (OR = 0.41, 95% CI: 0.18 - 0.94), more milk and milk product consumption (OR =
      0.82, 95% CI: 0.68 - 0.99), vegetable (OR = 0.70, 95% CI: 0.55 - 0.91) and fruit
      consumption (OR = 0.78, 95% CI: 0.64 - 0.94) were protective factors of
      urolithiasis. CONCLUSION: Dietary habits were the major influencing factors of
      urinary calculi. Positive history of family with urolithiasis and social-economic
      factors were also associated with the disease.

PMID- 12411073
TI  - [Study on temporal patterns of stroke onset from community-based cohort in
      Beijing].
AB  - OBJECTIVE: To Study the temporal patterns of stroke onset, and to provide
      insights into the triggers which might cause the acute onset of stroke and to
      develop preventive strategies. METHODS: Using a 10-year period of the SINO-MONICA
      Beijing study cohort a total number of 700 000 people, aged 25 to 74 years was
      recruited. The diagnostic criteria exactly followed the WHO MONICA project. Date
      of the week, season and month occurrence of stroke were ascertained. Percentage
      of stroke onset on date in the week, season and month were calculated. chi(2)
      test was used to identify the deviation from expected frequencies. Multiple
      stepwise regression was carried out for multivariate analysis. RESULTS: Most
      stroke occurred and recurred (chi(2) = 7.02, P = 0.008 in male and chi(2) =
      12.32, P = 0.000 4 in female) in winter. The most frequent occurrence on the
      dates of stroke events were Monday in the urbans and Saturday in the rurals. The
      finding were confirmed (the stroke occurrence and recurrence positively
      correlated with season, correlation coefficient 0.032, P = 0.01) by correlation
      and multiple stepwise regression. CONCLUSION: It was important to find out the
      circadian variation and the external triggering factors together with unhealthy
      behaviour of life that would contribute to the prevention and reduction of stroke
      onset.

PMID- 12411074
TI  - [Prevalence survey and molecular characterization of alpha and beta thalassemia
      in Liuzhou city of Guangxi].
AB  - OBJECTIVE: To investigate the gene frequencies and mutation patterns of alpha
      thalassemia (alpha-thal) and beta thalassemia (beta-thal) in Liuzhou city of
      Guangxi Zhuang Autonomous Region. METHODS: Cluster sampling was used. A total of
      1 028 of umbilical blood samples were collected for a prevalence study of alpha
      thal and a total of 1 312 healthy young people when receiving pre-marriage
      consultation were recruited for a beta-thal prevalence survey. Individuals live
      in city or town area of Liuzhou. A complete blood count as well as hemoglobin
      electrophoresis analysis were done in all of samples for phenotyping of alpha and
      beta-thals. Those with Hb Bart's for alpha-thal indicator and those with both
      microcytosis (MCV < 85 fl) and elevated levels of Hb A(2) (>/=4.0%) for beta-thal
      were further studied by DNA analysis. PCR-based methodologies were used to
      characterize the mutation contributions of alpha and beta-thals. All the subjects
      were tested for the state of carrying beta-thala alleles for evaluating the
      situation of the compound heterozygotes of alpha-thal with beta-thal. RESULTS: Of
      1 028 random samples of umbilical blood screened, 112 of subjects were defined to
      be the gene carriers of alpha-thal. The alpha-thal carrier rate was as high as
      11.19% including 3 compound heterozygotes. Five well-known types of alpha-thal
      alleles were detected with gene contributions of 37.4% (--(SEA) deletion), 31.3%
      (-alpha(3.7) deletion), 17.4% (-alpha(4.2) deletion), 12.1% (alpha(CS)alpha
      mutation), and 0.9% (alpha(QS)alpha mutation), successively. Of the 1 312 adult
      specimens studied, 89 with beta-thal including 14 of the compound higher Hb F
      subjects were detected. All of the 89 phenotypic beta-thal carriers had the
      mutations in the beta-globin gene, making the overall prevalence 6.78%. The
      commonly seen three mutations, beta CD41 - 42 (-CTTT) frameshift, beta CD17 (T-A)
      nonsense mutation and beta-28 (A-G) promoter variation were accounted for 90% of
      the beta-thal alleles in Liuzhou. Of these beta-thal subjects, 16 (accounting for
      18%) were found to be the compound heterozygosity for a beta-thal and an alpha
      thal with 9 different types of gene defects with a detection rate 1.22%.
      CONCLUSION: Data from ecidation of alpha and beta-thal gene frequencies and
      mutation spectrum in Liuzhou city was useful for genetic counselling and prenatal
      diagnosis of this disease.

PMID- 12411075
TI  - [Detection and sequential analysis of Granulocytic ehrlichia 444-Epank gene].
AB  - OBJECTIVE: To provide further pathogenic evidence of Granulocytic ehrlichia
      infection in China. METHODS: Specific primers derived from 444-Epank gene were
      used to amplify Granulocytic ehrlichia DNA from specimens of ticks, animals and
      human blood. PCR products of ticks were cloned and sequenced. RESULTS: 444 bp
      specific DNA fragments were amplified from 2 of 62 pools of Ixodes persulcatus
      collected from Heilongjiang province and 1 of 129 blood specimens from forest
      workers in Inner Mongolia. Eight animal specimens were negative. PCR products
      from ticks were then cloned and sequenced. It differed at 23 positions in
      comparison to American strain (AF047897) with 94.9% homology. The homology of
      deduced ammonia was 88.44%. CONCLUSION: Our findings further confirmed that
      Granulocytic ehrlichia infection did exist in China.

PMID- 12411076
TI  - [Polymorphisms of methylenetetrahydrofolate reductase C677T and the risk of
      stomach cancer].
AB  - OBJECTIVE: In order to study the relation between polymorphisms of
      methylenetetrahydrofolate reductase C677T (MTHFR) and susceptibility of stomach
      cancer (SC). METHODS: We conducted a case-control study with 107 cases of SC and
      200 population-based controls in Huaian city of Jiangsu province, China. The
      epidemiological data were collected, and DNA of peripheral blood leukocytes was
      obtained from all of the subjects. MTHFR genotypes were detected by PCR-RFLP
      method. RESULTS: (1) The frequency of MTHFR variant genotypes (C/T + T/T) among
      the cases (79.4%) was significantly higher than the controls (68.5%) (P = 0.041
      6); the crude OR for SC was 1.78 (95% CI: 0.99 - 3.22). After adjustment for sex
      and age, the OR for SC was 1.89 (95% CI: 1.08 - 3.32). (2) Subjects who had MTHFR
      variant genotypes and having smoking habit were at a significantly higher risk of
      developing SC (OR = 7.72, 95% CI: 2.23 - 26.79) compared with those who had wild
      type homozygotes (C/C) genotype and no smoking habit. Individuals who had variant
      genotypes and who had habit of frequent alcohol drinking were at an increased
      risk of developing SC (OR = 3.08, 95% CI: 1.30 - 7.23) compared with those with
      C/C genotype and low consumption of alcohol. As compared with subjects with C/C
      genotype and low consumption of alcohol and no smoking habit, individuals who had
      variant genotypes and who had habits of frequent alcohol drinking and smoking had
      12.96 (95% CI: 2.76 - 70.46) folds risk developing SC. CONCLUSIONS: These results
      in the present study suggested that the polymorphisms of MTHFR C677T was
      associated with risk of developing SC, and there was a coordinated effect between
      MTHFR genotypes and habits of smoking and alcohol drinking in the development of
      SC.

PMID- 12411077
TI  - [Case control study on the risk factors of primary open angle glaucoma in China].
AB  - OBJECTIVE: The purpose of this study is to comprehensively explore the risk
      factors of primary open angle glaucoma (POAG) in China. METHODS: Two groups of
      data based on distinct resources were analyzed to explore the risk factors of
      POAG. One group of data was based on hospital records between 1995 and 2000 which
      composed of 107 patients with POAG and 149 controls without POAG. The other group
      of data was based on 40 patients with POAG and 120 matched controls without POAG.
      The former was designed by non-matched case control study, the latter was done by
      1:3 matched case control study. The relationships between POAG and the factors
      such as age, sex, family history, diabetes, hypertension, intraocular pressure
      (IOP), cardiovascular diseases, smoking, drinking and mutation of TIGR gene were
      studied by logistic regression analysis. RESULTS: The simple factor analysis
      showed that the risk of POAG was related to age, family history, hypertension,
      IOP, cardiovascular diseases, smoking, drinking and the mutation of TIGR gene
      (T353I). However, logistic regression analysis confirmed that POAG mainly related
      to IOP, family history, hypertension, smoking, alcohol intake and the mutation of
      TIGR gene. CONCLUSION: The most important risk factor of POAG was IOP. Family
      history, hypertension, smoking and the mutation of TIGR gene were also important
      risk factors of POAG. However, alcohol intake was a protective factor for POAG.

PMID- 12411078
TI  - [Case control study on the association of coronary artery disease and cigarette
      smoking].
AB  - OBJECTIVE: To determine the association of cigarette smoking and coronary artery
      diseases (CAD). METHODS: A case-control study involving 355 people classified as
      CAD or without CAD was performed. But people treated with diuretic, aspirin,
      lipid-lowering agents, heparin or those with renal, hepatic diseases were
      excluded. Gender, age, body mass index, plasma glucose under fasting, total
      cholesterol, triglyceride, high-density lipoprotein cholesterol, low-density
      lipoprotein cholesterol, fibrinogen, cigarette smoking consumption grade (0: no
      smoking, 1: less or equal 100 cigarette year, 2: one hundred cigarette year <
      cigarette index </=200 cigarettes year, 3: greater than 200 cigarette year), CAD
      family history, essential hypertension and CAD severity were analyzed. RESULTS:
      In multiple logistic regression, age, gender, fasting plasma glucose, fibrinogen
      and cigarette smoking showed significant independent association with CAD.
      Compared with non-smoker, the odds ratio (OR) of CAD of grade 3-cigarette smoking
      was 3.519 (95% CI: 1.538 - 8.053, P = 0.003). However with grade 1 cigarette
      smoking group, no significant independent association was found with CAD (OR =
      0.948, P = 0.959). With more than grade 2 [grade 2 + 3, compared with less than
      grade 2 (0 + 1)] and grade 3 [compared with less than grade 3 (0 + 1 + 2)]
      cigarette smoking, ORs of CAD were 2.094 (P = 0.027), 3.463 (P = 0.002)
      respectively. Three hundred fifty-five people were divided into 3 groups:
      control, stable angina (SA) and unstable angina (UA) groups. In multinomial
      logistic regression, when comparing with UA, parameter estimate of cigarette
      smoking degree in the SA group were beta = -0.220, s(x) = 0.138, P = 0.112, OR =
      0.803 respectively. CONCLUSIONS: Cigarette smoking was a significant independent
      risk factor for CAD. With more cigarettes smoked, a higher odds ratio of CAD was
      seen. Gender, age, fibrinogen and plasma glucose during fasting were also
      independent factors significantly associated with CAD. No significant independent
      association between cigarette smoking and unstable angina was found.

PMID- 12411079
TI  - [Study on intervention and comparison of rational use of antibiotics on
      perioperative period of clean incision and clean-defiled incision].
AB  - OBJECTIVE: To explore a set of scientific evaluation and intervention methods on
      perioperatur period which fits for China's situation, and to promote the
      development of rational drug use. METHODS: Two would tertiary general hospitals
      were selected and separated in to intervention group and control group.
      Intervention was carried out and compared at the same period on inpatient
      surgical cases of thryroidectomy, mastectomy, cholescystectomy, and
      hysteromyomectomy plus appendix. RESULTS: The average drug costs was decreased
      from 1 601.27 yuan to 1 489.59 yuan and the average antibiotics use from 740.20
      yuan to 352.03 yuan (P < 0.01) in the intervention group pre and post
      intervention. There was a remarkable improvement on the rationality of
      antibiotics use in intervention group, from 31.35% to 91.81% (P < 0.01) pre and
      post intervention, implemented in the hospital. CONCLUSION: It is practicable and
      effective to implement rational drug use where intervention was carried out,
      since it plays an active role on promoting safely, effectively and economic
      antibiotic use in China.

PMID- 12411080
TI  - [Blood lead level of children in the urban areas in China].
AB  - OBJECTIVE: The purpose of this study was to investigate the blood lead level of 3
      - 5 year old children living in the cities in China and to provide scientific
      data for making policy on environmental lead pollution for children health
      protection. METHODS: Six thousand five hundred and two vein blood samples from 3 
      5 year old children in nineteen cities of nine provinces were sampled.
      Inductively coupled plasma-mass spectrometry (ICP-MS) were employed to determine
      lead level in whole blood after microwave digestion for sample preparation and
      questionnaire survey was also performed. Data were analyzed with multiple
      regression on factors which affecting blood lead levels. RESULTS: Results showed
      that mean blood lead level was 88.3 micro g/L for 3 - 5 year old children living
      in the cities in China and mean blood lead level of boys (91.1 micro g/L) was
      higher than that of girls (87.3 micro g/L). Twenty-nine point nine one per cent
      of the children's blood lead level exceeded 100 micro g/L. The research finding
      showed: (1) higher blood lead levels had negative effects on children's physical
      growth, language ability etc. (2) behavior of parents had certain effects on
      children's blood lead levels. (3) blood lead levels of children were affected by
      unhealthy habits. CONCLUSIONS: Problem of childhood lead poisoning in China has
      become more serious. During the past ten years, blood lead levels of children has
      been increased in China while decreasing in developed countries. Blood lead
      levels of children in China are higher than that of developed countries, which
      called for special concern by government and society.

PMID- 12411081
TI  - [Study on the effects of lead from small industry of battery recycling on
      environment and children's health].
AB  - OBJECTIVE: In order to minimize lead pollution and to protect the identified
      individuals with high blood lead level from lead contamination, an
      epidemiological study was carried on children living around the village and
      township-owned lead industries in Tianying town. METHODS: Environmental
      monitoring: lead levels in air, soil, drinking water and crops were measured.
      Biological monitoring: 959 children aged 5 - 12 years were selected from villages
      where the lead smelters located near the residential areas and the battery
      disassembling was done in some families. The control children (207 pupils) were
      from other villages without lead exposure. Blood lead, ZnPP and teeth lead were
      determined. Height, weight and head circle of children and IQ scores were
      measured. RESULTS: The environment was seriously polluted. The average lead
      concentrations in air and soils were 8.5 times and 10 times of the MACs (national
      health standard) respectively. Eighty-five per cent the air samples with lead
      concentrations higher than the national health standard. Local crops and wheat at
      farmers' home were also contaminated by lead dust, with. Lead content being 24
      times higher than the standard. The mean blood lead and ZnPP levels of children
      lived in the polluted areas were 496 microgram/L and 9.41 microgram/g Hb
      respectively. The lead exposure caused adverse effects on children's IQ and
      physical development. CONCLUSION: It is necessary to remove and reduce currently
      active sources of lead pollution in the community and to increase public
      awareness of potential health effects of lead exposure.

PMID- 12411082
TI  - The trends of changes in children's blood lead levels since the introduction of
      lead free gasoline in Shanghai.
AB  - OBJECTIVE: To describe trends of changes in blood lead levels in children aged 1 
      6 years during the time period before and after introducing lead free gasoline
      in Shanghai 1997 and 1999. METHODS: Blood lead levels of 1 969 children aged 1 -
      6 years were determined by a sampling survey in five districts of Shanghai in
      August and September, 1997. Blood lead levels of the same population were re
      determined by the same method from April to June in 1998 and from August to
      September in 1999. Filter paper blood lead test was carried out monthly using the
      filter paper blood lead proficiency testing program of Centers for Disease
      Control in the United States. The results from blood lead samples were under
      acceptable ranges during the study. RESULTS: The geometric means of blood lead
      levels were 83 microgram/L in 1997, 80 microgram/L in 1998 and 76 microgram/L in
      1999, respectively. The prevalence rates of childhood lead poisoning (blood lead
      level was equal or more than 100 microgram/L) were 37.8% in 1997, 25.7% in 1998
      and 24.8% in 1999. The amounts of decrease on average blood lead levels in the
      five districts between 1997 and 1999 were 10 microgram/L, 11 microgram/L, 6
      microgram/L, 4 microgram/L and 2 microgram/L, respectively. CONCLUSION: Lead
      poisoning is a preventable disease. The average levels of lead in young children
      in Shanghai decreased significantly after the introduction of lead free gasoline
      to Shanghai. Lead emissions from vehicles running on leaded gasoline was one of
      the important contributors to increase the children's blood lead levels in
      Shanghai. Lead poisoning is not evenly distributed among children in Shanghai,
      resulting in the different levels of decline.

PMID- 12411083
TI  - [A molecular epidemiological study of childhood lead poisoning in lead-polluted
      environment].
AB  - OBJECTIVE: The relationship between polymorphisms of ALAD and VDR genes and
      individual susceptibility of lead poisoning was investigated in children highly
      exposed to lead. METHOD: Four hundred and sixty-nine children were recruited into
      this study and the blood lead, ZPP, hemoglobin as well as three physical
      developmental indexes (head circumference, height and weight) were measured. VDR
      and ALAD gene polymorphisms were analyzed by the methods of PCR-RFLP. RESULTS:
      The subjects with ALAD2 allele had higher ZPP level (10.12 micro mol/L vs 12.87
      micro mol/L) (P = 0.017). The subjects with B allele has larger head
      circumference than only with b allele (51.19 cm vs 50.75 cm) (P = 0.028).
      CONCLUSIONS: It was suggested that the ALAD gene polymorphism modified the
      relationship between blood lead and ZPP and the VDR gene variants influenced the
      skull development in children living under lead-polluted environment. The
      polymorphism of ALAD and VDR genes might serve as the molecular inherited factors
      modifying the susceptibility of lead poisoning.

PMID- 12411084
TI  - [Serologic studies of Xinjiang hemorrhagic fever in Bachu county, 2001].
AB  - OBJECTIVE: To investigate the situation of Xinjiang hemorrhagic fever (XHF) in
      patients who have been diagnosed as XHF by clinical methods and to predict the
      condition in people who were liable to infection and in the host-animals.
      METHODS: Sera collected from XHF patients and some peasants under the risk of
      contracting the disease, followed by checking the specific antibody against XHF
      with IgG-ELISA and IgM capture ELISA, and XHF viral antigen with antigen capture
      ELISA. In addition, 80 sheep/goats serums were collected from two places where
      there were more XHF cases and specific IgG antibody against XHF checked by ELISA
      method. RESULTS: Positive rate of IgG and IgM antibodies were 39.62% (21/53) and
      20.75% (11/53) respectively in the serums of patients; one patient's serum showed
      XHFV antigen positive by antigen capture ELISA. IgG antibody positive rate for
      peasants' sera was 21.05% (4/19), but IgM antibody detection showed negative for
      all sera. In sera from 80 sheep and goats, 70% (56/80) showed IgG positive.
      CONCLUSION: Results showed that XHF broke out in Bachu county from April to June
      2001 while recessive infection of the disease remained serious.

PMID- 12411085
TI  - [Prevalence and relevant factors on echocardiographic left ventricular
      hypertrophy among community-based hypertensive patients in Shanghai].
AB  - OBJECTIVE: To investigate the prevalence and relevant factors on the
      echocardiographic left ventricular hypertrophy (LVH). METHOD: A cross-sectional
      study was conducted among the hypertensive patients in an urban community.
      RESULTS: The prevalence of LVH was 29.2% in 1 686 hypertensive patients, with
      25.4% in males and 34.5% in females, respectively. The prevalence was
      significantly higher in females than in males (chi(2) = 16.17, P < 0.01). The
      rate was increasing with age and significantly higher prevalence was observed in
      45-, 55-, 65- age groups of females (P < 0.05). Moreover, elevated systolic blood
      pressure and higher BMI were related to the LVH in hypertensive patients, while
      higher education level seemed a protective factor. CONCLUSION: These results
      implied that a comprehensive intervention should be taken in the prevention of
      LVH.

PMID- 12411086
TI  - [A prospective study on smoking, quitting and mortality in a cohort of elderly in
      Xi'an, China].
AB  - OBJECTIVE: To prospective examine the relationship between smoking, quitting and
      mortality in older Chinese men by in Xi'an, China. METHODS: The design was a
      cohort analytic study. One thousand two hundred and sixty-eight retired male
      military veterans aged 60 or older were examined in 1987. At baseline, there were
      388 never-smokers, 461 former smokers and 419 current smokers. Main outcome
      measure was all-cause and tobacco-associated mortality. RESULTS: Through 1999,
      299 had died, 943 were alive and 26 lost. The mean follow-up time was 11 years
      and total person-year of follow-up was 14 163. After adjusting for age, blood
      pressure, body mass index, total cholesterol, triglycerides, alcohol intake,
      exercise and existing diseases, using Cox proportional hazard regression model,
      the relative risks (95% confidence intervals) for ever-smoking, deaths resulting
      from all causes, chronic obstructive pulmonary disease (COPD), lung cancer and
      coronary heart disease (CHD) were 1.34 (1.02 - 1.76), 3.23 (0.95 - 10.91), 2.31
      (0.95 - 5.61) and 1.60 (0.81 - 3.19) respectively. The risks increased
      significantly with increasing amount and duration of smoking. Compared with
      current smokers, former smokers had lower risks of total mortality (excess risk
      reduction of 56%) and from CHD death (93%), but had higher risks for COPD death
      (excess risk increased 174%). CONCLUSIONS: Smoking is a major cause of death in
      older Chinese men and quitting can save lives. These results showing that higher
      risks of COPD death in former smokers with or without existing diagnosed COPD at
      baseline than those in current smokers could be explained by either the "healthy
      smoker effect" or the "ill quitter effect" or both. Early recognition of the
      significance of COPD symptoms followed by prompt quitting should be emphasized as
      strategies in the control of the growing tobacco epidemic.

PMID- 12411087
TI  - [Study on risk factors of cryptorchidism].
AB  - OBJECTIVE: Cryptorchidism is the most common urogenital congenital malformations
      in males, which increases male infertility and testicular tumors. It is necessary
      to identify its risk factors. METHODS: A hospital-based case-control study was
      conducted. Cases were 99 boys with cryptorchidism with two matched controls per
      case were randomly selected. Both cases and controls were interviewed with a
      uniformed questionnaire by face to face. Conditional logistic regression model
      was used for univariable and multivariate analysis by SAS6.12 computer software
      was used to estimate odds ratios (OR) and their 95 per cent confidence internals
      (95% CI). RESULTS: Multiple conditional logistic regression analysis showed that
      cryptorchidism was positively associated with maternal common cold accompanied
      fever in the first trimester (OR = 9.37, 95% CI: 2.25 - 39.09), with threatened
      abortion in the first and/or second trimester (OR = 4.66, 95% CI: 2.02 - 10.74),
      maternal preeclampsia during pregnancy (OR = 16.33, 95% CI: 1.40 - 191.20),
      paternal exposure to pesticides occupationally (OR = 12.79, 95% CI: 2.90 -
      56.43), neonatal low birth weight (OR = 5.77, 95% CI: 1.39 - 23.98), and maternal
      age under 24 years (OR = 2.89, 95% CI: 1.29 - 4.06). CONCLUSIONS: The risk
      factors of cryptorchidism were maternal common cold accompanied fever in the
      first trimester, threatened abortion in the first and/or second trimester,
      maternal preeclampsia during pregnancy, paternal exposure to pesticides
      occupationally, neonatal low birth weight, maternal age under 24 years.

PMID- 12411088
TI  - [Study on the life expectancy of residents in Xinjiang Production and
      Construction Group, from 1997 to 1999].
AB  - OBJECTIVE: To understand the life expectancy of residents in Xinjiang production
      and Construction Group, from 1997 to 1999. METHODS: Stratified cluster sampling
      method was used to obtain mortality rate, sequence of death causes, life
      expectancy, life eliminated major cause of deaths, years of potential life lost
      (YPLL) and level of long life. These indeices were used to compare and analyze
      health status on residents in the area. RESULTS: The life expectancy on residents
      in the area was 75.61 years old for all residents, 72.73 years old for males,
      80.02 years old for females from 1997 to 1999. The life expectancy for people
      living in agricultural and livestock farms was lower (73.97 years old). It was
      found that life expectancy was parallel to the level of economy. Life expectancy
      of northern residents was higher than those living in the southern and eastern
      parts of the area. The annual average mortality rate of the residents was 5.17
      per thousand (standard mortality rate 4.02 per thousand ). The sequence of major
      causes of death was shown as below: malignant tumors, cerebrovascular diseases,
      respiratory system diseases, cardiac diseases, accidental deaths, infectious
      diseases, certain conditions originated in the perinatal period. In the life
      eliminated major cause of deaths, respiratory system diseases and certain
      conditions originated in the perinatal period were higher than others. In both
      sequences of YPLL and SYPLL for major causes of death, accidental death was
      always in the leading place. There was a higher longevity on residents from the
      better economic area. CONCLUSIONS: Higher life expectancy in the area was
      noticed, but the differences among the different area were bigger. In order to
      improve the level of health on all residents in the area, it is necessary to
      strengthen the administration on social and natural environment of the area.
      Furthermore, decreasing accidental deaths, controlling respiratory system
      diseases (especially for infant) and improving health care of infants in
      perinatal period are very important tasks in the area.

PMID- 12411089
TI  - [Effect of environmental supplementation of iodine on infant mortality and growth
      in children in Xinjiang, China].
AB  - OBJECTIVE: To study the effect of iodine supplementation on infant mortality and
      growth in Xinjiang. METHODS: Urine iodine, height and head circumference (HC) of
      children aged 5 years in two townships was measured before and yearly after
      iodine supplementation of irrigation water. Height and HC were expressed as Z
      scores (United States children used as the reference group). Neonatal and infant
      mortality rates were obtained from official records in three counties from 1988
      to 1999, and analyzed by a logistic regression model. RESULTS: The odds ratio of
      infant mortality decreased 56.49% and neonatal mortality 65.71% respectively
      after iodination; there was no significant difference in the odds ratio of infant
      or neonatal mortality between experimental and control areas without iodination.
      In Langru township, the mean height of 5 year-old children increased from 95 cm
      in 1992 to 106.9 cm in 1998 - 1999, and HC from 48.4 cm to 50.5 cm. Median urine
      iodine increased from <10 to 176 micro g/L. In Bakechi township, mean height
      increased from 91 cm in 1993 to 106.5 cm in 1998 - 1999, HC from 48.7 to 49.6 cm,
      and median urine iodine from 39 to 138 micro g/L. CONCLUSION: In Xinjiang,
      adequate iodine treatment markedly decreased infant and neonatal mortality, and
      largely preventing stunting of height and HC in children.

PMID- 12411090
TI  - [A study on genetic polymorphism of rRNA gene pattern of Vibrio cholerae O139 in
      China].
AB  - OBJECTIVE: To investigated the genetic polymorphism of the isolated strains using
      ribotyping method. METHODS: One hundred twenty-two strains of V. cholerae O139
      isolated from different areas of China from 1993 to 1999 were selected and
      characterized with ribotyping, including 16s rDNA and 23s rDNA probes. RESULTS:
      One hundred twenty-two strains were differentiated into 10 different ribotypes
      (RT1-RT10) on the basis of rRNA gene probes hybridization (with Bgl I digestion),
      which consisted of 7 - 9 bands between 12 and 1.5 kb in size. RT1 and RT3, as two
      predominant ribotypes, comprised most number of the strains which spread to the
      extensive range. Nine strains, which are negative to ctxAB, zot and RS
      individually, belong to 4 special ribotypes. The dendrogram revealing genetic
      relationship among different clones of V. cholerae O139 showed that the clones
      belonging to RT1 and RT2 had genetic similarity on high degree, although they
      were isolated from different regions. The two predominant ribotypes (RT1 and RT3)
      were distant in genetic relationship. CONCLUSION: Results showed the clonal
      diversity and the wide area distribution of V. cholerae O139 strains in China,
      suggesting the multiple origins of O139 epidemics.

PMID- 12411091
TI  - [Value of BCL-2 and P53mt proteins in screening skin carcinoma caused by
      arseniasis].
AB  - OBJECTIVE: To discuss the value of P53mt and BCL-2 proteins in screening skin
      carcinoma due to arseniasis. METHODS: P53mt and BCL-2 proteins were detected by
      immunohistochemical staining. chi(2) test was used to analyze the difference of
      positive rate between two groups. Screening value of the two biomarkers was also
      evaluated through the analysis of relative indexes. RESULTS: Positive percentages
      of P53mt and BCL-2 in carcinoma group were 88.89% and 94.44% respectively, both
      were higher than those of 36.0% and 66.0% in non-carcinoma group (for P53mt, P <
      0.01; for BCL-2, P < 0.05). ORs of P53mt and BCL-2 were 14.22 (2.93 - 68.97) and
      8.76 (1.07 - 71.51), respectively. Youden's Index and specificity of P53mt were
      0.529 and 64.0%, which were much higher than those of BCL-2. Serial tests
      improved the value of screening with Youden's Index 0.569, but parallel test
      lowered it to 0.244. CONCLUSIONS: P53mt and BCL-2 were practical biomarkers to
      screen skin carcinoma due to arseniasis, and the former was better than the
      latter. The value of screening can be improved by a series of tests.

PMID- 12411092
TI  - [Exploratory study on natural focus and its causative agent of genotype of Lyme
      disease by polymerase chain reaction in the forest areas of Beijing].
AB  - OBJECTIVE: To learn the existence of natural focus of Lyme disease and its
      distribution. METHODS: A semi-nested polymerase chain reaction (PCR) method was
      developed for detection and genotyping of Borrelia burgdorferi on basis of outer
      surface protein A (OspA) gene. Ticks and mice collected from 6 forest areas in
      Beijing were detected with above methods. The positive PCR products were cloned
      and sequenced. The sequences were compared with published sequences for homology.
      IFA as used to detect IgG antibody on Borrelia burgdorferi. Lyme disease
      spirochete were isolated from H. longicornis were also attempted. RESULTS: B.
      Burgdorferi sensu lato were detected from 939 ticks and 250 mice specimens
      collected from above 6 study sites using primer pairs OA(1)/OA(4) and SL/OA(4).
      Only the specimens collected from Dongling mountain showed positive
      amplification. One in three adult Ixodes persulcatus with one of 57 nymph Ixodes
      persulcatus showed positive while 9 of 119 (7.56%) mice specimens showed
      positive, of which 8 were B. grinii and one B. afzelii. In this study, we
      attempted to isolate B. burgdorferi sensu lato strains from 160 H. longicornis
      ticks (20/group) but failed. Serological survey showed a 9.1% (5/55) infection
      rate with B. burgdorferi sensu lato in the mice of Dongling mountain forest
      areas. CONCLUSIONS: The natural focus of Lyme disease including B. garinii and B.
      afzelii might have existed in Dongling mountain of Mentougou district, Beijing.
      Ixodes persulcatu and mice may serve as vectors and reservoirs, respectively.

PMID- 12411093
TI  - [Retrospective study of adverse events in patients with rheumatoid arthritis
      treated with second-line drugs].
AB  - OBJECTIVE: To evaluate rates on the adverse side effect and discontinuation of
      second-line drugs frequently used in the treatment of rheumatoid arthritis (RA).
      METHOD: Eight hundred and sixty-four RA patients were studied in a retrospective
      program. RESULTS: Upper abdominal discomfort was most commonly seen when using
      second-line drugs. Rash was often associated with D-penicillamine (20.6%) and
      Sinomenium therapy (13.7%). Methotrexate (MTX) was uniquely characterized by
      substantial upper GI toxicity (32.2%) and Tripterygium wilfordii Hook. f. (TWH)
      (14.4%) by menstrual abnormality. Sulfasalazine users reported adverse events
      including upper abdominal trouble (39.0%), nausea (7.3%) and anorexia (7.3%)
      while the risk of GI malaise was greater. Patients taking hydroxychloroquine
      complained of blurred vision (19.6%) but no one went blind. Toxic side effects
      seemed to be the most common reasons for stoppages, and the patients taking MTX
      had the lowest discontinuation rate. Combination of D-penicillamine and
      Methotrexate did not increase the incidence of adverse events. CONCLUSIONS:
      Knowledge on these different patterns of toxicity provided choices in the
      selection of second line agents for particular RA patients. However, long-term
      monitor are required when drugs are being used.

PMID- 12411094
TI  - [The effectiveness of an intervention program in the promotion of condom use
      among sexually transmitted disease patients].
AB  - OBJECTIVE: To assess the effectiveness of an educational intervention program in
      sexually transmitted disease (STD) and condom-related knowledge and promoting
      condom use among STD patients. METHODS: STD clinic patients were randomly
      assigned to three groups (A, control group; B, video viewing group; group C,
      video viewing plus education with talk) after administered with baseline
      questionnaire. Each patient was then scheduled to complete the questionnaire
      regarding the change of STD knowledge and use of condom in two weeks and 3
      months. RESULTS: Six hundred and forty-eight patients entered the study. More
      than half of the patients were aware of STD-related knowledge. However the rate
      of condom use was very low. When having intercourse with the casual sexual
      partners the percentage of condom use was only 20%. Seventeen per cent of the
      patients knew nothing about how to use condom correctly. Follow up results showed
      that the education program increased the knowledge about STD to some degree.
      However the percentage of condom use in the latest sexual intercourse increased
      greatly both in intervention and control groups, but more in intervention groups
      (P < 0.05). CONCLUSION: STD education should be focused on advocating and
      correcting condom use.

PMID- 12411095
TI  - Complications of percutaneous transluminal septal myocardial ablation in
      hypertrophic obstructive cardiomyopathy.
AB  - OBJECTIVE: To assess the complications of percutaneous tansluminal septal
      myocardial ablation (PTSMA) for the treatment of hypertrophic obstructive
      cardiomyopathy (HOCM). METHODS: Seventy-two patients with symptomatic left
      ventricular outflow tract obstruction were diagnosed by echocardiography or
      catheterization procedures. Absolute ethanol was injected into the target
      coronary artery branch (branches) for septal myocardial ablation. Documented
      complications were recorded. RESULTS: Sixty-nine patients had severe chest pain,
      19 developed different degrees of heart block during the periprocedural period,
      but only one developed a complete AV block, requiring permanent pace-maker
      implantation. Temporary right bundle branch block occurred in 50% of patients and
      permanent block occurred in 38.9% of patients. Acute inferior myocardial
      infarction occurred in six patients (8.3%) and acute anterior myocardial
      infarction occurred in one patient. During two-year follow-up of 24 cases, there
      were no deaths. All patients had improvement in heart function and none
      experienced heart failure. CONCLUSION: The most common complication of PTSMA is
      right bundle branch block. The most significant complication of the procedure is
      heart block. PTSMA is a good technical, non-surgical treatment for HOCM.

PMID- 12411096
TI  - Apoptosis, myocardial fibrosis and angiotensin II in the left ventricle of
      hypertensive rats treated with fosinopril or losartan.
AB  - OBJECTIVE: To investigate the different effects of an angiotensin II type 1
      (AT(1)) receptor antagonist, losartan, and an angiotensin converting enzyme (ACE)
      inhibitor, fosinopril, on cardiomyocyte apoptosis, myocardial fibrosis, and
      angiotensin II (Ang II) in the left ventricle of spontaneously hypertensive rats
      (SHRs). METHODS: SHRs of 16-week-old were randomly divided into 3 groups: SHR-L
      (treated with losartan, 30 mg.kg(-1) x d(-1)), SHR-F (treated with fosinopril, 10
      mg x kg(-1) x d(-1)), and SHR-C (treated with placebo). Each group consisted of
      10 rats. Five rats, randomly selected from each group, were killed at the 8th and
      16th week after treatment. Cardiomyocyte apoptosis, collagen volume fraction
      (CVF), perivascular collagen area (PVCA) and Ang II concentrations of plasma and
      myocardium were examined. RESULTS: Compared with the controls at the 8th and 16th
      week, systolic blood pressures were similarly decreased in both treatment groups.
      Left ventricular weight and left ventricular mass indexes were significantly
      lower in both treatment groups. However, the latter parameter at the 16th week
      was reduced to a less extent in the fosinopril group than that in the losartan
      group. Compared with the controls, cardiomycyte apoptotic index was significantly
      reduced at the 8th week only in the fosinopril group, and at the 16th week in
      both treatment groups. The index of the fosinopril group was lower than that of
      the losartan group at the latter endpoint examined. Compared with the controls,
      the left ventricular collagen volume fraction and perivascular collagen area at
      the 8th and 16th weeks were significantly reduced in the SHRs treated with either
      fosinopril or losartan. However, the collagen volume fraction at the latter
      endpoint in the fosinopril group was lower than that in the losartan group.
      Compared with the controls at endpoints, plasma and myocardium Ang II levels were
      significantly increased in the losartan group. However, plasma Ang II
      concentrations were not altered, and myocardium Ang II concentrations at the 8th
      and 16th weeks were significantly reduced in the fosinopril group. CONCLUSIONS:
      Both losartan and fosinopril could effectively inhibit cardiomyocyte apoptosis
      and myocardial fibrosis and reverse heart hypertrophy. Fosinopril may be more
      effective in these cardioprotective effects, suggesting that the effects of both
      drugs are related to the inhibition of myocardium renin-angiotension-aldsterone
      system.

PMID- 12411097
TI  - Differences between hepatic and biliary lipid metabolism and secretion in
      genetically gallstone-susceptible and gallstone-resistant mice.
AB  - OBJECTIVE: To investigate differences between hepatic and biliary lipid
      metabolism and secretion of genetically gallstone-susceptible (C57L) and
      resistant (AKR) mice and the mechanism of cholesterol gallstone formation.
      METHODS: The inbred C57L and AKR mice were fed a lithogenic diet containing 15%
      fat, 1.25% cholesterol and 0.5% cholic acid for four weeks. Hepatic cholesterol
      content and secretion rates of biliary lipids, as well as phenotypes of the liver
      and gallbladder were determined and examined before and after the feeding of the
      lithogenic diet. RESULTS: Both before and after ingestion of the lithogenic diet,
      hepatic secretion rates of all biliary lipids in C57L mice were markedly higher
      than that of AKR mice (P < 0.05, P < 0.01, respectively), whereas hepatic
      cholesterol contents of C57L mice were significantly lower than that of AKR mice
      (P < 0.05). Furthermore, after consumption of the lithogenic diet, the increase
      in hepatic secretion rate of biliary cholesterol in C57L mice was significantly
      higher than that in AKR mice (P < 0.01). Cholesterol gallstones formed in C57L
      mice and fatty livers developed in AKR mice. CONCLUSIONS: Biliary cholesterol
      hypersecretion is the key pathophysiological defect of gallstone formation, lith
      genes have effects on biliary cholesterol hypersecretion and susceptibility to
      cholesterol gallstone formation in C57L mice. Lithogenic bile is formed at the
      canalicular membrane and precedes the development of cholesterol gallstones. It
      is most likely that cholesterol and bile acid hyposecretion make the AKR strain
      susceptible to the development of fatty livers and resistant to gallstone
      formation.

PMID- 12411098
TI  - Serum-free culture of dendritic cells from patients with chronic myeloid leukemia
      in vitro and estimation of their cytotoxicity.
AB  - OBJECTIVE: To establish a serum-free culture system of dendritic cells (DCs) from
      chronic myeloid leukemia (CML) cells so that DCs vaccine may be applied to the
      adoptive immunotherapy of CML in the near future. METHODS: Fetal calf serum,
      serum-free medium and autologous serum were used for culture of DCs. The usage of
      cytokines was classified into two groups: group A (stem cell factor,
      granulocyte/macrophage colony-stimulating-factor, tumor necrosis factor-alpha and
      interleukin-4) and group B (granulocyte/macrophage colony-stimulating-factor,
      tumor necrosis factor-alpha and interleukin-4). The phenotypes of DCs were
      analyzed by using indirect immunofluorescence and flow cytometry. Mixed leukocyte
      responses were performed by methyl thiazolyl tetrazolium (MTT) assay. Chromosome
      analysis of DCs can be achieved by displaying G banding. T cells from CML
      patients were stimulated with autologous DCs and T-cell cytotoxicity was measured
      by (MTT) assay. RESULTS: CD34(+) cells or mononuclear cells were obtained from
      peripheral blood or bone marrow samples of eight patients of chronic-phase CML.
      Group A of serum-free medium was better than group B in expansion of total cell
      numbers and the rate of DCs. These results of serum-free medium were not
      significantly different from those of fetal calf serum medium, but the results of
      autologous serum medium were inferior to two groups above. The expression of
      major histocompatibility complex class II antigen on the surface of DCs was
      notable (> 50%), but the expression of CD83 and the costimulatory molecules CD86
      was not noticeable (10% - 50%). Although CD1a(+)/CD14(-) DCs were potent
      stimulators of allogeneic lymphocytes, expansion of T cells from normal
      volunteers were not significant (average 27.2 fold at DCs: T cells ratio of
      1:10). At day 12, CD1a(+) cells from three patients were studied by displaying G
      banding and Ph(+) cells in these populations were 100%, 98% and 60%,
      respectively. At an effector: target ratio of 40:1, 32% to 45% cytotoxicity was
      noted with DC-stimulated T cells against autologous leukemia cells. CONCLUSIONS:
      A stable serum-free culture system of CML-DCs was established. The expression of
      CD83 and CD86 on the surface of CML-DCs and DCs' potent stimulation of allogeneic
      lymphocytes were not notable. DCs in CML patients can be derived from the
      malignant clone and these malignant DCs could induce anti-leukemic reactivity in
      autologous T lymphocytes without the necessity for additional exogenous antigens.

PMID- 12411099
TI  - Glomerular chemokine expression and the effect of steroid and cyclophosphamide
      pulse therapy in human crescentic glomerulonephritis.
AB  - OBJECTIVE: To study glomerular expression of C-C chemokines, monocyte
      chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1alpha and
      beta (MIP-1alpha, MIP-1beta) and the effect of steroid and cyclophosphamide (CTX)
      intermittent intravenous pulse therapy on expression in patients with crescentic
      glomerulonephritis (CGN) to further investigate the underlying mechanism of the
      treatment. METHODS: Twelve patients with initial biopsy-proven CGN(2), 6 with
      lupus nephritis (lupus-CGN, LN-CGN) and 6 with vasculitis, (vasculitis-CGN, V
      CGN) were enrolled in this study. They underwent an initial biopsy before steroid
      and CTX intermittent intravenous pulse therapy and were biopsied again one to
      three months later. Expression of MCP-1, MIP-1alpha, MIP-1beta, and CD68 in
      glomeruli with cellular and fibrocellular crescents were examined by
      immunohistochemical analysis in serial sections of renal biopsies. The effect of
      the pulse therapy on histopathological changes was also observed. RESULTS:
      Although steroid and CTX intermittent intravenous pulse therapy markedly reduced
      the degree of glomerular crescent formation both in LN-CGN and V-CGN, the effect
      of the therapy on glomerular chemokine expression was significantly different
      between LN-CGN and V-CGN. It was found that steroid and CTX intermittent
      intravenous pulse therapy reduced the expression of CD68, MCP-1, and MIP-1alpha,
      but had no effect on MIP-1beta in glomeruli with cellular crescents of patients
      with LN-CGN. In patients with V-CGN, the therapy also reduced the expression of
      CD68, but had no effect on MCP-1, MIP-1alpha, and MIP-1beta in glomeruli with
      cellular crescents. It was noted that the degree of glomerulosclerosis and
      tubular interstitial fibrosis increased more significantly at the second biopsy
      in V-CGN as compared to LN-CGN. CONCLUSIONS: The efficacy of steroid and CTX
      intermittent intravenous pulse therapy in CGN might be affected by reduction of
      glomerular chemokine expression. The different changes in glomerular expression
      of MCP-1 and MIP-1alpha in patients with LN-CGN and V-CGN after pulse therapy may
      correlate to different responses to treatment and prognosis.

PMID- 12411100
TI  - Association of GYS1 and beta(3)-AR gene with postprandial hyperglycemia and serum
      uric acid in type 2 diabetes mellitus.
AB  - OBJECTIVE: To determine the relationships of Met416Val and XbaI polymorphism of
      muscle glycogen synthase (GYS1) gene and Trg64Arg variant of the beta(3)
      adrenergic-receptor (beta(3)-AR) gene with type 2 diabetes mellitus (DM) and its
      intermediate phenotypes in the Chinese population. METHODS: Polymerase chain
      reaction-oligonucleotide ligation assay and restriction fragment length
      polymorphism assay were used to evaluate the GYS1 and beta(3)-AR gene
      polymorphisms in 102 pairs of case-control Chinese spouses. RESULTS: Subjects
      with Met416Val variant had a significantly higher 2-hour post-glucose level than
      subjects without this variant had in diabetic group (P = 0.032). The Met416Val
      polymorphism of GYS1 gene was not significantly associated with the risk of type
      2 DM (adjusted OR = 1.67; 95% CI: 0.73 - 3.81, P = 0.223). Subjects with Trp64Arg
      variant had a significantly higher serum uric acid level than subjects without
      this variant had in diabetic group (P = 0.034). The combination of BMI and Arg64
      allele carrier of the beta(3)-AR gene increased the diabetic risk over four-fold
      (adjusted OR = 4.00; 95% CI: 1.53 - 10.45, P = 0.005). CONCLUSIONS: In the
      Chinese population, Met416Val polymorphism is identified in a subgroup of
      diabetic subjects with high 2-hour post-glucose. It will explain why some
      diabetic patients appear to be genetically predisposed to developing high
      postpradial glucose level. The presence of the Arg64 allele in the beta(3)-AR
      gene may predispose patients to higher serum uric acid level.

PMID- 12411101
TI  - A clinical study of eosinophilic meningoencephalitis caused by
      angiostrongyliasis.
AB  - OBJECTIVE: To improve the clinician's awareness of angiostrongyliasis. METHODS:
      The clinical and laboratory data as well as the epidemiological information
      concerning 18 patients with eosinophilic meningoencephalitis caused by
      Angiostrongylus cantonensis were analyzed. RESULTS: All patients had a history of
      eating raw fresh water snail (Ampularium canaliculatus) before the onset of the
      disease. Incubation period ranged from 1 to 25 days. The major symptoms of the
      patients had severe headache and pain in the trunk and limbs. Increased
      eosinophlic count in peripheral blood and cerebrospinal fluid was noted. Tested
      by enzyme-linked immunoadsorbent assay (ELISA), sera were specifically IgG
      antibody positive against Angiostrougylus cantonensis antigen, but were negative
      against other parasitic antigens such as Paragonimus westermani, Cysticerus,
      Cellulosae hominis, Echinococcus granulosus and Trichinella spiralis. Abnormal
      spotty signals were found in 2 cases with brain magnetic resonance imaging.
      Electroencephalogram (EEG) showed slow alpha rhythm. All the patients were
      effectively treated with combined administration of albendazole and
      dexamethazone. CONCLUSIONS: Angiostrongyliasis is one of the common causes
      leading to eosinophilic meningoencephalitis. To our knowledge, Wenzhou is the
      first small outbreak site of angiostrongyliasis discovered in Chinese mainland.

PMID- 12411102
TI  - Protective effects of Ginkgo biloba extract on rats during cerebral
      ischemia/reperfusion.
AB  - OBJECTIVE: To study the effect of Ginkgo biloba extract on rats during
      ischemia/reperfusion and its influence on intracellular calcium in hippocampal
      neurons. METHODS: Model of intraluminal occlusion of the middle cerebral artery
      (MCAO) was used to prepare the ischemia/reperfusion cortex tissue. Concentration
      of MDA was determined by measuring thiobarbituric acid-reactive substance. GSH-PX
      was quantified using the thiobarbituric acid (TBA) technique. SOD was assayed
      througha xanthine method. Endogenous amino acids were quantified by high
      performance liquid chromatographic (HPLC) analysis. Primary culturs of
      hippocampal neurons were prepared for a free intracellular calcium ([Ca(2+)]I)
      assay by Fura-2 based single cell microfluoremetric technique. RESULTS: Comparing
      control and treatment groups, the concentration of SOD and GSH-PX were higher,
      whereas that of MDA was much lower; the concentration of glutamate and aspartate
      decreased and that of GABA increased markedly at all time point (P < 0.01), Gly
      also decreased at some time points (P < 0.05). The differences were significant
      between the groups of 10 mg/kg, 15 mg/kg and the groups of 5 mg/kg. When 1 x 10(
      5) mol/L glutamate was applied with 25 micro g/ml ginkgo biloba extract to
      cultured neurons, the increase in [Ca(2+)]I was lower than that caused by
      applying glutamate alone. Its peak value was much lower and increased phase was
      longer, its declining phase was shorter. After returning to baseline, the
      application of 1 x 10(-5) mol/L glutamate could induce the reaction to recover.
      CONCLUSIONS: Ginkgo biloba extract could protect damaged neurons by keeping the
      balance of inhibitory/excitatory aminoacids, enhancing the free radical
      scavengers system, and inhibiting the effect of glutamate on [Ca(2+)]I.

PMID- 12411103
TI  - Contrast study on cognitive function with MRI and positron emission tomography
      imaging in transient global amnesia.
AB  - OBJECTIVE: To study cognitive function and cerebral metabolic changes in patients
      with transient global amnesia (TGA). METHODS: Three patients with TGA were given
      mini-mental state examination (MMSE), revised Wechsler memory scale (WMS-R)
      examination and magnetic resonance imaging (MRI) scans after they had been
      diagnosed as TGA. Using (18)F labelled deoxyglucose as tracer, patients were
      given a positron emission tomography (PET) examination at different periods
      during recovery. RESULTS: No obvious abnormality was found in MMSE and MRI scans
      in the three patients. However, WMS-R examination and cerebral PET imaging
      displayed cognitive dysfunction of varying degrees and low metabolism in local
      areas related to memory in 2 of 3 patients. CONCLUSIONS: In TGA patients,
      cognitive function and cerebral metabolic levels are closely correlated with
      duration of symptoms. It is necessary to stop the TGA attack as quickly as
      possible early time.

PMID- 12411104
TI  - Characterization and E protein expression of mutant strains during persistent
      infection of KN73 cells with Japanese encephalitis virus.
AB  - OBJECTIVE: To study the character of mutants originating from Japanese
      encephalitis viruses and the relationship between the characterization of mutant
      strains and E protein expression. METHODS: Persistent infection was established
      with standard strains of Japanese encephalitis viruse, known as parental viruse,
      in a human hepatoma cell line, KN73. Cells were subcultured weekly using
      trypsinization techniques. Cell-associated viruses of persistently infected cells
      were collected by a freeze and thaw method. Virus titers were examined by plaque
      method using baby hamster kidney (BHK) cells. Indirect immunofluorescence assays
      were used to examine E and NS3 protein antigens. Western blot analysis was used
      to test expression of E and NS3 proteins. RESULTS: In the early phase (24 - 36 h)
      post-infection, virus titer in culture fluid from KN73 cells infected with
      parental viruses were 10(6) PFU/ml. They were 10(3 - 4) PFU/ml in the late phase
      (3 years) post-infection. The titer of cell-associated viruse was 10(2 - 3)
      PFU/ml. A virus super-infection assay found that virus titers in culture fluid
      from persistently infected KN73 cells acutely super- infected with parental
      viruses were much lower than that of culture fluids in acutely infected normal
      KN73 at the same phase. Indirect immunoflurescence assay revealed that the
      quantity of viral antigens in persistently infected KN73 cells was lower than
      that in acutely infected KN73 cells with parental viruses. Western blot analyses
      indicated that the molecular weights of E and NS3 proteins were 53 kD and 73 kD,
      respectively. Expression of NS3 protein in persistently infected KN73 cells was
      stable but expression of E protein was markedly suppressed. CONCLUSIONS: The
      virulence and reproduction of viruses obtained from persistently infected KN73
      cells, which have some features of DI viruses and were involved in persistent
      infection, was lower than that of parental viruses. These mutants may have be
      related to the decrease in E protein expression.

PMID- 12411105
TI  - Fractionated-clamping for thoracoabdominal aortic aneurysm repair: a modified
      Crawford technique.
AB  - OBJECTIVE: To apply fractionated-clamping for repair of thoracoabdominal aortic
      aneurysm (TAA), and evaluate its effects in decreasing surgical mortality and
      severe complications, such as renal failure and paraplegia, a modified crawford
      procedure were prospectively evaluated. METHODS: Using modified shunting and
      cross-clamping techniques, modified Crawford repair in 13 thoracoabdominal aorta
      patients were performed in the Vascular Division at Peking Union Medical College
      Hospital. TAA Crawford classification: 1 type I, 2 type II, 2 type III and 3 type
      IV TAA. Debakey classification: 1 type I, 4 type III (including 2 ruptured
      aneurysms), and 1 aortic coarctation. RESULTS: Thirteen procedures were performed
      successfully. One died of ventricular fibrillation just before completing the
      operation. Surgical mortality rate was 7.7% (1/13). Postoperative complications
      included 1 acute necrotic pancreatitis, 1 ARDS, 1 paraplegia, 1 acute renal
      failure, and 2 thoracic cavity bleeding. Total complication rate was 53.8%
      (7/13). CONCLUSIONS: Fractionated-clamping in thoracoabdominal aortic aneurysm
      repair is our modified Crawford procedure and aortic bypass. Clinical results
      demonstrate that our procedure decreased surgical mortality and major
      complication rate, and also alleviated viscera ischemic injury. Fractionated
      clamping in aorta replacement is a practical procedure for TAA repair under
      general anesthesia at normal temperature.

PMID- 12411106
TI  - High-intensity focused ultrasound in patients with late-stage pancreatic
      carcinoma.
AB  - OBJECTIVES: To observe the efficacy of high intensity focused ultrasound (HIFU)
      in the treatment of late-stage pancreatic carcinoma and evaluate its influence on
      cell-mediated immunity in the host. METHODS: Fifteen patients with late-stage
      pancreatic carcinoma had their tumor tissue completely destroyed with HIFU.
      Evaluation of efficacy was made on the basis of clinical symptom changes,
      variations in tumor echo, changes in pancreatic amylase, serum CA19-9 and CA242,
      CD3(+), CD4(+) subsets, CD4(+)/CD8(+) ratios and NK cell activity. RESULTS:
      Clinical symptoms such as pain were significantly alleviated, echo of tumor was
      enhanced with B-US, CA19-9 and CA242 were decreased and pancreatic amylase showed
      no change. Eating, sleeping and mental status were all markedly improved; no
      serious complications were seen. On the other hand, NK cell activity was
      significantly enhanced in 10 patients (P < 0.05), and CD3(+) and CD4(+) subsets
      as well as CD4(+)/CD8(+) ratios increased to different degrees. CONCLUSIONS: The
      use of HIFU in the treatment of late-stage pancreatic carcinoma is feasible and
      safe. It is effective in destroying the carcinoma and alleviating abdominal pain;
      it may enhance cell-mediated immunity in the host. This technique may offer a
      noninvasive therapy for the treatment of late-stage pancreatic carcinoma.

PMID- 12411107
TI  - Effect of surgical castration on risk factors for arteriosclerosis of patients
      with prostate cancer.
AB  - OBJECTIVE: To analyze the effect of castration on risk factors for
      arteriosclerosis of patients with prostate cancer. METHODS: Thirty patients with
      primary regional prostate adenocarcinoma limited to the prostate theca were
      selected in this study. Serum levels of testosterone (T), free testosterone (FT),
      dehydroepiandrosterone (DHEA), sex hormone-binding globulin (SHBG), prostatic
      specific antigen (PSA), triglyceride (TG), total cholesterol (TC), high density
      lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C),
      apoprotein alpha(1) (APOalpha(1)) and apoprotein beta (APObeta), insulin, plasma
      fibrinopeptide A (FPA), plasminogen activator inhibitor-1 (PAI-1) and fibrinogen
      were determined just prior to, 1 week and 1, 4 and 8 months after castration.
      RESULTS: T, FT and PSA decreased significantly 1 week after castration (21.12 +/-
      15.11 ng/ml vs 383.9 +/- 62.6 ng/ml, P < 0.001; 4.08 +/- 3.29 pmol/L vs 34.11 +/-
      11.59 pmol/L, P < 0.001; 14.34 +/- 7.77 ng/ml vs 23.51 +/- 6.57 ng/ml, P = 0.001,
      respectively) and continued to decrease until reaching their lowest levels 8
      months after castration. DHEA and SHBG did not undergo any changes. TG, fasting
      insulin and glucose, 2-hour insulin and glucose levels were significantly
      elevated 1 month after castration (1.84 +/- 0.61 mmol/L vs 1.30 +/- 0.40 mmol/L,
      P < 0.05; 18.16 +/- 5.57 mU/L vs 9.47 +/- 3.81 mU/L, P < 0.05; 4.77 +/- 0.66
      mmol/L vs 3.92 +/- 0.34 mmol/L, P < 0.05; 65.52 +/- 14.78 mU/L vs 36.94 +/- 17.12
      mU/L, P < 0.01; 6.98 +/- 0.79 mmol/L vs 6.01 +/- 0.23 mmol/L, P = 0.001,
      respectively). TC, LDL-C, FPA and PAI-1 levels were elevated 4 months after
      castration (6.56 +/- 0.99 mmol/L vs 5.29 +/- 0.75 mmol/L, P < 0.01; 4.09 +/- 0.86
      mmol/L vs 3.04 +/- 0.15 mmol/L, P < 0.01; 3.39 +/- 1.67 nmol/L vs 1.48 +/- 0.50
      nmol/L, P < 0.01; 27.02 +/- 5.98 ng/ml vs 21.78 +/- 3.16 ng/ml, P < 0.05,
      respectively), continuing to increase after that point. Insulin sensitive index
      (ISI) decreased significantly 1 month after surgery (-4.42 +/- 0.36 vs -3.50 +/-
      0.39, P < 0.001), and continued to decrease from that point forward. HDL-C,
      APOalpha(1), APObeta and fibrinogen remained at pre-operative levels. There was a
      negative linear correlation between FT and TG, TC, LDL-C, PAI-1, FPA, fasting
      insulin and glucose, 2-hour insulin and glucose (r = -0.311, -0.384, -0.385, 
      0.339, -0.353, -0.381, -0.303, -0.460 and -0.395, respectively; P < 0.05). A
      similar phenomenon occurred with T (r = -0.308, -0.309, -0.356, -0.320, -0.430, 
      0.453, -0.435, -0.483 and -0.512, respectively; P < 0.05). T and FT were
      positively associated with ISI (r = 0.555 and 0.501; P < 0.001). CONCLUSIONS: At
      8 months follow-up of the study subjects, we found that lower androgen levels
      have adverse effects on lipid metabolism, coagulative function and insulin
      sensitivity, related to arteriosclerosis in men.

PMID- 12411108
TI  - Multicentricity and its associated factors in renal cell carcinoma.
AB  - OBJECTIVE: To investigate the incidence and associated factors of multicentricity
      in renal cell carcinoma (RCC) in Chinese patients. METHODS: One hundred and two
      kidney samples from radical nephrectomy due to RCC were step sectioned at 3 mm
      intervals and examined. All tissue abnormalities were removed, stained and
      examined for multicentricity. Then, on each slice of the sample, both the
      parenchymal margin of 15 mm beyond the pseudocapsule and tissue around the renal
      sinus were continuously sectioned and examined for completeness of the
      pseudocapsule and vascular and lymph node invasion. The relationship between
      muliticentricity and other pathological parameters was evaluated. RESULTS: The
      incidence of multicentricity was 15.7% (16/102); it was significantly lower in
      primary tumors < or = 4.0 cm than in tumors > 4.0 cm (4.9%, 2/41 vs 23.0%, 14/61;
      chi(2) = 6.055, P = 0.014). The incidence was 9.8% (8/82) in tumors without
      vascular invasion and 40.0% (8/20) in those with it (P = 0.003, Fisher's exact
      test). The incidence of multicentricity was 1.9% (1/53) in tumors with a complete
      pseudocapsule and 30.6% (15/49) in those without it (chi(2) = 15.885, P = 0.000).
      The grade, stage, subtypes and lymph node invasion of the primary tumor were not
      significantly associated with multicentricity. Multiple logistic regression
      analysis showed that pseudocapsular incompleteness and vascular invasion were two
      significant predictors of RCC multicentricity (P = 0.005 and 0.023). CONCLUSIONS:
      The incidence of multicentricity of RCC in this group of patients was in
      accordance with published studies. Multifocality was significantly associated
      with tumor size, pseudocapsule completeness and vascular invasion. NSS should be
      limited to tumors less than 4.0 cm when the contralateral kidney is normal and
      careful long-term follow-up is necessary in tumors with positive vascular
      invasion and incomplete pseudocapsule.

PMID- 12411109
TI  - Implementation of percutaneous dilatational tracheostomy on neurosurgical coma
      patients.
AB  - OBJECTIVE: To present the authors' experience with percutaneous dilatational
      tracheostomy (PDT), with special attention to early and late complications,
      outcomes, and primary disease influence. METHODS: Between November 2000 and May
      2001, 22 PDTs were performed with the aid of dilatating forceps in 21
      neurosurgical coma patients. A Seldinger wire was introduced through a cannula
      into the trachea serving as a guide. The guidewire was threaded through the
      clamped guidewire dilating forceps and the forceps was advanced through the
      tracheal wall. The trachea was dilated by opening forceps. The guidewire was then
      threaded through the obturator of the tracheostomy tube and both were advanced
      into the trachea. Demographic data, patient disease variables and patient
      anatomical features, as well as perioperative and late complications were
      recorded prospectively. RESULTS: Completion of the procedure consumed 4 - 16
      minutes (mean, 12 minutes). The procedure caused complications in 3 operations: 2
      cases of stomal bleeding, 1 of intratracheal bleeding, but there was no severe
      tracheal injury or mediastinal emphysema. Furthermore, none of the cases required
      intervention due to complications. All patients were followed up for 1 to 6
      months. Tracheostomy tubes were removed in 16 patients. All cervical incisions
      were closed with cosmetic demand. Two patients with tracheostomy tubes were
      retained for primary diseases. Causes of death in 3 others were unrelated to the
      PDT. No patient developed tracheomalacia or tracheal stenosis as a late
      complication. CONCLUSIONS: Percutaneous dilatational tracheostomy is a fast, safe
      and simple procedure for neurosurgical coma patients and can be safely performed
      by neurosurgeons.

PMID- 12411110
TI  - Decline in the expression of IL-2 after trauma and changes in the nuclear
      transcription factors NFAT and AP-1.
AB  - OBJECTIVE: To investigate whether the decrease in expression of interleukin-2 (IL
      2) after trauma is associated with changes in DNA binding activity of nuclear
      factor of activated T cells (NFAT) and activator protein-1 (AP-1). METHODS: Mice
      with closed impact injury with fracture in both hind limbs were adopted as the
      trauma model. Spleen lymphocytes were isolated from traumatized mice and
      stimulated with Con-A. Culture supernatants were assayed for IL-2 activity, and
      total RNA was extracted from spleen lymphocytes and assayed for IL-2 mRNA. DNA
      binding activity of NFAT and AP-1 were measured by electrophoretic mobility shift
      assay (EMSA). The expression of c-Fos, c-Jun and JunB proteins was determined by
      the Western blot analysis. RESULTS: DNA binding activity of NFAT and AP-1
      gradually decreased to a minimum of 41% and 49%, respectively, of the control on
      the 4th day after injury, which was closely followed by the decline in IL-2
      activity and IL-2 mRNA. A decrease in the expression of c-Fos on the 1st and 4th
      day after trauma had no significant effect on c-Jun expression; the increase in
      expression of JunB was only on the 1st day after injury. CONCLUSION: Decreased IL
      2 expression is, at least in part, due to a decline in the activation of NFAT and
      AP-1 in traumatized mice. The decline in DNA binding activity of NFAT and AP-1 is
      partly due to a trauma-induced block in the expression of c-Fos.

PMID- 12411112
TI  - Diagnostic significance of ultrasonography and CT for large upper abdominal mass.
AB  - OBJECTIVE: To assess the effect of ultrasonography and computerized tomography
      (CT) in the diagnosis of large upper abdominal mass. METHODS: Data from 43 cases
      that were clinically and pathologically confirmed were retrospectively analyzed
      and the effect of their preoperative ultrasonography and CT was compared.
      RESULTS: Four of 10 (40 percent) cases of liver mass were diagnosed correctly
      using ultrasonic device, nineteen of 25 (76 percent) cases of adrenal gland mass
      and 2 of 4 cases of kidney mass. Two of 10 (20 percent) cases of liver mass were
      correctly diagnosed by CT, and so were 6 of 22 (27.2 percent) cases of adrenal
      gland mass. In 4 patients with spleen mass, neither ultrasonography nor CT
      diagnosis was correct. CONCLUSION: Because upper abdomen organs are closely
      connected with each other, correct imaging localization of a large mass in this
      region is not easy. In this study, we compared the accuracy of ultrasonography
      and CT in diagnosing large upper abdominal masses, and found that ultrasonography
      works better for adrenal rather than liver or kidney. Neither ultrasonography or
      CT could accurately diagnose a large mass in the spleen.

PMID- 12411111
TI  - Recombinant human heparin-binding neurite-promoting factor expressed with yeast
      stimulates neurites outgrowth.
AB  - OBJECTIVES: Heparin-binding neurite-promoting factor (HBNF) is a heparin-binding
      protein primarily found in the brain, which can stimulate neurite outgrowth in
      vitro. We expressed recombinant human heparin-binding neurite-promoting factor
      (hrHBNF) using a yeast system, and observed its activity in stimulating neurite
      outgrowth in vitro. METHODS: cDNA encoding mature human HBNF was amplified from
      total RNA isolated from an 18-week aborted human fetal brain by RT-PCR method.
      After amplification, the HBNF cDNA gene was cloned into pPIC9K, a shuttle
      expression vector for yeast system. The positive clone of expression vector
      bearing HBNF cDNA gene was obtained by screening. Verified recombinant vector was
      then used to transform Pichia strain GS115 by electroporation. His(+)
      transformants were selected on minimal dextrose medium (MD) plates which were
      histidine free. His(+) yeast recombinants with multi-copy inserts were screened
      in vivo by their resistance to G418. PCR analysis was used to confirm the
      integration of the HBNF cDNA gene into the Pichia genome. Secreted expression of
      hrHBNF protein in culture medium was obtained when the positive clone containing
      the HBNF cDNA gene was induced by methanol. The hrHBNF product purified by gel
      chromatography was added to cultured rat pheochromocytoma (PC12) cells to observe
      its ability to stimulate neurite outgrowth. RESULTS: In the recombinant
      expression vector, the insert was sequenced to show exactly the sequence encoding
      human HBNF according to Genbank data. The HBNF cDNA gene was cloned downstream to
      the alpha-factor, and its open reading frame was in frame with the alpha-factor
      signal sequence in pPIC9K. SDS-PAGE showed that the molecular weight of the
      induced expression product was about 18 kDa, consistent with that of human HBNF
      reported in the literature. The protein product did promote neurite outgrowth in
      cultured rat pheochromocytoma (PC12) cells. CONCLUSION: Recombinant human heparin
      binding neurite-promoting factor can be expressed with a yeast system, and its
      product possesses the biological activity to promote neurite outgrowth.

PMID- 12411113
TI  - Role of exocrine cells in pancreatic enhancement using Mn-DPDP-enhanced MR
      imaging.
AB  - OBJECTIVE: To investigate role of exocrine cells in the pancreatic enhancement
      images at Manganese (II) N, N'-dipyridoxylethlenediamine-N, N'-diacetate 5, 5'
      bisc (Mn-DPDP)-enhanced magnetic resonance (MR) imaging. METHODS: Artificial
      pancreatic leakage was constructed in six dogs using a fistula tube inserted into
      the duodenum papillae. Pancreatic juice was collected before and after
      intravenous infusion of 2 ml/kg of Mn-DPDP at a rate of 2 - 3 ml/min. The Mn
      content of pancreatic juice was measured by atomic absorption spectroscopy. T(1)
      weighted spin-echo images and T(1)-weighted spoiled phase gradient-echo (SPGR)
      images were obtained prior and approximately 30 min after the administration of
      Mn-DPDP at 1.5T. RESULTS: The Mn content of pancreatic secretion increased 60.47
      +/- 21.83 micro g/dl after the administration of Mn-DPDP (t = 6.785, P < 0.01).
      The signal/noise ratio (S/N) of the pancreas increased 53 percent +/- 49 percent
      and 62 percent +/- 44% on T(1)W spin echo images and SPGR images, respectively.
      CONCLUSIONS: Exocrine cells of the pancreas can absorb manganese and excrete it
      through the pancreatic juice. Exocrine cells play an important role in the
      enhancement of the pancreas in MR imaging with Mn-DPDP.

PMID- 12411114
TI  - Significance of changes in local immunity in patients with hepatocellular
      carcinoma after percutaneous microwave coagulation therapy.
AB  - OBJECTIVE: To assess the local immune response in patients with hepatocellular
      carcinoma after percutaneous microwave coagulation therapy (PMCT). METHODS:
      Seventy-eight patients with hepatocellular carcinoma underwent PMCT. Both
      cancerous and adjacent liver tissue were taken before, and 3, 17 and 30 days
      after PMCT using ultrasound-guided liver biopsy. Specimens were stained by
      immunohistochemical techniques for detecting CD3, CD45RO, CD56, CD68, and CD20
      positive cells. RESULTS: A few CD3, CD45RO, CD56, CD68 and CD20 positive cells
      were observed in the cancer stroma and surrounding sinusoids in liver tissue pre
      PMCT. The number of immunocytes, except for CD20 positive cells, was
      significantly increased both within the cancer and the adjacent liver tissue,
      with a larger increase in tumor tissue at day 3 post-PMCT compared with pre-PMCT.
      These immunocytes were enlarged in size. The number of CD3, CD45RO and CD56
      positive cells peaked at day 17 and CD68 positive cells peaked at days 3 post
      PMCT. At day 30 post-PMCT, this increase still existed. These infiltrating
      immunocytes distributed in the parenchyma of the tumor, and within the lumen of
      small blood vessels after PMCT. In addition, more infiltrated immune cells were
      seen in cancer cell spaces. CONCLUSIONS: A change in immunocyte infiltration
      takes place in number, configuration and location after patients with HCC are
      treated with percutaneous microwave coagulation, suggesting that local immune
      function is enhanced post-PMCT.

PMID- 12411115
TI  - Prediction of pulmonary arterial wedge pressure from arterial pressure or pulse
      oximetry plethysmographic waveform.
AB  - OBJECTIVE: To assess the possibility of using arterial pressure waveform or pulse
      oximetry plethysmographic waveform variation to estimate the pulmonary arterial
      wedge pressure (PAWP). METHODS: Fourteen American Society of Anesthesiologists
      grade I - II patients aged 33 - 69 years and weighing 62.0 +/- 9.5 kg scheduled
      for elective abdominal tumor surgery were studied. Their hemoglobin exceeded 120
      g/L and hematocrit exceeded 35 percent. Pre-operative acute hypervolemic
      hemodilution was applied immediately after general anesthestic induction and
      tracheal intubation. PAWP, systolic pressure variation (SPV), delta down (dDown),
      SPV(plet), dDown(plet) and other hemodynamic parameters were measured and
      recorded when total fluid volume (crystalloid and colloid) infused reached 10
      ml/kg and 20 ml/kg and again at the end of the operation. Central venous pressure
      was maintained at 10 - 12 mm Hg during operation. Systolic blood pressure at the
      end of Valsalva maneuver (airway pressure was kept at 22 mm Hg) and the systolic
      pressure before the Valsalva manoeuvre during apnea were used to calculate
      arterial pressure ratio (APR). RESULTS: APR, SPV, dDown, SPV(plet) and
      dDown(plet) all correlated well with PAWP (r = 0.717, -0.695, -0.680, -0.522 and 
      0.624 respectively, P < 0.01). There was a closer linear correlation between APR
      and PAWP than between the other parameters. The regression equation was PAWP (mm
      Hg) = 0.207 x APR (%) - 0.382. CONCLUSION: During positive pressure mechanical
      ventilation, APR, SPV, dDown, SPV(plet) and dDown(plet) can be used to estimate
      PAWP effectively.

PMID- 12411116
TI  - Clinical manifestations of low bone mass in amenorrhea patients with elevated
      follicular stimulating hormone.
AB  - OBJECTIVE: To study the characteristics of low bone mass in amenorrhea patients
      with elevated follicular stimulating hormone (FSH). METHODS: Amenorrhea patients
      with elevated FSH: Primary amenorrhea 18 cases, secondary amenorrhea 171 cases
      and age matched controls with normal menstruation, 180 cases. The descriptive
      parameters were: estrogen, alkaline phosphatase, urinary excretion of calcium to
      creatine ratio, cortical bone mineral density at the right radius measured by
      single photon absorptiometry and trabecular bone mineral density at the lumbar
      vertebra body measured by quantitative computerized tomography. RESULTS: Average
      E(2) levels in amenorrhea patients is under 150 pmol/L with significantly higher
      alkaline phosphatase and urine calcium to creatine ratio values than the normal
      menstruation group. Cortical bone mineral density in the secondary amenorrhea
      group (655 +/- 69 mg/cm(2)) was significantly lower than that of the normal
      menstruation group (677 +/- 56 mg/cm(2), P < 0.01). Trabecular bone mineral
      density in the secondary amenorrhea group (145 +/- 26 mg/cm(3)) was significantly
      lower than that of the NOR group (192 +/- 28 mg/cm(3), P < 0.001). The disparity
      with the normal menstruation group is even greater in the primary amenorrhea
      group. Bone mineral density of the amenorrhea patients was negatively correlated
      with duration of the menopause. CONCLUSIONS: Serum estrodiol levels in amenorrhea
      patients was so low that bone turnover was accelerated. This led to insufficient
      bone accumulation and a dramatically drop in trabecular bone mineral density. The
      extent was closely related to age of onset of amenorrhea and the duration of
      ovarian failure.

PMID- 12411118
TI  - Effect of glucocorticoid treatment on insulin like growth factor-I and its
      binding proteins in children with nephrotic syndrome.
AB  - OBJECTIVE: To identify the changes in serum insulin like growth factor-I (IGF-I)
      and IGF binding proteins (IGFBPs) in children with nephrotic syndrome (NS) and
      the effect of glucocorticoid on serum IGF-I and IGFBPs. METHODS: We measured
      serum IGF-I and IGFBPs levels by radioimmune assay and immune radiomagnetic assay
      in 36 children with NS, consisting of an active stage group (ANS, n = 12), a
      remission stage group (RE, n = 12), an active stage group with glucocorticoid
      treatment (GNS, n = 12), and a normal control group (NC, n = 10). RESULTS: 1)
      Compared to NC, serum levels of IGF-I and IGFBP-3 were decreased (P < 0.01);
      serum levels of IGFBP-1 and IGFBP-2 were increased (P < 0.01) in the ANS group.
      2) Serum levels of IGF-I and IGFBP-3 were higher and IGFBP-1 and IGFBP-2 were
      lower in the RE Group than in theANS Group (P < 0.01). 3) Compared to the ANS
      group, serum levels of IGF-I and IGFBP-3 were increased (P < 0.01) and serum
      levels of IGFBP-1 and IGFBP-2 were decreased (P < 0.01) in the GNS group. 4) A
      correlation was found between serum levels of IGFBP-3 and albumin in the active
      stage group (r = 0.76, P < 0.01). There was also a correlation between serum
      levels of IGF-I and IGFBP-3 and an inverse correlation between the serum level of
      IGF-I and serum levels of IGFBP-1 and IGFBP-2 in the ANS group. No other
      correlations were observed. CONCLUSIONS: The serum levels of IGF-I and IGFBPs are
      altered in children in the active stage of NS, but return to normal in the
      remission stage. GC treatment may influence serum IGF-I and IGFBPs in children
      with NS. Changes in IGF-I and IGFBPs levels may play a role in the growth
      retardation of NS children.

PMID- 12411117
TI  - Mechanism of peripheral blood mononuclear cell invasion by HBV on artificial
      immunization in newborns.
AB  - OBJECTIVE: To study the effect and mechanism of the peripheral blood mononuclear
      cell (PBMC) invasion by HBV on artificial immunization in newborns. METHODS:
      Fifty-two newborns of HBsAg positive mothers were immunized with HBIG (hepatitis
      B immunoglobulin) and HBVac (hepatitis B vaccine) and were followed up for 7
      months. The newborns' HBV-DNA in serum and in the PBMCs was detected with nested
      PCR; anti-HBs was tested with solid phase radioimmunoassay (SP-RIA). PBMCs
      isolated from newborn peripheral blood were incubated in the presence of PHA or
      purified HBsAg. Interleukin-2 (IL-2) level in culture supernatants of activated
      cells was detected by ELISA. RESULTS: The failure rate of immunization was higher
      in infants with positive HBV-DNA in PBMCs than those with negative HBV-DNA (P <
      0.05); IL-2 level in PBMC culture supernatants was lower in former than in the
      latter and in normal controls (P < 0.05). The level of IL-2 in the immunization
      failure newborns was lower than that in the successfully immunized newborns and
      in normal controls (P < 0.05). CONCLUSIONS: Intrauterine invasion of PBMCs by HBV
      is one of the important reasons for immunization failure in newborns. IL-2
      production is closely related to the invasion of PBMCs by HBV, which may
      contribute to the failure of artificial immunization in newborns.

PMID- 12411119
TI  - Concentration, distribution and expression of interleukin-5 in human nasal polyp
      tissues.
AB  - OBJECTIVES: To study the concentration, distribution and expression of IL-5 in
      nasal polyp tissues and explore its significance in micro-environment
      differentiation of eosinophil accumulation. METHODS: The concentration and
      expression of IL-5 in nasal polyp tissues of 40 patients were determined by ELISA
      and immunohistochemistry and inferior turbinate mucosa from patients with nasal
      polyps and healthy volunteers were used as control. RESULTS: IL-5 concentration
      in polyp tissues was significantly higher than that in turbinate mucosa (P <
      0.05). There was no significant difference in the turbinate mucosae between
      patients with nasal polyps and healthy volunteers (P > 0.05). IL-5 concentrations
      in polyp tissues were markedly higher in patients with allergic rhinitis compared
      with those without (P < 0.05). IL-5 concentrations had no correlation with age
      and sex (P > 0.05). 80.1% of the eosinophils were positive for IL-5 and 90.9% of
      IL-5 positive cells were eosinophils. Only 3.7% of lymphocytes and neutrophils
      were positive for IL-5; IL-5 was not detectable in epithelial cells. IL-5
      expression in eosinophils of polyp tissues was remarkably stronger than that of
      the turbinate mucosa (P < 0.05); there was no significant difference in the the
      turbinate mucosae between patients with nasal polyps and healthy volunteers (P >
      0.05). IL-5 expression of eosinophils in polyp tissue was significantly stronger
      in patients with allergic rhinitis compared with those without (P < 0.05). There
      was no significant difference in IL-5 expression in lymphocytes and neutrophils
      between polyp tissues and turbinate nasal mucosa (both P > 0.05). CONCLUSION: IL
      5 is the key cytokine in eosinophilic pathologic mechanisms in nasal polyp
      tissues.

PMID- 12411120
TI  - Cochlear mitochondrial DNA3867bp deletion in aged mice.
AB  - OBJECTIVES: To study the status of cochlear mitochondrial DNA (mtDNA) and to
      determine the location of mtDNA deletion in aged mice. METHODS: We detected
      cochlear mtDNA in 2, 7 - 10 and 17 - 19 month old mice by nested polymerase chain
      reaction (PCR) and DNA sequencing. RESULTS: mtDNA3867bp deletions were found in
      the cochleae of aged mice. The deletion occurred within nt9103-nt12970 and were
      flanked by 15 base pair direct repeats. Comparing the incidence of mtDNA3867bp
      deletions, 17 - 19 month old mice (7/8) were significantly higher than 7 - 10
      month old mice (4/16). The deletion was not observed in 2 month old mice (0/7).
      The ratio of deleted mtDNA/total mtDNA in 17 - 19 month old mice was higher than
      in 7 - 10 month old mice (P < 0.001). CONCLUSION: Cochlear mtDNA 3867bp deletion
      in aged mice may be related to presbycusis.

PMID- 12411121
TI  - Protection of retinal ganglion cells against glaucomatous neuropathy by
      neurotrophin-producing, genetically modified neural progenitor cells in a rat
      model.
AB  - OBJECTIVE: To investigate in vivo survival of retinal ganglion cells (RGCs) after
      partial blockage of optic nerve (ON) axoplasmic flow by sub-retinal space or
      vitreous cavity injection of brain-derived neural factor (BDNF) produced by
      genetically modified neural progenitor cells (NPCs). METHODS: Adult Sprague
      Dawley (SD) rat RGCs were labeled with granular blue (GB) applied to their main
      targets in the brain. Seven days later, the left ON was intra-obitally crushed
      with a 40 g power forceps to partially block ON axoplasmic flow. Animals were
      randomized to three groups. The left eye of each rat received a sham injection,
      NPCs injection or an injection of genetically modified neural progenitors
      producing BDNF (BDNF-NPCs). Seven, 15 and 30 days after ON crush, retinas were
      examined under a fluorescence microscope. By calculating and comparing the
      average RGCs densities and RGC apoptosis density, RGC survival was estimated and
      the neuro-protective effect of transplanted cells was evaluated. RESULTS: Seven,
      15 and 30 days after crush, in the intra-vitreous injection group, mean RGC
      densities had decreased to 1885 +/- 68, 1562 +/- 20, 1380 +/- 7 and 1837 +/- 46,
      1561 +/- 58, 1370 +/- 16, respectively with sham injection or neural progenitors
      injection. However, RGCs density in the groups treated with intra-vitreous
      injection of BDNF-NPC was 2101 +/- 15, 1809 +/- 19 and 1625 +/- 34. Similar
      results were found in groups after sub-retinal injection. Higher densities were
      observed in groups treated with BDNF-NPCs. There were statistically significant
      differences among groups through nonparametric tests followed by the Mann-Whitely
      test. RGC apoptosis density in BDNF-NPC at each follow-up time was less than in
      other groups. CONCLUSIONS: A continuous supply of neurotrophic factors by the
      injection of genetically modified neural progenitors presents a highly effective
      approach to counteract optic neuropathy and RGC degeneration after partial ON
      axoplasmic flow blockage.

PMID- 12411122
TI  - Expression of betaig-h3 in keratoconus and normal cornea.
AB  - OBJECTIVES: To observe the expression of betaig-h3 in normal cornea and
      keratoconus and to elucidate the role of extracellular matrix in keratoconus.
      METHODS: In situ hybridization was used to detect the expression of betaig-h3 in
      the cornea. The cDNA library was screened with human betaig-h3 cDNA probe to
      locate betaig-h3 mRNA in cells. RESULTS: Expression of betaig-h3 was found mainly
      in the stroma of the normal cornea and keratoconus, but decrease depending on the
      degree of keratopathy. In some serious cases, no expression signal was detected.
      The strongest expression was seen at the border of the normal region and
      keratoconus. CONCLUSIONS: betaig-h3, the structural component of the
      extracellular matrix, can affect cell adhensiveness in the development of corneal
      fibrous interstitial organization. During the development of keratoconus,
      decreasing levels of betaig-h3 cause the diminution of corneal steadiness, which
      is related to formation of keratoconus.

PMID- 12411123
TI  - Telomerase activity analysis of esophageal carcinoma using microdissection-TRAP
      assay.
AB  - OBJECTIVES: To investigate telomerase activity in esophageal squamous cell
      carcinoma (SCC) and its preneoplasia lesions, and to study the relationships
      between telomerase activity and cancer differentiation, cancer invasiveness, and
      lymphatic metastasis. METHODS: Telomerase activity in esophageal SCC tissues,
      adjacent dysplasia tissues and normal epithelia from the surgical edge were
      assessed by microdissection-TRAP (telomeric repeat amplification protocol)-silver
      staining assay. RESULTS: Telomerase activity was detected in 37 (82.2%) of 45
      esophageal tumors, 23 (79.3%) of 29 dysplasias, and 2 (5%) of 40 normal
      epithelia. There was a significant difference in activity between dysplasia and
      normal epithelium, as well as between tumor and normal epithelium. Twenty-six
      (92.9%) of 28 tumors with lymphatic metastasis had detectable telomerase activity
      compared to 11 (64.7%) of 17 non-lymphatic metastasis tumors. These relationships
      were statistically significant (P < 0.05), but the one between telomerase
      activity and tumor grade was not. CONCLUSION: Telomerase activity was high both
      in esophageal SCC and their preneoplasia lesions. The telomerase activity in SCC
      tissue was related to lymphatic metastasis, but not to cancer differentiation.

PMID- 12411124
TI  - Clinical course and cause of death in elderly patients with idiopathic
      Parkinson's disease.
AB  - OBJECTIVE: To improve the therapeutic and preventive measure for elderly patients
      (75 years and over) with idiopathic Parkinson's disease (OEIPD). METHODS: Fifteen
      OEIPD patients were observed prospectively over a long period of time. Their
      diagnosis was confirmed by autopsy. Based on clinical and pathological data, the
      causes of death were analyzed. RESULTS: The mean clinical course in OEIPD
      patients was 6.2 +/- 3.6 years. The majority of the 15 patients were the akinetic
      type and the akinetic type with tremor (80.0%). In the late stages of disease
      (4.8 +/- 3.5 year), choking occurred in 12 OEIPD patients who received nasal
      feeding for an average of 4 months after the occurrence of choking. The most
      common complication in 12 patients was repeated pulmonary infections with an
      average rate of 2.9 +/- 1.9. The causes of death were bronchial pneumonia and
      shock induced by pulmonary infection (11 cases, accounted for 73.3%), acute
      myocardial infarction (2 cases), one case with cardiac rupture and one case with
      rupture of aortic aneurysm. CONCLUSIONS: The clinical course was shorter in OEIPD
      patients. Levodopa therapy should be started early in OEIPD patients. Bronchial
      pneumonia and infectious shock constitute the major cause of death and choking
      was one of the main causes of aspiration pneumonia. Nasal feeding should be
      started as early as possible after the appearance of choking. Silent aspiration
      can be reduced by teaching the patient to protect the airway by 'supraglottic
      swallowing'.

PMID- 12411125
TI  - Clinical pathological analysis and immunohistochemical study of ten solitary
      fibrous tumors.
AB  - OBJECTIVE: To study the clinical and pathological characteristics of solitary
      fibrous tumor (SFT). METHODS: Clinical pathological analysis and
      immunohistochemical studies were performed on ten patients with SFT. RESULTS: The
      SFTs located variously and showed different histological features. All cases
      showed positive staining for CD(34), VM (vimentin) and Bcl-2, but negative
      staining for Desmin, S-100, CK (cytokeratin) and EMA (epithelial membrane
      antigen). CONCLUSIONS: SFT is described as a "patternless" growth pattern.
      According to clinical pathological features and immunohistochemistry, it is
      different from other soft tissue tumors. Long-term clinical follow-up is
      necessary for this kind of tumor.

PMID- 12411126
TI  - Identification of Streptococcus species and Haemophilus influenzae by direct
      sequencing of PCR products from 16S-23SrDNA intergenic spacer regions.
AB  - OBJECTIVE: To set up a rapid and simple method for identificating bacteria by 16S
      23SrDNA intergenic spacer regions (ISRs). METHODS: Polymorphic products of PCR
      from ISRs were selected on agarose gel and sequenced directly using purified
      fragments by excising the gel without cloning. Nucleotide sequences were compared
      with GenBank databases and analyzed by DNAMAN program. RESULTS: There was only a
      single product in streptococcus genus after PCR amplification of 16S-23SrDNA
      ISRs. Five streptococcal species were obtained from 7 strains of streptococcus.
      Two major amplicons were consistently generated for 8 strains of Haemophilus
      influenzae (H. influenzae). The sequence data showed that they all belonged to H.
      influenzae type b on GenBank databases. CONCLUSION: PCR and direct sequencing of
      16S-23SrDNA ISRs were very successful methods for bacterial species
      identification.

PMID- 12411127
TI  - Intramedullary spinal cord germinoma: a case report.

PMID- 12411128
TI  - Strangulated obturator hernia: report of 2 cases.

PMID- 12411129
TI  - [The long-term effects of retrograde liberated highly selective vagotomy in
      treatment of duodenal ulcer].
AB  - OBJECTIVE: To evaluate the long-term effects of retrograde liberated highly
      selective vagotomy (RLHSV) in the treatment of duodenal ulcer. METHODS: Seventy
      patients with duodenal ulcers complicated by stenosis, bleeding, or perforation
      were operated on by retrograde liberated highly selective vagotomy. Among these
      patients, 61 had perforated duodenal ulcers, 6 bleeding and 3 stenosis. RESULTS:
      Followed up for 30 to 120 months in 65 patients showed a recurrence rate 7.69%
      and no hemorrhage occurs. According to the modified Visick grading system, 56
      patients (86.2%) were of Visick I, 4 (6.1%) of Visick II, 2 (3.0%) Visick III, 3
      (4.6%) Visick IV, and (92.3%) Visick I or II. CONCLUSIONS: This modified
      procedure is rapid, easy and radical operation with excellent long-term results.
      It can be considered an effective alternative for the treatment of duodenal ulcer
      with complication.

PMID- 12411130
TI  - [Long-term curative effects of suture plus proximal gastric vagotomy or triad
      therapy for duodenal ulcer with acute perforation].
AB  - OBJECTIVE: To study the long-term curative effects of suture plus proximal
      gastric vagotomy (PGV) and suture plus triad-therapy (omeprazole, amoxycillin and
      flagyl taken orally) for the treatment of duodenal ulcer with acute perforation.
      METHODS: Three hundred and twenty-nine patients with duodenal ulcer and acute
      perforation were treated with 2 different methods, respectively. Method A was
      suture plus PGV (group A, 153 cases), and method B was suture plus triad-therapy
      (group B, 176 cases). Follow-up was made by means of correspondence, outpatient
      reexamination and cooperation with local hospitals in 5 to 8 years after
      operation. The contents of follow-up included symptom acquisition (such as upper
      abdominal pain or distention, pyrosis, belch, acid regurgitation, vomiting,
      diarrhea and conditions of living or working), gastroscopy and Helicobacter
      pylori (HP) detection. The curative effects were evaluated by the Visick scale.
      RESULTS: Three hundred and one patients were followed up (group A 142 and group B
      159). According to the Visick scale, 97 (68.3%), 19 (13.4%), 13 (9.15%) and 13
      (9.15%) patients in group A, and 31 (19.5%), 28 (17.6%), 24 (15.1%) and 76
      (47.8%) in group B were classified as Visick I, II, III and IV respectively (Z = 
      9.818, P < 0.01). As for HP detection, there were 130 (91.5%) patients in group A
      and 94 (59.1%) in group B (chi(2) = 41.438, P < 0.01). CONCLUSIONS: The long-term
      curative effects of suture plus PGV were superior to those of suture plus triad
      therapy for duodenal ulcer with acute perforation although HP positive rate was
      higher in group A than in group B. HP infection is one of the etiological factors
      of duodenal ulcer. The increased excitability of the vagus nerve remains to play
      an important role in duodenal ulcer.

PMID- 12411131
TI  - [Long-term clinical results after highly selective vagotomy plus pylorus
      preserved mucosal antrectomy].
AB  - OBJECTIVE: To study the long-term clinical results of 34 chronic duodenal ulcer
      patients treated with high selective vagotomy plus pylorus-preserved mucosal
      antrectomy (HSV + PPMA). METHODS: Clinical follow-up results of the patients from
      8 approximately 14 years were analyzed. RESULTS: Thirty-tow patients (94.1%)
      followed-up for 8 approximately 14 years after operation achieved Visick grades I
      II. No patient died. Gastric acid secretion and infection rate of Helicobacter
      pylori in the antral mucosa were significantly reduced after operation. No
      significant difference was found in bile acids, total bacterial counts in gastric
      juice, and the level of serum gastrin after operation. Gastric emptying was
      normal. No ulcer recurrence was found by barium meal and endoscopy. CONCLUSIONS:
      HSV + PPMA is a better operative treatment for duodenal ulcer, which not only can
      decrease acid secretion and ulcer recurrence rate but also can preserve the
      function of antrum and pylorus and prevent post-operation bile reflux and
      intragastric bacterial overgrowth.

PMID- 12411132
TI  - [Long-term results of extended parietal cell vagotomy in treatment of duodenal
      ulcers and their complications: report of 321 cases].
AB  - OBJECTIVE: To study the long-term results of extended parietal cell vagotomy
      (EPCV) in the treatment of patients with duodenal ulcer and their complications.
      METHODS: Form 1979 to 2001, EPCV was performed in 321 patients with duodenal
      ulcer and their complications. Of these patients 56 had chronic duodenal ulcer,
      204 perforation, 16 hemorrhage and 40 stenosis. The following items were
      evaluated: complications of operation, gastric secretion, gastric emptying,
      endoscopical and radiographical findings, nutritional status, absorption
      function, and Visick scale. RESULTS: Postoperative follow-up ranged from 0.5 to
      22.0 years (mean 11.3 years) in 289 of the 321 patients with a follow-up rate of
      90.0%. Neither operative mortality nor dumping syndrome was noted. Episodic
      postprandial fullness occurred in 19 patients (6.5%), acid regurgitation in 17
      (5.8%) and adhesive ileus in 4 (1.4%). Ulceration recurred in 16 patients (5.5%).
      Duodenal ulcer was seen in 8 patients (19.5%), hemorrhage in 0 (0%), stenosis in
      2 (5.3%), and perforation in 6 (3.1%). Ulcers healed rapidly after medical
      therapy in 10 patients. Six patients received antrectomy and gastrectomy. In 289
      (91.7%) patients of Grade I and II of Visick scale, 191 (95.3%) had perforation.
      CONCLUSIONS: EPCV is easy to perform with a low rate of post operative
      complication and ulcer recurrence. It should be a treatment of choice for acute
      perforation, hemorrhage or stenosis due to duodenal ulcer.

PMID- 12411133
TI  - [Operative treatment of acetebular fractures].
AB  - OBJECTIVE: To discuss the diagnosis and operative technology of acetabular
      fracture. METHODS: 41 cases of displaced acetabular fractures were enrolled. CT
      and 3D-CT were performed before operation to understand the classification of
      fractures and to determine operative regimen. All cases were fixed by
      reconstruction plates and screws through the best approach. RESULTS: 39 cases
      were followed up for 1 - 4 years, with an average of 1.5 years. Curative outcomes
      were assessed by Matta's criteria. Clinically, 16 (53.3%) 30 fresh fractures were
      excellent, 11 (36.7%) good, 3 (10%) fair. The rate of excellence and goodness was
      90%. In 9 cases of old fractures, 2 were excellent, 3 good, 2 fair and 2 poor.
      The rate of excellence and goodness was 55.6%. Complications consisted of sciatic
      never injury, necrosis of the femoral head, and heterotopic ossification.
      CONCLUSIONS: The time of operation, degree of injury, and quality of reduction of
      fracture are important factors affecting the postoperative function of the hip.
      The key to enhance the outcome is to verdict the type of fracture, select the
      proper approach before operation, and precise reduction and appropriate internal
      fixation during operation.

PMID- 12411134
TI  - [Mosaicplasty osteochondral grafting to repair cartilaginous defects under
      arthroscopy].
AB  - OBJECTIVE: To study mosaicplasty a as method of autogenous osteochondral
      transplantation in the treatment of cartilaginous defects. METHODS: The technique
      involves obtaining small cylindrical grafts from the non-weight bearing periphery
      of the femur at the patellar femoral joint, and transporting them to the prepared
      recipient site by arthroscopy. RESULTS: Fifteen patients with defects
      cartilaginous received mosaicptasty osteochondral grafting. Follow up for 12 to
      21 months (mean 15 months) showed good results. CONCLUSION: The treatment is
      indicated for patients with focal cartilaginous defects under the age of 45.

PMID- 12411135
TI  - [Cancellous bone allograft in management of bone defect following tumor
      resection].
AB  - OBJECTIVE: To determine whether cancellous bone allograft is the best biological
      material for filling a cavity bone defect. METHODS: Between 1992 and 1998, deep
      frozen cancellous bone allograft was used in the treatment of bone defect in 57
      patients following tumor resection. The age of the patients varied from 6 to 56
      years (mean 17.4 years). RESULTS: Bone unions were achieved in 56 patients, and
      the average time for union was 4.5 months; One patient had the graft removed for
      infection. The time for union was different according to the volume of graft. The
      longer time for union was always accompanied with the larger volume of graft. To
      compare the union time of admixture of cancellous autograft and allograft with
      that of cancellous allograft alone, the time for union was same in both group. No
      immune response and infection was observed in this group. And infection happened
      in 1 of the 57 patients. The local recurrence rate of tumor was 7%. CONCLUSIONS:
      The feasibility and security of this packing method are better than other.
      Compared with cancellous autograft, no significant difference was found in the
      time for union and complication rate except local tumor recurrence.

PMID- 12411136
TI  - [Treatment of infected total knee arthroplasty].
AB  - OBJECTIVE: To investigate the treatment of infected total knee arthroplasty
      (TKA). METHODS: Between 1983 and 2000, 6 patients with infection after TKAs were
      treated, including 2 men and 4 women, aged on average 63 years (44 - 75 years).
      Initial knee arthroplasty was performed for osteoarthritis in 4 patients and for
      rheumatoid arthritis in 2 knees. The timing of diagnosis of infection after knee
      arthroplasty averaged 50 months (range, 1 month-11 years). Simple debridement and
      antibiotic treatment were prescribed for 3 patients, debridement and one-stage
      reimplantation for 1, debridement and two-stage reimplantation for 1, and
      athrodesis for 1. RESULTS: Of the 3 patients with simple debridement, one was
      cured, one failed but underwent athrodesis later, and one lost to follow up. Two
      patients with reimplantation were cured and had good function recovery. All of
      the 6 patients were followed up on average for 4 years. No infection recurred
      except one who lost to follow-up. CONCLUSIONS: Management of infection after
      total knee arthroplasty includes antibiotic suppression and debridement with
      prosthesis retention, insertion of another prosthesis as a one-stage or two-stage
      exchange technique, knee arthrodesis and amputation. These treatments have
      specific indications. To treat infection after total knee arthroplasty, suitable
      method should be taken according to patient's condition. Arthrodesis is the best
      salvage operation, though it may handicap patients' daily life. Reimplantation of
      another prosthesis could maintain a functional joint.

PMID- 12411137
TI  - [Association of VEGF, uPA, ICAM-1 and PCNA expression with metastasis and
      recurrence in hepato cellular carcinoma].
AB  - OBJECTIVE: To detect the biological factor association with metastasis and
      recurrence of hepato cellular carcinoma (HCC). METHODS: Labeled streptavidin
      biotin method was performed to study VEGF, uPA and ICAM-1 protein, and antigen of
      PCNA expression in 123 patients with HCC. Venous invasion was observed under
      microscope at the same time. RESULTS: The expression rate of VEGF was higher in
      HCC with intra-hepatic metastasis in group B than in HCC without PVTT/metastasis
      in group A (P < 0.01) and higher in HCC with PVTT in group C and PVTT in group D
      higher than in group B (P < 0.05). The expression rate of uPA protein was higher
      in group B than in group A (P < 0.01), but no significant difference in groups B
      and C. The expression rate of ICAM-1 showed no significant difference in the four
      groups. MVD and PCNA-LI increased gradually from group A to D. The rate of
      microscopic venous invasion in group B was higher than in group A (P < 0.05), in
      group D higher than in group B (P < 0.05), but no significant difference was
      observed between groups B and C, groups C and D (P = 0.16, 0.13 respectively).
      The rate of postoperative recurrence of HCC was higher in group B than in group
      A, and lower than in group C. Multivariate regression analysis: showed
      postoperative recurrence was correlated very well with microscopic venous
      invasion (r = 0.783, P < 0.01), and MVD (r = 0.143, P < 0.05). Metastasis of HCC
      were associated very well with PCNA-LI (r = 0.590, P < 0.01) and MVD (r = 0.179,
      P < 0.05), and negatively correlated with the rate of ICAM-1 expression (r = 
      0.183, P < 0.01). CONCLUSIONS: VEGF, uPA and ICAM-1 protein expression and
      proliferation of cancer cells could contribute to the formation of PVTT,
      metastasis and postoperative recurrence of HCC. Over-proliferated cancer cells in
      HCC could be the direct factor of intrahepatic metastasis and formation of PVTT,
      and microscopic venous invasion may be a significant factor to predict
      postoperative recurrence of HCC.

PMID- 12411138
TI  - [Diagnosis and surgical management of mediastinal neurogenic tumors].
AB  - OBJECTIVE: To study the clinical manifestations, diagnostic methods, surgical
      management and prognosis of patients with neurogenic tumors of the mediastinum.
      METHOD: One hundred and ten patients with neurogenic tumors of the mediastinum
      were analyzed retrospectively. RESULTS: After operation, 2 patients died in
      hospitalization and 8 experienced such complications as Horner's syndrome or
      laryngeal recurrent nerve paralysis. In 102 patients with benign tumors, 2
      patients had recurrence, and 4 patients with neurofibrosarcoma or malignant
      neurilemmoma died within 3 years postoperatively. CONCLUSIONS: Most neurogenic
      tumors of the mediastinum are benign and could be diagnosed by chest X-ray or CT.
      The clinical manifestations, diagnosis methods, surgical management of the
      dumbbell tumors differ from others. Minimal invasive surgery and video assist
      thoracoscopy surgery are of special value in treatment of the selected neurogenic
      tumors of the mediastinum. Benign neurogenic tumors rarely recur after complete
      resection, and malignant neurogenic tumors have poor prognosis.

PMID- 12411139
TI  - [Effect of non-pulsatile blood flow on the secretion of calcitonin-gene-related
      peptide in patients undergoing total cavopulmonary connection].
AB  - OBJECTIVE: To study the changes of calcitonin gene-related peptide (CGRP) in
      patients who underwent total cavopulmonary connection (TCPC) and to assess the
      effects of non-pulsatile blood flow on the secretion function of the lung.
      METHODS: Twenty-six patients were divided into 2 groups: study group, 13 patients
      who underwent extracardiac TCPC, and control group, 13 patients who underwent
      definitive repair for ventricular septal or atrial septal defect. Blood samples
      for measurement of CGRP were obtained preoperatively, postoperatively or in the
      follow-up period. Cardiac index (CI) and pulmonary vascular resistance (PVR) were
      measured by cardiac catheter. RESULTS: The plasma level of CGRP was significantly
      higher in the study group than in the control group. CGRP was negatively
      correlated with PVR (r = -0.99, t = 9.82, P < 0.05), and positively correlation
      with CI (r = 0.98, t = 6.95, P < 0.05). CONCLUSIONS: After total right heart
      bypass, the non-pulsatile blood flow in pulmonary circulation may stimulate the
      lung to secrete CGRP, leading to the decrease of PVR and improve early
      postoperative recovery.

PMID- 12411140
TI  - [Interventional treatment of dural arteriovenous fistula].
AB  - OBJECTIVES: To summarize the characteristics of interventional treatment of dural
      arteriovenous fistulae (DAVFs) and improve clinical curative effects. METHODS:
      The clinical data from 135 patients with DAVFs were analyzed retrospectively.
      RESULTS: Seventy-four patients were cured, 53 were significantly improved, 8
      unchange, and 1 died of intracranial haemorrhage. CONCLUSIONS: Clinical
      presentations and prognosis of DAVF depend on the types of venous drainage.
      Compression of the affected carotid artery and endovascular embolization are safe
      and effective.

PMID- 12411141
TI  - [Lung protection by perfusion with hypothermic protective solution to pulmonary
      artery during total correction of tetralogy of Fallot].
AB  - OBJECTIVE: To study lung protection by perfusion with hypothermic protective
      solution to the pulmonary artery during total correction of tetralogy of Fallot
      (TOF). METHODS: Sixty-four consecutive children with TOF were randomly divided
      into control group (n = 30) and lung protective group (n = 34). The way of lung
      protection in the lung protective group was to perfuse with hypothermic
      protective solution to the pulmonary artery. Patients in the control group were
      subjected to routine approach. Patients' hemodynamics and lung functions were
      monitored. Plasma malondialdehyde (MDA), TNF-alpha and IL-6, IL-8 in tracheal
      suction were measured. Lung biopsy specimens were obtained after operations to
      study histological changes. RESULTS: The oxygen index was higher in the lung
      protect group than in the control group at 6 h, 12 h and 24 h after operation (t
      = 2.400, P < 0.05; t = 3.898, P < 0.01; t = 3.339, P < 0.01, respectively). The
      time for ICU and mechanical ventilation was significantly less in the lung
      protective group than in the control group (t = -2.652, P < 0.05; t = -2.081, P <
      0.05). The level of MDA was lower in the lung protective group than in the
      control group at 0 h and 6 h after operations (t = -4.255, P < 0.01; t = -2.372,
      P < 0.05 respectively). The level of TNF-alpha was lower in the lung protective
      group than in the control group at 0 h, 6 h and 24 h after operation (t = 3.112,
      P < 0.01; t = 3.072, P < 0.01; t = 2.306, P < 0.05, respectively). The levels of
      IL-6, IL-8 in tracheal suction were lower in the lung protective group (t = 
      2.419, P < 0.05; t = -2.613, P < 0.01). Tissue examination showed intraalveolar
      edema, capillary hyperemia, leukocytes accumulated, and mitochondria swelling in
      the control group, whereas no change in the lung protective group. CONCLUSION:
      Perfusion with hypothermic protective solution to the pulmonary artery in CPB
      could reduce lung injury during the total correction of TOF.

PMID- 12411142
TI  - [Bulbourethral suspension in treatment of male incontinence].
AB  - OBJECTIVE: To explore whether bulbourethral suspension procedure is effective for
      the treatment of male urinary incontinence of post-prostatectomy and posterior
      urethroplasty. METHODS: Twelve male patients with urinary incontinence undergone
      bulbourethral suspensive operation were reviewed and analyzed with regard to the
      operation method, postoperative urinary dynamics and clinical results. RESULTS:
      Ten patients resumed complete control of urination and 1 was improved. In one
      patient, postoperative difficulty occurred in voiding but corrected by
      transurethral bladder neck revision for free passage of urine and continence.
      Urodynamic study showed that the maximum urethral pressure ranged from 85 to 115
      cm H(2)O (mean 98 cm H(2)O, 1 cm H(2)O = 0.098 kPa). The functional urethral
      length ranged from 3.5 to 4.5 cm (mean 3.75 cm). CONCLUSION: Bulbourethral
      suspension procedure is effective in the treatment of male urinary incontinence
      after prostatectomy and posterior urethroplasty.

PMID- 12411143
TI  - [Inhibitory effect of endostatin mediated by retroviral gene transfer on human
      liver carcinoma SMMC7721 in vivo].
AB  - OBJECTIVE: To explore the effect of human endostatin expressed by host cells on
      the growth of human liver carcinoma in vivo. METHODS: Human endostain gene was
      transferred into SMMC7721 cells by retroviral pLncx to build endostatin
      transfected cell line. PCR, immunohistochemistry and Western blot analysis were
      applied to examine the transfection, expression and secretion of endostatin.
      Endothelial cell proliferation assay was used to determine the biological
      activity of expressed endostatin. The in vivo and in vitro growth rates of the
      endostatin-transfected and control SMMC7721 cells were also observed. RESULTS:
      PCR proved that the genome of endostatin-transfected SMMC7721 cells contained a
      550 bp specific fragment of endostatin. The expression and secretion of human
      endostatin from endostatin-transfected SMMC7721 cells were confirmed by
      immunohistochemistry and Western blot analysis. Endostatin expressed by host
      cells could inhibit the proliferation of human umbilical vein endothelial cells
      by 48% (P < 0.01). In vitro proliferation assay showed that endostatin
      transfected SMMC7721 cells had no change in proliferation rate compared to
      control SMMC7721 cells. In comparison with control group, however, tumor growth
      rate in vivo from endostatin-transfected SMMC7721 cells was inhibited greatly by
      94.5%, 22 days after inoculation into nude mice (P < 0.01). CONCLUSION: Human
      endostatin mediated by retroviral gene transfer can inhibit greatly the growth of
      human liver carcinoma SMMC7721 in vivo.

PMID- 12411144
TI  - [Effect of pneumoperitoneum on the liver blood flow in cirrhotic rats].
AB  - OBJECTIVE: To determine the effect of pneumoperitoneum on liver indocyanine green
      (ICG) metabolism and the hepatic blood flow in normal and cirrhotic rats.
      METHODS: Thirty male Wistar rats were randomized into five groups: normal
      anaesthesia group, normal laparotomy group, normal pneumoperitoneum group,
      cirrhosis + anaesthesia group, and cirrhosis + pneumoperitoneum group. Liver
      cirrhosis was induced in two groups by injecting carbon tetrachloride
      subcutaneously plus drinking 5% alcohol. ICG clearance tests were performed in
      all the rats. RESULTS: The ICG level in the normal laparotomy group (0.662 micro
      g/ml) was higher than that in the normal anesthesia group (0.645 micro g/ml), but
      the difference was not significant (P > 0,05). The ICG level in the normal
      pneumoperitoneum group (0.967 micro g/ml) was significantly higher than that in
      the normal anesthesia and normal laparotomy groups (P < 0.05). The ICG levels in
      two cirrhotic groups were significantly higher than those in the other three
      groups (P < 0.05). The ICG level in the cirrhosis + pneumoperitoneum (1.348 micro
      g/ml) was significantly higher than that in the cirrhosis + anesthesia group
      (1.198 micro g/ml) (P < 0.05). CONCLUSIONS: During laparoscopic surgery,
      pneumoperitoneum could decrease the liver ICG clearance rate and the hepatic
      blood flow, which are of clinical significance in determining the state of liver
      cirrhotic.

PMID- 12411145
TI  - [Expression of macrophage migration inhibitory factor mRNA in Schwann cells].
AB  - OBJECTIVES: To investigate the expression of macrophage migration inhibitory
      factor (MIF) mRNA in Schwann cells after peripheral nerve injury and roles of
      Schwann cells and MIF in macrophages activation and nerve regeneration. METHODS:
      Fifty SD rats were divided into 10 groups. One group served as normal control.
      The rest were anesthetized with 3% sodium pentobarbital (30 - 60 mg/kg, i.p) and
      sciatic nerves were transected distal to the obturator tendon respectively 1 h,
      12 h, 1 d, 3 d, 7 d, 10 d, 14 d, 17 d and 21 d before being killed. Sciatic
      nerves were resected and connective tissues excised. Schwann cells were obtained
      by digesting the nerve tissues with trypsin and collagenase. RNA was isolated and
      reverse-transcription-polymerase chain reaction (RT-PCR) was carried out. cDNA
      was analyzed by automatic system and the parameters were assessed to define the
      status of MIF mRNA expression in different groups. RESULTS: The level of MIF mRNA
      started to increase 12 h after the nerve transection. The level remained high
      from day 7 up to 10 after the injury. During the period from days 10 to 21, MIF
      mRNA decreased slowly to the pre-transection level. CONCLUSION: After peripheral
      nerve injury, Schwann cells can secrete MIF which may play a pivotal role as an
      immunomodulatory cytokine in macrophage activation and inflammatory reaction.

PMID- 12411146
TI  - [Expression and significance of bcl-2 and bcl-xL in rat neuron after acute brain
      trauma].
AB  - OBJECTIVE: To observe the expression of bcl-2 and bcl-xL in rat brain neuron
      after acute brain trauma. METHODS: The rat model of mild and sever brain trauma
      were made by diffused brain injury. The expression of bcl-2 and bcl-xL in rat
      brain neuron was examined by immunohistochemical staining. Rat neuron apoptosis
      was detected by TUNEL method. RESULTS: There were few bcl-2 (cortex: 4.40 +/-
      1.67, hippocampal: 3.20 +/- 1.30) and lots of bcl-xL (cortex: 45.60 +/- 4.34,
      hippocampal: 50.20 +/- 3.50) expression in normal controls. After impact, the
      expression of bcl-2 in rat brain neuron increased, most distinctly on day
      1(cortex: 30.0 +/- 4.3, hippocampal: 46.6 +/- 3.2), in mild group. A negative
      correlation was seen between bcl-2 expression and neuronal apoptosis (-1 < r < 
      0.847, P< 0.01, n = 10). No change was seen in bcl-xL expression. CONCLUSIONS:
      bcl-2 expression increased after acute brain trauma but bcl-xL did not change
      much. Both bcl-2 and bcl-xL are concerned with anti-apoptosis in neuron after
      acute brain trauma.

PMID- 12411147
TI  - [Changes in skeletal muscle protein metabolism in burned rats with sepsis and the
      role of glucocorticoid in skeletal muscle proteolysis].
AB  - OBJECTIVE: To study the effects of glucocorticoid on skeletal muscle protein
      metabolism in burn sepsis and its possible mechanism. METHODS: The rats were
      randomly divided into four groups with 15 rats in each group. Group B, 30% TBSA
      full-thickness burn was produced on the back and endotoxin (6 mg/kg bw) was given
      intraperitoneally after the injury to simulate burn sepsis. Groups C and D,
      glucocorticoid receptor antagonist RU38486 (10 mg/kg bw) was given by gavage 2
      hours before or 2 hours after burn with endotoxin, respectively. Group A, the
      rats received only normal saline in same volume as endotoxin. Plasma levels of
      cortisol were determined with standard procedure. Extensor digitorium longus
      muscles (EDL) were procured from both legs 12 hours after the injury. After
      weighing, the proteolytic rate was determined in vitro in an incubation system
      with oxygen rich environment by high performance liquid chromatography. The gene
      expressions of ubiquitin, E(2)-14kDa and C2 in the muscles were determined by
      Northern blot analysis. RESULTS: The weight of EDL was significantly lower in
      group B than in group A (t = 9.03, P < 0.01). Although the weight of EDL muscles
      was also lower in groups C and D than in group A, it was significantly higher
      than in group B (t = 2.26, 6.42, P < 0.05 or P < 0.01). The concentrations of
      plasma cortisol were markedly higher in groups B, C and D than in group A (t =
      9.03 - 22.94, P < 0.01). A 58.8% (210/357) of the total and 335.5% (4.16/1.24) of
      myofibrillar proteolytic rate in group B was higher than in group A (t = 36.99
      and t = 46.19, P < 0.01), respectively. The total and myofibrillar proteolytic
      rate in group D was 28.3% (161/567) and 49.6% (2.68/5.40) and in group C 18.9%
      (108/567) and 23.2% (1.25/5.40), which were lower than those in group B (t = 5.34
      approximately 34.68, P < 0.01), respectively. Although the expressions of
      ubiquitin mRNA (2.4 kb), E(2)-14 kDa mRNA (1.2 kb) and C2 mRNA in groups C and D
      were significantly higher than in group A, all the values were lower than those
      in group B (t = 3.22, 11.32, P < 0.01), especially in group C. CONCLUSIONS: The
      proteolytic rate of skeletal muscle, especially the myofibrillar proteolytic
      rate, was enhanced during burn with sepsis. Hypersecretion of glucocorticoid
      could upgrade the gene expression of ubiquitin system, resulting in
      hyperdegradation of skeletal muscle protein during burn with sepsis.
      Glucocorticoid receptor antagonist RU38486 could decrease the hyperdegradation of
      skeletal muscle during burn with sepsis.

PMID- 12411149
TI  - Frequency of loss expression of the DPC4 protein in various locations of biliary
      tract carcinoma.
AB  - OBJECTIVE: To clarify the relationship between the loss of expression of the
      deleted in pancreatic carcinoma locus 4 (DPC4) proteins and the pathogenesis of
      biliary tract carcinoma. METHODS: 71 primary biliary tract carcinoma (BTCa),
      including 38 common bile duct (CBD) carcinomas, 18 gallbladder carcinomas, 15
      hilar bile ducts (HBD) carcinomas were examined by immunohistochemical staining.
      In addition, the CBD carcinomas were divided into two groups: tumors with
      metastasis (M(+) group, 27 cases) and tumors without metastasis (M(-) group, 11
      cases). RESULTS: The frequency of loss of the expression of DPC4 protein was
      32.8% in BTCa, 47.3% in CBD carcinoma, 11% in gallbladder carcinoma, 13% in HBD
      carcinoma. Comparison of the frequency of loss expression of DPC4 was significant
      statistical difference in CBD carcinoma versus gallbladder carcinoma and HBD
      carcinoma (P < 0.01). The frequency of loss expression of DPC4 was 48.1% in the
      M(+) group and 45.4% in the M(-) group. CONCLUSION: There are a close
      relationship between pathogenesis of BTCa and inactivation of DPC4 and different
      frequencies of DPC4 gene alternation in various locations of the biliary tract,
      which are not significantly increased with tumor metastasis in BTCa.

PMID- 12411148
TI  - [The effect of an antioxidant tea polyphenols on cell apoptosis in rat model of
      cyclosporine-induced chronic nephrotoxicity].
AB  - OBJECTIVE: To investigate the effect of tea polyphenols on cell apoptosis in rat
      model of cyclosporine-induced chronic nephrotoxicity. METHODS: Four groups of
      animals in rat model of cyclosporine-induced chronic nephrotoxicity were
      respectively treated by olive oil (n = 6), tea polyphenols (TP, n = 6),
      cyclosporine A (CsA, n = 8) and TP plus CsA (n = 8). At the end of 28th day of
      treatment, all animals were sacrificed and blood was analyzed for blood serum
      creatinine and creatinine clearance, kidney tissue for pathologic analysis. The
      TUNEL assay, caspase-3 mRNA expression detected by reverse transcription
      polymerase chain reaction (RT-PCR) and caspase-3 activity were used for the
      analysis of cell apoptosis. RESULTS: CsA plus TP ameliorated the CsA-induced
      decrease of renal function and interstitial fibrosis. There was a significant
      increase in the number of apoptosis-positive cells in the CsA-vs-CsA plus TP
      treated group at four weeks (18.9 +/- 3.3 vs. 7.7 +/- 1.4, P < 0.05). The
      expression of caspase-3 mRNA and caspase-3 activity of CsA-treated group was
      significantly higher than that of CsA plus TP-treated group (P < 0.05).
      CONCLUSION: These results indicate that antioxidant tea polyphenols significantly
      inhibit apoptosis of tubular and interstitial cells in rat model of chronic
      cyclosporine-induced nephrotoxicity, and suggest that the decrease of cell
      apoptosis exerted by tea polyphenols may be one of mechanisms to protect renal
      function and tissue structure.

PMID- 12411150
TI  - mRNA of MAGE genes as specific markers in detection of tumor cells in the
      peripheral blood of patients with hepatocellular carcinoma.
AB  - OBJECTIVE: To detect tumor cells in the peripheral blood of patients with
      hepatocellular carcinoma (HCC) by using the mRNA of the MAGE-1 and MAGE-3 genes
      as specific tumor markers. METHODS: Peripheral blood was obtained from 25 HCC
      patients and 20 healthy volunteers. The mRNA of the MAGE-1 and MAGE-3 genes in
      the peripheral blood mononuclear cells (PBMCs) was detected by nested RT-PCR. The
      MAGE-1 and MAGE-3 transcripts in the tumor tissues of these HCC patients were
      also detected by RT-PCR. RESULTS: Of the 25 HCC patients, MAGE-1 and MAGE-3 mRNA
      were positive in 44% (11/25) and 36% (9/25) of PBMCs respectively, and in 68%
      (17/25) and 56% (14/25) of HCC tissues respectively. In the PBMCs of the 25 HCC
      patients, 16 (64%) samples were detected to express at least one type of MAGE
      mRNA. MAGE mRNA were not detected in the PBMCs from the patients whose tumors did
      not express the MAGE genes, nor in the PBMCs from the 20 healthy donors. The
      positive rate of MAGE mRNA in the PBMCs was closely correlated with the TNM
      stages and the diameter of tumors, but there was no correlation between the
      positive rate of MAGE mRNA in PBMCs and tumor differentiation degree or serum
      alpha-FP level. Of 9 HCC patients whose serum alpha-FP was normal or slightly
      elevated (< 50 ng/ml), 6 were MAGE-1 and/or MAGE-3 mRNA positive in their PBMCs.
      CONCLUSION: MAGE-1 and MAGE-3 mRNA could be specifically detected with high
      percentage in the PBMCs of HCC patients by our method. They can be used as
      specific tumor markers for the detection of the circulating HCC cells, and the
      detection results may be helpful to evaluate the prognosis of HCC patients.

PMID- 12411151
TI  - Ehlers-Danlos syndrome: case and pedigree report and review.
AB  - OBJECTIVE: To report a case and a firstly described pedigree with Ehlers-Danlos
      syndrome in China. METHODS: Clinical materials of a case of Ehlers-Danlos
      syndrome type IV and a pedigree of 6 members with 4 generations were analyzed.
      Dilated internal jugular vein in the proband was removed operatively. The
      diagnosis, surgical treatment, and postoperative complications were
      retrospectively summarized. Etiology, clinical characteristics and classification
      of Ehlers-Danlos syndrome were also analysed. RESULTS: Vessels of the proband in
      the pedigree were crisp and easily lacinated during the precedure for removal of
      his internal jugular vein. Repeat postoperative hemotomas were found though
      complete stanching was made during operation. The patient successfully recovered
      after prompt debridement in operative theatre and needle sucking. The other 5
      members of the pedigrees all had the triads of Ehlers-Danlos syndrome, but no
      combined vascular diseases were found in them. CONCLUSIONS: Though the morbidity
      rate was extremely low, green attention should be paid to the high mortality rate
      and complication of Ehlers-Danlos syndrome during surgical management of in
      patients with Ehlers-Danlos syndrome type IV. Surgeons should be aware of the
      ponderance of its complications and combined diseases to avoid fatal
      intraoprative vascular lacination and incontrollable hamorrhage.

PMID- 12411152
TI  - Regulative effect of IFN-gamma on the Fas/Fas L system of cholangiocarcinoma
      cells.
AB  - OBJECTIVE: To detect the regulative effects of IFN-gamma on the expression of Fas
      and FasL of cholangiocarcinoma cells. METHODS: We studied that the expression of
      Fas and FasL gene by the human cholangiocarcinoma cell line QBC939 by RT-PCR,
      Western blot, immunohistochemistry. At the same time, we investigated the
      regulative effect of IFN-gamma on them. RESULTS: Fas and FasL mRNA and protein
      were expressed by cholangiocarcinoma cells. We also found IFN-gamma could
      upregulate the expression of the two genes (P < 0.01). However, IFN-gamma could
      also downregulate the ability of them to make Jurkat cells apoptotic. With the
      increasing of dosage and time, the effect was enhanced. CONCLUSIONS: IFN-gamma
      could regulate the expression of Fas and FasL by cholangiocarcinoma cells,
      therefore it could reduce the ability of cholangiocarcinoma to occur immune
      escape. This provides new theoretical basis for immunological therapy of
      cholangiocarcinoma.

PMID- 12411153
TI  - Detection of aberrant p16 methylation in the serum of colorectal cancer patients.
AB  - OBJECTIVES: To detect aberrant p16 promoter methylation in serum of patients with
      colorectal cancer (CRC), and to explore the possibility of using this assay in
      early detection or as a prognostic marker. METHODS: Methylation-specific PCR was
      used to detect p16 methylation in DNA extracted from 52 CRCs and corresponding
      serum samples. Serum samples from 34 patients with adenomatous polyps and 10
      healthy individuals were used as controls. The association of p16
      hypermethylation in serum DNA of CRC patients with clinicopathological
      characteristics was analyzed. RESULTS: p16 methylation was found in 38% (20 of
      52) of CRC tissues. Among the 20 patients with aberrant methylation in the tumor
      tissues, similar changes were also detected in the serum of 14 (70%) patients. No
      methylated p16 sequences were detected in the peripheral serum of the 32 CRC
      patients without these changes in the tumor, in 34 paitents with adenomatous
      polyps, or in 10 healthy controls. Clinicopathological analysis revealed that p16
      methylation in serum was significantly associated with later Dukes' stage (chi(2)
      = 5.7, P = 0.03). CONCLUSION: This assay offers a potential means for the serum
      based detection and/or monitoring of CRC patients.

PMID- 12411154
TI  - Diagnosis and treatment of primary gastric non-Hodgkin's lymphoma: analysis of
      157 patients.
AB  - OBJECTIVE: To seek the optimum treatment for patients with primary gastric non
      Hodgkin's lymphoma and factors associated with prognosis. METHODS: A
      retrospective study was conducted on 157 primary gastric non-Hodgkin's lymphoma
      patients who had received operation for 45 years. RESULTS: The X-ray diagnosis
      rate was 39.4% before operation. The diagnosis rate by gastroscopy was 52.7%.
      Among the 157 patients, 32 belonged to stage I(E), 40 stage II(E), 29 stage
      III(E), and 56 stage IV(E). All of the patients were received chemotherapy or
      radiation. The 3-, 5-, 10-, 15-year survival rates were 51.1% (69/135), 42.3%
      (55/130), 20.7% (23/111), and 13.5% (14/104). CONCLUSIONS: The 3-, 5-year
      survival rates in stage I(E) and stage II(E) were 2 to 5 times higher than those
      in stage III(E) and IV(E) (P < 0.01). The 3-, 5-year survival rates of primary
      gastric non-Hodgkin's lymphoma were 60.2% (65/108) and 50.0% (52/104)
      respectively. The prognosis was better than the 5-year survival rate of gastric
      cancer patients with D(2) lymphodenectomy (33.3%). Early diagnosis and treatment
      are effective to prevent complications, enhance quality of patient's life, and
      prolong the survival.

PMID- 12411155
TI  - Vascular endothelial growth factor gene expression in patients' ischemic skeletal
      muscle with diabetic foot.
AB  - OBJECTIVE: To investigate the relationship between the endogenous vascular
      endothelial growth factor (VEGF) gene expression in diabetics' calf ischemic
      skeletal muscle and the pathogeny of diabetic foot. METHODS: Twenty-four patients
      (33 limbs) were divided into 3 groups: diabetes mellitus (DM) without lower
      extremity ischemia (n = 5) (10 limbs); arteriosclerosis obliterans (ASO) without
      diabetes mellitus (n = 10) (13 limbs); diabetic lower limb arteriosclerosis
      obliterans (DLASO) (n = 9) (10 limbs). Control group consisted of normal
      volunteers (NOR) (n = 5) (10 limbs). The calf skeletal muscle tissue was obtained
      through muscle biopsy. RT-PCR was applied to determine the expression of
      hVEGF165mRNA. RESULTS: There was no expression in the calf skeletal muscle tissue
      of normal volunteers and DM. The calf skeletal muscle tissue in DLASO had the
      expression of hVEGF165mRNA (0.021 +/- 0.013) micro g, but obviously lower than
      ASO (0.133 +/- 0.024) micro g, (t = 13.32, P < 0.01). CONCLUSIONS: The endogenous
      VEGF gene expression in ischemic lower extremity of DLASO is obviously lower than
      that of ASO. It is the important endogenic cause of the genesis and development
      of diabetic foot ulcer.

PMID- 12411156
TI  - Treating external chylous fistula with retroperitoneal lymphangiectomy plus lymph
      vein shunting.
AB  - OBJECTIVE: To discuss the diagnosis and therapy of chylous reflux and external
      chylous fistula. METHODS: All of 6 patients were diagnosed with direct
      lymphagiography, lymphscintigraphy. Among them, 2 patients received CT after
      direct lymphagiography. Retroperitoneal lymphangiectomy plus lymph-vein shunting
      was performed in 5 patients, and retroperitoneal lymphangiectomy in 1 patient.
      RESULTS: The 6 patients were followed up from 6 months to 6 years. In 5 patients,
      chylous cysts disappeared and chylous fistula closed, and in 1 patient, chylous
      fistula didn't cicatrize, and chyle still leak out from the scrotum. CONCLUSIONS:
      Retroperitoneal lymphangiectomy plus lymph-vein shunting has curative effect on
      chylous external fistula of the lower extremity and genitalia, but it has the
      chance to not obstruct all paths of chylous reflex.

PMID- 12411157
TI  - Significance and expression of vascular endothelial growth factor and E-cadherin
      in non-small cell lung Carcinomas.
AB  - OBJECTIVES: To study the expression of vascular endothelial growth factor (VEGF)
      and E-cadherin (E-cd) in non-small cell lung carcinomas (NSCLC) and explore the
      mechanism of invasion and metastasis of tumor cell. METHOD: The expression of
      VEGF and E-cd was analyzed in surgical specimens (43 cases of NSCLC) by SP
      immunohistochemical method. RESULTS: The positive rates of VEGF in the case of
      good-differentiation and poor-middle-differentiation were 60.0% and 86.9%
      respectively, and those of E-cd were 65.0% and 34.9%. The expression of VEGF and
      E-cd in the case of metastasis was significantly different from that in the case
      without metastasis. CONCLUSION: The expression of VEGF and E-cd is correlated
      well with invasion and metastasis of NSCLC.

PMID- 12411158
TI  - Multiple suppressor gene p16 of human brain gliomas.
AB  - OBJECTIVE: To study the relationship among p16, genesis, and development of brain
      gliomas. METHODS: We detected the deletion and point mutation of p16 exon 2 by
      PCR-TGGE. Methylation sensitivity ristriction enzyme polymerase chain reaction
      was used to detect whether methylation is correlated with happening of glioma.
      RESULTS: p16 homozygous deletion was detected in 14 of 48 gliomas. No deletions
      were found in low grade gliomas. Of the 48 gliomas, 5 anaplastic gliomas (WHO
      grade III) and 9 glioblastomas (WHO grade IV) showed homozygous deletion of exon
      2 with a deletion rate of 33.33% (5/15) and 50.00% (9/18) respectively. The
      mutations of 34 gliomas with p16 positive amplification were detected point
      mutations in two gliomas, in which one was anaplatic glioma and the other was
      glioblastoma. Six of the 48 gliomas (12.5%) showed exon1 methylations.
      CONCLUSIONS: p16 may play an important role in genesis of brain glioma. The main
      alteration of p16 in brain gliomas was homozygous deletion of exon 2, the
      methylation of p16 exon 1 was subcardinal, however, point mutation was rare. The
      deletion of p16 was found especially in high grade gliomas, so we could propose
      that it may be the late event of tumor occurrence.

PMID- 12411159
TI  - Monocyte chemoattractant protein-1 mRNA in human intracranial aneurysm walls.
AB  - OBJECTIVE: To investigate the pathological course in intracranial aneurysms.
      METHODS: Normal intracranial artery tissue (cortex fistulization) from 1 case,
      ruptured aneurysms tissuses from 11 cases, unruptured aneurysm tissues from 2
      cases were obtained by neurosurgical excision. Routine HE staining was used to
      observe histological characteristics. In situ hybridization was used to observe
      the expression of the monocyte chemoattractant protein-1 (MCP-1) mRNA in the
      walls of the normal artery and aneurysms. RESULTS: By the HE staining showed that
      the wall of the ruptured aneurysms (10 cases) and unruptured ones (2 cases) had
      increased intima and connectivum extima. The fibroblast in the intima was arrayed
      in the disorder. Monocyte-like cells can be seen in the whole aneurysm wall. In
      one case aneurysms wall (ruptured) glass-like fiber structure was left over, few
      cells could be seen. In 9 cases, mural thrombus was found. The thrombus
      represented with organization. In situ hybridization, MCP-1 mRNA was not
      detectable in the normal artery. The hybridization signal could be observed in
      the ruptured aneurysms (10 cases) and unruptured ones (2 cases) often in the
      intima. MCP-1 mRNA appeared to be expressed by fibroblast cells in its cytoplasm.
      Monocyte-like cells had little cytoplasm, and the signal was seldom seen. The
      hybridization signal was discontinuous in the intima, MCP-1 mRNA expressed where
      fibroblast and monocyte-like cells assembled. One ruptured aneurysm had no signal
      because there were no cells only glass-like fiber. Mural thrombus showed
      upregulated hybridization signal in the cytoplasm of fibroblasts, phlogocytes and
      endotheliocytes of its micrangium. CONCLUSION: The pathological representation of
      the ruptured and unruptured aneurysms and the upregulated expresion of MCP-1 in
      the aneurysm wall suggest that the development of aneurysm may be a course of
      chronic inflammation in which main inflammatory cells are monocyte-like cells.

PMID- 12411160
TI  - Urethral reconstruction with colonic mucosa in treatment of complex urethral
      stricture.
AB  - OBJECTIVE: To investigate the possibility of urethral reconstruction with colonic
      mucosa for the treatment of complex longer urethral stricture (>/= 10 cm).
      METHODS: From October 2000 to September 2001, 6 patients with complex longer
      urethral stricture were treated with colonic mucosal graft urethroplasty. They
      had under gone 3 previous unsuccessful urethral repairs on average. Urethral
      reconstruction with a free graft of colonic mucosa ranged from 10 to 15 cm (mean
      12.17 cm). Follow-up included retrograde urethrography, urethroscopy, and
      uroflowmetry. RESULTS: The patients were followed up 3 - 14 months
      postoperatively (mean 7.8 months). Meatal stenosis developed in one patient 3
      months after operation needed reoperation. The patient voided very well with
      urinary peak flow 28.7 ml per second duing follow-up for 12 months
      postoperatively. The other patients voided well with urinary peak flow greater
      than 15 ml per second. At urethroscopy, colonic mucosa was macroscopically
      difficult to distinguish from normal original urethral mucosa in 4 patients over
      6 months after the operation. CONCLUSIONS: Colonic mucosa graft urethroplasty is
      feasible for the treatment of complex longer anterior urethral stricture. The
      technique is useful for urethral reconstruction when penial skin and bladder
      mucosa are not available.

PMID- 12411161
TI  - Experience in diagnosis and treatment of ectopic ACTH syndrome.
AB  - OBJECTIVES: To increase the diagnosis and treatment of ectopic ACTH syndrome.
      METHODS: The data of 12 ectopic ACTH syndrome patients treated from 1985 to 1999
      were retrospectively analyzed. RESULTS: Twelve patients were diagnosed as having
      ACTH syndrome by endocrinary test and primary tumors were ascertained by imaging
      examination. Follow-up from 7 months to 8 years showed 3 out of 5 patients with
      radical resection of primary tumor died. One patient with bilateral adrenorectomy
      was still alive. All patients received only chemotherapy except one died.
      CONCLUSIONS: Patients with Cushing's syndrome should be evaluated by endocrine
      test and followed up by imaging screen examination. The key points to increase
      treatment effect include early detection, localization and resection of primary
      tumors.

PMID- 12411162
TI  - Hemorheology and expression of neutrophil adhesion molecules CD18 and CD62L in
      pancreatic microcirculation of Caerulein induced experimental acute pancreatitis.
AB  - OBJECTIVE: To explore the changes in hemorheology and expression of neutrophil
      adhesion molecules CD18 and CD62L in pancreatic microcirculation of Caerulein
      induced experimental acute pancreatitis (AP). METHODS: The Wistar rats (n = 21)
      were randomized into three groups. The model of AP was established by
      subcutaneous injection of Caerulein. The changes of apparent viscosity of whole
      blood were measured by Low- shear 30 rheometer. The expression of adhesion
      molecules on the surface of neutrophil in duced by shear stress was used with
      stationary control. CD18 expression was increased on neutrophils treated with
      shear rate, and andanalyzed using flow cytometry. RESULTS: Rat treated with
      Caerulein showed hyperamyleimia (t = 69.029, t = 79.734, P < 0.05). Blood
      viscosity of two AP groups were significantly elevated (0.512 s(-1): t = 10.725,
      t = 16.945; 5.96 s(-1): t = 12.781, t = 11.992, P < 0.05). Compared with
      stationary control, CD18 expression was increased on neutrophil treated with
      shear rate, and significantly induced with shear rate >/= 94.5 s(-1) (94.5 s(-1):
      t = 7.403, t = 13.323, t = 16.655; 128.5 s(-1): t = 10.092, t = 28.531, t =
      24.563, P < 0.05). The expression of CD62L was less sensitive to low shear rate,
      and began to be down-regulated significantly when the shear rate >/= 94.5 s(-1)
      (94.5 s(-1): t = 10.687, t = 19.376, t = 12.848; 128.5 s(-1): t = 26.152, t =
      48.402, t = 56.814, P < 0.05). CONCLUSIONS: The changes of apparent viscosity of
      whole blood, and the effect of fluid shear stress on the expression of neutrophil
      adhesion molecules CD18, CD62L may play an important role in the pancreatic
      microcirculatory failure of acute pancreatitis.

PMID- 12411163
TI  - Reconstruction and transplantation of composite skin containing keratinocytes and
      fibroblasts.
AB  - OBJECTIVE: To investigate the role of fibroblasts in reconstruction of composite
      skin, and evaluate the effect of composite skin on full-thickness skin defect.
      METHODS: Keratinocytes and fibroblasts were seeded on the surface of acellular
      dermal matrix and cultivated in vitro to reconstruct the composite skin.
      Adherence of keratinocytes to dermal matrix was observed. Then take rate and
      histological construction were investigated after the composite skin was used to
      cover full-thickness skin defect wound in nude mice (n = 16). RESULTS:
      Keratinocytes grew and proliferated to reach tho confluence on the surface of the
      acellular dermal matrix. Keratinocytes adhered more stablely and could not be
      torn down from dermal matrix in operation when few fibroblasts were seeded on the
      epidermal surface of the dermal matrix. After grafting, the composite skin closed
      the full-thickness wound in nude mouse. The total survival was achived in 10 mice
      (62.5%). The newly generated skin was with intact histological construction of
      base membrance containing laminin and type IV collagen. CONCLUSION: Composite
      skin could close the full-thickness wound, and fibroblasts could improve
      adherence of keratinocytes to dermal matrix, which should benefit the survival of
      composite skin.

PMID- 12411164
TI  - The relationship between bone-loss of steroid-induced osteonecrosis and local
      expression of OPG/OCIF.
AB  - OBJECTIVE: To probe the relationship between the
      osteoprotegerin/osteoclastogenesis inhibitory factor (OPG/OCIF) expression of
      bone and the relative bone-loss. METHODS: Steroid-induced osteonecrosis-model was
      reproduced in thirty-one new Zealand hares, and 24 ones were alive 3 days after
      administration of endotoxin and methylprednisolone. The alive creatures were
      divided into control group and trial groups randomly. After the creatures being
      executed, bone-density measurement of the femurs, HE staining, Ca(+ +) staining
      and OPG/OCIF immunohistochemistry staining were performed, followed by image
      processing and statistical analysis. RESULTS: In the early period of steroid
      induced osteonecrosis, the local OPG/OCIF expression significantly decreased,
      with a large number of osteoclasts in the local medulla, followed by a
      progressively bone-loss. CONCLUSION: Corticosteroid could inhibit OPG/OCIF
      expression in the bone, increase the activity and differentiation of osteoclast
      relatively, and worsen bone-loss in steroid-induced osteonecrosis.

PMID- 12411165
TI  - The effect of metal copper on fracture healing in chicken.
AB  - OBJECTIVE: To observe the effect of copper on bone fracture healing. METHODS: 160
      growing chickens aged 70 days were fed in 32 cages, each consisting of five. The
      fracture with 1 approximately 2 mm defects at the bilateral radius of wings was
      created by osteotomy. The chickens were divided into four groups, 40 each. Every
      morning, chickens of the first group, served as controls, were fed orally 0.8% Na
      CMC solution (sodium carboxymethyl cellulose), those of the other three groups
      were fed with copper-Na-CMC suspension (copper powder suspended in 0.8% Na-CMC)
      with different doses of 20, 40 and 80 mg Cu/kg body weight. Each group was
      sacrificed 14, 21, 28 and 35 days postoperatively. Liver was taken for analysis
      of Cu and Zn. Both radius were removed by dissection. CT was performed
      quantitatively for the ment of the gray values of the callus. The biomechanical
      properties of the healing radius were analyzed by a three point bending test.
      Afterwards, the contents of calcium, magnesium, phosphorus, copper, zinc, iron
      and hydroxyproline in the callus were determined. RESULTS: The gray values of the
      callus increased along with the increase of copper dose and the duration of
      observation. 21 and 35 days after operation, the gray values of the callus were
      significantly higher in the high-Cu group than in the controls respectively (909
      +/- 220 vs. 597 +/- 155; 973 +/- 100 vs. 763 +/- 179 HU, P < 0.05). The level of
      calcium and magnesium in the callus 35 days after operation was much higher in
      the mid and high Cu groups than in the controls respectively (Ca: 177 +/- 26.7,
      176 +/- 20.5 and 137 +/- 34.7 mg/g; Mg: 2.98 +/- 0.57, 3.06 +/- 0.46 and 2.43 +/-
      0.53 mg/g P < 0.05). The contents of hydroxyproline in the callus 35 days after
      operation were significantly higher in the high-Cu group than in the controls
      (34.23 +/- 1.96 vs. 32.17 +/- 1.93 mg/g respectively). The biomechanical
      properties of the repaired radius had a better improvement tendency in the three
      Cu-fed groups than in the controls. CONCLUSION: Copper is helpful in fracture
      healing; however, the effect of copper on fracture healing needs further study.

PMID- 12411166
TI  - Antropyloroduodenal motility after resection of esophageal cancer.
AB  - OBJECTIVE: To study the mechanism of delayed emptying indigestible solids in
      thoracic stomach after the resection of esophageal cancer by monitoring the
      variety of antropyloroduodenal migrating motor complex (MMC) during
      interdigestion. METHODS: Esophagectomy and gastroesophagostomy in the neck was
      performed in 5 men with esophageal cancer. An eight-lumen manometric sleeve
      assembly was passed through a nostril into the duodenum during operation. The
      sleeve was astride the pylorus. Antropyloroduodenal manometry was performed for
      at least 300 min with a polygraphic system (PC POLYGRAF HR) 7 - 11 days after
      operation. RESULTS: Twenty-eight MMCs were recorded in the pylorus and duodenum,
      12 MMC(s) in the antrum, and 33% (4/12) of the motility frequency of antral
      phases III started after that of pyloroduodenal phases III. The number of MMC in
      the antrum was lower than that in the duodenum after the operation. The mean
      duration of MMC of the antrum, pylorus and duodenum was (49.2 +/- 10.5) min,
      (46.5 +/- 10.4) min and (45.9 +/- 10.0) min respectively. The mean duration of
      phases III was respectively (6.7 +/- 3.5) min in the antrum, (10.0 +/- 3.5) min
      in pylorus, and (8.0 +/- 3.9) min in duodenum. The mean wave amplitude of phases
      III was respectively (83 +/- 30) mm Hg in the antrum, (60 +/- 12) mm Hg in
      pylorus, and (55 +/- 4) mm Hg in duodenum. The mean duration of MMC of the antrum
      and duodenum was shorter in patients than that in healthy volunteers, and the
      mean wave amplitude of phases III of the antrum was lower in patients than that
      in healthy volunteers. CONCLUSIONS: Diminution of the number of MMC and the mean
      wave amplitude of phases III in the antrum, incoordination of the
      antropyloroduodenal phases III should be the most important one of the mechanisms
      of delayed emptying of indigestible solids in thoracic stomach after the
      resection of esophageal cancer.

PMID- 12411167
TI  - Application of alginate three-dimensional culture system for in vitro culture of
      mandibular condylar chondrocytes from human osteoarthritic temporomandibular
      joint.
AB  - OBJECTIVE: To evaluate the use of alginate three-dimensional culture system for
      mandibular condylar chondrocytes culture in vitro from human osteoarthritic
      temporomandibular joint. METHODS: The cultured mandibular condylar chondrocytes
      from the operatively removed cartilage from a patient with osteoarthritic
      temporomandibular joint were harvested by mechanical dissection and enzyme
      digestion. Partial chondrocytes were suspended in the aqueous sodium alginate
      beads with high seeding density and cultured for 4 weeks, while the others were
      cultured in monolayer culture condition for 1 week. Thereafter, the alginate
      beads were embedded in paraffin and sectioned, then studied immunologically with
      type II collagen antibody and aggrecan antibody, same studies were adopted for
      the monolayer cultures. RESULTS: The monolayer cultures were confirmed as
      chondrocytes. The chondrocytes cultured in the alginate medium showed well. These
      cells exhibited the excellent differentiated phenotype after 4 weeks culture in
      alginate gel. CONCLUSIONS: The condylar chondrocytes from human osteoarthritic
      temporomandibular joint were successfully cultured in vitro. The alginate three
      dimensional culture system was successfully adopted for in vitro culture of
      condylar chondrocytes from human osteoarthritic temporomandibular joint, in which
      the chondrocytes exhibited the excellent differentiated phenotype.

PMID- 12411168
TI  - A comparative study on the intercuspal occlusion among TMD patients, malocclusion
      patients and university students.
AB  - OBJECTIVE: The relationship between occlusion and temporomandibular disorders
      (TMD) remains disputed. The related epidemiological studies have been carried out
      focused on the occlusal characteristics in motion, for example in protrusion,
      retrusion or laterally extension and on some of malocclusion features. Very few
      studies were carried out on the intercuspal occlusion which is the most important
      occlusal relationship. Angle's classification of occlusion and the relationship
      of over-jet and over-bite are two prominent features now generally used in
      clinical practice for occlusal evaluation. In present study two kinds of features
      of occlusion were compared among TMD patients, malocclusion patients and
      university student volunteers, who of the laters represented nature population.
      METHODS: 100 continued cases visiting our TMD Clinic during the year of 2 000
      with complain of TMD problem, 100 malocclusion patients in continued orthodontic
      department records, and 268 university student volunteers were included. All
      subjects were with complete dentitions, except of age-related third or second
      molar tooth eruption difference. Study cast were obtained for all 468 subjects
      involved and following characters were studied. 1. Angle's classification; 2.
      Over-jet and over-bite relationship. Anteriorly it included cross-bite, cusp-to
      cusp bite, deep over-bite (without deep over-jet), deep over-jet (with or without
      deep-bite), open bite, and others. Posteriorly it included cross-bite, reverse
      cross-bite and others. 3. Abnormal occlusal index: For the purpose of
      quantitatively comparing the abnormal occlusal relationship of over-bite and over
      jet, the occlusal index was introduced. The anterior continued abnormal was
      scored as 3 while posterior continued oclcusal abnormal scored as 5. The sum of
      the scores in the same subject was taken as his abnormal occlusion index.
      RESULTS: 1. Ratio of Angle's I patients in malocclusion group was significantly
      lower than those in TMD group and US group (P < 0.05), while the later two groups
      had no difference (P > 0.05). 2. The ratios of anterior cross-bite and deep over
      jet were higher in malocclusion group than those in other two groups. No
      significant difference for the other kinds of abnormal over-jet and over-bite
      relationship were found among the three groups. 3. The abnormal occlusion index
      of malocclusion group was higher than that of US group, but not than that of TMD
      group which had no difference with US group either. CONCLUSIONS: 1. Aesthetic
      related anterior abnormal occlusion such as anterior cross-bite and deep-over-jet
      attract more attention of popular. But they had no relationship with TMD. 2. TMD
      patients had not significant occlusal features on Angle's classification and over
      jet and over-bite relationship compared to malocclusion and nature population
      subjects.

PMID- 12411169
TI  - Clinical study of alveolar vertical distraction osteogenesis for implant.
AB  - OBJECTIVE: To evaluate the clinical result of alveolar vertical distraction
      osteogenesis for implant. METHODS: 19 cases with severe vertical alveolar defects
      (more than 10 mm defect) underwent vertical distraction procedure before implant
      placement. 15 cases were male and 4 cases were female. The alveolar bone defects
      were caused by tumor resection in 10 cases, by trauma in 8 cases, and due to
      congenital defect in 1 case. The vertical defects in all cases were over 10 mm. X
      ray examination were taken prior to operation and in 1 week, 2 week, 4 week, the
      end of active distraction and before removing distractor. Implants were placed in
      17 cases after removing distractors. The prosthesis were finished 6 month later.
      RESULTS: 11 cases out of 19 had implant prosthesis. 6 cases had implant in the
      jaw but waiting for the prosthesis. Altogether 65 dental implants were placed, 2
      cases did not receive further implant treatment because of cost problem. The
      study showed that new bone formed after distraction in all 19 cases. Average
      gained height of new bone was 13 mm. COMPLICATIONS: Unexpected mandible fracture
      in 2 cases, infection in 1 case. CONCLUSIONS: Alveolar vertical distraction is a
      good alterative for severe alveolar defects. The distractor should be further
      developed and modified.

PMID- 12411170
TI  - Research on expression of telomerase in human odontogenic lesions.
AB  - OBJECTIVE: To study hTERT mRNA expression in ameloblastoma (AB) and odontogenic
      keratocyst (OKC) and to investigate genesis, development and biological
      characteristics of AB and OKC. METHODS: hTERT mRNA expression in 54 cases of AB,
      16 cases of OKC, 7 cases of oral normal mucosa was detected by in situ
      hybridization. RESULTS: The positive rates of hTERT mRNA in AB, OKC, and oral
      normal mucosa were 94.4% (51/54), 87.5% (14/16), 1/7, respectively. There was
      significant statistical difference (P < 0.001). About clinicalpathology of AB,
      there was no difference for hTERT expression (P > 0.05) hTERT mRNA was positive
      in peripheral and stellate reticula cells. CONCLUSIONS: (1) hTERT activity plays
      an important role in genesis, development of AB. (2) hTERT positive rate is
      related to cell differentiation and clinical biological behavior.

PMID- 12411171
TI  - Study on some mechanism of leucite microcrystallization to reinforce dental glass
      ceramics.
AB  - OBJECTIVE: To research the influence of K(2)O composition in the raw material on
      leucite microcrystallization and to study the effect of leucite content on
      compressive strength of the dental glass ceramics reinforced by leucite
      microcrystallization. METHODS: The raw materials with different K(2)O content
      were treated by a decided thermal treatment system. The products were analyzed by
      polaring microscope and X-ray diffractometer, and their compressive strength was
      also tested. RESULTS: The microstructure of products from high K(2)O component
      was remarkably good, at microcrystal size of 0.8 micro m and the compressive
      strength was 206.6 MPa. A positive correlation was found between leucite volume
      and the compressive strength when leucite volume was less than 50% (Vol%).
      CONCLUSIONS: The component of K(2)O has a great effect on the microstructure and
      the properties of the leucite-microcrystal-reinforced dental glass ceramics and
      the content of leucite microcrystals has a notable influence on the compressive
      strength of the dental glass ceramics.

PMID- 12411172
TI  - The relationship between apical root resorption and orthodontic tooth movement in
      growing subjects.
AB  - OBJECTIVE: To investigate the relationship between apical root resorption and
      orthodontic tooth movement in growing subjects. METHODS: 58 growing subjects were
      collected randomly into the study sample and another 40 non-treated cases were
      used as control. The apical resoption of the upper central incisors was measured
      on periapical film and the incisor displacement was measured on lateral
      cephalogram. Using multiple linear regression analysis to examine the
      relationship between root resoption and the displacement of the upper incisor
      apex in each of four direction (retraction, advancement, intrusion and
      extrusion). RESULTS: The statistically significant negative association were
      found between resorption and both intrusion (P < 0.001) and extrusion (P < 0.05),
      but no significant association was found between resorption and both retraction
      and advancement. The regression analysis implied an average of 2.29 mm resorption
      in the absence of apical displacement. CONCLUSIONS: The likelihood that the
      magnitude of displacement of the incisor root is positively associated with root
      resoption in the population of treated growing subjects is very small.

PMID- 12411173
TI  - The study of biocompatibility of super high molecular weight poly D,L-lactic acid
      implant.
AB  - OBJECTIVE: To evaluate the biocompatibility of the super high molecular weight
      poly D,L-lactic acid (SHMW-PDLLA) implant. METHODS: The SHMW-PDLLA plates were
      implanted into the SD-rats between the masseter and ramus of the mandible. The
      blood specimens were gained at 3, 6, 9, 12 months after the operation. The
      proteins, electrolyte, enzyme and other indices were tested by use of Beckman
      automatic biochemical analysis device. The soft tissue specimens around the SHMW
      PDLLA plates were gained at 3, 6, 9, 12 months after the operation and the tissue
      reaction was observed with the pathological and haematological methods. RESULTS:
      There were not any abnormal findings in the blood after the SHMW-PDLLA plates
      implanted in the body of SD-rats. The implanted SHMW-PDLLA plates were degraded
      gradually in 6 to 12 months after the operation. There was not any abnormal
      tissue reaction found to the soft tissue around the SHMW-PDLLA plates by
      histological and pathological observations. CONCLUSIONS: The SHMW-PDLLA implant
      has a good biocompatibility to SD-rats.

PMID- 12411174
TI  - Experimental study on effects of vitamin B(6) on dexamethason-induced palatal
      cleft formation in the rat.
AB  - OBJECTIVE: To evaluate whether or not administration of vitamin B(6) (vitB(6))
      has preventive effects on cleft palate formation. METHODS: On the 14, 15 day of
      gestation, the pregnant rats were treated with administration of vitB(6) (10
      mg/kg weight im) before and simultaneously with dexamethason (DEX). Compared the
      palatal cleft incidence of their fetuses with those whose mother were given DEX
      only. RESULTS: Treatment with administration of vitB(6) before and simultaneously
      with DEX, the palatal cleft incidence of subject group fetuses (32.35%) was
      significantly less than that given DEX only (64.52%). The proportion of the
      palatal cleft type was also changed significantly. CONCLUSIONS: VitB(6) decrease
      both the incidence and the severity of cleft palate induced by DEX in rats, which
      indicates VitB(6) may have preventive effects on cleft palate formation.

PMID- 12411175
TI  - The effect of para-aminobenzoic acid on growth and metabolism of Porphyromonas
      gingivalis.
AB  - OBJECTIVE: To study the effect of para-aminobenzoic acid (PABA) on the growth and
      metabolism of Porphyromonas gingivalis (P.g). METHODS: After adding different
      concentrations of PABA into the medium, anaerobic technique was applied to
      culture P.g. The products' A value and action of TLP was assayed, and P.g grew in
      the medium was observed by a scanning electron microscope. RESULTS: PABA promoted
      the growth of P.g and action of TLP, which would reach the highest level when
      PABA was 1 mg/L, and would decrease with the increasing of concentration of PABA.
      When the concentration arrived at 100 mg/L, PABA had no effect on them. In the
      mean time, PABA had effect on the form and adherence of P.g. When the
      concentration was 1 mg/L and 100 mg/L, this effect was strong, but as the
      concentration was 10 mg/L, the effect disappeared. CONCLUSIONS: PABA influences
      the growth and metabolism of P.g, which indicate that Streptococcus sanguis has
      regulative effect on the microecology of subgingival plaque.

PMID- 12411176
TI  - Cloning of full length cDNA sequence of the mouse ameloblastin.
AB  - OBJECTIVE: Screening for special genes of matrix proteins of dentin and enamel of
      mouse dental germ. METHODS: A cDNA library of dental germ of mouse was screened
      by differential display. The interesting clones were sequenced. RESULTS: Six
      positive clones were isolated from the cDNA library. The sequence of one of the
      six positive clones was homologous with the ameloblastin sequence of rat. There
      are 497 homologous base pairs between the 526 base pairs sequenced by pTriplEX 3'
      primer of this clone and the 32-580 sequence of the rat ameloblastin gene; and
      there are 533 homologous base pairs between the 567 base pairs sequenced by
      pTriplEX 5' primer of this clone and the 1285-1854 sequence of the rat
      ameloblastin gene. CONCLUSIONS: The full length cDNA sequence of the mouse
      ameloblastin was cloned.

PMID- 12411177
TI  - Detection of cariogenic Streptococcus mutans by quantitative polymerase chain
      reaction.
AB  - OBJECTIVE: To establish a kind of molecular biology clinical detective method to
      cariogenic S. mutans. METHODS: Using the coamplification of target and reference
      genes. One pair of specific primers were designed according to a portion of the
      dextranase (dexA) gene of S. mutans. The reference gene was plasmid pET23b DNA.
      The saliva samples of 196 children were quantitative detected. The PCR method was
      compared with the routine culture method. RESULTS: The rate of S. mutans counts
      >/= 10(8) CFU/L (colony-forming unit per millilitre) saliva by quantitative PCR
      was 91.3%. The results of coincidence rate between the new method and the routine
      way was 94.9%. CONCLUSIONS: The new quantitative detective method is fast and
      provides with high scoincidence rate and high specificity, so have extensive
      clinical practice foreground.

PMID- 12411178
TI  - Isolation, culture and identification of human venous malformation endothelial
      cells.
AB  - OBJECTIVE: To establish a method of culturing endothelial cells (EC) from human
      vascular malformation. METHODS: Venous malformation specimens obtained from the
      patient undergoing oral surgery were plated into glass, plastic and gelatin
      coated dishes. Pure cultures of human vascular malformation endothelial cells
      (VMEC) were isolated by the ways of discarding the tissues at early stage of
      primary culture, scraping and trypsinizing. Morphological characteristics were
      studied under phase-contrast microscope and electron microscope (EM), and
      determined by immunohistochemistry. RESULTS: The cells were pure and could be
      maintained in culture up to 4 approximately 5 passages, or 40 approximately 50
      days. VMEC formed contact-inhibited "cobblestone" monolayer on glass and plastic,
      and capillary-like "tubes" on gelatin. EM revealed that there were Weibel-Palade
      bodies in the culture cells. The cells showed positive staining for CD(34), vWF,
      and negative for alpha-SMA. CONCLUSIONS: The culture technique for growing VMEC
      has been established. And these cells can provide a useful tool for studying
      biological characteristics of human vascular malformation in vitro.

PMID- 12411179
TI  - Element mixing distribution and structure feature of fusion zone in laser welding
      between different alloys and pure titanium.
AB  - OBJECTIVE: To study micro morphology and element-mixing distribution of different
      alloys welded in laser and analyze the feasibility of laser welding different
      alloys. METHODS: Alloys and titanium were matched into 4 groups: Au-Pt with Ni
      Cr; Au-Pt with pure Ti; pure Ti with Ni-Cr; Ni-Cr with Co-Cr. They were welded in
      laser. Changes in metallography after hybridization of crystalline grain, ranges
      of heat-affected zone and pores were observed through SEM with ultra-thin
      windowed X-ray energy atlas. Meanwhile 10 testing points were chosen with area of
      300 micro m x 900 micro m along the welding surface from the side A alloy to the
      side B alloy, than the element mixing distribution and tendency were analyzed
      with X-ray energy atlas. RESULTS: 1. Hybridization of different alloys: (l) in
      the group of Au-Pt with Ti, there was titanium element mixing into Au-Pt tissue
      gradually and evenly on the Au-Pt side of the interface without clear boundary
      and increasing in size of crystalline grain. However, there was titanium
      crystalline grain increasing in size, irregular morphology and small sacks on the
      titanium side with clear boundary. (2) in the group of Ni-Cr with Ti, there was
      mixing regularly, slow transition and interlocks between crystalline grains on
      the Ni-Cr side of the in terface. Poor transition, clear boundary and small
      cracks were observed on titanium side. (3) in the group of Co-Cr with Ni-Cr,
      there was good transition, obscure boundary on both sides resulting from network,
      cylinder and branch structure growing. 2. Element-mixing distribution of
      different alloys. In fusion zone, the metal elements in matched groups mixed well
      and hybridized into new alloys except titanium blocks. The location of wave peak
      depended on the composition of alloys. Most of elements were from the alloy far
      from the fusion zone. CONCLUSION: The hybridization between pure titanium and any
      other alloys is not good The effect of laser welding different alloys is ideal
      except with pure titanium.

PMID- 12411180
TI  - The effects of local administration of Zoledronate solution on the tooth movement
      and periodontal ligament.
AB  - OBJECTIVE: To investigate the effects of local administration of Zoledronate
      solution on the tooth movement and periodontal ligament. METHODS: Orthodontic
      tooth movement of upper first molar was performed in 42 rats with coil spring.
      Zoledronate solution was injected into the palatal submucosal area adjacent to
      the left upper first molar in experimental group 3 days prior to the use of the
      appliance. In control group, same amount of 0.9% NaCl solution was injected into
      the palatal submucosal area adjacent to the left and right upper first molar. The
      injection was applied every third day. The application of mesial force lasted
      0.3, 7, 14, 21 days respectively. After the rats were sacrificed, the distance of
      tooth movement was measured. Sections were stained and then observed with
      microscope. RESULTS: 1. The distance of tooth movement in the experimental group
      was significantly smaller than that in the control group. 2. The number of
      osteoclast on the pressure side in the experiment group was significantly smaller
      than that in the control group through the experimental period, but there was no
      distinct difference between experimental group and control group (except for 14
      days) for the number of odontoclast in interradicular area. 3. The osteoclasts
      and odontoclasts were the main target cell of Zoledronate in periodontal tissue.
      CONCLUSIONS: Zoledronate may be a useful agent for anchorage control and reducing
      the number of osteoclast on pressure side of alveolar bone.

PMID- 12411181
TI  - Expression of epidermal growth factor and epidermal growth factor receptor in rat
      periodontal tissues during orthodontic tooth movement.
AB  - OBJECTIVE: To detect the expression and distribution of epidermal growth factor
      (EGF) and epidermal growth factor receptor (EGFR) in periodontal tissues, and
      analyze the role of EGF in orthodontic tooth movement. METHODS: According to
      Kings methods, 40 g mesial force was applied to pull the left maxillary first
      molar in the rat. Using immunohistochemical method (HI-SABC method) to localize
      and examine the expression of EGF and EGFR in decalcified alveodental connective
      tissues at 24 hours and 168 hours of tooth movement. RESULTS: EGF and EGFR were
      stained at some of periodontal ligament of furcation and radical regions in
      control group. These expressions of EGF and EGFR increased in periodontal tissues
      (P < 0.01), with the expressions at 168 hours higher than those at 24 hours (P <
      0.01). And levels of EGF and EGFR at tension side were higher than those at
      pressure side at the same time (P < 0.01). CONCLUSIONS: Epidermal growth factor
      participated in the tissues remodeling during orthodontic tooth movement and
      especially played a more important role in orthodontic bone formation.

PMID- 12411182
TI  - Analysis of N-terminal amino acid sequence of 12 000-protein in gingival
      crevicular fluid and its clinical significance.
AB  - OBJECTIVES: To study the essence of N-terminal amino acid sequence of 12 000
      protein in gingival crevicular fluid (GCF). METHODS: GCF samples from patients
      with RPP and AP were collected. 12 000-protein was separated by SDS-PAGE and
      transformed to PVDF by electronic transformation. The aim band was cut to be
      analyzed in 491 Protein Sequencer. RESULTS: The first ten of N-terminal amino
      acid sequence of 12 000-protein in GCF was Met, Leu, Thr, Glu, Leu, Glu, Lys,
      Ala, Leu, Asn. Through checking up in MS-Edman, the sequence was similar to "Ca
      binding protein, MRP8" which is the light subunit of Calprotectin. CONCLUSIONS:
      Calprotectin is a major protein in granulocytes and monocytes, and is related to
      many inflammatory diseases, maybe served as a effective marker for evaluating the
      inflammation of periodontium.

PMID- 12411183
TI  - The relationship between oral malodor, VSCs levels in the mouth air with
      periodontitis and tongue coating.
AB  - OBJECTIVE: To assess the relationship between oral malodor, volatile sulphur
      compounds (VSCs) levels in the mouth air and periodontal index; the role of
      tongue in the production of VSCs and halitosis. METHODS: 60 periodontitis
      patients with oral malodor were included. Oral malodor was estimated by
      organoleptic method (organoleptic rating, OR); VSCs level measurements before and
      after cleaning the tongue coating were made with a portable sulphide monitor
      (halimeter), respectively; periodontal probing depth (PD) and the proportion of
      PD >/= 4 mm sites, bleeding index (BI) and plaque index (PLI) were examined;
      tongue coating was estimated with thickness (Tt) and area (Ta) on the dorsal
      surface of tongue. RESULTS: The correlation was analyzed with Spearman method.
      There was a significantly positive correlation between OR, VSCs levels and BI,
      PLI, and Tt, respectively (P < 0.01). OR and VSCs levels was also related with Ta
      (P < 0.05). There was a weakly correlation between VSCs levels and PD, and the
      proportion of PD >/= 4 mm sites (r = 0.26, P < 0.05). No correlation between OR
      and PD, and the proportion of PD >/= 4 mm sites was existed. Reduction of VSCs
      levels after cleaning tongue coating was statistically significant (t = 10.15, P
      < 0.01), and also significantly related with thickness and area of tongue coating
      (P < 0.01). CONCLUSIONS: In present study, OR and VSCs levels were significantly
      correlated with gingival inflammation (BI), condition of oral hygiene (PLI), and
      tongue coating. The relationship between OR, VSCs levels and periodontal probing
      depth was not found obviously. VSCs levels were significantly reduced after
      cleaning tongue coating, but the percentage of reduction was less than that of
      the previous studies.

PMID- 12411184
TI  - [The microarray study on the stress gene transcription profile in human retina
      pigment epithelial cells exposed to microwave radiation].
AB  - OBJECTIVE: To study the difference in stress and apoptosis related genes
      transcription between hTERT-RPE1 cells exposed to simulated microwave radiation
      and the cells with heat water bath, and the effects of microwave on gene
      transcription in cultured human retina pigment epithelial cells. METHODS: cDNA
      microarray technique was used to detect the mRNA isolated from hTERT-RPE1 cells
      exposed to 2 450 MHz simulated microwave radiation and with heat water bath,
      respectively. RESULTS: Among the 97 related aim genes, there were seven genes up
      regulating its transcription, i.e., M31166 (2.52fold), L24123 (2.66fold),
      AF039704 (2.22fold), U67156 (2.07fold), AF040958 (2.13fold), NM-001423 (2.63fold)
      and NM-005346 (3.68fold). But, no notably down-regulating gene in transcription
      was detected. CONCLUSIONS: Microwave could induce up-regulating in multiple
      stress and apoptosis related genes transcription in cultured human retina pigment
      epithelial cells, hTERT-RPE1 cells. Microwave radiation has unique effect itself
      in addition to its heat effect.

PMID- 12411185
TI  - [The acute toxic effects of microcystin LR in SD rats].
AB  - OBJECTIVE: To assess Microcystin LR (MCLR)-induced acute toxic effects in male
      Sprague-Dawley rats. METHODS: The rats were injected with MCLR intraperitoneally
      in different doses for different days. The organs and serum with rats were
      collected at 1 and 7 days after injection, and 7 days after the final injection
      (total 14 days). Pathological and enzymatic changes were observed. RESULTS: The
      rats injected with 122 microg/kg MCLR showed myocardial cells damage including
      pyknosis, plasma dissolve and myofibrilla (pls check with dictionary) necrosis in
      the heart muscles after 24 hours. At the same time, the activities of serum
      glutamate-oxaloacetate transaminase (GOT), lactate dehydrogenase (LDH) and
      creatine phosphonase (CPK) were higher than these in the other groups (P < 0.01).
      The kidney was also damaged, kidney cell degeneration, and the increase of blood
      creatine (BCr) and blood urea nitrogen (BUN) were also seen. In liver
      pathological study, liver cell hemorrhage, degeneration and/or necrosis was
      observed. In serum the activities of glutamate-pyruvate transaminase (GPT),
      alkaline phosphatase (LDH) and GOT were higher than these in the other groups (P
      < 0.01). CONCLUSION: These results suggested that MCLR can injure the heart,
      kidney and the liver in SD rats, and there is a dose-response relationship
      between MCLR and the toxic effect.

PMID- 12411186
TI  - [The prevalence of metabolic syndrome in a 11 provinces cohort in China].
AB  - OBJECTIVE: To explore the prevalence feature of the metabolic syndrome in a
      cohort of 11 provinces in China. METHODS: A cohort study was carried out in
      population of 27,739 subjects (age 35-64 years). The baseline survey for risk
      factor of cardiovascular disease was completed in 1992. The prevalence rate,
      means and standard deviation of various risk factors associated with metabolic
      syndrome were analysis. RESULTS: (1) The prevalence rate of high waist
      circumference was highest among the components in metabolic syndrome (89.0% in
      males and 85.1% in females to metabolic syndrome patients). (2) The prevalence
      rate of metabolic syndrome was 13.3% (12.7% in males, 14.2% in females, P <
      0.0001), and it was increased with age. (3) Multivariable logistic analysis
      showed that the risk factors of the metabolic syndrome were the waist
      circumference and familial history of diabetes mellitus in males; and the waist
      circumference and familial history of high blood pressure in females.
      CONCLUSIONS: The prevalence of metabolic syndrome was high in 11 provinces in
      China. The high waist circumference would be an important factor in metabolic
      syndrome.

PMID- 12411187
TI  - [Aristolochic acid induced transdifferentiation and apoptosis in human tubular
      epithelial cells in vitro].
AB  - OBJECTIVE: To examine the possible role of aristolochic acid (AA) in
      transdifferentiation and apoptisis of human tubular epithelial cell line (HKC).
      METHODS: Cultured HKC cells were divided into five groups: serum-free (negative
      control) and treatment with AA at the concentrations of 5 mg/L, 10 mg/L, 20 mg/L
      and 40 mg/L for 48 hours, respectively. Transdifferentiation of HKC cells was
      observed with the following methods: detection of the expression of vimentin and
      cytokeratin of HKC cells with indirect immunoflourescence, determination of
      expression of E-cadherin and alpha-smooth muscle actin (alpha-SMA) by indirect
      immunohistochemical double staining, and determination of the proportion of alpha
      SMA (+) HKC cells by flow cytometry. The apoptosis of HKC cells was observed with
      Giemsa staining, TUNEL reaction and agarose gel electrophoresis, and the ratio of
      apoptotic HKC cells was quantitatively analyzed by flow cytometry with propidium
      iodide staining. RESULTS: The expression of cytokeratin and E-cadherin reduced
      and that of vimentin increased in HKC cells treated with 10 mg/L of AA for 48
      hours, and the expression of alpha-SMA (+) in HKC cells treated with 10 mg/L of
      AA (14.17 +/- 0.61)% was significantly higher than that in serum-free controls
      (3.57 +/- 0.52)%. Apoptosis of HKC cell treated with 40 mg/L of AA for 48 hours
      was 53.4%, significantly higher than that in serum-free controls (2%). Treatment
      with 5 mg/L of AA and 20 mg/L of AA could not induce apoptosis and
      transdifferentiation of cells. CONCLUSIONS: Treatment with relatively low
      concentration of AA (10 mg/L) might induce slight transdifferentiation in
      cultured HKC cells and that with higher concentration of AA (40 mg/L) for 48
      hours might induce apparent apoptosis of these cells, which suggested that
      transdifferentiation and apoptosis of tubular epithelial cells probably played
      important roles in aristolochic acid-induced nephropathy.

PMID- 12411188
TI  - [An epidemiological study on vitamin K deficiency bleeding in infants under six
      months].
AB  - OBJECTIVE: To understand the incidence and relevant affecting factors of infant
      vitamin K deficiency bleeding (VKDB) in Shandong Province. METHODS: With
      stratified cluster sampling, 28 156 live newborns from five districts and six
      counties were surveyed for the condition of bleeding from their birth to 6 months
      based on standard diagnostic criteria. A 1:2 matched case-control study of VKDB
      was performed. RESULTS: An overall incidence of VKDB was 3.27 per thousand in
      Shandong; higher in the rural areas (4.96 per thousand ) than in the urban areas
      (1.19 per thousand ). Most of the bleeding cases were breast-fed babies (about
      95.57%) and incidence of VKDB in pre-term babies (22.52 per thousand ) was higher
      than that in term ones (2.96 per thousand ). Mothers' drug taking during
      pregnancy, asphyxia at birth, breast-feeding and illness within two weeks after
      birth were risk factors for it. Use of vitamin K after birth and bottle-feeding
      were protective factors for it. CONCLUSIONS: Incidence of VKDB is higher in
      Shandong Province, as compared to other areas all over the country at the same
      time period. It is very important to prevent VKDB, focusing on high-risk babies
      in the rural areas, including those of preterm, breast-fed and suffering illness
      after birth.

PMID- 12411189
TI  - [Variation of plasma folate levels in adults between some areas and different
      seasons in China].
AB  - OBJECTIVE: To describe the distribution of plasma folate concentrations and
      prevalence of folate deficiency in adults aged 35 to 64 years in some areas and
      different seasons in China. METHODS: Study subjects were sampled from the
      representative rural and urban areas in the south and north of China aged 35 to
      64 years totaling 2 545, and their plasma folate concentrations were determined
      and analyzed. RESULTS: Plasma concentrations of folate in the southern population
      were significantly higher (16.9 nmol/L) than those in the north (8.3 nmol/L), and
      the prevalence of folate deficiency in the south (5.8%) was significantly lower
      than that in the north (37.1%). Plasma folate concentration varied with season
      either in the south or north. Plasma concentrations of folate were lower during
      the summer and the fall (15.0 nmol/L) than those during the winter and the spring
      (18.8 nmol/L) in the south, but without significant changes in the prevalence of
      folate deficiency in different seasons. However, the plasma folate concentrations
      were significantly higher during the summer and the fall (9.7 nmol/L) than those
      during the winter and the spring (7.1 nmol/L) in the north. And the prevalence of
      folate deficiency in the north was significantly higher in winter and spring
      (48.0%) than that in summer and fall (26.2%). CONCLUSIONS: There existed
      significant difference in plasma folate concentrations in adults between varied
      geographic areas in China, which differed from their seasonal changes.

PMID- 12411190
TI  - [Reactivation and aging of acetylcholinesterase in human brain inhibited by
      phoxim and phoxim oxon in vitro].
AB  - OBJECTIVE: Inhibition of acetylcholinesterase (AChE) in human brain caused by
      phoxim or phoxim oxon, their reactivation with oxime and aging of phosphorylated
      AChE were studied and compared in vitro. METHODS: Micro-colorispectrophotometric
      assay was used to determine the activity of AChE. RESULTS: The pI(50) of
      inhibition of AChE in human brain by phoxim and phoxim oxon were 5.39 and 5.77,
      respectively, whereas the pI(90) were 4.60 and 5.00, respectively. The
      reactivation rate of 0.1 mmol/L of pralidoxime (2-PAM), obidoxime (LuH(6)),
      trimedoxime (TMB-4) and pyramidoxime (HI-6) for phoxim-inhibited AChE in human
      brain was 65%, 97%, 91% and 56%, respectively, and their reactivation rate for
      phoxim oxon-inhibited AChE in human brain was 97%, 87%, 99% and 89%,
      respectively. The optimal reactivator for phoxim and phoxim oxon-inhibited AChEs
      was LuH(6) and TMB-4, respectively. The half aging time of phoxim and phoxim oxon
      inhibited phosphorylated AChEs were 39 and 28 hours, respectively, and the 99%
      aging time were 256 and 186 hours, respectively. CONCLUSIONS: LuH(6) or TMB-4
      should be used at the earlier as possible after poisoning with phoxim and phoxim
      oxon, and the reactivator should be consecutively used for more than seven days,
      even after their acute symptoms have been well controlled.

PMID- 12411191
TI  - [Survey on vitamin A deficiency in children under-6-years in China].
AB  - OBJECTIVE: To understand the prevalence and spatial distribution of vitamin A
      deficiency (VAD) in China among children at ages under six years. METHODS: About
      8,600 children under 6 years of age in 14 cities and 28 counties of 14 provinces
      were selected with stratified cluster sampling for survey, including interview
      with questionnaire for their family information and nutritional status. Blood
      specimens were collected for measuring serum level of VA with fluorescent
      spectrophotometry in laboratory. RESULTS: Totally, 8,669 children under 6 (2,877
      in urban area and 5,792 in rural area) were surveyed in 14 provinces, with 4,629
      males and 4,040 females. Eight cases of night blindness and seven cases of
      xerophthalmia were found among the children at ages of two to five years. Sixty
      one mothers of the children in this group were also found suffering from night
      blindness. All the cases of night blindness and xerophthalmia both in children
      and mothers were living in rural areas. Based on their serum levels of VA, 11.7%
      of the all 1 018 children were diagnosed as VAD, with serum VA concentrations
      below or equal to 0.70 micro mol/L. Prevalence of VAD was 15.0% and 5.8% in rural
      (23.3% in the poverty-stricken counties) and urban areas, respectively, and 5.8%,
      11.5% and 16.8% in the coastal, inland and remote areas, respectively. The
      average serum level of VA was 1.20 micro mol/L and 0.99 micro mol/L for urban and
      rural areas, respectively, with a national average of 1.06 micro mol/L. And,
      babies under six months of age with an average serum levels of VA < or = 0.70
      micro mol/L accounted for 33.4%, and those at ages of four to five years with the
      same level of VA accounted for 8%. There was significant difference in serum
      levels of VA between ages, but no significant difference between genders.
      CONCLUSION: VAD did exist in children of China, especially in the remote and
      poverty-stricken rural areas and VA supplementation is urgently needed for the
      children in these regions.

PMID- 12411192
TI  - [Effects of exposure to asbestos on plasma activity of glutathione S
      transferases].
AB  - OBJECTIVE: To understand the effects of exposure to asbestos and GSTM1 genotypes
      on plasma activity of glutathione S-transferases (GSTs). METHODS: Ninety-four
      workers exposed to asbestos and 51 controls were selected, and their general
      information, occupational history and personal behavior were collected by
      questionnaire. Venous blood specimen was collected from each of them and plasma
      was separated for detection of GSTs activity and lymphocytes for DNA extraction
      and GSTM1 genotyping. RESULTS: Plasma activity of GSTs in the asbestos-exposed
      workers (23.0 +/- 6.9) U/L was significantly lower than that in the controls
      (32.6 +/- 11.8) U/L, which declined with the length of employment in asbestos
      industry and the increase of cumulated dose of asbestos. Stratification of
      workers by GSTM1 genotypes showed that plasma activity of GSTs in asbestos
      exposed workers with GSTM1+/+ or GSTM1-/- were (24.0 +/- 6.1) and (22.5 +/- 7.3)
      U/L, respectively, lower than those in the controls with the same genotypes (38.1
      +/- 13.2) and (26.8 +/- 6.6) U/L. Plasma activity of GSTs in the control workers
      with GSTM-/- was significantly lower than in those with GSTM+/+, and, so did in
      asbestos-exposed workers, but without statistically significant difference.
      CONCLUSION: Exposure to asbestos could significantly decrease plasma activity of
      GSTs, and GSTM1 genotypes could affect on the activity of GSTs in the control
      workers, which was not so obvious in asbestos-exposed workers.

PMID- 12411193
TI  - [Evaluation of risk factors associated with cerebral palsy in children of Leshan
      Prefecture, Sichuan: a case control study on 308 cases].
AB  - OBJECTIVE: To evaluate the risk factors associated with pathogenesis of cerebral
      palsy (CP) in young children. METHODS: A cross-sectional survey on the prevalence
      of CP was conducted in young children aged one to six years in Leshan area,
      Sichuan Province. Cluster sampling and a 1:2 case-control design were used to
      investigate the risk factors for pathogenesis of CP. RESULTS: Totally, 148,723
      children were surveyed, in which 308 (2.07 per thousand ) were diagnosed as CP.
      Low birth weight, twins and premature birth were associated with significantly
      increased prevalence of CP, 16.32, 4.16 and 22.21 times as that in normal birth
      weight, single birth and full-term birth, respectively. Simple factor analysis
      showed varied factors involved in pathogenesis of CP. The multivariate analysis
      revealed that delivery at home, low Apgar score in five minutes, illness during
      the first month of life, maternal "cold" with fever in their early gestation, low
      protein (meat and egg) intake during pregnancy and lower education level of
      mother were risk factors for CP. CONCLUSIONS: Prevalence and clinical features of
      CP in Leshan was comparable to those in the developed countries. Relevant risk
      factors could be seen primarily in gestational and perinatal periods, which might
      involve in mothers, children, environment and heredity, etc. To attach more
      importance in gestational and perinatal care for mothers and babies will be
      crucial measures to reduce occurrence of CP in young children.

PMID- 12411194
TI  - [The trend of injury epidemic in Ningxia].
AB  - OBJECTIVE: To study the epidemiological transition of injuries in Ningxia.
      METHODS: Demographic and mortality data during 1990s in Ningxia were collected
      and analyzed for temporal trend with linear regression model. RESULTS: During the
      past decade, mortality of injury raised by 28.22% among the residents in Ningxia
      and ranked the 3rd place in the causes of deaths. In 1999, the top four leading
      causes of injury deaths were traffic accident, suicide, drowning and poisoning.
      Overall injury mortality and mortalities of traffic accident and suicide
      increased, but mortality of drowning decreased during the past decade. As
      predicted, suicide will rank the 1st place in the causes of deaths among the
      residents in Ningxia by 2005. CONCLUSIONS: Injury was one of major risk factors
      influencing health and death among the residents in Ningxia, with a temporal
      trend in its incidence. Effective research, prevention and control of traffic
      accident, suicide, drowning and poisoning should be focused.

PMID- 12411195
TI  - [Studies on blood viscosity and external thrombus in patients with silicosis and
      silicosis complicated with tuberculosis].
AB  - OBJECTIVE: To explore the changes of blood viscosity and external thrombus in
      patients with silicosis and silicosis complicated with tuberculosis (TB). METHOD:
      Blood viscosity and external thrombus were measured in 288 patients with
      silicosis, 178 patients with silicosis complicated by TB and 150 healthy
      subjects. RESULTS: Blood viscosity and external thrombus value were significantly
      higher in the patients of silicosis and silicosis complicated with TB than in the
      healthy controls, except for patients of phase I of silicosis. Blood viscosity in
      the silicotics increased significantly with the advance of the disease, but no
      significant difference in external thrombus between patients in different phases.
      Apparent viscosity of whole blood significantly increased in the high-shear rate
      (200 s(-1)) and middle-shear rate (30 s(-1)) in patients of silicosis complicated
      with TB than in those without complication of TB at the same phases, but not seen
      in the low-shear rate (5 s(-1)) and in plasma viscosity, and the length and dried
      weight of external thrombus increased significantly too. There was no significant
      difference in blood viscosity and external thrombus between patients of silicosis
      at phase III and those of silicosis complicated with TB at the same phase.
      CONCLUSION: Blood in patients with silicosis appeared highly viscous and highly
      coagulant status. Blood viscosity and external thrombus value significantly
      increased with the advance of the disease, especially in the patients complicated
      with TB.

PMID- 12411196
TI  - [Nonsteroidal anti-inflammatory drugs and the risk of polyposis, colon carcinoma
      and rectal carcinoma].
AB  - OBJECTIVE: To probe the risk of colorectal polyp, colon and rectal carcinoma and
      the intake of NSAIDs. METHODS: Case-control study participants were from patients
      who underwent colonoscopy at different hospitals, the persons with the above
      disease was as cases, and those without the above diseases was as controls. Use
      of NSAIDs was assessed by interviewing the participants with a questionnaire
      which include a list of NSAIDs and related dietary and life style factors and
      family history. RESULTS: There are 37 cases of colorectal polyp, 105 cases of
      colon carcinoma and 142 cases of rectal carcinoma and 66 controls. Adjusted for
      potential confounders, the risk of colorectal polyposis, colon carcinoma and
      rectal carcinoma were markedly reduced by NSAIDs. The OR values were 0.21 (95% CI
      0.07-0.65, P = 0.007), 0.13 (95% CI 0.05-0.35, P < 0.001), 0.15 (95% CI 0.11
      0.58, P < 0.001) respectively. The risk of the above diseases were also reduced
      markedly by aspirin, the OR values were 0.265 (95% CI 0.07-0.96, P = 0.044), 0.10
      (95% CI 0.03-0.35, P < 0.001), 0.15 (95% CI 0.04-0.49, P = 0.002) respectively.
      The risk of colon carcinoma was also reduced by profen, with the OR being 0.11
      (95% CI 0.02-0.64, P = 0.014). CONCLUSIONS: Aspirin and other NSAIDs could
      reduced the risk of colorectal polyp, colon carcinoma and rectal carcinoma
      markedly. Aspirin was the most prospective chemopreventive agents for colorectal
      polyp, colon and rectal carcinoma for its capability of reducing the risk of
      cardio-cerebral vascular disease as well.

PMID- 12411197
TI  - [Effects of selenium and zinc on rat renal apoptosis and change of cell cycle
      induced by fluoride].
AB  - OBJECTIVE: This study was conducted to study the effects of sodium fluoride (NaF)
      on rat renal apoptosis and proliferation, the antagonistic effect of selenium
      zinc preparation (Se-Zn) to NaF. METHODS: Wistar rats were provided with
      distilled water containing NaF (50 mg/L) and administered by gavage with
      different dosed of Se-Zn for six months. Kidney cell apoptosis and the cell cycle
      of proliferation were detected by TUNEL (TdT-mediated dUTP Nick End Labelling)
      and flow cytometry. RESULTS: NaF caused rat renal apoptosis, reduce the cell
      number of G(2)/M period in cell cycle and decrease the relative content of DNA
      significantly. Se-Zn inhibited the effects of NaF on apoptosis and increased the
      cell number of G(2)/M period in cell cycle, but failed to increase relative
      content of DNA. CONCLUSION: It was suggested that NaF could induce apoptosis and
      change the cell cycle in rat renal cells and Se-Zn could antagonize apoptosis and
      the changes of cell cycle induced by NaF.

PMID- 12411198
TI  - [Studies on DNA damage and apoptosis in rat brain induced by fluoride].
AB  - OBJECTIVE: To explore the DNA damage effects and apoptosis in brain cells of rats
      induced by sodium fluoride. METHODS: SD rats were divided into two groups, i.e.
      control group and fluoride treated group, which were injected intraperitoneally
      with distilled water and sodium fluoride (20 mg.kg(-1).d(-1)) respectively. On
      the hand, 5 mmol/L NaF were used in in vitro study. Single Cell Gel Electrophosis
      (SCGE or Comet Assay) was utilized to measured DNA damage and apoptosis was
      detected by the TUNEL method and Flow Cytometry (FCM). RESULTS: The DNA damage in
      pallium neurons in rats of the fluoride group was much more serious compared with
      those of the control group, with the Ridit value being 0.351 and 0.639
      respectively (P < 0.01) in vivo, and 0.384 4 and 0.650 1 respectively (P < 0.01)
      in vitro. TUNEL positive cells were found in pallium, hippocampus and cerebellar
      granule cells in rats of fluoride group, whereas those in the control group were
      rare. It was demonstrated by FCM results that the percentages of apoptotic cells
      both in pallium and hippocampus were significantly higher (P < 0.01) in rats of
      fluoride group (27.12 +/- 3.08, 34.97 +/- 5.46) than those in control group (4.63
      +/- 0.98, 5.35 +/- 0.79), (P < 0.01). CONCLUSION: Sodium fluoride could induce
      DNA damage and apoptosis in rats brain.

PMID- 12411199
TI  - [Effects of tea polyphenols and tea pigments on cell cycle regulators in rat
      liver precancerous lesions].
AB  - OBJECTIVES: This study is to investigate the effects of tea polyphenols and tea
      pigments on cell cycle regulators in rat liver precancerous lesions. METHODS: The
      modified Solt-Farber precancerous liver rat model was used. Rats were given
      water, tea polypheol solution (0.1%) or tea pigment solution (0.1%) throughout
      the whole experiment (56 days). Cyclin D1, P21(WAF1/CIP1), GADD45 and PCNA
      protein expression were detected by Western blotting and the RT-PCR method was
      applied to study the expression of Cdk4. RESULTS: Cyclin D1, Cdk4 and PCNA
      expressions were significantly inhibited, and the expression of P21(WAF1/CIP1)
      and GADD45 were significantly induced by tea polyphenols and tea pigments
      treatments. CONCLUSION: Tea polyphenols and tea pigments induced cell cycle
      arrest and inhibited cell proliferation by regulating cell cycle regulators.

PMID- 12411200
TI  - [Induction effects of sulfur dioxide inhalation on chromosomal aberrations in
      mouse bone marrow cells].
AB  - OBJECTIVE: To investigate the induction effects of sulfur dioxide (SO(2))
      inhalation on chromosomal aberrations (CA) in mouse bone marrow cells. METHODS:
      The mice were treated with SO(2) for 4 h/day x 7 days at various concentrations
      of SO(2), then mitotic indices and CA in the bone marrow cells were analyzed.
      RESULTS: SO(2) increase the frequencies of CA and aberrant cells in mouse bone
      marrow cells in dose-dependent manner. The frequencies (%) of the aberrant cells
      in mouse bone marrow cells induced by SO(2) at concentrations of 0, 14, 28, 56
      and 84 mg/m(3) were 1.81, 3.00, 3.58, 4.26 and 4.86, respectively. SO(2) at low
      concentrations induced only chromatid-type CA, but at high concentrations it
      induced both chromatid-type and chromosome-type CA. SO(2) inhalation decreased
      the mitotic indices of the bone marrow cells. CONCLUSIONS: SO(2) inhalation may
      inhibit mitoses and increase CA frequencies of the bone marrow cells; therefore,
      it is a clastogenetic and genotoxic agent. It implies that long time exposure of
      SO(2) pollutant at low concentration in air may be a potential risk to induce
      damage of cytogenetic material in humans.

PMID- 12411201
TI  - [Distribution of hemorrhagic fever with renal syndrome virus in gamasid mites and
      chigger mites].
AB  - OBJECTIVE: To study the distribution of hemorrhagic fever with renal syndrome
      virus (HFRSV) in mites. METHODS: In situ reverse transcription-polymerase chain
      reaction (IS RT-PCR) was used for detecting the distribution of HFRSV in mites.
      RESULTS: HFRSV RNA was mainly located in ovary and mid-gut tissues of gamasid
      mites and chigger mites. The positive signal intensity in the third and fourth
      generations of gamasid mite was stronger than that in the first and second
      generations, and that in nymph of chigger mite more than larva. CONCLUSION: Both
      chigger mite and gamasid mite could play an important role in the transmission of
      HFRSV.

PMID- 12411202
TI  - [Effects of selenium and fluoride on apoptosis and lipid peroxidation in human
      hepatocytes].
AB  - OBJECTIVE: To study the influence of selenium and fluoride on apoptosis and lipid
      peroxidation in human hepatocytes in vitro. METHODS: The apoptosis, cell cycle,
      GSH content and lipid peroxides (LPO) level in human hepatocytes, LPO level and
      LDH, AST and ALT activity in cell culture supernatants were investigated after
      hepatocytes were incubated with selenium and/or fluoride for around 12 hours
      periods in vitro. RESULTS: The percentage of hepatocyte apoptosis bodies (15.557
      +/- 2.056)%, the number of cells in S phase (4.823 +/- 0.454)% and LPO level in
      liver tissue and supernatant [(2.884 +/- 0.589) and (3.547 +/- 0.561) nmol/L
      MDA/mg.prot, respectively], AST and LDH activity in supernatants (91.1 +/- 36.4
      and 140.4 +/- 7.6 U/L, respectively) in the fluoride treated group was higher
      than the control group [(10.313 +/- 1.023)%, (3.253 +/- 0.743)%, (1.473 +/-
      0.401) nmol/L MDA/mg.prot, (1.694 +/- 0.443) nmol/L MDA/mg.prot, (54.5 +/- 3.2)
      U/L and (126.4 +/- 2.6) U/L, respectively], The GSH content in live tissue
      [(4.225 +/- 0.781) microgram/mg.prot] is lower than control group [(7.595 +/-
      1.042) microgram/mg.prot]. Selenium treatment reduced these kinds of toxicity of
      fluoride through raising GSH content, reducing LPO level, LDH and AST activity
      and percentage of apoptosis bodies. CONCLUSIONS: Selenium can antagonist
      apoptosis and lipid peroxidation of hepatocytes induced by fluoride.

PMID- 12411203
TI  - [The expression of bcl-2 and bax genes during microcystin induced liver
      tumorigenesis].
AB  - OBJECTIVE: To study the molecular mechanism of microcystin (MC) induced liver
      tumorigenesis in rats. METHODS: The two-stage-medium-term tumorigenesis theory
      was applied to establish the animal model, and the effect of MC in liver tumor
      formation was evaluated by the Albert gamma-GT methods, and then, the
      immunohistochemical technique and image analysis were used to study the
      expression of the bcl-2 and bax genes during tumorigenesis. RESULTS: (1) MC
      enhanced the formation of gamma-GT foci in liver (100%), which was significantly
      higher than the diethylnitrosamine (DEN) control group (22.22%) (P < 0.05). (2)
      MC decreased the expression of bax gene. The intensity and area of bax gene
      expression in the pure MC toxin group were 0.028 3 AODV and 0.007 3 ( micro m(2)/
      micro m(2)) and in the DEN control group were 0.065 5 AODV and 0.024 4 ( micro
      m(2)/ micro m(2)), respectively. The intensity and areas of bax gene expression
      in the pure MC toxin group were significantly lower than those in the DEN control
      group (P < 0.05). (3) MC increased the expression of bcl-2 gene. The intensity
      and area of bcl-2 gene expression in the pure MC toxin group wee 0.097 7 AODV and
      0.031 5 ( micro m(2)/ micro m(2)), respectively, and in the DEN control group
      were 0.046 0 AODV and 0.020 5 ( micro m(2)/ micro m(2)) respectively (P < 0.05).
      CONCLUSION: (1) MC can strongly promote liver tumorigenesis. (2) The changes of
      bcl-2 and bax gene expression possibly play an important role in the MC induced
      liver tumor formation.

PMID- 12411205
TI  - [Effects of exposure to aluminum on some metal elements contents in hippocampus
      of rat].
AB  - OBJECTIVE: To investigate the effects of exposure to aluminum (Al) on Zn, Fe, Cu
      and Ca contents in hippocampus of rats. METHODS: AlCl(3).6H(2)O was administered
      orally through diet (8% of body weight) to SD rats at doses of 0 (A), 11.2 (B),
      55.9 (C), 111.9 (D) mg Al(3+)/kg BW for successive 90 days. Then Al, Zn, Fe, Cu
      and Ca contents in hippocampi of rats were determined by atomic absorption
      spectrophotometry. RESULTS: After oral exposure to Al, the Al content in
      hippocampus of rat increased significantly with a remarkable dose-effect
      relationship (r = 0.731, P < 0.001), The Zn, Fe, Ca and Cu contents in these four
      groups are as follows: Group A (18.29 +/- 2.48, 24.86 +/- 1.97, 48.69 +/- 22.08,
      4.53 +/- 0.99) mg/g, Group B (17.22 +/- 2.06, 27.54 +/- 2.87, 42.79 +/- 14.42,
      4.06 +/- 0.41) mg/g, Group C (14.46 +/- 1.90, 20.18 +/- 2.79, 29.95 +/- 7.33,
      3.98 +/- 0.25) mg/g, Group D (15.85 +/- 2.54, 20.96 +/- 2.83, 36.14 +/- 12.66,
      4.53 +/- 0.58) mg/g. Compared with the control group A, the Zn and Fe contents in
      group B and group C decreased significantly (P < 0.05), and the Ca content in
      group C also decreased significantly. CONCLUSION: Oral exposure to Al may result
      in accumulation of Al in hippocampus of brain and thus affect some essential
      elements (Zn, Fe, Cu and Ca) contents in the hippocampus at different degrees.

PMID- 12411204
TI  - [Green tea extracts protected against carbon tetrachloride-induced chronic liver
      damage and cirrhosis].
AB  - OBJECTIVE: Using the carbon tetrachloride liver cirrhosis rat model, the
      protective effect of the green tea extractive (GTE) on the liver cirrhosis was
      studied. METHODS: Male SD rats were randomly divided into three groups: normal
      group, GTE group and cirrhosis group. The GTE group and the cirrhosis group were
      injected subcutanuously 2 times/wk over 9 weeks with 40% CCl(4). In the second
      and the ninth week, the rats were sacrificed to measure MDA and hydroxyproline
      concentrations and TGF-beta(1) mRNA expression in liver tissue, as well as to
      conduct histological examination on various organs. RESULTS: Compared with the
      cirrhosis group, the MDA and the hydroxyproline concentrations in the GTE group
      were significantly reduced (P < 0.05). The liver necrosis and cirrhosis were
      extenuated in the GTE group by means of histologic examination. The expression of
      the TGF-beta(1) mRNA was reduced significantly in the GTE group. CONCLUSION:
      Dietary supplementation of GTE can protect against CCl(4)-induced liver damage
      and cirrhosis in rats.

PMID- 12411206
TI  - [Effects of dietary lipids on serum lipid levels of hypertensive patients].
AB  - OBJECTIVE: To survey the intake of dietary lipids and analyze serum lipid levels
      in hypertensive patients, and to study the effects of changing dietary lipids
      intake on the serum lipid levels. METHODS: To estimate the intake of dietary fat
      and to measure the level of serum lipids in hypertensive patients before and
      after intervention. RESULTS: The baseline survey showed that the intake of
      dietary fat and cholesterol were high in those patients. Their fat intake is more
      than 30% of the total energy intake; serum total cholesterol (TC), triglycerides
      (TG) and LDL-cholesterol (LDL-C) levels were higher than the normal level.
      Correlation analysis showed that body mass index (BMI) and saturated fatty acid
      (SFA) intake were positively correlated with serum TC, TG and LDL-C; serum HDL
      C/TC ratio was positively correlated with monounsaturated fatty acid (MUFA)
      intake, and negatively correlated with BMI and SFA. The results implicated that
      MUFA is the protective factor against hypertension and hyperlipidemia. After one
      year community-based nutrition intervention, the serum TC and LDL-C levels of the
      intervened subjects were reduced dramatically. CONCLUSION: The results indicate
      that reducing the intake of dietary fat and cholesterol and properly increasing
      dietary MUFA intake have significant effects on lowering serum lipids levels and
      controlling blood pressure in hypertensive patients.

PMID- 12411207
TI  - [The effects of carotenoids on the proliferation of human breast cancer cell and
      gene expression of bcl-2].
AB  - OBJECTIVE: To investigate the effects of various carotenoids on the
      proliferation, cell cycle, apoptosis and expression of bcl-2 gene in breast
      cancer cell MCF-7. METHODS: Time and dose effects of individual carotenoids were
      detected using the MTT assay. The effects of individual carotenoids on cell cycle
      and the apoptosis were observed by flow cytometry. The expression of bcl-2 mRNA
      gene was detected using the RT-PCR method. RESULTS: All 4 carotenoids tested
      inhibited the proliferation of MCF-7 cell line, but with different potencies.
      beta-carotene and lycopene were the most active inhibitors (inhibition rate 88.2%
      and 87.8%, respectively) followed by zeaxanthin and astaxanthin. All 4
      carotenoids did not induce cell apoptosis. Cell cycle progression was blocked at
      G(2)/M phase with 60 micromol/L lycopene and at G(0)/G(1) phase with 60
      micromol/L zeaxanthin dipalmitate. Carotenoids down regulated bcl-2 gene
      expression. CONCLUSION: Carotenoids could inhibit the proliferation of human
      beast cancer MCF-7 cell line in vitro and the action of carotenoids may be worked
      through different pathways.

PMID- 12411208
TI  - [Changes of serum sex hormone levels in male workers exposed to cadmium].
AB  - OBJECTIVE: To investigate the changes in serum levels of sex hormones in male
      workers occupationally exposed to cadmium (Cd). METHODS: Eighty-five Cd-exposed
      workers in a cadmium refinery in the south China and 76 local healthy subjects as
      control were selected in the study. Air samples in the workplaces were collected
      and detected for Cd concentration. Urinary Cd (UCd) level of the workers was
      measured by graphite atomic absorption spectrometry (AAS) and adjusted by urine
      level of creatinine (Cr), as an indicator of Cd-burden in the body of all
      subjects. Also, their serum levels of testosterone (T), follicle stimulating
      hormone (FSH) and luteinizing hormone (LH) were determined with radioimmunoassay
      and enzyme immunoassay, respectively, and dose-effect relationship was evaluated.
      RESULTS: The serum testosterone levels in Cd-exposure group with 10.9-21.9 and >
      21.9 micro mol/mol Cr were 13.00 and 11.37 nmol/L, significantly higher than that
      (9.31 nmol/L) in those with 0.0-2.2 micro mol/mol Cr. Significantly more
      increased level of LH (4.11 and 4.32 U/L) was detected in heavy exposure group in
      the workshop for electrolysis than in control group (2.52 U/L) and in the group
      with 0.0-2.2 micro mol/mol Cr of UCd (2.64 U/L). No changes in serum level of FSH
      were found related to Cd exposure. CONCLUSION: Occupational Cd exposure could
      independently contribute to the changes of serum levels of sex hormone in male
      workers.

PMID- 12411209
TI  - [Effects of gasoline on syntheses of DNA, protein and sebum in keratinocyte and
      fibroblast].
AB  - OBJECTIVE: To study the cellular and molecular mechanism of gasoline-induced
      adverse effects on skin, particularly on keratinocyte and fibroblast in vitro.
      METHODS: The primary cell culture of keratinocyte and fibroblast were treated
      with 0, 0.001%, 0.01%, 0.1% and 1.0% gasoline, respectively. (3)H-thymidine ((3)H
      TdR), (3)H-leucine ((3)H-Leu), (3)H-proline ((3)H-Pro) and (14)C-linoleic acid
      incorporation tests were applied to elucidate their capacity of synthesizing DNA,
      protein and sebum. RESULTS: The incorporation of (3)H-TdR in keratinocyte and
      (3)H-TdR and (3)H-Pro in fibroblast inhibited significantly after exposure to
      0.01% gasoline (P < 0.05), with inhibition rates 68.5%, 45.1% and 40.6% for (3)H
      TdR in keratinocyte, and (3)H-TdR and (3)H-Pro in fibroblast, respectively.
      Significant depression in incorporation of (3)H-Leu and (14)C-linoleic acid in
      keratinocyte were found even in the group treated with 0.001% gasoline (P <
      0.05), with inhibition rates of 20.2% and 41.2%, respectively. CONCLUSIONS:
      Solvent gasoline has certain toxic effect on keratinocyte and fibroblast,
      intervening their normal metabolic and physiological process and affecting their
      ability of synthesizing DNA, protein and sebum, and their physiological
      functions, which could be one of the mechanisms causing skin damage by gasoline.
      The results also indicated that keratinocyte was more susceptible to gasoline
      than fibroblast.

PMID- 12411210
TI  - Brain imaging in affective disorders: more questions about causes versus effects.

PMID- 12411211
TI  - Privacy in psychiatric treatment: threats and responses.
AB  - OBJECTIVE: The author provides an overview of the current status of privacy in
      psychiatric treatment, with particular attention to the effects of new federal
      regulations authorized by the Health Insurance Portability and Accountability Act
      (HIPAA). METHOD: The author reviews the ethical and legal underpinnings for
      medical privacy, including the empirical data supporting its importance;
      discusses those portions of the new federal regulations most relevant to
      psychiatric practice; and suggests steps that psychiatrists can take to maintain
      their patients' privacy in the new environment. RESULTS: Medical ethics and law,
      in keeping with patients' preferences, traditionally have provided strong
      protection for the information that patients communicate while receiving medical
      care. In general, release of information has required patients' explicit consent.
      However, limitations of the consent model and technological innovations that
      permit the aggregation of computerized medical information have led to pressure
      for greater access to these data. Although the new federal regulations offer
      patients some additional protections (including security for psychotherapy
      notes), they also mark a retreat from reliance on patient consent and open up
      records to previously unauthorized uses, among them law enforcement
      investigations and marketing and fundraising by health care organizations.
      However, states retain the power to provide higher levels of protection.
      CONCLUSIONS: The new regulatory environment is less friendly to medical privacy
      but still leaves a great deal of discretion in physicians' hands. A commitment to
      protecting privacy as an ethical norm can be advanced by psychiatrists'
      requesting patients' consent even when it is not required, by ensuring that
      patients are aware of the limits on confidentiality, and by avoiding unnecessary
      breaches of privacy in the course of providing psychiatric care.

PMID- 12411212
TI  - Liability for the psychiatrist expert witness.
AB  - OBJECTIVE: An increasing number of general psychiatrists are acting as expert
      witnesses in the legal system. The purpose of this article is to help
      psychiatrists who are interested in doing forensic work by informing them of the
      risks entailed. METHOD: The author reviews the medical and legal literature about
      expert witness immunity. RESULTS: The author explains the traditional concept of
      expert witness immunity and shows how a variety of factors have led to the
      erosion of this immunity. These factors include the proliferation of experts, the
      inadequacy of traditional safeguards of potential prosecution for perjury and
      cross-examination, the growth of attorney malpractice, the lack of protection of
      the injured party from unscrupulous witnesses, and the ineffectiveness of Daubert
      v. Merrell Dow Pharmaceuticals. Examples are given of how expert witnesses are
      being held accountable by professional associations and state medical boards and
      through tort liability. CONCLUSIONS: The author provides risk-management
      strategies and guidelines for psychiatrists who are considering engaging in
      forensic work.

PMID- 12411213
TI  - Diseases of the mind and brain: depression: a disease of the mind, brain, and
      body.

PMID- 12411214
TI  - Board exams.

PMID- 12411215
TI  - Donald J. Cohen, M.D., 1940-2001.

PMID- 12411216
TI  - Unmasking disease-specific cerebral blood flow abnormalities: mood challenge in
      patients with remitted unipolar depression.
AB  - OBJECTIVE: Remitted major depressive disorder is a vulnerable clinical state,
      suggesting persistence of an underlying disease diathesis between episodes. To
      investigate neural correlates of such risk and to identify potential depression
      trait markers, euthymic unipolar patients in remission, acutely depressed
      patients, and never-depressed volunteers were studied before and after transient
      sad mood challenge. METHOD: Common and differential changes in regional blood
      flow among the groups relative to the baseline state were examined with
      [(15)O]H(2)O positron emission tomography after provocation of sadness with
      autobiographical memory scripts. RESULTS: Mood provocation in both depressed
      groups resulted in regional cerebral blood flow (rCBF) decreases in medial
      orbitofrontal cortex Brodmann's area 10/11, which were absent in the healthy
      group. In the remitted group, mood provocation produced a unique rCBF decrease in
      pregenual anterior cingulate 24a. The main effects in healthy subjects, an rCBF
      increase in subgenual cingulate Brodmann's area 25 and a decrease in right
      prefrontal cortex Brodmann's area 9, were not present in the depressed groups.
      CONCLUSIONS: Mood challenge in unipolar euthymic patients in full remission
      unmasks an apparent depression trait marker. The pattern of acute CBF changes is
      distinct from that seen in euthymic healthy volunteers and mirrors the untreated
      depressed state seen during a major depressive episode and the pattern of change
      seen in depressed patients. These findings suggest that disease-specific
      modifications of pathways mediating transient mood changes are present in
      unipolar depression independent of clinical illness status. These findings have
      implications for understanding the vulnerability of remitted patients for illness
      relapse.

PMID- 12411217
TI  - Ventricular and periventricular structural volumes in first- versus multiple
      episode bipolar disorder.
AB  - OBJECTIVE: Ventriculomegaly has been reported in bipolar disorder, although
      whether it occurs at illness onset or progresses during the course of the
      disorder is unknown. In addition, it is unknown whether ventriculomegaly in
      bipolar disorder reflects acquired volume loss or underdevelopment of
      periventricular structures. METHOD: Magnetic resonance imaging was used to
      measure the volumes of the lateral and third ventricles and periventricular
      structures (caudate, putamen, thalamus, hippocampus). Patients with DSM-IV
      bipolar disorder, 18 who were having a first episode and 17 with multiple
      episodes, were compared with 32 healthy subjects. RESULTS: The lateral ventricles
      were significantly larger in the patients with multiple-episode bipolar disorder
      than in the first-episode patients or the healthy subjects, even after
      periventricular and total cerebral volumes were taken into account. Having larger
      lateral ventricles was associated with a higher number of prior manic episodes.
      The multiple-episode patients had a smaller total cerebral volume than the
      healthy subjects but not the first-episode patients. The putamen was
      significantly larger in the first-episode patients (and nearly so in the multiple
      episode patients) than in the healthy subjects, although there was no difference
      between patient groups. CONCLUSIONS: Lateral ventriculomegaly was greater in
      bipolar disorder patients who had had repeated manic episodes, but it does not
      appear to be secondary to small critical periventricular structures. A larger
      than normal striatum, which has been reported in previous studies, was observed
      in first-episode patients. These results support the importance of prospectively
      studying neuroanatomic changes in bipolar disorder.

PMID- 12411218
TI  - Are there differences between women's and men's antidepressant responses?
AB  - OBJECTIVE: The study examined a large data set to determine whether patients' sex
      affected the outcome of antidepressant treatment. METHOD: Data for 1,746 patients
      aged 18-65 years who had been treated with tricyclic antidepressants, monoamine
      oxidase inhibitors (MAOIs), fluoxetine, or placebo were examined in a
      retrospective analysis to determine whether men and women differed in their
      responses to antidepressants. To examine the effect of menopausal status in the
      absence of data on individual patients' menopausal status, results for female
      patients younger or older than age 50, 52, 54, and 56 were compared. RESULTS: Men
      and women both younger and older than age 50 had equivalent response rates to
      tricyclics and fluoxetine. Women had a statistically superior response to MAOIs.
      Placebo response was equivalent across all groups. CONCLUSIONS: Neither sex nor
      menopausal status may be relevant in antidepressant treatment of adult depressed
      patients up to 65 years of age. Although women had a statistically superior
      response to MAOIs, this difference may not be clinically relevant.

PMID- 12411219
TI  - Prevalence of depressive episodes with psychotic features in the general
      population.
AB  - OBJECTIVE: The study evaluated the prevalence of major depressive episodes with
      psychotic features in the general population and sought to determine which
      depressive symptoms are most frequently associated with psychotic features.
      METHOD: The sample was composed of 18,980 subjects aged 15-100 years who were
      representative of the general populations of the United Kingdom, Germany, Italy,
      Portugal, and Spain. The participants were interviewed by telephone by using the
      Sleep-EVAL system. The questionnaire included a series of questions about
      depressive disorders, delusions, and hallucinations. RESULTS: Overall, 16.5% of
      the sample reported at least one depressive symptom at the time of the interview.
      Among these subjects, 12.5% had either delusions or hallucinations. More than 10%
      of the subjects who reported feelings of worthlessness or guilt and suicidal
      thoughts also had delusions. Feelings of worthlessness or guilt were also
      associated with high rates of hallucinations (9.7%) and combinations of
      hallucinations and delusions (4.5%). The current prevalence of major depressive
      episode with psychotic features was 0.4% (95% CI=0.35%-0.54%), and the prevalence
      of a current major depressive episode without psychotic features was 2.0% (95%
      CI=1.9%-2.1%), with higher rates in women than in men. In all, 18.5% of the
      subjects who fulfilled the criteria for a major depressive episode had psychotic
      features. Past consultations for treatment of depression were more common in
      depressed subjects with psychotic features than in depressed subjects with no
      psychotic features. CONCLUSIONS: Major depressive episodes with psychotic
      features are relatively frequent in the general population, affecting four of
      1,000 individuals. Feelings of worthlessness or guilt can be a good indicator of
      the presence of psychotic features.

PMID- 12411221
TI  - Transdermal selegiline in major depression: a double-blind, placebo-controlled,
      parallel-group study in outpatients.
AB  - OBJECTIVE: The authors investigated the efficacy and safety of transdermal
      selegiline in adult outpatients with major depressive disorder. METHOD: Following
      a 1-week placebo lead-in, 177 adult outpatients with major depressive disorder
      were randomly assigned to receive transdermal selegiline (20 mg applied once
      daily by means of a 20-cm(2) patch) (N=89) or placebo (N=88) for 6 weeks. The
      patients followed a tyramine-restricted diet during the medication trial and for
      2 weeks after completion of treatment. Response to medication or placebo was
      measured by using the 17-item and 28-item versions of the Hamilton Depression
      Rating Scale, the Montgomery-Asberg Depression Rating Scale, and the Clinical
      Global Impression (CGI) severity and improvement measures. RESULTS: Greater
      improvement was observed after 6 weeks in patients treated with transdermal
      selegiline than in those given placebo according to all measures. A statistically
      significant difference between drug and placebo was seen in Hamilton depression
      scale and Montgomery-Asberg Depression Rating Scale scores as early as week 1 of
      treatment. There were no differences in the adverse event profile of the patients
      given selegiline and those given placebo with the exception of application-site
      reactions, which were more common with the selegiline transdermal system. No
      orthostatic hypotensive or hypertensive reactions were observed. CONCLUSIONS:
      Transdermal selegiline (20 mg applied once daily by means of a 20-cm(2) patch)
      administered for 6 weeks was an effective and well-tolerated treatment for adult
      outpatients with major depression. The typical side effects commonly seen with
      traditional monoamine oxidase inhibitor antidepressants were not observed.

PMID- 12411220
TI  - Depressive symptoms and severity of illness in multiple sclerosis: epidemiologic
      study of a large community sample.
AB  - OBJECTIVE: Previous research has shown high prevalence rates of depression in
      multiple sclerosis patients seen in specialty clinics. The relationships among
      depressive symptoms and severity, duration, and course of multiple sclerosis are
      controversial. METHOD: A survey was mailed to members of the Multiple Sclerosis
      Association of King County (Wash.). Of the 1,374 eligible participants, 739
      returned the survey, a response rate of 53.8%. Data about demographic
      characteristics, employment, and duration and course of multiple sclerosis were
      collected. Severity of multiple sclerosis was determined by the Expanded
      Disability Status Scale, self-report version. Severity of depressive symptoms was
      evaluated with the Center for Epidemiologic Studies Depression Scale (CES-D
      Scale). Analysis of covariance was used to compare mean CES-D Scale scores across
      categories of multiple sclerosis, and logistic regression was used to identify
      variables associated with clinically significant depression. RESULTS: Clinically
      significant depressive symptoms (CES-D Scale score > or =16) were found in 41.8%
      of the subjects, and 29.1% of the subjects had moderate to severe depression
      (score > or =21). Subjects with advanced multiple sclerosis were much more likely
      to experience clinically significant depressive symptoms than subjects with
      minimal disease. Shorter duration of multiple sclerosis was associated with a
      greater likelihood of significant depressive symptoms, but the pattern of illness
      progression was not. CONCLUSIONS: In this large community sample, the severity of
      multiple sclerosis was more strongly associated with depressive symptoms than was
      pattern of illness. Clinicians should evaluate depression in patients with recent
      diagnoses of multiple sclerosis, major changes in functioning, or limited social
      support.

PMID- 12411222
TI  - Effects of metergoline on symptoms in women with premenstrual dysphoric disorder.
AB  - OBJECTIVE: The authors investigated the role of acute serotonergic modulation in
      the efficacy of selective serotonin reuptake inhibitors (SSRIs) in women with
      premenstrual dysphoric disorder. METHOD: Patients with premenstrual dysphoric
      disorder (whose symptoms had remitted during treatment with fluoxetine) and a
      group of unmedicated healthy comparison women received the serotonin receptor
      antagonist metergoline as part of a double-blind, placebo-controlled crossover
      study. RESULTS: The patients with premenstrual dysphoric disorder experienced a
      return of symptoms 24 hours after treatment with metergoline but not
      diphenhydramine (active placebo). The comparison women experienced no changes in
      mood. CONCLUSIONS: These data support the role of altered serotonergic
      transmission in the efficacy of SSRI treatment for premenstrual dysphoric
      disorder.

PMID- 12411223
TI  - Accuracy of adult recall of childhood attention deficit hyperactivity disorder.
AB  - OBJECTIVE: Although reports of childhood status are necessary for making a
      diagnosis of adult attention deficit hyperactivity disorder (ADHD), systematic
      investigation of the accuracy of retrospective self-reports has been limited.
      This study examined accuracy of adult recall of childhood ADHD. METHOD:
      Participants were from a controlled, prospective 16-year follow-up of children
      with ADHD. At a mean age of 25 years, 176 probands (85% of the 207 subjects in
      the initial cohort) and 168 non-ADHD comparison subjects were interviewed by
      clinicians who were unaware of the subjects' childhood status. Subjects were
      asked about specific childhood ADHD behaviors, and the diagnosis of childhood
      ADHD was retrospectively established. RESULTS: Seventy-eight percent of the
      probands and 11% of the comparison subjects were identified as having childhood
      ADHD. Six symptoms demonstrated high discriminating power in differentiating the
      subject groups: distractibility, concentration difficulties, complaints of
      inattention, acting before thinking, being on the go, and fidgeting/squirming.
      When findings were adjusted for the prevalence of ADHD in the general population,
      the power of prediction was low. Positive predictive value was 0.27, i.e., of all
      adults retrospectively given a diagnosis of childhood ADHD, only 27% would be
      correctly identified. As expected, positive predictive value increased with
      increases in the estimated prevalence of ADHD. CONCLUSIONS: Retrospective
      diagnoses of childhood ADHD made on the basis of self-reports will in most cases
      be invalid in settings such as epidemiological surveys and primary care
      facilities. Greater accuracy can be expected in settings in which childhood ADHD
      is frequent. The results stress the importance of obtaining contemporaneous
      information on childhood symptoms in establishing a childhood history of ADHD.
      Future directions and implications for DSM-V are discussed.

PMID- 12411224
TI  - Child development following exposure to tricyclic antidepressants or fluoxetine
      throughout fetal life: a prospective, controlled study.
AB  - OBJECTIVE: Previous work suggested that first-trimester exposure to tricyclic
      antidepressants or fluoxetine does not affect adversely child IQ and language
      development. However, many women need antidepressants throughout pregnancy to
      avoid morbidity and suicide attempts. Little is known about the fetal safety of
      tricyclic antidepressants and fluoxetine when taken throughout pregnancy. The
      goal of this study was to assess the effects of tricyclic antidepressants and
      fluoxetine used throughout gestation on child IQ, language, and behavior. METHOD:
      In a prospective study, mother-child pairs exposed throughout gestation to
      tricyclic antidepressants (N=46) or fluoxetine (N=40) and an unexposed, not
      depressed comparison group (N=36) were blindly assessed. The three groups were
      compared in terms of the children's IQ, language, behavior, and temperament
      between ages 15 and 71 months. The authors adjusted for independent variables
      such as duration and severity of maternal depression, duration of pharmacological
      treatment, number of depression episodes after delivery, maternal IQ,
      socioeconomic status, cigarette smoking, and alcohol use. RESULTS: Neither
      tricyclic antidepressants nor fluoxetine adversely affected the child's global
      IQ, language development, or behavior. IQ was significantly and negatively
      associated with duration of depression, whereas language was negatively
      associated with number of depression episodes after delivery. CONCLUSIONS:
      Exposure to tricyclic antidepressants or fluoxetine throughout gestation does not
      appear to adversely affect cognition, language development, or the temperament of
      preschool and early-school children. In contrast, mothers' depression is
      associated with less cognitive and language achievement by their children. When
      needed, adequate antidepressant therapy should be instituted and maintained
      during pregnancy and postpartum.

PMID- 12411225
TI  - Once-daily atomoxetine treatment for children and adolescents with attention
      deficit hyperactivity disorder: a randomized, placebo-controlled study.
AB  - OBJECTIVE: The authors assessed the efficacy of once-daily atomoxetine
      administration in the treatment of children and adolescents with attention
      deficit hyperactivity disorder (ADHD). METHOD: In a double-blind study, children
      and adolescents with ADHD (N=171, age range=6-16 years) were randomly assigned to
      receive 6 weeks of treatment with either atomoxetine (administered once daily) or
      placebo. RESULTS: Outcomes among atomoxetine-treated patients were superior to
      those of the placebo treatment group as assessed by investigator, parent, and
      teacher ratings. The treatment effect size (0.71) was similar to those observed
      in previous atomoxetine studies that used twice-daily dosing. Parent diary
      ratings suggested that drug-specific effects were sustained late in the day.
      Discontinuations due to adverse events were low (less than 3%) for both treatment
      groups, and no serious safety concerns were observed. CONCLUSIONS: Once-daily
      administration of atomoxetine is an effective treatment for children and
      adolescents with ADHD.

PMID- 12411226
TI  - Abuse, bullying, and discrimination as risk factors for binge eating disorder.
AB  - OBJECTIVE: This study examined whether sexual and physical abuse, bullying by
      peers, and ethnicity-based discrimination are associated with an increased risk
      for developing binge eating disorder in black women and in white women and
      whether any increase in risk is specific for the development of binge eating
      disorder. METHOD: A community sample of 162 women with binge eating disorder and
      251 healthy and 107 psychiatric comparison subjects was interviewed for exposure
      to the risk factors under investigation. RESULTS: White subjects with binge
      eating disorder reported significantly higher rates of sexual abuse, physical
      abuse, bullying by peers, and discrimination than healthy comparison subjects.
      Only rates of discrimination were significantly higher in white women with binge
      eating disorder than in matched psychiatric comparison subjects. In black women
      with binge eating disorder, rates of sexual abuse, physical abuse, and bullying
      by peers-but not discrimination-were significantly higher than in healthy
      comparison women. Rates of sexual abuse were significantly higher in black women
      with binge eating disorder than in psychiatric comparison subjects. CONCLUSIONS:
      Consistent with previous research examining ethnicity-specific patterns of risk
      for psychiatric disorder, we found both ethnic similarities (physical abuse and
      bullying by peers) and differences (sexual abuse and discrimination) in the risk
      for binge eating disorder.

PMID- 12411227
TI  - Childhood abuse in patients with conversion disorder.
AB  - OBJECTIVE: Despite the fact that the assumption of a relationship between
      conversion disorder and childhood traumatization has a long history, there is
      little empirical evidence to support this premise. The present study examined
      this relation and investigated whether hypnotic susceptibility mediates the
      relation between trauma and conversion symptoms, as suggested by Janet's
      autohypnosis theory of conversion disorder. METHOD: A total of 54 patients with
      conversion disorder and 50 matched comparison patients with an affective disorder
      were administered the Structured Trauma Interview as well as measures of
      cognitive (Dissociative Experiences Scale) and somatoform (20-item Somatoform
      Dissociation Questionnaire) dissociative experiences. RESULTS: Patients with
      conversion disorder reported a higher incidence of physical/sexual abuse, a
      larger number of different types of physical abuse, sexual abuse of longer
      duration, and incestuous experiences more often than comparison patients. In
      addition, within the group of patients with conversion disorder, parental
      dysfunction by the mother-not the father-was associated with higher scores on the
      Dissociative Experiences Scale and the Somatoform Dissociation Questionnaire.
      Physical abuse was associated with a larger number of conversion symptoms
      (Structured Clinical Interview for DSM-IV Axis I Disorders). Hypnotic
      susceptibility proved to partially mediate the relation between physical abuse
      and conversion symptoms. CONCLUSIONS: The present results provide evidence of a
      relationship between childhood traumatization and conversion disorder.

PMID- 12411228
TI  - National trends in the use of outpatient psychotherapy.
AB  - OBJECTIVE: This article reports recent trends in the use of outpatient
      psychotherapy in the United States. METHOD: Data from the household sections of
      the 1987 National Medical Expenditure Survey and the 1997 Medical Expenditure
      Panel Survey were analyzed. Trends in the rate of psychotherapy use from these
      nationally representative samples are presented by age, sex, race/ethnicity,
      marital status, education, employment status, and income. Psychotherapy users are
      compared over time by provider specialty, concomitant psychotropic medication
      use, number of annual visits, and costs. In addition, trends in payment source
      and primary diagnosis are assessed for psychotherapy visits. RESULTS: Between
      1987 and 1997, there was no statistically significant change in the overall rate
      of psychotherapy use (3.2 per 100 persons in 1987 and 3.6 per 100 in 1997).
      However, significant increases were observed in psychotherapy use by adults aged
      55-64 years and by unemployed adults. Among psychotherapy patients, there was a
      marked increase in the use of antidepressant medications (14.4% to 48.6%), mood
      stabilizers (5.3% to 14.5%), stimulants (1.9% to 6.4%), and psychotherapy
      provided by physicians (48.1% to 64.7%). A smaller proportion of patients made
      more than 20 psychotherapy visits in 1997 (10.3%) than in 1987 (15.7%). Over this
      period, psychotherapy visits for mood disorders became more common. In 1997, 9.7
      million Americans spent $5.7 billion on outpatient psychotherapy. CONCLUSIONS:
      From 1987 to 1997, access to psychotherapy in the United States remained constant
      overall but was characterized by increased use by some socioeconomically
      disadvantaged groups. However, the number of visits per user markedly decreased
      during this period. Psychotherapy was increasingly administered by physicians and
      provided in conjunction with psychotropic medications. These changes occurred
      during a period of expansion in the number of available psychotropic medications
      and growth in managed behavioral health care.

PMID- 12411229
TI  - Applications of errorless learning for improving work performance in persons with
      schizophrenia.
AB  - OBJECTIVE: Until recently, few training methods used in the psychosocial
      rehabilitation of persons with schizophrenia have taken into account the
      neurocognitive deficits common to this illness. The present study tested a
      training method called errorless learning (which theoretically compensates for
      neurocognitive impairments) for efficacy at teaching entry-level job tasks to
      persons with serious and persistent mental illness. METHOD: Sixty-five
      unemployed, clinically stable outpatients with schizophrenia or schizoaffective
      disorder were randomly assigned to training by means of either errorless learning
      or conventional instruction for two entry-level job tasks (index card filing and
      toilet tank assembly). Training was conducted in small groups of four subjects
      for 90-120 minutes in a simulated workshop. Efficacy-as measured by accuracy,
      speed, and overall productivity-was assessed immediately after training and at a
      3-month follow-up evaluation. RESULTS: Significant group differences in accuracy
      that favored errorless learning were found on both job tasks. In terms of
      productivity, the errorless learning group was superior to the conventional
      instruction group on the card filing task, and differences for the tank assembly
      task approached significance. There were no significant group differences in
      speed. Both groups showed significant drops in accuracy and productivity on the
      tank assembly task from immediately after training to the 3-month follow-up
      evaluation; performance levels were more stable for both groups on the card
      filing task. CONCLUSIONS: Errorless learning appears to be a useful training
      method for establishing introductory high levels of performance in the work
      rehabilitation of persons with schizophrenia. Future studies may wish to test its
      long-term durability by embedding it within supported employment programs.

PMID- 12411230
TI  - Self-reported adherence to treatment with mood stabilizers, plasma levels, and
      psychiatric hospitalization.
AB  - OBJECTIVE: The authors explored the relationship of adherence to treatment with
      mood stabilizers (lithium, carbamazepine, and sodium valproate) and plasma levels
      of these drugs to future psychiatric hospitalizations. METHOD: They prospectively
      followed 98 patients with mood disorders who were prescribed mood stabilizers.
      These patients participated in an initial interview and completed a questionnaire
      regarding their adherence to the medications. Data on their plasma levels of
      these drugs were taken from assays done in the 3 months before the interview.
      RESULTS: Six of the 98 patients were not classified as to medication adherence or
      plasma levels. Twenty-nine (32%) of the remaining patients reported partial
      adherence to the medication regimen, and 33 (36%) had an index plasma level that
      was suboptimal. At 18 months, rates of admission to a psychiatric hospital were
      significantly higher in the 16 partially adherent patients with subtherapeutic
      plasma levels (N=13, 81%) than in the 46 adherent patients with therapeutic
      plasma levels (N=4, 9%). However, hospital admission was also more likely in
      partially adherent patients with therapeutic plasma levels than in adherent
      patients with subtherapeutic plasma levels. CONCLUSIONS: Adherence to medication
      regimens may be a proxy measure of other healthy behaviors.

PMID- 12411231
TI  - Frontal white matter microstructure and treatment response of late-life
      depression: a preliminary study.
AB  - OBJECTIVE: This study tested the hypothesis that microstructural abnormalities in
      white matter areas of the brain containing frontostriatal tracts are associated
      with a low rate of remission of geriatric depression. METHOD: Thirteen older
      patients with major depression received open, but controlled, treatment with
      citalopram at a target daily dose of 40 mg for 12 weeks. Diffusion tensor imaging
      was used to determine fractional anisotropy in preselected white matter regions.
      RESULTS: Survival analysis with Cox's proportional hazards model revealed that
      lower fractional anisotropy of the right and the left frontal white matter
      regions 15 mm above the anterior commissure-posterior commissure plane was
      associated with a low remission rate after age was considered. Remission was not
      significantly associated with fractional anisotropy of lower frontal regions or a
      temporal region. CONCLUSIONS: Microstructural white matter abnormalities lateral
      to the anterior cingulate may be associated with a low rate of remission of
      geriatric depression.

PMID- 12411233
TI  - Psychopharmacologic treatment of generalized anxiety disorder and the risk of
      major depression.
AB  - OBJECTIVE: The authors sought to determine the association between treatment for
      generalized anxiety disorder and the risk of major depression among adults in the
      community. METHOD: Data were drawn from the National Comorbidity Survey
      (N=8,098), a representative sample of the United States population age 15-54. Cox
      proportional hazards were used to determine the association between specific
      forms of treatment for generalized anxiety disorder and the risk of major
      depression. RESULTS: Psychopharmacologic treatment of generalized anxiety
      disorder was associated with a significantly lower risk of major depression.
      There was no significant association between either having seen a mental health
      professional for generalized anxiety disorder or having been prescribed a
      medication for generalized anxiety disorder and the risk of depression.
      CONCLUSIONS: These results suggest an association between treatment for
      generalized anxiety disorder and lower risk of depression, which appears specific
      to pharmacologic treatment. Future research that leads to a more precise
      delineation of the underlying mechanism of the observed association is needed to
      identify and develop effective strategies to prevent onset of depression.

PMID- 12411232
TI  - Inpatient antipsychotic drug use in 1998, 1993, and 1989.
AB  - OBJECTIVE: Patterns of clinical use of antipsychotic agents have changed greatly
      in the past decade. The authors' goal was to examine these patterns. METHOD: They
      evaluated medication use in all McLean Hospital inpatients treated with
      antipsychotic drugs during 3 months in 1998 (N=349) and compared the results with
      McLean Hospital inpatients treated with antipsychotics in 1993 (N=299) and Boston
      area inpatients in 1989 (N=50). RESULTS: The most commonly prescribed
      antipsychotics in 1998 were atypical agents; olanzapine was prescribed more often
      than risperidone or quetiapine, which were prescribed more often than other
      antipsychotics. Two or more antipsychotics were prescribed at some time during
      their hospitalization for 150 (43%) of the patients in 1998. The total discharge
      dose in chlorpromazine equivalents for the 349 patients for whom antipsychotics
      were prescribed at discharge was 371 mg/day, 29% higher than the total discharge
      dose for patients in 1993 and 46% greater than the dose in 1989. The dose of
      antipsychotics was greater for patients with psychotic illnesses than for those
      with affective illnesses. Higher doses were associated with greater clinical
      improvement, polypharmacotherapy, and younger patient age. CONCLUSIONS: Emerging
      trends toward higher total antipsychotic doses and polypharmacotherapy require
      critical assessments of cost-benefit relationships.

PMID- 12411234
TI  - Mineralocorticoid receptor function in patients with posttraumatic stress
      disorder.
AB  - OBJECTIVE: The study examined whether enhanced limbic mineralocorticoid receptor
      activity resulting in negative glucocorticoid feedback could contribute to the
      diminished basal and stress-induced cortisol output reported in patients with
      posttraumatic stress disorder (PTSD). METHOD: The effects of acute
      antimineralocorticoid (spironolactone) versus placebo pretreatment on levels of
      plasma cortisol at baseline and after stimulations with corticotropin-releasing
      hormone (CRH) and on adrenocorticotropic hormone (ACTH) level were measured in 12
      PTSD patients and 12 healthy comparison subjects. RESULTS: Spironolactone
      significantly elevated basal cortisol and ACTH concentrations as well as cortisol
      secretion after CRH stimulation, but no differential effect between PTSD patients
      and comparison subjects was detected. CONCLUSIONS: The results indicate intact,
      but not enhanced, mineralocorticoid receptor function in PTSD. The study's
      experimental conditions did not allow determination of whether other compensatory
      factors might have masked the putative mineralocorticoid receptor changes.

PMID- 12411235
TI  - Is comorbidity of posttraumatic stress disorder and borderline personality
      disorder related to greater pathology and impairment?
AB  - OBJECTIVE: The authors examined whether patients with comorbid borderline
      personality disorder and posttraumatic stress disorder (PTSD) have a more severe
      clinical profile than patients with either disorder without the other. METHOD:
      Outpatients with borderline personality disorder without PTSD (N=101), PTSD
      without borderline personality disorder (N=121), comorbid borderline personality
      disorder and PTSD (N=48), and major depression without PTSD or borderline
      personality disorder (N=469) were assessed with structured interviews for
      psychiatric disorders and for degree of impairment. RESULTS: Outpatients with
      diagnoses of comorbid borderline personality disorder and PTSD were not
      significantly different from outpatients with borderline personality disorder
      without PTSD, PTSD without borderline personality disorder, or major depression
      without PTSD or borderline personality disorder in severity of PTSD-related
      symptoms, borderline-related traits, or impairment. CONCLUSIONS: The additional
      diagnosis of PTSD or borderline personality disorder does little to augment the
      pathology or dysfunction of patients who have either disorder without the other.

PMID- 12411236
TI  - Glutamate and glutamine measured with 4.0 T proton MRS in never-treated patients
      with schizophrenia and healthy volunteers.
AB  - OBJECTIVE: This in vivo (1)H magnetic resonance spectroscopy study examined
      levels of glutamate, glutamine, and N-acetylaspartate in patients experiencing
      their first episode of schizophrenia. METHOD: Localized in vivo (1)H spectra were
      acquired at 4.0 T from the left anterior cingulate and thalamus of 21 never
      treated patients with schizophrenia and 21 comparable healthy volunteers.
      RESULTS: The level of glutamine was significantly higher in the left anterior
      cingulate cortex and thalamus of the patients with schizophrenia than in the
      healthy subjects. No differences were found between groups in the levels of other
      metabolites in the anterior cingulate or thalamus. CONCLUSIONS: Higher than
      normal glutamine levels in the left anterior cingulate and thalamus provide in
      vivo evidence of greater than normal glutamatergic activity proposed by
      glutamatergic models of schizophrenia. In contrast to other studies in
      chronically ill patients, no differences were seen in the levels of N
      acetylaspartate in either location, suggesting that the findings in patients with
      chronic schizophrenia may be related to the effect of medication or the
      progression of the illness.

PMID- 12411237
TI  - Modafinil for social phobia and amphetamine dependence.

PMID- 12411238
TI  - Sweet's syndrome and polyserositis with clozapine.

PMID- 12411239
TI  - Mirtazapine for PTSD nightmares.

PMID- 12411240
TI  - Tardive dyskinesia with risperidone and anticholinergics.

PMID- 12411241
TI  - "Rehospitalization" versus "recidivism".

PMID- 12411257
TI  - Stress and the progression of the developmental hypothesis of schizophrenia.

PMID- 12411258
TI  - Surviving disaster: what comes after the trauma?

PMID- 12411259
TI  - Brain ageing and dementia: what makes the difference?

PMID- 12411260
TI  - Why are we not getting any closer to preventing suicide?

PMID- 12411261
TI  - International differences in home treatment for mental health problems. Results
      of a systematic review.
AB  - BACKGROUND: It is perceived that North American home treatment studies reveal
      greater success in reducing days in hospital than do European studies. There are
      difficulties in extrapolating findings internationally. AIMS: We aimed to
      determine whether North American studies find greater reductions in days in
      hospital and whether experimental service patients in North American studies
      spend less time in hospital. METHOD: The results of a systematic review were
      analysed with respect to study location. Service components ascertained through
      follow-up were utilised to interpret the meta-analyses conducted. RESULTS: Most
      of the 91 studies found were from the USA and UK. North American studies found a
      difference of one hospital day (per patient per month) more than European studies
      but there was no difference in experimental data between the two locations.
      CONCLUSIONS: North American studies demonstrate greater differences in days in
      hospital but patients in their experimental services seem to spend no fewer days
      in hospital, implying a disparity in control services.

PMID- 12411262
TI  - Social adversity and mental functions in adolescents at high risk of
      psychopathology. Position paper and suggested framework for future research.
AB  - BACKGROUND: Social adversities are accepted as critical factors in the
      development of psychopathology in young people, but the precise mechanisms of
      this relationship are unknown. AIMS: To explore sources of evidence and suggest
      future lines of research to clarify the relationship between exposure to negative
      circumstances and development of psychopathology in young people. METHOD:
      Selective survey of the literature to collect a series of hypotheses that might
      serve as a framework for future research. RESULTS: and conclusions Evidence to
      date suggests there is no simple relationship between adverse life events and the
      subsequent emergence of psychopathology. The interplay of acute and chronic
      stressors over the lifespan with affective temperament; the interrelationship of
      'sensitivity' and 'performance' cognitions in response to life events; and limbic
      cortical neural networks are all indicated as important avenues of future
      research.

PMID- 12411263
TI  - Adult psychosis, common childhood infections and neurological soft signs in a
      national birth cohort.
AB  - BACKGROUND: Neurological soft signs preceding adult-onset schizophrenia suggest a
      neurodevelopmental origin and could reflect physical illness in childhood. AIMS:
      To investigate possible associations of adult-onset psychosis with neurological
      soft signs and common infectious illnesses in childhood. METHOD: Using data from
      the UK National Child Development Study, a longitudinal general population
      sample, odds ratios were calculated for clinical diagnoses of common childhood
      viral illnesses and later adult psychotic illness, childhood epilepsy and a range
      of neurological soft signs. RESULTS: The number of illnesses per individual did
      not relate either to the number of soft signs, or to any particular adult
      outcome. Schizophrenia, affective psychosis and epilepsy were not associated with
      common childhood illness but were associated with neurological soft signs and an
      increased, but small, frequency of previous meningitis and tuberculosis.
      CONCLUSIONS: Overall the data support the notion of neurological soft signs as
      markers of disordered neurodevelopment in schizophrenia (but the early
      neurological abnormalities are not caused by infectious illness) and an
      association between meningitis or tuberculosis in childhood and a small
      proportion of cases of epilepsy, affective psychosis and schizophrenia.

PMID- 12411264
TI  - Psychosis and drug dependence: results from a national survey of prisoners.
AB  - BACKGROUND: The links between drug use and psychosis are of major aetiological
      and prognostic significance. Psychosis and drug dependence frequently co-occur
      within the prison population, providing the opportunity to study this link more
      closely. AIMS: To explore the relationship between psychosis and drug dependence
      in a sample of prisoners. METHOD: A total of 3142 prisoners were surveyed
      nationally, and structured clinical data were obtained from a subsample of 503
      respondents. Psychiatric assessment was based on the Schedules for Clinical
      Assessment in Neuropsychiatry (version 1.0). Measures of amphetamine, cannabis,
      cocaine and heroin use and dependence were obtained through self-report. RESULTS:
      Logistic regression analyses indicated that first use of amphetamines or cocaine
      before the age of 16 years and severe cannabis or cocaine dependence were related
      to an increased risk of psychosis. In contrast, severe dependence on heroin was
      associated with a reduced risk of this classification. CONCLUSIONS: Severe
      dependence on cannabis and psychostimulants is associated with a higher risk of
      psychosis and is in contrast to severe dependence on heroin, which has a negative
      relationship with psychosis.

PMID- 12411265
TI  - Mental disorder and perceived threat to the public: people who do not return to
      community living.
AB  - BACKGROUND: In the UK, people with mental disorder thought to pose a high risk of
      harm to others are usually put in a high-security (special) hospital. Little is
      known about what happens after that. AIMS: To test a hypothesis that, under
      current services and laws (from the mid-1980s), no one leaving high-security
      hospitals remains indefinitely institutionalised. METHOD: The special hospitals'
      case register was used for case ascertainment and admission data; post-discharge
      data were collected from multiple sources on patients discharged in 1984 (census
      date 31.12.1995). RESULTS: In this discharge cohort (n=223), 36 (17%) did not
      return to the community: 17 died in special hospital and 19 continuously lived in
      other institutions until death or the census date. Over two-thirds of these had
      mental illness, were older on admission and had lived longer in special hospital
      than their better-rehabilitated peers. Offending history was irrelevant to this.
      Most post-discharge institution time was in open psychiatric hospital, or back in
      special hospital, not in medium secure units or prison. CONCLUSIONS: The
      hypothesis was not sustained, but fewer people never reached the community than
      before the mid-1980s. Atypical antipsychotics might reduce this number. We found
      no justification for a new tier of long-term medium secure units.

PMID- 12411266
TI  - Depressive symptoms and cognitive decline in elderly people. Longitudinal study.
AB  - BACKGROUND: Depressive symptoms are associated with cognitive decline in elderly
      people, but the nature of their temporal relationship remains equivocal. AIMS: To
      test whether depressive symptoms predict cognitive decline in elderly people with
      normal cognition. METHOD: The Center for Epidemiologic Study depression scale
      (CES-D) and the Mini-Mental State Examination (MMSE) were used to evaluate
      depressive symptomatology and cognitive functioning, respectively. A sample of
      1003 persons aged 59-71 years and with a MMSE score of 26 or over was selected.
      Cognitive decline was defined as a drop of at least 3 points on the MMSE at 4
      year follow-up. RESULTS: Baseline high levels of depressive symptoms predicted a
      higher risk of cognitive decline at 4-year follow-up. The MMSE score of
      participants with depression was more likely to fall below 26 at 2-year follow-up
      and to remain below at 4-year follow-up than the MMSE score of those without
      depressive symptoms. Persistent but not episodic depressive episodes were
      associated with cognitive decline. CONCLUSIONS: High levels of depressive
      symptoms, when persistent, are associated with cognitive decline in a sample of
      elderly people.

PMID- 12411267
TI  - Cerebellar responses during anticipation of noxious stimuli in subjects recovered
      from depression. Functional magnetic resonance imaging study.
AB  - BACKGROUND: Subjects recovered from depression have a substantial risk for
      recurrence of depression, suggesting persistent abnormalities in brain activity.
      AIMS: To test whether women recovered from depression show abnormal brain
      activity in functional magnetic resonance imaging (fMRI) during a conditioning
      paradigm with a noxious pain stimulus. METHOD: Ten unmedicated women who had
      recovered from major depression and eight healthy control women each received
      either noxious hot or non-noxious warm stimuli, the onset of which was signalled
      by a specific coloured light during 3-tesla echo planar imaging-based fMRI.
      RESULTS: Similar patterns of brain activation were found during painful
      stimulation for both patients and healthy controls. However, relative to healthy
      controls, subjects recovered from depression showed a reduced response in the
      cerebellum during anticipation of the noxious stimulus compared with anticipation
      of the non-noxious stimulus. CONCLUSIONS: Our data suggest that abnormal
      cerebellar function could be a marker of vulnerability to recurrent depression.
      This could provide a new target for therapeutic interventions.

PMID- 12411268
TI  - Conduct problems, gender and adult psychiatric outcome of children with attention
      deficit hyperactivity disorder.
AB  - BACKGROUND: Attention-deficit hyperactivity disorder (ADHD) is a common childhood
      condition, and is more prevalent in boys. The adult outcome of girls with ADHD
      has never been studied. AIMS: To identify predictors for adult psychiatric
      outcome of children with ADHD, including gender and comorbidity. METHOD: Children
      aged 4-15 years, referred for hyperactivity/inattention and treated with
      stimulants were included (n=208). The Psychiatric Case Register provided follow
      up data on psychiatric admissions in adulthood until a mean age of 31 years.
      RESULTS: A total of 47 cases (22.6%) had a psychiatric admission in adulthood.
      Conduct problems in childhood were predictive (hazard ratio HR=2.3; 95% CI 1.22
      4.33). Girls had a higher risk compared with boys (HR=2.4; 95% CI 1.1-5.6).
      CONCLUSIONS: Girls with ADHD had a higher risk of adult psychiatric admission
      than boys. Conduct problems were also associated with a higher risk. Girls with
      ADHD with conduct problems had a very high risk of a psychiatric admission in
      adulthood.

PMID- 12411269
TI  - Nithsdale Schizophrenia Surveys 23: movement disorders. 20-year review.
AB  - BACKGROUND: In the past 10 years the new atypical antipsychotic drugs have
      stimulated further interest in the pharmacological management of schizophrenia.
      The risk of movement disorders has been reported to be less with these new
      agents. AIMS: To examine the current prevalence of movement disorders among all
      people with schizophrenia in a discrete geographical area, to compare the
      prevalence in patients receiving and not receiving atypical antipsychotic drugs;
      and to compare current prevalence with prevalence over the past 20 years. METHOD:
      In Nithsdale, south-west Scotland, in 1999/2000, we replicated previous studies
      by using the Abnormal Involuntary Movements Scale, Simpson-Angus scale and Barnes
      Akathisia Rating Scale to measure tardive dyskinesia, parkinsonism and akathisia,
      respectively. Mental state was assessed by the Positive and Negative Syndrome
      Scale. RESULTS: In 136 patients the prevalence of probable tardive dyskinesia was
      43%, of parkinsonism 35% and of akathisia 15%. Parkinsonism was present as often
      in those receiving atypicals as in those receiving standard oral antipsychotics.
      The prevalence of tardive dyskinesia has doubled over 20 years. CONCLUSIONS:
      Movement disorders remain significant problems for patients despite the
      introduction of atypical antipsychotic drugs.

PMID- 12411270
TI  - Long-term outcome of long-stay psychiatric in-patients considered unsuitable to
      live in the community. TAPS Project 44.
AB  - BACKGROUND: Whereas the majority of long-stay in-patients have been successfully
      resettled in the community, there is a group of such patients who are too
      disturbed or disturbing to be managed in standard community homes. AIMS: To study
      the long-term outcome of a group of 72 long-stay psychiatric inpatients, regarded
      as unsuitable for community placement. METHOD: A prospective cohort study with
      follow-ups at 1 year and 5 years. RESULTS: The patients' mental state remained
      unchanged after 1 year and 5 years. The level of functioning and social behaviour
      showed minimal change after 1 year, but then improved over the next 4 years. The
      profile of problematic behaviours changed significantly over 5 years, with a
      reduction of 50% in their frequency. Physical aggression practically disappeared.
      The improvements in behaviour enabled 29 patients (40% of the study group)
      finally to be resettled in various care homes, gaining better access to community
      amenities and living more independently. CONCLUSIONS: A high proportion of
      patients with severe disabilities, designated as 'difficult to place' in the
      community, could benefit from slow-stream rehabilitation within specialised
      facilities, enabling them to move into ordinary community homes.

PMID- 12411271
TI  - Survivors of the Piper Alpha oil platform disaster: long-term follow-up study.
AB  - BACKGROUND: The long-term psychological effects of surviving a major disaster are
      poorly understood. We undertook a survey of survivors of the Piper Alpha oil
      platform disaster (1988). AIMS: To examine the role of factors relating to the
      trauma, the survivors and the survivors' circumstances. METHOD: Ten years after
      the disaster, 78% (46/59) of the survivors were located, of whom 72% (33/46)
      agreed to be interviewed. A further three individuals completed postal measures.
      RESULTS: The most stringent diagnostic criteria for post-traumatic stress
      disorder (PTSD) were met by 21% (7/33) of the survivors over 10 years after the
      disaster. Features such as physical injury, personal experience and survivor
      guilt were associated with significantly higher levels of post-traumatic
      symptoms. CONCLUSIONS: A narrow definition of factors affecting outcome will
      limit the potential for improving survivor well-being in the long-term after
      major disasters. Specific symptoms that are not included in the criteria for the
      diagnosis of PTSD, together with issues such as re-employment, need to be
      addressed.

PMID- 12411272
TI  - Cognitive-behavioural therapy for schizophrenia.

PMID- 12411273
TI  - Antenatal anxiety, parenting and behavioural/emotional problems in children.

PMID- 12411274
TI  - Cognitive impairment in bipolar disorder.

PMID- 12411275
TI  - Brain weight in suicide revisited.

PMID- 12411276
TI  - Outcome measurement in mental health: the Italian experience in psychogeriatrics.

PMID- 12411277
TI  - Vascular events associated with pharmacotherapy.

PMID- 12411278
TI  - Recruitment in old age psychiatry.

PMID- 12411279
TI  - The verdict of 'suicide while insane'.

PMID- 12411282
TI  - Increasing concentration of inhaled saline with or without amiloride: effect on
      mucociliary clearance in normal subjects.
AB  - Mucociliary clearance is determined by ciliary activity and rheology of airway
      surface liquid. To test the hypothesis that mucociliary clearance would increase
      after inhalation of an osmotically active agent that would increase the volume of
      airway surface liquid, we measured mucociliary clearance in 16 normal subjects
      after inhalation of varying tonicities of saline alone, and after pretreatment
      with a Na+ channel blocker (amiloride). Subjects inhaled vehicle (0.12% saline)
      or amiloride, followed by inhalation of 0.12, 0.9, or 7% saline. Subsequently,
      mucociliary clearance rates were measured by gamma scintigraphy of inhaled 99mTc
      Fe2O3. Mucociliary clearance of whole and peripheral lung was increased
      (approximately twofold) after inhalation of increasing concentrations of saline
      (p < 0.04). Pretreatment with amiloride increased mucociliary clearance rates
      (approximately twofold) after inhalation of 0.12 and 0.9% saline (p < 0.05), but
      not 7% saline. The rates of mucociliary clearance by pretreatment with amiloride
      and 7% saline alone (approximately 1.4% per minute) approached the rapid
      mucociliary clearance rates (approximately 2.0% per minute) reported in systemic
      pseudohypoaldosteronism, which has loss-of-function mutations of the epithelial
      Na+ channel and an increased volume of airway surface liquid. We conclude that
      maneuvers that increase the volume of airway surface liquid are associated with
      increased rates of mucociliary clearance in normal subjects.

PMID- 12411283
TI  - CD8+ T lymphocytes in viral hyperreactivity and M2 muscarinic receptor
      dysfunction.
AB  - In the airways, inhibitory M2 muscarinic receptors (M2Rs) on parasympathetic
      nerves limit acetylcholine release. Viral infection causes M2R dysfunction, which
      increases acetylcholine release and leads to airway hyperreactivity. In these
      studies we tested the role of CD8+ T cells in parainfluenza virus-induced
      hyperreactivity and M2R dysfunction in normal guinea pigs and in guinea pigs
      previously sensitized to ovalbumin. Depleting CD8+ T cells prevented virus
      induced M2R dysfunction and hyperreactivity in sensitized animals, but not in
      nonsensitized animals. Sensitization increased the number of eosinophils in close
      relation to the airway nerves where, when activated, they release major basic
      protein, which binds to and blocks the M2Rs. Regardless of sensitization, viral
      infection decreased the number of visible tissue eosinophils, likely reflecting
      eosinophil degranulation via cytolysis. Depleting CD8+ T cells prevented this
      virus-induced eosinophil degranulation. In addition, an antiviral effect of
      sensitization, which we previously showed to be eosinophil mediated, was again
      seen. This was prevented by depletion of CD8+ Tcells. Thus, CD8+ T cells play a
      role in airway hyperreactivity and M2R dysfunction of sensitized virus-infected
      guinea pigs by mediating eosinophil degranulation near airway nerves. In
      contrast, CD8+ T cells are not necessary for virus-induced hyperreactivity and
      M2R dysfunction in nonsensitized guinea pigs.

PMID- 12411284
TI  - Aldehydes and glutathione in exhaled breath condensate of children with asthma
      exacerbation.
AB  - Oxidative stress is implicated in the pathogenesis of asthma, and clinical
      studies show an imbalance in the level of oxidants to the level of antioxidants
      in subjects with asthma. Aldehydes and glutathione are examples of biomarkers of
      oxidant-induced damage and antioxidant status in asthma, respectively. In the
      study, we applied analytical techniques based on liquid chromatography for the
      assessment of aldehydes and glutathione in the exhaled breath condensate of
      children with asthma and in control subjects without asthma. Twelve subjects with
      asthma were evaluated at exacerbation and after 5 days of therapy with
      prednisone. At exacerbation, malondialdehyde levels were higher in patients with
      asthma (30.2 +/- 2.4 nM) than in control subjects (19.4 +/- 1.9 nM, p = 0.002)
      and were reduced after steroid therapy (18.5 +/- 1.6 nM, p = 0.001). At
      exacerbation, glutathione levels were lower in subjects with asthma (5.96 +/- 0.6
      nM) than in control subjects (14.1 +/- 0.8 nM, p < 0.0001) and were increased
      after the therapy (8.44 +/- 1.2 nM, p = 0.04). Malondialdehyde and glutathione
      both in subjects with asthma and control subjects were negatively correlated (r =
      -0.5, p = 0.001). The study shows that aldehydes and glutathione are detectable
      in the exhaled breath condensate of children with asthma and healthy children and
      that their levels are modified during asthma exacerbation and after a 5-day
      course of therapy with oral prednisone.

PMID- 12411285
TI  - The upper airway in pregnancy and pre-eclampsia.
AB  - Snoring is common in pregnancy, and snoring pregnant women have increased rates
      of pre-eclampsia. Patients with pre-eclampsia show upper airway narrowing during
      sleep. The present study aimed to compare upper airway dimensions in pregnant and
      nonpregnant women and in patients with pre-eclampsia. A total of 50 women in the
      third trimester of pregnancy and 37 women with pre-eclampsia were recruited
      consecutively from the antenatal service and matched with 50 nonpregnant women.
      Upper airway dimensions were measured using acoustic reflection. Comparisons were
      made by analysis of variance and Student-Newman-Keuls tests. Snoring was reported
      by 14% of nonpregnant women, 28% of pregnant women, and 75% of pre-eclamptic
      women (p < 0.001). When seated, pregnant women had wider upper airways than
      nonpregnant women (p < 0.02), but there was no difference when supine.
      Oropharyngeal junction area in the seated position was less (p < 0.01) in the
      women with pre-eclampsia (mean +/- SD: 0.9 +/- 0.1 cm2) than either nonpregnant
      (1.1 +/- 0.1 cm2) or pregnant women (1.3 +/- 0.1 cm2). Supine oropharyngeal
      junction area was less in the women with pre-eclampsia than in the nonpregnant
      women (0.8 +/- 0.1 versus 1.0 +/- 0.1 cm2; p = 0.01) but similar in women with
      pre-eclampsia and pregnant women (0.9 +/- 0.1 cm2; p > 0.3). The study showed
      that women with pre-eclampsia have upper airway narrowing in both upright and
      supine postures. These changes could contribute to the upper airway resistance
      episodes during sleep in patients with pre-eclampsia, which may further increase
      their blood pressure.

PMID- 12411286
TI  - The clinical spectrum of severe imported falciparum malaria in the intensive care
      unit: report of 188 cases in adults.
AB  - Little is known about severe imported malaria in nonendemic industrialized
      countries. The purpose of this retrospective study was to describe the clinical
      spectrum of severe imported malaria in adults and to determine factors that were
      present at admission and were associated with in-intensive care unit mortality.
      This retrospective study evaluated the 188 patients who were admitted to our
      intensive care unit in 1988-1999 with severe and/or complicated imported malaria.
      Among them, 93 had strictly defined severe malaria, and 95 had less severe
      malaria. The mean age was 38 years, 51% of patients were nonimmune whites, 94%
      acquired Plasmodium falciparum in sub-Saharan Africa, and 96% had taken
      inadequate antimalarial chemoprophylaxis. Mortality was 11% (10 patients) in the
      severe malaria group, whereas no patients died in the less severe malaria group
      (p = 0.002). In the bivariable analysis, the main factors associated with death
      in the severe malaria group were the Simplified Acute Physiology Score, shock,
      acidosis, coma, pulmonary edema (p < 0.001 for each), and coagulation disorders
      (p = 0.002). Bacterial coinfection is not infrequent and may contribute to death.
      Severe imported malaria remains a major threat to travelers. In our population,
      the most relevant World Health Organization major defining criteria were coma,
      shock, pulmonary edema, and acidosis.

PMID- 12411287
TI  - Recurrent lymphangiomyomatosis after transplantation: genetic analyses reveal a
      metastatic mechanism.
AB  - Lymphangiomyomatosis (LAM) is characterized by the proliferation of abnormal
      smooth muscle cells and cystic degeneration of the lung. LAM affects almost
      exclusively young women. Although lung transplantation provides effective therapy
      for end-stage LAM, there are reports of LAM recurrence after lung
      transplantation. Whether these recurrent LAM cells arise from the patient or the
      lung transplant donor is an area of controversy. We used microsatellite marker
      fingerprinting and TSC2 gene mutational analysis to study a patient with
      recurrent LAM after single-lung transplantation. The DNA microsatellite marker
      pattern indicated the presence of patient-derived LAM cells in the allograft. A
      somatic one base pair deletion in exon 18 of the TSC2 gene was identified in
      pulmonary and lymph node LAM cells before transplantation. The same mutation was
      in the recurrent LAM, demonstrating that the recurrent LAM was derived from the
      patient. Fluorescence in situ hybridization revealed that cells immunoreactive
      with the monoclonal antibody HMB-45 did not contain a Y chromosome. These data
      indicate that histologically benign LAM cells can migrate or metastasize in vivo
      to the transplanted lung. In addition, the patient had no evidence of a renal
      angiomyolipoma at autopsy and therefore demonstrated for the first time that
      somatic TSC2 mutations cause LAM in patients without angiomyolipomas.

PMID- 12411288
TI  - Is weaning failure caused by low-frequency fatigue of the diaphragm?
AB  - Because patients who fail a trial of weaning from mechanical ventilation
      experience a marked increase in respiratory load, we hypothesized that these
      patients develop diaphragmatic fatigue. Accordingly, we measured twitch
      transdiaphragmatic pressure using phrenic nerve stimulation in 11 weaning failure
      and 8 weaning success patients. Measurements were made before and 30 minutes
      after spontaneous breathing trials that lasted up to 60 minutes. Twitch
      transdiaphragmatic pressure was 8.9 +/- 2.2 cm H2O before the trials and 9.4 +/-
      2.4 cm H2O after their completion in the weaning failure patients (p = 0.17); the
      corresponding values in the weaning success patients were 10.3 +/- 1.5 and 11.2
      +/- 1.8 cm H2O (p = 0.18). Despite greater load (p = 0.04) and diaphragmatic
      effort (p = 0.01), the weaning failure patients did not develop low-frequency
      fatigue probably because of greater recruitment of rib cage and expiratory
      muscles (p = 0.004) and because clinical signs of distress mandating the
      reinstitution of mechanical ventilation arose before the development of fatigue.
      Twitch pressure revealed considerable diaphragmatic weakness in many weaning
      failure patients. In conclusion, in contrast to our hypothesis, weaning failure
      was not accompanied by low-frequency fatigue of the diaphragm, although many
      weaning failure patients displayed diaphragmatic weakness.

PMID- 12411289
TI  - Von Willebrand disease type 1: a diagnosis in search of a disease.
AB  - Von Willebrand disease (VWD) type 1 is reported to be common but frequently is
      difficult to diagnose. Many people have nonspecific mild bleeding symptoms, von
      Willebrand factor (VWF) levels display low heritability, and low VWF levels (15%
      to 50% of normal) are weak risk factors for bleeding. Therefore, bleeding and low
      VWF levels often associate by chance. Even with stringent diagnostic criteria
      based on a triad of bleeding symptoms, a low VWF level, and a positive family
      history, the prevalence of "false-positive" VWD type 1 is comparable to the
      published prevalence of the disease. Consequently, many patients diagnosed with
      VWD type 1 do not have a specific hemorrhagic disease at all, which limits the
      utility of the diagnosis. This unfortunate reality is a consequence of trying to
      force patients into binary categories of "diseased" or "healthy" that are
      incompatible with the continuous biologic context in which VWF functions. The
      problem may be avoided by substituting an empirical epidemiologic approach like
      that applied to other modest risk factors for disease such as elevated
      cholesterol and high blood pressure. Such a risk management strategy could be
      generalized to include other hemorrhagic and thrombotic risk factors.

PMID- 12411290
TI  - Antithymocyte globulin has limited efficacy and substantial toxicity in
      unselected anemic patients with myelodysplastic syndrome.
AB  - Antithymocyte globulin (ATG) has recently been popularized as an effective
      treatment in myelodysplastic syndrome (MDS). We treated 8 anemic MDS patients
      (refractory anemia [RA] and refractory anemia with excess blasts [RAEB-1]) with
      ATG (40 mg/kg/d for 4 days) and prednisone in a phase 2 trial. The study was
      stopped early according to a preset termination rule because of lack of efficacy.
      There were no salutary responses. Toxicities included serum sickness (in all
      patients), transient neutropenia and thrombocytopenia, diarrhea, vomiting, and
      syncope with a generalized seizure. At least 3 patients had the HLA-DR15 (DR2)
      allele. We conclude that the risk-benefit ratio of ATG in an unselected
      population of MDS patients may be unfavorable, and more work is needed to define
      the subset of patients who will respond to ATG before its widespread use can be
      recommended.

PMID- 12411291
TI  - Recombinant factor VIIa enhances deposition of platelets with congenital or
      acquired alpha IIb beta 3 deficiency to endothelial cell matrix and collagen
      under conditions of flow via tissue factor-independent thrombin generation.
AB  - A novel approach to treat bleeding episodes in patients with Glanzmann
      thrombasthenia (GT) and perhaps also in patients receiving alpha IIb beta 3
      inhibitors is the administration of recombinant factor VIIa (rFVIIa). The
      mechanism of action of rFVIIa in these patients is, however, still unclear. We
      studied the effect of rFVIIa-mediated thrombin formation on adhesion of alpha IIb
      beta 3-deficient platelets under flow conditions. Adhesion of alpha IIb beta 3
      deficient platelets to the extracellular matrix (ECM) of stimulated human
      umbilical vein endothelial cells or to collagen type III was studied using a
      model system with washed platelets and red cells. When alpha IIb beta 3-deficient
      platelets were perfused over the surface at arterial shear rate for 5 minutes, a
      low surface coverage was observed (GT platelets, mean +/- SEM, 37.5% +/- 5.0%;
      normal platelets preincubated with an RGD-containing peptide, 7.4% +/- 2.1%).
      When rFVIIa, together with factors X and II, was added to the perfusate, platelet
      deposition significantly increased (GT platelets, mean +/- SEM, 67.0% +/- 4.3%;
      normal platelets preincubated with an RGD-containing peptide, 48.2% +/- 2.9%).
      The same effect was observed when normal platelets were pretreated with the
      commercially available anti-alpha IIb beta 3 drugs abciximab, eptifibatide, or
      tirofiban. It was shown that tissue factor-independent thrombin generation
      (presumably induced by binding of rFVIIa to adhered platelets) was responsible
      for the increase in platelet deposition. In conclusion, defective adhesion of
      alpha IIb beta 3-deficient platelets to ECM can be restored by tissue factor
      independent rFVIIa-mediated thrombin formation. The enhanced generation of
      platelet procoagulant surface facilitates fibrin formation, so that lack of
      platelet aggregate formation might be compensated for.

PMID- 12411292
TI  - Primary immune responses to human CMV: a critical role for IFN-gamma-producing
      CD4+ T cells in protection against CMV disease.
AB  - The correlates of protective immunity to disease-inducing viruses in humans
      remain to be elucidated. We determined the kinetics and characteristics of
      cytomegalovirus (CMV)-specific CD4(+) and CD8(+) T cells in the course of primary
      CMV infection in asymptomatic and symptomatic recipients of renal transplants.
      Specific CD8(+) cytotoxic T lymphocyte (CTL) and antibody responses developed
      regardless of clinical signs. CD45RA(-)CD27(+)CCR7(-) CTLs, although classified
      as immature effector cells in HIV infection, were the predominant CD8 effector
      population in the acute phase of protective immune reactions to CMV and were
      functionally competent. Whereas in asymptomatic individuals the CMV-specific
      CD4(+) T-cell response preceded CMV-specific CD8(+) T-cell responses, in
      symptomatic individuals the CMV-specific effector-memory CD4(+) T-cell response
      was delayed and only detectable after antiviral therapy. The appearance of
      disease symptoms in these patients suggests that functional CD8(+) T-cell and
      antibody responses are insufficient to control viral replication and that
      formation of effector-memory CD4(+) T cells is necessary for recovery of
      infection.

PMID- 12411293
TI  - Low-penetrance genetic susceptibility and resistance loci implicated in the
      relative risk for radiation-induced acute myeloid leukemia in mice.
AB  - Inbred CBA/H mice are susceptible to radiation-induced acute myeloid leukemia (r
      AML), and C57BL/6 mice are resistant. A genome-wide screen for linkage between
      genotype and phenotype (r-AML) of 67 affected (CBA/H x C57BL/6)F1 x CBA/H
      backcross mice has revealed at least 2 suggestive loci that contribute to the
      overall lifetime risk for r-AML. Neither is necessary or sufficient for r-AML,
      but relative risk is the net effect of susceptibility (distal chromosome 1) and
      resistance (chromosome 6) loci. An excess of chromosome 6 aberrations in mouse r
      AML and bone marrow cells up to 6 months after irradiation in vivo suggests the
      locus confers a proliferative advantage during the leukemogenic process. The stem
      cell frequency regulator 1 (Scfr1) locus maps to distal chromosome 1 and
      determines the frequency of hemopoietic stem cells (HSCs) in inbred mice,
      suggesting that target size may be one factor in determining the relative
      susceptibility of inbred mice to r-AML.

PMID- 12411294
TI  - Increased inflammation in lysozyme M-deficient mice in response to Micrococcus
      luteus and its peptidoglycan.
AB  - More than 70 years ago, Alexander Fleming discovered lysozyme and proposed that
      nonpathogenic bacteria fail to cause disease because they are very susceptible to
      destruction by lysozyme, an enzyme that is one of the principal proteins of
      phagocytes. Although much has been learned about the effects of lysozyme in
      vitro, its biological role in vivo has not been determined. We examined
      transgenic mice deficient in lysozyme M after challenge by the normally
      nonpathogenic and highly lysozyme-sensitive bacterium Micrococcus luteus. Despite
      partial compensation by newly expressed lysozyme P in macrophages, lysozyme M
      deficient mice developed much more severe lesions than wild-type mice. The tissue
      injury was due to the failure of lysozyme M-deficient mice to inactivate
      peptidoglycan, resulting in an intense and prolonged inflammatory response. Our
      data indicate that tissue injury is normally limited by prompt degradation of
      bacterial macromolecules that trigger innate immunity and inflammation.

PMID- 12411295
TI  - IL-7 therapy dramatically alters peripheral T-cell homeostasis in normal and SIV
      infected nonhuman primates.
AB  - Interleukin-7 (IL-7) is important for thymopoiesis in mice and humans because IL
      7 receptor alpha (IL-7Ralpha) mutations result in a severe combined
      immunodeficiency phenotype with severe thymic hypoplasia. Recent evidence has
      indicated that IL-7 also plays an important role as a regulator of T-cell
      homeostasis. Here we report the immunologic effects of recombinant human IL-7
      (rhIL-7) therapy in normal and simian immunodeficiency virus (SIV)-infected
      nonhuman primates. Cynomolgus monkeys receiving 10 days of rhIL-7 showed
      substantial, reversible increases in T-cell numbers involving a dramatic
      expansion of both naive and nonnaive phenotype CD4(+) and CD8(+) subsets.
      Although IL-7 is known to have thymopoietic effects in mice, we observed marked
      declines in the frequency and absolute number of T-cell receptor excision circle
      positive (TREC(+)) cells in the peripheral blood and dramatic increases in the
      percentage of cycling T cells in the peripheral blood as measured by Ki-67
      expression (baseline less than 5% to approximately 50% after 6 days of therapy)
      and ex vivo bromodeoxyuridine (BrdU) incorporation. Similarly, moderately CD4-
      depleted SIV-infected macaques treated with rhIL-7 also had significant increases
      in peripheral blood CD4(+) and CD8(+) T cells following rhIL-7 therapy. Thus,
      rhIL-7 induces dramatic alterations in peripheral T-cell homeostasis in both T
      cell-replete and T-cell-depleted nonhuman primates. These results further
      implicate IL-7 as a promising immunorestorative agent but illustrate that a major
      component of its immunorestorative capacity reflects effects on mature cells.
      These results also raise the possibility that IL-7 therapy could be used to
      temporarily modulate T-cell cycling in vivo in the context of immunotherapies
      such as vaccination.

PMID- 12411296
TI  - Fludarabine uptake mechanisms in B-cell chronic lymphocytic leukemia.
AB  - Nucleoside derivatives are currently used in the treatment of hematologic
      malignancies. Although intracellular events involved in the pharmacologic action
      of these compounds have been extensively studied, the role of plasma membrane
      transporters in nucleoside-derived drug bioavailability and action in leukemia
      cells has not been comprehensively addressed. We have monitored the amounts of
      mRNA for the 5 nucleoside transporter isoforms cloned so far (CNT1, CNT2, CNT3,
      ENT1, and ENT2) in several human cell types and in normal human leukocytes. We
      then examined the expression patterns of these plasma membrane proteins in
      patients with chronic lymphocytic leukemia (CLL) and correlated them with in
      vitro fludarabine cytotoxicity. Despite a huge individual variability in the mRNA
      amounts for every transporter gene expressed in CLL cells (CNT2, CNT3, ENT1, and
      ENT2), no relationship between mRNA levels and in vitro fludarabine cytotoxicity
      was observed. Fludarabine accumulation in CLL cells was mostly, if not
      exclusively, mediated by ENT-type transporters whose biologic activity was
      clearly correlated with fludarabine cytotoxicity, which reveals a role of ENT
      mediated uptake in drug responsiveness in patients with CLL.

PMID- 12411297
TI  - The degree of phenotypic correction of murine beta -thalassemia intermedia
      following lentiviral-mediated transfer of a human gamma-globin gene is influenced
      by chromosomal position effects and vector copy number.
AB  - Increased fetal hemoglobin (HbF) levels diminish the clinical severity of beta
      thalassemia and sickle cell anemia. A treatment strategy using autologous stem
      cell-targeted gene transfer of a gamma-globin gene may therefore have therapeutic
      potential. We evaluated oncoretroviral- and lentiviral-based gamma-globin vectors
      for expression in transduced erythroid cell lines. Compared with gamma-globin,
      oncoretroviral vectors containing either a beta-spectrin or beta-globin promoter
      and the alpha-globin HS40 element, a gamma-globin lentiviral vector utilizing the
      beta-globin promoter and elements from the beta-globin locus control region
      demonstrated a higher probability of expression. This lentiviral vector design
      was evaluated in lethally irradiated mice that received transplants of transduced
      bone marrow cells. Long-term, stable erythroid expression of human gamma-globin
      was observed with levels of vector-encoded gamma-globin mRNA ranging from 9% to
      19% of total murine alpha-globin mRNA. The therapeutic efficacy of the vector was
      subsequently evaluated in a murine model of beta-thalassemia intermedia. The
      majority of mice that underwent transplantation expressed significant levels of
      chimeric m(alpha)(2)h(gamma)(2) molecules (termed HbF), the amount of which
      correlated with the degree of phenotypic improvement. A group of animals with a
      mean HbF level of 21% displayed a 2.5 g/dL (25 g/L) improvement in Hb
      concentration and normalization of erythrocyte morphology relative to control
      animals. gamma-Globin expression and phenotypic improvement was variably lower in
      other animals due to differences in vector copy number and chromosomal position
      effects. These data establish the potential of using a gamma-globin lentiviral
      vector for gene therapy of beta-thalassemia.

PMID- 12411298
TI  - Emergence of clonal cytogenetic abnormalities in Ph- cells in some CML patients
      in cytogenetic remission to imatinib but restoration of polyclonal hematopoiesis
      in the majority.
AB  - Chronic myelogenous leukemia (CML) is characterized by the presence of a Bcr-Abl
      fusion protein with deregulated tyrosine kinase activity that is required for
      maintaining the malignant phenotype. Imatinib, a selective inhibitor of Bcr-Abl,
      induces major cytogenetic remission (MCR) or complete cytogenetic remission (CCR)
      in the majority of patients with CML in first chronic phase. However, thorough re
      evaluation of cytogenetics in a cohort of patients in MCR or CCR demonstrated
      clonal karyotypic abnormalities in more than 10% of cases, some of which were
      clinically associated with a myelodysplastic syndrome (MDS). Further analysis
      identified previous exposure to cytarabine and idarubicin as significant risk
      factors for the subsequent occurrence of abnormalities in Philadelphia chromosome
      negative (Ph-) cells. To investigate if cytogenetically normal but clonal
      hematopoiesis might be present in other patients in cytogenetic remission, we
      studied X-chromosome inactivation as a marker of clonality by polymerase chain
      reaction analysis of the human androgen receptor (HUMARA). We find that imatinib
      restores a polyclonal pattern in most patients in CCR and MCR. Nonetheless, our
      results are consistent with the notion that targeted therapy of CML with imatinib
      favors the manifestation of Ph- clonal disorders in some patients. They indicate
      that patients on imatinib should be followed with conventional cytogenetics, even
      after induction of CCR.

PMID- 12411299
TI  - A highly sensitive strategy for SCID-repopulating cell assay by direct injection
      of primitive human hematopoietic cells into NOD/SCID mice bone marrow.
AB  - To measure the ability of human hematopoietic stem cells (HSCs), the SCID
      repopulating cell (SRC) assay has been widely used. Conventionally, human HSCs
      are transplanted into a nonobese diabetic/severe combined immunodeficient
      (NOD/SCID) mouse via a tail vein. However, those cells must go through various
      obstacles until they reach the mouse marrow environment, which could explain the
      generally low homing efficiency in this system. Thus, the capability of HSCs may
      not be studied accurately by this intravenous transplantation method. In our
      attempt to reveal actual SRC potential, ie, self-renewal and multilineage
      differentiation in recipient bone marrow, we introduced cells into mouse marrow
      directly (intrabone marrow [iBM]) to minimize the effect of factors that may
      interfere with the homing of HSCs and compared the results obtained by
      intravenous and iBM methods. When cord blood CD34(+)CD38(-) cells were
      transplanted in NOD/SCID mice by iBM, a 15-fold higher frequency of SRC, 1 in 44
      CD34(+)CD38(-) cells, was achieved compared with 1 in 660 by the intravenous
      method. Furthermore, the iBM transplant showed high levels of engraftment in the
      secondary transplantation. Pretreatment of CD34(+) cells with antibodies that
      block either very late antigen 4 (VLA-4) or VLA-5 reduced engraftment partially,
      whereas blockage of both molecules resulted in complete inhibition of
      engraftment, which suggests that VLA-4 and VLA-5 are involved in different
      processes in engraftment or have complementary roles. Our results indicate that
      the iBM injection strategy is a more sensitive and direct way to measure the
      capability of human SRCs and is useful to investigate the interaction of HSCs and
      marrow environment in vivo.

PMID- 12411300
TI  - Efficacy of the farnesyl transferase inhibitor R115777 in chronic myeloid
      leukemia and other hematologic malignancies.
AB  - We investigated the clinical activity of the farnesyl transferase inhibitor
      R115777 in 22 patients with chronic myelogenous leukemia (CML) in chronic,
      accelerated, or blastic phase and in 8 patients with myelofibrosis (MF) and 10
      patients with multiple myeloma (MM). R115777 was administered at 600 mg orally
      twice daily for 4 weeks every 6 weeks. Seven patients with CML (6 in chronic
      phase, 1 in advanced phase) achieved complete or partial hematologic response.
      Four of them had a minor cytogenetic response. Responses were transient, with a
      median duration of 9 weeks (range, 3-23 weeks). Two patients discontinued therapy
      because of toxicity while in complete hematologic response. Two MF patients had a
      significant decrease in splenomegaly, one had normalization of white blood cell
      count and differential, and one became transfusion independent. One patient with
      MM had a reduction in monoclonal protein of 34%. Adverse events included nausea
      in 22 patients (55%; all grade 2 or lower) and fatigue in 19 (48%; grade 3 or
      higher in 1). Other grade 3 or 4 toxicities included skin rash (4 patients, 10%),
      peripheral neuropathy (2 patients, 5%), and liver toxicity (2 patients, 5%).
      Patients who responded to therapy had significantly higher plasma vascular
      endothelial growth factor (VEGF) concentrations prior to treatment than
      nonresponders. Plasma concentrations decreased significantly during therapy among
      responders. R115777 showed clinical activity in patients with CML and MF. The
      effect on VEGF needs to be further investigated to determine whether this might
      be a possible mechanism of action of R115777.

PMID- 12411301
TI  - Differential regulation of CXCR2 trafficking by Rab GTPases.
AB  - Intracellular trafficking of chemokine receptors plays an important role in fine
      tuning the functional responses of neutrophils and lymphocytes in the
      inflammatory process and HIV infection. Although many chemokine receptors
      internalize through clathrin-coated pits, regulation of the receptor trafficking
      is not fully understood. The present study demonstrated that CXCR2 was
      colocalized with transferrin and low-density lipoprotein (LDL) after agonist
      treatment for different periods of time, suggesting 2 intracellular trafficking
      pathways for this receptor. CXCR2 was colocalized with Rab5 and Rab11a, which are
      localized in early and recycling endosomes, respectively, in response to agonist
      stimulation for a short period of time, suggesting a recycling pathway for the
      receptor trafficking. However, overexpression of a dominant-negative Rab5-S34N
      mutant significantly attenuated CXCR2 sequestration. The internalized CXCR2 was
      recycled back to the cell surface after removal of the agonist and recovery of
      the cells, but receptor recycling was inhibited by overexpression of a dominant
      negative Rab11a-S25N mutant. After prolonged (4-hour) agonist treatment, CXCR2
      exhibited significantly increased colocalization with Rab7, which is localized in
      late endosomes. The colocalization of CXCR2 with LDL and LAMP-1 suggests that
      CXCR2 is targeted to lysosomes for degradation after prolonged ligand treatment.
      However, the colocalization of CXCR2 with Lamp1 was blocked by the overexpression
      of a dominant-negative Rab7-T22N mutant. In cells overexpressing Rab7-T22N, CXCR2
      was retained in the Rab5- and Rab11a-positive endosomes after prolonged (4-hour)
      agonist treatment. Our data suggest that the intracellular trafficking of CXCR2
      is differentially regulated by Rab proteins.

PMID- 12411302
TI  - Combined effects of Notch signaling and cytokines induce a multiple log increase
      in precursors with lymphoid and myeloid reconstituting ability.
AB  - We investigated whether combined signaling induced by engineered Notch ligands
      and hematopoietic growth factors influences hematopoietic stem-cell
      differentiation. We show that incubation of murine marrow precursors with
      Delta1(ext-IgG), a Notch ligand consisting of the Delta1 extracellular domain
      fused to the Fc portion of human immunoglobulin G1 (IgG1), and growth factors
      stem cell factor (SCF), interleukin 6 (IL-6), IL-11, and Flt3-l inhibited myeloid
      differentiation and promoted a several-log increase in the number of precursors
      capable of short-term lymphoid and myeloid repopulation. Addition of IL7 promoted
      early T-cell development, whereas addition of granulocyte-macrophage colony
      stimulating factor (GM-CSF) led to terminal myeloid differentiation. These
      results support a role for combinatorial effects by Notch and cytokine-induced
      signaling pathways in regulating hematopoietic cell fate and suggest the
      usefulness of Notch ligand in increasing hematopoietic precursor numbers for
      clinical stem-cell transplantation.

PMID- 12411303
TI  - CD44-stimulated human B cells express transcripts specifically involved in
      immunomodulation and inflammation as analyzed by DNA microarrays.
AB  - A number of studies have implicated a role for the cell surface glycoprotein CD44
      in several biologic events, such as lymphopoiesis, homing, lymphocyte activation,
      and apoptosis. We have earlier reported that signaling via CD44 on naive B cells
      in addition to B-cell receptor (BCR) and CD40 engagement generated a germinal
      center-like phenotype. To further characterize the global role of CD44 in B
      differentiation, we examined the expression profile of human B cells cultured in
      vitro in the presence or absence of CD44 ligation, together with anti
      immunoglobulin (anti-Ig) and anti-CD40 antibodies. The data sets derived from DNA
      microarrays were analyzed using a novel statistical analysis scheme created to
      retrieve the most likely expression pattern of CD44 ligation. Our results show
      that genes such as interleukin-6 (IL-6), IL-1alpha, and beta(2)-adrenergic
      receptor (beta(2)-AR) were specifically up-regulated by CD44 ligation, suggesting
      a novel role for CD44 in immunoregulation and inflammation.

PMID- 12411304
TI  - Unmutated immunoglobulin variable heavy-chain gene status remains an adverse
      prognostic factor after autologous stem cell transplantation for chronic
      lymphocytic leukemia.
AB  - An unmutated germ line configuration of the immunoglobulin variable heavy-chain
      gene (VH) has emerged to be a crucial adverse prognostic factor in chronic
      lymphocytic leukemia (CLL) under conventional treatment. The purpose of the
      present study was to investigate whether the VH mutational status retains its
      prognostic value in CLL also in the setting of autologous stem cell
      transplantation (SCT). Therefore, we investigated the mutational status in 58
      patients with CLL who underwent myeloablative radiochemotherapy with SCT.
      Rearranged VH genes were analyzed by multiplex polymerase chain reaction (PCR)
      and direct sequencing using FR1 family-specific primers and JH consensus primers.
      Twenty patients (34%) showed less than 98% homology compared with germ line VH
      sequences and were considered as mutated, whereas 38 patients (66%) had an
      unmutated VH status (median mutational rate of 0%; range, 0%-1.7%). An unmutated
      VH configuration was strongly correlated with the presence of short lymphocyte
      doubling time (P =.003) and high lymphocyte count (P =.005). Time to clinical
      relapse and time to recurrence of monoclonal B cells as assessed by consensus IgH
      CDR3 PCR was significantly shorter in the group with unmutated VH genes (2-year
      probability 19% versus 0%, P =.0008, and 34% versus 9%, P =.0006, respectively).
      These results show that in CLL, an unmutated VH gene status of the tumor clone
      remains an adverse prognostic factor after SCT. Nevertheless, the hitherto only 3
      deaths and the median treatment-free interval of 49 months in the unmutated
      cohort suggest a beneficial effect of SCT for this high-risk population in
      comparison to conventional treatment.

PMID- 12411305
TI  - Regulation of osteoclast development by Notch signaling directed to osteoclast
      precursors and through stromal cells.
AB  - Osteoclasts are derived from hematopoietic precursor cells belonging to the
      monocyte/macrophage lineage. Osteoclast development has been reported to be
      regulated by several molecules such as macrophage colony-stimulating factor (M
      CSF), receptor activator of nuclear factor (NF)-kappaB ligand (RANKL), and a
      decoy receptor of RANKL, osteoprotegerin (OPG). Recently, it was demonstrated
      that the Notch signaling pathway regulates myeloid differentiation and
      antagonizes cell fate determination, however, the effect of Notch signaling on
      the osteoclast lineage has not been reported. In this study, we examined the
      effect of signaling via Notch receptors on the differentiation into osteoclasts
      by using cells from the bone marrow, spleen, and peritoneal cavity, and a cloned
      macrophagelike cell line. Osteoclastogenesis was inhibited by an immobilized
      Notch ligand, Delta-1. The dish-adherent bone marrow cells precultured with M-CSF
      expressed both Mac-1 and M-CSF receptors, c-Fms; osteoclastogenesis of these
      cells was efficiently inhibited. The immobilized Delta-1 also down-regulated the
      surface c-Fms expression, while the c-Fms gene expression was not changed. Genes
      for Notch receptors and Notch ligands are expressed in not only hematopoietic
      cells but also stromal cells that support osteoclast development. Constitutively
      active Notch1-transfected stromal cells showed increased expression of RANKL and
      OPG genes, and strong inhibition of M-CSF gene expression, resulting in reduction
      of their ability to support osteoclast development. Taken together, these
      findings indicate that Notch signaling affects both osteoclast precursors and
      stromal cells and thereby negatively regulates osteoclastogenesis.

PMID- 12411306
TI  - Generating CTLs against the subdominant Epstein-Barr virus LMP1 antigen for the
      adoptive immunotherapy of EBV-associated malignancies.
AB  - The Epstein-Barr virus (EBV)-encoded LMP1 protein is expressed in EBV-positive
      Hodgkin disease and is a potential target for cytotoxic T-lymphocyte (CTL)
      therapy. However, the LMP1-specific CTL frequency is low, and so far the
      generation of LMP1-specific CTLs has required T-cell cloning. The toxicity of
      LMP1 has prevented the use of dendritic cells (DCs) for CTL stimulation, and we
      reasoned that an inactive, nontoxic LMP1 mutant (DeltaLMP1) could be expressed in
      DCs and would enable the activation and expansion of polyclonal LMP1-specific
      CTLs. Recombinant adenoviral vectors expressing LMP1 or DeltaLMP1 were tested for
      their ability to transduce DCs. LMP1 expression was toxic within 48 hours whereas
      high levels of DeltaLMP1 expression were achieved with minimal toxicity.
      DeltaLMP1-expressing DCs were able to reactivate and expand LMP1-specific CTLs
      from 3 healthy EBV-seropositive donors. LMP1-specific T cells were detected by
      interferon-gamma (IFN-gamma) enzyme-linked immunospot assay (ELISPOT) assays
      using the HLA-A2-restricted LMP1 peptide, YLQQNWWTL (YLQ). YLQ-specific T cells
      were undetectable (less than 0.001%) in donor peripheral blood mononuclear cells
      (PBMCs); however, after stimulation the frequency increased to 0.5% to 3.8%.
      Lysis of autologous target cells by CTLs was dependent on the level of LMP1
      expression. In contrast, the frequency of YLQ-specific CTLs in EBV-specific CTLs
      reactivated and expanded using lymphoblastoid cell lines was low and no LMP1
      specific cytotoxic activity was observed. Thus, DeltaLMP1 expression in DCs is
      nontoxic and enables the generation of LMP1-specific CTLs for future adoptive
      immunotherapy protocols for patients with LMP1-positive malignancies such as EBV
      positive Hodgkin disease. Targeting LMP1 in these malignancies may improve the
      efficacy of current adoptive immunotherapy approaches.

PMID- 12411307
TI  - Interleukin-17 promotes angiogenesis and tumor growth.
AB  - Interleukin-17 (IL-17) is a CD4 T-cell-derived proinflammatory cytokine. We
      investigated the effects of locally produced IL-17 by tumors as a means to
      evaluate its biologic function. Although recombinant IL-17 protein or retroviral
      transduction of IL-17 gene into tumors did not affect in vitro proliferation, IL
      17 transfectants grew more rapidly in vivo when compared with controls.
      Immunostaining for Factor VIII revealed that tumors transduced with IL-17 had
      significantly higher vascular density when compared with controls. IL-17 indeed
      elicited neovascularization in rat cornea. In addition, angiogenic activity
      present in the conditioned media of CD4 T cells was markedly suppressed by
      neutralizing monoclonal antibody to IL-17. IL-17 had no direct effect on the
      growth of vascular endothelial cells, whereas IL-17 significantly stimulated
      migration. IL-17 also markedly promoted the cord formation of vascular
      endothelial cells. In addition, IL-17 up-regulated elaboration of a variety of
      proangiogenic factors by fibroblasts as well as tumor cells. These findings
      reveal a novel role for IL-17 as a CD4 T-cell-derived mediator of angiogenesis
      that stimulates vascular endothelial cell migration and cord formation and
      regulates production of a variety of proangiogenic factors. Furthermore, they
      suggest that inhibition of biologic action of IL-17 may have therapeutic benefits
      when applied to angiogenesis-related disorders.

PMID- 12411308
TI  - The function of the bcl-x promoter in erythroid progenitor cells.
AB  - The protein Bcl-x(L) is essential for survival of erythroid progenitor cells, and
      it increases substantially during late erythrocyte differentiation due to an
      increase of mRNA. We mapped the transcription start sites of bcl-x mRNA in mouse
      and human erythroblasts, and we analyzed the function of the mouse bcl-x promoter
      by transient and stable transfection assays in a mouse erythroid cell line using
      plasmids containing the bcl-x promoter fused to a luciferase reporter gene. In
      mouse erythroblasts, a cluster of start sites at positions -664, -655, and -644
      relative to the ATG initiation codon account for almost all transcripts. Human
      erythroblasts exhibit a start site at -654 that is homologous to the triplet in
      the mouse. A short sequence element in the mouse bcl-x promoter that includes
      nucleotides -1804 through -1734 was identified as very important for
      transcription. This element also showed strong enhancerlike activity in concert
      with the SV40 promoter in an enhancer test vector. Analyses of mutations
      indicated that 2 short sequences within the element, about 15 base pair apart,
      are necessary for full enhancer activity. Gel shift experiments with
      oligonucleotides representing these sequences revealed specific binding of
      nuclear proteins from erythroblasts. Some of these proteins are regulated during
      the late erythroid differentiation.

PMID- 12411309
TI  - T-cell activation and cytokine production via a bispecific single-chain antibody
      fragment targeted to blood-stage malaria parasites.
AB  - A novel bispecific single-chain antibody fragment (biscFv) has been constructed
      to address the possibility of a new approach to malaria therapeutic drug
      development. The biscFv consists of 2 different single-chain antibody fragments
      linked by a flexible peptide linker (Gly(4)-Ser)(3). Of the 2 scFv fragments, one
      is directed against a conserved epitope of the 19-kDa C-terminal fragment of the
      major surface protein of human malignant malaria parasite, Plasmodium falciparum,
      and the other is directed against the CD3 antigen of human T cells. The biscFv
      expressed by a recombinant baculovirus retained the antigen-binding properties of
      the corresponding univalent single-chain antibody fragments and formed a bridge
      between P falciparum and T cells. In cooperation with T cells, the biscFv
      specifically induced not only interferon gamma and tumor necrosis factor alpha,
      but also a significant increase of merozoite phagocytosis and growth inhibition
      of P falciparum in vitro. Thus, the biscFv possesses highly selective malaria
      targeting properties and stimulates T cells to induce cytokines, presumably
      resulting in activation of macrophages, neutrophils, and natural killer cells,
      and parasite killing in vivo.

PMID- 12411310
TI  - Cellular response to hypoxia involves signaling via Smad proteins.
AB  - The transforming growth factor-beta (TGF-beta) family of cytokines regulates
      vascular development and inflammatory responses. We have recently shown that
      exposure of human umbilical vein endothelial cells (HUVECs) to hypoxia (1% O(2))
      increases gene expression and bioactivation of TGF-beta2 and induces its
      downstream effectors, Smad proteins (Smads), to associate with DNA. In the
      present study, we show that hypoxia-induced TGF-beta2 gene expression is
      dependent on thrombospondin-1-mediated bioactivation of latent TGF-beta. Blocking
      TGF-beta2 but not TGF-beta1 in hypoxic endothelial cell cultures inhibited
      induction of the TGF-beta2 gene, indicating that an autocrine mechanism driven by
      bioactivation of TGF-beta2 leads to its gene expression in hypoxic HUVECs.
      Exposure of HUVECs to hypoxia resulted in phosphorylation and nuclear
      transportation of Smad2 and Smad3 proteins as well as stimulation of
      transcriptional activities of Smad3 and the transcription factor hypoxia
      inducible factor-1alpha and culminated in up-regulation of TGF-beta2 gene
      expression. Autocrine regulation of TGF-beta2 production in hypoxia may involve
      cross-talk between Smad3 and HIF-1alpha signaling pathways, and could be an
      important mechanism by which endothelial cells respond to hypoxic stress.

PMID- 12411311
TI  - Constitutive exclusion of Csk from Hck-positive membrane microdomains permits Src
      kinase-dependent proliferation of Theileria-transformed B lymphocytes.
AB  - Infection of bovine T cells and B cells with the intracellular protozoan parasite
      Theileria parva induces a transformed phenotype with characteristics comparable
      to leukemic cells. The transformed phenotype reverts on drug-induced parasite
      death, and the cured lymphocytes acquire a resting phenotype and eventually die
      by apoptosis if not further stimulated. Here, we show that both lymphocyte
      proliferation and activation of the transcription factor AP-1 are mediated by Src
      family protein tyrosine kinases (PTKs) in a parasite-dependent fashion. Src
      family PTKs are known to be present in glycolipid-enriched microdomains (GEMs),
      also called lipid rafts, and to be negatively regulated by PTK Csk complexed to
      tyrosine-phosphorylated transmembrane adapter protein PAG (phosphoprotein
      associated with GEMs) also called Cbp (Csk-binding protein). We, therefore,
      purified GEMs from proliferating infected B cells and from growth-arrested cells
      that had been drug-cured of parasites. Proliferation arrest led to a striking
      increase of PAG/Cbp expression; correspondingly, the amount of Csk associated
      with PAG/Cbp in GEMs increased markedly, whereas PTK Hck accumulation in GEM
      fractions did not alter on growth arrest. We propose that Theileria-induced
      lymphocyte proliferation and permanent activation of Hck stems from down
      regulation of PAG/Cbp and the concomitant constitutive loss of the negative
      regulator Csk from the GEMs of transformed B cells.

PMID- 12411314
TI  - Introduction: congenital methemoglobinemia revisited.

PMID- 12411315
TI  - Recombinant human thrombopoietin: basic biology and evaluation of clinical
      studies.
AB  - Thrombocytopenia is a common medical problem for which the main treatment is
      platelet transfusion. Given the increasing use of platelets and the declining
      donor population, identification of a safe and effective platelet growth factor
      could improve the management of thrombocytopenia. Thrombopoietin (TPO), the c-Mpl
      ligand, is the primary physiologic regulator of megakaryocyte and platelet
      development. Since the purification of TPO in 1994, 2 recombinant forms of the c
      Mpl ligand--recombinant human thrombopoietin (rhTPO) and pegylated recombinant
      human megakaryocyte growth and development factor (PEG-rHuMGDF)--have undergone
      extensive clinical investigation. Both have been shown to be potent stimulators
      of megakaryocyte growth and platelet production and are biologically active in
      reducing the thrombocytopenia of nonmyeloablative chemotherapy. However, neither
      TPO has demonstrated benefit in stem cell transplantation or leukemia
      chemotherapy. Other clinical studies have investigated the use of TPO in treating
      chronic nonchemotherapy-induced thrombocytopenia associated with myelodysplastic
      syndromes, idiopathic thrombocytopenic purpura, thrombocytopenia due to human
      immunodeficiency virus, and liver disease. Based solely on animal studies, TPO
      may be effective in reducing surgical thrombocytopenia and bleeding, ex vivo
      expansion of pluripotent stem cells, and as a radioprotectant. Ongoing and future
      studies will help define the clinical role of recombinant TPO and TPO mimetics in
      the treatment of chemotherapy- and nonchemotherapy-induced thrombocytopenia.

PMID- 12411316
TI  - Fibroblast growth factor receptor-1 is expressed by endothelial progenitor cells.
AB  - Recent experiments show that hematopoietic progenitor cell populations contain
      endothelial precursor cells. We have isolated a population of CD34(+) cells that
      expresses fibroblast growth factor receptor-1 (FGFR-1) and that differentiates
      into endothelial cells in vitro. We find that 4.5% +/- 2.1% of CD34(+) cells
      isolated from bone marrow, cord blood, and mobilized peripheral blood express
      FGFR-1 and that viable CD34(+)FGFR(+) cells are small, with little granularity,
      and express both primitive hematopoietic and endothelial markers on their
      surface. The primitive hematopoietic markers AC133, c-kit, and Thy-1 are
      coexpressed by 75%, 85%, and 64% of CD34(+)FGFR(+) cells, respectively. Most of
      the CD34(+)FGFR(+) cells also express antigens found on endothelial cells, such
      as CD31, vascular endothelial growth factor receptor-2, and the endothelial
      specific cell surface marker, vascular endothelial cadherin (VE-cadherin),
      whereas 56% to 60% of the cells express Tie, Tek, and the endothelial-specific
      marker, P1H12. The CD34(+)FGFR(+) population is enriched in cells expressing
      endothelial-specific antigens compared with the CD34(+) population. Isolated
      CD34(+)FGFR(+) cells grow slowly in culture, are stimulated by fibroblast growth
      factor-2 and vascular endothelial growth factor, and give rise to cells that
      express von Willebrand factor and VE-cadherin and that incorporate acetylated low
      density lipoprotein. These experiments show that FGFR-1 is expressed by a
      subpopulation of CD34(+) cells that give rise to endothelial cells in vitro,
      indicating that this population contains endothelial stem/progenitor cells.

PMID- 12411317
TI  - hnRNP-K and Pur(alpha) act together to repress the transcriptional activity of
      the CD43 gene promoter.
AB  - CD43 is an abundant, heavily glycosylated molecule expressed specifically on the
      surface of leukocytes and platelets. When leukocytes are at rest, CD43 acts to
      prevent both homotypic and heterotypic interactions. However, during leukocyte
      activation CD43 expression is repressed, facilitating the intercellular contact
      required for chemotaxis, phagocytosis, aggregation, adhesion to endothelium, and
      transendothelial migration. Consequently, CD43 repression plays a vital role both
      in innate and acquired immunity. Here we report that a dramatic down-regulation
      of CD43 mRNA levels occurs during activation of the leukocytic cell line K562.
      This repression coincides with repression of the transcriptional activity of the
      CD43 gene promoter. We have determined that heterogeneous nuclear
      ribonucleoprotein K (hnRNP-K) and Pur(alpha) act together to mediate repression
      of the CD43 promoter during K562 activation. The hnRNP-K molecule and Pur(alpha)
      bind single-stranded DNA. Therefore, exposure of single-stranded structures
      within the CD43 promoter probably plays a major role in effecting CD43
      repression.

PMID- 12411318
TI  - In vivo trafficking, cell cycle activity, and engraftment potential of
      phenotypically defined primitive hematopoietic cells after transplantation into
      irradiated or nonirradiated recipients.
AB  - Recent interest in bone marrow (BM) transplantation in nonconditioned or
      minimally conditioned recipients warrants investigation of homing patterns of
      transplanted hematopoietic progenitor cells (HPCs) in irradiated and
      nonirradiated recipients. To this end, phenotypically defined populations of BM
      cells were tracked in lethally irradiated or nonirradiated mice at 1, 3, 6, and
      24 hours after transplantation. Recovery of transplanted cells at all time points
      was higher in BM of nonirradiated mice, similar to earlier suggestions. The
      percentage of lineage-negative Sca-1(+) cells and Sca-1(+) cells expressing CD43,
      CD49e, and CD49d steadily increased in BM of nonirradiated mice up to 24 hours,
      while fluctuating in irradiated mice. Cell cycle status and BrdU incorporation
      revealed that less than 20% of Sca-1(+) cells and fewer Sca-1(+)lin(-) cells had
      cycled by 24 hours after transplantation. To more directly examine trafficking of
      primitive HPCs, purified grafts of CD62L(-) or CD49e(+) subfractions of Sca
      1(+)lin(-) cells, previously shown to be enriched for long-term repopulating
      cells, also were tracked in vivo. Recovery of purified cells was similarly
      increased in BM of nonirradiated mice. When 50 to 100 of these BM-homed cells
      were examined in serial transplantation studies, BM-homed cells from initially
      nonirradiated mice were enriched 5- to 30-fold for cells capable of long-term
      hematopoiesis in secondary recipients. Collectively, these data suggest that
      homing or survival of transplanted cells in irradiated recipients is less
      efficient than that in nonirradiated recipients, implicating an active role of
      radiation-sensitive microenvironmental cues in the homing process. These results
      may have important clinical implications in the design of BM transplantation
      protocols.

PMID- 12411319
TI  - Characterization of gene expression of CD34+ cells from normal and
      myelodysplastic bone marrow.
AB  - Gene patterns of expression in purified CD34(+) bone marrow cells from 7 patients
      with low-risk myelodysplastic syndrome (MDS) and 4 patients with high-risk MDS
      were compared with expression data from CD34(+) bone marrow cells from 4 healthy
      control subjects. CD34(+) cells were isolated by magnetic cell separation, and
      high-density oligonucleotide microarray analysis was performed. For confirmation,
      the expression of selected genes was analyzed by real-time polymerase chain
      reaction. Class membership prediction analysis selected 11 genes. Using the
      expression profile of these genes, we were able to discriminate patients with low
      risk from patients with high-risk MDS and both patient groups from the control
      group by hierarchical clustering (Spearman confidence). The power of these 11
      genes was verified by applying the algorithm to an unknown test set containing
      expression data from 8 additional patients with MDS (3 at low risk, 5 at high
      risk). Patients at low risk could be distinguished from those at high risk by
      clustering analysis. In low-risk MDS, we found that the retinoic-acid-induced
      gene (RAI3), the radiation-inducible, immediate-early response gene (IEX1), and
      the stress-induced phosphoprotein 1 (STIP1) were down-regulated. These data
      suggest that CD34(+) cells from patients with low-risk MDS lack defensive
      proteins, resulting in their susceptibility to cell damage. In summary, we
      propose that gene expression profiling may have clinical relevance for risk
      evaluation in MDS at the time of initial diagnosis. Furthermore, this study
      provides evidence that in MDS, hematopoietic stem cells accumulate defects that
      prevent normal hematopoiesis.

PMID- 12411320
TI  - Vav1, but not Vav2, contributes to platelet aggregation by CRP and thrombin, but
      neither is required for regulation of phospholipase C.
AB  - We have investigated the role of the Rho and Rac family small guanine
      triphosphate (GTP) exchange factors (RhoGEFs), Vav1 and Vav2, in the activation
      of platelets by the immunoreceptor tyrosine-based activation motif (ITAM)-coupled
      collagen receptor GPVI and by the G protein-coupled receptor agonist thrombin.
      The glycoprotein VI (GPVI)-specific agonist collagen-related peptide (CRP) and
      thrombin stimulated tyrosine phosphorylation of Vav1 but not Vav2 in human
      platelets. Surprisingly, however, CRP did not activate the low-molecular-weight G
      protein Rac and stimulated only a small increase in activity of p21-associated
      kinase 2 (PAK2), despite the fact that both proteins are regulated downstream of
      Vav1 in other cells. Further, activation of Rac and PAK2 by thrombin was
      maintained in platelets from mice deficient in Vav1. Activation of phospholipase
      C (PLC) by GPVI and thrombin was unaltered in Vav1-, Vav2-, and Vav1/Vav2
      deficient platelets. A weak inhibition of late-stage aggregation to CRP and
      thrombin was observed in platelets deficient in Vav1 but not Vav2, whereas
      spreading on fibrinogen was not changed. The present results demonstrate that
      neither Vav1 nor Vav2 lie upstream of PLC or Rac in platelets, highlighting an
      important difference in their role in signaling by ITAM-coupled receptors in
      other cell types. The present study has provided evidence for a possible role of
      Vav1 but not Vav2 in the later stages of platelet aggregation.

PMID- 12411321
TI  - Furin gene (fur) regulation in differentiating human megakaryoblastic Dami cells:
      involvement of the proximal GATA recognition motif in the P1 promoter and impact
      on the maturation of furin substrates.
AB  - The convertase furin is involved in the maturation of key growth/aggregation
      mediators synthesized by the platelet producers, megakaryocytes, but the
      regulation of furin in these cells remains unknown. Computer-assisted search of
      the furin promoter sequence revealed multiple potential binding motifs for GATA
      1, suggesting that furin is expressed and regulated in these cells. Using
      megakaryoblastic Dami cells, we observed that fur mRNA expression increased
      gradually on phorbol 12-myristate 13-acetate-induced differentiation, reaching
      maximum levels (8.3-fold increase) at 10 days. Transient transfections with P1,
      P1A, or P1B fur-LUC-promoter constructs revealed that in Dami cells, the P1
      promoter is the strongest and the most sensitive to forced expression of GATA-1.
      Coexpression of GATA-1 and its comodulator, Friend of GATA-1 (FOG-1), resulted in
      a cooperative increase in P1 activity. Deletion analysis indicated that important
      GATA-1-regulated sequences are located in the most proximal region of the P1
      promoter. Further analysis revealed 2 potential GATA-binding motifs at positions 
      66 and +62. Point mutation of each of the 2 motifs indicated that the intactness
      of the first GATA site is required for full basal and GATA-1-stimulated promoter
      activity. Finally, the inhibition of furin activity through gene transfer of the
      inhibitor alpha1-AT-PDX led to a block in maturation of the furin substrates
      transforming growth factor-beta1 and platelet-derived growth factor. Taken
      together, these results indicate that the most proximal GATA element in the P1
      promoter is needed for fur gene expression in megakaryoblastic cells. They also
      suggest that proper regulation of the fur gene in megakaryocytes has an impact on
      the activation of furin substrates involved in megakaryocyte maturation and
      platelet functions.

PMID- 12411322
TI  - Tumor necrosis factor receptor-associated factor 1 gene overexpression in B-cell
      chronic lymphocytic leukemia: analysis of NF-kappa B/Rel-regulated inhibitors of
      apoptosis.
AB  - B-cell chronic lymphocytic leukemia (B-CLL) is characterized by a resistance
      toward apoptosis-inducing agents. Nuclear factor-kappaB (NF-kappaB)/Rel has been
      shown to regulate the expression of antiapoptotic genes, such as members of the
      inhibitor of apoptosis protein (IAP) and tumor necrosis factor receptor
      associated factor (TRAF) gene families. Expression and regulation of NF
      kappaB/Rel-dependent inhibitors of apoptosis have not been collectively studied
      in B-CLL. We examined expression of known NF-kappaB/Rel-regulated antiapoptotic
      genes by RNAse protection assay, real-time polymerase chain reaction, and
      immunoblotting in patients with B-CLL. TRAF1 and to a lesser extent TRAF2 were
      overexpressed in B-CLL lymphocytes as compared with normal CD19(+) B cells. TRAF1
      overexpression did not correlate with markers of disease progression or overall
      survival. Furthermore, we found high constitutive expression of the IAP genes c
      IAP-1, c-IAP-2, and XIAP both in normal and B-CLL lymphocytes. Focusing on the
      regulation of TRAF1, NF-kappaB/Rel activity in B-CLL nuclear extracts was shown
      to bind to TRAF1 promoter elements. However, IkappaB kinase (IKK) activity was
      not increased in CLL lymphocytes as compared with normal CD19(+) B cells. The
      known IKK inhibitor sulfasalazine did not compromise TRAF1 expression. Thus,
      although our study revealed a common expression pattern of NF-kappaB/Rel
      regulated inhibitors of apoptosis, our findings indicate an IKK-independent
      regulation of TRAF1 in B-CLL.

PMID- 12411323
TI  - A naturally occurring point substitution in Cdc25A, and not Fv2/Stk, is
      associated with altered cell-cycle status of early erythroid progenitor cells.
AB  - The Friend virus susceptibility gene 2 (Fv2) controls the polyclonal expansion of
      infected cells that occurs early during Friend erythroleukemia virus infection.
      Fv2 has recently been shown to encode a truncated form of the Stk receptor
      tyrosine kinase (Sf-Stk). This observation, coupled with earlier work, suggested
      that Sf-Stk drives the expansion of infected cells by forming a complex with the
      Friend virus envelope glycoprotein, gp55, and the erythropoietin receptor. Fv2
      has also been implicated in the control of cell cycling in early erythroid
      progenitors (erythroid blast-forming units [BFU-Es]). Mouse strains that are
      homozygous for the resistant allele of Fv2 (Fv2(rr)) have few actively cycling
      BFU-Es. In this report, we demonstrate that the control of BFU-E cycling is
      encoded by a gene linked to, but distinct from, Fv2, and suggest that this gene
      is the dual-specific protein phosphatase Cdc25A, which regulates the G1- to S
      phase transition of the cell cycle. We show that a naturally occurring allele of
      Cdc25A, which increases Cdc25A phosphatase activity and promotes cell-cycle
      progression, segregates in mouse strains that exhibit high levels of BFU-E cell
      cycling. In wild-type mice, this allele of Cdc25A does not overtly affect
      erythropoiesis; however, when this allele is combined with a mutation of the Kit
      receptor (Kit(WV)), the anemia of the mice is enhanced. Furthermore,
      overexpression of Cdc25A in bone marrow cells causes a defect in the BFU-E colony
      formation. These results suggest that proper regulation of the cell cycle through
      Cdc25A is required for normal erythropoiesis.

PMID- 12411324
TI  - Phenotypes and phosphatidylinositol glycan-class A gene abnormalities during cell
      differentiation and maturation from precursor cells to mature granulocytes in
      patients with paroxysmal nocturnal hemoglobinuria.
AB  - To define the phosphatidylinositol glycan-class A (PIG-A) gene abnormality in
      precursor cells and the changes of expression of glycosylphosphatidylinositol
      anchored protein and contribution of paroxysmal nocturnal hemoglobinuria (PNH)
      clones with PIG-A gene abnormalities among various cell lineages during
      differentiation and maturation, we investigated CD59 expression on bone marrow
      CD34(+) cells and peripheral granulocytes from 3 patients with PNH and the PIG-A
      gene abnormalities in the CD59(-), CD59(+/-), and CD59(+) populations by
      nucleotide sequence analyses. We also performed clonogeneic assays of
      CD34(+)CD59(+) and CD34(+)CD59(-) cells from 2 of the patients and examined the
      PIG-A gene abnormalities in the cultured cells. In case 1, the CD34(+) cells and
      granulocytes consisted of CD59(-) and CD59(+) populations and CD59(-), CD59(+/-),
      and CD59(+) populations, respectively. Sequence analyses indicated that mutation
      1-2 was in the CD59(+/-) granulocyte population (20 of 20) and the CD34(+)CD59(-)
      population (2 of 38). In cases 2 and 3, the CD34(+) cells and granulocytes
      consisted of CD59(+) and CD59(-) cells. Sequence analyses in case 3 showed that
      mutation 3-2 was not in CD34(+)CD59(-) cells and was present in the CD59(-)
      granulocyte population. However, PIG-A gene analysis of cultured CD34(+)CD59(-)
      cells showed that they had the mutation. This analysis also revealed that there
      were some other mutations, which were not found in CD34(+)CD59(-) cells and CD59(
      ) or CD59(+/-) granulocytes in vivo, and that sometimes they were distributed
      specifically among different cell lineages. In conclusion, our findings suggest
      that PNH clones might contribute qualitatively and quantitatively differentially
      to specific blood cell lineages during differentiation and maturation of
      hematopoietic stem cells.

PMID- 12411325
TI  - Polymorphism G80A in the reduced folate carrier gene and its relationship to
      methotrexate plasma levels and outcome of childhood acute lymphoblastic leukemia.
AB  - Methotrexate (MTX) is a key compound of chemotherapeutic regimens used in the
      treatment of childhood acute lymphoblastic leukemia (ALL). Resistance to this
      drug may arise by, among other factors, altered cellular uptake that may hamper
      the efficacy of the treatment. Recently, a G(80)A polymorphism has been described
      in the reduced folate carrier gene (RFC1), which encodes the major MTX
      transporter. Here, we assessed the association between the genetic polymorphisms
      G(80)A and both MTX plasma levels and childhood ALL outcome. Children with the
      A(80) variant had worse prognoses than patients with the GG genotype (P =.04), as
      shown by event-free survival estimates. Patients homozygous for A(80) had higher
      levels of MTX (P =.004) than the other genotype groups. Possible explanations for
      observed associations are discussed; however, additional experiments are required
      to achieve understanding of the underlying mechanism.

PMID- 12411326
TI  - Two distinct HLA-A0201-presented epitopes of the Wilms tumor antigen 1 can
      function as targets for leukemia-reactive CTL.
AB  - Using the allo-restricted T-cell approach to circumvent tolerance, we have
      previously identified a cytotoxic T-lymphocyte (CTL) epitope in the transcription
      factor Wilms tumor antigen 1 (WT1) presented by HLA-A0201 (A2) class I molecules.
      Here we describe an additional A2-presented epitope and show that CTLs against
      both epitopes kill WT1-expressing leukemia cell lines. Colony-forming assays
      demonstrated that both types of CTL killed CD34(+) progenitor cells from A2(+)
      leukemia patients, but not from A2(+) healthy individuals. The long-term culture
      initiating cell (LTC-IC) assay was used to analyze the killing activity of WT1
      specific CTLs against the more immature fraction of CD34(+) cells. The CTLs
      killed LTC-ICs of patients with chronic myelogenous leukemia (CML), whereas the
      function of normal CD34(+) progenitor/stem cells was not inhibited. Together, the
      data show that CTLs specific for 2 distinct peptide epitopes of WT1 can
      discriminate between normal and leukemia LTC-ICs, suggesting that such CTLs have
      the potential to selectively kill CML progenitor/stem cells.

PMID- 12411327
TI  - Chromosome 19 abnormalities are commonly seen in AML, M7.

PMID- 12411328
TI  - Deficiency of ADAMTS13 and thrombotic thrombocytopenic purpura.

PMID- 12411329
TI  - CMV infection following nonmyeloablative allogeneic stem cell transplantation
      using Campath.

PMID- 12411330
TI  - Smoke detectors and house fires.

PMID- 12411331
TI  - Treating acute gouty arthritis with selective COX 2 inhibitors.

PMID- 12411332
TI  - Mattresses, microenvironments, and multivariate analyses.

PMID- 12411333
TI  - A POEM a week for the BMJ.

PMID- 12411334
TI  - A theme issue for medics and an increasingly health informed public.

PMID- 12411335
TI  - Simple measures could increase life expectancy by 5-10 years.

PMID- 12411337
TI  - Three out of four Germans have used complementary or natural remedies.

PMID- 12411338
TI  - Wellcome Trust promotes ethical research in developing world.

PMID- 12411339
TI  - UK heart surgery results similar to those in the United States.

PMID- 12411340
TI  - Second long term HRT trial stopped early.

PMID- 12411341
TI  - Protestors lobby parliament over proposed change in mental health law.

PMID- 12411342
TI  - US mammography programme beset by flaws.

PMID- 12411345
TI  - Charity calls for ban on cluster bombs.

PMID- 12411346
TI  - Aspirin use to be banned in under 16 year olds.

PMID- 12411347
TI  - Unsafe abortions cause 20 000 deaths a year in Nigeria.

PMID- 12411352
TI  - Government paints too rosy a picture of A&E, report says.

PMID- 12411353
TI  - MEPs reject US-style direct advertising of drugs.

PMID- 12411354
TI  - Meta-analysis of effects and side effects of low dosage tricyclic antidepressants
      in depression: systematic review.
AB  - OBJECTIVE: To compare the effects and side effects of low dosage tricyclic
      antidepressants with placebo and with standard dosage tricyclics in acute phase
      treatment of depression. DESIGN: Systematic review of randomised trials comparing
      low dosage tricyclics (< or =100 mg/day) with placebo or with standard dosage
      tricyclics in adults with depression. MAIN OUTCOME MEASURES: Relative risk of
      response in depression (random effects model), according to the original authors'
      definition but usually defined as 50% or greater reduction in severity of
      depression. Relative risks of overall dropouts and dropouts due to side effects.
      RESULTS: 35 studies (2013 participants) compared low dosage tricyclics with
      placebo, and six studies (551 participants) compared low dosage tricyclics with
      standard dosage tricyclics. Low dosage tricyclics, mostly between 75 and 100
      mg/day, were 1.65 (95% confidence interval 1.36 to 2.0) and 1.47 (1.12 to 1.94)
      times more likely than placebo to bring about response at 4 weeks and 6-8 weeks,
      respectively. Standard dosage tricyclics failed, however, to bring about more
      response but produced more dropouts due to side effects than low dosage
      tricyclics. CONCLUSIONS: Treatment of depression in adults with low dose
      tricyclics is justified. However, more rigorous studies are needed to
      definitively establish the relative benefits and harms of various dosages.

PMID- 12411355
TI  - Incidence of fires and related injuries after giving out free smoke alarms:
      cluster randomised controlled trial.
AB  - OBJECTIVE: To measure the effect of giving out free smoke alarms on rates of
      fires and rates of fire related injury in a deprived multiethnic urban
      population. DESIGN: Cluster randomised controlled trial. SETTING: Forty electoral
      wards in two boroughs of inner London, United Kingdom. PARTICIPANTS: Primarily
      households including elderly people or children and households that are in
      housing rented from the borough council. INTERVENTION: 20 050 smoke alarms,
      fittings, and educational brochures distributed free and installed on request.
      MAIN OUTCOME MEASURES: Rates of fires and related injuries during two years after
      the distribution; alarm ownership, installation, and function. RESULTS: Giving
      out free smoke alarms did not reduce injuries related to fire (rate ratio 1.3;
      95% confidence interval 0.9 to 1.9), admissions to hospital and deaths (1.3; 0.7
      to 2.3), or fires attended by the fire brigade (1.1; 0.96 to 1.3). Similar
      proportions of intervention and control households had installed alarms (36/119
      (30%) v 35/109 (32%); odds ratio 0.9; 95% confidence interval 0.5 to 1.7) and
      working alarms (19/118 (16%) v 18/108 (17%); 0.9; 0.4 to 1.8). CONCLUSIONS:
      Giving out free smoke alarms in a deprived, multiethnic, urban community did not
      reduce injuries related to fire, mostly because few alarms had been installed or
      were maintained.

PMID- 12411356
TI  - Prevalence of working smoke alarms in local authority inner city housing:
      randomised controlled trial.
AB  - OBJECTIVES: To identify which type of smoke alarm is most likely to remain
      working in local authority inner city housing, and to identify an alarm tolerated
      in households with smokers. DESIGN: Randomised controlled trial. SETTING: Two
      local authority housing estates in inner London. PARTICIPANTS: 2145 households.
      INTERVENTION: Installation of one of five types of smoke alarm (ionisation sensor
      with a zinc battery; ionisation sensor with a zinc battery and pause button;
      ionisation sensor with a lithium battery and pause button; optical sensor with a
      lithium battery; or optical sensor with a zinc battery). MAIN OUTCOME MEASURE:
      Percentage of homes with any working alarm and percentage in which the alarm
      installed for this study was working after 15 months. RESULTS: 54.4% (1166/2145)
      of all households and 45.9% (465/1012) of households occupied by smokers had a
      working smoke alarm. Ionisation sensor, lithium battery, and there being a smoker
      in the household were independently associated with whether an alarm was working
      (adjusted odds ratios 2.24 (95% confidence interval 1.75 to 2.87), 2.20 (1.77 to
      2.75), and 0.62 (0.52 to 0.74)). The most common reasons for non-function were
      missing battery (19%), missing alarm (17%), and battery disconnected (4%).
      CONCLUSIONS: Nearly half of the alarms installed were not working when tested 15
      months later. Type of alarm and power source are important determinants of
      whether a household had a working alarm.

PMID- 12411357
TI  - Effect of patients' age on management of acute intracranial haematoma:
      prospective national study.
AB  - OBJECTIVE: To determine whether the management of head injuries differs between
      patients aged > or =65 years and those <65. DESIGN: Prospective observational
      national study over four years. SETTING: 25 Scottish hospitals that admit trauma
      patients. PARTICIPANTS: 527 trauma patients with extradural or acute subdural
      haematomas. MAIN OUTCOME MEASURES: Time to cranial computed tomography in the
      first hospital attended, rates of transfer to neurosurgical care, rates of
      neurosurgical intervention, length of time to operation, and mortality in
      inpatients in the three months after admission. RESULTS: Patients aged > or =65
      years had lower survival rates than patients <65 years. Rates were 15/18 (83%) v
      165/167 (99%) for extradural haematoma (P=0.007) and 61/93 (66%) v 229/249 (92%)
      for acute subdural haematoma (P<0.001). Older patients were less likely to be
      transferred to specialist neurosurgical care (10 (56%) v 142 (85%) for extradural
      haematoma (P=0.005) and 56 (60%) v 192 (77%) for subdural haematoma (P=0.004)).
      There was no significant difference between age groups in the incidence of
      neurosurgical interventions in patients who were transferred. Logistic regression
      analysis showed that age had a significant independent effect on transfer and on
      survival. Older patients had higher rates of coexisting medical conditions than
      younger patients, but when severity of injury, initial physiological status at
      presentation, or previous health were controlled for in a log linear analysis,
      transfer rates were still lower in older patients than in younger patients
      (P<0.001). CONCLUSIONS: Compared with those aged under 65 years, people aged 65
      and over have a worse prognosis after head injury complicated by intracranial
      haematoma. The decision to transfer such patients to neurosurgical care seems to
      be biased against older patients.

PMID- 12411359
TI  - Used infant mattresses and sudden infant death syndrome in Scotland: case-control
      study.
AB  - OBJECTIVE: To examine the proposition that a used infant mattress is associated
      with an increased risk of sudden infant death syndrome. DESIGN: Case-control
      study. SETTING: Scotland (population 5.1 million, with about 53 000 births a
      year). PARTICIPANTS: 131 infants who died of sudden infant death syndrome between
      1 January 1996 and 31 May 2000 and 278 age, season, and obstetric unit matched
      control infants. MAIN OUTCOME MEASURES: Routine use of an infant mattress
      previously used by another child and place of last sleep. RESULTS: Routine use of
      an infant mattress previously used by another child was significantly associated
      with an increased risk of sudden infant death syndrome (multivariate odds ratio
      3.07, 95% confidence interval 1.51 to 6.22). Use of a used infant mattress for
      last sleep was also associated with increased risk (6.10, 2.31 to 16.12). The
      association was significantly stronger if the mattress was from another home
      (4.78, 2.08 to 11.0) than if it was from the same home (1.64, 0.64 to 4.2).
      CONCLUSION: A valid significant association exists between use of a used infant
      mattress and an increased risk of sudden infant death syndrome, particularly if
      the mattress is from another home. Insufficient evidence is available to judge
      whether this relation is cause and effect.

PMID- 12411358
TI  - Birth order, gestational age, and risk of delivery related perinatal death in
      twins: retrospective cohort study.
AB  - OBJECTIVE: To determine whether twins born second are at increased risk of
      perinatal death because of complications during labour and delivery. DESIGN:
      Retrospective cohort study. SETTING: Scotland, 1992 and 1997. PARTICIPANTS: All
      twin births at or after 24 weeks' gestation, excluding twin pairs in which either
      twin died before labour or delivery or died during or after labour and delivery
      because of congenital abnormality, non-immune hydrops, or twin to twin
      transfusion syndrome. MAIN OUTCOME MEASURE: Delivery related perinatal deaths
      (deaths during labour or the neonatal period). RESULTS: Overall, delivery related
      perinatal deaths were recorded for 23 first twins only and 23 second twins only
      of 1438 twin pairs born before 36 weeks (preterm) by means other than planned
      caesarean section (P>0.99). No deaths of first twins and nine deaths of second
      twins (P=0.004) were recorded among the 2436 twin pairs born at or after 36 weeks
      (term). Discordance between first and second twins differed significantly in
      preterm and term births (P=0.007). Seven of nine deaths of second twins at term
      were due to anoxia during the birth (2.9 (95% confidence interval 1.2 to 5.9) per
      1000); five of these deaths were associated with mechanical problems with the
      second delivery following vaginal delivery of the first twin. No deaths were
      recorded among 454 second twins delivered at term by planned caesarean section.
      CONCLUSIONS: Second twins born at term are at higher risk than first twins of
      death due to complications of delivery. Previous studies may not have shown an
      increased risk because of inadequate categorisation of deaths, lack of
      statistical power, inappropriate analyses, and pooling of data about preterm
      births and term births.

PMID- 12411360
TI  - Protection from HIV on electives: questionnaire survey of UK medical schools.

PMID- 12411361
TI  - Maternal smoking and risk of hypertrophic infantile pyloric stenosis: 10 year
      population based cohort study.

PMID- 12411362
TI  - Socioeconomic variation in incidence of epilepsy: prospective community based
      study in south east England.
AB  - OBJECTIVE: To determine the incidence of epilepsy in a general practice
      population and its variation with socioeconomic deprivation. DESIGN: Prospective
      surveillance for new cases over an 18 or 24 month period. PARTICIPANTS: All
      patients on practice registers categorised for deprivation with the Carstairs
      score of their postcode. SETTING: 20 general practices in London and south east
      England. MAIN OUTCOME MEASURE: Confirmed diagnosis of epilepsy. RESULTS: 190 new
      cases of epilepsy were identified during 369 283 person years of observation
      (crude incidence 51.5 (95% confidence interval 44.4 to 59.3) per 100 000 per
      year). The incidence was 190 (138 to 262) per 100 000 in children aged 0-4 years,
      30.8 (21.3 to 44.6) in those aged 45-64 years, and 58.7 (42.5 to 81.0) in those
      aged > or =65 years. There was no apparent difference in incidence between males
      and females. The incidence showed a strong association with socioeconomic
      deprivation, the age and sex adjusted incidence in the most deprived fifth of the
      study population being 2.33 (1.46 to 3.72) times that in the least deprived fifth
      (P=0.001 for trend across fifths). Adjustment for area (London v outside London)
      weakened the association with deprivation (rate ratio 1.62 (0.91 to 2.88), P=0.12
      for trend). CONCLUSIONS: The incidence of epilepsy seems to increase with
      socioeconomic deprivation, though the association may be confounded by other
      factors.

PMID- 12411363
TI  - Detection of depression and anxiety in primary care: follow up study.

PMID- 12411364
TI  - Case report of paroxysmal atrial fibrillation and anticoagulation.

PMID- 12411365
TI  - Wound botulism associated with subcutaneous drug use.

PMID- 12411366
TI  - Antithrombotic therapy for atrial fibrillation.

PMID- 12411367
TI  - Lethal injection: a stain on the face of medicine.

PMID- 12411368
TI  - A strategy for tackling health inequalities in the Netherlands.

PMID- 12411369
TI  - Local funding would reduce waiting lists for cataracts.

PMID- 12411370
TI  - Outbreak of legionnaires' disease in the United Kingdom. Vigilance must be
      eternal but balanced.

PMID- 12411371
TI  - Antenatal screening policies for Down's syndrome. Audit of Down's syndrome
      screening is not valid.

PMID- 12411372
TI  - Myopia. Confusing myopia with hypermetropia is dangerous.

PMID- 12411373
TI  - Message about hormone replacement therapy is unclear.

PMID- 12411374
TI  - Authors' refute careless talk about ADP receptor antagonists.

PMID- 12411375
TI  - Prophylaxis for early onset group B streptococcal sepsis is not so effective in
      practice.

PMID- 12411376
TI  - Epidurals and backache: again?

PMID- 12411377
TI  - Antibiotic prophylaxis after CSF leaks lacks evidence base.

PMID- 12411378
TI  - Growth hormone in growth hormone deficiency. Ignore the evidence and keep going
      wrong.

PMID- 12411379
TI  - Local warming does help when inserting cannulas.

PMID- 12411380
TI  - Supportive evidence is lacking for report on animal studies.

PMID- 12411381
TI  - New heart risk equations do not affect existing guidelines.

PMID- 12411382
TI  - Role of emotional capacity in consent should be clarified.

PMID- 12411384
TI  - Gaining further experience and qualifications in teaching.

PMID- 12411385
TI  - The processing cycle.

PMID- 12411388
TI  - Alteration in endothelial estrogen receptor expression: a potential key of
      vasculoprotection by estrogens?

PMID- 12411389
TI  - Development of the coronary vessel system.
AB  - Formation of the coronary vessels is a fundamental event in heart development.
      Congenital abnormalities in the coronary system can have major deleterious
      effects on heart function. It is also possible that subtle variation in the
      patterning of coronary vessels has significant but uncharacterized effects on
      myocardial structure and function. In addition, generation of the coronary
      vascular system represents a complex system for analysis of regulation of cell
      fate determination, cell and epithelial migration, epithelial/mesenchymal
      transition, and patterning of a complex three-dimensional structure. In this
      review, we present the descriptive embryology of this process as well as the
      recent data that shed light on the unique developmental mechanisms underlying
      generation of coronary vessels. This review also attempts to identify areas where
      additional research is needed and highlights the questions that must be answered
      for a meaningful understanding of coronary vessel development.

PMID- 12411390
TI  - Role of integrins in endothelial mechanosensing of shear stress.
AB  - The focal pattern of atherosclerotic lesions in arterial vessels suggests that
      local blood flow patterns are important factors in atherosclerosis. Although
      disturbed flows in the branches and curved regions are proatherogenic, laminar
      flows in the straight parts are atheroprotective. Results from in vitro studies
      on cultured vascular endothelial cells with the use of flow channels suggest that
      integrins and the associated RhoA small GTPase play important roles in the
      mechanotransduction mechanism by which shear stress is converted to cascades of
      molecular signaling to modulate gene expression. By interacting dynamically with
      extracellular matrix proteins, the mechanosensitive integrins activate RhoA and
      many signaling molecules in the focal adhesions and cytoplasm. Through such
      mechanotransduction mechanisms, laminar shear stress upregulates genes involved
      in antiapoptosis, cell cycle arrest, morphological remodeling, and NO production,
      thus contributing to the atheroprotective effects. This review summarizes some of
      the recent findings relevant to these mechanotransduction mechanisms. These
      studies show that integrins play an important role in mechanosensing in addition
      to their involvement in cell attachment and migration.

PMID- 12411391
TI  - Involvement of extracellular signal-regulated kinases 1/2 in cardiac hypertrophy
      and cell death.
AB  - In response to pathophysiological stress, the adult heart undergoes hypertrophic
      enlargement characterized by an increase in the cross-sectional area of
      individual myofibers. Although cardiac hypertrophy is initially a compensatory
      response, sustained hypertrophy is a leading predictor for the development of
      heart failure. At the molecular level, disease-related stimuli invoke endocrine,
      paracrine, and autocrine regulatory circuits, which directly influence
      cardiomyocyte hypertrophy, in part, through membrane bound G protein-coupled
      receptors and receptor tyrosine kinases. These membrane receptors activate
      intermediate signal transduction pathways within the cytoplasm such as mitogen
      activated protein kinases (MAPKs), protein kinase C (PKC), and calcineurin, which
      directly modify transcriptional regulatory factors promoting alterations in
      cardiac gene expression. This review will weigh an increasing body of literature
      implicating the intermediate signaling pathway consisting of MEK1 and
      extracellular signal-regulated kinases (ERK1/2) as important regulators of
      cardiac hypertrophy and myocyte survival. The MEK1-ERK1/2 pathway likely occupies
      a central regulatory position in the signaling hierarchy of a cardiac myocyte
      given its unique ability to respond to virtually every characterized hypertrophic
      agonist and stress stimuli examined to date and based on its ability to promote
      myocyte growth in vitro and in vivo.

PMID- 12411392
TI  - Inhibition of hypoxia-induced apoptosis by modulation of retinoblastoma protein
      dependent signaling in cardiomyocytes.
AB  - Apoptotic cell death is an important mode of cell loss contributing to heart
      dysfunction. To analyze the importance of the E2F-dependent regulation of gene
      transcription in cardiomyocyte apoptosis, the function of cell cycle factors
      impinging on the retinoblastoma protein (pRb)/E2F pathway was investigated. In
      isolated neonatal ventricular myocytes, apoptotic cell death induced by hypoxia
      (deferoxamine, 100 micro mol/L) specifically activated cyclin-dependent kinases
      (cdks) 2 and 3. Apoptotic cell death was inhibited by ectopic expression of cdk
      inhibitors p21(CIP) and p27(KIP1) but not p16(INK4). In addition, apoptosis was
      also abrogated by forced expression of kinase dead mutant proteins of cdk2/3 but
      not of cdk4/6. Introduction of cdk inhibitors or dominant-negative cdk2/3 blocked
      pRb hyperphosphorylation and abrogated E2F-dependent gene transcription,
      including that of the E2F-responsive genes of proapoptotic caspase 3 and caspase
      7. Moreover, introduction of constitutively active pRb and transcriptionally
      inert mutant E2F1/DP1 efficiently protected cardiomyocytes from apoptosis. In
      conclusion, these data demonstrate that cdk-specific inactivation of pRb and the
      subsequent activation of E2F-dependent gene transcription are required for
      cardiomyocyte apoptosis.

PMID- 12411393
TI  - Comparison of ion-channel subunit expression in canine cardiac Purkinje fibers
      and ventricular muscle.
AB  - Although Purkinje fibers (PFs) play an important role in cardiac
      electrophysiology, almost nothing is known about the expression of ion-channel
      subunits in PFs. We applied competitive reverse transcription-polymerase chain
      reaction, Western blotting, and immunocytochemistry to compare the expression of
      ion-channel subunit mRNA and protein in canine PFs versus ventricular muscle
      (VM). For transient outward current-related subunits, Kv4.2 was not detected, and
      Kv1.4 expression was extremely low. Kv4.3 expression was of the same order for VM
      and PFs. The tetraethylammonium chloride-sensitive subunit Kv3.4 was expressed
      much more strongly in PFs than in VM, and Kv channel-interacting protein
      transcript expression was 25-fold stronger in VM than in PFs. For delayed
      rectifiers, ERG and KvLQT1 expression was lower in PFs at both mRNA and protein
      levels. Although minK transcripts were more numerous in PFs, minK protein was
      significantly more strongly expressed in VM. L-type Ca2+ current alpha-subunit
      (Ca(V)1.2) and Na+-Ca2+ exchanger proteins were more strongly expressed in VM
      than in PFs. For T-type Ca2+ current, Ca(V)3.1, Ca(V)3.2, and Ca(V)3.3
      transcripts were all more strongly expressed in PFs. For the nonselective cation
      current, hyperpolarization-activated cation channel 1 (HCN1) expression was
      subquantifiable, HCN2 transcript expression was comparable in PFs and VM, and
      HCN4 mRNA expression was strong in PFs but below the detection threshold in VM.
      HCN2 and HCN4 protein expression was much stronger in PFs than in VM. We conclude
      that ion-channel subunit expression in PFs differs from that in VM in ways that
      are consistent with, and shed light on the molecular basis of, well-recognized
      fundamental PF ionic properties.

PMID- 12411394
TI  - Rac-dependent monocyte chemoattractant protein-1 production is induced by
      nutrient deprivation.
AB  - Under ischemic conditions, the vessel wall recruits inflammatory cells. Human
      aortic endothelial cells (HAECs) exposed to hypoxia followed by reoxygenation
      produce monocyte chemoattractant protein-1 (MCP-1); however, most experiments
      have been performed in the presence of nutrient deprivation (ND). We hypothesized
      that ND rather than hypoxia mediates endothelial MCP-1 production during
      ischemia, and that the small GTP-binding protein Rac1 and reactive oxygen species
      (ROS) are involved in this process. ND was generated by shifting HAECs from 10%
      to 1% FBS. Superoxide production by HAECs was increased 6 to 24 hours after ND,
      peaking at 18 hours. MCP-1 production was increased over a similar time frame,
      but peaked later at 24 hours. These effects were blocked by treatment with
      antioxidants such as superoxide dismutase mimetic and N-acetylcysteine (NAC), or
      NADPH oxidase inhibitors, DPI and gp91ds-tat. Superoxide and MCP-1 production
      were enhanced by RacV12 (constitutively active) in the absence of ND, and were
      inhibited by RacN17 (dominant-negative) adenoviral transduction under ND,
      suggesting that the small G-protein Rac1 is required. In conclusion, ND, an
      important component of ischemia, is sufficient to induce MCP-1 production by
      HAECs, and such production requires a functional Rac1, redox-dependent pathway.

PMID- 12411395
TI  - Smad2 mediates transforming growth factor-beta induction of endothelial nitric
      oxide synthase expression.
AB  - Transforming growth factor-beta (TGF-beta) increases expression of endothelial
      nitric oxide synthase (eNOS), although the precise mechanism by which it does so
      is unclear. We report that Smad2, a transcription factor activated by TGF-beta,
      mediates TGF-beta induction of eNOS in endothelial cells. TGF-beta induces Smad2
      translocation from cytoplasm to nucleus, where it directly interacts with a
      specific region of the eNOS promoter. Overexpression of Smad2 increases basal
      levels of eNOS, and further increases TGF-beta stimulation of eNOS expression.
      Ectopic expression of Smurf, an antagonizer of Smad2, decreases Smad2 expression
      and blocks TGF-beta induction of eNOS. Because Smad2 can interact with a variety
      of transcription factors, coactivators, and corepressors, Smad2 may thus act as
      an integrator of multiple signals in the regulation of eNOS expression.

PMID- 12411396
TI  - Estrogen causes dynamic alterations in endothelial estrogen receptor expression.
AB  - Estrogen receptor (ER)alpha mediates many of the effects of estrogen on the
      vascular endothelium. The purpose of the present study was to determine whether
      estrogen modifies endothelial ERalpha expression. In experiments in cultured
      ovine endothelial cells, physiological concentrations of 17beta-estradiol (E2,
      10(-10) to 10(-8) mol/L) caused an increase in ERalpha protein abundance that was
      evident after 6 hours of hormone exposure. Shorter (2-hour) E2 treatment caused
      ERalpha downregulation. In contrast to the upregulation in ERalpha after long
      term E2, the expression of the other ER isoform, ERbeta, was downregulated. Both
      nonselective ER antagonism with ICI 182,780 and the inhibition of gene
      transcription with actinomycin D blocked the increase in ERalpha with E2. In
      studies using the human ERalpha gene promoter P-1 coupled to luciferase, an
      increase in ERalpha gene transcription was evident in endothelial cells within 4
      hours of E2 exposure. The transcriptional activation was fully blocked by ICI
      182,780, whereas the specific ERbeta antagonist RR-tetrahydrochrysene yielded
      partial blockade. Overexpression of ERalpha or ERbeta caused comparable 10- and 8
      fold increases, respectively, in ERalpha promoter activation by E2. Thus, long
      term exposure to E2 upregulates ERalpha expression in endothelial cells through
      the actions of either ERalpha or ERbeta on ERalpha gene transcription; in
      contrast, E2 causes ERbeta downregulation in the endothelium. We postulate that
      E2-induced changes in ERalpha and ERbeta expression modify the effects of the
      hormone on vascular endothelium.

PMID- 12411397
TI  - Ras/Erk signaling is essential for activation of protein synthesis by Gq protein
      coupled receptor agonists in adult cardiomyocytes.
AB  - The Gq protein-coupled receptor agonists phenylephrine (PE) and endothelin-1 (ET
      1) induce cardiac hypertrophy and stimulate protein synthesis in cardiomyocytes.
      This study aims to investigate how they activate mRNA translation in adult
      cardiomyocytes. PE and ET-1 do not activate protein kinase B but stimulate Ras
      and Erk, and their ability to activate protein synthesis was blocked by
      inhibition of Ras or MEK and by rapamycin, which inhibits mTOR (mammalian target
      of rapamycin). These agonists activated ribosomal protein S6 kinase 1 (S6K1) and
      induced phosphorylation of eIF4E-binding protein-1 (4E-BP1) and its release from
      eIF4E. These effects were blocked by inhibitors of MEK. Furthermore, adenovirus
      mediated expression of constitutively-active MEK1 caused activation of S6K1,
      phosphorylation of 4E-BP1, and activation of protein synthesis in a rapamycin
      sensitive manner. Expression of N17Ras inhibited the regulation of S6K1 and
      protein synthesis by GqPCR agonists. These data point to a signaling pathway
      involving Ras and MEK that acts, with mTOR, to control regulatory translation
      factors and activate protein synthesis. This study provides new insights into the
      mechanisms underlying the stimulation of protein synthesis by hypertrophic agents
      in heart.

PMID- 12411398
TI  - Hydralazine reduces the quantal size of secretory events by displacement of
      catecholamines from adrenomedullary chromaffin secretory vesicles.
AB  - The effects of the antihypertensive agent hydralazine (1 to 100 nmol/L) on the
      exocytotic process of single adrenal chromaffin cells have been studied using
      amperometry. Hydralazine does not reduce the frequency of exocytotic spikes but
      rapidly slows the rate of catecholamine release from individual exocytotic events
      by reducing the quantal size of catecholamine exocytosis. Confocal and standard
      epifluorescence microscopy studies show that hydralazine rapidly accumulates
      within secretory vesicles. The blockade of the vesicular H+ pump with bafilomycin
      A1 inhibits hydralazine uptake. Experiments with permeabilized cells show that
      hydralazine displaces catecholamines from secretory vesicles. The drug also
      displaces vesicular Ca2+, as shown by fura-2 microfluorimetry. These data suggest
      that hydralazine acts, at least partially, by interfering with the storage of
      catecholamines. These effects of hydralazine occurred within seconds, and at the
      tissue concentrations presumably reached in antihypertensive therapy; these
      concentrations are a thousand times lower than those described for relaxing
      vascular tissues in vitro. We proposed that these novel effects could explain
      many of the therapeutic and side effects of this drug that are likely exerted in
      sympathetic nerve terminals.

PMID- 12411399
TI  - Inhibitors of histone deacetylation downregulate the expression of endothelial
      nitric oxide synthase and compromise endothelial cell function in vasorelaxation
      and angiogenesis.
AB  - The histone deacetylase (HDAC) inhibitor trichostatin A (TSA) inhibits hypoxia
      stimulated angiogenesis. Endothelial nitric oxide synthase (eNOS)-derived NO is
      central to angiogenesis signaling in endothelial cells (ECs). We hypothesized
      that the HDAC-dependent regulation of angiogenesis may involve a modulatory
      effect on eNOS expression. The HDAC inhibitors TSA, butyric acid (BuA), and MS
      275 time- and concentration-dependently suppressed eNOS protein levels to 41+/
      2%, 46+/-12%, and 40+/-12% of control, respectively. In parallel, TSA and BuA
      also downregulated eNOS mRNA expression to 21+/-4% and 37+/-4% of control. TSA
      also attenuated the NO-dependent relaxation of porcine coronary arteries
      (P<0.0001, TSA 1 micromol/L) and prevented tube formation in a human angiogenesis
      assay. Although vascular endothelial growth factor substitution did not
      compensate for the inhibitory effect of TSA, exogenous NO reversed the inhibition
      of angiogenesis by TSA. To address the underlying signaling mechanism, we
      characterized the effect of TSA on eNOS gene transcription and mRNA half-life.
      Although TSA decreased both eNOS protein and mRNA levels, TSA paradoxically
      enhanced the activity of the eNOS promoter, and did not alter the eNOS
      transcription rate in nuclear run-on experiments, suggesting that TSA
      posttranscriptionally targets eNOS mRNA. These data indicate that HDAC-dependent
      mechanisms contribute to the regulation of eNOS expression in ECs.

PMID- 12411400
TI  - Matrix metalloproteinase-9 is necessary for the regulation of smooth muscle cell
      replication and migration after arterial injury.
AB  - Matrix metalloproteinases (MMPs) and, in particular, MMP-9 are important for
      smooth muscle cell (SMC) migration into the intima. In this study, we sought to
      determine whether MMP-9 is critical for SMC migration and for the formation of a
      neointima by using mice in which the gene was deleted (MMP-9(-/-) mice). A
      denuding injury to the arteries of wild-type mice promoted the migration of
      medial SMCs into the neointima at 6 days, and a large neointimal lesion was
      observed after 28 days. In wild-type arteries, medial SMC replication was
      approximately 8% at day 4, 6% at day 6, and 4% at day 8 and had further decreased
      to 1% at day 14. Intimal cell replication was 65% at 8 days and had decreased to
      approximately 10% at 14 days after injury. In MMP-9(-/-) arteries, SMC
      replication was significantly lower at day 8. In addition, SMC migration and
      arterial lesion growth were significantly impaired in MMP-9(-/-) arteries. SMCs,
      isolated from MMP-9(-/-) mouse arteries, showed an impairment of migration and
      replication in vitro. Thus, our present data indicate that MMP-9 is critical for
      the development of arterial lesions by regulating both SMC migration and
      proliferation.

PMID- 12411401
TI  - Targeted disruption of the matrix metalloproteinase-9 gene impairs smooth muscle
      cell migration and geometrical arterial remodeling.
AB  - Matrix remodeling plays an important role in the physiological and pathological
      remodeling of blood vessels. We specifically investigated the role of matrix
      metalloproteinase (MMP)-9, an MMP induced during arterial remodeling, by
      assessing the effects of genetic MMP-9 deficiency on major parameters of arterial
      remodeling using the mouse carotid artery flow cessation model. Compared with
      remodeling of matched wild-type (WT) arteries, MMP-9 deficiency decreased intimal
      hyperplasia, reduced the late lumen loss, eliminated the correlation between
      intimal hyperplasia and geometric remodeling, and led to significant accumulation
      of interstitial collagen. Biochemical analysis of MMP-9 knockout (KO) arterial
      tissue and isolated smooth muscle cells (SMCs) confirmed the lack of MMP-9
      expression or compensation by other gelatinases. To investigate potential
      mechanisms for the in vivo observations, we analyzed in vitro effects of MMP-9
      deficiency on the migration, proliferation, and collagen gel contracting capacity
      of aortic SMCs isolated from MMP-9 KO and WT mice. Although proliferation was
      comparable, we found that MMP-9-deficient cells had not only decreased migratory
      activity, but they also had decreased capacity to contract collagen compared with
      WT cells. Thus, MMP-9 appears to be involved not only in degradation, but also in
      reorganization of a collagenous matrix, both facets being essential for the
      outcome of arterial remodeling. Our results also establish MMP-9 as an attractive
      therapeutic target for limiting the effects of pathological arterial remodeling
      in restenosis and atherosclerosis.

PMID- 12411403
TI  - Effects of pharmacological preconditioning with U50488H on calcium homeostasis in
      rat ventricular myocytes subjected to metabolic inhibition and anoxia.
AB  - 1. The effects of pharmacological preconditioning with U50488H (U(50)), a
      selective kappa-opioid receptor agonist, on Ca(2+) homeostasis in rat ventricular
      myocytes subjected for 9 min to metabolic inhibition (MI) and anoxia (A),
      consequences of ischaemia, were studied and compared with those of
      preconditioning with brief periods of MI/A. 2. Precondition with 30 micro M of
      U(50) for three cycles of 1 min each cycle separated by 3 min of recovery (UP)
      significantly increased the percentage of non-blue cells following MI/A. The
      effect of UP is the same as that of preconditioning with an inhibitor of
      glycolysis and an oxygen scavenger for three 1-min cycles separated by three
      minute recovery (MI/AP). The results indicate that like MI/AP, UP also confers
      cardioprotection. 3. MI/A increased intracellular Ca(2+) ([Ca(2+)](i)) and
      reduced the amplitude of caffeine-induced [Ca(2+)](i) transients, an indication
      of Ca(2+) content in the sarcoplasmic reticulum (SR). MI/A also reduced the
      electrically-induced [Ca(2+)](i) transient, that indicates Ca(2+)-release during
      excitation-contraction coupling, and Ca(2+) sparks in unstimulated myocytes, that
      indicates spontaneous Ca(2+)-release from SR. It also prolonged the decline of
      the electrically-induced [Ca(2+)](i) transient and slowed down the recovery of
      the electrically-induced [Ca(2+)](i) transient after administration of caffeine.
      In addition, MI/A prolonged the decline of caffeine induced [Ca(2+)](i)
      transient, an indication of Na(+)-Ca(2+) exchange activity, and UP prevented it.
      So UP, that confers cardioprotection, prevented the changes induced by MI/A. With
      the exception of Ca(2+)-spark, which was not studied, the effects of MI/AP are
      the same as those of UP. 4. It is concluded that pharmacological preconditioning
      with U(50), that confers immediate cardioprotection, prevents changes of Ca(2+)
      homeostasis altered by MI/A in the rat heart. This may be responsible, at least
      partly, for the cardioprotective action. 5. The study also provided evidence that
      MI/A causes mobilization of Ca(2+) from SR to cytoplasm causing Ca(2+)-overload
      which may be due to reduced Ca(2+)-uptake by SR. MI/A also reduces spontaneous
      and electrically induced Ca(2+) release from SR.

PMID- 12411402
TI  - Contractile responses to adenosine, R-PIA and ovalbumen in passively sensitized
      guinea-pig isolated airways.
AB  - 1. Responses to adenosine, R-PIA and ovalbumen were examined in guinea-pig
      isolated superfused tracheal spirals to determine the effects of passive
      sensitization by overnight incubation in serum from ovalbumen (OA)-sensitized or
      non-sensitized guinea-pigs. 2. Tissues incubated with serum from non-sensitized
      and OA-sensitized guinea-pigs contracted (0.07+/-0.02 and 0.04+/-0.01 g,
      respectively) to adenosine (300 micro M) whereas non-incubated or Krebs-incubated
      tissues produced no contractions to adenosine or ovalbumen (10 micro g).
      Ovalbumen caused substantial contractions (0.40+/-0.09 g) after OA-sensitized
      serum incubation and significantly (P<0.05) smaller contractions (0.08+/-0.03 g)
      after non-sensitized serum incubation. Tracheae from guinea-pigs actively
      sensitized to ovalbumen 14-21 days beforehand also contracted to adenosine, R-PIA
      (3 micro M) and ovalbumen. 3. The A(1)/A(2) adenosine receptor antagonist, 8
      phenyltheophylline (8-PT, 3 micro M), failed to antagonize these contractions,
      suggesting that A(1)/A(2) adenosine receptors were not involved. 4. Unlike
      adenosine, R-PIA (3 micro M) produced contractions in non-incubated (0.23+/-0.04
      g) or Krebs-incubated (0.15+/-0.04 g) tracheae, as well as after passive and
      active sensitization. None of these responses were blocked by 8-PT. 5. The A(3)
      receptor agonist, IB-MECA, in the presence of 8-PT produced small contractions in
      passively sensitized tracheae (10 micro M, 0.02+/-0.003 g) and, in larger doses
      (100 micro M and 1 mM), contracted actively sensitized tracheae. 6. In actively
      sensitized trachea, the A(3) receptor antagonist, MRS-1220 (100 nM),
      significantly (P<0.05) attenuated adenosine contractions in the presence of 8-PT
      from 0.23+/-0.07 g to 0.07+/-0.03 g. 7. These results show that passive, like
      active sensitization, reveals bronchoconstrictions to adenosine of isolated
      tracheae. The insensitivity to 8-PT blockade, the antagonism by MRS-1220, and the
      fact that the A(3) receptor agonist, IB-MECA, mimics this response, suggest
      involvement of A(3) receptors. R-PIA, however, has a different profile of
      adenosine receptor activity.

PMID- 12411404
TI  - A novel phenoxazine derivative suppresses surface IgM expression in DT40 B cell
      line.
AB  - 1. 2-amino-4, 4alpha-dihydro-4alpha, 7-dimethyl-3H-phenoxazine-3-one (Phx) has
      been demonstrated to be an actinomycin D-like phenoxazine, and to display anti
      tumour activity. 2. In this study, we report on the effect of Phx on B cell
      antigen receptor (BCR) and receptor-mediated signalling in DT40 B cells. 3.
      Treatment of B cells with Phx for 12 h inhibited BCR-stimulated tyrosine
      phosphorylation of cellular proteins. 4. B cells exposed to Phx exhibited down
      regulation of surface IgM which is part of BCR. In contracts with actinomycin D,
      Phx rapidly reduced the expression of IgM without decreasing the expression of
      other signalling molecules. 5. Analysis with confocal microscopy demonstrated
      that Phx treatment reduced IgM expression both at the cell surface and inside the
      cell. 6. Treatment of B cells with Phx resulted in the reduction of IgM
      secretion. Since MG-132, a proteasomal inhibitor, restored IgM contents to the
      control levels, Phx has the specific effect of accelerating IgM degradation. 7.
      These results suggest that Phx down-regulates the expression of IgM and inhibits
      BCR-mediated signalling and IgM secretion. Phx may be useful as an
      immunosuppressive agent for therapeutic purposes.

PMID- 12411405
TI  - Differential effects of organic calcium-channel blockers on diastolic SR calcium
      handling in the frog heart.
AB  - 1. Gradual loss of sarcoplasmic reticular (SR) calcium during a rest-period is
      responsible for the rest-induced decay (RID) of force in mammalian myocardium.
      Effect of verapamil and diltiazem on a similar RID in the frog myocardium
      suggests a new mechanism of action of these drugs. 2. Strips of frog-ventricle
      were paced at 0.2 Hz and the rhythm was interrupted by varying rest-periods
      ranging from 10 to 180 s. In control conditions, the amplitude of the post-rest
      beat was significantly lower than that of the pre-rest beat for rest-periods more
      than 40 s (RID). 3. Verapamil and diltiazem (which are organic calcium-channel
      blockers (OCCB)) changed the pattern of RID in the control solution to a 'rest
      induced potentiation' (RIP) in the same preparation while another OCCB nifedipine
      and the inorganic calcium-channel blocker cadmium did not alter the post-rest
      phenomenon. 4. We propose that verapamil and diltiazem produce an RIP due to
      either blockade of SR calcium-leak during rest or enhancement of SR calcium
      uptake during rest.

PMID- 12411406
TI  - Inhibitors of poly(ADP-ribose) polymerase-1 suppress transcriptional activation
      in lymphocytes and ameliorate autoimmune encephalomyelitis in rats.
AB  - 1. In the presence of genotoxic stress poly(ADP-ribose) polymerase-1 (PARP-1)
      leads to NAD(+) and ATP depletion, participating in the pathogenesis of several
      disorders including inflammation. Accordingly, chemical inhibitors of PARP-1 are
      efficacious anti-inflammatories, albeit the underlying molecular mechanisms are
      still under debate. 2. This study investigated the effect of the PARP-1
      inhibitors 6(5H)-phenanthridinone and benzamide as well as that of benzoic acid,
      an inactive analogue of benzamide, on development of experimental allergic
      encephalomyelitis (EAE) in rats. Both 6(5H)-phenanthridinone and benzamide
      attenuated development of EAE, reducing clinical score, neuroimmune infiltration
      and expression of inflammatory mediators such as inducible nitric oxide synthase,
      interleukin-1beta and -2, cyclooxygenase-2, tumour necrosis factor-alpha and
      interferon-gamma in the spinal cord of myelin-immunized rats. Importantly, no
      evidence of NAD(+) and ATP depletion as well as poly(ADP-ribose) formation was
      detected in the spinal cord. 3. By contrast, a robust formation of poly(ADP
      ribose) occurred in B- and T-cell areas in lymph nodes of myelin-immunized rats
      and was suppressed by the treatment with 6(5H)-phenanthridinone and benzamide. In
      cultures of activated rat lymphocytes, 6(5H)-phenanthridinone and benzamide
      reduced the DNA-binding activity of NF-kappaB and AP-1 and transcription of pro
      inflammatory cytokines such as interleukin-2, interferon-gamma and tumour
      necrosis factor-alpha. 4. Notably, benzoic acid did not reproduce the in vivo and
      in vitro effects of its parent compound. 5. These findings indicate that PARP-1
      promotes transcriptional activation in lymphocytes and inhibitors of its
      enzymatic activity are useful for the treatment of autoimmune disorders of the
      central nervous system.

PMID- 12411407
TI  - Cyclosporine A regulate oxidative stress-induced apoptosis in cardiomyocytes:
      mechanisms via ROS generation, iNOS and Hsp70.
AB  - 1. Previous study suggested that cyclosporine A (CsA) could partially reduce
      ischaemia/reperfusion-induced injury in isolated heart, but the mechanism was
      still unclear. In this study, the possible mechanisms of cyclosporine A in
      regulating oxidative stress-induced cardiomyocyte apoptosis were examined. 2.
      Morphological (cell shrinkage, apoptotic body formation, and DNA fragmentation)
      and biochemical (annexin-V staining for exposed phosphatidylserine residues)
      evidences showed that both hydrogen peroxide (H(2)O(2)) and hypoxia/reoxygenation
      could induce apoptotic change in the embryonal rat heart myoblast-derived cells
      (H9c2). These effects were inhibited by pre-treatment with CsA at concentration
      of 0.01-1.0 micro M for 24 h, but were increased with 10.0 micro M CsA. 3. While
      examining the mechanisms of CsA in protecting cardiomyocyte apoptosis, we found
      that the collapse of mitochondria membrane potential (DeltaPsim) induced by
      oxidative stress was partially reversed by CsA (0.01-1.0 micro M). 4. Compared to
      the control, CSA at the concentration of 0.1 and 10.0 micro M significantly
      increased the level of intracellular reactive oxygen species (ROS) to 117.2+/
      12.4% and 234.4+/-9.3%, respectively. Co-incubating with the antioxidant,
      ascorbic acid (10.0 micro M), could partially reduce the protective effect of CsA
      (0.01-1.0 micro M) and the toxic effect of 10.0 micro M CsA. 5. Pre-treatment
      with CsA at concentration of 0.01-1.0 micro M for 24 h produced up-regulation of
      heat shock protein 70 (Hsp 70), inducible nitric oxide synthase (iNOS) and also
      induced NO production, indicating that these factors might be associated with the
      cell protective effects of CsA. 6. These results suggest that CsA could protect
      the oxidative stress-induced cardiomyocyte apoptosis not only by preventing the
      loss of DeltaPsim in mitochondria, but also through ROS generation, Hsp70, and
      iNOS up-regulation.

PMID- 12411409
TI  - Gingerols: a novel class of vanilloid receptor (VR1) agonists.
AB  - 1. Gingerols, the pungent constituents of ginger, were synthesized and assessed
      as agonists of the capsaicin-activated VR1 (vanilloid) receptor. 2. [6]-Gingerol
      and [8]-gingerol evoked capsaicin-like intracellular Ca(2+) transients and ion
      currents in cultured DRG neurones. These effects of gingerols were blocked by
      capsazepine, the VR1 receptor antagonist. 3. The potency of gingerols increased
      with increasing size of the side chain and with the overall hydrophobicity in the
      series. 4. We conclude that gingerols represent a novel class of naturally
      occurring VR1 receptor agonists that may contribute to the medicinal properties
      of ginger, which have been known for centuries. The gingerol structure may be
      used as a template for the development of drugs acting as moderately potent
      activators of the VR1 receptor.

PMID- 12411408
TI  - Zebrafish M2 muscarinic acetylcholine receptor: cloning, pharmacological
      characterization, expression patterns and roles in embryonic bradycardia.
AB  - 1. A zebrafish M2 muscarinic acetylcholine receptor (mAChR) gene was cloned. It
      encodes 495 amino acids in a single exon. The derived amino acid sequence is
      73.5% identical to its human homologue. 2. Competitive binding studies of the
      zebrafish M2 receptor and [(3)H]-NMS gave negative log dissociation constants
      (pK(i)) for each antagonist as follows: atropine (9.16)>himbacine (8.05)>/=4-DAMP
      (7.83)>AF-DX 116 (7.26)>/=pirenzepine (7.18)>/=tropicamide (6.97)>/=methoctramine
      (6.82)>/=p-F-HHSiD (6.67)>carbachol (5.20). The antagonist affinity profile
      correlated with the profile of the human M2 receptor, except for pirenzepine. 3.
      Reverse transcription polymerase chain reaction and Southern blotting analysis
      demonstrated that the M2 mAChR mRNA levels increased during the segmentation
      period (12 h post-fertilization; h.p.f.) in zebrafish. By whole-mount in situ
      hybridization, the M2 mAChR was first detectable in the heart, vagus motor
      ganglion, and vagus sensory ganglion at 30, 48 and 60 h.p.f., respectively. 4.
      The muscarinic receptor that mediates carbachol (CCh)-induced bradycardia was
      functionally mature at 72 h.p.f. The effect of CCh-induced bradycardia was
      antagonized by several muscarinic receptor antagonists with the order of potency
      (pIC(50) values): atropine (6.76)>methoctramine (6.47)>himbacine (6.10)>4-DAMP
      (5.72)>AF-DX 116 (4.77), however, not by pirenzepine, p-F-HHSiD, or tropicamide
      (<10 micro M). 5. The effect of CCh-induced bradycardia was abolished completely
      before 56 h.p.f. by M2 RNA interference, and the bradycardia effect gradually
      recovered after 72 h.p.f. The basal heart rate was increased in embryos injected
      with M2 mAChR morpholino antisense oligonucleotide (M2 MO) and the effect of CCh
      induced bradycardia was abolished by M2 MO in a dose-dependent manner. In
      conclusion, the results suggest that the M2 mAChR inhibit basal heart rate in
      zebrafish embryo and the M2 mAChR mediates the CCh-induced bradycardia.

PMID- 12411410
TI  - Leptin potentiates IFN-gamma-induced expression of nitric oxide synthase and
      cyclo-oxygenase-2 in murine macrophage J774A.1.
AB  - 1. Leptin, a pleiotropic hormone believed to regulate body weight, has recently
      been associated with inflammatory states and immune activity. Here we have
      studied the effect of leptin on expression of IFN-gamma-induced nitric oxide
      synthase (iNOS) and cyclo-oxygenase-2 (COX-2), both prominent markers of
      macrophage activation, using the murine macrophage J774A.1 cell line. 2. After 24
      h of incubation, leptin (1-10 micro g ml(-1)) potently synergized with IFN-gamma
      (100 U ml(-1)) in nitric oxide (NO) release, evaluated as nitrite and nitrate
      (NO(x)), and prostaglandin E(2) (PGE(2)) production in culture medium. 3. The
      observed increase of NO and PGE(2) was related to enhanced expression of the
      respective inducible enzyme isoforms, measured in mRNA and protein by RT-PCR and
      Western blot analysis, respectively. 4. When cells were stimulated only with
      leptin, a weak induction of NO and PGE(2) release and of the expression of
      related inducible enzymes was observed. 5. Moreover IFN-gamma increased the
      expression of the functional form of leptin receptor (Ob-Rb) and this effect was
      potentiated by leptin in a concentration-dependent manner. 6. These data suggest
      that macrophages, among the peripheral immune cells, represent a target for
      leptin and confirm the relevance of this hormone in the pathophysiology of
      inflammation.

PMID- 12411411
TI  - Involvement of T-type calcium channels in excitatory junction potentials in rat
      resistance mesenteric arteries.
AB  - 1. We investigated the role of voltage-operated calcium channels in sympathetic
      transmission and depolarization-induced contractions in the rat mesenteric
      artery. In particular, we investigated the role of the T-type voltage-operated
      calcium channels (T-channels) in mediating excitatory junction potentials (EJPs).
      2. EJPs were evoked by electrical field stimulation (trains of five stimuli at
      0.9 Hz) in small mesenteric arteries. The average resting membrane potential was 
      59.8+/-0.5 mV (n=65). Trains of stimuli evoked individual EJPs with the peak EJP
      of 6+/-0.2 mV (n=34) occurring with the second stimulus. Trains of EJPs were
      inhibited 90% by tetrodotoxin (0.1 micro M) or by omega-conotoxin GVIA (GVIA, 10
      nM) indicating their neural origin. 3. The EJPs were not inhibited by the L-type
      calcium channel blocker nicardipine at 0.1 micro M, a concentration sufficient to
      abolish the contraction to potassium depolarization. However, mibefradil (3 micro
      M), considered a relatively selective T-channel antagonist, inhibited the EJPs by
      about 50%. This concentration of mibefradil did not inhibit GVIA-sensitive
      electrically-evoked twitches of the rat vas deferens. Thus the action of
      mibefradil in reducing EJPs is unlikely to be due to either inhibition of L- or N
      type channels but is probably due to inhibition of T-channels. 4. The finding
      that Ni(2+) (300 micro M), an inhibitor of T-type calcium channels, also reduced
      EJP amplitude by about 80% but did not block electrically-evoked twitches in the
      rat vas deferens, further supports an important role of T-channels in mediating
      small depolarizations associated with the EJPs evoked by sympathetic nerve
      stimulation.

PMID- 12411412
TI  - Impact of ageing on the antinociceptive effect of reference analgesics in the
      Lou/c rat.
AB  - 1. Research on the evolution of experimental pain perception and on the
      achievement of analgesia with ageing has led so far to contradictory results. 2.
      This study investigated in the rat the impact of ageing on the antinociceptive
      effect of reference analgesics, acetaminophen (50, 100, 200, 400 mg kg(-1) po),
      aspirin (50, 100, 200, 400 mg kg(-1) sc), clomipramine (5, 10, 20, 40 mg kg(-1)
      sc) and morphine (1.25, 2.5, 5, 10 mg kg(-1) sc). 3. Lou/c rats were chosen
      because they provide a model of healthy ageing and they do not develop obesity
      with age. Three groups of 40 rats each (mature (4 months), middle-aged (18
      months) and old (26 months)), were treated with each drug at 14 days interval.
      Two tests were used: a thermal test (tail immersion in 48 degrees C water and
      measurement of reaction latency) and a mechanical test (paw pressure and
      measurement of struggle threshold). 4. Results confirm the increased mechanical
      sensitivity to pain and no change in thermal sensitivity for old rats compared to
      mature and middle-aged animals. They show a marked decrease in the effect of
      morphine with age and no age-related effect for acetaminophen, aspirin or
      clomipramine. Plasma levels of morphine and metabolites are not different in the
      three age groups. 5. It is likely that the influence of age on morphine analgesia
      is linked mainly to pharmacodynamic rather than pharmacokinetic changes.

PMID- 12411413
TI  - Nitric oxide inhibits capacitative Ca2+ entry by suppression of mitochondrial
      Ca2+ handling.
AB  - 1. Nitric oxide (NO) is a key modulator of cellular Ca(2+) signalling and a
      determinant of mitochondrial function. Here, we demonstrate that NO governs
      capacitative Ca(2+) entry (CCE) into HEK293 cells by impairment of mitochondrial
      Ca(2+) handling. 2. Authentic NO as well as the NO donors 1-[2
      (carboxylato)pyrrolidin-1-yl]diazem-1-ium-1,2-diolate (ProliNO) and 2-(N,N
      diethylamino)-diazenolate-2-oxide (DEANO) suppressed CCE activated by
      thapsigargin (TG)-induced store depletion. Threshold concentrations for
      inhibition of CCE by ProliNO and DEANO were 0.3 and 1 micro M, respectively. 3.
      NO-induced inhibition of CCE was not mimicked by peroxynitrite (100 micro M), the
      peroxynitrite donor 3-morpholino-sydnonimine (SIN-1, 100 micro M) or 8
      bromoguanosine 3',5'-cyclic monophosphate (8-BrcGMP, 1 mM). In addition, the
      guanylyl cyclase inhibitor 1H-[1,2,4] oxadiazole[4,3-a] quinoxalin-1-one (ODQ, 30
      micro M) failed to antagonize the inhibitory action of NO on CCE. 4. DEANO (1-10
      micro M) suppressed mitochondrial respiration as evident from inhibition of
      cellular oxygen consumption. Experiments using fluorescent dyes to monitor
      mitochondrial membrane potential and mitochondrial Ca(2+) levels, respectively,
      indicated that DEANO (10 micro M) depolarized mitochondria and suppressed
      mitochondrial Ca(2+) sequestration. The inhibitory effect of DEANO on Ca(2+)
      uptake into mitochondria was confirmed by recording mitochondrial Ca(2+) during
      agonist stimulation in HEK293 cells expressing ratiometric-pericam in
      mitochondria. 5. DEANO (10 micro M) failed to inhibit Ba(2+) entry into TG
      stimulated cells when extracellular Ca(2+) was buffered below 1 micro M, while
      clear inhibition of Ba(2+) entry into store depleted cells was observed when
      extracellular Ca(2+) levels were above 10 micro M. Moreover, buffering of
      intracellular Ca(2+) by use of N,N'-[1,2-ethanediylbis(oxy-2,1-phenylene)] bis [N
      [25-[(acetyloxy) methoxy]-2-oxoethyl]]-, bis[(acetyloxy)methyl] ester (BAPTA/AM)
      eliminated inhibition of CCE by NO, indicating that the observed inhibitory
      effects are based on an intracellular, Ca(2+) dependent-regulatory process. 6.
      Our data demonstrate that NO effectively inhibits CCE cells by cGMP-independent
      suppression of mitochondrial function. We suggest disruption of local Ca(2+)
      handling by mitochondria as a key mechanism of NO induced suppression of CCE.

PMID- 12411414
TI  - Anandamide induces cough in conscious guinea-pigs through VR1 receptors.
AB  - 1. Endogenous neuronal lipid mediator anandamide, which can be synthesized in the
      lung, is a ligand of both cannabinoid (CB) and vanilloid receptors (VR). The
      tussigenic effect of anandamide has not been studied. The current study was
      designed to test the direct tussigenic effect of anandamide in conscious guinea
      pigs, and its effect on VR1 receptor function in isolated primary guinea-pig
      nodose ganglia neurons. 2. Anandamide (0.3-3 mg.ml(-1)), when given by aerosol,
      induced cough in conscious guinea-pigs in a concentration dependent manner. When
      guinea-pigs were pretreated with capsazepine, a VR1 antagonist, the anandamide
      induced cough was significantly inhibited. Pretreatment with CB1 (SR 141716A) and
      CB2 (SR 144528) antagonists had no effect on anandamide-induced cough. These
      results indicate that anandamide-induced cough is mediated through the activation
      of VR1 receptors. 3. Anandamide (10-100 micro M) increased intracellular Ca(2+)
      concentration estimated by Fluo-4 fluorescence change in isolated guinea-pig
      nodose ganglia cells. The anandamide-induced Ca(2+) response was inhibited by two
      different VR1 antagonists: capsazepine (1 micro M) and iodo-resiniferatoxin (I
      RTX, 0.1 micro M), indicating that anandamide-induced Ca(2+) response was through
      VR1 channel activation. In contrast, the CB1 (SR 141716A, 1 micro M) and CB2 (SR
      144528, 0.1 micro M) receptor antagonists had no effect on Ca(2+) response to
      anandamide. 4. In conclusion, these results provide evidence that anandamide
      activates native vanilloid receptors in isolated guinea-pig nodose ganglia cells
      and induces cough through activation of VR1 receptors.

PMID- 12411415
TI  - Selective inhibitors of cyclo-oxygenase-2 (COX-2) induce hypoalgesia in a rat paw
      model of inflammation.
AB  - 1. It is well-established that inhibitors of cyclo-oxygenase (COX) and hence of
      prostaglandin (PG) biosynthesis reverse inflammatory hyperalgesia and oedema in
      both human and animal models of inflammatory pain. 2. Paw oedema and hyperalgesia
      in rats were induced by injecting carrageenan (250 micro g paw(-1)) into a
      hindpaw. Both inflammatory responses were followed for 24 h after the injection,
      measuring hyperalgesia by decreased pain threshold in the paws and oedema by
      plethysmography. 3. Three selective inhibitors of cyclo-oxygenase-2 (COX-2),
      celecoxib, rofecoxib and SC 236, given systemically in a range of doses, before
      the inflammatory stimulus, abolished carrageenan-induced hyperalgesia with little
      reduction of oedema. These inhibitors also induced hypoalgesia, increasing
      nociceptive thresholds in the inflamed paw above normal, non-inflamed levels.
      This hypoalgesia was lost at the higher doses of the selective inhibitors,
      although hyperalgesia was still prevented. 4. In paws injected with saline only,
      celecoxib, given at the dose inducing the maximum hypoalgesia after carrageenan,
      did not alter the nociceptive thresholds. 5. Two non-selective inhibitors of COX
      2, indomethacin and piroxicam, abolished hyperalgesia and reduced oedema but did
      not induce hypoalgesia. 6. Celecoxib given locally into the paw also abolished
      inflammatory hyperalgesia and induced hypoalgesia without reducing oedema. 7. We
      conclude that hypoalgesia is expressed only over a critical range of COX-2
      inhibition and that concomitant inhibition of COX-1 prevents expression of
      hypoalgesia, although hyperalgesia is still prevented. 8 Our results suggest a
      novel anti-nociceptive pathway mediating hypoalgesia, involving COX-2 selectively
      and having a clear peripheral component. This peripheral component can be further
      explored for therapeutic purposes.

PMID- 12411416
TI  - The mechanisms for tachykinin-induced contractions of the rabbit corpus
      cavernosum.
AB  - 1. This study was designed to investigate the mechanisms for the contractions
      induced by tachykinins (substance P (SP), neurokinin A (NKA) and neurokinin B
      (NKB)) in the rabbit corpus cavernosum strips, using fura-PE3 fluorimetry and
      alpha-toxin permeabilization. 2. Tachykinins induced contractions in the rabbit
      corpus cavernosum in a concentration-dependent manner. The potency order was
      SP>NKA>NKB. 3. The tachykinin-induced contractions were enhanced by
      phosphoramidon (PPAD), an endopeptidase inhibitor, but not by N(omega)-nitro-L
      arginine methylester (L-NAME). 4. The NK(1) receptor selective antagonist, SR
      140333 significantly inhibited the tachykinin-induced contractions. Although the
      NK(2) receptor selective antagonist, SR 48968 alone did not influence the effects
      of tachykinins, it potentiated the inhibitory effect of SR 140333. The NK(3)
      receptor selective antagonist, SR142801 had no effect. 5. In the rabbit corpus
      cavernosum, tachykinins induced sustained increases in [Ca(2+)](i) and tension in
      normal PSS, while only small transient increases in [Ca(2+)](i) and tension were
      observed in Ca(2+)-free solution. 6. In alpha-toxin permeabilized preparations,
      tachykinins induced an additional force development at a constant [Ca(2+)](i). 7.
      These results indicated that in the rabbit corpus cavernosum: (1) Tachykinins
      induced contractions by increasing both the [Ca(2+)](i) and myofilament Ca(2+)
      sensitivity; (2) The tachykinin-induced [Ca(2+)](i) elevations were mainly due to
      the Ca(2+) influx; (3) Tachykinin-induced contractions were mainly mediated
      through the activation of NK(1) receptor expressed in the rabbit corpus
      cavernosum smooth muscle, and affected by the endopeptidase activity and (4)
      Tachykinins may thus play a role in controlling the corpus cavernosum tone.

PMID- 12411417
TI  - Guanidinoethyl sulphonate is a glycine receptor antagonist in striatum.
AB  - 1. Guanidinoethyl sulphonate (GES) is an analogue of taurine and an inhibitor of
      taurine transport. Interactions of GES with GABA(A) and glycine receptors are
      studied by whole cell recording and fast drug application in isolated striatal
      neurons of the mouse. 2. We confirm that GES is a weak agonist at GABA(A)
      receptors, and is able to antagonize GABA-evoked responses. GES did not gate
      GlyR. 3. GES antagonized glycine responses in a concentration-dependent and
      surmountable manner. Glycine dose-response curves were shifted to the right by
      GES (0.5 mM), yielding EC(50)s and Hill coefficients of 62 micro M and 2.5 in
      control, 154 micro M and 1.3 in the presence of GES. 4. GlyR-mediated taurine
      responses were competitively antagonized by GES. Taurine dose-response curves, in
      contrast to the glycine dose-response curves were shifted by GES to the right in
      a parallel manner. 5. The GlyR-block by GES was not voltage-dependent. 6. In
      contrast to our findings in the mouse, in rat striatal neurons which lack
      expression of the alpha3 GlyR subunit, GES shifted the glycine dose-response
      curve to the right in a parallel way without affecting the maximal response.
      Subtype-specificity of the GES action at GlyR must await further investigation in
      artificial expression systems. 7. We conclude that GES is a competitive
      antagonist at GlyR. The antagonistic action of GES at inhibitory ionotropic
      receptors can explain its epileptogenic action. Care must be taken with the
      interpretation of data on GES evoked taurine release.

PMID- 12411418
TI  - Modulation of reflexly evoked vagal bradycardias by central 5-HT1A receptors in
      anaesthetized rabbits.
AB  - 1. The role of central 5-HT(1A) receptors in the control of the bradycardia and
      changes in central respiratory drive, renal nerve activity and blood pressure
      evoked by stimulating cardiopulmonary afferents with phenylbiguanide,
      baroreceptors by electrical stimulation of the aortic nerve and chemoreceptors by
      injections of sodium cyanide (NaCN) in atenolol-pretreated anaesthetized rabbits
      were studied. 2. Buspirone (100 micro g kg(-1); i.c.) potentiated the bradycardia
      (increase in R-R interval) and the changes in blood pressure and renal nerve
      activity evoked by all three reflexes. These effects could be attenuated by
      pretreatment with the 5-HT(1A) receptor antagonist WAY-100635 (100 micro g kg(
      1)); i.v.), which alone had no effect on these reflex-evoked changes. However,
      WAY-100635 (100 micro g kg(-1); i.c.) did attenuate these reflex-evoked responses
      produced by activation of cardiopulmonary and aortic baroreceptors but not that
      caused by stimulation of chemoreceptors. When given i.v., buspirone was less
      effective in modulating the responses evoked by these three reflexes. 3. The
      present data are consistent with the view that central 5-HT(1A) receptors play a
      role in the reflex activation of cardiac preganglionic vagal motoneurones.
      However, although antagonists of 5-HT(1A) receptors affected the responses evoked
      by cardiopulmonary and aortic nerve afferents, they were not effective on
      chemoreceptor reflex-evoked changes. This suggests that 5-HT(1A) receptors play a
      different role in chemoreceptor pathways compared to that for the other reflexes.
      This may relate to the fact that the chemoreceptor afferents travel in the IXth
      (glossopharyngeal) nerve whilst the other afferents travel in the Xth (vagus)
      nerve and thus may use different central circuitry and neurotransmitters.

PMID- 12411419
TI  - Possible role of histamine (H1- and H2-) receptors in the regulation of meningeal
      blood flow.
AB  - 1. Vasodilatation in the dura mater has been suggested to play an important role
      in the pathophysiology of vascular headaches. Histamine may contribute to these
      vascular changes. The aim of the present study was to examine the role of
      different histamine receptors in histamine-induced meningeal hyperperfusion using
      laser Doppler flowmetry. 2. The blood flow in the medial meningeal artery was
      monitored in the exposed parietal dura mater encephali of barbiturate
      anaesthetized rats. Local application of histamine (10(-5) and 10(-4) M) onto the
      dura caused increases in flow to 114.2+/-9.6 and 135.1+/-19.1%, respectively, of
      the basal flow. 3. Flow increases induced by topical application of histamine
      (10(-4) M) were reduced by local pretreatment with the H(2)-receptor antagonist
      cimetidine (0.4 and 4 mM) to 63.4+/-17 and 37.8+/-18.8%, respectively. Systemic
      pre-administration of cimetidine (5 mg kg(-1) i.v.) did not change histamine
      induced flow increases. 4. Local pretreatment with the H(1)-receptor antagonist
      cetirizine (2 micro M) further increased the flow evoked by topical histamine
      administration (10(-4) M) to 123.5+/-14.7% of the histamine control. 5. Increases
      in blood flow induced by i.v. administration of histamine (10 micro g kg(-1))
      were reduced by i.v. pre-injection of cetirizine (50 micro g kg(-1)) to 31.9+/-9%
      but not by i.v. cimetidine (5 mg kg(-1)). 6. We conclude that histamine-induced
      relaxation of dural arterial vessels is mediated by H(2)-receptors, most likely
      located on vascular smooth muscle cells, and by endothelial H(1)-receptors. In
      addition, H(1)-receptors on smooth muscle cells may mediate vasoconstriction.

PMID- 12411420
TI  - Hypoxia-induced down-regulation of CYP1A1/1A2 and up-regulation of CYP3A6
      involves serum mediators.
AB  - 1. Acute moderate hypoxia modifies the catalytic activity and expression of
      certain isoenzymes of hepatic cytochrome P450 (P450). The aim of this study was
      to document whether hypoxia affects hepatic P450 directly or through the release
      of serum mediators. 2. Rabbits were subjected to a FiO(2) of 8% for 48 h,
      sacrificed, and serum and hepatocytes were isolated; hepatocytes from control and
      rabbits with hypoxia were incubated with serum from control and hypoxic rabbits
      for 4 and 24 h, and total P450 content, CYP1A1, 1A2 and 3A6 activities and
      expressions were assessed. Sera were fractionated by size exclusion
      chromatography and fractions tested for their ability to modify activity and
      amount of P450, and serum mediators were identified through neutralization
      experiments. 3. Total serum and fractions with proteins of 15-23 and 65-94 kDa of
      M(r) reduced P450 content and expression of CYP1A1, 1A2 and 3A6, as well as
      CYP1A1, 1A2 and 3A6 mRNA. Total serum and the fraction with 32-44 kDa proteins
      increased CYP3A6 activity and protein and mRNA. The serum mediators implicated in
      the decrease in activity and expression of CYP1A1, 1A2 and 3A6 were interferon
      gamma (IFN-gamma), interleukin-1beta (IL-1beta) and IL-2. Erythropoietin (Epo)
      was partly responsible for the increase in P450 content and CYP3A6 expression. 4.
      In conclusion, acute moderate hypoxia diminishes the activity and expression of
      CYP1A1, 1A2 and CYP1A1, 1A2 mRNA, and increases CYP3A6 protein, activity and
      CYP3A6 mRNA. Several mechanisms contribute to these changes in P450, among them
      the release of cytokines acting as serum mediators.

PMID- 12411421
TI  - The antihistamine fexofenadine does not affect I(Kr) currents in a case report of
      drug-induced cardiac arrhythmia.
AB  - 1. The human HERG gene encodes the cardiac repolarizing K(+) current I(Kr) and is
      genetically inactivated in inherited long QT syndrome 2 (LQTS2). The
      antihistamine terfenadine blocks HERG channels, and can cause QT prolongation and
      torsades de pointes, whereas its carboxylate fexofenadine lacks HERG blocking
      activity. 2. In the present study the ability of fexofenadine to block the K897T
      HERG channel variant was investigated. The underlying single nucleotide
      polymorphism (SNP) A2960C was identified in a patient reported to develop
      fexofenadine-associated LQTS. 3. K897T HERG channels produced wild-type-like
      currents in Xenopus oocytes. Even at a concentration of 100 micro M, fexofenadine
      did not inhibit wild-type or K897T HERG channels. Coexpression of wild-type and
      K897T HERG with the ss-subunit MiRP1, slightly changed current kinetics but did
      not change sensitivity to terfenadine and fexofenadine. 4. Western blot analysis
      and immunostaining of transiently transfected COS-7 cells demonstrated that
      overall expression level, glycosylation pattern and subcellular localization of
      K897T HERG is indistinguishable from wild-type HERG protein, and not altered in
      the presence of 1 micro M fexofenadine. 5. We provide the first functional
      characterization of the K897T HERG variant. We demonstrated that K897T HERG is
      similar to wild-type HERG, and is insensitive to fexofenadine. Although the
      polymorphism changes PKA and PKC phosphorylation sites, regulation of K897T HERG
      by these kinases is not altered. 6. Our results strongly indicate that QT
      lengthening and cardiac arrhythmia in the reported case of drug-induced LQT are
      not due to the K897T exchange or to an inhibitory effect of fexofenadine on
      cardiac I(Kr) currents. British Journal of

PMID- 12411422
TI  - Inhibitory mechanism of vascular endothelial growth factor (VEGF) by bucillamine.
AB  - 1. Vascular endothelial growth factor (VEGF) plays an important role in the
      neovascularization of ischaemic retinal diseases such as proliferative diabetic
      retinopathy. We determined that bucillamine, an anti-rheumatic drug, inhibits the
      VEGF production induced by hypoxia in bovine retinal microcapillary endothelial
      cells (BREC). To further clarify the inhibitory mechanism, we investigated the
      possible mechanism by which bucillamine exerts this inhibitory effect. 2.
      Bucillamine (100 micro M) decreased the hypoxia-induced increase of VEGF mRNA by
      54.5% (P<0.001). Bucillamine (100 micro M) reduced the hypoxia-induced VEGF
      content in culture media by 29.0% (P<0.001), while monosulfydryl drugs, N
      acetylcysteine and D-penicillamine, did not. 3. Bucillamine (100 micro M) did not
      affect VEGF mRNA half-life (hypoxia, 4.3 h; hypoxia+bucillamine, 3.9 h; normoxia,
      2.7 h; normoxia+bucillamine, 2.7 h). 4. Reporter gene studies revealed that
      bucillamine reduced transcriptional activity in the 5'-flanking region of the
      VEGF gene by 74.0%. Hypoxia stimulated binding activity of BREC nuclear protein
      to a hypoxia responsive element (HRE), which was decreased by bucillamine. 5.
      Bucillamine inhibited hypoxic-induction of HIF-1alpha mRNA by 73.1% (P<0.001).
      Bucillamine also inhibited spontaneous VEGF mRNA expression by 26.6%.
      Furthermore, it inhibited activity of VEGF promoter and decreased binding
      activity to Sp1 and HRE, but did not alter AP1 and AP2 activity in normoxia. 6.
      These data suggest that bucillamine inhibits hypoxic induction of VEGF through
      inhibition of HIF-1 induction and binding activity in BREC. Bucillamine also
      inhibits the spontaneous expression of VEGF mRNA by its effect on Sp1 and HRE
      binding.

PMID- 12411424
TI  - Respiratory actions of vanilloid receptor agonists in the nucleus of the solitary
      tract: comparison of resiniferatoxin with non-pungent agents and anandamide.
AB  - 1. Activation of vanilloid receptors on sensory nerve terminals in the
      commissural nucleus of the solitary tract (cNTS) of rats with capsaicin, produces
      respiratory slowing. In this study, we used microinjection techniques employing
      pungent and non-pungent vanilloids to further characterize vanilloid receptors in
      the cNTS. 2. Microinjection of the pungent vanilloid, resiniferatoxin (RTX), into
      the cNTS of urethane-anaesthetized rats, dose-dependently reduced respiratory
      rate without affecting tidal volume. RTX was 20 fold more potent at slowing
      respiration ( approximately ED(50), 100 pmol) than capsaicin ( approximately
      ED(50), 2 nmol). Doses of RTX greater than 100 pmol caused either irregular
      (dyspnoeic) breathing or terminal apnoea (>250 pmol). The respiratory slowing
      response to RTX (75 pmol), was dose-dependently attenuated by injecting RTX (but
      not vehicle) into the same site 60 min earlier. 3. The non-pungent phorbol
      derivative of RTX, phorbol 12-phenylacetete 13-acetate 20-homovanillate (PPAHV,
      0.1-1 nmol), also slowed respiration (ED(50), approximately 1 nmol) and almost
      abolished response to RTX (75 pmol) injected into the same site 60 min later. 4.
      In contrast to RTX, PPAHV and capsaicin, the putative endogenous vanilloid
      receptor agonist, arachidonyl ethanolamide (AEA), and non-pungent capsaicin
      derivative, olvanil, had no direct effect on respiration. However, both AEA and
      olvanil dose-dependently reduced the respiratory response to injection of RTX (75
      pmol) 60 min later into the same site (EC(50)s, for AEA and olvanil,
      approximately 2 and 0.2 nmol, respectively). 5. These studies suggest that both
      pungent and non-pungent vanilloids interact with vanilloid receptors in the cNTS.
      However, whereas RTX and PPAHV activate and subsequently desensitize vanilloid
      receptors on sensory nerve terminals in the cNTS, olvanil and AEA fail to
      activate despite readily desensitizing responses to RTX in this region.

PMID- 12411423
TI  - Activation of the extraneuronal monoamine transporter (EMT) from rat expressed in
      293 cells.
AB  - 1. The extraneuronal monoamine transporter from rat (EMTr) was heterologously
      expressed by stable transfection in human embryonic kidney 293 cells and
      characterized in radiotracer experiments. 2. EMTr-mediated uptake of 1-methyl-4
      phenylpyridinium (MPP(+)) was saturable, with a K(m) of 151 micro mol l(-1) and
      V(max) of 7.5 nmol min(-1) mg protein(-1). 3. Compared to the human orthologue
      EMTh (gene symbol SLC22A3), EMTr was about two orders of magnitude more resistant
      to most inhibitors, including disprocynium24 and corticosterone. 4. Strikingly,
      inhibitors and substrates at low concentration stimulated EMTr-mediated transport
      above control level with MPP(+) and noradrenaline as substrate, but not with
      cimetidine. Results were confirmed with EMT from mouse. 5. With different IC(50)
      values for different substrates, the standard method to calculate K(i)-values is
      not applicable. 6. Our experiments suggest that activation is not caused by
      changes in membrane potential or trans-stimulation. Since the extent of
      activation depends markedly on the chemical structure of the monitored substrate,
      involvement of a receptor-mediated signalling pathway or recruitment of
      transporter reserve are implausible. 7. To explain activation, we present a
      kinetic model which assumes two binding sites for substrate or inhibitor per
      transporter entity, possibly resulting from the assembly of homodimers. 8.
      Activation explains previous reports about inhibitor-insensitive catecholamine
      transport in rat brain. 9. We speculate that activation may serve to keep the
      transporter working for specific substrates in the face of inhibitors.

PMID- 12411425
TI  - Mechanism of lonidamine inhibition of the CFTR chloride channel.
AB  - 1. The cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel
      is blocked by a broad range of organic anionic compounds. Here we investigate the
      effects of the indazole compound lonidamine on CFTR channels expressed in
      mammalian cell lines using patch clamp recording. 2. Application of lonidamine to
      the intracellular face of excised membrane patches caused a voltage-dependent
      block of CFTR currents, with an apparent K(d) of 58 micro M at -100 mV. 3. Block
      by lonidamine was apparently independent of channel gating but weakly sensitive
      to the extracellular Cl(-) concentration. 4. Intracellular lonidamine led to the
      introduction of brief interruptions in the single channel current at
      hyperpolarized voltages, leading to a reduction in channel mean open time.
      Lonidamine also introduced a new component of macroscopic current variance.
      Spectral analysis of this variance suggested a blocker on rate of 1.79 micro M(
      1) s(-1) and an off-rate of 143 s(-1). 5. Several point mutations within the
      sixth transmembrane region of CFTR (R334C, F337S, T338A and S341A) significantly
      weakened block of macroscopic CFTR current, suggesting that lonidamine enters
      deeply into the channel pore from its intracellular end. 6. These results
      identify and characterize lonidamine as a novel CFTR open channel blocker and
      provide important information concerning its molecular mechanism of action.

PMID- 12411426
TI  - Pulmonary hypertension, left ventricular dysfunction and plasma serotonin:
      commentary on Deuchar et al.

PMID- 12411428
TI  - Citron kinase is a cell cycle-dependent, nuclear protein required for G2/M
      transition of hepatocytes.
AB  - Citron Kinase (Citron-K) is a cell cycle-dependent protein regulating the G(2)/M
      transition in hepatocytes. Synchronization studies demonstrated that expression
      of the Citron-K protein starts at the late S and/or the early G(2) phase after
      that of cyclin B1. Expression of Citron-K is developmentally regulated. Levels of
      Citron-K mRNA and protein are highest in embryonic liver and gradually decrease
      after birth. Citron-K exists in interphase nuclei and begins to disperse into the
      cytoplasm at prophase. It concentrates at the cleavage furrow and midbody during
      anaphase, telophase, and cytokinesis, implicating a role in the control of
      cytokinesis. However, studies with knockouts show that Citron-K is not essential
      for cytokinesis in hepatocytes. Instead, loss of Citron-K causes a significant
      increase of G(2) tetraploid nuclei in one-week-old rat and mouse liver. In
      addition, Citron-K deficiency triggers apoptosis in a small subset of embryonic
      liver cells. In summary, our data demonstrate that Citron-K has a distinct cell
      cycle-dependent expression pattern and cellular localization as a downstream
      target of Rho-GTPase and functions in the control of G(2)/M transition in the
      hepatocyte cell cycle.

PMID- 12411429
TI  - A dominant allele of PDR1 alters transition metal resistance in yeast.
AB  - A yeast mutant was found to have defective growth on low iron medium despite a
      normal high affinity iron transport system. The phenotype results from a gain of
      function mutation in PDR1, which encodes a transcription factor that acts as a
      regulator of pleiotropic drug resistance in Saccharomyces cerevisiae. The mutant
      allele, PDR1(R821H), was found to result in increased expression of at least 19
      genes, three of which are ATP-binding cassette (ABC) transporters. Expression of
      at least six genes was required to show the low iron growth defect. Wild type
      cells transformed with the PDR1(R821H) allele or a PDR1 dominant allele (PDR1-3)
      showed the low iron growth defect as well as increased resistance to drugs such
      as cycloheximide and oligomycin. Transformation of PDR1(R821H) into Deltaccc1
      cells, which were previously shown to have increased sensitivity to high iron
      medium because of defective vacuolar iron storage (Li, L., Chen, O. S., Ward, D.
      M., and Kaplan, J. (2001) J. Biol. Chem. 276, 29515-29519), conferred resistance
      to high iron medium. Cells expressing PDR1(R821H) also showed increased
      resistance to copper and manganese because of increased metal export. These
      results suggest that expression of PDR1-regulated genes affects both efflux and
      storage of transition metals.

PMID- 12411430
TI  - Role for RFX transcription factors in non-neuronal cell-specific inactivation of
      the microtubule-associated protein MAP1A promoter.
AB  - Microtubule-associated protein MAP1A is expressed abundantly in mature neurons
      and is necessary for maintenance of neuronal morphology and localization of some
      molecules in association with the microtubule-based cytoskeleton. Previous
      studies indicated that its complementary expression together with MAP1B during
      nervous system development is regulated at the transcriptional level and that the
      mouse Map1A gene is transcribed under the control of 5' and intronic promoters.
      In this study, we investigated the regulatory mechanisms that govern the neuronal
      cell-specific activation of the MAP1A 5' promoter. We found that two regulatory
      factor for X box (RFX) binding sites in exon1 of both the mouse and human genes
      are important for effective transcriptional repression observed only in non
      neuronal cells by reporter assays. Among RFX transcription factor family members,
      RFX1 and 3 mainly interact with repressive elements in vitro. Cotransfection
      studies indicated that RFX1, which is expressed ubiquitously, down-regulated the
      MAP1A 5' promoter activity in non-neuronal cells. Unexpectedly, RFX3, which is
      abundantly expressed in neuronal cells, down-regulated the transactivity as well,
      when it was expressed in non-neuronal cells. Both RFX1 and 3 did not down
      regulate the transactivity in neuronal cells. These results suggest that RFX1 and
      3 are pivotal factors in down-regulation of the MAP1A 5' promoter in non-neuronal
      cells. The cell type-specific down-regulation, however, does not depend simply on
      which RFX interacts with the elements, but seems to depend on underlying profound
      mechanisms.

PMID- 12411431
TI  - Cell-penetrating peptides. A reevaluation of the mechanism of cellular uptake.
AB  - Cellular uptake of a family of cationic cell-penetrating peptides (examples
      include Tat peptides and penetratin) have been ascribed in the literature to a
      mechanism that does not involve endocytosis. In this work we reevaluate the
      mechanisms of cellular uptake of Tat 48-60 and (Arg)(9). We demonstrate here that
      cell fixation, even in mild conditions, leads to the artifactual uptake of these
      peptides. Moreover, we show that flow cytometry analysis cannot be used validly
      to evaluate cellular uptake unless a step of trypsin digestion of the cell
      membrane-adsorbed peptide is included in the protocol. Fluorescence microscopy on
      live unfixed cells shows characteristic endosomal distribution of peptides. Flow
      cytometry analysis indicates that the kinetics of uptake are similar to the
      kinetics of endocytosis. Peptide uptake is inhibited by incubation at low
      temperature and cellular ATP pool depletion. Similar data were obtained for Tat
      conjugated peptide nucleic acids. These data are consistent with the involvement
      of endocytosis in the cellular internalization of cell-penetrating peptides and
      their conjugates to peptide nucleic acids.

PMID- 12411432
TI  - Identification and characterization of a novel human sphingosine-1-phosphate
      phosphohydrolase, hSPP2.
AB  - Sphingosine 1-phosphate (S1P) is a bioactive lipid molecule that acts as both an
      extracellular signaling mediator and an intracellular second messenger. S1P is
      synthesized from sphingosine by sphingosine kinase and is degraded either by S1P
      lyase or by S1P phosphohydrolase. Recently, mammalian S1P phosphohydrolase (SPP1)
      was identified and shown to constitute a novel lipid phosphohydrolase family, the
      SPP family. In this study we have identified a second human S1P phosphohydrolase,
      SPP2, based on sequence homology to human SPP1. SPP2 exhibited high
      phosphohydrolase activity against S1P and dihydrosphingosine 1-phosphate. The
      dihydrosphingosine-1-phosphate phosphohydrolase activity was efficiently
      inhibited by excess S1P but not by lysophosphatidic acid, phosphatidic acid, or
      glycerol 3-phosphate, indicating that SPP2 is highly specific to sphingoid base 1
      phosphates. Immunofluorescence microscopic analysis demonstrated that SPP2 is
      localized to the endoplasmic reticulum. Although the enzymatic properties and
      localization of SPP2 were similar to those of SPP1, the tissue-specific
      expression pattern of SPP2 was different from that of SPP1. Thus, SPP2 is another
      member of the SPP family that may play a role in attenuating intracellular S1P
      signaling.

PMID- 12411433
TI  - Characterization of the peroxisomal cycling receptor, Pex5p, using a cell-free in
      vitro import system.
AB  - According to current models of peroxisomal biogenesis, Pex5p cycles between the
      cytosol and the peroxisome transporting newly synthesized proteins to the
      organelle matrix. However, little is known regarding the mechanism of this
      pathway. Here, we show that Pex5p enters and exits the peroxisomal compartment in
      a process that requires ATP. Insertion of Pex5p into the peroxisomal membrane is
      blocked by anti-Pex14p IgGs. At the peroxisomal level, two Pex14p-associated
      populations of Pex5p could be resolved, stage 2 and stage 3 Pex5p, both exposing
      the majority of their masses into the organelle lumen. Stage 3 Pex5p can be
      easily detected only under ATP-limiting conditions; in the presence of ATP it
      leaves the peroxisomal compartment rapidly. Our data suggest that translocation
      of PTS1-containing proteins across the peroxisomal membrane occurs concomitantly
      with formation of the Pex5p-Pex14p membrane complex and that this is probably the
      site from which Pex5p leaves the peroxisomal compartment.

PMID- 12411434
TI  - Overexpression of kinin B1 receptors induces hypertensive response to des-Arg9
      bradykinin and susceptibility to inflammation.
AB  - We demonstrated that rat kinin B(1) receptors displayed a ligand-independent
      constitutive activity, assessed through inositol phosphate production in
      transiently or stably transfected human embryonic kidney 293A cells. Substitution
      of Ala for Asn(130) in the third transmembrane domain resulted in additional
      constitutive activation of the B(1) receptor. The constitutively active mutant
      N130A receptor could be further activated by the B(1) receptor agonist des-Arg(9)
      bradykinin. To gain insights into the physiological function of the B(1)
      receptor, we have generated transgenic mice overexpressing wild-type and
      constitutively active mutant receptors under the control of human cytomegalovirus
      immediately early gene enhancer/promoter. The rat B(1) receptor transgene
      expression was detected in the aorta, brain, heart, lung, liver, kidney, uterus,
      and prostate of transgenic mice by reverse transcription-polymerase chain
      reaction/Southern blot analysis. Transgenic mice were fertile and normotensive.
      Overexpression of B(1) receptors exacerbated paw edema induced by carrageenan and
      rendered transgenic mice more susceptible to lipopolysaccharide-induced endotoxic
      shock. Interestingly, the hemodynamic response to kinins was altered in
      transgenic mice, with des-Arg(9)-bradykinin inducing blood pressure increase when
      intravenously administered. Our study supports an important role for B(1)
      receptors in modulating inflammatory responses and for the first time
      demonstrates that B(1) receptors mediate a hypertensive response to des-Arg(9)
      bradykinin.

PMID- 12411435
TI  - Isolation and characterization of TgVP1, a type I vacuolar H+-translocating
      pyrophosphatase from Toxoplasma gondii. The dynamics of its subcellular
      localization and the cellular effects of a diphosphonate inhibitor.
AB  - Here we report the isolation and characterization of a type I vacuolar-type H(+)
      pyrophosphatase (V-PPase), TgVP1, from an apicomplexan, Toxoplasma gondii, a
      parasitic protist that is particularly amenable to molecular and genetic
      manipulation. The 816-amino acid TgVP1 polypeptide is 50% sequence-identical (65%
      similar) to the prototypical type I V-PPase from Arabidopsis thaliana, AVP1, and
      contains all the sequence motifs characteristic of this pump category. Unlike
      AVP1 and other known type I enzymes, however, TgVP1 contains a 74-residue N
      terminal extension encompassing a 42-residue N-terminal signal peptide sequence,
      sufficient for targeting proteins to the secretory pathway of T. gondii.
      Providing that the coding sequence for the entire N-terminal extension is omitted
      from the plasmid, transformation of Saccharomyces cerevisiae with plasmid-borne
      TgVP1 yields a stable and functional translation product that is competent in
      aminomethylenediphosphonate (AMDP)-inhibitable K(+)-activated pyrophosphate
      (PP(i)) hydrolysis and PP(i)-energized H(+) translocation. Immunofluorescence
      microscopy of both free and intracellular T. gondii tachyzoites using purified
      universal V-PPase polyclonal antibodies reveals a punctate apical distribution
      for the enzyme. Equivalent studies of the tachyzoites during host cell invasion,
      by contrast, disclose a transverse radial distribution in which the V-PPase is
      associated with a collar-like structure that migrates along the length of the
      parasite in synchrony with and in close apposition to the penetration furrow.
      Although treatment of T. gondii with AMDP concentrations as high as 100 microm
      had no discernible effect on the efficiency of host cell invasion and
      integration, concentrations commensurate with the I(50) for the inhibition of
      TgVP1 activity in vitro (0.9 microm) do inhibit cell division and elicit nuclear
      enlargement concomitant with the inflation and eventual disintegration of
      acidocalcisome-like vesicular structures. A dynamic association of TgVP1 with the
      host cell invasion apparatus is invoked, one in which the effects of inhibitory V
      PPase substrate analogs are exerted after rather than during host cell invasion.

PMID- 12411436
TI  - Fragmentation of the Golgi apparatus. A role for beta III spectrin and synthesis
      of phosphatidylinositol 4,5-bisphosphate.
AB  - Phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P(2)) synthesis has been
      implicated in maintaining the function of the Golgi apparatus. Here we
      demonstrate that the inhibition of PtdIns(4,5)P(2) synthesis in vitro in response
      to primary alcohol treatment and the kinetics of Golgi fragmentation in vivo were
      very rapid and tightly coupled. Preloading Golgi membranes with short chain
      phosphatidic acid abrogated the alcohol-mediated inhibition of PtdIns(4,5)P(2)
      synthesis in vitro. We also show that fragmentation of the Golgi apparatus in
      response to diminished PtdIns(4,5)P(2) synthesis correlated with both the
      phosphorylation of a Golgi form of beta III spectrin, a PtdIns(4,5)P(2)
      interacting protein, and changes in its intracellular redistribution. The data
      are consistent with a model suggesting that the decreased PtdIns(4,5)P(2)
      synthesis and the phosphorylation state of beta III spectrin modulate the
      structural integrity of the Golgi apparatus.

PMID- 12411437
TI  - Intramolecular proton transfers and structural changes during the photocycle of
      the LOV2 domain of phototropin 1.
AB  - The phototropins are a family of membrane-associated flavoproteins that function
      as the primary blue light receptors regulating phototropism, chloroplast
      movements, stomatal opening, and leaf expansion in plants. Phot1, a member of
      this family, contains two FMN-binding domains, LOV1 and LOV2, within the N
      terminal region and a C-terminal serine-threonine protein kinase domain. Light
      irradiation of oat phot1 LOV2 produces a cysteinyl adduct (Cys-39) at the flavin
      C(4a) position, which decays thermally back to the dark state. We measured pH and
      isotope effects on the photocycle. Between pH 3.7 and 9.5, adduct formation
      showed minimal pH dependence, and adduct decay showed only slight pH dependence,
      indicating that the pK values of mechanistically relevant groups are outside this
      range. LOV2 showed a nearly 5-fold slowing of adduct formation in D(2)O relative
      to H(2)O, indicating that the rate-limiting step involves proton transfer(s).
      Light-induced changes in the far UV CD spectrum of LOV2 revealed putative protein
      structural perturbations. The light minus dark CD difference spectrum resembles
      an inverted alpha-helix spectrum, suggesting that alpha-helicity is reversibly
      lost upon light irradiation. Decay kinetics for CD spectral changes in the far UV
      region occur at the same rate as those in the visible region, indicating
      synchronous relaxation of protein and chromophore structures.

PMID- 12411438
TI  - Properties and regulation of the bifunctional enzyme HPr kinase/phosphatase in
      Bacillus subtilis.
AB  - The bifunctional allosteric enzyme HPr kinase/phosphatase (HPrK/P) from Bacillus
      subtilis is a key enzyme in the main mechanism of carbon catabolite
      repression/activation (i.e. a means for the bacteria to adapt rapidly to
      environmental changes in carbon sources). In this regulation system, the enzyme
      can phosphorylate and dephosphorylate two proteins, HPr/HPr(Ser(P)) and
      Crh/Crh(Ser(P)), sensing the metabolic state of the cell. To acquire further
      insight into the properties of HPrK/P, electrospray ionization mass spectrometry,
      dynamic light scattering, and BIACORE were used to determine the oligomeric state
      of the protein under native conditions, revealing that the enzyme exists as a
      hexamer at pH 6.8 and as a monomer and dimer at pH 9.5. Using an in vitro
      radioactive assay, the influence of divalent cations, pH, temperature, and
      different glycolytic intermediates on the activity as well as kinetic parameters
      were investigated. The presence of divalent cations was found to be essential for
      both opposing activities of the enzyme. Furthermore, pH values equal to the
      internal pH of vegetative cells seem to favor the kinase activity, whereas lower
      pH values increased the phosphatase activity. Among the glycolytic intermediates
      evaluated, fructose 1,6-diphosphate and fructose 2,6-diphosphate were found to be
      allosteric activators in the kinase assay, whereas high concentrations inhibited
      the phosphatase activity, except for fructose 1,6-diphosphate in the case of
      HPr(Ser(P)). Phosphatase activity was induced by inorganic phosphate as well as
      acetyl phosphate and glyceraldehyde 3-phosphate. Kinetic parameters indicate a
      preference for binding of HPr compared with Crh to the enzyme and supported a
      strong positive cooperativity. This work suggests that the oligomeric state of
      the enzyme is influenced by several effectors and is correlated to the kinase or
      phosphatase activity. The phosphatase activity is mainly supported by the
      hexameric form.

PMID- 12411439
TI  - HLA-E allelic variants. Correlating differential expression, peptide affinities,
      crystal structures, and thermal stabilities.
AB  - Previous studies of HLA-E allelic polymorphism have indicated that balancing
      selection may be acting to maintain two major alleles in most populations,
      indicating that a functional difference may exist between the alleles. The
      alleles differ at only one amino acid position, where an arginine at position 107
      in HLA-E*0101 (E(R)) is replaced by a glycine in HLA-E*0103 (E(G)). To
      investigate possible functional differences, we have undertaken a study of the
      physical and biochemical properties of these two proteins. By comparing
      expression levels, we found that whereas steady-state protein levels were
      similar, the two alleles did in fact differ with respect to cell surface levels.
      To help explain this difference, we undertook studies of the relative differences
      in peptide affinity, complex stability, and three-dimensional structure between
      the alleles. The crystal structures for HLA-E(G) complexed with two distinct
      peptides were determined, and both were compared with the HLA-E(R) structure. No
      significant differences in the structure of HLA-E were induced as a result of
      binding different peptides or by the allelic substitution at position 107.
      However, there were clear differences in the relative affinity for peptide of
      each heavy chain, which correlated with and may be explained by differences
      between their thermal stabilities. These differences were completely consistent
      with the relative levels of the HLA-E alleles on the cell surface and may indeed
      correlate with functional differences. This in turn may help explain the apparent
      balancing selection acting on this locus.

PMID- 12411440
TI  - Structure and binding mode of a ribosome recycling factor (RRF) from mesophilic
      bacterium.
AB  - X-ray and NMR analyses on ribosome recycling factors (RRFs) from thermophilic
      bacteria showed that they display a tRNA-like L-shaped conformation consisting of
      two domains. Since then, it has been accepted that domain I, consisting of a
      three-helix bundle, corresponds to the anticodon arm of tRNA and domain II and a
      beta/alpha/beta sandwich structure, corresponds to the acceptor arm. In this
      study, we obtained a RRF from a mesophilic bacterium, Vibrio parahaemolyticus, by
      gene cloning and carried out an x-ray analysis on it at 2.2 A resolution. This
      RRF was shown to be active in an in vitro assay system using Escherichia coli
      polysomes and elongation factor G (EF-G). In contrast, the above-mentioned RRFs
      from thermophilic bacteria were inactive in such a system. Analysis of the
      relative orientations between the two domains in the structures of various RRFs,
      including this RRF from mesophilic bacterium, revealed that domain II rotates
      about the long axis of the helix bundle of domain I. To elucidate the ribosome
      binding site of RRF, the peptide fragment (RRF-DI) corresponding to domain I of
      RRF was expressed and characterized. RRF-DI is bound to 70 S ribosome and the 50
      S subunit with an affinity similar to that of wild-type RRF. But it does not bind
      to the 30 S subunit. These findings caused us to reinvestigate the concept of the
      mimicry of RRF to tRNA and to propose a new model where domain I corresponds to
      the acceptor arm of tRNA and domain II corresponds to the anticodon arm. This is
      just the reverse of a model that is now widely accepted. However, the new model
      is in better agreement with published biological findings.

PMID- 12411441
TI  - A functionally relevant conformational epitope on the CD9 tetraspanin depends on
      the association with activated beta1 integrin.
AB  - Tetraspanins associate on the cell membrane with several transmembrane proteins,
      including members of the integrin superfamily. The tetraspanin CD9 has been
      implicated in cell motility, metastasis, and sperm-egg fusion. In this study we
      characterize the first CD9 conformation-dependent epitope (detected by monoclonal
      antibody (mAb) PAINS-13) whose expression depends on changes in the activation
      state of associated beta(1) integrins. MAb PAINS-13 precipitates CD9 under
      conditions that preserve the association of this tetraspanin with integrins, but
      not under conditions that disrupt these interactions. Induction of activation of
      beta(1) integrins by temperature, divalent cation Mn(2+), or mAb TS2/16
      correlated with enhanced expression of the PAINS-13 epitope on a variety of
      cells. Through the use of different K562 myeloid leukemia transfectant cells
      expressing specific members of the beta(1) integrin subfamily we show that the
      expression of the PAINS-13 epitope depends on CD9 association with
      alpha(6)beta(1) integrin. The mAb PAINS-13 reactivity has been mapped to the CD9
      region comprising residues 112-154 in the NH(2) half of the large extracellular
      loop. Also, we show that the CD9 conformation recognized by mAb PAINS-13 is
      functionally relevant in beta(1) integrin-mediated cellular processes including
      wound healing migration, tubular morphogenesis, cell adhesion and spreading and
      in signal transduction involving phosphatidylinositol 3-kinase activation.

PMID- 12411442
TI  - The binding surface and affinity of monomeric and dimeric chemokine macrophage
      inflammatory protein 1 beta for various glycosaminoglycan disaccharides.
AB  - Chemokines comprise a family of proteins that function in the immune response to
      recruit leukocytes to sites of infection. This recruitment is believed to be
      carried out by the establishment of a chemokine gradient by the binding of
      chemokines to sulfated polysaccharides known as glycosaminoglycans (GAGs) located
      on the extracellular surface of endothelial cells. In the present studies,
      multidimensional NMR spectroscopy was used to study the interaction of monomeric
      and dimeric chemokine macrophage inflammatory protein (MIP)-1 beta variants with
      a series of differentially sulfated disaccharides. The data define a GAG binding
      surface, including both basic and uncharged residues such as Arg(18), Asn(23),
      Val(25), Thr(44), Lys(45), Arg(46), and Ser(47). Dissociation constants
      determined from these NMR studies consistently show for each disaccharide that
      dimeric wild type MIP-1 beta binds more tightly than monomeric MIP(9).
      Furthermore, analysis of the binding surface suggests that participation in the
      dimer of residues Met(3), Gly(4), and Ser(5) may be responsible for this higher
      affinity. These studies also indicate that the specificity of MIP-1 beta for
      particular GAG disaccharides is directly related not only to the degree of
      disaccharide sulfation but also to the position of the sulfate moiety, with O
      sulfation at position 2 of the hexuronic acid unit and position 6 of the D
      glucosamine being major determinants for binding.

PMID- 12411443
TI  - ERdj5, an endoplasmic reticulum (ER)-resident protein containing DnaJ and
      thioredoxin domains, is expressed in secretory cells or following ER stress.
AB  - A complex array of chaperones and enzymes reside in the endoplasmic reticulum
      (ER) to assist the folding and assembly of and the disulfide bond formation in
      nascent secretory proteins. Here we characterize a novel human putative ER co
      chaperone (ERdj5) containing domains resembling DnaJ, protein-disulfide
      isomerase, and thioredoxin domains. Homologs of ERdj5 have been found in
      Caenorhabditis elegans and Mus musculus. In vitro experiments demonstrated that
      ERdj5 interacts via its DnaJ domain with BiP in an ATP-dependent manner. ERdj5 is
      a ubiquitous protein localized in the ER and is particularly abundant in
      secretory cells. Its transcription is induced during ER stress, suggesting
      potential roles for ERdj5 in protein folding and translocation across the ER
      membrane.

PMID- 12411444
TI  - Automatic sequence design of major histocompatibility complex class I binding
      peptides impairing CD8+ T cell recognition.
AB  - An automatic protein design procedure was used to compute amino acid sequences of
      peptides likely to bind the HLA-A2 major histocompatibility complex (MHC) class I
      allele. The only information used by the procedure are a structural template, a
      rotamer library, and a well established classical empirical force field. The
      calculations are performed on six different templates from x-ray structures of
      HLA-A0201-peptide complexes. Each template consists of the bound peptide backbone
      and the full atomic coordinates of the MHC protein. Sequences within 2 kcal/mol
      of the minimum energy sequence are computed for each template, and the sequences
      from all the templates are combined and ranked by their energies. The five lowest
      energy peptide sequences and five other low energy sequences re-ranked on the
      basis of their similarity to peptides known to bind the same MHC allele are
      chemically synthesized and tested for their ability to bind and form stable
      complexes with the HLA-A2 molecule. The most efficient binders are also tested
      for inhibition of the T cell receptor recognition of two known CD8(+) T
      effectors. Results show that all 10 peptides bind the expected MHC protein. The
      six strongest binders also form stable HLA-A2-peptide complexes, albeit to
      varying degrees, and three peptides display significant inhibition of CD8(+) T
      cell recognition. These results are rationalized in light of our knowledge of the
      three-dimensional structures of the HLA-A2-peptide and HLA-A2-peptide-T cell
      receptor complexes.

PMID- 12411445
TI  - Activation of CCR5 by chemokines involves an aromatic cluster between
      transmembrane helices 2 and 3.
AB  - CCR5 is a G protein-coupled receptor responding to four natural agonists, the
      chemokines RANTES (regulated on activation normal T cell expressed and secreted),
      macrophage inflammatory protein (MIP)-1 alpha, MIP-1 beta, and monocyte
      chemotactic protein (MCP)-2, and is the main co-receptor for the macrophage
      tropic human immunodeficiency virus strains. We have previously identified a
      structural motif in the second transmembrane helix of CCR5, which plays a crucial
      role in the mechanism of receptor activation. We now report the specific role of
      aromatic residues in helices 2 and 3 of CCR5 in this mechanism. Using site
      directed mutagenesis and molecular modeling in a combined approach, we
      demonstrate that a cluster of aromatic residues at the extracellular border of
      these two helices are involved in chemokine-induced activation. These aromatic
      residues are involved in interhelical interactions that are key for the
      conformation of the helices and govern the functional response to chemokines in a
      ligand-specific manner. We therefore suggest that transmembrane helices 2 and 3
      contain important structural elements for the activation mechanism of chemokine
      receptors, and possibly other related receptors as well.

PMID- 12411446
TI  - Alternate activation of two divergently transcribed mouse genes from a
      bidirectional promoter is linked to changes in histone modification.
AB  - Thymidine kinase (TK) is a growth factor-inducible enzyme that is highly
      expressed in proliferating mammalian cells. Expression of mouse TK mRNA is
      controlled by transcriptional and posttranscriptional mechanisms including
      antisense transcription. Here we report the identification of a novel gene that
      is divergently transcribed from the bidirectional TK promoter. This gene encodes
      kynurenine formamidase (KF), an enzyme of the tryptophan metabolism. Whereas the
      TK gene is induced upon interleukin-2-mediated activation of resting T cells, the
      KF gene becomes simultaneously repressed. The TK promoter is regulated by E2F,
      SP1, histone acetyltransferases, and deacetylases. The binding site for the
      growth-regulated transcription factor E2F is beneficial for TK promoter activity
      but not required for KF expression. In contrast, the SP1 binding site is crucial
      for transcription in both directions. Inhibition of histone deacetylases by
      trichostatin A leads to increased histone acetylation at the TK/KF promoter and
      thereby to selective activation of the TK promoter and simultaneous shut-off of
      KF expression. Similarly, TK gene activation by interleukin-2 is linked to
      histone hyperacetylation, whereas KF expression correlates with reduced histone
      acetylation. The KF gene is the rare example of a mammalian gene whose expression
      is linked to histone hypoacetylation at its promoter.

PMID- 12411447
TI  - Mutations in the estrogen receptor DNA-binding domain discriminate between the
      classical mechanism of action and cross-talk with Stat5b and activating protein 1
      (AP-1).
AB  - Estrogen receptors (ERs) efficiently potentiate the transcriptional activity of
      prolactin-activated Stat5b through a mechanism that involves the ER DNA-binding
      domain (DBD) and the hinge domain. We have identified residues within the DBD of
      ER that are critical for the functional interaction of ER with Stat5b. We show
      that disruption of the second zinc finger structure abrogated cross-talk between
      ER and Stat5b, while the structure of the first zinc finger was not important.
      Furthermore, we confirm that intact DNA binding activity was not required for
      potentiation of Stat5b activity and that the dimerization of ER did not seem to
      be involved. Ligand-bound ERs also modulated activating protein 1-dependent
      transcription, and our data demonstrate that both zinc finger structures of the
      ER DBD are important for an intact response. We show that introduction of various
      point mutations within the DBD altered the response of the receptor to 17beta
      estradiol and to the estrogen antagonists 4-hydroxytamoxifen and ICI 182,870 on
      the collagenase promoter. These findings provide new insights into the mechanisms
      by which ERs act in cross-talk with non-related transcription factors.

PMID- 12411448
TI  - Progressive hypertension in a patient with "incidental" renal artery stenosis.

PMID- 12411450
TI  - Nonnarcotic analgesic use and the risk of hypertension in US women.
AB  - Acetaminophen, aspirin, and other nonsteroidal anti-inflammatory drugs (NSAIDs)
      are widely consumed. Each is theoretically capable of elevating blood pressure by
      altering prostaglandin homeostasis; however, there is little prospective
      information on the relation between these agents and physician-diagnosed
      hypertension. We examined the association between the use of aspirin,
      acetaminophen, or NSAIDs and incident hypertension in a prospective cohort study
      of 51 630 women 44 to 69 years of age in 1990 who had no history of hypertension
      or chronic renal insufficiency. Analgesic use was assessed in 1990 by a mailed
      questionnaire, and the women were followed for 8 years. The primary outcome was
      physician-diagnosed hypertension reported on a follow-up biennial questionnaire.
      During 381 078 person-years of follow-up, 10 579 incident cases of hypertension
      were identified. Compared with nonusers, women who used aspirin or acetaminophen
      at least 1 day per month or NSAIDs 5 or more days per month were at a
      significantly higher risk for development of hypertension. After adjusting for
      potential confounders, the odds ratios for women in the highest frequency of use
      category (> or =22 days per month) compared with no use were as follows: aspirin,
      1.21 (95% CI, 1.13 to 1.30); acetaminophen, 1.20 (1.08 to 1.33); and NSAIDs, 1.35
      (1.25 to 1.46). For each analgesic type, there was a significant trend toward an
      increased risk of incident hypertension with increasing frequency of use
      (P<0.001). Given the observed odds ratios, biologic plausibility, and the
      sizeable population at risk, health professionals should consider potential
      hypertensive effects of aspirin, acetaminophen, and NSAIDs when counseling their
      patients about the use of nonnarcotic analgesics.

PMID- 12411451
TI  - Angiotensin blockade prevents type 2 diabetes by formation of fat cells.
AB  - Obesity is the prime risk factor for the development of type 2 diabetes. Recent
      clinical trials have shown that blockade of the renin-angiotensin system, either
      by inhibiting the angiotensin-converting enzyme or blocking the angiotensin type
      1 receptor, may substantially lower the risk for type 2 diabetes. The mechanism
      underlying this effect is unknown. Based on our recent observation that
      angiotensin II markedly inhibits adipogenic differentiation of human adipocytes
      via the angiotensin type I receptor and that expression of angiotensin II-forming
      enzymes in adipose tissue is inversely correlated with insulin sensitivity, we
      propose the hypothesis that blockade of the renin-angiotensin system prevents
      diabetes by promoting the recruitment and differentiation of adipocytes.
      Increased formation of adipocytes would counteract the ectopic deposition of
      lipids in other tissues (muscle, liver, pancreas), thereby improving insulin
      sensitivity and preventing the development of type 2 diabetes.

PMID- 12411452
TI  - Results of the Diet, Exercise, and Weight Loss Intervention Trial (DEW-IT).
AB  - National guidelines for the prevention and treatment of hypertension recommend
      sodium reduction, weight loss, the Dietary Approach to Stop Hypertension (DASH)
      diet, and regular aerobic exercise. However, no trial has assessed the efficacy
      of simultaneously implementing all of these recommendations. The objective of
      this study was to determine the effects on blood pressure and other
      cardiovascular disease risk factors of a comprehensive lifestyle intervention. We
      conducted a randomized controlled trial of 44 hypertensive, overweight adults on
      a single blood pressure medication. Participants were randomized to a lifestyle
      or control group. For 9 weeks, the lifestyle group was fed a hypocaloric version
      of the DASH diet that provided 100 mmol/d of sodium. This group also participated
      in a supervised, moderate-intensity exercise program 3 times per week. The
      control group received no intervention. Outcomes were ambulatory blood pressure,
      serum lipids, weight, and fitness. At the end of the intervention, mean weight
      loss in the lifestyle group, net of control, was 4.9 kilograms. In the lifestyle
      group mean net reductions in 24-hour ambulatory systolic and diastolic blood
      pressures were 9.5 mm Hg (P<0.001) and 5.3 mm Hg (P<0.002), respectively.
      Corresponding changes in daytime systolic and diastolic blood pressures were 12.1
      mm Hg (P<0.001) and 6.6 mm Hg (P<0.001). The lifestyle group experienced mean
      reductions in total cholesterol (-25 mg/dL, P<0.001), low-density lipoprotein
      cholesterol (-18 mg/dL, P=0.005), high-density lipoprotein cholesterol (-5 mg/dL,
      P<0.001), net of control. In conclusion, among hypertensive overweight adults
      already on antihypertensive medication, a comprehensive lifestyle intervention
      can substantially lower blood pressure and improve blood pressure control.

PMID- 12411453
TI  - Genomic association/linkage of sodium lithium countertransport in CEPH pedigrees.
AB  - Little is known about genetic determinants explaining variation in the
      erythrocyte sodium-lithium countertransport (SLC), an intermediate phenotype of
      essential hypertension. We characterized the SLC in immortalized lymphoblasts and
      showed that its behavior is similar to that of erythrocyte SLC. We then performed
      association and linkage analyses of the SLC in immortalized lymphoblasts from 5
      large pedigrees from the Center d'Etude du Polymorphisme Humain (CEPH) genomics
      repository. The results of these analyses showed that a number of genomic regions
      harboring genes involved in glutathione metabolism might explain variations in
      SLC activity. These findings support evidence that thiol groups play a central
      role in SLC activity.

PMID- 12411454
TI  - Genome scan among Nigerians linking blood pressure to chromosomes 2, 3, and 19.
AB  - An understanding of the genetic influences on hypertension would help unravel the
      pathophysiology of this complex disorder and improve our understanding of causal
      mechanisms. Contemporary technology makes it possible to examine enough genetic
      markers to support a generalized search across the entire genome for candidate
      regions. In the present study, a family set was recruited from southwest Nigeria,
      and 378 microsatellite markers were typed on 792 individuals in 196 families.
      Multipoint variance component analysis identified linkage signals (logarithm of
      the odds [LOD] 1.74, P<0.0023) for systolic blood pressure on 19p (D19S714) and
      19q (D19S246), whereas for diastolic blood pressure, linkage was observed on 2p
      (D2S1790), 3p (D3S1304), 5q (D5S1462), 7p (D7S3046), 7q (D7S821), and 10q
      (D10S1221). Other regions of interest (1.18<LOD<1.74, 0.0023<P<0.01) were found
      on chromosomes 1, 6, 8, 9, and 11. These results provide additional evidence of
      linkage between blood pressure and several genomic regions reported in previous
      studies. Some of these regions additionally harbor hypertension candidate genes.
      Although evidence of linkage for blood pressure has been very slow to accumulate,
      even in comparison to other complex traits, the sum of current evidence appears
      to implicate, in particular, 2p, 3p, and 19p. Study designs that make it possible
      to confirm these results with association analysis and narrow the genomic
      interval are needed in order to make progress in this field.

PMID- 12411455
TI  - Identification of hypertension-related QTLs in African American sib pairs.
AB  - To link hypertension-related phenotypes with chromosomal loci, genome scans were
      performed in 150 African American sib pairs concordant for essential
      hypertension. Phenotypes included blood pressure, anthropomorphic measurements,
      and estimates of body fluid compartments as determined by impedance
      plethysmography. These phenotypes were also measured in 335 normotensive African
      Americans. Phenotypes with LOD scores >3.3 were further evaluated for
      significance by use of permutation procedures. Significant linkage was detected
      for body mass index (BMI) on chromosomes 1 and 8 and for the ratio of
      extracellular water to total body water (ECF/TBW) on chromosomes 3, 5, 6, and 7.
      Both BMI and ECF/TBW were greater in hypertensive sibs than in normotensive
      subjects (P<0.001). In a subset of hypertensive sibs and normotensive subjects,
      average 24-hour blood pressures were correlated with ECF/TBW (P<0.01). A region
      linked to BMI in the hypertensive sibs corresponds to a region of conserved
      synteny containing blood pressure-related QTLs in an F2 cross of Brown
      NorwayxDahl salt-sensitive rats. Focusing on hypertension-related phenotypes is a
      promising approach for identifying the genetic determinants of hypertension.

PMID- 12411456
TI  - Treatment and control of hypertension in the community: a prospective analysis.
AB  - Cross-sectional national data indicate poor levels of treatment and control of
      hypertension. We identified factors that prospectively predict initiation of
      antihypertensive therapy and attainment of blood pressure control in the
      community. We included all Framingham Heart Study subjects examined between 1987
      and 1999 who had untreated or uncontrolled hypertension (systolic > or =140 or
      diastolic > or =90 mm Hg) at a baseline examination and presented for follow-up
      examination 4 years later. Clinical covariates were examined for their
      association with initiation or control at follow-up. Among 1103 hypertensive
      participants who were untreated at baseline, 350 (31.7%) subjects were receiving
      therapy at follow-up, including 25.7% of subjects with stage 1 and 51.2% of those
      with stage > or =2 hypertension at baseline. Multivariate predictors of
      initiation of therapy included higher systolic and diastolic pressure, prevalent
      and interim cardiovascular disease, and left ventricular hypertrophy. Other
      cardiovascular risk factors did not predict initiation of treatment. Among 2475
      hypertensive participants who were uncontrolled (treated or untreated) at
      baseline, 988 (39.9%) were controlled at follow-up. Prevalent cardiovascular
      disease and interim initiation of therapy predicted control; older age and higher
      baseline systolic levels predicted lack of control. These data provide estimates
      of longitudinal rates of treatment and control of hypertension in the community.
      It appears that global risk was not taken into consideration when making
      decisions for initiation of therapy. Greater emphasis is needed on achieving
      blood pressure control in all patients but particularly among older subjects and
      those with systolic hypertension.

PMID- 12411457
TI  - Aldosterone antagonist improves diastolic function in essential hypertension.
AB  - Experimental studies demonstrated that mineralocorticoid antagonists prevent or
      reverse myocardial fibrosis. Therefore, we tested the hypothesis that the
      aldosterone antagonist canrenone can improve left ventricular diastolic function
      in essential hypertension. Using digitized M-mode echocardiography and 24-hour
      blood pressure monitoring (ABPM), we realized a prospective, randomized,
      controlled study on 34 never-treated essential hypertensives with left
      ventricular diastolic dysfunction. Echocardiogram and ABPM were repeated after 6
      months of effective antihypertensive treatment with ACE inhibitors and calcium
      antagonists (second evaluation) and then after a 6-month period with 17 patients
      randomly assigned to add canrenone 50 mg/d to the previous treatment (third
      evaluation). At the basal evaluation 32 patients had left ventricular concentric
      hypertrophy, and 2 patients had left ventricular concentric remodeling. All the
      patients had normal left ventricular systolic function. At the second evaluation
      blood pressure was reduced (P<0.0001), left ventricular mass index decreased
      (P<0.0001), and diastolic function improved (P<0.0001). After randomization, the
      canrenone and control groups had similar 24-hour blood pressure and left
      ventricular morpho-functional characteristics. At the third evaluation, despite
      unchanged blood pressure and similar decrease of left ventricular mass index, the
      canrenone group, compared with control group, showed a significantly greater
      increase in left ventricular diastolic indices. In essential hypertension, a low
      dose of aldosterone antagonist added to antihypertensive treatment significantly
      improved left ventricular diastolic function. This improvement, not accounted for
      by changes in blood pressure and left ventricular mass, can be therefore ascribed
      to a direct action of the drug on the myocardium.

PMID- 12411458
TI  - Kallikrein gene delivery improves cardiac reserve and attenuates remodeling after
      myocardial infarction.
AB  - In this study, we used the somatic gene delivery approach to explore the role of
      the kallikrein-kinin system (KKS) in cardiac remodeling and apoptosis after
      myocardial infarction (MI). Rats were subjected to coronary artery ligation to
      induce MI, and adenovirus carrying the human tissue kallikrein or luciferase gene
      was injected into the tail vein at 1 week after surgery. Cardiac output gradually
      decreased from 2 to 6 weeks after MI, whereas delivery of the kallikrein gene
      prevented this decrease. Cardiac responses to dobutamine-induced stress were
      improved in rats receiving kallikrein gene as compared with rats receiving
      control virus at 6 weeks after MI. Kallikrein significantly improved cardiac
      remodeling by decreasing collagen density, cardiomyocyte size, and left
      ventricular internal perimeter and increasing capillary density in the heart at 6
      weeks after MI. Kallikrein gene transfer attenuated myocardial apoptosis, which
      was positively correlated with remodeling parameters in the heart at 2 weeks
      after MI. Endothelial dysfunction, characterized by increased vascular
      resistance, decreased left ventricular blood flow, and decreased cardiac nitric
      oxide levels, existed in remodeled hearts at 2 weeks after MI, whereas kallikrein
      gene transfer improved these parameters. Kallikrein gene delivery improved cell
      survival parameters as shown by increased phospho-Akt and reduced caspase-3
      activation at 2 weeks after MI. This study indicates that the kallikrein-kinin
      system plays an important role in preventing the progression of heart failure by
      attenuating cardiac hypertrophy and fibrosis, improving endothelial function, and
      inhibiting myocardial apoptosis through the Akt-mediated signaling pathway.

PMID- 12411459
TI  - Gq-coupled receptor agonists mediate cardiac hypertrophy via the vasculature.
AB  - The Gq-coupled receptor-signaling pathway has been implicated in the cardiac
      hypertrophic response to stress, but little is actually known about the
      contributions of Gq signaling in either the heart or the vasculature. Therefore,
      we developed a line of transgenic mice that express a peptide inhibitor of Gq
      (GqI) in vascular smooth muscle to determine if vascular Gq signaling was
      important in the cardiac hypertrophic response. After chronic administration of
      the Gq agonists phenylephrine, serotonin, and angiotensin II, we observed an
      attenuation of mean arterial blood pressure and an inhibition of cardiac
      hypertrophy in the transgenic mice with vascular-specific GqI expression. In
      contrast, cardiac GqI peptide expression did not attenuate the hypertension or
      the cardiac hypertrophy. Importantly, all mice were capable of cardiac
      hypertrophy, because direct beta-adrenergic receptor stimulation induced a
      similar level of hypertrophy in both lines of transgenic mice. This clearly
      suggests that after chronic Gq-coupled receptor agonist administration, it is the
      hypertensive state induced by vascular Gq activation that mediates remodeling of
      the heart, rather than direct stimulation of cardiac Gq-coupled receptors. Thus,
      the contribution of vascular Gq-coupled signaling to the development of cardiac
      hypertrophy is significant and suggests that expression of the GqI peptide is a
      novel therapeutic strategy to lower Gq-mediated hypertension and cardiac
      hypertrophy.

PMID- 12411460
TI  - Long-term adrenomedullin administration in experimental heart failure.
AB  - Short-term administration of adrenomedullin, a recently discovered peptide with
      potent vasodilator, natriuretic, and aldosterone-inhibitory actions, has
      beneficial effects in experimental and clinical heart failure. The effects of
      prolonged adrenomedullin administration have not previously been assessed in this
      setting. Consequently, in 16 sheep with pacing-induced heart failure, we infused
      either adrenomedullin (10 ng/kg per minute; n=8) or a vehicle control (Hemaccel;
      n=8) for 4 days. Compared with control data, infusion of adrenomedullin
      persistently increased circulating levels of the peptide (by approximately 9.5
      pmol/L; P<0.001), in association with prompt (15 minutes) and sustained (4 days)
      increases in cardiac output (day 4, 27%), and reductions in peripheral resistance
      (30%), mean arterial pressure (13%), and left atrial pressure (24%; all,
      P<0.001). Adrenomedullin also significantly enhanced urinary sodium excretion
      (day 4, 3-fold; P<0.05), creatinine excretion (1.2-fold; P<0.001), and creatinine
      clearance (1.4-fold; P<0.001) over the 4 days of treatment, whereas urine volume
      and cAMP excretion tended to be elevated (both, 0.1>P>0.05). Plasma renin
      activity was increased (P<0.05), whereas aldosterone levels were reduced in a
      sustained fashion (P<0.01). Plasma endothelin rose transiently (hours 1 to 6)
      after initiation of treatment (P<0.05). Despite substantial cardiac unloading,
      plasma concentrations of the natriuretic peptides were not significantly
      different from control. In conclusion, long-term administration of adrenomedullin
      induces pronounced and sustained cardiovascular and renal effects in experimental
      heart failure, including reductions in cardiac preload and afterload, as well as
      augmentation of cardiac output, sodium excretion, and glomerular filtration.
      These findings support the concept of adrenomedullin as a protective hormone
      during hemodynamic compromise with therapeutic potential in heart failure.

PMID- 12411461
TI  - Left ventricular mass: reliability of M-mode and 2-dimensional echocardiographic
      formulas.
AB  - The study of left ventricular (LV) hypertrophy is hindered by problems with LV
      mass measurement by echocardiography. Both the M-mode and 2D area-length formulas
      for calculating LV mass assume a fixed geometric shape, which may be a source of
      error. We examined this hypothesis by using cardiovascular magnetic resonance
      images to eliminate the confounding effects of acoustic access and image quality.
      LV mass was measured directly in 212 healthy subjects by means of a standard 3D
      cardiovascular magnetic resonance technique. LV mass was also calculated by using
      the cube-function and area-length formulas with measurements from the magnetic
      resonance images. A comparison of serial measurements was made by examining the
      changes in LV mass by all 3 techniques in those completing an exercise program
      (n=140). The cube-function technique showed a consistent underestimation of LV
      mass of 14.3 g, and there were wide 95% limits of agreement (+/-57.6 g and +/
      46.3 g for cube-function and area-length techniques, respectively) when compared
      with 3D measurement. There were similarly wide limits of agreement for the change
      in mass (+/-55.2 g and +/-44.8 g for cube-function and area-length,
      respectively). The assumption of geometric shape in the cube-function and area
      length formulas resulted in significant variation in LV mass estimates from
      direct measurement by using a 3D technique. The technique cannot be recommended
      either at a single time point or for serial studies in small populations; 3D
      imaging techniques, such as cardiovascular magnetic resonance, are preferable.

PMID- 12411463
TI  - Antiinflammatory and antiarteriosclerotic effects of pioglitazone.
AB  - Peroxisome proliferator-activated receptor-gamma (PPARgamma) ligands are widely
      used in patients with insulin resistance and diabetes. Because coronary artery
      disease is a major complication for such patients, it is important to determine
      the effects of PPARgamma activation on arteriosclerosis. Long-term inhibition of
      endothelial NO synthesis by administration of N(omega)-nitro-L-arginine methyl
      ester (L-NAME) to rats induces coronary vascular inflammation (monocyte
      infiltration, monocyte chemoattractant protein-1 [MCP-1] expression) and
      subsequent arteriosclerosis. We examined the effects of pioglitazone (a PPARgamma
      ligand) in this rat model to determine whether PPARgamma activation with
      pioglitazone inhibits arteriosclerosis by its indirect effects on metabolic
      conditions or by direct effects on the cells participating to the pathogenesis of
      arteriosclerosis. We found that pioglitazone did not affect metabolic states,
      systolic blood pressure, or serum NO levels, but did prevent the L-NAME-induced
      coronary inflammation and arteriosclerosis. Pioglitazone did not reduce local
      expression of MCP-1 but markedly attenuated increased expression of the MCP-1
      receptor C-C chemokine receptor 2 (CCR2) in lesional and circulating monocytes.
      PPARgamma activation with pioglitazone prevented coronary arteriosclerosis,
      possibly by its antiinflammatory effects (downregulation of CCR2 in circulating
      monocytes). Inhibition of the CCR2-mediated inflammation may represent novel
      antiinflammatory actions of pioglitazone beyond improvement of metabolic state.

PMID- 12411464
TI  - Central ghrelin modulates sympathetic activity in conscious rabbits.
AB  - Ghrelin is an orexigenic peptide originally isolated from the stomach.
      Intravenous administration of ghrelin has been shown to elicit a decrease in
      arterial pressure without a significant change in heart rate (HR), suggesting
      that ghrelin may act on the central nervous system to modulate sympathetic
      activity. The aim of the present study was to determine the central effects of
      ghrelin on cardiovascular and sympathetic responses in conscious rabbits.
      Intravenous injection of ghrelin elicited dose-related decreases in arterial
      pressure and HR, without a significant change in renal sympathetic nerve
      activity. On the other hand, intracerebroventricular injection of 1 nmol of
      ghrelin decreased arterial pressure, HR, and renal sympathetic nerve activity.
      Peak depressor or sympathoinhibitory responses of mean arterial pressure and
      renal sympathetic nerve activity (-19.0+/-1.5 mm Hg and -43.3+/-5.4%) were
      observed at 50 and 40 minutes, respectively, after intracerebroventricular
      injection of 1 nmol of ghrelin. Furthermore, a subdepressor dose of
      intracerebroventricular infusion of ghrelin (0.3 nmol/150 micro L per hour)
      significantly augmented the baroreflex sensitivities assessed by renal
      sympathetic nerve activity and HR compared with those of vehicle infusion
      (G(max); -17.8+/-3.1 versus -9.4+/-1.6%/mm Hg, P<0.05; -12.5+/-1.8 versus -6.6+/
      1.2 bpm/mm Hg, P<0.05; respectively). These results suggest that intravenous
      injection of ghrelin acts, at least in part, on the central nervous system to
      decrease arterial pressure and renal sympathetic nerve activity, and that central
      ghrelin participates in the regulations of the sympathetic nerve activity to the
      kidney and the baroreceptor reflex in conscious rabbits.

PMID- 12411462
TI  - Hypertension, insulin, and proinsulin in participants with impaired glucose
      tolerance.
AB  - The association of insulin resistance and hyperinsulinemia to blood pressure has
      remained controversial. We examined the association of insulinemia to
      hypertension and blood pressure using baseline measurements for participants of
      the Diabetes Prevention Program (DPP). The DPP is a multicenter randomized
      controlled trial of 3819 participants with impaired glucose tolerance, and is
      designed to evaluate interventions for the delay or prevention of type 2
      diabetes. The relationship between hypertension and insulinemia is described
      overall and by ethnicity. The effects of demographics (age and gender),
      adiposity, and glucose on the relationship are also presented. Asian Americans
      and African Americans had a similarly high prevalence of hypertension as did
      whites; American Indians had a lower prevalence of hypertension. Among
      participants not on antihypertensive medications, systolic blood pressure was
      significantly (but weakly) correlated with fasting insulin (r=0.12), homeostasis
      model assessment of insulin resistance (HOMA IR; r=0.13), and fasting proinsulin
      (r=0.10) when adjusted for age and gender (all, P<0.001). Systolic blood pressure
      showed similar correlations to fasting insulin in each ethnic group. After
      further adjustment for body mass index, the association of fasting insulin to
      systolic and diastolic blood pressures weakened considerably but remained
      significant (systolic: r=0.06, P=0.002; DBP: r=0.06, P<0.001). We conclude that a
      weak but significant association between insulin, (and proinsulin and HOMA IR)
      and blood pressure exists but is largely explained by overall adiposity. This
      association is similar among ethnicities, with the possible exception of
      Hispanics. The relation between insulin concentrations and blood pressure
      explains relatively little of the ethnic differences in hypertensive prevalence.

PMID- 12411465
TI  - Angiotensin II triggers EGFR tyrosine kinase-dependent Ca2+ influx in afferent
      arterioles.
AB  - We previously reported that inhibition of epidermal growth factor receptor
      tyrosine kinase activity attenuates renal arteriolar contractile responses to
      angiotensin II. We performed the present experiments to determine if epidermal
      growth factor receptor tyrosine kinase activity contributes to the afferent
      arteriolar intracellular [Ca2+] response to angiotensin II. Afferent arterioles
      were dissected from rat kidney and intracellular [Ca2+] was monitored with the
      use of fura-2. In normal Ringer's bath containing 1.5 mmol/L Ca2+, basal
      intracellular [Ca2+] averaged 95+/-7 nmol/L and 100 nmol/L angiotensin II caused
      a rapid rise (peak Delta=75+/-10 nmol/L) that waned to a plateau averaging 24+/-5
      nmol/L above baseline. Pretreatment with 100 nmol/L AG1478 (epidermal growth
      factor receptor tyrosine kinase inhibitor) reduced both the peak and the plateau
      stages of the angiotensin II response (peak Delta=42+/-7 nmol/L; plateau
      Delta=8+/-4 nmol/L). A structurally unrelated epidermal growth factor receptor
      tyrosine kinase inhibitor also suppressed the peak response to angiotensin II,
      whereas tyrosine phosphatase inhibition enhanced the plateau phase of the
      response. In the presence of 100 nmol/L extracellular Ca2+, the angiotensin II
      response was characterized by a peak of diminished magnitude (Delta=49+/-10
      nmol/L; P<0.05 versus the response in normal Ringer's bath) with no plateau, and
      this response was unaffected by AG1478. Moreover, angiotensin II stimulation of
      divalent cation influx (Mn2+ quench of fura-2 fluorescence) was decreased
      significantly by AG1478. We conclude that epidermal growth factor receptor
      tyrosine kinase activity contributes to the afferent arteriolar intracellular
      [Ca2+] response to angiotensin II and that this process involves promotion of
      Ca2+ influx.

PMID- 12411466
TI  - Biphasic regulation of Na+-HCO3- cotransporter by angiotensin II type 1A
      receptor.
AB  - Although angiotensin (Ang) II is known to regulate renal proximal transport in a
      biphasic way, the receptor subtype(s) mediating these Ang II effects remained to
      be established. To clarify this issue, we compared the effects of Ang II in wild
      type mice (WT) and Ang II type 1A receptor-deficient mice (AT(1A) KO). The Na+
      HCO3- cotransporter (NBC) activity, analyzed in isolated nonperfused tubules with
      a fluorescent probe, was stimulated by 10(-10) mol/L Ang II but was inhibited by
      10(-6) mol/L Ang II in WT. Although valsartan (AT1 antagonist) blocked both
      stimulation and inhibition by Ang II, PD 123,319 (AT2 antagonist) did not modify
      these effects of Ang II. In AT1A KO, in contrast, this biphasic regulation was
      lost, and only stimulation of NBC activity by 10(-6) mol/L Ang II was observed.
      This stimulation was blocked by valsartan but not by PD 123,319. More than 10(-8)
      mol/L Ang II induced a transient increase in cell Ca2+ concentrations in WT,
      which was again blocked by valsartan but not by PD 123,319. However, up to 10(-5)
      mol/L Ang II did not increase cell Ca2+ concentrations in AT1A KO. Finally, the
      addition of arachidonic acid inhibited the NBC activity similarly in WT and
      AT(1A) KO, suggesting that the inhibitory pathway involving P-450 metabolites is
      preserved in AT(1A) KO. These results indicate that AT(1A) mediates the biphasic
      regulation of NBC. Although low-level expression of AT(1B) could be responsible
      for the stimulation by 10(-6) mol/L Ang II in AT1A KO, no evidence was obtained
      for AT2 involvement.

PMID- 12411467
TI  - Endoglin upregulation during experimental renal interstitial fibrosis in mice.
AB  - The goal of the present study was to evaluate the role of endoglin, a
      transforming growth factor-beta1 (TGF-beta1) accessory receptor, in the
      pathogenesis of renal fibrosis. This was achieved by testing a model of tubulo
      interstitial fibrosis induced by unilateral ureteral obstruction in endoglin
      heterozygous (Eng(+/-)) mice. Northern and Western blot analysis revealed that
      endoglin expression in kidneys of these mice was significantly reduced compared
      with Eng(+/+) littermates. Pronounced interstitial fibrosis induced by ureteral
      obstruction was confirmed histologically by Masson's trichromic staining and by
      increased immunostaining for fibronectin and laminin without significant
      differences between Eng(+/-) and Eng(+/+) mice. Ureteral obstruction induced
      significant increases in alpha2(I) and alpha1(IV) collagen, fibronectin, and TGF
      beta1 mRNA levels, as well as in total kidney collagen but changes were similar
      in Eng(+/-) and Eng(+/+) mouse kidneys. Ureteral obstruction also induced a 2
      fold increase in endoglin mRNA levels in both Eng(+/+) mice and Eng(+/-) mice,
      which was confirmed by Western blot analysis. Thus, the present study provides
      clear evidence that endoglin is upregulated in the kidneys of mice with
      interstitial fibrosis induced by unilateral ureteral ligation. However, Eng(+/-)
      mice do not show any changes in the severity of renal disease induced in this
      model when compared with normal mice, suggesting that the absolute level of
      endoglin is not critical for the effects of TGF-beta1 in the renal fibrosis
      process.

PMID- 12411468
TI  - Role of cyclooxygenase-2 in the prolonged regulation of renal function.
AB  - The role of cyclooxygenase-2 (COX-2) in the prolonged regulation of renal
      function was evaluated during changes in sodium intake and reduction of NO
      synthesis. It was evaluated in conscious dogs by administering a selective
      inhibitor (nimesulide) during 8 consecutive days. Nimesulide administration to
      dogs with normal or high sodium load did not modify glomerular filtration rate
      but reduced renal blood flow (16%; P<0.05). The vasoconstriction elicited by COX
      2 inhibition was greater when NO production was inhibited because glomerular
      filtration rate decreased by >25% when nimesulide was administered to dogs with a
      reduced NO synthesis. During low sodium intake, COX-2 inhibition elicited a
      decrease (P<0.05) of both glomerular filtration rate (34%) and renal blood flow
      (31%). Sodium excretion only decreased (P<0.05) during the first day of COX-2
      inhibition in dogs with normal or high sodium load. The increase in plasma
      potassium levels elicited by COX-2 inhibition was greater in dogs with low sodium
      intake and was enhanced when NO production was inhibited. This change in
      potassium was not secondary to a decrease in plasma aldosterone levels. The
      results of this study suggest that COX-2-derived metabolites (1) play a more
      important role in the long-term regulation of renal hemodynamic when sodium
      intake is low, (2) protect the renal vasculature from the vasoconstriction
      secondary to a reduction in NO, (3) are only acutely involved in regulating
      urinary sodium excretion, and (4) play a more important role in regulating plasma
      potassium concentration when NO synthesis is reduced.

PMID- 12411469
TI  - Programming effects of short prenatal exposure to dexamethasone in sheep.
AB  - Recent studies have linked fetal exposure to a suboptimal intrauterine
      environment with adult hypertension. The aims of the present study were to see
      whether prenatal dexamethasone administered intravenously to the ewe between 26
      to 28 days of gestation (1) resulted in high blood pressure in male and female
      offspring and whether hypertension in males was modulated by testosterone status,
      and (2) altered gene expression for angiotensinogen and angiotensin type 1 (AT1)
      receptors in the brain in late gestation and in the adult. Basal mean arterial
      pressure (MAP) at 2 years of age was significantly higher in wethers exposed to
      prenatal dexamethasone (group D; 106+/-5 mm Hg, n=9) compared with the control
      group (group S; 91+/-3 mm Hg, n=8; P<0.01). Infusion of testosterone for 3 weeks
      had no effect on MAP in either treatment group. At 130 days of gestation,
      dexamethasone administered between 26 to 28 days of gestation (group DF; n=8),
      resulted in an increased expression of angiotensinogen in hypothalamus (in
      arbitrary units: 2.5+/-0.3 versus 1.3+/-0.3 in the saline group [group SF], n=10;
      P<0.05). In addition, there was higher expression of the AT1 receptors in medulla
      oblongata in group DF (2.6+/-0.6 versus 1.1+/-0.2 in group SF; P<0.01). This
      effect of prenatal dexamethasone treatment was still evident in females at 7
      years of age (group DA; n=5; 2.6+/-0.5 versus 1.1+/-0.2 in group SA; n=6,
      P<0.05). In conclusion, brief prenatal exposure of the pregnant ewe to
      dexamethasone leads to hypertension in adult animals of both sexes. Most
      interestingly, the mechanism leading to programming of hypertension might be
      linked with the brain angiotensin system.

PMID- 12411470
TI  - Essential role of AT1A receptor in the development of 2K1C hypertension.
AB  - The aims of this study were to delineate the relative contribution of angiotensin
      II (ANG II) subtype 1A (AT1A) and 1B (AT1B) receptors to the development of two
      kidney, one-clip (2K1C) Goldblatt hypertension in mice, to examine if increased
      nitric oxide synthase (NOS) activity counteracts the vasoconstrictor influences
      of ANG II in 2K1C hypertensive mice, and to determine the role of ANG II type 2
      (AT2) receptors in 2K1C hypertension in mice. AT(1A) ANG II receptor knockout
      (AT1A-/-) and wild-type (AT1A+/+) mice underwent clipping of the right renal
      artery. Systolic blood pressure (SBP) was significantly lower in AT1A-/- compared
      with AT1A+/+ mice, and neither clip placement nor AT2 receptor blockade with PD
      123319 (PD) altered SBP in AT1A-/- mice. A significant and sustained rise in SBP
      from 119+/-5 to 163+/-6 mm Hg was observed in the 2K1C AT1A+/+ mice from day 10
      to day 26. Chronic PD infusion did not alter the course of hypertension in
      2K1C/AT1A+/+. Acute PD infusion did not alter mean arterial pressure (MAP) in
      AT1A+/+, PD/AT1A+/+, 2K1C/AT1A+/+, PD/2K1C/AT1A+/+, AT1A-/-, PD/AT1A-/-, and
      PD/2K1C/AT1A-/- mice compared with basal levels. In contrast, acute PD infusion
      caused significant increases in MAP in 2K1C/AT1A-/- mice. The subsequent acute
      NOS inhibition caused greater increases in MAP in 2K1C/AT1A+/+ and
      PD/2K1C/AT1A+/+ mice than in AT1A+/+ and PD/AT1A+/+ mice. These results support
      the essential role of AT1A receptors in mediating 2K1C hypertension and support
      the hypothesis that augmented NO production serves as a counteracting system in
      this model of hypertension.

PMID- 12411472
TI  - Leptin induces endothelial cell migration through Akt, which is inhibited by
      PPARgamma-ligands.
AB  - Migration of endothelial cells (EC) is a key event in angiogenesis that
      contributes to neovascularization in diabetic vasculopathy. Leptin induces
      angiogenesis and is elevated in obesity and hyperinsulinemia. The antidiabetic
      thiazolidinediones (TZD) inhibit leptin gene expression and vascular smooth
      muscle cell migration through activation of the peroxisome proliferator-activated
      receptor-gamma (PPARgamma). This study investigates the role of leptin in EC
      migration, the chemotactic signaling pathways involved, and the effects of the
      TZD-PPARgamma ligands troglitazone (TRO) and ciglitazone (CIG) on EC migration.
      We demonstrate that leptin induces EC migration. Because activation of two
      signaling pathways, the phosphatidylinositol-3 kinase (PI3K)-->Akt-->eNOS and the
      ERK1/2 MAPK pathway, is known to be involved in cell migration, we used the
      pharmacological inhibitors wortmannin and PD98059 to determine if chemotactic
      signaling by leptin involves Akt or ERK1/2, respectively. Both wortmannin and
      PD98059 significantly inhibited leptin-induced migration. Treatment with the TZD
      PPARgamma-ligands TRO and CIG significantly inhibited the chemotactic response
      toward leptin. Both PPARgamma-ligands inhibited leptin-stimulated Akt and eNOS
      phosphorylation, but neither attenuated ERK 1/2 activation in response to leptin.
      The inhibition of Akt-phosphorylation was accompanied by a PPARgamma-ligand
      mediated upregulation of PTEN, a phosphatase that functions as a negative
      regulator of PI3K-->Akt signaling. These experiments provide the first evidence
      that activation of Akt and ERK 1/2 are crucial events in leptin-mediated signal
      transduction leading to EC migration. Moreover, inhibition of leptin-directed
      migration by the PPARgamma-ligands TRO and CIG through inhibition of Akt
      underscores their potential in the prevention of diabetes-associated
      complications.

PMID- 12411471
TI  - Is cardiovascular reactivity associated with atherosclerosis among hypertensives?
AB  - Exaggerated cardiovascular reactivity to behavioral challenges among otherwise
      healthy individuals has been associated with carotid atherosclerosis. We
      evaluated whether a similar relationship exists among hypertensives, who are at a
      heightened atherosclerotic risk. Untreated, hypertensive men (n=251; age range,
      40 to 70 years; 197 white, 54 black) completed a standardized battery of
      behavioral challenges while their blood pressure responses to the battery were
      measured. Mean and maximum carotid intima-media thickness and the occurrence of
      carotid plaques were subsequently determined using B-mode ultrasonography.
      Although greater systolic and diastolic responses to the battery were associated
      with greater mean and maximum intima-media thickness in univariate analyses
      (P<0.01), only diastolic reactivity showed a unique association with mean and
      maximum carotid intima-media thickness after multivariate adjustment for age,
      race, socioeconomic status, smoking and alcohol use, body mass index, lipid
      profile, glucose and insulin concentrations, and resting blood pressure (P<0.05).
      Carotid plaque occurrence was associated with greater systolic reactivity
      (P=0.05) and was marginally associated with greater diastolic reactivity (P=0.07)
      in univariate analyses, but neither systolic nor diastolic reactivity was
      uniquely associated with the presence of carotid plaques after multivariate risk
      factor adjustment. Among hypertensives, exaggerated behaviorally evoked
      cardiovascular reactivity appears to be uniquely associated with greater carotid
      intima-media thickness but not with carotid plaque occurrence.

PMID- 12411473
TI  - NAD(P)H oxidase inhibition improves endothelial function in rat and human blood
      vessels.
AB  - The NO/superoxide (O2-) balance is a key regulator of endothelial function. O2-
      levels are elevated in many forms of cardiovascular disease; therefore,
      decreasing O2- should improve endothelial function. To explore this hypothesis,
      internal mammary arteries and saphenous veins, obtained from patients undergoing
      coronary artery revascularization, and aortic and carotid arteries from Wistar
      Kyoto and spontaneously hypertensive stroke-prone rats were incubated with O2-
      dismutase or NAD(P)H oxidase inhibitors. O2- levels were measured using lucigenin
      chemiluminescence; NO bioavailability was assessed in organ chambers; and mRNA
      expression of NAD(P)H oxidase components was quantified by use of a Light Cycler.
      In rat arteries, phenylarsine oxide, 4-(2-aminoethyl)-benzenesulfanyl fluoride,
      and apocynin all decreased NADH-stimulated O2- production, but only apocynin
      increased NO bioavailability. In human internal mammary arteries and saphenous
      veins, apocynin decreased NAD(P)H-stimulated O2- generation and caused
      vasorelaxation that was endothelium dependent and reversed on addition of the NO
      synthase inhibitor N(G)-nitro-L-arginine methyl ester. In addition, it increased
      NO production from cultured human endothelial saphenous vein cells. Polyethylene
      glycolated O2- dismutase also increased NO bioavailability in rat carotid
      arteries and human blood vessels, but the effects were smaller than those
      observed with apocynin. NADH-generated O2- and mRNA expression of p22(phox),
      gp91(phox), and nox-1 were comparable between the 2 strains of rat. This is the
      first study to demonstrate pharmacological effects of apocynin in human blood
      vessels. The increases in NO bioavailability shown here suggest that the NAD(P)H
      oxidase pathway may be a novel target for drug intervention in cardiovascular
      disease.

PMID- 12411474
TI  - Interaction of sildenafil with cAMP-mediated vasodilation in vivo.
AB  - Sildenafil inhibits cGMP breakdown by phosphodiesterase 5. In vitro, increased
      cGMP levels inhibit cAMP breakdown by phosphodiesterase 3. It is uncertain,
      however, whether sildenafil increases biological effects of interventions
      increasing cAMP levels in vivo. The objective of the present study in 40 healthy
      male volunteers was to determine the existence and extent of interactions with
      sildenafil and vasodilators acting via cGMP or cAMP or independently from these
      mediators on the arterial tone of the human forearm. Forearm blood flow (FBF)
      responses (plethysmography) to brachial artery infusions of 3 doses each of
      nitroglycerin, which increases cGMP levels; of isoprenaline and milrinone, which
      increase cAMP levels; and of verapamil as a control were assessed at baseline and
      80 minutes after 50 mg oral sildenafil in 10 volunteers each. Sildenafil
      increased FBF (2.5+/-0.1 to 3.5+/-0.2 mL/min per 100 mL, P<0.001; n=40). At
      equipotent vasodilator dosages, sildenafil increased FBF from 7.5+/-1.0 to 9.8+/
      1.2 mL/min per 100 mL for nitroglycerin, from 8.3+/-1.0 to 10.4+/-1.4 mL/min per
      100 mL for isoprenaline, and from 8.1+/-1.0 to 10.3+/-1.2 mL/min per 100 mL for
      milrinone and slightly decreased FBF from 7.7+/-1.3 to 7.1+/-1.2 mL/min per 100
      mL for verapamil. ANOVA for repeated measures revealed a significant interaction
      between sildenafil and the type of vasodilator on FBF (P<0.01). The responses of
      FBF to nitroglycerin, milrinone, and isoprenaline after sildenafil were similarly
      increased compared with the response to verapamil (P<0.01). Sildenafil markedly
      enhanced the arterial vasodilator response to nitroglycerin, milrinone, and
      isoprenaline. The response to milrinone and isoprenaline is compatible with an
      interaction between cGMP and phosphodiesterase 3 or an enhancement of the NO
      component of cAMP-mediated vasodilation, and raises the possibility of enhanced
      biological effects of interventions leading to increases of cAMP in the presence
      of sildenafil.

PMID- 12411475
TI  - Circadian differences in stress-induced pressor reactivity in mice.
AB  - The objective of this study was to determine the effect of chronic stress
      exposure on the circadian pattern of cardiovascular responses in mice. Using male
      C57BL6 mice with carotid arterial catheters, we tested the effect of 7 days of
      intermittent shaker stress on body weight, food intake, drinking activity, plasma
      corticosterone, mean arterial pressure (MAP), and heart rate. The stress was
      delivered automatically for 2-minute periods (150 cycles/min), 45 times/d for 7
      days. Plasma corticosterone was significantly increased in acutely and
      chronically stressed mice, with a partial attenuation in the chronic condition.
      Stress increased water intake, produced no change in food intake, and
      significantly decreased body weight (5% change). MAP and heart rate were measured
      continuously on stress days 1, 3, and 7 and during the basal and recovery
      periods. Chronic stress did not produce a sustained increase in MAP; however,
      there was an increase in MAP during the first stress day and a decrease during
      the recovery period. There was a circadian pattern in the pressor responses, with
      greater increases seen during the light period (nonactive phase) than in the dark
      period (+24% versus +11% on stress day 3, light versus dark). The results suggest
      that a stress delivered during the nonactive phase represents a higher
      cardiovascular risk.

PMID- 12411476
TI  - Antithrombotic effect of captopril and losartan is mediated by angiotensin-(1-7).
AB  - It is well established that renin-angiotensin system blockers exert
      NO/prostacyclin-dependent antithrombotic effects. Because some beneficial effects
      of these drugs are mediated by angiotensin (Ang)-(1-7), in the present study we
      examined if their antithrombotic action could be mediated by Ang-(1-7).
      Intravenous infusion of Ang-(1-7) (1, 10, or 100 pmol/kg per minute for 2 hours)
      into rats developing venous thrombosis caused 50% to 70% reduction of the
      thrombus weight. This effect was dose-dependently reversed by cotreatment with A
      779 (selective Ang-[1-7] receptor antagonist) or EXP 3174 (angiotensin type 1
      receptor antagonist) but not by PD 123,319 (angiotensin type 2 receptor
      antagonist). Similarly, the antithrombotic effects of captopril (ACE inhibitor)
      and losartan (angiotensin type 1 receptor blocker) were attenuated by A-779 in a
      dose-dependent manner. The effect of Ang-(1-7) was completely abolished by
      concomitant administration of NO synthase inhibitor (N(G)-nitro-L-arginine methyl
      ester) and prostacyclin synthesis inhibitor (indomethacin), as has been shown
      previously for captopril and losartan. Thus, the antithrombotic effect of renin
      angiotensin system blockers involves Ang-(1-7)-evoked release of NO and
      prostacyclin.

PMID- 12411477
TI  - Molecular architecture and mechanism of an icosahedral pyruvate dehydrogenase
      complex: a multifunctional catalytic machine.
AB  - Electron cryo-microscopy of 'single particles' is a powerful method to determine
      the three-dimensional (3D) architectures of complex cellular assemblies. The
      pyruvate dehydrogenase multi-enzyme complex couples the activity of three
      component enzymes (E1, E2 and E3) in the oxidative decarboxylation of pyruvate to
      generate acetyl-CoA, linking glycolysis and the tricarboxylic acid cycle. We
      report here a 3D model for an 11 MDa, icosahedral pyruvate dehydrogenase sub
      complex, obtained by combining a 28 A structure derived from electron cryo
      microscopy with previously determined atomic coordinates of the individual E1 and
      E2 components. A key feature is that the E1 molecules are located on the
      periphery of the assembly in an orientation that allows each of the 60 mobile
      lipoyl domains tethered to the inner E2 core to access multiple E1 and E2 active
      sites from inside the icosahedral complex. This unexpected architecture provides
      a highly efficient mechanism for active site coupling and catalytic rate
      enhancement by the motion of the lipoyl domains in the restricted annular region
      between the inner core and outer shell of the complex.

PMID- 12411478
TI  - Structural basis for the oxidation of thiosulfate by a sulfur cycle enzyme.
AB  - Reduced inorganic sulfur compounds are utilized by many bacteria as electron
      donors to photosynthetic or respiratory electron transport chains. This
      metabolism is a key component of the biogeochemical sulfur cycle. The SoxAX
      protein is a heterodimeric c-type cytochrome involved in thiosulfate oxidation.
      The crystal structures of SoxAX from the photosynthetic bacterium Rhodovulum
      sulfidophilum have been solved at 1.75 A resolution in the oxidized state and at
      1.5 A resolution in the dithionite-reduced state, providing the first structural
      insights into the enzymatic oxidation of thiosulfate. The SoxAX active site
      contains a haem with unprecedented cysteine persulfide (cysteine sulfane)
      coordination. This unusual post-translational modification is also seen in
      sulfurtransferases such as rhodanese. Intriguingly, this enzyme shares further
      active site characteristics with SoxAX such as an adjacent conserved arginine
      residue and a strongly positive electrostatic potential. These similarities have
      allowed us to suggest a catalytic mechanism for enzymatic thiosulfate oxidation.
      The atomic coordinates and experimental structure factors have been deposited in
      the PDB with the accession codes 1H31, 1H32 and 1H33.

PMID- 12411479
TI  - Inducible gene deletion reveals different roles for B-Raf and Raf-1 in B-cell
      antigen receptor signalling.
AB  - Engagement of the B-cell antigen receptor (BCR) leads to activation of the Raf
      MEK-ERK pathway and Raf kinases play an important role in the modulation of ERK
      activity. B lymphocytes express two Raf isoforms, Raf-1 and B-Raf. Using an
      inducible deletion system in DT40 cells, the contribution of Raf-1 and B-Raf to
      BCR signalling was dissected. Loss of Raf-1 has no effect on BCR-mediated ERK
      activation, whereas B-Raf-deficient DT40 cells display a reduced basal ERK
      activity as well as a shortened BCR-mediated ERK activation. The Raf-1/B-Raf
      double deficient DT40 cells show an almost complete block both in ERK activation
      and in the induction of the immediate early gene products c-Fos and Egr-1. In
      contrast, BCR-mediated activation of nuclear factor of activated T cells (NFAT)
      relies predominantly on B-Raf. Furthermore, complementation of Raf-1/B-Raf double
      deficient cells with various Raf mutants demonstrates a requirement for Ras-GTP
      binding in BCR-mediated activation of both Raf isoforms and also reveals the
      important role of the S259 residue for the regulation of Raf-1. Our study shows
      that BCR-mediated ERK activation involves a cooperation of both B-Raf and Raf-1,
      which are activated specifically in a temporally distinct manner.

PMID- 12411480
TI  - GW domains of the Listeria monocytogenes invasion protein InlB are SH3-like and
      mediate binding to host ligands.
AB  - InlB, a surface-localized protein of Listeria monocytogenes, induces phagocytosis
      in non-phagocytic mammalian cells by activating Met, a receptor tyrosine kinase.
      InlB also binds glycosaminoglycans and the protein gC1q-R, two additional host
      ligands implicated in invasion. We present the structure of InlB, revealing a
      highly elongated molecule with leucine-rich repeats that bind Met at one end, and
      GW domains that dissociably bind the bacterial surface at the other.
      Surprisingly, the GW domains are seen to resemble SH3 domains. Despite this, GW
      domains are unlikely to act as functional mimics of SH3 domains since their
      potential proline-binding sites are blocked or destroyed. However, we do show
      that the GW domains, in addition to binding glycosaminoglycans, bind gC1q-R
      specifically, and that this binding requires release of InlB from the bacterial
      surface. Dissociable attachment to the bacterial surface via the GW domains may
      be responsible for restricting Met activation to a small, localized area of the
      host cell and for coupling InlB-induced host membrane dynamics with bacterial
      proximity during invasion.

PMID- 12411481
TI  - P53-mediated induction of Cox-2 counteracts p53- or genotoxic stress-induced
      apoptosis.
AB  - The identification of transcriptional targets of the tumor suppressor p53 is
      crucial in understanding mechanisms by which it affects cellular outcomes.
      Through expression array analysis, we identified cyclooxygenase 2 (Cox-2), whose
      expression was inducible by wild-type p53 and DNA damage. We also found that p53
      induced Cox-2 expression results from p53-mediated activation of the Ras/Raf/MAPK
      cascade, as demonstrated by suppression of Cox-2 induction in response to p53 by
      dominant-negative Ras or Raf1 mutants. Furthermore, heparin-binding epidermal
      growth factor-like growth factor (HB- EGF), a p53 downstream target gene, induced
      Cox-2 expression, implying that Cox-2 is an ultimate effector in the p53-->HB-EGF
      ->Ras/Raf/MAPK-->Cox-2 pathway. p53-induced apoptosis was enhanced greatly in Cox
      2 knock-out cells as compared with wild-type cells, suggesting that Cox-2 has an
      abrogating effect on p53-induced apoptosis. Also, a selective Cox-2 inhibitor, NS
      398, significantly enhanced genotoxic stress-induced apoptosis in several types
      of p53+/+ normal human cells, through a caspase-dependent pathway. Together,
      these results demonstrate that Cox-2 is induced by p53-mediated activation of the
      Ras/Raf/ERK cascade, counteracting p53-mediated apoptosis. This anti-apoptosis
      effect may be a mechanism to abate cellular stresses associated with p53
      induction.

PMID- 12411482
TI  - Direct binding of ubiquitin conjugates by the mammalian p97 adaptor complexes,
      p47 and Ufd1-Npl4.
AB  - The multiple functions of the p97/Cdc48p ATPase can be explained largely by
      adaptors that link its activity to different cellular pathways, but how these
      adaptors recognize different substrates is unclear. Here we present evidence that
      the mammalian adaptors, p47 and Ufd1-Npl4, both bind ubiquitin conjugates
      directly and so link p97 to ubiquitylated substrates. In the case of Ufd1-Npl4,
      which is involved in endoplasmic reticulum (ER)-associated degradation and
      nuclear envelope reassembly, binding to ubiquitin is mediated through a putative
      zinc finger in Npl4. This novel domain (NZF) is conserved in metazoa and is both
      present and functional in other proteins. In the case of p47, which is involved
      in the reassembly of the ER, the nuclear envelope and the Golgi apparatus,
      binding is mediated by a UBA domain. Unlike Ufd1-Npl4, it binds ubiquitin only
      when complexed with p97, and binds mono- rather than polyubiquitin conjugates.
      The UBA domain is required for the function of p47 in mitotic Golgi reassembly.
      Together, these data suggest that ubiquitin recognition is a common feature of
      p97-mediated reactions.

PMID- 12411483
TI  - Identification and reconstitution of the yeast mitochondrial transporter for
      thiamine pyrophosphate.
AB  - The genome of Saccharomyces cerevisiae contains 35 members of a family of
      transport proteins that, with a single exception, are found in the inner
      membranes of mitochondria. The transport functions of the 15 biochemically
      identified mitochondrial carriers are concerned with shuttling substrates,
      biosynthetic intermediates and cofactors across the inner membrane. Here the
      identification of the mitochondrial carrier for the essential cofactor thiamine
      pyrophosphate (ThPP) is described. The protein has been overexpressed in
      bacteria, reconstituted into phospholipid vesicles and identified by its
      transport properties. In confirmation of its identity, cells lacking the gene for
      this carrier had reduced levels of ThPP in their mitochondria, and decreased
      activity of acetolactate synthase, a ThPP-requiring enzyme found in the
      organellar matrix. They also required thiamine for growth on fermentative carbon
      sources.

PMID- 12411484
TI  - A molecular mechanism for aberrant CFTR-dependent HCO(3)(-) transport in cystic
      fibrosis.
AB  - Aberrant HCO(3)(-) transport is a hallmark of cystic fibrosis (CF) and is
      associated with aberrant Cl(-)-dependent HCO(3)(-) transport by the cystic
      fibrosis transmembrane conductance regulator (CFTR). We show here that HCO(3)(-)
      current by CFTR cannot account for CFTR-activated HCO(3)(-) transport and that
      CFTR does not activate AE1-AE4. In contrast, CFTR markedly activates Cl(-) and
      OH(-)/HCO(3)(-) transport by members of the SLC26 family DRA, SLC26A6 and
      pendrin. Most notably, the SLC26s are electrogenic transporters with isoform
      specific stoichiometries. DRA activity occurred at a Cl(-)/HCO(3)(-) ratio > or
      =2. SLC26A6 activity is voltage regulated and occurred at HCO(3)(-)/Cl(-) > or
      =2. The physiological significance of these findings is demonstrated by
      interaction of CFTR and DRA in the mouse pancreas and an altered activation of
      DRA by the R117H and G551D mutants of CFTR. These findings provide a molecular
      mechanism for epithelial HCO(3)(-) transport (one SLC26 transporter-electrogenic
      transport; two SLC26 transporters with opposite stoichiometry in the same
      membrane domain-electroneutral transport), the CF-associated aberrant HCO(3)(-)
      transport, and reveal a new function of CFTR with clinical implications for CF
      and congenital chloride diarrhea.

PMID- 12411485
TI  - Topology of polytopic membrane protein subdomains is dictated by membrane
      phospholipid composition.
AB  - In Escherichia coli, the major cytoplasmic domain (C6) of the polytopic membrane
      protein lactose permease (LacY) is exposed to the opposite side of the membrane
      from a neighboring periplasmic domain (P7). However, these domains are both
      exposed on the periplasmic side of the membrane in a mutant of E.coli lacking
      phosphatidylethanolamine (PE) wherein LacY only mediates facilitated transport.
      When purified LacY was reconstituted into liposomes lacking PE or
      phosphatidylcholine (PC), C6 and P7 were on the same side of the bilayer. In
      liposomes containing PE or PC, C6 and P7 were on opposite sides of the bilayer.
      Only the presence of PE in the liposomes restored active transport function of
      LacY as opposed to restoration of only facilitated transport function in the
      absence of PE. These results were the same for LacY purified from PE-containing
      or PE-lacking cells, and are consistent with the topology and function of LacY
      assembled in vivo. Therefore, irrespective of the mechanism of membrane
      insertion, the subdomain topological orientation and function of LacY are
      determined primarily by membrane phospholipid composition.

PMID- 12411486
TI  - The behaviour of polyamino acids reveals an inverse side chain effect in amyloid
      structure formation.
AB  - Amyloid fibrils and prions are proteinaceous aggregates that are based on a
      unique form of polypeptide configuration, termed cross-beta structure. Using a
      group of chemically distinct polyamino acids, we show here that the existence of
      such a structure does not require the presence of specific side chain
      interactions or sequence patterns. These observations firmly establish that
      amyloid formation and protein folding represent two fundamentally different ways
      of organizing polypeptides into ordered conformations. Protein folding depends
      critically on the presence of distinctive side chain sequences and produces a
      unique globular fold. By contrast, the properties of different polyamino acids
      suggest that amyloid formation arises primarily from main chain interactions that
      are, in some environments, overruled by specific side chain contacts. This side
      chain effect can be thought of as the inverse of the one that characterizes
      protein folding. Conditions including Alzheimer's and Creutzfeldt-Jakob diseases
      represent, on this basis, pathological cases in which a natural polypeptide chain
      has aberrantly adopted the conformation that is primarily defined by main chain
      interactions and not the structure that is determined by specific side chain
      contacts that depend on the polypeptide sequence.

PMID- 12411487
TI  - The cytoplasmic domain of the LDL receptor-related protein regulates multiple
      steps in APP processing.
AB  - The low-density lipoprotein receptor-related protein (LRP) has recently been
      implicated in numerous intracellular signaling functions, as well as in
      Alzheimer's disease pathogenesis. Studies have shown that the beta-amyloid
      precursor protein (APP) interacts with LRP and that this association may impact
      the production of amyloid beta-protein (Abeta). In this report, we provide
      evidence that LRP regulates trafficking of intracellular proteins independently
      of its lipoprotein receptor functions. We show that in the absence of LRP, Abeta
      production, APP secretion, APP internalization, turnover of full-length APP and
      stability of APP C-terminal fragments are affected. Importantly, these changes
      are not APP isoform dependent. Using deletion constructs, the critical region in
      LRP that modulates APP processing was mapped to a seven peptide domain around the
      second NPXY domain (residues 4504-4510). Therefore, we propose a model by which
      LRP functionally modulates APP processing, including those steps critical for
      Abeta production, through interactions of the cytosolic domains.

PMID- 12411488
TI  - Reversible stages of the low-pH-triggered conformational change in influenza
      virus hemagglutinin.
AB  - The refolding of the prototypic fusogenic protein hemagglutinin (HA) at the pH of
      fusion is considered to be a concerted and irreversible discharge of a loaded
      spring, with no distinct intermediates between the initial and final
      conformations. Here, we show that HA refolding involves reversible conformations
      with a lifetime of minutes. After reneutralization, low pH-activated HA returns
      from the conformations wherein both the fusion peptide and the kinked loop of the
      HA2 subunit are exposed, but the HA1 subunits have not yet dissociated, to a
      structure indistinguishable from the initial one in functional, biochemical and
      immunological characteristics. The rate of the transition from reversible
      conformations to irreversible refolding depends on the pH and on the presence of
      target membrane. Importantly, recovery of the initial conformation is blocked by
      the interactions between adjacent HA trimers. The existence of the identified
      reversible stage of refolding can be crucial for allowing multiple copies of HA
      to synchronize their release of conformational energy, as required for fusion.

PMID- 12411489
TI  - An endogenous hybrid mRNA encodes TWE-PRIL, a functional cell surface TWEAK-APRIL
      fusion protein.
AB  - TWEAK and APRIL are two recently identified tumour necrosis factor (TNF) ligand
      family members, implicated in angiogenesis and immune regulation, respectively.
      TWEAK is a transmembrane protein expressed on the cell surface, whereas APRIL
      acts solely as a secreted factor. In this report, using RACE, RT-PCR, cDNA
      library screening and an RNase protection assay, we characterize a hybrid
      transcript between TWEAK and APRIL mRNAs. The encoded TWE-PRIL protein is
      composed of TWEAK cytoplasmic and transmembrane domains fused to the APRIL C
      terminal domain. TWE-PRIL mRNA is expressed and translated in human primary T
      cells and monocytes, and endogenous TWE-PRIL protein was detected in primary
      human T lymphocytes and monocytic cell lines. TWE-PRIL is membrane anchored and
      presents the APRIL receptor-binding domain at the cell surface. It is a
      biologically active ligand, as it stimulates cycling in T- and B-lymphoma cell
      lines. Much like membrane-bound and secreted TNF-alpha, the different cellular
      localizations of TWE-PRIL and APRIL suggest that they exert distinct biological
      roles.

PMID- 12411491
TI  - Hinge-mediated dimerization of SMC protein is essential for its dynamic
      interaction with DNA.
AB  - Structural maintenance of chromosomes (SMC) proteins play central roles in
      regulating higher order chromosome dynamics from bacteria to humans. As judged by
      electron microscopy, the SMC homodimer from Bacillus subtilis (BsSMC) is composed
      of two antiparallel, coiled-coil arms with a flexible hinge. Site-directed cross
      linking experiments show here that dimerization of BsSMC is mediated by a hinge
      hinge interaction between self-folded monomers. This architecture is conserved in
      the eukaryotic SMC2-SMC4 heterodimer. Analysis of different deletion mutants of
      BsSMC unexpectedly reveals that the major DNA-binding activity does not reside in
      the catalytic ATPase domains located at the ends of a dimer. Instead, point
      mutations in the hinge domain that disturb dimerization of BsSMC drastically
      reduce its ability to interact with DNA. Proper hinge function is essential for
      BsSMC to recognize distinct DNA topology, and mutant proteins with altered hinge
      angles cross-link double-stranded DNA in a nucleotide-dependent manner. We
      propose that the hinge domain of SMC proteins is not a simple dimerization site,
      but rather it acts as an essential determinant of dynamic SMC-DNA interactions.

PMID- 12411490
TI  - Structure of the sporulation-specific transcription factor Ndt80 bound to DNA.
AB  - Progression through the middle phase of sporulation in Saccharomyces cerevisiae
      is promoted by the successful completion of recombination at the end of prophase
      I. Completion of meiotic recombination allows the activation of the sporulation
      specific transcription factor Ndt80, which binds to a specific DNA sequence, the
      middle sporulation element (MSE), and activates approximately 150 genes to enable
      progression through meiosis. Here, we isolate the DNA-binding domain of Ndt80 and
      determine its crystal structure both free and in complex with an MSE-containing
      DNA. The structure reveals that Ndt80 is a member of the Ig-fold family of
      transcription factors. The structure of the DNA-bound form, refined at 1.4 A,
      reveals an unexpected mode of recognition of 5'-pyrimidine- guanine-3'
      dinucleotide steps by arginine residues that simultaneously recognize the 3'
      guanine base through hydrogen bond interactions and the 5'-pyrimidine through
      stacking/van der Waals interactions. Analysis of the DNA-binding affinities of
      MSE mutants demonstrates the central importance of these interactions, and of the
      AT-rich portion of the MSE. Functional similarities between Ndt80 and the
      Caenorhabditis elegans p53 homolog suggest an evolutionary link between Ndt80 and
      the p53 family.

PMID- 12411492
TI  - Plo1(+) regulates gene transcription at the M-G(1) interval during the fission
      yeast mitotic cell cycle.
AB  - The regulation of gene expression plays an important part in cell cycle controls.
      We describe the molecular machinery that co-ordinates gene transcription at the M
      G(1) interval during the fission yeast mitotic cell cycle. A sequence is
      identified in the cdc15(+) promoter that we call a PCB (pombe cell cycle box),
      which confers M-G(1)-specific transcription. Sequences similar to the PCB are
      present in the promoters of seven other genes, spo12(+), cdc19(+), fin1(+),
      sid2(+), ppb1(+), mid1(+)/dmf1(+) and plo1(+), which we find to be transcribed at
      M-G(1). A transcription factor complex is identified that binds to the PCB
      sequence, which we name PBF, for PCB-binding factor. Finally, we show that PBF
      binding activity and consequent gene transcription are regulated by the Plo1p
      protein kinase, thus invoking a potential auto-feedback loop mechanism that
      regulates mitotic gene transcription and passage through septation and
      cytokinesis.

PMID- 12411493
TI  - Stress-induced decrease in TRAF2 stability is mediated by Siah2.
AB  - TRAF2 serves as a central regulator of the cellular response to stress and
      cytokines through the regulation of key stress-signaling cascades. Here we
      demonstrate that wild-type, but not RING mutant, Siah2 targets TRAF2 for
      ubiquitylation and degradation in vitro. Siah2 mediates equally efficient
      ubiquitylation of RING mutant TRAF2. In vivo, Siah2 primarily targets TRAF2 for
      degradation under stress conditions. Tumor necrosis factor-alpha (TNF-alpha) and
      actinomycin D treatment results in accelerated TRAF2 degradation in wild-type
      mouse embryo fibroblasts (MEFs), as compared with Siah2(-/-) cells. Similarly,
      TRAF2 half-life is prolonged in Siah2(-/-) compared with wild-type MEFs subjected
      to stress stimuli. Siah2 efficiently decreases TNF-alpha-dependent induction of
      JNK activity and transcriptional activation of NF-kappaB. Apoptosis induced by
      TNF-alpha and actinomycin D treatment is increased upon expression of Siah2, or
      attenuated upon expression of TRAF2 or RING mutant Siah2. Identifying Siah2 as a
      regulator of TRAF2 stability reveals its role in the regulation of TRAF2
      signaling following exposure to stress.

PMID- 12411494
TI  - The Src family kinase Hck couples BCR/ABL to STAT5 activation in myeloid leukemia
      cells.
AB  - Signal transducer and activator of transcription 5 (STAT5) is constitutively
      activated by BCR/ABL, the oncogenic tyrosine kinase responsible for chronic
      myelogenous leukemia. The mechanism of BCR/ABL-mediated STAT5 activation is
      unknown. We show here that the BCR/ABL SH3 and SH2 domains interact with
      hematopoietic cell kinase (Hck), leading to the stimulation of Hck catalytic
      activity. Active Hck phosphorylated STAT5B on Tyr699, which represents an
      essential step in STAT5B stimulation. Moreover, a kinase-dead Hck mutant and Hck
      inhibitor PP2 abrogated BCR/ABL-dependent activation of STAT5 and elevation of
      expression of STAT5 downstream effectors A1 and pim-1. These data identify a
      novel BCR/ABL-Hck-STAT5 signaling pathway, which plays an important role in
      BCR/ABL-mediated transformation of myeloid cells.

PMID- 12411495
TI  - Interaction of YY1 with E2Fs, mediated by RYBP, provides a mechanism for
      specificity of E2F function.
AB  - To explore mechanisms for specificity of function within the family of E2F
      transcription factors, we have identified proteins that interact with individual
      E2F proteins. A two-hybrid screen identified RYBP (Ring1- and YY1-binding
      protein) as a protein that interacts specifically with the E2F2 and E2F3 family
      members, dependent on the marked box domain in these proteins. The Cdc6 promoter
      contains adjacent E2F- and YY1-binding sites, and both are required for promoter
      activity. In addition, YY1 and RYBP, in combination with either E2F2 or E2F3, can
      stimulate Cdc6 promoter activity synergistically, dependent on the marked box
      domain of E2F3. Using chromatin immunoprecipitation assays, we show that both
      E2F2 and E2F3, as well as YY1 and RYBP, associate with the Cdc6 promoter at
      G(1)/S of the cell cycle. In contrast, we detect no interaction of E2F1 with the
      Cdc6 promoter. We suggest that the ability of RYBP to mediate an interaction
      between E2F2 or E2F3 and YY1 is an important component of Cdc6 activation and
      provides a basis for specificity of E2F function.

PMID- 12411496
TI  - Loss of spr-5 bypasses the requirement for the C.elegans presenilin sel-12 by
      derepressing hop-1.
AB  - Presenilins are part of a protease complex that is responsible for the
      intramembraneous cleavage of the amyloid precursor protein involved in
      Alzheimer's disease and of Notch receptors. In Caenorhabditis elegans, mutations
      in the presenilin sel-12 result in a highly penetrant egg-laying defect. spr-5
      was identified as an extragenic suppressor of the sel-12 mutant phenotype. The
      SPR-5 protein has similarity to the human polyamine oxidase-like protein encoded
      by KIAA0601 that is part of the HDAC-CoREST co-repressor complex. Suppression of
      sel-12 by spr-5 requires the activity of HOP-1, the second somatic presenilin in
      C.elegans. spr-5 mutants derepress hop-1 expression 20- to 30-fold in the early
      larval stages when hop-1 normally is almost undetectable. SPR-1, a C.elegans
      homologue of CoREST, physically interacts with SPR-5. Moreover, down-regulation
      of SPR-1 by mutation or RNA interference also bypasses the need for sel-12. These
      data strongly suggest that SPR-5 and SPR-1 are part of a CoREST-like co-repressor
      complex in C.elegans. This complex might be recruited to the hop-1 locus
      controlling its expression during development.

PMID- 12411497
TI  - Selective interaction between the chromatin-remodeling factor BRG1 and the
      heterochromatin-associated protein HP1alpha.
AB  - Mammalian heterochromatin protein 1 (HP1) alpha, HP1beta and HP1gamma are closely
      related non-histone chromosomal proteins that function in gene silencing,
      presumably by organizing higher order chromatin structures. Here, we show by co
      immunoprecipitation that HP1alpha, but neither HP1beta nor HP1gamma, forms a
      complex with the BRG1 chromatin-remodeling factor in HeLa cells. In vitro, BRG1
      interacts directly and preferentially with HP1alpha. The region conferring this
      preferential binding has been mapped to residues 106-180 of the HP1alpha C
      terminal chromoshadow domain. Using site-directed mutagenesis, we have identified
      three amino acid residues I113, A114 and C133 in HP1alpha (K, P and S in HP1beta
      and HP1gamma) that are essential for the selective interaction of HP1alpha with
      BRG1. Interestingly, these residues were also shown to be critical for the
      silencing activity of HP1alpha. Taken together, these results demonstrate that
      mammalian HP1 proteins are biochemically distinct and suggest an entirely novel
      function for BRG1 in modulating HP1alpha-containing heterochromatic structures.

PMID- 12411498
TI  - The imprinting mechanism of the Prader-Willi/Angelman regional control center.
AB  - The 2 Mb domain on chromosome 15q11-q13 that carries the imprinted genes involved
      in Prader-Willi (PWS) and Angelman (AS) syndromes is under the control of an
      imprinting center comprising two regulatory regions, the PWS-SRO located around
      the SNRPN promoter and the AS-SRO located 35 kb upstream. Here we describe the
      results of an analysis of the epigenetic features of these two sequences and
      their interaction. The AS-SRO is sensitive to DNase I, and packaged with
      acetylated histone H4 and methylated histone H3(K4) only on the maternal allele,
      and this imprinted epigenetic structure is maintained in dividing cells despite
      the absence of clearcut differential DNA methylation. Genetic analysis shows that
      the maternal AS-SRO is essential for setting up the DNA methylation state and
      closed chromatin structure of the neighboring PWS-SRO. In contrast, the PWS-SRO
      has no influence on the epigenetic features of the AS-SRO. These results suggest
      a stepwise, unidirectional program in which structural imprinting at the AS-SRO
      brings about allele-specific repression of the maternal PWS-SRO, thereby
      preventing regional activation of genes on this allele.

PMID- 12411499
TI  - The phage N4 virion RNA polymerase catalytic domain is related to single-subunit
      RNA polymerases.
AB  - In vitro, bacteriophage N4 virion RNA polymerase (vRNAP) recognizes in vivo sites
      of transcription initiation on single-stranded templates. N4 vRNAP promoters are
      comprised of a hairpin structure and conserved sequences. Here, we show that
      vRNAP consists of a single 3500 amino acid polypeptide, and we define and
      characterize a transcriptionally active 1106 amino acid domain (mini-vRNAP).
      Biochemical and genetic characterization of this domain indicates that, despite
      its peculiar promoter specificity and lack of extensive sequence similarity to
      other DNA-dependent RNA polymerases, mini-vRNAP is related to the family of T7
      like RNA polymerases.

PMID- 12411500
TI  - An active role for endogenous beta-1,3-glucanase genes in transgene-mediated co
      suppression in tobacco.
AB  - Post-transcriptional gene silencing (PTGS) is characterized by the accumulation
      of short interfering RNAs that are proposed to mediate sequence-specific
      degradation of cognate and secondary target mRNAs. In plants, it is unclear to
      what extent endogenous genes contribute to this process. Here, we address the
      role of the endogenous target genes in transgene-mediated PTGS of beta-1,3
      glucanases in tobacco. We found that mRNA sequences of the endogenous glucanase
      glb gene with varying degrees of homology to the Nicotiana plumbaginifolia gn1
      transgene are targeted by the silencing machinery, although less efficiently than
      corresponding transgene regions. Importantly, we show that endogene-specific
      nucleotides in the glb sequence provide specificity to the silencing process.
      Consistent with this finding, small sense and antisense 21- to 23-nucleotide RNAs
      homologous to the endogenous glb gene were detected. Combined, these data
      demonstrate that a co-suppressed endogenous glucan ase gene is involved in signal
      amplification and selection of homologous targets, and show that endogenous genes
      can actively participate in PTGS in plants. The findings are introduced as a
      further sophistication of the post-transciptional silencing model.

PMID- 12411501
TI  - Importin alpha can migrate into the nucleus in an importin beta- and Ran
      independent manner.
AB  - A classical nuclear localization signal (NLS)-containing protein is transported
      into the nucleus via the formation of a NLS-substrate/importin alpha/beta
      complex. In this study, we found that importin alpha migrated into the nucleus
      without the addition of importin beta, Ran or any other soluble factors in an in
      vitro transport assay. A mutant importin alpha lacking the importin beta-binding
      domain efficiently entered the nucleus. Competition experiments showed that this
      import pathway for importin alpha is distinct from that of importin beta. These
      results indicate that importin alpha alone can enter the nucleus via a novel
      pathway in an importin beta- and Ran-independent manner. Furthermore, this
      process is evolutionarily conserved as similar results were obtained in
      Saccharomyces cerevisiae. Moreover, the import rate of importin alpha differed
      among individual nuclei of permeabilized cells, as demonstrated by time-lapse
      experiments. This heterogeneous nuclear accumulation of importin alpha was
      affected by the addition of ATP, but not ATPgammaS. These results suggest that
      the nuclear import machinery for importin alpha at individual nuclear pore
      complexes may be regulated by reaction(s) that require ATP hydrolysis.

PMID- 12411502
TI  - The mRNA export machinery requires the novel Sac3p-Thp1p complex to dock at the
      nucleoplasmic entrance of the nuclear pores.
AB  - Yra1p and Sub2p are components of the TREX complex, which couples transcription
      elongation with nuclear export of mRNAs. Here, we report a genetic interaction
      between Yra1p and a conserved protein Sac3p, which previously was found to
      interact with Sub2p. In vivo, Sac3p forms a stable complex with Thp1p, which was
      reported to function in transcription elongation. In addition, Sac3p binds to the
      mRNA exporter Mex67p-Mtr2p and requires the nucleoporin Nup1p to dock at the
      nuclear side of the nuclear pore complex (NPC). Significantly, mutations in Sac3p
      or Thp1p lead to strong mRNA export defects. Taken together, our data suggest
      that the novel Sac3p-Thp1p complex functions by docking the mRNP to specific
      nucleoporins at the nuclear entrance of the NPC.

PMID- 12411503
TI  - Assisted RNP assembly: SMN and PRMT5 complexes cooperate in the formation of
      spliceosomal UsnRNPs.
AB  - Although spliceosomal Sm proteins can assemble spontaneously onto UsnRNA in
      vitro, this process requires assisting factors in vivo. SMN, the protein involved
      in spinal muscular atrophy, is part of a complex that contains the Sm proteins
      and serves as a critical factor for this reaction. Here, we have reconstituted
      the SMN-dependent assembly of UsnRNPs in vitro. We demonstrate that the SMN
      complex is necessary and sufficient for the assembly reaction. The PRMT5 complex,
      previously implicated in methylation and storage of Sm proteins, interacts with
      the SMN complex and enhances its activity in an ATP-dependent manner. These data
      uncover the SMN-PRMT5 complex as a functional entity that promotes the assisted
      assembly of spliceosomal UsnRNPs, and potentially other, RNA-protein complexes.

PMID- 12411505
TI  - Human Dicer preferentially cleaves dsRNAs at their termini without a requirement
      for ATP.
AB  - Dicer is a multi-domain RNase III-related endonuclease responsible for processing
      double-stranded RNA (dsRNA) to small interfering RNAs (siRNAs) during a process
      of RNA interference (RNAi). It also catalyses excision of the regulatory
      microRNAs from their precursors. In this work, we describe the purification and
      properties of a recombinant human Dicer. The protein cleaves dsRNAs into
      approximately 22 nucleotide siRNAs. Accumulation of processing intermediates of
      discrete sizes, and experiments performed with substrates containing modified
      ends, indicate that Dicer preferentially cleaves dsRNAs at their termini. Binding
      of the enzyme to the substrate can be uncoupled from the cleavage step by
      omitting Mg(2+) or performing the reaction at 4 degrees C. Activity of the
      recombinant Dicer, and of the endogenous protein present in mammalian cell
      extracts, is stimulated by limited proteolysis, and the proteolysed enzyme
      becomes active at 4 degrees C. Cleavage of dsRNA by purifed Dicer and the
      endogenous enzyme is ATP independent. Additional experiments suggest that if ATP
      participates in the Dicer reaction in mammalian cells, it might be involved in
      product release needed for the multiple turnover of the enzyme.

PMID- 12411504
TI  - Ribonuclease activity and RNA binding of recombinant human Dicer.
AB  - RNA silencing phenomena, known as post-transcriptional gene silencing in plants,
      quelling in fungi, and RNA interference (RNAi) in animals, are mediated by double
      stranded RNA (dsRNA) and mechanistically intersect at the ribonuclease Dicer.
      Here, we report cloning and expression of the 218 kDa human Dicer, and
      characterization of its ribonuclease activity and dsRNA-binding properties. The
      recombinant enzyme generated approximately 21-23 nucleotide products from dsRNA.
      Processing of the microRNA let-7 precursor by Dicer produced an apparently mature
      let-7 RNA. Mg(2+) was required for dsRNase activity, but not for dsRNA binding,
      thereby uncoupling these reaction steps. ATP was dispensable for dsRNase activity
      in vitro. The Dicer.dsRNA complex formed at high KCl concentrations was
      catalytically inactive, suggesting that ionic interactions are involved in dsRNA
      cleavage. The putative dsRNA-binding domain located at the C-terminus of Dicer
      was demonstrated to bind dsRNA in vitro. Human Dicer expressed in mammalian cells
      colocalized with calreticulin, a resident protein of the endoplasmic reticulum.
      Availability of the recombinant Dicer protein will help improve our understanding
      of RNA silencing and other Dicer-related processes.

PMID- 12411506
TI  - Direct eIF2-eIF3 contact in the multifactor complex is important for translation
      initiation in vivo.
AB  - Translation initiation factor 3 (eIF3) of Saccharo myces cerevisiae forms a
      multifactor complex (MFC) with eIFs 1, 2, 5 and Met-tRNA(i)(Met). We previously
      constructed a subunit interaction model for the MFC. Here we incorporated
      affinity tags into the three largest eIF3 subunits (eIF3a/TIF32, eIF3b/PRT1 and
      eIF3c/NIP1) and deleted predicted binding domains in each tagged protein. By
      characterizing the mutant subcomplexes, we confirmed all key predictions of our
      model and uncovered new interactions of NIP1 with PRT1 and of TIF32 with eIF1. In
      addition to the contact between eIF2 and the N-terminal domain (NTD) of NIP1
      bridged by eIF5, the C-terminal domain (CTD) of TIF32 binds eIF2 directly and is
      required for eIF2-eIF3 association in vivo. Overexpressing a CTD-less form of
      TIF32 exacerbated the initiation defect of an eIF5 mutation that weakens the NIP1
      eIF5-eIF2 connection. Thus, the two independent eIF2-eIF3 contacts have additive
      effects on translation in vivo. Overexpressing the NIP1-NTD sequestered eIF1-eIF5
      eIF2 in a defective subcomplex that derepressed GCN4 translation, providing the
      first in vivo evidence that association with eIF3 promotes binding of eIF2 and
      Met-tRNA(i)(Met) to 40S ribosomes.

PMID- 12411507
TI  - Human L1 element target-primed reverse transcription in vitro.
AB  - L1 elements are ubiquitous human transposons that replicate via an RNA
      intermediate. We have reconstituted the initial stages of L1 element
      transposition in vitro. The reaction requires only the L1 ORF2 protein, L1 3'
      RNA, a target DNA and appropriate buffer components. We detect branched molecules
      consisting of junctions between transposon 3' end cDNA and the target DNA,
      resulting from priming at a nick in the target DNA. 5' junctions of transposon
      cDNA and target DNA are also observed. The nicking and reverse transcription
      steps in the reaction can be uncoupled, as priming at pre-existing nicks and even
      double-strand breaks can occur. We find evidence for specific positioning of the
      L1 RNA with the ORF2 protein, probably mediated in part by the polyadenosine
      portion of L1 RNA. Polyguanosine, similar to a conserved region of the L1 3' UTR,
      potently inhibits L1 endonuclease (L1 EN) activity. L1 EN activity is also
      repressed in the context of the full-length ORF2 protein, but it and a second
      cryptic nuclease activity are released by ORF2p proteolysis. Additionally,
      heterologous RNA species such as Alu element RNA and L1 transcripts with 3'
      extensions are substrates for the reaction.

PMID- 12411509
TI  - Rpb4 and Rpb9 mediate subpathways of transcription-coupled DNA repair in
      Saccharomyces cerevisiae.
AB  - Rpb9, a non-essential subunit of RNA polymerase II, mediates a transcription
      coupled repair (TCR) subpathway in Saccharomyces cerevisiae. This subpathway
      initiates at the same upstream site as the previously identified Rad26
      subpathway. However, the Rpb9 subpathway operates more effectively in the coding
      region than in the region upstream of the transcription start site, whereas the
      Rad26 subpathway operates equally in the two regions. Rpb4, another non-essential
      subunit of RNA polymerase II, plays a dual role in regulating the two
      subpathways, suppressing the Rpb9 subpathway and facilitating the Rad26
      subpathway. Simultaneous deletion of RPB9 and RAD26 genes completely abolishes
      TCR in both the coding and upstream regions, indicating that no other TCR
      subpathway exists in RNA polymerase II-transcribed genes.

PMID- 12411508
TI  - Regulation of G(2)/M events by Cdc25A through phosphorylation-dependent
      modulation of its stability.
AB  - DNA replication in higher eukaryotes requires activation of a Cdk2 kinase by
      Cdc25A, a labile phosphatase subject to further destabilization upon genotoxic
      stress. We describe a distinct, markedly stable form of Cdc25A, which plays a
      previously unrecognized role in mitosis. Mitotic stabilization of Cdc25A reflects
      its phosphorylation on Ser17 and Ser115 by cyclin B-Cdk1, modifications required
      to uncouple Cdc25A from its ubiquitin-proteasome-mediated turnover. Cdc25A binds
      and activates cyclin B-Cdk1, accelerates cell division when overexpressed, and
      its downregulation by RNA interference (RNAi) delays mitotic entry. DNA damage
      induced G(2) arrest, in contrast, is accompanied by proteasome-dependent
      destruction of Cdc25A, and ectopic Cdc25A abrogates the G(2) checkpoint. Thus,
      phosphorylation-mediated switches among three differentially stable forms ensure
      distinct thresholds, and thereby distinct roles for Cdc25A in multiple cell cycle
      transitions and checkpoints.

PMID- 12411510
TI  - The flexible loop of human FEN1 endonuclease is required for flap cleavage during
      DNA replication and repair.
AB  - The conserved, structure-specific flap endonuclease FEN1 cleaves 5' DNA flaps
      that arise during replication or repair. To address in vivo mechanisms of flap
      cleavage, we developed a screen for human FEN1 mutants that are toxic when
      expressed in yeast. Two targets were revealed: the flexible loop domain and the
      catalytic site. Toxic mutants caused G(2) arrest and cell death and were unable
      to repair methyl methanesulfonate lesions. All the mutant proteins retained flap
      binding. Unlike the catalytic site mutants, which lacked cleavage of any 5'
      flaps, the loop mutants exhibited partial ability to cut 5' flaps when an
      adjacent single nucleotide 3' flap was present. We suggest that the flexible loop
      is important for efficient cleavage through positioning the 5' flap and the
      catalytic site.

PMID- 12411512
TI  - IgG transcytosis and recycling by FcRn expressed in MDCK cells reveals ligand
      induced redistribution.

PMID- 12411511
TI  - DNA base excision repair of uracil residues in reconstituted nucleosome core
      particles.
AB  - The human base excision repair machinery must locate and repair DNA base damage
      present in chromatin, of which the nucleosome core particle is the basic
      repeating unit. Here, we have utilized fragments of the Lytechinus variegatus 5S
      rRNA gene containing site-specific U:A base pairs to investigate the base
      excision repair pathway in reconstituted nucleosome core particles in vitro. The
      human uracil-DNA glycosylases, UNG2 and SMUG1, were able to remove uracil from
      nucleosomes. Efficiency of uracil excision from nucleosomes was reduced 3- to 9
      fold when compared with naked DNA, and was essentially uniform along the length
      of the DNA substrate irrespective of rotational position on the core particle.
      Furthermore, we demonstrate that the excision repair pathway of an abasic site
      can be reconstituted on core particles using the known repair enzymes, AP
      endonuclease 1, DNA polymerase beta and DNA ligase III. Thus, base excision
      repair can proceed in nucleosome core particles in vitro, but the repair
      efficiency is limited by the reduced activity of the uracil-DNA glycosylases and
      DNA polymerase beta on nucleosome cores.

PMID- 12411513
TI  - Identification of a site involved in the block by extracellular Mg(2+) and Ba(2+)
      as well as permeation of K(+) in the Kir2.1 K(+) channel.
AB  - The inward rectifier potassium channel Kir2.1 is more sensitive to the weakly
      voltage-dependent block by extracellular Mg(2+) (Mg2+o) than Kir2.2 and Kir2.3.
      We identified Glu125 in an extracellular loop before the pore region of Kir2.1 as
      a site responsible for this sensitivity to M2+o block, based on the observations
      that the Glu125Gln (E125Q) mutation strongly decreased the sensitivity, while a
      mutation to Glu at the corresponding sites of Kir2.2 and 2.3 led to an increase.
      The negative charge proved to be crucial since the Glu125Asp (E125D) mutant
      showed similar properties to the wild type (WT). A similar weakly voltage
      dependent block was also caused by extracellular Ca(2+) and La(3+) in Kir2.1 WT
      but not in the E125Q mutant. The sensitivity to block by extracellular Ba(2+)
      (Ba2+o) was also decreased in the E125Q mutant, although the voltage dependency
      of half-inhibition concentration was not changed, as reported previously. We
      additionally observed that the speed of Ba2+o block and recovery was decelerated
      by the presence of Mg2+o in WT, but not in the E125Q mutant. The sensitivity to
      the block by Mg2+o was increased by lowering extracellular K(+) (K+o), suggesting
      a competitive interaction of Mg2+o and K+o. The single-channel conductance of the
      WT in 140 mM K(+) was 39.6 pS (0 mM Mg2+o) and 11.5 pS (10 mM), while that of the
      E125Q mutant was 26.0 pS (0 mM) and 19.6 pS (10 mM). These results demonstrate
      that Mg(2+) competes with K(+) permeation in the WT and that E125 is required for
      efficient K(+) permeation in the absence of Mg2+o. We conclude that E125 in an
      extracellular loop of Kir2.1 is a site which facilitates K(+) permeation and
      entry of Ba(2+) toward a deeper plugging site, and that Mg2+o competes with K+o
      and Ba2+o at this site.

PMID- 12411514
TI  - Regulation of the sodium bicarbonate cotransporter kNBC1 function: role of
      Asp(986), Asp(988) and kNBC1-carbonic anhydrase II binding.
AB  - The HCO(3)(-) : Na(+) cotransport stoichiometry of the electrogenic sodium
      bicarbonate cotransporter kNBC1 determines the reversal potential (E(rev)) and
      thus the net direction of transport of these ions through the cotransporter.
      Previously, we showed that phosphorylation of kNBC1-Ser(982) in the carboxy
      terminus of kNBC1 (kNBC1-Ct), by cAMP-protein kinase A (PKA), shifts the
      stoichiometry from 3 : 1 to 2 : 1 and that binding of bicarbonate to the
      cotransporter is electrostaticaly modulated. These results raise the possibility
      that phosphorylated kNBC1-Ser(982), or other nearby negatively charged residues
      shift the stoichiometry by blocking a bicarbonate-binding site. In the current
      study, we examined the role of the negative charge on Ser(982)-phosphate and
      three aspartate residues in a D986NDD custer in altering the stoichiometry of
      kNBC1. mPCT cells expressing kNBC1 mutants were grown on filters and mounted in
      an Ussing chamber for electrophysiological studies. Enhanced green fluorescence
      protein (EGFP)-tagged mutant constructs expressed in the same cells were used to
      determine the phosphorylation status of kNBC1-Ser(982). The data indicate that
      both kNBC1-Asp(986) and kNBC1-Asp(988), but not kNBC1-Asp(989), are required for
      the phosphorylation-induced shift in stoichiometry. A homologous motif (D887ADD)
      in the carboxy-terminus of the anion exchanger AE1 binds to carbonic anhydrase II
      (CAII). In isothermal titration calorimetry experiments, CAII was found to bind
      to kNBC1-Ct with a K(D) of 160 +/- 10 nM. Acetazolamide inhibited the short
      circuit current through the cotransporter by 65 % when the latter operated in the
      3 : 1 mode, but had no effect on the current in the 2 : 1 mode. Acetazolamide did
      not affect the cotransport stoichiometry or the ability of 8-Br-cAMP to shift the
      stoichiometry. Although CAII does not affect the transport stoichiometry, it may
      play an important role in enhancing the flux through the transporter when kNBC1
      Ser(982) is unphosphorylated.

PMID- 12411515
TI  - Halothane, isoflurane and sevoflurane inhibit NADH:ubiquinone oxidoreductase
      (complex I) of cardiac mitochondria.
AB  - We have investigated the effects of volatile anaesthetics on electron transport
      chain activity in the mammalian heart. Halothane, isoflurane and sevoflurane
      reversibly increased NADH fluorescence (autofluorescence) in intact ventricular
      myocytes of guinea-pig, suggesting that NADH oxidation was impaired. Using pig
      heart submitochondrial particles we found that the anaesthetics dose-dependently
      inhibited NADH oxidation in the order: halothane > isoflurane = sevoflurane.
      Succinate oxidation was unaffected by either isoflurane or sevoflurane,
      indicating that these agents selectively inhibit complex I (NADH:ubiquinone
      oxidoreductase). In addition to inhibiting NADH oxidation, halothane also
      inhibited succinate oxidation (and succinate dehydrogenase), albeit to a lesser
      extent. To test the hypothesis that complex I is a target of volatile
      anaesthetics, we examined the effects of these agents on NADH:ubiquinone
      oxidoreductase (EC 1.6.99.3) activity using the ubiquinone analogue DBQ
      (decylubiquinone) as substrate. Halothane, isoflurane and sevoflurane dose
      dependently inhibited NADH:DBQ oxidoreductase activity. Unlike the classical
      inhibitor rotenone, none of the anaesthetics completely inhibited enzyme activity
      at high concentration, suggesting that these agents bind weakly to the
      'hydrophobic inhibitory site' of complex I. In conclusion, halothane, isoflurane
      and sevoflurane inhibit complex I (NADH:ubiquinone oxidoreductase) of the
      electron transport chain. At concentrations of approximately 2 MAC (minimal
      alveolar concentration), the activity of NADH:ubiquinone oxidoreductase was
      reduced by about 20 % in the presence of halothane or isoflurane, and by about 10
      % in the presence of sevoflurane. These inhibitory effects are unlikely to
      compromise cardiac performance at usual clinical concentrations, but may
      contribute to the mechanism by which volatile anaesthetics induce pharmacological
      preconditioning.

PMID- 12411516
TI  - Contributions of the non-alpha subunit residues (loop D) to agonist binding and
      channel gating in the muscle nicotinic acetylcholine receptor.
AB  - The agonist binding site of the nicotinic acetylcholine receptor has a loop-based
      structure, and is formed by residues located remotely to each other in terms of
      primary structure. Amino acid residues in sites delta57 and delta59, and the
      equivalent residues in the epsilon; subunit, have been identified as part of the
      agonist binding site and designated as loop D. The effects of point mutations in
      sites delta57, delta59, epsilon;55 and epsilon;57 on agonist binding and channel
      gating were studied. The mutated receptors were expressed transiently in HEK 293
      cells and the currents were recorded using the cell-attached single-channel patch
      clamp technique. The results demonstrate that the mutations mainly affect channel
      gating with the major portion of the effect due to a reduction in the channel
      opening rate constant. For both the delta57/epsilon;55 and the delta59/epsilon;57
      site, a mutation in the epsilon; subunit had a greater effect on channel gating
      than a mutation in the delta subunit. In all instances, agonist binding was
      affected to a lesser degree than channel gating. Previous data have placed the
      delta57 and delta59 residues in or near the agonist binding pocket. The data
      presented here suggest that these two residues (and the homologous sites in the
      epsilon; subunit) are not involved in specific interactions with the nicotinic
      agonist and that they affect the activation of the nicotinic receptor by shaping
      the overall structure of the agonist binding site.

PMID- 12411517
TI  - Decreased shortening velocity and altered myosin isoforms in guinea-pig
      hypertrophic intestinal smooth muscle.
AB  - The aims of this study were to investigate whether hypertrophy of the small
      intestinal smooth muscle leads to alterations of myosin isoform composition and
      shortening velocity and whether possible changes correlate with a change in the
      sensitivity to ADP of shortening velocity in this tissue. A partial occlusion was
      introduced in the distal part of the ileum of guinea-pigs. After 2 weeks, the
      part of the small intestine just proximal of the stenosis was hypertrophied
      (indicated by a significantly increased cross-sectional area). The most proximal
      part of the small intestine was used as control, thus enabling comparisons
      between hypertrophic and normal tissue from the same animal. The outer
      longitudinal layer of the intestinal wall was gently peeled off and used for
      biochemistry, RT-PCR and mechanical experiments. The desmin/actin ratio was
      significantly increased following hypertrophy, although myosin and actin
      expression were similar in control and hypertrophic tissue. In hypertrophic
      tissue, the myosin heavy chain mRNA with a 21 base pair insert decreased
      significantly. The composition of the mRNA encoding the myosin essential light
      chains changed towards more of the basic type (LC17b). No change in the
      expression of non-muscle myosin heavy chains A and B was detected. The maximal
      shortening velocity (V(max)) of maximally activated skinned preparations was
      significantly lower in the hypertrophic tissue (~50 % of control). The
      sensitivity of V(max) to ADP was increased in the hypertrophic smooth muscle
      tissue. We conclude that myosin expression is altered following intestinal
      hypertrophy and that these alterations affect reactions in the cross-bridge
      interaction, leading to a slower and more economical contractile function.

PMID- 12411518
TI  - Serotonin 5-HT(3) receptors in rat CA1 hippocampal interneurons: functional and
      molecular characterization.
AB  - The molecular makeup of the serotonin 5-HT(3) receptor (5-HT(3)R) channel was
      investigated in rat hippocampal CA1 interneurons in slices using single-cell RT
      PCR and patch-clamp recording techniques. We tested for the expression of the 5
      HT(3A) (both short and long splice variants) and 5-HT(3B) subunits, as well as
      the expression of the alpha4 subunit of the neuronal nicotinic ACh receptors
      (nAChRs), the latter of which has been shown to co-assemble with the 5-HT(3A)
      subunit in heterologous expression systems. Both the 5-HT(3A)-short and alpha4
      nAChR subunits were expressed in these interneurons, but we could not detect any
      expression of either the 5-HT(3B) or the 5-HT(3A)-long subunits. Furthermore,
      there was a strong tendency for the 5-HT(3A)-short and alpha4-nAChR subunits to
      be co-expressed in individual interneurons. To assess whether there was any
      functional evidence for co-assembly between the 5-HT(3A)-short and alpha4-nAChR
      subunits, we used the sulphydryl agent 2-aminoethyl methanethiosulphonate
      (MTSEA), which has previously been shown to modulate expressed 5-HT(3)Rs that
      contain the alpha4-nAChR subunit. In half of the interneurons examined, MTSEA
      significantly enhanced the amplitude of the 5-HT(3)R-mediated responses, which is
      consistent with the notion that the alpha4-nAChR subunit co-assembles with the 5
      HT(3A) subunit to form a native heteromeric 5-HT(3)R channel in rat CA1
      hippocampal interneurons in vivo. In addition, the single-channel properties of
      the 5-HT(3)R were investigated in outside-out patches. No resolvable single
      channel currents were observed. Using non-stationary fluctuation analysis, we
      obtained an estimate of the single-channel conductance of 4 pS, which is well
      below that expected for channels containing both the 5-HT(3A) and 5-HT(3B)
      subunits.

PMID- 12411519
TI  - Fast synaptic transmission mediated by alpha-bungarotoxin-sensitive nicotinic
      acetylcholine receptors in lamina X neurones of neonatal rat spinal cord.
AB  - Using patch clamp recordings on neonatal rat spinal cord slices, we have looked
      for the presence of alpha-bungarotoxin-sensitive nicotinic ACh receptors (nAChRs)
      on sympathetic preganglionic neurones (SPNs) surrounding the central canal of the
      spinal cord (lamina X) and examined whether they were implicated in a fast
      cholinergic synaptic transmission. SPNs were identified either by their
      morphology using biocytin in the recording electrode and/or by antidromic
      stimulation of the ventral rootlets. The selective alpha7-containing nAChR
      (alpha7*nAChR) agonist choline (10 mM) induced a fast, rapidly desensitizing
      inward current, which was fully blocked by alpha-bungarotoxin (alpha-BgT; 50 nM)
      and strychnine (1 microM), two antagonists of alpha7*nAChRs. The I-V relationship
      of the choline-induced current showed a strong inward-going rectification.
      Electrically evoked excitatory postsynaptic currents (eEPSCs) could be recorded.
      At -60 mV, eEPSCs peaked at -26.2 pA and decayed monoexponentially with a mean
      time constant of 8.5 ms. The current-voltage relationship for eEPSCs exhibited a
      strong inward rectification and a reversal potential close to 0 mV, compatible
      with a non-selective cationic current. The appearance of eEPSCs was entirely
      suppressed by the application of 100 microM ACh or nicotine. Choline (10 mM) and
      1,1-dimethyl-4-phenylpiperazinium iodide (DMPP; 100 microM) both reduced the
      amplitude of eEPSCs, whereas cytisine (100 microM) had no effect. Strychnine (1
      microM) and alpha-BgT (50 nM) both suppressed the eEPSCs. Blocking the P2X
      purinergic and 5-HT(3) receptors had no effect on eEPSCs. DMPP induced four types
      of current, which differed in their onset and desensitization rate. The most
      frequently encountered responses were insensitive to the action of strychnine and
      alpha-BgT, and were reproduced by ACh and nicotine but not by cytisine. We
      conclude that SPNs of the lamina X express several classes of nAChRs and in
      particular alpha-BgT-sensitive nAChRs. This is the first demonstration in a
      mammalian spinal cord preparation of a fast cholinergic neurotransmission in
      which alpha-BgT-sensitive nicotinic receptors are involved.

PMID- 12411520
TI  - Differential exocytosis from human endothelial cells evoked by high intracellular
      Ca(2+) concentration.
AB  - Endothelial cells secrete a range of procoagulant, anticoagulant and inflammatory
      proteins by exocytosis to regulate blood clotting and local immune responses. The
      mechanisms regulating vesicular exocytosis were studied in human umbilical vein
      endothelial cells (HUVEC) with high-resolution membrane capacitance (C(m))
      measurements. The total whole-cell C(m) and the amplitudes and times of discrete
      femtoFarad (fF)-sized C(m) steps due to exocytosis and endocytosis were monitored
      simultaneously. Intracellular calcium concentration [Ca(2+)](i) was elevated by
      intracellular photolysis of calcium-DM-nitrophen to evoke secretion and monitored
      with the low-affinity Ca(2+) indicator furaptra. Sustained elevation of
      [Ca(2+)](i) to > 20 microM evoked large, slow increases in C(m) of up to 5 pF in
      1-2 min. Exocytotic and endocytotic steps of amplitude 0.5-110 fF were resolved,
      and accounted on average for ~33 % of the total C(m) change. A prominent
      component of C(m) steps of 2.5-9.0 fF was seen and could be attributed to
      exocytosis of von-Willebrand-factor-containing Weibel-Palade bodies (WPb), based
      on the near-identical distributions of capacitance step amplitudes, with
      calculated estimates of WPb capacitance from morphometry, and on the absence of
      2.5-9.0 fF C(m) steps in cells deficient in WPb. WPb secretion was delayed on
      average by 23 s after [Ca(2+)](i) elevation, whereas total C(m) increased
      immediately due to the secretion of small, non-WPb granules. The results show
      that following a large increase of [Ca(2+)](i), corresponding to strong
      stimulation, small vesicular components are immediately available for secretion,
      whereas the large WPb undergo exocytosis only after a delay. The presence of
      events of magnitude 9-110 fF also provides evidence of compound secretion of WPb
      due to prior fusion of individual granules.

PMID- 12411521
TI  - Increased incidence of gap junctional coupling between spinal motoneurones
      following transient blockade of NMDA receptors in neonatal rats.
AB  - Neonatal rat motoneurones are electrically coupled via gap junctions and the
      incidence of this coupling declines during postnatal development. The mechanisms
      involved in this developmental regulation of gap junctional communication are
      largely unknown. Here we have studied the role of NMDA receptor-mediated
      glutamatergic synaptic activity in the regulation of motoneurone coupling. Gap
      junctional coupling was demonstrated by the presence of graded, short latency
      depolarising potentials following ventral root stimulation, and by the transfer
      of the low molecular weight tracer Neurobiotin to neighbouring motoneurones.
      Sites of close apposition between the somata and/or dendrites of the dye-coupled
      motoneurones were identified as potential sites of gap junctional coupling. Early
      postnatal blockade of the NMDA subtype of glutamate receptors using the non
      competitive antagonist dizocilpine maleate (MK801) arrested the developmental
      decrease in electrotonic and dye coupling during the first postnatal week. These
      results suggest that the postnatal increase in glutamatergic synaptic activity
      associated with the onset of locomotion promote the loss of gap junctional
      connections between developing motoneurones.

PMID- 12411522
TI  - Reversible changes in Ca(2+)-activation properties of rat skeletal muscle exposed
      to elevated physiological temperatures.
AB  - Exposure of relaxed rat extensor digitorum longus (EDL; predominantly fast
      twitch) muscle to temperatures in the upper physiological range for mammalian
      skeletal muscle (43-46 degrees C) led to reversible alterations of the
      contractile activation properties. These properties were studied using the
      mechanically skinned fibre preparation activated in Ca(2+)-buffered solutions.
      The maximum Ca(2+)-activated force (maximum force per cross-sectional area) and
      the steepness of force-pCa (-log(10)[Ca(2+)]) curves as measured by the Hill
      coefficient (n(H)) reversibly decreased by factors of 8 and 2.5, respectively,
      when the EDL muscle was treated at 43 degrees C for 30 min and 5 and 2.8,
      respectively, with treatment at 46 degrees C for 5 min. Treatment at 47 degrees C
      for 5 min produced an even more marked depression in maximum specific force,
      which fully recovered after treatment, and in the Hill coefficient, which did not
      recover after treatment. After all temperature treatments there was no change in
      the level of [Ca(2+)] at which 50 % maximum force was generated. The temperature
      induced depression in force production and steepness of the force-pCa curves were
      shown to be associated with superoxide (O(2)(-)) production in muscle (apparent
      rate of O(2)(-) production at room temperature, 0.055 +/- 0.008 nmol min(-1) (g
      wet weight)(-1); and following treatment to 46 degrees C for 5 min, 1.8 +/- 0.2
      nmol min(-1) (g wet weight)(-1)) because 20 mM Tiron, a membrane-permeant O(2)(-)
      scavenger, was able to markedly suppress the net rate of O(2)(-) production and
      prevent any temperature-induced depression of contractile parameters. The
      temperature-induced depression in force production of the contractile apparatus
      could be reversed either by allowing the intact muscle to recover for 3-4 h at
      room temperature or by treatment of the skinned fibre preparation with
      dithiothreitol (a potent reducing agent) in the relaxing solution. These results
      demonstrate that mammalian skeletal muscle has the ability to uncouple force
      production reversibly from the activator Ca(2+) as the temperature increases in
      the upper physiological range through an increase in O(2)(-) production.

PMID- 12411523
TI  - Recruitment of Ca(2+) release channels by calcium-induced Ca(2+) release does not
      appear to occur in isolated Ca(2+) release sites in frog skeletal muscle.
AB  - Ca(2+) release from the sarcoplasmic reticulum (SR) in skeletal muscle in
      response to small depolarisations (e.g. to -60 mV) should be the sum of release
      from many isolated Ca(2+) release sites. Each site has one SR Ca(2+) release
      channel activated by its associated T-tubular voltage sensor. The aim of this
      study was to evaluate whether it also includes neighbouring Ca(2+) release
      channels activated by Ca-induced Ca(2+) release (CICR). Ca(2+) release in frog
      cut muscle fibres was estimated with the EGTA/phenol red method. The fraction of
      SR Ca content ([Ca(SR)]) released by a 400 ms pulse to -60 mV (denoted f(Ca))
      provided a measure of the average Ca(2+) permeability of the SR associated with
      the pulse. In control experiments, f(Ca) was approximately constant when [Ca(SR)]
      was 1500-3000 microM (plateau region) and then increased as [Ca(SR)] decreased,
      reaching a peak when [Ca(SR)] was 300-500 microM that was 4.8 times larger on
      average than the plateau value. With 8 mM of the fast Ca(2+) buffer BAPTA in the
      internal solution, f(Ca) was 5.0-5.3 times larger on average than the plateau
      value obtained before adding BAPTA when [Ca(SR)] was 300-500 microM. In support
      of earlier results, 8 mM BAPTA did not affect Ca(2+) release in the plateau
      region. At intermediate values of [Ca(SR)], BAPTA resulted in a small, if any,
      increase in f(Ca), presumably by decreasing Ca inactivation of Ca(2+) release.
      Since BAPTA never decreased f(Ca), the results indicate that neighbouring
      channels are not activated by CICR with small depolarisations when [Ca(SR)] is
      300-3000 microM.

PMID- 12411524
TI  - Slow feedback inhibition in the CA3 area of the rat hippocampus by synergistic
      synaptic activation of mGluR1 and mGluR5.
AB  - Interneurons are critical in regulating the excitability of principal cells in
      neuronal circuits, thereby modulating the output of neuronal networks. We
      investigated synaptically evoked inhibitory responses in CA3 pyramidal cells
      mediated by metabotropic glutamate receptors (mGluRs) expressed
      somatodendritically by interneurons. Although pharmacological activation of
      mGluRs in interneurons has been shown to enhance their excitability, the
      inability to record mGluR-mediated synaptic responses has precluded detailed
      characterization of mGluR function in hippocampal interneurons. We found that a
      single extracellular pulse in CA3 stratum pyramidale was sufficient to induce
      disynaptic inhibitory responses mediated by postsynaptic mGluRs of the
      interneurons in CA3 pyramidal cells of hippocampal slice cultures. The disynaptic
      inhibitory response followed a short-latency monosynaptic inhibitory response,
      and was observed at stimulus intensities evoking half-maximal monosynaptic IPSCs.
      Synergistic activation of mGluR1 and mGluR5 was required to induce the full
      inhibitory response. When recordings were obtained from interneurons in CA3
      stratum radiatum or stratum oriens, a single extracellular stimulus induced a
      slow inward cationic current with a time course corresponding to the slow
      inhibitory response measured in pyramidal cells. DCG IV, a group II mGluR
      agonist, which specifically blocks synaptic transmission through mossy fibres,
      had no effect on mGluR-mediated synaptic responses in interneurons, suggesting
      that feed-forward inhibition via mossy fibres is not involved. Thus, postsynaptic
      mGluR1 and mGluR5 in hippocampal interneurons cooperatively mediate slow feedback
      inhibition of CA3 pyramidal cells. This mechanism may allow interneurons to
      monitor activity levels from populations of neighbouring principal cells to adapt
      inhibitory tone to the state of the network.

PMID- 12411525
TI  - Dopamine mediates circadian clock regulation of rod and cone input to fish
      retinal horizontal cells.
AB  - A circadian (24-hour) clock regulates the light responses of fish cone horizontal
      cells, second order neurones in the retina that receive synaptic contact from
      cones and not from rods. Due to the action of the clock, cone horizontal cells
      are driven by cones in the day, but primarily driven by rods at night. We show
      here that dopamine, a retinal neurotransmitter, acts as a clock signal for the
      day by increasing cone input and decreasing rod input to cone horizontal cells.
      The amount of endogenous dopamine released from in vitro retinae was greater
      during the subjective day than the subjective night. Application of dopamine or
      quinpirole, a dopamine D(2)-like agonist, during the subjective night increased
      cone input and eliminated rod input to the cells, a state usually observed during
      the subjective day. In contrast, application of spiperone, a D(2)-like
      antagonist, or forskolin, an activator of adenylyl cyclase, during the subjective
      day reduced cone input and increased rod input. SCH23390, a D(1) antagonist, had
      no effect. Application of R(p)-cAMPS, an inhibitor of cAMP-dependent protein
      kinase, or octanol, an alcohol that uncouples gap junctions, during the night
      increased cone input and decreased rod input. Because D(2)-like receptors are on
      photoreceptor cells, but not horizontal cells, the results suggest that the clock
      induced increase in dopamine release during the day activates D(2)-like receptors
      on photoreceptor cells. The resultant decrease in intracellular cyclic AMP and
      protein kinase A activation then mediates the increase in cone input and decrease
      in rod input.

PMID- 12411526
TI  - Effect of stimulation rate, sarcomere length and Ca(2+) on force generation by
      mouse cardiac muscle.
AB  - The relations between stress, stimulation rate and sarcomere length (SL) were
      investigated in 24 cardiac trabeculae isolated from right ventricles of mice (CF
      1 males, 25-30 g) and superfused with Hepes solution ([Ca(2+)](o) = 1 mM, pH 7.4,
      25 degrees C). Stress and SL were measured by a strain gauge transducer and laser
      diffraction technique, respectively. Stress versus stimulation frequency formed a
      biphasic relation (25 degrees C, [Ca(2+)](o) = 2 mM) with a minimum at 0.7-1 Hz
      (~15 mN mm(-2)), a 150 % decrease from 0.1 to 1 Hz (descending limb) and a 75 %
      increase from 1 to 5 Hz (ascending limb). Ryanodine (0.1 microM) inhibited
      specifically the descending limb, while nifedipine (0.1 microM) affected
      specifically the ascending limb. This result suggests two separate sources of
      Ca(2+) for stress development: (1) net Ca(2+) influx during action potentials
      (AP); and (2) Ca(2+) entry into the cytosol from the extracellular space during
      diastolic intervals; Ca(2+) from both (1) and (2) is sequestered by the SR
      between beats. Raising the temperature to 37 degrees C lowered the stress
      frequency relation (SFR) by approximately 0-15 mN mm(-2) at each frequency.
      Because the amount of Ca(2+) carried by I(Ca,L) showed a approximately 3-fold
      increase under the same conditions, we conclude that reduced Ca(2+) loading of
      the SR was probably responsible for this temperature effect. A simple model of
      Ca(2+) fluxes addressed the mechanisms underlying the SFR. Simulation of the
      effect of inorganic phosphates (P(i)) on force production was incorporated into
      the model. The results suggested that O(2) diffusion limits force production at
      stimulation rates >3 Hz. The stress-SL relations from slack length (approximately
      1.75 microm) to 2.25 microm showed that the passive stress-SL curve of mouse
      cardiac trabeculae is exponential with a steep increase at SL >2.1 microm. Active
      stress (at 1 Hz) increased with SL, following a curved relation with convexity
      toward the abscissa at [Ca(2+)] = 2 mM. At [Ca(2+)] from 4 to 12 mM, the stress
      SL curves superimposed and the relation became linear, which revealed a
      saturation step in the activation of force production. EC coupling in mouse
      cardiac muscle is similar to that observed previously in the rat, although
      important differences exist in the Ca(2+) dependence of force development. These
      results may suggest a lower capacity of the SR for buffering Ca(2+), which makes
      the generation of force in mouse cardiac ventricle more dependent on Ca(2+)
      entering during action potentials, particularly at high heart rate.

PMID- 12411527
TI  - Membrane properties of an unusual intrinsically oscillating, wide-field teleost
      retinal amacrine cell.
AB  - In the retina, amacrine cells modulate the transfer of information from bipolar
      to ganglion cells. The nature of the modulation depends on the synaptic input and
      the membrane properties of the cells. In the retina of white bass, we identified
      a class of bistratified, wide-field amacrine cell characterized by immunopositive
      labelling for GABA and calmodulin. In isolation, the cells presented resting
      membrane potentials averaging -69 mV although some cells settled at more
      depolarized values (-30 mV). Injection of depolarizing current pulses induced
      oscillatory membrane responses. When elicited from depolarized cells, the
      oscillations were short-lived (< 40 ms). For the most part, the oscillatory
      potentials of hyperpolarized cells remained unattenuated throughout the
      depolarizing pulse. The frequency of the oscillations increased logarithmically
      with mean membrane potential, ranging from 74 to 140 Hz. Cells exhibiting
      depolarized membrane potentials oscillated at twice that rate. When the membrane
      potential of these cells was hyperpolarized to -70 mV, the oscillations became
      unattenuated and slowed. We found the cells expressed voltage-gated sodium,
      potassium and calcium currents and calcium-dependent potassium currents. We
      demonstrate that the oscillatory potentials arose as a result of the interplay
      between calcium and potassium currents. The cells responded to local application
      of GABA and glycine, both of which modulate the oscillatory potentials. Glutamate
      and its analogues depolarized the cell and induced oscillatory potentials. Our
      results indicate that oscillatory responses of a type of wide-field amacrine cell
      are an intrinsic feature of the cell and not due to circuit properties.

PMID- 12411528
TI  - Contraction-induced muscle damage in humans following calcium channel blocker
      administration.
AB  - Following contraction-induced damage of skeletal muscle there is a loss of
      calcium homeostasis. Attenuating the damage-induced rise in myocellular calcium
      concentration may reduce proteolytic activation and attenuate other indices of
      damage; calcium channel blockers have been shown to be effective in this regard.
      The effect of administration of a calcium channel blocker (CCB), amlodipine, on
      indices of muscle damage following a unilateral 'damage protocol', during which
      subjects performed 300 maximal isokinetic (0.52 rad s(-1)) eccentric contractions
      with the knee extensors was investigated. The design was a randomized, double
      blind crossover. On one occasion, prior to the damage protocol, subjects consumed
      CCB for 7 days prior to and for 7 days following the damage protocol. Biopsies
      were taken from the vastus lateralis prior to (baseline) and following the damage
      protocol at 4 h and 24 h post-damage. Isometric peak knee extensor torque was
      reduced (P < 0.05) immediately post-, 24 h post- and 48 h post-damage protocol
      compared to pre-exercise values with no effect of treatment. Desmin disruption
      was attenuated (P < 0.05) with CCB versus placebo at 4 h post-damage. Z-band
      streaming was significantly (P < 0.05) elevated compared to baseline at both
      times post-damage, but was lower with CCB at 4 h (P < 0.05). Damage resulted in
      increased inflammatory cell (macrophage) infiltration into skeletal muscle at
      both 4 h and 24 h post-damage, with no effect of CCB. Neutrophil number was
      elevated by the damage protocol, but was higher at 24 h post-damage in the CCB
      condition (P < 0.05). Creatine kinase (CK) activity was higher (P < 0.05) at 24 h
      and 48 h following the damage protocol compared to baseline, with no effect of
      treatment. In conclusion, the reduction in desmin disruption and Z-band streaming
      indicates that CCB attenuated, or delayed, the contraction-induced damage to
      sarcomeric proteins.

PMID- 12411529
TI  - Excitation of rat colonic afferent fibres by 5-HT(3) receptors.
AB  - The gastrointestinal tract contains most of the body's 5-hydroxytryptamine (5-HT)
      and releases large amounts after meals or exposure to toxins. Increased 5-HT
      release occurs in patients with irritable bowel syndrome (IBS) and their peak
      plasma 5-HT levels correlate with pain episodes. 5-HT(3) receptor antagonists
      reduce symptoms of IBS clinically, but their site of action is unclear and the
      potential for other therapeutic targets is unexplored. Here we investigated
      effects of 5-HT on sensory afferents from the colon and the expression of 5-HT(3)
      receptors on their cell bodies in the dorsal root ganglia (DRG). Distal colon,
      inferior mesenteric ganglion and the lumbar splanchnic nerve bundle (LSN) were
      placed in a specialized organ bath. Eighty-six single fibres were recorded from
      the LSN. Three classes of primary afferents were found: 70 high-threshold serosal
      afferents, four low-threshold muscular afferents and 12 mucosal afferents.
      Afferent cell bodies were retrogradely labelled from the distal colon to the
      lumbar DRG, where they were processed for 5-HT(3) receptor-like immunoreactivity.
      Fifty-six percent of colonic afferents responded to 5-HT (between 10(-6) and 10(
      3) M) and 30 % responded to the selective 5-HT(3) agonist, 2-methyl-5-HT (between
      10(-6) and 10(-2) M). Responses to 2-methyl-5-HT were blocked by the 5-HT(3)
      receptor antagonist alosetron (2 x 10(-7) M), whereas responses to 5-HT were only
      partly inhibited. Twenty-six percent of L1 DRG cell bodies retrogradely labelled
      from the colon displayed 5-HT(3) receptor-like immunoreactivity. We conclude that
      colonic sensory neurones expressing 5-HT(3) receptors also functionally express
      the receptors at their peripheral endings. Our data reveal actions of 5-HT on
      colonic afferent endings via both 5-HT(3) and non-5-HT(3) receptors.

PMID- 12411530
TI  - Endogenous cyclo-oxygenase activity regulates mouse gastric surface pH.
AB  - In the stomach, production of prostaglandins by cyclo-oxygenase (COX) is believed
      to be important in mucosal defence. We tested the hypothesis that endogenous COX
      activity is required for protective gastric surface pH control. Intact stomachs
      of anaesthetized mice were perfused with a weakly buffered solution (150 mM NaCl
      + 4 mM Homopipes) at pH values from 2.5 to 7.0. Gastric effluents were collected
      to measure pH and estimate amounts of acid or alkali secretion in nanomoles
      secreted per minute. A switch from net acid to net alkali secretion was seen in
      response to acidifying luminal pH with an apparent 'set point' between pH 4 and
      5. At luminal pH 3, the net alkali secretion (12.7 +/- 2.8 nmol OH(-) equivalents
      min(-1)) was abolished (2.2 +/- 1.7 nmol OH(-) min(-1)) by the non-specific COX
      inhibitor indomethacin (5 mg kg(-1) I.P.). Similar inhibition was observed using
      a COX-1 inhibitor (SC-560; 10 mg kg(-1) I.P.), but not a COX-2 inhibitor (NS-398;
      10 mg kg(-1) I.P.). Subsequent treatment with 16,16-dimethyl prostaglandin E(2)
      (dm-PGE(2); 1 mg kg(-1) I.P.) rescued the alkali secretion (21.8 +/- 2.7 nmol OH(
      ) min(-1)). In either the absence or presence of the H(+),K(+)-ATPase inhibitor
      omeprazole (60 mg kg(-1) I.P.), indomethacin blocked similar amounts of net
      alkali secretion (10.5 +/- 2.7 and 16.4 +/- 3.4 nmol OH(-) min(-1),
      respectively). We also used in vivo confocal microscopy to examine pH near the
      mucosal surface. The gastric mucosal surface of anaesthetized mice was exposed
      and mucosal surface pH was imaged using the fluorescence intensity ratio of Cl
      NERF as a pH indicator. Results showed a switch from a continuous net acid to net
      alkali secretion by the stomach in response to changing superfusate pH from 5 to
      3. At luminal pH 3, the relatively alkaline surface pH (4.3 +/- 0.1) was
      acidified (3.6 +/- 0.2) by indomethacin, and subsequent dm-PGE(2) restored
      surface pH (4.2 +/- 0.2). We conclude that the pre-epithelial alkaline layer is
      regulated by endogenous COX activity.

PMID- 12411531
TI  - ACh-induced endothelial NO synthase translocation, NO release and vasodilatation
      in the hamster microcirculation in vivo.
AB  - Studies in cultured cells show that activation of endothelial nitric oxide (NO)
      synthase (eNOS) requires the dissociation of this enzyme from its inhibitory
      association with caveolin-1 (Cav-1), and perhaps its translocation from plasma
      membrane caveolae to other cellular compartments. We investigated the hypothesis
      that in vivo NO-dependent vasodilatation is associated with the translocation of
      eNOS from the cell membrane. To this end, we applied ACh topically (10-100 microM
      for 10 min) to the hamster cheek pouch microcirculation and measured NO
      production, blood flow and vessel diameter, and assessed subcellular eNOS
      distribution by Western blotting. Baseline NO production was 54.4 +/- 5.2 pmol
      min(-1) (n = 16). ACh increased NO release, caused arteriolar and venular
      dilatation and elevated microvascular flow. These responses were inhibited by
      N(G)-nitro-L-arginine (30 microM). The maximal increase in NO production induced
      by 10 microM and 100 microM ACh was 45 +/- 20 % and 111 +/- 33 %, respectively;
      the corresponding blood flow increases were 50 +/- 10 % and 130 +/- 24 %,
      respectively (n = 4-6). Both responses followed a similar time course, although
      increases in NO preceded flow changes. In non-stimulated tissues, eNOS was
      distributed mainly in the microsomal fraction. ACh-induced vasodilatation was
      associated with eNOS translocation to the cytosolic and Golgi-enriched fractions.
      After 1.5, 3.0 or 6.0 min of application, 10 microM ACh decreased the level of
      membrane-bound eNOS by -13 +/- 4 %, -60 +/- 4 % and -19 +/- 17 %, respectively;
      at the same time points, 100 microM ACh reduced microsomal eNOS content by -38 +/
      9 %, -61 +/- 16 % and -40 +/- 18 %, respectively (n = 4-5). In all cases,
      microsomal Cav-1 content did not change. The close ACh concentration dependence
      and the concomitance between eNOS subcellular redistribution and NO release
      support the concept that eNOS translocation from the plasma membrane is part of
      an activation mechanism that induces NO-dependent vasodilatation in vivo.

PMID- 12411532
TI  - Activated platelets contribute to stimulation of cardiac afferents during
      ischaemia in cats: role of 5-HT(3) receptors.
AB  - Myocardial ischaemia activates blood platelets and cardiac sympathetic afferents,
      which mediate chest pain and cardiovascular reflex responses. We have
      demonstrated that activated platelets stimulate ischaemically sensitive cardiac
      sympathetic afferents. Platelets absorb and release 5-hydroxytryptamine (5-HT)
      when they are activated. In the present study we hypothesized that, by releasing
      5-HT, activated platelets stimulate cardiac afferents during ischaemia through a
      5-HT(3) receptor mechanism. Platelet-rich plasma (PRP) and platelet-poor plasma
      (PPP) were obtained from cats. Activation of platelets in PRP was induced by
      thrombin (5 units ml(-1)) or collagen (2 mg kg(-1)). Using high-performance
      liquid chromatography, we observed that the concentration of 5-HT was increased
      significantly in suspensions of platelets activated with thrombin (PRP+thrombin,
      28 +/- 1.7 microM) or collagen (PRP+collagen, 27 +/- 2.5 microM) compared with
      suspensions of unactivated platelets (PRP+saline, 2.3 +/- 0.8 microM) and PPP.
      During myocardial ischaemia and reperfusion, tirofiban, a specific inhibitor of
      platelet glycoprotein (GP) IIb-IIIa receptors (100 microg kg(-1), I.V., followed
      by 5 microg kg(-1) min(-1)), significantly reduced the increase in the
      concentration of 5-HT in cardiac venous plasma from ischaemic region. Nerve
      activity of single-unit cardiac afferents was recorded from the left sympathetic
      chain (T2-T5) in anaesthetized cats. Eighty ischaemically sensitive and seven
      ischaemically insensitive cardiac afferents were identified. Tirofiban reduced
      the ischaemia-related increase in activity of seven cardiac sympathetic afferents
      by 50 %. Injection of 1.5 ml of PRP+collagen or PRP+thrombin into the left atrium
      (LA) increased activity of 16 cardiac afferents. Tropisetron (300 microg kg(-1),
      I.V.), a selective 5-HT(3) receptor antagonist, eliminated the afferent's
      responses to platelets activated with collagen or thrombin. Moreover, LA
      injection of 5-HT (20-40 microg kg(-1)) and PBG (100 microg kg(-1)), a 5-HT(3)
      receptor agonist, stimulated nine ischaemically sensitive cardiac sympathetic
      afferents, significantly increasing the activity of these afferents. However,
      injection of alpha-M-5-HT (100 microg kg(-1), LA), a 5-HT(2) receptor agonist,
      stimulated only two of the nine ischaemically sensitive cardiac afferents, and
      thus did not significantly alter impulse activity of this group of afferents.
      Both the 5-HT(1) (5-CT, 100 microg kg(-1), LA) and 5-HT(4) receptor agonists
      (SC53116, 100 microg kg(-1), LA) did not stimulate any of the nine afferents
      tested. Tropisetron (300 microg kg(-1), I.V.) also eliminated the response of
      seven ischaemically sensitive cardiac afferents to exogenous 5-HT and attenuated
      the ischaemia-related increase in activity of nine cardiac sympathetic afferents
      by 41 %. Conversely, LA injection of 5-HT (40 microg kg(-1)) did not stimulate
      any of seven ischaemically insensitive cardiac afferents, although this group of
      afferents consistently responded to bradykinin (3 microg, LA). These data
      indicate that during myocardial ischaemia the activated platelets stimulate
      cardiac sympathetic afferents, at least in part, through a 5-HT(3) receptor
      mechanism.

PMID- 12411533
TI  - The effect of tezosentan, a non-selective endothelin receptor antagonist, on
      shear stress-induced changes in arterial diameter of the anaesthetized dog.
AB  - The effects of changes in the mean (S(m)) and pulsatile (S(p)) components of
      arterial wall shear stress on arterial dilatation of the iliac artery of the
      anaesthetized dog were examined in the absence and presence of the endothelin
      receptor antagonist tezosentan (10 mg kg(-1) I.V.; Ro 61-0612; [5-isopropyl
      pyridine-2-sulphonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1H
      tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-ylamide]). Changes in shear stress were
      brought about by varying local peripheral resistance and stroke volume using a
      distal infusion of acetylcholine and stimulation of the left ansa subclavia. An
      increase in S(m) from 1.81 +/- 0.3 to 7.29 +/- 0.7 N m(-2) (means +/- S.E.M.)
      before tezosentan caused an endothelium-dependent arterial dilatation which was
      unaffected by administration of tezosentan for a similar increase in S(m) from
      1.34 +/- 0.6 to 5.76 +/- 1.4 N m(-2) (means +/- S.E.M.). In contrast, increasing
      the S(p) from 7.1 +/- 0.8 to a maximum of 11.5 +/- 1.1 N m(-2) (means +/- S.E.M.)
      before tezosentan reduced arterial diameter significantly. Importantly, after
      administration of tezosentan subsequent increases in S(p) caused arterial
      dilatation for the same increase in S(p) achieved prior to tezosentan, increasing
      from a baseline of 4.23 +/- 0.4 to a maximum of 9.03 +/- 0.9 N m(-2) (means +/-
      S.E.M.; P < 0.001). In conclusion, the results of this study provide the first in
      vivo evidence that pulsatile shear stress is a stimulus for the release of
      endothelin from the vascular endothelium.

PMID- 12411534
TI  - Oestrogen augments the fetal ovine hypothalamus- pituitary-adrenal axis in
      response to hypotension.
AB  - In the fetal sheep, parturition is triggered by an increase in the activity of
      the fetal hypothalamus- pituitary-adrenal (HPA) axis which, in turn, augments the
      biosynthesis of oestrogen by the placenta. Parturition can be prevented or
      delayed by destruction of the paraventricular nucleus (PVN), pituitary or
      adrenal, or stimulated by infusions of adrenocorticotropin (ACTH) or
      glucocorticoids. We have previously reported that physiological increases in
      fetal plasma concentrations of oestradiol have a neuroendocrine effect to
      increase both basal and hypotension-stimulated ACTH secretion. The present study
      was performed to test the effect of oestradiol on the central baroreceptor and
      chemoreceptor reflex pathways. We used immunohistological techniques to identify
      various neuroanatomical regions which are activated by hypotension and,
      subsequently, those areas modified by oestrogen's action and baroreceptor and
      chemoreceptor denervation. We assessed cellular activation in these brain regions
      by immunostaining for Fos, the protein product of c-fos, an immediate early
      response gene. We found that oestradiol increased Fos abundance in nucleus
      tractus solitarius (NTS), rostral ventrolateral medulla (RVLM), and PVN, and
      augmented the increase in Fos in these regions in response to a 10 min period of
      brachiocephalic arterial occlusion (BCO). Carotid sinus denervation blocked the
      Fos response to BCO, but not to oestrogen alone, in these regions. In contrast,
      the hippocampus responded to BCO with increase Fos in intact fetuses, but did not
      respond to oestrogen treatment. None of the treatments altered Fos expression in
      cerebral cortex or in cerebellum. We conclude that oestradiol augments the
      activity of the central baroreceptor and chemoreceptor reflex pathways, and that
      it may influence fetal ACTH secretion via this site of action.

PMID- 12411535
TI  - Antioxidants prevent depression of the acute hypoxic ventilatory response by
      subanaesthetic halothane in men.
AB  - We studied the effect of the antioxidants (AOX) ascorbic acid (2 g, I.V.) and
      alpha-tocopherol (200 mg, P.O.) on the depressant effect of subanaesthetic doses
      of halothane (0.11 % end-tidal concentration) on the acute isocapnic hypoxic
      ventilatory response (AHR), i.e. the ventilatory response upon inhalation of a
      hypoxic gas mixture for 3 min (leading to a haemoglobin saturation of 82 +/- 1.8
      %) in healthy male volunteers. In the first set of protocols, two groups of eight
      subjects each underwent a control hypoxic study, a halothane hypoxic study and
      finally a halothane hypoxic study after pretreatment with AOX (study 1) or
      placebo (study 2). Halothane reduced the AHR by more than 50 %, from 0.79 +/-
      0.31 to 0.36 +/- 0.14 l min(-1) %(-1) in study 1 and from 0.79 +/- 0.40 to 0.36
      +/- 0.19 l min(-1) %(-1) in study 2, P < 0.01 for both. Pretreatment with AOX
      prevented this depressant effect of halothane in the subjects of study 1 (AHR
      returning to 0.77 +/- 0.32 l min(-1) %(-1), n.s. from control), whereas placebo
      (study 2) had no effect (AHR remaining depressed at 0.36 +/- 0.27 l min(-1) %(
      1), P < 0.01 from control). In a second set of protocols, two separate groups of
      eight subjects each underwent a control hypoxic study, a sham halothane hypoxic
      study and finally a sham halothane hypoxic study after pretreatment with AOX
      (study 3) or placebo (study 4). In studies 3 and 4, sham halothane did not modify
      the control hypoxic response, nor did AOX (study 3) or placebo (study 4). The 95
      % confidence intervals for the ratio of hypoxic sensitivities, (AOX + halothane)
      : halothane in study 1 and (AOX - sham halothane) : sham halothane in study 3,
      were [1.7, 2.6] and [1.0, 1.2], respectively. Because the antioxidants prevented
      the reduction of the acute hypoxic response by halothane, we suggest that this
      depressant effect may be caused by reactive species produced by a reductive
      metabolism of halothane during hypoxia or that a change in redox state of carotid
      body cells by the antioxidants prevented or changed the binding of halothane to
      its effect site. Our findings may also suggest that reactive species have an
      inhibiting effect on the acute hypoxic ventilatory response.

PMID- 12411536
TI  - Modulation of arterial baroreflex dynamic response during muscle metaboreflex
      activation in humans.
AB  - We aimed to investigate the interaction between the arterial baroreflex and
      muscle metaboreflexes (as reflected by alterations in the dynamic responses shown
      by muscle sympathetic nerve activity (MSNA), mean arterial blood pressure (MAP)
      and heart rate (HR)) in humans. In nine healthy subjects (eight male, one female)
      who performed a sustained 1 min handgrip exercise at 50 % maximal voluntary
      contraction followed by forearm occlusion, a 5 s period of neck pressure (NP) (30
      and 50 mmHg) or neck suction (NS)(-30 and -60 mmHg) was used to evaluate carotid
      baroreflex function at rest (CON) and during post-exercise muscle ischaemia
      (PEMI). In PEMI (as compared with CON): (a) the augmentations in MSNA and MAP
      elicited by 50 mmHg NP were both greater; (b) MSNA seemed to be suppressed by NS
      for a shorter period, (c) the decrease in MAP elicited by NS was smaller, and (d)
      MAP recovered to its initial level more quickly after NS. However, the HR
      responses to NS and NP were not different between PEMI and CON. These results
      suggest that during muscle metaboreflex activation, the dynamic arterial
      baroreflex response is modulated, as exemplified by the augmentation of the MSNA
      response to arterial baroreflex unloading (i.e. NP) and the reduction in the
      suppression of MSNA induced by baroreceptor stimulation (i.e. NS).

PMID- 12411537
TI  - Carbohydrate ingestion reduces skeletal muscle acetylcarnitine availability but
      has no effect on substrate phosphorylation at the onset of exercise in man.
AB  - This study investigated the effect of reduced acetylcarnitine availability on
      oxidative metabolism during the transition from rest to steady-state exercise.
      Eight male subjects completed two randomised exercise trials at 68 % of the peak
      rate of O(2) uptake (V((O(2)),peak)). On one occasion subjects ingested 1 g (kg
      body mass)(-1) glucose 75 min prior to exercise (CHO), whereas the other trial
      acted as a control (CON). Muscle samples were obtained pre- and 75 min post
      ingestion, and following 1 and 10 min of exercise. Plasma glucose and insulin
      were elevated (P < 0.05), and plasma free fatty acids (FFA) were lower at the
      onset of exercise in CHO. Acetylcarnitine (CON, 4.8 +/- 1.8; CHO, 1.5 +/- 0.9
      mmol (kg dry mass (d.m.))(-1), P < 0.05) and acetyl CoA (CON, 13.2 +/- 2.3; CHO,
      6.3 +/- 0.6 micromol (kg d.m.)(-1), P < 0.05) were lower at rest, whereas
      pyruvate dehydrogenase activation (PDHa) was greater in CHO compared with CON
      (CON, 0.78 +/- 0.07; CHO, 1.44 +/- 0.19 mmol min(-1) (kg wet mass (w.m.))(-1)).
      Respiratory exchange ratio (RER) was significantly elevated during exercise in
      CHO. The acetyl groups increased at similar rates at the onset of exercise (1
      min) and there was no difference in substrate phosphorylation as determined from
      lactate accumulation and phosphocreatine degradation between trials.
      Subsequently, oxidative metabolism during the transition from rest to steady
      state exercise was not affected by prior carbohydrate ingestion. Although
      exercise resulted in the rapid activation of PDH in both trials, PDHa was greater
      at 1 min in CHO (CON, 2.36 +/- 0.22; CHO, 2.91 +/- 0.18 mmol min(-1) (kg w.m.)(
      1)). No differences in muscle metabolite levels and PDHa were observed after 10
      min of moderate exercise between trials. In summary, at rest, carbohydrate
      ingestion induced multiple metabolic changes which included decreased
      acetylcarnitine availability and small increases in PDHa. The prior changes in
      PDHa and acetylcarnitine availability had no effect on substrate phosphorylation
      and oxidative metabolism at the onset of exercise. These data suggest that
      acetylcarnitine availability is unlikely to be the site of metabolic inertia
      during the transition from rest to steady-state moderate intensity exercise.

PMID- 12411538
TI  - Exercise induces hepatosplanchnic release of heat shock protein 72 in humans.
AB  - Physical exercise results in the appearance of heat shock protein (HSP) 72 in the
      circulation that precedes any increase in gene or protein expression in
      contracting skeletal muscle. In rodents, exercise increases liver HSP72
      expression and the hepatosplanchnic viscera are known to release many acute phase
      proteins. In the present study, we tested the hypothesis that the splanchnic
      tissue beds release HSP72 during exercise. Seven male subjects performed 120 min
      of semi-recumbent cycling at 62 +/- 2 % of maximal oxygen uptake. Blood samples
      were obtained simultaneously from a brachial artery, a femoral vein and the
      hepatic vein prior to and at 30, 60 and 120 min of exercise. Leg blood flow (LBF)
      was measured by thermodilution in the femoral vein, and hepatosplanchnic blood
      flow (HBL) was measured using indocyanine green dye. Net leg and net
      hepatosplanchnic HSP72 balance were calculated as the product of LBF and femoral
      venous-arterial HSP72 difference and the product of HBF and hepatic venous
      arterial HSP72 difference, respectively. Arterial plasma HSP72 was only detected
      in one subject at rest but progressively appeared in the arterial samples
      throughout exercise such that at 120 min it was detected in all subjects (0.88 +/
      0.35 pg l(-1); P < 0.05 compared with rest). The contracting muscle did not,
      however, contribute to this increase since there was no difference in the femoral
      venous-arterial HSP72 concentration at any time. Rather, the increase in arterial
      HSP72 was accounted for, at least in part, by release from the hepatosplanchnic
      viscera with values increasing (P < 0.05) from undetectable levels at rest to 5.2
      +/- 0.2 pg min(-1) after 120 min. These data demonstrate that the splanchnic
      tissues release HSP72 during exercise and this release is responsible, in part,
      for the elevated systemic concentration of this protein during exercise.

PMID- 12411539
TI  - Lactate and glucose interactions during rest and exercise in men: effect of
      exogenous lactate infusion.
AB  - To test the hypothesis that lactate plays a central role in the distribution of
      carbohydrate (CHO) potential energy for oxidation and glucose production (GP), we
      performed a lactate clamp (LC) procedure during rest and moderate intensity
      exercise. Blood [lactate] was clamped at approximately 4 mM by exogenous lactate
      infusion. Subjects performed 90 min exercise trials at 65 % of the peak rate of
      oxygen consumption (V(O(2))(,peak); 65 %), 55 % V(O(2))(,peak) (55 %) and 55 %
      V(O(2))(,peak) with lactate clamped to the blood [lactate] that was measured at
      65 % V(O(2))(,peak) (55 %-LC). Lactate and glucose rates of appearance (R(a)),
      disappearance (R(d)) and oxidation (R(ox)) were measured with a combination of [3
      (13)C]lactate, H(13)CO(3)(-), and [6,6-(2)H(2)]glucose tracers. During rest and
      exercise, lactate R(a) and R(d) were increased at 55 %-LC compared to 55 %.
      Glucose R(a) and R(d) were decreased during 55 %-LC compared to 55 %. Lactate
      R(ox) was increased by LC during exercise (55 %: 6.52 +/- 0.65 and 55 %-LC: 10.01
      +/- 0.68 mg kg(-1) min(-1)) which was concurrent with a decrease in glucose
      oxidation (55 %: 7.64 +/- 0.4 and 55 %-LC: 4.35 +/- 0.31 mg kg(-1) min(-1)). With
      LC, incorporation of (13)C from tracer lactate into blood glucose (L GNG)
      increased while both GP and calculated hepatic glycogenolysis (GLY) decreased.
      Therefore, increased blood [lactate] during moderate intensity exercise increased
      lactate oxidation, spared blood glucose and decreased glucose production.
      Further, exogenous lactate infusion did not affect rating of perceived exertion
      (RPE) during exercise. These results demonstrate that lactate is a useful
      carbohydrate in times of increased energy demand.

PMID- 12411540
TI  - Arm blood flow and metabolism during arm and combined arm and leg exercise in
      humans.
AB  - The cardiovascular response to exercise with several groups of skeletal muscle
      suggests that work with the arms may decrease leg blood flow. This study
      evaluated whether intense exercise with the legs would have a similar effect on
      arm blood flow (Y(arm)) and O(2) consumption (V(O(2))(,arm)). Ten healthy male
      subjects (age 21 +/- 1 year; mean +/- S.D.) performed arm cranking at 80 % of
      maximum arm work capacity (A trial) and combined arm cranking with cycling at 60
      % of maximum leg work capacity (A + L trial). The combined trial was a maximum
      effort for 5-6 min. Y(arm) measurement by thermodilution in the axilliary vein
      and arterial and venous blood samples permitted calculation of V(O(2))(,arm).
      During the combined trial, Y(arm) was reduced by 0.58 +/- 0.25 l min(-1) (19.1 +/
      3.0 %, P < 0.05) from the value during arm cranking (3.00 +/- 0.46 l min(-1)).
      The arterio-venous O(2) difference increased from 122 +/- 15 ml l(-1) during the
      arm trial to 150 +/- 21 ml l(-1) (P < 0.05) during the combined trial. Thus,
      V(O(2))(,arm) (0.45 +/- 0.06 l min(-1)) was reduced by 9.6 +/- 6.3 % (P < 0.05)
      and arm vascular conductance from 27 +/- 4 to 23 +/- 3 ml min(-1) (mmHg)(-1) (P <
      0.05) as noradrenaline spillover from the arm increased from 7.5 +/- 3.5 to 13.8
      +/- 4.2 nmol min(-1) (P < 0.05). The data suggest that during maximal whole body
      exercise in humans, arm vasoconstriction is established to an extent that affects
      oxygen delivery to and utilisation by working skeletal muscles.

PMID- 12411541
TI  - Interaction of pre-programmed control and natural stretch reflexes in human
      landing movements.
AB  - Pre-programmed mechanisms of motor control are known to influence the gain of
      artificially evoked stretch reflexes. However, their interaction with stretch
      reflexes evoked in the context of unimpeded natural movement is not understood.
      We used a landing movement, for which a stretch reflex is an integral part of the
      natural action, to test the hypothesis that unpredicted motor events increase
      stretch reflex gain. The unpredicted event occurred when a false floor, perceived
      to be solid, collapsed easily on impact, allowing the subjects to descend for a
      further 85 ms to a solid floor below. Spinal stretch reflexes were measured
      following solid floor contact. When subjects passed through the false floor en
      route to the solid floor, the amplitude of the EMG reflex activity was double
      that found in direct falls. This was not due to differences in joint rotations
      between these conditions. Descending pathways can modify H- and stretch-reflex
      gain in man. We therefore manipulated the time between the false and real floor
      contacts and hence the time available for transmission along these pathways. With
      30 ms between floors, the enhancement of the reflex was extinguished, whereas
      with 50 ms between floors it reappeared. This excluded several mechanisms from
      being responsible for the doubling of the reflex EMG amplitude. It is argued that
      the enhanced response is due to the modulation of reflex gain at the spinal level
      by signals in descending pathways triggered by the false platform. The results
      suggest the future hypothesis that this trigger could be the absence of afferent
      signals expected at the time of false floor impact and that salient error signals
      produced from a comparison of expected and actual sensory events may be used to
      reset reflex gains.

PMID- 12411542
TI  - Automated detection of local normalization areas for ictal-interictal subtraction
      brain SPECT.
AB  - Whole-brain activity is often chosen to quantitatively normalize peri-ictal and
      interictal SPECT scans before their subtraction. This use is not justified,
      because significant and extended modification of the cerebral blood flow can
      occur during a seizure. We validated and compared 2 automatic methods able to
      determine the optimal reference region, using simulation and clinical data.
      METHODS: In the first method, the selected reference region is the intersection
      of peri-ictal-interictal areas with no significantly different z values. The
      other method relies on a 3-dimensional iterative voxel aggregation. The increase
      of the selected volume is stopped by using 2 different variance tests (Levene and
      SE). These algorithms were tested on 39 epileptic patients and were validated
      using 1 interictal and 10 peri-ictal scans simulated from the mean image of 22
      healthy subjects. RESULTS: In the patient studies, the mean relative activity of
      the selected regions, compared with whole-brain activity (classic normalization),
      was 122.6%. Their average relative size (compared with the size of the whole
      brain) was 33.2% for the z map method, 22.8% for the SE test, and 11.8% for the
      Levene test. After application of our automatic processes, subtraction of the
      simulated images revealed a recovery of abnormal regions up to 45% larger than
      the region obtained with classic normalization. CONCLUSION: These results
      illustrate the role of normalization on the subtracted peri-ictal and interictal
      images. Our methods are automatic and objective and give good results on various
      simulated images. The z map construction is worth considering because it is
      simple, selects large parts of the brain, and requires little computation time.

PMID- 12411543
TI  - Toward clinical application of neuropsychological activation probes with SPECT: a
      spatial working memory task.
AB  - The concept of working memory is central to theories of human cognition, because
      it is essential to human skills such as decision making and deductive reasoning.
      Although PET and functional MRI have provided robust data on the recruitment of
      specific pathways in working memory tasks, the experimental settings of these
      studies may not be transferable to a clinical situation. Hence, to develop
      neuropsychological SPECT activation probes that are suitable for daily clinical
      practice, this study reports on a neuropsychological activation task of spatial
      working memory under classical neuropsychological test conditions in healthy
      subjects. METHODS: Reaction times and accuracy were measured as behavioral
      parameters and functional imaging data were analyzed with statistical parametric
      mapping to determine significant voxel-wise changes between the perception task
      and the memory task. RESULTS: Subjects reacted more slowly and performed less
      accurately during the memory task compared with the perception task, findings
      that are in keeping with other neuropsychological studies. Also, the overall
      pattern of brain activations revealed in our experiment is consistent with the
      data of the literature, thereby validating our test probe. CONCLUSION: From a
      practical viewpoint, the close resemblance of the test conditions of the SPECT
      procedure with those of the investigation room and the relative simplicity of the
      task under study probably constitute major advantages for future clinical
      application of the SPECT procedure in patients with cognitive impairments.

PMID- 12411544
TI  - Usefulness of whole-body (18)F-FDG PET in patients with suspected metastatic
      brain tumors.
AB  - The aim of this study was to evaluate the diagnostic value of whole-body (18)F
      FDG PET imaging in the differentiation of metastatic brain tumor from primary
      brain tumor and in the localization of the primary lesion in patients with
      metastatic brain tumor. METHODS: The subjects consisted of 127 patients (77 men,
      50 women; mean age +/- SD, 55 +/- 12 y) with brain masses that were suspected to
      be metastatic brain tumors on radiologic studies: 77 with confirmed metastatic
      brain tumor and 50 with primary brain tumor. Whole-body (18)F-FDG PET was
      performed on all patients. When the abnormal lesion was detected outside the
      brain, we interpreted the brain lesion as metastatic brain tumor. RESULTS: In 61
      of the 77 patients with metastatic brain tumor, primary lesions were detected
      using whole-body (18)F-FDG PET. Of the remaining 16 patients (all false-negative
      cases), 7 were classified as metastases of unknown origin. In 47 of the 50
      patients with primary brain tumor, whole-body (18)F-FDG PET did not show any
      other abnormal lesions. The sensitivity, specificity, positive and negative
      predictive values, and accuracy of PET for the detection of primary origin were
      79.2%, 94.0%, 95.3%, 74.6%, and 85.0%, respectively. The most common primary
      origin of metastatic brain tumors on PET examination was lung cancer (48/61,
      78.7%). The concordance rate between (18)F-FDG PET and conventional radiologic
      work-up was 80% in identifying primary lesion. Unknown bone or bone marrow
      metastases and unsuspected distant metastases were found in 14 patients (18%) and
      24 patients (31%), respectively, on PET examination. CONCLUSION: Screening the
      patients with suspected metastatic brain tumors using whole-body (18)F-FDG PET
      could be helpful in differentiating metastatic brain tumor from primary brain
      tumor and in detecting the primary lesion.

PMID- 12411545
TI  - Evaluation of pediatric CNS malignancies with (99m)Tc-methoxyisobutylisonitrile
      SPECT.
AB  - SPECT has the potential to add valuable information to the diagnosis and
      management of central nervous system (CNS) malignancy. Radioactive tracers
      including (99m)Tc-methoxyisobutylisonitrile (MIBI), or sestamibi, have been shown
      to be sensitive markers for brain tumors; however, their role in imaging children
      is poorly defined. METHODS: We undertook a pilot study of 29 pairs of (99m)Tc
      MIBI and MRI images from 20 children to explore the clinical usefulness of this
      tracer in CNS malignancy. RESULTS: Tumor types that took up (99m)Tc-MIBI included
      brain stem glioma, fibrillary astrocytoma, other low-grade astrocytomas, and
      glioblastoma multiforme. Most tumors positive for (99m)Tc-MIBI uptake were
      astrocytomas, including those in the brain stem, cerebellum, and cortex. This
      method of nuclear imaging not only was able to identify the presence of a tumor
      but also could identify changes in the same tumor over time. Some correlation
      between histologic grade and (99m)Tc-MIBI uptake was observed. Several tumors,
      including craniopharyngioma, medulloblastoma, and optic glioma, were evident on
      MRI but not on (99m)Tc-MIBI SPECT. CONCLUSION: The results suggest that this
      modality is a potentially useful tool in the diagnosis and management of CNS
      malignancies, particularly higher-grade astrocytomas, in children.

PMID- 12411546
TI  - PET imaging drug distribution after intratumoral injection: the case for (124)I
      iododeoxyuridine in malignant gliomas.
AB  - Locoregional administration may yield higher tumor drug concentrations compared
      with intravenous injection and may reduce the risk of systemic adverse effect.
      Furthermore, in the case of brain tumors, it may circumvent limited drug delivery
      imposed by the blood-brain barrier. We used PET to study the retention and
      spatial distribution of iododeoxyuridine (IUdR), which has been used as a DNA
      targeting radiosensitizing drug and which can be charged with therapeutic
      nuclides. METHODS: Locoregional (resection cavity, tumor) instillation of 5-19
      MBq (124)I-IUdR was achieved in 7 postoperative patients with malignant gliomas
      through a reservoir implanted in the skull. Patients were scanned with PET during
      the first hour and at 2, 24, and 48 h after (124)I-IUdR instillation. (124)I-IUdR
      metabolism was measured in the reservoir fluid in the presence or absence of a
      degradation inhibitor (5'-butyryl-IUdR [butyryl-IUdR]). Region-of-interest
      analysis was applied to calculate intratumoral retention (K(local)) of (124)I
      IUdR from the PET images after a 24-h washout phase using an autoradiographic
      method. RESULTS: At 24 h, radioactivity concentration in the reservoir was
      approximately 1% of the concentration 5 min after tracer instillation. The major
      metabolite of (124)I-IUdR in the reservoir was (124)I-iodouracil. (124)I-IUdR
      degradation could be partially inhibited by butyryl-IUdR. In the plasma,
      radioactivity peaked between 2 and 6 h. The area of tissue radioactivity
      increased with time up to 3-fold compared with the initial distribution. Tumor
      (124)I-IUdR retention (K(local)) ranged from 0.006 to 0.017 micro L/g/min, which
      is substantially lower compared with the IUdR-DNA incorporation reported recently
      after intravenous injection of (124)I-IUdR (K(i), 3.9 +/- 2.3 micro L/g/min,
      where K(i) is the DNA incorporation rate of (124)I-IUdR after intravenous tracer
      injection). CONCLUSION: Although a single injection of (124)I-IUdR resulted in
      radioactivity distribution over the tumor, retention at 24 h was substantially
      lower compared with intravenous injection of (124)I-IUdR. Slow diffusion after
      locoregional administration, in contrast to fast delivery via tumor capillaries
      after intravenous injection, may account for our findings, resulting in a low
      amount of drug incorporation into DNA before degradation and washout from tissue.

PMID- 12411547
TI  - Prediction of myocutaneous adverse side effect due to intra-arterial chemotherapy
      by intra-arterial (99m)Tc-macroaggregated albumin administration in patients with
      bone and soft-tissue tumors.
AB  - In malignant bone and soft-tissue tumors, intra-arterial chemotherapy and limb
      saving surgery have become popular. Myocutaneous inflammatory change and necrosis
      are the major local side effects of intra-arterial chemotherapy. (99m)Tc
      macroaggregated albumin (MAA) imaging with intra-arterial tracer administration
      was performed to evaluate drug distribution, and the ability of (99m)Tc-MAA
      imaging to predict local side effects was assessed. METHODS: In 24 patients, 42
      (99m)Tc-MAA images were obtained with tracer injection through an intra-arterial
      catheter that was inserted into the proximal portion of the tumor-feeding artery.
      Abnormal uptake other than by tumor was assessed visually and quantitatively.
      RESULTS: In visual analysis, abnormal (99m)Tc-MAA accumulation was observed in 21
      of 42 images. In the first consecutive 13 of these 21 images, intra-arterial
      chemotherapy with cisplatin, doxorubicin, and caffeine was administered, and
      myocutaneous inflammation or necrosis in the area corresponding to the abnormal
      (99m)Tc-MAA uptake was observed in 11. In contrast, none of the 21 images without
      abnormal (99m)Tc-MAA uptake demonstrated any local adverse effect from intra
      arterial chemotherapy. In the last consecutive 8 images with abnormal (99m)Tc-MAA
      uptake, intra-arterial chemotherapy was initiated with only cisplatin, and
      doxorubicin and caffeine administration was changed to the intravenous route. In
      all 8 of these images, no local adverse effects from chemotherapy were observed.
      Overall, the sensitivity, specificity, and accuracy of (99m)Tc-MAA imaging for
      the detection of myocutaneous damage were 100% (11/11), 91% (21/23), and 94%
      (32/34), respectively, and positive and negative predictive values were 85%
      (11/13) and 100% (21/21), respectively. In quantitative analysis, when the
      diagnostic threshold of the uptake ratio was set at 2.5, sensitivity,
      specificity, and accuracy for the detection of myocutaneous complications were
      91% (10/11), 96% (22/23), and 94% (32/34), respectively, and positive and
      negative predictive values were 91% (10/11) and 96% (22/23), respectively.
      CONCLUSION: (99m)Tc-MAA imaging with intra-arterial infusion before intra
      arterial chemotherapy for bone and soft-tissue tumors can facilitate prediction
      of local myocutaneous adverse effects due to chemotherapy.

PMID- 12411548
TI  - Whole-body (18)F-FDG PET identifies high-risk myeloma.
AB  - The purpose of this study was to evaluate the clinical utility of whole-body PET
      with (18)F-FDG in patients with multiple myeloma and related monoclonal diseases.
      METHODS: Between July 1, 1996, and July 2000, 98 (18)F-FDG PET scans were
      obtained for 66 patients, with 25 patients having 2 or more scans. The results
      were compared with routine clinical and staging information, including CT and MRI
      scans, as indicated. Of the 66 patients, 16 had previously untreated active
      myeloma, 14 had monoclonal gammopathy of undetermined significance (MGUS), 10 had
      disease in remission, and 26 had relapsing disease. RESULTS: Negative whole-body
      (18)F-FDG PET findings reliably predicted stable MGUS. Of the 14 MGUS patients
      with follow-up of 3-43+ mo, myeloma has developed in only 1 (7%), at 8 mo.
      Conversely, the 16 previously untreated patients with active myeloma all had
      focal or diffusely positive scan findings. Four (25%) of 16 previously untreated
      patients with positive (18)F-FDG PET findings had negative full radiologic
      surveys. Another 4 (25%) of 16 patients had focal extramedullary disease. This
      was confirmed by biopsy or other imaging techniques. Extramedullary uptake also
      occurred in 6 (23%) of 26 patients with relapse. This extramedullary uptake was a
      very poor prognostic factor both before treatment and at relapse. For example,
      median survival was 7 mo for patients with disease relapse. Persistent positive
      (18)F-FDG PET findings after induction therapy predicted early relapse. In 13
      (81%) of 16 patients with relapsing disease, new sites of disease were
      identified. The (18)F-FDG PET results were especially helpful in identifying
      focal recurrent disease in patients with nonsecretory or hyposecretory disease
      amenable to local irradiation therapy, which was used in 6 patients. CONCLUSION:
      Whole-body (18)F-FDG PET provides important prognostic information, which is
      clinically useful and complementary to conventional methods of evaluating plasma
      cell disorders. (18)F-FDG PET is a unique tool for evaluation of nonsecretory
      myeloma. Residual or recurrent disease after therapy, especially extramedullary
      disease, is a poor prognostic factor.

PMID- 12411549
TI  - Dual-isotope SPECT using (99m)Tc-hydroxymethylene diphosphonate and (201)Tl
      chloride to assess mandibular invasion by intraoral squamous cell carcinoma.
AB  - We examined mandibular invasion of intraoral squamous cell carcinoma by
      simultaneous bone and tumor dual-isotope SPECT using (99m)Tc-hydroxymethylene
      diphosphonate ((99m)Tc-HMDP) and (201)Tl-chloride ((201)Tl) and by CT. METHODS:
      Early and delayed simultaneous bone and tumor dual-isotope SPECT and CT were
      performed on 39 patients suspected of having tumor invasion of the mandible by
      intraoral squamous cell carcinoma. SPECT images were superimposed to project
      tumor location from tumor SPECT onto the osseous structures shown by bone SPECT.
      The CT imaging protocol consisted of 5-mm contiguous axial images. RESULTS:
      Histopathologic examination revealed invasion of the mandible in 13 patients and
      no tumor invasion in 26 patients. The results of delayed dual-isotope SPECT were
      exactly the same as those of early dual-isotope SPECT. On early and delayed dual
      isotope SPECT, the sensitivity, specificity, and accuracy in detecting mandibular
      invasion by intraoral squamous cell carcinoma were 100% (13/13), 88.5% (23/26),
      and 92.3% (36/39), respectively. The corresponding values using CT were 45.5%
      (5/11), 94.7% (18/19), and 76.7% (23/30), respectively, when 9 patients were
      excluded because of dental artifacts. CONCLUSION: Our results suggest that
      superimposed early bone and tumor dual-isotope SPECT images alone may be
      sufficient in the diagnostic evaluation of mandibular invasion by intraoral
      squamous cell carcinoma.

PMID- 12411550
TI  - Accuracy of image coregistration of pulmonary lesions in patients with non-small
      cell lung cancer using an integrated PET/CT system.
AB  - The purpose of this study was to evaluate the accuracy of image coregistration of
      PET and CT (PET/CT) images in patients with lung lesions and the influence of the
      breathing protocol during CT. METHODS: Seventy-five patients with a solitary and
      well-circumscribed pulmonary lesion (non-small cell lung cancer; size, 10-30 mm)
      underwent PET/CT on a combined scanner. CT was acquired during shallow breathing
      in 37 patients and during normal expiration (i.e., the level reached when the
      patient exhaled without forcing expiration and then held the breath) in 38
      patients. The volume of interest of each lesion was defined separately on PET and
      CT images, and the geometric center of gravity (COG) was assessed. The distance
      of COGs between the PET image and the CT image was measured. All lesions were
      classified according to 4 lung regions: apical, peripheral, central, and lung
      base. The mismatch between COG(PET) and COG(CT) was compared between regions and
      patient groups using a 2-way ANOVA with the Bonferroni-Dunn test for post hoc
      comparisons. RESULTS: The range of COG distance between PET and CT was 1.7-5.4 mm
      in the apex, 0.5-14.7 mm in the periphery, 0.7-5.9 mm centrally, and 2.9-11.3 mm
      in the lung base. The match between PET and CT was significantly better in
      patients who had the CT scan obtained during normal expiration than in patients
      who performed shallow breathing during CT scanning (P = 0.024). No reciprocal
      effects were found (interaction P = 0.76). The mismatch of lesions depends
      significantly on lung region (P < 0.0001). Post hoc analysis showed a significant
      difference between the upper 2 regions and the lower 2 regions (all P < or =
      0.002) but not between the apex and the central region (P = 0.95) and between the
      peripheral region and the lung base (P = 0.15). The lesion size had no influence
      on the COG mismatch. CONCLUSION: The match of lung lesions in coregistered PET/CT
      images is better when acquiring the CT scan during normal expiration. The
      coregistration accuracy is better in the upper and central parts of the lung. The
      normal expiration protocol is suggested to be superior to shallow breathing
      during CT scanning.

PMID- 12411551
TI  - Myocardial sympathetic denervation, fatty acid metabolism, and left ventricular
      wall motion in vasospastic angina.
AB  - Although various noninvasive methods have been used to detect vasospasm, none of
      them are sensitive enough for patients with sporadic attacks. Because abnormal
      fatty acid metabolism and cardiac adrenergic neuronal damage are observed in
      ischemic myocardium, (123)I-15-(p-iodophenyl)-3-R,S-methyl pentadecanoic acid
      (BMIPP) and (123)I-metaiodobenzylguanidine (MIBG) have recently been proposed as
      useful tracers for detection of myocardial damage. This study investigated the
      relationships among the coronary vasospastic regions, abnormal left ventricular
      regional wall motion, fatty acid metabolism, and sympathetic nerve functions and
      their changes during treatment in patients with vasospastic angina. METHODS: We
      evaluated 50 patients with vasospastic angina (25 with clinically documented
      vasospasm [group A] and 25 with vasospasm induced by ergonovine provocation
      [group B]) and 25 control subjects who had chest pain but had normal coronary
      arteries without ergonovine provocation of spasm. Sixteen patients in group A
      were reevaluated 6 mo after medical treatment. The territorial regions of the
      vasospasm-induced coronary artery, wall motion determined by left
      ventriculography, and BMIPP and MIBG uptake were compared. RESULTS: Regions
      exhibiting a positive reaction to the ergonovine provocation were observed in the
      right coronary artery in 41 patients, the left anterior descending artery in 33,
      and the left circumflex artery in 21. Provocation occurred in multiple vessels in
      29 patients (58%). Reduction of wall motion was observed in 19 patients (38%).
      Sensitivity and specificity for the identification of vasospastic angina were 86%
      (43/50 patients) and 88% (22/25 control subjects), respectively, for BMIPP
      scintigraphy and 100% (50/50 patients) and 56% (14/25 control subjects),
      respectively, for MIBG scintigraphy. In the region exhibiting a reduction in left
      ventricular wall motion, BMIPP or MIBG uptake was decreased. The sensitivity and
      specificity of determination of vasospasm-induced coronary arteries were 71%
      (67/95 arteries) and 95% (71/75 arteries), respectively, for BMIPP scintigraphy
      and 96% (91/95 arteries) and 55% (41/75 arteries), respectively, for MIBG
      scintigraphy. After 6 mo, during treatment, vasospasm was reinduced by ergonovine
      provocation in 6 patients (group I) and was not reinduced in 10 patients (group
      II). Improvements of decreased BMIPP and MIBG uptake were lower in group I (25%
      +/- 4% and 16% +/- 4%, respectively) than in group II (69% +/- 4% and 50% +/- 3%,
      respectively; both P < 0.01). The regions in which vasospasm was reinduced
      exhibited decreased BMIPP and MIBG uptake. CONCLUSION: Abnormal fatty acid
      metabolism and cardiac sympathetic denervation were observed more frequently than
      were wall motion abnormalities in the vasospastic region in patients with
      vasospastic angina. BMIPP and MIBG scintigraphy are highly accurate and
      noninvasive techniques for determining the presence and location of vasospasm.

PMID- 12411552
TI  - A retrospective review of the effectiveness of recombinant human TSH as a
      preparation for radioiodine thyroid remnant ablation.
AB  - Radioiodine remnant ablation (RRA) is frequently used after a thyroidectomy for
      differentiated thyroid carcinoma because it has been reported to reduce the
      number of local recurrences and to increase overall survival. Although the
      traditional method of preparation for RRA is thyroid hormone withdrawal, several
      physicians at our medical center have offered the option of having RRA after
      preparation by recombinant human thyroid-stimulating hormone (thyrotropin; TSH)
      over the past 2 y. During this same time period, other patients at our center
      were prepared for RRA by hormone withdrawal. METHODS: We took this opportunity to
      retrospectively review the rate of complete remnant ablation in patients having
      RRA after hormone withdrawal compared with those having RRA after recombinant
      human TSH. Only patients who had RRA after January 1, 1999, and follow-up
      diagnostic studies at our medical center, were included in the analysis. A
      successful ablation was defined as no visible radioiodine uptake on the follow-up
      diagnostic scans, performed with 185 MBq (5 mCi) (131)I. The 2 groups had
      comparable patient and tumor characteristics and received similar ablative
      activities of (131)I. RESULTS: We found that 84% of those prepared by recombinant
      human TSH, and 81% of those prepared by hormone withdrawal, had complete
      resolution of visible thyroid bed uptake after RRA (P = not significant).
      CONCLUSION: Given the biases that exist in retrospective studies, we cannot yet
      recommend RRA preparation by recombinant human TSH for routine use. However,
      these preliminary findings are favorable enough to support the design of a
      prospective randomized trial comparing RRA success rates after preparation by
      either thyroid hormone withdrawal or recombinant human TSH.

PMID- 12411553
TI  - Radiation synovectomy with (166)Ho-ferric hydroxide: a first experience.
AB  - Radiation synovectomy (RS) is indicated when conventional pharmacologic treatment
      of chronic synovitis has not relieved its symptoms. The use of radionuclides that
      are bound to ferric hydroxide (FH) particles has been shown to be effective and
      safe for this procedure. (166)Ho-FH macroaggregates offer promising properties
      for RS but there is a lack of clinical data. We investigated the efficacy and
      safety of (166)Ho-FH in a prospective clinical trial in patients suffering from
      chronic synovitis. METHODS: Twenty-four intraarticular injections were performed
      in 22 patients receiving a mean activity of 1.11 GBq (range, 0.77-1.24 GBq)
      (166)Ho-FH. Blood activity measurements and monitoring of activity distribution
      were performed by whole-body gamma-camera imaging for control of leakage 3 and 24
      h after injection of (166)Ho-FH. The patients were evaluated clinically before
      RS, 1 wk and 1 mo after the treatment, and thereafter in 3-mo intervals by
      assessing joint effusion, pannus, local pain, range of motion, and the patient's
      satisfaction. RESULTS: In 18 of 24 treatments, no leakage to nontarget organs was
      visible, whereas small amounts of activity could be detected in the local
      inguinal lymph nodes in 6 patients and to the lungs and to the liver in 1 patient
      (<0.1%). In all cases leakage to the lymph nodes was <1%. Leakage to the blood
      was negligible. Clinically, 17 patients (71%) exhibited a complete or partial
      response. CONCLUSION: RS with (166)Ho-FH was safe and effective in patients with
      chronic synovitis of different origin. Controlled clinical trials are necessary
      to evaluate the therapeutic efficacy and safety compared with the treatment with
      other radionuclides and glucocorticosteroids.

PMID- 12411554
TI  - Comparison of various requirements of the quality assurance procedures for (18)F
      FDG injection.
AB  - The quality assurance (QA) requirements (i.e., test procedure, acceptance
      criteria, and testing schedule) for fludeoxyglucose (18)F ((18)F-FDG) injection
      listed in the U.S. Pharmacopeia (USP); the draft Chemistry, Manufacturing, and
      Controls (CMC) issued by the U.S. Food and Drug Administration (FDA); and the
      European Pharmacopeia (EP) were compared. The FDA Modernization Act of 1997
      requires that the QA of compounded PET drug products be in compliance with the
      PET compounding standards and official monographs included in the USP. However,
      the "sunset" clause of the PET section within the FDA Modernization Act of 1997
      stipulates that all PET drug products, in due course, must meet the requirements
      for drug approval procedures and current good manufacturing practice, and the FDA
      has issued a draft CMC that includes QA specifications for (18)F-FDG injection.
      The purpose of this article is to discuss the pros and cons of each of the QA
      tests stated in the USP, CMC, and EP and to propose a practical testing method
      for each required test, thereby helping end users to ensure the quality of the
      (18)F-FDG injection product. It is hoped that this article will stimulate further
      cooperation among various countries worldwide in the development of a set of
      harmonized and sensible QA standards for all PET drug products.

PMID- 12411555
TI  - Radioimmunotherapy of B-cell non-Hodgkin's lymphoma: from clinical trials to
      clinical practice.
AB  - Radioimmunotherapy (RIT) is a new treatment modality for B-cell non-Hodgkin's
      lymphoma (NHL). Recent clinical trials have clearly established its efficacy in
      NHL patients refractory to standard chemotherapy or immunotherapy with the widely
      used unconjugated rituximab monoclonal antibody (mAb). The Food and Drug
      Administration has approved (90)Y-ibritumomab tiuxetan anti-B-cell NHL mAb as the
      first commercially available radiolabeled antibody for cancer therapy. This comes
      only a few years after the introduction of rituximab into clinical practice as
      the first unconjugated antibody for cancer treatment, underscoring the success of
      both immunotherapy and RIT in the treatment of NHL. With the approval of (90)Y
      ibritumomab tiuxetan, and based on the results of numerous clinical trials with
      radiolabeled anti-B-cell NHL mAbs, RIT promises to become integral to nuclear
      medicine practice. In this article, the basic concepts of RIT are reviewed with
      important milestones in its development for B-cell NHL treatment and particular
      emphasis on phase II and III clinical trials establishing its efficacy in clearly
      defined patient populations. Finally, the prospects for the expected widespread
      clinical use of RIT in the management of B-cell NHL, alone or in combination with
      other more established therapies, are discussed. This article provides both
      investigative and clinical nuclear medicine physicians with a better
      understanding of RIT capabilities and limitations in B-cell NHL and their role as
      consultants in the care of NHL patients.

PMID- 12411556
TI  - Comparison of 1-(11)C-glucose and (18)F-FDG for quantifying myocardial glucose
      use with PET.
AB  - In this study, we compared the accuracy of the rate of myocardial glucose use
      (rMGU) measured using PET and 1-(11)C-glucose with the rate measured using PET
      and the more conventional tracer (18)F-FDG. METHODS: PET measurements of
      myocardial tracer uptake (K, in mL/g/min) and rMGU (in nmol/g/min) were obtained
      with 1-(11)C-glucose and (18)F-FDG in 21 dogs using kinetic modeling and the
      Patlak graphical method, respectively. Eighteen dogs were studied during
      hyperinsulinemic-euglycemic clamp performed either at rest or combined with
      phenylephrine, dobutamine, intralipid infusion, or intralipid infusion and
      dobutamine. Three dogs were studied during intralipid infusion alone under
      resting conditions. Arterial-coronary sinus sampling was performed to measure the
      K of both tracers (n = 14) and rMGU by the Fick method (n = 21). RESULTS: PET
      derived values for K from either 1-(11)C-glucose or (18)F-FDG correlated closely
      with directly measured tracer K values (glucose: y = 0.98x + 0.01, r = 0.79, P <
      0.001; (18)F-FDG: y = 0.74x + 0.03, r = 0.77, P < 0.001). In contrast,
      correlation with K values of unlabeled glucose measured directly was better for 1
      (11)C-glucose (y = 0.92x + 0.02, r = 0.96, P < 0.0001) than for (18)F-FDG (y =
      0.66x + 0.05, r = 0.72, P < 0.01) (P < 0.001 for comparison of correlation
      coefficients). As a consequence, PET-derived values for rMGU correlated more
      closely with Fick-derived measurements of unlabeled glucose using 1-(11)C-glucose
      (y = 0.82x + 168, r = 0.97, P < 0.0001) than with (18)F-FDG (y = 0.81x + 278, r =
      0.79, P < 0.001) (P < 0.001 for comparison of correlation coefficients).
      CONCLUSION: Over a wide range of conditions, PET-derived measurements of rMGU are
      obtained more accurately with 1-(11)C-glucose than with (18)F-FDG.

PMID- 12411557
TI  - 18F-FDG in cardiology and oncology: the bitter with the sweet.

PMID- 12411558
TI  - Comparative evaluation of lesion detectability for 6 PET imaging platforms using
      a highly reproducible whole-body phantom with (22)Na lesions and localization ROC
      analysis.
AB  - The lesion detectability performance of 6 PET imaging platforms has been compared
      using a highly reproducible whole-body phantom and localization receiver
      operating characteristic (LROC) analysis. METHODS: A realistic whole-body phantom
      consisting of brain, thorax with lungs and liver, and pelvis with bladder was
      assembled and outfitted with 27 semipermanent (22)Na lesions of various sizes and
      activity concentrations. The background compartments were reproducibly filled
      with (18)F solutions. The phantom was imaged under the condition of equal
      emission scan time on 7 PET platforms: Advance, HR+, HR961, C-PET, IRIX, MCD, and
      AXIS. Imaging data were processed using manufacturer-supplied software and
      defaults, and LROC evaluation was performed using 11 human observers. RESULTS:
      Near-nominal counting rates were obtained for the NaI systems, and the bismuth
      germanate (BGO) systems were operated well below nominal counting rates. The BGO
      systems provided the highest lesion detection performance, followed by the large
      area dedicated NaI system, and hybrid PET gamma cameras. Lesion detectability was
      highly dependent on lesion size, with all systems exhibiting similar performance
      for 16-mm lesions but differentiated performance for lesions < or =12 mm.
      CONCLUSION: Reconstruction methodology can have a significant effect on lesion
      detectability. PET lesion detectability performance is correlated with system
      cost and imaging characteristics. For a particular imaging task, care should be
      taken to ensure that the scanner being used is appropriate and that the scan time
      is adjusted accordingly to ensure good lesion detectability.

PMID- 12411559
TI  - Interpreting results from a comparative study of lesion detectability for 6
      different PET systems.

PMID- 12411560
TI  - Delineation of hypoxia in canine myocardium using PET and copper(II)-diacetyl
      bis(N(4)-methylthiosemicarbazone).
AB  - Copper(II)-diacetyl-bis(N(4)-methylthiosemicarbazone) (copper-ATSM) is a hypoxia
      avid tracer for the selective identification of hypoxic tissue. Using canine
      models of hypoxic myocardium, we report our findings on *Cu-ATSM PET (*Cu is
      defined as either (60)Cu, (61)Cu, or (64)Cu) for the delineation of ischemic and
      hypoxic myocardium. METHODS: In protocol I, myocardial hypoxia was induced by
      global hypoxia (n = 3). In protocol II, myocardial ischemia was generated by
      occlusion of the left anterior descending coronary artery (n = 9). In protocol
      III, coronary artery stenosis was induced by a stenosis in the left anterior
      descending coronary artery (n = 4). PET dynamic data were acquired immediately
      after tracer injection. Tracer retention kinetics were analyzed using either
      monoexponential analysis (1/k(mono)) or a simple 2-compartment model (1/k(4)).
      RESULTS: In protocol I, tracer retention in hypoxic myocardium was 2-fold greater
      than in normal myocardium, despite a 7-fold increase in blood flow (normal, 0.70
      +/- 0.42 mL.min(-1).g(-1); hypoxic, 4.94 +/- 3.00 mL.min(-1).g(-1) [P < 0.005]).
      In protocol II, approximately 3 h after occlusion, retention of *Cu-ATSM within
      20 min was greater in ischemic regions (myocardial blood flow, 0.28 +/- 0.26
      mL.min(-1).g(-1)) than in normal tissue (myocardial blood flow, 0.52 +/- 0.19
      mL.min(-1).g(-1)) (1/k(mono), 40.72 +/- 39.0 min vs. 26.69 +/- 22.29 min [P <
      0.05]; 1/k(4), 6.85 +/- 4.90 min vs. 3.51 +/- 1.97 min [P < 0.05]). In selected
      dogs, tracer retention decreased at 24 h, suggesting the development of necrosis
      with no subsequent retention of *Cu-ATSM. In protocol III, dobutamine infusion
      after stenosis placement resulted in increased tracer retention consistent with
      hypoxia in the damaged regions. CONCLUSION: *Cu-ATSM PET has shown quantitative
      selective uptake in hypoxic myocardium within 20 min of tracer administration in
      3 canine models of hypoxia.

PMID- 12411561
TI  - In vivo comparative imaging of dopamine D2 knockout and wild-type mice with (11)C
      raclopride and microPET.
AB  - The use of mice with targeted gene deletions (knockouts [KOs]) provides an
      important tool to investigate the mechanisms underlying behavior, neuronal
      development, and the sequella of neuropsychiatric diseases. MRI has been used to
      image brain structural changes in KO mice but, to our knowledge, the feasibility
      of using PET to investigate brain neurochemistry in KO mice has not been
      demonstrated. METHODS: We have evaluated the sensitivity of the microPET to image
      dopamine D2 receptor (DRD2) KO mice (D2-/-). PET measurements were performed in
      wild-type (D2+/+) mice and KO (D2-/-) mice using a microPET scanner. Briefly,
      each animal was anesthetized and injected intravenously with (11)C-raclopride, a
      DRD2-specific ligand, and dynamic PET scanning was performed for 60 min. RESULTS:
      The (11)C-raclopride images of the KO mice showed significantly lower binding in
      the striatum (ST) than those of the wild-type (WT) mice, which was confirmed by
      the time-activity curves that revealed equivalent binding in the ST and
      cerebellum (CB) in KO mice, whereas the WT mice had significantly higher binding
      in the ST than in the CB. The ST/CB ratio was significantly higher in WT mice
      than in KO mice (ST/CB = 1.33 +/- 0.13 and 1.05 +/- 0.03, respectively; P <
      0.002; n = 10). The microPET images were compared qualitatively with conventional
      autoradiography images. CONCLUSION: These data support the use of microPET as an
      effective in vivo imaging tool for studying noninvasively KO mice. These same
      tools can be extended to investigate other genetically engineered murine models
      of disease. Future studies will seek to use microPET to investigate the
      relationships between genes, neuronal activity, and behavior.

PMID- 12411562
TI  - An observer study evaluating dual-plane circular-orbit cone-beam brain SPECT.
AB  - Dual-plane circular-orbit cone-beam (DPCB) SPECT uses a pair of dissimilar cone
      beam collimators to expand the axial field of view for brain SPECT. We applied
      observer study methodology to evaluate the improvement in detection of small
      defects in brain perfusion provided by DPCB SPECT, compared with conventional
      parallel-beam imaging. We also evaluated the effect of changing the radius of
      rotation on DPCB imaging. METHODS: Images were realistically simulated using a
      brain phantom. High-count Monte Carlo simulations were performed for 4 imaging
      configurations: low-energy high-resolution parallel-beam imaging at a radius of
      rotation of 18 cm and DPCB imaging (52-cm focal length) at radii of rotation of
      20, 24, and 28 cm. These distances corresponded to those required for our camera
      to clear the shoulders of a patient in the 5th, 50th, and 95th percentiles of
      shoulder width. Perfusion defects of approximately 1.8-cm diameter were simulated
      at 4 locations in the brain. Poisson noise was simulated, and images were
      reconstructed to create a set of 200 images for each of the 4 configurations. All
      reconstructions used ordered-subset expectation maximization with attenuation
      modeling. Eight observers viewed images on which the possible location of the
      defect was marked. The observers were trained using 384 images, were tested using
      416 images, and rated on a continuous scale their confidence about the presence
      of a defect. RESULTS: Using a paired t test for the estimated areas under the
      receiver operating characteristic (ROC) curve for each observer, we found that
      all 3 DPCB configurations resulted in higher areas under the ROC curve than did
      the parallel-beam configuration. Further, area under the ROC curve for the DPCB
      configurations improved with decreasing radius of rotation. All comparisons were
      significant at P < 0.05, except for DPCB 20 cm to DPCB 24 cm (P = 0.089).
      CONCLUSION: Use of a dual-plane cone beam is feasible for brain SPECT and better
      detects small perfusion defects than does a parallel beam, despite the
      possibility that the radius of rotation will need to be increased significantly
      to clear the patient's shoulders. A dual-plane cone beam should be used with the
      shortest radius of rotation possible to maximize the detectability of small
      perfusion defects.

PMID- 12411563
TI  - Challenging epidemiological strategy for paradoxical evidence on the risk of
      gastric cancer from Helicobacter pylori infection.

PMID- 12411564
TI  - Risk factors for stomach cancer in Brazil (I): a case-control study among non
      Japanese Brazilians in Sao Paulo.
AB  - BACKGROUND: Stomach cancer is an important health problem in Brazil, with an
      estimated 20 000 new cases per year and it was the most frequent cancer site in
      men and the third most frequent site in women in Sao Paulo in 1993. Nevertheless,
      there are no reports of analytical epidemiological study on stomach cancer in
      Brazil. METHODS: A hospital-based case-control study was conducted among
      Brazilian residents with a non-Japanese background in the city; 236 consecutive
      cases of histologically confirmed stomach cancer were matched to the same number
      of controls admitted for non-neoplastic diseases by age (+/-5 years) and gender.
      The socio-demographic characteristics, personal and family medical history,
      lifetime history of tobacco use and dietary habits were determined by interview
      using a structured questionnaire. RESULTS: Non-white race, lower educational
      background and lower family income were more frequent in stomach cancer patients.
      After adjustment for race and educational background, cigarette smoking, frequent
      use of oil and frequent consumption of egg were significantly associated with
      increased risk of stomach cancer, while frequent consumption of fruit and
      vegetables decreased the risk. These associations did not change substantially
      after mutual adjustment of the other variables. CONCLUSIONS: The present study
      confirmed that low socio-economic status, cigarette smoking and low consumption
      of fruit and vegetables were risk factors of stomach cancer in Sao Paulo, Brazil.

PMID- 12411565
TI  - Risk factors for stomach cancer in Brazil (II): a case-control study among
      Japanese Brazilians in Sao Paulo.
AB  - BACKGROUND: Although stomach cancer is the most frequent cancer among Japanese
      Brazilians, the risk factor of this cancer has not been investigated among them.
      METHODS: A case-control study was conducted among Japanese residents in the city
      of Sao Paulo. Ninety-six consecutive cases of histologically confirmed stomach
      cancer were matched to 192 controls admitted for non-neoplastic diseases or
      healthy volunteer (n = 80) by age (+/-5 years) and gender. The socio-demographic
      characteristics, personal and family medical history, lifetime history of tobacco
      use and dietary habits were probed using a structured questionnaire. RESULTS:
      Frequent consumption of beef was associated with increased risk: odds ratio (OR)
      = 4.0 and 95% confidence interval (CI) = 1.9-8.4 for daily consumption, OR = 2.1
      and 95% CI = 1.0-4.3 for 3-4 days/week) when compared with the category of lower
      consumption (<3 days/week) after adjustment for country of birth (Japan or
      Brazil), showing a dose-response pattern (P for trend = 0.001). These ORs became
      higher after further adjusted for fruit consumption: OR = 4.4, 95% CI = 2.1-9.4
      and OR = 2.4 and 95% CI = 1.1-5.0, respectively. Daily consumption of fruit was
      associated with a reduction in risk (OR = 0.5, 95% CI = 0.3-1.0) after adjustment
      for country of birth and became statistically significant further adjusted for
      beef consumption (OR = 0.4, 95% CI = 0.2-0.9). There were no statistically
      significant associations with smoking or any other factors tested. Although some
      attenuation was observed in beef consumption, the observed associations were
      similar after excluding volunteer controls. CONCLUSIONS: The introduction of the
      habit of daily beef consumption among Japanese immigrants and their descendants
      may be associated with stomach cancer risk. The protective effect of fruit
      consumption was confirmed in this population.

PMID- 12411566
TI  - Clinical outcome of surgical resection for renal cell carcinoma.
AB  - PURPOSE: To evaluate prognostic factors for patients with renal cell carcinoma
      (RCC) who had undergone surgical resection. PATIENTS AND METHODS: We analyzed
      data from 371 patients with RCC who had undergone surgical resection. Prognostic
      factors were identified from clinical and pathological data using univariate and
      multivariate analysis. RESULTS: When we analyzed all patients including lymph
      node metastasis, multivariate analysis showed that only pN factor was an
      independent prognostic factor. We then analyzed 359 patients without lymph node
      metastasis, and the presence of symptoms, pT, grade, IFN and venous involvement
      were considered significant. However, pT (pT1 vs pT2-4), tumor grade and presence
      of symptom were judged to be independent prognostic factors by multivariate
      analysis. When the patients were stratified according to the tumor size (2.5, 4,
      7 cm), a significant difference in disease specific survival was found by 4 and 7
      cm, but not by 2.5 cm. CONCLUSIONS: The current TNM staging accurately predicts
      patient survival. Tumor grade is also an important prognostic factor for patients
      with RCC.

PMID- 12411567
TI  - Is daidzein non-metabolizer a high risk for prostate cancer? A case-controlled
      study of serum soybean isoflavone concentration.
AB  - BACKGROUND: It has been postulated that soybean isoflavones act as inhibitory
      factors in prostate cancer. However, to date there have been no case-controlled
      clinical studies carried out to compare the circulating concentrations of
      isoflavones in prostate cancer patients and control subjects. METHODS: The serum
      levels of genistein, daidzein and equol were determined and compared in 253
      experimental subjects (141 prostate cancer patients and 112 cancer-free
      controls). RESULTS: The serum concentrations of isoflavones were compared in
      hospitalized and non-hospitalized subjects and for both the prostate cancer
      patients and the controls the concentrations were lower in the hospitalized
      subjects. The serum concentrations of genistein and daidzein were compared in
      subjects <70 years of age and subjects >/=70 years old and the levels were
      significantly lower in the younger group. Contrary to our expectation, comparison
      of the patient group and the control group revealed the serum concentrations of
      isoflavones to be higher in the patient group. Daidzein non-metabolizers were
      compared in the hospitalized experimental subjects of the patient group and the
      control group and they were significantly more common in the patient group. The
      poorly differentiated cancer patient group included a significantly lower
      percentage of daidzein metabolizers. CONCLUSIONS: The above findings revealed
      that equol itself or some unknown factor regulating the metabolism of daidzein is
      deeply involved in the biology of prostate cancer. Future studies are urgently
      needed to compare the incidence of daidzein metabolizers among various countries.

PMID- 12411568
TI  - Geographic distribution of the incidence of adult T-cell leukemia/lymphoma and
      other malignancies in nagasaki prefecture, Japan.
AB  - BACKGROUND: It remains unclear whether human T-cell lymphotropic virus type-I
      (HTLV-I) infection is associated with an increased risk of malignancies other
      than adult T-cell leukemia/lymphoma. METHODS: The authors investigated the
      geographic distribution of the incidence of adult T-cell leukemia/lymphoma and
      other malignancies in Nagasaki Prefecture, Japan, where HTLV-I is endemic. The
      world age-standardized incidence rates of adult T-cell leukemia/lymphoma and five
      cancers of other sites were calculated in 15 areas, using the data from the
      Nagasaki Prefectural Cancer Registry (1985-97). RESULTS: The incidence of adult T
      cell leukemia/lymphoma was found to be positively correlated with that of biliary
      tract cancer in men (person-years-weighted r = 0.49, P = 0.06) and liver cancer
      in women (r = 0.56, P = 0.03), but not with cancer of the stomach, lung or cervix
      uteri. CONCLUSIONS: The results may not support the hypothesis that HTLV-I
      infection is strongly associated with an increased risk of cancer of the stomach,
      lung or cervix uteri. The association between HTLV-I infection and cancer of the
      biliary tract and the possible interaction between hepatitis C virus and HTLV-I
      in the development of liver cancer should be evaluated by prospective cohort
      studies.

PMID- 12411569
TI  - A case of pulmonary adenocarcinoma accompanied by superior vena caval thrombosis
      in a patient with peutz-jeghers syndrome.
AB  - A case of lung adenocarcinoma and extensive deep vein thrombosis in a patient
      with Peutz-Jeghers syndrome (PJS) is presented. A 31-year-old Chinese man
      complained of shoulder pain and swelling of the right arm. A series of diagnostic
      procedures revealed a primary adenocarcinoma in the left upper lobe with cervical
      and supraclavicular lymph node metastases accompanied by deep vein thrombosis in
      the superior vena cava and right jugular vein. In addition, typical pigmentation
      of the lips and oral mucosa and multiple hamartomas in the stomach, duodenum and
      colon led to the diagnosis of PJS. PJS is known to be associated with increased
      risk of malignancies, especially in the gastrointestinal tract, breast, genitals
      and pancreas. As bronchoscopic examination showed no hamartomatous lesions in the
      bronchi, the development of primary lung cancer in this young patient might be
      independent of any hamartomatous lesion and might be associated with some genetic
      factors relating to PJS.

PMID- 12411570
TI  - A case of advanced esophageal cancer with extensive lymph node metastases
      successfully treated with multimodal therapy.
AB  - Advanced esophageal cancer patients with extensive lymph node metastases show
      extremely poor prognosis and the long-term outcome is poorer with the involvement
      of more lymph nodes. We report here a long-surviving case of advanced esophageal
      cancer with histologically 34 lymph node metastases, in which surgical resection
      with three-field lymphadenectomy followed by adjuvant chemotherapy and
      radiotherapy was performed. A 53-year-old male was diagnosed as advanced middle
      esophageal cancer with multiple regional lymph node metastases such as
      paraesophageal, pretracheal, tracheobronchial and bifurcational lymph nodes and
      three intramural metastatic lesions. Subtotal esophagectomy with three-field
      lymphadenectomy was performed for the tumor. Histopathologically, the tumor was
      poorly differentiated squamous cell carcinoma and 34 lymph nodes including
      ligamentum arteriosum lymph nodes and pretracheal lymph nodes were proved to be
      metastatic. Numerous tumor cells were found in the lymphatic vessels near the
      metastatic lymph nodes. Chemotherapy [3000 mg of 5-fluorouracil (5-FU), 50 mg of
      cisplatin (CDDP) and 30 mg of methotrexate (MTX)] was administered in two
      courses, followed by radiation therapy (field size 21 x 20 cm in mediastinum, 10
      MV X-rays, 2 Gy/fr, 5 fr/week, total 46 Gy). Subsequently, 1000 mg of 5-FU and
      200 mg of CDDP were administered every 3-4 months without any significant
      toxicities. The patient has been alive and well without recurrence for 5 years
      following operation. For treatment of advanced esophageal cancer with extensive
      lymph node metastases, a wide resection of the tumor and regional lymph nodes
      should be performed, followed by adjuvant chemotherapy and radiotherapy.

PMID- 12411571
TI  - Pancreatic metastasis from renal cell carcinoma extending into the main
      pancreatic duct: a case report.
AB  - While metastasis to the pancreas is uncommon, it may occur from renal cell
      carcinomas (RCCs). We here present a case of pancreatic metastasis from RCC
      extending into the main pancreatic duct (MPD) in a 66-year-old Japanese man. The
      patient had a history of RCC treated with a radical nephrectomy 17 years
      previously and was found to have a mass approximately 2 cm in diameter in the
      body of the pancreas on radiological images. The patient was suspected of having
      pancreatic metastasis from RCC and underwent a distal pancreatectomy with
      splenectomy. Histologically, the tumor consisted of cells arranged in trabecular
      and alveolar structures with clear or eosinophilic granular cytoplasm, compatible
      with a metastatic RCC. The pancreatic tumor extended into the MPD with the stream
      of pancreatic juice. This condition is similar to RCC extension into the renal
      vein and the inferior vena cava. In conclusion, although extension into the MPD
      may be rare, such a growth pattern may be characteristic of metastases from RCCs.

PMID- 12411572
TI  - Cancer incidence and incidence rates in Japan in 1997: estimates based on data
      from 12 population-based cancer registries.

PMID- 12411573
TI  - Small nuclear ribonucleoprotein remodeling during catalytic activation of the
      spliceosome.
AB  - Major structural changes occur in the spliceosome during its activation just
      before catalyzing the splicing of pre-messenger RNAs (pre-mRNAs). Whereas changes
      in small nuclear RNA (snRNA) conformation are well documented, little is known
      about remodeling of small nuclear ribonucleoprotein (snRNP) structures during
      spliceosome activation. Here, human 45S activated spliceosomes and a previously
      unknown 35S U5 snRNP were isolated by immunoaffinity selection and were
      characterized by mass spectrometry. Comparison of their protein components with
      those of other snRNP and spliceosomal complexes revealed a major change in
      protein composition during spliceosome activation. Our data also suggest that the
      U5 snRNP is dramatically remodeled at this stage, with the Prp19 complex and
      other factors tightly associating, possibly in exchange for other U5 proteins,
      and suggest that after catalysis the remodeled U5 is eventually released from the
      postsplicing complex as a 35S snRNP particle.

PMID- 12411575
TI  - Determination of the equation of state of dense matter.
AB  - Nuclear collisions can compress nuclear matter to densities achieved within
      neutron stars and within core-collapse supernovae. These dense states of matter
      exist momentarily before expanding. We analyzed the flow of matter to extract
      pressures in excess of 10(34) pascals, the highest recorded under laboratory
      controlled conditions. Using these analyses, we rule out strongly repulsive
      nuclear equations of state from relativistic mean field theory and weakly
      repulsive equations of state with phase transitions at densities less than three
      times that of stable nuclei, but not equations of state softened at higher
      densities because of a transformation to quark matter.

PMID- 12411574
TI  - Long-distance signaling in nodulation directed by a CLAVATA1-like receptor
      kinase.
AB  - Proliferation of legume nodule primordia is controlled by shoot-root signaling
      known as autoregulation of nodulation (AON). Mutants defective in AON show
      supernodulation and increased numbers of lateral roots. Here, we demonstrate that
      AON in soybean is controlled by the receptor-like protein kinase GmNARK (Glycine
      max nodule autoregulation receptor kinase), similar to Arabidopsis CLAVATA1
      (CLV1). Whereas CLV1 functions in a protein complex controlling stem cell
      proliferation by short-distance signaling in shoot apices, GmNARK expression in
      the leaf has a major role in long-distance communication with nodule and lateral
      root primordia.

PMID- 12411576
TI  - No time loophole in Bell's theorem: the Hess-Philipp model is nonlocal.
AB  - Hess and Philipp recently claimed [(2001) Proc. Natl. Acad. Sci. USA 98, 14224
      14227 and 14228-14233] that proofs of Bell's theorem have overlooked the
      possibility of time dependence in local hidden variables, hence the theorem has
      not been proven true. Moreover they present what is claimed to be a local
      realistic model of the EPR correlations. If this is true then Bell's theorem is
      not just unproven, but false. We refute both claims. First, we explain why time
      is not an issue in Bell's theorem, and second, we show that their hidden
      variables model violates Einstein separability. Hess and Philipp have overlooked
      the freedom of the experimenter to choose settings of a measurement apparatus at
      will: any setting could be in force during the same time period.

PMID- 12411578
TI  - A single point mutation in ecdysone receptor leads to increased ligand
      specificity: implications for gene switch applications.
AB  - The ecdysone receptor (EcR), a member of the nuclear receptor superfamily, plays
      an important role in regulating development and reproduction in insects. The EcR
      binds to ecdysteroids and regulates transcription of genes that contain ecdysone
      response elements. The EcR has been used to develop inducible gene switches for
      efficient regulation of foreign genes in applications such as gene therapy,
      protein production, and functional genomics. An EcR [Choristoneura fumiferana EcR
      (CfEcR)] homology model was constructed, and 17 amino acid residues were
      identified as critical for 20-hydroxyecdysone binding. Mutation of these amino
      acids followed by analysis of these mutants in transactivation (in insect and
      mammalian cells and in vivo in mice) and ligand-binding assays identified one
      particular mutant (A110P) that failed to respond to steroids, but its response to
      the diacylhydrazine nonsteroidal ligands RG-102240 (GS(TM)E) and RG-102317 was
      unaffected. This steroid-insensitive EcR mutant has potential gene switch
      applications in insects and plants that have endogenous ecdysteroids. In
      addition, this mutant would be also useful for developing orthogonal EcR-ligand
      pairs for simultaneous regulation of multiple genes in the same cell.

PMID- 12411577
TI  - Cag pathogenicity island-specific responses of gastric epithelial cells to
      Helicobacter pylori infection.
AB  - Helicobacter pylori infects over half the world's population and causes a wide
      range of diseases, including gastritis, peptic ulcer, and two forms of gastric
      cancer. H. pylori infection elicits a variety of phenotypic responses in cultured
      gastric epithelial cells, including the expression of proinflammatory genes and
      changes in the actin cytoskeleton. Both of these responses are mediated by the
      type IV secretion system (TFSS) encoded by the cag pathogenicity island (cag
      PAI). We used human cDNA microarrays to examine the temporal transcriptional
      profiles of gastric AGS cells infected with H. pylori strain G27 and a panel of
      isogenic mutants to dissect the contributions of various genes in the cag PAI.
      Infection with G27 induced expression of genes involved in the innate immune
      response, cell shape regulation, and signal transduction. A mutant lacking the
      cagA gene, which encodes an effector molecule secreted by the TFSS and required
      for the host cell cytoskeletal response, induced the expression of fewer
      cytoskeletal genes. A mutant lacking cagE, which encodes a structural component
      of the TFSS, failed to up-regulate a superset of host genes, including the cagA
      dependent genes, and many of the immune response genes. A mutant lacking the
      entire cag PAI failed to induce both the cagE-dependent genes and several
      transiently expressed cagE independent genes. Host cell transcriptional profiling
      of infection with isogenic strains offered a detailed molecular picture of H.
      pylori infection and provided insight into potential targets of individual
      virulence determinants such as tyrosine kinase and Rho GTPase signaling
      molecules.

PMID- 12411579
TI  - Presentation of antagonist peptides to naive CD4+ T cells abrogates spatial
      reorganization of class II MHC peptide complexes on the surface of dendritic
      cells.
AB  - By using dendritic cells (DCs) transduced with retroviruses encoding covalent
      A(b)beta/peptide fusion proteins tagged with fluorescent proteins, we followed
      the relocation of class II MHC molecules loaded with agonist or null peptides
      during the onset of activation of naive and effector CD4(+) T cells. Clusters of
      T cell receptor (TCR)/CD3 complex formed in parallel with clusters of agonist
      class II MHC/peptide complexes on the surface of DCs. However, activation of
      naive but not effector T cells was accompanied by expulsion of the null class II
      MHC/peptide complexes from the T cell-DC interface. These effects were perturbed
      in the presence of exogenously supplied antagonist peptide. These results suggest
      that interference with selective relocation of agonist and null MHC/peptide
      complexes in the immunological synapse contributes to the inhibitory effect of
      antagonist peptides on the response of naive CD4(+) T cells to agonist ligands.

PMID- 12411580
TI  - Pre-steady-state DNA unwinding by bacteriophage T4 Dda helicase reveals a
      monomeric molecular motor.
AB  - Helicases are molecular motor enzymes that unwind and translocate nucleic acids.
      One of the central questions regarding helicase activity is whether the process
      of coupling ATP hydrolysis to DNA unwinding requires an oligomeric form of the
      enzyme. We have applied a pre-steady-state kinetics approach to address this
      question with the bacteriophage T4 Dda helicase. If a helicase can function as a
      monomer, then the burst amplitude in the pre-steady state might be similar to the
      concentration of enzyme, whereas if the helicase required oligomerization, then
      the amplitude would be significantly less than the enzyme concentration. DNA
      unwinding of an oligonucleotide substrate was conducted by using a Kintek rapid
      quench-flow instrument. The substrate consisted of 12 bp adjacent to 12
      nucleotides of single-stranded DNA. Dda (4 nM) was incubated with substrate (16
      nM) in buffer, and the unwinding reaction was initiated by the addition of ATP (5
      mM) and Mg(2+) (10 mM). The reaction was stopped by the addition of 400 mM EDTA.
      Product formation exhibited biphasic kinetics, and the data were fit to the
      equation for a single exponential followed by a steady state. The amplitude of
      the first phase was 3.5 +/- 0.2 nM, consistent with a monomeric helicase. The
      burst amplitude of product formation was measured over a range of enzyme and
      substrate concentrations and remained consistent with a functional monomer. Thus,
      Dda can rapidly unwind oligonucleotide substrates as a monomer, indicating that
      the functional molecular motor component of a helicase can reside within a single
      polypeptide.

PMID- 12411581
TI  - The structure and evolution of the major capsid protein of a large, lipid
      containing DNA virus.
AB  - Paramecium bursaria Chlorella virus type 1 (PBCV-1) is a very large, icosahedral
      virus containing an internal membrane enclosed within a glycoprotein coat
      consisting of pseudohexagonal arrays of trimeric capsomers. Each capsomer is
      composed of three molecules of the major capsid protein, Vp54, the 2.0-A
      resolution structure of which is reported here. Four N-linked and two O-linked
      glycosylation sites were identified. The N-linked sites are associated with
      nonstandard amino acid motifs as a result of glycosylation by virus-encoded
      enzymes. Each monomer of the trimeric structure consists of two eight-stranded,
      antiparallel beta-barrel, "jelly-roll" domains related by a pseudo-sixfold
      rotation. The fold of the monomer and the pseudo-sixfold symmetry of the capsomer
      resembles that of the major coat proteins in the double-stranded DNA
      bacteriophage PRD1 and the double-stranded DNA human adenoviruses, as well as the
      viral proteins VP2-VP3 of picornaviruses. The structural similarities among these
      diverse groups of viruses, whose hosts include bacteria, unicellular eukaryotes,
      plants, and mammals, make it probable that their capsid proteins have evolved
      from a common ancestor that had already acquired a pseudo-sixfold organization.
      The trimeric capsid protein structure was used to produce a quasi-atomic model of
      the 1,900-A diameter PBCV-1 outer shell, based on fitting of the Vp54 crystal
      structure into a three-dimensional cryoelectron microscopy image reconstruction
      of the virus.

PMID- 12411583
TI  - A chemoattractant for ascidian spermatozoa is a sulfated steroid.
AB  - Sperm chemotaxis toward eggs before fertilization has been demonstrated in many
      animals and plants, and several peptides and small organic compounds acting as
      chemoattractants have been identified. We previously showed that sperm of the
      ascidians Ciona intestinalis and Ciona savignyi are activated and then attracted
      toward the egg by a common factor released from the egg. In this study, we
      purified sperm-activating and -attracting factor (SAAF) from the egg-conditioning
      medium of C. intestinalis by using several steps of column chromatography.
      Determination of the molecular structure by NMR and MS/MS analysis revealed that
      SAAF is a previously uncharacterized sulfated steroid: 3,4,7,26
      tetrahydroxycholestane-3,26-disulfate. Furthermore, it was shown that the SAAF of
      C. savignyi was indistinguishable from that of C. intestinalis in terms of the
      chromatographic behavior and molecular weight, indicating that the same compound
      might be responsible for sperm activation and chemotaxis in both the species.
      Furthermore, we established a method for quantitative analysis of sperm
      chemotaxis and showed that the chemotactic behavior of Ciona sperm is controlled
      by the "chemotactic turn" associated with decrease in the concentration of SAAF.

PMID- 12411582
TI  - Nrdp1/FLRF is a ubiquitin ligase promoting ubiquitination and degradation of the
      epidermal growth factor receptor family member, ErbB3.
AB  - The epidermal growth factor receptor (EGFR/ErbB) family of receptor tyrosine
      kinases plays fundamental roles in the regulation of cell survival,
      proliferation, and differentiation. Here, we present evidence that ErbB3 is
      degraded by proteasomes, and that Nrdp1 (referred to as FLRF in mice) associates
      with ErbB3 and stimulates its ubiquitination and degradation by proteasomes.
      Nrdp1 mRNAs are expressed in a variety of human tissues. The N-terminal half of
      Nrdp1 possesses an atypical RING finger domain, which is required for enhancing
      ErbB3 degradation. Its C-terminal half by itself associates with ErbB3 and raises
      ErbB3 levels in cells, probably by acting as a dominant-negative form of Nrdp1.
      In cell-free systems, Nrdp1 has ubiquitin ligase (E3) activity and ubiquitinates
      ErbB3, as well as itself, in the presence of the ubiquitin-carrier protein (E2),
      UbcH5. These data indicate that Nrdp1 is a RING finger-type of ubiquitin ligase,
      which promotes degradation of ErbB3 by proteasomes and, thus, may be an important
      factor influencing cell growth.

PMID- 12411584
TI  - Certification in molecular pathology in the United States (Training and Education
      Committee, The Association for Molecular Pathology).

PMID- 12411585
TI  - Quantification of PCR bias caused by a single nucleotide polymorphism in SMN gene
      dosage analysis.
AB  - Approximately 94% of patients with spinal muscular atrophy lack both copies of
      SMN1 exon 7, and most carriers have only one copy of SMN1 exon 7. We described
      previously the effect of SMN1/SMN2 heteroduplex formation on SMN gene dosage
      analysis, which is a multiplex quantitative PCR assay to determine the copy
      numbers of SMN1 and SMN2 using DraI digestion to differentiate SMN2 from SMN1. We
      describe herein the quantification of PCR bias between SMN1 exon 7 and SMN2 exon
      7, which differ by only one nucleotide that is not present in either primer
      binding site. Using samples from 272 individuals with various SMN genotypes, we
      found that the amplification efficiency of SMN2 was consistent only approximately
      80% that of SMN1. Thus, even a single nucleotide polymorphism, not in primer
      binding sites, can cause reproducible PCR bias. The precision and accuracy of our
      SMN gene dosage analysis are high because our assay design and controls take
      advantage of the consistency of the PCR bias. As additional clinically
      significant single nucleotide polymorphisms (SNPs) are discovered, assessment of
      PCR bias, and judicious selection of standards and controls, will be increasingly
      important for quantitative PCR assays.

PMID- 12411586
TI  - Molecular validation of the modified Vienna classification of colorectal tumors.
AB  - Although the Vienna classification has been introduced to resolve discrepancies
      in histological diagnoses of colorectal tumors between Western and Japanese
      pathologists, practical applications of this classification scheme have been
      problematic because invasion of the lamina propria of tumor cells is often
      difficult to recognize. Therefore, the following refinements of the
      classification criteria are needed: category 3, low-grade adenoma/dysplasia;
      category 4, intramucosal borderline neoplasia; 4-a, high-grade adenoma/dysplasia;
      4-b, well-differentiated adenocarcinoma; category 5, definite carcinoma; 5-a,
      intramucosal moderately-differentiated adenocarcinoma; and 5-b, submucosal
      carcinoma. We attempted to test whether molecular genetic alterations are related
      to the modified classification scheme and whether they may help to further
      categorize the various intramucosal neoplasia grades of colorectal tumors. Two
      hundred-thirty-two colorectal tumors were examined using flow cytometric analysis
      of DNA content, polymerase chain reaction microsatellite assays, and single
      strand conformational polymorphism assays to detect abnormalities of DNA content,
      chromosomal allelic loss, and Ki-ras and p53 gene mutations. Microsatellite
      instability (MSI) was also examined. Frequencies of genetic alterations and DNA
      aneuploid states increased with an increase in the grade assigned according to
      the modified Vienna classification. MSI was a rare event in colorectal adenomas
      and their frequency of MSI did not correlate with tumor grade. The combined
      genetic and DNA ploidy data support the conclusion that analysis of genetic
      alterations and DNA aneuploid states may help in appropriate categorization of
      colorectal tumors according to the modified Vienna scheme. In addition, MSI
      positive tumors may represent a specific subtype of colorectal adenomas.

PMID- 12411587
TI  - Determination of cyclin D1 and CD20 mRNA levels by real-time quantitative RT-PCR
      from archival tissue sections of mantle cell lymphoma and other non-Hodgkin's
      lymphomas.
AB  - Cyclin D1 overexpression is a valuable marker for the diagnosis of mantle cell
      lymphoma (MCL). We used a real-time quantitative reverse transcription-polymerase
      chain reaction (qRT-PCR) method to quantify levels of cyclin D1, CD20, and
      cyclophilin A mRNA in manually microdissected, paraffin-embedded tissue sections
      using an ABI 7700 qRT-PCR system. The study group included 21 cases of MCL and 37
      cases of other types of B-cell non-Hodgkin's lymphoma. Cyclin D1 mRNA copy number
      was normalized to CD20 and cyclophilin A mRNA and evaluated statistically by
      analysis of variance. The relative cyclin D1 levels were similar whether
      normalized to CD20 or cyclophilin A, indicating that CD20 levels are stable and
      can be used as a B-cell-specific normalizer. Statistically significant
      differences were found in the median levels of cyclin D1 mRNA (expressed as %
      CD20 mRNA) among cases of MCL (87.6), small lymphocytic lymphoma (9.9),
      follicular lymphoma (2.4), diffuse large B-cell lymphoma (5.9), marginal zone B
      cell lymphoma (39.8), and Burkitt lymphoma (7.1) (P < 0.05). We conclude that qRT
      PCR can be used to quantify cyclin D1 mRNA levels in archival tissue sections.
      Normalization of cyclin D1 to a B-cell-specific marker more accurately reflects
      overexpression by MCL than other methods that normalize using constitutively
      expressed mRNA species.

PMID- 12411588
TI  - Template-directed dye-terminator incorporation with fluorescence polarization
      detection for analysis of single nucleotide polymorphisms implicated in sepsis.
AB  - Sepsis continues to be a common source of morbidity and mortality in critically
      ill patients. Single nucleotide polymorphisms (SNPs) present in genes encoding
      inflammatory mediators have been associated with predisposition and outcome in
      this syndrome. The use of high throughput SNP analysis in large epidemiological
      studies is necessary to more fully understand the genetic underpinnings of this
      disease. We adapted template-directed dye-terminator incorporation with
      fluorescence polarization detection (TDI-FP) to the analysis of eight SNPs
      implicated in mediating the sepsis syndrome: TNF-alpha (-308), TNF-alpha (-238),
      TNF-beta (+250), IL-1beta (+3953), IL-6 (-174), IL-10 (-592), plasminogen
      activator inhibitor-1 (PAI-1 (-675)), and TLR4 299 (+1032). Optimization of PCR,
      amplicon purification, and template-directed dye-terminator incorporation
      reactions were necessary to achieve acceptable performance characteristics for
      these assays. Sequence validated samples served as controls. Using this method we
      were able to assign genotype in 99.3% of assays and identified 64 unique
      genotypes in samples obtained from 90 individuals. TDI-FP is a flexible and
      robust method of SNP detection that can be optimized in a systematic fashion.
      This method has potential advantages compared with other high throughput
      genotyping techniques and appears well suited to clinical situations requiring
      analysis of large numbers of samples.

PMID- 12411589
TI  - Rapid and accurate detection of monoclonal immunoglobulin heavy chain gene
      rearrangement by DNA melting curve analysis in the LightCycler System.
AB  - The detection of immunoglobulin heavy chain gene rearrangement (IgH-R) is a
      standard tool for distinguishing polyclonal from monoclonal B-cell populations.
      Current DNA-based polymerase chain reactions (PCR) strategies can diagnose
      monoclonal IgH-R either by measuring the length of the amplicon or by detecting
      gel mobility variations owing to sequence-dependent conformational changes.
      However, amplification and analysis remain sequential operations usually
      requiring manual transfer. We have developed a novel PCR strategy for detecting
      monoclonal IgH-R that monitors fluorescence of the specific double-stranded DNA
      binding dye SYBR Green I during melting curve analysis using the LightCycler
      System. We compared polyacrylamide gel electrophoresis (PAGE) versus melting
      curve analysis in 130 clinical DNA samples from formalin-fixed, paraffin-embedded
      (FFPE) tissues (mostly skin biopsies) of 128 patients. The identical FR3 primers
      were used to amplify the IgH variable region for both analytic techniques. We
      detected IgH-R in 24 DNA samples from FFPE tissue of 22 patients. Melting curve
      analysis, compared to PAGE, revealed no false negative and no false positive
      results, yielding both sensitivity and specificity equal to 100%. We also
      compared Southern blot analysis versus melting curve analysis in 23 clinical DNA
      samples from fresh-frozen lymph nodes of 23 patients. We detected IgH-R by
      melting curve analysis in 7 DNA samples from fresh-frozen lymph nodes. Melting
      curve analysis, compared to Southern blot analysis, revealed sensitivity equal to
      58.3% (7 of 12) and specificity equal to 100% (11 of 11). We conclude that
      continuous fluorescence monitoring of PCR products with DNA melting curve
      analysis can rapidly and reproducibly distinguish polyclonal from monoclonal B
      cell populations.

PMID- 12411590
TI  - Quantification of bcl-2/JH fusion sequences and a control gene by multiplex real
      time PCR coupled with automated amplicon sizing by capillary electrophoresis.
AB  - Follicular lymphoma is characterized by the presence of the t(14;18)(q32;q21)
      chromosomal translocation which juxtaposes the bcl-2 gene at 18q21 with the
      immunoglobulin heavy chain locus at 14q32. Quantification of t(14;18) carrying
      cells in FL patients can be achieved by real-time PCR, a highly sensitive
      technique for evaluating treatment efficacy and minimal residual disease. Despite
      the many advantages of real-time technology for this purpose, one disadvantage is
      that current real-time t(14;18) PCR assays amplify a control gene as a normalizer
      in a separate reaction. Since each PCR reaction has its own kinetics, separate
      PCR assays for target and control sequences can potentially result in inaccurate
      quantification of t(14;18)-positive cells. In addition, the real-time t(14;18)
      PCR assays do not determine the size of the amplified fusion sequence, which is
      helpful for excluding contamination and is commonly used to demonstrate clonal
      identity between pre- and post-treatment specimens from a patient. To address
      these limitations, we designed a multiplex real-time PCR protocol that allows
      amplification of control and target genes in the same reaction and precise size
      determination of bcl-2/JH fusion sequences by capillary electrophoresis. This
      multiplex PCR assay is equally sensitive to previous assays, allows more accurate
      quantification of bcl-2/JH fusion sequences, and is more convenient.

PMID- 12411591
TI  - Bone marrow transplant engraftment analysis with loss of an informative allele.
AB  - Short tandem repeats (STRs) are highly polymorphic DNA sequences in the human
      genome. STR genotype analysis is used for human identity testing and to monitor
      bone marrow engraftment after allogeneic transplantation. Engraftment analysis
      requires one or more informative STR loci that distinguish recipient from donor.
      The following case illustrates that chromosome loss in tumor cells during the
      course of disease may cause corresponding loss of an STR locus. This circumstance
      is a potential source of error in the interpretation of engraftment analysis,
      especially if only one informative allele is used to monitor engraftment.

PMID- 12411592
TI  - A novel use of equilibrium frequencies in models of sequence evolution.
AB  - Current mathematical models of amino acid sequence evolution are often applied in
      variants that match their expected amino acid frequencies to those observed in a
      data set under analysis. This has been achieved by setting the instantaneous rate
      of replacement of a residue i by another residue j proportional to the observed
      frequency of the resulting residue j. We describe a more general method that
      maintains the match between expected and observed frequencies but permits
      replacement rates to be proportional to the frequencies of both the replaced and
      resulting residues, raised to powers other than 1. Analysis of a database of
      amino acid alignments shows that the description of the evolutionary process in a
      majority (approximately 70% of 182 alignments) is significantly improved by use
      of the new method, and a variety of analyses indicate that parameter estimation
      with the new method is well-behaved. Improved evolutionary models increase our
      understanding of the process of molecular evolution and are often expected to
      lead to improved phylogenetic inferences, and so it seems justified to consider
      our new variants of existing standard models when performing evolutionary
      analyses of amino acid sequences. Similar methods can be used with nucleotide
      substitution models, but we have not found these to give corresponding
      significant improvements to our ability to describe the processes of nucleotide
      sequence evolution.

PMID- 12411593
TI  - Genes of the Pseudoviridae (Ty1/copia retrotransposons).
AB  - A comprehensive survey of the Pseudoviridae (Ty1/copia) retroelement family was
      conducted using the GenBank sequence database and completed genome sequences of
      several model organisms. Plant genomes were the most abundant sources of
      Pseudoviridae, with the Arabidopsis thaliana genome having 276 distinct elements.
      A reverse transcriptase amino acid sequence phylogeny indicated that the
      Pseudoviridae comprises highly divergent members. Coding sequences for a
      representative subset of elements were analyzed to identify conserved domains and
      differences that may underlie functional divergence. With the exception of some
      fungal elements (e.g., Ty1), most Pseudoviridae encode Gag and Pol on a single
      open reading frame. In addition to the nearly ubiquitous RNA-binding motif of
      nucleocapsid, three new conserved domains were identified in Gag. pol-encoded
      aspartic protease was similar to the retroviral enzyme and could be mapped onto
      the HIV-1 structure. Pol was highly conserved throughout the family. The greatest
      divergence among Pol sequences was seen in the C-terminus of integrase (IN). We
      defined a large motif (GKGY) after the IN catalytic domain that is unique to the
      Pseudoviridae. Additionally, the extreme C-terminus of IN is rich in simple
      sequence motifs. A distinct lineage of Pseudoviridae in plants have envlike
      genes. This lineage has undergone a large expansion of Gag characterized by an
      alpha-helix-rich domain containing coiled-coil motifs. In several elements, this
      domain is flanked on both sides by RNA-binding domains. We propose that this
      monophyletic lineage defines a new Pseudoviridae genus, herein referred to as the
      AGROVIRUS:

PMID- 12411594
TI  - The pattern of amino acid replacements in alpha/beta-barrels.
AB  - The determinants of site-to-site variability in the rate of amino acid
      replacement in alpha/beta-barrel enzyme structures are investigated. Of 125
      available alpha/beta-barrel structures, only 25 meet a variety of phylogenetic
      and statistical criteria necessary to ensure sufficient data for reliable
      analysis. These 25 enzyme structures (from a wide variety of taxa with diverse
      lifestyles in diverse habitats) differ greatly in size, number, and topology of
      domains in addition to the alpha/beta-barrel, quaternary structure, metabolic
      role, reaction catalyzed, presence of prosthetic groups, regulatory mechanisms,
      use of cofactors, and catalytic mechanisms. Yet, with the exception of ribulose
      1,5-bisphosphate carboxylase, all structures have similar frequency distributions
      of amino acid replacement rates. Hence, site-specific variability in rates of
      evolution is largely independent of differences in biology, biochemistry, and
      molecular structure. A correlation between site-specific rate variation and (1)
      distance from the active site, (2) solvent accessibility, and (3) treating
      glycines in unusual main-chain conformations as a separate class, explains
      approximately half the causal variation. Secondary structure exerts little
      influence on the pattern and distribution of replacements. Additional domains and
      subunits, side-chain hydrogen bonds, unusual side-chain rotamers, nonplanar
      peptide bonds, strained main-chain conformations, and buried hydrophilic-charged
      residues contribute little to variability among sites because they are rare.
      Nonlinear models do not improve the fits. In several enzymes, deviations from the
      typical pattern of replacements suggest the possible action of natural selection.
      A statistical analysis shows that, in all cases, much of the remaining
      unexplained variation is not attributable to chance and that other, as yet
      unidentified, causal relations must exist.

PMID- 12411595
TI  - Simulation study of the reliability and robustness of the statistical methods for
      detecting positive selection at single amino acid sites.
AB  - Inferring positive selection at single amino acid sites is of biological and
      medical importance. Parsimony-based and likelihood-based methods have been
      developed for this purpose, but the reliabilities of these methods are not well
      understood. Because the evolutionary models assumed in these methods are only
      rough approximations to reality, it is desirable that the methods are not very
      sensitive to violation of the assumptions made. In this study we show by computer
      simulation that the likelihood-based method is sensitive to violation of the
      assumptions and produces many false-positive results under certain conditions,
      whereas the parsimony-based method tends to be conservative. These observations,
      together with those from previous studies, suggest that the positively selected
      sites inferred by the parsimony-based method are more reliable than those
      inferred by the likelihood-based method.

PMID- 12411596
TI  - Strong positive selection and habitat-specific amino acid substitution patterns
      in MHC from an estuarine fish under intense pollution stress.
AB  - Population-level studies using the major histocompatibility complex (Mhc) have
      linked specific alleles with specific diseases, but data requirements are high
      and the power to detect disease association is low. A novel use of Mhc population
      surveys involves mapping allelic substitutions onto the inferred structural
      molecular model to show functional differentiation related to local selective
      pressures. In the estuarine fish Fundulus heteroclitus, populations experiencing
      strong differences in antigenic challenges show significant differences in amino
      acid substitution patterns that are reflected as variation in the structural
      location of changes between populations. Fish from a population genetically
      adapted to severe chemical pollution also show novel patterns of DNA substitution
      at a highly variable Mhc class II B locus including strong signals of positive
      selection at inferred antigen-binding sites and population-specific signatures of
      amino acid substitution. Heavily parasitized fish from an extreme PCB
      contaminated (U.S. Environmental Protection Agency Superfund) site show enhanced
      population-specific substitutions in the a-helix portion of the inferred antigen
      binding region. In contrast, fish from an unpolluted site show a significantly
      different pattern focused on the first strand of the B-pleated sheet. Whether Mhc
      population profile differences represent the direct effects of chemical toxicants
      or indirect parasite-mediated selection, the result is a composite habitat
      specific signature of strong selection and evolution affecting the genetic
      repertoire of the major histocompatibility complex.

PMID- 12411597
TI  - Serpins in prokaryotes.
AB  - Members of the serpin (serine proteinase inhibitor) superfamily have been
      identified in higher multicellular eukaryotes (plants and animals) and viruses
      but not in bacteria, archaea, or fungi. Thus, the ancestral serpin and the origin
      of the serpin inhibitory mechanism remain obscure. In this study we characterize
      12 serpin-like sequences in the genomes of prokaryotic organisms, extending this
      protein family to all major branches of life. Notably, these organisms live in
      dramatically different environments and some are evolutionarily distantly
      related. A sequence-based analysis suggests that all 12 serpins are inhibitory.
      Despite considerable sequence divergence between the proteins, in four of the 12
      sequences the region of the serpin that determines proteinase specificity is
      highly conserved, indicating that these inhibitors are likely to share a common
      target. Inhibitory serpins are typically prone to polymerization upon heating;
      thus, the existence of serpins in the moderate thermophilic bacterium
      Thermobifida fusca, the thermophilic bacterium Thermoanaerobacter tengcongensis,
      and the hyperthermophilic archaeon Pyrobaculum aerophilum is of particular
      interest. Using molecular modeling, we predict the means by which heat stability
      in the latter protein may be achieved without compromising inhibitory activity.

PMID- 12411598
TI  - Identification of neurotransmitter receptor genes under significantly relaxed
      selective constraint by orthologous gene comparisons between humans and rodents.
AB  - Neurotransmitter receptors (neuroreceptors) are classified into two types, G
      protein-coupled receptors (GPCRs) and ligand-gated ion channels. The former
      occupies a small part of the large GPCR superfamily, whereas the latter consists
      of three superfamilies. In these superfamilies, humans and rodents share almost
      the same set of neuroreceptor genes. This neuroreceptor gene set is good material
      to examine the degree of selective constraint exerted on each member gene of a
      given superfamily. If there are any neuroreceptor genes under the degree of
      selective constraint that is very different from that of the other member genes,
      they may have influenced the functional features characteristic of human neural
      activities. With the aim of identifying such neuroreceptor genes, we collected
      sequence data of orthologous neuroreceptor genes for humans, mice, and rats by
      database searches. This data set included ortholog pairs for 141 kinds of
      neuroreceptor genes, which covered almost the whole set of neuroreceptor genes
      known to be expressed in the human brain. The degree of selective constraint was
      estimated by computing the ratio (d(N)/d(S)) of the number of nonsynonymous
      substitutions to that of synonymous substitutions. We found that the d(N)/d(S)
      ratio ranged widely and its distribution fitted a gamma distribution. In
      particular, we found that four neuroreceptor genes are under the significantly
      relaxed selective constraint. They are an ionotropic glutamate receptor subunit
      NMDA-2C, two GABA(A) receptor subunits, i.e., GABA(A)-epsilon and GABA(A)-theta,
      and a dopamine receptor D4. Interestingly, these neuroreceptors have been
      reported to be associated with cognitive abilities such as memory and learning,
      and responsiveness to novel stimuli. These cognitive abilities can influence the
      behavioral features of an individual. Thus, it suggests that the relaxed
      constraint neuroreceptor genes have evolved, assuring that the nervous system
      responds to a variety of stimuli with proper flexibility.

PMID- 12411599
TI  - A comparative mitogenomic analysis of the potential adaptive value of Arctic
      charr mtDNA introgression in brook charr populations (Salvelinus fontinalis
      Mitchill).
AB  - Wild brook charr populations (Salvelinus fontinalis) completely introgressed with
      the mitochondrial genome (mtDNA) of arctic charr (Salvelinus alpinus) are found
      in several lakes of northeastern Quebec, Canada. Mitochondrial respiratory
      enzymes of these populations are thus encoded by their own nuclear DNA and by
      arctic charr mtDNA. In the present study we performed a comparative sequence
      analysis of the whole mitochondrial genome of both brook and arctic charr to
      identify the distribution of mutational differences across these two genomes.
      This analysis revealed 47 amino acid replacements, 45 of which were confined to
      subunits of the NADH dehydrogenase complex (Complex I), one in the cox3 gene
      (Complex IV), and one in the atp8 gene (Complex V). A cladistic approach
      performed with brook charr, arctic charr, and two other salmonid fishes (rainbow
      trout [Oncorhynchus mykiss] and Atlantic salmon [Salmo salar]) revealed that only
      five amino acid replacements were specific to the charr comparison and not shared
      with the other two salmonids. In addition, five amino acid substitutions
      localized in the nad2 and nad5 genes denoted negative scores according to the
      functional properties of amino acids and, therefore, could possibly have an
      impact on the structure and functional properties of these mitochondrial
      peptides. The comparison of both brook and arctic charr mtDNA with that of
      rainbow trout also revealed a relatively constant mutation rate for each specific
      gene among species, whereas the rate was quite different among genes. This
      pattern held for both synonymous and nonsynonymous nucleotide positions. These
      results, therefore, support the hypothesis of selective constraints acting on
      synonymous codon usage.

PMID- 12411600
TI  - Multiple ribonuclease H-encoding genes in the Caenorhabditis elegans genome
      contrasts with the two typical ribonuclease H-encoding genes in the human genome.
AB  - Database searches of the Caenorhabditis elegans and human genomic DNA sequences
      revealed genes encoding ribonuclease H1 (RNase H1) and RNase H2 in each genome.
      The human genome contains a single copy of each gene, whereas C. elegans has four
      genes encoding RNase H1-related proteins and one gene for RNase H2. By analyzing
      the mRNAs produced from the C. elegans genes, examining the amino acid sequence
      of the predicted protein, and expressing the proteins in Esherichia coli we have
      identified two active RNase H1-like proteins. One is similar to other eukaryotic
      RNases H1, whereas the second RNase H (rnh-1.1) is unique. The rnh-1.0 gene is
      transcribed as a dicistronic message with three dsRNA-binding domains; the mature
      mRNA is transspliced with SL2 splice leader and contains only one dsRNA-binding
      domain. Formation of RNase H1 is further regulated by differential cis-splicing
      events. A single rnh-2 gene, encoding a protein similar to several other
      eukaryotic RNase H2L's, also has been examined. The diversity and enzymatic
      properties of RNase H homologues are other examples of expansion of protein
      families in C. elegans. The presence of two RNases H1 in C. elegans suggests that
      two enzymes are required in this rather simple organism to perform the functions
      that are accomplished by a single enzyme in more complex organisms. Phylogenetic
      analysis indicates that the active C. elegans RNases H1 are distantly related to
      one another and that the C. elegans RNase H1 is more closely related to the human
      RNase H1. The database searches also suggest that RNase H domains of LTR
      retrotransposons in C. elegans are quite unrelated to cellular RNases H1, but
      numerous RNase H domains of human endogenous retroviruses are more closely
      related to cellular RNases H.

PMID- 12411601
TI  - Ancient DNA and the population genetics of cave bears (Ursus spelaeus) through
      space and time.
AB  - The cave bear spread from Western Europe to the Near East during the Riss
      glaciation (250 KYA) before becoming extinct approximately 12 KYA. During that
      period, the climatic conditions were highly dynamic, oscillating between glacial
      and temperate episodes. Such events have constrained the geographic repartition
      of species, the movements of populations and shaped their genetic diversity. We
      retrieved and analyzed ancient DNA from 21 samples from five European caves
      ranging from 40 to 130 KYA. Combined with available data, our data set accounts
      for a total of 41 sequences of cave bear, coming from 18 European caves. We
      distinguish four haplogroups at the level of the mitochondrial DNA control
      region. The large population size of cave bear could account for the maintenance
      of such polymorphism. Extensive gene flow seems to have connected European
      populations because two haplogroups cover wide geographic areas. Furthermore, the
      extensive sampling of the deposits of the Scladina cave located in Belgium
      allowed us to correlate changes in climatic conditions with the intrapopulational
      genetic diversity over 90 KY.

PMID- 12411602
TI  - The Opitz syndrome gene Mid1 is transcribed from a human endogenous retroviral
      promoter.
AB  - Human endogenous retroviruses (HERVs) and other long terminal repeat (LTR)
      containing elements comprise a significant portion (8%) of the human genome and
      are likely vestiges of retroviral infections during primate evolution. Many of
      the HERVs present in human DNA have retained functional promoter, enhancer, and
      polyadenylation signals, and these regulatory sequences have the potential to
      modify the expression of nearby genes. To identify retroviral elements that
      contribute to the transcription of human genes, we screened sequence databases
      for chimeric (viral-cellular) transcripts. These searches revealed a fusion
      transcript containing the LTR of an HERV-E element linked to the Opitz syndrome
      gene Mid1. We confirmed the authenticity of the chimeric transcript by 5' rapid
      amplification of cDNA ends (RACE) and established that the Mid1 mRNA isoform was
      transcribed from a retroviral LTR. The identification of a retroviral first exon
      suggested the existence of alternative promoters for Mid1 because nonretroviral
      (native) 5' untranslated regions (UTRs) had been reported previously for this
      gene. Although Mid1 transcripts could be detected in all tissues tested,
      quantitative real-time reverse transcription-polymerase chain reaction indicated
      that the retroviral promoter contributes significantly to the level of Mid1
      transcripts in placenta and embryonic kidney, where chimeric mRNAs were found to
      represent 25% and 22% of overall Mid1 mRNAs, respectively. Transient transfection
      studies supported a role for the LTR as a strong tissue-specific promoter in
      placental and embryonic kidney cell lines and suggested a function for the LTR as
      an enhancer. These findings provide further evidence that some endogenous
      retroviruses have evolved a biological function by contributing transcriptional
      regulatory elements to cellular genes.

PMID- 12411603
TI  - Evolution of a perfect simple sequence repeat locus in the context of its
      flanking sequence.
AB  - Microsatellites, which have rapidly become the preferred markers in population
      genetics, reliably assign individual chinook salmon to the winter, fall, late
      fall, or spring chinook runs in the Sacramento River in California's Central
      Valley (Banks et al. 2000. Can. J. Fish. Aquat. Sci. 57:915-927). A substantial
      proportion of this discriminatory power comes from Ots-2, a simple CA repeat,
      which is expected to evolve rapidly under the stepwise mutation model. We have
      sequenced a 300-bp region around this locus and typed 668 microsatellite-flanking
      sequence haplotypes to explore further the basis of this microsatellite
      divergence. Three sites of nucleotide polymorphism in the Ots-2 flanking sequence
      define five haplotypes that are shared by the Californian and Canadian
      populations. The Ots-2 microsatellite alleles are nonrandomly distributed among
      these five haplotypes in a pattern of gametic disequilibrium that is also shared
      among populations. Divergence between the winter run and other Central Valley
      stocks appears to be caused by a combination of surprisingly static evolution at
      Ots-2 within a context of more rapidly changing haplotype frequencies.

PMID- 12411604
TI  - Improvement of distance-based phylogenetic methods by a local maximum likelihood
      approach using triplets.
AB  - We introduce a new approach to estimate the evolutionary distance between two
      sequences. This approach uses a tree with three leaves: two of them correspond to
      the studied sequences, whereas the third is chosen to handle long-distance
      estimation. The branch lengths of this tree are obtained by likelihood
      maximization and are then used to deduce the desired distance. This approach,
      called TripleML, improves the precision of evolutionary distance estimates, and
      thus the topological accuracy of distance-based methods. TripleML can be used
      with neighbor-joining-like (NJ-like) methods not only to compute the initial
      distance matrix but also to estimate new distances encountered during the
      agglomeration process. Computer simulations indicate that using TripleML
      significantly improves the topological accuracy of NJ, BioNJ, and Weighbor, while
      conserving a reasonable computation time. With randomly generated 24-taxon trees
      and realistic parameter values, combining NJ with TripleML reduces the number of
      wrongly inferred branches by about 11% (against 2.6% and 5.5% for BioNJ and
      Weighbor, respectively). Moreover, this combination requires only about 1.5 min
      to infer a phylogeny of 96 sequences composed of 1,200 nucleotides, as compared
      with 6.5 h for FastDNAml on the same machine (PC 466 MHz).

PMID- 12411605
TI  - Characterization of novel Alu- and tRNA-related SINEs from the tree shrew and
      evolutionary implications of their origins.
AB  - We characterized two novel 7SL RNA-derived short interspersed nuclear element
      (SINE) families (Tu types I and II) and a novel tRNA-derived SINE family (Tu type
      III) from the tree shrew (Tupaia belangeri). Tu type I contains a monomer unit of
      a 7SL RNA-derived Alu-like sequence and a tRNA-derived region that includes
      internal RNA polymerase III promoters. Tu type II has a similar hybrid structure,
      although the monomer unit of the 7SL RNA-derived sequence is replaced by a dimer.
      Along with the primate Alu, the galago Alu type II, and the rodent B1, these two
      families represent the fourth and fifth 7SL RNA-derived SINE families to be
      identified. Furthermore, comparison of the Alu domains of Tu types I and II with
      those of other 7SL RNA-derived SINEs reveals that the nucleotides responsible for
      stabilization of the Alu domain have been conserved during evolution, providing
      the possibility that these conserved nucleotides play an indispensable role in
      retropositional activity. Evolutionary relationships among these 7SL RNA-derived
      SINE families, as well as phylogenetic relationships of their host species, are
      discussed.

PMID- 12411606
TI  - Mammalian sperm proteins are rapidly evolving: evidence of positive selection in
      functionally diverse genes.
AB  - A growing number of genes involved in sex and reproduction have been demonstrated
      to be rapidly evolving. Here, we show that genes expressed solely in spermatozoa
      represent a highly diverged subset among mouse and human tissue-specific
      orthologs. The average rate of nonsynonymous substitutions per site (K(a)) is
      significantly higher in sperm proteins (mean K(a) = 0.18; N = 35) than in
      proteins expressed specifically in all other tissues (mean K(a) = 0.074; N =
      473). No differences, however, are found in the synonymous substitution rate
      (K(s)) between tissues, suggesting that selective forces, and not mutation rate,
      explain the high rate of replacement substitutions in sperm proteins. Four out of
      19 sperm-specific genes with characterized function demonstrated evidence of
      strong positive Darwinian selection, including a protein involved in gene
      regulation, Protamine-1 (PRM1), a protein involved in glycolysis, GAPDS, and two
      egg-binding proteins, Adam-2 precursor (ADAM2) and sperm-adhesion molecule-1
      (SAM1). These results demonstrate the rapid evolution of sperm-specific genes and
      highlight the molecular action of sexual selection on a variety of characters
      involved in mammalian sperm function.

PMID- 12411607
TI  - Genetic evidence for long-term population decline in a savannah-dwelling primate:
      inferences from a hierarchical bayesian model.
AB  - The purpose of this study was to test for evidence that savannah baboons (Papio
      cynocephalus) underwent a population expansion in concert with a hypothesized
      expansion of African human and chimpanzee populations during the late
      Pleistocene. The rationale is that any type of environmental event sufficient to
      cause simultaneous population expansions in African humans and chimpanzees would
      also be expected to affect other codistributed mammals. To test for genetic
      evidence of population expansion or contraction, we performed a coalescent
      analysis of multilocus microsatellite data using a hierarchical Bayesian model.
      Markov chain Monte Carlo (MCMC) simulations were used to estimate the posterior
      probability density of demographic and genealogical parameters. The model was
      designed to allow interlocus variation in mutational and demographic parameters,
      which made it possible to detect aberrant patterns of variation at individual
      loci that could result from heterogeneity in mutational dynamics or from the
      effects of selection at linked sites. Results of the MCMC simulations were
      consistent with zero variance in demographic parameters among loci, but there was
      evidence for a 10- to 20-fold difference in mutation rate between the most slowly
      and most rapidly evolving loci. Results of the model provided strong evidence
      that savannah baboons have undergone a long-term historical decline in population
      size. The mode of the highest posterior density for the joint distribution of
      current and ancestral population size indicated a roughly eightfold contraction
      over the past 1,000 to 250,000 years. These results indicate that savannah
      baboons apparently did not share a common demographic history with other
      codistributed primate species.

PMID- 12411608
TI  - Abundant raw material for cis-regulatory evolution in humans.
AB  - Changes in gene expression and regulation--due in particular to the evolution of
      cis-regulatory DNA sequences--may underlie many evolutionary changes in
      phenotypes, yet little is known about the distribution of such variation in
      populations. We present in this study the first survey of experimentally
      validated functional cis-regulatory polymorphism. These data are derived from
      more than 140 polymorphisms involved in the regulation of 107 genes in Homo
      sapiens, the eukaryote species with the most available data. We find that
      functional cis-regulatory variation is widespread in the human genome and that
      the consequent variation in gene expression is twofold or greater for 63% of the
      genes surveyed. Transcription factor-DNA interactions are highly polymorphic, and
      regulatory interactions have been gained and lost within human populations. On
      average, humans are heterozygous at more functional cis-regulatory sites
      (>16,000) than at amino acid positions (<13,000), in part because of an
      overrepresentation among the former in multiallelic tandem repeat variation,
      especially (AC)(n) dinucleotide microsatellites. The role of microsatellites in
      gene expression variation may provide a larger store of heritable phenotypic
      variation, and a more rapid mutational input of such variation, than has been
      realized. Finally, we outline the distinctive consequences of cis-regulatory
      variation for the genotype-phenotype relationship, including ubiquitous epistasis
      and genotype-by-environment interactions, as well as underappreciated modes of
      pleiotropy and overdominance. Ordinary small-scale mutations contribute to
      pervasive variation in transcription rates and consequently to patterns of human
      phenotypic variation.

PMID- 12411609
TI  - Fossil calibration of molecular clocks and the divergence times of geminate
      species pairs separated by the isthmus of panama.
AB  - Calibration of nucleotide sequence divergence rates provides an important method
      by which to test many hypotheses of evolution. In the absence of an adequate
      fossil record, geological events, rather than the first appearances of sister
      taxa in the geological record, are often used to calibrate molecular clocks. The
      formation of the Isthmus of Panama, which isolated the tropical western Atlantic
      and eastern Pacific oceans, is one such event that is frequently used to infer
      rates of nucleotide sequence divergence. Isthmian calibrations assume that
      morphologically similar "geminate" species living now on either side of the
      isthmus were isolated geographically by the latest stages of seaway closure 3.1
      3.5 MYA. Here, I have applied calibration dates from the fossil record to
      cytochrome c oxidase-1 (CO1) and nuclear histone-3 (H3) divergences among six
      pairs of geminates in the Arcidae to test this hypothesis. Analysis of CO1 first
      and third positions yield geminate divergences that predate final seaway closure,
      and on the basis of CO1 first positions, times for all six geminates are
      significantly greater than 3.5 Myr. H3 sequences produce much more recent
      geminate divergences, some that are younger than 3.1 Myr. But H3-derived
      estimates for all arcid geminates are not significantly different from both 0 and
      15 Myr. According to CO1, one of the two most divergent pairs, Arca mutabilis and
      A. imbricata, split more than 30 MYA. This date is compatible with the fossil
      record, which indicates that these species were morphologically distinct at least
      16-21 MYA. Across all CO1 nucleotide sites, divergence rates for arcids are
      slower than the rates reported for other taxa on the basis of isthmian
      calibrations, with the exception of rates determined from the least divergent
      species pair in larger surveys of multiple transisthmian pairs. Rate differences
      between arcids and some taxa may be real, but these data suggest that divergence
      rates can be greatly overestimated when dates corresponding to final closure of
      the Central American Seaway are used to calibrate the molecular clocks of marine
      organisms.

PMID- 12411610
TI  - Group-I intron containing a putative homing endonuclease gene in the small
      subunit ribosomal DNA of Beauveria bassiana IFO 31676.

PMID- 12411611
TI  - 5' genomic structure of human Sp3.

PMID- 12411612
TI  - Parallel patterns of sequence variation within and between populations at three
      loci of Arabidopsis thaliana.

PMID- 12411613
TI  - Sequence gaps join mice and men: phylogenetic evidence from deletions in two
      proteins.

PMID- 12411614
TI  - Upstream from death.

PMID- 12411615
TI  - Health services for women with chronic pelvic pain.

PMID- 12411616
TI  - What happens when elderly people die?

PMID- 12411617
TI  - Relations between offending, injury and illness.
AB  - The objectives of this study were to determine relations between offending and
      health, and how illness and injury relate to concurrent offending--whether
      offending predicts health or vice versa, and whether relations persist after
      adjustment for childhood predictors of offending. Data collected in the Cambridge
      Study in Delinquent Development were analysed. This is a prospective longitudinal
      survey of 411 South London males first recruited at age 8. Information about
      injuries and illnesses between ages 16 and 18 was set against information on
      offending and other types of antisocial behaviour. Males who were injured
      (especially in assaults) tended to be convicted, to be violent, to have unskilled
      manual jobs and to be generally antisocial. Respiratory tract illnesses were
      negatively related to convictions and antisocial behaviour in general. Drug users
      were significantly likely to be ill. Adult convictions were predicted by
      childhood troublesome behaviour, daring/hyperactivity, low IQ/attainment, a
      convicted parent, family disruption/poor supervision and poverty. Assault
      injuries and respiratory tract illnesses did not predict adult convictions
      independently of these childhood factors. It was concluded that injury is one
      symptom of an antisocial personality that arises in childhood and persists into
      adulthood. Therefore, measures that lead to a reduction in offending should also
      lead to a reduction in concurrent injuries. Negative relations between a range of
      antisocial behaviours and respiratory tract illness deserve further study.

PMID- 12411618
TI  - Illegible handwriting in medical records.
AB  - In clinical records many items are handwritten and difficult to read. We examined
      clinical histories in a representative sample of case notes from a Spanish
      general hospital. Two independent observers assigned legibility scores, and a
      third adjudicated in case of disagreement. Defects of legibility such that the
      whole was unclear were present in 18 (15%) of 117 reports, and were particularly
      frequent in records from surgical departments. Through poor handwriting, much
      information in medical records is inaccessible to auditors, to researchers, and
      to other clinicians involved in the patient's care. If clinicians cannot be
      persuaded to write legibly, the solution must be an accelerated switch to
      computer-based systems.

PMID- 12411619
TI  - Pathologists' views on consent for autopsy.
AB  - Consent to autopsy is usually obtained by a doctor other than the one who will
      perform the procedure. There is an argument that, for proper informed consent, a
      pathologist should participate. We ascertained the views of consultant
      pathologists in south-east England. 53 (87%) of 61 consultants responded, of whom
      50 currently do autopsies. Only 2 at present participate directly in obtaining
      consent, and 10 of the remaining 48 expressed willingness to do so. The general
      view was that consent is best obtained by a senior clinician from the team that
      has looked after the patient. Pathologists see their primary role as to provide
      guidance to clinicians. Few see it as their function to obtain consent for
      autopsy.

PMID- 12411620
TI  - Clinical performance measurement: part 2--avoiding the pitfalls.

PMID- 12411621
TI  - Treatment of long-duration atrial fibrillation by modified maze procedure.

PMID- 12411622
TI  - Ventriculoperitoneal shunt fractured by a closing car window.

PMID- 12411623
TI  - Liver abscess metastasizing to prostate and lung.

PMID- 12411624
TI  - Acute glaucoma with abdominal pain.

PMID- 12411625
TI  - Bruising in a man with aortic aneurysms.

PMID- 12411626
TI  - Dyspnoea worsened by salmeterol.

PMID- 12411628
TI  - William Budd and typhoid fever.

PMID- 12411629
TI  - The law on dying.

PMID- 12411630
TI  - Please give us objectives we can aim at.

PMID- 12411631
TI  - Stevens' cure for tuberculosis.

PMID- 12411632
TI  - Stevens' cure for tuberculosis.

PMID- 12411633
TI  - Stevens' cure for tuberculosis.

PMID- 12411634
TI  - Expert witnesses, courts and the law.

PMID- 12411635
TI  - Mendel--both ignored and forgotten.

PMID- 12411636
TI  - Feral children.

PMID- 12411637
TI  - The real Dr Frankenstein: Christian Gottlieb Kratzenstein?

PMID- 12411639
TI  - Clopidogrel plus aspirin for stroke prevention.

PMID- 12411640
TI  - Blood pressure and clinical outcome in acute ischemic stroke.

PMID- 12411641
TI  - Anatomy of stroke, Part I: an MRI-based topographic and volumetric System of
      analysis.
AB  - BACKGROUND AND PURPOSE: The clinical diagnosis and treatment of stroke, as well
      as investigations into the underlying pathophysiology of the disease, hinge on
      inferences from the anatomy of the stroke lesion. We describe an MRI-based system
      of topographic and volumetric analysis that considers distribution of infarct
      with respect to neuroanatomic structures, superficial and deep perfusion
      compartments, and gray and white matter tissue types. METHODS: MRI-based 3
      dimensional topographic and volumetric analysis of presumed MCA embolic stroke
      was performed months after the acute event in 21 subjects ranging in age from 34
      to 75 years. RESULTS: The topography of infarction was greatly variable, with
      virtually all regions of the MCA territory involved in at least 1 stroke in the
      series. In 14, there was involvement of the M1 as well as the M2 through M4
      territories; in 6, there was involvement of only the M2 through M4 territories;
      and in 2, there was involvement of only the M1 territory. The volumes varied from
      3.1 to 256 cm3, corresponding approximately to a range of 1% to 90% of the total
      MCA territory. CONCLUSIONS: The system of topographic and volumetric analysis is
      generally applicable to all strokes in the forebrain where the infarct is
      visualized in MRI, independent of vascular territory, clinical correlates, and
      interval between stroke and MRI. The results emphasize the variety of topographic
      patterns and lesion volumes of strokes. Intended long-range applications include
      correlation of outcome of stroke with predictions from acute-phase diffusion- and
      perfusion-weighted imaging and investigations of the potential benefit of
      therapeutic agents.

PMID- 12411642
TI  - Anatomy of stroke, Part II: volumetric characteristics with implications for the
      local architecture of the cerebral perfusion system.
AB  - BACKGROUND AND PURPOSE: The margin of a stroke is assumed to approximate a trace
      of the isobar of the perfusion threshold for infarction at the time that
      infarction occurred. Working from this hypothesis, we have analyzed stroke
      topography and volume in MR images obtained at a time remote from the stroke
      event. We have derived parameters from these images that may give information on
      local perfusion competence and microvascular architecture because they influenced
      the contour of stroke at the time infarction occurred. METHODS: MR images were
      obtained months after presumed embolic middle cerebral artery stroke in 21
      subjects. Volumetric analyses of image data were undertaken with respect to the
      tissue shape of stroke and scaling ratios of anatomic partitions involved in
      stroke. RESULTS: For stroke confined to a single volume, the 3-dimensional form
      conforms to a parabola in which the height-to-width ratios are variable. The
      ratio for cortex is greater than that for underlying white matter. Scaling ratios
      indicate a close correlation between volume of cortex and radiata destroyed and
      total volume of stroke, but the relative proportions vary as a function of
      location within the M4 territory. CONCLUSIONS: Scaling ratios for cortex and
      radiata to stroke volume are consistent with vascular studies that depict a
      modular microvascular perfusion architecture for the cortex and underlying white
      matter. The stroke descriptors are inferred to be related to the competence of
      collateral perfusion at the time that stroke occurred. This inference may be
      tested by serial volumetric analysis of the perfusion-diffusion examination
      mismatch immediately and over the longer-term evolution of stroke.

PMID- 12411643
TI  - Arterial changes in cerebral autosomal dominant arteriopathy with subcortical
      infarcts and leukoencephalopathy (CADASIL) in relation to pathogenesis of diffuse
      myelin loss of cerebral white matter: examination of cerebral medullary arteries
      by reconstruction of serial sections of an autopsy case.
AB  - BACKGROUND AND PURPOSE: There is little information regarding the pathogenesis
      underlying diffuse myelin loss in the cerebral white matter and sparing of the U
      fibers in cerebral autosomal-dominant arteriopathy with subcortical infarcts and
      leukoencephalopathy (CADASIL), in which the medial smooth muscle cells of
      systemic arteries are characteristically involved. We sought to examine the
      precise extent and severity of changes in the cerebral arteries in an autopsy
      case of CADASIL in relation to pathogenesis of the diffuse myelin loss. METHODS:
      We reconstructed 1000 serial sections of the frontal cerebral medullary arteries
      of an autopsy subject, which was the first identified Japanese case of CADASIL,
      as confirmed by the presence of ultrastructural deposits of granular osmiophilic
      material in the media of some visceral arteries and by genetic analysis. RESULTS:
      We reconstructed 11 medullary arteries of the frontal lobe showing diffuse myelin
      loss and atrophy of the white matter with sparing of the U fibers. All of these
      showed complete loss of medial smooth muscle cells over their entire length and
      severe adventitial fibrosis. Although intimal fibrosis or hyalinosis was present,
      luminal occlusion was scarce. These changes were also observed in the small and
      large arachnoidal arteries but were relatively mild in the latter and in the
      cortical and subcortical medullary arteries. CONCLUSIONS: These arterial changes
      resulted in transformation of the cerebral arteries, in particular almost all the
      medullary arteries, to a so-called earthen pipe state. This supports the reported
      findings of a reduction in vascular reactivity to fluctuations in CO2 levels and
      systemic blood pressure in CADASIL.

PMID- 12411644
TI  - Course of platelet activation markers after ischemic stroke.
AB  - BACKGROUND AND PURPOSE: The aim of this study was to evaluate the time course of
      platelet activation after ischemic stroke and to investigate whether platelet
      activation and inflammation are correlated with each other. METHODS: We serially
      determined expression of p-selectin (CD62p) and lysosome-associated membrane
      protein (CD63) by platelets using flow cytometry at 10 time points between days 1
      and 90 in patients after ischemic stroke (n=50), in healthy subjects (n=30), and
      in risk factor control subjects (n=20). Furthermore, we correlated leukocyte
      count, C-reactive protein, and fibrinogen levels with platelet activation
      markers. RESULTS: CD62p and CD63 expression was higher on day 1 after stroke than
      in both control groups (P<0.005 for both). CD62p expression rapidly declined,
      whereas CD63 expression remained significantly elevated until day 90. Stroke
      severity and different medication for secondary stroke prevention did not
      influence CD62p or CD63 expression. Platelet activation markers and inflammatory
      parameters were not correlated with each other at any time point after stroke.
      CONCLUSIONS: The initial increase in both CD62p and CD63 expression by platelets
      is followed by a differential regulation of both parameters after stroke. The
      rapid decrease in CD62p expression may be caused by shedding from the cell
      surface. Its persistent elevation makes CD63 a good candidate for studies on
      predictors for stroke recurrence. Our findings suggest that the expression of
      CD62p and CD63 by platelets is regulated independently from inflammatory indexes.

PMID- 12411645
TI  - Bilateral symmetry of human carotid artery atherosclerosis.
AB  - BACKGROUND AND PURPOSE: Atherosclerosis is a principal cause of stroke and
      myocardial infarction. The carotid arteries provide a site at which progression
      of atherosclerosis can be monitored reproducibly and noninvasively. This study
      was conducted to determine the similarity of atherosclerotic plaques in the left
      and right carotid arteries. This question was explored with the use of perfusion
      fixed cadaveric carotid arteries and 2 noninvasive clinical imaging techniques,
      MRI and electron-beam CT. METHODS: Fifty pairs of carotid arteries from cadaveric
      donors (aged 48 to 98 years) were imaged with MRI and electron-beam CT. Thirty
      eight of the pairs met the criteria for rigorous analysis. Carotid artery wall
      volumes were measured from the MRI images, and calcification scores were computed
      from the electron-beam CT images. RESULTS: Total wall volumes of the left
      (972.5+/-241.6 mm3) and right (1016.3+/-275.0 mm3) carotid arteries were
      moderately correlated (concordance correlation coefficient [r(c)]=0.71).
      Calcification scores were highly correlated, with r(c)=0.95 for the Agatston
      scores and r(c)=0.94 for the calcium volume scores. CONCLUSIONS: Total wall
      volume and plaque calcification in the left and right human carotid arteries are
      substantially similar. These results suggest that atherosclerosis of the human
      carotid arteries is generally a bilaterally symmetrical disease. This evidence of
      symmetry suggests that diagnostic information about atherosclerotic plaque in one
      carotid artery can be used to infer information about the composition and volume
      of atherosclerotic plaque in the contralateral artery.

PMID- 12411646
TI  - Impact of infectious burden on progression of carotid atherosclerosis.
AB  - BACKGROUND AND PURPOSE: Recent findings suggest a causative role of infections in
      the pathogenesis of atherosclerosis. The extent of atherosclerosis and the
      prognosis of patients with atherosclerosis seem to be increased by the number of
      infections to which an individual has been exposed. In a prospective study, we
      evaluated the effect of 8 pathogens and the aggregate pathogen burden on the
      progression of carotid atherosclerosis. METHODS: In 504 patients (74.9% men; age,
      62.9+/-10 years), we measured intima-media thickness and prevalence of carotid
      artery stenosis. Follow-up measurements after a mean of 2.5 years were available
      in 427 patients (85%). Blood samples were taken, and IgG or IgA antibodies to
      Chlamydia pneumoniae, Helicobacter pylori, Haemophilus influenzae, Mycoplasma
      pneumoniae, cytomegalovirus, Epstein-Barr virus, and herpes simplex virus types 1
      and 2 were measured. Statistical evaluation was performed with logistic
      regression procedures. RESULTS: Elevated IgA antibodies against C pneumoniae
      (P<0.04) and IgG antibodies against Epstein-Barr virus (P<0.01) and herpes
      simplex virus type 2 (P<0.04) were associated with progression of atherosclerosis
      (increase of intima-media thickness > or =0.1 mm/y or progression of carotid
      stenosis) after adjustment for age, sex, cardiovascular risk factors, highly
      sensitive C-reactive protein, and statin intake. Infectious burden, divided into
      0 to 3, 4 to 5, and 6 to 8 seropositivities, was significantly associated with
      progression of atherosclerosis, with odds ratios of 1.8 (95% confidence interval,
      1.1 to 2.9) for 4 to 5 and 3.8 (95% CI, 1.6 to 8.8) for 6 to 8 compared with 0 to
      3 seropositivities after adjustment. CONCLUSIONS: Our results support the
      hypothesis that the number of infectious pathogens to which an individual has
      been exposed independently contributes to the progression of carotid
      atherosclerosis.

PMID- 12411647
TI  - Leukocyte count is associated with aortic arch plaque thickness.
AB  - BACKGROUND AND PURPOSE: Leukocyte count has been associated with cardiovascular
      and cerebrovascular disease, including carotid plaque thickness, in several
      studies. We hypothesized that white blood cell count is associated with aortic
      arch plaque thickness (AAPT). METHODS: Leukocyte count was measured in randomly
      selected stroke-free community participants undergoing transesophageal
      echocardiography. AAPT was measured for each subject and dichotomized into <4 and
      > or =4 mm (thick plaque). Multivariate linear and logistic regression was used
      to calculate the effect of leukocyte count on AAPT after adjustment for potential
      confounding factors. Mean age of the 145 participants was 68.5+/-8.3 years; 43.5%
      were women; 15.9% were white; 31.7% were black; and 49.0% were Hispanic. RESULTS:
      Mean leukocyte count was 5.88+/-1.76x10(9)/L. Each unit increase in leukocyte
      count was associated with a mean 0.28-mm increase in AAPT (P=0.0036). After
      adjustment for other atherosclerosis risk factors, including age, sex,
      hypertension, diabetes, hyperlipidemia, and smoking, the relationship persisted
      (mean increase in AAPT, 0.24 mm; P=0.0064). Thirty-five participants (24.1%) had
      AAPT > or =4 mm. Mean leukocyte count among those with thick plaque was
      significantly higher than among those with plaque <4 mm (6.54+/-1.60 versus
      5.65+/-1.76x10(9)/L, respectively; P=0.009). Each unit increase in leukocyte
      count was associated with an increased risk of thick plaque (adjusted odds ratio,
      1.38; 95% CI, 1.05 to 1.79). The relationships were similar for men and women and
      for those <70 or > or =70 years of age. CONCLUSIONS: Leukocyte count is
      associated with AAPT and is specifically correlated with AAPT > or =4 mm, a
      degree of thickening associated with increased stroke risk. These findings are
      consistent with current hypotheses regarding the inflammatory or infectious
      etiology of risk of atherosclerosis and stroke.

PMID- 12411648
TI  - Evaluation of proxy responses to the Stroke Impact Scale.
AB  - BACKGROUND AND PURPOSE: The purposes of this study were to compare proxy-patient
      responses on each domain of the Stroke Impact Scale (SIS) and the SIS-16,
      estimate the bias, and evaluate the validity of proxy scores. METHODS: Two
      hundred eighty-seven patient and proxy pairs from the Kansas City Stroke Registry
      participated in the study. All patients were assessed in their home or nursing
      facility between 90 and 120 days after stroke with the use of the modified Rankin
      Scale Motricity Index (strength), Barthel Index (activities of daily living),
      Lawton assessment (instrumental activities of daily living), Folstein Mini-Mental
      State Examination (cognition), and the SIS. Eligible proxies were individuals who
      were aged > or =18 years, had known the patient for at least 1 year, and saw the
      patient at least once each week. All proxy interviews were conducted within 7
      days of (before or after) the patient's interview. RESULTS: Three hundred seventy
      seven patients from the Kansas City Stroke Registry were eligible for the study.
      Seventy-seven patients or proxies refused participation. Thirteen patients of the
      consenting patient-proxy pairs were too aphasic or cognitively impaired to
      complete the interviews and were dropped from the study. Proxies scored patients
      as more severely affected than patients scored themselves on the SIS-16 and in 7
      of 8 domains of the full SIS (5 were statistically significant at alpha=0.05).
      The proxy bias toward overrating the severity of the patient's condition tended
      to increase as the severity of the stroke increased. However, the magnitude of
      the biases between patient and proxy means, as measured by effect size, was small
      (range, -0.1 to 0.4). The strength of the agreement, as measured by intraclass
      correlation coefficients, between proxy and patient ranged from 0.50 to 0.83.
      Agreement was best for the observable physical domains. Both patient and proxy
      scores in all domains were significantly different across Rankin categories.
      Concurrent validity for both patient and proxy correlations with the Folstein
      Mini-Mental State Examination, Barthel Index, Lawton instrumental activities of
      daily living, and Motricity Index was good to excellent (range, 0.37 to 0.78).
      CONCLUSIONS: Proxies provide valid information for assessment of stroke outcomes.
      There are significant differences between patient and proxy reporting on SIS
      domains and the SIS-16. However, the observed biases are small and not clinically
      meaningful.

PMID- 12411649
TI  - Echo contrast-enhanced transcranial ultrasound: frequency of use, diagnostic
      benefit, and validity of results compared with MRA.
AB  - BACKGROUND AND PURPOSE: The present study was undertaken to determine the
      frequency of use of the ultrasound contrast agent (UCA) Levovist in routine
      transcranial ultrasound (TU). Additionally, we evaluated the diagnostic validity
      of contrast-enhanced TU using 3-dimensional time of flight MR angiography.
      METHODS: Indication for the UCA was an insufficient evaluation of the
      intracranial arteries after a combined approach with transcranial color-coded
      Duplex and transcranial Doppler examination. We prospectively analyzed every
      patient referred for TU over 6 months. Additionally, over a 3-month period, TU
      results were compared with 3-dimensional time-of-flight MR angiography. RESULTS:
      Indication for use of UCA was met in 61 of 687 patients (8.8%). After UCA
      application, a diagnostic result was achieved in 75% of cases during
      transtemporal and in 81% during transforaminal insonation. The sensitivity and
      specificity of TU in the diagnosis of intracranial stenosis were 83% and 82%,
      respectively. CONCLUSIONS: Use of UCA was necessary in 8.8% of the patients. A
      diagnostic benefit was achieved in 75% to 80% of cases. Contrast-enhanced TU
      demonstrated a high sensitivity and specificity in the diagnosis of intracranial
      stenosis.

PMID- 12411650
TI  - Does acupuncture improve motor recovery after stroke? A meta-analysis of
      randomized controlled trials.
AB  - BACKGROUND AND PURPOSE: Acupuncture may be a promising treatment for poststroke
      paralysis. We conducted a meta-analysis, assessing the efficacy of acupuncture
      with and without stroke rehabilitation. METHODS: We identified randomized trials
      comparing acupuncture with no acupuncture within 6 months of stroke by searching
      MEDLINE, CINAHL, EMBASE, Cochrane Library, and Chinese medical literature
      databases. Two reviewers independently extracted data on study characteristics,
      patient characteristics, and impairment and disability outcomes. The outcome
      measures were internationally recognized or nationally approved. The fixed- and
      random-effects models were used to combine effect size and odds ratio across
      studies. RESULTS: Fourteen trials with 1213 patients met all the inclusion
      criteria. For the comparison of acupuncture with no acupuncture in addition to
      stroke rehabilitation, the pooled random-effects estimates of the change in motor
      impairment and disability were 0.06 (95% CI, -0.12 to 0.24) and 0.49 (95% CI,
      0.03 to 0.96), respectively, with heterogeneity in disability measures (P=0.05,
      chi(2) test). For the comparison of real with sham acupuncture, the pooled random
      effects estimate of the change in disability was 0.07 (95% CI, -0.34 to 0.48).
      For the comparison of acupuncture with no acupuncture without stroke
      rehabilitation, the pooled random-effects estimate of the change in motor
      impairment was 0.46 (95% CI, -0.20 to 1.12), and the pooled random-effects odds
      ratio for disability was 12.5 (95% CI, 4.3 to 36.2), with no statistically
      significant heterogeneity (P=0.97 and P=0.12, respectively, chi(2) test), but the
      study quality was poor. CONCLUSIONS: This meta-analysis suggests that with stroke
      rehabilitation, acupuncture has no additional effect on motor recovery but has a
      small positive effect on disability, which may be due to a true placebo effect
      and varied study quality. The efficacy of acupuncture without stroke
      rehabilitation remains uncertain, mainly because of the poor quality of such
      studies.

PMID- 12411651
TI  - Endovascular treatment of ruptured intracranial aneurysms in patients aged 65
      years and older: follow-up of 52 patients after 1 year.
AB  - BACKGROUND AND PURPOSE: We sought to describe the clinical outcome and results
      obtained in the endovascular therapy of ruptured cerebral aneurysms in the
      elderly over an 8-year period. We compared endovascular therapy results in
      patients aged > or =65 and <65 years. METHODS: During 1993-1999, 52 patients aged
      65 to 85 years (mean age, 71.5+/-4.7 years) were embolized with the use of
      Guglielmi detachable coils (group I). During the same period, 143 patients aged
      <65 years (mean age, 47+/-11 years) with ruptured cerebral aneurysm were treated
      with the same technique (group II). A clinical assessment was made on admission
      with the Hunt and Hess (HH) classification and again in the 12th month with the
      Glasgow Outcome Scale (GOS), with arteriographic control in months 3 and 12.
      RESULTS: In group I, clinical grades on admission were as follows: HH 1, 9.5%; HH
      2, 33%; HH 3, 21%; HH 4, 34.5%; HH 5, 2%. Outcome was favorable in 48% of
      patients (GOS 1 or 2); the mortality rate was 23%. No rebleeding was observed.
      Patients presenting lesions > or =10 mm had an unfavorable outcome in >77% of
      cases. Thromboembolic complications were present in 13% of cases. In group II,
      clinical grades on admission were as follows: HH 1, 14.5%; HH 2, 47%; HH 3, 11%;
      HH 4, 24%; HH 5, 3.5%. Favorable outcome (GOS 1 or 2) was observed in 77% of
      cases, with 14% mortality. Complications due to the endovascular procedure were
      present in 4.2% of cases. Patients with HH grades 1 or 2 on admission showed a
      positive outcome (GOS 1 or 2) in 77% of cases in group I and in 88.5% of cases in
      group II. Mortality was 9% in the first subgroup compared with 2.8% in the
      second. Patients who had a high clinical grade on admission (HH 4 or 5) showed a
      favorable outcome (GOS 1 or 2) in 16% of cases in group I compared with 41% in
      group II. CONCLUSIONS: Endovascular treatment of ruptured intracranial aneurysms
      in patients aged > or =65 years appears to be effective against rebleeding and
      represents an alternative to surgery. However, perioperative thromboembolic
      complications are more frequent in the elderly population.

PMID- 12411652
TI  - Trunk control as an early predictor of comprehensive activities of daily living
      function in stroke patients.
AB  - BACKGROUND AND PURPOSE: Prediction of activities of daily living (ADL) functions
      at an early stage after a stroke is critical because it enables clinicians to set
      treatment programs and goals. The objective of this study was to assess the
      relationship between trunk control at an early stage and comprehensive ADL
      function (as assessed by combining basic ADL and instrumental ADL [IADL]) in
      patients at 6 months after stroke. METHODS: A total of 169 stroke patients
      participated in this prospective study. Trunk control was measured with the use
      of the trunk control items of the Postural Assessment Scale for Stroke Patients
      (PASS-TC). In addition to the PASS-TC score, age, sex, type of stroke, side of
      hemiparesis, urinary incontinence, limb paresis (measured by the Fugl-Meyer motor
      test), balance (measured by the Fugl-Meyer balance test), and basic ADL (measured
      by the Barthel Index) were also selected as predictor variables. These variables
      were assessed at 14 days after stroke or earlier. The Barthel Index and Frenchay
      Activities Index (measuring IADL) were administered at 6 months after stroke. The
      sum of the standardized Barthel Index and standardized Frenchay Activities Index
      scores was used to assess comprehensive ADL function. RESULTS: Multivariable
      stepwise linear regression analysis showed that PASS-TC score, age, Fugl-Meyer
      motor test score, and Barthel Index score (listed by the order of forward
      selection) were the strongest predictors of comprehensive ADL function. These
      results were internally validated with the use of the bootstrap resampling
      technique. The PASS-TC score alone accounted for 45% of the variance in
      predicting comprehensive ADL function. Results also indicated that the PASS-TC
      score had slightly more power in predicting comprehensive ADL function than
      either the Fugl-Meyer motor test score or Barthel Index score. CONCLUSIONS: The
      findings of this study provide strong evidence of the predictive value of trunk
      control on comprehensive ADL function in stroke patients. The results imply that
      early assessment and management of trunk control after stroke should be
      emphasized.

PMID- 12411653
TI  - Natural history of perihematomal edema in patients with hyperacute spontaneous
      intracerebral hemorrhage.
AB  - BACKGROUND AND PURPOSE: The natural history of perihematomal edema in human
      hyperacute spontaneous intracerebral hemorrhage (ICH) has not been well
      described. METHODS: This study was a secondary analysis of a previously reported
      prospective, population-based study of hematoma growth in 142 patients with
      spontaneous ICH. Patients were first imaged within 3 hours of onset, then 1 and
      20 hours later. We excluded patients with anticoagulant use (n=7), underlying
      aneurysm/vascular malformation (n=9), trauma (n=1), incomplete data (n=20),
      infratentorial ICH (n=17), and no consent (n=2), leaving an overall study
      population of 86 patients. From this overall group we further excluded patients
      with intraventricular extension (n=38), subsequent surgery (n=5), or death (n=2)
      before 20-hour postbaseline CT. This second, "restricted" analysis group of 41
      patients was relatively devoid of clinical or radiological variables likely to
      confound edema measurement. Absolute and relative edema volumes (edema volume
      divided by hematoma volume) were descriptively summarized. Correlations between
      baseline edema volumes and relevant clinical and radiological variables were then
      performed. RESULTS: Overall, median absolute edema volume increased from 6.93 to
      14.4 cm(3) during the first 24 hours after ICH, and median relative edema volume
      increased from 0.47 to 0.81. In the restricted group, median absolute edema
      volume was 7.4 cm(3) at baseline and 11.0 cm(3) at 24 hours after ICH, and median
      relative edema volume increased from 0.55 to 0.81. Baseline relative edema volume
      was significantly negatively correlated with subsequent change in relative edema
      volume from baseline to 20-hour CT (r=0.57, P=0.0002) but was not significantly
      correlated with other clinical and radiological variables, including hematoma
      volume or change in hematoma volume. CONCLUSIONS: Perihematomal edema volume
      increases by approximately 75% during the first 24 hours after hyperacute
      spontaneous ICH. Patients with the least amounts of baseline relative edema
      volume were most likely to develop significant additional amounts of edema during
      the first 24 hours after spontaneous ICH.

PMID- 12411654
TI  - Relative edema volume is a predictor of outcome in patients with hyperacute
      spontaneous intracerebral hemorrhage.
AB  - BACKGROUND AND PURPOSE: Little is known about the relationship between
      perihematomal edema in spontaneous intracerebral hemorrhage (ICH) and outcome.
      The purpose of this study was to determine whether absolute or relative edema
      volume (edema volume divided by hematoma volume) predicts mortality or functional
      outcome in patients with hyperacute spontaneous ICH. We hypothesized that
      increasing baseline relative edema volume is associated with greater probability
      of poor functional outcome. METHODS: This was a secondary analysis of a
      prospective, population-based study of hematoma growth in 142 patients with
      spontaneous ICH. Patients were imaged within 3 hours of onset, then 1 and 20
      hours later. Our primary analysis excluded patients with anticoagulant use (n=7),
      underlying aneurysm/vascular malformation (n=9), trauma (n=1), incomplete data
      (n=20), infratentorial ICH (n=17), intraventricular extension (n=38), and no
      consent (n=2). We analyzed whether associations existed between baseline edema
      volumes or other clinical/radiological variables and either 12-week modified
      Rankin Scale score >2 or 30-day mortality. Secondary analyses used 20-hour CT
      scan data, all patients with supratentorial ICH, and 12-week Barthel Index score
      <85. RESULTS: By multivariable logistic regression analysis, baseline relative
      edema was the strongest independent predictor of functional outcome and was
      associated with lesser odds of poor 3-month functional outcome (odds ratio, 0.09
      per 1.0-unit [100%] increase; 95% CI, 0.01 to 0.64; P=0.016) and 12-week Barthel
      Index score <85 (odds ratio, 0.12; 95% CI, 0.02 to 0.91; P=0.039) but did not
      predict mortality. Secondary analyses confirmed this result. Absolute edema
      volume predicted neither mortality nor functional outcome. CONCLUSIONS: Relative
      edema is strongly predictive of functional outcome in patients with hyperacute
      supratentorial spontaneous ICH without intraventricular extension.

PMID- 12411655
TI  - Somatosensory gating and recovery from stroke involving the thalamus.
AB  - BACKGROUND AND PURPOSE: In the undamaged brain, sensory input to the cortex is
      intricately controlled via sensory gating mechanisms. Given the role of
      corticothalamic pathways in this control, it was hypothesized that in patients
      recovering from thalamic stroke there would be evidence of disrupted sensory
      gating and that efficient control of cortical sensory inputs would emerge during
      recovery. METHODS: Four patients were tested serially after stroke from 1 to 24
      weeks after injury. Perceptual thresholds, somatosensory evoked potential
      amplitudes, and functional MRI activations under specific somatosensory
      stimulation conditions were measured. RESULTS: All patients demonstrated
      comparable results, revealing disrupted threshold detection to vibrotactile
      stimuli in the presence of a concurrent competing, contralateral input. In
      contrast, threshold detection was comparable between the affected and unaffected
      sides when there were no competing stimuli. This compromised capacity to inhibit
      competing sensory inputs was paralleled by a reduction in the measured activation
      of cortical representation in the stroke-affected hemisphere (functional MRI and
      somatosensory evoked potential) during bilateral stimulation. After recovery,
      perceptual detection improvements during bilateral stimulation were paralleled by
      enhancements of primary somatosensory cortical activation in the stroke-affected
      hemisphere. CONCLUSIONS: These results provide insight into potential mechanisms
      that contribute to sensory gating and suggest that the ability to control sensory
      input through effective gating mechanisms, in addition to primary somatosensory
      representation, may be important for poststroke sensory recovery.

PMID- 12411656
TI  - Control of hypertension and risk of stroke recurrence.
AB  - BACKGROUND AND PURPOSE: We investigated whether low blood pressure increases the
      risk of stroke recurrence. METHODS: A cohort of 662 patients, obtaining care at
      the 8 acute care hospitals serving the Lehigh Valley in Pennsylvania, was
      enrolled within 1 month of an initial stroke and was followed twice annually for
      up to 4 years. Cox proportional hazard models were developed to examine the
      relationship between risk of recurrent stroke and blood pressure, controlling for
      other significant risk factors. Our analyses investigated both lowest follow-up
      and average follow-up blood pressures as predictors of stroke recurrence.
      RESULTS: There were 52 recurrent strokes among the 535 patients (mean age, 71
      years; 51% men) with follow-up blood pressure. The risk ratio for stroke
      recurrence for diastolic blood pressure > or =80 mm Hg compared with <80 mm Hg
      was 2.4 (95% CI, 1.38 to 4.27) and for systolic blood pressure > or =140 mm Hg
      compared with <140 mm Hg was also 2.4 (95% CI, 1.39 to 4.15). For isolated
      systolic blood pressure (>140/<90 mm Hg), the risk ratio was 2.2 (95% CI, 1.23 to
      3.79) relative to <140/<90 mm Hg. Using the Cox model, we also showed that
      patients who had at least 1 measured diastolic blood pressure <80 mm Hg during
      follow-up had a reduced risk of stroke recurrence compared with those with
      diastolic blood pressures 80 to 90 mm Hg (0.4 versus 1.0; 95% CI, 0.21 to 0.88)
      even after controlling for the possible confounding factors of hypertension and
      atrial fibrillation on ECG. Myocardial infarction on ECG, history of transient
      ischemic attack, and diabetes mellitus were not significant predictors of
      increased risk of recurrent stroke. CONCLUSIONS: Our results imply that "lower is
      better" for blood pressure control as a goal in reducing stroke recurrence risk.

PMID- 12411657
TI  - Long-term durability of carotid endarterectomy for symptomatic stenosis and risk
      factors for late postoperative stroke.
AB  - BACKGROUND AND PURPOSE: Carotid endarterectomy (CEA) reduces the risk of stroke
      ipsilateral to recently symptomatic severe carotid stenosis. Other techniques
      such as percutaneous transluminal angioplasty with stenting are currently being
      compared with CEA. Thus far, case series and several small, randomized,
      controlled trials of CEA versus percutaneous transluminal angioplasty (with and
      without stenting) have focused primarily on the 30-day procedural risks of stroke
      and death. However, long-term durability is also important. To determine the long
      term risk of stroke after CEA and to identify risk factors, we studied patients
      in the European Carotid Study Trial (ECST), the largest published cohort with
      long-term follow-up by physicians after CEA. METHODS: Risks of ipsilateral
      carotid territory ischemic stroke were calculated by Kaplan-Meier analysis
      starting on the 30th day after CEA in 1728 patients who underwent trial surgery.
      Risk factors were determined by Cox regression. For comparison, we also
      determined the "background" risk of stroke on medical treatment in the ECST in
      the territory of 558 previously asymptomatic contralateral carotid arteries with
      <30% angiographic stenosis (ECST method) at randomization. RESULTS: The risks of
      disabling ipsilateral ischemic stroke and any ipsilateral ischemic stroke were
      constant after CEA, reaching 4.4% [95% confidence interval (CI), 3.0 to 5.8] and
      9.7% (95% CI, 7.6 to 11.7), respectively, by 10 years. The equivalent ischemic
      stroke risks distal to contralateral <30% asymptomatic carotid stenoses were 1.9%
      (95% CI, 0.8 to 3.2) and 4.5% (95% CI, 1.5 to 7.4). Presentation with cerebral
      symptoms, diabetes, elevated systolic blood pressure, smoking, male sex,
      increasing age, and a lesser severity of preoperative stenosis were associated
      with an increased risk of late stroke after CEA, but plaque morphology and patch
      grafting were not. CONCLUSIONS: Although the risk of late ipsilateral ischemic
      stroke after CEA for symptomatic stenosis is approximately double the background
      risk in the territory of <30% asymptomatic stenosis, it is still only
      approximately 1% per year and remains low for at least 10 years after CEA. This
      is the standard against which alternative treatments should be judged. Several
      risk factors may be useful in identifying patients at particularly high risk of
      late postoperative stroke.

PMID- 12411658
TI  - Prevalence of atrial fibrillation and antithrombotic prophylaxis in emergency
      department patients.
AB  - BACKGROUND AND PURPOSE: The emergency department (ED), as the point of first
      medical contact for many complaints referable to atrial fibrillation (AF) and a
      common source of primary care, occupies a unique position to identify AF patients
      at risk of stroke. This study evaluates that potential by determining the
      prevalence of AF in an ED population and assessing antithrombotic use in those
      patients with recurrent AF. METHODS: This was a multicenter, retrospective, cross
      sectional study of consecutive records of ED patients with AF identified by ECG
      between January and June 1998. American Heart Association and modified Stroke
      Prevention in Atrial Fibrillation criteria established high-risk patients and
      contraindications to anticoagulation, respectively. RESULTS: We identified 866
      records with ECG-proven AF in 78 787 patient visits for an estimated prevalence
      of 1.10% (95% CI, 1.03 to 1.17). We found that 556 records had a prior history of
      AF; of these, 221 (40%) used warfarin alone, 155 (28%) had antiplatelet therapy
      alone, 28 (5%) used both, and 152 (27%) had no antithrombotic therapy identified.
      Sixty-eight patients (12%; 95% CI, 0.10 to 0.15) were warfarin eligible and
      without antithrombotic therapy. An additional 64 (12%; 95% CI, 0.09 to 0.14) had
      antiplatelet therapy alone. In warfarin-eligible patients, no differences were
      identified between the anticoagulated and nonanticoagulated groups on the basis
      of age, sex, or race. Of patients on warfarin with a measured international
      normalized ratio, 61% (95% CI, 0.55 to 0.67) were outside the AHA-recommended
      range of 2.0 to 3.0. CONCLUSIONS: AF is a common finding in an ED population.
      Many are warfarin eligible and untreated or undertreated. Methods to increase
      anticoagulant use in this at-risk population warrant further investigation.

PMID- 12411659
TI  - Prediction of length of stay of first-ever ischemic stroke.
AB  - BACKGROUND AND PURPOSE: Accurate information about hospital resource utilization
      is necessary for management of healthcare service. The purpose of this study was
      to determine the demographic and clinical predictors of length of hospital stay
      (LOS) of acute care hospitalization for first-ever ischemic stroke patients.
      METHODS: A group of 330 patients who suffered from first-ever ischemic stroke and
      were consecutively admitted to a medical center in southern Taiwan were followed
      prospectively. Because our intention was to identify the major predictors of LOS
      from the information available at admission, we evaluated only those factors that
      could be assessed at the time of admission. Univariate analysis and multiple
      regression analysis were used to identify the main predictors of LOS. RESULTS:
      The median LOS was 7 days (mean, 11 days; range, 1 to 122 days). Among the
      prespecified demographic and clinical characteristics, National Institutes of
      Health Stroke Scale (NIHSS) score at admission, the quadratic term of the initial
      NIHSS score, modified Barthel Index score at admission, small-vessel occlusion
      stroke, sex, and smoking were the main explanatory factors for LOS. In
      particular, for each 1-point increase in the total score of NIHSS, LOS increased
      approximately 1 day for patients with mild or moderate (score 0 to 15 points)
      neurological impairments, while LOS decreased approximately 1 day for patients
      with severe (score >15 points) neurological impairments. CONCLUSIONS: The
      severity of stroke, as rated by the total score on NIHSS, is an important factor
      that influences LOS after acute stroke hospitalization.

PMID- 12411660
TI  - Sildenafil (Viagra) induces neurogenesis and promotes functional recovery after
      stroke in rats.
AB  - BACKGROUND AND PURPOSE: We tested the hypothesis that sildenafil, a
      phosphodiesterase type 5 (PDE5) inhibitor, promotes functional recovery and
      neurogenesis after stroke. METHODS: Male Wistar rats were subjected to embolic
      middle cerebral artery occlusion. Sildenafil (Viagra) was administered orally for
      7 consecutive days starting 2 or 24 hours after stroke onset at doses of 2 or 5
      mg/kg per day. Ischemic rats administered the same volume of tap water were used
      as a control group. Functional outcome tests (foot-fault, adhesive removal) were
      performed. Rats were killed 28 days after stroke for analysis of infarct volume
      and newly generated cells within the subventricular zone and the dentate gyrus.
      Brain cGMP levels, expression of PDE5, and localized cerebral blood flow were
      measured in additional rats. RESULTS: Treatment with sildenafil significantly
      (P<0.05) enhanced neurological recovery in all tests performed. There was no
      significant difference of infarct volume among the experimental groups. Treatment
      with sildenafil significantly (P<0.05) increased numbers of bromodeoxyuridine
      immunoreactive cells in the subventricular zone and the dentate gyrus and numbers
      of immature neurons, as indicated by betaIII-tubulin (TuJ1) immunoreactivity in
      the ipsilateral subventricular zone and striatum. The cortical levels of cGMP
      significantly increased after administration of sildenafil, and PDE5 mRNA was
      present in both nonischemic and ischemic brain. CONCLUSIONS: Sildenafil increases
      brain levels of cGMP, evokes neurogenesis, and reduces neurological deficits when
      given to rats 2 or 24 hours after stroke. These data suggest that this drug that
      is presently in the clinic for sexual dysfunction may have a role in promoting
      recovery from stroke.

PMID- 12411661
TI  - Prevention of experimental cerebral vasospasm by intracranial delivery of a
      nitric oxide donor from a controlled-release polymer: toxicity and efficacy
      studies in rabbits and rats.
AB  - BACKGROUND AND PURPOSE: A reduction in the local availability of nitric oxide
      (NO) may play a role in the etiology of chronic cerebral vasospasm after
      subarachnoid hemorrhage (SAH). We investigated the toxicity and efficacy of a
      locally delivered NO donor from a controlled-release polymer in preventing
      experimental cerebral vasospasm in rats and rabbits, respectively. METHODS:
      Diethylenetriamine/NO (DETA/NO) was incorporated into controlled release ethylene
      vinyl acetate (EVAc) polymers. Twenty-eight rats were used in a dose-escalation
      toxicity study to establish a maximally tolerated dose of DETA/NO-EVAc polymer.
      In the efficacy experiment, 20 rabbits were assigned to 4 experimental groups
      (n=5 per group): sham operation; SAH only; SAH+empty EVAc polymer; and
      SAH+DETA/NO-EVAc polymer. Treatment was initiated 30 minutes after blood
      deposition. Basilar artery lumen patency was assessed 72 hours after hemorrhage
      to evaluate the efficacy of DETA/NO in preventing cerebral vasospasm. RESULTS: In
      the toxicity study, a dose of 3.4 mg/kg was identified as the LD(20) (dose with
      20% mortality during the study period) of this DETA/NO formulation. Brain
      histology revealed hemorrhage and ischemic changes at the implantation site
      associated with high concentrations of DETA/NO. In the efficacy study, treatment
      with DETA/NO-EVAc polymer resulted in a significant decrease in basilar artery
      vasospasm compared with no treatment (93.0+/-4.9% versus 71.4+/-11.9%; P=0.035)
      or compared with treatment with blank EVAc polymer (93.0+/-4.9% versus 73.2+/
      6.4%; P=0.003). CONCLUSIONS: Local delivery of DETA/NO prevents vasospasm in the
      rabbit basilar artery. Local delivery of DETA/NO via polymers is a safe and
      effective strategy for preventing cerebral vasospasm after SAH in this model.

PMID- 12411662
TI  - Vascular NAD(P)H oxidase triggers delayed cerebral vasospasm after subarachnoid
      hemorrhage in rats.
AB  - BACKGROUND AND PURPOSE: To clarify the role of vascular NAD(P)H oxidase in the
      pathogenesis of cerebral vasospasm after subarachnoid hemorrhage (SAH), both the
      activity and/or activation mechanisms of NAD(P)H oxidase in the cerebral
      vasculature and the effect of oxidase inhibition on SAH-induced cerebral
      vasospasm were assessed. METHODS: The changes in the luminal perimeter of the
      middle cerebral artery were measured histologically after SAH was induced
      according to a 2-hemorrhage model in rats. The NAD(P)H oxidase activity in the
      cerebral vasculature was measured with a lucigenin assay at different time
      intervals from 12 hours to 14 days after injection of autologous blood into
      cisterna magna. The membrane translocation of p47phox and the protein expression
      of membrane subunits (gp91phox and p22phox) of NAD(P)H oxidase were analyzed
      using Western blot analysis. RESULTS: The luminal perimeter of the middle
      cerebral artery started to decrease on day 1 and peaked on day 5 after a second
      injection of blood, and these changes were significantly ameliorated by treatment
      with an NAD(P)H oxidase inhibitor, diphenyleneiodonium. At 24 hours after the
      second injection of blood, both vascular production of superoxide anion and
      NAD(P)H oxidase activity were markedly increased with enhanced membrane
      translocation of p47phox, but by 48 hours the enzyme activity had regained normal
      values. However, no significant changes in the expression of gp91phox and p22phox
      were observed throughout the experiments. CONCLUSIONS: These findings suggest
      that the activation of NAD(P)H oxidase through enhanced assembly of the oxidase
      components in the early stages of SAH might contribute to the delayed cerebral
      vasospasm in SAH rats.

PMID- 12411663
TI  - Mechanism of extracellular K+-induced local and conducted responses in cerebral
      penetrating arterioles.
AB  - BACKGROUND AND PURPOSE: Extracellular concentration of potassium ion ([K+]o) may
      have a significant influence on the cerebral circulation in health and disease.
      Mechanisms of [K+]o-induced conducted vasomotor responses in cerebral arterioles,
      possibly linking microvascular regulation to neuronal activity, have not been
      examined. METHODS: We analyzed vascular responses to small increases of [K+]o (up
      to 5 mmol/L) in isolated, cannulated, and pressurized rat cerebral arterioles
      (36.5+/-1.4 micro m). [K+]o was elevated globally through extraluminal
      application or locally through micropipette, while arteriolar diameter was
      measured online. RESULTS: Elevation of [K+]o (5 mmol/L) produced dilation that
      was inhibited by ouabain but not BaCl2. Locally applied [K+]o (3 to 5 mmol/L)
      produced a biphasic response (initial constriction followed by dilation), both of
      which were conducted to the remote site (distance 1142+/-68 microm). Endothelial
      impairment inhibited conducted but not local biphasic responses. Extraluminal
      ouabain attenuated local and conducted secondary dilation but not initial
      constriction. The local biphasic response was unaffected by extraluminal or
      intraluminal BaCl2. Extraluminal but not intraluminal BaCl2 impaired both
      conducted constriction and dilation. CONCLUSIONS: In rat penetrating arteriole,
      (1) [K+]o (3 to 5 mmol/L) strongly regulates arteriolar tone and causes conducted
      vasomotor responses; (2) local responses to elevated [K+]o are endothelium
      independent but conducted responses are dependent on an intact endothelium; (3)
      smooth muscle Na+-K+-ATPase activation is the generator of conducted dilation;
      and (4) smooth muscle inward rectifier potassium channels sustain conduction. Our
      findings suggest that potassium-induced conducted vasomotor responses may link
      local neuronal activity to microvascular regulation, which may be attenuated in
      pathological conditions.

PMID- 12411664
TI  - Comparison of tibolone and conjugated equine estrogens effects on carotid artery
      atherosclerosis of postmenopausal monkeys.
AB  - BACKGROUND AND PURPOSE: Tibolone is a tissue-specific compound that has favorable
      effects on bone and menopausal symptoms without stimulating endometrium or
      breast, but lowers concentrations of plasma high-density lipoprotein (HDL)
      cholesterol (HDLC). This study was designed to determine whether the HDL lowering
      with tibolone exacerbated common or internal carotid artery atherosclerosis and
      to evaluate tibolone treatment relative to conjugated equine estrogens (CEE)
      alone or in combination with medroxyprogesterone acetate (MPA). METHODS: Carotid
      artery atherosclerosis was compared in groups of surgically postmenopausal
      cynomolgus monkeys treated with CEE, CEE+MPA, or either of 2 doses of tibolone
      versus untreated monkeys. RESULTS: Despite a 30% to 52% lowering of HDLC with
      tibolone, there was no significant effect on carotid artery atherosclerosis. CEE
      and CEE+MPA, however, inhibited carotid artery atherosclerosis by approximately
      60%. CONCLUSIONS: In surgically postmenopausal cynomolgus monkeys, CEE and
      CEE+MPA inhibited common and internal carotid artery atherosclerosis. Despite the
      potentially adverse effects of tibolone on HDLC, tibolone did not exacerbate
      atherosclerosis.

PMID- 12411665
TI  - Transient focal ischemia increases endothelial nitric oxide synthase in cerebral
      blood vessels.
AB  - BACKGROUND AND PURPOSE: Production of NO by endothelial NO synthase (eNOS) plays
      a protective role in cerebral ischemia. We studied the effects of transient focal
      ischemia on eNOS expression. METHODS: Wistar rats (n=72) underwent reversible
      filament occlusion of the right middle cerebral artery for 75 minutes. After 6,
      24, 72, or 168 hours of reperfusion, brains were removed and coronal sections cut
      for eNOS immunohistochemistry, eNOS-alkaline phosphatase costaining, and
      hematoxylin-eosin staining. Samples for eNOS immunoblots were taken from
      corresponding striatum and overlying parietal cortex bilaterally. RESULTS: eNOS
      protein occurred in virtually all blood vessels and was consistently increased in
      microvessels in the ischemic striatum after 24 to 168 hours of reperfusion but
      not at 6 hours. eNOS upregulation in the parietal cortex was only present in
      animals with evidence of cortical infarcts documented on adjacent HE-stained
      sections. Costaining of endogenous alkaline phosphatase and eNOS demonstrated
      eNOS expression in all segments of cerebral microvessels. Quantitative analysis
      of eNOS immunostaining and immunoblots showed no attenuated increase in animals
      that were treated with indomethacin (5 mg/kg IP), NS398 (20 mg/kg IP), or L
      arginine-methyl ester (10 mg/kg IP). In contrast to eNOS, levels of brain NOS did
      not increase after ischemia. CONCLUSION: eNOS protein is upregulated in pre- and
      postcapillary microvessels and upregulation appears slower after transient
      compared with permanent ischemia. Cyclooxygenase and NOS products do not play a
      major role in postischemic eNOS induction.

PMID- 12411666
TI  - Blood-brain barrier disruption and matrix metalloproteinase-9 expression during
      reperfusion injury: mechanical versus embolic focal ischemia in spontaneously
      hypertensive rats.
AB  - BACKGROUND AND PURPOSE: Most experimental models of cerebral ischemia use
      mechanical methods of occlusion and reperfusion. However, differences between
      mechanical reperfusion versus clot thrombolysis may influence reperfusion injury
      profiles. In this study we compared blood flow recovery, blood-brain barrier
      (BBB) permeability, and matrix metalloproteinase-9 (MMP-9) expression in cortex
      after mechanical versus thrombolytic reperfusion in rat focal ischemia. METHODS:
      Male spontaneously hypertensive rats were used. Mechanical ischemia/reperfusion
      was achieved with the use of an intraluminal filament to occlude the middle
      cerebral artery for 2 hours. Thrombolytic reperfusion was achieved by
      administering tissue plasminogen activator at 2 hours after embolic focal
      ischemia. Regional cortical blood flow was monitored by laser-Doppler flowmetry.
      BBB permeability in cortex was measured by Evans blue dye leakage. Cortical MMP-9
      levels were assessed with zymography and immunohistochemistry. RESULTS: Blood
      flow recovery during mechanical reperfusion was complete in both central and
      peripheral areas of ischemic cortex. However, after thrombolysis, reperfusion was
      incomplete, with moderate recovery in the periphery only. BBB permeability was
      mainly increased in the central regions of the ischemic cortex after mechanical
      reperfusion but was increased in both central and peripheral areas after
      thrombolysis. Overall, MMP-9 levels were higher after embolic versus mechanical
      ischemia/reperfusion, even though ischemic injury was similar in both models at
      24 hours. CONCLUSIONS: There are significant differences in the profiles of blood
      flow recovery, BBB leakage, and MMP-9 upregulation in mechanical versus
      thrombolytic reperfusion after focal ischemia.

PMID- 12411667
TI  - Characterization of incident stroke signs and symptoms: findings from the
      atherosclerosis risk in communities study.
AB  - BACKGROUND AND PURPOSE: Although patterns of stroke occurrence and mortality have
      been well studied, few epidemiological data are available regarding the clinical
      characteristics of stroke events. METHODS: We evaluated hospitalized stroke
      events reported in the Atherosclerosis Risk in Communities (ARIC) Study to
      describe the clinical characteristics of incident stroke. Confirmed stroke cases
      (n=474) were evaluated for stroke symptoms (headache, vertigo, gait disturbance,
      convulsions) and stroke signs (hemianopia, diplopia, speech deficits, paresis,
      paresthesia/sensory deficits) and their univariate associations with race, sex,
      and stroke subtype. RESULTS: Over 9.2 years of follow-up, 402 (85%) ischemic and
      72 (15%) hemorrhagic strokes occurred. Frequency of stroke symptoms (95% CIs)
      were as follows: headache (27.4%; 23.4% to 31.4%), gait disturbance (10.8%; 7.9%
      to 13.6%), convulsions (4.4%; 2.6% to 6.3%), and vertigo (2.1%; 0.8% to 3.4%).
      Speech deficits occurred in 24.0% (20.2% to 27.9%), hemianopia in 14.6% (11.4% to
      17.7%), and diplopia in 5.5% (3.4% to 7.5%) of cases. Most cases involved paresis
      (81.6%; 78.1% to 85.1%), while fewer cases experienced sensory deficits (44.5%;
      40.0% to 49.0%). Blacks were more likely than whites to experience paresis (85.4%
      versus 78.2%; P=0.044). Men were more likely than women to experience a gait
      disturbance (14.4% versus 6.7%; P=0.007). Persons with hemorrhagic strokes had a
      higher proportion of headaches (55.6% versus 22.4%; P=0.001) and convulsions
      (11.1% versus 3.2%; P=0.003) than those with ischemic events, while speech and
      sensory deficits were more common in ischemic strokes (26.1% versus 12.5%,
      P=0.013, and 49.0% versus 19.4%, P=0.001, respectively). CONCLUSIONS: We present
      epidemiological data concerning the clinical characteristics of incident stroke
      in a population-based cohort. Although minor differences by race, sex, and stroke
      subtype were observed, data from additional follow-up are required to confirm
      observed variations.

PMID- 12411668
TI  - Atrial fibrillation, stroke, and acute antithrombotic therapy: analysis of
      randomized clinical trials.
AB  - BACKGROUND: Strokes in patients with atrial fibrillation (AF) are typically
      larger, are associated with higher early mortality, and occur in older patients
      versus strokes in patients with sinus rhythm. Until recently, the value of
      antithrombotic therapies for acute stroke management has been based on empiric
      evidence. SUMMARY OF REVIEW: We present a critical review of 3 randomized
      clinical trials testing aspirin, heparin/heparinoid, or both involving 5029
      patients with AF and acute stroke. Early recurrent ischemic stroke occurred in
      about 5% of patients during the 2 to 4 weeks after initial stroke. Data conflict
      about whether early use of heparin/heparinoid reduced early recurrent ischemic
      stroke but are consistent regarding its lack of overall benefit on long-term
      functional outcome. Modest benefits for reduction of early recurrent stroke and
      functional outcome were associated with aspirin use, based largely on subgroup
      analysis from a single, large, unblinded trial. CONCLUSIONS: No benefit of
      heparin has been demonstrated for acute stroke patients with AF; whether selected
      subgroups would respond differently remains to be proven. Aspirin followed by
      early initiation of warfarin for long-term secondary prevention is reasonable
      antithrombotic management.

PMID- 12411669
TI  - Spatial neglect: is rehabilitation effective?

PMID- 12411670
TI  - Origin and significance of Archean quartzose rocks at Akilia, Greenland.

PMID- 12411671
TI  - Human subjects in weapons research.

PMID- 12411673
TI  - Astronomy. Iron deficiency reveals nearly pristine star.

PMID- 12411672
TI  - Amphibian declines. Conflict brewing over herbicide's link to frog deformities.

PMID- 12411674
TI  - Fisheries science. Scientists recommend ban on North Sea cod.

PMID- 12411675
TI  - Human genome. HapMap launched with pledges of $100 million.

PMID- 12411676
TI  - Women's health. More questions about hormone replacement.

PMID- 12411677
TI  - Anthropology. Going head-to-head over Boas's data.

PMID- 12411678
TI  - Pfiesteria debate. Is sugary toxin the smoking gun?

PMID- 12411679
TI  - Evolutionary biology. Placentas may nourish complexity studies.

PMID- 12411680
TI  - International cooperation. NATO ordered to cut science program.

PMID- 12411681
TI  - DNA sequencing. Venter's next goal: 1000 human genomes.

PMID- 12411682
TI  - Structural genomics. Tapping DNA for structures produces a trickle.

PMID- 12411683
TI  - Structural genomics. Big biology without the big commotion.

PMID- 12411685
TI  - Nuclear trafficking. Crime and (puny) punishment.

PMID- 12411684
TI  - Japan. Postdocs get primer on how to survive abroad.

PMID- 12411686
TI  - Evolutionary biology. Evo-devo enthusiasts get down to details.

PMID- 12411687
TI  - Society of Vertebrate Paleontology meeting. A bonanza of bones.

PMID- 12411688
TI  - Portraits of science. Proof, amazement, and the unexpected.

PMID- 12411689
TI  - Ecology. On the crest of a population wave.

PMID- 12411690
TI  - Environment. Fishing for microbes.

PMID- 12411691
TI  - Materials science. A synchrotron look at steel.

PMID- 12411692
TI  - Materials science. Molecular "ghosts".

PMID- 12411693
TI  - Immunology. Versatile defensins.

PMID- 12411694
TI  - Auroral and space physics. The heavens in a pile of sand.

PMID- 12411695
TI  - Advanced technology paths to global climate stability: energy for a greenhouse
      planet.
AB  - Stabilizing the carbon dioxide-induced component of climate change is an energy
      problem. Establishment of a course toward such stabilization will require the
      development within the coming decades of primary energy sources that do not emit
      carbon dioxide to the atmosphere, in addition to efforts to reduce end-use energy
      demand. Mid-century primary power requirements that are free of carbon dioxide
      emissions could be several times what we now derive from fossil fuels
      (approximately 10(13) watts), even with improvements in energy efficiency. Here
      we survey possible future energy sources, evaluated for their capability to
      supply massive amounts of carbon emission-free energy and for their potential for
      large-scale commercialization. Possible candidates for primary energy sources
      include terrestrial solar and wind energy, solar power satellites, biomass,
      nuclear fission, nuclear fusion, fission-fusion hybrids, and fossil fuels from
      which carbon has been sequestered. Non-primary power technologies that could
      contribute to climate stabilization include efficiency improvements, hydrogen
      production, storage and transport, superconducting global electric grids, and
      geoengineering. All of these approaches currently have severe deficiencies that
      limit their ability to stabilize global climate. We conclude that a broad range
      of intensive research and development is urgently needed to produce technological
      options that can allow both climate stabilization and economic development.

PMID- 12411696
TI  - Estimating the size of the world's threatened flora.

PMID- 12411697
TI  - Cell dynamics during somite boundary formation revealed by time-lapse analysis.
AB  - We follow somite segmentation in living chick embryos and find that the shaping
      process is not a simple periodic slicing of tissue blocks but a much more
      carefully choreographed separation in which the somite pulls apart from the
      segmental plate. Cells move across the presumptive somite boundary and violate
      gene expression boundaries thought to correlate with the site of the somite
      boundary. Similarly, cells do not appear to be preassigned to a given somite as
      they leave the node. The results offer a detailed picture of somite shaping and
      provide a spatiotemporal framework for linking gene expression with cell
      movements.

PMID- 12411698
TI  - Guest transport in a nonporous organic solid via dynamic van der Waals
      cooperativity.
AB  - A well-known organic host compound undergoes single-crystal-to-single-crystal
      phase transitions upon guest uptake and release. Despite a lack of porosity of
      the material, guest transport through the solid occurs readily until a
      thermodynamically stable structure is achieved. In order to actively facilitate
      this dynamic process, the host molecules undergo significant positional and/or
      orientational rearrangement. This transformation of the host lattice is triggered
      by weak van der Waals interactions between the molecular components. In order for
      the material to maintain its macroscopic integrity, extensive cooperativity must
      exist between the molecules throughout the crystal, such that rearrangement can
      occur in a well-orchestrated fashion. We demonstrate here that even weak
      dispersive forces can exert a profound influence over solid-state dynamics.

PMID- 12411699
TI  - Grain nucleation and growth during phase transformations.
AB  - The mechanical properties of polycrystalline materials are largely determined by
      the kinetics of the phase transformations during the production process. Progress
      in x-ray diffraction instrumentation at synchrotron sources has created an
      opportunity to study the transformation kinetics at the level of individual
      grains. Our measurements show that the activation energy for grain nucleation is
      at least two orders of magnitude smaller than that predicted by thermodynamic
      models. The observed growth curves of the newly formed grains confirm the
      parabolic growth model but also show three fundamentally different types of
      growth. Insight into the grain nucleation and growth mechanisms during phase
      transformations contributes to the development of materials with optimal
      mechanical properties.

PMID- 12411700
TI  - Colloidosomes: selectively permeable capsules composed of colloidal particles.
AB  - We present an approach to fabricate solid capsules with precise control of size,
      permeability, mechanical strength, and compatibility. The capsules are fabricated
      by the self-assembly of colloidal particles onto the interface of emulsion
      droplets. After the particles are locked together to form elastic shells, the
      emulsion droplets are transferred to a fresh continuous-phase fluid that is the
      same as that inside the droplets. The resultant structures, which we call
      "colloidosomes," are hollow, elastic shells whose permeability and elasticity can
      be precisely controlled. The generality and robustness of these structures and
      their potential for cellular immunoisolation are demonstrated by the use of a
      variety of solvents, particles, and contents.

PMID- 12411701
TI  - Stronger constraints on the anthropogenic indirect aerosol effect.
AB  - The anthropogenic indirect aerosol effects of modifying cloud albedo and cloud
      lifetime cannot be deduced from observations alone but require a modeling
      component. Here we validate a climate model, with and without indirect aerosol
      effects, by using satellite observations. The model agrees better with
      observations when both indirect aerosol effects are included. However, the
      simulated clouds are more susceptible to aerosols than the observed clouds from
      the POLDER satellite, thus overestimating the indirect aerosol effect. By taking
      the difference in susceptibilities into account, the global mean total
      anthropogenic aerosol effect is reduced from -1.4 to -0.85 watts per square
      meter.

PMID- 12411702
TI  - Climate change and latitudinal patterns of intertidal thermal stress.
AB  - The interaction of climate and the timing of low tides along the West Coast of
      the United States creates a complex mosaic of thermal environments, in which
      northern sites can be more thermally stressful than southern sites. Thus, climate
      change may not lead to a poleward shift in the distribution of intertidal
      organisms, as has been proposed, but instead will likely cause localized
      extinctions at a series of "hot spots." Patterns of exposure to extreme climatic
      conditions are temporally variable, and tidal predictions suggest that in the
      next 3 to 5 years "hot spots" are likely to appear at several northern sites.

PMID- 12411703
TI  - Independent origins and rapid evolution of the placenta in the fish genus
      Poeciliopsis.
AB  - The evolution of complex organs is a source of controversy because they require
      the contributions of many adaptations to function properly. We argue that
      placentas are complex, that they have evolved multiple times in Poeciliopsis, and
      that there are closely related sister taxa that have either no placentas or
      intermediate stages in the evolution of a placenta. Furthermore, placentas can
      evolve in 750,000 years or less, on the same time scale as suggested by
      theoretical calculations for the evolution of complex eyes. Independent origins
      of such complexity, accompanied by sister taxa that either lack or have
      intermediate stages in the evolution of the trait, present an opportunity to
      study the evolution of novelty and complexity from a comparative, evolutionary
      perspective.

PMID- 12411704
TI  - Waves of larch budmoth outbreaks in the European alps.
AB  - Spatially extended population models predict complex spatiotemporal patterns,
      such as spiral waves and spatial chaos, as a result of the reaction-diffusion
      dynamics that arise from trophic interactions. However, examples of such patterns
      in ecological systems are scarce. We develop a quantitative technique to
      demonstrate the existence of waves in Central European larch budmoth (Zeiraphera
      diniana Gn.) outbreaks. We show that these waves travel toward the northeast-east
      at 210 kilometers per year. A theoretical model involving a moth-enemy
      interaction predicts directional waves, but only if dispersal is directionally
      biased or habitat productivity varies across the landscape. Our study confirms
      that nonlinear ecological interactions can lead to complex spatial dynamics at a
      regional scale.

PMID- 12411705
TI  - Microbial dehalorespiration with 1,1,1-trichloroethane.
AB  - 1,1,1-Trichloroethane (TCA) is a ubiquitous environmental pollutant because of
      its widespread use as an industrial solvent, its improper disposal, and its
      substantial emission to the atmosphere. We report the isolation of an anaerobic
      bacterium, strain TCA1, that reductively dechlorinates TCA to 1,1-dichloroethane
      and chloroethane. Strain TCA1 required H2 as an electron donor and TCA as an
      electron acceptor for growth, indicating that dechlorination is a respiratory
      process. Phylogenetic analysis indicated that strain TCA1 is related to gram
      positive bacteria with low DNA G+C content and that its closest relative is
      Dehalobacter restrictus, an obligate H2-oxidizing, chloroethene-respiring
      bacterium.

PMID- 12411706
TI  - Toll-like receptor 4-dependent activation of dendritic cells by beta-defensin 2.
AB  - beta-Defensins are small antimicrobial peptides of the innate immune system
      produced in response to microbial infection of mucosal tissue and skin. We
      demonstrate that murine beta-defensin 2 (mDF2beta) acts directly on immature
      dendritic cells as an endogenous ligand for Toll-like receptor 4 (TLR-4),
      inducing up-regulation of costimulatory molecules and dendritic cell maturation.
      These events, in turn, trigger robust, type 1 polarized adaptive immune responses
      in vivo, suggesting that mDF2beta may play an important role in
      immunosurveillance against pathogens and, possibly, self antigens or tumor
      antigens.

PMID- 12411707
TI  - Cytoprotective role of Ca2+- activated K+ channels in the cardiac inner
      mitochondrial membrane.
AB  - Ion channels on the mitochondrial inner membrane influence cell function in
      specific ways that can be detrimental or beneficial to cell survival. At least
      one type of potassium (K+) channel, the mitochondrial adenosine triphosphate
      sensitive K+ channel (mitoKATP), is an important effector of protection against
      necrotic and apoptotic cell injury after ischemia. Here another channel with
      properties similar to the surface membrane calcium-activated K+ channel was found
      on the mitochondrial inner membrane (mitoKCa) of guinea pig ventricular cells.
      MitoKCa significantly contributed to mitochondrial K+ uptake of the myocyte, and
      an opener of mitoKCa protected hearts against infarction.

PMID- 12411708
TI  - Hijacking of host cell IKK signalosomes by the transforming parasite Theileria.
AB  - Parasites have evolved a plethora of mechanisms to ensure their propagation and
      evade antagonistic host responses. The intracellular protozoan parasite Theileria
      is the only eukaryote known to induce uncontrolled host cell proliferation.
      Survival of Theileria-transformed leukocytes depends strictly on constitutive
      nuclear factor kappa B (NF-kappaB) activity. We found that this was mediated by
      recruitment of the multisubunit IkappaB kinase (IKK) into large, activated foci
      on the parasite surface. IKK signalosome assembly was specific for the
      transforming schizont stage of the parasite and was down-regulated upon
      differentiation into the nontransforming merozoite stage. Our findings provide
      insights into IKK activation and how pathogens subvert host-cell signaling
      pathways.

PMID- 12411709
TI  - RNA polymerase II transcription in murine cells lacking the TATA binding protein.
AB  - Inactivation of the murine TATA binding protein (TBP) gene by homologous
      recombination leads to growth arrest and apoptosis at the embryonic blastocyst
      stage. However, after loss of TBP, RNA polymerase II (pol II) remains in a
      transcriptionally active phosphorylation state, and in situ run-on experiments
      showed high levels of pol II transcription comparable to those of wild-type
      cells. In contrast, pol I and pol III transcription was arrested. Our results
      show a differential dependency of the RNA polymerases on TBP and provide evidence
      for TBP-independent pol II transcriptional mechanisms that allow reinitiation and
      maintenance of gene transcription in vivo.

PMID- 12411712
TI  - The effect of intrathecal baclofen on muscle co-contraction in children with
      spasticity of cerebral origin.
AB  - AIM: Investigation of the effect of intrathecal baclofen administration on the
      time course of electrical patterns of muscle activation in patients with
      spasticity due to upper motor neuron syndrome. METHODS: Six children with
      clinical signs of upper motor neuron syndrome resulting from an acquired cerebral
      hypoxic injury were tested. Simultaneous multichannel acquisition of surface EMG
      activity from flexor/extensor muscle groups of the upper and lower limbs was
      recorded. Investigated muscle group pairs included biceps/triceps brachii, wrist
      flexors/extensors, rectus/biceps femoris and tibialis anterioris/gastrocnemius.
      Time-frequency analysis of EMG activity at rest and while eliciting a stretch
      reflex was performed. The non-linear cross-correlation coefficient and time lag
      estimation were computed between paired channel groups both for baseline and post
      intrathecal baclofen injection conditions for epochs consisting of 2 s prior to
      and 2 s after voluntary contraction. The effect of baclofen was assessed 3 h
      following single-bolus intrathecal injections of 25 or 50 microg during the
      baclofen trial and 6 months after baclofen pump implantation. RESULTS: In the
      baseline condition, the stretch reflex resulted in a synchronous increase in
      spectral EMG power in both the agonist and the antagonist muscles. The mean
      correlation coefficient between agonist and antagonist muscles was 0.948 (SD =
      0.034), and the mean time lag was 4.64 ms (SD = 1.84 ms). After intrathecal
      administration of baclofen, a dramatic decrease in the correlation coefficient
      between agonist and antagonists (mean value = 0.342) during voluntary contraction
      was observed. This corresponded to a significant reduction of tone and spasticity
      in all four limbs, and reduction of the Ashworth score by 2 points on average.
      CONCLUSION: After intrathecal baclofen administration, we observed a significant
      decrease in the co-contraction pattern typically associated with upper motor
      neuron spasticity. This was evident clinically and was quantitatively expressed
      by the significantly decreased degree of coupling in EMG activity of
      agonist/antagonist muscles. Although a relatively small sample was investigated
      in this study, we were able to demonstrate the efficacy of this procedure in
      restoring selective activation of agonists during voluntary contraction. This is
      one of the prerequisites of an improvement of motor function in patients with
      spasticity.

PMID- 12411713
TI  - The effectiveness of Hering's nerve stimulation in controlling penicillin-induced
      seizures in the rat is dependent on the amygdala.
AB  - OBJECTIVE: This study tests the hypothesis that the ability of Hering's nerve
      stimulation (HNS) to blunt seizure activity is dependent on the availability of
      dopamine in the amygdala. METHODS: In 10 rats, Hering's nerve (HN) on the right
      side was isolated and placed on an electrode and penicillin was locally placed on
      each rat's left frontoparietal region to induce seizures. After the initiation of
      seizures, HN was stimulated. After the recurrence of seizure activity, the left
      basolateral amygdala was injected with 1.0 microl of normal saline, dopamine,
      haloperidol or 1% lidocaine in sequential tests. HN was stimulated after each
      injection and the latency and amplitude of the seizure activity were assessed.
      RESULTS: Focal cortical penicillin induced seizures that resulted in tonic-clonic
      movement of the limbs and face that lasted 35-45 min. Tonic-clonic movements of
      the limbs and face of similar latency and amplitude were induced by repeated
      reapplication of penicillin in untreated rats. HNS decreased seizure activity,
      but infusion of haloperidol or lidocaine into the basolateral amygdala blocked
      this antiseizure effect of HNS. In contrast, infusion of saline or dopamine had
      no effect on the ability of HNS to blunt seizure activity. None of the amygdala
      injections altered the latency or amplitude of seizure activity. CONCLUSION:
      These results demonstrate that the ability of HNS to blunt seizure activity in
      the rat is dependent on an intact dopamine system in the basolateral amygdala.
      These data will hopefully be useful in furthering our understanding of the
      circuitry that allows peripheral nerve stimulation to alter seizure activity.

PMID- 12411714
TI  - Cortical representation of Hering's nerve: a possible anatomical pathway for
      seizure cessation following electrical stimulation.
AB  - OBJECTIVE: We recently found that Hering's nerve stimulation (HNS) effectively
      blunts seizure activity. This study characterizes the cortical areas that are
      activated by HNS. METHODS: Hering's nerve (HN) was stimulated in 3 dogs and 6
      pigs, and then the brains of the animals were removed. The insular and mesial
      temporal cortices were removed and evaluated for increased neuronal activity by
      examining Fos-like activity. RESULTS: In both the dogs and pigs, Fos activity was
      elevated in the anterior insular and mesial temporal cortices. Increased cortical
      activity was not noted in adjacent areas such as the frontal cortex. CONCLUSION:
      This study demonstrates that the mesial temporal and anterior insular cortices
      are selectively activated by stimulation of HN, thus suggesting cortical loci at
      which HNS might blunt seizure activity.

PMID- 12411715
TI  - Split cord malformation in two sisters.
AB  - Split cord malformations (SCMs) are uncommon congenital spinal anomalies and are
      seen mostly in females. SCMs in siblings are extremely rare. We report two
      sisters with SCM. These 10- and 8-year-old girls were the first and second
      children, respectively, of nonconsanguineous parents. Both sisters had a
      hypertrichosis and pes cavus deformity. The first child had a type I SCM and the
      second a type II SCM. They had additional spinal lesions, with tethering of the
      spinal cord. They were operated on and showed an uneventful postoperative course.
      All reported siblings with SCM have been female. The present data are not
      sufficient to account for the sex predilection. Therefore, further data and
      knowledge are needed.

PMID- 12411716
TI  - Infantile subdural hematomas due to traffic accidents.
AB  - The most common cause of subdural hematomas (SDH) in infants is shaken-baby
      syndrome (SBS). The pathogenesis and natural history of infantile SDH (ISDH) are
      poorly documented, because in SBS, the date of shaking is usually imprecise and
      the assault is often repeated. Victims of traffic accidents (TA) form a study
      group close to experimental conditions, because the trauma is unique, witnessed
      and dated. We reviewed 18 cases of SDH due to TA in infants under the age of 24
      months. Our goal was to investigate the clinical and radiological data and
      natural history of SDH. A subdural collection was found on the day of trauma in 7
      cases. In 3 of these, the collection was already hypodense. The perifalcine
      region was the most frequent site of intracranial bleeding. Blood hyperdensity
      was always found on CT scans performed during the first week, and turned
      hypodense on about the 9th day. Three patients had retinal hemorrhage, of a type
      distinct from that found in SBS. Drainage of the SDH was required in 14 cases
      after a mean delay of 13.5 +/- 5.8 days after trauma. Four patients also required
      a ventriculoperitoneal shunt because of associated hydrocephalus. Our data
      suggest that impaired CSF drainage plays a large role in the pathogenesis of
      ISDH. The fact that a single and recent trauma can result in mixed-density ISDH
      can be of great importance in forensic medicine.

PMID- 12411717
TI  - Unique presentation of pleomorphic xanthoastrocytoma as a lytic skull lesion in
      an eight-year-old girl.
AB  - Pleomorphic xanthoastrocytomas (PXAs) are rare primary central nervous system
      neoplasms of childhood and early adulthood. While PXAs are intimately associated
      with the leptomeninges, there has never been a description of an extradural
      extracranial manifestation of PXA until now. We describe a case of PXA where the
      patient presented with a calvarial lesion. We also review the differential
      diagnoses of lytic skull lesions in addition to PXA.

PMID- 12411718
TI  - Perimesencephalic nonaneurysmal subarachnoid hemorrhage in the pediatric
      population: case report and review of the literature.
AB  - In approximately 15% of children with atraumatic subarachnoid hemorrhage (SAH),
      the cause of the hemorrhage cannot be determined despite detailed imaging
      studies. Perimesencephalic nonaneurysmal subarachnoid hemorrhage (PNSH) is well
      recognized as a distinct type of SAH in the adult population and may account for
      up to two thirds of these SAHs of unknown cause. PNSH in the pediatric
      population, however, is not well recognized. In this report, we confirm the
      existence of PNSH in the pediatric population by describing a 4-year-old boy who
      presented with acute SAH in the perimesencephalic cisterns and subsequently had
      two negative angiograms with a benign clinical course. Recognition of PNSH in the
      pediatric population is important, especially in view of its benign nature.

PMID- 12411719
TI  - Latex allergy and sensitization in children with spina bifida.
AB  - BACKGROUND: The purpose of this study was to investigate the prevalence rate of
      latex sensitization and latex allergy among children with spina bifida and to
      evaluate risk factors for natural rubber latex hypersensitivity. METHODS: A total
      of 34 children between 2.5 and 17 years of age participated in the study.
      Participants completed a questionnaire and underwent skin prick tests with latex,
      common aeroallergens and food allergens as well as measurements of specific IgE
      to latex and food allergens (RAST CAP). RESULTS: The prevalence of latex
      sensitization and latex allergy was estimated to be 32.4 and 18.8%, respectively.
      The most common reported clinical manifestation of latex allergy was urticaria.
      Three out of six symptomatic patients reported anaphylactic reactions.
      CONCLUSION: We found that major risk factors for latex sensitization were atopy
      and a history of numerous operations.

PMID- 12411720
TI  - Prenatal sonographic diagnosis of lateral ventricle choroid plexus papilloma in
      an in vitro fertilization-induced pregnancy.
AB  - This is a report of a prenatal sonographic diagnosis of a lateral ventricle
      choroid plexus papilloma in an in vitro fertilization (IVF)-induced pregnancy of
      a 40-year-old woman. The baby was delivered at 35 weeks of gestation and surgery
      was performed 5 days later with a good outcome. Several cases of malignancies
      associated with IVF are reported in the literature. To the best of the authors'
      knowledge, this is the first report of a prenatal diagnosis of choroid plexus
      papilloma in an IVF-induced pregnancy. The authors also review other cases of
      choroid plexus papilloma diagnosed prenatally by ultrasound. The theoretical
      association between IVF and neoplasia is also considered.

PMID- 12411721
TI  - Primary intracerebral malignant fibrous histiocytoma in a child.
AB  - We report herein a rare case of pediatric intracerebral malignant fibrous
      histiocytoma (MFH). A 2-year-old boy gradually developed mild left hemiparesis
      and became somnolent. Magnetic resonance imaging upon admission revealed a well
      enhanced mass lesion in the right frontotemporal operculum. Subtotal removal of
      the tumor was successfully performed using a right transsulcal and transcortical
      approach. The tumor developed as an extraaxial mass with brain adhesion to the
      arterial wall of the branch of the middle cerebral artery rather than to cerebral
      tissue. Pathological examination confirmed the presence of inflammatory-type MFH.
      Pediatric cases of intracerebral MFH are rare, and the possible origin of the
      tumor is discussed based on clinicopathological findings.

PMID- 12411722
TI  - Two anatomical specimens after hemispherectomy.

PMID- 12411723
TI  - Tuberous sclerosis.

PMID- 12411724
TI  - Hemangioma of the transverse sinus.

PMID- 12411725
TI  - The renin-angiotensin system and progression of renal disease: from hemodynamics
      to cell biology.
AB  - The renal community is faced with an ever increasing number of patients reaching
      end-stage renal failure. Clinical studies have provided clear evidence that
      angiotensin-converting enzyme (ACE) inhibitors, and probably also AT1 receptor
      antagonists, at least in patients suffering from type 2 diabetes, slow disease
      progression to end-stage renal failure. This protective effect of drugs
      interfering with the renin-angiotensin system (RAS) are in part independent of
      reduction in systemic blood pressure, but involve normalization of glomerular
      hyperperfusion and hyperfiltration, restoration of altered glomerular barrier
      function, and reduction of stimulated tubular fluid reabsorption. Angiotensin II
      (ANG II) has emerged in the last decade as a multifunctional cytokine exhibiting
      many non-hemodynamic properties such as acting as a growth factor and
      profibrogenic cytokine, and even having proinflammatory properties. This review
      tries to bridge the classical hemodynamic actions of ANG II in the kidney with
      the more recently characterized effects of this vasopeptide. Finally, clinical
      implications are suggested based on data from clinical studies. A thorough
      understanding of the RAS is important to recognize the potential of
      nephroprotective strategies through inhibition of its components.

PMID- 12411726
TI  - Dietary citrate treatment of polycystic kidney disease in rats.
AB  - Progression of autosomal-dominant polycystic kidney disease (ADPKD) in the
      heterozygous male Han:SPRD rat is dramatically slowed by ingestion of potassium
      or sodium citrate. This study examined the efficacy of delayed therapy with
      sodium citrate, the effect of sodium citrate therapy on kidney cortex levels of
      transforming growth factor-beta (TGF-beta), and the response to calcium citrate
      ingestion. Rats were provided with citrate salts in their food, and renal
      clearance, blood pressure, blood chemistry, and survival determinations were
      made. Sodium citrate therapy was most effective when started at age 1 month, and
      delay of therapy until age 3 months produced no benefit. Kidney cortex TGF-beta
      levels were elevated in 3- and 8-month-old rats with ADPKD, but not in 6-week-old
      rats. Sodium citrate treatment, started at age 1 month, lowered TGF-beta levels
      to normal in 3-month-old rats, but this is probably not the primary mechanism of
      citrate's beneficial effect. Calcium citrate had only a modest effect in
      preserving glomerular filtration rate. Effective treatment of ADPKD in this rat
      model requires early administration of a readily absorbed alkalinizing citrate
      salt. Existing data on ADPKD patients on vegetarian diets or with kidney stones
      should be studied in light of these findings.

PMID- 12411727
TI  - Effect of sertraline hydrochloride on cardiac autonomic dysfunction in patients
      with hemodialysis-induced hypotension.
AB  - BACKGROUND/AIMS: It was previously shown that sertraline hydrochloride treatment
      improved hemodynamic parameters of patients with dialysis induced hypotension
      (DIH). The aim of this study was to examine the effect of sertraline on the
      autonomic functions of patients with DIH. METHODS: Ten patients with DIH, 10
      hemodialysis patients without DIH and 10 healthy control subjects were included
      into the study. All of the patients were treated with sertraline 50 mg per day
      for 4 weeks. Pre-treatment and post-treatment heart rate variability (HRV) in
      supine and tilt position was evaluated. In order to evaluate the autonomic
      response to tilt position, gap values were calculated by subtracting the HRV in
      supine position from the HRV in tilt position. RESULTS: Analysis of the HRV
      response to tilt, demonstrated a paradoxical reduction in the indices of
      sympathetic modulation and sympathovagal balance in the patients with DIH while
      there was an increase in normalized powers of low frequency components (LFNU) and
      low frequency to high frequency components ratio (LFP/HFP) in the patients
      without DIH and control group. The number of therapeutic interventions for
      restoration of DIH decreased significantly in the sertraline period (p < 0.001).
      The gap values of the patients with DIH in LFNU (sympathetic modulation) (p <
      0.05) and LFP/HFP (sympathovagal balance) increased in the sertraline period (p <
      0.01). The decrease in gap value of normalized powers of high frequency
      components (parasympathetic modulation) was pronounced in the sertraline period
      in the patients with DIH (p < 0.05). CONCLUSION: The preventive effect of
      sertraline on DIH might be related to the improvement of regulation of autonomic
      response to hypovolemia.

PMID- 12411728
TI  - Reliability of the El Escorial diagnostic criteria for amyotrophic lateral
      sclerosis.
AB  - BACKGROUND: The El Escorial diagnostic criteria are the most commonly used in
      clinical studies and therapeutic trials in patients with amyotrophic lateral
      sclerosis (ALS). The accuracy of the El Escorial criteria was tested in clinical
      practice, but the reliability is unknown when the diagnosis of ALS must be
      assessed on the basis of medical records. OBJECTIVE: To assess the reliability of
      the El Escorial criteria for the diagnosis of ALS in different settings. DESIGN
      AND METHODS: Semistructured forms were used to include the main diagnostic
      information on 20 patients with definite (n = 6), probable (n = 6), possible (n =
      6), and suspected ALS (n = 2) and 19 patients with clinical conditions considered
      in the differential diagnosis. Agreement was tested by comparing the diagnosis
      made by the attending physician (the 'gold standard') with that of 4 raters with
      different backgrounds: a teaching neurologist with research and practical
      experience in the field of motor neuron disorders, a neurologist with specific
      interest in motor neuron disorders and neurophysiological background, a
      neurophysiologist, and a general neurologist with only occasional ALS patients.
      Sources of disagreement were discussed and the agreement was tested further on
      the medical records of 98 additional cases taken from an ongoing ALS registry.
      Eight additional cases (ALS: 4; other conditions: 4) were examined directly by
      the 4 raters. RESULTS: The interrater agreement on the medical records was poor
      (overall kappa 0.05-0.29). When the differential diagnosis was made between ALS
      (all diagnostic levels) and other conditions, interrater agreement was at best
      modest, with moderate variations when raters were compared in pairs (kappa 0.03
      0.58) and when each rater was compared with the physician (kappa 0.27-0.51).
      Agreement was higher after direct examination of the patients (kappa 0.33-1) and
      increased significantly on the medical records after training (overall kappa 0.52
      0.79). However, concordance was low (overall kappa 0.08-0.36), even after
      training, at the lowest diagnostic level (definite to suspected ALS vs. other
      conditions). CONCLUSIONS: The El Escorial criteria are a poor diagnostic
      indicator when patients' records are examined. Although medical education
      significantly improves the reliability of the criteria, concordance is still
      modest when the diagnosis includes suspected ALS.

PMID- 12411729
TI  - Quantitative vibration perception thresholds in normal and diabetic chinese:
      influence of age, height and body mass index.
AB  - In this study, we established normality data of vibration perception thresholds
      (VPT) in a Chinese population. Over 1,400 healthy subjects were recruited to
      create age-related centile charts of VPT after pretesting for reliability.
      Another 273 diabetic (DM) patients were recruited to assess the impact of age,
      height and body mass index (BMI) on VPT values in DM and non-DM subjects. The
      present study is the first one which reports normality data of VPT from a large
      Chinese population. The VPT values were higher in male and female DM patients
      than in the non-DM counterparts. Age significantly contributed to the variance of
      VPT in both DM and non-DM subjects. Height was positively associated with VPT in
      men, so was BMI in non-DM subjects with much smaller magnitudes of effect than
      for age.

PMID- 12411730
TI  - Different aetiology of familial low-grade and high-grade glioma? A nationwide
      cohort study of familial glioma.
AB  - An increased risk for first-degree relatives (FDR) of glioma patients has
      previously been observed. The novel objective of this study was to investigate
      differences in familial risk among FDR of low-grade glioma (LGG) and high-grade
      glioma (HGG) cases, respectively. Two cohorts were constructed, one from 15,321
      FDR of LGG cases and the other from 26,635 FDR of HGG cases calculating
      standardised incidence ratios (SIR). The risk for LGG among FDR of LGG cases was
      significantly increased, SIR 3.65 (95% CI 2.31-5.47). The risk was even higher in
      the cohort of siblings, SIR 7.00 (95% CI 3.35-12.87), and especially in the
      younger siblings (<40 years), SIR 9.01 (95% CI 4.31-16.57). When calculating the
      risk for HGG in the LGG cohort and the risk for HGG in the HGG cohort, there was
      a generally twofold increased risk, but no trends of increased risk in relatives
      of younger probands. Two different methods calculating familial risk displayed
      similar results. LGG families apparently have features manifesting a distinct
      pedigree pattern with sibpairs affected at a young age. These families could
      provide new insights into the aetiology of glioma.

PMID- 12411731
TI  - Vasovagal syncope in emergency room patients: analysis of a metropolitan area
      registry.
AB  - The aim of this study was to assess the epidemiology of syncope in unselected
      patients referred to an emergency room and eventually admitted to the clinical
      wards to perform a complete work-up, and to analyze the costs of hospitalization.
      The clinical charts of all patients referred for all causes to the emergency
      rooms of three hospitals in the Florence area during the year 2000 and of all
      patients admitted from the emergency rooms to the clinical wards with a diagnosis
      of lone-related (vasovagal) or disease-related syncope were revised. A total of
      1,290 (3.36%) cases of syncope out of 38,330 presentations were registered; among
      these, 702 cases (1.83% of all presentations, 54% of all syncopes) were directly
      discharged, and 443 cases (1.14% of all presentations, 34% of all syncopes) were
      hospitalized. The remaining 149 cases (12% of all syncopes) refused admission.
      Following admission, 500 patients were discharged with the diagnosis of syncope:
      115 lone-related (23%) and 385 disease-related syncopes (77%). A cost-benefit
      analysis of the hospitalized patients showed that admitting patients with lone
      syncope leads to an economical loss to the hospital.

PMID- 12411732
TI  - Female preponderance of Parkinson's disease in Japan.
AB  - A male preponderance of Parkinson's disease (PD) has been reported in European
      countries and the USA. To verify this issue in Japanese patients with PD, we
      examined the age- and gender-specific prevalence of PD in Yamagata Prefecture
      (population 1,244,040), Japan. The prevalence of PD was 61.3/100,000 men and
      91.0/100,000 women, showing that women were significantly more affected by PD
      than men (p < 0.001). Contrary to the findings in Europe and the USA, the results
      indicate a female preponderance of PD among the Japanese population.

PMID- 12411733
TI  - Descriptive epidemiology of head injury in Romagna and Trentino. Comparison
      between two geographically different Italian regions.
AB  - We studied the occurrence of head injury in two different Italian regions:
      Romagna and Trentino. Both geographical areas attract large numbers of seasonal
      tourists. The study was carried out over 1 year (January 1, 1998 to December 31,
      1998), prospectively in Romagna and retrospectively in Trentino because of their
      different head injury management protocols. The study was based on all admissions
      to hospital extracted by medical staff from the case records, and all cases were
      identified by the ICD-9 codes (ranges: 800.0-800.3, 801.0-801.3, 803.0-803.3,
      850, 851.0-851.1, 852.0-852.1, 853.0-853.1, 854.0-854.1). The annual incidence of
      hospitalization for head injury was 314/100,000, 297 for Romagna and 332 for
      Trentino. The causes of head trauma and the type of injuries were similar to
      those reported in the international literature, and so were the characteristics
      of the population at risk. Romagna recorded a higher incidence of head injury
      among the elderly, probably due to the widespread use of bicycles without safety
      helmets. In Romagna, where neurosurgery departments exist, hospital mortality was
      low (8/100,000/year). Based on similar international literature findings,
      different prevention measures are suggested to reduce the occurrence and severity
      of head injury.

PMID- 12411734
TI  - The curious negative (protective?) associations between Parkinson's disease and
      certain behavioral risk factors.

PMID- 12411735
TI  - Elimination of childhood diseases: possible influence on the incidence of
      multiple sclerosis soon detectable.

PMID- 12411736
TI  - Role of gamma-aminobutyric acid neurons in the release of gonadotropin-releasing
      hormone in cultured rat embryonic olfactory placodes.
AB  - We recently established a primary cell culture system of gonadotropin-releasing
      hormone (GnRH) neurons originating from olfactory placodes of rat embryos at
      E13.5 and showed that cultured olfactory placodes released GnRH into the medium
      in a pulsatile fashion with an interpulse interval of about 30 min. Since the
      reported presence of gamma-aminobutyric acid (GABA) neurons in the culture of rat
      olfactory placode raises questions as to the role played by these GABA neurons in
      the GnRH pulse generation, we immunostained GnRH neurons and GABA neurons in this
      culture system to examine the interrelationship between both types of neurons,
      and determined the effects of GABA and the GABA(A) receptor antagonist,
      bicuculline, on GnRH release. The immunohistochemical study showed that GnRH
      neurons received fiber terminals from GABA neurons. GnRH neurons in culture
      released GnRH into the medium at intervals of 30-40 min, confirming our previous
      study. Treatment with 20 microM GABA prolonged the interpulse interval and
      decreased the amplitude of GnRH pulses. Bicuculline administered at 20 microM did
      not affect either parameter, but 50 microM bicuculline elevated the mean GnRH
      level, although it did not affect either the interpulse interval or the amplitude
      of GnRH pulses. In addition, 50 microM bicuculline increased the mean trough
      levels of GnRH pulses, although 20 microM bicuculline did not. In light of the in
      vivo studies performed previously, we suggest that the GnRH pulse generator,
      which probably consists of a small population of GnRH neurons in the culture,
      does not involve GABA neurons to generate the pulsatile GnRH release, although it
      may be responsive to the inhibitory transmitter GABA. We also found that there
      may be another population of GnRH neurons in the culture whose activity is
      strongly suppressed by the tonic inhibition of GABA neurons. Although it is
      speculative, these latter GnRH neurons may be responsible for the surge of GnRH
      release.

PMID- 12411737
TI  - Tamoxifen but not other selective estrogen receptor modulators antagonizes
      estrogen actions on luteinizing hormone secretion while inducing gonadotropin
      releasing hormone self-priming in the rat.
AB  - Selective estrogen receptor modulators (SERMs) are compounds which may function
      as agonists or antagonists depending upon the target tissue. This study compares
      the actions of different SERMs on luteinizing hormone (LH) secretion, and on
      gonadotropin-releasing hormone (GnRH) self-priming in the rat. To do this, 4-day
      cyclic rats were injected twice, on day 2 (metestrus) and day 3 of the estrous
      cycle, with one of the following SERMs: 0.25 mg ICI 182,780, 3 mg tamoxifen (TX),
      LY139481-HCl or LY117018-HCl, or 0.5 mg RU58668. Control rats were given
      subcutaneous injections of 0.2 ml oil. On the morning of day 4 (proestrus in
      controls), rats from each group were either injected intraperitoneally with
      pentobarbital (40 mg/kg) for in vivo study or decapitated and their pituitaries
      collected for incubation (in vitro study). Additionally, pituitaries taken on
      each day of the estrous cycle from control rats as well as on day 4 from SERM
      treated rats were processed for immunohistochemical determination of the estrogen
      receptor-alpha (ERalpha) gonadotrope. The plasma concentration or accumulation of
      LH in the medium was determined after 1 h (basal secretion). Thereafter, an
      intravenous bolus of GnRH (50 ng/0.5 ml/100 g BW) or 10(-8) M GnRH was injected
      or added to the medium, respectively. After 1 h of GnRH exposure, blood or medium
      were taken, and another challenge of GnRH was made. At the end of the 3rd h of
      the experiment, blood or medium samples were taken again and the LH plasma
      concentration or accumulation in the medium were determined. All SERM treatments
      reduced uterus weight and decreased basal and stimulated LH secretion. Also, on
      day 4, rats treated with any SERM other than TX showed vaginal smears infiltrated
      by leukocytes and a reduction in GnRH self-priming. TX-treated rats exhibited
      cornified vaginal smears and an estrogenic effect on GnRH self-priming. Moreover,
      15-min exposure to two consecutive GnRH (10(-8) M) challenges 1 h apart in
      incubated pituitaries with estradiol (E(2), 10(-8) M), TX (10(-7) M), E(2) + TX,
      or medium alone form ovariectomized rats injected for 3 days with estradiol
      benzoate (25 microg), TX (3 mg), estradiol benzoate + TX, or 0.2 ml oil,
      respectively, showed that TX increased GnRH self-priming, as did E(2), whereas it
      reduced the E(2)-sensitizing effect on GnRH-stimulated LH secretion and cancelled
      the E(2)-dependent GnRH self-priming. All SERMs prevented the physiological
      nucleocytoplasmic shuttling of ERalpha exhibited during proestrus in control
      rats, and TX, in addition, induced a significantly larger number of gonadotropes
      displaying strong cytosolic immunosignals corresponding to ERalpha than the rest
      of the experimental groups. Overall, data from this study indicated that, in
      contrast to the general antagonistic effect of the tested SERMs, TX seemed to
      display both selective agonist and antagonist activity at the gonadotrope level
      and on GnRH self-priming of LH secretion respectively.

PMID- 12411738
TI  - Estrogenic properties of raloxifene, but not tamoxifen, on D2 and D3 dopamine
      receptors in the rat forebrain.
AB  - The present study investigated the estrogenic specificity of the modulation of
      dopamine D(2) and D(3) receptors by comparing the effects of estradiol with
      tamoxifen or raloxifene. These compounds have estrogenic and/or antiestrogenic
      activity depending on the target tissue. Two weeks after ovariectomy of female
      rats, we observed a 60% decrease in the uterine weight, which was prevented by a
      replacement therapy of 2 weeks with 17beta-estradiol. A tamoxifen or raloxifene
      treatment of 2 weeks increased uterine weights by 35 and 15%, respectively, but
      significantly less than estradiol treatment. Ovariectomy decreased dopamine D(2)
      receptor specific binding (20%) in the dorsolateral part of the anterior striatum
      and these receptors were left unchanged in the other parts of the striatum as
      well as in the olfactory tubercle and the nucleus accumbens. 17beta-Estradiol and
      raloxifene, but not tamoxifen treatment prevented this decrease. Ovariectomy left
      dopamine D(3) receptor specific binding unchanged. However, estradiol and
      raloxifene treatment decreased dopamine D(3) receptor binding in the islands of
      Calleja, the core and shell of the nucleus accumbens and the dorsal part of the
      anterior striatum, compared with ovariectomized rats. Our results show that
      raloxifene, but not tamoxifen, has an agonist estrogenic activity on dopamine
      receptors. Furthermore, estradiol and raloxifene have opposite effects on
      specific binding to dopamine D(2) and D(3) receptors.

PMID- 12411739
TI  - Effects of 17beta-estradiol and xenoestrogens on the neuronal survival in an
      organotypic hippocampal culture.
AB  - Xenoestrogens are man-made compounds that mimic the actions of estrogens through
      interactions with estrogen receptors (ERs). Although xenoestrogens have received
      a great deal of attention as possible causes of brain disfunctions, little
      information concerning the effects of xenoestrogens on the central nervous system
      is available. In this study, we investigated the effects of 17beta-estradiol
      (E(2)) and four xenoestrogens (17alpha-ethynylestradiol, diethylstilbestrol, p
      nonylphenol and bisphenol A (BPA)) on the neuronal survival using organotypic
      hippocampal slice cultures. When the cultured hippocampal slices were exposed to
      glutamate (1 mM, 15 min), the CA1-selective neuronal damage was induced.
      Pretreatment with E(2) and the xenoestrogens (24 h) selectively exacerbated the
      CA3 neuronal damage caused by glutamate. In spite of the marked difference of
      binding affinities to ERs, all compounds revealed maximal effects at 1 nM. ER
      antagonists, tamoxifen and ICI 182,780, did not affect responses to E(2) and the
      xenoestrogens, indicating that these effects are mediated through mechanisms
      other than ERs. In spite of the fact that BPA has little interaction with ERs at
      1 nM, E(2) and BPA equally increased the expression of N-methyl-D-aspartate
      receptor in CA3 and upregulated the spine density of the apical portion of CA3
      dendrites at 1 nM. These compounds also enhanced the sprouting of mossy fibers to
      CA3 neurons. These results suggest that exposure to E(2) and xenoestrogens during
      the developmental stage results in a marked influence on synaptogenesis and
      neuronal vulnerability through mechanisms other than ERs.

PMID- 12411740
TI  - Estrogen modulation of mu-opioid receptor-stimulated [35S]-GTP-gamma-S binding in
      female rat brain visualized by in vitro autoradiography.
AB  - The mu-opioid receptor (OR) is involved in several aspects of female reproductive
      neuroendocrinology, such as the control of gonadotropin release and the display
      of lordosis behavior. Even though the neuroendocrine events modulated by mu-ORs
      are steroid hormone-dependent, few studies have shown how steroid hormones such
      as estrogen and/or progesterone can affect mu-OR function. Therefore, the present
      study investigated if in vivo estrogen or estrogen plus progesterone treatment of
      ovariectomized (OVX) rats affects mu-OR coupling to its G proteins. We used
      autoradiographic analysis of agonist-stimulated [(35)S]-GTPgammaS binding, in
      which brain sections were incubated in the presence or absence of the mu-OR
      agonist [D-Ala(2), N-Me-Phe(4), Gly(2)ol]-enkephalin (DAMGO). Film images were
      quantified using calibrated [(14)C] standards. Analysis was performed in steroid
      responsive hypothalamic regions such as the medial preoptic area (mPOA) and the
      ventromedial nucleus of the hypothalamus, as well as in non-hypothalamic brain
      regions. Treatment with estrogen, alone or with progesterone, significantly
      increased DAMGO-stimulated [(35)S]-GTPgammaS binding in the mPOA when compared to
      control OVX animals. In addition, estrogen increased mu-OR coupling in the
      caudate putamen. Steroid treatment had no effect on either basal or DAMGO
      stimulated binding in the other brain regions examined. These findings suggest
      that estrogen modulates mu-OR function in a brain region-specific fashion. This
      could have important implications in terms of how these hormones synchronize
      reproductive behavior and gonadotropin release.

PMID- 12411741
TI  - Altered control of the hypothalamo-pituitary-adrenal axis in adult male rats
      exposed perinatally to food deprivation and/or dehydration.
AB  - Dehydration, a classic homeostatic stressor in rats, leads to a series of well
      characterized endocrine responses including stimulation of the hypothalamo
      pituitary-adrenal (HPA) axis. In this study, the hypothesis to be tested was that
      a 50% maternal food restriction (FR50) in late gestation and lactation may have
      long-term repercussions on HPA axis responsiveness to dehydration in offspring.
      For this purpose, we studied HPA axis activity in 4-month-old control (C) and
      perinatally malnourished male rats after a 72-hour water deprivation period.
      Furthermore, we investigated the long-lasting effects of perinatal maternal
      malnutrition on the basal activity of the HPA axis. Under basal conditions, rats
      exposed to perinatal malnutrition showed reduced body weight, enhanced
      mineralocorticoid receptor (MR) mRNA levels in CA2 and CA3 hippocampal areas, but
      decreased glucocorticoid receptor (GR) mRNA levels in CA1, CA3 and dentate gyrus
      (DG) areas. In contrast, the levels of corticotropin-releasing hormone (CRH) and
      vasopressin (VP) mRNAs in the hypothalamic paraventricular nucleus (PVN) as well
      as of VP mRNA in the supraoptic nucleus (SON) were unaffected by maternal
      undernutrition. Expression of proopiomelanocortin (POMC) in the adenohypophysis
      was significantly enhanced, whereas prohormone convertase-1 (PC1) was not
      affected. Perinatal malnutrition reduced absolute adrenal weight but did not
      affect circulating levels of adrenocorticotropin (ACTH), corticosterone and free
      corticosterone as well as corticosteroid-binding globulin (CBG) binding capacity.
      Seventy-two hours of dehydration induced a decrease in body weight and CRH mRNA
      levels in PVN of controls as well as of FR50 rats, but also led to a rise in
      plasma corticosterone and free corticosterone without changing CBG binding
      capacity. Dehydration also induced an increase in adenopituitary POMC (C) and PC1
      (FR50), PVN and SON VP (C) and GR in CA1 hippocampal area (FR50) mRNA levels and
      plasma ACTH (C), but a decrease in MR in DG (C) and GR in CA3 and DG (C) mRNA
      levels. We conclude that maternal food restriction during the perinatal period
      affects (1) the adult basal activity of the HPA axis with mainly opposite effects
      on hippocampal MR and GR gene expression and an increase in adenopituitary POMC
      gene expression, and (2) the responsiveness to water deprivation in adults. In
      the latter case, the rise in plasma ACTH levels, adenopituitary POMC gene
      expression, hypothalamic VP gene expression, and the decrease in hippocampal MR
      gene expression in DG and GR gene expression in CA3 and DG observed in controls
      are lacking in FR50 rats. In contrast, drastic adenopituitary PC1 gene expression
      occurred in FR50 rats but not in control animals.

PMID- 12411742
TI  - Increased expression of tyrosine hydroxylase immunoreactivity in paraventricular
      and supraoptic neurons in illnesses with prolonged osmotic or nonosmotic
      stimulation of vasopressin release.
AB  - Our previous studies indicated that in the human paraventricular (PVN) and
      supraoptic (SON) nuclei, tyrosine hydroxylase (TH)--the first and rate-limiting
      enzyme in catecholamine synthesis--is localized mainly in magnocellular neurons
      and that antemortem factors regulate its expression. The purpose of the present
      study was to investigate the distribution of TH-immunoreactive (TH-IR) perikarya
      of the hypothalami of a large sample of well-documented adult subjects without
      neurological, psychiatric or endocrinological disease in order to identify
      factors that could regulate the expression of TH in the human neurosecretory
      neurons. Our material consisted of the hypothalami of 38 subjects studied
      immunohistochemically for TH using the peroxidase-antiperoxidase method. Striking
      individual differences were observed among the subjects studied concerning the
      number and distribution of TH-IR perikarya within the PVN and SON. These
      differences were evident throughout the entire rostrocaudal length of the
      hypothalamus and appeared to be related neither to the age or sex of the subjects
      nor to the postmortem interval or staining procedures. In the sample studied, a
      large number of TH-IR perikarya were observed specifically in all subjects that
      had suffered from right-sided heart failure due to pulmonary hypertension, liver
      cirrhosis or dehydration. In all the above illnesses, increased production and
      secretion of vasopressin (VP) are reported to occur due to a decrease in
      'effective' blood volume or to osmotic stimulation. We conclude that somatic
      illnesses leading to prolonged osmotic or nonosmotic stimulation of VP release
      may induce increased expression of TH immunoreactivity in the human
      neurosecretory neurons related to neuronal activation.

PMID- 12411743
TI  - Molecular complexes formed with polycystins.
AB  - Polycystins are a family of novel transmembrane proteins with at least six
      members already identified in humans. Defects in polycystins-1 and -2 are
      responsible for nearly all cases of autosomal-dominant polycystic kidney disease
      (ADPKD), a major cause of end-stage renal failure. With the progress made in
      elucidating the genetic basis of ADPKD, the challenges are to understand the
      functions of polycystins and to delineate the biochemical and cellular mechanisms
      of cyst development and progression. In this review, we summarize the recent
      advances in our knowledge of the functions of polycystins with emphasis on the
      molecular composition of polycystin protein complexes in the kidney.

PMID- 12411744
TI  - Towards understanding the polycystins.
AB  - Autosomal dominant polycystic kidney disease (ADPKD) is a very common inherited
      disease caused by mutations in PKD1 or PKD2 genes characterized by progressive
      enlargement of fluid-filled cysts and loss of renal function [1]. Previous
      studies proposed a role for human polycystin-1 in renal morphogenesis acting as a
      matrix receptor in focal adhesions and for polycystin-2 as a putative calcium
      channel [2, 3]. The genome of Caenorhabditis elegans contains 2 new members of
      the polycystin family: lov-1, the homolog for PKD1; and pkd-2, the homolog for
      PKD2 [4; this paper]. Mutation analysis in C. elegans showed similarly
      compromised male mating behaviors in all single and double lov-1 and pkd-2
      mutants, indicating their participation in a single genetic pathway. Expression
      analysis localized LOV-1 and PKD-2 to the ends of sensory neurons in male tails
      and to the tips of CEM neurons in the head, consistent with functions as chemo-
      or mechanosensors. Human and C. elegans PKD1 and PKD2 homologs, transfected into
      mammalian renal epithelial cells, co-localized with paxillin in focal adhesions
      suggesting function in a single biological pathway. Based on the role of
      polycystins in C. elegans sensory neuron function and the conservation of PKD
      pathways we suggest that polycystins act as sensors of the extracellular
      environment, initiating, via focal adhesion assembly, intracellular transduction
      events in neuronal or morphogenetic processes.

PMID- 12411745
TI  - Organisation of bone morphogenetic proteins in renal development.
AB  - Bone morphogenetic proteins (BMPs) comprise the largest subfamily of the
      transforming growth factor-beta (TGF-beta) superfamily of secreted proteins.
      Evidence for the involvement of BMPs in metanephric development emerged recently
      when renal phenotypes were observed in BMP7 null mutant mice. Since then, several
      other BMPs, BMP receptor serine/threonine kinases and BMP signal transduction
      molecules (Smads) have been implicated in mammalian metanephric development. It
      appears that particular BMPs have pivotal roles in specific aspects of
      metanephric development. Current knowledge and evidence of specific roles of
      particular BMPs are presented in this review.

PMID- 12411746
TI  - Redox signaling in mesangial cells.

PMID- 12411747
TI  - Renal alpha-actinin-4: purification and puromycin aminonucleoside-binding
      property.
AB  - Mutations in the gene encoding nonmuscle alpha-actinin-4 (actinin-4), an actin
      cross-linking protein, lead to congenital nephrosis. This suggests that actinin-4
      is an essential component of the glomerular filtration barrier. In the present
      study, we attempted to purify actinin-4 from the mammalian kidney. We also
      examined an interaction of the protein with puromycin aminonucleoside (PAN),
      which can induce nephrosis in animals. A 100-kD protein reactive with antibody
      against muscle alpha-actinin was purified from the Triton-insoluble cytoskeleton
      of porcine kidney, by MgCl2 treatment, ammonium sulfate fractionation, and
      subsequent DEAE-cellulose chromatography and hydroxyapatite chromatography. Its
      partial amino acid sequence was then determined. A filamentous actin (F-actin)
      binding activity of the purified protein was examined by a cosedimentation assay.
      Interactions of the purified protein and its fragments with PAN were analyzed by
      an affinity assay using PAN-Sepharose. Determined 134 amino acid sequences of the
      purified porcine renal 100-kD protein were completely identical with those
      deduced from nucleotide sequence of the cDNA encoding human actinin-4. The
      purified protein possessed the known function of alpha-actinin, the F-actin
      binding activity, and was tightly bound to PAN. The PAN-binding site was mapped
      within a central rod domain of the protein, which is a possible interaction site
      for various cytoskeletal and transmembrane proteins. We have established an
      efficient purification method for renal actinin-4. Moreover, our findings
      indicate that the central rod domain of actinin-4 has a high affinity to PAN. In
      the PAN nephrosis animal model, actinin-4 might be a target protein from PAN
      nephrotoxicity.

PMID- 12411748
TI  - Oxytocin induces apical and basolateral redistribution of aquaporin-2 in rat
      kidney.
AB  - The aquaporin-2 (AQP2) water channel is mainly located in the apical plasma
      membrane of collecting duct epithelial cells, but there has been some evidence of
      a moderate amount of basolateral localization of AQP2 at least in the inner
      medullary collecting duct (IMCD). Previous in vitro microperfusion studies showed
      that oxytocin has an antidiuretic action, most likely mediated by the vasopressin
      V2 receptor (V2R) in rat IMCD. By using immunohistochemistry in kidneys from male
      Sprague-Dawley rats, we observed acute effects of oxytocin on AQP2 localization
      which were prevented by a V2R antagonist. After intraperitoneal administration of
      oxytocin (10 U), immunohistochemistry of IMCD revealed that AQP2 was shifted from
      diffuse cytoplasmic localization in controls to the apical and basolateral
      membrane domains in oxytocin-treated rats. This pattern of AQP2 redistribution
      was noted in connecting tubule, cortical collecting duct and outer medullary
      collecting duct as well as in IMCD, although the tendency to basolateral
      localization was somewhat less. The pretreatment using a V2R antagonist blocked
      redistribution of AQP2 in response to oxytocin. We conclude that oxytocin induces
      a V2R-mediated redistribution of AQP2-containing cytoplasmic vesicles to both
      apical and basolateral plasma membrane domains in rat kidney. Oxytocin may be one
      of the factors that accounts for vasopressin-independent AQP2 targeting in the
      kidney.

PMID- 12411749
TI  - A model for ex vivo renal angiogenesis.
AB  - Attempts to study renal angiogenesis have been hampered by the lack of an
      appropriate model. Here we present data on a successful ex vivo culture of renal
      medullary explants in three-dimensional collagen 1 or Matrigel lattices and
      characterize the dynamics of capillary formation by sprouting endothelial cells.
      Initially, endothelial cells represented 71 +/- 3% among the sprouting cells, but
      within a week growing capillaries were comprised exclusively of endothelial
      cells. The quantitative analysis showed that the number of sprouting capillaries
      progressively increased until 12 days in culture, after which capillaries
      underwent involution. Occasional formation of glomeruloid bodies was noted.
      Capillaries were characterized by a well-defined lumen, whereas glomeruloid
      bodies showed cellular debris occupying the luminal space. In view of the
      existing controversy regarding angiogenic competence in diabetic nephropathy, we
      applied this ex vivo culture system to Zucker diabetic rat model of diabetes
      mellitus. Comparative analysis of capillary sprouting in Zucker diabetic fat and
      lean nondiabetic control rats showed no differences in angiogenic properties of
      renal explants obtained at the age of 11 weeks. However, when kidneys were
      obtained from rats at age of 21 weeks, the capillary sprouting was significantly
      reduced in Zucker diabetic rats compared to age-matched lean rats. The rate of
      capillary involution was unaffected in Zucker diabetic rats. In conclusion, the
      data presented herein delineate the first successful ex vivo model of
      angiogenesis initiated from the renal medullary explants of adult rats and
      provide evidence of impaired angiogenesis in Zucker diabetic rats with the
      established, but not with incipient diabetes mellitus.

PMID- 12411751
TI  - Loss of bone mass after renal transplantation.

PMID- 12411752
TI  - Radiocontrast media-induced renal injury--saline is effective in prevention.

PMID- 12411753
TI  - Management of lupus nephropathy.
AB  - This review is an evidence- and experience-based approach to the management of
      SLE, particularly its kidney manifestations. Specific protocols in substantial
      clinical detail are provided for management and monitoring, according to the
      severity of the SLE manifestations. The protocols are adapted from those used in
      a major SLE trial. The adaptations are based on subsequent extensive clinical use
      of these protocols. Also described is the concomitant use of cardio- and kidney
      protective therapies to optimize patient outcomes.

PMID- 12411754
TI  - Prevention of acute renal failure in the critically ill.
AB  - Acute renal failure (ARF) is a common and important complication of critical
      illness and many interventions have been proposed to prevent it. The pathogenesis
      of acute renal failure during critical illness is poorly understood. Animal
      models are based on the induction of renal ischemia and do not reflect the
      dominance of sepsis as a cause of ARF in the clinical arena. Although biological
      rationale exists for several interventions, none have been shown to be effective
      in large randomized double-blind multicentre trials. The only interventions with
      close to level I evidence are confined to the attenuation of radiocontrast
      nephropathy. The effect on such interventions is, however, of limited clinical
      relevance to critically ill patients. The maintenance of adequate intravascular
      filling, cardiac output and renal perfusion pressure and the avoidance of
      hypoxemia, marked anemia and nephrotoxins remain the only justifiable
      interventions at this time.

PMID- 12411755
TI  - Abnormal vitamin D metabolism and loss of bone mass after renal transplantation.
AB  - BACKGROUND/AIM: Osteoporosis is a major complication after renal transplantation.
      The most important causative factor is the use of corticosteroids, but
      abnormalities in vitamin D metabolism and persisting hyperparathyroidism could
      also be involved. The present study examines changes in vitamin D metabolites,
      intact parathyroid hormone, and bone mineral density (BMD) during the first 2
      years after renal transplantation. METHODS: Sixty-one patients (38 male, 23
      female; age 42 +/- 13 years) who received a renal transplant participated in the
      study. Immunosuppressive treatment consisted of ciclosporin and prednisone.
      Laboratory parameters and BMD (lumbar spine and hip) were measured at baseline
      and 1 (laboratory only), 3, 6, 12, and 24 months after transplantation. RESULTS:
      At the time of transplantation, the 1,25-dihydroxyvitamin D levels were low in
      all patients. Although we observed a gradual increase, subnormal values were
      still present in 39 (64%) and 29 (47%) patients 3 and 6 months after
      transplantation, respectively. From 3 months after transplantation the 1,25
      dihydroxyvitamin D level correlated with the creatinine clearance. After
      transplantation, the intact parathyroid hormone levels declined rapidly to values
      slightly above normal. The lumbar BMD was nearly normal at the time of
      transplantation, but decreased rapidly within 6 months (-6.5 +/- 4.5%; p <
      0.001). A smaller decrease occurred in the femoral neck (-4.1 +/- 6.5%; p <
      0.001), in Ward's triangle (-2.4 +/- 13.0%; p < 0.01), and in the trochanter (
      5.1 +/- 6.3%; p < 0.001). After 6 months, the bone mass stabilized. CONCLUSIONS:
      The vitamin D metabolism remains disturbed for a considerable time after renal
      transplantation. In nearly half of the patients, the levels of active vitamin D
      remain abnormal for at least 6 months. The BMD decreased during the first 6
      months after transplantation and remained stable thereafter. We speculate that
      the observed abnormalities in vitamin D metabolism may contribute to the early
      bone loss after renal transplantation.

PMID- 12411756
TI  - A randomized prospective trial to assess the role of saline hydration on the
      development of contrast nephrotoxicity.
AB  - Though simple and attractive, the role of hydration for the prophylaxis of
      contrast nephrotoxicity has not been definitively established. We prospectively
      evaluated the role of deliberate saline hydration in patients undergoing
      nonemergency cardiac catheterization. Patients (n = 53) were randomized on the
      day prior to scheduled catheterization to one of two groups - group 1 (n = 27)
      received normal saline for 24 h (at a rate of 1 ml/kg/h) beginning 12 h prior to
      scheduled catheterization, and group 2 (n = 26) were allowed unrestricted oral
      fluids. Serum creatinine measured 24 and 48 h postcardiac catheterization was
      compared to the pre-randomization baseline value. The mean baseline calculated
      creatinine clearance was 79.6 +/- 31.9 ml/min and the mean baseline creatinine
      was 106 +/- 28 micromol/l. An increase in serum creatinine by at least 44.2
      micromol/l (0.5 mg/dl), within 48 h of contrast exposure, was considered to
      represent clinically significant acute renal insufficiency. Ten subjects (18.9%)
      developed acute renal insufficiency. The incidence of acute renal insufficiency
      was significantly lower in group 1 (1 out of 27) as compared to group 2 (9 out of
      26; p = 0.005 for comparison between groups; relative risk 0.11, 95% confidence
      interval 0.015 to 0.79). Twenty-four hours after contrast exposure, the mean
      increase in creatinine was less in group 1 vs. group 2 (8 +/- 11 vs. 20 +/- 21
      micromol/l, p = 0.02). The increase in creatinine was not significantly different
      in group 1 vs. group 2 48 h after contrast exposure (12 +/- 21 vs. 29 +/- 40
      micromol/l, p = 0.17). Deliberate saline hydration decreases the incidence of
      contrast-related acute renal failure and the severity of contrast-induced renal
      dysfunction in patients undergoing non-emergency cardiac catheterization.

PMID- 12411757
TI  - Long-term effects of reflux nephropathy on blood pressure and renal function in
      adults.
AB  - AIMS: We investigated whether the grade of renal damage assessed by urography in
      adult patients with vesicoureteral reflux can be used to identify patients at
      risk of developing hypertension and/or deterioration of renal function. In
      addition, maternal and fetal outcome of pregnancy was studied. METHODS:
      Vesicoureteral reflux was diagnosed at a median age of 27 years (range 16-60) in
      115 patients (98 women). Excluding patients subjected to nephrectomy or
      heminephrectomy after inclusion (n = 12), 88 patients had renal damage at
      inclusion urography and a median follow-up time of 16 years. The median follow-up
      time was 18 years in 15 patients without renal damage. Grading of renal damage
      was performed and blood pressure, serum creatinine concentration and albuminuria
      were measured. Hypertension was considered to be present if the systolic blood
      pressure was > or =140 mm Hg and/or the diastolic blood pressure was > or =90 mm
      Hg. It was classified as mild (<180 mm Hg systolic and <105 mm Hg diastolic), or
      moderate to severe (> or =180 mm Hg systolic and/or > or =105 mm Hg diastolic).
      Renal function was classified as stable or deteriorating. RESULTS: There was no
      significant difference in the frequency of hypertension among those with (52%) or
      without (33%) renal damage, but moderate to severe hypertension (16 patients) was
      only seen in patients with renal damage. Median systolic and diastolic blood
      pressure were higher in patients with than in those without renal damage.
      Malignant hypertension developed in 4 patients, all had extensive renal damage.
      Deterioration of renal function occurred in 25 patients, 1 with unilateral and 24
      with extensive renal damage (bilateral or in a solitary kidney). This was
      associated with a high frequency of hypertension (92%) and albuminuria (88%).
      Sixteen patients developed end-stage renal disease. A total of 242 pregnancies
      occurred in 89 of the 98 women. Preeclampsia occurred in 16 (18%) women.
      CONCLUSION: Hypertension in adult patients with reflux nephropathy occurs with
      any grade of renal damage, whereas deterioration of renal function was strongly
      associated with extensive bilateral renal damage or damage in a solitary kidney.

PMID- 12411758
TI  - Clinical and neuropathological correlates of apolipoprotein E genotype in
      dementia with Lewy bodies.
AB  - Dementia with Lewy bodies (DLB) represents the second commonest cause of dementia
      in the elderly following Alzheimer's disease (AD). Whilst the presence of Lewy
      bodies is essential, DLB shares with AD the presence of senile plaques (SP), but
      neurofibrillary tangles (NFT) are not a necessary feature. The apolipoprotein E
      (APO E) epsilon4 allele is the most consistently associated genetic risk factor
      for AD and has also been shown to associate with DLB. We have therefore analysed
      the APO E epsilon4 allele in a large series of DLB cases coming to autopsy to:
      (1) determine if the epsilon4 allele describes a similar risk in DLB development
      as in AD and (2) determine how APO E epsilon4 allele status correlates with
      clinical and neuropathological findings in DLB, and in AD, as an indication of
      the role of APO E in underlying disease biology. Both DLB and AD share an
      increased epsilon4 allele frequency, though in DLB the epsilon2 allele frequency
      is not reduced and there is a relative lack of epsilon4 homozygotes. In contrast
      to previous studies, no association of the epsilon4 allele with age at onset or
      duration of disease was found in either disorders. In DLB cases, overall a
      significantly shorter duration of illness was observed when compared with AD
      cases, though no significant effect of the epsilon4 allele on disease onset or
      duration was seen. The survival rate was reduced by the presence of the epsilon4
      allele in DLB, as with AD. No effect on SP or NFT counts was seen with the
      epsilon4 allele, though DLB cases showed a lower SP burden in addition to the
      expected lower NFT counts. This study demonstrates that DLB shares the APO
      epsilon4 allele with AD as a common risk factor, but that there are differences
      in the way the epsilon4 allele affects the phenotypic expression of disease.

PMID- 12411759
TI  - Cutoff scores of the cognitive abilities screening instrument, Chinese version in
      screening of dementia.
AB  - The purpose of this study of dementia screening was to obtain different cutoff
      scores of the Cognitive Abilities Screening Instrument, Chinese versions (CASI C
      2.0) for subjects with different educational backgrounds. The diagnosis of
      dementia was based on the Diagnostic and Statistical Manual of Mental Disorders,
      ed 3 revised or ed 4 criteria. To diagnose Alzheimer's disease, the guidelines of
      the National Institute of Neurological and Communicative Disorders and Stroke and
      Alzheimer's Disease and Related Disorders Association was followed. The severity
      of dementia was determined on the Clinical Dementia Rating scale. Altogether
      2,096 subjects, aged 65 years and more, were included. Of them, 1,178 were normal
      and 918 were demented. Their performance on CASI C-2.0 was influenced by their
      education and age. Gender difference on CASI C-2.0 scores was only significant in
      the illiterate, but not in the literate group. We recommend that the population
      be divided into three levels, namely those who (1) had no formal education (Edu =
      0); (2) received 1-5 years of schooling (Edu = 1-5), and (3) received 6 or more
      years of education (Edu >/=6). The cutoff scores of CASI C-2.0 in the diagnosis
      of dementia in these three educational groups were as follows: Edu = 0: 49/50
      (sensitivity = 0.83; specificity = 0.85); Edu = 1-5: 67/68 (sensitivity = 0.83;
      specificity = 0.91), and Edu >/=6: 79/80 (sensitivity = 0.89; specificity =
      0.90).

PMID- 12411760
TI  - Cerebrospinal fluid phospho-tau, total tau and beta-amyloid(1-42) in the
      differentiation between Alzheimer's disease and vascular dementia.
AB  - The two most frequently examined biomarkers in the diagnosis of dementia are
      cerebrospinal fluid (CSF) tau and beta-amyloid(1-42) (Abeta(1-42)). An assay for
      tau phosphorylated at threonine 181 (phospho-tau) has recently been developed. We
      studied these three markers in patients with possible Alzheimer's disease (AD; n
      = 23), probable AD (n = 50), AD with relevant cerebrovascular disease (AD with
      CVD; n = 14), possible vascular dementia (VaD; n = 39), probable VaD (n = 36),
      cognitively impaired (n = 13) and 27 neurologically healthy controls. Compared
      with the controls, tau levels were significantly increased in possible AD,
      probable AD, AD with CVD and probable VaD. Abeta(1-42) was decreased in all
      dementia groups compared with the controls. In contrast, phospho-tau levels were
      increased only in probable AD compared with the controls. From the results of the
      present study, it is concluded that neither measurement of phospho-tau, tau nor
      Abeta(1-42) in CSF can discriminate entirely between dementia and cognitively non
      disturbed controls or between dementia of different aetiologies in the clinical
      diagnostic procedure.

PMID- 12411761
TI  - Biological correlates of clinical subgroups of Alzheimer's disease.
AB  - We considered it possible that the differences in clinical symptoms between two
      suggested subgroups of Alzheimer's disease (AD), AD type I and AD type II, have
      biological correlates, for instance different metabolic profiles. Therefore, we
      performed regional cerebral blood flow (rCBF) measurements and investigated the
      cerebrospinal fluid (CSF) levels of the monoamine metabolites homovanillic acid
      (HVA), 5-HIAA, and HMPG in 15 patients with AD type I, in 36 patients with AD
      type II, in a control group and in a contrast group consisting of 16 patients
      with frontotemporal dementia. The results suggest that there are underlying
      biological correlates of the phenomenological discrepancies between AD type I and
      AD type II. For instance, a decreased CSF level of HVA (p < 0.001) was specific
      to AD type I and decreased rCBF (p < 0.05 to <0.001) in three particular regions
      was specific to AD type II.

PMID- 12411762
TI  - Comparative diagnostic utility of different MR modalities in mild cognitive
      impairment and Alzheimer's disease.
AB  - This study compares the diagnostic accuracy of magnetic resonance (MR)-based
      hippocampal volumetry, single voxel (1)H MR spectroscopy ((1)H MRS) and MR
      diffusion-weighted imaging (DWI) measurements in discriminating patients with
      amnestic mild cognitive impairment (MCI), Alzheimer's disease (AD) and normally
      aging elderly. Sixty-one normally aging elderly, 24 MCI and 22 AD patients
      underwent MR-based hippocampal volumetry, (1)H MRS and DWI. (1)H MRS voxels were
      placed over both of the posterior cingulate gyri, and N-acetyl aspartate
      (NAA)/creatine (Cr), myoinositol (MI)/Cr and NAA/MI ratios were obtained.
      Apparent diffusion coefficient (ADC) maps were derived from DWI, and hippocampal
      borders were traced to measure hippocampal ADC. At 80% specificity, the most
      sensitive single measurement to discriminate MCI (79%) and AD (86%) from controls
      was hippocampal volumes. The most sensitive single measurement to discriminate AD
      from MCI was posterior cingulate gyrus NAA/Cr (67%). At high specificity (>85
      90%), combinations of MR measures had superior diagnostic sensitivity compared
      with any single MR measurement for the AD vs. control and control vs. MCI
      comparisons. The MR measures that best discriminate more from less affected
      individuals along the cognitive continuum from normal to AD vary with disease
      severity. Selection of imaging measures used for clinical assessment or
      monitoring efficiency of therapeutic intervention should be tailored to the
      clinical stage of the disease.

PMID- 12411763
TI  - Behavioural pathology in Alzheimer's disease with special reference to
      apolipoprotein E genotype.
AB  - The aim of this study was to define the co-occurrence of behavioural symptoms and
      Alzheimer's disease (AD) in relation to apolipoprotein E (APOE) genotype.
      Probable AD patients from the Alzheimer's Day Clinic (n = 139) were assessed with
      the 'Behavioural Pathology in Alzheimer's Disease' rating scale, and their APOE
      genotype was determined. This study demonstrated no relationship between presence
      of the APOE epsilon4 allele and any of the behavioural symptoms assessed,
      including delusions, hallucinations, depression, activity disturbances,
      aggressiveness and anxiety. Activity disturbances, delusions, hallucinations and
      aggressiveness paralleled the severity of AD, increasing in frequency with the
      severity of the dementia. The prevalence of delusions, hallucinations,
      aggressiveness and depression were found to be associated with lower levels of
      education.

PMID- 12411764
TI  - Opportunistic 'Rediscovery' of mental disorders by the pharmaceutical industry.

PMID- 12411765
TI  - Leisure sickness: a pilot study on its prevalence, phenomenology, and background.
AB  - AIM: To explore the prevalence, phenomenology, and background of leisure
      sickness, i.e., the condition of people developing symptoms of sickness during
      weekends and/or vacations. METHOD: In order to obtain an estimate of its
      prevalence, a representative Dutch sample consisting of 1,128 men and 765 women
      was asked to indicate to what extent they recognized themselves in our
      description of weekend and vacation sickness. For the investigation of the
      phenomenology and background of this condition and the characteristics of the
      patients suffering from it, questionnaire data were collected in new samples
      consisting of 114 cases and 56 controls. Questions referred to symptoms, onset,
      duration, appreciation of weekend and vacation activities, and appraisal of work
      and workload. RESULTS: In the case of male respondents, 3.6 and 3.2% recognized
      themselves in the description of the weekend and the vacation syndrome,
      respectively, compared with 2.7 and 3.2% women. Most frequently reported symptoms
      were headache/migraine, fatigue, muscular pains, and nausea. In addition, viral
      infections (flue-like, common cold) were often reported in relation to vacations.
      Cases had generally suffered from leisure sickness for over 10 years and the
      onset was associated with stressful conditions. They attributed their condition
      to difficulties with the transition from work to nonwork, stress associated with
      travel and vacation, as well as workload and personality characteristics. There
      were no significant group differences in the appreciation of weekend and leisure
      activities or lifestyle during days off. Most striking differences were found
      with respect to experienced workload, sense of responsibility, and inability to
      relax. CONCLUSION: Leisure sickness is a relatively common condition. Specific
      lifestyle factors or leisure activities seem to be less relevant for its
      development. Concerning risk factors, the data tend to point to high workload and
      person characteristics, namely, the inability to adapt to the nonworking
      situation, a high need for achievement, and a high sense of responsibility with
      respect to work. Future studies should be designed for testing specific
      hypotheses concerning the underlying mechanisms and evaluating the effectiveness
      of psychological and/or physical activity interventions.

PMID- 12411766
TI  - Predictors of course and outcome in hypochondriasis after cognitive-behavioral
      treatment.
AB  - BACKGROUND: Predictors of treatment outcome were evaluated in a clinical sample
      suffering from hypochondriasis. METHODS: The sample consisted of 96 patients with
      hypochondriacal disorder according to DSM-IV or high syndrome scores on the
      Illness Attitude Scales (IAS) or Whiteley Index (WI). After intense inpatient
      cognitive-behavioral treatment (CBT), 60% of the patients were classified as
      responders because of substantial improvements or recovery from hypochondriacal
      symptomatology. RESULTS: Non-responders were characterized by a higher degree of
      pre-treatment hypochondriasis, more somatization symptoms and general
      psychopathology (SCL-90R), more dysfunctional cognitions related to bodily
      functioning, higher levels of psychosocial impairments, and more utilization of
      the health care system as indicated by the number of hospital days and costs for
      inpatient treatments and medication. No predictive value was found for
      sociodemographic variables, comorbidity with other mental disorders and
      chronicity. Multiple linear regression showed that pre-treatment variables
      significantly predicted IAS scores at post-treatment (R(2) = 0.59), changes
      during treatment (0.10), IAS scores at follow-up two years later (0.41) and
      changes between baseline and follow-up (0.25). CONCLUSIONS: The results
      demonstrate the relevance of various psychopathological variables and health care
      utilization as important indicators for outcome and further course of clinical
      hypochondriasis.

PMID- 12411767
TI  - A community-based psychoeducational group approach to hypochondriasis.
AB  - BACKGROUND: This open trial investigates the feasibility and effectiveness of a
      cognitive-educational approach to hypochondriasis in a self-referred community
      sample. METHOD: Twenty-seven of 43 interested applicants fulfilled DSM-criteria
      for hypochondriasis and resembled a hypochondriacal reference group according to
      the Groningen Illness Attitude Scale. Subjects participated in small groups for
      six 2-hour sessions aimed at educating them about hypochondriasis. RESULTS: The
      results showed that the 21 completers improved between pre- and post-test on
      parameters for hypochondriasis and depression, and that this improvement was
      maintained at 4 weeks and 6 months follow-up. Six subjects dropped out for
      various reasons, showing no decrease in relevant variables. CONCLUSION:
      Hypochondriacal subjects can be reached outside mental health settings, and a
      psychoeducational group approach may be an acceptable and effective method to
      reduce hypochondriacal psychopathology.

PMID- 12411768
TI  - Preliminary validation of PRISM (Pictorial Representation of Illness and Self
      Measure) - a brief method to assess suffering.
AB  - BACKGROUND: Alleviation of suffering is widely acknowledged as one of the main
      goals of medicine. However, no measure to assess this crucial aspect of illness
      has been developed to date. AIMS: To validate PRISM (Pictorial Representation of
      Illness and Self-Measure) as a simple quantitative method of assessing the
      perceived burden of suffering due to illness. METHODS: Validity and reliability
      studies to date have involved over 700 patients with a variety of chronic
      physical illnesses. RESULTS: Reliability of PRISM is good (test-retest
      reliability r = 0.95; p < or = 0.001, interrater reliability r = 0.79; p < or =
      0.001). Qualitative data indicate that the interpretation of the PRISM task is
      not only consistent among patients, but also consistent with that expected from
      existing literature on suffering. As expected, PRISM shows strong correlations
      with psychological variables (notably depression and coping resilience) and also
      correlates with SF-36 subscale scores. Prospective longitudinal data demonstrate
      that PRISM is sensitive to therapeutic change. It is very acceptable to patients
      and takes less than 5 min to administer. CONCLUSION: In the absence of a 'gold
      standard' measure of suffering, our validation data must be interpreted with
      caution. However, the performance of PRISM is entirely consistent with what would
      be expected of a measure of suffering, based on current published work.

PMID- 12411769
TI  - Emotional stress, psychosocial variables and coping associated with hepatitis C
      virus and human immunodeficiency virus infections in intravenous drug users.
AB  - BACKGROUND: The increasing health problem of hepatitis C virus (HCV) infection
      has only recently attracted the attention of psychosocial research, especially
      among subjects at higher risk (e.g. intravenous drug users; IDUs). The aim of the
      present study was to compare emotional stress symptoms, psychosocial variables
      (i.e. social support, external locus of control and emotional repression) and
      coping strategies in HCV-seropositive, human immunodeficiency virus (HIV)
      seropositive and HCV/HIV-noninfected IDUs. METHODS: IDUs followed by the
      Infectious Diseases Outpatient clinic were enrolled in the study over a period of
      1 year. HCV-positive (n = 62) and HIV-positive (n = 76) IDUs and HCV/HIV
      seronegative IDUs (n = 152) completed the Brief Symptom Inventory, the Social
      Provision Scale, the Locus of Control scale and the affective inhibition scale of
      the Illness Behavior Questionnaire. Coping with illness among HCV-positive and
      HIV-positive subjects was assessed through a modified version of the Mental
      Adjustment to Cancer Scale. RESULTS: No significant differences were found
      between the samples with respect to individual and interpersonal variables. HCV
      positive subjects showed higher scores on several psychological stress dimensions
      (i.e. obsessive-compulsive, phobic anxiety, paranoid ideation, psychoticism) and
      lower scores on fighting spirit, hopelessness and anxious preoccupation towards
      illness than HIV-positive patients. HCV-positive and HCV/HIV-seronegative IDUs
      reported comparable scores on most of the psychological measures. CONCLUSIONS:
      The findings indicate that routine assessment of psychosocial variables and
      coping mechanisms should be integrated into all HCV and HIV services, especially
      those dedicated to treatment of patients with substance abuse, as a vulnerable
      segment of the population at risk for life-threatening physical illness such as
      HCV and HIV infections.

PMID- 12411770
TI  - Circadian blood pressure patterns and life stress.
AB  - BACKGROUND: Scarce data are available on the influence of psychological aspects
      on 24-hour ambulatory blood pressure patterns either in normotensive or
      hypertensive subjects. This study was designed to evaluate the relationship
      between psychological profile and changes in daytime/nighttime blood pressure
      rhythm. METHODS: Nocturnal dipping was defined as the night/day ratio of
      ambulatory mean systolic and/or diastolic blood pressure < or =0.87. Three
      hundred and two outpatients (M/F = 174/128; mean age = 49.8 years, SD = 13.6;
      range, 16-80 years) underwent 24-hour ambulatory blood pressure monitoring. They
      were administered a self-rating scale, the Psychosocial Index, as an indicator of
      stress, psychological distress, sleep disturbances, well-being, abnormal illness
      behavior and quality of life. There were 242 patients taking antihypertensive
      medication (146 adequately controlled and 96 not controlled) and 60 who were drug
      free (33 never-treated hypertensive and 27 normotensive subjects). Patients were
      divided according to the presence (n = 125) or absence (n = 177) of night blood
      pressure dipping. The two groups were compared using analysis of covariance, with
      age as a covariate. RESULTS: Dippers had lower (p < 0.001) nocturnal systolic and
      diastolic blood pressure than nondippers, and higher (p < 0.05) daytime diastolic
      blood pressure. Patients with nocturnal blood pressure decline had a markedly
      higher (p < 0.001) level of stress than nondippers. When the sample was divided
      according to the presence or absence of hypertension, only subjects with normal
      blood pressure showed nocturnal dipping associated with increased stressful life
      circumstances. CONCLUSIONS: Our findings indicate that dippers experience
      stressful life circumstances, both in terms of life events and chronic stress.
      This suggests that stress-reducing techniques may be particularly helpful in the
      setting of hypertension characterized by nighttime blood pressure dipping.

PMID- 12411771
TI  - Interpersonal psychotherapy as augmentation treatment in depressed elderly
      responding poorly to antidepressant drugs: a case series.
AB  - BACKGROUND: Medication is often the first choice in the treatment of depression,
      even though large numbers of depressed patients do not respond to antidepressant
      drugs or fail to achieve symptom remission or recovery. Generally, other drugs,
      rather than other therapeutic approaches such as psychotherapy, are used as
      augmentation treatment. This applies in particular to elderly patients. The aim
      of this work is to assess whether augmentation with interpersonal psychotherapy
      (IPT) can bring about symptom remission in depressed elderly responding poorly to
      medication. METHOD: Five cognitively intact patients aged over 60 and suffering
      from major depression were first treated for 6 weeks with a selective serotonin
      reuptake inhibitor compound. Owing to poor outcome, IPT was added to the
      treatment. IPT is a brief psychotherapy addressing the interpersonal problems
      linked to depression, and has been modified for use with elderly patients.
      RESULTS: All patients achieved symptom remission after a cycle of psychotherapy
      lasting a minimum of 16 and a maximum of 20 weekly sessions. CONCLUSIONS: The
      methodological limitations of this open study do not allow us to generalize from
      the positive outcomes. Further studies might confirm these initial observations
      and establish whether an equally satisfactory therapeutic response can be
      attained if medication is discontinued after the start of psychotherapy.

PMID- 12411772
TI  - Audibility-index functions for the connected speech test.
AB  - OBJECTIVE: A study was performed to derive a frequency importance function (FIF),
      a performance-intensity funcTIon (PIF), and a transfer function (TF) for the
      audio compact disc version of the Connected Speech Test (CST). DESIGN: CST
      passages were masked with talker-spectrum-matched (TSM) noise and presented to
      two groups of normal-hearing adult subjects. One group (N = 48) listened through
      a wideband filter, seven low-pass filters, and eight high-pass filters at six
      signal-to-noise (S/N) ratios. The other group (N = 12) listened through just the
      wideband filter at 12 S/N ratios. The FIF was based on the data for the first
      group while the PIF was based on the data for the second group. The results of
      both groups were used to determine the TF between CST scores and audibility-index
      (AI) values. RESULTS: The FIF, in 1/3-octave bands, is a bimodal curve with a
      minor peak at 500 Hz, a major peak at 1600 to 2000 Hz, and a midpoint of 1619 Hz.
      The PIF in TSM noise and the TF are both asymmetric S-shaped curves; their
      respective slopes are 12%/dB and 11%/0.0333 AI. CONCLUSIONS: Comparisons between
      these results and the findings of other studies reconfirm that different speech
      materials have different AI functions. The FIF for the CST overlaps 1/3-octave
      band functions for continuous discourse and average speech but does not have the
      same shape as those functions. The TF indicates that CST passages are generally
      more intelligible than isolated monosyllabic words (NU6 lists) and somewhat less
      intelligible than continuous discourse. The former result is probably due at
      least partly to the effects of context whereas the latter result may be due
      primarily to how clearly the talkers pronounced the speech materials.

PMID- 12411773
TI  - Effects of sensorineural hearing loss on cortical event-related potential and
      behavioral measures of speech-sound processing.
AB  - OBJECTIVE: To investigate systematically the effects of sensorineural hearing
      loss on cortical event-related potentials (ERPs) N1, MMN, N2 and P3 and their
      associated behavioral measures (d' sensitivity and reaction time) to the speech
      sounds /ba/ and /da/ presented at 65 and 80 dB ppe SPL. DESIGN: Cortical ERPs
      were recorded to /ba/ and /da/ speech stimuli presented at 65 and 80 dB ppe SPL
      from 20 normal-hearing adults and 20 adults who are hearing impaired. The degree
      of sensorineural impairments at 1000 to 2000 Hz ranged from mild losses (defined
      as 25 to 49 dB HL) to severe/profound losses (75 to 120 dB HL). The speech
      stimuli were presented in an oddball paradigm and the cortical ERPs were recorded
      in both active and passive listening conditions for each stimulus intensity.
      RESULTS: Both ERP amplitudes and behavioral discrimination (d') scores were lower
      for listeners with sensorineural hearing loss than for those with normal hearing.
      However, these differences in response strength were evident only for those
      listeners whose average hearing loss at 1000 to 2000 Hz exceeded 60 dB HL for the
      lower intensity stimuli and exceeded 75 dB HL for the higher intensity stimuli.
      In contrast, prolongations in the ERP and behavioral latencies, relative to
      responses from normal-hearing subjects, began with even mild (25 to 49 dB HL)
      threshold elevations. The amplitude and latency response changes that occurred
      with sensorineural hearing loss were significantly greater for the later ERP
      peaks (N2/P3) and behavioral discrimination measures (d' and RT) in comparison
      with earlier (N1, MMN) responses. CONCLUSIONS: The results indicate that latency
      measures are more sensitive indicators of the early effects of decreased
      audibility than are response strength (amplitude, d' or percent correct)
      measures. Sensorineural hearing loss has a greater impact on higher level or
      "nonsensory" cortical processing in comparison with lower level or "sensory"
      cortical processing. Possible physiologic mechanisms within the cortex that may
      be responsible for these response changes are presented. Lastly, the possible
      clinical significance of these ERP and behavioral findings is discussed.

PMID- 12411774
TI  - Tympanometric norms for Chinese young adults.
AB  - OBJECTIVE: To obtain tympanometric norms in Southern Chinese young adult
      population and compare the results with data obtained for a Caucasian population.
      DESIGN: Ear canal volume (Vea), tympanometric compensated static acoustic
      admittance (Peak Ytm), tympanometric width (TW) and tympanometric peak pressure
      (TPP) were obtained on 100 Southern Chinese young adults. Results were compared
      with findings from Roup et al. (1998). Inter-tester reliability was established.
      RESULTS: Compared with the results obtained by Roup et al. (1998) on non-Hispanic
      Caucasian population, Southern Chinese subjects were found to have lower Peak
      Ytm, wider TW and more positive TPP values. No gender difference was noted for
      Peak Ytm, TW and TPP values in Chinese subjects. Inter-tester reliability was
      good. CONCLUSION: The tympanometric norms obtained in this study are recommended
      when evaluating middle ear function among Southern Chinese young adults.

PMID- 12411775
TI  - A comparison of two measures of hearing aid satisfaction in a group of elderly
      hearing aid wearers.
AB  - OBJECTIVE: The objective of this study was to compare the results of two measures
      of hearing aid satisfaction, an indirect measure (Satisfaction with Amplification
      in Daily Living, SADL; Cox & Alexander, 1999) and a direct measure (an expanded
      version of the MarkeTrak-IV survey; Kochkin, 1996), in a group of elderly hearing
      aid wearers. DESIGN: A total of 43 elderly hearing aid wearers completed both
      satisfaction measures (order counterbalanced across wearers) after 1 mo of
      wearing 2-channel wide dynamic range compression (WDRC) in-the-canal (ITC)
      hearing aids. A correlational research design was employed. RESULTS: The elderly
      hearing aid wearers in this study yielded results on each measure of hearing aid
      satisfaction that were generally consistent with those found previously in larger
      groups of similar samples. The correlation between each measure of satisfaction
      (r = 0.75) was positive, moderately strong, and significant (p < 0.01) for the
      global scores of the SADL and MarkeTrak-IV scales. CONCLUSIONS: Although
      different approaches to the measurement of satisfaction were followed in the
      development of the SADL (indirect approach) and the MarkeTrak-IV (direct
      measurement) scales, similar results were obtained with each scale. The 15-item
      SADL instrument, however, is much shorter than the MarkeTrak-IV instrument and,
      as a result, is more efficient to administer clinically.

PMID- 12411776
TI  - Longitudinal changes in hearing aid satisfaction and usage in the elderly over a
      period of one or two years after hearing aid delivery.
AB  - OBJECTIVE: The objective of this study was to measure hearing aid satisfaction
      and usage for extended periods of time, up to 2 yr after hearing aid delivery, to
      determine whether longitudinal changes occur in the elderly for these outcome
      measures. DESIGN: A longitudinal study of hearing aid satisfaction and usage was
      performed in a group comprised of 134 elderly hearing aid wearers with these
      outcome measures obtained at 1, 6, and 12 mo postfit. A total of 49 of the
      original 134 elderly returned 2 yr after hearing aid delivery to complete the
      satisfaction and usage measures again. Multiple self-report measures of hearing
      aid satisfaction and hearing aid usage were obtained at each follow-up session.
      RESULTS: Most between-interval comparisons of the various measures of
      satisfaction and usage failed to reveal significant changes over time. However,
      some significant changes were observed in both satisfaction and usage. When such
      changes occurred, they were always in a direction that suggested a decrease in
      satisfaction or usage over time. Correlations across various postfit interval
      pairs were found to be positive, statistically significant, and moderate to
      strong in strength for all measures of satisfaction and usage. CONCLUSIONS:
      Although there were slight declines in hearing aid usage and satisfaction over
      time, measures of hearing aid satisfaction obtained at 1 mo postfit and of
      hearing aid usage obtained at 6 mo postfit are generally stable for up to 2 yr
      after hearing aid delivery.

PMID- 12411777
TI  - Auditory-visual speech perception and aging.
AB  - OBJECTIVE: This experiment was designed to assess the integration of auditory and
      visual information for speech perception in older adults. The integration of
      place and voicing information was assessed across modalities using the McGurk
      effect. The following questions were addressed: 1) Are older adults as successful
      as younger adults at integrating auditory and visual information for speech
      perception? 2) Is successful integration of this information related to
      lipreading performance? DESIGN: The performance of three groups of participants
      was compared: young adults with normal hearing and vision, older adults with
      normal to near-normal hearing and vision, and young controls, whose hearing
      thresholds were shifted with noise to match the older adults. Each participant
      completed a lipreading test and auditory and auditory-plus-visual identification
      of syllables with conflicting auditory and visual cues. RESULTS: The results show
      that on average older adults are as successful as young adults at integrating
      auditory and visual information for speech perception at the syllable level. The
      number of fused responses did not differ for the CV tokens across the ages
      tested. Although there were no significant differences between groups for
      integration at the syllable level, there were differences in the response
      alternatives chosen. Young adults with normal peripheral sensitivity often chose
      an auditory alternative whereas, older adults and control participants leaned
      toward visual alternatives. In additions, older adults demonstrated poorer
      lipreading performance than their younger counterparts. This was not related to
      successful integration of information at the syllable level. CONCLUSIONS: Based
      on the findings of this study, when auditory and visual integration of speech
      information fails to occur, producing a nonfused response, participants select an
      alternative response from the modality with the least ambiguous signal.

PMID- 12411778
TI  - Recognition of lexically controlled words and sentences by children with normal
      hearing and children with cochlear implants.
AB  - OBJECTIVE: The purpose of this study was to investigate the combined lexical
      effects of word frequency and neighborhood density (acoustic-phonetic similarity)
      on the recognition of words spoken in isolation and words spoken in sentences for
      children with normal hearing and children with cochlear implants. DESIGN:
      Lexically controlled sentences were created from a subset of words obtained from
      the spoken vocabulary of children between the ages of 3 and 5 yr. Two sentence
      lists were generated, applying the definitions and procedures of Kirk, Pisoni,
      and Osberger (1995) in accordance with the Neighborhood Activation Model ( Luce,
      1986; Luce & Pisoni, 1998). One list was composed of lexically "easy" words
      (those high in frequency of occurrence but phonemically dissimilar to other
      words) and the other list was composed of lexically "hard" words (those low in
      frequency of occurrence but phonemically similar to other words). Each list
      consisted of five practice and 20 test sentences that were syntactically correct
      but semantically neutral (low in predictability). Three key words were used in
      constructing each of the 5- to 7-word sentences, resulting in 15 practice and 60
      key words per test list. In the first of three experiments, 48 normal-hearing
      children between the ages of 5 and 12 yr were asked to repeat the words and
      sentences at one of six presentation levels to establish performance-intensity
      functions. In the second experiment, 12 normal-hearing children between the ages
      of 5 and 14 yr repeated the words and sentences under spectrally degraded
      conditions. Twelve children with cochlear implants ages 5 to 14 yr repeated the
      unprocessed stimuli in a third experiment. RESULTS: The lexically easy stimuli
      were recognized with greater accuracy than the lexically hard stimuli for the
      children tested in all three experiments. Sentence scores were significantly
      higher than word scores for the normal-hearing children (Experiments 1 and 2) and
      nine high-performing children with cochlear implants (Experiment 3). Word scores
      were higher than sentence scores for the three low-performing children with
      cochlear implants. There was a statistically significant relationship between
      chronological age and sentence score for the normal-hearing children listening
      under spectrally degraded conditions. For the children with cochlear implants,
      the relationship between language quotient and sentence and word scores was
      statistically significant. CONCLUSION: Sensitivity to the combined lexical
      properties of word frequency and neighborhood density was evident both for words
      and sentences. Lexically easy stimuli were recognized with greater accuracy than
      lexically hard stimuli across groups, affirming the robustness of this effect and
      verifying that words were being organized in relation to the frequency and
      acoustic-phonetic properties of other words. Syntactic context facilitated word
      recognition for the children with normal hearing and the high-performing implant
      group. The three low-performing children with cochlear implants recognized words
      more accurately than sentences, reflecting limitations in linguistic and
      cognitive capacity.

PMID- 12411779
TI  - Effects of stimulation rate with the Nucleus 24 ACE speech coding strategy.
AB  - OBJECTIVE: The primary objective of the study was to determine whether individual
      cochlear implant recipients recognize speech better with an electrical
      stimulation rate of 720 or 1800 pulses per second per channel (pps/ch) using the
      Nucleus 24 Advanced Combination Encoder (ACE) speech coding strategy. The
      secondary objective was to determine, for each active electrode, the relation
      between psychophysical measures and MAP minimum and maximum stimulation levels
      for each rate, as well as the stability of MAP minimum and maximum levels during
      the study. DESIGN: Eight postlinguistically deaf adults implanted with the
      Nucleus 24 device participated in this study comparing the effect of a moderate
      (720 pps/ch) and a fast (1800 pps/ch) rate of electrical stimulation on speech
      recognition of words in quiet and sentences in noise presented at 50, 60, and 70
      dB SPL in the laboratory and on listening to sound in everyday life over a 14-wk
      time period. At the beginning of the study, psychophysical measures (i.e.,
      counted threshold and maximum acceptable loudness [MAL] levels) were obtained for
      each active electrode with each of the two rates to initially set MAP minimum and
      maximum stimulation levels. These levels were then adjusted to make speech and
      environmental sound clear and comfortable in everyday life. Threshold and MAL
      levels were obtained again half way through the study to monitor possible hearing
      changes. A four-phase test design for evaluation of speech recognition was
      followed; an equal number of subjects started with each of the two rates and
      alternated rates for each phase. In the last 2 wk of each phase, word and
      sentence scores were obtained, and subjects responded to a questionnaire. For the
      group, factorial analyses of variance were conducted for subject, stimulation
      rate, and time period (first two phases versus second two phases) for words,
      phonemes within words, and sentences at each level. Additional analyses were
      obtained for individual subjects. RESULTS: Group mean scores across time periods
      were significantly higher for 1800 pps/ch than 720 pps/ch for phonemes and
      sentences in noise at 50 dB SPL. There was no significant difference in scores
      for phonemes and sentences at 60 and 70 dB SPL or for words at any of the three
      levels. Group mean scores across stimulation rate were significantly higher
      during the second half than the first half of the study for words, phonemes, and
      sentences at 50 dB SPL. This result is consistent with subjects learning to
      recognize speech cues near threshold. A subject by rate interaction was seen for
      sentences at 70 dB SPL and for all three speech measures at 50 dB SPL. These
      interactions reflect the fact that two subjects performed significantly better
      with 720 pps/ch, whereas two other subjects performed significantly better with
      1800 pps/ch. Responses to the questionnaire indicated that two subjects preferred
      720 pps/ch, three preferred 1800 pps/ch, and three had no preference. The minimum
      and/or maximum levels in most subjects' final MAPs differed from the
      psychophysical measures for both rates. Changes in Current Level at threshold and
      MAL were minimal from the first to the second half of the study for each rate.
      CONCLUSIONS: More than half the subjects preferred one of the two rates for use
      in everyday life, and four subjects performed significantly better with one of
      the two rates on at least one test measure. These findings underscore the
      clinical importance of creating MAPs for each implant recipient that include at
      least a moderate and a fast rate within ACE during the first months of device
      use. Given the significant learning effects for soft speech that occurred over
      several weeks use of each rate in this study, it is suggested that each rate be
      used alone for a week or two before comparing them and deciding which provides
      more benefit. In addition, adjustments in an individual's MAP minimum and maximum
      levels are needed at each rate so soft and normal conversational speech as well
      as loud sound are clear and comfortable in everyday life.

PMID- 12411780
TI  - Evaluation of electroacoustic test signals I: comparison with amplified speech.
AB  - OBJECTIVE: To evaluate the ability of clinical test signals to match the aided
      levels of real speech, across a range of hearing aid circuit types and strengths.
      DESIGN: Hearing aids (N = 41) were set to DSL targets for moderate, severe, and
      profound hearing losses. These hearing aids were tested with three test signals
      (Fonix Pure Tones, Fonix Composite Noise, and Audioscan Swept), as well as with
      running speech. The difference between the aided test signal and the aided speech
      was calculated. RESULTS: Accuracy of matches between aided test signals and aided
      speech levels depended on circuit type, signal type, and test level. CONCLUSIONS:
      Clinical test signals can more accurately match the aided levels of speech for
      all types of hearing aids if they are 1) speech-weighted and 2) temporally
      modulated. Matches were more accurate at low to moderate test levels (i.e., 50 to
      70 dB SPL), and less accurate at high test levels (i.e., 85 dB SPL).

PMID- 12411781
TI  - Evaluation of electroacoustic test signals II: development and cross-validation
      of correction factors.
AB  - OBJECTIVE: To develop and cross-validate corrections for improving the match
      between amplified speech levels and frequency response measurements with hearing
      aids. DESIGN: Previously published correction approaches were reviewed. Two
      regression-based corrections and two nonregression corrections were developed
      from an existing database of hearing aid responses measured with clinically
      available test signals and speech (Scollie & Seewald, 2002). Corrections were
      evaluated on a second database of digital hearing aid responses for test signals
      and speech. The second data set was constructed specifically to challenge three
      hypothesized threats to the robustness of the corrections. RESULTS: The error for
      each signal (corrected and uncorrected) was calculated. Correction procedures
      produced a significant improvement in the match between predicted and measured
      aided levels of speech. Inclusion of compression-related variables provided small
      but significant improvements. Results generalized to the second data set.
      CONCLUSIONS: Correction procedures may be applied to improve the match between
      aided test signal levels and aided levels of speech.

PMID- 12411782
TI  - Postoperative sleeping patterns tracked in children undergoing outpatient
      surgery.

PMID- 12411783
TI  - "Noninvasive" testing for malignant hyperthermia susceptibility.

PMID- 12411784
TI  - Safety in numbers: how do we study toxicity of spinal analgesics?

PMID- 12411785
TI  - Fact and fantasy about sleep and anesthesiology.

PMID- 12411786
TI  - Patients with malignant hyperthermia demonstrate an altered calcium control
      mechanism in B lymphocytes.
AB  - BACKGROUND: Altered Ca2+ homeostasis in skeletal muscle is a key molecular event
      triggering malignant hyperthermia (MH) in malignant hyperthermia-susceptible
      (MHS) individuals. Genetic studies have shown that mutations in the type 1
      ryanodine receptor (RYR1) are associated with MH susceptibility. Because human B
      lymphocytes express the RYR1, it is hypothesized that Ca2+ homeostasis in B
      lymphocytes is altered in MHS individuals. METHODS: This study investigated the
      Ca2+ response of B cells to caffeine and 4-chloro-m-cresol in 13 MHS and 21 MH
      negative (MHN) individuals who had been diagnosed by caffeine halothane
      contracture test (CHCT) and 18 healthy volunteers. Changes in [Ca2+]i in B cells
      were measured directly in fluo-3 loaded cells using a dual-color flow cytometric
      technique. Further, B cell phenotype was correlated with CHCT results in a family
      with the Val2168Met (G6502A) mutation. RESULTS: Caffeine-induced (50 mm)
      increases in [Ca2+]i in B cells were significantly greater in MHS than in MHN (P
      = 0.0004), control (P = 0.0001) or non-MHS (MHN and control) individuals (P <
      0.0001). The 4-chloro-m-cresol-induced (400 microm) increases in [Ca2+]i were
      also significantly different between MHS and controls (P = 0.003) or between MHS
      and non-MHS (MHN and control) individuals (P = 0.0078). A study of a family with
      the Val2168Met mutation demonstrated expression of the RYR1 mRNA mutant in B
      cells from the family members with MHS phenotype and a clear segregation of
      genotype with B-cell phenotype. CONCLUSION: The Ca2+ responses to caffeine or 4
      chloro-m-cresol in B lymphocytes showed significant differences between MHS and
      MHN (or control) individuals. Although the molecular mechanisms of these
      alterations are currently undetermined, the results suggest that the enhanced
      Ca2+ responses are associated with mutations in the RYR1 gene in some MHS
      individuals.

PMID- 12411787
TI  - Detection of proton release from cultured human myotubes to identify malignant
      hyperthermia susceptibility.
AB  - BACKGROUND: Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal
      muscle. During general anesthesia, a life-threatening hypermetabolic state may
      occur resulting from increased release of Ca2+ from the sarcoplasmic reticulum in
      skeletal muscle. Diagnosis of MH susceptibility requires surgical muscle biopsies
      to measure force in response to chemical stimulation (in vitro contracture test,
      IVCT). Here, the authors investigated an alternative way of discriminating MH
      susceptible (MHS) from normal (MHN) subjects by using cultured human myotubes and
      measuring proton release as an indicator of cellular metabolism. METHODS:
      Myotubes were stimulated with the Ca2+ release channel agonist 4-chloro-m-cresol
      (4-CmC), leading to metabolic activation and proton secretion. The rate of
      extracellular acidification was recorded with a silicon sensor chip. RESULTS: A
      stepwise increase in 4-CmC concentration led to a phasic-tonic increase in the
      acidification rate. The response, measured at different concentrations of 4-CmC,
      was considerably larger in cultures from MHS compared with MHN subjects and
      correlated well with the force response in the IVCT. CONCLUSIONS: The enhanced
      metabolism of cultured skeletal myotubes, likely originating from an increased
      myoplasmic Ca2+ concentration, can be monitored by studying the proton secretion
      rate. Because the method seems to be able to distinguish normal from pathologic
      phenotypes, it is a promising technique for possible future use in less invasive
      MH testing.

PMID- 12411788
TI  - Presence of two different genetic traits in malignant hyperthermia families:
      implication for genetic analysis, diagnosis, and incidence of malignant
      hyperthermia susceptibility.
AB  - BACKGROUND: Malignant hyperthermia susceptibility (MHS), an uncommon syndrome
      often inherited as an autosomal dominant trait, is characterized by a genetic and
      clinical heterogeneity. In this article, the authors described six pedigrees in
      which both parents of MHS patients were diagnosed with MHS by an diagnostic test.
      Haplotype and mutation analysis revealed that more than one MHS genetic trait was
      present in these families. METHODS: A panel of 104 MHS families were investigated
      with a caffeine halothane contracture test on muscle biopsy specimens. When
      possible, blood creatine kinase concentrations of MHS patients were measured.
      Haplotyping studies were conducted with chromosome 19q13.2 polymorphic markers
      and mutations were searched for in patients' DNA. RESULTS: In six families, the
      diagnostic test and genetic studies demonstrated that both, apparently unrelated,
      parents of MHS patients were MHS. In three families, homozygous or compound
      heterozygous individuals for RYR1 mutations were characterized at a molecular
      level. In one family, a compound heterozygous patient harboring a RYR1 mutation
      and a CACNA1S mutation was identified. While patients with two mutated alleles
      did not show differences in their muscle response to halothane or caffeine, their
      creatinine kinase concentrations were significantly elevated compared with the
      heterozygous patients. CONCLUSIONS: Based on genetic and diagnostic test data,
      more than one MHS allele associated with the MHS phenotype was evidenced in four
      families. These data should be considered in view of the use of genetics for the
      diagnosis of MHS and when reaching conclusions of genetic heterogeneity in MHS
      families. Taking into account the usual dominant mode of transmission of MHS and
      the size of the investigated population, the authors propose an evaluation of the
      incidence of the MHS in the general population based on genetic data.

PMID- 12411789
TI  - Comparative efficacy of acustimulation (ReliefBand) versus ondansetron (Zofran)
      in combination with droperidol for preventing nausea and vomiting.
AB  - BACKGROUND: Antiemetic drugs are costly, are associated with variable efficacy,
      and can produce unwanted side effects when used for prophylaxis against
      postoperative nausea and vomiting. This clinical study was designed to compare
      the efficacy of transcutaneous electrical acupoint stimulation using a ReliefBand
      to ondansetron (Zofran) when utilized alone or in combination for preventing
      postoperative nausea and vomiting after plastic surgery. METHODS: A single
      center, randomized, double-blind, placebo- and sham-controlled study design was
      conducted to compare three prophylactic antiemetic treatment regimens in 120
      outpatients undergoing plastic surgery procedures with routine low-dose
      droperidol prophylaxis: (1) ondansetron (n = 40), 4 mg intravenous ondansetron
      and a sham ReliefBand; (2) acustimulation (n = 40), 2 ml intravenous saline and
      an active ReliefBand; and (3) combination (n = 40), 4 mg intravenous ondansetron
      and an active ReliefBand. The incidences of postoperative nausea and vomiting, as
      well as the need for "rescue" antiemetics, were determined at specific time
      intervals for up to 72 h after surgery. The outcome variables assessed included
      recovery times, quality of recovery score, time to resumption of normal diet, and
      patient satisfaction with the prophylactic antiemetic therapy. RESULTS: Use of
      the ReliefBand in combination with ondansetron significantly reduced nausea (20
      vs. 50%), vomiting (0 vs. 20%), and the need for rescue antiemetics (10 vs. 37%)
      compared with ondansetron alone at 24 h after surgery. Furthermore, the ability
      to resume a normal diet (74 vs. 35%) within 24 h after surgery was significantly
      improved when the ReliefBand was used to supplement ondansetron (vs. ondansetron
      alone). Finally, the quality of recovery (90 +/- 10 vs.70 +/- 20) and patient
      satisfaction (94 +/- 10 vs. 75 +/- 22) scores were significantly higher in the
      combination group the ondansetron group. There were no significant differences
      between the ReliefBand and ondansetron when administered as adjuvants to
      droperidol for antiemetic prophylaxis. CONCLUSIONS: The ReliefBand compared
      favorably to ondansetron (4 mg intravenously) when used for prophylaxis against
      postoperative nausea and vomiting. Furthermore, the acustimulation device
      enhanced the antiemetic efficacy of ondansetron after plastic surgery.

PMID- 12411790
TI  - Concentration-effect relation of succinylcholine chloride during propofol
      anesthesia.
AB  - BACKGROUND: The pharmacokinetics and pharmacodynamics of succinylcholine were
      studied simultaneously in anesthetized patients to understand why the drug has a
      rapid onset and short duration of action. A quantitative model describing the
      concentration-effect relation of succinylcholine was proposed. The correlation
      between hydrolysis in plasma and elimination was also examined. METHODS: Before
      induction of anesthesia, blood was drawn for analysis in seven adults. Anesthesia
      was induced with propofol and remifentanil. Single twitch stimulation was applied
      at the ulnar nerve every 10 s, and the force of contraction of the adductor
      pollicis was measured. Arterial blood was drawn frequently after succinylcholine
      injection to characterize the front-end kinetics. Plasma concentrations were
      measured by mass spectrometry, and pharmacokinetic parameters were derived using
      compartmental and noncompartmental approaches. Pharmacokinetic-pharmacodynamic
      relations were estimated. RESULTS: The mean degradation rate constant in plasma
      (1.07 +/- 0.49 min(-1)) was not different from the elimination rate constant
      (0.97 +/- 0.30 min(-1)), and an excellent correlation (r2 = 0.94) was observed.
      Total body clearance derived using noncompartmental (37 +/- 7 ml x min(-1) x kg(
      1)) and compartmental (37 +/- 9 ml x min(-1) x kg(-1)) approaches were similar.
      The plasma-effect compartment equilibration rate constant (k(eo)) was 0.058 +/-
      0.026 min(-1), and the effect compartment concentration at 50% block was 734 +/-
      211 ng/ml. CONCLUSION: Succinylcholine is a low-potency drug with a very fast
      clearance that equilibrates relatively slowly with the effect compartment. Its
      disappearance is greatly accountable by a rapid hydrolysis in plasma.

PMID- 12411791
TI  - Sleeping characteristics of children undergoing outpatient elective surgery.
AB  - BACKGROUND: A significant number of children undergoing anesthesia and surgery
      exhibit new-onset sleep-related problems postoperatively. The aim of this
      longitudinal cohort study was to expand previous research in this area by using a
      new objective technology. METHODS: This study compared children undergoing
      general anesthesia and outpatient surgery (n = 92) to a community-based control
      group of children (n = 77). Data regarding coping, temperament, anxiety, surgical
      procedures, and postoperative pain were collected. Subjects underwent actigraphy
      sleep monitoring for at least 3 nights before surgery and 5 postoperative days
      (POD). Sleep assessment was performed with actigraphy sleep monitoring and the
      Post Hospitalization Behavioral Questionnaire (PHBQ). RESULTS: Forty-three
      children (47%) in the surgery group experienced postoperative sleeping
      disturbances as determined by either the actigraphy or the PHBQ. Only 13 children
      (14.4%), however, experienced a decrease of at least 1 SD in percentage sleep as
      assessed by actigraphy. Postoperative pain scores on POD 1 and POD 2 were
      significantly higher among children who exhibited sleep problems as diagnosed by
      actigraphy (F = 4.283; P= 0.047). Also, children who exhibited actigraph-based
      sleep problems scored lower sociability-temperament (14.1 +/- 4.3 vs. 17.5 +/-
      3.4; P= 0.04) scores compared with the community group and had a higher rate of
      change in their perioperative anxiety levels (group x time interaction, F = 5.1;
      P= 0.03). CONCLUSION: A significant number of children undergoing outpatient
      surgery experience postoperative sleep-related problems. The clinical
      significance of this finding, however, is unclear.

PMID- 12411792
TI  - Impact of alloantigens and storage-associated factors on stimulated cytokine
      response in an in vitro model of blood transfusion.
AB  - BACKGROUND: Transfusion of blood may contribute to immunosuppression in major
      surgery. The authors assessed the impact of alloantigens and storage on function
      of peripheral blood mononuclear cells cultured in their physiologic environment.
      METHODS: Blood units (whole blood, packed erythrocytes) were prepared with or
      without prestorage leukodepletion and stored for 24-26 days. Blood samples were
      coincubated with allogeneic fresh blood, autologous, or allogeneic stored blood.
      Endotoxin-stimulated release of tumor necrosis factor-alpha (TNF-alpha) and
      interleukin 10 (IL-10) was measured after 24 h of culture by enzyme-linked
      immunosorbent assay. RESULTS: Coincubation with equal amounts of allogeneic fresh
      blood showed almost no influence on TNF-alpha (-12%, not significant) and IL-10
      (+11%, not significant) release. Stored allogeneic whole blood resulted in a
      significant TNF-alpha depression (-61%) and IL-10 induction (+221%). These
      effects were diminished but not prevented by prestorage leukodepletion (TNF-alpha
      -42%, IL-10 +110%) and required the presence of soluble factors (TNF-alpha
      suppression) and cellular components (IL-10 induction). TNF-alpha decrease and IL
      10 increase were in the same order of magnitude (-40%, +134% with, -65%, +314%
      without leukodepletion) after coincubation with autologous blood. In contrast,
      allogeneic erythrocytes had only little effects (TNF-alpha -6%, IL-10 +36%) even
      at this high transfusion equivalent. CONCLUSION: These data suggest that banked
      whole blood has an immunosuppressive effect that is largely attributable to
      storage-dependent factors. These factors are partially removed by prestorage
      leukodepletion, while the contribution of alloantigens is of minor significance.
      Immunosuppressive effects are least apparent with leukodepleted erythrocytes,
      suggesting that the presence of plasma during storage is required for the
      immunosuppressive effect to develop.

PMID- 12411793
TI  - Synchronous rhythmical vasomotion in the human cutaneous microvasculature during
      nonpulsatile cardiopulmonary bypass.
AB  - BACKGROUND: The origin, control mechanisms, and functional significance of
      oscillations in microvascular flow are incompletely understood. Although the
      traditional belief has been that only low-frequency oscillations (0.04-0.10 Hz)
      can originate at the microvascular level, recent evidence in healthy volunteers
      has suggested that high-frequency oscillations (> 0.10 Hz) also may have a
      microvascular origin (as opposed to being mechanically transmitted respiratory
      induced variations in stroke volume). The current study determined if such
      oscillations would emerge in the absence of cardiac and respiratory activity
      during nonpulsatile cardiopulmonary bypass (NP-CPB). METHODS: Forehead and finger
      laser Doppler flow, arterial pressure, and core temperature were simultaneously
      recorded in eight patients during NP-CPB. Analyses included time- domain indices,
      frequency-domain indices (auto power spectral density), and a measure of
      regularity (approximate entropy) for standardized time segments. RESULTS:
      Nonpulsatile cardiopulmonary bypass was associated with the emergence of
      rhythmical oscillations in laser Doppler flow, with characteristic frequencies
      for the forehead (0.13 +/- 0.03 Hz) and finger (0.07 +/- 0.02 Hz). Forehead
      vasomotion became progressively synchronized, with a gain in high-frequency
      spectral power from 17.5 (minute 1) to 89.1 (minute 40) normalized units, and a
      decrease in approximate entropy from 1.2 (before NP-CPB) to less than 0.5 (minute
      40). CONCLUSIONS: The emergence of forehead microvascular oscillations at greater
      than 0.10 Hz (characteristic of parasympathetic frequency response), in the
      absence of cardiac and respiratory variability, demonstrates their peripheral
      origin and provides insights into parasympathetic vasoregulatory mechanisms. The
      progressive synchronization of forehead vasomotion during NP-CPB, suggestive of
      increased coupling among microvascular biologic oscillators, may represent a
      microcirculatory homeostatic response to systemic depulsation, with potential
      implications for end-organ perfusion.

PMID- 12411794
TI  - Platelet PlA2 polymorphism and platelet activation are associated with increased
      troponin I release after cardiopulmonary bypass.
AB  - BACKGROUND: The PlA2 polymorphism of platelet glycoprotein IIIa has been
      identified as a prothrombotic risk factor in a number of cardiovascular settings.
      The aim of this study was to determine whether the PlA2 polymorphism of platelet
      glycoprotein IIIa and degree of platelet activation were associated with more
      severe myocardial injury as indicated by troponin I release following
      cardiopulmonary bypass. METHODS: The PlA2 genotype was determined in 66 patients
      undergoing elective coronary artery bypass grafting requiring cardiopulmonary
      bypass. Troponin I concentrations and the percentage of circulating, activated
      (CD62P+) platelets were measured at predetermined intervals perioperatively.
      RESULTS: Forty-six patients were Pl(A1,A1), and 20 were Pl(A1,A2) or Pl(A2,A2).
      Patients with at least one PlA2 allele had significantly greater postoperative
      troponin I concentrations than PlA1 homozygotes (P = 0.006, analysis of
      variance). Peak troponin I concentrations also correlated significantly with the
      increase in circulating, activated platelets (P = 0.02, Spearman rank
      correlation). CONCLUSIONS: The PlA2 allele of platelet glycoprotein IIIa is
      associated with higher troponin I concentrations following cardiopulmonary bypass
      surgery, suggesting that this platelet polymorphism contributes to perioperative
      myocardial injury.

PMID- 12411795
TI  - Abnormal echogenic findings detected by transesophageal echocardiography and
      cardiorespiratory impairment during total knee arthroplasty with tourniquet.
AB  - BACKGROUND: In patients undergoing total knee arthroplasty, intraoperative
      pulmonary embolic events are rare, and most occur following tourniquet deflation.
      This embolization can be observed using transesophageal echocardiography.
      However, the authors have encountered sudden decreases in arterial oxygen partial
      pressure while a tourniquet is still inflated. Therefore, the current
      investigation was designed to detect emboli during the tourniquet inflation phase
      and to identify the composition of the echogenic material. METHODS: Forty-six
      patients were randomly assigned to undergo total knee arthroplasty without
      (control, n = 24) or with a tourniquet (n = 22). Hemodynamic monitoring, blood
      gas analysis, and continuous transesophageal echocardiography were performed
      during the total knee arthroplasty procedure. Right jugular blood specimens were
      collected whenever echogenic material was seen in the atrium. RESULTS: In the
      tourniquet group, embolic events occurred in 27% of patients during femoral
      reaming and in 100% after tourniquet deflation. In the control group, emboli were
      detected in 54% of patients during femoral reaming. Most of the patients
      exhibited cardiopulmonary impairment after severe echogenic embolism, even while
      the tourniquet was inflated (two patients). None of the blood samples aspirated
      from the central catheters contained detectable material. CONCLUSIONS: This
      prospective study showed that embolic events occurred during total knee
      arthroplasty, even while a tourniquet was inflated. An inflated tourniquet does
      not completely prevent pulmonary emboli.

PMID- 12411796
TI  - The minimum alveolar concentration of xenon in the elderly is sex-dependent.
AB  - BACKGROUND: The minimum alveolar concentration (MAC) of xenon in the elderly has
      not been determined. Moreover, because xenon inhibits the activity of the N
      methyl-D-aspartate receptors, and because N-methyl-D-aspartate receptor
      antagonists such as ketamine and MK-801 exert sex-dependent actions, we
      hypothesized that the MAC of xenon would also be sex-dependent. METHODS: Forty
      eight patients of both sexes (24 patients of each sex), who were aged 65 yr or
      older and were undergoing elective laparotomy, were anesthetized with
      inhalational induction of xenon. Those who demonstrated marked agitation received
      supplemental propofol intravenously. After tracheal intubation, the end-tidal
      concentration of xenon was maintained at 45 (women only), 50, 55, 60, 65, 70, or
      75% (men only) for at least 15 min before skin incision. These concentrations
      were randomly allocated to four patients of each sex. Each patient was monitored
      for the presence or absence of any purposeful bodily movement for 1 min following
      skin incision. The MAC of xenon was calculated separately for men and women using
      logistic regression analysis. RESULTS: The MAC of xenon was 69.3% (95% CI, 63.0
      75.6%) for men and 51.1% (44.6-57.6%) for women. The two 95% confidence intervals
      did not overlap, indicating a statistically significant difference (P < 0.05).
      CONCLUSIONS: The MAC of xenon in the elderly is higher in men than in women.

PMID- 12411797
TI  - Renal responses to desflurane and isoflurane in patients with renal
      insufficiency.
AB  - BACKGROUND: The most consistent risk factor for postoperative renal failure is
      poor preoperative renal function. Desflurane is not contraindicated in patients
      with renal disease, but the data regarding its effects on renal function in these
      patients are sparse. METHODS: Only patients with preexisting renal disease were
      recruited into the study. In 51 adults undergoing elective surgery, general
      anesthesia was maintained using randomly desflurane or isoflurane according to a
      standardized protocol. Creatinine, creatinine clearance, and blood urea nitrogen
      were measured pre- and postoperatively. RESULTS: The administered amounts of the
      inhaled anesthetic agents were 1.8 +/- 2.1 minimum alveolar concentration hours
      (mean +/- SD) of isoflurane (24 patients) and 2.2 +/- 1.8 minimum alveolar
      concentration hours of desflurane (27 patients), respectively. No deterioration
      in renal parameters was noted when comparing the pre- and postoperative values
      between the groups and within the groups over time. CONCLUSION: General
      anesthesia with desflurane or isoflurane did not aggravate renal impairment in
      patients with preexisting renal insufficiency.

PMID- 12411798
TI  - Intravenous magnesium sulfate administration reduces propofol infusion
      requirements during maintenance of propofol-N2O anesthesia: part I: comparing
      propofol requirements according to hemodynamic responses: part II: comparing
      bispectral index in control and magnesium groups.
AB  - BACKGROUND: The authors investigated whether an intravenous administration of
      magnesium sulfate reduces propofol infusion requirements during maintenance of
      propofol-N2O anesthesia. METHODS: Part I study: 54 patients undergoing total
      abdominal hysterectomy were randomly divided into two groups (n = 27 per group).
      The patients in the control group received 0.9% sodium chloride solution, whereas
      the patients in the magnesium group received magnesium (50 mg/kg as a bolus, then
      8 mg x kg(-1) x h(-1)). To maintain mean arterial blood pressure (MAP) and heart
      rate (HR) at baseline value, the propofol infusion rate was changed when the MAP
      or the HR changed. The amount of propofol infused excluding the bolus dosage was
      divided by patient's body weight and total infusion time. Part II study: Another
      20 patients were randomly divided into two groups (n = 10 per group). When the
      MAP and HR had been maintained at baseline value and the propofol infusion rate
      had been maintained at 80 microg x kg(-1) x min(-1) (magnesium group) and 160
      microg x kg(-1) x min(-1) (control group), bispectral index (BIS) values were
      measured. RESULTS: Part I: The mean propofol infusion rate in the magnesium group
      (81.81 +/- 13.09 microg x kg(-1) x min(-1)) was significantly less than in the
      control group (167.57 +/- 47.27). Part II: BIS values in the control group (40.70
      +/- 3.89) were significantly less than those in the magnesium group (57.80 +/-
      7.32). CONCLUSION: Intravenous administration of magnesium sulfate reduces
      propofol infusion requirements. These results suggest that magnesium
      administration may have an effect on anesthesia or analgesia and may be a useful
      adjunct to propofol anesthesia.

PMID- 12411799
TI  - Remifentanil requirements during sevoflurane administration to block somatic and
      cardiovascular responses to skin incision in children and adults.
AB  - BACKGROUND: The authors found no studies comparing intraoperative requirements of
      opioids between children and adults, so they determined the infusion rate of
      remifentanil to block somatic (IR50) and autonomic response (IRBAR50) to skin
      incision in children and adults. METHODS: Forty-one adults (aged 20-60 yr) and 24
      children (aged 2-10 yr) undergoing lower abdominal surgery were studied. In
      adults, anesthesia induction was with sevoflurane during remifentanil infusion,
      whereas in children remifentanil administration was started after induction with
      sevoflurane. After intubation, sevoflurane was administered in 100% O2 and was
      adjusted to an ET% of 1 MAC-awake corrected for age at least 15 min before
      surgery. Patients were randomized to receive remifentanil at a rate ranging from
      0.05 to 0.35 microg x kg(-1) x min(-1) for at least 20 min before surgery. At the
      beginning of surgery, only the skin incision was performed, and the somatic and
      autonomic responses were observed. The somatic response was defined as positive
      with any gross movement of extremity, and the autonomic response was deemed
      positive with any increase in heart rate mean arterial pressure equal to or more
      than 10% of preincision values. Using logistic regression, the IR50 and IRBAR50
      were determined in both groups of patients and compared with unpaired Student t
      test. A P value less than 0.05 was considered significant. RESULTS: The IR50 +/-
      SD was 0.10 +/- 0.02 microg x kg(-1) x min(-1) in adults and 0.22 +/- 0.03 microg
      x kg(-1) x min(-1) in children (P < 0.001). The IRBAR50 +/- SD was 0.11 +/- 0.02
      microg x kg(-1) x min(-1) in adults and 0.27 +/- 0.06 microg x kg(-1) x min(-1)
      in children (P < 0.001). CONCLUSIONS: To block somatic and autonomic responses to
      surgery, children require a remifentanil infusion rate at least twofold higher
      than adults.

PMID- 12411800
TI  - Negative and positive inotropic effects of propofol via L-type calcium channels
      and the sodium-calcium exchanger in rat cardiac trabeculae.
AB  - BACKGROUND: Conflicting opinions are present in the literature regarding the
      origin of the negative inotropic effect of propofol on the myocardium. This study
      aims to resolve these discrepancies by investigating the inotropic effects of
      propofol the L-type calcium channels and the sodium-calcium exchanger (NCX).
      METHODS: The effect of 20 microg/ml propofol on force development was determined
      in rat cardiac trabeculae at different pacing frequencies and different
      extracellular calcium concentrations. Postrest potentiation, sodium withdrawal
      during quiescence, and the NCX inhibitor KB-R7943 were used to study changes in
      the activity of the reverse mode of the NCX by propofol. RESULTS: The effect of
      propofol on steady state peak force depended on pacing frequency and calcium
      concentration. A negative inotropic effect was observed at pacing frequencies
      greater than 0.5 Hz, but a positive inotropic effect was observed at 0.1 Hz and
      low calcium, which cannot be explained by an effect on the L-type calcium
      channel. Propofol enhanced postrest potentiation in a calcium-dependent manner.
      Sodium withdrawal during quiescence and the use of the specific NCX inhibitor KB
      R7943 provided evidence for an enhancement of calcium influx by propofol the
      reverse mode of the NCX. CONCLUSIONS: The effects of propofol on the myocardium
      depend on pacing frequency and calcium concentration. The positive inotropic
      effect of propofol is associated with increased calcium influx the reverse mode
      of the NCX. The authors conclude that the net inotropic effect of propofol is the
      result of its counteracting influence on the functioning of the L-type calcium
      channel and the NCX.

PMID- 12411801
TI  - Influence of hemorrhage on propofol pseudo-steady state concentration.
AB  - BACKGROUND: A small induction dose has been recommended in cases of hemorrhagic
      shock. However, the influence of hemorrhage on the amplitude of plasma propofol
      concentration has not yet been fully investigated during continuous propofol
      infusion. The authors hypothesized that the effect of hemorrhage on plasma
      propofol concentration is variously influenced by the different stages of shock.
      METHODS: After 120 min of steady state infusion of propofol at a rate of 2 mg x
      kg(-1) x h(-1), nine instrumented immature swine were studied using a stepwise
      increasing hemorrhagic model (200 ml of blood every 30 min until 1 h, then
      additional stepwise bleeding of 100 ml every 30 min thereafter, to the point of
      circulatory collapse). Hemodynamic parameters and plasma propofol concentration
      were recorded at every step. RESULTS: Before total circulatory collapse, it was
      possible to drain 976 +/- 166 ml (mean +/- SD) of blood. Hemorrhage of less than
      600 ml (19 ml/kg) was not accompanied by a significant change in plasma propofol
      concentration. At individual peak systemic vascular resistance, when cardiac
      output and mean arterial pressure decreased by 31% and 14%, respectively, plasma
      propofol concentration increased by 19% of its prehemorrhagic value. At maximum
      heart rate, when cardiac output and mean arterial pressure decreased by 46% and
      28%, respectively, plasma propofol concentration increased by 38%. In
      uncompensated shock, it increased to 3.75 times its prehemorrhagic value.
      CONCLUSIONS: During continuous propofol infusion, plasma propofol concentration
      increased by less than 20% during compensated shock. However, it increased 3.75
      times its prehemorrhagic concentration during uncompensated shock.

PMID- 12411802
TI  - Sulfite supported lipid peroxidation in propofol emulsions.
AB  - BACKGROUND: Sodium metabisulfite is added to a commercial propofol emulsion as an
      antimicrobial agent. The sulfite ion (SO3(-2)) is capable of undergoing a number
      of reactions, including autooxidation and the promotion of lipid peroxidation.
      This study evaluated sulfite reactivity in propofol emulsions by determining
      thiobarbituric acid reacting substances (TBARS), sulfite depletion, and emulsion
      pH in emulsions containing sulfite or EDTA. METHODS: Commercial EDTA and sulfite
      propofol emulsions were compared, and 10% soybean oil emulsion containing various
      additives were evaluated for TBARS, sulfite, and pH. TBARS were analyzed with a
      modified thiobarbituric acid method. Sulfite was analyzed by the reaction of
      sulfite with 5,5'-dithiobis(2-nitrobenzoic acid). pH was measured by glass
      electrode methodology. RESULTS: Thiobarbituric acid reacting substances were
      detectable in commercial sulfite propofol emulsions in concentrations ranging
      from 0.02 to 0.22 microg/ml based on malondialdehyde. No TBARS were detected in
      EDTA propofol emulsions. Incubation (37 degrees C, up to 6 h) of sulfite propofol
      emulsions in air resulted in further increases in TBARS (35-160%). No increases
      occurred in incubated EDTA propofol emulsions. Metabisulfite (0.25 mg/ml) alone
      added to 10% soybean oil resulted in large increases in TBARS that were inhibited
      in part by propofol (10 mg/ml) and completely by ascorbic acid (0.05 mg/ml).
      Soybean oil emulsion pH declined rapidly on the addition of metabisulfite (0.25
      mg/ml). The addition of propofol (10 mg/ml) partially inhibited the decline in pH
      and ascorbic acid (0.05 mg/ml) completely inhibited it. CONCLUSION: These results
      show that sulfite supports the peroxidation of lipids in soybean oil emulsions
      and propofol functions to partially inhibit these processes.

PMID- 12411803
TI  - Bupivacaine attenuates contractility by decreasing sensitivity of myofilaments to
      Ca2+ in rat ventricular muscle.
AB  - BACKGROUND: Bupivacaine exhibits a cardiodepressant effect, the molecular
      mechanism(s) of which have yet to be fully understood. Bupivacaine may directly
      act on contractile proteins and thereby decrease myofibrillar Ca2+ sensitivity.
      METHODS: Rat ventricular muscle was used. First, the effect of bupivacaine was
      examined on tetanic contractions in isolated intact myocytes. Next, Triton X-100
      treated ventricular trabeculae were used to investigate the effect of bupivacaine
      on the pCa (= -log [Ca2+ ])-tension relation as well as on maximal Ca2+ 
      activated tension. Furthermore, to test whether bupivacaine inhibits the pathway
      downstream from Ca2+ binding to troponin C, tension was elicited in the skinned
      preparations by lowering the Mg-adenosine triphosphate (MgATP) concentration in
      the absence of Ca2+. The effect of bupivacaine on the pMgATP (= -log [MgATP])
      tension relation was examined. RESULTS: In myocytes, 3 microm bupivacaine
      significantly (P < 0.01) increased intracellular Ca2+ concentration required for
      5% cell shortening from the resting cell length. In skinned preparations,
      bupivacaine shifted the pCa-tension relation to the lower pCa side; the midpoint
      of the pCa curve (pCa50) was significantly (P < 0.05) changed by 10 and 100
      microm bupivacaine. A highly correlated linear relation (R = 0.81; P< 0.0005) was
      present between pCa50 and maximal Ca2+ -activated tension. Bupivacaine (10 and
      100 microm) significantly (P < 0.05) shifted the midpoint of the pMgATP-tension
      relation to the higher pMgATP side. CONCLUSIONS: Bupivacaine decreases
      myofibrillar Ca2+ sensitivity in ventricular muscle, and this is coupled with the
      compound's inhibitory effect on the pathway beyond Ca2+ binding to troponin C,
      possibly on the actomyosin interaction. The current results may partly explain
      the overall cardiodepressant effect of bupivacaine in vivo.

PMID- 12411804
TI  - Transmission through the dorsal spinocerebellar and spinoreticular tracts:
      wakefulness versus thiopental anesthesia.
AB  - BACKGROUND: Most of what is known regarding the actions of injectable barbiturate
      anesthetics on the activity of lumbar sensory neurons arises from experiments
      performed in acute animal preparations that are exposed to invasive surgery and
      neural depression caused by coadministered inhalational anesthetics. Other
      parameters such as cortical synchronization and motor ouflow are typically not
      monitored, and, therefore, anesthetic actions on multiple cellular systems have
      not been quantitatively compared. METHODS: The activities of antidromically
      identified dorsal spinocerebellar and spinoreticular tract neurons, neck
      motoneurons, and cortical neurons were monitored extracellularly before, during,
      and following recovery from the anesthetic state induced by thiopental in intact,
      chronically instrumented animal preparations. RESULTS: Intravenous administration
      of 15 mg/kg, but not 5 mg/kg, of thiopental to awake cats induced general
      anesthesia that was characterized by 5-10 min of cortical synchronization,
      reflected as large-amplitude slow-wave events and neck muscle atonia. However,
      even though the animal behaviorally began to reemerge from the anesthetic state
      after this 5-10-min period, neck muscle (neck motoneuron) activity recovered more
      slowly and remained significantly suppressed for up to 23 min after thiopental
      administration. The spontaneous activity of both dorsal spinocerebellar and
      spinoreticular tract neurons was maximally suppressed 5 min after administration
      but remained significantly attenuated for up to 17 min after injection.
      Peripheral nerve and glutamate-evoked responses of dorsal spinocerebellar and
      spinoreticular tract neurons were particularly sensitive to thiopental
      administration and remained suppressed for up to 20 min after injection.
      CONCLUSIONS: These results demonstrate that thiopental administration is
      associated with a prolonged blockade of motoneuron output and sensory
      transmission through the dorsal spinocerebellar and spinoreticular tracts that
      exceeds the duration of general anesthesia. Further, the blockade of glutamate
      evoked neuronal responses indicates that these effects are due, in part, to a
      local action of the drug in the spinal cord. The authors suggest that this
      combination of lumbar sensory and motoneuron inhibition underlies the prolonged
      impairment of reflex coordination observed when thiopental is used clinically.

PMID- 12411805
TI  - Mild hypothermia has minimal effects on the tolerance to severe progressive
      normovolemic anemia in Swine.
AB  - BACKGROUND: The benefits of hypothermia during acute severe anemia are not
      entirely settled. The authors hypothesized that cooling would improve tolerance
      to anemia. METHODS: Eight normothermic (38.0 +/- 0.5 degrees C) and eight
      hypothermic (32.0 +/- 0.5 degrees C) pigs anesthetized with midazolam-fentanyl
      vecuronium-isoflurane (0.5% inspired concentration) were subjected to stepwise
      normovolemic hemodilution (hematocrit, 15%, 10%, 7%, 5%, 3%). Critical hemoglobin
      concentration (Hgb(CRIT)) and critical oxygen delivery (DO(2CRIT)), i.e., the
      hemoglobin concentration (Hgb) and oxygen delivery (DO2) at which oxygen
      consumption (VO2, independently measured by indirect calorimetry) was no longer
      sustained, and Hgb at the moment of death, defined prospectively as the point
      when VO2, decreased below 40 ml/min, were used to assess the tolerance of the two
      groups to progressive isovolemic anemia. RESULTS: At hematocrits of 15% and 10%
      (Hgb, 47 and 31 g/l), VO2 was maintained in both groups by an increase (P <
      0.001) in cardiac output (CO) and extraction ratio (ER; P< 0.001) with unchanged
      mean arterial lactate concentration (L(art)). At hematocrit of 7% (Hgb, 22 g/l),
      all normothermic but no hypothermic animals had DO2-dependent VO2. No
      normothermic and three hypothermic animals survived to 5% hematocrit (Hgb, 15
      g/l), and none survived to 3%. Hgb(CRIT) was 23 +/- 2 g/l and 19 +/- 6 g/l (mean
      +/- SD) in normothermic and hypothermic animals, respectively (P = 0.053). Hgb at
      death was 19 +/- 3 g/l versus 14 +/- 4 g/l (P = 0.015), and DO(2CRIT) was 8.7 +/-
      1.7 versus 4.6 +/- 0.8 ml x kg(-1) x min(-1) (P < 0.001). CONCLUSION: During
      progressive normovolemic hemodilution in pigs, hypothermia did not significantly
      change Hgb(CRIT), but it decreased the Hgb at death, i.e., short-term survival
      was prolonged.

PMID- 12411806
TI  - Protein tyrosine kinase-dependent modulation of isoflurane effects on cardiac
      sarcolemmal K(ATP) channel.
AB  - BACKGROUND: Cardiac adenosine triphosphate-sensitive potassium (K(ATP)) channels
      and protein tyrosine kinases (PTKs) are mediators of ischemic preconditioning,
      but the interaction of both and a role in myocardial protection afforded by
      volatile anesthetics have not been defined. METHODS: Whole cell and single
      channel patch clamp techniques were used to investigate the effects of isoflurane
      and the PTK inhibitor genistein on the cardiac sarcolemmal K(ATP) channel in
      acutely dissociated guinea pig ventricular myocytes. RESULTS: At 0.5 mm internal
      ATP, genistein (50 microm) elicited whole cell K(ATP) current (22.5 +/- 7.9
      pA/pF). Genistein effects were concentration-dependent, with an EC50 of 32.3 +/-
      1.4 microm. Another PTK inhibitor, tyrphostin B42, had a similar effect. The
      inactive analog of genistein, daidzein (50 microm), did not elicit K(ATP)
      current. Isoflurane (0.5 mm) increased genistein (35 microm)-activated whole cell
      K(ATP) current from 14.5 +/- 3.1 to 32.5 +/- 6.6 pA/pF. Stimulation of receptor
      PTKs with epidermal growth factor, nerve growth factor, or insulin attenuated
      genistein and isoflurane effects, and the protein tyrosine phosphatase inhibitor
      orthovanadate (1 mm) prevented their actions on K(ATP) current. In excised inside
      out membrane patches, and at fixed 0.2 mm internal ATP, genistein (50 microm)
      increased channel open probability from 0.053 +/- 0.016 to 0.183 +/- 0.039, but
      isoflurane failed to further increase open probability (0.162 +/- 0.051) of
      genistein-activated channels. However, applied in the presence of genistein and
      protein tyrosine phosphatase 1B (1 microg/ml), isoflurane significantly increased
      open probability to 0.473 +/- 0.114. CONCLUSIONS: These results suggest that the
      PTK-protein tyrosine phosphatase signaling pathway may be one of the regulators
      of cardiac sarcolemmal K(ATP) channel and may play a role in modulating its
      responsiveness to isoflurane. Relative importance of this modulation for
      cardioprotection by volatile anesthetics remains to be established.

PMID- 12411807
TI  - Biphasic effects of isoflurane on the cardiac action potential: an ionic basis
      for anesthetic-induced changes in cardiac electrophysiology.
AB  - BACKGROUND: The mechanism underlying isoflurane modulation of cardiac
      electrophysiology is not well understood. In the present study, the authors
      investigated the effects of isoflurane on the cardiac action potential (AP)
      characteristics. The results were correlated to modulation of the L-type calcium
      (I(Ca,L)), the delayed-rectifier potassium (I(Kdr)), and the inward-rectifier
      potassium (I(Kir)) currents. METHODS: Single ventricular myocytes were
      enzymatically isolated from guinea pig hearts. The current clamp and whole cell
      voltage clamp configurations of the patch clamp technique were used to monitor
      the cardiac AP and ionic currents, respectively. A dynamic AP voltage protocol
      that mimicked changes in membrane potential during an AP was used to monitor the
      I(Ca,L), I(Kdr) and I(Kir). RESULTS: Isoflurane produced a concentration
      dependent, biphasic effect on the AP duration (APD). At 0.6 mm (1.26 vol%),
      isoflurane significantly increased APD50 and APD90 by 50.0 +/- 7.6% and 48.9 +/-
      7.2%, respectively (P < 0.05; n = 6). At 1.0 mm (2.09 vol%), isoflurane had no
      significant effect on APD (n = 6). In contrast, at 1.8 mm (3.77 vol%), isoflurane
      decreased APD50 and APD90 by 38.3 +/- 5.4% and 32.2 +/- 5.5%, respectively (P <
      0.05; n = 7). The inhibitory effects of isoflurane on I(Kdr) chord conductance
      were greater than those on I(Ca,L) (P < 0.05; n = 6/group). Both I(Ca,L)
      inactivation and I(Kdr) activation kinetics were accelerated by isoflurane.
      Isoflurane had no significant effects on I(Kir) chord conductance (n = 6).
      CONCLUSION: At the lower anesthetic concentration, the prolongation of the APD
      may be the result of the dominant inhibitory effects of isoflurane on I(Kdr). At
      the higher concentration, the shortening of the APD may be caused by the
      inhibitory effects on I (Ca,L) combined with the isoflurane-induced acceleration
      of I(Ca,L) inactivation kinetics. Because I(Kdr) is significantly inhibited by
      isoflurane, I(Kir) appears to be the major repolarizing current, which is
      minimally affected by isoflurane.

PMID- 12411808
TI  - Influence of hypovolemia on the pharmacokinetics and electroencephalographic
      effect of gamma-hydroxybutyrate in the rat.
AB  - BACKGROUND: Hypovolemia alters the effect of propofol in the rat by influencing
      the pharmacokinetics and the end organ sensitivity. We now studied the effect of
      hypovolemia on the anesthetic gamma-hydroxybutyrate (GHB) because in contrast
      with propofol it increases blood pressure. METHODS: Thirty-two rats were randomly
      assigned to undergo moderate hypovolemia or a control procedure. Each rat
      received either an infusion of sodium-GHB (390 mg x kg(-1) x 5 min(-1)) or the
      same volume of an equimolar solution of sodium chloride (6.9%). Plasma samples
      were taken for GHB assay (high-performance liquid chromatography) and the
      electroencephalography and blood pressure values were recorded. A two-compartment
      model with Michaelis-Menten elimination was fitted to the concentration-time data
      and a sigmoid E(max) model to the electroencephalographic effect effect site
      concentration curve allowing the study of the end organ sensitivity. RESULTS:
      Plasma concentration-time curves and the total volume of distribution in
      hypovolemic and normovolemic rats were comparable with only small but significant
      differences in central volume of distribution and the intercompartmental
      clearance. There was no significant difference either in the distribution from
      the plasma to the brain (k(e0)) or in the end organ sensitivity (EC50 = 335 +/-
      76 microg/ml in control vs. 341 +/- 89 microg/ml in hypovolemic rats). GHB
      temporarily increased mean arterial pressure in both groups, which cannot be
      explained by the sodium salt alone. CONCLUSIONS: Hypovolemia does not influence
      the overall concentration-time curve of GHB and induces no changes in the
      electroencephalographic effect of GHB in the rat. This difference with propofol
      may be due to the fact that it increases blood pressure but also due to its
      different pharmacokinetic properties.

PMID- 12411809
TI  - Reactive oxygen species scavengers attenuate endotoxin-induced impairment of
      hypoxic pulmonary vasoconstriction in mice.
AB  - BACKGROUND: Sepsis and endotoxemia attenuate hypoxic pulmonary vasoconstriction
      (HPV), thereby impairing systemic oxygenation. Reactive oxygen species (ROS) are
      implicated in the pathogenesis of sepsis-induced lung injury. The authors
      investigated whether treatment with scavengers of ROS prevents impairment of HPV
      in mice challenged with endotoxin. METHODS: The pulmonary vasoconstrictor
      response to left mainstem bronchus occlusion (LMBO) was studied in anesthetized
      mice 22 h after an intraperitoneal challenge with saline solution or 10 mg/kg
      Escherichia coli endotoxin. In some mice, challenge with saline solution or
      endotoxin was followed after 1 h with intraperitoneal or intratracheal
      administration of the ROS scavengers N-acetylcysteine or EUK-8. Myeloperoxidase
      activity and nitric oxide synthase-2 gene expression were measured in lung
      tissues. RESULTS: The LMBO increased left pulmonary vascular resistance by 106 +/
      24% in saline-challenged control mice but by only 23 +/- 12% (P < 0.05) in
      endotoxin-challenged mice. Intraperitoneal administration of N-acetylcysteine or
      EUK-8 1 h after endotoxin challenge attenuated the endotoxin-induced impairment
      of HPV (58 +/- 6% and 68 +/- 10%, respectively; both P< 0.05 endotoxin-challenged
      mice). Intratracheal administration of ROS scavengers 1 h after endotoxin
      challenge was equally effective but required lower doses than systemic treatment.
      Administration of the ROS scavengers 22 h after endotoxin challenge did not
      restore HPV. CONCLUSIONS: Administration of N-acetylcysteine or EUK-8 1 h after
      endotoxin challenge in mice prevented the impairment of HPV after LMBO. Early
      therapy with ROS scavengers, either systemically or by inhalation, may provide a
      means to preserve HPV in sepsis-associated acute lung injury.

PMID- 12411811
TI  - Brachial plexus nerve block exhibits prolonged duration in the elderly.
AB  - BACKGROUND: Upper limb trauma occurs frequently in elderly patients for whom
      peripheral nerve blocks are often preferred for anesthesia. The characteristics
      of such regional blocks have, however, never been described in an elderly
      population. Therefore, the authors assessed prospectively the onset and duration
      of upper extremity peripheral nerve block (the mid-humeral block) in elderly and
      young patients undergoing emergency upper extremity surgery. METHODS: Consecutive
      patients aged > 70 yr or < 70 yr received a mid-humeral block with a small volume
      of ropivacaine, 0.75%. Five milliliters was injected onto each of the
      musculocutaneous, radial, ulnar, and median nerves. Time to complete sensory and
      motor block and durations of complete sensory and motor block were assessed.
      Results are shown as median and its 95% confidence interval. RESULTS: Median ages
      were 77 yr (95% CI, 72-81 yr) and 39 yr (95% CI, 27-46 yr) in the two groups.
      Both groups had similar times to complete sensory blockade. The elderly group had
      longer durations of complete sensory (390 min [range, 280-435 min] vs.150 min
      [range, 105-160 min]; P< 0.05) and motor (357 min [range, 270-475 min] vs. 150
      min [range, 90-210 min]; P< 0.05) blockade. Duration of complete sensory block
      was significantly correlated with age (rho = 0.56; P< 0.05). CONCLUSIONS: Age is
      a major determinant of duration of complete motor and sensory blockade with
      peripheral nerve block, perhaps reflecting increased sensitivity to conduction
      failure from local anesthetic agents in peripheral nerves in the elderly
      population.

PMID- 12411810
TI  - Long-term pain and activity during recovery from major thoracotomy using thoracic
      epidural analgesia.
AB  - BACKGROUND: Pain following thoracotomy can persist for years with an undetermined
      impact on quality of life. Factors hypothesized to modulate this painful
      experience include analgesic regimen, gender, and type of incision. METHODS: A
      total of 157 generally healthy patients of both genders scheduled for
      segmentectomy, lobectomy, or bilobectomy through a posterolateral or muscle
      sparing incision were randomly assigned to receive thoracic epidural analgesia
      initiated prior to incision or at the time of rib approximation. Pain and
      activity scores were obtained 4, 8, 12, 24, 36, and 48 weeks after surgery.
      RESULTS: Overall, there were no differences in pain scores between the control
      and intervention groups during hospitalization (P >or= 0.165) or after discharge
      (P>or= 0.098). The number of patients reporting pain 1 yr following surgery (18
      of 85; 21.2%) was not significantly different (P = 0.122) from the number
      reporting preoperative pain (15 of 120; 12.5%). During hospitalization, women
      reported greater pain than men (worst pain, P= 0.007; average pain, P= 0.016).
      Women experienced fewer supraventricular tachydysrhythmias (P = 0.013) and were
      thus discharged earlier (P = 0.002). After discharge women continued to report
      greater discomfort than men (P <or= 0.016), but did not differ from men in their
      level of physical activity (P = 0.241). CONCLUSIONS: Initiation of thoracic
      epidural analgesia prior to incision or the use of a muscle-sparing incision did
      not significantly impact pain or physical activity. Although women reported
      significantly greater pain during hospitalization and after discharge, they
      experienced fewer complications, were more likely to be discharged from the
      hospital sooner, and were just as active after discharge as men.

PMID- 12411812
TI  - Comparative spinal neurotoxicity of prilocaine and lidocaine.
AB  - BACKGROUND: Reports of major and minor sequelae following lidocaine spinal
      anesthesia have generated interest in an alternative short-acting intrathecal
      agent. Of the available anesthetics suitable for short-duration spinal
      anesthesia, prilocaine is perhaps the most promising agent. However, data
      comparing the neurotoxicity of these agents are lacking. Accordingly, the present
      experiments investigate whether prilocaine and lidocaine differ with respect to
      sensory impairment and histologic damage when administered intrathecally in the
      rat. METHODS: Ninety rats were divided into three groups to receive an
      intrathecal infusion of 2.5% prilocaine in saline, 2.5% lidocaine in saline, or
      normal saline. The animals were assessed for persistent sensory impairment 4 days
      after anesthetic administration using the tail-flick test. Three days later, the
      animals were killed, and specimens of the spinal cord and nerve roots were
      obtained for histopathologic examination. RESULTS: Prilocaine and lidocaine
      produced equivalent elevations in tail-flick latency that differed significantly
      from saline. Histologic injury scores with prilocaine were greater than with
      lidocaine, but this difference did not reach statistical significance.
      CONCLUSIONS: The propensity for persistent functional impairment or morphologic
      damage with intrathecal prilocaine is at least as great as with lidocaine.
      Although the substitution of prilocaine for lidocaine may reduce the incidence of
      transient neurologic symptoms, it is unlikely to reduce the risk of actual neural
      injury. This discrepancy may indicate that transient neurologic symptoms and
      neurologic deficits after spinal anesthesia are not mediated by the same
      mechanism.

PMID- 12411813
TI  - Role of prostaglandin receptor EP1 in the spinal dorsal horn in carrageenan
      induced inflammatory pain.
AB  - BACKGROUND: Prostaglandin E2 (PGE2) and the receptor for PGE2 (EP receptor) are
      key factors contributing to the generation of hyperalgesia caused by
      inflammation. The current study was designed to investigate the roles of PGE2 and
      EP1 receptors in the spinal cord in the development and maintenance of
      inflammatory pain, using behavioral, microdialysis, and intracellular calcium ion
      concentration ([Ca2+]i) assays. METHODS: Inflammation was induced by an injection
      of carrageenan into the plantar surface of the rat hind paw. The effects of
      inflammation were evaluated at the time points of 3 h (early phase) and 15 h
      (late phase) after carrageenan injection. In behavioral assays, withdrawal
      thresholds to mechanical stimuli were evaluated. The effect of an intrathecally
      administered selective EP1 antagonist, ONO-8711, on the carrageenan-induced
      hyperalgesia was examined. Using a spinal microdialysis method, PGE2
      concentration in the spinal dorsal horn was measured. In [Ca2+]i assays, we
      measured [Ca2+]i in the spinal dorsal horn in transverse spinal slices and
      examined the effects of pretreatment with ONO-8711. Sensitivities of the changes
      in [Ca2+]i to PGE2 perfusion were also assessed. RESULTS: Mechanical hyperalgesia
      and paw edema were observed in both the early and late phases. The hyperalgesia
      was inhibited by intrathecal ONO-8711 in the late, but not early, phase. The
      concentration of PGE2 in the spinal dorsal horn increased in the late phase. The
      [Ca2+]i in the dorsal horn increased on the ipsilateral side to the inflammation
      in the late, but not early phase. This increase was suppressed by the
      pretreatment with ONO-8711. Magnitude of the increase in [Ca2+]i on the
      ipsilateral side in response to PGE2 perfusion was greater in the late phase than
      in the early phase. CONCLUSION: The results suggested that activation of spinal
      EP1 receptors was crucial in the carrageenan-induced mechanical hyperalgesia in
      the late phase. It seems that some of the mechanisms underlying inflammation
      induced plastic changes are mediated by time-dependent increase in PGE2
      concentration, activation of EP1 receptors, and increase in [Ca2+]i in the spinal
      dorsal horn.

PMID- 12411814
TI  - Gabapentin and pregabalin can interact synergistically with naproxen to produce
      antihyperalgesia.
AB  - BACKGROUND: Gabapentin and pregabalin are anticonvulsants with antihyperalgesic
      effects in animal models of neuropathic and inflammatory nociception. This study
      characterized the manner in which gabapentin or pregabalin interacts with
      naproxen to suppress thermal hyperalgesia and inflammation in the carrageenan
      model of peripheral inflammation. METHODS: Gabapentin, pregabalin, naproxen, or a
      fixed-dose ratio of gabapentin + naproxen or pregabalin + naproxen was
      administered orally to rats after the induction of inflammation by intraplantar
      injection of lambda-carrageenan in one hind paw. Nociceptive thresholds were
      determined by the radiant heat paw-withdrawal test. Paw edema was measured by
      plethysmometry. Drug plasma concentrations were determined by a liquid
      chromatography-mass spectroscopy-mass spectroscopy method. RESULTS: Gabapentin,
      pregabalin, and naproxen alone reversed thermal hyperalgesia with ED50 values of
      19.2, 6.0, and 0.5 mg/kg, respectively. Mixtures of gabapentin + naproxen in
      fixed-dose ratios of 50:1, 10:1, or 1:1 interacted synergistically to reverse
      carrageenan-induced thermal hyperalgesia. However, 1:50 gabapentin + naproxen
      produced only additive effects. No combination of gabapentin + naproxen decreased
      paw edema in a manner greater than additive. Plasma concentrations of gabapentin
      and naproxen were unaltered by the addition of the other drug. The mixture of
      10:1 of pregabalin + naproxen interacted synergistically to reverse thermal
      hyperalgesia on the inflamed hind paw, whereas mixtures of 1:1 or 1:10 produced
      additive effects. CONCLUSIONS: These data suggest that gabapentin + naproxen and
      pregabalin + naproxen can interact synergistically or additively to reverse
      thermal hyperalgesia associated with peripheral inflammation. Therefore, the use
      of gabapentin or pregabalin in low-dose combinations with naproxen may afford
      therapeutic advantages for clinical treatment of persistent inflammatory pain.

PMID- 12411815
TI  - Major complications of regional anesthesia in France: The SOS Regional Anesthesia
      Hotline Service.
AB  - BACKGROUND: Several previous surveys have estimated the rate of major
      complications that occur after regional anesthesia. However, because of the
      increase in the use of regional anesthesia in recent years and because of the
      introduction of new techniques, reappraisal of the incidence and the
      characteristics of major complications is useful. METHODS: All French
      anesthesiologists were invited to participate in this 10-month prospective survey
      based on (1) voluntary reporting of major complications related to regional
      anesthesia occurring during the study period using a telephone hotline service
      available 24 h a day and managed by three experts, and (2) voluntary reporting of
      the number and type of regional anesthesia procedures performed using pocket
      booklets. The service was free of charge for participants. RESULTS: The
      participants (n = 487) reported 56 major complications in 158,083 regional
      anesthesia procedures performed (3.5/10,000). Four deaths were reported. Cardiac
      arrest occurred after spinal anesthesia (n = 10; 2.7/10,000) and posterior lumbar
      plexus block (n = 1; 80/10,000). Systemic local anesthetic toxicity consisted of
      seizures only, without cardiac toxicity. Lidocaine spinal anesthesia was
      associated with more neurologic complications than bupivacaine spinal anesthesia
      (14.4/10,000 vs. 2.2/10,000). Most neurologic complications were transient. Among
      12 that occurred after peripheral nerve blocks, 9 occurred in patients in whom a
      nerve stimulator had been used. CONCLUSION: This prospective survey based on a
      free hotline permanent telephone service allowed us to estimate the incidence of
      major complications related to regional anesthesia and to provide a detailed
      analysis of these complications.

PMID- 12411816
TI  - Fatigue in anesthesia: implications and strategies for patient and provider
      safety.

PMID- 12411817
TI  - Current techniques for perioperative lung isolation in adults.

PMID- 12411818
TI  - Decrease in bispectral index preceding intraoperative hemodynamic crisis:
      evidence of acute alteration of propofol pharmacokinetics.

PMID- 12411819
TI  - Visual loss after use of nitrous oxide gas with general anesthetic in patients
      with intraocular gas still persistent up to 30 days after vitrectomy.

PMID- 12411820
TI  - Permanent postoperative vision loss associated with expansion of intraocular gas
      in the presence of a nitrous oxide-containing anesthetic.

PMID- 12411821
TI  - Cardiopulmonary bypass following severe transfusion-related acute lung injury.

PMID- 12411822
TI  - Successful management of severe life-threatening hypoxemia due to pulmonary
      arteriovenous malformation.

PMID- 12411823
TI  - Hyperinflation resulting in hemodynamic collapse following living donor lobar
      transplantation.

PMID- 12411824
TI  - Differential effects of volatile anesthetics on hepatic heme oxygenase-1
      expression in the rat.

PMID- 12411825
TI  - Does acute normovolemic hemodilution work in cardiac surgery?

PMID- 12411826
TI  - Hepatic failure after cardiopulmonary bypass is unlikely to be isoflurane
      hepatitis.

PMID- 12411827
TI  - Oral to nasal endotracheal tube exchange in a difficult airway: a novel method.

PMID- 12411828
TI  - Use of the Arndt wire-guided endobronchial blocker.

PMID- 12411829
TI  - Use of a LMA and a sequential technique for unanticipated difficult intubations.

PMID- 12411830
TI  - Radiolabelled white blood cells in inflammatory bowel diseases.

PMID- 12411831
TI  - Fluorodeoxyglucose positron emission tomography in clinical oncology: the
      referrer's perspective.
AB  - From January 2000 to April 2002 a prospective audit based on a questionnaire was
      carried out concerning the attitudes and viewpoints of clinicians referring
      patients to fluorodeoxyglucose positron emission tomography (FDG PET) scanning. A
      standard and structured audit form was posted to each referring doctor with the
      formal clinical report issued by the nuclear medicine consultant. Three hundred
      and thirty evaluable forms were analysed, a return rate of approximately 22%,
      from a total of 1500 PET patients studied during this period. FDG PET scanning
      was deemed by the referring physician to have altered the staging of cancer
      patients in 39% of all cases. Twenty-five per cent of patients were upstaged with
      FDG PET and 14% of patients downstaged. Patient management was changed in 39% of
      cases whilst a change in treatment occurred in 10% of cases. The reported FDG PET
      study was judged as being helpful in over 75% of all cases. These data further
      support evidence of the increasing role of FDG studies in the investigation of
      patients with cancer.

PMID- 12411832
TI  - The feasibility of statistical parametric mapping for the analysis of positron
      emission tomography studies using 11C-2-beta-carbomethoxy-3-beta-(4-fluorophenyl)
      tropane in patients with movement disorders.
AB  - Movement disorders, including Parkinson's disease and parkinsonian syndromes,
      e.g. progressive supranuclear palsy, multiple system atrophy, and Lewy body
      dementia, may be difficult to differentiate among each other at an early stage,
      since they may share similar clinical features and response to dopaminergic
      drugs. As new tracers for imaging the dopamine transporters become available, the
      use of positron emission tomography (PET) for the differential diagnosis of
      movement disorders is gaining clinical relevance. Visual interpretation is
      generally used for PET image analysis. However, the use of some form of less
      subjective analysis is desirable in order to detect subtle changes that may be
      difficult to identify by visual interpretation and to achieve an operator
      independent analysis. To this end this study was aimed at assessing the
      feasibility of using statistical parametric mapping (SPM) for the clinical
      evaluation of single PET scans performed with 2-beta-carbomethoxy-3-beta-(4
      fluorophenyl)-tropane ( C-beta-CIT-FE). Eleven healthy volunteers and five
      patients with movement disorders (Parkinson's disease, essential tremor, PSP and
      Lewy body dementia) were included in this study. Each subject underwent a PET
      study after i.v. injection of C-beta-CIT-FE. The PET images of C-beta-CIT-FE
      distribution acquired between 60 and 90 min were spatially fitted into the
      Talairach and Tournoux space. A template of normal C-beta-CIT-FE distribution was
      derived from studies in the 11 normal control subjects. Different patterns of
      reduction of the uptake of the tracer were detected in the basal ganglia of the
      five patients, in relation to each pathological condition. The patterns of
      distribution were all consistent with the severity and type of disease. The
      results of this study demonstrate the feasibility of differentiating among
      different states of dopaminergic impairment, due to Parkinson's disease and
      parkinsonian syndromes, by using PET scans with C-beta-CIT-FE and by using the
      SPM procedure for analysis of the data.

PMID- 12411833
TI  - Measurement of cerebral perfusion volume and 99mTc-HMPAO uptake using SPECT in
      controls and patients with Alzheimer's disease.
AB  - Methods for quantifying the changes in brain function observed in single photon
      emission computed tomography (SPECT) using hexamethylenepropylene amine oxime
      (HMPAO) for patients with Alzheimer's disease have the potential of improving the
      diagnostic accuracy of the procedure and its ability to monitor response to
      treatment. The absolute percentage uptake of HMPAO and the cerebral perfusion
      volume (CPV) of the brain were assessed using SPECT in 26 patients with mild to
      moderate Alzheimer's disease (AD) and 24 control subjects. A subset of 15 control
      subjects, which was age-matched to the AD patients, was selected to allow fair
      statistical comparison of parameters between groups. The percentage of brain
      volume with reduced perfusion (R) and a volume loss index (VLI), given by /CPV,
      were also calculated. Eight of the control subjects were studied on a second
      occasion after a mean period of 6 months. There was no significant difference in
      percentage uptake between controls and AD patients, the mean value being 5.8%.
      Cerebral perfusion volume in controls was found to depend on sex (mean value in
      males and females being 1327 ml and 1222 ml, respectively) and on age. The volume
      loss index corrected for age and sex provided good discrimination between
      controls and AD subjects giving a sensitivity and specificity of 81% and 96%,
      respectively. The repeatability coefficient, the 95% confidence limit for the
      difference between repeat measurements, on controls was 67 ml (5%). The
      measurement of cerebral perfusion volume and related indices may be of value in
      identifying patients with early Alzheimer's disease and in following their
      response to treatment.

PMID- 12411834
TI  - Could automated template based quantification of benzodiazepine receptors in
      brain single photon emission tomography with 123I NNC 13-8241 be used to
      demonstrate neuronal damage in traumatic brain injury?
AB  - Automated methods are required for the analysis of brain single photon emission
      tomography images. We applied an automated method to assess the benzodiazepine
      receptor distribution in the brain. Images of 19 patients with mild traumatic
      brain injury who had received I NNC 13-8241 were compared with a mean brain
      template accumulated from 18 healthy volunteers. To obtain more information, we
      calculated the neuronal benzodiazepine receptor binding in the brain by using pre
      defined anatomical regions and a voxel-by-voxel technique. The group of patients
      with mild traumatic brain injury differed significantly (P =0.015) from the group
      of healthy volunteers in the distribution of benzodiazepine receptors. This
      methodological work suggests that a reference based template and a three
      dimensional brain model help in regional analysis and quantification and could be
      useful in demonstrating permanent neuronal damage after head injury.

PMID- 12411835
TI  - Positive predictive value of 99mTc sestamibi scintimammography in patients with
      non-palpable, mammographically detected, suspicious, breast lesions.
AB  - The purpose of this study was to analyse whether the use of Tc sestamibi
      scintimammography improves the positive predictive value of X-ray mammography. A
      series of 73 women (median age 51 years, range 35-79 years) with non-palpable,
      mammographically suspicious, breast lesions was reviewed. There were 41 (56.2%)
      pre-menopausal, and 32 (43.8%) post-menopausal women. All patients underwent
      sestamibi scintimammography prior to open breast biopsy. Definitive histology
      showed breast cancer (pT1a=1 (1.9%), pT1b=47 (90.4%), pT1c=4 (7.7%)) in 52
      (71.2%) patients, and benign breast lesions in 21 (28.8%). Patients with cancer
      were significantly older (P <0.01), while the greatest dimension (size) of the
      excised lesion did not differ (8.47+/-1.51 vs 8.30+/-1.53 mm; P =0.66) between
      the two groups. Overall, the positive predictive values of mammography and
      sestamibi scintimammography were 71.2% and 95.7%, respectively (P =0.004).
      Patients with false positive mammography were significantly younger than those in
      whom cancer was diagnosed correctly (45.35+/-7.56 vs 53.96+/-10.60 years; P
      =0.001), while age did not affect the sensitivity of sestamibi scintimammography,
      which reached 100% in patients with breast lesions > or =8 mm in size. In this
      subgroup the positive predictive value of mammography, sestamibi
      scintimammography, and mammography+sestamibi scintimammography together were
      63.4%, 95.1% (P =0.001), and 97.6%, respectively, and the majority of the
      patients with benign lesions (13 of 15 (86.7%)) could have avoided biopsy. It is
      concluded that the use of Tc sestamibi scintimammography in conjunction with
      mammography may potentially reduce unnecessary surgical procedures, and should be
      performed in all patients with mammographically suspicious breast lesions of 8 mm
      or greater in size.

PMID- 12411836
TI  - 18FDG PET versus high-dose 67Ga scintigraphy for restaging and treatment follow
      up of lymphoma patients.
AB  - To date, only one published study has directly compared 67Ga scintigraphy (low
      dose, planar) with planar dual-head gamma camera 18F-fluorodeoxyglucose (18FDG)
      imaging for the purpose of treatment follow-up monitoring in lymphoma patients,
      and no data on restaging are available. The present study reports the direct
      comparison of high-dose (297-370 MBq) 67Ga planar and single photon emission
      computed tomography (SPECT) imaging and conventional 18FDG positron emission
      tomography (PET) for restaging and treatment follow-up of lymphoma patients
      versus a gold standard consisting of morphological imaging, including plain
      radiography and computed tomography (CT) scanning, bone marrow examination and
      long-term follow-up (<12 months). Sixteen patients, 10 with non-Hodgkin's
      lymphoma and six with Hodgkin's disease, were included (10 men, six women; median
      age, 43 years; range, 16-64 years). The median follow-up time was 27 months
      (range, 12-34 months). In two patients, 67Ga and 18FDG PET (370 MBq) were
      performed twice, resulting in 18 cross-sectional episodes. In 11 episodes, the
      results obtained by both imaging modalities were in agreement with regard to the
      presence or absence of disease when compared with the gold standard. However, the
      abnormalities found on 18FDG PET were always more extensive. In two episodes,
      67Ga imaging normalized after treatment, whereas PET showed significant
      regression followed by subsequent normalization. In four additional episodes,
      67Ga images were negative, whereas 18FDG PET visualized non-tumour-related
      pathology, such as lung infection, rib fracture or dense thymic tissue. In one
      gold standard-negative patient, the underlying cause of sternal FDG uptake
      remained undetermined. The data presented, although limited in number, suggest
      that 18FDG PET performs better than Ga imaging in monitoring lymphoma disease
      status. However, a correlation with clinical history and a knowledge of the
      characteristics of benign lesions are mandatory. Further studies are recommended.

PMID- 12411837
TI  - The labelling of human serum transferrin with 99mTc and a study concerning uptake
      of the complex by tumour cells.
AB  - The direct labelling of serum transferrin (sTf) with 99mTc on high-affinity
      binding sites, producing a complex of excellent stability, is described. The high
      affinity binding sites were prepared by pre-treating sTf with 2-mercaptoethanol.
      For the radiolabelling step, thiourea was used as an exchange ligand and a
      filtration procedure used to remove 99mTc that had not complexed with the
      protein. RT112 bladder tumour cells incubated in the presence of labelled sTf
      showed a rapid initial uptake of 99mTc, reaching a plateau after about 20 min.
      Radiolabelling was also carried out without a pre-reduction step in an attempt to
      form a co-ordination complex between 99mTc and the Fe3+-binding site of sTf,
      analogous to that formed by Fe3+. The tumour cell uptake of sTf labelled without
      pre-reduction was then examined. In contrast to 59Fe3+ and other radio-metals co
      ordinated with the Fe3+-binding site which show a continuous increase in
      incorporation with time, the uptake of 99mTc rapidly reached a plateau.

PMID- 12411838
TI  - Large-body radiation doses following radioiodine therapy.
AB  - In accordance with the recommendations of the International Radiological
      Protection Commission, the current maximum acceptable radiation dose limits for
      members of the public have been reduced to 1 mSv in the United States, Canada,
      and European Union countries including the United Kingdom. This has had a
      significant impact on radiation protection guidelines for contacts of patients
      treated with 131I. Many previous recommendations have relied upon models which
      may overestimate dose rates at short distances. We therefore undertook
      measurements of 131I dose rates using adult and infant phantoms that more
      accurately reflected true geometry. Effective dose calculations and patient
      contact restrictions were then derived from these direct dose measurements. Doses
      received by the adult phantom were measured at three distances (contact, 1.0 m,
      2.0 m) and doses received by the infant phantom were measured at contact in two
      orientations (adult cradling infant over shoulder and at waist). The doses
      measured were significantly lower than previously predicted for the adult and
      infant phantom. Our measurements suggest that patient contact restrictions could
      be made less stringent than those currently in widespread use.

PMID- 12411839
TI  - 153Sm EDTMP for bone marrow ablation prior to stem cell transplantation for
      haematological malignancies.
AB  - This study examined the safety of adding 153Sm lexidronam to standard
      conditioning regimens in patients undergoing stem cell transplantation for marrow
      based haematological malignancies in whom total-body irradiation as part of
      conditioning was desirable but not feasible. Ten such patients were enrolled,
      seven with multiple myeloma. An escalating regimen of 19-45 GBq of 153Sm
      lexidronam was added 12-14 days prior to the standard transplantation regimen.
      Evaluation parameters included time to engraftment, status at day +100 by
      International Bone Marrow Transplant Registry (IBMTR) criteria and toxicity
      during this period. Absorbed marrow radiation doses were estimated using the
      MIRDOSE 3 program. No adverse events were attributable to 153Sm lexidronam. Of
      the seven patients with multiple myeloma, four achieved complete response, two
      partial response, and another had stable monoclonal band at 3 months post
      transplant. One patient with Refractory Anaemic with Excess Blasts in
      transformation (RAEBt) died of a presumed fungal infection, whilst another with
      acute myeloid leukaemia relapsed, dying at day +153. A patient with low-grade
      lymphoma showed no evidence of residual disease at day +100. The total marrow
      absorbed dose was estimated to be 0.7+/-0.2 mGy x MBq(-1). Regional uptake was
      markedly non-uniform with poor uptake in the appendicular skeleton. Dose-limiting
      toxicity was not attained. At the activities used 153Sm lexidronam was not
      associated with additional toxicity in this population. Adequate absorbed
      radiation dose to appendicular marrow is unlikely to be deliverable by this
      approach alone.

PMID- 12411840
TI  - Is a lung perfusion scan obtained by using single photon emission computed
      tomography able to improve the radionuclide diagnosis of pulmonary embolism?
AB  - Planar pulmonary scintigraphy is still regularly performed for the evaluation of
      pulmonary embolism (PE). However, only about 50-80% of cases can be resolved by
      this approach. This study evaluates the ability of tomographic acquisition
      (single photon emission computed tomography, SPECT) of the perfusion scan to
      improve the radionuclide diagnosis of PE. One hundred and fourteen consecutive
      patients with a suspicion of PE underwent planar and SPECT lung perfusion scans
      as well as planar ventilation scans. The final diagnosis was obtained by using an
      algorithm, including D-dimer measurement, leg ultrasonography, a V/Q scan and
      chest spiral computed tomography, as well as the patient outcome. A planar
      perfusion scan was considered positive for PE in the presence of one or more
      wedge shaped defect, while SPECT was considered positive with one or more wedge
      shaped defect with sharp borders, three-plane visualization, whatever the
      photopenia. A definite diagnosis was achieved in 70 patients. After exclusion of
      four 'non-diagnostic' SPECT images, the prevalence of PE was 23% (n =15).
      Intraobserver and interobserver reproducibilities were 91%/94% and 79%/88% for
      planar/SPECT images, respectively. The sensitivities for PE diagnosis were
      similar for planar and SPECT perfusion scans (80%), whereas SPECT had a higher
      specificity (96% vs 78%; P =0.01). SPECT correctly classified 8/9 intermediate
      and 31/32 low probability V/Q scans as negative. It is concluded that lung
      perfusion SPECT is readily performed and reproducible. A negative study
      eliminates the need for a combined V/Q study and most of the 'non-diagnostic' V/Q
      probabilities can be solved with a perfusion image obtained by using tomography.

PMID- 12411841
TI  - A new method for measuring dynamic change of tracer distribution using dynamic
      single photon emission tomography with a slip-ring rotational gamma camera.
AB  - The clinical applicability of dynamic single photon emission tomograpy (SPET)
      using a dual-head gamma camera equipped with a slip-ring rotational mechanism,
      referred to as serial SPET, was examined in the present investigation. Serial
      SPET enables the production of tomographic images for any arbitrary time frame
      from an arbitrary range of data to 360 degrees. In a pre-clinical evaluation, a
      correlation between radioactivity concentration and serial SPET counts was
      evaluated in a phantom with continuous changes in 99mTc concentration. A
      differential value was obtained from each pair of SPET images; moreover, moving
      average approximation processing was investigated with respect to the elimination
      of noise in the data. In 11 and one patient presenting with cerebrovascular
      disease and meningioma, respectively, changes in SPET counts were evaluated when
      99mTc ethyl cysteinate dimer (99mTc-ECD) was continuously administered at a
      constant rate in the resting state. Furthermore, in six of 11 subjects with
      cerebrovascular disease, changes occurring in SPET counts were examined by using
      acetazolamide loading while continuously administering 99mTc-ECD at a constant
      rate. Consequently, serial SPET enabled the evaluation of changes in
      radioactivity concentration over time in both the phantom and preliminary
      clinical studies. Data analysis by differential processing utilizing moving
      average approximation processing enabled the detection of minor changes in
      radioactivity concentration. An increase of 15.1+/-5.4% was observed in SPET
      counts of the unaffected cerebral hemisphere with acetazolamide loading. The
      response of the affected hemisphere was less prominent. These findings suggest
      that serial SPET would be an effective technique for the pharmacokinetic analysis
      of radiopharmaceuticals.

PMID- 12411842
TI  - Abnormal 201Tl myocardial single photon emission computed tomography in energetic
      male patients with myocardial bridge.
AB  - Myocardial bridge is a relatively benign condition where a major coronary artery
      is bridged by a band of muscle and narrows during systole, particularly during
      rapid heart rates. Its clinical presentation and electrocardiogram (ECG) changes
      overlap with that of coronary artery disease. 201Tl myocardial perfusion imaging
      is thus frequently prescribed for further evaluation. This retrospective study
      was carried out to determine the 201Tl image patterns in patients with myocardial
      bridge. A total of 17 male patients (aged from 30 to 63 years) who had a positive
      exercise ECG and angiographic evidence of myocardial bridge in the mid-third of
      the left anterior descending coronary artery were recruited. Most of them were
      robust and received routine physical check-ups. They had no known heart disease
      or medication that affected cardiac function. The patients' clinical
      presentations, echocardiograph and exercise ECG findings were analysed. 201Tl
      single photon emission computed tomography (SPECT) was performed by intravenous
      injection of 201Tl (111 MBq) immediately following stress (treadmill or
      dipyridamole induced) and 4 h after stress, using a fixed, right angle camera
      equipped with a low energy, general purpose collimator. The images were
      interpreted independently by two experienced nuclear medicine physicians. Nine of
      the 17 patients had anterior chest pain during exercise. All patients had an
      abnormal ECG during exercise, including ST-T wave depression in leads II, III and
      aVF, and v4-6. Except for eight patients revealing reversible perfusion defect
      (R), 16 of the 17 patients also exhibited a partial reversible perfusion defect
      (PR) or a significant reverse redistribution (RR) scan pattern in the anterior or
      inferior walls of the left ventricle. Myocardial bridge should be taken into
      consideration in energetic male patients who had abnormal exercise ECGs and the
      corresponding patterns of Tl SPECT abnormalities including R, PR and RR.

PMID- 12411843
TI  - Prolonged diastolic dysfunction following exercise induced ischaemia: a gated
      myocardial perfusion SPECT study.
AB  - Prolonged impairment of left ventricular (LV) systolic function following
      exercise induced ischaemia has been well demonstrated. The objective of this
      study was to examine the effect of exercise induced ischaemia on the post-stress
      LV diastolic function in patients with coronary artery disease (CAD). Seventy
      four subjects with known or suspected CAD underwent gated myocardial single
      photon emission computed tomography (SPECT) 1 h after administration of 99mTc
      tetrofosmin according to a standard same day exercise rest protocol. LV volumes
      and ejection fractions (LVEFs) were determined by the Cedars-Sinai program.
      Fourier transformation of the gated SPECT volume curve was performed retaining
      the fourth order harmonics, and peak filling rate (PFR) and time-to-PFR (TPFR)
      were calculated from the derivative curve. In patients with exercise induced
      ischaemia (n =26), 1 h post-stress PFR (2.66+/-0.75 s(-1)) and TPFR (119+/-12 ms)
      were significantly impaired in comparison to the resting PFR (3.06+/-0.74 s;
      P=0.0002) and TPFR (114+/-10 ms; P=0.03), respectively. In normal subjects (n
      =26) and in patients with infarction (n =22), the post-stress indices were
      similar to the resting values. When reduction of PFR or LVEF greater than the
      variability (2SD) of differences between the post-stress and resting values in
      the normal group was defined as significant impairment, six of the 26 ischaemic
      patients (23%) had such changes in PFR. All these patients exhibited severe
      ischaemia and five of them had simultaneous systolic impairment. Only one (4%) of
      the normal subjects and none of the patients in the infarction group showed such
      impairments. Stepwise logistic regression analysis of stress, scan and coronary
      variables revealed that the summed reversibility score, a scintigraphic index of
      ischaemic severity, was the only determinant of post-stress changes in LVEF and
      PFR. In conclusion, exercise induced LV diastolic impairment persists for a
      prolonged period after resolution of the ischaemic episode. The incidence and
      magnitude of the diastolic impairment are determined by the severity of the
      exercise provoked ischaemia.

PMID- 12411844
TI  - 111Indium labelled leukocyte scintigraphy in the detection of acute prostatitis.
AB  - Although prostatitis is a common problem the diagnosis is still controversial
      despite the availability of a wide variety of diagnostic tools. In fact, there is
      still no accurate method of localizing the infected tissue. The aims of the
      present study were to assess whether 111In labelled leukocytes (ILLs) accumulated
      in the infected tissue of acute prostatitis and if such uptake responded to
      treatment. We prospectively studied 10 adult male patients who had community
      acquired prostatitis and compared them with six male patients who had urinary
      tract infections but without prostatitis. An initial urinary culture and two
      blood cultures were carried out for each patient. All patients were followed up
      for 8 weeks after therapy was completed. Pre- and post-treatment scintigraphies
      were performed. Before treatment, all patients with prostatitis showed uptake of
      ILLs in the prostate area. After the patients had completed treatment with
      antibiotics, the scintigraphy results showed no uptake in the prostate area in
      9/10 patients. The remaining patient showed a marked decrease in the uptake of
      ILLs. None of the six patients with urinary tract infection showed ILL uptake in
      the prostate region. It is suggested that ILLs could be useful for detecting
      acute prostatitis, especially in clinically ambiguous patients with urological
      infections. Furthermore, scintigraphy with 111In labelled leukocytes could help
      to determine the most appropriate course of therapy.

PMID- 12411845
TI  - Radioiodine therapy and Graves' ophthalmopathy.

PMID- 12411846
TI  - The nurses' voice is heard.

PMID- 12411847
TI  - Hypodermoclysis for control of dehydration in terminal-stage cancer.
AB  - Many of those involved in palliative care have justifiable objections to the
      introduction of intravenous hydration in patients with dehydration-associated
      symptoms and advanced cancer. Researchers from the University of Buenos Aires
      carried out a randomized, comparative and prospective trail to determine the
      usefulness of hypodermoclysis in the control of thirst, chronic nausea and
      delirium. Forty-two patients were randomized into two groups. Both groups
      received drugs subcutaneously (haloperidol 2.5 mg every 4 hours to control
      delirium and/or metoclopramide 10 mg every 4 hours to control chronic nausea).
      The study group also received 1000 ml 5% dextrose in water infusion plus 140
      milliequivalent per litre (mEq/L) sodium chloride, at a rate of 42 ml/hour per
      day. Both groups showed significant and equal improvements in relief of thirst
      and chronic nausea at 24 hours. After 48 hours, this improvement was maintained
      in the group that received hydration, but only for the relief of chronic nausea.
      Delirium did not improve significantly in either group during the 48-hour trial
      period. Current data suggest that decisions on rehydration of patients with
      terminal-phase cancer should be based more on the patient's comfort than on
      providing optimal hydration.

PMID- 12411848
TI  - Audit in practice: the referral of dying patients to palliative care.
AB  - Audit should be an integral part of any palliative care service. Terminal care is
      a continuum of palliative care. When looking for an objective measure for
      referrals to a new palliative care service within a specialist cancer hospital in
      Ireland, patient death was used as an end point. Audits were carried out looking
      at inpatient deaths during two separate 8-month periods. All inpatient deaths
      during the study periods were noted and records compared to find those who were
      referred to the palliative care service before death. The first audit revealed
      that relatively few dying patients were referred to the newly formed palliative
      care team; by the time the second audit was carried out, referrals had increased.
      For many patients their final hospital admission was for active anti-cancer
      treatment and was of short duration. Data from these audits were presented on
      several different occasions to both nursing and medical staff. This article
      describes these audits in detail and highlights some of the issues raised. Audit
      in palliative care is discussed.

PMID- 12411849
TI  - Improving standards for palliative care services in Northern Ireland.

PMID- 12411850
TI  - Exploring the use of CircAid legging in the management of lymphoedema.
AB  - Lymphoedema is a potentially disfiguring chronic condition that can have
      significant physical, psychological and social consequences for the affected
      individual. Treatment consists of a combination of exercises and massage to
      increase lymph drainage, and the use of compression hosiery to maintain
      improvements. This intensive treatment is delivered by trained therapists over
      several seeks, and is time-consuming for both patient and therapist. Maintaining
      improvements following intensive therapy is difficult, and there is often a need
      for further courses of intensive therapy. In the maintenance phase of treatment
      the patient is taught to care for the swollen limb with a routine of skin care,
      exercise, simple lymphatic drainage and compression hosiery. Compression is the
      mainstay of this phase of management, but a regular supply of high-compression
      garments is costly. The CircAid legging is a non-elastic adjustable compression
      appliance worn on the lower leg which can be an effective adjunct to compression
      garments. Three case studies are presented to show that the use of the CircAid
      legging in the management of patients following intensive therapy can enhance the
      effect of standard compression hosiery. Implications for clinical practice are
      discussed, as is the need for further research.

PMID- 12411851
TI  - Sexuality in cancer and palliative care 1: Effects of disease and treatment.
AB  - All cancers and related treatments have the potential to affect sexuality and
      sexual function. This may result from impaired body function or altered body
      image, or from the emotional and psychological distress that often accompany
      diagnosis and treatment. It is increasingly acknowledged that issues surrounding
      sexuality are an important factor in quality of life for patients with cancer,
      and that sexuality is a legitimate area of concern for nurses in oncology and
      palliative care. However, issues relating to sexuality remain among the most
      poorly addressed in cancer care--possibly owing to lack of knowledge and
      expertise. There are also societal norms, myths and assumptions that may prevent
      nurses from broaching these issues. To provide this component of care, nurses
      need to have good communication skills, an open and non-judgmental approach, and
      knowledge of the potential ramifications of disease and treatment on sexuality.

PMID- 12411852
TI  - Truth telling and the dying patient: a conspiracy of silence?
AB  - This article reports on the findings of an ethnographic study of the terminal
      care of older dying patients in hospital. The study focused on the information
      given to 22 patients diagnosed with a life-threatening illness. Using data from
      participant observation and ethnographic interviews, the research examined the
      strategies used to control information about terminal diagnosis. Several ethical
      implications were raised, such as truth telling and collusion. The article
      examines the implications of implementing ward disclosure norms based on closed
      awareness. It also considers the issues associated with developing a truth
      telling culture.

PMID- 12411853
TI  - Assessment of quality of life in palliative care.
AB  - Assessment of palliative care and the evolution of interest in quality of life
      (QoL) measures are inextricably linked. Several validated QoL measures have
      become accepted for use, so it is increasingly unlikely that a 'gold-standard'
      measure will emerge. This range of current measures is potentially valuable
      because it provides the user with a degree of choice. However, such a range also
      brings to light methodological uncertainties. The aim of this article is not to
      identify the best measures, but to explore some of the factors that should guide
      that choice.

PMID- 12411855
TI  - New clinical guidelines for patients with stroke.

PMID- 12411856
TI  - Tuberculosis: a challenge for community nurses.

PMID- 12411857
TI  - Guidelines for use of the MS26 daily rate syringe driver in the community.
AB  - Many patients cared for in the community have complex care and treatment needs
      and syringe drivers are commonly used to administer a range of drugs to patients
      at home. However, serious problems have been associated with this route of
      administration. In Scotland between 1989 and 1994 there were 23 incidents
      including 4 fatalities associated with the use of small volume syringe pumps
      reported to the Common Services Agency supplies division (Scottish Office Home
      and Health Department (SOHHD), 1995). The four fatalities were attributed to over
      infusion (SOHHD, 1995). In those fatal inadvertent incidents no fault was found
      with the infusion device, suggesting that an inadvertent error had been made by
      attendants in setting up or in using the device, or that some form of tampering
      had taken place. The Department of Health issued a hazard warning in 1994 (DoH,
      1994) about confusion between the two Sims Graseby syringe drivers the MS16A and
      the MS26. This article outlines guidance on the use of the Sims Graseby MS26 in
      the community. Community nurses have a vital role to play in management of
      syringe drivers, and it is through increased awareness of correct procedures that
      incidents and fatalities will be avoided.

PMID- 12411858
TI  - An audit of drug incidents in learning disability group homes.
AB  - The implementation of clinical governance (Department of Health, 1997) requires
      the review of practice by consideration of complaints and clinical incidents. A
      systematic review of the clinical incident forms in group homes for those with
      learning disabilities, within an NHS community trust, highlighted issues for
      concern. This led to an audit being conducted of drug administration procedures
      involving examination of records and observation of practice. It demonstrated
      that there was general adherence to the trust's policies. The audit stimulated
      debate, and a number of potential areas for action were identified. The review of
      drug administration with clients who have learning difficulties raised wider
      questions about the scarcity of evidence in this area to support practice, the
      culture of client-centred homes and whether monitoring systems are sufficiently
      robust.

PMID- 12411859
TI  - The scope for community based intervention in stroke rehabilitation.
AB  - The aftermath of stroke is commonly managed in the community, often exclusively
      by the GP. However, a significant proportion of community stroke patients have
      considerable impairments and disabilities which often go undetected and
      consequently untreated by the primary healthcare team. This article describes and
      quantifies the disabilities experienced by stroke patients living in the
      community and reviews the evidence for community rehabilitation. The roles of the
      occupational therapist and community nurse in the management of stroke
      rehabilitation are discussed. The authors conclude that an opportunity exists for
      better collaboration between the occupational therapist and the community nurse.

PMID- 12411860
TI  - Community nursing and stroke: a reassessment of the issues.
AB  - Recent research has highlighted the difficulties that stroke patients and carers
      experience in navigating a recovery path through a complex array of service
      providers. Many of these difficulties relate to continuing recovery from stroke
      at home, often when professional help is decreasing. A study by Gibbon (1994)
      demonstrated a potential role for community nurses in helping patients and carers
      to cope with the aftermath of stroke. This article reassesses the issues that
      affect the capacity of community nurses to develop this role. A focus group
      conducted with community nursing students identified a number of barriers to the
      expansion of service provision for this patient group, including workload
      pressures, training and management support. Understanding of the problems faced
      by stroke patients and their carers in the current organization of continuing
      care and rehabilitation is required to support expansion of nursing practice in
      this area.

PMID- 12411861
TI  - Legal issues arising in community nursing 5: nurse prescribing.
AB  - Major changes are recommended in prescribing which will extend prescribing powers
      to many other professional groups on a restricted basis. Nurse prescribing in the
      community was made possible following the recommendations of the first Crown
      report (Department of Health (DoH), 1989) by the Medicinal Products (Prescription
      by Nurses etc) Act 1992 and by changes to Section 41 of the National Health
      Service Act 1977. However, prescribing by nurses on the basis of group protocols
      has taken place in hospitals and in primary care with no clear basis in law. A
      further inquiry to review prescribing, supply and administration of medicines
      reported in March 1998 on group protocols and published its final report in March
      1999 (DoH, 1999). A recent press release announced that the Government will
      implement the Crown proposals by July 2000 (DoH, 2000). This article examines
      these proposals and their potential impact on community nursing.

PMID- 12411863
TI  - District nursing assessment practice: case study findings.
AB  - Patient assessment is widely acknowledged as a core element of community nursing
      expertise (Griffiths and Luker, 1994). With the current drive towards evidence
      based practice, it is becoming increasingly important to provide sound evidence
      about this key aspect of community nursing practice. This article describes how
      district nurses' assessments of a carefully constructed simulated patient have
      provided new insight into community nursing expertise. The innovative approach
      used in this study of district nursing assessment practice is outlined. One of
      the simulated patients developed for the study is then described. A case study of
      one nurse participant who assessed this simulated patient forms the main focus of
      the article. The case study (one of four) is based on a synthesis of simulation
      and interview findings relating to a particular study participant. It reveals
      some interesting associations between various elements of nursing knowledge and
      provides important insight into how the quality and effectiveness of patient
      assessment may be affected by a practitioner's approach and knowledge base. The
      usefulness of this approach and the relevance of the findings for nursing
      practice and education are also addressed.

PMID- 12411862
TI  - The prevalence of breast-feeding in south Leicestershire.
AB  - The consultative document, 'Our Healthier Nation' (Department of Health, 1998a),
      outlined areas for health improvement, and offers health professionals an
      opportunity to use the Government's programme to raise breast-feeding rates. This
      article reports the results of an audit to establish local breast-feeding
      prevalence rates in south Leicestershire, and when and why women stop breast
      feeding. A simple questionnaire was used by health visitors to collect data on
      all babies born over a 3-month period (October 1997 - December 1997). The audit
      found that 57% of mothers were breast-feeding at birth compared with national
      breast-feeding figures of 64%. The rate at which women stopped breast-feeding
      substantially increased between 10 days and 6-8 weeks postpartum. Women stopped
      breast-feeding for a variety of reasons. The information provided by the audit
      will be used to inform health-visiting practice and in the long term will
      hopefully help to increase breast-feeding rates in this area.

PMID- 12411864
TI  - E-healthcare cannot be ignored.

PMID- 12411865
TI  - Past, current and future developments of nuclear medicine techniques.

PMID- 12411866
TI  - The basics of renal imaging and function studies.
AB  - Many radiotracers are available for kidney studies. They are classified into
      glomerular tracers (DTPA, EDTA), tubular tracers (OIH, MAG3) and cortical tracers
      (DMSA, GHA). Renal function is best assessed by glomerular filtration rate.
      Camera studies provide a relative function assessment, whereas clearance
      techniques provide a precise and reliable assessment of absolute renal function.
      The combination of both therefore gives a comprehensive study of glomerular
      function. Attempts to assess absolute function from camera studies only resulted
      in gross inaccuracy. Tubular tracers have a higher extraction rate. This could be
      used to estimate renal plasma flow (by assessing the effective renal plasma
      flow), or to determine relative function when renal function is low, or to study
      the urine flow in the urinary tract. Cortical tracers provide a high imaging
      quality. They are more adapted to infection assessment and relative function
      measurements. This paper reviews the most commonly used tracers and their
      relationship with renal physiology. Techniques for camera static and dynamic
      studies and plasma and urinary clearances are detailed. Procedures follow the
      recommendations of the most recent international consensus conferences on the
      topics.

PMID- 12411867
TI  - Renovascular hypertension: nuclear medicine techniques.
AB  - Angiotensin converting enzyme inhibition (ACEI) renography is the only imaging
      examination that tests directly for the presence of renovascular hypertension
      (RVH); other imaging examinations test for the presence of renal artery stenosis
      (RAS). The goals of ACEI renography are two-fold: 1) to detect those patients
      with hypertension who have renal artery stenosis as the cause of their
      hypertension and who would benefit from revascularization, and 2) to determine
      which hypertensive patients do not have renovascular hypertension and obviate the
      expense and risk of angiography and, potentially, revascularization. This review
      summarizes general components of renal scintigraphy (pretest voiding, hydration,
      patient position, relative uptake, time to peak height of the renogram curve, 20
      min/max ratio, postvoid images, quality control) as well as those components
      specific to ACEI renography (choice of radiopharmaceutical, choice of ACE
      inhibitor, angiotensin II receptor blockers, diuretics, parenchymal mean transit
      time, monitoring of blood pressure, 1 versus 2 day protocols and omission of the
      baseline study). ACEI renography is highly accurate in patients with suspected
      RVH who have normal or near normal renal function. In this patient population,
      the sensitivity and specificity of ACEI renography for renovascular hypertension
      exceed 90%; angiography as an initial approach is not cost effective. Data from
      10 studies evaluating cure or improvement in blood pressure in 291 patients
      undergoing revascularization showed the mean positive predictive value of ACEI
      renography to be 92%. When azotemic patients present with suspected RVH, as many
      as 50% of patients may have an intermediate probability ACEI renogram and the
      sensitivity of detecting RVH falls to approximately 80% even when intermediate
      and high probability tests are combined.

PMID- 12411868
TI  - Renovascular hypertension. Radiographic methods.
AB  - In recent years the choice of radiographic methods available in the investigation
      of renovascular hypertension has increased significantly. It can be difficult for
      the clinician to decide which patients will benefit from screening and which
      modality to choose. This article seeks to address some of these issues. The role
      of the plain radiograph and intravenous urogram are briefly mentioned. Doppler
      ultrasound, MR, CT and conventional arteriography are discussed in detail. Their
      advantages and pitfalls are reviewed. In our institution ultrasound to document
      renal size and gadolinium-enhanced 3-D MRA are our recommended first-line
      investigations unless MRA is contraindicated. Digital subtraction arteriography
      is reserved for the small subgroup in which MRA fails to obtain an answer, for
      whatever reason.

PMID- 12411869
TI  - Obstructive uropathy.
AB  - Obstructive uropathy refers to the condition of obstruction to urine flow from
      the kidney to the bladder. Such obstruction may be acute or chronic, complete or
      incomplete, and unilateral or bilateral. It has many diverse causes each with
      their own specific features and yet each producing similar disturbances to renal
      function and urine flow. This paper discusses the unique role of nuclear medicine
      techniques in the diagnosis and management of urinary tract obstruction in
      current urological practice.

PMID- 12411870
TI  - Urinary tract infection and other pediatric considerations.
AB  - Urinary tract infection in childhood can lead to chronic sequelae, particularly
      in the presence of vesico-ureteric reflux or obstruction. The renal complications
      of acute pyelonephritis or residual chronic renal cortical scarring are most
      accurately evaluated with scintigraphy using (99m)Tc dimercaptosuccinic acid. The
      diagnosis of renal obstruction can be problematic, particularly in infants and
      children. Diuresis renography is an established tool in diagnosing and assessing
      the severity of obstruction. However the methodology for performing diuresis
      renography is a very controversial area in paediatric nuclear medicine, due to
      the lack of a gold standard. The surgical management of neonatal hydronephrosis
      is similarly controversial.

PMID- 12411871
TI  - Exercise renography in essential hypertension.
AB  - Exercise renography is an investigative procedure used to visualize a renal
      functional disturbance of essential hypertension (EH). The exercise protocol was
      developed to intensify a renal functional abnormality observed in standing
      hypertensive patients, when it appeared that this disturbance was directly
      associated with EH. Clearance determinations during light ergometric exercise
      showed that the abnormal scintigraphic images of the exercise renogram result
      from a prominent contraction of glomerular filtration rate (GFR), while effective
      renal plasma flow (ERPF) remained comparatively stable. The results obtained at
      present with exercise renography and clearance determinations suggest that
      afferent-efferent glomerular vessel dysfunction disrupts the stable relationship
      between GFR and ERPF in EH. This relationship is severely disturbed, and most
      readily recognized, during exercise. It is suspected that this functional
      abnormality results in the activation of the renin-angiotensin axis. A
      particularly exciting consequence of this research is the recognition that
      scintigraphy permits recognition of a disruption of the stable relationship of
      GFR and ERPF. This opens the door to a broad area of research unrelated to EH,
      since initial results in renovascular disease and urinary tract obstruction
      indicate that the fixed relationship between GFR and ERPF can be disturbed in
      these and other diseases as well.

PMID- 12411872
TI  - High-sensitive 2nd generation thyroglobulin immunoradiometric assay. Clinical
      application in differentiated thyroid cancer management.
AB  - BACKGROUND: Circulating human thyroglobulin (hTG) measurements have a pivotal
      role in the management of patients affected by differentiated thyroid cancer
      (DTC). The present study was undertaken by employing a new developed high
      sensitive hTG immunoradiometric assay to evaluate its diagnostic performance in
      patients affected by radically cured and relapsing DTC and to set the most
      appropriate cut-off point for DTC management. METHODS: We retrospectively
      selected 172 patients without signs of recurrence after primary treatment and 45
      patients with recurrences from DTC. Serum samples were collected during l
      thyroxine (T4) suppressive therapy (onT4) and 4 weeks after T4 withdrawal (offT4)
      and hTG measured by a specific high-sensitive IRMA assay (DYNOtest Tg-plus,
      BRAHMS Diagnostica GmbH, Berlin, Germany). Sera showing the presence of AbhTG or
      hTG-recovery less than 80% were excluded from the study. ROC curve analysis was
      performed to select the best cut-off levels and diagnostic performance of the
      marker evaluated. RESULTS: By using onT4 cut-off level of 0.2 ng/mL and offT4 cut
      off level of 0.5 ng/mL we obtained a sensitivity/specificity/accuracy profile of
      0.91/0.98/0.96 and 0.98/0.97/0.97, respectively. We found onT4-hTG false-negative
      results in 4 patient with local recurrence (n=2) or cervical lymph-node
      metastasis (n=2) while only 1 patient with local recurrence showed negative offT4
      hTG. However, onT4 and offT4-hTG false-negative results were observed in 9 and 5
      patients when 1.0 ng/mL cut-off level was employed. CONCLUSIONS: On the basis of
      our data, we conclude that DYNOtest Tg-plus assay is very effective and accurate
      in the evaluation of patients with DTC.

PMID- 12411873
TI  - Nuclear medicine procedures in cardiovascular diseases. An evidence based
      approach.
AB  - The aim of evidence-based medicine is to integrate individual clinical expertise
      with the best available external clinical evidence from systematic research. The
      aim of this article is to introduce the concept of evidence based medicine and to
      review the evidence for applying cardiovascular nuclear medicine in various
      clinical settings. A systematic review is defined as a scientific technique to
      identify and summarize evidence on effectiveness of interventions and to allow
      the consistency of research. Different clinical applications of nuclear medicine
      procedures in cardiology have been reviewed. Radionuclide imaging techniques
      appear to be appropriate in risk assessment, prognosis and evaluation of therapy
      in patients after acute myocardial infarction. In patients with unstable angina,
      radionuclide testing is indicated in the identification of ischemia within the
      distribution of the "culprit" lesion or in remote areas. Exercise and
      pharmacological cardiac perfusion imaging are appropriate and useful in the
      diagnosis and prognosis of chronic coronary artery disease. Nuclear medicine
      procedures are also useful in the assessment of myocardial viability in patients
      with left ventricular dysfunction, in the assessment of interventions for the
      evaluation of patients after percutaneous transluminal coronary angioplasty and
      coronary artery bypass grafting. There has been rapid evolution in radionuclide
      imaging technologies and both the number and the complexity of choices for the
      clinician have increased. Further progress in technology and clinical
      applications of nuclear cardiology may be expected. The development of new
      instrumentation and of new agents will allow consistent progress and improve the
      state-of-art of nuclear cardiology. Thus, guidelines for the use of cardiac
      radionuclide imaging have been difficult to develop and apply. An evidence-based
      approach may be useful for the best use of nuclear medicine procedures in
      cardiovascular diseases.

PMID- 12411874
TI  - Personal dosimetry of the staff during treatment of neuroendocrine tumours with a
      high dose of Indium-111 Octreotide.
AB  - BACKGROUND: Therapeutic doses with Indium-111 (In-111)-DTPA-Octreotide are
      currently used in patients with somatostatin receptor positive tumours. It may
      result in tumour regression in some patients and this effect is ascribed to cell
      and receptor specific cytotoxicity by Auger or conversion electrons. Personnel
      being involved in this treatment may receive high radiation doses due to the
      emission of 173 keV and 247 keV photons. The aim of the present study was to
      assess the radiation dose to the personnel at different time intervals during
      treatment with Indium-111 Octreotide. METHODS: Five consecutive patients
      suffering from a neuroendocrine tumour were included in this dosimetry study. In
      total, 18 treatments with Indium-111 Octreotide have been given with a mean dose
      of 8000 MBq every three weeks. Three dosimeters (whole body, left and right hand)
      and a dose rate monitor were used to register doses and dose rates during
      labelling, administration and in-patient follow-up and whole body scintigraphy.
      These procedures were performed by a pharmacist, a nuclear physician and a
      technologist, respectively. RESULTS: The whole body dose received during the
      labelling procedure was 5 microSv. The mean total exposure time during
      administration, whole body scintigraphy and clinical follow-up was 47 minutes
      revealing a mean whole body dose of 45 microSv. The mean radiation dose to the
      hands was 60 microSv per treatment. CONCLUSIONS: The radiation risk to staff
      members and technologists seems to be very low during in-patient treatments with
      high dose Indium-111 Octreotide. According to the safety regulations no special
      radiation protection measures or personal dosimetry is required.

PMID- 12411875
TI  - Investigation of brain tumours with (99m)Tc-MIBI SPET.
AB  - The aim of this paper is to give the reader an updated overview of (99m)Tc-MIBI
      SPET applications in investigating brain tumours. Elements determining MIBI
      uptake at the level of the brain are first mentioned. (99m)Tc-MIBI SPET features
      in different malignant and benign brain lesions (low and high grade gliomas,
      glioblastoma multiforme, metastasis, lymphoma, meningioma, neuroma, radiation
      necrosis and other rarer brain lesions) are reviewed. The ability of 99mTc-MIBI
      SPET, alone or in combination with other radiotracers, in the differential
      diagnosis of brain lesions is discussed. We outline (99m)Tc-MIBI SPET value in
      determining brain tumours grading and in distinguishing tumour recurrence from
      radiation necrosis. Clinical applications of 99mTc-MIBI in the management of AIDS
      patients, where discrimination between lymphoma and several different lesions
      only on the basis of CT or MRI findings is often impossible, are reported. In
      addition the relationships among (99m)Tc-MIBI SPET, P-glycoprotein (MDR-1 gene
      product) expression in brain neoplasms and chemotherapy response are mentioned.

PMID- 12411876
TI  - Research topics--past, present, and future.

PMID- 12411877
TI  - Reliability of a 3D surface laser scanner for orthodontic applications.
AB  - A device for recreating three-dimensional (3D) objects on a computer is the
      surface laser scanner. By triangulating distances between the reflecting laser
      beam and the scanned surface, the surface laser scanner can detect not only an
      object's length and width but also its depth. The scanner's ease of use has
      opened various possibilities in laboratory research and clinical investigation.
      We assessed the reliability of generating 3D object reconstructions using the
      Minolta Vivid700 3D surface laser scanner (Minolta USA, Ramsey, NJ). Accuracy and
      reproducibility were tested on a geometrical calibrated cylinder, a dental study
      model, and a plaster facial model. Tests were conducted at varying distances
      between the object and the scanner. It was found that (1) in the calibrated
      cylinder tests, spatial distance measurement was accurate to 0.5 mm (+/- 0.1 mm)
      in the vertical dimension and 0.3 mm (+/- 0.3 mm) in the horizontal dimension;
      (2) in the study model test, molar width was accurate to 0.2 mm (+/- 0.1 mm, P
      >.05), and palatal vault depth could be measured to 0.7 mm (+/- 0.2 mm, P >
      0.05); and (3) for the facial model, an accuracy of 1.9 +/- 0.8 mm was obtained.
      The findings suggest that the surface laser scanner has great research potential
      because of its accuracy and ease of use. Treatment changes, growth, surgical
      simulations, and many other orthodontic applications can be approached 3
      dimensionally with this device.

PMID- 12411878
TI  - Managing the developing Class III malocclusion with palatal expansion and
      facemask therapy.

PMID- 12411879
TI  - Anterior open bite in the deciduous dentition: longitudinal follow-up and
      craniofacial growth considerations.
AB  - The aim of this longitudinal cephalometric study was to evaluate craniofacial
      growth changes in subjects with an anterior open bite in the deciduous dentition.
      From longitudinal records of untreated subjects, an open bite group (n = 14) was
      selected at the age of 5 years based on the presence of a negative overbite and
      compared with a control group (n = 14) with a regular overbite at this age.
      Cephalometric measurements were analyzed at ages 5, 9, and 12 years. Although
      only 1 subject in the deciduous dentition open bite group had an open bite at 12
      years of age, the overbite remained lower during the longitudinal follow-up.
      Early cephalometric characteristics of the open bite group included a reduced
      overbite depth indicator and a lower ANB angle. At ages 9 and 12 years, the open
      bite sample was also characterized by shorter ramus height. An underlying
      skeletal pattern seems to be present in the deciduous dentition open bite sample
      that persists during the longitudinal follow-up. The overbite depth indicator
      might help to identify patients with anterior open bite tendencies.

PMID- 12411880
TI  - Efficacy of a wax containing benzocaine in the relief of oral mucosal pain caused
      by orthodontic appliances.
AB  - During orthodontic treatment, pain and discomfort of the oral mucosa can be
      experienced as a result of trauma from the appliances caused by increased
      friction between mucosal tissue and the surface of the brackets. Currently,
      orthodontists have few remedies to prevent or relieve this mucosal irritation.
      The orthodontist can give the patient wax to cover the brackets as a prophylactic
      measure or to use as needed on specific irritating appliances. Orthodontic wax
      contains no analgesic components. The purpose of this study was to determine the
      efficacy of an orthodontic wax containing benzocaine that is released over time
      in a controlled manner. This randomized, prospective, double-blind, clinical
      trial compared patients' responses to the wax with benzocaine and the currently
      used unmedicated orthodontic wax. Seventy patients, 35 in each treatment group,
      were instructed to apply the wax in a specific manner, and their pain levels were
      recorded at 6 different time points. The pain levels were analyzed with a
      repeated-measure analysis of variance (ANOVA) model with factors of treatment
      (medicated wax vs unmedicated wax) and times (6 levels). Post-hoc pair-wise
      comparisons were made on the basis of the Fisher least significant difference
      procedure. The results of this study clearly indicated that the pain profile over
      time of the group that received the wax containing benzocaine was significantly
      different from that of the subjects who received the unmedicated wax. The
      medicated group had significantly lower pain levels at every time point after the
      first hour (P <.0003 in each case) compared with the unmedicated group. The
      medicated wax was effective immediately and continued to reduce pain in greater
      magnitude than did the unmedicated wax. A wax applied to orthodontic brackets
      that slowly and continuously releases benzocaine is significantly more effective
      at reducing the pain associated with mucosal irritation than is the current
      option used by most orthodontists.

PMID- 12411881
TI  - Evaluation of the relationship between the anterior component of occlusal force
      and postretention crowding.
AB  - The aim of this study was to investigate whether a relationship exists between
      the anterior component of occlusal force (ACF) and postretention crowding in the
      mandibular incisor area. The study group comprised 32 adults who had undergone
      fixed orthodontic treatment in the department clinic at Marmara University in
      Istanbul, Turkey. In 13 subjects, the mandibular arch was treated without
      extractions; in 19, it was treated with bilateral first premolar extractions. The
      average postretention period was 3.5 years. The ACF created in the left side of
      the mandibular dentition was determined by measuring interdental frictional
      forces at each contact point mesial to the first molar and distal to the canine.
      Anatomic contact point displacements between the left mandibular anterior teeth
      (lateral incisor-canine, central incisor-lateral incisor, and central incisor
      central incisor) were measured on plaster casts and summed to provide the
      irregularity index for these teeth. Correlation analysis was used to assess the
      relationship between the ACF values at each contact and the irregularity index.
      In the nonextraction group, statistically significant positive correlations were
      observed between the ACF and the irregularity index at the 3 contact points that
      were measured. The strongest correlation was found at the canine-first premolar
      contact (r = 0.65). In the extraction group, a positive correlation was found
      between the ACF and the irregularity index (r = 0.49, P <.05) at the second
      premolar-first molar contact, but no correlation was found at the canine-second
      premolar contact.

PMID- 12411882
TI  - Influence of mandibular protruding device on airway passages and dentofacial
      characteristics in obstructive sleep apnea and snoring.
AB  - The aim of the study was to evaluate the influence of a mandibular protruding
      device (MPD) after 2 years of nocturnal use on the upper airway and its
      surrounding structures. Lateral cephalograms in the upright position were taken
      of patients with obstructive sleep apnea (OSA) and of patients with snoring
      problems at the beginning of treatment and at the 2-year follow-up. Two computer
      programs were used to analyze the cephalograms. A total of 65 patients, 44 with
      OSA and 21 snorers, were analyzed. The linear distances in the pharynx had
      increased significantly at the 2-year follow-up; the calculated pharyngeal area
      had increased on average by 9% (mean, +58.3 mm(2)). The velum area had decreased
      (mean, -31.5 mm(2)), which accounts for about half the increase in the relative
      area of the pharynx. The average linear distances between the hyoid bone and the
      2 reference lines, ie, nasal line (NL) and mandibular line (ML), had increased
      significantly. Mandibular protrusion (SNB) was slightly reduced, on average -0.4
      degrees (P <.01), and the lower incisors were proclined (ILi/ML), on average +1.5
      degrees (P <.05). In conclusion, nocturnal use of an MPD for 2 years increased
      the airway passage because of an increase in the relative area of the pharynx by
      a mean of 9% in OSA patients and snorers. A mandibular posterior rotation and a
      proclination of the lower incisors were observed but considered modest.

PMID- 12411883
TI  - Cervical vertebral bone age in girls.
AB  - The purpose of this study was to establish cervical vertebral bone age as a new
      index for objectively evaluating skeletal maturation on cephalometric
      radiographs. Using cephalometric radiographs of 176 girls (ages 7.0-14.9 years),
      we measured cervical vertebral bodies and determined a regression formula to
      obtain cervical vertebral bone age. Next, using cephalometric and hand-wrist
      radiographs of another 66 girls (ages 8.0-13.9 years), we determined the
      correlation between cervical vertebral bone age and bone age using the Tanner
      Whitehouse 2 method. The following results were obtained: (1) a regression
      formula was determined to obtain cervical vertebral bone age based on ratios of
      measurements in the third and fourth cervical vertebral bodies; (2) the
      correlation coefficient for the relationship between cervical vertebral bone age
      and bone age (0.869) was significantly (P <.05) higher than that for the
      relationship between cervical vertebral bone age and chronological age (0.705);
      and (3) the difference (absolute value) between the cervical vertebral bone age
      and bone age (0.75 years) was significantly (P <.001) smaller than that between
      cervical vertebral bone age and chronological age (1.17 years). These results
      suggest that cervical vertebral bone age reflects skeletal maturity because it
      approximates bone age, which is considered to be the most reliable method for
      evaluating skeletal maturation. Using cervical vertebral bone age, it might be
      possible to evaluate maturity in a detailed and objective manner on cephalometric
      radiographs.

PMID- 12411884
TI  - Role of cranial base flexure in developing sagittal jaw discrepancies.
AB  - The aim of this longitudinal cephalometric study was to investigate skeletal
      features in patients with small and large cranial base angles. Two groups of
      untreated subjects were formed on the basis of a small and large cranial base
      angle N-S-Ar at the age of 5 years: the large cranial base angle group (n = 22)
      consisted of subjects with an N-S-Ar angle larger than 125 degrees (mean, 128.1
      degrees ), and the small cranial base angle group (n = 20) included subjects with
      an N-S-Ar angle of less than 120 degrees (mean, 117.6 degrees ). Cephalometric
      data of the 2 groups were analyzed at subject ages 5 and 12 years. At both ages,
      the groups showed significant differences of the variables SNA, SNB,
      individualized ANB, and Y axis. The unadjusted ANB angle and the angle of
      convexity N-A-Pg were not significantly different between the 2 groups. According
      to the individualized norm of the ANB angle, subjects with a large cranial base
      angle in the primary dentition demonstrated a skeletal Class II tendency both at
      the initial observation and at the longitudinal follow-up. On the basis of
      cephalometric variables at 12 years of age, it was possible to classify 88.1% of
      the initial large and small cranial base angle individuals, indicating a
      constancy of the skeletal pattern during the longitudinal follow-up. The
      relationship between cranial base flexure and skeletal pattern of the jaws seems
      to be established before the age of 5 years.

PMID- 12411885
TI  - Role of suprahyoid musculature on mandibular morphology and growth orientation in
      rats.
AB  - This study was undertaken in rats to study the influence of the suprahyoid
      muscles on mandibular growth, morphology, and orientation. The aim was to
      investigate the effect of bilateral suprahyoid muscle myectomy on the skeletal
      growth and orientation of the mandible and on its orientation in rats. Forty
      eight 4-week-old rats were divided into 2 experimental and 2 control groups as
      follows: A, 12 animals in which bilateral excision of the anterior digastric
      muscle was performed; B, 12 animals in which bilateral excision of the anterior
      digastric, transverse mandibular, and mylohyoid muscles was performed; C, 12
      animals that were sham-operated bilaterally without any muscular excision; D, 12
      control animals not subjected to any operation. The experimental period was 30
      days. Lateral and dorsoventral radiographs were taken on days 1 and 30, after
      muscular excision. Cephalometric analysis was performed for each animal according
      to a method and procedure established in our laboratory and described earlier.
      The findings support the occurrence of decreased mandibular growth in the group
      in which bilateral digastric, transverse mandibular, and mylohyoid excision was
      performed as compared with controls. In addition, the mandible in the bilateral
      digastric excision group exhibited a more upward orientation. It was thus proven
      that the absence of the suprahyoid musculature does affect both skeletal growth
      and orientation of the mandible.

PMID- 12411886
TI  - Factors regulating mandibular condylar growth.
AB  - Factors regulating condylar growth have not been identified before. This study
      was designed to identify a series of these factors, such as Sox 9 transcription
      factor and vascular endothelial growth factor (VEGF), and also to correlate the
      amount of type X collagen expressed during natural growth to the amount of bone
      newly formed. We used 115 Sprague-Dawley rats, 35 days old, in this study. The
      expression of these factors was identified on protein level by using
      immunostaining. Type X collagen was identified on mRNA and protein levels. Sox 9
      was expressed by cells in the proliferative layer and by chondrocytes. Type X was
      expressed only by hypertrophic chondrocytes, and its expression precedes the
      onset of endochondral ossification. VEGF is expressed by hypertrophic
      chondrocytes, and its maximum level of expression precedes the maximum level of
      bone formation. Condylar growth involves a sequence of transitory stages uniquely
      defined by molecules that are intrinsically synthesized by cells in the condyles.

PMID- 12411887
TI  - Effect of zinc on rat mandibles during growth.
AB  - Zinc is a constituent of enzymes such as alkaline phosphatase and is an essential
      trace element involved in bone formation. The purpose of this study was to
      examine the effects of low levels of zinc intake on bone density and the area of
      cortical and trabecular bone in rat mandibles during the growth stage with
      peripheral quantitative computed tomography. The cartilaginous ossification in
      the femur was also measured. In the mandible, the low-zinc group showed
      significantly lower trabecular bone density compared with the control group,
      whereas the zinc-deficient group showed significantly lower levels of cortical
      bone density and trabecular bone density in the area. On the other hand, in the
      femur, both the zinc-deficient group and the low-zinc group showed a
      significantly lower value in cortical bone density and trabeculae bone density
      when compared with those of the control group. Moreover, the area of cortical
      bone and trabecular bone in the zinc-deficient group showed significantly lower
      values than those of the control group, whereas the low-zinc group only showed a
      significantly lower area of cortical bone than that of the control group. These
      results suggested that changes in zinc intake might exert an effect on the
      osseous tissue of the mandible and femur, and the femur was more sensitive to
      change of dietary zinc content than mandibles.

PMID- 12411888
TI  - Controlling third-party expenditures and improving quality assurances: a plea for
      change.
AB  - Growing demands to contain health care's inflationary expenditures have
      particular relevance for elective (eg, orthodontic) services, because their
      progressively increasing provision will ultimately jeopardize the resources for
      others (eg, restorative dentistry). Some form of rationalization is therefore
      inevitable, especially in services eligible for payments from third-party
      benefits. These are central concerns of the ongoing debate on whether
      rationalization should be driven by service efficiency and cost efficiency and
      who should make such decisions. The adaptation of contemporary computer-based
      technology could resolve this dilemma, especially if real-time comprehensive
      assessments of 3-dimensional craniofacial forms before and after treatment are
      incorporated into local and national databases. Such a facility would then help
      to develop clinical guidelines to optimize the provision of specific orthodontic
      services for particular malocclusions. Referring individual cases to these
      databases would subsequently help to control service expenditures and maintain or
      even improve their outcomes to the ultimate benefit of both the profession and
      the public.

PMID- 12411890
TI  - Periodontic and orthodontic treatment in adults.
AB  - The purpose of this article is to provide an update of the interrelationship
      between periodontics and orthodontics in adults. Specific areas reviewed are the
      reaction of periodontal tissue to orthodontic forces, the influence of tooth
      movement on the periodontium, the effect of circumferential supracrestal
      fiberotomy in preventing orthodontic relapse, the effect of orthodontic treatment
      on the periodontium, microbiology associated with orthodontic bands, and
      mucogingival and esthetic considerations. In addition, the relationship between
      orthodontics and implants (eg, using dental implants for orthodontic anchorage)
      is discussed.

PMID- 12411891
TI  - Orthodontic treatment of bilaterally impacted maxillary canines in an adult.
AB  - This case report discusses the management of bilaterally labially impacted
      maxillary canines and a deepbite Class II malocclusion in a 21-year-old woman. An
      interdisciplinary approach to treatment with different mechanical strategies led
      to the achievement of the desired esthetic, functional, and occlusal treatment
      goals. The problems associated with impacted maxillary canines and the
      biomechanical interventions used for this patient are discussed.

PMID- 12411892
TI  - Litigation, legislation, and truth. Truth or consequences.

PMID- 12411893
TI  - Coronary flow reserve assessment by Doppler echocardiography in children with and
      without congenital heart defect: comparison with invasive technique.
AB  - To evaluate whether transthoracic Doppler echocardiography can reliably measure
      coronary flow velocity (CFV) and CFV reserve (CFVR) in the left anterior
      descending coronary artery (LAD) in children, we examined 12 patients who had a
      history of Kawasaki disease without stenosis or aneurysm formation of coronary
      artery and 9 patients who had congenital heart disease (ventricular septal defect
      in 6, patent ductus arteriosus in 2, tricuspid atresia in 1). The pulmonary-to
      systemic flow ratio ranged from 1.7 to 2.8. CFV in the proximal LAD was measured
      by transthoracic Doppler echocardiography at the time of Doppler guidewire
      examination. CFV in the proximal LAD was measured at baseline and hyperemic
      conditions by both transthoracic Doppler echocardiography and Doppler guidewire
      techniques. CFVR was defined as "the ratio of peak hyperemic to basal CFV in the
      proximal LAD." Clear envelopes of basal and hyperemic CFV in the proximal LAD
      were obtained in 19 of 21 patients by transthoracic Doppler echocardiography.
      There was a significant correlation between transthoracic Doppler
      echocardiography and Doppler guidewire methods for the measurements of CFV (r =
      0.84, P <.0001). The mean difference between the 2 methods was -0.5 +/- 5.9 cm/s.
      CFVR from transthoracic Doppler echocardiography correlated well with that from
      Doppler guidewire examinations (r = 0.83, P <.0001). The mean difference between
      the 2 methods was 0.06 +/- 0.24. Noninvasive measurement of CFV and CFVR in the
      proximal LAD using transthoracic Doppler echocardiography accurately reflects
      invasive measurement of CFV and CFVR by Doppler guidewire method in pediatric
      patients with various heart diseases.

PMID- 12411894
TI  - What is the feasibility of imaging coronary arteries during routine
      echocardiograms in children?
AB  - BACKGROUND: Abnormalities of coronary artery (CA) origins may be associated with
      sudden death. No data exist regarding the feasibility of routine
      echocardiographic imaging of CA in pediatrics. OBJECTIVE: Our aim was to
      determine the feasibility of imaging CA origins during routine echocardiograms.
      METHODS: One hundred randomly selected children without clinical evidence of
      heart disease were studied. The mean age was 13.8 +/- 6.4 years. Location of CA
      origins were tallied with clock-face reference. RESULTS: The left CA origin was
      imaged in 98% with the origin most commonly at 3:30 o'clock. The right CA origin
      was imaged in 95% with the origin most commonly at 11 o'clock. Four abnormalities
      of CA were discovered: right CA origin from the left coronary sinus n = 2,
      circumflex from right CA origin n = 1, and small left CA origin to pulmonary
      artery fistula n = 1. CONCLUSION: We conclude that imaging of CA origins during
      routine pediatric echocardiograms is feasible with a potentially life-saving
      result.

PMID- 12411895
TI  - Effect of unilateral diaphragm paralysis on branch pulmonary artery flow.
AB  - BACKGROUND: Respiration is known to be a significant contributor to pulmonary
      flow in patients who have had Glenn or Fontan procedures. OBJECTIVE: The purpose
      of this study was to evaluate the effect of respiration on branch pulmonary
      artery flow in normal participants, in those with uncomplicated Glenn or Fontan
      procedures, and in those with uncomplicated biventricular (2V) repairs, and to
      compare them with similar groups of postoperative patients who had unilateral
      diaphragm paralysis. METHODS: Twenty-one normal infants and children were
      studied, along with 10 who had undergone uncomplicated bidirectional Glenn or
      Fontan palliation. Also studied were 10 patients with uncomplicated 2V repairs
      and 17 patients having ultrasound demonstration of diaphragm paralysis. Nine had
      undergone Glenn or Fontan procedures and 8 had undergone 2V repair. With the use
      of conventional pulsed Doppler, branch right and left pulmonary artery waveforms
      were recorded during spontaneous respiration. The velocity time integral (VTI);
      heart rate (HR); and systolic, diastolic, and mean velocities were measured at
      end-expiration and during inspiration. The pulsatility index (PI) (PI = systolic
      velocity - diastolic velocity/mean velocity) was calculated for each condition.
      RESULTS: In normal participants PI was 1.69 with a 4.7% increase with
      inspiration; VTI x HR was 1859. In patients who had undergone uncomplicated
      Glenn/Fontan procedures PI was 1.06 with a 27.5% increase with inspiration; VTI x
      HR was 1303, all P =.001 versus normal participants. In patients with 2V repairs
      PI was 1.7 with a 5.6% increase with inspiration; VTI x HR was 1850, all P = ns
      versus normal participants. Patients with Glenn/Fontan connections and diaphragm
      paralysis had lower PI (0.81), inspiratory increase (7.9%), and VTI x HR (610) on
      the affected side, all P =.001 versus the normal side, and versus patients who
      had undergone uncomplicated Glenn/Fontan procedures. Patients with 2V repair with
      a pulsatile source of pulmonary flow had a smaller significant difference in the
      measured indices. Three patients underwent diaphragm plication with improvement
      in PI, inspiratory increase in PI, and VTI x HR postplication. CONCLUSION: In
      normal participants and patients with uncomplicated 2V repair, inspiration has
      little effect on PI in branch pulmonary arteries. In patients who have undergone
      uncomplicated Glenn/Fontan procedures, PI is less than that of normal
      participants and the effect of inspiration is approximately 5-fold greater. This
      significant effect of inspiration on pulmonary flow is lost on the affected side
      in patients with Glenn/Fontan connections and diaphragm paralysis, and is blunted
      on the affected side in patients with 2V repair and diaphragm paralysis. Loss of
      diaphragm function is associated with redistribution of pulmonary flow away from
      the affected side.

PMID- 12411896
TI  - Is Doppler an accurate predictor of catheterization gradients for postoperative
      branch pulmonary stenosis?
AB  - Branch pulmonary stenosis may develop after repair of congenital heart disease.
      Echocardiography, used for the serial evaluation of these patients, yields
      Doppler gradients that are used in decisions regarding the need for intervention
      for branch pulmonary stenosis. The purpose of this study was to assess the value
      of Doppler echocardiography in quantifying the degree of branch pulmonary
      stenosis in patients who were postoperative. Patients after repair of
      transposition of the great arteries (n = 14), truncus arteriosus (n = 12), or
      tetralogy of Fallot (n = 14) who underwent echocardiography within 3 months of a
      postoperative catheterization were identified. Doppler peak instantaneous
      gradients were compared with catheter peak-to-peak gradients. Despite significant
      correlation between Doppler and catheterization peak gradients, Doppler gradients
      tended to overestimate the catheterization gradients, and the agreement between
      the 2 measurements was poor. These findings suggest that Doppler gradients should
      be interpreted cautiously in this setting.

PMID- 12411897
TI  - Echocardiographic assessment of the right ventricular response to hypertension in
      neonates on the basis of average-shaped contraction models.
AB  - BACKGROUND AND METHOD: We evaluated a new method of shape analysis in defining
      right ventricle (RV) response to pressure overload. Twenty-five neonatal patients
      (13 with RV hypertension, 12 without) underwent echocardiographic imaging and
      reconstruction of RV regional chamber volumes over 1 cardiac cycle. Group tracing
      data in coronal, sagittal, and transverse echocardiography planes were then shape
      averaged to construct normal- and hypertensive-average-shape contraction models.
      Each patient's RV was classified as more similar to the normal- or hypertensive
      average-shape model on the basis of the median tangent-angle difference, a
      quantitative technique of shape comparison. RESULTS: Ejection fraction, time of
      end systole, and ejection rate demonstrated significant regional differences
      between normotensive and hypertensive contractions. The normal-average-shape
      contraction model correctly diagnosed all patients who were normotensive
      (specificity 100%) and the hypertensive-average-shape model identified 11 of 13
      patients who were hypertensive (sensitivity 85%). CONCLUSION: Reconstructed-shape
      contraction models throughout 1 cardiac cycle identify altered patterns of RV
      contraction in the presence of pulmonary hypertension.

PMID- 12411898
TI  - Comprehensive assessment of patent ductus arteriosus by echocardiography before
      transcatheter closure.
AB  - BACKGROUND: Anatomic type and angiographic measurements of patent ductus
      arteriosus (PDA) are used to determine the suitability of transcatheter closure
      (TCC). The purpose of this study is to evaluate whether these PDA features can be
      obtained by 2-dimensional echocardiography (2DE). METHODS: We retrospectively
      compared PDA measurements and type from 36 patients submitted to TCC between
      November 1995 and October 2000. RESULTS: The patient age ranged between 2 months
      to 10.5 years (median = 1.2 years). A significant correlation was found between
      measurements of PDA minimal diameter (R(2) = 0.88) and diameter at aortic ostium
      (R(2) = 0.72); whereas a poor correlation existed between measurements of the
      ampulla length. The 2DE and angiographic PDA classification were concordant in 31
      of 36 (86%) patients. CONCLUSION: Our data support the use of 2DE measurements of
      PDA minimal diameter and PDA diameter at the aortic end to assess suitability for
      TCC. In the majority of cases, PDA type can be diagnosed by 2DE.

PMID- 12411899
TI  - Right atrial size and tricuspid regurgitation severity predict mortality or
      transplantation in primary pulmonary hypertension.
AB  - Primary pulmonary hypertension (PPH) is a fatal illness. In advanced stages only
      transplantation is able to increase survival. Echocardiography is useful for the
      assessment of these patients, but there is limited information about its
      prognostic value. With this goal, 25 consecutive patients, age: 36.7 +/- 12.7
      years, were studied and followed up for a mean period of 29 months (range: 0.2
      84). Eleven echocardiographic parameters of cardiac anatomy, function, and
      hemodynamics were assessed. Age and sex were also analyzed. Death and heart-lung
      transplantation were considered end-points. Thirteen events (Death: 8;
      transplantation: 5) occurred in the follow-up (11 of 13 in the first year).
      Kaplan-Meier estimated survival free from transplantation at 5 years was 40% (95%
      CI: 23%-70%). In the univariate analysis, RAA (HR: 1.1, P =.0004), TR (HR: 2.7, P
      =.02), and RVET (HR: 0.98, P =.02) showed statistically significant relation with
      survival free from transplantation. Multivariate analysis showed that RAS (HR:
      1.10, 95% CI: 1.04-1.17, P =.001) and TR (HR: 2.52, 95% CI: 1.01-6.3, P =.047)
      were independent risk factors of transplantation and death. The use of these
      findings on the management of patients with PPH should be tested in larger
      studies.

PMID- 12411900
TI  - Respiratory variation in superior vena cava flow in patients with chronic
      obstructive pulmonary disease: estimation of pulmonary hypertension using Doppler
      flow index.
AB  - Patients with chronic obstructive pulmonary disease (COPD) are difficult to
      assess by conventional transthoracic echocardiography (TTE) because of
      emphysematous lungs or mediastinal deviation. We hypothesized that superior vena
      cava (SVC) flow is related to pulmonary circulation and may be useful for the
      detection of pulmonary hypertension (PH) in patients with COPD that cannot been
      assessed by direct evaluation using the tricuspid regurgitant Doppler velocity.
      SVC Doppler flow velocities were examined in 46 patients with COPD and the
      pressure gradient between the right ventricular and right atrial pressure (RV
      RADeltaP) was calculated by tricuspid regurgitant Doppler velocities. The
      patients were divided into 2 groups: 11 patients with PH (RV-RADeltaP > 25 mm Hg)
      were compared with 35 without PH. There was no significant difference in the
      maximal SVC peak systolic forward flow velocity during inspiration (INS) between
      these 2 groups. However, the minimal SVC peak systolic forward flow velocity
      during expiration (EXP) in the group with PH was significantly higher than that
      in the group without PH (37.4 +/- 20.0 cm/s vs 26.4 +/- 8.5 cm/s, P =.01). Linear
      regression analysis revealed a significant correlation between RV-RADeltaP and
      the EXP/INS ratio (r = 0.61, P <.001). In COPD patients with PH, the increased
      expiratory SVC systolic flow supplemented the preload for the impaired right
      ventricular filling flow caused by PH, thereby maintaining the transtricuspid
      driving pressure. Our observation suggests that respiratory variation in SVC
      systolic forward flow may be a sensitive Doppler flow index for evaluating
      severity of PH in patients with COPD that cannot been assessed by conventional
      TTE.

PMID- 12411901
TI  - Measurement of aortic valve anatomic regurgitant area using transesophageal
      echocardiography: implications for the quantitation of aortic regurgitation.
AB  - BACKGROUND: Various echocardiographic methods for the assessment of the severity
      of the aortic regurgitation (AR) by have been described with no general
      consensus. AIM: To assess the feasibility and reproducibility of direct
      planimetric measurement of the end-diastolic gap between aortic cusps on the
      transesophageal echocardiography (TEE) images in patients with AR. We also
      analyzed the correlation of this anatomic aortic regurgitanty area with
      angiographic AR severity. METHODS: Ninety patients (38 males, 52 females, mean
      age 41 +/- 24 years) with AR who underwent TEE and contrast aortography in a
      single institution. The AR was graded angiographically as mild (n = 45), moderate
      (n = 31), and severe (n = 14). The anatomic regurgitant area was measured on the
      end-diastolic short-axis TEE images of the aortic valve by planimetering the
      central gap bordered by the commisural edges of the aortic cusps. RESULTS: The
      intraobserver and interobserver variability for the measurement of aortic
      anatomic regurgitant area were small (mean absolute differences 0.01 +/- 0.01
      cm(2), and 0.015 +/- 0.013 cm(2), respectively). The average values of anatomic
      regurgitant area for angiographically mild, moderate, and severe AR were 0.15 +/-
      0.05 cm(2), 0.30 +/- 0.08 cm(2), and 0.68 +/- 0.33 cm(2), respectively (P <.001).
      When the anatomic regurgitant area was graded as small (> 0.2 cm(2)), moderate (>
      0.2 and > 0.4 cm(2)) and large (> 0.4 cm(2)), the sensitivity, specificity,
      positive and negative predictive value, and the diagnostic accuracy for
      predicting the angiographically mild AR were 85%, 97%, 97%, 87%, and 91%,
      respectively. For the moderate angiographic AR the same values were 84%, 92%,
      81%, 93%, and 90%, and for the severe angiographic AR they were 98%, 93%, 93%,
      98% and 97%. CONCLUSION: The planimetric measurement of aortic anatomic
      regurgitant area by TEE is feasible and reproducible for the assessment of the
      severity of AR.

PMID- 12411902
TI  - Intraoperative transesophageal echocardiographic assessment of the effect of
      protamine on paraprosthetic aortic insufficiency immediately after stentless
      tissue aortic valve replacement.
AB  - Mild paravalvular aortic insufficiency (AI) is common immediately after stentless
      bioprosthetic aortic valve replacement. Although resolution of paraprosthetic
      jets with protamine has been described, the predictability of resolution has not
      been addressed. Intraoperative transesophageal echocardiography was performed
      before and after protamine administration among 2 groups. The first group (n =
      20) was used to define the prevalence and severity of paravalvular AI after
      stentless tissue AVR, and define a threshold value for jet size associated with
      resolution with protamine. A second group (n = 18) was used to prospectively test
      the determined threshold. Paravalvular AI occurred in 13 of 20 (65%) patients.
      Using a threshold value of 0.3 cm or less jet width, prospective testing revealed
      positive and negative predictive values for AI resolution with protamine of 93%
      (14 of 15) and 100% (3 of 3), respectively. Protamine administration is
      associated with resolution of small AI jets immediately after implantation of a
      stentless aortic bioprosthesis, with a jet width 0.3 cm or less strongly
      predictive of resolution.

PMID- 12411904
TI  - Quantification of instantaneous flow rate and dynamically changing effective
      orifice area using a geometry independent three-dimensional digital color Doppler
      method: An in vitro study mimicking mitral regurgitation.
AB  - OBJECTIVE: Our study was intended to test the accuracy of a 3-dimensional (3D)
      digital color Doppler flow convergence (FC) method for assessing the effective
      orifice area (EOA) in a new dynamic orifice model mimicking a variety of mitral
      regurgitation. BACKGROUND: FC surface area methods for detecting EOA have been
      reported to be useful for quantifying the severity of valvular regurgitation.
      With our new 3D digital direct FC method, all raw velocity data are available and
      variable Nyquist limits can be selected for computation of direct FC surface area
      for computing instantaneous flow rate and temporal change of EOA. METHODS: A 7.0
      MHz multiplane transesophageal probe from an ultrasound system (ATL HDI 5000) was
      linked and controlled by a computer workstation to provide 3D images. Three
      differently shaped latex orifices (zigzag, arc, and straight slit, each with
      cutting-edge length of 1 cm) were used to mimic the dynamic orifice of mitral
      regurgitation. 3D FC surface computation was performed on parallel slices through
      the 3D data set at aliasing velocities (14-48 cm/s) selected to maximize the
      regularity and minimize lateral dropout of the visualized 3D FC at 5 points per
      cardiac cycle. Using continuous wave velocity for each, 3D-calculated EOA was
      compared with EOA determined by using continuous wave Doppler and the flow rate
      from a reference ultrasonic flow meter. Simultaneous digital video images were
      also recorded to define the actual orifice size for 9 stroke volumes (15-55
      mL/beat with maximum flow rates 45-182 mL/s). RESULTS: Over the 9 pulsatile flow
      states and 3 orifices, 3D FC EOAs (0.05-0.63 cm(2)) from different phases of the
      cardiac cycle in each pump setting correlated well with reference EOA (r = 0.89
      0.92, SEE = 0.027-0.055cm(2)) and they also correlated well with digital video
      images of the actual orifice peak (r = 0.97-0.98, SEE = 0.016-0.019 cm(2)),
      although they were consistently smaller, as expected by the contraction
      coefficient. CONCLUSION: The digital 3D FC method can accurately predict flow
      rate, and, thus, EOA (in conjunction with continuous wave Doppler), because it
      allows direct FC surface measurement despite temporal variability of FC shape.

PMID- 12411903
TI  - Pulmonary venous flow determinants of left atrial pressure under different
      loading conditions in a chronic animal model with mitral regurgitation.
AB  - BACKGROUND: The aim of our study was to quantitatively compare the changes and
      correlations between pulmonary venous flow variables and mean left atrial
      pressure (mLAP) under different loading conditions in animals with chronic mitral
      regurgitation (MR) and without MR. METHODS: A total of 85 hemodynamic conditions
      were studied in 22 sheep, 12 without MR as control (NO-MR group) and 10 with MR
      (MR group). We obtained pulmonary venous flow systolic velocity (Sv) and
      diastolic velocity (Dv), Sv and Dv time integrals, their ratios (Sv/Dv and Sv/Dv
      time integral), mLAP, left ventricular end-diastolic pressure, and MR stroke
      volume. We also measured left atrial a, x, v, and y pressures and calculated the
      difference between v and y pressures. RESULTS: Average MR stroke volume was 10.6
      +/- 4.3 mL/beat. There were good correlations between Sv (r = -0.64 and r = 
      0.59, P <.01), Sv/Dv (r = -0.62 and r = -0.74, P <.01), and mLAP in the MR and NO
      MR groups, respectively. Correlations were also observed between Dv time integral
      (r = 0.61 and r = 0.57, P <.01) and left ventricular end-diastolic pressure in
      the MR and NO-MR groups. In velocity variables, Sv (r = -0.79, P <.001) was the
      best predictor of mLAP in both groups. The sensitivity and specificity of Sv = 0
      in predicting mLAP 15 mm Hg or greater were 86% and 85%, respectively.
      CONCLUSION: Pulmonary venous flow variables correlated well with mLAP under
      altered loading conditions in the MR and NO-MR groups. They may be applied
      clinically as substitutes for invasively acquired indexes of mLAP to assess left
      atrial and left ventricular functional status.

PMID- 12411905
TI  - Detection of early right ventricular dysfunction in Chagas' disease using Doppler
      tissue imaging.
AB  - BACKGROUND: The involvement of the right ventricle (RV) in Chagas' disease is
      frequent. Although echocardiography plays an important role in noninvasive
      assessment of cardiac function, evaluation of RV is challenging because of the
      anatomic and functional complexity of this chamber. METHODS: To study early
      functional abnormalities in the RV, we selected 18 patients with Chagas' disease,
      no other disease, and a normal echocardiogram; and 12 normal individuals as a
      control group. All participants were submitted to Doppler tissue imaging and the
      parameters of systolic (systolic wave and regional isovolumic contraction time)
      and diastolic (early and late expansion waves) function were analyzed at the
      level of the interventricular septum and free wall of the RV. RESULTS: Regional
      isovolumic contraction time values showed a statistically significant difference
      between the 2 groups both in the RV free (P =.0003) and septal (P =.003) walls.
      With respect to diastolic function, we observed a significant difference between
      groups involving the early expansion wave (P =.014) and e/a ratio (P =.004) of
      the RV free wall. CONCLUSION: Doppler tissue imaging proved to be useful in early
      detection of RV dysfunction in Chagas' disease, with potential use in risk
      stratification of these patients.

PMID- 12411906
TI  - Perioperative tissue Doppler echocardiography and bypass graft flowmetry in
      patients undergoing coronary revascularization: predictive power for late
      recovery of regional myocardial function.
AB  - To assess if recovery of regional myocardial function can be predicted by
      perioperative Doppler tissue echocariography, 20 patients undergoing coronary
      artery bypass graft surgery (mean 4.1 grafts) had serial transthoracic and
      transesophageal echocardiography. Systolic velocities were lower in basal
      posterior and anterior segments, and higher in the midanterior septum, at
      intraoperative transesophageal echocardiography compared with preoperative
      transthoracic echocardiography (-45%, -30%, +18%, respectively), but comparable
      elsewhere. After bypass, velocities were increased in midposterior, basal
      lateral, basal anterior, and midanterior septal segments (+41%, 25%, 27%, 44%,
      respectively, P <.05). Increased velocities in circumflex segments at 6 weeks
      (midposterior, basal lateral, and midlateral +54%, 45%, 39%, respectively, P
      <.05) were not predicted by perioperative changes or related to graft flow
      (transit-time flowmetry; R -0.09, -0.14, and -0.32, respectively, not
      significant). Myocardial velocities measured by transthoracic and transesophageal
      echocardiography are not comparable in segments with different angles of
      insonation. Perioperative changes in resting myocardial systolic velocity are
      highly variable and do not predict late recovery.

PMID- 12411907
TI  - The role of short- and long-axis function in determining late diastolic left
      ventricular filling in patients with hypertension: assessment by pulsed Doppler
      tissue imaging.
AB  - Left ventricular (LV) wall motion velocity during atrial systole is mediated by
      both transmitral flow and LV myocardial compliance at end-diastole. LV wall
      distensibility along the long- and short-axis during atrial systole and late
      diastolic LV filling may vary according to the remodeling of LV morphology. We
      measured LV wall motion velocities along the long and short axes using pulsed
      Doppler tissue imaging in 127 patients with hypertension to evaluate the
      relationship between the hemodynamic changes and LV morphology and to determine
      the role of both long- and short-axis function in late diastolic LV filling.
      Participants were classified into 3 groups according to LV dimension and end
      diastolic wall thickness determined by M-mode echocardiography: group A (n = 62)
      without LV dilation or hypertrophy, group B (n = 55) with LV hypertrophy, and
      group C (n = 10) with LV dilation and systolic dysfunction. The time constant of
      the LV pressure decay during isovolumic diastole and the LV end-diastolic
      pressure were longest and greatest, respectively, in group C, compared with
      groups B and A. There were no significant differences in active left atrial
      emptying volume during atrial contraction determined by computerized
      echocardiographic 3-dimensional reconstruction among patient and control groups.
      The peak atrial systolic motion velocity of the LV posterior wall along the long
      axis was significantly lower in groups B and C, particularly in the latter group,
      than in group A. The peak atrial systolic motion velocity of the LV posterior
      wall along the short axis was greatest in group B and was lowest in group C
      compared with the other groups, respectively. The peak atrial systolic motion
      velocity of the LV posterior wall was greater along the long axis than the short
      axis in group A, but was less than the short axis in group B. In conclusion, the
      long- and short-axis function of the LV wall during atrial systole varies in
      patients with hypertension according to the severity of hemodynamic and
      morphologic abnormalities. The degree of LV wall expansion along the short axis
      is an important factor resulting from the atrial kick, and a determinant of its
      effectiveness.

PMID- 12411908
TI  - Characterization of peripheral arterial wall motion by Doppler tissue echography:
      a validation study.
AB  - Doppler tissue echography (DTE) has been proposed for arterial wall-motion
      analysis. However, it is not known if DTE gives precise measurements of arterial
      displacement. Therefore, we used a pig aorta, in vitro model to study arterial
      wall velocities. High resolution color B-mode DTE acquisitions gave accurate
      estimations of velocities as compared with those obtained by a referenced wall
      tracking system, with a slight underestimation of values calculated from DTE
      (14.4 +/- 0.1 for DTE vs 16.1 +/- 0.2 at 5 L/min output, P >.05). Excellent
      correlations were obtained between both methods (r(2) = 0.94, P <.001), and Bland
      Altman analysis revealed no significant differences between measurements. We also
      compared common carotid arterial wall velocities obtained in 16 healthy
      volunteers by DTE and a wall-tracking system, which gave similar wave profiles.
      As expected, arterial distensions calculated from DTE were lower than those from
      a wall-tracking system (6.8 +/- 1.7% vs 7.4 +/- 2.1%, respectively, P =.02).
      These results indicate that DTE may be used to study arterial wall displacement.

PMID- 12411909
TI  - Mitral annulus velocities by Doppler tissue imaging: practical implications with
      regard to preload alterations, sample position, and normal values.
AB  - Because it appears to be less affected by changes in preload, mitral annulus
      Doppler tissue imaging (DTI) has been proposed as an alternate mean of
      identifying pseudonormal patterns of left ventricular filling. We thus studied
      the practical implications of DTI in 40 patients classified according to the
      Canadian Consensus on Diastolic Function (9 control participants, 9 with impaired
      relaxation, and 22 pseudonormal participants). Using DTI, the early diastolic
      velocity (Ea) was the most reproducible parameter whereas the late diastolic
      velocity (Aa) and Ea/Aa ratio varied significantly. Nonetheless, Ea missed 23% of
      pseudonormal participants and its sensitivity, specificity, and positive and
      negative predictive values to identify diastolic dysfunction were 81%, 89%, 96%,
      and 57%, respectively; improving to 94%, 89%, 97%, and 80%, respectively, if used
      during Valsalva's maneuver. Thus, DTI is not totally preload independent and
      should be interpreted in light of the other Doppler parameters and the use of
      Valsalva's maneuver. Moreover, consistent with recent studies, these results
      suggest that the threshold value of Ea used to identify diastolic dysfunction
      should be approximately 12.5 cm/s.

PMID- 12411910
TI  - Acute effects of smoking on diastolic function in healthy participants: studies
      by conventional doppler echocardiography and doppler tissue imaging.
AB  - The acute effects of smoking on left ventricular (LV) function were studied in 36
      healthy participants (mean age 38 +/- 10 years). The studies were made before and
      immediately and 30 minutes after smoking a cigarette. From apical 4- and 2
      chamber views, the mitral annular velocities, determined by pulsed wave Doppler
      tissue imaging, were measured at 4 LV sites corresponding to the septum and the
      anterior, lateral, and inferior walls. A mean value from the 4 sites was used to
      assess LV function. The peak systolic, early diastolic, late diastolic, and the
      ratio of early to late diastolic velocities were recorded. In addition, other
      conventional Doppler echocardiographic diastolic parameters were also determined.
      Heart rate was increased immediately after smoking (from 67 +/- 8 to 74 +/- 10
      bpm, P <.001). There was no change in systolic mitral annular velocity. Diastolic
      LV function was changed significantly immediately after smoking. The transmitral
      A wave increased (0.55 +/- 0.1 vs 0.7 +/- 0.1 m/s, P <.001), the transmitral E/A
      ratio decreased (1.5 +/- 0.6 vs 1.1 +/- 0.3, P <.001), and the transmitral E-wave
      deceleration time increased (186 +/- 42 vs 211 +/- 44 ms, P <.05). The diastolic
      myocardial velocity at the mitral annulus also changed significantly: the early
      diastolic velocity decreased (16 +/- 3 vs 15 +/- 3 cm/s, P <.001), the late
      diastolic velocity increased (10.9 +/- 2.2 vs 12 +/- 2.4 cm/s, P <.001), and the
      ratio of early to late diastolic annular velocities decreased (1.5 +/- 0.5 vs 1.2
      +/- 0.4, P <.001). The changes in the transmitral flow velocities remained
      unaltered even 30 minutes afterward, although the heart rate returned to normal.
      The results were similar in both smokers and nonsmokers. Acute smoking of a
      cigarette influences LV diastolic function in healthy participants. The mechanism
      behind this effect cannot be explained only by changes in the heart rate or
      loading conditions. The mechanism is probably more complex.

PMID- 12411911
TI  - Prevalence of left ventricular diastolic dysfunction by Doppler echocardiography:
      clinical application of the Canadian consensus guidelines.
AB  - We evaluated diastolic filling patterns using Doppler echocardiography in 520
      consecutive patients referred to our laboratory for transthoracic echocardiograms
      retrospectively and applied the standard guidelines used to characterize left
      ventricular (LV) diastolic function. Patients were classified by the Canadian
      consensus guidelines using transmitral and pulmonary venous Doppler
      echocardiographic parameters to have normal diastolic function or mild (abnormal
      relaxation), mild-to-moderate, moderate (pseudonormal), or severe (restrictive)
      diastolic dysfunction. LV diastolic dysfunction was present in 290 (56%)
      patients, whereas 167 (45%) patients with a normal LV ejection fraction had
      abnormal diastolic function. Patients with progressively more abnormal diastolic
      patterns had greater structural abnormalities with larger left atrial and LV size
      and lower LV ejection fractions. In the subset of patients with clinical evidence
      of congestive heart failure (99 patients), the prevalence of primary diastolic
      heart failure was 38% and most patients had underlying coronary or hypertensive
      heart disease. Standard guidelines of Doppler echocardiographic parameters allow
      semiquantitation of diastolic function and can be applied to studying large
      number of patients in a large clinical practice.

PMID- 12411912
TI  - Comparison of Doppler echocardiography, color M-mode Doppler, and Doppler tissue
      imaging for the estimation of pulmonary capillary wedge pressure.
AB  - To overcome the limitations of mitral inflow parameters for predicting pulmonary
      capillary wedge pressure (PCWP), combined indices (with Doppler tissue imaging or
      color M-mode Doppler) have been developed. This study was aimed to compare the
      accuracy of these indices to predict PCWP. Sixty-one patients were studied. The
      best correlations with PCWP were found for indices that combined isovolumic
      relaxation time with flow propagation velocity (color M-mode) or early diastolic
      velocity of the lateral mitral annulus (Doppler tissue). Both closely tracked
      changes in PCWP. The color M-mode-derived index was the most accurate in patients
      with normal systolic function.

PMID- 12411913
TI  - Influence of propranolol infusion on cyclic variation of myocardial integrated
      backscatter in hypertrophic obstructive cardiomyopathy.
AB  - It has been demonstrated that cyclic variation, assessed by myocardial integrated
      backscatter, reflects regional myocardial contractile function. The aim of this
      study was to investigate the influence of administration of beta-blocker
      propranolol on cyclic variation in patients with hypertrophic cardiomyopathy and
      persistent left ventricular (LV) pressure gradient and to test the hypothesis
      that the reduction of LV pressure gradient would be related to the change in
      regional contractile function. Before and after 2 mg propranolol infusion,
      transthoracic echocardiography with integrated backscatter analysis was performed
      on 11 patients (8 men and 3 women, mean age 54 +/- 12 years old). Integrated
      backscatter curves were obtained from the ventricular septum and LV posterior
      walls. With propranolol infusion, there was a significant reduction of LV
      fractional shortening (0.39 +/- 0.08 to 0.34 +/- 0.09, P <.01) and LV pressure
      gradient (83 +/- 40 mm Hg to 42 +/- 32 mm Hg, P <.001). In the posterior wall,
      the magnitude of cyclic variation significantly decreased (7.1 +/- 2.2 dB to 5.6
      +/- 1.8 dB, P <.01), whereas in the septum, no apparent change in this parameter
      was observed (5.8 +/- 2.1 dB to 4.7 +/- 1.9 dB). Our findings suggest that in
      this form of cardiomyopathy, (1) the posterior wall myocardium is more
      susceptible to negative inotropic effects than the septum; (2) the reduction of
      LV pressure gradient is not related to that of regional wall motion; and (3) poor
      response of the ventricular septum is possibly because of more severe myocardial
      disarray and hypertrophy.

PMID- 12411914
TI  - Use of transesophageal contrast echocardiography for excluding left atrial
      appendage thrombi in patients with atrial fibrillation before cardioversion.
AB  - Transesophageal echocardiographic (TEE) guidance of cardioversion in patients
      with atrial fibrillation is an alternative method to conventional
      anticoagulation. Although TEE is considered the gold standard for excluding left
      atrial (LA) thrombi, in some patients dense spontaneous echo contrast (SEC) and
      artifacts may hamper the identification or exclusion of LA thrombi. Often those
      patients are refused cardioversion. The purpose of this study was to determine
      whether the application of echo contrast (Optison, Mallinckrodt, San Diego,
      Calif) facilitates the exclusion of LA appendage thrombi in this patient group
      and allows for safer cardioversion. Forty-one patients with atrial fibrillation
      and dense SEC or inconclusive TEE findings were given echo contrast. Fourteen
      patients with sinus rhythm served as control participants. Echo contrast
      completely reduced artifacts in 13 of 22 patients. In 12 of 19 patients with SEC,
      the LA appendage was completely filled after the application of echo contrast
      and, thus, SEC was completely suppressed. In 13 of 41 patients, it was filled
      incompletely and in 9 of 41 patients, a new mass resembling a thrombus was
      detected. In total, of 25 of 41 patients with inconclusive TEE findings an atrial
      thrombus was definitively excluded. Those patients underwent cardioversion. None
      of those patients had a cerebral embolic complication as assessed by cranial
      magnetic resonance imaging. Thus, the application of echo contrast may facilitate
      the TEE exclusion of LA appendage thrombi and, hence, improve the safety of TEE
      guided cardioversion.

PMID- 12411915
TI  - Optimal analysis of intravenous myocardial contrast echocardiography for
      predicting myocardial functional recovery in patients with acute myocardial
      infarction.
AB  - OBJECTIVE: This study attempted to determine the optimal interpretation method of
      intravenous myocardial contrast echocardiography (MCE) for predicting myocardial
      functional recovery in patients with acute myocardial infarction. BACKGROUND:
      Assessment of the myocardial contrast effect is subjective and there is currently
      no universal agreement on the pulsing interval (PI) for imaging. METHODS: Twenty
      nine patients underwent percutaneous transluminal coronary angioplasty (PTCA) 4.8
      +/- 1.9 days after acute myocardial infarction and intravenous MCE before and 24
      hours after PTCA by using intermittent harmonic angioimaging at a series of PIs
      of 4, 8, 12, and 16 cardiac cycles. Adequate contrast enhancement was defined by
      homogeneous (MCEhomo score) and heterogeneous patterns (MCEheter score), and by a
      combination of intensity threshold and computed planimetry (MCEcom score).
      Adequate contrast enhancement at a shorter PI defined a higher MCE score (1 vs
      5). The regional wall motion in the risk area was assessed before PTCA and 2
      months after PTCA to evaluate functional recovery. RESULTS: A significant
      improvement after PTCA was noted in the MCEhomo score (3.2 +/- 1.7 vs 3.6 +/-
      1.7, P =.008) and the MCEcom score (2.9 +/- 1.6 vs 3.3 +/- 1.5, P <.0001), but
      not in the MCEheter score (4.3 +/- 1.3 vs 4.5 +/- 1.1, P =.058). Twenty-four
      hours after PTCA, segments with functional recovery had a higher MCEheter score
      (4.9 +/- 0.5 vs 3.8 +/- 1.6, P =.002), MCEhomo score (4.2 +/- 1.4 vs 2.6 +/- 1.9,
      P <.0001), and MCEcom score (3.8 +/- 1.2 vs 2.1 +/- 1.4, P <.0001) than those
      without. For the prediction of function recovery, MCEheter generally had a higher
      sensitivity but a lower specificity and accuracy than did MCEhomo and MCEcom.
      MCEcom had the best accuracy (83%) with a sensitivity of 95% and specificity of
      61% at a PI of 16 cardiac cycles. CONCLUSION: Using a combination of intensity
      threshold and computed planimetry for interpreting myocardial contrast
      enhancement at a long PI can optimize the value of MCE in predicting functional
      recovery after PTCA in patients with acute myocardial infarction.

PMID- 12411916
TI  - Influence of microbubble shell properties on ultrasound signal: Implications for
      low-power perfusion imaging.
AB  - Low mechanical index perfusion imaging relies on the detection of signals
      produced by microbubble oscillation at low acoustic powers that results in
      minimal microbubble destruction. We hypothesized that the optimal acoustic power
      for real-time imaging would differ for microbubbles with different shell
      characteristics. Three microbubble agents with varying shell elastic properties
      according to their polymer composition were studied. Differences in the elastic
      properties of these microbubbles was demonstrated by: (1) measurement of their
      bulk modulus and (2) evaluation of their acoustic lability by microscopic
      visualization of microbubble destruction during insonification at incremental
      acoustic powers. The ultrasound signal generated by these microbubbles at various
      mechanical indexes and the degree of microbubble destruction during continuous
      imaging was determined both in an in vitro flow system and during in vivo imaging
      in an open-chest canine model. Both studies indicated that optimal power for
      achieving maximal signal intensity with minimal microbubble destruction was
      influenced by the shell elastic properties. We conclude that the acoustic power
      for maximizing acoustic signal without destroying microbubbles during low
      mechanical index imaging varies according to shell characteristics.

PMID- 12411917
TI  - Radio frequency dual-spectra analysis of regional myocardial perfusion:
      Comparison with harmonic densitometric method.
AB  - Our objective was to compare harmonic-to-fundamental frequency ratio peak (HFRp)
      analysis with conventional harmonic gray-scale densitometric analysis on the
      basis of ability to eliminate heterogeneity in ultrasound signals. Broadband
      radio frequency and harmonic data were obtained by using intermittent short-axis
      scans in 10 open-chest pigs before and during infusion of contrast microbubbles.
      HFRp and gray-scale intensity values were measured in 6 segments of left
      ventricular myocardium. In baseline images, the influence of anisotropy on HFRp
      values was significantly less than that in gray-scale intensities. In perfusion
      assessment with subtraction, contrast heterogeneity in HFRp values was
      significantly smaller than that in gray-scale intensities. The increase in HFRp
      values after subtraction was significantly greater than that in gray-scale
      intensities in lateral (P <.001), posterior (P <.0001), and inferior (P <.01)
      myocardium. HFRp analysis can compensate for baseline myocardial anisotropy and
      regional contrast heterogeneity. With background subtraction, HFRp analysis
      allows better quantification of myocardial perfusion.

PMID- 12411918
TI  - Stress echocardiography for risk stratification of patients with chest pain and
      normal or slightly narrowed coronary arteries.
AB  - One hundred twenty-five patients (60 +/- 10 years old, 60 women) with known (35,
      previous myocardial infarction) or suspected (90) coronary artery disease (CAD)
      and no more than 50% coronary stenoses underwent pharmacologic (48 dipyridamole
      and 77 dobutamine) stress echocardiography (SE) and prospective follow-up (36 +/-
      22 months) for cardiac death, nonfatal infarction, and unstable angina. The
      ability of clinical and SE variables to predict the outcome was assessed by the
      Cox model. A significant increase in the global chi-square of the model indicated
      an incremental prognostic value. Nine events occurred: 2 fatal and 5 nonfatal
      infarctions and 2 hospitalizations for unstable angina. Hypertension, positive
      SE, and peak wall motion score index were multivariate predictors of outcome, but
      SE provided an 87.5% increase in the global chi-square (P <.001). Patients with
      positive SE had a significantly lower event-free survival compared with those
      with negative SE. Therefore, we conclude that SE provides incremental prognostic
      information in patients with chest pain without critical coronary artery disease.

PMID- 12411920
TI  - Central-nervous side effects of midazolam during transesophageal
      echocardiography.
AB  - BACKGROUND: Midazolam is a broadly used drug that can enhance tolerance to
      transesophageal echocardiography (TEE) in patients with cardiac conditions.
      Adverse reactions to midazolam have been described previously. We describe
      central-nervous side effects in 6 of 104 consecutive patients. METHODS: One
      hundred four patients undergoing TEE-diagnostic procedure were investigated. TEE
      was performed using a SSA 360 Power Vision ultrasound unit (Toshiba, Tokyo,
      Japan) and a 5- to 6-MHz probe. Indication for TEE was evaluation of cardiac
      valves (6), search for cardiac embolism (23), patent foramen ovale or atrial
      septum defect (20), left ventricular dysfunction (11), aortic dissection (7), and
      other (37). Midazolam and, if necessary, the benzodiazepine antagonist flumazenil
      (0.25-0.5 mg) were administered intravenously. RESULTS: The mean cumulative dose
      of midazolam administered in small fractions was 4.8 +/- 2 mg. In 6 of 104
      patients (5.7%) clinically significant adverse effects to midazolam occurred. The
      reactions were aggressiveness, euphoria, depression, and intense hiccups
      (singultus) despite low doses of midazolam. The severest forms of these adverse
      effects to midazolam could be successfully treated with intravenous infusion of
      flumazenil (0.25-0.5 mg intravenously). CONCLUSION: Adverse effects including
      aggressive, euphoric, or depressive behavior can occur in a significant
      proportion (6%) of patients with cardiac conditions undergoing TEE after
      intravenous administration of midazolam. The administration of the benzodiazepine
      antagonist flumazenil can reverse the adverse effects to midazolam successfully.

PMID- 12411919
TI  - Relation between changes in coronary flow velocity and in wall motion for
      assessing contractile reserve during dobutamine stress echocardiography.
AB  - The purpose of this study was to determine the relationship between coronary flow
      velocity (CFV) measured by transthoracic Doppler echocardiography (TTDE) and wall
      motion during dobutamine stress echocardiography (DSE) in patients with resting
      wall motion abnormalities (WMAs). One hundred fifty patients with resting WMA in
      the left anterior descending coronary artery (LAD) territory underwent CFV
      recording in the distal LAD by TTDE during contrast-enhanced DSE. Regional wall
      motion, CFV, and CFV ratio, defined as a ratio of CFV at each stage of dobutamine
      stress to basal CFV, were obtained. Patients were divided into 4 groups
      (sustained improvement, biphasic response, worsening response, and no change).
      CFV was successfully recorded in 129 patients during DSE (86%). The mean value of
      basal CFV did not differ among the 4 groups. Although CFV ratio during DSE
      progressively increased in patients with sustained improvement, this increase was
      blunted with biphasic response and almost lost with worsening or no change
      response (P <.001, ANOVA). CFV ratio at peak stress was significantly higher in
      patients with sustained improvement (2.73 +/- 0.69) than that with the other 3
      groups (P <.001). The value with biphasic response (1.68 +/- 0.56) was also
      higher than that with worsening (0.98 +/- 0.15, P <.005) and no change (1.28 +/-
      0.38, P <.08). The simultaneous assessment of CFV and function in the LAD
      territory is feasible, and flow and function are closely correlated. TTDE
      provides flow information that may complement conventional echocardiographic
      assessment of myocardial viability.

PMID- 12411921
TI  - Clinical use of AcuNav diagnostic ultrasound catheter imaging during left heart
      radiofrequency ablation and transcatheter closure procedures.
AB  - BACKGROUND: AcuNav ultrasound catheter (UC) (10F, 5.5-10 MHz) has unique
      advantages for left heart imaging with its 4-way tip flexible maneuverability,
      maximal 16-cm intracardiac imaging depth, and Doppler and color flow imaging
      capability. METHODS: We assessed the initial use of this UC in 40 consecutive
      patients (34 men; age 53 +/- 11 years old). All patients were also undergoing
      transseptal catheterization for percutaneous catheter mapping and ablation of
      either left atrium (focal initiated atrial arrhythmia/fibrillation, n = 32) or
      left ventricle (ventricular tachycardia, n = 4), or transcatheter atrial septal
      defect closure (n = 4) procedures. During each procedure, the UC was placed in
      the right atrium, superior vena cava, or right ventricular inflow/outflow tract.
      RESULTS: In all patients, UC successfully guided transseptal catheterization and
      provided imaging of normal or aberrant anatomy of the right/left atrial
      (interatrial septum, fossa ovalis, appendages, 4 pulmonary vein ostia) and
      right/left ventricular (valves and papillary muscles) structures. UC was
      important in early identification procedure complications, including pericardial
      effusion (n = 2, detected before systematic hemodynamic deterioration) and
      thrombus formation on sheaths deployed in the right atrium (n = 9) and left
      atrium (n = 2, early elimination with management of the sheath). With Doppler and
      color flow imaging, UC provided effective monitoring of increased flow velocity
      of all ablated pulmonary vein ostia and detection of patent foramen ovale (n = 6)
      or residual trivial/small atrial septal defect posttransseptal catheterization (n
      = 2). UC was also used to successfully image and guide transcatheter closure of
      atrial septal defect with positioning of the cardioseal septal occluder (Nitinol
      Medical Technologies Inc, Boston, Mass) and color Doppler imaging of no
      significant residual shunt. CONCLUSION: AcuNav UC with Doppler and color flow
      imaging has significant use, especially during left heart ablation. Uses include
      guidance of transseptal and mapping/ablation catheters and closure devices, and
      prompt diagnosis of cardiac complications.

PMID- 12411922
TI  - Phased-array intracardiac echocardiographic imaging of acute cardiovascular
      emergencies: Experimental studies in dogs.
AB  - BACKGROUND: We evaluated a newly developed phased-array intracardiac
      echocardiographic catheter. OBJECTIVE: Our aim was to evaluate the imaging
      capability of this new ICE catheter in an animal model simulating acute
      cardiovascular abnormalities. METHODS: ICE images were obtained from the right
      atrium during (1) acute left ventricular dysfunction; (2) acute coronary
      occlusion; (3) pericardial effusion and tamponade; and (4) pulmonary embolism.
      RESULTS: Left ventricular dysfunction, induced experimentally by halothane
      inhalation, resulted in a fall in echocardiography-calculated ejection fraction
      from 47% +/- 11% to 25% +/- 10%, P <.01. Regional contraction abnormalities after
      acute coronary occlusion were identified without and with the ultrasound contrast
      agent Optison. Pericardial effusion produced by saline infusion into the
      pericardium was detected in amounts as small as 15 mL. Right ventricular and
      atrial compression and respiratory variation in right ventricular inflow during
      tamponade were demonstrated. After injection of intravenous thrombin to create
      venous thromboembolism, we demonstrated right ventricular dilatation and
      dysfunction and thrombi attached to the tricuspid and pulmonary valves and in the
      pulmonary artery. CONCLUSION: This new phased-array ICE catheter may be a useful
      clinical tool for the diagnosis of heart failure, ischemia, tamponade, and
      pulmonary embolism.

PMID- 12411923
TI  - Echocardiography improves detection of rejection after heterotopic mouse cardiac
      transplantation.
AB  - BACKGROUND: Current assessments of cardiac rejection in murine transplant models
      rely on subjective estimates of the force of the palpable heart beat that have
      limited sensitivity and precision. METHODS: We used 2-dimensional
      echocardiography to evaluate changes in left ventricular posterior wall thickness
      (PWT) in a heterotopic cardiac mouse transplant model of rejection. Nine
      allografts and 6 isografts were imaged daily for 6 days and harvested. Thirteen
      allografts were imaged daily and harvested at day 3. RESULTS: Intraobserver
      variability on PWT was 0.003 +/- 0.09 mm, interobserver variability 0.09 +/- 0.11
      mm. Allograft PWT increased after transplantation (0.74 +/- 0.02 mm to 1.28 +/-
      0.05 mm at day 5, P <.0001). For isografts, PWT remained constant (0.73 +/- 0.03
      mm to 0.85 +/- 0.01 mm) after an initial increase at day 1. Palpation failed to
      identify rejection at day 3 whereas PWT was already increased (1.15 +/- 0.02 mm
      in the allografts at day 3 vs 0.85 +/- 0.02 mm in the isografts, P <.0001). There
      was a relation between histologic score and PWT (P <.0001). CONCLUSION: Two
      dimensional echocardiography allows the noninvasive detection and follow-up of
      cardiac rejection after transplantation. It eliminates the subjectivity of
      palpation and provides quantitative and reliable indices of rejection.

PMID- 12411924
TI  - Early warning.

PMID- 12411925
TI  - Pharmacological prevention of Parkinson disease in Drosophila.

PMID- 12411926
TI  - Hypothalamic gray matter changes in narcoleptic patients.

PMID- 12411927
TI  - Leukemia case triggers tighter gene-therapy controls.

PMID- 12411928
TI  - Big bucks for autism research.

PMID- 12411930
TI  - More rare disease money.

PMID- 12411931
TI  - Genome scientists' paths diverge.

PMID- 12411933
TI  - Nadia Rosenthal.

PMID- 12411936
TI  - New hope for Alzheimer disease vaccine.

PMID- 12411937
TI  - Converting p53 from a killer into a healer.

PMID- 12411938
TI  - Parasite packs a punch.

PMID- 12411939
TI  - Muscling in on rhabdomyosarcoma.

PMID- 12411941
TI  - Bad chaperone.

PMID- 12411943
TI  - A new regulatory pathway for fragile X syndrome?

PMID- 12411947
TI  - Atherogenesis in perspective: hypercholesterolemia and inflammation as partners
      in crime.

PMID- 12411948
TI  - Innate and acquired immunity in atherogenesis.

PMID- 12411949
TI  - Platelets in atherothrombosis.

PMID- 12411950
TI  - The macrophage foam cell as a target for therapeutic intervention.

PMID- 12411951
TI  - The liver X receptor gene team: potential new players in atherosclerosis.

PMID- 12411952
TI  - Vascular proliferation and atherosclerosis: new perspectives and therapeutic
      strategies.

PMID- 12411953
TI  - Stabilization of atherosclerotic plaques: new mechanisms and clinical targets.

PMID- 12411958
TI  - Human fMRI evidence for the neural correlates of preparatory set.
AB  - We used functional magnetic resonance imaging (fMRI) to study readiness and
      intention signals in frontal and parietal areas that have been implicated in
      planning saccadic eye movements-the frontal eye fields (FEF) and intraparietal
      sulcus (IPS). To track fMRI signal changes correlated with readiness to act, we
      used an event-related design with variable gap periods between disappearance of
      the fixation point and appearance of the target. To track changes associated with
      intention, subjects were instructed before the gap period to make either a pro
      saccade (look at target) or an anti-saccade (look away from target). FEF
      activation increased during the gap period and was higher for anti- than for pro
      saccade trials. No signal increases were observed during the gap period in the
      IPS. Our findings suggest that within the frontoparietal networks that control
      saccade generation, the human FEF, but not the IPS, is critically involved in
      preparatory set, coding both the readiness and intention to perform a particular
      movement.

PMID- 12411959
TI  - Quantal events shape cerebellar interneuron firing.
AB  - Many small synaptic inputs or one large input are needed to influence principal
      cell firing, whereas individual quanta exert little influence. However, the role
      of a quantum may be greater for small interneurons with high input resistances.
      Using dynamic clamp recordings, we found that individual quanta strongly
      influence rat cerebellar stellate cell firing. When the frequency of synaptic
      inputs was low, the timing of recent spikes regulated the influence of excitatory
      quanta. In contrast, when input frequency was high, spike timing was less
      important than interactions with other inputs. Inhibitory quanta rapidly
      terminated firing, whereas small numbers of coincident excitatory quanta reliably
      and rapidly triggered firing. Our results suggest that stellate cells achieve
      temporal precision through coincidence detection and disynaptic inhibition,
      despite their high resistances and long membrane time constants. Thus, we propose
      that small interneurons can process synaptic inputs in a fundamentally different
      way from principal cells.

PMID- 12411960
TI  - The caudal ganglionic eminence is a source of distinct cortical and subcortical
      cell populations.
AB  - During development, the mammalian ventral telencephalon is comprised of three
      major proliferative zones: the medial (MGE), lateral (LGE) and caudal (CGE)
      ganglionic eminences. Through gene expression studies, in vitro migration assays,
      genetic mutant analysis and in vivo fate mapping in mice, we found that the CGE
      is a progenitor region that is distinct from both the MGE and LGE. Notably, CGE
      cells showed a unique in vivo pattern of migration, and the CGE contributed cells
      to nuclei distinct from those populated by the MGE and LGE. Moreover, we report
      that the migratory fate of cells from the CGE is intrinsically determined by
      embryonic day 13.5 (E13.5). Together, these results provide the first insights
      into the development and fate of the CGE.

PMID- 12411962
TI  - The impact of the 21st century on rugby injuries.
AB  - STUDY DESIGN: This is a review article concerning rugby injuries resulting in
      tetraplegia between the years of 1965 and 2000. It is based on a review of
      worldwide literature. OBJECTIVES: The objective is to evaluate research that has
      taken place in the last 10 years. SETTING: The author first became interested in
      this problem in 1965 when there were few papers on the subject. Understanding of
      these injuries has changed decade by decade and the number of spinal injuries has
      increased dramatically. For the first three decades the author was actively
      engaged in gathering material particularly at the National Spinal Injuries
      Centre. During the last 10 years there has been a greater understanding in the
      mechanism of these injuries. METHODS: The following subjects were reviewed in the
      literature: (1). mechanism of injury; (2). the diameter of the spinal canal; (3).
      arthritis; (4). treatment; (5). fitness and (6). medico-legal aspects. RESULTS:
      These injuries are no longer regarded as an Act of God or bad luck but mechanisms
      of injury have been clearly defined. CONCLUSION: To prevent these injuries
      occurring there is a need for: (1). better statistics; (2). enforcement of the
      laws; (3). improved standards of refereeing; (4). higher standards of fitness and
      training in particular to de-power the set scrum; (5). study of the cervical
      spine to look for abnormalities which would predispose the player to tetraplegia;
      (6). the use of MRI and CT scans to monitor the spinal cord anatomy; (7). the
      importance of pathology and the status of the cervical spine; (8). the awareness
      of the dangers to the cord of congenital and acquired abnormalities that could
      prejudice spinal cord function and (9). the awareness of the necessity for
      comprehensive insurance.

PMID- 12411963
TI  - The functional impact of the Freehand System on tetraplegic hand function.
      Clinical Results.
AB  - STUDY DESIGN: A B design with subjects acting as their own control when the
      device is turned off. OBJECTIVE: Evaluation of the efficacy of the NeuroControl
      Freehand System. SETTING: A supra regional spinal unit in the UK. METHODS: The
      Freehand system is an implanted Functional Electrical Stimulation (FES) device
      for restoration of lateral and palmar grasps following C5 or C6 tetraplegia. Its
      use was assessed using the Grasp Relies Test (GRT), Activities of Daily Living
      (ADL), Grip strength and two-point discrimination. RESULTS: Seven out of nine
      subjects are currently daily users of the device. There were statistically
      significant increases in the number of types of task achieved and the number of
      repetitions of those tasks in the Grasp Release Test. The system produced a
      functionally strong grasp where no grip strength at all was possible prior to
      implantation. Three of the four subjects who had sensory ability prior to implant
      showed improvements in two-point discrimination. Most of the selected tasks were
      achieved in the ADL assessment indicating a significant improvement in
      independence. CONCLUSION: The Freehand system can significantly improve the
      functional ability of C5 and C6 lesion tetraplegics. SPONSORSHIP: This study was
      funded by the charity INSPIRE.

PMID- 12411964
TI  - Motor evoked potentials elicited from erector spinae muscles in patients with
      thoracic myelopathy.
AB  - STUDY DESIGN: A prospective study was conducted to test the utility of the motor
      evoked potentials (MEPs) from the erector spinae muscles as a measure to estimate
      the motor level of thoracic compression myelopathies in 13 consecutive patients.
      OBJECTIVE: To confirm whether this test is a useful addition to the neurological
      examination in non-invasively localizing the level responsible for the main
      functional change in mild to moderate thoracic myelopathy. SETTING: Department of
      Orthopaedic Surgery, Kochi Medical School, Kochi, Japan. METHODS: This
      electrophysiological study consisted of transcranial magnetic stimulation (TMS)
      of the brain and surface recording of MEPs from voluntarily contracted erector
      spinae muscles with the patient in the prone position. The recordings were
      obtained unilaterally from the same side as the lower-limb affected at 12 serial
      interspinous levels from T5-6 to L4-5. The results were compared to the MEP data
      from normal subjects and to neurological and MRI findings. RESULTS:
      Multisegmental MEP studies demonstrated a focal conduction block in one patient,
      a single site of conduction delay in seven, and normal conduction in five. The
      conduction block was characterized by an abrupt reduction in amplitude of the
      MEPs. Examination of the sites conduction delay showed that the latency
      difference between the two adjacent levels was longer than the corresponding
      normal upper limit by 1.00+/-0.40 ms (range, 0.62-1.61 ms). The site of
      conduction abnormalities approximated to the compressive lesion site shown by
      MRI. All five patients with false-negative MEP findings had the lesion site at or
      caudal to the T10-11 vertebral level. CONCLUSION: This method has the advantage
      of instantaneously testing multisegments of the thoracic spinal cord. The
      technique is of particular value in estimating the motor level of the lesions
      rostral to T10-11 vertebral level, which can not be achieved by clinical
      examinations or MEP recordings from the lower limb.

PMID- 12411965
TI  - Improvements in activities of daily living following functional hand surgery for
      treatment of lesions to the cervical spinal cord: self-assessment by patients.
AB  - STUDY DESIGN: Tetraplegic patients were tested for hand strength before and after
      hand surgery. They also answered questions about how they rated the results of
      surgery. OBJECTIVES: Presentation of the efficacy of reconstruction of hand
      raising, lateral grip, and cylindrical grip in the tetraplegic hand. SETTING: The
      study was conducted in the Werner Wicker Clinic, Bad Wildungen, Germany, from
      1991 to 1998. METHODS: The results of reconstruction surgery performed on 23
      tetraplegic hands, as reflected in lifting the hand (n=3), lateral grip (n=21),
      and cylindrical grip (n=14), are presented. In a follow-up study in 22 patients,
      their management of activities of daily living 34.1 months (9-51 months) after
      the surgery is compared with the preoperative situation. Subjective satisfaction
      levels were elicited for each of the 22 patients by means of a questionnaire.
      RESULTS: The gain in force corresponded to 893 g (150-1500 g) for cyclindrical
      grip and 488 g (100-1200 g) for lateral grip, while they were able to develop
      grade 4 force for lifting the hand. After the operation 28 aids/appliances that
      patients had formerly used regularly were no longer necessary. There were 75
      separate activities listed in the questionnaire, and on average the 22 patients
      were able to perform 8.7 (0-20) more of these. Most patients (19) said they would
      advise others to have the operation and 18, that they would have the operation
      again. There were 12 complications in nine patients. CONCLUSION: Reconstructive
      surgery on the hands of tetraplegic patients leads to gains in both cylindrical
      grip and lateral grip force and to increased manual dexterity. Patient
      satisfaction with the procedure is high.

PMID- 12411966
TI  - Awareness and use of advance directives in the spinal cord injured population.
AB  - STUDY DESIGN: Research was conducted through the use of semi-structured patient
      interviews. Subjects were recruited through the Saskatchewan branch of the
      Canadian Paraplegic Association (CPA) and through the clinical practice of the
      primary investigator. A total of twenty-one patients were interviewed. A
      qualitative outcome analysis was performed on information collected. OBJECTIVES:
      Advance directives (or living wills) serve to communicate the wishes of
      individuals in the event that they should no longer be capable of making those
      wishes known. This can include directives on issues such as resuscitation status
      and withdrawal or withholding of care. The goal of this study was to determine
      the present level of knowledge and interest of spinal cord injured (SCI) patients
      on the topic of advance directives, and to determine what specific issues they
      felt need to be addressed in such a document in this population. SETTING: The
      study was performed in Saskatoon, Saskatchewan, Canada. Although design and
      analysis were done in a tertiary care centre, the interviews themselves were
      conducted in the homes of the participants. RESULTS AND CONCLUSION: The results
      show that spinal cord injured patients have some knowledge of what is involved in
      the preparation of an advance directive and that they feel these documents are
      important. A relatively small percentage have completed their own written
      directives but a large percentage planned to do so after completing this survey.
      There is some disagreement about when after the injury the topic should first be
      discussed. Information about medical conditions which are more likely to arise
      following a SCI should be included in an SCI-specific document. A template for an
      SCI-specific living will (the SCIAD) is provided.

PMID- 12411967
TI  - Survival following spinal cord injury in Israel.
AB  - BACKGROUND: Survival following spinal cord injury (SCI) has greatly improved
      since the unsuccessful attempts to repair the damaged spinal cord were replaced
      by systematic prevention and treatment of complications caused by the neural
      damage. OBJECTIVE: To evaluate the main outcome measures in patients with spinal
      cord injury. DESIGN: Retrospective cohort study. SETTING: Loewenstein
      Rehabilitation Hospital, the major referral center for rehabilitation medicine
      for hospitals throughout Israel. SUBJECTS: 250 consecutive patients, injured
      between 1959 and 1992. MAIN OUTCOME MEASURES: Survival rates and mortality risk
      factors. METHOD: Demographic, clinical, and mortality data were collected from
      the hospital charts and from the Population Registry of the Israel Ministry of
      Internal Affairs. Survival rates were estimated using the product limit (Kaplan
      Meyer) method, and their association with known risk factors was analyzed with
      the Cox proportional hazard model. RESULTS: The survival rate after injury was
      81% after 10 years, 75% after 20 years, and 62% after 30 years, and 50% after
      about 36.5 years. Survival was found to be negatively associated with age
      (P=0.01) and with high spinal level of injury (P=0.003). CONCLUSIONS: Survival
      rates in the studied population are similar to those reported in other countries,
      and are close to those of the general population living in Israel in the same
      time period. The study demonstrates that developing countries can reach survival
      rates comparable to those of developed countries, and may contribute to better
      survival predictions of patients with SCI.

PMID- 12411968
TI  - Muscular weakness as side effect of botulinum toxin injection for neurogenic
      detrusor overactivity.

PMID- 12411969
TI  - PTFE-fascia patch inlay method for the anterior approach for cervical intradural
      spinal lesion.
AB  - STUDY DESIGN: A new method for prevention of cerebrospinal fluid leakage was
      studied. OBJECTIVE: To prevent cerebrospinal fluid leakage, we developed a
      polytetrafluoroethylene fascia patch inlay method. BACKGROUND: One of the major
      risks of the anterior approach for intra-dural spinal cord lesions is the
      cerebrospinal fluid leakage. METHODS: A small hemangioblastoma located on the
      ventral side of the cervical cord was resected with an anterior approach. The
      dural closure was performed using this polytetrafluoroethylene fascia patch inlay
      method. RESULTS: The patient had a satisfactory clinical course with no
      cerebrospinal fluid leakage. CONCLUSION: This polytetrafluoroethylene fascia
      patch inlay method is very effective. This method may provide both prevention of
      CSF leakage and future spinal cord adhesion to the dura.

PMID- 12411970
TI  - Tuberculosis of the spine (Pott's disease) presenting as 'compression fractures'.
AB  - STUDY DESIGN: Case reports and survey of literature. OBJECTIVE: Case reports of
      two women with tuberculosis (TB) of the spine (Pott's disease) presenting with
      severe back pain and diagnosed as compression fracture are described. Physicians
      should include Pott's disease in the differential diagnosis when patients present
      with severe back pain and evidence of vertebral collapse. SETTING: Ohio, USA
      METHODS: A review of the literature on the pathogenesis, pathophysiology,
      clinical presentation, diagnostic methods, treatment and prognosis of spinal TB
      was conducted. RESULTS: After initial delay, proper diagnosis of spinal TB was
      made in our patients. Microbiologic diagnosis confirmed M. tuberculosis, and
      appropriate medical treatment was initiated. CONCLUSIONS: Although uncommon,
      spinal TB still occurs in patients from developed countries, such as the US and
      Europe. Back pain is an important symptom. Vertebral collapse from TB may be
      misinterpreted as 'compression fractures' especially in elderly women. Magnetic
      resonance imaging scan (MRI) is an excellent procedure for the diagnosis of TB
      spine. However, microbiologic diagnosis is essential. Mycobacterium tuberculosis
      may be cultured from other sites. Otherwise, biopsy of the spine lesion should be
      done for pathologic diagnosis, culture and stain for M. tuberculosis. Clinicians
      should consider Pott's disease in the differential diagnosis of patients with
      back pain and destructive vertebral lesions. Proper diagnosis and anti
      tuberculosis treatment with or without surgery will result in cure.

PMID- 12411971
TI  - Atrophy of kidney following extra corporeal shock wave lithotripsy of renal
      calculus in a paraplegic patient with marked spinal curvature.
AB  - OBJECTIVES: To discuss a rare complication of extra corporeal shock wave
      lithotripsy (ESWL) of renal calculus in a paraplegic patient, who had marked
      curvature of thoracic and lumbar spine. DESIGN: A case report of a paraplegic
      patient, who developed renal atrophy and hypertension after undergoing ESWL of
      staghorn calculus. SETTING: Regional Spinal Injuries Centre, Southport and Mersey
      Regional Lithotripsy Unit, Royal Liverpool University Hospital, Liverpool, UK.
      PARTICIPANT: A 28-year-old male with spina bifida, paraplegia at L-1 level and
      considerable curvature of spine and tilting of pelvis. METHOD: ESWL was carried
      out in three sessions by delivering 1934, 1876, and 2025 shock waves
      respectively. Localisation of the staghorn calculus was difficult because of
      spinal curvature and pelvic tilt. RESULTS: A follow-up IVU, performed 3 months
      after last ESWL treatment, revealed no residual stone in the left kidney, apart
      from a little low-density calcification in the renal parenchyma adjacent to the
      lower pole calyx. There were no calculi in the left ureter. The left kidney had
      become small, though still functioning. MAG-3 isotope renogram showed the left
      kidney to be markedly atrophic. Relative renal function: right kidney, 94%; and
      left kidney, 6%. He developed hypertension and a laparoscopic left nephrectomy
      was performed at another hospital. CONCLUSION: Difficulty in localisation of
      renal calculi for ESWL must be anticipated in spinal bifida and spinal cord
      injury patients, who have significant spinal curvature. Because of problems in
      the positioning of a patient with marked curvature of spine and pelvic tilt, and
      consequent difficulties in accurate localisation of renal calculi for
      lithotripsy, these patients may be at increased risk of developing renal
      parenchymal and vascular damage following ESWL.

PMID- 12411972
TI  - Ion channels in pulmonary arterial hypertension.
AB  - Pulmonary arterial hypertension (PAH) is a hemodynamic abnormality that
      ultimately results in mortality due to right heart failure. Although the clinical
      manifestations of primary and secondary PAH are diverse, medial hypertrophy and
      arterial vasoconstriction are key components in the vascular remodeling leading
      to PAH. Abnormalities in the homeostasis of intracellular Ca(2+), transmembrane
      flux of ions, and membrane potential may play significant roles in the processes
      leading to pulmonary vascular remodeling. Decreased activity of K(+) channels
      causes membrane depolarization, leading to Ca(2+) influx. The elevated
      cytoplasmic Ca(2+) is a major trigger for pulmonary vasoconstriction and an
      important stimulus for vascular smooth muscle proliferation. Dysfunctional K(+)
      channels have also been linked to inhibition of apoptosis and contribute further
      to the medial hypertrophy. This review focuses on the relative role of K(+) and
      Ca(2+) ions and channels in human pulmonary artery smooth muscle cells in the
      development of PAH.

PMID- 12411973
TI  - Primary pulmonary hypertension: Current therapy.
AB  - Because the causes of primary pulmonary hypertension (PPH) remains unknown, the
      therapeutic approach of the disease can be only empirical, based on the pathology
      and pathobiology of pulmonary circulation. Despite the inability to cure the
      disease, therapeutic advances over the past 20 years have contributed to an
      improvement of quality of life and prolonged survival in PPH patients. Current
      therapeutic approach of PPH mostly includes limitation of physical activity, long
      term anticoagulation, and vasodilator therapy. Among all tested oral
      vasodilators, calcium-channel blockers are the most efficient long-term therapies
      by improving symptoms and hemodynamics in a subset of PPH patients (10% to 15%)
      who acutely respond to such drugs. Acute pulmonary vasodilator response to
      inhalation of nitric oxide can predict acute and chronic responses to oral
      calcium-channel blockers. A better understanding of the pathogenesis of PPH has
      changed the focus of medical treatments from purely chronic vasodilator therapy
      to the evaluation of agents, such as prostaglandins, that may reverse the
      proliferation of pulmonary vascular cells and result in regression of the
      pulmonary vascular hypertrophy and remodeling. Long-term treatment with
      intravenous epoprostenol (prostaglandin I(2) or prostacyclin) improves exercise
      capacity, hemodynamics and survival in most patients with PPH in functional class
      NYHA III or IV, and may be currently considered as the "gold standard" therapy
      for severe patients. However, response to long-term epoprostenol therapy may be
      incomplete, adverse effects are common, and survival remains unsatisfactory (55%
      at 5 years). In such patients with severe pulmonary hypertension refractory to
      medical therapy, atrioseptostomy and lung transplantation can be indicated.

PMID- 12411974
TI  - Eisenmenger's syndrome: current management.
AB  - Eisenmenger's syndrome describes the elevation of pulmonary arterial pressure to
      the systemic level caused by increased pulmonary vascular resistance with
      reversal or bi-directional shunting through a large intracardiac or extracardiac
      congenital heart defect. This article reviews the natural history and
      pathophysiology of Eisenmenger's syndrome untreated and medical and surgical
      treatment options presently available. Although there is no cure for this
      condition at present, recent advances in management have improved the quality of
      life for many patients with Eisenmenger's syndrome.

PMID- 12411975
TI  - The role of low-molecular-weight heparin in cardiovascular diseases.
AB  - Unfractionated heparin continues to have important limitations in clinical
      practice. It has an inconsistent anticoagulant effect, needs frequent monitoring,
      and is inactivated by several plasma proteins. Low-molecular-weight heparins have
      a more predictable anticoagulant effect than unfractionated heparin, are easier
      to administer, and may not require monitoring. The anticoagulation effect of low
      molecular-weight heparins is caused by a combination of inhibition of thrombin
      generation and inhibition of thrombin activity. Low-molecular-weight heparins
      have now been evaluated for a number of cardiovascular conditions and have been
      found to be safe and effective. We review and summarize the existing data
      regarding the use of low-molecular-weight heparins in cardiovascular diseases,
      including venous thromboembolism, percutaneous coronary interventions, and acute
      coronary syndromes such as ST-segment elevation myocardial infarction.

PMID- 12411976
TI  - Chronic heart failure-related myopathy and exercise training: A developing
      therapy for heart failure symptoms.

PMID- 12411977
TI  - Heart Failure Society of America: a society with a mission.

PMID- 12411978
TI  - Diastolic heart failure in the community: clinical profile, natural history,
      therapy, and impact of proposed diagnostic criteria.
AB  - BACKGROUND: Diastolic heart failure (DHF) has been broadly defined as "signs and
      symptoms of congestive heart failure (CHF) with normal/near normal systolic
      function." The clinical profile and natural history of the syndrome remain
      controversial. Furthermore, the frequency with which patients with CHF and normal
      ejection fraction (EF) fulfill recently proposed standardized diagnostic criteria
      for DHF is unclear. Our objective was to determine the clinical profile, Doppler
      echocardiographic features, current management, prognosis, and predictors of
      outcome of all patients with new onset CHF who had normal EF in Olmsted County,
      Minnesota, during 1996-1997. The frequency with which patients met recently
      proposed standardized criteria for diagnosis of DHF was assessed. METHODS: Using
      the resources of the Rochester Epidemiology Project, all residents of Olmsted
      County, Minnesota, with a new diagnosis of CHF in 1996-1997, an ejection fraction
      >45%, and no valve disease (n = 83) were identified. RESULTS: Patients were
      elderly (79 +/- 13 yr), predominantly female (76%), and had hypertension and/or
      coronary artery disease (85%). New-onset atrial fibrillation, ischemia, and
      medical comorbidities were frequently present at diagnosis. Although most
      patients (81%) met criteria for "probable DHF" by recently proposed clinical
      criteria, only half of patients met European criteria in which evidence of
      abnormal function/filling is required. The 1-, 2-, and 3-year mortality rates
      were 29%, 39%, and 60%, respectively. Angiotensin-converting enzyme inhibition (P
      =.0008) and beta-blocker (P =.02) therapy were independently associated with
      improved survival. CONCLUSION: This population-based study provides a
      comprehensive clinical profile, current management, prognosis, and predictors of
      outcome of patients with new onset CHF who had normal ejection fraction.

PMID- 12411979
TI  - Role of brain natriuretic peptide in the diagnosis and management of heart
      failure: current concepts.
AB  - BACKGROUND: Progression of heart failure is related to ventricular remodeling, a
      process associated to neurohormonal activation. Brain natriuretic peptide (BNP),
      a member of the natriuretic peptide family, has recently emerged as an important
      neurohormone in the pathophysiology of heart failure. METHODS: In this update,
      some of the recent advances on the role of BNP in heart failure are summarized.
      In particular, the role of BNP in diagnosis of heart disease, as a prognostic
      marker of cardiovascular events and as a possible guide to optimize heart failure
      therapy is discussed. RESULTS: Recent results from 4,300 patients enrolled in the
      Valsartan Heart Failure Trial (Val-HeFT) confirmed that BNP is the strongest
      predictor of outcome in heart failure, when compared to other neurohormones and
      clinical markers. The current use of BNP in the screening and diagnosis of heart
      failure and its possible future roles are presented. CONCLUSION: In recent years,
      there has been an impressive accumulation of data supporting an important role of
      BNP as a diagnostic and prognostic marker of heart failure. Development of rapid,
      accurate and affordable diagnostic methods will allow the routine monitoring of
      BNP in a wide spectrum of settings, from general practice to controlled clinical
      trials.

PMID- 12411980
TI  - Emotional well-being of heart failure patients and their caregivers.
AB  - BACKGROUND: Heart failure (HF) dramatically affects the lives of both patients
      and their caregivers, yet limited research exists examining the relationship
      between emotional well-being of HF patients and their caregivers. Therefore, we
      conducted a study to (1) describe and compare the emotional well-being of HF
      patients and their caregivers, (2) determine if gender differences exist in
      emotional well-being of patients and caregivers, and (3) identify factors
      associated with emotional well-being of HF patients. METHODS: The emotional well
      being of 103 patient-caregiver dyads was assessed using the mental health
      subscale of the SF-12. RESULTS: Patients were 57.6 +/- 12.1 years, predominantly
      Caucasian (76.7%) and male (67.0%). Caregivers were 59.5 +/- 17.6 years,
      predominantly females (70.9%) and spouses of patients with HF (82.6%). Patients
      had significantly lower (poorer) emotional well-being scores than caregivers.
      Both gender and age were associated with patients' emotional well-being; male and
      younger participants had higher (better) scores than female and older patients (P
      <.05). In a multivariate model, patient's age, gender, and caregivers' emotional
      well-being accounted for 54% of the variance in patients' emotional well-being.
      CONCLUSION: We found that the emotional well-being of caregivers is associated
      with the emotional well-being of HF patients. Our findings suggest the need to
      focus on supporting caregivers and providing them with the strategies they need
      to support their loved ones with HF.

PMID- 12411981
TI  - Preclinical and clinical assessment of the safety and potential efficacy of
      thalidomide in heart failure.
AB  - BACKGROUND: Inflammatory mediators, especially tumor necrosis factor (TNF), have
      been implicated in heart failure (HF). Thalidomide has anti-inflammatory
      properties and selectively inhibits TNF. Thus far, thalidomide or thalidomide
      analogues have not been evaluated in patients with heart failure. METHODS:
      Thalidomide was assessed in preclinical and clinical studies. First, isolated
      cardiac myocytes were pretreated with thalidomide or thalidomide analogues, and
      TNF production was assessed after lipopolysaccharide (LPS) provocation. Second,
      to determine the safety and potential efficacy of thalidomide, an open-label dose
      escalation safety study was conducted in seven patients with advanced heart
      failure. RESULTS: Thalidomide and thalidomide analogues inhibited LPS-induced TNF
      biosynthesis in cardiac myocytes in a dose-dependent manner. Thalidomide
      analogues had a greater inhibitory effect on TNF production than did thalidomide.
      In patients with advanced HF, thalidomide was safe and potentially effective when
      used at lower doses. However, dose-limiting toxicity was observed in two
      patients. There was a significant increase in the 6-minute walk distance and a
      trend toward improvement in left ventricular ejection fraction and quality of
      life after 12 weeks of maintenance therapy with thalidomide. CONCLUSIONS: Taken
      together these results suggest that thalidomide or its derivatives may be useful
      in selected patients with HF. This potential needs to be studied in larger
      clinical trials.

PMID- 12411982
TI  - Plasma levels of TNF-alpha and IL-6 are inversely related to cytochrome P450
      dependent drug metabolism in patients with congestive heart failure.
AB  - BACKGROUND: Cytochrome P450 (CYP) enzymes are important mediators of drug
      metabolism, and activity of these enzymes is a major determinant of the duration
      and intensity of drug effect. Circulating plasma concentrations of pro
      inflammatory cytokines (e.g., tumor necrosis factor [TNF]-alpha and interleukin
      [IL]-6) are elevated in patients with heart failure and these cytokines have been
      shown to down-regulate CYP enzyme activity. The purpose of this study was to
      evaluate the relationship between plasma cytokine concentrations and CYP enzyme
      activities in patients with heart failure. METHODS AND RESULTS: Sixteen patients
      with congestive heart failure (New York Heart Association classes II-IV) received
      a metabolic probe cocktail consisting of caffeine, mephenytoin, dextromethorphan,
      and chlorzoxazone to assess the activities of the CYP enzymes 1A2, 2C19, 2D6, and
      2E1. Blood and urine samples were collected for drug and metabolite
      determinations by high-performance liquid chromatography (HPLC); cytokine
      concentrations were measured by enzyme-linked immunosorbent assay (ELISA). We
      found a striking inverse relationship between both TNF-alpha and IL-6 plasma
      concentrations and the activity of CYP2C19; metabolism of caffeine (CYP1A2) also
      had a negative association with IL-6 plasma concentrations. CONCLUSIONS: Cytokine
      mediated decreases in drug metabolism may contribute to observed variability in
      drug response and augment the risk of adverse drug effects in CHF patients.

PMID- 12411983
TI  - Examination of the in vivo cardiac electrophysiological effects of nesiritide
      (human brain natriuretic peptide) in conscious dogs.
AB  - BACKGROUND: Human brain natriuretic peptide (hBNP) is a new therapeutic agent,
      nesiritide, indicated in patients with decompensated congestive heart failure, a
      group at significant risk of developing cardiac arrhythmias. Whether hBNP has
      cardiac electrophysiologic effects has not been reported. METHODS AND RESULTS: In
      9 healthy, chronically instrumented, conscious dogs, hemodynamic and
      electrophysiologic parameters were assessed at baseline and during recombinant
      hBNP (nesiritide) infusion at 0.03 and 0.09 microg/kg/min after 1 hour at each
      dose. Infusion of hBNP produced dose-related increases (P <.001) in hBNP and
      cyclic GMP plasma levels and reductions (P <.05) in mean arterial pressure. Mean
      central venous pressure and sinus cycle length did not change significantly.
      Infusion of hBNP produced no significant changes in any of the electrophysiologic
      parameters including no change in surface ECG variables (P wave duration, PR
      interval, QRS duration, and QTc interval), corrected sinus node recovery time,
      atrioventricular nodal Wenckebach cycle length, and atrial and ventricular
      effective refractory periods measured at a 400 ms cycle length. Spontaneous or
      induced arrhythmias were not observed during hBNP infusion. CONCLUSIONS: In
      conscious, healthy dogs, short-term infusion of recombinant hBNP has no
      significant effects on atrial or ventricular electrophysiologic parameters.

PMID- 12411984
TI  - Selective endothelin receptor blockade reverses mitochondrial dysfunction in
      canine heart failure.
AB  - OBJECTIVE: Mitochondrial enzymatic activity reductions in both myocardial and
      skeletal muscle tissues have been reported in a canine model of pacing-induced
      congestive heart failure (CHF). Endothelin-1 (ET-1), a vasoconstrictor peptide
      with diverse biological properties, has been implicated in CHF pathogenesis, and
      ET-1 receptor blockade has been shown to attenuate CHF progression. We
      hypothesized that the beneficial effect of ET-1 receptor blockade may be mediated
      in part by improved mitochondrial function. METHODS: Myocardium and skeletal
      muscle tissues were evaluated for respiratory complex I-V and citrate synthase
      activity levels in paced animals treated with and without LU 135252, a specific
      type A ET-1 receptor (ET(A)) antagonist. RESULTS: Specific activity levels of
      complex V and III, which were 65% to 85% lower in both cardiac and skeletal
      muscle in paced compared to unpaced animals, were significantly increased in
      ET(A) antagonist-treated animals (50%-300% compared to untreated paced animals).
      Levels of other mitochondrial respiratory complex activities including complex I,
      II, and IV as well as citrate synthase were not significantly changed.
      CONCLUSIONS: These findings suggest that endothelin activation may be involved in
      the myocardial dysfunction and mitochondrial enzyme deficiencies observed in
      pacing-induced CHF. Improvement of mitochondrial function may be a novel
      mechanism mediating the beneficial effect of ET(A) receptor blockade in CHF.

PMID- 12411985
TI  - Prevention of heart failure.
AB  - BACKGROUND: The number of people in the United States with heart failure (HF) is
      expected to rise dramatically as the population ages unless efforts to prevent HF
      improve. METHODS AND RESULTS: PubMed/MEDLINE searches were conducted to identify
      treatment trials of hypertension, hypercholesterolemia, asymptomatic left
      ventricular systolic dysfunction, and diabetes that reported HF incidence.
      Treatment of hypertension reduces the incidence of HF by approximately 50%, even
      among very elderly patients. Diuretics, beta-blockers, and angiotensin-converting
      enzyme (ACE) inhibitors appear more effective than calcium channel blockers and
      doxazosin. Hydroxy methylglutaryl coenzyme A (HMG CoA) reductase inhibitors
      reduce the incidence of HF by approximately 20% among patients with
      hypercholesterolemia and coronary artery disease. ACE inhibitors reduce HF
      incidence by 37% among patients with reduced systolic function and by 23% among
      patients with coronary artery disease and normal systolic function. Observational
      studies have shown lower HF incidence among people with diabetes with better
      glycemic control. Unfortunately, all of these effective therapies appear to be
      underused, and control of hypertension is particularly poor. CONCLUSIONS: If
      clinical practice can live up to the potential shown from clinical trials, the
      suffering and economic toll imposed by HF can be dramatically reduced. Improved
      control of hypertension, primary prevention of myocardial infarction, and more
      widespread use of secondary prevention measures are essential.

PMID- 12411986
TI  - Understanding the impact of mitochondrial defects in cardiovascular disease: a
      review.
AB  - OBJECTIVE: Defects in mitochondrial structure and function have been found in
      association with cardiovascular diseases such as dilated and hypertrophic
      cardiomyopathy, cardiac conduction defects and sudden death, ischemic and
      alcoholic cardiomyopathy, and myocarditis. A genetic basis has been established
      for some mitochondrial abnormalities (eg, mitochondrial DNA changes leading to
      oxidative phosphorylation dysfunction, fatty acid beta-oxidation (FAO) defects
      resulting from specific nuclear mutations) whereas other abnormalities appear to
      be due to a more sporadic or environmental cardiotoxic insult or have not yet
      been characterized. METHODS: This article reviews mitochondrial abnormalities in
      structure or function reported in cardiac diseases highlighting information about
      their potential etiology, significance in cardiac pathogenesis, and diagnostic
      and therapeutic options available to the clinician. We also provide a brief
      background concerning mitochondrial biogenesis and bioenergetic pathways in
      cardiac growth, development, and aging. CONCLUSIONS: Although aberrations in
      bioenergetic functioning of mitochondria appear to be most often related to
      cardiac dysfunction, the primary defect(s) causing bioenergetic dysfunction may
      reside in a nonbioenergetic pathway (eg, signaling between mitochondria and
      nucleus) or in overall mitochondrial biogenesis or degradation pathways.

PMID- 12411987
TI  - How closely do thyroid fine-needle aspirates need to be screened?

PMID- 12411988
TI  - Characterization of foam cells in nipple aspirate fluid.
AB  - Foam cells with abundant vacuolated cytoplasm are prominent in most samples of
      spontaneous nipple discharge, nipple aspirate fluid, and ductal lavage. Although
      several investigators have attempted to characterize these cells, there is no
      consensus about whether these cells are derived entirely from macrophages or from
      both ductal epithelial cells and macrophages. Using immunocytochemical methods,
      we studied 20 paired specimens of nipple aspirate fluid containing abundant foam
      cells obtained from the involved breast of women with in situ or invasive
      carcinoma and from the contralateral normal breast. We used a cocktail of
      anticytokeratin antibodies including AE1, AE3, and CAM5.2 and the macrophage
      marker KP1 (CD68). In addition, we examined samples by electron microscopy. The
      foam cells were consistently negative for cytokeratin and positive for CD68. In
      every case electron microscopy of these cells revealed irregular outlines with
      short cytoplasmic processes. The cytoplasm was abundant and contained numerous
      lysosomes, a small Golgi complex, lipid droplets, mitochondria, and short
      profiles of rough endoplasmic reticulum. There was no evidence, however, of cell
      junctions or tonofilaments. The immunocytochemical and electron microscopic
      findings of our study together clearly support a macrophage derivation for foam
      cells in nipple aspirate fluid.

PMID- 12411990
TI  - Diagnostic role of fine-needle aspiration of pancreatic allograft to detect
      rejection.
AB  - The purpose of this study was to assess whether the same principles to evaluate
      renal transplant by fine-needle aspiration (FNA) for rejection could be applied
      to pancreatic allograft. Between 1996-1998, 25 ultrasound-guided FNAs on 13
      patients with pancreatic allograft were performed and ThinPrep made. The
      percentage of lymphocytes, lymphoblasts, monocytes, eosinophils, plasma cells,
      immunoblasts, and macrophages were calculated. Simultaneous peripheral smear was
      obtained and "total corrected increment" score calculated. Subsequent core biopsy
      was available in six patients. A total of seven FNAs on three patients were
      inadequate because of insufficient epithelial cells. No evidence of rejection
      reported in nine patients was confirmed on biopsy in five patients. One patient
      reported as suspicious later showed rejection on biopsy. Thus, FNA may be used to
      monitor the graft status with faster turnaround times. Rejection may be a focal
      process and FNA may be used for sampling multiple sites. Cytologic diagnosis
      fairly accurately detects early rejection. Core biopsies are warranted in
      unsatisfactory specimens and when FNA is suspicious for rejection.

PMID- 12411991
TI  - Lymphoid and myeloid neoplasms involving cerebrospinal fluid: comparison of
      morphologic examination and immunophenotyping by flow cytometry.
AB  - We studied 53 samples of cerebrospinal fluid (CSF) by cytologic examination and
      immunophenotyping by flow cytometry. The samples were taken from 43 patients; 25
      had a previous diagnosis of malignant lymphoma/leukemia and the remaining 18 a
      variety of other diseases involving the central nervous system (CNS).
      Lymphoma/leukemia was detected in 21 samples: 12 by morphologic examination and
      immunophenotyping and nine by immunophenotyping alone. There were two cases with
      a suspicious morphologic examination and negative immunophenotyping in which the
      final diagnosis were cryptococcal and viral meningitis. In the group of 18
      patients, one was diagnosed as a primary malignant lymphoma of the CNS and was
      positive with cytology and immunophenotyping. The other 17 were negative with
      both methods and follow-up showed no evidence of lymphoma/leukemia. This study
      shows that morphologic examination combined with flow cytometry enhances the
      detection rate by 75% over morphologic examination alone in CSF samples.

PMID- 12411992
TI  - Bronchoscopy-guided transtracheal and transbronchial fine-needle aspiration
      biopsy: a 5-year institutional review of 111 cases.
AB  - We reviewed 111 bronchoscopy-guided transtracheal and transbronchial fine-needle
      aspiration (TT/TBNA) specimens from 97 patients to determine the sensitivity and
      specificity for diagnosing neoplasia compared to surgical biopsy and clinical
      follow-up and to determine the optimal number of passes. Fifty were positive for
      neoplasia, seven were suspicious, one was atypical, 51 were negative, and two
      were unsatisfactory. Of 57 positive/suspicious cases, 56 were confirmed
      neoplastic, with one patient lost to follow-up (specificity with follow-up:
      100%). A positive diagnosis was rendered on the first pass in 29 cases (58%),
      second in six (12%), third in five (10%), fourth in three (6%), fifth in four
      (8%), and sixth, ninth, and eleventh passes in one case each (2% each). Twenty
      seven negative cases had confirmed malignancies after their index FNA
      (sensitivity for neoplasia: 67%). We conclude that TT/TBNA is a highly specific
      but not always successful diagnostic technique. It appears to be limited by
      mechanical difficulties that prevent tumor access and cellular uptake in some
      masses. Little information is gained by procuring more than six samples.

PMID- 12411993
TI  - Large B-cell lymphomas: fine-needle aspiration plays an important role in initial
      diagnosis of cases which are falsely negative by flow cytometry.
AB  - Large B-cell lymphomas (LBCLs) have significant false-negative results when
      immunophenotyped by flow cytometry (FC). To clarify the role fine-needle
      aspiration (FNA) in reducing this false-negative rate, 28 cases ultimately
      diagnosed as LBCL that had FNA as part of the workup and a negative FC were
      identified. We examined their clinical and cytologic features, in comparison with
      cases of LBCL with FNAs that were positive by FC. In 24/28 FC-negative cases
      (86%) a cytologic diagnosis of suspicious or positive for malignancy was
      rendered. We conclude that cytologic analysis is more sensitive than FC in the
      diagnosis of malignancy in FNA of LBCL, particularly in aspirates with low
      cellularity and/or low viability. Examination of cytospin preparations of the
      actual material analyzed by FC may provide an indication that an FC result is
      falsely negative. It is important to recognize the potential of false-negativity
      by FC of LBCLs when interpreting FNAs with features suggesting lymphoma.

PMID- 12411994
TI  - Cytomorphologic features of fine-needle aspiration of metastatic and recurrent
      melanoma.
AB  - Melanoma is an aggressive malignancy with a growing prevalence. Although early
      detection and excision offer a potential cure, recurrences and metastases are not
      uncommon. Fine-needle aspiration (FNA) can play a vital role in their detection
      as a relatively noninvasive, rapid, and economical alternative for tracking
      disease evolution. Prior clinical history and classic cytological features of
      melanoma (loosely cohesive smear pattern and single cells with large nuclei,
      prominent nucleoli, and melanin pigment) aid in cytological diagnoses. However,
      not all melanomas contain melanin pigment or characteristic cytologic features.
      We examined a large series of melanoma cases to determine the incidence of
      melanin pigment, the most common cell morphology, and the presence or absence of
      apoptosis/necrosis associated with this highly aggressive neoplasm.

PMID- 12411995
TI  - Primary squamous cell carcinoma of the endometrium: case history, pathologic
      findings, and discussion.
AB  - Primary squamous cell carcinoma of the endometrium (PSCCE) is an exceedingly rare
      tumor. Rarely are cytological criteria discussed. We report our experience in the
      cytological diagnosis of a case. A postmenopausal, 64-yr-old woman suffered from
      pyometria. An endometrial Pap smear displayed some malignant squamous cells.
      Curettage of the cervix and the uterine cavity only recovered some fragments of
      atypical squamous epithelium whose origin could not be precisely identified. A
      hysterectomy with bilateral adnexectomy was decided upon. Pathological study
      evidenced a primary squamous cell carcinoma in the uterine cavity while the
      cervix was tumor-free and the lymph nodes were devoid of metastases (pT1, pN0,
      pM0). The patient died 46 mo PO with multiple pulmonary and renal metastases. The
      histological feature of PSCCE is identical to that of any tumor of a similar
      nature, whatever the site, especially the cervix. Confirmation of the primary
      endometrial nature is only possible on the hysterectomy specimen.

PMID- 12411996
TI  - Intrarenal neuroblastoma diagnosed by fine-needle aspiration: a report of two
      cases.
AB  - Neuroblastoma is an infrequent tumor of childhood usually located at any site
      containing sympathetic neural tissue-retroperitoneum and adrenal gland being the
      most common locations, followed by thoracopulmonary region, mediastinum, head and
      neck, and pelvis. Two primary renal neuroblastomas were diagnosed in a 6-yr-old
      boy and a 7-mo-old boy by computed tomography (CT)-guided fine-needle aspiration
      (FNA) cytology. The smears contained numerous individually scattered small and
      round cells, with scanty cytoplasm, related to a fibrillary matrix. Scattered
      larger cells with slightly more cytoplasm were seen among the smaller ones. No
      tubular or glomeruloid differentiation was noted. Considering the age and
      cytomorphology, a diagnosis of intrarenal neuroblastoma was made in both cases.
      An intrarenal mass in a child may occasionally be a neuroblastoma. Our cases
      demonstrate the usefulness of CT-guided FNA in diagnosing intrarenal masses in
      children.

PMID- 12411997
TI  - Fine-needle aspiration cytology diagnosis of metastatic gastrointestinal stromal
      tumor in the liver: a report of three cases.
AB  - Gastrointestinal stromal tumor (GIST) is the designation for a major subset of
      gastrointestinal mesenchymal tumors that histologically, immunocytochemically,
      and genetically differ from leiomyomas, leiomyosarcomas, and schwannomas. GISTs
      derive from the interstitial cells of Cajal and, in addition to variable
      expression of smooth muscle and neural markers, they characteristically express
      CD34 and CD117. The cytological appearance, including immunocytochemical and
      mutational analysis of c-kit gene in primary GIST has been well described. To our
      knowledge, only two cases of metastatic GIST diagnosed by fine-needle aspiration
      (FNA) have been reported. We illustrate three cases of metastatic GIST in the
      liver. Two cases had no prior history of gastrointestinal tumor and the third
      case had a 4-yr previous history of duodenal tumor. Consistent
      immunocytochemistry and ultrastructual studies supported the diagnosis of GIST.
      We emphasize that in the appropriate clinical and radiological setting, a
      confident diagnosis of GIST can be established by FNA of metastatic lesions.

PMID- 12411998
TI  - Subcutaneous myxopapillary ependymoma presenting as a childhood sacrococcygeal
      tumor: a case report.
AB  - Subcutaneous myxopapillary ependymoma in a sacrococcygeal location is an uncommon
      lesion. We report such a case in a 16-mo-old female child, who presented with a
      sacrococcygeal mass since birth. The cytological picture was that of a malignant
      small round cell tumor and the diagnosis was missed on cytology, which was
      retrospectively confirmed on comparison with histology. Although rare, this
      lesion can be a potential diagnostic pitfall and needs to be distinguished from
      other malignant tumors occurring at this age and at a similar location, like
      sacrococcygeal teratoma with immature elements, primitive neuroectodermal tumor
      (PNET), and PNET with ependymal differentiation.

PMID- 12411999
TI  - Ultrafast Papanicolaou stain and cell-transfer technique enhance cytologic
      diagnosis of Hodgkin lymphoma.
AB  - Diagnosis of Hodgkin lymphoma (HL) by fine-needle aspiration (FNA) is often
      hampered by aspirated blood that camouflage scattered Hodgkin cells and Reed
      Sternberg (HRS) cells, and the absence of HRS cells in the smears submitted for
      immunophenotyping. The objective of this study was to develop a simple protocol
      to overcome these problems. The visibility of HRS cells in Diff-Quik,
      traditional, and Ultrafast Papanicolaou (UFP) stains in FNA smears were compared
      in 73 cases of HL. HRS cells were found to be most visible in UFP because of the
      hemolysis of aspirated blood and the highlighting of HRS cells by the red
      staining nucleoli. UFP-stained smears containing HRS cells were subsequently
      immunophenotyped via the cell-transfer technique. UFP staining was found to have
      no deleterious effect on the immunoreactivity of cellular CD15 and CD30 antigens
      of HRS cells. This simple protocol enhances the cytologic diagnosis of HL,
      feasible even with a single smear.

PMID- 12412000
TI  - PREPmate automated processor: comparison of automated and manual methods of
      liquid-based gynecologic sample preparation.
AB  - The development of procedures for fully automated processing of liquid-based
      gynecologic samples has been the focus of considerable interest to the cytology
      laboratory. Liquid-based collection and processing technology has been shown to
      improve sample adequacy, resulting in an overall improvement in quality of sample
      preparations. PREPmate, an accessory to the PrepStain slide processor, automates
      the initial enrichment process of mixing and dispensing the specimen over a
      density gradient. This report describes a study evaluating cellularity and
      diagnostic reproducibility in SurePath samples processed using the PREPmate
      accessory compared to samples processed using a manual technique. Samples
      processed using the PREPmate accessory contained 8.3% more squamous cells. Exact
      diagnostic reproducibility between preparation types was 83.3%; when considering
      negative vs. abnormal (ASCUS+), in adequate samples, reproducibility was 100%.

PMID- 12412001
TI  - Cytology of anaplastic large cell lymphoma.

PMID- 12412003
TI  - Cytopathology in malaysia.

PMID- 12412004
TI  - Different patterns of anti-Mullerian hormone expression, as related to DMRT1, SF
      1, WT1, GATA-4, Wnt-4, and Lhx9 expression, in the chick differentiating gonads.
AB  - In mammals, anti-Mullerian hormone (AMH) is produced by Sertoli cells from the
      onset of testicular differentiation and by granulosa cells after birth. In birds,
      AMH starts to be expressed in indifferent gonads of both sexes at a similar level
      and is later up-regulated in males. We previously demonstrated that, unlike in
      mammals, the onset of AMH expression occurs in chick embryo in the absence of
      SOX9. We looked for potential factors that might be involved in regulating AMH
      expression at different stages of chick gonad differentiation by comparing its
      expression pattern in embryos and young chicken with that of DMRT1, SF-1, WT1,
      GATA-4, Wnt-4, and Lhx9, by in situ hybridization. The results allowed us to
      distinguish different phases. (1) In indifferent gonads of both sexes, AMH is
      expressed in dispersed medullar cells. SF-1, WT1, GATA-4, Wnt-4, and DMRT1 are
      transcribed in the same region of the gonads, but none of these factors has an
      expression strictly coincident with that of AMH. Lhx9 is present only in the
      cortical area. (2) After this period, AMH is up-regulated in male gonads. The up
      regulation is concomitant with the beginning of SOX9 expression and a sex
      dimorphic level of DMRT1 transcripts. It is followed by the aggregation of the
      AMH-positive cells (Sertoli cells) into testicular cords in which AMH is
      coexpressed with DMRT1, SF-1, WT1, GATA-4, and SOX9. (3) In the females, the low
      level of dispersed medullar AMH expression is conserved. With development of the
      cortex in the left ovary, cells expressing AMH accumulate in the juxtacortical
      part of the medulla, whereas they remain dispersed in the right ovary. At this
      stage, AMH expression is not strictly correlated with any of the studied factors.
      (4) After hatching, the organization of left ovarian cortex is characterized by
      the formation of follicles. Follicular cells express AMH in conjunction with SF
      1, WT1, and GATA-4 and in the absence of SOX9, as in mammals. In addition, they
      express Lhx9 and Wnt-4, the latter being also found in the oocytes. (5) Moreover,
      unlike in mammals, the chicken ovary retains a dispersed AMH expression in
      cortical interstitial cells between the follicles, with no obvious correlation
      with any of the factors studied. Thus, the dispersed type of AMH expression in
      indifferent and female gonads appears to be bird-specific and not controlled by
      the same factors as testicular or follicular AMH transcription.

PMID- 12412005
TI  - Role of VEGF family members and receptors in coronary vessel formation.
AB  - The specific roles of vascular endothelial growth factor (VEGF) family members
      and their receptors (VEGFRs) in coronary vessel formation were studied. By using
      the quail heart explant model, we found that neutralizing antibodies to VEGF-B or
      VEGF-C inhibited tube formation on the collagen gel more than anti-VEGF-A.
      Soluble VEGFR-1, a receptor for VEGF-A and -B, inhibited tube formation by 87%, a
      finding consistent with that of VEGF-B inhibition. In contrast, addition of
      soluble VEGFR-2, a receptor for VEGF family members A, C, D, and E, inhibited
      tube formation by only 43%. Acidic FGF-induced tube formation dependency on VEGF
      was demonstrated by the attenuating effect of a soluble VEGFR-1 and -2 chimera.
      The localization of VEGF R-2 and R-3 was demonstrated by in situ hybridization of
      serial sections, which documented marked accumulations of transcripts for both
      receptors at the base of the truncus arteriosus coinciding with the temporal and
      spatial formation of the coronary arteries by means of ingrowth of capillary
      plexuses. This finding suggests that both VEGFR-2 and R-3 may play a role in the
      formation of the coronary artery roots. In summary, these experiments document a
      role for multiple members of the VEGF family and their receptors in formation of
      the coronary vascular bed.

PMID- 12412006
TI  - Pineal-specific expression of green fluorescent protein under the control of the
      serotonin-N-acetyltransferase gene regulatory regions in transgenic zebrafish.
AB  - Zebrafish serotonin-N-acetyltransferase-2 (zfAANAT-2) mRNA is exclusively
      expressed in the pineal gland (epiphysis) at the embryonic stage. Here, we have
      initiated an effort to study the mechanisms underlying tissue-specific expression
      of this gene. DNA constructs were prepared in which green fluorescent protein
      (GFP) is driven by regulatory regions of the zfAANAT-2 gene. In vivo transient
      expression analysis in zebrafish embryos indicated that in addition to the 5'
      flanking region, a regulatory sequence in the 3'-flanking region is required for
      pineal-specific expression. This finding led to an effort to produce transgenic
      lines expressing GFP under the control of the 5' and 3' regulatory regions of the
      zfAANAT-2 gene. Embryos transiently expressing GFP were raised to maturity and
      tested for germ cell transmission of the transgene. Three transgenic lines were
      produced in which GFP fluorescence in the pineal was detected starting 1 to 2
      days after fertilization. One line was crossed with mindbomb and floating head
      mutants that cause abnormal development of the pineal and an elevation or
      reduction of zfAANAT-2 mRNA levels, respectively. Homozygous mutant transgenic
      embryos exhibited similar effects on GFP expression in the pineal gland. These
      observations indicate that the transgenic lines described here will be useful in
      studying the development of the pineal gland and the mechanisms that determine
      pineal-specific gene expression in the zebrafish. Published 2002 Wiley-Liss, Inc.

PMID- 12412007
TI  - Multiple mechanisms of perichondrial regulation of cartilage growth.
AB  - We previously observed that the perichondrium (PC) and the periosteum (PO)
      negatively regulate endochondral cartilage growth through secreted factors.
      Conditioned medium from cultures of PC and PO cells when mixed (PC/PO-conditioned
      medium) and tested on organ cultures of embryonic chicken tibiotarsi from which
      the PC and PO have been removed (PC/PO-free cultures) effect negative regulation
      of growth. Of potential importance, this regulation compensates precisely for
      removal of the PC and PO, thus mimicking the regulation effected by these tissues
      in vivo. We have now examined whether two known negative regulators of cartilage
      growth (retinoic acid [RA] and transforming growth factor-beta1 [TGF-beta1]) act
      in a manner consistent with this PC/PO-mediated regulation. The results suggest
      that RA and TGF-beta1, per se, are not the regulators in the PC/PO-conditioned
      medium. Instead, they show that these two factors each act in regulating
      cartilage growth through an additional, previously undescribed, negative
      regulatory mechanism(s) involving the perichondrium. When cultures of
      perichondrial cells (but not periosteal cells) are treated with either agent,
      they secrete secondary regulatory factors into their conditioned medium, the
      action of which is to effect precise negative regulation of cartilage growth when
      tested on the PC/PO-free organ cultures. This negative regulation through the
      perichondrium is the only activity detected with TGF-beta1. Whereas, RA shows
      additional regulation on the cartilage itself. However, this regulation by RA is
      not "precise" in that it produces abnormally shortened cartilages. Overall, the
      precise regulation of cartilage growth effected by the action of the
      perichondrial-derived factor(s) elicited from the perichondrial cells by
      treatment with either RA or TGF-beta1, when combined with our previous results
      showing similar--yet clearly different--"precise" regulation by the PC/PO
      conditioned medium suggests the existence of multiple mechanisms involving the
      perichondrium, possibly interrelated or redundant, to ensure the proper growth of
      endochondral skeletal elements.

PMID- 12412008
TI  - Expression patterns of Wnts, Frizzleds, sFRPs, and misexpression in transgenic
      mice suggesting a role for Wnts in pancreas and foregut pattern formation.
AB  - It is well established that gut and pancreas development depend on epithelial
      mesenchymal interactions. We show here that several Wnt, Frizzled, and secreted
      frizzled-related protein (sFRP) encoding mRNAs are present during mouse
      pancreatic morphogenesis. Wnt5a and 7b mRNA is broadly expressed in foregut
      mesenchyme starting around embryonic day 10 in mice. Other members expressed are
      Wnt2b, Wnt5b, and Wnt11. In addition, genes for the Wnt receptors, Frizzled2, 3,
      4, 5, 6, 7, 8, and 9 are expressed. To understand potential Wnt functions in
      pancreas and foregut development in vivo, we analyzed transgenic F0 mouse fetuses
      expressing Wnt1 and 5a cDNAs under control of the PDX-1 gene promoter. In PDX
      Wnt1 fetuses, the foregut region normally comprising the proximal duodenum
      instead resembles a posterior extension of the stomach, often associated with
      complete pancreatic and splenic agenesis. Furthermore, the boundary between
      expression domains of gastric and duodenal markers is shifted in a posterior
      direction. In PDX-Wnt5a fetuses, several structures derived from the proximal
      foregut are reduced in size, including the pancreas, spleen, and stomach, without
      any apparent shift in the stomach to duodenum transition. In these fetuses,
      overall pancreatic morphology is changed and the pancreatic epithelium is dense
      and compact, consistent with Wnt5A effects on cell movements and/or attachment.
      Taken together, these results suggest that Wnt genes participate in epithelial
      mesenchymal signaling and may specify region identity in the anterior foregut.

PMID- 12412009
TI  - Evidence that nitric oxide regulates cell-cycle progression in the developing
      chick neuroepithelium.
AB  - In all developing epithelia, the nuclei continually migrate between the apical
      and basal sides of the cell during the cell cycle, with S phase occurring basally
      and mitosis occurring apically. The purpose and mechanism of this nuclear
      migration are unknown. Here, we show that nitric oxide (NO) is endogenously
      produced in the developing chicken neural tube, where it apparently regulates
      cell-cycle progression. We provide evidence that high NO levels promote entry
      into S phase basally, whereas low levels of NO facilitate entry into mitosis
      apically.

PMID- 12412010
TI  - Anteroposterior axis formation in Xenopus limb bud recombinants: a model of
      pattern formation during limb regeneration.
AB  - We previously showed that recombinant limb buds with dissociated and reaggregated
      mesenchyme develop more than 30 digits in Xenopus laevis, which exhibits
      different capacities for limb regeneration at different developmental stages
      (Yokoyama et al. [1998] Dev Biol 196:1-10). Cell-cell contact among anterior- and
      posterior-derived mesenchymal cells is required for anteroposterior (AP) axis
      formation of recombinant limbs in an intercalary manner. However, whether one-way
      induction from posterior cells to anterior cells as proposed by the polarizing
      zone model or interactions between anterior and posterior cells evoke the AP axis
      formation in recombinant limbs remains unclear. In this study, we found, by a
      combination of X-ray irradiation and a recombinant limb technique, that not one
      way induction but interactions between anterior and posterior cells accompanied
      by cell contribution are indispensable for AP axis formation in recombinant
      limbs. Shh was expressed in posterior-derived not anterior-derived cells. We
      propose that the recombinant limb is an excellent model for examining the axis
      formation mechanism in regenerating limbs because, as in recombinant limbs, cell
      cell contact among cells derived from different positions of an amputation plane
      occurs in the blastema of regenerating limbs.

PMID- 12412011
TI  - An amphioxus winged helix/forkhead gene, AmphiFoxD: insights into vertebrate
      neural crest evolution.
AB  - During amphioxus development, the neural plate is bordered by cells expressing
      many genes with homologs involved in vertebrate neural crest induction. However,
      these amphioxus cells evidently lack additional genetic programs for the cell
      delaminations, migrations, and differentiations characterizing definitive
      vertebrate neural crest. We characterize an amphioxus winged helix/forkhead gene
      (AmphiFoxD) closely related to vertebrate FoxD genes. Phylogenetic analysis
      indicates that the AmphiFoxD is basal to vertebrate FoxD1, FoxD2, FoxD3, FoxD4,
      and FoxD5. One of these vertebrate genes (FoxD3) consistently marks neural crest
      during development. Early in amphioxus development, AmphiFoxD is expressed
      medially in the anterior neural plate as well as in axial (notochordal) and
      paraxial mesoderm; later, the gene is expressed in the somites, notochord,
      cerebral vesicle (diencephalon), and hindgut endoderm. However, there is never
      any expression in cells bordering the neural plate. We speculate that an
      AmphiFoxD homolog in the common ancestor of amphioxus and vertebrates was
      involved in histogenic processes in the mesoderm (evagination and delamination of
      the somites and notochord); then, in the early vertebrates, descendant paralogs
      of this gene began functioning in the presumptive neural crest bordering the
      neural plate to help make possible the delaminations and cell migrations that
      characterize definitive vertebrate neural crest.

PMID- 12412012
TI  - VEGF signaling is required for the assembly but not the maintenance of embryonic
      blood vessels.
AB  - Here we investigated the importance of vascular endothelial growth factor (VEGF)
      signaling to the de novo formation of embryonic blood vessels, vasculogenesis, as
      opposed to the maintenance of blood vessels. We found that antagonizing the
      activity of the VEGF signaling pathway by using soluble VEGF receptor 1 (sFlt1)
      or VEGF antibodies inhibited vasculogenesis that occurs in embryos and in
      cultures of 7.5 days postcoitus prevascular mesoderm. Antagonist treatment
      resulted in the formation of clusters of endothelial cells not normally observed
      during vasculogenesis. In contrast, when embryos with established vasculatures or
      cultures of vascularized mesoderm were treated with sFlt1 or VEGF antibodies, no
      discernible alterations to the preexisting blood vessels were observed. These
      observations indicate that, although VEGF signaling is required to promote the
      mesenchymal to epithelial transition by which angioblasts assemble into nascent
      endothelial tubes, it is not required by endothelial cells to maintain their
      organization as an endothelium.

PMID- 12412013
TI  - Targeted insertion results in a rhombomere 2-specific Hoxa2 knockdown and ectopic
      activation of Hoxa1 expression.
AB  - Recent studies indicated that retention of selectable marker cassettes in
      targeted Hox loci may cause unexpected phenotypes in mutant mice, due to
      neighborhood effects. However, the molecular mechanisms have been poorly
      investigated. Here, we analysed the effects of the targeted insertion of a PGK
      neo cassette in the 3' untranslated region of Hoxa2. Even at this 3' position,
      the insertion resulted in homozygous mutants that unexpectedly did not survive
      beyond 3 weeks of age. Molecular analysis of the targeted allele revealed a
      selective "knockdown" of Hoxa2 expression in rhombomere 2 and associated
      patterning abnormalities. Moreover, Hoxa1 was ectopically expressed in the
      hindbrain and branchial arches of mutant embryos. Of interest, we demonstrated
      that the ectopic expression was due to the generation of neo-Hoxa1 fusion
      transcripts, resulting from aberrant alternative splicing. These defects could be
      rescued after removal of the PGK-neo cassette by Flp-mediated recombination.
      These results underscore the complexity of transcriptional regulation at Hox loci
      and provide insights into the in vivo regulation of Hoxa2 segmental expression.
      They also provide a molecular basis for the interpretation of unexpected Hox
      knockout phenotypes in which the targeted selectable marker is retained in the
      locus.

PMID- 12412014
TI  - PI-3 kinase activity is required for epithelial-mesenchymal transformation during
      palate fusion.
AB  - Epithelial-mesenchymal transformation (EMT) is the primary mechanism for the
      disappearance of medial edge epithelia (MEE) during palate fusion. This phenotype
      transition is highly regulated by growth factors, extracellular matrix, cell
      surface receptors, and a variety of intracellular signaling. Phosphatidylinositol
      3 (PI-3) kinase regulates cytoskeleton reorganization, cell migration, and
      transforming growth factor (TGF) beta-regulated EMT. Therefore, we investigated
      the role of PI-3 kinase in EMT during palatal fusion in vitro. Palatal shelves
      from embryonic (E) 13.5 day mouse embryos were collected and cultured for up to
      72 hr. A specific PI-3 kinase inhibitor, LY294002, was added to the medium at
      concentrations of 100 etaM, 1 microM, and 10 microM. The fate of midline
      epithelia was traced by carboxyfluorescence labeling and analyzed by confocal
      microscopy. Harvested tissues were also processed for immunohistochemical
      analysis of a specific marker for basal lamina (laminin). Palatal fusion stages
      were scored on a scale of 1 to 5, with 1 equal to complete nonfusion and 5 equal
      to complete fusion. The mean fusion score (MFS) was calculated for each treatment
      group. Palatal shelves fused after 72 hr of culture in control and 100 etaM
      LY294002 inhibitor-treated groups, with MFS of 4.67 and 4.5, respectively.
      Laminin was absent in the midline and epithelia transformed into mesenchyme.
      However, when cultured palates were treated with 1 and 10 microM LY294002, MEE
      persisted in the midline and the basal lamina remained intact after 72 hr. The
      MFS was significantly less in the 1 and 10 microM LY294002-treated tissues at
      2.08 and 1.33, respectively. Our results demonstrate that EMT during palatal
      fusion in vitro is dependent on PI-3 kinase activity.

PMID- 12412015
TI  - Isolation and developmental expression analysis of Tbx22, the mouse homolog of
      the human X-linked cleft palate gene.
AB  - Mutations in the TBX22 gene have been identified recently in patients with the X
      linked cleft palate and ankyloglossia syndrome, suggesting that the TBX22
      transcription factor plays an important role in palate development. However,
      because ankyloglossia has been reported in the majority of patients with TBX22
      mutations, it has been speculated that the cleft palate phenotype is secondary to
      defective fetal tongue movement. To understand the role of TBX22 in disease
      pathogenesis and in normal development, it is necessary to carry out a detailed
      temporal and spatial gene expression analysis. We report here the isolation and
      developmental expression analysis of the mouse homolog Tbx22. The mouse Tbx22
      gene encodes a putative protein of 517 amino acid residues, which shares 72%
      overall amino acid sequence identity with the human TBX22 protein. By using
      interspecific backcross analysis, we have localized the Tbx22 gene to mouse
      chromosome X, in a region syntenic to human chromosome Xq21, where the TBX22 gene
      resides, indicating that Tbx22 is the ortholog of human TBX22. Our in situ
      hybridization analysis shows that Tbx22 is expressed in a temporally and
      spatially highly restricted pattern during mouse palate and tongue development.
      Together with the mutant phenotypes in human patients, our data indicate a
      primary role for Tbx22 in both palate and tongue development.

PMID- 12412016
TI  - Expression of oncostatin M in hematopoietic organs.
AB  - Murine oncostatin M (OSM), a member of the interleukin-6 (IL-6) -related cytokine
      subfamily, stimulates definitive hematopoiesis and liver development. The OSM
      gene was cloned as a cytokine-inducible early response gene in some hematopoietic
      cell lines. In this study, we performed in situ hybridization to examine the
      tissue distribution of cells expressing OSM mRNA in the developing and the adult
      mice. Its gene expression was seen in hematopoietic cells of developing liver
      from 11.5 days postcoitum (dpc), and persisted to the neonates. From 17.5 dpc,
      OSM mRNA-positive cells were found in other hematopoietic organs, including bone
      marrow, thymus, and spleen. The highest levels of gene expression were observed
      in the adult bone marrow. Most OSM-expressing cells expressed IL-5 receptor alpha
      subunit, a marker for eosinophil lineage. In addition, some positive cells
      expressed neutrophil elastase, which was used as a polymorphonuclear neutrophil
      (PMN) marker. After birth, OSM mRNA was expressed in tissue eosinophils in
      nonhematopoietic organs, including small intestine, lung, and skin. Our data
      revealed that eosinophil progenitors and eosinophils as well as PMNs are also an
      important cellular source of OSM in mice.

PMID- 12412017
TI  - Tooth development is independent of a Hox patterning programme.
AB  - Hox genes have a critical role in controlling the patterning processes of many
      tissues by imparting positional information in embryogenesis. Patterning of the
      pharyngeal component of the skull (the visceroskeleton) has been proposed to be
      influenced by this "Hox code." Recently, it has been shown that Hox genes are
      associated with the evolution of jaws, loss of Hox gene expression in the first
      branchial arch being necessary for the transition from the agnathan condition to
      the gnathostome condition. Teeth develop on the first branchial arch in mammals
      and, therefore, might be expected to be under the control of Hox genes in a
      manner similar to that of the cranial skeletal elements. However, we show that,
      unlike cartilage and bone, the development of teeth is not affected by
      alterations in Hoxa2 expression. Tooth development in the first arch was
      unaffected by overexpression of Hoxa2, whereas recombinations of second arch
      mesenchyme with first arch epithelium led to tooth development within a Hoxa2
      positive environment. These data demonstrate that teeth develop from local
      interactions and that tooth formation is not under the axial patterning program
      specified by the Hox genes. We propose that the evolutionary development of teeth
      in the first branchial arch is independent of the loss of Hox expression
      necessary for the development of the jaw.

PMID- 12412018
TI  - PLEXIN-D1, a novel plexin family member, is expressed in vascular endothelium and
      the central nervous system during mouse embryogenesis.
AB  - The genetic defect in Mobius syndrome 2 (MBS2, MIM 601471), a dominantly
      inherited disorder characterised by paralysis of the facial nerve, is situated at
      chromosome 3q21-q22. We characterised the cDNA and predicted protein, and
      examined the expression pattern during mouse embryogenesis of a positional
      candidate gene, PLEXIN-D1 (PLXND1). The cDNA for PLXND1 is 7095 base pairs in
      length, coding for a predicted protein of 1925 amino acids. The protein features
      all known domains of plexin family members, with the exception of the third Met
      related sequence. Northern analysis revealed a very low expression of PLXND1 in
      adult mouse and adult human tissues. To investigate the expression of PlxnD1
      during embryogenesis, RNA in situ hybridisation was performed on mouse embryos
      from various stages. This investigation revealed expression of PlxnD1 in cells
      from the central nervous system (CNS) and in vascular endothelium. Early
      expression in the CNS is located in the ganglia, cortical plate of the cortex,
      and striatum. At later embryologic stages, neural expression was also seen in the
      external granular layer of the cerebellum and several nerve nuclei. The
      expression in the vascular system resides solely in the endothelial cells of
      developing blood vessels. Based on our results, we suggest that this expression
      of a member of the plexin family in vascular endothelium could point toward a
      role in embryonic vasculogenesis.

PMID- 12412019
TI  - Embryonic retinal gene expression in sonic-you mutant zebrafish.
AB  - Hedgehog (Hh) signaling is required for proper eye development in vertebrates;
      known roles for Hh in the zebrafish include regulation of eye morphogenesis,
      ganglion cell neurogenesis, and photoreceptor differentiation. To gain insight
      into the mechanisms by which Hh signaling influences these developmental events,
      we have examined proliferation, cell death, and expression patterns of several
      retinal genes in the eyes of embryonic zebrafish lacking the sonic hedgehog gene.
      We find that features of the eye phenotype of the sonic-you (syu) mutant are
      consistent with multiple roles for the Hh signal during retinal development. Most
      interestingly, half of the mutant retinas failed to initiate cell differentiation
      and, instead, retained a neuroepithelial appearance. In the other half of the
      mutants, retinal cell differentiation was initiated, but not fully propagated. We
      also find that Hh signaling is important for retinal cell proliferation and
      retinal cell survival; together, these functions provide an explanation for
      progressive microphthalmia in the syu-/- mutant.

PMID- 12412020
TI  - Prox1 is a master control gene in the program specifying lymphatic endothelial
      cell fate.
AB  - Early during development, one of the first indications that lymphangiogenesis has
      begun is the polarized expression of the homeobox gene Prox1 in a subpopulation
      of venous endothelial cells. It has been shown previously that Prox1 expression
      in the cardinal vein promotes and maintains the budding of endothelial cells that
      will form the lymphatic vascular system. Prox1-deficient mice are devoid of
      lymphatic vasculature, and in these animals endothelial cells fail to acquire the
      lymphatic phenotype; instead, they remain as blood vascular endothelium. To
      investigate whether Prox1 is sufficient to induce a lymphatic fate in blood
      vascular endothelium, Prox1 cDNA was ectopically expressed by adenoviral gene
      transfer in primary human blood vascular endothelial cells and by transient
      plasmid cDNA transfection in immortalized microvascular endothelial cells.
      Transcriptional profiling combined with quantitative real-time reverse
      transcription-polymerase chain reaction and Western blotting analyses revealed
      that Prox1 expression up-regulated the lymphatic endothelial cell markers
      podoplanin and vascular endothelial growth factor receptor-3. Conversely, genes
      such as laminin, vascular endothelial growth factor-C, neuropilin-1, and
      intercellular adhesion molecule-1, whose expression has been associated with the
      blood vascular endothelial cell phenotype, were down-regulated. These results
      were confirmed by the use of specific antibodies against some of these markers in
      sections of embryonic and adult tissues. These findings validate our previous
      proposal that Prox1 is a key player in the molecular pathway leading to the
      formation of lymphatic vasculature and identify Prox1 as a master switch in the
      program specifying lymphatic endothelial cell fate. That a single gene product
      was sufficient to re-program the blood vascular endothelium toward a lymphatic
      phenotype corroborates the close relationship between these two vascular systems
      and also suggests that during evolution, the lymphatic vasculature originated
      from the blood vasculature by the additional expression of only a few gene
      products such as Prox1.

PMID- 12412021
TI  - Prep2: cloning and expression of a new prep family member.
AB  - We describe Prep2, a new murine homeobox-containing gene closely related to
      Prep1. The PREP2 protein belongs to the three amino acid loop extension (TALE)
      superclass of homeodomain-containing proteins and encodes a polypeptide of 462
      residues. As for PREP1, PREP2 binds an appropriate site on DNA as a heterodimer
      with PBX1A. Northern analysis, immunoblotting, immunohistochemistry, and in situ
      hybridization show widespread Prep2 expression during organogenesis and in the
      adult. The data suggest that Prep2 functions to varying degrees in a broad array
      of tissues and developmental processes.

PMID- 12412022
TI  - Expression of the ETS transcription factor ER81 in the developing chick and mouse
      hindbrain.
AB  - ER81 is an ETS domain-containing transcription factor, which is expressed in
      various developing tissues and organs of the embryo and in pools of developing
      spinal motor neurons and proprioceptive sensory neurons. Analysis of mice lacking
      ER81 function showed that this gene played an important role in the establishment
      of sensory-motor circuitry in the spinal cord. Here, we investigate the
      expression pattern of er81 in the hindbrain of both chick and mouse embryos. We
      find that er81 is expressed in a subpopulation of inferior olive neurons, which
      send their projections to the caudal cerebellum.

PMID- 12412023
TI  - Surface imaging microscopy, an automated method for visualizing whole embryo
      samples in three dimensions at high resolution.
AB  - Modern biology is faced with the challenge of understanding the specification,
      generation, and maintenance of structures ranging from cells and tissues to
      organs and organisms. By acquiring images directly from the block face of an
      embedded sample, surface imaging microscopy (SIM) generates high-resolution
      volumetric images of biological specimens across all of these scales. Surface
      imaging microscopy expands our range of imaging tools by generating three
      dimensional reconstructions of embryo samples at high resolution and high
      contrast. SIM image quality is not limited by depth or the optical properties of
      overlying tissue, and intrinsic or extrinsic alignment markers are not required
      for volume reconstruction. These volumes are highly isotropic, enabling them to
      be virtually sectioned in any direction without loss of image quality. Surface
      imaging microscopy provided a more accurate three-dimensional representation of a
      chick embryo than confocal microscopy of the same sample. SIM offers excellent
      imaging of embryos from three major vertebrate systems in developmental biology:
      mouse, chicken, and frog. Immediate applications of this technology are in
      visualizing and understanding complex morphogenetic events and in making detailed
      comparisons between normal and genetically modified embryos.

PMID- 12412025
TI  - Magnetic resonance safety update 2002: implants and devices.
AB  - The preservation of a safe magnetic resonance (MR) environment requires constant
      vigilance by MR healthcare professionals, particularly with regard to the
      management of patients with metallic biomedical implants or devices. The variety
      and complexity of implants and devices constantly changes, requiring continuous
      attention and diligence with regard to obtaining the most current and accurate
      information about these objects relative to the MR environment. This review
      article discusses MR safety and MR compatibility issues and presents important
      information for a variety of implants and devices, with an emphasis on those
      objects that have recently undergone evaluation or that require additional
      consideration because of existing controversy or confusion.

PMID- 12412026
TI  - Acoustic noise and functional magnetic resonance imaging: current strategies and
      future prospects.
AB  - Functional magnetic resonance imaging (fMRI) has become the method of choice for
      studying the neural correlates of cognitive tasks. Nevertheless, the scanner
      produces acoustic noise during the image acquisition process, which is a problem
      in the study of auditory pathway and language generally. The scanner acoustic
      noise not only produces activation in brain regions involved in auditory
      processing, but also interferes with the stimulus presentation. Several
      strategies can be used to address this problem, including modifications of
      hardware and software. Although reduction of the source of the acoustic noise
      would be ideal, substantial hardware modifications to the current base of
      installed MRI systems would be required. Therefore, the most common strategy
      employed to minimize the problem involves software modifications. In this work we
      consider three main types of acquisitions: compressed, partially silent, and
      silent. For each implementation, paradigms using block and event-related designs
      are assessed. We also provide new data, using a silent event-related (SER)
      design, which demonstrate higher blood oxygen level-dependent (BOLD) response to
      a simple auditory cue when compared to a conventional image acquisition.

PMID- 12412027
TI  - Changes in oxygenation of intracranial tumors with carbogen: a BOLD MRI and EPR
      oximetry study.
AB  - PURPOSE: To examine, using blood oxygen level dependent (BOLD) MRI and EPR
      oximetry, the changes in oxygenation of intracranial tumors induced by carbogen
      breathing. MATERIALS AND METHODS: The 9L and CNS-1 intracranial rat tumor models
      were imaged at 7T, before and during carbogen breathing, using a multi-echo
      gradient-echo (GE) sequence to map R(2)*. On a different group of 9L tumors,
      tissue pO(2) was measured using EPR oximetry with lithium phthalocyanine as the
      oxygen-sensitive material. RESULTS: The average decline in R(2)* with carbogen
      breathing was 13 +/- 1 s(-1) in the CNS-1 tumors and 29 +/- 4 s(-1) in the 9L
      tumor. The SI vs. TE decay curves indicate the presence of multiple components in
      the tumor. Tissue pO(2) in the two 9L tumors measured was 8.6 +/- 0.5 and 3.6 +/-
      0.6 mmHg during air breathing, and rose to 20 +/- 7 and 16 +/- 4 mmHg (mean +/-
      SE) with carbogen breathing. Significant changes were observed by 10 minutes, but
      changes in pO(2) and R(2)* continued in some subjects over the entire 40 minutes.
      CONCLUSION: EPR results indicate that glial sarcomas may be radiobiologically
      hypoxic. Both EPR and BOLD data indicate that carbogen breathing increases brain
      tumor oxygenation. These data support the use of BOLD imaging to monitor changes
      in oxygenation in brain tumors.

PMID- 12412028
TI  - Multiplanar MR temperature-sensitive imaging of cerebral thermal treatment using
      interstitial ultrasound applicators in a canine model.
AB  - PURPOSE: To study the feasibility of an interleaved gradient-echo, echo-planar
      imaging (iGE-EPI) sequence for multiplanar magnetic resonance temperature imaging
      (MRTI) to monitor intracerebral thermal treatment three-dimensionally using
      multielement ultrasound applicators. MATERIALS AND METHODS: Transmissible
      venereal tumor (TVT) fragments were injected into the right cerebral hemisphere
      of five dogs. Guided by MRI, an interstitial ultrasound applicator was inserted
      into the tumor or normal brain tissue. The iGE-EPI sequence was used to estimate
      temperature changes by computing the complex phase-difference induced by
      temperature-dependent shifts in the proton resonance frequency of water. The
      thermal dose maps were updated every 6-8 seconds for five to seven image planes
      during treatment. The results of MRTI were compared with those of post-treatment
      MRI and histologic analysis. RESULTS: The multiplanar MRTI monitored temperature
      and thermal dose distributions in tumor and normal brain tissue over the entire
      user-defined treatment volume. The ultrasound applicators produced contiguous
      areas of coagulative necrosis, resulting in 1.5-4.0 cm(3) volumes of tissue
      necrosis. MRTI-based assessments of thermal-dose distributions were consistent
      with the results of post-treatment MRI and histologic analysis. CONCLUSION:
      Multiplanar MRTI is feasible for measuring necrosing thermal doses during
      intracerebral thermal delivery by interstitial ultrasound applicators.

PMID- 12412029
TI  - Single-voxel long TE 1H-MR spectroscopy of the normal brainstem and cerebellum.
AB  - PURPOSE: To evaluate the feasibility of single voxel 1H-MRS of the CNS structures
      contained in the posterior cranial fossa and to determine the distribution of the
      normal metabolite ratios, concentrations, and T2 relaxation times in the
      midbrain, pons, medulla, dentate nucleus and cerebellar vermis. MATERIALS AND
      METHODS: A total of 147 single voxel 1H-MR spectra with a point-resolved proton
      spectroscopy sequence (PRESS) sequence and echo time (TE) of 136 or 272 msec were
      obtained in the midbrain, pons, medulla, dentate, and vermis of 31 healthy
      volunteers. In seven additional patients; the concentrations and T2 relaxation
      times of metabolites were obtained in the same locations (except the medulla)
      with an external phantom calibration method and a four TE PRESS technique.
      RESULTS: Ten (27%) of 36 spectra acquired in the medulla were of poor quality. A
      similar ranking of the N-acetyl aspartate (NAA)/creatine (Cr) ratio and
      choline(Cho)/Cr ratios in the five locations for the two TEs was observed, with
      the highest values in the pons (mean NAA/Cr = 4.16 +/- 0.6 and Cho/Cr =2.66 +/-
      0.6 at TE 272) and the lowest values in the dentate and vermis (mean NAA/Cr =
      1.66 +/- 0.2 and Cho/Cr = 1.20 +/- 0.2 at TE 272). The analysis of variance
      showed significant regional differences of the NAA and Cr concentrations, which
      had the highest values in the dentate. Non-significant regional differences were
      observed for the concentration of Cho and for the T2 of the metabolites.
      CONCLUSION: With the exception of the medulla, single voxel 1H-MRS enables an in
      vivo biochemical analysis of the CNS structures contained in the posterior
      cranial fossa. Regional differences in the metabolite ratios and concentrations
      must be considered when employing 1H-MRS for evaluation of diseases of the
      brainstem and cerebellum.

PMID- 12412030
TI  - Proton magnetic resonance spectroscopy with metabolite nulling reveals regional
      differences of macromolecules in normal human brain.
AB  - PURPOSE: To quantify the macromolecular content in different anatomic brain
      regions and to evaluate an age dependency of the macromolecular concentrations.
      MATERIAL AND METHODS: A short echo time Stimulated Echo Acquisition Mode (STEAM)
      sequence was used without and with inversion recovery metabolite nulling in 8-12
      healthy volunteers. Quantitation was achieved by an extended LCModel, and
      macromolecular resonances at 0.9, 1.4, 2.1, and 3.0 ppm were evaluated. RESULTS:
      In the cerebellum, the 1.4, 2.1, and 3.0 ppm resonances were highest compared to
      all other regions (P < 0.02); the 0.9 ppm resonance was significantly higher than
      that of pons (P < 0.01). In the motor cortex, the 0.9, 1.4, and 2.1 ppm
      resonances were higher than those of white matter and pons (P < 0.02). Pons and
      white matter did not differ significantly from each other. A significant
      correlation of the macromolecular concentrations with the age could not be found.
      CONCLUSION: There were higher macromolecular concentrations in the cerebellum and
      motor cortex than in pons or white matter. These were probably due to the higher
      portions of gray matter in these volumes of interest (VOIs) than in the other
      regions.

PMID- 12412031
TI  - Structure of the water resonance in small voxels in rat brain detected with high
      spectral and spatial resolution MRI.
AB  - PURPOSE: To acquire high spectral and spatial resolution (HiSS) MR images of the
      water resonance in rat brain, evaluate the lineshape of the water resonance in
      small voxels, and compare images derived from HiSS data with conventional images.
      MATERIALS AND METHODS: Spectroscopic images of rat brain were obtained at 4.7
      Tesla using phase encoding gradients only. Spectral resolution in each voxel was
      approximately 8 Hz and bandwidth was 1,000 Hz. Spatial resolution was
      approximately 250 microns in 1-mm slices. Images were synthesized to show the
      water signal integral, peak height, linewidth, resonance frequency, and
      asymmetry. RESULTS: Two or more resolved components of the water resonance were
      detected in approximately 14% +/- 6% of voxels in the brains of eight rats. The
      water resonances in approximately 20% +/- 10% of voxels (n = 8) were highly
      asymmetric. Images with intensity proportional to water signal peak height,
      T(2)*, or to selected components of the water resonance showed features that were
      not evident in conventional images. CONCLUSIONS: The complexity of the water
      signal reflects the anatomy and physiology of the sub-voxelar environment, and
      may be a useful source of image contrast. HiSS imaging of brain provides accurate
      anatomic information, and may improve image contrast and delineation of subtle
      anatomic features.

PMID- 12412032
TI  - Functional imaging of the rat cervical spinal cord.
AB  - PURPOSE: To examine functional magnetic resonance imaging (fMRI) of the rat
      cervical spinal cord using painful stimulation. MATERIALS AND METHODS: fMRI of
      the rat cervical spinal cord was performed at 9.4 T. Stimuli included injection
      of 25 microL of capsaicin (128 microg/mL in 7.5% dimethylsulfoxide (DMSO)) into
      the right dorsal forepaw and electrical stimulation (15 V, 0.3 msec, 3 Hz) of the
      left dorsal forepaw. RESULTS: Activation in the dorsal horn of the spinal cord,
      which is known to be associated with the transmission of pain, was found in all
      rats (N = 4) following injection of capsaicin into the dorsal forepaw. It was
      possible to reproduce the pain response in a given animal several times
      throughout the course of an experiment, provided that sufficient time was allowed
      between capsaicin injections. Regions of the spinal cord associated with motor
      and pain response were observed in functional imaging experiments involving
      subcutaneous electrical stimulation of the dorsal forepaw. CONCLUSION: Spinal
      fMRI using electrical stimulation and capsaicin-induced painful stimulation can
      be a useful tool in an animal model of pain and injury.

PMID- 12412033
TI  - MR assessment of left ventricular function: quantitative comparison of fast
      imaging employing steady-state acquisition (FIESTA) with fast gradient echo cine
      technique.
AB  - PURPOSE: To evaluate the agreement of fast imaging employing steady-state
      acquisition (FIESTA) cine technique with segmented k-space fast gradient echo
      (GRE) cine technique when using them for assessment of cardiac function.
      MATERIALS AND METHODS: Eleven MR cine studies were performed on six healthy
      volunteers and five patients, using FIESTA and fast GRE techniques. The
      quantitative measurements of ventricular function obtained from the two
      techniques were compared. The data analysis was performed by two observers
      independently. RESULTS: Compared to fast GRE cine technique, FIESTA cine
      technique consistently resulted in higher end-diastolic volume (10.2%) and end
      systolic volume (21.6%), but lower myocardial mass of left ventricle (19.2%) and
      ejection fraction (9.9%). The stroke volume obtained from the two techniques was
      very close. The primary explanation for this variability is that the two
      techniques have different mechanisms on establishing signal contrast. CONCLUSION:
      Compared to fast GRE technique, FIESTA provides significantly different results
      when using it for assessment of left ventricular function. It is important to
      consider this difference in the assessment of cardiac function.

PMID- 12412034
TI  - Preoperative evaluation of patients awaiting liver transplantation: comparison of
      multiphasic contrast-enhanced 3D magnetic resonance to helical computed
      tomography examinations.
AB  - PURPOSE: To determine the feasibility of using a multiphasic magnetic resonance
      (MR) examination to evaluate the hepatic arterial anatomy and parenchyma in
      patients awaiting orthotopic liver transplantation (OLT). MATERIALS AND METHODS:
      Twenty consecutive patients awaiting OLT underwent multiphasic MR (using a T1
      weighted 3D gadolinium-enhanced gradient-echo (GRE) sequence and two separate
      injections of contrast material) and computed tomography (CT) imaging; both
      imaging studies were performed within a 1-week period for each patient.
      Quantitative and qualitative assessment of the hepatic arterial system on MR data
      was performed. Two independent observers classified the hepatic arterial anatomy
      and evaluated the hepatic parenchyma from the MR data. The prospective CT
      interpretation was used as the gold standard. RESULTS: Overall qualitative rating
      of hepatic arterial system-to-background contrast on MR data was good to
      excellent (average pooled score of 2.00 +/- 0.27), with no significant difference
      between the two observers after the first or second injections of contrast
      material. Classification of hepatic arterial anatomy by MR angiography (MRA) and
      CT angiography (CTA) was concordant in 85% (17/20) of patients and discordant in
      15% (3/20) of patients. Focal parenchymal lesions were detected in 25% (5/20) of
      patients by MR and CT; however, two lesions in one patient with multiple lesions
      were detected only with MR. CONCLUSION: Multiphasic T1-weighted 3D gadolinium
      enhanced MR examination can provide comprehensive evaluation of the hepatic
      arterial anatomy and parenchyma in patients awaiting OLT. MR may offer an
      advantage over CT in the detection of focal parenchymal lesions.

PMID- 12412035
TI  - MR-guided microwave thermocoagulation therapy of liver tumors: initial clinical
      experiences using a 0.5 T open MR system.
AB  - PURPOSE: To utilize a microwave coagulator for MR-guided interstitial thermal
      therapy of liver tumors as a clinically feasible heating device. MATERIALS AND
      METHODS: MR-guided microwave thermocoagulation therapy was carried out 34 times
      in 30 patients with liver tumors (eight hepatocellular carcinoma, 22 metastatic
      tumors) using a 0.5 T open configuration MR system. RESULTS: Percutaneous
      puncture could be accomplished both accurately and safely while monitoring real
      time magnetic resonance imaging (MRI). Using a notch filter, MR images could be
      observed without electromagnetic interference even during microwave ablation.
      Temperature monitoring during ablation was possible using the proton resonance
      frequency method. All procedures could be successfully carried out without any
      complications, and the therapeutic effects were deemed satisfactory. CONCLUSION:
      MR-guided microwave thermocoagulation therapy could be one promising procedure of
      minimally invasive treatment for liver tumors.

PMID- 12412036
TI  - Combined high-resolution and real-time imaging: a technical feasibility study on
      coronary magnetic resonance angiography.
AB  - PURPOSE: To propose a new approach to combining high-resolution and real-time
      imaging and to show its technical feasibility on the example of coronary magnetic
      resonance angiography. MATERIALS AND METHODS: The insertion of fast two
      dimensional (2D) acquisitions into time intervals that have not been utilized by
      triggered or gated 2D or three-dimensional (3D) acquisitions so far is suggested,
      as well as the immediate reconstruction and display of the additional data. For a
      technical validation of this concept, a 2D ventricular function protocol was
      interleaved into a cardiac-triggered and respiratory-gated 3D coronary
      angiography protocol. Dedicated hardware was employed to rapidly process the data
      originating from the former. Since the sampling of the latter was restricted to
      intervals with minimal motion, remaining periods of time could be used to
      simultaneously image the cardiac and respiratory motion. RESULTS: The technical
      feasibility of the proposed approach was demonstrated by successful measurements
      with the combined high-resolution and real-time protocol in volunteers. All
      examinations provided short axis views during the acquisition and angiograms of
      selected parts of the coronary system after its completion. CONCLUSION: The
      investigated concept allows high-resolution measurements to be complemented with
      real-time imaging functionality without affecting the scan time or image quality.
      In the particular application considered, an image-based patient monitoring or
      motion correction is enabled, indicating potential benefits of combining two very
      dissimilar methods of data acquisition in one measurement.

PMID- 12412037
TI  - Correction for displacement artifacts in 3D phase contrast imaging.
AB  - PURPOSE: To correct for displacement artifacts in 3D phase contrast imaging.
      MATERIALS AND METHODS: A 3D phase contrast pulse sequence was modified so that
      displacements of velocity measurements were restricted to one direction. By
      applying a postprocessing method, displaced measurements could be traced back to
      their accurate positions. Flow studies were performed using a phantom that
      generated flow through a stenosis, directed oblique relative to the phase and
      frequency encoding directions. Velocity profiles and streamline visualization
      were used to compare displaced and corrected velocity data to a reference.
      RESULTS: Velocity profiles obtained from the original measurement showed skewed
      profiles due to the displacement artifact, both at close proximity to the orifice
      as well as further downstream. After correction, concordance with the reference
      improved considerably. CONCLUSION: The displacement artifact, which restricts the
      accuracy of phase contrast measurements, can be corrected for using the proposed
      method. Correction of the phase contrast velocity data may improve the accuracy
      of subsequent flow analysis and visualization.

PMID- 12412038
TI  - Tissue thermal conductivity by magnetic resonance thermometry and focused
      ultrasound heating.
AB  - PURPOSE: To investigate the combined use of magnetic resonance (MR) temperature
      imaging and focused ultrasound (FUS) for the noninvasive determination of tissue
      thermal properties. MATERIALS AND METHODS: Brief, spatial impulses of temperature
      elevation were created in tissue using a spherical, air-backed transducer
      operating at 1.68 MHz and measured using MR temperature imaging in a 1.5-Tesla
      clinical scanner. A novel technique based on thermal washout is applied in an
      analysis of the acquired MR temperature images to estimate tissue thermal
      conductivity and perfusion. RESULTS: Numerical simulations and experiments in
      vitro and in vivo demonstrate that thermal conductivity can be measured to within
      10% of the true value with MR thermometry at 1.5 Tesla. With the temperature
      precision available at 1.5 Tesla, however, robust perfusion estimation is
      feasible only in highly perfused organs or tumors. CONCLUSION: This study has
      developed a method for determining tissue thermal properties specific to the
      patient and organ at the site of interest, and allows repeated application. This
      capability is relevant in thermal therapy planning of tumor ablation using MR
      guided FUS systems.

PMID- 12412039
TI  - MR assessment of cerebral vascular response: a comparison of two methods.
AB  - PURPOSE: To compare the results and reproducibility of two MR-based methods of
      measuring the cerebrovascular response (CVR). MATERIALS AND METHODS: In eight
      volunteers, CVR was assessed with two MR-based methods upon a challenge with
      acetazolamide. CVR was assessed by measuring changes in total cerebral blood flow
      (TCBF) using phase contrast (PC) MRI, and by measuring perfusion MRI. To assess
      reproducibility the measurements were repeated after 1 week. RESULTS: The average
      CVR with the PC-MRI method was 46% (SD = 16%), and for perfusion MR the measured
      CVR was 44% (SD = 16%). The coefficient of variation (COV) for PC-MRI was 28%,
      while perfusion MR had a COV of 26%. The limits of agreement between the two
      methods were -49% and 45%, demonstrating a lack of agreement between the two
      methods in terms of CVR estimation. CONCLUSION: CVR estimates based on PC-MRI and
      perfusion MRI showed reproducibility but a lack of agreement in healthy
      volunteers. This lack of agreement can be attributed to the different aspects of
      the CVR reflected by these methods: TCBF reflects changes in CBF, whereas our
      perfusion MRI method reflects cerebral blood volume (CBV).

PMID- 12412042
TI  - Targeting gene expression in the preimplantation mouse embryo using morpholino
      antisense oligonucleotides.
AB  - Morpholino antisense oligonucleotides act by blocking translation of their target
      gene products and are effective tools for down-regulating gene expression. The
      current study was conducted to define treatment conditions for the use of
      morpholino oligonucleotides (MOs) in mammalian preimplantation embryos, and to
      employ MOs to target genes and study gene function in the early embryo. For the
      first time, ethoxylated polyethylenimine (EPEI), Lipofectin or Lysolecithin
      delivery agents were employed in combination with a fluorescent control MO and an
      alpha-catenin specific MO, to down-regulate gene expression during murine
      preimplantation development. Experiments applied to both two- and eight-cell
      stage murine preimplantation embryos contrasted the efficacy of MO concentrations
      of 1, 2, 5, 10, and 20 microM and treatment delivery times of 3, 6, 24, and 48
      hr. Continuous treatment of two-cell embryos with Lipofectin and 20 microM alpha
      catenin MO for 48 hr resulted in a significant (P < 0.05) reduction in
      development to the blastocyst stage and was accompanied by a marked reduction in
      alpha-catenin protein. These results indicate that morpholino antisense
      oligonucleotides are effective tools for down-regulating gene expression during
      mammalian preimplantation development.

PMID- 12412043
TI  - Myosin heavy chain expression in cranial, pectoral fin, and tail muscle regions
      of zebrafish embryos.
AB  - To investigate whether different myosin heavy chain (MHC) isoforms may constitute
      myofibrils in the trunk and tail musculature and if their respective expression
      may be regulated by spadetail (spt) and no tail (brachyury), we identified and
      characterized mRNA expression patterns of an embryonic- and tail muscle-specific
      MHC gene (named myhz2) during zebrafish development in wild type, spt, and ntl
      mutant embryos. The identified myhz2 MHC gene encodes a polypeptide containing
      1,935 amino acids. Deduced amino acid comparisons showed that myhz2 MHC shared
      92.6% sequence identity with that of carp fast skeletal MHC. Temporal and spatial
      myhz2 MHC mRNA expression patterns were analyzed by quantitative RT-PCR and whole
      mount in situ hybridization using primer pairs and probes designed from the 3'
      untranslated region (UTR). Temporally myhz2 MHC mRNA appears in pharyngula
      embryos and peaks in protruding-mouth larvae. The expression level decreased in 7
      day-old hatching larvae, and mRNA expression was not detectable in adult fish.
      Spatially in pharyngula embryos, mRNA was localized only in the tail somite
      region, while in long-pec embryos, transcripts were also expressed in the two
      cranial muscle elements of the adductor mandibulae and medial rectus, as well as
      in pectoral fin muscles and the tail muscle region. Myhz2 MHC mRNA was expressed
      in most cranial muscle elements, pectoral fin muscles, and the tail muscle region
      of 3-day-old hatching larvae. In contrast, no expression of myhz2 MHC mRNA could
      be observed in spt prim-15 mutant embryos. In spt long-pec mutant embryos,
      transcripts were expressed in two cranial muscle elements and the tail muscle
      region, but not in pectoral fin muscles, while only trace amounts of myhz2 MHC
      mRNA were expressed in the remaining tail muscle region of 38 hpf and long-pec
      ntl mutant embryos.

PMID- 12412044
TI  - PLAC1, a trophoblast-specific gene, is expressed throughout pregnancy in the
      human placenta and modulated by keratinocyte growth factor.
AB  - Plac1, a placenta-specific gene, is expressed exclusively by cells of
      trophoblastic lineage in the mouse, and maps to a region of the X chromosome
      known to be important in placental growth. These studies were undertaken to
      define the cellular location of the mRNA for the human orthologue, PLAC1, within
      the human placenta, and to examine its expression throughout gestation. By
      Northern analysis, PLAC1 mRNA was detected in term human placenta, migrating as a
      single 1.7 kb transcript, but in no other fetal or adult tissues tested.
      Expression was observed throughout gestation, whereas mouse Plac1 is
      significantly reduced after 12.5 dpc. Using an (35)S-labeled riboprobe, PLAC1
      expression was trophoblast-specific at all stages of gestation (8-41 weeks); no
      expression was seen in cells within the stromal compartment or decidua. Using
      BeWo choriocarcinoma cells as a trophoblast model, keratinocyte growth factor
      (KGF) stimulated steady-state PLAC1 mRNA expression approximately twofold by
      Northern analysis and quantitative real-time PCR. Stimulation was observed only
      after 24 hr of exposure, suggesting that the stimulatory effect of KGF is
      secondary to the promotion of trophoblast growth or differentiation. No change in
      mRNA levels resulted from exposure to insulin-like growth factor II (IGF-II).
      Trophoblast-specific expression throughout gestation and responsiveness to KGF
      are consistent with a fundamental role for PLAC1 at the maternal-fetal interface.

PMID- 12412045
TI  - Transgenic goats produced by DNA pronuclear microinjection of in vitro derived
      zygotes.
AB  - This study was undertaken to investigate various factors affecting the outcomes
      of in vitro fertilization (IVF) of oocytes retrieved by laparoscopic ovum pick-up
      (LOPU) technique from prepubertal and adult goats, as well as to evaluate the
      developmental competence of in vitro produced embryos. Oocyte-cumulus complexes
      recovered by LOPU from donors stimulated with gonadotrophins were matured in
      vitro. Fresh semen was used for IVF following various capacitation treatments. In
      vitro produced zygotes were either cultured to assess in vitro development or
      were transferred into recipients for full term development. The results indicated
      that successful IVF of the goat oocytes was affected by factors such as sperm
      capacitation treatment, oocyte quality, and abundance of cumulus cells on zona
      pellucida. Oocytes from both prepubertal and adult goats demonstrated similar
      full term developmental competence despite the fact that in vitro developmental
      rates were lower for prepubertal goats. The births of transgenic offspring
      demonstrated that the established LOPU-IVF technology combined with pronuclear
      microinjection can be successfully used to produce transgenic goats.

PMID- 12412046
TI  - Inhibition of luteinizing hormone receptor expression during the development of
      caprine corpora lutea by administration of gonadotropin-releasing hormone
      antagonist.
AB  - The present study was conducted to examine effects of a potent GnRH antagonist
      (GA), which suppresses release of luteinizing hormone (LH), on LH receptor
      expression during the development of the caprine corpus luteum (CL). Goats were
      divided into control and GA-treated groups. The goats were treated with saline or
      GA (50 microg/kg, s.c.) on days 0 (day of ovulation), 4 and 8 (control only), and
      CL collected on a subset of goats (n = 3 for each day) on days 0 (no saline), 4,
      8, or 14 (control only). Ribonuclease protection assay and [(125)I]-hCG binding
      assay were performed to quantitate mRNA and protein of the LH receptor in the CL,
      respectively. On day 4, CL weight, levels of LH receptor mRNA and protein in the
      GA-treated group were similar to those of the control group. By day 8, CL weight
      and levels of LH receptor mRNA and protein in the GA-treated group were reduced
      relative to those of the control group (P < 0.05). There was no difference of
      affinity of the LH receptor between both groups on day 8. These results suggest
      that the treatment with GA inhibits gene and protein expressions of the LH
      receptor during the development of CL in the goat, and thus, support an idea that
      endogenous LH participates in the increase of its own receptor.

PMID- 12412047
TI  - Quantification and distribution of equine oocyte cortical granules during meiotic
      maturation and after activation.
AB  - In vitro fertilization (IVF) is being routinely used in humans and several
      domestic species, however, limited success has been achieved in the horse.
      Although immature equine oocytes are capable of completing meiosis in vitro,
      subsequent fertilization, and embryonic development of those oocytes are
      questionable. The lack of development of these oocytes could be attributed to an
      impaired cytoplasmic maturation. In the horse, the study of oocyte cytoplasmic
      maturation and post-fertilization development has been hindered by the lack of
      progress in IVF. In mammalian oocytes, migration of cortical granules (CG) has
      been used as an important criterion to evaluate cytoplasmic maturation. The aim
      of this study was to describe and quantify the CG distribution of equine oocytes
      during in vitro meiotic maturation and to assess activation of oocytes with
      calcium ionophore based upon fluorescein isothiocyanate (FITC)-labeled Lens
      culinaris agglutinin (LCA) and laser confocal microscopy. The results of this
      study indicate that CG are distributed throughout the cytoplasm of oocytes at the
      germinal vesicle (GV) stage (immature). As maturation proceeds, a progressive
      centripetal migration of CG to the oocyte cortex occurs with the formation of a
      monolayer adjacent to the plasma membrane starting by the end of a 30 hr
      incubation period and increasing significantly after 36 hr. After activation,
      significant reduction in the number of CG was observed (P < 0.001) suggesting
      that oocytes cultured under the present conditions possess the ability to release
      CG in response to the elevation of intracellular free calcium.

PMID- 12412048
TI  - Motor apparatus in human spermatozoa that lack central pair microtubules.
AB  - Electron microscopic examination of the spermatozoa from a man suffering from
      asthenozoospermia (poor or low sperm motility) showed that approximately 92% of
      the sperm flagella lacked central pair microtubules but possessed dynein arms and
      radial spokes while a small percentage of the spermatozoa had complete flagella.
      The characteristics of the motor apparatus of the spermatozoa and the effects of
      caffeine on the sperm motility were examined, as were the reactivation of
      demembranated spermatozoa and the sliding of doublet microtubules. Almost all
      spermatozoa were immotile in a Tyrode solution while only a small percentage of
      spermatozoa showed slow forward movement or feeble flagellar vibration, whereas
      addition of caffeine to the sperm suspension induced forward swimming of
      approximately half of the spermatozoa. The reactivation of demembranated
      spermatozoa with MgATP(2-) could not succeed because of disintegration of the
      demembranated flagella. However, when the demembranated spermatozoa were exposed
      to MgATP(2-) and then treated with elastase, the microtubular doublets of
      approximately half the number of the flagella slid from the end or middle of the
      flagella. These results suggest that the motor apparatus in the sperm flagella
      that lack the central pair microtubules is functionally assembled and
      intrinsically capable of undergoing flagellar movement but not strong enough to
      beat normally.

PMID- 12412050
TI  - Use of atomic force microscopy for morphological and morphometric analyses of
      acrosome intact and acrosome-reacted human sperm.
AB  - The objective of this study was to use atomic force microscopy (AFM), with
      submicron resolution, for morphophologic and morphometric analyses of acrosome
      intact and acrosome-reacted human sperm heads. A mixed population of acrosome
      intact and reacted sperm was produced by treating capacitated sperm with A23187,
      which induced the acrosome reaction in approximately 50% of total sperm
      population. This A23187-treated sperm suspension was then plated onto a coverslip
      and acrosome reacted sperm were preidentified by their specific staining with
      rhodamine-conjugated Concanavalin A. The sperm coverslip was then air-dried and
      scanned by a Nanoscope IIIa atomic force microscope, using the contact mode. Top
      and side view images processed through the illuminate mode revealed three
      dimensional sperm head contour, with the highest point situated in the head
      posterior in both acrosome intact and acrosome reacted sperm. Maximum height,
      length, and width measured in 50 acrosome intact and 50 acrosome-reacted sperm
      were the same in both populations. However, head length at half maximum height
      was significantly decreased in acrosome reacted sperm (2.99 +/- 0.24 microm vs.
      3.56 +/- 0.32 microm of acrosome intact sperm), due to the sudden change of the
      height contour from the maximum peak to the anterior tip of acrosome-reacted
      sperm. Our results described here can therefore be used to differentiate acrosome
      intact and reacted sperm from each other. This would allow future studies on
      subcellular changes, related to the acrosome reaction, at the submicron
      resolution level under more physiological conditions, since AFM does not require
      fixing or staining of the samples.

PMID- 12412049
TI  - Microtubulin configuration and mitochondrial distribution after ultra-rapid
      cooling of bovine oocytes.
AB  - Considerable attention has been focused on the cryopreservation of mammalian
      oocytes, as a consequence of poor development of cryopreserved bovine oocytes in
      vitro, in order to enhance the application of genetic engineering. Experiments
      were carried out to evaluate the viability and ultra-structural changes of bovine
      oocytes cryopreserved by ultra rapid cooling methods. Oocytes that had been
      allowed to mature for 22 hr were exposed to a mixture of cryoprotectants (3.2 M
      ethylene glycol, 2.36 M dimethyl sulfoxide (DMSO), 0.6 M sucrose), and were
      cryopreserved by very rapid cooling either within glass capillaries or as
      droplets on copper electron microscope grids. After being warmed, the oocytes
      were cultured in in vitro maturation (IVM) medium for an additional 2 hr.
      Viability was assessed by determining the development rate after fertilization
      with frozen-thawed semen from which motile sperm had been recovered using a
      Percoll density gradient, and by immunochemical evaluation of microtubule and
      mitochondrial morphology. Cleavage and development rates were significantly (P <
      0.05) lower in oocytes cryopreserved by vitrification than in in vitro
      fertilization (IVF) control group, but did not differ in the open-pulled glass
      (OPG) or copper grid (CG) groups. In most oocytes cryopreserved by vitrification,
      the microtubules were partially or completely broken. Similarly mitochondria
      appeared to be abnormal compared to that of unfrozen oocytes. Oocytes cultured in
      IVM medium supplemented with both cytochalasin B (a protein synthesis inhibitor)
      and 2-mercaptoethanol (an antioxidant) showed less damage to microtubules, but
      not to mitochondria after cryopreservation. In conclusion, this study showed that
      bovine oocytes can be cryopreserved by vitrification within small droplets using
      CGs. While damage to microtubules and mitochondria may be involved in reduced
      viability, supplementation of IVM medium with cytochalasin B appears to enhance
      stabilization of microtubules during oocyte cryopreservation.

PMID- 12412051
TI  - Inhibitory effects of cAMP and protein kinase C on meiotic maturation and MAP
      kinase phosphorylation in porcine oocytes.
AB  - The regulation of MAP kinase phosphorylation by cAMP and protein kinase C (PKC)
      modulators during pig oocyte maturation was studied by Western immunoblotting. We
      showed that both forskolin and IBMX inhibited MAP kinase phosphorylation and
      meiosis resumption in a dose-dependent manner, and this inhibitory effect was
      overcome by the protein phosphatase inhibitor, okadaic acid. Pharmacological PKC
      activator phorbol myristate acetate or physiological PKC activator diC8 also
      delayed MAP kinase phosphorylation and meiosis resumption, and their effect was
      abrogated by PKC inhibitors, staurosporine, and calphostin C. The results suggest
      that meiotic resumption is inhibited by elevation of cAMP or delayed by
      activation of PKC probably via down-regulation of MAP kinase activation, which is
      mediated by protein phosphatase, during pig oocyte maturation.

PMID- 12412053
TI  - Characterization of secretory proteins from cultured cauda epididymal cells that
      significantly sustain bovine sperm motility in vitro.
AB  - Epididymis provides a safe environment in which stored-spermatozoa could survive
      for days before ejaculation. In vitro studies suggested that epididymal proteins
      seem to be implicated in sperm survival during coincubation with cultured
      epididymal cells. This study was basically designed to confirm if secretory
      proteins from bovine epididymal cell cultures provide sperm protection against
      rapid loss of sperm motility in vitro. Bovine spermatozoa were incubated in
      conditioned media (CM), which were prepared from cultured cauda epididymal cell
      (CEC). Motion parameters were recorded using a computer-assisted sperm analyzer.
      Sperm-free protein extracts from CM were fractionated by ultrafiltration through
      a 10-kDa cut off membrane. A significantly positive effect on sperm motility was
      observed when spermatozoa were incubated in CM (54 +/- 4%) and CM > 10 kDa (57 +/
      4%) compared to CM < 10-kDa fraction (30 +/- 3%) or fresh media (34 +/- 3%),
      after a 6-hr incubation period. This beneficial effect on sperm motility was
      abolished when the CM > 10-kDa fraction was heat-treated at 100 degrees C for 10
      min. The CM > 10 kDa fraction provides factors that remained active even though
      spermatozoa were washed twice after a 2-hr preincubation period. To identify
      potential beneficial factors, bovine spermatozoa were incubated with radiolabeled
      proteins obtained using (35)S-methionine in culture medium. SDS-PAGE analysis of
      proteins extracted from CM-preincubated spermatozoa revealed the presence of a 42
      kDa protein strongly associated to the sperm surface. This 42-kDa spot was
      trypsin-digested and identified by matrix-assisted laser desorption ionization
      time of flight (MALDI-TOF) as a protein homologue to a 35-kDa bovine estrogen
      sulfotransferase. This protein can play a role in epididymal biology and sperm
      function. Taken together, these results suggest that specific epididymal proteins
      can be implicated in the sperm protection in vitro, and can be characterized in
      our cell culture system.

PMID- 12412052
TI  - Identification of a novel GPI-anchored CRISP glycoprotein, MAK248, located on the
      posterior head and equatorial segment of cynomolgus macaque sperm.
AB  - To identify a sperm-surface component that is highly antigenic, we immunized
      female cynomolgus macaques with glycosylphosphatidylinositol (GPI)-anchored sperm
      surface proteins that were released following treatment with phosphatidylinositol
      specific phospholipase C (PI-PLC). Five different adjuvants were used in
      combination with the PI-PLC-released proteins, and three of these proteins (24,
      48, and 53 kDa) were shown to be potent antigens for immunization of female
      monkeys. The 53 kDa protein was found to be a surface coating protein and not a
      GPI-anchored protein. Polyclonal antibodies to the 24 kDa protein and the 48 kDa
      protein were produced in rabbits. The two antibodies recognized both proteins on
      Western blots. The same rabbit antibodies recognized 28, 18, and 10 kDa bands on
      a Western blot of chemically reduced PI-PLC-released proteins, suggesting that
      the 48 kDa protein is a dimer of the 24 kDa protein, which we refer to as MAK248.
      Rabbit polyclonal antibodies developed to reduced fragments of the 24 kDa protein
      showed that the 18 and 10 kDa bands are proteolytic peptide fragments of the 24
      kDa protein. Screening of tissues from male macaques showed that MAK248 is
      expressed only in the epididymis. Microsequencing of two proteolytic fragments of
      the 18 kDa component showed 100% amino acid homology to a 233 deduced amino acid
      sequence previously identified in human testes genome. Antibodies to MAK248
      recognized a 24 kDa protein released from human sperm exposed to PI-PLC.
      Antibodies to MAK248 recognized the equatorial segment and posterior head regions
      of capacitated cynomolgus macaque sperm. Structural analysis suggests that MAK248
      is a novel CRISP protein and a member of the CAP (CRISP, Ag 5, PR-1) family of
      proteins. Based on amino acid sequence homology, it is possible that MAK248
      functions as a protease inhibitor.

PMID- 12412054
TI  - Evolution of mRNA polyadenylation between oocyte maturation and first embryonic
      cleavage in cattle and its relation with developmental competence.
AB  - In this study we analyzed the pattern of polyadenylation changes that takes place
      between the resumption of meiosis and the first cleavage of bovine oocytes.
      Moreover, we investigated whether the delayed occurrence of the first cleavage
      division, which characterizes embryos of low developmental competence, is
      accompanied by an altered polyadenylation pattern of individual transcripts. We
      determined the polyadenylation status of a group of genes that characterize
      physiological processes, involved in early differentiation (Oct-4), compaction,
      and cavitation (beta-actin, plakophilin, connexin-32, connexin-43), energy
      metabolism (glucose transporter type 1, pyruvate dehydrogenase phosphatase), RNA
      processing (RNA poly(A) polymerase), and stress (heat shock protein 70). RNA was
      isolated from pools of 20 oocytes or embryos at the germinal vesicle (GV) stage,
      at the end of in vitro maturation, at the end of in vitro fertilization, and at
      the time of the first cleavage. Cleavage was assessed 27, 30, 36, 42 hr post
      insemination (hpi), and at the latter time the remaining uncleaved oocytes were
      retained as a group. Between oocyte isolation and first cleavage at 27 hpi (best
      quality embryos), the poly(A) tail of individual transcripts followed four
      patterns: no changes (beta-actin, PDP); gradual reduction (Cx-43, Oct-4, Plako);
      gradual elongation (Cx-32, TPA); reduction followed by elongation (PAP, HSP-70,
      Glut-1). If the interval between insemination and first cleavage was longer than
      27 hpi (progressively lower quality embryos) further changes of polyadenylation
      were observed, which differed for each gene considered. These data indicated that
      specific changes in polyadenylation contribute to the modulation of gene
      expression in bovine embryos at this stage of development. Defective
      developmental competence is accompanied by abnormal polyadenylation levels of
      specific maternal mRNAs with synchrony between polyadenylation and cleavage
      emerging as an apparently important factor.

PMID- 12412055
TI  - Cytochalasin-D retards sperm incorporation deep into the egg cytoplasm but not
      membrane fusion with the egg plasma membrane.
AB  - The fertilization process is impaired when spermatozoa are previously incubated
      with Cytochalasin-D (Cyt-D). Although this fact reveals the participation of
      polymerized actin in fertilization, the specific event obstructed by Cyt-D
      treatment has not been determined. To identify this event, we capacitated guinea
      pig spermatozoa in minimal capacitating medium with pyruvate and lactate (MCM-PL)
      with Cyt-D, to inseminate hamster zona pellucida (ZP)-free eggs. Cyt-D (70
      microM) decreased F-actin relative concentration in capacitated spermatozoa to a
      larger extent than in spermatozoa incubated under control conditions. Cyt-D also
      cancelled the F-actin increase normally observed in acrosome-reacted cells, and
      decreased the number of these cells with normal F-actin localization at the
      equatorial zone. Insemination of eggs with Cyt-D treated spermatozoa did not
      change early fertilization events such as the egg cortical reaction (CR),
      membranes fusion, and egg F-actin new localization, but clearly retarded, by 16
      hr, spermatozoa incorporation deep into the egg cytoplasm, and decondensation of
      egg metaphase II chromosomes. These results show that actin polymerization is
      necessary for spermatozoa incorporation deep into the egg cytoplasm, but not for
      plasma membrane fusion nor egg activation early steps.

PMID- 12412056
TI  - Chemical approaches untangling sequence-specific DNA binding by proteins.
AB  - Structure-based design of novel DNA-binding proteins provides an ultimate test of
      our understanding of protein-DNA interactions. A combination of synthetic,
      organic, biochemical and molecular biological approaches has been developed to
      study the principle of molecular recognition associated with the protein-DNA
      interactions. The strategies enabled a specific formation of noncovalent peptide
      dimers and determination of the preferential DNA-binding sequence of short
      peptides.

PMID- 12412057
TI  - Oligothiophene isothiocyanates as fluorescent markers.
AB  - Thiophene oligomers have been studied so far mainly for their semiconductor and
      charge-transport properties. However, these compounds are also highly fluorescent
      and soluble. Solubility and fluorescence frequencies and efficiencies can be
      tailored by means of appropriate functionalization of the aromatic backbone.
      Functionalization with the isothiocyanate group (-N=C=S) allows these molecules
      to form covalent bonds with NH2-containing biomolecules and give rise to
      optically and chemically very stable fluorescent bioconjugates. Examples of
      photostable conjugates formed with monoclonal antibodies are reported.

PMID- 12412059
TI  - Hydrogen-bonded networks through second-sphere coordination.
AB  - The reaction of 4, 7-phenanthroline (1) with aqueous transitionmetal complexes
      [Mn(H2O)6][NO3]2, [Co(H2O)6][NO3]2, [Ni(H2O)6[NO3]2, [Mn(H2O)6][ClO4]2, and
      [Co(H2O)6][ClO4]2 does not produce coordination complexes between these metal
      cations and the N-donor ligand as expected. Instead, supramolecular
      hydrogenbonded networks are formed between the nitrogen donor atoms of 4, 7
      phenanthroline and the OH groups of coordinated water molecules: M-O-H...N
      interactions. This motif of second-sphere coordination for 1 can be exploited as
      a tool for crystal engineering. As a demonstration of the generality of this new
      interaction as a supramolecular building block, five X-ray crystal structures are
      reported that utilise this hydrogen bonding scheme; [Co(H2O)4(NO3)2].(1)2 (2a),
      [Co(MeCN)2(H2O)4][ClO4]2.(1)2 (2b), [Ni(H2O)4(NO3)2].(1)2 (3a),
      [Mn(H2O)4(NO3)2].(1)2 (4a), and [Mn(H2O)6][ClO4]2.(1)(4).4H2O (4b). Each network
      involves complete saturation of the hydrogen-bond donor sets between the aqua
      complex and 1 using primarily M-O-H...N(1) and M-O-H...O(anion), interactions.
      Thermogravimteric analysis shows these materials to have stabililities similar to
      coordination polymers involving metal-ligand bonds; this demonstrates that second
      sphere hydrogen bonding has potential for the construction of polymeric metal
      containing materials.

PMID- 12412058
TI  - Separation of N2@C60 and N@C60.
AB  - We describe the HPLC separation and identification of N@C60 and N2@C60. These
      species were observed after eleven sequential HPLC separations. Their retention
      times are in the same range as those of the other noninteractive endohedral
      species of C60, such as noble gas endohedral C60. The separation factors of these
      endohedrals were evaluated by using a mixture of hexane/toluene as eluent. We
      note that this is the first evidence for the N2@C60 molecule existing in the form
      of endohedral C60 complex.

PMID- 12412060
TI  - Synthesis of 1-azaspiro[2.4]hepta-1,4,6-trienes and azaspiroconjugation studied
      by photoelectron spectroscopy.
AB  - 1-Azaspiro[2.4]hepta-1,4,6-trienes 3a-c have been prepared by photolysis or
      thermolysis of 6-azidofulvenes 5a-c, which were accessible by nucleophilic
      substitution reactions of the precursors 4a,b or by nucleophilic addition of
      hydrazoic acid to ethenylidene-cyclopentadiene (6c). The UV photoelectron
      spectrum of 2-methyl-1-azaspiro[2.4]hepta-1,4,6-triene (3c) has been recorded and
      analyzed by making use of density functional theory (DFT) B3LYP calculations.
      Substantial homoconjugative interactions have been determined. The lone-pair
      orbital n(N) of the 2H-azirine nitrogen atom interacts with the pi 1 orbital of
      the cyclopentadiene ring. The energies of these orbitals are lowered or increased
      by 0.95 or 0.91 eV with respect to the two parent compounds cyclopentadiene (7)
      and 3-methyl-2H-azirine (9), respectively. In addition, in compound 3c the pi
      (C=N) orbital of the three-membered ring interacts with a sigma orbital of the
      cyclopentadiene unit and is destabilized by 0.47 eV by this effect.

PMID- 12412062
TI  - Heterodinuclear transition-metal complexes with multiple metal-metal bonds.
AB  - Interactions between a pair of transition-metals can range from weak
      antiferromagnetic coupling to bonds of the highest multiplicity known in
      chemistry, for example, quadruple in isolatable compounds. Tremendous effort has
      been invested in studying homodinuclear transition-metal-metal bonds. In
      contrast, relatively little attention has been devoted to heterodinuclear
      analogues, as it is substantially more challenging to prepare and handle such
      entities. Yet, in this largely unexplored area of transition-metal chemistry,
      novel chemical interactions with unprecedented reactivities are likely to be
      found. Heterodinuclear analogues of diatomic transition-metal dimers being yet
      inaccessible, dinuclear complexes with Werner-type ligands provide examples of
      high-multiplicity bonds between different d elements in their least-perturbed
      form. Such compounds provide an opportunity to probe fundamental issues of
      chemical bonding between transition-metals, by revealing how and to what extent
      such bonds are affected by differences in the two metals. Complexes wherein
      electronically unsaturated heterodinuclear cores are stabilized by pi-acidic
      ligands (such as CO) hold the potential of new chemical reactions (including
      catalytic) that capitalize on the synergetic effect of two transition-metal
      centers.

PMID- 12412063
TI  - Modern separation techniques for the efficient workup in organic synthesis.
AB  - The shift of paradigm in combinatorial chemistry, from large compound libraries
      (of mixtures) on a small scale towards defined compound libraries where each
      compound is prepared in an individual well, has stimulated the search for
      alternative separation approaches. The key to a rapid and efficient synthesis is
      not only the parallel arrangement of reactions, but simple work-up procedures so
      as to circumvent time-consuming and laborious purification steps. During the
      initial development stages of combinatorial synthesis it was believed that
      rational synthesis of individual compounds could only be achieved by solid-phase
      strategies. However, there are a number of problems in solid-phase chemistry:
      most notably there is the need for a suitable linker unit, the limitation of the
      reaction conditions to certain solvents and reagents, and the heterogeneous
      reaction conditions. Further disadvantages are: the moderate loading capacities
      of the polymeric support and the limited stability of the solid support. In the
      last few years several new separation techniques have been developed. Depending
      on the chemical problem or the class of compounds to be prepared, one can choose
      from a whole array of different approaches. Most of these modern separation
      approaches rely on solution-phase chemistry, even though some of them use solid
      phase resins as tools (for example, as scavengers). Several of these separation
      techniques are based on liquid-liquid phase separation, including ionic liquids,
      fluorous phases, and supercritical solvents. Besides being benign with respect to
      their environmental aspects, they also show a number of advantages with respect
      to the work-up procedures of organic reactions as well as simplicity in the
      isolation of products. Another set of separation strategies involves polymeric
      supports (for example, as scavengers or for cyclative cleavage), either as solid
      phases or as soluble polymeric supports. In contrast to solid-phase resins,
      soluble polymeric supports allow reactions to be performed under homogeneous
      conditions, which can be an important factor in catalysis. At the same time, a
      whole set of techniques has been developed for the separation of these soluble
      polymeric supports from small target molecules. Finally, miscellaneous separation
      techniques, such as phase-switchable tags for precipitation by chemical
      modification or magnetic beads, can accelerate the separation of compounds in a
      parallel format.

PMID- 12412064
TI  - "Polyunsaturated" cyclophanes.

PMID- 12412065
TI  - Odd-electron bonds and biradicals in main group element chemistry.

PMID- 12412066
TI  - Remarkable cooperativity between a ZnII ion and guanidinium/ammonium groups in
      the hydrolysis of RNA.

PMID- 12412067
TI  - Fabrication of ultrafine conducting polymer and graphite nanoparticles.

PMID- 12412068
TI  - Novel capsules with high stability and controlled permeability by hierarchic
      templating.

PMID- 12412069
TI  - RuII complexes of "large-surface" ligands.

PMID- 12412070
TI  - Modular, well-behaved reversible polymers from DNA-based monomers.

PMID- 12412071
TI  - Molecular clips that undergo heterochiral aggregation and self-sorting.

PMID- 12412072
TI  - Novel liquid-crystalline phases with layerlike organization.

PMID- 12412073
TI  - A practical and highly active ruthenium-based catalyst that effects the cross
      metathesis of acrylonitrile.

PMID- 12412074
TI  - A highly efficient ruthenium catalyst for metathesis reactions.

PMID- 12412075
TI  - Nanoscopic Pt colloids in the "embryonic state".

PMID- 12412076
TI  - Stereoselective cyclopolymerization of 1,6-heptadiynes: access to alternating cis
      trans-1,2-(cyclopent-1-enylene)vinylenes by fine-tuning of molybdenum
      imidoalkylidenes.

PMID- 12412077
TI  - Ambiphilicity: a characteristic reactivity principle of pi-bound phosphorus
      heterocycles.

PMID- 12412078
TI  - Enantioselective stereoinversion in the kinetic resolution of rac-sec-alkyl
      sulfate esters by hydrolysis with an alkylsulfatase from Rhodococcus ruber DSM
      44541 furnishes homochiral products.

PMID- 12412079
TI  - A new synthesis route to enantiomerically pure jasmonoids.

PMID- 12412080
TI  - Palladium-catalyzed coupling of alkyl chlorides and grignard reagents.

PMID- 12412081
TI  - IBX-mediated oxidation of primary alcohols and aldehydes to form carboxylic
      acids.

PMID- 12412082
TI  - Cation control in functional helical programming: structures of a D,L-peptide ion
      channel.

PMID- 12412083
TI  - Global replacement of tryptophan with aminotryptophans generates non-invasive
      protein-based optical pH sensors.

PMID- 12412084
TI  - Heteropolymolybdates of AsIII, SbIII, BiIII, SeIV, and TeIV functionalized by
      amino acids.

PMID- 12412085
TI  - Preparation and characterization of a model bimetallic catalyst: Co-Pd
      nanoparticles supported on Al2O3.

PMID- 12412086
TI  - A route to 5-substituted dibenzofurans by anionic cycloaromatization of 2-(6
      substituted 3-hexen-1,5-diynyl)phenyl tert-butyldimethyl ethers and related
      molecules.

PMID- 12412088
TI  - Planar hypercoordinate carbons joined: wheel-shaped molecules with C-C axles.

PMID- 12412087
TI  - The HfCl4-mediated Diels-Alder reaction of furan.

PMID- 12412089
TI  - Rational synthesis of tetranuclear ruthenium polyhydride clusters and their mixed
      ligand analogues.

PMID- 12412090
TI  - Reactivity-based one-pot synthesis of a Lewis Y carbohydrate hapten: a colon
      rectal cancer antigen determinant.

PMID- 12412091
TI  - Concise and efficient total synthesis of Lycopodium alkaloid magellanine.

PMID- 12412093
TI  - Dynamic acylhydrazone metal ion complex libraries: a mixed-ligand approach to
      increased selectivity in extraction.

PMID- 12412092
TI  - Highly selective disaccharide recognition by a tricyclic octaamide cage.

PMID- 12412094
TI  - Total synthesis of leucascandrolide A.

PMID- 12412095
TI  - Control of H-C(sp3) bond cleavage stoichiometry: clean reversible alkyl ligand
      exchange with alkane in [LPt(Alk)(H)2]+ (L=[2.1.1]-(2,6)-pyridinophane).

PMID- 12412097
TI  - Framework topology of ERS-10 zeolite.

PMID- 12412096
TI  - Directing otherwise incompatible reactions in a single solution by using DNA
      templated organic synthesis.

PMID- 12412098
TI  - Direct electrophilic insertion into a twelve-vertex metallacarborane.

PMID- 12412100
TI  - Fluorous biphasic esterification directed towards ultimate atom efficiency.

PMID- 12412099
TI  - Conformation-dependent ionization energies of L-phenylalanine.

PMID- 12412101
TI  - Simple mixed tricyclohexylphosphane-triarylphosphite complexes as extremely high
      activity catalysts for the Suzuki coupling of aryl chlorides.

PMID- 12412102
TI  - Synthesis of cis,cis,cis,cis-[5.5.5.5]-1-azafenestrane.

PMID- 12412103
TI  - Efficient synthesis of a tricyclic BCD analogue of ouabain: Lewis acid catalyzed
      Diels-Alder reactions of sterically hindered systems.

PMID- 12412104
TI  - Towards main-chain-polyoxometalate-containing hybrid polymers: a highly efficient
      approach to bifunctionalized organoimido derivatives of hexamolybdates.

PMID- 12412105
TI  - A three-phase emulsion/solid-heterogenization method for transport and catalysis.

PMID- 12412106
TI  - Facile construction of anionic silver(I) aggregates with embedded acetylide and
      cyanide ions.

PMID- 12412107
TI  - Cobalt-catalyzed coupling reaction of alkyl halides with allylic grignard
      reagents.

PMID- 12412108
TI  - Distal Cu ion protects synthetic heme/Cu analogues of cytochrome oxidase against
      inhibition by CO and cyanide.

PMID- 12412113
TI  - Components for integrated poly(dimethylsiloxane) microfluidic systems.
AB  - This review describes the design and fabrication of microfluidic systems in
      poly(dimethylsiloxane) (PDMS). PDMS is a soft polymer with attractive physical
      and chemical properties: elasticity, optical transparency, flexible surface
      chemistry, low permeability to water, and low electrical conductivity. Soft
      lithography makes fabrication of microfluidic systems in PDMS particularly easy.
      Integration of components, and interfacing of devices with the user, is also
      convenient and simpler in PDMS than in systems made in hard materials.
      Fabrication of both single and multilayer microfluidic systems is straightforward
      in PDMS. Several components are described in detail: a passive chaotic mixer,
      pneumatically actuated switches and valves, a magnetic filter, functional
      membranes, and optical components.

PMID- 12412114
TI  - A world-to-chip socket for microfluidic prototype development.
AB  - We report a prototype for a standard connector between a microfluidic chip and
      the macroworld. This prototype is the first to demonstrate a fully functioning
      socket for a microchip to access the outside world by means of fluids, data, and
      energy supply, as well as providing process visibility. It has 20 channels for
      the input and output of liquids or gases, as well as compressed air or vacuum
      lines for pneumatic power lines. It also contains 42 pins for electrical signals
      and power. All these connections were designed in a planar configuration with
      linear orthogonal arrays. The vertical space was opened for optical measurement
      and evaluation. The die (29.1 mm x 27.5 mm x 0.9 mm) can be easily mounted and
      dismounted from the socket. No adhesives or solders are used at any contact
      points. The pressure limit for the connection of working fluids was 0.2 MPa and
      the current limit for the electrical connections was 1 A. This socket supports
      both serial and parallel processing applications. It exhibits great potential for
      developing microfluidic systems efficiently.

PMID- 12412115
TI  - A hybrid microdevice for electrophoresis and electrochromatography using UV
      detection.
AB  - We have designed a new class of microdevices composed of a supporting plastic
      (polyvinyl chloride, PVC) plate integrated with a groove for a piece of fused
      silica capillary (the separation channel), a slit for on-tube detection, an
      "islet" for the application of sample, electrode vessels and platinum electrodes.
      The design permits electrophoretic, electrochromatographic and chromatographic
      separations with on-tube UV detection. The efficient heat dissipation allows
      relatively high field strengths. This article is the first one dealing with
      microdevices where polymer solutions are replaced by homogeneous gels. A new type
      of gels synthesized from acrylamide and 2-hydroxy-3-allyloxy-propyl-beta
      cyclodextrin (allyl-beta-CD) as a cross-linker was employed for electrophoresis
      and electrochromatography. 2-Acrylamido-2-methylpropanesulfonic acid was added to
      the monomer solution to create a high electroendosmotic flow in
      electrochromatographic runs. These gels have excellent electrochromatographic and
      electrophoretic properties for low-molecular-weight compounds and DNA, as shown
      previously, namely high resolution combined with high stability. The unique cross
      linker can be used for specific interaction with the alkyl and phenyl groups. The
      tripeptide glutathione (gamma-L-glutamyl-L-cysteinyl-glycine) and its benzyl
      conjugates were selected as model compounds to study the resolving power of the
      gel because they are difficult to separate by free zone electrophoresis. The
      limit of detection (LOD) for S-benzyl-glutathione was determined (ca. 7 microM).
      Run-by-run reproducibility was high (the separation factor of glutathione in the
      gel was 0.3 with 2.5% coefficient of variation, CV). Neutral compounds (acetone,
      acetophenone, propiophenone and butyrophenone) were separated
      electrochromatographically in the gel. The influence of organic solvent
      (acetonitrile) on the electroendosmotic mobility was similar to that in reversed
      phase separations, although the separation mechanism is different. ATP, ADP and
      AMP were separated in less than 10 s by free-zone electrophoresis.

PMID- 12412116
TI  - Towards a microchip-based chromatographic platform. Part 1: Evaluation of sol-gel
      phases for capillary electrochromatography.
AB  - Silica monolithic columns suitable for implementation on microchips have been
      evaluated by ion-exchange capillary electrochromatography. Two different silica
      monoliths were created from the alkyl silane, tetramethyl orthosilicate (TMOS),
      by introducing a water-soluble organic polymer, poly(ethylene oxide) (PEO), with
      varying molecular weights into the prehydrolyzed sol. Silica monoliths created
      using 10 kDa PEO were found to have a much more closed gel structure with a
      smaller percentage of pores in the microm size range than gels created using 100
      kDa PEO. Additionally, the size of the mesopores in the 100 kDa PEO monolith was
      5 nm, while those in the 10 kDa PEO gel were only 3 nm. This resulted in a strong
      dependence of the electroosmotic flow (EOF) on the ionic strength of the
      background electrolyte, with substantial pore flow through the nm size pores
      observed in the 10 kDa PEO gel. The chromatographic performance of the monolithic
      columns was evaluated by ion-exchange electrochromatography, with ion-exchange
      sites introduced via dynamic coating with the cationic polymer,
      poly(diallyldimethylammonium chloride) (PDDAC). Separating a mixture of inorganic
      anions, the 10 kDa PEO monolithic columns showed a higher effective capacity than
      the 100 kDa PEO column.

PMID- 12412117
TI  - Continuous separation of biomolecules by the laterally asymmetric diffusion array
      with out-of-plane sample injection.
AB  - The laterally asymmetric diffusion array, a biomolecule sorting device, was used
      to continuously separate a mixture of T2 and T7 coliphage DNA molecules into its
      constituents. A two-dimensional array of obstacles (in the presence of an average
      flow v) can be used to rectify the Brownian motion of particles (in this case DNA
      molecules) so that they diffuse preferentially in one direction, and
      perpendicular to the direction of the applied field (in this case an electric
      field). This type of device had not yet been used for actual fractionation of
      biomolecules, due to difficulties in injection of the sample. Here we show that
      with a new injection strategy a well-defined, narrow and continuous stream of
      molecules can be injected into the separation channel, thus enabling this
      separation technique to be used in a working device. We expect this type of
      device could now be employed for separation of a variety of different
      biomolecules, ranging from long dsDNA to small proteins.

PMID- 12412118
TI  - Microfabrication of a tapered channel for isoelectric focusing with thermally
      generated pH gradient.
AB  - A simple microfabrication technique for the preparation of a tapered microchannel
      for thermally generated pH gradient isoelectric focusing (IEF) has been
      demonstrated. The tapered channel was cut into a plastic sheet (thickness was 120
      microm), and the channel was closed by sandwiching the plastic sheet between two
      glass microscope slides. The length of the microchannel was 5 cm. The width of
      the separation channel was 0.4 mm at the narrow end and 4 mm at the wide end. The
      channel was coated with polyacrylamide to prevent electroosmotic flow (EOF)
      during focusing. Two electrolyte vials were mounted on top of each end of the
      channel with the wide end of the channel connected to the cathodic vial and the
      narrow to the anodic vial. The feasibility of the thermally generated pH gradient
      in a tapered channel was demonstrated. Important parameters that determined the
      feasibility of using a thermally generated pH gradient in a tapered channel were
      analyzed. Parameters to be optimized were control of EOF and hydrodynamic flow,
      selection of power supply mode and prevention of local overheating and air bubble
      formation. Tris-HCl buffer, which has a high pK(a) dependence with temperature,
      was used both to dissolve proteins and as the electrolyte. The thermally
      generated pH gradient separation of proteins was tested by focusing dog, cat and
      human hemoglobins with a whole column detection capillary IEF (CIEF) system.

PMID- 12412119
TI  - Fabrication of a glass-implemented microcapillary electrophoresis device with
      integrated contactless conductivity detection.
AB  - Glass microdevices for capillary electrophoresis (CE) gained a lot of interest in
      the development of micrototal analysis systems (microTAS). The fabrication of a
      microTAS requires integration of sampling, chemical separation and detection
      systems into a microdevice. The integration of a detection system into a
      microchannel, however, is hampered by the lack of suitable microfabrication
      technology. Here, a microfabrication method for integration of insulated
      microelectrodes inside a leakage-free microchannel in glass is presented. A
      combination of newly developed technological approaches, such as low-temperature
      glass-to-glass anodic bonding, channel etching, fabrication of buried metal
      interconnects, and deposition of thin plasma-enhanced chemical vapour deposition
      (PECVD) silicon carbide layers, enables the fabrication of a CE microdevice with
      an integrated contactless conductivity detector. The fabrication method of this
      CE microdevice with integrated contactless conductivity detector is described in
      detail. Standard CE separations of three inorganic cations in concentrations down
      to 5 microM show the viability of the new microCE system.

PMID- 12412120
TI  - Optimization of the high-frequency contactless conductivity detector for
      capillary electrophoresis.
AB  - Two constructions of the high-frequency contactless conductivity detector that
      are fitted to the specific demands of capillary zone electrophoresis are
      described. The axial arrangement of the electrodes of the conductivity cell with
      two cylindrical electrodes placed around the outer wall of the capillary column
      is used. We propose an equivalent electrical model of the axial contactless
      conductivity cell, which explains the features of its behavior including
      overshooting phenomena. We give the computer numerical solution of the model
      enabling simulation of real experimental runs. The role of many parameters can be
      evaluated in this way, such as the dimension of the separation channel, dimension
      of the electrodes, length of the gap between electrodes, influence of the
      shielding, etc. The conception of model allows its use for the optimization of
      the construction of the conductivity cell, either in the cylindrical format or in
      the microchip format. The ability of the high-frequency contactless conductivity
      detector is demonstrated on separation of inorganic ions.

PMID- 12412121
TI  - Performance of an in-plane detection cell with integrated waveguides for UV/Vis
      absorbance measurements on microfluidic separation devices.
AB  - A microfluidic device with integrated waveguides and a long path length detection
      cell for UV/Vis absorbance detection is presented. The 750 microm U-cell
      detection geometry was evaluated in terms of its optical performance as well as
      its influence on efficiency for electrophoretic separations in the microdevice.
      Stray light was found to have a strong effect on both, the sensitivity of the
      detection and the available linear range. The long path length U-cell showed a 9
      times higher sensitivity when compared to a conventional capillary
      electrophoresis (CE) system with a 75 microm inner diameter (ID) capillary, and a
      22 times higher sensitivity than with a 50 microm ID capillary. The linear range
      was comparable to that achieved in a 75 microm ID capillary and more than twice
      as large as in a 50 microm ID capillary. The use of the 750 microm U-cell did not
      contribute significantly to band broadening; however, a clear quantification was
      made difficult by the convolution of several other band broadening sources.

PMID- 12412122
TI  - An integrated solid-phase extraction system for sub-picomolar detection.
AB  - A microchip structure etched on a glass substrate for packed column solid-phase
      extraction (SPE) and capillary electrochromatography (CEC) is described. A 200
      microm long, octadecylsilane (ODS) packed column was secured using two different
      approaches: solvent lock or polymer entrapment. The former method was utilized
      for SPE while the latter approach was applied for CEC. In SPE, the ODS packed
      chamber gave a detection limit of 70 fM for a nonpolar BODIPY (493/503) dye when
      concentrated for 3 min at an electroosmotic flow rate of 4.14 nL/min, compared to
      30 pM for this detector without the SPE step. SPE beds showed reproducible,
      linear calibration curves (R(2) = 0.9989) between 1 and 100 pM BODIPY at fixed
      preconcentration times. Breakthrough curves for the 330 pL (ODS-packed) bed
      indicated a capacity for BODIPY dye of 8.1 x 10(-14) mmol, or 0.25 mmol dye per
      liter of bed. The ODS-chamber could also be used to analyze dilute amino acid and
      peptide solutions. In the CEC format, two neutral dyes (BODIPY and acridine
      orange) were baseline-separated in an isocratic run with a theoretical plate
      count of 84 (420 000 plates/m) and a reduced plate height of about 1. A labeled
      peptide was also analyzed by CEC, using the acidic eluent (84% acetonitrile, and
      26% aqueous trifluoroacetic acid (0.05%)) preferred for peptide separations on
      ODS-coated silica particles.

PMID- 12412123
TI  - Increase of separation resolution through field enhancement in microchips.
AB  - An enhanced ability to separate charged species from neutral compounds in a
      microfluidic chip is demonstrated using a chip design with low-resistance
      electrode channels operating with a multiport pressure/voltage controller. A
      factor of 2.7 improvement in resolution was obtained from chips made using
      identical mask designs but different etch depth protocols. Greater separation
      power allows one to cover a wider dynamic range for compounds with different
      electrophoretic mobilities.

PMID- 12412124
TI  - Automation for continuous analysis on microchip electrophoresis using flow
      through sampling.
AB  - Automation of electrophoretic microchips for sequential analysis of different
      samples is demonstrated. This system used an autosampler, which was on-line
      connected to the microchip and the whole process including sample loading and
      injection, analysis and data acquisition as well as washing were all automated.
      Rhodamin B at different concentrations was first loaded into a hydrodynamic flow
      stream by an autosampler, delivered to the microchip, and then sequentially
      injected into the electrophoretic microchannel for analysis and detection.
      Automation was achieved by running two independent programs, one for sample
      loading by an autosampler and the other one for electrophoretic injection by
      voltage switching, on the same computer. Using this sampling chip, each loaded
      volume (0.2-1 microL) can be injected for dozens of electrophoretic analyses (1
      10 nL for each injection). The variances caused by the external connections,
      which did not affect the electrophoretic analysis but would cause band broadening
      of the loaded sample in the hydrodynamic flow stream, were theoretically deduced.
      Results indicate that the dead volume (approximately 300 nL) due to the
      connection fitting on the chip could lead to dilution of the loaded sample by a
      factor of one when 0.2 microL of sample was loaded. Such a design allows
      sequential analysis of a series of samples while the running buffer is
      continuously pumped into the connection capillary as well as microchannels for
      washing between two loaded samples to minimize cross contamination without human
      intervention. Using this sampling chip, the required sample amount and handling
      time can be greatly reduced compared to the manual method.

PMID- 12412125
TI  - A dynamically modified microfluidic poly(dimethylsiloxane) chip with
      electrochemical detection for biological analysis.
AB  - Separation and direct detection of amino acids, glucose and peptide in a 3.1 cm
      separation channel made of poly(dimethylsiloxane) (PDMS) with end-column
      amperometric detection at a copper microdisk electrode was developed. This system
      is the integration of a normal sized working electrode with electrochemical
      detection on a PDMS microfabricated device. The PDMS channels dynamically
      modified by 2-morpholinoethanesulfonic acid (MES) show less adsorption and more
      enhanced efficiency than that of unmodified ones when applied to separations of
      these biological molecules. The migration time is less than 100 s and the
      reproducibility of migration time is satisfactory with relative standard
      deviation (RSD) of 2.8% in 19 successive injections. The limits of detection of
      arginine (Arg), glucose, and methionine-glycine (Met-Gly) are estimated to be
      2.0, 8.5, and 64.0 microM at S/N = 3, approximately 0.5-16.0 fmol, respectively.
      Variances influencing the separation efficiency and amperometric response,
      including injection, separation voltage, detection potential, or concentration of
      buffer and additive, are assessed and optimized.

PMID- 12412126
TI  - Poly(vinyl alcohol)-coated microfluidic devices for high-performance microchip
      electrophoresis.
AB  - The channels of microfluidic glass chips have been coated with poly(vinyl
      alcohol) (PVA). Applied for microchip electrophoresis, the coated devices
      exhibited a suppressed electroosmotic flow and improved separation performance.
      The superior performance of PVA-coated channels could be demonstrated by
      electrophoretic separations of labeled amines and by video microscopy. While a
      distorted sample zone is injected using uncoated channels the application of PVA
      coated channels results in an improved shape of the sample zone with less band
      broadening. Applying PVA-coated microchips for the separation of amines labeled
      with Alexa Fluor 350 even sub-second separations, utilizing a separation length
      of only 650 microm, could be obtained, while this was not possible using uncoated
      devices. By using PVA-coated devices rather than an uncoated chip a threefold
      increase in separation efficiencies could be observed. As the electroosmotic flow
      (EOF) was suppressed, the anionic compounds were detected at the anode whereas
      the dominant EOF in uncoated devices resulted in an effective mobility to the
      cathode. Besides improved separation performance another important feature of the
      PVA-coated channels was the suppressed adsorption of fluorescent compounds in
      repetitive runs which results in an improved robustness and detection
      sensitivity. Applying PVA-coated channels, rinsing or etching steps could be
      omitted while this was necessary for a reliable operation of uncoated devices.

PMID- 12412127
TI  - Electroosmotic flow in capillary channels filled with nonconstant viscosity
      electrolytes: exact solution of the Navier-Stokes equation.
AB  - The partial differential equation describing unsteady velocity profile of
      electroosmotic flow (EOF) in a cylindrical capillary filled with a nonconstant
      viscosity electrolyte was derived. Analytical solution, based on the general
      Navier-Stokes equation, was found for constant viscosity electrolytes using the
      separation of variables (Fourier method). For the case of a nonconstant viscosity
      electrolyte, the steady-state velocity profile was calculated assuming that the
      viscosity decreases exponentially in the direction from the wall to the capillary
      center. Since the respective equations with nonconstant viscosity term are not
      solvable in general, the method of continuous binding conditions was used to
      solve this problem. In this method, an arbitrary viscosity profile can be
      modeled. The theoretical conclusions show that the relaxation times at which an
      EOF approaches the steady state are too short to have an impact on a separation
      process in any real systems. A viscous layer at the wall affects EOF
      significantly, if it is thicker than the Debye length of the electric double
      layer. The presented description of the EOF dynamics is applicable to any
      microfluidic systems.

PMID- 12412128
TI  - Integration of a membrane-based desalting step in a microfabricated disposable
      polymer injector for mass spectrometric protein analysis.
AB  - A simple desalting procedure for the coupling of a polymer microchip injector to
      mass spectrometry is proposed. The overall process is based on the adsorption of
      proteins on a poly(vinylidene difluoride) (PVDF) membrane, which are then
      directly eluted in the spraying solution. This microchip-based approach has been
      successfully applied to small drugs, peptides and proteins originally diluted in
      phosphate-buffered saline (PBS). Moreover, when eluting the retained proteins in
      small volumes, a preconcentration is obtained. The combination of single-use,
      mass-produceable, low-sample-consumption, easy-to-automate, miniaturized polymer
      injectors with easy-to-handle solution-exchange membranes makes this system
      particularly amenable to screening applications.

PMID- 12412129
TI  - Integration of solid-phase extraction membranes for sample multiplexing:
      application to rapid protein identification from gel-isolated protein extracts.
AB  - The present report describes the design and application of a dual sprayer system
      for high-throughput proteome analysis. This system comprises parallel solid-phase
      extraction cartridges used for preconcentration and desalting of proteolytic
      digests prior to nanoelectrospray mass spectrometry analyses. Tryptic peptides
      from in-gel digest of protein bands/spots are first adsorbed on styrene divinyl
      benzene membrane and subsequently eluted with a short plug of organic buffer
      prior to infusion to the mass spectrometer at a flow rate of typically 500
      nL/min. Tryptic peptide eluting from the membrane are analyzed by the mass
      spectrometer by moving in turn each sprayer in front of the sampling orifice.
      Sequential injection, preconcentration and analyses of tryptic digests are
      typically achieved with a throughput of up to 3.5 min/sample and a detection
      limit of approximately 8-80 fmol per injection. Replicate injections of peptide
      mixtures indicated that reproducibility of peak areas ranged from relative
      standard deviations (RSD) of 1.1% to 4.5%. The application of this device is
      demonstrated for digests of gel-isolated proteins obtained from sodium dodecyl
      sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) separation of rat liver
      plasma membrane and from two-dimensional gel electrophoresis of total cell lysate
      extracts from human prostatic cancer cell.

PMID- 12412130
TI  - A miniaturized multichamber solution isoelectric focusing device for separation
      of protein digests.
AB  - A miniaturized multichamber device was constructed for solution isoelectric
      focusing (IEF) separation of complex peptide mixtures. The system, based on
      immobilized pH gels, consisted of 96 minichambers ( approximately 75 nuL each)
      arranged in eight rows. Neighboring chambers in a given row were separated by
      short glass tubes (4 mm inner diameter, 3 mm long), within which Immobiline gels
      of specific pH values were polymerized. During focusing, the device was
      sandwiched between two supporting blocks incorporating the reservoirs for anolyte
      and catholyte. In principle, multiple samples could be simultaneously
      fractionated, each separated into 12 fractions of various pI ranges. A variety of
      standard peptide mixtures and tryptic digests of proteins were separated by IEF
      using this device, and the fractions were characterized by mass spectrometry. For
      a codigested nine-protein mixture, both the total number of peptides identified
      and the average sequence coverage were similar to the results of ion-exchange
      chromatography (IEC), according to matrix assisted laser/desorption/ionization-
      time of flight (MALDI-TOF) data. The IEF separation provided concentrated and
      desalted fractions, suitable for an additional separation liquid chromatography,
      capillary electrophoresis (LC, CE) or mass spectrometry (MS) detection without
      additional sample cleanup. High loading capacity was achieved for the
      miniaturized multichamber IEF device. Importantly, a linear correlation was found
      between the experimentally determined and calculated pI values of peptides.

PMID- 12412131
TI  - DNA separation by microchip electrophoresis using low-viscosity
      hydroxypropylmethylcellulose-50 solutions enhanced by polyhydroxy compounds.
AB  - Low-viscosity polymer solutions have potential for double-stranded (ds) DNA
      separations in micrototal analysis systems (micro-TAS). In this paper, we report
      dilute, low-viscosity hydroxypropylmethylcellulose-50 (HPMC-50, 11.5 kDa)
      solutions containing polyhydroxy additives as separation media. Predominant
      operational variables, such as applied electric field strength, fluorescent
      intercalator (YOPro-1) concentration, polymer concentration, and additive
      concentration, are thoroughly investigated. Fast (within 170 s) and excellent
      separation of DNA restriction fragments ranging in size from 72 to 1353 base
      pairs (bp) is achieved in a 30 mm length channel of polymethylmethacrylate (PMMA)
      microchips at an electric field strength of 300 V/cm, by introducing 8% mannitol,
      8% glucose or 10% glycerol additives into a 2% HPMC-50/1 x Tris-borate-EDTA (TBE)
      solution. The low-viscosity (40 cP) matrix formulation provides both coating of
      the microchannels and separation of DNA in one step. The performance in the
      solution surpasses that in highly concentrated HPMC-50 solution. In addition,
      separation using 1xTris-EDTA buffer in the 2% HPMC-50 matrix containing
      polyhydroxy additives also exhibits a notably increased performance. This is
      presumably due to formation of hydrogen-bonding interactions of polyhydroxy
      additives with HPMC-50 matrix and DNA so as to increase the coupling interactions
      between matrix and DNA molecules during electrophoresis. The result reflects that
      boric acid is not a prerequisite in polyhydroxy-enhanced HPMC-50 solution for
      separation.

PMID- 12412132
TI  - Low-density lipoprotein analysis in microchip capillary electrophoresis systems.
AB  - Due to the mounting evidence for altered lipoprotein and cholesterol-lipoprotein
      content in several disease states, there has been an increasing interest in
      analytical methods for lipoprotein profiling for diagnosis. The separation of low
      and high-density lipoproteins (LDL and HDL, respectively) has been recently
      demonstrated using a microchip capillary electrophoresis (CE) system [1]. In
      contrast to this previous study, the present report demonstrates that LDL
      analysis can be performed in an uncoated glass microchannel. Moreover, by adding
      sodium dodecyl sulfate (SDS) to the sample at a concentration well below the
      critical micellar concentration prior to injection, the LDL peak undergoes a
      focusing effect and exhibits an apparent efficiency of 2.2 x 10(7) plates/m.
      Laser light scattering experiments demonstrate that the low concentration of SDS
      used does not significantly alter lipoprotein particle size distribution within
      the time course that the analysis is performed. It is thus hypothesized that SDS
      nondisruptively coats LDL particles. The peak sharpening effect, observed only
      when SDS is added solely to the sample, is probably due to a mobility gradient
      created between the sample and the running buffer. The chip-based method
      demonstrated here has the potential for rapid analysis and sensitive detection of
      different LDL forms of clinical relevance.

PMID- 12412133
TI  - Determination of monoclonal antibody production in cell culture using novel
      microfluidic and traditional assays.
AB  - This study compares microfluidic technology (Protein 200 LabChip Assay kit,
      Agilent 2100 Bioanalyzer, referred to here as Protein 200) to the traditional
      approach for protein analysis, one-dimensional sodium dodecyl sulfate
      polyacrylamide gel electrophoresis (SDS-PAGE), for the sizing and quantification
      of immunoglobulin G (IgG) in hybridoma cell cultures. Internal references differ
      between each method: purified IgG was used alone in SDS-PAGE while myosin (the
      upper marker) was added to each sample in Protein 200. The IgG used here were
      produced in cultures propagated in either a serum-free or a serum-containing
      medium. With serum-containing samples, there was a significant difference in the
      IgG concentrations (p < 0.05) between SDS-PAGE and Protein 200. The concentration
      determined by SDS-PAGE was significantly higher (> 30%) than by Protein 200 or by
      high-pressure liquid chromatography (HPLC) because the large amounts of serum
      albumin in the samples affect the accuracy of SDS-PAGE. Protein 200 can determine
      size similarly to SDS-PAGE in serum-free samples (standard error of the mean,
      SEM, < 1%, 95% confidence < +/-1%), unlike in serum-containing samples. The
      Protein 200 assay was more effective than the traditional one-dimensional SDS
      PAGE in determining concentration and size of IgG in cell culture samples and it
      provided a miniaturized and convenient platform for rapid analysis.

PMID- 12412134
TI  - Determination of bromate in drinking water by zone electrophoresis
      isotachophoresis on a column-coupling chip with conductivity detection.
AB  - The use of capillary zone electrophoresis (CZE) on-line coupled with
      isotachophoresis (ITP) sample pretreatment (ITP-CZE) on a
      poly(methylmethacrylate) chip, provided with two separation channels in the
      column-coupling (CC) arrangement and on-column conductivity detection sensors, to
      the determination of bromate in drinking water was investigated. Hydrodynamic and
      electroosmotic flows of the solution in the separation compartment of the chip
      were suppressed and electrophoresis was a dominant transport process in the ITP
      CZE separations. A high sample load capacity, linked with the use of ITP in this
      combination, made possible loading of the samples by a 9.2 microL sample
      injection channel of the chip. In addition, bromate was concentrated by a factor
      of 10(3) or more in the ITP stage of the separation and, therefore, its transfer
      to the CZE stage characterized negligible injection dispersion. This, along with
      a favorable electric conductivity of the carrier electrolyte solution,
      contributed to a 20 nmol/L (2.5 ppb) limit of detection for bromate in the CZE
      stage. Sample cleanup, integrated into the ITP stage, effectively complemented
      such a detection sensitivity and bromate could be quantified in drinking water
      matrices when its concentration was 80 nmol/L (10 ppb) or slightly less while the
      concentrations of anionic macroconstituent (chloride, sulfate, nitrate) in the
      loaded sample corresponding to a 2 mmol/L (70 ppm) concentration of chloride were
      still tolerable. The samples containing macroconstituents at higher
      concentrations required appropriate dilutions and, consequently, bromate in these
      samples could be directly determined only at proportionally higher
      concentrations.

PMID- 12412135
TI  - Miniaturized capillary isoelectric focusing in plastic microfluidic devices.
AB  - We report the demonstration of miniaturized capillary isoelectric focusing (CIEF)
      in plastic microfluidic devices. Conventional CIEF technique was adapted to the
      microfluidic devices to separate proteins and to detect protein-protein
      interactions. Both acidic and basic proteins with isoelectric points (pI) ranging
      from 5.4 to 11.0 were rapidly focused, mobilized, and detected in a 1.2 cm long
      channel (50 microm deep x 120 microm wide) with a total analysis time of 150 s.
      In a device with a focusing distance of 4.7 cm, the separation efficiency for a
      basic protein, lysozyme, was achieved as high as 1.5 x 10(5) plates,
      corresponding to 3.2 million plates per meter. We also experimentally confirmed
      that IEF resolution is essentially independent of focusing length when the
      applied voltage is kept the same and within a range that it does not cause Joule
      heating. Further, we demonstrated the use of miniaturized CIEF to study the
      interactions between two pairs of proteins, immunoglobulin G (IgG) with protein G
      and anti-six histidine (anti-6xHis) with 6xHis-tagged green fluorescent protein
      (GFP). Using this approach, protein-protein interactions can be detected for as
      little as 50 fmol of protein. We believe miniaturized CIEF is useful for studying
      protein-protein interactions when there is a difference in pI between a protein
      protein complex and its constitutent proteins.

PMID- 12412137
TI  - Expression of synapsin III in nerve terminals and neurogenic regions of the adult
      brain.
AB  - We have examined the distribution of synapsin III in the adult mouse brain.
      Expression of synapsin III was observed in puncta throughout the brain, but
      demonstrated greater regional variation than that of synapsins I or II. This
      punctate staining is typical for synaptic vesicle proteins located at nerve
      terminals. These findings are also consistent with the well-established role for
      synapsins in regulating neurotransmitter release. However, unexpectedly, synapsin
      III was also highly expressed in the cell body and processes of immature neurons
      in neurogenic regions of the adult brain, such as the hippocampal dentate gyrus,
      rostral migratory stream, and olfactory bulb. Many synapsin III-positive neurons
      also reacted with an antibody directed toward polysialylated-neuronal cell
      adhesion molecule, a marker of immature, migrating neurons. These results suggest
      that synapsin III may also play a role in adult neurogenesis.

PMID- 12412138
TI  - Estrogen receptor-alpha distribution in the human hypothalamus in relation to sex
      and endocrine status.
AB  - The present study reports the first systematic rostrocaudal distribution of
      estrogen receptor-alpha immunoreactivity (ERalpha-ir) in the human hypothalamus
      and its adjacent areas in young adults. Postmortem material taken from 10
      subjects (five male and five female), between 20 and 39 years of age, was
      investigated. In addition, three age-matched subjects with abnormal levels of
      estrogens were studied: a castrated, estrogen-treated 50-year-old male-to-female
      transsexual (T1), a 31-year-old man with an estrogen-producing tumor (S2), and an
      ovariectomized 46-year-old woman (S8). A strong sex difference, with more nuclear
      ERalpha-ir in women, was observed rostrally in the diagonal band of Broca and
      caudally in the medial mamillary nucleus. Less robust sex differences were
      observed in other brain areas, with more intense nuclear ERalpha-ir in men, e.g.,
      in the sexually dimorphic nucleus of the medial preoptic area, paraventricular
      nucleus, and lateral hypothalamic area, whereas women had more nuclear ERalpha-ir
      in the suprachiasmatic nucleus and ventromedial nucleus. No nuclear sex
      differences in ERalpha were found, e.g., in the central part of the bed nucleus
      of the stria terminalis. In addition to nuclear staining, ERalpha-ir appeared to
      be sex-dependently present in the cytoplasm of neurons and was observed in
      astrocytes, plexus choroideus, and other non-neuronal cells. ERalpha-ir in T1,
      S2, and S8 suggested that most of the observed sex differences in ERalpha-ir are
      "activational" (e.g., ventromedial nucleus/medial mamillary nucleus) rather than
      "organizational." Species similarities and differences in ERalpha-ir distribution
      and possible functional implications are discussed.

PMID- 12412139
TI  - Projections of the claustrum to the primary motor, premotor, and prefrontal
      cortices in the macaque monkey.
AB  - The claustrum is interconnected with the frontal lobe, including the motor
      cortex, prefrontal cortex, and cingulate cortex. The goal of the present study
      was to assess whether the claustral projections to distinct areas within the
      frontal cortex arise from separate regions within the claustrum. Multiple
      injections of tracers were performed in 15 macaque monkeys, aimed toward primary
      motor area (M1), pre-supplementary motor area (pre-SMA), SMA-proper, rostral (PMd
      r) and caudal (PMd-c) parts of the dorsal premotor cortex (PM), rostral (PMv-r)
      and caudal (PMv-c) parts of the ventral PM, and superior and inferior parts of
      area 46. The distribution of retrogradely labeled neurons showed no clear
      segregation along the rostrocaudal axis of the claustrum; they were usually
      located along the entire anteroposterior extent of the claustrum. For all motor
      cortical areas, there was a general trend of the labeled neurons to occupy the
      dorsal and intermediate parts of the claustrum along the dorsoventral axis. The
      same territories were labeled after injection in area 46, but in addition
      numerous labeled neurons were found in the most ventral part of the claustrum. At
      higher resolution, however, there was clear evidence that the territories
      projecting to pre-SMA and SMA-proper formed separate, interdigitating, clusters
      along the dorsoventral axis. A comparable local segregation was observed for the
      two subdivisions of area 46, whereas there was more local overlap among the
      subareas of PM. The projections from the claustrum to the multiple subareas of
      the motor cortex and to area 46 arise from largely overlapping territories, with,
      however, some degree of local segregation.

PMID- 12412140
TI  - Expression of nitric oxide synthase and nitric oxide-sensitive guanylate cyclase
      in the crustacean cardiac ganglion.
AB  - The cardiac ganglion is a simple central pattern-generating network that controls
      the rhythmic contractions of the crustacean heart. Enzyme assays and Western
      blots show that whole heart homogenates from the crab Cancer productus contain
      high levels of nitric oxide synthase (NOS), an enzyme that catalyzes the
      conversion of arginine to citrulline with concomitant production of the
      transmitter nitric oxide (NO). Crab heart NOS is calcium-dependent and has an
      apparent molecular weight of 110 kDa. In the cardiac ganglion, antibodies to NOS
      and citrulline indicate the presence of a NOS-like protein and NOS enzymatic
      activity in the four small pacemaker neurons and the five large motor neurons of
      the cardiac network. In addition, all cardiac neurons label positively with an
      antibody to cyclic guanosine monophosphate (cGMP). The NO donor sodium
      nitroprusside (SNP, 10 mM) stimulates additional cGMP production in the isolated
      ganglion. This increase is blocked by [(1)H](1,2,4)oxadiazole(4,3-a)quinoxalin-1
      one (ODQ, 50 microM), an inhibitor of the NO-sensitive soluble guanylate cyclase
      (sGC). Taken together, our data indicate that NO- and cGMP-mediated signaling
      pathways are enriched in the cardiac system relative to other crab tissues and
      that the cardiac network may be a target for extrinsic and intrinsic
      neuromodulation via NO produced from the heart musculature and individual cardiac
      neurons, respectively. The crustacean cardiac ganglion is therefore a promising
      system for studying cellular and synaptic mechanisms of nitrergic neuromodulation
      in a simple pattern-generating network.

PMID- 12412141
TI  - Horizontal cell density and mosaic regularity in pigmented and albino mouse
      retina.
AB  - The present study has examined the density and mosaic regularity of the
      population of horizontal cells in the pigmented and albino mouse retina. Retinal
      wholemounts were immunostained for calbindin, and labeled cells within sampled
      fields were analyzed to determine horizontal cell soma size and density. The X-Y
      positional coordinates of each cell were determined, from which the geometrical
      properties of the mosaic were examined using nearest neighbor and Voronoi domain
      analyses, and regularity indices were derived from those measures.
      Autocorrelation and density recovery profile analyses were also conducted to
      identify the presence of exclusion zones within the population of horizontal
      cells. For each sampled field, random simulations of matched density, constrained
      by the physical size of the horizontal cells, were generated and analyzed in
      parallel. Neither retinal area, nor horizontal cell soma size, nor density
      differed between the pigmented and albino retinas. Mosaic regularity in pigmented
      and albino retinas did not differ, but each differed significantly from random
      simulations of identical density. Horizontal cells in the mouse retina exhibit
      exclusion zones extending beyond the physical size of the soma, but these were
      identical in size in the pigmented and albino retina. Such exclusion zones are
      suggested to reflect homotypic interactions between horizontal cells during early
      development that mediate cellular repulsion and tangential movement. The lack of
      any discernable effect brought about by the albino mutation, despite numerous
      developmental abnormalities associated with the retinal neuroepithelium in albino
      mice, is consistent with other results showing that homotypic interactions are
      sufficient for the genesis of the global patterning characteristic of mature
      retinal mosaics.

PMID- 12412142
TI  - Associations between the morphology and physiology of ventral-horn neurons in the
      adult turtle.
AB  - This study compared some morphologic and physiological properties of adult turtle
      spinal motoneurons (MNs) vs. interneurons (INs). Reconstructions were made of 20
      biocytin-stained cells, which had been previously studied physiologically in 2-mm
      thick slices of lumbosacral spinal cord. The intracellularly measured
      physiological properties included resting potential, input resistance (R(N)),
      threshold (rheobase, I(Rh)), and slope of the stimulus current (I) -spike
      frequency (f) relation. The seven morphologic properties that were quantified for
      each cell included three indices of somal size (diameter, area, volume), and four
      of dendritic size: the number of first- and last-order branches, rostrocaudal
      extent, and sigma individual lengths. Significant differences were shown between
      all seven morphologic parameters for MNs vs. INs. Despite the small sample size,
      significant differences were also shown for five of seven parameters for high
      threshold vs. low-threshold MNs, and three of seven for low-threshold MNs vs.
      INs. These latter three parameters were the number of terminal dendritic
      branches, their rostrocaudal extent, and the sigma dendritic lengths. Linear
      associations for the MN + IN and the MN samples were stronger between the four
      dendritic parameters than between soma-dendritic ones. Exponential associations
      between morphologic and physiological properties were mostly significant (28 of
      30), and their strength was in the order I(Rh) < R(N) < f/I slope for the MN +IN
      sample and I(Rh) < R(N) = f/I slope for the MN sample. There is discussion of the
      relevance of the above findings to the provisional classification of turtle
      ventral-horn neurons on the basis of electrophysiology alone.

PMID- 12412143
TI  - Neurochemical characterization of receptor-expressing cell populations by in vivo
      agonist-induced internalization: insights from the somatostatin sst2A receptor.
AB  - Characterization of both neurochemical phenotype of G protein-coupled receptor
      (GPCR)-expressing cells and receptor compartmentalization is a prerequisite for
      the elucidation of receptor functions in the central nervous system. However, it
      is often prevented by the diffuse and homogeneous distribution of receptor
      immunoreactivity. This is particularly true for the somatostatin (SRIF) sst2A
      receptor, which is largely distributed in the mammalian brain. By using this
      receptor as a model, we investigated whether receptor internalization, a
      biochemical property shared by numerous GPCRs, would reveal sst2A-expressing cell
      populations in the rat dorsolateral septum (LSD), a region in which SRIF might
      play an important modulatory role. Thirty minutes to 1 hour after
      intracerebroventricular injection of the sst2A receptor agonist octreotide,
      numerous sst2A-immunoreactive neurons and processes became apparent due to
      intracytoplasmic accumulation of intensely stained granules. Double
      immunolabeling experiments with synaptophysin and MAP2 provided evidence that
      internalized sst2A receptors are predominantly localized in the somatodendritic
      compartment. Revealing sst2A receptor-expressing cell bodies permitted to analyze
      their neurotransmitter content. Quantitative analysis demonstrated an extensive
      overlap (approximately 85%) between SRIF- and sst2A-expressing neuronal
      populations. Additionally, numerous SRIF-immunoreactive axon-like terminals were
      found in close apposition with sst2A-positive cell bodies and dendrites. Taken
      together, these data suggest that the sst2A receptor is predominantly expressed
      in LSD neurons as a postsynaptic autoreceptor, thus providing novel neuroanatomic
      clues to elucidate SRIF neurotransmission in this region. More generally, in vivo
      agonist-induced internalization appears as a rapid and powerful tool for the
      neurochemical characterization of GPCR-expressing cell populations in the
      mammalian brain.

PMID- 12412145
TI  - Bent but not broken: an introduction to the issue on chronic illness.
AB  - What is the difference between sackcloth and ashes and chronic illness? You can
      always take a shower and change shirts.

PMID- 12412144
TI  - Cystitis-induced upregulation of tyrosine kinase (TrkA, TrkB) receptor expression
      and phosphorylation in rat micturition pathways.
AB  - This study examined tyrosine kinase receptor (Trk) expression and phosphorylation
      in lumbosacral dorsal root ganglia (DRG) after acute (8 or 48 hours) or chronic
      (10 days) cyclophosphamide (CYP)-induced cystitis. Increases in the number of
      TrkA-immunoreactive (IR) cell profiles were detected in the L1 and L6 DRG (four
      fold; P < or = 0.01) and the S1 DRG (1.5-fold; P < or = 0.05) but not in the L2,
      L4, and L5 DRG with CYP-induced cystitis of acute and chronic duration compared
      with control rats. The number of TrkB-IR cell profiles increased in the L1 and L2
      DRG (L1: 2.6-fold; L2: 1.4-fold; P < or = 0.05) and in the L6 and S1 DRG (L6: 2.2
      fold; S1: 1.3-fold; P < or = 0.05) only after acute CYP treatment (8 hours).
      After CYP treatment, the percentage of bladder afferent cell profiles expressing
      TrkA-IR (approximately 50%; P < or = 0.05) increased in L1 and L6 DRG. The
      percentage of bladder afferent cell profiles expressing TrkB-IR (approximately
      45%; P < or = 0.05) in L1, L2, L6, and S1 DRG also increased compared with
      control cell profiles. The increase in TrkA-IR in bladder afferent cells occurred
      8 hours after CYP treatment and was maintained in L1 DRG with chronic (10 days)
      CYP-induced cystitis. However, the increase in bladder afferent cells expressing
      TrkB-IR only occurred at the most acute time point examined (8 hours). TrkA-IR
      and TrkB-IR cell profiles also demonstrated phosphorylated Trk-IR with acute
      and/or chronic CYP-induced cystitis. These results demonstrated that CYP-induced
      cystitis increases the expression and phosphorylation of Trk receptors in
      lumbosacral DRG. Expression of neurotrophic factors in the inflamed urinary
      bladder may contribute to this increased expression, and neurotrophic factor and
      Trk interactions may play unique roles in decreased urinary tract plasticity with
      CYP-induced cystitis.

PMID- 12412146
TI  - Ambiguous loss from chronic physical illness: clinical interventions with
      individuals, couples, and families.
AB  - The theory of ambiguous loss is applied to chronic illness in individuals,
      couples, and families. Lack of clarity about prognosis, daily physical condition,
      and fluctuating capabilities create relationship confusion, preoccupation with
      the illness, or avoidance of the ill individual. Immobilization, depression, and
      relationship collapse may occur in response to features of chronic illness over
      which there is no control. A case study illustrates helpful therapeutic
      interventions for couples and families with chronically ill members.

PMID- 12412147
TI  - Mind's response to the body's betrayal: Gestalt/Existential therapy for clients
      with chronic or life-threatening illnesses.
AB  - In the literature on chronic or life-threatening illness, there is an overriding
      emphasis on clients' psychological coping styles and how they relate to
      psychological functioning. By contrast, in our approach, we look at the
      subjective mind/body experiences that clients have of their illness and how their
      lives are impacted by their illness. As psychotherapists, we address their
      existential distress, pain, body experience, thoughts, and feelings, as well as
      their efforts to cope or find meaning in their illness. We summarize
      Gestalt/Existential therapy for chronic illness, illustrate the approach with
      three case-vignettes, and stress the importance of attending to each client's
      unique responses to illness.

PMID- 12412148
TI  - Chronic illness as a family process: a social-developmental approach to promoting
      resilience.
AB  - This paper describes a social-developmental approach to interventions in chronic
      illness using naturally occurring processes of change during family life-cycle
      transitions to promote more positive developmental outcomes. Clinical
      interventions can help build resilience by creating a therapeutic collaboration
      designed to help patients improve their use of existing and new resources in
      multiple systems. They can then better meet demands of the illness as it impacts
      on shared development. A case example of a 13-year-old daughter with complex,
      chronic health problems and developmental disabilities illustrates clinical
      interventions designed to promote family resilience during the entry into
      adolescence and a transition in schooling. This approach involves focusing on the
      family's own definition of the current problem and relevant history, constructing
      a multidimensional, coherent story of the illness and its impact that recognizes
      stressors yet highlights strengths, and normalizing their strategies for
      stability under circumstances of developmental stress. These interventions with
      mother, daughter, and family helped improve health efficacy, communication toward
      mutual understanding and shared problem solving, and better use of existing and
      new resources to enhance current and future developmental adaptation.

PMID- 12412150
TI  - Beyond a sense of safety: a psychologist's tale of serious chronic illness.
AB  - Based on a narrative account, this paper highlights and reviews the experiences
      of the author, a psychologist, experiencing a chronic illness. Areas covered
      include coping with doctors and medical personnel, adjusting to illness,
      complying, actively coping, and even, at times, resisting unwarranted medical
      procedures. Experiences such as loss of trust, a sense of isolation, re-working
      relationships, and generative reaching-out are also covered. Some positive
      consequences of chronic illness for personal growth are suggested. Suggestions
      for conducting psychotherapy with clients who are dealing with serious chronic
      illness are made.

PMID- 12412149
TI  - Chronic pain: psychological approaches for the front-line clinician.
AB  - Many of the techniques and skills the average front-line practitioner possesses
      (such as intake, psychological testing, cognitive behavior therapy, and
      relaxation therapy) can be readily and effectively applied to a chronic-pain
      population. More specialized techniques for pain reduction, such as biofeedback
      training, can be easily learned by the generalist clinician with a minimum of
      additional training. In this article, four general steps to assess and reduce
      chronic pain are reviewed. Through careful use of the available research
      literature, and by consulting with a colleague who has expertise in chronic pain,
      most psychologists can straightforwardly begin to help individuals suffering from
      chronic pain.

PMID- 12412151
TI  - Pushing through solid rock: words of wisdom for clinicians from four patients
      with life-threatening conditions.
AB  - Four subjects living with profoundly debilitating and life-threatening illnesses
      reflect on how psychotherapy has contributed to their ability to cope and
      survive. With frankness and eloquence they address issues related to cancer,
      heart disease, fibromyalgia, and AIDS.

PMID- 12412152
TI  - Caregiving at the end of life.
AB  - Meeting the demands of chronic illness and disease states is challenging, at
      best. Too often, the chronicity of the illness hastens death. The physical,
      psychological, and sociological changes that accompany the death of an individual
      require attention and forethought if the life transition is to be made with
      elegance and grace. This article addresses the caregiving demands for the
      professional and familial/social support surrounding the chronically ill
      individual at the end of life. Focus is placed on the preparation of advance
      directives-legal documents that set clear boundaries for honoring the wishes of
      the patient.

PMID- 12412153
TI  - Compassion fatigue: psychotherapists' chronic lack of self care.
AB  - Psychotherapists who work with the chronic illness tend to disregard their own
      self-care needs when focusing on the needs of clients. The article discusses the
      concept of compassion fatigue, a form of caregiver burnout among psychotherapists
      and contrasts it with simple burnout and countertransference. It includes a multi
      factor model of compassion fatigue that emphasizes the costs of caring, empathy,
      and emotional investment in helping the suffering. The model suggests that
      psychotherapists that limiting compassion stress, dealing with traumatic
      memories, and more effectively managing case loads are effective ways of avoiding
      compassion fatigue. The model also suggests that, to limit compassion stress,
      psychotherapists with chronic illness need to development methods for both
      enhancing satisfaction and learning to separate from the work emotionally and
      physically in order to feel renewed. A case study illustrates how to help someone
      with compassion fatigue.

PMID- 12412154
TI  - Inside every chronic patient is an acute patient wondering what happened.
AB  - This In Session describes how chronic illness erodes connections, eludes
      definition, and reduces one's ability to manage daily life. The contributors
      compassionately and competently provide an array of perspectives, pragmatic
      techniques, and caveats. This concluding article seeks to integrate the articles
      in this issue and to deepen the clinician's ability to meet the needs of a
      chronically ill individual requesting psychotherapy. Particular emphasis is given
      to three models of psychotherapy with chronically ill individuals, care giving at
      the end of life, and compassion fatigue found in professionals working with this
      population. Multiple case examples are provided to illustrate psychotherapy and
      psychosocial intervention strategies.

PMID- 12412155
TI  - How to compare results after surgery or radiation for localized prostate
      carcinoma.

PMID- 12412156
TI  - Phase II trial combining paclitaxel with 24-hour infusion cisplatin for
      chemotherapy-naive patients with locally advanced or metastatic breast carcinoma.
AB  - BACKGROUND: Both paclitaxel and cisplatin are active as second-line chemotherapy
      for patients with breast carcinoma. A synergistic cytotoxicity of these two drugs
      has been demonstrated in vitro. This study sought to determine the efficacy of
      combining these two drugs in the treatment of chemotherapy-naive patients with
      breast carcinoma. METHODS: The inclusion criteria for the study were 1) women
      with histologically proven breast carcinoma; 2) locally advanced disease, as
      defined by American Joint Committee on Cancer (AJCC) Stage T4 (locally advanced
      breast carcinoma [LABC]) or clinically proven metastases (metastatic breast
      carcinoma [MBC]); and 3) no prior cytotoxic chemotherapy. The regimen consisted
      of paclitaxel 175 mg/m(2) intravenously by 3-hour infusion immediately followed
      by cisplatin 50 mg/m(2) intravenously by 24-hour infusion on Day 1 and repeated
      every 3 weeks. After a maximal response to chemotherapy was achieved, patients
      with LABC underwent resection of their primary tumor if the procedure was not
      contraindicated. RESULTS: From July, 1999 to January, 2001, 46 patients were
      enrolled into this study (28 patients with LABC and 18 patients with MBC). Their
      median age was 49.5 years (range, 29.8-65.5 years). A total of 205 cycles of
      chemotherapy were given. All patients were evaluable for toxicity, and 45
      patients were evaluable for response. There were 3 complete responses (CRs) and
      24 partial responses (PRs), for an overall response rate of 58.7% (95% confidence
      interval, 44.5-72.9%). Grade 4 hypersensitivity (asthma) to paclitaxel occurred
      in one patient. Grade 3-4 nausea and emesis and Grade 3-4 myelosuppression
      occurred in six patients and four patients, respectively. Of the 28 patients with
      LABC, 2 patients achieved a CR, and 14 patients achieved a PR. Twenty-seven
      patients underwent mastectomy patients after chemotherapy. A pathologic CR was
      documented in one patient. Postoperatively, 23 patients with LABC received
      adjuvant chemotherapy, and 18 patients with LABC received adjuvant radiotherapy.
      During a median follow-up of 14.6 months, 5 of 28 patients with LABC developed
      recurrent disease, and 2 patients died of progressive disease, whereas 3 of 18
      patients with MBC died of progressive disease. CONCLUSIONS: The combination of
      paclitaxel by 3-hour infusion and cisplatin by 24-hour infusion appears to be an
      active and well-tolerated regimen for chemotherapy-naive patients with LABC or
      MBC.

PMID- 12412157
TI  - Factors influencing mortality among young women with second primary breast
      carcinoma.
AB  - BACKGROUND: Tumor characteristics are strong predictors of survival among women
      with breast carcinoma, yet the variability in prognosis among women presenting
      with similar stages suggests other factors may also play an important role. We
      examine the prognostic significance of etiologic risk factors for breast
      carcinoma to determine whether factors that influence the development of breast
      carcinoma also affect the course of the disease among a prospective cohort of
      young women with bilateral breast carcinoma. METHODS: The 369 U.S. women included
      in this study were from the Cancer and Steroid Hormone Study who were diagnosed
      with an invasive first primary breast carcinoma between 1980 and 1982 and a
      second primary breast carcinoma before 1999. Cox proportional hazards models were
      used to evaluate factors known and suspected to be associated with breast
      carcinoma and with survival, based on reporting at the time of the first primary.
      RESULTS: One hundred sixty women died during the 16-18-year follow-up period. The
      adjusted 1, 5, 10, and 15-year survival rates following diagnosis of second
      primary breast carcinoma were 94%, 70%, 55%, and 49%, respectively. Survival
      rates werepoorest among the youngest women, those diagnosed with a second primary
      within 5 years of their first, poor African American women, women with either
      primary diagnosed at a later stage, those with less than 12 years of school,
      single women, and those with major weight gain between age 18 and adulthood.
      CONCLUSIONS: This study provided little evidence that important etiologic factors
      for breast carcinoma predict mortality following diagnosis of a second primary
      breast carcinoma.

PMID- 12412158
TI  - Classifying local disease recurrences after breast conservation therapy based on
      location and histology: new primary tumors have more favorable outcomes than true
      local disease recurrences.
AB  - BACKGROUND: To distinguish true local recurrences (TR) from new primary tumors
      (NP) and to assess whether this distinction has prognostic value in patients who
      develop ipsilateral breast tumor recurrences (IBTR) after breast-conserving
      surgery and radiotherapy. METHODS: Between 1970 and 1994, 1339 patients underwent
      breast-conserving surgery at The University of Texas M. D. Anderson Cancer Center
      for ductal carcinoma in situ or invasive carcinoma. Of these patients, 139
      (10.4%) had an IBTR as the first site of failure. For the 126 patients with
      clinical data available for retrospective review, we classified the IBTR as a TR
      if it was located within 3 cm of the primary tumor bed and was of the same
      histologic subtype. All other IBTRs were designated NP. RESULTS: Of the 126
      patients, 48 (38%) patients were classified as NP and 78 (62%) as TR. Mean time
      to disease recurrence was 7.3 years for NP versus 5.6 years for TR (P = 0.0669).
      The patients with NP had improved 10-year rates of overall survival (NP 77% vs.
      TR 46%, P = 0.0002), cause-specific survival (NP 83% vs. TR 49%, P = 0.0001), and
      distant disease-free survival (NP 77% vs. TR 26%, P < 0.0001). Patients with NP
      more often developed contralateral breast carcinoma (10-year rate: NP 29% vs. TR
      8%, P = 0.0043), but were less likely to develop a second local recurrence after
      salvage treatment of the first IBTR (NP 2% vs. TR 18%, P = 0.008). CONCLUSIONS:
      Patients with NP had significantly better survival rates than those with TR, but
      were more likely to develop contralateral breast carcinoma. Distinguishing new
      breast carcinomas from local disease recurrences may have importance in
      therapeutic decisions and chemoprevention strategies. This is because patients
      with new carcinomas had significantly lower rates of metastasis than those with
      local disease recurrence, but were more likely to develop contralateral breast
      carcinomas.

PMID- 12412159
TI  - HER-2/neu status and tumor morphology of invasive breast carcinomas in Ashkenazi
      women with known BRCA1 mutation status in the Ontario Familial Breast Cancer
      Registry.
AB  - BACKGROUND: The prevalence of BRCA1 germline mutations is greater in the
      Ashkenazi Jewish population than in the general North American population. The
      Ontario Familial Breast Cancer Registry collects clinical and family history data
      in familial breast carcinoma cases, and unselected Ashkenazi breast carcinomas,
      and acts as a tumor tissue repository. METHODS: Using this resource, we examined
      the tumor morphology, hormone receptor status, and HER-2/neu protein
      overexpression in Canadian Ashkenazi breast carcinoma patients whose germline
      BRCA1 mutation status is known. RESULTS: Thirty-eight tumors from 32 BRCA1
      carriers and 354 tumors from 334 noncarriers were analyzed. The tumors in BRCA1
      mutation carriers were more likely to be high grade (P < 0.0001) and estrogen
      receptor negative (P < 0.004). There was an increased frequency of typical
      medullary carcinomas in mutation carriers when all tumors were analyzed. However,
      this difference did not remain statistically significant when only the first
      tumor diagnosed in each patient was included in the analysis. There was no
      difference in HER-2/neu protein overexpression between the two groups overall (P
      = 0.07). However, when the analysis was restricted to Grade III tumors, there
      were significantly fewer HER-2/neu-positive tumors in the mutation carriers
      versus noncarriers (3.1% vs. 21.5%, P = 0.012). No significant differences were
      found in the incidence of lymph node status, progesterone receptor status,
      lymphatic vessel invasion, degree of lymphocytic infiltration, or in the presence
      of ductal carcinoma in situ associated with the invasive tumors. CONCLUSIONS:
      Increasing awareness of the morphologic and immunophenotypic features more
      commonly found in BRCA1-associated breast carcinomas may lead to a wider use of
      these characteristics in genetic screening programs and provide further clues to
      their pathogenesis.

PMID- 12412160
TI  - Long-term outcome of patients with insular carcinoma of the thyroid: the insular
      histotype is an independent predictor of poor prognosis.
AB  - BACKGROUND: Insular thyroid carcinoma was described originally as a tumor with
      aggressive behavior. However, whether a predominant insular component is an
      independent factor for poor prognosis is unclear. METHODS: The authors compared
      the clinical behavior of tumors in three groups of patients with thyroid
      carcinoma--13 patients with insular thyroid carcinoma, 18 patients with
      follicular thyroid carcinoma, and 26 patients with papillary thyroid carcinoma-
      who were selected based on similar tumor size and similar age. Disease free
      survival and disease specific deaths were assessed in the three groups with a
      Kaplan-Meier analysis and were compared using the log-rank test. Cox regression
      analysis was used to evaluate the influence of histotype and other prognostic
      factors on the occurrence of distant metastases and disease specific death.
      RESULTS: Patient follow-up ranged from 5.2 months to 190.0 months. At last follow
      up, only 1 of 13 patients (7.7%) with insular carcinoma, compared with 8 of 18
      patients (44.4%) with follicular carcinoma and 12 of 26 patients (46.1%) with
      papillary carcinoma, were disease free. The disease specific death rate was 61.5%
      among patients in the insular carcinoma group compared with 16.7% and 15.4% among
      patients in the follicular carcinoma group (P = 0.006) and the papillary
      carcinoma group (P = 0.025), respectively. At multivariate analysis, the insular
      histotype was the only variable that was related independently to disease
      specific death (hazard ratio = 4.27; P = 0.005). Distant metastases occurred in
      84.6% of patients in the insular carcinoma group compared with 50% and 19.2% of
      patients in the follicular carcinoma group (P = 0.039) and the papillary
      carcinoma group (P = 0.0003), respectively. All metastases from patients with
      insular carcinomas (n = 11 patients) showed radioiodine uptake, but a clinical
      benefit from this treatment was observed only in 1 patient. CONCLUSIONS: Patients
      with insular thyroid carcinoma have a poorer outcome compared with patients of
      similar age who have differentiated types of thyroid carcinoma with tumors of a
      similar size. Because radioiodine rarely is effective in the treatment of
      patients with metastatic insular thyroid carcinoma, novel and possible multimodal
      therapies should be explored for the treatment of patients with these aggressive
      tumors.

PMID- 12412161
TI  - Overexpression of the insulin-like growth factor I receptor in human colon
      carcinomas.
AB  - BACKGROUND: High concentrations of insulin-like growth factor (IGF)-I and IGF-II
      have been demonstrated in human colonic adenocarcinomas and exert mitogenic
      effects through paracrine/autocrine interactions with the IGF-I receptor (IGF
      IR). However, definitive studies of IGF-IR expression in these tissues have not
      been performed. METHODS: To study changes in the levels of the IGF-IR in
      colorectal carcinoma, we analyzed the expression of IGF-IR in 40 paired samples
      of normal and carcinomatous colonic tissue by quantitative reverse-transcription
      polymerase chain reaction (RT-PCR), immunohistochemistry, and ligand binding.
      RESULTS: As measured by RT-PCR, the IGF-IR mRNA ratio in paired tumor and
      adjacent normal mucosa was higher than 2.0 in 32 of 40 (80%) samples. The overall
      mean IGF-IR mRNA level was five-fold higher in tumor versus adjacent normal
      mucosa (P < 0.0001). Overexpression of IGF-IR in colon carcinomas was confirmed
      at the protein level by immunohistochemistry and receptor-binding studies. Colon
      carcinoma cells exhibited a positive staining for IGF-IR in 91% of all tumors (30
      of 33) whereas the adjacent normal colonic epithelial cells showed only a very
      faint or no significant IGF-IR immunoreactivity. Radioligand assays and Scatchard
      analysis in both tissue types revealed a single class of high-affinity IGF-IR
      binding sites with a similar dissociation constant (K(d;) 0.14 +/- 0.02 nmol/L, n
      = 18). However, specific (125)IGF-I-binding and receptor concentrations were
      elevated in tumor membranes compared with normal mucosa (33.6 +/- 5.6 vs. 22.7 +/
      3.4 fmol/mg protein, P < 0.05). IGF-I affinity crosslinking and sodium dodecyl
      sulfate-polyacrylamide gel electrophoresis displayed specific bands corresponding
      to the size of the normal alpha-subunit of the IGF-IR that were more intense in
      carcinomatous samples. IGF-II mRNA levels were significantly elevated in
      colorectal carcinomas (P < 0.0001). The IGF-II mRNA ratio in tumor versus normal
      tissue was elevated more than twofold in 28 of 40 paired samples and a positive
      correlation was observed between the overexpression of IGF-II and IGF-IR in the
      tumors. CONCLUSIONS: Our results demonstrate that, in addition to IGF-II, a
      strong overexpression of IGF-IR is found in the majority of colorectal
      carcinomas, supporting the hypothesis of an important role of the IGF system in
      the pathogenesis of colorectal carcinoma.

PMID- 12412162
TI  - Marked regional variation in adenocarcinomas of the esophagus and the gastric
      cardia in the United States.
AB  - BACKGROUND: Adenocarcinomas of the esophagus and the gastric cardia recently have
      experienced rapidly increasing incidence rates. Although these sites frequently
      are combined, they may have different risk factors. METHODS: The authors compared
      regional incidence rates of esophageal adenocarcinoma, gastric cardia
      adenocarcinoma, and esophageal squamous cell carcinoma within the U.S.
      Surveillance, Epidemiology, and End Results (SEER) cancer registry for the years
      1973-1998. RESULTS: Regional incidence rates varied considerably. The Seattle
      Puget Sound registry's recent average esophageal adenocarcinoma rates were over
      twice as high as those of the Utah registry (5.3 vs. 2.4 per 100,000 persons per
      year; P < 0.01); gastric cardia rates also differed (4.0 vs. 2.8 per 100,000
      persons per year; P < 0.01). The incidence rate increase also varied markedly
      between regions. Since 1974, white male esophageal adenocarcinoma rates increased
      by 800% in Seattle compared with an increase of only 300% in Utah. In contrast,
      white male cardia adenocarcinoma rates increased by only 16% in Seattle (from 3.1
      per 100,000 persons per year in 1974 to 3.6 per 100,000 persons per year in 1998)
      compared with 300% in Utah (from 0.7 to 2.2 per 100,000 persons per year). Both
      types of adenocarcinoma were more common in males and in the white population in
      all regions, but recent esophageal adenocarcinoma rates for black males in
      Connecticut were significantly higher than the U.S. black male average (3.1 vs.
      0.8 per 100,000 persons per year; P < 0.01) and equaled the rates for the white
      population in some areas. Esophageal adenocarcinoma rates continued rising for
      white males through 1998, whereas cardia adenocarcinoma rates stabilized after
      1988. CONCLUSIONS: There are substantial regional, temporal, and ethnic
      differences between esophageal adenocarcinoma incidence rates and gastric cardia
      adenocarcinoma incidence rates within a single cancer registry system. Thus,
      these malignancies may differ in important ways and should not be combined
      routinely in research studies. Individual-level studies are needed to explain
      these substantial regional and ethnic differences.

PMID- 12412163
TI  - Prognostic potential of the telomerase subunit human telomerase reverse
      transcriptase in tumor tissue and nontumorous mucosa from patients with
      colorectal carcinoma.
AB  - BACKGROUND: The stabilization of telomere lengths by telomerase activation is an
      important step in carcinogenesis and cell immortalization. Human telomerase
      reverse transcriptase (hTERT) is the catalytic subunit of this enzyme. The
      objective of this study was to evaluate the use of real-time reverse
      transcriptase-polymerase chain reaction (RT-PCR) analysis for the quantification
      of hTERT in tumor and nontumorous tissue samples. METHODS: Matched samples of
      tumor and adjacent nontumorous mucosa samples from 57 patients with completely
      resected colorectal carcinoma (International Union Against Cancer Stage I-IV) who
      underwent complete resection (R0) were quantified for hTERT mRNA expression using
      real-time RT-PCR. The expression levels were correlated with histopathologic
      findings and with survival. The median follow-up was 76 months. RESULTS: hTERT
      mRNA was expressed in all tumor samples and in all samples of adjacent mucosa. In
      12 patients (21%), there was higher hTERT expression in tumor samples compared
      with nontumorous samples. Compared with tumor samples, the expression of hTERT in
      samples of nontumorous mucosa decreased with age (P = 0.06). hTERT mRNA
      expression in both tumor tissue and adjacent mucosa was correlated significantly
      with the histologic grade of colorectal carcinoma (P < 0.04 and P < 0.05,
      respectively). Patients with hTERT expression in tumor tissue in relation to the
      adjacent mucosa of > 0.57 had a significantly poorer overall survival compared
      with patients with lower hTERT ratios (P < 0.02). In addition to the established
      prognostic factor lymphatic vessel invasion, the hTERT ratio proved to be of
      independent prognostic value (P < 0.05). CONCLUSIONS: The prognostic potential of
      hTERT in patients with colorectal carcinoma and the correlation of hTERT with
      tumor grade underlines the role of hTERT as a molecular marker for biologic tumor
      staging.

PMID- 12412164
TI  - The diagnostic accuracy of the age-adjusted and prostate volume-adjusted biopsy
      method in males with prostate specific antigen levels of 4.1-10.0 ng/mL.
AB  - BACKGROUND: The authors evaluated a new age-adjusted and prostate volume-adjusted
      biopsy method for the detection of prostate carcinoma through the transperineal
      and the transrectal approaches in men with PSA levels of 4.1-10.0 ng/mL. METHODS:
      The value of the adjusted biopsy method was calculated by using the following
      four factors: 1) life expectancy in Japanese men in 1998, 2) prostate volume
      estimated by transrectal ultrasonography, 3) tumor doubling time (4 years), and
      4) tumor volume that influenced death (20 cc). The number of biopsy sites was set
      at 8-20. Between August, 1999 and December, 2001, 100 men age <or= 79 years with
      prostate specific antigen (PSA) levels of 4.1-10.0 ng/mL underwent age-adjusted
      and volume-adjusted, systematic prostate biopsy. RESULTS: The detection rate for
      the adjusted biopsy method was 46% (46 of 100 men). The clinical stage of
      prostate carcinoma was Stage II in 85% of patients and Stage III in 15% of
      patients. If routine six-sextant biopsy had been performed in all of the men who
      underwent adjusted systematic biopsy, then 15 of 46 patients (33%) with prostate
      carcinoma would have been missed. The detection rates of prostate carcinoma in
      men who underwent adjusted biopsies were relatively high, especially in men with
      PSA levels of 6.1-10.0 ng/mL, men age <or= 64 years, men with prostate volumes
      >or= 50 cc, and men with PSA density (PSAD) levels <or= 0.15 ng/mL/cc compared
      with the detection rates from six-sextant and directed biopsies. The high
      detection rates were observed from biopsy sites at the posterior aspect of the
      lateral lobe through both the transperineal approach and the transrectal approach
      and at the anterior aspect of the transition zone through the transperineal
      approach. CONCLUSIONS: The age-adjusted and prostate volume-adjusted prostate
      biopsy method was more useful for detecting clinically significant disease
      compared with the traditional six-sextant biopsy method. This adjusted biopsy
      method was especially useful in patients age <or= 64 years, patients with large
      prostate volumes (>/= 50 cc), and patients with PSAD levels <or= 0.15 ng/mL/cc.
      The authors recommend that patients undergo an additional transition zone biopsy
      at the anterior aspect through the transperineal approach.

PMID- 12412165
TI  - Prognostic significance of thymidine kinase activity in bladder carcinoma.
AB  - BACKGROUND: Thymidine kinase (TK) plays a key role in the complimentary or
      alternative salvage pathway of pyrimidine synthesis. Little is known about the
      significance of TK activity in bladder carcinoma. The authors examined the
      activity of TK in 55 patients with bladder carcinoma to determine the prognostic
      significance of TK activity. METHODS: TK activity in nonfixed, fresh-frozen
      specimens of bladder carcinoma and normal bladder tissue was determined by using
      the diethylaminoethanol cellulose disc method. RESULTS: The activity of TK was
      approximately two-fold higher in bladder carcinoma specimens compared with normal
      bladder tissues. The TK activity in muscle-invasive bladder carcinoma was two
      fold higher compared with the activity in superficial bladder carcinoma (Ta and
      T1). In addition, the activity of TK in T1 tumors was two-fold higher compared
      with the TK activity in Ta tumors. The level of TK activity in Grade 3 bladder
      tumors was two-fold higher compared with the activity in Grade 1 and Grade 2
      tumors. Patients with Ta and T1 bladder carcinoma who had low TK activity had a
      longer postoperative tumor free period compared with the patients who had high TK
      activity during the 2 years of follow-up. TK activity was correlated with the
      activity of thymidine synthase, which is a key enzyme for pyrimidine synthesis in
      the de novo pathway. CONCLUSIONS: This study is the first to demonstrate that the
      level of TK activity is correlated with both disease stage and tumor grade in
      patients with bladder carcinoma and that elevated TK activity predicts early
      recurrence in patients with Ta and T1 disease. These results suggest that the
      level of TK activity may be used as a prognostic parameter and that TK may be a
      molecular therapeutic target in patients with bladder carcinoma.

PMID- 12412166
TI  - An interinstitutional and interspecialty comparison of treatment outcome data for
      patients with prostate carcinoma based on predefined prognostic categories and
      minimum follow-up.
AB  - BACKGROUND: The optimal management of patients with clinically localized prostate
      carcinoma remains undefined due in part to the absence of well-designed,
      prospective, randomized trials. The current study was conducted to compare and
      contrast outcomes with different forms of therapy for patients with prostate
      carcinoma who were treated at several institutions using predefined prognostic
      categories. METHODS: A retrospective study of 6877 men with prostate carcinoma
      who were treated between 1989 and 1998 at 7 different institutions with 6
      different types of therapy was conducted. Five-year actuarial rates of prostate
      specific antigen (PSA) failure were calculated based on predefined prognostic
      categories, which included combinations of pretreatment PSA level, tumor stage,
      and Gleason score. In addition, outcome was calculated using consistent
      biochemical failure definitions and a minimum, median length of follow-up.
      RESULTS: Substantial differences in outcome were observed for the same type of
      treatment and at the same institution, depending on the number of prognostic
      variables used to define treatment groups. However, estimates of 5-year PSA
      outcomes after all forms of therapy for low-risk and intermediate-risk patient
      groups were remarkably similar (regardless of the type of treatment) when all
      three pretreatment variables were used to define prognostic categories. For
      patients in high-risk groups, the 5-year PSA outcomes were suboptimal, regardless
      of the treatment technique used. CONCLUSIONS: The current data suggest that
      interinstitutional and interspecialty comparisons of treatment outcome for
      patients with prostate carcinoma are possible but that results must be based on
      all major prognostic variables to be meaningful. Analyzed in this fashion, 5-year
      PSA results were similar for patients in low-risk and intermediate-risk groups,
      regardless of the form of therapy. Findings from prospective, randomized trials
      using survival (cause specific and overall) as the end point for judging
      treatment efficacy and longer follow-up will be needed to validate these findings
      and to identify the most appropriate management option for patients with all
      stages of disease.

PMID- 12412167
TI  - Low bone density and high percentage of body fat among men who were treated with
      androgen deprivation therapy for prostate carcinoma.
AB  - BACKGROUND: Men with prostate carcinoma who are treated with androgen deprivation
      therapy (ADT) are reported to be at an increased risk of bone loss and weight
      changes due to the sudden disruption of hormonal levels. In the current case
      control study, the authors examined the prevalence and magnitude of low bone
      density and obesity among men with prostate carcinoma who were treated with ADT.
      METHODS: Sixty-two men with prostate carcinoma who had been receiving ADT for 1-5
      years were included as cases. Healthy men (n = 47) with a prostate specific
      antigen level < 4.0 ng/mL were recruited as controls. Body composition and bone
      mineral density (BMD) were measured using dual-energy X-ray absorptiometry. The
      average age was 74.3 years for the cases and 72.8 years for the controls.
      RESULTS: The results of the current study demonstrate that prostate carcinoma
      cases had significantly higher body weight (86.5 kg vs. 80.6 kg), a higher
      percentage of body fat (30% vs. 26%), and a lower total body BMD (1.12 mg/cm(2)
      vs. 1.17mg/ cm(2)) compared with controls (P < 0.05). Cases were more likely to
      be obese (27.4% vs 43%) and have low BMD at trochanter (32.3% vs. 10.6%),
      intertrochanter (48.4% vs. 29.8%), and total hip measurements (50.0% vs. 25.3%).
      CONCLUSIONS: The results of the current study indicate that men with prostate
      carcinoma who are treated with ADT have a significantly increased risk of low
      bone density and obesity.

PMID- 12412168
TI  - Absolute risk of a subsequent abnormal pap among oncogenic human papillomavirus
      DNA-positive, cytologically negative women.
AB  - BACKGROUND: The addition of human papillomavirus (HPV) DNA testing to cytologic
      screening for cervical carcinoma is now being considered. The majority of women
      in screening cohorts who test positive for oncogenic types of HPV DNA have
      concurrent negative Pap tests. The absolute risk of a subsequent abnormal Pap
      test for these women is uncertain. Therefore, the proper counseling and clinical
      management of these women is also uncertain. METHODS: A subcohort of 2020 women
      with a negative Pap test who tested positive at enrollment for oncogenic HPV DNA
      types using the Hybrid Capture 2 Test were followed for 57 months at Kaiser
      Permanente (Portland, OR). Absolute risks of new abnormal cytologic
      interpretations were computed using Kaplan-Meier methods. Logistic regression
      models were used to evaluate determinants of a new abnormal Pap test. RESULTS:
      The cumulative incidence for a Pap test interpreted as atypical squamous cells or
      more severe (>or= ASC) was 16.8% (95% confidence interval [CI] = 15.0-18.6%),
      6.4% (95% CI = 5.2-7.6%) for low-grade squamous intraepithelial lesions or more
      severe, and 2.2% (95% CI = 1.5-2.9%) for high-grade squamous intraepithelial
      lesions or more severe. By comparison, the cumulative incidence of greater than
      or equal to ASC among HPV-negative women was 4.2% (95% CI = 3.9-4.6%). The
      highest viral load (100 relative light units per the positive control or greater)
      was associated with a greater risk of an abnormal Pap test (odds ratio= 2.7, 95%
      CI = 1.7-4.1) than lower viral loads. CONCLUSIONS: These results suggest that
      about 15% of women in annual screening programs who concurrently have a negative
      Pap test and a positive oncogenic HPV test will have a subsequent abnormal Pap
      test within 5 years. This risk estimate will be useful to the many clinicians and
      patients likely to be diagnosed with an HPV infection and negative cytology if
      HPV DNA is added to general screening.

PMID- 12412169
TI  - Potential marker of oral squamous cell carcinoma aggressiveness detected by
      fluorescence in situ hybridization in fine-needle aspiration biopsies.
AB  - BACKGROUND: Amplification of chromosome 11q13 is a frequent event in
      carcinogenesis of the head and neck squamous cell carcinomas including oral
      carcinoma. METHODS: Fluorescence in situ hybridization (FISH), using a BAC clone
      specific for the cyclin D1 gene (CCND1), was performed on specimens obtained by
      fine-needle aspiration biopsy (FNAB) from 50 patients with primary oral squamous
      cell carcinomas (OSCCs.). RESULTS: The CCND1 numerical aberration was identified
      in 21 (42.0%) of 50 patients with primary OSCCs. The CCND1 amplification was
      determined in 16 (32.0%) of these patients. Immunohistochemical staining revealed
      that all 21 tumors showing the CCND1 numerical aberration overexpressed the CCND1
      protein. The CCND1 numerical aberration was associated significantly with
      histopathologic grading (P = 0.032), the mode of invasion (P = 0.047), the
      presence of cancer cells at the resection margin (P = 0.033), pathologic lymph
      nodestatus (P = 0.045), disease recurrence (P = 0.004), and survival (P = 0.004).
      The disease-free and overall survival period of patients with the CCND1 numerical
      aberration was significantly shorter than that of patients without the CCND1
      numerical aberration (P = 0.0016 and P = 0.0019, respectively). Moreover, a
      multivariate analysis showed that the CCND1 numerical aberration retained an
      independent prognostic value. CONCLUSIONS: The CCND1 numerical aberration is
      useful both as a prognostic indicator that is independent of the TNM
      classification, and an indicator to assist in determination of the appropriate
      treatment for patients with OSCCs. Analysis of the CCND1 numerical aberration
      using FISH on FNABs may be a useful and practical method for predicting
      aggressive tumors, recurrence, and clinical outcome in patients with OSCCs.

PMID- 12412170
TI  - A Phase II trial of pegylated liposomal doxorubicin, vincristine, and reduced
      dose dexamethasone combination therapy in newly diagnosed multiple myeloma
      patients.
AB  - BACKGROUND: Patients with multiple myeloma (MM) have increased bone marrow
      angiogenesis, a low plasma cell labeling index, and multidrug resistance (the
      primary cause of chemotherapy failure). MM patients receiving the vincristine,
      doxorubicin, and dexamethasone (VAD) regimen develop resistance and cardiac and
      steroid toxicity. Pegylated liposomal doxorubicin (Doxil/CAELYX) could
      potentially extend the duration of malignant plasma cell exposure to therapeutic
      levels of doxorubicin. This Phase II study evaluates combination pegylated
      liposomal doxorubicin, vincristine, and reduced-dose dexamethasone in MM
      patients. METHODS: Thirty-three newly diagnosed patients with MM received
      intravenous pegylated liposomal doxorubicin (40 mg/m(2)), vincristine (2.0 mg,
      Day 1), and oral or intravenous dexamethasone (40 mg per day for 4 days) every 4
      weeks for six or more cycles and/or for two cycles after the best response.
      RESULTS: The overall response rate was 88%: 4 (12%) patients achieved a complete
      response, 18 (55%) a major response, and 7 (21%) a minor response. Three patients
      (9%) had stable and one (3%) had progressive disease. The median time to
      progression was 23.1 months, with 2-year and 3-year progression-free survival
      rates of 42% and 23%, respectively. The patient survival rate at 3 years was 67%.
      No patients discontinued treatment due to adverse events. Myelosuppression was
      manageable. The most common toxicities were Grade 3 palmar-plantar
      erythrodysesthesia, mucositis, and neutropenia. Only one patient experienced
      cardiotoxicity. CONCLUSIONS: Substituting pegylated liposomal doxorubicin for
      doxorubicin in the VAD regimen and reducing the dose of dexamethasone in patients
      with MM improve the safety profile and convenience of the treatment regimen
      without compromising efficacy.

PMID- 12412171
TI  - Treatment of patients with advanced or bulky Hodgkin disease with a 12-week
      doxorubicin, bleomycin, vinblastine, and dacarbazine-like chemotherapy regimen
      followed by extended-field, full-dose radiotherapy: long-term results of the
      Groupe Ouest et Est des Leucemies et Autres Maladies de Sang H90-A/B Multicenter
      Randomized Trial.
AB  - BACKGROUND: This Phase II study was performed in patients with advanced or bulky
      Hodgkin disease (HD) to evaluate the results of a 7-drug chemotherapy (CT)
      regimen that was administered over 12 weeks according to 2 randomized modalities
      followed by high-dose lymph node irradiation. METHODS: From 1990 to 1996, 162
      patients with HD at clinical stages (CS) I-III with bulky disease (mediastinal
      mass ratio >or= 0.45 and/or unilateral or bilateral pelvic plus lumboaortic
      disease; 86 patients) or CS IV (76 patients) were randomized to receive the same
      cumulated dose of a CT regimen consisting of epirubicin (240 mg/m(2)), bleomycin
      (60 mg/m(2)), vinblastine (20 mg/m(2)), vincristine (4 mg/m(2)), cyclophosphamide
      (4000 mg/m(2)), etoposide (900 mg/m(2)), and methotrexate (180 mg/m(2)) plus
      methylprednisolone (1500 mg/m(2)) over 12 weeks either every 4 weeks (Arm Y, 79
      patients) or every 3 weeks (Arm Z, 83 patients). Patients with disease in
      complete remission (CR) or partial remission after CT received extended-field
      lymph node irradiation (involved areas, 40 grays [Gy]; noninvolved areas, 30 Gy).
      RESULTS: Forty-two percent of patients achieved a post-CT CR, and 86% of patients
      achieved a CR after the completion of irradiation (there was no difference
      between Arm Y and Arm Z). Thirty-five patients developed recurrent disease; most
      of those patients were in post-CT partial remission. The 10-year freedom from
      first progression rate was 63.9% (there was no difference between Arm Y and Arm
      Z). Thirty-eight patients died: 24 patients from HD, 3 patients from CT-related
      early sepsis, 1 patient from radiation-induced pneumonitis, 6 patients from a
      second malignancy, and 4 patients from causes unrelated to treatment. The overall
      10-year survival rate was 76.7%. Survival was slightly higher among patients in
      Arm Y (83.3%) compared with patients in Arm Z (70.2%; P = 0.12). CONCLUSIONS: No
      differences were found when the same amount of CT was delivered in three courses
      or in four courses. In 1997, because most recurrences of the H90-A/B trial
      occurred in patients who achieved a post-CT partial remission, the authors
      decided to reinforce the intensity of the initial CT and designed a new
      randomized study comparing two modalities of more intensive CT plus consolidative
      radiotherapy (H97-LM trial).

PMID- 12412172
TI  - Hepatic intraductal oncocytic papillary carcinoma.
AB  - BACKGROUND: There has been an increasing incidence and mortality from peripheral
      cholangiocarcinoma (PC) in the United States over the past 24 years. PC has been
      classified into two principal types, a mass-forming type and a periductal
      infiltrating type, with a significant difference in the clinical behavior between
      the two. A third type, demonstrating a noninvasive intraductal growth of PC, was
      described as papillary PC. Rarely, papillary hepatic tumors composed of oncocytic
      cells have been described. Intraductal oncocytic papillary carcinomas (IOPCs) of
      the liver present as large, mucin-filled, cystic lesions lined by noninvasive or
      focally microinvasive oncocytic tumors. METHODS: From June 1999 to August 2001,
      three patients with hepatic IOPCs were identified in the files of the
      Hepatobiliary Service, Department of Surgery, and the Department of Pathology at
      Memorial Sloan-Kettering Cancer Center. They form the basis of this study. We
      report the clinicopathologic presentation, as well as the outcome, with a review
      of the literature. RESULTS: All three cases presented with well defined
      intrahepatic cystic masses ranging in size from 7.2 to 21.1 cm. The most
      prominent cells of the lining epithelium were columnar with oncocytic features
      showing abundant eosinophilic granular cytoplasm and centrally located nucleoli.
      All three patients underwent resection with one demonstrating local bile duct
      recurrence that was managed with stenting. Review of the literature has
      identified 39 patients with papillary PC and 2 patients with IOPC. The biology of
      these reported cases has been variable with overall survival better than that of
      nonpapillary PC patients, with recurrence in 15% of the reported cases.
      CONCLUSION: Papillary PC is a rare type of cholangiocarcinoma that includes an
      interesting variant: IOPC. These tumors are predominantly found in men, who
      present with large (> 5 cm) mucinous cystic lesions of the bile duct. A
      noninvasive histology is seen, and long-term survival may be achieved with
      complete resection. Invasive variants of IOPC have been reported in the
      literature and have a worse overall prognosis.

PMID- 12412173
TI  - Serum endostatin predicts tumor vascularity in hepatocellular carcinoma.
AB  - BACKGROUND: Tumor angiogenesis is a strong prognostic factor in patients with
      hepatocellular carcinoma (HCC). However, to the authors' knowledge, details
      regarding the serum levels of proangiogenic and antiangiogenic growth factors
      controlling this process are not yet known. METHODS: Serum endostatin, vascular
      endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF)
      levels were measured by the enzyme immunoassay method in prospectively collected
      samples from 33 HCC patients who had received no preoperative therapy. The
      angiogenic score (AS) and endostatin localization were evaluated using
      immunohistochemistry. RESULTS: Significant decreases in serum endostatin (P =
      0.0007) and bFGF (P = 0.0004) were observed in postoperative samples compared
      with the preoperative values. A very strong direct correlation was noted between
      VEGF and endostatin (P < 0.0001). Only the preoperative serum endostatin was
      found to have a significant (P = 0.0025) inverse correlation with the AS.
      Furthermore, the combined positivity for bFGF and VEGF and negativity for
      endostatin was found to have a significantly (P = 0.0069) positive correlation
      with AS. Significantly high levels of endostatin were noted in patients with
      trabecular-type tumors (P = 0.0446) and in patients with hepatitis B infection (P
      = 0.0183). The serum endostatin level was found to be significantly (P = 0.0166)
      higher in living patients and patients with high serum endostatin levels had a
      tendency (P = 0.0871) toward long survival. Tissue endostatin expression was
      found to have a direct correlation with the serum endostatin level (P = 0.0117).
      CONCLUSIONS: The measurement of serum endostatin can predict tumor vascularity
      and may serve as a promising tool in the antiangiogenic therapy for patients with
      HCC.

PMID- 12412174
TI  - Neuropilin 1 and neuropilin 2 co-expression is significantly correlated with
      increased vascularity and poor prognosis in nonsmall cell lung carcinoma.
AB  - BACKGROUND: Cell-retained isoforms of vascular endothelial growth factor A (VEGF
      A) have been reported to play an essential role in tumor progression through
      stromal neovascularization in malignant solid tumors. While more than 95% of
      nonsmall cell lung carcinoma (NSCLC) expresses cell-retained VEGF-A isoform, the
      clinicopathologic implications of neuropilin (NRP), considered the specific
      receptor for limited types of VEGF-A isoform, are not well understood. METHODS:
      The authors examined NRP1 and NRP2 mRNA expression in 68 NSCLCs and 15
      extraneoplastic tissues by a densitometry-assisted, semi-quantitative reverse
      transcription-polymerase chain reaction. The authors determined the distinct
      expression of NRPs using the expression level of NRPs relative by optical density
      to beta2-microglobulin. The authors also investigated VEGF-A isoforms, their
      receptors, and the clinical implications. Vascularity of NSCLC was
      morphologically estimated on sections immunostained with anti-CD34 antibody.
      RESULTS: Eleven of 15 extraneoplastic specimens showed NRP1 expression (73.3%)
      and 8 showed NRP2 expression (53.3%). The expression level of NRP1 or NRP2 of
      neoplasmic tissue was higher than that of extraneoplastic tissues (P < 0.01, Mann
      Whitney U test). Fifty-five and 44 NSCLCs expressed NRP1 and NRP2, respectively.
      Forty patients co-expressing NRP1 and NRP2 showed significantly poorer prognosis
      and increased vessel counts as compared to those 28 cases without co-expression
      (P < 0.05, log-rank test; P < 0.05, Mann-Whitney U test). CONCLUSIONS: The co
      expression of NRP1 and NRP2 genes is significantly correlated with tumor
      progression through neovascularization in NSCLC. These results suggest that both
      NRP1 and NRP2 are key molecules for stromal vascularization by cell-retained VEGF
      in NSCLC.

PMID- 12412175
TI  - Can cure in patients with osteosarcoma be achieved exclusively with chemotherapy
      and abrogation of surgery?
AB  - BACKGROUND: Contemporary therapy for osteosarcoma is comprised of initial
      treatment with chemotherapy and surgical extirpation of the primary tumor in the
      affected bone. In view of the major advances forged by chemotherapy in the
      treatment of the primary tumor, an attempt was made to destroy the tumor
      exclusively with this therapeutic modality and abrogate surgery. METHODS: Thirty
      one consecutive patients were treated. All had localized disease (absence of
      metastases) at the time of diagnosis. Initial treatment with chemotherapy was
      comprised of high-dose methotrexate and leucovorin rescue (MTX-LF) in 3 patients
      and intraarterial cisplatin in 28 patients. Clinical, radiologic, angiographic,
      radionuclide, and histologic investigations were utilized to assess the efficacy
      of treatment. After a response at 3 months, entry into the study was permitted
      and treatment was maintained for a total of 18-21 months with a combination of
      agents comprised of MTX-LF, intraarterial cisplatin, and doxorubicin. Patients
      were monitored closely for disease recurrence with the investigations outlined
      earlier. Two informed consents were required: one at the time of diagnosis and
      another at 3 months after the initial response had been attained. RESULTS: Only 3
      of 31 patients were cured with the administration of chemotherapy alone. Local
      recurrence and pulmonary metastases were not reported to develop in these 3
      patients during a follow-up period of 204+ to 225+ months. Four other patients
      also possibly were cured with chemotherapy alone. At their request, several
      months after the cessation of chemotherapy, they underwent surgical extirpation
      of the tumor. No evidence of viable tumor was found. These patients remained free
      of disease for 192+ to 216+ months. Thus, only seven patients did not develop
      local recurrence and/or pulmonary metastases. Among the remaining 24 patients, 9
      developed local recurrences without pulmonary metastases 14-74 months (median, 30
      months) after the initial response. Eight of the nine patients were rendered
      tumor free by extirpation of the local recurrence. Two of these eight patients
      subsequently died, one of the acquired immunodeficiency syndrome (AIDS) and the
      other of varicella septicemia. The ninth patient refused amputation and died of
      metabolic complications. Three other patients developed local recurrences 20-69
      months and pulmonary metastases 10-98 months after achievement of the initial
      response. These patients were rendered tumor free by extirpation of the local
      recurrence and metastasectomy. One of these patients also later died of AIDS. In
      the remaining 12 patients, local recurrences developed 5-29 months (median, 14
      months) after the initial response was achieved. The patients also developed
      pulmonary metastases 11-60 months after the initial response. In eight patients
      the local recurrences were extirpated and metastasectomy was performed; however,
      these patients later died of recurrent pulmonary metastases. The remaining four
      patients refused to undergo extirpation of the local recurrence. The pulmonary
      metastases were not resected. They failed to respond to alternate therapy. Thus,
      the tumor-free survival rate was 23% (7 of 31 patients): 3 patients who were
      treated with chemotherapy only and 4 patients who were treated with chemotherapy
      plus surgery. The overall survival rate (patients who remained free of disease
      and those who underwent resection for local recurrence and metastasectomy) was
      48% (15 of 31 patients). Prior to the deaths from AIDS and varicella septicemia,
      the overall survival was 58% (18 of 31 patients). CONCLUSIONS: Utilizing the
      regimen employed in the current study, only 3 of 31 patients with osteosarcoma
      (10%) were cured exclusively with chemotherapy. Four additional patients who
      underwent extirpation of the primary tumor without disease recurrence and in whom
      no viable tumor was found in the resected specimens possibly could increase the
      number of patients who potentially were cured with chemotherapy to 7 (23%). With
      an overall expected cure rate of 50-65% with "conventional" sin whom no viable
      tumor was found in the resected specimens possibly could increase the number of
      patients who potentially were cured with chemotherapy to 7 (23%). With an overall
      expected cure rate of 50-65% with "conventional" strategies, the results of the
      current study do not justify the adoption of current forms of chemotherapy as
      exclusive treatments for osteosarcoma.

PMID- 12412176
TI  - Breast, cervical, and colorectal carcinoma screening in a demographically defined
      region of the southern U.S.
AB  - BACKGROUND: The "Southern Black Belt," a term used for > 100 years to describe a
      subregion of the southern U.S., includes counties with high concentrations of
      African Americans and high levels of poverty and unemployment, and relatively
      high rates of preventable cancers. METHODS: The authors analyzed data from a
      state-based telephone survey of adults age >or= 18 years to compare the cancer
      screening patterns of African-American and white men and women in nonmetropolitan
      counties of this region, and to compare those rates with those of persons in
      other southern counties and elsewhere in the U.S. The primary study groups were
      comprised of 2165-5888 women and 1198 men in this region interviewed through the
      Behavioral Risk Factor Surveillance System. The respondents lived in
      predominantly rural counties in 11 southern states with sizeable African-American
      populations (>or= 24.5% of county residents). The main outcome measures were
      recent use of the Papanicolau (Pap) test, mammography, test for fecal occult
      blood in the stool (FOBT), and flexible sigmoidoscopy or colonoscopy. RESULTS:
      Between 1998-2000, 66.3% (95% confidence interval [95% CI] +/- 2.7%) of 1817
      African-American women in the region age >or= 40 years had received a mammogram
      within the past 2 years, compared with 69.3% (95% CI +/- 1.8%) of 3922 white
      women (P = 0.066). The proportion of African-American and white women who had
      received a Pap test within the past 3 years was similar (85.7% [95% CI +/- 1.9%]
      vs. 83.4% [95% CI +/- 1.5%]; P = 0.068]. In 1997 and 1999, 29.3% of African
      American women in these counties reported ever receiving an FOBT, compared with
      36.9% in non-Black Belt counties and 42.5% in the remainder of the U.S. Among
      white women, 37.7% in Black Belt counties, 44.0% in non-Black Belt counties, and
      45.3% in the remainder of the U.S. ever received an FOBT. Overall, similar
      patterns were noted among both men and women with regard to ever-use of FOBT,
      flexible sigmoidoscopy, or colonoscopy. Screening rates appeared to vary less by
      race than by region. CONCLUSIONS: The results of the current study underscore the
      need for continued efforts to ensure that adults in the nonmetropolitan South
      receive educational messages, outreach, and provider recommendations concerning
      the importance of routine cancer screening.

PMID- 12412177
TI  - Phase I study of pegylated liposomal doxorubicin and gemcitabine in patients with
      advanced malignancies.
AB  - BACKGROUND: Pegylated liposomal doxorubicin (PEG-LD) and gemcitabine have single
      agent activity in breast and ovarian carcinoma patients. We conducted a Phase I
      trial to evaluate the maximum tolerated dose (MTD) and toxicities of this
      combination in patients with advanced malignancies. METHODS: Twenty-six patients
      with refractory or recurrent malignancies were enrolled in this dose escalation
      trial. Dose escalation proceeded from a starting level of PEG-LD 20 mg/m(2) and
      gemcitabine 1000 mg/m(2) administered on Days 1 and 15 of a 28-day cycle.
      RESULTS: The MTD was PEG-LD 20 mg/m(2) and gemcitabine 2000 mg/m(2) administered
      on Days 1 and 15 of a 28-day cycle. Dose-limiting toxicity, a Grade 3 rash, was
      observed in one patient during Cycle 1 and Grade 3 stomatitis and a rash were
      observed in a second patient during Cycle 2 after administration of PEG-LD 25
      mg/m(2) and gemcitabine 2000 mg/m(2). Other side effects included palmar-plantar
      erythrodysesthesia, nausea, and fatigue. One complete and two partial responses
      were observed. CONCLUSIONS: The recommended Phase II dose is PEG-LD 20 mg/m(2)
      with gemcitabine 2000 mg/m(2) on Days 1 and 15 of a 28-day cycle. A trial with
      this combination is currently ongoing at this institution comprising patients
      with refractory ovarian carcinoma.

PMID- 12412178
TI  - Effect of topical morphine for mucositis-associated pain following concomitant
      chemoradiotherapy for head and neck carcinoma.
AB  - BACKGROUND: Oral mucositis is the dose-limiting toxicity for patients receiving
      concurrent chemoradiotherapy regimens for tumors of the head and neck area.
      Currently, the management of established mucositis includes the use of topical
      anesthetics and systemic analgesics. Based on the clinical evidence of pain
      alleviation by topical morphine in patients with some inflammatory and painful
      conditions, a clinical study was undertaken to determine this effect on mucositis
      associated pain. METHODS: Twenty-six patients with head and neck malignancies
      treated with concomitant chemoradiotherapy for head and neck carcinoma who had
      severe painful mucositis (World Health Organization Grade 2 or higher) were
      enrolled. Patients were randomly assigned to morphine mouthwash (MO; 14 patients)
      or magic mouthwash (MG), a mixture of equal parts of lidocaine, diphenhydramine,
      and magnesium aluminum hydroxide (12 patients). RESULTS: The duration of severe
      pain was 3.5 days less in the MO group compared with the MG group (P = 0.032).
      The intensity of oral pain was also significantly lower in the MO group compared
      with the MG group (P = 0.038). No patient in the MO group required third-step
      opiates for alleviation of the mouth pain. There was a significant difference in
      duration of severe functional impairment (P = 0.017). Five patients in the MG
      group complained of local side effects and only one in the MO group (P = 0.007).
      CONCLUSIONS: For patients with head and neck carcinomas receiving concomitant
      chemoradiotherapy, MO is a simple and effective treatment to decrease the
      severity and duration of pain and the duration of functional impairment.

PMID- 12412179
TI  - Cancer incidence in parents who lost a child: a nationwide study in Denmark.
AB  - BACKGROUND: It has been debated whether psychological stress causes cancer, but
      the scientific evidence remains contradictory. The objective of this study was to
      investigate whether the death of a child is related to cancer risk in bereaved
      parents. METHODS: The authors undertook a follow-up study based on national
      registers. All 21,062 parents who lost a child from 1980 to 1996 were recruited
      for the exposed cohort together with 293,745 randomly selected, unexposed
      parents. Cox proportional hazards regression models were used to evaluate the
      relative risk of cancer incidence up to 18 years after the bereavement. The main
      outcomes of interest were all incident cancers, breast carcinoma, smoking-related
      malignancies (International Classification of Diseases [ICD] 7 codes 140, 141,
      143-149, 150, 157, 160-162, 180, and 181), alcohol-related malignancies (ICD7
      codes 141, 143-146, 148-150, 155, and 161), virus/immune-related malignancies
      (ICD7 codes 155, 171, 191, 200-202, and 204), lymphatic/hematopoietic
      malignancies (ICD7 codes 200-205), and hormone related malignancies (ICD7 codes
      170, 172, 175, and 177). RESULTS: The authors observed a slightly increased
      overall cancer risk in bereaved mothers (relative risk [RR], 1.18; 95% confidence
      interval [95%CI], 1.01-1.37; P = 0.028) at 7-18 years of follow-up. There was an
      increased risk for smoking-related malignancies (RR, 1.65; 95%CI, 1.05-2.59; P =
      0.010) among bereaved mothers during the 7-18 years of follow-up. The authors
      observed no significantly increased relative risk of breast carcinoma, alcohol
      related malignancies, virus/immune-related malignancies, or hormone-related
      malignancies. CONCLUSIONS: The current data suggest that the death of a child was
      associated with a slightly increased overall cancer risk in mothers and that the
      increase may be related to stress-induced adverse life styles.

PMID- 12412180
TI  - Peroxisome proliferator-activated receptor gamma ligand troglitazone induces cell
      cycle arrest and apoptosis of hepatocellular carcinoma cell lines.
AB  - BACKGROUND: Ligand activation of peroxisome proliferator-activated receptor gamma
      (PPARgamma) results in the inhibition of proliferation of various cancer cells.
      The aim of this study is to investigate the mechanisms of cell growth inhibition
      of hepatocellular carcinoma (HCC) cell lines by the PPARgamma ligand,
      troglitazone. METHODS: Six HCC cell lines were used to study the effects of
      troglitazone on cell growth by 3-[4,5-dimethylthiazol-2-yl]-2,5
      diphenyltetrazolium bromide (MTT) assay, on cell cycle by flow cytometry, and on
      the cell cycle-regulating factors of late G1 phase by Western blotting. Apoptosis
      assays were performed by flow cytometry using membrane, nuclear, cytoplasmic, and
      mitochondrial markers. Caspase inhibitors were used to analyze the mechanisms of
      apoptosis induced by troglitazone. RESULTS: Troglitazone showed a potent dose
      dependent effect on the growth inhibition of all six HCC cell lines, which were
      suppressed to under 50% of control at the concentration of 10 micromol/L. The
      growth inhibition was linked to the G1 phase cell cycle arrest through the up
      expression of the cyclin-dependent kinase inhibitors, p21 and p27 proteins, and
      the hypophosphorylation of retinoblastoma protein. Troglitazone induced apoptosis
      by caspase-dependent (mitchondrial transmembrane potential decrease, cleavage of
      poly [adenosine diphosphate ribose] polymerase, 7A6 antigen exposure, Bcl-2
      decrease, and activation of caspase 3) and caspase-independent
      (phosphatidylserine externalization) mechanisms. CONCLUSIONS: Our data suggest
      that ligand activation of PPARgamma by troglitazone or modified analogs of the
      thiazolidinedione class of drugs is a novel target for effective therapy against
      HCC, because of the significant antiproliferative and programmed cell death
      induction capabilities demonstrated by troglitazone.

PMID- 12412181
TI  - Serum folate and homocysteine levels in head and neck squamous cell carcinoma.

PMID- 12412183
TI  - Influence of delay to diagnosis on prognostic indicators of screen-detected
      breast carcinoma.

PMID- 12412185
TI  - [Annual self-assessment of perioperative complications and early success: the
      best way to improve the medical results in the Vascular Surgery Department].
AB  - In spite of many recent advances, vascular surgery is still weighed down with
      serious complications which occur in 1 to 5% of open surgery cases and 0 to 2% of
      endovascular cases. Some of them are due to the specific characteristics of
      atherosclerotic and aneurysmal diseases; others are associated with the technics
      of arterial reconstructions; but others are surgeon-dependant as their rate vary
      from on center to another. Quality of results depend on the experience of one
      surgeon and his team. This experience is based on an unquantified analysis of
      past success and failures. However currently, it is necessary to take in account
      the scientific guidelines as well as the personal results of the surgical team.
      The latter are known only when they are periodically checked in a systematic
      process. We report a 23 years experience of annual self assessment of the
      perioperative complications covering all the arterial reconstructions performed
      during the previous year. These evaluation had five effects: they linked the
      physicians and nurses in the quest of optimal efficacy; they focused all the team
      on the cares and results which needed to be improved; complications and success
      rates were a guide for the therapeutic choices; reliable results rates allowed a
      precise information of patients, hospital-managers and lawyers when necessary;
      they were one of the most important factors of continuing medical education. No
      other mean can replace these self-assessment procedures: retrospective studies
      are focused on limited areas; mortality-mobidity conferences are devoted to the
      recent complications without statistical analysis; the PMSI is directed towards
      cost-containment rather than quality of results. When a team do not know which
      results are poor, it is unlikely that they will be improved. We hope that the
      hospital accreditation which has been introduced in France in 1996, will make
      mandatory the practice of mortality-morbidity conferences, annual evaluation of
      perioperative complications and periodic studies of long term results. For
      medical and economical reasons, the population may require that we systematically
      monitor our results and take them in account before deciding a treatment.
      Physicians who are unaware of there own results cannot inspire confidence.

PMID- 12412186
TI  - [Epidemiology of nosocomial infections after cataract surgery and role of the
      Infection Control Committee in prevention].
AB  - Despite of a low incidence (3 for 1,000), post-cataract surgery endophthalmitis
      remains a serious complication with a poor prognosis. The nosocomial definition
      is almost always present despite the endogenous origin; the latter is associated
      with the risk prone operative procedure, and the presence of numerous normal
      flora on skin and conjunctiva. Within this context, the incriminated bacteria are
      coagulase-negative Staphylococcus. Micro-outbreaks of postoperative Pseudomonas
      aeruginosa endophthalmitis have an exogenous origin. In order to prevent these
      nosocomial infections, the role of the "infection control committee" and the
      operational hygiene team is very important: 1) survey of new infectious cases and
      of the hospital environment; 2) infection control measures about pre and intra
      operative preparation of the patient; 3) operating room maintenance.

PMID- 12412187
TI  - [Prevention of bacterial endophthalmitis after cataract surgery in adults].
AB  - Technical progress in cataract surgery has led to the phacoemulsification of the
      eye lens by ultrasound followed by the intraocular lens implantation. In spite of
      rigorous preventive hygiene and sterilization measures taken before, during and
      after the operation, two clinical forms of endophthalmitis seriously threaten
      vision in the operated eye: externally induced endophthalmitis, specifically with
      pyocyanic bacillus, which often follows the irregular use of reuseable tubings
      and internally induced endophthalmitis due to the inevitable penetration during
      the intraocular operation of conjunctival micro-organisms especially
      staphylococci. A zero-risk level is non-existent and it would be unjust to hold
      the ophthalmologist responsible for it, when he has done everything possible to
      reduce the risk. The question of bacteriological examinations, the problem of
      antibioprophylaxis, and the danger of the reuseable tubings and of the ambulatory
      surgery, concerning at-risk patients, are discussed in this paper.

PMID- 12412188
TI  - [Major reconstructions of the hip by allograft composite prostheses (long-term
      follow-up of 34 cases)].
AB  - Reconstruction after major resections of malignant tumors can be achieved by
      association of prostheses and of massive allografts. In 34 patients, we could
      reconstruct: the proximal femur in 21 cases, after an average resection of 180
      mm, with a "composite" allograft prosthesis (with a bone graft around the stem)
      or a "composite and combined" allograft prosthesis (in which the femur allograft
      was associated with the trochanteric tendons, to facilitate the reinsertion of
      the glutei muscles); 10 hemipelvis in which the cup was inserted in an hemipelvic
      allograft; 3 proximal femurs and acetabulum (with composite cups and stems). In
      comparison with metallic reconstruction prostheses, composite prostheses improved
      function, limited complications, and increased longevity. The association of
      allografts and prostheses not only allows reconstructions which could be hardly
      achieved with only prostheses (especially for the pelvis), but also improves
      functional result and longevity, thanks to the biological fixation of the osseous
      and tendinous allografts. Considering our 15 years follow up in oncology, we have
      now extended these procedures to the major bone losses of the femur and pelvis
      following iterative revisions of standard prostheses for arthritis.

PMID- 12412189
TI  - [New insights about immunopathology of lipoid nephrosis].
AB  - Clinical and experimental observations suggest that Lipoid Nephrosis (Minimal
      change nephrotic syndrome) results from T cell dysfunction due to still unknown
      mechanisms. By subtractive screening library, we identified 84 transcripts, of
      which twelve match with proteins of yet unknown function and thirty are unknown
      clones. Among the 42 known transcripts, at least 18 are closely involved in the
      TCR-mediated complex signaling cascade. This includes genes encoding components
      of the T cell receptor and proteins associated with the cytoskeleton scaffold, as
      well as transcription factors such as NF-kappa B and c-maf. During the relapse
      phase, we have found significant alterations of the NF-kappa B/I kappa Ba
      regulatory pathway, whereas very low levels of IL12R beta 2 mRNA were detected
      suggesting that T cell activation evolves toward a Th2 phenotype. We have shown
      that c-maf is highly induced, shuttling between nuclear and cytoplasmic
      compartment during the relapse and the remission phases, respectively.
      Contrasting with the nuclear expression of c-maf, low IL4 levels were detected in
      relapse. This suggests that the downstream target gene of c-maf in Lipoid
      Nephrosis, is not IL4 and provides new directions in research leading to identify
      the target gene, possibly an unknown Th2 cytokine, which might play a critical
      role in the pathophysiology of this disease. Thus, the combination of subtractive
      cloning and differential screening constitutes an efficient approach to identify
      genes likely to be involved in the pathophysiology of MCNS.

PMID- 12412190
TI  - [Diagnosis and treatment of disturbances in eating behavior among adolescents:
      anorexia nervosa and bulimia nervosa].
AB  - Anorexia nervosa and bulimia nervosa among youngsters mean heavy disturbances in
      eating behaviour, but they can be cured. The physician in charge of the treatment
      has to set up a contract with the patient and his family. The family has to be
      reassured because she is not responsible.

PMID- 12412191
TI  - Community based study to estimate prevalence, burden of illness and help seeking
      behavior in rheumatic diseases in Mexico City. A COPCORD study.
AB  - OBJECTIVE: To estimate the prevalence, burden of illness and help seeking
      behavior of musculoskeletal complaints and provide point prevalence estimates of
      osteoarthritis, low back pain, fibromyalgia, rheumatoid arthritis and gout among
      adult population in a suburban community in Mexico city. METHODS: Home survey of
      adults in a balanced and stratified sample validated against physical exam. Three
      trained interviewers applied a validated COPCORD core questionnaire. Subjects
      with pain (in the last seven days or ever) > or = 4 (0-10) and no trauma; or with
      current or past disability were evaluated preferably the same day by a trained
      clinician in a structured interview. A diagnosis using ACR criteria when
      available, recommendation or referral was provided as required. Analysis was
      based on descriptive statistics of participant characteristics, pain site and
      distribution, patterns of help seeking behavior. Point prevalence with 95%
      confidence intervals of most common diseases and associated disability rate.
      RESULTS: 1169 men and 1331 women were included. Pain in the last 7 days not
      associated with trauma was reported in 419 (17%) participants. The most common
      sites of involvement were knee (12.3%); low back (6.3%); ankles (6%) and
      shoulders (5.3%). The mean/SD pain score was 4.8/2.5. Thirteen percent of the
      total sample had some treatment. The general practitioner treated 72% of those;
      75% perceived good efficacy with medications. Point prevalence estimates and 95%
      CI were: disability: 1.4% (0.0-1.9); osteoarthritis: 2.3% (1.7-2.9);
      fibromyalgia: 1.4 (1.0-2.0); low back pain: 6.3% (5.4-7.3); rheumatoid arthritis:
      0.3% (0.1-0.6) and gout 0.4% (0.1-0.7). CONCLUSION: Pain in the last 7 days due
      to musculoskeletal disorders is 17% in this community. Medications were commonly
      prescribed. Point prevalence estimates of most common diagnoses was similar to
      other community surveys using COPCORD methodology but very different help seeking
      behavior.

PMID- 12412192
TI  - Aberrant expression of Fas ligand on anti-DNA autoantibody secreting B
      lymphocytes in patients with systemic lupus erythematosus: "immune privilege"
      like state of the autoreactive B cells.
AB  - BACKGROUND: Fas/Fas ligand (FasL) system has been assigned a pivotal role in the
      development and maintenance of peripheral tolerance, and mice with defects in
      their Fas/FasL system develop lupus-like symptoms. In this study we examined FasL
      expression of peripheral blood lymphocytes in patients with systemic lupus
      erythematosus (SLE). METHODS: We assessed FasL mRNA and protein expression by
      reverse transcription (RT)-PCR and immunoblotting and immunocytochemical
      staining, respectively, in patients with SLE. Anti-DNA antibody secreting B cells
      were purified using biotin labeled DNA and streptavidin-bead. RESULTS: Expression
      of FasL protein was not or very weakly detected in freshly isolated PBMC in
      normal individuals. In contrast, freshly isolated SLE PBMC exhibited the enhanced
      expression of FasL protein without in vitro stimulation. Not only purified T
      cells but also purified B cells expressed FasL on their cell surface
      spontaneously. In addition, freshly isolated anti-DNA autoantibody secreting B
      cells express FasL without in vitro stimulation. CONCLUSION: The results suggest
      that autoreactive B lymphocytes which aberrantly express FasL may kill Fas+
      immunoregulatory T lymphocytes. Thus aberrantly expressed FasL may facilitate
      escape of the autoreactive B cells from the immune tolerance system, and may
      contribute to the sustained secretion of autoantibodies in patients with SLE.

PMID- 12412193
TI  - Subtyping of osteoarthritic synoviopathy.
AB  - OBJECTIVE: Osteoarthritis research is traditionally concentrating on events
      within the degenerated articular cartilage. Changes in the synovial membrane are
      largely neglected. In fact, they are generally interpreted as secondary to the
      cartilage changes and not pathogenetically involved in the disease process. In
      this study, we present a systematic analysis of the synovial reaction pattern in
      early and late stages of the osteoarthritic disease process. METHODS: A large
      series of synovial specimens derived from early and late stage osteoarthritic
      cartilage disease were investigated by histological and immunohistochemical means
      for tissue architecture and inflammatory cell infiltrates. For comparison, also
      samples with rheumatoid arthritis, seronegative arthritis, and septic arthritis
      were included as well as normal synovial membrane specimens. RESULTS: In all
      specimens derived from patients with diagnosed osteoarthritis alterations of the
      synovial tissue were observed. A large spectrum of alterations was found in
      different stages of osteoarthritic joint disease and four different basic pattern
      of synovial reactions could be identified: (i) hyperplastic, (ii) inflammatory,
      (iii) fibrotic, and (iv) detritus-rich synoviopathy. CONCLUSION: We show that in
      all cases of clinically overt osteoarthritic joint disease significant synovial
      pathology is associated. Furthermore, our study clearly documents that in
      osteoarthritic synovium significant inflammation can occur. This is suggestive of
      a distinct pathogenetic role of the synovium also in osteoarthritic cartilage
      degeneration at least in a subset of cases.

PMID- 12412194
TI  - Increased but imbalanced expression of VEGF and its receptors has no positive
      effect on angiogenesis in systemic sclerosis skin.
AB  - OBJECTIVE: To investigate the expression of vascular endothelial growth factor
      (VEGF) and its vascular and lymphatic receptors in skin in systemic sclerosis
      (SSc) compared to systemic lupus erythematosus (SLE), Raynaud's phenomenon (RP)
      and normal healthy control skin. METHODS: Staining was performed using rabbit
      anti-human antibodies in DAKO TechMate Horizon staining robot programmed for the
      biotin-streptavidin protocol. RESULTS: VEGF was sporadically and weakly expressed
      in normal skin, but in spite of vascular damage in diseased skin, VEGF expression
      was only slightly upregulated. In contrast, its vascular receptors VEGFR-1 (Flt
      1) and VEGFR-2 (Flk-1), were clearly upregulated. Finally, the lymphatic VEGFR-3
      (Flt-4) receptor was also upregulated in diseased skin and ectopically expressed
      also in blood vessels. Negative staining and positive sample controls confirmed
      the specificity of the staining. CONCLUSION: The imbalanced expression of VEGF
      and its vascular receptors suggest that the compensatory efforts to angiogenesis
      fail in SSc, in part due to insufficient local production of VEGF, which was low
      compared to VEGFR expression. This is compatible with the recent observations on
      the lack of alpha V beta 3+ newly formed blood vessels in SSc skin. Since
      microvascular angiogenic stimuli normally induce first VEGF and then VEGFR, these
      findings also suggest that the angiogenic cascade is turned on, but there is a
      defect in the finalization of its effects. Normalization of angiogenic cascade in
      SSc could provide a future therapeutic target.

PMID- 12412195
TI  - NF-kappa B and I-kappa B overexpression in articular chondrocytes with
      progression of type II collagen-induced arthritis in DBA/1 mouse knees.
AB  - OBJECTIVE: To investigate the roles of NF-kappa B and I-kappa B in chondrocytes
      in the cartilage destruction of mouse collagen-induced arthritis. METHODS: DBA/1
      mice were immunized with bovine type II collagen (C II) emulsified with Freund's
      incomplete adjuvant. Histological abnormalities in the mouse knees were evaluated
      in sections stained with hematoxylin and eosin, or toluidine blue. Immunostaining
      using anti-NF-kappa B and anti-I-kappa B antibodies was performed to observe the
      expression and nuclear shift of NF-kappa B and I-kappa B in articular
      chondrocytes. RESULTS: Loss of metachromasia of perichondrial cartilage was found
      in 8 out of 10 knees of the mice at 5 weeks, and in all 10 knees at 7 weeks after
      C II-immunization. The mean percentage of NF-kappa B-positive chondrocytes at 3,
      5 and 7 weeks and in the control was 33.6 +/- 7.6, 54.9 +/- 2.7, 75.9 +/- 1.0 and
      27.9 +/- 3.8%, respectively. The mean percentage of NF-kappa B-positive nuclei
      was 9.1 +/- 0.7, 19.5 +/- 3.7, 47.5 +/- 3.0 and 8.6 +/- 0.1%, respectively. NF
      kappa B-positive chondrocytes significantly increased from 3 to 7 weeks in a time
      dependent manner (p < 0.0001). The percentage of I-kappa B-positive chondrocytes
      at 3, 5 and 7 weeks and in the control was 15.5 +/- 1.7, 41.1 +/- 2.5, 51.2 +/-
      5.7 and 12.1 +/- 2.1%, respectively. I-kappa B-positive chondrocytes
      significantly increased from 3 to 5 weeks (p < 0.005). CONCLUSION: These findings
      suggest that nuclear shift of NF-kappa B localization causes cartilage
      destruction in the early stage of arthritis in DBA/1 mice immunized with C II.

PMID- 12412196
TI  - Neutrophils from systemic lupus erythematosus patients demonstrate increased
      nuclear DNA damage.
AB  - OBJECTIVE: (i) To determine the levels of nuclear DNA damage in freshly isolated
      and cultured neutrophils from SLE patients (SLE), rheumatoid arthritis patients
      (RA) and healthy individuals and relate these to the percentage of apoptotic
      neutrophils. (ii) To assess rates of repair of neutrophil oxidative DNA damage.
      METHODS: The comet assay was used to quantify nuclear DNA damage in neutrophils
      from SLE patients (n = 20), control subjects (n = 15) and RA patients (n = 15).
      Levels of DNA damage were related to apoptosis as assessed by annexin V binding
      and morphology. Rates of repair of neutrophil oxidative DNA damage was measured
      by incorporating formamidopyrimidine-DNA glycosylase (FPG) into the comet assay.
      RESULTS: Nuclear DNA damage in freshly isolated and cultured (20 h) neutrophils
      was significantly greater in SLE patients (median = 12.5%, 27.3%; respectively)
      compared with RA patients (median = 9.4%, p = 0.002; 19.3%, p = 0.002;
      respectively) and control subjects (median = 8.2%, p = 0.003; 18.7%, p = 0.01,
      respectively). Significantly higher levels of circulating apoptotic neutrophils
      were demonstrated in SLE patients compared to RA and control subjects. Similar
      findings were observed following 20 h cultured neutrophil preparations. However,
      no significant direct correlation between neutrophil apoptosis and DNA damage was
      observed. Neutrophils from 3 of 5 SLE patients demonstrated an impaired ability
      to repair oxidatively modified DNA. CONCLUSION: Neutrophils from SLE patients
      display increased DNA damage and, additionally, may demonstrate defective repair
      of oxidative DNA damage. These features, in addition to increased rates of
      neutrophil apoptosis, may act as contributing factors to autoantigen excess and
      immune activation.

PMID- 12412197
TI  - Relationship between ossification of the stylohyoid ligament and enthesopathy: a
      comparative study.
AB  - OBJECTIVE: Stylohyoid apparatus might be an anatomic region in the cervical spine
      involved by enthesopathy. The aim of this study was to assess the elongation
      and/or ossification at the stylohyoid apparatus in the degenerative or
      inflammatory diseases such as ankylosing spondylitis (AS), psoriatic arthropathy
      (PsA) and cervical spondyloarthrosis (CS) in which cervical spine involvement can
      be seen. METHODS: Twenty-eight patients with AS, 25 patients with PsA, 31
      patients with CS and 50 controls who did not have any complaints or symptoms
      related with elongated styloid process (SP) were included in the study. On the
      lateral cervical radiographs, the anterior and posterior aspects of each
      vertebral body and intervertebral disk were carefully evaluated for the presence
      and severity of syndesmophytes, osteophytes or ossification of the adjacent
      longitudinal ligaments in the patient group. The entire osseous length of the SP
      was measured on the lateral and lateral oblique mandibular or cervical views or
      the anteroposterior views radiographs in the patients and controls. RESULTS:
      There were statistically significant differences between the patients with AS and
      control group and between the patients with PsA and control group with respect to
      the length of SP. The dimension of syndesmophytes or ligamentous ossification of
      the cervical spine involving C5-6 intervertebral disk level were significantly
      correlated with length of SP in the patients with AS. CONCLUSION: Elongated SP
      might be another manifestation of enthesopaty in cervical spine of the
      spondyloarthropathies.

PMID- 12412198
TI  - Influence of polysulphated polysaccharides and hydrocortisone on the
      extracellular matrix metabolism of human articular chondrocytes in vitro.
AB  - OBJECTIVE: To evaluate the influence of hydrocortisone and two polysulphated
      polysaccharides (xylosan polysulphate and chondroitin polysulphate) on the
      extracellular matrix metabolism of chondrocytes cultured in gelled agarose.
      METHODS: Isolated chondrocytes from normal femoral cartilage of the knee joints
      of 7 donors were cultured in gelled agarose to maintain their differentiated
      phenotype. After two weeks of culture, hydrocortisone (0.2 microgram/ml), xylosan
      polysulphate (10 micrograms/ml) and chondroitin polysulphate (10 micrograms/ml)
      were added to the culture media supplemented with or without interleukin (IL)-1
      beta. After one week of incubation, the cells were liberated from the agarose
      with agarase. Isolated cells were labelled with antibodies against aggrecan and
      type II collagen, as well as biotinylated hyaluronic acid binding protein to
      analyse the extracellular matrix (ECM) molecules in the cell-associated matrix
      (CAM). The levels of matrix metalloproteinase (MMP)-1, -3, and -13, as well as
      tissue inhibitor of metalloproteinase (TIMP)-1 and -3 were determined after the
      cells had been permeabilised and stained with the appropriate antibodies.
      Triplicate samples were analysed with flow cytometry. RESULTS: IL-1 beta
      decreased the accumulation of aggrecan, hyaluronan and type II collagen in the
      CAM and increased intracellular MMP-1, -3 and -13 at a concentration of 100
      pg/ml. Xylosan polysulphate and chrondroitin polysulphate restored the expression
      of these CAM molecules in these IL-1 beta-treated cultures. Hydrocortisone
      stimulated the accumulation of CAM aggrecan and hyaluronan whether or not under
      the exposure to IL-1 beta. Intracellular MMP-1, -3, -13 and TIMP-1 and -3 of IL-1
      beta-treated cells was downregulated after treatment with hydrocortisone.
      CONCLUSION: Both hydrocortisone and the two polysulphated polysaccharides could
      stimulate the accumulation of CAM macromolecules of IL-1 beta-treated
      chondrocytes. This effect probably resulted in part from the downregulation of
      MMPs. These agents showed cartilage structure modifying effects in vitro.

PMID- 12412199
TI  - Efficacy of an EMG-biofeedback therapy in fibromyalgia patients. A comparative
      study of patients with and without abnormality in (MMPI) psychological scales.
AB  - OBJECTIVE: The aim of the present study was to investigate the efficacy of EMG
      biofeedback in female fibromyalgia patients with and without abnormality in the
      MMPI. METHODS: According to their MMPI profile out of a total of 24 patients, 12
      patients were classified as 'psychologically abnormal' (at least one scale with a
      T-score higher than 70) and 12 as 'normal'. In a quasi-experimental setting, all
      patients underwent EMG-biofeedback therapy (12 sessions, twice weekly), after a
      waiting period of six weeks. Clinical symptoms (pressure point sensitivity,
      secondary symptoms), subjective pain dimensions as well as quality of life were
      assessed before and after the waiting period, immediately after the biofeedback
      training and at a three month follow up. RESULTS: Within the 'psychologically
      abnormal' patients primarily depressive, hypochondriacal and hysterical symptoms
      were found. Statistical evaluation showed that 'psychologically normal' patients
      experience long-term relief from pain measured in terms of pressure point
      sensitivity; vitality and mental health. 'Psychologically abnormal' patients, on
      the other hand, showed improvements in all the measured parameters (clinical
      symptoms, sensory and affective pain components, quality of life) after EMG
      biofeedback. Long-term improvement, however, was observed only in pressure point
      sensitivity and the sensory pain dimension. CONCLUSION: The results suggest, that
      assessment of FM-patients should not only consist of commonly used ACR diagnostic
      criteria but should also include psychodiagnostic criteria, as these may co
      determine treatment outcome. One approach to treating FM patients with additional
      psychological abnormality might be combining EMG-biofeedback that enhances self
      efficacy with psychotherapy that helps patients to become aware of their basic
      psychological problems.

PMID- 12412200
TI  - Gold sodium thiomalate suppresses the differentiation and function of human
      dendritic cells from peripheral blood monocytes.
AB  - OBJECTIVE: Gold sodium thiomalate (GST) is a drug commonly used for the treatment
      of rheumatoid arthritis (RA). To clarify the mechanism of therapeutic effects of
      GST on RA, we investigated if GST affects the differentiation of dendritic cells
      (DC), which are thought to play a pivotal role in RA pathogenesis. METHODS: We
      generated immature DC (iDC) in vitro from PB monocytes during the 5 to 7-day
      culture in the presence of IL-4 and GM-CSF. Mature DC (mDC) were induced by
      adding TNF alpha on day 5 of the 7-day culture with GM-CSF and IL-4. DC capacity
      of stimulating T cells was examined in allogenic MLR using generated DC as
      stimulators. IL-12 production from DC was assayed with ELISA. RESULTS: We found
      that: 1) mDC generated in the presence of GST showed lower expression of CD1a,
      CD83, CD80, CD86, HLA-ABC and HLA-DR compared to control mDC on FACS analysis. 2)
      GST-treated mDC showed reduced capacity of stimulating allogenic T cells in mixed
      leukocyte reaction. 3) IL-12p70 production after stimulation with SAC or LPS plus
      IFN gamma was markedly reduced in GST-treated mDC. CONCLUSION: GST suppresses the
      differentiation and function of DC generated from peripheral blood monocytes.
      This previously unknown action may explain the in vivo effects of GST in the
      treatment of RA.

PMID- 12412201
TI  - The Dougados Functional Index with the 5-point Likert scale is sensitive to
      change due to intensive physiotherapy and exercise in spondyloarthropathy.
AB  - OBJECTIVE: The aim of the present study was to evaluate whether the Dougados
      Functional Index (DFI) with 5-point Likert scale is sensitive enough to
      demonstrate the efficacy of intensive physiotherapy and exercise. METHODS: Eight
      one consecutive patients with spondyloarthropathy (SpA) completed self
      administered questionnaires on functional analysis, the Bath Ankylosing
      Spondylitis Functional Index (BASFI) and the DFI with 5-point Likert scale, at
      the beginning and end of a 3-week in-patient course based on intensive
      physiotherapy and exercise. The objective effect of the course was measured with
      10 ranges of movement. After a 6-month follow-up the patients completed the
      questionnaires by mail for analysis of the lasting impact of rehabilitation on
      function. RESULTS: The in-patient course was highly effective: all ranges of
      movement and both functional indices including the DFI with 5-point Likert scale
      improved to a highly significant degree. Six months later functional ability as
      measured by the DFI remained significantly better than at baseline before the in
      patient course, but the BASFI had returned to the baseline level. CONCLUSION: The
      DFI with 5-point Likert scale is sensitive enough to demonstrate the effect of
      intensive physiotherapy and exercise.

PMID- 12412202
TI  - Thyroid cancer in HCV-related mixed cryoglobulinemia patients.
AB  - OBJECTIVE: The prevalence of thyroid cancer in a series of unselected HCV-related
      mixed cryoglobulinemic patients was investigated in comparison with a control
      group. METHODS: Among 107 consecutive patients with mixed cryoglobulinemia (MC),
      94 were eligible for the study. A control group was obtained from a sample of the
      general population (2,401 subjects), age > 50 years, who had undergone thyroid
      ultrasonography (582 subjects); 5 sex-matched controls were randomly assigned to
      each MC patients (470 individuals). The mean age was similar in the MC patients
      and controls (64.2 +/- 10.0 vs. 63.4 +/- 7.0). RESULTS: The prevalence of thyroid
      nodules was higher, although not significantly so, in control subjects than in MC
      patients (65.3 vs. 54.8%). Two patients with papillary thyroid cancer were found
      in the MC series, while no case was observed among controls (p = 0.001, chi
      square P value; p = 0.02, Fisher's exact test). In both MC patients with
      papillary thyroid cancer lymphocytic infiltration was observed in the thyroid
      tissue. CONCLUSION: The possible association between HCV-related MC and thyroid
      cancer indicates that a careful monitoring of the thyroid would be opportune
      during the clinical follow-up of HCV-associated MC patients, especially in those
      with signs of thyroid autoimmune disorders.

PMID- 12412203
TI  - Pregnancy associated osteoporosis: the familial effect.
AB  - OBJECTIVE: The etiology and pathogenesis of pregnancy associated osteoporosis is
      unclear. Whether pregnancy has simply been an aggravating factor or is a direct
      etiologic cause responsible for severe bone loss needs to be elucidated. METHODS:
      In order to evaluate the contribution of familial factors to pregnancy
      osteoporosis, we analyzed the bone mass of 15 relatives of 5 women with pregnancy
      osteoporosis. Most of the patients suffered from severe back pain associated with
      vertebral fractures in their first pregnancy. Extensive clinical, laboratory and
      radiological investigations were performed to exclude secondary causes of
      osteoporosis. Bone mineral density measurements were performed on 15 first order
      family members and the results were compared with those of a control group of 20
      healthy members of 5 families. RESULTS: Osteoporosis was present in 53% of the
      relatives of patients with pregnancy osteoporosis and in 15% of the controls (P <
      0.05). CONCLUSION: These results highly suggest that some patients with pregnancy
      associated osteoporosis have a genetic determination of low peak bone mass, and
      gestation, due to its association with physiological metabolic disturbances,
      constitutes a risk factor for the development of skeletal fractures in these
      patients.

PMID- 12412204
TI  - CC chemokine receptor 5 and interleukin-1 receptor antagonist gene polymorphisms
      in patients with primary Sjogren's syndrome.
AB  - OBJECTIVE: Interleukin-1 receptor antagonist (IL-1Ra) and also mononuclear cell
      attractant chemokines CCL3, CCL4 and CCL5 have been implicated in the
      immunopathogenesis of primary Sjogren syndrome (pSS). Both the gene coding for
      receptor CCR5 binding the aforementioned CCL ligands and the gene for IL-1Ra are
      polymorphic. We have therefore in a case control study assessed the putative role
      of these "candidate" polymorphic genes in the inflammatory process in Sjogren
      syndrome. METHODS: DNA was obtained from 39 unrelated patients with primary
      Sjogren's syndrome and 76 unrelated healthy controls; all subjects were
      Caucasians of Slovak origin. CCR5 delta 32 and IL-1Ra VNTR polymorphisms were
      genotyped by PCR-SSP. RESULTS: The frequencies of CCR5 delta 32 in patients with
      pSS were different from that in control subjects: there was an apparent decrease
      of the mutant allele in the patient group. CCR5 delta 32/CCR5 heterozygosity was
      associated with a reduced relative risk of pSS (OR 0.35, p = 0.043). There was no
      difference in the distribution of the alleles of the IL-1Ra VNTR polymorphism
      between the groups of pSS patients and control subjects. CONCLUSION: In this
      population of patients with Sjogren's syndrome, the frequency of CCR5 delta
      32/CCR5 genotype is significantly decreased. The data suggests that carrier
      status for the CCR5 delta 32 allele may contribute to protection from the
      development of primary Sjogren's syndrome. In contrast, IL-1Ra VNTR polymorphism
      does not confer susceptibility to primary Sjogren's syndrome in Slovak
      Caucasians.

PMID- 12412205
TI  - Coronary stent implantation in Behcet's disease.
AB  - Behcet's disease (BD) is a systemic vasculitis that rarely involves the coronary
      arteries. Coronary arteritis may lead to myocardial infarction and death, and the
      management of coronary lesions due to BD has been described only in a small
      number of patients. The outcome of a young patient with BD is reported who was
      admitted with acute coronary syndrome and underwent balloon angioplasty and
      coronary stent implantation. Coronary stent implantation is an alternative
      treatment for coronary artery lesions of BD but careful monitoring is mandatory
      due to the progressive vasculities.

PMID- 12412206
TI  - A case of limb-girdle muscular dystrophy with serum anti-nuclear antibody which
      led to a mistaken diagnosis of polymyositis.
AB  - A 45-year-old woman had first been diagnosed with polymyositis because of the
      presence of focal necrosis, regeneration and inflammatory infiltration in the
      muscle fibers, and elevated creatinine phosphokinase levels. However, a
      pathological re-evaluation and family history led to the definite diagnosis of
      limb-girdle muscular dystrophy (MD). This case suggests that MD should be taken
      into consideration in the differential diagnosis of the inflammatory myopathies
      and genetic surveys including dystrophin molecule may be necessary if the
      condition manifests during or after adolescence, or when the family history is
      uninformative. In this case, the serum anti-nuclear antibody was positive, and it
      may represent the first time that ANA positivity has been found in limb-girdle
      MD.

PMID- 12412207
TI  - Thalidomide: focus on its employment in rheumatologic diseases.
AB  - Thalidomide is an immunomodulatory agent; although its mechanisms of action are
      not fully understood, many authors have described its anti-inflammatory and
      immunosuppressive properties. More interestingly, thalidomide has shown the
      ability to suppress tumor necrosis factor alpha (TNF alpha) production and to
      modify the expression of TNF alpha induced adhesion molecules on endothelial
      cells and on human leukocytes. Thalidomide has been used in several diseases
      (i.e. dermatological, autoimmune, gastrointestinal). In this review we focus
      specifically on the use of this drug in disorders with rheumatological features
      such as lupus erythematosus, rheumatoid arthritis and Still's disease, ankylosing
      spondylitis, and Behcet's disease. Despite its well known side effects, first of
      all peripheral nerve involvement and teratogenesis, which can be avoided by
      following strict guidelines, thalidomide could represent an alternative drug in
      some rheumatological conditions, particularly in patients who show resistance,
      contraindication or toxicity with other conventional treatments.

PMID- 12412208
TI  - Treatment of juvenile idiopathic arthritis with intra-articular triamcinolone
      hexacetonide: evaluation of clinical effectiveness correlated with circulating
      ANA and T gamma/delta + and B CD5+ lymphocyte populations of synovial fluid.
AB  - OBJECTIVE: The aims of the study were to assess the effect of intra-articular
      treatment with triamcinolone hexacetonide (TH) in juvenile idiopathic arthritis
      (JIA) and to investigate whether treatment response correlates with the presence
      of antinuclear antibodies (ANA) in the serum and/or B CD5+ and T gamma/delta +
      lymphocytes in the synovial fluid. METHODS: A total of 37 patients (81% females,
      56% ANA+) with oligoarticular JIA involving knees were treated with intra
      articular injections of TH after failing to respond to NSAIDs for two months.
      Eighteen patients were treated within 6 months of onset, 19 were treated more
      than 6 months after onset. RESULT: Mean duration of remission was 13.9 months.
      Twelve patients (7 ANA+) had stable remission after a single injection; 13
      patients (3 ANA+) experienced more than 6 months' remission but subsequently had
      a relapse; 12 patients (11 ANA+) had a relapse within six months of injection. Of
      20 patients treated within 6 months of onset, 17 had stable remission whereas
      only 8 out of 17 who were treated during relapse attained stable remission (p =
      0.03). The mean percentage of T gamma/delta + and of B CD5+ lymphocytes in
      synovial fluid was the same as in peripheral blood of normal subjects.
      CONCLUSION: Our data indicate that local treatment with slow-release steroids is
      very effective in oligoarticular JIA. Prolonged remission was less likely in the
      presence of ANA positivity, probably because the disease is immunologically more
      active. Finally, our data suggest that the earlier the treatment, the easier it
      is to obtain a protracted, and possibly permanent, response.

PMID- 12412209
TI  - Etanercept in systemic juvenile idiopathic arthritis.
AB  - OBJECTIVE: To evaluate the effectiveness of etanercept in patients with systemic
      juvenile idiopathic arthritis (SJIA) refractory to methotrexate (MTX) therapy in
      a pediatric rheumatology practice. METHODS: Fifteen patients with SJIA with
      active polyarthritis refractory to higher dose MTX (> or = 20 mg/m2/week) for at
      least 3 months were included. Patients received etanercept 0.4 mg/Kg twice weekly
      concomitantly with MTX. Observed period of treatment ranged from 5 to 12 months
      (median 9 months). RESULTS: Improvement of ESR, swollen and limited joint counts,
      functional capacity, and general wellbeing was achieved by 14/15 patients. The
      most significant impact on these variables was observed 3 to 5 months after
      treatment onset. Mean time to improvement was 2 months. In the 4 patients who
      presented fever and rash, these signs disappeared after the beginning of
      etanercept treatment and reappeared during flares. Three patients showed
      sustained clinical and biochemical remission on low dose MTX (< or = 5
      mg/m2/week). Thirteen relapses were observed in 9 (60%) patients at a mean of 7.6
      months after therapy was begun. Etanercept was discontinued due to lack of
      efficacy in 7 patients, only after higher dose (1 mg/kg/dose) was used. MTX and
      corticosteroid doses were decreased during the observation period. No serious
      side effects were observed. CONCLUSIONS: Etanercept, in combination with MTX,
      demonstrated benefit soon after initiation of treatment in patients with
      refractory SJIA, but flares and progressive loss of effectiveness were observed
      with continued treatment in most patients. Sharp decreases in the dose of MTX and
      corticosteroids may have contributed to subsequent occurrence of flares. Changes
      in MTX and corticosteroids doses should probably need to be made gradually, and
      it is possible that patients on SJIA should continue on therapeutic doses of MTX
      while being on etanercept in order to maintain therapeutic benefit.

PMID- 12412210
TI  - A short-term follow-up of enthesitis and arthritis in the active phase of
      juvenile onset spondyloarthropathies.
AB  - OBJECTIVE: To describe the characteristics of enthesitis and arthritis in the
      active inflammatory stage of juvenile onset spondyloarthropathies (SpA) during a
      short-term follow-up. PATIENTS AND METHODS: The study group included data of 33
      patients with juvenile-onset SpA with enthesitis in > or = 3 sites, arthritis in
      > or = 4 joints, and erythrocyte sedimentation rate (ESR) of > or = 25 mm/h
      despite treatment, who participated in a 26-week, double-blind, sulfasalazine
      versus placebo trial that showed no significant differences between groups in
      regard to enthesitis and arthritis. RESULTS: Twenty-seven boys and 6 girls (mean
      age: 15.3 +/- 3.5 years; mean disease duration: 4.1 +/- 2.7 years) with the
      seronegative enthesopathy and arthropathy (SEA) syndrome (n = 20) or ankylosing
      spondylitis (AS; n = 13) comprised the group. Throughout the study, the mean (+/-
      SD) number of swollen joints and tender entheses were 4.6 +/- 2.5 and 8.3 +/-
      5.4. The entheses and joints most frequently involved were the calcaneal
      attachments of the plantar fascia (87.9%) and Achilles tendon (81.8%) and the
      ankle (87.9%) and knee (72.7%), respectively. There was pain in the cervical,
      thoracic, and lumbar spine in 39.4%, 69.7%, and 63.6% of patients and in the
      sacroiliac joints in 48.5%. Mid-foot involvement (or tarsitis) occurred in 29
      patients (87.9%). Except for the feet, the simultaneous occurrence of enthesitis
      and arthritis in other sites was rare. Overall, there were no significant
      differences between SEA syndrome and AS patients. CONCLUSIONS: Disease activity
      shows a significant trend for entheses and joints of the feet and a significant
      prevalence of axial enthesitis in juvenile onset SpA. Mid-foot involvement
      appears to be the most characteristic and potentially, the most severe form of
      disease in these patients.

PMID- 12412211
TI  - Infection related arthritis induced by tonsillar Chlamydia trachomatis and
      Streptococcal infection.

PMID- 12412212
TI  - Reactive arthritis induced by Gardnerella vaginalis.

PMID- 12412213
TI  - Treatment of recurrent oral aphthous ulcers with etanercept.

PMID- 12412214
TI  - Lack of evidence for herpesvirus, retrovirus, or parvovirus infection in Henoch
      Schonlein purpura.

PMID- 12412215
TI  - Transient remission of systemic manifestations following intraarticular
      triamcinolone hexacetonide injection in a boy with systemic juvenile idiopathic
      arthritis.

PMID- 12412216
TI  - Invasive aspergillosis in juvenile systemic lupus erythematosus. A clinico
      pathologic case.

PMID- 12412217
TI  - Is methotrexate plus cyclosporine A a useful salvage therapy for rheumatoid
      arthritis patients unresponsive to other types of methotrexate combination
      treatment?

PMID- 12412218
TI  - The cervical spine in patients with ankylosing spondylitis.

PMID- 12412219
TI  - [Will the third millenium fulfill expectations for the role of molecular biology,
      genetics and immunology in medicine?].

PMID- 12412220
TI  - [Jozef Strus from Poznan--Physician of Kings].

PMID- 12412221
TI  - [Use of clinical tests to detect anti-neutrophil cytoplasmic antibodies in
      vasculitis].

PMID- 12412222
TI  - [Contribution of inflammation factors to etiology of atherosclerosis and
      aneurysms].

PMID- 12412223
TI  - [Sjogren's syndrome--an example of integration in the medical sciences].

PMID- 12412224
TI  - [Lymphomas as a complication of Sjogren's syndrome].

PMID- 12412225
TI  - [Early diagnosis of rheumatoid arthritis].

PMID- 12412226
TI  - [Myocarditis--etiology and clinical manifestation].

PMID- 12412227
TI  - [Laboratory diagnosis of myocarditis].

PMID- 12412228
TI  - [Treatment of myocarditis].

PMID- 12412229
TI  - [The role of inflammation factors in the development of atherosclerosis--clinical
      significance].

PMID- 12412231
TI  - [Inherited thrombophilia and complications of pregnancy].

PMID- 12412230
TI  - [Estrogens and aging in women].

PMID- 12412232
TI  - [Venous thromboembolic risk in women].

PMID- 12412233
TI  - [Antithrombotic prophylaxis in pregnancy].

PMID- 12412234
TI  - [G-CSF and GM-CSF in neutropenia of various origins].

PMID- 12412235
TI  - [Use of hematopoietic growth factors after bone marrow transplantation].

PMID- 12412236
TI  - [Cytokines in kidney diseases--inflammation mediators and treatment targets].

PMID- 12412237
TI  - [Possible applications of cytokines in clinical oncology].

PMID- 12412238
TI  - [Indications and hematopoietic stem cell transplantation in disease of blood].

PMID- 12412239
TI  - [High dose chemotherapy and hematopoietic stem cell transplantation in patients
      with myeloma].

PMID- 12412240
TI  - [High dose therapy and hematopoietic stem cell transplantation in Hodgkin's
      disease].

PMID- 12412241
TI  - [High dose therapy and hematopoietic stem cell transplantation in non-Hodgkin's
      lymphomas].

PMID- 12412242
TI  - [Allogenic transplantation of hemopoietic sells in aplastic anemia].

PMID- 12412243
TI  - [High dose chemotherapy procedures supported by hemopoietic stem cell
      transplantation in treatment of autoimmune diseases].

PMID- 12412244
TI  - [Non-myeloablative therapy and allogeneic hematopoietic stem cell transplantation
      in hematologic malignancies].

PMID- 12412245
TI  - [Hypo- and hyperkalemia--practical aspects of diagnosis and therapy].

PMID- 12412246
TI  - [Metabolic disturbances as a cause of diseases in civilized areas. Significance
      for internal medicine practice].

PMID- 12412247
TI  - [Modern treatment for obesity and its role in prophylaxis of disease involving
      internal organs].

PMID- 12412249
TI  - [Rationalization of nutrition in treatment of metabolic diseases. New problems in
      light of progress in science].

PMID- 12412248
TI  - [Treatment of dyslipidemia. Progress in cardiologic practice].

PMID- 12412250
TI  - [Early diagnosis of COPD].

PMID- 12412251
TI  - [Lung volume reduction surgery].

PMID- 12412252
TI  - [Role of corticosteroids in chronic obstructive pulmonary disease].

PMID- 12412253
TI  - [Noninvasive mechanical ventilation].

PMID- 12412254
TI  - [Principles of inhalation treatment--does the drug always reach its receptor?].

PMID- 12412255
TI  - [Epidemiology of arterial hypertension with emphasis on population studies
      conducted in Poland].

PMID- 12412256
TI  - [Non-pharmacologic treatment for hypertension--theory and practice].

PMID- 12412257
TI  - [Strategy for pharmacologic treatment of hypertension].

PMID- 12412258
TI  - [Criteria and diagnostic methods or evaluations of therapeutic quality for
      directing prevention of symptoms in diabetes].

PMID- 12412259
TI  - [Advances in pharmacotherapy of diabetes mellitus].

PMID- 12412260
TI  - [Diabetes problems in elderly patients].

PMID- 12412261
TI  - [Contemporary problems with respiratory tract infections with special regard to
      viral infections].

PMID- 12412262
TI  - [Immunology of influenza].

PMID- 12412263
TI  - [Surveillance of influenza and its prophylaxis].

PMID- 12412264
TI  - [Chemokines in the pathomechanisms of viral infection].

PMID- 12412266
TI  - [The role of genetic studies in the pathogenesis, diagnosis and therapy of type 1
      diabetes].

PMID- 12412265
TI  - [The significance of genetic investigations in diabetology].

PMID- 12412267
TI  - [MODY diabetes: differences in the clinical picture caused by genetic
      heterogeneity in clinical practice].

PMID- 12412269
TI  - [Genetics of late complications of diabetes--importance of gene candidates in
      development of diabetic nephropathy].

PMID- 12412268
TI  - [Genetic basis of impaired insulin secretion, insulin resistance, the clinical
      picture and treatment of type 2 diabetes].

PMID- 12412270
TI  - [What predisposes patients with diabetes to hypertension?].

PMID- 12412271
TI  - [Acute myeloid leukemia--diagnosis and prognostic classification].

PMID- 12412272
TI  - [Treatment of acute myeloid leukemias depending on risk group].

PMID- 12412273
TI  - [Treatment of acute myelogenous leukemia in elderly patients].

PMID- 12412274
TI  - [Chronic myeloid leukemia--contemporary diagnosis and treatment possibilities].

PMID- 12412275
TI  - [Transplantation of hemopoietic stem cells in treatment of chronic myeloid
      leukemia].

PMID- 12412276
TI  - [Interferon-alpha in treatment of patients with chronic myeloid leukemia-
      indications and results].

PMID- 12412277
TI  - [Treatment of myelodysplastic syndromes].

PMID- 12412278
TI  - [Pathology of hepatocytes in light of cell membrane pathology].

PMID- 12412279
TI  - [Chronic viral hepatitis: therapy in the turn of the century].

PMID- 12412280
TI  - [Intrahepatic cholestatic syndromes].

PMID- 12412281
TI  - [Alcoholic and nonalcoholic liver steatosis].

PMID- 12412282
TI  - [The role of depression and anxiety in somatic diseases].

PMID- 12412283
TI  - [Treatment of patients with osteoporosis].

PMID- 12412284
TI  - [Local and generalized lymphadenopathy--diagnostic difficulties].

PMID- 12412285
TI  - [Antiphospholipid antibodies in children with idiopathic thrombocytopenic
      purpura].
AB  - Three antiphospholipid antibodies (aPLs), namely, antiphosphatidylinositol
      antibody (antiinositol antibody), antiphosphatidylserine antibody (antiserine
      antibody), and anticardiolipin. beta 2-glycoprotein I complex antibody (antiCL.
      beta 2-GPI antibody), were determined in 49 children with idiopathic
      thrombocytopenic purpura (ITP) consisting of 14 newly-diagnosed cases and 35
      chronic cases. Determination of aPL was performed twice in the newly-diagnosed
      patients, once each during the acute and convalescent phases, and once in the
      chronic patients. The positive rates in the acute and convalescent phases of the
      newly-diagnosed group and in the chronic group were, respectively, 14.3%, 28.6%,
      and 18.8% for the antiinositol antibody, 14.3%, 14.3%, and 15.6% for the
      antiserine antibody, and 21.4%, 28.6%, and 25.0% for either of these 2
      antibodies. Thus, antiinositol and antiserine aPLs were present at high
      incidences; however, all patients were negative for the antiCL. beta 2-GPI
      antibody. No correlation was noted between either the antiinositol or the
      antiserine antibody and peripheral platelet count, anti-GP IIb/IIIa antibody or
      PAIgG. Thus, although some aPLs are present in both acute and chronic pediatric
      ITP, the aPLs seems to be of an infectious disease type. No results that suggest
      possible involvement of aPLs in ITP pathology were obtained.

PMID- 12412286
TI  - [Acute myeloid leukemia with infective endocarditis].
AB  - We present here a patient with acute myeloid leukemia (M2) who developed fatal
      infective endocarditis. On admission, the patient (67-year-old male) had mitral
      stenosis and atrial fibrillation. Complete remission was achieved after induction
      chemotherapy. During the course of consolidation therapy, he developed sepsis
      caused by coagulase-negative staphylococcus, which was successfully treated with
      antibiotics. Thereafter, blood culture yielded multidrug-resistant staphylococcus
      epidermidis. An echocardiogram revealed mitral valve regurgitation with
      vegetation. He was diagnosed as having infectious endocarditis. In spite of
      prolonged antibiotic therapy, destruction of the mitral valve progressed, and the
      patient underwent valve replacement therapy. He died of cardiac tamponade 5 days
      after the surgery.

PMID- 12412287
TI  - [Basedow disease occurring after allogeneic bone marrow transplantation for acute
      lymphoblastic leukemia].
AB  - It has been reported that autoimmunity might be sometimes transferred from a
      donor to a recipient following allogenic bone marrow transplantation (allo-BMT).
      We report a patient to whom Basedow disease was transferred from the donor
      through an allo-BMT. A 18-year-old man with acute lymphoblastic leukemia,
      received the allo-BMT from his HLA-identical sister. Two-years later, he
      developed symptoms of palpitations and general fatigue. He was diagnosed as
      having Basedow disease because of hyperthyroidism, and high levels of the anti
      thyroid stimulating hormone receptor antibody and antithyroid antibody. When he
      received the allo-BMT, his donor had neither the clinical symptoms of Basedow
      disease, nor abnormal findings on examination to determine her eligibility as a
      the donor. We retrospectively assayed anti-thyroid antibodies from their
      cryopreserved sera, and found the donor's anti-thyroid antibody was positive,
      while her serum was negative before transplantation. It was apparent that the
      donor had subclinical Basedow disease. The patient has remained in complete
      remission without any signs of chronic graft-versus-host disease (GVHD) up till
      the time of writing. It is believed that an anti-thyroid tissue reactive B-cell
      clone was transferred from the donor to the patient and commenced to produce
      antibodies. It is suggested that thorough investigation of the donor's
      autoimmunity is needed before allo-BMT. If the recipient develops an autoimmune
      disease after allo-BMT, we should definitely investigate the donor's
      autoimmunity.

PMID- 12412288
TI  - [Acute lymphoblastic leukemia with p190 type bcr/abl chimeric mRNA at relapse].
AB  - We describe the case of a 23-year-old man with acute lymphoblastic leukemia in
      whom the Philadelphia chromosome was first detected in the late stage of the
      disease. At diagnosis, the patient's leukocyte count was 39,400/microliter and
      leukemic cells were positive for CD10, 19, 20, 33, 34 and HLA-DR. Karyotypic
      analysis at diagnosis revealed 46,XY. Complete remission was achieved after the
      first induction therapy, but the disease recurred after 9 months. The patient
      underwent allogeneic peripheral blood stem cell transplantation from his HLA
      identical mother, but relapse occurred on day 80. The proportion of bone marrow
      lymphoblasts decreased transiently after donor lymphocyte infusion but later
      increased, and the patient died on day 362. The Philadelphia chromosome was first
      detected by karyotypic analysis on day 256. p190-type bcr/abl mRNA transcripts
      were negative following RT-PCR at the initial diagnosis, but became positive from
      the first relapse through the late stage. Generally, the product of the bcr/abl
      fusion gene has been thought to play an important role in leukemogenesis, however
      the present case suggests that this gene product is also related to disease
      progression.

PMID- 12412290
TI  - [Four cases of spinal non-Hodgkin's lymphoma].
AB  - We report four cases with spinal non-Hodgkin's lymphoma (3 male and 1 female, 33
      to 58 years old). On administration, back pain progressing to paraplegia was
      observed in all cases. Sphincter dysfunction was observed in two cases. Magnetic
      resonance imaging (MRI) studies were most useful for the clinical diagnosis of
      spinal lymphoma. Diffuse large B cell lymphoma was revealed from
      immunohistochemical studies of bone biopsies. The patients' clinical stagings
      were IV in three and I E in one case. One case treated by surgery followed by
      chemotherapy (CMT) and radiation therapy (RT) resulted in progressive disease. RT
      followed by CMT was given in the other cases. Two cases showed a partial response
      and one died from progressive disease. In all cases, either surgical or radiation
      therapy was helpful for the amelioration of the patients' progressive paraplegia
      and sphincter dysfunction.

PMID- 12412289
TI  - [Angioimmunoblastic T cell lymphoma (AITL) with autoimmune thrombocytopenia].
AB  - We present a case of angioimmunoblastic T cell lymphoma (AITL) with autoimmune
      thrombocytopenia. A 85-year-old man was admitted to our hospital with
      thrombocytopenia, generalized lymphadenopathy, pleural effusion, and splenomegaly
      in June 2000. Blood chemistry revealed hemoglobin and platelet counts of 8.8 g/dL
      and 26 x 10(9)/L, respectively. The level of platelet-associate-IgG was 2568.9
      ng/10(7) cells. The direct Coombs test was positive. The level of serum IL-6 was
      10.2 pg/ml. Megakaryocytes in the bone marrow increased. Lymph node biopsy showed
      diffuse proliferation of atypical lymphoid cells with a clear cytoplasm
      accompanied by plasma cells and small vessels. He was diagnosed as having AITL
      with autoimmune thrombocytopenia and hemolytic anemia. He received repeated
      platelet transfusion, and a limited effect of prednisolone therapy on his
      platelet count was observed. Combination chemotherapy lessened the extent of the
      lymphadenopathy and slightly elongated the interval of platelet transfusion. We
      next performed splenic irradiation and a slight increase in the platelet count
      was observed. He died of pneumonia in August 2000. Autoimmune thrombocytopenia
      associated with AITL is rare and the therapy containing prednisolone and
      chemotherapy is reported to be partly effective. Our case showed a minor response
      of autoimmune thrombocytopenia to splenic irradiation. Therapeutic intervention
      for hypersplenism should be considered if thrombocytopenia is not improved by
      chemotherapy alone.

PMID- 12412291
TI  - [Primary adrenal lymphoma: a case report and literature review in Japan].
AB  - A 78-year-old male was admitted to our hospital complaining of nausea, general
      fatigue and anorexia in November, 1999. Clinical findings on admission were
      weight loss and dehydration but surface lymph nodes were not palpable. Masses in
      the bilateral adrenal glands were detected by ultrasonography, computed
      tomography and magnetic resonance imaging. Laboratory examinations revealed
      hyponatremia and hyperkalemia. Subsequent endocrine function tests showed normal
      serum cortisol and increased adrenocorticotropic hormone (ACTH) levels. Rapid
      ACTH test and cortico-hormone releasing hormone (CRH) test revealed insufficient
      secretion of cortisol. The histological diagnosis of the adrenal gland by
      laparotomy was diffuse large B-cell lymphoma. We diagnosed primary adrenal
      lymphoma with adrenal insufficiency. The patient underwent hormone supplementary
      therapy and chemotherapy, but he died two months later. We report on this rare
      primary adrenal lymphoma case and summarize the reports of this disease in the
      Japanese literature.

PMID- 12412292
TI  - [Hodgkin's disease presenting with progressive liver failure].
AB  - We report an unusual case of a 70-year-old man with a diagnosis of Hodgkin's
      disease, who presented with fever and liver dysfunction. A few cervical lymph
      nodes, less than 1 cm in diameter were palpable, but other lymph nodes were not
      detected even by CT scan. Blood cell counts showed thrombocytopenia (platelet
      counts 6.8 x 10(4)/microliter), and some values for liver enzymes were out of the
      normal range (AST 56 U/l, ALT 87 U/l, LDH 347 U/l, ALP 1,529 U/l, and gamma-GTP
      190 U/l). Abdominal CT scan showed diffuse enlargement of the liver and spleen.
      Endoscopic retrograde biliary cholangiopancreatography was performed because of
      progressive jaundice, but no abnormality was found in the biliary tract. A few
      granulomas were observed in bone marrow clot specimens, but tumor cells were not
      detected. A diagnosis of Hodgkin's disease was established by a cervical lymph
      node biopsy. Chemotherapy was immediately instituted, and both the jaundice and
      fever improved dramatically. Because cervical lymph nodes were not detected at
      one month after the onset and liver dysfunction appeared before cytopenia, it is
      suggested that the site of the primary lesion in this case was the liver.

PMID- 12412293
TI  - [T-cell chronic lymphocytic leukemia associated with adenocarcinoma of colon].
AB  - A 72-year-old woman had been diagnosed in 1998 as having colonic adenocarcinoma
      associated with lymphocytosis, and had undergone an operation. Three years later
      she was referred to our hospital with the chief complaint of blood stools. She
      again developed adenocarcinoma of the sigmoid colon. Blood chemistry showed a
      leukocyte count of 26,850/ml without anemia or thrombocytopenia. Bone marrow
      aspiration gave a nucleated cell count of 109,600/ml with 50.2% lymphocytes.
      Lymphocytes surface marker showed T-cell characteristics with CD4+/CD-. The
      serological test showed negative anti-HTLV-1 antibody and the TCRab chain was
      rearranged in her bone marrow aspirate. From these results she was diagnosed as
      having T-CLL.

PMID- 12412294
TI  - [Double t (3; 21) in acute myelomonocytic leukemia transformed from chronic
      myelomonocytic leukemia].
AB  - A 63-year-old male was diagnosed as chronic myelomonocytic leukemia with normal
      karyotype in September 1998. He developed acute myelogenous leukemia (AML-M4Eo)
      in September 2001. The cytogenetic analysis disclosed double t(3;21) at a ratio
      of 1/20, and the reverse transcriptase-polymerase chain reaction showed AML1/EVI
      1 mRNA. He could not achieve complete remission after two courses of induction
      chemotherapy, and his leukemia cells carrying double t(3;21) were relatively
      increased. He died of interstitial pneumonia in December 2001. This is the first
      leukemia case with double t(3;21) and this chromosomal abnormality might play a
      role in leukemia cell proliferation by generating two AML1/EVI-1 genes.

PMID- 12412295
TI  - [Chronic myeloid leukemia associated with sustained severe pancytopenia after
      imatinib mesylate therapy].
AB  - A 73-year-old woman with chronic myeloid leukemia was treated with interferon
      alpha, hydroxyurea, and busulfan before imatinib mesylate treatment. The
      leukocyte count was 8,400/; hemoglobin concentration, 12.0 g/; and platelet
      count, 19.7 x 10(4)/. She received 400 mg of imatinib mesylate for 17 days before
      the agent was discontinued because of pancytopenia. A bone marrow biopsy on the
      87th day after the last imatinib mesylate administration demonstrated severe
      hypocellularity. She needed many RBC and Plt transfusions and filgrastim
      administration. Grade 4 neutropenia continued for 35 days and Grade 3
      thrombocytopenia continued for over 122 days. Imatinib mesylate, an agent
      targeting BCR-ABL, is expected to be useful as an effective therapeutic agent for
      chronic myeloid leukemia. However the present case suggests that its appropriate
      dose is individually variable and we should carefully consider the former
      treatment, and the clinical stage of the disease before initiating imatinib
      treatment.

PMID- 12412296
TI  - [Invasive aspergillosis and pulmonary alveolar proteinosis in acute myeloid
      leukemia].
AB  - A 53-year-old woman with refractory acute myeloid leukemia had a cough and chest
      pain. Chest X-ray and computed tomography demonstrated a cavity for which
      antibiotics, antituberculosis and antifungal agents were not effective. A
      diagnosis of pulmonary aspergillosis and pulmonary alveolar proteinosis (PAP) was
      made on the basis of the detection of aspergillus using transbronchial lung
      biopsy and PAS-positive materials in the sputum. Even though some cases with PAP
      in hematological malignancy have been reported, the diagnosis of PAP was obtained
      in most of them at autopsy. In our experience three of seven cases of
      hematological malignancy had concomitant occurrence of aspergillosis and PAP. We
      should therefore pay particular attention to the possibility of PAP in patients
      with hematological neoplasia exhibiting pulmonary fungal infection, especially
      aspergillosis.

PMID- 12412297
TI  - [Practice guidelines in Europe: from intentions to execution].

PMID- 12412298
TI  - [Bourneville, humanist and reformer].

PMID- 12412299
TI  - [Diagnosis of pancreatic tumors].
AB  - Ductal carcinoma is the most frequent pancreatic neoplasm. The other tumours are
      cystic tumours, intraductal neoplasms, and endocrine tumours; some of these
      neoplasms have a malignant potential. Main symptoms of ductal carcinoma are
      epigastric pain, weight loss, and cholestatic jaundice for cephalic tumours;
      other tumours have varying symptoms and can be discovered fortuitously. Serum
      assay of CA 19-9 is neither sensitive nor specific for diagnosis of ductal
      carcinoma. For diagnosis of ductal carcinoma, helical CT scan has a 90%
      sensitivity and only fails to detect tumours less than 2 cm. Endoscopic
      ultrasound is efficient for diagnosis of small tumours and allows fine needle
      aspiration for pathological examination whatever tumour diameter. Staging
      (locoregional and metastatic extension) is mainly done by helical CT scan.

PMID- 12412300
TI  - [Treatment of pancreatic adenocarcinoma].
AB  - Better results of resections for pancreatic adenocarcinoma are reported in
      published data from 1990: 1. the lower mortality rate is probably not the only
      reason why these results are better; 2. the palliative resections rate seem to be
      lower (as the rates of exploratory laparotomies and by-pass procedures); 3. the
      impact of resection's quality on the results is difficult to demonstrate and the
      benefit of extended lymphadenectomy remains unclear; 4. moreover, in recent
      published series, many patients had adjuvant or neoadjuvant therapy, but often in
      uncontrolled studies. Multimodality treatment is probably useful for better local
      control and better disease free survival; this therapeutic approach is widely
      used today but the results remain to be confirmed by clinical trials.
      Unfortunately, 90% of the patients had locally advanced or metastatic disease at
      the time of diagnosis; in these patients clinical research is a challenge in
      order to change the prognosis; actually, epidemiological studies are still
      showing that quite all the patients die.

PMID- 12412301
TI  - [Cystic and intraductal tumors of the pancreas].
AB  - The management of cystic and intraductal pancreatic tumours has changed over the
      last ten years due to increasing fortuitous discovery of incidental cystic
      lesions of the pancreas and better knowledge of these lesions. CT-scan or MRI can
      usually differentiate the two most frequent cystic tumours: benign serous
      cystadenoma and potentially malignant mucinous cystadenoma. Conservative
      management is wholly justified for serous cystadenoma without complications,
      whereas mucinous cystadenoma can be cured by pancreatic resection. In case of
      doubt, endoscopic ultrasonography and study of cystic fluid may be helpful.
      Recently identified intraductal papillary mucinous neoplasms of the pancreas are
      premalignant or malignant tumours of the pancreatic ducts clearly visualized by
      magnetic resonance pancreatography. Curative pancreatic resection should be
      performed before the invasive adenocarcinoma stage.

PMID- 12412302
TI  - [Treatment of pancreatic-duodenal endocrine tumors].
AB  - Control of symptoms due to hormonal secretion is an integral first-step in the
      management of patients with functional tumours of the pancreatico-duodenal
      region. Symptomatic drugs should be employed, as well as systemic chemotherapy
      for nonresectable tumours on the basis of histological differentiation and tumour
      evolution. Hepatic chemoembolization yields objective response rate of 50%.
      Surgery however remains the only curative option. Well-differentiated and
      resectable tumours should be treated by resection, associated with hepatectomy in
      cases of resectable metastases. Liver transplantation should be reserved for
      patients with well-differentiated slowly-progressive tumours demonstrating
      multiple hepatic metastases with a resectable primary in the absence of other
      metastatic disease. When medical options are inefficacious in the control of
      hormonal symptoms, cytoreductive surgery can be an effective option.

PMID- 12412303
TI  - [Acute pancreatitis: diagnosis and therapeutic principles].
AB  - The diagnosis of acute pancreatitis is based on the association of acute upper
      abdominal pain and hyper lipasemia. The CT scan confirms the diagnosis and assess
      the severity of the pancreatitis, as do several bioclinical indexes. Alcohol and
      biliary lithiasis, seeked by ultrasound, are the two main causes of acute
      pancreatitis. Most of acute pancreatitis are oedematous and resolve spontaneously
      without sequella. Severe necrotizing pancreatitis lead to death in 10 to 20% of
      cases, because of multiple organ failure or intra-abdominal complications of
      necrosis. Treatment of severe acute pancreatitis involves intensivists,
      radiologists and surgeons. Surgery is restricted to drainage of super-infected
      necrosis and treatment of causative biliary lithiasis.

PMID- 12412304
TI  - [Diagnosis and management of chronic pancreatitis].
AB  - Chronic calcifying pancreatitis is mainly due to chronic alcohol consumption. The
      first years of its evolution are marked by a painful disease and often weightloss
      as well as complications including acute pancreatitis, pseudocysts, compression
      of common bile duct, pleural effusion ascitis, and gastrointestinal bleedings.
      Between five and ten years evolution, pain is less frequent but risk for
      pseudocyst or jaundice still remains. Ten years after the onset of the disease
      pancreatic pain disappears while pancreas becomes calcified and fibrotic. Only
      diabetes and exocrine insufficiency are present at this stage. Medical treatment
      is mainly based on alcohol withdrawal, analgesics and restoration of normal
      nutritional status. Pain could be decreased but sometimes endoscopic, radiologic
      or surgical procedures are required. Insulin is often proposed for diabetes while
      exocrine insufficiency is substituted by gastro-resistant microgranules
      pancreatic extracts.

PMID- 12412305
TI  - [Endoscopic and surgical treatment of chronic pancreatitis].
AB  - Therapeutic management of patients with chronic pancreatitis is a
      multidisciplinary approach. Although interventional endoscopy and external
      lithotripsy have an important role to play, surgery keeps a prominent position in
      the therapeutic armentarium. The progress in radiology and endoscopy, the
      possibility of a preliminary therapeutic approach by a nonsurgical therapy have
      led to precise guidelines in the management. Surgery is indicated not only for
      rescue when endoscopic treatment is unsuccessful, but also as a one step
      procedure when failure of nonsurgical therapy can be anticipated right away. A
      key point is that nonsurgical and surgical therapeutic modalities are now
      complementary instead of being competitive.

PMID- 12412306
TI  - [Functional results of pancreatic surgery].
AB  - Indications of pancreatectomy for benign diseases and a better knowledge of
      natural history of chronic pancreatitis need precise evaluation of functional
      results of pancreatic surgery. Pancreaticoduodenectomy generally results in
      weight loss when indicated for cancer and weight gain when indicated for chronic
      pancreatitis. Even when pancreatic parenchyma is normal, pancreaticoduodenectomy
      usually leads to exocrine insufficiency needing enzyme therapy. The risk of
      diabetes related to pancreaticoduodenectomy is less than 10%; in case of chronic
      pancreatitis, the over-risk due to surgery is less than 10% too. Left
      pancreatectomy does not result in exocrine insufficiency. Conversely, left
      pancreatectomy can induce diabetes even when pancreatic parenchyma is normal, and
      especially when pancreatic resection exceeds 75%. When performed for chronic
      pancreatitis, left pancreatectomy strongly increases the risk of diabetes related
      to the disease. Total pancreatectomy results in total exocrine insufficiency and
      diabetes with high risk of hypoglycemia. Limited pancreatectomies (isolated head
      resection for chronic pancreatitis, medial pancreatectomy, enucleation), rarely
      indicated, do not result in pancreatic failure. Among by-pass procedures,
      wirsungo-jejunostomy does not improve exocrine function and could reduce (or at
      the least delay) the risk of diabetes occurrence related to chronic pancreatitis.

PMID- 12412307
TI  - [Guide to diseases].

PMID- 12412308
TI  - [Acute and chronic chest pain].

PMID- 12412309
TI  - [Micturation disorders. Diagnostic approach].

PMID- 12412310
TI  - [Autonomy and dependence in the elderly].

PMID- 12412311
TI  - [Viral hepatitis. Biological hepatic anomalies in an asymptomatic patient].

PMID- 12412312
TI  - Supreme Court rejects preemption in ERISA benefits dispute. Rush Prudential, Inc.
      v. Moran.

PMID- 12412313
TI  - Maryland Court rejects challenge to peer review processes. Sadler v. Dimensions
      Health Corporation.

PMID- 12412314
TI  - Which risk adjustment model is right for you?

PMID- 12412315
TI  - Don't let rising tide of transplant cases destroy your bottom line.

PMID- 12412316
TI  - Double-digit cap increases coming too late for CA groups?

PMID- 12412317
TI  - 2002 HEDIS data mark big changes for high-performing physicians.

PMID- 12412318
TI  - Risk contracting is a regional phenomenon, data show.

PMID- 12412319
TI  - Single specialty capitation tough, but survivors prosper.

PMID- 12412320
TI  - Lack of cash on hand providers' Achilles heel.
AB  - A new report outlines the reasons for the spate of IPA and medical group failures
      in California. The conclusion? The organizations failed to develop sufficient
      skills in information technology, actuarial risk analysis, utilization
      management, administration, and management leadership to manage capitated
      arrangements. Find out what they did right and what else they did wrong.

PMID- 12412321
TI  - Multispecialty group struggles to fund programs developed under capitation as
      patients shift to FFS.
AB  - A decline in capitation revenue the past five years has put Palo Alto Medical
      Foundation in a difficult bind. How can it pay for preventive care services that
      contain costs, improve health, and increase efficiency if no one will reimburse
      the group for it? See how they are coping.

PMID- 12412322
TI  - University Affiliates closes two years after expanding into new market.

PMID- 12412323
TI  - Doctor-patient relationship not affected by financial incentives.

PMID- 12412324
TI  - Need for software savvy in push for patient safety.

PMID- 12412325
TI  - Can robots make good models of biological behaviour?
AB  - How should biological behaviour be modelled? A relatively new approach is to
      investigate problems in neuroethology by building physical robot models of
      biological sensorimotor systems. The explication and justification of this
      approach are here placed within a framework for describing and comparing models
      in the behavioural and biological sciences. First, simulation models--the
      representation of a hypothesis about a target system--are distinguished from
      several other relationships also termed "modelling" in discussions of scientific
      explanation. Seven dimensions on which simulation models can differ are defined
      and distinctions between them discussed: 1. RELEVANCE: whether the model tests
      and generates hypotheses applicable to biology. 2. Level: the elemental units of
      the model in the hierarchy from atoms to societies. 3. Generality: the range of
      biological systems the model can represent. 4. Abstraction: the complexity,
      relative to the target, or amount of detail included in the model. 5. Structural
      accuracy: how well the model represents the actual mechanisms underlying the
      behaviour. 6. Performance match: to what extent the model behaviour matches the
      target behaviour. 7. Medium: the physical basis by which the model is
      implemented. No specific position in the space of models thus defined is the only
      correct one, but a good modelling methodology should be explicit about its
      position and the justification for that position. It is argued that in building
      robot models biological relevance is more effective than loose biological
      inspiration; multiple levels can be integrated; that generality cannot be assumed
      but might emerge from studying specific instances; abstraction is better done by
      simplification than idealisation; accuracy can be approached through iterations
      of complete systems; that the model should be able to match and predict target
      behaviour; and that a physical medium can have significant advantages. These
      arguments reflect the view that biological behaviour needs to be studied and
      modelled in context, that is, in terms of the real problems faced by real animals
      in real environments.

PMID- 12412326
TI  - Precis of How children learn the meanings of words.
AB  - Normal children learn tens of thousands of words, and do so quickly and
      efficiently, often in highly impoverished environments. In How Children Learn the
      Meanings of Words, I argue that word learning is the product of certain cognitive
      and linguistic abilities that include the ability to acquire concepts, an
      appreciation of syntactic cues to meaning, and a rich understanding of the mental
      states of other people. These capacities are powerful, early emerging, and to
      some extent uniquely human, but they are not special to word learning. This
      proposal is an alternative to the view that word learning is the result of simple
      associative learning mechanisms, and it rejects as well the notion that children
      possess constraints, either innate or learned, that are specifically earmarked
      for word learning. This theory is extended to account for how children learn
      names for objects, substances, and abstract entities, pronouns and proper names,
      verbs, determiners, prepositions, and number words. Several related topics are
      also discussed, including naive essentialism, children's understanding of
      representational art, the nature of numerical and spatial reasoning, and the role
      of words in the shaping of mental life.

PMID- 12412327
TI  - The chosen people.

PMID- 12412328
TI  - Clinical networks. Sum of the parts.
AB  - A simulation exercise intended to ease the development of clinical networks found
      that primary care trusts were eager to co-operate with one other. Acute trusts
      emerged as the most confident 'players'; they were perceived as a 'provider
      cabal' by PCTs. Participants felt the legacy of the internal market might have
      impeded joint-working across trusts. The regulator role of strategic health
      authorities was crucial.

PMID- 12412329
TI  - Capacity planning. Model behavior.
AB  - A model in use in a primary care trust enables the prediction of acute admissions
      to hospital over a two-year period. The results show that the rise in emergency
      medical admissions threatens the local hospital's capacity to meet waiting-time
      targets for planned work. The research also showed that the establishment of a
      local diagnostic and treatment centre would reduce levels of occupancy in the
      acute hospitals to a level that could threaten its survival.

PMID- 12412330
TI  - Primary care trusts. A room with a view.
AB  - Research at an acute hospital, with the aim of providing indicators for hospital
      developments, found the important factors for patients were privacy, ease of
      access, provision for relatives and more lavatories and washing facilities.
      Patients want a sense of connection with the outdoors through windows, courtyards
      and balconies. Patients prefer single rooms and small bays to wards. Developers
      should aim for buildings that are aesthetically pleasing and minimise feelings of
      insecurity.

PMID- 12412331
TI  - Buildings. LIFT doors still open.

PMID- 12412332
TI  - Building. Stopping short.

PMID- 12412333
TI  - Buildings. Home, sweetloan.

PMID- 12412334
TI  - [Role of science in specification and actualization of prophylactic measures (on
      the 80th anniversary of the organization of the Sanitary-Epidemiologic Service].

PMID- 12412335
TI  - [Biologic effects and hygienic regulation of electromagnetic fields caused by
      mobile communication devices].
AB  - The authors present results of hygienic, physiologic and experimental studies and
      mathematic simulation of biologic effects. Experimental studies (by functional
      state of CNS and immune system, cytologic examination of rats' lens epithelium)
      on 450 and 900 MHz frequencies prove the intensity of 1,900 MW/cm2 to be
      hazardous for animals and supraliminal.

PMID- 12412336
TI  - [Effective methods of protection from technogenic electromagnetic irradiation and
      information-wave diagnostic means].
AB  - Using electric puncture software complex "ROFES", the authors studied functional
      state of pilots having protective device "VITA" and assessed before and after the
      flights. The data obtained proved efficiency and safety of the device that
      improved the pilots' functional state, increased fatigue threshold, caused higher
      number of the flights.

PMID- 12412337
TI  - [In vitro and in vivo studies of the "VITA" device].
AB  - Many in vitro and in vivo experiments using contemporary methods supported safety
      and efficiency of "VITA" device protecting humans and living beings from
      electromagnetic fields. Therefore, bioenergetic safety device "VITA" is advisable
      for use.

PMID- 12412338
TI  - [Health of computer complex users (review of -the literature)].

PMID- 12412339
TI  - [Basic science to evaluate efficiency of means protecting from electromagnetic
      fields].
AB  - Theory of EMF's informational influence, besides the heat effect, on biologic
      objects is generally accepted nowadays. Also, EMF sources are widely used both
      for industrial and household purposes, and become an increasing hazard for public
      health. All that necessitates individual protective means including "VITA"
      device, the leading one, efficiency and safety of which are supported by research
      in some scientific institutions.

PMID- 12412340
TI  - [Current problems of hygienic regulation of atmospheric ions].

PMID- 12412341
TI  - [Objectivenesss and mechanism underlying protective effect of "VITA" type
      bioenergetic devices].

PMID- 12412342
TI  - [Influence of electromagnetic field caused by PC display on microflora growth in
      absence or presence of "VITA" device].

PMID- 12412343
TI  - [Mercury dissemination in dust waste and soils of industrial grounds in Saransk].

PMID- 12412344
TI  - [Pelvic inflammatory disease in adolescents--medical and social aspects].

PMID- 12412345
TI  - [Treatment of obstetric and gynecologic diseases with anti-inflammatory drug
      cedax].

PMID- 12412346
TI  - [Tumor markers and ovarian cancer].

PMID- 12412347
TI  - [Microbiological investigation of the vaginal flora during pregnancy].
AB  - The infections complications during pregnancy and delivery are jet unsolved
      problem in obstetrics and neonatology. Most of them are due to anaerobic and
      aerobic organisms. The authors show the rate and distribution of the bacterial
      vaginal infections during pregnancy. 1330 pregnant women are investigated, 10% of
      them are with normal vaginal flora, 27% anaerobic organisms, 15% aerobic
      organisms, then Candida albicans and Gardnerella vaginalis. Those results are
      seen most frequently during the last trimester of pregnancy, which leads to the
      complications in delivery and postpartum.

PMID- 12412348
TI  - [Congenital malformations in newborns during the period of 1995-1999 according to
      the department of obstetrics and gynecology--Stara Zagora].
AB  - During the last 2-3 decades there is a tendency for increasing the rate of the
      congenital malformation of the fetus and newborn. Every year in Bulgaria 5000
      6500 children are born with some defects. The purpose of this investigation is to
      show the rate of the congenital malformation as a reason for death among the
      newborn/babies in the Clinic of Obstetrics Stara Zagora during the period of 1995
      1999 and some rick factors for the malformations. RESULTS: Perinatal lethality
      for this period is 20.03% (190 children), 40 (21.05%) are with heavy lethal
      malformations. The authors annualize the localization of the malformations.

PMID- 12412349
TI  - [Family planning--exceptional factor influencing reproductive health in
      adolescents].

PMID- 12412351
TI  - [Reproductive health--new hormonal agents to treat infertility].

PMID- 12412350
TI  - [Legofer--a new approach in the treatment of iron deficiency. Pharmacological and
      biopharmacological characteristics of legofer (ferric protein succinylate)].

PMID- 12412352
TI  - [First express noninvasive menopausal test in Bulgaria ].

PMID- 12412353
TI  - [Lubrication reduces difficulties during sexual intercourse after gynecological
      surgery].

PMID- 12412354
TI  - ["Cathejell with lidocain"--lubrication gel with unique characteristics and
      clinical effect].

PMID- 12412355
TI  - [Fluorides in practice--is it a dental problem itself?].

PMID- 12412357
TI  - Concentrated strategy: building a foundation for the future.

PMID- 12412356
TI  - [Pantogar--modern treatment of hair loss, structural hair lesions, early
      alopecia, and dystrophy of nails].

PMID- 12412358
TI  - Financial and coding terms for clinical cardiovascular program leaders.

PMID- 12412359
TI  - Women's Heart Advantage program: motivating rapid and assertive behavior.

PMID- 12412360
TI  - FDA approves release of Medtronic's revolutionary Stormer Balloon Catheter.

PMID- 12412361
TI  - A proactive approach to reimbursement in the era of drug-eluting stents.

PMID- 12412362
TI  - [Central nervous system germinoma: retrospective study of six cases].
AB  - PURPOSE: Retrospective analysis of six patients with intracranial germinoma
      treated in INO and a literature review. MATERIALS AND METHODS: Six patients were
      treated from 1993 to 1998, for histologically verified primary intracranial
      germinoma. Median age was 18 years (range: 14-26 years). All patients received
      chemo-radiotherapy (4FP + radiotherapy from 30 to 50 Gy). RESULTS: 4 tumours were
      in complete remission. Two patients have kept non-evolutive residual cyst. Five
      patients are alive with non-evolutive disease after 15-40 months of follow-up
      (average: 27 months). One patient was lost to follow-up, 14 months after
      treatment, without disease. CONCLUSION: The treatment of intracranial germinoma
      is currently first line chemotherapy followed by low-dose and limited
      irradiation.

PMID- 12412363
TI  - [Cerebral localization of Hodgkin disease: case report and review of the
      literature].

PMID- 12412365
TI  - [Intracranial Hodgkin disease: case report].
AB  - Hodgkin disease intracranial lesions are uncommon. We report the case of a 24
      year-old man who presented with an intracranial relapse without other evidence of
      disease 24 months after multiple drug therapy and extended field radiation
      therapy for stage III Bb type 3 Hodgkin disease. The patient was treated by whole
      brain irradiation (40 Gy/20 fractions/4 weeks). Six months after completion of
      therapy, the patient had a second relapse, with bilateral inguinal metastatic
      nodes, which were treated by a second line polychemotherapy. The patient was free
      of disease 9 months later.

PMID- 12412364
TI  - [Radiation recall dermatitis after docetaxel and external beam radiotherapy.
      Report of two cases and review of the literature].
AB  - Radiation recall refers to a tissue reaction produced by a chemotherapeutic agent
      in a previously irradiated field that would not occur in a nonirradiated field.
      Docetaxel is a member of the taxane group of antineoplastic agents that cause
      disruption of cell division by enhancing microtubule assembly and inhibiting
      tubulin depolymerisation. As well as in breast cancer and lung cancer treatment,
      its association in a chemoradiation planned treatment becomes frequent and
      effective. Most of radiation recall dermatitis (RDD) reported in literature
      concerned paclitaxel or other drugs. We report two particularly striking cases of
      RDD with docetaxel and radiotherapy. Even if etiology remains undetermined, a
      number of hypotheses can be formulated. Familiarity with this phenomenon and
      potential complications of chemotherapy following tumor irradiation may expedite
      early diagnosis and appropriate lifesaving treatment.

PMID- 12412366
TI  - [Radiation-induced retinopathy].
AB  - Radiation retinopathy is a retinal microangiopathy, observed after irradiation of
      the eye. It can rarely lead to neovascular glaucoma and enucleation due to pain.
      It is due to a progressive retinal capillary then vascular occlusion. Total
      irradiation dose, dose fraction, and surface of the irradiated retina seem to be
      strong predictive factors for radiation retinopathy. Patients who underwent an
      irradiation near the eye (skull base tumors, nasal and paranasal tumors, or brain
      tumors) should be followed by periodic ophthalmologic examination to detect and
      treat when necessary the non perfusion areas.

PMID- 12412367
TI  - [In vivo dosimetry and radiation therapy of breast cancer].
AB  - INTRODUCTION: Verification of absorbed dose in target volume is a key factor for
      quality assurance in radiotherapy. In vivo measurements allow evaluation of the
      variations in dose with time and variations between measured doses and calculated
      doses by TPS. The aim of this work were to evaluate reproducibility of patient
      positioning and to compare calculated doses by 2 different TPS. PATIENTS AND
      METHODS: Twenty patients were divided in 2 groups according to the thickness of
      their breast (mean SSD = 92.9 cm). In vivo measurement was performed within the
      first two sessions. RESULTS: Reproducibility of SSD evaluation was made on 12
      beams between 2 fractions. With a tolerance margin of 0.5 cm, positioning errors
      were present in 33% (4/12). The 2 TPS were in agreement in 75% (30/40).
      CONCLUSION: In vivo dosimetry can be a very interesting tool to assess patients
      positioning variations and TPS dose calculation.

PMID- 12412368
TI  - [Study of a new commercial film for high energy photon dosimetry].
AB  - Dosimetric properties of a new film, the Extended Dose Range-EDR2, manufactured
      by Kodak, have been studied. We have established the response of the film versus
      dose and compared it with that of X-OMAT V films. We found a linear response with
      dose, for the range from 0.5 to 4 Gy. No dependence of this curve with beam
      quality and with depth is observed. EDR2 films are useful for dosimetric study of
      high-energy photon beam, especially when high dose gradient occurs such as for
      Intensity Modulated Radiotherapy Treatment.

PMID- 12412369
TI  - [Quality control of intensity modulated treatments in radiotherapy].
AB  - Since January 2001, radiotherapy treatments with modulated intensity beams (IMRT)
      have started at the Centre Oscar-Lambret. This paper presents the tests and
      measurements made before the clinical implementation as well the quality control
      performed before each routine treatment. We use the treatment planning system
      Helax-TMS (MDS-Nordion) and the Primus accelerator (Siemens) linked to the Lantis
      network with Primeview and Simtec modules (Siemens) allowing to deliver intensity
      modulated beams with Step-and-Shoot technique. A prostate case and a head and
      neck case have been studied and have permitted to evaluate the benefit of IMRT
      compared to a "classical" conformal radiotherapy. In a second time, we have
      tested the accelerator's capabilities to deliver these intensity modulated beams,
      id-est, the accuracy of the leaf positions and the linearity of the monitor
      chamber. The third step has been the verification of the dose distributions
      calculated by Helax-TMS, id-est, the dose for different segment sizes, the dose
      profiles for an intensity modulated beam and the dose distribution for all the
      traitment beams. The used phantom has been especially developed at the Centre
      Oscar-Lambret for IMRT. The results have allowed to start clinical treatments and
      to establish a quality control set for this technique. The next step is the real
      time dosimetry with a portal imager.

PMID- 12412370
TI  - [Influence of thermoplastic masks on the absorbed skin dose for head and neck
      tumor radiotherapy].
AB  - The influence of thermoplastic masks used in clinical routine for patient
      immobilization in head and neck radiotherapy treatment on the absorbed skin dose
      has been investigated at Gustave-Roussy Institute. The measurements were
      performed in 60Co gamma-rays, 4 and 6MV X-rays and in 8 and 10MeV electron beams.
      Initially, the measurements were performed with thermoluminescent dosimeters
      (LiF) and a NACP chamber on a polystyrene phantom in order to study the influence
      of physical parameters (distance, field size, energy...) on first millimeters
      depth variation dose. The study was completed with in vivo measurements on 14
      patients using various dosimeters (thermoluminescent detectors, diodes) in order
      to assess the increase of dose on first millimeters depth and to verify the
      delivered dose during treatment sessions (quality control). In treatment
      conditions, masks lead to an important increase of dose on the first millimeter
      in 60Co gamma-rays beams (dose value normalized to maximum of dose increase from
      57.1% to 77.7% for 0.5 mm-water depth and from 78.5% to 88% for 1 mm-water
      depth); its contribution is less important in 4 and 6 MV X-rays beams (dose value
      normalized to maximum of dose increase from 49.5% to 63.2% for 0.5 mm-water depth
      and from 59% to 70.1% for 1 mm-water depth). Concerning 8 and 10 MeV electron
      beams, the normalized dose value increase respectively from 78.4% to 81.7% and
      from 82.2% to 86.1% for 0.5 mm-water depth. In vivo dosimetry enabled the quality
      control of delivered dose during treatment. Measured dose is in agreement within
      +/- 5% with the prescribed dose for 92.3% of cases. In routine, in vivo dosimetry
      allowed to quantify the increase of skin dose induced by thermoplastic masks for
      various energies of photon and electron beams as well as quality control.

PMID- 12412371
TI  - [Orthostatic tolerance after spaceflight or simulated weightlessness by head-down
      bed-rest].
AB  - Cardiovascular modifications, specially orthostatic intolerance (OI) are well
      known after spaceflight or long duration head-down bed-rest (HDBR) There is no
      agreement about their mechanisms. The aim of the study was to compare OI after a
      42 day HDBR (n = 7) and after a 90 to 198 day spaceflight (n = 10). The studies
      were made during a stand test of 10 minutes for HDBR following 10 min in supine
      position and 5 min in sitting position. In both groups the variables measured
      were blood pressure (BP by transcutaneous plethysmography, Finapres) and ECG for
      RR interval (RRi) determination which allowed us to calculate autonomic indexes
      by spectral analysis of RRi and to determine spontaneous baroreflex sensitivity.
      In the cosmonaut group, 1 subject experienced a vaso-vagal syncope and 2 asked to
      stop the test without a decrease in BP. In HDBR, 4 subjects out of 7 did not
      perform the whole stand test (1 vaso-vagal syncope, 1 tachycardia and 2
      hypotensions). Cosmonauts or HDBR subjects had common profiles: tachycardia and a
      decrease in parasympathetic index and baroreflex sensitivity. Both groups have an
      OI (30% of the subjects). However the mechanisms are different even if they have
      a common postural orthostatic tachycardia syndrome (POTS). The spaceflight
      duration was not determinant and we have no indice to predict OI which was one of
      the aims of the study.

PMID- 12412372
TI  - [Retinoic acid nuclear receptors: a common molecular basis for liver cancer and
      acute promyelocytic leukemia].
AB  - Our team was at the origin of the discovery of the relationship between
      rearrangements in genes encoding the retinoic acid receptors and tumorigenesis in
      human. Studying the molecular basis for hepatitis B virus (HBV)-associated liver
      cancer, we demonstrated that the viral DNA can behave as an insertional mutagen.
      This work also led to the identification of the first gene (RAR beta) encoding a
      receptor for the active derivative of vitamin A, retinoid acid. In collaboration
      with L. Degos, we then demonstrated the existence a systematic alteration of
      another retinoic acid receptor, RAR alpha, in acute promyelocytic leukemia (APL).
      Most recent work allowed us to involve a novel subnuclear organelle, the so
      called PML Nuclear Bodies, in APL pathogenesis, underlying the major role played
      by the functional organization of the nucleus both in the normal and the
      pathological cell.

PMID- 12412373
TI  - [The specificity of adolescent psychiatry].
AB  - Adolescent psychiatry is a new discipline implied in mental health and individual
      health as suicide attempts, substance abuse and drug addiction, anxiety
      disorders, mood disorders, eating disorders.... This disorders appears at this
      age and often continue with the adult. Adolescent psychiatry is an original
      practice with young people in development which had to learn the self-care. This
      work is an illustration of this point of view.

PMID- 12412374
TI  - [Genetic, epidemiologic and clinical study of familial prostate cancer].
AB  - Prostate cancer (CaP) is the most frequent cancer among men over 50 and its
      frequency increases with age. It has become a significant public health problem
      due to the ageing population. Epidemiologists report familial aggregation in 15
      to 25% of cases and inherited susceptibility with autosomal dominant or X-linked
      model in 5 to 10% of cases. Clinical and biological features of familial CaP
      remain controversial. OBJECTIVES: To perform: (1) Genetic study of familial Cap
      (mapping of susceptibility genes), (2) epidemiologic study (prevalence,
      associated cancers in the genealogy, model of transmission), and clinical study
      of familial CaP. METHODOLOGY AND RESULTS: (I) conducting a nationwide family
      collection (ProGene study) with 2+ CaP we have performed a genomewide linkage
      analysis and identified a predisposing locus on 1q42.2-43 named PCaP
      (Predisposing to Cancer of the Prostate); (II) conducting a systematic genealogic
      analysis of 691 CaP followed up in 3 University departments of urology (Hospitals
      of Brest, Paris St Louis and Nancy) we have observed: (1) 14.2% of familial and
      3.6% of hereditary CaP, (2) a higher risk of breast cancer in first degree
      relatives of probands (CaP+) in familial CaP than in sporadic CaP and in early
      onset CaP (< 55 years) when compared with late onset CaP ([dG]75 years), (3) an
      autosomal dominant model with brother-brother dependance), (4) the lack of
      specific clinical or biological feature (except for early onset) in hereditary
      CaP when compared with sporadic CaP. CONCLUSION: (1) The mapping of a
      susceptibility locus will permit the cloning of a predisposing gene on 1q42.2-43,
      offer the possibility of genetic screening in families at risk and permit
      genotype/phenotype correlation studies; (2) the transmission model will improve
      parameteric linkage studies; (3) the lack of distinct specific clinical patterns
      suggest diagnostic and follow up modalities for familial and hereditary CaP
      similar to sporadic cancer while encouraging early screening of families at risk,
      given the earlier onset (5 to 10 years earlier) observed.

PMID- 12412375
TI  - [Food irradiation].

PMID- 12412376
TI  - [The epidemiology of human cryptosporidiosis].
AB  - Cryptosporidiosis, as an emerging disease, has generated a tremendous amount of
      research. Our purpose is a survey of the epidemiology of this disease,
      emphasizing: the features of the parasites and the species and genotypes that may
      infect Man, the most frequent of which is Cryptosporidium parvum and its two
      genotypes "Cattle" and "Human"; the means of dissemination of the infective stage
      and of human contamination; the factors that put Man at risk of catching a severe
      infection; the basis of a suitable control.

PMID- 12412377
TI  - [French results of enzyme replacement therapy in Gaucher's disease].
AB  - Gaucher disease is an inborn recessive autosomal disease due to a partial
      deficiency of the lysosomal enzyme beta glucocerebrosidase. The deficient
      activity leads to accumulation of the lipid glucocerebroside in the liver, the
      spleen and bone marrow with concomitant anemia and thrombocytopenia. Patients
      with Gaucher disease have been classified in three types: type I is the more
      common, neurological manifestations occur in types II and III. Enzyme replacement
      therapy (ERT) with modified placental human glucocerebrosidase (ceredase) or
      recombinant glucocerebrosidase (cerezyme) is effective in most type I Gaucher
      disease and has become the current standard care administered to thousand of
      patients worldwide. ERT has obviated the need for bone marrow transplantation and
      virtually eliminated the need for splenectomy. We report here the French study
      including adults and children. ERT of 30 to 60 U/K every two weeks as starting
      dose was administrated to 108 patients with severe type I Gaucher disease. ERT
      fully reverse many of the manifestations of the disease. ERT regimen alleviated
      fatigue, and hematological and visceral signs and symptoms in nearly all severely
      ill patients. Skeletal responses to treatment develop much more slowly than
      hematological or visceral responses. Studies in pediatrics show that the disease
      is more severe in children. These children should be treated early in the course
      of their disease to avoid irreparable damage. Hematological manifestation in type
      II cannot be reversed with enzyme replacement. In type III treatment can rarely
      reverse neurological deficit. Gaucher disease is also an excellent candidate for
      gene therapy.

PMID- 12412378
TI  - [Preimplantation genetic diagnosis: update of the Parisian group].
AB  - To report the birth of the first fourteen infants conceived after preimplantation
      genetic diagnosis (PGD) in our unit. Fifty-nine couples were enrolled between
      January 2000 and July 2001. They had a total of 71 oocyte pick-up cycles. The
      collected oocytes were inseminated by intracytoplasmic sperm injection. The
      resulting embryos were biopsied on the third day of development and the genetic
      analysis was performed on the same day. Most of the embryo transfers were carried
      out on the fourth day. The 71 oocyte pick-up cycles yielded 872 oocytes of which
      731 were suitable for intracytoplasmic sperm injection. Among the 505 embryos
      obtained, 421 embryos were biopsied and genetic diagnosis was performed for 312
      (74%) of these 127 embryos were transferred during the course of 58 transfer
      procedures. There were 18 biochemical and 12 ongoing (7 singles, 4 twins and 1
      triple) pregnancies. Sixteen infants have been born and 2 are expected. PGD has
      gained a place among the choices offered to couples at risk of transmission of a
      serious and incurable genetic disease.

PMID- 12412380
TI  - [From genomics to post-genomics: back to the origins?].
AB  - The purpose of this review is to emphasize the multiplicity and importance,
      physiological and pathological, of gene regulation levels which operate after the
      initiation step of transcription. Albeit crucial, this step is only the first one
      of a long cascade of events which eventually end up in the selection of
      functional messengers appropriate to the nature of the cells and to their
      immediate needs. Throughout this long pathway, of which only a few steps will be
      mentioned here, this review will attempt to address the central role played by
      RNA, not only as a substrate but as an actor of its own regulation. Emphasis will
      be put on the numerous connections with pathology up to the development of new
      therapeutics specifically targeting RNA. It highlights the perennity of basic
      questions, nearly half a century old, for which genomics, short of new concepts,
      will provide the databases and tools required to access to the immense field of
      functional genomics, the only one likely to bring relevant answers for
      therapeutics.

PMID- 12412379
TI  - [Treatment of excretory azoospermia. Biological aspects of surgery].
AB  - The therapeutical strategy for excretory azoospermia is very efficient at the
      present time. It is represented by two complementary methods very different both
      in their concept and their practical aspects. The surgery for recanalisation of
      the seminal tract is the old method, associated with reproducible and validated
      results providing a sophisticated operative methodology which implies
      microsurgery. The recent introduction of the assisted reproduction technics with
      better or at least equal results than those of surgery and with a growing
      therapeutical power already nowadays offers satisfying opportunities of treatment
      in some selected indications. The evolution of the therapeutical strategy is
      analyzed through our proper practice and the data of the literature.

PMID- 12412381
TI  - Advances in unrelated donor hematopoietic cell transplantation: improved matching
      and use of blood stem cells.

PMID- 12412382
TI  - Bone marrow or peripheral blood as a source of stem cells for allogeneic
      transplantation.
AB  - BACKGROUND AND OBJECTIVES: Peripheral blood (PB) stem cell transplants are being
      increasingly used in the allogeneic setting, and are often preferred to the
      conventional bone marrow (BM) source. The aim of this report is to review
      available data on PB vs BM hematopoietic stem cell transplantation (HSCT). The
      discussion is restricted to unmanipulated HLA identical sibling transplants.
      EVIDENCE AND INFORMATION SOURCES: Data with appropriate follow-up are available
      only for this type of comparison: we have preliminary data on the use of PB from
      unrelated donors, and on the use of T-cell depletion/CD34+ selection methods. The
      latter are rapidly evolving and it may be difficult to find a concurrent group of
      patients receiving T-cell depleted or CD34-selected marrow. STATE OF ART: The
      results of retrospective and prospective studies are quite similar: hematologic
      and immune recovery is faster after PB grafts, acute graft-versus-host disease
      (GvHD) is comparable, whereas chronic GvHD is increased in recipients of PB
      transplants. Transplant-related mortality (TRM) is similar in the two groups,
      whereas disease recurrence is lower after PB grafts. PERSPECTIVES: The general
      feeling is that PB grafts are indicated for patients with advanced disease,
      whereas for early phase patients the two sources may give comparable results.

PMID- 12412383
TI  - Full haplotype mismatched hematopoietic stem cell transplants.
AB  - BACKGROUND AND OBJECTIVES: Clinical outcome in leukemia patients transplanted
      from one-haplotype mismatched donors has been largely disappointing because of
      the high incidence of severe graft-vs-host disease in T-replete transplants or
      high rejection rates in T-cell-depleted transplants. EVIDENCE AND INFORMATION
      SOURCES: The breakthrough came with the use of a megadose of T-cell-depleted
      progenitor cells after a high intensity conditioning regimen. STATE OF ART:
      Today, high risk acute leukemia patients are treated at less advanced stages of
      disease, receive a well-tolerated conditioning regimen, and benefit from advances
      in post-transplant immunologic reconstitution. Overall, event-free survival and
      transplant-related mortality compare favorably with those reported for unrelated
      matched transplants. PERSPECTIVES: T-cell depleted megadose stem cell transplant
      from a mismatched family member, who is immediately available, can be offered as
      a viable option to candidates with high-risk acute leukemias.

PMID- 12412384
TI  - Non-myeloablative allogeneic hematopoietic stem cell transplants.

PMID- 12412385
TI  - Hematopoietic stem cell transplantation in the treatment of pediatric acute
      lymphoblastic leukemia: a pediatric single center experience.

PMID- 12412386
TI  - Historical perspectives, rationale and future directions for hematopoietic stem
      cell transplantation for severe autoimmune diseases.

PMID- 12412387
TI  - Legislative and ethical aspects of administering granulocyte colony-stimulating
      factor to normal donors.

PMID- 12412388
TI  - The use of cytokine-stimulated healthy donors in allogeneic stem cell
      transplantation.
AB  - Treatment of healthy donors with recombinant human granulocyte colony-stimulating
      factor (rhG-CSF) allows the mobilization and peripheralization into circulating
      blood of an adequate number of CD34+ cells that can then be collected by
      leukapheresis (PBSC). This procedure avoids the invasiveness of bone marrow
      harvest and the risks related to general anesthesia. The main adverse effects of
      rhG-CSF are: bone pain, 84%, headache, 54%, fatigue, 31%, and nausea, 13%, which
      are usually scored by the donors as moderate to severe, resolving within 2-3 days
      after discontinuation of the cytokine. Analgesics, mainly acetaminophen, are
      sufficient to control the pain. Less than 5% of the donors experience non-cardiac
      chest pain, a local reaction at the injection site, insomnia, dizziness or a low
      grade fever. Discontinuation of the PBSC procedure because of adverse effects of
      rhG-CSF or leukapheresis is rarely necessary (0.5%) but this good tolerability
      can be hampered by the need, in 5-20% of cases, for an adequate venous access
      that requires insertion of a central or venous catheter. There are no absolute
      contraindications to the stimulation of healthy donors with rhG-CSF but the
      description of cases of non-traumatic splenic rupture, iritis, cardiac ischemia,
      and gouty arthritis suggests that further precautionary restrictions are
      advisable when deciding eligibility for PBSC collection. The main advantages for
      patients receiving an allogeneic PBSC transplant are the faster hematologic and
      immunologic recovery and the potential for a greater efficacy in advanced disease
      by lowering the transplant-related mortality. One of the major concerns regarding
      the use of rhG-CSF in unrelated healthy donors is the uncertainty about its
      possible role in triggering malignancy, in particular myelodysplastic syndrome
      and acute myeloid leukemia. There are no studies with an adequate sample size and
      follow-up that can answer this question but two recent retrospective studies
      reported that in the medium term rhG-CSF is not associated with an excess of
      lymphoproliferative disorders. Currently, caution on the long-term safety of the
      use of rhG-CSF in healthy donor is still warranted but the data so far
      accumulated on allogeneic PBSC transplants are encouraging both as far as
      concerns the good short-medium tolerability profile of G-CSF-stimulation of the
      donor and the potential major efficacy in leukemia patients.

PMID- 12412389
TI  - Role of a hematopoietic stem cell transplant registry in childhood: the
      experience of the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP).

PMID- 12412390
TI  - Allogeneic bone marrow transplantation versus chemotherapy in childhood very high
      risk acute lymphoblastic leukemia in first complete remission: a controversial
      issue.
AB  - BACKGROUND AND OBJECTIVES: Improvements in the management of childhood acute
      lymphoblastic leukemia (ALL) did not prevent 20% to 30% of patients suffering
      from relapse. Moreover, the probability of relapse can rise up to 50% for some
      children presenting with very high risk (VHR) factors. Intensive chemotherapy and
      especially hematopoietic stem cell transplantation improved their outcome. The
      aim of this review is to assess the role of different approaches in the treatment
      of childhood VHR ALL on the basis of current data. EVIDENCE AND INFORMATION
      SOURCES: Information on the ongoing international studies was obtained via
      Medline. Preliminary data from a prospective cooperative study are mentioned.
      STATE OF ART: During the last decade, different definitions of VHR factors in
      childhood ALL have been a crucial issue, so that therapeutic results of single or
      multicenter studies were difficult to compare. All investigators agreed in
      adopting most aggressive treatments in patients with poor prognostic factors such
      as molecular biological markers, chromosomal abnormalities and biological factors
      including poor prednisone response and resistance to initial chemotherapy.
      Allogeneic bone marrow transplantation (AlloBMT) in childhood VHR ALL in first
      complete remission is expected to yield better event-free survival than
      chemotherapy. The lack of valid information in the current literature about the
      real impact of both chemotherapy and hematopoietic stem cell transplantation is
      essentially the result of the difficulty in setting up multicenter prospective
      studies. On the other hand, the principal biases of retrospective studies are the
      lack of homogeneous eligibility criteria, different first-line therapies adopted
      before AlloBMT and above all the waiting time to transplant which could have
      accounted for some of the survival advantage shown by AlloBMT patients compared
      to those treated with chemotherapy. PERSPECTIVES: Preliminary results of an
      ongoing international prospective study are presented and compare favorably with
      previous reports. The current scenario serves as an example of how to reach a
      consensus in the controversial treatment of childhood VHR ALL.

PMID- 12412391
TI  - Unrelated donor marrow transplantation in childhood: a report from the
      Associazione Italiana Ematologia e Oncologia Pediatrica (AIEOP) and the Gruppo
      Italiano per il Trapianto Midollo Osseo (GITMO).
AB  - BACKGROUND AND OBJECTIVES: Unrelated donor bone marrow transplant (UD-BMT) has
      become an attractive, alternative source of hematopoietic cells for patients
      lacking a matched sibling. The aim of this paper is to report on 520 patients
      below 19 years of age undergoing UD BMT in 31 Italian centers between September
      1989 and December 2001, and to focus on the results achieved in the 423 patients
      grafted before December 2000. DESIGNS AND METHODS: In 1989 the Italian Bone
      Marrow Transplant Group (GITMO) and the Italian Association for Pediatric
      Hematology and Oncology (AIEOP) established the Italian Bone Marrow Donor
      Registry (IBMDR) to facilitate donor search and marrow procurement for patients
      lacking an HLA identical sibling. By the end of December 2001, 296,720 HLA-A, B
      typed volunteer donors had been cumulatively registered and 3,411 searches had
      been activated for Italian patients. At least one HLA-A, B, DRB1 matched donor
      was found for 54% of the patients and 520 UD BMTs were performed in patients
      below 19 years of age before December 2001. Since 1999 more than 90% of the
      patients < or = 14 years old, and more than 50% of the patients 15-18 years old
      undergoing UD BMT have been treated in AIEOP institutions. In 50% of the cases
      donors were found in the IBMDR, and in 50% they were found in 14 other
      Registries. The average time from search activation to transplant was 6 months
      for diseases other than chronic myeloid leukemia (CML), while for CML it was 8.7
      months. RESULTS: Actuarial 100-day transplant-related mortality (TRM) was 32% in
      patients grafted between 1989 and 1997, and 21% for patients grafted after 1998
      (p = 0.003). Twenty-eight per cent of the patients developed grade III or IV
      acute graft-versus-host disease (GvHD), and 20% developed extensive chronic GvHD.
      The rate of disease-free survival at three years was 37% for patients with acute
      lymphoblastic leukemia, 38% for acute myeloid leukemia or myelodysplastic
      syndrome patients, 59% for patients with inborn errors, and 51% for patients with
      CML. INTERPRETATION AND CONCLUSIONS: We conclude that the IBMDR has benefited a
      substantial number of patients lacking a matched sibling and has facilitated the
      recruitment of UDs into the international donor pool. Results show a positive
      trend after 1998, mainly due to a decrease in transplant-related-mortality.

PMID- 12412393
TI  - The therapeutic role of dendritic cells in cancer immunotherapy.

PMID- 12412394
TI  - Obesity, diets and lifestyle modification.

PMID- 12412392
TI  - Unrelated bone marrow transplantation in thalassemia. The experience of the
      Italian Bone Marrow Transplant Group (GITMO).
AB  - BACKGROUND AND OBJECTIVES: Allogeneic bone marrow transplantation (BMT) is a
      widely accepted therapeutic approach in homozygous beta-thalassemia. However, the
      majority of patients do not have a genotypically identical donor within the
      family. This prompted us to conduct a pilot study to investigate the feasibility
      of matched unrelated bone marrow transplantation in thalassemia. The major
      drawback was the high risk of immunologic and transplant-related complications,
      mainly graft-versus-host disease (GvHD) and graft failure. DESIGN AND METHODS:
      Our aim was to reduce this risk through careful selection of donor/recipient
      pairs. HLA haplotypes that show a high linkage disequilibrium among their class
      I, class II and class III alleles are considered extended or ancestral
      haplotypes. RESULTS: These haplotypes are conserved and can be shared by
      apparently unrelated individuals. Our study shows that matching for these
      haplotypes significantly improves the outcome of unrelated bone marrow
      transplantation in thalassemia. In fact, results were comparable to those
      obtained in transplants using HLA-identifical family donors. INTERPRETATION AND
      CONCLUSIONS: Better results were obtained in patients with lesser iron overload
      and when the donor shared an identity for the DPB1 alleles.

PMID- 12412396
TI  - Protect your family from carbon monoxide fumes.

PMID- 12412395
TI  - About children and fevers.

PMID- 12412397
TI  - Pre-sports physicals. Play it safe.

PMID- 12412398
TI  - Children's earaches: medicate? Or watch and wait?

PMID- 12412399
TI  - Shaping up: little by little.

PMID- 12412400
TI  - Plan and pack an a-plus lunch.

PMID- 12412402
TI  - Magnets and health. Still more hype than hope.

PMID- 12412401
TI  - What happens if your child has ADHD?

PMID- 12412403
TI  - Hon strong is our net?

PMID- 12412404
TI  - [Physicians charter. Medical professionalism in the new millennium].

PMID- 12412405
TI  - [The erythrocyte sodium-proton exchanger activity in patient with primary
      hypertension].
AB  - A sodium-proton exchanger (NHE) is a membrane transport system taking part in
      intracellular sodium homeostasis. An increased NHE activity was observed in
      erythrocytes of primary hypertension (NTP) patients. Study group consisted of 25
      NTP patients and 24 control (K). NTP patients were significantly heavier (p <
      0.01) than control group (BMI 26.0 +/- 2.9 vs. 23.1 +/- 2.7, respectively). They
      also had significantly higher systolic, diastolic and mean arterial pressure than
      K (SBP 167 +/- 24.6 vs. 120 +/- 10.5; DBP 98 +/- 16.7 vs. 76 +/- 6.4; MAP 118.6
      +/- 17.9 vs. 89 +/- 6.4, respectively). There was positive correlation between
      MAP and BMI (p < 0.02) in NTP patients. Mean NHE activity was significantly
      higher in NTP than in K group (9.6 +/- 3.6 vs. 8.2 +/- 2.6 mmol/L RBC/h) p =
      0.05. A bimodal distribution of NHE activity in NTP group was observed. There was
      no correlation between NHE activity and BMI, MAP, SBP, DBP, age or positive
      family history of hypertension in NTP or K groups.

PMID- 12412406
TI  - [Circadian rhythm and variability of blood pressure and target organ damage in
      essential hypertension].
AB  - The aim of this study was to evaluate the influence of blood pressure variability
      and circadian rhythm on left ventricular mass and urinary albumin excretion rate
      (UAE) in patients with essential hypertension. 82 untreated patients (35 women
      and 47 men; mean age 41.1 +/- 13.7) were recruited to this study. Mean office
      blood pressure at entry was 152/97 mmHg. Ambulatory blood pressure monitoring
      (ABPM) was performed using an Medilog ABP recorder (Oxford). Blood pressure
      variability was estimated as the standard deviation (SD) of systolic and
      diastolic ambulatory blood pressure. Urinary albumin excretion (UAE) was
      estimated by the radioimmunoassay during two separate days. Echocardiography was
      used to measure left ventricular mass and left ventricular mass index (LVMI). The
      median urinary albumin excretion for the whole group was 8.2 mg/day; in 18
      patients (21.9%) microalbuminuria was present. Left ventricular mass index in a
      whole group was 109.1 g/m2; in 23 subjects (28.0%) left ventricular hypertrophy
      (LVH) was found. Patients with microalbuminuria as well as with left ventricular
      hypertrophy had higher office and 24 hour ambulatory systolic and diastolic blood
      pressure and higher systolic blood pressure variability. During ABPM 18 patients
      with absent nocturnal fall in blood pressure (non-dippers) were found; they did
      not display more frequent prevalence of target organ damage. Increased 24-hour
      blood pressure variability present in hypertensive subjects with both
      microalbuminuria and left ventricular hypertrophy may suggest that this
      phenomenon plays role in development of target organ damage.

PMID- 12412407
TI  - [Ear lobe crease as a factor of potential risk for coronary artery disease?-
      World news review and own research].
AB  - The aim of this study was to define the value of ear-lobe crease as the marker of
      potential risk of coronary artery disease on the basis of world's reports and own
      research. The test group consisted of 92 patients who were classified to coronary
      artery bypass graft using coronarography. Patients were divided into 3 groups (A
      without ELC, B-ELC on one ear, C-ELC bilateral). Detailed statistical analysis of
      coronarography results and incidence of coronary disease risk factors in each
      group was done. Obtained data allowed to evaluate the correlation between
      existence of the crease and extent of atherosclerotic changes in coronary
      vessels.

PMID- 12412408
TI  - [Estimation of head-up tilt test in diagnosis of syncope of unknown origin. Can
      we come up with better results?].
AB  - Optimal conditions in assessment of diagnostic head-up tilt test (TT) value
      required classification, which identified reactions with syncope and discreet
      disturbance of consciousness. The aim of the study was to assess of usefulness TT
      in diagnosis of syncope of unknown origin investigated by classification, which
      take into consideration vasovagal and nonvasovagal types of neurocardiogenic
      reactions. We studied 218 pts (115M, 103F), mean age 39.7 +/- 16.1 and 35.2 +/-
      17.7 years (adequately for male and female), with 2 or more syncope on unknown
      origin in last 6 months. Control group was 84 healthy volunteers (43M, 41F), mean
      age 37.41 +/- 2.6 years, range 18 to 73 years, with no syncope in anamnesis. All
      patients and controls underwent a TT in Westminster protocol. In case of negative
      TT, we performed next 20 min TT with 0.25 mg NTG sublinqualis (TT with NTG). Type
      of vasovagal syncope was defined according to American Experts Classification
      described in official guidelines of American College of Cardiology (ACC). In the
      case of vasovagal syncope, detailed specification of syncope was performed
      according to VASIS classification (the vasovagal Syncope International Study).
      Passive TT was positive in 51 (23%) pts. In control group passive TT was positive
      in 6 (7%) pts. TT with NTG generates syncope in additional 99 (45%) pts resulting
      in number of diagnosed group to 150 (68%) pts. In control group TT with NTG was
      positive in additional 21 (25%) pts. False positive TT with NTG was diagnosed in
      19 (9%) pts in study group and 11 (13%) in control group. Subpopulation of study
      group with vasovagal syncope was larger than subpopulation with other,
      nonvasovagal type of reaction (108 vs. 23; p < 0.0001). Taking into consideration
      this dual types of reaction (vaso- and nonvasovagal) allowed to reveal that there
      were no statistical significance between sex, age, type of syncope provocation
      and defined types of vasovagal reactions. ACC classification in comparison to
      VASIS criteria, was more sensitive (60% vs. 49%), have better diagnostic value to
      positive (89% vs. 84%) and negative (44% vs. 39%) result of TT and accuracy of
      diagnosis (66% vs. 47%) with slightly worse specificity of TT (81% vs. 83%).
      CONCLUSIONS: 1. TT results assessment according to ACC classification is more
      sensitive and almost the same specificity method in diagnosing patients with
      syncope of unknown origin than VASIS classification. 2. Improvement in diagnostic
      values of TT concerns passive TT and NTG TT. 3. Nonvasovagal types of reaction of
      cardiovascular system to orthostatic stress defined in ACC classification are, as
      the symptomatically syncope, significant clinical indicator of vegetative system
      instability.

PMID- 12412409
TI  - [Proinflammatory cytokines (IL-6, TNF-alpha) and cardiac troponin I (cTnI) in
      serum of young people with ventricular arrhythmias].
AB  - In the most cases the origin of ventricular arrhythmias is ischaemic, necrosis
      focus or presence of the connective tissue in cardiac muscle. The aim of the
      study was to evaluate troponin I (cTnI), interleukin 6 (IL-6) and tumor necrosis
      factor alpha (TNF-alpha) vs in young subject with ventricular arrhythmias. Into
      the study group included young people without organic heart diseases,
      dyselectrolitemia, with normal ECG which has not elevated levels of C-reactive
      protein (55 persons). The control group consisted of 22 healthy persons. The
      values of cTnI were not increased. The TNF-alpha concentrations were elevated in
      persons with ventricular arrhythmias (92 +/- 232 pg/mL vs. 2 +/- 1 pg/mL, p <
      0.001). The IL-6 concentrations were slightly elevated without statistical
      significance (1.5 +/- 4.5 pg/mL i 0.1 +/- 0.04 pg/mL, p = 0.06). CONCLUSIONS:
      There was no evidence of myocardial injury in young people with ventricular
      arrhythmias (cTnI). We noted increase levels of proinflammatory cytokines. It
      might suggest that the background of ventricular arrhythmias is inflammation.

PMID- 12412410
TI  - [Enzymatic activity of cathepsin B, cathepsin B and L, plasmin, trypsin and
      collagenase in hepatocellular carcinoma].
AB  - Hepatocellular carcinoma is one of the most common malignancies worldwide.
      Invasiveness of this tumour seems to be related to degradation of extracellular
      matrix. Such proteolytic enzymes as: cathepsin B and L, plasmin, collagenase and
      trypsin are thought to play a pivotal role in this process. Enzymatic activity
      depends on balance between enzymes and their inhibitors and--moreover--on
      interactions among these enzymes. The purpose of our study was to evaluate
      enzymatic activity of cathepsin B, cathepsin B and L, plasmin, collagenase and
      trypsin in patients with hepatocellular carcinoma in liver tissue and in
      peripheral blood. Then correlations between activity of enzymes (mentioned above)
      and clinical status, pathological findings and laboratory tests were assessed.
      Our study was conducted on 14 patients who underwent surgery because of
      hepatocellular carcinoma. Tissue samples were obtained during surgery from
      neoplastic area and from non-neoplastic area. Peripheral blood was withdrawn
      before surgery and within early post-operative period. Proteolytic activity of
      these enzymes was determined with use of fluorometric assay. Enzymatic activity
      in tissue samples was referred to protein concentration (BCA assay) and to DNA
      concentration (fluorometric assay). RESULTS: Proteolytic activity of plasmin and
      trypsin in neoplastic tissue were significantly lower as compared to non
      neoplastic area of these patients (p = 0.0356; p = 0.0412, respectively).
      Activity of the remaining enzymes: cathepsin B, cathepsin B and L and collagenase
      did not differ significantly. No difference was demonstrated between activity of
      enzymes in peripheral blood withdrawn before surgery and in postoperative period.
      There was a statistically significant inverse correlation between serum AFP level
      and enzymatic activity of cathepsin B, cathepsin B and L and collagenase in tumor
      tissue. Lower activity of all investigated enzymes was observed in tumor tissue
      of HBV related hepatocellular carcinoma in comparison with the remaining tissue
      samples. Correlation between patients age and activity of enzymes was not
      statistically significant. CONCLUSION: Although the evaluation of presented
      enzymatic profile did not allow for the assessment of associations between
      investigated enzymes, our results demonstrated correlations between proteolytic
      activity of enzymes and serum AFP level, viral status, but it requires further
      investigations.

PMID- 12412411
TI  - [Permanent junction reciprocating tachycardia--treatment with radiofrequency
      current ablation].
AB  - The patients with WPW syndrome demonstrate wide scale of clinical manifestation,
      from asymptomatic course to sudden cardiac death. Among this patients it is
      possible to identify the small group of patients with rare kind of
      atrioventricular reentrant tachycardia named permanent junctional reciprocating
      tachycardia (PJRT) associated with increased risk of development tachycardia
      induced cardiomyopathy. This patients should be successful treated by
      radiofrequency catheter ablation (RFCA). Aim of the study was assessment of
      efficacy and safety of RFCA procedure in patients with preexcitation syndrome and
      PJRT. Analyzed group consisted of 7 patients with PJRT selected from 163
      consecutive patients with symptomatic WPW--syndrome undergo electrophysiological
      study (EPS) and RFCA. Analyzed group consist of 4 women and 3 men. Mean age of
      patients was 22.71 SD +/- 7.99 (from 14 to 38 years). Every patients underwent
      EPS and RFCA simultaneously. Success-rate in first session was 71.42% (5 patients
      were successful ablated). Two women underwent second ablation one who has
      recurrent symptomatic arrhythmia and another who initially was unsuccessfully
      treated in first session. This two additional procedures were successful. RFCA
      duration time was average 107.85 minutes SD +/- 21.95 (min-80, max-145 min) and
      fluoroscopy--time amount from 28 min to 55 min average 38.58 min (SD +/- 11.14).
      Among analyzed patients we did not noticed any complications during ablation
      procedure. Patients with PJRT could be safe and successfully treated using RFCA.

PMID- 12412412
TI  - [Dermatosis bullosa in patient with chronic renal failure under hemodialysis
      treatment--case report].
AB  - A case of 45-year-old patient with chronic renal failure treated by hemodialysis
      associated with skin changes typical for porphyria cutanea tarda is reported. The
      diagnosis was based on clinical manifestations and on histopathologic examination
      of the skin segment. The skin was low sensitive for UVA rays, serum levels of
      aluminium and lead were significantly elevated. We did not find porphyrins in the
      urine (24-hour collection 100 ml) as well as in the dialysis fluid.

PMID- 12412413
TI  - [Prinzmetal's variant angina with transient complete atrio-ventricular block-
      case report].
AB  - A case of 44-year-old women with episodes of chest pain with ST-T segment
      elevation and paroxysmal atrioventricular complete block with syncopal episodes
      is presented. Coronary angiography did not reveal atheromatous lesions. A patient
      was treated with nitrates and calcium channel blockers. However syncopal episodes
      with A-V block reoccurred. A single-chamber (ventricular demand) pacemaker was
      implanted. A six month follow-up was uneventful.

PMID- 12412414
TI  - [Interstitial lung diseases--diagnostic problems].

PMID- 12412415
TI  - [Pathophysiology and etiopathogenesis of gestational diabetes mellitus].

PMID- 12412416
TI  - [The role of CD44 glycoprotein in pathogenesis of vascular diseases and diabetes
      mellitus].

PMID- 12412417
TI  - [Endothelin---biosynthesis, function and role in cardiovascular diseases].

PMID- 12412418
TI  - Employer attitudes and practices affecting health benefits and the uninsured.

PMID- 12412419
TI  - [The expression of intercellular adhesion molecules in inferior turbinate mucosa
      of allergic rhinitis and its significance].
AB  - OBJECTIVE: To study the expression of intercellular adhesion molecules in
      turbinate mucosa of allergic rhinitis and its significance. METHOD: Samples of
      turbinate mucosa were from 20 cases of chronic hypertrophic rhinitis, 24 cases of
      non provocation period allergic rhinitis and 20 cases of provocation period
      allergic rhinitis and their paraffin sections were studied with
      immunohistochemical technique staining with ICAM 1 and LFA 1 monoclone
      antibodies. RESULT: Expression of ICAM 1 and LFA 1 were higher in turbinate
      mucosa of provocation period allergic rhinitis than in chronic hypertrophic
      rhinitis and non provocation period allergic rhinitis turbinate mucosa(P < 0.01).
      CONCLUSION: High expression of ICAM 1 and LFA 1 in turbinate mucosa of allergic
      rhinitis shows that the interaction of ICAM-1/LFA-1 may participate in the
      inflammatory reaction of allergic rhinitis and may play an important role in the
      pathogenesis and development of allergic rhinitis.

PMID- 12412420
TI  - [The effects of hypoxia on the expression of inducible isoform of nitric oxide
      syntheses in nasal mucosal epithelial cells].
AB  - OBJECTIVE: To study the synthesis of inducible isoform of nitric oxide synthase
      (iNOS) in human nasal mucosal epithelial cells (HNMECs) under hypoxia, and the
      role of dexamethasone on this process. METHOD: HNMECs were cultured without serum
      under normal condition and hypoxia for 3-48 hours, parts of them were cultured
      with dexamethasone. Cell cycle of epithelial cells was observed by flowcytometer.
      INOS mRNA was detected by in situ hybridization. RESULT: Cell cycle of epithelial
      cells became long under hypoxia. iNOS mRNA expression increased with time
      dependence after hypoxia for 3 h compared with controls. The peak appeared after
      12 h hypoxia (P < 0.01). Increased iNOS mRNA expressions were reduced
      significantly by dexamethasone, but higher doses of dexamethasone (> 4.0 g/L) did
      not result in further suppression. CONCLUSION: Hypoxia can regulate expression of
      iNOS mRNA significantly in HNMECs, and dexamethasone can restrain this process
      significantly.

PMID- 12412422
TI  - [Study on the factors in the complications of endonasal sinus surgery].
AB  - OBJECTIVE: To investigate the cause of complications occurring in the operations
      of endonasal sinus surgery(ESS) and how to deal with. METHOD: 526 patients
      performed with ESS were analyzed. 31 patients had complications. The incidence of
      the complications in patients operative history was 38.9%, the incidence of
      bleeding in which the bleeding amount was over 200 ml was 30.2%, the incidence in
      patients whose medical history was less than 10 years was 2.8%. RESULT: Except
      for one patient whose eyesight decreased without recovery, the rest recovered.
      CONCLUSION: The cause of the complications in ESS was related with the destroy of
      normal structure, sinus bony anatomic variations, amount of intraoperative
      bleeding and the time of medical history.

PMID- 12412421
TI  - [Preliminary clinical study on the correlation between allergic rhinitis and food
      factors].
AB  - OBJECTIVE: To study the correlation between the onset of allergic rhinitis(AR)
      and food factors. METHOD: All participants involving 101 patients with AR(10
      cases accompanied with asthma) and 112 patients with nonallergic rhinitis(NAR)
      were studied in the form of prevalence survey. The components of food such as
      fat, salt and sugar intake were estimated through a food frequency questionnaire
      completed by the patients and controls. Scores were obtained depended on the food
      components. Histamine, dispensed in different concentrations, was dropped in the
      inferior turbinate to detect the nasal hyperreactivity(NH). RESULT: A significant
      difference (P < 0.05) was found between the food scores in AR and NAR groups.
      There was a greater significant difference (P < 0.01) between AR and NAR groups
      in NH. There was a negative correlation between food scores and histamine dosage
      both in AR group and AR and NAR group (P < 0.05). CONCLUSION: There is a
      correlation between the onset of AR and the food factors. The more the fat, salt
      and sugar are contained in the food, the more obvious the NH is.

PMID- 12412423
TI  - [Cytokeratin expression in the epithelial cells of nasal polyp].
AB  - OBJECTIVE: To study the expression of cytokeratin in epithelial cells of nasal
      polyp and its significance. METHOD: The monoclonal antibody of AE1, AE3, CK7,
      CK14, CK19, CK20 were used to determined the corresponding cytokeratin expression
      in epithelial cells of nasal polyp with immunohistochemical staining. RESULT: 1.
      AE1, CK7, CK19 staining were positive in various pathological epithelium of nasal
      polyp. AE1, CK19 showed positive in total layer of epithelium. CK7 was positive
      in goblet cells and basal cells of the pseudostratified epithelium. 2. AE3, CK20
      staining were positive in part of simple epithelium and stratified epithelium. 3.
      AE1, AE3, CK7, CK19 staining showed focal positive in transitional epithelium.
      CONCLUSION: CK7, CK19 are the one of the essential assembly type of cytokeratin
      in epithelium of nasal polyp. During the process of inflammatory reaction, the
      expression of partial cytokeratin subtype would lose while a new cytokeratin
      pattern would appear.

PMID- 12412424
TI  - [The expression of transforming growth factor alpha, beta 1 in hyperplastic
      tissue after endoscopic polypectomy and the effect of corticosteroid].
AB  - OBJECTIVE: To study the expression of transforming growth factor alpha, beta 1 in
      hyperplastic tissue after endoscopic polypectomy and the effect of
      corticosteroid. METHOD: Forty patients with nasal polyps were divided into two
      groups randomly: corticosteroid group (n = 20) with topical application of
      Budesonide (BUD, 400 micrograms/d) after endoscopic polypectomy and control group
      (n = 20) without corticosteroid after surgery. The hyperplastic tissues in
      operative cavity obtained in the 1st and 8th weeks after operation were studied
      with HE staining and immunohistochemistry technique respectively. RESULT:
      Morphological changes of hyperplastic tissue after endoscopic polypectomy
      included pseudostratified epithelium, highly edematous lamina proper and
      inflammatory cells infiltration, in which the main infiltrative cells were
      eosinophils (67.5%). Transforming growth factor alpha(TGF alpha) protein was
      highly expressed in epithelial cells, grand cells and inflammatory cells in the
      hyperplastic tissue. Transforming growth factor beta 1 (TGF beta 1) protein was
      highly expressed in inflammatory cells in the hyperplastic tissue. The expression
      of TGF alpha and beta 1 was significantly decreased after topical BUD spray (P <
      0.01, 0.05). CONCLUSION: Transforming growth factor alpha and beta 1 may play an
      important role in the formation and recurrence of nasal polyps.

PMID- 12412425
TI  - [Study on the expression of connexin 43 in human nasopharyngeal carcinoma].
AB  - OBJECTIVE: To study the relationship of the expression of connexin 43 (Cx43) in
      human nasopharyngeal carcinoma (NPC). METHOD: The cell shape and the expression
      of Cx43 in 18 cases of NPC and 10 cases of chronic inflammation disease of
      nasopharyngeal epitheliems (CIDNE) were observed under the laser scanning
      confocal microscopy and technology of fluorescence. RESULT: The scanning images
      displayed that the fluorescence signal of Cx43 in cell membrane of NPC was
      significantly lower than in CIDNE (P < 0.01). CONCLUSION: The expression of Cx43
      plays an important role in the development of NPC. The reduced or loss of gap
      junctional intercellular communication may be one of the important factors in the
      development of a normal nasopharyngeal epithelium cell into a neoplastic one.

PMID- 12412426
TI  - [Evaluation on hemorrhage factors secondary to endoscopic sinus surgery with
      multiple stepwise regression analysis].
AB  - OBJECTIVE: To investigate the factors relating to bleeding secondary to
      endoscopic sinus surgery. METHOD: 193 patients suffered from nasal polyps,
      chronic sinusitis and underwent endoscopic sinus surgery between May 1995 and
      February 2001 were analyzed. These patients's state of operation affairs tallies
      with this study's selecting condition and their clinic data was complete. The
      factors relating to bleeding secondary to endoscopic sinus surgery were analyzed
      with multiple stepwise regression analysis with STATA31 statistic computer
      software. RESULT: 20 selected hemorrhage factors were analyzed with multiple
      stepwise regressions. With these factors progressively removed, 5 items as
      follows showed relation to the hemorrhage: X18, X19, X9, X11, X20. An optimal
      regression equation for predicting hemorrhage has been established. According to
      this equation, the blood loss of endoscopic sinus surgery could be estimated.
      CONCLUSION: The clinical signification of 5 factors were recognized: 1. X18:
      Anatomy mark was broken down in former operation and showed difficulty when
      identified. 2. X19: Sinus presented proliferation such as scar forming, blood
      vessel showed hyperemia, sinus wall showed hyperplasia, Aperture being narrow and
      small. 3. X9: Sinusitis showed late stages. 4. X11: Estimated blood loss was
      significantly greater under general anesthesia. 5. X20: Operation went on over 2
      hours. If aforementioned condition appears, blood loss may exceed 200 ml.

PMID- 12412427
TI  - [Related structures of the lateral sphenoid wall anatomy studies in CT and MRI].
AB  - OBJECTIVE: To study the anatomy of the Lateral Sphenoid Wall in CT and MRI in
      normal adults so as to provide a theoretical basis for imagine science. METHOD:
      High resolution CT in axial and coronal planes was conducted on 25 normal adults.
      MRI in axial and coronal planes, using SE T1 WI and FSE T2 WI was conducted on 20
      volunteers. RESULT: 1. The pneumatisation of sphenoid sinus can be divided into
      two types: Pneumatisation of the sphenoid body and the one of sphenoid process.
      The former one can be subdivided into three categories: concha (2%), pre sellar
      (20%), sellar (78%). The latter can be subdivided into four categories: lesser
      wing (38%), greater wing (40%), pterygoid process (34%) and dorsum sellar (6%).
      2. The thinnest part (< 1 mm) of the LSW is located at the inner wall of the
      optic nerve canal (96%), at the bony wall in the plane of sphenoethmoid recess
      (86%), the bony wall in the plane of the internal carotid artery (66%). 3. Over
      pneumatised sphenoid sinus could make the foramen rotumdum (64%) and pterygoid
      canal (44%) protrudes into the sphenoid cavity. CONCLUSION: Attention should be
      paid to the various mode of pneumatization around the optic nerve canal.

PMID- 12412428
TI  - [36 case idiopathic orbital inflammatory pseudotumor with sinus involvement].
AB  - OBJECTIVE: To study the incidence of sinusitis in patients with idiopathic
      orbital inflammatory pseudotumor(IOIP) and the relationship between sinusitis and
      IOIP. METHOD: 209 IOIP cases from Jan 1, 1978 to Dec 31, 1999 in Eye Hospital,
      Zhongshan Ophthalmic Center, Sun Yat Sen University of Medical Sciences were
      reviewed. Data showed that 36 of 209 IOIP cases suffered from sinusitis including
      21 cases of maxillary sinusitis, 15 case of ethmoid sinusitis, 3 case of frontal
      sinusitis and 3 case of sphenoid sinusitis. The total incidence of sinusitis is
      17.2%. Proptosis, restrictive movement of the involved eye, eyelid or conjunctive
      congestion, decreased eyesight and palpable orbital masses were the main clinical
      findings. All patients showed a space occupied lesion in their orbits. 27
      patients received combined surgical management and corticosteroids treatment. 9
      patients received systemic corticosteroids treatment. RESULT: Therapy showed that
      the full recovery response rate was 33.3% (12/36) and the partial recovery
      response was 50.0% (18/36). The recurrence rate was 16.7% (6/36). CONCLUSION:
      Some patients suffered from sinusitis and sinusitis may be a cause in the
      etiology of IOIP.

PMID- 12412429
TI  - [Treatment of the paranasal sinuses mycosis with endoscopic sinus surgery].
AB  - OBJECTIVE: To evaluate the treatment effect of endoscopic sinus surgery on the
      paranasal sinuses mycosis. METHOD: 29 cases of paranasal sinuses mycosis were
      treated with endoscopic sinus surgery from 1998. The wound was washed with 1%
      H2O2 and 0.9% NaCl solution after operation. RESULT: In the follow up of 6-36
      months, all cases were cured. CONCLUSION: With the endoscopic sinus surgery, the
      surgeons can get better illumination and the function of nasal cavity and sinuses
      can be preserved as many as possible. The success rate was high.

PMID- 12412430
TI  - [Nasopharyngeal tuberculosis: an analytical study and report on 12 cases].
AB  - OBJECTIVE: To understand the nasopharyngeal tuberculosis better. METHOD: 12 cases
      of nasopharyngeal tuberculosis collected from 1993 to 2000 were retrospectively
      analyzed and the clinical features were studied. RESULT: Only one case had known
      the previous history of pulmonary tuberculosis(8.33%). Cervical lymphadenopathy
      was the most common presenting symptom in our series (9 cases, 75%). 9 cases were
      diagnosed as nasopharyngeal malignant tumors by mistake at the beginning (75%),
      Anti tuberculous medical treatment was successful in all patients after follow-up
      from 6 months to 2 years. CONCLUSION: Nasopharyngeal tuberculosis may occur more
      frequently as part of an isolated upper respiratory tract infection than as
      secondary to pulmonary infection. It could get rise to cervical lymphadenopathy
      and should be taken into account when cervical lymphadenopathy is found.
      Nasopharyngeal malignant tumour is the most important disease in differential
      diagnosis for their similar clinical features. Antituberculous chemotherapy is
      usually effective.

PMID- 12412431
TI  - [Choice of anesthetic method and prevention of ophthalmic complication in
      sphenoid sinus endoscopic surgery].
AB  - OBJECTIVE: To evaluate the anesthetic method and the prevention of the ophthalmic
      complication in endoscopic surgery for sphenoid sinus disease. METHOD: All 65
      patients underwent local anesthesia with improved surface anesthesia. Arrest
      blood completely in the surgical operation. The position of sphenoid sinus, the
      assimilation and destruction of sinus wall, the location and the appearance of
      lesion were determined carefully. To avoid damaging the optic nerve, the behavior
      of eyes was observed intently. RESULT: The follow up period ranged from 6 months
      to 2 years. Five patients were lost to follow up. 53 of 60 patients recovered. 7
      patients had recurrence among them with 2 cases of inverted papilloma and 5 cases
      of spheniod sinusitis with nose polyp, but they were successfully resected by
      endoscopic endonasal sinus surgery. Ophthalmic complication occurred in 5
      patients. CONCLUSION: Endoscopic sphenoid sinus surgery can be performed
      successfully under local anesthesia with improved surface anesthesia. Familiarity
      with the anatomic marker and variable anatomy, and meticulous surgical technique
      are essential for reducing ophthalmic complication.

PMID- 12412432
TI  - [Endoscopic sinus surgery, clinical observation with 40 cases].
AB  - OBJECTIVE: To study the curative effect of endoscopic sinus surgery(ESS). METHOD:
      The clinical data of ESS on 40 cases(70 sides) of chronic sinusitis and nasal
      polyps were analyzed. RESULT: In 34 of the 40 cases followed up over six months,
      25 cases(73.5%) were cured, 7 cases(20.6%) were improved, 2 cases(5.9%) were
      ineffective. The effective rate was 94.1%. The serious operation complication was
      absent. Bleeding after operation was found in 1 case, middle turbinate synechiae
      with nasal septum were found in 2 cases. CONCLUSION: ESS is effective in the
      treatment of chronic sinusitis and nasal polyps. The success of operation is
      directly related to the excellent surgical skills. A regularly follow up and
      cleaning to the operation cavity after operation are important elements for
      securing optimal long-term result.

PMID- 12412433
TI  - [Uplift of the larynx and advance of the part larynx in the management of the
      epiglottic dysfunction caused by neck trauma].
AB  - OBJECTIVE: To study the surgical management of epiglottic dysfunction caused by
      neck trauma. METHOD: 3 patients underwent operation as To lift the larynx 0.5-0.8
      mm and advance the upper part of the larynx 0.6-0.8 mm. RESULT: No aspiration
      occurred after operation in 0.5-2 years. CONCLUSION: This treatment may be
      considerable for the patients with the epiglottic dysfunction.

PMID- 12412434
TI  - [One stage repair of soft tissue defects in facial and pharynx malignant tumor
      operations with radical forearm flap].
AB  - OBJECTIVE: To explore the applications of radial forearm flap(RFF) in malignant
      tumor operations in otolaryngology head neck surgery. METHOD: During the
      operation, the radical artery and cephalic vein were usually anastomosed to the
      upper thyroid artery and facial vein separately. RESULT: In all six RFF
      reconstruction patients, 4 cases succeeed and 2 failed. CONCLUSION: The RFF is a
      ready source of thin, pliable skin flap and it's also a reliable, well developed
      reconstruction technique. Its dissection can be easily made with the long
      vascular pedicle and large caliber vessels. This reconstruction technique can be
      widely adopted in otolaryngology head neck surgery operation.

PMID- 12412435
TI  - [Expression of IL-12 mRNA in the nasal mucosa of experimental allergic rhinitis].
AB  - OBJECTIVE: To study the relation between the level of IL-12 expression and the
      pathogenesis of allergic rhinitis, we investigated the expression of interleukin
      12 (IL-12) mRNA in the nasal mucosa of experimental allergic rhinitis. METHOD: 24
      healthy guinea pigs were randomly divided into two groups. A model of allergic
      rhinitis (AR) in guinea pig was established by using ovalbumin intraperitoneal
      immunization and nasal antigen challenge. The nasal mucosa obtained from AR
      models as well as normal controls were studied for histopathological changes with
      stain HE, and expression of IL-12 mRNA with RT-PCR. RESULT: IL-12 was expressed
      in all the samples from AR models to normal controls. The mean expression level
      of IL-12 gene, however, in AR models was lower than that in normal controls
      (0.667 +/- 0.104 vs 0.847 +/- 0.071, P < 0.01). CONCLUSION: IL-12 expression was
      decreased in the nasal mucosa of allergic rhinitis, which plays an important role
      in the pathogenesis of allergic rhinitis. It is also suggested that IL-12
      replacement therapy may be a new approach to the treatment of allergic rhinitis.

PMID- 12412436
TI  - [Localization of nitric oxide synthase in the chicken vestibular system].
AB  - OBJECTIVE: To locate nitric oxide synthase (NOS) in the chicken vestibular
      system. METHOD: The frozen section were processed for NADPH-d histochemistry in a
      solution containing NADPH and nitroblue tetnazolium (NBT) to demonstrate NOS
      positive reactivity. RESULT: NOS positive staining, black-blue in color, was seen
      at the nerve ending, nerve fibers of the utricul and saculla and ampiculium.
      Ganglion cells had different activity. The shape of the cells seems to be round
      or oral. CONCLUSION: Collectively, data indicate the presence of active NOS in
      these tissue and suggest modulation of vestibular neurotransmission by nitric
      oxide.

PMID- 12412437
TI  - Enhance pursuit of excellence by integrating ISO 9000, Baldrige.
AB  - Integration links strategic approach to customer-oriented philosophy. ISO
      provides essential fundamentals for a business model. Breaking down silo effect
      key to performance improvement.

PMID- 12412438
TI  - ED diversions reduced by tight monitoring.
AB  - Hospital had no good system for measuring flow through the organization.
      Mechanism to ensure action is a key element in program's success. Giving nurses
      greater control drops staff vacancy rates and boosts satisfaction.

PMID- 12412439
TI  - Consortium approach gets results in prostate cancer.
AB  - Benchmarking national centers for excellence hones diagnoses. Patient advocates
      help achieve balanced approach to treatment. Nearly 80% of eligible patients go
      on to national clinical trials.

PMID- 12412440
TI  - Study links nursing shortage, poor quality.
AB  - Associated complications include pneumonia, upper gastrointestinal bleeding,
      shock, and cardiac arrest. Large sample helps bolster validity of findings.
      Quality managers should look beyond charts for issues to address.

PMID- 12412441
TI  - Organizational learning: could it be the key to higher quality and increased
      revenues?
AB  - Collective learning process creates a sense of staff empowerment. Flattening of
      leadership levels leads to improved communication. Three core competencies
      currently are lacking in most organizations.

PMID- 12412443
TI  - CHA takes three-step journey to improvement.
AB  - Process requires far more time and energy than staff anticipated. Benchmarking
      processes lead to environment of continuous improvement. Data collection tool
      organized around current critical issues.

PMID- 12412442
TI  - Prisoner HIV program has 85% completion rate.
AB  - Program intensity and staff professionals are cited as keys to success. Project
      builds on earlier work within the state's prison system. CD4 counts increase,
      while viral loads are lower.

PMID- 12412444
TI  - PDAs help nurses improve care and save time.
AB  - If physicians can benefit from using PDAs, then why can't nurses? Technology
      enables targeting of diabetes patients requiring rapid intervention. Using
      devices can save nurses nearly two hours a day.

PMID- 12412445
TI  - AHRQ: IT/DSS can aid in bioterror response.
AB  - Only a small minority of hospitals have adequate systems in place. Many existing
      systems may be adaptable to bioterrorism preparedness. Benchmarking opportunities
      are available for facilities with inadequate systems.

PMID- 12412446
TI  - Patient safety alert. Closer link made between nursing shortage, safety.

PMID- 12412447
TI  - Patient safety alert. Joint Commission issues patient safety goals.

PMID- 12412448
TI  - HLA informatics. Accessing HLA sequences from sequence databases.

PMID- 12412449
TI  - Accessing HLA sequencing data through the 6ace database.

PMID- 12412450
TI  - HLA typing by restriction fragment length polymorphism analysis.

PMID- 12412451
TI  - PCR-restriction fragment length polymorphism typing of class I and II alleles.

PMID- 12412452
TI  - PCR-sequence-specific oligonucleotide probe typing for HLA-A, -B, and -DR.

PMID- 12412453
TI  - HLA-DPA1 and -DPB1 typing using the PCR and nonradioactive sequence-specific
      oligonucleotide probes.

PMID- 12412454
TI  - PCR-sequence-specific primer typing of HLA class I and class II alleles.

PMID- 12412455
TI  - HLA typing with reference strand-mediated conformation analysis.

PMID- 12412456
TI  - Sequencing protocols for detection of HLA class I polymorphism.

PMID- 12412457
TI  - HLA-E and HLA-G typing.

PMID- 12412458
TI  - Typing alleles of HLA-DM.

PMID- 12412459
TI  - Typing alleles of TAP1 and TAP2.

PMID- 12412460
TI  - Determining alleles of the C2 gene by Southern Blotting.

PMID- 12412461
TI  - Complement C4 protein and DNA typing methods.

PMID- 12412462
TI  - Typing of tumor necrosis factor alleles.

PMID- 12412463
TI  - Molecular typing of the MHC class I chain-related gene locus.

PMID- 12412464
TI  - HLA microsatellite analysis.

PMID- 12412465
TI  - Generation of antibody molecules through antibody engineering.

PMID- 12412466
TI  - Application of recombinant antibodies in cancer patients.

PMID- 12412467
TI  - DNA immunization as a means to generate antibodies to proteins.

PMID- 12412468
TI  - Chimerization of a monoclonal antibody for treating Hodgkin's lymphoma.

PMID- 12412469
TI  - Humanization of monoclonal antibodies by CDR grafting.

PMID- 12412470
TI  - Generation and screening of a modular human scFv expression library from multiple
      donors.

PMID- 12412471
TI  - Construction of semisynthetic antibody libraries.

PMID- 12412472
TI  - Single-domain VH antibody fragments from a phage display library.

PMID- 12412473
TI  - Isolation of human Fab fragments against ovarian carcinoma using guided
      selection.

PMID- 12412474
TI  - Human recombinant Fab antibodies with T-cell receptor-like specificities
      generated from phage display libraries.

PMID- 12412475
TI  - Engineering hot spots for affinity enhancement of antibodies.

PMID- 12412477
TI  - Tailoring kinetics of antibodies using focused combinatorial libraries.

PMID- 12412476
TI  - Simultaneous humanization and affinity optimization of monoclonal antibodies.

PMID- 12412478
TI  - Engineering scFvs for improved stability.

PMID- 12412480
TI  - Generation of recombinant immunotoxins for specific targeting of tumor-related
      peptides presented by MHC molecules.

PMID- 12412479
TI  - Recombinant single-chain and disulfide-stabilized Fv immunotoxins for cancer
      therapy.

PMID- 12412481
TI  - Construction and characterization of RNase-based targeted therapeutics.

PMID- 12412482
TI  - Bispecific diabodies for cancer therapy.

PMID- 12412483
TI  - Generation and characterization of bispecific tandem diabodies for tumor therapy.

PMID- 12412484
TI  - Generation of recombinant multimeric antibody fragments for tumor diagnosis and
      therapy.

PMID- 12412485
TI  - Construction and characterization of minibodies for imaging and therapy of
      colorectal carcinomas.

PMID- 12412487
TI  - Tailoring natural effector functions. Antibody engineering beyond humanization.

PMID- 12412486
TI  - Generation, expression, and monitoring of recombinant immune receptors for use in
      cellular immunotherapy.

PMID- 12412488
TI  - Single-chain Fv-based affinity purification of the cellular stress protein gp96
      for vaccine development.

PMID- 12412489
TI  - Recombinant adenoviruses for in vivo expression of antibody fragments.

PMID- 12412490
TI  - Production of antibody fragments in a bioreactor.

PMID- 12412491
TI  - Large scale production of recombinant antibodies by utilizing cellulose-binding
      domains.

PMID- 12412492
TI  - Production of tumor-specific antibodies in tobacco.

PMID- 12412493
TI  - "He's guilty!": investigator bias in judgments of truth and deception.
AB  - Detecting deception is an inherently difficult task, but one that plays a
      critical role for law enforcement investigators in the interrogation room. In
      general, research has failed to indicate that performance in this domain is
      improved by training or prior experience. A signal detection framework is applied
      to the paradigm to better conceptualize the influence of these two factors. We
      found that although neither factor influenced discrimination accuracy, there was
      an effect on response bias such that training and prior experience appeared to
      increase the likelihood of responding "deceit" as opposed to "truth." This
      "investigator bias" was observed both in a review of the literature and in this
      study of North American law enforcement investigators who took part in a
      forensically based deception-detection task. Possible theoretical mechanisms and
      practical implications of these findings are discussed.

PMID- 12412494
TI  - An examination of the relationship between competency to stand trial, competency
      to waive interrogation rights, and psychopathology.
AB  - This study compared the legal abilities of defendants (N = 212) with current
      primary psychotic disorders (n = 44), affective disorders (n = 42), substance
      abuse disorders (n = 54), and no diagnosed major mental illness (n = 72).
      Defendants with primary psychotic disorders demonstrated more impairment than did
      other defendants in their understanding of interrogation rights, the nature and
      object of the proceedings, the possible consequences of proceedings, and their
      ability to communicate with counsel. Psychosis was of limited value as a
      predictor however, and high rates of legal impairment were found even in
      defendants with no diagnosed major mental illness. Sources of within-group
      variance were examined to further explain this finding. Policy and clinical
      implications of these results are discussed.

PMID- 12412495
TI  - Validity beliefs and ideology can influence legal case judgments differently.
AB  - Jurors sometimes enter a case both with prior beliefs about its likely validity
      and with more general ideologies that are relevant to the case. Although prior
      validity beliefs may serve as heuristics, directly biasing decisions when
      cognitive capacity is low, we hypothesized that ideology may bias systematic
      thought even when cognitive capacity is high. This experiment studied simulated
      individual juror decisions in a sex-discrimination case, measuring validity
      beliefs about such cases as well as feminist ideology, and exposing participants
      to 1 of 3 case versions under time pressure or no time pressure. Validity beliefs
      had a direct, heuristic impact on judgment only under time pressure. However,
      feminist ideology had a mediated influence on judgment via valenced thoughts
      about the evidence, even under no time pressure. Also, people with initially
      proplaintiff beliefs judged a woman's sex-discrimination suit more negatively
      than did prodefendants if the evidence was weak. The results suggest that when
      jurors can fully process information, validity expectancies might backfire if not
      supported by case evidence, but ideology can have a more pervasive influence on
      the decision-making process.

PMID- 12412496
TI  - Trial by polygraph: reconsidering the use of the guilty knowledge technique in
      court.
AB  - Polygraph test results are by and large ruled inadmissible evidence in criminal
      courts in the US, Canada, and Israel. This is well-conceived with regard to the
      dominant technique of polygraph interrogation, known as the Control Question
      Technique (CQT), because it indeed does not meet the required standards for
      admissible scientific evidence. However, a lesser known and rarely practiced
      technique, known as the Guilty Knowledge Test (GKT), is capable, if carefully
      administered, of meeting the recently set Daubert criteria. This paper describes
      the technique, and argues for considering its admissibility as evidence in
      criminal courts.

PMID- 12412497
TI  - Identifying stalking: the relevance of intent in commonsense reasoning.
AB  - One method of distinguishing stalking from law-abiding behavior is to determine
      whether the accused intended to cause fear or harm to the target. However, this
      distinction may not capture community concerns regarding intrusive or harassing
      behavior. The present research examines the effect of intent, persistence,
      relationship, and consequences on community perceptions of stalking. Responses of
      1,080 members of the community to a series of scenarios indicated that the
      presence of explicit evidence of intent was not the only way stalking behavior
      was identified. Behavior was also identified as stalking as a greater degree of
      persistence was depicted. Females more often than males perceived the behavior as
      stalking and inferred intent to cause fear or harm. Most participants who
      identified the behavior as stalking also indicated that it should be illegal.
      These results may assist in guiding ongoing debates over appropriate stalking
      legislation and strategies to reduce the incidence of stalking, as well as
      indicating whether education regarding stalking laws is required.

PMID- 12412498
TI  - Some contrarian concerns about law, psychology, and public policy.
AB  - I discuss six issues that may cut against the majoritarian grain. They are: (1)
      The U.S. Supreme Court's view of children; (2) the American Psychological
      Association's view of people with mental retardation; (3) the dilution of
      autonomy in favor of beneficence; (4) Tarasoff's undermining of fidelity to
      therapy clients; (5) the misuse of the PCL-R in death penalty litigation; and (6)
      the criminal law's rejection of determination.

PMID- 12412499
TI  - [Disorders of renal hydrodynamics as a major factor of hypertension progression
      (pathogenic aspects and laboratory methods for evaluation of efficacy of
      hypotensive therapy) (a literature review)].

PMID- 12412500
TI  - [Properties and expression of the human activated alpha2-macroglobulin receptor].
AB  - A multi-step purification procedure has been used for isolation of alpha 2M/LRP
      receptor from human placenta. Enzymatic properties of complexes of purified alpha
      2M trypsin with alpha 2M/LRP receptor were studied. This complex is characterized
      by enzymatic activity measured by a kinetic procedure based on the trypsin
      reaction with synthetic substrate alpha 2N-benzoyl-D,L-arginine nitroparaanilide.
      Purified triple complexes of alpha 2M trypsin with alpha 2M/LRP had 22-28%
      residual trypsin activity, while that of trypsin complex with alpha 2
      macroglobulin was 52-53%. Patients' blood samples were characterized by a high
      level of residual activity of the studied double and triple complexes only
      initially. A decrease in the activities of these complexes was observed in
      patients with high levels of malonic dialdehyde (by TBA-reactive products)
      combined with decreased level of superoxidedismutase-like activity.

PMID- 12412501
TI  - [Electrophoretic alkaline phosphatase isoforms in the placenta in complicated
      pregnancy].
AB  - A clinical study showed that 2 types of changes in electrophoretic spectrum of
      alkaline phosphatase (AIP) isoforms are distinguished in the chorion of delivered
      placenta after gestosis. In type I new AIP isoforms appear, while in type II some
      AIP isoforms disappear or are united in one, which reflects the development of
      adaptation or pathological processes in the fetoplacental system.

PMID- 12412502
TI  - [Detection of vitamin B12 and folic acid by the immunoenzyme technique].

PMID- 12412503
TI  - [Comparative analysis of serum analyte level measurements by commercial
      diagnostic kits from four manufacturers (Alkor-Bio, Roche, Diagnostic Products
      Corporation-DCP, and Bayer Corporation)].
AB  - Hydrocortisone, progesterone, testosterone, triiodothyronine, thyroxine,
      chorionic gonadotropin, prolactin, alpha-fetoprotein, luteinizing, follicle
      stimulating, and thyrotropic hormones were measured in human sera and in
      Lyphochek Immunoassay Plus Control reference sera (Bio-Rad Laboratories, USA)
      using 4 commercial kits (Alkor Bio Inc. and Roche, automated analyzer Roche Cobas
      Core; DPC, automated analyzer Immulite; Bayer, automated analyzer ACS:180).
      Coordination and correlation between these kits was observed, the coordination
      decreasing in the series Alkor Bio/Bayer, Alkor Bio/Roche, and Alkor Bio/DPC.

PMID- 12412504
TI  - [Bedside laboratory testing (a lecture)].

PMID- 12412505
TI  - [Control of heavy metal (Cu, Pb, Zn) levels in human plasma].
AB  - A new method for wet ashing of biological objects (plasma) with a mixture of
      concentrated perchloric and nitric acids is proposed. Optimal conditions for
      measuring heavy metals in human plasma with simultaneous inverse voltammeter were
      determined. The concentrations of copper, lead, and zinc were measured in the
      plasma of cardiovascular patients by a solvent photometric, inverse voltammeter,
      and atomic absorption methods (Cu), by oscillographic, atomic absorption, and
      inverse voltammeter methods (Pb), and by atomic absorption and inverse
      voltammeter methods (Zn).

PMID- 12412506
TI  - [Interaction of cationic surface-active antiseptics and serum albumin by the
      bacterial bioluminescence method].
AB  - Human serum albumin binding of cationic surface-active antiseptics was studied
      using a Photobacterium phosphoreum K3 strain isolated by the authors in the Black
      sea. Binding of cationic surface-active proteins to serum albumin led to
      disappearance of toxic and antibacterial characteristics of miramistine,
      ethonium, and decametoxin, but not chlorohexidine. The activity of chlorohexidine
      was reduced by 45-48% in the presence of albumin. Albumin binding capacity
      towards miramistine was 7.0-8.7%, towards ethonium 8.2-10%, and towards
      decametoxin 2.4-3%.

PMID- 12412507
TI  - [Haptoglobin phenotype in patients with spondyloarthritis and healthy
      individuals].
AB  - Haptoglobin (Hp) phenotype distribution was evaluated in 95 patients with
      seronegative spondylarthritis and 100 normal controls. The incidence of three Hp
      types was virtually the same in acute patients and controls. Reactive arthritis
      was associated with Hp2-1 type, psoriatic arthritis with Hp1-1 type, ankylosing
      spondylarthritis with Hp2-2 type. The authors suggest that the presence of Hp2-2
      type is one of genetic factors of seronegative spondylarthritis.

PMID- 12412508
TI  - [Ratio of erythrocyte number to erythrocyte size in peripheral blood].
AB  - The count and size of erythrocytes are normally stable. In order to evaluate
      their ratio in health, some hematological diseases and during exposure to some
      ecological factors, peripheral blood erythrocytes were studied in 747 subjects
      (115 healthy controls aged 18-80 years, 56 subjects chronically exposed to
      ionizing radiation sources, 105 subjects working with aggressive liquids, 117
      patients with anemias, and 81 with Hodgkin's disease). No relationship between
      erythrocyte count and MCV was detected in normal subjects and patients with
      anemia and Hodgkin's disease. It seems that this relationship is rather specific
      for hemopoiesis shifts associated with cell cycle delay, as it was detected in
      patients with B12 and folic deficiency anemias, in subjects chronically exposed
      to ionizing radiation sources, and in those handling nitrogen oxide in
      combination with heptyl.

PMID- 12412509
TI  - [Additional potentialities of using blood cell characteristics for diagnosis of
      nonspecific ulcerative colitis].
AB  - The potentialities of increasing the resolving capacity of standard hematological
      parameters used for the diagnosis of chronic nonspecific ulcerative colitis were
      investigated. The mean volume of erythrocytes decreases and the shape of
      population erythrogram is modified in this disease. White blood is characterized
      by qualitative changes (mean cell volume and parameters of its distribution for
      neutrophils lymphocytes, and monocytes). Consideration for the corpuscular volume
      of these cells helps differentiate between slight, medium, and severe chronic
      nonspecific ulcerative colitis.

PMID- 12412510
TI  - [Laser DNA flow cytometry in patients with ovarian epithelial tumors].
AB  - Despite the use of new drugs in therapy of ovarian cancer, remote results remain
      unsatisfactory. Traditional prognostic factors, which are often subjective, do
      not reflect the individual features of a tumor in a certain patient. The authors
      compare classical prognostic factors, the data of laser DNA flow cytometry, and
      the receptor status of the tumor. Tumor ploidy is the most informative
      independent prognostic factor: the period without relapses in patients with
      aneuploid tumors is significantly shorter in comparison with patients with
      diploid tumors. Study of tumor cell distribution by the cell cycle phases can
      also provide additional information for predicting the disease course in ovarian
      cancer.

PMID- 12412511
TI  - [External evaluation of quality of cytological studies in laboratories in
      Russia].

PMID- 12412512
TI  - [Effect of plasmapheresis on anti-platelet antibody activity].

PMID- 12412513
TI  - Being solicitous or getting even?

PMID- 12412514
TI  - A tale of rats, plague and people.

PMID- 12412515
TI  - The burden of injury in Rhode Island.

PMID- 12412516
TI  - Alcohol-related motor vehicle crashes in Rhode Island.

PMID- 12412517
TI  - Impaired drivers: a call to action for Rhode Island physicians.

PMID- 12412518
TI  - Alcohol, marijuana, and injury in the emergency department.

PMID- 12412519
TI  - Firearm injury surveillance in Rhode Island.

PMID- 12412520
TI  - Injuries in Rhode Island elders.

PMID- 12412522
TI  - High fidelity medical simulation: a new paradigm in medical education.

PMID- 12412521
TI  - The Providence Safe Communities Partnership.

PMID- 12412523
TI  - A case study: pedestrian-motor vehicle trauma.

PMID- 12412524
TI  - Surgical infection prevention--the new Medicare quality improvement project.

PMID- 12412525
TI  - Asthma mortality in Rhode Island and the United States, 1979-1998.

PMID- 12412526
TI  - The prevalence of HIV and AIDS among high-risk populations in Rhode Island, 2002.

PMID- 12412527
TI  - JCAHO's approach to disaster.

PMID- 12412528
TI  - The bonuses of saving money.

PMID- 12412529
TI  - A handy sanitizer. CHG becoming primary sterilization agent.

PMID- 12412531
TI  - Stats. Capitalizing on expenditures.

PMID- 12412530
TI  - Forcing costs down.

PMID- 12412532
TI  - New drug approved for colorectal cancer.

PMID- 12412533
TI  - New palm test for cholesterol.

PMID- 12412534
TI  - HHS to study ephedra, step up enforcement against illegal marketing.

PMID- 12412535
TI  - FDA steps up seafood sampling.

PMID- 12412536
TI  - HHS: POUFA reauthorization good for Americans.

PMID- 12412537
TI  - 'Nicotine water' is unapproved drug.

PMID- 12412538
TI  - Labeling changes for arthritis drug.

PMID- 12412539
TI  - Advisory for Norplant contraceptive kits.

PMID- 12412540
TI  - FDA warning on Chinese diet pills containing fenfluramine.

PMID- 12412541
TI  - Xyrem approved for muscle problems in narcolepsy.

PMID- 12412543
TI  - Information source on rare diseases.

PMID- 12412542
TI  - FDA clears two glucose test meters.

PMID- 12412544
TI  - Air pollution linked with risk for exercise-induced heart damage.

PMID- 12412545
TI  - Cardiovascular benefits of long-term fruit and vegetable consumption.

PMID- 12412547
TI  - Vaccine shortages: an update.

PMID- 12412546
TI  - Checking up on blood pressure monitors.

PMID- 12412548
TI  - Osteoporosis and men.

PMID- 12412549
TI  - Imported drugs raise safety concerns.

PMID- 12412550
TI  - Generic drugs: what you need to know.

PMID- 12412551
TI  - Food freshness and 'smart' packaging.

PMID- 12412552
TI  - Treating minor species: a major animal health concern.

PMID- 12412554
TI  - FDA: a science-based agency.

PMID- 12412555
TI  - Should parents buy antibacterial products?

PMID- 12412553
TI  - Love and illegal drugs on the Internet.

PMID- 12412556
TI  - Smallpox vaccine: who should get it?

PMID- 12412557
TI  - Another reason for pregnant women to take vitamins?

PMID- 12412558
TI  - Comparing temple and rectal temperatures in young children.

PMID- 12412559
TI  - Allergens in foods: food labels can be wrong...and it's easy to misinterpret
      correct food labels.

PMID- 12412560
TI  - Parent/child. Some thoughts about Halloween...

PMID- 12412561
TI  - Product recalls: konjac candy--again... Playskool toy chests sold at Target...and
      "Bottle Cap Bear" key chains.

PMID- 12412562
TI  - New studies highlight racial disparity, treatment access among HIV patients.
      Differences chiefly due to economic disparity.
AB  - The latest research finds that HIV treatment disparities among minority
      populations are not a big problem within specific HIV programs, but they can be
      measured when all states and programs are added into the picture. One of the main
      reasons for the disparity is that African-Americans are more likely to receive
      their HIV care and medications through Medicaid programs than through AIDS Drug
      Assistance Programs.

PMID- 12412563
TI  - Progress reported on curbing disparities. One type of program doesn't fit all.
AB  - As researchers examined the issue of racial disparity in HIV care and treatment,
      they found that some clinics and states have made progress in reducing disparity
      through a variety of programs and measures. Through studying various HIV programs
      in four states, researchers have found that the chief obstacles and solutions
      vary by region and minority culture, so there probably will never be one model
      for care that would work for all states and programs.

PMID- 12412564
TI  - Special report: club drugs & HIV. Drug treatment best hope for meth-using MSMs.
      Researchers want to get word out about problem.
AB  - New unpublished and published research show that gay and bisexual men who use
      methamphetamine have a greater prevalence of HIV infection than men who have sex
      with men who do not use the drug. This finding has led some researchers to
      speculate that methamphetamine use could result in a resurgence of the virus
      among gay men. And it highlights the need for targeted substance abuse programs
      directed toward MSM who use methamphetamine.

PMID- 12412565
TI  - Debt cancellation tops agenda of international groups. Issue receives increasing
      political clout.
AB  - International AIDS activists have begun to succeed in bringing the issue of debt
      relief/cancellation to the attention of political leaders--and the general public
      -and express optimism that some major changes have begun.

PMID- 12412566
TI  - UNAIDS guidelines update includes expanded agenda. Changes occur with sixth
      guideline.
AB  - Recent changes made to the 'HIV/AIDS and Human Rights International Guidelines'
      include recommendations that hold governments accountable for developing policies
      that will improve HIV treatment and care.

PMID- 12412567
TI  - Behavioral intervention for meth-using MSM. Researchers want to spread word.
AB  - While there is no shortage of substance abuse treatment programs, it's rare that
      such interventions focus on the particular problems involving methamphetamine
      abuse, a problem that new research indicates is linked to HIV transmission among
      men who have sex with men (MSM) across the country. However, researchers in Los
      Angeles have developed a program that targets the meth-abusing gay men
      specifically.

PMID- 12412568
TI  - Pharmacy project assists with meds adherence. Structured PharmD involvement
      crucial.
AB  - An adherence intervention created at the University of Buffalo provides
      individualized care that appears to be a better way to keep HIV-infected patients
      on track with their medication regimens.

PMID- 12412569
TI  - FDA notifications. FDA studies private sector patient information.

PMID- 12412570
TI  - FDA notifications. New treatment approved for chronic hepatitis B.

PMID- 12412571
TI  - [High frequency of precancerous lesions of gastric cancer associated with
      Helicobacter pylori and response to treatment, in Chiapas, Mexico].
AB  - Stomach cancer is the second cause of death in Mexico in patients with malignant
      tumors. This disease represents a public health problem. A strong association has
      been described between chronic infection with Helicobacter pylori and gastric
      cancer. This malignancy is preceded by a series of preneoplastic conditions,
      including chronic atrophic gastritis (CAG), intestinal metaplasia (IM), and
      dysplasia. The objective of this study was to establish the prevalence of
      preneoplastic conditions associated with infection of Helicobacter pylori in the
      state of Chiapas and its eradication with antibiotics. Persons infected with
      Helicobacter pylori and with CAG were identified by serology against CagA protein
      and serologic levels of gastrin. An endoscopy with biopsy was performed at the
      beginning of the study, and at 6 weeks and 1 year thereafter. A total of 281
      people were enrolled and randomly assigned to treatment or placebo group. CAG was
      found in 59%, IM in 51%, and dysplasia in 13%. In intent-to-treat and per
      protocol analysis, Helicobacter pylori was eliminated in 70 and 76%,
      respectively. These results indicate high frequency of preneoplastic conditions
      associated with Helicobacter pylori and an excellent eradication rate. They also
      offer a possible alternative for preventing gastric cancer.

PMID- 12412572
TI  - Vale, Professor Ettore Biocca.

PMID- 12412574
TI  - Retail health care: gaining advantage by dropping below the radar screen.
AB  - There are many examples throughout the country of providers that are getting into
      retail medicine themselves, and of companies that are helping providers do this.
      Carolinas Healthcare System, e-Cleveland Clinic and the aforementioned partners
      of Health Ventures are examples. Orlikoff believes that retail medicine is a key
      piece in building an infrastructure that is relevant to the future for healthcare
      providers, and as he often says, "The riches are in the niches." "It's an
      exciting time for providers," Firestone says, "but they've got to risk doing
      things very differently, driven by their patients, the consumer."

PMID- 12412573
TI  - Perineal pilonidal sinus. Case report.
AB  - Pilonidal sinus is a very common disease and its most frequent location is in the
      presacral area. Other locations are extremely rare. We describe the case of a 28
      year-old white man, a baker by profession, with a swelling around the right side
      of the anus, pain with burning, itching and seropurulent secretion which had been
      present for 7 months. A physical examination demonstrated the presence of
      multiple cutaneous fistulas. A fistulography and the endoscopy demonstrated the
      absence of fistulas-in-ano. Moreover, MRI confirmed the diagnosis of a perianal
      mass not communicating with the anal canal. Surgical exploration revealed the
      presence of hair and an excision of the mass with fistulas was performed. Healing
      was rapid and uncomplicated. Perineal pilonidal sinus with foreign body
      inflammatory reaction was the histological diagnosis.

PMID- 12412575
TI  - Intron factor VIII gene inversion in a population of Italian hemophilia A
      patients.

PMID- 12412576
TI  - Lack of p21(CIP1) DNA methylation in acute lymphocytic leukemia.

PMID- 12412577
TI  - Managing cutaneous reactions to imatinib therapy.

PMID- 12412578
TI  - Cytogenetic characterization reveals that the SAM-1 erythroid cell line is
      derived from K-562 cells.

PMID- 12412579
TI  - Adult acute myeloid leukemia cells do not express nonfunctional Ikaros isoforms.

PMID- 12412580
TI  - Position statement on the role of government in securing emergency medical care.

PMID- 12412581
TI  - T-20 being called "miraculous".

PMID- 12412582
TI  - Two drugs reduce transmission.

PMID- 12412583
TI  - Tipranavir reduces viral load.

PMID- 12412584
TI  - Vaccine study begins.

PMID- 12412585
TI  - Blacks bear brunt of epidemic.

PMID- 12412587
TI  - Hepatitis C does not increase AIDS.

PMID- 12412586
TI  - Better monitoring of liver enzymes needed.

PMID- 12412588
TI  - [The law of patent medicine and the separation of drug dispensaries from medical
      practice].
AB  - On March 30, 1914, the law of patent medicine was enacted in Japanese, though it
      took three years for this to be accomplished. One reason why it took such a long
      time for enactment is because the doctors and drugstore owners raised strong
      objections to the law. They feared that pharmacists might try to take over all
      rights to sell drugs. The pharmacists, however, believed this law to be very
      important, making it possible for them not only to expand the business rights and
      the establishment of their status, but also to hold exclusive rights to the sales
      of drugs. On the other hand, doctors were very cautious about this law. They
      considered it to be a preliminary stage toward the enactment of the separation of
      drug dispensing by the medical practice. On March 19, 1914, Dr. Miyake former
      dean of the School of Medicine, University of Tokyo, and a member of the House of
      Lords, delivered his opinion on the "needlessness of pharmacists" by quoting
      European cases in the House of Lords, to members of the Special Committee of the
      Drug Trade Bill. He stated that a separation of the dispensary from the medical
      practice was a turning point in the field of medicine that should be
      reconsidered, and he tried to suppress the pharmacists' movements to pursue this
      issue. Probably Dr. Miyake was afraid that someone might submit a bill calling
      for dispensary separation. The proceedings of the Imperial Diet revealed a close
      relation between the law and the separation of dispensaries.

PMID- 12412589
TI  - Staining from silver nitrate.

PMID- 12412590
TI  - Mercury amalgam-gold crown interaction.

PMID- 12412591
TI  - Paediatric dentistry.

PMID- 12412592
TI  - Proceedings of the HEALFO Conference: Food and Nutrition for Better Health. 13-15
      June 2001, Italy.

PMID- 12412594
TI  - Actions and Interactions at the Pituitary. Proceedings of a meeting.
      Christchurch, New Zealand, 24-25 August 2001.

PMID- 12412593
TI  - [Dispensing drugs without prescriptions and the separation of drug dispensaries
      from the medical practice].
AB  - Many cases of dispensing drugs without doctors' prescriptions were reported
      throughout Japan during 1914-16. Some cases were brought to the courts.
      Pharmacists had been selling prescription drugs to their customers without
      prescriptions. This dispensing act was admitted by the Ministry of Internal
      Affairs after 1913. However, doctors claimed that the act of dispensing drugs
      without a prescription infringed on Law No. 10, and the Japan Pharmacists
      Association hired a notable lawyer and fought a lawsuit against eight pharmacists
      who dispensed prescription drugs without prescription in Shiba Ward, in Tokyo.
      This case occurred because at that time no practice existed that allowed drugs to
      be dispensed separately from medical practice.

PMID- 12412595
TI  - Introduction: an international perspective on occupational health and hygiene.

PMID- 12412596
TI  - [A case of a mispreparation of medicine on Yokohama and the separation of drug
      dispensaries from the medical practice].
AB  - On June 10, 1921, a fatal drug administration case occurred in Yokohama. A
      nontitled dispenser of drugs with little knowledge about drugs working in a
      hospital dispensary gave a patient a capsule of strychnine nitrate instead of one
      containing strychnine hydrochloride. This patient died 20 minutes later. A
      pharmacist revealed the case to the public. Pharmacists insisted that this
      unfortunate event occurred because of a current hospital system handling both
      medicine and drug dispensation. Therefore they argued that the responsibilities
      of doctors and of drug dispensaries must immediately be separated out of respect
      for the lives of patients. Pharmacists publicized the importance of separating
      drug dispensaries from the medical practice through newspapers, magazines, and
      public lectures. We are quite doubtful about this appeal to the public being
      effective. We question how many people could understand what the pharmacists were
      saying under such the era when people were not much educated. It became a great
      fear to doctors that pharmacists appealed the necessity of the separation of drug
      dispensaries from medical practice directly to the public.

PMID- 12412597
TI  - [The 50th Imperial Diet and the separation of drug dispensaries from the medical
      practice].
AB  - At the session of the 50th Imperial Diet held on January 22, 1925, the Government
      submitted two drafts for a law governing pharmacists and one governing drug
      products. These drafts were very important for pharmacists because both the laws
      governing pharmacists and drug products could stipulate not only the
      qualifications and activities of pharmacists, but also their roles in the
      society. However, doctors were afraid of giving such power to pharmacists and
      feared that these laws might lead to a practical separation of drug dispensaries
      from the medical practice. Then objected that the Law of Drugs No. 10, which gave
      pharmacists the right to dispense drugs without a doctor's prescription, would
      infringe on the domain of doctor activities. Legislator also doctors strongly
      disagreed with both drafts presented to the Imperial Diet. Speculation was that
      neither draft would pass. As a result, the Law of Pharmacists, which was less
      damaging to the rights of doctors than the other law, was approved and ultimately
      became law. The Law of Drug Products was suspended.

PMID- 12412598
TI  - [Doctors and jurists who objected to the separation of drug dispensaries from the
      medical practice in the Taisho Era].
AB  - Doctors were very nervous about the movements of pharmacists toward achievement
      of the separation of drug dispensaries in the medical practices and drug
      dispensation in 1914 and 1915. They specifically blamed one person, Professor
      Tokichiro Niwa of Tokyo Imperial University who strongly advocated the separation
      of dispensaries in the medical practices. Furthermore, they were also very
      anxious that the Japan Pharmacists Association had supported legislators who had
      stood by the separation of dispensaries from medical practice at the twelfth
      general election held on March 25, 1915. They were concerned that the domain of
      doctors' activities would be narrowed by such a separation. Professor Kunika
      Katayama of the Tokyo Imperial University School of Medicine published a thesis
      at his own cost advocating a modification of the doctor's law to prohibit the
      separation of dispensaries be legislation and insisting that the right prescribe
      a drug to a patient must remain with the doctor. Moreover, Professor Mitsue
      Ichimura of Kyoto Imperial University also insisted that a doctor has the right
      to give drugs to patients, and that as a jurist he disagreed with the separation
      of dispensaries from medical practice.

PMID- 12412599
TI  - [A historical study of coffee in Japanese and Asian countries: focusing the
      medicinal uses in Asian traditional medicines].
AB  - The medicinal properties of coffee, making it a diuretic and stimulant, because
      of the effects of caffeine, have been known since ancient times, and coffee is
      today a popular beverage worldwide. In Japan it was introduced at the end of the
      eighteenth century through overseas trading with the Netherlands. During this
      period, various Western cultures flowed into Japan, and coffee was one of the
      subjects introduced through the translations of Dutch medical books. The
      pharmacological effects of coffee have been presented by Yamamoto in "Komo
      Honzou, (--, 1783)"; by K. Takahashi, G. Ohtsuki, and Y. Udagawa et al. in "Kosei
      Shimpen (--, 1811)"; and by Kai Hirokawa in "Nagasaki Bunkenroku (--, 1795)." In
      the Chinese and Arabic traditional systems of medicine, the uses of coffee were
      based on its diuretic and central nervous system stimulant properties, attributed
      in general to caffeine. This study dealt with the uses of coffee in the
      traditional medicines of Asian countries and with some biological activities
      related to aging, infectious diseases, and cardioprotective effects. In various
      biological tests, the water extract of coffee showed no notable effect on
      myocardial cell beating; however, it did show superoxide anion-scavenging
      effects, inhibitory activity of lipid peroxidation, and suppression of hepatitis
      B virus surface antigen. These biological activities are closely related to the
      presence of caffeic acid derivatives, especially chlorogenic acid. The findings
      suggest that besides its stimulant effect, coffee has properties to prevent the
      deleterious actions of free radicals and viral infections.

PMID- 12412600
TI  - [A 50-year history of new drugs in Japan: the developments of antileprosy drugs
      and their epidemiological aspects].
AB  - The developments of antileprosy drugs and their influences on the epidemiological
      aspects of Hansen's disease (leprosy) in Japan are investigated. 1. Hydnocarpus
      oil (Daifushi-Yu) products were the only useful drugs for the treatment of
      Hansen's disease (leprosy) in Japan from the early 1900's to just after the World
      War II. In those days leprosy was considered to be incurable malady. 2. The
      chemotherapy of leprosy, progressing from 1943 in the United States, was
      introduced to Japan in 1948. Promin(R) (sulfoxone sodium) for injection in 1948
      and Diasone(R), and Promizole(R) for oral use in 1949 were available for the
      treatment of leprosy patients in the National Hansen's Disease Sanatorium in
      Japan. Because DDS (dapsone, diaphenylsulfone) was proved to be the main
      ingredient of sulfone drugs, since 1958 it has been the drug of choice for all
      forms of leprosy. Monotherapy with DDS has continued for more than 30 years, and
      sulfone-resistant bacillus has appeared occasionally. 3. Clofazimine (a new type
      of chemotherapeutic drug) and rifampicin (an antibiotic for tuberculosis) was
      added to therapy treatment for leprosy in 1996. In 1983, WHO recommended
      multidrug therapy (MDT) to prevent resistance to sulfones. The Japanese Leprosy
      Association published "Guidlines" for the Treatment of Hansen's Disease in Japan"
      in 2000, which proposes a multidrug therapy with rifampicin, DDS, and clofazimine
      for a 6-month or 2-year treatment. 4. The number of leprosy patients has slowly
      decreased since the application of chemotherapy with sulfone drugs, and newly
      infected patients in Japan have decreased to less than 10 per million persons
      (Figs. 1 & 2). Therefore the "Leprosy Prevention Law" (1953), which compels the
      controlled isolation of patients, was abolished in 1996. Effective chemotherapy
      with sulfone and other drugs has changed incurable leprosy to a curable infective
      disease.

PMID- 12412601
TI  - [A 50-year year history of new drugs in Japan: the developments of
      antituberculosis drugs and their influences on the epidemiological aspects].
AB  - Drugs used in the treatment of tuberculosis (Tb) in Japan are investigated.
      Especially the chemotherapy for Tb and its influences on epidemiological aspects
      are discussed. 1. Various drugs were used for Tb patients before the World War
      II, but none was effective in curing this infectious disease. Creosote and
      guajacol groups were used frequently to relieve symptoms of pulmonary
      tuberculosis, but the disease could not cure itself. Because of the sacrifice of
      young patients, the mortality rate of Tb from 1935 to 1950 was ranked as the
      worst in Japan. So until the advent of chemotherapeutic drugs, Tb was known as
      the most formidable fatal plague. 2. Streptomycin (SM), the first effective
      chemotherapeutic drug, was imported into Japan and widely used from 1947. PAS in
      1950 and isoniazid (INH) in 1952 were introduced to Tb therapy. The triple
      combination therapy of these drugs was considered the most favorable regimen for
      Tb from the 1950s to the early 1970s. Excellent results were obtained in this
      period. The mortality rate of Tb had dropped rapidly from its peak to half in
      1952 and to a fourth in 1956 (Figs. 2, 3). 3. Several anti-Tb drugs, such as
      pyrazinamide ethionacide, ethambutol, and some antibiotics (kanamycin,
      cyloserine, and capreomycin) had been discovered and used in practice. These were
      not used singly, because of their weak clinical efficacies and severe side
      effects. They were mostly used to prevent the development of bacillus resistance
      to SM or INH. In the guidelines of the Japanese Society for Tuberculosis, in
      1974. drugs used for Tb could be divided into two major categories: first-line
      and second-line groups. The second-line drugs included those that prevent a high
      resistance to the main (first-line) drugs. 4. Rifampicin (RFP), the most valuable
      drug for Tb, was introduced in therapy in Japan in 1971. RFP has a low incidence
      of severe side-effects, but because of the rapidity with which resistance may
      develop, it cannot be used alone. RFP in combination with INH is the most
      effective therapy for all forms of the disease. The guidelines, newly proposed in
      1986 by the Japanese Society for Tuberculosis recommended the short 6-month
      course of treatment that used combination of RFP and INH. The advent of RFP had
      contributed to the cure of the individual patient, but it did not effect the
      mortality or the morbidity rate of Tb. Chemotherapy is the most effective means
      of suppressing tuberculosis, which was formerly nearly always fatal, but it could
      not completely eradicate the disease. Preventing the development of resistance to
      chemotherapeutic drugs might be a special problem.

PMID- 12412602
TI  - Insulin-like growth factors decrease catecholamine content in PC12 rat
      pheochromocytoma cells.
AB  - Insulin-like growth factors (IGFs) stimulate proliferation and differentiation of
      PC12 rat pheochromocytoma cells and modulate catecholamine release in bovine
      adrenal medullary cells. Dexamethasone increases catecholamine synthesis in PC12
      cells. We therefore studied the effects of IGFs and dexamethasone on
      catecholamine content in PC12 cells. Dopamine (DA) and norepinephrine (NE)
      content of PC12 cells were measured after incubation for 72 h with IGFs (100
      ng/ml) and/or dexamethasone (500 nM). IGF-I (100 ng/ml) and IGF-II (100 ng/ml)
      decreased DA and NE content to approximately 35% and approximately 25% of
      control, respectively. [Leu27]IGF-II, which binds to the IGF-I receptor with
      markedly decreased affinity, did not reduce catecholamine levels, indicating that
      the effect is likely to be mediated by the IGF-I receptor. Dexamethasone (500 nM)
      increased levels of DA and NE to 173 +/- 20% and 331 +/- 48% of controls,
      respectively. Coincubation with IGFs did not significantly affect the stimulation
      of DA by dexamethasone, but abolished the rise in NE. Levels of tyrosine
      hydroxylase mRNA, protein and activity were increased following incubation with
      dexamethasone, but were unchanged by IGFs. These results indicate that IGFs
      decrease catecholamine content in PC12 cells via the IGF-I receptor. Complex
      regulation involving multiple synthetic and/or degradative steps is implicated in
      this process.

PMID- 12412603
TI  - Fraud is a serious offence in nursing.

PMID- 12412604
TI  - Nursing must become more assertive.

PMID- 12412605
TI  - [Transition of Japanese societies related to clinical chemistry in the mid-Showa
      period (1955-1980) (part 3) - related to the medical field].
AB  - Remarkable progress in the Japanese clinical chemical field was observed in the
      mid-Showa period (1955-1980). Many biochemists, pharmacists, medical doctors, and
      medical technologists started their studies and reported their accomplishments in
      the clinical chemical societies during this period. I recently reported on the
      transition of pharmaceutical science societies in the clinical chemical field in
      JJHP, Vol. 35, No. 2, in 2000, and Vol. 36, No. 1, in 2001. In these reports, the
      transition of medical societies in the clinical chemical field and social
      insurance medical fee payments were discussed. The Japan Society of Clinical
      Pathology (JCCP) was started in 1951 and the Japanese Association of Medical
      Technologists (JAMT) in 1952. The former mainly consists of biochemists and
      medical doctors and the latter of medical technologists in Japanese hospitals.
      Because many clinical examinations in hospitals were undertaken with the support
      of instruments (for example, the Auto Analyzer AA-1), the Japan Society for
      Clinical Laboratory Automation (JSCLA) started in 1969. The Japan Committee for
      Clinical Laboratory Standards started in 1984. The Japan Medical Association
      helped to promote clinical chemical examinations in the medical field, especially
      since 1957, by increasing the social insurance medical fee payment.

PMID- 12412606
TI  - A nurse with a mission.

PMID- 12412607
TI  - [Gambir revisted].
AB  - Preparations made from Uncaria gambir or Acacia catechu are called hai-er-cha,
      bai-yao-jian, or a-sen-yaku. Their identification and relation to one another are
      discussed historically and etymologically. Hai-er must have been derived from
      khadira (Sanskrit), khayer (Bengalese), or khair (Hindi). A-sen is supposed to be
      formed by the combination of er and sen; the latter may be a euphonic
      transformation from sen, to (--, to decoct).

PMID- 12412608
TI  - Data trends. Profits are up for most U.S. hospitals, but outlook remains dismal
      for some.

PMID- 12412609
TI  - [Eaglewood and eagle].
AB  - The etymology of eaglewood (chen xiang, --) and its related terms with particular
      reference to its relation to eagle (aquilaria) is discussed. It is pointed out
      that this fragrant wood has nothing to do with eagle. A Portuguese aguila
      transcribed from akil (Malay, the name of wood), perhaps underwent phonetic
      traction to aguia (Portuguese, eagle) in the process of being translated into
      French. Thus pau d'aguila (Portuguese) was transformed to bois d'aigle (French,
      aigle=eagle), which led to eagle-wood (English) and Adlerholz (German).

PMID- 12412610
TI  - Motion--Laparoscopic Nissen fundoplication is more cost effective than oral PPI
      administration: arguments for the motion.
AB  - Gastroesophageal reflux disease is a mechanical disorder of the foregut. While
      medications can only provide symptom relief, surgery can correct the
      pathophysiological abnormality of the lower esophageal sphincter. The costs of
      medical and surgical therapy are much greater than the costs of medication or
      hospitalization alone. In the case of medical therapy, one must consider the
      costs of serial monitoring and of failed treatment. The effectiveness of
      treatment also depends on patient-related factors, including weight,
      socioeconomic factors, smoking, alcohol use, dietary habits and the use of
      nonsteroidal anti-inflammatory drugs. Surgical results depend on the experience
      and skill of the surgeon, as well as the attributes of the institution in which
      the procedure is undertaken. Therefore, studies that come from specialized
      centres may not be applicable to the community. Data from the author's facility
      indicate that laparoscopic Nissen fundoplication is the most cost effective
      option when it is undertaken by experienced surgeons on otherwise healthy
      patients who have documented gastroesophageal reflux disease.

PMID- 12412611
TI  - Toledo offers plan to help uninsured.

PMID- 12412612
TI  - Re: Recommendations for the appropriate use of anti-inflammatory drugs in the era
      of the coxibs: defining the role of the gastroprotective agents.

PMID- 12412613
TI  - Surveillance for AIDS-defining opportunistic illnesses, 1992-1997.
AB  - PROBLEM/CONDITION: Acquired immunodeficiency syndrome (AIDS)-defining
      opportunistic illnesses (OIs) are the major cause of morbidity and mortality
      among persons infected with human immunodeficiency virus (HIV). As a result of
      new treatments that reduce mortality for persons with AIDS, the number of persons
      living with AIDS is increasing, and the incidence of AIDS is decreasing. In 1997,
      an estimated 271,245 persons were living with AIDS in the United States and thus
      were at high risk for OIs. In 1997, an estimated 21,909 HIV-infected persons died
      with AIDS, nearly all as a result of OIs. REPORTING PERIOD COVERED: Aggregate
      data and trends for 1992-1997 were examined to determine a) the frequencies at
      which OIs occurred first; b) the incidence of OIs; c) the percentage of persons
      among those who have died who had had a given OI during their course of AIDS, and
      d) the frequency of prescriptions for antiretroviral therapy and prophylaxis for
      Pneumocystis carinii pneumonia (PCP) and for Mycobacterium avium complex disease
      (MAC). DESCRIPTION OF SYSTEM: Data were analyzed from the Adult/Adolescent
      Spectrum of HIV Disease (ASD) sentinel surveillance project, a prospective
      medical record review of HIV-infected persons aged > or = 13 years conducted in
      11 U.S. cities. ASD data were standardized to national AIDS surveillance data for
      1992-1997 by age; race; sex; country of birth; year of AIDS diagnosis; HIV
      exposure mode; and for incidence calculations, by CD4+ T-lymphocyte distribution.
      RESULTS: The incidence declined significantly for each of 15 of the 26 specific
      AIDS-defining OIs (p<0.05). PCP was the most common AIDS-defining OI to occur
      first (PCP was the first OI to occur for 36% of HIV-infected persons), the most
      common incident AIDS-defining OI (274 cases per 1000 person-years), and the most
      common AIDS-defining OI to have occurred during the course of AIDS (53% of
      persons who died with AIDS had PCP diagnosed at some time during their course of
      AIDS). Of persons with CD4+ T-lymphocyte counts <500 cells/microL, the number
      with prescriptions for triple combination therapy increased from zero in 1992 to
      40% in 1997, and 80% of persons had a prescription for any antiretroviral therapy
      in 1997. Of persons with CD4+ T-lymphocyte counts <200 cells/microL, the
      percentage with prescriptions for PCP prophylaxis remained stable from 1992
      through 1997 (range: 75% to 80%). Of persons with CD4+ T-lymphocyte counts <50
      cells/microL, the percentage with prescriptions for MAC prophylaxis increased
      from 9% in 1992 to 44% in 1997. INTERPRETATIONS: The incidences of many OIs are
      decreasing primarily because of advances in HIV-related therapy. However, OIs are
      still occurring, especially when patients access care late during the course of
      disease. Even after accessing care, persons may develop OIs because of lack of
      prescription for prophylaxis, antiretroviral drug resistance, or poor adherence
      to therapy. During 1992-1997, most patients in need of PCP prophylaxis received a
      prescription for it; however, even in 1997, most patients in need of MAC
      prophylaxis did not receive a prescription for it. ACTIONS TAKEN: These
      surveillance data are used by persons involved with developing guidelines for
      preventing OIs to determine the importance of and trends in OIs and preventive
      therapy. CDC is developing population-based approaches for surveillance of HIV
      disease progression, OIs, and therapies with the goal of making these data
      available in more geographic areas to help assess public health and health-care
      programs.

PMID- 12412614
TI  - Youth risk behavior surveillance--United States, 1999.
AB  - PROBLEM/CONDITION: Priority health-risk behaviors, which contribute to the
      leading causes of mortality and morbidity among youth and adults, often are
      established during youth, extend into adulthood, are interrelated, and are
      preventable. REPORTING PERIOD: February-May 1999. DESCRIPTION OF THE SYSTEM: The
      Youth Risk Behavior Surveillance System (YRBSS) monitors six categories of
      priority health-risk behaviors among youth and young adults --behaviors that
      contribute to unintentional and intentional injuries; tobacco use; alcohol and
      other drug use; sexual behaviors that contribute to unintended pregnancy and
      sexually transmitted diseases (STDs) (including human immunodeficiency virus
      [HIV] infection); unhealthy dietary behaviors; and physical inactivity. The YRBSS
      includes a national school-based survey conducted by CDC as well as state,
      territorial, and local school-based surveys conducted by education and health
      agencies. This report summarizes results from the national survey, 33 state
      surveys, and 16 local surveys conducted among high school students during
      February-May 1999. RESULTS AND INTERPRETATION: In the United States,
      approximately three fourths of all deaths among persons aged 10-24 years result
      from only four causes: motor-vehicle crashes, other unintentional injuries,
      homicide, and suicide. Results from the 1999 national Youth Risk Behavior Survey
      demonstrate that numerous high school students engage in behaviors that increase
      their likelihood of death from these four causes--16.4% had rarely or never worn
      a seat belt; during the 30 days preceding the survey, 33.1% had ridden with a
      driver who had been drinking alcohol; 17.3% had carried a weapon during the 30
      days preceding the survey; 50.0% had drunk alcohol during the 30 days preceding
      the survey; 26.7% had used marijuana during the 30 days preceding the survey; and
      7.8% had attempted suicide during the 12 months preceding the survey. Substantial
      morbidity and social problems among young persons also result from unintended
      pregnancies and STDs, including HIV infection. In 1999, nationwide, 49.9% of high
      school students had ever had sexual intercourse; 42.0% of sexually active
      students had not used a condom at last sexual intercourse; and 1.8% had ever
      injected an illegal drug. Two thirds of all deaths among persons aged > or = 25
      years result from only two causes--cardiovascular disease and cancer. The
      majority of risk behaviors associated with these two causes of death are
      initiated during adolescence. In 1999, 34.8% of high school students had smoked
      cigarettes during the 30 days preceding the survey; 76.1% had not eaten > or = 5
      servings/day of fruits and vegetables during the 7 days preceding the survey;
      16.0% were at risk for becoming overweight; and 70.9% did not attend physical
      education class daily. ACTIONS TAKEN: These YRBSS data are already being used by
      health and education officials at national, state, and local levelsto analyze and
      improve policies and programs to reduce priority health-risk behaviors among
      youth. The YRBSS data also are being used to measure progress toward achieving 16
      national health objectives for 2010 and 3 of the 10 leading health indicators.

PMID- 12412615
TI  - High-dose antithrombin therapy for sepsis: mechanisms of action.

PMID- 12412616
TI  - Immediate S-100B and neuron-specific enolase plasma measurements for rapid
      evaluation of primary brain damage in alcohol-intoxicated, minor head-injured
      patients.
AB  - The neuroproteins S-100B and neuron-specific enolase (NSE) released into the
      circulation are suggested to be reliable markers for primary brain damage.
      However, safe identification of relevant post-traumatic complications after minor
      head injury (MHI) is often hampered by acute intoxication of the patients. The
      objective of this study was to determine the diagnostic validity of immediate
      plasma measurements of S-100B and NSE in comparison with neurological
      examinations and cerebral computed tomography (CCT) findings in alcohol
      intoxicated MHI patients. One hundered thrity-nine MHI individuals were enrolled
      in this prospective study during Munich's Oktoberfest 2000. Plasma levels of S
      100B and NSE as well as serum alcohol and glucose values were determined by fully
      automated assays immediately after admission. The results were compared with
      Glasgow Coma Scale score, a brief neurological examination, and the CCT findings.
      Without being influenced by alcohol, median S-100B levels of the CCT+ group were
      significantly increased compared with those of the CCT- group (P < 0.001). NSE,
      alcohol, and glucose levels showed no significant group differences. As
      calculated by the ROC analysis, a cutoff value of 0.21 ng/mL with an area under
      the curve of 0.864 clearly differentiates between CCT+ and CCT- patients at a
      sensitivity of 100%, a specificity of 50.0%, and a positive likelihood ratio of
      2.0. Although acute alcohol intoxication did not confound plasma measurements of
      S-100B and NSE, only S-100B levels below the cutoff level of 0.21 ng/mL seem to
      indicate absence of primary brain damage. Thus, in addition to routine
      neurological examinations, S-100B measurements immediately after admission might
      help to reduce CCT scans in alcohol-intoxicated patients early after MHI.

PMID- 12412617
TI  - Activation of mitogen-activated protein kinases during granulocyte apoptosis in
      patients with severe sepsis.
AB  - Reduction of neutrophil apoptosis represents a major cause for granulocytosis and
      increases the destructive potential of theses cells during systemic inflammatory
      response syndrome (SIRS) and sepsis. In this light, the role of protein kinases
      for the regulation of altered neutrophil apoptosis under infectious conditions
      was investigated. Neutrophils, obtained from patients with severe sepsis (n =
      18), were incubated ex vivowith either LPS (1 microg/mL) or interferon-gamma (IFN
      gamma; 10 ng/mL) for 16 h. Apoptosis was determined by propidium iodine (PI)
      staining of DNA fragments and was compared with the rate of spontaneous
      apoptosis. Tyrosine kinases were inhibited by herbimycin (1 microM), the mitogen
      activated protein (MAP) kinase ERK was inhibited with PD98059 (50 microM), and
      p38 MAP kinase was inhibited with SB203580 (5 microM). Herbimycin reconstituted
      LPS-reduced apoptosis in neutrophils from controls (39.9 +/- 3.8%) and patients
      (20.8 +/- 2.8%) to levels seen in spontaneous apoptosis (70.9 +/- 2.8% and 40.7
      +/- 3.7%, respectively). Inhibition of the ERK kinase yielded similar results,
      whereas SB203580 had no effect on LPS-reduced apoptosis. However, inhibition of
      p38 partially reconstituted IFN-gamma-reduced apoptosis (51.3 +/- 7.7% and 25.6
      +/- 5.8%) and increased spontaneous apoptosis (82.4 +/- 3.3% and 42.0 +/- 5.8%)
      in controls and patients, respectively. Western blot analysis revealed
      phosphorylation of both MAP kinases by LPS, but not by IFN-gamma. Inhibition of
      MAP kinases did not augment neutrophil apoptosis in patients to the level seen in
      controls, indicating that other mechanisms must be involved in the regulation of
      neutrophil apoptosis. Although the ERK kinase regulates LPS-induced reduction of
      apoptosis, the p38 MAP kinase might be involved in IFN-gamma signaling and the
      feedback regulation of neutrophil apoptosis.

PMID- 12412618
TI  - Cardiovascular and respiratory interactions of hyperosmolar saline, scorpion
      toxin, and veratridine in rats.
AB  - This study evaluates the cardiovascular and respiratory effects evoked by
      hypertonic sodium chloride solution (HSS) and the possible interactions of these
      effects with scorpion toxin (TX) or veratridine (V). Groups 1 (1 mL/kg, rapid), 2
      (4 mL/kg, rapid), and 3 (4 mL/kg, slow) were used for comparison of HSS
      administered by rapid or slow injection. HSS (4 mL/kg) was injected after
      bilateral vagotomy (group 4) or administration of atropine (group 5). In groups 6
      (1 mL/kg in bolus), 7 (4 mL/kg in bolus), and 8 (4 mL/kg/60 s), HSS was injected
      20 min after the administration of TX (250 microg/kg). In group 9, two doses of V
      (25 microg/kg, i.v.) were injected 10 min apart. Concomitantly with the second
      dose of V, HSS (4 mL/kg) was injected into the jugular vein. HSS administered by
      rapid injection (1 mL/kg) resulted in hypotension, hyperventilation, and a slight
      decrease in heart rate. However, when HSS was administered after TX, only
      bradypnea was observed. HSS (4 mL/kg, rapid) induced a rapid and marked fall in
      blood pressure, bradycardia, and apnea. However, when HSS was administered after
      TX, a more pronounced bradycardia and a smaller reduction in mean arterial
      pressure were observed. Slow injection of HSS (60 s) evoked hypotension,
      hyperventilation, and bradycardia. The same dose injected after TX resulted in
      bradypnea and a smaller reduction in blood pressure. The HSS-induced hypotension
      was attenuated by previous administration of atropine or by vagotomy, whereas
      bradycardia was prevented by previous injection of atropine, but not by bilateral
      vagotomy. Like vagotomy, atropinization prevented the apnea and bradypnea
      produced by HSS (4 mL/kg in bolus). V evoked a slight bradycardia, hypotension,
      and apnea. These effects were potentiated when V was injected concomitantly with
      HSS. The effects of HSS are dependent on both volume and speed of injection, and
      are affected by previous injection of TX or concomitant injection of V.

PMID- 12412619
TI  - Potentiated hepatic microcirculatory response to endothelin-1 during
      polymicrobial sepsis.
AB  - We conducted this study to elucidate the role of endothelins (ET-1) in mediating
      the hepatic microcirculatory dysfunction observed in response to sepsis.
      Following 24 h of cecal ligation and puncture (CLP), we performed intravital
      microscopy both in vivo and on isolated perfused livers. Portal resistance
      increased in response to ET-1 in both sham and septic rats, with no significant
      difference between the two in either in vivo or in isolated livers. Sinusoidal
      volumetric flow (Qs) was evaluated using red blood cell velocity (V(RBC)) and
      sinusoidal diameter (Ds) to determine microvascular hemodynamic integrity. Qs
      decreased in response to ET-1 in livers from CLP rats compared with sham (P <
      0.05, CLP vs. sham) in both in vivo and isolated livers. In vivo infusion of ET-1
      resulted in greater constriction of sinusoids in the CLP group compared with sham
      (P < 0.05), resulting in higher sinusoidal resistance. Microvascular hyper
      responsiveness was accompanied by hepatocellular injury in CLP rats, but not in
      sham rats. RT-PCR was performed to measure mRNA levels of ET-1, its receptors
      ET(A) and ET(B), inducible and constitutive nitric oxide (NO) synthase (iNOS and
      eNOS, respectively), and heme oxygenase 1 (HO-1). After CLP, both ET-1 and ET(B)
      mRNA increased, whereas ET(A) mRNA tended to decrease, although the change was
      not statistically significant. Livers from CLP rats showed no significant change
      in levels of eNOS mRNA, but showed a significant increase in iNOS expression
      (13.5-fold over sham). There was no change in the level of HO-1 mRNA between sham
      and CLP groups. Taken together, these results suggest that sepsis sensitizes the
      hepatic microcirculation to ET-1. More importantly, an impaired microcirculatory
      flow due to ET-1 in sepsis contributes to hepatic injury. Further, localized
      imbalances between endothelins and NO may mediate the altered microvascular
      response during sepsis.

PMID- 12412620
TI  - In vivo visualization of reactive oxidants and leukocyte-endothelial adherence
      following hemorrhagic shock.
AB  - The generation of oxygen radicals during leukocyte-endothelial cell interaction
      is considered to represent one of the fundamental steps of microvascular injury
      following ischemia and reperfusion. Indirect evidence also suggests that this
      relationship may be important following hemorrhagic shock. The purpose of this
      study was to characterize the temporal changes of reactive oxygen species (ROS)
      in the mesenteric microvascular endothelium, in vivo, as a consequence of
      hemorrhagic shock and reperfusion, and to correlate this ROS production to
      leukocyte adherence. Following a control period, blood was withdrawn to reduce
      the mean arterial pressure to 40 mmHg for 1 h in urethane-anesthetized rats.
      Mesenteric venules in a transilluminated segment of small intestine were examined
      to quantitate changes in ROS generation and leukocyte adherence. Sprague-Dawley
      rats were injected with dihydrorhodamine 123, a hydroperoxide-sensitive
      fluorescent probe that is trapped within viable cells as a nonfluorescent form
      and then converted to the mitochondrion-selective form rhodamine 123 by
      hydroperoxides. The fluorescent light emission from rhodamine 123 was recorded
      with digital microscopy and downloaded to a computerized image analysis program.
      Our results demonstrated an 80% increase in ROS generation beginning within 5 min
      into resuscitation and a 10-fold increase in leukocyte adherence that occurred at
      10 min after resuscitation. Both ROS generation and leukocyte adherence were
      attenuated with pre-shock administration of platelet activating factor (PAF)
      antagonist, WEB 2086, and the CD11/CD18a antibody, anti-LFA-1beta. Our findings
      suggest that ROS production in endothelial cells is increased during reperfusion
      following hemorrhagic shock and that the mechanism of expression is mediated in
      part by both PAF expression and subsequent leukocyte adherence.

PMID- 12412621
TI  - Acute lung injury in experimental pancreatitis in rats: pulmonary protective
      effects of crotapotin and N-acetylcysteine.
AB  - Respiratory complications are major factors contributing to death in acute
      pancreatitis. However, the mechanisms of these pulmonary complications are not
      completely elucidated. We studied the effects of pretreatment with purified
      crotapotin (a phospholipase A2 inhibitor), N-acetylcysteine (a reactive oxygen
      species inhibitor), and a combination of both on the pulmonary mechanical and
      morphometric changes secondary to severe acute necrohemorrhagic pancreatitis in
      Wistar rats. A total of 69 male Wistar rats were studied. Pancreatitis was
      induced by infusion of 0.5 mL of a 4% solution of sodium taurocholate into the
      biliopancreatic duct. Crotapotin, N-acetylcysteine, or a combination of both was
      given intraperitoneally 30 min before inducing pancreatitis. Data were compared
      with data from sham-operated animals with or without those pretreatments. The
      severity of pancreatic and pulmonary injuries was evaluated 4 h after inducing
      pancreatitis by morphometric and pulmonary mechanical studies. N-acetylcysteine
      prevented the development of alveolar edema, alveolar distention, and collapse.
      Crotapotin prevented alveolar distention and collapse, and pulmonary dynamic
      elastance increase. When used in combination, crotapotin and N-acetylcysteine
      prevented both pulmonary morphological and mechanical changes induced by acute
      pancreatitis, suggesting an increase in protective effect when these drugs are
      used together compared with individual effects. However, the severity of
      pancreatic necrosis and the increase in polymorphonuclear cells in alveolar septa
      induced by pancreatitis were not reduced by previous administration of
      crotapotin, N-acetylcysteine, or both. These results suggest that the protective
      effects of these drugs are probably due to an extra-pancreatic action in the
      circulation, or even directly in the lung.

PMID- 12412622
TI  - Role of tight junction derangement in the endothelial dysfunction elicited by
      exogenous and endogenous peroxynitrite and poly(ADP-ribose) synthetase.
AB  - DNA single-strand breakage and activation of the nuclear enzyme poly(ADP-ribose)
      synthetase (PARS) triggers an energy consuming, inefficient repair cycle, which
      contributes to peroxynitrite-induced cellular injury. Here, we investigated
      whether peroxynitrite and PARS activation are involved in tight junctions (tight
      junction) derangement in the endothelial dysfunction in cells exposed to
      peroxynitrite and in vascular rings of animals subjected to zymosan non-septic
      shock. In human umbilical vein endothelial cells (HUVEC) in vitro, peroxynitrite
      caused a dose-dependent suppression of mitochondrial respiration, as measured by
      the mitochondrial-dependent conversion of the dye 3-(4,5-dimethylthiazol-2-yl)
      2,5-diphenyltetrazolium bromide to formazan. Moreover, peroxynitrite caused
      activation of PARS. Inhibition of PARS by 3-aminobenzamide (3-AB; 1 mM) reduced
      the peroxynitrite-induced suppression of mitochondrial respiration in HUVECs.
      Vascular rings exposed to peroxynitrite exhibited reduced endothelium-dependent
      relaxant responses in response to acetylcholine. Peroxynitrite incubation also
      caused a significant derangement of zonula occludens (ZO)-1, which was
      significantly affected by pharmacological inhibition of PARS. 3-AB ameliorated
      the development of this peroxynitrite-induced endothelial dysfunction. In
      vascular rings obtained from the zymosan-treated rats, there was a marked
      suppression of the endothelium-dependent relaxation ex vivo, which was reduced by
      in vivo 3-AB treatment. A significant derangement of ZO-1 was observed in
      vascular rings from zymosan-treated rats. Tight junction alteration was
      significantly reduced by in vivo 3-AB treatment. Thus, activation of PARS by
      exogenous and endogenous peroxynitrite may be involved in the tight junction
      derangement associated with endothelial dysfunction. Inhibition of PARS may be a
      novel pharmacological approach to preserve endothelial tight junction function in
      shock and inflammation.

PMID- 12412623
TI  - Regional tissue oxygenation during hemorrhage: can near infrared spectroscopy be
      used to monitor blood loss?
AB  - We investigated whether near infrared spectroscopy could be used to monitor
      regional tissue oxygenation during uncompensated hemorrhage in man. A Somanetics
      INVOS 4100 oximeter was used to measure regional hemoglobin oxygen saturation in
      the cerebral cortex (CsO2, left frontal area) and from the left calf muscle
      (PsO2) in 40 volunteers donating 470 mL of the whole blood. A Critikon 2001
      Cerebral Redox Instrument was used to monitor total (tHb), oxygenated (O2Hb), and
      deoxygenated (HHb) hemoglobin in the right calf muscle. The oxygenation index,
      [HbD] = [O2Hb] - [HHb] was derived. CsO2 decreased by a mean (95% CI) of 2 (1
      3.3%) (P < 0.001), PsO2 decreased by a mean (95% CI) of 3.2 (1.7-4.6%) (P <
      0.001), and HbD decreased by a median (95% CI) of 6.4 (2.65-10.16) delta
      microM/cm (P < 0.001) during blood collection. There was an inverse correlation
      between blood loss and CsO2 (R = -0.59, P < 0.001), PsO2 (R = -0.61, P < 0.001),
      and HbD (R = -0.5, P < 0.001). Regional tissue oxygenation decreases in
      proportion to uncompensated blood loss. Near infrared spectroscopy may
      potentially be developed into a transfusion trigger.

PMID- 12412624
TI  - Dehydroepiandrosterone (DHEA) modulates the activity and the expression of
      lymphocyte subpopulations induced by cecal ligation and puncture.
AB  - Dehydroepiandrosterone (DHEA) exerts a variety of positive effects on the
      immunologic alterations after trauma and sepsis. We therefore measured the
      therapeutic efficacy of DHEA after cecal ligation and puncture (CLP) on the
      expression of lymphocyte subpopulations and on the delayed type hypersensitivity
      (DTH) reaction. Male NMRI-mice were randomly assigned to four different treatment
      groups. Treatment consisted of DHEA or saline (S) administration after CLP or
      laparotomy only. Flow cytometry was performed (CD4+, CD8+, and CD56 lymphocytes)
      after 96 hours. DTH-reaction, activity and mortality rate were documented. The
      CLP-induced reduction in activity and survival (mortality: 34/40) was
      significantly (p < 0.03) less sustained in CLP-DHEA (mortality: 22/40). The DTH
      ratio (before vs. after secondary challenge) was significantly lowered in CLP-S
      (1.01 +/- 0.15) compared to CLP-DHEA (1.35 +/- 0.1) after 48 hours (p < 0.01).
      CLP-DHEA (22.2 +/- 7.9%) was associated with a statistically significant less
      sustained increase of CD56+ cells (p < 0.01) compared with CLP-S (49.0 +/- 6.9%).
      DHEA-treatment after CLP was associated with less reduction in the CD8+ T
      lymphocyte subsets (p < 0.01 vs. all other groups). DHEA treatment after CLP was
      associated with fewer alterations in the changes of CD8+ and CD56, cells, and the
      DTH reaction compared with animals submitted to CLP without any treatment. This
      difference was associated with improved outcome (reactivity, mortality). These
      results suggest a modulation at specific immune reactions by DHEA treatment.

PMID- 12412625
TI  - The beneficial effects of protein tyrosine kinase inhibition on the circulatory
      failure induced by endotoxin in the rat.
AB  - Implication of enhanced activity of tyrosine kinases has been established in the
      pathophysiology of many diseases associated with local (e.g., atherosclerosis) or
      systemic (e.g., septic shock) inflammation. The main objective of this study was
      to elucidate whether tyrosine kinase and nitric oxide were involved in endotoxin
      induced impairment of vascular responses to sympathetic nerve stimulation (SNS)
      in rat isolated mesenteric bed. Therefore, the effects of genistein, an inhibitor
      of protein tyrosine kinase, and L-NAME (N-nitro-L-arginine methyl ester), an
      inhibitor of nitric oxide synthase, on endotoxin-induced shock were investigated
      in the thiopental-anesthetized rats. We also studied the effects of endotoxin on
      the vasoconstrictor responses to SNS in the rat isolated perfused mesenteric bed.
      Endotoxin injection (10 mg kg(-1), i.p.) produced a marked hypotension and a
      reduction of the pressor responses elicited by phenylephrine (0.1, 0.3, and 3
      microg kg(-1), i.v.). Pretreatment of the rats with either genistein (10 mg kg(
      1) i.p., 2 h before endotoxin injection), L-NAME (0.1 mg kg(-1), i.p., 30 min
      before endotoxin injection), or a combination of both attenuated the hypotension
      caused by endotoxin. SNS in the rat isolated perfused mesenteric bed caused a
      frequency-dependent vasoconstrictor response, which was abolished by tetrodotoxin
      (10(-7) M), prazoscin (10(-7) M), and guanethidine (10(-7)M). In mesenteric
      vascular beds removed from rats injected with endotoxin, the vasoconstrictor
      responses to SNS were markedly impaired. Although genistein and L-NAME
      pretreatment attenuated the vascular hyporeactivity to phenylephrine, they did
      not improve the impaired SNS response of the isolated vascular bed of endotoxin
      treated animals. These results indicate that genistein and L-NAME pretreatment
      prevent the hypotension and the delayed hyporeactivity to phenylephrine induced
      by endotoxin, but they failed to restore the vascular hyporeactivity to SNS.

PMID- 12412626
TI  - Intestinal nitric oxide in the normal and endotoxemic pig.
AB  - The gut is considered a central organ in the pathogenesis of sepsis and multiple
      organ failure, where several mediators, including endothelin (ET) and nitric
      oxide (NO), are involved. The aim of the current study was to characterize, by
      direct measurements, the intestinal NO production in the anesthetized pig during
      normal and endotoxemic conditions. In pigs subjected to endotoxin infusion, there
      was a progressive decrease in jejunal luminal NO levels, as well as portal venous
      blood flow and blood pressure. The ET- blocker 4-tert-butyl-N-[6-(2-hydroxy
      ethoxy)-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4-yl]-benzenesulfonamide
      (bosentan) completely reversed the reduction in portal venous blood flow without
      affecting intestinal NO levels. In control pigs, the NO synthase inhibitor
      N(omega)-nitro-L-arginine methyl ester dose-dependently decreased intestinal NO
      levels and mesenteric blood flow--effects that were reversed by L-arginine. We
      conclude that intestinal NO is a product of mucosal NO synthase activity, and is
      profoundly decreased during endotoxemia in the pig.

PMID- 12412627
TI  - Murine beta-defensin-3 is an inducible peptide with limited tissue expression and
      broad-spectrum antimicrobial activity.
AB  - Beta-defensins are cationic peptides produced by epithelial cells that have been
      proposed to be an important component of immune function at mucosal surfaces.
      Similarities between mammalian beta-defensins may permit the use of murine models
      to further define the role of these peptides in innate host defense. Murine beta
      defensin-3 (mBD-3) is a peptide that exhibits homology at the gene level to human
      beta-defensin-2 (hBD-2), one of four beta-defensins identified in man. The
      purpose of this study was to determine the antimicrobial activity of mBD-3, the
      tissue distribution of mBD-3 expression, and the effect of gram-negative
      bacterial infection on mBD-3 expression. Based on the sequence deduced from mBD-3
      cDNA, a 40-amino acid peptide was assembled using automated [n-(9
      fluorenyl)methoxycarbonyl] solid-phase synthesis. The antimicrobial activity of
      synthetic mBD-3 was evaluated in microdilution broth assays using bacterial and
      fungal organisms. mBD-3 mRNA expression was assayed by polymerase chain reaction
      (PCR) using cDNA derived from a panel of tissues. Expression of mBD-3 was also
      evaluated in tissues obtained from mice 24 h after intraperitoneal infection with
      Escherichia coli using reverse transcriptase (RT)-PCR. Synthetic mBD-3 inhibited
      the growth of E. coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Candida
      albicans at concentrations from 25 to 50 microg/mL. Constitutive expression of
      mBD-3 mRNA was not consistently found in any organ using RT-PCR. In an E. coli
      peritonitis model, expression of mBD-3 mRNA was upregulated only in the esophagus
      and tongue. We conclude that mBD-3 is an inducible peptide with limited tissue
      expression during E. coli peritonitis. Because it exhibits broad-spectrum
      antimicrobial activity, this peptide may serve as an innate defense against
      microbial invasion at specific mucosal surfaces in the mouse.

PMID- 12412629
TI  - Effect of linomide on gut immune cell distribution and on TNF-alpha in plasma and
      ascites: an experimental study in the septic rat.
AB  - A significant reduction of the pan T lymphocytes as well as CD4+ and CD8 subsets
      of cells in the gut mucosa of the septic rats has previously been demonstrated.
      In contrast, the populations of major histocompatibility complex (MHC) class II
      positive cells and macrophages increased. The aim of this study was to evaluate
      if the immunomodulator Linomide influenced the immune cell distribution in the
      small intestinal mucosa in sepsis and, furthermore, if these changes coincide
      with changes in the concentration of tumor necrosis factor-alpha (TNF-alpha) in
      plasma or ascites. Polymicrobial sepsis was induced in rats by cecal ligation and
      puncture (CLP). Three different experimental groups were used: CLP, Linomide p.o.
      + CLP, and Linomide i.p.+ CLP, with adequate controls. Specimens were taken from
      the small bowel for immunohistologic staining and grading of mucosal injury. The
      following monoclonal antibodies were used: W3/25, OX8, R73, OX6, and ED1. All
      slides were examined by one "blinded" examiner. Mucosal injury was graded from 0
      to 5. The immunostained tissues were also analyzed by an automatic color-based
      image system. All controls had a normal appearance of the mucosa (grade 0-1),
      whereas the septic animals had a median grade of III (II-IV) mucosal injury.
      Linomide i.p. + CLP decreased mucosal damage to median I (0-IV, P < 0.05).
      Linomide had no effects on the immune cell distribution in controls. In CLP rats,
      a significant reduction in both CD4+ and CD8+ T lymphocytes as well as an
      increased number of macrophages and MHC class II-positive cells was seen in the
      villi as compared with sham-operated controls (P < 0.05). Linomide attenuated
      these changes for CD8+ and T lymphocytes and macrophages. Sepsis caused increased
      concentrations of TNF-alpha in portal blood and ascites 3 h from CLP induction.
      This increase was attenuated by Linomide.

PMID- 12412628
TI  - Growth stimulation of intestinal commensal Escherichia coli by catecholamines: a
      possible contributory factor in trauma-induced sepsis.
AB  - Trauma is well recognized to result in the immediate and sustained release of
      stress-related neurochemicals such as the catecholamine norepinephrine. Past work
      has shown that in addition to their ability to function as neurotransmitters,
      catecholamines can also directly stimulate the growth of a number of pathogenic
      bacteria. The development of trauma-associated sepsis has often been linked to
      the ability of otherwise normal commensal bacteria to invade and penetrate the
      gut mucosal barrier. Therefore, the aim of our study was to examine whether
      catecholamines could also stimulate the growth of commensal Escherichia coli
      strains of the type present in the intestinal tract at the time of a traumatic
      event. Herein we report that the growth of a range of non-pathogenic isolates of
      E. coli of human and environmental origin was significantly increased in the
      presence of catecholamines. A primary mechanism by which catecholamines increase
      bacterial growth was shown to be iron removal from lactoferrin and transferrin
      and subsequent acquisition by bacteria. The 3,4-dihydroxybenzoyl (catechol)
      structure of the catecholamines was further demonstrated to be critical to iron
      acquisition. The synthetic catecholamine inotropes dobutamine and isoprenaline,
      as well as norepinephrine metabolites that retained the catechol structure were
      also active, whereas norepinephrine metabolites in which the catechol moiety had
      been modified were not. A role for catecholamine-mediated bacterial iron supply
      in the pathophysiology of gut-derived sepsis due to trauma is proposed.

PMID- 12412630
TI  - Intestinal ischemic preconditioning protects the intestine and reduces bacterial
      translocation.
AB  - Ischemic preconditioning (IPC) was first demonstrated in the heart, but this
      protective effect has been also recently described in the intestine. The aim of
      this study was to determine the effects of intestinal ischemic preconditioning on
      the morphology of intestine and bacterial translocation. Twenty-four male Wistar
      rats weighting 250 to 300 g were randomized into three groups. A control group of
      rats (n = 8) were subjected laparotomy. In an ischemic group (n = 8), laparotomy
      was performed and the superior mesenteric artery was occluded by an atraumatic
      clamp for 30 min. In the preconditioned group (n = 8), before the ischemia
      reperfusion (I/R) period (as in ischemic group), rats were subjected to an
      initial 10 min of intestinal ischemia and 10 min of reperfusion. Twenty-four
      hours later, to evaluate whether the I/R induced intestinal injury and bacterial
      translocation (BT), tissue and blood samples were collected, and liver, spleen,
      and mesenteric lymph node specimens were obtained under sterile conditions for
      microbiological analysis. Samples of ileum were removed for both biochemical and
      histopathological evaluation. In the I/R group, the incidence of bacteria
      isolated mesenteric lymph nodes, spleen, liver, and blood was significantly
      higher than other groups (P < 0.05). IPC prevented I/R-induced BT and it
      significantly reduced the I/R-induced intestinal injury (P < 0.05). Increased
      inducible nitric oxide (NO) synthase (iNOS) expression observed on the ileal
      specimens of the I/R group was found to be prevented by IPC. Our data suggest IPC
      as a key factor that reduces BT and iNOS activation in intestinal I/R. This is
      the first study showing that intestinal IPC blocks the cascade of events that
      causes BT and intestinal injury that may lead to sepsis.

PMID- 12412631
TI  - Brain specific proteins in serum: do they reliably reflect brain damage?

PMID- 12412632
TI  - Bugs, guts, and iron.

PMID- 12412633
TI  - The effects of dietary calcium during lactation on lead in bone mobilization:
      implications for toxicology.
AB  - Under a normal 1.0% calcium (Ca) concentration in the diet during and after
      chronic lead (Pb) intoxication, there was a significant increment in the
      concentration of Pb in the blood, kidney, liver and brain during lactation,
      parallel to a decrement of Pb in the bone. The increment of Pb in the brain was
      accompanied by an enhanced lipid oxidation (increase in conjugated dienes).
      During lactation, on the first 14 days, when dietary Ca was reduced to 0.05%,
      bone Ca concentration was decreased by 15%, bone resorption measured as acid
      phosphatase activity in plasma increased three times and Pb bone concentration
      dropped by 30%. Under a 0.05% Ca in the diet in the nonlactating rats, Ca in the
      bone decreases also, but there were neither increments in bone resorption nor Pb
      efflux from the bone. These results suggested that Pb efflux in the bone was
      related to bone resorption during lactation. Interestingly, when dietary Ca was
      enhanced to 2.5% in lactating rats, Ca concentration in the bone increased by
      21%, but resorption did not decrease and Pb bone concentration decreased by 28%,
      enhancing toxicity. In the control Pb-exposed nonlactating rats under a 2.5% Ca
      in the diet, Ca concentration in the bone was increased (18%), and Pb
      concentration in the bone was unaltered. Since Ca metabolism changes drastically
      in humans during pregnancy and lactation, and it is likely that bone Pb is
      mobilized and transferred to the more available compartments of the maternal
      circulation, the increment in daily intake of Ca during lactation could enhance
      Pb efflux from the bone.

PMID- 12412634
TI  - Dieldrin induces human neutrophil superoxide production via protein kinases C and
      tyrosine kinases.
AB  - We have recently found that dieldrin is a potent human neutrophil agonist in
      vitro and induces neutrophilic inflammation in vivo. Among the responses observed
      in vitro, dieldrin was found to induce superoxide (O2-) production by a yet
      unknown mechanism. In the present study, dieldrin- and phorbol 12-myristate 13
      acetate (PMA)-induced O2- responses were compared. For this purpose, cells were
      preincubated with a panel of signal transduction inhibitors including genistein,
      H-7, HA-1077, pertussis toxin, staurosporine, calphostin C, SB203580, PD098059,
      and wortmannin. Dieldrin-induced O2- response was significantly reduced with
      treatment with genistein, H-7, HA-1077, staurosporine, and calphostin C, whereas
      PMA-induced response was significantly reduced by treatment with H-7, HA-1077,
      and staurosporine. This indicates that dieldrin mediates its effect via protein
      kinases C (PKCs) and tyrosine kinases. Involvement of tyrosine kinases in
      dieldrin-induced human neutrophils was further demonstrated by an increase in
      tyrosine phosphorylated protein level expression. Finally, we found that
      treatment with the mitochondrial stabilizer bongkrekic acid and with the
      inhibitor of vesicular transport brefeldin A did not reverse dieldrin-induced O2-
      response.

PMID- 12412635
TI  - The effect of hexaaza- and hexathia-macrocyclic ligands on transition metal
      cytotoxicity in human hepatoma-derived cultured cells.
AB  - The effect of macrocyclic ligands on cytotoxic concentrations of the transition
      metal ions of copper, zinc, and cadmium was investigated. For this purpose, a
      hexaaza- [3,6,9,17,20,23-hexaazatricyclo[23.3.1.1(11,15)] triaconta
      1(29),11(30),12,14,25,27-hexaene (L2)] and hexathia-chelating ligand
      [1,4,7,10,13,16-hexathiacyclooctadecane (L3)] were used in the human hepatoma
      derived HepG2 cell line. The cytotoxicity was measured by the neutral red uptake
      inhibition assay. First, the NI50 of the ligands, i.e., the concentration of the
      ligand inducing a 50% inhibition in neutral red uptake compared to control cells,
      was determined. In several metal/ligand combination experiments, the effects for
      L2 were difficult to interpret, whereas for L3 in combination with copper ions, a
      severe increase -- and for zinc ions, a significant decrease of cell toxicity --
      relative to the metal control was observed. To further examine the different
      effects observed with L3 in combination with, respectively, Cu2+ and Zn2+, the
      glutathione (GSH) content was measured. The relative GSH content decreased as the
      concentration of L3 increased. It was proposed that the increased toxicity of the
      combination Cu(2+)/L3 could be caused by the depletion of GSH and a subsequent
      inability to scavenge the produced reactive oxygen species (ROS). This hypothesis
      was supported by experiments during which vitamin E or C was added to the
      Cu(2+)/L3 system.

PMID- 12412636
TI  - Biology and toxicology of PPARgamma ligands.
AB  - The peroxisome proliferator activated receptor-gamma (PPARgamma) is an attractive
      target for therapeutic intervention, as modulation of PPARgamma-regulated
      pathways is potentially beneficial in a number of disease areas. This review
      provides an overview of what is known about the biology of PPARgamma, and an
      indication of what progress has been made towards drug development in several
      therapy areas. As well as efficacy, the safety of drugs is of course an important
      issue, and a substantial volume of preclinical and clinical information has
      already accumulated for PPARgamma agonists. Here we discuss some of the major
      toxicology issues with PPARgamma agonists, and give a perspective on likely
      issues concerning the development of PPARgamma modulators in the future.

PMID- 12412637
TI  - When should a substance be designated as sensitizing for the skin ('Sh') or for
      the airways ('Sa')?
AB  - In the List of MAK and BAT Values compounds are designated with 'Sa'
      ('sensitizing for the airways') or 'Sh' ('sensitizing for the skin') if,
      according to scientific evidence, they are allergens. Mainly based on suggestions
      by a WHO working group and based on our own experience, extended criteria have
      been elaborated by the working group 'skin and allergy' of the Commission of the
      Deutsche Forschungsgemeinschaft for the Investigation of Health Hazards of
      Chemical Compounds in the Work Area, which are presented in this article. They
      serve as guidelines for deciding which substances have to be labelled 'Sa' and
      'Sh', respectively, for the prevention of sensitization and subsequent allergic
      diseases in workers. Although in some special cases their strict application may
      not be deemed necessary or possible, the proposed new criteria should be used to
      make the procedure of classification of substances: 1) more rational, 2) more
      consistent, 3) more comprehensible, and 4) more transparent. This paper informs
      readers working scientifically or administratively in this field and invites a
      critical discussion of the issue.

PMID- 12412638
TI  - NTA and Fe(III)NTA: differential patterns of renal toxicity in subchronic
      studies.
AB  - Differential patterns in terms of nephropathology and 8-hydroxyguanine formation
      in the course of oral 28-day studies were observed with nitrilotriacetic acid
      (NTA) and FeNTA. FeNTA, but not NTA, caused enhanced 8-hydroxyguanine formation
      in kidney DNA after oral and intraperitoneal administration. Enhanced lipid
      peroxidation in the kidney homogenate was observed with FeNTA as well as with
      NTA. For NTA, the low dose (9 mg/kg per day) was without adverse effect. The
      kidney toxicity of oral FeNTA (50, 200, and 1000 mg/kg per day) was only mild, 50
      mg/kg per day; however, it still led to an increased 8-hydroxyguanine content.
      The relevance of Iron(III) (Fe(III)) or Fe(III)NTA formation as a relevant
      mediator of NTA-related toxicity was excluded on the basis of these data. Also, a
      thermodynamic consideration presented here, supports the view that zinc (Zn), and
      not Fe, is likely to mediate the tubular cell cytotoxicity of NTA.

PMID- 12412639
TI  - A study of the in vitro clinical interaction between lidocaine and premedications
      using rat liver microsomes.
AB  - In this study, we have investigated the relationship between lidocaine metabolism
      and premedication, i.e., psychotropic and anti-anxiety agents (diazepam,
      midazolam), hypnotics (pentobarbital, thiamylal), depolarizing muscular relaxants
      (vecuronium, pancuronium and suxamethonium), an active anti-hypertensive
      (clonidine) and an H2 receptor antagonist (cimetidine) using rat hepatic
      microsomes in vitro. Lidocaine metabolism was noncompetitively inhibited by
      midazolam (Ki=29.0 microM). Thilamylal was a moderate competitive inhibitor of
      lidocaine metabolism (Ki=77.8 microM). Pentobarbital, diazepam and cimetidine
      weakly inhibited lidocaine metabolism formation in a concentration-dependent
      manner at high substrate concentrations. On the other hand, vecuronium,
      pancuronium, suxamethonium and clonidine did not inhibit lidocaine metabolism
      over the therapeutic range. These results show that the interaction between
      lidocaine and midazolam and thiamylal, catalyzed by a similar cytochrome P450, is
      of potential importance in toxicological and clinical studies.

PMID- 12412640
TI  - Effect of triethyltin on Ca2+ movement in Madin-Darby canine kidney cells.
AB  - The effects of the environmental toxicant, triethyltin, on Ca2+ mobilization in
      Madin-Darby canine kidney (MDCK) cells have been examined. Triethyltin induced an
      increase in cytosolic free Ca2+ levels ([Ca2+]i) at concentrations larger than 2
      microM in a concentration-dependent manner. Within 5 min, the [Ca2+]i signal was
      composed of a gradual rise and a sustained phase. The [Ca2+]i signal was partly
      reduced by removing extracellular Ca2+. In Ca(2+)-free medium, pretreatment with
      thapsigargin (1 microM), an endoplasmic reticulum Ca2+ pump inhibitor, reduced 50
      microM triethyltin-induced [Ca2+]i increase by 80%. Conversely, pretreatment with
      triethyltin abolished thapsigargin-induced Ca2+ release. Pretreatment with U73122
      (2 microM) to inhibit phospholipase C-coupled inositol 1,4,5-trisphosphate
      formations failed to alter 50 microM triethyltin-induced Ca2+ release. Incubation
      with triethyltin at a concentration (1 microM) that did not increase basal
      [Ca2+]i for 3 min did not alter ATP (10 microM)- and bradykinin (1 microM)
      induced [Ca2+]i increases. Collectively, this study shows that triethyltin
      altered Ca2+ movement in renal tubular cells by releasing Ca2+ from multiple
      stores in an inositol 1,4,5-trisphosphate-independent manner, and by inducing
      Ca2+ influx.

PMID- 12412641
TI  - Venlafaxine poisoning complicated by a late rise in creatine kinase: two case
      reports.
AB  - Newer anti-depressants are often considered to be safer than more established
      anti-depressants. However, clinical experience of the effects of these agents in
      overdose is limited. Here, we present two cases of venlafaxine overdose that were
      complicated by a delayed rise in plasma creatine kinase. Although the clinical
      consequences were not serious, physicians should be alerted to the possibility of
      delayed rhabdomyolysis or serotonin syndrome in patients who have taken
      venlafaxine in overdose.

PMID- 12412642
TI  - Herbal medicine causing likely strychnine poisoning.
AB  - 'Maqianzi' (the dried ripe seed of Strychnos nux-vomica L.) contains 1.0-1.4%
      each of strychnine and brucine. After processing to reduce its toxicity,
      'maqianzi' was used as a herbal remedy for rheumatism, musculoskeletal injuries
      and limb paralysis. A 42-year old woman with neck pain was prescribed 15 g of
      'maqianzi' to be taken in two doses at 7 hours apart, although the recommended
      dose was 0.3-0.6 g. She was apparently well after drinking the first of two bowls
      of 'maqianzi' decoction. One hour after she drank the second bowl of herbal
      decoction, she suddenly developed tonic contractions of all her limb muscles and
      carpopedal spasm lasting 5 min, difficulty in breathing, chest discomfort and
      perioral numbness. The second bowl of decoction probably became more concentrated
      because of evaporation of water during continued boiling and contained a larger
      amount of 'maqianzi'. On arrival in the hospital 1 hour later, she complained of
      muscle pain and tiredness. She was found to have hyperventilation and weakness of
      four limbs, with muscle power of grade 5(-)/5. All her symptoms gradually
      subsided over the next few hours. This case illustrated that 'maqianzi' can cause
      strychnine poisoning even after processing, especially when the recommended dose
      is greatly exceeded. In any patient with 'unexplained' muscle spasms or
      convulsions, strychnine poisoning should be included in the differential
      diagnosis and they should be asked about the use of herbal medicines.

PMID- 12412643
TI  - Optical trap detector for calibration of optical fiber powermeters: coupling
      efficiency.
AB  - The optical trap detector is based on two, 1 cm x 1 cm silicon photodiodes and a
      spherical mirror contained in a package that is highly efficient for measuring
      light diverging from the end of an optical fiber. The mathematical derivation of
      the coupling efficiency relies on the integral directional response weighted by
      the angular intensity distribution of an idealized parabolic optical beam.
      Results of directional-uniformity measurements, acquired with the aid of a six
      axis industrial robotic arm, indicate that the trap has a collection efficiency
      greater than 99.9% for a fiber numerical aperture of 0.24. Spatial uniformity
      measurements indicate that the variation of detector response as a function of
      position is less than 0.1%. The detector's absolute responsivity at 672.3, 851.7,
      and 986.1 nm is also documented by comparison with other optical detectors and
      various input conditions and indicates that the design is well suited for laser
      and optical fiber power measurements.

PMID- 12412644
TI  - Photon absorption in resonant-cavity-enhanced gaas far-infrared detectors.
AB  - Interface reflection has been demonstrated to play an important role in GaAs
      multilayer homojunction far-infrared (FIR) detectors. A transfer matrix method
      that is able to provide a true optical field distribution within an FIR detector
      has been employed to optimize photon absorption and structure. The dependence of
      photon absorption on the reflectivity and the phase shift of the bottom mirror in
      a resonant-cavity-enhanced GaAs FIR detector has been investigated. Weak
      wavelength selectivity has been observed for both resonant and off-resonant FIR,
      which is a unique advantage for detector application. In comparison with the
      experimental result, a 20.8% increase in quantum efficiency was found in an
      optimized FIR detector.

PMID- 12412645
TI  - Relative performance of filled and feedhorn-coupled focal-plane architectures.
AB  - Modern far-infrared and submillimeter instruments require large-format arrays. We
      consider the relative performance of filled-array (bare pixel) and feedhorn
      coupled architectures for bolometer focal planes. Based on typical array
      parameters, we quantify the relative observing speeds and comment on the merits
      of the different architectures. Filled arrays can provide higher mapping speed
      (by a factor of as much as 3.5) and simpler observing modes at the expense of
      reduced sensitivity for pointed observations, increased detector numbers, and
      greater vulnerability to stray light and electromagnetic interference. Taking
      advantage of the filled-array architecture requires strongly background-limited
      detectors. At millimeter wavelengths, filled arrays must be surrounded by a
      sufficiently cold enclosure to minimize the background power from the instrument
      itself.

PMID- 12412646
TI  - Transmission two-modulator generalized ellipsometry measurements.
AB  - The two-modulator generalized ellipsometer has been used to measure samples in
      transmission. In this configuration, the instrument can completely characterize a
      linear diattenuator and retarder, measuring birefringence, diattenuation, the
      angle of the principal axis, and the sample depolarization simultaneously and
      accurately. This instrument can be operated in two modes: (1) spectroscopic, in
      which measurements are made through the entire sample aperture as a function of
      wavelength, and (2) spatially resolved, in which measurements are made at a
      single wavelength and a birefringence picture is made of the sample. Current
      spatially resolved measurements have been made at a resolution of approximately
      40 microm. Four samples have been examined with this instrument: (1) a mica
      plate, (2) a Polaroid polarizer, and (3) two quartz plates.

PMID- 12412648
TI  - Analysis of cladding-mode couplings for a lensed fiber integrated with a long
      period fiber grating by use of the beam-propagation method.
AB  - The beam-propagation method (BPM) is employed to analyze the coupling behavior of
      our scheme proposed previously, which combines a lensed fiber and a long-period
      fiber grating (LPFG) [Chen and Wang, Appl. Opt. 39,4490-4500 (2000)]. The
      influences of a core within the fiber lens are investigated. As for the fiber
      dependence of our coupling scheme, two typical fibers are studied: dispersion
      shifted and single-mode, step-index fibers. With the BPM, the optimal coupling
      efficiencies for various source waists with corresponding lens radii and working
      distances are determined. We also compare the results with those obtained by use
      of the ABCD method and found that the BPM gives better agreement with
      experimental results.

PMID- 12412647
TI  - Athermalized low-loss echelle-grating-based multimode dense wavelength division
      demultiplexer.
AB  - A high-density wavelength division demultiplexer (DEMUX) capable of
      demultiplexing eight-channel 200-GHz optically spaced signals into a 62.5-microm
      multimode-fiber array is reported. The wavelength range of operation is from
      1549.32 to 1560.61 nm within the International Telecommunication Union grid. The
      measured wavelength accuracy is within 0.04 nm. The mean insertion loss of this
      DEMUX is 1.95 dB. Thermal analysis and temperature testing results are reported.
      The temperature test cycling from 20 degrees C to 60 degrees C indicates that the
      wavelength thermal drift is less than 0.8 pm/degrees C. Adjacent cross talk is
      measured to be better than -45 dB. The measured data transmission bit rate of
      this device is higher than 3.5 Gb/s.

PMID- 12412649
TI  - Dual temperature and strain measurement with the combined fluorescence lifetime
      and Bragg wavelength shift approach in doped optical fiber.
AB  - We have constructed fiber-optic sensors to measure temperature and strain by
      combining the properties of fiber Bragg gratings with the fluorescent lifetimes
      of various doped fibers. Sensors have been made with the fiber Bragg grating
      written directly into the doped fiber to ensure the collocation of the strain and
      temperature measurement points. Results are compared with those obtained
      previously from a Bragg grating written into standard photosensitive fiber
      spliced to doped fiber. Standard deviation errors of 7 microepsilon and 0.8
      degrees C have been obtained for strain and temperature ranges of up to 1860
      microepsilon and 120 degrees C, respectively.

PMID- 12412650
TI  - Eye rotation and vignetting in visual instruments.
AB  - The eye can rotate to accommodate the angular position of an object and the
      distance of the object from it. The rotation of the eye inside its socket to
      align its visual axis in the direction of an off-axis image may introduce full or
      partial vignetting when one is looking through a visual instrument with a real
      exit pupil. We analyze the effects of vignetting owing to rotation of the eye in
      visual instruments with real exit pupils.

PMID- 12412651
TI  - Limits and possibilities of laser speckle and white-light image-correlation
      methods: theory and experiments.
AB  - A laser-speckle method and a white-light image-correlation method are used for
      strain mapping. A schematic model of the correlation function of two speckle
      patterns is proposed for investigation of strain influence on displacement
      measurement accuracy. A specific software has been developed to calculate by
      direct correlation the displacement values between two pictures with a grainy
      pattern at any point on an object's surface. Its efficiency is demonstrated in
      several tests. Moreover, theoretical results are checked through experimental
      measurements. The limitations and performances of both optical techniques are
      discussed.

PMID- 12412653
TI  - Sampling field sensor with anisotropic fan-out.
AB  - We describe a new common-path, phase-shift, and shearing interferometric device
      capable of single-shot detection of optical phase profiles. It samples the input
      field and uses birefringent plates to fan out phase-shifted copies of the samples
      in the empty space between them. The phase shifts are given by the thickness of
      the plates and not by the relative position of the components, as in classical
      interferometers. This makes the device insensitive to vibrations. We recorded
      repeatability better than lambda/100, even though strong shocks were applied to
      the air table in proximity to the system. We recorded better than lambda/1000
      repeatability under quiet conditions and estimated the accuracy to be better than
      lambda/3000 at the shot-noise limit. In addition, the device is compact and easy
      to integrate in a variety of setups that require the measurement of optical phase
      profiles.

PMID- 12412652
TI  - Parallel flow measurements in microstructures by use of a multifocal 4 x 1
      diffractive optical fan-out element.
AB  - We have developed a multifocal optical fluorescence correlation spectroscopy
      system for parallel flow analyses. Multifocal excitation was made possible
      through a 4 x 1 diffractive optical fan-out element, which produces uniform
      intensity in all four foci. Autocorrelation flow analyses inside a 20 microm x 20
      microm square microchannel, with the 4 x 1 fan-out foci perpendicular to the flow
      direction, made it possible to monitor different flows in all four foci
      simultaneously. We were able to perform cross-correlation flow analyses by
      turning the microstructure, thereby having all four foci parallel to the
      direction of flow. Transport effects of the diffusion as a function of flow and
      distance could then also be studied.

PMID- 12412654
TI  - Full-field optical coherence tomography with thermal light.
AB  - A simple optical coherence tomography system has been developed based on a white
      light Linnik interferometric microscope with its reference mirror mounted on a
      piezoelectric translator. The geometrical extension of the optics allows
      efficient illumination of this device with a low-power (3-W) light bulb, yielding
      full-field interferometric images at 50 Hz with a fast CCD camera. Owing to the
      very broad spectral width of the light source and of the camera response, we
      achieved axial resolutions equal to 1.1 microm in free space and 0.7 microm
      through a standard microscope cover plate. Tomographic images of an epithelial
      cell smear and of an hematological sample are shown.

PMID- 12412655
TI  - Calibration of subnanometer motion with picometer accuracy.
AB  - We have developed a method for calibrating subnanometer movements of a
      piezoelectric actuator with picometer accuracy and for a wide range of
      frequencies. This range make this calibration useful for scanning probe
      microscopes, particularly for an apertureless scanning near-field optical
      microscope in which the tip is dithered to modulate the optical signal. The setup
      consists of a Michelson interferometer that has a mobile arm capable of moving
      more than one fringe. The piezoelectric actuator to be calibrated vibrates at the
      desired frequency in the other arm. Net displacement can be calculated by
      simultaneous measurement of an interferometric signal and its derivative.
      Hysteresis of the system can be also measured. It will be shown that the actuator
      response is linear only for the low-frequency region (in our case as much as
      approximately 10 kHz). Above that frequency range, higher harmonics appear and
      cannot be neglected to obtain real displacement. Finally, it will be shown that
      the use of higher harmonics in calibration or detection schemes (that rely on the
      linearity of the response) must be validated, and this technique has proved
      adequate for that purpose.

PMID- 12412656
TI  - Subwavelength size determination by spatially modulated illumination virtual
      microscopy.
AB  - A new approach for determining the sizes of individual, small fluorescent objects
      with diameters considerably below the optical resolution limit is described in
      which spatially modulated illumination (SMI) microscopy and 360-647-nm excitation
      wavelengths are used. The results of SMI virtual microscopy computer simulations
      indicate that, in this wavelength range, reliable measurements of sizes as small
      as approximately 20 nm are feasible if the low numbers of fluorescence photons
      that are usually detected from such small objects are taken into account. This
      method is based on the well-known fact that the modulation of the diffraction
      image in a SMI microscope is disturbed by the size of the object. Using
      appropriately calculated calibration functions, one can use this disturbance of
      the modulation to determine the size of the original object.

PMID- 12412657
TI  - Performance of submillimeter square hollow waveguides.
AB  - Propagation losses are determined for 100 microm x 100 microm square, hollow
      waveguides constructed from glass capillaries. The small size makes it possible
      to observe optical effects not easily seen with larger waveguides. The depletion
      of higher-order even modes creates a large, nonlinear loss. Over a distance of a
      meter the loss approaches the smaller, linear value expected for the fundamental
      mode. Additionally, the lowest two even modes beat to produce an oscillatory loss
      with a period of approximately 2 cm. Making the focal radius 0.35 the waveguide
      width minimizes these two effects. In a related study, 50-microm waveguides
      embossed in polydimethylsiloxane are shown to have losses similar to glass
      capillaries.

PMID- 12412658
TI  - Fluid velocity measurements in a microchannel performed with two new optical
      heterodyne microscopes.
AB  - Two laser Doppler microscopes (LDMs) based on an optical heterodyne
      interferometer have been developed for measuring fluid velocity in a
      microchannel. One of LDMs receives light from a Zeeman laser, and one easily
      obtains the standard heterodyne signal because a polarizer is set in front of a
      photomultiplier tube. The other LDM, with light from a He-Ne laser, employs a
      diffractive grating as a frequency shifter that is modulated in a sinusoidal
      movement by a piezoelectric transducer stack. By this modulation the nonstandard
      heterodyne signal is further processed by a new synthetic heterodyne algorithm.
      Finally, the phase shift related to the fluid velocity in both LDMs is
      demodulated by digital postprocessing in fast-Fourier-transform, bandpass
      filtering, inverse-fast-Fourier-transform, and arctangent algorithms.

PMID- 12412659
TI  - Derivation of a Monte Carlo method for modeling heterodyne detection in optical
      coherence tomography systems.
AB  - A Monte Carlo (MC) method for modeling optical coherence tomography (OCT)
      measurements of a diffusely reflecting discontinuity embedded in a scattering
      medium is presented. For the first time to the authors' knowledge it is shown
      analytically that the applicability of an MC approach to this optical geometry is
      firmly justified, because, as we show, in the conjugate image plane the field
      reflected from the sample is delta-correlated from which it follows that the
      heterodyne signal is calculated from the intensity distribution only. This is not
      a trivial result because, in general, the light from the sample will have a
      finite spatial coherence that cannot be accounted for by MC simulation. To
      estimate this intensity distribution adequately we have developed a novel method
      for modeling a focused Gaussian beam in MC simulation. This approach is valid for
      a softly as well as for a strongly focused beam, and it is shown that in free
      space the full three-dimensional intensity distribution of a Gaussian beam is
      obtained. The OCT signal and the intensity distribution in a scattering medium
      have been obtained for several geometries with the suggested MC method; when this
      model and a recently published analytical model based on the extended Huygens
      Fresnel principle are compared, excellent agreement is found.

PMID- 12412660
TI  - Analysis of nanostructured porous films by measurement of adsorption isotherms
      with optical fiber and ellipsometry.
AB  - An optical method to determine the nanostructure and the morphology of porous
      thin films is presented. This procedure is based on the response of a side
      polished optical fiber with the film under study, when an adsorption-desorption
      cycle is carried out. Spectroscopic ellipsometry provides additional information
      about the optical properties and adsorption behavior of the film. Pore size
      distribution, anisotropy, and inhomogeneity of films can be determined by use of
      these two complementary techniques. To check the performances and suitability of
      the optical method, we have characterized a typical porous material: a TiO2 film
      deposited by evaporation. Water vapor has been used for the adsorption cycles.
      The well-known columnar structure of the evaporated TiO2 has been evidenced, and
      the relation between the nanostructure and the optical properties of the film is
      showed.

PMID- 12412661
TI  - Sputtered Si:H alloys for edge filters: application to thermophotovoltaics.
AB  - Si:H alloys are being investigated for the high-index material in an interference
      filter to provide spectral control in an application of thermophotovoltaic energy
      conversion. In particular, a multilayer edge filter is being developed to provide
      high transmission of photons with wavelengths between 1.0 and 2.4 microm and high
      reflectance for wavelengths outside this range. Thin films of Si:H were deposited
      by means of rf reactive sputtering. Deposition parameters were varied to optimize
      the H content in Si:H coatings such that the refractive index was greater than 3.
      Optical absorption near 1 microm and Si:H infrared absorptions near 5 and 12
      microm were minimized.

PMID- 12412662
TI  - Dopant-dependent reflectivity and refractive index of microcrystalline HxWO3 and
      LixWO3 bronze thin films.
AB  - Reflectivity spectra of HxWO3 and LiWO3 thin films were measured over the photon
      energy range from 0.4 to 4.2 eV. It was found that microcrystalline tungsten
      bronzes have reflectances of 8%-30% over the dopant concentration range x (0 < or
      = x < or = 0.25). Values for the real part of refractive index n were also
      determined from the refined reflectivity data. The optical data are interpreted
      by use of a modified Drude-Zener model together with a single-oscillator model to
      differentiate between bound and free electronic states. The values of high
      frequency dielectric constant epsilon(hf) of MxWO3 (M = H+, Li+) bronzes were
      determined from the refractive-index data for estimation of the effective
      electronic masses involved in optical and polaronic transitions. A single
      oscillator model showed that oscillator energy Ea and dispersion energy Ed
      increased and decreased, respectively, with increasing x values, opposite what
      occurs in crystalline tungsten bronzes. These findings support the fact that
      Bloch electrons are almost absent; instead, the polaronic species (W5+ and W4+)
      are assumed to control the reflectivity modifications (or variations in the
      refractive index) that are associated with the microcrystalline tungsten bronzes.

PMID- 12412663
TI  - Method for evaluating optical characteristics of endoscopes for recording
      fluorescence-related cardiac electrical activity.
AB  - Nondestructive methods were used to evaluate marketed fiber-optic endoscopes
      (intended for simple viewing) for fluorescence recording. Our application is for
      optical recording from the heart. For one angioscope, we measured a focal length
      of 0.33 mm, a field of view of 45 degrees, an aperture of 0.26 mm, and an
      efficiency of 43%. We calculated that the angioscope would give a signal-to-noise
      ratio of 1.0 for a cardiac action potential, if its field of view were divided
      into a nine-pixel array (for safe continuous illumination). Our methods are
      useful in designing and evaluating fluorescence fiber-optic systems with superior
      signal quality and spatial resolution.

PMID- 12412664
TI  - The Confronting COPD International Survey: patients hardly know they have COPD.

PMID- 12412665
TI  - Consultation on basic asthma research strategy.

PMID- 12412666
TI  - Medical therapy for COPD: lessons from the real world.

PMID- 12412667
TI  - Impact of COPD in North America and Europe in 2000: subjects' perspective of
      Confronting COPD International Survey.
AB  - To date, no international surveys estimating the burden of chronic obstructive
      pulmonary disease (COPD) in the general population have been published. The
      Confronting COPD International Survey aimed to quantify morbidity and burden in
      COPD subjects in 2000. From a total of 201,921 households screened by random
      digit dialling in the USA, Canada, France, Italy, Germany, The Netherlands, Spain
      and the UK, 3,265 subjects with a diagnosis of COPD, chronic bronchitis or
      emphysema, or with symptoms of chronic bronchitis, were identified. The mean age
      of the subjects was 63.3 yrs and 44.2% were female. Subjects with COPD in North
      America and Europe appear to underestimate their morbidity, as shown by the high
      proportion of subjects with limitations to their basic daily life activities,
      frequent work loss (45.3% of COPD subjects of <65 yrs reported work loss in the
      past year) and frequent use of health services (13.8% of subjects required
      emergency care in the last year), and may be undertreated. There was a
      significant disparity between subjects' perception of disease severity and the
      degree of severity indicated by an objective breathlessness scale. Of those with
      the most severe breathlessness (too breathless to leave the house), 35.8%
      described their condition as mild or moderate, as did 60.3% of those with the
      next most severe degree of breathlessness (breathless after walking a few minutes
      on level ground). This international survey confirmed the great burden to society
      and high individual morbidity associated with chronic obstructive pulmonary
      disease in subjects in North America and Europe.

PMID- 12412668
TI  - Chronic bronchitis among French adults: high prevalence and underdiagnosis.
AB  - The aims of this survey were to determine the prevalence of symptoms indicative
      of chronic bronchitis (CB) in the French adult population, to identify the role
      of risk factors for CB, and to assess rates of CB diagnosis and pulmonary
      function testing (PFT) in the presence of CB. A representative sample of 14,076
      individuals aged > or = 25 yrs completed a self-administered questionnaire on
      symptoms, comorbidities, smoking history, sociodemographical data, and diagnosis
      and care by physicians. The prevalence of CB was 4.1% and the prevalence of
      chronic cough and/or expectoration was 11.7%. In individuals with comorbidity,
      these figures were 10.4% and 24.4%, respectively. Smoking was associated with an
      increased frequency of CB. In subjects with CB, 44.6% had PFT (spirometry or peak
      expiratory flow measurement), 24% were diagnosed as having CB, and 7.2% received
      care. Rates of diagnosis, PFT, and follow-up were lower in young individuals and
      in those without comorbidity. PFT and follow-up were less common in current
      smokers. Prevalence of chronic bronchitis in French adults is high and similar in
      magnitude to that of other industrialised countries. Comorbidities and tobacco
      smoking increase the frequency of chronic bronchitis symptoms. Chronic bronchitis
      is too infrequently diagnosed, investigated and cared for.

PMID- 12412669
TI  - Vaccination of COPD patients with a pneumococcus type 6B tetanus toxoid conjugate
      vaccine.
AB  - This paper examines how pneumococcal type 6B polysaccharide conjugated to tetanus
      toxoid (Pn6B-TT) compares to a 23 valent pneumococcal vaccine (pneumococcal
      polysaccharide (PPS)-23) with respect to immunogenicity and serum opsonic
      activity in patients with chronic obstructive pulmonary disease (COPD). Patients
      with COPD aged 55-75 yrs were vaccinated with Pn6B-TT (n=10) or with PPS-23
      (n=9). Healthy young adults (HA) were vaccinated with Pn6B-TT as controls. Total
      antibodies to serotype 6B polysaccharide were measured by radioimmunoassay and
      immunoglobulin (Ig)G antibodies by enzyme-linked immunosorbent assay. Opsonic
      activity was measured by a phagocytosis assay using human neutrophils as effector
      cells. The patient groups were comparable by age, smoking history, lung function
      and use of steroids. COPD patients vaccinated with Pn6B-TT or PPS-23 showed an
      increase in IgG antibodies and a nonsignificant increase in opsonic activity.
      This was similar to the increase in IgG and opsonic activity seen in HA. There
      was a significant correlation between antibody levels and opsonic activity in
      COPD patients vaccinated both with Pn6B-TT and PPS-23. Pneumococcal antibodies
      have been shown to confer protection from infection. The results of the present
      study indicate that protective immunity can be expected in elderly chronic
      obstructive pulmonary disease patients vaccinated with conjugate vaccines.

PMID- 12412670
TI  - Survival in COPD patients after regular use of fluticasone propionate and
      salmeterol in general practice.
AB  - Despite substantial evidence regarding the benefits of combined use of inhaled
      corticosteroids and long-acting beta2-agonists in asthma, such evidence remains
      limited for chronic obstructive pulmonary disease (COPD). Observational data may
      provide an insight into the expected survival in clinical trials of fluticasone
      propionate (FP) and salmeterol in COPD. Newly physician-diagnosed COPD patients
      identified in primary care during 1990-1999 aged > or = 50 yrs, of both sexes and
      with regular prescriptions of respiratory drugs were identified in the UK General
      Practice Research Database. Three-year survival in 1,045 COPD patients treated
      with FP and salmeterol was compared with that in 3,620 COPD patients who
      regularly used other bronchodilators but not inhaled corticosteroids or long
      acting beta2-agonists. Standard methods of survival analysis were used, including
      adjustment for possible confounders. Survival at year 3 was significantly greater
      in FP and/or salmeterol users (78.6%) than in the reference group (63.6%). After
      adjusting for confounders, the survival advantage observed was highest in
      combined users of FP and salmeterol (hazard ratio (HR) 0.48 (95% confidence
      interval 0.31-0.73)), followed by users of FP alone (HR 0.62 (0.45-0.85)) and
      regular users of salmeterol alone (HR 0.79 (0.58-1.07)) versus the reference
      group. Mortality decreased with increasing number of prescriptions of FP and/or
      salmeterol. In conclusion, regular use of fluticasone propionate alone or in
      combination with salmeterol is associated with increased survival of chronic
      obstructive pulmonary disease patients managed in primary care.

PMID- 12412671
TI  - Apparent but not real increase in asthma prevalence during the 1990s.
AB  - The authors investigated changes in asthma prevalence and perception of
      bronchoconstriction over 6 yrs in adults of Newcastle-upon-Tyne. Postal
      questionnaires were sent to 6,000 subjects aged 20-44 yrs in 1992-1993 and 1998
      1999. Random samples of 600 responders had assessments of atopy, airway
      responsiveness, and their ability to perceive methacholine-induced
      bronchoconstriction. The prevalences of asthmatic symptoms, physician-diagnosis,
      and medication use increased by an average of 4.4%, particularly in subjects aged
      <30 yrs (8.7 versus 2.7). Atopy prevalence increased from 25% to 31% but atopics
      and nonatopics had similar mean changes in questionnaire data (5.2 versus 3.4).
      The probability of a positive methacholine test decreased as did the mean
      methacholine dose/response slope (0.00527 to 0.00379), indicating lower levels of
      airway responsiveness. This can be largely explained by an increase in use of
      inhaled corticosteroids (5.0-9.3%). The proportion of subjects perceiving
      bronchoconstriction during methacholine tests increased from 63 to 77%. The
      authors conclude that current changes in asthma epidemiology in adults may result
      from increased awareness of symptoms (and/or an increased willingness to report
      them), and from an increased willingness of physicians to make the diagnosis and
      prescribe treatment, not from increased disease prevalence.

PMID- 12412672
TI  - Chlamydia pneumoniae immunoglobulin A reactivation and airway inflammation in
      acute asthma.
AB  - Infection with Chlamydia pneumoniae can trigger acute asthma and is associated
      with severe chronic asthma. The aim of the present study was to examine the
      relationship between airway inflammation and serological response to C.
      pneumoniae in acute severe asthma. Subjects (n=54) were recruited within 4 h of
      presentation to the emergency department with an acute exacerbation of asthma.
      Clinical history taking, sputum induction (0.9% saline), spirometry and acute and
      convalescent serology for C. pneumoniae immunoglobulins A and G were performed.
      At presentation, 47% of subjects had antibodies directed against C. pneumoniae,
      and 38% (20) demonstrated an increase in C. pneumoniae antibody levels, with 15
      demonstrating a rise in immunoglobulin A concentration. C. pneumoniae responders
      exhibited significantly higher sputum neutrophil levels (4.6 x 10(6) cells x mL(
      1)) compared to nonresponders (1.2 x 10(6) cells x mL(-1), p=0.02) and elevated
      sputum eosinophil cationic protein concentration (3,981 versus 1,122 ng x mL(-1),
      p=0.02). An acute antibody response to Chlamydia pneumoniae is common in
      exacerbations of asthma. The serological features suggest that Chlamydia
      pneumoniae reactivation may trigger neutrophilic airway inflammation in acute
      asthma.

PMID- 12412673
TI  - Increased alveolar nitric oxide concentration in asthmatic patients with
      nocturnal symptoms.
AB  - Nocturnal asthma symptoms and impaired lung function at night are related to
      inflammatory activity in the peripheral lung compartment. Exhaled nitric oxide
      (NO) measurement at multiple exhalation flow rates can be used to separately
      assess alveolar and bronchial NO production and inflammation. The authors
      hypothesised that asthmatic patients with nocturnal symptoms have a higher
      alveolar NO concentration than those with only daytime symptoms. The authors
      asked 40 patients with newly-diagnosed steroid-naive asthma about their nocturnal
      asthma symptoms through the use of a written questionnaire. Alveolar NO
      concentration and bronchial NO flux were assessed in the 40 asthmatics and 40
      healthy controls. Nineteen of the 40 patients reported nocturnal symptoms.
      Patients with nocturnal symptoms had a higher alveolar NO concentration (1.7+/
      0.3 (mean+/-SEM) parts per billion (ppb)) than patients without nocturnal
      symptoms (0.8+/-0.3 ppb, p=0.012) or healthy controls (1.0+/-0.1 ppb, p=0.032).
      Bronchial NO flux was higher both in patients with (2.4+/-0.4 nL x s(-1),
      p<0.001) and without (2.6+/-0.4 nL x s(-1), p<0.001) nocturnal symptoms, compared
      to controls (0.7+/-0.1 nL x s(-1)). Nocturnal symptoms in asthmatic patients are
      related to a higher alveolar nitric oxide concentration. The results suggest that
      assessment of alveolar nitric oxide concentration can be used to detect the
      parenchymal inflammation in asthmatic patients with nocturnal symptoms.

PMID- 12412674
TI  - Efficacy of acupuncture in asthma: systematic review and meta-analysis of
      published data from 11 randomised controlled trials.
AB  - Contradictory results from randomised controlled trials of acupuncture in asthma
      suggest both a beneficial and detrimental effect. The authors conducted a formal
      systematic review and meta-analysis of all randomised clinical trials in the
      published literature that have compared acupuncture at real and placebo points in
      asthma patients. The authors searched for trials published in the period 1970
      2000. Trials had to measure at least one of the following objective outcomes:
      peak expiratory flow rate, forced expiratory volume in one second (FEV1) and
      forced vital capacity. Estimates of the standarised mean difference, between
      acupuncture and placebo were computed for each trial and combined to estimate the
      overall effect. Hetereogeneity was investigated in terms of the characteristics
      of the individual studies. Twelve trials met the inclusion criteria but data from
      one could not be obtained. Individual patient data were available in only three.
      Standardised differences between means ranging from 0.071 to 0.133, in favour of
      acupuncture, were obtained. The overall effect was not conventionally significant
      and it corresponds to an approximate difference in FEV1 means of 1.7. After
      exploring hetereogenenity, it was found that studies where bronchoconstriction
      was induced during the experiment showed a conventionally significant effect.
      This meta-analysis did not find evidence of an effect of acupuncture in reducing
      asthma. However, the meta-analysis was limited by shortcomings of the individual
      trials, in terms of sample size, missing information, adjustment of baseline
      characteristics and a possible bias against acupuncture introduced by the use of
      placebo points that may not be completely inactive. There was a suggestion of
      preferential publication of trials in favour of acupuncture. There is an obvious
      need to conduct a full-scale randomised clinical trial addressing these
      limitations and the prognostic value of the aetiology of the disease.

PMID- 12412675
TI  - Montelukast versus fluticasone: effects on lung function, airway responsiveness
      and inflammation in moderate asthma.
AB  - Whether leukotriene receptor antagonists exhibit adequate anti-inflammatory
      effects in the treatment of asthma is still a controversial issue. The aim of the
      present study was to perform a direct comparison of the effects of a 4-week
      treatment with either montelukast (10 mg, once a day) or low-dose inhaled
      fluticasone (100 microg b.i.d.) on functional and inflammatory parameters in
      steroid-naive patients with moderate asthma. Forty patients (forced expiratory
      volume in one second (FEV1), 60-80% predicted) were studied in a double-blind,
      randomised, crossover design. Treatment periods were separated by 3-8 weeks of
      washout. At the beginning and end of each period, FEV1, airway responsiveness to
      inhaled methacholine (provocative concentration causing a 20% fall in FEV1
      (PC20)), the level of exhaled nitric oxide (NO) and sputum differential cell
      counts were determined. Only short-acting beta2-agonists were allowed for relief
      of symptoms. FEV1 increased by 0.50+/-0.07 L (mean+/-SEM) after fluticasone and
      by 0.37+/-0.07 L after montelukast (p<0.001, each), and PC20 by 1.33+/-0.13
      (p<0.001) and 0.15+/-0.17 (NS) doubling doses, respectively. Correspondingly,
      percentages of sputum eosinophils were reduced by factor 2.7 (p<0.01) and 1.4
      (nonsignificant (NS)), and the levels of exhaled NO (at 50 mL x s(-1)) by factor
      2.1 (p<0.01) and 1.1 (NS). These data indicate a comparable bronchodilator action
      of montelukast and fluticasone in patients with moderate asthma, but additional
      attenuation of airway inflammation by fluticasone as detectable through
      noninvasive methods.

PMID- 12412676
TI  - Safety of formoterol by Turbuhaler as reliever medication compared with
      terbutaline in moderate asthma.
AB  - The present study compared the safety of 4.5 microg formoterol with 0.5 mg
      terbutaline, both by Turbuhaler and used as needed, in addition to regular
      formoterol in moderate asthma. In this double-blind parallel-group study, 357
      patients taking a moderate-to-high dose of inhaled corticosteroids and additional
      terbutaline (2-5 inhalations x day(-1) during run-in) were randomised to either
      formoterol or terbutaline as needed in addition to formoterol 9 microg b.i.d.
      over 12 weeks. Adverse events, serum potassium levels, electrocardiogram, vital
      signs and lung function were assessed monthly; peak expiratory flow and severe
      asthma exacerbations were recorded daily. Patients used 2.16 (range 0.0-6.3)
      formoterol and 2.34 (range 0.1-7.5) terbutaline relief inhalations x day(-1). No
      clinically significant differences in safety variables were found between
      treatments. Statistically greater increases in cardiac frequency (2.6 beats x
      min(-1), p=0.03) were found on terbutaline. There were 44 and 52 severe asthma
      exacerbations with formoterol and terbutaline, respectively, with no significant
      difference in time to first exacerbation. There was also no difference between
      treatments for other efficacy measures (peak expiratory flow, forced expiratory
      volume in one second and morning/evening symptom scores). Formoterol 4.5 microg
      as needed was at least as safe, well tolerated and effective as terbutaline 0.5
      mg in stable patients (requiring up to 6 relief inhalations x day(-1)) taking
      formoterol plus inhaled corticosteroids regularly over 12 weeks.

PMID- 12412677
TI  - Sodium cromoglycate and doxantrazole are oxygen radical scavengers.
AB  - The effects of two mast cell stabilisers, sodium cromoglycate (SCG) and
      doxantrazole, on the formation of reactive oxygen species (ROS) were studied.
      Guinea-pig alveolar macrophages (AMs) generated lucigenin-dependent
      chemiluminescence (LDCL). This was increased when the cells were stimulated by
      phorbol myristate acetate (PMA) or zymosan (by 133% and 464%, respectively, in
      total LDCL over 60 min). SCG decreased PMA-induced LDCL at higher concentrations
      (10 mM, by 55%) than doxantrazole (1 mM, by 75%). SCG decreased radical
      production by AMs in response to zymosan in a concentration-dependent manner by <
      or = 72%. Doxantrazole (0.1-1 mM) diminished total LDCL by 30-80%. In addition,
      glucose oxidase led to LDCL generation when incubated with glucose in a cell-free
      medium. This was inhibited by 47-83% in the presence of SCG or doxantrazole. SCG
      and doxantrazole inhibited the hydrogen peroxide- and peroxynitrite-induced LDCL
      by < or = 92%. Moreover, these drugs slightly increased the survival rate of the
      AMs. It is concluded that doxantrazole- and sodium cromoglycate-inhibited
      lucigenin-dependent chemiluminescence production by guinea-pig alveolar
      macrophages is due to a direct scavenging effect on reactive oxygen species.
      Doxantrazole is approximately 10-times more potent. Mast cell stabilisers may be
      effective in allergic asthma not only by preventing the allergen-induced mediator
      release, but also by preventing radical-induced lung damage.

PMID- 12412678
TI  - Dose-related effect of inhaled fluticasone on allergen-induced airway changes in
      rats.
AB  - To examine whether fluticasone propionate (FP) dose-dependently inhibits
      inflammatory as well as structural changes, Brown Norway rats were sensitised to
      ovalbumin (OA) on day 0 and 7. From day 14-28, rats were exposed to aerosolised
      OA (1%) or phosphate buffered saline every 2 days. Thirty minutes before each
      allergen exposure, animals were pre-treated with aerosolised placebo or FP (0.1,
      1 or 10 mg) or prednisolone 3 mg x kg(-1) i.p. At day 29, 0.1 mg FP had no
      measurable effect, either on inflammatory or structural changes, such as goblet
      cell hyperplasia and airway wall thickening. The allergen-induced increase in
      eosinophilic inflammation in bronchoalveolar lavage fluid and in the airway
      mucosa, as well as increased fibronectin deposition, were inhibited by treatment
      with FP from a dose of 1 mg onwards. Inhibition of goblet cell hyperplasia and
      thickening of the airway wall required 10 mg inhaled FP. At this dose, systemic
      effects were observed. However, for a comparable degree of systemic activity,
      prednisolone was far less effective at preventing airway changes. The dose of
      inhaled fluticasone propionate required to inhibit allergen-induced structural
      alterations was higher than to prevent eosinophil influx, and caused systemic
      side-effects. However, for a similar systemic activity, prednisolone was
      ineffective in preventing airway remodelling.

PMID- 12412679
TI  - Age-related differences in perceived asthma control in childhood: guidelines and
      reality.
AB  - Current guidelines specify the goals of asthma treatment in children and propose
      a stepwise approach to achieve them. The authors sought to determine whether
      these goals were attained in children of different age groups in the community
      and to assess treatment in those with unsatisfactory asthma control. A cross
      sectional postal questionnaire survey was performed in 1998 in all members of the
      major Swiss parents organisation for childhood asthma. With a response rate of
      85%, data from 572 Swiss-German children aged 4-16 yrs with wheeze were analysed.
      Asthma control was excellent in 18% of the children, satisfactory (only episodic
      symptoms) in 33%, and unsatisfactory in 49% with disturbed sleep, restricted
      activities and school absences. When stratified by age, excellent or satisfactory
      control was attained by 66% of children aged 13-16 yrs, but only by 56%, 44%, and
      38% of those aged 10-12, 7-9 and 4-6 yrs, respectively. Although the majority
      were followed-up by a doctor (95%) and were receiving beta2-agonists (82%) and
      inhaled corticosteroids (68%), intensity and duration of treatment were not
      sufficiently matched to asthma severity. In virtually all children there was
      scope to improve medical treatment, preventive measures and knowledge of asthma
      management, with very few if any children with therapy-resistant asthma. Even in
      children with poor asthma control, 89% of parents were satisfied with the results
      of treatment. The goals of asthma treatment were attained in one-half of the
      children, particularly in younger age groups. Although inhaler use was common,
      detailed assessment showed evidence for undertreatment, especially in the
      youngest age group, and insufficient adherence to preventive measures. Parental
      expectations of asthma control, which were lower than those outlined in
      guidelines, might be an important but underestimated factor in paediatric asthma
      management.

PMID- 12412680
TI  - Respiratory symptoms, bronchitis and asthma in children of Central and Eastern
      Europe.
AB  - The multicentre Central European Study of Air Pollution and Respiratory Health
      (CESAR) aimed to measure the respiratory health of schoolchildren using a
      standardised questionnaire in six countries of Central and Eastern Europe (CEE),
      allowing comparisons within this region and with other European countries. A
      cross-sectional study was conducted in 25 urban areas of Bulgaria, Czech
      Republic, Hungary, Poland, Romania, and Slovakia in 1996. Parents of 21,743
      schoolchildren of age 7-11 yrs completed a questionnaire based on items from the
      World Health Organization and International Study of Asthma and Allergies in
      Childhood questions on cough and wheeze symptoms, as well as on diagnoses by
      doctors. Life-time prevalence of bronchitis was 55.9%, asthma 3.9%, and
      asthmatic, spastic or obstructive bronchitis 12.3%. In CEE countries the
      prevalence of bronchitis is higher and prevalence of asthma appears lower than in
      Western Europe. However, if asthma is defined as a diagnosis of either asthma or
      asthmatic, spastic or obstructive bronchitis, then its prevalence is comparable
      to Western Europe, or higher. In this region, within-country variation for most
      respiratory parameters is less than between-country variation. Between-country
      comparisons in doctors' diagnoses appear dependent on the choice of definition of
      asthma. Europe-wide comparisons in prevalence of respiratory symptoms and
      diagnosis are reported in this study. Some of the East-West difference in asthma
      prevalence may be attributable to differences in diagnostic practice.

PMID- 12412681
TI  - Short-term health effects of particulate and photochemical air pollution in
      asthmatic children.
AB  - In a previous panel study in Paris, France, detrimental effects of moderately
      high levels of winter air pollution on the symptoms and lung function of
      asthmatic children were demonstrated. A new study was conducted, with the aim of
      assessing the short-term effects of photo-oxidant and particulate air pollution
      on childhood asthma during spring and early summer in Paris. Eighty-two medically
      diagnosed asthmatic children were followed up for 3 months. Outcomes included the
      incidence and prevalence of asthma attacks, nocturnal cough, supplementary use of
      beta2-agonists, symptoms of airway irritation, and peak expiratory flow (PEF)
      value and its variability. The statistical methods controlled for the lack of
      independence between daily health outcomes, temporal trends and pollen and
      weather conditions. Black smoke and nitrogen dioxide (NO2) were associated with
      increases in the occurrence of nocturnal cough and respiratory infections. Ozone
      (O3) was associated with an increase in the occurrence of asthma attacks and
      respiratory infections and with changes in lung function, as shown by an increase
      in PEF variability and a decrease in PEF. Statistically significant interactions
      were demonstrated between O3 and temperature and between O3 and pollen count for
      asthma attacks. O3 levels had a greater effect on additional bronchodilator use
      and on irritations of the eyes, nose and throat on days on which no steroids were
      used. Particulate matter was associated with eye irritation only. This study
      showed that, although within international air quality standards, the prevailing
      levels of photo-oxidant and particulate pollution in spring and early summer had
      measurable short-term effects on children with mild-to-moderate asthma.

PMID- 12412682
TI  - Measurements of interrupter resistance: reference values for children 3-13 yrs of
      age.
AB  - The interrupter technique is a convenient and sensitive technique for studying
      airway function in subjects who cannot actively participate in (forced)
      ventilatory function tests. Reference values for preschool children exist but are
      lacking for children >7 yrs. Reference values were obtained for expiratory
      interrupter resistance (R(int,e)) in 208 healthy Dutch Caucasian children 3-13
      yrs of age. A curvilinear relationship between R(int,e) and height was observed,
      similar to published airways resistance data measured by plethysmography. No
      significant differences in cross-sectional trend or level of R(int,e) were
      observed according to sex. It was found that Z-scores could be used to express
      individual R(int,e) values and to describe intra- and interindividual differences
      based on the reference equation: 10logR(int,e)=0.645-0.00668x standing height
      (cm) kPa x L(-1) x s(-1) and residual SD (0.093 kPa x L(-1) x s(-1)). Expiratory
      interrupter resistance provides a tool for clinical and epidemiological
      assessment of airway function in a large age range.

PMID- 12412683
TI  - Measurement of lung volume and ventilation distribution with an ultrasonic flow
      meter in healthy infants.
AB  - Small airway disease in infants is characterised by abnormal lung volume and
      uneven ventilation distribution. An inert tracer gas washin/washout technique
      using a pulsed ultrasonic flow meter is presented to measure functional residual
      capacity (FRC) and ventilation distribution in spontaneously breathing and
      unsedated infants. With a pulsed ultrasound sent through the main stream of the
      flow meter, flow, volume and MM of the breathing gas can be calculated. Sulphur
      hexafluoride was used as a tracer gas. In a mechanical lung model (volume range
      53-188 mL) and in 12 healthy infants (aged 38.3+/-9.2 days; mean+/-SD) accuracy
      and reproducibility of the technique was assessed. Indices of ventilation
      distribution such as alveolar-based mean dilution number (AMDN) and pulmonary
      clearance delay (PCD) were calculated. Mean error of volume measurement in the
      lung model was 0.58% (coefficient of variance (CV) 1.3%). FRC was in the low
      predicted range for normal infants (18.0+/-2.0 mL x kg(-1)) and highly
      reproducible (5.5+/-1.7% intra-subject CV). AMDN was 1.63+/-0.15 and PCD was
      52.9+/-11.1%. Measurement of functional residual capacity and ventilation
      distribution using a sulphur hexafluoride washin/washout and an ultrasonic flow
      meter proved to be highly accurate and reproducible in a lung model and in
      healthy, spontaneously breathing and unsedated infants.

PMID- 12412684
TI  - Exhaled nitric oxide measurements with dynamic flow restriction in children aged
      4-8 yrs.
AB  - Fractional exhaled nitric oxide concentration (FENO) depends on exhalation flow;
      however, children often are unable to perform controlled flow procedures.
      Therefore, a device was developed for off-line FENO sampling, with dynamic flow
      restriction (DFR). The authors compared off-line with on-line FENO, assessed
      feasibility, and obtained normal values for FENO in children aged 4-8 yrs.
      Subjects inhaled nitric oxide (NO)-free air and exhaled into the device, where
      DFR kept exhalation flow constant at 50 mL x s(-1). Dead space air was discarded.
      Exhaled air was collected in a 150 mL mylar balloon. On-line measurements were
      performed and values compared with off-line FENO in 19 adult volunteers. Seventy
      nine children performed off-line sampling. All samples were analysed with a
      chemiluminescence NO-analyser. Normal values were obtained in 34 healthy
      children. There was an excellent correlation between on- and off-line values.
      Bland and Altman plots showed good agreement between on- and off-line FENO.
      Seventy-four out of 79 children were able to perform a correct off-line
      procedure. Geometric mean+/-SEM FENO in healthy children was 4.9+/-1.2 parts per
      billion (ppb) for male children and 7.6+/-1.1 ppb for female children. It can be
      concluded that off-line fraction of exhaled nitric oxide measurements with
      dynamic flow restriction are feasible in young children and correspond to on-line
      values.

PMID- 12412685
TI  - Different modes of assisted ventilation in patients with acute respiratory
      failure.
AB  - The aim of the present study was to verify that the patient/ventilator
      interaction is similar, regardless of the mode of assisted mechanical ventilation
      (i.e. pressure- or volume-limited) used, if tidal volume (VT) and peak
      inspiratory flow (PIF) are matched. Therefore, the authors compared the effects
      of three different modes of assisted ventilation on the work of breathing (WOB)
      and gas exchange in patients with acute respiratory failure. For Protocol 1, in
      seven patients, the authors compared pressure support, assist pressure control
      and assist control (with square and decelerating wave inspiratory flow pattern)
      set to deliver the same VT and PIF. For Protocol 2, in another 10 patients, the
      authors compared pressure support and assist control with high (0.8 L x s(-1))
      and low (0.6 L x s(-1)) PIFs set to deliver the same VT. In Protocol 1, there was
      no difference in WOB and gas exchange between the three modes of assisted
      ventilation tested. In Protocol 2, the decrease of PIFs during assist control
      significantly increased WOB. In conclusion, different modes of assisted
      ventilation similarly reduce work of breathing and provide adequate gas exchange
      at fixed tidal volume and peak inspiratory flow only. During assist control,
      tidal volume and peak inspiratory flow (set by the physician) are the main
      determinants of the patient/ventilator interaction.

PMID- 12412686
TI  - Assisted ventilation for heart failure patients with Cheyne-Stokes respiration.
AB  - Patients with chronic congestive cardiac failure (CCF) frequently suffer from
      central sleep apnoea syndrome (CSAS). Continuous positive airway pressure (CPAP)
      has been suggested as a treatment. The authors hypothesised that bilevel
      ventilation might be easier to initiate and superior to CPAP at correcting the
      sleep-related abnormality of breathing in patients with CCF. After excluding
      those with a history suggestive of obstructive sleep apnoea, 35 patients with CCF
      (left ventricular ejection fraction <35%) were screened with overnight oximetry
      and the diagnosis of CSAS was established with polysomnography in 18. Two 14-day
      cycles of CPAP (0.85 kPa (8.5 mbar)) or bilevel ventilation (0.85/0.3 kPa (8.5/3
      mbar)) in random order, were compared in a crossover study. Sixteen patients (13
      males), mean age 62.0+/-7.4 yrs completed the study. The pretreatment
      apnoea/hypopnoea index of 26.7+/-10.7 was significantly reduced by CPAP and
      bilevel ventilation to 7.7+/-5.6 and 6.5+/-6.6, respectively. The arousal index
      fell from 31.1+/-10.0 per hour of sleep to 15.7+/-5.4 and 16.4+/-6.9,
      respectively. Significant and equal improvements with CPAP and bilevel
      ventilation were found for sleep quality, daytime fatigue, circulation time and
      New York Heart Association class. The authors conclude that continuous positive
      airway pressure and bilevel ventilation equally and effectively improve Cheyne
      Stokes respiration in patients with congestive cardiac failure.

PMID- 12412687
TI  - An overnight comparison of two ventilators used in the treatment of chronic
      respiratory failure.
AB  - Differences between bilevel ventilators used for noninvasive intermittent
      positive pressure ventilation (NIPPV) have been demonstrated during bench
      testing. However, there are no clinical studies comparing these machines. The
      authors have previously shown that the Quantum pressure support ventilator and
      Sullivan variable positive airway pressure II ST differ in performance during
      bench testing. To examine the clinical significance of this, these two machines
      were compared in the overnight treatment of subjects with chronic respiratory
      failure. Ten clinically-stable subjects with thoracic scoliosis were recruited.
      The subjects were already established on NIPPV, but none were using either of the
      ventilators to be tested. After familiarisation, the patients used the two
      ventilators in random order on consecutive nights. Peripheral oxygen saturation
      and transcutaneous carbon dioxide tension (Pt,CO2) were measured continuously,
      and sleep was recorded using polysomnography. There were no significant
      differences in arterial oxygen saturation, Pt,CO2 or sleep duration and quality
      between the two nights. Despite previously illustrated variation in laboratory
      performance, no differences were seen between the two ventilators when comparing
      overnight gas exchange and sleep in vivo. Further study is required to evaluate
      the significance of the differences found during bench testing in the clinical
      setting.

PMID- 12412688
TI  - Ventilation-induced activation of the mitogen-activated protein kinase pathway.
AB  - Mechanical ventilation of patients can be a life-saving treatment, but also
      imposes additional stress on the lung. Mitogen-activated protein kinases (MAPK)
      represent a family of protein kinases that become phosphorylated and activated by
      many different forms of stress. Using Western blot analysis, the present study
      analysed the effects of high distending pressure ventilation on the activation of
      the MAPK extracellular signal-related kinases (ERK)-1/2, c-Jun amino-terminal
      kinases (JNK) and p38 kinase, and on the MAPK-activated transcription factors c
      Jun, ETS-like protein (Elk)-1 and activating transcription factor (ATF)-2. In
      adult rats, ventilation with high pressure (45/10 peak inspiratory
      pressure/positive end-expiratory pressure in cmH2O) for 30 or 60 min did not
      affect arterial oxygenation, but resulted in enhanced phosphorylation of ERK-1/2,
      JNK, c-Jun, Elk-1 and ATF-2 compared to normally ventilated (13/3) rats. The
      activation of ERK-1/2 and JNK was located to cells resembling alveolar type II
      cells. In addition, high pressure ventilation enhanced phosphorylation of the
      inhibitor of nuclear factor (NF)-kappaB and nuclear translocation of the
      transcription factor NF-kappaB. In isolated perfused mouse lungs, the MAPK/ERK
      kinase inhibitor U0126 prevented ventilation-induced activation of ERK-1/2 and
      Elk-1, but had no effect on ventilation-induced cytokine release. The present
      authors conclude that mechanical ventilation triggers specific signalling
      pathways, such as the mitogen-activated protein kinase and the nuclear factor
      kappaB pathways, which may contribute to pulmonary inflammation and
      proliferation.

PMID- 12412689
TI  - Methylene blue reduces pulmonary oedema and cyclo-oxygenase products in
      endotoxaemic sheep.
AB  - The authors recently demonstrated that methylene blue (MB), an inhibitor of the
      nitric oxide (NO) pathway, reduces the increments in pulmonary capillary
      pressure, lung lymph flow and protein clearance in endotoxaemic sheep. In the
      present study, the authors examined whether MB influences pulmonary haemodynamics
      and accumulation of extravascular lung water (EVLW) by mechanisms other than the
      NO pathway. Sixteen awake, chronically-instrumented sheep randomly received
      either an intravenous injection of MB 10 mg x kg(-1) or isotonic saline. Thirty
      minutes later, all sheep received an intravenous infusion of Escherichia coli
      endotoxin 1 microg x kg(-1) for 20 min and either an intravenous infusion of MB
      2.5 mg x kg(-1) x h(-1) or isotonic saline for 6 h. MB markedly attenuated the
      endotoxin-induced pulmonary hypertension and right ventricular failure, and
      reduced the accumulation of EVLW. Moreover, MB reduced the increments in plasma
      thromboxane B2 and 6-keto-prostaglandin F1alpha, and abolished the febrile
      response. However, MB had no effect on the changes in circulating neutrophils,
      serum hyaluronan, and total haemolytic activity of the alternative complement
      pathway. The authors conclude that in sheep, methylene blue attenuates the
      endotoxin-induced pulmonary hypertension and oedema, at least in part, by
      inhibiting the cyclo-oxygenase products of arachidonic acid. This is a novel
      effect of methylene blue in vivo.

PMID- 12412690
TI  - The effect of hypertonic saline dextran solutions on hypoxic pulmonary
      vasoconstriction in anaesthetised piglets.
AB  - Hypoxic pulmonary vasoconstriction (HPV) is a regulatory mechanism by which blood
      is diverted from poorly ventilated to better ventilated areas of the lung. The
      aim of the present study was to assess the extent to which hypertonic saline
      dextran and dextran solutions modify the magnitude of HPV during isovolumic
      haemodilution in intact acutely instrumented piglets. Eighteen large white
      piglets were anesthetised and assigned to two groups. Mean pulmonary arterial
      pressure (PAP) and cardiac output (Q), systemic arterial pressure and left
      arterial pressure (LAP) were measured. A decrease in Q was obtained by reducing
      venous return. This enabled measurement of transpulmonary pressures (mean PAP
      minus LAP) at four levels of Q in hyperoxia (inspiratory oxygen fraction
      (FiO2)=0.4) then in hypoxia (Fi,O2=0.1) in the two groups before blood
      soustraction (10 mL x kg(-1)) and after loading with sodium chloride (NaCl) 7.5%
      and dextran 6% or with dextran 6% alone. Dextran alone led to a decrease in mean
      PAP-LAP/Q values, and NaCl with dextran was associated with a significant shift
      of mean PAP-LAP/Q plots to higher pressures in hypoxia. Hypertonic saline dextran
      solution, as replacement fluid in isovolaemic haemodilution increased the
      magnitude of hypoxic pulmonary vasoconstriction, whereas dextran solution reduced
      it.

PMID- 12412691
TI  - Endobronchial ultrasound-guided transbronchial lung biopsy in solitary pulmonary
      nodules and peripheral lesions.
AB  - Transbronchial biopsy (TBBX) for peripheral lung lesions is usually performed
      with the help of fluoroscopy, but the yield varies widely. This feasibility study
      aimed to assess the ability of endobronchial ultrasound (EBUS) to provide imaging
      guidance for TBBX. In a prospective study, 50 consecutive patients referred for
      TBBX for peripheral lesions underwent fluoroscopy-guided and EBUS-guided TBBX in
      random order. Diagnostic yields were compared for both modalities and feasibility
      was assessed for EBUS. Diagnostic material was obtained in 80% of patients with
      EBUS and 76% of patients with fluoroscopy. There was a nonsignificant trend for
      EBUS to be better than fluoroscopy for lesions <3 cm in diameter. Four lesions
      could not be visualised with EBUS. There were no significant complications
      associated with the use of EBUS. Endobronchial ultrasound-guided transbronchial
      biopsy is feasible. It appears to be at least equivalent to fluoroscopy without
      the accompanying radiation exposure. Further large-scale studies are indicated to
      assess the possible role of endobronchial ultrasound as a potential imaging
      method of choice for the biopsy of peripheral lung lesions.

PMID- 12412692
TI  - The role of EGF-R expression on patient survival in lung cancer: a systematic
      review with meta-analysis.
AB  - The prognostic value of epidermal growth factor receptor (EGF-R) for survival of
      patients with lung cancer remains controversial. The authors performed a
      systematic review of the literature in order to clarify its impact. Published
      studies were identified using an electronic search in order to aggregate the
      available survival results, after a methodological assessment using a scale
      specifically designed by the European Lung Cancer Working Party (ELCWP). To be
      eligible, a study had to have dealt with EGF-R assessment in lung cancer patients
      on the primary site and to have analysed survival according to EGF-R expression.
      Among the 16 eligible studies, 14 assessed any nonsmall-cell lung cancer (NSCLC)
      subtype, one adenocarcinoma only and one squamous-cell carcinoma only. The
      overall median quality score was 56.3%, with no significant difference either
      between studies assessable or not assessable for meta-analysis or between studies
      with significant and nonsignificant results. One individual trial reported a
      survival benefit for patients with EGF-R expression, three a survival
      disadvantage and 12 no statistically significant difference. Eleven studies
      (2,185 patients) provided sufficient data to allow a meta-analysis of the
      survival results. EGF-R expression positivity was determined according to the cut
      off as determined by the authors. The meta-analysis showed that EGF-R expression
      was not a statistically significant prognostic factor for survival in NSCLC. In
      the subgroup of studies using immunohistochemistry, statistical tests reached a
      significant level against EGF-R. Epidermal growth factor receptor might be a poor
      prognostic factor for survival in nonsmall-cell lung cancer. The amplitude of the
      impact is small, however, and may be subject to publication bias.

PMID- 12412693
TI  - Meta-analysis of diagnostic procedures for Pneumocystis carinii pneumonia in HIV
      1-infected patients.
AB  - Sputum induction is a simple and noninvasive procedure for Pneumocystis carinii
      pneumonia (PCP) diagnosis in human immunodeficiency virus-1-positive patients,
      although less sensitive than bronchoalveolar lavage (BAL). In order to obtain an
      overview of the diagnostic accuracy of sputum induction, a systematic review and
      meta-analysis of studies reporting the comparative sensitivity and specificity of
      BAL (the "gold standard") and sputum induction was performed. The odds ratio and
      related 95% confidence interval were calculated using summary receiving operating
      characteristic curves as well as fixed-effect and random-effect models. Based on
      pooled data, the negative and positive predictive values were calculated for a
      range of PCP prevalence using a Bayesian approach. Seven prospective studies
      assessed the comparative accuracy of BAL and sputum induction. On the whole,
      sputum induction demonstrated 55.5% sensitivity and 98.6% specificity. The
      sensitivity of sputum induction was significantly higher with immunofluorescence
      than with cytochemical staining (67.1 versus 43.1%). In settings of 25-60%
      prevalence of PCP, the positive and negative predictive values ranged 86-96.7 and
      66.2-89.8, respectively, with immunofluorescence, and 79-94.4 and 53-83.5% with
      cytochemical staining. In conclusion, in a setting of low prevalence of
      Pneumocystis carinii pneumonia, sputum induction, particularly with
      immunostaining, appears to be adequate for clinical decision-making.

PMID- 12412694
TI  - Systemic cytokine levels in community-acquired pneumonia and their association
      with disease severity.
AB  - Pro-inflammatory and anti-inflammatory cytokines are important mediators in the
      host response to infection. In contrast to the pro-inflammatory cytokines little
      is known about anti-inflammatory cytokines in community-acquired pneumonia (CAP)
      and their relation to disease severity. Circulating levels of three pro
      inflammatory cytokines (interleukin (IL)-1beta, IL-6 and tumour necrosis factor
      (TNF)-alpha) and two anti-inflammatory cytokines (IL-10, IL-1 receptor antagonist
      (IL-1ra)) were measured using an enzyme immunoassay on admission, day 3 and day 5
      in 24 patients with CAP. The modified British Thoracic Society (BTS) prognostic
      rule and Acute Physiology and Chronic Health Evaluation (APACHE) II score were
      used to assess disease severity. IL-6, TNF-alpha, IL-10 and IL-1ra concentrations
      were detected in most patients on admission and decreased significantly on day 3
      and day 5 in all survivors. A significant difference between the BTS high-risk
      and low-risk groups was only found for IL-6 (median (range) 477 pg x mL(-1) (7.6
      1402 pg x mL(-1)) versus 81.6 pg x mL(-1) (0-943 pg x mL(-1)); p<0.05). IL-6 also
      correlated with the APACHE II scores on admission. Concentrations of anti
      inflammatory cytokines were elevated on admission in community-acquired pneumonia
      but they did not correlate with disease severity scores.

PMID- 12412695
TI  - Effect of pattern and severity of respiratory muscle weakness on carbon monoxide
      gas transfer and lung volumes.
AB  - In clinical practice, an elevated carbon monoxide (CO) transfer coefficient (KCO)
      and restrictive ventilatory defect are taken as features of respiratory muscle
      weakness (RMW). However, the authors hypothesised that both pattern and severity
      of RMW effect gas transfer and lung volumes. Measurements of CO transfer and lung
      volumes were performed in patients with isolated diaphragm weakness (n=10),
      inspiratory muscle weakness (n=12), combined inspiratory and expiratory muscle
      weakness (n=5) and healthy controls (n=6). Patients with diaphragm weakness and
      inspiratory muscle weakness had reduced total lung capacity (TLC) (83.6%
      predicted and 68.9% pred, respectively), functional residual capacity (FRC)
      (83.9% pred and 83.6% pred) and transfer factor of the lung for CO (TL,CO) (86.2%
      pred and 66.2% pred) with increased KCO (114.1% pred and 130.2% pred). Patients
      with combined inspiratory and expiratory muscle weakness had reduced TLC (80.9%
      pred) but increased FRC (109.9% pred) and RV (157.4% pred) with decreased TL,CO
      (58.0% pred) and KCO (85.5% pred). In patients with diaphragm weakness, the
      increase in carbon monoxide transfer coefficient was similar to that of normal
      subjects when alveolar volume was reduced. However, the increase in carbon
      monoxide transfer coefficient in inspiratory muscle weakness was often less than
      expected, while in combined inspiratory and expiratory muscle weakness, the
      carbon monoxide transfer coefficient was normal/reduced despite further
      reductions in alveolar volume, which may indicate subtle abnormalities of the
      lung parenchyma or pulmonary vasculature. Thus, this study demonstrates the
      limitations of using carbon monoxide transfer coefficient in the diagnosis of
      respiratory muscle weakness, particularly if no account is taken of the alveolar
      volume at which the carbon monoxide transfer coefficient is made.

PMID- 12412697
TI  - Automatic regulation of the cuff pressure in endotracheally-intubated patients.
AB  - To avoid tracheal wall damage or inadvertent falls of the endotracheal tube cuff
      pressure (Pcuff) in intubated and mechanically-ventilated patients, the authors
      devised a simple procedure for automatic and continuous regulation of Pcuff. The
      procedure, only requiring a simple aquarium air pump and conventional tubing, was
      first tested at the bench when applied to an intubated and ventilated lung model,
      including an artificial trachea with an externally-variable section. The clinical
      performance of the procedure was tested in eight intubated patients, in whom the
      endotracheal tube cuff was connected to the designed Pcuff regulator during 24 h.
      The bench test showed that the procedure was able to maintain Pcuff constant,
      regardless of the changes imposed in the tracheal section. It was also effective
      in maintaining Pcuff during routine mechanical ventilation. Actual Pcuff recorded
      over the 24-h period always coincided with the target value within +/-2 cmH2O in
      all the patients. The procedure devised to maintain endotracheal tube cuff
      pressure is readily implemented, cheap, easy to operate and can be used
      regardless of the specific ventilator or tube used. Routine implementation of
      this procedure may be useful for protecting the trachea from tissue damage and
      for reducing the risk of ventilator-associated pneumonia.

PMID- 12412696
TI  - Talcage by medical thoracoscopy for primary spontaneous pneumothorax is more cost
      effective than drainage: a randomised study.
AB  - Simple thoracoscopic talcage (TT) is a safe and effective treatment of primary
      spontaneous pneumothorax (PSP). However, its efficacy has not previously been
      estimated in comparison with standard conservative therapy (pleural drainage
      (PD)). In this prospective randomised comparison of two well-established
      procedures of treating PSP requiring at least a chest tube, cost-effectiveness,
      safety and pain control was evaluated in 108 patients with PSP (61 TT and 47 PD).
      Patients in both groups had comparable clinical characteristics. Drainage and
      hospitalisation duration were similar in TT and PD patients. There were no
      complications in either group. The immediate success rate was different: after
      prolonged drainage (>7 days), 10 out of 47 PD patients, but only 1 out of 61 TT
      patients required a TT as a second procedure. Total costs of hospitalisation
      including any treatment procedure were not significantly different between TT and
      PD patients. Pain, measured daily by visual analogue scales, was statistically
      higher during the first 3 days in TT patients but not in those patients receiving
      opiates. One month after leaving hospital, there was no significant difference in
      residual pain or full working ability: 20 out of 58 (34%) versus 10 out of 47
      (21%) and 36 out of 61 (59%) versus 26 out of 39 (67%) in TT versus PD groups,
      respectively. After 5 yrs of follow-up, there had been only three out of 59 (5%)
      recurrences of pneumothorax after TT, but 16 out of 47 (34%) after conservative
      treatment by PD. Cost calculation favoured TT pleurodesis especially with regard
      to recurrences. In conclusion, thoracoscopic talc pleurodesis under local
      anaesthesia is superior to conservative treatment by chest tube drainage in cases
      of primary spontaneous pneumothorax that fail simple aspiration, provided there
      is efficient control of pain by opioids.

PMID- 12412698
TI  - Histopathological studies on the effects of peroxynitrite on the lungs and
      trachea of rabbits.
AB  - Peroxynitrite (ONOO-) is the reaction product between nitric oxide and the
      superoxide anion. It is a biological oxidant and cytotoxic anion, produced in
      vivo, which might cause inflammation and damage to the lungs. This study was
      designed to investigate whether direct contact with peroxynitrite could cause
      pathological changes in the airways. Twenty New Zealand rabbits were divided into
      four experimental groups. They were anesthetised by intravascular injection of
      thiopental sodium, and peroxynitrite (0.5 mL of a 10 mM solution) was inoculated
      intratracheally. At 2 h, 24 h, 48 h, and 72 h postinoculation trachea and lungs
      were isolated for histopathology. The histopathological observations in the lungs
      were congestion, serous exudation, infiltration of leukocytes and degeneration,
      which were found to be time-dependent. Changes were similar at 48 and 72 h.
      Degenerative changes were not progressive. The changes in the trachea were
      congestion, oedema, leukocyte infiltration, and degeneration of tracheal
      epithelium. This study shows that peroxynitrite formation in the respiratory
      tract induces lung inflammation and degenerative changes.

PMID- 12412699
TI  - Prone position in acute respiratory distress syndrome.
AB  - In the last few years prone positioning has been used increasingly in the
      treatment of patients with acute respiratory distress syndrome (ARDS) and this
      manoeuvre is now considered a simple and safe method to improve oxygenation.
      However, the physiological mechanisms causing respiratory function improvement as
      well as the real clinical benefit are not yet fully understood. The aim of this
      review is to discuss the physiological and clinical effects of prone positioning
      in patients with ARDS. The main physiological aims of prone positioning are: 1)
      to improve oxygenation; 2) to improve respiratory mechanics; 3) to homogenise the
      pleural pressure gradient, the alveolar inflation and the ventilation
      distribution; 4) to increase lung volume and reduce the amount of atelectatic
      regions; 5) to facilitate the drainage of secretions; and 6) to reduce ventilator
      associated lung injury. According to the available data, the authors conclude
      that: 1) oxygenation improves in approximately 70-80% of patients with early
      acute respiratory distress syndrome; 2) the beneficial effects of oxygenation
      reduce after 1 week of mechanical ventilation; 3) the aetiology of acute
      respiratory distress syndrome may markedly affect the response to prone
      positioning; 4) extreme care is necessary when the manoeuvre is performed; 5)
      pressure sores are frequent and related to the number of pronations; 6) the
      supports used to prone and during positioning are different and nonstandardised
      among centres; and 7) intensive care unit and hospital stay and mortality still
      remain high despite prone positioning.

PMID- 12412700
TI  - Equipment needs for noninvasive mechanical ventilation.
AB  - Noninvasive mechanical ventilation (NIV) has a long tradition for the treatment
      of chronic respiratory failure and more recently has also been applied in acute
      respiratory failure. Based on this experience both critical care ventilators and
      portable ventilators are used to perform NIV. The individual choice of ventilator
      type should depend on the patient's condition and also on the expertise of
      attending staff, therapeutic requirements and the location of care. The majority
      of studies have used pressure-targeted ventilation in the assist mode. Positive
      qualities of pressure support ventilation (PSV) are leak compensation, good
      patient/ventilator synchrony and the option of integrated positive end-expiratory
      pressure to counteract the effect of dynamic hyperinflation. In this article,
      some crucial issues concerning PSV (i.e. triggering into inspiration,
      pressurisation, cycling into expiration and carbon dioxide rebreathing) and some
      corrective measures are discussed. The parameters which should be monitored
      during noninvasive ventilation are presented. The interface between patient and
      ventilator is a crucial issue of noninvasive ventilation. Advantages and
      disadvantages of face and nasal masks are discussed. Finally, causes and possible
      remedies of significant air leaks and some technical accessories for noninvasive
      ventilation are dealt with.

PMID- 12412701
TI  - The new clinical trials on pharmacological treatment in pulmonary arterial
      hypertension.
AB  - Past medical therapy for pulmonary arterial hypertension included the use of
      calcium-channel antagonists in acute vasoreactive subjects and oral
      anticoagulants and continuous intravenous administration of epoprostenol in the
      more severe cases. Recently, the thromboxane inhibitor terbogrel, the
      prostacyclin analogues treprostinil, beraprost and iloprost, and the endothelin
      receptor antagonist bosentan have been tested in clinical trials in >1,100
      patients. Except for terbogrel, all compounds improved the mean exercise capacity
      by different degrees, as assessed by the 6-min walk test. In the evaluation of
      the clinical relevance of exercise capacity improvements, additional elements
      need to be considered, such as baseline functional class and concomitant
      favourable effects on combined clinical events (including hospitalisations,
      mortality and rescue therapies), quality of life and haemodynamics. No trials
      have shown effects on mortality, as the study protocols were not designed for
      assessing this end-point. Each new compound presents side-effects that are
      unpredictable in the individual patient and require appropriate attention upon
      treatment initiation and maintenance. These new therapeutic options will be
      available in the near future and will allow tailoring of the most appropriate
      treatment to the single patient, according to an individualised benefit-to-risk
      ratio.

PMID- 12412702
TI  - Alpha1-antitrypsin deficiency: a report from the 2nd meeting of the Alpha One
      International Registry, Rapallo (Genoa, Italy), 2001.
AB  - The Alpha One International Registry is a scientific foundation established to
      comply with a World Health Organization recommendation to develop a multinational
      registry of alpha1-antitrypsin deficiency, with the aim of creating a common
      database of subjects recognised in a standardised way. A commitment of the Alpha
      One International Registry members, belonging to 15 national registries, is to
      meet every 2 yrs in an open scientific conference to provide a scientific and
      clinical update on the deficiency. The second Alpha One International Registry
      meeting was held in Rapallo (Genoa, Italy) on September 27th-28th, 2001, and 26
      speakers provided an exhaustive overview of all aspects of alpha1-antitrypsin
      deficiency, including epidemiology, genetics, biochemistry, associated
      conditions, established and novel therapeutic options, and markers of efficacy.
      In the framework of a rare and often under-recognised condition, this meeting is
      likely to be central to improving understanding and increasing awareness of
      alpha1-antitrypsin deficiency.

PMID- 12412703
TI  - Broncholithiasis and lithoptysis associated with silicosis.
AB  - A case of broncholithiasis associated with massive silicosis is reported, showing
      a rare aspect of parenchymal lesions generating broncholiths as well as the
      presence of recurrent lithoptysis, with subsequent regression of radiological
      lesions. Aetiological, clinical, physiopathological, and radiological aspects of
      the disease are discussed, demonstrating the importance of the use of computed
      tomography in diagnosis. The mineralogical analysis of expectorated fragments is
      also shown.

PMID- 12412704
TI  - An African male with cough, haemoptysis, weight loss and hypercalcaemia: TB or
      not TB?

PMID- 12412705
TI  - Questions with inconclusive answers.

PMID- 12412706
TI  - Regular follow-up for patients irradiated for early stage nonsmall-cell lung
      cancer too!

PMID- 12412707
TI  - Abdominal aortic aneurysmorrhaphy and cholelithiasis in the era of endovascular
      surgery.
AB  - The incidence of acute cholecystitis complicating standard abdominal aortic
      aneurysm (AAA) repair has been reported between 0.3 and 18 per cent. This has
      prompted considerable debate regarding the management of cholelithiasis
      discovered incidentally during open aortic reconstruction. This study seeks to
      determine the incidence of cholelithiasis and acute cholecystitis after
      endovascular AAA repair and evaluate options for management. Between February
      1996 and October 2001 492 patients underwent endovascular AAA repair. All the
      procedures were performed in the operating room under fluoroscopic guidance.
      Epidural (98.9%), local (0.5%), or general (1.7%) anesthesia was used during
      these cases. The incidence of cholelithiasis and acute cholecystitis was
      evaluated by CT scan and abdominal ultrasound. Serum measurements of alanine
      aminotransferase, aspartate aminotransferase, alkaline phosphatase, total and
      direct bilirubin, and amylase were performed and clinical assessment was
      conducted at 1, 6, and 12 months postoperatively and annually thereafter. The
      mean age of these patients was 76.6 years; 84% were male. Comorbid medical
      conditions were present in all patients (average 3.5 conditions/patient). Follow
      up ranged from 2 to 35 months (mean 12.8 months). Endovascular stent graft
      deployment was successful in 486 of the 492 patients (98.8%). Six patients were
      converted to standard open repair because of inability to achieve successful
      endovascular aneurysm repair. The perioperative major morbidity rate was 14.9 per
      cent. Minor morbidity rate was 8.5 per cent. The perioperative mortality rate was
      1.9 per cent. No deaths were related to biliary disease. Cholelithiasis was
      identified in 64 (13%) patients preoperatively. One of 64 patients with a prior
      Billroth II reconstruction for peptic ulcer disease developed jaundice 8 days
      after AAA repair as a result of choledocholithiasis that required surgical
      repair. One patient without gallstones developed acute acalculous cholecystitis
      on postoperative day 16 as determined on pathologic analysis of the gallbladder.
      A third patient who had gallstones identified on preoperative CT scan developed
      calculous cholecystitis 16 months after endovascular AAA repair. These two
      patients underwent uncomplicated laparoscopic cholecystectomy and recovered
      uneventfully. The incidence of postoperative symptomatic cholelithiasis is 1.6
      per cent (one of 64). The incidence of postoperative acute cholecystitis was 0.2
      per cent (one of 486) and was unrelated to the presence of gallstones. The
      incidence of delayed symptomatic cholelithiasis was 1.6 per cent (one of 64).
      Endovascular repair of AAA does not appear to predispose the patient to the
      development of symptomatic cholelithiasis during the perioperative period.
      Therefore a preoperative or intraoperative diagnosis of cholelithiasis does not
      necessitate cholecystectomy in the setting of planned endovascular AAA repair.
      Patients who develop cholecystitis after endovascular AAA repair may be
      effectively treated by standard laparoscopic techniques.

PMID- 12412708
TI  - Acute respiratory distress syndrome in blunt trauma: identification of
      independent risk factors.
AB  - Acute respiratory distress syndrome (ARDS) is a major contributor to morbidity
      and mortality in trauma patients. Although many injuries and conditions are
      believed to be associated with ARDS independent risk factors in trauma patients
      and their relative importance in development of the syndrome are undefined. The
      aim of this project is to identify independent risk factors for the development
      of ARDS in blunt trauma patients and to examine the contributions of each factor
      to ARDS development. Patients with ARDS were identified from the registry of a
      Level I trauma center over a 4.5-year period. Records were reviewed for
      demographics, injury characteristics, transfusion requirements, and hospital
      course. Variables examined included age >65 years, Injury Severity Score (ISS)
      >25, hypotension on admission (systolic blood pressure <90), significant
      metabolic acidosis (base deficit <-5.0), severe brain injury as shown by a
      Glasgow Coma Scale score (GCS) <8 on admission, 24-hour transfusion requirement
      >10 units packed red blood cells, pulmonary contusion (PC), femur fracture, and
      major infection (pneumonia, empyema, or intra-abdominal abscess). Both univariate
      and stepwise logistic regression were used to identify independent risk factors,
      and receiver operating characteristic curve (ROC) analysis was used to determine
      the relative contribution of each risk factor. A total of 4397 patients having
      sustained blunt trauma were admitted to the intensive care unit and survived >24
      hours between October 1995 and May 2000. Of these patients 200 (4.5%) developed
      ARDS. All studied variables were significantly associated with ARDS in univariate
      analyses. Stepwise logistic regression, however, demonstrated age >65 years, ISS
      >25, hypotension on admission, 24-hour transfusion requirement >10 units, and
      pulmonary contusion as independent risk factors, whereas admission metabolic
      acidosis, femur fracture, infection, and severe brain injury were not. Using a
      model based on the logistic regression equation derived yields better than 80 per
      cent discrimination in ARDS patients. The risk factors providing the greatest
      contribution to ARDS development were ISS >25 (ROC area 0.72) and PC (ROC area
      0.68) followed by large transfusion requirement (ROC area 0.56), admission
      hypotension (ROC area 0.57), and age >65 (ROC area 0.54). Independent risk
      factors for ARDS in blunt trauma include ISS >25, PC, age >65 years, hypotension
      on admission, and 24-hour transfusion requirement >10 units but not admission
      metabolic acidosis, femur fracture, infection, or severe brain injury. Assessment
      of these variables allows accurate estimate of risk in the majority of cases, and
      the most potent contributors to the predictive value of the model are ISS >25 and
      PC. Improvement in understanding of which patients are actually at risk may allow
      for advances in treatment as well as prevention in the future.

PMID- 12412709
TI  - High-frequency percussive ventilation as a salvage modality in adult respiratory
      distress syndrome: a preliminary study.
AB  - Despite multiple advances in critical care patients with severe adult respiratory
      distress syndrome (ARDS) can exhaust the capability of conventional ventilation;
      this results in respiratory failure and death. High-frequency percussive
      ventilation (HFPV), which was initially utilized for salvage of burn patients
      with smoke inhalation injury refractory to conventional ventilation, has evolved
      as a standard of burn care. Based on our experience with HFPV in burn patients
      the burn team was consulted to provide salvage ventilation for non-burn surgical
      intensive care unit patients with refractory respiratory failure. Over a 14-month
      period ten patients with refractory ARDS from multiple causes were treated.
      Retrospective chart review was performed. Respiratory parameters were assessed
      before and 24 hours after initiation of HFPV. Mean values of fraction of inspired
      oxygen (FiO2), pH, partial pressure of O2 in arterial blood (PaO2), partial
      pressure of CO2 in arterial blood (PaCO2), HCO3, oxygen saturation in arterial
      blood (SaO2), PaO2/FiO2, and peak inspiratory pressure were compared. Significant
      improvement in oxygenation was reflected by increases in SaO2, PaO2, and the
      PaO2/FiO2 ratio in the first 24 hours of HFPV. No significant increase in peak
      inspiratory pressure was documented by conversion from conventional ventilation
      to HFPV. No hemodynamic changes directly associated with HFPV were noted. Seven
      of ten patients failing conventional ventilation survived to hospital discharge
      after salvage therapy with HFPV. We advocate further studies of HFPV in non-burn
      patients with ARDS both as salvage therapy and as replacement for conventional
      ventilation for the initial treatment for ARDS.

PMID- 12412710
TI  - Transplantation of pediatric en bloc cadaver kidneys into adult recipients: a
      single-center experience.
AB  - Faced with an extreme shortage of organs transplant professionals continue to
      explore various strategies to expand the donor pool. Transplantation of kidneys
      from older and very young donors are two such options. Although kidneys from
      young donors (less than 5 years of age) have been associated with a high rate of
      technical complications and suboptimal results, use of these kidneys en bloc has
      been advocated to improve the outcomes. We reviewed our experience with en bloc
      kidney transplantation at the University of Kentucky over the past 10 years.
      Between 1991 and 2000 ten patients underwent kidney transplantation using kidneys
      en bloc from donors <5 years age. The mean age of the donors was 2.8 years with a
      mean weight of 16 kg (range 13-21). Mean age of the recipients was 42 years. One
      patient lost the graft on day one from venous thrombosis. One patient lost the
      graft 7 years post-transplant from chronic rejection. All of the remaining
      patients are doing well with functioning grafts (mean follow-up 4.5 years; range
      6 months to 10 years). Both one-year and five-year graft survival rates are 89
      per cent. The present study confirms that excellent results can be achieved with
      kidney transplantation using kidney transplantation using kidneys en bloc from
      donors younger than 5 years of age.

PMID- 12412711
TI  - In vitro immunomodulatory effects of herbal products.
AB  - Immunosuppressive drugs have been developed from natural products such as soil
      and fungi, which are also the sources of some commonly used herbal products.
      However, the effect of herbal products on immune response has not been
      investigated. Because these products can affect the host immune system they can
      induce either rejection or tolerance after a transplant procedure. To investigate
      the effects of ten commonly used herbal products on transplant-related immune
      function we performed in vitro lymphocyte proliferation tests using
      phytohemagglutinin, mixed lymphocyte culture (MLC) assay, and interleukin (IL)-2
      and IL-10 production from MLC. Dong quai, ginseng, and milk thistle had
      nonspecific immunostimulatory effects on lymphocyte proliferation, whereas ginger
      and green tea had immunosuppressive effects. Dong quai and milk thistle increased
      alloresponsiveness in MLC, whereas ginger and tea decreased these responses. The
      immunostimulatory effects of dong quai and milk thistle were consistently seen in
      both cell-mediated immune response and nonspecific lymphoproliferation, whereas
      that of ginseng was not. The immunosuppressive effect of green tea and ginger
      were mediated through a decrease in IL-2 production, but the immunostimulatory
      effects of dong quai and milk thistle were not. We conclude that green tea, dong
      quai, ginseng, milk thistle, and ginger have effects on in vitro immune assays
      that may be relevant in transplantation in humans.

PMID- 12412712
TI  - The regained referral ground and clinical practice of vena cava filter placement
      in vascular surgery.
AB  - Interventional radiologist rather than vascular surgeons have become the
      predominant clinicians placing inferior vena cava (IVC) filters since the
      percutaneous device was introduced more than a decade ago. We conducted a
      retrospective analysis of 592 patients treated at a single institution between
      1987 and 2000 to determine the indications, referral pattern, and clinical
      outcome of IVC filter placement between the radiologist and surgeon groups.
      Before 1989 all filters were placed by surgeons in the operating room. The
      adoption of the percutaneous delivery method by radiologists in 1989 led to a
      dramatic increase in its practice volume accounting for 99 per cent of all
      filters placed from 1991 to 1993 (P < 0.001). The development of an endovascular
      program by the vascular surgeons in 1994 led to a steady increase in its IVC
      filter practice annually (P < 0.05) and accounted for 42 per cent of all filter
      placements in 2000. A distinct referral pattern also emerged as 74 per cent of
      all filter placements by surgeons were referred by surgical services. The
      proportion of filter placement for strict indications remained constant over time
      between the two groups (P = 0.86). The complications and survival rates were not
      significantly different between the two groups (P = 0.24). Percutaneous devices
      have dramatically increased the clinical volume of IVC filter placement by
      interventional radiologists. Vascular surgeons with endovascular interest are
      well suited to perform the procedure and can regain referral ground of IVC filter
      placement.

PMID- 12412713
TI  - Colorectal cancer in patients younger than 40 years of age.
AB  - Previous studies have suggested a poor outcome for patients presenting with
      colorectal cancer under the age of 40 years. This study was conducted to evaluate
      the outcomes of these patients during a 10-year period at the Medical Center of
      Louisiana in New Orleans. A retrospective study was designed to review all
      patients under the age of 40 with a diagnosis of colorectal cancer from January
      1990 to December 2000. There were 664 patients presenting with colorectal cancer
      during the 10-year period; of these 24 presented for surgery under the age of 40.
      There were 17 male and seven female patients. The median age was 35 years (range
      22-39). Eleven (44%) patients had a positive family history of colorectal cancer.
      Seven lesions were right sided, one transverse, eight left sided, and eight
      rectal. Histologically 20 lesions were typical adenocarcinomas and four were
      mucinous. Twelve were stage IV, six stage III, five stage II, and one stage I.
      Twenty-one patients underwent resection, six with stoma formation; three patients
      had stoma formation only for a total of nine stomas (38%). The mean operative
      duration was 3.3 +/- 1.9 hours. The operative mortality was 4 per cent with a
      complication rate of 17 per cent. The eight rectal cancer patients received
      preoperative chemoradiation therapy (33%). Twelve (50%) patients with colon
      cancer received postoperative 5-fluorouracil-based chemotherapy. The mean
      survival for all patients was 24.7 +/- 23.2 months. Estimated 5-year survival
      using Kaplan-Meier analysis was 30 per cent. We conclude that colorectal cancer
      patients less than 40 years of age present at an advanced stage and tend to have
      a positive family history. In general patients tolerate surgery well, with stoma
      formation in more than one-third. Long-term survival is as predicted for their
      advanced stage of presentation. The study highlights the need for early diagnosis
      in this patient group.

PMID- 12412714
TI  - Intraoperative insertion of Greenfield filters: lessons learned in a personal
      series of 152 cases.
AB  - The objective of this study was to define outcomes of 151 patients who underwent
      insertion of 152 Greenfield filters in the operating room by general and vascular
      surgery residents with supervision by one attending vascular surgeon. Each
      patient was taken to the operating room for inferior vena cava (IVC) interruption
      immediately after a vena cavagram was performed. One patient required a
      subsequent return to the operating room after developing paradoxical arterial
      embolism from a large venous thromboembolism which was trapped by and spanned
      both sides of the first IVC filter. In this case a second suprarenal filter was
      placed at the time of arterial embolectomy. In each of these 152 cases
      intraoperative venacavography was performed using a mobile C-arm. Complications
      such as hemothorax, filter misplacement, and vena cava perforation were
      identified. Late survival was defined using the Social Security Death Index. Of
      the 151 patients undergoing intraoperative insertion of Greenfield filters there
      was one hemothorax from attempts at acquiring venous access via percutaneous
      puncture of the internal jugular vein. This required transfusion but not
      thoracotomy, and IVC interruption was achieved. A separate patient had insertion
      of a Greenfield filter into a gonadal vein which required placement of a second
      filter into the IVC. There was one IVC perforation from a transfemoral filter
      insertion which required placement of a second filter above this perforation and
      laparotomy to retrieve the filter and repair the IVC. In one more patient the IVC
      filter initially failed to open, and a second filter was placed above the first
      filter. In this experience the misplacement rate was 0.7 per cent and the serious
      complication rate was 1.3 per cent. None of the patients was adversely affected
      per se by transfer to the operating room for Greenfield filter insertion. No
      patient died from filter insertion, but in two cases serious associated
      complications contributed to the adverse outcomes in these already terminally ill
      patients. Overall 30-day mortality rate was 6.6 per cent. Late survival was
      defined as follows: survival at one year after filter insertion was 75 per cent,
      at 2 years 63 per cent, at 3 years 60 per cent, at 4 years 57 per cent, and at 5
      years 54 per cent. Mean survival after filter placement was 4.96 years. We
      conclude that Greenfield filters can be inserted in the operating room by general
      and vascular surgery residents with attending supervision with reasonable safety
      and with a low rate of filter misplacement. The caval perforation and gonadal
      vein filter misplacement could both have been avoided by use of an over-the-wire
      filter deployment system, which at the time of these specific complications was
      not available. Vena cava filter insertion should remain within the scope of
      practice of surgeons and can be done with reasonable safety under C-arm guidance
      in the operating room. Use of over-the-wire systems could have helped reduce the
      likelihood of all but one of the filter-related complications experienced in this
      series.

PMID- 12412715
TI  - Malignant hyperthermia in an adult trauma patient.

PMID- 12412716
TI  - Nonfunctioning islet cell carcinoma of the pancreas: case report.
AB  - Islet cell carcinomas have an incidence of 5 per million per year; 50 per cent of
      these are nonfunctioning islet cell tumors. The presenting symptoms mimic
      pancreatic ductal adenocarcinoma. The CT finding of a pancreatic head mass that
      spares the main duct may distinguish between the two. The treatment of choice is
      resection. Most nonfunctioning islet cell tumors are not discovered until
      metastases are present. However, favorable survival rates have been reported in
      locally advanced tumors that have undergone resection. Liver metastases carry an
      unfavorable prognosis. Five-year survival over 60 per cent has been reported.
      Node-negative patients have a median survival of more than 10 years, and node
      positive patients who have undergone resection have a median survival of 75
      months. Streptozotocin and 5-fluorouracil are used postoperatively in patients
      with advanced disease. Considering the favorable survival with resection
      aggressive surgical treatment is mandated in cases of nonfunctioning islet cell
      tumors.

PMID- 12412717
TI  - Villous adenoma of the extrahepatic biliary tract: a rare entity.
AB  - Patients presenting with large obstructing extrahepatic biliary tumors often are
      presumed to have cholangiocarcinoma and are labeled with a grim disease with a
      poor prognosis, given little hope for a cure, and may actually opt for palliative
      care only. In some instances, however, the diagnosis is that of biliary adenoma
      (benign until it undergoes malignant degeneration), which can be confirmed via
      resection and pathologic evaluation of the lesion. Removal of the tumor in its
      benign stage then provides curative treatment of the obstructing lesion with
      excellent patient recovery and overall prognosis. We present a rare instance of
      observation of the presence of high-grade dysplasia in a large villous adenoma
      arising from the left hepatic duct with relief of biliary obstruction and
      curative resection.

PMID- 12412718
TI  - Massive incisional hernia of the bowel and urinary bladder: a case report.
AB  - Abdominal hernias are not rare in women, but incisional bladder herniation is
      uncommon. Incisional hernias are an iatrogenic condition caused by protrusion of
      the abdominal viscera through the abdominal fascia. Omentum and small intestines
      are by far the most common viscera involved, and the condition is diagnosed on
      clinical examination either visually or by palpation of an abdominal bulge. We
      describe a case of bladder and bowel herniation through a lower transverse
      abdominal incision (Pfannenstiel), which followed emergent operative intervention
      for ectopic pregnancy.

PMID- 12412719
TI  - Spontaneous cystic duct perforation associated with acalculous cholecystitis.
AB  - Spontaneous perforation of the extrahepatic biliary tree is rare in adults.
      Although perforation of the hepatic, common hepatic, common bile, and cystic
      ducts has been reported, review of the English literature reveals only four cases
      of cystic duct perforation, each attributed to calculi. We herein report the
      first known case of spontaneous perforation of the cystic duct in the absence of
      biliary calculi.

PMID- 12412720
TI  - An alternative approach to the treatment of mammary duct fistulas: a combination
      of microwave and ultrasound.
AB  - Between 1994 and 1999, 11 women with recurrent mammary duct fistula underwent
      nonsurgical treatment with microwave and ultrasound. An initial ultrasonographic
      examination was performed during the recurrence of mammary duct fistula, and in
      ten cases it revealed a small superficial periareolar anechoic, hypoechoic, or
      heterogenic lesion with poorly defined edges and without posterior reinforcement
      (marked distal sound enhancement). Findings indicated an extraglandular
      inflammatory process; duct ectasia was not seen in any of the 11 patients. A
      combination of microwave and ultrasound was administered on an outpatient basis
      for 20 days. Clinical improvement was rapid after the first few sessions of
      treatment. In nine of the 11 patients there has been no recurrence during more
      than 2 years of follow-up. The two current episodes were resolved by a second
      application of the same treatment. In one of those patients (with recurrence at 6
      months) an infiltration of steroids was also administered, and this patient is
      without recurrence after 23 months' follow-up.

PMID- 12412721
TI  - Parathyroid carcinosarcoma: a previously unreported entity.
AB  - Parathyroid carcinoma is a rare disease. The first report of parathyroid
      carcinoma with sarcomatous differentiation is presented. A parathyroid mass
      measuring 6 x 8 x 9 cm was surgically excised from the left side of the neck in a
      54-year-old man who had mild hypercalcemia. Light microscopic examination of the
      mass showed carcinoma with areas of rhabdomyosarcoma and chondrosarcoma.
      Immunohistochemical studies confirmed the light microscopic impression.
      Resolution of hypercalcemia followed excision of the mass, but multiple pulmonary
      and adrenal masses subsequently developed and led to the patient's death despite
      aggressive trials of chemotherapy with doxorubicin, ifosfamide, and cisplatin.
      The sarcomatous elements of the mass excised from this patient are presumed to
      represent aberrant cellular differentiation previously described in uterine and
      other tissue but not in parathyroid glands. Sarcomatous differentiation itself
      appears to be a poor prognostic factor in parathyroid carcinoma.

PMID- 12412722
TI  - Dialysis access-induced superior vena cava syndrome.
AB  - Vascular thrombosis is a complication of dialysis access and thrombosis of the
      superior vena cava by indwelling dialysis catheters access can cause superior
      vena cava syndrome. We describe a case of superior vena cava syndrome resulting
      from a dialysis access catheter placed in the internal jugular vein. Although
      surgical intervention is often needed to treat dialysis access-related superior
      vena cava syndrome this patient required only conservative measures for
      resolution of the syndrome. In this paper we describe the presentation,
      diagnosis, and management of this case. A review of dialysis access thrombosis
      complications and treatment options is also presented.

PMID- 12412723
TI  - Can fine-needle aspiration biopsy of thyroid nodule help in determining the
      extent of surgery in follicular and Hurthle cell neoplasm at a community teaching
      institution?
AB  - Fine-needle aspiration biopsy (FNAB) was used to evaluate cold thyroid nodules in
      179 patients treated between 1990 and 1998. The purpose of this study was to see
      whether FNAB findings of follicular or Hurthle cells could help in planning the
      extent of thyroid surgery. Group I patients (47) had findings suggestive of
      follicular or Hurthle cell neoplasm. Group II patients (132) had inconclusive
      results. In group I FNAB was 100 per cent correct in diagnosing follicular or
      Hurthle cell neoplasm with a high percentage of malignant findings (malignancy 85
      per cent and benign adenoma 15 per cent). In Group II malignancy was found in 16
      per cent and benign pathology in 84 per cent. Women were more likely to have
      malignancy than men. The average age was over 50 years in patients with either
      malignant or benign nodules. In addition there was no significant difference in
      average size of benign or malignant nodules (2.9 vs 2.6 cm respectively). When an
      FNAB finding was suggestive of neoplasm malignancy was found in 85 per cent. On
      the other hand when an FNAB was inconclusive malignancy was present in 16 per
      cent. Thus we conclude that using FNAB finding can guide surgical resection and
      recommend performing total or subtotal thyroidectomy when FNAB is suggestive of
      neoplasm and lobectomy when FNAB is inconclusive.

PMID- 12412724
TI  - Spontaneous nontraumatic hemoperitoneum due to a bleeding arteriovenous
      malformation on the serosal surface of the transverse colon: a case report.
AB  - Arteriovenous malformations of the gastrointestinal tract are a very common
      entity and a frequently cited cause of lower gastrointestinal bleeding in adults.
      They are characteristically found in the mucosa or submucosa of the bowel wall,
      and the vast majority do not cause any symptoms. We discuss the rare case of an
      extraluminal arteriovenous malformation of the transverse colon in an elderly
      woman who presented to the emergency department in hypovolemic shock after
      collapsing at home. An exploratory laparotomy was performed after a diagnostic
      peritoneal lavage yielded gross blood. The patient was found to have a
      spontaneously bleeding lesion confined to the serosal surface of the right
      transverse colon, which histological examination revealed to be an arteriovenous
      malformation. The lesion was excised and the patient recovered without sequelae.
      To date there have been no other documented cases of an arteriovenous
      malformation on the serosal surface of a visceral abdominal organ.

PMID- 12412725
TI  - Periappendicitis: is it a clinical entity?
AB  - The aim of this study was to identify clinical parameters that may help
      distinguish periappendicitis from the more common clinical entity of acute
      appendicitis. Serosal inflammation of the appendix without mucosal involvement
      constitutes the condition known as periappendicitis. In most situations this is a
      sequel of extra-appendicular sepsis and is likely to benefit from treatment
      targeted to the underlying pathology. But the majority of these cases are
      initially treated for acute appendicitis as clinical distinction between the two
      conditions is difficult. In this study some commonly used clinical yardsticks
      have been analyzed with respect to their value in this subtle diagnosis. We
      reviewed 231 successive cases clinically diagnosed as acute appendicitis; of
      these 18 had histologically demonstrated periappendicitis. Eight parameters were
      studied: age, gender, temperature, white blood cell count, location and duration
      of pain, associated symptoms, and peritoneal signs. Significant statistical
      differences were found between the two groups with regard to pain location, pain
      duration, and the presence of peritoneal signs. It may be possible to suspect
      periappendicitis preoperatively with meticulous clinical assessment. This may be
      of value in avoiding missed nonappendicular pathologies.

PMID- 12412726
TI  - Can appendiceal CT scanning be utilized effectively in widespread general
      surgical practice?
AB  - Appendiceal CT was first reported in the radiological literature, and has only
      recently begun to appear in the surgical literature. Much of the enthusiasm
      surrounding appendiceal CT has come from several publications by relatively few
      authors. We report the feasibility of implementing an appendiceal CT scanning
      technique and our initial results. The charts (940) of all patients evaluated for
      possible appendicitis during a 3-month period were reviewed. A new appendiceal CT
      scanning technique was performed when the indication was solely to exclude
      appendicitis. The accuracy of this new technique was determined. Eighty-seven
      patients were evaluated. Twenty-nine underwent appendiceal CT scanning. The
      accuracy of interpretation was 85 per cent. In 58 patients who did not receive an
      appendiceal CT scan the accuracy of surgical decision-making was 82 per cent.
      These values were not statistically different. We found appendiceal CT scanning
      to be relatively easy to implement; and its accuracy was better than expected.
      Our accuracy does not match that reported in the literature by the pioneers of
      appendiceal CT scanning. More experience with this technique will be required to
      achieve consistently successful accuracy; the technique can then be utilized in
      surgical practice and potentially change the diagnostic approach to acute
      appendicitis.

PMID- 12412727
TI  - Benign anatomical mistakes: inferior pulmonary ligament.
AB  - The term inferior pulmonary ligament needs to be revised. There is no superior
      component to oppose the inferior. By all means the pulmonary ligament is not a
      ligament, and the term ligament should be reserved for regularly oriented thick
      connective tissue bundles between bones. The term triangular ligament describes
      its shape but not its topography. For most surgeons the broad ligament refers,
      rather, to the ligament of the uterus. Embryologically pulmonary ligament is a
      "meson" i.e., a remnant of the developmental pathway--the pleural fold in this
      case--and taking this into consideration the most convenient term seems to be
      mesopneumonium. Its upper part is related to the hilar area, and its lower free
      border is what we call pulmonary ligament. We suggest the term mesopneumonium to
      describe the whole "meson" from the mediastinum to the hilum, which corresponds
      better to topography, embryology, and function.

PMID- 12412728
TI  - From warriors to guardians: the Assyrians and their role in the history of
      medicine.

PMID- 12412730
TI  - Epidural involvement in Hodgkin's disease.
AB  - Epidural involvement is analyzed retrospectively in 512 patients with primary
      treatment and follow up for Hodgkin's disease (HD) between 1970 and 1999. In one
      case (0.2%) epidural manifestation was the first symptom and in six cases (1.2%)
      it occurred later, at a disseminated, advanced stage. All seven patients were
      male: three had mixed cellularity and four nodular sclerosis histological
      subtype. The thoracic segment was involved in four cases, the lumbar in two and
      the cervical segment in one case. The most frequent symptoms were back pain, limb
      weakness, paresis/plegia, incontinence. Computer tomography, magnetic resonance
      imaging and myelography were used as diagnostic procedures and in planning the
      treatment. Functional recovery was achieved by laminectomy, loco-regional
      irradiation and adjuvant polychemotherapy with remission of HD for 6-100 months.
      Later, however, six patients died due mainly to relapse/progression of HD. We
      emphasize the importance of an interdisciplinary approach in the treatment of HD
      with this relatively rare appearance, which requires close co-operation among
      oncohematologists, neurologists, radiologists, neurosurgeons, radiotherapists and
      physiotherapists.

PMID- 12412729
TI  - Inhibition of natural killer cytotoxicity in vitro by clinical grade serine
      protease inhibitors.
AB  - The effects of clinical grade serine protease inhibitors on natural killer (NK)
      activity were compared. Cytotoxicity was measured with the Calcein-AM release
      method, using K562, Raji as a target. There is a significant correlation between
      measurements of NK activity by the Calcein-AM method and the 51Cr release assay.
      Cytotoxicity was inhibited with a calcium chelating agent or a perform inhibitor.
      Although up to 65% of cytotoxicity was inhibited by nafamostat mesilate with an
      E/T ratio of 10:1, and by 55% by ulinastatin, neither gabexate mesilate nor
      antithrombin III inhibited any cytotoxicity. None of these agents inhibited
      lymphokine-activated killer cell activity. In clinical applications, it should be
      noted that some protease inhibitors have been proven to have immunosuppressive
      effects.

PMID- 12412731
TI  - Association of the platelet glycoprotein Ia C807T/G873A gene polymorphism and
      thrombosis in Behcet patients.
AB  - Thrombosis is a common complication of Behcet disease and the pathogenic
      mechanism of thrombotic tendency in Behcet disease is not well known. Several
      platelet membrane glycoprotein gene polymorphisms have been identified as risk
      factors for thrombosis. This study aimed to evaluate the possible role of the GP
      Ia C807T/G873A polymorphism as a risk factor for thrombosis in Behcet disease. We
      determined the prevalence of platelet glycoprotein Ia C807T/G873A gene
      polymorphism in Behcet patients. Genomic DNA was obtained from 20 patients with
      Behcet disease and 61 controls. All individuals were of Turkish ancestry and were
      genotyped for the GP Ia C807T/G873A polymorphism with real-time PCR method by
      LightCycler system. The 807 CC, CT and TT genotypes corresponded with 873 GG, GA
      and AA genotypes, respectively. Complete linkage between the 807 and 873 sites
      was found in all samples. The 807CC(873 GG), 807CT(873GA), 807TT(873AA) genotypes
      found to be 45.9%, 45.9% and 8.1% in controls and 30.0%, 55.0% and 15.0% in
      patients with Behcet disease, respectively. The Odds Ratio for BD (OR = 1.97; 95%
      confidence interval (CI): 0.42-9.13) is high for the 807 TT genotype compared
      with controls. Thrombosis was found in 7 cases of Behcet disease group: five
      cases have 807CT, one case has 807TT genotype and one case has 807CC genotype.
      Our data indicate hat patients with BD are affected by the glycoprotein Ia gene
      807TT genotypes and carrying 807T allele. The risk of thrombosis is significantly
      higher in patients who have 807TT and 807CT genotypes than in patients who have
      807CC genotype.

PMID- 12412732
TI  - Efficiency of premarital screening of beta-thalassemia trait using MCH rather
      than MCV in the population of Fars Province, Iran.
AB  - Iran is a country with high prevalence of about 5-10% of beta-thalassemia trait.
      The prevalence of Cooly's anemia has declined from 11.6 in 10000 population to
      7.2 in 10000 in a five-year period due to screening program of beta-thalassemia
      trait before marriage. This study was conducted to compare the sensitivity of
      mean corpuscular hemoglobin (MCH) < 27 pg and mean corpuscular volume (MCV) < 80
      fl as a screening test in first step of screening of beta-thalassemia trait. From
      2449 couples (4898 cases) participating in the premarital screening to our
      clinic, 902 cases with either MCH < 27 pg, MCV < 80 fl, anemia, pallor or family
      history of beta-thalassemia were enrolled in the study. MCV, MCH as well as Hb A2
      were measured in all cases. MCH and MCV had sensitivities of 98.5% and 97.6% for
      the diagnosis of beta-thalassemia trait, respectively. A false negative value of
      MCH is about 1% lower than that of MCV. MCH is a more sensitive screening test
      for detecting beta-thalassemia minor before marriage.

PMID- 12412733
TI  - The use of single-donor fibrin glue prepared by recycled cryoprecipitation in
      experimental liver surgery.
AB  - The purpose of the study was to evaluate the hemostatic effectiveness of fibrin
      glue (FG) prepared by a modification of cryoprecipitation technique in
      experimental rat liver surgery. FG component 1 was prepared by triple or
      'recycled' cryoprecipitation method from single-donor plasma. Rats subjected to
      liver incision, partial and total lobectomy were treated with FG on the surgical
      cut surface or underwent standard surgical technique. The efficacy of FG
      treatment was evaluated on the basis of the 24-hour survival ratio and peripheral
      blood hematological parameters. The mean values of fibrinogen, FXIII, fibronectin
      and horizontal tensile strength of FG were 54.2 +/- 19.9 g/l, 13.5 +/- 3.6 IU/ml,
      3103.1 +/- 148.9 mg/l, and 1.076 +/- 0.18 N/cm2, respectively. The survival of FG
      treated rats subjected to partial and total lobectomy was significantly higher in
      comparison to the FG-nontreated animals, accompanied with higher values of red
      blood cell counts, hemoglobin concentration and hematocrit. When liver incision
      was performed, although there were no differences in survival rate, FG-treated
      animals had significantly higher values of the tested hematological parameters.
      The presented results demonstrated that by using 'recycled' cryoprecipitation it
      is possible to obtain high quality single-donor FG with successful hemostatic
      therapeutical effects, as confirmed in the experimental rat model of liver
      surgery.

PMID- 12412734
TI  - Serum sialyl Lewis(x) levels in patients with various haematologic malignancies.

PMID- 12412735
TI  - Bacteremia caused by Brevibacterium species in a patient with chronic lymphocytic
      leukemia.
AB  - We report a case of bacteremia caused by Brevibacterium species which is one of
      the coryneform bacteria, in a patient with chronic lymphocytic leukemia. We
      conclude that, if a coryneform bacteria is isolated from sterile body sites, it
      must be carefully evaluated, and especially in immunocompromised patients,
      Brevibacterium species should be considered as potential pathogens.

PMID- 12412736
TI  - Idiopathic myelofibrosis with prominent postsplenectomy erythroblastosis
      terminating in acute myeloid transformation.
AB  - Idiopathic myelofibrosis is a myeloproliferative disease with poor prognosis and
      without sufficient therapy. Acute leukemic transformation occurs in 15% of
      patients. The authors report the case of a 63 year old myelofibrotic patient
      treated with splenectomy. During the clinical course they observed unusually
      prominent and persistent erythroblastosis in the peripherial blood. After a two
      years long, relatively stable period the disease terminated in acute myeloid
      leukemia.

PMID- 12412737
TI  - Autoimmune hemolytic anemia in Philadelphia positive chronic myeloid leukemia
      with t(7;14) anomaly after 5 years of interferon alpha treatment.
AB  - A 41-year-old woman, Philadelphia positive chronic myeloid leukemia patient, had
      progressive decline in hemoglobin levels. She had been receiving interferon alpha
      treatment for five years. Autoimmune hemolytic anemia was diagnosed. Subsequent
      bone marrow examination revealed translocation t(7;14). She was placed on
      prednisone treatment. The patient responded to prednisone as treatment for the
      hemolytic process. The result of a direct Coombs' test remained positive. The
      patient died shortly after the diagnosis of autoimmune hemolytic anemia.
      Autoimmune hemolytic anemia should be considered in the evaluation of chronic
      myeloid leukemia patients with a sudden decrease in hemoglobin levels.

PMID- 12412738
TI  - Low dose melphalan is a treatment option in elderly patients with high risk
      myelodysplastic syndrome or secondary acute myeloblastic leukaemia.
AB  - We present the case of a 71 year-old man with secondary acute myeloblastic
      leukemia, who was successfully treated with low dose melphalan plus Epo plus G
      CSF. We treated the patient with 2 mg of melphalan once a day orally, G-CSF 5
      mg/kg 3 times a week and Epo 10.000 ui subcutaneously 3 times a week until the
      maximum response was obtained. Complete remission was achieved after 16 weeks of
      continuous treatment. Treatment-related toxicity was not significant. We
      recommend the use of low dose melphalan in elderly patients with high risk MDS as
      a treatment option.

PMID- 12412739
TI  - The current status of neutrophil cytoplasmic antibodies.
AB  - Several studies in the past 10 years have demonstrated the occurrence of
      autoantibodies against cytoplasmic constituents in patients with vasculitis and
      glomerulonephritis. In this review the nomenclature of these antibodies is
      discussed and assays and clinical associations are summarized. Although the
      antigens involved are not completely identified, antibodies and T cells reactive
      with myeloid lysozomal enzymes may both play a significant role in pathogenesis.

PMID- 12412740
TI  - Incidence of selective IgG2 deficiency in patients with vasculitis.
AB  - IgG2 deficiency has been recently associated with the appearance of vasculitis.
      None of the 42 patients with IgG2 deficiency whom we studied has a history of
      vasculitis. We have also studied 56 patients with vasculitis, and found four of
      them with IgG2 levels below the normal range for their age. As a group, the
      vasculitis patients did not differ in the incidence of low IgG2 levels from a
      normal population. Three of the four vasculitis patients with low IgG2 levels had
      a Henoch-Schonlein syndrome, and the association between both features was
      statistically significant.

PMID- 12412741
TI  - Altered IgG-subclass distribution in lymph node cells and serum of adults
      infected with human immunodeficiency virus (HIV).
AB  - The relative distribution of cells producing subclasses of IgG or IgA was
      examined by immunohistochemistry in lymph node biopsy specimens from 15 adults
      with persistent generalized lymphadenopathy due to infection with HIV and from 11
      adults with lymph nodes enlarged from other causes. The IgG1 immunocyte fraction
      was significantly higher and the IgG2 fraction significantly lower associated
      with HIV infection than in the controls. The proportions of cells producing IgG3,
      IgG4, IgA I or IgA2 were similar in the two lymph node categories. The altered
      IgG-subclass distribution of immunocytes in HIV lymphadenopathy concorded with
      the serum levels that were significantly elevated for IgG1 and lowered for IgG2
      compared with a panel of blood donor samples.

PMID- 12412742
TI  - Suppression of in vitro immunoglobulin synthesis by CD16(Leu11a)+ CD56
      (NKH1,Leu19)+non-T lineage NK cells; lack of suppression of cells from
      immunodeficient patients.
AB  - We examined the effect of both CD3-CD16(Leul la)+CD56(NKH1,Leu19)+ non-T lineage
      natural killer (NK) cells and CD3+CD8+CD16-CD56+ T lineage NK cells on B cell
      proliferation and differentiation. Fluorescence-activated cell sorter (FACS)
      purified CD16+CD56+ cells suppressed pokeweed mitogen (PWM) induced
      immunoglobulin synthesis. However, the T lineage NK cells tended to suppress
      immunoglobulin synthesis only when CD8+ cells were eliminated from the culture,
      and even then CD16+ NK cells suppressed antibody production more efficiently than
      did CD3+CD8+ NK cells. CD16+ NK cells did not suppress B cell proliferative
      responses to several mitogens. CD16+ NK cells from patients with Wiskott-Aldrich
      syndrome, who showed the high percentage of CD16+ NK cells, did not inhibit
      immunoglobulin synthesis. We concluded that non-T NK cells are the major
      immunoregulatory NK cells for immunoglobulin synthesis in normal immune systems,
      and that they suppress immunoglobulin synthesis through their action on B cell
      differentiation.

PMID- 12412743
TI  - Influence of systemic cyclosporin A on interleukin-2 and epidermal growth factor
      receptor expression in psoriatic skin lesions.
AB  - Lesional and non-lesional skin biopsies from patients with chronic plaque
      psoriasis receiving systemic cyclosporin A (CyA; 2.5 or 5 mg/kg(-1) per day) were
      examined for changes in T cell populations, Langerhans cells and the expression
      of interleukin-2 (IL-2) and epidermal growth factor receptors (EGFR) by
      immunohistochemistry. After 4 weeks of treatment a striking reduction in disease
      activity was observed, accompanied by a marked reduction in the numbers of CD4+
      and CD8+ cells in the epidermis and dermis. As early as 7 days after initiation
      of treatment, a substantial reduction in the number of CD4+ lymphocytes in the
      dermis was detected. At the same time there was a significant reduction in the
      number of cells expressing IL-2 receptors (IL-2R); this was greater than the
      corresponding decrease in CD3+ cells, a finding that suggests that CyA may reduce
      the number of activated lymphocytes preferentially at this early stage of
      treatment. In contrast, the number of epidermal Langerhans cells increased within
      1 week and more markedly by 4 weeks. The expression of EGFR on keratinocytes in
      all layers of the epidermis persisted during CyA treatment, despite resolution of
      the lesions. These results suggest that, rather than preventing keratinocyte
      hyperproliferation via interference with the expression of EGFR, the anti
      psoriatic effects of CyA may be mediated, at least in part by interference with T
      cell activation evident within I week of instigation of therapy.

PMID- 12412744
TI  - Responsiveness of systemic lupus erythematosus T cells to signals provided
      through LCA T200 (CD45) and T1 (CD5) antigens.
AB  - It is currently unclear whether the T cell defective capacity to proliferate and
      to secrete interleukin-2 (IL-2) observed in systemic lupus erythematosus (SLE)
      reflects an intrinsic disorder of the T cell or defects secondary to a monocyte
      dysfunction. In order to clarify whether the disorder is intrinsic to the T cell,
      we have studied the proliferative capacity of cells highly depleted of monocytes,
      activated by Seph-CD3, as 'first signal,' and by monoclonal antibodies (MoAbs)
      CD45 and CD5 as 'second signal,' in 14 SLE patients. There were no significant
      differences between SLE patients and healthy volunteers in the response of the
      monocyte-depleted cells to Seph-CD3+CD45; Seph-CD3+CD5; Seph-CD3+IL-2; and Seph
      CD3+phorbol myristate acetate (PMA). However, active SLE compared with non-active
      SLE had an impaired response of peripheral blood mononuclear cells (PBMC) to Seph
      CD3 and to Seph-CD3+IL-2. The good responses obtained to second signals provided
      through CD45 and CD5 indicate that at least these mechanisms are not
      intrinsically impaired in SLE T cells. These findings, together with the abnormal
      response of PBMC suggest that a monocyte dysfunction plays an important role in
      SLE T cells hyporesponsiveness.

PMID- 12412745
TI  - Pattern of humoral reactivity to type II collagen in rheumatoid arthritis.
AB  - Humoral immunity directed against type II collagen (CII) is a common although not
      specific feature of rheumatoid arthritis (RA). We have shown that 10 to 15% of
      the sera either from RA patients (n = 88) or from healthy controls (n = 149)
      reacted with native human CII. Conversely, autoantibodies to the alpha-1 (II)
      chains were significantly more frequent in the RA group (26.1% versus 6.0%,
      P<0.001), suggestingthatdenaturedCII may bean autoantigenin RA. Thus, human CII
      was cleaved with cyanogen bromide (CB), and immunoblotting techniques were
      performed on 19 RA and 21 normal sera. Among the four major CB peptides, CB10 and
      CB11 were recognized by most of the sera tested without distinction between
      normal or RA sera. Inhibition experiments using an ELISA have shown that: (i)
      antibodies to the native CII molecule did not cross-react with those recognizing
      the CB peptides, and vice-versa; (ii) the binding of the sera to native CII was
      partially inhibited by pre-incubation with alpha-1 (II) chains, and vice-versa;
      (iii) pre-incubation of the sera with CB peptides partially blocked the binding
      to alpha-1 (II) chains, whereas pre-incubation of the sera with alpha-1 (II)
      chains totally inhibited the reactivity against CB peptides; and (iv) a
      substantial proportion of the epitopes recognized by anti-CII autoantibodies was
      neither species specific nor type specific. Taken together, these findings reveal
      the existence of several populations of anti-CII autoantibodies: some antibodies
      react exclusively with conformational determinants of the CII molecule, and
      others are directed towards linear structures of alpha-1 (II) chains.

PMID- 12412746
TI  - Impaired autologous mixed lymphocyte reaction (AMLR) reactivity of peripheral
      blood T cell subsets in rheumatoid arthritis.
AB  - We examined AMLR reactivity of unseparated T cells and CD4+ and CD8+ T cell
      subsets in peripheral blood from 11 rheumatoid arthritis (RA) patients and 10
      healthy controls. T cell subsets were isolated by negative selection using
      complement mediated cytotoxicity. AMLR reactivity of six patients (designated RA
      L was reduced below the range of the controls' responses. Five patients
      (designated RA-N) exhibited normal AMLR reactivity. We observed impaired AMLR
      reactivity of CD4+ T cells from RA-L relative to RA-N and healthy controls (P <
      0.05). CD4+ T cell reactivity of RA-L was reconstituted to normal with
      pharmacological doses of recombinant interleukin-2 (IL-2) (100 U/ml). In
      contrast, CD8+ T cells from RA-L in the presence of 100 U/ml IL-2 exhibited
      markedly impaired AMLR reactivity relative to RA-N and healthy controls (P <
      0.05). Dose-response studies revealed partial reconstitution of CD4 T cells with
      physiological concentrations of IL-2 (10 U/ml). To examine the possibility that
      in vivo pre-activation of T cells in RA accounted for the findings, T cells or
      subsets were cultured alone for 7 days in the presence of 100 U/ml IL-2. A trend
      toward enhanced reactivity of CD4+ and CD8+ T cells in L-RA relative to N-RA and
      healthy controls was observed, but the differences were not statistically
      significant. There was no correlation between reactivity of T cells alone in the
      presence of IL-2 and AMLR reactivity. The results suggest the possibility that
      abnormal AMLR reactivity of CD4+ and CD8+ T cell subsets in RA may arise as a
      consequence of different pathophysiological mechanisms.

PMID- 12412747
TI  - Immunohistology of oral lesions from patients with recurrent oral ulcers and
      Behcet's syndrome.
AB  - A qualitative and quantitative immunohistological investigation was performed on
      biopsies of oral ulcers from patients with Behcet's syndrome (BS) and those with
      recurrent oral ulcers (ROU). The results were compared with control oral biopsies
      from patients with other diseases and normal oral mucosa. The expression of HLA
      DR on the cell membrane of keratinocytes was found in 13 out of 15 lesions from
      patients with BS and ROU, as compared with only one out of 15 controls. The
      relative density of HLA-DR was investigated quantitatively by microdensitometry
      and this confirmed that DR expression in the epithelial cells of patients with BS
      and ROU was significantly greater than in diseased and normal control oral
      tissues. A prominent mononuclear cell infiltration consisted predominantly of T
      lymphocytes and mature macrophages. Analysis of the CD4 and CD8 subsets of T
      cells failed to show significant differences between BS, ROU and control diseased
      tissues. Increased numbers of Langerhans cells were found in the epithelium by
      morphometric analysis with the CD1 monoclonal antibody in BS and ROU but an
      increased number was also found in lichen planus. The results suggest that the
      immunohistological changes in oral lesions of BS and ROU manifest an enhanced
      immune response in the epithelium, keratinocytes express HLA-class II antigen and
      increased number of Langerhans cells as well as in the lamina propria with a
      prominent infiltration of CD4, CD8 and macrophage-like cells. The characteristic
      pattern of exacerbations and remissions of oral ulceration can be interpreted by
      the hypothesis that an initiating microbial agent may induce a mononuclear cell
      infiltration, with the release of cytokines, expression of class II antigen in
      keratinocytes and causing ulceration, followed by down-regulation of immunity by
      tolerant T cells induced by the class II positive keratinocytes, leading to a
      remission.

PMID- 12412748
TI  - Marked increase of CD5 + B cells in hyperthyroid Graves' disease.
AB  - We examined the proportions of B lymphocytes bearing CD5 cell surface antigen
      (CD5+ B cells), which are capable of making autoantibodies, in peripheral blood
      from patients with various thyroid diseases. The level of CD5+ B cells was
      markedly increased (>9.0%) above the normal range (0.5-7.7%) in untreated,
      hyperthyroid patients with Graves' disease, although about 10% of the patients
      had no detectable serum thyroid-stimulating hormone (TSH) receptor antibody
      (TRAb). However, the levels of CD5+ B cells were normal in untreated patients
      with destructive thyrotoxicosis due to aggravation of Hashimoto's thyroiditis or
      subacute thyroiditis. In patients with stimulated hyperthyroid Graves' disease
      the levels of CD5+ B cells were correlated with those of thyroid hormones and
      TRAb, all significantly increased. However, once hyperthyroidism was controlled
      by anti-thyroid drugs, CD5+ B cells were decreased, followed in turn by reduction
      of TRAb. We conclude that the proportion of CD5+ B cells is useful as a
      therapeutic index and for diagnosis of Graves' disease and its differentiation
      from destruction-induced thyrotoxicosis.

PMID- 12412749
TI  - Immune adherence of nascent hepatitis B surface antigen-antibody complexes in
      vivo in humans.
AB  - Upon i.v. injection into humans, pre-formed immune complexes bind complement and
      adhere to complement receptor type I (CR1, CD35) on erythrocytes (immune
      adherence). However, in most circumstances antigen and antibody react in the
      presence of complement; such nascent immune complexes may have properties
      different from pre-formed immune complexes. To define whether nascent immune
      complexes would also adhere to erythrocytes in vivo in humans, we studied immune
      complexes that formed upon i.v. injection of radiolabelled hepatitis B surface
      antigen (HBsAg) into immunized volunteers (eight subjects with anti-HBsAb levels
      ranging from undetectable to 50 U/ml.; and three control non-immune individuals).
      Immune complexes formed immediately in the subjects with detectable levels of
      specific antibody, and the clearance rate of these immune complexes correlated
      with the anti-HBsAb level (r = 0.78, P < 0.01). A fraction of the circulating
      immune complexes bound to erythrocytes in the three individuals with the highest
      antibody level (8-15% at 10 min). The effect of CR1 number per erythrocytes was
      analysed in two subjects with similar antibody levels and immune complexes
      clearance rates: immune adherence was higher in the subject with more CR1 per
      erythrocytes. The same immune complexes model studied in vitro provided similar
      results: a fraction of nascent immune complexes bound to human erythrocytes; this
      immune adherence was observed only when immune complexes formed in the presence
      of antibody excess, and correlated with CR1 number per erythrocytes (r = 0.99, P
      < 0.01). Finally, adherence of nascent HBsAg-antibody immune complexes to
      platelets was demonstrated in rabbits. Although immune adherence involves only a
      small fraction of nascent immune complexes at any given time, it may be essential
      for the safe disposal of large nascent immune complexes.

PMID- 12412750
TI  - Characterization of hepatitis B surface antigen (HBsAg) induced interleukin-2
      secretion in chronic asymptomatic carriers of HBsAg.
AB  - Peripheral T lymphocytes from asymptomatic HBsAg carriers and hepatitis B (HB)
      immune (naturally acquired or vaccine induced) donors were induced into
      interleukin-2 (IL-2) secretion by plasma-derived HBsAg and the translational
      products of the S- and pre-S2+S gene of HB virus (HBV) in vitro. Biphasic time
      courses of IL-2 secretion were obtained for all donors tested. The first peak
      seemed to be mitogenically induced, as it was demonstrated in T cell cultures
      from asymptomatic HBsAg carrier, HB-immune donors as well as HB-susceptible
      controls and exhibited similar kinetics to that of the mitogen
      phytohaemagglutinin (PHA) induced IL-2 secretion. The mitogenically induced IL-2
      secretion was prompt in T cell cultures from asymptomatic HBsAg carriers compared
      with HB-immune and HB-susceptible donors, and significantly higher after
      stimulation with high (100-1,000 ng/ml) compared with low (0.1-1.0 ng/ml)
      concentrations of HBsAg, indicating that T lymphocytes from asymptomatic HBsAg
      carriers are mitogenically pre-activated by circulatory HBsAg in high
      concentrations in vivo. In contrast, the second peak obtained after 4-7 days of
      antigen stimulation was antigen-specifically induced as it was not registered in
      control culture supernatants from HB-susceptible individuals. T cells from six
      out of seven asymptomatic HBsAg carriers exhibited reduced responsiveness to the
      translational product of the S-gene of HBV, whereas T cells from HB-immune donors
      responded equally well to pre-S2 containing and non-containing HBsAg
      preparations. An HBsAg-induced mitogenic T cell activation and aberrant T cell
      sensitization towards S-gene-encoded determinants may result in altered
      immunoregulatory functions within the T cell compartment, with consequences for
      the development of an adequate antibody response to HBsAg in asymptomatic HBsAg
      carriers.

PMID- 12412751
TI  - Antibody response to phenolic glycolipid I and Mycobacterium w antigens and its
      relation to bacterial load in M. leprae-infected mice and leprosy patients.
AB  - Twenty-six inbred BALB/cBy mice were infected with live Mycobacterium leprae by
      injecting 6 x 10(3) bacilli in the hind footpad. Bleeds were collected at monthly
      intervals. After 6 months, acid-fast bacilli (AFB) were harvested monthly from
      the footpad of mice. The sera were analysed in enzyme immunoassay for antibodies
      against phenolic glycolipid I (PGL-I) of M. leprae and antigens of Mycobacterium
      w (M. w); 21 out of 26 (80.7%) mice demonstrated the presence of antibodies
      against PGL-I and M. w . Anti-M. w antibodies appeared slightly earlier than did
      anti-PGL-I antibodies. The titre of anti-M. w antibodies was higher than that of
      anti-PGL-I antibodies. The mice giving a positive antibody response had more than
      7 x 10(5) AFB/footpad. The coefficient of correlation (r) between the number of
      AFB and antibody titres at the time of harvest was 0.566 for PGL-I and 0.628 for
      M. w. The value of r for bacterial index and antibody titres in 188 leprosy
      patients was 0.510 for PGL-I and 0.418 for M. w; these values were statistically
      significant (P < 0.001). The decrease in bacterial index and antibody titres in
      treated lepromatous leprosy patients correlated with increase in the duration of
      chemotherapy. The measurement of anti-PGL-I antibodies of IgM class may serve as
      an adjunct to skin biopsy and skin-slit smear for serial monitoring of the
      bacterial load in the course of chemotherapy in leprosy control programmes.

PMID- 12412752
TI  - Antibodies in human filariasis sera react with diethylcarbamazine.
AB  - We demonstrate by an ELISA the presence of antibodies in human filarial sera that
      react with diethylcarbamazine (DEC); they appear to be primarily filarial
      antibodies cross-reacting with DEC skeleton, since affinity-purified DEC
      antibodies strongly react with Wuchereria bancrofti microfilariae. These
      observations indicate a possible antigenic mimicry between the drug and some
      parasite component.

PMID- 12412753
TI  - Inhibitory effect of corticosteroids on the secretion of tumour necrosis factor
      (TNF) by monocytes is dependent on the stimulus inducing TNF synthesis.
AB  - The cytokine tumour necrosis factor (TNF) is believed to be involved in the
      pathophysiology of several human disease states, both septic and non-septic.
      Different pathways of induction are involved in the generation ofTNF in these
      disease states. We therefore used four different stimulatory agents,
      lipopolysaccharide, phorbol myristate acetate, silica quartz, and anti-human IgG
      antibody to study the influence of the corticosteroids prednisolone and
      budesonide on the secretion of TNF by human monocytes. Both prednisolone and
      budesonide inhibited TNF secretion induced by these four stimulating agents in a
      different degree. Inhibition was strong when TNF secretion was induced by
      lipopolysaccharide or anti-human IgG antibody. A weaker inhibitory effect was
      observed when TNF secretion was induced by silica quartz. Only minimal inhibition
      of phorbol myristate acetate induced TNF secretion was observed. Furthermore, it
      is shown that inhibition is dependent on the dose of corticosteroid, but not or
      only minimally on the dose of stimulating agent, indicating that inhibition
      cannot be overcome by increasing the cell-activating stimulus. Finally, optimal
      inhibition of TNF secretion by corticosteroids is shown to be dependent on the
      presence of corticosteroids during the phase of cell stimulation.

PMID- 12412754
TI  - Inhibition of delayed hypersensitivity reactions by colchicine. II. Colchicine
      inhibits interferon-gamma induced expression of HLA-DR on gut epithelial cell
      line.
AB  - The effects of colchicine and vinblastine on interferon-gamma (IFN-gamma) induced
      expression of HLA-DR antigens on the HT-29 colonic carcinoma cell line was
      investigated in vitro. Both drugs prevented the expression of HLA-DR only if
      applied before or together with IFN-gamma. Methotrexate, an antimitotic drug,
      failed to inhibit DR expression by these cells. Colchicine and vinblastine, but
      not methotrexate, act on the cellular microtubules, interfering with the
      transport of proteins from the protoplasm to the cell surface and thus preventing
      the appearance of HLA-DR antigens. The reported findings may explain the role of
      colchicine in preventing delayed hypersensitivity reactions.

PMID- 12412755
TI  - IgG anti-cardiolipin antibodies in murine lupus.
AB  - The frequency and nature of IgG anti-cardiolipin and anti-ds-DNA antibodies among
      MRL/lpr, MRL/+ and NZB/W F1 mice (murine lupus strains) and non-autoimmune inbred
      strains of mice (NIH/Swiss and Balb/c) were analysed by ELISA. High titres of
      anti-ds-DNA were detected in autoimmune strains (MRL/lpr, 69%; MRL/+, 50%; and
      NZB/W, 80% positive), whereas anti-cardiolipin antibodies were detected only in
      MRL/lpr (69%) and MRL/+ (17%) mice. IgG subclass analysis of these antibodies in
      20 MRL/lpr sera revealed that all four subclasses were represented. When tested
      for fine antigenic specificity, anti-cardiolipin antibodies in MRL/lpr and MRL/+
      mice bound to acidic phospholipids rather than to neutral phospholipids and were
      not inhibited by DNA. In MRL/lpr mice, anti-cardiolipin antibodies were first
      detected at 2 months, peaked around 5 months and then declined preterminally. To
      determine whether complications associated with anti-cardiolipin antibodies were
      present in MRL/lpr mice, blood counts were performed and litter sizes were
      determined. Although no significant decreases in the red and white blood cell
      counts were observed in MRL/lpr mice, platelet counts were significantly lower
      compared with NIH/Swiss (P < 0.001) and Balb/c (P < 0.005) mice. MRL/lpr mice had
      significantly fewer pups per delivery compared with a normal strain (MRL/lpr,
      5.3+2.6; NIH/Swiss, 72 +/- 2.1; P < 0002). These observations indicate that the
      serological characteristics of IgG anti-cardiolipin antibodies in MRL/ lpr mice
      are similar to those of anti-cardiolipin antibodies in humans with lupus. Whether
      these autoantibodies are pathogenetically related to thrombocytopenia and a small
      litter size in MRL/lpr mice remains to be determined.

PMID- 12412756
TI  - Beneficial effects of a polyamine biosynthesis inhibitor on lupus in MRL-lpr/lpr
      mice.
AB  - Difluoromethylornithine (DFMO), an experimental drug that inactivates ornithine
      decarboxylase and thus reduces the production of polyamines has a beneficial
      effect on the mean survival time and the clinical and laboratory manifestations
      of murine lupus in female MRL-lpr/lpr mice. DFMO-treated mice showed a 29%
      increase in the mean survival time compared with age- and sex-matched control
      mice of the same strain. Lymphadenopathy was evident in untreated mice at 14
      weeks of age, but was delayed until 19 weeks of age in DFMO-treated mice. In
      addition, the sera of DFMO-treated mice contained a significantly lower
      concentration of anti-DNA antibodies compared with untreated mice. These results
      open the possibility of development of a new class of therapeutic agents based on
      polyamine biosynthesis inhibitors for the treatment of human autoimmune disease.
      Possible mechanisms for the action of DFMO include its inhibitory action on cell
      proliferation as well as its ability to prevent DNA from assuming an immunogenic
      left-handed Z-DNA conformation.

PMID- 12412757
TI  - Suppression and augmentation of rat adjuvant arthritis with monoclonal anti
      interferon-gamma antibody.
AB  - The effects of a monoclonal antibody (MoAb DB-1), which neutralized rat
      interferon-gamma (IFN-gamma), on the induction and progression of adjuvant
      arthritis in Lewis rats induced by intraplantar injection of Freund's complete
      adjuvant was studied. The animals were treated intraperitoneally with MoAb DB-1
      (0.3-5 mg) for various times. Prophylactic treatment with MoAb DB-1, starting 2
      days prior to arthritis induction, inhibited oedema in both the injected and non
      injected hind paws and delayed joint destruction as shown by radiography.
      However, despite continued MoAb treatment, the disease progressed. High doses of
      MoAb DB-1 exacerbated the disease. A control MoAb of the same isotype did not
      have significant effects on adjuvant arthritis. Therapeutic treatment with the
      MoAb DB-1 starting 8 days after arthritis induction caused only slight and short
      lived inhibitory effects. IFN-gamma appears to be a critical lymphokine for the
      development of adjuvant arthritis.

PMID- 12412758
TI  - Mouse monoclonal antibodies against human sperm: evidence for immunodominant
      glycosylated antigenic sites.
AB  - Thirty mouse monoclonal antibodies (MoAbs) raised against human sperm detect
      common antigenic determinants on human lymphocytes, erythrocytes, bacteria and
      endotoxin. Specific chemical, enzymatic and lectin blocking studies indicate that
      the sperm-associated antigens defined by these MoAbs are glycoconjugates. Further
      studies including reactivity of these MoAbs with organic sperm extracts indicate
      that the predominant carriers of these carbohydrate antigens are glycolipids and
      that the terminal immunodominant monosaccharide may be N-acetyl-glucosamine or N
      acetylgalactosamine.

PMID- 12412759
TI  - Synergistic effects of locally administered cytostatic drugs and a surfactant on
      the development of delayed-type hypersensitivity to keyhole limpet haemocyanin in
      mice.
AB  - The immunomodulating effects of two locally administered cytostatic drugs, the
      active cyclophosphamide-derivative Z 7557 and the plant alkaloid VP-16, were
      compared with the effects of systemically administered cyclophosphamide and
      several established adjuvants: Freund's complete adjuvant, dextran sulphate, and
      dimethyl dioctadecyl ammonium bromide (DDA). All agents tested promoted the
      development of delayed-type hypersensitivity (DTH) to keyhole limpet haemocyanin
      (KLH) in mice. Locally administered cytostatic drugs were the most effective
      immunostimulatory compounds, whereas DDA was the least toxic agent tested. In
      order to increase the effectiveness and/ or reduce the toxicity of these agents
      we tested the efficacy of combinations of cytostatic drugs and DDA to enhance
      DTH. The results show that DDA and suboptimal amounts of locally administered
      cytostatic drugs act synergistically on DTH.

PMID- 12412760
TI  - Immunosuppression with cyclosporin A alters the thymic microenvironment.
AB  - The effect of cyclosporin A (CyA) immunosuppression on the murine thymic
      microenvironment and T lymphocyte development has been analysed using monoclonal
      antibodies to epithelial and lymphocyte subpopulations, macrophages and major
      histocompatibility complex (MHC) class II antigens in immunohistochemistry and
      flow cytometry. The major microenvironmental target for CyA-induced damage was
      the thymic medulla, where a reduction in all epithelial cell subsets, dendritic
      cells and macrophages was observed. In contrast, the thymic cortex appeared
      essentially normal. CyA had no detectable effect on the intensity of
      microenvironmental expression of MHC class II molecules in either cortex or
      medulla, although the number of MHC class II positive medullary cells was reduced
      after CyA treatment. CyA also had a differential effect on the thymic lymphocyte
      populations where there was little change in the Thy-1 bright, CD5 dull, CD4+,
      CD8+ cortical thymocytes but a depletion of the Thy-1 dull, CD5 bright, CD4 or
      CD8 single-positive medullary cells. This lymphocyte loss may be due partly to
      increased migration from thymus to spleen and other peripheral lymphoid organs,
      and partly to a block in the differentiation stage from cortical to medullary
      lymphocyte. The thymic microenvironment and lymphocyte subpopulations recover
      rapidly after cessation of CyA treatment, although there may be longer term
      functional defects resulting from the CyA-induced injury.

PMID- 12412761
TI  - Reactivity of human anti-alpha-galactosyl IgG antibody with alpha(1-->3)-linked
      galactosyl epitopes exposed on basement membranes and on glomerular epithelial
      cells: an in vitro and in vivo study in the mouse.
AB  - Anti-alpha-galactosyl antibody (a-Gal Ab) is a human natural antibody belonging
      to the IgG class, found in high titres in all normal sera regardless of blood
      group, and specifically recognizing alpha (1-->3)-linked galactosyl residues. We
      have observed by radioimmunoassay, ELISA, passive haemagglutination and
      immunofluorescence blocking studies that affinity-purified a-Gal Ab reacted with
      mouse laminin, but not with the other mouse basement membrane proteins tested; it
      was able to fix complement in vitro. When injected intravenously into mice, the a
      Gal Ab was found to mainly accumulate in kidneys, liver, spleen and lungs. No
      acute respiratory distress syndrome was observed shortly after the i.v. injection
      of 100 or 200 microg of antibodies. These doses of a-Gal Ab were also unable to
      induce acute glomerular injury. However, in primary cultures, the a-Gal Ab (100
      or 200 microg per ml of medium) was shown to impair the attachment of mouse
      glomerular epithelial cells to mouse laminin and to elicit complement-dependent
      cell damage. The data indicate that the a-Gal Ab can interact in vitro and/or in
      vivo with alpha (1-->3)-linked galactosyl residues exposed on murine laminin or
      on murine cultured glomerular epithelial cells. Although this antibody fails to
      be pathogenic when administered at low doses in the intact animal, similar doses
      can alter some metabolic properties of these cells in vitro.

PMID- 12412762
TI  - Demonstration of hepatic Fc receptor function in vivo.
AB  - We describe an investigation of the Fc-receptor dependent function of the hepatic
      component of the mononuclear phagocyte system (MPS) in rats. Erythrocytes
      sensitized with the rat IgG2b monoclonal antibody (JY1/98) were cleared by the
      liver in decomplemented splenectomized rats. This immune clearance was Fc
      receptor dependent since it was effectively inhibited by immune complexes of
      bovine serum albumin (BSA) and rabbit-anti-BSA antibody formed either in vivo or
      in vitro. Immune complexes formed with F (ab')2 fragment of the rabbit anti-BSA
      antibody had no effect. Heat-aggregated human gamma globulin was virtually
      without any competitive activity in the Fc-mediated clearance system. Immune
      complexes inhibited the hepatic clearance of antibody-sensitized erythrocytes but
      did not have a significant effect on the early rapid removal of erythrocytes pre
      coated with antibody and complement.

PMID- 12412763
TI  - Granulocyte-macrophage colony-stimulating activity in the serum of mice
      stimulated with homogenates of Trypanosoma gambiense.
AB  - Infection of mice with Trypanosoma gambiense induced a rapid and transient
      increase in levels of serum granulocyte-macrophage colony-stimulating activity
      (GM-CSA) followed by an increase in the numbers of circulating neutrophils and
      large mononuclear cells. Similar phenomena were observed in mice injected with a
      trypanosomal homogenate. In such mice, levels of GM-CSA were markedly elevated as
      early as 1-2 days after administration of the homogenate and then rapidly
      decreased. Numbers of circulating neutrophils and large mononuclear cells
      increased within 2 and 3 days after injection of the homogenate, respectively.
      Induction of GM-CSA by the trypanosomal homogenate promoted colony formation by
      normal spleen cells, but did not support colony formation by spleen cells from
      mice treated with 5-fluorouracil. Serum levels of GM-CSA were elevated by
      injection of crude trypanosomal membrane fractions, but not by soluble components
      found in supernatants from centrifuged trypanosomal homogenates. GM-CSA-inducing
      ability of the crude membrane fraction was sensitive to heating at 60 degrees C
      for 30 min, treatment at pH 2.0, pronase digestion, periodate oxidation, and
      exposure to 0.1% sodium dodecyl sulphate. This biological activity was also
      reduced by trypsinization of living trypanosomes before preparation of membrane
      fractions. These findings suggest that the active component of parasites to
      induce GM-CSA is associated with a glycoprotein in the surface coat of T.
      gambiense. GM-CSA may be related to the haematological and immunopathological
      alterations that occur in African trypanosomiasis.

PMID- 12412764
TI  - Protective immune responses with trickle infections of third-stage filarial
      larvae of Wuchereria bancrofti in mice.
AB  - Groups of inbred BALB/c mice were immunized with trickle doses of 20 live third
      stage larvae (L3) of Wuchereria bancrofti each subcutaneously or with 150 microg
      of sonicated microfilarial antigens emulsified in Freund's adjuvant
      intramuscularly. An antibody response was distinctly seen after seven trickle
      doses of L3 and following with the sonicated microfilarial immunization. Due to
      the non-permissive nature of inbred mice to W. bancrofti infections, a novel
      immunization approach was adopted using appropriate age- and sex-matched
      controls. The anti-L3 response in terms of antibody-dependent cell-mediated
      adhesion and killing was assessed in the immunized animals by implanting live L3
      in micropore chambers subcutaneously. About 75% L3 W. bancrofti were affected in
      animals sensitized with seven trickle doses of L3. When sensitizations were
      continued, as high as 92% of L3 were seen affected with ten trickle doses
      compared with 27% in age-matched controls. Immunization with sonicated
      microfilarial antigen affected about 70% of L3 as opposed to only 12% in
      controls. A positive correlation was observed in the antibody response with
      protectivity. This method of induction and assessment of the anti-L3 response
      involving a small set of animals has not only allowed quantification of affected
      L3 but has also enabled us to visualize larval conditions in immunologically
      activated animals. The micropore chamber system, would be useful in monitoring
      the induction of protective immune response against W. bancrofti in inbred mice.
      Experimentation on large numbers of animals is required to elucidate further the
      response of mice towards L3 and also to pinpoint the putative protective
      antigens.

PMID- 12412765
TI  - Effects of two types of cobra venom factor on porcine complement activation and
      pulmonary artery pressure.
AB  - Autologous porcine plasma that has been incubated with cuprophan haemodialysis
      membranes causes pulmonary hypertension and peripheral leucopenia following
      reinfusion into swine. These effects appear to be mediated by biologically active
      fragments of C3 and C5 that are generated as a consequence of ex vivo activation
      of complement. Putatively, C5a induces the leucopenia; however, the specific
      contributions of products of C3 and C5 activation to the pulmonary
      vasoconstriction have not been elucidated. In the present study, the effects of
      in vivo infusion of two different types of cobra venom factor (CVF) on peripheral
      leucocyte count and pulmonary artery pressure in the swine are reported. The CVF
      from Naja n. naja (CVF(TN)) was shown to activate both porcine C3 and C5, whereas
      the CVF from Naja h. haje (CVF(NH)) activated only C3. Both types of CVF produced
      pulmonary hypertension. Significant peripheral leucopenia, however, was observed
      only with CVF(TN). These results suggest that activation products of C3
      contribute to the pulmonary hypertension but not to the peripheral leucopenia
      observed during haemodialysis using dialysis membranes that activate complement.

PMID- 12412766
TI  - Second antibody for improvement of antibody imaging: liposome-entrapped and free
      preparations in animal and human studies.
AB  - When anti-tumour antibodies are given systematically for tumour imaging or
      therapy, second antibody directed against the first (anti-tumour) antibody can be
      used to accelerate clearance of first antibody, thus improving discrimination
      between tumour and normal tissues. Liposome-entrapped, and free second antibodies
      (LESA and FSA, respectively) have been compared in an animal tumour model system
      and in patients with cancer. Nude mice bearing xenografts of human colon
      carcinoma were given goat antibody to carcino-embryonic antigen (CEA) as first
      antibody and horse anti-goat second antibody. Patients with gastrointestinal
      carcinomas received i.v. 131I-labelled goat anti-CEA or mouse monoclonal 17-1A
      first antibody and unlabelled horse angi-goat or rabbit anti-mouse second
      antibody, respectively. Antibody distribution was studied by serial gamma camera
      imaging. The effectiveness of LESA and FSA depended on dose. Tumour-to-blood
      ratios were increased up to eight-fold by either method in animals. Tumour
      imaging was enhanced among 15 patients with gastrointestinal cancer and tumour
      was correctly identified at five sites where it was not seen by a background
      subtraction method. No significant toxicity occurred in patients nor in rabbits
      studied for evidence of immune complex mediated disease. LESA and FSA appear to
      be equally effective.

PMID- 12412767
TI  - Feedback suppression of B cell colony formation in healthy individuals.
AB  - Proliferation and differentiation of B cells has been extensively studied and the
      study of feedback suppression of B cell proliferation has been limited to humoral
      factors. However, very little is known about feedback suppression of B cell
      proliferation by cellular influences. We have previously reported on the role of
      T cells and their subsets on B cell proliferation in that we did not observe
      suppression of B cell colony growth by T cells. We now report on the role of B
      cells in limiting B cell proliferation. B cell colonies were grown in methyl
      cellulose for either 3 days or 5-6 days utilizing 2 x 10(5) T cells irradiated
      with 9,000 rads, and 2 x 10(5) B cells. The B cells were then obtained from these
      colonies and increasing numbers of cells were added to fresh autologous B cells
      that were further cultured for 5 days to form new B cell colonies. At the end of
      this period, B cell colony numbers were determined. Our data show that addition
      of CD19- and CD20- positive B cells recovered from mature colonies after 5 days
      to fresh B cells suppressed further B cell colony growth in all cases tested,
      whereas addition of CD19-positive B cells recovered from immature colonies after
      3 days of culture did not suppress further B cell colony growth. Elimination of
      CD 19- or CD20-positive cells with monoclonal antibody to CD19 and complement or
      by the technique of panning enhanced colony growth. Supernatants obtained from B
      cell colonies did not suppress B cell colony formation. Our data suggest that
      there is feedback suppression of normal progenitor B cell proliferation by
      constituent B cells and that this effect develops during maturation of colonies
      during the growth phase.

PMID- 12412768
TI  - Surveillance for chronic fatigue syndrome--four U.S. cities, September 1989
      through August 1993.
AB  - PROBLEM/CONDITION: Although chronic fatigue syndrome (CFS) has been recognized as
      a cause of morbidity in the United States, the etiology of CFS is unknown. In
      addition, information is incomplete concerning the clinical spectrum and
      prevalence of CFS in the United States. REPORTING PERIOD COVERED: This report
      summarizes CFS surveillance data collected in four U.S. cities from September
      1989 through August 1993. DESCRIPTION OF SYSTEM: A physician-based surveillance
      system for CFS was established in four U.S. metropolitan areas: Atlanta, Georgia;
      Wichita, Kansas; Grand Rapids, Michigan; and Reno, Nevada. The objectives of this
      surveillance system were to collect descriptive epidemiologic information from
      patients who had unexplained chronic fatigue, estimate the prevalence and
      incidence of CFS in defined populations, and describe the clinical course of CFS.
      Patients aged > or = 18 years who had had unexplained, debilitating fatigue or
      chronic unwellness for at least 6 months were referred by their physicians to a
      designated health professional(s) in their area. Those patients who participated
      in the surveillance system a) were interviewed by the health professional(s); b)
      completed a self-administered questionnaire that included their demographic
      information, medical history, and responses to the Beck Depression Inventory, the
      Diagnostic Interview Schedule, and the Sickness Impact Profile; c) submitted
      blood and urine samples for laboratory testing; and d) agreed to a review of
      their medical records. On the basis of this information, patients were assigned
      to one of four groups: those whose illnesses met the criteria of the 1988 CFS
      case definition (Group I); those whose fatigue or symptoms did not meet the
      criteria for CFS (Group II); those who had had an identifiable psychological
      disorder before onset of fatigue (Group III); and those who had evidence of other
      medical conditions that could have caused fatigue (Group IV). Patients assigned
      to Group III were further evaluated to determine the group to which they would
      have been assigned had psychological illness not been present, the epidemiologic
      characteristics of the illness and the frequency of symptoms among patients were
      evaluated, and the prevalence and incidence of CFS were estimated for each of the
      areas. RESULTS: Of the 648 patients referred to the CFS surveillance system, 565
      (87%) agreed to participate. Of these, 130 (23%) were assigned to Group I; 99
      (18%), Group II; 235 (42%), Group III; and 101 (18%), Group IV. Of the 130 CFS
      patients, 125 (96%) were white and 111 (85%) were women. The mean age of CFS
      patients at the onset of illness was 30 years, and the mean duration of illness
      at the time of the interview was 6.7 years. Most (96%) CFS patients had completed
      high school, and 38% had graduated from college. The median annual household
      income/for CFS patients was $40,000. In the four cities, the age-, sex-, and race
      adjusted prevalences of CFS for the 4-year surveillance period ranged from 4.0 to
      8.7 per 100,000 population. The age-adjusted 4-year prevalences of CFS among
      white women ranged from 8.8 to 19.5 per 100,000 population. INTERPRETATION: The
      results of this surveillance system were similar to those in previously published
      reports of CFS. Additional studies should be directed toward determining whether
      the data collected in this surveillance system were subject to selection bias
      (e.g., education and income levels might have influenced usage of the health-care
      system, and the populations of these four surveillance sites might not be
      representative of the U.S. population). ACTIONS TAKEN: In February 1997, CDC
      began a large-scale, cross-sectional study at one surveillance site (Wichita) to
      describe more completely the magnitude and epidemiology of unexplained chronic
      fatigue and CFS.

PMID- 12412769
TI  - Tetanus surveillance--United States, 1991-1994.
AB  - PROBLEM/CONDITION: Despite the widespread availability of a safe and effective
      vaccine against tetanus, 201 cases of the disease were reported during 1991-1994.
      Of patients with known illness outcome, the case-fatality rate was 25%. REPORTING
      PERIOD COVERED: 1991-1994. DESCRIPTION OF SYSTEM: Physician-diagnosed cases of
      tetanus are reported to local and state health departments, the latter of which
      reports these cases on a weekly basis to CDC's National Notifiable Disease
      Surveillance System. Since 1965, state health departments also have submitted
      supplemental clinical and epidemiologic information to CDC's National
      Immunization Program. RESULTS: During 1991-1994, 201 cases of tetanus were
      reported from 40 states, for an average annual incidence of 0.02 cases per
      100,000 population. Of the 188 patients for whom age was known, 101 (54%) were
      aged > or = 60 years and 10 (5%) were aged < 20 years. No cases of neonatal
      tetanus were reported. Among adults, the risk for tetanus increased with age; the
      risk for persons aged > or = 80 years was more than 10 times greater than the
      risk for persons aged 20-29 years. All deaths occurred among persons aged > or =
      30 years. The case-fatality rate (overall: 25%) increased with age, from 11% in
      persons aged 30-49 years to 54% in persons aged > or = 80 years. Only 12% of all
      patients were reported to have received a primary series of tetanus toxoid before
      onset of illness. For 77% of patients, tetanus occurred after an acute injury was
      sustained. Of patients who obtained medical care for their injury, only 43%
      received tetanus toxoid as part of wound prophylaxis. INTERPRETATION: The
      epidemiology of reported tetanus in the United States during 1991-1994 was
      similar to that during the 1980s. Tetanus continued to be a severe disease
      primarily of older adults who were unvaccinated or inadequately vaccinated. Most
      tetanus cases occurred after an acute injury was sustained, emphasizing the need
      for appropriate wound management. ACTIONS TAKEN: In addition to decennial booster
      doses of tetanus-diphtheria toxoid during adult life, the Advisory Committee on
      Immunization Practices (ACIP) recommends vaccination visits for adolescents at
      age 11-12 years and for adults at age 50 years to enable health-care providers to
      review vaccination histories and administer any needed vaccine. Full
      implementation of the ACIP recommendations should virtually eliminate the
      remaining tetanus burden in the United States.

PMID- 12412770
TI  - Malaria surveillance--United States, 1993.
AB  - PROBLEM/CONDITION: Malaria is caused by infection with one of four species of
      Plasmodium (P. falciparum, P. vivax, P. ovale, and P. malariae), which are
      transmitted by the bite of an infective female Anopheles sp. mosquito. Most
      malaria cases in the United States occur among persons who have traveled to areas
      (i.e., other countries) in which disease transmission is ongoing. However, cases
      are transmitted occasionally through exposure to infected blood products, by
      congenital transmission, or by local mosquito-borne transmission. Malaria
      surveillance is conducted to identify episodes of local transmission and to guide
      prevention recommendations. REPORTING PERIOD COVERED: Cases with onset of illness
      during 1993. DESCRIPTION OF SYSTEM: Malaria cases confirmed by blood smear are
      reported to local and/or state health departments by health-care providers and/or
      laboratories. Case investigations are conducted by local and/or state health
      departments, and the reports are transmitted to CDC. RESULTS: CDC received
      reports of 1,275 cases of malaria in persons in the United States and its
      territories who had onset of symptoms during 1993; this number represented a 40%
      increase over the 910 malaria cases reported for 1992. P. vivax, P. falciparum,
      P. ovale, and P. malariae were identified in 52%, 36%, 4%, and 3% of cases,
      respectively. The species was not determined in the remaining 5% of cases. The
      278 malaria cases in U.S. military personnel represented the largest number of
      such cases since 1972; 234 of these cases were diagnosed in persons returning
      from deployment in Somalia during Operation Restore Hope. In New York City, the
      number of reported cases increased from one in 1992 to 130 in 1993. The number of
      malaria cases acquired in Africa by U.S. civilians increased by 45% from 1992; of
      these, 34% had been acquired in Nigeria. The 45% increase primarily reflected
      cases reported by New York City. Of U.S. civilians who acquired malaria during
      travel, 75% had not used a chemoprophylactic regimen recommended by CDC for the
      area in which they had traveled. Eleven cases of malaria had been acquired in the
      United States: of these cases, five were congenital; three were induced; and
      three were cryptic, including two cases that were probably locally acquired
      mosquito-borne infections. Eight deaths were associated with malarial infection.
      INTERPRETATION: The increase in the reported number of malaria cases was
      attributed to a) the number of infections acquired during military deployment in
      Somalia and b) complete reporting for the first time of cases from New York City.
      ACTIONS TAKEN: Investigations were conducted to collect detailed information
      concerning the eight fatal cases and the 11 cases acquired in the United States.
      Malaria prevention guidelines were updated and disseminated to health-care
      providers. Persons who have a fever or influenza-like illness after returning
      from a malarious area should seek medical care, regardless of whether they took
      antimalarial chemoprophylaxis during their stay. The medical evaluation should
      include a blood smear examination for malaria. Malaria can be fatal if not
      diagnosed and treated rapidly. Recommendations concerning prevention and
      treatment of malaria can be obtained from CDC.

PMID- 12412771
TI  - Summary statement from a workshop on asymptomatic primary hyperparathyroidism: a
      perspective for the 21st century.

PMID- 12412772
TI  - The epidemiology of primary hyperparathyroidism in North America.
AB  - The impact of primary hyperparathyroidism (HPT) on the population has not been
      well documented, particularly with respect to asymptomatic HPT. Only 83 deaths
      were attributed to hyperparathyroidism in the United States in 1999, for a
      reported death rate of just 0.3 per million per year. Many more patients are
      affected, of course, and the national hospitalization rate for HPT was 8.0 per
      100,000 in 1999, counting 22,000 "all-listed" diagnoses, and 1.8 per 100,000
      counting only the 5000 admissions where HPT was the first-listed discharge
      diagnosis. Surgery was performed on approximately 12,000 hospitalized patients in
      the United States in 1999, for a parathyroidectomy rate of about 4.4 per 100,000
      per year. Overall, the annual incidence of HPT was 20.8 per 100,000 in Rochester,
      MN, during 1983-1992, although this represented a substantial decline from
      incidence rates reported a decade earlier. There are no estimates of HPT
      prevalence from this country, but the figure was 4.3 per 1000 in one Swedish
      survey. By any of these measures, HPT is more common in women than men and
      increases with aging in both sexes. Other risk factors are obscure. The cost of
      parathyroidectomies for HPT has been estimated at $282 million annually in the
      United States, but no reliable estimate of overall expenditures for HPT has been
      made, and no formal assessment of the cost-effectiveness of any treatment
      approach has been carried out. Better data on the disability and costs related to
      HPT and its treatment will be needed to devise the most efficient approaches to
      patient management.

PMID- 12412773
TI  - Epidemiology of primary hyperparathyroidism in Europe.
AB  - Primary hyperparathyroidism (PHPT) is one of the most common endocrine diseases.
      Its clinical presentation has dramatically changed in the last 40 years, and now
      the disease typically affects elderly women and is characterized by mild
      hypercalcemia and few traditional classic (bone and kidney) manifestations. The
      change in clinical presentation was largely caused by development of automated
      serum calcium measurement in the early 1970s that made possible the introduction
      of serum calcium determination in the routine biochemical screening and the
      identification of a large number of "asymptomatic" patients. This led also to a 5
      fold increase in the apparent incidence of PHPT for the identification of
      patients who were never diagnosed before (catch-up effect). From the most recent
      and accurate study, a 21/1000 PHPT prevalence was found in women aged 55-75
      years, which is equivalent to 3/1000 prevalence in the general population.
      Epidemiological studies performed in Rochester, Minnesota, have shown an apparent
      decline in the annual incidence from 75 to approximately 20/100,000 in the last
      decade. Most of this apparent decline in the incidence of PHPT is explained by
      the decline of the "catch-up effect," although a number of factors that might
      result in changes in PHPT incidence have been identified. Vitamin D deficiency is
      particularly common in people living in Southern European countries, and this may
      contribute to underestimating the prevalence of PHPT, because total serum calcium
      may be normal in these patients. On the other hand vitamin D deficiency may be
      associated with more severe clinical expression of the disease, which may make
      clinically manifest otherwise mild asymptomatic cases. Irradiation of the neck
      and upper chest for benign diseases is a well-known risk factor for the
      development of PHPT, and a history of irradiation can be obtained in as many as
      15-25% of PHPT patients. Because this therapeutic procedure is no longer used,
      the number of radiation-associated cases of PHPT is expected to progressively
      decline in the future. Restriction of healthcare financing may also contribute to
      the apparent decrease in the incidence of PHPT because calcium measurement is now
      performed only in patients who have a suspected abnormality in calcium
      homeostasis is. On the other hand, the screening for osteoporosis, which often
      includes serum calcium determination, is increasingly carried out in women around
      the sixth decade of life, when the incidence of PHPT is by far more frequent. In
      conclusion, the introduction of serum calcium screening in the early 1970s
      exerted an impressive effect on the epidemiology of PHPT, with an apparent
      incidence initially rising and then falling by the 1990s secondary to the
      diminution of the "catch-up effect." Other environmental, nutritional, or
      iatrogenic factors might influence the incidence of the disease, but the overall
      effect is unlikely to be relevant.

PMID- 12412774
TI  - The pathophysiology of primary hyperparathyroidism.
AB  - The parathyroid glands play a key role in maintaining near constancy of the
      extracellular calcium concentration ( Ca(o)2+) through their capacity to sense
      even minute changes in the level of blood calcium from its normal level. The G
      protein-coupled, Ca(o)(2+)-sensing receptor (CaSR) is the mechanism through which
      the parathyroid chief cells senses changes in Ca(o)2+. In primary
      hyperparathyroidism (PHPT), Ca(o)2+ is reset upward from its normal level. This
      defect likely arises from increases in both the mass of pathological parathyroid
      tissue as well as the set point for Ca(o)(2+)-regulated parathyroid hormone (PTH)
      release. The former likely arises from somatic mutations that enhance parathyroid
      cellular proliferation, although our understanding of the mechanism(s) underlying
      the latter is incomplete. However, substantial insights have been achieved
      through the study of inherited disorders caused by mutations in CaSR gene. In
      familial hypocalciuric hypercalcemia (FHH), heterozygous inactivating mutations
      in the CaSR gene produce mild, generally asymptomatic hypercalcemia, whereas in
      neonatal severe hyperparathyroidism (NSHPT), homozygous inactivating mutations
      cause severe hypercalcemia and hyperparathyroidism. Thus, the body's "calciostat"
      is reset upward in FHH and NSHPT because of resistance of CaSR-expressing cells,
      including the parathyroid cells, to Ca(o)2+. In FHH, there is a reduced
      complement of normal CaSRs (e.g., haploinsufficiency) that likely provides an
      explanation for the Ca(o)(2+)-resistance in this condition, whereas in NSHPT,
      there are no normally functioning CaSRs, thereby engendering more severe Ca(o)2+
      resistance. Although somatic mutations in the CaSR gene could provide an
      explanation for the Ca(o)(2+)-resistance in PHPT, no such mutations have been
      found. Instead, in PHPT, the resistance of pathological parathyroid glands to
      Ca(o)2+ results, at least in part, from a reduced expression of otherwise
      apparently structurally normal CaSRs. Thus, PTH-dependent hypercalcemia can occur
      in the setting of either inherited, generalized resistance to Ca(o)2+ (i.e., FHH
      and NSHPT) or acquired tissue selective resistance of pathological parathyroid
      glands to Ca(o)2+ (e.g., PHPT).

PMID- 12412775
TI  - Molecular pathogenesis of primary hyperparathyroidism.
AB  - This article will primarily focus on the molecular pathogenesis of common,
      sporadic (nonfamilial) parathyroid adenomas; two genes currently have established
      roles in the development of these tumors. The cyclin D1/PRAD1 gene was identified
      as a clonally activated oncogene in parathyroid adenomas and has subsequently
      been established as a major contributor to human neoplasia. Overexpression of
      cyclin D1, a key regulator of the cell cycle, has been implicated in the
      pathogenesis of 20-40% of sporadic parathyroid adenomas. That such cyclin D1
      overexpression indeed constitutes a stimulus to excessive parathyroid cell
      proliferation has been confirmed experimentally by the development of a
      transgenic mouse model with parathyroid-targeted overexpression of cyclin D1.
      Parathyroid hormone (PTH)-cyclin D1 transgenic mice develop parathyroid
      hypercellularity, biochemical hyperparathyroidism, and a shifted in vivo
      parathyroid-calcium setpoint; these mice constitute an animal model of human
      hyperparathyroidism in which aspects of tumorigenesis, parathyroid secretory
      setpoint control, and the pathophysiology of the chronic hyperparathyroid state
      can be further investigated. The MEN1 tumor suppressor is the only other gene to
      date with an established role in the pathogenesis of sporadic parathyroid
      adenomatosis. Specific clonal alterations involving somatic mutation and/or
      deletion of both MEN1 alleles have been demonstrated in about 15-20% of sporadic
      parathyroid adenomas. Allelic losses on 11q occur in roughly twice this number of
      adenomas, raising the still-unresolved possibility that an additional tumor
      suppressor gene on 11q may be the functional target of many of these acquired
      deletions. A mouse model of MEN1 deficiency causes a phenotype that includes
      parathyroid hypercellularity albeit unaccompanied by biochemical
      hyperparathyroidism, and additional mouse models in which menin deficiency is
      targeted to the parathyroids will likely provide additional important insights.
      The MEN1 gene product menin may have a role in transcriptional regulation
      involving JunD; several other menin-interacting proteins have also been
      identified. The in vivo mechanism of menin's actions, with special attention to
      its role as a parathyroid oncosuppressor, will be important to establish, as will
      the potential interrelationships between these pathways and those involving
      cyclin D1. A number of genes, put forth as candidate tumor suppressors based on
      their genomic locations, roles in familial disease, and/or other relevant
      biological functions, have been examined for pathogenetic mutations in sporadic
      parathyroid tumors with negative results; these include the calcium-sensing
      receptor protein (CaR), vitamin-D receptor (VDR), and RET. However, the CaR,
      which when partially or markedly deficient because of germline mutation can cause
      familial hypocalciuric hypercalcemia or neonatal severe hyperparathyroidism, must
      still be considered as having a potentially important secondary role in the
      manifestations of sporadic parathyroid tumors. Future goals include identifying
      additional parathyroid oncogenes and tumor suppressor genes; exploiting tools of
      complex trait genetics to ascertain whether development of "sporadic"
      hyperparathyroidism might be influenced by predisposing polymorphic alleles in
      the population; obtaining molecular insights into the relationship between
      proliferative and hormone regulatory abnormalities of hyperparathyroidism; and
      obtaining molecular insights into the observed association of parathyroid
      neoplasia with exposure to ionizing irradiation and with the postmenopausal
      state.

PMID- 12412776
TI  - Hyperparathyroidism in hereditary syndromes: special expressions and special
      managements.
AB  - Hyperparathyroidism (HPT) in its hereditary variants assumes special forms, has
      special associations, and requires special managements. Familial hypocalciuric
      hypercalcemia (FHH or FBHH) and neonatal severe primary hyperparathyroidism
      (NSHPT) reflect heterozygous or homozygous mutations, respectively, in the
      calcium-sensing receptor. FHH and NSHPT represent the mildest and severest
      variants of HPT. Both cause hypercalcemia from birth and atypical HPT that always
      and uniquely persists after subtotal parathyroidectomy. Their HPT is likely
      polyclonal and nonneoplastic. In contrast, mono- or oligo-clonal parathyroid
      neoplasia underlays most other HPT variants: multiple endocrine neoplasia type 1
      (MEN1), multiple endocrine neoplasia type 2A (MEN2A), and hyperparathyroidism-jaw
      tumor syndrome (HPT-JT). Familial-isolated HPT combines several diagnoses,
      including occult forms of the above syndromes. Each neoplastic variant has tumors
      in multiple parathyroids and a delayed, but still early age of onset for HPT
      (average age, 25-35 years). Each justifies special and similar approaches to
      parathyroidectomy: typically, identification of four glands, subtotal
      parathyroidectomy, rapid intraoperative parathyroid hormone (PTH) assays, and
      parathyroid cryopreservation. Outcomes of parathyroidectomy remain suboptimal in
      each. Each syndrome of parathyroid neoplasia associates with characteristic
      cancer(s): enteropancreatic neuroendocrine or foregut carcinoid tissues (MEN1),
      thyroidal C cells (MEN2A), or parathyroid (HPT-JT). HPT has promoted gene
      discovery more through its rare hereditary variants than through common adenoma;
      the main genes causing four of six hereditary variants are known. The RET
      mutation test became essential in management of MEN2A. The MEN1 test is less
      urgent, because it rarely guides a major patient benefit. The CASR test, perhaps
      least urgent, has largely been unavailable. Further progress in molecular
      genetics will enhance understandings, diagnosis, and therapy of HPT.

PMID- 12412777
TI  - Primary hyperparathyroidism in children and adolescents: the Johns Hopkins
      Children's Center experience 1984-2001.
AB  - Primary hyperparathyroidism (PHPT) generally affects older adults, yet it also
      occurs in a small number of children, adolescents, and young adults. The early
      presentation of PHPT in children and adolescents suggests that these parathyroid
      tumors may differ in pathobiology from more typical tumors that occur in older
      adults. We performed a retrospective analysis of cases of PHPT treated surgically
      at the Johns Hopkins Children's Center between 1984 and 2001. Patients were
      ascertained by review of surgical pathology records, which confirmed the
      diagnosis of PHPT, and clinical and biochemical characteristics were extracted
      from medical records. We retrieved data on 16 of 17 patients; these patients (9
      male, 7 female) were aged 10.5-20 years (16.3 +/- 2.9 years, median 16.8 years)
      at the time of diagnosis. Five patients had known metabolic risk factors for
      development of hyperparathyroidism, whereas 11 patients had spontaneous PHPT. The
      preoperative serum calcium level was markedly elevated (2.98 +/- 0.25 mM) in all
      13 patients with normal renal function. Nearly all (77%) of these patients were
      found to have at least one symptom or sign of PHPT, most commonly hypercalciuria
      (83%) or nephrolithiasis (54%). Of these patients, 11 (85%) had single adenomas
      (mean weight, 597 mg; median, 600 mg; range, 170-1550 mg) while 2 had multiple
      gland disease, including 1 patient with multiple endocrine neoplasia type 2
      (MEN2). In all cases, surgery was curative. These data suggest that PHPT in
      children is a more severe disease than in older adults, which may reflect a bias
      of ascertainment or a difference in fundamental parathyroid pathobiology.

PMID- 12412778
TI  - Familial benign hypocalciuric hypercalcemia.
AB  - Clinical, biochemical, and pathophysiological observations over several decades
      on familial benign hypocalciuric hypercalcemia (FBHH) ultimately culminated in
      the 1990s in the unraveling of the genetic basis of this calcium-sensing familial
      disorder. An intuitive pursuit of the pathophysiology of this "experiment of
      nature" in a series of elegant molecular biological studies linked FBHH, in the
      majority of cases, to the short arm of chromosome 3 (FBHH3q), where the calcium
      sensing receptor (CaSR) is located. FBHH is a rare autosomal dominant disorder
      exhibiting benign hypercalcemia, inappropriately normal parathyroid hormone (PTH)
      levels, and relative hypocalciuria, thus reflecting partial resistance to the
      normal effects of extracellular calcium on parathyroid glands and kidneys.
      Patients with FBHH are asymptomatic, and if diagnosed at an early age, seem to
      have normal longevity and usually do not suffer any of the skeletal
      (demineralization or fractures) or renal complications of classical primary
      hyperparathyroidism. Before an adequate recognition of the syndrome, patients
      with FBHH were misdiagnosed as having primary hyperparathyroidism and may have
      been subjected to unnecessary and unsuccessful parathyroidectomy. FBHH3q seems to
      be, in the majority of cases, the clinical manifestation of heterozygous
      reduction or loss of CaSR function in the parathyroid glands and renal tubules.
      In general, in view of the benign nature of FBHH, no particular intervention is
      needed except reassurance and counseling against parathyroidectomy.

PMID- 12412779
TI  - Asymptomatic primary hyperparathyroidism: new issues and new questions--bridging
      the past with the future.
AB  - The earliest clinical descriptions of PHPT pointed to an inexorably progressive
      disorder. Now, in many asymptomatic individuals who do not meet any surgical
      guidelines. PHPT in general, does not seem to be progressive. Most asymptomatic
      patients seem to remain asymptomatic over many years of observation. In those
      with major clinical manifestations, nephrolithiasis is by far the most common. In
      these patients, surgery is clearly indicated. Bone densitometry is an
      indispensable component of the evaluation as well as in monitoring because there
      is evidence of bone involvement in most patients. This contrasts with the
      skeletal X-ray, which is invariably negative. Nevertheless, patients with PHPT
      can show a bone mass measurement either at the cortical or cancellous skeleton
      that is more than 2 SDs below age- and sex-matched control subjects. Bone
      density, serum calcium concentration, and/or urinary calcium excretion per se can
      show evidence for progression in as many as 25% of patients with asymptomatic
      PHPT. There are newer pharmacologic approaches to PHPT that are the subject of
      intense investigation. The bisphosphonates and the calcimimetics show particular
      promise in this regard. Unanswered are such questions as whether the lower bone
      density in the milder patients will increase substantially as in those who
      undergo successful parathyroidectomy and whether fracture risk would therefore be
      reduced. Can medical therapy reduce serum calcium. parathyroid hormone levels,
      and other biochemical indices of PHPT? Can medical therapy improve bone density
      without the need for surgery. The issues outlined in this presentation and
      further amplified in other presentations given in this workshop lead to a series
      of questions that, in turn, may lead to modified guidelines for the management of
      these patients. The questions are as follows. (1) Should there be any changes in
      diagnostic criteria for PHPT? (2) Should the guidelines for surgery in PHPT be
      changed in light of new data over the past decade? What should those guidelines
      be? (3) At present, is there sufficient evidence of clinical benefit with
      specific medical therapies to recommend their use? In which patients? (4) Can
      some patients be followed without surgery? If so, how should they be monitored?
      (5) When surgery is the preferred option, what are the relative merits of
      minimally invasive procedures compared with more conventional surgery? (6) What
      is the role of localization techniques in identifying abnormal parathyroid tissue
      preoperatively and intraoperatively? Are they sufficiently helpful and cost
      effective to warrant their use in all patients who undergo parathyroid surgery?
      If not, in what patients should they be recommended? (7) What items should be
      placed on the research agenda for PHPT over the next decade?

PMID- 12412780
TI  - Clinical presentation of primary hyperparathyroidism in Europe--nationwide cohort
      analysis on mortality from nonmalignant causes.
AB  - Primary hyperparathyroidism (PHPT) in developing countries is characterized by
      severe skeletal and renal complications and apparent mortality. This is in
      contrast with the Western hemisphere where research interests, rather than
      characteristics of PHPT, seem to differ between regions. In Europe, the
      "nontraditional" aspects of mild-to-moderate PHPT have attracted particular
      attention. These symptoms and signs include risk factors for cardiovascular
      disease such as hypertension, phenotype IV lipoproteinemia, insulin resistance,
      cardiac and vascular dysfunction, and morbidity in cardiovascular diseases.
      Mortality in cardiovascular diseases has been found to be increased in studies
      that include over 6500 European patients; this risk could not be verified in
      North American patients. By use of the nationwide Cancer Registry and Causes-of
      Death Registry, mortality was analyzed in 10,995 Swedish patients (> 20 years of
      age) subjected to extirpation of single parathyroid adenoma of PHPT during 1958
      1997. The Swedish population standardized for age, sex, and calendar year was
      used as control. The first postoperative year was excluded from the analysis. In
      total, the study included 102,515 observed person-years in the patients. Results
      verify an increased risk of dying after operation for PHPT (standard mortality
      ratio, 1.2; 95% CI, 1.19-1.27). The increased risk persisted far beyond 15 years
      postoperatively and occurred in both sexes and in all investigated age groups.
      Principal causes of excess mortality were cardiovascular diseases, diabetes
      mellitus, and urogenital diseases in all age groups. However, in patients
      operated on between 1985 and 1997 (n = 6386), overall mortality did not differ
      from that of the normal population, although there was maintained excess death in
      stroke, diabetes mellitus, and urogenital diseases. These findings infer that
      modern paradigms of surgical treatment normalize the risk of dying from PHPT.
      This improvement may be a late consequence of liberalized calcium screenings that
      were introduced about 30 years ago and indicate that operation at early disease
      stages may offer a survival advantage. An association between diabetes mellitus
      and PHPT is substantiated.

PMID- 12412781
TI  - Role of vitamin D and calcium nutrition in disease expression and parathyroid
      tumor growth in primary hyperparathyroidism: a global perspective.
AB  - Since the classic description by Fuller Albright in the 1940s, primary
      hyperparathyroidism has evolved from a disease with classic signs and symptoms to
      a disease in search of symptoms! Since that time, two major events have occurred.
      First, in the United States, United Kingdom, and in most European countries,
      there has been a steady rise in the apparent incidence of the disease. Second,
      there has been a dramatic shift in the pattern of presentation. A majority of
      patients with primary hyperparathyroidism in countries with multichannel
      screening panels are asymptomatic. Skeletal and renal complications are uncommon,
      and osteitis fibrosa is rare. In contrast, the clinical presentation of primary
      hyperparathyroidism has changed very little in other regions such as the East,
      the Middle East, and some parts of the southern hemisphere over the same period
      of observation. Accordingly, we assessed the influence of vitamin D and calcium
      nutrition on the disease expression and parathyroid tumor growth in patients with
      primary hyperparathyroidism from different parts of the world. Between 1945 and
      1950, both the prevalence of osteitis fibrosa and parathyroid tumor weight
      declined dramatically in the United States, coinciding with fortification of milk
      with vitamin D. In contrast, osteitis fibrosa and parathyroid tumor weight
      changed very little in parts of the world where vitamin D depletion is endemic.
      Furthermore, for a comparable degree of vitamin D depletion, Asian Indians have
      significantly larger tumors compared with Americans (3.95 +/- 2.23 vs. 0.66 +/-
      2.84 g; p < 0.001). Within the United States, blacks have larger tumors compared
      with whites (0.78 +/- 2.87 vs. 0.58 +/- 2.78 g; p < 0.01). However, the slopes of
      regression between serum 25-hydroxyvitamin D, the best index of vitamin D
      nutrition, and parathyroid tumor weight, the best available index of parathyroid
      growth, were not significantly different between Asian Indians, whites, and
      blacks. We conclude that vitamin D and calcium nutrition of the population affect
      both the clinical expression and parathyroid tumor growth in patients with
      primary hyperparathyroidism. It will be of interest to see if the pattern of
      presentation of primary hyperparathyroidism changes when better nutritional
      policies are implemented in developing countries.

PMID- 12412782
TI  - Immunoassays for the detection of parathyroid hormone.
AB  - Biologically active parathyroid hormone (PTH) in humans with normal renal
      function circulates predominantly as an 84 amino acid peptide. PTH fragments of
      varying length arise either from metabolism of the intact hormone within the
      parathyroid glands or in peripheral tissues, such as liver, and the resulting
      carboxyl-terminal peptides are eliminated mainly by glomerular filtration and
      subsequent tubular degradation. Most of the initially raised anti-PTH antisera
      were directed against epitopes within the mid- or carboxyl-terminal regions of
      the hormone. These antibodies were used for the development of conventional,
      displacement-type radioimmunoassays, but provided only an index of the
      biologically active PTH(1-84) in the circulation. Subsequently developed
      immunometric assays use two distinct antibodies, a capture antibody usually
      directed against a carboxyl-terminal portion of PTH(1-84) and a radio- or enzyme
      labeled detection antibody usually directed against the amino-terminal portion of
      the hormone. Such assays were thought to detect largely, if not exclusively,
      intact PTH, thus providing the concentration of biologically active hormone in
      blood, which is especially important for establishing the diagnosis of
      hyperparathyroidism. However, serum samples from normal subjects and patients
      with primary or secondary hyperparathyroidism have demonstrated that most
      immunometric two-site sandwich assays detect, besides PTH(1-84), one or more
      recently discovered large carboxyl-terminal PTH fragments that lack a portion of
      the amino-terminal end of the molecule. Some of these amino-terminally truncated
      PTH molecules [ntPTH(1-84)] exhibit an elution profile on high performance liquid
      chromatography (HPLC) that is indistinguishable from that of synthetic PTH(784).
      Such peptides were previously thought to be of minimal if any biological
      activity, but recent studies have shown that synthetic PTH(7-84) has hypocalcemic
      properties in vivo and that it inhibits osteoclastic bone resorption and the
      formation of mature osteoclasts in vitro. It is currently unclear whether
      important differences in disease states can be revealed by comparing results
      obtained with older immunometric assays that measure the full-length hormone and
      ntPTH(1-84) versus newer assays that measure only PTH(1-84). Therefore, whereas
      most immunometric PTH assay systems are appropriate for the diagnosis of primary
      hyperparathyroidism, it is possible that immunometric assays designed to detect
      only PTH(1-84) will be more useful in certain diagnostic studies, for
      intraoperative PTH monitoring and for assessing the pulsatility of PTH secretion.
      In addition, the ability to distinguish between the relative concentrations of
      ntPTH(1-84) versus PTH(1-84) may reveal previously unsuspected roles for the
      ntPTH(1-84) fragments in the pathophysiology of patients with end-stage renal
      disease and/or other disorders involving parathyroid hormone.

PMID- 12412783
TI  - Primary hyperparathyroidism and the kidney: biochemical and clinical spectrum.
AB  - Primary hyperparathyroidism manifests biochemically as a disturbance in serum
      calcium homeostasis. The central organ setting serum calcium level is the kidney.
      It not only has the highest rate of active calcium transport, but the kidney also
      modulates serum calcium homeostasis by virtue of its endocrine role in 1,25
      hydroxyvitamin D secretion. Receptors for PTH are widely expressed throughout the
      renal tubule and are involved in both calcium transport and endocrine function.
      Biochemical manifestations of primary hyperparathyroidism by the kidney include
      increased tubular reabsorption of calcium, decreased reabsorption of phosphate
      and bicarbonate, and hypercalciuria. A reduction in glomerular filtration may
      occur in some patients with primary hyperparathyroidism, which perturbs the
      diagnostic relationships among biochemical variables and induces further
      increases in PTH secretion. Parathyroidectomy rapidly restores the biochemical
      abnormalities to normal apart from chronic reduced glomerular filtration.
      Clinical manifestations are nephrolithiasis, which is common, and
      nephrocalcinosis, which is uncommon. Nephrocalcinosis may occur with or without
      nephrolithiasis. Risk factors for nephrolithiasis are oversaturation of urine
      with calcium phosphate and with calcium oxalate. Risk factors for
      nephrocalcinosis are not clearly defined. Parathyroidectomy greatly reduces the
      incidence of nephrolithiasis but has little effect on nephrocalcinosis.

PMID- 12412784
TI  - Primary hyperparathyroidism: lessons from bone histomorphometry.
AB  - The chronic excessive hypersecretion of parathyroid hormone (PTH) in primary
      hyperparathyroidism (PHPT) has significant impact on bone remodeling. Bone
      turnover increases by about 50%, leading to increased resorption at the endosteal
      envelope, increased cortical porosity, and thinning of cortical bone. In
      cancellous bone a different response is seen. Despite stimulation of bone
      resorption and formation at the tissue level, osteoclastic resorption and
      osteoblastic bone formation at individual bone multicellular units (BMUs) are
      reduced. This causes reduced erosion depth, reduced bone formation rate, and
      decreased thickness of bone structural units (BSUs), and bone balance at
      individual BMUs is preserved and may even improve. Thus, PHPT causes cortical
      bone loss. At the same time, however, cancellous bone structure remains unchanged
      or even improved, which may offset cortical bone loss. This probably explains the
      preservation of bone mass demonstrated in long-term follow-up studies of patients
      with mild PHPT (S-Ca2+ < 2.80 mM). In severe cases of PHPT (S-Ca2+ > 3.00 mM),
      the negative effects on cortical bone may override the positive impact on
      cancellous bone, and lead to bone loss and increased risk of fracture.

PMID- 12412785
TI  - Bone densitometry in asymptomatic primary hyperparathyroidism.

PMID- 12412786
TI  - Fracture risk in primary hyperparathyroidism.
AB  - A key component in the decision to perform surgery on patients with primary
      hyperparathyroidism (HPT) is their skeletal status. Consequently, fracture risk
      in these patients has been investigated in a number of observational studies. Our
      group reported on a population-based cohort of residents from Rochester, MN, with
      primary HPT recognized during a 28-year period (1965-1992). The majority of these
      patients were asymptomatic, and most (77%) were managed conservatively. By
      contrast, a recent Danish study reported on a cohort of 674 patients, all of whom
      had surgery for primary HPT. Nonetheless, the risk of fracture was increased
      remarkably similarly in the two populations: vertebrae, approximately 3-fold;
      forearm, approximately 2-fold; hip, approximately 1.5-fold; and all fractures,
      approximately 1.5-fold. In both studies, parathyroid surgery seemed to have a
      protective effect. These (and previous studies) indicate that overall fracture
      risk is increased in primary HPT patients. An increase in forearm fracture risk
      is a relatively uniform finding and is consistent with known effects of
      parathyroid hormone (PTH) on cortical bone. However, the increase in vertebral
      fracture risk seen in most (but not all) studies does not fit with the
      observation that cancellous bone mass/structure is preserved in primary HPT
      patients. Based on these findings, future directions for research include (1)
      rigorously testing, in prospective studies, whether vertebral fracture risk is,
      in fact, increased in this disorder, and if so, determining the possible
      biomechanical mechanism(s) for this increase; and (2) testing whether the trend
      to increased hip fracture risk seen in some studies is real and whether it is
      more closely linked to cervical or intertrochanteric fractures.

PMID- 12412787
TI  - Role of the interleukin-6/interleukin-6 soluble receptor cytokine system in
      mediating increased skeletal sensitivity to parathyroid hormone in perimenopausal
      women.
AB  - We have observed a strong correlation between circulating levels of both
      interleukin-6 (IL-6) and interleukin-6 soluble receptor (IL-6sR) and rates of
      bone turnover in patients with primary hyperparathyroidism. Furthermore, we have
      found that serum levels of IL-6sR predict rates of bone loss in postmenopausal
      women with this disease. Estrogen modulates parathyroid hormone (PTH)-induced
      increases in serum IL-6/IL-6sR, such that, in the estrogen-deficient state, there
      is an exaggerated release of these cytokines. We therefore propose that the
      perimenopausal period represents a time when skeletal sensitivity to the
      resorbing actions of PTH increases because of augmented release of IL-6 and IL
      6sR. To test this hypothesis, we retrospectively examined data from 91 women with
      primary hyperparathyroidism who were seen over the last 5 years at our
      institution. Women were categorized, based on their age, as premenopausal (n =
      20, 41 +/- 2 years), perimenopausal (n = 17, 54 +/- 1 years), or postmenopausal
      (n = 54, 64 +/- 1 years). Despite having similar mean values for PTH,
      perimenopausal women had a mean serum IL-6 value that was significantly higher
      than that in the premenopausal group (13 +/- 2 vs. 8 +/- 2 pg/ml; p = 0.03). This
      difference in cytokine profile was mirrored by higher mean values for urine N
      telopeptides of type I collagen (NTX) in the perimenopausal group compared with
      premenopausal women (114 +/- 9 vs. 80 +/- 11 nM bone collagen equivalents
      (BCE)/mM creatinine, p = 0.01). Of the three groups of patients, values for IL-6
      and urine NTX were highest in the postmenopausal group. We conclude that the
      perimenopausal period may be a time of increased risk for the skeletal
      complications of hyperparathyroidism. This is because of increased skeletal
      sensitivity to the resorbing actions of PTH, mediated in part, by the IL-6/IL-6sR
      cytokine system.

PMID- 12412788
TI  - Non-classical target organs in primary hyperparathyroidism.
AB  - Classical primary hyperparathyroidism (PHPT) was a multisystem disorder with
      clear neurologic, psychiatric, gastrointestinal, and cardiovascular consequences.
      The nature and extent of involvement of these target organs in the modern
      presentation of the disease are controversial. Although hypertension has been
      associated with PHPT, it is not cured after parathyroidectomy, nor is it easier
      to control. Despite significant data on European patients, information on the
      incidence of cardiovascular abnormalities in American patients with mild disease
      are limited. Investigation is turning to more subtle abnormalities, such as
      vascular reactivity and endothelial function, where data are conflicting. Many
      patients complain of nonspecific neuropsychiatric symptoms. This has been a
      difficult area to study quantitatively. Classical neuromuscular disease is rare
      in mild PHPT, although weakness and easy fatigability remain common complaints.
      These nonspecific symptoms may or may not improve with surgery. While no clear
      causal association exists between sporadic PHPT and peptic ulcer disease, this is
      not the case in patients with multiple endocrine neoplasia type 1 (MEN1).
      Gastrinoma is more severe in those with coexisting PHPT, and Zollinger-Ellison
      Syndrome improves with treatment of PHPT. Further efforts are necessary to
      characterize the cardiovascular and neuropsychological profiles of mild PHPT and
      to determine the longitudinal course of such alterations. With available data
      suggesting that many asymptomatic patients with PHPT can be safely followed
      without parathyroidectomy, this information will be of key importance in the
      management of such individuals.

PMID- 12412789
TI  - Surgery in primary hyperparathyroidism: the patient without previous neck
      surgery.
AB  - The indications for surgical exploration in the "asymptomatic" patient with
      primary hyperparathyroidism (1 degrees HPTH) have changed since the 1990 National
      Institutes of Health Consensus Development Conference. This seems to be, at least
      in part, caused by the introduction of minimally invasive parathyroidectomy (MIP)
      techniques. The concept of MIP is based on the fact that the majority of patients
      (80-85%) with 1 degrees HPTH have a single adenoma that can usually be identified
      on preoperative imaging. The incident adenoma can be resected under local or
      regional anesthesia, and an intraoperative adjunct, such as the rapid parathyroid
      hormone (PTH) assay, can be used to show an adequate decrement in plasma PTH
      levels. There are no randomized prospective trials comparing the results obtained
      with conventional and MIP techniques. However, a recent series of 656 consecutive
      parathyroid explorations compared the results obtained using conventional (n =
      401) and MIP (n = 255) surgery. The success rate for the entire series was 98%,
      and there were no significant differences in cure rates between traditional (97%)
      and MIP (99%) techniques. The overall complication rates were also similar.
      However, MIP was associated with a 50% reduction in operating time, a 7-fold
      reduction in length of hospital stay, and a mean cost savings of $2693 per case.
      It seems likely that the majority of patients with 1 degrees HPTH can now be
      cured on an outpatient basis with MIP, which has already replaced conventional
      parathyroid exploration in several endocrine centers. Limitations to this
      procedure include the need for sophisticated adjuncts and a surgeon highly
      experienced in this new technique.

PMID- 12412790
TI  - Role of preoperative localization and intraoperative localization maneuvers
      including intraoperative PTH assay determination for patients with persistent or
      recurrent hyperparathyroidism.
AB  - Patients with recurrent or persistent primary hyperparathyroidism have increased
      operative risk because of scarring in the operative field and the frequent
      presence of an ectopic gland. Preoperative imaging studies will identify the
      hyperfunctioning parathyroid gland in the majority of circumstances. The best
      types or combination of imaging tests has not been definitely established.
      However, because of their wide availability and demonstrated sensitivity, US and
      sestamibi scans are most commonly obtained. Based on the clinical setting,
      additional tests including CT or MRI may be useful. In circumstances when the
      noninvasive imaging modalities are inconclusive, invasive imaging tests including
      selective angiography venous sampling and/or direct fine needle aspiration should
      be used. IOUS, MIRP, and intraoperative PTH determination are useful adjuncts to
      the safe and successful conduct of reoperative parathyroid surgery: however, the
      benefit of the routine use of these modalities in reoperative parathyroid surgery
      has yet to be critically determined.

PMID- 12412791
TI  - Calcimimetics in the treatment of primary hyperparathyroidism.

PMID- 12412792
TI  - The role of estrogens and related compounds in the management of primary
      hyperparathyroidism.

PMID- 12412793
TI  - Bisphosphonates and primary hyperparathyroidism.
AB  - Bisphosphonates (BP) are pyrophosphate analogs that include very potent
      inhibitors of bone resorption. BPs act directly on the osteoclast, suppressing
      isoprenylation by inhibiting farnesyl diphosphate synthase in the cholesterol
      pathway, which causes osteoclast inactivation. BPs should therefore reduce the
      bone loss produced by any cause, including hyperparathyroidism and hypercalcemia
      of malignancy (MIH), caused by parathyroid hormone (PTH) and PTH-related protein
      (PTHrP), respectively. BPs at higher doses than used in osteoporosis are indeed
      the treatment of choice for malignancy-induced hypercalcemia. Limited, but
      convincing, data show that BPs at doses effective in osteoporosis also reverse
      bone loss associated with mild primary hyperparathyroidism (PHPT).

PMID- 12412794
TI  - The basis for the post-parathyroidectomy increase in bone mass.
AB  - The bone remodeling transient is a self-limited change in measurable bone mass,
      detectable by dual-energy X-ray absorptiometry (DXA) or by calcium balance
      methods, which occurs whenever the skeleton undergoes a shift in bone remodeling
      activity from one steady state to another. Assessing the true effect on bone mass
      of therapy that alters remodeling requires both a period of observation long
      enough to characterize the new steady state and explicit provision for the
      transient. To help with such analysis, a multivariate computer model of the bone
      remodeling system has been developed and applied usefully to a variety of data
      sets describing the response to treatment. Because parathyroid hormone (PTH) is
      the principal determinant of the quantity of bone remodeling, it follows that
      efficacious treatment of hyperparathyroidism will produce a bone remodeling
      transient. Using published values for the level of bone remodeling activity in
      postmenopausal women with mild hyperparathyroidism, it can be calculated that
      successful treatment would produce an increase in measurable spine bone mineral
      density (BMD) of about 12% by 1 year after surgery. In more severe cases, with
      higher levels of remodeling, one-time BMD increases of more than 30% will occur.
      In general, it can be said that, in typical postmenopausal women, a doubling of
      remodeling rate in the hyperparathyroid state will, on successful treatment,
      produce a positive transient amounting to about 8% above the presurgery BMD
      level.

PMID- 12412795
TI  - Recurrent or persistent hyperparathyroidism.
AB  - Approximately 90% of patients with primary hyperparathyroidism (PHPT) are cured
      by parathyroidectomy at the initial neck exploration. Those not cured either
      remain hypercalcemic in the immediate postoperative period or develop
      hypercalcemia after a long period of normocalcemia. Almost all cases of
      hypercalcemia after neck exploration for PHPT are evident early in the
      postoperative period and are caused either by an overlooked parathyroid adenoma
      or an incomplete resection of hyperplastic parathyroid tissue. Less commonly, the
      surgeon has failed to recognize, and adequately treat, parathyroid carcinoma, or
      the diagnosis of PHPT was incorrect and there is another cause of the
      hypercalcemia. A successful neck exploration for PHPT is primarily dependent on
      the experience of the operating surgeon, the anatomic location of the parathyroid
      glands, either in "normal" or "ectopic" sites, and the presence of a single
      enlarged parathyroid gland as opposed to multiglandular disease or parathyroid
      carcinoma. In cases where an enlarged parathyroid gland is not identified at
      operation, noninvasive or invasive radiographic imaging procedures are useful in
      localizing the gland. Currently, the most reliable and practical procedure is
      technetium 99m sestamibi scanning. This technique identifies an enlarged
      parathyroid gland in 65-80% of cases. Single photon emission computed tomography
      (SPECT) in association with sestamibi scanning increases the sensitivity of the
      procedure to 85%. These imaging procedures are least reliable in patients with
      multiglandular disease. Ultrasound and computed tomographic scanning are less
      sensitive; however, they are commonly used as confirmatory tests in association
      with sestamibi scanning. When noninvasive imaging procedures fail to identify an
      enlarged parathyroid gland, invasive procedures, such as selective arteriography,
      are performed. Whereas invasive procedures are useful, they are associated with
      significant morbidity. Reoperations for persistent or recurrent
      hyperparathyroidism, compared with the initial operations, are associated with
      higher complication rates. In 90% of cases, the abnormal pathology can be reached
      through a cervical incision. The success rate of the reoperation depends
      primarily on the results of the localization procedure and whether the patient
      has a single enlarged parathyroid gland or multiglandular disease. Resection of a
      single enlarged gland is curative in virtually all patients. If, however, the
      patient has multiple gland disease, the operation is successful less often,
      especially in those with certain familial endocrinopathies.

PMID- 12412797
TI  - Bisphosphonate induces remission of refractory osteolysis in langerhans cell
      histiocytosis.

PMID- 12412796
TI  - Role of the bone marrow microenvironment in multiple myeloma.
AB  - On June 26-27, 2001, the Sixth Research Roundtable in Multiple Myeloma, entitled
      "The Role of the Bone Microenvironment in Multiple Myeloma," was held and focused
      on the biology of cell-to-cell interactions, the mediators of bone disease, and
      novel treatment strategies for myeloma. Studies on cell-cell interactions showed
      that vascular cell adhesion molecule 1, expressed by local endothelial and
      stromal cells, binds to tumor cell surface integrins in which expression may be
      increased by tumor cell-derived chemokines such as macrophage inflammatory
      protein (MIP) 1alpha. These adhesive interactions increase production and release
      of vascular endothelial growth factor (VEGF). Studies on myeloma bone disease
      showed the ligand for receptor activator of nuclear transcription factor-kappaB
      (RANKL) was expressed on tumor cells and stromal cells associated with myeloma
      cells and was critical for osteoclast-induced osteolysis. Blockade of RANKL
      suppressed osteoclast maturation, bone resorption, and tumor development.
      Bisphosphonates, in addition to reducing osteoclast mobility and inducing
      osteoclast apoptosis, also decreased tumor cell adhesion to stroma.
      Immunomodulatory drugs such as thalidomide analogues targeted these tumor cell
      stromal cell interactions, blocking both secretion of cytokines and activation of
      intracellular signaling pathways required for tumor survival and growth. These
      agents induced tumor cell apoptosis, decreased neovascularization, and
      potentiated natural killer cell activity. The proteasome inhibitor PS-341 also
      prevented expression of adhesion molecules and cytokines and triggered tumor cell
      apoptosis, even in drug-resistant cell lines, while showing minimal activity in
      healthy cells. In addition, potential therapeutic agents under investigation,
      which included RANKL antagonists, protein prenylation inhibitors, and osteoblast
      growth factors, were discussed.

PMID- 12412798
TI  - Magnetic resonance imaging presentation of lytic Paget's disease of the cervical
      spine.

PMID- 12412799
TI  - Cell-type-dependent up-regulation of in vitro mineralization after overexpression
      of the osteoblast-specific transcription factor Runx2/Cbfal.
AB  - Functional expression of the transcriptional activator Runx2/Cbfal is essential
      for osteoblastic differentiation and bone formation and maintenance. Forced
      expression of Runx2 in nonosteoblastic cells induces expression of osteoblast
      specific genes, but the effects of Runx2 overexpression on in vitro matrix
      mineralization have not been determined. To examine whether exogenous Runx2
      expression is sufficient to direct in vitro mineralization, we investigated
      sustained expression of Runx2 in nonosteoblastic and osteoblast-like cell lines
      using retroviral gene delivery. As expected, forced expression of Runx2 induced
      several osteoblast-specific genes in NIH3T3 and C3H10T1/2 fibroblasts and up
      regulated expression in MC3T3-E1 immature osteoblast-like cells. However, Runx2
      expression enhanced matrix mineralization in a cell-type-dependent manner. NIH3T3
      and IMR-90 fibroblasts overexpressing Runx2 did not produce a mineralized matrix,
      indicating that forced expression of Runx2 in these nonosteogenic cell lines is
      not sufficient to direct in vitro mineralization. Consistent with the pluripotent
      nature of the cell line, a fraction (25%) of Runx2-expressing C3H10T1/2
      fibroblast cultures produced mineralized nodules in a viral supernatant-dependent
      manner. Notably, bone sialoprotein (BSP) gene expression was detected at
      significantly higher levels in mineralizing Runx2-infected C3H10T1/2 cells
      compared with Runx2-expressing cultures which did not mineralize. Treatment of
      Runx2-infected C3H10T1/2 cultures with dexamethasone enhanced osteoblastic
      phenotype expression, inducing low levels of mineralization independent of viral
      supernatant. Finally, Runx2 overexpression in immature osteoblast-like MC3T3-E1
      cells resulted in acceleration and robust up-regulation of matrix mineralization
      compared with controls. These results suggest that, although functional Runx2 is
      essential to multiple osteoblast-specific activities, in vitro matrix
      mineralization requires additional tissue-specific cofactors, which supplement
      Runx2 activity.

PMID- 12412800
TI  - Function of mutant (G1144A) tissue-nonspecific ALP gene from hypophosphatasia.
AB  - Hypophosphatasia (HOPS) is a clinically heterogeneous heritable disorder
      characterized by defective skeletal mineralization, deficiency of tissue
      nonspecific alkaline phosphatase (TNSALP) activity, and premature loss of
      deciduous teeth. The gene for TNSALP is located on chromosome 1p34-36.1 and
      consists of 12 exons and 11 introns. In our previous study, we found the novel
      point mutations (G1144A and T979C) from the genomic TNSALP gene of a patient with
      childhood HOPS. In this study, we have characterized the protein translated from
      the mutant G1144A gene. Wild-type and G1144A mutant-type TNSALP cDNA expression
      vector pcDNA3 have been constructed and transfected to COS-1 cells by lipofectin
      technique. After 48-h or 72-h transfection, cells were collected and homogenized
      using polytron homogenizer. After centrifugation at 10,000 g for 10 minutes, the
      supernatant was assayed. ALP activity was determined with 10 mM of p
      nitrophenylphosphate as a substrate in 100 mM of 2-amino-2-methyl-1,3-propanediol
      HCl buffer containing 5 mM of MgCl2. ALP activity of cells transfected with the
      mutant cDNA (G1144A) plasmid after 48-h or 72-h transfection exhibited 0.063 +/-
      0.012 U/mg and 0.054 +/- 0.012 U/mg, respectively. As the enzymatic activity of
      the wild type was taken as 100%, the value of the mutant was estimated as 2.7%
      and 1.7%, respectively. These values were not significantly different from those
      found with mock-transfected cells, that is, 2.5% and 1.5%, respectively. This
      study indicated that the mutation (G1144A) produced the inactive ALP enzyme and
      would be a disease-causing mutation of the childhood-type HOPS.

PMID- 12412801
TI  - Bone mineralization in polyostotic fibrous dysplasia: histomorphometric analysis.
AB  - Fibrous dysplasia (FD) of bone can be complicated by renal phosphate wasting. The
      effect of hypophosphatemia on normal and dysplastic bone of FD patients has not
      been well characterized. In this study, we compared serum phosphorus (sPi) levels
      to histomorphometric findings in 27 iliac bone samples from 23 children and
      adolescents (aged 4.2-16.4 years) with polyostotic FD. The samples were separated
      into two groups, based on the presence (n = 10) or absence (n = 17) of a
      dysplastic lesion within the specimen. Histomorphometric results were compared
      with those from 18 age-matched control subjects without metabolic bone disease.
      In dysplastic lesions, trabeculae were clearly thinner and increased in number.
      Osteoid indices, osteoblast surface per bone surface, and mineralization lag time
      were elevated in dysplastic areas, but there was no detectable effect of sPi
      concentrations on these indices. In nondysplastic bone tissue, low sPi levels
      were associated with mildly increased osteoid thickness and prolonged
      mineralization lag time. None of the 13 patients in whom hand X-rays were
      available at the time of biopsy had radiological signs of rickets. In conclusion,
      low sPi can cause a mild systemic mineralization defect in FD, but the more
      severe mineralization defect seen in dysplastic lesions is independent of sPi
      levels. It is debatable whether the mild systemic mineralization defect warrants
      treatment with oral phosphorus supplementation if signs of rickets are absent.

PMID- 12412802
TI  - Greatly increased cancellous bone formation with rapid improvements in bone
      structure in the rat maternal skeleton after lactation.
AB  - There is a decrease in cancellous bone mass and strength during lactation but
      these are partially or completely reconstituted in the postlactational period.
      The purpose of this study was to determine changes in cancellous bone structure
      and formation after lactation in established breeder rats. For this, rats were
      taken at the end of the second pregnancy (Preg-2) and second lactation (Lac-2)
      and 2, 4, and 6 weeks after weaning. Nulliparous (NP) groups were included for
      comparisons. Bone structure was measured using morphometric methods and bone
      dynamics by histomorphometry. Tibial metaphyseal cancellous bone was lost during
      the first reproductive cycle, as expected, and again depleted during the Lac-2.
      Bone formation indices were elevated at the end of Lac-2, compared with those at
      the end of the second pregnancy or in the nulliparous animals. Within 2 weeks
      after the second weaning, the amount of double-labeled surface (dLS) increased
      approximately 800%, the mineralizing surface (MS) increased >400% with similar
      increases in bone formation rates (BFRs), compared with already elevated bone
      formation measured at the end of Lac-2. From 2 to 4 weeks after lactation, there
      were commensurate increases in cancellous bone mass and structural indices with
      essentially complete restoration of cancellous bone volume and structure compared
      with that measured at the end of Preg-2. The results show rapid and substantial
      increases in bone formation with reconstitution of cancellous bone mass and
      structure after lactation in rats. The skeletal changes that occur during the
      postlactational period may serve to prepare and protect the maternal skeleton for
      subsequent reproductive cycles.

PMID- 12412803
TI  - Decreased bone density, elevated serum osteoprotegerin, and beta-cross-laps in
      Wilson disease.
AB  - Osteopathia has been reported in Wilson disease (WD), but bone density has not
      been measured; therefore, we performed bone mineral density (BMD), bone mineral
      content (BMC), and quantitative bone ultrasound (QUS) assessments, as well as
      measured the serum levels of osteocalcin (OCN), beta-cross-laps (beta-CTx's), and
      the recently discovered osteoprotegerin (OPG) and its ligand RANKL to investigate
      the underlying mechanism of osseous disorders. Serum OCN, beta-CTx, OPG, and
      RANKL levels were measured by ELISA in 21 WD patients and in 20 age- and gender
      matched healthy subjects. BMD, BMC, and QUS parameters were also determined.
      Osteoporosis was present in 9/21 (43%) WD patients. Abnormal QUS parameters were
      found in 7 (33%) of the patients. Although serum OCN levels were similar in
      patients and controls (29.93 +/- 24.65 mg/ml vs. 29.84 +/- 6.89 mg/ml), beta-CTx
      and OPG levels were significantly increased in WD compared with the healthy
      controls (625.4 +/- 312.3 pg/ml vs. 423.6 +/- 144.3 pg/ml and p = 0.022 and 7.2
      +/- 3.4 pM vs. 3.5 +/- 1.0 pM and p < 0.001, respectively). No difference was
      observed in the RANKL level. There was a positive correlation between OCN and
      beta-CTx (r = 0.55; p = 0.01). We proved high occurrence of osteoporosis in WD.
      Negative bone remodeling balance is a consequence of increased bone resorption,
      which is indicated by elevated beta-CTx. The novel finding of elevated serum OPG
      may reflect a compensatory reaction to enhanced osteoclast activity, despite the
      normal OCN level.

PMID- 12412805
TI  - Effects of liver-derived insulin-like growth factor I on bone metabolism in mice.
AB  - Insulin-like growth factor (IGF) I is an important regulator of both skeletal
      growth and adult bone metabolism. To better understand the relative importance of
      systemic IGF-I versus locally expressed IGF-I we have developed a transgenic
      mouse model with inducible specific IGF-I gene inactivation in the liver (LI-IGF
      I-/-). These mice are growing normally up to 12 weeks of age but have a disturbed
      carbohydrate and lipid metabolism. In this study, the long-term effects of liver
      specific IGF-I inactivation on skeletal growth and adult bone metabolism were
      investigated. The adult (week 8-55) axial skeletal growth was decreased by 24% in
      the LI-IGF-I-/- mice whereas no major reduction of the adult appendicular
      skeletal growth was seen. The cortical cross-sectional bone area, as measured in
      the middiaphyseal region of the long bones, was decreased in old LI-IGF-I-/-
      mice. This reduction in the amount of cortical bone was caused mainly by
      decreased periosteal circumference and was associated with a weaker bone
      determined by a decrease in ultimate load. In contrast, the amount of trabecular
      bone was not decreased in the LI-IGF-I-/- mice. DNA microarray analysis of 30
      week-old LI-IGF-I-/- and control mice indicated that only four genes were
      regulated in bone whereas approximately 40 genes were regulated in the liver,
      supporting the hypothesis that liver-derived IGF-I is of minor importance for
      adult bone metabolism. In summary, liver-derived IGF-I exerts a small but
      significant effect on cortical periosteal bone growth and on adult axial skeletal
      growth while it is not required for the maintenance of the trabecular bone in
      adult mice.

PMID- 12412804
TI  - Role of protein kinase C alpha in primary human osteoblast proliferation.
AB  - Protein kinase C (PKC) isoforms have been shown to have specific expression
      profiles and individual isoforms are believed to play distinct roles in the cells
      in which they are found. The goal here was to determine which specific isoform(s)
      is involved in proliferation of primary human osteoblasts. In primary human
      osteoblasts, 10 microM of acute sphingosine-1-phosphate (S1P) treatment induced
      an increase in proliferation that correlated with an increase in PKCalpha and
      PKCiota expression. To further delineate which isoforms are involved in
      osteoblastic cell proliferation, the effect of low versus high serum culture
      conditions on PKC isoform expression was determined. Likewise, the effect of
      antisense oligodeoxynucleotides (ODNs) to specific PKC isoforms on proliferation
      and MAPK activation was studied. The effect of S1P on intracellular translocation
      of activated PKC isoforms was also evaluated. The results indicated that in
      primary human osteoblasts, PKCalpha was not expressed under conditions of low
      proliferative rate while PKCdelta and PKCiota expression was not affected. The
      specific inhibition of PKCalpha by antisense ODNs resulted in inhibition of MAPK
      activity leading to a significant decrease in proliferation. S1P up-regulated
      antisense ODN inhibited PKCalpha expression and MAPK activity and led to an
      increase in proliferation. Subsequent experiments using platelet-derived growth
      factor (PDGF) as an additional mitogen generated similar data. PDGF stimulation
      resulted in a significant increase in proliferation that correlated with an up
      regulation of inhibited PKCalpha expression in antisense ODN-treated cells.
      Immunofluorescence methods showed that mitogenic stimulation of PKCa resulted in
      nuclear translocation. Our findings present original data that PKCalpha is the
      isoform specifically involved in the proliferation of primary human osteoblasts.

PMID- 12412806
TI  - Two-year results of once-weekly administration of alendronate 70 mg for the
      treatment of postmenopausal osteoporosis.
AB  - The aim of this study was to provide confirmation that once-weekly dosing with 70
      mg of alendronate (seven times the daily oral dose) and twice-weekly dosing with
      35 mg is equivalent to the 10-mg once-daily regimen and to gain more extensive
      safety experience with this new dosing regimen. Twelve hundred fifty-eight
      postmenopausal women (aged 42-95 years) with osteoporosis (bone mineral density
      [BMD] of either lumbar spine or femoral neck at least 2.5 SDs below peak young
      adult mean or prior vertebral or hip fracture) were assigned to receive oral once
      weekly alendronate, 70 mg (n = 519); twice-weekly alendronate, 35 mg (n = 369);
      or daily alendronate 10 mg (n = 370) for a total of 2 years of double-blind
      experience. Mean BMD increases from baseline (95% CI) at 24 months in the once
      weekly, twice-weekly, and daily treatment groups, respectively, were 6.8% (6.4,
      7.3), 7.0% (6.6,7.5), and 7.4% (6.9,7.8) at the lumbar spine and 4.1% (3.8,4.5),
      4.3% (3.9,4.7), and 4.3% (3.9,4.7) at the total hip. These increases in BMD as
      well as the BMD increases at the femoral neck, trochanter, and total body and the
      reductions of biochemical markers of bone resorption (urinary cross-linked N
      telopeptides of type I collagen [NTx]) and bone formation (serum bone-specific
      alkaline phosphatase [BSAP]) were similar for the three dosing regimens. All
      treatment regimens were well tolerated with a similar incidence of upper
      gastrointestinal (GI) adverse experiences. The incidence rates of clinical
      fractures, captured as adverse experiences, were similar among the groups. The 2
      year results confirm the conclusion reached after 1 year that once-weekly
      alendronate is therapeutically equivalent to daily dosing, providing patients
      with a more convenient dosing option that may potentially enhance adherence to
      therapy.

PMID- 12412807
TI  - Role of the cholesterol biosynthetic pathway in osteoblastic differentiation of
      marrow stromal cells.
AB  - Cholesterol is an important molecule that plays a key role in regulating cellular
      differentiation and function. Although the possible role of lipids has been
      implicated in regulating osteoblastic cells, the role of cholesterol in that
      process is not well defined. In this study we have examined the role of the
      cellular cholesterol biosynthetic pathway on osteoblastic differentiation of
      marrow stromal cells (MSCs). Treatment of pluripotent mouse MSCs M2-10B4 with
      inhibitors of the cholesterol biosynthetic pathway mevastatin or mevinolin
      inhibited the maturation of these cells into functional osteoblastic cells. This
      was determined by the inhibition of the activity and expression of alkaline
      phosphatase (ALP), a key enzyme involved in differentiation and mineralization of
      osteoblastic cell cultures, as well as inhibition of mineralization. Mevastatin
      treatment did not affect expression of the osteoblast-specific gene osteocalcin
      (OCN). Furthermore, promoter-reporter studies in MSCs showed that mevastatin
      inhibited activity of the ALP gene promoter, suggesting regulation by derivatives
      of the cholesterol biosynthetic pathway. The effects of mevastatin and mevinolin
      were reversed by mevalonate but not by geranylgeraniol or farnesol, intermediates
      in the cholesterol biosynthetic pathway. Altogether, these results suggest that
      products of the cholesterol biosynthetic pathway are important for proper
      development of MSCs into functional osteoblastic cells capable of forming a
      mineralized matrix. Identification of those molecules may provide new therapeutic
      approaches to prevent the decline in osteoblastic activity in osteoporosis and
      aging.

PMID- 12412808
TI  - Simvastatin improves fracture healing in mice.
AB  - Recently, several articles have been published dealing with the anabolic effects
      on bone by statins. Mundy and associates discovered that several statins were
      able to activate the promotor of bone morphogenetic protein (BMP) 2.
      Additionally, oral simvastatin and lovastatin increased the cancellous bone
      volume in rats, presumably an effect of the increase of BMP-2. Other studies have
      followed, with conflicting results; some have found a positive bone metabolic
      effect of statins and others have not. Studies published so far have focused on
      osteoporosis. In this study, femur fractures were produced in 81 mature male
      BALB/c mice and stabilized with marrow-nailing. Forty-one mice were given a diet
      prepared with simvastatin, so that each mouse received an approximate dose of 120
      mg/kg of body weight per day. The remaining mice received the same diet with the
      exception of the simvastatin. Bilateral femurs were harvested at 8, 14, and 21
      days postoperatively (po), the marrow-nail was extracted, and diameters were
      measured. Biomechanical tests were performed on 42 mice, by way of three-point
      bending. Histological specimens were prepared using standard techniques. For
      statistical analysis, ANOVA with Scheffes post hoc test was used. At 8 days, the
      fracture callus was too soft for meaningful biomechanical testing. At 14 days,
      the callus of the simvastatin-treated mice had a 53% larger transverse area than
      controls (p = 0.001), the force required to break the bone was 63% greater (p =
      0.001), and the energy uptake was increased by 150% (p = 0.0008). Stiffness and
      modulus of elasticity were not significantly affected. At 21 days, the fractures
      were histologically healed and the mechanical differences had disappeared. The
      contralateral unbroken bone showed a slight increase in transverse area because
      of the simvastatin treatment, but there was no significant effect on the force
      required to break the bone or on energy uptake. These results point to a new
      possibility in the treatment of fractures.

PMID- 12412809
TI  - Pleiotrophin/Osteoblast-stimulating factor 1: dissecting its diverse functions in
      bone formation.
AB  - OSF-1, more commonly known as pleiotrophin (PTN) or heparin-binding growth
      associated molecule (HB-GAM), belongs to a new family of secreted HB proteins,
      which are structurally unrelated to any other growth factor family. The aims of
      this study were to dissect the diverse functions of PTN in bone formation. The
      study showed that PTN was synthesized by osteoblasts at an early stage of
      osteogenic differentiation and was present at sites of new bone formation, where
      PTN was stored in the new bone matrix. Low concentrations (10 pg/ml) of PTN
      stimulated osteogenic differentiation of mouse bone marrow cells and had a modest
      effect on their proliferation, whereas higher concentrations (ng/ml) had no
      effect. However, PTN did not have the osteoinductive potential of bone
      morphogenetic proteins (BMPs) because it failed to convert C2C12 cells, a
      premyoblastic cell line, to the osteogenic phenotype, whereas recombinant human
      BMP-2 (rhBMP-2) was able to do so. When PTN was present together with rhBMP-2
      during the osteoinductive phase, PTN inhibited the BMP-mediated osteoinduction in
      C2C12 cells at concentrations between 0.05 pg/ml and 100 ng/ml. However, when
      added after osteoinduction had been achieved, PTN enhanced further osteogenic
      differentiation. An unusual effect of PTN (50 ng/ml) was the induction of type I
      collagen synthesis by chondrocytes in organ cultures of chick nasal cartilage and
      rat growth plates. Thus, PTN had multiple effects on bone formation and the
      effects were dependent on the concentration of PTN and the timing of its
      presence. To explain these multiple effects, we propose that PTN is an accessory
      signaling molecule, which is involved in a variety of processes in bone
      formation. PTN enhances or inhibits primary responses depending on the prevailing
      concentrations, the primary stimulus, and the availability of appropriate
      receptors.

PMID- 12412810
TI  - A case for strain-induced fluid flow as a regulator of BMU-coupling and osteonal
      alignment.
AB  - Throughout life, human bone is renewed continuously in a tightly controlled
      sequence of resorption and formation. This process of bone remodeling is
      remarkable because it involves cells from different lineages, collaborating in so
      called basic multicellular units (BMUs) within small spatial and temporal
      boundaries. Moreover, the newly formed (secondary) osteons are aligned to the
      dominant load direction and have a density related to its magnitude, thus
      creating a globally optimized mechanical structure. Although the existence of
      BMUs is amply described, the cellular mechanisms driving bone remodeling
      particularly the alignment process-are poorly understood. In this study we
      present a theory that explains bone remodelling as a self-organizing process of
      mechanical adaptation. Osteocytes thereby act as sensors of strain-induced fluid
      flow. Physiological loading produces stasis of extracellular fluid in front of
      the cutting cone of a tunneling osteon, which will lead to osteocytic disuse and
      (continued) attraction of osteoclasts. However, around the resting zone and the
      closing cone, enhanced extracellular fluid flow occurs, which will activate
      osteocytes to recruit osteoblasts. Thus, cellular activity at a bone remodeling
      site is well related to local fluid flow patterns, which may explain the
      coordinated progression of a BMU.

PMID- 12412811
TI  - The role of interstitial fluid flow in the remodeling response to fatigue
      loading.
AB  - Load-induced fluid flow enhances molecular transport through bone tissue and
      relates to areas of bone resorption and apposition. Remodeling activity is highly
      coordinated and necessitates a means for cellular communication via intracellular
      and extracellular means. Osteocytes, osteoblasts, and osteoclasts, which reside
      in disparate locations within the tissue, communicate intracellularly via the
      cellular syncytium and extracellularly via the pericellular fluid space of the
      lacunocanalicular system. Both of these communications systems are physically
      disrupted by microdamage incurred during fatigue loading of bone. The purpose of
      this study was to develop an analytical model to understand the role of
      interstitial fluid flow in the remodeling response to fatigue loading. Adequate
      transport was assumed a prerequisite for maintenance of cell viability in bone.
      Diffusive and convective transport were simulated through the lacunocanalicular
      network in a healthy undamaged state as well as in a damaged state after fatigue
      loading. The model predicts that fatigue damage impedes transport from the blood
      supply, depleting the concentration of molecular entities in and downstream from
      areas of damage. Furthermore, the presence of microcracks alters the distribution
      of molecular entities between individual lacunae. These effects were confirmed by
      the results of an in vivo pilot study in which fluorescent, flow-visualizing
      agents pooled within microcracks and were absent from areas surrounding
      microcracks, corresponding to areas deprived of fluid flow. Loss of osteocyte
      viability is coupled to targeting and initiation of new remodeling activity.
      Taken as a whole, these data suggest a link between interstitial fluid flow, mass
      transport, maintenance of osteocyte viability, and modulation of remodeling
      activity.

PMID- 12412812
TI  - Mechanisms for the enhancement of fracture healing in rats treated with
      intermittent low-dose human parathyroid hormone (1-34).
AB  - Recent reports have demonstrated that intermittent treatment with parathyroid
      hormone (1-34) [PTH(1-34)] increases callus formation and mechanical strength in
      experimental fracture healing. However, little is known about the optimal dose
      required for enhancement of fracture repair or the molecular mechanisms by which
      PTH regulates the healing process. In this study, we analyzed the underlying
      molecular mechanisms by which PTH affects fracture healing and tested the
      hypothesis that intermittent low-dose treatment with human PTH(1-34) can increase
      callus formation and mechanical strength. Unilateral femoral fractures were
      produced and a daily subcutaneous injection of 10 microg/kg of PTH(1-34) was
      administered during the entire healing period. Control animals were injected with
      vehicle solution alone. The results showed that on day 28 and day 42 after
      fracture, bone mineral content (BMC), bone mineral density (BMD), and ultimate
      load to failure of the calluses were significantly increased in the PTH-treated
      group compared with controls (day 28, 61, 46, and 32%; day 42, 119, 74, and 55%,
      respectively). The number of proliferating cell nuclear antigen (PCNA)-positive
      subperiosteal osteoprogenitor cells was significantly increased in the calluses
      of the PTH-treated group on day 2, and TRAP+ multinucleated cells were
      significantly increased in areas of callus cancellous bone on day 7. The levels
      of expression of type I collagen (COLlA1), osteonectin (ON), ALP, and osteocalcin
      (OC) mRNA were increased markedly in the PTH-treated group and accompanied by
      enhanced expression of insulin-like growth factor (IGF)-I mRNA during the early
      stages of healing (days 4-7). The increased expression of COL1A1, ON, ALP, and OC
      mRNA continued during the later stages of healing (days 14-21) despite a lack of
      up-regulation of IGF-I mRNA. These results suggest that treatment of fractures
      with intermittent low dose PTH(1-34) enhances callus formation by the early
      stimulation of proliferation and differentiation of osteoprogenitor cells,
      increases production of bone matrix proteins, and enhances osteoclastogenesis
      during the phase of callus remodeling. The resultant effect to increase callus
      mechanical strength supports the concept that clinical investigations on the
      ability of injectable low-dose PTH(1-34) to enhance fracture healing are
      indicated.

PMID- 12412813
TI  - Association of polymorphisms of the estrogen receptor alpha gene with bone
      mineral density and fracture risk in women: a meta-analysis.
AB  - The contribution of genetic polymorphisms to bone mineral density (BMD) and
      fracture risk in women is a controversial topic. We evaluated the effect of the
      XbaI and PvuII polymorphisms of the estrogen receptor a to BMD and fracture risk
      in a meta-analysis, including published data and additional information from
      investigators. Five thousand eight hundred thirty-four women from 30 study groups
      were analyzed with fixed and random effects models. The PvuII polymorphism was
      not associated with BMD at any skeletal site examined and 95% CIs exclude effects
      over 0.015 g/cm2 for both the femoral neck and the lumbar spine. Conversely, XX
      homozygotes (women carrying two copies of the gene variant without an XbaI
      restriction site) consistently had higher BMD than other subjects. The magnitude
      of the effect was similar in the femoral neck and lumbar spine (0.014 g/cm2 [95%
      CI, 0.003-0.025] and 0.015 g/cm2 [95% CI, 0.000-0.030], respectively; no between
      study heterogeneity for either). Total body BMD was also significantly higher in
      XX homozygotes (by 0.039 g/cm2 and 0.029 g/cm2 compared with Xx and xx,
      respectively). Available data on fractures suggested a protective effect for XX
      (odds ratio [OR], 0.66 [95% CI, 0.47-0.93] among 1591 women), but not PP (OR,
      0.93 [95% CI, 0.72-1.18] among 2,229 women). In summary, we have found that XX
      homozygotes may have higher BMD and also a decreased risk of fractures when
      compared with carriers of the x allele, whereas the PvuII polymorphism is not
      associated with either BMD or fracture risk.

PMID- 12412814
TI  - When should densitometry be repeated in healthy peri- and postmenopausal women:
      the Danish osteoporosis prevention study.
AB  - Intervention should be considered in postmenopausal women with bone mineral
      density (BMD) > or = 1 SD below the reference (T or Z score < -1). However, it is
      unclear when densitometry should be repeated. This study aimed at determining the
      need for repeat DXA within 5 years in untreated peri-/postmenopausal women to
      detect declines of T or Z score to below -1 with 85% confidence. A cohort of 925
      healthy women (aged 51.2 +/- 2.9 years) were followed within the Danish
      Osteoporosis Prevention Study (DOPS) for 5 years without hormone-replacement
      therapy (HRT). DXA of spine, hip, and forearm was done at 0,1, 2, 3, and 5 years
      (Hologic QDR-1000/2000). The annual loss in SD units was 0.12 +/- 0.10 at the
      spine (1.3%), 0.10 +/- 0.09 at the femoral neck (1.2%), and 0.07 +/- 0.09 at the
      ultradistal (UD) forearm (1.0%). Accordingly, T scores below -1 developed earlier
      at the spine. The need for a future DXA scan to predict declines of T and Z
      scores below -1 depended strongly on baseline BMD. In subjects with a positive T
      score, the risk of developing T < -1 remained at <15% for 5 years at all measured
      sites. A new scan was needed after 1 year if the T score was below -0.5, and
      after 3 years if the T score was between 0 and -0.5. Slightly longer intervals
      apply if Z scores are used. Follow-up densitometry in untreated women should be
      individually targeted from baseline BMD rather than scheduled at fixed time
      intervals. An algorithm for planning repeat densitometry in perimenopausal women
      is provided.

PMID- 12412815
TI  - MLO-Y4 osteocyte-like cells support osteoclast formation and activation.
AB  - Osteocytes are terminally differentiated cells of the osteoblast lineage that
      have become embedded in mineralized matrix and may send signals that regulate
      bone modeling and remodeling. The hypothesis to be tested in this study is that
      osteocytes can stimulate and support osteoclast formation and activation. To test
      this hypothesis, an osteocyte-like cell line called MLO-Y4 and primary murine
      osteocytes were used in coculture with spleen or marrow cells. MLO-Y4 cells
      support osteoclast formation in the absence of 1,25-dihydroxyvitamin D3
      [1,25(OD)2D3] or any other exogenous osteotropic factor. These cells alone
      stimulate osteoclast formation to the same extent or greater than adding
      1,25(OH)2D3. Coaddition of 1,25(OH)2D3 with MLO-Y4 cells synergistically
      increased osteoclast formation. Optimal osteoclast formation and pit formation on
      dentine was observed with 200-1,000 MLO-Y4 cells per 0.75-cm2 well. No osteoclast
      formation was observed with 2T3, OCT-1, or MC3T3-E1 osteoblast cells (1,000
      cells/well). Conditioned media from the MLO-Y4 cells had no effect on osteoclast
      formation, indicating that cell contact is necessary. Serial digestions of 2-week
      old mouse calvaria yielded populations of cells that support osteoclast formation
      when cocultured with 1,25(OH)2D3 and marrow, but the population that remained in
      the bone particles supported the greatest number of osteoclasts with or without
      1,25(OH)2D3. To examine the mechanism whereby these cells support osteoclast
      formation, the MLO-Y4 cells were compared with a series of osteoblast and stromal
      cells for expression of macrophage colony-stimulating factor (M-CSF), RANKL, and
      osteoprotegerin (OPG). MLO-Y4 cells express and secrete large amounts of M-CSF.
      MLO-Y4 cells express RANKL on their surface and their dendritic processes. The
      ratio of RANKL to OPG mRNA is greatest in the MLO-Y4 cells compared with the
      other cell types. RANK-Fc and OPG-Fc blocked the formation of osteoclasts by MLO
      Y4 cells. These studies suggest that both RANKL and OPG may play a role in
      osteocyte signaling, OPG and M-CSF as soluble factors and RANKL as a surface
      molecule that is functional in osteocytes or along their exposed dendritic
      processes.

PMID- 12412816
TI  - Evidence from the aged orchidectomized male rat model that 17beta-estradiol is a
      more effective bone-sparing and anabolic agent than 5alpha-dihydrotestosterone.
AB  - This study was designed to evaluate the impact of estrogen versus androgen action
      on orchidectomy (ORX)-induced bone loss and associated changes in body
      composition. During an experimental period of 4 months, aged (12-month-old) ORX
      rats were treated with 17beta-estradiol (E2; 0.75 microg/day) or different doses
      of the nonaromatizable androgen 5alpha-dihydrotestosterone (DHT; 45, 75, and 150
      microg/day, respectively), via subcutaneous (sc) silastic implants. Low doses of
      DHT and E2 inhibited the ORX-induced rise of bone turnover markers (serum
      osteocalcin and urinary deoxypyridinoline [DPD]) to a similar extent. High-dose
      DHT prevented the ORX-induced decrease of trabecular bone density but had no
      significant effect on cortical thinning as assessed by peripheral quantitative
      computed tomography (pQCT). This bone-sparing action of DHT occurred at the
      expense of hypertrophy of the ventral prostate and seminal vesicles. On the other
      hand, E2 restored both trabecular bone density and cortical thickness in ORX rats
      and even prevented age-related bone loss. In contrast to DHT, E2 increased lean
      body mass and inhibited the ORX-associated increase of fat mass, as measured by
      DXA. Administration of E2 was associated with increased serum concentrations of
      insulin-like growth factor (IGF) I and decreased circulating levels of leptin. We
      conclude that, in the aged ORX rat model, E2 is more effective in preventing ORX
      induced bone loss than DHT. Additionally, E2 has anabolic effects on muscle
      tissue and prevents the ORX-related increase of fat mass. Overall, these data
      suggest that androgen action on bone and body composition is dependent on
      stimulation of both androgen receptors (ARs) and estrogen receptors (ERs).

PMID- 12412817
TI  - Plasminogen activator inhibitor-1: physiologic role, regulation, and the
      influence of common pharmacologic agents.
AB  - Plasminogen activator inhibitor-1 (PAI-1) is the major inhibitor of endogenous
      thrombolysis, thereby promoting thrombosis. PAI-1 is also a primary contributor
      to the development and recurrence of acute myocardial infarction. The renin
      angiotensin system, hypertriglyceridemia, hyperglycemia and hyperinsulinemia, and
      estrogen all influence the fibrinolytic system and PAI-1 in particular. Available
      data strongly suggest that angiotensin-converting enzyme (ACE) inhibitors and
      hormone replacement therapy with estrogen beneficially reduce PAI-1 production.
      Metformin, an agent commonly used for non-insulin-dependent diabetes mellitus
      (NIDDM), appears to favorably decrease PAI-1 production in NIDDM patients but not
      nondiabetic patients. Among the cholesterol-lowering statins, clinical literature
      evaluating pravastatin provides the most compelling data to support this agent's
      favorable effect on PAI-1. Other available statins either have not displayed an
      effect on PAI-1 or do not have clear data to conclusively define their effects on
      the fibrinolytic system.

PMID- 12412818
TI  - Bioequivalence testing for locally acting gastrointestinal products: what role
      for gamma scintigraphy?
AB  - Bioequivalence testing for locally acting gastrointestinal products is a
      challenging issue for both the pharmaceutical industry and the global regulatory
      authorities. It is widely accepted that for medicinal products not intended to be
      delivered into the systemic circulation, pharmacokinetic bioavailability cannot
      be used. However, it is becoming increasingly accepted that local availability
      may be assessed, where appropriate, by approaches that qualitatively reflect the
      presence of the active substance at the site of action. These methods must be
      specifically chosen for that combination of active substance and route of drug
      delivery. This paper argues for the use of gamma scintigraphy as a validated
      measure of local availability and bioequivalence for topically acting products
      administered to the gastrointestinal tract by the oral and rectal route.

PMID- 12412819
TI  - Effect of terbinafine on the pharmacokinetics and pharmacodynamics of desipramine
      in healthy volunteers identified as cytochrome P450 2D6 (CYP2D6) extensive
      metabolizers.
AB  - Terbinafine-CYP2D6 inhibition was evaluated by assessing 48-hour concentration
      time profiles of the tricyclic antidepressant desipramine in 12 healthy
      volunteers identified as extensive cytochrome P450 2D6 (CYP2D6) metabolizers by
      genotyping and phenotyping. Pharmacokinetics was evaluated at baseline (50 mg
      oral desipramine given alone), steady state (after 250 mg oral terbinafine for 21
      days), and 2 and 4 weeks after terbinafine discontinuation. Pharmacodynamics was
      evaluated before and 2 hours after each desipramine administration, using Mini
      Mental Status Examination (MMSE) and EGG. Terbinafine administration inhibited
      CYP2D6 metabolism, as indicated by the significant increase in desipramine C(max)
      (19 ng/ml vs. 36 ng/ml) and AUC0-infinity (482 ng.h/ml vs. 2383 ng.h/ml) and
      decrease in AUC0-24 and C(max) of the CYP2D6-mediated metabolite, 2
      hydroxydesipramine. In addition, the C(max) and AGUC0-infinity of desipramine and
      metabolite were still elevated 4 weeks after terbinafine discontinuation. Caution
      should be exercised when coprescribing terbinafine and drugs metabolized by
      CYP2D6, particularly those with a narrow therapeutic index.

PMID- 12412820
TI  - Effect of potent CYP2D6 inhibition by paroxetine on atomoxetine pharmacokinetics.
AB  - The purpose of this study was to characterize the effect of potent CYP2D6
      inhibition byparoxetine on atomoxetine disposition in extensive metabolizers.
      This was a single-blind, two-period, sequential studyin 22 healthy individuals.
      In period 1, 20 mg atomoxetine bid was administered to steady state. In period 2,
      20 mg paroxetine was administered qd for 17 days. On days 12 through 17, 20 mg
      atomoxetine bid were coadministered. Plasma pharmacokinetics of atomoxetine, 4
      hydroxyatomoxetine, and N-desmethylatomoxetine was determined at steady state in
      each treatment period. Plasma pharmacokinetics of paroxetine were determined
      after the 11th and 17th doses. Paroxetine increased C(ss,max), AUC0-12, and t1/2
      of atomoxetine by approximately 3.5-, 6.5-, and 2.5-fold, respectively. After
      coadministration with paroxetine, increases in N-desmethylatomoxetine and
      decreases in 4-hydroxyatomoxetine concentrations were observed. No changes in
      paroxetine pharmacokinetics were observed after coadministration with
      atomoxetine. It was concluded that inhibition of CYP2D6 by paroxetine markedly
      affected atomoxetine disposition, resulting in pharmacokinetics similar to poor
      metabolizers of CYP2D6 substrates.

PMID- 12412821
TI  - Pharmacokinetics and pharmacodynamics of zoledronic acid in cancer patients with
      bone metastases.
AB  - The pharmacokinetics, pharmacodynamics, and safety of zoledronic acid (Zometa), a
      new-generation bisphosphonate, were evaluated in 36 patients with cancer and bone
      metastases. Zoledronic acid (by specific radioimmunoassay) and markers of bone
      turnover were determined in plasma and urine after three consecutive infusions
      (qx28 days) of 4 mg/5 min (n = 5),4 mg/l5 min (n = 7),8 mg/15 min (n = 12), or 16
      mg/15 min (n = 12). Zoledronic plasma disposition was multiphasic, with half
      lives of 0.2 and 1.4 hours representing an early, rapid decline of concentrations
      from the end-of-infusion C(max) to < 1% of C(max) at 24 hours postdose and half
      lives of 39 and 4526 hours describing subsequent phases of very low
      concentrations between days 2 and 28 postdose. AUC0-24 h and C(max) were dose
      proportional and showed little accumulation (AUC0-24 h ratio between the third
      and first dose was 1.28). Prolonging the infusion from 5 to 15 minutes lowered
      C(max) by 34%, with no effect on AUC0-24 h. Urinary excretion of zoledronic acid
      was independent of infusion duration, dose, or number of doses, showing average
      Ae0-24 h of 38% +/- 13%, 41% +/- 14%, and 37% +/- 17%, respectively, after 4, 8,
      and 16 mg. Only trace amounts of drug were detectable in post 24-hour urines.
      Renal clearance (Ae0-24 h)/(AUC0-24 h) was on average 69 +/- 28,81 +/- 40, and 54
      +/- 34 ml/min after 4,8, and 16 mg, respectively, and showed a moderate
      correlation (r = 0.5; p < 0.001) with creatinine clearance, which was 84 +/- 23,
      82 +/- 25, and 80 +/- 40 ml/min for the dose groups at baseline. Adverse events
      and changes from baseline in vital signs and clinical laboratory variables showed
      no relationship in terms of type, frequency, or severity with zoledronic acid
      dose or pharmacokinetic parameters. Zoledronic acid produced significant declines
      from baseline in serum and/or creatinine-corrected urine C-telopeptide (by 74%),
      N-telopeptide (69%), pyridinium cross-links [19-33%), and calcium (62%), with an
      increasing trend (by 12%) in bone alkalinephosphatase. There was no relationship
      of the magnitude and duration of these changes with zoledronic acid dose, Ae0-24
      h, AUC0-24 h or C(max). The antiresorptive effects were evident within 1 day
      postdose and were maintained over 28 days across all dose levels, supporting
      monthly dosing with 4 mg zoledronic acid.

PMID- 12412822
TI  - Preliminary studies of the pharmacokinetics and tolerability of zolmitriptan
      nasal spray in healthy volunteers.
AB  - Two preliminary studies of the pharmacokinetics and tolerability of zolmitriptan
      nasal spray were conducted, each involving 12 healthy volunteers. In study 1, an
      initial double-blind, dose escalation phase (placebo or 2.5, 5.0, or 10 mg
      zolmitriptan intranasally) was followed by an open crossover phase in which all
      subjects received 10 mg zolmitriptan as a nasal spray, tablet, and oral solution.
      In study 2, subjects received, on three separate occasions, zolmitriptan 2.5 mg
      as an intranasal solution at pH 7.4, at pH 5.0, and as an oral tablet. In study
      1, plasma concentrations of zolmitriptan and its active metabolite, 183C91, were
      broadly dose proportional. Plasma concentrations of zolmitriptan were detected
      earlier following nasal spray administration than after either tablet or oral
      solution. Similarly, in study 2, zolmitriptan was absorbed more rapidly following
      nasal spray administration with detectable plasma concentrations 5 minutes after
      dosing. Plasma levels were maintained at a plateau between 1 and 6 hours
      postdose, then decreased with a half-life of approximately 3 hours. There was no
      statistically significant difference for AUG or C(max) values between the two
      nasal spray solutions or between nasal spray and oral formulations. Other
      pharmacokinetic parameters for zolmitriptan were similar between the
      formulations. Plasma concentrations of 183C91 were higher for the first 2 hours
      after oral than after nasal spray administration. All formulations of
      zolmitriptan were well tolerated.

PMID- 12412823
TI  - Pharmacokinetics, dose proportionality, and tolerability of single and repeat
      doses of a nasal spray formulation of zolmitriptan in healthy volunteers.
AB  - The objective of this study was to investigate the pharmacokinetics, dose
      proportionality, and tolerability of a range of single and multiple doses of a
      nasal spray formulation of zolmitriptan in a randomized, double-blind, placebo
      controlled, balanced, incomplete crossover study. Thirty healthy male or female
      volunteers received two of five dose levels of zolmitriptan nasal spray: 0
      (placebo), 0.5, 1, 2.5, and 5 mg. At each level, treatment comprised a single
      dose on day 1 and two doses (separated by 2 h) on each of days 2, 3, and 4.
      Zolmitriptan was well tolerated, and symptoms were generally mild and of short
      duration. The most commonly reported adverse events were taste disturbance,
      paresthesia, hyperesthesia, headache, and nasal/throat discomfort. Volunteers
      generally reported fewer adverse events during the multiple-dose phase than after
      the single-dose phase. Zolmitriptan was detectable in plasma within 15 minutes,
      and t(max) was similar for each dose and after single and multiple dosing. Dose
      proportionality was shown for the C(max) and AUC of both zolmitriptan and its
      active metabolite, 183C91. Mean t1/2 for zolmitriptan and 183C91 was
      approximately 3 hours. It was concluded that the pharmacokinetics (C(max) and
      AUC) for both zolmitriptan and 183C91 was proportional to dose after both single
      and multiple dosing. Nasal spray zolmitriptan was well tolerated; the frequency
      and nature of adverse events did not increase after multiple dosing.

PMID- 12412824
TI  - Effect of estrogen treatment and vitamin D status on differing bioavailabilities
      of calcium carbonate and calcium citrate.
AB  - The authors hypothesized that estrogen treatment or vitamin D status may affect
      the bioavailability of two common calcium supplements differently. Using data
      derived from a recent trial in 25 postmenopausal women, the authors found that
      deltaAUC of serum calcium after subtraction of placebo was significantly higher
      after calcium citrate (median, 0.85; 25th to 75th percentile, 0.70 to 3.15) than
      after calcium carbonate (0.25; -0.58 to 1.00) in non-estrogen-treated patients.
      There was no difference in the bioavailability of calcium between the two calcium
      formulations in estrogen-treated patients. Bioavailability was also significantly
      higher with the citrate salt for the subgroups with lower serum 25-hydroxyvitamin
      D and higher serum 1,25-dihydroxyvitamin D concentrations. In summary,
      bioavailability of calcium from the calcium carbonate product was more dependent
      on estrogen treatment and vitamin D status than that of calcium citrate. This may
      explain the variable results of reported calcium supplementation studies.

PMID- 12412825
TI  - Sequential first-pass metabolism of nortilidine: the active metabolite of the
      synthetic opioid drug tilidine.
AB  - The disposition of nortildine, the active metabolite of the synthetic opioid drug
      tilidine, was investigated in healthy volunteers in a randomized, single-dose,
      three-way crossover design. Three different treatments were administered:
      tilidine 50 mg intravenously, tilidine 50 mg orally, and nortilidine 10 mg
      intravenously. The plasma concentrations of tilidine, nortilidine, and
      bisnortilidine were determined and subjected to pharmacokinetic analysis using
      noncompartmental methods. The systemic bioavailability of tilidine was low (7.6%
      +/- 5.3%) due to a pronounced first-pass metabolism. The areas under the plasma
      concentration versus time curves (A UC) of nortilidine were similar following
      either oral or intravenous administration of tilidine 50 mg (375 +/- 184 vs. 364
      +/- 124 ng.h.ml(-1)). AUC of nortilidine was 229 +/- 42 ng.h.ml(-1) after IV
      infusion of nortilidine 10 mg and thus much greater than after IV tilidine
      corrected for differences in dose. Nortilidine had a much lower volume of
      distribution (275 +/- 79 vs. 1326 +/- 477 L) and a somewhat lower clearance (749
      +/- 119 vs. 1198 +/- 228 ml/min) than tilidine. About two-thirds of the dose of
      tilidine was metabolized to nortilidine, although only half of the latter
      fraction was available in the peripheral circulation. Nortilidine was
      subsequently metabolized to bisnortilidine. The mean ratio of the AUC of
      bisnortilidine to nortilidine was 0.65 +/- 0.14 following IV administration of
      nortilidine but 1.69 +/- 0.38 and 1.40 +/- 0.27 following oral and intravenous
      administration of tilidine, respectively. The shapes of the plasma concentration
      time curves of the metabolites and parent drug declined in parallel, indicating
      that the disposition of the metabolites is formation rate limited. Thus, although
      two-thirds of the dose of tilidine is metabolized to nortilidine, only one-third
      of the dose is available systemically as nortilidine for interaction with the
      opiate receptors after both intravenous and oral dosing of tilidine. The
      remaining part of nortilidine is retained in the liver and is subsequently
      metabolized to bisnortilidine and yet unknown compounds.

PMID- 12412826
TI  - Pharmacokinetics and pharmacodynamics of a new formulation of recombinant human
      growth hormone administered by ZomaJet 2 Vision, a new needle-free device,
      compared to subcutaneous administration using a conventional syringe.
AB  - The objective of the present study was to investigate the applicability of a new
      human growth hormone (Zomacton) formulation, administered both by a conventional
      syringe and by a new needle-free device (ZomaJet 2 Vision). The study was
      performed according to a randomized, controlled, three-period crossover design.
      On 3 separate days, all subjects received in a random order a single subcutaneous
      injection of 1.67 mg hGH as follows: Zomacton 4 mg/ml conventional syringe
      administration (Treatment A), Zomacton 10 mg/ml conventional syringe
      administration (Treatment B), or Zomacton 10 mg/ml ZomaJet 2 Vision
      administration (Treatment C). The pharmacokinetic parameters were assessed for
      the individual subjects in each group by noncompartmental methods. Bioequivalence
      was assessed based on log-transformed AUC and C(max) values. To investigate the
      effectiveness of two formulations and the different administration methods, the
      pharmacodynamic parameters (insulin-like growth factor-1 [IGF-1] and free fatty
      acids [FFA]) were also evaluated. No subjects were withdrawn due to adverse
      events. The local tolerance assessment (assessed by inspection)revealed no
      differences between ZomaJet2 Vision application and conventional injections by
      syringe. Administration of the new hGH formulation by syringe was found to be
      bioequivalent with the reference treatment, both based on AUC and C(max) values;
      the new formulation administered by use of ZomaJet 2 Vision was found to be
      bioequivalent based on AUC values only. When using the ZomaJet 2 Vision, the
      absorption of hGH was faster, resulting in higher C(max) values. The maximum hGH
      serum concentration of around 20 ng/ml was observed 3.5 to 4 hours after drug
      administration. The terminal half-life was found to be around 2.5 hours.
      Comparison of the pharmacodynamic profiles (both IGF-1 and FFA) demonstrated
      bioequieffectiveness. These results support the use of jet injectors as a viable
      alternative to the traditional injection pens.

PMID- 12412827
TI  - Fexofenadine transport in Caco-2 cells: inhibition with verapamil and ritonavir.
AB  - This study investigated fexofenadine (FXD) transport and the inhibition of FXD
      transport in Caco-2 cell monolayer transwells, using rhodamine 123 (RH123)
      transport as a positive control. FXD transport from the basolateral (B) to apical
      (A) compartment was fivefold higher than A to B transport. FXD transport was
      linear with respect to time (up to 270 min) and concentration (up to 300 microm).
      Similar results were seen with the positive control RH123. Ritonavir (100 PM) and
      verapamil (100 microm) reduced transport of FXD and RH123 by more than 80%,
      whereas transport was not inhibited by 100 m indomethacin or 2 mM probenecid.
      This suggests predominantly P-glycoprotein (P-gp)-mediated transport as opposed
      to transport by multidrug resistance protein. In concentration-response
      experiments, FXD transport was inhibited by verapamil and ritonavir with IC50
      values of 6.5 microm and 5.4 microm, respectively. Results from this in vitro
      study demonstrate differential transport of FXD across Caco-2 cell monolayers and
      inhibition of FXD transport by established P-gp inhibitors. Thefindings support
      the use of FXD as an index or probe compound to reflect P-gp activity in vivo.

PMID- 12412829
TI  - 5HT1B/1D agonists.

PMID- 12412828
TI  - Impairment of mycophenolate mofetil absorption by calcium polycarbophil.
AB  - The effect of calcium polycarbophil on the absorption of mycophenolate mofetil,
      an immunosuppressive agent, was evaluated in healthy subjects. In vitro studies
      were performed to further evaluate the mechanism of the potential interaction. In
      the in vitro study, the release of mycophenolate mofetil from a cellulose
      membrane in the presence or absence of metal cations was measured using the
      dissolution test procedure. In the in vivo study, a randomized crossover design
      with two phases was used. In one phase, 6 male healthy volunteers received 1000
      mg of mycophenolate mofetil alone (treatment 1); in the other phase, they
      received 1000 mg of mycophenolate mofetil and 2400 mg of calcium polycarbophil
      fine granules concomitantly (treatment 2). They received 30 mg of lansoprazole
      for 5 days and, on the 6th day, received mycophenolate mofetil and 2400 mg of
      calcium polycarbophil fine granules concomitantly (treatment 3). The serum
      concentration of mycophenolic acid was measured by high-performance liquid
      chromatography. In the in vitro study, the release from a cellulose membrane in
      the presence of calcium or iron ions was slower than that in the absence of these
      metal ions. In the in vivo study, the AUC0-12 and C(max) in treatment 2 were less
      than those in treatment 1. About 50% and 25% decreases in AUC0-12 in treatment 2
      and treatment 3 were observed compared with those in treatment 1, respectively.
      These findings suggest that when mycophenolate mofetil and calcium polycarbophil
      were coadministered concomitantly, a decrease in mycophenolate mofetil absorption
      was observed. Therefore, it appears clear that the concomitant administration of
      mycophenolate mofetil and calcium polycarbophil should be avoided.

PMID- 12412830
TI  - Clinical consequences of marijuana.
AB  - As documented in national surveys, for the past several years, marijuana has been
      the most commonly abused drug in the United States, with approximately 6% of the
      population 12 years and older having used the drug in the month prior to
      interview. The use of marijuana is not without significant health hazards.
      Marijuana is associated with effects on almost every organ system in the body,
      ranging from the central nervous system to the cardiovascular, endocrine,
      respiratory/pulmonary, and immune systems. Research presented in this special
      supplement will show that in addition to marijuana abuse/dependence, marijuana
      use is associated in some studies with impairment of cognitive function in the
      young and old, fetal and developmental consequences, cardiovascular effects
      (heart rate and blood pressure changes), respiratory/pulmonary complications such
      as chronic cough and emphysema, impaired immune function leading to vulnerability
      to and increased infections, and the risk of developing head, neck, and/or lung
      cancer. In general, acute effects are better studied than those of chronic use,
      and more studies are needed that focus on disentangling effects of marijuana from
      those of other drugs and adverse environmental conditions.

PMID- 12412831
TI  - Cannabidiol: an overview of some pharmacological aspects.
AB  - Over the past few years, considerable attention has focused on cannabidiol (CBD),
      a major nonpsychotropic constituent of cannabis. The authors present a review on
      the chemistry of CBD and discuss the anticonvulsive, antianxiety, antipsychotic,
      antinausea, and antirheumatoid arthritic properties of CBD. CBD does not bind to
      the known cannabinoid receptors, and its mechanism of action is yet unknown. It
      is possible that, in part at least, its effects are due to its recently
      discovered inhibition of anandamide uptake and hydrolysis and to its
      antioxidative effect.

PMID- 12412832
TI  - Marijuana withdrawal syndrome in the animal model.
AB  - Although the proposition that repeated marijuana use can lead to marijuana
      dependence has long been accepted, only recently has evidence emerged suggesting
      that abstinence leads to clinically significant withdrawal symptoms. Converging
      evidence from human and animal studies has increased our understanding of
      cannabinoid dependence. One of the most powerful tools to advance this area of
      research is the CB1 cannabinoid receptor antagonist SR 141716A, which reliably
      precipitates withdrawal syndromes in mice, rats, and dogs that have been treated
      repeatedly with cannabinoids. In addition, the use of CB1 receptor knockout mice
      has revealed that not only cannabinoid dependence is mediated through a CB1
      receptor mechanism of action, but CB1 receptors also modulate opioid dependence.
      Moreover, the results of other genetically altered mouse models suggest the
      existence of a reciprocal relationship between cannabinoid and opioid systems in
      drug dependence. Undoubtedly, these animal models will play pivotal roles in
      further characterizing cannabinoid dependence and elucidating the mechanisms of
      action, as well as developing potential pharmacotherapies for cannabinoid
      dependence.

PMID- 12412833
TI  - Development and consequences of cannabis dependence.
AB  - The past 10 to 15 years of clinical and basic research have produced strong
      evidence demonstrating that cannabis can and does produce dependence. Clinical
      and epidemiological studies indicate that cannabis dependence is a relatively
      common phenomenon associated with significant psychosocial impairment. Basic
      research has identified a neurobiological system specific to the actions of
      cannabinoids. Human and nonhuman studies have demonstrated a valid withdrawal
      syndrome that is relatively common among heavy marijuana users. Last, clinical
      trials evaluating treatments for cannabis dependence suggest that this disorder,
      like other substance dependence disorders, is responsive to intervention, yet the
      majority of patients have difficulty achieving and maintaining abstinence. Of
      concern, treatment seeking for marijuana dependence has increased almost twofold
      over the past 10 years. This report briefly reviews selected research literature
      relevant to our current understanding of cannabis dependence, its associated
      consequences, and treatment efficacy.

PMID- 12412834
TI  - Effects of smoked marijuana in healthy and HIV + marijuana smokers.
AB  - This article presents data from two avenues of marijuana research. First, the
      author shows that daily marijuana smoking in healthy individuals produces
      dependence, as demonstrated by withdrawal symptoms such as increased irritability
      and depression and decreased food intake. In addition, two antidepressant
      medications were evaluated to assess their potential effectiveness in the
      treatment of marijuana withdrawal symptoms: (1) sustained-release bupropion (0,
      300 mg/day) and (2) nefazodone (0, 450 mg/day). Research participants were
      regular marijuana smokers who lived in a residential laboratory in groups of two
      to four. While inpatients, participants smoked active marijuana (2.8%-3.1% THC)
      repeatedly for 4 days, followed by 8 to 12 days of placebo marijuana (0.0% THC).
      Results show that during marijuana abstinence, (1) bupropion increased ratings of
      irritability, depression, and stomach pain and decreased food intake and sleep
      quality compared to placebo maintenance, and (2) nefazodone decreased anxiety
      during marijuana withdrawal but did not alter ratings of irritability and misery.
      Thus, neither medication showed promise as potential treatments for symptoms of
      marijuana withdrawal. The second avenue of research focused on the effect of
      cannabinoids in individuals with muscle mass loss, an indicator of wasting in HIV
      illness. Given that there are little scientific data contributing to the debates
      concerning medical marijuana, this study directly compared the effects of oral
      delta9-THC (0, 10, 20, 30 mg PO) to smoked marijuana (0.0%, 1.8%, 2.8%, 3.9% THC)
      in HIV + marijuana smokers with muscle mass loss (< 90% body cell mass/height).
      Multiple dimensions of human behavior were measured, including food intake, mood,
      and cognitive performance. Drugs were administered using a within-subject, double
      blind, staggered, double-dummy design. Participants were free to self-select from
      a variety of foods throughout most of the session. Preliminary data (n = 9)
      suggest that oral THC was more effective at increasing food intake, but the
      volunteers "liked" the effects of smoked marijuana more than the effects of oral
      THC.

PMID- 12412835
TI  - Cognitive measures in long-term cannabis users.
AB  - The cognitive effects of long-term cannabis use are insufficiently understood.
      Most studies concur that cognitive deficits persist at least several days after
      stopping heavy cannabis use. But studies differ on whether such deficits persist
      long term or whether they are correlated with increasing duration of lifetime
      cannabis use. The authors administered neuropsychological tests to 77 current
      heavy cannabis users who had smoked cannabis at least 5000 times in their lives,
      and to 87 control subjects who had smoked no more than 50 times in their lives.
      The heavy smokers showed deficits on memory of word lists on Days 0, 1, and 7 of
      a supervised abstinence period. By Day 28, however, few significant differences
      were found between users and controls on the test measures, and there were few
      significant associations between total lifetime cannabis consumption and test
      performance. Although these findings may be affected by residual confounding, as
      in all retrospective studies, they suggest that cannabis-associated cognitive
      deficits are reversible and related to recent cannabis exposure rather than
      irreversible and related to cumulative lifetime use.

PMID- 12412836
TI  - Nonacute (residual) neuropsychological effects of cannabis use: a qualitative
      analysis and systematic review.
AB  - Because there is a possibility that cannabis or cannabis-like molecules might be
      used as treatments for certain conditions in the future, it becomes important to
      consider the possible adverse effects of these compounds. In this paper, the
      authors review the evidence for persisting effects of nonacute cannabis use on
      the central nervous system, as reflected by alteration in neuropsychological
      performance. From the 40 articles that met criteria for inclusion in this review,
      the authors could not detect consistent evidence for persisting
      neuropsychological deficits in cannabis users; however, 22 of the 40 studies
      reported at least some subtle impairments. The inability to reach a firm
      conclusion results largely from methodological limitations inherent in most
      studies. These are considered in detail to inform future studies on (nonacute)
      consequences of cannabis consumption on cognitive abilities.

PMID- 12412837
TI  - Cardiovascular system effects of marijuana.
AB  - Marijuana and delta9-tetrahydrocannabinol (THC) increase heart rate, slightly
      increase supine blood pressure, and on occasion produce marked orthostatic
      hypotension. Cardiovascular effects in animals are different, with bradycardia
      and hypotension the most typical response. Cardiac output increases, and
      peripheral vascular resistance and maximum exercise performance decrease.
      Tolerance to most of the initial cardiovascular effects appears rapidly. With
      repeated exposure, supine blood pressure decreases slightly, orthostatic
      hypotension disappears, blood volume increases, heart rate slows, and circulatory
      responses to exercise and Valsalva maneuver are diminished, consistent with
      centrally mediated, reduced sympathetic, and enhanced parasympathetic activity.
      Receptor-mediated and probably nonneuronal sites of action account for
      cannabinoid effects. The endocannabinoid system appears important in the
      modulation of many vascular functions. Marijuana's cardiovascular effects are not
      associated with serious health problems for most young, healthy users, although
      occasional myocardial infarction, stroke, and other adverse cardiovascular events
      are reported. Marijuana smoking by people with cardiovascular disease poses
      health risks because of the consequences of the resulting increased cardiac work,
      increased catecholamine levels, carboxyhemoglobin, and postural hypotension.

PMID- 12412838
TI  - Cardiovascular consequences of marijuana use.
AB  - This review describes what is known about effects of marijuana and cannabinoids
      in relation to human physiological and disease outcomes. The acute physiological
      effects of marijuana include a substantial dose-dependent increase in heart rate,
      generally associated with a mild increase in blood pressure. Orthostatic
      hypotension may occur acutely as a result of decreased vascular resistance.
      Smoking marijuana decreases exercise test duration in maximal exercise tests,
      increases the heart rate at submaximal levels of exercise. Tolerance develops to
      the acute effects of marijuana smoking and delta9-tetrahydrocannibol (THC) over
      several days to a few weeks. The cardiovascular responses that occur in response
      to THC are mediated by the autonomic nervous system, with recent findings also
      demonstrating that the human cannabinoid receptor system plays a role in
      regulating the cardiovascular response. Although several mechanisms exist by
      which marijuana use might contribute to the development of chronic cardiovascular
      conditions or acutely trigger cardiovascular events, there are few data regarding
      marijuana/THC use and cardiovascular disease outcomes. A large cohort study
      showed no association of marijuana use with cardiovascular disease
      hospitalization or mortality. However, acute effects of marijuana use include a
      decrease of the time until the onset of chest pain in patients with angina
      pectoris; one study has shown that marijuana may trigger the onset of myocardial
      infarction. Patients who have coronary heart disease or are at high risk for the
      development of CHD should be cautioned about the potential hazards of marijuana
      use as a precipitant for clinical events. Research directions might include more
      studies of cardiovascular disease outcomes and relationships of marijuana with
      cardiovascular risk factors, studies of metabolic and physiologic effects of
      chronic marijuana use that may affect cardiovascular disease risk, increased
      understanding of the role of the cannabinoid receptor system in cardiovascular
      regulation, and studies to determine if there is a therapeutic role for
      cannabinoids in blood pressure control or for neuroprotection after stroke.

PMID- 12412839
TI  - Respiratory and immunologic consequences of marijuana smoking.
AB  - Habitual smoking of marijuana has a number of effects on the respiratory and
      immune systems that may be clinically relevant. These include alterations in lung
      function ranging from no to mild airflow obstruction without evidence of
      diffusion impairment, an increased prevalence of acute and chronic bronchitis,
      striking endoscopic findings of airway injury (erythema, edema, and increased
      secretions) that correlate with histopathological alterations in bronchial
      biopsies, and dysregulated growth of the bronchial epithelium associated with
      altered expression of nuclear and cytoplasmic proteins involved in the
      pathogenesis of bronchogenic carcinoma. Other consequences of regular marijuana
      use include ultrastructual abnormalities in human alveolar macrophages along with
      impairment of their cytokine production, antimicrobial activity, and tumoricidal
      function. Cannabinoid receptor expression is altered in leukocytes collected from
      the blood of chronic smokers, and experimental models support a role for delta9
      tetrahydrocannabinol in suppressing T cell function and cell-mediated immunity.
      The potential for marijuana smoking to predispose to the development of
      respiratory malignancy is suggested by several lines of evidence, including the
      presence of potent carcinogens in marijuana smoke and their resulting deposition
      in the lung, the occurrence of premalignant changes in bronchial biopsies
      obtained from smokers of marijuana in the absence of tobacco, impairment of
      antitumor immune defenses by delta9-tetrahydrocannabinol, and several clinical
      case series in which marijuana smokers were disproportionately over represented
      among young individuals who developed upper or lower respiratory tract cancer.
      Additional well designed epidemiological and immune monitoring studies are
      required to determine the potential causal relationship between marijuana use and
      the development of respiratory infection and/or cancer.

PMID- 12412840
TI  - Short-term effects of cannabinoids on immune phenotype and function in HIV-1
      infected patients.
AB  - Cannabinoids, including smoked marijuana and delta9-tetrahydrocannabinol (THC)
      (dronabinol, Marinol), have been used to treat human immunodeficiency virus-1
      (HIV)-associated anorexia and weight loss. Concerns have been raised, however,
      that these compounds might have adverse effects on the immune system of subjects
      with HIV infection. To determine whether such effects occur, the authors designed
      a randomized, prospective, controlled trial comparing the use of marijuana
      cigarettes (3.95% THC), dronabinol (2.5 mg), and oral placebo in HIV-infected
      adults taking protease inhibitor-containing highly active antiretroviral therapy
      (HAART). Assays of immune phenotype (including flow cytometric quantitation of T
      cell subpopulations, B cells, and natural killer [NK] cells) and immunefunction
      (including assays for induced cytokine production, NK cell function, and
      lymphoproliferation) were performed at baseline and weekly thereafter. On the
      basis of these measurements and during this short 21-day study period, few
      statistically significant effects were noted on immune system phenotypes
      orfunctions in this patient population.

PMID- 12412841
TI  - Endocrine effects of marijuana.
AB  - In the 35 years since the active compound of marijuana, delta9
      tetrahydrocannabinol, was isolated, the psychological and physiological impact of
      marijuana use has been actively investigated. Animal models have demonstrated
      that cannabinoid administration acutely alters multiple hormonal systems,
      including the suppression of the gonadal steroids, growth hormone, prolactin, and
      thyroid hormone and the activation of the hypothalamic-pituitary-adrenal axis.
      These effects are mediated by binding to the endogenous cannabinoid receptor in
      or near the hypothalamus. Despite these findings in animals, the effects in
      humans have been inconsistent, and discrepancies are likely due in part to the
      development of tolerance. The long-term consequences of marijuana use in humans
      on endocrine systems remain unclear.

PMID- 12412842
TI  - Adolescents prenatally exposed to marijuana: examination of facets of complex
      behaviors and comparisons with the influence of in utero cigarettes.
AB  - For the purposes of this review, the impact of prenatal exposure to marijuana in
      adolescent offspring is discussed in the context that the effects may be apparent
      only when the multifaceted nature of complex behaviors is examined and that such
      exposure can be distinguished from those of prenatal exposure to cigarettes. The
      data are derived from adolescents participating in an on going longitudinal study
      for whom prenatal marijuana and cigarette exposure had been ascertained with the
      low-risk, predominantly middle-class sample that had been assessed since birth.
      In this report, cognitive functioning and visual perceptual performance in 9- to
      12-year-olds and facets of attention in 13- to 16-year-olds are examined. These
      three areas of behavior all appear to be affected differentially by maternal use
      of marijuana or cigarettes. Prenatal cigarette exposure was associated with
      lowered IQ, poorer impulse control, and poorer performance on tests requiring
      fundamental aspects of visuoperceptual performance. In contrast, prenatal
      marijuana did not have a negative impact on IQ or on basic visuoperceptual
      skills. Rather, in utero exposure to marijuana had an impact on the application
      of these skills in tasks in problem-solving situations requiring visual
      integration and analytical skills as well as sustained attention. These
      differential findings are discussed in terms of cigarette exposure having a
      "bottom-up" impact and marijuana exposure having a "top-down" impact. The latter
      is also discussed in terms of prenatal marijuana's negative association with
      aspects of executive function.

PMID- 12412843
TI  - Marijuana smoking and head and neck cancer.
AB  - A recent epidemiological study showed that marijuana smoking was associated with
      an increased risk of head and neck cancer. Among high school students and young
      adults, the prevalence of marijuana use was on the rise in the 1990s, with a
      simultaneous decline in the perception that marijuana use is harmful. It will be
      a major public health challenge to make people aware of the harmful effects of
      marijuana smoking, when some people view it as the illicit drug with the least
      risk. The carcinogenicity of delta9-tetrahydrocannabinol (THC) is not clear, but
      according to laboratory studies, it appears to have antitumor properties such as
      apoptosis as well as tumor-promoting properties such as limiting immune function
      and increasing reactive oxygen species. Marijuana tar contains similar
      carcinogens to tar from tobacco cigarettes, but each marijuana cigarette maybe
      more harmful than a tobacco cigarette since more tar is inhaled and retained when
      smoking marijuana. More molecular alterations have been observed in bronchial
      mucosa specimens of marijuana smokers compared to nonsmokers. Field cancerization
      may be occurring on the bronchial epithelium due to marijuana smoking exposure.
      Several case studies were suggestive of an association of marijuana smoking with
      head and neck cancers and oral lesions. However, in a cohort study with 8 years
      of follow-up, marijuana use was not associated with increased risks of all
      cancers or smoking-related cancers. Further epidemiological studies are necessary
      to confirm the association of marijuana smoking with head and neck cancers and to
      examine marijuana smoking as a risk factor for lung cancer. It will also be of
      interest to examine potential field cancerization of the upper aerodigestive
      tract by marijuana and to explore marijuana as a risk factor for oral
      premalignant lesions.

PMID- 12412844
TI  - Work-related exacerbation of asthma.
AB  - Adults with asthma who had been enrolled in an HMO for at least a year were
      requested to complete a questionnaire about their health status. Approximately
      25% of the 1,461 participants responded positively to "Does your current work
      environment make your asthma worse?" and were classified as having workplace
      exacerbation of asthma. Those with workplace exacerbation were more likely to
      have never attended college, be current or former smokers, have a history of
      other respiratory diseases, have missed work or usual activities at least one day
      in the past for weeks, and report their asthma was moderate, severe, or very
      severe. Percentages with workplace exacerbation of asthma were highest for mining
      and construction (36%), wholesale and retail trade (33%), and public
      administration (33%), and lowest for educational services (22%), finance,
      insurance, and real estate (22%), and non-medical and non-educational services
      (18%). Future studies are needed for objective validation of self-reported
      workplace exacerbation, and to follow subjects prospectively to clarify the
      temporal sequence of workplace exacerbation and asthma severity, and how other
      respiratory conditions and smoking might contribute to work-related worsening of
      asthma.

PMID- 12412845
TI  - Lung function and symptoms among cotton workers and dropouts three years after
      the start of work.
AB  - A longitudinal study of cotton workers was undertaken to assess the presence of
      work-related medical effects. A cohort of 110 subjects was examined before
      starting work and one year later. Measurements of pulmonary function were made
      before and after the work shift. Airway responsiveness was measured using a
      methacholine challenge test. A questionnaire was used to determine work-related
      symptoms. The 60 workers who remained after three years experienced an over-shift
      drop in FEV1 and an increase in airway responsiveness that did not increase after
      the first year. The data from the dropout group (n = 50) before work and after
      one year were compared with those for the active workers. The dropout group had a
      higher prevalence of symptoms of chest tightness and nasal irritation after one
      year of work. Atopy was not more common in this group. The results suggest that
      leaving work was related to symptoms of airways inflammation but not to atopy.

PMID- 12412846
TI  - Respiratory health and silica exposure of stone carvers in Thailand.
AB  - A cross-sectional study of dust exposures and health outcomes was conducted in a
      stone-carving company in Thailand. 147 respirable dust samples were collected and
      97 subjects participated. Exposure indices were constructed and health outcomes,
      including respiratory symptoms, pulmonary functions, and chest radiographs, were
      assessed. Severities of employees' current exposures to quartz were 0.5-8.8 times
      the ACGIH-TLV, depending on job and site. Durations of exposures ranged from 4
      months to 30 years. The prevalence of silicosis (profusion grade > or = 1/0) was
      2%. Pulmonary tuberculosis was also detected in 4%. Linear regression analyses
      revealed decreased lung function in workers with longer work durations (p <
      0.05), regardless of age, sex, height, and smoking status. No clear association
      was seen between cumulative exposure metrics and indicators of silicosis.
      Elevated silica exposure levels indicate an ongoing risk of silicosis in this
      industry. Exposures were increased by the use of grinding tools with no
      ventilation and by proximity to other workers. However, because the number of
      workers with dust-exposure histories was limited, exposure measurements were
      confined to current conditions.

PMID- 12412847
TI  - Welding and ischemic heart disease.
AB  - Metal welding and cutting are associated with inhalation of gases and respirable
      particles. The purpose of this study was to compare the mortality of male welders
      with that of all gainfully employed men in Sweden regarding ischemic heart
      disease (IHD). Male welders and gas cutters were identified in the Swedish
      National Censuses of 1970 and 1990. Two cohorts were established and followed
      until the end of 1995. The IHD mortality among the welders was compared with that
      of all gainfully employed men. An increased mortality due to IHD was observed
      among welders identified in the 1990 Census, SMR = 1.35, 95% confidence limits
      1.1-1.6. The observed increased mortality due to IHD was unlikely to be explained
      by different smoking habits. A general hypothesis linking inhalation of particles
      to the occurrence of IHD via an inflammatory process is discussed.

PMID- 12412848
TI  - Outcomes of pregnancy among women living in the proximity of oil fields in the
      Amazon basin of Ecuador.
AB  - Oil companies have released billions of gallons of untreated wastes and oil
      directly into the environment of the Ecuadorian Amazon. This cross-sectional
      study investigated the environmental conditions and reproductive health of women
      living in rural communities surrounded by oil fields in the Amazon basin and in
      unexposed communities. Water from local streams was analyzed for total petroleum
      hydrocarbons (TPH). The women, aged 17 to 45 years, had resided for at least
      three years in the study communities. Socioeconomic and reproductive histories of
      the last three pregnancies were obtained from interviews. Information from the
      questionnaire was available for 365 exposed and 283 non-exposed women. The study
      was conducted from November 1998 to April 1999. Streams of exposed communities
      had TPH concentrations above the allowable limit. After adjustment for potential
      confounders, the pregnancies of women in exposed communities were more likely to
      end in spontaneous abortion (OR: 2.47; 95% CI: 1.61-3.79; p < 0.01). No
      association was found between stillbirth and exposure. An environmental system to
      control and eliminate the sources of pollution in the area is needed.

PMID- 12412849
TI  - Self-reported occupational health hazards and measured exposures to airborne
      impurities and noise in shoe repair work.
AB  - The authors identified occupational risk factors of shoe repairers and measured
      their exposures to organic solvents, dust, chromium, degradation products of
      synthetic shoe materials, and noise. Exposures were measured in 11 shops selected
      from the workplaces of 82 repairers who responded to a questionnaire about their
      work environments. The questions dealt with, e.g., chemicals used, work related
      diseases, perceived hazards in the environment, ventilation, and use of personal
      protective equipment. Solvent vapor concentration averaged 1.95 (range 0.01-13.2)
      times the occupational limit (OL) of the mixture during gluing, with higher
      levels in facilities with no mechanical ventilation. TWA concentrations of
      organic solvents averaged 0.34 (range 0.01-1.23) times OLs in the breathing-zone
      samples. Of all shoe repair shops in Finland, 30% had no mechanical ventilation.
      Concentrations of airborne particles were 0.07-1.01 mg/m3, and those of insoluble
      and hexavalent chromium 0.10-0.32 and 0.01-0.08 microg/m3, respectively, near
      roughing, scoring and finishing machines. Several polymer degradation products
      were present in the air during machining of shoes. Ventilation exchange rates in
      shops with natural ventilation were less than once/hour. The repairers' average
      exposure to noise was below 85 dB. They reported many work-related diseases such
      as rhinitis (prevalence 21%), musculoskeletal disorders (16%), and dermatitis
      (9%). Measured dust concentrations were low, but the shoe repairers considered
      dust to be the most common hazard.

PMID- 12412850
TI  - Feasibility of maternity protection in early pregnancy.
AB  - Many countries have maternity protection laws for women who need job modification
      or medical leave during pregnancy. This approach will prevent birth defects only
      if maternal job changes can be made before the critical period of organogenesis,
      which begins at three weeks' gestation. The authors studied the gestational ages
      at which pregnant women working with chemicals, radiation, and noise presented
      for occupational safety and health consultations. The work setting promoted early
      presentation because the consultation was free, convenient, mandatory, and would
      not result in job loss. Among the 213 pregnant women evaluated between 1996 and
      2000, most (89.5%) had their occupational safety evaluations in the first
      trimester. Although this sounds ideal, the mean gestational age at presentation
      was 7.5 weeks, and only 3.3% of occupational health evaluations were initiated by
      three weeks' gestation. Environmental and biological monitoring showed that none
      of the women was exposed over occupational limits. These data suggest that a
      workplace free from reproductive hazards needs to be provided before conception.

PMID- 12412851
TI  - Risk factors for machinery-related injury among Iowa farmers: a case-control
      study nested in the Agricultural Health Study.
AB  - Farm machinery is a major cause of injury morbidity and mortality among farmers.
      This case-control study assessed risk factors for machinery-related injuries
      among Iowa farmers. A screener questionnaire sent to 6,999 farmers in 1998
      identified 205 farmers who had machinery-related injuries requiring medical
      advice/treatment in the previous year. Possible risk factors for injury were
      assessed among these farmers compared with 473 farmers with no injury in the
      previous year. A multiple logistic regression analysis showed significant
      associations between machinery-related injury and hours per week spent on
      farmwork (OR = 2.02; 95% CI 1.38-2.94), fewer years of farming experience (OR =
      1.79; 95% CI 1.14-2.79), wearing a hearing aid (OR = 4.37; 95% CI 1.55-12.25),
      and a high CAGE score suggesting problem drinking (OR = 2.49; 95% CI 1.00-6.19).
      This is the first study to show associations between machinery-related injury and
      hearing impairment, problem drinking, and fewer years of farming experience.
      These findings may be useful for future interventions to decrease injuries
      related to farm machinery.

PMID- 12412852
TI  - Musculoskeletal symptoms among farmers and non-farmers: a population-based study.
AB  - Farming has been considered a high-risk occupation for musculoskeletal disorders.
      However, documentation of the increased risk is weak except for hip
      osteoarthritis. 1,013 full-time farmers in nine Swedish municipalities and 769
      non-farmers (referents), matched for age, sex, and residential area, participated
      in the study. Information about medical history, consultations, and sick leave
      for musculoskeletal disorders was obtained by questionnaire and interview. The
      farmers reported significantly more symptoms affecting the hands and forearms,
      low back, and hips than did the non-farmers, and a non-significant trend in the
      same direction was found for symptoms from the neck, shoulders, and knees.
      However, the farmers did not seek medical advice more often than the referents,
      and they reported significantly less sick leave for these problems. Thus, farmers
      appear to have more musculoskeletal symptoms than do non-farmers.

PMID- 12412853
TI  - Occupational histories of cancer patients in a Canadian cancer treatment center
      and the generated hypothesis regarding breast cancer and farming.
AB  - Occupational exposures increase cancer risks. The Windsor Regional Cancer Centre
      in Windsor, Ontario, was the first Canadian cancer treatment center to collect
      the work histories of its patients, which were recorded using a computer-based
      questionnaire. Breast cancer cases represented the largest respondent group. The
      lifetime occupational histories of 299 women with newly diagnosed breast cancers
      were compared with those of 237 women with other cancers. Odds ratios (ORs) were
      calculated using logistic regression, adjusting for age, social class, and
      education. The OR for women < or = 55 years of age with breast cancer who had
      ever farmed, compared with women of the same age with other cancers, was 9.05
      (95% CI 1.06, 77.43). Patients' occupational histories can help to inform
      understanding of cancer etiology and prevention. This effort points to a need for
      investigation of the possible association between breast cancer and agricultural
      hazards such as pesticides.

PMID- 12412854
TI  - Hazard identification in occupational injury: reflections on standard
      epidemiologic methods.
AB  - To prevent workplace injuries, epidemiologic research must continue to progress
      beyond methods originally used for acute or chronic diseases. For injury
      research, exposure assessment requires increased sophistication because exposures
      comprise multiple, transient factors and complex work activities. Frequently
      reported risk factors such as age, gender, seniority, or prior injury are often
      confounders or effect-modifiers of unknown exposures. Injury rate calculations
      across nominal categories, e.g., department or job classification, identify where
      hazards are concentrated but provide little insight into their nature; injury
      counts often perform almost as well. Calculation of rates in relation to time
      actually spent in plausible etiologic exposure conditions usually is not
      feasible. Generalization of the Haddon approach for individual injury events to
      systematically analyze injury case series can identify both the mechanism of
      injury and the relative occurrences of high-risk conditions. In some contexts,
      case-crossover designs may elucidate injury causation. National databases and
      information systems of employers, insurers, and equipment suppliers could
      contribute case series for injury hazard identification. By enhancing exposure
      assessment through a focus on case series, epidemiologic research can expand its
      contribution to preventing workplace injuries.

PMID- 12412855
TI  - Methodologic aspects of the study of modern-age diseases: the example of sick
      building syndrome.
AB  - In recent decades, variously identified nebulous disorders such as sick-building
      syndrome, electrical hypersensitivity, and chronic fatigue syndrome,
      characterized by combinations of nonspecific symptoms and absence of demonstrable
      signs have appeared. Their similar nonspecific etiologic attributions have given
      rise to generic names such as "modern-age disease" and "symptom-based
      conditions." The lack of demonstrable biological correlates as well as the
      vagueness of the etiologic attributions makes modern-age diseases unusually
      problematic to study with epidemiologic methods, potentially leading to serious
      biases. Case studies of sick-building syndrome demonstrate that qualitative
      methods can help to elucidate the dynamic processes involved in syndrome
      development.

PMID- 12412857
TI  - The Bhopal syndrome: persistent questions about acute toxicity and management of
      gas victims.
AB  - A review of the health effects of the 1984 gas leak from the Union Carbide plant
      in Bhopal, India, shows continuing morbidity of a multisystemic nature in the
      exposed population. Scientific debates about the causes of the accident, the
      spectrum of health effects, and toxicology are presented with a view to
      understanding the toxic substances released in the gas cloud and their roles in
      the causation of health effects. Clinical dilemmas, medical management, and
      public health issues are also discussed.

PMID- 12412856
TI  - What ails the Bhopal disaster investigations? (And is there a cure?).
AB  - A review of the health effects of the 1984 disaster in Bhopal, India, shows
      continuing morbidity of a multi-systemic nature in the exposed population.
      Scientific questions about epidemiologic issues are discussed with a view to
      understanding appropriate methods of investigation into the disaster. Other major
      chemical incidents were reviewed to note some of the common problems associated
      with public health investigations of disasters, which have included the lack of
      accident-related and toxicologic information, expertise, and funds. The
      complexity of the Bhopal crisis was underscored by the severe mortality and
      morbidity it entailed as well as its occurrence in a developing nation that had
      little experience in dealing with chemical disasters. Lessons learned from the
      disaster are discussed, with recommendations for disaster preparedness, long-term
      monitoring, rehabilitation, and treatment of the gas victims.

PMID- 12412858
TI  - Carcinogenicity of saccharin in laboratory animals and humans: letter to Dr.
      Harry Conacher of Health Canada.
AB  - We appreciate this opportunity to provide input to the Health Protection Branch's
      (HPB's) review of the artificial sweetener saccharin. Concerns with regard to the
      safety of saccharin are of great public health significance and of great interest
      to the public because saccharin is consumed by tens of millions of people,
      including children and fetuses. Any evidence of carcinogenesis--and there is
      ample such evidence--of such a widely used chemical should spur health officials
      to minimize human exposure to it. It is worth noting that on October 31, 1997,
      the Board of Scientific Counselors of the National Toxicology Program, a unit of
      the National Institute of Environmental Health Sciences (NIEHS), voted not to
      delist saccharin from its Report on Carcinogens.

PMID- 12412859
TI  - Preventing obesity: the breast milk-leptin connection.

PMID- 12412862
TI  - Leptin levels in breast-fed and formula-fed infants.
AB  - AIM: Leptin, a hormone that regulates food intake and energy metabolism, is
      present in breast milk and thus may be involved in body composition differences
      between breastfed and formula-fed infants. The aim of this study was to evaluate
      whether diet and gender affect plasma leptin concentration in breastfed and
      formula-fed infants during the first months of life. METHODS: Anthropometric and
      bioelectrical impedance measurements [total body water (TBW) calculated with the
      Fjeld equation] were made and venous blood plasma samples were analysed for
      leptin concentration in healthy, exclusively breastfed or formula-fed Italian
      infants in the first year of life. Infants were subdivided in two ways: three
      groups (periods) in relation to age, and five groups in relation to weight.
      RESULTS: The average serum concentration of leptin was 7.35 ng x ml(-1). Serum
      leptin values were higher in breastfed than in formula-fed infants. Breastfed
      infants in group I had a statistically higher serum leptin concentration (2,500
      3,749 g). There were no significant differences in anthropometric measurements,
      body mass index or skinfold thickness between breastfed and formula-fed infants.
      In the periods I and II, breastfed infants had a significantly higher TBW than
      formula-fed infants. Males had a significantly higher TBW than females in periods
      I and II. Breastfed infants in group 2 (3,750-4,999 g) had a significantly higher
      TBW than formula-fed infants. CONCLUSION: The data on TBW, weight and skinfold
      thickness suggest that the higher leptin concentration observed in breastfed
      infants in the first months of life may be due not only to adipose tissue
      production but also to human milk.

PMID- 12412863
TI  - Fasting levels of serum glucose, cholesterol and triglyceride at age eleven to
      twelve years in stunted and non-stunted Jamaican children.
AB  - AIM: To determine whether fasting serum concentrations of glucose, cholesterol
      and triglyceride at age 11-12 y (a) differed between children stunted in early
      childhood and those who were never stunted, (b) were related to birthweight or
      current anthropometry and (c) were related to stunting after controlling for
      current size. METHODS: Anthropometry, serum glucose and lipid concentrations were
      measured in 112 children stunted in early childhood and 181 non-stunted children.
      RESULTS: Children who were stunted in infancy remained shorter, weighed less and
      were significantly less fat than non-stunted children but had a more central
      distribution of fat. They were also less likely to have entered puberty. Non
      stunted children had higher fasting serum triglyceride concentrations than
      stunted children (p < 0.05). There were no significant correlations between
      birthweight and fasting glucose or any measure of serum lipids. The percentage of
      variance in biochemical measures explained by anthropometry was low: between 2.1
      for HDL cholesterol and 14.6 for triglyceride. Nutritional status in early
      childhood (stunted or non-stunted) made no additional contribution to the
      variance. CONCLUSIONS: Linear growth retardation in early childhood was not
      independently related to fasting serum concentrations of glucose, cholesterol and
      triglyceride at age 11-12 y. However, despite being thinner, stunted children had
      a more central distribution of fat.

PMID- 12412864
TI  - Efficacy and safety of a home-made non-valved spacer for bronchodilator therapy
      in acute asthma.
AB  - The aim of this study was to assess the efficacy and safety of an alternative
      spacer to deliver salbutamol in acute asthma. A prospective randomized study was
      performed with 196 patients with acute asthma, aged 4-15 y. The clinical
      features, oxygen saturation (SaO2) and the best of three peak expiratory flow
      rate (PEFR) measurements were recorded in a standardized questionnaire. Each
      patient received up to three conventional doses of salbutamol through an
      alternative home-made non-valved spacer (NVS) (500 ml mineral water plastic
      bottle) or an oxygen-driven nebulizer (ODN). The clinical and functional
      respiratory parameters (PEFR and SaO2) were assessed 15 min after each
      administration of the bronchodilator. In the ODN (n = 99) and NVS (n = 97)
      groups, PEFR (p > 0.05) and SaO2 (p > 0.05) measurements improved in all stages
      of the treatment. During the asthma attacks, the ODN group needed a prolonged
      observation in the emergency room (p = 0.000000). Side effects of salbutamol,
      e.g. increased heart rate, were observed in 17.2% of the patients in the ODN
      group and 4.1% in the NVS group (p = 0.003). CONCLUSION: Both devices showed
      comparable efficacy in mild and moderate acute attacks, but the use of the
      alternative NVS resulted in a shorter observation period in the emergency room.
      The frequency of side effects was significantly higher in the ODN group than in
      the NVS group.

PMID- 12412865
TI  - Association of cytokine responses with disease severity in infants with
      respiratory syncytial virus infection.
AB  - AIM: To explore the relationship between cytokine responses and severity of
      respiratory syncytial virus (RSV) infection in infants. METHODS: Intracellular
      interleukin-4 (IL-4) and interferon-gamma (IFN-gamma) expression in peripheral
      blood CD3+ and CD8+ lymphocytes was measured by four-colour flow cytometry. Serum
      IL-12, IL-4 and IFN-gamma levels were also determined by enzyme-linked
      immunosorbent assay. RESULTS: The frequency of IL-4 and IFN-gamma expression in
      CD3+CD8- cells was the same in RSV-infected, non-RSV-infected and control infants
      and in those with RSV bronchiolitis or RSV pneumonia, indicating that no Th2
      predominance exists in the acute phase of RSV infection and RSV bronchiolitis.
      Furthermore, RSV-infected infants had a more frequent IFN-gamma expression in
      CD3+CD8+ cells than controls, and they also showed a much lower serum IL-4/ IFN
      gamma ratio because of decreased IL-4 and elevated IFN-gamma, the latter being
      most prominent in RSV bronchiolitis. The serum IL-12 level in RSV-infected
      infants was the same as in control infants, while those with non-RSV infections
      had a much higher level. Serum IL-12, IFN-gamma and frequency of IFN-gamma
      expression in CD3+CD8+ cells in mild RSV infection were much higher than in
      controls, while no difference existed between severe cases and controls.
      CONCLUSION: Type 2 cytokine predominance was not found in the acute phase of RSV
      infection and RSV bronchiolitis, but both were accompanied by enhanced production
      of IFN-gamma and a much higher serum IFN-gamma level than in healthy controls,
      especially in those with RSV bronchiolitis, suggesting a role in causing airway
      obstruction. IFN-gamma and IL-12 may also play a protective role in RSV
      infections by diminishing viral replication, and high levels of IL-12 and IFN
      gamma may be associated with lessening of the severity of infection.

PMID- 12412866
TI  - Plasma homocysteine and lipoprotein (a) levels as risk factors for
      atherosclerotic vascular disease in epileptic children taking anticonvulsants.
AB  - AIM: To assess the effect of anticonvulsant treatment on plasma homocysteine
      level and lipoprotein (a) in epileptic children. METHODS: Plasma total
      homocysteine, folate, vitamin B12 and lipoprotein (a) concentrations were
      measured in 111 epilectic children taking anticonvulsant drugs for longer than 12
      mo. Forty-six healthy, sex- and age-matched children served as controls. RESULTS:
      Patients and controls differed significantly in concentrations of homocysteine (p
      < 0.05) and lipoprotein (a) (p < 0.001). The number of patients with homocysteine
      concentrations of >9 microM was significantly higher in the patient group than in
      the control group. A significant inverse relationship was found between vitamin
      B12 folate levels and plasma homocysteine levels in the patient group; 28.8% of
      the patient group had lipoprotein (a) concentrations above the cut-off value (30
      mg/dl) for increased risk of early atherosclerosis, whereas none of the control
      patients had concentrations above this value. CONCLUSION: These data indicate
      that prolonged anticonvulsant treatment could increase plasma homocysteine and
      lipoprotein (a) concentrations and that it may be useful to measure the levels
      routinely in order to prevent atherosclerosis in epileptic children taking
      anticonvulsant drugs.

PMID- 12412867
TI  - Postnatal adaptation after Caesarean section or vaginal delivery, studied with
      the static-charge-sensitive bed.
AB  - AIM: To compare postnatal adaptation between Caesarean and vaginal deliveries, by
      studying sleep states, oxygenation, heart rate and body movements. Another aim
      was to follow the adaptation of healthy, term, vaginally born babies. METHODS:
      Ten vaginally born and 12 neonates born by elective Caesarean section were
      recorded with a movement sensor (SCSB, static-charge-sensitive bed),
      electrocardiogram and oximeter. The recordings started 1.5 h after birth and
      lasted for 12 h. For the vaginal group, another 12 h recording was performed
      during the third night postpartum. RESULTS: Delivery mode did not affect sleep
      state distribution. The vaginal group had more oxyhaemoglobin desaturation
      episodes <95% than the Caesarean section group (mean +/- SD: 59 +/- 10% vs 42 +/-
      22% of epochs, p = 0.03), especially in active sleep, but baseline saturation was
      similar (96 +/- 1% vs 95 +/- 3%, p = 0.93). The vaginal group had fewer movements
      during sleep than the Caesarean section group (movements of 5-10 s: 5 +/- 1 h(-1)
      vs 10 +/- 3 h(-1), p = 0.0001). During the first 3 d, the amount of sleeping and
      active sleep increased, whereas wakefulness and quiet sleep decreased. Baseline
      oxyhaemoglobin saturation and the number of movements of over 5 s increased.
      CONCLUSION: Delivery mode did not affect sleep state distribution but,
      unexpectedly, the vaginal group had more oxyhaemoglobin desaturation events and
      fewer body movements than the Caesarean section group. These differences during
      the first postnatal day remain unexplained, but they may reflect stress and pain
      during labour. After a few days, changes in sleep organization, and increases in
      oxyhaemoglobin saturation and frequency of body movements were noted in the
      vaginal group, which may represent recovery and adaptation to extrauterine life.

PMID- 12412868
TI  - Tracheobronchial aspirate fluid neutrophil lipocalin, elastase- and neutrophil
      protease-4-alpha1-antitrypsin complexes, protease inhibitors and free proteolytic
      activity in respiratory distress syndrome.
AB  - This study aimed to determine whether the protease/protease inhibitor balance and
      neutrophil activity is of pathophysiological importance in the severity and
      resolution of respiratory distress syndrome (RDS) and the eventual development of
      neonatal chronic lung disease (CLD). Ventilated preterm infants with RDS (n = 43)
      were studied during their first week of life. Tracheobronchial aspirate fluid
      (TAF) concentrations of neutrophil lipocalin, the elastase- and neutrophil
      protease-4 (NP4) complex concentrations, and alpha1-antitrypsin (alpha1AT),
      antichymotrypsin (ACT) and secretory leucocyte protease inhibitor (SLPI) levels
      were analysed. Free proteolytic and elastolytic activities were also determined.
      CLD correlated with low alpha1AT (p = 0.02) and ACT (p = 0.02) levels at 3-4 d of
      age and low SLPI (p = 0.03) at 7-8 d of age. No correlations were found between
      CLD or severity of RDS (as judged from radiological examination) and neutrophil
      lipocalin, elastase- and NP4-alpha1AT complexes during the first week of life,
      with one exception: RDS X-ray severity and the elastase-alpha1AT complex
      concentration were correlated at 3-4d of age (p = 0.02). Free proteolytic
      activity occurred in the TAF of 7/30 infants tested on day 3-4 and free
      elastolytic activity in 1 patient. During the rest of the first week of life no
      free elastolytic or proteolytic activities were observed. Caesarean section was
      correlated with low levels of SLPI on day 3-4 (p = 0.01), NP4 (p = 0.03) and ACT
      (p = 0.05) on day 5-6. Gestational age was positively correlated with protease
      inhibitors and their complexes at 3-4 d of age. CONCLUSION: Free proteolytic or
      elastolytic activity in the TAF of RDS infants in the first week of life occurred
      by way of exception. Elastase-/NP4-alpha1AT complex or neutrophil lipocalin
      levels were not correlated with the development of CLD. The correlation between
      CLD and low alpha1AT or ACT at 3-4 d and SLPI at 7-8 d of age may be due to
      either immaturity or complex formation. The severity of RDS as judged from
      radiological examination was correlated with elastase-alpha1AT complex on day 3
      4. The main hypothesis, that TAF protease/protease inhibitor levels or imbalance
      and leucocyte activity are important factors indicating a high risk of severe RDS
      and subsequent CLD development, was principally not confirmed.

PMID- 12412869
TI  - Effect of blood transfusions on cerebral haemodynamics in preterm infants.
AB  - AIM: To assess the possible cerebral haemodynamic changes occurring in preterm
      infants after blood transfusions. METHODS: Preterm infants who had undergone
      blood transfusions were prospectively studied using both near infrared
      spectroscopy and cerebral Doppler ultrasonography. RESULTS: Fourteen infants
      (mean gestational age 29.6 wk, SD 2.6; mean birthweight 1,430g, SD 332) were
      studied at the mean age of 29 (SD 14) d. A significant increase in oxygenated
      haemoglobin (O2Hb), deoxygenated haemoglobin (HHb), mixed cerebral oxygen
      saturation (SmO2) and change in cerebral blood volume occurred after transfusion.
      Between ultrasound parameters, we found a decrease in diastolic velocity and an
      increase in resistance index. CONCLUSION: Blood transfusions improve cerebral
      oxygen supply and induce a decrease in cerebral blood volume, probably due to an
      increase in cerebral vessel resistance.

PMID- 12412870
TI  - Dietary supplementation of long-chain polyunsaturated fatty acids in preterm
      infants: effects on cerebral maturation.
AB  - AIM: To study the influence of dietary-supplied long-chain polyunsaturated fatty
      acids on structural brain maturation in preterm infants and to investigate
      parameters of functional brain development, relating them to structural
      maturation. Other studies have suggested that dietary supplementation of long
      chain polyunsaturated fatty acids in preterm infants may enhance their visual
      development. The influence on structural brain development has never been
      evaluated. METHODS: In a prospective, double-blind study, 42 formula-fed
      premature infants were randomized to be fed either a standard preterm formula
      without long-chain polyunsaturated fatty acids or an identical formula
      supplemented with docosahexaenoic acid (0.015 g/100 ml) and arachidonic acid
      (0.031 g/100 ml). Infants with significant cerebral damage, retinopathy, chronic
      disease or feeding problems were excluded. Follow-up was focused on assessment of
      cerebral myelination by MRI. Psychomotor, mental and visual development was
      analysed and flash-visual evoked potentials were recorded. RESULTS: It was found
      that progress of myelination, mental and motor development and latencies of
      visual evoked potentials were not positively influenced by supplementation of
      long-chain polyunsaturated fatty acids. At each test age, visual acuity was
      slightly better in the supplemented infants than in the non-supplemented infants,
      but the difference never reached significance level CONCLUSION: Supplementation
      of long-chain polyunsaturated fatty acids did not have a demonstrable positive
      influence on structural brain maturation. Related to this finding, in this small
      cohort of preterm infants without significant neurological damage, sample size
      being restricted by strict inclusion criteria and MRI procedures, no significant
      positive effects were found on psychomotor, mental and visual development.

PMID- 12412871
TI  - Hyperphagia, weight gain and neonatal drug withdrawal.
AB  - Hyperphagia, a classical feature of neonatal drug withdrawal, has been reported
      not to lead to excessive weight gain, but this is contrary to our clinical
      experience. The aim of this study was to determine whether infants with neonatal
      drug withdrawal suffered excessive weight gain because of hyperphagia and, if so,
      to determine the risk factors. The study population comprised 48 infants
      consecutively admitted to the neonatal intensive care unit, 11 of whom gained
      weight by more than 20 g kg(-1) d(-1) for at least 10 d (excessive weight gain).
      All 11 infants were hyperphagic (>200 ml/kg) for at least part of the excessive
      weight gain period. During the perinatal period, the 11 infants had a greater
      fluid intake (p < 0.01) but similar weight gain to gestational-age-matched,
      neonatal drug-withdrawal infants who did not suffer any excessive weight gain.
      Compared to the rest of the cohort, the infants with excessive weight gain were
      more likely to require treatment with morphine/chlorpromzaine (p < 0.05) and had
      a higher maximum withdrawal score (p < 0.01). CONCLUSION: Hyperphagia can lead to
      excessive weight gain in infants with neonatal drug withdrawal. Our results
      suggest that hyperphagia occurs in those who require treatment for severe
      withdrawal.

PMID- 12412872
TI  - Predictors of coping strategy selection in paediatric patients.
AB  - AIM: To assess the prevalence of specific coping strategies and predictors of
      coping strategy selection in 179 patients (mean age = 10.2 y). The children were
      investigated one month after the occurrence of an accident (n = 105), diagnosis
      of cancer (n = 26) or diagnosis of diabetes mellitus type I (n = 48). RESULTS:
      Patients used a great variety of coping strategies. The most frequent strategies
      were cognitive avoidance, positive cognitive restructuring and avoidant actions.
      The strategies of seeking problem-focused support and emotion-focused support
      were rarely used. Diagnostic category, length of hospital stay, and gender were
      not associated with coping strategy use. Age, socioeconomic status and functional
      status of the patient were found to predict coping strategy selection. Younger
      children made less use of active coping, distraction and seeking support.
      Patients of lower socioeconomic status used religious coping strategies
      significantly more often, whereas patients with lower functional status used
      avoidance and support-seeking strategies more often. CONCLUSION: In this study it
      was found that paediatric patients used a wide variety of coping strategies,
      irrespective of diagnosis and gender. Age of the child and functional status were
      the most important predictors of coping strategy selection.

PMID- 12412873
TI  - Final height in psychosocial short stature: is there complete catch-up?
AB  - AIM: To determine whether children with psychosocial short stature attain their
      genetic height potential. METHODS: We report on 18 children (10 girls, 8 boys)
      diagnosed by a multidisciplinary team as having psychosocial short stature. All
      the children had had some kind of change in their environment (9 were separated
      from their families), and increased their mean height velocity standard deviation
      score (SDS) from -0.7 (1.3) to +3.6 (4.8) (p < 0.005) as well as their height SDS
      from -3.0 (0.3) to -2.6 (0.9) in the first year after the change. All the
      patients were postpubertal and had reached their near final height (mean age,
      20.0 y; range, 16.0-23.3). RESULTS: Only 3 out of 18 had a greater final height
      than the mid-parental target height, 14 out of 18 had a near final height within
      the mid-parental target range (95% tolerance limits of the mid-parental height
      (+/- 2 SD = +/- 10 cm). Nevertheless, mean final height expressed in height SDS
      for the whole group was significantly shorter with -2.4 SDS compared with the
      mean of the mid-parental target height of -1.5 SDS (p < 0.001). Surprisingly,
      initial catch-up growth did not correlate with final height attainment.
      CONCLUSION: The majority of patients will attain a stature within the range of
      mid-parental target height, although towards the lower limit of this range.

PMID- 12412874
TI  - Psychological functioning in boys of short stature: effects of different levels
      of growth hormone secretion.
AB  - AIM: To examine the relationship between growth hormone (GH) and psychological
      functioning, especially self-perception and well-being, in 60 prepubertal boys of
      short stature with a wide range of GH levels. METHODS: A comparison was made of
      the well-being and self-perception of children with GH insufficiency, children
      with idiopathic short stature (ISS), a normative sample and healthy boys with
      normal stature. RESULTS: Children with GH insufficiency had a more negative
      perception of their own physical appearance than the normative sample. They
      perceived themselves as more alert but also more inhibited than both the children
      with ISS and the healthy boys with normal stature. In comparison with the healthy
      boys with normal stature they perceived themselves as having more stability. The
      parents of the boys with GH insufficiency also perceived their children as being
      more stable compared with how the parents of boys with ISS perceived their
      children. To elucidate the effects of GH on psychological functioning a multiple
      regression analysis was performed. CONCLUSION: The lower the levels of GH the
      more inhibited were the boys of short stature, as perceived both by themselves
      and by their parents. The boys with GH insufficiency had a more negative
      perception of their physical appearance than the normative sample.

PMID- 12412875
TI  - Treatment of children with cystic fibrosis: central, local or both?
AB  - Owing to a lack of longitudinal studies, the effect of centralization of care on
      pulmonary function and survival remains unclear. Three different levels of
      involvement of centralized care in the treatment of paediatric cystic fibrosis
      patients were compared with regard to longitudinal pulmonary function and
      nutritional and microbiological status in a 3-y period, and the literature was
      reviewed on the possible advantages and disadvantages of centralized care. The
      study included 105 paediatric patients attending the Cystic Fibrosis Centre
      between January 1997 and January 2001. Twenty-three patients were treated by
      local paediatricians according to the protocol of the Centre and were seen only
      once a year at the Centre, for an annual check-up (local care). Forty-one
      patients were treated at the Centre only (centralized care). The remaining 41
      patients were treated in close cooperation between the Centre and local
      hospitals, with patients visiting the doctors alternately (shared care). The mean
      annual changes in pulmonary function and body mass index from all patients, as
      well as a microbiological survey, were reviewed. No significant differences were
      found between the three groups for annual changes in FEV1, FVC and body mass
      index, nor did the review of microbial colonization show any significant
      differences between the groups. Because the groups in this study were relatively
      small, the results might have been influenced by lack of power. CONCLUSION: In
      this relatively small group, no differences in pulmonary function, nutritional
      status or microbiological colonization between the three levels of involvement of
      centralized care could be found. This could signify that local paediatricians
      have a special role in the care for patients with cystic fibrosis, in close
      cooperation with the specialists at the Centre.

PMID- 12412876
TI  - Urge incontinence and voiding postponement in children: somatic and psychosocial
      factors.
AB  - AIM: To analyse the number of urinary tract infections, uroflowmetry, behavioural
      symptoms and intrafamilial interaction in two groups of daytime wetting children
      in a paediatric and a child psychiatric unit. METHODS: Ninety-four children with
      either voiding postponement (52) or urge incontinence (42) were examined
      prospectively for history of urinary tract infections (UTIs), uroflowmetry, the
      syndrome scales of the Child Behaviour Checklist (CBCL 4/18-Achenbach) and the
      Family Adaptability and Cohesion Evaluation Scales (FACES-III) (Olson)
      questionnaire. RESULTS: Children with urge incontinence had a significantly
      higher rate of previous urinary tract infections (50%) than children with voiding
      postponement (19.2%; p < 0.001), who showed a high rate of plateau (12.2%) and
      staccato (20.4%) curves and were characterized by a wide variety of behavioural
      symptoms, including withdrawn (11.6%), aggressive (11.8%), delinquent (19.6%)
      behaviour and attention problems (13.7%). Clinically relevant behavioural scores
      were 4-10 times higher for the voiding postponers, and 2-3 times higher for
      children with urge incontinence. Furthermore, families of voiding postponers had
      significantly fewer balanced types of intrafamilial function (FACES-III).
      Problematic "rigid/disengaged" and "rigid/separated" types predominated.
      CONCLUSION: Urge incontinence is characterized by a higher rate of UTIs, a lower
      urine volume in uroflowmetry, a lower rate of behavioural scores in the clinical
      range and well-functioning families. Voiding postponement children, on the other
      hand, have a higher, though not significant, rate of abnormal uroflow curves, a
      wide variety of clinically relevant behavioural symptoms, which were
      significantly higher for attention and delinquent problems. Conduct problems
      predominated; only 13.7% of the children had attention problems in the clinical
      range. The findings lend empirical support to the entity of voiding postponement
      as an acquired or behavioural syndrome characterized by wetting in association
      with a delay of micturition and other externalizing conduct problems.

PMID- 12412877
TI  - Sexual behaviour and early coitarche in a national sample of 17-year-old Swedish
      boys.
AB  - AIM: To describe sexual behaviour as reported by 17-year-old boys in Sweden.
      METHODS: The national cross-sectional SAM 73-90 questionnaire survey was
      performed in 1990, and comprised 2% of students and school non-attenders born in
      1973. The respondents included 814 students and 92 non-students, response rates
      90.6% and 40.2%, respectively. Data from the two groups are treated separately.
      RESULTS: In the student group, 54.2% of boys had experienced vaginal intercourse
      and 16.7% were "early starters" with coitarche before 15 y of age. Independent
      predictors for coital experience were the vocational study programme OR (odds
      ratio) 1.91 (95% CI 1.31-2.78), early puberty OR 1.69 (95% CI 1.11-2.57), use of
      tobacco OR 5.32 (95% CI 2.43-11.7) and alcohol OR 4.09 (2.79-5.98). Sexually
      transmitted infections (STIs) were reported by 4.1% of coitally active student
      boys, and impregnating a girlfriend by 4.3%. Of the early starters, 14.6%
      reported having more than 10 sex partners as compared with 2.5% of the later
      starters (p < 0.0001) and this was predictive of STI, OR 5.4 (95% CI 1.5-19.7).
      First-date intercourse more than twice was predictive of pregnancy, OR 14.4 (95%
      CI 3.8-54.5). Among school non-attenders, 74.2% reported coital experience, 33.7%
      were early starters, and 12.5% had impregnated a girl. CONCLUSION: Boys' early
      sexual experience was related to early puberty, and to general adolescent risk
      taking behaviour. Early coitarche per se was not predictive of STI or pregnancy,
      but the associated high number of "lifetime" sexual partners and first-date
      intercourse were predictive factors. School non-attenders constituted a group at
      risk.

PMID- 12412878
TI  - Born small for gestational age: relation to future allergy and asthma.
AB  - AIM: To evaluate whether intrauterine growth retardation (IUGR) protects against
      the development of allergy. METHODS: A case-control study of 1515 subjects (15-25
      y), of whom 430 were cases (birthweight/length below -2 SD for gestational age).
      Birth data were from the national birth register. The frequencies of allergic
      diseases were evaluated by questionnaire. RESULTS: For the 950 who replied, the
      frequencies of allergic diseases were similar in cases and controls. CONCLUSION:
      IUGR does not protect against the development of allergy.

PMID- 12412879
TI  - Hepatitis B immunization in low birthweight infants: do they need an additional
      dose?
AB  - AIM: To determine the influence of gestation and weight on the development of
      protective anti-HB levels and geometric mean titres after three doses of HBV
      vaccine and to ascertain the need for a fourth dose in low birthweight infants.
      METHODS: Hepatitis B vaccine (Enivac HB, Panacea Biotec Ltd., India) was given to
      82 preterm (PT) and 60 term intrauterine growth-retarded (T-IUGR) infants at
      birth and at 6, 10 and 14wk of life. RESULTS: Protective anti-HB levels (>10
      mIU/ml) were reached in 86.6% (71/82) of PT infants and 96.7% (58/60) of T-IUGR
      infants after three doses of HBV vaccine (p = 0.044). The odds of having a
      protective response after the third dose of HBV vaccine was 1.25 (95% CI 1.02
      1.53) with every one-week increase in gestation (p = 0.032). Birthweight was not
      associated with the development of a protective immune response. After the third
      dose, only 66.7% (8/12) of the PT infants whose mothers had anti-HB antibodies,
      developed protective anti-HB levels compared with 90% (63/70) of those with no
      maternal antibodies (p = 0.028). In PT infants after the fourth dose, there was a
      significant increase in the proportion of infants with protective antibody levels
      (8.6%, 95% CI 0.6-16.6%) among those with no maternal antibodies and 12.2%
      overall (95% CI 6.0-21.3) (p = 0.031 to 0.002) over that reached with the third
      dose. Administration of the fourth dose to T-IUGR infants did not confer such a
      benefit. CONCLUSION: In HBV-endemic areas, PT infants, irrespective of their
      birthweights, may benefit from an additional dose of hepatitis B vaccine in a
      schedule starting at birth. This approach will prevent vertical transmission and
      bring their immune response up to par with term infants. Term intrauterine growth
      retarded infants should be vaccinated as per the schedule recommended for normal
      term infants. However, studies in other settings with different vaccine
      formulations and a longer follow-up period will be required before this strategy
      can be practised more widely.

PMID- 12412880
TI  - Early diagnosis of primary ciliary dyskinesia in a newborn without situs
      inversus.
AB  - Primary ciliary dyskinesia has been reported as a rare cause of respiratory
      distress during the neonatal period. This diagnosis is readily suspected in cases
      presenting with accompanying situs inversus. The aim of this study was to report
      on a pair of siblings with primary ciliary dyskinesia. The first case was an
      infant diagnosed with primary ciliary dyskinesia at the age of 14 d despite lack
      of situs inversus. The infant had presented with respiratory distress and
      atelectasis almost immediately after birth. The sibling, born one year later,
      presented with situs inversus, therefore allowing diagnosis of primary ciliary
      dyskinesia to be made immediately after birth. CONCLUSIONS: Diagnosis of primary
      ciliary dyskinesia should be considered in newborns presenting with respiratory
      distress or atelectasis. Early institution of an adequate treatment programme and
      follow-up may reduce or prevent further complications of the disease.

PMID- 12412882
TI  - Cushing's syndrome due to pharmacological interaction in a cystic fibrosis
      patient.
AB  - Treatment of allergic bronchopulmonary aspergillosis with itraconazole is
      becoming more widespread in chronic lung diseases. A considerable number of
      patients is concomitantly treated with topical or systemic glucocorticoids for
      anti-inflammatory effect. As azole compounds inhibit cytochrome P450 enzymes such
      as CYP3A isoforms, they may compromise the metabolic clearance of
      glucocorticoids, thereby causing serious adverse effects. A patient with cystic
      fibrosis is reported who developed iatrogenic Cushing's syndrome after long-term
      treatment with daily doses of 800 mg itraconazole and 1,600 microg budesonide.
      The patient experienced symptoms of striae, moon-face, increased facial hair
      growth, mood swings, headaches, weight gain, irregular menstruation despite oral
      contraceptives and increasing insulin requirement for diabetes mellitus.
      Endocrine investigations revealed total suppression of spontaneous and stimulated
      plasma cortisol and adrenocorticotropin. Discontinuation of both drugs led to an
      improvement in clinical symptoms and recovery of the pituitary-adrenal axis after
      3 mo. CONCLUSION: This observation suggests that the metabolic clearance of
      buDesonide was compromised by itraconazole's inhibition of cytochrome P450
      enzymes, especially the CYP3A isoforms, causing an elevation in systemic
      budesonide concentration. This provoked a complete suppression of the endogenous
      adrenal function, as well as iatrogenic Cushing's syndrome. Patients on
      combination therapy of itraconazole and budesonide inhalation should be monitored
      regularly for adrenal insufficiency. This may be the first indicator of increased
      systemic exogenous steroid concentration, before clinical signs of Cushing's
      syndrome emerge.

PMID- 12412881
TI  - Reversible brain lesions in childhood hypertension.
AB  - Posterior leukoencephalopathy syndrome is characterized by an acute, usually
      reversible, encephalopathy with transient occipital lobe abnormalities detected
      on MRI that occur mostly in association with acute hypertension. The clinical
      presentation includes seizures, headache, altered mental status and blindness.
      Disturbed autoregulation of cerebral blood flow and endothelial injury are
      central to the pathogenesis of this disorder. Prompt control of hypertension
      results in rapid and complete neurological recovery. In this report we discuss
      the cases of two children with acute onset hypertension of different aetiologies
      that presented with the characteristic features of posterior leukoencephalopathy
      syndrome. CONCLUSION: Early recognition of this readily treatable condition may
      obviate the need for extensive and invasive investigations. Despite the alarming
      lesions on the MRI, prompt control of hypertension carries a uniformly favourable
      prognosis.

PMID- 12412883
TI  - Topical herbal medicine causing haemolysis in glucose-6-phosphate dehydrogenase
      deficiency.

PMID- 12412884
TI  - Consolidation theory and retrograde amnesia in humans.
AB  - Recent research on the cognitive dysfunctions experienced by human anmesic
      patients indicates that very long term (multidecade) changes may occur in memory.
      Flat retrograde amnesia (RA), consisting of a uniform memory deficit for
      information from all preamnesia time periods, indicates a simple, monolithic
      retrieval problem, whereas graded RA, with greater memory deficits for
      information from recent as opposed to remote time periods, suggests the presence
      of a gradual long-term encoding, or consolidation, process. An evaluation of 247
      outcomes from 61 articles provides strong evidence of graded RA across different
      cerebral injuries, materials, and test procedures, as well as in measures of both
      absolute and relative (patient vs. control) performance. Future
      conceptualizations of human memory should address the possibility that memories
      increase in resistance to forgetting, or reduction in trace fragility, across
      many decades.

PMID- 12412886
TI  - Estimating parameters of the diffusion model: approaches to dealing with
      contaminant reaction times and parameter variability.
AB  - Three methods for fitting the diffusion model (Ratcliff, 1978) to experimental
      data are examined. Sets of simulated data were generated with known parameter
      values, and from fits of the model, we found that the maximum likelihood method
      was better than the chi-square and weighted least squares methods by criteria of
      bias in the parameters relative to the parameter values used to generate the data
      and standard deviations in the parameter estimates. The standard deviations in
      the parameter values can be used as measures of the variability in parameter
      estimates from fits to experimental data. We introduced contaminant reaction
      times and variability into the other components of processing besides the
      decision process and found that the maximum likelihood and chi-square methods
      failed, sometimes dramatically. But the weighted least squares method was robust
      to these two factors. We then present results from modifications of the maximum
      likelihood and chi-square methods, in which these factors are explicitly modeled,
      and show that the parameter values of the diffusion model are recovered well. We
      argue that explicit modeling is an important method for addressing contaminants
      and variability in nondecision processes and that it can be applied in any
      theoretical approach to modeling reaction time.

PMID- 12412887
TI  - Self-control by pigeons in the prisoner's dilemma.
AB  - Pigeons played a repeated prisoner's dilemma game against a computer that
      reflected theirchoices: If a pigeon cooperated on trial n, the computer
      cooperated on trial n + 1; if the pigeon defected on trial n, the computer
      defected on trial n + 1. Cooperation thus maximized reinforcement in the long
      term, but defection was worth more on the current trial. Under these
      circumstances, pigeons normally defect. However, when a signal correlated with
      the pigeon's previous choice immediately followed each current trial choice, some
      pigeons learned to cooperate. Furthermore, cooperation was higher when trials
      were close together in time than when they were separated by long intertrial
      intervals.

PMID- 12412885
TI  - Memory deficits in Alzheimer's disease: the encoding hypothesis and cholinergic
      function.
AB  - Forgetting functions generated by delayed matching-to-sample procedures allow
      delay-dependent effects to be distinguished from delay-independent effects on
      working memory. Parameters of negative exponential functions estimate initial
      discriminability (intercept) and rate of forgetting (slope). Forgetting functions
      for patients with Alzheimer's disease indicate that they differ from normal
      controls in terms of reduced initial discriminability--that is, in the encoding
      component of memory performance--but not convincingly in rate of forgetting.
      Reanalyses of previous studies with different species suggest that pro- and
      anticholinergic drugs influence initial discriminability in delayed matching-to
      sample performance, but not rate of forgetting. The results of our reanalyses are
      consistent with the conclusion that the cholinergic system plays a role in the
      encoding component of working memory and that this is the main characteristic of
      the memory deficit shown by patients with Alzheimer's disease.

PMID- 12412888
TI  - Visual binding in the standing wave illusion.
AB  - When two video frames are alternated at the appropriate rate, one with a central
      bar and the other with two flanking bars, the central bar becomes invisible.
      Competing explanations for this standing wave illusion are examined, with the
      results showing an influence of higher level shape representations on lower level
      edge processes. In Experiment 1, flanking bar duration was found to be more
      important to masking than central bar duration. Experiment 2 showed strong
      nonlocal effects in that masking of the central bar depended critically on
      whether it appeared in the same video frame as other visible bars. Experiments 3
      and 4 showed that the contour shared by bars in separate frames was a less
      important factor than shape and surface similarity. This illusion is therefore an
      excellent tool for studying recursive interactions between higher level object
      representations and lower level contour processes.

PMID- 12412889
TI  - Cross-modality attentional blinks without preparatory task-set switching.
AB  - When two masked targets (T1 and T2), both requiring attention, are presented
      within half a second of each other, report of the second target is poor,
      demonstrating an attentional blink (AB). Potter, Chun, Banks, and Muckenhoupt
      (1998) argued that all previous demonstrations of an AB occurring when one or
      more targets were presented outside the visual modality did not represent true AB
      but were, instead, artifactual, resulting from switching of task set. In the
      present experiments, T1 and T2 modalities were independent and varied randomly
      from trial to trial, allowing no useful preparatory task-set switching from T1 to
      T2. However, reliable ABs were observed when both targets were visual, when both
      targets were auditory, and cross-modally when T2s were visual. Furthermore, the
      ABs observed for cross-modality visual T2s showed the characteristic U-shaped
      pattern often found in AB experiments in which two visual targets are used--a
      pattern that should not be observed under task-set switching conditions. These
      results provide evidence that cross-modality AB can be found under conditions
      that do not allow useful preparatory task-set switching.

PMID- 12412890
TI  - Are eyes special? It depends on how you look at it.
AB  - Recent behavioral data have shown that central nonpredictive gaze direction
      triggers reflexive shifts of attention toward the gazed-at location (e.g.,
      Friesen & Kingstone, 1998). Friesen and Kingstone suggested that this reflexive
      orienting effect is unique to biologically relevant stimuli. Three experiments
      were conducted to test this proposal by comparing the attentional orienting
      produced by nonpredictive gaze cues (biologically relevant) with the attentional
      orienting produced by nonpredictive arrow cues (biologically irrelevant). Both
      types of cues produced reflexive orienting in adults (Experiment 1) and
      preschoolers (Experiment 2), suggesting that gaze cues are not special. However,
      Experiment 3 showed that nonpredictive arrows produced reflexive orienting in
      both hemispheres of a split-brain patient. This contrasts with Kingstone,
      Friesen, and Gazzaniga's (2000) finding that nonpredictive gaze cues produce
      reflexive orienting only in theface-processing hemisphere of split-brain
      patients. Therefore, although nonpredictive eyes and arrows may produce similar
      behavioral effects, they are not subserved by the same brain systems. Together,
      these data provide important insight into the nature of the representations of
      directional stimuli involved in reflexive attentional orienting.

PMID- 12412891
TI  - Links between conscious awareness and response inhibition: evidence from masked
      priming.
AB  - Recent results from "subliminal priming" experiments have shown that masked prime
      stimuli which can not be consciously perceived can trigger response activation
      processes, but that these response activations can later be subject to
      inhibition. Links between conscious awareness and response inhibition were
      investigated by manipulating the visibility of masked prime stimuli, from clearly
      visible primes to prime stimuli that were inaccessible to conscious perception.
      Response inhibition was observed with unperceived prime stimuli, but not for
      suprathreshold primes. Correlations between individual prime identification
      thresholds and the onset of response inhibition indicate that the absence or
      presence of conscious awareness can predict whether or not response inhibition is
      elicited. These results demonstrate qualitative differences in the effects of
      conscious and unconscious information. It is argued that response facilitation
      produced by consciously available perceptual information can counteract automatic
      effects of self-inhibitory motor control circuits.

PMID- 12412892
TI  - The crucial roles of stimulus matching and stimulus identity in negative priming.
AB  - Negative priming refers to the situation in which an ignored item on an initial
      prime trial suffers slowed responding when it becomes the target item on a
      subsequent probe trial. In this experiment (and a replication), we demonstrate
      two ways in which stimulus consistency (matching) governs negative priming.
      First, negative priming for identical words occurred only when the prime
      distractor changed color when it became the probe target (i.e., constant cue to
      read the red word); negative priming disappeared when the prime distractor
      retained its color as the probe target (i.e., cue switches from read the red
      prime word to read the white probe word). Second, negative priming occurred for
      identical words, but not for semantically related words, whether related
      categorically or associatively. This pattern of results is consistent with a
      memory retrieval account, but not with an inhibition account of negative priming,
      and casts doubt on whether there is semantic negative priming for words.

PMID- 12412893
TI  - Morphological analysis by child readers as revealed by the fragment completion
      task.
AB  - Ten-year-old children performed a fragment completion task. Target fragments
      (e.g., T_ _N) were preceded by four types of study conditions. The identity
      condition consisted of the target (TURN). Themorphological condition included a
      related form (TURNED). The orthographic condition consisted of morphologically
      unrelated words (e.g., TURNIP). Finally, no similar word was presented in the
      study phase of the no-prime condition. Morphological relatives included
      orthographically transparent (TURNED-TURN) and orthographically opaque (RIDDEN
      RIDE) forms. The results indicated that performance of child readers on the
      fragment completion task was sensitive to morphological relationships. Completion
      rates following opaque, as well as transparent, morphological relatives were
      significantly greater than those following orthographically similar forms. In
      sum, the fragment completion task provides a viable new tool for examining
      morphological processing in children and for differentiating morphological
      effects from effects of similar form.

PMID- 12412894
TI  - Stroop interference effects in partially colored Stroop words.
AB  - In the Stroop task word reading is thought to be automatic since it runs without
      intentional monitoring and is difficult to avoid. This view has recently been
      challenged by observations that Stroop interference is reduced when only part of
      the Stroop word is colored. In this study we asked whether the extent of Stroop
      interference varies with the position of the colored letter(s). We observed that
      Stroop interference was smallest when the first letter(s) were colored and
      largest when either the last letter(s) or whole word were colored. On these
      findings we suggest that colored and noncolored parts of partially colored words
      are processed separately and differently, and that selection of the color
      dimension for explicit report entails inhibition of the to-be-ignored colored
      letters.

PMID- 12412895
TI  - The impact of feedback semantics in visual word recognition: number-of-features
      effects in lexical decision and naming tasks.
AB  - The notion of feedback activation from semantics to both orthography and
      phonology has recently been used to explain a number of semantic effects in
      visual word recognition, including polysemy effects (Hino & Lupker, 1996; Pexman
      & Lupker, 1999) and synonym effects (Pecher, 2001). In the present research, we
      tested an account based on feedback activation by investigating a new semantic
      variable: number of features (NOF). Words with high NOF (e.g., LION) should
      activate richer semantic representations than do words with low NOF (e.g., LIME).
      As a result, the feedback activation from semantics to orthographic and
      phonological representations should be greater for high-NOF words, which should
      produce superior lexical decision task (LDT) and naming task performance. The
      predicted facilitory NOF effects were observed in both LDT and naming.

PMID- 12412896
TI  - Addressees' needs influence speakers' early syntactic choices.
AB  - A current debate in psycholinguistics concerns how speakers take addressees'
      knowledge or needs into account during the packaging of utterances. In retelling
      stories, speakers are more likely to mention atypical instruments than easily
      inferrable, typical instruments; in a seminal study, Brown and Dell (1987)
      suggested that this is not an adjustment to addressees but is simply easiest for
      speakers. They concluded that manipulating addressees' knowledge did not affect
      speakers' mention of instruments. However, their addressees were confederates who
      heard the same stories repeatedly. We had speakers retell stories to naive
      addressees who either saw or did not see a picture illustrating the main action
      and instrument. When addressees lacked pictures, speakers were more likely to
      mention atypical instruments, to mention them early (within the same clause as
      the action verb), and to mark atypical instruments as indefinite. This suggests
      that with visual copresence, speakers can take addressees' knowledge into account
      in early syntactic choices.

PMID- 12412897
TI  - Grounding language in action.
AB  - We report a new phenomenon associated with language comprehension: the action
      sentence compatibility effect (ACE). Participants judged whether sentences were
      sensible by making a response that required moving toward or away from their
      bodies. When a sentence implied action in one direction (e.g., "Close the drawer"
      implies action away from the body), the participants had difficulty making a
      sensibility judgment requiring a response in the opposite direction. The ACE was
      demonstrated for three sentences types: imperative sentences, sentences
      describing the transfer of concrete objects, and sentences describing the
      transfer of abstract entities, such as "Liz told you the story." These dataare
      inconsistent with theories of language comprehension in which meaning is
      represented as a set of relations among nodes. Instead, the data support an
      embodied theory of meaning that relates the meaning of sentences to human action.

PMID- 12412898
TI  - Comparing techniques for estimating automatic retrieval: effects of retention
      interval.
AB  - Results from implicit memory (IM) tasks suggest that automatic retrieval remains
      stable or decreases over time. In contrast, results from the process dissociation
      approach (PDA) suggest that automatic retrieval may actually increase over time.
      One explanation for these discrepant results is that performance on IM tasks is
      contaminated by controlled retrieval strategies, thereby overestimating automatic
      retrieval, particularly at short retention intervals, when controlled retrieval
      strategies are high. An alternative explanation is that automatic and controlled
      retrieval are positively correlated, rather than independent as assumed by the
      PDA. If so, the PDA would underestimate automatic retrieval, particularly when
      controlled retrieval strategies are high. Results from a speeded IM task suggest
      that a standard IM task provided an accurate estimate of automatic retrieval,
      whereas the PDA underestimated automatic retrieval at a short retention interval.
      This pattern of underestimation by the PDA supports the conclusion that automatic
      and controlled retrieval were positively correlated rather than independent.

PMID- 12412899
TI  - Dissociating familiarity from recollection in human recognition memory: different
      rates of forgetting over short retention intervals.
AB  - Two functionally distinct forms of recognition memory have been identified in
      human and nonhuman species-the ability to recollect qualitative information about
      previous events, and the ability to differentiate between familiar and novel
      stimuli. Separate dual-process theories have been developed in the animal and
      human literatures to account for these findings. However, it is not clear whether
      these theories describe the same two underlying memory processes. On the basis of
      animal studies of medial temporal lobe function, familiarity is expected to
      exhibit disproportionately fast forgetting compared with recollection over short
      retention intervals. We tested this prediction in healthy human subjects by
      examining recognition forgetting rates across a range of 8-32 intervening items
      and found significant forgetting in the accuracy of familiarity-based
      discriminations and no evidence of forgetting in the accuracy of recollection
      based discriminations. In agreement with the results from nonhuman species, the
      present results indicate that item familiarity decreases more rapidly than
      recollection over short retention intervals.

PMID- 12412900
TI  - Electrophysiological dissociation of retrieval orientation and retrieval effort.
AB  - The neural correlates of retrieval orientation-the differential processing of
      retrieval cues according to the form of the sought-for information-and retrieval
      effort were investigated in a factorial design. ERPs elicited by test words were
      recorded during four recognition memory tests. Orientation was manipulated by
      varying study material: The study phases preceding two of the tests employed
      pictures, whereas the study phases preceding the other two tests employed words.
      Effort was manipulated by varying difficulty, using a combination of the
      variables of length of study list and study-test interval. ERPs elicited by
      correctly classified new test words were sensitive to both the study material
      and, to a much lesser extent, the difficulty of manipulations. Whereas difficulty
      effects onset early and were short-lived, the effects of study material onset
      later, extended for several hundred milliseconds, and did not vary according to
      difficulty. It was concluded that retrieval orientation exerts a major influence
      on the processing of recognition memory test items.

PMID- 12412901
TI  - The reliability of the DRM paradigm as a measure of individual differences in
      false memories.
AB  - Despite considerable research on the Deese-Roediger-McDermott (DRM) false memory
      paradigm, little attention has been paid to the reliability of the paradigm as a
      measure of individual differences. In the present research, we examined the
      reliability of the DRM paradigm in a 2-week test-retest design. This analysis
      showed that the false memories produced in the paradigm were quite stable across
      the 2-week period and that this stability had both global (cross-list) and list
      specific components. In contrast, correct memories showed only global stability
      across the testing period.

PMID- 12412902
TI  - A picture is worth a thousand lies: using false photographs to create false
      childhood memories.
AB  - Because image-enhancing technology is readily available, people are frequently
      exposed to doctored images. However, in prior research on how adults can be led
      to report false childhood memories, subjects have typically been exposed to
      personalized and detailed narratives describing false events. Instead, we exposed
      20 subjects to a false childhood event via a fake photograph and imagery
      instructions. Over three interviews, subjects thought about a photograph showing
      them on a hot air balloon ride and tried to recall the event byusing guided
      imagery exercises. Fifty percent of the subjects created complete or partial
      false memories. The results bear on ways in which false memories can be created
      and also have practical implications for those involved in clinical and legal
      settings.

PMID- 12412903
TI  - The demands of an ongoing activity influence the success of event-based
      prospective memory.
AB  - Four experiments were conducted to evaluate whether event-based prospective
      memory would be sensitive to the concurrent demands of the ongoing activity in
      which intention-related cues were embedded. In Experiments 1 and 2, random
      alternation between two judgments in the ongoing task reduced prospective memory
      as compared with having a single task throughout. In Experiment 3, participants'
      making two binary judgments on every trial resulted in worse prospective memory
      than did their making single four-alternative judgments. In Experiment 4,
      participants' making two related judgments resulted in better prospective memory
      than did their making two unrelated judgments. The results are consistent in
      spirit with a production rule account of the processing resources that are
      available when intention-related cues are encountered. Therefore, event-based
      prospective memory can inversely covary with the cognitive demands of the ongoing
      activity.

PMID- 12412904
TI  - I was always on my mind: the self and temporary forgetting.
AB  - Previous research has demonstrated that the act of remembering can prompt the
      temporary suppression of related items in memory-that is, retrieval-induced
      forgetting (Anderson, Bjork, & Bjork, 1994). In extending work of this kind, the
      present research sought to identify some important boundary conditions of this
      effect. As expected, temporary forgetting was eliminated under task conditions
      that elicited distinctive encoding operations-specifically, when material was
      relevant to the self. This result is noteworthy since it identifies spontaneous
      processing operations that protect information from temporary forgetting, a
      finding that has important implications both for the emergence of this inhibitory
      effect in everyday life and for theoretical treatments of memory function.

PMID- 12412905
TI  - Spatial location judgments: a cross-national comparison of estimation bias in
      subjective North American geography.
AB  - We examined alternate explanations for distortions in the subjective
      representation of North American geography. One explanation, based on physical
      proximity, predicts that bias in location estimates should increase with the
      distance from a participant's home city or region. An alternative is that biases
      arise from combining accurate and inaccurate beliefs about the cities and the
      superordinate regions to which they belong, including beliefs that may have
      social or cultural origins. To distinguish these, Canadians from Alberta and
      Americans from Texas judged the latitudes of cities in Canada, the U.S., and
      Mexico. The Texans' estimates of Mexican locations were 16" (approximately 1,120
      miles) more biased than their estimates of Canadian locations that were actually
      about 840 miles farther away. This finding eliminates proximity as a primary
      source of geographic biases and underscores the role of categorical beliefs as an
      important source of biased judgments.

PMID- 12412906
TI  - Identification and evaluation of major histocompatibility complex antigens in
      chicken chimeras and their relationship to germline transmission.
AB  - Chimeric chickens were evaluated as an intermediate for development of transgenic
      chickens. The transfer of Barred Plymouth Rock (BR) blastodermal cells into White
      Leghorn (WL) embryos results in BR-->WL chimeras, and some breeder males generate
      over 30% germline transmission of the BR genotype to offspring based on a feather
      color trait. The objectives of the current study were to 1) identify the MHC (B
      haplotypes) in resident BR and WL lines, 2) establish that B antigens could be
      detected and quantified in red blood cells (RBC) of chimeras, 3) establish if
      there is a correlation in chimeras between percentage of RBC with donor B
      antigens and percentage germline transmission, and 4) evaluate if the MHC
      genotype influences chimera development. The RBC agglutination data indicated
      three B haplotypes were present in each line. The B*2-like, and B*19-like genes
      were unique to the WL line, and B*13-like and B-15-like genes were unique to the
      BR line, whereas a B*21-like gene was present in both lines. In adult BR-->WL
      chimeras, as well as 10- to 14 d-old WL-->WL chimeras, donor-type B antigens were
      detectable and quantifiable on RBC using flow cytometry. In BR-->WL chimeras, the
      percentage germline transmission was significantly correlated with the percentage
      of RBC with donor B antigen, as well as percentage of black feathers in the
      plumage. In a retrospective study using previously developed BR-->WL chimeras,
      the level of chimerism and germline transmission was higher in B*21/*21 type
      recipients, but this was not statistically significant in two prospective
      studies. It was concluded that MHC antigens on RBC can be used for identifying,
      quantifying, and selecting chicken chimeras developed by the transfer of
      blastodermal cells.

PMID- 12412907
TI  - Genetic effects of aging on egg quality traits in the first laying cycle of White
      Leghorn strains and strain crosses.
AB  - Three White Leghorn strains, their two-way crosses, and two commercial lines were
      used to evaluate the effects of aging on heterosis (H), reciprocal effects, and
      additive (A), Z-chromosome (Z), and heterotic effects and their variances on egg
      quality traits during the first laying cycle. Egg weight (EW), specific gravity
      (SG), Haugh unit (HU), and albumen height (AH) were measured at 240, 350, and 450
      d of age from hens housed one per cage in a randomized block design. The mean
      heterosis was significant over time only for EW. For EW, heterosis increased in
      magnitude with age. The mean heterosis for both HU and AH was also influenced by
      age. Reciprocal effects were significant, on average, across periods for all
      traits and were influenced by age. The age-related changes in additive, Z
      chromosome, and heterotic effects varied significantly among strains, indicating
      differences by genetic group in response to aging for egg quality traits. The
      heterotic, environmental, and phenotypic variances increased with age for all
      traits, except for AH. The additive and Z-chromosome variances did not always
      increase with age. Their age trend varied, depending on the trait. Heritabilities
      decreased with advancing age, suggesting that selection to improve lifetime
      performance of egg quality traits can be done early in the cycle.

PMID- 12412908
TI  - Estimation of heritability for heterophil:lymphocyte ratio in chickens by
      restricted maximum likelihood. Effects of age, sex, and crossing.
AB  - The objectives of the current study were to estimate the heritability of the
      heterophil to lymphocyte ratio and to evaluate the effects of age, sex, and
      crossing on that ratio. There were three different experiments. In Experiment 1,
      we used a total of 711 birds from two generations with complete pedigree of a
      Spanish breed of chickens (Quail Castellana) to estimate the heritability for the
      leukocyte ratio at 36 wk of age by restricted maximum likelihood. The estimated
      heritability (0.59 +/- 0.09) indicated that leukocyte ratio should easily respond
      to selection. Heritabilities for heterophil and lymphocyte numbers were also high
      (0.56 +/- 0.07 and 0.65 +/- 0.07). In Experiment 2, leukocyte ratio differences
      among ages and sexes were investigated at 8, 12, 16, 20, 24, 28, 32, and 36 wk,
      in 576 birds from the same breed. Males showed significantly greater heterophil
      to lymphocyte ratios than females at the onset of sexual maturity and as adults.
      Significant variations with age for leukocyte ratio were observed in both sexes,
      which were mainly related to onset of sexual maturity, from which the leukocyte
      ratio increased more or less continuously. In females, the effect of age was also
      significant on heterophil and lymphocyte numbers. Finally, in Experiment 3,
      crossing effects were evaluated in 96 birds from a cross between the Quail
      Castellana and a White Leghorn population at 8 wk of age. The negative heterosis
      percentages found in the F1 and F2 generations were significant (-26% and -36%,
      respectively).

PMID- 12412909
TI  - Genotype-by-environment interaction with broiler genotypes differing in growth
      rate. 4. Association between responses to heat stress and to cold-induced
      ascites.
AB  - Males and females, selected from a commercial line to represent its phenotypic
      variation for BW, were mated with similarly ranked mates to produce sire families
      representing a wide genetic variation in potential growth rate (GR). Following 5
      wk of rearing at normal ambient temperatures, birds representing all sire
      families were exposed to cold (Days 37 to 47, Trial 1) or hot (Days 43 to 48,
      Trial 2) environments. Birds exhibiting ascites syndrome (AS) in the cold
      environment (Trial 1) were counted, and the incidence of AS (%AS) per family was
      calculated. Sire families' least-square means of BW at 37 d of age in Trial 1 and
      BW at 43 d of age in Trial 2 represented the families' potential GR (i.e., GR
      under normal conditions). A significant positive correlation was found between
      potential GR and %AS (r = 0.479, Trial 1), indicating that families with higher
      potential GR under normal conditions are more likely to suffer from AS under cold
      stress, compared to families with lower GR. Heat stress markedly reduced weight
      gain in all families (Trial 2); however, the genetic potential GR was negatively
      correlated with actual GR under heat stress (r = -0.411, Trial 2). Since
      offspring of the same sire families were exposed to the two stressful
      environmental conditions, correlations between sire families' means under the two
      environments could be calculated. A negative correlation was found between growth
      under heat stress (Trial 2) and %AS (Trial 1) (r = -0.439), indicating that
      families whose GR is more depressed under heat stress are more likely to suffer
      from AS under cold stress. These results suggest that the two stress responses
      may share similar control of the genetic variation in each trait and their
      negative genetic correlation with potential GR.

PMID- 12412910
TI  - Genetic diversity of Chinese native chicken breeds based on protein polymorphism,
      randomly amplified polymorphic DNA, and microsatellite polymorphism.
AB  - Genetic diversity of Chinese native chicken breeds was investigated using protein
      polymorphism, randomly amplified polymorphic DNA (RAPD), and microsatellite
      polymorphism. Imported broiler and layer breeds were also included in the
      analysis. The results from protein polymorphism did not show distinct differences
      between Chinese native chicken and imported broilers; however, there were small
      significant differences between these two types of chickens. The results from
      RAPD indicated that gene diversity within a population was large in Chinese
      native chickens, intermediate in broilers, and low in layers and that there were
      small differences between Chinese native chickens and both broilers and layers. A
      great difference between broilers and layers was observed. Microsatellite
      polymorphism data showed that genetic diversity was high in the Chinese native
      chickens and low in layers and that there was a close relationship between
      Chinese native chickens and broiler but a remote relationship between Chinese
      native chickens and layers. The wide genetic diversity of Chinese native breeds
      can meet different requirements of breeding for chicken quality in China.

PMID- 12412911
TI  - Campylobacter and Salmonella populations associated with chickens raised on
      acidified litter.
AB  - Two commercially available acidifying litter treatments, aluminum sulfate (alum)
      and sodium bisulfate, were tested to determine their effects on Campylobacter and
      Salmonella colonization frequencies and populations associated with broilers
      raised on treated pine litter. To produce contaminated litter, broiler chicks
      were inoculated with two bacterial cocktails (multistrain mixtures of
      campylobacters and salmonellae) and were allowed to shed on the litter for about
      6 wk. Upon bird removal, litter in duplicate pens was immediately treated with
      two levels of aluminum sulfate [3.63 or 7.26 kg/4.6 m2 (8 or 16 lb/50 ft2)] or
      sodium bisulfate 1.13 or 1.81 kg/4.6 m2 (2.5 or 4 lb/50 ft2)]; untreated pens
      served as controls. Immediately after treatment, day-of-hatch chicks were
      released in the pens. Frequency and populations of Campylobacter and Salmonella
      associated with ceca and whole carcass rinse (WCR) samples were determined for
      each duplicate pen at Weeks 1, 4, and 6. Both levels of the aluminum sulfate and
      sodium bisulfate litter treatments tested significantly (P < 0.05) reduced
      Campylobacter colonization frequency and populations in the ceca. Significantly,
      no Campylobacter was recovered from WCR samples associated with high level
      aluminum sulfate-treated pens at any time; although control pens were 95, 78, and
      38% positive at Weeks 1, 4, and 6, respectively. Salmonella colonization
      frequency and populations in the ceca were not significantly decreased by any of
      the treatments investigated. Although effective pathogen control will most likely
      require a combination of interventions, acidifying treatment of litter in poultry
      production may serve as a means to help control Campylobacter and to reduce
      horizontal transmission of pathogens in broiler flocks.

PMID- 12412912
TI  - Effects of F-strain Mycoplasma gallisepticum inoculation at twelve weeks of age
      on performance and egg characteristics of commercial egg-laying hens.
AB  - The effects of F-strain Mycoplasma gallisepticum (FMG) inoculation during the
      pullet period on the subsequent performance and egg characteristics of commercial
      Single Combed White Leghorn hens were evaluated. In two trials, BW, feed
      consumption, egg production (EP), egg weight, egg size class, relative eggshell
      water vapor conductance, and relative percentages of eggshell, yolk and albumen
      weights were determined through approximately 60 wk of age. In each trial,
      pullets at 12 wk of age were randomly assigned to negative pressure biological
      isolation units. Birds in one-half of the total units were inoculated with FMG,
      and the other half were sham-inoculated with sterile media. In both trials, onset
      of lay was delayed approximately 1 wk in layers inoculated with FMG. Control
      birds that had not been previously inoculated with FMG laid their first egg at 18
      wk of age, while birds that had been previously inoculated with FMG laid their
      first egg at 19 wk of age. In Trial 1, FMG-inoculated hens laid significantly
      fewer total eggs, which became apparent at each week after Week 42. In Trial 2, a
      numerical decrease in total EP occurred, and the percentage of undersized eggs
      laid by FMG-inoculated birds was significantly lower at 19 wk of age but was
      higher at 20 and 21 wk when compared to controls. Mortality was not significantly
      different between the treatments in either trial. These data demonstrate that
      when birds are housed in isolation facilities and inoculated with FMG at 12 wk of
      age, onset of lay is delayed. These data also suggest that FMG may lead to delays
      in undersize EP and decreases in total EP. However, because significant FMG
      effects on these parameters were observed in only one trial, additional studies
      may be necessary to verify these effects.

PMID- 12412913
TI  - Prevention of Escherichia coli infection in broiler chickens with a bacteriophage
      aerosol spray.
AB  - Bacteriophage to an Escherichia coli isolate that is pathogenic in poultry were
      isolated from municipal sewer treatment facilities or poultry processing plants.
      Three studies were conducted to determine the efficacy of aerosol administration
      of bacteriophage to prevent an E. coli respiratory infection in broiler chickens.
      In all three studies the experimental design consisted of nine treatments with
      three replicate pens of 10 birds. Three treatments were not challenged with E.
      coli and consisted of unsprayed birds, birds sprayed with a diluent control, and
      birds sprayed with a combination of two bacteriophages. Six treatments were
      challenged with E. coli by injecting 10(4) cfu into the thoracic air sac when
      birds were 7, 8, or 10 d of age after being sprayed at 7 d of age with either a
      diluent control or a combination of two bacteriophages. In Studies 1 and 2, BW at
      2 wk of age of all the birds challenged with E. coli, regardless of spray
      treatment, were decreased significantly from the unchallenged controls, except in
      Study 2 for the birds sprayed with bacteriophage and challenged at 10 d of age.
      There was a significant decrease in mortality in Studies 1 and 2 when the birds
      were challenged with E. coli immediately after bacteriophage administration and
      in Study 2 in birds challenged at 10 d of age. In Study 3 a suspected pre
      existing E. coli infection resulted in mortality in the unchallenged, unsprayed
      controls, and in the diluent sprayed controls of 20 and 27%, respectively. The
      mortality in the unchallenged bacteriophage sprayed birds was 3%, representing a
      significant decrease. Mortality in Study 3 was significantly decreased in the
      bacteriophage-sprayed birds challenged with E. coli immediately or 1 d later but
      not 3 d after bacteriophage administration. The decrease in BW at 2 wk of age in
      challenged birds indicates that bacteriophage treatment did not provide complete
      protection; however, in all three studies mortality was significantly decreased,
      indicating that aerosol spray of bacteriophage may be practical for
      administration of bacteriophage and may provide an alternative to the use of
      antibiotics in poultry production.

PMID- 12412914
TI  - Evaluation of the efficacy of a feed additive to ameliorate the toxic effects of
      4,15-diacetoxiscirpenol in growing chicks.
AB  - The possible protective effect of a feed additive (Mycofix) against the toxic
      effects of 4,15-diacetoxiscirpenol (DAS) in growing broiler chickens was
      investigated in a 21-d fully randomized trial consisting of seven dietary
      treatments (control with no DAS or Mycofix added, 1 ppm DAS alone, 1 ppm DAS
      supplemented with 0.75 g/kg Mycofix, 1 ppm DAS supplemented with 1.5 g/kg
      Mycofix, 2 ppm DAS alone, 2 ppm DAS supplemented with 0.75 g/kg Mycofix, and 2
      ppm DAS supplemented with 1.5 g/kg Mycofix). When no feed additive was included,
      both levels of dietary DAS significantly decreased BW and feed intake and caused
      oral lesions, with the effect of 2 ppm DAS being more severe. When 1 ppm DAS was
      added to the diet, supplementation of Mycofix protected against the adverse
      effects of DAS on feed intake and BW at both levels of inclusion (0.75 and 1.5
      g/kg); however, no protection against oral lesions was obtained by Mycofix
      supplementation. This finding suggests that the adverse effect of DAS on
      performance is not due to the oral lesions per se but it is likely the result of
      the systemic absorption of the mycotoxin. When 2 ppm dietary DAS was present in
      the diet, only partial protection on BW and feed intake was obtained by Mycofix
      supplementation. More studies are required to determine if a higher dose of
      Mycofix could be capable of counteracting the adverse effects of 2 ppm dietary
      DAS on chicken performance.

PMID- 12412915
TI  - Screening of Salmonella isolates from a turkey production facility for antibiotic
      resistance.
AB  - An ecological survey was conducted from April 1997 to June 1999 on four turkey
      flocks (F1 to F4). Turkey cecal contents, litter, waterers, feed, feeders, and
      environmental swabs were analyzed. Presence of Salmonella was determined using
      conventional microbiological screening techniques and confirmed by serology.
      Positive isolates were serotyped and screened for antibiotic resistance. From a
      total of 69 Salmonella isolates 25% were resistant to one or more antibiotics
      including gentamicin (G), spectinomycin (SP), streptomycin (S), tetracycline (T),
      tobramycin (TO), and trimethoprim/sulfamethoxazole. Isolates included 45 S.
      heidelberg, 13 S. senftenberg, 7 S. muenster, 2 S. anatum, and 2 S. worthington.
      Resistance to antibiotic(s) was highest among waterer isolates (55%) followed by
      environmental swabs (43%), feeder content samples (33%), turkey cecal contents
      (26%), and litter samples (5%). Frequencies of antibiotic-resistant Salmonella in
      F1, F2, and F4 were 27, 13, and 40%, respectively. Salmonella was undetected in
      F3. In F1, S. heidelberg from cecal content and waterer samples was resistant to
      G, SP, S, and T, whereas S. anatum from waterer samples was resistant to T and S.
      In F2, S. worthington from litter and feeder content samples was resistant to T,
      and in F4, S. muenster from environmental swabs was resistant to TO, S, SP, and
      G. Identifying preharvest sources and characterizing serotype and antibiotic
      resistance profile can assist poultry producers and integrators in tracking
      movement of Salmonella on turkey farms.

PMID- 12412916
TI  - Efficient selection of genomic clones from a female chicken bacterial artificial
      chromosome library by four-dimensional polymerase chain reactions.
AB  - A bacterial artificial chromosome (BAC) library consisting of 49,152 genomic
      clones was constructed from partially HindIII-digested female chicken embryo
      genomic DNA using the pBAC-Lac vector and maintained in 512 96-well plates. The
      mean insert size was approximately 150 kb, and the total library was estimated to
      contain about 3.2 times coverage of the diploid genome. In order to screen this
      library by the PCR, 296 BAC clone DNA samples were prepared: one sample each from
      8 superpools (64 plates per superpool) and 36 samples of four-dimensionally (4-D)
      mixed clones from each superpool. A BAC clone of interest was selected by two
      step PCR. First, 8 DNA samples representing superpools were subjected to PCR with
      a set of primers to amplify a part of the genomic sequence of interest. Second,
      36 4-D DNA samples from the superpool that contained BAC clone(s) of interest
      were subjected to PCR with the same set of primers. The second step identified a
      plate and a well containing the BAC clone of interest. Selection of target BAC
      clone(s) from the whole library with the above procedure can be achieved within 1
      to 4 d without using a radioactive probe. This procedure was applied successfully
      in the selection of BAC clones for Wpkci, chPKCI/HINT, ZOV3, and 17beta-HSD
      genes.

PMID- 12412917
TI  - Effect of vitamin A deficiency on host intestinal immune response to Eimeria
      acervulina in broiler chickens.
AB  - The effects of vitamin A (VitA) deficiency on the host intestinal immune response
      and disease susceptibility to coccidiosis were investigated in broiler chickens
      following oral infection with Eimeria acervulina (EA). Day-old male broilers were
      fed milo-soybean meal diets either with 8,000 IU VitA/kg feed (CONT) or without
      added VitA (A-DEF). At 25 d, a group of randomly selected birds from each
      treatment was inoculated orally with EA-sporulated oocysts. Intestinal immune
      response was assessed by the changes in the duodenum intraepithelial lymphocyte
      (IEL) subpopulations using flow cytometry at 35 d in in fected and noninfected
      birds. Concanavalin A (ConA)-induced spleen lymphocyte proliferation was tested
      using dimethylthiazol diphenyltetrazolium bromide colorimetric assay. Whether
      challenged or not with EA, A-DEF birds had fewer IEL expressing the surface
      markers CD3, CD4, CD8, alphabetaTCR, and gammabetaTCR. Without EA challenge, A
      DEF birds had more surface IgA-expressing cells than CONT birds. Upon challenge,
      A-DEF chickens showed lower CD4+ IEL than CONT chickens. Following EA infection,
      CD8+ IEL increased in the CONT group, whereas no change was found in CD8+ IEL of
      A-DEF birds. A higher number of EA oocysts was recovered from A-DEF birds than
      from CONT birds (9.2 x 10(8) vs 5.4 x 10(8), respectively; P < or = 0.05). Serum
      samples taken 10 d post challenge showed higher antibody level against a
      recombinant coccidial antigen in A-DEF birds than in CONT birds. The A-DEF birds
      showed depressed ConA-induced lymphoproliferation response and produced lower
      serum interferon-gamma than CONT birds. These data show that VitA deficiency
      compromised local immune defenses of challenged birds, as reflected in lymphocyte
      profiles, oocyst shedding, and interferon-gamma levels in A-DEF birds.

PMID- 12412918
TI  - Development of the indicator amino acid oxidation technique in chickens: L-[1
      (14)C]phenylalanine infusion dose and phenylalanine oxidation.
AB  - Amino acid requirements of broiler breeder chickens are not well known. The
      indicator amino acid oxidation (IAAO) technique was adapted for use in broiler
      breeders as a rapid and sensitive method to determine amino acid requirements.
      During IAAO, phenylalanine oxidation decreases, inversely to the changes in
      protein synthesis, as the intake of the limiting test amino acid increases from
      deficient to adequate. Above the adequate level, phenylalanine oxidation remains
      constant. Before IAAO can be employed, the optimum priming and constant infusion
      doses of phenylalanine must be determined. Prelaying catheterized birds aged 20
      to 24 wk were placed in closed oxidation chambers attached to a breath collection
      apparatus. A constant L-[1-(14)C]phenylalanine dose of 3.5 microCi/kg BW/h and
      priming doses of 4.5, 5.5, and 7.0 microCi/kg BW were used to determine optimal
      prime:constant dose ratios, minimum time taken for breath 14CO2 excretion to
      become constant (plateau), and adequate percentage of phenylalanine oxidized. At
      this constant infusion rate, the optimal priming dose of L-[1-(14)C]phenylalanine
      was 5.5 microCi/kg BW, resulting in a prime:constant dose ratio of 1.6:1. By
      using this ratio, the average time taken for breath 14CO2 to reach plateau was 60
      min. Average phenylalanine oxidation at plateau, corrected for bicarbonate
      retention, was 5.5 +/- 1.4% (mean +/- SD), which is adequate for IAAO studies
      using deficient-to-excess levels of test amino acids. To the authors' knowledge,
      this study is the first in chickens to establish a primed, constant infusion
      technique using L-[1-(14)C]phenylalanine. The IAAO technique will be used in
      future studies to determine amino acid requirements in chickens.

PMID- 12412919
TI  - Efficacy of supplementation of a phytase-producing bacterial culture on the
      performance and nutrient use of broiler chickens fed corn-soybean meal diets.
AB  - We evaluated the efficacy of supplementation of active Mitsuokella jalaludinii
      culture (AMJC) on the growth performance, nutrient use, and mineral
      concentrations in tibia bone and plasma of broiler chickens fed corn-soybean meal
      diets. Dietary treatments included low-nonphytate P (NPP) feed (containing 0.24%
      and 0.232% NPP for chicks from 1 to 21 and 22 to 42 d of age, respectively), low
      NPP feed added with different levels of AMJC (equivalent to 250, 500, 750, and
      1,000 U phytase/kg of feed), and normal-NPP feed (containing 0.46 and 0.354% NPP
      for chicks from 1 to 21 and 22 to 42 d of age, respectively). Supplementation of
      AMJC to low-NPP feed increased (P < 0.05) weight gain and feed intake and
      decreased (P < 0.05) feed:gain ratio of chickens during the whole experiment
      (Days 1 to 42). Supplementation of AMJC increased (P < 0.05) the AME value,
      digestibility of DM and CP, and retention of P, Ca, and Cu. Mn retention in
      broilers was only increased (P < 0.05) by AMJC supplementation from 18 to 20 d of
      age, and Zn retention was improved (P < 0.05) only at a high level of AMJC
      (equivalent to 1,000 U phytase/kg of feed) supplementation. Chicks fed low-NPP
      feed added with AMJC had similar tibia ash percentages as those fed the normal
      NPP diet. Generally, supplementing AMJC to low-NPP feed increased (P < 0.05) Ca,
      decreased significantly (P < 0.05) Mn and Cu, but did not affect Zn and P
      concentrations in tibia ash. Supplementing AMJC also increased (P < 0.05) plasma
      P but had no effect on plasma Ca or Mn. Plasma Zn concentration was increased
      only when a high level of AMJC (equivalent to 1,000 U phytase/kg of feed) was
      used. In conclusion, AMJC supplementation to low-NPP feed improved growth
      performance; AME value; digestibility of CP and DM; use of Ca, P, and Cu; and
      bone mineralization.

PMID- 12412920
TI  - Nutrient and fatty acid deposition in broilers fed different dietary fatty acid
      profiles.
AB  - The aim of this study was to determine the effect of different dietary fatty acid
      profiles on efficiency of energy, fat, nitrogen, and fatty acid deposition in
      broiler chickens. Sixty female broiler chickens were fed a basal diet without
      additional fat or with 4 other diets with different fats (tallow, olive,
      sunflower, and linseed oils) at 10% from 28 to 48 d of age. Among broilers fed
      diets with added fat, those fed linseed oil had less abdominal fat (in grams and
      percentage) than those fed tallow (P < 0.05). Absorbed fat losses were slightly
      higher for birds fed linseed oil, and nitrogen efficiency was lower in those fed
      tallow (P < 0.05). However, there were not significant differences in energy
      deposition among broilers fed diets with added fat. Fatty acid balance showed the
      highest values of fatty acid oxidation during the experimental period in broilers
      fed linseed oil (48.2 g), followed by those fed sunflower oil (23.2 g).
      Contribution of endogenous fat synthesis to total body fat deposition was minimal
      in birds fed diets with added fat accounting for 3, 1.2, 8.5, and 7.5 g for
      broilers fed tallow, olive, sunflower, and linseed oils, respectively. This
      reflects lipogenesis inhibition by dietary fat addition. Interestingly, between
      broilers fed diets with added fat, higher values of fatty acids from endogenous
      synthesis were found in broilers fed diets rich in polyunsaturated fatty acids
      (PUFA). Results suggest that reduction of abdominal fat in broilers fed linseed
      oil seems to be a consequence of higher lipid oxidation despite the higher
      synthesis of endogenous fatty acids.

PMID- 12412921
TI  - Muscle protein synthesis rate is altered in response to a single injection of
      insulin-like growth factor-I in seven-day-old Leghorn chicks.
AB  - To determine if a single injection of insulin-like growth factor-I (IGF-I) can
      affect muscle protein synthesis in chickens, 7-d-old male Single Comb White
      Leghorn chicks were injected s.c. with physiological saline (control) or 35
      microg of recombinant human IGF-I. After 2 h 30 min, or 6, 12, or 24 h the chicks
      were injected with 3H-phenylalanine and killed, and the fractional synthesis rate
      (Ks) of breast muscle protein was measured. The Ks of IGF-I-treated birds were
      lower (P = 0.03) than controls at 2 h 30 min post-injection, higher (P = 0.07)
      than controls at 6 h post-injection, but not different from controls at later
      times. A second experiment examined serum changes during the 6 h after chicks
      were injected with IGF-I or saline as in the first experiment. Serum IGF-I
      concentration increased relative to almost undetectable levels (1 ng/mL) of
      controls to 216 +/- 59 ng/mL at 20 min after IGF-I injection (P < 0.001) and
      decreased to 12 +/- 6 ng/ mL by 6 h. Serum glucose and nonprotein nitrogen
      concentrations were significantly decreased for all or most of the 3 h after IGF
      I injection, respectively, but only glucose concentration was the same as
      controls by 6 h. Low serum glucose and nonprotein nitrogen during the first few
      hours after IGF-I injection may contribute to the inhibition of Ks at 2.5 h, but
      the mechanisms behind the increased Ks at 6 h are not clear. These results
      support a role for IGF-I in the posthatching muscle development of chicks.

PMID- 12412922
TI  - The effect of dietary selenium source and level on the uptake of selenium by
      developing chick embryos.
AB  - We studied the effect of dietary source (organic or inorganic) and level of Se on
      the Se uptake of chick embryos. After receiving a low-Se diet for 16 wk, 126
      Leghorn laying hens were randomly assigned to one of seven dietary treatments.
      Treatments consisted of feeding a low-Se basal diet alone or with one of three
      levels of added Se (0.1,0.2, or 0.3 mg/kg Se) supplied by sodium selenite or Se
      enriched yeast. Fertile eggs were collected after 33 d of feeding the
      experimental diets. Eggs were subjected to no incubation or incubation for 5, 10,
      15, or 20 d. Non-incubated eggs were separated, and the yolk and albumen were
      assayed separately for Se. Incubated eggs were separated into the embryo and
      extra-embryonic portions, which were assayed separately for Se. Se concentrations
      of the yolk and albumen were significantly different among dietary treatments.
      Compared with eggs from hens fed sodium selenite, yolk and albumen Se
      concentrations were higher in eggs from hens fed Se yeast. Embryonic and extra
      embryonic Se concentrations were higher in eggs from hens fed Se yeast than eggs
      from hens fed sodium selenite. The largest increase in embryonic Se concentration
      was observed during Days 10 to 15 of incubation. It was concluded that Se source
      and dietary inclusion level influenced the Se concentration of portions of
      developing embryonated eggs and that embryonic Se concentration changed during
      incubation.

PMID- 12412923
TI  - Dietary linseed oil produces lower abdominal fat deposition but higher de novo
      fatty acid synthesis in broiler chickens.
AB  - Previous experiments have shown lower abdominal and body fat deposition in
      broilers fed polyunsaturated fatty acids (PUFA) compared with those fed saturated
      fatty acids (SFA) or monounsaturated fatty acids (MUFA). These changes in fat
      deposition may be related to different rates of lipid synthesis or lipid
      oxidation. In Experiment 1, in vivo lipogenesis of broilers fed different dietary
      fatty acid profiles (tallow, sunflower oil, or linseed oil) was investigated. In
      Experiment 2, liver fatty acid deposition of broilers fed a basal diet (without
      additional fat) or diets with added tallow, olive oil, sunflower oil, or linseed
      oil was studied. Results from Experiment 1 showed higher rates of de novo fatty
      acid synthesis in broilers fed the diet with added linseed oil (P < 0.05),
      compared with those fed tallow or sunflower oil. In Experiment 2, values of liver
      to-dietary-fatty-acid ratios of fatty acids from endogenous synthesis (SFA, n-7
      and n-9 fatty acids) were higher in broilers fed linseed oil and the basal diet.
      Results obtained in both experiments suggest that lower abdominal and body fat
      deposition of broilers fed PUFA compared with those fed SFA or monounsaturated
      fatty acids is mainly due to differences in lipid oxidation rates and that the
      higher in vivo lipogenesis found in broilers fed linseed oil would be another
      mechanism to dissipate energy, contributing to the lower fat deposition in these
      birds.

PMID- 12412924
TI  - Effect of hydrostatic pulmonary edema on the interparabronchial septum of the
      chicken lung.
AB  - Scanning electron microscopy (SEM) was utilized to examine the interparabronchial
      septum as a potential site of lymphatic drainage in the lungs of anesthetized
      chickens (Gallus domesticus). Birds were subjected to extracellular fluid volume
      expansion in order to produce hydrostatic pulmonary edema via increased pulmonary
      capillary fluid flux into the interstitial spaces of the lung. Micrographs
      obtained from freeze-dried lungs of volume-loaded birds were compared with
      similarly prepared lungs from normal control chickens, which were not volume
      loaded. The adjacent parabronchi of the control lungs were closely opposed by a
      minimal septal space, whereas the interparabronchial septal space of the volume
      loaded birds was measurably thickened and appeared to be engorged as a result of
      hydrostatic pulmonary edema. The results of this study are consistent with
      observations of the lungs of mammals subjected to hydrostatic pulmonary edema and
      suggest that the interparabronchial septum may be a potential route of lymphatic
      drainage in the avian lung.

PMID- 12412925
TI  - Variations in levels of acid phosphatase present in chicken whole leg meat.
AB  - Acid phosphatase (ACP) has been identified as a potential biomarker for endpoint
      temperature determination in further-processed poultry. Multiple analyses of the
      same sample for ACP have produced consistent results. The degree of variation in
      ACP levels present in different production lots has not been identified. This
      study was conducted utilizing a single flock of broilers. Birds were slaughtered
      on four separate days (replications), and whole leg, without skin, was
      homogenized. Proximate composition was analyzed for each replication. Water
      soluble proteins were extracted from raw meat and assessed for initial ACP
      levels. Samples of meat were cooked to an internal temperature of 71.1 C. There
      were differences (P < 0.05) between replications for both moisture and fat
      content. When dry fat content was analyzed, no significant differences occurred
      between replicates. Initial ACP levels were different (P < 0.0001) between
      replicates (500.33 to 348.97 units of activity/kg). Levels of ACP activity after
      cooking were also different (P < 0.0001) between replicates (17.61 to 10.82 units
      of activity/kg). Percentage degradation of activity during cooking was similar
      (96.98 to 95.89%) between replicates. ACP levels were consistently measured
      within a replicate. Differences between replicates for both initial and cooked
      levels indicate a threshold level for determination of thermal endpoint would be
      difficult to establish. ACP may not be a sensitive measure to estimate the degree
      of doneness of meat samples in which initial ACP concentration is unknown.
      Identical raw sample required for such a comparison would be difficult for the
      processing industry to maintain.

PMID- 12412926
TI  - Dietary conjugated linoleic acid with fish oil alters yolk n-3 and trans fatty
      acid content and volatile compounds in raw, cooked, and irradiated eggs.
AB  - We investigated the effect of dietary conjugated linoleic acid (CLA) along with n
      3 polyunsaturated fatty acid (n-3 PUFA) on yolk fatty acid composition and
      volatile compounds in eggs that were raw (RA), hard-boiled (HB), or hard-boiled,
      irradiated (HBI, 2.5 kGy). Single Comb White Leghorn laying hens (n = 40) were
      randomly assigned to one of the four experimental diets containing 0, 0.5, 1.0,
      or 2.0% CLA. Menhaden oil was used as the source of n-3 PUFA. Eggs collected
      after 6 wk of feeding were analyzed for fatty acids and volatile compounds. The
      content of docosahexaenoic acid (C22:6 n-3) was reduced (P < 0.05) in eggs from
      hens fed the 2.0% CLA diet. Eggs from hens fed 0.5% CLA incorporated the highest
      concentration of docosahexaenoic acid (P < 0.05) with a concomitant reduction in
      arachidonic acid (P < 0.05). The yolk contents of cis-9 trans-11 CLA and trans-10
      cis-12 CLA increased linearly (P < 0.05) as the dietary CLA supply increased.
      Total monounsaturates were reduced (P < 0.05) with an increase in saturates in
      yolk. No difference was observed in the total PUFA content of eggs. Total
      volatiles were reduced in RA eggs from 1.0 and 2.0% CLA diets. 2-Propanone,
      hexane, and methyl cyclopentane were the major volatiles in RA eggs and were
      reduced by dietary CLA at 1.0 and 2.0%. Acetaldehyde, pentane, propanol, acetic
      acid methyl ester, acetic acid ethyl ester, propionic acid methyl ester, 2
      methylmethyl propionic acid, 2-propanone, and octane were the major volatiles in
      HB eggs and were reduced by 2.0% CLA (P < 0.05). No difference was observed in
      the acetaldehyde, pentane, propanol, acetic acid ethyl ester, octane, or total
      volatile content of HBI eggs.

PMID- 12412927
TI  - Thermal inactivation D- and Z-values of Salmonella and Listeria innocua in fully
      cooked and vacuum packaged chicken breast meat during postcook heat treatment.
AB  - Studies were conducted to determine thermal inactivation D- and z-values of
      Salmonella and Listeria innocua in fully cooked and vacuum-packaged chicken
      breast meat. Fully cooked chicken breast meat products that were obtained from
      three different sources with differing formulations were uniformly inoculated
      with a cocktail of Salmonella (including Senftenberg, Typhimurium, Heidelberg,
      Mission, Montevideo, and California) or L. innocua at approximately 10(7) cfu/g.
      The inoculated meat samples were vacuum-packaged and then heat-treated at a
      temperature of 55 to 70 C for 5 to 90 min. After heat treatment, the samples were
      immediately cooled in an ice-water bath. Survivors of Salmonella and L. innocua
      were enumerated for each sample. D- and z-values of Salmonella and L. innocua
      were determined for each product and compared among the products. Source and
      formulation did not cause significant differences in the D- and z-values of
      Salmonella or L. innocua among the three fully cooked and vacuum-packaged chicken
      breast meat products.

PMID- 12412928
TI  - The effect of age, dietary carbohydrate source, and feed withdrawal on broiler
      breast fillet color.
AB  - An experiment was conducted to determine the effect of bird age, diet (feeds
      formulated with 69.5% corn, 69.7% milo, or 73.6% wheat), and feed withdrawal
      times (0 or 8 hours) on color (CIE L*, lightness; a*, redness; and b*,
      yellowness) of raw broiler breast fillets. Broilers were placed on diets at 28 d
      of age. Replicate groups of 24 birds (eight each from different diet and four
      each either full fed or feed withdrawn) were processed (slaughtered and
      eviscerated under simulated commercial conditions) each day from 42 to 45 and 49
      to 52 d of age (n = 192). Carcasses were chilled and deboned 4 h postmortem, and
      triplicate color measurements taken from the medial (bone) side of the fillet.
      Bird age did not significantly affect fillet color values. Fillets from the birds
      fed the wheat diet were significantly lighter than fillets from the corn or milo
      fed birds (48.9 vs. 46.9 and 46.7, respectively). The milo diet resulted in
      significantly redder fillets than corn or wheat (3.9 vs. 3.5 and 3.3,
      respectively). The corn diet produced significantly more yellow fillets than milo
      or wheat (4.8 vs. 2.4 and 2.6, respectively). Feed withdrawal significantly
      increased fillet lightness from an average of 46.1 to 48.9, decreased redness
      from 4.1 to 3.1, and increased yellowness from 2.8 to 3.7. Raw broiler breast
      fillet color is significantly affected by both diet and feed withdrawal, but not
      by age.

PMID- 12412929
TI  - Broiler skin and meat color changes during storage.
AB  - The importance of poultry skin and meat color (both absolute and variations in
      color) in the market place have been well established. It has also been reported
      that these colors change over time. With the development of computer-assisted
      vision grading systems, the changes in skin and meat color during and after
      processing have become important, based on calibrations and assessment values
      based on color. Four independent experiments were conducted to determine the
      pattern of color change in broiler skin and meat during processing and storage.
      Skin color change was measured on subscald (57 C) and semiscald (50 C) breast
      skin surfaces and on breast and leg meat, on the carcass and following deboning
      and packaging. A reflectance colorimeter was used to determine lightness (L*),
      redness (a*), and yellowness (b*) at 20-min intervals for the first 3 h, at 30
      min intervals between 3 and 8 h, hourly between 8 and 12 h, and daily up to 8 d
      postmortem. Results clearly show that color values for both skin and meat changed
      dramatically for the first 6 h postmortem, after which the changes were less
      pronounced. The skin from semiscalded birds showed less change than the skin from
      subscalded birds. These results indicate that on-line vision systems need to take
      into account the dramatic changes in skin and meat color during the first 6 h
      postmortem, after which the color changes may be less important.

PMID- 12412931
TI  - Time for a collective approach from medical specialists to clinical governance.

PMID- 12412930
TI  - Comparison of electrolyzed oxidizing water with various antimicrobial
      interventions to reduce Salmonella species on poultry.
AB  - Foodborne pathogens in cell suspensions or attached to surfaces can be reduced by
      electrolyzed oxidizing (EO) water; however, the use of EO water against pathogens
      associated with poultry has not been explored. In this study, acidic EO water [EO
      A; pH 2.6, chlorine (CL) 20 to 50 ppm, and oxidation-reduction potential (ORP) of
      1,150 mV], basic EO water (EO-B; pH 11.6, ORP of -795 mV), CL, ozonated water
      (OZ), acetic acid (AA), or trisodium phosphate (TSP) was applied to broiler
      carcasses inoculated with Salmonella Typhimurium (ST) and submerged (4 C, 45
      min), spray-washed (85 psi, 25 C, 15 s), or subjected to multiple interventions
      (EO-B spray, immersed in EO-A; AA or TSP spray, immersed in CL). Remaining
      bacterial populations were determined and compared at Day 0 and 7 of aerobic,
      refrigerated storage. At Day 0, submersion in TSP and AA reduced ST 1.41 log10,
      whereas EO-A water reduced ST approximately 0.86 log10. After 7 d of storage, EO
      A water, OZ, TSP, and AA reduced ST, with detection only after selective
      enrichment. Spray-washing treatments with any of the compounds did not reduce ST
      at Day 0. After 7 d of storage, TSP, AA, and EO-A water reduced ST 2.17, 2.31,
      and 1.06 log10, respectively. ST was reduced 2.11 log10 immediately following the
      multiple interventions, 3.81 log10 after 7 d of storage. Although effective
      against ST, TSP and AA are costly and adversely affect the environment. This
      study demonstrates that EO water can reduce ST on poultry surfaces following
      extended refrigerated storage.

PMID- 12412932
TI  - Quality of care of patients hospitalized with acute coronary syndromes.
AB  - BACKGROUND: Measurement and improvement of quality of care is a priority issue in
      health care. Patients hospitalized with acute coronary syndromes (ACS) constitute
      a high-risk population whose care, if shown to be suboptimal on the basis of
      available research evidence, may benefit from quality improvement interventions.
      AIM: To evaluate the quality of in-hospital care for patients with ACS, using
      explicit quality indicators. METHODS: Retrospective case note review was
      undertaken of 397 patients admitted to three teaching hospitals in Brisbane,
      Queensland, Australia, between 1 October 2000 and 17 April 2001. The main outcome
      measures were 12 process-of-care quality indicators, calculated as either: (i)
      the proportion of all patients who received specific interventions or (ii) the
      proportion of ideal patients who received specific interventions (i.e. patients
      with clear indications and lacking contraindications). RESULTS: Quality
      indicators with values above 80% included: (i) patient selection for thrombolysis
      (100%) and discharge prescription of beta-blockers (84%), (ii) antiplatelet
      agents (94%) and (iii) lipid-lowering agents (82%). Indicators with values
      between 50% and 80% included: (i) timely performance of electrocardiogram (ECG)
      on admission (61%), (ii) early coronary angiography (75%), (iii) measurement of
      serum lipids (71%) and (iv) discharge prescription of angiotensin-converting
      enzyme (ACE) inhibitors (73%). Indicators with values <50% included: (i) timely
      administration of thrombolysis (35%), (ii) non-invasive risk assessment (23%) and
      (ii) formal in-hospital, and post-hospital cardiac rehabilitation (47% and 7%,
      respectively). CONCLUSION: There were delays in performing ECG and administering
      thrombolysis to patients who presented to emergency departments with ACS.
      Improvement is warranted in use of non-invasive procedures for identifying high
      risk patients who may benefit from coronary revascularization as well as use of
      serum lipid measurements, ACE inhibitors and cardiac rehabilitation.

PMID- 12412933
TI  - Laboratory cross-contamination of Mycobacterium tuberculosis: an investigation
      and analysis of causes and consequences.
AB  - BACKGROUND: The misdiagnosis of Mycobacterium tuberculosis infection has many
      ramifications. These include medical and psychological implications for patients
      and their families and financial and public health implications for health-care
      institutions. Microbiology laboratory procedures should minimize the possibility
      of laboratory cross-contamination of specimens and maximize the ability to
      recognize a cluster of false-positive cultures. Newer molecular typing methods
      provide rapid, accurate and effective means of identifying false-positive M.
      tuberculosis cultures. AIMS: To investigate a cluster of patients with positive
      M. tuberculosis cultures that were processed in the mycobacteriology laboratory
      on the same day. METHODS: Five patients' medical records and radiology results
      were reviewed to determine whether the cases were epidemiologically linked and
      whether there was clinical suspicion of tuberculosis. Restriction fragment length
      polymorphism (DNA fingerprinting) was performed using repetitive elements IS6110
      and pTBN12. Laboratory processing procedures were analysed. RESULTS: On the basis
      of DNA fingerprinting using IS6110, the isolates from all five patients were
      identical. Molecular typing using pTBN12 was performed on four of the five
      isolates. All four had identical patterns. There was no epidemiological link
      between the patients. At least three (and probably four) of the five patients
      were misdiagnosed with tuberculosis. CONCLUSION: Microbiology laboratories should
      ensure that appropriate methodologies are in place to avoid cross-contamination
      of specimens. Clinicians need to critically interpret any positive laboratory
      result, especially in an unlikely clinical setting.

PMID- 12412934
TI  - Causes of elevated troponin I with a normal coronary angiogram.
AB  - BACKGROUND: The new definition of myocardial infarction (MI) emphasizes the pre
      eminent role of troponin for diagnosis. Troponin rise indicates myocardial
      injury, but is not synonymous with infarction or ischaemia. AIMS: To review the
      precipitating event for troponin elevation in patients with angiographically
      normal coronary arteries, in a district general hospital. METHODS: Consecutive
      patients with elevated troponin I (TnI) who underwent angiography for suspected
      coronary disease were included in the present study if they had normal or mild
      disease (<50% diameter loss without complex features or thrombus). Precipitating
      event for TnI elevation was assigned on the totality of clinical evidence.
      RESULTS: Twenty-one patients qualified, with an average age of 50 years (range 33
      73). Sixty-two per cent of participants were female. Troponin release was
      attributed to tachycardia in six patients, only two of whom had haemodynamic
      compromise. Physical exertion was the precipitating factor in two patients;
      pericarditis in two patients; and severe congestive heart failure in one patient.
      Ten of 21 patients had no identifiable cause for a rise in TnI concentration.
      Five of 21 patients had left-ventricular wall motion abnormalities. There were no
      deaths or MI at 41 +/- 24 weeks follow up. CONCLUSION: Troponin is a sensitive
      marker of myocardial injury and may rise following apparently minor insults. A
      rise in TnI concentration may have a cause other than acute coronary syndrome and
      may occur without significant angiographic coronary artery disease.

PMID- 12412936
TI  - Rational care before rationed care.

PMID- 12412935
TI  - The Victorian CPAP program: is there a need for additional education and support?
AB  - BACKGROUND: The Victorian Continuous Positive Airways Pressure (CPAP) Program
      provides CPAP services to financially disadvantaged individuals with moderate to
      severe sleep apnoea. AIMS: To evaluate health outcomes in patients referred to
      the pilot program in order to: (i) assess the magnitude of health benefit from
      treatment in this highly selected population and (ii) identify patient
      characteristics or factors related to service provision that may influence
      outcome. METHODS: We adopted a simple before-after research design. Patients who
      were referred to the program were recruited from five sleep centres.
      Questionnaires were administered at baseline and 1 and 3 months after commencing
      CPAP. Generic and disease-specific quality of life were assessed using the MOS 36
      Item Short-form Health Survey and the Sleep Apnoea Quality-of-life Index,
      respectively. Subjective daytime sleepiness was measured using the Epworth
      Sleepiness Scale and the Sleep-Wake Activity Inventory. RESULTS: Of the 68
      subjects enrolled in the study, 59 were available for follow up. There were
      significant improvements in daytime sleepiness (P < 0.0005). Treatment-related
      symptoms had a negative impact on overall disease-specific quality of life,
      however there were significant improvements in all other domains of disease
      specific quality of life (P < 0.0005). Improvements in generic quality of life
      were small but statistically significant (P < 0.05). Hospital, disease severity,
      baseline sleepiness, gender and CPAP-machine type were not predictors of outcome
      (P > 0.05). CONCLUSION: This review of the Victorian CPAP Program identified
      significant improvements in subjective daytime sleepiness and quality of life,
      despite the negative impact of treatment-related symptoms. Future research should
      explore whether services can be modified to help reduce the impact of treatment
      related side-effects.

PMID- 12412937
TI  - Dementia: an update to refresh your memory.
AB  - The number of people with dementia and cognitive impairment is predicted to rise
      exponentially in the future. The increasing awareness of dementia in the
      community has led to a better understanding of the impact of this condition on
      individuals, their families and their carers. There is burgeoning research in the
      pathogenesis of dementia, and advances have been made in pharmacological
      treatments for the management of symptoms, including behavioural and
      psychological disturbances. However, the mainstay of management rests in
      comprehensive clinical assessment, education, counselling and provision of
      support for those affected and their families. The present paper provides a
      clinical update on recent advances in diagnosis and management of the most common
      forms of dementia.

PMID- 12412938
TI  - Parasitic worms of the central nervous system: an Australian perspective.
AB  - The diagnosis and management of parasitic diseases of the central nervous system
      (CNS) is difficult, even for infectious diseases physicians and neurologists.
      Furthermore, few overviews of the spectrum of causative helminths and clinical
      syndromes have been published. In the present study, we review the seven most
      common parasitic diseases of the CNS: (i) cysticercosis, (ii)
      neuroschistosomiasis, (iii) paragonimiasis, (iv) angiostrongyliasis, (v) hydatid
      disease, (vi) sparganosis and (vii) gnathostomiasis. Major syndromes of parasitic
      disease of the CNS and their differential causes are discussed, including: (i)
      cystic lesions, (ii) enhancing granulomas (with and without creeping subcutaneous
      eruptions), (iii) eosinophilic meningoencephalitis and (iv) spinal cord disease.
      Specific risk factors that predispose to these infections are also discussed and
      particular attention is drawn to the situation in Australia.

PMID- 12412939
TI  - Prevention of autoimmune attack and disease progression in multiple sclerosis:
      current therapies and future prospects.
AB  - Multiple sclerosis (MS) is an important cause of progressive neurological
      disability, typically commencing in early adulthood. There is a need for safe and
      effective therapy to prevent the progressive central nervous system (CNS) damage
      and resultant disability that characterize the disease course. Increasing
      evidence supports a chronic autoimmune basis for CNS damage in MS. In the present
      study, we review current concepts of autoimmune pathogenesis in MS, assess
      current therapies aimed at countering autoimmune attack and discuss potential
      therapeutic strategies. Among currently available therapies, beta-interferon and
      glatiramer acetate have a modest effect on reducing relapses and slowing the
      accumulation of disability in relapsing-remitting MS. Beta-interferon is of
      doubtful efficacy in secondary progressive MS and appears to aggravate primary
      progressive MS, possibly by increasing antibody-mediated CNS damage through
      inhibition of B-cell apoptosis. Mitoxantrone may reduce relapses and slow
      disability progression in relapsing-remitting and secondary progressive MS, but
      its use is limited by the risk of cardiomyopathy. There are currently no
      effective treatments for primary progressive MS. Many therapies that are
      effective in the animal model, experimental autoimmune encephalomyelitis (EAE),
      are either ineffective in MS or--in the case of gamma-interferon, lenercept and
      altered peptide ligands--actually make MS worse. This discrepancy may be
      explained by the occurrence in MS of defects in immunoregulatory mechanisms, the
      integrity of which is essential for the efficacy of these treatments in EAE. It
      is likely that the development of safe, effective therapy for MS will depend on a
      better understanding of immunoregulatory defects in MS.

PMID- 12412940
TI  - Eosinophilic Meckel's diverticulitis.

PMID- 12412941
TI  - Magnetic resonance imaging diagnosis of gouty tophi in a man with gout and
      Bartter's syndrome.

PMID- 12412942
TI  - Conquering adult onset/type II diabetes mellitus--not yet!!

PMID- 12412943
TI  - Can we be certain of PRO accuracy and accountability? Inaccurate "report cards"
      generated by medicare claims data as a marker for laboratory testing in diabetic
      patients.
AB  - Quality of care attributed to individual physicians will be made public more
      frequently in the future. Inaccurate reports could damage physicians both
      professionally and financially. Using claims data for services rendered to
      Medicare patients from 1997 through 2000, The New Jersey Peer Review Organization
      (PRO) reported the percentage of each physician's patients who received testing
      for HgB A1c and for lipid profiles. We reviewed the patient records kept by these
      physicians to calculate the actual percentage of patients who received these
      tests. A statistically significant difference existed between the PRO's data and
      our results. Use of claims data as a marker for services provided can lead to
      inaccurate inferences about the quality of care provided by individual
      physicians, which can have potentially negative consequences to these providers.

PMID- 12412944
TI  - Standardizing sliding scale insulin orders.
AB  - The objective of this study was to decrease variation in an inpatient setting in
      diagnosing and treating patients with a secondary diagnosis of type II diabetes
      mellitus. Physician ordering practices were reviewed in a 262-bed acute care
      hospital with 489 physicians on the active medical staff. Using standard quality
      improvement methodology, the diagnosis of and care of hyperglycemia and type II
      diabetes mellitus was analyzed and changes in ordering practice recommended.
      Standardized sliding-scale orders were implemented with widespread staff
      acceptance as demonstrated by 80% use after 6 months, and over 500 undiagnosed
      hyperglycemic patients will be counseled in 2001. The costs for the program were
      more than covered by the estimated annualized savings of 687 bed days and
      $134,832. This project demonstrates that standardizing care for inpatients with
      type II diabetes mellitus is possible. The cost savings (not including the value
      of good will and perceived increase in quality by the patients) justifies the
      time and effort to make these changes.

PMID- 12412945
TI  - Measuring and improving preventive care for patients with diabetes in primary
      health centers.
AB  - Diabetes care among medically underserved patients is suboptimal. Few studies,
      however, have described successful strategies to improve diabetes care in these
      patient populations. To address this issue, 4 Montana community health centers
      and 1 urban Indian health center implemented quality improvement efforts along
      with an office-based electronic system for monitoring diabetes care. After a
      median of 17 months follow-up, preventive services and clinical outcomes were
      assessed for all patients at baseline (N = 332) and follow-up (N = 590), and for
      a cohort (N = 164) who had 1 or more visits 6 months after baseline. In cross
      sectional analyses, there were increases from baseline to follow-up in the
      percent of patients who had received an annual foot examination (50% to 68%),
      microalbuminuria testing (34% to 62%), annual retinal examination (14% to 30%),
      pneumococcal immunization (30% to 61%), and smoking assessment (77% to 91%). But
      neither HbA1c testing in the previous 6 months (64% to 55%) nor annual LDL-C
      testing (59% to 61%) showed any improvement. There were no significant changes
      from baseline to follow-up in the median hemoglobin A1c (HbAlc), low density
      lipoprotein-cholesterol (LOL-C), or in systolic and diastolic blood pressure
      values. Similar improvements in preventive care were seen in the cohort of
      patients with diabetes. But overall outcomes were not improved. Our findings
      suggest that office-based monitoring systems can support systems' changes to
      improve the delivery of preventive services to patients with diabetes in primary
      care facilities for the underserved, but outcomes are more difficult to enhance
      over a short period of follow-up. Also, our findings suggest that over a
      relatively short-term period, cross-sectional and cohort analyses of quality
      improvement measures do yield similar measures of diabetes care in such settings.

PMID- 12412946
TI  - Outcome of subcutaneously implanted catheters in a teaching hospital.
AB  - Subcutaneously implanted catheters (SIC) are commonly used for long-term
      intravenous access. This article examines SIC outcome data in a series of
      patients in a teaching center. The study was performed as a retrospective review.
      The study is descriptive in nature. Patients were entered into the study at the
      time of SIC removal, and demographics, diagnoses, and reasons for removal were
      recorded. Reasons for removal, lifespans of catheter, and outcome are analyzed.
      All catheters were implanted and removed at the Long Island Jewish Medical
      Center. Statistical analysis was by Student's t test. Significance is defined as
      P < .05. The average duration of catheter life was 14.4 +/- 17.1 months. Three
      reasons were identified for catheter removal: completion of therapy (44%),
      catheter malfunction (28%), and infection (28%). Our total infection rate was
      0.65/1000 catheter days, which decreased to 0.19/1000 for catheters in place
      between 1 and 24 months. Catheters left in place for more than 24 months were
      noted to have an increased infection rate. SICs are a safe and effective mode of
      intravenous access. Our data indicate that infectious complications are low when
      proper technique is employed and catheters are removed before 24 months.

PMID- 12412947
TI  - Rational and irrational clinical strategies for collaborative medicine.
AB  - Individual practitioners and health care systems/organizations increasingly
      understand the rationale for collaborative medicine. An absence of collaboration
      can compromise the quality and safety of patient care. But having a rationale to
      provide collaborative medicine without also having a rational clinical strategy
      can be equally compromising to the quality and safety of patient care. Reasonable
      evidentiary criteria must be used to determine whether specific therapies merit
      inclusion or exclusion in a collaborative medicine model. Ranking therapies
      hierarchically on the basis of their risk-benefit ratio simplifies matching of
      therapies with the needs of the patient. A unifying taxonomy that categorizes all
      therapies (complementary/alternative and conventional) on the basis of how we
      think they work (presumed mechanisms of action) facilitates development of a
      clinical strategy for collaborative medicine. On the basis of these principles, a
      rational clinical strategy for collaborative medicine is described to help
      optimize the quality and safety of patient care.

PMID- 12412948
TI  - An evidence-based clinical pathway for bronchiolitis safely reduces antibiotic
      overuse.
AB  - The overuse of antibiotics in the management of bronchiolitis is widely known,
      yet physician practice has been slow to change. We report here on the success of
      a clinical pathway in reducing antibiotic overuse in the inpatient management of
      bronchiolitis. The charts of 181 children admitted for bronchiolitis were
      reviewed to determine whether antibiotic use was reduced in patients managed
      using a clinical pathway compared with a matched group of patients managed
      without use of the pathway (non-pathway group). Only 9% of the pathway patients
      received antibiotics compared with 27% of the nonpathway group. No negative
      effects were seen on other quality measures including unplanned return for care.
      Furthermore, for patients managed using the clinical pathway, cost and length of
      stay were significantly reduced. Overall, the study suggests that implementation
      of a clinical pathway may be an effective means to change physician practice and
      reduce the unnecessary use of antibiotics, while maintaining or improving other
      aspects of quality of care.

PMID- 12412949
TI  - The relationship between the fiscal structure of mental health care systems and
      cost.
AB  - The authors, using State Mental Health Agency (SMHA) data from the National
      Association of State Mental Health Program Directors' Research Institute, show
      that the amount of state hospital (SH) expenditures is related to suicide rate
      (SR) as well as to cost per capita for mental health care. The relationship is
      much stronger for cost per capita especially when the range of SH expenditures is
      31-55%, or 43 +/- 12%, of total expenditures. This article hypothesizes that
      maximum system efficiency occurs when the funding structure of the delivery
      system reflects a 57%:43% (community [C]/SH) ratio. This ratio was the mean for
      the 50 states of the United States in 1997, when the national mean SR was 13 per
      100,000 of general population. This ratio is identical to the C-to-SH inpatient
      bed ratio derived theoretically in a previously reported study focusing on
      fractal (self-similar on all scales) demand for mental health services. The
      potential for national saving with the redistribution of funding may be as high
      as $4.5 billion per year, or 23% of SMHA expenditures.

PMID- 12412950
TI  - Developing a consensus for restorative procedures in paediatric dentistry.

PMID- 12412951
TI  - Pediatric Restorative Dentistry Consensus Conference. April 15-16, 2002--San
      Antonio, Texas.

PMID- 12412952
TI  - Risk assessment and epidemiology of dental caries: review of the literature.
AB  - The epidemiology of dental caries in the pediatric population demonstrates that
      caries is no longer pandemic in the US population. The incidence is confined to a
      subset of the total population of our children. The disease is also increasingly
      isolated to specific teeth and tooth morphology types in both the pediatric and
      the mixed dentitions, with pits and fissures being the predominate diseased
      sites. This sequestration of the disease into specific populations, individuals
      and tooth sites mandates a risk assessment strategy. In the past, universal
      preventive strategies were appropriate because of the extensive penetration of
      caries in the population. Our health care system does not have adequate resources
      to treat the entire population when a substantial portion of the population is
      not at risk for this disease process. Validated risk assessment strategies may
      prove adjunctive for the practicing dentist. Certainly knowledge of the known
      risk factors will assist the practitioner in performing risk assessment within
      their patient populations. This paper presents a review of the known risk factors
      for dental caries in child and adolescent populations.

PMID- 12412953
TI  - Clinical decision making for caries management in children.
AB  - The aim of this review of clinical decision making for caries management in
      children is to integrate current knowledge in the field of cariology into
      clinically usable concepts and procedures. Current evidence regarding the carious
      process and caries risk assessment allows the practitioner to go beyond
      traditional surgical management of dental caries. Therapy should focus on patient
      specific approaches that include disease monitoring and preventive therapies
      supplemented when necessary by restorative care. The type and intensity of these
      therapies should be determined utilizing clinical data as well as knowledge of
      the caries process for that child. Changes in the management of dental caries
      will require health organizations and dental schools to educate students,
      practitioners, and patients in evidence- and risk-based care.

PMID- 12412954
TI  - Pit and fissure sealant: review of the literature.
AB  - For this literature review of pit and fissure sealant, 1,465 references were
      selected by a search for "sealants" on PubMed. References were limited to dental
      journals and papers in the English language. The search comprised papers from
      1971 to October 2001. Additional papers of historical significance prior to 1971
      were added from memory and from reference lists published in early papers. This
      paper reviewed the literature on pit and fissure sealants under the following
      subheadings: (1) laboratory studies, (2) clinical technique and tooth
      preparation, (3) etching time, (4) auxiliary application of pit and fissure
      sealant, (5) retention and caries prevention, (6) fluoride used with sealants and
      fluoride-containing sealant, (7) glass ionomer materials as sealants, (8) options
      in sealant: filled vs unfilled; colored vs clear; autocure vs light-initiated,
      (9) sealant placed over caries in a therapeutic manner, (10) cost effectiveness
      of sealant application, (11) underuse of pit and fissure sealant, (12) the
      estrogenicity issue, (13) use of an intermediate bonding layer to improve
      retention, (14) new developments and projections, and (15) summary and
      conclusions. From a careful and thorough review of peer-reviewed publications on
      pit and fissure sealant, it is clear that sealants are safe, effective and
      underused (at least underused in the United States). Pit and fissure sealant is
      best applied to high-risk populations by trained auxiliaries using sealant that
      incorporates the benefit of an intermediate bonding layer, applied under the
      rubber dam or with some alternative short-term, but effective, isolation
      technique, onto an enamel surface that has been cleaned with an air polishing
      technique and etched with 35% phosphoric acid for 15 seconds. The dental
      profession awaits with enthusiasm, and some impatience, the incorporation of
      dentin-bonding technology into the development of a modern, more durable, resin
      based sealant.

PMID- 12412955
TI  - The use of pit and fissure sealants.
AB  - This paper reviews key issues of sealant use and methodology and poses
      recommendations to inform the discussion toward a consensus statement by
      participants. A comprehensive review of sealant literature, including policy
      recommendations from previous conferences that reviewed best practices for
      sealant use, was completed. Building on the review paper by Simonsen and on
      previous policy statements by dental and public health groups, this paper
      discusses key questions about sealant use in light of contemporary caries data
      and cost-benefit analyses. In addition, newest material advancements are reviewed
      to establish the next step in sealant improvement for young patients.

PMID- 12412956
TI  - Glass ionomer cements in pediatric dentistry: review of the literature.
AB  - Glass ionomer cement systems have become important dental restorative and luting
      materials for use in preschoolers, children and teenagers. These materials form
      chemical bonds to tooth structure, are biocompatible, release fluoride ions for
      uptake by enamel and dentin, and are able to take up fluoride ions from
      dentifrices, mouthwashes, and topically applied solutions. Unlike early glass
      ionomers, the new cement systems are easy and practical to use. Resin-modified
      glass ionomer cements not only have improved physical characteristics, but the
      photopolymerizable resin component reduces initial hardening time substantially.
      This article reviews the development and history of glass polyalkenoate cement
      systems and their ongoing role in dentistry for children.

PMID- 12412957
TI  - Glass ionomer cements.
AB  - Glass ionomer cements have been used in pediatric restorative dentistry for 20
      years. Their usefulness in pediatric restorative dentistry is preferential
      relative to other materials because of their fluoride release, chemical adhesion
      to tooth structure, and availability to use in a variety of clinical scenarios.
      This paper reviews the use of glass ionomer materials in pediatric restorative
      dentistry. The paper provides a look at glass ionomer cements' use as sealants
      and restorative materials and examines glass ionomers as adhesives, as a stand
      alone material and in the sandwich technique. This paper also provides a useful
      guide to connecting to other references regarding specific aspects of glass
      ionomers in children.

PMID- 12412958
TI  - The use of dental amalgam in pediatric dentistry: review of the literature.
AB  - Dental amalgam is widely used as a restorative material even though it is not
      esthetic and there has been extensive anti-amalgam rhetoric. Although other
      materials have improved greatly, amalgam has the proven safety record and best
      cost-to-benefit ratio. Clinical evidence indicates that, in the posterior
      permanent dentition--where esthetics is not a primary concern--the small,
      minimally prepared, amalgam restoration, with its margins and any caries
      susceptible fissures sealed with resin fissure sealant, is the restoration with
      the best survival. Amalgam also remains the best direct restorative option when
      larger restorations are required. In the primary dentition, the data indicates
      that resin-based composite and resin-modified glass-ionomer serve very well.

PMID- 12412959
TI  - The use of amalgam in pediatric dentistry.
AB  - Amalgam has been widely utilized to restore posterior teeth in pediatric
      dentistry, and is still taught as the material of choice for Class I and Class II
      restorations in many dental schools in the United States and Canada. Results of
      clinical trials are difficult to compare due to their heterogenicity, mainly due
      to differences in caries risk, operator skills, study duration, or patients' age.
      Thus, the different studies report failure rates of amalgams ranging from 12% to
      over 70%. Treatment of caries should meet the needs of each particular patient,
      based on his/her caries risk. In general, for small occlusal lesions, a
      conservative preventive resin restoration, using composite or compomer in
      conjunction with sealant, would be more appropriate than the classic Class I
      amalgam preparation. For proximal lesions, amalgam would be indicated for 2
      surface Class II preparations that do not extend beyond the line angles of
      primary teeth. This recommendation might not be appropriate for high-risk
      patients or for restoring first primary molars in children 4 years of age and
      younger where stainless steel crowns have demonstrated better longevity.
      Currently, amalgam demonstrates the best clinical success for Class II
      restorations that extend beyond the proximal line angles of permanent molars.

PMID- 12412960
TI  - Dentin/enamel adhesives: review of the literature.
AB  - This paper describes the development of dentin bonding systems, and describes the
      current strategies for bonding composite resin materials to dentin. Two main
      strategies are available--total-etch or self-etch--and each has unique advantages
      and disadvantages. For each category, simplified systems that reduce the number
      of application steps are available. Currently, the market is moving towards self
      etching materials, largely because these are associated with less post-operative
      tooth sensitivity. However, the clinical performance of most of these materials
      is not yet proven.

PMID- 12412961
TI  - Dentin/enamel adhesives in pediatric dentistry.
AB  - The improvements in adhesives and composite technology have made resin-based
      composite resins and polyacid-modified resin-based composites (compomers) very
      popular as materials to restore primary and permanent anterior and posterior
      teeth. More conservative preparations can be performed maintaining more tooth
      structure due to the adhesive properties of the adhesives used with composites
      and compomers. Meticulous care in the placement of adhesives and, subsequently,
      resin-based composites and compomers is necessary to produce long-term
      satisfactory results.

PMID- 12412962
TI  - Posterior resin-based composite: review of the literature.
AB  - The use of direct posterior resin-based composite has increased primarily due to
      patient esthetic desires and product improvements. Other factors (substantiated
      or not) contributing to increased use of resin-based composite are environmental
      and health concerns with dental amalgam. New visible light cured resin-based
      composite products are introduced yearly, as manufacturers continue to improve
      this tooth-colored restorative material. This paper will characterize current
      posterior resin-based composite materials (hybrid, microfill, flowable, and
      packable), review recent in vitro and clinical research, and recommend
      indications for these materials. In addition, the literature on compomers will be
      reviewed and recommendation made for their use. The data indicates that composite
      resin is a technique sensitive restorative material that can be used in large
      preparations if proper manipulation and isolation can be maintained. Compomers
      may also be used as an esthetic posterior restorative if proper isolation is
      provided.

PMID- 12412963
TI  - The use of resin-based composite in children.
AB  - Resin-based composites are an integral component of contemporary pediatric
      restorative dentistry. They can be utilized effectively for preventive resin
      restorations, moderate Class II restorations, Class III restorations, Class IV
      restorations, Class V restorations and strip crowns. Tooth isolation to prevent
      contamination is a critical factor, and high-risk children may not be ideal
      candidates for resin-based composite restorations. Important factors to consider
      during composite placement are isolation, polymerization shrinkage and extent of
      restoration. When utilized correctly, resin-based composites can provide
      excellent restorations in the primary and permanent dentition.

PMID- 12412964
TI  - Preformed metal crowns for primary and permanent molar teeth: review of the
      literature.
AB  - The aim of this study was to carry out a review of the use and efficiency of
      preformed metal crowns (PMCs) for primary and permanent molar teeth. A literature
      search of English language journals was carried out using MEDLINE. Papers that
      addressed areas related to the use of PMCs regarding indications for use,
      placement techniques, risks, longevity, cost effectiveness and utilization were
      included in the review. Eighty-three papers were traced which fulfilled the above
      criteria, the majority addressing PMCs in primary molar teeth. Over half the
      papers were concerned with placement techniques and indications for use, with
      fewer papers reporting on clinical studies. The clinical data on PMCs spanned a
      considerable number of years and involved heterogeneous populations of patients,
      different makes and designs of crown, and differences among the operators and
      evaluators who were involved in the studies. The results, however, were in
      agreement that PMCs are superior to amalgam restorations for multisurface
      cavities in primary molar teeth.

PMID- 12412965
TI  - The use of stainless steel crowns.
AB  - The stainless steel crown (SSC) is an extremely durable restoration with several
      clear-cut indications for use in primary teeth including: following a
      pulpotomy/pulpectomy; for teeth with developmental defects or large carious
      lesions involving multiple surfaces where an amalgam is likely to fail; and for
      fractured teeth. In other situations, its use is less clear cut, and caries risk
      factors, restoration longevity and cost effectiveness are considerations in
      decisions to use the SSC. The literature on caries risk factors in young children
      indicates that children at high risk exhibiting anterior tooth decay and/or molar
      caries may benefit by treatment with stainless steel crowns to protect the
      remaining at-risk tooth surfaces. Studies evaluating restoration longevity,
      including the durability and lifespan of SSCs and Class II amalgams demonstrate
      the superiority of SSCs for both parameters. Children with extensive decay, large
      lesions or multiple surface lesions in primary molars should be treated with
      stainless steel crowns. Because of the protection from future decay provided by
      their feature of full coverage and their increased durability and longevity,
      strong consideration should be given to the use of SSCs in children who require
      general anesthesia. Finally, a strong argument for the use of the SSC restoration
      is its cost effectiveness based on its durability and longevity.

PMID- 12412966
TI  - Restoration of primary anterior teeth: review of the literature.
AB  - This paper reviews the published data on restorations of primary anterior teeth.
      The discussion includes Class III restorations, Class V restorations, various
      forms of full coronal restorations, atraumatic restorative technique (ART) and
      recommendations for future research.

PMID- 12412967
TI  - Restoring primary anterior teeth.
AB  - A variety of esthetic restorative materials are available for restoring primary
      incisors. Knowledge of the specific strengths, weakness, and properties of each
      material will enhance the clinician's ability to make the best choice of
      selection for each individual situation. Intracoronal restorations of primary
      teeth may utilize resin composites, glass ionomer cements, resin-modified
      ionomers, or polyacid-modified resins. Each has distinct advantages and
      disadvantages and the clinical conditions of placement may be a strong
      determining factor as to which material is utilized. Full coronal restoration of
      primary incisors may be indicated for a number of reasons. Crowns available for
      restoration of primary incisors include those that are directly bonded onto the
      tooth, which generally are a resin material, and those crowns that are luted onto
      the tooth and are some type of stainless steel crown. However, due to lack of
      supporting clinical data, none of the crowns can be said to be superior to the
      others under all circumstances. Though caries in the mandibular region is rare,
      restorative solutions for mandibular incisors are needed. Neither stainless steel
      crowns nor celluloid crown forms are made specifically for mandibular incisors.
      Many options exist to repair carious primary incisors, but there is insufficient
      controlled, clinical data to suggest that one type of restoration is superior to
      another. This does not discount the fact that dentists have been using many of
      these crowns for years with much success. Operator preferences, esthetic demands
      by parents, the child's behavior, and moisture and hemorrhage control are all
      variables which affect the decision and ultimate outcome of whatever restorative
      treatment is chosen.

PMID- 12412968
TI  - The comprehensive written section: a brief overview.

PMID- 12412969
TI  - Unenhanced spiral CT scan in the initial evaluation of renal colic: AUBMC
      experience.
AB  - BACKGROUND AND OBJECTIVE: Until recently, intravenous urography and
      ultrasonography have been the standard diagnostic modalities in the initial
      evaluation of acute flank pain. However, since 1995 the role of non-enhanced CT
      scan (NECT) has become more important in establishing the diagnosis of renal
      colic. In this retrospective descriptive study, we evaluated the usefulness of
      NECT in the diagnosis and management of patients with suspected urinary tract
      stones at the American University of Beirut-Medical Center (AUBMC). MATERIALS AND
      METHODS: We reviewed the records of 102 patients who presented to AUBMC over a
      period of two years for flank pain with or without hematuria. NECT were obtained
      in all patients. We studied the images for the presence of stones and frequency
      of associated urinary findings. Incidental abdominal and pelvic abnormalities
      were recorded. RESULTS: Fifty-four patients were found to have positive CT
      examinations for the presence of urinary tract stones on the ipsilateral side of
      the flank pain. Twenty-two stones were present in the kidneys, 23 in the ureters
      and 16 at the ureterovesical junction (UVJ). In these 54 patients with stone
      disease, 31 had associated pelvicalyceal dilatation (57%), and 16 had perinephric
      streaking (29.6%). In the 39 patients with ureteral and UVJ stones, 26 had
      ureteral dilatation (66.6%), and 17 had periureteral streaking (43.5%). In the 23
      patients with only ureteral stones, 10 had a positive rim sign (43.4%).
      CONCLUSION: A diagnosis of urinary tract stone is not always readily apparent on
      the basis of physical exam and laboratory studies. NECT is now universally
      accepted as a preferred method for the evaluation of ureteral and kidney stones
      in patients with suspected renal colic.

PMID- 12412970
TI  - Biochemical and metabolic peculiarities of some parasites availing as targets for
      therapy.
AB  - Biochemical and metabolic peculiarities of some parasites involved in their
      interactions with their hosts are reviewed according to (1) carbohydrate
      metabolism comprising glycolysis, Pasteur effect, CO2 fixation and electron
      transport system; (2) amino acid and protein metabolism ; (3) purine and
      pyrimidine nucleotides metabolism. These peculiarities are becoming targets for
      treatment without affecting the host.

PMID- 12412971
TI  - Isolated septic arthritis of a lumbar facet joint.
AB  - This is a report of an isolated septic arthritis of a lumbar facet joint where
      the infectious agent was Bacteroides sp. and where an early diagnosis was made
      using MRI.

PMID- 12412973
TI  - New Arabic transliteration system for computer use and for printing.

PMID- 12412972
TI  - Imaging of an exceptional tumor: myxoid chondrosarcoma of the jugular foramen.
AB  - We report on an unusual tumor of the jugular foramen in a 26-year-old male. The
      lesion showed moderate enhancement on CT scan and a higher signal intensity on T2
      weighted MR images than on T1, with a massive enhancement after gadolinium. Tumor
      was entirely removed surgically and histology was consistent with a low-grade
      myxoid chondrosarcoma, an exceptional tumor in this location. The differential
      diagnosis includes paragangliomas, schwannomas, metastases and meningiomas.
      Radiological and histological features can also mimic chordomas. However,
      immunohistochemical analysis certifies the diagnosis.

PMID- 12412974
TI  - Prevalence and risk factors for asthma and chronic bronchitis in the capitals
      Helsinki, Stockholm, and Tallinn.
AB  - The aim of this part of the FinEsS-studies was to assess whether differences
      existed in prevalence of asthma, chronic bronchitis, and respiratory symptoms
      between three Baltic capitals, and to examine risk factor profiles for
      respiratory conditions. In 1996, a postal survey was performed in these cities
      with a response rate of 72% in Stockholm, 76% in Helsinki, and 68% in Tallinn.
      The prevalence of physician-diagnosed asthma was 76% in Stockholm, 6.2% in
      Helsinki, and 2.3% in Tallinn, while respiratory symptoms were most common in
      Tallinn. The prevalence of physician-diagnosed chronic bronchitis was 10.6% in
      Tallinn, 3.4% in Helsinki, and 3.0% in Stockholm. Risk factor analyses revealed a
      significantly increased risk for those living in Tallinn compared to that of
      Stockholm for wheezing conditions, OR 1.56-1.69, longstanding cough, OR 1.92
      (1.74-2.13), attacks of shortness of breath during the previous 12 months, OR
      1.35 (1.20-1.52), and chronic productive cough, OR 1.49 (1.28-1.74). Subjects
      having symptoms common in asthma were more likely to have physician-diagnosed
      asthma in Stockholm and Helsinki than in Tallinn, while subjects having
      bronchitis symptoms had more often physician-diagnosed chronic bronchitis in
      Tallinn. Prevalence of respiratory symptoms was higher in Tallinn than in
      Stockholm and Helsinki, while physician-diagnosed asthma was more common in
      Stockholm and Helsinki. The prevalence of physician-diagnosed chronic bronchitis
      was three times as high in Tallinn as in Helsinki or Stockholm. Our results also
      suggest large differences in diagnostic practices between the three countries,
      while the differences between the capitals in true prevalence of disease may be
      small.

PMID- 12412975
TI  - The appearance of S-100 protein-positive dendritic cells and the distribution of
      lymphocyte subsets in idiopathic nonspecific interstitial pneumonia.
AB  - Idiopathic interstitial pneumonia (IIP) is a progressive interstitial lung
      disease of unknown etiology. We investigated dendritic cells in idiopathic
      nonspecific interstitial pneumonia (NSIP) immunohistochemically, using anti-S-100
      protein antibody and anti-HLA-DR antibody and also evaluated the relationship
      between the distribution of S-100 protein-positive dendritic cells (S- 100 DCs)
      and the lymphocytic subsets in the lung tissue of NSIP. Fifteen patients with the
      pathological diagnosis of idiopathic NSIP and six patients with usual
      interstitial pneumonia (UIP) were recruited into this study. Many S-100 DCs were
      observed in all the cases of idiopathic NSIP but S-100 DCs were not recognized in
      UIP cases invariably. In the mirror section method, most S-100 DCs showed a
      positive reaction of anti-HLA-DR antibody but a negative reaction for anti-CD1a
      antibody. CD8 and CD4 positive lymphocytes were infiltrated diffusely around S
      100 DCs. It was demonstrated that the infiltration of CD8 positive lymphocytes
      predominated in the fibrosing areas and lymphoid follicles around S-100 DCs more
      so than CD4 positive lymphocytes.We speculate that the pathogenesis of NSIP is
      different from UIP and that DC and T cell-mediated immune mechanisms may play a
      role in the development and perpetuation of NSIP.

PMID- 12412976
TI  - Noninvasive positive pressure home ventilation in restrictive disorders: outcome
      and impact on health-related quality of life.
AB  - Noninvasive positive-pressure home ventilation (NIPPHV) improves arterial blood
      gases, dyspnea and health-related quality of life (HRQL) in patients with
      restrictive thoracic diseases. Whether these changes persist during the follow-up
      remains unclear. The aim of this study was to investigate the long-term effects
      of NIPPHV upon dyspnea, HRQL, lung function and hospitalization rate in 35
      patients with kyphoscoliosis and 27 individuals with several neuromuscular
      disorders. So, we measured dyspnea, HRQL, lung function and nocturnal oxygen
      saturation (SaO2) before and after 3, 6, 9, 12 and 18 months after NIPPHV.
      Dyspnea was assessed with the Borg scale and HRQL was measured using the Spanish
      validated version of the SF-36 questionnaire. The kyphoscoliosis group showed
      significant improvement of PaCO2 and SaO2 at 3 months and minor dyspnea changes
      at 6 months after NIPPHV had been started. These patients also showed improved
      health status in the following categories: "physical role" and "emotional role"
      at 3 months and in the categories "social functioning", "vitality" and "mental
      health" at 6 months after NIPPHV; some of these changes persisted at 9, 12 and 18
      months. In the neuromuscular group, a significant improvement of SaO2 was
      observed at 3 months and this persisted for 18 months. Changes of HRQL in this
      group included a significant improvement in "physical role" at 3 months,
      "emotional role" and "social functioning" at 6 months and "physical functioning"
      at 9 months. The hospitalization rate decreased significantly in all patients
      from a mean annual admission rate of 1.1 (1.4) before NIPPHV to 0.6 (1.1) after
      12 months of ventilatory support (P<0.005). We conclude that: (a) NIPPHV had a
      higher impact on arterial blood gases, dyspnea and health-related quality of life
      in patients with kyphoscoliosis than in those with neuromuscular disorders; (b)
      most clinical and functional changes persisted at long term and (c) a significant
      decrease in the hospitalization rate after NIPPHV occurred in both groups.

PMID- 12412977
TI  - A new HFA-134a propellant in the administration of inhaled BDP via the Jet
      spacer: controlled clinical trial vs the conventional CFC.
AB  - This study was carried out with the aim of demonstrating the efficacy and
      tolerability of beclomethasone dipropionate (BDP) aerosol spray 500 microg b.i.d.
      via a spacer device (Jet, Chiesi Farmaceutici S.p.A.) using a new HFA-134a
      formulation or chlorofluorocarbon (CFC) propellant. After having completed a 2
      week run-in period, 154 adult patients (77 in each group) with mild-to-moderate
      persistent asthma were randomised into two groups to receive the study treatment
      for a duration of 12 weeks in a double-blind, multinational, multicentre,
      parallel-group design. Morning and evening peak expiratory flow rate (PEFR), use
      of rescue salbutamol, number of day- and night-time asthma attacks, number of
      night-time awakenings due to asthma and clinical symptoms were recorded daily by
      patients on diary cards. Pulmonary function tests (FEV1, FVC, PEFR, FEF25-75%,
      MEF50 and FEF25) and vital signs were measured at the clinic at study entry, at
      the start of treatment and every 2 weeks thereafter. Morning serum cortisol (8.00
      10.00 a.m.) was measured at the start and at the end of the treatment period.
      Adverse events were recorded throughout the total study period. Significant
      improvements over baseline were reported in both groups in terms of lung
      function, symptoms and use of rescue inhaled salbutamol. Equivalence between
      groups was demonstrated for the primary end-point morning PEFR, as well as for
      evening PEFR and FEV1. No statistically significant differences in the
      comparisons between groups, except for FEF25 (P=0.044), were observed in any of
      the other efficacy variables. Adverse events were reported in 31% of patients in
      the BDP-HFA group and in 32% in the CFC group. Adverse drug reactions were 4 and
      2 in the two groups, respectively. No drug-related serious adverse events were
      reported in either of the groups. No signs of relevant adrenal suppression were
      observed in both groups: 2 patients in each group had final values below the
      normal range. In conclusion, the BDP-HFA-134a formulation proved to be equivalent
      in efficacy and comparable in safety to the standard BDP-CFC product over 12
      weeks in adult patients with mild-to-moderate persistent asthma.

PMID- 12412978
TI  - Acute effects of higher than customary doses of salmeterol and salbutamol in
      patients with acute exacerbation of COPD.
AB  - Worsening of underlying bronchospasm may be associated with acute exacerbations
      of chronic obstructive pulmonary disease (COPD). As airway obstruction becomes
      more severe, the therapeutic option is to add salbutamol, but not salmeterol, as
      needed to cause rapid relief of bronchospasm. Unfortunately the most effective
      dosage of beta2-agonists may increase above that recommended during acute
      exacerbations. In this study, we compared the acute effects of higher than
      customary doses of salmeterol and salbutamol in 20 patients with acute
      exacerbation of COPD. A dose-response curve to salmeterol pMDI, 25 microg/puff or
      salbutamol pMDI, 100 microg/puff, was constructed using 1, 1, and 2 puff' i.e., a
      total cumulative dose of 100 microg salmeterol or 400 microg salbutamol on 2
      consecutive days. After baseline measurements, dose increments were given at 30
      min intervals with measurements being made 25 min after each dose. Hear rate (HR)
      and pulse-oximetry (SpO2) measurements were then taken. Both salmeterol and
      salbutamol induced a larg and significant (P < 0.05) dose-dependent increase in
      FEV1 [mean differences from baseline (L) = after 100 microg salmeterol 0.174 (95%
      CI: 0.112 to 0.237); after 400 microg salbutamol: 0.165 (95% CI: 0.080 to
      0.249)], in IC [mean differences from baseline (L) = after 100 microg salmeterol:
      0.332 (95% CI: 0.165 to 0.499); after 400 microg salbutamol: 0.281 (95% CI: 0.107
      to 0.456)] (Fig. 2), and in FVC mean differences from baseline (L) = after 100
      microg salmeterol: 0.224 (95% CI: 0.117 to 0.331); after 400 microg salbutamol:
      0.242 (95% CI: 0.090 to 0.395)]. There was no significant difference between the
      FEV1 values (P=0.418), the ICvalues (P=0.585), and the FVCvalue (P=0.610) after
      100 microg salmeterol and 400 microg salbutamol. HR [mean differences from
      baseline (beats/min) = after 100 microg salmeterol: 3.15 (95% CI: -0.65 to 6.96);
      after 400 microg salbutamol: 2.30 (95% CI: -0.91 to 5.51)] and SpO2 [mean
      differences from baseline (%) = after 100 microg salmeterol: -0.20 (95% CI: -1.00
      to 0.60); after 400 microg salbutamol: -0.11 (95% CI: -1.00 to 0.79)] did not
      change significantly from baseline (P > 0.05). These data indicate that
      salmeterol is effective and safe in the treatment of acute exacerbation of COPD
      and support its use in this clinical condition.

PMID- 12412979
TI  - Gender differences in the impact of adolescent smoking on lung function and
      respiratory symptoms. the Nord-Trondelag Health Study, Norway, 1995-1997.
AB  - Girls take up smoking at least as frequently as boys. Few studies have focused on
      gender differences in the impact of adolescent smoking. We evaluated the sex
      specific effect of adolescent smoking on respiratory symptoms and lung function.
      All students in junior high and high schools in Nord-Trondelag County Norway,
      1995-97, were invited to participate in a cross-sectional study. Information on
      smoking habits and respiratory symptoms was obtained by self-administered
      questionnaires. Spirometry was performed in accordance with ATS standards. Eight
      thousand-three-hundred and five students (83%) completed both questionnaire and
      spirometry. Among 6811 students aged 13-18 years (50.3% girls) with no history of
      asthma, 2993 (43.9%) reported never smoking, 665 (98%) reported occasional
      smoking, and 667 (9.9%) reported daily smoking (mean initiation age: 13.9 years).
      More boys than girls were heavy smokers. In all smoking categories, smokers
      reported a higher prevalence of respiratory symptoms than nonsmokers; symptoms
      increased with smoke burden. Girls reported more symptoms compared to boys with
      comparable smoke burden. A dose-response relation between smoking and reduced
      lung function was found only in girls. Girls were more vulnerable than boys to
      the impact of smoking on respiratory symptoms and lung function.

PMID- 12412980
TI  - Cephalosporin-resistant pneumococcal pneumonia: does it, affect outcome?
AB  - STUDY OBJECTIVES: Penicillin resistance has been reported in various studies to
      have no impact on the outcome of pneumococcal pneumonia. However, the importance
      of cephalosporin resistance has not been systematically studied. We conducted an
      analysis of patients with high-level cephalosporin-resistant Streptococcus
      pneumoniae pneumonia (H-CRSPP). DESIGN: Retrospective matched, case-control
      study. SETTING: Two inner-city academic hospitals. PATIENTS: Twenty-six patients
      with H-CRSPP admitted to the hospital between 1995 and 1999 were identified. Each
      patient was matched with two controls with cephalosporin-sensitive but oxacillin
      resistant pneumococcal pneumonia admitted during the same time period. Matching
      was done based on pneumonia severity of illness index (PSI) and for other
      factors. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: We evaluated a number of
      outcomes including mortality length of stay in the hospital, and time to respond
      to treatment. Patients with H-CRSPP took longer to respond to treatment (6.5 +/-
      0.9 days vs 4.1 +/- 0.7 days, P=0.05) and had a longer length of stay in hospital
      (15.4 +/- 2.2 days vs 92 +/- 1.6 days, P=0.02). None of the other outcomes were
      different between the two groups. CONCLUSIONS: Overall, we have found that the
      presence of cephalosporin resistance does impact the course of pneumococcal
      pneumonia.

PMID- 12412981
TI  - Comparison of the distances covered during 3 and 6 min walking test.
AB  - AIMS: To determine the reproducibility of the distance covered in 3 min and its
      correlation with the 6 min walking test, as well as compare the distances covered
      at different time intervals. Secondly, to evaluate the relationship between the
      distances covered during these time periods and the maximum oxygen intake
      obtained during a bicycle ergometer test. METHODS: Forty-five Chronic Obstructive
      Pulmonary Disesase patients were included in the study. Subjects who were either
      physically limited or familiar with the test, or those with acute exacerbation in
      the month prior to the study, were excluded. Three walking tests were carried out
      each day. In 30 patients for three consecutive days, and the distances covered in
      periods of 3 and 6 min were measured with 20 min rest between each walk. No
      incentive was given and the patients knew that the distances covered in 3 and 6
      min would be quantified. Oxygen saturation, heart rate and degree of
      breathlessness (modified Borg scale) were registered at baseline. After 3 min,
      the distance covered and degree of breathlessness were also measured. After 6
      min, oxygen saturation, heart rate, degree of breathlessness and distance covered
      in meters were registered. Spirometry was performed daily on each patient, and
      those with an FEV1 variation of less than 10% were considered clinically and
      functionally stable. An exercise test using bicycle ergometer was carried out to
      determine maximum oxygen intake. A 3 min walking test was performed in 15
      patients, independently on the same day, which was followed after 20 min rest
      with a 6 min walking test. RESULTS: A significant increase was observed in the
      distance covered over 3 and 6 min in the first 5 walks, with the greatest
      increase seen in the first 3 walks. The correlation between the distance covered
      in 3 and 6 min was 0.98. The correlation between the distance covered in 3 min
      and oxygen intake was 0.64. No significant differences were observed between the
      distances covered in the 0-3 and 3 to 6 min periods. During the walking test,
      breathlessness was measured using the modified Borg scale, which was 1.8 after 3
      min, and 3.2 after six min and 8.6 at the end of bicycle ergometer test. No
      significant differences were observed between the distance covered during the 3
      minute test and the distance in the first 3 min of the 6 min walking test.
      CONCLUSIONS: A learning effect was observed when the walking test is carried out
      repeatedly over short time periods, with a significant increase in the first 5
      walks. Correlation between the distances covered in 3 and 6 min is very good, and
      acceptable when the distance covered over these periods is compared with oxygen
      intake and walking speed is constant.

PMID- 12412982
TI  - Vascular endothelial growth factor and proinflammatory cytokines in pleural
      effusions.
AB  - To evaluate the predictive value of vascular endothelial growth factor (VEGF) in
      the differential diagnosis of pleuritis and its association with other
      proinflammatory cytokines in pleural effusion, we measured VEGF together with
      interleukin-1beta (IL-1beta), tumor necrosis factor alpha (TNF-alpha) and soluble
      intercellular adhesion molecule-1 (sICAM-1) in pleural effusions. We investigated
      127 patients with pleural effusion (congestive heart failure: 21; parapneumonic:
      27; tuberculous: 41; malignant: 38). We examined standard parameters of pleural
      effusion and measured pleural effusion VEGF, IL-1beta, TNF-alpha and sICAM-1
      using enzyme-linked immunosorbent assay. VEGF level was significantly higher in
      malignant effusion than in other groups. TNF-alpha level was significantly higher
      in tuberculous pleurisy than in other groups. In tuberculous pleurisy VEGF level
      showed significant positive correlations with mononuclear cell counts and all
      investigated cytokines. The sensitivity and specificity of VEGF in the diagnosis
      of malignancy was 100 and 84%, respectively (cutoff = 2000 pg/ml). The
      sensitivity and specificity of VEGF and TNF-alpha in the diagnosis of tuberculous
      pleurisy (VEGF titer <2000 pg/ml and TNF-alpha titer > 55 pg/ml) was 88.9 and
      77.1%, respectively. We propose that measurement of VEGF together with TNF-alpha
      is helpful in differentiating between tuberculous pleurisy and malignant pleural
      effusion and that VEGF correlates with proinflammatory cytokines especially in
      tuberculous pleurisy. We also propose that measurement of pleural VEGF is helpful
      for the diagnosis of malignant pleural effusion.

PMID- 12412983
TI  - A pilot study examining the relationship between stress and serum cortisol
      concentrations in women with asthma.
AB  - The mechanism (s) by which stress exacerbates asthma is unknown. One explanation
      could be a reduction in endogenous serum cortisol concentrations as a result of
      stress. Our objective was to determine if a reduction in morning serum cortisol
      concentrations is associated with higher levels of stress in women with asthma.
      In this pilot study, seven women with a history of allergic-asthma were
      prospectively assigned to either low, moderate, or high stress groups based on a
      combination of their level of current stress and their resources to cope with the
      stress. After stress group assignment, women donated a morning blood sample,
      which was analyzed for serum cortisol concentration by an independent laboratory
      whose personnel were blinded to the subjects' stress status. Three women were
      assigned to the low stress group, two to the moderate stress group and two to the
      high stress group. Serum cortisol concentrations ranged from 8 to 23 microg/dl,
      averaging 14 +/- 6 microg/dl. A Spearman rank correlation indicated that serum
      cortisol concentrations were significantly inversely related to the stress
      groupings (r(s) = -0.915; P = 0.025). These results suggest that a reduction in
      morning serum cortisol concentration may be associated with higher levels of
      stress and lower resources to cope with the stress in women with allergic-asthma.

PMID- 12412984
TI  - Serum levels of tumor necrosis factor-alpha (TNF-alpha), interleukin 6 (IL-6),
      and their soluble receptors in coal workers' pneumoconiosis.
AB  - The aim of this study was to investigate whether systemic tumor necrosis factor
      alpha (TNF-alpha), soluble TNF-alpha receptors (p55, p75), interleukin 6 (IL-6),
      and soluble IL-6 receptor could be markers of biological activities of coal
      workers' pneumoconiosis (CWP). The study population was composed of 182 Chinese
      retired coal miners who had similar dust exposure histories. Among them, 71 were
      cases with CWP and 111 were controls. Chest radiographs were classified according
      to International Labour Organization Criteria (ILO, 1980). Individual dust
      exposure variables were estimated from work histories, and smoking information
      was obtained from interviews. Serum concentrations of TNF-alpha, TNF-alpha
      receptors (p55, p75), IL-6, and IL-6 receptor were measured by ELISA techniques.
      Mean serum levels of p55, p75 and IL-6 were significantly higher in cases than in
      controls (P < or = 0.01 for each comparison by crude analyses). Results from
      logistic regression models, adjusted for age, dust exposure variables, and
      smoking habits, found similar associations between soluble p55 and p75 levels and
      the presence of CWP. Linear regression analysis revealed that CWP radiographic
      stage (by ILO criteria) was significantly correlated with the individual serum
      concentrations of p55, p75 and IL-6. Serum concentrations of all measured
      cytokines were notcorrelated to age, dust exposure, or smoking, but there were
      correlations between soluble p75 and p55 levels, and between p75 and IL-6 levels.
      The results of this study suggest that serum levels of TNF receptors and IL-6 are
      associated with the fibrotic process of CWP and serum cytokine levels may be
      correlated with the severity of CWP.

PMID- 12412985
TI  - Barriers in the management of asthma and attitudes towards complementary
      medicine.
AB  - BACKGROUND: Undertreatment is said to be an important problem for those with
      asthma. Misconceptions regarding the nature and treatment of asthma may
      contribute to this. This study was planned to evaluate the perception of those
      with asthma about various aspects of their condition. METHODS: A total of 1012
      patients with asthma volunteered to complete the questionnaire. Questions
      included those regarding severity, nature, regularity of use of medicine and
      attitudes towards trying complementary medicine. Forced expiratory volume in 1 s
      (FEV1) was measured to assess the severity of airway obstruction. RESULTS: Only
      9% of patients took treatment for asthma according to the advice of the doctor.
      The remainder reported stopping treatment when they became free of symptoms or
      were able to tolerate their symptoms. A majority of the patients had moderately
      severe airway obstruction as determined by spirometer and reported being unable
      to assess the severity of their disease with only 11.9% reporting that they could
      perceive the warning symptoms of an acute attack. Seventy-nine percent of the
      patients had used complementary medicine. Home remedies, such as tea, hot water,
      walking, ginger and turmeric, were perceived to provide relief in asthma.
      CONCLUSION: Patients with asthma have many barriers in the way of optimal
      treatment. These include a failure to recognize warning symptoms, belief in a
      permanent cure; not continuing treatment for as long as needed; and, an
      inclination to seek complimentary medicines.

PMID- 12412986
TI  - Chronic obstructive pulmonary disease hospital admissions: comparing East with
      West.

PMID- 12412987
TI  - Cattle TB crisis--cause and cure, and further risk to human health.

PMID- 12412988
TI  - Unilateral multiple mottling of the lung in an asymptomatic patient.

PMID- 12412989
TI  - Treatment of primary pulmonary hypertension.

PMID- 12412990
TI  - Hot spring bath as the reservoir of Legionella bacterium.

PMID- 12412991
TI  - Fulminant Guillain-Barre syndrome after Campylobacter jejuni enteritis and anti
      ganglioside antibody.

PMID- 12412992
TI  - Genetic disorders affecting proteins of iron and copper metabolism: clinical
      implications.
AB  - Iron and copper are essential transition metals that permit the facile transfer
      of electrons in a series of critical biochemical pathways. Recent work has
      identified the specific proteins involved in the absorption, transport,
      utilization, and storage of iron and copper. Remarkable progress is being made in
      understanding the molecular basis of disorders of human iron and copper
      metabolism. This review describes these proteins and examines the clinical
      consequences of new insights into the pathophysiology of genetic abnormalities
      affecting iron and copper metabolisms. Hereditary hemochromatosis is the most
      common genetic disorder of iron metabolism caused by mutations in the HFE gene.
      Aceruloplasminemia is a rare iron metabolic disorder that results from deficiency
      of ceruloplasmin ferroxidase activity as a consequence of mutations in the
      ceruloplasmin gene. Menkes disease and Wilson's disease are inherited disorders
      of copper metabolism resulting from the absence or dysfunction of homologous
      copper-transporting ATPases.

PMID- 12412993
TI  - Translational study in cancer research.
AB  - Recent progress in molecular biology has led to the identification of numerous
      molecular targets of cancer chemotherapy, and the strategies for new drug
      discovery have concentrated on target-based screening. In the development of
      target-based drugs, translational research is considered to be essential. In this
      review, the definition of translational research is clearly explained, and the
      points of misunderstanding of Japanese researchers are discussed and resolved.
      The primary goal of translational research is to integrate the advanced
      informations of molecular biology in moving forward from phase I and II trials to
      phase III trials of target-based drugs.

PMID- 12412994
TI  - Improvement of alanine aminotransferase by administration of suplatast tosilate
      plus ursodeoxycholic acid in patients with resistance to ursodeoxycholic acid
      monotherapy on hepatitis C virus-related chronic liver disease.
AB  - OBJECTIVE: Inflammatory liver damage and viral persistence after hepatitis C
      virus (HCV) infection are known to be related in host immunity. Suplatast
      tosilate is an immunomodulator that selectively inhibits type 2 cytokine
      production by helper T cells. We investigated the efficacy and safety of the
      administration of suplatast tosilate for patients with HCV infection by examining
      the level of serum alanine aminotransferase (ALT) and viremia. PATIENTS AND
      METHODS: Thirty-eight patients who had shown resistance to ursodeoxycholic acid
      (UDCA) therapy (600 mg/day tid) over 6 months for HCV-related chronic liver
      disease were randomized into two groups and received UDCA alone (600 mg/day tid)
      or UDCA (600 mg/day tid) plus suplatast tosilate (300 mg/day tid) by means of
      sealed envelopes. RESULTS: After 24 weeks, serum ALT was decreased in the
      patients receiving UDCA plus suplatast tosilate, with the mean reduction being
      40.2% (from 132 to 79 IU/l; p=0.001). In the patients receiving UDCA alone, ALT
      decreased by 8.3% (from 133 to 122 IU/l; ns). Multiple comparison of individual
      ALT changes showed that the UDCA plus suplatast tosilate achieved significantly
      greater improvement (p = 0.001). However, serum HCV RNA was unchanged in both
      groups. Two patients developed adverse reactions to suplatast tosilate, which
      resolved promptly after the discontinuation of the therapy. CONCLUSION: These
      findings suggest that suplatast tosilate promotes biochemical improvement in the
      patients with chronic hepatitis C.

PMID- 12412995
TI  - A new serum antibody test kit (E plate) for evaluation of Helicobacter pylori
      eradication.
AB  - OBJECTIVE: Serological antibody test have been widely performed to detect the
      presence of H. pylori, but they have not been used to evaluate the status of H.
      pylori after eradication. In this study we evaluated the diagnostic accuracy of a
      new serological test kit (E-plate) after eradication. METHOD: Eradication of H.
      pylori was performed in 100 patients by proton pump inhibitor (PPI)+amoxicillin
      (AMPC)+clarithromycin (CAM) or PPI+AMPC therapy. Evaluation of H. pylori was done
      by culture, histology and rapid urease test before, and 8 weeks after, the
      treatment. Serological tests were also performed before and after treatment using
      the E plate. Cure was defined as no evidence of H. pylori at 8 weeks after the
      treatment. Receiver operating characteristic (ROC) analysis was performed to
      determine the ideal cut-off value for percentage change in the serological test.
      RESULT: Success was obtained in 73 patients, failure in 20 patients and there
      were 7 dropouts. Serological test value was significantly decreased after
      treatment (44.3 +/- 29.6 U/ ml) compared to before treatment (94.8 +/- 73.2 U/ml)
      in the successful cases. In contrast, those with no significant change after
      treatment (62.7 +/- 31.3 U/ml) compared to before treatment (72.9 +/- 47.7 U/ml)
      were considered as failure cases. ROC analysis revealed that cut-off values of a
      20%, 30%, and 40% decrease on E plate result yielded a sensitivity of 95.5%,
      92.4%, 71.2% and a specificity of 73.3%, 84.2%, 94.7%, respectively. CONCLUSION:
      The new E plate serological test kit for H. pylori was useful for distinguishing
      success from failure 8 weeks after completion of eradication therapy for H.
      pylori.

PMID- 12412996
TI  - Effects and problems of continuous infusion of epoprostenol for patients with
      primary pulmonary hypertension.
AB  - OBJECTIVE: We examined the usefulness and the problems of epoprostenol (Epo)
      therapy in adult Japanese with primary pulmonary hypertension (PPH). SUBJECTS AND
      METHODS: In eleven cases with PPH, both acute and chronic effects, and clinical
      effects of Epo were assessed. RESULTS: In the acute challenge test (n = 6), Epo
      reduced both systemic and pulmonary vascular resistance and increased the cardiac
      output, but did not change the ratio of pulmonary to systemic vascular
      resistance, while the systemic and pulmonary blood pressure also did not change.
      In the chronic study (n = 9), Epo decreased the pulmonary blood pressure without
      changes in systemic blood pressure, and increased the cardiac output. Both
      systemic and pulmonary vascular resistance decreased with a decrease in the ratio
      of the pulmonary to systemic vascular resistance. The level of brain natriuretic
      peptide and atrial natriuretic peptide, NYHA functional class and 6-minute
      walking distance were improved by Epo therapy. In spite of Epo therapy, two
      patients did not improve and died. Another patient improved in terms of symptoms
      but then died suddenly from massive lung bleeding. Two patients who improved
      physically could not be discharged because of psychiatric problems. One patient
      underwent lung transplantation. Five out-patients have been continuing Epo
      therapy. CONCLUSION: We demonstrated that the chronic effect of Epo treatment is
      sufficient even at the dose used in our hospital. However, it was shown that
      there was resistance to this therapy in some of the cases and that we should pay
      attention to the severe adverse effects of Epo.

PMID- 12412997
TI  - Characteristic clinical findings of reversible left ventricular dysfunction.
AB  - OBJECTIVE: In this study, clinical findings were evaluated in 16 patients with
      reversible left ventricular dysfunction (RLVD) who showed a clinical picture
      similar to that of acute myocardial infarction, in addition to akinesis or
      dyskinesis of the left ventricular apex without showing any abnormalities in the
      coronary artery. RESULTS: The frequency of RLVD was markedly higher in women than
      in men in these 16 patients (men:women = 1:7). In addition, these patients showed
      ECG changes similar to those observed in ischemic heart diseases, such as ST
      elevation or depression, negative T waves and QT prolongation. However, the serum
      cardiac markers were only slightly increased, and no specific changes were
      detected by histological examinations of the heart muscle. CONCLUSION: These
      patients also showed a clinical picture similar to the stunned myocardium caused
      by myocardial ischemia. However, the frequency of RLVD was higher in women than
      in men compared to the frequency of other coronary artery diseases, and there was
      no severe stenosis in the coronary artery. Moreover, most of these patients
      showed negative results for the coronary spasm provocation test. Therefore, RLVD
      may be an atypical ischemic heart disease if it is caused by coronary
      arteriosclerosis. Since RLVD developed during the course of other diseases or
      under severe mental stress, autonomic nerves may be involved in the etiology of
      RLVD. Furthermore, 2 patients who received the coronary spasm provocation test
      during the acute phase showed positive results. Therefore, other factors that
      transiently increase the sensitivity of the coronary artery may also be involved
      in the etiology of RLVD.

PMID- 12412998
TI  - Effect of the angiotensin II receptor antagonist losartan on uric acid and
      oxypurine metabolism in healthy subjects.
AB  - OBJECTIVE: The acute effects of the angiotensin II receptor antagonist losartan
      on uric acid and oxypurine metabolism were evaluated. METHODS: Losartan (50 mg)
      was administered orally to 6 healthy males. Blood and urine samples for uric acid
      and oxypurine were collected before and up to 6 hours after losartan
      administration. The same examinations were performed later using enalapril (5
      mg). RESULTS: Losartan decreased the serum uric acid concentration (from 5.9 +/-
      0.9 to 5.2 +/- 1.0 mg/dl) and increased its fractional clearance, which reached a
      maximum after 2 hours, while enalapril did not. Losartan also induced an increase
      in the plasma concentration of hypoxanthine, peaking in the fourth hour, and a
      decrease in its urinary clearance, while the plasma xanthine concentration and
      its urinary clearance were unchanged. The extent of uric acid excretion was much
      greater than that of the oxypurines. CONCLUSIONS: Losartan, which has a high
      affinity for the urate/anion exchanger, has a transient uricosuric effect. Our
      data indicate that losartan induces a significant decrease in the urinary
      excretion of hypoxanthine without changes in xanthine.

PMID- 12412999
TI  - Effects of fluticasone propionate on bone mineral density in patients with
      persistent bronchial asthma.
AB  - OBJECTIVE: To evaluate osteoporosis in asthmatic patients. METHODS: Bone mineral
      density (BMD) was measured using three different methods, namely computed X-ray
      densitometry (CXD), digital image processing (DIP), and dual energy X-ray
      absorptiometry (DXA). The BMD data were standardized using the sex- and age
      matched mean value of BMD. PATIENTS: One hundred and twenty-eight patients with
      persistent asthma. RESULTS: The standardized BMD expressed as Z-score in
      asthmatic patients was significantly lower than the norm (Z-score -0.48 +/- 1.17,
      mean +/- SD). In patients who had been continuously treated with oral
      corticosteroids (OCS), the standardized BMD was significantly lower than that in
      patients treated without OCS. In addition, the standardized BMD in patients 60
      years and over (Z-score -0.71 +/- 1.10, mean +/- SD, n = 58) had decreased to a
      greater extent than the decrease seen in patients under 60 years (Z-score -0.30
      +/- 1.21, n=70). Moreover, BMD in these older patients decreased after a 6-month
      treatment protocol involving the use of an inhaled corticosteroid, fluticasone
      propionate (FP). During the 6 months, the treatment did not affect BMD in
      patients who were receiving FP for the first time. Although the BMD did not
      decrease in patients treated with FP without OCS, the BMD in patients treated
      with both FP and OCS decreased during the 6 months. CONCLUSION: These results
      indicate that the continuous administration of OCS in patients with severe
      persistent asthma, particularly in older patients, may affect BMD in the short
      term even at a low OCS dose.

PMID- 12413000
TI  - Cross-over comparison between respiratory muscle stretch gymnastics and
      inspiratory muscle training.
AB  - OBJECTIVES: To compare the effect of respiratory muscle stretch gymnastics
      (RMSG), proposed as a possible additional form of rehabilitation for patients
      with chronic obstructive pulmonary disease (COPD), with that of inspiratory
      muscle training (IMT). PATIENTS: Twelve naive outpatients with COPD at a
      university hospital. METHOD: The patients performed IMT (2 sessions of 10 minutes
      of training at 30% of PImax, daily) for 4 weeks and RMSG (3 sessions of 5 RMSG
      patterns 4 times each, daily) for 4 weeks, in randomized order, with a 4-week
      washout period between the two interventions. MEASUREMENTS AND RESULTS: PImax
      increased with IMT (mean 66.1 to 79.1 cmH2O), but not with RMSG (mean 66.0 to
      69.4 cmH2O). RMSG and IMT similarly increased maximum chest wall expansion. FRC
      was significantly decreased by 158 ml with RMSG, but not with IMT. There were no
      significant changes in VC, FEV1, or PEF nor in arterial blood gases with either
      form of rehabilitation. Six-minute walking distance was more significantly
      increased with RMSG (mean 383 to 430 m), than with IMT (mean 386 to 412 m).
      CONCLUSIONS: RMSG may have clinically significant benefits, which may be somewhat
      different from the benefits of IMT, in patients with COPD.

PMID- 12413002
TI  - Current perception threshold and sympathetic skin response in diabetic and
      alcoholic polyneuropathies.
AB  - OBJECTIVE: Correlation between current perception threshold and sympathetic skin
      response was investigated in patients with diabetic or alcoholic polyneuropathy.
      METHODS: Current perception threshold was measured using Neurometer CPT/C, and
      the sympathetic skin response was measured using Neuropack sigma. PATIENTS:
      Fourteen patients with diabetic polyneuropathy and 10 patients with alcoholic
      polyneuropathy were studied. RESULTS: There was a significant negative
      correlation between the current perception threshold to 5 Hz stimulation and the
      amplitude of sympathetic skin response. CONCLUSION: Since both current perception
      threshold to 5 Hz stimulation and sympathetic skin response are related to C
      fibers, these two are considered to be impaired concurrently in diabetic and
      alcoholic polyneuropathies.

PMID- 12413001
TI  - MCP-1 and MIP-1A gene polymorphisms in Japanese patients with sarcoidosis.
AB  - OBJECTIVES: Monocyte chemoattractant protein (MCP)-1 and macrophage inflammatory
      protein (MIP)-1alpha exhibit chemotactic activity toward macrophages/monocytes
      and induce the production of inflammatory cytokines affecting granuloma
      formation. Recently, a single nucleotide polymorphism (SNP) in the MCP-1 distal
      regulatory region and a dinucleotide repeat in the MIP-1A gene promoter region
      were identified. We investigated the relationships between the polymorphisms and
      susceptibility to sarcoidosis, clinical manifestations, and BALF findings of
      sarcoidosis. METHODS: The polymorphisms of the MCP-1 and MIP-1A genes in 118
      patients with sarcoidosis and 145 healthy control subjects were examined. The MCP
      1 polymorphism was genotyped by a PCR-restriction fragment length polymorphism
      method and the MIP-1A genotype was determined using PCR. RESULTS: No significant
      difference in the genotype distribution or in the allele frequency between the
      patients and control subjects was observed. We found no relationship between the
      polymorphisms and the serum ACE level, organ involvement, roentgenographic
      stages, or deterioration in chest radiographs during the follow-up. A significant
      difference in the absolute counts of AMs in BALF of 51 patients among the
      genotypes of the MCP-1 gene was found (p = 0.048). The AM counts in BALF of the
      G/A and G/G genotypes were significantly increased compared with that of the A/A
      genotype (p < 0.05). CONCLUSION: The polymorphisms of the MCP-1 and MIP-1A genes
      do not play a substantial role in genetic predisposition for sarcoidosis or in
      clinical manifestations of sarcoidosis in this Japanese population. The MCP-1 SNP
      might be related to the recruitment of monocytes/macrophages to the alveolar
      spaces in sarcoidosis.

PMID- 12413003
TI  - The 4,752 C/T polymorphism in the presenilin 1 gene increases the risk of
      Alzheimer's disease in apolipoprotein E4 carriers.
AB  - OBJECTIVE: We sought to establish an association between sporadic Alzheimer's
      disease (AD) and presenilin 1 (PSEN1) gene polymorphisms in the Japanese
      population. METHODS: A 5 kb fragment containing the putative promoter of the
      PSEN1 gene for randomly selected control subjects was subcloned into plasmid and
      sequenced to screen novel polymorphisms in this region. Patients and controls
      were genotyped for five polymorphic markers in the PSEN1 region. We then
      constructed haplotypes using the computer program HAPLO and compared the
      frequencies between cases and controls. SUBJECTS: A total of 189 AD cases (NINCDS
      ADRDA criteria) and 240 controls were studied. RESULTS: We discovered a novel
      polymorphism with high heterozygosity on -4,752 of the PSEN1 promoter region. A
      significant association was observed between the -4,752 C/T polymorphism and late
      onset AD. The odds ratio for AD associated with the CC vs non-CC genotype was
      1.59 (95% CI = 1.01-2.51), while that of epsilon 4 vs non-epsilon 4 in APOE gene
      was 4.41 (95% CI = 2.72-7.16). The C allele was associated with a further
      increase in the risk of AD in APOE epsilon 4 carriers. We found 12 major
      haplotypes using five polymorphisms. The distribution pattern was significantly
      different between cases and controls. CONCLUSION: The PSEN1 gene -4,752 C/T
      polymorphism modifies the risk for AD.

PMID- 12413004
TI  - Six-month follow-up of takotsubo cardiomyopathy with I-123-beta-metyl-iodophenyl
      pentadecanoic acid and I-123-meta-iodobenzyl-guanidine myocardial scintigraphy.
AB  - A 69-year-old man with a history of transient chest pain was diagnosed takotsubo
      cardiomyopathy. In I-123-beta-metyl-iodophenyl pentadecanoic acid myocardial
      scintigraphy, decreased uptake of apex was seen in the acute phase, and it
      recovered in 3 months. In I-123-meta-iodobenzyl-guanidine myocardial
      scintigraphy, decreased uptake of apex persisted for 6 months, and there was a
      discrepancy between apical and total washout rate in the acute phase and after 3
      months, which disappeared after 6 months. We speculate that the discrepancy of
      sympathetic innervation between the apical and basal region is the cause of the
      characteristic left ventricular apical akinesia of takotsubo cardiomyopathy.

PMID- 12413005
TI  - Cerebral hemorrhagic infarction after radiation for pituitary adenoma.
AB  - We report a case of cerebral hemorrhagic infarction after radiation for pituitary
      adenoma. A 55-year-old woman was hospitalized to check for aldosteronism, post
      operative pituitary function, and recurrence of thyroid cancer. She had short
      term memory disturbance beginning two months prior to admission. Brain MRI showed
      a T1 and T2 high intensity lesion of her left anterolateral thalamus. Brain MRA
      revealed a narrowing in her left middle cerebral artery. The abnormal brain
      lesion was diagnosed as cerebral hemorrhagic infarction. She had received
      radiation therapy for pituitary adenoma 20 years earlier. It was considered that
      her cerebral hemorrhagic infarction was caused by radiation therapy.

PMID- 12413006
TI  - An insulinoma for which secretin test and selective arterial calcium injection
      test were useful.
AB  - A 76-year-old woman suffered from somnolence while fasting for almost 2 years.
      Fasting plasma glucose (FPG) (40 mg/dl) and the immunoreactive insulin (IRI)
      level (8.8 microU/ml) were not compatible with Fajan's ratio or Turner's ratio
      observed in typical insulinoma. The secretin test showed no response to insulin
      secretion, suggesting the presence of insulinoma. Abdominal dynamic computed
      tomography (CT) revealed a 12-mm hypervascular lesion in the head of the
      pancreas. A selective arterial calcium infusion test (SACI) was performed, during
      which IRI in the hepatic venous blood was measured following selective
      intraarterial calcium infusion. An increase in IRI levels in the gastroduodenal
      and superior mesenteric arteries suggested the presence of a functional
      insulinoma in the head of the pancreas. Enucleation of the tumor improved FPG and
      IRI levels to 138 mg/dl and 3.8 microU/ml, respectively. After surgery, a
      secretin test showed a 5-fold increase in IRI levels, suggesting normal beta cell
      function. This case illustrates the value of the secretin test for the diagnosis
      of insulinoma and for the postoperative assessment of beta cell function. It
      further illustrates the value of the SACI for localizing an insulinoma.

PMID- 12413007
TI  - Diabetes mellitus associated with Klinefelter's syndrome: a case report and
      review in Japan.
AB  - We report a case of Klinefelter's syndrome in a 48-year-old man who had diabetes
      mellitus associated with severe insulin resistance. We diagnosed him with
      Klinefelter's syndrome from his atrophic testicles, primary hypogonadism in
      hormonal examination, and a chromosomal aberration of 47,XXY. He showed severe
      decreased insulin sensitivity in a hyper-insulinemic euglycemic clamp test. He
      had injected over 100 units of insulin per day, however, testosterone replacement
      and administration of pioglitazone improved his glycemic control, which resulted
      in a decrease of insulin dose to less than 50 units per day. Here, we discuss the
      characteristics of diabetes mellitus associated with Klinefelter's syndrome in
      Japanese patients including this case.

PMID- 12413008
TI  - Maturity-onset diabetes of the young resulting from a novel mutation in the HNF
      4alpha gene.
AB  - A 52-year-old woman with early-onset diabetes mellitus, severe diabetic
      retinopathy, and a family history of a dominant inheritance pattern was referred
      to our hospital. Direct sequencing revealed a novel mutation in the HNF-4alpha
      gene (R244Q). The position of the mutation in the amino-acid sequence of the gene
      is well conserved among species and transcriptional activity of the mutant gene
      was significantly reduced. Therefore, a diagnosis of maturity-onset diabetes of
      the young (MODY)-1 was made. Genetic testing enabled early diagnosis of diabetes
      in the patient's 20-year-old daughter, which we consider to be important for the
      prevention of diabetic complications.

PMID- 12413009
TI  - Antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis with
      intrarenal aneurysms and renal arteriovenous fistulaes.
AB  - A 78-year-old Japanese man was admitted with a complaint of slight fever and
      weight loss. At admission, he tested positive for myeloperoxidase (MPO)-ANCA and
      had renal failure. An abdominal angiography revealed atrophy of the right kidney,
      two or more arteriovenous fistulae (AVF) in the right renal interlobular
      arteries, and multiple aneurysms in both kidneys. A renal biopsy specimen showed
      diffuse crescentic glomerulonephritis accompanied by tubulo-interstitial changes.
      This case suggests the possibility of some relationship between ANCA-associated
      vasculitides and the formation of aneurysms and AVFs.

PMID- 12413010
TI  - Hot spring bath and Legionella pneumonia: an association confirmed by genomic
      identification.
AB  - A 59-year-old man developed pneumonia 9 days after bathing in a hot spring spa.
      Bilateral shadows on his chest radiograph rapidly progressed after admission. He
      was successfully treated with erythromycin and rifampicin. Legionella pneumophila
      serogroup 6 was recovered from an intratrachial specimen and a significant
      elevation was observed in a paired indirect fluorescent antibody to Legionella.
      Persistent slight fever and chest rentogenographic shadows resolved after
      administering low-dose prednisolone to treat organizing pneumonia shown by
      transbronchial lung biopsy. The same serotype of Legionella was recovered from
      the water of the hot spring spa where the man had bathed. When the extracted DNA
      of these two strains showed identical restriction fragments by pulsed-field gel
      electrophoresis, we had direct evidence that hot spring spas can be a source of
      Legionella pneumonia.

PMID- 12413011
TI  - Severe abdominal pain associated with allergic reaction to nafamostat mesilate in
      a chronic hemodialysis patient.
AB  - A 33-year-old woman was referred from an outside dialysis clinic to our hospital
      because of severe abdominal pain during hemodialysis. She had been on chronic
      hemodialysis for the past 11 years due to chronic glomerulonephritis. Nafamostat
      mesilate was used as an anticoagulant for hemodialysis, because it was during her
      menstrual period with hypermenorrhea. On admission, she had no abdominal pain or
      gynecological abnormalities. On the second day, she had similar abdominal pain
      during hemodialysis with nafamostat mesilate in our dialysis unit. The abdominal
      pain disappeared within 60 minutes after discontinuing the hemodialysis. We re
      started dialysis using heparin instead of nafamostat mesilate and she had no
      symptoms. The titer of total immunoglobulin E was high. The drug lymphocyte
      stimulation test was positive for nafamostat mesilate and antigen specific
      immunoglobulin E to nafamostat mesilate was highly positive in her blood.
      Although an allergic reaction to nafamostat mesilate is a rare complication, it
      should be one of the differential diagnoses of abdominal pain occurring during
      hemodialysis.

PMID- 12413012
TI  - Nonspecific interstitial pneumonia/fibrosis completely recovered by adding
      cyclophosphamide to corticosteroids.
AB  - Nonspecific interstitial pneumonia/fibrosis (NSIP) was first described by
      Katzenstein and Fiorelli in 1994 (Am J Surg Pathol 18: 136-147). Many reports
      have described that corticosteroids are effective for NSIP. We describe a case of
      group II idiopathic NSIP in whom cyclophosphamide was administered since the
      initial response to corticosteroids had been insufficient. Lung biopsy was
      performed by video-assisted thoracoscopic surgery and NSIP was diagnosed
      pathologically, clinically and radiologically. Although the initial response to
      corticosteroids was insufficient, interstitial infiltrates on chest computed
      tomography improved dramatically after adding intravenous cyclophosphamide
      followed by oral cyclophosphamide. This case demonstrates that the addition of
      cyclophosphamide to corticosteroids might be a useful treatment for patients with
      NSIP.

PMID- 12413013
TI  - Interleukin-6-producing thymic squamous cell carcinoma associated with
      Castleman's disease and nephrotic syndrome.
AB  - When a 63-year-old man was hospitalized with nephrotic syndrome due to focal
      segmental glomerulosclerosis, a mediastinal mass was discovered. A biopsy
      specimen obtained by mediastinoscopy showed findings compatible with the plasma
      cell type of Castleman's disease. Fever, anemia, and anti-nuclear antibody were
      present. Serum concentrations of gamma globulin, acute phase proteins, and, most
      strikingly, interleukin-6 (IL-6) were elevated. Methylprednisolone pulse therapy
      resulted in no clinical improvement. Pathologic examination of the resected
      thymic tumor showed a squamous cell carcinoma immunoreactive for IL-6. To our
      knowledge, this case represents the first reported IL-6-producing thymic squamous
      cell carcinoma associated with Castleman's disease and nephrotic syndrome.

PMID- 12413014
TI  - Intralobar pulmonary sequestration presenting increased serum CA19-9 and CA125.
AB  - A 39-year-old man was admitted to our hospital for further evaluation of a
      consolidated shadow and clarification of the cause of serum tumor marker
      elevation (CA19-9 496.2 U/ml, CA125 160.6 U/ml). Chest computed tomography
      revealed a well-defined homogeneous nodule in the left S(10). Angiography showed
      one aberrant artery, branching from the ascending aorta. Intralobar pulmonary
      sequestration was diagnosed and the sequestrated lung was resected. Microscopic
      findings of the sequestrated lung showed a mucus-containing cystically dilated
      bronchus, which was covered with ciliated cylindrical epithelium.
      Immunohistochemical staining showed positive staining for CA19-9 and CA125 in
      both the ciliated cylindrical epithelium and mucus. Serum values of tumor markers
      returned to their normal range after surgery.

PMID- 12413015
TI  - Pulmonary lymphangioleiomyomatosis; unusual radiological manifestation of
      multiple large nodules.
AB  - A 44-year-old woman was admitted to our hospital in August 1999 for multiple
      large nodules detected on chest roentgenogram in an annual health check. Chest CT
      scans showed bilateral large nodules (>10 mm in diameter) with irregular margins
      and multiple thin walled cystic lesions. From these radiologic examinations, we
      suspected pulmonary Langerhans cell histiocytosis. Histological examination of
      the biopsy specimen by video-assisted thoracoscopy revealed a marked
      proliferation of the spindle cells, which were immunologically positive for alpha
      smooth muscle actin and HMB-45, in the cyst walls and lung parenchyma. The large
      nodules consisted of proliferation of the smooth muscle cells surrounded by a
      dense layer of hemosiderinladen macrophages. During the two years subsequent to
      these 1999 examinations, the opacities have gradually diminished and the patient
      was found to have pulmonary lymphangioleiomyomatosis. This case exhibited rare
      radiologic manifestations of multiple large nodules mimicking Langerhans cell
      histiocytosis.

PMID- 12413016
TI  - Alpha-FP normalization as a prognostic factor for mediastinal origin embryonal
      carcinoma: report of five cases.
AB  - It is well known that a subgroup of germ cell tumors, embryonal carcinoma of
      extra-gonadal origin have a poor prognosis. We have encountered five cases of
      mediastinal embryonal carcinoma treated with high-dose chemotherapy (HD-CT)
      supported by auto-PBSCT in four, and resection in three. Our cases indicated that
      normalization of the alpha-FP tumor marker level during standard chemotherapy is
      a very important factor for cure, and the resection of the residual mass after
      chemotherapy is indicated due to the great risk of remnant malignant cells
      despite HD-CT.

PMID- 12413017
TI  - Fulminant Guillain-Barre syndrome after Campylobacter jejuni enteritis and
      monospecific anti-GT1a IgG antibody.
AB  - A 21-year-old man developed rapid progression of tetraplegia, bulbar palsy, and
      respiratory paralysis after Campylobacterjejuni enteritis. Based on the diagnosis
      of Guillain-Barre syndrome, he received plasmapheresis and intravenous
      immunoglobulin. Serum anti-GT1a IgG antibody which lacked cross-reactivity with
      GQ1b was detected. Four months after the onset, the patient still had severe
      muscle weakness of the lower limbs. This case suggests that anti-GT1a IgG
      antibody can be associated with severe paralysis in Guillain-Barre syndrome after
      C. jejuni enteritis.

PMID- 12413018
TI  - Polyarteritis associated with hypopharyngeal carcinoma.
AB  - A rare case of polyarteritis associated with a solid tumor is presented. A 66
      year-old man was referred to our hospital, because of gangrene in the bilateral
      fingers and toes, right pleural effusion, and an abnormal sensation in the
      throat. A diagnosis of polyarteritis was made based on pleuritis, digital
      gangrene and the arteriography findings. He also had a hypopharyngeal carcinoma.
      After being treated with intermittent intravenous cyclophosphamide, oral
      corticosteroid, alprostadil and aspirin, the pleural effusion rapidly
      disappeared, while the digital gangrene gradually improved. For the treatment of
      hypopharyngeal carcinoma, radiation therapy was initiated and resulted in
      complete disappearance.

PMID- 12413019
TI  - AIDS-related Pneumocystis carinii pneumonia with disappearance of cystic lesions
      after treatment.
AB  - A 21-year-old hemophiliac with human immunodeficiency virus (HIV) infection was
      admitted to our hospital because of bilateral pneumothoraces associated with
      Pneumocysis carinii pneumonia (PCP). He underwent chest tube drainages and
      intravenous pentamidine therapy, resulting in clinical improvement. Two months
      after treatment for PCP, cystic lesions that had existed before treatment
      disappeared on chest computed tomography. We concluded that Pneumocystis carinii
      infection might be associated with lung destruction and cyst formation, and that
      inflammatory exudates in the small bronchioles might act as a ball-valve with
      subsequent spontaneous pneumothoraces.

PMID- 12413020
TI  - A patient with acute-onset HAM/TSP after blood transfusion complicated with
      pseudopseudohypoparathyroidism.

PMID- 12413021
TI  - Acute poisoning from polychlorinated biphenyls released by the explosion of a
      capacitor in an electric light.

PMID- 12413022
TI  - Cerebral arterial air embolism associated with esophageal carcinoma.

PMID- 12413023
TI  - Lingual thyroid.

PMID- 12413024
TI  - Coronary intramural hematoma.

PMID- 12413025
TI  - RNAStudio, a full-featured object-oriented program for visualizing RNA secondary
      structures.
AB  - The function of a RNA molecule relies on the underlying physical mechanisms and
      geometric properties in terms of secondary or tertiary structure, in which one of
      the most important properties is topological connectivity. RNAStudio, available
      at http://rnastudio.51.net, brings the convenience of Windows to the
      representation of RNA folding topology including the sections mentioned below.

PMID- 12413026
TI  - The three-dimensional model of Dictyostelium discoideum racE based on the human
      rhoA-GDP crystal structure.
AB  - The three-dimensional structure of racE was modeled using several homologous
      small G proteins, and the best model obtained using the human rhoA as modeling
      template is reported. The three-dimensional fold of the racE model is remarkably
      similar to the cellular form of human ras p21 crystal structure. Its secondary
      structure consists of six alpha-helices, six beta-strands and three 3(10)
      helices. The model retains its secondary structure after a 300 K, 300 ps
      molecular dynamics (MD) simulation. Important domains of the protein include its
      effector loop (residues 34-46), the insertion domain (residues 121-136), and the
      polybasic motif (between 210 and 220) not modeled in the current structure. The
      effector loop is inherently flexible and the structure docked with GDP exhibits
      the effector loop moving significantly closer to the nucleotide binding pocket,
      forming a tighter complex with the bound GDP. The mobility of the effector loop
      is conferred by a single residue 'hinge' point at residue 34Asp, also allowing
      the Switch I region, immediately preceding the effector loop, to be equally
      mobile. In comparison, the Switch II region shows average mobility. The insertion
      domain is highly flexible, with the insertion taking the form of a helical
      domain, with several charged residues forming a complex charged interface over
      the entire insertion region. While the GDP moiety is loosely held in the active
      site, the metal cation is extensively co-ordinated. The critical residue 38Thr
      exhibits high mobility, and is seen interacting directly with the metal ion at a
      distance of 2.64 A, and indirectly via an intervening water molecule. 64Gln, a
      key residue involved in GTP hydrolysis in ras, is seen facing the beta-phosphate
      group and the metal ion. Certain residues (i.e. 51Asn, 38Thr and 65Glu) exhibit
      unique characteristics and these residues, together with 158Val, may play
      important roles in the maintenance of the protein's integrity and function. There
      is strong consensus of secondary structural elements between models generated
      using various templates, such as h-rac1, h-rhoA and h-cdc42 bound to RhoGDI, all
      sharing only 50-55% sequence identity with racE, which suggests that this model
      is in all probability an accurate prediction of the true tertiary structure of
      racE.

PMID- 12413027
TI  - Motion of an antiviral compound in a rhinovirus capsid under rotational symmetry
      boundary conditions.
AB  - A molecular dynamics (MD) simulation of a complex of a rhinovirus protein shell
      referred to as a "capsid" and an anti-rhinovirus drug, WIN52084s, was performed
      under the rotational symmetry boundary conditions. For the simulation, the energy
      parameters of WIN52084s in all-atom approximations were determined by ab initio
      calculations using a 6-31G* basis set and the two-conformational two-stage
      restricted electrostatic potential fit method. The motion of WIN52084s and the
      capsid was focused on in the analysis of the trajectory of the simulation. The
      root mean square deviations of WIN52084s from the X-ray structure were decomposed
      to conformational, translational, and rotational components. The translation was
      further decomposed to radial, longitudinal, and lateral components. The
      conformation of WIN52084s was rigid, but moving in the pocket. The easiest path
      of motion for WlN52084s was on the longitudinal line, providing a track for the
      binding process required of the anti-rhinovirus drug to enter the pocket. The
      conformation of the pocket was also preserved in the simulation, although the
      position of the pocket in the capsid fluctuated in the lateral and radial
      directions.

PMID- 12413028
TI  - QSAR studies of the pyrethroid insecticides. Part 3. A putative pharmacophore
      derived using methodology based on molecular dynamics and hierarchical cluster
      analysis.
AB  - Previous studies of the conformational behaviour of a group of synthetic
      pyrethroid insecticides have been extended to a more structurally diverse set.
      This includes compounds with different backbones and differing stereochemistry,
      with both Types I and II biological activity. These compounds also encompass a
      large range of biological activities. A parameterisation of the CHARMM force
      field for these compounds has been performed and the extra parameters are
      reported. Conformational sampling, using molecular dynamics (MD), has been
      performed for each of the 41 active structures. The accessible conformations of
      each have been characterised by the values of the common torsion angles using
      hierarchichal cluster analysis (HCA). A further CA, based on the centroids
      derived from the conformational sampling, identified a conformation common to at
      least 39 of the 41 structures. The critical torsion angles of this conformation
      lie at the centre of the molecule about the ester linkage and are defining an
      extended conformation, which differs from the minimum energy conformation of
      deltamethrin used previously. This may represent a putative pharmacophore for
      kill. The methods used here improve significantly on those used previously. The
      CHARMM force field was parameterised for the compounds and an improved method of
      conformational sampling, based on centroid clustering, has also been used.

PMID- 12413029
TI  - Molecular modeling and QSAR studies on K(ATP) channel openers of the benzopyran
      type.
AB  - The present paper describes our molecular modeling and quantitative structure
      activity relationships (QSARs) studies on K(ATP) channel openers (KCOs) of the
      benzopyran type. In the first part we performed molecular modeling investigations
      with seven benzopyrans, varied at the C3- and C4-positions, in order to
      understand which molecular features at these positions are essentially effecting
      the biological activity. The impact of C6-substitution on biological activity was
      studied in the second part via HANSCH analysis. For this purpose physicochemical
      properties (charge distributions, lowest unoccupied molecular orbital (LUMO)
      energies, desolvation energies, volumes and dipole moments) were calculated for a
      set of 50 C6-varied benzopyrans. A QSAR equation was developed showing a
      relationship between the vasodilator activity and the direction of the dipole
      vector of the ligands. The conclusion can be drawn that a direct interaction
      between the C6-substituents and the receptor structure is not of primary
      importance. However, the substitutents influence the orientation of the whole
      ligand approaching the binding site. An unfavorably oriented ligand cannot bind
      to the binding site, thus exhibiting weak activity.

PMID- 12413030
TI  - VEGA: a versatile program to convert, handle and visualize molecular structure on
      Windows-based PCs.
AB  - We here propose the program VEGA, that was developed to create a bridge between
      the most popular molecular software packages. In this tool some features are
      implemented some features to analyze, display and manage the three dimensional
      (3D) structure of the molecules. The most important features are (1) file format
      conversion (with assignment of the atom types and atomic charges), (2) surface
      calculation and (3) trajectory analysis. The executable and the source code can
      be free downloaded from [URL: see text].

PMID- 12413031
TI  - Modeling through-space magnetic shielding over ethynyl, cyano, and nitro groups.
AB  - In a strong magnetic field, covalently bonded hydrogen nuclei located over a pi
      bonded functional group experience magnetic shielding (or deshielding) that
      results from the combined effect of the magnetic anisotropy of the pi bond and
      various other intramolecular shielding effects. Gauge including atomic orbital
      (GIAO)-HF in Gaussian 98 was employed to calculate isotropic shielding values and
      to predict the net through-space proton NMR shielding increment for a simple
      model system: the proximate proton of methane held in various positions over
      simple molecules that contain a carbon-carbon triple bond, a carbon-nitrogen
      triple bond, or a nitro group. These net shielding increments of the proximate
      proton of methane, plotted against their Cartesian coordinates, led to the
      development of a single empirical equation for predicting the NMR shielding
      experienced by a covalently bonded proton over each group. The predictive
      capability of each equation has been validated by calculating shielding
      increments of protons over the functional group in known structures. These
      shielding increments are then used to adjust predicted chemical shifts for
      through-space shielding effects, and the adjusted values are compared to
      experimentally observed chemical shifts. The algorithms for predicting the
      shielding increment for a proton over these functional groups can be used in a
      spreadsheet or incorporated into software that estimates chemical shifts using
      additive substituent constants or a database of structures. Their use can
      substantially improve the accuracy of the estimated chemical shift of a proton in
      the vicinity of these functional groups, and thus assist in spectral assignments
      and in correct structure determination.

PMID- 12413032
TI  - A semiempirical study on the electronic structure of 10-deacetylbaccatin-III.
AB  - We performed a conformational and electronic analysis for 10-deacetylbaccatin-III
      (DBAC) using well-known semiempirical methods (parametric method 3 (PM3) and
      Zerner's intermediate neglect of differential overlap (ZINDO)) coupled to the
      concepts of total and local density of states (LDOS). Our results indicate that
      regions presented by paclitaxel (Taxol) as important for the biological activity
      can be traced out by the electronic features present in DBAC. These molecules
      differ only by a phenylisoserine side chain. Compared to paclitaxel, DBAC has a
      simpler structure in terms of molecular size and number of degrees of freedom
      (d.f.). This makes DBAC a good candidate for a preliminary investigation of the
      taxoid family. Our results question the importance of the oxetane group, which
      seems to be consistent with recent experimental data.

PMID- 12413033
TI  - A simple method for visualizing the differences between related receptor sites.
AB  - Pastor and Cruciani [J. Med. Chem. 38 (1995) 4637] and Kastenholz et al. [J. Med.
      Chem. 43 (2000) 3033] pioneered methods for comparing related receptors, with the
      ultimate goal of designing selective ligands. Such methods start with a
      reasonable superposition of high-resolution three-dimensional (3D) structures of
      the receptors. Next, molecular field maps are calculated for each receptor. Then
      the maps are analyzed to determine which map features are correlated with a
      particular subset of receptors. We present a method FLOGTV, based on the trend
      vector paradigm [J. Chem. Inf. Comput. Sci. 25 (1985) 64] to perform the
      analysis. This is mathematically simpler than the GRID/CPCA method of Kastenholz
      et al. and allows for the simultaneous comparison of many receptor structures.
      Also, the trend vector paradigm provides a method of selecting isopotential
      contours that are well above "noise". We demonstrate the method on four examples:
      HIV proteases versus two-domain acid proteases, thrombin versus trypsin and
      factor Xa, bacterial dihydrofolate reductases (DHFRs) versus vertebrate DHFRs,
      and P38 versus ERK protein kinases.

PMID- 12413034
TI  - 2002 Refshauge Lecture. When to retire after concussion?
AB  - The management of an athlete with recurrent concussions, whether persistently
      symptomatic or not, remains anecdotal. There are no evidence-based guidelines
      upon which a team physician can advise the athlete. All doctors involved in
      athlete care need to be aware of the potential for medicolegal problems if
      athletes are inappropriately returned to sport prematurely or in the case of
      professional athletes held out of sport or retired on the basis of non-scientific
      recommendations.

PMID- 12413035
TI  - Body mass changes and voluntary fluid intakes of elite level water polo players
      and swimmers.
AB  - Calculated sweat rates (measured by body mass changes) and voluntary fluid
      intakes were monitored in elite level water polo players and swimmers during
      normal exercise sessions to determine fluid requirements to maintain fluid
      balance, and the degree of fluid replacement of these athletes. Data were
      collected from training and competition sessions for male water polo players (n =
      23) and training sessions only for swimmers (n = 20 females; n = 21 males). The
      calculated average sweat rate and fluid intake rate during training sessions for
      male water polo players was 287 ml/h and 142 ml/h, respectively, with a rate of
      786 ml/h and 380 ml/h during matches. During training sessions for male swimmers,
      the calculated average sweat rate and fluid intake rate per kilometre was 138
      ml/km and 155 ml/km, respectively; and for female swimmers, 107 ml/km and 95
      ml/km. There was a wide individual variation in fluid intake and sweat loss of
      both water polo players and swimmers. Dehydration experienced by athletes in this
      study was less than typically reported for "land-based" athletes. Errors inherent
      in the technique used in this study are acknowledged and may be significant in
      the calculation of reported sweat losses and levels of fluid balance in aquatic
      athletes.

PMID- 12413036
TI  - The relationships between aerobic fitness, power maintenance and oxygen
      consumption during intense intermittent exercise.
AB  - This study examined the relationships between VO2max, power maintenance and
      oxygen consumption during intense intermittent work. Female recreational soccer
      players were assigned to either a low aerobic power group (LOW, n = 6, mean (SD)
      VO2max = 34.4 (2.4) mL.kg(-1)min(-1) or to a moderate aerobic power group (MOD, n
      = 7, VO2max = 47.6 (3.8) mL.kg(-1).min(-1)). VO2 was measured while subjects
      performed 10 6-s all-out sprints (30-s passive recovery) on a Monark cycle
      ergometer. LOW and MOD subjects generated similar peak 6-s power (p = .58) but
      MOD had a smaller decrement in power (% DO) over the 10 sprints (LOW vs MOD: 18.0
      (7.6) vs 8.8 (3.7) % DO, p = .02). The MOD group also consumed significantly more
      oxygen than LOW in 9 of the 10 sprint-recovery cycles (p < .05). Significant
      relationships were seen between VO2max and the aerobic response to the sprint
      recovery series (r = .78, p =.002) as well as between VO2max and % DO (r = -.65,
      p = .02), while a non-significant relationship was seen between the oxygen
      consumed during the sprint-recovery cycles and % DO (r = -.41, p = .16). Thus,
      VO2max appears to be related to both an increased aerobic contribution to sprint
      recovery bouts and the enhanced ability of the MOD group to resist fatigue during
      intense intermittent exercise.

PMID- 12413037
TI  - Is recovery from muscle damage retarded by a subsequent bout of eccentric
      exercise inducing larger decreases in force?
AB  - The aim of this study was to investigate whether a subsequent bout of eccentric
      exercise inducing larger decreases in force than the initial bout would
      exacerbate muscle damage and retard recovery. Changes in indirect markers of
      muscle damage were measured over 14 days when 24 maximal eccentric actions of the
      elbow flexors were performed on days 1 (ECC1) and 7 (ECC2], with electrical
      stimulation superimposed percutaneously to the elbow flexors during maximal
      eccentric actions in ECC2. Maximal isometric force (MIF), range of motion (ROM),
      upper arm circumference, muscle soreness, B-mode ultrasound, and several muscle
      proteins in the blood were assessed before, immediately after and for 5 days
      after both bouts. Magnetic resonance Imaging (MRI) was assessed 4 days after both
      bouts. MIF decreased to 45% of the pre-exercise value immediately after ECC 1 and
      recovered to 59% by day 7 post-exercise. MIF decreased to 22% of pre-ECC1 value
      immediately after ECC2, but recovered to 105% of pre-ECC2 value 5 days following
      ECC2. Recovery of MIF and ROM was slightly retarded for 1-2 days after ECC2.
      However circumference, muscle soreness, and biochemical parameters did not
      increase following ECC2. There were no signs of additional damage in ultrasound
      and MRI after ECC2. It was concluded that a second bout of maximal eccentric
      exercise with electrical stimulation slightly retarded recovery of muscle
      function with minimal muscle damage.

PMID- 12413038
TI  - Continuous versus intermittent exercise effects on urinary excretion of albumin
      and total protein.
AB  - Several studies have reported post-exercise increases of urinary concentrations
      of plasma proteins. However, under normal conditions, through mechanisms of size
      and electrical charge selection, the kidney restricts the clearance of molecules
      as large as albumin. Post-exercise increases in albuminuria occur following the
      physiological stress of intense exercise, most likely as a result of the exercise
      induced blood acidity changes which lead to a change in the arrangement of the
      albumin molecule, and subsequently the filtration characteristics of the
      glomerular capillary wall. The purpose of the present study was therefore to
      determine the extent to which different types of exercise could induce a
      transient condition of post-exercise increases in the urinary output of total
      protein and albumin. All 14 males, who agreed to participate in the study,
      performed a continuous and an intermittent cycling protocol on a stationary
      bicycle ergometer. The results showed that: a) intermittent exercise had a
      greater influence than continuous exercise on the total output of urine albumin,
      and of urine total protein; b) concentrations of blood pH and blood lactate, were
      associated with changes in the clearance of urine albumin and urine total
      protein. Post-exercise proteinuria response seems to be transient and therefore
      renal trauma is not suspected at the early stages of observation. Furthermore,
      these results indicate that the kidney undergoes distinct physiological
      adjustments during exercise, and that these adjustments are relative to the
      intensity of the exercise stress.

PMID- 12413039
TI  - A comparison of peak power in the shoulder press and shoulder throw.
AB  - The ability to generate peak power is central for performance in many sports.
      Currently two distinct resistance training methods are used to develop peak
      power, the heavy weight/slow velocity and light weight/fast velocity regimes.
      When using the light weight/fast velocity power training method it was proposed
      that peak power would be greater in a shoulder throw exercise compared with a
      normal shoulder press. Nine males performed three lifts in the shoulder press and
      shoulder throw at 30% and 40% of their one repetition maximum (1RM). These lifts
      were performed identically, except for the release of the bar in the throw
      condition. A potentiometer attached to the bar measured displacement and duration
      of the lifts. The time of bar release in the shoulder throw was determined with a
      pressure switch. ANOVA was used to examine statistically significant differences
      where the level of acceptance was set at p < 0.05. Peak power was found to be
      significantly greater in the shoulder throw at 30% of 1 RM condition [F, (1, 23)
      = 2.325 p < 0.051 and at 40% of 1 RM [F, (1, 23) = 2.905 p < 0.05] compared to
      values recorded for the respective shoulder presses. Peak power was also greater
      in the 30% of 1 RM shoulder throw (510 +/- 103W) than in the 40% of 1 RM shoulder
      press (471 +/- 96W). Peak power was produced significantly later in the shoulder
      throw versus the shoulder press. This differing power reflected a greater bar
      velocity of the shoulder throw at both assigned weights compared with the
      shoulder press.

PMID- 12413040
TI  - Differences in physiological test results and cross country skiing race
      performance of a pair of identical twins.

PMID- 12413041
TI  - The research agenda.

PMID- 12413042
TI  - Fundamental movement skills--how do primary school children perform? The 'Move it
      Groove it' program in rural Australia.
AB  - Child Fundamental Movement Skills (FMS) underpin active lifestyles yet little is
      known of their distribution and mastery. 'Move it Groove it' project rated
      proficiency of primary school children (n = 1045, 18 schools) in skills of
      balance, throw, catch, sprint, hop, kick, side gallop and jump. Rating categories
      were 'mastery', 'near mastery' or 'poor' (ie mastered all, all but one, or less
      of the five to six components of an FMS). Less than half of all child tests were
      rated at mastery (21.3%) or near mastery (25.7%) level. In grade three, 75.4% of
      children achieved mastery or near mastery (MNM) in static balance but less than
      half did so for any other FMS. In grade four, 59.0% achieved MNM in the side
      gallop and 56.0% in the catch but less than half did so for any other FMS.
      Although the highest percent mastery for both genders was for the balance, the
      skills best performed thereafter by boys (throw and kick) rated poorest for
      girls. Conversely the hop and side gallop which rated, after balance, as the
      skills best mastered by girls, were among the more poorly performed skills for
      boys. The low prevalence of FMS mastery found in this survey suggests that there
      may be great potential to improve fundamental movement skills of primary aged
      children in many parts of rural Australia. Even if the aim were for children to
      achieve near mastery levels, the improvement could be substantial in every skill
      category. Where appropriate, gender differences in mastery might easily be
      addressed by tailored physical education programs and modification of social and
      physical environments.

PMID- 12413043
TI  - How active are rural children in Australian physical education?
AB  - Physical education lessons offer a venue for children to accrue valuable and
      health-conferring time being physically active. The first Australian direct
      observational data are presented on activity of year 3 and 4 children during
      physical education. Analysis accounts for the nested nature of the data through
      multi level logistic regression using 13,080 records within 231 lessons within 18
      randomly selected schools. Activity was analysed in relation to lesson context
      (focus of lesson), child gender, school year of child, teacher gender, lesson
      duration and start time. Children spent 36.7% of a lesson in moderate to vigorous
      and 12.9% in vigorous activity. Most of the lesson was spent in the context of
      management/instruction (37.4%), followed by games (25.0%), skill (21.4%), and
      fitness (14.7%). The highest level of moderate to vigorous activity was observed
      in the fitness lesson context (61.9%). followed by skill (46.4%), games (42.6%)
      and management/instruction (17.1%). Moderate to vigorous activity was
      significantly higher for boys than girls. There was no significant difference in
      moderate to vigorous activity in lessons led by male or female teachers. However
      vigorous activity was significantly higher for female led lessons. Children
      participated in less physical activity during physical education lessons
      timetabled in the afternoon, compared to physical education lessons time-tabled
      in the morning. Physical activity levels were not related to lesson duration.
      Physical education lessons can potentially be more active. However improvement
      rests on school capacity and may require a health promoting schools approach to
      implement curricular policy.

PMID- 12413044
TI  - The playing habits and other commitments of elite junior Australian football
      players.
AB  - The Victorian Football League Under 18 (VFL U18) competition provides a pathway
      to the elite senior level of Australian football. Players involved in the VFL U18
      competition also play football in other contexts, including for school and local
      clubs, and can have considerable additional work and educational demands. A total
      of 103 elite junior Australian football players from six VFL U18 clubs
      participated in a survey that asked about their football playing habits and other
      commitments. The median age of players when they first joined their VFL U18 squad
      was 16.3 years. The players participated in a median of five weekly training
      sessions during the last two weeks of the 1999 preseason and played a median of
      five preseason games. Fifty percent of the players expected to participate in 3-4
      training sessions per week and 25% expected to play more than two games per week
      during the 1999 season. Half of the players reported ambitions to play Australian
      Football League (AFL) football. Further research is needed to determine whether
      or not high participation levels have negative impacts on performance and injury
      risk in these players.

PMID- 12413045
TI  - Pregnancy in sport.

PMID- 12413046
TI  - Serum and tissue trace elements in patients with breast cancer in Taiwan.
AB  - The objective of this study was to compare levels of four elements (zinc, copper,
      selenium, and iron) in the serum and tissue of 68 breast tumor patients (benign
      and malignant), from a teaching hospital in central Taiwan. Samples of normal
      tissue (5 cm away from tumor) were also taken from patients with malignant
      tumors. Only serum was taken from the 25 healthy persons in the control group.
      Results showed that Zn, Cu, Se, Fe, Cu/Zn, Cu/Se, and Cu/Fe were present in
      different amounts in the serum of each of the three groups. Zn and Se levels were
      lower in the serum of the two tumor groups compared to the control group. In
      tissue samples, Zn, Cu, Se, and Fe concentrations were different in each of the
      three groups. The malignant tissue had the highest levels of all four elements.
      In advanced-stage malignant tumors, levels of Cu and the ratios of Cu/Fe and
      Cu/Zn (in both serum and tissue) were highest. The ratios of serum Cu/Zn, Cu/Fe,
      and Cu/Se were also higher in malignant patients. The cutoff value of serum Cu/Zn
      was 1.2 (sensitivity and specificity were both 100%). The Cu/Zn ratio was highest
      in the advanced stages of cancer and was a better diagnostic tool for breast
      cancer than Cu/Se and Cu/Fe. The authors suggest that change of trace elements in
      serum and tissue might be useful and significant as biomarkers involving the
      initial plastic process.

PMID- 12413047
TI  - Selenium status of pregnant women and newborns in the former Soviet Union.
AB  - The estimation of the selenium status during pregnancy is of great importance
      because of the significance of selenium for fetus growth and antioxidant
      protection of neonates. This problem is especially urgent for Russia and its
      neighbors because very little data are available and because data on soil
      selenium predict low intake levels of selenium. A large epidemiological
      investigation made in various areas of the former USSR allowed us to obtain the
      first information concerning the subject. Serum samples were obtained during 1990
      1998 from 556 female blood donors aged 20-53 yr and 722 pregnant women (18-33 yr)
      during different times of gestation. The mean serum selenium concentration of
      nonpregnant women varied from 0.87 micromol/L (Slavutich, Ukraine) to 1.74
      micromol/L (Ioshkar-Ola, Mary-El) and that of women at delivery from 0.66
      micromol/L (Zaporozie, Ukraine) to 1.34 micromol/L (Sakhalin, Russia).
      Compilation of literature and present data on serum selenium showed the following
      relationships: nonpregnant women versus women at delivery, y = x -0.25, r = 0.94;
      women at delivery versus umbilical serum, log y = log x -0.2, r = 0.97. The two
      relationships were used to predict serum selenium values for pregnant women
      taking into account the progressive serum selenium decrease during advancing
      pregnancy. In almost half of the towns (i.e. 22-50%), pregnant women were
      considered to have relative selenium deficiency.

PMID- 12413048
TI  - Selenoprotein P in subjects exposed to mercury and other stress situations such
      as physical load or metal chelation treatment.
AB  - In plasma, Se is found in plasma glutathione peroxidase (pGSH-Px), selenoprotein
      P (Sel-P), and albumins. The aim of the present study was to determine the
      influence of lifelong exposure to various levels of mercury vapor (Hg0) on plasma
      Se content and the fraction bound to Sel-P. Second, a pilot study was performed
      on the influence of short-term excessive physical stress and metal chelation
      (DIMAVAL) treatment. Samples of human plasma/serum obtained from a control group,
      Idrija residents living in a Hg-polluted environment because of the vicinity of
      the Idrija mercury mine (closed 1994), a few Idrija residents exposed to
      excessive physical stress, and two retired miners treated with the drug DIMAVAL
      were investigated. Selenoprotein P was isolated by affinity chromatography
      (heparin-Sepharose), and the concentrations of selenium were determined by
      radiochemical neutron activation analysis and hydride generation-atomic
      fluorescence spectrometry. Regardless of the group investigated, plasma Se
      average values were very similar (about 70-90 ngSe/g). A significant change of
      Sel P (7-24% decrease) was noted only in the group exposed to physical stress as
      compared to the same subjects before the test, to the control group, and to the
      Hg exposed group. The decrease of Se bound on Sel-P was accompanied by its
      increase in fraction of pGSH-Px with albumin.

PMID- 12413049
TI  - Effects of excessive copper intake on hematological and hemorheological
      parameters.
AB  - Copper plays an important role in the structure and function of metalloproteins
      and in the absorption of iron. The present study deals with the effects of
      excessive copper intake on hematological and hemorheological parameters. Drinking
      water containing 250 microg/mL copper for a period of 9 wk, Wistar albino rats
      showed increased erythrocyte count, blood viscosity, and hematocrit values
      (p<0.05) and lower hemoglobin (p<0.05) than controls fed a normal diet. The two
      groups also had differences in the erythrocyte deformability index. The results
      suggest that excessive copper intake results in hematological and hemorheological
      changes affecting both the protein content of the erythrocyte membrane and heme
      synthesis.

PMID- 12413050
TI  - Influence of dietary factors on calcium bioavailability: a brief review.
AB  - There are several factors that affected calcium bioavailability, such as
      physiological and dietary factors. These dietary factors help to achieve an
      appropiate status of calcium for a correct bone mineralization. In this pathway,
      recently some compounds present in milk that seem improve calcium absorption such
      as lactose and certain caseinophosphopeptides formed during digestion of caseins
      have been studied. On the other hand, the possible inhibitatory effect of fiber
      has been also studied, without conclusive results between in vitro and in vivo
      studies and the role of phytic acid on impairs calcium bioavailability could be
      prevented by using fructo-oligosaccharides, which cannot be digested in the small
      intestine and arrive practically intact to the colon, where are fermented.
      Finally, calcium fortification must be executed by suitable compounds with high
      bioavailability, better technological properties, and a correct
      calcium:phosphorus ratio. For that reason, the objective of the present article
      is to review the influence of all these conditional factors on calcium
      bioavailability.

PMID- 12413051
TI  - Optimal dietary concentration of chromium for alleviating the effect of heat
      stress on growth, carcass qualities, and some serum metabolites of broiler
      chickens.
AB  - This study was conducted to determine the effects of chromium (chromium
      picolinate, CrPic) supplementation at various levels (0, 200, 400, 800, or 1200
      microg/kg of diet) on performance, carcass characteristics, and some serum
      metabolites of broiler chickens (Ross) reared under heat stress (32.8 degrees C).
      One hundred fifty old male broilers were randomly assigned to 5 treatment groups,
      3 replicates of 10 birds each. The birds were fed either a control diet or the
      control diet supplemented with either 200, 400, 800, or 1200 microg Cr/kg of
      diet. Increased supplemental chromium resulted in an increase in body weight (p =
      0.01, linear), feed intake (p < or = 0.05, linear), and carcass characteristics
      (p < or = 0.05, linear) and improved feed efficiency (p = 0.01, linear).
      Increased supplemental chromium decreased serum corticosterone concentration (p =
      0.01, linear), whereas it increased serum insulin and T3 and T4 concentrations (p
      = 0.01). Serum glucose and cholesterol concentrations decreased (p = 0.01),
      whereas protein concentrations increased linearly (p = 0.001) with higher dietary
      chromium supplementation. Results of the present study conclude that a
      supplementation of diet with chromium at 1200 ppb can alleviate the detrimental
      effects of heat stress in broiler.

PMID- 12413052
TI  - Serum trace elements status of rabbits supplemented with Nigella sativa, vitamins
      C and E, and selenium against damage by N-methyl-N'-nitro-N-nitrosoguanidine.
AB  - In this study, we investigated the effects of Nigella sativa, vitamins C and E,
      and selenium on the levels of trace elements in the serum of N-methyl-N'-nitro-N
      nitrosoguanidine (MNNG)-injected rabbits. The rabbits were separated into one
      control and three experimental groups, each consisting of eight rabbits. MNNG was
      administered to all rabbits at a dose of 20 mg/kg. Group A received a suspension
      of N. sativa, group B received a combination of vitamins C and E and selenium,
      and group C received MNNG without any additional treatment. Group D did not
      receive any treatment and acted as control. The concentrations of serum zinc,
      copper, and iron were determined for groups A, B, C, and D. The zinc levels were
      155.3+/-25.8, 304.7+/-14.22, 117.2+/-27.9, and 87.0+/-8 ng/dL for groups A-D,
      respectively; copper was measured at 234.8+/-31.9, 214.3+/-14.2, 196.5+/-19.3,
      and 359.2+/-19.9 ng/dL and iron levels were 276.3+/-10.71, 260.8+/-7.15, 211.2+/
      13.47, and 223.4+/-9.5 ng/dL, in the stated group order. There were statistically
      significant differences between groups (p<0.05). The results obtained in this
      work may be of use for monitoring and preventing the nocive effects of N-methyl
      N'-nitro-N-nitrosoguanidine and similar carcinogens.

PMID- 12413053
TI  - Different responses of metallothionein and leptin induced in the mouse by fasting
      stress.
AB  - Changes in metallothionein (MT) and leptin under fasting stress were studied. MT
      content in the liver of mice increased markedly during continuous fasting periods
      up to 66 h. Hepatic content of MT increased significantly in mice during the
      first three cycles of alternate daily fasting-feeding, and then the rate of
      increase gradually decreased with repetition of this cycle. At the end of 10
      cycles, the hepatic MT content was still greater in stressed mice than in the
      control, although the rate of increase decreased. On the other hand, the plasma
      concentration of leptin decreased dramatically during continuous fasting. The
      plasma leptin level recovered to the basal level at the end of 10 cycles of
      fasting-feeding. These data indicate that MT induction was strongly increased,
      but leptin was scarcely induced under the continuous fasting stress, and that
      rates of the changes in MT and leptin levels were gradually reduced under the
      repeated fasting stress, which may result from an inborn tolerance. Fasting
      presumably causes translocation of zinc from intracellular to extracellular
      space, from which it is taken into target organs. The increased zinc-bound MT
      under the continuous fasting may partly result from the need to maintain zinc and
      protect tissues against oxidative damage.

PMID- 12413054
TI  - Gender difference regarding selenium penetration into the mouse brain.
AB  - A sex difference in the penetration of selenium into the brain was observed using
      lipopolysaccharide (LPS)-injected mice. The selenium concentration increased in
      the brains of sodium selenite-injected LPS-treated female mice, but not males.
      The selenium concentration peaked when selenite was injected 3 h after the
      injection of LPS into female mice. In addition, selenium in the brain increased
      when a dosage of 30 micromol/kg and more of selenite was injected into LPS
      treated female mice. Also, the selenium concentration in the brain increased and
      peaked 2-3 h after selenite injection; 24 h later, the level was similar to the
      Se-only group. The penetration of selenium into the brain was inhibited by
      pretreatment with aminoguanidine, an inhibitor of nitric oxide synthetase. From
      the present results, selenium more easily penetrated into the brains of female
      mice compared to males after LPS treatment, and nitric oxide may have affected
      the penetration. However, the sex difference mechanism for selenium penetration
      needs further investigation.

PMID- 12413055
TI  - Biology and pathology of the placenta in relation to antiphospholipid antibody
      associated pregnancy failure.
AB  - The placenta is a complex organ composed of maternal and foetal components whose
      anatomy and function is often greatly simplified in order to explain a range of
      presumed placenta-related pregnancy complications. Since one of the major roles
      of the placenta is its materno-foetal transfer function, abnormalities at the
      materno-foetal interface may be responsible for a range of pregnancy
      complications manifesting from the first through third trimesters according to
      the severity of the pathological process in each case. This article reviews some
      aspects of abnormal early placental development and its consequences, with
      particular regard to recurrent pregnancy failure and obstetric complications in
      association with primary antiphospholipid antibody syndrome.

PMID- 12413056
TI  - The fetal allograft.

PMID- 12413057
TI  - The biology of foetal development and injury.
AB  - This oversimplified view of foetal development and the risk to injury aims to
      highlight the following: assuming there is a normal environment, gene expression
      will generate a protein chain that should fold to the expected stereological
      shape to function normally. Here we must take into consideration the important
      role played by external (environmental) factors. Abnormal organogenesis or foetal
      injury are, in all likelihood, due to abnormal genes or genes expressing
      themselves 'out of sinc', that is to say 'outside' their time allocated for
      expression. This type of injury is difficult to correct. Morphogenesis, or the
      continuous remodelling of formed organ/systems can be more amenable to correction
      since the basic layout of the organ already exists. The common denominator to
      organogenesis and morphogenesis, at cellular/tissue levels, is the harmonic
      interplay between cell multiplication, cell migration, cell differentiation, cell
      death, the generation of intercellular matrix and its resorption. All of this
      must take place at the 'right time'. Any departure from it may lead to injury,
      whether clinically detectable or not.

PMID- 12413058
TI  - Pregnancy and neonatal outcome in primary antiphospholipid syndrome.

PMID- 12413059
TI  - Pathogenetic associations of maternal anti-Ro/SSA antibodies.

PMID- 12413060
TI  - Microchimerism and human autoimmune diseases.
AB  - Cells traffic in both directions between the fetus and the mother during
      pregnancy. Recent studies indicate that a low level of fetal cells commonly
      persists in the maternal circulation for years after pregnancy completion. The
      harboring of DNA or cells from another individual at low levels is called
      microchimerism. Chronic graft-vs-host disease is a condition of human chimerism
      that shares similarities to some autoimmune diseases and for which the specific
      HLA genes of donor and host are known to be of central importance. Considered
      together with the female predilection to autoimmunity, these observations led to
      the hypothesis that microchimerism and HLA genes of host and non-host cells are
      involved in autoimmune disease. The hypothesis also extends to men and females
      who have not been pregnant because there are other sources of microchimerism.
      Maternal cells are now know to persist in her progeny and microchimerism can also
      derive from a twin or from a blood transfusion. Studies of systemic sclerosis,
      primary biliary cirrhosis, Sjogrens syndrome, polymorpyhic eruption of pregnancy,
      myositis and thyroid disease have both lent support and raised doubts about the
      role of microchimerism in autoimmune disease.

PMID- 12413061
TI  - Risks to the children born to mothers with autoimmune diseases.
AB  - This article reviews current information regarding the development and long-term
      effects on children born to women with connective tissue diseases. There are few
      data on specific effects attributed to the underlying maternal disease, but fetal
      growth restriction and preterm birth are relatively common. Antenatal use of
      prednisone as treatment for these disorders appears to be safe, and most children
      have developed normally. However, there is growing concern that prolonged fetal
      exposure to other glucocorticoids such as dexamethasone or betamethasone may lead
      to decreased growth and abnormal neuronal development. Low birth weight is
      reportedly associated with long-term medical complications such as adult-onset
      hypertension. Evidence also suggests that immunosuppressive agents taken during
      pregnancy might predispose the progeny to autoimmune disorders, malignancies and
      reproductive problems. Further research is warranted to determine that there are
      no unrecognized long-term risks to the offspring of these women.

PMID- 12413062
TI  - Perinatal outcome of pregnancies in women with connective tissue disease.

PMID- 12413063
TI  - Sex ratio and rheumatic disease: excerpts from an Institute of Medicine report.
AB  - Some autoimmune diseases have high female/male (F/M) ratios. Definitions and
      classifications of autoimmune diseases differ, as do the F/M ratios themselves.
      The sex ratio of lupus is the single most prominent, little explored clinical
      fact that may lead to understanding of how lupus and other autoimmune diseases
      occur. The objective of this study was to evaluate evidence for causes of high
      F/M ratios of autoimmune and non-immunologic diseases. This was done by a
      literature review. Some thyroid, rheumatic and hepatic diseases consistently have
      high F/M ratios; other autoimmune diseases have low ratios. Because F/M ratios
      reflect disease incidence, not disease severity, an intrinsic biologic cause for
      the F/M ratios (such as estrogen) would be likely to act through a threshold or
      permissive mechanism rather than through quantitative immunomodulation. Sex
      differences related to environmental exposure, X-inactivation, imprinting, X or Y
      chromosome genes and intrauterine influences are other possible explanations for
      sex differences of incidence. The epidemiology of the sex discrepant autoimmune
      diseases, young, female, suggests that an explanation for sex discrepancy lies in
      differential exposure, vulnerable periods or thresholds, rather than in
      quantitative aspects of immunomodulation.

PMID- 12413064
TI  - Sex steroids, meibomian gland dysfunction and evaporative dry eye in Sjogren's
      syndrome.

PMID- 12413065
TI  - Sex hormones and the connective tissue diseases II: the pros and cons of
      estrogens and estrogen receptor modulators in patients with connective tissue
      diseases.

PMID- 12413066
TI  - Sex hormone adjuvanting therapy in rheumatoid arthritis.

PMID- 12413067
TI  - Osteoporosis in the rheumatic disease patient.
AB  - Rheumatic disease patients often have both systemic and localized inflammatory
      processes. The result of this inflammation is tissue destruction and this
      translates into bone loss. Recent studies have highlighted the importance of
      systemic factors that either directly or indirectly activate receptor activator
      of nuclear factor-kappaB ligand (RANKL) dependent osteoclast activation and
      induce bone loss. In this article we will review the pathogenesis of inflammatory
      bone loss and explore the possible interventions to prevent it.

PMID- 12413068
TI  - Heparin and osteoporosis during pregnancy: 2002 update.
AB  - Although significant bone mass loss is rare during pregnancy, some situations may
      increase the risk of symptomatic osteoporosis. Heparin may be necessary for a
      number of pregnant women with systemic lupus erythematosus and antiphospholipid
      syndrome. The osteopenic effect of heparin is low even during pregnancy, and
      recent data point to a more favourable profile of low-molecular-weight heparins
      as compared with unfractionated heparin. Lactation results in a significant
      increase of calcium demands and may be a higher risk period for women at risk for
      osteoporosis.

PMID- 12413069
TI  - Antirheumatic drugs in pregnancy.

PMID- 12413070
TI  - Autoimmune neuromuscular diseases: the implications of pregnancy.

PMID- 12413071
TI  - Effect of ammonium sulfate fertilization on bahiagrass quality and copper
      metabolism in grazing beef cattle.
AB  - To assess the impact of S fertilization on bahiagrass (Paspalum notatum) quality
      and Cu metabolism in cattle, two studies were conducted during the summer grazing
      season (1999 and 2000). Pasture replicates (16.2 ha; n = 2/treatment) received
      the same fertilizer treatment in each growing season, consisting of 1) 67 kg N/ha
      from ammonium sulfate (AS), 2) 67 kg N/ha from ammonium nitrate (AN), and 3)
      control (no fertilizer; C). Forage sampling was conducted at 28-d intervals
      following fertilization by the collection of whole plants (four samples/pasture)
      in randomly distributed 1-m2 grazing exclusion cages and analyzed for CP, in
      vitro organic matter digestibility, S, P, Ca, K, Mg, Na, Fe, Al, Mn, Cu, and Zn.
      To determine the effect of fertilizer treatment on liver trace mineral
      concentrations in grazing cattle, random liver tissue samples were collected (n =
      12; four/treatment) at the start and end of the study period in 2000. Ammonium
      sulfate fertilization increased (P < 0.001) forage S concentration in both years.
      Plant tissue N concentrations were increased by N fertilization, regardless of
      source, in 2000, but not in 1999. Cows grazing AS pastures had lower (P < 0.05)
      liver Cu concentrations at the end of the study period in 2000 compared to AN and
      C. In Exp. 2, 37 Cu-deficient heifers grazing AS fertilized pastures were
      obtained from the same location and allocated to one of two treatments,
      consisting of supplements providing 123 mg/d of either inorganic (Cu sulfate; n =
      12) or organic (Availa-Cu; n = 15) Cu. Treatments were delivered for 83 d. Liver
      Cu increased over time in all heifers regardless of treatment; however, heifers
      supplemented with Availa-Cu tended (P = 0.09) to have higher mean liver Cu
      concentrations than those receiving Cu sulfate. The results of these studies
      indicate that AS fertilization of bahiagrass increases forage S concentrations.
      When provided free-choice access to a complete salt-based trace mineral
      supplement, cows grazing AS-fertilized pastures had lower liver Cu concentrations
      than cows grazing pastures fertilized with AN; upon removal from high-S pastures,
      cattle were able to respond to Cu supplementation.

PMID- 12413072
TI  - Alpha-tocopherol concentrations and case life of lamb muscle as influenced by
      concentrate or pasture finishing.
AB  - Two experiments were conducted to evaluate alpha-tocopherol accumulation in
      muscle of lambs finished on pasture or concentrates. The objective for Exp. 1 was
      to compare accumulation of alpha-tocopherol in the longissimus muscle of pasture
      fed lambs to that of lambs fed three concentrations (15, 150, and 300 IU/kg of
      DM) of supplemental vitamin E (all rac alpha-tocopheryl acetate) in all
      concentrate diets. The objective in Exp. 2 was to investigate the effect of
      duration of supplemental vitamin E feeding on alpha-tocopherol content and color
      change during display case storage of lamb muscle. Treatments evaluated in Exp. 2
      were: 15 IU of supplemental vitamin E/kg DM fed to finish; 15 IU/kg followed by
      300 IU/kg of DM during the last 21 d; and 15 IU/kg DM until 7 d prior to finish,
      then 300 IU/kg DM. In Exp. 1, alpha-tocopherol concentration of rotational grazed
      alfalfa and perennial ryegrass averaged 137 and 169 mg/kg of DM. Vitamin E
      treatments for lambs fed concentrate diets did not affect ADG (P > 0.15), but ADG
      was greater (P < 0.01) for concentrate-fed lambs than for grazing lambs. For the
      concentrate-fed lambs, alpha-tocopherol in longissimus muscle increased
      quadratically (P < 0.05) as dietary concentrations of vitamin E increased.
      Predicted maximum alpha-tocopherol concentration in muscle occurred at about 400
      IU/kg of diet DM. Longissimus muscle from lambs grazing alfalfa or ryegrass had
      similar (P > 0.50) alpha-tocopherol concentrations, and those concentrations were
      similar to values obtained when the concentrate diet supplemented with 150 IU of
      vitamin E/kg was fed. In Exp. 2, no differences (P > 0.10) in ADG were observed.
      Concentrations of longissimus alpha-tocopherol were highest when 300 IU
      supplemental vitamin E was fed for 21 d prior to slaughter. During a 6-d display
      period, semimembranosus steaks from lambs fed 300 IU of supplemental vitamin E/kg
      for either 7 or 21 d had higher a* and b* color readings than steaks from lambs
      fed 15 IU/kg of supplemental vitamin E. Increased consumption of vitamin E either
      via pasture or supplementation results in higher alpha-tocopherol concentrations
      in meat.

PMID- 12413073
TI  - Relationship of milk yield and quality to preweaning gain of calves from Angus,
      Brahman and reciprocal-cross cows on different forage systems.
AB  - Interactions of the regression of preweaning ADG on dam milk yield and quality
      with breed group and forage environment were evaluated in a two-phase study.
      Phase I consisted of milk yield and quality and calf gain records from 1989 to
      1991 for purebred Angus (n = 64) and Brahman (n = 62) cows mated to sires of both
      breeds. Phase II consisted of milk yield and quality and calf gain records from
      1991 to 1997 for Angus (n = 94), Brahman (n = 85), Angus x Brahman (n = 86) and
      Brahman x Angus (n = 93) mated to Polled Hereford sires. In Phase I, forage
      environments included common bermudagrass and endophyte-infected tall fescue. In
      Phase II, forage environments included common bermudagrass and endophyte-infected
      tall fescue (1991 to 1995) and a rotational system of both forages (1995 to 1997)
      in which each forage was grazed during its appropriate growing season, usually
      June through October for bermudagrass and November through May for tall fescue.
      Milk yield was estimated monthly six times during lactation from spring through
      fall and converted to a 24-h basis. Milk fat, milk protein, and somatic cell
      count were analyzed by a commercial laboratory. In Phase I, the relation of
      preweaning ADG to milk yield, milk fat yield, and protein yield was greater (P <
      0.05) in Brahman cows on bermudagrass than Angus on bermudagrass. The regression
      of preweaning ADG on milk yield in Phase I was greater (P < 0.05) for cows on
      tall fescue than cows which grazed bermudagrass. In Phase II, the relation of
      preweaning ADG to milk yield, milk fat yield, and milk protein yield was greater
      or tended to be greater (P < 0.01, P < 0.11, P < 0.01, respectively) in purebred
      cows compared to reciprocal-cross cows. The regression of preweaning ADG on milk
      yield and milk protein yield was greater (P < 0.05) on tall fescue than
      bermudagrass in Phase II. These results suggest that the influence of milk yield
      and quality on calf growth may differ among breed types and production system,
      and the efficacy of genetic improvements in milk traits may depend on the breed
      type and forage environment.

PMID- 12413074
TI  - Linkage analysis using direct and indirect counting and relative efficiencies for
      codominant and dominant loci.
AB  - A method based on direct and indirect counting is developed for rapid and
      accurate linkage analysis for codominant and dominant loci. Methods for
      estimating gender-specific recombination frequencies are available for cases
      where at least one of the two loci is multiallelic and for biallelic loci with
      mixed parental linkage phases where at least one locus is codominant. Most of the
      estimates of gender-average and gender-specific recombination frequencies
      required iterative solutions. The new method makes use of the full data set,
      yields exact estimates of the recombination frequencies when the observed and
      expected genotypic frequencies are equal, and are computationally efficient.
      Relative efficiency of various data types is affected by the inheritance mode and
      by parental linkage phases of biallelic loci, but unaffected by the locus
      polymorphism when using the full data set for linkage analysis. The ability to
      determine parental linkage phases is affected by the locus polymorphism as well
      as inheritance mode. Intercross (or F-2 design) is more efficient for mapping
      codominant loci, whereas backcross is more efficient if dominance is involved.
      Mixed parental linkage phases of biallelic loci are less efficient than coupling
      or repulsion linkage phases. Ignoring noninformative offspring results in biased
      estimates of recombination frequency for biallelic loci only and reduced LOD
      scores for all cases.

PMID- 12413075
TI  - Multivariate analysis of litter size for multiple parities with production traits
      in pigs: I. Bayesian variance component estimation.
AB  - A total of 66,620 records from the first six parities for number of piglets born
      alive (NBA) from 20,120 Landrace sows and 24,426 records for weight (WT) and
      backfat thickness (BT) at 175 d of age were analyzed to estimate genetic
      parameters. The pedigree consisted of 47,186 individuals, including 392 sires and
      5,394 dams. Estimates were based on marginal posterior distribution of the
      genetic parameters obtained using Bayesian inference implemented via the Gibbs
      sampling procedure with a Data Augmentation step. The posterior means and
      posterior standard deviation (PSD) for heritability of NBA ranged from 0.064 (PSD
      0.005) in the first parity to 0.146 (PSD 0.019) in the sixth parity, always
      increasing with the order of the parity. The posterior means for genetic
      correlations of litter size between adjacent parities were, in most cases,
      greater than 0.80. However, genetic correlation were much lower between
      nonadjacent parities. For example, the genetic correlation was 0.534 (PSD 0.061)
      between the fourth and the sixth parity for NBA. The posterior means of
      heritability for WT and BT were 0.229 (PSD 0.018) and 0.350 (PSD 0.019),
      respectively. Posterior mean for genetic correlation between WT and BT was 0.339
      (PSD 0.044). The posterior means for genetic correlation between production (WT
      and BT) and reproduction traits (NBA in different parities) were close to zero in
      most cases. Results from this study suggest that different parities should be
      considered as different traits. Moreover, selection for growth and backfat should
      result in no or very little correlated response in litter size.

PMID- 12413076
TI  - Multivariate analysis of litter size for multiple parities with production traits
      in pigs: II. Response to selection for litter size and correlated response to
      production traits.
AB  - Litter size and production trait responses to experimental selection for
      increased litter size in a Landrace pig population are reported. The numbers of
      sows and litters available for the first cycle of selection were 3,034 and 961,
      respectively. Selection was carried out using a BLUP repeatability animal model
      for number of piglets born alive (NBA). The experiment included one selection and
      one control line, each with three nonoverlapping generations. The selection line
      (H) consisted of the 160 sows with the highest breeding values and one boar from
      each of 25 full-sib families with the highest breeding values. The control line
      (C) consisted of 160 sows and 25 boars randomly chosen. The two subsequent
      generations in each line were obtained by random selection. A Bayesian analysis
      of genetic response using a multivariate model was carried out by Gibbs sampler.
      Marginal posterior distributions were obtained for direct response in NBA, and
      for correlated response in weight (WT), and backfat thickness (BT) at 175 d of
      age. The posterior means and posterior standard deviation (PSD) for direct
      genetic response of NBA ranged from 0.32 (PSD 0.08) in the first parity to 0.64
      (PSD 0.08) in the fourth. The posterior means for correlated genetic response in
      WT and BT were -0.66 kg (PSD 0.36) and 0.20 mm (PSD 0.10), respectively. For WT
      and BT, the 95% highest posterior density regions (HPD) contain zero-correlated
      genetic response. Marginal posterior distributions of selection differentials
      were investigated. The posterior means for standardized selection differentials
      for NBA in different parities ranged from 0.70 (PSD 0.12) to 0.94 (PSD 0.06) in
      females for line H, from 0.22 (PSD 0.19) to 0.34 (PSD 0.10) in males for line H,
      and from 0.08 (PSD 0.08) to 0.13 (PSD 0.07) in females for line C. All available
      males were used in line C. Results from this experiment showed that selection for
      increased litter size is effective. Responses to selection were heterogeneous
      across parities, suggesting that litter size in each parity may have a different
      genetic background. No correlated genetic response to growth and backfat
      thickness was observed.

PMID- 12413077
TI  - Correlated response to selection for litter size in pigs: I. Growth, fat
      deposition, and feeding behavior traits.
AB  - Data on individually tested pigs from a line selected for litter size (H) and a
      control line (C) were used to estimate the correlated responses to litter size in
      growth, fat, and feeding behavior patterns from 75 to 165 d of age. During the
      test period, BW and ultrasonic midback (UMB) and loin (ULB) backfat were recorded
      periodically on the same animal. Individual voluntary feed intake (DFI), number
      of visits (NVD), and feeding time (FTD) were measured on a daily basis using an
      automatic feeding system. Third degree polynomial models with random regression
      coefficients were used to describe BW, UMB, ULB, DFI, NVD, and FTD as a function
      of age. The first derivative of the model for BW was used to estimate growth
      rate. Several measurements of efficiency were obtained using polynomial models on
      accumulated DFI, NVD, and FTD. The difference between the genetic means of
      animals from line H and line C was used to estimate correlated responses. The H
      pigs showed higher BW throughout most of the test period (2.29 +/- 0.90 kg at 135
      d of age, P < 0.05) but they were not different (P = 0.18) from C pigs at the end
      of the test (102 kg, SD 9). Thus, despite both lines showing similar average
      growth rate on the test, line H grew faster at the start of the test (34 +/- 11
      g/d, P < 0.01), but it grew more slowly by the end (-68 +/- 27 g/d, P < 0.05).
      Fat deposition rate differed between lines, with H pigs showing higher UMB (1.26
      +/- 0.23 mm, P < 0.01) and ULB (1.32 +/- 0.28 mm, P < 0.01) at 165 d of age. The
      difference between lines in total on-test feed intake was not significant (P=
      0.10), but intake was slightly higher in line H between 105 and 135 d of age
      (2.28 +/- 1.25 kg, P = 0.07). Line H showed a higher feed efficiency up to about
      100 d of age, whereas line C performed better from this age until 165 d of age.
      However, differences never exceeded 18 +/- 6 g of weight gain per kilogram of
      feed consumption (P < 0.01). Total feed efficiency throughout the test period was
      slightly higher in line C (1.37 +/- 0.77 kg of weight gain after eating 185 kg of
      feed, P = 0.08). Lines H and C had distinct feeding patterns with regard to
      eating frequency. Pigs from line H ate less frequently, but instead they spent
      more time and ate more per visit. In the long term, selection for litter size
      could result in pigs with less capacity of lean growth.

PMID- 12413078
TI  - Correlated response to selection for litter size in pigs: II. Carcass, meat, and
      fat quality traits.
AB  - Data on a pig line selected for litter size (H) and a control line (C) were used
      to estimate the correlated responses to litter size in carcass, meat, and fat
      quality traits. The differences between the genetic means of animals from line H
      and line C were used to estimate correlated responses. No differences were found
      between the two lines in carcass measurements except backfat depth, which was
      higher (P < 0.05) in line H (0.69 +/- 0.28 mm). This led to a decrease (P < 0.05)
      in predicted carcass lean content (-6.0 +/- 2.7 g/kg). Differences in joint
      weight distribution between lines were primarily due to belly weight, which was
      higher (P < 0.05) in line H (6.3 +/- 1.2 g/kg). There were no important changes
      in meat quality traits. Chemical composition of semimembranosus muscle (SM) and
      subcutaneous backfat (SB) differed between lines only for DM in SB, which was
      higher (P < 0.05) in line H (15.1 +/- 7.1 mg/g), and for the fatty acid
      composition of intramuscular fat. The fatty acid profile in line H showed a lower
      (P < 0.01) proportion of polyunsaturated fatty acids (-14.7 +/- 4.8 mg/g FA),
      particularly with regard to the content of linoleic acid (-12.5 +/- 3.9 mg/g FA).
      It is concluded that selection for litter size reduced the lean content in the
      carcass but the proportion of high-priced cuts and meat quality traits were not
      affected. However, selection may lead to changes in the composition of
      intramuscular fat lipids towards a lower content of polyunsaturated fatty acids.
      The observed correlated effects can be interpreted assuming that selected pigs
      are more mature at the same weight, though the underlying genetic and physiologic
      processes that cause them are unknown. The results of this experiment indicate
      that the metabolic pathways taking part in fat metabolism should be considered
      first.

PMID- 12413079
TI  - Does nutritive and non-nutritive sucking reduce other oral behaviors and
      stimulate rest in calves?
AB  - After a milk meal, bucket-fed calves show non-nutritive oral activities,
      including cross-sucking, and this can discourage producers from rearing them in
      groups. Sucking is known to induce a quiet state in humans and rats. We examined
      if nutritive sucking affects non-nutritive oral activities in calves, if it
      reduces arousal (assessed through behavior and cardiac activity), and if sucking
      a dry teat can compensate for the lack of nutritive sucking. In Exp. 1, the
      behavior and the cardiac activity of individually housed calves fed milk from a
      bucket were compared to those of calves fed milk through a teat. During the meal,
      the heart rate of bucket-fed calves was higher than that of teat-fed calves (P <
      0.0001). After the meal, only bucket-fed calves displayed bar sucking. Compared
      to the teat-fed calves, they spent more time licking their pen or their neighbor
      (P < 0.001 and P < 0.05), their heart rate was less variable (P < 0.01), and they
      lay down with the head unsupported by the neck less quickly (latency to lie down:
      51 min vs 42 min, P < 0.05). In Exp. 2, individually-housed bucket-fed and teat
      fed calves were observed with or without access to a non-nutritive teat after the
      meal. Bucket-fed calves sucked the dry teat for longer than teat-fed calves (P <
      0.001). In bucket-fed calves, access to the dry teat reduced the time spent
      nibbling (P < 0.01) and tended to shorten the latency to lie down (P < 0.10). In
      Exp. 3, group-housed bucket-fed calves were compared with group-housed calves fed
      with an automatic teat feeder system. Bucket-fed calves spent more time nibbling
      at 1 mo, but at 3 mo they spent less time nibbling and cross-sucking; they drank
      more milk and put on more weight. We conclude that, for calves housed
      individually, teat-feeding reduces non-nutritive oral activities after the meal
      and induces a calmer state than bucket-feeding. Providing calves with a dry teat
      partly compensates for the lack of nutritive sucking. For calves housed in
      groups, the use of an automatic teat feeder may not reduce calves' motivation for
      sucking. No improvement of growth was observed with teat-feeding either with a
      teat-bucket or with an automatic feeder.

PMID- 12413080
TI  - Ram mating behavior after long-term selection for reproductive rate in
      Rambouillet ewes.
AB  - Mating behavior is known to be heritable in several species, but it is not known
      if selection schemes for ewe reproductive traits affect mating behavior of rams.
      Therefore, our objectives were to determine if divergent (high vs low index)
      selection of a female reproductive trait (lambs born divided by age of ewe minus
      one) affects mating behavior patterns of male offspring during training to
      service an artificial vagina (AV) in a less than natural setting (Exp. 1) or
      during serving capacity tests (SCT) in simulated natural mating conditions (Exp.
      2). The method for evaluating male mating behavior was a series of serving
      capacity tests to estimate sexual performance. For Exp. 1, five, 30-min
      observations were conducted to assess the mating behavior of 29 rams (22 mo old)
      being trained to service an AV. In Exp. 1, percentages of rams mounting (73 vs
      36%) and ejaculating (67 vs 29%) differed (P < 0.05) between rams from high and
      low Rambouillet ewe selection lines, respectively. In Exp. 2, ram classification
      consisted of exposing each 22- to 24-mo-old ram (n = 48) to three unrestrained
      ewes in estrus for 18, 30-min tests. Any ram that had not mounted or ejaculated
      during SCT was evaluated for sexual orientation in a 30-min preference test in
      which each ram had access to both restrained estrual ewes and restrained rams. In
      Exp. 2, there was no difference (P > 0.2) in percentages of rams mounting (92 vs
      78%) and ejaculating (88 vs 74%) between rams from high and low Rambouillet ewe
      selection lines, respectively. There was no difference (P > 0.33) between high
      and low ewe selection line rams for mounts or ejaculations for 18 SCT. Only one
      male-oriented ram was identified, which was from the high line. In Exp. 2, six
      SCT were necessary to obtain 95% reliability in sexual performance scores.
      Results of these studies indicate that long-term selection of ewes for litter
      size did not alter ram sexual performance after SCT under simulated natural
      mating conditions or affect incidence of male-oriented rams. Mating behavior
      observed during training to service an AV was lower for rams from ewes of the low
      selection line than for rams from ewes of the high selection line. We concluded
      that long-term selection for reproductive rate in ewes did not alter mating
      behavior patterns of male offspring; however, test conditions, such as restrained
      and unrestrained ewes and number of serving capacity tests, may affect
      conclusions in studies that evaluate sexual performance of rams.

PMID- 12413081
TI  - Mapping intramuscular tenderness variation in four major muscles of the beef
      round.
AB  - The objective of this study was to quantify intramuscular tenderness variation
      within four muscles from the beef round: biceps femoris (BF), semitendinosus
      (ST), semimembranosus (SM), and adductor (AD). At 48 h postmortem, the BF, ST,
      SM, and AD were dissected from either the left or right side of ten carcasses,
      vacuum packaged, and aged for an additional 8 d. Each muscle was then frozen and
      cut into 2.54-cm-thick steaks perpendicular to the long axis of the muscle.
      Steaks were broiled on electric broilers to an internal temperature of 71 degrees
      C. Location-specific cores were obtained from each cooked steak, and Warner
      Bratzler shear force was evaluated. Definable intramuscular shear force variation
      (SD = 0.56 kg) was almost twice as large as between-animal shear force variation
      (SD = 0.29 kg) and 2.8 times as large as between-muscle variation (SD = 0.20 kg).
      The ranking of muscles from greatest to least definable intramuscular shear force
      variation was BF, SM, ST, and AD (SD = 1.09, 0.72, 0.29, and 0.15 kg,
      respectively). The BF had its lowest shear force values at the origin (sirloin
      end), intermediate shear force values at the insertion, and its highest shear
      force values in a middle region 7 to 10 cm posterior to the sirloin-round break
      point (P < 0.05). The BF had lower shear force values toward the ST side than
      toward the vastus lateralis side (P < 0.05). The ST had its lowest shear force
      values in a 10-cm region in the middle, and its highest shear force values toward
      each end (P < 0.05). The SM had its lowest shear force values in the first 10-cm
      from the ischial end (origin), and its highest shear force values in a 13-cm
      region at the insertion end (P < 0.05). Generally, shear force was lower toward
      the superficial (medial) side than toward the deep side of the SM (P < 0.05).
      There were no intramuscular differences in shear force values within the AD (P >
      0.05). These data indicate that definable intramuscular tenderness variation is
      substantial and could be used to develop alternative fabrication and(or)
      merchandising methods for beef round muscles.

PMID- 12413082
TI  - Effect of a preparation of Saccharomyces cerevisiae on microbial profiles and
      fermentation patterns in the large intestine of horses fed a high fiber or a high
      starch diet.
AB  - Eight horses were allotted into pairs consisting of one cecum- and right ventral
      colon-fistulated animal and one cecum-fistulated animal. They were fed daily at
      the same level of intake either a high-fiber (HF) or a high-starch (HS) diet
      without or with 10 g of a Saccharomyces cerevisiae preparation, in a 4 x 4 Latin
      square design. The HS diet provided a starch overload (i.e., 3.4 g starch x kg(
      1) BW x meal(-1)) while maintaining a high amount of fiber intake (i.e., dietary
      NDF/starch ratio was 1.0). A 21-d period of adaptation to the treatments occurred
      before cecal and colonic contents were withdrawn 4 h after the morning meal to
      count total anaerobic, cellulolytic, and lactic acid-utilizing bacteria,
      lactobacilli, and streptococci. Lactic acid, volatile fatty acids, ammonia
      concentrations, and pH were measured on cecal and colonic fluid samples collected
      hourly during the first 12-h postfeeding. When the HS diet was fed, the
      concentration of total anaerobic and lactic acid-utilizing bacteria increased (P
      < 0.001), whereas that of cellulolytic bacteria decreased (P < 0.05) in the
      cecum. The concentration of lactobacilli and streptococci increased (P < 0.001)
      in the cecal and colonic contents. These alterations of the microbial profiles
      were associated with decreases (P < 0.001) of pH, (acetate + butyrate)/propionate
      ratio and with an increase (P < 0.001) of lactic acid concentration.
      Supplementing the S. cerevisiae preparation increased (P < 0.01) the
      concentration of viable yeast cells, averaging 4.3 x 10(6) and 4.5 x 10(4) cfu/mL
      in the cecal and colonic contents, respectively. Yeast supplementation had almost
      no effect on microbial counts in the cecum and colon. The supplementation of S.
      cerevisiae appeared to modify (P < 0.05) pH, concentrations of lactic acid and
      ammonia, molar percentages of acetate and butyrate with the HS diet and [(acetate
      + butyrate)/propionate] ratio when the HF diet was fed. The effects of the S.
      cerevisiae preparation were greater in the cecum than in the colon, which
      coincided with the abundance of yeast cells. When the digestion of starch in the
      small intestine was saturated, the effect of the addition of a S. cerevisiae
      preparation appeared to limit the extent of undesirable changes in the intestinal
      ecosystem of the horse.

PMID- 12413083
TI  - Degree of amino acid restrictions during the grower phase and compensatory growth
      in pigs selected for lean growth efficiency.
AB  - A total of 32 select line (SL) and 32 control line (CL) Duroc pigs were used in
      two trials to determine the effect of dietary amino acid contents during the
      grower (G) phase and selection for lean growth efficiency on growth performance,
      carcass traits, and meat quality. In each trial, pigs weighing 20 kg were
      assigned to 16 pens with two gilts or two castrated males per pen, and pens were
      randomly assigned within the genetic line to corn-soybean meal G diets formulated
      to contain 5.0, 7.0, 9.0, or 11.0 g lysine/kg. After 50 kg, all pigs were fed
      common finisher 1 (F1) and finisher 2 (F2) diets. Pigs were allowed ad libitum
      access to feed and water. After the initial statistical analyses, the data sets
      from the two trials were combined. During the G phase, pigs consumed less feed
      [linear (Ln), P < 0.001] and more lysine (Ln, P < 0.001), grew faster (Ln, P <
      0.05) but utilized feed more and lysine less efficiently (Ln, P < 0.001) for
      weight gain as the amino acid content of G diets increased. Increasing dietary
      amino acids resulted in less ultrasound backfat (Ln, P < 0.001) and more serum
      urea nitrogen [Ln, P < 0.001; quadratic (Qd), P < 0.01] at the end of the G
      phase. Pigs grew more slowly during the F1 (Ln, P < 0.01 and Qd, P = 0.05) and F2
      (Ln, P = 0.07) phases and utilized feed and lysine less efficiently (Ln, P <
      0.05) for weight gain during the F1 phase as the amino acid content of G diets
      increased. The grower diet had no effect on overall weight gain and feed
      efficiency, carcass traits, or meat quality scores. The efficiency of lysine
      utilization for overall weight gain (Ln, P < 0.001) and lean accretion (Ln, P <
      0.05) improved as the amino acid content of G diets decreased. The SL pigs grew
      faster (P < 0.05) and had less (P < 0.001) ultrasound backfat throughout the
      study compared with the CL pigs. The SL pigs had less 10th rib backfat (P <
      0.001) and tended to have larger longissimus muscle area (P = 0.09) than the CL
      pigs, which were reflected in greater rate (P < 0.001) and efficiency (P < 0.05)
      of lean accretion. Marbling (P < 0.05) and meat color (P = 0.07) scores were
      lower in the SL pigs. No grower diet x genotype interactions were observed in
      response criteria of interest. The results indicate that pigs subjected to
      dietary amino acid restrictions during the G phase (as low as 5.0 g lysine/kg)
      compensated completely in terms of growth rate and body composition regardless of
      the genotype. Compensatory growth can have a positive impact not only on the
      overall efficiency of pig production but also on the environment by reducing
      excretion of unused nutrients.

PMID- 12413084
TI  - Brewers dried yeast as a source of mannan oligosaccharides for weanling pigs.
AB  - Brewers dried yeast, a source of mannan oligosaccharides (MOS), was assessed as
      an alternative to an antimicrobial agent (carbadox) for young pigs in two
      experiments. The yeast contained 5.2% MOS. Agglutination tests confirmed
      adsorption of several serovars of E. coli and Salmonella spp. onto the yeast
      product. In Exp. 1, seven replicates (five pigs per pen) of 22-d-old pigs were
      fed a nonmedicated basal diet or the basal diet with carbadox (55 mg/kg), yeast
      (3%), or a combination of 3% yeast and 2% citric acid for 28 d. Carbadox did not
      improve growth performance. Growth rate and feed intake were depressed (P < 0.05)
      in pigs fed yeast alone or in combination with acid. Log counts of total
      coliforms, Escherichia coli, and Clostridium perfringens in feces were not
      affected by diet, but Bifidobacteria spp. counts were lower (P < 0.05) in pigs
      fed the yeast + acid diet and lactobacilli counts were higher (P < 0.05) in pigs
      fed yeast. Fecal pH and VFA concentrations and intestinal morphological traits
      were not consistently affected by diet. Serum IgG levels were elevated in the
      yeast + acid (P < 0.01) group. In Exp. 2, the effects of yeast and carbadox
      additions to the diet on enteric microbial populations in young pigs housed in
      isolation units were evaluated. Pigs (n = 24) were weaned at 11 d of age (4.1 kg
      BW) and placed in isolation chambers (two pigs per chamber) equipped with
      individual air filtering systems and excrement containers. Treatments were a
      nonmedicated basal diet and the basal diet with 55 mg/kg of carbadox or with 3%
      yeast. Diets were fed for 29 d, then each pig was orally dosed with approximately
      9.5 x 10(8) CFU of E. coli K88. Daily fecal E. coli K88 counts were not different
      (P > 0.05) among treatments, but fecal shedding of carbadox-resistant coliforms
      was higher (P < 0.01) during the 9-d period in pigs fed carbadox. Total fecal
      coliforms were consistently lower throughout the postinoculation period in pigs
      fed yeast (P < 0.05). Yeast reduced colonization oftotal coliforms in the
      duodenum,jejunum, cecum, and colon, but it did not have a consistent effect on
      colonization of E. coli K88. Pigs fed yeast tended (P < 0.10) to have higher
      serum IgG levels than controls. In these experiments, brewers dried yeast and
      carbadox had minimal effects on growth, microbial populations, and intestinal
      health traits of early-weaned pigs, but certain serum immunological traits were
      enhanced by feeding yeast.

PMID- 12413085
TI  - The nutritional value of degermed, dehulled corn for pigs and its impact on the
      gastrointestinal tract and nutrient excretion.
AB  - Three experiments were designed to assess the feeding value and potential
      environmental benefits of feeding degermed, dehulled corn, a low fiber by-product
      originating from the corn dry milling process, to pigs. Twelve 27-kg (SE = 0.8)
      barrows were used in Exp. 1 to measure the apparent fecal digestibility of DM, GE
      and N of degermed, dehulled corn compared with corn grain. Two diets were
      formulated to contain either 96.4% of degermed, dehulled corn or corn grain plus
      supplemental vitamins and minerals. Digestibilities of DM, GE, and N were greater
      in degermed, dehulled corn (96.2, 96.0, and 93.6%, respectively) compared with
      corn grain (89.0, 89.0, and 78.4%, respectively) (P < 0.01). Overall, a 67 and
      29% reduction in DM and N excretion, respectively, was observed. In Exp. 2, eight
      70-kg (SE =1.8) barrows were surgically fitted with ileal cannulae and fed the
      same diets as in Exp. 1, to measure the ileal digestibility of nutrients in
      degermed, dehulled corn. Ileal digestibility of DM, energy, and N was 13, 15, and
      7% greater in degermed, dehulled corn (P < 0.05). Apparent ileal digestibility
      coefficients of leucine, methionine, and phenylalanine were greater in degermed,
      dehulled corn compared with corn grain (P < 0.05) while a trend for a lower
      tryptophan digestibility in degermed, dehulled corn was observed (P = 0.067). In
      Experiment 3, 96 nursery pigs with an initial average BW of 8.8 kg (SE = 0.08),
      fed a starter diet formulated with degermed, dehulled corn or corn grain as the
      major grain source, were used in a 28-d growth performance study. At the end of
      the study, 24 pigs (1 pig per pen) were sacrificed and gastrointestinal tract
      measurements were taken. Daily growth rates of pigs were the same between diets
      (0.64 kg/d). A trend for reduced feed intake (P = 0.073) in pigs fed degermed,
      dehulled corn led to a 4% improvement in gain to feed (P < 0.05). Feeding
      degermed, dehulled corn had no effect on gut fill, gastrointestinal tract weight,
      or liver weight (P > 0.05). Ileal villus lengths and crypt depths were not
      affected by feeding degermed, dehulled corn although ileal villus widths were
      greater in pigs fed corn grain. Results from these trials suggest that corn
      processed to remove poorly digestible fiber fractions provides more digestible
      nutrients than corn grain. As a result, degermed, dehulled corn reduces fecal and
      N excretion, thus providing a means to reduce nutrient excretion.

PMID- 12413086
TI  - Nutrient database for distiller's dried grains with solubles produced from new
      ethanol plants in Minnesota and South Dakota.
AB  - A study was conducted to evaluate the nutrient content and variability of
      distiller's dried grains with solubles (DDGS) originating from new (less than 5
      yr old) ethanol plants in Minnesota and South Dakota. Ten plants (8 MN, 2 SD)
      participated in the study, submitting a total of 118 samples. Samples were
      collected every 2 mo from ten ethanol plants in the Minnesota-South Dakota (MNSD)
      region from 1997 to 1999 and were analyzed for amino acid levels, DM, CP, crude
      fiber, crude fat, ash, ADF, NDF, Ca, P, K, Mg, S, Na, Zn, Mn, Cu, and Fe
      analysis. Digestible energy (DE), ME, and NFE levels were also calculated. Means
      (dry-matter basis) and coefficients of variation for each nutrient among all
      plants during 1997 to 1999 were DM (88.9%, 1.7%), CP (30.2%, 6.4%), crude fat
      (10.9%, 7.8%), crude fiber (8.8%, 8.7%), ash (5.8%, 14.7%), NFE (45.5%, 6.1%),
      ADF (16.2%, 28.4%), NDF (42.1%, 14.3%), calculated DE (3,990 kcal/kg, 3.24%),
      calculated ME (3,749 kcal/kg, 3.28%), Arg (1.20%, 9.1%), His (0.76%, 7.8%), Ile
      (1.12%, 8.7%), Leu (3.55%, 6.4%), Lys (0.85%, 17.3%), Met (0.55%, 13.6%), Phe
      (1.47%, 6.6%), Thr (1.13%, 6.4%), Trp (0.25%, 6.7%), Val (1.50%, 7.2%), Ca
      (0.06%, 57.2%), and P (0.89%, 11.7%), respectively. Among the amino acids
      analyzed, Lys was the most variable (CV = 17.3%), followed by Met (CV = 13.6%).
      Nutrient levels of MNSD DDGS were higher in crude fat, NDF, DE, ME, P, Lys, Met,
      and Thr and lower for DM, ADF, and Ca than NRC (1998) values. Nutrient values
      differed between years for ash, DE, Mn, Zn, Cys (P < 0.10), Fat, TDN, ME, Met,
      Ile (P < 0.05), Ca, P, K, Mg, and Cu (P < 0.01). These results suggest that gross
      energy; P; and total Lys, Met, and Thr levels are higher in DDGS from MNSD
      ethanol plants compared to published values and chemical analysis values of a
      DDGS sample obtained from an older Midwestern plant.

PMID- 12413087
TI  - The tryptophan requirement of nursery pigs.
AB  - Five experiments were conducted to determine the true digestible Trp (dTrp)
      requirement of nursery pigs. Treatments were replicated with four or five pens of
      five or six pigs each. Pigs were weaned at 21 (Exp. 1, 2, and 5) or 19 d (Exp. 3
      and 4), and fed common diets for various times and then experimental diets for 8
      (Exp. 1), 13 (Exp. 2 and 3), or 14 d (Exp. 4 and 5). Experiment 1 (160 pigs,
      initial and final BW of 8.4 and 11.4 kg) evaluated six protein sources low in Trp
      relative to a positive control diet to identify the protein source to be used in
      subsequent experiments. The results indicated that a diet with Canadian field
      peas (CFP) supplemented with Trp resulted in ADG, ADFI, and gain:feed (GF) equal
      to (P > 0.10) the positive control diet. In Exp. 2, 75 pigs (initial and final BW
      of 13.2 and 19.2 kg) were fed 1) Trp-deficient diet (0.13% dTrp) with CFP, 2)
      Diet 1 with added Trp (0.23% dTrp), or 3) positive control diet (0.22% dTrp).
      Daily gain, ADFI, and GF were decreased (P < 0.01) in pigs fed Diet 1 compared
      with pigs fed Diets 2 and 3, but ADG, ADFI, and GF were equal (P > 0.10) in pigs
      fed Diets 2 and 3. Experiments 3 (180 pigs, initial and final BW of 5.2 and 7.3
      kg), 4 (120 pigs, initial and final BW of 6.3 and 10.2 kg), and 5 (144 pigs,
      initial and final BW of 10.3 and 15.7 kg) were conducted to estimate the dTrp
      requirement of nursery pigs with diets using CFP as a primary protein source. The
      diets used in Exp. 3, 4, and 5 contained 1.35, 1.19, or 1.01% dLys, respectively,
      and other amino acids were provided at 105% the ratio relative to Lys. Response
      variables were ADG, ADFI, GF, and plasma urea N concentrations, and data were
      analyzed using the broken-line model. The levels of dTrp in the diets for Exp. 3
      (Phase I, 5.2 to 7.3 kg) were 0.14, 0.17, 0.20, 0.23, 0.26, and 0.29%. The
      average dTrp requirement was estimated to be 0.21% (0.24% total Trp). The levels
      of dTrp in the diets for Exp. 4 (Phase II, 6.3 to 10.2 kg) were 0.13, 0.16, 0.19,
      0.22, 0.25, and 0.28%. The average dTrp requirement was estimated to be 0.20%
      (0.23% total Trp). The levels of dTrp in the diets for Exp. 5 (Phase III, 10.3 to
      15.7 kg) were 0.130, 0.155, 0.180, 0.205, 0.230, and 0.255%. The average dTrp
      requirement was estimated to be 0.18% (0.22% total Trp). These results indicate
      that the true dTrp requirement is 0.21, 0.20, and 0.18% for Phase I (5.2 to 7.3
      kg), II (6.3 to 10.2 kg), and III (10.3 to 15.7 kg) nursery pigs, respectively.

PMID- 12413088
TI  - Production of amines in equine cecal contents in an in vitro model of
      carbohydrate overload.
AB  - Acute laminitis can be induced experimentally in horses by the administration of
      carbohydrate, resulting in fermentation within the cecum and ischemia-reperfusion
      of the digits. The products of fermentation that trigger acute laminitis are as
      yet unknown; however, compounds such as amines might play a role due to their
      potential vasoactive properties. The objectives of this study were to quantify
      the amines present in equine cecal contents and to use a model of carbohydrate
      overload in vitro to test the hypothesis that carbohydrate fermentation is
      associated with increased amine production. Cecal contents from each horse were
      divided into aliquots and incubated anaerobically with either cornstarch or
      inulin (a form of fructan carbohydrate; both 1 g/100 mL). The pH was measured and
      samples were taken at the same time for amine measurement by HPLC at 2-h
      intervals over a 24-h period. In a second set of experiments, the effects of the
      antibiotic virginiamycin (1 mg/100 mL), calcium (CaPO4; 0.3 g/100 mL), and plant
      steroidal saponin (Yucca schidigera extract; 0.1 g/100 mL) were examined on pH
      and amine concentrations in cecal contents incubated with starch or inulin. Both
      starch and inulin caused significant time-dependent falls in pH, from 6.7 +/- 0.1
      at 0 h to 5.2 +/- 0.1 (starch) and 5.0 +/- 0.1 (inulin) at 24 h. Fermentation of
      carbohydrate was also associated with increased production of phenylethylamine
      and isoamylamine (two- to threefold increases) as well as putrescine and
      cadaverine (1.5- to twofold increases). Virginiamycin inhibited the fall in pH
      and increases in production of phenylethylamine and isoamylamine, while calcium
      phosphate moderated the changes in pH only. Yucca schidigera extract was without
      effect. These data show that fermentation of carbohydrate by equine cecal
      microbiota may lead to increased production of amines.

PMID- 12413089
TI  - Low-phytic acid barley improves calcium and phosphorus utilization and growth
      performance in growing pigs.
AB  - Thirty-five crossbred barrows averaging 13.5 kg starting BW were used in a 35-d
      experiment to compare the availability of P and the nutritional value of two near
      isogenic progeny of the barley cultivar 'Harrington'. Low-phytic acid barley
      (LPB, 0.35% total P, 0.14% phytic acid P) was homozygous for the low-phytic acid
      1-1 allele, and the normal barley (NB, 0.35% total P, 0.24% phytic acid P) was
      homozygous for the normal allele of that gene. Pigs were fed individually twice
      daily in metabolism pens. Barley was the only source of phytate in semipurified
      diets, 1 to 3. Diet 1 contained 75% NB, 0.14% estimated available P (aP), and
      0.50% Ca. Diet 2 contained 75% LPB, 0.22% aP, and 0.50% Ca. No inorganic P (iP)
      was added to Diets 1 and 2 in order to measure the animal response to the
      different concentrations of aP in these cultivars. Diet 3 was NB Diet 1
      supplemented with iP to equal the concentration of aP in LPB Diet 2. Practical
      barley-soybean meal (SBM)-type diets, NB Diet 4 and LPB Diet 5, were formulated
      to meet all minimum nutrient requirements, and contained 0.30% aP and 0.65% Ca.
      For the semipurified diets, pigs fed LPB Diet 2 had higher (P < or = 0.05) bone
      ash weight, bone breaking strength, P absorption and retention, and Ca absorption
      and retention compared with pigs fed NB Diet 1, with a trend (P = 0.10) for pigs
      fed LPB Diet 2 to have a higher ADG and gain:feed ratio than pigs fed NB Diet 1.
      However, pigs fed LPB Diet 2 or NB Diet 3 were not different (P > or = 0.3) in
      growth performance, fresh bone weight, fat-free dry bone weight, bone ash, bone
      breaking strength, or N utilization. This indicates that LPB and NB were equal in
      nutritional value after supplementation of NB with iP to equal the estimated aP
      in LPB. For the practical barley-SBM diets, there were no differences (P > or =
      0.4) between pigs fed NB Diet 4 or LPB Diet 5 for growth performance, fresh bone
      weight, bone breaking strength, the percentages of P and Ca utilization, or N,
      DE, and ME utilization. The use of LPB in pig diets reduced P excretion in swine
      waste by 55% and 16% in our semipurified and practical diets, respectively,
      compared with NB. Using our in vitro procedure designed to mimic the digestive
      system of the pig, the availability of P for pigs was estimated at 52% for LPB
      and 32% for NB.

PMID- 12413090
TI  - Factors affecting cellular outgrowth from porcine inner cell masses in vitro.
AB  - During early embryonic development, endodermal cells leave the inner cell mass
      (ICM) and migrate over an extracellular matrix located on the blastocoelic side
      of the trophectoderm to form extraembryonic endoderm. Two experiments were
      conducted to evaluate factors supporting porcine endodermal cell migration in
      vitro. In Exp. 1, porcine ICM were cultured on matrices of collagen IV,
      fibronectin, or laminin. Percentages of ICM generating cellular outgrowth on
      fibronectin (5/11; 45%) and laminin (4/10; 40%) were similar (P > 0.10); however,
      collagen IV (0/10; 0%) failed (P < 0.05) to support cellular outgrowth. Inner
      cell mass and outgrowth areas and numbers of cells in outgrowths were similar (P
      > 0.10) for fibronectin and laminin, and increased (P < 0.05) with time in
      culture. In Exp. 2, ICM were cultured on fibronectin or laminin in medium
      containing 0 or 500 microg/mL of the inhibitory tripeptide, arg-gly-asp (RGD), or
      on laminin in medium containing 0 or 10 microg/mL recombinant human tissue
      inhibitor of matrix metalloproteinases-2 (rhTIMP-2). Inner cell mass and
      outgrowth areas and numbers of cells in the outgrowths for ICM cultured on
      fibronectin did not differ (P > 0.10) due to the presence of RGD. Inner cell
      masses cultured on laminin in medium containing 500 microg/mL RGD had fewer cells
      in the outgrowths and slower rates of cell migration compared with 0 microg/mL (P
      < 0.05). No differences (P > 0.10) in ICM and outgrowth areas and numbers of
      cells in the outgrowths were observed for ICM cultured on laminin in medium
      containing 0 or 10 microg/mL rhTIMP-2. Both fibronectin and laminin supported
      porcine ICM outgrowth in vitro; however, because outgrowth on fibronectin was not
      inhibited by RGD, endodermal cells must express an integrin that recognizes an
      alternative sequence in fibronectin. Cell migration on laminin was inhibited by
      RGD, suggesting either RGD competes with laminin for binding sites on endodermal
      cells or binding RGD alters endodermal cell migration on laminin. Because rhTIMP
      2 had no effect on cell outgrowth, porcine ICM do not appear to be responsive to
      the proliferative effects of rhTIMP-2.

PMID- 12413091
TI  - Pituitary responsiveness to GnRH in mares following deslorelin acetate
      implantation to hasten ovulation.
AB  - The present experiment characterized the pituitary responsiveness to exogenous
      GnRH in the first 10 d after ovulation following commercially available
      deslorelin acetate implantation at the normal dosage for hastening ovulation in
      mares. Twelve mature, cyclic mares were assessed daily for estrus and three times
      weekly for ovarian activity starting May 1. Mares achieving a follicle at least
      25 mm in diameter or showing signs of estrus were checked daily thereafter for
      ovarian characteristics. When a follicle >30 mm was detected, mares were
      administered either a single deslorelin acetate implant or a sham injection and
      then assessed daily for ovulation. On d 1, 4, 7, and 10 following ovulation, each
      mare was challenged i.v. with 50 microg GnRH, and blood samples were collected to
      characterize the LH and FSH responses. The size of the largest follicle on the
      day of treatment did not differ (P = 0.89) between groups. The number of days
      from treatment to ovulation was shorter (P < 0.001) by 2.0 d for the treated
      mares indicating a hastening of ovulation. The size of the largest follicle
      present on the days of GnRH challenge was larger in the treated mares on d 1 (P =
      0.007) but smaller on d 10 (P = 0.02). In addition, the interovulatory interval
      was longer (P = 0.036) in the treated mares relative to controls by 4.4 d.
      Concentrations of FSH in plasma of the treated mares were lower (P < 0.05) than
      control concentrations from d 3 to 12; LH concentrations in the treated mares
      were lower (P < 0.05) relative to controls on d 0 to 5, d 7, and again on d 20 to
      23. Progesterone values were the same (P = 0.99) for both groups from 2 d before
      ovulation though d 23. There was an interaction of treatment, day, and time of
      sampling (P < 0.001) for LH and FSH concentrations after injection of GnRH. Both
      the LH and FSH responses were suppressed (P < 0.009) in the treated mares
      relative to controls on d 1, 4, and 7; by d 10, the responses of the two groups
      were equivalent. In conclusion, deslorelin administration in this manner
      increased the interovulatory interval, consistently suppressed plasma LH and FSH
      concentrations, and resulted in a complete lack of responsiveness of LH and FSH
      to GnRH stimulation at the dose used during the first 7 d after the induced
      ovulation. Together, these results are consistent with a temporary down
      regulation of the pituitary gland in response to deslorelin administered in this
      manner.

PMID- 12413092
TI  - Retinol and estradiol regulation of retinol binding protein and prostaglandin
      production by porcine uterine epithelial cells in vitro.
AB  - Secretion into the uterine lumen follows a precise pattern during early
      pregnancy. Near the end of the second week of pregnancy and coincident with
      elongation of conceptuses, retinol, retinol binding protein (RBP), estradiol
      (E2), and prostaglandins E (PGE) and F (PGF) increase in the uterine lumen, and
      RBP mRNA increases in the endometrium. In the present studies the potential for
      E2 (0.1 microM) and retinol (10 microM) to regulate RBP and PG production by
      cultured luminal (LEC) and glandular (GEC) epithelial cells collected from
      postpubertal females and LEC from prepubertal gilts was examined. Endometrial
      tissue was collected surgically from cyclic and pregnant females (n = 8) on d 10
      and 13 postestrus (first day of estrus = d 0) and from 120- and 150-d-old
      prepubertal gilts that were treated with progesterone (P4) (2.2 mg x kg(-1) x d(
      1), n = 6) or corn oil (n = 6) for 14 d prior to tissue collection. The LEC from
      postpubertal females responded to retinol with increased (P < 0.05) RBP, PGE, and
      PGF in culture medium and increased (P < 0.07) RBP mRNA but E2 decreased (P <
      0.05) RBP and RBP mRNA and had no effect on prostaglandins. No E2 or retinol
      effects on secretions of GEC occurred in vitro, but a day x pregnancy status
      interaction (P < 0.06) affected PGE output by the GEC. Secretion of PGE was
      greater when GEC were collected on d 10 of pregnancy than from d-10 cyclic or d
      13 pregnant or cyclic females. Both E2 and retinol stimulated (P < 0.05)
      secretion of RBP by LEC isolated from prepubertal gilts, but their effects were
      not additive. In vivo treatment of prepubertal gilts with P4 increased (P < 0.05)
      RBP and decreased (P < 0.05) PG production by LEC in vitro. Therefore responses
      to E2 and retinol differ between pre- and post-pubertal females, and retinol may
      function in the regulation of endometrial RBP and PG secretion.

PMID- 12413093
TI  - The relationship between body condition, leptin, and reproductive and hormonal
      characteristics of mares during the seasonal anovulatory period.
AB  - An experiment was conducted to determine the effects of high vs low body
      condition scores (BCS) produced by restricted feeding on reproductive
      characteristics, hormonal secretion, and leptin concentrations in mares during
      the autumnal transition and winter anovulatory period. Mares with BCS of 6.5 to
      8.0 were maintained on pasture and/or grass hay, and starting in September, were
      full fed or restricted to produce BCS of 7.5 to 8.5 (high) or 3.0 to 3.5 (low) by
      December. All but one mare with high BCS continued to ovulate or have follicular
      activity during the winter, whereas mares with low BCS went reproductively
      quiescent. Plasma leptin concentrations varied widely before the onset of
      restriction, even though all mares were in good body condition. During the
      experiment, leptin concentrations gradually decreased (P < 0.0001) over time in
      both groups, but were higher (P < 0.009) in mares with high vs low BCS after 6 wk
      of restriction, regardless of initial concentration. No differences (P > 0.1)
      between groups were detected for plasma concentrations of LH, FSH, TSH, GH,
      glucose, or insulin in samples collected weekly; in contrast, plasma prolactin
      concentrations were higher (P < 0.02) in mares with high BCS, but also decreased
      over time (P < 0.008). Plasma IGF-I concentrations tended (P = 0.1) to be greater
      in mares with high vs low BCS. The prolactin response to sulpiride injection on
      January 7 did not differ (P > 0.1) between groups. During 12 h of frequent blood
      sampling on January 12, LH concentrations were higher (P < 0.0001), whereas GH
      concentrations (P < 0.0001) and response to secretagogue (EP51389; P < 0.03) were
      lower in mares with high BCS. On January 19, the LH response to GnRH was higher
      (P < 0.02) in mares with high BCS; the prolactin response to TRH also was higher
      (P < 0.01) in mares with high BCS. In conclusion, nutrient restriction resulting
      in low BCS in mares resulted in a profound seasonal anovulatory period that was
      accompanied by lower leptin, IGF-I, and prolactin concentrations. All but one
      mare with high BCS continued to cycle throughout the winter or had significant
      follicular activity on the ovaries. Although leptin concentrations on average are
      very low in mares with low BCS and higher in well-fed mares, there is a wide
      variation in concentrations among well-fed mares, indicating that some other
      factor(s) may determine leptin concentrations under conditions of high BCS.

PMID- 12413094
TI  - Apparent ruminal degradation and rumen escape of soluble nitrogen fractions in
      grass and grass silage administered intraruminally to lactating dairy cows.
AB  - The main objective of this study was to investigate in vivo ruminal degradation
      and rumen escape of soluble N fractions in grass and grass silage. Soluble
      protein and long-chain peptides (PLP), small peptides (SP) and free AA (FAA) were
      obtained from fresh grass and grass silages fertilized with different levels of
      N. Soluble extracts from the forages were pulse dosed into the rumen of three
      cannulated lactating dairy cows, and a simple or complex model was used to
      examine the kinetics of the soluble N fractions in the rumen. When soluble
      extracts from silage were investigated, pulse dosages of total nonammonia N (NAN)
      were 21, 27, and 32 g, while for fresh grass only dosages of 20 g were ruminally
      administered. In the silage extracts, mean proportions of PLP-N, SP-N, and FAA-N
      in the NAN were 30, 52, and 18%, respectively, whereas in the fresh grass the
      corresponding values were 67, 20, and 13%. From silage extracts, all three
      soluble N fractions showed a linear decrease (P < 0.05) in degradation rate and
      an increase (P < 0.05) in ruminal escape with increasing dosage. In silage, mean
      degradation rates, parameterized from the complex model, were 230, 214, and
      334%/h for PLP-N, SP-N, and FAA-N, respectively, and the ruminal escape was
      highest (P < 0.05) for SP-N (11.2% of dose) and lowest (P < 0.05) for FAA-N (5.0%
      of dose). No differences in degradation rate and ruminal escape between fresh
      grass and silage were observed. However, the proportion of N dose converted to
      ammonia was only 24% in the fresh grass, whereas for the silages a mean value of
      76% was found. From this study, it is concluded that a significant amount of
      dietary soluble N escapes ruminal degradation, and thus contributes to the
      intestinal AA supply. Moreover, if the main aim is to study degradation kinetics
      of individual N fractions, a complex model should be used in the evaluation. This
      model can also be used to study ruminal synchronization of N and energy for
      microbial growth.

PMID- 12413095
TI  - Effects of supplementation on intake and growth of nursing calves grazing native
      range in southeastern North Dakota.
AB  - A 2-yr study was conducted to determine the first limiting nutrient for gain in
      nursing calves grazing native range in southeastern North Dakota. Thirty-two
      calves (20 steers, 12 heifers) in Trial 1 (169 +/- 5 kg initial BW) and 31 (16
      steers, 15 heifers) in Trial 2 (214 +/- 5 kg initial BW) grazed common pastures.
      Calves were blocked by sex and stratified by weight. Calves were stratified by
      age of dam in Trial 1 and by pretrial milk intake (MI) in Trial 2. Treatments
      were nonsupplemented control (CON); energy supplement (ENERGY; 100% soyhulls);
      degradable intake protein supplement (DIP; 68% soyhulls, 32% SBM); and degradable
      with undegradable intake protein supplement (DIP+UIP; 80% sulfite-liquor treated
      SBM, 16% feather meal, 4% blood meal). In Trial 2, 5% molasses was added to all
      supplements with the ratios of other ingredients held constant. Supplements were
      formulated to be similar in NE. The DIP and DIP+UIP supplements supplied equal
      amounts of degradable protein. Supplemented calves were fed individually, with
      similar supplement DMI. Weight and MI were measured in July, August, and
      September. Forage intake (FI) was measured in July, August, and September of
      Trial 1 and July and August of Trial 2. Gain data were analyzed as a randomized
      complete block and MI and FI as a split-plot in time. Orthogonal contrasts were
      used to separate means and included CON vs supplemented, ENERGY vs protein, and
      DIP vs DIP+UIP. No trial effect or trial x treatment interactions (minimum P
      value = 0.30) were detected for ADG. Supplemented calves gained faster than CON
      (P = 0.06). No other contrast differences were observed (minimum P-value = 0.50).
      Treatment did not affect FI (P > or = 0.55). Forage intake was lower (P < 0.001)
      in Trial 1 than in Trial 2. A linear increase (P = 0.0001) in FI (kg OM/d and
      percentage BW) occurred over time. Calves in Trial 2 consumed more (P = 0.004)
      fluid milk than calves in Trial 1, though no difference (P = 0.28) was observed
      relative to BW. No treatment or period differences were detected for fluid MI
      (minimum P-value = 0.23). Relative to BW, MI declined linearly (P = 0.0001) with
      successive periods. Energy may be limiting weight gain of nursing calves grazing
      native range in southeastern North Dakota.

PMID- 12413096
TI  - Effects of restricted versus conventional dietary adaptation on feedlot
      performance, carcass characteristics, site and extent of digestion, digesta
      kinetics, and ruminal metabolism.
AB  - Three experiments were conducted to determine effects of restricting intake of
      the final finishing diet as a means of dietary adaptation compared with diets
      increasing in grain over a period of 20 to 22 d on overall cattle performance,
      carcass characteristics, digestibility, digesta kinetics, and ruminal metabolism.
      In Exp. 1, 84 Angus x Hereford yearling steers (initial BW = 418 +/- 29.0 kg)
      were fed for 70 d. Restricting intake during adaptation had no effect (P > 0.10)
      on overall ADG:DMI, but decreased (P < 0.05) DMI compared with ad libitum access
      to adaptation diets, which resulted from differences during the initial 28 d of
      the experiment. In Exp. 2, 150 mixed crossbred steer calves (initial BW = 289 +/-
      22.9 kg) were fed for an average of 173 d. Restricting intake decreased (P <
      0.01) overall daily gain (1.51 vs 1.65 kg/d) and DMI (8.68 vs 9.15 kg/d) compared
      with ad libitum fed steers; however, ADG:DMI was not influenced (P > 0.10) by
      adaptation method. Experiment three used eight ruminally and duodenally
      fistulated steers (initial BW = 336 +/- 20 kg) in a completely random design.
      Total tract digestibility, digesta kinetics and ruminal metabolism were
      determined. Restricting intake reduced (P < 0.10) daily DMI variation from d 1
      through 7, 8 through 14, and 22 through 28 compared with ad libitum feeding of
      three adaptation diets. Restricted steers had reduced (adaptation method x period
      interaction, P < 0.05) intakes and fecal excretions of ADF and greater OM
      digestibilities on d 4 through 7, 11 through 14, and 18 through 21. Digesta
      kinetics and ruminal metabolism were generally not affected (P > 0.10) by
      adaptation method. Our results suggest that restricted-feeding of the final diet
      as a means of dietary adaptation can be used in finishing cattle with few
      problems from acidosis or related intake variation. In light-weight steers (Exp.
      2), disruptions in intake during the adaptation period might have resulted in
      restriction for an extended period, which decreased (P < 0.01) hot carcass weight
      compared with calves fed ad libitum. Effects of limit feeding during the initial
      28 d of the feeding period on site and extent of digestion, digesta kinetics, and
      ruminal metabolism were minimal, supporting few differences in performance across
      the finishing period for yearling cattle.

PMID- 12413097
TI  - Influence of food deprivation on the transport of 3-O-methyl-alpha-D-glucose
      across the isolated ruminal epithelium of sheep.
AB  - Recent studies provided evidence that the ruminal epithelium is able to absorb D
      glucose even at physiologically low intraruminal concentrations. To elucidate
      whether ruminal D-glucose transport shows adaptive responses during food
      deprivation, transport of 3-0-methyl-alpha-D-glucose (3-OMG), a hardly
      metabolizable D-glucose analogue, was measured in isolated ruminal epithelia
      obtained from hay-fed or food-deprived adult sheep. In both groups, a significant
      net absorption of 3-OMG to the serosal side (in vivo: blood side oriented) could
      be detected at 3-OMG concentrations between 0.25 mM and 5 mM. Net absorption of 3
      OMG was abolished by mucosal (in vivo: lumen side oriented) addition of
      phlorizin, an inhibitor of the sodium glucose-linked transporter 1 (SGLT-1). Net
      absorption of 3-OMG followed Michaelis-Menten kinetics, but apparent affinity and
      maximal transport capacity were lower in epithelia obtained from food-deprived
      sheep. In contrast to the decrease of the (secondary) active 3-OMG transport,
      serosal-to-mucosal permeation of 3-OMG increased after food deprivation,
      suggesting an elevated passive 3-OMG transfer. It is concluded that the altered
      transport characteristics are either part of a global energy-sparing process
      during food deprivation (i.e., a lowered activity of the Na+/K+-ATPase) or result
      from specific down-regulation of SGLT-1.

PMID- 12413098
TI  - Effect of zinc source (zinc oxide vs zinc proteinate) and level on performance,
      carcass characteristics, and immune response of growing and finishing steers.
AB  - Sixty Angus and Angus x Hereford steers (246 kg initial BW) were used to
      determine the effects of Zn level and source on performance, immune response, and
      carcass characteristics of growing and finishing steers. Treatments consisted of
      1) control (no supplemental Zn), 2) ZnO, 3) Zn proteinate-A (ZnProt-A, 10% Zn),
      and 4) ZnProt-B (15% Zn). Treatments 2, 3, and 4 supplied 25 mg of supplemental
      Zn/kg diet. Steers were individually fed a corn silage-based diet during the 84-d
      growing phase and a high corn diet during the finishing phase. Cell-mediated and
      humoral immune response measurements were obtained between d 67 and 74 of the
      growing phase. Equal number of steers per treatment were slaughtered after
      receiving the finishing diets for 84 or 112 d. Performance and carcass
      measurements were similar in steers fed the two ZnProt sources. Zinc
      supplementation, regardless of source, increased (P < 0.05) ADG during the
      growing phase. In the finishing phase, ADG (P = 0.10) and gain/feed (P = 0.07)
      tended to be higher for steers fed ZnProt compared with those supplemented with
      ZnO. Gain and feed efficiency were similar for control and ZnO-supplemented
      steers during the finishing phase. Steers fed ZnProt had heavier (P < 0.05) hot
      carcass weights and slightly higher (P < 0.05) dressing percentages than those in
      the control or ZnO treatments. Quality grade, yield grade, marbling, and backfat
      were increased by Zn supplementation, but were not affected by Zn source. In
      vitro response of lymphocytes to mitogen stimulation and in vivo swelling
      response following intradermal injection of phytohemagglutinin were not affected
      by Zn level or source. Humoral immune response following vaccination with
      infectious bovine rhinotracheitis also was not affected by treatment. Soluble
      concentrations of Zn in ruminal fluid were higher (P < 0.05) in steers fed ZnProt
      compared to ZnO steers. Results indicate that ZnProt may improve performance of
      finishing steers above that observed with inorganic Zn supplementation.

PMID- 12413099
TI  - Validity of specifically applied rare earth elements and compartmental models for
      estimating flux of undigested plant tissue residues through the gastrointestinal
      tract of ruminants.
AB  - The validity of using rare earth elements as flow markers of undigested residues
      was evaluated by comparing mean gastrointestinal residence time (GMRT) of rare
      earths specifically applied to cottonseed hulls (CSH) to that of the indigestible
      fiber of CSH. Feces were collected from five lambs fed a mineral supplemented
      diet of CSH containing 52 g CP/kg DM and five lambs fed a CSH plus cottonseed
      meal diet (CSH+CSM) containing 123 g CP/kg DM. Rare earth elements (La, Yb, and
      Tb) specifically bound to CSH were included in the diet for a 5-d period and then
      deleted from the diet for a 3-d period. Following the last fecal collection,
      lambs were slaughtered for collection of digesta from segments of the
      gastrointestinal tract. Potentially indigestible NDF (PIF) was determined in
      diets and digesta from each segment of the gastrointestinal tract. Mean turnover
      rate, time delay, and GMRT for each rare earth element was estimated by fitting
      an age-dependent compartment model to profiles of markers appearing in the feces
      (compartmental model-marker method, CMM). The GMRT also was computed by the
      indigestible entity pool dilution method (IEPD) as grams of PIF in sampled
      segment/mean intake rate of PIF proceeding slaughter, g/h. The GMRT computed by
      the CMM and the IEPD methods did not significantly (P < 0.05) differ (99.6 vs
      94.8 h and 58.9 vs 59.5 h for CMM vs IEPD and CSH and CSH+CSM diets,
      respectively). Regression of GMRT estimated for rare earths vs PIF yielded a
      highly significant regression (P = 0.001) with a regression coefficient of 0.94
      +/- 0.016. It was concluded that rare earth elements applied to specific feeds
      are valid flow markers for the undigested residues derived from such marked
      feeds.

PMID- 12413100
TI  - Relationship between aging and nutritionally controlled growth rate on heat
      production of ewe lambs.
AB  - The hypothesis of this study is that ewes that have equal body weights, but
      differ in chronological age due to nutrient restriction, do not differ in
      metabolic rate. The objective of this study was to determine how reducing growth
      rate nutritionally alters the relationship between heat production per unit body
      weight and aging. Fasting heat production of 12 Dorset ewe lambs at 114 +/- 2 d
      of age was determined, and ewes were assigned to treatments. Treatments consisted
      of two different feeding levels of the same diet (ME = 2.5 Mcal/kg DM and 16.6%
      CP). The High treatment was offered 4.5% of their weekly BW per day, and the Low
      treatment was offered 2.5% of their weekly BW per day. Each treatment consisted
      of six animals that remained within treatment for the remainder of the study.
      Indirect-calorimetry measurements were repeated every 6 wk. Treatments differed
      in both the linear and quadratic term for fasted BW on age (P < 0.001). The rate
      of BW gain decreased as ewes aged in the High treatment, and the rate of BW gain
      increased as ewes aged in the Low treatment. The heat production:BW (HP:BW) ratio
      decreased in the High treatment as ewes aged and was described well by a
      previously reported prediction equation, but the ratio in the Low treatment was
      not described by this same equation. Describing the HP:BW ratio on age response
      with treatment-specific decay functions fit the data better than the pooled
      treatment function (P < 0.001). The HP:BW ratio decreased rapidly in the Low
      treatment following feed restriction, but remained elevated compared to the High
      treatment as animals aged. After excluding the initial measurements in the Low
      treatment that were taken before nutritional treatments were imposed, the HP:BW
      ratio was best described by a linear decrease. In conclusion, this study suggests
      that a previous model taking into account proportion of mature body size is a
      reasonable predictor for heat production across breeds of sheep growing in
      nutritionally adequate environments; however, it cannot be extended to sheep that
      are proportionally smaller in their mature BW due to nutritional restriction.

PMID- 12413101
TI  - Oregon State University's Steer-a-Year program: integrating classroom learning
      and hands-on experience.
AB  - The Steer-a-Year course is designed to provide classroom and hands-on experience,
      industry-student interaction, and student group problem-solving opportunities. It
      is a cooperative agreement between the Department of Animal Sciences and the
      Oregon Cattlemen's and Cattlewomen's Associations. Steers are donated to the
      program by beef producers, fed a high concentrate ration to a target BW and
      condition, and marketed as either carcass or retail beef. After feed and
      management expenses are deducted, the Department of Animal Sciences retains one
      half of the profit to be used for beef facilities improvements, and the other
      half is distributed to the donor's choice of either the Oregon Cattlemen's or
      Cattlewomen's Association. Approximately 30 steers have been donated to the
      program annually each of the past eight years. The donor receives updates
      regarding steer performance during the feeding period and carcass data following
      harvest of the animal. Students and instructors feed and manage the steers. The
      instructor uses classroom time to provide information to enable students to make
      informed management decisions. Officers are elected from within the class each
      term. Student officers are responsible for ensuring that cattle are managed and
      fed appropriately, and they lead the class in writing and sending producer
      updates. An evolving facet of the program is processing and marketing. Steers are
      sold locally through the Clark Meat Science Center. Students are encouraged to
      participate in a separate course in which they process the steers into retail
      product. In this manner, students can be involved in procurement, management,
      processing, and marketing. The course is challenging for the instructor since it
      requires management of lecture material, cattle health and feeding, producer and
      employee rapport, and student participation to ensure annual success of the
      program in terms of student learning and public relations. The course is very
      well received by students, most of whom have labeled it as a great learning
      experience.

PMID- 12413102
TI  - African American youth in the new millennium: an overview.
AB  - African American youth today are facing a fast changing world of high technology
      and diminishing opportunities. This generation brings a new attitude and a
      challenging perspective to service providers and policy makers. The policies and
      interventions of the past may need an upgrade to meet the needs of this new
      generation. The issues of poverty and meaningful opportunities are important to
      this generation that opposes many mainstream philosophies.

PMID- 12413103
TI  - Youth development: a positive strategy for African American youth.
AB  - The concept of positive youth development has been discussed and implemented for
      over ten years. The more recent emphasis on the connection between community and
      youth development is as important to the African American community in general as
      it is to African American youth. Opportunities to experience responsibility and
      involvement in their community, under the guidance of supportive adults, provide
      youth the chance of success for themselves and, ultimately, their communities.

PMID- 12413104
TI  - The plight of the African American student: a result of a changing school
      environment.
AB  - Educational problems of African American students are examined in the context of
      why young, successful early elementary school students are suddenly struggling in
      the late elementary and middle school years. Educators need to explore the
      educational environment, teacher attitudes and expectations, student empowerment,
      and the appropriateness of the curriculum.

PMID- 12413105
TI  - Health concerns for African American youth.
AB  - African American youth today face many challenges that can result in poor
      decisions and lead to high risk behavior. This nation has experienced a decrease
      in the number of teen pregnancies, but among African American youth the rates are
      still too high. African American youth also struggle with alcohol and drug
      addiction and limited access to health care. In short, there are many challenges
      to providing appropriate health care to our youth.

PMID- 12413106
TI  - Child support and African American teen fathers.
AB  - Our nation has turned its focus to personal responsibility and has subsequently
      formulated polices that have reformed welfare and strengthened child support
      enforcement. Teen fathers continue to present dilemmas for policy makers because
      of their status as minors, their lack of understanding of the policy implications
      for parenthood, their lack of skills, and their high unemployment status. African
      American teen fathers shoulder a larger burden in respect to the high
      unemployment rates and high drop out rates for African American males. Policies
      and programs must be developed that not only involve teen fathers with their
      children, but also provide them with the skills necessary to financially support
      themselves and their children.

PMID- 12413107
TI  - African American girls and the challenges ahead.
AB  - The research on the psychosocial development of African American girls is
      limited. Information that is available focuses on teen pregnancy and health
      issues such as nutrition and physical activity. African American girls are facing
      challenges, including poverty, crime, poor self-esteem, and peer pressure.
      Despite some of the negative characteristics attributed to African American
      girls, many are achieving some success. Policy makers and service providers need
      to recognize the resiliency and unique needs of African American girls and
      develop services that ensure their needs are being fully met.

PMID- 12413108
TI  - African American teens and the neo-juvenile justice system.
AB  - African American youth continue to be overrepresented in the juvenile justice
      system. As a result of the current political environment and the perceived
      increase in crime among young people, the nation has moved away from
      rehabilitation and toward harsher treatment of delinquents. The African American
      community must encourage policy makers and community leaders to continue to
      address the disproportionate representation of African American youth in the
      system. Current policing and prosecutorial policies must also be examined and
      challenged to end the perception of an unjust system.

PMID- 12413109
TI  - African American males at a crossroad.
AB  - With the recent debates regarding school drop outs, limited parental support,
      peer pressure, and social isolation, African American males are at a crossroad.
      For much too long attention has focused on factors that reflect poor self image
      and a lower sense of control over their destinies. Options are very limited, and
      it is important to consider the new public policy response to male responsibility
      utilizing natural support systems. Mentoring is a key variable to establishing
      greater community responsibility through primary prevention.

PMID- 12413110
TI  - Strengthening qualitative nursing research in Ghana.

PMID- 12413111
TI  - Psychometric assessment and clinical application of the Correa-Barrick Depression
      Rating Scale.
AB  - This article reports on the psychometric results of a new sef-report depression
      rating scale from three separate methodological research studies (pilot, main,
      and replication). Based on classical test theory, psychometric findings supported
      preliminary validity and reliability in the original study (N = 503), which
      consisted of a pilot study of 116 participants and a main study of 337 faculty
      and staff at a mid-Atlantic metropolitan university and 50 outpatients being
      treated for depression in a private psychiatric practice. The validity and
      reliability of the new scale was further supported in the replication study (N =
      121), which consisted of 96 outpatients and 25 inpatients under treatment for
      depression. In all three studies, results revealed that severe depression is
      associated with altered perception, particularly impairment in color sensitivity.
      Implications for clinical application are discussed.

PMID- 12413112
TI  - Minimizing fire risk during eye surgery.
AB  - Supplemental oxygen under the drapes in high concentrations can lead to fires in
      ophthalmic theaters. This study attempted to eliminate the fire risk while
      maintaining the required therapeutic effect. The sample consisted of 201 patients
      undergoing ophthalmic surgery, with 104 subjects in the control group and 97 in
      the experimental group. A quasi-experimental design compared the existing method
      of oxygen administration (100% supply) with a new method (experimental) providing
      24% oxygen supply. Measurements of the oxygen concentration were taken along with
      the fractional inspiratory carbon dioxide (FiCO2), the peripheral oxygen
      saturation (SpO2), the end tidal carbon dioxide (ETCO2), and the respiratory rate
      (RR). There was a significant difference in oxygen and carbon dioxide
      concentrations under the drapes (p <.05). The fractional inspiratory carbon
      dioxide was reduced in the experimental group. The new method was adopted to
      reduce the risk of fire in ophthalmic operating theaters.

PMID- 12413113
TI  - Evaluation of an educational video for cardiac patients.
AB  - Prehospital delay is a major problem in the management of patients with acute
      cardiac ischemia. The authors created a patient teaching program consisting of an
      educational video and written instructions designed to reduce prehospital delays
      in patients with chest pain. Patients who received standard discharge
      instructions served as the control group, whereas those who received the new
      patient teaching in addition to standard discharge instructions served as the
      intervention group. Of the 500 enrolled, 19% were rehospitalized within 1 year.
      Analysis of rehospitalizations showed no significant difference between the two
      groups on the three outcome variables: percentage who presented within thefirst
      hour of pain, use of ambulance, and time from anginal onset to emergency
      department arrival. In a comparison of the index hospitalization to the
      rehospitalization, there was a significant increase in the use of ambulances for
      the intervention group, p = .03, but not for the control group.

PMID- 12413114
TI  - Is self-reported height or arm span a more accurate alternative measure of
      height?
AB  - The purpose of this study was to determine whether self-reported height or arm
      span is the more accurate alternative measure of height. A sample of 409 people
      between the ages of 19 and 67 (M = 35.0) participated in this anthropometric
      study. Height, self-reported height, and arm span were measured by 82 nursing
      research students. Mean differences from criterion measures were 0.17 cm for the
      measuring rules, 0.47 cm for arm span, and 0.85 cm and 0.87 cm for heights. Test
      retest reliability was r = .997 for both height and arm span. The relationships
      of height to self-reported height and arm span were r = .97 and .90,
      respectively. Mean absolute differences were 1.80 cm and 4.29 cm, respectively.
      These findings support the practice of using self-reported height as an
      alternative measure of measured height in clinical settings, but arm span is an
      accurate alternative when neither measured height nor self-reported height is
      obtainable.

PMID- 12413115
TI  - Nurse practitioners and preventive screening in the hospital.
AB  - The purpose of this study was to investigate a reminder to discuss cervical
      cancer screening with hospitalized females. A quasi-experimental design was used
      to compare the association of a reminder intervention for nurse practitioners
      with two outcomes: prevalence of cervical cancer screening as documented in
      patients' charts and patients' self-report of cervical cancer screening 4 months
      after discharge. Data were collected by chart review and phone survey. The sample
      consisted of nurse practitioners caring for eligible female patients at a
      university teaching hospital. Chi-square was used to test all research questions.
      The rate of documentation of cervical cancer screening increased from 2% to 69%
      after implementation of the reminder intervention. The reminder intervention did
      not impact patients actually receiving Pap smears after discharge. The
      significant increase in documentation of screening associated with the use of the
      single reminder in the patients' charts support the use of this low-cost
      intervention.

PMID- 12413116
TI  - Computer-assisted self-interview and nutrition education in pregnant teens.
AB  - The purpose of this study was to conduct computer-assisted self-interview (CASI)
      nutrition assessment in a pregnant, adolescent African American population to
      compare the effect of a nutrition education intervention with the standard
      dietitian consult on gestational weight gain patterns and postpartum weight
      retention. Control group (n = 24) and experimental group (n = 22) data obtained
      from the nutritional assessment and measurement of gestational weight
      gain/postpartum weight retention patterns were compared during the second
      trimester, third trimester, and 6 weeks postpartum to evaluate the effectiveness
      of the program. The experimental group gained signficantly less weight during the
      first and second trimesters than the control group. During the third trimester
      gestational weight gain was significantly higher for the experimental group.
      Postpartum weight retention was signifcantly higher for the control group. There
      were no significant differences between maternal characteristics of the two
      groups. Fat content and daily caloric content of participants in the control
      group were significantly higher than the experimental group.

PMID- 12413117
TI  - Detection of relative and uniform motion.
AB  - We measured the lowest velocity (velocity threshold) for discriminating motion
      direction in relative and uniform motion stimuli, varying the contrast and the
      spatial frequency of the stimulus gratings. The results showed significant
      differences in the effects of contrast and spatial frequency on the threshold, as
      well as on the absolute threshold level between the two motion conditions, except
      when the contrast was 1% or lower. Little effect of spatial frequency was found
      for uniform motion, whereas a bandpass property with a peak at approximately 5
      cycles per degree was found for relative motion. It was also found that contrast
      had little effect on uniform motion, whereas the threshold decreased with
      increases in contrast up to 85% for relative motion. These differences cannot be
      attributed to possible differences in eye movements between the relative and the
      uniform motion conditions, because the spatial-frequency characteristics differed
      in the two conditions even when the presentation duration was short enough to
      prevent eye movements. The differences also cannot be attributed to detecting
      positional changes, because the velocity threshold was not determined by the
      total distance of the stimulus movements. These results suggest that there are
      two different motion pathways: one that specializes in relative motion and one
      that specializes in uniform or global motion. A simulation showed that the
      difference in the response functions of the two possible pathways accounts for
      the differences in the spatial-frequency and contrast dependency of the velocity
      threshold.

PMID- 12413118
TI  - Monochromatic aberrations of human eyes in the horizontal visual field.
AB  - We measured the monochromatic aberrations of five subjects' right eyes both
      temporally and nasally out to 40 degrees from fixation. We used a Hartmann-Shack
      sensor with modifications to equipment and software to enable off-axis
      measurements. Results were standardized for 6-mm pupils. There was considerable
      variation among subjects in the pattern of aberrations. Aberrations were
      generally greater in the nasal visual field than in the temporal visual field; in
      the case of third-order aberrations, this was true for all subjects. The
      contribution of third-order Zernike aberrations to the root-mean-square
      aberration increased up to four times from the center to the edge of the field,
      but the contribution of fourth- to sixth-order Zernike aberrations varied little
      across the visual field. Results were similar to those of a previous
      investigation using laser ray tracing and were of the order of those predicted by
      Navarro's finite schematic eye.

PMID- 12413119
TI  - Theories for the design of diffractive superresolution elements and limits of
      optical superresolution.
AB  - We suggest using the theory of linear programming to design diffractive
      superresolution elements if the upper bound of the intensity distribution on the
      input plane is restricted, and using variation theory of functional or wide-sense
      eigenvalue theory of matrix if the upper bound of the radiation flux through the
      input plane is restricted. Globally optimal solutions can be obtained by each of
      these theories. Several rules of the structure and the superresolution
      performance of diffractive superresolution elements are provided, which verify
      the validity of these theories and set some limits of optical superresolution.

PMID- 12413120
TI  - Hybrid diffraction tomography without phase information.
AB  - We introduce a hybrid tomographic method, based on recent investigations
      concerning the connection between computed tomography and diffraction tomography,
      that allows direct reconstruction of scattering objects from intensity
      measurements. This technique is noniterative and is intuitively easier to
      understand and easier to implement than some other methods described in the
      literature. The manner in which the new method reduces to computed tomography at
      short wavelengths is discussed. Numerical examples of reconstructions are
      presented.

PMID- 12413122
TI  - Generalized Bessel pulse beams.
AB  - A generalization of type 3 ultrashort pulses (also known as pulse beams or
      isodiffracting pulses) is introduced. The Bessel beam form of this generalized
      beam consists of pulses that propagate in free space, without spreading, with a
      velocity that can be less than that of light. A model spectral distribution that
      is zero outside a finite range is investigated.

PMID- 12413121
TI  - Minimizing stochastic moire in frequency-modulated halftones by means of green
      noise masks.
AB  - In color halftoning, moire is the low-frequency spatial artifact generated by the
      interference of superimposed primary color dot screens that adds an unwanted
      artificial texture to the printed image. When these overlapping dot screens are
      irregular, as in the case of stochastic dot screens, this interference pattern
      follows a random spatial distribution resulting in 'stochastic" moire. This
      stochastic moire is at its most visible when the overlapping dither patterns have
      the same relative spacing between dots. We study the occurrence of stochastic
      moire in green-noise halftones where dither patterns are composed of clusters of
      varying sizes and where the visibility of stochastic moire6 can be reduced by
      varying the coarseness of dither patterns between the component cyan, magenta,
      yellow, and black colors.

PMID- 12413123
TI  - Experimental study of the phenomenon of 1 x N spectral switch due to diffraction
      of partially coherent light.
AB  - Spectral properties of a class of partially coherent light with spectral profiles
      of varying bandwidths are studied on diffraction by a circular aperture in the
      far zone for different diffractive angles, i.e., for on-axis and off-axis points
      on the observation plane. It is found that the spectrum of the light in the far
      zone is different from that at the aperture plane. This change in the spectrum is
      termed spectral shift, which is found to be different at different diffractive
      angles. The spectral shift for a fixed diffactive angle shows a gradual change.
      However, for a critical value of the coherence at the aperture plane, the
      spectral shift shows a rapid transition, termed spectral switch. For different
      diffractive angles the coherence that causes the spectral switch also differs.
      Therefore the phenomenon of 1 x N spectral switch (consisting of one input port
      and N output ports) is studied experimentally.

PMID- 12413124
TI  - Reconstruction of gratings from noisy reflection data.
AB  - The worst-case error amplification factor in reconstructing a grating from its
      complex reflection spectrum is shown to be of the order 1/T(min), where T(min) is
      the minimum transmissivity through the grating. For a uniform grating with
      coupling coefficient-length product kappaL, the error amplification is
      exp(2kappaL). The exponential dependence on the grating strength shows that
      spatial characterization of gratings from a measured reflection spectrum is
      impossible if the grating is sufficiently strong. For moderately strong gratings,
      a simple regularization technique is proposed to stabilize the solution of the
      inverse-scattering problem of computing the grating structure from the reflection
      spectrum.

PMID- 12413125
TI  - Formation of three-dimensional periodic microstructures by interference of four
      noncoplanar beams.
AB  - A newly reported method of making three-dimensional microstructures or photonic
      crystals by holographic lithography has some obvious advantages over other
      techniques with the same purpose. A systematic and comprehensive analysis of
      interference of four noncoplanar beams (IFNB) is provided. It shows that all 14
      Bravais lattices can be formed by means of IFNB and gives explicit relationships
      between each lattice and the corresponding recording geometry. The concept of
      pattern contrast is extended to the case of IFNB, and it is indicated that a
      uniform contrast for each interference term can be obtained by properly choosing
      the beam ratio and polarization. A calculation algorithm is then developed to
      optimize the direction of polarization of each beam to ensure maximum uniform
      contrast. These results, verified by computer simulations, may lay a theoretical
      foundation for fabrication of photonic crystals with the approach of IFNB.

PMID- 12413126
TI  - Numerical integration schemes used on the differential theory for anisotropic
      gratings.
AB  - Several formulations of the differential theory for anisotropic gratings are
      investigated numerically. Conventional formulations and recent formulations based
      on Li's Fourier factorization rules are applied to a sinusoidal-profiled grating
      made of an anisotropic and conducting material. For both types of formulation,
      the numerical results of the differential and the rigorous coupled-wave methods
      are presented, and only the differential method based on Li's Fourier
      factorization rules provides a reliable convergence. Moreover, several numerical
      integration schemes used on the differential method are examined, and the
      advantage of the implicit integration schemes is shown.

PMID- 12413127
TI  - Fresnel zones in tapered gradient-index media.
AB  - The free propagation of a wave front in an inhomogeneous medium with parabolic
      refractive-index profile and the division of the wave front into Fresnel zones
      are studied. We determine the radius and the area of each zone as well as the
      zone contribution to the total wave at an observation point inside the medium. We
      find the condition that the optical path must fulfill from each zone to that
      point so that the disturbance due to successive zones will be in phase
      opposition. Once this condition is settled the concept of zone plate in gradient
      index media is introduced.

PMID- 12413128
TI  - Three-dimensional electromagnetic diffraction of a Gaussian beam by a perfectly
      conducting half-plane.
AB  - Formulas are derived for the diffraction of a three-dimensional electromagnetic
      Gaussian beam by a perfectly conducting half-plane. The beam can be incident from
      any direction, and the main component of the electric field can point in any
      direction on the plane of the beam waist. The center of the beam waist is on the
      edge of the half-plane. The incident beam is constructed as a superposition of
      plane waves, and the total diffracted field is obtained from a superposition of
      the diffracted fields that are due to each plane wave. Physical constraints that
      limit the size and direction of the beam relative to the half-plane are described
      and incorporated into the theory. The scattered field in the far zone is obtained
      by asymptotic evaluation of the general formulas. Graphical results for the near
      field as well as far-field patterns are presented and discussed.

PMID- 12413129
TI  - General perturbation technique for the calculation of radiative effects in
      scattering and absorbing media.
AB  - Recently it has been shown that the perturbation technique, based on joint use of
      both the direct and the adjoint solutions of the radiative transfer equation, is
      a powerful tool to solve and analyze various time-independent one-dimensional
      problems of atmospheric physics such as the calculation of weighting functions,
      prediction of radiative effects, and development of retrieval algorithms. Our
      primary goal is to obtain a general formulation of the perturbation technique for
      the most general case of the radiative transfer problem: time-dependent problems,
      with regard to polarization, and any possible external sources of radiation such
      as laser beams and solar illumination. Possible areas of application of the
      perturbation technique are discussed, and several examples to illustrate them are
      provided. The accuracy of this technique is discussed by considering the
      particular examples.

PMID- 12413130
TI  - Guided-mode analysis by the Lanczos-Fourier expansion.
AB  - The Lanczos-Fourier series expansion is employed to analyze the guided-mode field
      in an asymmetrical slab waveguide, the core of which has an anisotropic and
      inhomogeneous dielectric permittivity. A system of linear homogeneous equations
      is derived by the collocation technique with consideration of the wave equation
      and the appropriate boundary conditions at the interfaces between the core and
      cladding media. The propagation constants are found from a determinant equation
      that ensures the existence of a nontrivial solution of the system. Numerical
      results are presented for several cases of dielectric permittivity, including the
      constant, parabolic, linear, and anisotropic cases. This approach is found to
      converge reasonably fast, and Richardson's extrapolation technique is applied to
      accelerate the convergence further. The approach can be easily generalized from
      the scalar to the vector equation, and, as an example, we consider the guided
      modes of a circular fiber.

PMID- 12413131
TI  - Multispectrum, spatially addressable polarization interference filter.
AB  - We review current synthesis techniques for generating and improving birefringent
      filters. The relationship between wave-plate orientation and the resulting
      spectral output is shown to be that of a simple Fourier transform. By using this
      relationship and starting from the fan Solc configuration, we easily generated
      plate orientations providing lower sidelobe levels and improved finesse. We
      outline a method by which filters can be constructed to provide from 0 to 100% of
      the desired passband in a continuous fashion. Such a filter can be stacked to
      allow rapid control of any number of passbands and is shown, as an example in a
      novel design employing super-twisted nematic liquid crystal elements, to control
      a maximum of three color bands.

PMID- 12413132
TI  - Criteria for correction of quadratic field-dependent aberrations.
AB  - Aberrations of imaging systems can be described by using a polynomial expansion
      of the dependence on field position, or the off-axis distance of a point object.
      On-axis, or zero-order, aberrations can be calculated directly. It is well-known
      that aberrations with linear field dependence can be calculated and controlled by
      using the Abbe sine condition, which evaluates only on-axis behavior. We present
      a new set of relationships that fully describe the aberrations that depend on the
      second power of the field. A simple set of equations is derived by using
      Hamilton's characteristic functions and simplified by evaluating astigmatism in
      the pupil. The equations, which we call the pupil astigmatism criteria, use on
      axis behavior to evaluate and control all aberrations with quadratic dependence
      on the field and arbitrary dependence on the pupil. These relations are explained
      and are validated by using several specific optical designs.

PMID- 12413133
TI  - Long-term effect of total cycle time and aerobic/anoxic phase ratio on nitrogen
      removal in a sequencing batch reactor.
AB  - A laboratory-scale sequencing batch reactor was used to study nitrogen removal
      from a synthetic wastewater with an ammonium-nitrogen concentration of 50 mg/L.
      The effect of two key parameters (i.e., the total cycle time and the
      aerobic/anoxic phase duration ratio) on the performance of the reactor was
      investigated. Four sets of operational parameters resulting from the combination
      of 6 and 8 hours of cycle time and 1:1 and 1:3 aerobic/anoxic ratios were
      studied. Denitrification was based mainly on endogenous carbon sources as long as
      organic carbon, provided in the form of acetate, was quickly removed from the
      mixed liquor during the aerobic phase of the reactor operation. In terms of
      nitrogen removal efficiency, the set of 8 hours of cycle time and 1:3
      aerobic/anoxic phase ratio was found to be superior in that it consistently
      yielded an effluent total nitrogen concentration of less than 15 mg/L (consisting
      almost exclusively of nitrate-nitrogen) and exhibited a percentage nitrogen
      removal rate of 77 +/- 2.5%. In terms of wastewater throughput (i.e., wastewater
      volume treated per day), however, the implementation of 6 hours of cycle time and
      1:3 aerobic/anoxic phase ratio was satisfactory for nitrogen removal efficiency
      (72 +/- 2%), although elevated amounts of ammonium- and nitrite-nitrogen were
      found in the effluent. It was also demonstrated that under certain operating
      conditions nitrogen removal via nitrite is observed, as nitratification (i.e.,
      oxidation of nitrite-nitrogen to nitrate) and denitratification (i.e., reduction
      of nitrate-nitrogen to nitrite) are bypassed.

PMID- 12413134
TI  - Biological denitrification of hydrolysates from octahydro-1,3,5,7 tetranitro
      1,3,5,7-tetrazocine.
AB  - Alternatives for the destruction of common military explosives, including
      trinitrotoluene; hexahydro-1,3,5-trinitro-1,3,5-triazine; and octahydro-1,3,5,7
      tetranitro-1,3,5,7-tetrazocine (HMX) are being investigated in the post-cold war
      period. One alternative combines chemical treatment (i.e., base hydrolysis of the
      explosives) and biological treatment (i.e., denitrification of the hydrolysate).
      This paper focuses on results of the biological part of the treatment process,
      during which Hyphomicrobium sp. bacteria were isolated from a seed obtained from
      a denitrification facility. The bacteria were enriched and maintained on a
      surrogate waste with methanol as the carbon source. The resulting culture is
      capable of anoxic growth in waste solutions containing up to 5000 mg/L of nitrite
      nitrogen. The culture efficiently denitrifies both surrogate and actual
      hydrolysate wastes. A substrate inhibition model was used to accurately predict
      denitrification rates. Comparisons are made between denitrification rates
      obtained for surrogate versus actual wastes. Denitrification rates were higher
      when actual waste streams were used. This work demonstrates the feasibility of
      using Hyphomicrobiun sp. bacteria to treat HMX hydrolysate and presents a model
      that can be used to design a large-scale system.

PMID- 12413135
TI  - Significance of aqueous cation composition on heavy metal mobility in a natural
      clay.
AB  - Heavy metal mobility in soils is influenced by various soil variables and
      environmental factors, including the composition of the soil-aqueous phase. This
      study used the sequential extraction technique to study how major cations could
      affect heavy metal sorption and speciation in a natural clay. The sorption of Zn,
      Pb, and Cd by the soil in the presence of Na+ and Ca2+ and the resulting metal
      speciation in the sorbed phases were examined. Sorption experiments were
      performed at pH levels of 3 to 8. Sorptions occurring in both single and multiple
      heavy metal systems were investigated. The results show that Na+ and Ca2+
      significantly inhibited Zn, Pb, and Cd sorption in the acidic pH range only. The
      reduction in the exchangeable sorption was responsible for a large part of the
      reduction in the total Zn, Pb, and Cd sorption in the presence of Na+ and Ca2+.
      Specific adsorptions of heavy metals in other fractions of sorbed phases were
      only marginally affected by the composition of cations. The reduction in the
      exchangeable sorption increased with increasing concentration of Na+ and Ca2+. In
      the presence of a major cation, the competitive adsorption among the heavy metals
      seemed to have only a minor effect on individual heavy metal sorption.

PMID- 12413137
TI  - Determination of the inactivation rate of Ascaris eggs in wastewater
      stabilization pond sludge using dialysis chambers and sludge cores.
AB  - The inactivation rate of Ascaris eggs was studied in the sludge layer of a
      primary, facultative wastewater stabilization pond located in Mexico City. Two
      independent methods, sludge cores and dialysis chambers, were used, to determine
      the inactivation rates through which a comprehensive picture of the inactivation
      was gained. The dialysis chambers provided a detailed picture of the initial
      inactivation (14 months) at one location in the pond, whereas the sludge cores
      provided less precise information about the inactivation rate at several
      locations and over the entire lifetime of the pond (10 years). The inactivation
      curve was characterized by an initial lag phase, a period of roughly first-order
      inactivation, and a tailing region. During the first year, 50 to 60% of the eggs
      were inactivated, after which the rate decreased. Although the observed, initial
      first-order rate constant was greater than 0.002 d(-1), the average, long-term
      rate constant was closer to 0.001 d(-1).

PMID- 12413136
TI  - Physical enrichment of polyphosphate-accumulating organisms in activated sludge.
AB  - Two methods that physically separate polyphosphate-accumulating organisms (PAO)
      from other organisms in activated sludge were developed. The first method used
      4'6-diamidino-2-phenylindole dihydrochloride (DAPI) to selectively stain PAO.
      When excited with light at 340 nm, polyphosphate granules in DAPI-stained cells
      fluoresce yellow while cells without polyphosphate fluoresce blue. This
      difference in fluorescent response was used to separate PAO from non-PAO using
      flow cytometry. The second method consisted of a simple gradient centrifugation
      to physically separate PAO from non-PAO based on their density differences. Both
      methods produced cell suspensions with an increased PAO concentration. From an
      average PAO concentration of approximately 14% in a full-scale process, the DAPI
      flow cytometry method produced sorted samples with PAO representing more than 70%
      of the total cells, while the density gradient method produced an approximate 43
      to 48% PAO enrichment. The physical enrichment methods described herein should
      facilitate the identification and study of PAO that are relevant in full-scale
      enhanced biological phosphorus removal processes.

PMID- 12413138
TI  - Factors affecting photosynthetic rates of periphyton in shallow streams of
      southeastern Pennsylvania.
AB  - Photosynthetic rates during low-flow summer conditions were examined for eight
      reaches of the Christina Watershed in southeastern Pennsylvania with respect to
      light and nutrient availability. Photosynthetic rates in these shallow streams
      ranged from 0.9 to 25.4 g O2/m2 d. Soluble orthophosphorus concentrations ranged
      from 0.004 to 0.63 mg/L, and phosphorus was considered the limiting nutrient for
      periphyton growth based on a nitrogen/phosphorus ratio exceeding 10 (by weight).
      Light availability varied among reaches from densely wooded canopies to open
      pasture. Nutrient availability was examined in terms of concentration and
      advective flux, which was calculated as the product of stream velocity and
      nutrient concentration. Cluster analyses were applied to group the nutrient and
      light availability factors and the photosynthetic rate responses into low,
      moderate, and high levels. The most consistent predictor of high photosynthetic
      rates was the joint occurrence of moderate-to-high levels of light and nutrient
      flux.

PMID- 12413139
TI  - Food-processing wastes.

PMID- 12413140
TI  - Activated sludge and other aerobic suspended culture processes.

PMID- 12413141
TI  - Of: Microbial risks from wastewater irrigation of salad crops: a screening-level
      risk assessment, S. R. Petterson; N. J. Ashbolt; A. Sharma, 73, 667 (2001).

PMID- 12413142
TI  - The brain and other sites of erythropoietin production.
AB  - Ischemic hypoxia of the head induced in dogs by carotid compression produces EPO
      secretion, upon direct cerebral stimulation, and adaptive carotid-respiratory
      reflexes via sino-carotid stimulation. During hypoxic hypoxia, there also occurs
      extrarenal EPO production, as shown in binephrectomized rats compared to
      controls. Ischemic hypoxia of a single kidney transplanted in the neck area (the
      other kidney being removed) does not induce EPO secretion. An additional factor,
      of extra-renal origin, is required for the renal production of EPO in a non
      hypoxic organism. Section of the spinal cord at C6 level in rats does not abolish
      EPO secretion induced by hypobaric hypoxia, a fact that suggests that there is no
      nervous center to control EPO release into a peripheral organ, but EPO might be
      produced in the brain itself, possibly crossing the blood-brain barrier to reach
      the blood flow. Stereotactical attempts to locate nervous centers of
      erythropoiesis regulation also failed. EPO secretion obtained by electrical
      stimulation of different brain areas suggests the existence of widespread
      secretory cells, which might be the astrocytes. EPO production along the lymph
      forming territories and the involvement of the lining macrophages is reported.

PMID- 12413143
TI  - Free radicals between health and disease.

PMID- 12413144
TI  - Influence of light-dark cycle alteration on free radical level in rat cns.
AB  - The experiment analysed the evolution of several redox parameters caused by light
      dark cycle alteration in different rat brain segments: cortex, brain stem,
      diencephalon. Continuous light (L:L) enhanced SOD, CAT, GPX and GSH levels to
      different extents in the various central nervous system regions investigated,
      depending on the entrainment period: 24 h, 48 h, 72 h, 7 days. Continuous
      darkness (D:D -24 h, 48 h, 72 h, 7 days) generally diminished SOD, CAT and GSH
      values, but increased GPX at 48 h and CAT at 72 h. MDA levels were higher in D:D,
      too. After 7 days L:L or D:D redox indices tended to reach the normal range
      again. Redox system spatio-temporal versatility and complementarity suggested the
      existence of a possible biochemical radical cell clock gear.

PMID- 12413145
TI  - Stress assessment by means of questionnaires.
AB  - A comprehensive methodology for the measurement of stress comprises objective
      physiological and biochemical methods as well as application of self-reporting
      scales. This overview focuses on the subjective procedures, their psycho
      physiological theoretical background and practical issues. We discuss the most
      valuable procedures used to assess stress factors, reactions to stress and
      relationships between the stressed subject and the physical and psychosocial
      environment. The strengths and limitations of self-reports and the conditions to
      obtain reliable data and to interpret the findings are outlined. The results of
      several investigations performed by our teams concern especially the assessment
      of occupational stress.

PMID- 12413146
TI  - Circannual period of physical performance analysed by means of standard cosinor
      analysis: a case report.
AB  - Variation of physical fitness during the day is well investigated and is used
      both in athletes training as well as during sports contests. Circannual
      periodicities, on the other hand, seem to exist but have not been investigated
      systematically so far. The present case report shows that absolute increase in
      the number of press-ups varies during the year and can be modelled by means of
      standard cosinor analysis. Moreover, published data dealing with circannual
      rhythm of muscle strength could be fitted into a cosinor model. These results
      indicate a circannual increase of performance and warrant further controlled
      investigations. Due to methodological problems in trials for circannual rhythms,
      population cosinor models may be a suitable approach.

PMID- 12413147
TI  - The "patholog" of the genes expression profile, a new tool in defining,
      evaluating, and classifying genetic diseases.
AB  - The paper introduces the pre-Hilbert space of standard gene expression (SSGE)
      based on the normal variability in gene profiles, as revealed by the "spotting"
      microarray technique. In this space, every point represents a possible gene
      profile and every continuous curve a possible genetic evolution. The gene
      "patholog" is defined as the Euclidean distance separating the representative
      point of the gene profile from the unit, 0-centered hyperball. It is the most
      general quantification of the alteration in digital genes expression, suitable to
      define, evaluate, and classify the genetic diseases. Our mathematical model and
      the afferent computer package allow the researcher to identify the patterns of
      various genetic afflictions in the SSGE. A publicly available database will be
      opened where every interested experimentalist could introduce his/her results and
      process them according to our procedure.

PMID- 12413148
TI  - New protocol in spotting microarray technique.
AB  - The "spotting" microarray technique, consisting in large sets of DNA sequences
      spotted on poly-L-lysine-coated glass microscope slides, has been developed to
      comparatively analyze genome-wide patterns of mRNA expression. It is now a
      valuable tool employed in order to quantitatively monitor gene expression
      profiles, as well as to analyze the alterations produced in case of genetic
      diseases, or induced by different treatments, abnormal nutrition and toxin. Our
      group improved the standard protocol as well as the results spreadsheet, adding
      new experiments and mathematical processing procedures in order to increase the
      accuracy of the data and get new information. In this contribution, we propose
      and verify two procedures to correct the spot ratios and a new protocol to get
      the normal variability of the digital gene expression.

PMID- 12413149
TI  - Alterations induced by lithium in gfap expression and in the proteinic
      composition of glial cells in vitro.
AB  - In the adult brain, astrocytes account for about 40% of the cell population in
      the central nervous system. Normal, reactive and neoplastic astrocytes can be
      identified in immunohistochemical preparations by means of glial fibrillary acid
      proteins (GFAP) expression. This protein is considered to be a sensitive
      indicator of xenobiotics toxicity. Previous studies have demonstrated that 2 mM
      LiCl induce alterations of astrocyte morphology after 18-20 days of treatment in
      vitro. We have decided to study GFAP expression under such conditions.
      Immunodetection and Western blotting assays have shown 2 mM of LiCl to induce
      alterations of GFAP expression both after 12 days of treatment and after 18-20
      days. Moreover, 2 mM of LiCl induce an alteration of the proteinic composition of
      cells.

PMID- 12413150
TI  - Preclinical qualitative evaluation of the antitumoral pharmacodynamic action of
      some natural polyphenolic biopreparations.
AB  - We have investigated the impact of POLYAS I and POLYAS II polyphenolic
      biopreparations - specifically separated and purified from Asclepias syriaca
      leaves, and characterized in vitro as cytotoxic and/or cytostatic agents - on the
      tumor generation process. A series of in vivo tests of their effect on the
      development of Guerin T-8 lymphotropic epithelioma and Walker 256 carcinosarcoma
      were conducted. In a first stage of preclinical trial we had used several tests
      meant to evaluate their antitumoural activity indices. The same tests were then
      used under similar experimental conditions in the solid tumoral systems
      mentioned. A comparative analysis of the antitumoral activity evaluation indices
      resulting from our tests with the reference indices set by the American and
      German preclinical screening programs pointed to their compatibility. Thus, we
      found similar values of mean tumoral regressions, of the ratio between mean
      tumoral weights of the treated and control groups, respectively, of the T/C
      products resulting from successive re-tests. Also T/C values resulting from
      retests were within the limits of admissible variability range. All those results
      highlighted the antineoplastic pharmacotherapeutic effect of the polyphenolic
      biopreparations and also proved that effect to be replicable. The qualitative
      evaluation of the pharmacodynamic action of those preparations was a condition
      for their further quantitative pharmacological evaluation in point of antitumoral
      therapeutic effectiveness in a preclinical stage.

PMID- 12413151
TI  - Preclinical trial of the antitumoral therapeutic effectiveness of some natural
      polyphenolic biopreparations.
AB  - We have assessed the antitumoral action of the POLYAS I and POLYAS II vegetal
      polyphenolic biopreparations--separated and purified from Asclepias syriaca
      leaves - in rats with various experimental tumoral lines. We studied the
      therapeutic effect of different doses on the tumor generation process and
      compared it with the experimental oncostatic action of several standard
      chemotherapeutic drugs of clinical use (thiotepa, methotrexate, melphalan and
      cyclophosphamide). In our experimental treatment with the bioactive polyphenolic
      agents, we have used various doses, both higher and lower than the dose that had
      conditioned the expression of their antitumoral action upon Guerin T-8
      lymphotropic epithelioma and upon Walker 256 carcinosarcoma. We found the
      antineoplastic effectiveness of those aromatic biopreparations from phytomass to
      be dose-dependent. We compared the evaluation indices of the antitumoral
      pharmacodynamic effect we obtained in the treatment with the POLYAS
      biopreparations with those of reference cytostatic agents. The antitumoral
      potential of the new natural biopreparations is higher than, equal or close to
      that of the standard oncochemotherapeutic agents. Antitumoral effectiveness can
      be improved by an experimental manipulation of the therapeutic doses--which
      proves the existence of a dose-response relationship. POLYAS I and POLYAS II
      polyphenolic biopreparations are compatible in point of effectiveness with the
      standard cytostatic agents, a fact that we considered relevant for the
      characterization of the POLYAS I and POLYAS II vegetal extracts as potential
      antineoplastic agents. The quantitative preclinical evaluation of the specific
      pharmacodynamic effect will be complemented by the investigation of the new
      polyphenolic biopreparations therapeutic effectiveness in tumors with various
      degrees of development.

PMID- 12413152
TI  - Fifty years of the American Academy of the History of Dentistry.

PMID- 12413153
TI  - Gardner P.H. Foley: colorful dean of dental historians.
AB  - Gardner P. H. Foley, A.B., A.M, D.Sc. (1902-1997) served 41 years as professor of
      dental literature and history at the Baltimore College of Dental Surgery, Dental
      School University of Maryland. As "dean of dental historians," Dr. Foley had an
      illustrious career that spanned 70 years. During his lengthy tenure at Maryland,
      Foley, who was not a dentist, taught over 3,000 dental students. Foley's Irish
      background, New England drawl and his early childhood memories and experiences in
      the charming seaside village, Gloucester, Massachusetts, influenced him
      throughout his life. Throughout his career, Dr. Foley was motivated to
      investigate aspects of literature and recorded history pertaining to teeth and
      dentistry. His extensive research, prodigious memory and numerous published
      columns, books and articles, have helped establish the important role that
      dentists have played in historic events throughout the ages. As a founding member
      of the American Academy of the History of Dentistry, Gardner Foley prepared the
      first draft of a constitution for the Academy. Dr. Foley left a legacy of
      accomplishment in the literature and the history of dentistry, which remains a
      source of pride to all those associated with this profession.

PMID- 12413154
TI  - 19th Century dentistry advertising trade cards.

PMID- 12413155
TI  - Gleanings about dentistry from the world of literature (Twenty-eight in a
      series).

PMID- 12413156
TI  - Dentistry on currency.

PMID- 12413157
TI  - A history of dental amalgam.
AB  - OBJECTIVES: Silver amalgam alloy has been used as a dental restorative material
      since the beginnings of restorative dentistry. It rose as an easily manipulated
      and low cost material in comparison to other restorative techniques of the time,
      but it had poor dimensional stability and clinical behavior. Successive research
      led to the standardization of both its composition and some aspects of its
      mechanical properties, which have contributed to its widespread acceptance.
      Nevertheless, the risk of environmental toxicity generated by mercury and its
      poor esthetics have given rise to the search for alternative and more promising
      materials. This article endeavors to give a brief historical description of the
      main events which have led to development of modern silver amalgam alloys.
      SIGNIFICANCE: It is concluded that extensive knowledge of the use of silver
      amalgam alloy has made it the most widely used restorative material for the
      posterior oral cavity. However, in recent years its preponderance has been
      brought into question even though some innovative ideas have been suggested which
      could help improve this material in the future.

PMID- 12413158
TI  - Johann Friedrich Dieffenbach (1792-1847) pioneer in oral maxillofacial surgery.
AB  - After Carl Ferdinand von Graefe laid down the principles of rhinoplasty and
      related operations it was Johann Friedrich Dieffenbach (1792-1847) who became a
      pioneer of plastic surgery in the 19th century. His biography and scientific work
      with emphasis on craniofacial surgery are presented in this article on the
      history of medicine.

PMID- 12413159
TI  - Women dentists, Hobbs and after.
AB  - Many important events in dentistry took place in the U.S. in the mid-eighteenth
      century. It was changing from a craft usually transmitted by a preceptor to a
      science taught in established schools. Among the changes was founding of the
      first dental school, founding of the first dental journal, and 19 years later
      founding of the National Dental Association, which in time became the American
      Dental Association. Following Lucy Beaman Hobbs and Henriette Hirschfeld and
      their initial struggles, many women applied to dental school and received their
      degrees. While some of these women may not have practiced dentistry after
      graduation, many did. Several were active in organized dentistry and published
      articles on a variety of dental topics. Not much is known about many of the
      pioneers and the purpose of this work is to study the demographics of the first
      women who were accepted for study in dental schools of the United States and,
      where possible, their professional activities and contributions to the profession
      once they graduated.

PMID- 12413160
TI  - The era of high speed development in dentistry.
AB  - The development of the high-speed handpiece is a story of fast-moving change. Few
      of today's practicing dentists worked during the days in which use of low-speed,
      belt-driven handpieces was the norm for cavity preparation and there were no high
      speed drills. During the decade of the 1950s, sweeping changes came about with
      the introduction of the high-speed handpiece and the associated promulgation of
      air abrasion and ultrasonic methods for cavity preparation. Researchers and
      developers from New Zealand, Sweden and the United States played parts in this
      chronology of events. Dental practitioners have used the high-speed handpiece for
      over forty years and, although laser technology has been introduced and air
      abrasion has been re-introduced, there is no prospect of replacement of the high
      speed handpiece in the foreseeable future.

PMID- 12413161
TI  - How a patient expressed her feelings in poetry.

PMID- 12413162
TI  - A straight-forward pathway to success.

PMID- 12413163
TI  - Food sugar substitutes: a brief review for dental clinicians.
AB  - The frequent ingestion of fermentable sugars such as sucrose, fructose, glucose
      and maltose is conducive to the development of caries in the teeth of susceptible
      individuals. Natural and artificial alternatives to these sugars have been and
      continue to be developed as non/low-caloric sweeteners. The US Food and Drug
      Administration have approved four non-caloric sweeteners at present. However,
      there are several other non-caloric sweeteners being commonly used in other
      countries. A review of these sweeteners is provided with information on a
      promising new agent that has not yet gained FDA approval.

PMID- 12413164
TI  - Clinical management of hypohidrotic ectodermal dysplasia with anodontia: case
      report.
AB  - Ectodermal dysplasia is a rare hereditary disorder with a characteristic
      physiognomy. The case of a 5-year-old child with hypohidrotic ectodermal
      dysplasia and complete anodontia is presented. Because of the anodontia and the
      need for treatment at an early age, the prosthetic management of such a young
      child can be difficult. Complete dentures were provided to encourage a normal
      psychological development and to improve the function of the stomatognathic
      system.

PMID- 12413165
TI  - Complete intrusion of maxillary permanent central incisors.
AB  - Orthodontic extrusion can be time consuming and has a long retention period,
      making cooperation a critical factor. On the other hand, it has also been shown
      that surgical techniques may be useful to extrude and save the root. Surgical
      methods need at least 3 week for root stabilization in new position. This is a
      case report of a surgical method to treat intruded teeth.

PMID- 12413166
TI  - Treatment planning in the presence of congenitally absent second premolars: a
      review of the literature.
AB  - One of the most common dental anomalies encountered by the pediatric dentist is
      the congenital absence of second premolars. Once diagnosed, the appropriate
      treatment necessitates the formulation of a comprehensive treatment plan, which
      is dependent upon a number of factors. Considerations include: the condition of
      the deciduous molar, dental and skeletal relationships, dental age of the
      patient, willingness of the patient to undergo extensive dental treatment and
      financial considerations. Approaches to the management of congenitally missing
      premolars have been described in the literature, including the more recently
      available option of dental implant placement. The objective of this paper is to
      present a review of the literature with emphasis on the considerations needed for
      appropriate treatment planning when the practitioner is confronted with this
      diagnostic challenge.

PMID- 12413168
TI  - Oropharyngeal airway appliance for infant with upper airway obstruction: report
      of a case.
AB  - A palatal appliance with oropharyngeal tube that reduces the upper airway
      obstructions of an eleven-month-old male infant with severe cerebral palsy is
      presented. The palatal appliance was composed of the base plate, the outer guide
      tube that held the oropharyngeal tube inside it, and the extra outer guide tube
      for the suction catheter. After the setting of the appliance, respiratory
      distress was improved without side effects.

PMID- 12413167
TI  - Orthodontically guided eruption of mandibular second premolar following
      enucleation of an inflammatory cyst: case report.
AB  - This case study describes the surgical management of an inflammatory cyst
      combined with the orthodontically assisted eruption of an impacted mandibular
      second premolar.

PMID- 12413169
TI  - The positional changes of hyoid bone in children.
AB  - The purpose of this study was to investigate the developmental changes of the
      hyoid bone position in children from deciduous dentition to early permanent
      dentition. There was no sexual dimorphism in hyoid bone positions. The growth of
      the structures around the hyoid bone began to decline from late mixed dentition
      stage. During growth, Go-H was almost equal to C3-H and the hyoid bone was
      located near and above the line that connected C3 and Me.

PMID- 12413170
TI  - Tensile bond strength of intracanal posts in primary anterior teeth: an in vitro
      study.
AB  - The aim of this study was to measure in vitro; the tensile bond strength of three
      intracanal posts used in anterior primary teeth. A total of 45 single rooted
      primary anterior teeth were selected for the study and the crowns sectioned
      leaving 1mm above the cement-enamel junction. The roots were then assigned to
      three groups according the type of retention used. All roots were endodonticaly
      treated, a 4-mm of the canal was cleansed and a base of glass ionomer cement was
      put at the bottom of the prepared canal. The roots were then prepared to receive
      intracanal posts using a # 4137 diamond bur (KG Sorensen) used in a depth of 3-mm
      of the length of the canal All the prepared roots were acid etched with a 37%
      phosphoric acid gel for 15 seconds, rinsed, dried and the dentin adhesive Single
      Bond (3M) was applied. Group I received intracanal posts and cores made of
      composite resin (Filtek Z 250, 3M). Group II intracanal posts were made from a
      0.6mm orthodontic wire bent as a Greek letter type (gamma), fixed with the Z 250
      composite resin and cores were built with the same composite. Finally Group III
      received intracanal retention made of a fiber glass post (Fibrekor Post,
      Generic/Pentron) with 1.25 mm diameter, fixed with Z 250 and cores were made like
      the other groups. The samples were submitted to tension in a universal-testing
      machine (Instron, model 4444). Statistical analysis (ANOVA) revealed that there
      were no statistically significant differences between the groups. On the basis of
      the results of this in vitro study it was concluded that the type of intracanal
      post did not interfere with the tensile strength and the most frequent type of
      failure was of adhesive type, corresponding to 74% of the sample.

PMID- 12413171
TI  - Root fillings with Endoflas in primary teeth: a retrospective study.
AB  - The aim of this retrospective study is to report the success rate of root canal
      treatments (RCT) using Endoflas as a filling material in primary teeth. Fifty
      five (55 teeth, 27 maxillary incisors and 28 molars) of 47 children fulfilled the
      criteria to be included in the study. The immediate post-operative radiograph was
      evaluated and the root filling was rated overfilled, flush or underfilled. Thirty
      one (31) teeth were overfilled; of these 9 (29%) were normal pre-operatively and
      the remaining 22 (71%) presented with bone pathology. Twenty-four (24) teeth were
      flush or underfilled; of these, 50% had preoperative bone pathology. The children
      were examined clinically and radiographically at follow-up visits ranging from 6
      to 52 months. Approximately 70% of the cases were successful at the last followup
      examination. The remaining 30% presented with pathology (Po); however, only one
      tooth had to be extracted (Pi). Overfilling led to a success rate of 58%, while
      in the combined flush and underfilled the success rate was 83%.

PMID- 12413172
TI  - Detection of potentially cariogenic strains of Streptococcus mutans using the
      polymerase chain reaction.
AB  - Streptococcus mutans is a pathogen related to the occurrence of human dental
      caries. The determination of total amounts of mutans streptococci, as well as the
      proportion related to other oral bacteria, is of interest when assessing the risk
      of developing caries. In this context, it is better to use a sensitive, specific
      and non-time consuming method such as the polymerase chain reaction (PCR), than
      to use culture and biochemical identification methods. In this work we identified
      potentially cariogenic strains of S. mutans and assessed the relationship with
      the dmft, DMFT or dmft/DMFT index. Using DNA isolated from dental plaque, a 192
      bp sequence was identified and amplified from the spaP gene and a 722 bp sequence
      from the dexA gene. The results suggest that it is important to evaluate the
      presence of cariogenic S. mutans strains in plaque content rather than the
      accumulation of plaque itself However, other factors like diet, hygiene, genetic
      background, the flow rate of saliva and the presence of specific antibodies, also
      play a key role in the development of caries.

PMID- 12413173
TI  - Time dependent changes of variables associated with malocclusion in patients with
      Duchenne muscular dystrophy.
AB  - Time dependent changes of parameters associated with malocclusion in patients
      with Duchenne muscular dystrophy (DMD) were examined in four dental developmental
      stages in 34 patients. We adopted activities of daily living (ADL) score, dental
      arch, craniofacial morphology, and electromyograms of the masseter and temporalis
      muscle as parameters. A comparison was made with the results in DMD subjects to
      data from healthy subjects with normal occlusion reported in the literature. In
      DMD subjects, manifestations of open-bite were related to ADL score, sagittal
      shortening and transverse expansion of the dental arch and vertical overgrowth of
      the lower jaw. Posterior cross-bite malocclusion was associated with differences
      in the time dependent changes between the jaws in transverse expansion. The
      malocclusion in DMD subjects was also related to the time dependent
      disproportional changes in masticatory muscle function by EMG. Occlusal deviation
      in DMD subjects became apparent at the late mixed dentition and malocclusion
      became definitely manifest from early permanent dentition.

PMID- 12413174
TI  - Focal epithelial hyperplasia: report of six cases from Ghana, West Africa.
AB  - Focal epithelial hyperplasia is a proliferative growth of the oral mucosa with
      distinct clinical and histopathological features. Although focal epithelial
      hyperplasia is frequently reported in children of American Indian and Eskimo
      descent, it is rarely seen in Africans. This report presents six new cases of
      focal epithelial hyperplasia observed in African children. The age of the
      patients ranged from 4 to 12 years, and all except one were females. Clinical
      variants, the papillary and the papular types were noted in the same patient.
      There was spontaneous regression of focal epithelial hyperplasia in four patients
      during the study period. However, the lesions still persist in two patients three
      years after the initial presentation.

PMID- 12413175
TI  - Oro-dental manifestations of the Schwartz-Jampel syndrome.
AB  - A boy with the Schwartz-Jampel syndrome (chondrodystrophic myotonia) had a number
      of oro-dental complications. These included difficulty in tooth extraction and
      orthodontic care due to a small oral aperture and rigidity of the temporo
      mandibular joints. General anaesthesia was hazardous because of a propensity to
      malignant hyperthermia, and endotracheal intubation was difficult because of
      shortness and rigidity of the neck and the small size of the laryngeal
      structures. Awareness of these potential problems is crucial for anaesthesia and
      comprehensive dental management. The radiological demonstration of dentigerous
      cysts is a hitherto unreported observation in this disorder.

PMID- 12413176
TI  - Stevens-Johnson syndrome: case presentation.
AB  - Erythema Multiforme (EM) is a rare mucocutaneous disease with a variety of
      clinical manifestations. EM it was recognized in the early 1800's, and still the
      etiology is unknown. It has been recently suggested erythema multiforme (EM)
      major and Stevens-Johnson Syndrome (SJS) could be separated as two distinct
      clinical disorders with similar mucosal erosions, but different patterns of
      cutaneous lesions. In particular SJS should be used for a syndrome characterized
      by mucous membrane erosions and widespread small blisters that appear on
      erythematous or purpuric maculae, which are different from classic targets. In
      SJS mouth, eyes, skin, genitalia and occasionally the esophagus and respiratory
      track may be affected. Oral lesions may cause severe pain and usually lips may
      become encrusted. Concerning ocular involvement, if there is conjunctivitis or
      uveitis this may lead to scarring and blindness. Also, the course of disease and
      the prognosis are in most cases severe.

PMID- 12413177
TI  - Infantile osteopetrosis: a case report with osteomyelitis of the maxilla.
AB  - A case of a pediatric patient diagnosed with osteopetrosis complicated by
      osteomyelitis in the maxilla is presented. The combined medical-surgical
      treatment for this type of patient is discussed.

PMID- 12413178
TI  - Prevalence of malocclusion in 4-6 year old Brazilian children.
AB  - The prevalence of malocclusion and the relationship with oral habits in Brazilian
      children from two public primary schools was evaluated. The sample was composed
      of 112 children with mean age of 61 +/- 6.67 months. The results demonstrated the
      presence of malocclusions in 75.8% (n = 85). The oral habits was related by 34.8%
      (n = 39). The open bite was the most prevalent malocclusion in the studied
      population and the oral habits was the decisive etiological factor.

PMID- 12413179
TI  - Perceptions of pediatric patients and guardians about prosthetic appliances.
AB  - Forty patients that received prosthetic appliances as part of dental treatment
      were interviewed about satisfaction with the apparatus. The opinions of the
      guardians were also considered. The majority of children had complained about
      missing teeth, but even a greater percentage expressed satisfaction during wear
      of the prosthetic appliance. Among the guardians, only one of them expressed
      dissatisfaction with the appliance design. Rehabilitation plan should be
      discussed with children and guardians considering their perceptions and adequate
      indications for each case.

PMID- 12413180
TI  - A study of manual toothbrushing skills in children aged 3 to 11 years.
AB  - The aim of the study was to evaluate toothbrushing management and ability of
      children in relation to age and gender. The study population consisted of 75
      children and were divided into three equal groups as 3-5, 6-8 and 9-11 years of
      age. The grip type during toothbrushing was recorded on videotape, The most
      preferred grip types were distal (73%) followed by power (43%) and oblique grips
      (29%). There were a statistically significant differences between age groups and
      the grip types (p < 0.0041) but no significant difference was seen between boys
      and girls in grip preferences (p > 0.05). The mean duration of toothbrushing was
      shorter in 3-5 years of age group (28 seconds) than the 6-8 and 9-11 age groups
      (35 and 47 seconds respectively).

PMID- 12413181
TI  - Validating the effects of social desirability on self-reported condom use
      behavior among commercial sex workers.
AB  - Most studies on the transmission of HIV depend upon self-reports of risky
      behaviors. This study examines if there is social desirability bias with respect
      to self-reported condom use behavior, assesses the reliability of a self-reported
      condom use scale, and validates the self-reported findings with clinical sexually
      transmitted infection (STI) diagnosis for commercial sex workers (N = 1,383) in
      the Philippines. The reliability of the condom use scale is .81, and results from
      confirmatory factor analysis indicate that the data fit the model well. Sex
      workers who reported using condoms consistently had significantly lower rates of
      sexually transmitted infections compared to those who never used a condom (t =
      7.79, p < .01). It was concluded that no social desirability bias existed with
      the self-reported condom use scale. Furthermore, the condom use measure was found
      to have a high level of concurrent validity with STI outcomes.

PMID- 12413182
TI  - Differences between chat room and e-mail sampling approaches in Chinese men who
      have sex with men.
AB  - In a study to determine sampling differences between Internet sites, we obtained
      data on 353 men who have sex with men in Chinese gay chat rooms and through e
      mail web sites. Respondents were approached by the investigator and agreed to
      fill out an anonymous questionnaire on their Internet use and sexual activity.
      All materials and contacts were in Chinese characters. Data indicated that there
      were few differences between the chat room and Internet samples, but that those
      using e-mail appear to be more isolated, more homosexually-identified (rather
      than bisexual), have more experience with casual partners on a number of sexual
      activities, and were less likely to carry condoms and to have safe sex. E-mail
      respondents were more likely to want to discuss HIV/AIDS prevention on a web site
      or other site. These data suggest that the two recruiting methods are largely
      comparable in respondent characteristics, but that e-mail respondents are likely
      to be more isolated and at higher HIV risk than chat room participants.

PMID- 12413183
TI  - Risk behaviors by audio computer-assisted self-interviews among HIV-seropositive
      and HIV-seronegative injection drug users.
AB  - Audio computer assisted self-interview (ACASI) has been shown to elicit
      significantly higher reports of sensitive HIV risk behaviors compared with
      interviewer-administered questionnaires (IAQ). Injection drug users were
      randomized to either ACASI (n = 556) or IAQ (n = 586) in order to evaluate
      reporting differences. A significant interaction was found between mode of
      administration (ACASI/IAQ) and HIV status. HIV-seropositive respondents on ACASI
      compared with IAQ were less likely to report condom use (odds ratio [OR] = .42, p
      < .01) and condom use frequency (OR = .28, p < .002), compared with HIV
      seronegative respondents. Based on ACASI results, HIV-seropositive individuals
      engaged in fewer preventive behaviors than suggested by IAQ. These findings
      support the validity of ACASI as an important mode of data collection in reducing
      socially desirable responding, especially among HIV-seropositive subjects.

PMID- 12413184
TI  - Diffusion of HIV/AIDS knowledge, positive attitudes, and behaviors through
      training of health professionals in China.
AB  - A study evaluated a training-of-trainers strategy to update HIV/AIDS knowledge
      and improve attitudes and behavior among health professionals and the public. A
      survey was carried out among health workers and villagers. An initial workshop
      was given to 55 staff from several health institutions. Trainees were provided
      limited funds to conduct secondary workshops at local levels. They were requested
      to diffuse knowledge to patients during routine health visits. A follow-up survey
      was conducted 18 months later in counties in which workshops were not held.
      Knowledge, attitudes, and behavior were compared both at the baseline and follow
      up surveys, and before and after the intervention. Nearly 95% (94.8%, or 13,782)
      of health workers in Fuyang Prefecture were trained secondarily at local levels.
      Knowledge was significantly higher in intervention (88.5-99.8%) compared with
      nonintervention (37.4-53.7%) counties, and after intervention (22.2-66.6%),
      respectively (p < .01). Attitudes toward people with HIV/AIDS improved
      significantly in intervention counties. Condom use during last sexual intercourse
      increased from 11.0% to 33.5% in health workers (p < .01) and from 8.7% to 18.5%
      among villagers (p <.01). The strategy wascost effective for improving knowledge
      and attitudes and promoting condom use.

PMID- 12413185
TI  - Teaching and learning by example: empowerment principles applied to development,
      delivery, and evaluation of community-based training for HIV service providers
      and supervisors.
AB  - This article describes and recommends a participatory method of developing,
      implementing, and evaluating a learner-driven community-based continuing
      education effort for HIV workers and supervisors. The Boston University School of
      Social Work (BUSSW) created and delivered a training program in partnership with
      the Massachusetts Department of Public Health HIV/AIDS Bureau (the Bureau).
      Because teaching empowerment-based practice was an overarching goal, every step
      of the process modeled collaboration and self-determination. The program was
      unusual in several ways: the workshops focused on basic helping skills rather
      than the medical aspects of HIV; community stakeholders shaped the workshops in
      consultation with staff from the Bureau and BUSSW; a formative evaluation led to
      adaptations of the curriculum in the first few months of the project; objectives
      were set in part by learners, who evaluated themselves on goal attainment; and
      follow-up interviews explored the effects of the workshops on practice. Most
      supervisors and direct care workers reported that the workshops were highly
      relevant to their work and that they were able to incorporate their learning into
      practice, suggesting that the empowerment approach has utility. The report
      includes the genesis and necessity of the project; the principles underpinning
      it; the use of empowerment at each stage; and implications for administrators,
      service providers, and educators in the HIV field. We propose that resources
      dedicated to collaborative or participatory curriculum development,
      implementation, and evaluation are well spent.

PMID- 12413186
TI  - Structure of HIV knowledge, attitudes, and behaviors among American Indian young
      adults.
AB  - Although present incidence and prevalence rates are still low, dramatic increases
      have been noted in the percentages of American Indians (AIs) diagnosed with HIV
      and AIDS, perhaps indicating groups that are increasing in their risk for the
      infection. High rates of sexually transmitted diseases among AIs who are 20-24
      years old also raise concern about the vulnerability of these young adults. In a
      community-based group of 706 AI young adults, knowledge about sexuality and HIV
      transmission was rather low; efficacy and outcome expectations were high. Levels
      of some risk behaviors (e.g., exchanging sex for drugs or money) were low, while
      others (e.g., inconsistent condom use) were considerably higher. Knowledge and
      attitudes were modestly related; neither was related to risk behaviors.
      Suggestions are made about interventions focusing on specific high-risk groups
      and broad-based knowledge and skill-based interventions.

PMID- 12413187
TI  - Surveillance of HIV/AIDS-related attitudes and perceptions among the general
      public in Hong Kong from 1994 to 2000.
AB  - The present study monitored the trends of HIV/AIDS-related attitudes and
      perceptions including awareness, knowledge, self-perceived risk of HIV infection,
      and program evaluation among the general public in Hong Kong over a period of 7
      years. Six cross-sectional telephone surveys were conducted. A total of 6,795
      respondents aged 18-50 randomly selected from the general population participated
      in the study. Over the study period, the level of HIV/AIDS-related knowledge has
      improved slightly for most of the studied items. Condom use has been more widely
      accepted as an efficacious means of HIV prevention. However, the public seemed to
      be losing interest in HIV/AIDS-related issues and were not satisfied with the
      efficacy and adequacy of HIV/AIDS programs in Hong Kong. Sustaining efforts to
      remove misconceptions and to raise the public's interest, formulation of more
      effective programs, and ongoing evaluation are necessary.

PMID- 12413188
TI  - Evaluating outcomes of HIV prevention programs: lessons learned from Houston,
      Texas.
AB  - The Centers for Disease Control and Prevention (CDC) fund state and local health
      departments to contract with community-based organizations for HIV prevention
      tailored to the needs of populations at risk. In 1999, the CDC began requiring
      health departments to develop the capacity to evaluate the outcomes of these
      programs. The CDC requirements create the need for practical, low-cost methods of
      outcome monitoring that can be applied at the local level. We describe the
      development of a multisite evaluation of seven city health department funded (via
      CDC) HIV counseling programs in Houston, Texas. Initial findings indicate that
      (1) behavioral change information that reflects program objectives can be
      obtained through a brief survey; (2) community providers were not able, or were
      unwilling, to follow the evaluation protocol related to surveying their clients;
      (3) that asking clients to mail back posttest surveys resulted in low response;
      and (4) a one-contact intervention made establishing rapport, commitment, and/or
      trust difficult for evaluation purposes. These findings suggest areas for
      improvement, including providing staff training and/or better motivation to
      ensure protocol fidelity, considering the use of an external evaluator to conduct
      pre-post surveys, and developing a different design to evaluate one-shot
      interventions.

PMID- 12413189
TI  - Prisoner risk taking in the Russian Federation.
AB  - For a pilot prevention program in Russian prisons, Medecins Sans Frontieres
      conducted research on prisoner risk behaviors with full support from Russian
      prison authorities. Analysis of data from 1,044 15-30-year-old prisoners produced
      evidence of HIV/AIDS risks in prisons. One percent of prisoners surveyed reported
      all three prison risk activities--engaging in sex, injecting drugs, and getting a
      tattoo. Two-by-two table analysis consistently showed statistically significant
      associations between risk activities. These results conservatively describe the
      presence and nature of such risks: Risks do occur, risks vary and the
      relationships between risks vary, and Russian prisoners already take steps to
      reduce risk. This evidence helps to justify and informs HIV/AIDS prevention and
      health promotion interventions in the Russian prison system.

PMID- 12413190
TI  - Impulsivity and HIV risk among adjudicated alcohol- and other drug-abusing
      adolescent offenders.
AB  - Although impulsivity is likely to be related to HIV risk--particularly in
      incarcerated substance-abusing youth--this area of research has been
      understudied. To investigate the relationship between impulsivity and various
      HIV/AIDS risk behaviors and attitudes, a sample of court-referred and
      incarcerated culturally diverse inner-city adolescents (males: N = 266; females:
      N = 111) were divided into high and low impulsive groups based on the Millon
      Adolescent Clinical Inventory Impulsivity Scale. Findings showed that compared to
      the less impulsive group, the highly impulsive adolescents reported more frequent
      marijuana and alcohol use in the last 3 months as well as a significantly higher
      proportion of unprotected sex when high on alcohol and marijuana, higher
      perceived susceptibility to HIV, more AIDS-related anxiety, greater HIV
      knowledge, less sexual self-efficacy, and less favorable sexual attitudes.
      Implications for interventions among incarcerated youth are discussed.

PMID- 12413191
TI  - Developing an AIDS prevention intervention for incarcerated male adolescents in
      Brazil.
AB  - The objective of this study was to investigate knowledge, attitudes, and
      practices regarding AIDS among incarcerated male adolescents in Brazil and to
      develop an AIDS prevention intervention for this population. A questionnaire
      administered to 275 boys in Sao Paulo covered demographic and social
      characteristics, drugs, and HIV risk perception and behavior. Subsequently, we
      collected qualitative data on the development and implementation of a prevention
      program. Ninety-eight percent of adolescents were sexually experienced, most
      initiating by age 13; 22% were fathers. Injection drug use was reported by 5.5%,
      12% had exchanged sex for money, 35% had more than 15 partners and 8% had
      homosexual experience. Although 72% had used condoms, only 9% used them
      consistently, and only 35% used one in their last intercourse before
      incarceration. Predictors of condom use included carrying condoms and endorsing
      the statement "I would use condoms with my girlfriend." Many said their lives
      include other risks more important than AIDS, such as survival in the crime
      scene. Initial efforts at prevention based on commonly used approaches of
      providing information to guide future rational decisions generated limited
      participation. However, when we worked with them to develop interventions based
      on their interests and needs, using modalities such as music, hip-hop arts,
      graffiti, and helping them to create an AIDS prevention compact disk, they
      responded with enthusiasm. These incarcerated adolescents are at extremely high
      social risk and report high levels of risk behavior for HIV infection.
      Interventions for these youth were better received when developed in
      collaboration with them and based on their beliefs, aspirations, and culture. The
      intervention that resulted went beyond AIDS to include issues such as violence,
      drugs, sexuality and human rights.

PMID- 12413192
TI  - The importance of routine HIV testing in the incarcerated population: the Rhode
      Island experience.
AB  - Routine HIV testing in the correctional setting offered to all inmates at entry
      has played an important role in the diagnosis of HIV in Rhode Island. Diagnosis
      and treatment of HIV in prisons can further public health goals of HIV control,
      prevention, and education. Routine HIV testing can be incorporated into primary
      and secondary prevention programs in correctional facilities. In Rhode Island,
      where HIV testing is routine at entry into the correctional facility,
      approximately one third of all persons who test positive are identified in the
      correctional facility. The proportion of males and females testing positive in
      the correctional facility versus those testing positive in other facilities has
      shown a gradual decrease, with positive female HIV tests declining more
      substantially in recent years. Specific groups, such as males, African Americans,
      and injection drug users continue to be more likely diagnosed in the state
      correctional facility than in other testing sites. These differences may reflect
      barriers to health care access that other community initiatives have failed to
      address.

PMID- 12413193
TI  - Intraprison HIV transmission: an assessment of whether it occurs, how it occurs,
      and who is at risk.
AB  - The prevalence of AIDS infection is approximately five times higher in state and
      federal prisons than among the general U.S. population. It is also apparent that
      high-risk HIV transmission behaviors occur inside prison; however, data validly
      documenting instances of intraprison HIV transmission are rare. This study
      validly identifies 33 inmates in a large sample of state prison inmates who
      contracted HIV inside prison and presents data on how they likely contracted HIV.
      It further compares these inmates to inmates who did not contract HIV inside
      prison in terms of age, race, and level of education. Documenting the burden
      posed by HIV transmission inside prison, providing insight into how they contract
      HIV inside prison, and what types of inmates are at risk will help public and
      correctional health officials reform their current education and prevention
      practices and ultimately reduce or prevent HIV transmission both inside and
      outside prison.

PMID- 12413194
TI  - HIV surveillance methods for the incarcerated population.
AB  - In the United States, monitoring the HIV/AIDS epidemic among the incarcerated
      population is done by (a) conducting a census of persons in prisons and jails
      reported to be infected with HIV or diagnosed with AIDS, (b) seroprevalence
      surveys in selected correctional facilities, and (c) population-based HIV/AIDS
      case surveillance by state health departments. We describe methods for HIV/AIDS
      case surveillance in correctional settings and present data from the HIV/AIDS
      Reporting System (HARS) and the Supplement to HIV and AIDS Surveillance (SHAS) to
      describe the demographic, behavioral, and clinical characteristics of HIV
      infected persons who were incarcerated at the time of diagnosis. HARS data showed
      a higher proportion of females and a lower proportion of injection drug users for
      incarcerated persons diagnosed with HIV (not AIDS) compared to those initially
      diagnosed with AIDS. The SHAS data showed a high prevalence of injection drug
      use, crack use, alcohol abuse, and exchanging sex for money or drugs. Together,
      HARS and SHAS collect fairly comprehensive information of risk behaviors from
      persons with HIV infection and AIDS. Advances in HIV prevention and care for the
      incarcerated community will require an accurate and timely description of the
      magnitude of the HIV epidemic in correctional settings. These data are needed to
      guide programmatic efforts to reduce HIV transmission in prisons and jails and in
      the general community upon release and ensure needed risk reduction and health
      care services for incarcerated persons.

PMID- 12413195
TI  - Community-based organizations and HIV prevention for incarcerated populations:
      three HIV prevention program models.
AB  - Inevitably, challenges result from the disconnect between the objectives of
      correctional facilities, which are safety and conformity, and community-based
      organizations (CBOs), whose primary function is to provide inmates with primary
      and secondary HIV prevention and information. This is cause for concern because
      prisons have a high potential for serving as a reservoir for HIV transmission.
      CBOs, when accessible, may be the only source of HIV/AIDS prevention, education,
      and information for incarcerated populations. People living with HIV/AIDS in
      correctional settings face unique challenges. Among other populations, condoms
      and bleach kits have been successful in reducing HIV transmission. However,
      because these prevention tools are not available to incarcerated populations, new
      HIV prevention strategies are needed. This article focuses on successful
      intervention practices such as peer-led education and discharge planning services
      that have been essential components of HIV prevention and provides a context for
      operating such programs within correctional facilities. The article also
      highlights the challenges CBOs encounter in providing HIV prevention in various
      correctional institutions throughout the United States.

PMID- 12413196
TI  - Acceptability of condom availability in a U.S. jail.
AB  - Studies have documented the transmission of HIV in incarcerated populations
      resulting from injection drug use or sexual activity. Less than 1% of the jails
      and prisons in the United States allow inmates access to condoms, and none allows
      access to needles. Results of a survey to measure the acceptability of a condom
      distribution program at the Washington, DC. Central Detention Facility, where
      condoms are available to inmates, are presented here. Three hundred seven inmates
      and 100 correctional officers were surveyed from October 2000 through October
      2001. The surveys demonstrate that the program is generally supported and thought
      to be important by inmates and correctional staff. The program has not resulted
      in any major security infractions and could be replicated in other correctional
      settings.

PMID- 12413197
TI  - Research capacity building and collaboration between South African and American
      partners: the adaptation of an intervention model for HIV/AIDS prevention in
      corrections research.
AB  - This article examines a partnership between researchers from the United States
      who are involved in corrections health issues and scientists from South Africa
      who conduct prison health research, a previously underresearched area in South
      Africa. The article discusses some of the challenges as well as opportunities for
      knowledge and skills exchange via capacity building and collaboration strategies.
      Through historical and contemporary perspectives, it also discusses barriers and
      benefits of collaboration when forging links between researchers from developed
      and less developed nations. A focus on conducting public health research in South
      Africa, and on HIV/AIDS studies in particular, is placed within the context of
      the 2001 document of the Council on Health Research for Development. The South
      African prison health study represents a collaborative between the South African
      National Health Promotion Research and Development Group of the Medical Research
      Council, the South African Department of Correctional Services, and Emory
      University in Atlanta, Georgia. The article illuminates the process of adapting a
      model for a postapartheid prison study from one designed for use in the American
      correctional system.

PMID- 12413198
TI  - HIV/AIDS in correctional settings: a salient priority for the CDC and HRSA.
AB  - Correctional facilities constitute an excellent opportunity to provide treatment,
      care, and prevention services for a population that may not otherwise access
      these services. The Centers for Disease Control and Prevention (CDC) and the
      Health Resources and Services Administration (HRSA) recognize the public health
      importance of correctional settings and have begun to develop formal strategies
      to address the HIV/AIDS-relevant needs of incarcerated individuals. The Centers
      for Disease Control and Prevention and HRSA have implemented policies,
      activities, and strategic plans to reduce the HIV/AIDS disease burden among the
      high-risk populations that pass through the nation's prisons and jails. They have
      also collaborated to address the HIV/AIDS needs of incarcerated populations and
      have initiated processes for expanding collaboration on these issues to include
      other federal agencies and prevention partners.

PMID- 12413199
TI  - Building an HIV continuum for inmates: New York State's criminal justice
      initiative.
AB  - The benefits of public health, corrections, and community-based organization
      (CBO) collaboration to meet HIV prevention needs of inmates are recognized. Each
      year over 100,000 inmates, most of whom have a history that put them at HIV risk,
      pass through the New York State (NYS) prison system. The NYS Department of Health
      AIDS Institute, the NYS Department of Correctional Services, the NYS Division of
      Parole, and a statewide network of CBOs collaborate to meet HIV prevention and
      support services needs of inmates and parolees through a continuum of
      interventions and services. This article describes the evolution of the
      prevention, supportive services, and transitional planning continuum within the
      NYS prison system. It identifies other agencies involved, obstacles to service
      delivery, describes approaches to overcome them, discusses ways to meet capacity
      building and technical assistance needs of CBOs, identifies challenges remaining,
      and provides practical advice from actual experience in NYS.

PMID- 12413200
TI  - Synaptic plasticity, metaplasticity and BCM theory.
AB  - In many regions of the brain, the activity-dependent changes in synaptic strength
      depend on the frequency and timing of presynaptic stimulation and postsynaptic
      activity (synaptic plasticity), as well as the history of activity at those
      synapses (metaplasticity). The Bienenstock, Cooper and Munro (BCM) theory made
      several assumptions about how synapses modify and these have helped to guide
      various neurobiological and neurocomputational experiments. There does appear to
      be a good correspondence of the synaptic plasticity and metaplasticity
      experimental data with the BCM model. (Fig. 1, Ref. 57.).

PMID- 12413201
TI  - Optimizing delivery of therapeutics: percutaneous technologies.
AB  - The purpose of this communications is to 1) demonstrate the potential of
      percutaneous drug-delivery on the example of female reproductive steroids, 2)
      point out the differences between transdermal and conventional drug dosing, and
      3) outline new technologies and innovations that are looming on the horizon,
      specifically in the area of pain control. Transdermal delivery systems are of two
      basic types. The first ones employ principles of passive diffusion, and they are
      used for hormonal replacement therapy (HRT) and contraception. Patches for HRT,
      designed to release estradiol (E2) only, require a simultaneous dosing with oral
      progestogens. Patches employing both E2 and a progestogen release the combination
      either continuously or sequentially. In the latter method, estrogen-only patches
      are applied for 14 days, followed by a 14-day application of patches releasing
      both hormones. Both methods successfully cope with symptoms and signs of
      menopause, including bone loss. Contraceptive transdermal patches deliver
      ethinylestradiol in combination with the progestogen norelgestromin. This system
      provides high contraceptive protection with predictable withdrawal bleeding and
      without major adverse events and weight changes. Hormones delivered by the skin
      avoid first-pass liver metabolism. Other advantages include rapid onset and
      termination of action, self-administration, and attainment of therapeutic hormone
      levels with low daily doses. A disadvantage is the variable intra- and inter
      individual percutaneous absorption. In some patients, patches can cause skin
      irritation. Active systems deliver therapeutics across intact skin non-invasively
      by means of an electric potential (electrotransport). A system consisting of
      tooth-like titanium microprojections that penetrate only the keratinized
      epidermis facilitates painless and needle-free transport of complex molecules to
      the capillaries of the dermis. Other devices use low frequency ultrasound. These
      systems enable precise dosage, delivery of large molecules, such as growth
      hormone and vaccines, and dosing of analgesics "on demand". Novel transdermal
      technologies are profoundly changing the current methods of pain management.
      (Fig. 6, Ref. 47.).

PMID- 12413202
TI  - Orofacial clefts and their influence on chosen anthropometric parameters of
      craniofacial part children at the age of eight.
AB  - The aim of this study was to choose and to measure craniofacial parameters that
      were expected to be influenced by cleft defects. Eight-year-old children (both
      boys and girls) with operated clefts (15 antropometric parameters) were measured.
      The measurements were carried out at the Department of Reconstructive Surgery,
      Hospital Ruzinov, Bratislava. The obtained parameters were compared to 4 types of
      clefts by means of modification t-test, and also with healthy population by means
      of normalization indices, on the base of which morphograms were performed. On the
      base of our results, we can say that the most significant deviations when
      compared with healthy population were found in children with the worst type of
      cleft, i.e. complete bilateral cleft.

PMID- 12413203
TI  - Effects of red wine polyphenolic compounds on the cardiovascular system.
AB  - Phenolic phytochemicals are widely distributed in the plant kingdom. Regarding
      the protective effects on organisms, the polyphenol group is the most important.
      In different experiments, it has been shown that selected polyphenols, mainly
      flavonoids, possess protective effects on the cardiovascular system, as well as
      anticancer, antiviral and antiallergic properties. In coronary heart disease, the
      protective effects include mainly antithrombic, antioxidant, anti-ischaemic and
      vasorelaxant properties of flavonoids. It has been hypothesised that the
      phenomenon of a low incidence of coronary heart disease in French people may be
      partially related to the pharmacological properties of polyphenolic compounds
      included in red wine. Many epidemiological studies have shown that regular
      flavonoid intake is associated with reduced risk of cardiovascular diseases. This
      review article discusses the chemical structure of polyphenols and their
      beneficial properties in the cardiovascular system. (Fig. 1, Ref 74.).

PMID- 12413204
TI  - Chronic venous insufficiency--epidemiology.
AB  - Chronic venous insufficiency (CVI) of lower limbs is one of the most widespread
      diseases occurring in developed countries worldwide. Literature data concerning
      its prevalence and incidence differ depending on evaluation criteria or on the
      definition of CVI. By comparing the available epidemiological literature
      published in the last decade, the authors point out the fact that the disunity in
      evaluation criteria of CVI is the weakness of all comparative studies. In spite
      of this, it is evident that, in addition to age and sex, the main risk factors of
      CVI include also the influence of working environment, genetic influences and
      geographic factors. Solely the acceptance of a unified classification of CVI and
      multinational collaborative studies could bring new information on epidemiology,
      etiology, prevention and therapy of this chronic disease, as in the case of
      coronary heart diseases in the past. (Tab. 1, Fig. 2, Ref 19.).

PMID- 12413205
TI  - Intraoperative mild hypothermia therapy in patients scheduled for neurosurgical
      procedures.
AB  - BACKGROUND: Deliberate mild hypothermia has been proposed as a means of providing
      cerebral protection during neurosurgicals procedures complicated by cerebral
      ischaemia. Our prospective study was designed to examine the safety of deliberate
      mild hypothermia and to evaluate our techniques for cooling and rewarming.
      MATERIALS AND METHODS: With institutional approval, 20 patients scheduled for
      elective neurosurgery were enrolled into our prospective study. After the
      induction of anaesthesia, the core temperature was measured by urinary catheters
      with probes (Kendall). The patients were cooled (temperature of blankets set at
      15 degrees C) and rewarmed (temperature set at 40 degrees C) by two circulating
      water blankets (Blanketrol III, Cincinnati Sub-Zero, Cincinnati). The variables
      are expressed as a mean +/- standard deviation. RESULTS: The time of anaesthesia
      was 316+/-53 min. The core temperature was 36.5+/-0.4 degrees C at the start of
      anaesthesia. The minimal temperature reached 34.4+/-0.4 degrees C. The patients
      were cooled at a rate of 1.1+/-0.3 degrees C/h and rewarmed at a rate of 0.9+/
      0.4 degrees C/h. The temperature was 35.8+/-0.5 degrees C after the neurosurgical
      procedure. Deliberate mild hypothermia with rewarming did not cause delays in
      emerging from anaesthesia. On the control CT scan, no ischaemic changes were
      observed after surgery. CONCLUSIONS: Our findings indicate that patients can be
      cooled and rewarmed by two circulating water blankets, and core temperatures
      about 34 degrees C were easily achieved. The deliberate mild hypothermia is
      together with careful anaesthesia management a safe technique of cerebral
      protection from ischaemic insult during elective neurosurgical procedures. (Tab.
      1, Ref. 11.).

PMID- 12413206
TI  - Homocysteine and vitamin C.
AB  - Homocysteine has a pro-oxidative activity. This amino acid, a lipid-independent
      vascular disease risk factor, might cause atherosclerosis by damaging the
      endothellium either directly or by altering the oxidative status. Levels of
      plasma homocysteine and vitamin C concentrations were determined in the adult
      majority population of Southern Slovakia (n=146) and in the ethnic Romany
      minority (n=119) in this region. Average homocysteine and vitamin C values in
      Romanies are similar to those in the majority group (non-significantly changed)
      with an equal finding of hyperhomocysteinemia, as well as with similar frequency
      of deficient, suboptimal and optimal vitamin C values. Under the condition of
      suboptimal (23-50 micromol/l) and optimal (>50 micromol/l) vitamin C levels,
      homocysteine values in connected groups are significantly lower with comparison
      to the value at deficient vitamin C level (<11.5 micromol/l), reduction from
      10.74 micromol/l to 9.35 and 9.17 micromol/l. Multiple regression showed a
      negative linear correlation of homocysteine and folic acid, vitamin B12
      (determinants of homocysteine metabolism), vitamin C (antioxidative effect)
      together (n=265, r=-0.282, p<0.00008). The significance for vitamin B12 alone,
      was p=0.0199, for folic acid p=0.0046, for vitamin C p=0.0499. The results
      express a significant effect of vitamin C in prevention of vascular damage. (Tab.
      1, Fig. 1, Ref; 19.).

PMID- 12413207
TI  - Current palliative treatment of malignant jaundice.
AB  - When selecting the most suitable palliation of malignant jaundice, the following
      factors are to be considered: 1) patient's overall condition, 2) presumption of
      patient's survival, 3) technical, personal, and economic factors, 4)
      effectiveness of procedure, 5) morbidity and mortality of palliative treatment.
      (Tab. 2, Ref. 3.).

PMID- 12413208
TI  - Stabilisation of thoracic wall in patients with chest injury.
AB  - The authors analyse a group of 38 polytraumatised patients with unstable thoracic
      injury who were subdued to internal surgical stabilisation of the thoracic wall
      during the period from 1st October 1994 to 30th September 2001. The average
      period of controlled pulmonary ventilation (CPV) was 3 days and the average
      period of hospitalisation at the Anaesthesiology and Intensive Care Department
      (AICD) was 10 days. In indicated cases, the authors recommend an active surgical
      approach in the treatment of patients with unstable thoracic injuries. (Tab. 2,
      Fig. 2, Ref. 3.).

PMID- 12413209
TI  - Prostacyclins in pulmonary hypertension treatment.
AB  - Pulmonary hypertension is a rare, treacherous disease affecting the lungs and
      heart. Elevated pulmonary artery pressure (above 2.67 kPa) and pathologically
      high pulmonary vascular resistance are characteristic for this disease. This
      disease is insidiously progressive and often leads to sudden death mainly in
      middle and younger middle ages. Exhausting the traditional conservative means of
      treatment, lung/heart-lung transplantation offers the only possibility to improve
      the quality of patient's life. Nowadays more and more reports about the
      successful application of intravenous prostacyclin for treatment of this disease
      appear in specialized literature. Epoprostenol (prostacyclin PGI2) represents a
      new, potent drug for the treatment of pulmonary hypertension. The objective of
      this paper is to introduce prostacyclin PGI2 to experts and demonstrate new
      possibilities, procedures, trends in treatment of pulmonary hypertension. (Tab.
      1, Ref. 30.).

PMID- 12413210
TI  - Groundwater contamination downstream of a contaminant penetration site. I.
      Extension-expansion of the contaminant plume.
AB  - This study concerns the possible use of boundary layer (BL) approach for the
      analysis and evaluation of contaminant transport in groundwater due to
      contaminant penetration into the groundwater aquifer through a site of limited
      size. The contaminant penetration may occur through either the upper (surface) or
      lower (bedrock) boundary of the aquifer. Two general cases of contaminant
      penetration mechanisms are considered: (1) the contaminant is transferred through
      an interface between a contaminating and freshwater fluid phases, and (2) the
      contaminant arrives at groundwater by leakage and percolation. For the purpose of
      BL evaluation the contaminant plume is divided into three different sections: (1)
      the penetration section, (2) the extension-expansion section, and (3) the
      spearhead section. In each section a different BL method approach yields simple
      analytical expressions for the description of the contaminant plume migration and
      contaminant transport. Previous studies of the BL method can be directly applied
      to the evaluation of contaminant transport at the contaminant penetration
      section. The present study extends those studies and concerns the contaminant
      transport in the two other sections, which are located downstream of the
      penetration section. This study shows that the contaminant concentration profiles
      in sections 2 and 3 incorporate two BLs: (1) an inner BL adjacent to the aquifer
      bottom or surface boundary, and (2) an outer BL, which develops above or below
      the inner one. The method developed in the present study has been applied to
      practical issues concerning salinity penetration into groundwater in south
      central Kansas.

PMID- 12413211
TI  - Groundwater contamination downstream of a contaminant penetration site. II.
      Horizontal penetration of the contaminant plume.
AB  - Part I of this study (Rubin, H.; Buddemeier, R.W. Groundwater Contamination
      Downstream of a Contaminant Penetration Site Part 1: Extension-Expansion of the
      Contaminant Plume. J. of Environmental Science and Health Part A (in press).)
      addressed cases, in which a comparatively thin contaminated region represented by
      boundary layers (BLs) developed within the freshwater aquifer close to
      contaminant penetration site. However, at some distance downstream from the
      penetration site, the top of the contaminant plume reaches the top or bottom of
      the aquifer. This is the location of the "attachment point," which comprises the
      entrance cross section of the domain evaluated by the present part of the study.
      It is shown that downstream from the entrance cross section, a set of two BLs
      develop in the aquifer, termed inner and outer BLs. It is assumed that the
      evaluated domain, in which the contaminant distribution gradually becomes
      uniform, can be divided into two sections, designated: (a) the restructuring
      section, and (b) the establishment section. In the restructuring section, the
      vertical concentration gradient leads to expansion of the inner BL at the expense
      of the outer BL, and there is almost no transfer of contaminant mass between the
      two layers. In the establishment section, each of the BLs occupies half of the
      aquifer thickness, and the vertical concentration gradient leads to transfer of
      contaminant mass from the inner to the outer BL. By use of BL approximations,
      changes of salinity distribution in the aquifer are calculated and evaluated. The
      establishment section ends at the uniformity point, downstream from which the
      contaminant concentration profile is practically uniform. The length of the
      restructuring section, as well as that of the establishment section, is
      approximately proportional to the aquifer thickness squared, and is inversely
      proportional to the transverse dispersivity. The study provides a convenient set
      of definitions and terminology that are helpful in visualizing the gradual
      development of uniform contaminant concentration distribution in an aquifer
      subject to contaminant plume penetration. The method developed in this study can
      be applied to a variety of problems associated with groundwater quality, such as
      initial evaluation of field data, design of field data collection, the
      identification of appropriate boundary conditions for numerical models, selection
      of appropriate numerical modeling approaches, interpretation and evaluation of
      field monitoring results, etc.

PMID- 12413212
TI  - Analysis of some aromatic amines by means of derivative spectrophotometry.
AB  - Derivative spectrophotometry (DS) was applied for the determination of selected
      aromatic amines in two-compound mixtures. Following pairs were analysed: o- and m
      toluidine, o- and p-toluidine, m- and p-toluidine; o- and m-phenylenediamine
      (PDA), o- and p-PDA, m- and p-PDA; p,p'-diaminodiphenylmethane (DADPMe) and p
      toluidine. The developed method of DS was used as a complementary technique to
      HPLC with DAD detector as it allows the determination of compounds, which give a
      common peak in a chromatographic system.

PMID- 12413213
TI  - The influence of non-ionic radiation on the chicken hatching.
AB  - The study considers the influence of non-ionic radiation (white and monochromatic
      light) on the hatching of the Hampshire breed chickens. The chicken embryos were
      most sensitive to the white light (El), reaching the hatching time of 503.63 +/-
      3.17 h, the hatchability of 95.12 +/- 3.72% and an average weight of incubated
      chickens 46.83 +/- 2.82 g. Of the monochromatic lights, the chicken embryos were
      most sensitive to yellow and green lights (E5, E4) with the hatching time of
      505.22 +/- 4.03 and 507.14 +/- 3.95 h, respectively, the hatchability of 94.89 +/
      3.02 and 94.47 +/- 2.93%, respectively and the average weight of incubated
      chickens 45.72 +/- 1.93 and 45.05 +/- 2.66 g, respectively. The least reaction of
      chicken was observed with violet light (E2) with the hatching time of 510.04+/-
      1.97 h, hatchability of 90.81 +/- 4.05% and the average weight of incubated
      chickens 42.02 +/- 3.72 g. The effect of violet light brings the same results as
      we observed in the case of hatching in darkness (control group C), when the
      hatching time was 510.41 +/- 2.82 h, hatchability 90.42 +/- 3.35% and average
      weight of incubated chickens 41.98 +/- 3.05 g.

PMID- 12413214
TI  - Environmental applicability of chitosan and zeolite for amending sewage sludge.
AB  - This study investigated the potential leachability of toxic heavy metals and
      pathogenic reduction in sewage sludge using chitosan and zeolite as adsorbing
      materials. Experiments were conducted on chitosan-sludge and zeolite-sludge
      mixtures in the application ratio of 0.1:10, 0.5:10, 1.0:10, 2.0:10, 3.0:10, and
      4.0:10, respectively, and examined their capacities to bind some heavy metals
      (Zn, Cu, Ni and Pb) deriving from sewage sludge. Acrylic columns packed with
      chitosan and zeolite-sewage sludge mixtures in optimum ratio 1.0:10 and 3.0:10,
      respectively, were leached with tap water and sewage effluent at different pH
      levels. Seven eluate fractions were collected from the leaching test at
      leachant/dry sludge (L/S) ratio fixed to 0.48, 0.95, 1.43, 1.90, 2.38, 2.85, and
      3.33 L/kg, respectively, and monitored for heavy metal and fecal coliform
      reductions. Results from leaching test studies for amended sludge showed that the
      variation of the observed heavy metal contents were influenced by the pH and
      eluate fractions of leachants. It was found that from neutral to acid conditions,
      the mobility of heavy metals in amended sludge mixtures was increased with the
      decrement of pH value in leachants. Zeolite-sludge was found to have higher
      percentage of reduced metal bioavailability than chitosan-sludge. It can be seen
      in column studies, pathogenic reduction in amended sludge mixtures were dependent
      with eluate fractions and type of amended materials. It was also revealed that
      chitosan can reduce greater fecal coliform counts in sewage sludge than that of
      zeolite.

PMID- 12413215
TI  - The role of pH in mesophilic anaerobic sludge solubilization.
AB  - The effect of pH on anaerobic solubilization of synthetic sludge (dog food) and
      domestic primary sludge was investigated and compared. Anaerobic solubilization
      was carried out in Continuously Stirred Anaerobic Reactors at mesophilic
      temperature (35 degrees C) and pH was fixed at 6.5 (pH-controlled). The aim of pH
      control in the reactors consisting of synthetic and primary sludge, was the
      evaluation of retardation in hydrolysis/acidogenesis at low pH values. Since
      synthetic and primary sludge have different biodegradation characteristics, the
      results were compared. In both sludges, acetic acid was the main Volatile Fatty
      Acids (VFAs) produced. Volatile Suspended Solid (VSS) reduction was found as 67%
      in about 20 days in the anaerobic digestion of synthetic sludge. whereas for the
      same interval VSS reduction could only be achieved by 32% in primary sludge at 35
      degrees C in the pH-controlled reactors. When both types of sludges were used as
      substrates, the reactors removed VSS with a corresponding production of VFAs and
      Soluble Chemical Oxygen Demand (SCOD). However, in the pH-controlled reactors
      production of VFAs and SCOD was ceased after 5 days in primary sludge whereas
      VFAs and SCOD production continued after 5 days in synthetic sludge which
      indicated that hydrolysis and fermentation in the anaerobic solubilization
      reactors were not complete and continued longer. On the other hand, in the pH
      controlled reactor of primary sludge, methanogenic phase could operate after 5
      days of operation as hydrolysis/acidogenesis stopped.

PMID- 12413216
TI  - MB Chenoweth was right!!

PMID- 12413217
TI  - Short- and long-term clinical evaluation of post-operative sensitivity of a new
      resin-based restorative material and self-etching primer.
AB  - This study evaluated the post-operative sensitivity of posterior restorations
      restored with a resin-based restorative material and a self-etching primer. Forty
      six restorations, 28 Class I and 18 Class II were placed by two clinicians in 25
      patients. After cavity preparations were completed under rubber dam isolation,
      they were restored using a self-etching primer (Fluorobond, Shofu Inc, Kyoto,
      Japan) and a resin-based restorative material (Beautifil, Shofu Inc, Kyoto,
      Japan). Patients were contacted on days 2 and 7 post-operatively and questioned
      regarding the presence of sensitivity, the stimuli that created sensitivity, the
      length of time the sensitivity lasted and its intensity using a rating scale from
      slight to severe. If sensitivity was experienced on day 7, patients were also
      contacted on days 14, 30 and 90 to assess the degree of sensitivity. All patients
      were recalled after 6-, 12- and 24-months for further evaluation of any
      sensitivity experienced. Chi-Square and Fisher's Exact Test were used for
      statistical analysis. At day 2, six restorations were sensitive to cold with no
      statistical difference (p > 0.05) from the restorations that were not sensitive.
      At day 7, only two restorations were sensitive. No sensitivity was present after
      day 14, which was also confirmed at the six-month recall. No correlation could be
      established among the duration of the sensitivity, the degree of pain and the
      causes that initiated sensitivity (p > 0.05). At one-year recall, one restoration
      was replaced due to post-operative sensitivity that started after the six-month
      recall. No sensitivity was noted at the 24-month recall. No correlation (p >
      0.05) was found between sensitive restorations and those with a normal response
      throughout the study. The study showed that Fluorobond self-etching primer and
      Beautifil resin-based restorative material, when placed in posterior
      restorations, do not result in long-term post-operative sensitivity.

PMID- 12413218
TI  - The effectiveness of four-cavity treatment systems in sealing amalgam
      restorations.
AB  - Amalgam does not bond to tooth tissue; therefore, restorations using such
      material are prone to leakage despite the deposition of corrosion products. This
      study evaluated the effectiveness of four cavity treatment systems placed in vivo
      in sealing restorations of amalgam. Four cavity treatment systems were
      investigated in this study: Cervitec, Gluma One Bond, Panavia 21 and Copaliner
      Dentin Varnish and Sealant. No cavity treatment was placed in an additional group
      to serve as a control. The teeth were extracted within 15 minutes of restoration
      placement. The specimens were thermocycled (5-55 +/- 2 degrees C, 500 cycles),
      immersed in a dye solution, sectioned and scored for leakage. Scanning electron
      microscopy also examined features of the tooth/restoration interfaces. There were
      statistically significant differences among the groups regarding leakage scores
      (p = 0.00). None of the materials tested consistently prevented leakage; however,
      use of Copaliner Dentin Varnish and Sealant resulted in less overall, occlusal
      and cervical microleakage than any other systems tested. Significantly more
      leakage was observed in relation to the cervical portions of the cavities (p =
      0.00). No significant differences were identified between the leakage scores
      obtained for the buccal and palatal (lingual) cavities and the different tooth
      types (p = 0.52 and 0.83, respectively). A level of significance of 0.05 was
      selected in all cases. The benefits of the materials tested in this study need to
      be evaluated using robust, long-term clinical studies. Further work should
      continue to develop laboratory tests that predict the behavior and performance of
      cavity sealants in clinical service.

PMID- 12413219
TI  - Effect of light curing modes and filling techniques on microleakage of posterior
      resin composite restorations.
AB  - This in vitro study evaluated the microleakage of a posterior resin composite
      restoration (P60-3M ESPE) filled with two techniques and light cured with three
      different modes. Standardized Class V cavities were prepared on the enamel buccal
      surface of freshly extracted inferior bovine incisors. Teeth were randomly
      divided into six experimental groups: two filling techniques (bulk and
      incremental filling) and three polymerization methods (conventional-680 mW/cm2/30
      seconds; soft-start-380 mW/cm2/10 seconds + 680 mW/cm2/20 seconds; 1.3 cm light
      tip distanced -200 mW/cm2/10 seconds + 680 mW/cm2/20 seconds). All specimens were
      thermocycled for 3,000 cycles at 5 degrees C and 55 degrees C before immersion in
      a 2% methylene blue solution for 12 hours. Specimens were then washed and
      prepared for spectrophotometric analysis in order to quantify the dye
      infiltration around each restoration. Results showed that three polymerization
      modes presented no statistically significant differences for the incremental
      filling groups, whereas for the bulk filling group, conventional polymerization
      presented the highest leakage means that was statistically different from the
      other two polymerization modes. It was concluded that even though polymerization
      with initial low intensity light and bulk filling resulted in lower leakage
      means, no polymerization or filling techniques avoided microleakage.

PMID- 12413220
TI  - Effect of residual water on dentin bond strength and hybridization of a one
      bottle adhesive system.
AB  - This research investigated the effects of wet and dry conditions of phosphoric
      acid etched dentin on resin bonding and determined the optimum moisture condition
      for resin bonding using an ethanol-based one-bottle adhesive system. Bovine
      dentin surfaces were etched with 35% phosphoric acid and rinsed with water. Under
      four wet and dry conditions (overwet, blot dry, one-second dry and desiccated),
      resin composite was bonded using Single Bond. Tensile bond strength was measured
      and the results analyzed by one-way ANOVA and Fisher's PLSD test at the 5% level.
      The resin-dentin interfaces of bonded specimens were observed with SEM. The bond
      strength of overwet, blot dry, one-second dry and desiccated groups were 5.2 MPa,
      12.6 MPa, 11.9 MPa and 4.4 Mpa, respectively. The blot dry group and one-second
      dry groups revealed significantly higher bond strengths than the desiccated and
      overwet groups (p < 0.05). The formation of hybrid layers approximately 5 microm
      thick (overwet and blot dry), 2 microm (one-second dry) and 3 microm (desiccated)
      were observed. The coefficient of variation in the blot dry group was very high,
      even though a higher mean was observed. In the one-second dry group, the moisture
      content of the collagen network was possibly too low, such that hybrid layer
      formation was not as good even though the bond strength was high.

PMID- 12413221
TI  - Composite restorations: influence of flowable and self-curing resin composite
      linings on microleakage in vitro.
AB  - This in vitro study evaluated the microleakage at enamel (occlusal) and dentin
      (gingival) margins of MOD resin composite restorations made with different
      incremental insertion techniques. MOD cavities were prepared on 60 extracted
      human molars with the proximal margins placed 1 mm below the cemento-enamel
      junction. All teeth were acid-etched and treated with One-Step adhesive, then
      restored with a hybrid resin composite (Renew) with and without a flowable
      composite (AEliteflo) or a self-curing composite (Bisfil 2B) as the first
      increment in the proximal boxes. The time of placement of the second increment in
      relation to curing of the first increment was also varied. After polishing, the
      teeth were soaked in 0.5% basic fuchsin for 24 hours, sectioned and evaluated for
      dye penetration. None of the restorative techniques prevented microleakage at the
      enamel and dentin margins. However, microleakage at dentin margins were
      significantly reduced by the use of a flowable composite as the first increment
      in the proximal boxes. Time of placement in relation to curing had no influence
      on microleakage. Microleakage was lower at enamel margins than at dentin margins;
      however, besides microleakage at the enamel-restoration interface, 37 of the 60
      restored teeth (62%) displayed at least one white line in enamel adjacent to the
      composite restoration.

PMID- 12413222
TI  - Effects of professionally applied topical fluorides on surface hardness of
      composite-based restoratives.
AB  - This study investigated the effects of professionally applied topical fluorides
      on the surface hardness of a composite (Spectrum TPH), a compomer (DyractAP) and
      a giomer (Reactmer). Thirty specimens of each material were fabricated and stored
      in distilled water at 37 degrees C for one week. These specimens were then
      randomly divided into five groups of six and treated for 36 hours at 37 degrees C
      with one of the following: distilled water (control), 1.23% acidulated phosphate
      fluoride (APF) foam, 0.9% neutral foam, 1.23% APF gel and 0.4% stannous fluoride
      gel. The treated specimens were subsequently subjected to microhardness testing
      (load = 500 gf; dwell time = 15 seconds). Results were analyzed using
      ANOVA/Scheffe's test (p<0.05). The effects of topical fluoride application on
      surface hardness was material dependent. For all materials, treatment with APF
      gel and foam significantly reduced surface hardness when compared to the control.
      KHN values after exposure to APF gel were consistently the lowest and ranged from
      4.53 to 15.97. Control KHN values were higher, ranging from 32.88 to 47.47. The
      surface hardness of the compomer was also significantly reduced after exposure to
      neutral foam. Therefore, the use of professionally applied topical fluorides,
      especially APF gel and foam, may be detrimental to the long-term durability of
      composite-based restoratives.

PMID- 12413223
TI  - Evaluation of microleakage using different bonding agents.
AB  - This study evaluated microleakage in vitro using different bonding agents. Forty
      two freshly extracted caries-free human teeth were randomly divided into seven
      groups of six teeth and restored with different adhesive systems: Single Bond,
      Prime&Bond NT, Excite, Durafill Bond, Etch&Prime 3.0, Prompt L-Pop and Vitremer
      as the control group. All groups were treated according to manufacturers'
      instructions. Class V cavities were prepared on buccal and lingual surfaces (3 x
      2.5 x 1.5 mm) of each tooth (12 restorations per group), with gingival margins in
      dentin. The teeth were restored with Charisma resin composite. After finishing
      and polishing with Denco-Flex disks, the teeth were thermocycled for 200 cycles
      (5 degrees C-55 degrees C +/- 2 degrees C, 60-second dwell time). Apical foramina
      and surfaces around restorations were coated with nail varnish, stained in 50%
      AgNO3 solution for 12 hours and longitudinally sectioned. Microleakage was
      evaluated with a stereomicroscope. Marginal penetration was scored on a 0-4
      scale. Statistical analysis using the Kruskal-Wallis test revealed significant (p
      < or = 0.05) leakage at dentin margins for all adhesive systems when compared to
      the control. Except for Durafill Bond, no significant difference was found
      between the self-etching adhesives and one-bottle adhesives.

PMID- 12413224
TI  - Dentin sealers' effect on the diameter of pulpal microvessels: a comparative
      vitalmicroscopic study.
AB  - After crown preparation, exposed and untreated dentinal tubules can result in
      bacterial penetration into pulp. Treating the exposed dentin involves closing the
      tubules. Dentin sealers are often applied on a very thin dentin layer that covers
      the pulp chamber. In these cases, the sealers may have some effect on local micro
      circulation through dentin. This study examined the acute effects of different
      dentin sealers on the vascular-diameter of pulpal vessels measured by
      vitalmicroscopic technique in rats. Gluma Desensitizer in Group 1 (n = 10), Seal
      & Protect with acid etching in Group 2 (n = 10) and Seal & Protect without acid
      etching in Group 3 (n = 10) were applied on a very thin layer of dentin in the
      left lower incisor of male Sprague-Dawley rats weighing 336 +/- 93SE/g. Saline
      served as the untreated control. After one-hour equilibration time, changes in
      vessel diameter were recorded with a digital camera connected to a microscope at
      baseline and at 5, 15, 30 and 60 minutes after the investigated materials were
      administered on dentin. The results were evaluated by ANOVA. In each group,
      diameter changes were averaged (compared to the baseline diameters) and standard
      errors of the mean were calculated for each examined time. The results suggest
      that Gluma Desensitizer caused the most severe pulpal vessel-diameter changes,
      followed by Seal & Protect with acid etching, while the least change was recorded
      in Seal & Protect without acid etching.

PMID- 12413225
TI  - Depths of cure and effect of shade using pulse-delay and continuous exposure
      photo-curing techniques.
AB  - This study investigated the extent of cure (monomer conversion into polymer) of a
      variety of photo-initiated resin composites and different shades. Cure values
      were measured at the top surface and at simulated lighting conditions 0.5, 1.0
      and 2.0 mm below the top. The exposure methods used were continuous output at 600
      mW/cm2 (10, 20 or 40 seconds), initial component of the pulse-delay technique
      (pulse) (3 seconds at 200 mW/cm2) and the entire pulse-delay technique (pulse, 3
      minute delay, 10 seconds at 600 mW/cm2). The results showed very little
      difference in conversion values between A2 and D2 shades of the same composite
      with respect to depth. Conversion values using only the pulse method were
      remarkably low at the top surface and diminished rapidly at depths. Conversion
      using the pulse-delay technique produced similar values as that of the continuous
      10-second exposure at similar depths but still decreased remarkably at depth.
      Conversion values using the pulse-delay technique and a 20-second continuous
      exposure were significantly lower than those obtained using continuous 40-second
      exposure.

PMID- 12413226
TI  - Microleakage of Class II packable resin composites lined with flowables: an in
      vitro study.
AB  - Flowable resin materials have been suggested as liners beneath packable
      composites to improve marginal integrity. This investigation evaluated the effect
      of low-viscosity liners on microleakage in Class II packable composite
      restorations. Twenty Class II cavities were prepared in extracted third molars
      for each of four packable composites (Heliomolar HB, Prodigy Condensable, Surefil
      and Tetric Condense). Ten restorations were placed for each material with their
      corresponding bonding agent per manufacturer's suggestion; in addition, 10 were
      placed with the flowable liner recommended by the manufacturer for that material.
      Samples were finished, stored in distilled water for at least 24 hours and
      thermocycled for 1,000 cycles between 5 degrees and 55 degrees C with a one
      minute dwell time. Apices were sealed with epoxy cement and the teeth were
      varnished to within 1 mm of the margins. Samples were placed in 0.5% basic
      fuschin dye for 24 hours, rinsed, embedded in resin and sectioned to produce
      multiple sections. Microleakage was rated (0-4 ordinal scale) at both the
      occlusal and cervical margins. Data were analyzed with Kruskal-Wallis ANOVA for
      main effect and ranked sum analysis for pairwise testing (alpha = 0.05). All
      materials, either separately or in combination with a flowable liner, had greater
      leakage scores at the cervical margin compared to the occlusal margin. All
      packable systems tested did not yield a reduction in microleakage with the use of
      a flowable liner in vitro; however, the packable system with the flowable
      compomer used as a liner yielded significantly less overall microleakage compared
      to the three systems that used a resin composite liner.

PMID- 12413227
TI  - Validity of electrical conductance measurements in evaluating marginal leakage
      around resin composite restorations.
AB  - This in vitro study evaluated the influence of the cavity size of restoratives on
      a new electrical method for detecting marginal leakage. Cavities were prepared on
      the buccal coronal and root surfaces of 32 extracted non-carious human molars and
      were divided into four groups having different cavity depths (0.5 approximately
      4.0mm) or margin sizes (long axis or diameter: 2.0 approximately 4.0mm). All
      cavities were filled with resin composites without a bonding system. After
      physiological saline was applied, then wiped off, the change in conductance was
      measured continuously across the margin from the composite surface to the tooth
      surface. Conductance was measured at the same location after filling and before
      cavity preparation. In coronal and root surface cavities, the change in
      conductance after filling increased as the depth of cavity increased. There were
      significant differences in the change of conductance among the three groups with
      different cavity depths (p < 0.05). The differences between large and small
      cavity margin groups were not significant for either surface cavities. This
      method was shown to discriminate between deep and shallow marginal leakage, with
      the detection of marginal leakage being independent of margin size.

PMID- 12413228
TI  - Removal of amalgam, glass-ionomer cement and compomer restorations: changes in
      cavity dimensions and duration of the procedure.
AB  - This study investigated changes in the dimensions of Class II cavities following
      the removal of amalgam, glass ionomer and compomer restorations. In 30 extracted
      caries-free human molars, preparation for 60 mesio-occlusal and occluso-distal
      cavities (two cavities per tooth) occurred. With a CEREC 3 laser triangulation
      sensor and software-based construction analysis, the dimensions of the cavities
      at seven defined sites were measured. The cavities were randomized into four
      groups. Group 1 was restored with Ketac-Fil glass-ionomer cement, Group 2 with
      amalgam and Group 3 with Compoglass F compomer. In Group 4, Compoglass F was used
      in combination with photochromic Tetric Flow Chroma as a cavity liner. The
      completed restorations were then removed using 2x magnification and the cavities
      were once again controlled using the laser system. The duration of the removal
      procedure was also recorded. Changes in cavity dimensions (depth, height and
      width) following removal of the restorations were significantly smaller in Groups
      1 and 2. Groups 3 and 4 were characterized by a significant overextension of the
      cavities compared to Groups 1 and 2 in all three dimensions. Group 4, with Tetric
      Flow Chroma as a cavity liner, showed better results than Group 3, but this
      improvement was not statistically significant. The duration of the removal
      procedure was significantly shorter in Group 2 than in the other groups.

PMID- 12413229
TI  - Re-attachment of anterior fractured teeth: fracture strength using different
      materials.
AB  - This study compared the fracture strength of two different techniques (bonded
      only and buccal chamfer) and different material combinations used to reattach
      tooth fragments. An axial load applied to the buccal area fractured 110 sound
      permanent lower incisors. Fifty teeth were designated for the bonded only group
      (no additional preparation) and 50 teeth were designated for a buccal chamfer
      group. For each group teeth were subdivided into five subgroups (n = 10)
      according to the restorative material combinations used: 1) adhesive system (A);
      2) A + light cured luting cement; 3) A + dual cured luting cement; 4) A +
      flowable resin and 5) A + hybrid resin. In a control group (resin composite build
      up), in the remaining 10 teeth, the crown portion was rebuilt with adhesive and
      resin composite. Restored teeth were subjected to the same loading in the same
      buccal area. Fracture strength after restorative procedures for all groups was
      expressed as a percentage of the original fracture strength and the results were
      analyzed by two-way ANOVA and Tukey's test for pair-wise comparison. The
      interaction and the material factor were not statistically significant (p = 0.140
      and p = 0.943, respectively). The chamfer group showed higher fracture strength
      recovery (67.9%) than the bonded only group (41.1%), and both were statistically
      lower than the resin composite build-up (103.2%). It was concluded that the
      material used to reattach the fragment is less important than the chosen
      technique.

PMID- 12413230
TI  - Comparison of two methods of measuring dye penetration in restoration
      microleakage studies.
AB  - This study compared the slice method of measuring microleakage to the whole-wall
      method. Forty-eight Class V direct metal restorations were placed in the buccal
      and lingual surfaces of 24 human molars. Following thermocycling and storage in
      2% methylene blue stain for 12 hours, the teeth were sectioned and the
      restorations removed to expose the intact occlusal and gingival cavity walls.
      Maximum dye penetration axially was determined along either one or two imaginary
      slices or over the whole wall. Data were statistically evaluated by ANOVA and
      Tukey's test. Non-uniform staining occurred with 38 of the 96 walls available for
      evaluation. The average maximum dye penetration depth of the 38 walls was 0.61 mm
      and 0.70 mm for the slice method using one slice or two, respectively, and 1.29
      mm for the whole-wall method. About half of these walls had leakage depths that
      were more than twice as great as when measured by the slice methods. All 12 of
      the 38 walls with no leakage when measured by the slice method, showed leakage at
      least somewhere along the margin when measured by the whole-wall method. This
      study shows that the whole-wall method detects significantly more leakage than
      does the slice method (p < 0.0001) and that using two rather than one slice does
      not improve the detection of leakage (p < 0.1534). Slicing the tooth restoration
      interface into only two or three sections may seriously underestimate the degree
      of leakage.

PMID- 12413231
TI  - Shedding new light on composite polymerization.
AB  - Life usually gets simpler, but in the case of photocuring dental restorative
      materials, just the opposite is true. Confusing and contradictory barrages of
      clinical claims have been made with the ever-growing variety of light-curing
      sources available today. Often, laboratory research or clinical studies related
      to these systems are lacking prior to their being introduced to the market,
      leaving the clinician to become the "testing ground." Manufacturers prefer to
      market the newest technology available, yet, depending on the type of practice
      and composite system in use, such "state-of-the-art" devices may offer no
      advantage. For some clinicians, changing to a "fast cure" composite in
      combination with a traditional QTH light, instead of purchasing a $4,000 PAC
      light, may be the only improvement in efficiency needed. However, others may want
      to spend as little time as possible per procedure and do not mind investing in
      the newest, yet "unproven" technology. Either way, today's clinician needs to be
      wary of the many claims made by manufacturers of all light-curing units. It is
      prudent that the clinician, prior to selecting a device, aggressively ask
      questions and dig for the truth before "buying into" a particular unit or system
      philosophy. At stake are the durability of restorations, the satisfaction of
      patient and the well-earned reputation of the operator.

PMID- 12413233
TI  - Groundhog Day: cause and effect and the primary importance of the finite
      population induced by randomization.
AB  - The logical structure that enables randomized clinical trials to establish cause
      and effect is reviewed. Statisticians have a major role to define this structure
      clearly and to help clinicians apply statistical inference in ways directly
      related to their trials. Scientific importance of establishing limited cause and
      effect should be accented rather than inferences to generalized populations
      beyond the scope of a trial's actual random sampling. Authors of clinical reports
      should clearly define the randomization-induced populations to which their
      inferences apply. Careful attention to identifying this population of inference
      can lead to resolution of some issues commonly debated in the analysis of
      clinical trials. If formal inferences to generalized populations are attempted,
      these populations should also be carefully described, the assumed random sampling
      process should be carefully defined, and appropriate methods should be used that
      correspond with the assumed random sampling process.

PMID- 12413232
TI  - Case report of a 40-year, five surface complex amalgam restoration.
AB  - Reports of longevity for multi-surface amalgam restoration have been limited.
      This paper reports a case where a five-surface complex amalgam restoration has
      been followed and documented for 40 years. The pictorial series will help to
      identify some of the factors a dentist should consider before replacing the
      restoration.

PMID- 12413234
TI  - Reconsidering some aspects of the two-trials paradigm.
AB  - A common standard for the demonstration of efficacy in a clinical submission is a
      statistically significant outcome in at least two pivotal trials ("two-trials
      convention"). When the data structures in different trials are sufficiently
      similar to allow pooling of the data across trials for a combined analysis, we
      argue here that such an analysis is a more logical and efficient basis for a
      judgment regarding efficacy. Criteria for combined analyses may be established,
      which ensure the same false positive rate protection as the two-trials
      convention. A combined analysis will generally have much more power than the
      corresponding application of the two-trials approach that has the same false
      positive rate protection. In addition, we describe the behavior of modified
      versions of pure combined analysis, which incorporate a formal standard for
      reproducibility of trial results by limiting the larger of the individual trial p
      values. These modifications are shown to maintain the desirable behavior of the
      pure combined analysis, namely, higher power compared to the two-trials
      convention.

PMID- 12413235
TI  - Bayesian hierarchical models for multi-level repeated ordinal data using WinBUGS.
AB  - Multi-level repeated ordinal data arise if ordinal outcomes are measured
      repeatedly in subclusters of a cluster or on subunits of an experimental unit. If
      both the regression coefficients and the correlation parameters are of interest,
      the Bayesian hierarchical models have proved to be a powerful tool for analysis
      with computation being performed by Markov Chain Monte Carlo (MCMC) methods. The
      hierarchical models extend the random effects models by including a (usually
      flat) prior on the regression coefficients and parameters in the distribution of
      the random effects. Because the MCMC can be implemented by the widely available
      BUGS or WinBUGS software packages, the computation burden of MCMC has been
      alleviated. However, thoughtfulness is essential in order to use this software
      effectively to analyze such data with complex structures. For example, we may
      have to reparameterize the model and standardize the covariates to accelerate the
      convergence of the MCMC, and then carefully monitor the convergence of the Markov
      chain. This article aims at resolving these issues in the application of the
      WinBUGS through the analysis of a real multi-level ordinal data. In addition, we
      extend the hierarchical model to include a wider class of distributions for the
      random effects. We propose to use the deviance information criterion (DIC) for
      model selection. We show that the WinBUGS software can readily implement such
      extensions and the DIC criterion.

PMID- 12413236
TI  - Robust estimation of the median lethal dose.
AB  - Alternatives to M-estimation for robust estimation of the median lethal dose in
      biological assays are developed. A class of link functions based on the Student-t
      distribution is proposed, where degrees of freedom are estimated from the data by
      maximum likelihood. Other alternatives include slash and finite mixture
      distributions. For bioassays from a pharmaceutical company, these methods extend
      the standard probit and logistic models, as well as the Huber's M-estimator. They
      are also applied to several standard examples from the literature.

PMID- 12413237
TI  - Adjusting pairwise nonparametric equivalence hypothesis tests and confidence
      intervals for period effects in 3 x 3 crossover trials.
AB  - In pharmacokinetic and pharmacodynamic 3 x 3 crossover trials, average
      bioequivalence and noninferiority between treatments need to be only assessed
      pairwise in most cases. Due to the restricted number of subjects in such trials,
      normal distribution assumptions cannot be checked and frequently outliers are
      encountered, so that a nonparametric approach is more adequate. Therefore, to
      assess average bioequivalence or noninferiority, a new method is proposed to
      derive period adjusted nonparametric confidence intervals for pairwise treatment
      differences.

PMID- 12413238
TI  - Investigating the criterion validity of psychiatric symptom scales using
      surrogate marker validation methodology.
AB  - This work investigates whether techniques that are generally used for the
      validation of surrogate markers in clinical trials can be applied in the
      validation of psychiatric health measurements (often scales) and more generally
      to investigate relationships between treatment effects on different measurements.
      However, the categorical nature of some scales makes these techniques
      inapplicable in the way they were originally defined. In this work, we show a
      possible extension of this methodology to the setting in which one of the scales
      is an ordinal categorical variable. When psychiatric health measurements are
      either developed or used in a new population, reliability and validity must be
      investigated. Reliability, more specifically internal consistency, test-retest
      reliability, and inter-rater reliability, is focused on the reproducibility of
      the measurement. Validity is defined as the degree to which the scale measures
      what it purports to measure. This can be performed through the analysis of
      content, construct, and criterion validity. We argue that recent methodology, in
      particular developed to study surrogate endpoints, can be used to examine
      criterion validity, concurrent validity, and predictive validity. In concurrent
      validity, we correlate the measurement with a criterion measure, both of which
      are given at the same time. In predictive validity, the criterion will not be
      available to some point in time in the future. The surrogate methods were applied
      on pooled data from five trials in schizophrenia.

PMID- 12413239
TI  - Do you know your total cholesterol (TC) number?
AB  - Total cholesterol (TC) measurements are subject to errors primarily because of
      temporal variations in cholesterol levels within each individual. These errors
      make it difficult to estimate the proportion of study subjects with true (error
      free) TC in a specific range, an extremely important parameter to policy makers
      in health care management. To properly address this issue, it is key to
      accurately estimate the distribution function of the true TC, which typically
      deviates from the normal distribution. To better approximate the distribution
      function of the true TC, we propose a constrained maximum likelihood estimator
      based on a mixture-of-normals model. A simulation study illustrates that the
      proposed estimator performs better than an estimator based on the normality
      assumption that is frequently used in the literature to address the same issue.
      Finally, the proposed estimator is applied to data from a study, and its
      performance is once again compared with that of an estimator based on the
      normality assumption.

PMID- 12413240
TI  - Strategies for changing the test statistic during a clinical trial.
AB  - This article discusses the design of a clinical trial where a new treatment will
      be compared to a control. For a specific type of endpoint, there are a wide
      variety of test statistics that can be used. Also, the investigator must decide
      how many patients to accrue in each arm as well as the duration of the study.
      After an interim look at the data, the investigator may decide that a different
      test statistic would be more powerful or that more patients or longer follow-up
      is needed. In this article, we discuss a strategy for making these types of
      changes. This strategy controls the probability of making a type I error and can
      result in a procedure that has higher power than the test without adaptation.

PMID- 12413241
TI  - Comparison of alternative strategies for analysis of longitudinal trials with
      dropouts.
AB  - PROBLEM: Patients may withdraw from longitudinal clinical trials for many
      reasons. Methods for handling the problem presented by missing data of patients
      who withdraw before reaching the time point of the primary measurement include
      carrying the last observation forward (LOCF), data as observed analysis (DAO),
      mixed model approaches, and pattern mixture models. METHOD: We evaluate a
      multiple imputation (MI) approach that has the flexibility to adjust inferences
      about the treatment effect for the withdrawn patients relative to currently used
      alternatives. Sensitivity analyses are performed under a collection of scenarios
      that include many circumstances that may arise in practice, including different
      assumptions about treatment effects post-withdrawal and about the missing data
      mechanism. Simulations are used to compare the results of analyses based on the
      MI approach with those based on the LOCF, DAO, and the mixed model approaches.
      RESULTS: The LOCF and DAO approaches cannot be recommended as strategies for
      handling missing responses, at least for these scenarios, because they provide
      biased estimates of treatment effects and biased tests of the null hypothesis of
      no treatment effect. Application of the various approaches to the analysis of
      clinical data from a longitudinal trial confirms the underestimation of the
      variability when the LOCF approach is used.

PMID- 12413242
TI  - Sample size calculation for a historically controlled clinical trial with
      adjustment for covariates.
AB  - We present a Bayesian approach to determining the optimal sample size for a
      historically controlled clinical trial. This work is motivated by a trial of a
      new coronary stent that uses a retrospective control group formed from seven
      trials of coronary stents currently marketed in the United States. In studies
      involving nonrandomized control groups, hierarchical regression, propensity score
      methods, or other sophisticated models are typically required to account for
      heterogeneity among groups which, if ignored could bias the results. Sample size
      calculations for historically controlled trials of medical devices are often
      based on formulae derived for randomized trials and fail to account for
      estimation of model parameters, correlation of observations, and uncertainty in
      the distribution of covariates of the patients recruited in the new trial. We
      propose methodology based on stochastic optimization that overcomes these
      deficiencies. The methodology is demonstrated using an objective function based
      on the power of the trial from a Bayesian approach. Analytic approximations based
      on a covariate-free analysis that convey features of the power function are
      developed. Our principle conclusions are that exact sample size calculations can
      be substantially different from current approximations, and stochastic
      optimization provides a convenient method of computation.

PMID- 12413243
TI  - A sequential procedure for comparing two experimental treatments with a control.
AB  - A procedure is described in which patients are randomized between two
      experimental treatments and a control. At a series of interim analyses, each
      experimental treatment is compared with control. One of the experimental
      treatments might then be found sufficiently superior to the control for it to be
      declared the best treatment, and the trial stopped. Alternatively, experimental
      treatments might be eliminated from further consideration at any stage. It is
      shown how the procedure can be conducted while controlling overall error
      probabilities. Data concerning evaluation of different doses of riluzole in the
      treatment of motor neurone disease are used for illustration.

PMID- 12413244
TI  - Sample size calculation for a proof of concept study.
AB  - Sample size calculation is vital for a confirmatory clinical trial since the
      regulatory agencies require the probability of making Type I error to be
      significantly small, usually less than 0.05 or 0.025. However, the importance of
      the sample size calculation for studies conducted by a pharmaceutical company for
      internal decision making, e.g., a proof of concept (PoC) study, has not received
      enough attention. This article introduces a Bayesian method that identifies the
      information required for planning a PoC and the process of sample size
      calculation. The results will be presented in terms of the relationships between
      the regulatory requirements, the probability of reaching the regulatory
      requirements, the goalpost for PoC, and the sample size used for PoC.

PMID- 12413245
TI  - Demand for, access to and use of community mental health care: lessons from a
      demonstration project in India and Pakistan.
AB  - BACKGROUND: A widely promoted model of mental health care and prevention
      appropriate to many low-income countries is one that is integrated into the local
      primary health care system. AIMS: To examine the influence of health-seeking
      behaviours (demand-side factors) and the access to/availability of services
      (supply-side factors) on local service utilisation patterns for people with
      common mental disorders. METHOD: Two rural catchment populations outside
      Bangalore (India) and Rawalpindi (Pakistan), one with the standard primary health
      care system, the other with additional mental health care training and support,
      were screened for common mental disorders. Diagnosed cases were interviewed about
      their use of and perceptions of local health care services (repeated three months
      later). RESULTS: Individuals' use of integrated mental health and other care was
      modest. Principal (self-rated) supply-side factors were the cost of care,
      distance from treatment centre, a perception that care would not be effective,
      and concerns regarding stigma. Perceptions improved over three months,
      accompanied by an increased preference for public over private providers, but
      this was not restricted to the integrated care localities. CONCLUSION: The use
      (and therefore effectiveness) of mental health services integrated into primary
      care is influenced by the health-seeking behaviours and perceptions of the local
      population. Efforts to integrate mental health into primary care need to be
      accompanied by educational activities in order to increase awareness, reduce
      stigma and draw attention to the availability of effective treatment.

PMID- 12413246
TI  - Mental health services in Slovenia.
AB  - BACKGROUND: Development of mental health services in Slovenia has some
      originalities described in the present article. Slovenia is a small Central
      European country with a population of 2 million. Its mental health system has
      been influenced by the western de-institutionalization movement and eastern
      models of care which are predominately institutional. AIMS: Mental health reform
      in the 1970s was a silent one with displacement of long-term psychiatric patients
      to old-people's homes, asylums and to their families. During the last decade
      community mental health services have been established in the non-government
      sector, primarily as social institutions providing support to patients with
      severe mental illness. Psychosocial rehabilitation movement changed some
      therapeutic approaches in hospitals and has been gaining more and more influence
      in the NGO services. RESULTS: The article describes Slovene psychiatric hospitals
      and community rehabilitation services. Mental health services in Slovenia are
      compared to services in Slovakia, the United Kingdom and The Netherlands.
      CONCLUSIONS: The authors are proposing guidelines for future development of
      mental health services for the severely mentally ill in our country in order to
      improve the present deficient state of care.

PMID- 12413247
TI  - Depression and quality of life: results of a follow-up study.
AB  - BACKGROUND: Although there is sufficient evidence that the quality of life of
      people suffering from depression is reduced hardly anything is known about their
      quality of life after the remission of a depressive episode. AIMS: We therefore
      set out to study the quality of life of patients with depression (ICD-10 F32,
      F33) one, four and seven months after discharge from hospital. For comparison, a
      random sample of the general population was studied in addition. METHOD: Quality
      of life was assessed by means of the WHOQOL-100, a self-administered
      questionnaire developed by WHO. RESULTS: Although, shortly after discharge,
      quality of life of patients whose depression remitted was better than that of
      patients with persisting depression it was still slightly worse than that of the
      general population. During the subsequent six months, there was no further
      improvement of quality of life, i.e. even at the end of the follow-up period
      there was a slight lack of quality of life, especially as concerns the level of
      independence, spirituality/religion/personal beliefs and physical health.
      CONCLUSIONS: Thus, what already had been reported based on the objective
      assessment of quality of life, namely that depression implies a persisting
      impairment of social functioning and living conditions, can be replicated to some
      extent from the point of view of the patients themselves.

PMID- 12413248
TI  - An evaluation of two screening methods to identify cases with schizophrenia and
      affective disorders in a community survey in rural Ethiopia.
AB  - BACKGROUND: Detecting cases with psychiatric disorders in the general population
      is costly and it is not clear which is the method of choice for community surveys
      in low-income countries. AIM: To compare the performance of a standardized
      diagnostic layman interview instrument--the Composite International Diagnostic
      Interview (CIDI 2.1) versus the Key Informant method in identifying cases with
      schizophrenia and major affective disorders in a community survey. METHOD: Both
      screening methods were tested against an expert interview--the Schedule for
      Clinical Assessment in Neuropsychiatry (SCAN 2.1) in a rural district in Ethiopia
      with 25,632 inhabitants. RESULT: CIDI identified 524 and key informants 192
      individuals as probable cases who were invited for a further SCAN interview.
      Seventy-two individuals were identified by both methods. Of those identified as
      probable cases by either method, a total of 481 volunteered the SCAN interviews.
      The Key Informant method alone detected more cases of schizophrenia, 59 vs. 29
      for CIDI, whereas CIDI alone detected more cases of affective disorders, 45 vs.
      30. Key informants performed better in detecting chronic cases. CONCLUSION: For
      community surveys, which aim at identifying cases with major mental disorders in
      low-income countries like Ethiopia, the combined use of both CIDI and the Key
      Informant method is recommended.

PMID- 12413249
TI  - Determinants of attitude to volunteering in psychiatry: results of a public
      opinion survey in Switzerland.
AB  - BACKGROUND: The United Nations proclaimed 2001 the "International Year of
      Volunteers". Little is known about factors influencing the attitude to
      volunteering in psychiatry. However, knowledge about these factors is important
      as target groups to be addressed by an awareness and promotion campaign could be
      identified. AIMS: To determine the influence of demographic, psychological and
      sociological factors on the attitude to volunteering in psychiatry. METHODS:
      Multiple logistic regression analysis of the results of an opinion survey
      conducted on a representative population sample in Switzerland (n = 1737).
      RESULTS: Public attitude is mostly positive. It depends, however, on the form of
      volunteering. Two explanatory models for volunteering in psychiatry were found:
      first, the "antipathetic person" having social distance to and negative
      stereotypes towards the mentally ill. Second, the "people with social
      responsibility and commitment" who have former experience in volunteering, a
      positive attitude to community psychiatry, interest in mass media, a social
      profession and perceive discrimination of mentally ill persons. Age and gender
      are significant predictors. CONCLUSIONS: An awareness and promotion campaign to
      use the vast potential of people willing to volunteer in psychiatry can be
      primarily focused on those with a basic interest in social issues. Volunteering
      must be limited in time and responsibility. Contacting people with a positive
      attitude by mass media is a promising way.

PMID- 12413250
TI  - An exploration of eating disorders in a Georgian sample.
AB  - BACKGROUND: There is debate as to whether eating disorders may be culture-bound.
      However, accumulating evidence suggests that eating disorders may be found
      outside of the West, although the precise form of the eating disorder may differ.
      AIMS: There were two aims of this study: (1) to translate and establish the
      psychometric properties of standard questionnaires to measure eating pathology in
      a Georgian sample; (2) to use these measures to determine whether cases of eating
      disorders exist in Georgia. METHODS: We held focus groups of various health
      professionals to establish how eating disorders present in Georgia and to
      identify groups perceived to be at high risk of having an eating disorder. We
      obtained translated versions of a number of standardized questionnaires
      (measuring eating and general psychopathology) from 245 women from these
      identified high risk groups and a subsample were given a structured clinical
      interview. RESULTS: We estimated from the responses to the questionnaires, that
      as many as 5% may have clinically significant bulimia nervosa, 7% fell in the
      weight range for anorexia nervosa with a further 7% in the weight range for
      obesity. We interviewed a sample of the high scoring group which confirmed the
      presence of clinically significant eating pathology in the majority of those
      identified as possible cases. CONCLUSIONS: The results of this study suggest
      there may be women in Georgia with significant eating problems.

PMID- 12413251
TI  - Can personality predict suicidality? A study in two cultures.
AB  - Kuwaiti (n = 460) and American (n = 273) undergraduates responded to seven
      questionnaires in Arabic and English, respectively. It was found that Kuwaiti
      students attained significantly higher total mean scores on ego-grasping
      orientation (anti-Taoist orientation), death obsession, pessimism, obsession
      compulsion and anxiety scales than the American students, while the latter group
      had a significantly high mean score on an optimism scale. There were no
      significant differences between the groups in suicidal ideation. Almost all the
      Pearson inter-correlations between these scales were significant and positive,
      except that those between the scale scores and optimism scores were negative. The
      unrotated factor was bipolar, clear and high-loaded, labeled "Negative affect
      versus optimism". Multiple regression revealed that the best predictors of
      suicidal ideation were pessimism, death obsession and anxiety in the Kuwaiti
      students, while they were optimism (negatively), anxiety, pessimism, death
      obsession and male sex in the American students, respectively. The other scales
      did not contribute significantly to the prediction of suicidal ideation.

PMID- 12413252
TI  - Intravenous induction agents: propofol.

PMID- 12413253
TI  - Intubating laryngeal mask airway.
AB  - The Intubating Laryngeal Mask Airway (ILMA) was introduced into clinical practice
      in 1997 following numerous clinical trials involving 1110 patients. The success
      rate of blind intubation via the device after two attempts is 88% in "routine"
      cases. Successful intubation in a variety of difficult airway scenarios,
      including awake intubation, has been described, with the overall success rate in
      the 377 patients reported being approximately 98%. The use of the ILMA by the
      novice operator has also been investigated with conflicting reports as to its
      suitability for emergency intubation in this setting. Blind versus visualized
      intubation techniques have also been investigated. These techniques may provide
      some benefits in improved safety and success rates, although the evidence is not
      definitive. The use of a visualizing technique is recommended, especially whilst
      experience with intubation via the ILMA is being gained. The risk of oesophageal
      intubation is reported as 5% and one death has been described secondary to the
      complications of oesophageal perforation during blind intubation. Morbidity
      described with the use of the ILMA includes sore throat, hoarse voice and
      epiglottic oedema. Haemodynamic changes associated with intubation via the ILMA
      are of minimal clinical consequence. The ILMA is a valuable adjunct to the airway
      management armamentarium, especially in cases of difficult airway management.
      Success with the device is more likely if the head of the patient is maintained
      in the neutral position, when the operator has practised at least 20 previous
      insertions and when the accompanying lubricated armoured tube is used.

PMID- 12413254
TI  - Effects of diltiazem on in vitro cardiovascular actions of crude venom obtained
      from Okinawan box-jellyfish (Habu-kurage), Chiropsalmus quadrigatus.
AB  - The venom obtained from Okinawan box-jellyfish (Habu-kurage), Chiropsalmus
      quadrigatus, produced increases in contractions of isolated rat right atrial
      preparations in a concentration-dependent manner without changes in a spontaneous
      beating rate. These increases in contractions were significantly inhibited by
      diltiazem and did not show tachyphylaxis. The venom also produced increases in
      contractions of isolated rat aortic ring preparations (endothelium-intact) in a
      concentration-dependent fashion, which were reproducible with repeated
      application and were significantly inhibited by diltiazem or heating. These
      increases in vascular contractions were weakened in endothelium-denuded
      preparations, and almost abolished in a calcium-free medium. On the other hand,
      the venom at higher concentrations diminished contractions of both myocardial and
      vascular preparations and did not show reproducibility. These results suggest
      that the Habu-kurage venom is heat-labile and may increase contractions of
      cardiac muscle and aortic smooth muscle by increasing calcium influx into muscle
      cells, and that the venom at higher concentrations may produce dysfunction of
      muscle contractile systems due to calcium overload.

PMID- 12413255
TI  - Remifentanil concentration during target-controlled infusion of propofol.
AB  - After institutional approval and with written informed consent, eight surgical
      patients were infused intravenously with remifentanil at 250 ngkg lean body mass
      (LBM)(-1) x min(-1) for 30 min. Cardiovascular and respiratory parameters were
      recorded and arterial blood samples were taken at regular intervals. In each
      patient, the same protocol was repeated 40 min later during propofol infused to a
      target concentration of 3.0 microg x ml(-1). Blood concentrations of remifentanil
      and propofol were assayed using capillary gas chromatography and high performance
      liquid chromatography techniques respectively. The number of subjects enrolled
      was determined by testing the successive areas under the remifentanil time
      concentration curve (AUC) for significant difference or non-difference using
      sequential analysis. The median measured propofol concentration was 3.5 (range:
      2.6-4.5) microg x ml(-1) which did not change significantly during the second
      remifentanil infusion. The median AUC during propofol infusion was greater than
      control in all subjects, although there was considerable variation of 94.4 (64.3
      129.6) versus 64.6 (34.8-126.9) ng x ml(-1) x min; P=0.008, n=8. After 30 min,
      there was no significant difference in remifentanil concentration during propofol
      infusion when compared with remifentanil alone of 4.6 (3.2-5.7) versus 3.8 (1.6
      4.9) ng x ml(-1); P=0.73, n=8. Co-administration of propofol and remifentanil may
      result in greater remifentanil concentrations than when remifentanil is infused
      alone.

PMID- 12413256
TI  - Evaluation of induction doses of propofol: comparison between endstage renal
      disease and normal renal function patients.
AB  - Anaemia, hypoproteinaemia and acidic pH in renal failure patients can alter the
      pharmacokinetics and pharmacodynamics of anaesthetic agents, resulting in altered
      dose requirements. We evaluated the induction dose of propofol in adult patients
      with end-stage renal disease by titrating the hypnotic effect by means of a
      clinical parameter as well as using a more objective assessment of hypnosis, the
      Bispectral Index (BIS) monitor. The dose was compared with that for patients with
      normal renal function. Propofol doses that provided the clinical end-point of
      hypnosis (syringe drop method), as well as the end-point of a mean (SD) BIS value
      of 50 (5), were evaluated in 27 end-stage renal disease and 27 normal renal
      function patients. Propofol was administered at 0.2 mg/kg every 15 seconds until
      these end-points were achieved. End-stage renal disease patients required
      significantly higher propofol doses to achieve the clinical end-point of hypnosis
      (1.42 (0.24) mg/kg versus 0.89 (0.2) mg/kg in normal renalfunction patients,
      P<0.05 unpaired "t" test). Propofol dose required to achieve a BIS of 50 (5) was
      also higher in end-stage renal disease patients (2.03 (0.4) mg/kg versus 1.39
      (0.43) mg/kg in normal renal function patients, P<0.05). There was a significant
      negative correlation of propofol dose with preoperative haemoglobin
      concentration. A hyperdynamic circulation in renal failure patients with anaemia
      may be responsible for the higher propofol dose requirement in this group.

PMID- 12413257
TI  - Perioperative plasma concentrations of atrial and brain natriuretic peptides in
      patients undergoing hip arthroplasty.
AB  - Acute hypotension, transient hypoxaemia and elevation of pulmonary artery
      pressure are well known to occur during cemented arthroplasty. The aim of this
      prospective clinical study was to characterize the relationship between plasma
      concentrations of atrial and brain natriuretic peptides (ANP, BNP), and changes
      in blood pressure in patients undergoing hip arthroplasty. Elevated ANP and BNP
      levels may be markers of inadequate myocardial reserve. We measured plasma ANP
      and BNP levels before the operation and 20 minutes after the cementing in 18
      patients (54-90 yr). We defined a hypotensive response after cementing as a
      decrease in systolic blood pressure of more than 15 mm Hg below the pre-cementing
      value. In the hypotensive group, preoperative values of ANP were 123 +/- 48.5
      pg/ml and BNP, 138 +/- 71.7 pg/ml. These values are significantly greater than
      those in the normotensive group (ANP 35.9 +/- 7.7, and BNP 17.2 +/- 3.2 pg/ml).
      High preoperative values of ANP and BNP are associated with more hypotension
      during cemented arthroplasty and could provide an indication of which patients
      are at risk of this complication.

PMID- 12413258
TI  - The effects of sevoflurane on isolated gravid human myometrium.
AB  - The volatile anaesthetic agents are known to influence uterine muscle tone. All
      of the agents studied to date have been found to produce uterine relaxation. This
      property has been used to produce therapeutic uterine relaxation for difficult
      obstetric deliveries and the Ex Utero Intrapartum Treatment (EXIT) procedure.
      This study describes the effects of sevoflurane on isolated human myometrium at
      concentrations of 0.1, 0.25, 0.5, 0.75, 1.0, 1.5, 2.5 and 3.5 MAC. Sevoflurane
      produces dose-dependent depression of uterine muscle contractility with an ED50
      of 0.94 MAC. Frequency of contraction was increased at concentrations of 2.5 MAC
      and greater. At concentrations of 3.5 MAC and above, uterine activity was
      virtually abolished.

PMID- 12413259
TI  - Genotoxicity of waste anaesthetic gases.
AB  - BACKGROUND AND AIM: The possibility of a potential mutagenic or carcinogenic
      action of chronic exposure to low concentrations of inhalational anaesthetics has
      been previously studied, with conflicting results. The purpose of this study was
      to assess whether occupational exposure to waste anaesthetic gases increases
      genotoxic risk. We examined peripheral lymphocytes from anaesthetists for both
      sister chromatid exchange (SCE) and for cells with high-frequency SCEs (HFCs).
      METHOD: A group of 16 non-smoking anaesthetists with occupational exposure to
      anaesthetic gases and a sex- and age-matched group matched 16 non-smoking matched
      physicians without occupational exposure to anaesthetic gases were studied. The
      participants were also selected on the basis of similar responses to a
      questionnaire assessing risk of genotoxicity relating to other aspects of life.
      RESULT: SCEs, and HFC percentages obtained from the exposed anaesthetists (6.6+/
      2.4 and 12.2+/-15.9) were greater but not statistically significantly so than in
      the reference group (5.2+/-1.6 and 5.9+/-10.0). CONCLUSION: This study does not
      support the existence of an association between occupational exposure to waste
      anaesthetic gases and an increase in SCEs in lymphocytes. The nature of our
      anaesthesia practice suggests exposure was likely to be low. It should be noted
      that some anaesthetic gases produce lesions that can be efficiently repaired in
      mitogen-stimulated lymphocytes in vitro but not in circulating lymphocytes.

PMID- 12413260
TI  - Correct positioning of the venous port-a-cath catheter: comparison of
      intravascular electrocardiography signal from guidewire and sodium bicarbonate
      flushed catheter.
AB  - A prospective study comparing the efficacy of wire-conducted intravascular ECG
      (IVECG) signal and signal from the port with a sodium bicarbonate (NaHCO3)
      flushed catheter to correctly place a catheter tip was carried out in 100
      patients. The correct position of the catheter tip was confirmed as follows: with
      technique G, the IVECG signal was conducted from a guide wire to identify the tip
      position. With technique P, the IVECG signal was conducted from the port with a
      NaHCO3 (0.8 mmol/ml) flushed catheter to ascertain the tip position. Each patient
      received both technique G and technique P in a randomized sequence. The quality
      of IV-ECG signals, which included baseline drift, P wave pattern and QRS wave
      pattern, were assessed for ten seconds. Satisfactory quality of these IVECG
      signals was observed in all of the patients with technique P and 90 of the 100
      patients with technique G, and this difference was significant (P=0.001). There
      was no obvious difference between the techniques in catheter tip placement time
      or the measured optimal catheter length. The incidence of atrial premature
      contractions was higher with technique G than with technique P (13% vs 2%;
      P=0.003). Therefore, technique P is a practical alternative for correctly placing
      the catheter tip of a Port-A-Cath.

PMID- 12413261
TI  - Effect of age on haemodynamic response to tracheal intubation. A comparison of
      young, middle-aged and elderly patients.
AB  - The effect of age on the haemodynamic response to tracheal intubation was
      studied. Ninety ASA 1 or 2 patients were divided into three groups of 30 each
      based on age; ie., young (18-25 years), middle-aged (40-50 years) and elderly (65
      80 years). The haemodynamic response after tracheal intubation was observed as
      percentage change in heart rate and blood pressure compared to the baseline.
      Inter-group comparison was also done at different time points. The greatest
      percentage change in the systolic arterial pressure after tracheal tube insertion
      was seen in the elderly group (15%). The increase in systolic arterial pressure
      was significantly less in theyounggroup compared with the two older groups at
      one, two, three and four minutes post-intubation. The greatest percentage
      increase in the diastolic blood pressure compared to the baseline was seen in the
      middle aged group (24%). The elderly and young patients showed a significant
      difference in the diastolic blood pressure response only at one minute post
      intubation. The heart rate response was greatest in the middle-aged patients
      (40%) and least in the elderly (16%). These differences may have clinical
      significance and should be considered in assessing and performing research into
      the haemodynamic response to intubation.

PMID- 12413262
TI  - Bronchial diameters in children--use of the Fogarty catheter for lung isolation
      in children.
AB  - The right and left main bronchial diameters of 250 children were measured using
      computed tomography of the thorax. In 75% of the cases, the right main bronchial
      diameter was significantly larger than the left (95% CI 0.7-0.9, P<0.01). Age but
      not weight of a child is a good predictor of the bronchial diameter (Beta value
      is 2.81x10(-2) and 2.58x10(-2) for right and left main bronchial diameter
      respectively). A size 3 Fogarty catheter will provide effective bronchial
      blocking for children up to 4 years old. A size 5 Fogarty catheter can be used
      for most children from 5 to 12 years old. Larger Fogarty catheters or double
      lumen tubes can be used in older children. Overinflation of the cuff should be
      avoided by fibreoptic bronchoscopy of the balloon. Our clinical application of
      the technique is discussed.

PMID- 12413263
TI  - Acute tracheal trauma in sheep caused by percutaneous tracheostomy.
AB  - The aim of our study was to compare dilation forceps tracheostomy and sequential
      dilator tracheostomy in anaesthetized live adult sheep with respect to the
      characteristics of the stoma formed and the associated injury. We performed
      percutaneous tracheostomy on adult sheep randomly allocated to receive either
      dilation forceps or sequential dilators. Sheep were sacrificed immediately after
      insertion of the percutaneous tracheostomy and the tracheas dissected. Specimens
      were examined for site, shape and size of stoma, mucosal lacerations, and
      posterior wall trauma. Ten sheep had dilation forceps tracheostomy and ten had
      sequential dilator tracheostomy. All of the specimens were found to have cephalo
      caudal mucosal tears, usually crossing tracheal rings. The dilation forceps
      technique was found to have a larger stoma (28.8 mm vs 24.0 mm, P=0.023). The
      incidence of posterior needle trauma and mucosal lacerations were common (35% and
      50% respectively), but they were not statistically different between the two
      groups. The role of the mucosal tears in the development of tracheal stenosis is
      reviewed in the discussion.

PMID- 12413264
TI  - Gum-elastic bougie-guided insertion of the ProSeal laryngeal mask airway: a new
      technique.
AB  - We determined the success rates, cardiovascular responses and airway morbidity
      for gum-elastic bougie-guided insertion of the ProSeal laryngeal mask airway. One
      hundred anaesthetized, non-paralyzed adults (ASA 1-2 aged 18 to 80 years) were
      studied. The ProSeal LMA drainage tube was primed with a well-lubricated 16
      French gauge gum-elastic bougie with the curved end proximal and the straight end
      protruding 30 cm beyond the drainage tube tip. The straight end of the gum
      elastic bougie was inserted into the oesophagus under laryngoscopic guidance, the
      laryngoscope removed and the ProSeal LMA inserted using the standard insertion
      technique and the gum-elastic bougie as a guide. The following variables were
      recorded: ease of insertion, oropharyngeal leak pressure, ventilatory capability,
      ease of gastric tube insertion, blood staining on the bougie or LMA at removal,
      and postoperative airway morbidity. Haemodynamic data were recorded immediately
      pre-insertion and every minute for five minutes after insertion. Gum-elastic
      bougie and ProSeal LMA insertion was successful at the first attempt in all
      patients within 50 seconds. There were no significant increases in heart rate or
      blood pressure. Oropharyngeal leak pressure was 33 (17-40) cmH2O and ventilation
      was possible without leak in all patients at 9.5 ml x kg(-1) tidal volume. There
      were no drainage tube or gastric air leaks. Gastric tube insertion was successful
      at the first attempt in all patients. Blood staining at removal was not detected
      on the gum-elastic bougie, but was detected in 3% of ProSeal LMAs. The incidence
      of sore throat, dysphagia and dysarthria was 21%, 9% and 1% respectively. We
      conclude that gum-elastic bougie-guided insertion of the ProSeal LMA has a high
      success rate and is associated with minimal haemodynamic change and a low
      incidence of trauma.

PMID- 12413265
TI  - Outcome of stroke patients admitted to intensive care: experience from an
      Australian teaching hospital.
AB  - The objective of this study was to determine the mortality rate and the
      functional outcomes of stroke patients admitted to the intensive care unit (ICU)
      and to identify predictors of poor outcome in this population. The records of all
      patients admitted to the ICU with the diagnosis of stroke between January 1994
      and December 1999 were reviewed. Patients with subarachnoid haemorrhage were
      excluded. Data were collected on clinical and biological variables, risk factors
      for stroke and the presence of comorbidities. Mortality (ICU, in-hospital and
      three-month) and functional outcome were used as end-points. In the six-year
      period, 61 patients were admitted to the ICU with either haemorrhagic or
      ischaemic stroke. Medical records were available for only 58 patients. There were
      23 ischaemic and 35 haemorrhagic strokes. The ICU, in-hospital and three-month
      mortality rates were 36%, 47% and 52% respectively. There were no significant
      differences in the prevalence of premorbid risk factors between survivors and non
      survivors. The mean Barthel score was significantly different between the
      independent and dependent survivors (94+/-6 vs 45+/-26, P<0.001). A substantial
      number of patients with good functional outcomes had lower Rankin scores (92% vs
      11%, P<0.001). Only 46% of those who were alive at three months were functionally
      independent. Intensive care admission was associated with a high mortality rate
      and a high likelihood of dependent lifestyle after hospital discharge.
      Haemorrhagic stroke, fixed dilated pupil(s) and GCS <10 during assessment were
      associated with increased mortality and poor functional outcome.

PMID- 12413266
TI  - The ASA Physical Status Classification: inter-observer consistency. American
      Society of Anesthesiologists.
AB  - The American Society of Anesthesiologists (ASA) physical status classification
      system has previously been shown to be inconsistently applied by anaesthetists.
      One hundred and sixty questionnaires were sent out to all specialist
      anaesthetists in Hong Kong. Ten hypothetical patients, identical to those of a
      similar study undertaken 20 years ago, each with different types and degrees
      ofphysical disability were described. Respondents were asked about their country
      of training and type of anaesthetic practice and to assign an ASA classification
      status for each patient. Ninety-seven questionnaires were returned (61%) after
      two mailings. Agreement for each patient within groups, between groups and
      overall comparisons were made. Percentage of agreement was between 31 to 85%.
      Overall correlation was only fair in all groups (Kappa indices: 0.21-0.4). We
      found that the current pattern of inter-observer inconsistency of classification
      was similar to that 20 years ago and exaggerated between locally and overseas
      trained specialists (P<0.05). The validity of the ASA system, its usefulness and
      the need for a new, more precise scoring system is discussed.

PMID- 12413267
TI  - Paediatric day stay tonsillectomy service: development and audit.
AB  - Day stay paediatric tonsillectomy is well established in many parts of the world
      but not in Australia. This audit presents the protocol and results of the first
      one hundred and twenty-five patients managed this way at our hospital. Patients
      assessed as being at low risk of postoperative complications were offered the
      procedure as a day patient. All patients had a standardized relaxant anaesthetic
      technique with an intraoperative opioid and antiemetics. The patients were
      observed for six hours postoperatively in the Day Stay Unit and contacted the day
      following surgery to assess any problems. The overall incidence of postoperative
      vomiting was 15.6%. Two patients required overnight admission. One child was re
      admitted on day four for delayed postoperative haemorrhage. Forty-four of the
      first forty-nine patients' parents were contacted four to six weeks later to
      assess their experiences of the process. Although approximately three-quarters of
      the parents rated their child's pain as moderate or severe at some stage, all but
      one felt the analgesic regimen was good or adequate. Eighty per cent were
      satisfied with having the surgery as a day stay procedure.

PMID- 12413268
TI  - Airway management on placental support (AMPS)--the anaesthetic perspective.
AB  - Neonatal airway obstruction has been reported to have a high mortality. Antenatal
      diagnosis of this condition is now possible. Anaesthetic and surgical techniques
      have been developed that allow neonatal airway obstruction to be managed at
      delivery, while the fetus remains oxygenated via the placental circulation. Three
      case studies are presented, and the anaesthetic issues for mother and
      fetus/neonate are discussed with reference to previously published cases of
      airway management on placental support. In particular, techniques for uterine
      relaxation and maintenance of placental circulation are explored. The history of
      these procedures and issues of planning and logistics are also discussed.

PMID- 12413269
TI  - Systemic air embolism after intercostal chest drain insertion and positive
      pressure ventilation in chest trauma.
AB  - Systemic air embolism is a potentially lethal often unrecognised complication of
      severe chest trauma. We present a case of delayed diagnosis of cerebral air
      embolism in a patient with severe thoracic trauma. The initiation of positive
      pressure ventilation, systemic hypotension, intraparenchymal chest drains and
      aerial transfer to an intensive care unit were all factors contributing to the
      development of systemic air embolism. The common clinical features, diagnostic
      tests and management of systemic air emboli are discussed.

PMID- 12413270
TI  - Retroperitoneal haematoma associated with low molecular weight heparin.
AB  - Enoxaparin (a low molecular weight heparin) has been used extensively for its
      antithrombotic properties. Complications of its haemorrhagic side-effects have
      previously been described. We report two cases of extensive retroperitoneal
      haematoma requiring blood transfusion and inotropic support. One patient
      developed acute renal failure and did not respond to intensive resuscitative
      efforts.

PMID- 12413271
TI  - An undiagnosed phaeochromocytoma of the urinary bladder.
AB  - Phaeochromocytoma of the urinary bladder is rare. We report a case of a patient
      with undiagnosed bladder phaeochromocytoma who developed haemodynamic
      disturbances during routine diagnostic cystoscopy. The diagnosis was only
      confirmed postoperatively.

PMID- 12413272
TI  - The ProSeal laryngeal mask in myasthenia gravis.
AB  - This case describes the anaesthesia management of a patient with myasthenia
      gravis who required mastectomy with axillary lymph node clearance. After
      withholding medical therapy for the myasthenia preoperatively on the day of
      surgery, anaesthesia was maintained with halothane, nitrous oxide and a
      remifentanil infusion. Muscle relaxants were avoided, facilitated by the use of a
      ProSeal (Intravent, Orthofix, Maidenhead, United Kingdom) laryngeal mask airway
      for positive pressure ventilation. The ProSeal laryngeal mask airway is a new
      laryngeal mask device with a modified cuff and a drainage tube which has been
      shown to have advantages over older designs for use during positive pressure
      ventilation. The rationale for the management of this patient with myasthenia is
      discussed.

PMID- 12413273
TI  - Respiratory arrest during caesarean section after intrathecal administration of
      sufentanil in combination with 0.1% bupivacaine 10 ml.

PMID- 12413274
TI  - Different intradermal skin testing response to atracurium and cisatracurium after
      an anaphylactoid reaction during general anaesthesia.

PMID- 12413275
TI  - Ampoule identification.

PMID- 12413276
TI  - Hirudin anticoagulation for CPB.

PMID- 12413278
TI  - World Report on Violence and Health--exploring Australian responses.

PMID- 12413279
TI  - Understanding Indigenous violence.

PMID- 12413280
TI  - Intimate partner violence finally a 'legitimate' public health issue.

PMID- 12413281
TI  - Alcohol abuse and the risks of violence.

PMID- 12413282
TI  - Preventing growth in abuse of the elderly.

PMID- 12413283
TI  - A promise unfulfilled on child abuse.

PMID- 12413284
TI  - The quality of management of rheumatic fever/ heart disease in the Kimberley.
AB  - OBJECTIVE: To evaluate the quality of management of Kimberley patients with
      rheumatic fever (RF) and rheumatic heart disease (RHD). METHODS: A retrospective
      analysis of medical records for 215 residents of the Kimberley region of Western
      Australia, diagnosed with RF or RHD during the years 1982 to 1996. RESULTS: Among
      patients prescribed intramuscular penicillin for secondary prophylaxis, 67% of
      prescribed doses were given, with individuals receiving 8-100% of doses
      prescribed. Of patients recommended visiting specialist or echocardiographic
      review, 78% and 64% attended respectively. Only 34% of patients with RHD in 1996
      were recommended dental review in 1996 or 1997. Appropriate blood testing
      occurred in 34% of the months in which people had anticoagulant prescribed.
      CONCLUSIONS: A clinical audit can be used to evaluate the management received by
      this population and hence identify areas to improve management. We found much
      room for improvement if optimal clinical outcomes are to be obtained.

PMID- 12413285
TI  - Use of interstate services for the termination of pregnancy in Australia.
AB  - OBJECTIVE: To document the extent to which women in Australia access interstate
      termination of pregnancy services and to determine whether the pattern of these
      claims suggests that the legal and political climate in particular jurisdictions
      is related to the use of services interstate. METHODS: The differences between
      the number of claims for Medicare Benefits Schedule item 35643 by place of
      patient residence and by place of service provision were analysed for 1984/85 to
      1999/2000 inclusive. For States and Territories in which the differences were
      sufficiently large to be interpretable against the differences of contiguous
      States or Territories, the symmetry and correlation were assessed. RESULTS: Each
      year there were more claims by residents than there were claims for services
      provided in Tasmania (averaging 294 claims/year), Queensland (2,141) and the ACT
      (1,132). Conversely, each year there were fewer claims for services provided in
      Victoria (401) and in NSW/ACT combined (2,236). Strong correlations were found
      between time trends of the difference between claims by State of service and
      claims by State of residence for NSW/ACT and Queensland (0.983, p < 0.0001) and
      between trends for Tasmania and Victoria (0.774, p < 0.0005). After assuming that
      NSW provided all the estimated claims made by Queensland residents for interstate
      services, the correlation between the ACT and NSW was found to be very strong
      (0.931, p < 0.0001). CONCLUSIONS: Residents of some jurisdictions appeared to be
      accessing services interstate. IMPLICATIONS: States and Territories that do not
      provide appropriate services for their residents burden patients with additional
      costs and reduced support. Ensuring equitable access to termination of pregnancy
      services remains a public health issue that must be understood and addressed on a
      national level.

PMID- 12413286
TI  - An evaluation of tobacco brief intervention training in three indigenous health
      care settings in north Queensland.
AB  - OBJECTIVE: To evaluate the pilot phase of a tobacco brief intervention program in
      three Indigenous health care settings in rural and remote north Queensland.
      METHODS: A combination of in-depth interviews with health staff and managers and
      focus groups with health staff and consumers. RESULTS: The tobacco brief
      intervention initiative resulted in changes in clinical practice among health
      care workers in all three sites. Although health workers had reported routinely
      raising the issue of smoking in a variety of settings prior to the intervention,
      the training provided them with an additional opportunity to become more aware of
      new approaches to smoking cessation. Indigenous health workers in particular
      reported that their own attempts to give up smoking following the training had
      given them confidence and empathy in offering smoking cessation advice. However,
      the study found no evidence that anybody had actually given up smoking at six
      months following the intervention. Integration of brief intervention into routine
      clinical practice was constrained by organisational, interpersonal and other
      factors in the broader socioenvironmental context. CONCLUSIONS/IMPLICATIONS:
      While modest health gains may be possible through brief intervention, the
      potential effectiveness in Indigenous settings will be limited in the absence of
      broader strategies aimed at tackling community-identified health priorities such
      as alcohol misuse, violence, employment and education. Tobacco and other forms of
      lifestyle brief intervention need to be part of multi-level health strategies.
      Training in tobacco brief intervention should address both the Indigenous context
      and the needs of Indigenous health care workers.

PMID- 12413287
TI  - Immunity to poliomyelitis in Victorians.
AB  - OBJECTIVES: In view of WHO's goal for poliomyelitis eradication by 2005 and the
      possible introduction of IPV into the Australian Standard Vaccination Schedule,
      this investigation was conducted to assess current immunity to poliomyelitis
      across the Victorian community. METHODS: 1,775 sera collected from three
      population samples within the Victorian community between 1990 and 1995 were
      tested for neutralising antibody titres against each poliovirus type in
      accordance with WHO recommended procedure. RESULTS: In infants over three months
      and adults under 40 years, 76-100% of people in each age group were seropositive
      to all poliovirus types, with 90-100% seropositive to type I, 94-100%
      seropositive to type II and 80-97% seropositive to type III. Of the very small
      number of adults over 40 years tested (n = 13), 85% were seropositive to each of
      types I and II, and 62% to type III. 92% of vaccination histories taken and
      checked were confirmed, and reported immunisation rates were significantly below
      seropositive rates. CONCLUSIONS: According to poliovirus antibody seroprevalence,
      current immunity to poliomyelitis appears sufficient for herd immunity. When
      compared with vaccination histones, significantly more people demonstrated
      immunity to poliomyelitis than the number who reported having been vaccinated
      against it, indicating the possible role of intestinal vaccine strain poliovirus
      spread in maintaining high immunity levels. IMPLICATIONS: The current Australian
      Standard Vaccination Schedule has successfully provided protective levels of
      poliomyelitis immunity for the Victorian community in the absence of wild virus
      since at least 1972. This must be considered in assessing the future direction of
      Australia's poliomyelitis immunisation program.

PMID- 12413288
TI  - Prevalence and associations of partner abuse in women attending general practice:
      a cross-sectional survey.
AB  - OBJECTIVE: To determine the prevalence and socio-demographic associations of
      physical, emotional and sexual abuse by a partner or ex-partner for women
      attending Australian general practices. METHOD: In 1996, women attending 20
      randomly chosen Brisbane inner south region general practices were screened for a
      history of partner abuse using a self-report questionnaire. Multivariate analyses
      were conducted on the data, using presence of abuse or not adjusting for cluster
      effect to obtain prevalence rate ratios for socio-demographic background data and
      history of violence in the family of origin. RESULTS: Thirty-seven per cent (CI
      31.0-42.4) of the survey participants (n = 1,836, response rate 78.5%) admitted
      to having ever experienced abuse in an adult intimate relationship. One in four
      women (23.3%) had ever experienced physical abuse, one in three (33.9%) emotional
      abuse and one in 10 (10.6%) sexual abuse. Abused women were 64.1 (Cl 44.4-94.1)
      times more likely to have ever been afraid of any partner than non-abused women.
      Of women in current relationships (n = 1,344), 8.0% self-reported physical or
      emotional or sexual abuse in the past 12 months and 1.5% all three types of
      abuse. Associations of abuse included being younger (< 60 years), separated or
      divorced, having a history of child abuse or domestic violence between their
      parents. CONCLUSION: Partner abuse is very common in women attending general
      practices and clinicians need to be alert to possible indications of partner
      abuse (age, marital status, past history of abuse).

PMID- 12413289
TI  - Towards a standardised methodology for estimating alcohol-caused death, injury
      and illness in Australia.
AB  - Two key methodological issues underlying different methods for calculating
      estimates of the number of alcohol-caused deaths are identified and
      recommendations suggested for future work. 1. How to adjust alcohol aetiologic
      fractions across time and place to reflect different levels of risky drinking. A
      common approach is outlined for both acute and chronic alcohol-related
      conditions. In the absence of consistent, reliable and regionally specific
      measures of the prevalence of risky alcohol consumption from national surveys,
      the use of per capita consumption data as a means of adjusting alcohol population
      aetiologic fractions over time and across regions is recommended. 2. Whether
      abstainers or low-risk drinkers should be used as the reference group when
      assessing the impact of alcohol consumption and how the resulting information is
      best presented. It is recommended that when abstainers are used as the reference
      group, the costs and benefits for both 'low-risk' and 'risky/high-risk' drinking
      should be identified. Using this approach, it was estimated that for Australia in
      1998 there was a net benefit of 5,100 lives saved due to low-risk drinking, while
      there was a net loss of 2,737 lives due to risky/high-risk drinking. On its own,
      the figure of a net saving of 2,363 lives per year is a simplistic and
      potentially misleading picture of alcohol as a net benefit to public health and
      safety. For public health communications, there is still value in providing
      estimates using the low-risk drinking contrast, of the number of lives saved if
      risky/high-risk drinkers all became low-risk drinkers (n = 3,292 in 1998). The
      use of the abstinence contrast, however, allows the more complex picture of
      alcohol's impact on public health to be apparent, e.g. including the estimated
      1,505 deaths associated with low-risk drinking (mostly from cancer).

PMID- 12413290
TI  - Does capture-recapture analysis provide more reliable estimates of the incidence
      and prevalence of leg ulcers in the community?
AB  - OBJECTIVE: To determine whether capture-recapture analysis provides more reliable
      estimates of the cumulative incidence and prevalence of leg ulcers in Auckland,
      New Zealand. METHODS: A population-based, cross-sectional study was conducted in
      the Central and North Auckland health districts of New Zealand in 1998. Cases
      were identified through health professional referral and by self-notification.
      All ages and ulcer types were investigated. Both traditional and capture
      recapture methods of analysis were used to estimate the cumulative incidence and
      prevalence of leg ulcers in the study population. RESULTS: Four hundred and
      twenty-six people with current leg ulcers were identified during the 12-month
      study period. Using traditional methods of analysis, the annual cumulative
      incidence rate of leg ulcers in Auckland was 32 per 100,000, with a point
      prevalence of 39 per 100,000 and a period prevalence of 79 per 100,000 per year.
      Results from capture-recapture analysis, however, suggest an annual cumulative
      incidence rate of 252 per 100,000, with a point prevalence of 248 per 100,000 and
      a period prevalence of 530 per 100,000 per year. CONCLUSIONS: The traditional
      method of calculating cumulative incidence and prevalence clearly under-estimates
      the frequency of leg ulcers in the Auckland region. Capture-recapture analysis
      provides a more reliable estimate of disease frequency, since cases that remain
      unidentified in the population are considered.

PMID- 12413291
TI  - Geospatial analysis of childhood pertussis in Victoria, 1993-97.
AB  - OBJECTIVE: To demonstrate the feasibility of using Geographical Information
      Systems (GIS) in public health research. METHODS: Area-based relationships
      between the incidence of pertussis and immunisation coverage using data on
      Victorian children aged 0-4 years who contracted pertussis in 1993-97, were
      analysed at the Local Govemment Area (LGA) level. DTP3 immunisation uptake by LGA
      was first stratified into two groups: > or = 90% or < 90% (national target).
      Those under 90% were then divided into two equal bands. The incidence rates for
      LGAs were classified into quartiles. Immunisation records of children in the 1996
      97 birth cohort were reviewed. RESULTS: When the DTP3 immunisation uptake was >
      or = 90%, seven LGAs were in the upper quartile and eight LGAs in the lower
      quartile of childhood pertussis notifications incidence. An equal amount of LGAs
      were in the upper (n = 6) and lower quartiles (n = 6) of notified childhood
      pertussis incidence rates with an associated DTP3 coverage rate in the lowest
      band. Of children bom between 1996-97 who contracted pertussis under the age of
      two, 29% were not immunised and 78.6% were partially immunised at the time of
      pertussis onset. CONCLUSIONS: GIS enabled the integration of disparate
      immunisation-related datasets and identified geographic LGAs where immunisation
      rates were low and pertussis rates were high. IMPLICATIONS: Future research needs
      to explore the social and environmental factors associated with those not fully
      immunised at onset of pertussis disease, particularly those in geographic areas
      highlighted by this research. GIS has the potential to add value in the
      monitoring and surveillance of geographical patterns of child health, but
      investments in data quality are urgently required.

PMID- 12413292
TI  - Sports injury experiences from the Western Australian Sports Injury Cohort Study.
AB  - OBJECTIVE: The Western Australian Sports Injury Study is the first prospective
      cohort study of sports injuries sustained during community-level sports
      participation in Australia. METHODS: The players were nonprofessional/non-elite
      participants of hockey, Australian football, basketball and netball from
      metropolitan Perth. Players completed a baseline questionnaire relating to their
      sports injury history, training practices, protective equipment use, demographic
      profile, general health and lifestyle factors. Sports participation and injury
      experiences were monitored by monthly telephone surveys over two consecutive five
      month winter sporting seasons during 1997 and 1998. RESULTS: Of the 1,512 players
      recruited into the initial cohort, 966 (i.e. 64%) responded to at least 700% of
      the callback surveys over the two-year follow-up. Across all sports, the injury
      incidence rate was 16.1 injuries/ 1,000 exposure hours (both games and training).
      Injury rates were highest in Australian football and lowest in netball. Lower
      limb injuries were twice as common as those to the upper limb (67% vs. 31%).
      Three-quarters of injured players sought treatment from a health care
      practitioner. CONCLUSIONS AND IMPLICATIONS: This is the first longitudinal study
      of injuries to community-based sports participants in Australia. Compared with
      elite sports participants, the risk of injury is relatively low. The results
      provide valuable direction for the design and conduct of further aetiological
      studies.

PMID- 12413293
TI  - Socio-economic position and height in early adulthood.
AB  - OBJECTIVES: To examine the relationship between socio-economic position and
      height in early adulthood. METHOD: A representative probability sample of
      Australian households (part of the 1995 National Health Survey). Data were
      collected by face-to-face interviews. Socio-economic position was measured using
      occupation and family income. Participants comprised 9,577 Australian-born males
      and females aged 20-24 (n = 3,186), 25-29 (n = 3,184), and 30-34 (n = 3,207).
      Height was self-reported and operationalised in terms of mean height and 'short'
      stature (defined as 1 SD below mean height for each sex-age subgroup). RESULTS:
      Graded, positive associations were found between occupation, family income, and
      height for males and females in each age cohort. Among males, mean height
      differences between blue-collar employees and professionals were 1.1 cm to 1.5 cm
      (depending on age-cohort), and for females, 1.6 cm to 2.1 cm. The corresponding
      height differences for males and females living in the least and most affluent
      families were 1.6 cm to 2.3 cm, and 1.0 cm to 2.5 cm, respectively. Persons in
      blue-collar jobs and those in low-income families were more likely to be
      classified as 'short'. CONCLUSIONS AND IMPLICATIONS: Estimates of mortality risk
      associated with short stature suggest that these height differences translate to
      about a 2-5% increased risk of death for the most disadvantaged groups. Given
      that socioeconomic height differences in adulthood have their genesis in the
      formative stages of biological and social development, public health intervention
      efforts need to focus on early life exposures and environments. The greatest
      reduction in height inequalities, and by extension health inequalities, is likely
      to flow from macro-level public policies to alleviate poverty and minimise the
      social and economic divide.

PMID- 12413294
TI  - A comparison of self-reported and measured height, weight and BMI in Australian
      adolescents.
AB  - OBJECTIVE: To explore the relationship between self-reported weight and height to
      actual weight and height in older Australian adolescents. METHOD: Weights and
      heights of 572 adolescents aged 15-19 years who participated in the 1995
      Australian National Health Survey (NHS) and National Nutrition Survey (NNS) were
      examined. RESULTS: Self-reported heights were significantly higher than measured
      heights in participants. There were no differences in the accuracy of self
      reported heights among the adolescents by gender. Self-reported weights were
      significantly lower than measured weights among both boys and girls (p < 0.01).
      There were no differences in the accuracy of self-reported weights among the boys
      and girls. Differences between actual weight and self-reported weight were
      significantly greater for overweight or obese adolescents compared with
      normal/underweight adolescents (p < 0.01). The use of self-reported weight and
      height resulted in the correct classification of overweight or obesity in 69%
      boys and 70% of girls. CONCLUSIONS: There was no significant gender difference in
      reporting weight and height in older adolescents. Bias in reporting weight and
      height was much higher in overweight or obese adolescents than normal/underweight
      adolescents. IMPLICATIONS: The percentage of misclassification of overweight or
      obesity from self-reported data in this study was 31% for boys and 30% for girls,
      respectively. Therefore, the self-reported weight and height of older adolescents
      needs to be more cautiously utilised. Efforts to improve the accuracy of self
      reporting in older adolescents are needed if this measure is to be reliable.

PMID- 12413295
TI  - A preliminary investigation into the prevalence and trends of overweight and
      obesity of northern Tasmanian primary school children.
AB  - Obesity has many serious health consequences for adults and children alike.
      Despite such knowledge, the prevalence of overweight and obesity among
      Australians is rapidly increasing. OBJECTIVE: This study attempted to conduct
      initial research into the prevalence of overweight and obesity among primary
      school children in Launceston, Tasmania, and to compare the data with that of
      other Australian youth. METHODS: Weight and height for body mass index (BMI)
      calculations were obtained from four randomly selected schools in Launceston,
      Tasmania, using a portable stadiometer and Sohenle digital bathroom scales.
      RESULTS: Of 329 participants, 24% were regarded as being overweight and obese on
      the basis of BMI scores. When compared with BMI data from the 1985 Australian
      Health and Fitness Survey, six of the eight age and gender subgroups were
      significantly higher (p < 0.05). CONCLUSION AND IMPLICATIONS: Further research,
      using much larger and randomly selected samples, needs to be conducted so that
      trends can be monitored, baseline data for Tasmanian schoolchildren established,
      and both community and school intervention strategies implemented.

PMID- 12413296
TI  - The introduction of breast milk substitutes and solid foods: evidence from the
      1995 National Health Survey.
AB  - OBJECTIVE: To report the introduction of breast milk substitutes and solid foods
      to Australian children between 1992 and 1995. METHODOLOGY: Analysis of data from
      the 1995 Australian National Health Survey. Infant feeding questions were asked
      by personal interview in respect to 3,252 children aged under four years of age.
      RESULTS: By the age of 26 weeks, the majority of children had been given infant
      formula (56.9%) and solid food (61.5%). More than one-quarter (27.1%) of children
      received cow's milk regularly during the first 12 months. Only 7% of children
      were given solids in the first 12 weeks of life. Soy milk was given to 14.2% of
      children aged less than four years. CONCLUSION: The majority of children in
      Australia are not being exclusively breastfed for six months as recommended by
      the World Health Organization (WHO). The intake of cow's milk before 12 months of
      age and the timing of introduction of solids needs to be monitored. Future
      surveys should collect more detail about type of infant formula so that the
      proportion of infants receiving soy-based formula and other formula can be
      assessed.

PMID- 12413297
TI  - Purchasing of cigarettes by New Zealand secondary students in 2000.
AB  - OBJECTIVE: To examine the prevalence of under-age sales of cigarettes to New
      Zealand secondary school students in 2000 and to identify correlates of buying
      cigarettes. METHOD: A randomly selected sample of 53 secondary schools from five
      geographic regions took part, and 2,896 Year 10 and Year 12 students completed a
      self-report questionnaire. RESULTS: Some 30.3% reported smoking during the past
      30 days and 61.8% of these students usually obtained cigarettes by purchasing
      from shops, from other students or from someone else buying them on their behalf.
      Local corner stores and service stations were the most popular source. Buying
      cigarettes was associated with more frequent smoking, more money to spend, a
      higher school decile rating and higher proportion of schoolmates also purchasing.
      CONCLUSIONS: Prohibition of cigarette sales to minors needs much greater
      attention in NZ than it is receiving at present if smoking among young people is
      to be reduced.

PMID- 12413298
TI  - Representing inequities in the distribution of socio-economic benefits and
      environmental risk.
AB  - There is currently no standard method for analyzing claims of environmental
      inequity. Neither is there a database of statistics on the extent of relationship
      between regional indicators of environmental quality, likely sources of
      pollution, and the demographic characteristics of affected populations. The
      resolution of environmental disputes is often hampered by inadequate
      communication between stakeholder groups about their perceptions and
      prioritization of the issues in dispute and by differential access to information
      about the issues by each stakeholder group. This paper describes a web-based
      tool, ICEP, that uses multi-layered GIS maps to establish a standard method for
      analyzing claims of environmental inequity and establish a database of
      correlation coefficients between environmental indicators, industry type by SIC
      code, and demographic characteristics of the population in proximity to noxious
      facilities. The maps are generated from stakeholder reports of environmental
      quality and are designed to be accessible via the Internet. This provides
      stakeholders with direct access to graphical displays of the perceptions of their
      co-stakeholders and provides all groups with links to relevant information
      sources about the issues in dispute. ICEP enhances existing community
      environmental websites like Scorecard and Envirofacts by providing displays of
      median household income as a measure of the distribution of benefits accrued
      within an area.

PMID- 12413299
TI  - Comparative study of fluorogenic and chromogenic media for specific detection of
      environmental isolates of thermotolerant Escherichia coli.
AB  - In a field study 78 water samples were analysed employing Fluorocult Brilla Broth
      (BB) and its performance was compared with standard MPN procedure. Out of 78
      water samples analysed 56 (71.7%) samples yielded positive reactions in BB
      whereas, 50 (64.1%) samples were positive by standard fecal coliform test. A
      comparative study of fluorogenic and chromogenic media containing substrate beta
      D glucuronide for specific detection of environmental isolates of 313
      thermotolerant E. coli has been undertaken. Five fluorogenic media were used:
      Fluorocult MacConkey agar (MCA), Fluorocult ECD agar (ECD), Fluorocult VRB agar
      (VRB), Fluorocult E. coli 0157:H7 agar (ECH7) and Fluorocult Brilla Broth (BB)
      and Chromogenic Chromocult agar (CCA). BB and CCA were found to be highly
      specific and sensitive media to detect E. coli as all E. coli yielded positive
      reaction on them. On ECH7 and ECD agar 67.5 and 64.9 of E. coli isolates gave
      positive reaction, respectively. Low sensitivity was observed in case of MCA and
      VRB agar in detecting E. coli. The performance of BB appears to be better when
      compared with standard MPN procedure employing MacConkey broth/Brilliant green
      bile broth in detecting E. coli in drinking water.

PMID- 12413300
TI  - Methane emissions of differently fed dairy cows and corresponding methane and
      nitrogen emissions from their manure during storage.
AB  - This study investigated the effects of supplementing 40 g lauric acid (C12) kg(
      1) dry matter (DM) in feed on methane emissions from early-lactating dairy cows
      and the associated effects on methane, nitrous oxide and ammonia release from the
      manure during storage. Stearic acid (C18), a fatty acid without assumed methane
      suppressing potential in the digestive tract of ruminants, was added at 40 g kg(
      1) DM to a control diet. The complete feed consisted of forage and concentrate in
      a ratio of 1.5:1 (DM basis). The manure was stored for 14 weeks either as
      complete slurry or, separately, as urine-rich slurry and farmyard manure
      representing two common storage systems. Methane release of the cows, as measured
      in respiratory chambers, was lower with C12 by about 20%, but this was mostly
      resulting from a reduced feed intake and, partly, from a lower rate of fibre
      digestion. As milk yield declined less than feed intake, methane emission per kg
      of milk was significantly lower with C12 (11.4 g) than with C18 (14.0 g). Faeces
      of C12-fed cows had a higher proportion of undigested fibre and accordingly
      methane release from their manure was higher compared with the manure obtained
      from the C18-fed cows. Overall, manure-derived methane accounted for 8.2% and
      15.4% of total methane after 7 and 14 weeks of storage, respectively. The
      evolution of methane widely differed between manure types and dietary treatments,
      with a retarded onset of release in complete slurry particularly in the C12
      treatment. Emissions of nitrous oxide were lower in the manures from the C12
      treatment. This partially compensated for the higher methane release from the C12
      manure with respect to the greenhouse gas potential. The total greenhouse gas
      potential (cow and manure together) accounted for 8.7 and 10.5 kg equivalents of
      CO2 cow(-1) d(-1) with C12 and C18, respectively. At unaffected urine-N
      proportion ammonia and total nitrogen losses from stored manure were lower with
      C12 than with C18 corresponding to the differences in feed and nitrogen intake.
      The present results suggest that manure storage significantly contributes to
      total methane emission from dairy husbandry, and that the identification of
      effective dietary mitigation strategies has to consider both the digestive tract
      of the animals and the corresponding manure.

PMID- 12413301
TI  - Historical pollution trends in coastal environments of India.
AB  - Seventeen sediment cores were collected from different coastal ecosystems of
      Tamil Nadu, India that include coastal lagoon (Pulicat), polluted rivers in
      Chennai (Adyar and Cooum), Coral reef (Gulf of Mannar) and a perennial river
      (Tamiraparani). Radiometric dating has been used to determine the modern
      sedimentation rates in these ecosystems. The Pulicat Lake and the polluted rivers
      (Adyar and Cooum) yield an average sediment accumulation rate of 12.34 and 7.85
      mm yr(-1), respectively. In the Gulf of Mannar coral reef, the sedimentation rate
      averages 17.37 mm yr(-1), while the rate in Tamiraparani River is 11.00 mm yr(
      1). In the Tamiraparani River basin, the deposition rates were an order of
      magnitude higher when compared to the erosion rates, which may be due to bank
      erosion and the intense human activity. In general high rates of sedimentation
      observed in the coastal ecosystems not only reflect the capacity of the coastal
      regions as sinks for trace metals but also denote increased input of pollutants
      into the coastal environments in the recent past. The deposition rates of heavy
      metals--Fe, Mn, Zn, Cu, Cr and Ni in the depth profiles have been computed using
      sedimentation rates and their distribution is discussed. It can be seen that the
      mean deposition rates of all the measured elements in the Tamil Nadu coastal
      ecosystems are high compared with rates determined for the sediments of the
      deltaic regions of India and the Bay of Bengal.

PMID- 12413302
TI  - Effect of heavy metal contaminated shooting range soils on mycorrhizal
      colonization of roots and metal uptake by leek.
AB  - We grew leek (Allium porrum) in soils of two shooting ranges heavily contaminated
      with heavy metals in the towns of Zuchwil and Oberuzwil in Switzerland as a
      bioassay to test the activity of arbuscular mycorrhizal (AM) fungi in these
      soils. Soil samples were taken from (1) front of the shooting house (HOUSE), (2)
      the area between house and target (FIELD) and (3) the berm (BACKSTOP). Samples of
      Ribwort plantain (Plantago lanceolata) growing naturally within the shooting
      ranges were also collected and the colonization of its roots by mycorrhizal fungi
      was measured. The number of AM spores in the soils was significantly reduced
      concomitant with the increase in the degree of soil contamination with metals. In
      Zuchwil, mycorrhizal fungi equally colonized roots of Ribwort plantain sampled
      from BACKSTOP and HOUSE. In Oberuzwil, however, plants from BACKSTOP had lower
      colonization when compared with those sampled from HOUSE. Colonization of leek
      was strongly reduced in the BACKSTOP soil of Zuchwil and slightly reduced in the
      BACKSTOP soil of Oberuzwil when compared with plants grown in respective HOUSE
      soil. Concentrations of Cd, Cr, Cu, Ni, Pb and Zn in the leaves of leek grown in
      the BACKSTOP soil was within the range considered toxic for human consumption.
      This points to the high degree of bioavailability of these metal in these soils.
      Significant decrease in the number of mycorrhizal spores in the BACKSTOP soils in
      Zuchwil and the low colonization of leek roots grown in these soils point to
      possible changes in the species diversity of mycorrhizal fungi in these soils.

PMID- 12413304
TI  - Care of injection drug users with soft tissue infections in San Francisco,
      California.
AB  - CONTEXT: Illicit injection drug use results in serious soft tissue infections
      that are the number one nonpsychiatric reason for admission to San Francisco
      General Hospital (SFGH), San Francisco, Calif. OBJECTIVE: To establish a
      specialized clinic to provide accessible, high-quality, and cost-effective
      medical care to patients with soft tissue infections. DESIGN, SETTING,
      INTERVENTION, AND OUTCOME MEASURES: The Integrated Soft Tissue Infection Services
      (ISIS) Clinic was established to provide coordinated surgical intervention,
      substance abuse counseling, and social services for patients with soft tissue
      infections treated in a public hospital. Demographic information, treatment
      outcome, and hospital utilization data were analyzed. RESULTS: In the clinic's
      first year of operation, there were 3365 patient visits and 2255 surgical
      procedures. A large number of patients reported recent injection of illicit drugs
      (61%), were homeless (30%), and either had hepatitis C, hepatitis B, or human
      immunodeficiency virus infection (62%). Patients using heroin were enrolled in
      either a detoxification or maintenance program (42%). Few patients were
      designated as treatment failures (2%) or were lost to follow-up (14%). The ISIS
      Clinic dramatically reduced emergency department visits (-33.9%), surgical
      service admissions (-47.3%), inpatient acute care bed days (-33.7%), and
      operating room procedures (-71%), saving approximately $8 765 200 in the first
      year of operation. CONCLUSIONS: This clinical intervention was notably cost
      effective while preserving a high quality of medical services. Owing to limited
      data, we can only assume that other communities are similarly confronted with
      this public health problem. The ISIS Clinic could serve as a model intervention
      and thus have significant impact on the treatment of this prevalent but often
      overlooked challenge.

PMID- 12413303
TI  - Assessment of contamination and biomarker responses in two species of herons on
      the St. Lawrence river.
AB  - This study was undertaken to validate potential biomarkers of exposure and
      effects due to chemical contaminants in breeding colonies of the Great Blue Heron
      and the Black-crowned Night-Heron on the St. Lawrence River. Eggs and fledglings
      from both species were collected from many colonies along the River. The
      fledglings from colonies in freshwater and brackish water were more contaminated
      by mercury and PCBs than those from estuarine and gulf colonies. With respect to
      fledglings of the two heron species, some morphometric and blood biochemical
      measurements, including plasma thyroid hormones and retinol, were significantly
      different among colonies. Significant differences were also observed in liver
      retinoids, EROD and porphyrins among colonies. The results of this study suggest
      that plasma retinoids and thyroid hormones are good biomarkers of exposure and
      effects, and are sufficiently sensitive to reflect local and regional variations
      in contamination. Along with the measure of contaminants in egg and plasma, they
      constitute non-invasive biomarkers which represent an important criteria for long
      term monitoring of wildlife species. It is concluded that the Great Blue Heron is
      an appropriate sentinel species in the surveillance network for the St. Lawrence
      River.

PMID- 12413306
TI  - Protocol-driven ventilator management in a trauma intensive care unit population.
AB  - HYPOTHESIS: The use of weaning and sedation protocols affects the intensive care
      unit (ICU) course of a trauma population. DESIGN: Nonrandomized before-after
      trial. SETTING: A level I trauma center. PATIENTS: Three hundred twenty-eight
      consecutive trauma patients receiving mechanical ventilation treated in the ICU
      between October 1, 1997, and November 1, 1999. INTERVENTION: Sedation and weaning
      protocols were used to treat patients receiving mechanical ventilation during the
      second year of this study. MAIN OUTCOME MEASURES: Self-extubation rates,
      ventilator days, number of ICU days, and charges. RESULTS: There were 168
      patients in the preprotocol group (year 1: October 1, 1997, to October 31, 1998)
      and 160 patients in the postprotocol group (year 2: November 1, 1998, to November
      30, 1999). The groups were similar in age (P =.68), Injury Severity Score (P
      =.06), and Glasgow Coma Scale score (P =.29). There were no differences in self
      extubation rates (P =.57), ventilator days (P =.83), ventilator charges (P =.83),
      number of ICU days (P =.67), or ICU charges (P =.67) between the 2 groups. No
      statistical difference was identified in any of these categories when long-term
      ventilator patients (defined as ventilator length of stay > or =3 SDs above the
      mean) were excluded. CONCLUSIONS: Use of weaning and sedation protocols did not
      affect the measured outcomes in this study. These findings may reflect
      difficulties inherent in the protocols or with their utilization. Further
      subgroup analysis focusing on ventilator-associated pneumonias and mortality may
      demonstrate benefits not identified herein.

PMID- 12413307
TI  - The Kirschner operation in unresectable esophageal cancer: current application.
AB  - HYPOTHESIS: With the introduction of safe, effective nonoperative alternatives,
      bypass surgery for unresectable esophageal cancer is infrequently performed, but
      it has a limited role in palliation of esophageal cancer that needs to be
      defined. DESIGN: Retrospective cohort study. SETTING: Department of Surgery at
      Queen Mary Hospital in Hong Kong. PATIENTS: Patients who had unresectable
      esophageal cancer and underwent bypass surgery between January 1, 1991, and
      December 31, 1998. INTERVENTION: Bypass procedures were performed using a gastric
      or colonic conduit to the neck. MAIN OUTCOME MEASURES: Morbidity and mortality
      and quality of palliation. RESULTS: Thirty-eight patients underwent retrosternal
      bypass to the neck using a gastric (n = 27) or colonic (n = 11) conduit. Ten
      patients (26%) underwent unplanned bypass at the time of exploration for
      resection because of unexpected findings of T4 disease (n = 2) or technical
      difficulties in addition to advanced disease (n = 8). Between 1991 and 1994, 1 of
      26 bypasses was unplanned and the hospital mortality was 42% (11/26), while
      between 1995 and 1998, 9 of 12 bypasses were unplanned and the hospital mortality
      was 8% (1/12). There were 12 hospital deaths in the planned bypass group (n = 28)
      and none in the unplanned bypass (n = 10) group (43% vs 0%, P =.01). The median
      survival in patients who underwent unplanned bypass was 6.9 months, compared with
      1.9 months in patients who underwent planned bypass (P =.004). All patients were
      discharged from the hospital on at least a semisolid diet. CONCLUSIONS: The
      Kirschner operation is largely obsolete as a planned procedure because of high
      morbidity and mortality. Bypass surgery, however, is a reasonable option as an
      unplanned procedure when resection is precluded at the time of exploration
      because of unexpected adverse operative findings.

PMID- 12413308
TI  - Clinical and hemodynamic significance of the greater saphenous vein diameter in
      chronic venous insufficiency.
AB  - HYPOTHESIS: As the compliant greater saphenous vein (GSV) adjusts its luminal
      size to the level of transmural pressure, measurement of its diameter, reflecting
      the severity of hemodynamic compromise in limbs with GSV reflux, may simplify the
      hemodynamic criteria of patient selection for saphenectomy. OBJECTIVE: To
      evaluate the clinical significance of GSV diameter determined in the thigh and
      calf as a marker of global hemodynamic impairment and clinical severity in a
      model comprising patients with saphenofemoral junction and truncal GSV
      incompetence. DESIGN: A cohort study. SETTING: University-associated tertiary
      care hospitals in Brazil and England. PATIENTS: Eighty-five consecutive patients,
      aged 28 to 82 (mean, 46.2) years; 112 lower limbs with saphenofemoral junction
      and truncal GSV incompetence were investigated. INTERVENTIONS: Clinical
      examination was followed by clinical, etiological, anatomical, and
      pathophysiological classification (CEAP), vein duplex, and air plethysmography.
      The GSV diameter was measured on standing at the knee, and at 10, 20, and 30 cm
      above and below the knee, and in the thigh and calf, respectively, using B-mode
      imaging. The venous filling index (VFI), venous volume (VV), and residual volume
      fraction (RVF) were measured by air plethysmography. MAIN OUTCOME MEASURES: The
      GSV diameter was correlated with the VFI, VV, RVF, and CEAP. The value of the GSV
      diameter for predicting the presence of critical reflux (VFI >7 mL/s) or the
      absence of abnormal reflux (VFI <2 mL/s) was determined with receiver-operator
      curves. RESULTS: The GSV diameter increased significantly overall with CEAP
      (P<.001) and also increased progressively with proximity to the saphenofemoral
      junction. The VFI, VV, and RVF increased significantly from CEAP(0) through
      CEAP(4-6); the VFI correlated well with VV, RVF, and CEAP (P<.001 for all). The
      GSV diameter at all 7 limb levels studied correlated well with VV (except at the
      distal calf), VFI, RVF, and CEAP (P< or =.009 for all). A GSV diameter of 5.5 mm
      or less predicted the absence of abnormal reflux, with a sensitivity of 78%, a
      specificity of 87%, positive and negative predictive values of 78%, and an
      accuracy of 82%. A GSV diameter of 7.3 mm or greater predicted critical reflux
      (VFI >7 mL/s), with an 80% sensitivity, an 85% specificity, and an 84% accuracy.
      CONCLUSION: The GSV diameter proved to be a relatively accurate measure of
      hemodynamic impairment and clinical severity in a model of saphenofemoral
      junction and GSV incompetence, predicting not only the absence of abnormal
      reflux, but also the presence of critical venous incompetence, assisting in
      clinical decision making before considering greater saphenectomy.

PMID- 12413309
TI  - Esophageal cancer in patients with a history of distal gastrectomy.
AB  - HYPOTHESIS: There is an association between a history of distal gastrectomy and
      the development of esophageal cancer. Surgical treatment of esophageal cancer in
      patients with a history of gastrectomy is more complicated but will not result in
      increased mortality in an experienced center. DESIGN: Case-control study.
      SETTING: Tertiary care center for the treatment of esophageal cancer. PATIENTS:
      Forty patients with a history of gastrectomy and 1266 patients with intact
      stomachs who underwent esophagectomy for cancer. MAIN OUTCOME MEASURES: Patients'
      demographic characteristics, tumor characteristics, operative morbidity,
      mortality, and long-term survival. RESULTS: There were more squamous tumors
      located in the lower third of the esophagus in those who had a history of
      gastrectomy compared with those with intact stomachs (16 [41%] of 40 patients vs
      318 [25%] of 1266 patients; P=.04). This difference was more pronounced after
      Billroth I vs Billroth II gastrectomy (8 [73%] of 11 patients vs 8 [29%] of 28
      patients; P=.03). Twenty-four patients (60%) in the gastrectomy group and 738
      (58%) in the nongastrectomy group underwent surgical resection (P=.87). The
      operative time (300 [160-465] vs 220 [90-520] minutes; P<.001) was longer and
      more blood loss (1000 [300-2500] vs 700 [150-7000] mL;P<.001) was encountered for
      esophagectomy after previous gastrectomy (data are given as median [range]). A
      colon interposition was the substitute conduit of choice in the gastrectomy group
      (20 [83%] of 24 patients), and the stomach was the preferred loop in those with
      intact stomachs (729 [99%] of 738 patients). Postoperative complication rates
      were similar. In-hospital mortality rates also did not differ for those with a
      history of gastrectomy vs those without such a history (12% for both,P>.99).
      Median survival after resection was 13.8 and 12.5 months for patients who did and
      did not undergo prior gastrectomy, respectively (P=.62). CONCLUSIONS: A history
      of gastrectomy (especially the Billroth I type) is associated with more lower
      third squamous cell esophageal carcinomas. Surgical resections in patients with
      such a history were more complicated but resulted in similar outcomes.

PMID- 12413310
TI  - Thyroid surgery in the geriatric patient.
AB  - BACKGROUND: Although age itself is no contraindication for major surgical
      procedures, few patients 75 years and older undergo thyroid surgery. HYPOTHESIS:
      Thyroid surgery in the geriatric patient can be performed with low morbidity and
      mortality. DESIGN: Retrospective analysis of prospectively documented data.
      SETTING: University hospital referral center. PATIENTS: We included 738 patients
      undergoing thyroid surgery within 5 years, of whom 55 (7.5%) were 75 years or
      older (group 1) (mean +/- SD age, 79.9 +/- 4.1 years). MAIN OUTCOME MEASURES:
      Indication for surgery, surgical strategy, morbidity, and mortality were analyzed
      and compared with those in younger patients (<75 years; group 2). RESULTS:
      Malignancy was suspected or verified in 29 patients (52.7%) in group 1; 21
      (38.2%) had mechanical symptoms due to large bilateral nodular goiters; and 5
      (9.1%) presented with benign nodular goiter. The main indication in group 2 (n =
      683) was benign nodular goiter in 455 (66.6%); 142 patients (20.8%) presented
      with suspected malignancy and 21 (3.1%) with mechanical symptoms (P<.001). Most
      patients underwent total thyroidectomy, hemithyroidectomy, or near-total
      thyroidectomy (n = 50 [90.9%; group 1] vs n = 597 [87.4%; group 2]; P =.53).
      Frequency of malignancy was higher in group 1 ([n = 20 [36.4%] vs n = 179
      [26.2%]; P =.17). Morbidity of thyroid surgery was comparable in both groups. One
      (2.3%) of 44 patients in group 1 had permanent hypoparathyroidism, compared with
      10 (2.0%) of 502 in group 2 (P =.61); permanent recurrent laryngeal nerve
      paralysis occurred in 1 (1.05%) of 95 nerves at risk in group 1 compared with 3
      (0.26%) of 1172 nerves at risk in group 2 (P =.22). There was no perioperative
      mortality in either group. CONCLUSIONS: Thyroid surgery in patients 75 years or
      older can be performed with low morbidity. The guarantees for success include an
      individual risk-and-benefit analysis and careful preoperative preparation.

PMID- 12413311
TI  - Risk factors for lymph node metastases in breast ductal carcinoma in situ with
      minimal invasive component.
AB  - HYPOTHESIS: Clinical and pathological variables may be predictors of axillary
      dissemination in T1mic and T1a breast carcinoma. DESIGN: Retrospective medical
      chart review. SETTING: University-affiliated tertiary referral center. PATIENTS:
      All patients diagnosed as having ductal carcinoma in situ (DCIS) with
      microinvasion between January 1, 1988, and December 30, 1998. MAIN OUTCOME
      MEASURES: Pathology slides were reviewed according to the 1997 Cancer Staging
      Manual put forth by the American Joint Committee on Cancer. The number of
      involved ducts was noted. Patients with no invasive component or invasive
      components larger than 5 mm were excluded. Pathological and clinical variables
      were analyzed for their effect on axillary lymph node metastases. RESULTS: The
      study group included 57 women aged 37 to 71 years (median, 60 years), 37 with
      T1mic disease and 20 with T1a. Modified radical mastectomy was performed in 29
      patients (18 with T1mic and 11 with T1a) and breast-preserving surgery in 28 (19
      with T1mic and 9 with T1a). Forty-three patients (28 with T1mic and 15 with T1a)
      underwent axillary lymph node dissection. Axillary involvement was detected in 3
      patients in each group. Forty-seven patients received adjuvant therapy
      (radiotherapy alone, or with hormones or chemotherapy). Follow-up was 3 to 120
      months (median, 40 months). One patient was unavailable for follow-up, another
      died of disseminated disease, and a third developed contralateral primary
      carcinoma. Comedo DCIS (P<.03) and the number of DCIS-involved ducts (P<.002) in
      the T1mic group, and nuclear grade 3 (P<.001) in both groups, were independent
      significant predictors of axillary metastases. CONCLUSIONS: The significant rate
      of axillary metastases in T1a and T1mic breast tumors makes axillary staging a
      must. High nuclear grade, comedo DCIS, and high number of DCIS-involved ducts may
      predict axillary metastasis and should be considered when axillary dissection is
      done selectively.

PMID- 12413312
TI  - Lymphedema and quality of life in survivors of early-stage breast cancer.
AB  - BACKGROUND: The standard of care for early-stage breast cancer includes surgical
      removal of the tumor and axillary lymph node dissection (ALND). Despite increased
      use of breast-conserving surgery, lymphedema rates are similar to those with more
      radical surgery. HYPOTHESIS: Women who experience breast cancer-related
      lymphedema have a measurable reduction in quality of life compared with women
      without lymphedema. DESIGN: In a retrospective cohort study, we explored the
      association between lymphedema and quality of life, controlling for patient
      demographics, surgical factors, and treatment types. SETTINGS: An urban academic
      medical center and a community hospital. PARTICIPANTS: A total of 151 women
      surgically treated for early-stage breast cancer (stages 0-II) were assessed at
      least 1 year after their ALND. The women had been treated with either
      conservative surgery and radiation or mastectomy without radiation. MAIN OUTCOME
      MEASURES: Arm volume was measured by water displacement. Grip strength and range
      of-motion measurements assessed arm function. The Functional Assessment of Cancer
      Therapy-Breast (FACT-B) quality-of-life instrument assessed breast, emotional,
      functional, physical, and social well-being. RESULTS: Lymphedema (an arm volume
      difference > or =200 cm(3)) was measured in 42 women (27.8%). Mastectomy or
      conservative surgery patients had similar lymphedema rates. Women with lymphedema
      in both surgical groups scored significantly lower on 4 of the 5 subsections than
      women without lymphedema, even after adjusting for other factors influencing
      quality of life. CONCLUSIONS: Lymphedema occurs at appreciable rates, and its
      impact on long-term quality of life in survivors of early-stage breast cancer
      should not be underestimated.

PMID- 12413313
TI  - Use of ultrasonically activated shears improves the safety of
      pancreaticojejunostomy after pancreaticoduodenectomy.
AB  - OBJECTIVE: To study whether the use of ultrasonically activated shears (UAS)
      would improve the safety of pancreatojejunal anastomosis after
      pancreaticoduodenectomy. DESIGN: Retrospective analysis. SETTING: University
      teaching hospital. PATIENTS: Seventy patients underwent pancreaticoduodenectomy
      between April 1997 and May 2001. MAIN OUTCOME MEASURES: Leakage of
      pancreatojejunal anastomosis as judged from the contents of the drain within 7
      days after operation, and defined as a high amylase level of discharge that was 3
      times higher than that of serum. RESULTS: Leakage of pancreatojejunal anastomosis
      was observed in 1 (1.4%) of the 70 cases. Other complications were stomal ulcer,
      bile leakage, renal failure, and intra-abdominal abscess in one case each.
      CONCLUSIONS: Use of UAS to perform pancreatectomy eliminates bleeding and
      pancreatic juice leakage from the branches of the pancreatic duct. Therefore, the
      cut surface of the pancreas is kept dry, simplifying anastomosis. Use of UAS
      improves the safety of pancreatojejunal anastomosis after
      pancreaticoduodenectomy.

PMID- 12413314
TI  - The state of general surgery residency in the United States: program director
      perspectives, 2001.
AB  - HYPOTHESIS: Current demographic patterns and lifestyle factors of general surgery
      residents may contribute to recent changes in recruitment patterns. DESIGN:
      Survey addressing the characteristics of general surgery residency, including
      demographic data, 3-year recruitment and retention trends, and working conditions
      of general surgery residents. PARTICIPANTS: A convenience sample of all residency
      program directors in attendance at the 2001 Surgical Education Week was given the
      opportunity to voluntarily complete the survey. RESULTS: A total of 109 program
      directors responded to the survey. Women constitute 25% of all current general
      surgery residents: 66% of the program directors perceived a decline in the number
      of applicants for general surgery residency. Recruitment patterns differ
      significantly between small (< or =4 categorical residents per year) and large
      (>4 categorical residents per year) residency programs. Residents at large
      programs averaged a 95-hour workweek, whereas those at small programs averaged an
      88-hour workweek (P =.01). The mean 1-year attrition rate for general surgery
      residents was 20.2% in 2000, and attrition showed no relationship to program
      size, gender composition, or working conditions. CONCLUSIONS: Women remain
      underrepresented in general surgery residency. Recruitment and match statistics
      show some variation, but the relevance of a shrinking applicant pool to these
      changes is unclear. Resident working conditions remain a difficult issue, and
      attrition rates continue to be significant. A substantial research agenda remains
      in graduate surgical education.

PMID- 12413315
TI  - Open vs laparoscopic repair of spigelian hernia: a prospective randomized trial.
AB  - HYPOTHESIS: The elective treatment of a spigelian hernia is still under
      discussion, fundamentally owing to its rarity. The purpose of the study is to
      analyze the elective surgical treatment of spigelian hernia. DESIGN: A
      prospective, randomized controlled trial. SETTING: University teaching hospital.
      PATIENTS AND INTERVENTIONS: Two surgeons performed 11 conventional and 11
      laparoscopic repairs for a spigelian hernia, alternating roles as primary surgeon
      and assistant. Each time the type of technique was randomly chosen using a
      computerized program. MAIN OUTCOME MEASURES: Epidemiological, clinical, and
      surgical factors are analyzed according to treatment, ie, the open or
      laparoscopic approach. RESULTS: The statistical study shows no significant
      differences for epidemiological or diagnostic factors, but it does show
      significant advantages for laparoscopy in terms of morbidity (P<.05) and hospital
      stay (P<.001). CONCLUSION: The approach using extraperitoneal laparoscopy is the
      technique that offers best results in the elective treatment of spigelian hernia.

PMID- 12413316
TI  - Effects of supine intermittent compression on arterial inflow to the lower limb.
AB  - HYPOTHESIS: Intermittent pneumatic compression will affect the arterial blood
      flow in the lower limb at moderate pressure, without requiring dependency.
      DESIGN: Before-after trial. SETTING: Vascular ultrasound unit of a university
      hospital. PATIENTS: A volunteer sample of 19 healthy subjects without symptoms or
      history of vascular disease and 17 patients with peripheral arterial disease were
      studied. Six patients and 1 healthy volunteer were not included in the study
      group because of measurement difficulties or refusal when approached.
      INTERVENTIONS: Common femoral artery blood flow velocities were measured with
      Doppler ultrasound during 10 minutes of intermittent compression of the calf and
      thigh at 60 mm Hg, while the subject was supine. The data were collected every 5
      seconds from 4 minutes before to 4 minutes after the therapy period, and toe
      temperatures were also measured with an infrared radiometer. MAIN OUTCOME
      MEASURES: Resting to postcompression percentage increases in flow velocity were
      measured, along with more representative measures of the total flow change during
      the intermittent compression period. RESULTS: On compression, the blood flow
      velocity decreased slightly (15% in healthy subjects and 6% in patients) and
      increased on release (21% and 29%, respectively). Overall, blood flow did not
      decrease during therapy as expected (increases of 1% and 2%, respectively), and
      the toes of the patients warmed (by 2.2 degrees C). CONCLUSIONS: This work
      confirms the initial hypothesis in both subject groups. There appears to be
      physiological justification for investigating intermittent compression as a
      therapy for patients with intermittent claudication and rest pain in the supine
      position as well as seated.

PMID- 12413317
TI  - Intraductal papillary-mucinous tumors of the pancreas: predictive criteria of
      malignancy according to pathological examination of 53 cases.
AB  - BACKGROUND: One of the main problems in the management and treatment of
      intraductal papillary-mucinous tumors is the lack of a reliable predictive factor
      for malignancy. HYPOTHESIS: Surgical treatment could be adapted to macroscopic
      criteria (presence of mural nodules and diameter of the pancreatic duct and of
      the lesion) or to tumor location (main duct, branch duct, or combined lesions)
      associated with benign or malignant forms. DESIGN: Retrospective study. SETTING:
      Two university and tertiary referral centers. PATIENTS: Fifty-three consecutive
      patients who underwent pancreatic resection for intraductal papillary-mucinous
      tumors between January 1, 1985, and December 31, 2000. RESULTS: Macroscopic
      analyses of tumors showed 6 main duct lesions, 12 branch duct lesions, and 35
      combined lesions. A carcinoma was present in 33 cases (62%): 22 (41%) were
      invasive and 11 (21%) were noninvasive; 9 (17%) were borderline tumors and 11
      (21%) were benign. Carcinoma and invasive carcinoma forms were less frequent in
      branch duct lesions (P<.001 and P =.009, respectively). Mural nodules were more
      frequent in carcinomas (P =.006) and invasive carcinomas (P<.001), with a
      positive predictive value of malignancy of 81%. The diameter of lesions (branch
      duct lesion > or =30 mm) or main duct (main pancreatic duct > or =15 mm in
      combined or main pancreatic duct lesions) did not correlate with malignancy.
      CONCLUSIONS: No carcinoma occurred in branch duct types smaller than 30 mm
      without mural nodules. Limited resection may be appropriate only in this type of
      tumor.

PMID- 12413318
TI  - Effect of protocol Doppler ultrasonography and urgent revascularization on early
      hepatic artery thrombosis after pediatric liver transplantation.
AB  - HYPOTHESIS: Protocol Doppler ultrasonography of the liver (DUSL) is useful for
      detecting early hepatic artery thrombosis (HAT). Urgent exploration based on DUSL
      findings and immediate revascularization of the liver may avoid HAT-related
      sequelae, namely, biliary complications and retransplantation after pediatric
      liver transplantation. DESIGN: Case-control study. SETTING: University hospital.
      PATIENTS: Group 1 included 96 liver transplantations performed in 75 pediatric
      patients from June 1, 1994, to August 31, 1999. Group 2 included 43 liver
      transplantations performed in 39 pediatric patients from September 1, 1999, to
      September 30, 2001. INTERVENTION: In group 1, DUSL was performed on the first
      posttransplantation day or on request. Angiographic confirmation of suggested HAT
      was treated with thrombolysis, angioplasty, or thrombectomy. In group 2, protocol
      DUSL was performed every 12 hours in the first week and every 24 hours in the
      second week. The suspicion of HAT warranted urgent surgery without the patient
      undergoing angiography. MAIN OUTCOME MEASURES: Incidence of HAT, biliary
      complications, and retransplantation. Graft and patient survival. Hospital stay,
      and number of admissions and operations after undergoing HAT. RESULTS: The
      incidence of HAT was 10.4% (10 of 96 transplantations) in group 1 and 7.0% (3 of
      43 transplantations) in group 2. The incidence of biliary complications after HAT
      was 100% in group 1 and 0% in group 2 (P=.02). The incidence of retransplantation
      after HAT was 90.0% (9 of 10 patients) in group 1 and 0% in group 2 (P=.01). Of
      the 10 patients who experienced HAT in group 1, 5 patients underwent early
      retransplantation (mean length of time, 13.2 days). All 5 patients who did not
      undergo early retransplantation had biliary complications. Four of these 5
      patients underwent retrasplantation at a later time (mean length of time, 687
      days). In group 2, DUSL identified early HAT in 3 patients (7.0%). Emergent
      thrombectomy and arterial reconstruction were undertaken. All 3 (100%) have their
      original graft and are alive. None experienced biliary complications. One-year
      graft and patient survival is 72.0% and 84.0%, respectively, in group 1 and 80.0%
      and 85.0%, respectively, in group 2. Shorter hospital stay, fewer readmissions,
      and surgery after HAT were noted in group 2. CONCLUSIONS: Protocol DUSL detects
      early HAT and urgent revascularization based on DUSL can significantly reduce the
      incidence of biliary complication and graft loss requiring retransplantation in
      pediatric liver transplantation.

PMID- 12413319
TI  - Carotid endarterectomy in elderly patients: low complication rate with overnight
      stay.
AB  - HYPOTHESIS: Elderly patients undergoing carotid endarterectomy (CEA) can have a
      low complication rate and a short hospital stay. DESIGN: In this case series, we
      compared CEA results from January 1, 1994, through December 31, 1998, in 2
      different age groups: 71 to 80 years and 81 years and older. SETTING: A private
      vascular surgery practice. PATIENTS: We studied 271 patients who underwent 293
      CEAs; 124 procedures were for patients in the 71- to 80-year-old age group, and
      42 procedures were for patients aged 81 years and older. INTERVENTIONS: Classic
      CEA was performed on all patients. From 1994 through 1996, 179 operations were
      performed under general anesthesia with routine shunting. In 1997 and 1998, 114
      operations were performed under locoregional anesthesia with selective shunting.
      MAIN OUTCOME MEASURES: Length of hospital stay and 30-day morbidity and
      mortality. RESULTS: The mortality rate for the entire series was 0.7% (2 of 293
      patients). Major cardiac complications occurred in 3 patients (1.0%).
      Perioperative stroke occurred in 3 cases(1.0%); 2 strokes occurred in patients
      aged 71 to 80 years (2 [1.6%] of 124 patients), and 1 occurred in a patient aged
      81 years or older (1 [2.4%] of 42 patients). Two additional patients developed
      reversible ischemic neurological deficits but were not in the elderly group (> or
      =81 years and older). The mean hospital stay was 1.5 days for patients aged 71 to
      80 years and 1.2 days for patients aged 81 years and older. All outcome variables
      were statistically similar in both age groups. CONCLUSION: Octogenarians can
      undergo CEA with little morbidity and mortality and virtually an overnight
      hospital stay.

PMID- 12413321
TI  - In situ vs ex situ pancreatic duct stents of duct-to-mucosa
      pancreaticojejunostomy after pancreaticoduodenectomy with billroth I-type
      reconstruction.
AB  - BACKGROUND: Pancreatic fistula is a leading cause of morbidity and mortality
      after pancreaticoduodenectomy, and an external stent of pancreaticojejunostomy
      has been recommended to prevent pancreatic fistula. HYPOTHESIS: Duct-to-mucosa
      pancreaticojejunostomy should not require placement of an external stent. DESIGN:
      Nonrandomized control study. SETTING: University hospital. PATIENTS: Seventy-four
      patients undergoing pancreaticoduodenectomy with duct-to-mucosa
      pancreaticojejunostomy were allocated to either the ex situ group (external
      pancreatic stent drainage) or the in situ group (no external drainage). MAIN
      OUTCOME MEASURES: Operative mortality; postoperative complications, particularly
      pancreatic fistula; and patency of duct-to-mucosa pancreaticojejunostomy.
      RESULTS: Preoperative factors, indicated disorders, and intraoperative factors
      were similar for both groups. Mortality rates were 1% (1/74) overall, 3% (1
      death) for the in situ group, and 0% for the ex situ group. Morbidity rates were
      32% (12/37) for the in situ group and 35% (13/37) for the ex situ group. The
      incidence of pancreatic fistula was 5.4% and was the same for the in situ and ex
      situ groups. The incidence of delayed gastric emptying was similar for the in
      situ (19% [7/37]) and ex situ (14% [5/37]) groups. Ampullary tumors and
      pancreatic ducts 2 mm or less in diameter had a higher incidence of pancreatic
      fistula, but the incidence was similar in both treatment groups. Nasogastric tube
      drainage day, the median hospital stay, and pancreaticojejunostomy patency were
      similar in both groups. CONCLUSIONS: The results were considered to show
      equivalent outcomes for ex situ and in situ pancreatic stenting of the duct-to
      mucosa pancreaticojejunostomy after pancreaticoduodenectomy. The use of
      transanastomotic stents has to be selective according to the individual
      characteristics of each patient. We recommend their use with ampullary tumors or
      small ducts (< or =2 mm).

PMID- 12413322
TI  - Computed tomographic findings of colorectal liver metastases can be predictive
      for recurrence after hepatic resection.
AB  - BACKGROUND: We recently reported that the pathologic mode of infiltrative growth
      (infiltrative [INF]-alpha, INF-beta, and INF-gamma) of colorectal liver
      metastases had characteristic morphologic findings, and furthermore showed that
      the INF type was a prognostic factor for disease-free survival after hepatic
      resection. HYPOTHESIS: Preoperative computed tomographic (CT) findings of the
      liver nodules may be predictive for pathologic tumor growth pattern. DESIGN:
      Retrospective study. SETTING: Departments of Surgery and Radiology at a
      university hospital in Japan. PATIENTS: A total of 25 CT examinations (1985-1998)
      were reviewed, and a comparison was conducted on CT findings of 2 groups with INF
      alpha or INF-beta (hereafter noted as INF-alpha-beta) (n = 9 [ie, a patient with
      INF-alpha plus 8 with INF-beta]) and INF-gamma (n = 16) type liver metastases.
      MAIN OUTCOME MEASURES: chi(2) Analysis of CT morphologic features was performed
      between the study groups. The result of multivariate analysis was obtained using
      the Cox proportional hazards model. RESULTS: The morphologic features observed by
      CT showed a significant difference between the 2 groups (INF-alpha-beta, and INF
      gamma types) in the ratio of length to breadth of nodules (<1.5 vs > or =1.5, P
      =.008) and in the outline of nodules (regular vs irregular, P =.01). Of these CT
      imaging features, the outline of the nodule was an independent prognostic factor
      (P =.02). CONCLUSION: Computed tomographic findings of colorectal liver lesions
      correlated with the pathologic tumor growth pattern and a prognosis.

PMID- 12413323
TI  - Abdominal compartment syndrome in the open abdomen.
AB  - BACKGROUND: Multiple methods exist to manage in the intensive care unit the
      patient with an open abdomen. An increasingly common method is the vacuum packed
      technique. This method accommodates considerable expansion of intra-abdominal
      contents and should obviate the potential development of the abdominal
      compartment syndrome (ACS). Despite this, some patients with these temporary
      abdominal dressings will go on to develop ACS. For the purpose of this study we
      have defined this clinical entity as the open abdomen ACS. HYPOTHESIS: Patients
      with an open abdomen who develop ACS have a poor prognosis. Fluid requirements
      and resuscitative indices may predict which of these patients will develop open
      abdomen ACS. METHODS: A retrospective review was performed of patients with
      trauma who had an open abdomen treated with vacuum packed dressings at our urban
      level I trauma center. Over 1 year (July 1, 1999-June 30, 2000), 5 patients
      managed with an open abdomen developed ACS. These patients were compared with 15
      consecutive patients with an open abdomen who did not develop clinical ACS during
      that same period. Fluid resuscitation, base deficit, pH, lactate level, systolic
      blood pressure, prothrombin time, temperature, peak inspiratory pressure, and
      PCO(2) were abstracted. The Fisher exact test was used for statistical analysis.
      RESULTS: In patients managed with an open abdomen, ACS developed between 1.5 and
      12 hours (mean [SD], 7.5 [3.9] hours) after placement of the vacuum packed
      dressing. The base deficit, pH, peak inspiratory pressure, PCO(2,) and lactate
      level were more abnormal and the crystalloid requirements were significantly
      higher in the ACS group. The systolic blood pressure, temperature, and
      prothrombin time did not differ between groups. Three patients with ACS developed
      a second episode of ACS. Mortality in the ACS group was 3 (60%) of 5 patients vs
      1 (7%) of 15 patients in the control group. CONCLUSIONS: Management of the open
      abdomen with the temporary abdominal closure does not prevent the development of
      ACS. Mortality is high when ACS occurs in this scenario. Severe physiologic
      derangement and high crystalloid requirements may predict which patients will
      develop ACS.

PMID- 12413324
TI  - Evidence-based science: a worthwhile mode of surgical inquiry.

PMID- 12413325
TI  - Lesson learned from a louisiana surgeon.

PMID- 12413326
TI  - Claude Couinaud: a passion for the liver.

PMID- 12413327
TI  - Image of the month. Small-bowel stromal tumor.

PMID- 12413328
TI  - Hyaluronate does not prevent adhesions.

PMID- 12413330
TI  - Horatio Jameson and a "mouth stuffed in a wonderful manner".

PMID- 12413331
TI  - Comparison of hemolysis in blood samples collected using an automatic incision
      device and a manual lance.
AB  - OBJECTIVE: To evaluate the magnitude of hemolysis in blood specimens collected
      from the heels of newborns using an automated blood collection device that uses a
      spring-loaded lance with blood collected using a manual lance. DESIGN: A
      randomized controlled trial involving 134 newborns assigned to have blood
      collected using either an automated blood collection device or a manual lance. A
      single experienced individual performed all blood collections. Serum hemoglobin
      concentrations were measured in all samples to gauge the extent of hemolysis.
      SETTING: A neonatology unit in a 740-bed tertiary care teaching hospital.
      PATIENTS: Healthy newborns with gestational ages ranging from 33 weeks to 41
      weeks. Blood samples were collected from study participants at between 7 and 126
      hours postpartum. Group 1 consisted of 66 individuals who had blood collected
      using the manual lance. Group 2 contained 68 individuals with blood collected
      using a spring-loaded automatic lance. MAIN OUTCOME MEASURE: Plasma hemoglobin
      content as an indicator of the extent of hemolysis. RESULTS: There were no
      significant differences between newborns in groups 1 and 2 with respect to
      gestational age, birth weight, or time interval between birth and time of blood
      collection. We found a highly significant difference with respect to plasma
      hemoglobin concentrations in specimens collected with an automated lance
      (hemoglobin, 2.35 g/L) vs that collected using the hand-held lance (hemoglobin,
      4.85 g/L). CONCLUSION: Use of an automated spring-loaded lance allows for the
      collection of blood specimens with smaller levels of plasma hemoglobin.

PMID- 12413332
TI  - Longitudinal study of the number and choice of leisure time physical activities
      from mid to late adolescence: implications for school curricula and community
      recreation programs.
AB  - BACKGROUND: Physical activity (PA) declines during adolescence. There has been
      little research describing this decline or examining participation and
      nonparticipation in specific activities. OBJECTIVE: To describe the pattern of
      change in the number of physical activities, the time spent on specific
      activities, and the stability of participation and nonparticipation in specific
      activities during adolescence. DESIGN AND SETTING: A population-based 4-year
      longitudinal study of adolescents recruited from a single suburban school
      district near Pittsburgh, Pa. PARTICIPANTS: A total of 782 adolescents, aged 12
      to 15 years at baseline. MAIN OUTCOME MEASURES: Physical activity was measured
      annually via questionnaire. Outcome measures include hours per week of PA, number
      of reported activities, and participation (yes or no) in specific activities.
      RESULTS: Physical activity declined during the 4 years by 26%. The decline in PA
      was primarily due to a decrease in the number of reported activities. Adolescents
      who continued to report an activity during the 4 years of the study maintained or
      increased the time spent on that specific activity. Female adolescents were more
      likely to report individual activities, while male adolescents were more likely
      to report team activities. The probability of maintaining participation in a
      specific activity during the 4 years was low to moderate, 0.02 to 0.47 for female
      adolescents and 0.04 to 0.71 for male adolescents. The probability of not
      participating in a specific activity during the 4 years was extremely high and
      consistent for male and female adolescents, 0.70 to 1.00. CONCLUSIONS: The
      decline in PA during adolescence is primarily due to a decrease in the number of
      activities in which the adolescent is participating, and there is only a moderate
      probability that an adolescent will continue to participate in an activity during
      the 4-year period from junior to senior high. Future efforts should be directed
      at identifying factors associated with initiating and maintaining participation
      in specific activities.

PMID- 12413333
TI  - A recurring FBN1 gene mutation in neonatal Marfan syndrome.
AB  - BACKGROUND: Marfan syndrome is an autosomal dominant disorder of connective
      tissue caused by mutations in the fibrillin 1 gene (FBN1). FBN1 mutations have
      been associated with a broad spectrum of phenotypes. Neonatal Marfan syndrome has
      unique clinical manifestations and mutations. OBJECTIVE: To determine if there is
      a discernible genotypic-phenotypic correlation associated with the unique
      mutation in neonatal Marfan syndrome. STUDY DESIGN: A newborn exhibited many
      typical characteristics of neonatal Marfan syndrome, including arachnodactyly;
      contractures of both elbows, knees, and ankles; small-joint laxity; dilated
      cardiomyopathy; valvular dysplasia and insufficiency; congestive heart failure;
      and pulmonary emphysema. Three atypical features were also discovered: a right
      diaphragmatic hernia, a myocardial mass, and left main-stem bronchomalacia. She
      died at 3(1/2) months of age. Total RNA was extracted from skin fibroblasts and
      amplified by means of reverse transcriptase polymerase chain reaction
      amplification with FBN1-specific primers. The complementary DNA fragments were
      sequenced. RESULTS: A single T-to-C transition at nucleotide 3276 (T3276C) was
      identified and confirmed at the DNA level by sequencing of genomic DNA. This
      results in a substitution of threonine for isoleucine. CONCLUSIONS: Neonatal
      Marfan syndrome is a unique clinical entity with recurring mutation hot spots in
      exons 24 to 27 and 31 to 32 of the FBN1 gene. Some clinical features in this case
      report are unusual for neonatal Marfan syndrome. This is the third report of this
      T3276C mutation in the FBN1 gene with unusual clinical manifestations. We
      conclude that there is a genotypic-phenotypic correlation associated with this
      mutation.

PMID- 12413334
TI  - Use of a large national database for comparative evaluation of the effect of a
      bronchiolitis/viral pneumonia clinical care guideline on patient outcome and
      resource utilization.
AB  - OBJECTIVES: To use a large national comparative database to measure the internal
      effect of a set of evidence-based bronchiolitis/viral pneumonia clinical care
      guidelines on clinical practice at a children's hospital, and to compare these
      changes with those at other children's hospitals. DESIGN: Prospective cohort
      study with retrospective and concurrent (other hospital) controls. SETTING: The
      Children's Hospital, Denver, Colo. PARTICIPANTS: Hospitalized children with
      bronchiolitis and/or viral pneumonia. INTERVENTIONS: Our clinical guidelines
      focused on clear admission and discharge criteria, individualized transition
      anticipating orders, and "prove it or don't use it" criteria for the use of
      respiratory syncytial virus testing, bronchodilators, chest physiotherapy, and
      ribavirin. MAIN OUTCOME MEASURES: The effect of guideline implementation was
      determined by comparative measurement of internal changes in utilization and
      outcome (nosocomial infection rate) across time and by external comparison with
      other children's hospitals using standardized data from the Pediatric Health
      Information System database of the Child Health Corporation of America (Shawnee
      Mission, Kan). RESULTS: Overall, 10 636 bronchiolitis/viral pneumonia cases were
      studied: 1302 at the index hospital and 9334 at the 7 comparison hospitals.
      Internally, the index hospital's residents and attending physicians responded
      favorably to the bronchiolitis/viral pneumonia care guidelines, resulting in
      decreases in targeted resource utilization. There were no fatalities, and the
      number of days in the intensive care unit decreased even though the mean severity
      of admitted cases increased significantly. Targeted utilization was favorably
      affected, whereas untargeted utilization was not. Nosocomial infections did not
      increase with a decreased use of respiratory syncytial virus testing. The index
      hospital differed favorably from other children's hospitals in several
      categories. CONCLUSION: Evidence-based care guidelines can successfully influence
      utilization and clinical outcome.

PMID- 12413335
TI  - Berloque dermatitis mimicking child abuse.
AB  - Berloque dermatitis is a type of photocontact dermatitis. It occurs after
      perfumed products containing bergamot (or a psoralen) are applied to the skin
      followed by exposure to sunlight. Striking linear patterns of hyperpigmentation
      are characteristic, corresponding to local application of the scented product. In
      the acute phase, erythema and even blistering can be seen. We report a case of
      berloque dermatitis in a 9-year-old girl that was initially reported as child
      abuse. To our knowledge, this is the first report of berloque dermatitis
      mimicking child abuse. Questioning to elicit a history of perfume application
      coupled with sunlight exposure should help to prevent this misdiagnosis in
      children.

PMID- 12413336
TI  - Smoking patterns of household members and visitors in homes with children in the
      United States.
AB  - BACKGROUND: Environmental tobacco smoke (ETS), also called passive smoking, has
      been shown to have adverse effects on the health of children. OBJECTIVE: To
      determine the prevalence and pattern of ETS exposure in US homes with children
      younger than 18 years. DESIGN: We analyzed data from the 1994 National Health
      Interview Survey and Year 2000 Objectives supplement. A multistage sample design
      was used to represent the civilian, noninstitutionalized population of the United
      States. MAIN OUTCOME MEASURES: Frequency of smoking by household residents and
      visitors in homes with children. RESULTS: Thirty-five percent of children in the
      United States-21 million children-live in homes where residents or visitors smoke
      in the home on a regular basis (> or =1 d/wk). From the household perspective,
      regular smoking by residents and visitors occurs in 36% of homes in which
      children reside. In 92% of homes with children where residents smoke at home,
      they do so every day of the week. Sixteen percent of nonsmoking respondents with
      children report that other residents or visitors smoke in the home. In 6% of the
      homes where no residents smoke, there is nevertheless regular smoking by
      visitors. In multivariate regression analysis, the prevalence of regular smoking
      in homes with children varies by age of youngest child, race/ethnicity, number of
      parents in the home, parental educational level, income, and region of the
      country. CONCLUSIONS: Many children live in homes with ETS. Most respondents who
      smoke report that smoking occurs in the home every day. Visitors are an
      additional source of ETS in homes, including some homes where residents do not
      smoke. Clinicians who take care of children can advise parents, whether or not
      they smoke, on how to limit their children's ETS exposure.

PMID- 12413337
TI  - The longitudinal relationship between drug use and risky sexual behaviors among
      colombian adolescents.
AB  - OBJECTIVE: To identify the longitudinal relationships between drug use and risky
      sexual behaviors and early pregnancy in Colombian adolescents. DESIGN:
      Confidential survey of adolescents, consisting of structured individual
      interviews, at 2 time points, 2 years apart. A standard self-report questionnaire
      was adapted to ensure linguistic and cultural relevance. SETTING: Community
      samples representing differing levels of risky sexual behavior and drug use.
      Cohorts were drawn from higher- and lower-risk geographic areas and from various
      self-reported ethnic groups. PARTICIPANTS: Adolescents (N = 2226) randomly
      selected from 3 major Colombian cities: Bogota, Medellin, and Barranquilla. MAIN
      OUTCOME MEASURES: Data were collected concerning adolescent drug use, sexual
      behaviors, and a history of pregnancy. The youths' drug use included measures of
      all illegal drugs. RESULTS: By using regression analyses (controlling for
      demographic variables) a reciprocal longitudinal relationship between risky
      sexual behaviors and drug use was identified. Those adolescents who reported
      higher levels of drug use at time 1 also had more sexual partners, had higher
      frequencies of unprotected sex, and were more likely to have experienced early
      pregnancy at time 2. The reverse relationship was true as well. The level of
      violence experienced by the adolescent emerged as a moderator of some of these
      relationships. CONCLUSIONS: Reducing adolescent drug use may also reduce levels
      of risky sexual behavior and early pregnancy and vice versa. Furthermore, the
      importance of addressing violence as a risk factor for both problem behaviors is
      emphasized.

PMID- 12413338
TI  - Professional interpreters and bilingual physicians in a pediatric emergency
      department: effect on resource utilization.
AB  - OBJECTIVE: To determine the impact of interpreters and bilingual physicians on
      emergency department (ED) resource utilization. DESIGN: Cohorts defined by
      language concordance and interpreter use were prospectively studied preceding and
      following the availability of dedicated, professional medical interpreters.
      SETTING: Pediatric ED in Chicago, Ill. PARTICIPANTS: We examined 4146 visits of
      children (aged 2 months to 10 years) with a presenting temperature of 38.5
      degrees C or higher or a complaint of vomiting or diarrhea; 550 families did not
      speak English. In 170 cases, the treating physician was bilingual. In 239, a
      professional interpreter was used. In the remaining 141, a professional medical
      interpreter was unavailable. MAIN OUTCOME MEASURES: Incidence and costs of
      diagnostic testing, admission rate, use of intravenous hydration, and length of
      ED visit. RESULTS: Regression models incorporated clinical and demographic
      factors. Compared with the English-speaking cohort, non-English-speaking cases
      with bilingual physicians had similar rates of resource utilization. Cases with
      an interpreter showed no difference in test costs, were least likely to be tested
      (odds ratio [OR], 0.73; 95% confidence interval [CI], 0.56-0.97), more likely to
      be admitted (OR, 1.7; 95% CI, 1.1-2.8), and no more likely to receive intravenous
      fluids, but had longer lengths of visit (+16 minutes; 95% CI, 6.2-26 minutes).
      The barrier cohort without a professional interpreter had a higher incidence (OR,
      1.5; 95% CI, 1.04-2.2) and cost (+$5.78; 95% CI, $0.24-$11.21) for testing and
      was most likely to be admitted (OR, 2.6; 95% CI, 1.4-4.5) and to receive
      intravenous hydration (OR, 2.2; 95% CI, 1.2-4.3), but showed no difference in
      length of visit. CONCLUSION: Decision making was most cautious and expensive when
      non-English-speaking cases were treated in the absence of a bilingual physician
      or professional interpreter.

PMID- 12413339
TI  - Antibiotic prescribing by primary care physicians for children with upper
      respiratory tract infections.
AB  - OBJECTIVES: To determine if the rate of appropriate antibiotic use in the
      treatment of children with bronchitis, viral upper respiratory tract infections,
      sinusitis, otitis media, and pharyngitis has changed in recent years and to
      identify factors that are associated with the use of inappropriate antibiotic
      therapy. DESIGN: The National Ambulatory Medical Care Survey was used to examine
      the antimicrobial prescribing habits of physicians who provide primary care for
      children. Data were analyzed from 1995-1998. SETTING: Office-based physician
      practices. PARTICIPANTS: Pediatricians, family physicians, and generalists
      completing survey forms for patients younger than 18 years. MAIN OUTCOME MEASURE:
      The appropriate use of antibiotics for upper respiratory tract infections.
      RESULTS: Multivariate analyses were used to examine factors associated with the
      use of inappropriate antibiotics to treat either upper respiratory tract
      infections or bronchitis. Patients seen in 1998 and diagnosed as having upper
      respiratory tract infections were 0.69 (95% confidence interval, 0.59-0.81) times
      less likely to be treated with antibiotics compared with patients seen in 1995.
      Multivariate analyses were also used to assess factors associated with the use of
      antibiotics with a suboptimal therapeutic profile for the treatment of either
      sinusitis or otitis media. Children diagnosed as having either sinusitis or
      otitis media were 0.3 (95% confidence interval [CI], 0.16-0.48) times less likely
      to receive antibiotics with a suboptimal therapeutic effect in 1998 compared with
      1995. CONCLUSIONS: Physicians are slowly improving their antibiotic prescribing
      patterns but the use of inappropriate antibiotics is still common. Almost half of
      patients with upper respiratory tract infections receive antibiotics.

PMID- 12413340
TI  - Lychee-flavored gel candies: a potentially lethal snack for infants and children.
AB  - A 10 month-old infant was given a Lychee Mini Fruity Gel (AP Frozen Foods Ltd,
      Thailand) by his mother while shopping in a supermarket. The child was sucking on
      the gel when he began to choke and have difficulty breathing. Emergency medical
      services were called, and paramedics found the child to be in respiratory arrest
      with a palpable pulse of 40 beats/min. They transported him to the pediatric
      emergency department, performing bag-valve-mask ventilation with a manual
      resuscitator. The child was intubated and taken to the operating room for
      bronchoscopy and then the pediatric intensive care unit for critical care. The
      initial report was that he choked on gelatin. However, he was found to have
      aspirated a large hard gel found in the lychee-flavored candy that totally
      obstructed his airway. This is the third case of aspiration of a gel candy we
      have seen in 5 years. Parents should be warned not to give these candies to
      children younger than 5 years.

PMID- 12413341
TI  - Infant colic: empirical evidence of the absence of an association with source of
      early infant nutrition.
AB  - BACKGROUND: The etiology of infant colic remains unknown, despite an abundance of
      research on the topic. OBJECTIVE: To determine whether breastfeeding has a
      protective effect in colic's development. DESIGN: A prospective cohort study of
      856 mother-infant dyads. Eligible participants included English-speaking adult
      residents of a region in Ontario, who gave birth, at term, to a live singleton
      whose birth weight was appropriate for gestational age. Self-administered
      questionnaires, mailed to mothers at 1 and 6 weeks post partum, requested
      information on several infant and maternal factors, including source of infant
      nutrition (exclusively breastfed, complementary fed, and exclusively formula
      fed). Cases of colic were identified by applying modified Wessel criteria to data
      recorded in the Barr Baby Day Diary or by interpreting responses to the Ames Cry
      Score. MAIN OUTCOME MEASURES: Prevalence of colic among breastfed, formula-fed,
      and complementary-fed infants; and adjusted odds ratios (AORs) reflecting the
      prevalence of colic among formula- and complementary-fed infants relative to
      those who were breastfed. RESULTS: Of 856 mothers, 733 (86%) completed the first
      questionnaire and 617 (72%) completed the second questionnaire. Overall, the
      prevalence of colic at 6 weeks was 24%. No association was seen between the
      source of infant nutrition and colic's development. In multivariate analyses,
      higher levels of maternal trait anxiety (AOR, 1.22; 95% confidence interval [CI],
      0.96-1.54), maternal alcohol consumption at 6 weeks (AOR, 1.57; 95% CI, 1.03
      2.40), and shift work during pregnancy (AOR, 1.27; 95% CI, 0.73-2.21) were
      associated with an increased likelihood of colic, after controlling for feeding
      method, maternal age, and parity. In these same analyses, being married or having
      a common-law partner (AOR, 0.30; 95% CI, 0.10-0.87) and being employed full-time
      during pregnancy (AOR, 0.60; 95% CI, 0.32-1.14) were associated with a reduced
      likelihood of colic. CONCLUSIONS: Breastfeeding did not have a protective effect
      on the development of colic. Although colic was statistically associated with
      several variables, including preexisting maternal anxiety, much of colic's
      etiology remains unexplained.

PMID- 12413342
TI  - Perinatal outcome following third trimester exposure to paroxetine.
AB  - BACKGROUND: Paroxetine hydrochloride is commonly used for maternal depression,
      panic disorder, and obsessive-compulsive disorder. The drug readily crosses the
      human placenta. Although it does not appear to increase teratogenic risk, there
      have been case reports of neonatal withdrawal. Symptoms were described soon after
      birth and lasted up to 1 month. OBJECTIVE: To investigate whether there is a
      clinically important discontinuation syndrome in neonates exposed to paroxetine
      in utero. METHODS: Prospective, controlled cohort study. PATIENTS: Fifty-five
      pregnant women counseled prospectively by the Motherisk program in Toronto,
      Ontario, regarding third-trimester exposure to paroxetine and their infants were
      included in the study group. Pregnant women who discontinued paroxetine before
      the third trimester or those receiving other drugs known to cause withdrawal-type
      symptoms, such as opioids or benzodiazepines, were excluded. A comparison group
      of 27 women using paroxetine during the first or second trimester and 27 women
      using nonteratogenic drugs were matched for maternal age, gravity, parity, social
      drug use, and nonteratogenic drug use. RESULTS: Of the 55 neonates exposed to
      paroxetine in late gestation, 12 had complications necessitating intensive
      treatment and prolonged hospitalization. The most prevalent clinical picture was
      respiratory distress (n = 9), followed by hypoglycemia (n = 2), and jaundice (n =
      1). The symptoms disappeared within 1 to 2 weeks. In the comparison group, only 3
      infants experienced complications (P =.03). In logistic regression, only third
      trimester exposure to paroxetine was associated with neonatal distress (odds
      ratio, 9.53; 95% confidence interval, 1.14-79.3). CONCLUSION: When used near
      term, paroxetine is associated with a high rate of neonatal complications,
      possibly caused by its common discontinuation syndrome.

PMID- 12413343
TI  - The role of self-efficacy and relationship quality in partner notification by
      adolescents with sexually transmitted infections.
AB  - OBJECTIVE: To evaluate the role of self-efficacy, anticipated negative
      consequences, and relationship quality in patient-initiated sex partner
      notification following treatment for sexually transmitted infections. SUBJECTS:
      Two hundred forty-one 13- to 20-year-old subjects (83% women; 83% African
      American) diagnosed with gonorrhea, chlamydia, trichomonas, or nongonococcal
      urethritis. Subjects were patients at a public sexually transmitted diseases
      clinic or primary care adolescent clinics. METHODS: Structured interviews at
      enrollment and 1 month following treatment. At enrollment, recent sexual partners
      were identified. Coital frequency, partner-specific sexually transmitted
      infection notification self-efficacy, anticipated consequences of notification,
      and relationship quality were measured with multi-item scales. At 1 month,
      subjects were asked whether partners had been notified and about the timing of
      notification relative to treatment. RESULTS: Subjects reported 279 partners. Of
      these, 61% of women's partners and 52% of men's partners were notified. Multiple
      logistic regression adjusted by generalized estimating equations showed that
      notification was predicted by antecedent notification self-efficacy (adjusted
      odds ratio, 1.16; 95% confidence interval, 1.03-1.30) and relationship quality
      (adjusted odds ratio, 1.17; 95% confidence interval, 1.08-1.27). Age, sex,
      race/ethnicity, prior sexually transmitted infection, coital frequency, and
      anticipated consequences were not related to partner notification. CONCLUSIONS:
      Partner notification is increased among persons with higher levels of self
      efficacy and in relationships with stronger affiliative and emotional ties. Self
      efficacy and partner communication could be especially amenable to interventions
      to increase patient-initiated partner notification for curable sexually
      transmitted infections.

PMID- 12413344
TI  - Physical functioning in female caregivers of children with physical disabilities
      compared with female caregivers of children with a chronic medical condition.
AB  - OBJECTIVES: To evaluate if physical functioning is different in female caregivers
      of children with physical disabilities compared with female caregivers of
      children with nondisabling medical illnesses, and to investigate the factors
      associated with functioning level. DESIGN: Cross-sectional survey. SETTING:
      University-based clinics. PATIENTS: Ninety consecutive female caregivers of
      children presenting to a pediatric physical medicine and rehabilitation (PM&R)
      clinic, and 23 presenting to a pediatric endocrine clinic. INTERVENTION: Fifteen
      minute self-administered survey. MAIN OUTCOME MEASURES: The dependent variable
      measured was physical functioning (physical functioning subscale of the Short
      Form-36). Independent variables measured were the average back pain severity over
      the last week (100-mm visual analog scale), mood (using the Center for
      Epidemiologic Studies-Depression Scale), work status, amount of lifting at work,
      caregiver demographics, child demographics, and the physical functioning ability
      of the child (measured using the WeeFIM scale). RESULTS: The mean (SD) physical
      functioning score of caregivers of children in the pediatric PM&R clinic was 80.6
      (21.9), which was less than the score of 90.2 (17.6) for caregivers in the
      pediatric endocrine clinic (mean difference, 9.6; 95% confidence interval, -0.9
      to -18.4). The physical functioning score of 77.7 (22.9) in caregivers of PM&R
      clinic children with a WeeFIM scale score of 1 to 4 was significantly worse than
      the 90.5 (14.8) in female caregivers of children with a WeeFIM score of 5 to 7
      (mean difference, 12.8; 95% confidence interval, -2.0 to -23.6). This decrease is
      associated with the average pain severity, mood, and total length of time of back
      pain in the previous 12 months. Regression analysis shows that pain severity and
      caregiver mood are significantly related to the physical functioning status of
      the caregiver. CONCLUSIONS: Physical functioning is decreased in female
      caregivers of children with a physical disability. This decrease is associated
      with caregiver pain severity and mood.

PMID- 12413345
TI  - Employment in adults with congenital heart disease.
AB  - OBJECTIVE: To evaluate job participation, career-related problems, and actual job
      problems in adults with complex congenital heart disease (CHD) compared with
      adults with mild CHD and reference groups. DESIGN: Cross-sectional study.
      SETTING: Patients were randomly selected from the archives of the Department of
      Pediatric Cardiology, Leiden University Medical Center, Leiden, the Netherlands.
      PATIENTS AND MAIN OUTCOME MEASURES: In total, 76 patients with complex CHD and 80
      with mild CHD (age range, 17-32 years) completed a self-reported questionnaire on
      employment and handicaps, with reference data available (response rate, 70%).
      RESULTS: In the study groups, 45 (59%) of 76 patients with complex CHD had a paid
      job compared with 61 (76%) of 80 patients with mild CHD. Patients older than 25
      years with complex CHD had significantly lower job participation (64%) than the
      general population (83%). Multiple logistic regression showed that type of CHD
      and level of education were significantly and independently related to job
      participation (odds ratio, 4.8; 99% confidence interval, 1.2-19.6; and odds
      ratio, 4.7; 99% confidence interval, 1.3-17.2, respectively). Of the 76 patients
      with complex CHD, 42 (55%) experienced disease-related career problems, in
      contrast to only 1 patient with mild CHD. Both CHD groups had more job-related
      mobility handicaps than did the reference group. However, in the mild CHD group,
      handicaps could be attributed to additional noncardiac diseases. CONCLUSIONS:
      Patients with complex CHD have reduced job participation compared with patients
      with mild CHD and the general population. Many receive disability benefits or
      experience career problems or job handicaps. Career counseling focusing on
      physical abilities and level of education may help prevent or reduce these job
      related problems.

PMID- 12413346
TI  - Inflammatory tinea pedis/manuum masquerading as bacterial cellulitis.
AB  - BACKGROUND: Tinea pedis and tinea manuum in children are more common than
      previously recognized. Clinical presentations of dermatophyte infections may vary
      in children and may be difficult to diagnose. OBJECTIVE: To show the necessity of
      potassium hydroxide preparations and/or fungal cultures in assessing suspicious
      cases of cellulitis in children who may have dermatophyte infections. PATIENTS:
      We describe 4 children with inflammatory tinea pedis or tinea manuum who were
      initially misdiagnosed as having bacterial cellulitis. INTERVENTION: A potassium
      hydroxide examination was performed on 3 patients. Fungal cultures were performed
      on 2 patients. RESULTS: Inflammatory/bullous dermatophyte infections were
      detected by potassium hydroxide examination in all 4 patients and all 4 children
      successfully responded to topical antifungal therapy. CONCLUSIONS: These cases
      demonstrate that inflammatory tinnea pedis/manuum can masquerade as cellulitis in
      children. Early potassium hydroxide examination can allow appropriate antifungal
      treatment to be initiated before fungal culture results are finalized.

PMID- 12413347
TI  - Remembering Walt Tunnessen.

PMID- 12413348
TI  - Self-screening methods are the next public health improvement for sexually
      transmitted infection detection.

PMID- 12413349
TI  - Overstating the behavioral effects of the Seattle social development project.

PMID- 12413353
TI  - A piece of my mind. The changing room.

PMID- 12413354
TI  - Fear of frying: is acrylamide in foods a cancer risk?

PMID- 12413355
TI  - Raccoon parasite an emerging health concern.

PMID- 12413356
TI  - From the Centers for Disease Control and Prevention. Local transmission of
      Plasmodium vivax malaria--Virginia 2002.

PMID- 12413360
TI  - From the Food and Drug Administration.

PMID- 12413364
TI  - The ethics of underpowered clinical trials.

PMID- 12413365
TI  - The ethics of underpowered clinical trials.

PMID- 12413366
TI  - The ethics of underpowered clinical trials.

PMID- 12413367
TI  - Underpowered clinical trials of antiretroviral treatment.

PMID- 12413369
TI  - Radiologic diagnosis of brain death.

PMID- 12413370
TI  - Spontaneous and sporadic trypsinogen mutations in idiopathic pancreatitis.

PMID- 12413371
TI  - Hormone replacement therapy and incidence of Alzheimer disease in older women:
      the Cache County Study.
AB  - CONTEXT: Previous studies have shown a sex-specific increased risk of Alzheimer
      disease (AD) in women older than 80 years. Basic neuroscience findings suggest
      that hormone replacement therapy (HRT) could reduce a woman's risk of AD.
      Epidemiologic findings on AD and HRT are mixed. OBJECTIVE: To examine the
      relationship between use of HRT and risk of AD among elderly women. DESIGN,
      SETTING, AND PARTICIPANTS: Prospective study of incident dementia among 1357 men
      (mean age, 73.2 years) and 1889 women (mean age, 74.5 years) residing in a single
      county in Utah. Participants were first assessed in 1995-1997, with follow-up
      conducted in 1998-2000. History of women's current and former use of HRT, as well
      as of calcium and multivitamin supplements, was ascertained at the initial
      contact. MAIN OUTCOME MEASURE: Diagnosis of incident AD. RESULTS: Thirty-five men
      (2.6%) and 88 women (4.7%) developed AD between the initial interview and time of
      the follow-up (3 years). Incidence among women increased after age 80 years and
      exceeded the risk among men of similar age (adjusted hazard ratio [HR], 2.11; 95%
      confidence interval [CI], 1.22-3.86). Women who used HRT had a reduced risk of AD
      (26 cases among 1066 women) compared with non-HRT users (58 cases among 800
      women) (adjusted HR, 0.59; 95% CI, 0.36-0.96). Risk varied with duration of HRT
      use, so that a woman's sex-specific increase in risk disappeared entirely with
      more than 10 years of treatment (7 cases among 427 women). Adjusted HRs were 0.41
      (95% CI, 0.17-0.86) for HRT users compared with nonusers and 0.77 (95% CI, 0.31
      1.67) compared with men. No similar effect was seen with calcium or multivitamin
      use. Almost all of the HRT-related reduction in incidence reflected former use of
      HRT (9 cases among 490 women; adjusted HR, 0.33 [95% CI, 0.15-0.65]). There was
      no effect with current HRT use (17 cases among 576 women; adjusted HR, 1.08 [95%
      CI, 0.59-1.91]) unless duration of treatment exceeded 10 years (6 cases among 344
      women; adjusted HR, 0.55 [95% CI, 0.21-1.23]). CONCLUSIONS: Prior HRT use is
      associated with reduced risk of AD, but there is no apparent benefit with current
      HRT use unless such use has exceeded 10 years.

PMID- 12413372
TI  - Mortality at 1 year with combination platelet glycoprotein IIb/IIIa inhibition
      and reduced-dose fibrinolytic therapy vs conventional fibrinolytic therapy for
      acute myocardial infarction: GUSTO V randomized trial.
AB  - CONTEXT: Among patients with acute myocardial infarction, combination reperfusion
      therapy with a platelet glycoprotein IIb/IIIa receptor inhibitor (abciximab) and
      a half dose of a plasminogen activator (reteplase) did not significantly reduce
      mortality at 30 days compared with a full dose of reteplase. Rates of nonfatal
      ischemic complications were significantly diminished. OBJECTIVE: To determine if
      the beneficial effects of abciximab and reteplase (combination therapy) on early
      nonfatal complications would translate into a reduction in the risk of death by 1
      year. DESIGN, SETTING, AND PATIENTS: One-year follow-up of a randomized
      controlled trial (Global Use of Strategies To Open Coronary Arteries [GUSTO] V).
      Of 16 588 patients who had been treated in 820 community and referral hospitals
      in 20 countries between July 1999 and February 2001, mortality data were
      available for 16 453 (99.2%). INTERVENTION: Patients were randomly assigned to
      receive (intravenously) a standard dose of reteplase (two 10-U boluses, 30
      minutes apart) or the combination of a standard dose of abciximab (0.25 mg/kg
      bolus, 0.125 microg/kg per minute infusion [maximum 10 micro g/min for 12 hours])
      and a half dose of reteplase (two 5-U boluses, 30 minutes apart). MAIN OUTCOME
      MEASURE: One-year all-cause mortality rates. RESULTS: All-cause mortality at 1
      year occurred in 692 (8.38%) of 8260 patients in the reteplase group and 698
      (8.38%) of the 8328 patients in the combination therapy group (hazard ratio [HR],
      1.00; 95% confidence interval [CI], 0.90-1.11; P>.99). Reinfarction within the
      first 7 days occurred in 3.5% of patients in the reteplase group and 2.3% of
      patients in the combination therapy group, and was significantly associated with
      1-year mortality (22.6% in patients with reinfarction vs 8.0% in patients without
      reinfarction; HR, 3.08; 95% CI, 2.53-3.75; P<.001). However, treatment assignment
      did not significantly influence time of mortality regardless of reinfarction
      status. CONCLUSION: Combination therapy (abciximab and reteplase) did not reduce
      mortality over 1 year compared with fibrinolytic therapy with reteplase alone.

PMID- 12413373
TI  - Crosswalk markings and the risk of pedestrian-motor vehicle collisions in older
      pedestrians.
AB  - CONTEXT: Motor vehicles struck and killed 4739 pedestrians in the United States
      in the year 2000. Older pedestrians are at especially high risk. OBJECTIVE: To
      determine whether crosswalk markings at urban intersections influence the risk of
      injury to older pedestrians. DESIGN: Case-control study in which the units of
      study were crossing locations. SETTING: Six cities in Washington and California,
      with case accrual from February 1995 through January 1999. PARTICIPANTS: A total
      of 282 case sites were street-crossing locations at an intersection where a
      pedestrian aged 65 years or older had been struck by a motor vehicle while
      crossing the street; 564 control sites were other nearby crossings that were
      matched to case sites based on street classification. Trained observers recorded
      environmental characteristics, vehicular traffic flow and speed, and pedestrian
      use at each site on the same day of the week and time of day as when the case
      event had occurred. MAIN OUTCOME MEASURE: Risk of pedestrian-motor vehicle
      collision involving an older pedestrian. RESULTS: After adjusting for pedestrian
      flow, vehicle flow, crossing length, and signalization, risk of a pedestrian
      motor vehicle collision was 2.1-fold greater (95% confidence interval, 1.1-4.0)
      at sites with a marked crosswalk. Almost all of the excess risk was due to 3.6
      fold (95% confidence interval, 1.7-7.9) higher risk associated with marked
      crosswalks at sites with no traffic signal or stop sign. CONCLUSIONS: Crosswalk
      markings appear associated with increased risk of pedestrian-motor vehicle
      collision to older pedestrians at sites where no signal or stop sign is present
      to halt traffic.

PMID- 12413374
TI  - Pathophysiological characterization of isolated diastolic heart failure in
      comparison to systolic heart failure.
AB  - CONTEXT: Many older patients with symptoms of congestive heart failure have a
      preserved left ventricular ejection fraction (LVEF). However, the pathophysiology
      of this disorder, presumptively termed diastolic heart failure (DHF), is not well
      characterized and it is unknown whether it represents true heart failure.
      OBJECTIVE: To assess the 4 key pathophysiological domains that characterize
      classic heart failure by systematically performing measurements in older patients
      with presumed DHF and comparing these results with those from age-matched healthy
      volunteers and patients with classic systolic heart failure (SHF). DESIGN AND
      SETTING: Observational clinical investigation conducted in 1998 in a general
      community and teaching hospital in Winston-Salem, NC. PARTICIPANTS: A total of
      147 subjects aged at least 60 years. Fifty-nine had isolated DHF defined as
      clinically presumed heart failure, LVEF of at least 50%, and no evidence of
      significant coronary, valvular, or pulmonary disease. Sixty had typical SHF (LVEF
      < or =35%). Twenty-eight were age-matched healthy volunteer controls. MAIN
      OUTCOME MEASURES: Left ventricular structure and function, exercise capacity,
      neuroendocrine function, and quality of life. RESULTS: By echocardiography, mean
      (SE) LVEF was 60% (2%) in patients with DHF vs 31% (2%) in those with SHF and 54%
      (2%) in controls. Mean (SE) LV mass-volume ratio was markedly increased in
      patients with DHF (2.12 [0.14] g/mL) vs those with SHF (1.22 [0.14] g/mL)
      (P<.001) and vs controls (1.49 [0.17] g/mL) (P =.002). Peak oxygen consumption by
      expired gas analysis during cycle ergometry was similar in the DHF and SHF groups
      (14.2 [0.5] and 13.1 [0.5] mL/kg per minute, respectively; P =.40) and in both
      was markedly reduced compared with healthy controls (19.9 [0.7] mL/kg per minute)
      (P =.001 for both). Ventilatory anaerobic threshold was similar in the DHF and
      SHF groups (9.1 [0.3] and 8.7 [0.3] mL/kg per minute, respectively; P<.001) and
      in both was reduced compared with healthy controls (11.5 [0.4] mL/kg per minute)
      (P<.001). Norepinephrine levels were similar in the DHF (306 [64] pg/mL) and SHF
      (287 [62] pg/mL) groups (P =.56) and in both were markedly increased vs healthy
      controls (169 [80] pg/mL) (P =.007 and.03, respectively). Brain natriuretic
      peptide was substantially increased in both the DHF (56 [30] pg/mL) and the SHF
      (154 [28] pg/mL) groups compared with healthy controls (3 [38] pg/mL) (P =.02
      and.001, respectively). Quality-of-life decrement score as assessed by the
      Minnesota Living with Heart Failure Questionnaire was substantially increased
      from the benchmark score of 10 in both groups (SHF: 43.8 [3.9]; DHF: 24.8 [4.4]).
      CONCLUSION: Patients with isolated DHF have similar though not as severe
      pathophysiologic characteristics compared with patients with typical SHF,
      including severely reduced exercise capacity, neuroendocrine activation, and
      impaired quality of life.

PMID- 12413375
TI  - Physician staffing patterns and clinical outcomes in critically ill patients: a
      systematic review.
AB  - CONTEXT: Intensive care unit (ICU) physician staffing varies widely, and its
      association with patient outcomes remains unclear. OBJECTIVE: To evaluate the
      association between ICU physician staffing and patient outcomes. DATA SOURCES: We
      searched MEDLINE (January 1, 1965, through September 30, 2001) for the following
      medical subject heading (MeSH) terms: intensive care units, ICU, health
      resources/utilization, hospitalization, medical staff, hospital organization and
      administration, personnel staffing and scheduling, length of stay, and LOS. We
      also used the following text words: staffing, intensivist, critical, care, and
      specialist. To identify observational studies, we added the MeSH terms case
      control study and retrospective study. Although we searched for non-English
      language citations, we reviewed only English-language articles. We also searched
      EMBASE, HealthStar (Health Services, Technology, Administration, and Research),
      and HSRPROJ (Health Services Research Projects in Progress) via Internet Grateful
      Med and The Cochrane Library and hand searched abstract proceedings from
      intensive care national scientific meetings (January 1, 1994, through December
      31, 2001). STUDY SELECTION: We selected randomized and observational controlled
      trials of critically ill adults or children. Studies examined ICU attending
      physician staffing strategies and the outcomes of hospital and ICU mortality and
      length of stay (LOS). Studies were selected and critiqued by 2 reviewers. We
      reviewed 2590 abstracts and identified 26 relevant observational studies (of
      which 1 included 2 comparisons), resulting in 27 comparisons of alternative
      staffing strategies. Twenty studies focused on a single ICU. DATA SYNTHESIS: We
      grouped ICU physician staffing into low-intensity (no intensivist or elective
      intensivist consultation) or high-intensity (mandatory intensivist consultation
      or closed ICU [all care directed by intensivist]) groups. High-intensity staffing
      was associated with lower hospital mortality in 16 of 17 studies (94%) and with a
      pooled estimate of the relative risk for hospital mortality of 0.71 (95%
      confidence interval [CI], 0.62-0.82). High-intensity staffing was associated with
      a lower ICU mortality in 14 of 15 studies (93%) and with a pooled estimate of the
      relative risk for ICU mortality of 0.61 (95% CI, 0.50-0.75). High-intensity
      staffing reduced hospital LOS in 10 of 13 studies and reduced ICU LOS in 14 of 18
      studies without case-mix adjustment. High-intensity staffing was associated with
      reduced hospital LOS in 2 of 4 studies and ICU LOS in both studies that adjusted
      for case mix. No study found increased LOS with high-intensity staffing after
      case-mix adjustment. CONCLUSIONS: High-intensity vs low-intensity ICU physician
      staffing is associated with reduced hospital and ICU mortality and hospital and
      ICU LOS.

PMID- 12413376
TI  - Prospective screening for pediatric mitochondrial trifunctional protein defects
      in pregnancies complicated by liver disease.
AB  - CONTEXT: Acute fatty liver of pregnancy (AFLP) and hemolysis, elevated liver
      enzymes, and low platelets (HELLP) syndrome are serious complications of
      pregnancy. Studies in families with recessively inherited mitochondrial
      trifunctional protein defects documented an association between these maternal
      illnesses and fetal deficiency of long-chain 3-hydroxyacyl coenzyme A
      dehydrogenase; this enzyme resides in the alpha subunit of the trifunctional
      protein and catalyzes the third step in long-chain fatty acid beta oxidation.
      OBJECTIVE: To estimate the frequency of fetal long-chain 3-hydroxyacyl coenzyme A
      dehydrogenase deficiency in pregnancies complicated by AFLP or HELLP syndrome.
      DESIGN, SETTING, AND SUBJECTS: Cohort study in which 108 consecutive blood
      samples from women who developed AFLP or HELLP syndrome, from their offspring, or
      from their partners were referred to our laboratory for molecular screening from
      January 1997 to December 2001. Twenty-seven women had AFLP and 81 had HELLP
      syndrome. We screened the DNA for mutations in the alpha subunit of the
      trifunctional protein. MAIN OUTCOME MEASURE: Presence of mutations that cause 3
      hydroxyacyl coenzyme A dehydrogenase deficiency in the offspring. RESULTS: We
      detected mutations causing pediatric long-chain 3-hydroxyacyl coenzyme A
      dehydrogenase deficiency in 5 families (19%) with maternal history of AFLP (95%
      confidence interval, 9%-54%). The maternal allele carried a prevalent glutamic
      acid 474 to glutamine (E474Q) mutation. The paternal allele carried the E474Q
      mutation in 3 families and a stop codon mutation in the other 2 families. Only 1
      woman with HELLP syndrome was heterozygous for the E474Q mutation; no mutations
      were detected in the newborn. CONCLUSION: The association between AFLP and the
      E474Q mutation in the fetus is significant. Screening newborns for this mutation
      in pregnancies complicated by AFLP could allow early diagnosis and treatment in
      newborns and genetic counseling and prenatal diagnosis in subsequent pregnancies
      in affected families.

PMID- 12413377
TI  - Hyperglycemia in acutely ill patients.

PMID- 12413378
TI  - Hormone therapy and risk of Alzheimer disease: a critical time.

PMID- 12413379
TI  - Crosswalk markings and motor vehicle collisions involving older pedestrians.

PMID- 12413380
TI  - Pain management: a call for papers.

PMID- 12413382
TI  - Societal change to prevent obesity.

PMID- 12413383
TI  - Undertreatment of obesity.

PMID- 12413384
TI  - A public health approach to decreasing obesity.

PMID- 12413385
TI  - Food litigation: lessons from the tobacco wars.

PMID- 12413386
TI  - The impact of public schools on childhood obesity.

PMID- 12413387
TI  - The growing political movement against soft drinks in schools.

PMID- 12413394
TI  - JAMA patient page. Pedestrian safety.

PMID- 12413395
TI  - Conformational change in elastase following complexation with alpha1-proteinase
      inhibitor: a CD investigation.
AB  - The CD spectrum of porcine pancreatic elastase in complex with alpha1-proteinase
      inhibitor (alpha1-PI) was calculated by subtracting the CD spectrum of the
      proteolytically cleaved inhibitor from that of the elastase-alpha1-PI complex.
      Elastase undergoes a moderate secondary structure change: its beta-structure is
      partially disordered while its alpha-helix content is poorly affected. In
      contrast, its tertiary structure undergoes a significant structural loosening
      upon complexation. These alterations have been compared with those following
      chemical and thermal unfolding of free elastase. Inhibitor-bound elastase and the
      denaturation intermediate of free elastase share secondary but not tertiary
      structural features. On the other hand, both free and complexed elastases undergo
      a single-step transition in tertiary structure upon thermal unfolding. These data
      are discussed in terms of the inhibition and structural modification of elastase
      induced by alpha1-PI observed by previous investigators.

PMID- 12413396
TI  - Thermodynamic characterization of a tetrahaem cytochrome isolated from a
      facultative aerobic bacterium, Shewanella frigidimarina: a putative redox model
      for flavocytochrome c3.
AB  - The facultative aerobic bacterium Shewanella frigidimarina produces a small c
      type tetrahaem cytochrome (86 residues) under anaerobic growth conditions. This
      protein is involved in the respiration of iron and shares 42% sequence identity
      with the N-terminal domain of a soluble flavocytochrome, isolated from the
      periplasm of the same bacterium, which also contains four c -type haem groups.
      The thermodynamic properties of the redox centres and of an ionizable centre in
      the tetrahaem cytochrome were determined using NMR and visible spectroscopy
      techniques. This is the first detailed thermodynamic study performed on a
      tetrahaem cytochrome isolated from a facultative aerobic bacterium and reveals
      that this protein presents unique features. The redox centres have negative and
      different redox potentials, which are modulated by redox interactions between the
      four haems (covering a range of 8-56 mV) and by redox-Bohr interactions between
      the haems and an ionizable centre (-4 to -36 mV) located in close proximity to
      haem III. All of the interactions between the five centres are clearly dominated
      by electrostatic effects and the microscopic reduction potential of haem III is
      the one most affected by the oxidation of the other haems and by the protonation
      state of the molecule. Altogether, this study indicates that the tetrahaem
      cytochrome isolated from S. frigidimarina (Sfc) has the thermodynamic properties
      to work as an electron wire between its redox partners. Considering the high
      degree of sequence identity between Sfc and the cytochrome domain of
      flavocytochrome c(3), the structural similarities of the haem core, and that the
      macroscopic potentials are also identical, the results obtained in this work are
      rationalized in order to put forward a putative redox model for flavocytochrome
      c(3).

PMID- 12413397
TI  - Granular gland transcriptomes in stimulated amphibian skin secretions.
AB  - Amphibian defensive skin secretions are complex, species-specific cocktails of
      biologically active molecules, including many uncharacterized peptides. The study
      of such secretions for novel peptide discovery is time-limited, as amphibians are
      in rapid global decline. While secretion proteome analysis is non-lethal,
      transcriptome analysis has until now required killing of specimens prior to skin
      dissection for cDNA library construction. Here we present the discovery that
      polyadenylated mRNAs encoding dermal granular gland peptides are present in
      defensive skin secretions, stabilized by endogenous nucleic acid-binding
      amphipathic peptides. Thus parallel secretory proteome and transcriptome analyses
      can be performed without killing the specimen in this model amphibian system--a
      finding that has important implications in conservation of biodiversity within
      this threatened vertebrate taxon and whose mechanistics may have broader
      implications in biomolecular science.

PMID- 12413398
TI  - Ara12 subtilisin-like protease from Arabidopsis thaliana: purification, substrate
      specificity and tissue localization.
AB  - A C-terminal portion of Ara12 subtilisin-like protease (residues 542-757) was
      expressed in Escherichia coli cells as a fusion protein bound to maltose binding
      protein. Polyclonal antisera raised against the expressed protein were used to
      examine the tissue specificity and subcellular localization of Ara12. The
      protease was found predominantly in the silique and stem of plants, but was
      hardly detectable in leaf and not seen in root tissue. The distribution observed
      using immunological techniques is different from that seen by an RNA analysis
      study, which demonstrated similar mRNA abundance in the stem and leaves. Using
      immunogold labelling, Ara12 was shown to have an extracellular localization and
      was found in the intercellular spaces in stem tissue. Ara12 protease was purified
      to homogeneity from Arabidopsis thaliana cell suspension cultures by anion
      exchange and hydrophobic interaction chromatography. Proteolytic activity of
      Ara12 was inhibited by a number of serine protease inhibitors, but was almost
      unaffected by inhibitors of other catalytic classes of proteases. Optimal
      proteolytic activity was displayed under acidic conditions (pH 5.0). Ara12
      activity was relatively thermostable and was stimulated in the presence of Ca2+
      ions. Substrate specificity studies were conducted using a series of internally
      quenched fluorogenic peptide substrates. At the P1 position of substrates,
      hydrophobic residues, such as Phe and Ala, were preferred to Arg, whilst at the
      P1' position, Asp, Leu and Ala were most favoured. Possible functions of Ara12
      are discussed in the light of the involvement of a number of plant subtilisin
      like proteases in morphogenesis.

PMID- 12413399
TI  - Hypoxic activation of the atrial natriuretic peptide gene promoter through direct
      and indirect actions of hypoxia-inducible factor-1.
AB  - Atrial natriuretic peptide (ANP) is a cardiac peptide, the transcription of which
      is up-regulated in the ischaemic ventricle. However, the molecular mechanism of
      ANP induction is unclear. This study demonstrated that ANP mRNA expression in rat
      ventricular myocardium is induced in an early phase of ischaemia, preceded by
      hypoxia-inducible factor-1 (HIF-1) alpha expression. The ANP gene was also
      induced by hypoxia or HIF-1 inducers such as CoCl2 and desferrioxamine in H9c2
      and neonatal cardiomyocytes. The 2307 bp 5'-flanking region of the rat ANP gene
      was cloned and fused to the luciferase gene. Evidence of the promoter activity
      was only apparent in the myocytes and was induced by hypoxia and HIF-1 inducers.
      The overexpression of HIF-1alpha markedly enhanced ANP promoter activity, and a
      dominant-negative isoform completely suppressed it. We demonstrated that the
      promoter regions are essential for hypoxic ANP induction. One promoter region,
      containing the HIF-1-binding sequence, is regulated directly by HIF-1. The other
      region is also activated by HIF-1 despite having no HIF-1-binding sequence. These
      results suggest that HIF-1 enhances the transactivation of the ANP gene in
      hypoxic myocytes, implying that stimulation of the ANP promoter by HIF-1 may in
      fact be responsible for the induction of the ANP gene in ischaemic ventricular
      myocardium.

PMID- 12413400
TI  - Automated modelling of signal transduction networks.
AB  - BACKGROUND: Intracellular signal transduction is achieved by networks of proteins
      and small molecules that transmit information from the cell surface to the
      nucleus, where they ultimately effect transcriptional changes. Understanding the
      mechanisms cells use to accomplish this important process requires a detailed
      molecular description of the networks involved. RESULTS: We have developed a
      computational approach for generating static models of signal transduction
      networks which utilizes protein-interaction maps generated from large-scale two
      hybrid screens and expression profiles from DNA microarrays. Networks are
      determined entirely by integrating protein-protein interaction data with
      microarray expression data, without prior knowledge of any pathway intermediates.
      In effect, this is equivalent to extracting subnetworks of the protein
      interaction dataset whose members have the most correlated expression profiles.
      CONCLUSION: We show that our technique accurately reconstructs MAP Kinase
      signaling networks in Saccharomyces cerevisiae. This approach should enhance our
      ability to model signaling networks and to discover new components of known
      networks. More generally, it provides a method for synthesizing molecular data,
      either individual transcript abundance measurements or pairwise protein
      interactions, into higher level structures, such as pathways and networks.

PMID- 12413401
TI  - Epidural lysis of adhesions and myeloscopy.
AB  - Chronic low back pain is one of the most common ailments in modern medicine, with
      as many as 79% of patients with acute pain continuing to suffer with chronic or
      recurrent low back pain 1 year after its onset. Lumbar epidural fibrosis and post
      lumbar laminectomy syndrome are increasingly recognized as being responsible for
      persistent low back pain. Estimations show that approximately 5% to 40% of lumbar
      surgeries result in failed back surgery syndrome. Epidural adhesiolysis with
      myeloscopy is an interventional technique based on the premise that the three
      dimensional visualization of the contents of the epidural space provides the
      physician with the ability to directly visualize the structures, perform
      appropriate adhesiolysis, and administer drugs specifically to the target. This
      review describes pathophysiologic aspects, purposes and goals, rationale and
      indications, complications, and effectiveness of epidural lysis of adhesions with
      myeloscopy.

PMID- 12413402
TI  - Percutaneous vertebroplasty in the management of a patient with malignant pain
      and associated osteolytic compression fractures.
AB  - Percutaneous vertebroplasty is a minimally invasive procedure that is effective
      in the treatment of pain resulting from pathologic compression fractures,
      osteolytic bone metastases from solid tumors, myeloma, vertebral hemangioma, and
      osteoporotic compression fractures. A discussion of a patient with severe,
      aggressive metastatic breast cancer to the spine with compression and osteolysis
      of multiple lumbar vertebral bodies is presented. Despite treatment with opiates,
      chemotherapy, radiation therapy, and the implantation of a morphine pump, her
      pain was not adequately treated until she underwent multilevel vertebroplasty.
      The clinical and technical application of vertebroplasty in the context of the
      management of vertebral pain of malignant origin is presented as an integral part
      of multidisciplinary pain management.

PMID- 12413403
TI  - Acupuncture in pain medicine: an integrated approach to the management of
      refractory pain.
AB  - As the acupuncture nomenclature permeates medical literature, the artificial
      barriers to integration of acupuncture and allopathic medicine are disappearing.
      More patients are looking to their physicians for guidance on how to incorporate
      acupuncture into their health care, and pain physicians are accepting the
      challenge. Similar to allopathic medicine, acupuncture is an intricate diagnostic
      and therapeutic system. However, for practicing physicians, mastery of the skills
      necessary for safe and effective treatment of many conditions is well within
      reach. Used in an integrated medical model, acupuncture is well suited to deal
      with many of the functional problems that allopathic medicine is not equipped to
      address. The result is patient and physician satisfaction.

PMID- 12413404
TI  - Drug infusions for the diagnosis and treatment of chronic pain.
AB  - Diagnostic infusion therapy has several advantages over other routes of drug
      administration in the management of chronic pain. Although systemic side effects
      may occur, the procedure is relatively noninvasive and is generally well
      tolerated by patients. Infusion techniques have a potential use in the blinded
      evaluation of a patient's response to a specific therapy, and thus may minimize
      placebo responses associated with the more invasive diagnostic nerve blocks.
      Infusion tests may be useful prognostic indicators of the potential efficacy of a
      class of oral drugs in a patient. This article reviews the scientific and
      clinical background behind the major classes of drugs used in diagnostic infusion
      testing, namely local anesthetics, opioids, and a-adrenergic blockers. Clinical
      application of these agents in the management of chronic pain also is outlined.

PMID- 12413405
TI  - Botulinum toxin for the treatment of musculoskeletal pain and spasm.
AB  - The impressive pain relief experienced by sufferers of dystonia and spasticity
      from intramuscular injections of botulinum toxin suggested that patients with
      other chronic, musculoskeletal pain conditions also may benefit. However, there
      have been relatively few placebo-controlled studies of botulinum toxin in such
      non-neurologic conditions as myofascial pain syndrome, chronic neck and low back
      pain, and fibromyalgia; the results of these studies have not been impressive.
      One explanation for the lack of positive findings may be the lack of clinically
      evident muscle spasms (overactivity), despite the presence of muscle tenderness,
      tightness, or trigger points. Clinical observations of pain relief from
      injections of botulinum toxin for dystonia and spasticity and its apparent
      efficacy in treating migraine suggest an anti-nociceptive action independent of
      its neuromuscular junction-blocking action. Evidence from animal experiments
      supports this notion, and other data provide plausible physiologic mechanisms in
      the periphery and central nervous systems. These involve modulation of the
      activity of the neurotransmitters glutamate, substance P, calcitonin gene-related
      peptide, enkephalins, and others. However, even if botulinum toxin is firmly
      established as an analgesic, there is insufficient clinical evidence of its
      efficacy in treating non-neurologic, chronic, musculoskeletal pain conditions.

PMID- 12413406
TI  - Cognitive-behavioral issues in the treatment and management of chronic daily
      headache.
AB  - Chronic daily headache is a heterogeneous group of daily or near-daily headaches
      that afflicts close to 5% of the general population and accounts for close to 35%
      to 40% of patients at headache centers. First-line drug or cognitive-behavioral
      therapies administered alone have minimal impact on reducing the frequency or
      severity of headaches. However, combined drug and cognitive-behavioral therapy
      shows promise in providing the most benefit for this often intractable condition.
      Cognitive-behavioral therapies focus on preventing mild pain from becoming
      disabling pain, improving headache-related disability, affective distress, and
      quality of life, and reducing overreliance on medication. For cognitive
      behavioral therapies to be effective, it is important to address complicating
      factors, including medication overuse, psychiatric comorbidity, stress and poor
      coping, and sleep disturbance.

PMID- 12413407
TI  - Prophylaxis for chronic daily headache and chronic migraine with neuronal
      stabilizing agents.
AB  - Approaches to acute and prophylactic migraine and headache treatment are evolving
      as our understanding of some of the underlying pathophysiology improves. This
      article focuses on the emerging use of medications originally introduced for the
      treatment of seizures (anticonvulsants) as primary therapy for eradicating or
      reducing migraine and chronic daily headaches. A more accurate term for their
      pharmacologic mechanisms, if they are used to treat headaches and pain disorders,
      is neuromodulating or neuronal stabilizing agents. This term refers to their many
      cellular actions to reduce pain transmission supraspinally, in the spinal cord,
      and in the brainstem.

PMID- 12413408
TI  - Risk factors for chronic daily headache.
AB  - There are many people who experience headaches that are independent of illness,
      injury, or hangover. Approximately 4% of the population suffer from headaches on
      a daily or near-daily basis. It is apparent that patients with chronic daily
      headache in community samples differ in important ways from patients with chronic
      daily headache in subspecialty clinics. In this manuscript, we review clinic
      based data on risk factors for chronic daily headache and summarize the current
      data on the epidemiology of chronic daily headache.

PMID- 12413409
TI  - Psychiatric comorbidity in chronic daily headache: pathophysiology, etiology, and
      diagnosis.
AB  - Chronic daily headache is a challenge for clinical practitioners and researchers.
      Etiology, pathophysiology, diagnosis, treatment, and prognosis of chronic daily
      headache present many questions that need answers. A chance occurrence of
      psychiatric disorders (mostly anxiety and mood disorders) in patients with
      chronic daily headache should not be excluded. This results in the need to
      understand the involved mechanisms, which requires us to draw new insights into
      the etiology, diagnosis, treatment, and prognosis of chronic daily headache.
      Psychiatric comorbidity seems to be cross-related to each of these dimensions,
      although the meanings need to be drawn. Each domain is discussed, considering the
      status of knowledge and stressing the future lines of research.

PMID- 12413410
TI  - Chronic headache and sleep disturbance.
AB  - Headache and sleep disturbance are common health complaints. Both complaints
      often co-exist in the same patient, leading some to suspect a causal relationship
      or common underlying pathology. However, the empirical literature in this area is
      limited. Some attempts have been made to explore the relationship between
      headache and sleep disturbance, but few consistencies have emerged in the
      literature. There is no accepted model for understanding the link between
      headache and sleep disturbance. This paper reviews the available literature
      concerning comorbid headache and sleep disturbance and offers some preliminary
      suggestions based on the available literature to guide their evaluation and
      management. Information specific to the relationship between sleep disturbance
      and chronic daily headache, where available, is highlighted.

PMID- 12413411
TI  - Psychiatric comorbidity of chronic daily headache: impact, treatment, outcome,
      and future studies.
AB  - Patients with chronic daily headache have high frequencies of psychiatric
      comorbidity or psychologic distress in clinic-based studies. The presence of
      psychologic distress contributes to poor quality of life in patients with chronic
      daily headache. Antidepressants are effective in the treatment of chronic daily
      headache and its comorbid depression symptoms, although there is a discrepancy in
      the treatment response between chronic daily headache and comorbid depression.
      Comorbid major depression was a poor outcome predictor for chronic daily headache
      in clinic-based studies; however, the presence of psychologic distress did not
      predict the prognosis in population-based studies.A systematic investigation of
      psychiatric comorbidity is emphasized in patients with chronic daily headache and
      aims at a more comprehensive clinical management. Large-scale, longitudinal
      surveys and clinical trials specifically for psychiatric comorbidity of chronic
      daily headache are warranted to answer whether a syndromic relationship exists
      between different chronic daily headache subtypes and different psychiatric
      disorders, and to provide evidence-based treatment options for this large group
      of patients.

PMID- 12413413
TI  - Production methods for gene transfer vectors based on adeno-associated virus
      serotypes.
AB  - Vectors derived from adeno-associated virus serotype 2 (AAV-2) represent a most
      promising tool for human gene transfer because these vectors are neither
      pathogenic nor toxic to the target cell, and allow long-term gene expression in a
      large variety of tissues. However, they are rather inefficient at infecting a
      number of clinically relevant cell types, and transduction by these vectors is
      likely hampered by neutralizing antibodies that are highly prevalent in the human
      population. Therefore, an increasing number of researchers are currently turning
      their attention to the five other serotypes of AAV, to try and develop these as
      novel vectors for human gene transfer, hoping to overcome the problems associated
      with AAV-2 vectors. Here I describe and discuss the methodology to produce these
      alternative AAV vectors in tissue culture. In detail, two strategies are compared
      that rely on transfection of cells in culture with either two or three plasmids,
      containing the AAV vector genome and encoding AAV and adenoviral helper
      functions. Either of these protocols can be used to package a recombinant AAV
      genome into capsids of its own serotype (generation of "real" serotypes) or to
      "cross-package" this vector DNA into capsids derived from another AAV serotype
      ("pseudotyping"). As these approaches are still in their early stages, the
      existing limitations of current technology are discussed, and possible further
      improvements proposed.

PMID- 12413414
TI  - Production and purification of serotype 1, 2, and 5 recombinant adeno-associated
      viral vectors.
AB  - Recombinant adeno-associated viral (rAAV) vectors based on serotype 2 are
      currently being evaluated most extensively in animals and human clinical trials.
      rAAV vectors constructed from other AAV serotypes (serotypes 1, 3, 4, 5, and 6)
      can transduce certain tissues more efficiently and with different specificity
      than rAAV2 vectors in animal models. Here, we describe reagents and methods for
      the production and purification of AAV2 inverted terminal repeat-containing
      vectors pseudotyped with AAV1 or AAV5 capsids. To facilitate pseudotyping,
      AAV2rep/AAV1cap and AAV2rep/AAV5cap helper plasmids were constructed in an
      adenoviral plasmid backbone. The resultant plasmids, pXYZ1 and pXYZ5, were used
      to produce rAAV1 and rAAV5 vectors, respectively, by transient transfection.
      Since neither AAV5 nor AAV1 binds to the heparin affinity chromatography resin
      used to purify rAAV2 vectors, purification protocols were developed based on
      anion-exchange chromatography. The purified vector stocks are 99% pure with
      titers of 1 x 10(12) to 1 x 10(13)vector genomes/ml.

PMID- 12413415
TI  - Autonomous parvovirus vectors.
AB  - Parvoviruses are small, icosahedral viruses (approximately 25 nm) containing a
      single-strand DNA genome (approximately 5 kb) with hairpin termini. Autonomous
      parvoviruses (APVs) are found in many species; they do not require a helper virus
      for replication but they do require proliferating cells (S-phase functions) and,
      in some cases, tissue-specific factors. APVs can protect animals from spontaneous
      or experimental tumors, leading to consideration of these viruses, and vectors
      derived from them, as anticancer agents. Vector development has focused on three
      rodent APVs that can infect human cells, namely, LuIII, MVM, and H1. LuIII-based
      vectors with complete replacement of the viral coding sequences can direct
      transient or persistent expression of transgenes in cell culture. MVM-based and
      H1-based vectors with substitution of transgenes for the viral capsid sequences
      retain viral nonstructural (NS) coding sequences and express the NS1 protein. The
      latter serves to amplify the vector genome in target cells, potentially
      contributing to antitumor activity. APV vectors have packaging capacity for
      foreign DNA of approximately 4.8 kb, a limit that probably cannot be exceeded by
      more than a few percent. LuIII vectors can be pseudotyped with capsid proteins
      from related APVs, a promising strategy for controlling tissue tropism and
      circumventing immune responses to repeated administration. Initial success has
      been achieved in targeting such a pseudotyped vector by genetic modification of
      the capsid. Subject to advances in production and purification methods, APV
      vectors have potential as gene transfer agents for experimental and therapeutic
      use, particularly for cancer therapy.

PMID- 12413416
TI  - Adeno-associated viral vectors as agents for gene delivery: application in
      disorders and trauma of the central nervous system.
AB  - The use of viral vectors as agents for gene delivery provides a direct approach
      to manipulate gene expression in the mammalian central nervous system (CNS). The
      present article describes in detail the methodology for the injection of viral
      vectors, in particular adeno-associated virus (AAV) vectors, into the adult rat
      brain and spinal cord to obtain reproducible and successful transduction of
      neural tissue. Surgical and injection procedures are based on the extensive
      experience of our laboratory to deliver viral vectors to the adult rat CNS and
      have been optimized over the years. First, a brief overview is presented on the
      use and potential of viral vectors to treat neurological disorders or trauma of
      the CNS. Next, methods to deliver AAV vectors to the rat brain and spinal cord
      are described in great detail with the intent of providing a practical guide to
      potential users. Finally, some data on the experimental outcomes following AAV
      vector-mediated gene transfer to the adult rat CNS are presented as is a brief
      discussion on both the advantages and limitations of AAV vectors as tools for
      somatic gene transfer.

PMID- 12413417
TI  - Application of adeno-associated viral vectors in behavioral research.
AB  - Viral vectors afford the capability of genetically manipulating the expression of
      neurotransmitters, neuropeptides, hormones, and their receptors in specific brain
      sites of adult animals of any species. Hence, they are a powerful tool for
      investigating the neurochemistry underlying complex cognitive processes and
      behaviors. Here we discuss how the recombinant adeno-associated virus (rAAV) can
      be engineered for use in neurobehavioral studies, techniques for site-specific
      delivery of vector into the brain, characterization of expression profiles, and
      biosafety issues. Finally, we discuss issues of experimental design and
      interpretation of behavioral results in viral vector studies.

PMID- 12413418
TI  - Adeno-associated virus-mediated gene transfer to the neonatal brain.
AB  - For many metabolic diseases, early treatment is necessary to prevent irreversible
      developmental damage. This is particularly true for childhood diseases that
      affect the central nervous system (CNS). The development of effective techniques
      for gene transfer to the neonatal brain would provide a new set of therapeutic
      options for many of these disorders. Vectors based on adeno-associated virus
      (AAV) have shown promise as agents for neonatal CNS transduction. In preclinical
      animal models, a single treatment with AAV vectors at birth has been shown to
      produce persistent CNS expression of transduced genes into adulthood.
      Transduction of the neonatal brain has been accomplished by a variety of methods,
      including direct intraparenchymal injection, intraventricular infusion, and
      intravenous administration. Of these methods, intraparenchymal injection provides
      the highest levels of localized activity, while intraventricular infusion results
      in a more widespread distribution of activity when performed in the neonate. Here
      we describe a method for direct, intraparenchymal injection of AAV into the
      neonatal brain. This technique provides a method for investigators to evaluate
      the effects of in vivo expression of exogenous genes on the process of early
      brain development.

PMID- 12413419
TI  - Recombinant adeno-associated virus vector design and gene expression in the
      mammalian brain.
AB  - Efficiency and stability of recombinant adeno-associated virus (rAAV)-mediated
      gene expression within the mammalian brain are determined by several factors.
      These include the dose of infectious particles, the purity of the vector stock,
      the serotype of rAAV, the route of administration, and the intrinsic properties,
      most notably the rAAV receptor density, of the targeted area. Furthermore, the
      choice of appropriate regulatory elements in rAAV vector design is of fundamental
      importance to achieve high-level sustained in vivo transcription and translation.
      This review summarizes the characteristics of various transcriptional and
      posttranscriptional regulatory elements, and highlights their influence on the
      expression performance of rAAV vectors in the mammalian brain.

PMID- 12413420
TI  - Regulation of gene expression in adeno-associated virus vectors in the brain.
AB  - Regulated adeno-associated virus (AAV) vectors have broad utility in both
      experimental and applied gene therapy, and to date, several regulation systems
      have exhibited a capability to control gene expression from viral vectors over
      two orders of magnitude. The tetracycline responsive system has been the most
      used in AAV, although other regulation systems such as RU486- and rapamycin
      responsive systems are reasonable options. AAV vectors influence how regulation
      systems function by several mechanisms, leading to increased background gene
      expression and restricted induction. Methods to reduce background expression
      continue to be explored and systems not yet tried in AAV may prove quite
      functional. Although regulated promoters are often assumed to exhibit ubiquitous
      expression, the tropism of different neuronal subtypes can be altered
      dramatically by changing promoters in recombinant AAV vectors. Differences in
      promoter-directed tropism have significant consequences for proper expression of
      gene products as well as the utility of dual vector regulation. Thus regulated
      vector systems must be carefully optimized for each application.

PMID- 12413421
TI  - Promoters and regulatory elements that improve adeno-associated virus transgene
      expression in the brain.
AB  - Since the first demonstration of central nervous system (CNS) transduction with
      recombinant adeno-associated virus, improvements in vector production and
      promoter strength have lead to dramatic increases in the number of cells
      transduced and the level of expression within each cell. The improvements in
      promoter strength have resulted from a move away from the original
      cytomegalovirus (CMV) promoter toward the use of hybrid CMV-based promoters and
      constitutive cellular promoters. This review summarizes and compares different
      promoters and regulatory elements that have been used with rAAV as a reference
      toward achieving a high level of rAAV-mediated transgene expression in the CNS.

PMID- 12413422
TI  - Adeno-associated virus vectors for gene transfer to the brain.
AB  - Gene therapy is a novel method under investigation for the treatment of
      neurological disorders. Considerable interest has focused on the possibility of
      using viral vectors to deliver genes to the central nervous system. Adeno
      associated virus (AAV) is a potentially useful gene transfer vehicle for
      neurologic gene therapies. The advantages of AAV vector include the lack of any
      associated disease with a wild-type virus, the ability to transduce nondividing
      cells, the possible integration of the gene into the host genome, and the long
      term expression of transgenes. The development of novel therapeutic strategies
      for neurological disorder by using AAV vector has an increasing impact on gene
      therapy research. This article describes methods that can be used to generate
      rodent and nonhuman primate models for testing treatment strategies linked to
      pathophysiological events in the ischemic brain and neurodegenerative disorders
      such as Parkinson's disease.

PMID- 12413423
TI  - Adeno-associated virus-mediated antiapoptotic gene delivery: in vivo gene therapy
      for neurological disorders.
AB  - Apoptosis is an important mechanism of physiological and pathological cell death
      and is known to occur in various neurological disorders. Apoptosis is associated
      with activation of genetic programs in which apoptosis-effector genes promote
      cell death, thereby opposing repressor genes that enhance cell survival. In this
      review, we describe various apoptotic pathways, with a special reference to the
      caspase cascade and discuss the role of individual antiapoptotic factors in
      various target diseases. Apoptosis could be suppressed by in vivo gene delivery
      of antiapoptotic factors directly into the central nervous system. The adeno
      associated virus (AAV) vector is a good candidate for such gene therapy because
      it can infect postmitotic neurons. We also describe our in vivo system for
      overexpression of apoptotic protease activating factor-1 (Apaf-1) caspase
      recruitment domain as an Apaf1-dominant negative inhibitor (Apaf-1-DN) to
      regulate the mitochondrial caspase cascade. Apaf-1-DN delivery using an AAV
      vector system inhibited mitochondrial apoptotic signaling pathway and prevented
      dopaminergic cell death in a mouse model of Parkinson's disease. Our results
      suggest that AAV-Apaf-1-DN is potentially useful as an antimitochondrial
      apoptotic gene therapy for neurodegenerative disorders such as Parkinson's
      disease.

PMID- 12413424
TI  - Gene therapy for treatment of cerebral ischemia using defective recombinant adeno
      associated virus vectors.
AB  - In this review we present our results and experiences in performing gene therapy
      of cerebral stroke using recombinant adeno-associated virus (rAAV) vectors in a
      rat model. The methodologies involving the production of AAV vectors, gene
      transfer to the brain, and a trivessel ligation model of focal ischemic cerebral
      stroke in rats are described. Furthermore, a brief description of other viral
      vectors and candidates of therapeutic transgenes used for gene therapy of
      cerebral stroke are presented. The potential advantages and limitations of stroke
      gene therapy are also discussed with the intention of outlining the design of
      more appropriate experiments.

PMID- 12413425
TI  - Vigilant vectors: adeno-associated virus with a biosensor to switch on amplified
      therapeutic genes in specific tissues in life-threatening diseases.
AB  - There are many life-threatening and chronic diseases in which physiological
      signals could be used to switch on therapeutic protective genes. We are
      developing a gene therapy approach in which a systemically injected "vigilant
      vector" waits for these signals and switches on genes to protect specific tissues
      with high amplification. The concept of a vigilant vector requires four
      components. The first component is a safe and stable vector that can be
      administered by systemic injection and express transgenes in a particular organ
      or tissue. The adeno-associated virus vector is safe and stable for this purpose.
      The second component is a reversible gene switch which is a biosensor that can
      detect certain physiological signals. We are developing a hypoxia switch, based
      on the oxygen-dependent degradation domain of hypoxia-inducible factor. The third
      component is a tissue-specific promoter, and we have used the myosin light-chain
      2V promoter for specific expression in the heart. The fourth component is an
      amplification system. For this we have developed a double-plasmid/vector system
      based on the yeast GAL4 and human transcriptional activator p65 to produce a
      transactivating fusion protein that binds to a GAL4 activation sequence in an
      activating plasmid that then expresses high levels of cardioprotective genes.

PMID- 12413426
TI  - Gene delivery to the eye using adeno-associated viral vectors.
AB  - Adeno-associated virus (AAV) vectors provide a useful way to deliver genes to the
      eye. They have a number of important properties which make them suitable for this
      purpose, not least their lack of significant pathogenicity and the potential for
      long-term transfection of retinal cells. The optimal methods for AAV-mediated
      gene delivery are determined by the location and characteristics of the target
      cell type. Efficient gene delivery to photoreceptors and pigment epithelial cells
      following subretinal injection of AAV has been achieved in various animal models.
      AAV-mediated gene therapy has been shown to slow photoreceptor loss in rodent
      models of primary photoreceptor diseases and in dogs with a naturally occurring
      disease similar to human Leber's congenital amaurosis (LCA). Efficient gene
      delivery to other cell types such as retinal ganglion cells (RGCs), however, has
      been more problematic. In this article, we review the potential uses of AAV
      mediated gene delivery to the eye. We describe the selection of an appropriate
      AAV vector for ocular gene transfer studies and discuss the techniques used to
      deliver the virus to the eye and to assess ocular transfection. We emphasize our
      techniques for successful gene transfer to retinal ganglion cells, which have
      often proven challenging to transfect with high efficiency. Using a modified AAV
      incorporating a chicken beta-actin (CBA) promoter and the woodchuck hepatitis
      posttranscriptional regulatory element, we describe how our techniques allow
      approximately 85% of rat retinal ganglion cells to be transfected within 2 weeks
      of a single intravitreal virus injection. Our techniques facilitate the study of
      the pathogenesis of RGC diseases such as glaucoma and the development of novel
      new treatments based on gene therapy.

PMID- 12413427
TI  - Development of hammerhead ribozymes to modulate endogenous gene expression for
      functional studies.
AB  - Hammerhead ribozymes are catalytic RNAs that are being used to inhibit endogenous
      gene expression to study key components of basic biochemical pathways such as
      angiogenesis. In addition, these ribozymes have the potential to be used as
      components of gene therapy protocols for the treatment of disease states. We
      detail here a set of protocols for the design and testing of hammerhead ribozymes
      that will efficiently inhibit gene expression both in cell culture and in vivo.

PMID- 12413428
TI  - Measurements of vector-derived neurotrophic factor and green fluorescent protein
      levels in the brain.
AB  - Demonstrating consistently reliable levels of expression is a critical part of
      any gene transfer study in order to assess variability and determine effective
      gene dosages. This article highlights some of the key methods for studying the
      expression levels of green fluorescent protein and neurotrophic factors after
      injections of adeno-associated virus (AAV) vectors into the brain. The data
      demonstrate greater spread and higher levels of expression using the
      cytomegalovirus/chicken beta-actin (CBA) promoter coupled with the woodchuck
      hepatitis virus posttranscriptional regulatory element (WPRE), compared to
      earlier AAV serotype 2 vectors. Injections of either CBA-nerve growth factor
      (NGF)-WPRE or CBA-glial cell line-derived neutrotrophic factor-WPRE AAV vectors
      into the nucleus basalis of the basal forebrain led to clear and consistent
      elevation of the respective trophic factor as measured by enzyme-linked
      immunosorbent assay, with NGF vectors affecting the size and number of
      cholinergic neurons. AAV serotype may also be important for the spread of
      expression, since injecting an AAV-5 vector into the hippocampus led to higher
      frequency transfection of dentate gyrus granule neurons, suggesting altered
      tropism relative to AAV-2.

PMID- 12413429
TI  - Particle detection, number estimation, and feature measurement in gene transfer
      studies: optical fractionator stereology integrated with digital image processing
      and analysis.
AB  - Assessing the efficacy of in vivo gene transfer often requires a quantitative
      determination of the number, size, shape, or histological visualization
      characteristics of biological objects. The optical fractionator has become a
      choice stereological method for estimating the number of objects, such as
      neurons, in a structure, such as a brain subregion. Digital image processing and
      analytic methods can increase detection sensitivity and quantify structural
      and/or spectral features located in histological specimens. We describe a
      hardware and software system that we have developed for conducting the optical
      fractionator process. A microscope equipped with a video camera and motorized
      stage and focus controls is interfaced with a desktop computer. The computer
      contains a combination live video/computer graphics adapter with a video frame
      grabber and controls the stage, focus, and video via a commercial imaging
      software package. Specialized macro programs have been constructed with this
      software to execute command sequences requisite to the optical fractionator
      method: defining regions of interest, positioning specimens in a systematic
      uniform random manner, and stepping through known volumes of tissue for
      interactive object identification (optical dissectors). The system affords the
      flexibility to work with count regions that exceed the microscope image field
      size at low magnifications and to adjust the parameters of the fractionator
      sampling to best match the demands of particular specimens and object types.
      Digital image processing can be used to facilitate object detection and
      identification, and objects that meet criteria for counting can be analyzed for a
      variety of morphometric and optical properties.

PMID- 12413430
TI  - The influence of experimental pain intensity in the local and referred pain area
      on somatosensory perception in the area of referred pain.
AB  - The aim of this study was to investigate the influence of experimental pain
      intensity in the local and referred pain area on somatosensory perception
      thresholds in the area of referred pain. Pain was induced by intramuscular
      electrical stimulation of the left infraspinatus muscle in 12 healthy
      individuals. The stimulation corresponded to the local pain threshold ("mild
      local pain"), the referred pain threshold ("mild referred pain"), and a pain
      intensity corresponding to 2 on a 10-point category scale in the referred pain
      area ("moderate referred pain"). Quantitative sensory testing was performed to
      assess perception thresholds in the referred pain area and the homologous
      contralateral area before and during stimulation. Perception thresholds to light
      touch (LTTs), pressure pain (PPTs), and to innocuous as well as noxious warmth
      and cold were assessed. During stimulation the LTTs increased in the referred
      pain area compared to baseline, uninfluenced by pain intensity. Perception
      thresholds to innocuous cold and warmth increased bilaterally during the
      stimulation, without relation to pain intensity. Heat pain thresholds were not
      affected. Compared to baseline, PPTs increased bilaterally during stimulation
      corresponding to "mild local pain" and "mild referred pain", respectively, and a
      further increase was seen during "moderate referred pain". The decreased
      sensitivity to innocuous cold, warmth, and pressure pain was bilateral,
      indicating activation of endogenous net inhibitory mechanisms interacting
      bilaterally. We found no influence of pain intensity on somatosensory thresholds
      restricted to the referred pain area and light touch was the only affected
      modality in the referred pain area only.

PMID- 12413431
TI  - The association between psychological factors and oro-facial pain: a community
      based study.
AB  - OBJECTIVE: To examine the hypothesis that psychological factors of psychological
      distress, maladaptive response to illness and perception of happiness in
      childhood, are associated with self-reported oro-facial pain (OFP). METHOD: A
      cross-sectional population-based study was conducted in South-East Cheshire, UK.
      The adjusted participation rate was 74%, and 2504 adults aged 18-65 years
      participated in the study. RESULTS: A report of not having had a happy childhood
      was associated with risk of 1.6 (95% CI 1.4-2.0) of reporting OFP. An increased
      propensity to report symptoms associated with OFP was seen for those individuals
      with higher levels of psychological distress measured using the general health
      questionnaire (GHQ) with the risk of 2.7 (95% CI 2.3-3.2) in the highest
      category. All components of the illness behaviour questionnaire (IBQ) were
      associated with presence of OFP. There was a linear increase in risk (test for
      trend, P<0.01) associated with the report of OFP for general hypochondriasis,
      disease conviction, affective inhibition, affective disturbance, and
      irritability. However there was a significant decrease in risk with a high score
      for perception of illness (0.6; 95% CI 0.6-0.7) and denial (0.6; 95% CI 0.5-0.7).
      None of the factors showed significant change in estimates when adjusted for age
      and gender. CONCLUSIONS: This large cross-sectional community-based study showed
      significant association for all of the factors considered. The obtained data
      raise interesting questions of cause and effect for which further, longitudinal
      studies are required to establish temporal relationship between these factors and
      the onset, cause, and treatment of OFP.

PMID- 12413432
TI  - Prevention of postherpetic neuralgia with varicella-zoster hyperimmune globulin.
AB  - Recovery after an acute attack of herpes zoster is followed by postherpetic
      neuralgia (PHN) in 9-14% of all patients. Depending on the patient's age, the
      severity of the acute attack of herpes zoster and the dermatome involved, the
      incidence of PHN may be as high as 65%. The purpose of our study was to ascertain
      the incidence of PHN after a prophylactic intravenous injection of varicella
      zoster hyperimmune globulin (VZV-IG) (Varitect Biotest Pharma). For this double
      blind placebo-controlled randomised investigation we defined PHN as pain confined
      to the dermatome previously affected by herpes zoster, and we required a pain
      intensity of at least 15% points on a visual analogue scale (VAS) for this
      dermatome. The inclusion criteria were the dermatological diagnosis of herpes
      zoster together with age over 50 years. On Day 1, 20 patients received a single
      intravenous infusion of VZV-IG in a dose of 2mL/kg body weight, 20 patients
      (control group) received a single infusion of human albumin 5% in a dose of
      2mL/kg body weight. All patients received acyclovir intravenously in a dose of
      15mg/kg body weight per 24h for 5 days. The patients were followed up for a total
      of 42 days. The incidence of PHN at Day 42 was selected as the main outcome
      criterion for assessing the efficacy of prophylaxis. On reaching a significant
      difference between the groups (t test; alpha<0.05) in favour of the active
      treatment group, prophylaxis of PHN by VZV-IG was assessed as effective. Pain was
      assessed on a VAS and a NAS. As auxiliary outcome criteria, we used the McGill
      Pain-Rating Questionnaire in its German version, the revised multidimensional
      pain scale (RMSS) and the Freiburg symptom list (FBL). All results were assessed
      by the t test (alpha<0.05). The frequency of PHN in the placebo group was 70%
      (14/20), in the active treatment group it was 35% (7/20) at Day 42. The results
      of the McGill test showed the variability of the perception of pain in the
      placebo group significantly greater. No significant group differences were found
      in the FBL. Being tested with the RMSS, the patients of the placebo group
      assessed their pains as significantly "more obstinate" (p=0.047). The results can
      be summed up by saying that VZV-IG not only reduces the incidence of PHN, but
      also that in certain respects the patients' assessments of their pain experience
      were different. In our study we found a 50% reduction in PHN incidence However,
      the outcome time point of our trial was so close to the acute phase of the zoster
      illness that spontaneous remissions of PHN still have to be taken into account.
      Despite the widely varied approaches to the problem, reliably effective therapy,
      let alone 100% prevention of PHN, is still not feasible.

PMID- 12413433
TI  - Biphasic vasomotor reflex responses of the hand skin following intradermal
      injection of melittin into the forearm skin.
AB  - Melittin is the main toxin of honeybee venom. Previously, we have reported that
      intradermal injection of melittin into the volar aspect of forearm in humans
      produces a temporary pain and a subsequent sustained increase in the skin
      temperature due to axon reflex. To clarify the interaction between nociceptive
      inputs and vascular changes, we studied the influence of noxious stimulation by
      intradermal melittin on the vasomotor control of the distal extremities in human
      volunteers. Temperature changes of the bilateral palmar surface were recorded by
      means of a computer-assisted infrared thermography. Unexpectedly, we found a
      biphasic response of skin temperature. The skin temperature of both fingers and
      hands decreased immediately after the melittin injection and then increased well
      above the control level, prior to the injection. There was a considerable
      individual variation in the baseline skin temperature, prior to melittin. The
      skin temperature in a finger/hand with lower preinjection value increased more
      markedly in the second phase. Consequently, the individual variation in the peak
      temperature of the second phase was less pronounced. The initial decrease was
      interpreted as sympathetic vasoconstrictor reflex induced by noxious stimulation
      and the later increase as release of sympathetic vasomotor tone.

PMID- 12413434
TI  - Treatment with staphylococcus toxoid in fibromyalgia/chronic fatigue syndrome--a
      randomised controlled trial.
AB  - We have previously conducted a small treatment study on staphylococcus toxoid in
      fibromyalgia (FM) and chronic fatigue syndrome (CFS). The aim of the present
      study was to further assess the efficacy of the staphylococcus toxoid preparation
      Staphypan Berna (SB) during 6 months in FM/CFS patients. One hundred
      consecutively referred patients fulfilling the ACR criteria for FM and the 1994
      CDC criteria for CFS were randomised to receive active drug or placebo. Treatment
      included weekly injections containing 0.1 ml, 0.2 ml, 0.3 ml, 0.4 ml, 0.6 ml, 0.8
      ml, 0.9 ml, and 1.0 ml SB or coloured sterile water, followed by booster doses
      given 4-weekly until endpoint. Main outcome measures were the proportion of
      responders according to global ratings and the proportion of patients with a
      symptom reduction of > or =50% on a 15-item subscale derived from the
      comprehensive psychopathological rating scale (CPRS). The treatment was well
      tolerated. Intention-to-treat analysis showed 32/49 (65%) responders in the SB
      group compared to 9/49 (18%) in the placebo group (P<0.001). Sixteen patients
      (33%) in the SB group reduced their CPRS scores by at least 50% compared to five
      patients (10%) in the placebo group (P< 0.01). Mean change score on the CPRS (95%
      confidence interval) was 10.0 (6.7-13.3) in the SB group and 3.9 (1.1-6.6) in the
      placebo group (P<0.01). An increase in CPRS symptoms at withdrawal was noted in
      the SB group. In conclusion, treatment with staphylococcus toxoid injections over
      6 months led to significant improvement in patients with FM and CFS. Maintenance
      treatment is required to prevent relapse.

PMID- 12413435
TI  - Poststroke shoulder pain: a prospective study of the association and risk factors
      in 152 patients from a consecutive cohort of 205 patients presenting with stroke.
AB  - BACKGROUND AND PURPOSE: Shoulder pain is known to retard rehabilitation after
      stroke. Its causes and prognosis are uncertain. This study describes the
      incidence of poststroke shoulder pain prospectively, in an unselected stroke
      population in the first 6 months after stroke and identifies risk factors for
      developing pain. METHODS: 297 patients with possible stroke were screened and
      stroke diagnosed in 205 cases. The 152 patients entered the study of which 123
      patients were assessed up to 6 months. This cohort, with a mean age of 70.6
      years, was examined at 2 weeks, 2, 4, and 6 months. A history of shoulder pain,
      Barthel score, anxiety and depression score were recorded. Full neurological and
      rheumatological examination was undertaken, using the contralateral side as a
      control. Pain outcome and stroke outcome was recorded at subsequent visits.
      RESULTS: 52 (40%) patients developed shoulder pain on the same side of their
      stroke. There was a strong association between pain and abnormal shoulder joint
      examination, ipsilateral sensory abnormalities and arm weakness. Shoulder pain
      had resolved or improved at 6 months in 41 (80%) of the patients with standard
      current treatment. CONCLUSIONS: Shoulder pain after stroke occurred in 40% of 123
      patients surviving, consenting and not too unwell to participate. This included
      52 patients of an original cohort of 205 patients presenting with stroke. Eighty
      percent of patients made a good recovery with standard treatment Patients with
      sensory and or motor deficits represent at risk sub-groups.

PMID- 12413436
TI  - Modality-specific facilitation and adaptation to painful tonic stimulation in
      humans.
AB  - The study assessed the influence of stimulus modality on adaptation or
      facilitation of pain during tonic cold and tourniquet pressure stimulation.
      Experimental set-up for the cold stimulation consisted of a thermo-tank with
      water, cooled to 3 degrees C, circulation pump, electronic thermometer and an
      electronic 10 cm visual analogue scale (VAS). Experimental set-up for the tonic
      pressure stimulation consisted of a pneumatic tourniquet cuff, a computer
      controlled air compressor, and an electronic VAS. The first experiment assessed
      temporal profiles of pain intensity and skin temperature during immersion of the
      non-dominant hand and lower arm into cold water for 3 min or until the pain
      tolerance limit was reached. The second experiment assessed temporal profile of
      cuff pain intensity during constant compressions for 10 min beginning at pain
      intensities of 2, 4, and 6 cm on the VAS ("VAS 2", "VAS 4" and "VAS 6" sessions).
      Subjects enduring cold stimulation for less than 3 min were defined as non
      adapting to cold and vice versa. The intensity of cold pain in non-adapting
      subjects increased significantly faster than in adapting subjects and reached
      significantly higher magnitude. The course of pain intensity during constant
      compression, estimated by a linear regression line, was increasing or decreasing,
      representing facilitation or adaptation of pain, respectively. The typical
      profile of adaptation consisted of an "overshoot" in pain intensity, followed by
      a decrease in pain intensity. There was significant correlation in VAS slopes
      between sessions separated by 2-5 days, suggesting consistent pattern in pain
      responses to tonic pressure stimulation. Adaptation or facilitation rates and the
      overshoot magnitude were dependent on the initial pain intensity (2, 4, or 6 cm
      on the VAS). The facilitation rate was highest and the adaptation rate was lowest
      during the "VAS 2" session, while the facilitation rate was lowest and the
      adaptation rate was highest during the "VAS 6" session. The overshoot magnitude
      was lowest during "VAS 6" session. Adapting and non-adapting/facilitating
      responses to cold and to pressure during "VAS 6" session were not correlated,
      suggesting that pain course and therefore stimulus tolerance during tonic
      stimulation are modality-specific. The results of the study suggest that
      tolerance of tonic painful pressure and cold stimulations is specific to stimulus
      modality and may represent separate nociceptive mechanisms.

PMID- 12413437
TI  - Is core laboratory essential for using echocardiography in clinical trials?
      Controlled vs random error.

PMID- 12413438
TI  - Imaging methods for myocardial contrast echocardiography: what to expect in the
      near future.

PMID- 12413439
TI  - Isolated left ventricular non-compaction: increasing recognition of this
      distinct, yet 'unclassified' cardiomyopathy.

PMID- 12413440
TI  - Echocardiographic evaluation of right ventricular function.

PMID- 12413441
TI  - Differences between echocardiographic measurements of left ventricular dimensions
      and function by local investigators and a core laboratory in a 2-year follow-up
      study of patients with an acute myocardial infarction.
AB  - AIMS: To examine differences in measurements of left ventricular dimensions and
      function, and prognostic value between local investigators and a core laboratory
      in a multicentre serial echocardiographic study. METHODS AND RESULTS: Seven
      hundred and fifty-six patients with acute myocardial infarction and preserved
      left ventricular function were examined at baseline and after 3 months with
      measurements by the biplane Simpson's method, and followed prospectively from 3
      to 24 months. At baseline and 3 months local investigators relative to the core
      laboratory measured lesser end-diastolic volume by 8 and 6 ml (P<0.001), end
      systolic volume by 3 and 2 ml (P<0.01), and ejection fraction by 0.0 and 0.6%
      (P<0.01), respectively. Local investigators and the core laboratory measured an
      increase in left ventricular end-diastolic volume of 8.6 and 6.9 ml, and in left
      ventricular end-systolic volume of 5.2 and 4.3 ml, and a decrease in left
      ventricular ejection fraction of 0.6 and 0.0%. Using the Cox proportionate
      hazards model, the prognostic value for subsequent clinical endpoints was
      significant both for the 3-month values (P<0.05) and changes (P<0.005) measured
      by the core laboratory, but not by local investigators. CONCLUSION: Only
      measurements in the core laboratory had significant prognostic value for
      subsequent clinical endpoints. These results strongly support the use of a core
      laboratory in studies employing echocardiographic measurements.

PMID- 12413442
TI  - Myocardial contrast echocardiography yields best accuracy using quantitative
      analysis of digital data from pulse inversion technique: comparison with second
      harmonic imaging and harmonic power Doppler during simultaneous dipyridamole
      stress SPECT studies.
AB  - AIMS: This prospective study assesses the (1) feasibility of quantifying
      ultrasound myocardial perfusion studies based on the densitometric analysis of
      digital data and the (2) comparison of pulse inversion, second harmonic and
      harmonic power Doppler modalities with SPECT. METHODS AND RESULTS: Twenty-three
      patients with suspected ischaemic heart disease had i.v. injections of Tc
      Sestamibi and Optison during a dipyridamole stress test for echocardiography in
      pulse inversion, second harmonic and harmonic power Doppler mode. Analysis was
      (a) visual by scoring and (b) quantitative by densitometry of digital data for
      background subtracted myocardial opacification (a.u.) and normalized contrast
      effect (%). In the nine control patients, myocardial opacification at stress was
      greater (P< or =0.002) than in the pathologic group (5. +/- 3.3 vs 2.6 +/- 2.5
      a.u. in pulse inversion, 5.4 +/- 2.1 vs 2.4 +/- 1.8 in second harmonic and 7.1 +/
      3.7 vs 4.9 +/- 3.7 a.u. in harmonic power Doppler). In the pathologic group,
      normalized contrast effect decreased significantly during stress (23.7 +/- 18.8
      to 11.3 +/- 10.8%, P<0.003) only in pulse inversion. Kappa values for patient
      based diagnostic agreement with SPECT were 0.75 by pulse inversion, 0.62 by
      second harmonic and 0.52 by harmonic power Doppler for quantitative analysis, and
      0.51, 0.37 and 0.35 respectively, for visual assessment. CONCLUSION: Myocardial
      contrast echocardiography should be analysed using densitometry of digital data.
      The new technique pulse inversion demonstrates best agreement with SPECT data.

PMID- 12413443
TI  - Left atrial appendage emptying velocity does not predict postoperative atrial
      fibrillation in patients undergoing cardiopulmonary bypass.
AB  - BACKGROUND: Atrial fibrillation is a common complication of cardio-pulmonary
      bypass and improved pre-operative risk assessment could help guide prophylactic
      therapy. This study examined whether reduced left atrial appendage flow
      velocities measured by transoesophageal echocardiography pre-operatively in
      patients in sinus rhythm predicted development of postoperative atrial
      fibrillation. METHODS AND RESULTS: All patients who underwent transoesophageal
      echocardiography for clinical indications with measurements of left atrial
      appendage velocities within twelve months prior to cardio-pulmonary bypass were
      retrospectively identified. Postoperative records were reviewed and the patients
      divided into two groups based on the presence or absence of clinically
      significant atrial fibrillation during hospitalization following cardio-pulmonary
      bypass. Thirty-six patients (mean age 61.1 +/- 14.8 years, 18M/18F) were included
      in the study. The overall incidence of atrial fibrillation in the cohort was
      17/36 patients (47%). Mean left atrial appendage emptying velocity was 50.8 +/-
      23.3 cm/s2 (range 26-119) in the patients with sinus rhythm only and 41.5 +/-
      16.7 cm/s2 (range 16-76), in the patients with postoperative atrial fibrillation
      (P=ns). CONCLUSIONS: In our patient population there was no significant
      difference in left atrial appendage emptying velocity measured by
      transoesophageal echocardiography in patients with and without postoperative
      atrial fibrillation. Pre-operative measurement of left atrial appendage emptying
      velocity cannot be relied upon to risk stratify patients prior to cardio
      pulmonary bypass.

PMID- 12413444
TI  - Quantitative assessment of harmonic power Doppler myocardial perfusion imaging
      with intravenous Levovist in patients with myocardial infarction: comparison with
      myocardial viability evaluated by thallium-201 single-photon emission computed
      tomography and coronary flow reserve.
AB  - BACKGROUND: Intravenous myocardial contrast echocardiography with harmonic power
      Doppler imaging is a novel technique for assessing myocardial perfusion. AIMS:
      The aim of this study was to quantitatively assess myocardial perfusion by
      harmonic power Doppler imaging in patients with a previous myocardial infarction
      and compare myocardial contrast echocardiography results with myocardial
      viability evaluated by thallium-201 single-photon emission computed tomography
      ((201)Tl-SPECT) and the results of Doppler flow measurement of coronary flow
      velocity reserve. METHODS: Twenty-three patients with anterior myocardial
      infarction who were scheduled for adenosine stress (201)Tl-SPECT underwent
      myocardial contrast echocardiography with harmonic power Doppler imaging.
      Harmonic power Doppler imaging was performed at rest and during adenosine
      infusion (0.15 mg/kg/min) using an intravenous infusion of Levovist. The peak
      colour pixel intensity ratios of the risk area to the control area were used for
      quantitative analysis of myocardial perfusion by harmonic power Doppler imaging.
      Coronary blood flow velocity was measured using Doppler-tipped guidewire in the
      distal portion of left anterior descending artery and coronary flow velocity
      reserve was calculated. RESULTS: In patients with myocardial viability assessed
      by (201)Tl-SPECT, pixel intensity ratios both at rest and during hyperaemia were
      significantly higher compared with those in patients without myocardial viability
      (at rest: 0.62 +/- 0.28 vs 0.37 +/- 0.17, P=0.038, during hyperaemia 0.72 +/-
      0.19 vs 0.40 +/- 0.18, P=0.003). Coronary flow velocity reserve was significantly
      different between two groups (2.35 +/- 0.43 vs 1.49 +/- 0.53, P <0.01).
      CONCLUSIONS: Quantitative assessment of microvascular integrity by harmonic power
      Doppler imaging corresponds to the evaluation of the microcirculation by coronary
      flow velocity reserve.

PMID- 12413445
TI  - Non-compaction cardiomyopathy-echocardiographic diagnosis.
AB  - Non-compaction cardiomyopathy is a recently recognized disorder caused by a
      defect in endomyocardial morphogenesis. The disease can present with heart
      failure, systemic embolic events, and ventricular arrhythmias. Long-term
      prognosis is poor. Echocardiography is used to confirm the diagnosis; in the
      current case-report, we describe the typical abnormalities observed on
      echocardiography in a patient with non-compaction cardiomyopathy.

PMID- 12413447
TI  - Unusual appearance of the right coronary artery.

PMID- 12413446
TI  - Echocardiographic evidence of atrial myopathy in amyloidosis: a case report.
AB  - Cardiac involvement occurs in up to 50% of patients with primary amyloidosis.
      Diffuse amyloid deposits lead to impairment of myocardial systolic and diastolic
      function. Due to the severe left ventricular diastolic abnormality, left atrial
      contribution to left ventricular stroke volume remains critical. We report a case
      of primary amyloidosis where we assessed non-invasively left atrial systolic
      function.

PMID- 12413448
TI  - A colorimetric 96-well microtiter plate assay for the determination of urate
      oxidase activity and its kinetic parameters.
AB  - Urate oxidase (E.C.1.7.3.3; uricase, urate oxygen oxidoreductase) is an enzyme of
      the purine breakdown pathway that catalyzes the oxidation of uric acid in the
      presence of oxygen to allantoin and hydrogen peroxide. A 96-well plate assay
      measurement of urate oxidase activity based on hydrogen peroxide quantitation was
      developed. The 96-well plate method included two steps: an incubation step for
      the urate oxidase reaction followed by a step in which the urate oxidase activity
      is stopped in the presence of 8-azaxanthine, a competitive inhibitor. Hydrogen
      peroxide is quantified during the second step by a horseradish peroxidase
      dependent system. Under the defined conditions, uric acid, known as a radical
      scavenger, did not interfere with hydrogen peroxide quantification. The general
      advantages of such a colorimetric assay performed in microtiter plates, compared
      to other methods and in particular the classical UV method performed with
      cuvettes, are easy handling of large amounts of samples at the same time, the
      possibility of automation, and the need for less material. The method has been
      applied to the determination of the kinetic parameters of rasburicase, a
      recombinant therapeutic enzyme.

PMID- 12413449
TI  - Method for the determination of molar absorptivities of thiol adducts formed from
      diphenolic substrates of polyphenol oxidase.
AB  - Metabolic thiols such as cysteine and glutathione are involved in the
      biosynthetic pathway of phaeomelanins. They attack the o-quinones generated by
      polyphenol oxidase in its action on mono and o-diphenols and thus generate
      adducts. Determination of the molar absorptivities of these adducts is useful for
      spectrophotometric studies of phaeomelanin biosynthesis, antibrowning reagents in
      plants, and polyphenol oxidase assay methods. For their calculation, a method
      based on the depletion of o-diphenol by the action of polyphenol oxidase in the
      presence of thiol has been proposed. However, the method is slow and presents
      certain problems, for which reason we propose a new and faster method based on
      the action of polyphenol oxidase on o-diphenols which are in excess with respect
      to oxygen. Under these assay conditions there is rapid enzymatic formation of o
      quinones, which react stoichiometrically with a thiol giving rise to the
      corresponding thiol-diphenol adduct. The method has been successfully applied to
      adducts of cysteine and glutathione with several o-diphenolic substrates of
      polyphenol oxidase involved in phaeomelanin biosynthesis in skin, neurones, and
      plants.

PMID- 12413450
TI  - Physical methods to determine the binding mode of putative ligands for hepatitis
      C virus NS3 helicase.
AB  - Several small molecules identified by high-throughput screening (HTS) were
      evaluated for their ability to bind to a nonstructural protein 3 (NS3) helicase
      from hepatitis C virus (HCV). Equilibrium dissociation constants (K(d)'s) of the
      compounds for this helicase were determined using several techniques including an
      assay measuring the kinetics of isothermal enzyme denaturation at several
      concentrations of the test molecule. Effects of two nonhydrolyzable ATP analogs
      on helicase denaturation were measured as controls using the isothermal
      denaturation (ITD) assay. Two compounds, 4-(2,4-dimethylphenyl)-2,7,8-trimethyl
      4,5-quinolinediamine and 2-phenyl-N-(5-piperazin-1-ylpentyl)quinazolin-4-amine,
      were identified from screening that inhibited the enzyme and had low micromolar
      dissociation constants for NS3 helicase in the ITD assay. Low micromolar affinity
      of the quinolinediamine to helicase was also confirmed by nuclear magnetic
      resonance experiments. Unfortunately, isothermal titration calorimetry (ITC)
      experiments indicated that a more water-soluble analog bound to the 47/23-mer
      oligonucleotide helicase substrate with low micromolar affinity as did the
      substituted quinazolinamine. There was no further interest in these templates as
      helicase inhibitors due to the nonspecific binding to enzyme and substrate. A
      combination of physical methods was required to discern the mode of action of
      compounds identified by HTS and remove undesirable lead templates from further
      consideration.

PMID- 12413451
TI  - Size distribution measurement of vesicles by atomic force microscopy.
AB  - Vesicles have been utilized as nanoscale vehicles for reagents including
      potential drug delivery systems. When used to deliver drugs, vesicle size and the
      size distribution are important factors in the determination of the dosage, cell
      specificity, and rate of clearance from the body. Current size measurement
      techniques for vesicles are electron microscopy and dynamic light scattering, but
      their results are not equal. Therefore atomic force microscopy was attempted as
      another size measurement technique. After adsorption of the vesicles from a low
      concentration solution of vesicles on mica substrate, each vesicle is generally
      found as a flattened structure. The diameters of vesicles in these solutions and
      their distribution have been successfully estimated from the surface area of the
      flattened structure of each vesicle. At higher concentrations, we have found a
      monolayer crammed with dome-shaped vesicles on the substrate. The diameters of
      vesicles in these solutions have also been successfully estimated from the
      surface area of the dome-shaped structure of each vesicle. Diameters of vesicles
      in solution estimated from two different vesicle concentrations are not close to
      those reported by electron microscope studies but are close to those reported by
      dynamic light scattering studies.

PMID- 12413452
TI  - Radiometric solvent-partitioning assay for screening cocaine hydrolases and
      measuring cocaine levels in milligram tissue samples.
AB  - To permit rapid screening and characterization of novel cocaine hydrolases, as
      well as accurate measurement of cocaine levels in small samples of tissue, a
      radiometric assay was developed. The assay is based on selective, organic solvent
      partition of [3H]benzene-labeled cocaine or of [3H]benzoic acid liberated during
      enzymatic hydrolysis. With dilute samples the assay can be conducted entirely in
      scintillation vials and quantitated by addition of appropriate aqueous buffer and
      toluene-based fluor, making phase separation unnecessary. In this way, several
      hundred samples can be assayed in an afternoon, nanogram quantities of enzyme can
      be characterized without prior purification, and cocaine concentrations can be
      accurately measured in milligram samples of tissue after administration of
      [3H]cocaine in vivo.

PMID- 12413453
TI  - A new fluorescent quantitative polymerase chain reaction technique.
AB  - To perform real-time detection of specific genes, a new complex probe has been
      designed and synthesized. Based on fluorescence resonance energy transfer (FRET),
      this complex probe is composed of a long-fluorescent reporter probe and a short
      quenching probe. The 5' end of the fluorescent probe is connected to a
      fluorescein molecule, and its 3' end is linked to an extending blocking molecule.
      The 3' end of the quenching probe is connected to a quenching molecule-p-methyl
      red (Dabcyl). The quenching probe is complementary to the 5' end of the
      fluorescent probe. When there is no template, the two probes combine to form a
      complex probe and therefore no fluorescence is produced; when there are
      templates, the fluorescent probe hybridizes with the templates first, and the
      fluorescence is not quenched. The fluorescence intensity produced is in direct
      proportion to the template quantity. In accordance with the principles of
      reaction of the complex probe, we have studied the probe's FRET nature and the
      factors that affect it, including the quenching probe and amplified fragment
      length, the proper proportion of the fluorescent probe to the quenching probe,
      and the magnesium ion concentration. Experimental results showed that the
      quenching probe and its amplified fragment length had an obvious impact on the
      function of the complex probe. The quenching probe used in the present experiment
      is up to 21 nucleotides long, with an amplified fragment of 127bp. The most
      preferable reaction system is obtained when the proportion of the fluorescent
      probe to the quenching probe is 1:1, and the concentration of magnesium ions is
      3mmol/L. The complex probe is easy to synthesize. The quenching is thorough with
      good accuracy and specificity. The sensitivity reaches 10(2) copies with a very
      large dynamic quantitation range. Accurate quantitation can be achieved with
      samples detected within 10(2)-10(9) copies. The complex probe method can be used
      to detect virus infection levels, transgenic copy quantities, single nucleotide
      polymorphisms, etc.

PMID- 12413454
TI  - Hydroxyethylcellulose as an effective polymer network for DNA analysis in
      uncoated glass microchips: optimization and application to mutation detection via
      heteroduplex analysis.
AB  - The nature of the sieving matrix for DNA fragment separation is of immense
      importance in capillary and microchip electrophoresis. The chemical nature of the
      surface of the capillary or microchannel wall is equally as important,
      particularly with DNA electrophoresis where a substantial electroosmotic flow
      (EOF) may be detrimental to the separation. Although DNA analysis has been
      carried out successfully in both coated and uncoated capillaries, analysis of
      unpurified polymerase chain reaction products has been carried out primarily with
      covalently coated surfaces, especially with microchip electrophoresis. In this
      report, double-stranded (ds) DNA fragment analysis using hydroxyethylcellulose
      (HEC) buffered in 1xTris-borate-EDTA is demonstrated both in uncoated capillaries
      and in microchips. EOF was suppressed 20% in the presence of 1.5% HEC, and the
      effectiveness of HEC as a polymer for dsDNA fragment analysis was dependent on
      the pH, with pH 8.6 being optimal. Using separation efficiency (number of
      theoretical plates) and resolution to gauge the effectiveness of a variety of
      polymers for the capillary separation of dsDNA fragments in the size range 60
      587bp, HEC was found to be comparable in performance to polydimethylacrylamide
      (PDMA), and superior to linear polyacrylamide and polyethylene oxide for DNA
      analysis. With respect to longevity and robust performance, HEC could be used
      effectively in an uncoated capillary for more than 40 runs and for more than 90
      runs (without replenishing the polymer) in an uncoated microchip. Application of
      the optimized HEC conditions is demonstrated through its ability to facilitate
      heteroduplex analysis.

PMID- 12413455
TI  - Development of an assay for beta-lactam hydrolysis using the pH-dependence of
      enhanced green fluorescent protein.
AB  - An assay has been developed utilizing the pH-dependent fluorescence of enhanced
      green fluorescent protein (EGFP). This photoprotein allows for the study of
      kinetic properties of hydrolytic enzymes based on the production of protons. As a
      model system, beta-lactamase, a well-characterized enzyme responsible for
      antibiotic resistance in many bacteria, was used. More specifically, EGFP and
      beta-lactamase were genetically fused using overlap extension PCR and
      incorporated into a bacterial expression vector. The vector was subsequently
      transformed into Escherichia coli, and the fusion protein was expressed and
      purified. beta-Lactamase catalyzes the hydrolysis of the beta-lactam ring of
      ampicillin. This causes a decrease in the local pH, which in turn changes the
      spectral properties of EGFP. This property was utilized to perform enzyme kinetic
      studies on the new fusion protein as well as on the beta-lactamase inhibitor,
      sulbactam. The assay can be used to evaluate substrates and inhibitors of beta
      lactamase in a format that should be amenable to high-throughput screening.

PMID- 12413456
TI  - Development of a fluorescence resonance energy transfer assay for measuring the
      activity of Streptococcus pneumoniae DNA ligase, an enzyme essential for DNA
      replication, repair, and recombination.
AB  - DNA ligase is an enzyme essential for DNA replication, repair, and recombination
      in all organisms. Bacterial DNA ligases catalyze a NAD(+)-dependent DNA ligation
      reaction, i.e., the formation of a phosphodiester bond between adjacent 3'-OH and
      5'-phosphate termini of dsDNA. Due to their essential nature, unique cofactor
      requirement, and widespread existence in nature, bacterial DNA ligases appear to
      be valuable targets for identifying novel antibacterial agents. To explore
      bacterial DNA ligases as antibacterial targets and further characterize them, we
      developed a simple, robust, homogeneous time-resolved fluorescence resonance
      energy transfer assay (TR-FRET) for measuring Streptococcus pneumoniae DNA ligase
      activity. This assay involves the use of one dsDNA molecule labeled with biotin
      and another dsDNA molecule labeled with Cy5, an acceptor fluorophore. During
      ligation reactions, the donor fluorophore europium (Eu(3+)) labeled with
      streptavidin was added to the assay mixtures, which bound to the biotin label on
      the ligated products. This in turn resulted in the FRET from Eu(3+) to Cy5 due to
      their close proximity. The formation of ligation products was measured by
      monitoring the emission at 665nm. This assay was validated by the experiments
      showing that the DNA ligase activity required NAD(+) and MgCl(2), and was
      inhibited by NMN and AMP, products of the ligase reaction. Using this assay, we
      determined the K(m) values of the enzyme for dsDNA substrates and NAD(+), and the
      IC(50) values of NMN and AMP, examined the effects of MgCl(2) and PEG(8000) on
      the enzyme activity, optimized the concentrations of Eu(3+) in the assay, and
      validated its utilities for high-throughput screening and biochemical
      characterizations of this class of enzymes.

PMID- 12413457
TI  - Atomic force microscopy identification of transcription factor NFkappaB bound to
      streptavidin-pin-holding DNA probe.
AB  - A novel method for identifying DNA-binding proteins from image analysis using AFM
      was developed. Here, transcription factor NFkappaB, which a well-studied example
      of transcription activator proteins, was used as a target protein. 5'
      biotinlynated double-stranded DNA probe was labeled site specifically through
      high affinity with streptavidin. When the biotinylated DNA fragments were
      incubated with the streptavidin at a 1:2 molar ratio of DNA:streptavidin, the
      overall efficiency of labeling was over 90%. The double-stranded DNA probes were
      immobilized on a mica surface by the adsorption of streptavidin that attached to
      the 5'-end of DNA and applied for selection of the target protein NFkappaB in
      solution and then AFM was used to image the DNA probe-NFkappaB complexes. The
      length of the distance between 5'-labeled streptavidin and NFkappaB bound on DNA
      probes from AFM images is 0.64, the normalized position of the NFkappaB binding
      site, and this result is in close agreement with the expected 299 and 167bp
      values.

PMID- 12413458
TI  - Use of fluorescent DNA-intercalating dyes in the analysis of DNA via ion-pair
      reversed-phase denaturing high-performance liquid chromatography.
AB  - SYBR Green 1 is an asymmetrical cyanine DNA-binding dye that provides an
      opportunity for increasing the sensitivity of nucleic acid detection when used in
      conjunction with gel electrophoresis. In this paper, we summarize the general
      properties and specific uses of SYBR green 1 in ion-pair reversed-phase
      denaturing high-performance liquid chromatography (IP DHPLC). We describe several
      applications for the WAVE DHPLC platform that illustrate the generic potential of
      such intercalating dyes in mutation detection and gene expression profiling. We
      show that SYBR Green 1 obviates the need to use end-labeled oligodeoxynucleotides
      for the sensitive detection of nucleic acids during chromatography. Moreover the
      incorporation of SYBR Green 1 into samples and elution buffers does not impair
      resolution and has no significant effect on the retention times of DNA fragments
      compared with dye-free DHPLC.

PMID- 12413459
TI  - Toward optimized antibody microarrays: a comparison of current microarray support
      materials.
AB  - With the advent of protein and antibody microarray technology several different
      coatings and protocols have been published, which may be broadly divided into two
      types: gel-coated surfaces and plain non-gel-coated glass or plastic surfaces,
      some with chemical groups attached. We have screened 11 different array surfaces
      of both types and compared them with respect to their detection limit, inter- and
      intrachip variation, and storage characteristics. Five different antibodies were
      immobilized onto each type of microarray support, with total protein
      concentrations ranging from 40 fmol to 25 amol per spot. From these results, it
      was seen that some antibodies were more suited for use on antibody arrays. All
      measurements were performed in quadruplicate, and the results revealed high
      signal uniformity and reproducibility of most plain glass and plastic slides.
      Lower detection limits were obtained with polyacrylamide-coated slides, making
      them more suitable for the detection of very low concentrations of antigen. All
      microarray coatings could be stored for a period of 8 weeks; however, improved
      results were seen after 2 weeks of storage. In conclusion, the results indicate
      the need to test each antibody to be used on an antibody array and to select the
      microarray coating based on experimental requirements.

PMID- 12413460
TI  - Determination in serum of some barbiturates using micellar liquid chromatography
      with direct injection.
AB  - A procedure was developed for the determination of several barbiturates,
      amobarbital, barbital, hexobarbital, and secobarbital, using a C18 column (120 x
      4.6mm) and micellar liquid chromatography (MLC) mobile phases containing sodium
      dodecyl sulfate (SDS) and propanol, butanol, or pentanol as a modifier, with UV
      detection at 230nm. After the application of an interpretative strategy of
      optimization, the four barbiturates can be resolved and determined in serum
      samples, allowing the direct injection in 0.10M SDS-4% (v/v) butanol, pH 7, with
      an analysis time below 8 min. In the proposed MLC procedure, linearities (r
      >0.999), limits of detection (ngmL(-1)) in the 30-70 range, repeatabilities, and
      intermediate precision below 1.8% are adequate for the quantification. The
      proposed method could be applied to the determination of barbiturates in serum
      samples with recoveries that agreed with the concentration added.

PMID- 12413461
TI  - Simultaneous estimation of the association constants of glycoprotein glycoforms
      to a common protein by capillary electrophoresis.
AB  - The efficacy of our capillary electrophoresis method for simultaneous estimation
      of the association constants of glycoprotein glycoforms to a common target
      protein was demonstrated using ribonuclease and ovalbumin glycoforms as glycoform
      models and Lens culinaris agglutinin (LCA) as a protein model. The ribonuclease
      glycoforms were fairly well separated in the absence of LCA at pH 5.8, but the
      peaks were retarded without any change of separation profile in the presence of
      LCA, the retardation becoming greater as LCA concentration increased. The
      estimated values of apparent association constant (K(a)) were at the 10(6)M(-1)
      level for all the ribonuclease glycoforms, and there was no significant
      difference among glycoforms. The high-mannose-type N-glycans released from a
      mixture of ribonuclease glycoforms gave lower values of K(a) at the 10(4)-10(5)M(
      1) level to the same protein, and the glycans having a larger number of the
      mannose residue gave larger K(a) values. These results imply that the glycan
      moiety in this glycoprotein might contribute to its binding to the protein, but
      the polypeptide core played the major role. In contrast, ovalbumin glycoforms
      gave poorly resolved peaks in the absence of LCA, but they were separated into
      several peaks in the presence of LCA, which were tentatively assigned based on
      the knowledge of affinity to this lectin, and K(a) values were estimated
      simultaneously. The estimated K(a) values were smaller than those of the
      ribonuclease glycoforms, suggesting the major role of the N-glycan moiety. Thus,
      capillary electrophoresis allowed simultaneous estimation of K(a) values under
      common conditions using small amounts of glycoform mixtures and proteins without
      prior isolation and purification. Comparison of the obtained values will provide
      useful information on the glycan structure-affinity correlation.

PMID- 12413462
TI  - Application of kinetic-based biospecific affinity chromatographic systems to ATP
      dependent enzymes: studies with yeast hexokinase.
AB  - This study is concerned with the development of kinetic-based bioaffinity
      chromatographic systems for purification of ATP-dependent kinases, with a
      particular focus on the allosteric yeast hexokinase enzyme (EC 2.7.1.1).
      Synthesis and characterization of highly substituted N(6)-linked and S(6)-linked
      immobilized ATP derivatives are described using a rapid solid-phase modular
      approach. Evaluation of the new immobilized ATP derivatives has been carried out
      using model chromatographic studies with yeast hexokinase, employing specific
      substrate analogues (N-acetyl-D-glucosamine and suramin) to promote biospecific
      adsorption, in the presence and absence of citrate (a so-called allosteric
      activator of hexokinase activity). In this paper, successful bioaffinity
      chromatography systems were developed for yeast hexokinase and, as a result,
      interesting binding and catalytic properties of the enzyme were highlighted and
      explored. The overall results confirm the potential for extrapolation of the
      kinetic locking-on tactic, a general kinetic-based bioaffinity approach already
      developed for the NAD(P)(+)-dependent dehydrogenases, to ATP/ADP-dependent
      enzymes. However, in view of the enhancement of the intrinsic ATPase activity of
      hexokinase with glucosamine derivatives, and the coincidental hydrolysis of
      immobilized ATP to immobilized ADP, future developments necessary to support
      adaptation of the approach to ATP-dependent enzymes are discussed.

PMID- 12413463
TI  - Quantitative real-time reverse transcription polymerase chain reaction:
      normalization to rRNA or single housekeeping genes is inappropriate for human
      tissue biopsies.
AB  - Careful normalization is essential when using quantitative reverse transcription
      polymerase chain reaction assays to compare mRNA levels between biopsies from
      different individuals or cells undergoing different treatment. Generally this
      involves the use of internal controls, such as mRNA specified by a housekeeping
      gene, ribosomal RNA (rRNA), or accurately quantitated total RNA. The aim of this
      study was to compare these methods and determine which one can provide the most
      accurate and biologically relevant quantitative results. Our results show
      significant variation in the expression levels of 10 commonly used housekeeping
      genes and 18S rRNA, both between individuals and between biopsies taken from the
      same patient. Furthermore, in 23 breast cancers samples mRNA and protein levels
      of a regulated gene, vascular endothelial growth factor (VEGF), correlated only
      when normalized to total RNA, as did microvessel density. Finally, mRNA levels of
      VEGF and the most popular housekeeping gene, glyceraldehyde-3-phosphate
      dehydrogenase (GAPDH), were significantly correlated in the colon. Our results
      suggest that the use of internal standards comprising single housekeeping genes
      or rRNA is inappropriate for studies involving tissue biopsies.

PMID- 12413465
TI  - Negative-ion matrix-assisted laser desorption and ionization time-of-flight mass
      spectra of complex phospholipid mixtures in the presence of phosphatidylcholine:
      a cautionary note on peak assignment.

PMID- 12413464
TI  - Parallel assessment of CpG methylation by two-color hybridization with
      oligonucleotide arrays.
AB  - We have developed a method for the parallel analysis of multiple CpG sites in
      genomic DNA for their state of methylation. Hypermethylation of CpG islands
      within the promoters and 5' exons of genes has been found to be a mechanism of
      transcriptional inactivation associated with a variety of tumors. The method that
      we developed relies on the differential reactivity of methylated and unmethylated
      cytosines with sodium bisulfite, which exclusively converts unmethylated
      cytosines to deoxyuracils. The resulting sequence changes are determined with
      single-nucleotide resolution by hybridization to an oligonucleotide array.
      Cohybridization with a reference sample containing a different label provides an
      internal standard for assessment of methylation state. This method provides
      advantages in parallelism over existing methods of methylation analysis. We have
      demonstrated this technique with a region from the promoter of the tumor
      suppressor gene p16, which is hypermethylated in many cancers.

PMID- 12413466
TI  - hCMV IE Promoter is responsive to B cell receptor signaling in a Bruton's
      tyrosine kinase dependent manner: caution in their use as internal controls.

PMID- 12413467
TI  - Equilibrium expert: an add-in to Microsoft Excel for multiple binding equilibrium
      simulations and parameter estimations.
AB  - An add-in to Microsoft Excel was developed to simulate multiple binding
      equilibriums. A partition function, readily written even when the equilibrium is
      complex, describes the experimental system. It involves the concentrations of the
      different free molecular species and of the different complexes present in the
      experiment. As a result, the software is not restricted to a series of predefined
      experimental setups but can handle a large variety of problems involving up to
      nine independent molecular species. Binding parameters are estimated by nonlinear
      least-square fitting of experimental measurements as supplied by the user. The
      fitting process allows user-defined weighting of the experimental data. The
      flexibility of the software and the way it may be used to describe common
      experimental situations and to deal with usual problems such as tracer reactivity
      or nonspecific binding is demonstrated by a few examples. The software is
      available free of charge upon request.

PMID- 12413468
TI  - Construction of a Tc1-like transposon Sleeping Beauty-based gene transfer plasmid
      vector for generation of stable transgenic mammalian cell clones.
AB  - We have constructed a single plasmid-, Tc1-like transposon-based gene transfer
      vector, termed the Prince Charming vector (pPC). The pPC vector was constructed
      by ligating the CMV-driven "Sleeping Beauty" transposase gene downstream to the
      Tc1-like transposon inverted repeat (IR) elements and by inserting the RSV
      promoter (to drive expression of the gene-of-interest) along with a multiple
      cloning site (MCS), a polyadenylation signal, and the SV40 promoter-driven
      neomycin gene, at a site flanked by the transposon IR elements. To assess the
      utility of the pPC vector, we cloned a red fluorescent protein (RFP) gene into
      the pPC vector at the MCS and transfected human TE85 osteosarcoma cells with the
      pPC-RFP expression vector using Effectene. Stable transgenic cell clones
      expressing RFP were selected with G418 sulfate and individual clones were
      isolated. After 4 weeks of clonal isolation and expansion, 99% of cells in each
      randomly selected clone expressed RFP strongly. Aliquots of each clone were then
      maintained in either the presence or the absence of G418 sulfate and were
      passaged weekly. Even after 6 months in culture in the absence of G418 sulfate,
      approximately 90% of the cells in each clone still maintained a strong expression
      level of RFP, indicating that these transgenic cell clones were stable and that
      the clonal stability of these clones did not require a constant selection
      pressure. In conclusion, we have developed a single plasmid-, Tc1-like transposon
      based gene transfer vector that can be used to generate stable transgenic
      mammalian cell clones.

PMID- 12413469
TI  - Self-assembled monolayers of globotriaosylceramide (Gb3) mimics: surface-specific
      affinity with shiga toxins.
AB  - Self-assembled monolayers (SAMs) of Gb3 mimics having different lengths of alkyl
      chains were prepared on gold surfaces, and their interactions with galactose
      specific lectin (RCA(120)) and Shiga toxins (Stxs) were investigated by a quartz
      crystal microbalance (QCM) in aqueous solutions. Their interaction with RCA(120)
      was enhanced owing to the "cluster effect," regardless of the alkyl chain length
      of the SAMs. The interaction with Stxs was dependent on the alkyl chain length of
      Gb3 mimics. Stx-1 and Stx-2 showed a stronger affinity to the Gb3C2 SAM with
      ethyl disulfide and to the Gb3C10 with decyl disulfide, respectively. Gb3
      glycoconjugate polymer with no alkyl spacer inhibited the adsorption of Stx-1 to
      Gb3C10 SAM but did not inhibit the adsorption of Stx-2 to Gb3C10 SAM. The results
      suggest that the alkyl chain of the glycolipid takes part in the binding to Stx-2
      but not to Stx-1, which is also supported by the computer simulation of Stx-1
      with a Gb3 model substance.

PMID- 12413470
TI  - Detection of 2,4,6-trinitrotoluene in seawater using a reversed-displacement
      immunosensor.
AB  - Reported in this study are the experimental design and results of an immunosensor
      for the detection of the explosive, 2,4,6-trinitrotoluene (TNT) in seawater using
      a reversed-displacement format. This reversed-displacement immunosensor
      methodology has successfully measured TNT in seawater by direct injection,
      eliminating the need for preconcentration or pretreatment of samples. A
      microcolumn containing an Affi-Gel resin derivatized with a 2,4,6-trinitrobenzene
      (TNB) moiety and a fluorophore-labeled anti-TNT antibody composed the immunoassay
      reactive chamber. Fluorophore-labeled anti-TNT antibody was incubated with the
      modified Affi-Gel resin until binding equilibrium was reached. Under a constant
      flow, samples containing TNT were introduced into the flow stream displacing the
      fluorophore-labeled TNT antibody. Limits of detection were 2.5ng/mL or part-per
      billion (ppb) for TNT in saline buffer and 25ppb in seawater with an analysis
      time of 10 min. Two anti-TNT antibodies with differing binding affinities were
      compared in the reversed-displacement assay format, and a correlation between
      affinity and detection limits was observed. Furthermore, we have demonstrated
      that the reversed-displacement format can be used to screen seawater samples
      containing TNT, remains effective after dozens of cycles, and provides
      significant fluorescence response before regeneration is required.

PMID- 12413471
TI  - Determination of platinated purines in oligoribonucleotides by limited digestion
      with ribonucleases T1 and U2.
AB  - Platinum complexes which are known to react preferentially with guanine (G) and
      adenine (A) bases of oligonucleotides can be used as tools to analyze their
      tertiary structures and eventually to cross-link them. However, this requires
      efficient methods to allow the identification and quantification of the
      corresponding adducts which have so far been developed only for
      oligodeoxyribonucleotides. Maxam-Gilbert type digestions cannot be used for RNAs
      and HPLC techniques would require too large amounts of expensive material for
      separation and further characterization. We report a method to determine
      platination sites on oligoribonucleotides based on the cleavage activity of
      ribonucleases T1 and U2. To test the method, these enzymes were first used under
      conditions of limited digestion on 5-mer oligoribonucleotides platinated at a
      single defined purine. The phosphodiester bond on the 3' side of platinated G or
      A appeared fully resistant to cleavage by ribonuclease T1 or U2, respectively. An
      inhibitory effect was also observed due to neighboring platinated purines, which
      decreases with their distance (-2, -1, +1, +2) from the cleavage site and with
      the enzyme concentration. The method allowed the identification and
      quantification of the platination sites of a 17-mer oligoribonucleotide, based on
      the analysis of the mixture of monoplatinated adducts.

PMID- 12413472
TI  - Kinetics and inhibition of glutamate carboxypeptidase II using a microplate
      assay.
AB  - Glutamate carboxypeptidase II (GCPII or prostate-specific membrane antigen or
      NAALADase) is an enzyme that catalyzes the hydrolysis of the neuropeptide N
      acetylaspartylglutamate (NAAG) to N-acetylaspartate (NAA) and glutamate (G).
      Inhibitors of GCPII provide neuroprotection in a variety of animal models of
      central nervous system disorders. Neuroprotection is probably the result of
      increased NAAG concentrations and decreased levels of excess toxic glutamate.
      Consequently, GCPII inhibitors could be useful therapeutic agents where increased
      glutamate levels are the result of increased GCPII activity. Current GCPII in
      vitro activity assays are cumbersome or have limited sensitivity. In this report
      we describe a microplate assay to study GCPII inhibition that is most sensitive,
      efficient, and generates little waste. GCPII turnover number (k(cat)) was 4s(-1)
      and the binding constant (K(m)) for NAAG and GCPII was 130nM. The apparent
      association rate constant for GCPII and NAAG (k(cat)/K(m)) was 3 x 10(7)M(-1)s(
      1). Inhibition studies with the GCPII inhibitor 2-(phosphonomethyl)pentanedioic
      acid (2-PMPA) demonstrated competitive inhibition with a K(i)=0.2nM.

PMID- 12413473
TI  - Determination of ferrichrome binding to the FhuA outer membrane transport
      protein, periplasmic accumulation of ferrichrome, or transport of ferrichrome
      into cells using a three-layer oil technique.
AB  - A new method for the determination of ferrichrome binding to the FhuA transporter
      in the Escherichia coli outer membrane, ferrichrome accumulation in the
      periplasmic space, and ferrichrome transport into the cytoplasm was developed.
      Cells were separated from residual, soluble, radiolabeled ferrichrome by
      centrifugation in a micro-test tube containing three layers of nonmixable
      solutions of different densities. Cells in the upper aqueous layer passed through
      the middle silicone oil layer, but did not enter the underlying NaI layer,
      thereby accumulating on top of the NaI layer; soluble compounds remained in the
      upper aqueous layer. Cells were then easily recovered by centrifugation, and
      radioactivity was determined by liquid scintillation counting. Reproducible
      results for all applications tested were obtained without the need for any
      washing steps. The method was tested by determination of receptor binding and
      transport of ferrichrome with various FhuA mutants which, in contrast to their
      transport activity, showed only a weak binding of ferrichrome to FhuA and
      compared with the commonly used cellulose nitrate filter method. Similar
      transport rates were obtained with the two methods, but binding of ferrichrome to
      the mutated FhuA proteins and accumulation of ferrichrome in the periplasm could
      be measured only with the new method.

PMID- 12413474
TI  - A high-throughput assay for measurement of multidrug resistance protein-mediated
      transport of leukotriene C4 into membrane vesicles.
AB  - This study investigated a high-throughput assay to measure multidrug resistance
      associated protein (MRP1)-mediated uptake into membrane vesicles. Typically, a
      rapid filtration technique using a 12-filter vacuum manifold is used. We report
      here the development of a 96-well microtiter dish assay. MRP1-transfected HeLa
      cells (HeLa-T5) were used for the membrane vesicle preparations. The uptake of
      50nM [3H]leukotriene C(4) (LTC(4)) was measured in a 96-well microtiter dish with
      rapid filtration onto a Perkin Elmer unifilter GF/B plate using a Perkin Elmer
      Filtermate 196. Counting of the isotype was conducted with a Perkin Elmer Top
      Count NXT. Uptake was adenosine 5'-triphosphate-dependent and linear over a 120-s
      time course. Uptake was inhibited by the leukotriene D(4) antagonist, MK 571,
      with a k(i) of 0.67 microM, and by the anti-MRP1 monoclonal antibody QCRL-3 but
      not by QCRL-1. Inhibition by estradiol-17-beta-glucuronide was 35-fold greater
      than inhibition by estradiol-3-beta-glucuronide. The kinetic parameters for
      LTC(4) uptake were determined to be a K(m) of 157nM with a V(max) of
      344pmol/min/mg protein. The properties of MRP1-mediated transport of LTC(4) are
      consistent with those previously reported. The microtiter dish assay is a more
      expedient method for measuring transport into membrane vesicles and will have
      applications to other transporters.

PMID- 12413475
TI  - Development of a fluorescent F-actin blot overlay assay for detection of F-actin
      binding proteins.
AB  - Interactions between cellular proteins and filamentous (F) actin are key to many
      cellular functions, e.g., cell motility, endocytosis, cell:cell adhesion, and
      cell:substrate adhesion. Previously, a functional assay using 125I-labeled F
      actin to detect a subset of F-actin binding proteins by blot overlay was
      developed. We have modified this assay to use the fluorescent label, Alexa 488,
      in place of 125Iodine. The detection limit for Alexa 488-labeled actin using a
      Molecular Dynamics STORM 860 Fluorescence/PhosphorImager was as little as 100pg
      of labeled actin. The Alexa 488 F-actin assay detects the same proteins from
      Dictyostelium discoideum and with approximately the same sensitivity
      (approximately 10 microg/ml F-actin final concentration) as the analogous 125I
      labeled F-actin blot overlay. The use of Alexa 488 F-actin for blot overlay
      assays requires no radioactive materials and generates no hazardous waste. Assays
      can be performed on the laboratory bench top and the blots imaged directly with a
      blue laser scanner, either wet or dry. In addition, the Alexa 488 fluorophore is
      highly resistant to photobleaching, does not decay, and may be stored frozen or
      lyophilized. Alexa 488 F-actin is a stable, cost-effective, nonhazardous probe
      used for rapid identification of a subset of F-actin binding proteins.

PMID- 12413476
TI  - A high-throughput genetic system for assessing the inhibition of proteins:
      identification of antibiotic resistance and virulence targets and their cognate
      inhibitors in Salmonella.
AB  - This study describes the development of a high-throughput genetic system for
      producing oligopeptides that can be used to identify molecular interactions
      leading to inhibition of specific proteins. Using a pathogenic bacteria model, we
      screened a library of clones expressing intracellular oligopeptides in order to
      identify inhibitors of proteins involved in antibiotic resistance and virulence.
      This method involved transforming the pathogen with an oligopeptide-encoding
      plasmid library, constructed using polymerase chain reaction and an
      oligonucleotide template designed to produce random oligopeptides composed of 2
      16 amino acids, and high-throughput screening for phenotype alterations in the
      pathogen. A subsequent complementation phase enabled the identification of the
      full-length bacterial protein inhibited by the oligopeptide. Using this method we
      were able to identify oligopeptides that inhibit virulence and/or drug resistance
      in Salmonella, Shigella, and Escherichia coli; specific virulence and/or drug
      resistance proteins of Salmonella, Shigella, and E. coli that are sensitive to
      inhibition; and putative oligopeptide-binding sites on the inhibited proteins.
      This system is versatile and can be extended to other pathogens for analogous
      studies and it can be modified for used in eukaryotic models for identifying
      protein interactions that can be targeted for inhibition. Additionally, this
      system can be used for identifying protein domains involved in any biomolecular
      interaction.

PMID- 12413477
TI  - Measurement of green fluorescent protein concentration in single cells by image
      analysis.
AB  - The gene encoding the green fluorescent protein (GFP) has been widely used in
      studies of gene expression. The GFP can be detected nondestructively in living
      cells or tissues by the green fluorescence of the protein under blue light.
      Solutions of enhanced GFP (EGFP) of known concentration were filled in glass
      capillaries and used to calibrate a method for quantitative determination of EGFP
      or GFP-S65T in plant cells. Images captured by a digital camera were analyzed to
      determine the linear range for measurement of EGFP expression. The value of the
      method was illustrated by analysis of the relative levels of GFP expression under
      control of different promoters in aleurone cells of barley.

PMID- 12413478
TI  - Surface plasmon resonance characterization of drug/liposome interactions.
AB  - Using Biacore's surface plasmon resonance-based biosensor technology, we
      developed experimental protocols and probed test conditions required to study
      drugs interacting with liposome surfaces. Liposome capture on hydrophobic alkane
      surfaces (Pioneer L1 chip) was reproducible and stable under variable conditions
      of pH, temperature, lipid content, cholesterol content, and buffer
      dimethylsulfoxide concentration. Importantly, drug binding responses were
      directly proportional to the amount of lipid captured, while the kinetics of drug
      binding and the magnitude of the responses correlated with a drug's chemical
      composition. In general, anionic drugs tended to rapidly dissociate from the
      surface, while cationic drugs displayed heterogeneous binding, suggesting
      partitioning within the lipid bilayer itself. The results illustrate how surface
      plasmon resonance can be used to establish passive transport properties of drugs.

PMID- 12413479
TI  - An enzymatic method of analysis for GDP-L-fucose in biological samples, involving
      high-performance liquid chromatography.
AB  - To investigate the biological significance of GDP-L-fucose, we established a
      unique method for the determination of GDP-L-fucose levels in microsomal
      fractions, using an HPLC assay of alpha 1-6-fucosyltransferase (alpha1-6-FucT),
      an enzyme that catalyzes the synthesis of core fucosylation in N-glycans. A
      microsomal protein and a large excess of fluorescence-labeled synthetic
      oligosaccharide (a substrate) were incubated with a large excess of alpha1-6
      FucT. The fluorescent intensity of the fucosylated reaction product, which was
      analyzed by isocratic reverse phase HPLC, was proportional to the level of GDP-L
      fucose in the microsomal fractions over the range 0.20-10 pmol. This assay is
      applicable to the determination of the GDP-L-fucose content in various cancer
      cell lines as well as rat liver and would be useful in developing a better
      understanding of the fucosylation potential of such cells and tissues.

PMID- 12413480
TI  - Development of a biosensor-based method for detection and isotyping of antibody
      responses to adenoviral-based gene therapy vectors.
AB  - A biosensor-based assay, using a surface plasmon resonance detection system, was
      developed to detect and isotype anti-adenoviral antibodies in patients dosed with
      an adenoviral-based gene therapy vector. In the assay, whole, intact virus was
      immobilized onto the sensor chip surface. Electron microscopy and monoclonal
      antibody studies provide evidence that the virus remains intact after
      immobilization. The patients tested had preexisting serum levels of anti
      adenoviral antibodies. A classic anamnestic response was observed in patients
      dosed with the gene-therapy agent. Isotyping experiments indicated that IgG
      antibodies predominated in serum even at the predose time point. Analysis of
      ascites fluid samples from some patients indicated detectable levels of IgA in
      addition to IgG. Results obtained using the biosensor-based assay corresponded to
      an existing enzyme-linked immunosorbent assay. The assay was easy to perform and
      the automated instrument reduced the required "hands on" time. In addition to
      studying the development of anti-adenoviral antibodies, the techniques described
      may be applied to virus:receptor interaction studies or antiviral drug:virus
      interaction studies.

PMID- 12413481
TI  - Automated column-switching high-performance liquid chromatography system for
      quantifying N-methyl-D- and -L-aspartate.
AB  - The occurrence and biological significance of the D-amino acids, N-methyl-D
      aspartate (NMDA) and N-methyl-L-aspartate (NMLA), have been recently studied in a
      variety of living organisms. In this study, we established a highly sensitive and
      reliable fluorometric HPLC system for determining levels of N-methyl-aspartate
      (NMA). The system comprises fluorescent derivatization of NMA with 4-fluoro-7
      nitro-2,1,3-benzoxadiazole (NBD-F) and two chromatographic steps: one that
      separates NMA from other primary amino acids in reverse-phase mode and another
      that enantioseparates NMDA and NMLA in a normal-phase mode. These two steps are
      linked by an automated column-switching system. A simple pretreatment step with o
      phthalaldehyde to remove primary amino acids that can interfere with sensitivity
      is also described. The detection limit for NMDA is as low as 5fmol and the
      correlation between peak heights and concentrations between 5fmol and 1pmol is
      satisfactory (r=0.999). Following sample preparation and separation using the
      column-switching HPLC system, more than 80% of NMDA was recovered from rat liver
      homogenates spiked with NMDA. This method was employed to determine the levels of
      NMDA in tissues from bivalves and the results obtained were consistent with the
      values reported previously.

PMID- 12413482
TI  - Kinetic studies on the rate of hydrolysis of N-ethyl-N'
      (dimethylaminopropyl)carbodiimide in aqueous solutions using mass spectrometry
      and capillary electrophoresis.

PMID- 12413483
TI  - High-performance liquid chromatography method for detecting prostate-specific
      membrane antigen activity.

PMID- 12413484
TI  - Phosphatidylinositol 3,5-bisphosphate: metabolism and function.
AB  - Phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P(2)) is the most recently
      discovered PtdInsP(2) isomer. It is likely that PtdIns(3,5)P(2) is ubiquitous to
      eukaryotes, and that it performs a number of important cellular functions,
      including vacuolar homeostasis, retrograde trafficking from the vacuole, and
      protein sorting at the multivesicular body. This review describes the metabolism
      of PtdIns(3,5)P(2) and discusses the potential functions for this lipid.

PMID- 12413485
TI  - The cyclic-ADP-ribose signaling pathway in human myometrium.
AB  - Human myometrial contraction plays a fundamental role in labor. Dysfunction of
      uterine contraction is an important cause of failure in progression of labor. The
      mechanisms of control of uterine contractions are not completely understood. It
      appears that intracellular Ca(2+) mobilization may play an important role during
      uterine contraction. Several mechanisms of intracellular Ca(2+) mobilization have
      been described. However, in human uterus only the inositol 1,4,5-trisphosphate
      induced Ca(2+) release has been extensively studied to date. In view of the
      identification of the presence of functional ryanodine channels in myometrium, we
      explored the role of the endogenous regulator of the ryanodine channel cyclic-ADP
      ribose in human myometrial Ca(2+) regulation. Cyclic-ADP-ribose (cADPR) is a
      naturally occurring nucleotide implicated in the regulation of the gating
      properties of the ryanodine channel, in fact cADPR may be a second messenger that
      activates the ryanodine receptor. Here we explore the components of the cADPR
      system in human myometrium. We found that human myometrium contains all the
      components of the cADPR pathway including (1) cADPR-activated microsomal Ca(2+)
      release and (2) enzymes responsible for synthesis and degradation of cADPR and,
      furthermore, that intracellular levels of cADPR were detected in human myometrial
      tissue. These data indicate that the cADPR system is present and operational in
      human myometrial tissue. Further research is warranted to determine the role of
      this new signaling molecule in uterine contraction.

PMID- 12413486
TI  - Positive regulation of connexin32 transcription by hepatocyte nuclear factor
      1alpha.
AB  - Connexin32 (Cx32) encodes the predominant gap junction protein expressed by
      hepatocytes. We investigated the transcriptional control of Cx32 in expressing
      and nonexpressing rat liver cell lines and hypothesized that a putative
      hepatocyte nuclear factor-1 (HNF-1) binding site (centered at mp -187) in the
      liver-active, P1 promoter is essential for transcription of Cx32. HNF-1alpha was
      expressed by Cx32-expressing rat liver cell lines and bound the promoter at the 
      187 site, but was not expressed by non-Cx32-expressing hepatic lines. Stable
      transfection of non-Cx32-expressing WB-F344 rat liver epithelial cells with HNF
      1alpha stimulated a transfected Cx32 promoter element (mp -244 to -33), binding
      of HNF-1alpha to the -187 site, and expression of endogenous Cx32. Site-directed
      mutagenesis of this HNF-1 binding site abolished HNF-1alpha binding and proximal
      promoter activity. Hepatic Cx32 expression was also significantly decreased in
      HNF-1alpha(-/-) mice. These data indicate that HNF-1alpha is a positive regulator
      of Cx32 expression in hepatic cells.

PMID- 12413487
TI  - A putative DNA-binding domain in the NUCKS protein.
AB  - We have studied the DNA-binding properties of a NUCKS-derived, synthetic peptide
      containing an extended GRP motif. This peptide binds to random-sequence DNA, but
      did not bind preferentially to poly(dA-dT). A synthetic peptide with the same
      amino acid composition but with a random sequence did not bind to DNA, suggesting
      that the structure of the DNA-binding domain plays a pivotal role in the
      interaction with DNA. NMR and graphic modeling were employed to investigate the
      structure of the synthetic peptide. It was shown that the DNA-binding peptide
      constituted an alpha helix in phosphate buffer at pH 5.5. Docking results
      indicated an almost perfect fit for this small, helical peptide into the major
      groove of DNA with the possibility of four basic residues interacting with the
      phosphate backbone of DNA. One consensus site for phosphorylation by Cdk1 is
      located in the N-terminal end of the DNA-binding peptide. Upon phosphorylation of
      this site, the binding to DNA was completely prohibited. Immunofluorescence
      experiments showed that NUCKS was located in the nuclei in proliferating cells in
      interphase of the cell cycle, but was distributed throughout the cytoplasm in
      mitotic cells.

PMID- 12413488
TI  - Identification of histidine residues important in the catalysis and structure of
      aspartyl aminopeptidase.
AB  - Aspartyl aminopeptidase (DAP), a widely distributed and abundant cytosolic
      enzyme, removes glutamyl or aspartyl residues from N-terminal acidic amino acid
      containing peptides. DAP is a member of the M18 family of the MH clan of
      cocatalytic metallopeptidases. The human and mouse enzymes have been cloned. We
      have identified 8 highly homologous eukaryotic sequences that are probable
      aspartyl aminopeptidases. Eight histidine residues of human DAP were sequentially
      mutated to phenylalanine. Mutation of His94, His170, and His440 abolished
      enzymatic activity. His94 and His440 are postulated to be involved in binding
      cocatalytic zinc atoms by homology with other members of the MH clan. Mutation of
      His352 dramatically reduced enzyme activity. Gel-filtration analysis of the
      His352 mutant revealed destabilization of the quaternary structure and
      dissociation of the native 440-kDa enzyme. Mutation of His33 and of histidines
      residing in a cluster at residues 349, 359, and 363 all decreased k(cat). These
      studies reveal an important role for histidine residues both in catalysis and in
      the structural integrity of DAP.

PMID- 12413489
TI  - A new dipeptide, O-phosphoserylethanolamine isolated from Agkistroden blomhoffi
      (mamushi).
AB  - A new dipeptide was isolated from several tissues of Agkistroden blomhoffi
      (mamushi: a venomous snake in Japan), using ion-exchange resins and thin-layer
      chromatography. It was identified as O-phosphoserylethanolamine by mass
      spectrometry and comparison with synthetic compounds using several methods. This
      compound was contained in several mamushi tissues including the liver, heart,
      brain, bile, and muscle. The concentrations of O-phosphoserylethanolamine in the
      liver, brain, muscle, skin, heart, and bile were 7.17+/-3.11,16.98+/-4.25,37.37+/
      7.88,37.56+/-8.97,23.93+/-6.11, and 22.21+/-5.76 micromol/g, respectively.

PMID- 12413490
TI  - The destruction box of the cyclin Clb2 binds the anaphase-promoting
      complex/cyclosome subunit Cdc23.
AB  - Properly regulated cyclin proteolysis is critical for normal cell cycle
      progression. A nine-amino acid peptide motif called the destruction box (D box)
      is present at the N terminus of the yeast mitotic cyclins. This short sequence is
      required for cyclin ubiquitination and subsequent proteolysis. The anaphase
      promoting complex/cyclosome (APC/C) is a multisubunit E3 required for cyclin
      ubiquitination. We have tested the D box of five mitotic cyclins for interaction
      with six APC/C subunits. The APC/C subunit Cdc23, but not five other subunits
      tested, interacted by two-hybrid analysis with the N terminus of wild-type Clb2.
      None of these subunits interacted with the N termini of the cyclins Clb1, Clb3,
      or Clb5. Mutations in the D box sequences of Clb2 inhibited interaction with
      Cdc23 both in vivo and in vitro. Our results provide the first evidence for a
      direct interaction between an APC/C substrate (Clb2) and an APC/C subunit
      (Cdc23).

PMID- 12413491
TI  - Characterization of a human and mouse tetrapyrrole-binding protein.
AB  - The cDNA for p22HBP has been cloned from human and mouse, and the protein
      expressed, purified, and characterized. Both mouse and human proteins bind heme
      and porphyrins with micromolar K(d)s, are highly homologous, monomeric, and
      soluble, and have a cytoplasmic location. The proteins bind metalloporphyrins,
      free porphyrins, and N-methylprotoporphyrin with similar affinities, and
      mutations of a selected set of putative metal ligating residues did not have any
      significant effect on the measured K(d)s. That the presence or absence of metal
      in the porphyrin has no effect on the binding constants and the observation that
      the EPR signal for heme does not change upon binding to the protein strongly
      suggest that p22HBP is a generic tetrapyrrole-binding protein rather than a
      dedicated heme-binding protein. A role for p22HBP in cellular porphyrin
      metabolism is discussed.

PMID- 12413492
TI  - Transcobalamin II expression is regulated by transcription factor(s) binding to a
      hexameric sequence (TGGTCC) in the promoter region of the gene.
AB  - Transcobalamin II (TCII) is a plasma protein that transports cobalamin to tissues
      for cellular uptake by receptor-mediated endocytosis. Human umbilical vein
      endothelial cells (HUVEC) in culture constitutively express TCII. However, in
      other cell lines, TCII expression is dependent on high cell density. ECV304, a
      cell line with some properties of HUVEC, expresses TCII only when seeded at high
      density. An electrophoretic mobility-shift assay using nuclear extract from such
      high-density-seeded ECV 304 cells shifted a 24-bp oligonucleotide probe to
      generate an unique slow moving band that was competed out by unlabeled probe.
      This unique band was not observed with nuclear extract from low-density-seeded
      ECV304 cells. A 3(') sequence, 5(')-TGGTCC-3('), in the 24-bp oligonucleotide was
      identified as the binding site for the nuclear protein(s) because this band was
      not competed out when the hexameric sequence was scrambled to 5(')-CTTCTT-3(').
      Binding of a transcription factor(s) to this hexamer, that is located 121bp
      upstream of the transcription start site, appears to be essential for the
      regulated or constitutive expression of TCII.

PMID- 12413493
TI  - Purification and kinetic properties of UDP-glucose dehydrogenase from sugarcane.
AB  - In this study, UDP-glucose dehydrogenase has been purified to electrophoretic
      homogeneity from sugarcane (Saccharum spp. hybrid) culm. The enzyme had a pH
      optimum of 8.4 and a subunit molecular mass of 52 kDa. Specific activity of the
      final preparation was 2.17 micromol/min/mg protein. Apparent K(m) values of
      18.7+/-0.75 and 72.2+/-2.7 microM were determined for UDP-glucose and NAD(+),
      respectively. The reaction catalyzed by UDP-glucose dehydrogenase was
      irreversible with two equivalents of NADH produced for each UDP-glucose oxidized.
      Stiochiometry was not altered in the presence of carbonyl-trapping reagents. With
      respect to UDP-glucose, UDP-glucuronic acid, and UDP-xylose were competitive
      inhibitors of UDP-glucose dehydrogenase with K(i) values of 292 and 17.1 microM,
      respectively. The kinetic data are consistent with a bi-uni-uni-bi substituted
      enzyme mechanism for sugarcane UDP-glucose dehydrogenase. Oxidation of the
      alternative nucleotide sugars CTP-glucose and TDP-glucose was observed with rates
      of 8 and 2%, respectively, compared to UDP-glucose. The nucleotide sugar ADP
      glucose was not oxidized by UDP-glucose dehydrogenase. This is of significance as
      it demonstrates carbon, destined for starch synthesis in tissues that synthesize
      cytosolic AGP-glucose, will not be partitioned toward cell wall biosynthesis.

PMID- 12413494
TI  - Type I collagen contains at least 14 cryptic fibronectin binding sites of similar
      affinity.
AB  - There is uncertainty in the literature regarding the number and location of
      fibronectin binding sites on denatured collagen. Although most attention has
      focused on a single site near the collagenase-sensitive region of each alpha
      chain, there is evidence for additional sites in other regions. We treated bovine
      type I collagen with cyanogen bromide, labeled the resulting mixture with
      fluorescein, and separated the peptides by sodium dodecyl sulfate-polyacrylamide
      gel electrophoresis. Fluorescent bands were excised from the gel and dialyzed
      exhaustively to remove detergent. Titration of eight distinct fluorescent-labeled
      fragments with the 42-kDa gelatin-binding fragment of fibronectin caused
      increases in anisotropy that were fully reversible with unlabeled gelatin. By
      fitting the dose responses it was possible to calculate apparent K(d)'s whose
      values ranged between 1 and 4 microM. The largest fragment, alpha(2)-CB3,5,
      composing about 2/3 of the alpha(2) chain, when further digested with
      endoproteinase Lys-C, yielded at least three additional subfragments that also
      bound with similar affinities. Thus, there appear to be at least 14 distinct
      fibronectin binding sites of similar affinity in bovine type I collagen, five on
      each of the alpha(1) chains and four on the alpha(2) chain. Experiments with
      several synthetic peptides failed to reveal the exact nature of the binding site.

PMID- 12413495
TI  - Structural and immunological aspects of Polybia scutellaris Antigen 5.
AB  - Vespid venoms contain Antigen 5, an important allergen whose primary structure
      and immunological behavior have been extensively studied from venoms of vespids
      of the Northern Hemisphere. We report herein structural and immunological aspects
      of Antigen 5 from Polybia scutellaris subspecies rioplatensis (vulgar name:
      camoati) found in South America. Mast cell degranulation, histamine release, and
      IgE induction experiments performed in mice allow us to suggest that P.
      scutellaris Antigen 5 is a variant with reduced IgE response and anaphylactic
      activity. Sequence data indicate that the protein has a 72.5-90.3% similarity to
      that of members of the vespid Antigen 5 family with an already known primary
      structure. Moreover, results suggest that the protein-a new member of an
      extracellular protein superfamily-could be a good candidate for immunotherapy
      related to vespid allergy.

PMID- 12413496
TI  - Clofibric acid stimulates branched-chain amino acid catabolism by three
      mechanisms.
AB  - Clofibrate promotes catabolism of branched-chain amino acids by increasing the
      activity of the branched-chain alpha-keto acid dehydrogenase [BCKDH] complex.
      Depending upon the sex of the rats, nutritional state, and tissue being studied,
      clofibrate can affect BCKDH complex activity by three different mechanisms.
      First, by directly inhibiting BCKDH kinase activity, clofibrate can increase the
      proportion of the BCKDH complex in the active, dephosphorylated state. This
      occurs in situations in which the BCKDH complex is largely inactive due to
      phosphorylation, e.g., in the skeletal muscle of chow-fed rats or in the liver of
      female rats late in the light cycle. Second, by increasing the levels at which
      the enzyme components of the BCKDH complex are expressed, clofibrate can increase
      the total enzymatic activity of the BCKDH complex. This is readily demonstrated
      in livers of rats fed a low-protein diet, a nutritional condition that induces a
      decrease in the level of expression of the BCKDH complex. Third, by decreasing
      the amount of BCKDH kinase expressed and therefore its activity, clofibrate
      induces an increase in the percentage of the BCKDH complex in the active,
      dephosphorylated state. This occurs in the livers of rats fed a low-protein diet,
      a nutritional condition that causes inactivation of the BCKDH complex due to
      upregulation of the amount of BCKDH kinase. WY-14,643, which, like clofibric
      acid, is a ligand for the peroxisome-proliferator-activated receptor alpha
      [PPARalpha], does not directly inhibit BCKDH kinase but produces the same long
      term effects as clofibrate on expression of the BCKDH complex and its kinase.
      Thus, clofibrate is unique in its capacity to stimulate BCAA oxidation through
      inhibition of BCKDH kinase activity, whereas PPARalpha activators in general
      promote BCAA oxidation by increasing expression of components of the BCKDH
      complex and decreasing expression of the BCKDH kinase.

PMID- 12413497
TI  - Purification and characterization of a lectin from wild sunflower (Helianthus
      tuberosus L.) tubers.
AB  - A lectin (HTTL) was isolated from Helianthus tuberosus L. (wild sunflower) tubers
      using ion-exchange chromatography, gel filtration, and affinity chromatography.
      The lectin agglutinated both untreated and trypsin-treated rabbit erythrocytes
      and did not agglutinate human blood cells of groups A, B, and O. The gel
      filtration showed the native molecular mass of 72 kDa and subunit molecular
      masses of 17 and 18.5 kDa on 12% SDS-PAGE. The lectin activity was inhibited by D
      mannose. The tetrameric protein revealed a unique characteristic by forming a
      broad zone of protein in native PAGE at pH 8.3, which dissociated into seven
      subunits of varying e/m ratios on acid gel at pH 4.3. These seven bands revealed
      two polypeptide species of molecular masses 17 and 18.5 kDa on 12% SDS-PAGE, as
      in the case of the native protein. The result indicated that of the seven
      subunits, three were homotetramers of 17 kDa, one was a homotetramer of 18.5 kDa,
      and three were heterotetramers of 17 and 18.5 kDa. The lectin was thermostable
      with broad pH optima (pH 4-8) and had no requirement for divalent metal cations
      for its activity. The amino acid composition showed that the lectin contained
      higher amounts of glycine, alanine, and lysine, but no methionine. The sugar
      content was estimated to be 5.3% mannose equivalent. The HTTL was mitogenic to
      mouse spleen (total) cells at 25 microg/ml concentration. The lectin showed
      characteristics different from those of the earlier reported H. tuberosus tuber
      lectins and hence opens up a new avenue to investigate the structure-function
      relationship of lectin in Helianthus species.

PMID- 12413498
TI  - Impact of atrial fibrillation on mortality in patients with chronic heart
      failure.
AB  - Chronic heart failure and atrial fibrillation often occur together. The aim of
      the study is to review the available literature on the impact of atrial
      fibrillation on mortality in patients with heart failure. Using MEDLINE six full
      papers were identified. In the studies with severe heart failure atrial
      fibrillation did not emerge as an independent predictor of mortality beyond
      standard clinical variables. In contrast, atrial fibrillation was associated with
      increased mortality in case of mild-to-moderate heart failure.

PMID- 12413499
TI  - Thyronin treatment in adult and pediatric heart surgery: clinical experience and
      review of the literature.
AB  - Thyroid hormone has multiple direct and indirect effects on the heart and the
      vasculature. Many signs and symptoms of thyroid dysfunction are manifest by the
      cardiovascular system. Furthermore, many cardiovascular diseases are adversely
      affected by the concomitant presence of either hyper- or hypothyroidism: it is
      still being debated whether these alterations are the consequence of increased
      cardiac workload alone or are due to the intrinsic properties of thyroid hormone.
      There are three potential mechanisms by which thyroid hormone might exert a
      cardiovascular action: (1) direct effects at the cellular level (inotropic and
      chronotropic effect); (2) interaction with the sympathetic nervous system; and
      (3) alteration of the peripheral circulation through changes in preload,
      afterload and energy metabolism. We treated 54 adult and seven pediatric patients
      suffering from severe low cardiac output in different clinical conditions with a
      mean bolus dosage of 2+/-1.5 microg h(-1) of T(3), followed by a continuous
      infusion of 0.4+/-0.3 microg h(-1) for a mean duration of 48+/-12 h. In 45
      patients, stabilization of the hemodynamic situation with a decrease in inotropic
      support requirement was observed; however, in 11 patients no beneficial effects
      were observed. From this experience we suggest that T(3) treatment may improve
      hemodynamics in a substantial proportion of cardiac and cardiosurgical patients
      in whom more conventional treatment is unsuccessful.

PMID- 12413500
TI  - Simultaneous angiotensin converting enzyme inhibition moderates ventricular
      dysfunction caused by doxorubicin.
AB  - AIMS: The purpose of this study was to determine that the administration of an
      angiotensin converting enzyme (ACE) inhibitor enalapril would confer protection
      against doxorubicin-induced experimental heart failure, and attenuate the
      development of left ventricular dysfunction. METHODS: Seventeen dogs were
      chronically instrumented with an intracoronary catheter and received doxorubicin
      weekly for 4 weeks. Animals were assigned to two groups: group 1: untreated heart
      failure; and group 2: simultaneous enalapril administration (5 mg twice a week).
      Hemodynamic data were obtained at week 0 and 12. Echocardiography was performed
      weekly. RESULTS: Survival improved with simultaneous enalapril administration
      (36% in group 1 vs. 100% in group 2, P=0.04). The increase in the left
      ventricular end-diastolic pressure was significantly reduced at week 12 (17+/-1
      mmHg in group 1 vs. 9+/-1 mmHg in group 2, P=0.0042). The fall in left
      ventricular stroke work index was significantly prevented (52% in group 1 vs. 21%
      in group 2, P=0.006). The increase in right ventricular end-diastolic diameter
      was significantly reduced by enalapril prophylaxis. CONCLUSION: Simultaneous
      treatment with enalapril was beneficial in the prevention of doxorubicin-induced
      cardiomyopathy.

PMID- 12413501
TI  - Myocardial lactate dehydrogenase patterns in volume or pressure overloaded left
      ventricles.

PMID- 12413502
TI  - Increased levels of high sensitive C-reactive protein in patients with chronic
      rheumatic valve disease: evidence of ongoing inflammation.
AB  - The precise pathogenetic mechanism(s) of rheumatic fever and rheumatic heart
      disease have never been defined. C-reactive protein (CRP) is increased in
      patients with acute rheumatic fever, but it is not known whether plasma levels
      increase in patients with chronic rheumatic valve disease. The aim of this study
      was to determine the role of inflammation detected by high sensitivity CRP (hs
      CRP) levels in the progression of chronic rheumatic valve disease. A total of 113
      patients with chronic rheumatic valve disease (81 women, 32 men; mean age 40+/-14
      years, range 13-70), 51 patients with prosthetic valve(s) (31 women, 20 men; mean
      age 48+/-13 years, range 21-71) and 102 healthy subjects (68 women, 34 men, mean
      age 41+/-12 years, range 25-73), as a control group, were assessed. Patients with
      acute rheumatic fever, acute infection, inflammatory disease, malignancy, acute
      myocardial infarction and trauma were excluded. hs-CRP was determined using latex
      enhanced immunonephelometric assays on a BN II analyzer (Behring). Transthoracic
      echocardiography was performed in all patients in order to evaluate valvular
      disease. Levels of hs-CRP were significantly higher in patients with chronic
      rheumatic heart disease than in patients with prosthetic valve(s) and healthy
      subjects (0.62+/-0.64 vs. 0.35+/-0.41 vs. 0.24+/-0.18 mg/l, P<0.01 and P<0.001
      respectively). No correlation was observed between CRP and age, sex or functional
      capacity. We found that hs-CRP is increased in chronic rheumatic heart disease;
      this may indicate that inflammatory response still persists in the chronic phase.

PMID- 12413503
TI  - Serum to urinary sodium concentration ratio is an estimate of plasma renin
      activity in congestive heart failure.
AB  - We investigated the relationship between plasma renin activity (PRA) and serum
      ([sNa(+)]) and urinary ([uNa(+)]) sodium concentrations in 124 congestive heart
      failure (CHF) patients (II-IV NYHA class) and 20 healthy subjects. According to
      PRA (> or <3 ng ml(-1) h(-1)) and [sNa(+)] (> or <135 mEq l(-1)), patients were
      classified as Group A (normal PRA and normal [sNa(+)], n=39), Group B (increased
      PRA and normal [sNa(+)], n=62) and Group C (low [sNa(+)], n=23). Measurements
      were performed at rest and, in 26 cases, after extracorporeal ultrafiltration
      (UF). At rest, [sNa(+)] and [uNa(+)], and their difference ([sNa(+)]-[uNa(+)]),
      were linearly correlated with PRA, but the values did not allow differentiation
      of control subjects from patients or differentiation of patients with from those
      without renin-angiotensin system (RAS) activation. Conversely, the
      [sNa(+)]/[uNa(+)] ratio showed the best correlation with PRA (r=0.79, P<0.0001).
      UF-induced PRA changes were linearly correlated with [sNa(+)]/[uNa(+)] ratio
      changes (r=0.67, P=0.002), but not with those of [sNa(+)], [uNa(+)] and [sNa(+)]
      [uNa(+)]. In CHF, the [sNa(+)]/[uNa(+)] ratio best correlates with PRA and
      reflects the basal activity as well as the rapid changes (as those induced by UF)
      of the RAS. Therefore, it can be considered a strong and easily available marker
      of PRA.

PMID- 12413504
TI  - Autonomic function in elderly patients with chronic heart failure.
AB  - AIMS: Autonomic function (AF) is attenuated by heart failure (HF). Reports have
      been based on studies of young patients with systolic heart failure (SHF).
      However, HF is a disease of older patients who are more likely to have diastolic
      heart failure (DHF). We investigated whether age alters AF in elderly HF patients
      and whether the haemodynamic type of HF influences AF. METHOD AND RESULTS: Thirty
      six elderly HF (Framingham criteria) patients (11 with SHF, 25 with DHF) and 21
      matched healthy subjects underwent simple bedside AF tests. Compared with the
      reference values for healthy adults, the mean E:I ratios and the median 30:15
      ratios standing were all essentially normal. The median 30:15 ratios tilt and the
      mean Valsalva ratios were all significantly below the reference value (P for all
      cases <<0.050). Comparing three groups, there were no significant differences for
      mean E:I ratio (P=0.111), 30:15 tilt (P=0.619) and 30:15 standing (P=0.167),
      whereas there were significant differences for the mean Valsalva ratios
      (P=0.001). The mean Valsalva ratio of the SHF patients was significantly lower
      than that for the DHF patients (P<0.001) which in turn was significantly lower
      than the result of the healthy subjects (P<0.001). CONCLUSION: There is an age
      related impairment in AF with further impairment occurring in patients with HF.
      However, the severity of autonomic dysfunction is less in patients with DHF
      compared with patients with SHF.

PMID- 12413505
TI  - QT duration and dispersion response to exercise in coronary artery disease
      patients with and without myocardial infarction.

PMID- 12413506
TI  - Cardiorespiratory system dynamics in chronic heart failure.
AB  - AIMS: With the complex demodulation (CDM) method, we assessed the instantaneous
      amplitude and frequency of cardiovascular (CV) and respiratory oscillations, and
      the instant phase (IP) between the CV and respiratory signals using respiration
      as a periodic forced stimulation. We hypothesised a possible lack of
      synchronisation between CV and respiratory signals under regular breathing at
      different frequencies. METHODS: RR interval (ECG), blood pressure (SBP/DBP,
      Finapress), respiration (Respitrace) were monitored during two random-order
      periods of voluntary paced-breathing (0.15 Hz/0.25 Hz) in 10 moderate CHF
      patients and 10 age-matched controls. The CDM method provides the amplitude and
      frequency of a particular spectral component as a function of time in both LF and
      HF bands. IP between CV and respiratory oscillations was assessed using the real
      modulating breathing rate. RESULTS: (i) Continuous phase variations between CV
      oscillations and the respiratory signal were evidenced in CHF patients, the
      slower the breathing rate, the greater the phase variation (RR/Resp; 0.25 Hz,
      23+/-17 degrees; 0.15 Hz, 46+/-57 degrees, P<0.01; RR/Resp at 0.15 Hz 6+/-3 vs.
      46+/-57 P<0.01 controls vs. CHF). Phase was constant in controls. (ii) In
      patients, the instant amplitude of the cardiovascular oscillations in the high
      frequency domain is more markedly altered when the breathing rate was slowed down
      as compared to controls. CONCLUSION: The lack of synchronisation between
      physiological signals during voluntary breathing in CHF patients highlights a
      central uncoupling between CV and respiratory neuronal activities.

PMID- 12413507
TI  - Exercise and muscle strength training and their effect on quality of life in
      patients with chronic heart failure.
AB  - BACKGROUND: There is now evidence that moderate training plays an important role
      in the treatment of chronic heart failure. No clear instructions exist to date as
      to how such training programs should be carried out. AIM: to assess the
      efficiency of a training program including bicycle ergometer training, moderate
      muscle strength training and the 6-min walk test and their influence on quality
      of life, anxiety and depression. METHODS AND RESULTS: Patients (67 male, 21
      female) underwent a standardized 4-week training program. BASELINE DATA:
      LVEF=31+/-8%; LVEDD=143+/-59 ml; peak VO(2)=13.9+/-4.6 kg/ml. No adverse side
      effects could be observed. At discharge LVEF was 37+/-9%, (P=0.001); LVEDD=131+/
      44ml (P=0.01); and peak VO(2)=15.4+/-5.0 kg/ml. Quality of life improved
      significantly in nearly all domains and in summary score. There were no
      significant changes in anxiety and depression. There is a negative correlation
      between the initial workload and changes in physical health (r=-0.42, P=0.001)
      and only a weak correlation between age and positive changes in physical health
      (r=0.26, P=0.05). CONCLUSIONS: A standardized training program including moderate
      muscle strength training could be performed safely and demonstrated improvement
      in clinical parameters and quality of life.

PMID- 12413508
TI  - Neurohumoral prediction of left-ventricular morphologic response to beta-blockade
      with metoprolol in chronic left-ventricular systolic heart failure.
AB  - BACKGROUND: In order to tailor therapy in heart failure, a solution might be to
      develop sensitive and reliable markers that can predict response in individual
      patients or monitor effectiveness of therapy. AIMS: To evaluate neurohumoral
      factors as markers for left-ventricular (LV) antiremodelling from metoprolol
      treatment in patients with chronic LV systolic heart failure. METHODS: Forty-one
      subjects randomised to placebo or metoprolol were studied with magnetic resonance
      imaging and blood samples to measure LV dimensions and ejection fraction,
      epinephrine, norepinephrine, plasma renin activity, aldosterone, atrial (ANP) and
      brain natriuretic peptides, arginine-vasopressin and endothelin-1 at baseline, 5
      weeks and 6 months after randomisation. RESULTS: Baseline ANP was identified as
      sole independent marker for changes in LV end-diastolic (deltaLVEDVI: r=-0.70,
      P=0.002), and end-systolic (deltaLVESVI: r=-0.53, P=0.03) volumes during
      metoprolol treatment. Change in ANP during the study was an independent marker
      for deltaLVEDVI: r=0.66, P=0.004, and deltaLVESVI: r=0.69, P=0.002 in the entire
      metoprolol group, but at the individual patient level, results were less clear.
      CONCLUSION: The pre-treatment plasma level of ANP may be a predictor of LV
      antiremodelling from treatment with metoprolol in patients with chronic heart
      failure. However, the potential for individual neurohumoral monitoring of the
      effects on LV dimensions during beta-blockade appears limited.

PMID- 12413509
TI  - Antithrombotic therapy is associated with better survival in patients with severe
      heart failure and left ventricular systolic dysfunction (EPICAL study).
AB  - BACKGROUND: In patients with congestive heart failure (CHF), clinical trials have
      demonstrated the benefit of a number of drugs on morbidity and mortality.
      Nevertheless so far, there is no published controlled study of long-term
      antithrombotic therapy in patients with CHF. The aim of this work was to identify
      the relationship between cardiovascular drug use, especially antithrombotic
      therapy, and survival of CHF patients in current clinical practice, using an
      observational, population-based database. METHODS: The EPICAL study
      (Epidemiologie de l'Insuffisance Cardiaque Avancee en Lorraine) has identified
      prospectively all patients with severe CHF in the community of Lorraine.
      Inclusion criteria were age 20-80 years in 1994, at least one hospitalisation for
      cardiac decompensation, NYHA III/IV HF, ventricular ejection fraction < or =30%
      or cardiothoracic index > or =60% and arterial hypotension or peripheral and/or
      pulmonary oedema. A total of 417 consecutive patients surviving at hospital
      discharge were included in the database. The average follow-up period was 5
      years. Univariate Cox models were used to test the relationship of baseline
      biological and clinical factors to survival. Cardiovascular drug prescriptions
      were tested in a multivariate Cox model adjusted by other known predictive
      factors. RESULTS: Duration of disease >1 year, renal failure, serum sodium > or
      =138 mmol/l, old age, serious comorbidity, previous decompensation, high doses of
      furosemide and vasodilators use were independently associated with poor prognosis
      at 1 and 5 years. Oral anticoagulants, aspirin, lipid lowering drugs and beta
      blockers use were associated with better survival. There was no interaction
      between aspirin and angiotensin converting enzyme inhibitor use on survival.
      CONCLUSION: Antithrombotic therapy was associated with a better long-term
      survival in our study population of severe CHF. These results together with other
      previously published circumstantial evidence urge for a prospective, controlled
      and randomised trial specifically designed to evaluate optimal oral
      anticoagulants and aspirin in patients with congestive heart failure.

PMID- 12413510
TI  - Hypertensive crisis and acute, reversible, left ventricular systolic dysfunction:
      a case report.

PMID- 12413511
TI  - Clinical trials update from the European Society of Cardiology: CARMEN, EARTH,
      OPTIMAAL, ACE, TEN-HMS, MAGIC, SOLVD-X and PATH-CHF II.
AB  - This article continues a series of reports on research developments related to
      the field of heart failure. Reports of presentations made at the Hot Line
      sessions of the European Society of Cardiology XXIV Congress held in Berlin,
      Germany, between 31 August and 4 September 2002 are included. Summaries of the
      results of the following trials are presented: CARMEN, EARTH, OPTIMAAL, ACE, TEN
      HMS, MAGIC, SOLVD-X and PATH-CHF II.

PMID- 12413516
TI  - Molecular adapters in Fc(epsilon)RI signaling and the allergic response.
AB  - IgE-dependent activation of mast cells is central to the allergic response. The
      engagement of IgE-occupied receptors initiates a series of molecular events that
      cause the release of preformed, and de novo synthesis of, allergic mediators.
      Recent investigations demonstrate a critical role for non-enzymatic proteins that
      facilitate the activation and coordination of biochemical signals required for
      mast cell activation. Among these LAT, SLP-76 and Gab2 are critically important
      as adapters that facilitate events initiated by IgE receptor-dependent activation
      of Src family protein tyrosine kinases, Lyn and Fyn. An evaluation of the role of
      these adapters points to complementary but independent steps in early signaling
      and the possibility that preference for one or another adaptor complex may result
      in selective mast cell responses.

PMID- 12413517
TI  - How IgE upregulates the allergic response.
AB  - For several decades it has been known that IgE is central to the allergic
      response. In recent years, however, IgE has been described as having several
      actions in addition to passively arming the mast cell or basophil by binding to
      their high affinity IgE receptors. Recent studies have revealed roles for IgE in
      the regulation of its own receptor expression and in contributing to cell
      survival. Furthermore, the presence of trimeric high-affinity IgE receptors on
      leukocytes other than mast cells and basophils, together with the discovery of
      previously unknown functions of the beta subunit of the complex, has added to the
      complexity of IgE modulation of the allergic response.

PMID- 12413518
TI  - Inhibitory receptors and allergy.
AB  - Recent studies of the major cell types involved in the initiation and progression
      of allergic inflammation have revealed that they express an unexpectedly large
      number of surface receptors that inhibit the release of proinflammatory mediators
      from mast cells and basophils in vitro. Moreover, analyses of animals deficient
      in some of these receptors, for example, Fc(gamma)RIIB, gp49B1 and paired Ig-like
      receptor (PIR)-B, have shown that the molecules indeed suppress allergic
      responses driven by the adaptive immune response in vivo. These findings support
      the emerging concept that allergic diseases are caused not only by excessive
      activation of cells but also from deficiencies in receptors that suppress these
      activation responses.

PMID- 12413519
TI  - Complement in allergy and asthma.
AB  - The complement system is a vital link between innate and adaptive immunity.
      Recently, several investigators have implicated the complement anaphylatoxins C3a
      and C5a as potential effectors in Type 1 hypersensitivity reactions, including
      urticaria, rhinitis and asthma. Thus, complement activation may synergize with
      classical IgE mediated responses, and inhibition of complement may prove
      therapeutic.

PMID- 12413520
TI  - Present status on the genetic studies of asthma.
AB  - Asthma, one of the most common chronic diseases, is a complex and heterogeneous
      disorder. The results of genome screens for asthma-related traits in 11 different
      populations identified at least 18 regions of the genome that probably house
      asthma/atopy genes. The most consistently replicated regions are on chromosomes
      2q, 5q, 6p, 12q and 13q. Positional cloning projects are ongoing in laboratories
      around the world to identify the asthma susceptibility loci in these regions. In
      addition, many candidate genes have been associated with asthma phenotypes, such
      as the genes in the IL-4/IL-13 pathway.

PMID- 12413521
TI  - From allergen structure to new forms of allergen-specific immunotherapy.
AB  - During the past decade, genetic information for most of the common allergens has
      been obtained. Using these genetic blueprints it has become possible to
      reconstruct, by recombinant DNA technology, almost complete repertoires of the
      relevant allergens and their epitopes. Recombinant allergens with the allergenic
      features of naturally occurring allergens have promoted allergy research and form
      the basis of new multiallergen tests for refined allergy diagnosis. Allergen
      derivatives with reduced allergenic activity have also been produced by
      recombinant DNA technology to increase safety and specificity of allergen
      specific immunotherapy. These derivatives can be engineered to contain relevant T
      cell epitopes and to maintain those sequence motifs which are required for
      inducing protective antibody responses and therefore hold great promise for
      improving allergen-specific immunotherapy.

PMID- 12413522
TI  - The role of mast cells in allergy and autoimmunity.
AB  - Two potential outcomes of dysregulated immunity are allergy and autoimmunity.
      Both are characterized by localized inflammation that leads to the injury and/or
      destruction of target tissues. Until recently, it was generally accepted that the
      mechanisms that govern these disease processes are quite disparate; however, new
      discoveries suggest that the mast cell may underlie much of the pathology in both
      these disease syndromes. Amongst these discoveries is the observation that mast
      cell-deficient mice exhibit significantly reduced disease severity compared to
      wild-type littermates in a murine model of multiple sclerosis (MS) and drugs that
      block mast cell function can improve clinical symptoms in this model. In
      addition, gene microarray analysis has revealed that the expression of several
      mast cell-specific genes is increased in the central nervous system plaques of MS
      patients. Although well established as effector cells in allergic inflammation,
      the location of mast cells and the wealth of inflammatory mediators they express
      make it likely that they have profound effects on many other autoimmune
      processes.

PMID- 12413523
TI  - Immune regulation by histamine.
AB  - Histamine is a potent bioamine with multiple activities in various pathological
      and physiological conditions. In addition to its well-characterised effects in
      the acute inflammatory and allergic responses, histamine regulates several
      aspects of antigen-specific immune response development. Histamine affects the
      maturation of dendritic cells and alters their T cell-polarising capacity.
      Histamine also regulates antigen-specific T helper 1 and T helper 2 cells, as
      well as related antibody isotype responses. Apparently, diverse effects of
      histamine on immune regulation are because of differential expression of four
      types of histamine receptors and their distinct intracellular signals.

PMID- 12413525
TI  - Making and breaking tolerance.
AB  - The lymphocyte's decision between tolerance and immunity/autoimmunity is
      regulated at many levels. Two important parameters in this decision are the
      maturation state of the antigen presenting cells (APCs) and the amount of self
      antigen that is detected by the immune system. Maturation of APCs occurs as a
      consequence of signals received by the innate immune system and may lead to the
      breakdown of tolerance. Particularly relevant to this process are the Toll-like
      receptors and mechanisms of cross presentation of self antigens. In addition,
      genetic alterations in a variety of cell surface receptors, signalling components
      and regulators of apoptosis/survival can break tolerance and lead to autoimmunity
      in vivo.

PMID- 12413526
TI  - Autoimmune endocrine disease.
AB  - The immune system can attack almost any given organ in a very specific and
      directed fashion. The endocrine system appears to be particularly vulnerable to
      this kind of insult. Which endocrine organs are most susceptible and why? Genetic
      studies and animal models have revealed some commonalities for these diseases.
      The MHC locus appears to help control not only susceptibility to disease but also
      which endocrine organs are attacked. Autoimmune thymectomy models have revealed
      suppressor cell populations, which are being intensely sought after as a
      protective mechanism against endocrine autoimmunity. Finally, the recent cloning
      of the causative gene for autoimmune polyglandular syndrome type I, called AIRE,
      has brought central tolerance back into focus as an important mechanism in these
      endocrine diseases.

PMID- 12413527
TI  - Dendritic cells: inciting and inhibiting autoimmunity.
AB  - Dendritic cells are considered the most influential antigen presenting cells in
      the body because of their unique role in initiating immunity against threatening
      antigens. Recent studies addressing the consequences of self-antigen presentation
      by dendritic cells revealed the unexpected ability of these antigen presenting
      cells to inhibit T cell-mediated autoimmune diseases. The specific mechanisms by
      which dendritic cells suppress immune responses have been explored during the
      past year. These efforts indicate that extrathymic dendritic cells control
      autoimmunity by inducing peripheral T cell tolerance, a function intimately
      linked to their state of maturation.

PMID- 12413528
TI  - CD4(+) regulatory T cells in autoimmunity and allergy.
AB  - Regulatory T cells (also referred to as suppressor T cells) are important
      components of the homeostasis of the immune system, as impaired regulatory T cell
      activity can cause autoimmune diseases and atopy. It is now clear that the phrase
      'regulatory T cells' encompasses more than one cell type. For instance,
      CD4(+)CD25(+) regulatory T cells have received attention due to their
      immunosuppressive properties in vitro and in vivo, but in several instances it
      has been shown that CD4(+)CD25(-) T cell populations also contain potent
      regulatory activity. Recent progress in the field of regulatory T cells includes
      the discovery of the role of two tumor necrosis factor receptor (TNFR) family
      members (GITR and TRANCE-R/RANK) in Treg biology, the improved understanding of
      the role of co-stimulatory molecules and cytokines IL-10 and IL-2 in the
      induction and function of Tregs, and the generation of CD25(+) and CD25(-)
      regulatory T cells in vivo through high-avidity T cell receptor interactions.

PMID- 12413529
TI  - New regulatory co-receptors: inducible co-stimulator and PD-1.
AB  - Autoreactive lymphocytes are suppressed in healthy individuals by so-called
      peripheral tolerance. Accumulating evidence indicates that co-receptor signaling
      plays a pivotal role in the regulation of autoreactive lymphocytes. The positive
      regulatory co-receptors CD28 and inducible co-stimulator (ICOS) transduce
      stimulatory cosignals, whereas the negative regulatory co-stimulators CTLA-4 and
      PD-1 are critical for the regulation of peripheral tolerance and autoimmunity. PD
      1 deficient mice develop lupus-like glomerulonephritis and arthritis on a C57Bl/6
      background and autoimmune-dilated cardiomyopathy on a BALB/c background.

PMID- 12413530
TI  - TNF ligands and receptors in autoimmunity: an update.
AB  - Over two decades of research have increased the interest in factors from the
      tumor necrosis factor family. The vast majority of these factors are powerful
      modulators of critical immune functions and participate in pathogenic mechanisms
      leading to autoimmune disease. This field constantly evolves with the addition of
      new family members and the discovery of their function. During the past few years
      several additional factors from this family, such as BAFF, RANKL, TRAIL and
      GITRL, have emerged with novel functions that regulate both T and B cell immune
      tolerance and participate in tissue destruction in autoimmunity. These new
      findings revealed exciting innovative strategies for the treatment of autoimmune
      diseases.

PMID- 12413531
TI  - Cytokines: promoters and dampeners of autoimmunity.
AB  - Cytokines are the co-ordinators of the immune system and, as such, are important
      targets for immunomodulation. Progress has been made towards the use of IL-10 for
      immunosuppressive therapy to prevent autoimmunity. Interest has also recently
      focused on the role of cytokines in controlling the activation of dendritic cells
      and NK cells, and the consequences of this for the development of autoaggressive
      responses. Genes involved in IFN-activated pathways that control the survival of
      lymphocytes have been strongly linked to lupus susceptibility, and IFN-mediated
      defenses against viral infection have been shown to determine susceptibility to a
      model of viral-induced diabetes.

PMID- 12413532
TI  - Fc receptors are major mediators of antibody based inflammation in autoimmunity.
AB  - There is now renewed interest in the role of antibodies in autoimmunity. Recent
      compelling evidence indicates that autoantibodies and the effector mechanisms
      they induce, for example, Fc receptor activation of leukocytes and/or the
      complement cascade, are central players in the development of autoimmunity, by
      perpetuating inflammation and perhaps even regulating the process itself. Of
      increasing interest are Fc receptors, which have been more closely investigated
      in the past decade using recombinant proteins, gene deficient mice and mouse
      models of human disease. These analyses point towards major roles of Fc receptors
      in antibody hypersensitivity reactions and by extension autoimmune disease, and
      they reveal opportunities in the development of novel therapeutic approaches in
      the treatment of autoimmune diseases.

PMID- 12413533
TI  - Genetics of autoimmune diseases in humans and in animal models.
AB  - Recent applications of the genetic characterisation of autoimmunity in humans and
      in animal models have allowed the further mapping of many disease loci and, in
      some cases, the identification of disease genes. New approaches to the analysis
      of mapping, characterisation and identification of susceptibility genes have also
      been developed.

PMID- 12413537
TI  - Biological chemical processes continue to fascinate and to provide new ideas
      about chemistry.

PMID- 12413534
TI  - Therapy of autoimmune diseases: clinical trials and new biologics.
AB  - Successful clinical efficacy trials have been recently completed for a growing
      array of new biologics. Prospects are improving for rational therapeutic
      interventions that potently interrupt adaptive immune response pathways. By
      contrast, disappointing results with antigen-based therapeutics highlight the
      difficulties of achieving tolerance in the context of active autoimmunity.
      Combination immunotherapy is probably necessary to sequentially or simultaneously
      inhibit inflammation, uncouple innate immune pathways, interrupt or ablate the
      adaptive memory response and promote antigen-specific tolerance in a suitable
      immunological context.

PMID- 12413538
TI  - Two-state reactivity mechanisms of hydroxylation and epoxidation by cytochrome P
      450 revealed by theory.
AB  - Recent computational studies of alkane hydroxylation and alkene epoxidation by a
      model active species of the enzyme cytochrome P-450 reveal a two-state reactivity
      (TSR) scenario in which the information content of the product distribution is
      determined jointly by two states. TSR is used to reconcile the dilemma of the
      consensus 'rebound mechanism' of alkane hydroxylation, which emerged from
      experimental studies of ultra-fast radical clocks. The dilemma, stated succinctly
      as 'radicals are both present and absent and the rebound mechanism is both right
      and wrong', is simply understood once one is cognizant that the mechanism
      operates by two states, one low-spin (LS) the other high-spin (HS). In both
      states, bond activation proceeds in a manner akin to the rebound mechanism, but
      the LS mechanism is effectively concerted, whereas the HS is stepwise with
      incursion of radical intermediates.

PMID- 12413539
TI  - Soluble methane monooxygenase: activation of dioxygen and methane.
AB  - The mechanisms by which soluble methane monooxygenase uses dioxygen to convert
      methane selectively to methanol have come into sharp focus. Diverse techniques
      have clarified subtle details about each step in the reaction, from binding and
      activating dioxygen, to hydroxylation of alkanes and other substrates, to the
      electron transfer events required to complete the catalytic cycle.

PMID- 12413540
TI  - Fatty acid desaturation: variations on an oxidative theme.
AB  - Significant progress in our understanding of the mechanism of fatty acid
      desaturation has been achieved. The site of initial oxidation has been determined
      for several membrane-bound desaturases and a common cryptoregiochemical theme has
      been revealed. The results of several studies, including a detailed analysis of a
      soluble plant desaturase system, point to a close mechanistic relationship
      between dehydrogenation and hydroxylation pathways.

PMID- 12413541
TI  - New reactions in clavulanic acid biosynthesis.
AB  - Clavulanic acid is only a modestly effective antibiotic against bacterial
      infections in humans, but a potent inhibitor/inactivator of beta-lactamase
      enzymes that confer bacterial resistance. The biosynthetic pathway to clavulanic
      acid is considerably more complex than that to the structurally related
      penicillins and cephalosporins and has revealed several interesting reactions.

PMID- 12413542
TI  - Mechanisms of enzymatic CbondO bond cleavages in deoxyhexose biosynthesis.
AB  - In the past few years, significant progress has been made in our understanding of
      the biosynthesis of deoxyhexoses. Mechanistic studies have revealed how enzymes
      can cleave CbondO bonds of a hexose substrate to make unusual sugars. The
      increasing amount of knowledge about the biosynthesis of deoxysugars may allow
      the assembly of a repertoire of novel sugar structures through recruitment and
      collaborative action of genes from a variety of biosynthetic pathways to create
      diverse secondary metabolites in our search for novel antibiotic/antitumour
      agents.

PMID- 12413543
TI  - Coenzyme B(12) dependent glutamate mutase.
AB  - The crystal structure of glutamate mutase with bound coenzyme B(12) suggests a
      radical shuttling mechanism within the active site of the enzyme. Quantum
      chemical calculations of the rearrangement in combination with kinetic and
      mutational studies suggest the catalytic mechanism of this enzyme to proceed via
      a fragmentation/recombination sequence with intermediates stabilized by partial
      protonation/deprotonation. Crucial residues in the active site have been
      identified. Solution structure studies indicate the mechanism of B(12) binding to
      the apoenzyme.

PMID- 12413544
TI  - Anaerobic oxidation of aromatic compounds and hydrocarbons.
AB  - Aromatic compounds and hydrocarbons have in common a great stability due to
      resonance energy and inertness of CbondH and CbondC bonds. It has been taken for
      granted that the metabolism of these compounds obligatorily depends on molecular
      oxygen. Oxygen is required first to introduce hydroxyl groups into the substrate
      and then to cleave the aromatic ring. However, newly discovered bacterial enzymes
      and reactions involved in oxidation of aromatic and hydrocarbon compounds to
      CO(2) in the complete absence of molecular oxygen have been discovered. Of
      special interest are two reactions: the reduction of the aromatic ring of benzoyl
      coenzyme A and the addition of fumarate to hydrocarbons. These reactions
      transform aromatic rings and hydrocarbons into products that can be oxidized via
      more conventional beta-oxidation pathways.

PMID- 12413545
TI  - Electron transfer in DNA.
AB  - Electrons migrate over long distances along the DNA in a multistep hopping
      process where the rate of each step depends strongly upon its length. The
      efficiency of this process is not only determined by the electron transfer rates
      but also by competing reactions with water, in which the charge carriers are
      trapped. Because electron transfer through DNA can occur under the conditions of
      oxidative stress, biological consequences are highly likely. In addition, it has
      been observed that some DNA-binding enzymes influence this charge transport. The
      question of whether DNA is a suitable material for nanolelectronic devices
      remains unanswered.

PMID- 12413546
TI  - Glycosidase mechanisms.
AB  - The three-dimensional structure of glycosidases and of their complexes and the
      study of transition-state mimics reveal structural details that correlate with
      mechanism. Of particular interest are the transition-state conformations
      harnessed by individual enzymes and the substrate distortion observed in enzyme
      ligand complexes. 3D-structure in synergy with transition-state mimicry opens the
      way for mechanistic interpretation of enzyme inhibition and for the development
      of therapeutic agents.

PMID- 12413548
TI  - Implantable chemical sensors for real-time clinical monitoring: progress and
      challenges.
AB  - Recently, progress has been made in the development of implantable chemical
      sensors capable of real-time monitoring of clinically important species such as
      PO(2), PCO(2), pH, glucose and lactate. The need for developing truly
      biocompatible materials for sensor fabrication remains the most significant
      challenge for achieving robust and reliable sensors capable of monitoring the
      real-time physiological status of patients.

PMID- 12413549
TI  - Fluorescence-enhanced, near infrared diagnostic imaging with contrast agents.
AB  - The deep tissue propagation of near-infrared (NIR) light between 700-900 nm
      offers new opportunities for diagnostic imaging when employing sensitive
      detection techniques and NIR excitable fluorescent agents that target and report
      disease and metabolism. Herein, we highlight approaches for illuminating tissues
      and monitoring the re-emitted fluorescence for tomographic reconstruction,
      strategies for developing fluorescent dye constructs, and clinical opportunities
      for fluorescence-enhanced NIR optical imaging.

PMID- 12413550
TI  - Optical spectroscopy for detection of neoplasia.
AB  - Fluorescence and reflectance spectroscopy provide the ability to assess tissue
      structure and metabolism in vivo in real time, providing improved diagnosis of
      pre-cancerous lesions. Reflectance spectroscopy can probe changes in epithelial
      nuclei that are important in pre-cancer detection, such as mean nuclear diameter,
      nuclear size distribution and nuclear refractive index. Fluorescence spectroscopy
      can probe changes in epithelial cell metabolism, by assessing mitochondrial
      fluorophores, and epithelial-stromal interactions, by assessing the decrease in
      collagen crosslink fluorescence that occurs with pre-cancer. Thus, fluorescence
      and reflectance spectroscopy provide complementary information useful for pre
      cancer diagnosis. Tissue engineering provides three-dimensional cell cultures
      that can be used to further explore the relationship between tissue structure and
      biological events important in cancer development and progression. In the future,
      improving our understanding of the biological changes that can be assessed using
      spectroscopy will not only improve optical techniques but also provide new tools
      to better understand cancer biology.

PMID- 12413551
TI  - In vivo neurochemical monitoring by microdialysis and capillary separations.
AB  - Microdialysis is valuable for studying the neurochemical changes underlying
      behavior. Recent advances include the application of the high-sensitivity methods
      of capillary electrophoresis and capillary liquid chromatography with mass
      spectrometry to dialysate analysis. These methods have improved temporal
      resolution, spatial resolution, multi-analyte capability and potential for
      compound discovery.

PMID- 12413552
TI  - Analytical aspects of mass spectrometry and proteomics.
AB  - Mass spectrometry plays an essential role in proteomics analysis and research. In
      recent years, it has been increasingly recognized that a key to proteomics using
      mass spectrometry relies not only on the instrument itself, but also on the
      analytical strategies and front-end sample-handling techniques. The advances of
      separations and mass spectrometry are having an increasing impact on the
      discovery of disease biomarkers and the understanding of cellular processes.

PMID- 12413553
TI  - Imaging mass spectrometry: a new tool to investigate the spatial organization of
      peptides and proteins in mammalian tissue sections.
AB  - MALDI MS imaging mass spectrometry can be used to map the distribution of
      targeted compounds in tissue sections with a spatial resolution currently of
      about 50 microm, providing important molecular information in many areas of
      biological research. After matrix application, a raster of a section by the laser
      beam yields ions from compounds in a tissue mass-to-charge range from 1000 to
      over 100000. Two-dimensional intensity maps can then be reconstructed to provide
      specific molecular images of a tissue.

PMID- 12413554
TI  - Protein and peptide secondary structure and conformational determination with
      vibrational circular dichroism.
AB  - Vibrational circular dichroism (VCD) provides alternative views of protein and
      peptide conformation with advantages over electronic (UV) CD (ECD) or IR
      spectroscopy. VCD is sensitive to short-range order, allowing it to discriminate
      beta-sheet and various helices as well as disordered structure. Quantitative
      secondary structure analyses use protein VCD bandshapes, but are best combined
      with ECD and IR for balance. Much recent work has focused on empirical and
      theoretical VCD analyses of peptides, with detailed prediction of helix, sheet
      and hairpin spectra and site-specific application of isotopic substitution for
      structure and folding.

PMID- 12413555
TI  - Imaging optical sensor arrays.
AB  - Imaging optical fibres have been etched to prepare microwell arrays. These
      microwells have been loaded with sensing materials such as bead-based sensors and
      living cells to create high-density sensor arrays. The extremely small sizes and
      volumes of the wells enable high sensitivity and high information content sensing
      capabilities.

PMID- 12413556
TI  - Neurochemistry and electroanalytical probes.
AB  - Electroanalytical techniques have been applied to monitoring chemical events
      including neurotransmitter release during rodent behaviour and the release of
      zeptomoles of molecules from single cells. Transgenic mice models have been
      developed and studied to identify specific cell types in vitro. Characterization
      and surface modification of electroanalytical probes has enhanced the selectivity
      and sensitivity of measurements.

PMID- 12413558
TI  - Microscale NMR.
AB  - NMR spectroscopy is increasingly being used to characterize microliter and
      smaller-volume samples. Substances at picomole levels have been identified using
      NMR spectrometers equipped with microcoil-based probes. NMR probes that
      incorporate multiple sample chambers enable higher-throughput NMR experiments.
      Hyphenation of capillary-scale separations and microcoil NMR has also decreased
      analysis time of mixtures. For example, capillary isotachophoresis/NMR allows the
      highest mass sensitivity nanoliter-volume flow cells to be used with low
      microliter volume samples because isotachophoresis concentrates the microliter
      volume sample into the nanoliter volume NMR detection probe. In addition, the
      diagnostic capabilities of NMR spectroscopy allow the physico-chemical aspects of
      a capillary separation process to be characterized on-line. Because of such
      advances, the application of NMR to smaller samples continues to grow.

PMID- 12413557
TI  - The genesis of high-throughput structure-based drug discovery using protein
      crystallography.
AB  - Over the past 12 years, drugs have been developed using structure-based drug
      design relying upon traditional crystallographic methods. Established successes,
      such as the drugs designed against HIV-1 protease and neuraminidase, demonstrate
      the utility of a structure-based approach in the drug-discovery process. However,
      the approach has historically lacked throughput and reliability capabilities;
      these bottlenecks are being overcome by breakthroughs in high-throughput
      structural biology. Recent technological innovations such as submicroliter high
      throughput crystallization, high-performance synchrotron beamlines and rapid
      binding-site analysis of de novo targets using virtual ligand screening and small
      molecule co-crystallization have resulted in a significant advance in structure
      based drug discovery.

PMID- 12413559
TI  - Post-processing water-fat imaging technique for fat suppression in a low-field MR
      imaging system, evaluation in patients with rheumatoid arthritis.
AB  - PURPOSE: To evaluate the feasibility of the phase difference-based post
      processing water-fat imaging method for fat suppression at low-field in imaging
      of arthritic joints. MATERIALS AND METHODS: Thirty joints (wrist, 10; elbow, 10;
      knee, 10) in 30 patients with rheumatoid arthritis were imaged using a 0.23T MRI
      unit. Contrast-enhanced T1-weighted (T1w) three-dimensional (3D) gradient-echo
      (GRE) images with and without fat suppression along with short inversion time
      inversion-recovery (STIR) images were evaluated by two radiologists. Contrast
      enhanced T1w 3D GRE images and corresponding post-processed fat-suppressed images
      were scored for conspicuity and delineation of enhancing synovial hypertrophy.
      The uniformity of fat suppression was evaluated between T1w 3D GRE fat-suppressed
      images and STIR images, and general image quality was estimated for all of the
      three techniques by consensus. For a quantitative analysis, the enhancing
      synovial hypertrophy-to-fat contrast-to-noise (CNR) values for the T1W 3D GRE
      images with and without fat suppression were measured. For comparison, synovial
      bright signal-to-fat CNR values for the STIR images were measured. RESULTS: The
      post-processing water-fat imaging technique for fat suppression was successfully
      applied in all examinations. Conspicuity and delineation of enhancing tissue were
      superior in fat-suppressed T1w 3D GRE images compared to non-fat-suppressed
      images (P < 0.0001). As expected, the enhancing synovial hypertrophy tissue-to
      fat CNRs were significantly higher in fat-suppressed T1w 3D GRE images compared
      to non-fat-suppressed images (P < 0.0001). General image quality was assessed to
      be best in non-fat-suppressed images, and the difference was significant compared
      to fat-suppressed images (P < 0.05) and STIR images (P < 0.05). CONCLUSION: The
      phase difference-based post-processing water-fat imaging technique for fat
      suppression can be successfully used at low-field, and it provides high-quality
      fat suppression images in imaging of arthritic joints.

PMID- 12413560
TI  - Magnetization transfer short inversion time inversion recovery enhanced 1H MRI of
      the human lung.
AB  - The unique characteristics of the human lung arising from low proton density and
      multiple air-tissue interfaces of the alveoli cause difficulty in 1H lung
      magnetic resonance imaging. In addition, the dominating signal from sources such
      as the thoracic muscle and subcutaneous fat hampers the visualization of the lung
      parenchyma. In this contribution, an efficient tissue suppression technique is
      presented which allows one to significantly enhance lung parenchyma visibility. A
      short inversion time inversion recovery (STIR) experiment combined with a
      magnetization transfer (MT) experiment was used for magnetization preparation in
      order to suppress the signal from muscle. A half-Fourier single-shot turbo spin
      echo sequence was used as acquisition module. This approach was used to perform
      lung anatomical imaging in eight healthy human subjects and five patients with
      cystic fibrosis. The results obtained demonstrate that with MT-STIR approach high
      quality human lung images can be obtained and that this approach has the
      potential for the evaluation of lung pathologies.

PMID- 12413561
TI  - MR image reconstruction algorithms for sparse k-space data: a Java-based
      integration.
AB  - We have worked on multi-dimensional magnetic resonance imaging (MRI) data
      acquisition and related image reconstruction methods that aim at reducing the MRI
      scan time. To achieve this scan-time reduction we have combined the approach of
      'increasing the speed' of k-space acquisition with that of 'deliberately
      omitting' acquisition of k-space trajectories (sparse sampling). Today we have a
      whole range of (sparse) sampling distributions and related reconstruction
      methods. In the context of a European Union Training and Mobility of Researchers
      project we have decided to integrate all methods into one coordinating software
      system. This system meets the requirements that it is highly structured in an
      object-oriented manner using the Unified Modeling Language and the Java
      programming environment, that it uses the client-server approach, that it allows
      multi-client communication sessions with facilities for sharing data and that it
      is a true distributed computing system with guaranteed reliability using core
      activities of the Java Jini package.

PMID- 12413562
TI  - Functional magnetic resonance imaging of swine brain during change in thiopental
      anesthesia into EEG burst-suppression level--a preliminary study.
AB  - Deepening anesthesia produces well known changes in electroencephalogram (EEG)
      and evoked potentials, differing in pathological and normal brain. Yet, it is not
      known how the T2*-weighted signal changes in the healthy brain during deepening
      anesthesia. We studied the effect of thiopental bolus on functional magnetic
      resonance imaging (fMRI) in the healthy brain using porcine model. In five pigs
      (2-3 months, 20-25 kg), the control bolus prior to fMRI resulted in a change into
      burst-suppression. After the recovery of continuous EEG, fMRI (4 min) was
      performed with a single bolus of thiopental (11.4-17.1 mg/kg) administered 1 min
      after the onset of imaging. This was repeated in four of five pigs. Positive (6
      8%) or negative (-3 to -8%) signal intensity changes correlated to the thiopental
      bolus injection were seen in the group average fMRI response. Positive response
      was 1.6% and negative response 2.3% of the total brain region of interest (ROI)
      voxels. Responding voxels were distributed more prominently in the thalamic ROI
      (4.5%) than in the cortical ROI (2.2%). The group average of unthresholded voxel
      time courses showed that the net effect of thiopental bolus was a small (0.5%)
      but a clear positive change in the thalamic region, while variance changed in the
      global level. In conclusion, this study is the first to show that significant
      signal intensity changes occur in fMRI response during the sudden deepening of
      thiopental anesthesia. However, these responses are neither anatomically constant
      nor global in the healthy swine brain.

PMID- 12413563
TI  - A fast and accurate simulator for the design of birdcage coils in MRI.
AB  - The birdcage coils are extensively used in MRI systems since they introduce a
      high signal to noise ratio and a high radiofrequency magnetic field homogeneity
      that guarantee a large field of view. The present article describes the
      implementation of a birdcage coil simulator, operating in high-pass and low-pass
      modes, using magnetostatic analysis of the coil. Respect to other simulators
      described in literature, our simulator allows to obtain in short time not only
      the dominant frequency mode, but also the complete resonant frequency spectrum
      and the relevant magnetic field pattern with high accuracy. Our simulator
      accounts for all the inductances including the mutual inductances between
      conductors. Moreover, the inductance calculation includes an accurately birdcage
      geometry description and the effect of a radiofrequency shield. The knowledge of
      all the resonance modes introduced by a birdcage coil is twofold useful during
      birdcage coil design: --higher order modes should be pushed far from the
      fundamental one, --for particular applications, it is necessary to localize other
      resonant modes (as the Helmholtz mode) jointly to the dominant mode. The
      knowledge of the magnetic field pattern allows to a priori verify the field
      homogeneity created inside the coil, when varying the coil dimension and mainly
      the number of the coil legs. The coil is analyzed using equivalent circuit
      method. Finally, the simulator is validated by implementing a low-pass birdcage
      coil and comparing our data with the literature.

PMID- 12413564
TI  - Microscopic spin tagging (MiST) for flow imaging.
AB  - In this study, a new strategy for slow flow imaging is proposed. The basic idea
      is to generate flow contrast on a microscopic level below the spatial resolution
      of an imaging experiment. Since a microscopic spin tagging scheme is used, this
      concept is called MiST (Microscopic Spin Tagging). MiST is not a single specific
      measurement sequence, but rather a new flow sensitive preparation concept which
      is highly flexible and can be carried out in many ways. The common principle in
      all possible realizations of MiST is a periodic tagging of magnetization in thin
      planes (100-200 microm) within the imaging voxels by means of spatially selective
      RF-pulses. Therefore, flow sensitivity occurs via inflow of fresh spins on a
      microscopic scale. With this approach, short evolution times are sufficient to
      introduce inflow contrast and a spatial dependence of inflow times is avoided.
      The flow sensitive preparation and image orientation are also not connected as
      they are in conventional time-of-flight techniques. Another powerful feature of
      MiST is that it can be designed as a non-subtraction method, which results in no
      signal from stationary spins. Here we present a first realization of the MiST
      concept and its validation in quantitative flow measurements to demonstrate the
      feasibility of the proposed preparation concept.

PMID- 12413566
TI  - Emotional prosody: sex differences in sensitivity to speech melody.
AB  - Emotional prosody is defined as the ability to express emotions through
      variations of different parameters of the human speech, such as pitch contour,
      intensity and duration. A recent study has discovered clear differences between
      men and women in the time course of emotional prosodic processing. There are
      several interpretations of these intriguing results that hold promise for future
      studies on language comprehension.

PMID- 12413565
TI  - MR-velocity mapping in vascular stents to assess peak systolic velocity. In vitro
      comparison of various stent designs made of Stainless Steel and Nitinol.
AB  - INTRODUCTION: Peak systolic velocity (PSV) measurements of blood flow inside
      vascular stents allow reliable detection of in-stent re-stenosis. The purpose of
      this in vitro study was to evaluate the feasibility of obtaining PSV measurements
      inside vascular stents made of Stainless Steel and Nitinol, using a velocity
      encoded MR technique. MATERIALS/METHODS: In a flow phantom, stents of Stainless
      Steel and Nitinol were studied. The phantom was integrated into a closed-tubing
      circuit driven by a MR dedicated pulsatile flow pump. MR imaging was performed on
      a 1.5 T system. The PSV in the tube without stent was used as the gold standard
      to determine the accuracy and the variability (paired t-test and Pittman's test)
      of the PSV measurements inside the stents. RESULTS: PSV values inside the stents
      showed percentual difference in mean of -15 to 21% (P < 0.05) at a pump setting
      of 10 and 20 ml/s. CONCLUSION: PSV measurements can be accurately obtained inside
      stents made of Stainless Steel and Nitinol. MR-velocity measurements may be used
      in patients to non-invasively evaluate stent patency and in-stent re-stenosis.

PMID- 12413567
TI  - Minimizing rivalry in San Miniato.
AB  - A workshop on binocular rivalry and perceptual ambiguity was held in San Miniato,
      Italy, on 12-15 June, 2002.

PMID- 12413568
TI  - Tigers and teapots: what does it mean to be alive?
AB  - The Symposium entitled 'Conceptual Knowledge: Developmental, Biological,
      Functional and Computational Accounts' was held at the British Academy, London,
      UK on 24-26 June 2002. It was funded by the British Academy with support from the
      Novartis Foundation, and organized by Lorraine Tyler (University of Cambridge,
      UK) and Tim Shallice (University College London, UK).

PMID- 12413569
TI  - On Enigmas and Oracles: looking back to the future.
AB  - The Turing Day was held at the Swiss Federal Institute of Technology (EPFL) in
      Lausanne, Switzerland, on 28 June 2002.

PMID- 12413570
TI  - Consciousness: just more of the same in the visual brain?

PMID- 12413571
TI  - How does it fit?

PMID- 12413573
TI  - Theory of mind: the eyes have it.

PMID- 12413572
TI  - In Briefs.

PMID- 12413574
TI  - Degeneracy and cognitive anatomy.
AB  - Cognitive models indicate that there are multiple ways of completing the same
      task. This implicit degeneracy cannot be revealed by functional imaging studies
      of normal subjects if more than one of the sufficient neural systems is
      activated. Nor can it be detected by neuropsychological studies of patients
      because their performance might not be impaired when only one degenerate system
      is damaged. We propose that degenerate sets of sufficient neural systems can only
      be identified by an iterative approach that integrates the lesion-deficit model
      and functional imaging studies of normal and neurologically damaged subjects.

PMID- 12413575
TI  - When a good fit can be bad.
AB  - How should we select among computational models of cognition? Although it is
      commonplace to measure how well each model fits the data, this is insufficient.
      Good fits can be misleading because they can result from properties of the model
      that have nothing to do with it being a close approximation to the cognitive
      process of interest (e.g. overfitting). Selection methods are introduced that
      factor in these properties when measuring fit. Their success in outperforming
      standard goodness-of-fit measures stems from a focus on measuring the
      generalizability of a model's data-fitting abilities, which should be the goal of
      model selection.

PMID- 12413576
TI  - Mental models and counterfactual thoughts about what might have been.
AB  - Counterfactual thoughts about what might have been ('if only em leader ') are
      pervasive in everyday life. They are related to causal thoughts, they help people
      learn from experience and they influence diverse cognitive activities, from
      creativity to probability judgements. They give rise to emotions and social
      ascriptions such as guilt, regret and blame. People show remarkable regularities
      in the aspects of the past they mentally 'undo' in their counterfactual thoughts.
      These regularities provide clues about their mental representations and cognitive
      processes, such as keeping in mind true possibilities, and situations that are
      false but temporarily supposed to be true.

PMID- 12413577
TI  - The minimalist program in syntax.
AB  - The Minimalist program, a development of earlier work in transformational
      generative grammar, proposes that the computational system central to human
      language is a 'perfect' solution to the task of relating sound and meaning.
      Recent research has investigated the complexities evident in earlier models and
      attempted to eliminate them, or to show how they are only apparent, following
      from deeper but simpler properties. Examples of this include the reduction of the
      number of linguistic levels of representation in the model, and the deduction of
      constraints on syntactic derivations from general considerations of economy and
      computational simplicity.

PMID- 12413578
TI  - Connectionist natural language parsing.
AB  - The key developments of two decades of connectionist parsing are reviewed.
      Connectionist parsers are assessed according to their ability to learn to
      represent syntactic structures from examples automatically, without being
      presented with symbolic grammar rules. This review also considers the extent to
      which connectionist parsers offer computational models of human sentence
      processing and provide plausible accounts of psycholinguistic data. In
      considering these issues, special attention is paid to the level of realism, the
      nature of the modularity, and the type of processing that is to be found in a
      wide range of parsers.

PMID- 12413579
TI  - Detecting the wrong signals?

PMID- 12413580
TI  - Pretending primates.

PMID- 12413581
TI  - D-dimer: a characteristic of the coagulation state of each patient with chronic
      atrial fibrillation.
AB  - BACKGROUND AND OBJECTIVE: It is accepted that patients with atrial fibrillation
      (AF) are characterised by increased levels of plasmatic D-dimers, with a wide
      inter-individual variability depending on the patients and therapeutic
      characteristics, but it has not been established if this level was predictive of
      the risk of arterial thromboembolic event. In order to answer such a question, it
      has to be established if the D-dimer level in a given patient is characteristic
      of such a patient (stable over time) if also fluctuating with time (and useless
      to characterise the patient). METHODS AND RESULTS: One hundred thirty clinically
      stable patients with chronic AF were recruited (anticoagulant: group 1,
      antiaggregant aspirin: group 2, no antithrombotic: group 3). During the follow-up
      of patients without clinical events (n=63), it is notable that in patients with D
      dimer levels <500 ng/ml, these remained <1000 ng/ml, in patients with levels
      between 500 and 1000 ng/ml, these did not reach 1590 ng/ml, and in those with D
      dimers >1000 ng/ml, the levels remained relatively stable. Mean age and D-dimer
      levels were lower in group 1 (74.4 years and 509.1 ng/ml, respectively) than in
      group 2 (82.4 years, p=0.0003 and 1015.7 ng/ml, p<0.0001, respectively) and in
      group 3 (79.3 years and 1289.3 ng/ml, p<0.0001, respectively). The effect of the
      antithrombotic therapy was independent of the age of patients (p=0.017).
      CONCLUSION: D-dimer levels in patients with chronic AF remain in the same range
      over time. They are lower on anticoagulant therapy than on antiaggregant or no
      antithrombotic therapy, irrespective of age. Thus, D-dimers appear to be a useful
      parameter for assessing the degree of hypercoagulability of patients whatever
      their age.

PMID- 12413582
TI  - Markers of activated coagulation in patients with factor V Leiden and/or G20210A
      prothrombin gene mutation.
AB  - The activated protein C (APC) resistance phenotype associated with an abnormal
      factor V Leiden (FVL), and the G20210A prothrombin gene mutation are the most
      common findings in patients with venous thromboembolism (VTE). In a group of 210
      patients, we compared the levels of markers of coagulation activation in carriers
      of FVL (71 heterozygous, 30 homozygous), G20210A prothrombin mutation (88
      heterozygous) or both mutations combined (21 heterozygous), in order to assess
      whether these markers allow identification of a group of patients with a higher
      risk of thrombosis; they were also compared to normal values. A total of 143
      patients had a personal history of VTE and 67 were asymptomatic. None of them had
      other hereditary causes of thrombophilia or an antiphospholipid syndrome. None
      were currently treated with either anticoagulant or hormonal treatment. Pregnant
      women were excluded. No significant difference between the four groups of
      patients could be found in the levels of F1+2, TAT and DDI. Levels were all
      significantly higher than the control values (p<0.05). The levels of F1+2 and TAT
      were similar in patients with or without a history of VTE, regardless of the type
      of mutation. DDI levels were significantly higher in patients with a history of
      VTE than in asymptomatic subjects (443+/-248 vs. 333+/-222 ng/ml, p=0.02) but
      with only 57% sensitivity and specificity. In conclusion, our study confirms the
      hypercoagulable state found in mutation carriers and points out the inability of
      F1+2 and TAT assays to identify a group of subjects at higher risk of thrombosis,
      within carriers of genetic risk factors. Although the sensitivity and specificity
      of DDI assay are low, high DDI concentrations tend to be associated with the risk
      of VTE.

PMID- 12413584
TI  - Differences between neonates and adults in plasmin inhibitory and
      antifibrinolytic action of aprotinin.

PMID- 12413583
TI  - CBS 844ins68, MTHFR TT677 and EPCR 4031ins23 genotypes in patients with deep-vein
      thrombosis.
AB  - The role of methylenetetrahydrofolate reductase (MTHFR) TT677 genotype,
      cystathionine beta-synthase (CBS) 844ins68 mutation and endothelial cell protein
      C receptor (EPCR) 4031ins23 in the development of deep-vein thrombosis (DVT) was
      investigated in 300 consecutive DVT patients and 410 healthy blood donors. MTHFR
      TT677 was found in 40 (13.3%) patients and in 59 (14.4%) controls (OR 0.92; 95%
      C.I. 0.54-1.41); CBS 844ins68 in 20 (6.7%) patients and in 56 (13.7%) control
      subjects (OR 0.45; 95% C.I. 0.27-0.77); and the combination of MTHFR TT677 with
      CBS 844ins68 in 4 (1.3%) patients and in 7 (1.7%) controls (OR 0.78; 95% C.I.
      0.23-2.68). Logistic regression analysis did not show a further increase of risk
      for MTHFR TT677 or CBS 844ins68 in combination with the factor V Leiden or the
      prothrombin gene G20210A mutations. The EPCR 4031ins23 was observed in 2 patients
      (0.66%) and none of the controls. In conclusion, MTHFR TT677 does not appear to
      be an important risk factor for DVT, EPCR 403ins23 seems to be very rare, its
      role in the development of DVT unclear. A putative protective effect of CBS
      844ins68 should be further investigated.

PMID- 12413585
TI  - Protease action and generation of beta-thromboglobulin-like protein followed by
      platelet activation.
AB  - beta-Thromboglobulin (betaTG) is a platelet specific protein present in the alpha
      granules and secreted into the surrounding medium on cell activation. The sodium
      dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) of platelet
      releasate after inhibition of metalloproteinases with ethyleneglycol-bis-(beta
      aminoethyl ether)N,N'-tetra acetic acid (EGTA) showed disappearance of an 8.0-kDa
      band. In the absence of the cation chelators, a 48-kDa band disappeared and
      concurrently, the 8.0-kDa band intensity increased suggesting that the former may
      be the immediate precursor of the latter. The Western blot stained using specific
      antibodies, isolated from single-cell clones of hybridoma, against 8.0-kDa
      protein recognized not only 48- and 8.0-kDa bands but few others too. The data
      suggest that one or more high molecular weight (HMW) protein is released from
      alpha-granules and is broken down into smaller fragments after release to form
      beta-thromboglobulin (beta-TG)-like proteins by the action of metal-dependent
      proteases.

PMID- 12413586
TI  - Comparison between the effects of the rapid recombinant insulin analog aspart and
      those of human regular insulin on platelet cyclic nucleotides and aggregation.
AB  - INTRODUCTION: Insulin aspart is a rapid insulin analog used in clinical practice:
      aim of the present study is to evaluate in human platelets its influence on: (i).
      concentrations of guanosine 3':5'-cyclic monophosphate (cGMP) and adenosine 3':5'
      cyclic monophosphate (cAMP), mediators of platelet anti-aggregation; (ii).
      platelet aggregation to adenosine-5 diphosphate. MATERIALS AND METHODS: In human
      platelets, incubated with human regular insulin or with insulin aspart, we
      measured: (1). guanosine 3':5-cyclic monophosphate and adenosine 3':5'-cyclic
      monophosphate concentrations by radioimmunoassays, with and without nitric oxide
      synthase (NOS) inhibition by N(G)-monomethyl-L-arginine, and phosphatidylinositol
      3-kinase inhibition by wortmannin; (ii). aggregation to adenosine-5 diphosphate
      by Born's method. RESULTS: (i). Human regular insulin and insulin aspart
      increased both cyclic nucleotides; (ii). these effects were dependent on nitric
      oxide, being inhibited by N(G)-monomethyl-L-arginine, and mediated by the
      phosphatidylinositol-3-kinase pathway of insulin signalling, being inhibited by
      wortmannin; (iii). the effects exerted by insulin aspart on both cyclic
      nucleotides (ANOVA, p=0.0001) were more prolonged than those exerted by regular
      insulin; (iv) like human regular insulin, insulin aspart significantly decreased
      platelet response to ADP (ANOVA, p=0.0001): after 60 min of incubation, the anti
      aggregating effect exerted by insulin aspart was significantly greater than that
      exerted by human regular insulin (p=0.027). CONCLUSIONS: The effects of insulin
      aspart on platelet cyclic nucleotides and aggregation show kinetic differences
      compared to those of human regular insulin, resulting in more prolonged effects.

PMID- 12413587
TI  - Effects of combined therapy of clopidogrel and aspirin in preventing thrombus
      formation on mechanical heart valves in an ex vivo rabbit model.
AB  - BACKGROUND: The aim of our study was to investigate the efficacy of the
      combination of clopidogrel and aspirin in the prevention of thrombus formation on
      artificial heart valves in an experimental rabbit model as compared to
      anticoagulation with warfarin. METHODS: Studies were performed after oral
      administration of clopidogrel and aspirin in group I (n=9) for 5 days, after 5+/
      2 days treatment with warfarin in group II (n=9) and without medication in group
      III (n=9). Leaflets from Sulzer Carbomedics bileaflet valves were placed in a
      flow chamber. The flow chamber was filled with blood in a continuous circulation
      between the carotid artery and the jugular vein. RESULTS: In group III, the flow
      chamber was clotted after a median of 15 min of circulation. Weight analysis
      before and after 1 h of perfusion showed that the median thrombus weight was 9.1
      mg in group I, 14.4 mg in group II and 33.7 mg in group III. Further analysis by
      electron microscopy showed fewer platelets and erythrocytes on leaflets in group
      I than on leaflet surfaces in group II. CONCLUSION: Clopidogrel and aspirin were
      more effective than warfarin in preventing thrombus formation on artificial heart
      valve leaflets in our investigation. This rabbit model with a high dosage of
      clopidogrel and aspirin, and a short-time exposure of the heart valve leaflets to
      rabbit blood under laminar flow, should be further evaluated with respect to
      whether it can give information about antithrombotic regimens in patients after
      mechanical heart valve replacement.

PMID- 12413588
TI  - Resistance to aspirin in vitro is associated with increased platelet sensitivity
      to adenosine diphosphate.
AB  - BACKGROUND: Platelet activation plays an important role in arterial thrombosis
      and the widespread use of aspirin has reduced major events by 25% in the
      secondary prevention of cardiovascular diseases. However, it appears that aspirin
      antiplatelet effect is not uniform and 8-45% of the population are, in vitro,
      aspirin resistant, and it is well recognized that platelets can be activated by
      pathways that are not blocked by aspirin, such as adenosine diphosphate (ADP).
      OBJECTIVES: To investigate whether aspirin-resistant patients have a modified
      sensitivity to ADP-induced platelet activation MATERIALS AND METHODS: Seventy-two
      patients were enrolled. Platelet function was measured by the PFA-100(R)
      analyser; platelet GP IIb-IIIa activation by ADP 10 micro M was assessed by flow
      cytometry using PAC-1 MoAb. RESULTS: Using a collagen/epinephrine coated
      cartridge on the PFA-100(R), the prevalence of aspirin resistance was 29.2%
      (n=21). For aspirin-resistant patients, the collagen/ADP coated cartridge showed
      a closure time significantly shorter (p=0.004) compared to the sensitive and
      control groups. Platelets from aspirin-resistant patients bound PAC-1
      significantly more (p=0.03) than the aspirin-sensitive patients and controls when
      activated with 10 micro M ADP. CONCLUSIONS: Platelets from aspirin-resistant
      patients appear to be more sensitive and activable by ADP. This hypersensitivity
      could provide a possible explanation for the so-called aspirin resistance, and
      this could justify therapeutic improvement with alternative antiplatelet agents.

PMID- 12413589
TI  - Conformation sensitive gel electrophoresis for detection of factor X gene
      mutations.
AB  - Fifteen patients from five families with laboratory data suggesting factor X (FX)
      deficiency were screened for causative mutations by conformation sensitive gel
      electrophoresis (CSGE) followed by sequencing. All exonic and flanking intronic
      regions of factor X gene were amplified using PCR. After heteroduplex formation,
      samples were analyzed onto a polyacrylamide gel for possible mismatch. An
      abnormal CSGE profile indicating an heteroduplex was identified in 10/15 cases.
      All the 10 patients with a patter of migration suggesting a mismatch had a
      laboratoristic pattern of FX deficiency whereas the five cases with a normal CSGE
      aspect referred to the normal components of the families who did not carry any FX
      defect. Sequencing demonstrated that the 10 exons, which showed a suspect CSGE
      pattern, harbored a mutation responsible for the factor X defect. Of the five
      mutation identified, two were recognized to be novel mutations (a 871C>T
      substitution and a 1169G>T transversion in exon 8), both located in the catalytic
      portion of FX. CSGE may be an effective and simple procedure for screening factor
      X gene mutations.

PMID- 12413590
TI  - Elevated levels of Factor XI are associated with cardiovascular disease in women.
AB  - Coronary artery disease (CAD) continues to be the most frequent cause of death
      among women in the United States. Although elevated levels of clotting factors
      have been associated with CAD, few of these studies have been performed in women.
      Elevated levels of Factor XI have previously been associated with venous
      thrombosis, but little is known about its effect on arterial thrombosis. We
      selected women referred for cardiac catheterization who were found to have either
      normal coronaries or evidence of severe CAD and compared levels of homocysteine,
      anticardiolipin IgG/IgM antibodies, fibrinogen, platelet count, Factor VII,
      Factor VIII and Factor XI. Women with severe CAD had significantly higher levels
      of Factor XI than those without CAD (128% vs. 82%, p<0.04). Statistical
      adjustment for age, diabetes, hypertension, total cholesterol (TC), current
      smoking, or BMI had no effect on the independent association between CAD status
      and Factor XI. Factor XI was higher in women with total cholesterol levels >6.18
      mmol/l (>239 mg/dl) compared with normocholesteremic women and was also higher in
      the upper tertile of age, but even when adjusted for these, the association
      remained significant. This initial study suggests that Factor XI may be an
      important parameter in arterial as well as venous thrombosis.

PMID- 12413591
TI  - European Concerted Action on Anticoagulation (ECAA). Minimum number of centres
      for reliable International Sensitivity Index calibration of CoaguChek and TAS
      point-of-care whole blood monitors.
AB  - INTRODUCTION: Prothrombin time (PT) test systems require multicentre calibration
      for reliable International Sensitivity Index (ISI). Multicentre calibration of
      CoaguChek Mini and TAS PT-NC point-of-care test (POCT) systems is less precise
      than conventional PT testing. The aim of the present study was to determine the
      number of centres required to give reliable ISI and International Normalised
      Ratio (INR) with these two POCT whole blood PT monitors. MATERIALS AND METHODS: A
      simulation study, based on results of a 10-centre calibration exercise, was
      performed to assess reliability of ISI and INR when the number of centres was
      reduced from 10 to 2. RESULTS AND CONCLUSIONS: With both systems, the range of
      ISI and INR deviation increased as the number of centres was reduced. For the
      CoaguChek Mini, at least five centres were needed for satisfactory INR deviation
      in 95% of calibrations. With the TAS PT-NC, three centres gave satisfactory INR
      at this level. The number of centres required for multicentre calibration of
      these two POCT PT systems is greater than the two proposed by World Health
      Organisation (WHO) Guidelines for conventional PT testing.

PMID- 12413592
TI  - Inhibition of a thrombin anion-binding exosite-2 mutant by the glycosaminoglycan
      dependent serpins protein C inhibitor and heparin cofactor II.
AB  - Antithrombin (ATIII), heparin cofactor II (HCII) and protein C inhibitor (PCI;
      also named plasminogen activator inhibitor-3) are serine protease inhibitors
      (serpins) whose thrombin inhibition activity is accelerated in the presence of
      glycosaminoglycans. We compared the inhibition properties of PCI and HCII to
      ATIII using R93A/R97A/R101A thrombin, an anion-binding exosite-2 (exosite-2)
      mutant that has greatly reduced heparin-binding properties. Heparin-enhanced PCI
      inhibition of R93A/R97A/R101A thrombin was only approximately 2-fold compared to
      40-fold enhancement with wild-type recombinant thrombin. Thrombomodulin (TM)
      (with or without the chondroitin sulfate moiety) accelerated PCI inhibition of
      both wild-type and R93A/R97A/R101A thrombins. HCII achieved the same maximum
      activity in the presence of heparin with both wild-type and R93A/R97A/R101A
      thrombins; however, the optimum heparin concentration was 20 times greater than
      the reaction with wild-type thrombin, indicative of a decrease in heparin
      affinity. Dermatan sulfate (DSO4)-catalyzed HCII thrombin inhibition was
      unchanged in R93A/R97A/R101A thrombin compared to wild-type recombinant thrombin.
      These results suggest that PCI is similar to ATIII and depends upon ternary
      complex formation with heparin and these specific thrombin exosite-2 residues to
      accelerate thrombin inhibition. In contrast, HCII does not require Arg(93),
      Arg(97) and Arg(101) of thrombin exosite-2 and further supports the hypothesis
      that HCII uses an allosteric process following glycosaminoglycan binding to
      inhibit thrombin.

PMID- 12413593
TI  - Effects of homocysteine thiol group on fibrin networks: another possible
      mechanism of harm.
AB  - On the basis of growing clinical evidence, it is well known that elevated plasma
      homocysteine (Hcy) levels are associated with higher risk of venous and arterial
      thrombosis. Several experimental studies have been carried out in order to
      elucidate the mechanisms involved that still remain unclear. The aim of our study
      was to evaluate the homocysteine effects on formation and structure of plasmatic
      fibrin network. We also assayed homocystine and cysteine to determinate possible
      participation of thiol group in the tested activity. Aliquots of a pool of plasma
      incubated separately with sulfur compounds were clotting with thrombin.
      Fibringeneration and fibrin networks were evaluated by kinetic studies and
      scanning electronic microscopy, respectively. No significant differences were
      observed on fibrin generation of the substances assayed in comparison to control.
      The scanning electronic microscopy showed that Hcy-associated networks were
      different from control, with shorter, thicker and more branched fibers, resulting
      in a more compact structure and probably more resistant to fibrinolysis. The
      thiol group would be involved in this effect. Our findings would be a new
      contribution to elucidate the mechanisms involved in harmful effects associated
      to hyperhomocysteinemia.

PMID- 12413594
TI  - Platelet dysfunction, platelet function tests and cardiopulmonary bypass with
      heparin anticoagulation.

PMID- 12413596
TI  - Diffusion tensor MRI in temporal lobe epilepsy.
AB  - The purpose of this study was to investigate the diffusion characteristics of
      white matter in patients with focal temporal lobe epilepsy (TLE). Diffusion
      tensor imaging (DTI) was applied to patients and normal controls. Rotationally
      invariant mean diffusivity and diffusion anisotropy maps were calculated for all
      subjects. Comparisons between the two groups were performed for several white
      matter structures. Mean diffusivity and diffusion anisotropy of each selected
      structure were tested for correlations with age at onset and duration of
      epilepsy. Significantly lower diffusion anisotropy, and higher diffusivity in
      directions perpendicular to the axons, was detected in several white matter
      structures of the patients when compared to the controls. These structures were
      not located in the temporal lobes. No significant difference in mean diffusivity
      was detected between the selected structures from the two groups. Diffusion
      anisotropy was significantly correlated with age at onset of epilepsy in the
      posterior corpus callosum. Duration of epilepsy was not significantly correlated
      with the diffusion indices from any of the selected structures. The results of
      this study suggest that diffusion anisotropy may reveal abnormalities in patients
      with focal TLE. In addition, these abnormal changes are not necessarily
      restricted to the temporal lobes but might extend in other brain regions as well.
      Furthermore, the age at onset of epilepsy may be an important factor in
      determining the extent of the effect of epilepsy on white matter.

PMID- 12413597
TI  - BOLD signal compartmentalization based on the apparent diffusion coefficient.
AB  - Functional MRI (fMRI) can detect blood oxygenation level dependent (BOLD)
      hemodynamic responses secondary to neuronal activity. The most commonly used
      method for detecting fMRI signals is the gradient-echo echo-planar imaging (EPI)
      technique because of its sensitivity and speed. However, it is generally believed
      that a significant portion of these signals arises from large veins, with
      additional contribution from the capillaries and parenchyma. Early experiments
      using diffusion-weighted gradient-echo EPI have suggested that intra-voxel
      incoherent motion (IVIM) weighting inherent in the sequence can selectively
      attenuate contributions from different vessels based on the differences in the
      mobility of the blood within them. In the present study, we used similar approach
      to characterize the apparent diffusion coefficient (ADC) distribution within the
      activated areas of BOLD contrast. It is shown that the voxel values of the ADCs
      obtained from this technique can infer various vascular contributions to the BOLD
      signal.

PMID- 12413598
TI  - Quantification of neurons in Alzheimer and control brains with ex vivo high
      resolution magic angle spinning proton magnetic resonance spectroscopy and
      stereology.
AB  - Samples from human brains were examined with both stereologic methods for
      neuronal counting and high resolution magic angle spinning (HRMAS) proton
      magnetic resonance spectroscopy (1HMRS) for quantification of cellular
      metabolites. A statistically significant linear correlation between neuronal
      density and the concentration of N-acetylaspartate (NAA) in the superior temporal
      sulcus (STS) area was observed. Although NAA has been widely utilized as a
      neuronal marker in in vivo MRS, an emerging sub-discipline of diagnostic
      neuroradiology, the experimental proof of the unilateral relationship between NAA
      and neurons has yet to be confirmed. The observed correlation provides
      experimental evidence that NAA concentration is proportional to the neuronal
      density. Metabolite ratios measured from the STS area were compared to those from
      frontal association cortex for their sensitivities in differentiating Alzheimer
      disease brains from control brains.

PMID- 12413599
TI  - The influence of hyperoxia on regional cerebral blood flow (rCBF), regional
      cerebral blood volume (rCBV) and cerebral blood flow velocity in the middle
      cerebral artery (CBFVMCA) in human volunteers.
AB  - Conflicting results reported on the effects of hyperoxia on cerebral hemodynamics
      have been attributed mainly to methodical and species differences. In the present
      study contrast-enhanced magnetic resonance imaging (MRI) perfusion measurement
      was used to analyze the influence of hyperoxia (fraction of inspired oxygen
      (FiO2) = 1.0) on regional cerebral blood flow (rCBF) and regional cerebral blood
      volume (rCBV) in awake, normoventilating volunteers (n = 19). Furthermore, the
      experiment was repeated in 20 volunteers for transcranial Doppler sonography
      (TCD) measurement of cerebral blood flow velocity in the middle cerebral artery
      (CBFV(MCA)). When compared to normoxia (FiO2 = 0.21), hyperoxia heterogeneously
      influenced rCBV (4.95 +/- 0.02 to 12.87 +/- 0.08 mL/100g (FiO2 = 0.21) vs. 4.50
      +/- 0.02 to 13.09 +/- 0.09 mL/100g (FiO2 = 1.0). In contrast, hyperoxia
      diminished rCBF in all regions (68.08 +/- 0.38 to 199.58 +/- 1.58 mL/100g/min
      (FiO2 = 0.21) vs. 58.63 +/- 0.32 to 175.16 +/- 1.51 mL/100g/min (FiO2 = 1.0))
      except in parietal and left frontal gray matter. CBFV(MCA) remained unchanged
      regardless of the inspired oxygen fraction (62 +/- 9 cm/s (FiO2 = 0.21) vs. 64 +/
      8 cm/s (FiO2 = 1.0)). Finding CBFV(MCA) unchanged during hyperoxia is consistent
      with the present study's unchanged rCBF in parietal and left frontal gray matter.
      In these fronto-parietal regions predominantly fed by the middle cerebral artery,
      the vasoconstrictor effect of oxygen was probably counteracted by increased
      perfusion of foci of neuronal activity controlling general behavior and arousal.

PMID- 12413600
TI  - High-resolution gadolinium-enhanced 3D MRA of the infrapopliteal arteries.
      Lessons for improving bolus-chase peripheral MRA.
AB  - Peripheral magnetic resonance angiography (MRA) is growing in use. However,
      methods of performing peripheral MRA vary widely and continue to be optimized,
      especially for improvement in illustration of infrapopliteal arteries. The main
      purpose of this project was to identify imaging factors that can improve arterial
      visualization in the lower leg using bolus chase peripheral MRA. Eighteen healthy
      adults were imaged on a 1.5T MR scanner. The calf was imaged using conventional
      three-station bolus chase three-dimensional (3D) MRA, two dimensional (2D) time
      of-flight (TOF) MRA and single-station Gadolinium (Gd)-enhanced 3D MRA. Observer
      comparisons of vessel visualization, signal to noise ratios (SNR), contrast to
      noise ratios (CNR) and spatial resolution comparisons were performed. Arterial
      SNR and CNR were similar for all three techniques. However, arterial
      visualization was dramatically improved on dedicated, arterial-phase Gd-enhanced
      3D MRA compared with the multi-station bolus chase MRA and 2D TOF MRA. This
      improvement was related to optimization of Gd-enhanced 3D MRA parameters (fast
      injection rate of 2 mL/sec, high spatial resolution imaging, the use of dedicated
      phased array coils, elliptical centric k-space sampling and accurate arterial
      phase timing for image acquisition). The visualization of the infrapopliteal
      arteries can be substantially improved in bolus chase peripheral MRA if voxel
      size, contrast delivery, and central k-space data acquisition for arterial
      enhancement are optimized. Improvements in peripheral MRA should be directed at
      these parameters.

PMID- 12413601
TI  - Evaluation of endometrial cancer with 3D-VIBE (volume interpolated breath-hold
      examination) using intrauterine CO2 gas.
AB  - To evaluate the myometrial infiltration of the endometrial cancer prior to
      aggressive treatment, dynamic MRI (magnetic resonance imaging) has attracted
      attention. However, it has also been found that in a number of cases, MRI
      exhibits inconsistent results with regards to the extent of the infiltration into
      this component of the uterine body. To overcome this limitation, the authors
      designed a method to delineate the tumor morphology more clearly by injecting CO2
      gas into the uterine cavity. This procedure was combined with VIBE (volumetric
      interpolated breath-hold examination) to determine more precisely the depth of
      the tumor invasion. From our clinical results, the efficacy of the method was
      evaluated. On four patients with endometrial cancers (stage Ia-Ic), CO2 was
      injected to dilate the intra-uterine space through a catheter equipped with a
      balloon that had been introduced into the uterine cavity, after which VIBE was
      conducted. The images were interpreted by MPR (multiplanar reconstruction) and
      the findings from these images were compared against the histopathological
      findings. By employing this method, it was possible to delineate clearly the
      tumorous lesion in the uterine body, and three-dimensional images of the tumor
      invasion was acquired. The site and extent of tumor invasion in the myometrium
      were generally consistent with the histopathological findings. This method allows
      one to observe multiple planes by using thin slices. By dilating the uterine
      cavity, the site of involvement and the extent of invasion can be more precisely
      defined before treatment. It is truly a revolutionary procedure for determining
      prior to surgery-the depth of invasion of a cancer located in the uterine body.

PMID- 12413602
TI  - What is the recall rate of breast MRI when used for screening asymptomatic women
      at high risk?
AB  - Breast screening acceptability is dependent on sensitivity and recall rate. We
      aimed to establish the recall rate for MRI and mammography, separately and
      together, when screening a cohort of women at high genetic risk. Women aged 35-49
      years in the MARIBS study form the cohort. We analysed the recall rate, the
      number of extra tests and their effectiveness. Wilcoxon Rank test was used to
      estimate the effect of age and logistic regression with robust variance the
      effect of mammographic density on recall rates. The first 726 screening studies
      took place in 415 women. Following 86 of these recall occurred, comprising 140
      additional investigations. 28 of the cases were resolved without further MRI, and
      18 women had more than 2 additional tests. Neither age nor mammographic density
      was associated with recall. MRI had a recall of rate of 10.19%, and mammography
      4.00%. The two techniques largely recalled different cases and 10 cases only
      (11.62% of those recalled) were abnormal by both tests. The two together had a
      recall rate of 11.85%. Recall rates varied widely between centres of the study.
      Breast MRI in asymptomatic high-risk women age 35-49 years largely recalls
      different women from mammography. The combined figure of approximately 12% may be
      acceptable for screening and will be useful for planning similar studies.

PMID- 12413603
TI  - PFG NMR and internal magnetic field gradients in plant-based materials.
AB  - In this contribution, it is demonstrated that inner magnetic field gradients can
      seriously affect the results of stimulated echo PFG NMR experiments on plant
      based materials even if there is no notable content of paramagnetic substances.
      Such effects could be observed both in experiments on water in pharmaceutical
      grade cellulose powder materials and on eggplant fruit tissue. In both cases, it
      was observed that the effects of internal magnetic field gradients led to
      different relative values of the diffusion coefficient compared to values
      obtained with a gradient-compensating pulse sequence.

PMID- 12413604
TI  - Phage display technology: clinical applications and recent innovations.
AB  - Phage display is a molecular diversity technology that allows the presentation of
      large peptide and protein libraries on the surface of filamentous phage. Phage
      display libraries permit the selection of peptides and proteins, including
      antibodies, with high affinity and specificity for almost any target. A crucial
      advantage of this technology is the direct link that exists between the
      experimental phenotype and its encapsulated genotype, which allows the evolution
      of the selected binders into optimized molecules. Phage display facilitates
      engineering of antibodies with regard to their size, valency, affinity, and
      effector functions. The selection of antibodies and peptides from libraries
      displayed on the surface of filamentous phage has proven significant for routine
      isolation of peptides and antibodies for diagnostic and therapeutic applications.
      This review serves as an introduction to phage display, antibody engineering, the
      development of phage-displayed peptides and antibody fragments into viable
      diagnostic reagents, and recent trends in display technology.

PMID- 12413605
TI  - Proficiency testing performance: a case study with modeling.
AB  - OBJECTIVES: Previous literature has approached proficiency testing (PT)
      performance by defining the minimum levels, and combinations of imprecision and
      bias, necessary to meet PT requirements. In this case report, current PT
      performance was assessed and modeling performed to prioritize our quality
      improvement efforts. METHODS: A total of 1,006 chemistry challenge results from
      Ontario's Laboratory Proficiency Testing Program (LPTP, now QMPLS) performed on
      69 tests during 1999 and 2000 were used for this retrospective analysis. Peer
      group means, all method means and results from reference labs were used for
      comparison. QMPLS flagging and recommended performance criteria were compiled,
      and modeling performed to predict different levels of performance. RESULTS: Our
      internal imprecision is <5% for 72% of our 69 tests; however, only 20% of our
      tests had a CV/PT <25%. Of the 1,006 challenges performed, 136 (13.5%) results
      were outside PT limits, 55 (5.5%) results were flagged, and 12 requests were
      received from QMPLS seeking clarification on 24 (2.4%) results. Follow-up
      identified 9 (38%) nonanalytical errors, 8 (33%) method bias errors, 4 (17%)
      random errors, 2 poor methods, and one with no error identified. Modeling
      predicted flagging rates of 2.4% using QMPLS recommended precision performance,
      1.6% using our current internal imprecision, 2.2% or 7.0% if we included an
      overall 20% or 50% relative bias rate with our current imprecision levels, or
      15.0% when an estimate of our actual bias for each analyte was considered along
      with our current imprecision levels. CONCLUSIONS: If imprecision were the only
      cause of PT errors, our flagging rate for this study period would be 1.6%, and we
      would need to formally investigate 8 results a year. In practice, strict
      application of the QMPLS PT criteria would result in 68 investigations annually;
      however, judicial review of the results before request for clarification
      significantly reduced this number to 12 investigations (of which 38% were
      nonanalytical errors). At the present time bias is a significant cause of poor PT
      performance in a variety of assays. Individual laboratories need to address the
      problem of bias, and ultimately so do manufacturers. It would be helpful if PT
      programs also acknowledged this necessary evolution in both their criteria and
      processes.

PMID- 12413606
TI  - Alkaline phosphatases reduce toxicity of lipopolysaccharides in vivo and in vitro
      through dephosphorylation.
AB  - Intestinal alkaline phosphatase (AP), as a host defense factor, was first
      investigated in vivo using rats orally exposed to lipopolysaccharide (LPS). After
      the oral administration of LPS to rats, serum LPS content was increased within 2
      hr and then decreased to 6 hr. In contrast, when L-phenylalanine (L-Phe), an
      inhibitor of intestinal-type AP isozymes, was simultaneously administered with
      LPS, serum LPS content significantly increased from 1 hr and the area under the
      concentration-time curve of serum LPS was augmented approximately 2-fold,
      suggesting that APs in the gastrointestinal tract reduced serum LPS content. In
      addition, LPS toxicity diminished by a treatment in vitro with intestinal APs,
      were recovered by the treatment in the co-presence of L-Phe. In the experiment
      using human aortic endothelial cells (HAECs), we observed that the cell viability
      decreased in a dose-dependent manner of LPS-exposure, and the LPS dose,
      exhibiting 50% viability of the cells, was 0.05 microg/ml. When the cells were
      exposed to LPS pretreated with 50 nIU/ml of intestinal AP at pH 10.0 and 8.0, the
      50% viability was at 2.0 microg/ml of LPS. These results strongly suggest that
      the APs reduced the toxicity of LPS, as a host defense factor against LPS.

PMID- 12413607
TI  - Antinuclear antibodies (ANA) screening by enzyme immunoassay with nuclear HEp-2
      cell extract and recombinant antigens: analytical and clinical evaluation.
AB  - OBJECTIVES: Immunofluorescence assay (IFA) has been the standard method for
      antinuclear antibodies (ANA). To simplify and standardize the ANA test, generic
      ANA solid phase enzyme immunoassay has been promoted. The objective of the
      present work has been to study the relationship with IFA and the clinical
      usefulness of a generic EIA for ANA (COBAS Core HEp-2 ANA EIA, Roche
      Diagnostics). DESIGNS AND METHODS: We studied 74 healthy individuals, 119
      patients with defined systemic autoimmune diseases, 26 patients with other
      autoimmune diseases, and 490 routine samples sent to laboratory for ANA analysis.
      RESULTS: Precision study showed intra-assay coefficient of variations (CVs) below
      8% and inter-assay CVs below 10%. In relation to IFA, a 0.6 kappa index of
      agreement was obtained. COBAS-ANA concentrations increased according to IFA titer
      and greatest COBAS-ANA responses were obtained with pure or mixed homogeneous
      patterns and centromeric patterns. Analysis of COBAS-ANA response to particular
      antigenic specificities showed that SS-B, Scl-70 and U1sn-RNP specificities were
      saturating at high concentrations, whereas Jo-1, SS-A and nuclear and centromeric
      specificities exhibited lower responses. Elevated serum concentrations of IgG and
      IgM did not interfere COBAS-ANA, but high serum rheumatoid factor (RF)
      concentrations produced a decrease of ANA. For systemic lupus erythematosus (SLE)
      patients, the COBAS-ANA best efficiency was obtained with a cut-off of 0.9, with
      a sensitivity of 97% and a specificity of 88%, whereas the best IFA-ANA
      efficiency was obtained with a 1:80 dilution, giving a sensitivity of 90% and a
      specificity of 99%. There were no differences between areas under ROC curves for
      COBAS-ANA and IFA-ANA. For other systemic and nonsystemic autoimmune diseases
      sensitivity and specificity of COBAS-ANA were similar or higher than that of
      1:160 IFA-ANA titer. CONCLUSION: Sensitivity and specificity of COBAS Core ANA
      EIA for SLE and other systemic and nonsystemic autoimmune diseases, together with
      performance characteristics make it an adequate automated system for ANA
      screening.

PMID- 12413608
TI  - Intraindividual variation of PSA, free PSA and complexed PSA in a cohort of
      patients with prostate cancer managed with watchful observation.
AB  - OBJECTIVE: To determine the intraindividual variation of prostate-specific
      antigen (PSA) isoforms in prostate cancer patients managed conservatively with
      watchful observation. METHODS: Patients with favorable clinical parameters (stage
      T1b-T2b N0 M0, Gleason score </= 7, and PSA </= 15) were recruited to participate
      in a watchful observation program. Specimens were drawn for measurement of total
      (tPSA), free (fPSA) and complexed (cPSA) prostate-specific antigen isoforms.
      Total biologic variation and between-day analytical variation were used to
      calculate intraindividual variation. RESULTS: Total variation for each isoform
      and two ratios were not greatly affected by the time window for measurements in
      the interval 6 months to 2.7 yr. Analytical variation made only a small
      contribution to the total biologic variation. Intraindividual variation for a 1
      yr time interval for tPSA, fPSA, cPSA and the ratios of fPSA and cPSA to tPSA
      was, respectively, 21.6, 19.3, 25.4, 20.0 and 13.1%. The amount of change
      required for a significant difference between two readings (with 95% confidence)
      was, respectively, 59.8, 53.4, 70.4, 55.3 and 36.2%. CONCLUSIONS: There is a
      significantly higher intraindividual variation of cPSA (25.4%), and a
      significantly lower intraindividual variation of the ratio cPSA to tPSA (13.1%)
      compared to the other individual PSA isoforms and to the ratio of fPSA to tPSA.
      The amount of change required for a significant difference between two
      concentrations is large for all variables studied, but the lowest is the ratio of
      cPSA to tPSA (36.2%). These results have significance for diagnosis and
      monitoring of patients with prostate cancer.

PMID- 12413609
TI  - Trace elements analysis of ascitic fluid in benign and malignant diseases.
AB  - OBJECTIVES: To evaluate differences in ascitic fluid trace element concentrations
      which might be useful in discrimination between benign and malignant ascites.
      DESIGN AND METHODS: The concentrations of copper, zinc, magnesium and iron in
      ascitic fluid and venous blood in 17 patients were investigated. The relationship
      between these trace elements and type of disease were examined. Investigations
      were carried out in a group of 5 males and 5 females aged 54 to 77 yr who had
      cirrhosis ascites and in a group of 7 females aged 41 to 76 yr with ascites due
      to gynecologic neoplasms. RESULTS: The mean ascitic fluid and serum
      concentrations of copper were significantly higher in neoplastic diseases
      compared to benign disease states (118,43 vs. 97,50, 91,14 vs. 26.90) (p < 0,05
      and p < 0,01 respectively). The zinc levels in ascitic fluid and serum were
      significantly different between the groups (p < 0,01). Neoplastic patients had
      significantly higher ascitic fluid magnesium levels than the benign disease group
      (2,17 vs. 1,55, p < 0,001). The serum levels of iron were significantly lower in
      the neoplastic diseases group (92, 28 vs. 255, p < 0, 01). In benign diseases the
      concentration of zinc in ascitic fluid correlated positively with ascitic fluid
      copper concentrations. The concentrations of zinc and iron in malignant ascites
      correlate positively with the magnesium concentrations. Statistically significant
      negative correlations were found between ascites zinc and magnesium and magnesium
      and copper in cirrhotic patients and magnesium and copper in malignant diseases.
      CONCLUSIONS: The results showed that zinc, magnesium and iron levels were
      significantly different between cirrhotic and neoplastic illness. Analysis of
      serum and ascitic fluid trace element composition may be helpful in identifying
      and distinguishing the malignant and nonmalignant ascites and provides useful
      information on processes regulating passage of blood components into the
      peritoneal cavity.

PMID- 12413610
TI  - Plasma and peripheral leukocyte beta-N-acetylhexosaminidase isoenzymes and
      disease activity in rheumatoid arthritis.
AB  - OBJECTIVES: Recently it has been suggested that serum beta-N-acetylhexosaminidase
      (Hex) could be a joint destruction marker in rheumatoid arthritis (RA) patients.
      However, a large amount of serum Hex activity has its source from platelets, and
      the blood platelet-count is often increased in RA, which may have masked the
      significance of the results. The purpose of this study was to investigate the
      relationship between plasma activity of Hex and disease activity or severity.
      DESIGN AND METHODS: In 51 patients with RA, with an evolution period for the
      illness of 10.9 +/- 1.2 yr (range 1-40 yr), we determined the total Hex activity
      together with its Hex A and B isoenzymes in plasma and in mononuclear (MN) and
      polymorphonuclear (PMN) leukocytes. RESULTS: The plasma activity of total Hex and
      Hex B isoenzyme was slightly higher in the group of patients studied (p < 0.01),
      together with the specific activity of total Hex, Hex A and B in PMN leukocytes
      (p < 0.001) than in the control group. No significant correlation was found
      between plasma or leukocyte Hex and the radiologic evaluation of the disease
      (Sharp's modified method), or the patient's functional capacity (modified Health
      Assessment Questionnaire). Likewise, a significant correlation between Hex
      activity and laboratory inflammation markers (C reactive protein, sialic acid,
      erythrocyte sedimentation rate) or the evolution time of the disease was not
      found. CONCLUSIONS: The plasma activity of total Hex, or even of its isoenzymes
      Hex A and Hex B, does not appear to be a reliable marker of erosion and cartilage
      degradation in RA patients. Liver function appears to be the major determinant
      for the plasma Hex activity in these patients.

PMID- 12413611
TI  - Oxidant-antioxidant status in patients with oral squamous cell carcinomas at
      different intraoral sites.
AB  - OBJECTIVES: To compare the extent of lipid peroxidation and the status of
      antioxidants in tumor and venous blood of patients with oral squamous cell
      carcinoma (OSCC) at different intraoral sites. DESIGN AND METHODS: Twenty four
      patients with OSCC at different intraoral sites and an equal number of age- and
      sex-matched reference subjects were chosen for the study. The concentrations of
      lipid peroxides and reduced glutathione (GSH) and the activities of the
      antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), glutathione
      peroxidase (GPx) and glutathione-S-transferase (GST) were estimated in tissues
      and blood. RESULTS: Diminished lipid peroxidation in tumor tissue was accompanied
      by decreased activities of SOD and CAT with increase in GSH and GSH-dependent
      enzymes. In contrast, enhanced lipid peroxidation with decrease in antioxidants
      was observed in the venous blood of OSCC patients. CONCLUSION: No significant
      differences in lipid peroxidation and antioxidant levels were observed between
      patients with OSCC at different intraoral sites. However, our results revealed
      differences between the tumor and blood with respect to their susceptibility to
      lipid peroxidation and antioxidant status.

PMID- 12413612
TI  - Plasma homocyst(e)ine, folate and vitamin B(12) levels among school children in
      Taiwan: The Taipei Children Heart Study.
AB  - OBJECTIVE: The purpose of this study is to examine the association of plasma Hcy,
      folate and vitamin B(12) levels on CVD risk factors among children in Taiwan.
      METHODS: After multistage sampling, we selected randomly 1,235 children (609 boys
      and 626 girls) aged 12 to 15 yr. Plasma Hcy levels was measured using ABBOTT Imx
      analyzer, while plasma folate and vitamin B(12) were measured using ACS: 180
      automated chemiluminescence analyzer. Anthropometric, blood pressure (BP) and
      other biochemical CVD risk factors including serum total cholesterol (CHOL),
      triglyceride (TG), high density lipoprotein-cholesterol (HDL-C), apolipoprotein
      A1 (apoA1) and B (apoB) and lipoprotein(a) [Lp(a)]were measured using standard
      methods. We also calculated low density lipoprotein-cholesterol (LDL-C) and TCHR
      (total cholesterol to HDL-C ratio) as atherogenic indices. RESULTS: Boys were
      taller and heavier, having higher body mass index (BMI), systolic blood pressure
      (SBP) and plasma glucose levels but lower diastolic blood pressure (DBP), heart
      rate (HR), cholesterol, TG, HDL-C, LDL-C, TCHR, and Lp(a) levels than girls. Boys
      also had higher plasma Hcy and lower folate, vitamin B(12), levels than girls
      (for plasma Hcy, mean +/- SD, 10.50 +/- 4.13 vs. 8.95 +/- 2.61 micromol/L for
      boys vs. girls, respectively). Plasma Hcy levels were significantly correlated
      positively with body height, body weight, SBP and DBP in both genders. Body
      height, body weight, BMI and SBP levels were found to increase with trend among
      different quintile plasma Hcy subgroups on boys but not on girls. Plasma folate
      and vitamin B(12) were decreased significantly along with the higher quintile
      plasma Hcy subgroup in both genders. CONCLUSIONS: Boys had higher plasma Hcy
      levels than girls after adjusting for age. Furthermore, plasma Hcy levels were
      significantly associated with anthropometric parameters, such as body height and
      weight and blood pressure, but not related with lipid profiles among children in
      Taiwan.

PMID- 12413613
TI  - The toxicity of Callilepis laureola, a South African traditional herbal medicine.

PMID- 12413614
TI  - Post-abortion depot medroxyprogesterone acetate continuation rates: a randomized
      trial of cyclic estradiol.
AB  - Irregular menstrual bleeding is a common reason for discontinuation of depot
      medroyprogesterone acetate (DMPA) contraception. We conducted a double-blind,
      randomized placebo controlled trial to estimate if transdermal estradiol used in
      a cyclic fashion could make DMPA bleeding patterns more acceptable and improve
      DMPA continuation rates. Women initiating DMPA contraception immediately post
      abortion (N = 132) were randomized to receive either a low sustained dose of
      transdermal 17-beta estradiol (0.10 mg/day, Climara) or an identical placebo to
      be used in a cyclic manner for 3 months. Bleeding patterns, contraceptive use,
      and pregnancy rates were measured for 1 year after enrollment. Cyclic transdermal
      estrogen did not create regular bleeding patterns in new users of DMPA and had no
      effect on DMPA continuation rates (relative hazard = 0.93, 95%CI 0.65-1.33). By
      12 months after enrollment, 19.4% of those randomized to estrogen and 23.9% of
      those randomized to placebo were still using DMPA for contraception. There was no
      difference in the frequency of DMPA discontinuation primarily for abnormal
      uterine bleeding between groups (relative risk ratio = 0.95, 95%CI 0.40-2.23).
      Few women who discontinued DMPA switched to highly effective methods of
      contraception and within 1 year of an abortion, there were 18 repeat pregnancies
      (21.9%). Compliance with the estrogen patches was poor resulting in early study
      termination and inadequate statistical power to detect a clinically significant
      difference in DMPA continuation rates. Continuation rates of DMPA were low and
      repeat pregnancy rates were high among women initiating DMPA at the time of
      abortion. Cyclic transdermal estradiol use is an unacceptable regimen for
      preventing the irregular bleeding associated with DMPA initiation.

PMID- 12413616
TI  - Mifepristone and vaginal misoprostol on the same day for abortion from 50 to 63
      days' gestation.
AB  - In a previous study of 40 women up to 49 days' gestation, our research center
      demonstrated that mifepristone 200 mg followed on the same day by misoprostol 800
      microg vaginally produced abortion at rates similar to standard regimens which
      administer the two drugs 24 or 48 h apart. We performed this study to evaluate
      the same regimen in women with pregnancies at 50 to 63 days' gestation. Forty
      women from 50 to 56 days' gestation (Group 1) and 40 women from 57 to 63 days'
      gestation (Group 2) inserted misoprostol vaginally 6 to 8 h after taking
      mifepristone. Participants were instructed to return 24 +/- 1 h after using
      misoprostol for an evaluation that included transvaginal ultrasonography.
      Subjects who had not aborted received a second dose of misoprostol to administer
      48 h after the mifepristone. All participants were to return 2 weeks later.
      Ultrasound examinations were performed in those who required a second dose of
      misoprostol to confirm the abortion was successful. At 24 h after receiving
      misoprostol, 37/40 (93%, 95% CI 80, 98%) and 36/40 (90%, 95% CI 76, 97%) women
      from Groups 1 and 2, respectively, had expelled the pregnancy. By follow-up 2
      weeks after taking mifepristone, all 40 women in Group 1 (100%, 95% CI 91,100%)
      and 39/40 women in Group 2 (98%, 95% CI 87,100%) had complete abortions. One
      woman in the latter group who aborted within the first 24 h had an incomplete
      abortion treated by suction curettage. This pilot study suggests that
      mifepristone 200 mg, followed on the same day by misoprostol 800 microg
      vaginally, effects abortion in women 50 to 63 days' gestation at rates comparable
      to regimens using longer dosing intervals between medications. Though this
      regimen is promising, larger randomized trials comparing it to standard regimens
      are needed before widespread use.

PMID- 12413615
TI  - A randomized comparative study on mifepristone alone and in combination with
      tamoxifen for emergency contraception.
AB  - The purpose of the clinical study was to compare the efficacy and side effects of
      10 mg of mifepristone alone (Group 1) and with 20 mg of tamoxifen (Group 2) for
      emergency contraception, especially as used within 72-120 h after coitus. Four
      hundred female volunteers with one act of unprotected intercourse or
      contraception failure (200 cases in each group) were recruited and completed the
      study. There were 198 women treated < 72 h after coitus (100 in Group 1 and 98 in
      Group 2), whereas the remaining 202 patients were treated between 72-120 h (100
      in Group 1 and 102 in Group 2). In total, four pregnancies occurred; one treated
      < 72 h in each group, two between 72-120 h in Group 1. Efficacy for prevention of
      unwanted pregnancy by Trussell method is 84% for Group 1, and 95% for Group 2,
      and which is not significantly different between the two groups and even
      subgroups. The side effects (15.5% for Group 1 and 14.5% for Group 2) and changes
      in menstruation were infrequent and mild in both groups. Further studies should
      be conducted to determine whether tamoxifen combined with mifepristone for
      emergency contraception is more effective as compared with mifepristone alone.

PMID- 12413617
TI  - Accuracy of the peak day of cervical mucus as a biological marker of fertility.
AB  - The (PD) peak day of cervical mucus is an important biologic marker for the self
      determination of the optimal time of fertility in a woman's menstrual cycle. The
      purpose of this article is to provide evidence (literature and empiric) for the
      accuracy of the PD of cervical mucus as a biologic marker of peak fertility and
      the estimated day of ovulation. An analysis of data from four published studies
      that compared the self-determination of the PD of cervical mucus with the urinary
      luteinizing hormone (LH) surge was conducted. The four studies yielded 108
      menstrual cycle charts from 53 women participants. The 108 cycles ranged in
      length from 22 to 75 days (mean 29.4 SD 6.0). Ninety-three of the 108 cycles had
      both an identified PD and LH surge. Data charts showed that 97.8% of the PD fell
      within +/-4 days of the estimated day of ovulation. Use of a standardized mucus
      cycle scoring system indicated that the peak in cervical mucus ratings was
      highest on the day of the LH surge. Self-determination of the PD of cervical
      mucus is a very accurate means of determining peak fertility and a fairly
      accurate means of determining the day of ovulation and the beginning of the end
      of the fertile time.

PMID- 12413618
TI  - Efficacy of a mini version of the frameless GyneFix intrauterine system (IUS)
      with effective copper surface area of 200 mm2. dirk.wildemeersch@contrel.be.
AB  - This study was conducted to evaluate the efficacy of a 'mini' version of the
      frameless intrauterine system (IUS) (GyneFix) that has a copper surface area of
      approximately 200 mm(2). The GyneFix-mini consists of four copper cylinders
      instead of six and is only 2 cm long. A total of 301 insertions were performed in
      an open nonrandomized pilot study in parous (77%) and nulligravid/nulliparous
      (23%) women in Belgium and China. This interim analysis reports on 4110 women
      months of use. All women were followed-up for a minimum of 12 months. Two
      pregnancies occurred with the mini GyneFix IUS in this study. However, only one
      occurred with the device in situ. The cumulative removal rate for medical reasons
      (bleeding and pain) was 0.39 at 1 year. The expulsion rate was 1.04. These low
      event rates resulted in a high continuation rate (95.02 at 1 year). Neither
      perforations nor pelvic inflammatory disease cases were encountered in this
      study. This study indicates that only a minimal amount of copper, positioned in
      the upper part of the uterine cavity, is sufficient to provide a high
      contraceptive effect. This is made possible by anchoring the active contraceptive
      substance to the fundus of the uterus. The fact that 100% of the copper surface
      area of the frameless IUS is available for copper release is an additional
      advantage.

PMID- 12413619
TI  - Does contraceptive method change the Pap smear finding?
AB  - The aim of the present study was to investigate the effect of various types of
      contraceptives on morphological finding of Pap smear results. Pap smear results
      of 7,753 fertile women who presented to 15 different family planning services in
      Fars Province (south of Iran) were analyzed according to their methods of
      contraception. The population consisted of 2241 women who used intrauterine
      device (IUD) as a contraceptive method (Group 1), 2521 women who were oral
      contraceptive (OCP) users (Group 2), and the control group, which consisted of
      women who used other methods of contraceptive. Comparison between the Pap smear
      results showed a higher number of benign cellular changes among Group 1 (22.4%)
      than Group 2 (19.3%), and the differences were statistically significant (p =
      0.009). In addition, 80.6% women who used oral contraceptive pill (OCP) as
      contraceptive showed cellular changes within normal limits, while it were 77.6%
      for intrauterine device (IUD) users. Compared with Group 2, Group 1 had a
      significantly higher percentage of metaplastic cells in their Pap smear results
      (G1 7.4%, G2 5.8%, p < 0.05). No epithelial abnormalities were reported in Pap
      smears. Trichomonas vaginalis was higher in G1 than the other groups (p < 0.005),
      but the difference was not statistically significant for candidiasis. It may be
      concluded that in this population, IUD and OCP had no effect on morphological
      pattern of the Pap smears, but there was a significant increased rate of
      trichomonas infection in IUD users.

PMID- 12413620
TI  - Randomized trial of oral versus vaginal misoprostol 2 days after mifepristone 200
      mg for abortion up to 63 days of pregnancy.
AB  - This prospective, open-label, randomized trial of healthy adult women up to 9
      weeks pregnant compared mifepristone 200 mg followed 2 days later with
      misoprostol 400 microg orally versus misoprostol 800 microg vaginally. The study
      was interrupted after the oral misoprostol group experienced a higher than
      expected failure rate. This treatment was discontinued and another substituted
      consisting of oral misoprostol 800 microg divided into two doses two hours apart.
      Women returned for a follow-up visit from Day 4 to 8. All women with a continuing
      pregnancy received a repeat dose of misoprostol vaginally and returned before Day
      15. The primary outcome measure was a complete medical abortion without surgical
      intervention at the first visit. Of the 1045 women enrolled, 1011 had complete
      data: Group 1 (220) used oral misoprostol 400 microg, Group 2 (269) used oral
      misoprostol 800 microg, and Group 3 (522) used vaginal misoprostol 800 microg. At
      first follow-up visit, the primary outcome, that is, a complete abortion, was 84%
      for Group 1, 92% for Group 2, and 96% for Group 3, p < 0.001. After a second dose
      of vaginal misoprostol in women with on-going pregnancies at their first follow
      up visit, the complete abortion rates were 91%, 95%, and 98%, respectively, p <
      0.001. There were minimal differences in side effects, onset of bleeding and
      overall acceptability in the three groups. Mifepristone 200 mg followed by
      vaginal misoprostol 2 days later was more effective at inducing an abortion up to
      9 weeks of pregnancy than the same dose of mifepristone followed by oral
      misoprostol.

PMID- 12413621
TI  - Screening for Chlamydia trachomatis infection is indicated for women under 30
      using emergency contraception.
AB  - A total of 838 women attending a large family planning clinic in Scotland for
      emergency contraception were offered screening for Chlamydia trachomatis
      infection. 569 were screened using ligase chain reaction test in first void urine
      at the time of presenting for emergency contraception and were retested 1 or 2
      weeks later. Women aged under 20 and over 30 years were significantly more likely
      to decline to be tested than women aged 20 to 30. The prevalence of chlamydia was
      7.6% in woman aged 24 or less, 5.3% in women aged 25 to 29, and 1.2% in women
      aged 30 or more. Only two women (< 1%) who tested negative at the time of using
      EC were positive 1 or 2 weeks later. Women under age 30 who use EC should be
      offered screening for chlamydia infection and testing at the time they attend for
      EC is adequate to detect the great majority of infected women.

PMID- 12413622
TI  - Evaluation of an emergency contraception introduction project in Kenya.
AB  - The Consortium for Emergency Contraception introduced Postinor-2, a progestin
      only EC product, into Kenya as part of its work to expand access to EC in
      developing countries. Introduction activities included registering Postinor-2,
      training providers, and developing provider and client materials. We surveyed
      family planning clients and providers to assess the impact of these activities.
      Knowledge of EC among clients and providers improved between the baseline and
      evaluation surveys. More women and providers had heard of EC and more providers
      were distributing it. Support for access to EC in Kenya also improved. The
      results indicate, though, that further information is needed. Only one-fifth of
      women at the evaluation had heard of EC and almost half of the women expressed
      concerns about EC at baseline and evaluation. More research and experience using
      novel ways of informing women about EC in Africa is needed, and information needs
      to address women's concerns.

PMID- 12413623
TI  - Emergency contraception among university students in Kingston, Jamaica: a survey
      of knowledge, attitudes, and practices.
AB  - Emergency contraceptives (ECs) are an important option for young women in
      Jamaica, where rates of unplanned pregnancy are high. Few previous studies of EC
      exist in Jamaica. We surveyed a random sample of 205 students living on campus at
      the University of the West Indies in Kingston, Jamaica, to learn more about
      students' knowledge and opinions of EC pills (ECPs). General awareness of ECPs
      was high (84%), although many students were unaware of specific details regarding
      the method's appropriate use, such as the time frame. Twenty students (10%) had
      used ECPs themselves or had a partner who had used them. Most had used ECPs for
      the first time because they lacked contraception or because of contraceptive
      failure. Following their first use of ECPs, 55% adopted an ongoing method of
      contraception. Most students felt ECPs were an important option for women in
      Jamaica; however, some feared ECPs might be overused. Future educational
      campaigns should provide Jamaican university students with detailed information
      about this method.

PMID- 12413624
TI  - Comparative evaluation of the effectiveness and safety of two regimens of
      levonorgestrel for emergency contraception in Nigerians.
AB  - Emergency contraception was introduced in Nigeria over two decades ago, but few
      women have used this method even in emergency situations because of the side
      effects. To find an acceptable levonorgestrel regimen for emergency contraception
      in our community, the two-dose regimen 0.75-mg levonorgestrel 12 h apart (group
      A) and the single dose 1.5-mg levonorgestrel (group B) were studied in 1118
      volunteers. Mild side effects such as nausea, vomiting, lower abdominal pains,
      menorrhagia, dizziness, headache, and breast tenderness were reported.
      Significantly more women in the high-dose group reported headache, breast
      tenderness, and heavy menstrual flow. Eleven pregnancies (1.0%) were reported (7
      in group A and 4 in group B). The crude relative risk of pregnancies was similar
      in the two groups (RR = 0.71, 95% CI = 0.32-1.55; p > 0.05) [corrected]. On the
      other hand, the estimated effectiveness rate of 86.80% in group A was
      significantly lower than the 92.99% for group B (p < 0.05). The pregnancy rates
      increased with delay in starting treatment and if further acts of unprotected
      sexual intercourse took place after treatment. It was concluded that both
      regimens were effective and safe.

PMID- 12413625
TI  - Women's preferences for general or local anesthesia for pain during first
      trimester surgical abortion in India.
AB  - Women in India are rarely given a choice about their pain management methods for
      first trimester abortions. To investigate women's preferences and perceptions of
      pain, we allowed 100 women in Mumbai to choose between local and general
      anesthesia (60% selected general, while 40% elected local anesthesia). Using
      visual analog scales ranging from 1 to 7, women characterized their pain several
      times during their abortion visits. Local anesthesia clients reported more pain
      during (2.3 local vs. 1.0 general) and immediately after (1.9 vs. 1.0) the
      procedure. By three hours post-procedure, none of the women in either group
      reported any pain. General anesthesia clients reported that having no pain (95%)
      or anxiety (38%) were the best features, while local anesthesia clients liked
      being ambulatory (26%), avoiding side effects (26%), and feeling awake (21%).
      Though women in both groups were satisfied, local anesthesia clients were more
      likely to recommend it to friends (95% vs. 85%). Given these advantages, our
      study suggests that some women willingly accept additional pain incurred by
      exchanging local for general anesthesia.

PMID- 12413626
TI  - Characterization of a female controlled drug delivery system for microbicides.
AB  - In this study, the feasibility of a carbopol 934P-HPMC-based gel formulation as a
      vaginal drug delivery system was evaluated. A vaginal fluid simulant (VFS) was
      utilized to simulate human vaginal mucus. The viscosity of the carbopol-HPMC gel
      system and VFS was examined using a cone and plate viscometer. The surface
      tension of VFS was measured using a capillary rising method. Differential
      scanning calorimetry (DSC) was employed to investigate the effect of carbopol gel
      on the conformational changes of rat vaginal membrane. The viscosity of carbopol
      gel increased as the pH of the system increased from 4.0 to 6.0. The viscosity of
      HPMC gel remained the same irrespective of pH of the system. The viscosity of the
      carbopol gel significantly increased, when HPMC (0.5-1.5%) was added to the
      system. The optimal viscosity value (1.5-2.0 poises) was achieved at 1.0-1.5%
      carbopol (pH 4.0) with the presence of 1.0-1.5% HPMC. There were mucin
      concentration dependent changes in viscosity and surface tension of VFS. The
      results of DSC analysis of rat vaginal membrane showed that the profiles of
      thermal stability for both carbopol-treated and the untreated control at the
      temperature ranging from 40 to 90 degrees C were almost identical. The thermal
      denaturation temperatures (Td) of the carbopol-treated membrane and the untreated
      control were not significantly different from each other. The combination of
      carbopol and HPMC seems to be an ideal formulation as a vaginal delivery system.
      Mucin played an important role in the regulation of viscosity and surface tension
      of VFS. DSC study demonstrated that carbopol gel showed good biocompatibility and
      did not cause any conformational changes in rat vaginal membrane.

PMID- 12413627
TI  - Fetal growth in rats treated with lapachol.
AB  - Lapachol is a naphthoquinone well known for its therapeutic potential. Previous
      studies have shown that lapachol does not interfere with embryonic development
      during the pre-implantation period. However, when administered during the
      organogenic period at the same dose level, it induces a high fetal death
      incidence. To evaluate the effect of lapachol during fetogenesis, 20 pregnant
      Wistar rats were randomly divided into two groups: vehicle (10 mL of a 50%
      aqueous ethanol solution/kg body weight) and treated (100 mg of lapachol/kg body
      weight). Lapachol was administered from the 17th to 20th day of pregnancy. The
      following variables were analyzed: maternal body weight from 16th to 21st day of
      pregnancy, food intake from 17th to 21st day of pregnancy, clinical signs of
      physical discomfort, ovarian weights, implantations, resorptions and mortality
      indices, fetal and placenta weights, external malformations, and fetal organ
      weights. Results indicated that lapachol was not toxic to mothers, although it
      was fetotoxic leading to fetal growth retardation.

PMID- 12413629
TI  - Abstracts of the EUFEPS 2002. 7th European Congress of Pharmaceutical Sciences.
      21-23 October 2002, Stockholm, Sweden.

PMID- 12413628
TI  - Hormonal pregnancy test redux.

PMID- 12413630
TI  - Ras as a target in cancer therapy.
AB  - Ras proteins are guanine nucleotide-binding proteins that are central to the
      control of normal and transformed cell growth and that are mutated in
      approximately 30% of human cancers. Binding of ligands to various growth factor
      receptors activates Ras and subsequently a plethora of downstream effectors
      including the Raf-1/mitogen-activated protein kinase pathway. For effective ras
      functioning and for transformation, Ras proteins must undergo post-translational
      modifications that facilitate their attachment to the plasma membrane.
      Farnesylation, catalysed by farnesyl protein transferase (FPT), is the first and
      the most important of these modifications; inhibition of which ablates ras
      activity, resulting in significant anti-proliferative effect in vitro and in
      human cancer xenograft models. FPT inhibitors are being assessed in a range of
      phase I and phase II trials, which incorporate both pharmacokinetic and dynamic
      end-points. In addition, ras mutations can also generate neo-epitopes for
      cytotoxic and helper T-cell recognition, rendering ras-mutated tumours a
      potential target for immunotherapy. Though their clinical evaluation is still in
      infancy, these two modes of ras targeting represent rational therapeutic
      strategies that can undergo mechanistic evaluation in the clinic.

PMID- 12413631
TI  - Molecular alterations in sporadic breast cancer.
AB  - Breast cancer is a genetic disease. Like other human cancers, it is thought to
      occur as the result of progressive accumulation of genetic aberrations. These
      aberrations result in a deviation of the gene expression profiles from that of
      the normal progenitor cell. In up to 99% of cases, breast cancer is due to solely
      somatic genetic aberrations without germ-line ones. Considerable progress have
      already been made in understanding the genetic mechanisms underlying the
      development and progression of breast cancer. Several extensively studied genes
      are now well known to be involved. Unfortunately, our ability to make clinically
      useful interventions on the basis of these data is limited. Because of the
      involvement of multiple genes and complex pathways in a single cancer cell, the
      molecular dysfunctioning underlying breast cancer remains to be completely
      clarified. In a next future, studying the global gene expression of different
      types of tumors will allow the development of expression profiles unique for a
      breast cancer, its stage and prognostic category, leading to diagnostic assays
      and the identification of new therapeutic targets.

PMID- 12413632
TI  - A potential role of macrophage activation in the treatment of cancer.
AB  - One of the functions of macrophages is to provide a defense mechanism against
      tumor cells. In the last decades the mechanism of tumor cell killing by
      macrophages have been studied extensively. The tumor cytotoxic function of
      macrophages requires stimulation either with bacterial cell wall products such as
      lipopolysaccharide (LPS) or muramyldipeptide (MDP) or with cytokines such as
      interferon-gamma (IFN-gamma) and granulocyte-macrophage colony-stimulating factor
      (GM-CSF). Activated macrophages secrete several substances that are directly
      involved in tumor cell killing i.e. tumor necrosis factor (TNF) and nitric oxide
      (NO). On the other hand, substances are secreted that are able to stimulate tumor
      cell growth, depending on the stage and the nature of the tumor. Several clinical
      trials have been performed aiming at the activation of macrophages or dendritic
      cells, a subpopulation of the macrophages. In this review we will summarize and
      discuss experimental studies and clinical trials based on the activation of
      macrophages.

PMID- 12413633
TI  - Fever and neutropenia in cancer patients: the diagnostic role of cytokines in
      risk assessment strategies.
AB  - Cancer patients treated with chemotherapy are susceptible to bacterial
      infections. Therefore, all neutropenic cancer patients with fever receive
      standard therapy consisting of broad-spectrum antibiotics and hospitalization.
      However, febrile neutropenia in cancer patients is often due to other causes than
      bacterial infections. Therefore, standard therapy should be re-evaluated and new
      treatment strategies for patients with variable risk for bacterial infection
      should be considered. This paper reviews the changing spectrum of microorganisms
      and resistance of microorganisms to antibiotics in infection during neutropenia
      and discusses new strategies for the selection of patients with low-risk for
      bacterial infection using clinical and biochemical parameters such as acute phase
      proteins and cytokines. These low-risk patients may be treated with alternative
      therapies such as oral antibiotics, early discharge from the hospital or
      outpatient treatment.

PMID- 12413634
TI  - Critical review on non-myeloablative stem cell transplantation (NST).
AB  - Allogeneic stem cell transplantation is an established treatment modality for a
      variety of hematologic malignancies. Unfortunately, it carries a high risk of
      complications and toxicities related to the intensive preparative regimen which
      is traditionally used for pre-transplant myeloablation and the graft versus host
      disease, which may be life threatening. Thus allogeneic stem cell transplantation
      has been used only for younger patients with a good performance status, excluding
      many other potential candidates due to advanced age or comorbid conditions. Using
      reduced intensity preparative regimens for allogeneic stem cell transplantation
      (non-myeloablative stem cell transplantation (NST)) researchers attempted to
      overcome these barriers in patients' selection and tried to make hematopoietic
      stem cell (HSC) transplantation a safer procedure. The well-described graft
      versus malignancy effect would be the most curative element in this treatment.
      After more than 5 years of cumulative clinical experience, we know that NST is a
      feasible treatment option for patients with suboptimal performance status and is
      mostly effective in slow proliferating malignancies, which gives time for a graft
      versus malignancy effect to take place. Additionally achievement of stable donor
      cell engraftment with NSTs provides a platform for adoptive immune cell
      treatments and is promising for extended indications of stem cell transplantation
      in the future.

PMID- 12413635
TI  - New-onset diabetes and ketoacidosis with atypical antipsychotics.
AB  - Information from the Ohio Department of Mental Health (ODMH) database was
      reviewed retrospectively to identify patients at the Cincinnati center treated
      with an atypical antipsychotic and who had also been evaluated or treated for
      diabetes mellitus. Blood glucose levels, glucose tolerance, or other evaluations
      of diabetes had been conducted in 14 of the 126 patients treated with atypical
      antipsychotics. In 11 of the 14, new-onset, acute, and marked glucose intolerance
      developed after treatment with clozapine, olanzapine or quetiapine. Of these, six
      patients required insulin therapy (four only transiently) and five patients
      developed diabetic ketoacidosis (DKA). Also, glucose metabolism was labile in all
      cases, and was transient in two cases with subsequent resolution despite on-going
      antipsychotic therapy. Certain atypical antipsychotics may be associated with new
      onset glucose intolerance, including acute diabetes and ketoacidosis. Monitoring
      for changes in blood glucose levels in patients taking atypical antipsychotics
      may be indicated. More systematic study data are clearly needed.

PMID- 12413636
TI  - The effect of melperone, an atypical antipsychotic drug, on cognitive function in
      schizophrenia.
AB  - Melperone, a butyrophenone, has been shown to possess atypical antipsychotic
      properties, i.e. ability to produce an antipsychotic effect in man at doses that
      cause minimal extrapyramidal side effects. In addition, melperone shares the
      following with other atypical antipsychotic drugs: (1) effectiveness for
      ameliorating negative symptoms; (2) no prolactin elevation; and (3) effectiveness
      in the treatment of some patients with neuroleptic-resistant schizophrenia. Other
      atypical antipsychotic drugs have been reported to improve cognitive function.
      This study was performed to investigate the effect of melperone on cognitive
      function. Nineteen patients with schizophrenia or schizoaffective disorder,
      including 11 neuroleptic-resistant patients, were treated with melperone for 6
      weeks. A comprehensive neurocognitive test battery and psychopathological ratings
      (Brief Psychiatric Rating Scale, BPRS) were administered at baseline and after 6
      weeks of melperone treatment. Treatment with melperone was associated with
      improvement in executive function, as measured by the Wisconsin Card Sorting Test
      (WCST)-Categories and WCST-Percent Perseveration. On the other hand, visuospatial
      manipulation, as measured by the Wechsler Intelligent Scale for Children-Revised
      (WISC-R) Maze, worsened during melperone treatment. There were no significant
      changes in other domains of cognition, i.e. verbal learning and memory, verbal
      working memory, verbal fluency and sustained attention. Scores of WCST-Categories
      and Perseveration at 6 weeks were predicted from the relevant cognitive test
      scores at baseline and the change in BPRS Total and Positive scores. These
      results suggest the usefulness of melperone for facilitating work and social
      function in patients with schizophrenia. The differences in the cognition
      enhancing abilities between melperone and clozapine are discussed.

PMID- 12413637
TI  - Bone mineral density and prolactin associations in patients with chronic
      schizophrenia.

PMID- 12413638
TI  - Clozapine-induced weight gain predicts improvement in psychopathology.
AB  - BACKGROUND: Some, but not all, previous studies have indicated that weight gain
      is associated with greater improvement in psychopathology during clozapine
      treatment. Possible reasons for the inconsistent results include failure to
      adjust for initial body weight and level of psychopathology, differences in trial
      duration, outcome measures, reliability of assessment, concomitant medications
      and clozapine dosage. The purpose of this study was to test the hypothesis that
      clozapine-induced weight gain is related to antipsychotic efficacy at 6 weeks and
      6 months after adjusting for initial body weight and severity of illness.
      METHODS: Weight and psychopathology were determined in 74 patients with
      schizophrenia or schizoaffective disorder at baseline and after 6 weeks and 6
      months of open treatment with clozapine monotherapy. The primary measures of
      psychopathology were the Brief Psychiatric Rating Scale (BPRS) Total and Positive
      symptoms subscales, Schedule for Assessment of Negative Symptoms (SANS), Schedule
      for Assessment of Positive Symptoms (SAPS) and Global Assessment of Function
      Scale (GAFS). RESULTS: Significant improvement in the key measures of
      psychopathology was noted at 6 weeks and 6 months. Mean weight gains at 6 weeks
      and 6 months were 3.7+/-5.7 S.D. and 7.3+/-7.9 S.D. kg, respectively, with the
      increase between 6 weeks and 6 months being significant. Age, but not gender,
      initial body weight, clozapine dosage or plasma levels predicted weight gain at
      both time points. At 6 weeks and 6 months, after adjustment for age, initial
      weight and level of psychopathology, the percentage change in weight
      significantly predicted the improvement in the BPRS Total and Positive symptoms
      subscale, the SANS Global score, as well as other measures of psychopathology.
      CONCLUSIONS: Increase in weight with clozapine predicted improvement in
      psychopathology. This suggests that effects of clozapine on neurotransmitters
      which influence weight gain, e.g. 5-HT(2C) and 5-HT(1a) antagonism, in
      association with individual variations in these receptors and others molecules,
      e.g. peptides and transporters, due to polymorphisms or post-translational
      editing of mRNAs, may also contribute to the improvement in psychopathology.

PMID- 12413639
TI  - An open-labeled trial of adjunctive donepezil for cognitive impairments in
      patients with schizophrenia.
AB  - A pilot study was conducted to examine if donepezil could enhance cognitive
      function in patients with schizophrenia. Fifteen subjects who were on stable
      olanzapine treatment were entered into a 6-week open-labeled trial of donepezil.
      Subjects received baseline and end-of-study P50 and neuropsychological
      assessments. Donepezil treatment resulted in significant improvement in manual
      dexterity. There were moderate improvements in verbal recall memory and visual
      memory and processing speed, with smaller changes in P50 and verbal recognition
      memory. There was no effect on an attention measure. There were no changes in
      either positive or negative symptoms. These results suggest that cholinergic tone
      modulation may enhance selective behavioral functions in patients with
      schizophrenia, but further study is required to delineate the full extent of the
      potential benefit of this approach.

PMID- 12413640
TI  - Amoxapine shows atypical antipsychotic effects in patients with schizophrenia:
      results from a prospective open-label study.
AB  - OBJECTIVE: Amoxapine is marketed as an antidepressant. However, its receptor
      occupancy, in vitro and in vivo, and its effects in pre-clinical models are very
      similar to atypical antipsychotics. To examine if this leads to an atypical
      antipsychotic effect in the clinical context, the authors examined the
      antipsychotic and side-effect profile of amoxapine in acutely psychotic patients
      with schizophrenia. METHODS: Seventeen patients were enrolled and 15 completed a
      prospective open-label 6-week study of amoxapine starting with a fixed-starting
      dose (150 mg/h) with standardized titration up to 250 mg/h, if required.
      Positive, negative, affective symptoms and side-effects were monitored using
      standardized weekly assessments. RESULTS: Amoxapine (median final dose 210 mg/h)
      was well-tolerated and showed significant improvement in positive and negative
      symptoms (both p<0.001), with a trend towards improvement in mood symptoms and no
      treatment-emergent extrapyramidal side-effects, akathisia or weight gain.
      Prolactin elevation was observed. CONCLUSION: These clinical data lend support to
      the pre-clinical suggestions that amoxapine may be an atypical antipsychotic.
      Given its lack of weight gain and that it is considerably less expensive than
      current options, amoxapine could be a valuable alternative for some patients.
      These considerations strongly call for more systematic, double-blind studies of
      amoxapine as an atypical antipsychotic.

PMID- 12413641
TI  - Insight in schizophrenia: associations with executive function and coping style.
AB  - It has been suggested that lack of awareness of illness in schizophrenia may
      result from deficits in executive function and/or an avoidant style of coping. To
      examine this question, 132 persons with schizophrenia spectrum disorders were
      rated as either "aware," "partially unaware" or "unaware" of: (a) their illness,
      (b) need for treatment and (c) consequences of disorder on the abbreviated Scale
      to Assess Unawareness of Mental Disorder. We next compared the performance of the
      aware, partially unaware and unaware groups on the "escape-avoidance" and
      "positive reappraisal" subtests of the Ways of Coping Questionnaire and on two
      tests of executive function: the Letter Number Sequencing Subtest of the WAIS III
      and Wisconsin Card Sorting Test. MANCOVA followed by ANCOVA and planned
      comparisons, controlling for age indicated that the participants who were unaware
      of symptoms, treatment need and consequences generally performed more poorly than
      the aware groups on tests of executive function. Participants unaware of symptoms
      also had a greater preference for positive reappraisal than aware or partially
      unaware participants. The participants unaware of the consequences of disorder
      endorsed a greater preference for escape-avoidance than the partially unaware
      participants. Implications for understanding the etiology of lack of awareness in
      schizophrenia are discussed.

PMID- 12413642
TI  - Serum glucose and lipid changes during the course of clozapine treatment: the
      effect of concurrent beta-adrenergic antagonist treatment.
AB  - We examined the effects of long-term clozapine treatment, concurrent treatment
      with beta-adrenergic antagonists, and clozapine-induced weight gain on serum
      glucose and lipid measures. Fifty subjects met the DSM-III-R criteria for
      schizophrenia or schizoaffective disorder, participated in a 10-week, double
      blind comparison of haloperidol and clozapine and a 1-year, open-label clozapine
      trial, and had available serum glucose and lipid levels. Weight and glucose, and
      lipid laboratory values were measured at the baseline and throughout the double
      blind and year-long study. There were significant increases in serum
      triglyceride, total cholesterol, and glucose levels during the course of
      clozapine treatment. There were no significant changes in high-density
      lipoprotein (HDL) or low-density lipoprotein (LDL). Propranolol and atenolol had
      additive effects on changes in the total cholesterol and triglycerides, with
      propranolol having the most pronounced effects. Propranolol and atenolol had no
      significant effect on the serum glucose levels. There were significant
      correlations between the triglyceride and HDL level changes and clozapine
      associated weight gain during the study. There were no significant correlations
      between the change in serum total cholesterol, LDL, or glucose and weight gain.
      Clozapine therapy has adverse effects on glucose and lipid homeostasis, with
      clozapine-induced changes in serum glucose likely due to the inherent
      pharmacological properties of clozapine. Concurrent beta-adrenergic receptor
      antagonist treatment may have an additive effect on serum lipids, and clozapine
      associated weight gain also plays a modest role in triglyceride increases.

PMID- 12413643
TI  - Neurocognitive performance does not correlate with suicidality in schizophrenic
      and schizoaffective patients at risk for suicide.
AB  - BACKGROUND: Almost 50% of schizophrenic persons attempt suicide at some time in
      their lives and 9-13% of patients ultimately commit suicide. While numerous
      studies have elucidated the relationship between psychiatric symptomatology and
      neurocognition in patients with schizophrenia, this is the first report, to our
      knowledge, to investigate the relationship between suicidal behavior and
      neurocognition in schizophrenia and schizoaffective disorder. METHODS: A subgroup
      of 188 patients participating in the InterSePT trial was assessed at baseline
      with an extensive neurocognitive battery and measures of suicidality and
      psychiatric symptomatology. RESULTS: Measures of suicidality did not
      significantly correlate with neurocognitive performance. Confirmatory analyses
      between patients currently judged to be at high and low risk for suicide also
      revealed no neurocognitive differences. Consistent with previous studies, poor
      neurocognitive performance tended to be modestly correlated with the Positive and
      Negative Syndrome Rating Scale (PANSS) negative symptom scale. The relationship
      between suicidality and neurocognitive performance was similar for
      schizoaffective and schizophrenic patients. CONCLUSIONS: The findings suggest
      that suicidality in patients with schizophrenia and schizoaffective disorder is
      not correlated with cognition and may, in fact, be a separate domain worthy of
      investigation and intervention.

PMID- 12413644
TI  - Clinical characteristics and associated factors in antipsychotic-induced
      akathisia of Asian patients with schizophrenia.
AB  - OBJECTIVE: We studied the prevalence of akathisia and its relationship to a
      number of sociodemographic and clinical factors in a population of Chinese
      inpatients with Schizophrenia. METHOD: Six-hundred and forty-five patients were
      recruited for the study. Akathisia was assessed using the Barnes Akathisia Rating
      Scale (BARS), dyskinesia by the Abnormal Involuntary Movement Scale (AIMS) and
      extrapyramidal side effects (EPSE) were assessed by the Simpson-Angus Rating
      Scale (SARS). RESULTS: Only 35 (5%) patients were assessed to have akathisia.
      There was no gender or ethnic difference in the rates of akathisia. However, the
      majority of the patients (65%) were receiving an anticholinergic agent at the
      time of the study. CONCLUSION: Our findings of an overlap between TD and EPSE
      support the suggestion that there may be a common vulnerability for these
      movement disorders. The finding of a low rate of akathisia among our Asian
      patients suggests an inter-ethnic difference in the vulnerability for the
      development of akathisia. However, comparing our results with the rates reported
      from other countries may be hampered by the diagnostic and methodological
      differences across studies.

PMID- 12413645
TI  - Negative symptoms and neuroleptics in catatonic schizophrenia.
AB  - The association between neuroleptic treatment and the negative symptom dimension
      (ND) was evaluated in 1528 schizophrenia patients. In patients receiving more
      than 820 mg chlorpromazine (CPZ), those with catatonic-type disorder had
      significantly (p<0.05) higher ND scores than those in any of the other diagnostic
      subtypes. Even in patients receiving 450 mg CPZ or more, catatonic patients had
      significantly (p=0.046) higher ND scores than other patients. Patients with
      catatonic schizophrenia are highly vulnerable to negative symptoms related to
      neuroleptic drugs, probably because of a defect in their dopaminergic neuronal
      pathways.

PMID- 12413646
TI  - Cannabis use and dimensions of psychosis in a nonclinical population of female
      subjects.
AB  - OBJECTIVE: The aim of the present study was to explore the pattern of
      associations between cannabis use and dimensions of psychosis in a nonclinical
      population of female subjects. METHOD: The Community Assessment of Psychic
      Experiences (CAPE), a 42-item self-report questionnaire that evolved from the
      Peters et al. Delusions Inventory [Schizophr. Bull. 25 (1999) 553], was used to
      measure dimensions of psychosis in a sample of undergraduate female students
      (n=571). The participants were also asked to complete a self-report questionnaire
      collecting information on substance use. RESULTS: Three correlated dimensions of
      positive, negative and depressive experiences were identified using principal
      components factor analysis. Frequency of cannabis use was independently
      associated with the intensity of both positive and negative psychotic
      experiences. No significant association was found between cannabis use and the
      depressive dimension, or between alcohol use and any of the three positive,
      negative and depressive dimensions. CONCLUSION: This cross-sectional study
      supports the hypothesis that exposure to cannabis may induce the emergence of
      positive psychotic symptoms in subjects without clinical psychosis, and
      additionally suggests that cannabis users exhibit greater levels of negative
      symptoms. Prospective studies are required to explore the direction of causality
      and the impact of cannabis on the course of psychotic experiences in subjects
      from the general population.

PMID- 12413647
TI  - Psychosis proneness and ADHD in young relatives of schizophrenia patients.
AB  - Symptoms resembling the attentional deficit hyperactivity disorder (ADHD) are
      frequently observed in young relatives at risk for schizophrenia (HR). We
      examined the frequency of the ADHD syndrome and its relationship to psychosis
      related psychopathology and neurobehavioral abnormalities in young HR subjects
      (n=29) and healthy comparison subjects (HC; n=30). Thirty-one percent of HR
      subjects (n=9) had ADHD as a lifetime Axis-I diagnosis (HR-A). Compared to
      healthy comparison subjects, the HR-A group had impaired neurological function.
      The HR-A group but not the HR subjects without ADHD had higher scores on the
      Chapman's magical ideation and perceptual aberration scales. Thus, ADHD-like
      features are more prevalent in the HR population than the one described in the
      general population and are associated with more frequent psychosis-like clinical
      features. Longitudinal studies can clarify whether an "ADHD subgroup" within HR
      subjects predict an increased risk for future emergence of schizophrenia.

PMID- 12413648
TI  - A pilot cross-over design study on QTc interval prolongation associated with
      sulpiride and haloperidol.

PMID- 12413649
TI  - Neuroleptic dose reduction in stable chronic schizophrenia.

PMID- 12413650
TI  - Placebo response in a double-blind therapeutic supplementation trial in
      stabilized outpatients with schizophrenia.

PMID- 12413651
TI  - Neural responses in the primary visual cortex of the monkey during perceptual
      filling-in at the blind spot.
AB  - The phenomenon of perceptual filling-in demonstrates that physical stimuli
      presented on the retina do not necessarily correspond to surface perception, and
      that our visual system has mechanisms with which to interpolate missing
      information in order to construct continuous surfaces. Among its various forms,
      filling-in at the blind spot is one of the most remarkable. To study the neural
      mechanisms involved in filling-in at the blind spot, we recently conducted a
      recording experiment aimed at determining whether the neurons in the primary
      visual cortex (V1) that represent the visual field corresponding to the blind
      spot are activated when filling-in occurs. We found that neurons located in deep
      layers of the V1, particularly layer 6, respond to large stimuli that cover the
      blind spot and induce perceptual filling-in. These neurons tended to have very
      large receptive fields, which extended out of the blind spot, and preferred
      relatively large stimuli. We believe that neurons in the V1 region representing
      the blind spot encode information essential for perceptual filling-in at the
      blind spot.

PMID- 12413653
TI  - Changes in Na(+)-K(+)-Cl(-) cotransporter immunoreactivity in the gerbil
      hippocampus following transient ischemia.
AB  - We examined alterations in Na(+)-K(+)-Cl(-) cotransporter 1 (NKCC1)
      immunoreactivity following ischemia. Twelve hours after ischemia, NKCC1
      immunoreactivity in the CA1 region and in the hilar region was significantly
      diminished. Twenty-four hours after ischemia, NKCC1 immunoreactivity was
      intensified in these hippocampal regions as well as CA2-3. Two days after
      ischemia, NKCC1 immunoreactivity in the CA1 and the hilar neurons had
      disappeared, although in the CA2-3 and the granule cell layer NKCC1
      immunoreactivities had recovered to the sham level. This finding suggests that
      NKCC1 may play an important role in the ischemic neuronal injury induced by
      excitotoxicity as well as neuronal edema.

PMID- 12413652
TI  - Neuropeptide Y and somatostatin participate differently in the seizure-generating
      mechanisms following trimethyltin-induced hippocampal damage.
AB  - Trimethyltin (TMT) is an organic metal known to induce neuronal degeneration in
      the hippocampus, and abnormal behavior characterized by seizures, increased
      aggression and memory deficits. We administered TMT to rats and studied the
      changes of neuropeptide Y (NPY) and somatostatin (SOM) in the hippocampus.
      Phenobarbital (PB) was administered as an anticonvulsant to assess the effect of
      seizures on neuropeptide expressions in both dorsal and ventral hippocampus.
      Histochemically, NPY-immunoreactivity increased 4 days after TMT treatment in the
      hilus of the hippocampus, then progressively decreased and dropped to a level
      below control 16 days after TMT treatment. Detection of NPY mRNA by in situ
      hybridization preceded the detection of NPY by immunohistochemistry. NPY mRNA
      signals increased in the hilus 2 days after TMT treatment. SOM-immunoreactivity
      also increased in the hilus of the hippocampus 2 days after TMT treatment, then
      decreased rapidly to a normal level. Similar changes in SOM mRNA were
      demonstrated by in situ hybridization. PB treatment significantly inhibited
      changes of NPY in terms of both immunoreactivity and mRNA expression; however,
      the same treatment failed to affect changes in SOM expression. This suggests that
      NPY and SOM act by different mechanisms in TMT-induced neurodegeneration.

PMID- 12413654
TI  - Identification of brain proteins that interact with 2-methylnorharman. An analog
      of the parkinsonian-inducing toxin, MPP+.
AB  - N-Methylated beta-carbolines, including 2-methylnorharman, are structural and
      functional analogs of the parkinsonian-inducing toxin, MPP+. We are investigating
      N-methylated beta-carbolines, including 2-methylnorharman, as possible etiologic
      factors in the pathogenesis of Parkinson's disease. The cellular targets of N
      methylated beta-carboline-mediated cytotoxicity are unknown; therefore, we used
      the T7Select Phage Display System in a novel approach to identify brain proteins
      that bind to 2-methylnorharman. We incubated (biopanned) immobilized 2
      methylnorharman with a phage display cDNA library that expressed a library of
      human brain proteins on the surface of bacteriophage T7. We washed off unbound
      phage, amplified the phage that were bound to 2-methylnorharman, and enriched for
      toxin-interacting phage by repeating the biopanning and amplification steps. The
      cDNA sequences from the toxin-interacting phage were used to derive the amino
      acid sequences of the phage-displayed proteins. Five of the six 2-methylnorharman
      interacting proteins may have relevance to Parkinson's disease: alpha-tubulin,
      paraoxonase, dorfin, fatty acid binding protein, and platelet-activating factor
      acetylhydrolase. Dorfin has sequence homology with parkin, which is interesting
      because mutations in the parkin gene associate with early-onset Parkinson's
      disease. Our findings are the basis for future studies aimed at determining
      whether 2-methylnorharman affects the function of these specific proteins in
      vitro and in vivo.

PMID- 12413655
TI  - Serum cholesterol, uric acid and cholinesterase in victims of the Tokyo subway
      sarin poisoning: a relation with post-traumatic stress disorder.
AB  - Cholesterol and uric acid, which might correlate with steroidogenesis and
      monoamine functions, may change under emotionally stressful conditions and in
      mental disturbances. Among anxiety disorders, an increase of serum cholesterol
      has been observed in panic disorder. However, the issue has not been adequately
      investigated in other anxiety disorders, including post-traumatic stress disorder
      (PTSD). The present study investigated serum cholesterols, uric acid and
      cholinesterase in victims of the Tokyo subway sarin poisoning, 1995, in a series
      of 5-year follow-ups. Cholinesterase was studied, in relevance with serum lipid
      changes and symptoms of PTSD, and also in light of a biological effect of sarin.
      Out of 34 victims, eight developed PTSD and two were currently diagnosed with
      PTSD using the Clinician-Administered PTSD Scale (CAPS). No significant
      relationship was observed between PTSD and serum cholesterols or uric acid.
      Several factors including co-occurrence of other mental disturbances with PTSD,
      in addition to the limited sample size, might have affected the result. In
      contrast, serum cholinesterase level was significantly reduced in the victims
      with the development of PTSD, compared with the matched controls (P<0.02, t
      test). This might partly reflect a long-term remnant effect of sarin
      intoxication, although an effect of the psychological experience could not be
      totally excluded.

PMID- 12413656
TI  - Abnormal auditory neural networks in patients with right hemispheric infarction,
      chronic dizziness, and moyamoya disease: a magnetoencephalogram study.
AB  - The purpose of this study was to determine whether the auditory cortex is
      sensitive to cortical insults and to determine the specificity of the insults in
      three clinical situations with different cortical involvement. Auditory-evoked
      magnetic fields of ten normal subjects, 8 patients with right hemispheric
      infarction, 11 with chronic dizziness, and 2 with moyamoya disease were measured.
      To analyze the abnormality of auditory neural networks, the magnitude ratio and
      the angle difference (Deltatheta) between response vectors, which were determined
      from maximum current arrows corresponding to the N100m peak for contralateral and
      ipsilateral stimuli were used. A normal range of the parameters was defined so
      that abnormal values could be determined. Of the three parameters, Deltatheta was
      the most sensitive: 4 patients with right hemispheric infarction, 4 with chronic
      dizziness, and 1 with moyamoya disease had abnormal Deltatheta. The electrical
      activity in the patients with such abnormal Deltathetas had a circular current
      pattern. These findings suggest that right infarction lesions sometime affect the
      left auditory neural network, dizziness is caused by abnormal neural networks
      between the vestibular cortical area and the auditory cortex or by an imbalance
      between left and right auditory-cortex activities, and moyamoya-disease patients
      have almost normal auditory-electrical activity.

PMID- 12413657
TI  - Changes in Na(+)-K(+)-Cl(-) cotransporter immunoreactivity in the gerbil
      hippocampus following spontaneous seizure.
AB  - The immunoreactivity of Na(+)-K(+)-Cl(-) cotransporter (NKCC) in the gerbil
      hippocampus associated with various sequelae of spontaneous seizures were
      investigated in order to identify the roles of NKCC in the epileptogenesis and
      the recovery mechanisms in these animals. The NKCC immunoreactivities in the CA2
      3 regions, the subiculum and the entorhinal cortex, were significantly more
      intensified in the pre-seizure group of seizure sensitive (SS) gerbils than in
      the seizure resistant (SR) gerbils. Following the on-set of seizure, the
      immunoreactivity of NKCC was significantly changed. In the hippocampal complex
      except the CA1 region, NKCC immunoreactivity in GABAergic neurons was
      significantly decreased 30 min after seizure on-set, versus the pre-seizure
      group. On the other hand, NKCC immunoreactivity was dramatically elevated in the
      CA1 regions, and 3 h postictal NKCC immunoreactivity increased significantly in
      the dentate gyrus and the dendrites of the pyramidal cells in the CA2-3 regions.
      These findings suggest that altered NKCC expression may be associated with
      seizure activity, and have an important role in the postictal recovery by
      regulating GABA-mediated inhibitory circuit in the hippocampal complex of the
      gerbil.

PMID- 12413658
TI  - Bisindolylmaleimide I and V inhibit necrosis induced by oxidative stress in a
      variety of cells including neurons.
AB  - Although free radical-mediated necrosis is implicated in many diseases such as
      neurodegeneration, potent anti-necrotic drugs have not yet been exploited. We
      found that bisindolylmaleimide I (BMI or GF 109203X), a PKC inhibitor, protected
      a variety of cells, including neurons, from oxidant-induced necrosis, although
      calphostin C, another type of PKC inhibitor, and staurosporine, a broad kinase
      inhibitor, had no such effect. BMI was significantly protective in neuronal cells
      whereas chronic application of BMI induced neurotoxicity. BMV, a BMI-derivative
      devoid of PKC inhibition activity, exhibited cytoprotective effects similar to
      those of BMI but had no neurotoxic effects. Oxidation treatment of BMI and BMV
      did not impact their cytoprotective effects. These findings suggest that the
      cytoprotective mechanisms are independent of the inhibition of PKC and are not
      attributable to a direct free radical-scavenging effect. Moreover, the BM
      compounds did not affect classic, caspase-dependent apoptosis. These data suggest
      that BMV could act as a tool for elucidating necrotic mechanisms and as a lead
      for exploiting drugs to treat necrosis-involved diseases.

PMID- 12413659
TI  - Altered tone-induced Fos expression in the mouse inferior colliculus after early
      exposure to intense noise.
AB  - Mice become highly susceptible to audiogenic seizures (AGS) after being exposed
      to intense, high-frequency noise during a critical period of early life
      (priming). To determine the critical site for AGS priming in the auditory
      brainstem, animals in the experimental group were primed at 21 days, and the tone
      induced Fos immunoreactivity was examined 1, 7, and 14 days after priming as an
      index of excitability of neurons. Enhanced Fos immunoreactivity was observed in
      the inferior colliculus (IC) of the primed mice 7 and 14 days after priming as
      compared to that of non-primed mice and attenuated Fos expression was observed 1
      day after priming. No significant elevation of Fos expression was observed in the
      cochlear nucleus and the deep layer of the superior colliculus of either type of
      mice. These results strongly suggest that the IC is the target site of AGS
      priming.

PMID- 12413660
TI  - GABAergic input contributes to activity-dependent change in cell volume in the
      hippocampal CA1 region.
AB  - Swelling of brain cells is one of the physiological responses associated with
      neuronal activation. To investigate underlying mechanisms, we analyzed
      interactions between changes in cell volume and synaptic responses in the
      hippocampal slices from rodents. Swelling within the CA1 area was detected as
      increases in transmittance of near-infrared light (IR), and field excitatory
      postsynaptic potentials (fEPSPs) were recorded simultaneously. High frequency
      stimulation (HFS) of afferent fibers induced a transient increase in IR
      transmittance in both somatic and dendritic regions, which was temporally
      associated with fEPSPs. Stimulus-induced increases in transmittance were strongly
      reduced in the presence of DL-2-amino-5-phosphonovaleric acid and 6-cyano-7
      nitroquinoxaline-2,3-dione, indicating involvement of glutamate receptors.
      Application of a GABA-A receptor antagonist, bicuculline, increased the amplitude
      and time course of the fEPSPs but rather decreased HFS-induced optical signals.
      When the extracellular Cl(-) was reduced to 10.5 mM, HFS induced a decrease in
      transmittance, which was also blocked by bicuculline. In hippocampal slices
      obtained from mice deficient in the 65 kDa isoform of glutamic acid
      decarboxylase, HFS-induced signals were significantly smaller than in the wild
      type mice, although fEPSP profiles did not differ. These results suggest that Cl(
      ) influx through GABA-A receptors contributes to synaptically evoked swelling in
      the hippocampal CA1 region.

PMID- 12413661
TI  - Immunocytochemical localization of calretinin in the superficial layers of the
      cat superior colliculus.
AB  - We localized calretinin-immunoreactive (IR) fibers and cells in the superior
      colliculus (SC) of the cat and studied the distribution and effect of enucleation
      on the distribution of this protein. Calretinin was localized with antibody
      immunocytochemistry. A dense plexus of anti-calretinin-IR fibers was found within
      the upper part of the superficial gray layer. Almost all of the labeled fibers
      were small diameter fibers with few varicosities. Monocular enucleation produced
      an almost complete reduction of calretinin-IR fibers in the SC contralateral to
      the enucleation. Furthermore, many calretinin-IR cells appeared in the
      contralateral SC. The newly appeared cells had small- to medium-sized vertical
      fusiform, oval or round, or stellate cell bodies. Two-color immunofluorescence
      revealed that no cells in the superficial layers expressed both calretinin and
      GABA. Many retinal ganglion cells were labeled after injections of retrograde
      axonal transport horseradish peroxidase (HRP) in the superficial layers. However,
      no large cells were double-labeled with calretinin and HRP. More than 95% of the
      double-labeled cells were small cells (<15 microm). Based on the retinal ganglion
      cell size, we believe that the vast majority of calretinin-IR retinocollicular
      fibers in cat SC are small gamma type cells that have W type physiologies.

PMID- 12413662
TI  - The terminal nerve ganglion cells project to the olfactory mucosa in the dwarf
      gourami.
AB  - Single- and double-label immunocytochemical studies were conducted using antisera
      to salmon gonadotropin-releasing hormone (sGnRH) and molluscan cardioexcitatory
      peptide (FMRFamide) to determine whether terminal nerve ganglion cells project to
      the olfactory mucosa in the dwarf gourami, Colisa lalia. Both peptides were
      present in terminal nerve ganglion perikarya and fibers in brain and nasal
      cavity. Labeled fibers were present in the olfactory nerve and could be traced to
      the olfactory mucosa. All terminal nerve ganglion cells contained both sGnRH and
      FMRFamide-like peptides. This study suggests that the terminal nerve ganglion
      cells can influence both brain and chemoreceptive structures.

PMID- 12413663
TI  - Exploiting the genetic and biochemical capacities of bacteria for the remediation
      of heavy metal pollution.
AB  - The threat of heavy metal pollution to public health and wildlife has led to an
      increased interest in developing systems that can remove or neutralise its toxic
      effects in soil, sediments and wastewater. Unlike organic contaminants, which can
      be degraded to harmless chemical species, heavy metals cannot be destroyed.
      Remediating the pollution they cause can therefore only be envisioned as their
      immobilisation in a non-bioavailable form, or their re-speciation into less toxic
      forms. While these approaches do not solve the problem altogether, they do help
      to protect afflicted sites from noxious effects and isolate the contaminants as a
      contained and sometimes recyclable residue. This review outlines the most
      important bacterial phenotypes and properties that are (or could be) instrumental
      in heavy metal bioremediation, along with what is known of their genetic and
      biochemical background. A variety of instances are discussed in which valuable
      properties already present in certain strains can be combined or improved through
      state-of-the-art genetic engineering. In other cases, knowledge of metal-related
      reactions catalysed by some bacteria allows optimisation of the desired process
      by altering the physicochemical conditions of the contaminated area. The
      combination of genetic engineering of the bacterial catalysts with judicious eco
      engineering of the polluted sites will be of paramount importance in future
      bioremediation strategies.

PMID- 12413664
TI  - Salmonella vaccines for use in humans: present and future perspectives.
AB  - In recent years there has been significant progress in the development of
      attenuated Salmonella enterica serovar Typhi strains as candidate typhoid fever
      vaccines. In clinical trials these vaccines have been shown to be well tolerated
      and immunogenic. For example, the attenuated S. enterica var. Typhi strains CVD
      908-htrA (aroC aroD htrA), Ty800 (phoP phoQ) and chi4073 (cya crp cdt) are all
      promising candidate typhoid vaccines. In addition, clinical trials have
      demonstrated that S. enterica var. Typhi vaccines expressing heterologous
      antigens, such as the tetanus toxin fragment C, can induce immunity to the
      expressed antigens in human volunteers. In many cases, the problems associated
      with expression of antigens in Salmonella have been successfully addressed and
      the future of Salmonella vaccine development is very promising.

PMID- 12413665
TI  - The bacterial replication initiator DnaA. DnaA and oriC, the bacterial mode to
      initiate DNA replication.
AB  - The initiation of replication is the central event in the bacterial cell cycle.
      Cells control the rate of DNA synthesis by modulating the frequency with which
      new chains are initiated, like all macromolecular synthesis. The end of the
      replication cycle provides a checkpoint that must be executed for cell division
      to occur. This review summarizes recent insight into the biochemistry, genetics
      and control of the initiation of replication in bacteria, and the central role of
      the initiator protein DnaA.

PMID- 12413666
TI  - Carbohydrate cycling in micro-organisms: what can (13)C-NMR tell us?
AB  - The extension of (13)C-nuclear magnetic resonance (NMR) techniques to study
      cellular metabolism over recent years has provided valuable data supporting the
      occurrence, diversity and extent of carbon cycling in the carbohydrate metabolism
      of micro-organisms. The occurrence of such cycles, resulting from the
      simultaneous operation of different and sometimes opposite individual steps, is
      inherently related to the network organisation of cellular metabolism. These
      cycles are tentatively classified here as 'reversibility', 'metabolic' and
      'substrate' cycles on the basis of their balance in carbon and cofactors. Current
      hypotheses concerning the physiological relevance of carbohydrate cycles are
      discussed in light of the (13)C-NMR data. They most likely represent system-level
      mechanisms for coherent and timely partitioning of carbon resources to fit with
      the various biosynthetic, energetic or redox needs of cells and/or additional
      strategies in the adaptive capacity of micro-organisms to face variation in
      environmental conditions.

PMID- 12413667
TI  - Biochemistry, genetics and physiology of microbial styrene degradation.
AB  - The last few decades have seen a steady increase in the global production and
      utilisation of the alkenylbenzene, styrene. The compound is of major importance
      in the petrochemical and polymer-processing industries, which can contribute to
      the pollution of natural resources via the release of styrene-contaminated
      effluents and off-gases. This is a cause for some concern as human over-exposure
      to styrene, and/or its early catabolic intermediates, can have a range of
      destructive health effects. These features have prompted researchers to
      investigate routes of styrene degradation in microorganisms, given the potential
      application of these organisms in bioremediation/biodegradation strategies. This
      review aims to examine the recent advances which have been made in elucidating
      the underlying biochemistry, genetics and physiology of microbial styrene
      catabolism, identifying areas of interest for the future and highlighting the
      potential industrial importance of individual catabolic pathway enzymes.

PMID- 12413668
TI  - Is sensorineural hearing loss a possible side effect of nasopharyngeal and
      parotid irradiation? A systematic review of the literature.
AB  - BACKGROUND AND PURPOSE: Little has been published about permanent hearing loss
      due to radiotherapy, thus making it a rather unknown phenomenon. Therefore, we
      performed a study of the literature over the last 20 years. MATERIALS AND
      METHODS: Sixteen relevant clinical studies were found, reporting mostly on
      nasopharyngeal or parotid gland treatments. Hearing loss was measured using a
      pure tone audiogram. Studies were assessed using a simple scoring list. Nine
      studies were used for further analysis. Data on the pure tone audiogram were
      pooled. RESULTS: Results showed that, especially in the higher frequencies (> or
      =4 kHz), loss can be measured. When data were pooled, in 42 +/- 3% of the
      patients a hearing loss was found of 10 dB or more at 4 kHz. Averaged over all
      measured frequencies the effect is less prominent but still statistically
      significant (18 +/- 2%). No significant difference between nasopharyngeal and
      parotid gland treatment was found (P < 0.05). CONCLUSION: Only a few studies,
      mostly concerning small patient numbers, have investigated hearing damage due to
      radiotherapy. So far there has been no consensus on the subject. However, in this
      systematic review we found a significant effect. Dose to the inner ear therefore
      deserves more attention, especially in dose escalation studies and inverse
      planning.

PMID- 12413669
TI  - Sensori-neural hearing loss after radiotherapy for nasopharyngeal carcinoma:
      individualized risk estimation.
AB  - BACKGROUND AND PURPOSE: Sensori-neural hearing loss (SNHL) is a common
      complication to radiation therapy in the upper head and neck region. In this
      study, we estimated the dose response relationship for SNHL with adjustment for
      pre-therapeutic risk factors. PATIENTS AND METHODS: The pre- and post-therapeutic
      hearing levels were recorded in a previously published study of 20 patients
      receiving radiotherapy for nasopharyngeal carcinoma. In the present study, the
      dose to the inner ear of these patients was estimated with a computed tomography
      (CT) based treatment planning system. CT data from a 'proxy patient' were used
      for patients with no available CT scan. SNHL was analyzed as a function of
      radiation dose and potential risk factors were tested. RESULTS: The incidence of
      SNHL increased significantly with increasing dose to the cochlea. Increasing
      patient's age, and decreasing pre-therapeutic hearing level were statistically
      significantly associated with an increased risk of SNHL. A nomogram is presented
      for estimating individualized dose constraints of potential use in treatment
      planning. CONCLUSIONS: The inner ear is a critical structure in patients with
      nasopharyngeal carcinoma and the dose to the inner ear should be carefully
      considered when planning radiation treatment in this region.

PMID- 12413671
TI  - Outcome after salvage radiotherapy (brachytherapy +/- external) in patients with
      a vaginal recurrence from endometrial carcinomas.
AB  - BACKGROUND AND PURPOSE: The vagina is the site most commonly affected by loco
      regional failure in endometrial carcinoma (EC). The aim of this study was to
      evaluate the efficacy of vaginal brachytherapy (BT) combined or not with whole
      pelvic external radiotherapy (RT) for the treatment of patients with vaginal
      recurrences from endometrial cancer. PATIENTS AND METHODS: Between 1986 and 1999
      25 women were treated at the Institut Gustave Roussy (IGR) for a vaginal relapse
      (VR) from EC. Patient characteristics were as follows: median age 65 years (range
      43-84), histologic type: adenocarcinoma (21 patients); endometrioid carcinoma
      (three patients); adenoacanthoma (one patient); FIGO staging for initial disease:
      Ia, three; Ib, eight; Ic, four; II, seven; IIIa, two; IVa, one. The initial tumor
      was treated by surgery alone in 18 patients, or surgery combined with RT and/or
      BT in seven patients. A VR occurred in a median interval of 21 months (range 2
      89); 10/25 (40%) occurred within the first year following initial treatment. The
      recurrence was exclusively in the vagina in 18 patients and was associated with
      parametrial and or nodal involvement in seven patients; it was localized in the
      upper 1/3 of the vagina in nine patients, in the upper 2/3 or the entire vagina
      in 11 patients or in the lower 1/3 in five patients. The largest tumor diameter
      ranged from 10 to 70 mm (median: 25 mm). The treatment of the VR included low
      dose rate endocavitary BT in all cases: three patients received endocavitary BT
      alone, or it was associated with external RT in 22 patients or delivered after
      surgical removal of the lesion in nine patients. Seven patients were submitted to
      further irradiation combining endocavitary and interstitial BT. RESULTS: Local
      control was achieved in 23 patients (92%). With a follow-up ranging from 4 to 154
      months, 13 patients have died (ten due to metastasis, two of intercurrent disease
      and two due to local tumor progression) and ten patients are alive and disease
      free. The 3-year actuarial survival was 48%. Late radiation-related sequelae were
      observed in nine patients (mucous necrosis in one patient, moderate sclerosis in
      six patients) in an interval varying between 8 and 45 months. The majority of
      recurrences occurred in patients who had not previously received irradiation,
      which emphasizes the role of systematic prophylactic post-operative vaginal BT.
      Extra-vaginal extension (P < 0.001), the tumor size (P < 0.03) and the stage of
      initial disease (P < 0.01) appeared to have a significant impact on the
      prognosis. CONCLUSION: BT combined with external RT is an efficient treatment for
      VR from EC even in previously irradiated patients. Poor survival remains related
      to metastatic dissemination.

PMID- 12413672
TI  - Validation of a questionnaire for self-rating of urological and gynaecological
      morbidity after treatment of gynaecological cancer.
AB  - BACKGROUND AND PURPOSE: Patient self-assessment of symptom severity provides
      clinicians and researchers with important information. It is crucial to evaluate
      the validity of a self-assessment questionnaire in the context of its intended
      use. The objective of this study was to evaluate the validity of the uro
      gynaecological questionnaire (UGQ), a new instrument for patient self-assessment
      of urological-, genital-, menopausal-, and pain symptomatology in gynaecological
      cancer patients. MATERIAL AND METHODS: The UGQ was developed after literature
      review, patient- and expert interviews and pilot testing. From February 1992 to
      October 1992, 88 gynaecological cancer patients were invited to participate in a
      validation study after the initiation of their primary radiotherapy or
      chemotherapy. The method of validation investigated whether patients and
      researchers interpreted the items of the questionnaire in the same way. The
      patient's written response before interview was compared with an observer rating
      of the patient's open-ended audio-taped responses to the same questionnaire,
      administered as an interview. Qualitative recordings by the observer were made to
      describe potential misinterpretations. RESULTS: The agreement between the
      patient's and the observer's ratings was high: the median overall agreement was
      0.91 (range 0.71-1.00) and the median kappa was 0.88 (range 0.45-1.00). The
      quantitative and the qualitative results identified a few minor validity
      problems; especially, the issue of selective reporting, i.e. some patients only
      reporting those symptoms they considered relevant for the study, which may lead
      to systematic errors. CONCLUSIONS: The results strongly suggest that patients
      interpret the UGQ items as intended, i.e. they are valid. The UGQ is recommended
      for patient self-assessment of uro-gynaecological morbidity in gynaecological
      cancer patients.

PMID- 12413670
TI  - Does prophylactic treatment with proteolytic enzymes reduce acute toxicity of
      adjuvant pelvic irradiation? Results of a double-blind randomized trial.
AB  - PURPOSE: Does prophylactic treatment with proteolytic enzymes reduce acute
      toxicity of adjuvant pelvic radiotherapy? MATERIAL AND METHODS: Fifty-six
      patients with an indication for adjuvant pelvic irradiation after curative
      surgery were double-blind randomized. All patients took 3 x 4 capsules study
      medication daily during radiotherapy. Twenty-eight patients in the enzyme group
      (EG) received capsules containing papain, trypsin and chymotrypsin, 28 in the
      placebo group (PG) received placebo capsules. All patients were irradiated with 5
      x 1.8 Gy weekly to 50.4 Gy using four-field-box technique after CT-based
      planning. Primary objective was the grade of diarrhea, nausea, vomiting, fatigue
      and epitheliolysis during radiotherapy. Secondary objectives were the number of
      supportive medications and treatment interruptions due to acute toxicity.
      RESULTS: None/mild diarrhea: 43% EG, 64% PG. Moderate/severe diarrhea: 57% EG,
      36% PG (P = 0.11). Mean duration: 11 days in EG, 10 days in PG. None/mild nausea:
      93% EG, 93% PG. Moderate/severe nausea: 7% EG, 7% PG. None/mild vomiting: 100%
      EG, 97% PG. None/mild fatigue: 82% EG, 93% PG. Moderate/severe fatigue: 18% EG,
      7% PG (P = 0.23). None/mild epitheliolysis: 75% EG, 93% PG. Moderate/severe
      epitheliolysis: 25% EG, 7% PG (P = 0.16). Treatment interruption (mean days):
      2.44 in EG, 1.46 in PG. Number of supportive medication: 29 in EG, 19 in PG.
      CONCLUSIONS: The prophylactic use of proteolytic enzymes does not reduce acute
      toxicities, treatment interruptions and number of supportive medication and
      therefore does not improve tolerance of adjuvant pelvic radiotherapy.

PMID- 12413673
TI  - On-line correction of beam portals in the treatment of prostate cancer using an
      endorectal balloon device.
AB  - BACKGROUND: Reproducible target volume assessment is required in order to
      optimize portal field margins in the treatment of prostate cancer. The benefits
      of an endorectal balloon on target volume assessment remain unclear. MATERIAL AND
      METHODS: Nine patients were treated with a daily placed air filled rectal
      balloon. Portal films and computer-associated tomography during the treatment
      were used to determine the position of the structures of interest. Comparative
      planning with or without a balloon was performed in order to determine rectal
      wall exposure to radiation. RESULTS: The range of movements during treatment
      predicting the position of the prostate in relation to the symphysis was 0.05
      0.59 cm in the lateral direction, 0.27-2.2 cm in the antero-posterior direction,
      and 0.33-1.8 cm in the crano-caudal direction, as compared to the position of the
      prostate predicted by the balloon ranging from 0.18 to 0.76 cm in the lateral
      direction, 0.22-1.68 cm in the antero-posterior direction, and 0.58-2.99 cm in
      the crano-caudal direction. Planning target volumes (PTV) margins as defined by
      the position of the balloon were 10 mm in the antero-posterior direction, 6 mm in
      the lateral direction, and 16 mm in the crano-caudal direction. The volume of
      rectal wall exposed to radiation was reduced from 40 (+/- 12%) to 25% (+/- 19%)
      with an endorectal balloon (P < 0.05). CONCLUSIONS: Daily online correction with
      portal vision for external beam set-up is improved by an endorectal balloon
      device, leading to improved PTV margins and reduced radiation exposure of the
      rectal wall.

PMID- 12413674
TI  - The use of a leg holder immobilisation device in 3D-conformal radiation therapy
      of prostate cancer.
AB  - BACKGROUND AND PURPOSE: To evaluate the impact of a leg holder immobilisation
      device on patient positioning accuracy in the treatment of prostate cancer.
      MATERIAL AND METHODS: Twenty patients of similar age and stage of disease treated
      with curative external beam radiotherapy for prostate cancer were included
      prospectively. Ten patients were sequentially allocated to one of the two groups,
      and treated either with or without a leg holder. Treatment set-up alignment
      accuracy was assessed with an electronic portal imaging device (EPID). RESULTS:
      Set-up accuracy was 0.3, 0.3 and 0.2 cm for patients with a leg holder, and 0.3,
      0.4 and 0.2 cm for patients without a leg holder in the cranio-caudal, anterior
      posterior and in the lateral positions, respectively. The difference is not
      significant. The repositioning accuracy of combined (sagittal and lateral) in
      plane rotations on the other hand, was significantly improved with a leg holder
      device (P = 0.04). CONCLUSIONS: Set-up accuracy can be improved using a leg
      holder immobilisation device in terms of rotational movement accuracy, thus
      making on-line corrections more accurate using EPID in the treatment of prostate
      cancer.

PMID- 12413675
TI  - Acceptance tests and quality control (QC) procedures for the clinical
      implementation of intensity modulated radiotherapy (IMRT) using inverse planning
      and the sliding window technique: experience from five radiotherapy departments.
AB  - BACKGROUND AND PURPOSE: An increasing number of radiotherapy centres is now
      aiming for clinical implementation of intensity modulated radiotherapy (IMRT),
      but--in contrast to conventional treatment--no national or international
      guidelines for commissioning of the treatment planning system (TPS) and
      acceptance tests of treatment equipment have yet been developed. This paper
      bundles the experience of five radiotherapy departments that have introduced IMRT
      into their clinical routine. METHODS AND MATERIALS: The five radiotherapy
      departments are using similar configurations since they adopted the commercially
      available Varian solution for IMRT, regarding treatment planning as well as
      treatment delivery. All are using the sliding window technique. Different
      approaches towards the derivation of the multileaf collimator (MLC) parameters
      required for the configuration of the TPS are described. A description of the
      quality control procedures for the dynamic MLC, including their respective
      frequencies, is given. For the acceptance of the TPS for IMRT multiple quality
      control plans were developed on a variety of phantoms, testing the flexibility of
      the inverse planning modules to produce the desired dose pattern as well as
      assessing the accuracy of the dose calculation. Regarding patient treatment
      verification, all five centres perform dosimetric pre-treatment verification of
      the treatment fields, be it on a single field or on a total plan procedure.
      During the actual treatment, the primary focus is on patient positioning rather
      than dosimetry. Intracavitary in vivo measurements were performed in special
      cases. RESULT AND CONCLUSION: The configurational MLC parameters obtained through
      different methods are not identical for all centres, but the observed variations
      have shown to be of no significant clinical relevance. The quality control (QC)
      procedures for the dMLC have not detected any discrepancies since their
      initiation, demonstrating the reliability of the MLC controller. The development
      of geometrically simple QC plans to test the inverse planning, the dynamic MLC
      modules and the final dose calculation has proven to be useful in pointing out
      the need to remodel the single pencil beam scatter kernels in some centres. The
      final correspondence between calculated and measured dose was found to be
      satisfactory by all centres, for QC test plans as well as for pre-treatment
      verification of clinical IMRT fields. An intercomparison of the man hours needed
      per patient plan verification reveals a substantial variation depending on the
      type of measurements performed.

PMID- 12413676
TI  - Post treatment imaging in head and neck tumours.

PMID- 12413677
TI  - Posttreatment imaging of the nasopharynx.
AB  - Nasopharyngeal carcinoma (NPC) is the most common epithelial tumor of the
      nasopharynx. Radiation therapy is the mainstay of treatment while surgery or
      chemotherapy is used in selected patients. NPC usually regresses after 3 months
      of radiation therapy. Nonetheless, a residual mass may be present following
      treatment and this does not necessarily indicate viable tumor. Imaging studies
      are often used in conjunction with clinical examination following treatment.
      While computed tomography (CT) is widely used due to its greater availability,
      less expensive, and less time consuming, MR imaging is now becoming the preferred
      modality. MR imaging is more capable than CT for identifying mature scarring,
      tumor recurrence and postradiation complications. However, MR imaging cannot
      reliably demonstrate mucosal recurrence or differentiate tumor recurrence from
      postradiation tissue changes. Familiarity with the imaging findings of various
      posttreatment changes, tumor recurrence and postradiation complications is
      essential for management of NPC. Comparison with previous images or imaging
      guided biopsy facilitates definitive diagnosis.

PMID- 12413678
TI  - Imaging the treated oral cavity and oropharynx.
AB  - Cross-sectional imaging has become essential in the evaluation of the treated
      oral cavity and oropharynx. The purpose of this paper is to review the imaging
      guidelines for the evaluation of this region and to detail the typical changes
      encountered on imaging following surgical and radiation treatment for cancer.

PMID- 12413679
TI  - Imaging of the post-treatment larynx.
AB  - The treatment for squamous cell carcinoma of the upper aerodigestive tract
      includes surgery, radiation therapy (RT), chemotherapy or a combination of
      various modalities. Familiarization with the expected imaging changes following
      therapy allow accurate evaluation of imaging studies and may prevent
      misinterpretation of post-treatment changes as recurrent disease. The intent of
      this manuscript will be to review the post-treatment appearance of the larynx
      following RT and various types of laryngectomy.

PMID- 12413680
TI  - Neurological changes following radiation therapy for head and neck tumours.
AB  - Radiation therapy is widely used in the treatment of head and neck tumours either
      as a primary form of treatment or a supplementary modality. Although the benefits
      of radiation therapy are well established, this treatment modality is not without
      untoward consequences and complications. The intent of this paper is to highlight
      the neurological complications that may follow the treatment for head and neck
      malignancies, in particular, following radiation therapy for nasopharyngeal
      carcinoma.

PMID- 12413681
TI  - Flap reconstruction in the head and neck: expected appearance, complications, and
      recurrent disease.
AB  - INTRODUCTION: Reconstruction of large head and neck operative beds requires
      moving tissue from one region to another. These flaps may be rotated to cover a
      defect with the vascular supply intact, or the vascular supply can be transected
      and re-anastamosed to vessels in the operative bed. This article will review the
      types of flaps that have been developed to reconstruct treatment sites in the
      head and neck, describe the expected findings of a flap, and illustrate the
      appearance of flap complications, especially recurrent tumor. METHODS AND
      MATERIALS: Thirty-five patients with flap reconstruction were imaged either as a
      baseline study, or because of clinical suspicion for recurrent tumor. All
      patients had undergone resection of squamous cell carcinoma of the head and neck,
      with flap reconstruction. The computed tomographic (CT) and magnetic resonance
      (MR) images were retrospectively reviewed, with the clinical history and biopsy
      results, to determine the imaging findings of recurrent disease. RESULTS:
      Recurrent tumor in the resection bed or flap appeared as a focal mass, usually at
      the interface of the operative site and the flap. Induration of the fat around
      the flap, or the fat within the flap, was an indirect finding associated with
      recurrence. Nodal recurrence, either ipsi or contralateral to the primary, was
      common. CONCLUSION: It is important to be aware of the type of flap used to
      reconstruct head and neck surgical defects. The expected appearance of the flap,
      and findings associated with recurrent disease are predictable, and are
      illustrated in the article.

PMID- 12413682
TI  - Idiopathic hypertrophic cranial pachymeningitis associated with Sweet's Syndrome.
AB  - A case of hypertrophic cranial pachymeningitis associated with Sweet's Syndrome
      is presented. Both entities have been described in association with several other
      chronic systemic inflammatory diseases and autoimmune conditions. To our
      knowledge the coexistence between Sweet's Syndrome and hypertrophic cranial
      pachymeningitis has not been reported up to date. We suggest a possible
      autoimmune or dysimmune mechanism in the pathogenesis of these two entities.

PMID- 12413683
TI  - Gemella morbillorum deep brain abscess successfully treated with combined
      stereotactic, medical, and imaging approach.
AB  - A rare case of brain abscess due to Gemella morbillorum, a normal inhabitant of
      the oral cavity, is presented. The aim of this report is to draw the attention of
      radiology literature readers to this little known pathogen, which caused a
      potentially life-threatening condition in an immunocompetent young man, and to
      emphasise the usefulness of a combined stereotactic, medical, and imaging
      approach to deep-located brain abscesses.

PMID- 12413684
TI  - Engorged and tortuous intradural filum terminale vein as a sign of a sacral dural
      arteriovenous malformation.
AB  - Sacral spinal dural arteriovenous (AV) malformation is rare and its clinical
      features are not specific to differentiate sacral dural AV malformation from the
      superiorly located ones. A sacral dural AV malformation, therefore, is usually
      diagnosed after negative thoracic and lumbar arteriograms. In this report, we
      propose a myelographic or magnetic resonance (MR) sign of engorged and tortuous
      intradural filum terminale vein as an indication of a sacral dural AV
      malformation. When this sign is seen, pelvic arteriography should be performed
      first.

PMID- 12413685
TI  - Amyloid arthropathy.

PMID- 12413689
TI  - Structural biology of the C1 complex of complement unveils the mechanisms of its
      activation and proteolytic activity.
AB  - C1 is the multimolecular protease that triggers activation of the classical
      pathway of complement, a major element of antimicrobial host defense also
      involved in immune tolerance and various pathologies. This 790,000 Da complex is
      formed from the association of a recognition protein, C1q, and a catalytic
      subunit, the Ca2+-dependent tetramer C1s-C1r-C1r-C1s comprising two copies of
      each of the modular proteases C1r and C1s. Early studies mainly based on
      biochemical analysis and electron microscopy of C1 and its isolated components
      have allowed for characterization of their domain structure and led to a low
      resolution model of the C1 complex in which the elongated C1s-C1r-C1r-C1s
      tetramer folds into a more compact, "8-shaped" conformation upon interaction with
      C1q. A major strategy used over the past years has been to dissect the C1
      proteins into modular segments to characterize their function and solve their
      structure by either X-ray crystallography or nuclear magnetic resonance
      spectroscopy (NMR). The purpose of this review is to focus on this information,
      with particular emphasis on the architecture of the C1 complex and the mechanisms
      underlying its activation and proteolytic activity.

PMID- 12413690
TI  - Increase of the stimulatory effect of dendritic cells by pulsing with apoptotic
      bodies transfected with the MHC class II gene.
AB  - Dendritic cells (DC) are capable of capturing and processing antigens and can
      stimulate co-cultured effector cells in a specific manner. Here, we pulsed DC
      with apoptotic bodies (apb) from colorectal carcinoma. For enhancement of the
      immunogenic potential of apb, we transduced the tumor cells with the MHC class II
      gene before irradiation. After transfection, tumor cells, which are normally MHC
      class II negative, expressed MHC class II in 26.3%. Staining apb with PKH-2 and
      DC with PKH-26, we determined an apb-uptake of 27.6% by DC. Lytic activity of
      effector cells cocultured with DC pulsed with MHC class II transduced apb against
      the donor cell line at an effector to target ratio of 40:1 was 43.8% compared to
      35.3% for pulsing with mock transduced cells. Secretion of interleukin-12 (IL-12)
      by DC was significantly enhanced after pulsing with MHC class II transduced apb
      compared to DC pulsed with mock transduced apb. Coculture with apb-pulsed DC led
      to an increase of proliferation rate and can stimulate effector cells in a
      specific manner. The immunogenic potential could be enhanced by transducing tumor
      cells with the MHC class II gene.

PMID- 12413691
TI  - High affinity binding of long-chain polysialic acid to antibody, and modulation
      by divalent cations and polyamines.
AB  - Long-chain polysialic acid (PSA) is expressed on the vertebrate neural cell
      adhesion molecule (NCAM) during neuronal plasticity. Its structural similarity to
      the capsular PSAs of some pathogenic bacteria has hampered the development of
      polysaccharide vaccines against meningitis. The antibodies formed during
      immunization require a long epitope for binding, and cross-react with host tissue
      PSA. The nature of the epitope and possible external effectors involved are still
      unclear. We have evaluated the interaction of PSA with its antibody mAb735 by
      surface plasmon resonance. The influences of PSA chain length, pH, temperature,
      ionic environment, and polyamines were also determined. The antibody binding
      affinity was found to dramatically increase with PSA chain length. A sub
      nanomolar dissociation constant (K(D)=8.5 x 10(-10)M) was obtained for the
      binding of very long chain native MenB polysaccharides (approximately 200 Neu5Ac
      residues). Colominic acid from Escherichia coli K1 (approximately 100 residues)
      and shorter polymers exhibited progressively weaker affinities. The antibody also
      bound tightly (K(D) approximately 5 x 10(-9)M) to polysialylated glycopeptides
      from human embryonal brain. The effects of pH and ionic strength suggested that
      the interaction is largely electrostatic. Ca2+ and Mn2+ ions promoted the
      observed surface plasmon resonance response in a concentration dependent fashion.
      Spermine increased the response in a similar way. Our results suggest that
      divalent cations and polyamines may play significant role in the regulation of
      the PSA epitope presentation in vivo.

PMID- 12413692
TI  - Experimental study and mathematical modeling of the interaction between
      antibodies and antigens on the surface of liposomes.
AB  - Unilamellar liposomes with incorporated hapten-phospholipid conjugates were
      proposed as models of polyvalent antigens with migrating determinants for
      quantitative analysis of their interaction with antibodies. The monovalent
      pesticide atrazine was used as a model antigen. For its incorporation into the
      lipid bilayer, the atrazine carboxylated derivative was conjugated with
      dimyristoylphosphatidylethanolamine (DMPE). Unilamellar liposomes were prepared
      with dimyristoylphosphatidylcholine/atrazine-DMPE at molar ratios of 90:10, 95:5,
      98:2, 99:1 and 99.5:0.5. Their interaction with the peroxidase-labeled anti
      atrazine antibodies was studied by enzyme immunoassay and polarization
      fluoroimmunoassay techniques. It was shown that the increase in hapten content in
      the liposomes from 0.5 to 10 mol% led to an increase in the equilibrium constants
      of the interaction with antibodies from 0.093 x 10(8) to 0.303 x 10(8)M-1. The
      association rate constants varied from 1.45 x 10(5) to 15.5 x 10(5)M-1 s-1
      depending on the antigen content in liposomes and experimental conditions. The
      measured constants were applied for a mathematical model describing multi-step
      interaction between antibodies and polyvalent liposomal antigens. The model
      adequately describes the quantitative regularities of the influence of antigen
      content and the affinity of immunochemical interaction on the quantity and the
      dynamics of the immune complexes forming.

PMID- 12413693
TI  - Salivary cystatins induce interleukin-6 expression via cell surface molecules in
      human gingival fibroblasts.
AB  - Recently, family 2 cystatins have been demonstrated to upregulate interleukin-6
      (IL-6) production by human gingival fibroblasts [Biol. Chem. 381 (2000) 1143]. To
      elucidate the mechanism of the IL-6 inducing activity of cystatins, we tested NF
      kappa B activation with salivary cystatins SA1 and SA2-stimulated human gingival
      fibroblast whole cell lysates. The IL-6 production by human fibroblasts in
      response to these cystatins was inhibited by tyrosine kinase inhibitors and an
      inhibitor of NF-kappa B activation. The IL-6 inducing activity of the cystatins
      was depressed by the anti-CD58 monoclonal antibody. These findings supply
      evidence that cystatins SA1 and SA2 adhere to human fibroblasts and that the
      event results in tyrosine phosphorylation and upregulation of the release of IL-6
      mediated enhancement of NF-kappa B activity.

PMID- 12413694
TI  - The ubiquitin-proteasome pathway in thymocyte apoptosis: caspase-dependent
      processing of the deubiquitinating enzyme USP7 (HAUSP).
AB  - Programmed cell death (apoptosis) is crucial for thymocyte development. We
      analyzed the role of the ubiquitin (Ub)-proteasome pathway in dexamethasone
      triggered and TCR-mediated apoptosis in fetal thymic organ culture (FTOC).
      Proteasome activity was increased in apoptotic thymocytes, as visualized by
      active-site labeling of proteasomal beta subunits. The activity of
      deubiquitinating enzymes in murine apoptotic thymocytes was likewise examined by
      active-site labeling. We show that the deubiquitinating enzyme USP7 (HAUSP) is
      proteolytically processed upon dexamethasone-, gamma-irradiation-, and antigen
      induced cell death. Such processing of HAUSP does not occur in caspase 3-/-
      thymocytes, or upon pretreatment of wild type thymocytes with the general caspase
      inhibitor ZVAD-fmk. Thus, our results suggest that thymocyte apoptosis leads to
      modification of deubiquitinating enzymes by caspase activity and may provide an
      additional link between the ubiquitin-proteasome pathway and the caspase cascade
      during programmed cell death.

PMID- 12413695
TI  - Sequence-simplification and chimeric assembly: new models of peptide antigen
      modification.
AB  - Sequence-simplified variants of a 15-mer peptide antigen, identified by amino
      acid side chains in alternating positions were synthesized introducing glycine
      residues alternatively in the parent peptide sequence and used to induce
      antibodies in rabbit. They reacted to a significant extent with anti-parent
      peptide antibodies, and in addition, affinity purified antibodies against these
      halved forms recognized with similar affinity and specificity, the starting
      peptide in affinity chromatography, optical biosensor and enzyme linked
      immunosorbent assay (ELISA) experiments, while no cross-reactivity was detected
      between reduced antigens. These findings suggest that a peptide antigen can
      display two molecular surfaces of recognition, identified by side chains of
      residues in alternating positions. Each surface can even take part in
      antigen/antibody interaction independently, thus indicating the possibility to
      select and assembly sequence-simplified forms belonging to different epitopes,
      also deriving from different molecules, to generate new structures incorporating
      a two-fold antigen/antibody specificity. Two "chimeric" forms were then
      synthesized starting from the P15 and P13 complementary peptides, both able to
      bind interleukin 2. These structures, showing simultaneously trans-surfaces of
      recognition belonging to both parent forms, have been found to retain antigenic
      properties against antibodies of simplified P15 derivatives showing the same
      molecular surface of recognition. In addition, anti-chimeric antibodies
      recognized both P15 and P13 starting peptides, while no cross-antibody
      recognition was observed between chimeric antigens.

PMID- 12413696
TI  - Role of the human C8 subunits in complement-mediated bacterial killing: evidence
      that C8 gamma is not essential.
AB  - Human C8 is one of five complement components (C5b, C6, C7, C8 and C9) that
      interact to form the cytolytic membrane attack complex (MAC) on bacterial cell
      membranes. It is an oligomeric protein composed of a disulfide-linked C8 alpha
      gamma heterodimer and a non-covalently associated C8 beta chain. Previous studies
      revealed that C8 alpha and C8 beta have distinct roles in the formation of the
      MAC on simple cells such as erythrocytes and that both subunits are essential for
      cell lysis. These studies also determined that C8 gamma is not required for
      expression of MAC hemolytic activity. To determine if these conclusions are
      applicable to more biologically relevant systems, the C8 subunits were examined
      for their ability to support complement-mediated killing of Gram-negative
      bacteria. Results indicate: (1) C8 alpha-gamma, C8 alpha, C8 beta and C8 gamma
      have no independent bactericidal activity; (2) bacterial killing requires C8 beta
      and either C8 alpha-gamma or C8 alpha; (3) C8 alpha is an effective substitute
      for C8 alpha-gamma in bacterial killing; and (4) C8 gamma enhances, but is not
      required for C8 bactericidal activity. Together, these data suggest that C8 alpha
      and C8 beta have correspondingly similar roles in MAC-mediated lysis of
      erythrocytes and bacterial killing. Furthermore, they provide the first direct
      evidence that C8 gamma is not required for complement-mediated killing of Gram
      negative bacteria.

PMID- 12413697
TI  - IgE-binding epitopes of the American cockroach Per a 1 allergen.
AB  - Cockroach is one of the major indoor allergens for IgE-mediated allergic
      respiratory illnesses throughout the world. The American cockroach (Periplaneta
      americana) Per a 1 allergen is antigenically cross-reactive with the German
      cockroach (Blattella germanica) Bla g 1 allergen. The aim of this study was to
      identify linear B cell epitopes of Per a 1 that are recognized by human IgE. Per
      a 1 deletion mutants were generated from the recombinant Per a 1.0104 allergen
      (274 amino acid residues), and antigenicities were assessed by immunoblotting,
      enzyme-linked immunosorbent assay (ELISA), and binding inhibition. Human atopic
      sera were not able to recognize deletion mutants consisting of amino acids 1-77,
      86-205, and 200-266. However, human sera did recognize the N-terminal mutant
      containing amino acids 1-87 and the C-terminal mutant containing amino acids 200
      274, demonstrating positive IgE binding that was heterogeneously distributed
      among the different sera tested. Amino acid residues 78-85 and 267-274,
      containing internal repeats, were shown to be required for IgE binding to the Per
      a 1.0104 protein. Two peptides corresponding to these IgE-binding amino acid
      sequences were synthesized. Peptide 78-85 showed a positive IgE interaction with
      80% of the sera, while peptide 267-274 was capable of IgE binding to all of the
      sera tested. Moreover, preincubation of atopic sera with IgE-positive
      recombinants and peptides resulted in marked inhibition of the IgE binding to
      purified Per a 1.0104 allergen. Amino acid sequences 78LIRALFGL85 and
      267IRSWFGLP1274 of the American cockroach Per a 1.0104 allergen were involved in
      IgE binding. These findings will advance the understanding of the specific
      reactivity of the epitopes of cockroach allergens, thereby contributing to the
      development of specific immunotherapies for clinical use.

PMID- 12413698
TI  - Evaluation and clinical interest of mannan binding lectin function in human
      plasma.
AB  - The mannan binding lectin (MBL) plays a major role in innate immunity through its
      ability to activate complement upon binding to carbohydrate arrays on the surface
      of various microorganisms. The question of a possible association of the MBL
      structural gene polymorphism and the oligomeric state of MBL was poorly
      documented. For these reasons, it appears difficult to evaluate MBL in blood
      patients on the only basis of protein contents, even in combination with MBL
      genotyping. This study reports a method to calculate a specific activity for
      circulating MBL, that relies on: (i) the availability of purified MBL; and (ii) a
      simplified MBL activity assay based on complement activation. The three-step MBL
      purification from human plasma reported here is characterized by a highly
      purified MBL, that occurs in two different oligomeric forms. The results on the
      specific activity of these forms show that the higher oligomeric forms of MBL
      have the ability to induce C4 cleavage more efficiently than the corresponding
      lower oligomers. The usefulness of this approach is illustrated by its potential
      interest in the biological exploration of certain pathology, for example in the
      follow-up of chronic hepatitis C. Further investigation is needed to establish
      whether MBL specific activity (MBLsa) is correlated to the polymorphic state of
      the molecule. The relative simplicity of the test described here allows better
      investigation on the relationship between MBL biological activity and its
      genotype.

PMID- 12413699
TI  - LCPTP-MAP kinase interaction: permanent partners or transient associates?
AB  - LCPTP (leucocyte-phosphotyrosine phosphatase) is a 42kDa protein tyrosine
      phosphatase expressed predominantly in haematopoietic cells which has been
      implicated in the early stages of the T cell receptor signalling pathway. The
      substrates of LCPTP have been shown to include MAP kinase family members, but it
      remains unclear whether LCPTP is found in stable constitutive association with
      these enzymes, or associates transiently during dephosphorylation. Here we report
      on LCPTP/MAP kinase interactions in CD3-stimulated Jurkat T cells. Pull-downs
      from Jurkat T cells using a recombinant GST-LCPTP substrate-trap protein, but not
      wild-type LCPTP show a clear specific association with both ERK1 and ERK2. In
      Jurkat cells overexpressing LCPTP, a small fraction of cell ERK1 can be
      immunoprecipitated in stable association with LCPTP. However, in both
      unstimulated and anti-CD3 antibody stimulated Jurkat T cells, we were unable to
      demonstrate any constitutive interaction between endogenous LCPTP and any MAP
      kinase family members. We propose that both ERK1 and ERK2 interact transiently
      with LCPTP as substrates for the phosphatase rather than as constitutive protein
      partners.

PMID- 12413700
TI  - Different patterns of bcl-6 and p53 gene mutations in tonsillar B cells indicate
      separate mutational mechanisms.
AB  - Mutations within the 5'-non-coding region of the bcl-6 gene can occur in
      lymphomas that originate from germinal centers (GCs), as well as in normal memory
      and GC B cells. Mutations in the p53 gene occur in 50% of human cancers. Since
      both bcl-6 and p53 can be mutated in certain circumstances, we investigated the
      accumulation of mutations in these genes in individual tonsillar B and T cells to
      determine whether the mutations exhibited a pattern anticipated from the B-cell
      hypermutation machinery. In tonsillar GC B cells, the overall mutational
      frequencies in the 5'-non-coding region of the bcl-6 gene was 0.85 x 10(-3)/bp.
      In contrast, there were no mutations in a region 2.8 kb downstream of the
      promoter. RGYW (purine, guanine, pyrimidine, A/T) targeting and a significantly
      lower mutational frequency in nai;ve B and GC founder B cells compared with GC B
      cells suggested that a similar mutator mechanism was active on Ig genes and this
      non-Ig gene. The mutational frequency in the exon-7-region of p53 was similar in
      the GC, memory and nai;ve B-cell subsets (1.02 x 10(-3) to 1.25 x 10(-3)/bp).
      RGYW/WRCY motifs were not targeted preferentially in the p53 gene. Moreover, a
      comparable mutational frequency of p53 was noted in tonsillar B and T cells.
      Hence, mutations in p53 do not appear to be the result of the B-cell
      hypermutational mechanism.

PMID- 12413701
TI  - Commodification of the sacred through intellectual property rights.
AB  - Indigenous and traditional peoples have made major contributions to the
      enhancement and conservation of the world's biodiversity. Although this is
      increasingly recognized in international discourse, rights of these peoples to
      continue their traditional practices are threatened by the globalized economy.
      Science implicitly denies their contribution to biodiversity conservation and
      enhancement by referring to their lands as 'wild' or 'wilderness'. It also
      effectively undermines their rights by claiming that the biodiversity fostered by
      their traditional practices is a global resource. In order to counter these
      threats, we need not only to strengthen the rights of indigenous and traditional
      peoples, but also to reverse global trends that substitute economic and
      utilitarian models for the holistic concept of the 'sacred balance'.

PMID- 12413702
TI  - Comparative double-blind randomized placebo-controlled clinical trial of a herbal
      eye drop formulation (Qatoor Ramad) of Unani medicine in conjunctivitis.
AB  - Qatoor Ramad (QR) is an ophthalmic formulation of Unani medicine. It is reputed
      for its beneficial effects in the treatment of the inflammatory conditions of the
      eyes. The effect of QR eye drops was studied by a double-blind, randomized,
      prospective, placebo-controlled clinical trial, conducted in 70 patients (20-60
      yrs) suffering from different types of conjunctivitis, namely mucopurulent,
      phlyctenular and allergic conjunctivitis. Local application of two drops (3-4
      times/day) of QR was applied to the affected eyes for up to 14 days. Patients
      were examined at the time of diagnosis and after 2, 7 and 14 days. Clinical
      efficacy was measured as the cumulative sum score of several signs and symptoms
      of different types of conjunctivitis. Side effects, if any, were also noted
      during the study. In mucopurulent conjunctivitis QR showed excellent results. In
      the few cases of phlyctenular and allergic conjunctivitis it controlled the
      deterioration and seems to help in improvement. There were no side effects
      observed during the course of the study and the eye drop was well tolerated by
      the patients. It is considered to be a useful drug in all conditions studied.

PMID- 12413703
TI  - Intestinal anti-spasmodic effect of a phytodrug of Psidium guajava folia in the
      treatment of acute diarrheic disease.
AB  - Ancestral medicinal use of guava (Psidium guajava L. Fam. Myrtaceae) is today
      supported by numerous biomedical studies concerning the properties of leaf
      extracts. However, insufficient clinical studies are reported on the use of this
      plant resource in the treatment of gastrointestinal ailments. The present work
      reports a randomized, double-blinded, clinical study performed to evaluate the
      safety and efficacy of a phytodrug (QG-5) developed from guava leaves,
      standardized in its content of quercetin and orally administered to a group of
      adult patients with acute diarrheic disease. Capsules containing 500 mg of the
      product were administered to 50 patients every 8 h during 3 days. Results
      obtained showed that the used guava product decreased the duration of abdominal
      pain in these patients.

PMID- 12413704
TI  - Influence of aqueous extract of Agaricus blazei on rat liver toxicity induced by
      different doses of diethylnitrosamine.
AB  - The modifying potential of prior administration of an aqueous extract of the
      mushroom Agaricus blazei Murrill (Agaricaceae) (Ab) on hepatotoxicity induced by
      different doses of diethylnitrosamine (DEN) in male Wistar rats was evaluated.
      During 2 weeks, animals of groups G3 (Ab+DEN(50)), G5 (Ab+DEN(100)), G7
      (Ab+DEN(200)), and G8 (Ab-treated) were treated with the A. blazei through
      drinking water. After this period, groups G2 (DEN(50)), G3 (Ab+DEN(50)), G4
      (DEN(100)) G5 (Ab+DEN(100)), G6 (DEN(200)), and G7 (Ab+DEN(200)) were given a
      single i.p. injection of 50, 100 and 200 mg/kg of DEN, respectively, while groups
      G1 (non-treated) and G8 (Ab-treated) were treated with 0.9% NaCl only. All
      animals were killed 48 h after DEN or NaCl treatments. The hepatocyte replication
      rate was estimated by the index of the proliferating cell nuclear antigen (PCNA)
      positive hepatocytes and the appearance of putative preneoplastic hepatocytes
      through expression of the enzyme glutathione S-transferase placental form (GST
      P). After DEN-treatment, ALT levels, PCNA labeling index, and the number of GST-P
      positive hepatocytes were lower in rats that received A. blazei treatment and
      were exposed to 100 mg/kg of DEN. Our findings suggest that previous treatment
      with A. blazei exerts a hepatoprotective effect on both liver toxicity and
      hepatocarcinogenesis process induced by a moderately toxic dose of DEN.

PMID- 12413705
TI  - Acute effect of Bauhinia forficata on serum glucose levels in normal and alloxan
      induced diabetic rats.
AB  - Experimental diabetes was used to study the acute effect of the n-butanol
      fraction of Bauhinia forficata Link (Leguminosae) (BF) leaves on the serum
      glucose levels of rats. Body weight was measured on the day of diabetes induction
      and on the day of the experiment. Levels of glucose were determined at different
      doses and times following treatment with BF or with vehicle in normal, diabetic
      and hyperglycemic normal rats. Oral administration of n-BuOH fraction led to a
      significant blood glucose-lowering effect in normal and diabetic rats. However,
      in glucose-fed hyperglycemic normal rats, the maximum dose of this fraction
      failed to decrease blood glucose levels. The hypoglycemic effect was observed at
      doses of 500 and 600 mg/kg after 1 and 2 h treatment respectively, in normal
      rats. The maximum effect of BF was detected at 1 h with 800 mg/kg in diabetic
      animals and this profile was maintained for the next 3 h. Treatment of normal and
      alloxan-induced diabetic rats with BF decreased glucose levels, while this
      fraction was devoid of hypoglycemic effect in glucose-fed hyperglycemic normal
      rats.

PMID- 12413706
TI  - Medicinal plants used by Luo mothers and children in Bondo district, Kenya.
AB  - In a follow-up to studies of school-children's medical knowledge among the rural
      Luo of western Kenya, seven mothers were asked for their knowledge of plant
      medicine, and the 91 plant remedies mentioned by them were collected, 74 of these
      remedies were identified as 69 different species (in 13 cases, the material did
      not allow identification of the species, in two cases, only the family could be
      identified, and in two, not even this was possible). The results of this survey
      and some comments on Luo illness concepts are presented below and briefly
      discussed in relation to the earlier work on school-children and to another
      survey of Luo plant medicine in the same district. The article concludes that the
      consensual core of Luo plant medicine is known by ordinary mothers and their
      children as well as by recognised healers. It is a shared resource, that is used
      by women, mainly in the care for their children, and it is not an expert domain
      of knowledge, as is often, in studies of herbal or 'traditional' medicine are
      studied. The medicinal plants, upon which many mothers as well as healers agree
      should be examined further pharmacologically in order to assess their efficacy
      against the common infectious and parasitic diseases found in this area of
      western Kenya.

PMID- 12413707
TI  - Hypoglycemic effects of Potentilla fulgens L in normal and alloxan-induced
      diabetic mice.
AB  - Tap roots of Potentilla fulgens L. traditionally chewed along with betel nut
      (Areca catechu) and betel leaves (Piper betel), are commonly used by local
      practitioners for various types of ailments. The crude methanolic extract of the
      roots was tested for its effects in normoglycemic and alloxan-induced diabetic
      mice. Hypoglycemic activity was observed to be dose- and time- dependent. The
      extracts reduced blood glucose level 2 h following administration in both normal
      and alloxan-induced diabetic mice. In alloxan-induced diabetic mice blood glucose
      was markedly reduced by 63%, while in normal mice a 31% reduction was observed 24
      h after the effective dose of extract was administered. Further, in the diabetic
      mice a prolonged anti-hyperglycemic action was observed where glucose levels was,
      found to be significantly low (79%) when compared with control even on the third
      day. Glucose tolerance was also improved in both normal and diabetic mice. The
      results were compared against those of insulin, glibenclamide, metformin, and the
      probable mechanism of action is discussed.

PMID- 12413709
TI  - Screening seeds of Scottish plants for antibacterial activity.
AB  - Based on ethnopharmacological and taxonomic information, seeds of 21 Scottish
      plant species from 14 different families were obtained from authentic seed
      suppliers. Their n-hexane, dichloromethane and methanol extracts were assessed
      for antibacterial activity against 11 pathogenic bacterial species. Methanol
      extracts of 11 plant species showed significant antibacterial activity. Malva
      moschata and Prunus padus were active against five bacterial species, Reseda
      lutea against four, Centaurium erythraea and Crithmum maritimum against three,
      Calluna vulgaris against two, and Armeria maritima, Centaurea scabiosa, Daucus
      carota, Rosa canina and Stellaria holostea against one bacterial species. C.
      erythraea and P. padus were also active against methicillin resistant
      Staphylococcus aureus.

PMID- 12413708
TI  - Anti-oxidative, anti-inflammatory and hepato-protective effects of Ligustrum
      robustum.
AB  - Aqueous extract of processed leaves of Ligustrum robustum could dose-dependently
      scavenge superoxide radicals, inhibit lipid peroxidation, and prevent AAPH
      induced hemolysis of red blood cells. In comparison with green tea, oolong tea
      and black tea, processed leaves of L. robustum exhibited comparable antioxidant
      potency in scavenging superoxide radicals and in preventing red blood cell
      hemolysis. By activity-guided fractionation, a glycoside-rich fraction named
      fraction B2 was separated and demonstrated to possess strong antioxidant effect.
      It was evaluated for its anti-inflammatory and hepato-protective activities. A
      single oral dose of fraction B2 at 0.5 g/kg could provide 51.5% inhibition on the
      vascular permeability change induced by intraperitoneal injection of acetic acid,
      but it could not inhibit croton oil-induced ear edema. On the other hand,
      fraction B2 exhibited moderate hepato-protective effect. Intragastric application
      of fraction B2 at 1.25, 2.5 or 5 g/kg 6 h after carbon tetrachloride
      administration could reduce the elevations of serum levels of aminotransferases
      (AST and ALT). Also, liver integrity was preserved, as liver sections from rats
      post-treated with fraction B2 showed a milder degree of fatty accumulation and
      necrosis. These results offer partial support to the traditional uses of the
      leaves of L. robustum as Ku-Ding-Cha.

PMID- 12413710
TI  - Immunomodulatory functions of extracts from the Chinese medicinal fungus
      Cordyceps cicadae.
AB  - The effects of Cordyceps cicadae extracted fractions on human mononuclear cells
      (HMNC) proliferation were determined by tritiated thymidine uptake. The results
      indicated that aqueous methanol (50%) extracts of C. cicadae ascocarps portion
      (CC-1-2) enhanced HMNC proliferation activated with phytohemagglutinin (PHA) with
      an EC(50) of 13.8+/-4.6 micro g/ml. By contrast, the methanol (100%) extracts of
      C. cicadae insect-body portion (CC-2-1) suppressed HMNC proliferation stimulated
      by PHA with an IC(50) of 32.5+/-5.2 micro g/ml. Cell viability test indicated
      that inhibitory effects of CC-2-1 on HMNC proliferation were not through direct
      cytotoxicity. The action mechanisms of CC-1-2 and CC-2-1 may involve the
      regulation of interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) production in
      HMNC. Since CC-2-1 suppressed IL-2 and IFN-gamma production in HMNC induced with
      PHA. The CC-1-2 enhanced IL-2 and IFN-gamma production of HMNC stimulated with
      PHA in a concentration dependent manner. Therefore, the results demonstrated that
      C. cicadae contained growth modulators for HMNC.

PMID- 12413711
TI  - CNS inhibitory effects of barakol, a constituent of Cassia siamia Lamk.
AB  - The present study determined the pharmacological profile of barakol, a major
      constituent of Cassia siamea Lamk., in rodent behavioral and neurochemical tests.
      Barakol reduced spontaneous locomotor activity, increased the number of sleeping
      animals and prolonged the thiopental-induced sleeping time, indicating a sedative
      effect. As for interactions between barakol and convulsants (pentylenetetrazole
      (PTZ), picrotoxin, bicuculline and strychnine), only a high dose (100 mg/kg,
      i.p.) of barakol slightly prolonged the latency of clonic convulsion induced by
      picrotoxin. This suggests that the sedative effect may not be induced via the
      GABA or glycine systems. There was no evidence of an anxiolytic effect of barakol
      in the plus-maze test. However, barakol (25-100 mg/kg, i.p.) could suppress
      methamphetamine (1 mg/kg, i.p.)-induced hyper-locomotor activity in a dose
      dependent manner, indicating an effect on the dopaminergic system. In a
      microdialysis study, the dose of barakol (100 mg/kg) that inhibited spontaneous
      locomotor activity in mice did not affect the basal levels of extracellular
      dopamine (DA) or its metabolites in the striatum. However, pretreatment with
      barakol (100 mg/kg, i.p.) decreased the maximal dopamine release and dopamine
      turnover induced by methamphetamine (1 mg/kg, i.p.). This finding indicates that
      the inhibitory effect of barakol on dopamine release may account for the blocking
      effect of barakol on the striatum-related behavior induced by methamphetamine.

PMID- 12413712
TI  - Study on cardiac contractility of cycloeucalenol and cycloeucalenone isolated
      from Tinospora crispa.
AB  - This report describes the isolation of two triterpenes from the stems of
      Tinospora crispa, namely, cycloeucalenol (1). and cycloeucalenone (2). for the
      first time. It was found that cycloeucalenol (1). slightly increased the right
      atrial force of contraction whereas it showed an initial reduction followed by
      sustained reduction of about 10% on the left atria of the rat in vitro.
      Cycloeucalenone showed slight change from the control on the right and left
      atrial force. These results suggest that cycloeucalenol and cycloeucalenone
      produced mild cardiotonic effects.

PMID- 12413713
TI  - Toxicological studies on Stryphnodendron adstringens.
AB  - This study was carried out to determine the acute toxicity of total barbatimao
      extract (LD(50)) after oral administration to mice, and its effect on certain
      biochemical parameters in plasma of rats after 30 days of administration. The
      LD(50) value of the extract was 2699 mg/kg. A daily oral administration of
      extracts at 800 and 1600 mg/kg doses for 30 days caused a decrease in body
      weight, thymic involution, and an increase of plasma glucose and aspartate
      aminotransferase levels in the animals. The results showed that the extract
      administered in a prolonged period produced toxic effects in the experimental
      animals.

PMID- 12413714
TI  - Angiotensin converting enzyme inhibitors from Cuscuta japonica Choisy.
AB  - Bioassay-guided fractionation of the EtOAc-soluble extract of Cuscuta japonica
      afforded 3,5-Di-O-caffeoylquinic acid (1). methyl 3,5-Di-O-caffeoylquinate (2).
      3,4-Di-O-caffeoylquinic acid (3). and methyl 3,4-Di-O-caffeoylquinate (4).
      Purification of these compounds was conducted with the application of various
      chromatographic methods. The structures of the compounds were elucidated on the
      basis of MS and NMR data analysis. Compounds 1-4 inhibited the angiotensin I
      converting enzyme activity in a dose-dependent manner. Compounds 1-4 showed the
      50% inhibitory concentration values of 596, 483, 534, and 460 micro M,
      respectively. The presence of these active components may be responsible, at
      least in part, for the antihypertensive action of traditional crude drug Cuscuta
      Semen.

PMID- 12413715
TI  - Anti-diabetic activity of green tea polyphenols and their role in reducing
      oxidative stress in experimental diabetes.
AB  - An aqueous solution of green tea polyphenols (GTP) was found to inhibit lipid
      peroxidation (LP), scavenge hydroxyl and superoxide radicals in vitro.
      Concentration needed for 50% inhibition of superoxide, hydroxyl and LP radicals
      were 10, 52.5 and 136 micro g/ml, respectively. Administration of GTP (500 mg/kg
      b.wt.) to normal rats increased glucose tolerance significantly (P<0.005) at 60
      min. GTP was also found to reduce serum glucose level in alloxan diabetic rats
      significantly at a dose level of 100 mg/kg b.wt. Continued daily administration
      (15 days) of the extract 50, 100 mg/kg b.wt. produced 29 and 44% reduction in the
      elevated serum glucose level produced by alloxan administration. Elevated hepatic
      and renal enzymes produced by alloxan were found to be reduced (P<0.001) by GTP.
      The serum LP levels which was increased by alloxan and was reduced by
      significantly (P<0.001) by the administration of 100 mg/kg b.wt. of GTP.
      Decreased liver glycogen, after alloxan administration showed a significant
      (P<0.001) increase after GTP treatment. GTP treated group showed increased
      antioxidant potential as seen from improvements in superoxide dismutase and
      glutathione levels. However catalase, LP and glutathione peroxidase levels were
      unchanged. These results indicate that alterations in the glucose utilizing
      system and oxidation status in rats increased by alloxan were partially reversed
      by the administration of the glutamate pyruvate transaminase.

PMID- 12413716
TI  - Compositions and the in vitro antimicrobial activities of the essential oils of
      Achillea setacea and Achillea teretifolia (Compositae).
AB  - GC-MS analysis of the isolated essential oils from air-dried aerial parts of
      Achillea setacea and Achillea teretifolia, an endemic taxon, resulted in the
      identification of 51 constituents (79.8% of the total oil) and 42 constituents
      (87.1% of the total oil), respectively. Eucalyptol (1,8-cineole) was the major
      constituent of both oils studied (18.5 and 19.9%, respectively). The
      antimicrobial activities of the essential oils were individually evaluated
      against 14 microorganisms. Both oils exhibited inhibitory effects on Clostridium
      perfringens, Acinetobacter lwoffii and Candida albicans with a range of minimum
      inhibitory concentration values extended from 0.28 to 2.25 mg/ml. Camphor and
      their derivatives, borneol, terpinen-4-ol and eucalyptol (1,8-cineol) can be
      considered as the main antimicrobial constituents of the oils studied.

PMID- 12413717
TI  - Inhibition of cytokine production by the traditional oriental medicine, 'Gamcho
      Sasim-Tang' in mitogen-stimulated peripheral blood mononuclear cells from
      Adamantiades-Behcet's patients.
AB  - Gamcho-Sasim-Tang (GS-Tang) is a traditional Chinese medication, which has been
      successfully used in Korea for the treatment of Adamantiades-Behcet's disease
      (ABD). We investigated the modulation effects of GS-Tang on cytokine production
      from phytohaemagglutinin-stimulated peripheral blood mononuclear cells of
      Behcet's patients. ABD is a systemic inflammatory disorder and might involve
      immune dysfunction. Cytokines involved in the regulation of inflammatory
      reactions and immune responses may play a role in the pathogenesis of ABD. GS
      Tang (1 mg/ml) significantly inhibited the production of proinflammatory
      cytokines, tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1
      beta), compared to absence of GS-Tang (by 42.0+/-6.6% inhibition for TNF-alpha
      and 95.9+/-5.7% for IL-1 beta, P<0.05). GS-Tang also inhibited the production of
      IFN-gamma, immunoregulatory T helper cell type 1 cytokine, by 80.2+/-5.3%
      (P=0.001). The inhibitory effects of GS-Tang on cytokine production showed dose
      dependent manner. Our results suggest that GS-Tang might have anti-inflammatory
      and immuno-regulatory effects through the cytokine modulation.

PMID- 12413718
TI  - Antimicrobial activity of some plants used for the treatment of livestock disease
      in the Eastern Cape, South Africa.
AB  - Approximately 75% of rural livestock owners in the Eastern Cape province of South
      Africa use plants or plant based remedies to treat their livestock. Prominent
      among these plants are Combretum caffrum, Salix capensis and Schotia latifolia.
      Water, methanolic and acetonic extracts as well as decoctions of the three plants
      were screened against ten bacteria and five fungi. The results of the
      antibacterial assay indicated significant activity against all the Gram-positive
      bacteria tested with the minimum inhibitory concentrations ranging from 0.1 to
      5.0 mg/ml. A few of the extracts showed minimal activity, but the majority of
      extracts were not active on the Gram-negative bacteria. Generally, all the
      extracts showed some antifungal activity against the five test fungi. Methanolic
      extracts exhibited higher fungal growth inhibition, whereas the water extracts
      showed the least inhibition. It was noteworthy that some water extracts promoted
      fungal growth.

PMID- 12413719
TI  - Evaluation of hepatoprotective effect of Pistacia lentiscus, Phillyrea latifolia
      and Nicotiana glauca.
AB  - The hepatoprotective effect of the boiled and non-boiled aqueous extracts of
      Pistacia lentiscus, Phillyrea latifolia, and Nicotiana glauca, that are alleged
      to be effective in the treatment of jaundice in Jordanian folk medicine, was
      evaluated in vivo using carbon tetrachloride (CCl(4)) intoxicated rats as an
      experimental model. Plant extracts were administrated orally at a dose of 4 ml/kg
      body weight, containing various amounts of solid matter. Only total serum
      bilirubin level was reduced by treatment with non-boiled aqueous extract of N.
      glauca leaves, while the boiled and non-boiled aqueous extracts of the N. glauca
      flowers were non effective. Bilirubin level and the activity of alkaline
      phosphatase (ALP) were both reduced upon treatment with boiled aqueous extract of
      P. latifolia without reducing the activity of alanine aminotransferase (ALT) and
      aspartate aminotransferase (AST). Aqueous extract of P. lentiscus (both boiled
      and non-boiled) showed marked antihepatotoxic activity against CCl(4) by reducing
      the activity of the three enzymes and the level of bilirubin. The effect of the
      non-boiled aqueous extract was more pronounced than that of the boiled extract.

PMID- 12413720
TI  - Neuropharmacological screening of Diospyros mespiliformis in mice.
AB  - The neuropharmacological activities of the aqueous extract of Diospyros
      mespiliformis stem bark were screened in mice. The extracts effect on
      pentobarbital-induced sleeping time, pentylenetetrazole induced seizure,
      spontaneous motor activity (SMA), exploratory behaviour, and rota-rod performance
      (motor coordination) were evaluated. The extract (100 and 200 mg/kg p.o.)
      produced a significant (P<0.05) prolongation of pentobarbital-induced sleeping
      time, and reduced the SMA and exploratory behaviour. The extract prolonged onset
      of the phases of seizure activity but did not protect mice against lethality
      induced by pentylenetetrazole. It also failed to affect the motor coordination
      test. These results suggest that the extract contained an agent with
      neuropharmacological activity that may be sedative in nature.

PMID- 12413721
TI  - Diuretic and urolithiatic activities of the aqueous extract of the fruit of
      Randia echinocarpa on rats.

PMID- 12413722
TI  - Phenolic antibacterials from Piper betle in the prevention of halitosis.
AB  - Piper betle L. (Piperaceae) leaves which are traditionally used in India and
      China in the prevention of oral malodor was examined by bioassay-guided
      fractionation to yield allylpyrocatechol (APC) as the major active principle
      which showed promising activity against obligate oral anaerobes responsible for
      halitosis. The biological studies with APC indicated that the potential to reduce
      methylmercaptan and hydrogen sulfide was mainly due to the anti-microbial
      activity as established using dynamic in vitro models.

PMID- 12413723
TI  - Evaluation of natural products on inhibition of inducible cyclooxygenase (COX-2)
      and nitric oxide synthase (iNOS) in cultured mouse macrophage cells.
AB  - The inhibitors of prostaglandin biosynthesis and nitric oxide production have
      been considered as potential anti-inflammatory and cancer chemopreventive agents.
      In this study, we evaluated approximately 170 methanol extracts of natural
      products including Korean herbal medicines for the inhibition of prostaglandin
      E(2) production (for COX-2 inhibitors) and nitric oxide formation (for iNOS
      inhibitors) in lipopolysaccharide (LPS)-induced mouse macrophages RAW264.7 cells.
      As a result, several extracts such as Aristolochia debilis, Cinnamomum cassia,
      Cinnamomum loureirii, Curcuma zedoaria, Eugenia caryophyllata, Pterocarpus
      santalius, Rehmania glutinosa and Tribulus terrestris showed potent inhibition of
      COX-2 activity (>80% inhibition at the test concentration of 10 micro g/ml). In
      addition, the extracts of A. debilis, Caesalpinia sappan, Curcuma longa, C.
      zedoaria, Daphne genkwa and Morus alba were also considered as potential
      inhibitors of iNOS activity (>70% inhibition at the test concentration of 10
      micro g/ml). These active extracts mediating COX-2 and iNOS inhibitory activities
      are warranted for further elucidation of active principles for development of new
      cancer chemopreventive and/or anti-inflammatory agents.

PMID- 12413724
TI  - Antidepressant activity of aqueous extracts of Curcuma longa in mice.
AB  - Curcuma longa (turmeric) is a well-known indigenous herbal medicine. The aqueous
      extracts, when administered orally to the mice from 140 to 560 mg/kg for 14 days,
      were able to elicit dose-dependent relation of immobility reduction in the tail
      suspension test and the forced swimming test in mice. The effects of the extracts
      at the dose of 560 mg/kg were more potent than that of reference antidepressant
      fluoxetine. The extracts, at the dose of 140 mg/kg or above for 14 days,
      significantly inhibited the monoamine oxidize A (MAO) activity in mouse whole
      brain at a dose-dependent manner, however, oral administration of the extract
      only at a dose of 560 mg/kg produced observable MAO B inhibitory activity in
      animal brain. Fluoxetine showed only a tendency to inhibit MAO A and B activity
      in animal brain in the study. Neither the extracts of C. longa nor fluoxetine, at
      the doses tested, produced significant effects on locomotor activity. These
      results demonstrated that C. longa had specifically antidepressant effects in
      vivo. The activity of C. longa in antidepression may mediated in part through MAO
      A inhibition in mouse brain.

PMID- 12413731
TI  - Human regional lymph nodes draining cancer exhibit a profound dendritic cell
      depletion as comparing to those from patients without malignancies.
AB  - Dendritic cells (DCs) are bone-marrow derived 'professional' antigen presenting
      cells (APC). They are considered as the most potent APC able to induce primary
      immune responses. DC efficiently capture and process proteic and non-proteic
      antigens. They are widely distributed throughout the body and occupy sentinel
      positions such as epithelia. Establishment of an immune response against cancer
      may depend of the capacity of DCs to transfer (to capture, to process and to
      present) tumor antigens into regional lymph nodes where they can induce a
      specific response leading to tumor rejection. Because host 'professional' DCs are
      one of the most important elements in the induction of specific anti-tumor
      responses and lymph nodes are the places where the immune response takes place,
      we investigated the densities of DCs within regional metastasis-free lymph nodes
      from 47 patients with different malignant epithelial tumors as comparing with
      lymph nodes from 11 patients without malignancies using an immunohistochemistry
      method with anti-S100 protein, CD86 and CD1a antibodies. By means of morphometric
      analysis, we observed that S100+ and CD1a+ DCs densities in regional lymph nodes
      from cancer patients were significatively decreased as compared with control
      lymph nodes (P<0.0001 and 0.003, respectively). S100+ DCs and CD86+ DCs densities
      in lymph nodes draining cancer were similar. Taken together, these data indicated
      that lymph nodes draining cancer had significantly less CD1a+ DCs than S100+ and
      possibly CD86+ DCs. These findings may represent another mechanism by which
      tumors evade the immune recognition.

PMID- 12413732
TI  - Expression of interleukin-18, interferon-gamma and interleukin-10 in
      hepatocellular carcinoma.
AB  - This is the first report on the detection of IL-18, IFN-gamma and IL-10 proteins
      in hepatocelllular carcinoma. In the apparently normal surrounding tissue, 13 out
      of 17 paired specimens showed positive immunoreactivity to IL-18 (76.5%) compared
      with six out of 17 in the tumour portion (35.3% of specimens). Thus, a
      significantly higher number of IL-18 positive specimens was found in the
      hepatocytes of apparently normal surrounding tissue compared with the tumour
      (P=0.018). In contrast, the number of specimens with positive immunoreactivity to
      the antibody against the Th1 cytokine, IFN-gamma expression in the hepatocytes
      was lower. Only one specimen from the apparently normal surrounding tissue (one
      out of 17; 5.9%) and three other specimens from the tumour portion (three out of
      17; 17.6%) had positive immunoreactivity. Similarly, the expression of the Th2
      cytokine, IL-10 in normal (four out of 17; 23.5%) and tumour portions (five out
      of 17; 29.4%) was also low. Thus, there did not appear to be predominant Th2
      immune response as denoted by IL-10 expression. Using the Spearman correlation
      rank test, a significant correlation between IL-18 expression in the apparently
      normal surrounding tissue and high alpha-foetoprotein (AFP) levels of >350 IU/l.
      No correlation between IL-18 expression in the tumour portion and
      clinicopathological factors was found. There was also no correlation found
      between IL-18 and the other cytokines, namely, IFN-gamma and IL-10 expression
      These new findings provide additional information on the type of cytokines
      expressed in the tumour microenvironment and give a further insight into the role
      of cytokines in the pathogenesis of cancer which is critical for the development
      of effective immunotherapeutic approaches for cancer therapy in the future.

PMID- 12413733
TI  - Fibroblast-eosinophil interaction: modulation of adhesion molecules expression
      and chemokine release by human fetal lung fibroblasts in response to IL-4 and TNF
      alpha.
AB  - In addition to be involved in airway remodelling observed in asthmatic patients,
      lung fibroblasts may directly contribute to pulmonary inflammation through the
      release of mediators and through the expression of surface molecules involved in
      cell-cell interaction. The aim of the study was to evaluate whether two cytokines
      involved in asthma pathogenesis, IL-4 and TNF-alpha, could modulate the
      expression of adhesion molecules (VCAM-1 and ICAM-1) and the secretion of
      chemokines (eotaxin and MCP-1) related to eosinophil recruitment and activation.
      The constitutive expression of VCAM-1 by unstimulated fibroblasts was over 2-fold
      lower than that of ICAM-1 (P<0.05). Significant differences were also observed in
      the release of chemokines by unstimulated fibroblast, the levels of eotaxin being
      over 17-fold lower than those of MCP-1. Stimulation of the cells with IL-4 or TNF
      alpha induced a dose-dependent increase in VCAM-1, while ICAM-1 was overexpressed
      only in culture stimulated by TNF-alpha (P<0.05) but not in those exposed to IL-4
      (P>0.05 each comparison). In contrast, a significant increase in MCP-1 and
      eotaxin release was observed in the presence of TNF-alpha (P<0.05) but not of IL
      4 (P>0.05). These data show that two 'proinflammatory' cytokines, such as IL-4
      and TNF-alpha, may have different and complementary effects on functions involved
      in the cross-talking between fibroblasts and eosinophils.

PMID- 12413734
TI  - T-regulatory cells: are we re-discovering T suppressors?
AB  - Regulatory T cells are shown to originate form the thymus and their role is to
      maintain self-tolerance to intra-thymic as well as extra-thymic self-antigens.
      Their mode of action, using in vivo and in vitro systems, has led to different
      conclusions as to the need of cell-cell interactions or regulation upon
      suppressive cytokines. The more we study regulatory T cells the more we find
      similarities to the old notion of the suppressor T cell network. The limited
      knowledge in molecular technology in the early 70s and 80s discouraged
      investigators to further scrutinize the issue and the terms T suppressors and
      contra-suppressors that were coined back then have been forgotten over the years.
      It is now time to remember the work of these investigators and attempt to explain
      their findings using the current knowledge and technology.

PMID- 12413735
TI  - Efficacy of oral administration and oral intake of edible vaccines.
AB  - To evaluate whether vaccine administration via intragastric gavage is indicative
      for the outcome of edible vaccines, mice were orally immunised with ovalbumin
      (OVA) mixed with or without Vibrio cholerae toxin (CT) in various compositions
      via various routes: (1) OVA dissolved in saline and intragastrically (IG)
      administered ('IG'); (2) OVA mixed with food extract and administered IG ('food
      IG'); (3) food chow absorbed with OVA dissolved in saline and fed to the animals
      ('food'); and (4) OVA dissolved in saline and administered via drinking bottles
      ('drinking'). When given to naive mice, 'IG' and 'food IG' but not 'food' or
      'drinking' induced anti-OVA IgG1 responses in serum, but oral boost immunisations
      were necessary. Serum IgA was not induced. Oral boosting of subcutaneously (SC)
      primed mice enhanced the IgG1 and IgA response in serum regardless of the route
      of immunisation or the vaccine composition. CT did not dramatically enhance the
      immune response. All immunisation routes except 'drinking' induced antigen
      specific IgA antibody secreting cells (ASC) in the lamina propria of naive mice.
      But antigen-specific antibody responses in faeces were not observed. We concluded
      that oral (i.e. IG) administration is distinct from oral intake. The composition
      of the vaccine (food or saline) did not influence oral administration. We thus
      suggested that the route of administration greatly influenced the outcome of oral
      immunisation. Although oral administration is a well-accepted route to test the
      potentials of oral vaccines, our study demonstrated that it is merely indicative
      for the effectiveness of edible vaccines. Studies on the feasibility of edible
      vaccines should thus be performed by eating the vaccine.

PMID- 12413737
TI  - Flow cytometric analysis of procalcitonin expression in human monocytes and
      granulocytes.
AB  - Procalcitonin (PCT), a precursor of calcitonin is a useful indicator of severe
      systemic infection and sepsis. For a better understanding of the
      pathophysiological background of PCT induction, a study was made of the
      intracellular expression of PCT in various human white blood cell populations
      i.e. monocytes and polymorphonuclear granulocytes (PMNs)-and the role of TNF
      alpha in the stimulation of their PCT production. The expression of PCT was
      investigated by flow cytometric analysis with intracellular staining with
      antibodies to the PCT components calcitonin (CT) and katacalcin (KC). Both human
      peripheral monocytes and granulocytes expressed PCT, and increased intracellular
      amounts of the PCT components were demonstrated after stimulation with
      Staphylococcus aureus as TNF-alpha inducer. The S. aureus induced stimulation of
      PCT production was inhibited by anti-TNF-alpha monoclonal antibodies. The
      monocytic cell line U937 expressed considerable intracellular PCT, but S. aureus
      failed to induce an increase in PCT expression. The determination of
      intracellular PCT by flow cytometry is a promising and a sensitive method for
      further investigation of the effects of various cytokines and cytokine-inducing
      agents in PCT synthesis of human monocytes and granulocytes.

PMID- 12413736
TI  - Prostaglandin E2 and cAMP promote B lymphocyte class switching to IgG1.
AB  - Prostaglandins of the E series (PGE) have traditionally been considered as
      suppressive for immune responses; however, recent data suggest that PGE channels
      the immune response towards a T helper 2 type response and production of selected
      immunoglobulin isotypes. Herein, we present data showing that PGE(2) and other
      agents that induce intracellular rises in cAMP significantly increased B
      lymphocyte IgG1 production (up to sevenfold). PGE(2) acted on small resting B
      cells and on uncommitted B cells expressing high levels of surface IgM to
      increase the number of cells secreting IgG1. PGE(2) even increased IgG1 synthesis
      by purified B cells in the absence of exogenous IL-4. Finally, PGE(2) synergized
      with IL-4 to induce germline gamma1 transcripts through the switch region. This
      transcription is required for isotype switching. These data support the
      hypothesis that PGE(2) acts on uncommitted resting B cells at the level of
      germline gamma1 transcription to promote class switching to IgG1. PGE(2) is an
      important regulator of the immune response, shifting the balance towards a T
      helper type 2 response, directing selection of the isotypes produced, and
      promoting memory cell formation.

PMID- 12413738
TI  - A predefined epitope-specific monoclonal antibody recognizes ELDEWA-epitope just
      presenting on gp41 of HIV-1 O clade.
AB  - Diverse variation of HIV-1 is a grave challenge for prevention of viral infection
      and immunotherapy. Monoclonal antibody (mAb) 2F5 recognizing an epitope ELDKWA
      (aa669-674) on HIV-1 envelope protein gp41 showed broad neutralizing activity
      against a lot of HIV-1 strains including primary isolates. However, viral
      mutation from ELDKWA to ELDEWA resulted in viral evasion from neutralization by
      mAb 2F5. Using ELDEWA-epitope-peptide (C-GFLDEWAGELDEWA) conjugated with carrier
      protein keyhole limpet hemocyanin (KLH), a mAb 14D9 (IgGl) was prepared and
      identified as the mAb with predefined ELDEWA-epitope specificity. The mAb 14D9
      recognized the ELDEWA epitope, but not other three epitopes (ELDKWA, ELNKWA and
      ELEKWA). In comparison, mAb 2F5 could recognize only ELDKWA, but not three
      neutralization-resistant epitopes (ELDEWA, ELNKWA and ELEKWA). Interestingly, we
      searched several authoritative HIV sequence databases (http://hiv-web.lanl.gov)
      and found out that nearly all the viral isolates bearing the ELDEWA epitope
      belong to the O clade, the only exceptional viral isolate bearing the epitope
      ELDEWA has been demonstrated to be an intergroup M/O recombinant, which suggests
      that the ELDEWA-epitope on gp41 represents a specific epitope-marker of HIV-1 O
      clade. To confirm whether the mAb 14D9 recognizes gp41 of HIV-1 O clade, the
      rsgp41(IIIB), bearing ELDKWA-epitope was site-directed-mutated to the rsgp41
      bearing ELDEWA-epitope. The mAb 14D9 could bind to rsgp41 bearing ELDEWA-epitope
      in immunoblotting analysis, did not bind to rsgp41 bearing ELDKWA-epitope. These
      experimental results suggest that the mAb 14D9 with predefined ELDEWA-epitope
      specificity may be applied to HIV-1 O clade identification.

PMID- 12413739
TI  - Effect of chondroitin sulfate on murine splenocytes sensitized with ovalbumin.
AB  - Chondroitin sulfate (CS) is a glycosaminoglycan that is widely present in animals
      organisms, and it has anti-inflammatory and chondroprotective properties. To
      examine the effects of CS on the immune system, splenocytes obtained from
      ovalbumin (OVA)-sensitized BALB/c mice were challenged with OVA in the presence
      of CS, and cytokine levels in the medium of the cultured cells were measured. CS
      induced secretion of Th1-type cytokines (IFN-gamma, IL-2, and IL-12) by OVA
      sensitized splenocytes but suppressed secretion of Th2-type cytokines (IL-5 and
      IL-10). Flow cytometric assay showed a significantly higher percentage of helper
      T cells (CD4(+)CD8(-) cells) among the splenocytes cultured with OVA and CS than
      with OVA alone. Analysis of the IFN-gamma mRNA level of the splenocytes by the
      real-time quantitative RT-PCR technique revealed higher levels in the splenocytes
      cultured with OVA and CS than in the splenocytes cultured with OVA alone. This is
      the first demonstration that CS inhibits antigen-induced IgE production through
      induction of cytokine secretion by Th1 cells, and this finding suggests a
      potential use of CS in preventing IgE-mediated allergy.

PMID- 12413740
TI  - Endomorphin-1 alters interleukin-8 secretion in Caco-2 cells via a receptor
      mediated process.
AB  - Administration of opioids that bind to the classical mu opioid receptor has been
      shown to lead to unintended alterations in immune function. Traditionally,
      altered immune function has been investigated with circulating immune cells.
      Effects of mu agonists on intestinal epithelial immune function have not been
      described. Since the oral route of administration is frequently employed with
      opiates, we determined if the mu receptor specific agonist endomorphin-1 altered
      interleukin-8 (IL-8) production by Caco-2 cells. Using RT-PCR and
      immunocytochemistry, Caco-2 cells were found to constitutively express (mu) mu
      opioid receptors. Activation of the mu receptor by endomorphin-1 (1 and 10
      microM) resulted in significant increases in IL-8 when Caco-2 cells were
      stimulated with IL-1beta. Increased IL-8 secretion due to endomorphin-1 could be
      blocked by pre-incubating cells with the mu receptor antagonist, beta
      funaltrexamine. These results indicate that the intestinal epithelial IL-8
      response can be altered by a muopioid receptor mediated mechanism.

PMID- 12413741
TI  - Influences of anti-mouse interleukin-6 receptor antibody on immune responses in
      mice.
AB  - In the present study, we examined the effect of anti-IL-6 receptor antibody (MR16
      1) on humoral and cellular immune responses in mice. MR16-1 did not affect
      antigen-specific antibody production in either the primary or secondary response
      in mice immunized with dinitro-phenyl (DNP)-keyhole limpet haemocyanin (KLH) in
      saline. DNP-KLH immunization with complete Freund's adjuvant (CFA) markedly
      augmented anti-DNP antibody production and induced interleukin 6 (IL-6)
      production in serum. In this case, MR16-1 significantly suppressed antibody
      production and further increased serum IL-6 levels. Regarding the cellular
      response, we studied the effect on the delayed-type hypersensitivity (DTH)
      response. DTH response was induced in mice by the immunization with Mycobacterium
      butyricum with incomplete Freund's adjuvant and following antigen challenge into
      the footpad 14 days after immunization. When MR16-1 was injected immediately
      after immunization, the DTH response was significantly suppressed and enlargement
      of the spleen was also suppressed. This suppressive effect was observed, when
      MR16-1 was administered on day 0, but not on days 5 and 10. Again, serum IL-6
      levels were much higher in MR16-1-treated mice compared with controls.
      Furthermore, spleen cells from control mice released IL-2 and INFgamma by the
      stimulation of antigen in vitro. In contrast, spleen cells from MR16-1-treated
      mice produced these cytokines at a marginal level. In contrast, MR16-1 did not
      suppress the DTH response, when it was injected immediately after antigen
      challenge. Our results suggest that IL-6 does not always involve antibody
      production, although IL-6 augments antibody production, and that IL-6 is
      essential for the induction of Th1 cells.

PMID- 12413743
TI  - Long-term metastable conformation of human Fcgamma subunit.
AB  - It was found that the human (hu) myeloma IgG1 Ser, its Fcgamma fragment and the
      chimeric mouse-human monoclonal antibody (chim-mAb), containing the constant part
      of hu-gamma1-chain, can exist in a long-term metastable conformational state.
      This state arises as a result of short incubation of IgG molecules and their
      Fcgamma fragments at pH<2.8 and the consequent rapid neutralisation to pH 7.0
      8.0. At pH<2.8 the three-dimensional structure of C(gamma)2 domains is unfolded,
      but rapidly refolds after neutralisation. At the same time, non-covalent
      interactions between C(gamma)2 and C(gamma)3 domains are restored very slowly. A
      metastable state of IgG keeps 70% of complement-binding ability in comparison
      with the native state.

PMID- 12413742
TI  - Characterization of anti-mouse interleukin-6 receptor antibody.
AB  - Hybridoma that produces rat anti-mouse interleukin 6 receptor (IL-6R) antibody,
      MR16-1, was established by the fusion of mouse P3U1 myeloma cells and spleen
      cells from mouse soluble IL-6R (sIL-6R)-immunized Wistar rat. In the present
      study, we examined the characteristics of MR16-1 in vitro and in vivo. MR16-1
      bound to mouse sIL-6R dose-dependently. MR16-1 suppressed IL-6-induced
      proliferation of 7TD1 cells in a dose-dependent manner and this inhibitory effect
      was reversed by the addition of a higher concentration of IL-6. Cross-reactivity
      study using T cells from mouse, rat, and human revealed that MR16-1 did not cross
      react with human and rat IL-6R. Binding region analysis using several human-mouse
      chimeric IL-6Rs showed that half of the fibronectin domain II of mouse IL-6R
      (amino acids 214-285) was required for MR16-1 binding. Furthermore, MR16-1
      completely suppressed IL-6-induced antibody production in DNP-KLH immunized mice.
      These lines of evidence demonstrate that MR16-1 is useful to investigate the
      physiological and pathological roles of IL-6 and sIL-6R in mice.

PMID- 12413744
TI  - A theory of pragmatic information and its application to the quasi-species model
      of biological evolution.
AB  - 'Standard' information theory says nothing about the semantic content of
      information. Nevertheless, applications such as evolutionary theory demand
      consideration of precisely this aspect of information, a need that has motivated
      a largely unsuccessful search for a suitable measure of an 'amount of meaning'.
      This paper represents an attempt to move beyond this impasse, based on the
      observation that the meaning of a message can only be understood relative to its
      receiver. Positing that the semantic value of information is its usefulness in
      making an informed decision, we define pragmatic information as the information
      gain in the probability distributions of the receiver's actions, both before and
      after receipt of a message in some pre-defined ensemble. We then prove rigorously
      that our definition is the only one that satisfies obvious desiderata, such as
      the additivity of information from logically independent messages. This
      definition, when applied to the information 'learned' by the time evolution of a
      process, defies the intuitions of the few previous researchers thinking along
      these lines by being monotonic in the uncertainty that remains after receipt of
      the message, but non-monotonic in the Shannon entropy of the input ensemble. It
      also follows that the pragmatic information of the genetic 'messages' in an
      evolving population is a global Lyapunov function for Eigen's quasi-species model
      of biological evolution. A concluding section argues that a theory such as ours
      must explicitly acknowledge purposeful action, or 'agency', in such diverse
      fields as evolutionary theory and finance.

PMID- 12413745
TI  - Unlimited capacity and processibility of sequence information: prerequisites for
      a system of biological chains.
AB  - Both genetic chains in a cell and phonological chains in a human phonological
      working memory simultaneously store and process sequence information. Unlimited
      capacity and processibility of sequence information are two prerequisites for
      such a system of biological chains. It is demonstrated that information chains (I
      chains) and conformation chains (C-chains) satisfy these two prerequisites.
      Namely, in both kinds of chains constant efficiency and precision of intra- and
      inter-sequence interactions are guaranteed irrespective of the chain length.
      Nucleic acids and proteins are I-chains and C-chains of genetic chains,
      respectively. A 'molecular' model of a phonological chain is formulated based on
      the properties of phonological working memory. It is proposed that prose and
      verse are I-chains and C-chains of phonological chains, respectively. The
      correspondence between a system of genetic chains and a system of phonological
      chains is explored in detail. A critical difference between systems of biological
      chains and artificial information-processing systems is attributed to the
      existence of C-chains.

PMID- 12413746
TI  - Recurrent fractal neural networks: a strategy for the exchange of local and
      global information processing in the brain.
AB  - The regulation of biological networks relies significantly on convergent feedback
      signaling loops that render a global output locally accessible. Ideally, the
      recurrent connectivity within these systems is self-organized by a time-dependent
      phase-locking mechanism. This study analyzes recurrent fractal neural networks
      (RFNNs), which utilize a self-similar or fractal branching structure of dendrites
      and downstream networks for phase-locking of reciprocal feedback loops: output
      from outer branch nodes of the network tree enters inner branch nodes of the
      dendritic tree in single neurons. This structural organization enables RFNNs to
      amplify re-entrant input by over-the-threshold signal summation from feedback
      loops with equivalent signal traveling times. The columnar organization of
      pyramidal neurons in the neocortical layers V and III is discussed as the
      structural substrate for this network architecture. RFNNs self-organize spike
      trains and render the entire neural network output accessible to the dendritic
      tree of each neuron within this network. As the result of a contraction mapping
      operation, the local dendritic input pattern contains a downscaled version of the
      network output coding structure. RFNNs perform robust, fractal data compression,
      thus coping with a limited number of feedback loops for signal transport in
      convergent neural networks. This property is discussed as a significant step
      toward the solution of a fundamental problem in neuroscience: how is neuronal
      computation in separate neurons and remote brain areas unified as an instance of
      experience in consciousness? RFNNs are promising candidates for engaging neural
      networks into a coherent activity and provide a strategy for the exchange of
      global and local information processing in the human brain, thereby ensuring the
      completeness of a transformation from neuronal computation into conscious
      experience.

PMID- 12413747
TI  - A kinetic study of analyte-receptor binding and dissociation for biosensor
      applications: a fractal analysis for two different DNA systems.
AB  - A fractal analysis of DNA binding and dissociation kinetics on biosensor surfaces
      is presented. The fractal approach provides an attractive, convenient method to
      model the kinetic data taking into account the effects of surface heterogeneity
      brought about by ligand immobilization. The fractal technique can be used in
      conjunction or as an alternate approach to conventional modeling techniques, such
      as the Langmuir model, saturation model, etc. Examples analyzed include a DNA
      molecular beacon biosensor and a plasmid DNA-(cationic polymer) interaction
      biosensor. The molecular beacon example provides some insights into the nature of
      the surface and how it influences the binding rate coefficients. The DNA-cationic
      polymer interaction example provides some quantitative results on the binding and
      dissociation rate coefficients. Data taken from the literature may be modeled, in
      the case of binding, using a single-fractal analysis or a dual-fractal analysis.
      The dual-fractal analysis results indicate a change in the binding mechanism as
      the reaction progresses on the surface. A single-fractal analysis is adequate to
      model the dissociation kinetics in the example presented. Relationships are
      presented for the binding rate coefficients as a function of their corresponding
      fractal dimension, D(f), which is an indication of the degree of heterogeneity
      that exists on the surface. When analyte-receptor binding is involved, an
      increase in the heterogeneity of the surface (increase in D(f)) leads to an
      increase in the binding rate coefficient.

PMID- 12413748
TI  - Frequency distributions from birth, death, and creation processes.
AB  - The time-dependent frequency distribution of groups of individuals versus group
      size was investigated within a continuum approximation, assuming a simplified
      individual growth, death and creation model. The analogy of the system to a
      physical fluid exhibiting both convection and diffusion was exploited in
      obtaining various solutions to the distribution equation. A general solution was
      approximated through the application of a Green's function. More specific exact
      solutions were also found to be useful. The solutions were continually checked
      against the continuum approximation through extensive simulation of the discrete
      system. Over limited ranges of group size, the frequency distributions were shown
      to closely exhibit a power-law dependence on group size, as found in many
      realizations of this type of system, ranging from colonies of mutated bacteria to
      the distribution of surnames in a given population. As an example, the modeled
      distributions were successfully fit to the distribution of surnames in several
      countries by adjusting the parameters specifying growth, death and creation
      rates.

PMID- 12413750
TI  - The resuscitation greats. William Harvey.

PMID- 12413751
TI  - Common faults in resuscitation equipment--guidelines for checking equipment and
      drugs used in adult cardiopulmonary resuscitation.
AB  - Successful advanced life support relies, in part, upon the availability and
      correct functioning of resuscitation equipment. However, numerous publications
      report deficiencies and defects in key items of resuscitation equipment,
      particularly those relating to airway management and defibrillation. Some of
      these are generic and relate to basic device failure (e.g. intrinsic design
      faults, manufacturing errors, random component failure), external factors (e.g.
      power failure, gas supply failure, electromagnetic interference) and human error
      (notably, inadequate knowledge, lack of experience and training, inadequate
      checking, insufficient maintenance). However, others are device specific. This
      paper identifies the common, generic faults that lead to equipment malfunction
      and recommends the resuscitation equipment essential for successful
      cardiopulmonary resuscitation. It also describes examples of specific equipment
      malfunction and makes suggestions for the nature and frequency of resuscitation
      equipment and drug checks, using a structured, and easy-to-recall list.

PMID- 12413752
TI  - Effect of rescuer fatigue on performance of continuous external chest
      compressions over 3 min.
AB  - Guidelines for the performance of cardiopulmonary resuscitation (CPR) have been
      revised recently and now advocate that chest compressions are performed without
      interruption for 3 min in patients during asystole and pulseless electrical
      activity. The aim of the present study was to determine if rescuer fatigue occurs
      during 3 min of chest compressions and if so, the effects on the rate and quality
      of compressions. Forty subjects competent in basic life support (BLS) were
      studied. They performed continuous chest compressions on a Laerdal Skillmeter
      Resusci-Anne manikin for two consecutive periods of 3 min separated by 30 s. The
      total number of compressions attempted was well maintained at approximately 100
      min(-1) throughout the period of study. However, the number of satisfactory chest
      compressions performed decreased progressively during resuscitation (P < 0.001)
      as follows: first min, 82 min(-1); second, 68 min(-1); third, 52 min(-1); fourth,
      70 min(-1); fifth, 44 min(-1); sixth, 27 min(-1). We observed significant
      correlations between the number of satisfactory compressions performed and both
      height and weight of the rescuer. Female subjects achieved significantly fewer
      satisfactory compressions compared with males (P = 0.03). Seven subjects (five
      female, two male) were unable to complete the second 3-min period because of
      exhaustion. We conclude that rescuer fatigue adversely affects the quality of
      chest compressions when performed without interruption over a 3-min period and
      that this effect may be greater in females due to their smaller stature.
      Consideration should be given to rotating the rescuer performing chest
      compressions after 1 min intervals.

PMID- 12413753
TI  - Community competence in cardiopulmonary resuscitation.
AB  - The aim of this study was to determine community application of cardiopulmonary
      resuscitation (CPR) skills in an emergency, and, thus, assess the value of
      training programmes in raising community competence. A cross-sectional telephone
      survey of the Western Australian population was chosen randomly (n = 803). An
      urban sub-sample (n = 100) performed a practical demonstration of CPR skills
      using a simulated collapse scenario using a recording manikin as the victim.
      Performance was assessed by two observers using pre-determined criteria. Of all
      respondents, 64% had been trained in CPR. Practical and theoretical assessment
      scores were significantly better in trained versus untrained participants. The
      number of times a person was trained in CPR was more effective for retention and
      competence than time since last trained. Degree of training and theoretical
      competence were less in those aged over 65 years or with heart disease in the
      household. Theoretical competence poorly reflected practical performance in many
      tasks. This study provides a comprehensive database of CPR training and
      performance, and highlights future directions to ensure appropriate and cost
      effective training. Specific factors to be addressed include increasing frequency
      of training, targeting of high-risk groups, simplification in teaching, and
      emphasising early activation of the emergency medical system.

PMID- 12413754
TI  - The ABCs of recording paediatric cardiac arrests.
AB  - OBJECTIVE: To examine the quality and comprehensiveness of documentation in
      Paediatric 'cardiac arrests'. DESIGN: Retrospective chart review. SETTING:
      Tertiary care hospital wards, Paediatric Intensive Care and Accident and
      Emergency department. SUBJECTS: 41 children experiencing acute life-threatening
      events in hospital. RESULTS: Overall documentation of details related to time,
      place and personnel was highly variable but generally present in over half of the
      cases reviewed. Data relating to specific drug-related and interventional
      therapies was insufficient, as was documentation of time intervals and consequent
      therapeutic decisions. CONCLUSIONS: Documentation of critical resuscitation
      episodes in children is below recognised standards and this has potential quality
      of care and medicolegal implications. Current teaching needs to emphasise this
      essential aspect of clinical care from the earliest level of training.

PMID- 12413755
TI  - Efficacy of the laryngeal tube by inexperienced personnel.
AB  - We compared the laryngeal tube and the laryngeal mask in the ease of insertion,
      ventilation volume and the incidence of gastric insufflation by inexperienced
      personnel. In a randomized, cross-over design, each of 28 students of a Fire
      Defense Academy attempted to insert the laryngeal tube and laryngeal mask in turn
      using an airway management trainer manikin. A self-inflating bag (2000 ml) was
      attached and ventilation volume was measured. The number of attempts at the
      insertion and the presence or absence of gastric insufflation were also recorded.
      After completion of the study, each student was asked whether insertion of one
      device was easier than the other. All 28 students could insert the laryngeal tube
      at the first attempt. As for the laryngeal mask, 27 could insert it at the first
      attempt, whereas the remaining one student could insert it after two attempts.
      The tidal volume was significantly greater for the laryngeal tube (median 842 ml)
      than the laryngeal mask (median 716 ml) (95%CI for median difference: 10-116 ml;
      P < 0.02). The incidence of gastric insufflation was significantly lower for the
      laryngeal tube (2 times) than for the laryngeal mask (10 times) (P < 0.05).
      Twenty six of 28 students stated that insertion of the laryngeal tube was easier
      than insertion of the laryngeal mask, whereas the remaining two stated that there
      was no difference in the ease of insertion between two devices. Therefore, the
      laryngeal tube has a potential role in providing a clear airway during
      cardiopulmonary resuscitation.

PMID- 12413756
TI  - Defibrillation threshold and cardiac responses using an external biphasic
      defibrillator with pediatric and adult adhesive patches in pediatric-sized
      piglets.
AB  - Before recommendations for using an automatic external defibrillator on pediatric
      patients can be made, a protocol for the energy of a biphasic waveform energy
      dosing needs to be determined that will allow ventricular defibrillation of 8
      year olds while causing only a minimal amount of cardiac damage to infants.
      Pediatric- and adult-sized electrode patches were alternately applied to 10
      isoflurane-anesthetized piglets weighing 3.8-20.1 kg to approximate the body
      weights of newborns to children < 8 years old. The defibrillation threshold (DFT)
      was determined for biphasic truncated exponential waveform shocks. Additional
      shocks, varying from the DFT to 360 Joules (J), were delivered during sinus
      rhythm or following 30 s of ventricular fibrillation (VF). The DFT was 2.4+/-0.81
      and 2.1+/-0.65 J/kg for pediatric and adult patches, respectively (P = N.S.). The
      change in left ventricular (LV) dP/dt from baseline as a function of shock
      strength was significantly different at 1 and 10 s after shocks of increasing
      energy that were delivered in sinus rhythm, and 1, 10, 20, and 30 s after
      defibrillation shocks. There was no significant difference in LV dP/dt with
      increasing shock energy at 60 s with either patch size. The time to return of
      sinus rhythm, ST-segment deviation, and cardiac output were also not
      significantly different from baseline 60 s following shocks of up to 360 J
      delivered during sinus rhythm or VF with either patch. The same amount of energy
      delivered with a biphasic external defibrillator successfully defibrillated VF
      whether adult or pediatric patches were used. Cardiac rhythm and hemodynamic
      variables were unaltered at 60 s after shocks delivered at energies of up to 360
      J. These data suggest that there is a substantial safety margin above a DFT
      strength shock for this biphasic waveform in piglets.

PMID- 12413757
TI  - Post-resuscitation right ventricular dysfunction: delineation and treatment with
      dobutamine.
AB  - BACKGROUND: Left ventricular dysfunction after resuscitation from cardiac arrest
      has been well described. Treatment with dobutamine improves post-resuscitation
      left ventricular function. Right ventricular function following resuscitation has
      not been investigated. The purposes of this study were to examine right
      ventricular function following resuscitation and determine whether dobutamine
      would improve post-resuscitation right ventricular function. METHODS AND RESULTS:
      Right ventricular function was measured in 28 swine (29+/-1 kg) before and after
      resuscitation from 15 min of untreated ventricular fibrillation. Twelve animals
      received dobutamine at 10 mcg/kg/min while 16 animals served as untreated
      controls. Among controls, right ventricular dysfunction post-resuscitation was
      demonstrated by a decrease in right ventricular ejection fraction and an increase
      in right ventricular end-diastolic pressure. Among animals treated with
      dobutamine, there was a significant improvement in right ventricular function
      post-resuscitation compared to untreated controls. CONCLUSIONS: This study
      establishes that right ventricular systolic and diastolic dysfunction does occur
      after prolonged cardiac arrest from ventricular fibrillation. Dobutamine can
      ameliorate post-resuscitation right ventricular dysfunction.

PMID- 12413758
TI  - Neurological recovery by EEG bursting after resuscitation from cardiac arrest in
      rats.
AB  - INTRODUCTION: The return of neurological function during the early period after
      resuscitation from cardiac arrest (CA) has not been evaluated systematically. We
      report the temporal analysis of EEG bursting pattern during the very early
      periods after resuscitation. DESIGN/METHOD: A balanced group of good and poor
      outcome animals was selected from a population of rats subjected to either 5 or 7
      min of asphyxial cardiac arrest (ACA) on the basis of a single criteria: 24 h
      neurobehavioral function based on the neurodeficit score (NDS). The EEGs of six
      consecutive good outcome rats (NDS > or = 60) and six consecutive poor outcome
      rats (NDS < 60) were selected for the study. The EEGs of these animals were given
      to two EEG examiners who were blinded to the selection process, the experimental
      conditions and the neurobehavioral recovery. The EEG bursting characteristics,
      such as rate, peak and duration of bursting were studied. RESULTS: There was
      significantly higher EEG bursting in the good outcome animals (P < 0.05) and the
      burst complexes evolved into continuous activity by 90 min. Lower frequency
      bursting that persisted and failed to evolve into continuous activity was
      observed in the poor outcome group. CONCLUSION: Increased EEG bursting during
      first 30-40 min after resuscitation from moderate to severe ACA was observed in
      rats with good neurological outcome at 24 h. Early EEG bursting patterns may
      provide additional prognostication after resuscitation from CA.

PMID- 12413759
TI  - Resuscitation of hemorrhagic shock attenuates intrapulmonary nitric oxide
      formation.
AB  - Hemorrhagic shock has been shown to upregulate intrapulmonary inducible nitric
      oxide (NO) synthase (iNOS) expression. Increased intrapulmonary iNOS expression
      is reflected by increases in concentrations of NO in the airways. The purpose of
      this study was to examine the effects of resuscitation on this induction of
      intrapulmonary NO formation caused by hemorrhage. Eighteen rats were randomized
      to one of three groups. One group of rats was simply sham-instrumented and
      monitored. Two other groups experienced hemorrhagic shock (mean systemic blood
      pressure of 40-45 mmHg) for 60 min. In one of the hemorrhagic shock groups,
      resuscitation was performed by re-infusing the shed blood and supplementing it
      with normal saline. Compared with sham-instrumented rats, those exposed to
      hemorrhagic shock without subsequent resuscitation exhibited a 10-fold increase
      in exhaled NO concentrations. Additionally, concentrations of both intrapulmonary
      iNOS protein and mRNA increased. Resuscitation attenuated the hemorrhage-induced
      upregulation of exhaled NO, iNOS protein and iNOS mRNA. This data suggests that
      resuscitation attenuates the hemorrhagic shock-induced formation of
      intrapulmonary NO by downregulating iNOS transcription. We believe that exhaled
      NO concentrations provide a useful, non-invasive method of monitoring the
      intrapulmonary inflammatory sequelae of hemorrhagic shock.

PMID- 12413760
TI  - Tenecteplase for massive pulmonary embolus.
AB  - The treatment of massive pulmonary embolus remains controversial. We describe the
      first report of the successful use of the thrombolytic agent, tenecteplase, in
      treating a hypotensive elderly patient with a saddle embolus. A brief review of
      the current literature concerning thrombolysis for massive pulmonary embolus is
      given.

PMID- 12413761
TI  - Transient Brugada-type electrocardiographic abnormalities in renal failure
      reversed by dialysis.
AB  - The Brugada syndrome (BRS) is a hereditary cardiac condition (characteristically
      with a gene mutation affecting sodium channel function) identified by an elevated
      terminal portion of the QRS complex (prominent J wave) followed by a descending
      ST-segment elevation ending in a negative T wave in the right precordial leads,
      and malignant tachyarrhythmias in patients without demonstrable structural heart
      disease. We report a patient with a previous history of epilepsy treated with
      psychotropic drugs (with a sodium channel blocking effect) and chronic renal
      failure on haemodialysis who developed hyperkalaemia (6.6 mmol/l) and ECG
      findings resembling BRS. This condition was manifested by the prominent J wave,
      the coved-type ST-segment elevation and the negative T wave in the right
      precordial leads. These ECG changes disappeared after haemodialysis when the
      potassium became normal. Subsequently, a flecainide test did not reproduce ST
      segment elevation. We conclude that hyperkalaemia associated with cardiac
      membrane active drugs may cause ECG changes mimicking the Brugada syndrome.

PMID- 12413762
TI  - Intravenous calcium in the treatment of postoperative hypotension.

PMID- 12413763
TI  - Neuromediators--a crucial component of the skin immune system.
AB  - There is increasing evidence that the cutaneous nervous system modulates
      physiological and pathophysiological effects including cell growth and
      differentiation, immunity and inflammation as well as tissue repair. Both
      cutaneous nervous fibers and inflammatory cells are able to release
      neuromediators and thereby activate specific receptors on target cells in the
      skin or transient immunocompetent cells. Cutaneous neuromediators include
      classical neurotransmitters such as catecholamines and acetylcholine being
      released from the automatic nervous system or cutaneous cells. On the other hand
      neuropeptides including substance P, calcitonin gene related peptide (CRGP),
      vasointestinal peptide (VIP) or proopiomelanocortin (POMC) derived peptides such
      as alpha melanocyte stimulating hormone (alphaMSH) may be released from sensory
      or autonomic nerve fibers and several epidermal as well as dermal cells.
      Neuropeptides are known to activate a variety of cutaneous cells through high
      affinity neuropeptide receptors or by direct activation of intracellular G
      protein signalling cascades. Via the modulation of transcription factor
      activation (NF-kappaB, AP-1, STAT-3) they regulate the expression of adhesion
      molecules and proinflammatory cytokines in different cells and thereby function
      as modulators of immune and inflammatory reactions. Accordingly, neuropeptides
      such as CGRP or alphaMSH in vitro were found to downregulate costimulatory
      molecule expression on dendritic cells and in vivo via the generation of
      suppressor T-lymphocytes to induce hapten specific tolerance. Proteinases such as
      tryptase or neural endopeptidase inactivate neuropeptides in the extracellular
      space or at the cell surface thereby terminating neuropeptide induced
      inflammatory or immune responses. Proteinase-activated receptors (PAR) are
      recently described receptors that may have high impact in regulating cutaneous
      neurogenic inflammation. In the skin PAR-2 being expressed on sensory neurons and
      endothelial cells is self activated by tethered peptide ligands that are exposed
      after extracellular amino-terminal cleavage by trypsin or mast cell tryptase. PAR
      2 agonists were found to induce the release of CGRP and SP which mediate
      vasodilation, plasma extravasation as well as the expression of adhesion
      molecules on vascular endothelial cells and thus elicit neurogenic inflammation.
      These findings indicate that the neuromediator network including neuropeptide
      receptors as well as proteinases play an important role in the maintenance of
      tissue integrity and the regulation of inflammatory and immune responses in the
      skin.

PMID- 12413764
TI  - Extracellular regulated kinase and c-Jun N-terminal kinase are activated in
      psoriatic involved epidermis.
AB  - Psoriatic skin shows markedly increased keratinocyte proliferation and altered
      differentiation with various abnormal signalling pathways. In the present study,
      we investigated the expression of mitogen-activated protein kinases in psoriatic
      skin. Immunohistochemical study showed increased extracellular regulated kinase
      (ERK) and c-Jun N-terminal kinase (JNK) expression in the nuclei of involved
      epidermis. Western blot analyses confirmed the increased active phospho-ERK and
      phospho-JNK expression in the involved epidermis. In contrast, expression pattern
      of p38 was not different between the involved and uninvolved epidermis, which was
      confirmed by western blot analysis. These results indicate that psoriatic
      epidermis shows selective activation of ERK and JNK, which might be related to
      hyperproliferation and abnormal differentiation of psoriatic epidermis.

PMID- 12413765
TI  - Interleukin-13 gene polymorphism G4257A is associated with atopic dermatitis in
      Japanese patients.
AB  - Interleukin (IL)-13 plays an important role in the induction of immunoglobulin E
      (IgE) and in the pathogenesis of atopic dermatitis (AD). We investigated the
      allele and genotype frequencies of three IL-13 single nucleotide polymorphisms
      (SNPs) (A704C and C1103T in the promoter region and G4257A in exon 4) in Japanese
      patients with AD. For A704C and C1103T SNPs, there were no significant
      differences in allele or genotype frequencies between AD patients and controls.
      For G4257A SNP, A allele was significantly increased in AD patients (39.5%)
      compared with controls (29.4%) (P = 0.016). The same proportion of each genotype
      and allele was observed in the patient subgroup with and without asthma. Serum
      IgE levels and peripheral eosinophil counts were not significantly different
      among genotypes in G4257A SNP. There was also no significant difference in allele
      or genotype frequencies between AD patients with mild disease and those with
      severe disease, between those with family history of AD and those without it, or
      between those with family history of atopic disorders and those without it. This
      result suggests that 4257A allele is associated with susceptibility to AD and
      that it may function in the pathogenesis of AD itself, presumably by other
      mechanisms than inducing IgE production.

PMID- 12413766
TI  - Elevated expression of hepatocyte and keratinocyte growth factor in cultured
      buccal-mucosa-derived fibroblasts compared with normal-skin-derived fibroblasts.
AB  - Oral mucosa heals faster with less scar formation than skin and a hypertrophic
      scar is very rare in the oral cavity, but its mechanism has not been elucidated
      enough. To elucidate whether or not there are differences in growth factor
      expression between fibroblasts derived from buccal mucosal and normal skin, we
      investigated the expression of hepatocyte growth factor (HGF), keratinocyte
      growth factor (KGF) and stem cell factor (SCF) by cultured fibroblasts. The
      semiquantitative RT-PCR revealed that the expression of HGF and KGF transcripts
      by buccal mucosal fibroblasts was significantly elevated compared with that by
      dermal fibroblasts. In parallel, ELISA revealed the significant increase of HGF
      production by buccal mucosal fibroblasts. The level of production of SCF protein
      did not differ significantly. Our study suggests that increased expression of HGF
      and KGF by buccal mucosal fibroblasts may partly be responsible for the faster
      wound healing with less scar formation in the oral cavity compared with normal
      skin.

PMID- 12413767
TI  - Th1, Th2 and Th3 cytokines in the pathogenesis of bullous pemphigoid.
AB  - Bullous pemphigoid (BP) is an autoimmune bullous skin disease mediated by
      autoantibodies against hemidesmosomal proteins. In addition to humoral immunity,
      the contribute of infiltrating T-helper (Th) autoreactive lymphocytes and their
      related cytokines to the pathomechanism of blistering is now growing in interest.
      To investigate T-cell activation markers and the presence of inflammatory and
      fibrogenic cytokines (i.e. IL2, IL-4, IL-5, IFN-gamma, TGF-beta) in BP lesional
      skin, we performed an immunohistochemical study and an in situ hybridization
      procedure on five BP patients, comparing them with two psoriatic patients and
      four healthy subjects. Our aim was to expand suitable information about tissutal
      expression of cytokines, secondly to further investigate the role of TGF-beta (a
      Th3-like or T-regulatory (T-reg) cytokine) in a non-scarring disorder like BP, in
      order to highlight its pleiotropic activity. The immunohistochemical analysis
      revealed a moderate to strong staining for IL-4 and IL-5 with a prevalent
      perivascular localization in the upper dermis. The staining for IFN-gamma showed
      a moderate/focal expression on the dermal perivascular infiltrate. IL-2 protein
      was observed in four cases. While no positive staining for IL-4 mRNA was detected
      in all BP subjects with in situ hybridization, IL-5 mRNA was documented in four
      BP specimens. A focal nuclear staining for IFN-gamma was observed in the
      epidermal layers and on the cellular infiltrate of lesional skin. In all BP
      cases, a moderate/diffuse positivity for TGF-beta(1) mRNA was documented in both
      cytoplasm and nucleus of the infiltrating perivascular cells of lesional and
      perilesional skin. Our results suggest a balance between Th1, Th2 and Th3
      activity, with quantitatively different impact of the various cytokines on the
      pathomechanism of blistering, depending on the reciprocal network. The supposed
      participation of each cytokine analyzed in the pathogenesis of BP is discussed.
      The newest data obtained consist of TGF-beta detection in a non-scarring disease
      like PB, that had never been documented before, and in the confirmation of a
      mixed cytokine pattern in the fully developed phase of the disease.

PMID- 12413768
TI  - Acne phototherapy with a high-intensity, enhanced, narrow-band, blue light
      source: an open study and in vitro investigation.
AB  - The purpose of this study was to investigate the efficacy of phototherapy with a
      newly-developed high-intensity, enhanced, narrow-band, blue light source in
      patients with mild to moderate acne. An open study was performed in acne patients
      who were treated twice a week up to 5 weeks. Acne lesions were reduced by 64%.
      Two patients experienced dryness. No patient discontinued treatment due to
      adverse effects. In vitro investigation revealed that irradiation from this light
      source reduced the number of Propionibacterium acnes (P. acnes), but not
      Staphylococcus epidermidis that were isolated from the acne patients.
      Phototherapy using this blue light source was effective and well tolerated in
      acne patients and had an ability to decrease numbers of P. acnes in vitro,
      suggesting that this phototherapy may be a new modality for the treatment of
      acne.

PMID- 12413769
TI  - Expression of parathyroid hormone (PTH)/PTH-related peptide receptor messenger
      ribonucleic acid in mice hair cycle.
AB  - There is increasing evidence that parathyroid hormone (PTH) and PTH-related
      peptide (PTHrP) are involved in normal skin cell growth, influence the
      proliferation and differentiation of the epidermis and hair follicle. PTHrP and
      PTH/PTHrP receptor show prominent cutaneous expression, may exert important
      paracrine and/or autocrine functions. The expression of PTH/PTHrP receptor in
      different stages of hair cycle is unknown. Therefore, we examined the amount of
      PTH/PTHrP mRNA in C57BL/6 mice skin at different stages of hair cycle by
      relatively quantitative reverse transcription-polymerase chain reaction (RT-PCR),
      and investigated the localization of this receptor in mice skin by in situ
      hybridization. The expression of PTH/PTHrP receptor mRNA were higher in anagen,
      but significantly lower in catagen and telogen. Then, the PTH/PTHrP receptor mRNA
      was located in the inner root sheath (IRS) in anagen and catagen, but was not
      detected in telogen hair follicles, although it was expressed weakly in dermis.
      The variety of the PTH/PTHrP receptor mRNA expression during hair cycling suggest
      that PTH, PTHrP and their receptors might participate in the regulation of hair
      cycle in mice skin.

PMID- 12413770
TI  - Characterization of dermatitis arising spontaneously in DS-Nh mice maintained
      under conventional conditions: another possible model for atopic dermatitis.
AB  - DS-Nh (DS Nh/+) mice spontaneously develop dermatitis when they are housed in a
      conventional environment. In this study, we analyzed the clinical and
      histopathological features of dermatitis in DS-Nh mice, which is characterized by
      erythema, edema, and erosion on the face, neck, chest and flexor surfaces of
      their forelegs with marked scratching behavior. Histopathological examination,
      including immunohistochemistry, revealed that inflammatory cells consisting of
      mast cells, eosinophils, CD4-positive T cell-dominant lymphocytes and CD11b
      positive macrophages infiltrated the skin lesions. The cytokine production
      pattern of inflammatory cells in a lesional skin tissue was shifted to the Th2
      type (IL-4) rather than the Th1 type (IFN-gamma). Serum IgE levels were elevated
      and correlated with the severity of the clinical skin conditions. These skin
      symptoms were observed in association with a colonization of Staphylococcus
      aureus. Similar clinical and histopathological symptoms were inducible with
      repeated percutaneous immunization of heat-killed S. aureus on the back of SPF DS
      Nh mice. These results suggest that the spontaneous dermatitis that occurs in
      conventionally raised DS-Nh mice is comparable to a certain type of human atopic
      dermatitis (AD), which is associated with S. aureus, a recognized environmental
      factor. Thus, we consider that DS-Nh mice offer a useful model for investigating
      the pathogenesis of AD and for developing new therapeutic approaches or drugs for
      treating AD.

PMID- 12413771
TI  - TGF-beta1-mediated regulation of thymus and activation-regulated chemokine
      (TARC/CCL17) synthesis and secretion by HaCaT cells co-stimulated with TNF-alpha
      and IFN-gamma.
AB  - Thymus and activation-regulated chemokine (TARC/CCL17) contributes not only to
      the recruitment of leukocytes, but is also involved in immune disorders, such as
      atopic dermatitis (AD) and bronchial asthma. We have previously reported that the
      levels of TARC were high in patients with AD and that lesional epidermis were
      strongly immunoreactive for TARC. In this paper, the effects of transforming
      growth factor (TGF)-beta(1) on the expression of TARC/CCL17 were examined in
      HaCaT cells, a human keratinocytes (KCs) cell line, co-stimulated with TNF-alpha
      and IFN-gamma. We found that TGF-beta(1) down-regulated the TARC synthesis and
      secretion of HaCaT cells co-stimulated with TNF-alpha and IFN-gamma in a dose
      dependent manner. TGF-beta(1) at a concentration of 10ng/ml maximally inhibited
      this secretion. Northern blot analysis showed a similar inhibitory effect of TGF
      beta(1) on TARC mRNA expression by HaCaT cells. The TGF-beta(1)-induced down
      regulation of TARC/CCL17 in HaCaT cells suggests that TGF-beta(1) might regulate
      the TARC-related inflammatory processes, which may be important for understanding
      the pathogenesis of allergic diseases.

PMID- 12413772
TI  - Interleukin-12 p40 gene (IL12B) 3'-untranslated region polymorphism is associated
      with susceptibility to atopic dermatitis and psoriasis vulgaris.
AB  - Interleukin-12 (IL-12) is believed to play an important role in inducing Th1-type
      cytokine profiles. Atopic dermatitis (AD) and psoriasis vulgaris (PsV) are
      considered to be Th2 and Th1 type disease, respectively. The IL-12 p40 subunit
      gene (IL12B) is located at chromosome 5q31-33 and linkage findings of AD on 5q31
      were reported. Recently single nucleotide polymorphism (SNP) (1188A/C) of IL12B
      has been reported. In function, it has been reported that this SNP is associated
      with IL12B mRNA expression levels. To learn whether this SNP is associated with
      susceptibility to AD or PsV, we investigated the genotype and allele frequencies
      of the SNP in AD patients, in PsV patients and in controls, examining 164 AD
      patients, 143 PsV patients and 100 healthy individuals in Japanese population.
      Genotyping was performed using the polymerase chain reaction-restriction fragment
      length polymorphism method. The A allele was decreased in AD patients (40.9%, p =
      0.031) and increased in PsV patients (60.1%, p = 0.035) compared with controls
      (50.5%). This suggests that IL12B SNP is associated with susceptibility to AD and
      PsV, presumably by affecting the Th1/Th2 balance.

PMID- 12413773
TI  - Polymorphisms of vitamin D receptor gene in Japanese patients with psoriasis
      vulgaris.
AB  - We examined polymorphisms of vitamin D receptor (VDR) gene in Japanese patients
      with psoriasis vulgaris (PsV). We also studied the association between VDR gene
      polymorphisms and the response to vitamin D (VD) topical treatment in psoriatic
      patients. FokI, BsmI, ApaI and TaqI genotypes were determined by restriction
      fragment patterns in patients (n = 115) and controls (n = 69). In addition, 54
      psoriatic patients were divided into two groups in terms of their response to VD
      (tacalcitol) topical treatment: non-responsive (n = 30) and responsive (n = 24)
      patients. The frequencies of B allele and t allele were lower in patients than in
      controls (9 vs. 19%: p < 0.01, 7 vs. 14%: p < 0.05, respectively). In regard to
      response to VD treatment, F allele was lower in non-responsive patients than in
      controls (47 vs. 64%, p < 0.05). We show that polymorphisms of VDR gene are
      associated with Japanese patients with PsV. Allelic variance in the VDR gene or
      other genes in linkage disequilibrium with this gene might predispose to the
      development of PsV.

PMID- 12413774
TI  - Models of pancreatic regeneration in diabetes.
AB  - The number of functionally intact beta cells in the islet organ is of decisive
      importance for the development, course and outcome of diabetes mellitus.
      Generally speaking, the total beta-cell mass reflects the balance between the
      renewal and loss of these cells. Assuming that virtually all forms of diabetes
      mellitus are characterized by an insufficient extent of beta cell replication
      needed to compensate for the loss or dysfunction of beta cells occurring in
      diabetes, elucidation of the regenerating potential in experimentally induced
      diabetic animal would be of interest as alternative therapy for diabetes. Here we
      have attempted to take a stock of different models developed in the last few
      years, which permit investigation of regenerative process from various angles.
      The review focuses on factors responsible for induction of islet neogenesis in
      the diabetic pancreas, ultimately leading to pancreatic regeneration and possible
      reversal of diabetes. On the whole the study of these models will enhance our
      understanding of regenerative potential of diabetic pancreas and factors
      necessary to trigger stem cells' population within the pancreas so as to suggest
      an alternative therapeutic approach for the control and/or cure of diabetes.

PMID- 12413775
TI  - Clinical features of a young Japanese woman having marked obesity and abrupt
      onset of diabetes mellitus with ketoacidosis.
AB  - The subject was a 26-year-old Japanese woman of 148 cm height, 96.2 kg of body
      weight (BW) (body mass index (BMI) of 43.8 kg/m(2)). She was referred to our
      hospital on May 1, 2000 for the evaluation of marked hyperglycemia with clinical
      symptom of general malaise, polydipsia, and ketonuria (3+). She did not smoke, or
      drink alcohol. But, she tended to eat lots of sweet food every day before the
      onset of this symptom. Her father was diagnosed type 2 diabetes mellitus. Her
      fasting plasma glucose and HbA(1c), and serum C-peptide were 398 mg/dl, 7.8% and
      less than 0.05 ng/ml [normal range: 0.94-2.8], respectively. She tested negative
      for anti-glutamic acid decarboxylase (GAD) antibodies and islet-cell antibodies.
      C-peptide level in her urine was as low as 3.4 microg/day. We immediately started
      insulin treatment under the diagnosis of abrupt onset of diabetes mellitus with
      diabetic ketoacidosis on the day of her admission, and the insulin treatment was
      continued after her being discharged. She showed continuous BW reduction until
      her BW reached approximately 60 kg, followed by her BW being plateau. During the
      period, intra-abdominal visceral fat (VF) and subcutaneous fat (SF) volume
      assessed by helical computerized tomography (CT) showed a substantial reduction
      [3.9-0.5 l for VF, 19-3.2 l for SF volume]. Pre-heparin plasma lipoprotein lipase
      (LPL) mass showed a considerably lower value when she had continuous BW reduction
      than did it when her BW reduction discontinued. These findings suggest that in
      this subject, continuous BW reduction after the abrupt onset of diabetes is
      closely associated with intra-abdominal fat mass reduction, which may be related
      to decreased production of LPL.

PMID- 12413776
TI  - Excess maternal transmission and familial aggregation of Type 2 diabetes in Sri
      Lanka.
AB  - INTRODUCTION: An excess of maternal transmission of Type 2 diabetes mellitus has
      been reported in Europid populations, but not in South India. METHOD: A
      questionnaire-based survey was carried out in 1000 (502 male) people with Type 2
      diabetes to establish whether there is an excess of maternal transmission and
      familial aggregation in a Sri Lankan population. RESULTS: Mean age of onset was
      47+/-12 (+/-S.D.) years and duration of diabetes was 9+/-7 years. Thirty-seven
      percent reported parents with diabetes, 46.9% had no parents with diabetes, 16.1%
      did not know the diabetes status of at least one parent and there was no diabetes
      in the other. Of the probands, 59.4% had at least one affected relative. When
      both parents' diabetes status was known and only one was affected, diabetes was
      more common among mothers (n = 156) than fathers (n = 125) of probands (P <
      0.001). A further 54 probands had both parents with diabetes. Mean age of onset
      and duration of the disease among probands with parental diabetes was 43.1+/
      (11.1) and 9.6+/-(6.8). In the previous generation, 21.2% of maternal
      grandmothers and 17.3% of maternal grandfathers in the maternal diabetes group
      and 4.8% of maternal grandmothers and 17% of maternal grandfathers in the
      paternal diabetes group had diabetes. Diabetes in siblings and children was more
      common in those with mothers who had diabetes (53.8% and 4.5%) when compared with
      those in whom fathers had diabetes (42.4% and 1.6%) (P < 0.0001 and P < 0.01).
      CONCLUSION: Familial aggregation and excess maternal transmission were observed
      in people with Type 2 diabetes in Sri Lanka.

PMID- 12413777
TI  - Endothelial nitric oxide synthase gene and the development of diabetic
      nephropathy.
AB  - BACKGROUND: Endothelial nitric oxide synthase gene and the development of
      diabetic nephropathy BACKGROUND: Intron 4 insertion/deletion polymorphism of the
      constitutive endothelial nitric oxide synthase (ecNOS) gene may be related to
      diabetic nephropathy. METHODS: A case-control study was performed in three groups
      of Japanese patients with Type 2 diabetes mellitus, which including 123 patients
      with advanced diabetic nephropathy, 107 patients with overt proteinuria and
      normal serum creatinine level, and a control group of 203 patients with normal
      renal function despite having diabetes for over 10 years. Additionally, logistic
      regression analysis was used to assess the findings. RESULTS: When we examined
      the a-deletion/b-insertion in intron 4 of ecNOS gene, the genotype and allele
      frequencies were not significantly different between the patients with advanced
      diabetic nephropathy (a/a 2.4, a/b 21.9, b/b 75.5, 'a' 13.4, 'b' 86.6%), the
      patients with overt proteinuria (a/a 2.8, a/b 15.8, b/b 81.4, 'a' 10.7, 'b'
      89.3%) and the control group (a/a 1.4, a/b 21.6, b/b 76.8, 'a' 12.8, 'b' 87.7%).
      Logistic regression analysis showed that the ecNOS intron4 a-allele frequency was
      not the related to nephropathy (P = 0.88). CONCLUSION: We conclude that there is
      no association of the ecNOS gene polymorphism with the development of diabetic
      nephropathy in Japanese patients with type 2 diabetes.

PMID- 12413778
TI  - Retinopathy in older patients with diabetes mellitus.
AB  - PURPOSE: We studied the effects of the age and/or disease duration in diabetics
      on the progression of diabetic retinopathy (DR). METHODS: The population
      consisted of 3614 type 2 diabetes mellitus (DM) patients. The subjects were
      divided into three age groups (elderly, > or = 65 years old; middle-aged, 64-40
      years old, and younger < 40 years old) for disease duration-adjusted comparison
      with and without DR and proliferative diabetic retinopathy (PDR). Then, in 503
      patients with 8-year follow-up data available, the frequency of
      development/progression of DR and the rate of progression to PDR were compared
      among the three groups. Thirdly, in the elderly patients, DR prevalence and the
      frequency of the development/progression of DR were compared between two groups
      with different diabetes duration (> or = 6 years and < or = 5 years). RESULTS:
      The prevalence of DR increased significantly with age (P < 0.001). The prevalence
      of PDR decreased significantly with age (P < 0.001). The overall frequency of the
      development and/or progression of DR increased significantly with age (P =
      0.002); however, age was not related to the frequency of progression to PDR. In
      the patients with diabetes duration of 6-15 years, the frequency of the
      development/progression of DR and of progression to PDR after an 8-year follow up
      tended to decrease with age. Elderly patients with a diabetes duration of > or =
      6 years showed significantly higher rate of prevalence of DR and frequency of
      development/progression of DR in an 8-year period than those with diabetes of a
      shorter duration (P < 0.001 and P < 0.001, respectively). CONCLUSION: In elderly
      DM patients, the prevalence of DR was increased even in the short duration and
      development/progression rates of DR were increased, while the relative frequency
      of PDR was decreased. Older-onset DM patients appear to be at a lower risk for
      progression to PDR.

PMID- 12413779
TI  - Effects of insulin resistance and insulin secretion on the efficacy of
      interventions to retard development of type 2 diabetes mellitus: the DA Qing IGT
      and Diabetes Study.
AB  - OBJECTIVE: To investigate the effects of insulin resistance (IR) and insulin
      secretion (IS) on the development of diabetes mellitus in individuals with
      impaired glucose tolerance (IGT) who underwent lifestyle interventions. METHODS:
      284 out of 577 individuals with IGT identified by population-based screening in
      Da Qing, China, who were randomized to undergo diet change and/or increased
      physical activity had baseline fasting and 2 h post-load insulin determinations.
      They were followed for 6 years for the development of diabetes. IR and IS were
      assessed using calculated indices based on fasting plasma insulin and glucose.
      The interactions of IR, IS, obesity and plasma glucose and the effects of the
      lifestyle interventions were evaluated using Cox Proportional Hazards analysis.
      RESULTS: Both IR and IS were significantly associated with the development of
      diabetes. Lifestyle interventions were more effective in those with lower IT and
      higher IS at baseline. Diet plus exercise interventions resulted in significantly
      lower incidence of diabetes, even after controlling for IR, IS, BMI and 2hrPG.
      CONCLUSION: Both IR and beta-cell function were predictors of diabetes in Chinese
      with IGT. Lifestyle intervention reduced the incidence of DM and these
      interventions were more effective in those with less IR.

PMID- 12413780
TI  - Low prevalence of the substitution of adenine to guanine at the 3243 nucleotide
      position of mitochondrial DNA (MtDNA) among Indonesian diabetic subjects.

PMID- 12413781
TI  - Antimicrobial properties of the Escherichia coli R1 plasmid host killing peptide.
AB  - The 52 amino acid host killing peptide (Hok) from the hok/sok post-segregational
      killer system of the Escherichia coli plasmid R1 was synthesized using Fmoc (9
      fluorenylmethoxycarbonyl) chemistry, and its molecular weight was confirmed by
      mass spectroscopy. Hok kills cells by depolarizing the cytoplasmic membrane when
      it is made in the cytosol. Six microorganisms, E. coli, Bacillus subtilis,
      Pseudomonas aeruginosa, P. putida, Salmonella typhimurium, and Staphylococcus
      aureus were exposed to the purified peptide but showed no significant killing.
      However, electroporation of Hok (200 microgml(-1)) into E. coli cells showed a
      dramatic reduction (100000-fold) in the number of cells transformed with plasmid
      DNA which indicates that the synthetic Hok peptide killed cells. Electroporation
      of Hok into P. putida was also very effective with a 500-fold reduction in
      electrocompetent cells (100 microgml(-1)). Heat shock in the presence of Hok (380
      microgml(-1)) resulted in a 5-fold reduction in E. coli cells but had no effect
      on B. subtilis. In addition, three Hok fragments (Hok(1-28), Hok(31-52) and
      Hok(16-52)) killed cells when electroporated into E. coli at 200 microgml(-1)
      (over 1000-fold killing for Hok(1-28), 50-fold killing for Hok(16-52) and over
      1000-fold killing for Hok(31-52)). E. coli cells electroporated with Hok and
      visualized using transmission electron microscopy showed the same morphological
      changes as control cells to which Hok was induced using a plasmid inside the
      cell.

PMID- 12413782
TI  - Plant-cell bioreactors with simultaneous electropermeabilization and
      electrophoresis.
AB  - Experimental investigations on using low-level electric currents and voltages to
      extract, transport, and collect intracellular secondary metabolites from plant
      cells while maintaining their viabilities were conducted focusing on the
      production of: (1) ionic betalains, mainly negatively-charged betanin, from Beta
      vulgaris cells, and (2) ionic alkaloids, particularly positively-charged
      ajmalicine and yohimbine, from Catharanthus roseus cells. Three versions of
      tubular membrane reactors in which electropermeabilization of cell membranes and
      electrophoresis and diffusion of ionic products take place simultaneously, with
      or without convective flow, to achieve desirable extraction were developed.
      Concentrations of secondary metabolites produced from these plant-cell reactors
      under steady and oscillatory electrical forcings were recorded and the
      viabilities of treated cells examined. Oscillatory application of electrical
      field appears to produce more products while retaining higher cell viability.

PMID- 12413783
TI  - Simultaneous nitrification and denitrification by controlling vertical and
      horizontal microenvironment in a membrane-aerated biofilm reactor.
AB  - Nitrogen and carbon components in domestic modified wastewater were completely
      removed by simultaneous nitrification and denitrification using a membrane
      aerated biofilm reactor where biofilm was fixed on a hollow-fiber membrane. To
      measure the spatial distribution of pH, ammonium and nitrate ions and to observe
      microbes inside the biofilm fixed on the membrane, microelectrodes and the
      fluorescence in situ hybridization (FISH) method were applied. Due to plug flow
      in the vertical direction (from the bottom to the top of the reactor), ammonium
      nitrogen was gradually removed and negligible nitrate nitrogen was detected
      throughout the reactor. FISH revealed that ammonia-oxidizing bacteria were mainly
      distributed inside the biofilm and other bacteria, which included denitrifying
      bacteria, were mainly distributed outside the biofilm and over the suspended
      sludge. In order to characterize bacterial activity in the vertical direction of
      the reactor, nitrification rates at lower, central and upper points were
      calculated using microelectrode data. The nitrification rate at the lower point
      was 7 and 125 times higher than those at the central and upper points,
      respectively. These results show that the removal of carbon and nitrogen
      compounds was accomplished efficiently by using various kinds of bacteria
      distributed vertically and horizontally in a single reactor.

PMID- 12413784
TI  - Amplifying the cellular reduction potential of Streptococcus zooepidemicus.
AB  - The valuable pharmaceutical polymer, hyaluronic acid, is produced industrially
      using the gram-positive bacterium Streptococcus zooepidemicus. Synthesis of this
      polymer is a significant energetic burden upon the microorganism hence the native
      NADH oxidase gene was cloned and overexpressed to increase the energy yield of
      catabolism during aerobic cultivation on glucose. Elevated NADH oxidase levels
      led to a decline in lactic acid generation and prevented ethanol formation,
      leaving acetate as the main fermentation product. Biomass yield increased due to
      the energy gained from the formation of acetate. Evaluation of the acetate flux
      control coefficient over a range of NADH oxidase expression levels revealed that
      acetate production was sensitive to the NADH oxidase level. However, at high NADH
      oxidase levels, the acetate flux was mainly influenced by another factor. The
      concomitant excretion of pyruvate at high NADH oxidase levels suggested that the
      flux through the pyruvate dehydrogenase enzyme complex was limiting the
      conversion of pyruvate to acetate.

PMID- 12413785
TI  - Enhanced kefiran production by mixed culture of Lactobacillus kefiranofaciens and
      Saccharomyces cerevisiae.
AB  - In a batch mixed culture of Lactobacillus kefiranofaciens and Saccharomyces
      cerevisiae, which could assimilate lactic acid, cell growth and kefiran
      production rates of L. kefiranofaciens significantly increased, compared with
      those in pure cultures. The kefiran production rate was 36 mg l(-1) h(-1) in the
      mixed culture under the anaerobic condition, which was greater than that in the
      pure culture (24 mg l(-1) h(-1)). Under the aerobic condition, a more intensive
      interaction between these two strains was observed and higher kefiran production
      rate (44 mg l(-1) h(-1)) was obtained compared with that under the anaerobic
      condition. Kefiran production was further enhanced by an addition of fresh medium
      in the fed-batch mixed culture. In the fed-batch mixed culture, a final kefiran
      concentration of 5.41 g l(-1) was achieved at 87 h, thereby attaining the highest
      productivity at 62 mg l(-1) h(-1). Simulation study considered the reduction of
      lactic acid in pure culture was performed to estimate the additional effect of
      coculture with S. cerevisiae. Slightly higher cell growth and kefiran production
      rates in the mixed culture than those expected from pure culture by simulation
      were observed. These results suggest that coculture of L. kefiranofaciens and S.
      cerevisiae not only reduces the lactic acid concentration by consumption but also
      stimulates cell growth and kefiran production of L. kefiranofaciens.

PMID- 12413786
TI  - Integration of production and aqueous two-phase systems extraction of
      extracellular Fusarium solani pisi cutinase fusion proteins.
AB  - Genetic engineering was integrated with the production and purification of
      Fusarium solani pisi cutinases, in order to obtain the highest amount of enzyme
      activity units, after purification. An aqueous two-phase system (ATPS) of
      polyethylene glycol 3350, dipotassium phosphate and whole broth was used for the
      extraction of three extracellular cutinases expressed in Saccharomyces
      cerevisiae. The production/extraction process was evaluated regarding cutinases
      secretion in the medium, partition behaviour and extraction yields in the ATPS.
      The proteins studied were cutinase wild type and two fusion proteins of cutinase
      with the tryptophane-proline (WP) fusion tags, namely (WP)(2) and (WP)(4). The
      (WP)(4) fusion protein enabled a 300-fold increase of the cutinase partition
      coefficient when comparing to the wild type. However, the secretion of the fusion
      proteins was lower than of the wild type cutinase secretion. A batch extraction
      strategy was compared with a continuous extraction in a perforated rotating disc
      contactor (PRDC). The batch and continuous systems were loaded with as much as
      60% (w/w) whole cultivation broth. The continuous extraction strategy provided a
      2.5 higher separation capacity than the batch extraction strategy. Considering
      the integrated process, the cutinase-(WP)(2) proved to lead to the highest
      product activity, enabling five and six times more product activity than the wild
      type and the (WP)(4) fusion proteins, respectively.

PMID- 12413787
TI  - The use of Enterobacter cloacae ATCC 43560 in the development of a two-phase
      partitioning bioreactor for the destruction of hexahydro-1,3,5-trinitro-1,3,5-s
      triazine (RDX).
AB  - Research on the biodegradation of explosives has focussed exclusively on the
      treatment of contaminated soil and water. In the present work the anaerobic
      degradation of hexahydro-1,3,5-trinitro-1,3,5-s-triazine (RDX) by Enterobacter
      cloacae ATCC 43560 was investigated, and a two-phase partitioning bioreactor
      (TPPB) was developed for the destruction of pure, past-date munitions. TPPBs are
      characterized by a cell-containing aqueous phase, and an immiscible and
      biocompatible organic phase into which very large amounts of toxic and/or
      insoluble substrates can be dissolved. Based on equilibrium partitioning, the
      substrate is then transported to the cells, in response to their metabolic
      requirements, providing a means of demand-based substrate delivery, and high
      bioreactor productivity. Through consideration of the critical logP of E.
      cloacae, whether various classes of solvents could be used as sole carbon and
      energy sources, the capacity of various organics to dissolve RDX, and solvent
      cost, 2-undecanone was ultimately selected as the delivery solvent for the TPPB.
      Using this solvent, both batch and fed-batch operation of the TPPB were
      undertaken, and the volumetric degradation rate of RDX was found to be higher in
      this arrangement than any previous values reported in the literature. This work
      has demonstrated the potential of a method for the destruction of decommissioned
      munitions involving the dissolution of RDX in 2-undecanone, the use of the RDX
      rich solvent as the second phase in a TPPB to degrade this explosive, and the
      subsequent recycling and re-use of the solvent.

PMID- 12413788
TI  - Submerged and solid-state production of laccase and Mn-peroxidase by Panus
      tigrinus on olive mill wastewater-based media.
AB  - The possible use of olive-mill wastewater (OMW) as a growth medium for the
      production of extracellular laccase and manganese peroxidase (MnP) from the white
      rot fungus Panus tigrinus (P. tigrinus) CBS 577.79 was studied using a properly
      formulated OMW-based medium (2-fold diluted OMW supplemented with 0.5% sucrose
      and 0.1% yeast extract) either in a stirred-tank or an air-lift reactor. Solid
      state fermentation (SSF) was also performed in a rotary drum reactor using maize
      stalks moistened with the OMW-based medium. Highest levels of laccase and
      manganese peroxidase activity were obtained in the stirred-tank reactor (4600+/
      98 U l(-1) on day 13) and in the air-lift reactor (410+/-22 on day 7),
      respectively. Based on total enzyme activities, SSF appears to be more suitable
      than LSF but the latter exhibits better volumetric productivities.

PMID- 12413789
TI  - Microcystin-LR alters the growth, anthocyanin content and single-stranded DNase
      enzyme activities in Sinapis alba L seedlings.
AB  - Seedlings of the white mustard (Sinapis alba L.) are sensitive to the cell-free
      extracts of a toxigenic strain of Microcystis aeruginosa and to microcystin-LR.
      Fresh mass of plants, plant length, including hypocotyl and root length and
      lateral root formation is inhibited in microcystin-LR treated seedlings. The
      decrease of anthocyanin content is obtained in microcystin treated mustard
      cotyledons. The tissue necrosis of cotyledons is a characteristic consequence of
      microcystin treatment. Microcystin-LR induces an increase in single stranded
      deoxyribonucleases (ssDNases) activity of S. alba seedlings as shown by
      spectrophotometric assays and by ssDNase activity polyacrylamide gels. The
      significance of this phenomenon is discussed in relation to general stress
      responses in plants. We conclude that microcystin-LR affects the whole physiology
      and the growth of plants.

PMID- 12413790
TI  - The ecological effects of naphthenic acids and salts on phytoplankton from the
      Athabasca oil sands region.
AB  - To better elucidate the ecological effects of naphthenic acids and major ions
      liberated in oil sands development, the summer-time composition of phytoplankton
      communities in ten water bodies near Fort McMurray (northeastern Alberta) was
      studied in 1997. The water bodies varied in degree of process water influence,
      and in age, size and ancillary chemical characteristics. Community biomass of
      phytoplankton was not systematically related to naphthenic acid or major ion
      concentrations, even though the higher naphthenate concentrations exceeded
      published EC50's for acute effects on several different aquatic species.
      Chlorophyta were frequently dominant, particularly where naphthenate and major
      ion concentrations were highest. Canonical Correspondence Analysis (CCA) revealed
      gradients in taxonomic composition at a finer (genus and species) taxonomic
      level. Despite the simultaneous and uncontrolled variation of other environmental
      factors, naphthenate and major ion concentrations (as indexed by conductivity)
      explained a highly-significant 40% of the variation in taxonomic composition.
      Systems with naphthenates <6.5 mg l(-1) and conductivity <800 PhiS cm(-1) were
      clustered together near the origin of the CCA plots, suggesting little ecological
      effect at such concentrations. Taxa associated with elevated naphthenate and/or
      major ion concentrations were derived from six different algal divisions and
      included many that were identified as tolerant in previous bioassay experiments.
      Over the range of concentrations encountered (1.5-45 and 100-3000 mg l(-1) for
      naphthenates and ions, respectively), CCA indicated that the ecological effect of
      major ions appeared to be at least as great as that of naphthenates.

PMID- 12413791
TI  - Inhibition of cytochrome p450 enzymes by enrofloxacin in the sea bass
      (Dicentrarchus labrax).
AB  - Currently, there are no reports on the effects of enrofloxacin (EF), a
      fluoroquinolone antibiotic, on the cytochrome p450 enzymes in fish, although its
      use as antimicrobial agent in aquaculture has been put forward. Therefore, the in
      vivo and in vitro effects of EF on hepatic p450 enzymes of sea bass, a widespread
      food-producing fish, have been evaluated. Sea bass pretreated with a single dose
      of EF (3 mg/kg i.p.) or with three daily doses of EF (1 mg/kg i.p.) markedly
      depressed the microsomal N-demethylation of aminopyrine, erythromycin, the O
      deethylation of 7-ethoxycoumarin, ethoxyresorufin and the 6beta-testosterone
      hydroxylase. In vitro experiments showed that EF at 10 microM inhibited the above
      mentioned activities and, in particular, the erythromycin N-demethylase (ERND)
      and 6beta-testosterone-hydroxylase, likely dependant on a p450 3A isoform. When
      the nature of ERND inhibition by EF was specifically studied with sea bass liver
      microsomes, it was found that EF is a potent mechanism-based inhibitor, with K(i)
      of 3.7 microM and a K(inact) of 0.045 min(-1). An immunoblot analysis with anti
      p450 3A27 of trout showed that the p450 3A isoform, constitutively expressed in
      sea bass, is particularly susceptible to inactivation by EF. In vitro experiments
      with sea bass microsomes have also demonstrated that EF is oxidative deethylated
      by the p450 system to ciprofloxacin (CF) and that this compound maintains the
      ability to inactivate the p450 enzymes. The mechanism by which EF or CF
      inactivate the p450 enzymes has not been studied but an attack of p450 on the
      cyclopropan ring, present, both in EF and CF structure, with the formation of
      electrophilic intermediates (i.e. radicals) has been postulated. In conclusion,
      the EF seems to be a powerful inhibitor of p450s in the sea bass. Therefore, the
      clinical use of this antibiotic in aquaculture has to be considered with caution.

PMID- 12413792
TI  - Long-term effect of Sea-Nine on natural coastal phytoplankton communities
      assessed by pollution induced community tolerance.
AB  - Sea-Nine211 has been introduced as a new biocide in antifouling paints with an
      immediate degradation when it is released from ship hulls. The active component
      of Sea-Nine211 is 4,5-dichloro-2-n-octyl-isothiazoline-3-one (DCOI). In the
      present study, the toxicity of DCOI and the occurrence of Pollution Induced
      Community Tolerance (PICT) were tested in microcosms containing eutrophic coastal
      water with its natural composition of phytoplankton. The experiment was performed
      in closed systems with a single addition of the nominal concentrations 0, 3.2,
      10, 32 and 100 nM DCOI, for a period of 16 days. Pollution induced community
      tolerance (PICT) was observed in the phytoplankton communities exposed to the
      nominal concentrations 32 and 100 nM DCOI. Chemical analysis of DCOI in the
      coastal water utilised in the toxicity and PICT experiment was performed by GC-MS
      using a solid- phase extraction method. Half-life was calculated to be 2.5 days
      for the nominal concentrations 32 and 100 nM DCOI. The results of the present
      study show that nominal concentrations of 32 and 100 nM DCOI significantly
      increased the community tolerance already after 2 days of exposure and that the
      tolerance was maintained for a period of 16 days even when DCOI was degraded
      during this period. The causes for the persistent tolerance are discussed in
      relation to the degradation of DCOI and structural changes in the phytoplankton
      communities.

PMID- 12413793
TI  - Dehydroabietic acid, a major component of wood industry effluents, interferes
      with cellular energetics in rainbow trout hepatocytes.
AB  - We studied the effects of dehydroabietic acid (DHAA), a major toxic resin acid in
      wood industry effluents, on cellular energetics in rainbow trout (Oncorhynchus
      mykiss) hepatocytes. In addition, the role of DHAA-induced change in
      intracellular Ca(2+) in the energetic responses of the cells was evaluated. At
      sublytic concentrations, DHAA caused a reduction in cellular ATP content and a
      concomitant enhancement of glycolytic activity of the cells in a dose-dependent
      manner. No further decrease of cellular ATP content occurred after 60 min of DHAA
      treatment indicating establishment of new energetic steady state in cells. DHAA
      also caused a rapid dose-dependent increase in oxygen consumption and in cellular
      heat production of the hepatocytes. The effect of DHAA on ATP content and
      glycolytic activity was independent from Ca(2+), whereas, changes in oxygen
      consumption and heat production were Ca(2+) -dependent. These results show that
      DHAA induces energetic imbalance in rainbow trout hepatocytes, which is
      apparently not due to direct interference of DHAA with ATP production nor does it
      seem to be caused by an indirect effect of elevated intracellular Ca(2+)
      concentration on mitochondrial energetics. Therefore, the ATP depletion is likely
      due to increased cellular ATP consumption caused by amphiphilic action of DHAA on
      the cell membrane.

PMID- 12413794
TI  - Cd2+ and Hg2+ affect glucose release and cAMP-dependent transduction pathway in
      isolated eel hepatocytes.
AB  - Isolated hepatocytes of the European eel (Anguilla anguilla) have been used as
      experimental model to characterize the effects of Cd(2+) and Hg(2+) on either
      basal or epinephrine-stimulated glucose release. Cd(2+) strongly reduced glucose
      output from cells perifused in BioGel P4 columns and challenged with epinephrine,
      with a maximum inhibition of 95% reached at 10 microM (IC(50) 0.04 microM). The
      epinephrine-stimulated glucose output was also reduced by Hg(2+), although a
      significant inhibition of about 60% was achieved only at 10 microM (IC(50) 5
      microM). The possible influence of Cd(2+) and Hg(2+) on adenylyl cyclase/cAMP
      transduction pathway has been investigated, since this system is known to play a
      pivotal role in the regulation of fish liver glycogen breakdown and consequent
      glucose release. Micromolar concentrations of both heavy metals significantly
      reduced the epinephrine-modulated cAMP levels in isolated eel hepatocytes, in
      good agreement with the reduction of glucose output. Cd(2+) and Hg(2+) also
      significantly reduced basal and epinephrine-stimulated adenylyl cyclase activity
      in liver membrane preparations. A competitive inhibition with respect to Mg(2+)
      was shown by Cd(2+) and Hg(2+), which significantly reduced the affinity of the
      allosteric activator for the adenylyl cyclase system. Apparent Km for Mg(2+) was
      4.35 mM in basal conditions, and increased to 9.1 and 7.1 mM in the presence of
      10 microM Cd(2+) and Hg(2+), respectively. These results indicate that Cd(2+) and
      Hg(2+) may impair a crucial intracellular transduction pathway involved in the
      adrenergic control of glucose metabolism, but also in several other routes of
      hormonal regulation of liver functions.

PMID- 12413795
TI  - Quantitative PCR analysis of CYP1A induction in Atlantic salmon (Salmo salar).
AB  - Environmental pollutants are hypothesized to be one of the causes of recent
      declines in wild populations of Atlantic salmon (Salmo salar); across Eastern
      Canada and the United States. Some of these pollutants, such as polychlorinated
      biphenyls and dioxins, are known to induce expression of the CYP1A subfamily of
      genes. We applied a highly sensitive technique, quantitative reverse
      transcription-polymerase chain reaction (RT-PCR), for measuring the levels of
      CYP1A induction in Atlantic salmon. This assay was used to detect patterns of
      CYP1A mRNA levels, a direct measure of CYP1A expression, in Atlantic salmon
      exposed to pollutants under both laboratory and field conditions. Two groups of
      salmon were acclimated to 11 and 17 degrees C, respectively. Each subject then
      received an intraperitoneal injection (50 mg kg(-1)) of either beta
      naphthoflavone (BNF) in corn oil (10 mg BNF ml(-1) corn oil) or corn oil alone.
      After 48 h, salmon gill, kidney, liver, and brain were collected for RNA
      isolation and analysis. All tissues showed induction of CYP1A by BNF. The highest
      base level of CYP1A expression (2.56 x 10(10) molecules/microg RNA) was found in
      gill tissue. Kidney had the highest mean induction at five orders of magnitude
      while gill tissue showed the lowest mean induction at two orders of magnitude.
      The quantitative RT-PCR was also applied to salmon sampled from two streams in
      Massachusetts, USA. Salmon liver and gill tissue sampled from Millers River
      (South Royalston, Worcester County), known to contain polychlorinated biphenyls
      (PCBs), showed on average a two orders of magnitude induction over those
      collected from a stream with no known contamination (Fourmile Brook, Northfield,
      Franklin County). Overall, the data show CYP1A exists and is inducible in
      Atlantic salmon gill, brain, kidney, and liver tissue. In addition, the results
      obtained demonstrate that quantitative PCR analysis of CYP1A expression is useful
      in studying ecotoxicity in populations of Atlantic salmon in the wild.

PMID- 12413796
TI  - The dance of the clams: twists and turns in the family C GPCR homodimer.

PMID- 12413797
TI  - Antimicrobial peptides from animals: focus on invertebrates.

PMID- 12413798
TI  - Comfrey toxicity revisited.

PMID- 12413804
TI  - Disease genes: flattery and deception.
AB  - Completion of the human genome project raises the possibility of genetically
      based treatments for a multitude of human diseases. As yet only a handful of
      patients have benefited clinically from this approach. Why gene transfer is such
      a complex issue is discussed in this article. Theoretically, the easiest diseases
      to treat are single gene recessive diseases, where, presumably, gene delivery to
      somatic cells is all that is required. Two prime candidates for gene therapy are
      severe combined immunodeficiency disease (SCID) and cystic fibrosis (CF).
      Attempts to treat both of these diseases by gene therapy commenced in the late
      1980s. Some clinical benefit has been recorded with SCID, but none, as yet, has
      been recorded with CF.

PMID- 12413805
TI  - beta-Subunits: fine tuning of Ca(2+) channel block.
AB  - Ca(2+) channel blockers such as 1,4-dihydropyridines, phenylalkylamines,
      diltiazem and mibefradil exert their anti-arrhythmic and anti-hypertensive action
      by restricting Ca(2+) entry into myocardial cells and smooth muscle cells.
      Binding sites for these drugs are present on the pore-forming alpha(1)-subunits
      of voltage-dependent Ca(2+) (Ca(v)) channels. However, striking new data show
      that auxillary beta-subunits also influence drug sensitivity significantly. These
      findings are summarized and the underlying molecular mechanisms and their
      pharmacological relevance are discussed.

PMID- 12413806
TI  - Models and methods for studying insurmountable antagonism.
AB  - Insurmountable antagonists depress the concentration-response curves of
      subsequently added agonists. The longevity of the antagonist-receptor complex and
      the existence of allosteric binding sites are the most frequent explanations for
      this phenomenon. Yet, observed antagonist behaviour often depends on the tissue,
      the animal species, the duration of the measured response and the study design.
      Intact cell studies allow greater flexibility and tighter control of the
      experimental conditions and therefore have the potential to offer a better
      insight into the molecular basis of insurmountable antagonism.

PMID- 12413807
TI  - Modulation of glycine receptor function: a novel approach for therapeutic
      intervention at inhibitory synapses?
AB  - Transmitter-gated ion channels mediate rapid synaptic transmission in the CNS and
      constitute important targets for many neuroactive drugs. Inhibitory glycine
      receptors (GlyRs) are members of the nicotinic acetylcholine receptor superfamily
      and inhibit neuronal firing by opening Cl(-) channels following agonist binding.
      In this article, we discuss recent developments in GlyR pharmacology, delineate
      the receptor domains that are involved in binding of agonists and allosteric
      modulators, and present a molecular model of the extracellular architecture of
      the receptor. The recent discovery of compounds that act preferentially on
      specific GlyR isoforms and the differential expression of these isoforms in
      distinct regions of the developing and adult CNS show considerable promise
      towards the development of drugs that act in defined glycine-mediated pathways.
      In particular, compounds that can potentiate GlyR function should provide leads
      for novel muscle relaxants in addition to sedative and analgesic agents.

PMID- 12413808
TI  - Estrogen and cognitive aging in women.
AB  - The steady increase in female life expectancy has attracted attention to the
      importance of preventing cognitive aging and Alzheimer's disease (AD) in women.
      Evidence from randomized, controlled trials and from cross-sectional and
      longitudinal studies shows that estrogen-replacement therapy preferentially
      protects against a decline in verbal memory in healthy postmenopausal women and
      decreases the risk of AD. Although results are not consistent across studies,
      they indicate that treatment with estrogen during the postmenopausal years might
      protect against cognitive aging in women during the latter part of their life.

PMID- 12413809
TI  - G-protein-coupled receptor websites.

PMID- 12413811
TI  - Reverse engineers map the molecular switching yards.

PMID- 12413815
TI  - Tagging life's ups and downs.

PMID- 12413817
TI  - Models of intellectual property.

PMID- 12413818
TI  - Bioremediation meets biomedicine: therapeutic translation of microbial catabolism
      to the lysosome.
AB  - Lysosomal degradation of damaged macromolecules is imperfect: many cell types
      accumulate lysosomal aggregates with age. Some such deposits are known, or are
      strongly suspected, to cause age-related disorders such as atherosclerosis and
      neurodegeration. It is possible that they also influence the rate of aging in
      general. Lysosomal degradation involves extensive cooperation between the
      participating enzymes: each generates a substrate for others until breakdown of
      the target material to recyclable units (such as amino acids) is complete. Hence,
      the age-related accumulation of lysosomal aggregates might be markedly retarded,
      or even reversed, by introducing just a few bacterial or fungal enzymes 
      'xenohydrolases' - that can degrade molecules that our natural machinery cannot.
      This article examines the feasibility and biomedical potential of such lysosomal
      enhancement as an approach to retarding or treating age-related physiological
      decline and disease.

PMID- 12413819
TI  - Intellectual property protection of plant biotechnology inventions.
AB  - The intellectual property protection of biotechnology-related subject matter is
      undergoing significant change and several countries have revised their
      legislation and/or patent practice as a result of challenges from industry and
      members of the public. Plant-related subject matter can be protected using plant
      variety protection, utility patents or, in the USA, by plant patent. Although
      easier to obtain than a utility patent, plant variety protection does not provide
      the same scope of protection. Protecting a plant using a utility patent is
      permitted only in countries that allow the patenting of higher life forms and
      requires a higher degree of experimental support than is required for plant
      variety protection, although the scope of protection is being steadily reduced.

PMID- 12413820
TI  - In vivo-applied functional RNAs as tools in proteomics and genomics research.
AB  - Non-natural, functional RNA molecules, such as short interfering (si) RNAs,
      aptazymes, maxizymes and intramers, allow modulation of gene function at the mRNA
      or protein level. This review discusses recent advances made in the expression
      and application of these functional RNAs and illustrates how engineered,
      intracellularly active RNAs can serve as promising tools for understanding the
      function of genes and their protein products or as potential therapeutic agents.

PMID- 12413821
TI  - Gene networks: how to put the function in genomics.
AB  - An increasingly popular model of regulation is to represent networks of genes as
      if they directly affect each other. Although such gene networks are
      phenomenological because they do not explicitly represent the proteins and
      metabolites that mediate cell interactions, they are a logical way of describing
      phenomena observed with transcription profiling, such as those that occur with
      popular microarray technology. The ability to create gene networks from
      experimental data and use them to reason about their dynamics and design
      principles will increase our understanding of cellular function. We propose that
      gene networks are also a good way to describe function unequivocally, and that
      they could be used for genome functional annotation. Here, we review some of the
      concepts and methods associated with gene networks, with emphasis on their
      construction based on experimental data.

PMID- 12413822
TI  - Genetically tailored grapevines for the wine industry.
AB  - Grapevine biotechnology is one of the most promising developments in the global
      wine industry, which is increasingly faced with conflicting demands from markets,
      consumers and environmentalists. In the grapevine industries, this technology and
      its supporting disciplines entail the establishment of stress tolerant and
      disease resistant varieties of Vitis vinifera, with increased productivity,
      efficiency, sustainability and environmental friendliness, especially regarding
      improved pest and disease control, water use efficiency and grape quality. The
      implementation and successful commercialisation of genetically improved grapevine
      varieties will only be realized if an array of hurdles, both scientific and
      otherwise, can be overcome.

PMID- 12413823
TI  - Nonhuman primate transgenesis: progress and prospects.
AB  - The nonhuman primate is used extensively in biomedical research owing to its
      close similarities to human physiology and human disease pathophysiology.
      Recently, several groups have initiated efforts to genetically manipulate
      nonhuman primates to address complex questions concerning primate-specific
      development and physiological adaptation. Primates pose unique challenges to
      transgenesis and, although this field is still in its infancy, the potential for
      obtaining new insights into primate physiology and gene function is
      unprecedented. This review focuses on the methods and potential applications of
      genetically altered nonhuman primates in biomedical research.

PMID- 12413824
TI  - Profile - Robert Jackson interviewed by Suzanne Berry.

PMID- 12413826
TI  - Design and synthesis of novel imidazole derivatives as potent inhibitors of
      allene oxide synthase(CYP74).
AB  - Allene oxide synthase (AOS) is a key enzyme in the oxylipin pathway in plants
      leading to jasmonic acid and other jasmonates (JAs), important signal mediators
      of defense signal networks in plants. AOS uses hydroperoxylinolenic acid as an
      oxygen donor as well as the substrate, thus the biochemical conversion of 13(S)
      hydroperoxylinolenic acid to allene oxide can proceed in the absence of oxygen
      and NADPH. We have designed the synthesized of a series of novel imidazole
      derivatives and tested them in a bioassay as AOS inhibitors using a purified
      recombinant AOS enzyme isolated from Arabidopsis and expressed in E. coli. Among
      the derivatives prepared, heptyl 8-[1-(2,4-dichlorophenyl)-2
      imidazolylethoxy]octanoate (k) was found to be the most potent inhibitor, with an
      IC(50) of 10+/-5 nM, which is 250,000-fold and 1,000,000-fold more potent than
      the known AOS inhibitors, acetylsalicyclic acid (2.5 mM) and ketoconazole (10
      mM), respectively.

PMID- 12413827
TI  - 2D-QSAR in hydroxamic acid derivatives as peptide deformylase inhibitors and
      antibacterial agents.
AB  - Peptide deformylase catalyzes the removal of N-formyl group from the N
      formylmethionine of ribosome synthesized polypeptide in eubacteria. Quantitative
      structure-activity relationship (QSAR) studies have been carried out in a series
      of beta-sulfonyl and beta-sulfinyl hydroxamic acid derivatives for their PDF
      enzyme inhibitory and antibacterial activities against Escherichia coli DC2 and
      Moraxella catarrhalis RA21 which demonstrate that the PDF inhibitory activity in
      cell free and whole cell system increases with increase in molar refractivity and
      hydrophobicity. The comparison of the QSARs between the cell free and whole cell
      system indicate that the active binding sites in PDF isolated from E. coli and in
      M. catarrhalis RA21 are similar and the whole cell antibacterial activity is
      mainly due to the inhibition of PDF. Apart from this the QSARs on some
      matrixmetelloproteins (COL-1, COL-3, MAT and HME) and natural endopeptidase (NEP)
      indicate the possibilities of introducing selectivity in these hydroxamic acid
      derivatives for their PDF inhibitory activity.

PMID- 12413828
TI  - Synthesis of 3-alkyl(aryl)-4-alkylidenamino-4,5-dihydro-1H-1,2,4-triazol-5-ones
      and 3-alkyl-4-alkylamino-4,5-dihydro-1H-1,2,4-triazol-5-ones as antitumor agents.
AB  - A series of 3-alkyl-4-phenylethylidenamino- (8) and 3-alkyl-4-(3
      phenylallylidenamino)-4,5-dihydro-1H-1,2,4-triazol-5-ones (9) was synthesized
      from the reaction of the corresponding 3-alkyl(aryl)-4-amino-4,5-dihydro-1H-1,2,4
      triazol-5-ones (1), with phenylacetaldehyde and cinnamaldehyde. 3-Alkyl-4-(2
      phenylethylamino)- (10) and 3-alkyl-4-(3-phenylpropylamino)-4,5-dihydro-1H-1,2,4
      triazol-5-ones (11) were obtained from the selective reduction of compounds (8)
      and (9) with NaBH(4). The in vitro antitumor activity of the novel compounds was
      screened and the highest inhibition of tree tumor cell lines was observed for the
      compounds containing phenylethylenamino and phenylethylamino groups at position 4
      of 1,2,4-triazol ring.

PMID- 12413829
TI  - Xanthones as inhibitors of growth of human cancer cell lines and their effects on
      the proliferation of human lymphocytes in vitro.
AB  - Twenty-seven oxygenated xanthones have been assessed for their capacity to
      inhibit in vitro the growth of three human cancer cell lines, MCF-7 (breast
      cancer), TK-10 (renal cancer) and UACC-62 (melanoma). The effect of these
      xanthones on the proliferation of human T-lymphocytes was also evaluated.
      Differences on their potency towards the effect on the growth of the human cancer
      cell lines as well as on the proliferation of human T-lymphocytes can be ascribed
      to the nature and positions of the substituents on the xanthonic nucleus.

PMID- 12413830
TI  - Design, synthesis, conformational analysis, and biological studies of urotensin
      II lactam analogues.
AB  - Human urotensin II (hU-II; H-Glu-Thr-Pro-Asp-cyclo[Cys-Phe-Trp-Lys-Tyr-Cys]-Val
      OH) is a disulfide bridged undecapeptide recently identified as the ligand of an
      orphan G protein-coupled receptor. hU-II has been described as the most potent
      vasoconstrictor compound identified to date. With the aim of replacing the
      disulfide bridge by a chemically more stable moiety, we have synthesized and
      tested a series of lactam analogues of hU-II minimum active fragment, that is hU
      II(4-11). The contractile activity of the synthetic analogues on the rat isolated
      thoracic aorta was found to be dependent upon the dimension of the lactam bridge.
      The most active peptide, H-Asp-cyclo[Orn-Phe-Trp-Lys-Tyr-Asp]-Val-OH (3), is
      approximately 2 logs less potent than hU-II (pD(2)=6.3 vs 8.4). A conformational
      analysis in solution of the active peptide 3, one of the inactive analogues, and
      hU-II was performed, using NMR and molecular modelling techniques. A
      superposition of the calculated structures of hU-II and 3 clearly shows that
      three out of four key residues (i.e., Phe(6), Lys(8) and Tyr(9)) maintain the
      same side- chain orientation, while the fourth one, Trp(7), cannot be
      superimposed. This observation could explain the reduced biological activity of
      the synthetic analogue.

PMID- 12413831
TI  - Binding affinity prediction of novel estrogen receptor ligands using receptor
      based 3-D QSAR methods.
AB  - We have recently reported the development of a 3-D QSAR model for estrogen
      receptor ligands showing a significant correlation between calculated molecular
      interaction fields and experimentally measured binding affinity. The ligand
      alignment obtained from docking simulations was taken as basis for a comparative
      field analysis applying the GRID/GOLPE program. Using the interaction field
      derived with a water probe and applying the smart region definition (SRD)
      variable selection procedure, a significant and robust model was obtained
      (q(2)(LOO)=0.921, SDEP=0.345). To further analyze the robustness and the
      predictivity of the established model several recently developed estrogen
      receptor ligands were selected as external test set. An excellent agreement
      between predicted and experimental binding data was obtained indicated by an
      external SDEP of 0.531. Two other traditionally used prediction techniques were
      applied in order to check the performance of the receptor-based 3-D QSAR
      procedure. The interaction energies calculated on the basis of receptor-ligand
      complexes were correlated with experimentally observed affinities. Also ligand
      based 3-D QSAR models were generated using program FlexS. The interaction energy
      based model, as well as the ligand-based 3-D QSAR models yielded models with
      lower predictivity. The comparison with the interaction energy-based model and
      with the ligand-based 3-D QSAR models, respectively, indicates that the
      combination of receptor-based and 3-D QSAR methods is able to improve the quality
      of prediction.

PMID- 12413832
TI  - Highly potent inhibitors of TNF-alpha production. Part I: discovery of new
      chemical leads and their structure-activity relationships.
AB  - Discovery of new chemical leads of inhibitors for TNF-alpha production starting
      from the chemical modification of 1 is reported. Further biological studies of 1
      to disclose the site of its action strongly suggested that 1 inhibits LPS-induced
      TNF-alpha expression in the liver and spleen of mice. Structure-activity
      relationships (SARs) are also discussed and full details including the chemistry
      are reported.

PMID- 12413833
TI  - Highly potent inhibitors of TNF-alpha production. Part II: metabolic
      stabilization of a newly found chemical lead and conformational analysis of an
      active diastereoisomer.
AB  - Design and synthesis of metabolically stabilized inhibitors of TNF-alpha
      production, which could be new drug candidates, are reported. Conformational
      analysis of an active diastereoisomer was performed based on biological
      evaluations of the conformationally fixed indane derivatives 17 and 18. Structure
      activity relationships (SARs) based on biological evaluations of the optically
      active derivatives are also discussed. Full details including chemistry are
      reported.

PMID- 12413834
TI  - Discovery of novel phosphonic acid derivatives as new chemical leads for
      inhibitors of TNF-alpha production.
AB  - 2-(Acylamino)benzylphosphonic acid 6 derived from an artificial substrate of
      sphingomyelinase was found to show inhibitory activity of TNF-alpha production.
      Structural optimization was started with the chemical modification of 6. The
      discovery of another chemical leads 7, 8, 10 and 16 for the development of
      structurally new inhibitors of TNF-alpha production is reported.

PMID- 12413835
TI  - Synthesis and pharmacological evaluation of new arylpiperazines. 3-[4-[4-(3
      chlorophenyl)-1-piperazinyl]butyl]-quinazolidin-4-one - a dual serotonin 5
      HT(1A)/5-HT(2A) receptor ligand with an anxiolytic-like activity.
AB  - On the basis of systematic studies on the structure-activity relationships in
      arylpiperazine group of serotonin ligands, 12 new derivatives containing
      quinazolidin-4(3H)-one (1-4), 2-phenyl-2,3-dihydrophthalazine-1,4-dione (5-8) or
      1-phenyl-1,2-dihydropyridazine-3,6-dione (9-12) fragments were synthesized. The
      majority of the tested compounds (2, 4, 7, 8 and 10-12) showed a high affinity
      for 5-HT(1A) receptors (K(i)=11-54 nM) and two (1, 2) were found active at 5
      HT(2A) sites (16 and 68 nM, respectively). All the new 5-HT(1A) ligands tested in
      vivo revealed an antagonistic activity at postsynaptic 5-HT(1A) receptors, and
      three of them behaved as agonists at presynaptic ones. Additionally, both the
      meta-chlorophenylpiperazine derivatives containing quinazolidin-4-one fragment
      showed features of 5-HT(2A) receptor antagonists. The dual 5-HT(1A)/5-HT(2A)
      receptor ligand (2) was further tested for its potential psychotropic activity.
      It showed a distinct anxiolytic-like activity in a conflict drinking test in rats
      and the observed effect was more potent in terms of the active dose, than that
      produced by diazepam (used as a reference drug).

PMID- 12413836
TI  - Synthesis of derivatives of (1S,2R)-1-phenyl-2-[(S)-1-aminopropyl]-N,N
      diethylcyclopropanecarboxamide (PPDC) modified at the 1-aromatic moiety as novel
      NMDA receptor antagonists: the aromatic group is essential for the activity.
AB  - (1S,2R)-1-Phenyl-2-[(S)-1-aminopropyl]-N,N-diethylcyclopropanecarboxamide (PPDC,
      4a), which is a conformationally restricted analogue of antidepressant
      milnacipran [(+/-)-1], is a new class of potent noncompetitive NMDA receptor
      antagonists. A series of PPDC analogues modified at the 1-phenyl moiety, that is,
      the analogue 6 lacking 1-phenyl group, the 1-(fluorophenyl) analogues 4b,c,d, the
      1-(methylphenyl) analogues 4e-g and the 1-(naphthyl) analogues 4h,i were
      synthesized. Analogue 6, lacking the 1-phenyl group, was completely inactive
      showing that the aromatic moiety is essential for the NMDA receptor binding.
      Among the analogues synthesized, the 1-o-fluorophenyl and 1-m-fluorophenyl
      analogues 4b and 4c showed potent affinities for the NMDA receptor [IC(50)=0.16+/
      0.001 microM (4b), 0.15+/-0.02 microM (4c)], which were improved to some extent
      compared to those of the parent compound PPDC (IC(50)=0.20+/-0.02 microM). On the
      other hand, compounds 4b and 4c showed none of the 5-HT-uptake inhibitory effect,
      while PPDC turned out to be a weak 5-HT-uptake inhibitor.

PMID- 12413837
TI  - Synthesis and biological studies of novel neurotensin(8-13) mimetics.
AB  - Novel neurotensin (NT) (8-13) (Arg(8)-Arg(9)-Pro(10)-Tyr(11)-Ile(12)-Leu(13))
      mimetics 3, 4 were designed by adopting all intrinsic functional groups of the
      native neurotensin(8-13) and using a substituted indole as a template to mimic
      the pharmacophore of NT(8-13). Biological studies at subtype 1 of the NT receptor
      showed that 3 has a 55 and 580 nM binding affinity at rat and human neurotensin
      receptors, respectively. As a comparison, compounds 5 and 6 were also
      synthesized. The binding difference between 3, 4 and 5, 6 argues the importance
      of the carboxylic group in achieving higher potency NT(8-13) mimetics.

PMID- 12413838
TI  - Synthesis, conformation and T-helper cell stimulation of an O-linked glycopeptide
      epitope containing extended carbohydrate side-chains.
AB  - To answer the question whether or not T cells to immunodominant protein fragments
      recognize glycosylated antigens, we synthesized a series of glycopeptides
      corresponding to peptide 31D, a major T-helper cell epitope of the rabies virus
      nucleoprotein. Thr4 of the epitope is known to allow mono- or disaccharide side
      chain substitutions in either alpha- or beta-anomeric configuration without
      interfering with MHC-binding. To model naturally occurring glycoprotein fragments
      that carry extended sugar chains, we prepared Fmoc-Ser/Thr-OPfp building blocks
      containing alpha- and beta-linked linear tri- and heptasaccharides. Peptide 31D
      was synthesized with the complex carbohydrates attached to Thr4, and the T-helper
      cell activity of the glycopeptides was determined. Addition of alpha-linked
      carbohydrates, that mimic most of the natural O-linked glycoproteins, resulted in
      a major drop in the T-cell stimulatory ability in a sugar length-dependent
      manner. In contrast, the cytosolic glycoprotein mimicking beta-linked
      glycopeptides retained their T-cell stimulatory activity, with the trisaccharide
      containing analogue being almost as potent as the unglycosylated peptide. When
      the peptides were preincubated with diluted human serum, all peptides lost their
      ability to stimulate the 9C5.D8-H hybridoma. These findings indicated that (i) in
      contrast to cytosolic glycosylation, incorporation of long O-linked carbohydrates
      into T-helper cell epitopes abrogates the antigenicity of these protein
      fragments, and (ii) glycosylation is not a viable alternative to improve the
      immunogenic properties of subunit peptide vaccines. Glycosylation with all four
      carbohydrate moieties similarly destroyed the inducible alpha-helical structure
      of peptide 31D as detected by CD, indicating that the differences in the T-cell
      activity were not due to different peptide conformations.

PMID- 12413839
TI  - Combining molecular modeling with experimental methodologies: mechanism of
      membrane permeation and accumulation of ofloxacin.
AB  - The interaction between ofloxacin, as a model drug of the fluoroquinolone class,
      and biomembranes was examined as the possible initial step in a transmembrane
      diffusion process. Dipalmitoylphosphatidylcholine was used for the preparation of
      biomembrane models. The influence of environmental conditions and protonation on
      molecular physicochemical behavior, and hence on the membrane interaction, was
      investigated by differential scanning calorimetry (DSC). This technique has been
      shown to be very effective in the interpretation of interactions of drug
      microspeciations with biomembranes. These findings suggest that the interaction
      occurred owing to ionic and hydrophobic forces showing how the passage through
      the membrane is mainly favored in the pH interval 6-7.4. It was demonstrated that
      a pH gradient through model membranes may be responsible for a poorly homogeneous
      distribution of ofloxacin (or other related fluoroquinolones), which justifies
      the in vivo accumulation properties of this drug. DSC experiments, which are in
      agreement with computational data, also showed that the complexing capability of
      ofloxacin with regard to Mg(++) or Ca(++) may govern the drug entrance into
      bacterial cells before the DNA Girase inhibition and could ensure the formation
      of hydrophobic and more fluid phospholipid domains on the surface of the model
      membrane. These regions are more permeable with regard to various solutes, as
      well as ofloxacin, allowing a so-called 'self-promoted entrance pathway'. The
      combination of experimental methodologies with computational data allowed a
      further rationalization of the results and opened new perspectives into the
      mechanism of action of ofloxacin, namely its interaction with lipid bilayers and
      drug-divalent cation complex formation, which might be extended to the entire
      fluoroquinolone class. Ofloxacin accumulation within Escherichia coli ATCC 25922
      was measured as a function of time. Also in this example, the environmental
      conditions influenced ofloxacin penetration and accumulation. The in vitro
      experiments, reported here, show that a suitable balance of hydrophilic and
      hydrophobic fluoroquinolone properties needs to occur for there to be increased
      drug permeation.

PMID- 12413840
TI  - The product of the natural reaction catalyzed by 4-oxalocrotonate tautomerase
      becomes an affinity label of its mutant.
AB  - 4-Oxalocrotonate tautomerase (4-OT) catalyzes the isomerization of 4
      oxalocrotonate, 1, to 2-oxo-3E-hexenedioate, 3, using a general acid/base
      mechanism that involves a conserved N-terminal proline residue. The P1A and P1G
      mutants have been shown to catalyze this isomerization but at reduced rates.
      Analysis of these mutants by mass spectrometry demonstrated that P1A is
      susceptible to a 1,4-addition of the N-terminal primary amine across the double
      bond of enone 3 to form a covalent adduct. Although slower than the isomerization
      reaction, the addition is fast, with 50% of the active sites being alkylated
      within 12 min. By contrast, the wt4-OT shows no detectable modification over 24
      h. These results support the hypothesis that avoidance of nucleophilic reactions,
      such as the irreversible Michael addition to the product, could be a contributing
      factor in the evolutionary conservation of N-terminal proline residues in 4OT.

PMID- 12413841
TI  - Design, synthesis and antitumor activities of novel 7-arylseleno-7
      deoxydaunomycinone derivatives.
AB  - 7-Arylseleno-7-deoxydaunomycinone derivatives 3a-e and 7-thiophenyl-7
      deoxydaunomycinones (7 and 8) were synthesized and the antitumor activities of
      them were evaluated against human stomach cancer SGC-7901 and human leukaemia
      HL60. The cytotoxic assay show that seleno daunomycinone derivatives are much
      better inhibitory activity than thiodaunomycinone and the structure-activity
      relationship was discussed. 7-Deoxydaunomycinone 4 was obtained when
      selenophenols were used in excess and the possible mechanism was proposed.

PMID- 12413842
TI  - Straightforward syntheses of furanomycin derivatives and their biological
      evaluation.
AB  - Several types of furanomycin analogues were synthesized and investigated with
      respect to their antibacterial activity. Two different synthetic pathways were
      developed, based on aldol reactions/ring closing metathesis and an ester enolate
      Claisen rearrangement. Only the natural product and its desmethyl derivative
      showed antibacterial activity, pointing towards a narrow structure-activity
      relationship.

PMID- 12413843
TI  - Tetrapeptides as potent protease inhibitors of Hepatitis C Virus full-length NS3
      (protease-helicase/NTPase).
AB  - A library of tetrapeptides was evaluated for Hepatitis C Virus NS3 protease
      inhibitor activity in an in vitro assay system comprising the native bifunctional
      full-length NS3 (protease-helicase/NTPase) protein. Tetrapeptides with K(i)
      values in the high nanomolar range were identified, for example Suc-Chg-Glu-2-Nal
      Cys (K(i)=0.27+/-0.03 microM) and Suc-Dif-Glu-Glu-Cys (K(i)=0.40+/-0.10 microM).
      Furthermore, it was shown that the inhibitory potencies are not affected
      significantly by assay ionic strength. As suggested by molecular modelling,
      potential binding interactions of the tetrapeptide inhibitors with the helicase
      domain might explain the data and structure-activity relationships thus obtained.
      Hence, we postulate that the full-length NS3 assay is a relevant system for
      inhibitor identification, offering new opportunities for inhibitor design.

PMID- 12413844
TI  - Nitrophenyl derivatives as aldose reductase inhibitors.
AB  - Nitrophenyl derivatives were recently discovered as a new class of ALR2
      inhibitors by means of docking and database screening of the National Cancer
      Institute database of organic molecules. The nitro group was predicted to bind to
      the Tyr48 and His110 active site residues of the enzyme, the site where acidic
      ALR2 inhibitors such as carboxylic acids bind in their anionic form. Given the
      novelty of these compounds, we decided to expand their structure-activity
      relationships by synthesizing and testing a series of derivatives and the
      corresponding compounds having a carboxylic group instead of the nitro moiety;
      the results obtained were rationalized by means of docking and molecular dynamics
      simulations. On the whole there is an agreement between inhibitory data and the
      results of molecular modeling experiments, supporting the hypothesized binding
      mode of these compounds.

PMID- 12413845
TI  - Synthesis and structure-activity relationship of dehydroxymethylepoxyquinomicin
      analogues as inhibitors of NF-kappaB functions.
AB  - We previously found dehydroxymethylepoxyquinomicin (DHMEQ) inhibited NF-kappaB
      activation and showed anti-inflammatory activity in vivo. Here we designed and
      synthesized analogues of DHMEQ and tested their biological activity as NF-kappaB
      inhibitors in human T cell leukemia Jurkat cells. The hydroxyl group at the 2
      position of the benzamide moiety was found to be essential for the inhibitory
      activity. But etherification of this group did not diminish the activity
      completely. Thus, for further mechanistic studies the hydroxyl group at the 2
      position may be useful for extension with a linker and biotin moiety.

PMID- 12413846
TI  - Sulfamoyloxy-substituted 2-phenylindoles: antiestrogen-based inhibitors of the
      steroid sulfatase in human breast cancer cells.
AB  - Estrone sulfate (E1S) is an endogenous prodrug that delivers estrone and,
      subsequently, estradiol to the target cells following the hydrolysis by the
      enzyme estrone sulfatase which is active in various tissues including hormone
      dependent breast cancer cells. Blockade of this enzyme should reduce the estrogen
      level in breast cancer cells and prevent hormonal growth stimulation. Sulfamates
      of a variety of phenolic compounds have been shown to be inhibitors of estrone
      sulfatase. Our rational is based on findings that these inhibitors can undergo
      hydrolysis and the pharmacological effects of the free hydroxy compounds
      contribute to the bioactivity of the sulfamates. A desirable action of the
      metabolites would be an estrogen antagonism to block stimulatory effects of
      residual amounts of estrogens. Thus, we synthesized a number of sulfamoyloxy
      substituted 2-phenylindoles with side chains at the indole nitrogen that
      guarantee antiestrogenic activity. All of the new sulfamates were studied for
      their inhibitory effects on the enzyme estrone sulfatase from human breast cancer
      cells and their (anti)hormonal activities in stably transfected human MCF-7/2a
      mammary carcinoma cells. The hormonal profile of the sulfamates was partly
      reflected by the properties of the corresponding hydroxy precursors. Some of the
      sulfamoylated antiestrogens strongly inhibited estrone sulfatase activity with
      IC(50) values in the submicromolar range. They were devoid of agonist activity
      and suppressed estrone sulfate-stimulated gene expression mainly by blocking the
      enzyme. Examples are the disulfamates of the indoles ZK 119, 010 and ZK 164, 015.
      Their IC(50)s for sulfatase inhibition were 0.3 and 0.2 microM, respectively, and
      50 and 80 nM, respectively, for the inhibition of E1S-stimulated luciferase
      expression in transfected MCF-7 cells. With some of the new sulfamates an
      additional direct antiestrogenic effect was noticed which might be due to a
      partial hydrolysis during incubation and would improve the growth inhibitory
      effect on estrogen-sensitive breast cancer cells.

PMID- 12413847
TI  - 1-Alkoxycarbonyl-3-halogenoazetidin-2-ones as elastase (PPE) inhibitors.
AB  - A series of 1-alkoxycarbonyl-3-halogenoazetidin-2-ones, designed as potential
      suicide inhibitors of serine proteases, has been synthesized and evaluated
      against porcine pancreatic elastase (PPE). All the compounds were transient
      inhibitors, their activity depending mainly on the nature of the halogen
      substituent: bromo- and iodo- derivatives are more active (K(i) approximately 2
      22 microM) than 3-chloroazetidinones (K(i) approximately 20-150 microM). The
      lipophilicity of the N-1 substituent appeared to exert a slightly positive
      effect.

PMID- 12413848
TI  - A novel class of endothelin-A receptor antagonists, (R)-2-(benzo[1,3]dioxol-5-yl)
      6-isopropyloxy-2H-chromene-3-carboxylic acids (S-1255). Conformational analysis
      of basic structure, crucial for ET(A) antagonism, in solution and solid states.
AB  - Conformational studies of potent and selective endothelin-A (ET(A)) receptor
      antagonists, 4-substituted (R)-2-(benzo[1,3]-dioxol-5-yl)-6-isopropoxy-2H
      chromene-3-carboxylic acids, are reported. X-ray crystallography and NMR studies
      of the 4-anisyl derivative 2 (S-1255), the stable atropisomers 3 and the 4-n
      butyl derivative 4 reveal that the A-, B- and C-rings in these compounds adopt a
      L-like conformation in both solution and solid states. Molecular mechanics
      calculation shows that this L-like conformation is an inevitable conformation as
      determined by intramolecular steric repulsions. These 2H-chromene derivatives
      bound to an ET(A) receptor with IC(50) values of less than 1 nM, whereas the
      dihydro compounds 7 and 9 not having the L-like conformation showed weaker
      affinities. These results suggest that the L-like conformation is specifically
      recognized by the active site of the ET(A) receptor. The roles of the L-like
      conformation in the receptor binding are discussed.

PMID- 12413849
TI  - Stereoselectivity in reactions of amino acids catalyzed by pyridoxal derivatives
      carrying rigidly-attached chirally-mounted basic groups--transamination,
      racemization, decarboxylation, retro-aldol reaction, and aldol condensation.
AB  - A tetrahydroquinoline ring was used to mount the critical functional groups of
      pyridoxal, and also two examples of rigidly held chirally mounted basic groups.
      They were able to selectively catalyze decarboxylation, aldol reaction, and retro
      aldol reaction of amino acids rather than transamination, and with
      stereoselectivity. In the aldol reaction of glycine with acetaldehyde to
      synthesize threonine and allo-threonine, one of the catalysts reversed its
      stereoselectivity when the basic group was protonated. The observed
      stereoselectivities were all consistent with prediction.

PMID- 12413850
TI  - On the topological evidences for modelling lipophilicity.
AB  - Topological evidences for modelling lipophilicity of a large series of diversed
      compounds have been provided on the basis of distance-based topological indices.
      A pool of topological indices along with indicator parameters related to the type
      of the compounds present in the set of 140 compounds were used for this purpose.
      The results have shown that topology as well as the type of compounds are the
      responsible parameters for modelling lipophilicity.

PMID- 12413851
TI  - Synthesis and evaluation of anticancer benzoxazoles and benzimidazoles related to
      UK-1.
AB  - UK-1 is a structurally unique bis(benzoxazole) natural product isolated from a
      strain of Streptomyces. UK-1 has been reported to possess anticancer activity but
      no activity against bacteria, yeast, or fungi. Previous work has also
      demonstrated the ability of UK-1 to bind a variety of di- and tri-valent metal
      ions, particularly Mg(2+) ions, and to form complexes with double-stranded DNA in
      the presence of Mg(2+) ions. Here we report the activity of UK-1 against a wide
      range of human cancer cell lines. UK-1 displays a wide spectrum of potent
      anticancer activity against leukemia, lymphoma, and certain solid tumor-derived
      cell lines, with IC(50) values as low as 20 nM, but is inactive against
      Staphylococcus aureus, a methicillin-resistant strain of S. aureus, or
      Pseudomonas aeruginosa. A series of analogues of the bis(benzoxazole) natural
      product UK-1 in which the carbomethoxy-substituted benzoxazole ring of the
      natural product was modified were prepared and evaluated for their anticancer and
      antibacterial properties. An analogue of UK-1 in which the carbomethoxy
      substituted benzoxazole ring was replaced with a carbomethoxy-substituted
      benzimidazole ring was inactive against human cancer cell lines and the two
      strains of S. aureus. In contrast, a simplified analogue in which the
      carbomethoxy-substituted benzoxazole ring was replaced with a carbomethoxy group
      was almost as active as UK-1 against the four cancer cell lines examined but
      lacked activity against S. aureus. Metal ion binding studies of these analogues
      demonstrate that they both bind Zn(2+) and Ca(2+) ions about as well as UK-1. The
      non-cytotoxic benzimidazole UK-1 analogue binds Mg(2+) ions 50-fold weaker than
      UK-1, whereas the simple benzoxazole analogue binds Mg(2+) ions nearly as well as
      UK-1. These results support a role of Mg(2+) ion binding in the selective
      cytotoxicity of UK-1 and provide a minimal pharmacophore for the selective
      cytotoxic activity of the natural product.

PMID- 12413852
TI  - Inhibitors of nitric oxide production from the bark of Myrica rubra: structures
      of new biphenyl type diarylheptanoid glycosides and taraxerane type triterpene.
AB  - Three new biphenyl type diarylheptanoid glycosides, myricanol 11-O-beta-D
      glucopyranoside, myricanone 5-O-beta-D-glucopyranoside, and neomyricanone 5-O
      beta-D-glucopyranoside, and a new taraxerane type triterpene, myricetrione, were
      isolated from the bark of Chinese Myrica rubra. Their structures were elucidated
      on the basis of chemical and physicochemical evidence. Biphenyl type
      diarylheptanoids, triterpene, and their polyphenols showed potent inhibitory
      effects on nitric oxide production in lipopolysaccharide-activated macrophages.
      Furthermore, diarylheptanoids, myricanol and myricanone, were found to inhibit
      induction of inducible nitric oxide synthase.

PMID- 12413853
TI  - Facile synthesis of stable lipid analogues possessing a range of alkyl groups:
      application to artificial glycolipids.
AB  - Efficient preparation of lipid analogues is described in which various long
      alkoxy chains and 2-hydroxyethyl group were covalently linked with benzoic acid
      derivatives. An alpha-mannopyranosyl group was stereoselectively introduced by
      the conventional imidate method into the terminal hydroxy group without any
      alternation of other moieties in a molecule. The resulting new glycoconjugates
      acted as models of natural glycolipids for protein-carbohydrate interactions.

PMID- 12413854
TI  - Progress in arylpiperazine synthesis by the catalytic amination reaction.
AB  - Careful base and solvent optimization for catalytic amination is described. A Pd
      catalyzed amination between some arylbromide and unprotected piperazine (1equiv)
      was efficiently carried out with Pd/BINAP catalyst in a toluene-DBU solvent
      system, which is useful for the one-pot preparation of unsymmetrical piperazine
      through amination and in-situ N-protection. Reaction with N-BOC-piperazine was
      also successful in toluene-DBU or more polar NMP with Cs(2)CO(3) as a key base.
      No reports have previously reported such solvent and base optimization in
      arylpiperazine synthesis.

PMID- 12413855
TI  - Synthesis of silicon-containing azole derivatives with magnesium bromide diethyl
      etherate, and an investigation of their fungicidal activities.
AB  - Enhancement of magnesium bromide diethyl etherate in addition reaction of
      trimethylsilylmethylmagnesium chloride 5 to 2-(1H-1,2,4-triazol-1
      yl)acetophenones 6 allowed us to prepare silicon-containing azole derivatives,
      which were tested for fungicidal activity and phytotoxicity. Among them, 2-(4
      fluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-trimethylsilylpropan-2-ol 1a was
      determined to be the most effective and potential candidate for novel fungicide.

PMID- 12413856
TI  - Development of 3D-QSAR models for 5-lipoxygenase antagonists: chalcones.
AB  - 5-Lipoxygenase inhibitors are of current interest for asthma therapy and
      inflammatory diseases. In order to identify the essential structural and
      physicochemical requirements in terms of common biophoric sites (pharmacophore)
      and secondary sites for binding and interacting with 5-lipoxygenase, a series of
      51 compounds of chalcones has been used for the development of 3D-QSAR models on
      APEX-3D expert system. Among several models, the two models have been identified
      with the statistical criteria R(2)>0.75, Chance <0.001 and Match >0.7. Both the
      models (nos 1 and 2) with three biophoric sites and four secondary sites, showed
      very good correlation (r>0.9) between the observed and calculated or predicted
      activities.

PMID- 12413857
TI  - Membrane-permeant derivatives of mannose-1-phosphate.
AB  - For treatment of congenital disorder of glycosylation type Ia (CDG-Ia) membrane
      permeant derivatives of mannose-1-phosphate are required. Employing biologically
      cleavable phosphate protecting groups advantageous precursor derivatives could be
      synthesized following a facile approach. Their enzymatic cleavages using esterase
      from porcine liver (E.C. 3.1.1.1) were investigated.

PMID- 12413858
TI  - Synthesis and biological evaluation of new mannose 6-phosphate analogues.
AB  - Three new analogues of mannose 6-phosphate (M6P)--a sulphate and two carboxylates
      -have been synthesized and their affinity toward the M6P/IGFII receptor evaluated
      by affinity column chromatography. These compounds display strong binding to the
      receptor and therefore are new M6P analogues which may find some dermatological
      applications, for example healing of post-surgical scars.

PMID- 12413859
TI  - A cell-penetrating peptide from a novel pVII-pIX phage-displayed random peptide
      library.
AB  - A novel random peptide library was constructed using a phage-display format on
      the coat proteins pVII and pIX of filamentous bacteriophage. Panning against B
      lymphocyte WI-L2 cells yielded one unique peptide-phage, denoted CHL8, that
      specifically bound to and penetrated the cells. Studies of each peptide derived
      from CHL8, denoted pep7 and pep9, established that only pep7 mediated the
      observed activity and only as a homodimer. Peptide libraries displayed on pVII
      pIX should serve as a novel source of bioactive ligands for a variety of
      applications.

PMID- 12413860
TI  - Study on the multiple mechanisms underlying the reaction between hydroxyl radical
      and phenolic compounds by qualitative structure and activity relationship.
AB  - The activity-structure relationships (ASR) of phenolic compounds as hydroxyl
      radical scavengers have mostly been studied and discussed with regard to their
      iron-chelating and hydrogen-donation properties in Fenton-type system, but
      extensive elucidation of multiple mechanisms underlying the hydroxyl radical
      scavenging reaction is out of obtaining up to now. In the present paper, a series
      of phenolic compounds was studied for their reactivity with hydroxyl radical by
      computed chemistry and deoxyribose degradation assay. The rate constant (K(S)),
      an index dependent markedly on the reaction mechanism and intrinsic reactivity of
      antioxidants, was found to have good correlation with hydroxyl O-H bond strength
      (DeltaH(f)), electron-donating ability (ionization potential approximated by HOMO
      energy level), enthalpy of single electron transfer (E(a)), and spin distribution
      of phenoxyl radicals (Ds(r)) after H-abstraction. Moreover, the theoretical
      parameters were highly intercorrelated, suggesting that multiple mechanisms co
      exist in the hydroxyl-radical-scavenging reaction and interact with each other.
      Multi-linear regression analysis indicated that, in addition to H-atom transfer,
      electron transfer process and stability of the resulted phenoxyl radicals also
      significantly influence the reactivity of quenching hydroxyl radicals. The QSAR
      model so established here was based on the elucidation of the complex molecular
      mechanisms, and may reasonably predict the antioxidant activity using simple
      experimental and calculated parameters.

PMID- 12413861
TI  - Synthesis and estrogen receptor affinity of a 4-hydroxytamoxifen-labeled ligand
      for diagnostic imaging.
AB  - A 10-step synthesis of a novel 4-hydroxytamoxifen-DTPA ligand (HOTam-DTPA) is
      reported. Tamoxifen and its primary metabolite 4-hydroxytamoxifen are common
      estrogen receptor ligands. Consequently, tamoxifen has found utility as the
      targeting component of various diagnostic agents for selective imaging of
      estrogen receptor-rich tissue, specifically breast cancer. An L-aspartic acid
      derived DTPA analogue was attached to the ethyl side chain of 4-hydroxy-tamoxifen
      using N,N'-dimethylethylenediamine as a hydrophilic linker. A competitve estrogen
      receptor binding assay using [3H]-17beta-estradiol was performed to determine the
      effect of the ethyl side chain modification on estrogen receptor affinity. The
      results show that while the relative affinity of HOTam-DTPA for the estrogen
      receptor is approximately 10-fold lower than that of tamoxifen, it still remains
      a potent ligand at relatively low concentrations.

PMID- 12413862
TI  - Folded conformation of an immunostimulating tetrapeptide rigin: high temperature
      molecular dynamics simulation study.
AB  - Employing high temperature quenched molecular dynamics (QMD) stimulations the
      conformational energy space of an immunostimulating tetrapeptide rigin: H-Gly341
      Gln-Pro-Arg344-OH, is explored. Using distance dependent dielectric (epsilon
      =r(ij)) 31 different low energy starting structures with identical sequence were
      computed for their conformational preferences. According to the hypothesis of
      O'Connors et al. [J. Med. Chem. 35 (1992), 2870], 83 low-energy conformers
      resulted from unrestrained molecular dynamics (MD) simulations, could be
      classified into two energy minimized families: A and B, comprised of 64 (Pro
      C(gamma)-endo orientation) and 19 (Pro C(gamma)-exo orientation) structures,
      respectively. An examination of these families revealed the existence of a
      remarkably similar folded backbone conformation: torsion angles being phi(i+1)
      approximately -65 degrees, psi(i+1) approximately -65 degrees, phi(i+2)
      approximately -65 degrees, psi(i+2) approximately -60 degrees, characterizing a
      distorted type III beta-turn structure across the central Gln-Pro segment. The
      folded conformation of rigin is devoid of a classical 1 <-- 4 intra-molecular
      hydrogen bond nevertheless, the conformation is stabilized by an effective 'salt
      bridge', i.e., Gly H(3)N(+)...C(alpha)OO(-) Arg interaction. Surprisingly, in
      both the families the unusual folded side-chain dispositions of the Gln residue
      favor the formation of a unique intra-residue 'main-chain to side-chain' H-bond,
      i.e., N(alpha)-H...N(epsilon) interaction, encompassing a seven-membered ring
      motif. The conformational attributes may be valuable in de novo construction of
      structure-based drug candidates having sufficient stimulating activity.

PMID- 12413863
TI  - Novel (bisarylmethoxy)butylpiperidine analogues as neurotransmitter transporter
      inhibitors with activity at dopamine receptor sites.
AB  - A series of (bisarylmethoxy)butylpiperidine derivatives was prepared and
      evaluated in vitro and in vivo to determine the structural requirements necessary
      for dual activity at the DAT and DA/5-HT receptor sites. These hybrid ligands,
      constructed by combining pharmacophores specific for the DAT and DA/5-HT
      receptors, could be useful drugs for treating cocaine addiction by assisting
      cocaine addicts in maintaining abstinence. The series was evaluated in vitro for
      DAT and DA/5-HT receptor activity and then selected compounds were tested in vivo
      for their effects on cocaine-induced hyperlocomotor activity (LMA). The majority
      of the new compounds demonstrated high to moderate affinity (4-191 nM) for the
      DAT with 4-hydroxy-4-phenylpiperidine analogues 14 and 15 possessing the greatest
      affinity. Compounds 15 and 22 exhibited the highest ratio of reuptake inhibition
      to-binding (discrimination ratio, DR), 111 and 323, respectively. These
      derivatives had modest affinity and antagonistic activity for dopamine D(2)/D(3)
      receptors. Compounds 9 and 15 (DR=0.9 and 111, respectively) stimulated locomotor
      activity, whereas the other compounds suppressed this response. All compounds
      tested except for 17 and 21 attenuated cocaine-induced hyperlocomotion.

PMID- 12413864
TI  - Mechanism of biochemical action of substituted 4-methylbenzopyran-2-ones. Part 9:
      comparison of acetoxy 4-methylcoumarins and other polyphenolic acetates reveal
      the specificity to acetoxy drug: protein transacetylase for pyran carbonyl group
      in proximity to the oxygen heteroatom.
AB  - The evidences for the possible enzymatic transfer of acetyl groups (catalyzed by
      a transacetylase localized in microsomes) from an acetylated compound (acetoxy-4
      methylcoumarins) to enzyme proteins leading to profound modulation of their
      catalytic activities was cited in our earlier publications in this series. The
      investigations on the specificity for transacetylase (TA) with respect to the
      number and positions of acetoxy groups on the benzenoid ring of coumarin molecule
      revealed that acetoxy groups in proximity to the oxygen heteroatom (at C-7 and C
      8 positions) demonstrate a high degree of specificity to TA. These studies were
      extended to the action of TA on acetates of other polyphenols, such as flavonoids
      and catechin with a view to establish the importance of pyran carbonyl group for
      the catalytic activity. The absolute requirement of the carbonyl group in the
      pyran ring of the substrate for TA to function was established by the observation
      that TA activity was hardly discernible when catechin pentacetate and 7-acetoxy
      3,4-dihydro-2,2-dimethylbenzopyran (both lacking pyran ring carbonyl group) were
      used as the substrates. Further, the TA activity with flavonoid acetates was
      remarkably lower than that with acetoxycoumarins, thus suggesting the specificity
      for pyran carbonyl group in proximity to the oxygen heteroatom. The biochemical
      properties of flavonoid acetates, such as irreversible activation of NADPH
      cytochrome C reductase and microsome-catalyzed aflatoxin B(1) binding to DNA in
      vitro were found to be in tune with their specificity to TA.

PMID- 12413865
TI  - Anti-HIV-1 peptides derived from partial amino acid sequences of CC-chemokine
      RANTES. Regulated upon activation, normal T-cell expressed and secreted.
AB  - Fifteen acetyl-peptide-amides with partial amino acid sequences of RANTES
      (regulated upon activation, normal T-cell expressed and secreted), all Cys
      residues of which were substituted by Ala, were synthesized, and screened for
      anti-HIV-1 activity. Peptides corresponding to 1-10, 37-46, and 57-68 showed
      marked activity against CC-chemokine receptor 5-using HIV-1(JR-CSF) (% inhibition
      at 100 nM 69, 82, 76%, respectively). The results indicate that multiple regions,
      including the N-terminal part responsible for chemotactic activity, are involved
      in anti-HIV-1 activity of RANTES, yielding possible lead compounds for anti-HIV-1
      agents.

PMID- 12413866
TI  - 1-Methoxy-, 1-deoxy-11-hydroxy- and 11-hydroxy-1-methoxy-Delta(8)
      tetrahydrocannabinols: new selective ligands for the CB2 receptor.
AB  - Three series of new cannabinoids were prepared and their affinities for the CB(1)
      and CB(2) cannabinoid recptors were determined. These are the 1-methoxy-3-(1',1'
      dimethylalkyl)-, 1-deoxy-11-hydroxy-3-(1',1'-dimethylalkyl)- and 11-hydroxy-1
      methoxy-3-(1',1'-dimethylalkyl)-Delta(8)-tetrahydrocannabinols, which contain
      alkyl chains from dimethylethyl to dimethylheptyl appended to C-3 of the
      cannabinoid. All of these compounds have greater affinity for the CB(2) receptor
      than for the CB(1) receptor, however only 1-methoxy-3-(1',1'-dimethylhexyl)
      Delta(8)-THC (JWH-229, 6e) has effectively no affinity for the CB(1) receptor
      (K(i)=3134+/-110nM) and high affinity for CB(2) (K(i)=18+/-2nM).

PMID- 12413867
TI  - Characterization of a binding site for template competitive inhibitors of HIV-1
      reverse transcriptase using photolabeling derivatives.
AB  - Analogues of a novel class of template-competitive reverse transcriptase
      inhibitors (Li, K.; Lin, W.; Chong, K. H.; Moore, B. M.; Doughty, M. B. Bioorg.
      Med. Chem. 2002, 10, 507) were analyzed as photoprobes of HIV-1 reverse
      transcriptase (RT) heterodimer. The two photoprobes, 2-(4-azidophenacyl)thio
      1,N(6)-etheno-2'-deoxyadenosine 5'-triphosphate 2 and the tetrafluoro analogue 2
      (4-azido-2,3,5,6-tetrafluorophenacyl)thio-1,N(6)-etheno-2'-deoxyadenosine 5'
      triphosphate 3, photodecomposed at 3500 A with half-lives of 4.0 and 2.5 min,
      respectively. Analysis of the photoproducts of 2m demonstrated that the etheno
      group is stable but the azido decomposes primarily to the 2-(S-[3H-diazepinon-4
      yl]thio)-1,N(6)-etheno-dAMP. Photolysis of both 2 and 3 with RT resulted in a
      time-dependent loss of activity, with maximum inactivation of 83 and 60%,
      respectively. Both 2 and 3 showed concentration-dependent photoinactivation of RT
      in the concentration range from 0 to 100 microM, with EC(50)s of 20 and 25 microM
      and maximum inactivation of 80 and 60%, respectively. Both the time and
      concentration dependent photoinactivation were strongly protected by template
      primer, but only poorly inhibited by even high concentrations of TTP.
      Radiolabeled analogues [beta,gamma-(32)P]-2 and [beta,gamma-(32)P]-3
      photoincorporated into the p66 subunit, an incorporation also protected by
      template primer. Identification of the site of incorporation was problematic for
      both photoprobes, but evidence presented is consistent with labeling sites for
      the phenacyl side chains of both 2 and 3 in the template grip. Nevertheless, the
      photoinactivation and incorporation data are consistent with our earlier
      conclusions from the kinetic data that these inhibitors are specific for the free
      form of RT in competition with template/primer, and thus represent a novel class
      of inhibitors.

PMID- 12413868
TI  - Design of inhibitors of scytalone dehydratase: probing interactions with an
      asparagine carboxamide.
AB  - Among the active-site residues of scytalone dehydratase, the side-chain
      carboxamide of asparagine 131 has the greatest potential for strong electrostatic
      interactions. Structure-based inhibitor design aimed at enhancing interactions
      with this residue led to the synthesis of a series of highly potent inhibitors
      that have a five- or six-membered ring containing a carbonyl functionality for
      hydrogen bonding. To achieve a good orientation for hydrogen bonding, the
      inhibitors incorporate a phenyl substituent that displaces a phenylalanine
      residue away from the five- or six-membered rings. Without the phenyl
      substituent, inhibitor binding potency is diminished by three orders of
      magnitude. Larger K(i) values of a site-directed mutant (Asn131Ala) of scytalone
      dehydratase in comparison to those of wild-type enzyme validate the design
      concept. The most potent inhibitor (K(i)=15 pM) contains a tetrahydrothiophenone
      that can form a single hydrogen bond with the asparagine carboxamide. Inhibitors
      with a butyrolactam that can form two hydrogen bonds with the asparagine
      carboxamide demonstrate excellent in vivo fungicidal activity.

PMID- 12413869
TI  - New water-soluble prodrugs of HIV protease inhibitors based on O-->N
      intramolecular acyl migration.
AB  - To improve the low water-solubility of HIV protease inhibitors, we synthesized
      water-soluble prodrugs of KNI-272 and KNI-279 which are potent HIV-1 protease
      inhibitors consisting of an Apns-Thz core structure (Apns; allophenylnorstatine,
      Thz; thiazolidine-4-carboxylic acid) as an inhibitory machinery. The prodrugs,
      which contained an O-acyl peptidomimetic structure with an ionized amino group
      leading to the increase of water-solubility, were designed to regenerate the
      corresponding parent drugs based on the O-->N intramolecular acyl migration
      reaction at the alpha-hydroxy-beta-amino acid residue, that is
      allophenylnorstatine. The synthetic prodrugs 3, 4, 6, and 7 improved the water
      solubility (>300mg/mL) more than 4000-fold in comparison with the parent
      compounds, which is the practically acceptable value as water-soluble drugs.
      These prodrugs were stable as an HCl salt and in a strongly acidic solution
      corresponding to gastric juice (pH 2.0), and could be converted to the parent
      compounds promptly in the aqueous condition from slightly acidic to basic pH at
      37 degrees C, with the suitable migration rate, via a five-membered ring
      intermediate. Using a similar method, we synthesized a prodrug (12) of ritonavir,
      a clinically useful HIV-1 protease inhibitor as an anti-AIDS drug. In contrast to
      the prodrugs 3, 4, 6, and 7, the prodrug 12 was very slowly converted to
      ritonavir probably through a six-membered ring intermediate, with the t(1/2)
      value of 32h that may not be suitable for practical use.

PMID- 12413870
TI  - QSAR studies of HIV-1 integrase inhibition.
AB  - Compounds from a wide variety of structural classes inhibit HIV-1 integrase.
      However, a single unified understanding of the relationship between the
      structures and activities of these compounds still eludes researchers. We report
      herein the development of QSAR models for integrase inhibition. The genetic
      function approximation (GFA) was utilized to select descriptors for the
      development of the QSAR models. The best QSAR model derived for the complete set
      of 11 structural classes had a correlation coefficient (r(2)) of only 0.54 and a
      cross-validated correlation coefficient (q(2)) of only 0.42. This indicated that
      the compounds studied may differ in the exact relationship between structure and
      inhibition, perhaps through interactions with different subsets of amino acids in
      the binding pocket, or through the presence of non-overlapping binding pockets.
      Descriptor-based cluster analysis indicated that the 11 structural classes of
      integrase inhibitors studied belonged to two clusters, one consisting of five
      structural classes, and the other six. QSAR models for these two clusters had
      r(2) values of 0.79 and 0.82 and q(2) values of 0.71 and 0.74, a significant
      improvement over models obtained for the complete set of compounds. The two
      models were applied to predict the activities of compounds from the same
      structural classes as those used to build the models, giving r(2) values of 0.65
      and 0.78. The models were also used to predict the activities of compounds shown
      in crystallographic or docking studies to interact near the active site metal
      ion. The model describing the larger cluster of structural classes was better
      able to reproduce the biological activities of these five structures with an
      average percent residual error of 7.9 compared with the 19.3% residual error for
      predictions from the other model. This indicated that the six structural classes
      comprising the larger cluster may bind near the metal ion in a fashion similar to
      that observed in one publicly available co-crystal structure of an inhibitor
      bound to HIV-1 integrase. Flexible alignment of inhibitors in the two clusters
      found different pharmacophores that are consistent with previously published
      pharmacophores developed on the basis of individual structural classes that have
      produced novel inhibitory compounds. Thus we expect that these two QSAR models
      can be used in the search for novel HIV-1 integrase inhibitors as well as to
      provide insight into the binding modes of such diverse chemical compounds.

PMID- 12413871
TI  - Mapping of the active site of rat kidney gamma-glutamyl transpeptidase using
      activated esters and their amide derivatives.
AB  - The enzyme gamma-glutamyl transpeptidase (GGT), implicated in many physiological
      processes, catalyses the transfer of a gamma-glutamyl from a donor substrate to
      an acyl acceptor substrate, usually an amino acid or a peptide. In order to
      investigate which moieties of the donor substrate are necessary for recognition
      by GGT, the structure of the well-recognized substrate L-gamma-glutamyl-p
      nitroanilide was modified. Several activated esters and their amide derivatives
      were synthesized and used as substrates. Kinetic (K(m) and V(max)) and inhibition
      constants (K(i)) were measured and reveal that almost the entire gamma-glutamyl
      moiety is necessary for recognition in the binding site of the donor substrate.
      The implied presence of certain complementary amino acids in this substrate
      binding site will allow the more rational design of various substrate analogues
      and inhibitors.

PMID- 12413872
TI  - Axisymmetric bioconvection in a cylinder.
AB  - In three-dimensional bioconvection, the regions of rising and sinking fluid are
      dissimilar. This geometrical effect is studied for axisymmetric bioconvection in
      a cylindrical cell with stress-free (i.e. normal velocity and tangential stress
      vanish) lateral and top boundaries, and rigid bottom boundary. Using the
      continuum model of Pedley et al. (1988, J. Fluid Mech.195, 223-237) for
      bioconvection in a suspension of swimming, gyrotactic microorganisms, the
      structure and stability of an axisymmetric plume in a deep chamber are
      investigated. The system is governed by the Navier-Stokes equations for an
      incompressible fluid coupled with a microorganism conservation equation. These
      equations are solved numerically using a conservative finite-difference scheme.
      Comparisons are made with two-dimensional bioconvection.

PMID- 12413873
TI  - A mathematical model for germinal centre kinetics and affinity maturation.
AB  - We present a mathematical model which reproduces experimental data on the
      germinal centre (GC) kinetics of the primed primary immune response and on
      affinity maturation observed during the reaction. We show that antigen masking by
      antibodies which are produced by emerging plasma cells can drive affinity
      maturation and provide a feedback mechanism by which the reaction is stable
      against variations in the initial antigen amount over several orders of
      magnitude. This provides a possible answer to the long-standing question of the
      role of antigen reduction in driving affinity maturation. By comparing model
      predictions with experimental results, we propose that the selection probability
      of centrocytes and the recycling probability of selected centrocytes are not
      constant but vary during the GC reaction with respect to time. It is shown that
      the efficiency of affinity maturation is highest if clones with an affinity for
      the antigen well above the average affinity in the GC leave the GC for either the
      memory or plasma cell pool. It is further shown that termination of somatic
      hypermutation several days before the end of the germinal centre reaction is
      beneficial for affinity maturation. The impact on affinity maturation of
      simultaneous initiation of memory cell formation and somatic hypermutation vs.
      delayed initiation of memory cell formation is discussed.

PMID- 12413874
TI  - Antigen-driven T-cell turnover.
AB  - A mathematical model is developed to characterize the distribution of cell
      turnover rates within a population of T lymphocytes. Previous models of T-cell
      dynamics have assumed a constant uniform turnover rate; here we consider turnover
      in a cell pool subject to clonal proliferation in response to diverse and
      repeated antigenic stimulation. A basic framework is defined for T-cell
      proliferation in response to antigen, which explicitly describes the cell cycle
      during antigenic stimulation and subsequent cell division. The distribution of T
      cell turnover rates is then calculated based on the history of random exposures
      to antigens. This distribution is found to be bimodal, with peaks in cell
      frequencies in the slow turnover (quiescent) and rapid turnover (activated)
      states. This distribution can be used to calculate the overall turnover for the
      cell pool, as well as individual contributions to turnover from quiescent and
      activated cells. The impact of heterogeneous turnover on the dynamics of CD4(+) T
      cell infection by HIV is explored. We show that our model can resolve the paradox
      of high levels of viral replication occurring while only a small fraction of
      cells are infected.

PMID- 12413875
TI  - Estimating the instability parameters of plasmid-bearing cells. I. Chemostat
      culture.
AB  - What determines the stability of plasmid-bearing cells in natural and laboratory
      conditions? In order to answer this question in a quantitative manner, we need
      tools allowing the estimation of parameters governing plasmid loss in different
      environments. In the present work, we have developed two methods for the
      estimation of the instability parameters of plasmid-bearing cells growing in
      chemostat. These instability parameters are: (i) selection coefficient (or cost
      of the plasmid)alpha and (ii) the probability of plasmid loss at cell division
      tau(0). We have found that generally selection coefficient alpha changes during
      elimination of plasmid-bearing cells due to changes in substrate concentration;
      hence, methods which assume constancy of alpha are intrinsically imprecise.
      Instead, one can estimate selection coefficient at the beginning and the end of
      cultivation when the substrate concentration is approximately constant. Applying
      developed techniques to two sets of experimental data, we have found that (i) the
      cost of the plasmid pBR322 depended on the dilution rate in chemostat and was
      higher at low dilutions; (ii) high levels of plasmid gene expression led to a
      high cost of the plasmid pPHL-7; (iii) the probability of plasmid loss was lower
      at high levels of plasmid gene expression and independent of the dilution rate.
      We have also discussed the application of our results to understanding the basic
      biology of bacterial plasmids.

PMID- 12413876
TI  - Modelling natural burst firing in nigral dopamine neurons.
AB  - The natural burst firing observed in vivo in mesolimbic dopamine neurons is of
      great significance regarding these neurons' involvement in response to sensory
      stimuli associated with primary reward. The cellular mechanisms underlying a
      natural burst have been experimentally characterized previously and hypothesized
      to be caused by a calcium-sensitive inactivation of a potassium channel. We
      present a mathematical model of a mesolimbic neuron that demonstrates how such a
      mechanism can produce realistic bursting patterns, but only when combined with an
      appropriately timed membrane depolarization from an external source.

PMID- 12413877
TI  - Cancer cell dynamics in presence of telomerase inhibitors: analysis of in vitro
      data.
AB  - The inhibition of telomerase activity in actively dividing cells leads to
      suppression of cell growth after a time delay (inhibitory delay) required to
      reach a threshold telomeric DNA size. We developed a mathematical model of the
      dynamics of telomere size distribution and cell growth in the presence of
      telomere inhibitors that allowed quantification of the inhibitory delay. The
      model based on the solution of a system of differential equations described
      quantitatively recent experimental data on dynamics of cultured cells in presence
      of telomerase inhibitors. The analysis of the data by this model suggested the
      existence of at least two distinct subpopulations of cells with different
      proliferative activity. Size distribution of telomeres, fraction of proliferating
      cells, and tumor doubling times are of critical importance for the dynamics of
      cancer cells growth in presence of telomerase inhibitors. Rapidly growing cells
      with large telomeric DNA heterogeneity and small proliferating fractions as well
      as those with very short homogeneous telomeres would be the most sensitive to
      telomerase inhibitors.

PMID- 12413878
TI  - A mathematical model for estimating muscle tension in vivo during esophageal
      bolus transport.
AB  - We present a model of esophageal wall muscle mechanics during bolus transport
      with which the active and "passive" components of circular muscle tension are
      separately extracted from concurrent manometric and videofluoroscopic data. Local
      differential equations of motion are integrated across the esophageal wall to
      yield global equations of equilibrium which relate total tension within the
      esophageal wall to intraluminal pressure and wall geometry. To quantify the
      "passive" (i.e. inactive) length-tension relationships, the model equations are
      applied to a region of the esophagus in which active muscle contraction is
      physiologically inhibited. Combining the global equations with space-time
      resolved intraluminal pressure measured manometrically and videofluoroscopic
      geometry data, the passive model is used to separate active and "passive"
      components of esophageal muscle tension during bolus transport. The model is of
      general applicability to probe basic muscle mechanics including the space-time
      stimulation of circular muscle, the relationship between longitudinal muscle
      tension and longitudinal muscle shortening, and the contribution of the collagen
      matrix surrounding muscle fibers to passive tension during normal human
      esophageal bolus transport and in pathology. Example calculations of normal
      esophageal function are given where active tone is found to extend only over a
      short intrabolus segment near the bolus tail and segmental regions of active
      muscle squeeze are demonstrated.

PMID- 12413879
TI  - On the number of experiments required to find the causal structure of complex
      systems.
AB  - The need to capture the complexity of biological systems in a simpler formalism
      is the underlying impetus of biological sciences. Understanding the function of
      many biological complex systems, such as genetic networks or molecular signalling
      pathways, requires precise identification of the interactions between their
      individual components. A number of questions in the study of complex systems are
      then important-in particular, what can be inferred about the interactions in a
      complex system from an arbitrary set of experiments, and, what is the minimum
      number of experiments required to characterize the system? This paper shows that
      the problem of finding the minimal causal structure of a system based on a set of
      observations is computationally intractable for even moderately sized systems (it
      is NP-hard), but a reasonable approximation can be found in a relatively short
      (polynomial) time. Next, it is shown that the number of experiments required to
      characterize a complex system grows exponentially with the upper bound on the
      number of immediate upstream influences of each element, but only logarithmically
      with the number of elements in the system. This makes it possible to study
      biological systems with extremely large number of interacting elements and
      relatively sparse interconnections, such as gene regulatory and cell signalling
      networks. Finally, the construction of a randomized experimental sequence which
      achieves this bound is discussed.

PMID- 12413880
TI  - Modeling the tensile mechanical behavior of bone along the longitudinal
      direction.
AB  - The tensile stress-strain behavior of bone along its longitudinal axis is modeled
      by using a simple shear-lag theory, wherein, stresses and strains in a unit cell
      consisting of an organic matrix reinforced by overlapped mineral platelets are
      computed. It is assumed that loads are transferred between overlapped mineral
      platelets by shear in the organic matrix. The mechanical behavior of bone in
      which the matrix partially or completely debonds from the sides of the overlapped
      mineral platelets (after an ultimate interfacial shear stress value is exceeded)
      is modeled. It is shown that the tensile mechanical behavior of bone can be
      modeled only by assuming little or no debonding of the organic from the mineral.
      A physical phenomenon that explains the tensile behavior of bone is, after the
      interfacial shear stress has reached a constant value over the length of the
      mineral platelets, the collagen molecules/microfibrils (with the associated
      mineral platelets) move relative to one another. The tensile stress-strain curve
      of bovine bone is modeled using this model. The theory predicts the mechanical
      behavior of the tissue in the elastic, yield and post-yield region. The ultimate
      strain and strengths are not predicted in the present model.

PMID- 12413881
TI  - Human CD34+ hematopoietic progenitor cells hyperacetylate core histones in
      response to sodium butyrate, but not trichostatin A.
AB  - Cells positive for the cell surface marker CD34 from bone marrow or umbilical
      cord blood form a subset of quiescent, hematopoetic precursors that can establish
      human hematopoesis in immunodeficient mice and can progress down various
      differentiation pathways in vitro. They provide a valuable model system in which
      progression from quiescent to cycling to differentiated states can be linked to
      changes in chromatin and histone modification. We have used the deacetylase
      inhibitor sodium butyrate to show that turnover of histone H4 acetates is rapid
      and comparable in quiescent and cycling CD34+ cells from human umbilical cord
      blood (CD34+ UBC). Surprisingly, the widely used inhibitor trichostatin A (TSA)
      had little (cycling cells) or no (quiescent cells) effect on H4 acetylation in
      CD34+ UBC. Among five cell types examined, CD34+ UBC were unique in expressing
      all (putative) deacetylases tested (HDAC1, -2, -3, -4, -6, -7, and -8 and SIRT1
      4), but no single deacetylase correlated with their TSA resistance. Also, HDAC1, 
      2, -3, and -6 complexes isolated from CD34+ UBC by immunoprecipitation were all
      inhibited by TSA in vitro. Thus, TSA resistance of CD34+ UBC is not due to
      acquired or intrinsic TSA resistance of their deacetylases and may reflect an
      enhanced ability to process the drug.

PMID- 12413882
TI  - Dynamics of vascular endothelial-cadherin and beta-catenin localization by
      vascular endothelial growth factor-induced angiogenesis in human umbilical vein
      cells.
AB  - The adherens junctional molecule, vascular endothelial cadherin (VE-cadherin),
      functions to maintain adherens junction stability and to suppress apoptosis of
      endothelial cells by forming a complex with vascular endothelial growth factor
      (VEGF) receptor 2 and members of the armadillo family of cytoplasmic proteins. In
      order to investigate the dynamics of the association of VE-cadherin with adherens
      junctions during the initial stages of angiogenesis, human umbilical cord
      endothelial cells (HUVECs) were stimulated with VEGF to undergo angiogenesis in
      type-I collagen three-dimensional culture. In confluent monolayers of HUVECs, VE
      cadherin and its signaling partner, beta-catenin, as well as the paracellular
      transmembrane adhesion molecule platelet-endothelial cell adhesion molecule
      (PECAM-1), were all present in regions of cell-cell contact. Within 3 h of
      stimulation of angiogenesis, VE-cadherin and beta-catenin were lost from these
      regions. In contrast, the distribution pattern of PECAM-1 did not alter. After 6
      h the majority of endothelial cells had migrated to form a network of capillary
      cords with cell-cell contacts that contained all three molecules. By metabolic
      labeling of HUVECs it was found that de novo synthesis of VE-cadherin was not
      essential for the formation of new adherens junctions. Coimmunoprecipitation and
      immunoblotting experiments showed that the VE-cadherin and beta-catenin remained
      associated after they were lost from adherens junctions. Detergent extraction of
      cells with Triton X-100 indicted that the majority of VE-cadherin and beta
      catenin was Triton soluble, indicating that they are only weakly associated with
      the actin-based cytoskeleton.

PMID- 12413883
TI  - The urokinase plasminogen activator: an interesting way to improve myoblast
      migration following their transplantation.
AB  - Muscle cell migration plays an important role in the incorporation of
      transplanted myoblasts in muscle fibers. Understanding the mechanisms underlying
      the high migration capacity of the C(2)C(12) myoblast cell line may help to
      develop approaches to improve the migration of normal myoblasts and consequently
      to increase their participation to the host myofiber regeneration. We have
      previously shown that matrix metalloproteinases are implicated in the in vivo
      migration of C(2)C(12). Here, we studied the role of urokinase plasminogen
      activator (uPA) in this process. The expression of uPA mRNA and the enzymatic
      activity of uPA were studied in both normal myoblasts and the C(2)C(12) myoblast
      cell line. Reverse transcriptase polymerase chain reaction analysis showed that
      uPA mRNA was more strongly expressed in C(2)C(12) cells than in normal myoblasts.
      The enzymatic activity of secreted uPA analyzed by casein zymography is higher in
      medium conditioned by C(2)C(12) cells than in medium conditioned by normal
      myoblasts. Using our previously described microtube technique to assess in vivo
      cell migration, we showed that uPA is implicated in the in vivo migration of
      C(2)C(12) cells since this migration was abrogated in the presence of aprotinin
      (a general serine protease inhibitor) or amiloride (a uPA-specific inhibitor).
      We, therefore, hypothesized that increasing endogenous uPA expression by normal
      myoblasts may improve their migration capacity. Since an accumulating body of
      evidence has shown that growth factors regulate expression of uPA in a wide range
      of cells, we treated normal myoblasts with several growth factors alone or in
      combination with components of the extracellular matrix (ECM). All stimulants
      tested showed a minimal to strong effect on uPA enzymatic activity as assayed by
      zymography analysis. The positive effect of basic fibroblast growth factor (bFGF)
      on uPA enzymatic activity was slightly potentiated in the presence of
      fibronectin. Moreover, the pretreatment and coinjection of mouse myoblasts with
      bFGF alone or in combination with fibronectin improved significantly their in
      vivo migration throughout the tibialis anterior muscle of mdx mice. These results
      suggest that increasing uPA expression by an appropriate combination of growth
      factors and ECM components constitutes a possible approach to improving the
      migration of myogenic cells after transplantation.

PMID- 12413884
TI  - Mesenchymal cells potentiate vascular endothelial growth factor-induced
      angiogenesis in vitro.
AB  - The role of soluble factors (including angiogenic cytokines) and extracellular
      matrix components in the regulation of angiogenesis is clearly established.
      However, the interrelationship between these factors and perivascular mesenchymal
      cells is not well understood. Here we have used a three-dimensional collagen gel
      coculture system to assess the effect of mesenchymal C3H10T1/2 cells on vascular
      endothelial growth factor-A (VEGF-A)- and fibroblast growth factor-2 (FGF-2)
      induced angiogenesis in vitro. We found that coculture markedly potentiated the
      angiogenic activity of VEGF-A, irrespective of whether or not direct cell-to-cell
      contact occurred. In contrast, under conditions in which cell-to-cell contact was
      possible, FGF-2-induced angiogenesis was inhibited by cocultured 10T1/2 cells;
      this effect was not seen when cell-to-cell contact was prevented. Attempts to
      identify the molecules responsible for this effect allowed us to exclude FGF-2,
      transforming growth factorbeta1, platelet derived growth factor-BB, angiopoietin
      1, and NO as possible mediators of the potentiating effect of coculture on VEGF-A
      induced invasion. In the living organism, angiogenesis occurs in a three
      dimensional microenvironment. Contrary to the inhibitory effect of 10T1/2 cells
      previously reported by others in two-dimensional cultures, our data demonstrate
      that the paracrine interaction between endothelial and mesenchymal cells
      potentiates angiogenesis in vitro and that this is cytokine-specific, i.e., it
      occurs with VEGF-A but not with FGF-2.

PMID- 12413885
TI  - Interactions of opioid and chemokine receptors: oligomerization of mu, kappa, and
      delta with CCR5 on immune cells.
AB  - Activation of opioid receptors by morphine was previously shown to specifically
      induce the expression of chemokine receptor CCR5, promoting simian AIDS virus
      entry and replication in immune cells. The present study was undertaken to
      determine whether these two structurally and functionally distinct G-protein
      coupled receptors are in close proximity and form an oligomeric complex in the
      cell membrane so that the activation of one triggers the activity of the other.
      Both human CEM x174 and monkey lymphocytes were used in this study and gave
      similar results. Immunoprecipitation experiments showed that CCR5, but not CD4
      nor Na(+)/H(+) exchanger, coprecipitates with all three subtypes (mu, delta, and
      kappa) of opioid receptors. A single protein band immunoreactive with antibodies
      against both the CCR5 and the opioid receptors was identified after
      electrophoresis on nondenaturing polyacrylamide gels. Chemical crosslinking
      experiments using glutaraldehyde or BS(3) indicate that these receptors are
      closely situated on the cell membrane with an intermolecular distance less than
      11.4A. Functional studies revealed that a combination treatment of cells with
      morphine, an agonist for mu, and MIP-1beta, a ligand for CCR5, suppresses the
      inhibitory effect of MIP-1beta and increases the stimulatory effect of morphine
      on CCR5 expression. These results suggest that oligomerization of chemokine
      receptor CCR5 and opioid receptors on the cell membrane of human or monkey
      lymphocytes may modulate receptor functions.

PMID- 12413886
TI  - CD40-mediated apoptosis in murine B-lymphoma lines containing mutated p53.
AB  - Crosslinking CD40 induces normal B-cells to proliferate and differentiate but
      causes many tumor cell lines to undergo apoptosis. As p53 is required for many
      apoptotic pathways, we analyzed the effects of CD40 ligation and their
      correlation with p53 function in four murine B-lymphoma lines. A20 and M12 cells
      showed complete growth inhibition and an increase in the proportion of apoptotic
      cells upon CD40 crosslinking, but WEHI 231 and WEHI 279 cells were unaffected.
      IkappaBalpha protein levels were reduced in all four lines in response to CD40
      crosslinking, indicating that CD40 signaling was normal. NFkappaB activity was
      quantitated by reporter and gel shift assays and found to be equivalent in all
      four cell lines. P53 reporter constructs were activated in WEHI231 but not A20 or
      M12 cells, suggesting that p53 in the latter two cell lines may be mutated. These
      data are supported by the lack of detectable p21 mRNA in A20 and M12 cells. P21
      mRNA was increased to detectable levels in M12 cells upon CD40 ligation; however,
      blocking this effect with the p53 inhibitor pifithrin had no effect on CD40
      mediated apoptosis. Sequencing showed that p53 in A20 and M12 cells contained
      point mutations leading to amino acid substitutions in DNA binding regions, but
      was unmutated in WEHI231 and WEHI 279. These results suggest that CD40-mediated
      apoptosis can occur in the absence of functional p53.

PMID- 12413887
TI  - Ubc9 is essential for viability of higher eukaryotic cells.
AB  - Ubc9 is an enzyme involved in the conjugation of SUMO-1 (small ubiquitin related
      modifier 1) to target proteins. The SUMO-1 conjugation system is well conserved
      from yeasts to higher eukaryotes, but many SUMO-1 target proteins reported
      recently in higher eukaryotic cells, including IkappaBalpha, MDM2, p53, and PML,
      are not present in yeasts. To determine the physiological roles of SUMO-1
      conjugation in higher eukaryotic cells, we constructed a conditional UBC9 mutant
      of chicken DT40 cells containing the UBC9 transgene under control of a
      tetracycline-repressible promoter and characterized their loss of function
      phenotypes. Ubc9 disappeared 3 days after the addition of tetracycline and the
      increase in viable cell number stopped 4 days after the addition of drug. In
      contrast to the cases of ubc9 mutants of budding and fission yeasts, which show
      defects in progression of G2 or early M phase and in chromosome segregation,
      respectively, we did not observe accumulation of cells in G2/M phase or a
      considerable increase in the frequency of chromosome missegregation upon
      depletion of Ubc9 but we did observe an increase in the number of cells
      containing multiple nuclei, indicating defects in cytokinesis. A considerable
      portion of the Ubc9-depleted cell population was committed to apoptosis without
      accumulating in a specific phase of the cell cycle, suggesting that chromosome
      damages are accumulated in Ubc9-depleted cells, and apoptosis is triggered
      without activating checkpoint mechanisms under conditions of SUMO-1 conjugation
      system impairment.

PMID- 12413888
TI  - Expression and potential function of beta-amyloid precursor proteins during
      cutaneous wound repair.
AB  - sAPP, the secretory domain of the beta-amyloid precursor protein (APP), exerts a
      growth promoting and motogenic activity on keratinocytes. Here we report on the
      expression of APP and its homologue, the amyloid precursor like protein 2
      (APLP2), during cutaneous wound repair using a full-thickness excisional wound
      healing model in mice. In unwounded skin APP was predominantly expressed in the
      basal cell layer. During wound healing increased suprabasal expression of APP was
      observed in all cell layers of the hyperproliferative epithelium at the wound
      margin. APP mRNA was increased up to 2.3-fold, whereas the APLP2 mRNA was
      decreased. Immunocytochemically, all proliferation competent keratinocytes of the
      normal as well as the wound site epidermis showed increased expression of APP but
      not of APLP2. Using culture models of keratinocyte differentiation the release of
      sAPP was found to be significantly higher in proliferating cells, i.e., when
      cultured at subconfluency or at low [Ca(2+)], than in quiescent, partially
      differentiated keratinocytes cultured at confluency or at high [Ca(2+)]. Our
      results suggest that sAPP secretion is presumably also increased in proliferation
      competent keratinocytes of the wound margin and that sAPP due to its growth
      promoting and motogenic function might participate in the control of epidermal
      wound repair.

PMID- 12413889
TI  - Cell shape change precedes staurosporine-induced stabilization and accumulation
      of p27kip1.
AB  - The requirement of an intact cytoskeleton organization for G1/S cell cycle
      progression has been demonstrated in cultured cells. In the non-small-cell lung
      carcinoma cell line A549, the kinase inhibitor staurosporine induced G1 cell
      cycle arrest with an accumulation of the cyclin-dependent kinase inhibitor
      p27kip1. Staurosporine induced also a drastic change in cell shape that was
      accompanied by changes in the actin cytoskeleton. The cytoskeleton disruption
      agents, cytochalasin D (cyto D) and 2,3-butanedione 2-monoxime (BDM), also
      induced G1 cell cycle arrest in A549 cells but without an accumulation of
      p27kip1. A comparison of the cell shape changes caused by these agents revealed
      that a conversion from an epithelial polygonal shape to an elongated fibroblast
      like shape was specific for staurosporine. The shape change induced by
      staurosporine preceded the accumulation of p27kip1 by about 4 h. The accumulation
      of p27kip1 was not due to enhanced transcription but to stabilization of the
      protein resulting from the inhibition of proteolytic degradation. Staurosporine,
      however, did not inhibit directly the proteasome that was involved in the cell
      cycle-dependent p27kip1 degradation. The results indicate that the cell shape
      change caused by staurosporine correlates with the accumulation of p27kip1 and
      that staurosporine interferes with the p27kip1-specific proteolysis activity.

PMID- 12413890
TI  - Collagen modulates gene activation of plasminogen activator system molecules.
AB  - Skin extracellular matrix (ECM) molecules regulate a variety of cellular
      activities, including cell movement, which are central to wound healing and
      metastasis. Regulated cell movement is modulated by proteases and their
      associated molecules, including the serine proteases urinary-type plasminogen
      activator (uPA) and tissue-type plasminogen activator (tPA) and their inhibitors
      (PAIs). As a result of wounding and loss of basement membrane structure,
      epidermal keratinocytes can become exposed to collagen. To test the hypothesis
      that during wounding, exposed collagen, the most abundant ECM molecule in the
      skin, regulates keratinocyte PA and PAI gene expression, we utilized an in vitro
      model in which activated keratinocytes were cultured in dishes coated with
      collagen or other ECM substrates. tPA, uPA, and PAI-1 mRNA and enzymatic activity
      were detected when activated keratinocytes attached to fibronectin, vitronectin,
      collagen IV, and RGD peptide. In contrast, adhesion to collagen I and collagen
      III completely suppressed expression of PAI-1 mRNA and protein and further
      increased tPA expression and activity. Similarly, keratinocyte adhesion to
      laminin-1 suppressed PAI-1 mRNA and protein expression and increased tPA
      activity. The suppressive effect of collagen I on PAI-1 gene induction was
      dependent on the maintenance of its native fibrillar structure. Thus, it would
      appear that collagen- and laminin-regulated gene expression of molecules
      associated with plasminogen activation provides an additional dimension in the
      regulation of cell movement and matrix remodeling in skin wound healing.

PMID- 12413891
TI  - Keratinocyte apoptosis on type I collagen gel caused by lack of laminin 5/10/11
      deposition and Akt signaling.
AB  - Cultured human foreskin keratinocytes (HFKs) adhere to and grow on nonfibrous
      collagen via integrin alpha2beta1. During incubation, the receptors used for
      adhesion are changed to integrins alpha3beta1 and alpha6beta4 and those receptors
      bind to laminin 5 which is deposited by keratinocytes themselves. In this report,
      we examined the behaviors of HFKs and transformed keratinocytes on collagen
      fibril gels. These cells adhered to and spread on collagen gels using integrin
      alpha2beta1. After several hours on collagen gels, however, cells became round
      and apoptosis occurred. The behavior of keratinocytes contrasted to that of
      fibroblasts that grew well even on collagen gel. At the point of apoptosis,
      integrins alpha2beta1 and alpha3beta1 were not found in the contact region of
      HFKs. Also, deposition of laminin 5 on collagen gel was not found despite the
      synthesis of mRNA for laminin 5 and laminin 10/11, while soluble laminin 5
      protein is readily detectable. Phosporylation of Akt, which is known as a
      survival signal, was detected in HFKs cultured on coated collagen; however, the
      protein level and signals of Akt were dramatically decreased on collagen gel
      after 1 day of culture. These results indicate that collagen gel has different
      effects than nonfibrous collagen on HFKs and transformed keratinocytes and the
      interactions of integrin alpha3beta1 and laminin 5/10/11 are indispensable for
      maintenance of keratinocyte adhesion and survival.

PMID- 12413893
TI  - Human secreted frizzled-related protein is down-regulated and induces apoptosis
      in human cervical cancer.
AB  - To identify genes involved in cervical carcinogenesis, the mRNA differential
      display method was used. A 220-bp cDNA fragment called CA11 was present in normal
      cervical tissue but not in primary cervical cancer tissue or cervical cancer cell
      lines. CA11 exhibited 98% homology with the recorded human secreted frizzled
      related protein (hsFRP) sequence. A dominant hsFRP mRNA transcript of
      approximately 4.6 kb was present in three normal cervical tissues examined.
      Expression of the transcript was nearly absent from three cervical cancer tissues
      and from five human cervical cancer-derived cell lines. Results from in situ
      hybridization showed that the hsFRP transcript was confined to the normal
      cervical epithelial layer. When hsFRP-transfected HeLa and CUMC-6 cervical cancer
      cells were cultured in serum-free medium, most of the cells died within 8 days.
      This effect is associated with the apoptotic process. The caspase-3 inhibitor 1,
      Ac-DEVD-CHO, blocked hsFRP-induced apoptotic cell death. Additionally, cleavage
      of poly (ADP-ribose) polymerase in hsFRP-transfected cells was confirmed by
      colorimetric assay. These results indicate that the hsFRP gene probably functions
      as a tumor suppressor in normal cervical epithelium and down-regulation of hsFRP
      contributes to development of cervical cancer.

PMID- 12413894
TI  - Keeping the receptor tyrosine kinase signaling pathway in check: lessons from
      Drosophila.
AB  - The receptor tyrosine kinase (RTK) signaling network plays a central role in
      regulating cellular differentiation, proliferation, and survival in all metazoan
      animals. Excessive or continuous activation of the RTK pathway has been linked to
      carcinogenesis in mammals, underscoring the importance of preventing uncontrolled
      signaling. This review will focus on the inhibitory mechanisms that keep RTK
      mediated signals in check, with emphasis on conserved principles discerned from
      studies using Drosophila as a model system. Two general strategies of inhibition
      will be discussed. The first, threshold regulation, postulates that an effective
      way of antagonizing RTK signaling is to erect and maintain high threshold
      barriers that prevent inappropriate responses to moderate signaling levels.
      Activation of the pathway above this level overcomes the inhibitory blocks and
      shifts the balance to allow a positive flow of inductive information. A second
      layer of negative regulation involving induction of negative feedback loops that
      limit the extent, strength, or duration of the signal prevents runaway signaling
      in response to the high levels of activation required to surmount the threshold
      barriers. Such autoinhibitory mechanisms attenuate signaling at critical points
      throughout the network, from the receptor to the downstream effectors.

PMID- 12413892
TI  - Survival signaling in type II pneumocytes activated by surfactant protein-A.
AB  - Surfactant-associated protein-A (SP-A) is a component of pulmonary surfactant
      that acts as a cytokine through interaction with a cell-surface receptor (SPAR)
      on lung epithelial cells. SP-A regulates important physiological processes
      including surfactant secretion, gene expression, and protection against
      apoptosis. Tyrosine kinase and PI3K inhibitors block effects of SP-A, suggesting
      that SPAR may be a receptor tyrosine kinase and activate the PI3K-PKB/Akt
      pathway. Here we report that SP-A treatment leads to rapid tyrosine-specific
      phosphorylation of several important proteins in lung epithelial cells including
      insulin receptor substrate-1 (IRS-1), an upstream activator of PI3K. Analysis of
      anti-apoptotic signaling species downstream of IRS-1 showed activation of PKB/Akt
      but not of MAPK. Phosphorylation of IkappaB was minimally affected by SP-A as was
      NFkappaB gel shift activity. However, FKHR was rapidly phosphorylated in response
      to SP-A and its DNA-binding activity was significantly reduced. Since FKHR is pro
      apoptotic, this may play an important role in signaling the anti-apoptotic
      effects of SP-A. Therefore, we have characterized survival-enhancing signaling
      activated by SP-A leading from SPAR through IRS-1, PI3K, PKB/Akt, and FKHR. The
      activity of this pathway may explain, in part, the resilience of type II cells to
      lung injury and their survival to repopulate alveolar epithelium after peripheral
      lung damage.

PMID- 12413895
TI  - Temperature-sensitive inhibition of development in Dictyostelium due to a point
      mutation in the piaA gene.
AB  - The Dictyostelium mutant HSB1 is temperature-sensitive for development,
      undergoing aggregation and fruiting body formation at temperatures below 18
      degrees C but not above. In vivo G protein-linked adenylyl cyclase activation is
      defective in HSB1, and the enzyme is not stimulated in vitro by GTPgammaS;
      stimulation is restored upon addition of wild-type cytosol. Transfection with the
      gene encoding the cytosolic regulator PIA rescued the mutant. We excluded the
      possibility that HSB1 cells fail to express PIA and show that the HSB1 piaA gene
      harbors a point mutation, resulting in the amino acid exchange G(917)D. Both wild
      type and HSB1 cells were also transfected with the HSB1 piaA gene. The piaA(HSB1)
      gene product displayed a partial inhibitory effect on wild-type cell development.
      We hypothesize that PIA couples the heterotrimeric G protein to adenylyl cyclase
      via two binding sites, one of which is altered in a temperature-sensitive way by
      the HSB1 mutation. When overexpressed in the wild-type background, PIA(HSB1)
      competes with wild-type PIA via the nonmutated binding site, resulting in
      dominant-negative inhibition of development. Expression of GFP-fused PIA shows
      that PIA is homogeneously distributed in the cytoplasm of chemotactically moving
      cells.

PMID- 12413896
TI  - Disabled-2 is essential for endodermal cell positioning and structure formation
      during mouse embryogenesis.
AB  - The signal transduction adapter protein Disabled-2 (Dab2) is one of the two
      mammalian orthologs of the Drosophila Disabled. The brain-specific Disabled-1
      (Dab1) functions in positional organization of brain cells during development.
      Dab2 is widely distributed and is highly expressed in many epithelial cell types.
      The dab2 gene was interrupted by in-frame insertion of beta-galactosidase (LacZ)
      in embryonic stem cells and transgenic mice were produced. Dab2 expression was
      first observed in the primitive endoderm at E4.5, immediately following
      implantation. The homozygous Dab2-deficient mutant is embryonic lethal (earlier
      than E6.5) due to defective cell positioning and structure formation of the
      visceral endoderm. In E5.5 dab2 (-/-) conceptus, visceral endoderm-like cells are
      present in the deformed primitive egg cylinder; however, the visceral endoderm
      cells are not organized, the cells of the epiblast have not expanded, and the
      proamniotic cavity fails to form. Disorganization of the visceral endodermal
      layer is evident, as cells with positive visceral endoderm markers are scattered
      throughout the dab2 (-/-) conceptus. Only degenerated remains were observed at
      E6.5 for dab2 (-/-) embryos, and by E7.5, the defective embryos were completely
      reabsorbed. In blastocyst in vitro culture, initially cells with characteristics
      of endoderm, trophectoderm, and inner cell mass were observed in the outgrowth of
      the hatched dab2 (-/-) blastocysts. However, the dab2 (-/-) endodermal cells are
      much more dispersed and disorganized than those from wild-type blastocysts, the
      inner cell mass fails to expand, and the outgrowth degenerates by day 7. Thus,
      Dab2 is required for visceral endodermal cell organization during early mouse
      development. The absence of an organized visceral endoderm in Dab2-deficient
      conceptus leads to the growth failure of the inner cell mass. We suggest that
      Dab2 functions in a signal pathway to regulate endodermal cell organization using
      endocytosis of ligands from the blastocoel cavity as a positioning cue.

PMID- 12413897
TI  - Neurogenin1 defines zebrafish cranial sensory ganglia precursors.
AB  - Cells delaminate from epithelial placodes to form sensory ganglia in the
      vertebrate head. We describe the formation of cranial neurogenic placodes in the
      zebrafish, Danio rerio, using bHLH transcription factors as molecular markers. A
      single neurogenin gene, neurogenin1 (ngn1), is required for the development of
      all zebrafish cranial ganglia, which contrasts with other described vertebrates.
      Expression of ngn1 delineates zebrafish ganglionic placodes, including
      trigeminal, lateral line, and epibranchial placodes. In addition, ngn1 is
      expressed in a subset of cells within the otic vesicle that will delaminate to
      form the octaval (statoacoustic) ganglion. The trigeminal placode is the first to
      differentiate, and forms just lateral and adjacent to the neural crest.
      Expression of ngn1 is transient and prefigures expression of a related bHLH
      transcription factor, neuroD. Interfering with ngn1 function using a specific
      antisense morpholino oligonucleotide blocks differentiation of all cranial
      ganglia but not associated glial cells. Lateral line sensory neuromasts develop
      independently of ngn1 function, suggesting that two derivatives of lateral line
      placodes, ganglia and migrating primordia, are under separate genetic control.

PMID- 12413898
TI  - The dorsal-ventral axis of the neural retina is divided into multiple domains of
      restricted gene expression which exhibit features of lineage compartments.
AB  - The neural retina is a complex sensory structure designed to receive, integrate,
      and transmit visual information. An important aspect of retinal development is
      the establishment of pattern along the dorsal-ventral (D-V) and anterior
      posterior (A-P) axes. The recent identification and functional characterization
      of a dorsal-specific and a ventral-specific transcription factor suggested that
      the D-V axis is divided into two domains. This study characterizes the expression
      patterns of these and other D-V markers, and establishes that the retina is
      subdivided into at least four domains of gene expression along this axis. The
      composition and spatial relation of these expression domains alters our model of
      D-V patterning, suggesting more complexity in the way that the retina is
      patterned than was previously recognized. As domains of gene expression within
      developing tissues sometimes comprise compartments whose borders are not crossed
      by clonally related cells, we performed a retroviral lineage study. A strong
      preference for cells to remain in their original domain of gene expression was
      observed, suggesting that these borders comprise developmental compartments.

PMID- 12413899
TI  - Morphogenetic apoptosis: a mechanism for correcting discontinuities in morphogen
      gradients.
AB  - Smooth gradients of the morphogens Hh, Dpp, and Wg are required for proper
      development of Drosophila imaginal discs. Here, it is reported that, when a
      discontinuity is generated between two adjacent cells in the reception of either
      the Dpp or Wg signal, then cells on either side of the discontinuity boundary
      undergo apoptosis by activating the c-Jun N-terminal Kinase (JNK) pathway.
      Furthermore, in the medial region of the wing imaginal disc, the JNK pathway is
      also activated if cells do not receive the proper levels of Dpp and Hh signals.
      These observations suggest that cells within a developing field have the ability
      to access their spatial positions by comparing the level of morphogen signal they
      receive with that of their neighbors. This phenomenon is likely related to the
      process of cell competition, and we suggest that it is an evolutionarily
      important mechanism that helps prevent abnormal tissue specification and growth
      during development.

PMID- 12413900
TI  - Regulation of specific developmental fates of larval- and adult-type muscles
      during metamorphosis of the frog Xenopus.
AB  - During anuran metamorphosis, larval-type myotubes in both trunk and tail are
      removed by apoptosis, and only trunk muscles are replaced by newly formed adult
      type myotubes. In the present study, we clarified the regulatory mechanisms for
      specific developmental fates of adult and larval muscles. Two distinct (adult and
      larval) types of myoblasts were found to exist in the trunk, but no or very few
      adult myoblasts were found in the tail. Each type of myoblast responded
      differently to metamorphic trigger, 3,3',5-triiodo-L-thyronine (T(3)) in vitro.
      T(3)-induced cell death was observed in larval myoblasts but not in adult
      myoblasts. These results suggest that the fates (life or death) of trunk and tail
      muscles are determined primarily by the differential distribution of adult
      myoblasts within the muscles. However, a transplantation study clarified that
      each larval and adult myoblast was not committed to fuse into particular myotube
      types, and they could form heterokaryon myotubes in vivo. Cell culture
      experiments suggested that the following two mechanisms are involved in the
      specification of myotube fate: (1) Heterokaryon myotubes could escape T(3)
      induced death only when the proportion of adult nuclei number was higher than 70%
      in the myotubes. Apoptosis was not observed in any larval nuclei within the
      surviving heterokaryon myotubes, suggesting the conversion of larval nuclei fate.
      (2) Differentiation of adult myoblasts was promoted by the factor(s) released
      from larval myoblasts in a cell type-specific manner. Taken together, the
      developmental fate of myotubes is determined by the ratio of nuclei types, and
      the formation of adult nuclei-rich myotubes was specifically enhanced by larval
      myoblast factor(s).

PMID- 12413901
TI  - Radar is required for the establishment of vascular integrity in the zebrafish.
AB  - The precise assembly of an integrated network of blood vessels is essential for
      the survival of vertebrate embryos. However, the processes by which primitive
      endothelial cells form mature vessels capable of supplying oxygen and nutrients
      to developing tissues remain incompletely understood. Here, we propose a role for
      Radar, one of the zebrafish orthologues of gdf6, in establishing integrity of the
      trunk vasculature in zebrafish embryos. We show that radar expression is
      appropriately placed, both spatially and temporally, to perform such a role.
      Transcripts for radar are detected in the hypochord and the primitive gut
      endoderm. These tissues intimately flank developing axial vessels in the trunk
      and have been previously implicated in the regulation of vascular development.
      Morpholino-based targeted gene knock-down has generated a Radar-specific loss-of
      function zebrafish model. These embryos display normal initiation of vascular
      patterning and commencement of circulation. However, by day 2 of development, the
      integrity of the axial vasculature is compromised with hemorrhages and
      circulation short-circuits throughout the developing trunk. We show that this
      aberrant vascular development is specific to a reduction of the radar gene
      product. These results suggest that Radar is involved in a signaling pathway
      required for establishing the integrity of the axial vessels during zebrafish
      development.

PMID- 12413902
TI  - Apoptosis of premigratory neural crest cells in rhombomeres 3 and 5: consequences
      for patterning of the branchial region.
AB  - In the avian hindbrain, premigratory neural crest cells undergo programmed cell
      death (apoptosis) in rhombomeres 3 and 5 (r3, r5). Here, we have attempted to
      analyze the significance of the loss of neural crest cells from these odd
      numbered rhombomeres. When apoptosis is prevented in r3 and r5, r3 crest migrate
      into the first arch and r5 into the third arch. Interestingly, these extra neural
      crest cells contributed to the formation of ectopic muscle attachment sites that
      are also found in those species in which r3 and r5 neural crest cells do not
      undergo apoptosis. Thus, apoptosis in the odd-numbered rhombomeres appears to be
      an evolutionarily derived mechanism that is required to eliminate r3 and r5 crest
      migration into first and third arches and thereby remove these muscle attachment
      sites.

PMID- 12413903
TI  - The Fused toes (Ft) mouse mutation causes anteroposterior and dorsoventral
      polydactyly.
AB  - Mouse mutants have been proven to be a valuable system to analyze the molecular
      network governing vertebrate limb development. In the present study, we report on
      the molecular and morphological consequences of the Fused toes (Ft) mutation on
      limb morphogenesis in homozygous embryos. We show that Ft affects all three axes
      as the mutant limbs display severe distal truncations of skeletal elements as
      well as an anteroposterior and an unusual form of dorsoventral polydactyly.
      Ectopic activation of the Shh signalling cascade in the distal-most mesoderm
      together with malformations of the AER likely account for these alterations.
      Moreover, we provide evidence that a deregulated control of programmed cell death
      triggered by Bmp-4 and Dkk-1 significantly contributes to the complex limb
      phenotype. In addition, our analysis reveals a specific requirement of the genes
      deleted by the Ft mutation in hindlimb morphogenesis.

PMID- 12413904
TI  - The Wnt antagonist Frzb-1 regulates chondrocyte maturation and long bone
      development during limb skeletogenesis.
AB  - The Wnt antagonist Frzb-1 is expressed during limb skeletogenesis, but its roles
      in this complex multistep process are not fully understood. To address this
      issue, we determined Frzb-1 gene expression patterns during chick long bone
      development and carried out gain- and loss-of-function studies by misexpression
      of Frzb-1, Wnt-8 (a known Frzb-1 target), or different forms of the intracellular
      Wnt mediator LEF-1 in developing limbs and cultured chondrocytes. Frzb-1
      expression was quite strong in mesenchymal prechondrogenic condensations and then
      characterized epiphyseal articular chondrocytes and prehypertrophic chondrocytes
      in growth plates. Virally driven Frzb-1 misexpression caused shortening of
      skeletal elements, joint fusion, and delayed chondrocyte maturation, with
      consequent inhibition of matrix mineralization, metalloprotease expression, and
      marrow/bone formation. In good agreement, misexpression of Frzb-1 or a dominant
      negative form of LEF-1 in cultured chondrocytes maintained the cells at an
      immature stage. Instead, misexpression of Wnt-8 or a constitutively active LEF-1
      strongly promoted chondrocyte maturation, hypertrophy, and calcification.
      Immunostaining revealed that the distribution of endogenous Wnt mediator beta
      catenin changes dramatically in vivo and in vitro, from largely cytoplasmic in
      immature proliferating and prehypertrophic chondrocytes to nuclear in
      hypertrophic mineralizing chondrocytes. Misexpression of Frzb-1 prevented beta
      catenin nuclear relocalization in chondrocytes in vivo or in vitro. The data
      demonstrate that Frzb-1 exerts a strong influence on limb skeletogenesis and is a
      powerful and direct modulator of chondrocyte maturation, phenotype, and function.
      Phases of skeletogenesis, such as terminal chondrocyte maturation and joint
      formation, appear to be particularly dependent on Wnt signaling and thus very
      sensitive to Frzb-1 antagonistic action.

PMID- 12413905
TI  - The role of neural crest during cardiac development in a mouse model of DiGeorge
      syndrome.
AB  - The velo-cardio-facial syndrome (VCFS)/DiGeorge syndrome (DGS) is a genetic
      disorder characterized by phenotypic abnormalities of the derivatives of the
      pharyngeal arches, including cardiac outflow tract defects. Neural crest cells
      play a major role in the development of the pharyngeal arches, and defects in
      these cells are likely responsible for the syndrome. Most patients are hemizygous
      for a 1.5- to 3.0-Mb region of 22q11, that is suspected to be critical for normal
      pharyngeal arch development. Mice hemizygous for a 1.5-Mb homologous region of
      chromosome 16 (Lgdel/+) exhibit conotruncal cardiac defects similar to those seen
      in affected VCFS/DGS patients. To investigate the role of Lgdel genes in neural
      crest development, we fate mapped neural crest cells in Lgdel/+ mice and we
      performed hemizygous neural crest-specific inactivation of Lgdel. Hemizygosity of
      the Lgdel region does not eliminate cardiac neural crest migration to the forming
      aortic arches. However, neural crest cells do not differentiate appropriately
      into smooth muscle in both fourth and sixth aortic arches and the affected aortic
      arch segments develop abnormally. Tissue-specific hemizygous inactivation of
      Lgdel genes in neural crest results in normal cardiovascular development. Based
      on our studies, we propose that Lgdel genes are required for the expression of
      soluble signals that regulate neural crest cell differentiation.

PMID- 12413906
TI  - Constitutive expression of preproendothelin in the cardiac neural crest
      selectively promotes expansion of the adventitia of the great vessels in vivo.
AB  - Cardiac neural crest cells are essential for normal development of the great
      vessels and the heart, giving rise to a range of cell types, including both
      neuronal and non-neuronal adventitial cells and smooth muscle. Endothelin (ET)
      signaling plays an important role in the development of cardiac neural crest cell
      lineages, yet the underlying mechanisms that act to control their migration,
      differentiation, and proliferation remain largely unclear. We examined the
      expression patterns of the receptor, ET(A), and the ET-specific converting
      enzyme, ECE-1, in the pharyngeal arches and great vessels of the developing chick
      embryo. In situ hybridization analysis revealed that, while ET(A) is expressed in
      the pharyngeal arch mesenchyme, populated by cardiac neural crest cells, ECE-1
      expression is localized to the outermost ectodermal cells of the arches and then
      to the innermost endothelial cells of the great vessels. This dynamic pattern of
      expression suggests that only a subpopulation of neural crest cells in these
      regions is responsive to ET signaling at particular developmental time points. To
      test this, retroviral gene delivery was used to constitutively express preproET
      1, a precursor of mature ET-1 ligand, in the cardiac neural crest. This resulted
      in a selective expansion of the outermost, adventitial cell population in the
      great vessels. In contrast, neither differentiation nor proliferation of neural
      crest-derived smooth muscle cells was significantly affected. These results
      suggest that constitutive expression of exogenous preproET-1 in the cardiac
      neural crest results in expansion restricted to an adventitial cell population of
      the developing great vessels.

PMID- 12413907
TI  - The Caenorhabditis elegans presenilin sel-12 is required for mesodermal
      patterning and muscle function.
AB  - Mutations in presenilin genes impair Notch signalling and, in humans, have been
      implicated in the development of familial Alzheimer's disease. We show here that
      a reduction of the activity of the Caenorhabditis elegans presenilin sel-12
      results in a late defect during sex muscle development. The morphological
      abnormalities and functional deficits in the sex muscles contribute to the egg
      laying defects seen in sel-12 hermaphrodites and to the severely reduced mating
      efficiency of sel-12 males. Both defects can be rescued by expressing sel-12 from
      the hlh-8 promoter that is active during the development of the sex muscle
      specific M lineage, but not by expressing sel-12 from late muscle-specific
      promoters. Both weak and strong sel-12 mutations cause defects in the sex muscles
      that resemble the defects we found in lin-12 hypomorphic alleles, suggesting a
      previously uncharacterised LIN-12 signalling event late in postembryonic mesoderm
      development. Together with a previous study indicating a role of lin-12 and sel
      12 during the specification of the pi cell lineage required for proper vulva
      uterine connection, our data suggest that the failure of sel-12 animals to lay
      eggs properly is caused by defects in at least two independent signalling events
      in different tissues during development.

PMID- 12413910
TI  - Multislice computed tomography cardiac imaging: current status.
AB  - Non-invasive CT coronary artery imaging has previously had little relevance to
      most UK radiologists due to the limited availability of electron beam CT
      scanners. Major advances in CT technology have promoted new applications for
      helical CT, which include cardiac imaging. Widespread installation of
      'multislice' helical CT scanners will make CT coronary artery imaging available
      for the first time in many UK hospitals. The technical advances and early
      clinical trial data are reviewed and multislice helical CT cardiac imaging in
      general is discussed.

PMID- 12413911
TI  - Does testicular microlithiasis matter? A review.
AB  - Radiologists who regularly undertake ultrasound of the testes will occasionally
      encounter testicular microlithiasis (TM). Currently, the management of a patient
      with TM is a conundrum for clinician and radiologist alike: there are reported
      associations between TM and primary testicular malignancy and infertility.
      However, there is no consensus on the appropriate follow-up (clinical,
      radiological or otherwise) of patients with TM. Furthermore, it is not clear
      whether the incidence of de novotumours is increased in patients with pre
      existing TM. Similarly, there is limited evidence to support the association with
      infertility. Not surprisingly, algorithms for the follow-up of patients with TM
      on ultrasound have been difficult to formulate.

PMID- 12413912
TI  - Who writes guidelines, and who should?
AB  - AIM: To confirm or refute the impression that diagnostic radiology was often not
      represented on guideline writing committees, despite the fact that guidelines
      often made statements with implications for radiological practice. MATERIALS AND
      METHODS: We took two approaches. Firstly we examined all published Scottish
      Intercollegiate Guidelines Network (SIGN) guidelines and extracted the disease
      topic, the number of authors and peer reviewers, the number that were
      radiologists, and independently decided whether, given the content, radiologist
      input at the writing or review stage was necessary. We also searched for all
      guidelines on management of stroke worldwide (a single disease topic with major
      radiological implications) and extracted the proportion of authors that were
      radiologists. RESULTS: Of 47 SIGN guidelines on different diseases, 11 (23%) had
      a radiologist in the authorship (13/594, 2.2% total authors), and 5/47 (11%) had
      a radiologist specialist reviewer (10/529, 1.8% total reviewers). Independent
      review of the guidelines' content suggested that 76% of guidelines should have
      had a radiologist author and 91% a radiologist reviewer (discrepancy 53% and 80%
      respectively). Amongst 22 guidelines on acute stroke management in the world
      literature with 202 authors (where stated), there were only two radiologists
      (1%), both on one guideline which was specifically to do with imaging of stroke
      (5% of all stroke guidelines identified). CONCLUSION: Diagnostic radiology is
      poorly represented on guideline writing committees, although frequently
      guidelines have implications for radiological practice. Radiologists should try
      to be more involved in guideline production.

PMID- 12413913
TI  - Predictive value of benign percutaneous adrenal biopsies in oncology patients.
AB  - PURPOSE: Percutaneous CT guided biopsy is accepted as a safe procedure for the
      diagnosis of indeterminate adrenal masses in oncologic patients. The purpose of
      this study was to evaluate the accuracy of a 'negative for tumour' adrenal biopsy
      in the oncologic patient population by assessing subsequent outcome including
      clinical course, size and imaging characteristics of the adrenal lesions on
      follow-up imaging studies and pathological findings at re-biopsy or following
      adrenal mass resection. MATERIALS AND METHODS: Retrospective analysis of 225
      oncological patients (FM, 128;87; age range 33-87 years, mean age 66 years) who
      had undergone CT guided biopsies of an adrenal mass over a 5-year period was
      performed. Those patients with a report consistent with 'negative for malignancy'
      were evaluated by reviewing the medical records for patient demographics, primary
      malignancy, histology of adrenal tumour, subsequent surgical interventions,
      repeat adrenal biopsy under image guidance, by open surgery or at autopsy,
      subsequent abdominal imaging in which the adrenal gland was imaged, and long-term
      outcome including hospital admissions, or death. RESULTS: Of the 225 CT-guided
      adrenal biopsies performed, 41 (18%) were negative for neoplasm. The primary
      neoplasm in these 41 patients included lung cancer (n=32), breast (n=5), renal
      cell carcinoma (n=2), bladder (n=1), and prostate (n=1). The size of the adrenal
      lesions ranged from 2.8-5 cm. Of the 41 biopsies, which were negative for tumour;
      10 were identified as adenomas and the rest showed benign adrenal cortical cells
      or hyperplasia on cytopathology and histopathology. Repeat biopsies were obtained
      in 13/41 (31%) patients; whereas 2/41 (5%) had their adrenal gland analyzed on
      post mortem examination. None of these 15 repeat evaluations yielded tumour.
      CONCLUSION: In oncological patients, pathological analysis of tissue samples
      obtained by CT-guided percutaneous biopsy, suggesting benign aetiology, is
      reliable and predicts a benign course on long-term follow-up. A negative or
      benign pathology result for a CT guided percutaneous adrenal biopsy can be
      regarded as a true negative evaluation in oncological patients with no necessity
      to repeat the biopsy.

PMID- 12413914
TI  - Radiation dose reduction in chest radiography using a flat-panel amorphous
      silicon detector.
AB  - AIM: The aim of this study was to evaluate the image quality and the potential
      for radiation dose reduction with a digital flat-panel amorphous silicon detector
      radiography system. MATERIAL AND METHODS: Using flat-panel technology,
      radiographs of an anthropomorphic thorax phantom were taken with a range of
      technical parameters (125kV, 200mA and 5, 4, 3.2, 2, 1, 0.5, and 0.25mAs) which
      were equivalent to a radiation dose of 332, 263, 209, 127, 58.7, 29, and 14
      microGy, respectively. These images were compared to radiographs obtained by a
      conventional film-screen radiography system at 125kV, 200mA and 5mAs (equivalent
      to 252 microGy) which served as reference. Three observers evaluated
      independently the visibility of simulated rounded lesions and anatomical
      structures, comparing printed films from the flat-panel amorphous silicon
      detector and conventional x-ray system films. RESULTS: With flat-panel
      technology, the visibility of rounded lesions and normal anatomical structures at
      5, 4, and 3.2mAs was superior compared to the conventional film-screen
      radiography system. (P< or =0.0001). At 2mAs, improvement was only marginal
      (P=0.19). At 1.0, 0.5 and 0.25mAs, the visibility of simulated rounded lesions
      was worse (P< or =0.004). Comparing fine lung parenchymal structures, the flat
      panel amorphous silicon detector showed improvement for all exposure levels down
      to 2mAs and equality at 1mAs. CONCLUSION: Compared to a conventional x-ray film
      system, the flat-panel amorphous silicon detector demonstrated improved image
      quality and the possibility for a reduction of the radiation dose by 50% without
      loss in image quality.

PMID- 12413915
TI  - The role of follow-up imaging in paediatric blunt abdominal trauma.
AB  - AIM: To assess the role of follow-up imaging in paediatric blunt abdominal
      trauma. METHOD: All children who underwent CT scanning of their abdomen at our
      institution following acute blunt injury between January 1997 and December 2000
      were included in the study. Case notes where researched for details regarding
      mechanism of injury, initial clinical presentation, acute management,
      complications and follow-up until discharge. Reports of imaging investigations
      were retrieved from the RIS database. RESULTS: In the study period 75 children
      underwent CT scanning of their abdomen as a primary investigation for acute blunt
      abdominal trauma. Of these, 12 were normal, 52 showed evidence of intra-abdominal
      organ injury and 11 showed findings other than abdominal organ injury. Of the 52
      children that sustained intra-abdominal organ injury, 48 (92 percent) were
      treated conservatively. 4 (8 percent) underwent emergency surgery, 3 for bowel
      injury and 1 for renal trauma. Of the 48 that were treated conservatively, 9 had
      a complicated clinical course with 7 showing complications on follow-up imaging.
      The remaining 39 children had an uneventful clinical course with follow-up
      imaging by CT or US in 34. None showed complications that required a change in
      management. CONCLUSION: In our series, follow-up imaging did not contribute to
      further management in children with an uncomplicated clinical course following
      blunt abdominal trauma.

PMID- 12413916
TI  - Ultrasound and magnetic resonance imaging assessmentof active bowel segments in
      Crohn's disease.
AB  - AIM: Determining bowel disease activity in Crohn's patients can be difficult on
      clinical and laboratory assessment. Endoscopy is invasive and barium studies use
      ionising radiation. The aim of this study was to compare ultrasound and magnetic
      resonance imaging (MRI) in detecting Crohn's disease activity in the small or
      large bowel. MATERIALS AND METHODS: Thirty patients, previously diagnosed with
      Crohn's disease, had bowel ultrasound and MR imaging, and were deemed active or
      inactive on each test. The 'gold standard' was based on clinical assessment and
      one or more of the following: endoscopy, barium studies or surgery. RESULTS: For
      determining Crohn's disease activity, the sensitivities and specificities of
      bowel ultrasound and MRI were 87 percent and 100 percent, and 87 percent and 71
      percent, respectively. Significant parameters that defined disease activity were
      bowel wall thickening on ultrasound and MRI, and contrast enhancement of the
      bowel wall and mesenteric vascularity/stranding on MRI. CONCLUSION: Ultrasound
      and MRI were both sensitive for determining Crohn's disease activity in the
      bowel, but MRI with gadolinium enhancement was less specific.

PMID- 12413917
TI  - Tophaceous gout of the spine: MR imaging features.
AB  - AIM: To define the magnetic resonance (MR) imaging features of tophaceous gout of
      the spine. MATERIALS AND METHODS: We present the MR imaging examinations of 4
      patients with spinal tophaceous gout. Spin-echo T1-weighted and fast spin-echo T2
      weighted images were obtained for all patients, and 2 patients had gadolinium
      enhanced MR imaging studies. Corresponding computed tomography (CT) was performed
      in one patient. All images were evaluated for the characteristics of the gouty
      tophi. RESULTS: The gouty tophi were located at the lower thoracic (n=1) and
      lumbar (n=3) levels. All tophi yielded homogeneous intermediate to low signal on
      T1-weighted images and variable signal intensity on T2-weighted images,
      comprising small foci of very low signal intensity on all sequences. Gadolinium
      enhanced MR imaging studies revealed homogeneous enhancement or heterogeneous
      peripheral enhancement. Diffuse stippled calcifications were found in the tophi
      on CT images. Periarticular tophi with juxtaarticular bony erosions around facet
      joints occurred in 3 patients. CONCLUSION: Spinal tophaceous gout should be
      considered in the differential diagnosis when periarticular deposits contain very
      low signal foci on all MR imaging sequences.

PMID- 12413918
TI  - Magnetic resonance imaging appearances of the uterus following microwave
      endometrial ablation.
AB  - AIM: Microwave endometrial ablation (MEA) is a treatment for dysfunctional
      uterine bleeding. It is a second generation ablative technique which is as
      effective as hysteroscopic methods but quicker and easier to perform. Our aim is
      to describe the Magnetic Resonance Imaging (MRI) appearances of the uterus
      following this procedure. METHODS: 15 women underwent MRI immediately before MEA,
      and again at one day and 4 months after treatment. T1 and T2 sequences were
      performed at 1.0T using a body coil. Images were assessed by 2 independent
      observers for quantitative and qualitative changes. Clinical questionnaires were
      completed before treatment and at 4 months. RESULTS: On images obtained one day
      post-ablation, 14 patients had a low signal intensity band subjacent to the
      treated area of the endometrial cavity on T2 images. Imaging at 4 months showed
      significant amounts of endometrial tissue in 11 patients, including 3 of the 6
      patients who were amenorrhoeic. There were no changes in the appearances of
      myometrium or uterine dimensions and there were no haematometra. CONCLUSIONS: The
      detection of residual endometrium by MRI means that unopposed oestrogen hormone
      replacement therapy should be avoided after MEA, even in women who have
      amenorrhoea. Thepost-operative sub-endometrial low signal intensity zone
      corresponds to the region of tissue necrosis detected on vital staining of the
      treated uterus in in vivotesting. Depth of tissue destruction is a surrogate
      marker for clinical effectiveness. MRI may have a role in early assessment of
      patients participating in clinical research who are undergoing a modified MEA
      technique while retaining their uterus.

PMID- 12413919
TI  - The in vitro and in vivo ultrasonographic appearances of the angio-seal
      percutaneous closure device.
AB  - PURPOSE: To assess the ultrasound appearances of the Angio-Seal device in an
      animal model and in twenty patients following catheterization of the femoral
      artery. MATERIALS AND METHODS: Ten patients were scanned within 8 hours of their
      procedure (early group) and 10 at two to four days (delayed group) using Acuson
      Aspen and Sequoia scanners. Colour flow images were taken and Doppler spectral
      analysis was performed proximal proximal to, at and distal to the Angio-Seal
      device. Early and delayed in vitro images were taken in a water bath in which the
      Angio-Seal device was deployed across a normal porcine aorta for comparison.
      RESULT: In the ten early patients colour and Doppler drop out were seen in 100
      percent and 90 percent respectively compared with 90 percent and 60 percent in
      the delayed group. The device was seen in 30 percent and 90 percent in early and
      delayed groups respectively. In the in vitro study the components of the device
      were seen and a posterior acustic shadow noted. This shadow was less obvious and
      the polymer anchor more easily seen in the delayed group. CONCLUSION: The Angio
      Seal device produces a consistent artifact when scanned soon after deployment.
      These appearances could potentially be mistaken for a vascular occlusion by the
      unwary in the appropriate clinical setting of acute post catheterisation lower
      limb ischaemia however an awareness of the normal sonographic appearances of this
      device would make this misinterpretation unlikely.

PMID- 12413920
TI  - The use of carbon suspension as an adjunct to wire localisation of impalpable
      breast lesions.
AB  - AIM: To determine the accuracy and therapeutic success of localisation of
      impalpable breast lesions by hookwire with additional lesion marking with carbon
      suspension to mark screen detected abnormalities requiring surgical excision.
      MATERIALS AND METHODS: Retrospective review of all breast localisation procedures
      performed in our unit on women with a screen detected abnormality requiring
      excision over a 7 year period. RESULTS: One hundred and thirty eight women
      underwent breast localisation procedures. All of the mammographic abnormalities
      were excised at the initial surgical procedure. The benign to malignant ratio was
      1:2. Pre-operative cytology was used to guide the extent of surgical excision,
      with clear margins in 70 of the 92 patients (75 percent) with malignancy. Twenty
      patients had further surgery: mastectomy in 7 and further local excision in 14.
      The localisation procedure was a therapeutic success in the local excision of
      malignancy in 73 of the 92 patients (79 percent) with malignancy. CONCLUSION:
      This method of localisation biopsy is an accurate technique for surgical excision
      of mammographically detected impalpable abnormalities. The surgeon is able to
      choose the site of surgical incision to give the best cosmetic result, the lesion
      is easier to identify at operation and the confidence that the abnormality has
      been excised is improved.

PMID- 12413921
TI  - Air in the main pancreatic duct revealed by abdominal ultrasound: an additional
      diagnostic sign in paediatric patients with duodenal obstruction.

PMID- 12413922
TI  - Primary non-Hodgkin's lymphoma of the cranial vault; MRI features before and
      after treatment.

PMID- 12413923
TI  - Internal carotid artery hypoplasia in two cases.

PMID- 12413924
TI  - Reviewing interval cancers: time well spent?

PMID- 12413928
TI  - The genetics of ovarian cancer.
AB  - A family history of ovarian cancer confers an increased risk of ovarian cancer.
      We review the literature quantifying the familial risks associated with ovarian
      cancer and assess the evidence that the familial clustering of ovarian cancer is
      genetically determined. We then describe the known high-penetrance genes, the
      ovarian cancer risks attached to them and their contribution to ovarian cancer in
      families and in the general population. The evidence for the existence of other
      ovarian cancer genes is then considered.

PMID- 12413929
TI  - Screening for ovarian cancer.
AB  - There has been considerable interest in the prospect of early detection of
      ovarian cancer through screening asymptomatic women, in both the general and
      'high-risk' populations. Over the last decade screening strategies using the
      serum marker CA126 and transvaginal ultrasound have been refined and encouraging
      data have emerged on the impact of screening on ovarian cancer survival rates.
      Two randomized controlled trials are now underway in the general population to
      establish the impact of screening on ovarian cancer mortality while
      comprehensively tackling the issues of compliance, health economics and physical
      and psychological morbidity. In addition, trials in the high-risk population
      aimed at optimizing the current strategy have commenced in both the USA and the
      UK.

PMID- 12413930
TI  - Molecular aspects of ovarian cancer.
AB  - Ovarian cancer is caused by genetic alterations that disrupt proliferation,
      apoptosis, senescence and DNA repair. Approximately 10% of ovarian cancers arise
      in women who have inherited mutations in cancer susceptibility genes (BRCA1 or
      BRCA2). The ability to perform genetic testing allows identification of women at
      increased risk who can be offered prophylactic oophorectomy or other
      interventions aimed at preventing ovarian cancer. The vast majority of ovarian
      cancers are sporadic, resulting from the accumulation of genetic damage over a
      lifetime. Several specific genes involved in ovarian carcinogenesis have been
      identified, including the p53 tumour suppressor gene and HER2/ neu andPIC3KA
      oncogenes. The recent availability of expression microarrays has facilitated the
      simultaneous examination of thousands of genes, and this promises to extend
      further our understanding of the molecular events involved in the development of
      ovarian cancers. Hopefully, this knowledge can be translated into effective
      screening, treatment, surveillance, and prevention strategies in the future.

PMID- 12413931
TI  - Pathology of borderline (low malignant potential) ovarian tumours.
AB  - Recent studies suggest that the borderline group of ovarian tumours can be
      subclassified into benign and malignant neoplasms. The survival for patients with
      serous borderline tumours confined to the ovaries is virtually 100%. Patients
      with serous borderline tumours with invasive peritoneal implants, and with
      micropapillary serous carcinomas (a distinctive neoplasm previously included in
      the borderline category), have a 30-40% mortality rate and therefore these
      tumours are classified as carcinomas. After these neoplasms are excluded, the
      remaining advanced stage serous borderline tumours (those with non-invasive
      implants) have a survival rate of nearly 100% and should be considered benign.
      Similarly, nearly all mucinous borderline tumours reported to display aggressive
      behaviour have been associated with pseudomyxoma peritonei, a condition now known
      to be of appendiceal origin. The remaining mucinous borderline tumours are always
      confined to the ovaries and have a benign behaviour. Since borderline tumours can
      now be classified into benign and malignant types, the category has no further
      utility.

PMID- 12413932
TI  - Clinical management potential tumours of low malignancy.
AB  - Approximately 3000 American women are diagnosed with borderline ovarian tumours
      annually. Common signs and symptoms include abdominal/pelvic pain and a palpable
      adnexal mass. Pelvic sonography may be helpful, although not specific, in the
      diagnosis. Serum CA 125 is abnormal in only about 50% of patients. Primary
      surgery is the principal treatment; it consists of resection of the primary
      tumour(s) (frequently in the form of fertility-sparing surgery), frozen-section
      analysis and consideration of comprehensive surgical staging. The role of
      surgical staging remains unclear; further research is necessary. For patients
      with stage I disease, surgery alone is the standard. For patients with stage II
      IV disease (with non-invasive or invasive peritoneal implants), the role of post
      operative therapy remains unclear. Approximately 20-30% of the latter will
      relapse, frequently after several years. Most so-called recurrences are low-grade
      carcinomas. Potential predictive or prognostic factors include age, FIGO stage,
      residual disease and the micropapillary pattern. After fertility-sparing surgery,
      most patients retain normal reproductive function.

PMID- 12413933
TI  - Role of lymphadenectomy in ovarian cancer.
AB  - The exact role of lymphadenectomy in the management of ovarian cancer has been
      the object of controversy during recent years. The International Federation of
      Obstetrics and Gynecology has indicated that pelvic and para-aortic lymph node
      sampling is an integral part of the staging system of ovarian cancer. On the
      other hand the advantage of systematic sampling, resection of bulky nodes only,
      or no lymphadenectomy in terms of recurrence rate and survival of ovarian cancer
      patients has not yet been clearly defined. Thanks to the analysis of clinical
      studies on systematic lymphadenectomy, detailed anatomical studies to assess the
      location of lymph nodes and lymphatic spread have been recently reported. In this
      chapter we report the available data on clinical anatomy and pathological
      assessment of lymph node and lymphatic spread of ovarian cancer metastasis; we
      also review the clinical data on correlation of lymph node metastasis and disease
      status. Surgical techniques developed during years of dedication to this
      procedure are also described. Finally, we review and discuss the actual benefits
      of lymph node dissection in patients with ovarian cancer, analysing previously
      reported and ongoing trials.

PMID- 12413934
TI  - Chemotherapy for advanced epithelial ovarian carcinoma.
AB  - Advanced epithelial ovarian cancer (AOC) is the most common clinical presentation
      of ovarian cancer. Virtually all patients will require some form of chemotherapy
      with curative or palliative intent. Prognostic factors, first- and second-line
      therapy, as well as experimental approaches for AOC are reviewed.

PMID- 12413935
TI  - Interval debulking surgery in advanced epithelial ovarian cancer.
AB  - Cytoreductive surgery and chemotherapy are the mainstay for the treatment of
      advanced epithelial ovarian cancer. In order to minimize the tumour burden before
      chemotherapy, cytoreductive surgery is usually performed first. The importance of
      the amount of residual disease as the main prognostic factor for patients
      suffering from advanced disease has been almost universally accepted even in the
      absence of prospective randomized trials addressing the benefit of cytoreductive
      surgery. In the last decade, the value of debulking surgery after induction
      chemotherapy - interval debulking surgery, IDS - has been widely debated,
      especially after the completion of a prospective randomized study from the EORTC
      addressing the introduction of a surgical procedure with debulking intent
      preceded and followed by cytoreductive chemotherapy. The rationale of such a
      strategy in the context of the primary treatment of advanced ovarian cancer lies
      in a higher cytoreductibility to the 'optimal' status forwarded, and possibly
      facilitated, by chemotherapy. The results demonstrated a prolongation of both
      progression-free survival and median survival in favour of patients randomized to
      IDS (5 and 6 months, respectively). Multivariate analysis revealed IDS to be an
      independent prognostic factor which reduced the risk of death by 33% at 3 years
      and by 48% in subsequent re-evaluation after more than 6 years of observation.
      Despite the above, results have been questioned by many, leading the GOG to
      perform a similar study which has been concluded very recently. Nevertheless, the
      main concern regarding the application of IDS in all instances relates to the
      morbidity of two major surgical procedures integrated within a short period
      during which cytotoxic chemotherapy is also administered. Neoadjuvant
      chemotherapy has been recently proposed to avoid a non-useful surgical procedure
      in patients considered 'optimally unresectable' after diagnosis of advanced
      ovarian cancer. Whether or not this newer approach will translate into a longer
      survival with a better quality of life is going to be addressed by a novel EORTC
      study. Finally, the concept of a 'chemical' cytoreduction preceding and
      facilitating a subsequent 'surgical' effort has been recently introduced also in
      the treatment of recurrent disease. The EORTC has recently initiated a
      prospective randomized study (LOROCSON - Late Onset Recurrent Ovarian Cancer:
      Surgery or Not) to validate the importance of such an approach to be balanced
      with medical treatment alone not only in terms of survival but also as far as
      quality of life is concerned.

PMID- 12413936
TI  - Neoadjuvant chemotherapy for the management of ovarian cancer.
AB  - Neoadjuvant chemotherapy refers to the administration of chemotherapy before
      definitive surgery is performed; this approach was introduced into the management
      of ovarian cancer approximately one decade ago, initially for use in women who
      were medically unable to tolerate aggressive cytoreductive surgery. Subsequently,
      neoadjuvant chemotherapy was employed in women who, by diagnostic imaging
      analysis, were unlikely to undergo successful optimal cytoreductive surgery. Only
      very limited data are available on the use of neoadjuvant chemotherapy in the
      management of women with apparent advanced ovarian cancer; these data are derived
      mainly from single institution experiences and suggest that this approach may
      increase disease-free survival but does not improve overall survival for the
      patient. However, it has consistently enhanced the feasibility of optimum
      surgical cytoreduction once neoadjuvant chemotherapy has been administered.
      Reduced blood loss, and shorter operations, intensive care unit stays and overall
      hospitalizations have been well documented. The methods for selecting candidates
      for neoadjuvant chemotherapy vary among institutions. Non-optimal surgical
      cytoreducibility has been assessed on the basis of diagnostic imaging studies,
      laparoscopic assessment and/or laparotomies. Currently, neoadjuvant chemotherapy
      is most beneficial for women who are medically impaired and unable to tolerate
      aggressive cytoreductive surgery and for women who are found to have such
      aggressive cancers that optimal cytoreductive surgery does not appear by
      diagnostic imaging or direct visualization to be possible.

PMID- 12413937
TI  - Prophylactic oophorectomy.
AB  - Because of the lack of effective alternatives and the simplicity of the
      procedure, prophylactic oophorectomy is viewed as the best available tool for
      reducing the individual risk of ovarian cancer. The genetics of hereditary
      ovarian cancer are described in this chapter and a careful risk-versus-benefit
      assessment is provided with respect to two populations of patients that appear
      suitable candidates for this procedure. These include patients with increased
      risk of developing ovarian cancer due to hereditary genetic predisposition, in
      which the lifetime risk of ovarian cancer may be as high as 16-65%, depending on
      the penetrance of the germ-line mutation. Additionally, routine salpingo
      oophorectomy in patients over 40 years undergoing scheduled gynaecological
      surgery or colorectal surgery might reduce the overall incidence of ovarian
      cancer by as much as 5% in the general population.

PMID- 12413939
TI  - Impaired natural killer (NK) cell activity in leptin receptor deficient mice:
      leptin as a critical regulator in NK cell development and activation.
AB  - Leptin is an adipocyte-secreted hormone that centrally regulates weight control
      via targeting the leptin receptor in the central nervous system. Recently, the
      leptin receptor has also been detected in peripheral systems including immune
      tissues, suggesting that leptin may play an important role in the regulation of
      immune function. It has been shown that leptin modulates functions of T
      lymphocytes, B lymphocytes, and monocytes/macrophage. However, the effect of
      leptin on NK cells remains unknown. In the present paper, we observed that
      percentage of NK cells and total amount of NK cells in the liver, spleen, lung,
      and peripheral blood were declined in leptin receptor deficient mice (db/db B6
      mice), indicating that NK cell development was vigorously influenced by leptin
      receptor deficiency. Both basal and poly I:C-stimulated NK cell activation (CD69
      surface marker expression) were retarded in db/db mice. In addition, leptin
      treatment increased the basal or synergistically enhanced IL-15- and poly I:C
      induced specific lysis of splenocytes in normal littermates but not in db/db
      mice. Taken together, these findings suggest that leptin plays an important role
      in NK cell development and activation.

PMID- 12413940
TI  - GRK3 regulation during CRF- and urocortin-induced CRF1 receptor desensitization.
AB  - The EC(50) values for concentration-dependent stimulation of cAMP accumulation by
      CRF (1.3nM) and urocortin (1.0nM) were equivalent in human retinoblastoma Y79
      cells. The time course and magnitude of CRF- and urocortin-induced CRF(1)
      receptor desensitization were similar. A significant 3-fold increase in GRK3, but
      not GRK2, mRNA levels accompanied the emergence of CRF(1) receptor
      desensitization in Y79 cells exposed to CRF. In preliminary experiments,
      retinoblastoma GRK3 protein expression became upregulated during a 48-h CRF
      exposure. Neither GRK3 nor GRK2 expression increased in Y79 cells exposed to
      urocortin for 10 min to 48 h. We hypothesize that GRK3 upregulation may be a
      cellular negative feedback process directed at maximizing CRF(1) receptor
      desensitization by heightening GRK3 phosphorylating capacity during prolonged
      exposure to high CRF. Regulation of GRK expression associated with urocortin- and
      CRF-induced CRF(1) receptor desensitization appears to differ, despite a similar
      level of signaling via the cAMP-protein kinase A pathway.

PMID- 12413941
TI  - Dissociation of AMPK activity and ACCbeta phosphorylation in human muscle during
      prolonged exercise.
AB  - During prolonged, low intensity exercise, the type of substrate utilized varies
      with time. If 5' AMP-activated protein kinase (AMPK) regulates muscle metabolism
      during exercise, signaling through AMPK would be expected to change in
      concordance with changes in substrate utilization. Six healthy, young males
      cycled (approximately 45% VO(2peak)) until exhaustion (approximately 3.5h).
      During exercise, leg glucose uptake and rate of glycogenolysis gradually
      decreased whereas free fatty acid uptake gradually increased. In the thigh
      muscle, the alpha AMPK subunits became progressively more phosphorylated on
      Thr(172) during exercise eliciting a parallel increase in alpha2 but not alpha1
      AMPK activity. In contrast, after 1h of exercise, Ser(221) phosphorylation of
      acetyl-CoA carboxylase-beta (ACCbeta) peaked at 1h of exercise and returned to
      resting levels at exhaustion. Protein expression of alpha2 AMPK, alpha1 AMPK or
      ACCbeta did not change with time. These data suggest that AMPK signaling is not a
      key regulatory system of muscle substrate combustion during prolonged exercise
      and that marked activation of AMPK via phosphorylation is not sufficient to
      maintain an elevated ACCbeta Ser(221) phosphorylation during prolonged exercise.

PMID- 12413942
TI  - Concerted elevation of acyl-coenzyme A:diacylglycerol acyltransferase (DGAT)
      activity through independent stimulation of mRNA expression of DGAT1 and DGAT2 by
      carbohydrate and insulin.
AB  - Glucose and insulin are anabolic signals which upregulate the transcriptions of a
      series of lipogenic enzymes to convert excess carbohydrate into triglycerides for
      efficient energy storage. These enzymes include ATP-citrate lyase (ACL), acetyl
      coenzyme A carboxylase (ACC), fatty acid synthase (FAS), and glycerol-3-phosphate
      acyltransferase (G3PA). Acyl-coenzyme A:diacylglycerol acyltransferase (DGAT) is
      important to synthesize fatty acids into triglycerides. Two DGATs from different
      gene families have recently been identified. In the current study, we report that
      glucose preferentially enhances DGAT1 mRNA expression, whereas insulin
      specifically increases the level of DGAT2 mRNA. Treatment of adipocytes with
      glucose and insulin together results in higher DGAT activity in the membrane than
      cells treated with either of the agents alone, indicating that glucose and
      insulin have additive effect on DGAT activation. In mice treated with
      fast/refeeding protocol, DGAT2 mRNA decreased upon fasting and was replenished
      upon refeeding in adipose tissue and liver. This pattern of change was not
      observed for DGAT1. Inasmuch as DGAT1 mRNA is less abundant in liver, we suggest
      that DGAT1 is more involved in fat absorption in the intestine and in basal level
      triglyceride synthesis in adipose tissue where it is more highly expressed. In
      contrast, DGAT2 is more likely to play important roles in assembly of de novo
      synthesized fatty acids into VLDL particles in the liver.

PMID- 12413943
TI  - Effects of targeted overexpression of pleiotrophin on postnatal bone development.
AB  - Pleiotrophin (PTN) is an extracellular matrix-associated growth/differentiation
      factor that, in post-natal life, is found mainly in bone and brain. Bone
      development was investigated in ptn-overexpressing mice between 1 and 30 weeks.
      In transgenics and controls, PTN (and its receptor syndecan-3) was synthesized by
      osteoblasts and was present in striated muscle. ptn over-expression enhanced
      intramembranous bone formation and had multiple effects on long-term bone growth.
      The pubertal growth spurt did not take place in transgenic mice, in which the
      growth trajectory was steady and continuous until 25 weeks. By 30 weeks,
      transgenic and control mice were of the same size, but the calcium content/mg
      bone was approximately 10% higher in the transgenics. PTN was also localized in
      growth plate and articular chondrocytes, but only in transgenic mice. In these,
      synthesis of type I collagen by articular chondrocytes was observed, as well as
      an encroachment of subchondral bone into the articular cartilage. The results
      suggest that PTN has multiple roles during in vivo bone formation and remodeling,
      probably acting as a co-factor or accessory protein that modulates the effects of
      primary signaling molecules.

PMID- 12413944
TI  - Distribution of neurons containing leptin receptors in the hypothalamus of the
      pig.
AB  - Leptin, secreted by white adipocytes, has profound feeding, metabolic, and
      neuroendocrine effects. Leptin acts on the brain, but specific anatomical sites
      and pathways responsible for mediating these effects are still unclear. We have
      systematically examined the distribution of leptin receptor containing neurons in
      the porcine hypothalamus by means of immunohistochemical staining methods. Leptin
      receptor immunoreactivity (OBR-IR) was observed in both the preoptic area and
      anterior hypothalamic area. No immunoreactive structures were found in the median
      eminence. Only single, small neurons were observed in the arcuate nucleus. The
      most abundant OBR-IR cell bodies were located in the supraoptic nucleus. In the
      paraventricular nucleus, OBR-IR neurons were moderate in number. Single,
      dispersed neurons were found in the ventromedial nucleus. These findings indicate
      that there are distinct OBR-IR neuronal populations in the porcine hypothalamus
      and leptin not only plays an integrative role in feeding behavior, but also in
      neuroendocrine activity.

PMID- 12413945
TI  - Resistance to mitochondrial- and Fas-mediated apoptosis in human leukemic cells
      with acquired resistance to 9-beta-D-arabinofuranosylguanosine.
AB  - We have previously reported that in a MOLT-4 leukemia cell line the acquired
      resistance to 9-beta-D-arabinofuranosylguanine (Ara-G) is due to deficiency of
      the activating enzymes deoxyguanosine kinase and deoxycytidine kinase [Biochem.
      Biophys. Res. Commun. 293 (5) (2002) 1489]. In this study we investigated whether
      apoptotic pathways are affected in two human T-cell lymphoblastic MOLT-4 cell
      lines with acquired resistance to Ara-G. In contrast to the MOLT-4 wild type
      cells, Ara-G resistant cells displayed no increase in caspase-3 or caspase-9
      activity, DNA fragmentation, cytochrome c release or a drop in the mitochondrial
      membrane potential (DeltaPsi(mito)) upon Ara-G treatment. A drop in the
      DeltaPsi(mito) was induced in wild type cells after treatment with tributyltin,
      an inducer of mitochondrial permeability transition, and with carbonyl cyanide m
      chlorophenylhydrazone, an uncoupling agent that reduces the DeltaPsi(mito),
      although not in Ara-G resistant cells. Ara-G resistant cells displayed higher
      levels of the anti-apoptotic protein Bcl-xL in immunoblots. A recent study
      indicates that Ara-G-induced apoptosis is mediated in part via the Fas pathway
      [Cancer Res. 43 (2047) (2002) 411]. When cells were treated with anti-Fas
      antibody, the wild type cell line exhibited increased caspase-3-like activity but
      the Ara-G resistant cells did not. Using FACS analysis and semi-quantitative PCR,
      3-6-fold decreased protein levels and almost no detectable mRNA levels of Fas in
      the resistant cells were recorded. These data indicate that the inability to
      induce apoptosis via both the apoptosome pathway and the Fas pathway, due to
      increased levels of Bcl-xL and a lack of Fas, contributes to Ara-G resistance.
      This resistance to apoptosis in Ara-G resistant cells may serve to explain the
      overall resistance to a variety of anti-neoplastic drugs.

PMID- 12413946
TI  - Effect of metformin on adipose tissue resistin expression in db/db mice.
AB  - Resistin, a novel adipose-derived protein, has been proposed to cause insulin
      resistant states in obesity. To evaluate whether an insulin-sensitizing drug,
      metformin, regulates adipose tissue resistin expression, murine models of obesity
      and diabetes, db/db mice, were treated with metformin (metformin group), insulin
      (insulin group), and vehicle (control group) for 4 weeks, followed by analyzing
      resistin protein expression in their adipose tissues. Unexpectedly, resistin
      protein expression was increased by 66% in the metformin group relative to the
      control group, while it did not differ between the insulin and control groups.
      Hyperinsulinemia was improved in the metformin group, while the insulin group
      exhibited severe hyperinsulinemia, similar to the control group. Furthermore, in
      comparison between obese mice (db/db mice) and age-matched lean controls,
      resistin protein expression was reduced by 58% in the obese mice with severe
      hyperinsulinemia. These data collectively suggest that resistin expression may be
      suppressed by hyperinsulinemia and that metformin may upregulate resistin
      expression via the improvement of hyperinsulinemia in obesity.

PMID- 12413947
TI  - Reproducibility of targeted gene expression measurements in human islets of
      Langerhans.
AB  - The expression of 47 genes involved in the biosynthesis and secretion of insulin,
      apoptosis, and cellular stress was evaluated in isolated human islets using cDNA
      probes arrayed on nitrocellulose membranes. Isolated human islets were cultured
      for four days, or one month, with glucose present at a concentration of either
      5.5 or 16.7 mmol/L. Extracted islet total RNA was used to generate [32P]dATP
      labelled complex cDNA targets and hybridised with immobilised cDNA arrays. The
      positive expression of 45 mRNA transcripts in isolated human islets was
      documented. The coefficient of variance for relative levels of expression of
      transcripts was <25% for 9, 25-50% for 22, and 50-100% for 10, indicating good
      reproducibility between islet preparations from five different human pancreas
      donors. This study demonstrates the utility of nitrocellulose-based cDNA arrays
      for a focused reproducible analysis of gene expression changes in human islets of
      Langerhans.

PMID- 12413948
TI  - Intercellular trafficking of herpes simplex virus type 2 UL14 deletion mutant
      proteins.
AB  - The UL14 gene product of herpes simplex virus is a 32kDa protein expressed late
      in infection and is a minor component of the virion tegument. We recently showed
      that the wild-type UL14 protein has heat shock protein (HSP)-like and/or
      molecular chaperone-like functions. In this study, the intracellular localization
      of UL14 wild-type and deletion mutant proteins was examined in transfected cells
      by immunofluorescence. We found that N-terminus deleted but not wild-type/C
      terminus deleted mutant proteins showed a significant number of cytoplasmic,
      multi-cellular stains in transfected Vero cells. The effect was greatly
      intensified by subjecting cells to heat shock at 43 degrees C, whereas it was
      obstructed by treatment with the microfilament-disrupting drug cytochalasin D.
      The staining patterns of UL14 antigen-positive cells after heat shock suggested a
      cell-to-cell spread of the protein. Although the mechanism is unclear, the
      phenomenon seems to be an unprecedented type of intercellular trafficking.

PMID- 12413949
TI  - Regulation of Xenopus embryonic cell adhesion by the small GTPase, rac.
AB  - TGF-beta family signalling pathways are important for germ layer formation and
      gastrulation in vertebrate embryos and have been studied extensively using
      embryos of Xenopus laevis. Activin causes changes in cell movements and cell
      adhesion in Xenopus animal caps and dispersed animal cap cells. Rho family
      GTPases, including rac, mediate growth factor-induced changes in the actin
      cytoskeleton, and consequently, in cell adhesion and motility, in a number of
      different cell types. Ectopic expression of mutant rac isoforms in Xenopus
      embryos was combined with animal cap adhesion assays and a biochemical assay for
      rac activity to investigate the role of rac in activin-induced changes in cell
      adhesion. The results indicate that (1) the perturbation of rac signalling
      disrupts embryonic cell-cell adhesion, (2) that rac activity is required for
      activin-induced changes in cell adhesive behavior on fibronectin, and (3) that
      activin increases endogenous rac activity in animal cap explants.

PMID- 12413950
TI  - Molecular characterization and expression of an alternate proliferating cell
      nuclear antigen homologue, PfPCNA2, in Plasmodium falciparum.
AB  - The malaria parasite Plasmodium falciparum genome sequencing has revealed the
      existence of a second gene for proliferating cell nuclear antigen (PCNA), a key
      factor in a variety of DNA metabolic events. The alternate copy of PCNA (PfPCNA2)
      shows only 23% identity to an earlier reported P. falciparum PCNA homologue
      (PfPCNA1). Our analysis indicated structural conservation of PfPCNA2 compared to
      eukaryotic PCNAs. PfPCNA1 and 2 polypeptides showed differential expression in
      the intraerythrocytic cell cycle of the malaria parasite. PfPCNA1 expression
      slowly increases about threefold from the ring to the late schizont stage. In
      contrast PfPCNA2 showed robust expression in trophozoites and early schizonts
      with a sudden drop in expression in the late schizont stage, suggesting that the
      two PfPCNAs may function under different physiological conditions. Chemical cross
      linking indicated the presence of a trimeric PfPCNA2 protein, indicating the
      possible existence of a functional ring-like PfPCNA2 structure.

PMID- 12413951
TI  - Reduced cyclin D1 ubiquitination in UVB-induced murine squamous cell carcinomas.
AB  - Ubiquitination of cyclin D1 signals for its proteosomal degradation. To assess
      the possibility that reduced cyclin D1 proteolysis is a putative mechanism for
      its accumulation during UVB-induced skin tumorigenesis, ubiquitination activity
      of cyclin D1 was assessed in UVB-induced murine SCCs. Cyclin D1 was rapidly
      ubiquitinated by control skin extract, whereas ubiquitination of cyclin D1 was
      significantly reduced in SCCs. Mutant cyclin D1, in which residues important for
      GSK3beta-mediated degradation of cyclin D1 are altered to non-phosphorylatable
      alanine, was not ubiquitinated. We also observed phosphorylation-dependent
      inactivation of GSK3beta in SCCs. Our results indicate reduced ubiquitination of
      cyclin D1 in UVB-induced murine SCCs and suggest that inactivation of GSK3beta
      dependent cyclin D1 degradation pathway contributes to the accumulation of cyclin
      D1 in UVB-induced murine SCCs.

PMID- 12413952
TI  - Expression, purification, and characterization of subunit E, an essential subunit
      of the vacuolar ATPase.
AB  - A recombinant form of subunit E (Vma4p) from yeast vacuolar ATPases (V-ATPases)
      has been overexpressed in Escherichia coli, purified to homogeneity, and explored
      by mass spectrometry. Analysis of the secondary structure of Vma4p by circular
      dichroism spectroscopy indicated 32% alpha-helix and 23% beta-sheet content.
      Vma4p formed a hybrid-complex with the nucleotide-binding subunits alpha and beta
      of the closely related F(1) ATPase of the thermophilic bacterium PS3 (TF(1)). The
      alpha(3)beta(3)E-hybrid-complex had 56% of the ATPase activity of the native
      TF(1). By comparison, an alpha(3)beta(3)-formation without Vma4p showed about 24%
      of total TF(1) ATPase activity. This is the first demonstration of a
      hydrolytically active hybrid-complex consisting of F(1) and V(1) subunits. The
      arrangement of subunit E in V(1) has been probed using the recombinant Vma4p, the
      alpha(3)beta(3)E-hybrid-complex together with V(1) and an A(3)B(3)HEG-subcomplex
      of the V(1) ATPase from Manduca sexta, respectively, indicating that subunit E is
      shielded in V(1).

PMID- 12413953
TI  - Eotaxin induces migration of RBL-2H3 mast cells via a Rac-ERK-dependent pathway.
AB  - Eotaxin is a potent chemokine that acts via CC chemokine receptor 3 (CCR3) to
      induce chemotaxis, mainly on eosinophils. Here we show that eotaxin also induces
      chemotactic migration in rat basophilic leukemia (RBL-2H3) mast cells. This
      effect was dose-dependently inhibited by compound X, a selective CCR3 antagonist,
      indicating that, as in eosinophils, the effect was mediated by CCR3. Eotaxin
      induced cell migration was completely blocked in RBL-RacN17 cells expressing a
      dominant negative Rac1 mutant, suggesting a crucial role for Rac1 in eotaxin
      signaling to chemotactic migration. ERK activation also proved essential for
      eotaxin signaling and it too was absent in RBL-RacN17 cells. Finally, we found
      that activation of Rac and ERK was correlated with eotaxin-induced actin
      reorganization known to be necessary for cell motility. It thus appears that Rac1
      acts upstream of ERK to signal chemotaxis in these cells, and that a Rac-ERK
      dependent cascade mediates the eotaxin-induced chemotactic motility of RBL-2H3
      mast cells.

PMID- 12413954
TI  - Possible coupling of prostaglandin E receptor EP(1) to TRP5 expressed in Xenopus
      laevis oocytes.
AB  - We previously reported that the prostaglandin E(2) (PGE(2)) receptor subtype
      EP(1) is coupled to intracellular Ca(2+) mobilization in CHO cells, which is
      dependent on extracellular Ca(2+) in a pertussis toxin-insensitive manner [H.
      Katoh, et al., Biochim. Biophys. Acta 1244 (1995) 41-48]. However, it remains
      unknown about the signal transduction involved in this response. To investigate
      the mechanism regulating Ca(2+) mobilization mediated by EP(1) receptors in
      detail, we performed a series of experiments using the Xenopus laevis oocyte
      expression system and found that endogenous G(q) and/or G(11), and not G(i1) is
      involved in the Ca(2+) mobilization induced by PGE(2). We further investigated
      the receptor-activated Ca(2+) channel (RACC)-related response by introducing mRNA
      for mouse transient receptor potential 5 (TRP5), a possible candidate for the
      RACC, and found effective coupling between them. These results suggest that the
      EP(1) receptors induce Ca(2+) mobilization via G(q) and/or G(11) and Ca(2+)
      influx via TRP.

PMID- 12413955
TI  - Structural requirements for species-specific induction of the sperm acrosome
      reaction by sea urchin egg sulfated fucan.
AB  - The sulfated fucan (SF) of egg jelly induces the acrosome reaction (AR) of sea
      urchin sperm. Strongylocentrotus franciscanus (Sf) SF is sulfated only at the 2
      position. Strongylocentrotus purpuratus (Sp) has two SF isotypes, each one being
      female specific. One is rich in sulfate at both the 2- and 4-positionS (SF-1),
      and the other is rich in sulfate at the 4-position, but not the 2-position (SF
      2). Sf SF is poor at inducing the AR of Sp sperm, presumably due to lack of 4
      sulfation. Sp SF-1 is better at inducing the AR of Sf sperm than Sp SF-2,
      hypothetically due to increased 2-sulfation. Chemical oversulfation of Sf SF
      increases the percentage of AR of Sp sperm, showing that 4-sulfation is important
      for recognition of SF by Sp sperm. Chemically oversulfated Sp SF-2 is better at
      inducing the Sf sperm AR, presumably because of increased 2-sulfation. The
      species, Strongylocentrotus drobachiensis (Sd), has an SF-2 that is exclusively 2
      sulfated (like Sf), except the glycosidic linkage in Sd is alpha(1-->4), whereas
      in Sf it is alpha(1-->3). Sd SF-2 does not induce the AR of Sf sperm, showing the
      strict requirement for the alpha(1-->3) linkage in recognition between Sf sperm
      and SF. Egg jelly from Echinometra lucunter (El) contains sulfated galactan (SG)
      which differs from Sf SF only in that the monosaccharide is L-galactose, not L
      fucose. This SG and Sf SF are equally potent in inducing the AR of Sf sperm,
      showing that modification at C6 of L-fucose is not important for proper
      recognition between SF and Sf sperm receptors. This system permits study of the
      structural basis for recognition between sulfated polysaccharide and receptors
      controlling signal transduction pathways in animal cells.

PMID- 12413956
TI  - Identification of the LIM kinase-1 as a ceramide-regulated gene in renal
      mesangial cells.
AB  - Stimulation of rat renal mesangial cells with cell-permeable C6-ceramide for 6
      and 24h induces the expression of several genes as analyzed by a RNA
      fingerprinting arbitrarily primed-PCR method. Sequencing of the differentially
      expressed bands identified the serine/threonine protein kinase LIM kinase-1 (LIMK
      1), which is involved in the regulation of cytoskeletal organization, as a
      ceramide-induced gene. The ceramide-triggered upregulation of LIMK-1 was verified
      by semiquantitative reverse transcriptase-PCR. A detailed time course reveals a
      first detectable increase in RNA level after 2h of ceramide stimulation which
      reaches maximal levels after 6h of stimulation and remains elevated up to 24 h.
      This ceramide-induced gene transcription of LIMK-1 is accompanied by enhanced
      LIMK-1 protein levels with maximal protein expression seen after 6h of
      stimulation. Furthermore, cofilin, which is a specific substrate of LIMK-1, shows
      an increased phosphorylation at Ser-3 in mesangial cells exposed to C6-ceramide.
      Mechanistically, the ceramide-induced LIMK-1 expression is blocked by the Rho
      kinase inhibitor Y27632, but not by a farnesyl transferase inhibitor, suggesting
      the involvement of the small G protein Rho, but not Ras and Rac, in the
      expressional upregulation. Similar to exogenously added ceramide, also
      interleukin-1beta which is an established activator of the neutral
      sphingomyelinase that leads to endogenous ceramide formation upregulates LIMK-1
      protein expression and activity. In summary, these data demonstrate for the first
      time that LIMK-1 is a ceramide-induced gene, thus suggesting that LIMK-1 may act
      as a link between stress-induced ceramide formation and reorganization of the
      actin cytoskeleton.

PMID- 12413957
TI  - A specific binding protein/receptor for 1alpha,25-dihydroxyvitamin D(3) is
      present in an intestinal caveolae membrane fraction.
AB  - The steroid hormone 1alpha,25-dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)]
      produces biological responses by interaction with both a well-characterized
      nuclear receptor (VDR(nuc)) to regulate gene transcription and with an as-yet
      uncharacterized membrane-associated protein/receptor (VDR(mem)) to generate a
      variety of rapid, non-genotropic responses. We report for the first time that
      [3H]1alpha,25(OH)(2)D(3) binds with high affinity to a chick duodenal caveolae
      enriched membrane fraction (CMF) isolated without the use of detergents. Caveolae
      are plasma membrane invaginations implicated in signal transduction and molecular
      transport processes. Using the CMF fraction as a possible source of VDR(mem), we
      found that the in vitro binding of [3H]1alpha,25(OH)(2)D(3) was ligand dependent
      and saturable; the K(D) and B(max) were 1.3+/-0.6nM and 29+/-11fmol
      1,25(OH)(2)D(3)/mg protein (n=17), respectively. Immunoblot analysis of the CMF
      confirms the presence of caveolin-1, a marker protein for membranes with
      caveolae. Therefore, chick CMF may represent a good source for isolation and
      characterization of the putative VDR(mem) for 1alpha,25(OH)(2)D(3).

PMID- 12413958
TI  - Differential regulation between gene expression and histone H3 acetylation in the
      variable regions of the TCRbeta locus.
AB  - Histone acetylation is suggested to regulate gene expression in the TCR loci.
      Using R2CD3 mouse model, we previously showed that germline transcription of the
      TCRbeta chain gene is discrete between 5' Vbeta regions and Dbeta-Jbeta-Cbeta
      clusters plus Vbeta14 region. In this study, we investigated a role of histone H3
      acetylation in transcriptional regulation of the TCRbeta locus. Our results
      showed that DN-DP transition is accompanied by significant promotion of histone
      H3 acetylation in both Dbeta-Jbeta-Cbeta cluster and Vbeta14 region, correlating
      with up-regulation of germline transcription. Surprisingly, termination of
      germline transcription of the 5' Vbeta regions was inversely correlated with
      histone H3 hyperacetylation. Moreover, histone H3 acetylation showed equivalent
      level in both functionally rearranged Vbeta region with active transcription and
      unrearranged Vbeta region without transcription in mature T cells. These results
      suggest that histone acetylation is not a sole limiting factor in both
      terminating germline Vbeta transcription during DN-DP transition and maintaining
      functionally rearranged Vbeta gene expression.

PMID- 12413959
TI  - Adeno-associated viral gene transfer of dominant negative RhoA enhances erectile
      function in rats.
AB  - We previously reported the inhibition of Rho-kinase to result in increased
      intracavernosal pressure (ICP) in an in vivo rat model of erection. Expression of
      an upstream activator of Rho-kinase, RhoA, has been demonstrated in the penile
      vasculature; however, the functional role of RhoA in the regulation of erection
      remains unknown. We used adeno-associated viral gene transfer of a dominant
      negative RhoA mutant (T19NRhoA) into rat cavernosum to test the hypothesis that
      RhoA activation is physiologically important for maintenance of the non-erect
      state and inhibition of this pathway leads to erection. Anesthetized, male,
      Sprague-Dawley rats transfected with the T19NRhoA mutant exhibited an elevated
      baseline ICP/mean arterial pressure (MAP) and nerve stimulation-induced ICP/MAP
      as compared with beta-galactosidase-transfected controls. The novel findings of
      this study demonstrate a functional role of RhoA in maintaining the flaccid penis
      and provide support for the inhibition of RhoA as a potential therapy for the
      enhancement of erectile function.

PMID- 12413960
TI  - Identification of the novel splicing variants for the hPXR in human livers.
AB  - The human pregnane X receptor (hPXR) plays a key role in the regulation of both
      drug metabolism and efflux by inducing the expression of CYP3A4 and MDR1 gene.
      Using reverse transcription-polymerase chain reaction (RT-PCR) analysis, we
      identified seven novel splicing variants of hPXR in tissue from a single human
      liver. The expression of hPXR-related transcripts in the liver samples of 15
      Caucasian individuals was subsequently determined by RT-PCR assays. The pattern
      of expression levels of these transcripts varied among liver samples. These
      results suggest that the hPXR is expressed as several different transcripts in
      liver tissues, apparently due to alternative as well as defective gene splicing.
      Furthermore, because this study provides the possibility of interindividual
      differences in hPXR transcript profiles, these alternative splicings for hPXR may
      largely contribute to the interindividual variability in CYP3A4 and P
      glycoprotein induction.

PMID- 12413961
TI  - Correlation between hydrophobic properties and efficiency of carrier-mediated
      membrane transduction and apoptosis of a p53 C-terminal peptide.
AB  - Two membrane transporters, the 17 amino acid (aa) oligopeptide penetratin derived
      from the homeodomain of Antennapedia (Ant) and an analogue of the basic domain of
      TAT (aa 47-57) (TAT-a) from HIV-1, were tested as carriers for a p53 C-terminal
      peptide (aa 361-382) into human breast cancer cells. The studies were performed
      to determine whether the membrane-transduction efficiency of membrane carriers:
      Ant, TAT or TAT analogue (TAT-a) correlated with peptide hydrophobic features.
      Peptide-sequence analysis clearly demonstrated that the Ant sequence and p53
      peptide sequence (p53p) together created a peptide with enhanced hydrophobic
      characteristics; while the TAT or TAT analogue (TAT-a) and p53p sequence together
      created a peptide with significantly less hydrophobic qualities. The degree of
      hydrophobic moment and helical wheel plots for these peptides correlated directly
      with their ability to transduce the p53 peptide. Western blot analysis revealed
      that Ant was able to transduce p53 C-terminal peptide into human breast cancer
      cells as a highly efficient membrane transporter. Compared to Ant, TAT-a fused to
      the C-terminus of p53 peptide (p53p-TAT-a) was a less efficient carrier into
      these cells under the conditions of our study. Additionally, N-terminal linked
      TAT-a to p53p (TAT-a-p53p) showed even lower efficiency as a transporter than p53
      TAT-a. Apoptosis assays showed that the p53 peptide, fused at its C-terminus to
      Ant (p53p-Ant), induced a higher percentage of apoptotic cells in human breast
      cancer cell lines expressing mutant or wild-type p53 as compared to p53 peptide
      fused at its C-terminus to the TAT-a sequence (p53p-TAT-a) or when fused at the N
      terminus to TAT-a (TAT-a-p53p). These data suggested a direct correlation between
      hydrophobic characteristics and efficiency as a transporter. Sequence study,
      using hydrophobic moment and helical wheel analyses, may be useful predictive
      tools for choosing the best carrier for a peptide.

PMID- 12413962
TI  - Molecular bases for human complement C7 polymorphisms, C7*3 and C7*4.
AB  - Complement C7 is one of the components of membrane attack complex (MAC) generated
      by the terminal complement cascade. C7 protein is polymorphic and most of its
      polymorphisms have been identified using isoelectric focusing (IEF), which
      detects protein charge differences. To date, the molecular bases of the
      polymorphisms detected by IEF have not been determined. In this paper, we
      describe the structural bases of two C7 IEF-detected polymorphisms, C7*3 and
      C7*4, both of which are common in Asian populations. C7*3 resulted from
      substitution of cysteine (Cys) at amino acid residue 106 by charged arginine
      (Arg; C106R), while charged lysine (Lys) at amino acid residue 398 was replaced
      by neutral glutamine (Gln; K398Q) in C7*4. As C7*3 is hypomorphic, it is
      important to study its possible associations with diseases such as immunological
      disorders and infections. We present genetic bases for this C7 polymorphism,
      which we determined using polymerase chain reaction (PCR)-based genotyping, a
      simple and accurate method suitable for large-scale studies.

PMID- 12413963
TI  - Slide track analysis of eight contemporary hip simulator designs.
AB  - In an earlier paper, the authors presented a new method of computation of slide
      tracks in the relative motion between femoral head and acetabular cup of total
      hip prostheses. For the first time, computed tracks were verified experimentally
      and with an alternative method of computation. Besides being an efficient way to
      illustrate hip kinematics, the shapes of the slide tracks are known to be of
      fundamental importance regarding the wear behaviour of prostheses. The verified
      method was now applied to eight contemporary hip simulator designs. The use of
      correct motion waveforms and an Euler sequence of rotations in each case was
      again found to be essential. Considerable differences were found between the
      simulators. For instance, the shapes of the tracks drawn by the resultant contact
      force included a circle, ellipse, irregular oval, leaf, twig, and straight line.
      Computation of tracks correctly for the most widely used hip simulator, known as
      biaxial, was made possible by the insight that the device is actually three
      axial. Slide track patterns have now been computed for virtually all contemporary
      hip simulators, and both for the heads and for the cups. This comparative
      analysis forms a valuable basis for studies on the relationship between the type
      of multidirectional motion and wear. These studies can produce useful information
      for the design of joint simulators, and improve the understanding of wear
      phenomena in prosthetic joints.

PMID- 12413964
TI  - Lunate morphology.
AB  - Fifty healthy volunteers were subjected to the CT examination of the wrist joint
      to provide normal database of the shape and size of the lunate. The various
      parameters of the lunate were measured taking help of the reformatted images in
      sagittal, coronal and axial planes. The mean maximum antero-dorsal diameter of
      the lunate measured on axial section was 16.96mm (SD 1.60) with the range of 13
      19mm while the mean medio-lateral diameter of the lunate was 12.80mm (SD 1.37)
      with the range of 10-15mm. The mean axes of the scaphoid and the triquetral
      articular surfaces of the lunate were 11.83 degrees (SD 9.33) and 1.54 degrees
      (SD 9.70), respectively, while the mean axial index was 2.04 (SD 1.33). Lunate is
      reported to have shapes of three different types on plain radiographs. The CT
      measurements of most lunates failed to classify them into the described three
      shapes since many lunates showed dissimilar typing on the various chosen sagittal
      sections of the same lunate. The classical wedged lunate with its apex towards
      the dorsum has been described to have a tendency to extend under the capitate
      compressive force. However, in a study on plain radiography no correlation was
      reported between the radio lunate angle and the shape of the lunate measured in
      the direction of the lunate's axis. Our study confirmed the same on plain
      radiographs and on the CT also. We measured lunate's shape in the direction of
      the capitate's axis too, which demonstrated significant correlation with the RLA
      (p<0.001).

PMID- 12413965
TI  - Joint stiffness of the ankle and the knee in running.
AB  - The spring-mass model is a valid fundament to understand global dynamics of fast
      legged locomotion under gravity. The underlying concept of elasticity, implying
      leg stiffness as a crucial parameter, is also found on lower motor control
      levels, i.e. in muscle-reflex and muscle-tendon systems. Therefore, it seems
      reasonable that global leg stiffness emerges from local elasticity established by
      appropriate joint torques. A recently published model of an elastically
      operating, segmented leg predicts that proper adjustment of joint elasticities to
      the leg geometry and initial conditions of ground contact provides internal leg
      stability. Another recent study suggests that in turn the leg segmentation and
      the initial conditions may be a consequence of metabolic and bone stress
      constraints. In this study, the theoretical predictions were verified
      experimentally with respect to initial conditions and elastic joint
      characteristics in human running. Kinematics and kinetics were measured and the
      joint torques were estimated by inverse dynamics. Stiffnesses and elastic
      nonlinearities describing the resulting joint characteristics were extracted from
      parameter fits. Our results clearly support the theoretical predictions: the knee
      joint is always stiffer and more extended than the ankle joint. Moreover, the
      knee torque characteristic on the average shows the higher nonlinearity.
      According to literature, the leg geometry is a consequence of metabolic and
      material stress limitations. Adapted to this given geometry, the initial joint
      angle conditions in fast locomotion are a compromise between metabolic and
      control effort minimisation. Based on this adaptation, an appropriate joint
      stiffness ratio between ankle and knee passively safeguards the internal leg
      stability. The identified joint nonlinearities contribute to the linearisation of
      the leg spring.

PMID- 12413966
TI  - Registration of 6-DOFs electrogoniometry and CT medical imaging for 3D joint
      modeling.
AB  - The paper describes a method in which two data-collecting systems, medical
      imaging and electrogoniometry, are combined to allow the accurate and
      simultaneous modeling of both the spatial kinematics and the morphological
      surface of a particular joint. The joint of interest (JOI) is attached to a
      Plexiglas jig that includes four metallic markers defining a local reference
      system (R(GONIO)) for the kinematics data. Volumetric data of the JOI and the
      R(GONIO) markers are collected from medical imaging. The spatial location and
      orientation of the markers in the global reference system (R(CT)) of the medical
      imaging environment are obtained by applying object-recognition and
      classification methods on the image dataset. Segmentation and 3D isosurfacing of
      the JOI are performed to produce a 3D model including two anatomical objects-the
      proximal and distal JOI segments. After imaging, one end of a custom-made 3D
      electrogoniometer is attached to the distal segment of the JOI, and the other end
      is placed at the R(GONIO) origin; the JOI is displaced and the spatial kinematics
      data is recorded by the goniometer. After recording, data registration from
      R(GONIO) to R(CT) occurred prior to simulation. Data analysis was performed using
      both joint coordinate system (JCS) and instantaneous helical axis (IHA).Finally,
      the 3D joint model is simulated in real time using the experimental kinematics
      data. The system is integrated into a computer graphics interface, allowing free
      manipulation of the 3D scene. The overall accuracy of the method has been
      validated with two other kinematics data collection methods including a 3D
      digitizer and interpolation of the kinematics data from discrete positions
      obtained from medical imaging. Validation has been performed on both superior and
      inferior radio-ulna joints (i.e. prono-supination motion). Maximal RMS error was
      1 degrees and 1.2mm on the helical axis rotation and translation, respectively.
      Prono-supination of the forearm showed a total rotation of 132 degrees for 0.8mm
      of translation. The method reproducibility using JCS parameters was in average 1
      degrees (maximal deviation=2 degrees ) for rotation, and 1mm (maximal
      deviation=2mm) for translation. In vitro experiments have been performed on both
      knee joint and ankle joint. Averaged JCS parameters for the knee were 109
      degrees, 17 degrees and 4 degrees for flexion, internal rotation and abduction,
      respectively. Averaged maximal translation values for the knee were 12, 3 and 4mm
      posteriorly, medially and proximally, respectively. Averaged JCS parameters for
      the ankle were 43 degrees, 9 degrees and 3 degrees for plantarflexion, adduction
      and internal rotation, respectively. Averaged maximal translation values for the
      ankle were 4, 2 and 1mm anteriorly, medially and proximally, respectively.

PMID- 12413967
TI  - A comparison of deconvolution techniques for stress relaxation.
AB  - Stress relaxation (or equivalently creep) allows a large range of the relaxation
      (retardation) spectrum of materials to be examined, particularly at lower
      frequencies. However, higher frequency components of the relaxation curves
      (typically of the order of Hertz) are attenuated due to the finite time taken to
      strain the specimen. This higher frequency information can be recovered by
      deconvolution of the stress and strain during the loading period. This paper
      examines the use of three separate deconvolution techniques: numerical (Fourier)
      deconvolution, semi-analytical deconvolution using a theoretical form of the
      strain, and deconvolution by a linear approximation method. Both theoretical data
      (where the exact form of the relaxation function is known) and experimental data
      were used to assess the accuracy and applicability of the deconvolution methods.
      All of the deconvolution techniques produced a consistent improvement in the
      higher frequency data up to the frequencies of the order of Hertz, with the
      linear approximation method showing better resolution in high-frequency analysis
      of the theoretical data. When the different deconvolution techniques were applied
      to experimental data, similar results were found for all three deconvolution
      techniques. Deconvolution of the stress and strain during loading is a simple and
      practical method for the recovery of higher frequency data from stress-relaxation
      experiments.

PMID- 12413968
TI  - Spatial distribution of hip capsule structural and material properties.
AB  - Contemporary computational models potentially allow the practical incorporation
      of the effects of a joint capsule on both motion and the loads transmitted to the
      other parts of the joint. However, the required material properties have not been
      available for this purpose. To determine these properties we took both hip joints
      from five fresh-frozen, nondiseased cadavers. Following dissection and potting of
      the hemi-pelvis, distraction of the intact joint was conducted to measure the
      structural tangent stiffness of the joint capsule. Anatomical insertion points of
      the hip capsule were then recorded, and a complete capsulectomy was performed.
      Once excised, the capsule was sectioned into eight, approximately even sectors,
      and initial geometrical measurements were recorded for material property
      calculations. Material properties (i.e., structural tangent stiffness, failure
      load, ultimate strength, tangent modulus) were calculated using the load
      displacement and geometric data collected for each of the sectors. This specimen
      to-specimen thickness variability reveals significantly lower (p<0.01) average
      tangent structural stiffness values in the posterior-inferior portion of the
      capsule. Explorations of hip stability using numerical models can now be enhanced
      by incorporation of these experimental capsule data.

PMID- 12413969
TI  - Feasibility of using a video-based motion analysis system for measuring thumb
      kinematics.
AB  - While several different methods have been used to measure hand kinematics,
      fluoroscopy is generally considered to be the most accurate. Recently, video
      based motion analysis has been developed for the measurement of joint kinematics.
      This method is versatile, easy to use, and can measure motions dynamically.
      Surface markers are most commonly used in the video-based motion systems.
      However, whether the surface markers placed on the thumb accurately represent the
      true kinematics of the underlying bony segment is questionable. In this study,
      the feasibility of surface markers to represent thumb kinematics was investigated
      by fluoroscopy. Both the positions of surface markers and bony landmarks were
      simultaneous recorded and then digitized. The Ra(2) values comparing the angular
      changes of the thumb interphalangeal, metacarpal and carpometacarpal joints
      derived using the surface markers or bony landmarks were 0.9986, 0.9730 and
      0.9186 in the flexion/extension plane respectively, 0.8837, 0.9697 and 0.8775 in
      the abduction/adduction plane; and 0.9884, 0.9643 and 0.9431 in the opposition
      plane. The ranges, mean and standard deviation of the absolute differences
      between calculated angles of different marker sets were also compared. These data
      revealed that the similarities of the two different marker techniques throughout
      the motion cycle were high. The differences between the two methods were also
      within clinically allowable range of +/-5 degrees. It is concluded that the
      application of the video-based motion analysis system with surface markers to
      thumb kinematics is warranted.

PMID- 12413971
TI  - Microtensile measurements of single trabeculae stiffness in human femur.
AB  - In this paper, the authors perform microtensile tests of single trabeculae
      excised from a human femur head. One of the main issues of this work is to
      establish some experimental procedures for preparing and testing the specimens.
      The use of a well-characterized microtensile apparatus allows for a low
      intraspecimen dispersion of the measured stiffness. Tensile/compressive tests
      were chosen because they appear less sensitive to errors in the cross-sectional
      area measurements with respect to bending tests. By these considerations, some
      tensile/compressive tests of plate-like trabecular specimens have been carried
      out. Typical stiffness values are 74.2+/-0.7Nmm(-1) for tensile tests, and 58.9+/
      0.6Nmm(-1) for compressive test. Another compressive test performed on a shorter
      specimen yielded a stiffness value of 148.3+/-5.3Nmm(-1). The maximum applied
      load was about 0.5N. Rough measurements of specimens sizes yielded a Young's
      modulus value ranging from 1.41 to 1.89GPa.

PMID- 12413970
TI  - Static optimal estimation of joint accelerations for inverse dynamics problem
      solution.
AB  - In inverse dynamics computations, the accuracy of the solution strongly depends
      on the accuracy of the input data. In particular, estimated joint moments are
      highly sensitive to uncertainties in acceleration data. The aim of the present
      work was to improve classical inverse dynamics computations by providing an
      accurate estimation of accelerations. Accelerations are usually calculated from
      noise-polluted position data using numerical double differentiation, which
      amplifies measurement noise. The objective of the present paper is to use all
      available imperfect position and force measurements to extract optimum
      acceleration estimations. A weighted least-squares optimisation approach is used
      to provide optimal acceleration distributions most consistent with position and
      force data, and which account for the propagation of measurement uncertainties.
      The task chosen for comparing the solution methodology with other classical
      methods is a typical experimental postural movement, consisting in upper limb
      swings from an upright stance. The proposed method delivers a set of optimal
      accelerations well consistent with all available measurements. It also leads to
      an accurate prediction of ground reactions and it produces no residual moment at
      the top-most segment.

PMID- 12413972
TI  - Female genital anomalies affecting reproduction.
AB  - OBJECTIVE: A multitude of female congenital anomalies are uncommon. However,
      their impact on reproduction can be profound. The aim of this review is to remind
      the practicing physician of the clinically relevant embryology and summarize the
      studies that look at the impact of such various anomalies on a woman's fecundity.
      We review particular surgical therapies that possibly may improve fertility in
      such women. DESIGN: Review and critique of available studies in which particular
      surgical therapies were done and whether they truly improved fertility in these
      women with congenital reproductive anomalies. RESULTS: Clear evidence
      demonstrates that uterine septum resection is effective in women with
      demonstrated recurrent pregnancy losses. Arcuate uterus has little impact on
      reproduction. Other studies fail to definitively show that surgical correction
      will improve pregnancy retention or fertility except for specifically indicated
      clinical scenarios. CONCLUSIONS: The practicing reproductive specialist should
      have working knowledge of evidence-based therapeutic options for women with
      reproductive congenital anomalies. A summary chart has been devised to clearly
      associate embryologic structures with normal adult derivative as well as
      anomalous structures.

PMID- 12413973
TI  - Role of reproductive surgeons and the Society of Reproductive Surgeons.

PMID- 12413974
TI  - Assisted reproductive technology in the United States: 1999 results generated
      from the American Society for Reproductive Medicine/Society for Assisted
      Reproductive Technology Registry.
AB  - OBJECTIVE: To summarize the procedures and outcomes of ART initiated in the
      United States in 1999. DESIGN: Data were collected electronically by using the
      SART Clinical Outcome Reporting System software and submitted to the American
      Society for Reproductive Medicine/Society for Assisted Reproductive Technology
      Registry. PARTICIPANT(S): Three hundred sixty programs submitted data on
      procedures performed in 1999. Data were collated after November 2000 so that the
      outcome of all pregnancies established would be known. MAIN OUTCOME MEASURE(S):
      Incidence of clinical pregnancy, ectopic pregnancy, abortion, stillbirth, and
      delivery. RESULT(S): Programs reported initiating 88,077 cycles of ART treatment.
      Of these, 63,639 cycles involved IVF (with and without micromanipulation), with a
      delivery rate per retrieval of 29.4%; 838 were cycles of gamete intrafallopian
      transfer, with a delivery rate per retrieval of 27.9%; 945 were cycles of zygote
      intrafallopian transfer, with a delivery rate per retrieval of 29.8%. The
      following additional ART procedures were also initiated: 6,509 fresh donor oocyte
      cycles, with a delivery rate per transfer of 41.8%; 12,005 frozen embryo transfer
      procedures, with a delivery rate per transfer of 18.6%; 2,488 frozen embryo
      transfers using donated oocytes or embryos, with a delivery rate per transfer of
      23.6%, and 821 cycles using a host uterus, with a delivery rate per transfer of
      33.6%. In addition, 398 cycles were reported as combinations of more than one
      treatment type, 18 cycles as research, and 416 as embryo banking. As a result of
      all procedures, 21,904 deliveries were reported, resulting in 30,967 neonates.
      CONCLUSION(S): In 1999, more programs reported ART treatment and reported cycles
      increased significantly (7.5%) compared to 1998. In comparable cycle types, the
      overall success rate (deliveries per retrieval) increased by 0.4%, which
      represents an increase of 1.2% compared to the success rate for 1998.

PMID- 12413975
TI  - Regulation of assisted reproductive technologies in the United States.

PMID- 12413976
TI  - Progress we can be proud of: U.S. trends in assisted reproduction over the first
      20 years.
AB  - OBJECTIVE: Documentation of the significant progress of assisted reproductive
      technology (ART) therapy in the United States. DESIGN: Tabulation of data from
      the annual published reports of ART activity in the United States for the years
      1985 through 1999. SETTING: ART centers in the United States that report their
      results to the Centers for Disease Control and Prevention (CDC) via the Society
      for Assisted Reproductive Technology (SART). PATIENT(S): The annual reports
      included 647,208 cycles of treatment. INTERVENTION(S): None. MAIN OUTCOME
      MEASURE(S): The number of clinics and cycles, and the rates of pregnancy,
      delivery, miscarriage, and multiple pregnancy were examined. Practice trends were
      also examined. RESULT(S): The number of clinics and cycles has grown steadily.
      The 155,661 clinical pregnancies led to 128,608 births and 177,745 babies born.
      The advent of intracytoplasmic sperm injection (ICSI) and the fall of GIFT and
      zygote intrafallopian transfer (ZIFT) are noted. Pregnancy rates have risen
      steadily in all therapies, and the number of deliveries of triplets or more has
      declined dramatically in the most recent reporting years. CONCLUSION(S): Over the
      years, ART therapies have steadily become more effective, with notable reductions
      in multiple pregnancies, the ability to avoid laparoscopy (for egg retrieval and
      in some cases tubal transfers), and effective therapy for serious sperm, egg, and
      uterine problems, none of which was true in the early years. This has occurred
      owing to the dedication and ingenuity of practitioners, and, notably, without
      federal regulation of clinical practice.

PMID- 12413977
TI  - The randomized world is not without its imperfections: reflections on the Women's
      Health Initiative Study.
AB  - In May 2002, the Women's Heath Initiative (WHI) clinical trial, designed to
      clarify the risks and benefits of combination hormone replacement therapy, came
      to a premature halt. An interim safety review after an average follow-up of 5.2
      years found that a combination of estrogen and progestin often prescribed to
      postmenopausal women increased the risk of invasive breast cancer, heart disease,
      stroke, and pulmonary embolism. The combination hormone therapy reduced bone
      fractures and colorectal cancer, but not enough to outweigh the other risks. The
      WHI trial presents a challenge for patients, physicians, and epidemiologists,
      since many observational studies have shown cardiovascular benefits of long-term
      hormone replacement therapy (HRT). At the same time, a companion paper in the
      same journal reported an epidemiologic study with a 13.4-year mean follow-up
      suggesting that estrogen replacement therapy, when used alone for 10 years or
      more, increases the risk of ovarian cancer. The medical community is still
      recovering from these twin shocks and trying to digest the results of both of
      these studies. The WHI study calls into question the long-term use of HRT in
      healthy women. The benefit of the temporary use of estrogen in controlling
      disruptive symptoms of the menopause is not being contested. Absent from many
      news releases are the hedging and equivocation typical of other reported clinical
      trials. There are still some "hanging chads" out there, and this commentary is
      designed to examine the uncertainties that remain after the WHI report. It is
      also intended to suggest development of alternative strategies to control
      symptoms of the menopausal transition that will reduce risks of HRT. The evidence
      from the WHI study will need to be incorporated into medical decision making, but
      clinical decisions, like most human decisions, are complex and in the final
      analysis must be based on information from many sources.

PMID- 12413978
TI  - Donating spare embryos for embryonic stem-cell research.

PMID- 12413979
TI  - Consensus statement for the management of chronic pelvic pain and endometriosis:
      proceedings of an expert-panel consensus process.
AB  - OBJECTIVE: To develop recommendations for the medical and surgical care of women
      who present with chronic pelvic pain (CPP) and are likely to have endometriosis
      as the underlying cause. DESIGN: An expert panel comprised of practicing
      gynecologists from throughout the United States and experts in consensus
      guideline development was convened. After completion of a structured literature
      search and creation of draft algorithms by an executive committee, the expert
      panel of >50 practicing gynecologists met for a 2-day consensus conference during
      which the clinical recommendations and algorithms were reviewed, refined, and
      then ratified by unanimous or near-unanimous votes. PATIENT(S): Women presenting
      with CPP who are likely to have endometriosis as the underlying cause. MAIN
      OUTCOME MEASURE(S): None. CONCLUSION(S): Chronic pelvic pain frequently occurs
      secondary to nongynecologic conditions that must be considered in the evaluation
      of affected women. For women in whom endometriosis is the suspected cause of the
      pain, laparoscopic confirmation of the diagnosis is unnecessary, and a trial of
      medical therapy, including second-line therapies such as danazol, GnRH agonists,
      and progestins, is justified provided that there are no other indications for
      surgery such as the presence of a suspicious adnexal mass. When surgery is
      necessary, laparoscopic approaches seem to offer comparable clinical outcomes to
      those performed via laparotomy, but with reduced morbidity. The balance of
      evidence supports the use of adjuvant postoperative medical therapy after
      conservative surgery for CPP. There is some evidence that adjuvant presacral
      neurectomy adds benefit for midline pain, but currently, there is inadequate
      evidence to support the use of uterosacral nerve ablation or uterine suspension.
      Hysterectomy alone has undocumented value in the surgical management of women
      with endometriosis-associated CPP.

PMID- 12413980
TI  - Role of endocrine status and cell type in adhesion of human endometrial cells to
      the peritoneum in nude mice.
AB  - OBJECTIVE: To investigate the role of different cellular types (epithelial and
      stromal endometrial cells and peritoneal cells) in the ectopic implantation of
      endometrium and to evaluate the importance of endocrine environment on the
      adhesion of endometrial cells to the peritoneum. DESIGN: Experimental prospective
      study. SETTING: University hospital, department of cell biology. ANIMAL(S): One
      hundred one nude mice. INTERVENTION(S): Monolayer culture of human epithelial and
      stromal endometrial cells obtained from patients undergoing hysterectomy or
      laparoscopy for benign disease. Intraperitoneal injection of cells into nude
      mice. MAIN OUTCOME MEASURE(S): Two weeks after cell injection, adhesion of
      endometrial cells was evaluated by histological and immunohistochemical
      examination. RESULT(S): Mixed cultures of stromal and epithelial cells, but not
      purified epithelial or stromal cells alone, adhered to the mouse peritoneum and
      led to endometriotic-like nodules. Pretreatment of cells with estrogen alone or
      with estrogen and progestin resulted in a higher percentage of animals developing
      endometriotic-like nodules, whereas treatment with progestin alone did not affect
      endometriotic implantation. CONCLUSION(S): Our data indicate that the success of
      endometrial cell implantation is dependent on the cooperativeness between stromal
      and epithelial endometrial cells, as well as on the endocrine environment of
      endometrial cells, but not that of recipient animals. The results emphasize the
      role of both endometrial cell types for ectopic implantation.

PMID- 12413981
TI  - Coordinated regulation of HOX gene expression in myometrium and uterine
      leiomyoma.
AB  - OBJECTIVE: To measure HOXA10 gene expression in uterine myometrium and leiomyoma
      throughout the menstrual cycle. DESIGN: HOXA10 gene expression was measured in
      paired myometrium and leiomyoma from the same uterus. SETTING: University medical
      center. PATIENT(S): Thirty-one patients with leiomyoma. INTERVENTION(S):
      Collection of leiomyoma and myometrial tissue during hysterectomy. MAIN OUTCOME
      MEASURE(S): HOXA10 gene expression was analyzed by Northern analysis and
      quantified by laser densitometry. RESULT(S): Both myometrium and leiomyoma
      continued to express HOXA10 in the adult and menstrual cycle stage-specific
      regulation was evident in both tissues. During the mid-secretory phase of the
      menstrual cycle, HOXA10 expression decreased in both leiomyoma and myometrium. At
      all points in the menstrual cycle HOXA10 expression in leiomyoma was similar to
      expression in paired myometrium. CONCLUSION(S): HOXA10 is expressed in both
      myometrium and leiomyoma. Coordinated regulation of this transcript factor
      suggests similar gene activation in both leiomyoma and myometrium. Diminished
      expression of HOXA10, a gene that normally causes differentiation, may allow
      increased growth resulting in the increased mitosis seen in the secretory phase.
      The identification of this developmental control gene in myometrium and leiomyoma
      may lead to a better understanding of the molecular mechanisms responsible for
      growth and differentiation of these tissues.

PMID- 12413982
TI  - Expression of progesterone receptors A and B and insulin-like growth factor-I in
      human myometrium and fibroids after treatment with a gonadotropin-releasing
      hormone analogue.
AB  - OBJECTIVE: To determine mRNA and protein expression of the progesterone receptor
      (PR) and insulin-like growth factor-I (IGF-I) in myometrium and fibroids. DESIGN:
      Retrospective clinical study. SETTING: Hospital-based and university-affiliated
      research laboratories. PATIENT(S): Twelve women in the proliferative phase and
      six women treated with GnRH analogue (GnRH-a). INTERVENTION(S): Blood sampling
      and collection of myometrium and fibroids. MAIN OUTCOME MEASURE(S): PR and IGF-I
      mRNA levels in fibroids and myometrium were analyzed by solution hybridization
      and in situ hybridization whereas the proteins were localized by
      immunohistochemistry. RESULT(S): Fibroids and myometrium from women in the
      proliferative phase showed significantly higher PR mRNA than the corresponding
      tissues from GnRH-a-treated women. The amount of cells positively stained for PR
      AB and PR-B in fibroids and myometrium decreased after GnRH-a treatment compared
      with in the proliferative phase. The IGF-I mRNA in both fibroids and myometrium
      in the proliferative phase was significantly higher than those after GnRH-a
      treatment. The immunostaining of IGF-I showed no difference between the two
      tissues. There was weaker immunostaining in the GnRH-a-treated group compared
      with in the proliferative phase group. CONCLUSION(S): The shrinkage of fibroids
      after steroid deprivation is associated with alterations in PR and IGF-I
      expression.

PMID- 12413983
TI  - Effect of the opioid blockade on the feeding-induced growth hormone response to
      growth hormone-releasing hormone in women with polycystic ovary syndrome.
AB  - OBJECTIVE: To investigate the effect of naloxone, an opioid receptor antagonist,
      on the release of growth hormone (GH) induced by the growth hormone-releasing
      hormone (GHRH) in normal-weight and obese women with PCOS in relation to feeding.
      DESIGN: Prospective clinical study. SETTING: Academic research center.
      PATIENT(S): Seventeen women with PCOS (10 who were normal weight and 7 who were
      obese) and 14 control women (7 who were normal weight and 7 who were obese).
      INTERVENTION(S): A GHRH test (50 microg i.v.) and, on a different day, a GHRH
      test during a naloxone infusion (1.6 mg/h) during fasting. The same tests were
      repeated after a standard meal. MAIN OUTCOME MEASURE(S): GH response to GHRH
      (expressed as the area under the curve [AUC]) in different experimental
      conditions. RESULT(S): All normal-weight women showed a significantly higher AUC
      GH compared with obese women in the fasting state. Normal-weight controls had a
      decrease in GH response to GHRH after feeding, and naloxone did not reverse the
      decrease. In obese controls, feeding increased the GH response but naloxone
      induced a decrease in the AUC. In fasting, normal-weight women with PCOS,
      naloxone significantly decreased the AUC-GH; in these patients, food intake
      induced an inhibition of GH response to GHRH, reversed by naloxone infusion. In
      obese PCOS patients, GH levels did not increase significantly after GHRH
      stimulation, either in the fasting state or after a meal, and naloxone did not
      affect these responses. CONCLUSION(S): Factors other than obesity and insulin may
      be involved in disruption of GH secretion in women with PCOS.

PMID- 12413984
TI  - Use of dexamethasone and clomiphene citrate in the treatment of clomiphene
      citrate-resistant patients with polycystic ovary syndrome and normal
      dehydroepiandrosterone sulfate levels: a prospective, double-blind, placebo
      controlled trial.
AB  - OBJECTIVE: To evaluate the effects of short-course administration of
      dexamethasone (DEX) combined with clomiphene citrate (CC) in CC-resistant
      patients with polycystic ovary syndrome (PCOS) and normal DHEAS levels. DESIGN:
      Prospective, double-blind, placebo-controlled, randomized study. SETTING:
      Referral university hospitals. PATIENT(S): Two hundred thirty women with PCOS and
      normal DHEAS who failed to ovulate after a routine protocol of CC.
      INTERVENTION(S): The treatment group received 200 mg of CC from day 5 to day 9
      and 2 mg of DEX from day 5 to day 14 of the menstrual cycle. The control group
      received the same protocol of CC combined with placebo. MAIN OUTCOME MEASURE(S):
      Follicular development, hormonal status, ovulation rate, pregnancy rate.
      RESULT(S): Mean follicular diameters were 18.4124 +/- 2.4314 mm and 13.8585 +/-
      2.0722 mm for the treatment and control groups, respectively. Eighty-eight
      percent of the treatment group and 20% of the control group had evidence of
      ovulation. The difference in the cumulative pregnancy rate in the treatment and
      control groups was statistically significant. CONCLUSION(S): Hormonal levels,
      follicular development, and cumulative pregnancy rates improved with the addition
      of DEX to CC in CC-resistant patients with PCOS and normal DHEAS. This regimen is
      recommended before any gonadotropin therapy or surgical intervention.

PMID- 12413985
TI  - Effect of tibolone administration on heart rate variability and free fatty acid
      levels in postmenopausal women.
AB  - OBJECTIVE: To evaluate the effects of tibolone on heart rate variability and
      plasma free fatty acid levels in postmenopausal women. DESIGN: Randomized,
      placebo-controlled trial. SETTING: University hospital. PATIENT(S): Thirty
      postmenopausal women. INTERVENTION(S): Tibolone, 2.5 mg/d, or placebo for 4
      months. MAIN OUTCOME MEASURES: Variability in heart rate and changes in the lipid
      profile. RESULT(S): Anthropometric data were unchanged throughout the study.
      Compared with placebo, long-term tibolone administration was associated with a
      decrease in plasma levels of low-density lipoprotein cholesterol, triglyceride,
      and free fatty acid and homeostasis model assessment index. Furthermore, tibolone
      administration was associated with an increase in RR interval, total power, and
      high frequency and decrease in low frequency and the low frequency/high frequency
      ratio. Finally, the delta decrease in plasma free fatty acid levels correlated
      with delta low frequency/high frequency ratio independently of age, delta body
      mass index, delta homeostasis model assessment index, and low-density lipoprotein
      cholesterol levels. CONCLUSION(S): Long-term tibolone administration improves the
      ratio of cardiac sympathetic tone to parasympathetic tone in postmenopausal
      women.

PMID- 12413986
TI  - Vaginal rings delivering progesterone and estradiol may be a new method of
      hormone replacement therapy.
AB  - OBJECTIVE: To determine whether a low dose of P delivered together with E(2) from
      a vaginal ring on a continuous schedule can prevent endometrial proliferation and
      yield a bleeding pattern dominated by amenorrhea. DESIGN: Longitudinal clinical
      study. SETTING: Three university hospitals. PATIENT(S): Fifty-five women 45 to 75
      years of age, not hysterectomized, with E(2) levels of <20 pg/mL and hot-flash
      incidence of two or more per day in the past week. INTERVENTION(S): A vaginal
      ring delivering approximately 150 microg/d of 17beta-E(2) and approximately 5
      mg/d or approximately 9 mg/d of P used continuously for 4 and 6 months. MAIN
      OUTCOME MEASURE(S): Endometrial thickness, bleeding pattern, and hot flash
      incidence. RESULT(S): Endometrial proliferation was prevented by both P doses.
      Bleeding incidence decreased. In months 4, 5, and 6, 8 of 12 women had no
      bleeding. Incidence of hot flashes and night sweats decreased quickly and
      significantly. CONCLUSION(S): A vaginal ring delivering E(2) and a low dose of P
      merits further study as a method for long-term hormone replacement therapy.

PMID- 12413987
TI  - Naloxone decreases insulin secretion in hyperinsulinemic postmenopausal women and
      may positively affect hormone replacement therapy.
AB  - OBJECTIVE: To evaluate the influence of the opioid system on glyco-regulation in
      postmenopausal women before and after hormone replacement therapy (HRT). DESIGN:
      Prospective nonrandomized clinical study. SETTING: Academic research environment.
      PATIENT(S): Twenty-one healthy normo- or hyperinsulinemic postmenopausal women.
      INTERVENTION(S): Oral glucose tolerance test (OGTT) (saline study), OGTT with IV
      injection of naloxone (naloxone study), and hyperinsulinemic euglycemic clamp
      performed before treatment, after 12 weeks of estrogen replacement therapy (ERT),
      and after 12 additional weeks of estro-progestin combined therapy (i.e., HRT).
      MAIN OUTCOME MEASURE(S): Glucose, insulin, and c-peptide plasma levels assessed
      in fasting condition and during the two OGTTs (area under the curve [AUC]).
      Evaluation of fractional hepatic insulin extraction (FHIE) and peripheral
      sensitivity to insulin. RESULT(S): At baseline, there is a greater increase of
      the FHIE and a more significant reduction of the insulin AUC in the
      hyperinsulinemic patients during the naloxone study compared with the saline
      study. In these women, ERT enhanced the c-peptide AUC and improved the FHIE;
      naloxone infusion mainly increased these two parameters. HRT did not induce any
      further change. CONCLUSION(S): Endogenous opioid peptides are involved in the
      modulation of carbohydrate metabolism in menopause in hyperinsulinemic patients
      more than in other patients. The favorable changes of the glyco-insulinemic
      metabolism induced by HRT may be partially due to the induction of the
      opioidergic activity.

PMID- 12413988
TI  - Effect of ovarian stimulation with recombinant follicle-stimulating hormone,
      gonadotropin releasing hormone antagonists, and human chorionic gonadotropin on
      endometrial maturation on the day of oocyte pick-up.
AB  - OBJECTIVE: To assess the effect of ovarian stimulation with recombinant FSH, GnRH
      antagonists, and hCG on endometrial maturation on the day of oocyte pick-up.
      DESIGN: Prospective study. SETTING: Tertiary referral center. PATIENT(S): Fifty
      five women undergoing controlled ovarian hyperstimulation for
      IVF/intracytoplasmic sperm injection (ICSI). INTERVENTION(S): [1] Ovarian
      stimulation with recombinant FSH, starting on day 2 of the cycle and GnRH
      antagonist, starting after a median of 6 days of recombinant FSH stimulation
      (range, 5-12 days); [2] hCG administration for ovulation induction; and [3]
      aspirational biopsy of endometrium at oocyte pick-up. MAIN OUTCOME MEASURE(S):
      Endometrial histology at oocyte pick-up by Noyes criteria. RESULT(S): Advancement
      of endometrial maturation (2.5 +/- 0.1 days) as compared to the expected
      chronological date was observed in all antagonist cycles at oocyte retrieval.
      Endometrial advancement at oocyte pick-up increased in line with values of LH at
      initiation of stimulation and the duration of recombinant FSH treatment before
      the antagonist was started. CONCLUSION(S): The higher the values of LH at
      initiation of stimulation and the longer the duration of recombinant FSH
      treatment before the antagonist is started, the more advanced the endometrial
      maturation at oocyte pick-up.

PMID- 12413989
TI  - Intracytoplasmic sperm injection versus in vitro fertilization: a randomized
      controlled trial and a meta-analysis of the literature.
AB  - OBJECTIVE: To compare ICSI with IVF using two insemination concentrations in
      moderate male infertility and to compare these data with other randomized
      controlled trials (RCTs). DESIGN: Prospective, randomized, controlled trial and
      meta-analysis. SETTING: University-based tertiary referral center. PATIENT(S):
      Seventy-three couples undergoing ART. INTERVENTION(S): In one IVF group a
      standard insemination concentration of 0.2 x 10(6)/mL was used, whereas in the
      other group a high insemination concentration (HIC) of 0.8 x 10(6)/mL was used.
      Each protocol was compared with ICSI on sibling oocytes. MAIN OUTCOME MEASURE(S):
      Fertilization, fertilization failure, and embryonic development. RESULT(S): The
      overall fertilization rate was significantly lower after standard IVF than after
      ICSI: 37.4% vs. 64.3%. Where HIC IVF was used, the overall fertilization rate was
      not significantly different from that after ICSI: 59.6% vs. 67.6%. Eight
      randomized controlled trials were selected and reviewed together with the present
      randomized controlled trial by meta-analysis. The risk ratio for an oocyte to
      become fertilized was 1.9 (95% confidence interval of 1.4 to 2.5) in favor of
      ICSI, and 3.1 ICSI cycles may be needed to avoid one complete fertilization
      failure after conventional IVF (95% CI of 1.7 to 12.4). CONCLUSION(S): The data
      from this study and the meta-analysis show that ICSI is a more efficient
      technique in terms of fertilization, but not in comparison with HIC IVF.

PMID- 12413990
TI  - Clinical outcomes among recipients of donated eggs: an analysis of the U.S.
      national experience, 1996-1998.
AB  - OBJECTIVE: To evaluate the role of recipient age on the outcome of donor egg
      cycles. DESIGN: Retrospective cohort study of aggregated national cycles of donor
      egg therapy that are collected by Society for Assisted Reproductive Technology
      and the Centers for Disease Control and Prevention. SETTING: Assisted
      reproductive technology centers in the United States that report their results to
      the Centers for Disease Control and Prevention by way of the Society for Assisted
      Reproductive Technology. PATIENT(S): Recipients of embryos (17,339 cycles)
      derived from donated eggs between 1996 and 1998. INTERVENTION(S): None. MAIN
      OUTCOME MEASURE(S): Rates of implantation, clinical intrauterine pregnancy,
      pregnancy loss, and delivery based on the age of the recipient. RESULT(S):
      Success of donor egg therapy was remarkably constant among recipients aged 25
      years through those in their late forties. At higher ages, declining rates of
      implantation, clinical pregnancy, and delivery were seen, along with small
      increases of pregnancy loss. During the course of the 3 years studied, fewer
      embryos were transferred and higher rates of implantation were observed.
      CONCLUSION(S): The success of donor egg therapy is unaffected by recipient age up
      to the later 40s, after which they begin to decline. Although recipient age per
      se is likely to be the major cause of this effect, other factors may contribute
      to this observation.

PMID- 12413991
TI  - Mitochondrial deletions in luteinized granulosa cells as a function of age in
      women undergoing in vitro fertilization.
AB  - OBJECTIVE: To test the hypothesis that mitochondrial DNA (mtDNA) deletions are
      more prevalent in granulosa cells from women of advanced reproductive age than
      from younger women undergoing IVF. DESIGN: Granulosa cells screened for presence
      or absence of the 4977-bp deletion in human mtDNA. SETTING: University-based
      fertility clinic. PATIENT(S): Twenty-four women divided equally between two
      groups: </=34 years old and >/=38 years old. INTERVENTION(S): Patients were given
      gonadotropin stimulation in preparation for IVF with granulosa cells isolated at
      the time of follicular aspiration. MAIN OUTCOME MEASURE(S): Presence or absence
      of the 4977-bp deletion in human mtDNA. RESULT(S): Seven out of 12 women analyzed
      who were <38 years old and 0 out of 12 women who were >38 years old had normal
      mtDNA as indicated by the presence of the 4977-bp fragment. CONCLUSION(S): These
      data suggest that women over the age of 38 have granulosa cells that contain a
      substantial decrease in the level of normal mitochondria as compared with women
      </=34 years.

PMID- 12413992
TI  - Recombinant follicle-stimulating hormone versus human menopausal gonadotropin in
      the late follicular phase during ovarian hyperstimulation for in vitro
      fertilization.
AB  - OBJECTIVE: To study the effect of exogenous LH in the late follicular phase on
      ongoing pregnancies and at the different stages of IVF-ET (stimulation,
      fertilization, and implantation) in patients with low endogenous LH. DESIGN:
      Retrospective cohort study with modeling of the different phases of IVF-ET.
      SETTING: IVF center of the teaching hospital in Bordeaux, France. PATIENT(S):
      Women undergoing IVF and ICSI treatment. INTERVENTION(S): One group received
      recombinant FSH alone (FSH group) and the other received recombinant FSH and hMG
      in the late follicular phase (i.e., when the largest follicle reached 14 mm)
      (FSH/hMG group). MAIN OUTCOME MEASURE(S): Ongoing pregnancy, number of oocytes,
      and number of embryos. RESULT(S): The FSH/hMG group had a higher probability of
      having at least one oocyte (odds ratio [OR] = 2.75 [1.11-6.80]), of having at
      least one embryo after oocyte retrieval (OR = 2.84 [1.33-6.07]), and of ongoing
      pregnancy after ET (OR = 2.04 [0.83-5.01]), and globally had a higher probability
      of ongoing pregnancy (OR = 2.83 [1.19-6.71]). CONCLUSION(S): In ovarian
      hyperstimulation for IVF-ET, LH supplementation in the late follicular phase of
      women with low endogenous LH is beneficial for ongoing pregnancy by increasing
      the rate of success of all stages of the treatment.

PMID- 12413993
TI  - Cycle-to-cycle variation in utero-ovarian hemodynamic indices in ovarian
      stimulation and natural cycles of the same women and its effect on the outcome of
      assisted reproduction treatment.
AB  - OBJECTIVE: To investigate the blood flow parameters between cycles of the same
      women to assess whether parameters predicting a successful pregnancy in a
      stimulation cycle could be used to determine the outcome of subsequent natural
      cycles. DESIGN: A prospective study. SETTING: Assisted reproduction unit, the
      University of Hong Kong. PATIENT(S): Fifty-eight IVF cycles and 40 natural cycles
      were evaluated. INTERVENTION(S): Assessments of the utero-ovarian pulsatility
      indices (PIs), resistance indices (RIs), and endometrial color signals.
      RESULT(S): In IVF cycles, the pregnancy rate (27%) was similar to that in frozen
      thawed embryo transfer (FET) (28%) cycles. The utero-ovarian PIs and RIs in IVF
      cycles were significantly lower than those in the natural cycles. There was a
      significant correlation between the uterine PI in stimulation cycles and that in
      natural cycles. In IVF cycles, the pregnancy rate declined significantly when the
      uterine PI was >2.70 and the RI was >0.9. In FET cycles, no decline in pregnancy
      rate was seen. Conceptional FET cycles showed significantly higher uterine PI,
      uterine RI, and endometrial color signals compared with conceptional IVF cycles.
      CONCLUSION(S): Hemodynamic parameters in stimulation cycles are different from
      those in natural cycles, and the values of various parameters in predicting
      pregnancy are also different.

PMID- 12413994
TI  - Effect of highly purified urinary follicle-stimulating hormone on oocyte and
      embryo quality.
AB  - OBJECTIVE: To determine the effects of ovarian stimulation with highly purified
      urofollitropin on oocyte and embryo quality. DESIGN: Parallel randomized open
      label clinical study. SETTING: Assisted reproduction centers. PATIENT(S): Two
      hundred sixty-seven infertile couples undergoing IVF/ICSI. INTERVENTION(S): All
      participants underwent standard down-regulation with GnRH analogue. One hundred
      thirty-three participants received highly purified urinary FSH and 134 controls
      received recombinant FSH. MAIN OUTCOME MEASURE(S): Primary end points were number
      of morphologically mature oocytes retrieved, embryo quality, and pregnancy and
      implantation rates. Secondary end points were: total number of days of FSH
      stimulation, total dose of gonadotropin administered, fertilization rate per
      number of retrieved oocytes, embryo cleavage rate, live birth and miscarriage
      rates, endometrial thickness and estradiol level on the day of hCG
      administration, cancellation rate, and incidence of moderate or severe ovarian
      hyperstimulation syndrome. RESULT(S): Pregnancy and implantation rates were
      nonsignificantly higher in the urinary FSH group than the recombinant FSH group
      (46.5% vs. 36.8% and 22.1% vs. 15.8%, respectively). The grade 1 embryo score was
      significantly higher in the urinary FSH group than the recombinant FSH (42.1% vs.
      33.5%), and the live birth rate was nonsignificantly higher in the former group.
      CONCLUSION(S): Highly purified urinary FSH is as effective, efficient, and safe
      for clinical use as recombinant FSH.

PMID- 12413995
TI  - Minimal ovarian hyperstimulation for in vitro fertilization using sequential
      clomiphene citrate and gonadotropin with or without the addition of a
      gonadotropin-releasing hormone antagonist.
AB  - OBJECTIVE: To compare the results of a minimal-stimulation protocol with those of
      a standard protocol used for IVF. DESIGN: Retrospective, controlled study.
      SETTING: University center. PATIENT(S): Fifty-five patients undergoing IVF using
      a minimal-stimulation protocol with or without adjuvant therapy with a GnRH
      antagonist. A control group consisted of age- and diagnosis-matched patients
      undergoing a standard long GnRH agonist (GnRH-a)-gonadotropin stimulation during
      the same time period. INTERVENTION(S): Clomiphene citrate and gonadotropins, with
      or without the GnRH antagonist ganirelix. MAIN OUTCOME MEASURE(S): Oocytes
      recovered and pregnancy rates. RESULT(S): The number of oocytes retrieved was
      significantly lower for the minimal-stimulation regimen compared with the case of
      the long GnRH-a protocol (4.8 +/- 2.6 vs. 16.2 +/- 7.5, respectively). The
      clinical pregnancy rate per transfer, however, was not significantly different
      between the two regimens (37% vs. 41%, minimal stimulation vs. long GnRH-a
      protocol, respectively). The addition of ganirelix resulted in at least the same
      pregnancy outcome as compared with the case of cycles without the antagonist.
      CONCLUSION(S): Minimal stimulation using clomiphene citrate followed by
      gonadotropin for IVF results in pregnancy rates equal to the standard long GnRH-a
      gonadotropin protocol. The addition of ganirelix resulted in at least similar
      results with the advantage of eliminating the occurrence of a premature
      endogenous LH surge.

PMID- 12413996
TI  - Effect of vaginal sildenafil on the outcome of in vitro fertilization (IVF) after
      multiple IVF failures attributed to poor endometrial development.
AB  - OBJECTIVE: To evaluate the effects of vaginally administered sildenafil on
      endometrial thickness and IVF outcome in a large cohort of infertile women with
      poor endometrial development. DESIGN: Retrospective cohort analysis. SETTING:
      Private practice setting. PATIENT(S): A cohort of 105 infertile women aged <40
      years, with normal ovarian reserve and at least two consecutive prior IVF
      failures attributed to inadequate endometrial development. INTERVENTION(S):
      Patients underwent IVF using a long GnRH-a protocol with the addition of
      sildenafil vaginal suppositories (25 mg, 4 times per day) for 3-10 days. MAIN
      OUTCOME MEASURE(S): Peak endometrial development, pregnancy, and implantation
      rates. RESULT(S): Of 105 patients, 73 (70%; Group A), attained an endometrial
      thickness of >/=9 mm, whereas 32 (30%; Group B) did not. Implantation and ongoing
      pregnancy rates were significantly higher for Group A (29% and 45%) than for
      Group B (2% and 0). Of 11 women in Group B who had embryos transferred in that
      cycle, only one conception occurred, which resulted in a miscarriage. In Group B,
      59% of women had a history of endometritis, compared with 44% in Group A.
      CONCLUSION(S): Vaginal administration of sildenafil enhanced endometrial
      development in 70% of patients studied. High implantation and ongoing pregnancy
      rates were achieved in a cohort with a poor prognosis for success. Previous
      endometritis may decrease the response to sildenafil.

PMID- 12413997
TI  - Prediction of chromosome misalignment among in vitro matured human oocytes by
      spindle imaging with the PolScope.
AB  - OBJECTIVE: To examine whether spindle morphologic features imaged with the LC
      PolScope (Cambridge Research and Instrumentation, Woburn, MA) in living human
      oocytes matured in vitro can be used to predict chromosome configuration and
      select oocytes with normal chromosomes. DESIGN: Morphological study. SETTING:
      Academic IVF clinic. PATIENT(S): Women undergoing oocyte retrieval for ICSI
      treatment. INTERVENTION(S): Oocytes were examined after in vitro maturation. MAIN
      OUTCOME MEASURE(S): The study examined meiotic spindle morphologic features and
      chromosome alignments. RESULT(S): After culture for 22 to 24 hours, 77.1% of
      oocytes reached metaphase II stage, with 51.9% of oocytes showing birefringent
      spindles. Confocal microscopy revealed that 71% of oocytes with the birefringent
      spindles had normal chromosome alignment, and 29% of oocytes with birefringent
      spindles and all oocytes without birefringent spindles had abnormal microtubule
      organization and abnormal chromosome alignment. CONCLUSION(S): The spindle images
      obtained with the PolScope in living human oocytes are coordinate with those in
      fixed oocytes as imaged by confocal microscopy. Spindle images with the PolScope
      can be applied to human in vitro fertilization to help predict chromosomally
      normal oocytes for insemination.

PMID- 12413998
TI  - Influence of oocytes and spermatozoa on early embryonic development.
AB  - OBJECTIVE: To evaluate the effect of oocytes and spermatozoa on early embryonic
      development. DESIGN: Retrospective study. SETTING: Infertility Clinic, the Family
      Federation of Finland. PATIENT(S): Fifty-nine oocyte donation cycles with oocytes
      shared among 118 recipient couples. INTERVENTION(S): Culture of all fertilized
      oocytes. MAIN OUTCOME MEASURE(S): Standard sperm (concentration, progressive
      motility, and morphology according to Tygerberg strict criteria) and embryo
      (morphology and cleavage stage) characteristics. RESULT(S): A marked effect of
      the oocyte on both embryo morphology and blastomere cleavage rate was
      demonstrated. In addition, a significant sperm effect on blastomere cleavage rate
      was found. Sperm morphology as determined according to strict criteria rather
      than sperm count or progressive motility was positively associated with the
      blastomere cleavage rate. None of the measured sperm characteristics influenced
      embryo morphology. CONCLUSION(S): Embryo morphology, i.e., fragmentation and
      blastomere uniformity, are predominantly determined by oocyte quality, whereas
      both the oocyte and spermatozoa influence the blastomere cleavage rate.

PMID- 12413999
TI  - Effect of diagnosis, age, sperm quality, and number of preovulatory follicles on
      the outcome of multiple cycles of clomiphene citrate-intrauterine insemination.
AB  - OBJECTIVE: To determine how diagnosis, age, sperm quality, and number of
      preovulatory follicles affect pregnancy rates when multiple cycles of clomiphene
      citrate (CC)-IUI are performed. DESIGN: Fifteen-year prospective observational
      study. SETTING: Private infertility clinic. PATIENT(S): Three thousand, three
      hundred eighty-one cycles of husband or donor IUI. INTERVENTION(S): Ovulation
      induction with CC and IUI. MAIN OUTCOME MEASURE(S): Per-cycle pregnancy rate
      (PR), cumulative pregnancy rate (CPR). RESULT(S): Pregnancy rates remained
      constant through four cycles, then fell significantly for diagnoses other than
      ovulatory dysfunction. Mean PRs for cycles 1-4 were significantly lower for
      patients with the following characteristics: age >/=43 years, poor semen quality,
      single preovulatory follicles, and diagnoses other than ovulatory dysfunction.
      Additional cycles of CC-IUI compensated for low PRs because of age, semen
      quality, or number of follicles. After four cycles, CPRs were 46% for ovulatory
      dysfunction; 38% for cervical factor, male factor, and unexplained infertility;
      34% for endometriosis; and 26% for tubal factor. After six cycles, CPRs were 65%
      for ovulation dysfunction, 35% for endometriosis, and unchanged for other
      diagnoses. CONCLUSION(S): Clomiphene citrate-intrauterine insemination should be
      performed for a minimum of four cycles. Additional cycles of CC-IUI can
      compensate for low pregnancy rates due to age, semen quality, or follicle number
      in patients with ovulation dysfunction.

PMID- 12414000
TI  - Human chorionic gonadotropin suppresses ovarian epithelial neoplastic cell
      proliferation in vitro.
AB  - OBJECTIVE: To quantify the in vitro effects of gonadotropins on benign,
      borderline, and malignant ovarian cell lines. DESIGN: In vitro cell culture.
      SETTING: Research laboratory. PATIENT(S): None. INTERVENTION(S): Three hormonally
      sensitive ovarian neoplastic cell lines were exposed to control medium, FSH (40
      mIU/mL), hCG (200 mIU/mL), and a combination of FSH and hCG. MAIN OUTCOME
      MEASURE(S): Cellular proliferation measured by a colorimetric (MTT) assay.
      RESULT(S): Growth of the cell lines was similar when exposed to control or FSH.
      In the presence of hCG alone, the cell lines demonstrated decreased proliferation
      when compared to control or FSH alone. When hCG was given in combination with
      FSH, there was decreased proliferation of the cell lines compared to control or
      FSH alone. CONCLUSION(S): Growth of benign, borderline, and malignant ovarian
      epithelial cell lines is inhibited by hCG at levels, which are commonly achieved
      with hCG administration during ovulation induction or as a result of
      trophoblastic production in early pregnancy.

PMID- 12414001
TI  - An analysis of the pattern of pregnancy loss in women with recurrent miscarriage.
AB  - OBJECTIVE: To describe the pattern of pregnancy loss in women with a history of
      recurrent miscarriage (RM). DESIGN: Retrospective, observational study. SETTING:
      A tertiary referral center for RM. PATIENT(S): Five hundred thirty-eight subjects
      with RM. INTERVENTION(S): Women with antiphospholipid syndrome were treated with
      clexane and aspirin; some patients with uterine anomalies underwent corrective
      surgery, and some cases of retarded endometrium were treated with hMG. MAIN
      OUTCOME MEASURE(S): Pregnancy outcome, including the stage of pregnancy at which
      pregnancy loss occurred. RESULT(S): In women with a prothrombotic state, the
      miscarriage rate before the detection of fetal heart activity (early loss) in the
      untreated group (50%) was significantly higher than in the treatment group
      (17.5%). In women with a uterine anomaly, the early loss rate and the later loss
      rate (after detection of fetal heart activity) were both increased. Women with
      retarded endometrium, women with >/=6 losses, and older women (>/=41 years) are
      more likely to have a further early loss but not a later loss. CONCLUSION(S): An
      understanding of the patterns of pregnancy loss provides further insight into the
      mechanism of the reproductive failure, which has implications for treatment.

PMID- 12414002
TI  - Use of mandelic acid condensation polymer (SAMMA), a new antimicrobial
      contraceptive agent, for vaginal prophylaxis.
AB  - OBJECTIVE: To assess the contraceptive properties, antimicrobial activity, and
      safety of mandelic acid condensation polymer (SAMMA). DESIGN: Experimental study
      of SAMMA's in vitro and in vivo properties. SETTING: Academic research
      laboratories. PATIENT(S): Healthy volunteers for semen donation in an academic
      research environment. INTERVENTION(S): Inhibition of sperm function indicators,
      conception, sexually transmitted infection-causing pathogens (including HIV), and
      lactobacilli was evaluated. Safety indicators were studied. MAIN OUTCOME
      MEASURE(S): Quantitation of SAMMA's effect on microbial infectivity or
      multiplication and on sperm function in vitro; evaluation of contraceptive
      efficacy in vivo; assessment of safety in vitro and in vivo. RESULT(S): Mandelic
      acid condensation polymer is not cytotoxic toward lactobacilli, microbial host
      cells, and spermatozoa. The compound inhibits hyaluronidase and acrosin, induces
      sperm acrosomal loss, and is contraceptive in the rabbit model. Mandelic acid
      condensation polymer prevents infectivity of HIV and herpesviruses 1 and 2 and,
      to a lesser extent, of Chlamydia trachomatis. It inhibits the multiplication of
      Neisseria gonorrhoeae. Mandelic acid condensation polymer is not mutagenic, has
      low acute oral toxicity, and is safe in the rabbit vaginal irritation assay.
      CONCLUSION(S): Mandelic acid condensation polymer inhibits sperm function, is
      contraceptive, has broad-spectrum antimicrobial activity, and is highly safe.
      Further development as a microbicide is warranted.

PMID- 12414004
TI  - Ligneous change of the female genital tract.

PMID- 12414003
TI  - Transcervical intrauterine topical local anesthetic at hysterosalpingography: a
      prospective, randomized, double-blind, placebo-controlled trial.
AB  - OBJECTIVE: To assess whether transcervical intrauterine topical instillation of a
      local anesthetic agent reduces pain at hysterosalpingography. DESIGN:
      Prospective, randomized, double-blind, placebo-controlled study. SETTING:
      Department of reproductive medicine at a university teaching hospital.
      PATIENT(S): One hundred ten women undergoing hysterosalpingography (HSG).
      INTERVENTION(S): Subjects were randomized to receive either 2 mL of 2% plain
      lignocaine or 2 mL of 0.9% sodium chloride solution (placebo) topically into the
      uterine cavity before the HSG was performed. MAIN OUTCOME MEASURE(S): The degree
      of lower abdominal pain experienced both during the injection of contrast media
      at HSG and 10 minutes after the procedure using a 20-cm visual analogue scale
      (VAS) and a four-point verbal descriptor scale (VDS). RESULT(S): There was no
      difference in pain scores between lignocaine and placebo during the HSG. However,
      at 10 minutes after the HSG, subjects receiving lignocaine experienced more pain
      than those on placebo. CONCLUSION(S): Transcervical intrauterine topical
      instillation of 2 mL of 2% plain lignocaine does not reduce pain during HSG and
      may lead to increased pain immediately after the procedure.

PMID- 12414005
TI  - Treatment of vaginal agglutination associated with chronic graft-versus-host
      disease.
AB  - OBJECTIVE: To describe the presentation and clinical course of two patients after
      development of vaginal agglutination associated with chronic graft-versus-host
      disease. DESIGN: Case report. SETTING: Tertiary referral center for pelvic
      reconstructive surgery. PATIENT(S): Two patients with the diagnosis of chronic
      graft-versus-host disease who later developed vaginal agglutination requiring
      treatment. INTERVENTION(S): Surgical lysis of vaginal adhesions and postoperative
      use of vaginal dilators. MAIN OUTCOME MEASURE(S): Successful treatment of vaginal
      adhesions. RESULT(S): Both patients underwent successful surgical lysis of
      vaginal adhesions and maintained vaginal patency with postoperative use of
      vaginal dilators. CONCLUSION(S): Prompt diagnosis of vaginal agglutination in
      patients with chronic graft-versus-host disease and appropriate surgical
      correction of this complication rather than prophylaxis is the correct treatment
      course.

PMID- 12414006
TI  - Infertile spermatozoa in a human carrier of robertsonian translocation 14;22.
AB  - OBJECTIVE: To present the ultrastructural, functional, and chromosomal analyses
      of spermatozoa from an infertile man with normal phenotype and chromosomal
      translocation 14;22. DESIGN: Case report. SETTING: Regional Reference Center for
      Male Infertility in Siena, Italy. PATIENT(S): A 36-year-old man with primary
      infertility for 3 years and his parents. INTERVENTION(S): Family history and
      lymphocytic karyotypes, physical and hormonal assays, and semen analysis. MAIN
      OUTCOME MEASURE(S): Morphological sperm evaluation was performed by light,
      fluorescent, and electron microscopy; chromosomal constitution was examined by
      the fluorescence in situ hybridization (FISH) technique. The penetration ability
      of spermatozoa was checked by the hamster test. RESULT(S): The spermatozoa of the
      patient showed unusual ultrastructural defects. The nuclei were large,
      spheroidal, and generally uncondensed; the acrosomes were frequently absent or
      reduced; and the axonemes were often devoid of dynein arms or central singlet
      tubules. These characteristics are related to immaturity. The lymphocytic
      karyotype revealed a robertsonian translocation 14;22 in the sterile patient and
      his mother. FISH sperm analysis demonstrated a high frequency of diploidy for the
      chromosome 18,XY. The hamster penetration test gave negative results.
      CONCLUSION(S): The unusual structural sperm immaturity is associated with the
      translocation 14;22. This chromosomal anomaly may therefore negatively influence
      the spermatogenesis; an interchromosomal effect on meiosis segregation is also
      suggested.

PMID- 12414007
TI  - Use of ultrasonography to guide first-trimester pregnancy terminations obviates
      the need for sharp curettage.

PMID- 12414008
TI  - Variation of intratesticular blood flow in response to urinary follicle
      stimulating hormone treatment in men with severe oligoteratoasthenozoospermia.

PMID- 12414009
TI  - Executive summary? All about validating scales and stages.

PMID- 12414011
TI  - Executive summary? All about validating scales and stages.

PMID- 12414012
TI  - The future for aromatase inhibitors is bright.

PMID- 12414016
TI  - CHESS: 10 years of research and development in consumer health informatics for
      broad populations, including the underserved.
AB  - This paper reviews the research and development around a consumer health
      informatics system CHESS (The Comprehensive Health Enhancement Support System)
      developed and tested by the Center for Health Systems Research and Analysis at
      the University of Wisconsin. The review places particular emphasis on what has
      been found with regard to the acceptance and use of such systems by high risk and
      underserved groups.

PMID- 12414017
TI  - Use cases and DEMO: aligning functional features of ICT-infrastructure to
      business processes.
AB  - OBJECTIVES: The proper alignment of functional features of the ICT-infrastructure
      to business processes is a major challenge in health care organisations. This
      alignment takes into account that the organisational structure not only shapes
      the ICT-infrastructure, but that the inverse also holds. To solve the alignment
      problem, relevant features of the ICT-infrastructure should be derived from the
      organisational structure and the influence of this envisaged ICT to the work
      practices should be pointed out. The objective of our study was to develop a
      method to solve this alignment problem. METHODS: In a previous study we
      demonstrated the appropriateness of the business process modelling methodology
      Dynamic Essential Modelling of Organizations (DEMO). A proven and widely used
      modelling language for expressing functional features is Unified Modelling
      Language (UML). In the context of a specific case study at the University Medical
      Centre Utrecht in the Netherlands we investigated if the combined use of DEMO and
      UML could solve the alignment problem. RESULTS AND CONCLUSION: The study
      demonstrated that the DEMO models were suited as a starting point in deriving
      system functionality by using the use case concept of UML. Further, the case
      study demonstrated that in using this approach for the alignment problem, insight
      is gained into the mutual influence of ICT-infrastructure and organisation
      structure: (a) specification of independent, re-usable components-as a set of
      related functionalities-is realised, and (b) a helpful representation of the
      current and future work practice is provided for in relation to the envisaged ICT
      support.

PMID- 12414018
TI  - Errors in interpreting quantities as procedures: the case of pharmaceutical
      labels.
AB  - The purpose of this study is to investigate and characterize the errors in
      cognitive processes deployed in the comprehension of procedural texts found on
      pharmaceutical labels by subjects of different cultural and educational
      backgrounds. In this study, participants were asked to read and interpret three
      pharmaceutical labels related to children's medications of varying complexity:
      oral rehydration therapy (ORT); over-the-counter cough medicine; and over-the
      counter fever medicine. Results indicate that: (1) all groups of participants had
      considerable difficulty in interpreting the instructions; (2), cultural and
      educational background appeared to be only weakly related to the accuracy of
      dosage and administration; and (3) errors of comprehension were related to three
      features of the texts: situation-representational complexity, inherent
      quantification complexity, and conformity with intuitive models of therapy based
      on prior knowledge. The results are discussed in terms of the role of multiple
      representations (boundary objects) and theories of text comprehension to
      facilitate the reduction of errors.

PMID- 12414019
TI  - Impact of a physician's order entry (POE) system on physicians' ordering patterns
      and patient length of stay.
AB  - OBJECTIVE: To investigate the impact of a physician's order entry (POE) system on
      physicians' ordering patterns and patient length of stay. DESIGN: Prospective
      time series study at pre-POE, 3 months and 6 months after POE at a tertiary
      teaching hospital in Korea. The study period was from June 1999 to May 2000.
      MEASUREMENTS: The number of orders (doctor's, PRN, medication, changed, canceled
      orders), number of tests (complete blood count, chemistry, chest X-ray, stat
      laboratory, serum electrolytes tests), appropriateness and length of patient stay
      were measured through chart review of 171 in-patients (liver disease, renal
      disease, gastrectomy, simple mastectomy). RESULTS: The number of doctors' orders,
      PRN, and medication orders significantly increased after POE. The numbers of
      changed and canceled orders were not significantly different between pre- and
      post-POE. The number of stat lab tests significantly decreased after POE. There
      was no change in appropriateness of patients' hospital stay between pre- and post
      POE. Length of stay significantly decreased (P=0.049). CONCLUSION: POE
      contributed to improving the quality of care in two ways: improvement of
      auditability by recording the medical services for patients in more precise and
      transparent manner, and more appropriate utilization of resources by decreasing
      the number of stat diagnostic tests and length of stay.

PMID- 12414020
TI  - Metadata-driven creation of data marts from an EAV-modeled clinical research
      database.
AB  - Generic clinical study data management systems can record data on an arbitrary
      number of parameters in an arbitrary number of clinical studies without requiring
      modification of the database schema. They achieve this by using an Entity
      Attribute-Value (EAV) model for clinical data. While very flexible for creating
      transaction-oriented systems for data entry and browsing of individual forms, EAV
      modeled data is unsuitable for direct analytical processing, which is the focus
      of data marts. For this purpose, such data must be extracted and restructured
      appropriately. This paper describes how such a process, which is non-trivial and
      highly error prone if performed using non-systematic approaches, can be automated
      by judicious use of the study metadata-the descriptions of measured parameters
      and their higher-level grouping. The metadata, in addition to driving the
      process, is exported along with the data, in order to facilitate its human
      interpretation.

PMID- 12414021
TI  - The impact of mental health advance directives on patient perceptions of coercion
      in civil commitment and treatment decisions.

PMID- 12414022
TI  - Euthanasia trials in Japan: implications for legal and medical practice.

PMID- 12414023
TI  - Validity of the General Health Questionnaire (GHQ-28) in a prison population:
      data from a randomized sample of prisoners on remand.

PMID- 12414024
TI  - From one legal system to another? An examination of the relationship between
      involuntary hospitalization and arrest.

PMID- 12414025
TI  - Attitudes and practices among Ethiopian health care professionals in psychiatry
      regarding compulsory treatment.

PMID- 12414026
TI  - Individual and familial psychopathology among hospitalized minors at risk,
      juvenile delinquents, and psychiatric controls.

PMID- 12414027
TI  - Retrosternal pedicled jejunum interposition: an alternative for reconstruction
      after total esophago-gastrectomy.
AB  - OBJECTIVE: If the colon cannot be used for reconstruction after total esophago
      gastrectomy, alternatives have to be sought. METHODS: From 1990 to 2001,
      retrosternal jejunum loop interposition was performed in 35 patients
      (male/female: 29:6; mean age 59.2, range 16-83 years) due to cancer in 32 cases
      and to esophageal perforation in three cases. In all patients reconstruction with
      stomach or colon, respectively, was impossible on behalf of the underlying
      histology, of previous resection of the stomach and impedient colonic diseases. A
      jejunal segment with abundant arcades was chosen, preserving a strong, distal
      arteriovenous mesenteric pedicle, while 2-3 proximal mesenteric vessels were
      severed. The loop was pulled up retrosternally, establishing a cervical end-to
      side esophagojejunostomy. A Roux-en-Y anastomosis was done in a convenient
      position. RESULTS: Two patients died perioperatively due to mediastinitis and
      consecutive multiorgan failure (one Boerhaave's syndrome, one suicidal ingestion
      of acid). In one case the oral part of the loop developed venous congestion and
      was replaced by a free jejunal transplant. The perioperative course of 32
      patients was uneventful. Seventeen patients are up and well (1-8.5 years).
      Sixteen patients died of metastatic disease. The functional results are
      satisfactory. In about 50% of patients recurrent dilatations became necessary due
      to anastomotic scars. However, none of the patients complained about severe
      dysphagia. CONCLUSION: In cases of impedient colonic diseases, the pedicled,
      retrosternal jejunal loop with cervical anastomosis is an alternative for
      reconstruction after total esophagogastrectomy.

PMID- 12414028
TI  - Intravenous hydration versus naso-jejunal enteral feeding after esophagectomy: a
      randomised study.
AB  - OBJECTIVE: Patients undergoing esophagectomy are typically nutritionally depleted
      and cannot establish oral feeding for up to a week after surgery. We have
      investigated the routine use of enteral feeding via a naso-jejunal tube. METHODS:
      Forty consecutive patients undergoing a transthoracic esophagectomy for cancer
      were randomised to receive enteral feeding or intravenous crystalloid fluids
      after surgery. Nutritional indices were obtained prior to surgery and on the 7th
      post-operative day. RESULTS: There were no post-operative deaths. Non-fatal
      complications occurred in 10 patients, without difference in morbidity between
      the two groups. Lean body mass did not change in either group over the study
      period. No differences in any other parameters were identified between the two
      groups. CONCLUSION: Enteral feeding via a naso-jejunal tube is safe and well
      tolerated after esophagectomy. It is a simple method of providing nutritional
      support prior to the re-introduction of oral feeding. However it provides no
      measurable benefit over intravenous hydration only for patients undergoing
      routine esophagectomy.

PMID- 12414029
TI  - Morbidity of percutaneous tube thoracostomy in trauma patients.
AB  - OBJECTIVES: This prospective study was designed to evaluate the complications of
      percutaneous tube thoracostomy (PTT) performed for chest trauma in our
      institution and to determine predictive factors. METHODS: One hundred and thirty
      four primary PTTs were performed in 128 patients for blunt (83) and penetrating
      (45) chest traumas. Failure was defined as undrained hemothorax or pneumothorax,
      post-tube removal complications and empyema. Univariate and multivariate hazard
      analyses were used to assess the association between potential risk factors and
      complications. RESULTS: The overall complication rate was 25% including 30 (23%)
      failures and nine (7%) improper placement with iatrogenic injuries to the lung (n
      = 4) or subclavian vein (n = 1). Complications were managed with 18 repeat PTTs
      and ten early thoracotomies for clotted hemothorax (two), persistent air leak
      (two), fluid collection (three) or a combination (three) at a mean delay of 6.5
      +/- 2.4 days. Failure of additional PTT required late decortication for empyema
      (three) or decortication (three) at a mean delay of 23 +/- 7 days. One patient
      died postoperatively, the only death directly related to PTT failure among the
      four (3.1%) deaths that occurred in this study. Hospital length of stay was
      significantly increased in patients with PTT failure (24 +/- 19 vs. 15 +/- 8 days
      in uncomplicated PTT, P = 0.004). By univariate analysis, polytraumatism
      (relative risk (RR) 2.7, P < 0.05), the need for assisted ventilation (RR 2.7, P
      = 0.003) and tube insertion by emergency physicians (RR 8.7, P < 0.0001) were
      significantly associated with increased incidence of complications in blunt
      trauma. Multivariate analysis identified the performance of the procedure by
      operators other than thoracic surgeons and residents trained in thoracic surgery
      as the only independent risk factor in both blunt and penetrating trauma (RR 58
      and 71, respectively, P < 0.00001). CONCLUSIONS: PTT is associated with
      significant morbidity and extended hospitalizations, partly related to
      inappropriate training of all individuals dealing with trauma care. Additional
      training should be recommended and some conventional indications for PTT should
      be revised. A prospective study is currently in progress to evaluate the benefit
      of early videothoracoscopy in trauma and failure of primary PTT.

PMID- 12414030
TI  - Invasive staging of non-small cell lung cancer--a prospective study.
AB  - OBJECTIVES: Clinical prognosis and treatment schedules of non-small cell lung
      cancer (NSCLC) are dependent on tumor stage. This explains the importance of an
      exact pretreatment staging of the primary tumor and lymph nodes especially in
      locally advanced NSCLC, to differentiate between resectable and non-resectable
      disease. To assess the lymph node status of the upper mediastinum, the diagnostic
      value of mediastinoscopy is accepted to be superior to radiological methods. In
      contrast, thoracoscopy is not yet established as a standard staging tool.
      PATIENTS AND METHODS: Seventy-three consecutive patients with CT-based suspicion
      of advanced NSCLC have been investigated as part of a phase II study on
      neoadjuvant treatment of NSCLC. All patients underwent mediastinoscopy and
      mediastinal lymph node sampling. In the case of a negative result we performed
      additional thoracoscopy. RESULTS: In 52.1% (n = 38) of the patients the invasive
      diagnostic methods led to results that were effectively different from those of
      the radiological findings. In 11 patients (15.1%) CT-assessed lymph node
      metastases could invasively not be confirmed, whereas nine patients (12.3%) had
      positive mediastinal lymph nodes but no corresponding CT signs (diameter <1 cm).
      The results were achieved by mediastinoscopy in 15 (20.5%) and by thoracoscopy in
      five (6.8.%) patients. A radiologically unexpected T4 stage has been found in
      four (5.5%) and a M1 stage in four (5.5%) patients by thoracoscopy. On the
      contrary, in seven patients a suspected infiltration of mediastinum or parietal
      pleura could be thoracoscopically excluded. Four patients have been in an
      unexpected high stage of tumor progression at the moment of diagnostic procedures
      and therefore have been included in palliative therapy schedules. Ten patients
      have been 'overstaged' by radiological methods and benefited from a primarily
      curative resection after invasive staging. CONCLUSIONS: Of the 73 prospectively
      studied patients with locally advanced NSCLC, 12 (16.4%) have been staged too low
      and 13 (17.8%) too high. If exclusively staged by radiological methods, about 34%
      of lung cancers have been classified incorrectly. Therefore, these tools are not
      a sufficient basis for diagnosis of stage III NSCLC disease. Mediastinoscopy with
      consecutive thoracoscopy is an essential part of the therapeutic planning in
      locally advanced NSCLC, and results are significantly superior to clinical
      staging.

PMID- 12414031
TI  - Indications and results of sleeve carinal resection.
AB  - OBJECTIVE: Carinal resection is the most complicated procedure in
      tracheobronchial surgery. The main aspects of the technique are still debated at
      the present time. We present our experience of 231 carinal resections with
      analysis of operative techniques, complications and long-term survival. METHODS:
      Since 1979 we have performed 231 carinal resections. Indications for surgery
      included lung cancer in 151 cases (65.4%), non-bronchogenic carcinoma in 45
      (19.4%), main bronchus fistula with short stump in 25 (10.8%), stenosis of
      tuberculous and nonspecific etiology in nine (4%), and trauma in one case (0.4%).
      We have performed 156 right-sided resections (67.5%) and 75 left-sided (32.5%).
      In 162 cases carinal pneumonectomy was undertaken, carinal resection following
      pneumonectomy was performed in 28 cases, isolated resection of bronchial
      bifurcation was performed in 25 cases, and in 15 cases we combined lobectomy and
      resection of bifurcation. The length of resection extended from one to nine
      tracheal rings. The operative approach was lateral thoracotomy in 102 cases
      (44.2%), and sternotomy in 129 (55.8%). RESULTS: Thirty-seven patients died
      postoperatively (16%). Complications were observed in 82 patients (35.4%),
      dominated by anastomotic problems which occurred in 58 cases (25.1%). The most
      frequent causes of death were respiratory distress syndrome and anastomotic
      dehiscence (P < 0.05). Mortality and the incidence of complications were
      significantly correlated to length of resection, laryngeal nerves injury, and
      mode of intraoperative ventilation. CONCLUSIONS: The feasibility of carinal
      resection is limited by the patient's functional status and extension of tumor
      growth. Thorough selection of patients may improve immediate and long-term
      results.

PMID- 12414032
TI  - Recurrence-free survival and prognostic factors in resected pN2 non-small cell
      lung cancer.
AB  - OBJECTIVE: We sought to evaluate recurrence pattern and prognostic factors of
      recurrence-free survival in surgically resected N2 non-small cell lung cancer.
      METHODS: Between September 1994 and December 1999, 564 patients underwent
      operation for non-small cell lung cancer at our institute. Of these 564 patients,
      101 patients were found to have pathologic N2 disease. Systematic mediastinal
      lymph node dissection was performed in all these patients. Recurrence was
      determined and nineteen clinicopathologic prognostic factors were evaluated in
      relation to recurrence-free survival. RESULTS: Complete resection rate was 83.2%
      and overall 5-year survival was 23.3%. Locoregional and distant metastasis were
      detected in 50 of 101 patients (49.5%) during follow-up. Five-year recurrence
      free survival was 19.6%. Among 19 clinicopathologic prognostic factors,
      incomplete resection and non-downstaging after neoadjuvant therapy were
      unfavorable prognostic factors in univariate analyses. Clinical N2 status,
      multiple N2 nodes, and cell type of adenocarcinoma showed poor prognosis but were
      not statistically significant. Postoperative chemotherapy showed good prognosis
      but was not statistically significant. Multivariate analysis showed that
      significant favorable prognostic factors were complete resection and adjuvant
      chemotherapy. CONCLUSIONS: Complete resection and responsiveness to neoadjuvant
      therapy were the most important favorable prognostic factors in recurrence-free
      survival. Postoperative chemotherapy was also a favorable prognostic factor but
      not statistically significant in recurrence-free survival in pN2 non-small cell
      lung cancer.

PMID- 12414033
TI  - Lung tumors with mixed histologic pattern. Clinico-pathologic characteristics and
      prognostic significance.
AB  - OBJECTIVE: To analyze and compare clinico-pathologic characteristics and survival
      between lung tumors with mixed histologic pattern and our population of resected
      lung tumors with single histology in the same period. METHODS: From January 1993
      to December 1999, 1158 patients received resection for lung tumors. Of these, 59
      (5.1%) presented a mixed histologic pattern on the surgical specimen. There were
      48 men and 11 women (mean age 64 years, range 43-79). Three groups of tumors were
      identified: adenosquamous carcinoma, combined neuroendocrine + non-neuroendocrine
      carcinoma (NNEC) and biphasic tumors (epithelial + mesenchymal malignant
      components) represented by carcinosarcoma and blastoma. The combined
      neuroendocrine tumors were further divided in small cell lung carcinoma (SCLC) +
      large cell neuroendocrine carcinoma (LCNEC)/NNEC and other neuroendocrine
      tumors/NNEC. Clinico-pathologic characteristics, pTNM and survival were analyzed
      and compared to our population of resected lung tumors with single histology.
      RESULTS: There were 33 adenosquamous carcinomas, 19 combined SCLC+LCNEC/NNEC, two
      other neuroendocrine tumors/NNEC and five biphasic tumors (three carcinosarcomas
      and two blastomas). Among adenosquamous carcinomas, high cell grading (G2 or G3),
      advanced stage (IIIa or higher) and intratumoral perineural invasion were
      significantly more evident than in the single histology population. Among
      combined neuroendocrine/NNEC, high cell grading (G3) and intratumoral vascular
      invasion were significantly more evident than in the single histology population.
      Among biphasic tumors, all were at early stages and showed high cell grading
      (G3). Three-year survival rates were 46% in the single histology group, 28% in
      the adenosquamous group and 21% in the combined SCLC + LCNEC/NNEC. The difference
      among the three groups was significant (P = 0.013). Median survival of biphasic
      tumors was 19 months (range 8-37). CONCLUSIONS: Lung tumors with mixed histologic
      pattern are rare tumors. Adenosquamous carcinoma and combined SCLC + LCNEC/NNEC
      present a more aggressive clinico-pathologic behaviour and reduced survival as
      compared to the single histology population of resected lung tumors.

PMID- 12414034
TI  - Pulmonary blastoma: report of five cases and identification of clinical features
      suggestive of the disease.
AB  - OBJECTIVE: Identification of clinical features suggestive of pulmonary blastoma
      (PB) through a retrospective comparison with cases of non-small cell lung cancer
      (NSCLC) operated during the same period. METHODS: Between 1977 and 1999, five
      patients were operated for PB at Geneva University Hospital (four women and one
      man, aged 32-46 years--mean 36.8) versus 1913 consecutive patients (1558 men and
      355 women, mean age 61.2) for primary NSCLC. In the PB subgroup (0.3%), the
      pulmonary tumor was single, located in an upper lobe in all but one instance, and
      measured between 5 and 13 cm (mean 9.6), whereas in the total NSCLC group, 27% of
      patients had tumors <3 cm (T1), evenly distributed in both lungs. All but one PB
      patients were symptomatic, compared to 45% in the NSCLC group. RESULTS: The five
      patients with PB underwent curative pulmonary excisions (lobectomy in three and
      pneumonectomy in two) with mediastinal lymph node sampling. Pathological
      examination revealed extensive tumor necrosis in four, and N2 lymph node
      metastases in four (in the total NSCLC group, N2 disease was diagnosed in 21%).
      Postoperatively, three PB patients received radio- and/or chemotherapy. Four
      patients died between six and 30 months after the operation (mean 15), whereas 5
      year survival in the NSCLC group was 32%, with a median survival of 3.7 years;
      the fifth patient is alive 28 months later, without any sign of recurrence.
      CONCLUSIONS: Compared to operated NSCLC, PB are rare, large, and symptomatic
      tumors; they affect younger patients and carry a worse prognosis.

PMID- 12414035
TI  - Non-neoplastic mediastinal cysts.
AB  - OBJECTIVE: The non-neoplastic mediastinal cysts (NNMCs) form a group of uncommon
      benign lesions of a congenital origin. The significant controversy regarding
      these cysts is whether to manage with observation or surgical resection. The aim
      of this study is to analyse the utility of thoracic computed axial tomography
      (CT) in imaging diagnosis of the NNMCs and the results of surgery in these
      lesions. PATIENTS AND METHODS: Twenty NNMCs underwent surgery between 1980 and
      2000. The preoperative study of mediastinal cystic masses includes a complete
      blood test, chest radiography (CR) and, for the last 15 years, a thoracic CT
      and/or nuclear magnetic resonance. All the patients underwent surgery in our
      thoracic surgery department and were reviewed in outpatients at 1 month, 6
      months, 1 year and biannually thereafter. The form of manifestation, clinical
      features, imaging techniques, surgical operation, morbidity, mortality and follow
      up are analysed. RESULTS: Ten corresponded to bronchogenic cysts, the most common
      symptom of which was chest pain. CR showed a mass in the anterior-superior
      mediastinum in nine cases, and CT (five cases) revealed a cystic tumour in the
      anterior mediastinum. All were removed surgically, with three patients presenting
      with mild complications. Seven corresponded to pleuro-pericardial cysts, four
      being asymptomatic. CR showed a right paracardial mediastinal tumour, which was
      confirmed by CT (four cases). All were removed surgically, with two patients
      presenting with mild complications. Three corresponded to enteric cysts. CR
      showed a tumour in the posterior mediastinum, with CT confirming its cystic
      nature (two cases). Excision of the cyst was done in all cases, which
      corresponded to duplication cysts: two oesophageal and one gastric. All the
      patients are asymptomatic and recurrence-free after a follow-up of 11 +/- 10
      years. CONCLUSIONS: NNMCs are benign lesions in which the lesions in which the
      surgery can be done with a low morbidity and mortality rate, enables us to rule
      out malignancy and offers a definitive cure. Actually the thoracic CT permit a
      correct diagnosis pre-surgery in function of the radiologic characterisation and
      topography.

PMID- 12414036
TI  - Drainage patterns of middle lobe vein of right lung: an anatomical study.
AB  - OBJECTIVE: The purpose of the present study was to determine the variations in
      the drainage patterns of middle lobe vein of the right lung. METHODS: Right lungs
      of 30 formalin fixed cadavers, were dissected carefully to expose the variations
      in the venous drainage of their middle lobes. After identifying the pulmonary
      veins for each lobe, middle lobe vein (MLV) drainage patterns were followed to
      their openings. The diameters of the MLV and its lateral and medial parts were
      measured with a caliper. The length of the MLV trunk was also evaluated. RESULTS:
      Five different types of venous drainage patterns were observed. Type-I: Union of
      medial and lateral parts to form MLV as a trunk and opening of this vein to the
      right superior pulmonary vein (RSPV) (53.3%). Type-II: Opening of medial and
      lateral parts to the RSPV separately (16.6%). Type-III: Union of medial and
      lateral parts to form the MLV trunk and opening of this vein into the left atrium
      (16.6%). Type-IV: Opening of medial and lateral parts into the left atrium
      separately (10%). Type-V: Union of medial and lateral parts to form MLV trunk and
      opening of this vein to the right inferior pulmonary vein (3.3%). CONCLUSION: The
      venous drainage patterns of right middle lobe reveals great number of variations.
      Knowing the frequency of different types of drainage patterns classified in this
      study is extremely important for the surgeons performing pulmonary surgery,
      atrial fibrillation and imaging techniques.

PMID- 12414037
TI  - The role of tissue reperfusion in the reexpansion injury of the lungs.
AB  - OBJECTIVE: The aim was to discuss the balance between free radical damage and
      body defense mechanisms that occurred in reexpansed pulmonary tissue and to
      evaluate the relationship between the changes in the pulmonary circulation and
      the mentioned balance. METHODS: Twenty male Wistar Albino rats were used for
      these study results. Pneumothorax was created in the left hemithorax by
      percutaneous route in all the rats. After 7 days, the first group (n = 10) had a
      sternotomy under ketamine anesthesia. Following invasive measurement of pulmonary
      artery pressure, tissue samples were obtained from the lower lobes of the right
      and left lungs before reexpansion occurred. Tracheotomies were opened in the
      second group (n = 10) with a 16 gauge cannula. Following sternotomy, invasive
      mean pulmonary artery pressure measurements were obtained by the support of non
      invasive cardiac monitorization. The lungs were aerated with 4 cmH(2)O oxygen and
      fixed volume support and 1 h of reexpansion was obtained. Invasive mean pulmonary
      artery pressure measurements were repeated after reexpansion and tissue samples
      were obtained from the lower lobes of left and right lungs. Nitric oxide (NO),
      malondialdehyde (MDA) and superoxide dismutase (SOD) levels were measured in
      tissue samples, surfactant staining and light microscopic evaluations were
      performed. RESULTS: At the end of the reexpansion, there was a decrease in mean
      pulmonary artery pressure (P < 0.01), MDA (P < 0.01) and SOD (P < 0.05) levels
      and an increase in NO (P < 0.05) levels. Under the light microscopic examination,
      in the samples that were provided with reexpansion, the alveolo-capillary
      membrane was thickened due to increasing edema, increase in the number of
      lymphocytes and return of the neutrophil leukocytes to the area. There was no
      significant difference between the groups in terms of surfactant staining.
      CONCLUSION: The tissue reperfusion that is achieved with the restoration of blood
      flow during the reexpansion of collapsed lungs, can be the initial pathology in
      the chain of events that result in reexpansion injury.

PMID- 12414038
TI  - Invasive pulmonary aspergillosis: effects of early resection in a neutropenic rat
      model.
AB  - OBJECTIVE: Invasive pulmonary aspergillosis is frequent in neutropenic patients.
      Usually localized in the beginning, the disease spreads and mortality is high
      despite antifungal treatment. The role of early adjuvant surgery is not clear.
      Surgery may help to confirm fungal disease, may control fungal disease locally
      and may prevent systemic spreading. This study examines effects of early
      resection on survival and dissemination in a rat model of localized invasive
      pulmonary aspergillosis. METHODS: Forty persistently neutropenic male albino rats
      were challenged with standardized conidial aspergillus inoculum injected into
      peripheral lung tissue of the right upper lobe under direct vision. Animals were
      divided into four groups. Twenty animals were treated with amphotericin B at 1
      mg/kg per day beginning 48 h after inoculation, 20 animals were left untreated.
      In each group half the animals underwent early resection of localized invasive
      aspergillosis by lobectomy. Animals were checked daily and mortality was recorded
      up to 28 days after which surviving animals were sacrificed. RESULTS:
      Significantly higher survival was observed in resected animals in the non-Am B
      groups (survival: 10 +/- 19% without early resection and 50 +/- 32% with early
      resection; P = 0.044). However, early resection did not lead to improved survival
      in animals treated with amphotericin B (survival 70 +/- 29% without early
      resection and 50 +/- 32% with early resection; P = 0.316). CONCLUSIONS: In this
      rat model of localized invasive pulmonary aspergillosis effects of early
      resection on survival could be demonstrated only in animals not receiving
      amphotericin B treatment.

PMID- 12414039
TI  - Donor heart contractile dysfunction following prolonged ex vivo preservation can
      be prevented by gene-mediated beta-adrenergic signaling modulation.
AB  - OBJECTIVES: Reperfusion after myocardial ischemia goes together with alteration
      of the beta-adrenergic (betaAR) signaling. Especially the level and catalytic
      activity of beta AR kinase (betaARK1) are increased. We hypothesized that
      myocardial expression of a betaARK1 inhibitor (betaARKct) may protect from post
      reperfusion dysfunction. METHODS: Two groups of rabbits were treated by
      intracoronary delivery of either phosphate-buffered saline (PBS) or a solution of
      adenovirus carrying the betaARKct transgene (Adeno-betaARKct). At day 5, the
      hearts were explanted after cold cardioplegic arrest, and preserved at 4 degrees
      C for 4 h. Reperfusion was hemodynamically standardized on a Langendorff
      apparatus with oxygenated Krebs solution for 30 min before left ventricular (LV)
      pressure was recorded using an LV latex balloon connected to a pressure
      transducer. Non-arrested hearts immediately perfused on the Langendorff apparatus
      served as controls. RESULTS: LV contractility (LV dP/dt(max), P < 0.05) and
      relaxation (LV dP/dt(min), P < 0.05) were reduced, and end diastolic pressure (LV
      EDP) was increased after prolonged exposure to cold preservation solution as
      compared to normal control hearts, both under basal conditions and when
      stimulated with the betaAR agonist isoproterenol. However, these parameters
      remained within a normal range in Adeno-betaARKct-expressing hearts arrested and
      preserved for 4 h. Biochemical analysis shows a reduced betaAR density and an
      impaired signaling after reperfusion of hearts arrested for 4 h whereas it is
      normalized in Adeno-betaARKct-expressing hearts. CONCLUSION: Myocardial gene
      mediated inhibition of betaARK1 via betaARKct expression avoids ventricular
      dysfunction after prolonged preservation. Therefore, this may represent a way of
      improving early results of cardiac transplantation and perioperative function.

PMID- 12414040
TI  - The preload recruitable stroke work relationship as a measure of left ventricular
      contractile dysfunction in porcine cardiac allografts.
AB  - OBJECTIVE: Paradoxically, it has been reported that after 1.5-4 h of hypothermic
      ischaemic preservation there is complete recovery of contractile function in
      canine cardiac allografts, as assessed by the preload recruitable stroke work
      (PRSW) relationship. This raises questions about the suitability of the canine
      heart as a model for preservation research and the PRSW relationship as an end
      point. The aim of the present study was to evaluate the PRSW relationship as an
      index of left ventricular contractility in porcine cardiac allografts. METHODS:
      Eighteen orthotopic heart transplants were performed in inbred Westran pigs.
      Brain death was induced in the donor pigs 1 h prior to explantation. The donor
      hearts were arrested with extracellular cardioplegia, which was stored in ice
      prior to administration. On explantation, the donor hearts were immersed in
      cardioplegia and stored in ice. The donor hearts were subjected to either 4 (IT4,
      n = 6), 6 (IT6, n = 9) or 14 (IT14, n = 3) h of ischaemia. Post-transplant, all
      hearts were supported with dobutamine (10 mcg/kg per min). The PRSW relationship
      was derived from pressure-volume loops obtained by epicardial sonomicrometry and
      transmyocardial micromanometry. Multiple linear regression was used to describe
      and compare the PRSW relationship before brain death in the donor and after
      weaning from bypass in the recipient. RESULTS: Eleven hearts were weaned
      successfully from cardiopulmonary bypass: IT4 100% (6/6), IT6 56% (5/9) and IT14
      0% (0/3) (IT4 versus IT14: P = 0.012). Analysis of the PRSW relationship revealed
      a reduction in contractility in both the IT4 and IT6 groups (both P < 0.0001),
      but a greater reduction in the IT6 group (P < 0.0001). Notably, the volume-axis
      intercept of the PRSW relationship was found to be a better discriminator of post
      preservation contractile dysfunction than the slope of the PRSW relationship.
      CONCLUSIONS: The porcine heart's susceptibility to ischaemic injury makes it
      ideal for evaluating the effect of different preservation strategies on
      contractile recovery. The PRSW relationship can be used to evaluate the
      differences in contractile recovery, though the nature of the effect of ischaemic
      preservation necessitates analysis by multiple linear regression.

PMID- 12414041
TI  - Hemodynamic effects of inhaled aerosolized iloprost and inhaled nitric oxide in
      heart transplant candidates with elevated pulmonary vascular resistance.
AB  - OBJECTIVE: An elevated pulmonary vascular resistance (PVR) is described as a
      predictor of postoperative right heart failure and increased mortality in
      patients undergoing orthotopic heart transplantation. The use of intravenous
      vasodilators is limited by their systemic effects. We evaluated the pulmonary and
      systemic hemodynamic effects of inhaled nitric oxide (NO) and inhaled aerosolized
      iloprost (IP) in heart transplant candidates with elevated PVR. METHODS: Fourteen
      male heart transplant candidates due to dilative or ischemic cardiomyopathia with
      elevated PVR (> or = 180 dyn s cm(-5)) were included in the study. Increasing
      concentrations of NO (5, 10 and 30 ppm) and 50 microg aerosolized IP were
      administered by inhalation. Hemodynamic measurements preceded and followed
      administration of each agent. RESULTS: Inhalation of IP, 10, and 30 ppm NO
      reduced PVR and mean pulmonary artery pressure (MPAP), but did not affect blood
      pressure or systemic vascular resistance. Comparing the effectiveness of 10 ppm
      NO and IP, we found a significant higher reduction of MPAP in patients treated
      with IP. An increase of cardiac index and stroke index could only be shown with
      IP-inhalation. CONCLUSIONS: Inhaled iloprost induces pulmonary vasodilation which
      is significantly greater than the effects of 10 and 30 ppm NO. The results of our
      study show, that inhaled iloprost induces a reliable hemodynamic response in the
      evaluation of heart transplant candidates. Further advantages of iloprost
      inhalation are the lack of adverse reactions and toxic side effects and an easier
      administration. Due to this facts we recommend iloprost as a routine screening
      drug for vascular reactivity in HTx-candidates. Based on our results it would be
      of great interest to investigate the role of iloprost in management of
      postoperative right heart insufficiency following cardiac transplantation.

PMID- 12414042
TI  - The combined use of transmyocardial laser revascularization (TMLR) and
      fibroblastic growth factor (FGF-2) enhances perfusion and regional contractility
      in chronically ischemic porcine hearts.
AB  - OBJECTIVE: The purpose of this study was to determine the combined effect of
      transmyocardial laser revascularization (TMLR) and recombinant human basic
      fibroblastic growth factor (rhFGF-2) treatment in chronically ischemic hearts.
      METHODS: To employ this porcine ischemic model, an operative severe stenosis of
      the left anterior descending artery (LAD) was created (first operation). One week
      later, the animals were studied at baseline (second operation) by analyzing
      perfusion (microsphere technique) and regional contractility (ultrasonic
      crystals). Afterwards, pigs were randomized into one of the four groups: ischemic
      control group (n = 7), TMLR-group (n = 7), FGF-2-group receiving 500 microg rhFGF
      2 (n = 6), and FGF-2 + TMLR-group receiving TMLR with 500 microg rhFGF-2 (n = 6).
      Twelve weeks later, the animals were re-examined (third operation) and the hearts
      underwent additionally histochemical and immunohistologic analysis. RESULTS:
      Three months after therapy, regional myocardial blood flow (RMBF) in the LAD
      territory was significantly higher at rest in the FGF-2 group and FGF-2 + TMLR
      group compared to baseline, control and TMLR group (FGF-2 group: 1.17 +/- 0.10
      versus baseline 0.28 +/- 0.10, P = 0.028; versus control 0.49 +/- 0.12, P = 0.01;
      and versus TMLR 0.34 +/- 0.20, P = 0.0081; FGF-2 + TMLR group: 0.88 +/- 0.29
      versus baseline 0.41 +/- 0.14, P = 0.028; versus control 0.49 +/- 0.12, P = 0.019
      and versus TMLR group 0.34 +/- 0.20 ml/g per min, P = 0.0032). Furthermore, the
      FGF-2 + TMLR-group demonstrated higher RMBF values in the LAD territory under
      stress conditions compared to baseline (1.79 +/- 0.69 versus 0.41 +/- 0.14; P =
      0.028) and control (1.79 +/- 0.69 versus 0.78 +/- 0.55 ml/g per min; P = 0.038)
      at the end of the study. In contrast to these groups, RMBF in the control and
      TMLR group was unchanged. After 3 months, the FGF-2- and FGF-2 + TMLR-groups'
      regional contractility in the LAD territory revealed an improvement at rest (FGF
      2: 84.00 +/- 26.22 versus baseline: 53.76 +/- 13.49, P = 0.003; FGF-2 + TMLR:
      104.46 +/- 28.62 versus control: 61.27 +/- 5.13; P = 0.005 and versus TMLR: 59.74
      +/- 41.23%; P = 0.041), whereas control and TMLR animals did not show any
      difference. TMLR as well as FGF-2 + TMLR treatment resulted in an increased
      number of capillaries and of arterioles in the channel area compared to untreated
      ischemia (P < 0.005). CONCLUSIONS: In contrast to the TMLR- and control group,
      CO(2)-laser revascularization combined with the application of intramyocardial
      growth factor, FGF-2, significantly ameliorates perfusion at rest and stress in
      this model of chronic regional ischemia, whereas sole FGF-2 application showed an
      improvement at rest only. This was mirrored by an enhancement of regional
      contractility in the FGF-2 + TMLR- and FGF-2-group at rest.

PMID- 12414043
TI  - Surgery for ventricular tachycardia of left ventricular origin: risk factors for
      success and long-term outcome.
AB  - OBJECTIVES: To review 26 consecutive patients with sustained monomorphic
      ventricular tachycardia (VT) of left ventricular origin, who underwent direct VT
      surgery. METHODS: Economic factors precluded the use of an implantable
      cardioverter defibrillator (ICD) in the majority of these patients, and the
      indication for surgery in 81% of patients was for failed medical drug therapy and
      27% of patients had frequent or incessant life-threatening VT. The principles of
      direct VT surgery included intraoperative mapping, extended endocardial
      resection, cryoablation, left ventricular aneurysm repair by left ventricular
      remodelling and endoaneurysmorrhaphy, as well as coronary artery bypass grafting.
      RESULTS: Two patients with non-ischaemic VT were significantly younger (37.7 +/-
      19.4 years, P = 0.03), had lower preoperative New York Heart Association class (P
      = 0.03), and had better left ventricular ejection fractions of 59.5 +/- 2.1% (P =
      0.001) than the 24 ischaemic patients. No operative mortality or recurrence of VT
      occurred in this group. Ischaemic VT patients had an operative mortality of 8.3%;
      risk factors were concomitant valve surgery (P = 0.02), and perioperative intra
      aortic balloon pump (P = 0.02). Surgery improved the left ventricular ejection
      fraction from 28.4 +/- 9.8% to 43.2 +/- 8.2% (P = 0.0001). Freedom from
      recurrence or inducibility of VT in operative survivors was 78.8 +/- 9.6% at 10
      years; risk factors were arrhythmic focus remote to the left ventricular aneurysm
      (P = 0.015), and simple cryoablation or endocardial resection alone and not in
      combination (P = 0.003). Survival was 54.1 +/- 11.6% and 43.3 +/- 13.4% at 5 and
      10 years, respectively, and there were no arrhythmic or sudden cardiac deaths.
      Patients with immediately life-threatening VT unsuitable for ICD implantation
      requiring urgent or emergent VT surgery had a 10-year survival of 22.2 +/- 13.9%
      compared to the more elective surgical group with a rate of 73.3 +/- 13.9% (P =
      0.08). CONCLUSIONS: Direct VT surgery should remain an objective for symptomatic
      drug refractory VT of left ventricular origin.

PMID- 12414044
TI  - Surgical treatment of tachyarrhythmias due to postinfarction left ventricular
      aneurysm with endoaneurysmorrhaphy and cryoablation.
AB  - OBJECTIVE: In this study, the efficacy of left ventricular (LV)
      endoaneurysmorrhaphy and cryoablation without intraoperative electrophysiologic
      mapping was evaluated in patients with postinfarction LV aneurysm and sustained
      ventricular tachycardia (VT). METHODS: A prospective study was performed on all
      patients operated with malignant VT in the presence of a resectable LV aneurysm
      between July 1990 and February 2001. RESULTS: The study included 31 patients, 20
      men and 11 women, with a mean age of 65.5 years (47-84). Monomorphic, polymorphic
      VT or ventricular fibrillation was present in all patients prospectively, and VT
      was incessant in 11. Twenty-six patients had an anterior, four patients had an
      inferior and one patient a posterolateral myocardial wall infarction. All
      patients had a well-limited ventricular aneurysm. Ten patients had three, eight
      patients two and 13 patients had single vessel coronary artery disease. Mean
      preoperative ejection fraction was 34.8 +/- 14.5% (8-62) and mean end-diastolic
      volume index was 141.5 +/- 51.8 ml/m(2) (57-288). Six patients had mitral
      regurgitation grade III or IV. All patients underwent extensive cryoablation at
      the transition zone of scar and viable tissue and LV remodelling with prosthetic
      patch in 26 patients. Associated procedures were CABG in 19 patients (61%) and
      mitral valve reconstruction in six patients (19%). Postoperative
      electrophysiologic study (EPS) revealed freedom from VT induction in 25 patients
      and inducible VT in five patients. One patient had inducible polymorphic VT. Five
      patients received an implantable cardioverter defibrillator (ICD) and three
      patients had a permanent pacemaker implanted. After a mean follow-up of 30 +/- 27
      months (6-132) there was one arrhythmia-related death. There was one early
      hospital readmission for clinical VT and no need for late ICD implantation.
      CONCLUSIONS: In patients suffering from ventricular arrhythmias in the presence
      of a complicated postinfarction LV aneurysm, combined 'blind' cryoablation and
      endoaneurysmorrhaphy offers excellent arrhythmia control and clinical and
      haemodynamic outcome.

PMID- 12414045
TI  - Post-infarction cardiac rupture: surgical treatment.
AB  - OBJECTIVE: Rupture of ventricular free wall (VFWR) may complicate acute
      myocardial infarction and accounts for high mortality. Surgical repair is the
      only therapeutic option. A review of our surgical experience is presented.
      METHODS: Seventeen patients (11 men, mean age 68 years) underwent surgery for
      VFWR. Patch covering technique was used in 13 patients, infarctectomy with patch
      reconstruction in three patients, direct suture without patch in one patient.
      Coronary artery bypass grafting was performed in eleven patients. RESULTS:
      Hospital mortality was 17.6% (three patients). Three patients died of cancer
      during the follow-up. The remaining 11 patients are in good condition after a
      mean follow-up of 45.8 months (range 7.5-84.2). CONCLUSIONS: Postinfarction
      rupture of ventricular free wall treated surgically gives excellent long-term
      results. Our first choice for repair is the covering technique with a large
      pericardial patch anchored with biological glue and epicardial sutures.

PMID- 12414046
TI  - Does the use of bilateral internal mammary artery (IMA) grafts provide
      incremental benefit relative to the use of a single IMA graft? A meta-analysis
      approach.
AB  - OBJECTIVES: Does the use of bilateral internal mammary artery (IMA) grafts
      provide incremental benefit relative to the use of a single IMA graft? METHODS:
      Meta-analysis by qualitative and quantitative protocol of the studies published
      in the literature in the last 15 years. Only eight, out of 149 observational
      studies found, met our criteria: surgical results of bilateral versus single IMA,
      patient age range from 20 to 89 years, exclusion of emergency and diabetic
      patients, study group larger than 100 patients, minimal follow-up time. The final
      sample size included 16362 patients. RESULTS: Late survival was evaluated at 5
      and 10 years. The hazard ratio (HR) was calculated from seven studies, the
      difference of survival was from six and five studies, respectively. The effect
      size was summarized using a random effect model, suggested by the results of
      statistical test for homogeneity of the HR (P < 0.05) and of the survival
      difference at 5 (P < 0.05) and at 10 years (P < 0.05). The bilateral IMA estimate
      of combined HR was 0.79 (95% confidence limits, C.L. = 0.66/0.91). The combined
      difference of survival probability at 5 years was 0.014 (95% C.L. = -0.03/0.06)
      and at 10 years was 0.07 (95% C.L. = 0.003/0.170). CONCLUSION: There is
      significant evidence in favor of decreasing death risk of bilateral versus single
      IMA procedure.

PMID- 12414047
TI  - Risk of morbidity and in-hospital mortality in obese patients undergoing coronary
      artery bypass surgery.
AB  - OBJECTIVES: Obesity is often perceived to be a risk factor for adverse outcomes
      following coronary artery bypass graft (CABG) surgery. Several studies have been
      unclear about the relationship between obesity and the risk of adverse outcomes.
      The aim of this study was to examine the relationship between obesity and in
      hospital outcomes following CABG, while adjusting for confounding factors.
      METHODS: A total of 4713 consecutive patients undergoing isolated CABG between
      April 1997 and September 2001 were retrospectively analyzed. Body mass index
      (BMI) was used as the measure of obesity and was grouped as non-obese (BMI <30),
      obese (BMI 30-35), and severely obese (BMI > or =35). Associations between
      obesity and in-hospital outcomes were assessed by use of logistic regression to
      adjust for differences in patient characteristics. RESULTS: A total of 3429
      patients were defined as non-obese, compared to 1041 obese and 243 severely
      obese. There was no association between obesity and in-hospital mortality,
      stroke, myocardial infarction, re-exploration for bleeding and renal failure.
      Obesity was significantly associated with atrial arrhythmia (adjusted odds ratio
      (OR) 1.19, P = 0.037 for the obese; adjusted OR 1.52, P = 0.008 for the severely
      obese) and sternal wound infections (adjusted OR 1.82, P = 0.002 for the obese;
      adjusted OR 2.10, P = 0.038 for the severely obese). The severely obese patients
      were 4.17 (P < 0.001) times more likely to develop harvest site infections.
      Severely obese patients were also more likely to have prolonged mechanical
      ventilation and post-operative stays, compared to non-obese patients.
      CONCLUSIONS: Obese patients are not associated with an increased risk of in
      hospital mortality following coronary artery bypass surgery. In contrast, there
      is a significant increased risk of morbidities and post-operative length of stay
      in obese patients compared to non-obese patients.

PMID- 12414048
TI  - Medium-term survival and quality of life of Swedish octogenarians after open
      heart surgery.
AB  - OBJECTIVE: Operative mortality after open-heart interventions in the octogenarian
      population is relatively well known. Less has been reported on the medium term
      survival and quality of life of this growing subgroup of patients. METHODS: One
      hundred and eighty-three consecutive patients aged between 80 and 84 years when
      they underwent open-heart surgery between January 1995 and June 2000 were
      retrospectively analysed. The patients were followed up for 36 months as regards
      survival and compared, after matching for age and gender, to survival in the
      general Swedish population. The health-related quality of life (HRQOL) of
      surviving patients was assessed in February 2001 using the SWED-QUAL
      questionnaire. After matching for differences by age and gender, survival results
      were compared to Swedish national survival data, and functioning and well-being
      to the corresponding national norm data. Pre-, intra- and post-operative
      variables were evaluated as predictors for mortality, survival and quality of
      life. RESULTS: The 30-day mortality rate was 4.6% (n = 8). The 36-month survival
      rate, that was 85.6%, did not differ significantly (P = 0.078) from that of a
      cohort of the Swedish population matched for age and gender. There was no
      significant difference in survival between male and female patients (P = 0.545).
      Systemic hypertension was the only variable found to be a statistically
      significant predictor of 36-month mortality (P = 0.009). As concerns HRQOL,
      patients had significantly better physical functioning, satisfaction with
      physical functioning, relief of pain and emotional well-being (P < 0.01) and
      similar quality of sleep (P = 0.106) as the normal population. Male patients and
      male normal population responders had similar HRQOL (P > 0.05) while female
      patients reported significantly better HRQOL than their population counterparts
      on all five dimensions (P < 0.01). CONCLUSIONS: Patients 80-84 years of age may
      be operated on with acceptable operative mortality and benefit from improved
      functioning and well-being. Survival and quality of life after open-heart surgery
      among patients aged 80-84 years of age are comparable to, or even better than in
      the general Swedish population.

PMID- 12414049
TI  - Structural degeneration of pulmonary homografts used as aortic valve substitute
      underlines early graft failure.
AB  - OBJECTIVES: The limited availability of donor valves and experimental evidence
      that pulmonary valves can withstand systemic pressure made us use cryopreserved
      pulmonary homografts as aortic valve substitutes. We observed a high incidence of
      early reoperation because of severe graft insufficiency due to cuspal tears. The
      mid-term results are evaluated in this study and histological analysis of
      explanted homografts is performed to investigate the cause of graft failure.
      METHODS: From December 1991 to April 1994, 16 patients (13 male; mean age 37.3
      years, range 21-59 years) underwent aortic valve replacement with a cryopreserved
      pulmonary homograft. The indication was endocarditis (n = 4), bioprosthesis
      degeneration (n = 3) or congenital aortic valve disease (n = 9). All homografts
      were implanted freehand in the subcoronary position. All patients were contacted
      for follow-up and recent echo-Doppler studies were reviewed. Six explanted
      homografts were examined microscopically using routine histological techniques to
      analyze changes in cell population, collagen and elastic fiber structure.
      RESULTS: Follow-up was complete in all patients. Reoperation was required in ten
      patients because of severe graft incompetence (mean implantation time 5.9 years,
      range 2.8-8.0 years). In two patients, recurrent endocarditis was the cause of
      graft failure. In the other eight patients the leaflets looked pliable and thin
      with gross tearing in one or more cusps. The histopathologic changes observed
      were remarkably similar in all examined grafts: the cusp tissue was almost non
      cellular and the collagen fiber structure had mostly disappeared. At the site of
      rupture, the tissue had become thin with strongly degenerated collagen and
      elastic fiber structure. In the six patients with a homograft remaining in situ,
      echo-Doppler showed trivial to mild insufficiency in five cases and moderate to
      severe in one case, whereas no significant gradients were observed. CONCLUSIONS:
      We concluded that structural reduction of cell number and degenerative
      alterations in the molecular composition of the extracellular matrix in valve
      tissue is the main cause of early graft failure in this series. The use of
      cryopreserved pulmonary homografts in the systemic circulation is therefore not
      advised.

PMID- 12414050
TI  - The effects of mitral annuloplasty rings on mitral valve complex 3-D geometry
      during acute left ventricular ischemia.
AB  - OBJECTIVE: Annuloplasty rings are used to treat ischemic mitral regurgitation
      (IMR), but their exact effects on 3-D geometry of the overall mitral valve
      complex during acute left ventricular (LV) ischemia remain unknown. METHODS:
      Radiopaque markers were sutured to the mitral leaflet edges, annulus, papillary
      muscle tips, and ventricle in three groups of sheep. One group served as control
      (n = 5), and the others underwent Duran (n = 6) or Physio (n = 5) ring
      annuloplasty. One week later, 3-D marker coordinates at end-systole were obtained
      before and during balloon occlusion of the circumflex artery. RESULTS: In all
      control animals, acute LV ischemia was associated with: (i) septal-lateral
      separation of the leaflet edges, which was predicted by lateral displacement of
      the lateral annulus during septal-lateral mitral annular dilatation; (ii) apical
      restriction of the posterior leaflet edge, which was predicted by displacement of
      the lateral annulus away from the non-ischemic anterior papillary muscle; (iii)
      displacement of the posterior papillary muscle, which was not predictive of
      either septal-lateral leaflet separation or leaflet restriction; and (iv) mitral
      regurgitation. In the Duran group during ischemia, the posterior leaflet edge
      shifted posteriorly due to posterior movement of the lateral annulus, but no IMR
      occurred. In the Physio group during ischemia, neither the posterior leaflet edge
      nor the lateral annulus changed positions, and there was no IMR. In both the
      Duran and Physio groups, displacement of the posterior papillary muscle did not
      lead to IMR. CONCLUSIONS: Either annuloplasty ring prevented the perturbations of
      mitral leaflet and annular--but not papillary muscle tip--3-D geometry during
      acute LV ischemia. By fixing the septal-lateral annular dimension and preventing
      lateral displacement of the lateral annulus, annuloplasty rings prevented
      systolic septal-lateral leaflet separation and posterior leaflet restriction, and
      no acute IMR occurred. The flexible ring allowed posterior displacement of the
      posterior leaflet edge and the lateral annulus, which was not observed with a
      semi-rigid ring.

PMID- 12414051
TI  - The edge-to-edge technique as a trick to rescue an imperfect mitral valve repair.
AB  - OBJECTIVE: The edge-to-edge (E-to-E) technique in mitral valve repair (MVR) is
      promising especially to correct mitral insufficiency (MI) caused by complex
      mitral valve lesions. We tested this technique to improve residual MI straight
      after conventional MVR. METHODS: From September 1998 to January 2002, 108
      consecutive patients underwent MVR with current techniques for pure MI.
      Intraoperative transesophageal echocardiography was performed before and after
      MVR. At the end of cardiopulmonary bypass (CPB), 11 patients presented residual
      mitral regurgitant jet area (MRA) > or =2.0 cm(2). The E-to-E technique was used
      to improve this residual MI, without taking-down the original MVR. RESULTS: There
      were no hospital deaths. One patient died of non-valve-related cardiac death
      about 6 months after hospital discharge. At intraoperative ecocardiography,
      residual MRA improved from 3.0 +/- 0.8 cm(2), after conventional MVR, to 0.7 +/-
      0.9 cm(2), after the E-to-E technique (P = 0.00014). Additional CPB time of 14.9
      +/- 2.8 min was needed. These echocardiographic results were confirmed at follow
      up of 13.8 +/- 8.1 months. CONCLUSIONS: The E-to-E technique is a simple, rapid,
      effective, and durable option to reduce residual MI and rescue an imperfect
      conventional MVR.

PMID- 12414052
TI  - Scimitar syndrome: a rare cause of haemoptysis.

PMID- 12414053
TI  - The value of caval division in the maze procedure with valve surgery.
AB  - Operative predictors for successful elimination of atrial fibrillation (AF)
      following the maze procedure are not yet known. We have often divided the
      superior vena cava (SVC) during the maze procedure, not to eliminate AF but in
      order to explore the mitral valve. However, in multivariate analysis of 79
      patients, the division of SVC, as well as the duration of AF, was found to be the
      strongest predictor of AF elimination. The explanation of this observation is not
      clear, but denervation of the cardiac autonomic nervous system or the existence
      of paroxysmal AF originating from the SVC could be involved.

PMID- 12414054
TI  - Echocardiographic diagnosis of left ventricular outflow tract obstruction after
      mitral valve replacement with subvalvular preservation.
AB  - We describe two cases of left ventricular outflow tract obstruction after mitral
      valve replacement with complete retention of the subvalvular apparatus. The first
      patient deteriorated immediately after insertion of a high-profile bioprosthesis.
      In the second patient, chronic left ventricular outflow tract obstruction
      developed after the insertion of a low-profile mechanical prosthesis. The
      clinical course of left ventricular outflow tract obstruction after mitral valve
      replacement with complete retention of the subvalvular apparatus may differ
      greatly. Evaluation of the left ventricular outflow tract by perioperative
      transesophageal echocardiography or epicardial echocardiography is essential in
      the prevention and treatment of this complication.

PMID- 12414056
TI  - Pedicled intercostal muscle flap: a simple technique of closing pancreatico
      pleural fistula from a thoracic approach.
AB  - A simple technique to close a pancreatico-pleural fistula in the course of
      thoracotomy and decortication for multiloculated empyema complicating acute
      haemorrhagic pancreatitis is described. Friable diaphragmatic tissue around the
      fistula made direct closure not a suitable option. The intercostal muscle flap of
      the thoracotomy space was mobilized on the anterior intercostal artery, tagged
      around the fistula into healthy diaphragmatic tissue. This simple technique was
      successful in closing the fistula and helping control the sepsis.

PMID- 12414055
TI  - Videoscopic supradiaphragmatic thoracic duct division using ultrasonic
      coagulator.
AB  - Three consecutive male patients underwent videoscopic supradiaphragmatic thoracic
      duct division using the Harmonic Scalpel with a hook blade (Ethicon Endo-Surgery,
      Cincinnati, OH, USA) for treatment of chyle leaks that developed after left upper
      lobectomy, graft replacement of a descending aortic aneurysm and thyroidectomy
      with concomitant partial sternal resection. The thoracic duct was exposed and
      divided using just the Harmonic Scalpel. The operations lasted 40, 20 and 18 min.
      No mortality, morbidity or recurrence occurred during follow-up periods of 27, 17
      and 9 months. The Harmonic Scalpel with a hook blade can facilitate
      supradiaphragmatic exposure of the thoracic duct.

PMID- 12414057
TI  - Synchronous left lung transplantation and right pneumonectomy for end-stage
      bronchiectasis through Clamshell approach. Specific problems.
AB  - A synchronous right pneumonectomy and left lung transplantation is reported in a
      case of asymmetric thorax. An extreme shift of the mediastinum and over
      distension of the transplanted lung is shown 3 years later. Post pneumonectomy
      syndrome must be seeking in this alternative technique.

PMID- 12414058
TI  - Surgical treatment of atypical aortic coarctation associated with occlusion of
      all arch vessels in Takayasu's disease.
AB  - We report a patient with Takayasu's disease surgically treated who had presented
      severe manifestation due to aortic coarctation associated with occlusion of all
      arch branches. This patient had suffered cardiac failure and recurrent fainting
      attacks before surgery. The operative procedures included ascending to infra
      renal aortic bypass grafting combined with reconstruction of the right axillary
      artery. Cardio-pulmonary bypass (CPB) was used to facilitate the proximal aortic
      anastomosis. Regional oxygen saturation in the bilateral frontal lobes was
      measured intraoperatively using near-infrared spectroscopy to detect cerebral
      ischemia. Regional oxygen saturation was managed above the critical level
      throughout the CPB. No new cerebral complications occurred in the perioperative
      period.

PMID- 12414059
TI  - Bilateral elastofibroma dorsi: proper positioning for an accurate diagnosis.
AB  - Elastofibroma dorsi is a rare, slow-growing, ill-defined soft tissue tumor of the
      chest wall, most commonly located beneath the rhomboid major and latissimus dorsi
      muscles. It is usually unilateral, and bilateral involvement occurs in only 10%
      of patients. We report herein a case of a 56-year-old woman with bilateral
      elastofibroma dorsi. The patient was found to have bilateral involvement of the
      tumor following a physical examination with proper positioning. An elastofibroma
      should be considered in the differential diagnosis of tumors deeply located at
      the periscapular area. Meticulous physical examination may reveal a nonpalpable
      coexisting tumor with deep subscapular location and help the accurate diagnosis
      of bilateral elastofibroma dorsi, hence preventing a secondary operation.

PMID- 12414060
TI  - Papillary carcinoma arising on cervico-mediastinal thyroglossal ductal cyst
      resected via transcervical and partial upper sternotomy incision.
AB  - Thyroglossal cyst is the most common congenital cervical pathology of childhood.
      Malign transformation in thyroglossal cyst is very rare and seen generally in
      adults. Here, we report on a 40-year-old female patient who presented with
      progressive dyspnea and enlarging cervical masses. Radiological examination
      revealed multiple cystic lesions in cervical and mediastinal region. The cysts
      were resected surgically via transcervical and partial upper sternotomy incision.
      Pathological examination revealed malignant change in the cervico-mediastinal
      thyroglossal cysts.

PMID- 12414061
TI  - Traumatic cardiogenic shock due to massive air embolism. A possible role for
      cardiopulmonary bypass.
AB  - Systemic arterial embolism is a potentially lethal complication of
      bronchopulmonary venous fistula in trauma patients with blunt chest trauma or
      isolated penetrating lung injury on positive pressure ventilation. A high index
      of suspicion, early diagnosis and management in specialized centres are keys to a
      successful outcome.

PMID- 12414062
TI  - Malignant internal mammary lymph nodes during mobilization of the internal
      mammary artery.
AB  - Malignant internal mammary node involvement may occur with a primary neoplasm or
      with metastasis. The incidental discovery of malignant internal mammary nodes
      from an unknown primary origin has not been previously described. Cardiac
      surgeons should be aware of pathologic internal mammary artery (IMA) nodes and
      any abnormally enlarged nodes encountered in the course of IMA mobilization
      should be sent for histological examination. The incidental discovery of
      malignancy does not preclude the use of the IMA as a bypass conduit. Once a
      diagnosis of malignancy is established, meticulous exhaustive investigation may
      be indicated to identify the primary lesion and definitive treatment instituted
      if appropriate.

PMID- 12414063
TI  - Giant pseudoaneurysm of the right ventricular outflow tract after repair of
      truncus arteriosus: evaluation by MR imaging and surgical approach.
AB  - One year after surgical repair of the truncus arteriosus, a 1-year 8-month-old
      boy was found to have a pseudoaneurysm of the right ventricular outflow tract
      (RVOT). Cine-magnetic resonance imaging (MRI) showed a narrow communication
      between the RVOT and aneurysm. MRI was useful to evaluate the anatomical and
      spatial relations between the pseudoaneurysm and the surrounding structures,
      therefore an appropriate approach was chosen. Thus, a median sternotomy approach
      was carried out and ordinary central cannulation was feasible to establish a
      cardiopulmonary bypass. The defect was successfully repaired with reconstruction
      using a monocuspid outflow patch. MRI provided useful information for deciding
      the surgical approach.

PMID- 12414064
TI  - Haemodynamic changes during off-pump surgery.

PMID- 12414067
TI  - Working memory and schizophrenia: evidence for slowed encoding.
AB  - Previous studies have found impairments in working memory in individuals with
      schizophrenia, but have not identified the underlying information processing
      deficit. Because schizophrenia is associated with slowed cognitive processing,
      deficits on working memory tests may be due to decreased speed of encoding rather
      than an inability to maintain information over time. This hypothesis was examined
      using a Delayed Match to Sample (DMTS) Test. Task difficulty under 0-delay
      conditions was equated by individually establishing the stimulus presentation
      time needed to reach approximately 80% accuracy. Schizophrenia participants
      required longer presentation durations, but there were no group differences under
      delay conditions when performance was equated in the 0-delay condition. These
      results suggest that poor working memory performance in schizophrenia results
      from slowed encoding processes.

PMID- 12414066
TI  - Double outlet right ventricle.

PMID- 12414068
TI  - Electrodermal responsivity distinguishes ERP activity and symptom profile in
      schizophrenia.
AB  - BACKGROUND: Traditional averaging of late component Event Related Potentials
      (ERPs) might obscure important psychophysiological subprocesses underlying
      schizophrenia disturbances in cognitive functioning. One such subprocess could be
      the active orientation of attention to significant or novel stimuli. In this
      study, we used skin conductance responses (SCRs) to index orienting responses
      (ORs). ERP activity was examined in relation to concomitant ORs in a
      schizophrenia and nonpsychiatric control group. Schizophrenia responses were
      considered with respect to the Reality Distortion, Disorganisation and
      Psychomotor Poverty syndromes. METHOD: Forty schizophrenia and 40 age and sex
      matched control subjects were tested. The three schizophrenia syndromes were
      derived from a principal component analysis of Positive and Negative Syndrome
      Scale (PANSS) ratings. Auditory ERPs (N100, N200, P200, P300) were elicited using
      a conventional auditory oddball paradigm, and electrodermal SCR data were
      acquired simultaneously. RESULTS: ERP data were sub-averaged according to the
      presence/absence of an OR. For both 'with-' and 'without-OR' ERPs, schizophrenia
      subjects as a group showed reduced N100 (associated with vigilance level) and
      N200 (associated with response selection) amplitude, and for with-OR responses,
      they showed an additional reduction in P300 (context processing). Concerning
      schizophrenia syndromes, Reality Distortion was related primarily to frontal
      disturbances (earlier N100/N200 latency and decreased P200/P300 amplitude), and
      Psychomotor Poverty to a generally delayed P300 latency. Similarly delayed P300
      in Disorganisation was explained by medication effects. There were no
      associations with syndromes for without-OR ERPs. CONCLUSION: These results
      suggest that schizophrenia syndromes are dissociated with regard to both the
      direction and nature of speed of information processing disturbances, in relation
      to task-relevant information that produces active orientation.

PMID- 12414069
TI  - Probed recall for serial order deficits in short-term memory in schizophrenic
      patients.
AB  - BACKGROUND: Patients with schizophrenia frequently display problems in tasks
      demanding working memory. In a previous study, we examined short-term memory
      (STM) for serial order by having participants recall lists of letters from the
      first item to the last item in the order in which they were presented, and we
      examined the types of errors made (e.g., omissions, intrusions and movements;
      [Neuropsychology 15 (2001) 128]). We found that the disproportionate errors
      schizophrenic patients made were omissions at the end of six-item lists, a
      finding we suggested might reflect patients' longer output times, which adds to
      information maintenance demands. If this is the case, we predicted that the group
      difference in the terminal positions could be eliminated through the use of a
      probed recall paradigm. METHOD: In the current study, 26 schizophrenic patients
      and 33 control participants were tested on a probed recall task that was similar
      to our previous serial recall task except that instead of recalling the whole
      sequence of letters, participants were probed as to which letter appeared in a
      specific position in the sequence. RESULTS: We found that when participants were
      probed for later positions, recall was equivalent in the groups (i.e., recency),
      but disproportionately worse in patients for earlier positions. CONCLUSIONS: We
      suggest that schizophrenic patients' limited STM span for serial order is not
      attributable to a selective deficit in memory for serial order. Rather, we
      propose that it may be explicable in terms of impaired information maintenance
      and thus this becomes evident in conditions involving longer sequences of
      stimuli.

PMID- 12414070
TI  - Longitudinal study of symptoms and cognitive function in chronic schizophrenia.
AB  - There is conflicting evidence of a relationship between changes in symptoms and
      cognitive functioning in schizophrenia. This study investigated longitudinal
      changes in psychopathology and cognitive functioning in chronic schizophrenia
      utilising three different dimensional models of symptomatology. Sixty-two
      patients diagnosed with DSM-IV schizophrenia or schizoaffective disorder were
      examined on two occasions over a period of 6 months for symptom improvement,
      measured by Positive and Negative Syndrome Scale (PANSS) [Kay et al., Schizophr.
      Bull. 13 (1987) 261]. Participants also completed a comprehensive battery of
      neuropsychological tasks designed to assess attention, verbal and non-verbal
      memory, psychomotor processing and executive/frontal functioning on both
      occasions. Twenty-five control subjects were assessed for comparison purposes.
      Severity of negative symptoms predicted poor neuropsychological performance on
      IQ, verbal fluency and memory measures at occasion one. However, using regression
      analyses, significant improvements in symptom ratings over time using two-, three
      or five-dimensional models did not predict improvements in any aspect of
      cognitive functioning measured, except motor speed. The results do not suggest a
      causal relationship between the course of symptoms and neuropsychological
      functioning in chronic schizophrenia.

PMID- 12414071
TI  - Auditory P300 amplitude as a state marker for positive symptoms in schizophrenia:
      cross-sectional and retrospective longitudinal studies.
AB  - The amplitude of the P300 component of the auditory event-related brain potential
      (ERP) is consistently reduced in schizophrenia. To determine whether this P300
      abnormality can be used as a state marker to reflect the severity of symptoms, we
      examined both cross-sectionally and longitudinally the relationship between
      auditory P300 amplitude and symptom severity in patients with schizophrenia. For
      the cross-sectional study, ERP was elicited by an auditory oddball paradigm, and
      symptom severity was quantitatively measured by means of the Positive and
      Negative Syndrome Scale in 93 patients with schizophrenia or schizophreniform
      disorder (DSM-III-R). For the longitudinal study, ERP and psychopathology
      measured twice at an average interval of 238 days for 20 patients were
      retrospectively analyzed. The cross-sectional data showed that P300 amplitude
      correlated negatively with the positive but not with the negative syndrome scale
      score. The longitudinal data also showed a significant negative correlation
      between changes in P300 amplitude and in the positive syndrome scores of the
      first and second tests. In particular, P300 amplitude recorded at the left, but
      not right, posterior temporal region significantly correlated with the positive
      syndrome in both the cross-sectional and longitudinal studies. These findings
      support the hypotheses that auditory P300 amplitude recorded in the left
      hemisphere can be used as a state marker to reflect the severity of the positive
      symptoms and that the positive symptoms may be caused by a possible left
      hemisphere deficit in schizophrenia.

PMID- 12414072
TI  - Neuromagnetic correlates of impaired automatic categorical perception of speech
      sounds in schizophrenia.
AB  - Schizophrenia is associated with dysfunction in language processing. At the
      earliest stage of language processing, dysfunction of categorical perception of
      speech sounds in schizophrenia has been demonstrated in a behavioral task. The
      aim of this study was to assess automatic categorical perception of speech sounds
      as reflected by event-related changes in magnetic field power in schizophrenia.
      Using a whole-head magnetoencephalographic recording, the magnetic counterpart of
      mismatch negativity (MMNm) elicited by a phonetic change was evaluated in 16
      right-handed patients with chronic schizophrenia and in 19 age-, sex-, and
      parental socioeconomic status-matched normal control subjects. Three types of
      MMNm (MMNm in response to a duration decrement of pure-tone stimuli; a vowel
      within-category change [duration decrement of Japanese vowel /a/]; vowel across
      category change [Japanese vowel /a/ versus /o/]) were recorded. While the
      schizophrenia group showed an overall reduction in magnetic field power of MMNm,
      a trend was found toward more distinct abnormalities under the condition of vowel
      across-category change than under that of duration decrement of a vowel or tone.
      The patient group did not show abnormal asymmetries of MMNm power under any of
      the conditions. This study provides physiological evidence for impaired
      categorical perception of speech sounds in the bilateral auditory cortex in
      schizophrenia. The language-related dysfunction in schizophrenic patients may be
      present at the early stage of auditory processing of relatively simple stimuli
      such as phonemes, and not just at stages involving higher order semantic
      processes.

PMID- 12414073
TI  - Clock drawing test in institutionalized patients with schizophrenia compared with
      Alzheimer's disease patients.
AB  - The impaired performance of Alzheimer's disease (AD) patients on the clock
      drawing test (CDT) relative to age-matched normal controls is a well-documented
      finding in the literature. On the other hand, there is sparse information
      regarding the use of this test in schizophrenia. We examined three groups of
      subjects matched for gender and education: institutionalized patients with
      schizophrenia (n = 32), patients with AD (n = 32), and normal controls (n = 36).
      The CDT ("free-drawn", "pre-drawn", and three "examiner" conditions) and Mini
      Mental State Examination (MMSE) were administered to all participants. In
      patients with schizophrenia, symptom severity was assessed with the Brief
      Psychiatric Rating Scale (BPRS). Patients with schizophrenia were significantly
      younger than AD patients and normal controls (56.78 versus 71.41 and 66.25,
      respectively), and normal controls had significantly higher MMSE scores than
      patients with schizophrenia and AD (27.58 versus 20.75 and 18.44, respectively).
      In all of the clock conditions, the two patient groups performed significantly
      poorer than the normal controls, with the exception of the "pre-drawn" clock in
      which AD patients also performed worse than patients with schizophrenia. Age and
      duration of illness did not correlate significantly with CDT scores. When MMSE
      scores were used as a covariate, all significant differences on the CDT among the
      three groups disappeared, with the exception of the "pre-drawn" clock (AD
      patients had lower scores than both control and schizophrenia groups). In
      patients with schizophrenia, scores on the BPRS were not related with any CDT
      variable. Institutionalized patients with schizophrenia and AD patients showed
      similar deficits on a neuropsychological test sensitive to changes in visual
      analytic function, attention, receptive language, and executive functions such as
      planning, organization, and simultaneous processing.

PMID- 12414074
TI  - Increased automatic spreading of activation in thought-disordered schizophrenic
      patients.
AB  - Previous research on semantic priming in schizophrenia has produced conflicting
      findings. While several studies provided evidence for an enhanced cognitive
      spreading of activation in schizophrenia patients with formal thought disorder,
      other research has failed to replicate. The aim of the present study was to
      resolve some of the ambiguities in the literature. Thirty-two schizophrenic
      patients (12 with and 20 without symptoms of formal thought disorder according to
      the PANADSS) and 65 healthy controls were compared in a semantic priming task
      using word pronunciation. Irrespective of baseline condition (neutral or
      unrelated condition) patients with formal thought disorder (TD) exhibited a
      significantly greater indirect semantic priming effect than both non-TD patients
      and healthy controls. Known confounding variables such as length of illness,
      neuroleptic dosage and psychomotor slowness did not moderate priming. Results
      further strengthen the spreading activation model of formal thought disorder put
      forward by Maher/Manschreck and Spitzer. Data indicate that hyper-priming is not
      confined to lexical decision tasks. Possible reasons why several studies have
      failed to replicate greater priming in TD schizophrenic patients are discussed.

PMID- 12414075
TI  - Functional abnormalities of medial temporal cortex during novel picture learning
      among patients with chronic schizophrenia.
AB  - BACKGROUND: Learning deficits are prominent among patients with chronic
      schizophrenia and are associated with poor everyday functioning. Little is known,
      however, about the brain physiology underlying these difficulties with encoding
      new information. PURPOSE: The purpose of the current study was to compare the
      brain response during novel picture encoding between patients with chronic
      schizophrenia and healthy individuals using functional magnetic resonance imaging
      (fMRI). METHODS: Nine middle-aged patients with DSM-III-R or DSM-IV schizophrenia
      and 10 age- and education-comparable healthy individuals were studied. Using
      fMRI, the blood oxygenation level dependent (BOLD) signal was measured during
      novel picture encoding (experimental condition) and during presentation of a
      repeated picture (control condition). Encoding-related brain response was
      examined in both groups and compared between the patient and comparison groups in
      each voxel within four bilateral search regions (fusiform gyrus, parahippocampal
      gyrus, hippocampus, and inferior frontal gyrus). RESULTS: Despite comparable
      subsequent ability to recognize the presented pictures, patients with
      schizophrenia showed abnormal encoding-related brain response in regions of the
      hippocampus and parahippocampal and fusiform gyrii compared to healthy
      individuals. In medial temporal regions, patients showed greater BOLD response
      during the control condition (repeated picture) than during the experimental
      condition (novel pictures). CONCLUSION: Abnormalities of the medial temporal
      brain systems examined in this study may underlie learning deficits in
      schizophrenia. Further research is needed to illuminate the role of these brain
      dysfunctions in poor everyday functioning and their amenability to treatment.

PMID- 12414076
TI  - Visual backward-masking deficits in schizophrenia: relationship to visual pathway
      function and symptomatology.
AB  - Patients with schizophrenia have information processing deficits which can be
      measured using visual backward-masking (VBM) tasks. There are two types of visual
      pathways: transient and sustained. The former is more sensitive to low spatial
      frequency (LSF) and the latter to high spatial frequency (HSF) stimuli. It has
      been hypothesized that the VBM deficit in schizophrenia is due to an overactive
      transient channel response to the mask. To examine this hypothesis, patients with
      schizophrenia and comparison volunteers were tested on a traditional backward
      masking task as well as on tasks that altered the mask to bias stimulation toward
      transient (LSF) or sustained (HSF) channels. Medication effects and relationship
      to symptomatology were also examined. Patients with schizophrenia showed a
      significant deficit on the traditional backward-masking task and were also
      significantly impaired on the LSF- and HSF-masking tasks, though a differential
      deficit was not found on the latter two tasks. A U-shaped function, indicative of
      masking by interruption, was found on the LSF- and HSF-masking tasks. Masking
      performance was not altered when the same patients were tested on and off
      medication, and performance was related to positive and negative symptoms. In
      conclusion, the finding of a deficit in patients with schizophrenia on tasks
      producing a U-shaped function suggests that an aberrant transient response to the
      mask is producing increased interruption of the sustained response to the target.

PMID- 12414077
TI  - Audio-visual integration in schizophrenia.
AB  - Integration of information provided simultaneously by audition and vision was
      studied in a group of 18 schizophrenic patients. They were compared to a control
      group, consisting of 12 normal adults of comparable age and education. By
      administering two tasks, each focusing on one aspect of audio-visual integration,
      the study could differentiate between a spatial integration deficit and a speech
      based integration deficit. Experiment 1 studied audio-visual interactions in the
      spatial localisation of sounds. Experiment 2 investigated integration of auditory
      and visual speech. The schizophrenic group performed as the control group on the
      sound localisation task, but in the audio-visual speech task, there was an
      impairment in lipreading as well as a smaller impact of lipreading on auditory
      speech information. Combined with findings about functional and neuro-anatomical
      specificity of intersensory integration, the data suggest that there is an
      integration deficit in the schizophrenic group that is related to the processing
      of phonetic information.

PMID- 12414078
TI  - Neurocognition and community outcome in schizophrenia: long-term predictive
      validity.
AB  - The present study examined the predictive validity of neuropsychological measures
      to functional outcome in 26 schizophrenic patients 15-plus year post-testing.
      Outcome measures included score on the Resource Associated Functional Level Scale
      (RAFLS), number of state hospital admissions, and total duration of state
      hospital inpatient stay. Results of several stepwise multiple regressions
      revealed that verbal memory significantly predicted RAFLS score, accounting for
      nearly half of the variance. Trails B significantly predicted duration of state
      hospital inpatient status. Discussion focused on the utility of these measures
      for clinicians and system planners.

PMID- 12414079
TI  - Computer-assisted cognitive rehabilitation reduces negative symptoms in the
      severely mentally ill.
AB  - Thirty-four-day treatment program clients diagnosed with schizophrenia or
      schizoaffective disorder were randomly assigned to a computer-assisted cognitive
      rehabilitation (CACR) group or a wait-list Control group. CACR clients received
      16 CACR sessions over an 8-week period. Measures of cognitive functioning,
      negative symptoms and self-esteem were administered at the beginning and end of
      this period. CACR clients showed greater improvement in cognitive functioning
      (verbal memory and attention) and negative symptoms. Symptom reduction was not
      mediated by raised self-esteem. CACR's effects may go beyond cognitive
      remediation to include some of the most disabling and refractory clinical
      features of schizophrenia.

PMID- 12414080
TI  - Social perception and early visual processing in schizophrenia.
AB  - Persons with schizophrenia experience deficits in social cognition-the cognitive
      processes involved in how people perceive and interpret information about
      themselves, others, and social situations. These deficits may be related to the
      neurocognitive impairments often experienced by persons with schizophrenia. Our
      primary objective was to examine associations between social perception and early
      visual processing in schizophrenia. Our secondary objective was to examine
      whether outpatients with schizophrenia and healthy persons differ in social
      perception. Forty outpatients with schizophrenia and 30 healthy persons completed
      a measure of social perception (the Half-Profile of Nonverbal Sensitivity),
      visual masking procedures, and ratings of positive and negative symptoms. Within
      patients, performance on visual masking procedures was related to performance on
      the Half-Profile of Nonverbal Sensitivity. Patients with schizophrenia and the
      healthy persons differed significantly in their performance on the Half-Profile
      of Nonverbal Sensitivity, but this difference became nonsignificant when
      education was a covariate. These findings suggest that social perception in
      schizophrenia is related to very early aspects of visual processing.

PMID- 12414081
TI  - Cross-national cognitive assessment in schizophrenia clinical trials: a
      feasibility study.
AB  - Clinical trials for the treatment of schizophrenia now often include cognitive
      assessments in addition to clinical ratings of symptoms. Recently, these trials
      have included cross-national assessments. It is not clear if translated
      psychological tests produce consistent results across different languages. This
      paper presents the results of a study of the comparability of the results of
      cognitive assessments in different English-speaking countries and a number of
      countries where tests were translated into other languages. Performance on tests
      of executive functioning, verbal and visuo-spatial learning and memory, language
      skills, psychomotor speed, and vigilance was compared across the first episode
      patients with schizophrenia (n = 301) assessed in six different languages
      (English, French, Finnish, German, Hebrew, and Afrikaans), including two
      different countries where patients were assessed in English and other languages:
      Canada (French) and South Africa (Afrikaans). The variance in performance across
      the sites tested in English was as large as the variance between English and non
      English speakers when all tests were considered. Performance differences across
      English and other languages were found only for executive functions, vigilance,
      and psychomotor speed, with executive functioning differences nonsignificant when
      education was considered. No differences were found between English and non
      English speakers in Canada. These results suggest that the translation of tests
      of memory and verbal skills can lead to consistent results across translated
      versions of the tests. Differences between countries were greater than
      differences between languages, suggesting the need to consider representativeness
      of patient samples in terms of local educational attainment. In general, these
      data support the validity of cross-national neuropsychological assessments.

PMID- 12414082
TI  - Altered hemispheric asymmetry and positive symptoms in schizophrenia: equivalent
      current dipole of auditory mismatch negativity.
AB  - The abnormality of mismatch negativity (MMN) in schizophrenia is thought to be
      associated with perceptional disturbance and cognitive dysfunction. The purpose
      of the present study was to investigate the change of the normal functional
      hemispheric lateralization in schizophrenia by employing the equivalent current
      dipole (ECD) model of auditory MMN with individual MRI and high-density
      electroencephalography (EEG). The MMNs resulting from auditory stimuli with
      passive oddball paradigm in a group of schizophrenics (n = 15), and also a group
      of age-, sex-, and handedness-matched normal controls, were recorded by 128
      channel EEG. The location and power of ECD sources at the peak point were
      calculated. Individual 3-D brain magnetic resonance images (MRI) were used for
      realistic head modeling and for source localization. For both groups, the MMN
      source was determined to be located in the superior temporal gyrus (STG).
      However, the normal functional hemispheric asymmetry of ECD power was
      significantly altered in the schizophrenics (chi(2) test = 16.13, p < 0.001).
      Left MMN ECD power and the asymmetry coefficient (AC) were negatively correlated
      with the positive scores from Positive and Negative Syndrome Scale (PANSS) (r = 
      0.673, p = 0.008), especially with the hallucinatory behavior subscale (r = 
      0.677, p = 0.008). These findings support the deficits in preattentive automatic
      processing of auditory stimuli, especially in the left hemisphere, and indicate
      the correlation between positive symptoms, especially auditory hallucination, and
      left temporal lobe dysfunction in schizophrenia.

PMID- 12414083
TI  - Visual object working memory function and clinical symptoms in schizophrenia.
AB  - OBJECTIVE: The presence of working memory deficits suggests abnormalities of
      prefrontal cortex (PFC) in schizophrenia. Although much is known about spatial
      working memory deficits in schizophrenia, including its potential as a phenotypic
      marker, it is unclear whether object working memory is similarly affected. Our
      goal was to examine nonspatial, object working memory function in relation to
      clinical symptoms. METHODS: We assessed object working memory and clinical
      symptoms in 28 schizophrenia patients during acute psychotic episode and 4 months
      later during partial remission. Delayed-matching-to-sample tasks for familiar
      object (DMTS-F) and novel shapes (DMTS-N) were used. Symptoms were assessed by
      the Positive and Negative Syndrome Scale (PANSS). 33 age-matched normal subjects
      were also tested over the same time period. RESULTS: Acutely psychotic patients
      showed deficits in both DMTS-F and DMTS-N. Four months later, their DMTS-F
      performance improved significantly but deficits in DMTS-N were still present.
      During acute psychosis, symptoms correlated with DMTS-F but not with the DMTS-N.
      Four months later, negative symptoms correlated with both tasks. CONCLUSIONS:
      Object working memory as measured by DMTS-N was impaired in schizophrenia
      patients during both acute and chronic states. When schizophrenia patients were
      in partial remission, object working memory was associated with negative
      symptoms.

PMID- 12414084
TI  - Both processing speed and semantic memory organization predict verbal fluency in
      schizophrenia.
AB  - We systematically examined the relationship of both lexical retrieval and
      semantic memory organization to categorical verbal fluency performance in 40
      outpatient schizophrenic subjects and 16 healthy controls. Mean choice reaction
      time (RT) on a lexical decision task was used as a measure of lexical retrieval
      efficiency. The complexity of semantic memory organization was measured using a
      Pathfinder semantic network analysis (calculated as the number of inter-node
      links obtained from a similarity rating task). In the schizophrenia group only,
      RT and semantic network links were each significantly negatively correlated with
      fluency and, together, accounted for 23% of the variance in fluency. RT and links
      were not significantly correlated with one another. Findings were unrelated to
      age, sex, education, or medication dose. Controlling for IQ reduced but did not
      abolish the relationship between fluency and network links. We conclude that the
      restricted verbal output of schizophrenic subjects is related both to impaired
      lexical retrieval and to variation in semantic memory organization, which partly
      reflects general intelligence. The statistical independence of the retrieval
      speed and organizational factors suggests that individuals with schizophrenia
      differ in the underlying processes that contribute to their reduced verbal
      fluency.

PMID- 12414085
TI  - Visual object processing in schizophrenia: evidence for an associative agnosic
      deficit.
AB  - Early studies suggested visual form perception impairment in schizophrenia. To re
      examine this claim and characterise the deficit neuropsychologically, 41
      schizophrenic patients were administered tests sensitive to different levels of
      visual object perception and recognition. Intellectually well-preserved patients
      were examined separately on these and additional tests. Single case analysis was
      also applied to four patients showing varying degrees of general intellectual
      impairment. As a group, the patients showed little impairment on tests of early
      visual object perception, but greater impairment on higher-level visual
      processing tests, in particular object recognition and naming. This held true for
      patients with preserved general intellectual function. Single case analysis
      suggested that patients with schizophrenia have a selective deficit affecting
      object recognition and identification, with a pattern similar to visual
      associative agnosia in neurological patients.

PMID- 12414086
TI  - Learning (potential) and social functioning in schizophrenia.
AB  - Cognitive dysfunction in schizophrenia has well-known functional consequences.
      The ability to learn (learning potential) may be an important mediator. This
      study examines the relationship between learning and functional status in
      schizophrenia patients before and after participation in a rehabilitation
      program. We reasoned that learning is a broad construct, encompassing controlled,
      effortful as well as automatic (learning by doing) mechanisms, called explicit
      and implicit learning, respectively. Both types of learning ability are important
      in daily life. The study included 44 medicated schizophrenia patients and 79
      healthy controls. We included measures of implicit and explicit learning as well
      as measures of the cognitive domains for which significant relationships with
      functional outcome have been established: immediate and secondary verbal memory,
      card sorting and vigilance. Learning potential and the patient's 'learner status'
      were also assessed. The results show that learning, as assessed by measures of
      explicit and implicit learning and learning potential, was not associated with
      social functioning or rehabilitation outcome. The highest correlations between
      cognitive functioning and social functioning were found for more or less 'static'
      performance measures when they were assessed for a second time with or without
      instructions on how to do the test. Optimized cognitive performance (i.e.
      performance after instruction or training) seems to be a better predictor of
      complex domains of functioning than naive or everyday performance.

PMID- 12414087
TI  - Using figure ground perception to examine the unitary and heterogeneity models
      for psychopathology in schizophrenia.

PMID- 12414088
TI  - Effects of prenatal stress on maternal behavior in the rat.
AB  - Some authors reported a link between maternal stress and disturbances in their
      infants. Because of difficulties due to human research, the effects of prenatal
      stress have to be examined in animal models. Our approach was original in that
      the stressor was an ecological one and was applied at a given gestational day.
      Indeed, the stressor was a cat and the effects of stress on maternal behavior
      were investigated in five groups of 10 female rats: two groups were composed of
      females which were acutely stressed either at the 10th or the 14th gestational
      day; two other groups were composed of females which were repeatedly stressed
      either at the 10th or the 14th gestational day; the fifth group comprised non
      stressed females. Plasma corticosterone concentrations measured in blood samples
      collected from dams just after stress were significantly higher than in controls
      showing that cat represents an efficient stressor for rats. Maternal behavior was
      recorded during 30 min at the 2nd, 4th, and 6th postnatal days. In all cases,
      stressed dams' activities directly directed towards the pups (retrieving,
      sniffing and licking), those non-directly directed towards the pups (carrying its
      tail and digging the sawdust), and those directed towards themselves (eating,
      drinking and resting) were altered to different degrees. These alterations in
      maternal behavior can explain, at least in part, the mortality and the low growth
      rate observed in pups born from stressed dams.

PMID- 12414089
TI  - Nestin-containing cells express glial fibrillary acidic protein in the
      proliferative regions of central nervous system of postnatal developing and adult
      mice.
AB  - We are interested in the expression patterns of nestin, an embryonic intermediate
      filament that represent a neural precursor marker, in the mammalian central
      nervous system. With an immunohistochemical approach, distribution of nestin
      containing cells and their colocalization with glial fibrillary acidic protein
      (GFAP) or neuronal nuclear specific protein (NeuN) were studied in adult and
      postnatal days 2-30 (P2-30) mice. Nestin-immunoreactivity was predominately
      distributed in certain proliferative regions, such as cerebral cortex,
      hippocampus, hypothalamus, subfornical organ, cerebellar cortex, area postrema,
      midline raphe glial structures, as well as ependymal and subependymal zones of
      the brain and spinal cord. The majority of nestin-immunoreactive cells,
      characterized by astroglial profiles of multiple and radial processes, showed a
      partial overlapping distribution with that of GFAP-immunoreactive astroglial
      cells. Double immunofluorescence confirmed that about 77% of these nestin
      immunoreactive cells exhibited GFAP-immunoreactivity, indicating that a large
      percentage of nestin-expressing cells may have committed to astroglial cells. In
      developing mice, down-regulation of nestin expression was observed between P7 and
      P14. Although co-expression of nestin and NeuN occurred in cortical neurons of P2
      7 mice, nestin-containing cells showing NeuN-immunoreactivity disappeared in CNS
      in older animals. Our results reveal the distribution pattern of nestin
      containing neural precursors in the postnatal CNS and provide evidence on their
      differentiation fate to neurons and astrocytes, suggesting that nestin-containing
      glial cells may play an important role in remodeling and repairing in the
      postnatal and adult central nervous system.

PMID- 12414090
TI  - Age dependent NMDA contribution to impaired hypotensive cerebral hemodynamics
      following brain injury.
AB  - Previous studies have observed that fluid percussion brain injury (FPI) impaired
      NMDA induced pial artery dilation (PAD) in an age dependent manner. Unrelated
      studies observed a similar age dependent impairment of hypotensive cerebral
      autoregulation after FPI. This study was designed to test the hypothesis that
      NMDA receptor activation contributes to impairment of cerebral autoregulation
      during hypotension after FPI in an age dependent manner. Therefore, the role of
      NMDA in impaired hypotensive cerebrovascular regulation after FPI was compared in
      newborn and juvenile pigs equipped with a closed cranial window. Ten minutes of
      hypotension (10-15 ml blood/kg) decreased mean arterial blood pressure uniformly
      in both groups (approximately 44%). In the newborn, hypotensive PAD was blunted
      within 1 h of FPI but partially protected by pretreatment with the NMDA
      antagonist MK801 (1 mg/kg i.v.) (34+/-1 vs. 8+/-1 vs. 25+/-2% for sham control,
      FPI, and FPI-MK801, respectively). Cerebral blood flow (CBF) was reduced during
      normotension by FPI, further reduced by hypotension, but both were partially
      protected by MK801 in the newborn (56+/-5, 35+/-2, and 16+/-1 vs. 62+/-6, 45+/-3,
      and 30+/-2 ml/min 100 g for normotension, normotension-FPI, and hypotension-FPI
      in the absence and presence of MK801, respectively). In contrast, blunted
      hypotensive PAD was protected significantly less by MK801 in the juvenile (32+/-2
      vs. 7+/-2 vs. 16+/-2% for sham control, FPI, and FPI-MK801, respectively).
      Similarly, MK801 had less protective effect on normotensive and hypotensive CBF
      values post FPI in the juvenile. These data indicate that NMDA receptor
      activation contributes to impaired hypotensive cerebral hemodynamics following
      brain injury in an age dependent manner.

PMID- 12414091
TI  - Protein kinase C inhibitors counteract the ethanol effects on myelin basic
      protein expression in differentiating CG-4 oligodendrocytes.
AB  - Abnormal formation of myelin appears to be one defect contributing to the
      development of the neuropathology associated with the fetal alcohol syndrome.
      Using the CG-4 cell line we previously showed that 25-75 mM EtOH downregulates
      the expression of myelin basic protein (MBP) in differentiating oligodendrocytes
      (OLGs) without affecting morphological development (Dev. Brain Res. 128 (2001)
      9). Here we showed that a relatively low concentration of 12-phorbol-13-myristate
      acetate (PMA) mimicked the EtOH-caused inhibition of MBP expression without
      affecting morphology. The inhibition of MBP expression by 100 mM EtOH or 1 nM PMA
      was completely counteracted by three inhibitors of protein kinase C (PKC),
      bisindolylmaleimide I, chelerythrine chloride, and calphostin C, indicating that
      EtOH downregulated MBP expression by activating PKC. We investigated whether the
      EtOH activation resulted, in part, from upregulation of the expression of PKC
      isozymes. Of 11 PKC isozymes examined, CG-4 OLGs expressed nine; PKCs alpha,
      beta1, beta2; delta, epsilon, eta; lambda, zeta; mu; while PKC isozymes gamma and
      theta were not detected. Only five PKC isozymes, alpha, beta1, beta2, eta, and
      mu, displayed developmental changes in expression. However, EtOH did not
      upregulate the early expression of any PKC isozyme during the first 2 days of
      differentiation, the developmental stage when it downregulates MBP expression in
      CG-4 cells. The similar effects of PMA and EtOH indicate that EtOH delays MBP
      expression by activating at least one phorbol ester-sensitive PKC isozyme in
      oligodendrocytes without upregulating its expression.

PMID- 12414092
TI  - The HPA system during the postnatal development of CD1 mice and the effects of
      maternal deprivation.
AB  - In this study we describe in 9- and 18-day-old CD1 mice (i) the basal and stress
      induced activity of markers of the HPA system in blood, brain and pituitary, (ii)
      the effects of a 24-h maternal deprivation and (iii) the influence of anogenital
      stimulation (stroking) in deprived pups on these markers. We found low basal
      concentrations of ACTH and corticosterone at postnatal day (pnd) 9 and no or
      little response to a mild stressor at this age, confirming the existence of a
      SHRP in mice. At pnd 18 the mice displayed an adult-like ACTH and corticosterone
      response following a mild stressor. Maternal deprivation resulted in enhanced
      basal and stress levels of corticosterone at both ages. Interestingly, basal ACTH
      levels were elevated following maternal deprivation at pnd 9. At pnd 18 maternal
      deprivation resulted in a blunted ACTH response. Maternal deprivation resulted in
      a down-regulation of GR, MR, CRH and POMC transcript in the brain. However,
      maternally deprived 18-day-old pups displayed increased levels of CRH and POMC
      transcript, while GR and MR mRNA was also down-regulated. Anogenital stroking
      could reverse maternal deprivation effects on ACTH and MR mRNA, but not CRH mRNA.
      We conclude that (i) at the two measured time points the HPA axis develops
      similar in mice as in rats, (ii) maternal deprivation has pronounced effects in
      mice, which are similar to that found in the rat and (iii) there are a number of
      significant differences, which mainly concern the central CRH-ACTH components of
      the axis.

PMID- 12414093
TI  - Distribution of alpha-amino-3-hydroxy-5-methyl-4 isoazolepropionic acid and N
      methyl-D-aspartate receptor subunits in the vestibular and spiral ganglia of the
      mouse during early development.
AB  - We investigated the distribution of the glutamate receptor subunits, alpha-amino
      3-hydroxy-5-methyl-4 isoazolepropionic acid (AMPA) GluR2 and GluR2/R3, and N
      methyl-D-aspartate (NMDA) NR1, and the timing of their appearance during early
      development of the mouse vestibular and spiral ganglia. NMDA NR1 was the first to
      be expressed, in the statoacoustic ganglion neurons on E11. GluR2/R3
      immunoreactivity was detected in these neurons on E12. This signal probably
      corresponded exclusively to GluR3, as no signal was obtained for GluR2 alone at
      this stage. The appearance of these proteins began much earlier than previously
      reported. GluR2 staining was observed later, on E14 in the vestibular neurons and
      on E17 in the spiral neurons. The sequence in which these three glutamate
      receptors appeared suggested possible differences in their roles in the
      establishment of neuronal circuitry in the inner ear sensory epithelia. The
      production of NR1 and GluR2/R3 began during the early period of neuron growth and
      fasciculation. GluR2 appeared later and its expression paralleled synaptogenesis
      in the vestibular sensory epithelia and in the organ of Corti.

PMID- 12414094
TI  - Developmental changes in KCC1, KCC2, and NKCC1 mRNA expressions in the rat brain.
AB  - We investigated the expressions of KCC1, KCC2 and NKCC1 mRNAs in the developing
      rat brain. The neuroepithelium showed abundant KCC1 and NKCC1 mRNA expressions,
      while KCC2 mRNA was not detected there. In contrast, KCC2 mRNA was preferentially
      expressed in postmitotic mature neurons. These results suggest that the
      appearance of KCC2 expression mainly depends on the maturation of individual
      neurons.

PMID- 12414095
TI  - Postnatal development of synaptic inputs to rat masseter motoneurons.
AB  - We examined postnatal changes in rat masseter motoneuron morphology and the
      density of synaptic inputs to masseter motoneurons using retrograde labeling
      combined with synaptophysin immunohistochemistry. The cross-sectional area and
      perimeter of masseter motoneurons increased through P21 whereas synaptic input
      density increased throughout the time frame sampled. Data suggest that changes in
      masseter motoneuron morphology and the density of its synaptic input contribute
      to the maturation of mastication behavior.

PMID- 12414096
TI  - Nicotinic acetylcholine receptors on NT2 precursor cells and hNT (NT2-N) neurons.
AB  - This is the first report, to our knowledge, of prominent, natural expression of
      nAChR alpha4, alpha6 and alpha9 subunits in a human, neuronally-committed cell
      line. We performed studies with specific reference to the expression of nicotinic
      acetylcholine receptors (nAChR) to further characterize a human, postmitotic,
      transplantable, with a neuronal phenotype, cell line called hNT (also called NT2
      N). hNT cells acquire a distinctive neuronal phenotype upon differentiation from
      their NT2 precursors. Immunocytochemical studies showed that NT2 cells were
      strongly immunopositive for alpha4 or alpha7 subunits, moderately immunopositive
      for alpha3/alpha5 subunits, and weakly immunopositive for beta2 or beta4
      subunits, whereas hNT neurons showed positive, strong-to-moderate immunostaining
      for all of these nAChR subunits. Reverse transcription-polymerase chain reaction
      (RT-PCR) mRNA analyses indicated that levels of alpha7 subunit messages were
      similar in both NT2 and hNT cells, whereas alpha2, alpha10, and beta3 subunit
      transcripts were not detected. Levels of alpha3, alpha5, and beta4 subunit
      messages were lower in hNT neurons than in NT2 precursors. However, alpha4 and
      beta2 subunit messages were present in NT2 precursors but were greatly induced in
      hNT neurons. Levels of alpha6 and alpha9 subunit messages, not detectable in NT2
      precursors, rose to high levels in hNT neurons. hNT cell nAChR subunit message
      levels were comparable to (alpha4, alpha5, beta4) or higher than (alpha6, alpha9,
      beta2) levels in adult human brain. NT2 and hNT cells may provide an excellent
      model for studies of neurogenesis, roles played by nAChR in differentiation and
      neurodegeneration, and effects of neuronal differentiation on nAChR expression.

PMID- 12414097
TI  - Developmental mRNA expression of the alpha10 nicotinic acetylcholine receptor
      subunit in the rat cochlea.
AB  - A recently discovered alpha10 subunit of the nicotinic acetylcholine receptor
      (nAChR) family is believed to form a heteromeric receptor with the alpha9 nAChR
      subunit in auditory hair cells. In the present study, the alpha10 nAChR subunit
      expression in the developing and adult rat inner ear was analyzed by PCR and
      localized using isotopic in situ hybridization. Unlike the alpha9 subunit, the
      alpha10 subunit was not detected at embryonic day 18 (E18). From E21 through
      postnatal day 15 (P15), the alpha10 subunit was localized over both inner hair
      cell (IHC) and outer hair cell (OHC) regions, but in the mature cochlea
      detectable levels of alpha10 mRNA were found only over the OHC region. From E21
      through adult ages, there was also a small but consistent basal to apical
      gradient of alpha10 expression; that is, higher levels in basal regions and lower
      levels in apical regions. Previously, we detected the alpha9 nAChR subunit over
      IHCs as early as E18 and throughout adult ages with a clear basal-apical gradient
      of expression. Our studies raise the question of whether the alpha9 and alpha10
      subunits are differentially regulated during embryonic and postnatal development.

PMID- 12414098
TI  - Valproate prevents the induction and the expression of MK-801 sensitization.
AB  - Repeated administration of psychostimulants such as amphetamine, cocaine, and
      methylphenidate has been shown to induce behavioral sensitization. Sodium
      valproate, an anticonvulsant agent that enhances GABA activity, and dizocilpine
      (MK-801), a non-competitive NMDA receptor antagonist, can block the sensitization
      elicited by psychostimulants. MK-801 also has been demonstrated to sensitize to
      itself. The objective of the present study was to determine whether valproate
      disrupts the behavioral sensitization elicited by MK-801. Male Sprague-Dawley
      rats were given a regimen of repeated MK-801 injections (0.3 mg/kg, i.p.) that
      produced behavioral sensitization. They were also given valproate, at a dosage
      (50 mg/kg, i.p.) that prevented behavioral sensitization to stimulants, either
      during or after multiple MK-801 injections. After the washout period, animals
      were then re-challenged with MK-801 to determine whether valproate disrupted the
      behavioral sensitization elicited by MK-801. An activity monitoring system
      recorded horizontal activity, total distance, and vertical activity of the
      animals following drug treatment. Results of their locomotor responses
      demonstrated that valproate disrupted the development/induction and the
      expression of sensitization to MK-801, as it did to methylphenidate.

PMID- 12414099
TI  - Early neonatal 192 IgG saporin induces learning impairments and disrupts cortical
      morphogenesis in rats.
AB  - We have shown previously that neonatal intraventricular injections of the
      selective cholinergic immunotoxin 192 IgG saporin on postnatal day 7 (pnd 7)
      induce marked cholinergic loss in hippocampus and neocortex and a learning
      impairment on pnd 15. In the present study, we analysed the behavioural,
      morphological and neurochemical effects of earlier intraventricular injection of
      the immunotoxin 192 IgG saporin (pnd 1 and 3). We hypothesised that these earlier
      lesions would interrupt a critical stage in neocortical maturation, and impair
      behavior more profoundly than the later lesions. Passive avoidance (PA) learning
      and locomotor activity during the PA test were assessed on pnd 15. Retention of
      the PA task was assessed on pnd 16. Reactivity to spatial and object novelty was
      assessed on pnd 180 in a spatial open field test with five objects. Choline
      acetyltransferase (ChAT) activity was measured in basal forebrain targets on pnd
      20 and pnd 180. Neonatal administration of 192 IgG saporin resulted in a slower
      acquisition of the PA task in females; retention and locomotor activity were not
      affected. On pnd 180, reaction to spatial novelty was mildly impaired in lesioned
      rats of both sexes. There was a marked reduction of ChAT in the hippocampus and
      neocortex of lesioned rats of both sexes, at both ages. Morphological analysis of
      the somatosensory cortex of lesioned rats revealed alterations in cortical
      development with sex specific variations in total cortical thickness. These
      results suggest that interrupting cholinergic basal forebrain innervation of
      neocortex and hippocampus during the first postnatal days affects the development
      of cognitive behaviour, neurochemistry and cortical organisation in a sex
      specific manner. Furthermore, the alterations in cortical organization are more
      profound than those noted after a lesion later in postnatal development. These
      behavioural and morphological abnormalities could be considered a model for
      several neurodevelopmental disorders associated with mental retardation.

PMID- 12414100
TI  - Effects of sex, age, and aggressive traits in man on brain serotonin 5-HT1A
      receptor binding potential measured by PET using [C-11]WAY-100635.
AB  - Serotonin (5-HT) 1A receptors have been implicated in a variety of conditions
      including, depression, suicidal behavior, and aggression. Post-mortem brain
      studies and in vivo imaging studies report a variety of age and sex effects on
      brain 5-HT(1A) binding. Behavioral data from 5-HT(1A) specific pharmacological
      challenges suggest a role for 5-HT(1A) receptors in aggression. The goal of the
      present study was to determine age, sex, and severity of life-time aggression
      effects on 5-HT(1A) binding potential (BP) in vivo using positron emission
      tomography (PET) and the high affinity 5-HT(1A) antagonist, [carbonyl-C-11]WAY
      100635 in 12 healthy females (ages 41.0+/-15.7 years) and 13 healthy males (ages
      39.6+/-15.5 years). Regions of interest included the dorsal raphe, anterior
      cingulate cortex, cingulate body, hippocampus, amygdala, medial prefrontal cortex
      (PFC), and orbital PFC. No significant correlation between age and BP was
      detected in any brain region. MANOVA of the first three principle components
      demonstrated a significantly higher BP in females compared with males (P=0.0127).
      Post-hoc tests confirmed sex differences (P<0.05) in the following regions:
      dorsal raphe, amygdala, anterior cingulate, cingulate body, medial PFC, and
      orbital PFC. The cerebellar volume of distribution was also significantly higher
      in females. There is a significant negative correlation between binding in
      several regions and lifetime aggression. We have replicated our post-mortem
      finding of higher 5-HT(1A) binding in females compared to males. We did not
      detect an age dependent decrease in binding in males or females. Lower 5-HT(1A)
      binding in more aggressive individuals is consistent with pharmacological
      challenge studies. Future studies should determine whether the binding is a state
      or trait effect.

PMID- 12414101
TI  - Cerebral hemodynamics measured with simultaneous PET and near-infrared
      spectroscopy in humans.
AB  - Near-infrared spectroscopy (NIRS) enables continuous non-invasive quantification
      of blood and tissue oxygenation, and may be useful for quantification of cerebral
      blood volume (CBV) changes. In this study, changes in cerebral oxy- and
      deoxyhemoglobin were compared to corresponding changes in CBF and CBV as measured
      by positron emission tomography (PET). Furthermore, the results were compared
      using a physiological model of cerebral oxygenation. In five healthy volunteers
      changes in CBF were induced in a randomized order by hyperventilation or
      inhalation of 6% CO(2). Arterial content of O(2) and CO(2) was measured several
      times during each scanning. Changes in deoxyhemoglobin (deltaHb), oxyhemoglobin
      (deltaHbO(2)) and total hemoglobin (deltaHb(tot)) were continuously recorded with
      NIRS equipment. CBF and CBV was also determined in MRI-coregistered PET-slices in
      regions determined by the placement of the two optodes, as localized from the
      transmission scan. The PET-measurements showed an average CBV of 5.5+/-0.74 ml
      100 g(-1) in normoventilation, with an increase of 29% during hypercapnia,
      whereas no significant changes were seen during hyperventilation. CBF was 51+/-10
      in normoventilation, increased by 37% during 6% CO(2) and decreased by 25% during
      hyperventilation. NIRS showed significant increases in oxygenation during
      hypercapnia, and a trend towards decreases during hyperventilation. Changes in
      CBV measured with both techniques were significantly correlated to CO(2) levels.
      However, deltaCBV(NIRS) was much smaller than deltaCBV(PET), and measured NIRS
      parameters smaller than those predicted from the model. It is concluded that
      while qualitatively correct, NIRS measurements of CBV should be used with caution
      when quantitative results are needed.

PMID- 12414102
TI  - Benzodiazepine receptors in the medial-posterior hypothalamus mediate the
      reduction of hippocampal theta frequency by chlordiazepoxide.
AB  - Separate sub-populations of benzodiazepine receptors are involved in determining
      hippocampal theta frequency in freely moving rats. Systemic injection of the
      benzodiazepine chlordiazepoxide (CDP) reduced the frequency of theta elicited by
      stimulation of the brainstem reticular formation, and theta recorded during fixed
      interval (FI) bar pressing. Infusion of the benzodiazepine receptor antagonist
      flumazenil into the supramammillary nucleus (mSuM) or the posterior hypothalamic
      nucleus (PH) antagonised CDP in both cases. Flumazenil was similarly effective in
      mSuM and PH, suggesting that these nuclei are jointly involved in the coding of
      theta frequency during FI and during high levels of reticular activation.
      However, benzodiazepine receptors in other brain regions probably participate in
      determining the frequency of theta at other times.

PMID- 12414103
TI  - Involvement of 5-HT7 receptors in serotonergic effects on spike afterpotentials
      in presumed jaw-closing motoneurons of rats.
AB  - Intracellular recordings were obtained from rat presumed jaw-closing motoneurons
      in slice preparations to investigate the involvement of the serotonin(7) (5
      HT(7)) receptors in serotonergic inhibition of the postspike medium-duration
      afterhyperpolarization (mAHP) and enhancement of the afterdepolarization (ADP). 5
      HT-induced suppression of the mAHP and enhancement of the ADP were mimicked by
      application of the 5-HT(1A/7) receptor agonist 8-hydroxy-2-(di-n
      propylamino)tetralin (8-OH-DPAT) and antagonized by the 5-HT(2/6/7) receptor
      antagonist clozapine, whereas the 5-HT(2) receptor agonist alpha-methyl-5
      hydroxytryptamine (alpha-methyl-5-HT) did not affect the mAHP and ADP. 8-OH-DPAT
      induced attenuation of the mAHP and enhancement of the ADP were also antagonized
      by clozapine and another 5-HT(2/6/7) receptor antagonist ritanserin, whereas the
      5-HT(1A) receptor antagonist pindolol failed to block the 8-OH-DPAT-induced
      effects on the mAHP and ADP. 8-OH-DPAT-induced suppression of the mAHP and
      enhancement of the ADP were also antagonized by a protein kinase A (PKA)
      inhibitor H89, whereas 8-OH-DPAT could inhibit the mAHP and enhance the ADP in
      the presence of a protein kinase C (PKC) inhibitor chelerythrine. The 8-OH-DPAT
      induced suppression of the mAHP was enhanced under raised [Ca(2+)](o) and this
      enhancement was reduced by chelerythrine. It is suggested that the 5-HT(7)
      receptors are involved in 5-HT-induced attenuation of the mAHP and enhancement of
      the ADP through activation of PKA, and the attenuation of mAHP through the 5
      HT(7) receptors is enhanced under raised [Ca(2+)](o) by PKC activation.

PMID- 12414104
TI  - The role of sub-maximal force production in the enslaving phenomenon.
AB  - When individuals perform a force task involving only one finger, they
      involuntarily move other fingers as well. This phenomenon is referred to as the
      enslaving force or the interdependency of fingers. Given that previous literature
      on the enslaving force has focused on maximal isometric force production, the
      present research was designed to study the role of sub-maximal force production
      in the enslaving phenomenon. To this end, we examined behaviorally three levels
      of force production with a constant rate of force development. We also examined
      the temporal organization of enslaving separating the achievement of the desired
      force (ramp phase) and its maintenance (static phase). During the static phase we
      found: (i) the amount of enslaving increased with the increment of nominal force
      level whether the index, middle, ring or little fingers were used as the master
      finger; (ii) enslaving is strongest in the finger directly adjacent to the master
      finger; and (iii) in terms of enslaving, the index finger was more 'independent'
      than the other three fingers, regardless of nominal force produced, followed by
      the little, middle, and ring fingers. In terms of temporal organization, we found
      that the time-lag of activation of 'slave fingers' during the ramp phase was
      reduced as the amount of force level increased. Overall, our data suggest that
      enslaving effect is a task specific phenomenon and depends on the amount of force
      produced by the master finger.

PMID- 12414105
TI  - Effect of transient hippocampal inhibition on amygdaloid kindled seizures and
      amygdaloid kindling rate.
AB  - In this study the effect of transient inhibition of the CA1 region of the dorsal
      hippocampus by lidocaine on amygdala kindling rate and amygdaloid kindled
      seizures was investigated. In experiment 1, rats were divided into four groups.
      In group 1, animals were implanted only with a tripolar electrode into the
      amygdala but in groups 2-4, two guide cannulae were also implanted into the CA1
      regions of the dorsal hippocampi. Animals were stimulated daily to be kindled. In
      groups 3 and 4, saline or 2% lidocaine (1 microl/2 min) was also injected
      respectively into the hippocampus, 5 min before each stimulation. Results
      obtained showed that amygdala kindling rate and the number of stimulations to
      receive from stage 4 to stage 5 seizure were significantly increased in group 4.
      In experiment 2, lidocaine (1% and 2%) was infused (1 microl/2 min) into the
      hippocampus of amygdala kindled rats bilaterally and animals were stimulated at
      5, 15 and 30 min after drug injection. Twenty four h before lidocaine injection,
      saline was also infused (1 microl/2 min) into the hippocampus as control.
      Obtained results showed that afterdischarge duration was reduced 5 min after
      lidocaine (1% and 2%) injection. Stage 5 seizure duration was also decreased 5
      and 15 min after 2% lidocaine. Thus, it may be suggested that in amygdala
      kindling, activation of the hippocampal CA1 region has a role in seizure
      acquisition and seizure severity so that inhibition of this region results in
      decreasing of seizure severity and retards amygdala kindling rate.

PMID- 12414106
TI  - [125I]Epibatidine-labelled nicotinic receptors in the extended striatum and
      cerebral cortex: lack of association with serotonergic afferents.
AB  - In rat extended striatum, most nicotinic cholinoceptors are likely to be
      presynaptic. A previous report suggested that DA and 5-HT afferents each account
      for at least 30% of nicotinic binding sites in the striatum. To explore this
      question further, rats received unilateral infusions of the neurotoxins 5,7
      dihydroxytryptamine, 6-hydroxydopamine or vehicle into the medial forebrain
      bundle, and were sacrificed 3 weeks later. Denervation was quantified by
      [125I]RTI-55 autoradiography, using separate assay conditions that revealed DA
      and 5-HT transporters (i.e. DAT and SERT). Nicotinic cholinoceptors were
      quantified by [125I]epibatidine autoradiography. Infusion of 6-hydroxydopamine
      depleted DAT but not SERT labelling in all striatal areas (i.e. caudate-putamen,
      nucleus accumbens core and shell, olfactory tubercle). The serotonergic
      neurotoxin 5,7-dihydroxytryptamine depleted SERT and, to a lesser extent, DAT
      labelling. Both neurotoxins reduced [125I]epibatidine binding in striatal areas.
      Multiple linear regression analysis showed that these reductions in
      [125I]epibatidine binding were entirely associated with loss of DAT rather than
      SERT. The DAT-associated proportion of total [125I]epibatidine binding was 36+/
      2% (caudate-putamen), 28+/-3% (accumbens core), 27+/-4% (accumbens shell) and
      44+/-5% (olfactory tubercle). Cortical [125I]epibatidine binding was unaltered by
      5,7-dihydroxytryptamine lesions that reduced SERT labelling by 46 to 73%. In all
      brain areas, even small (3.4 to 8.8%) SERT-associated reductions in
      [125I]epibatidine binding would have been detected as statistically significant.
      In conclusion, we report the failure to detect nAChRs on 5-HT terminals in
      extended striatum or cerebral cortex, using a sensitive [125I]epibatidine
      autoradiographic assay.

PMID- 12414107
TI  - Localization of sepiapterin reductase in the human brain.
AB  - Sepiapterin reductase (SPR) is the enzyme that catalyzes the final step of the
      synthesis of tetrahydrobiopterin (BH4), the cofactor for phenylalanine
      hydroxylase, tyrosine hydroxylase (TH), tryptophan hydroxylase, and nitric oxide
      synthase (NOS). Although SPR is essential for synthesizing BH4, the distribution
      of SPR in the human brain has not yet been clarified. In the present study, we
      purified recombinant human SPR from cDNA, raised an antibody against human SPR
      (hSPR), and examined the localization of SPR protein and SPR activity. Human
      brain homogenates from the substantia nigra (SN), caudate nucleus (CN), gray and
      white matters of the cerebral cortex (CTX), and dorsal and ventral parts of the
      medulla oblongata (MO) were subjected to Western blot analysis with anti-hSPR
      antibody or with anti-TH antibody. Whereas TH protein showed a restricted
      localization, being mainly detected in the SN and CN, SPR protein was detected in
      all brain regions examined. SPR activity was relatively high compared with the
      activity of GTP cyclohydrolase I (GCH), the rate-limiting biosynthetic enzyme of
      BH4, and was more widely distributed than GCH activity. Immunohistochemistry
      revealed SPR immunoreactivity in pyramidal neurons in the cerebral CTX, in a
      small number of striatal neurons, and in neurons of the hypothalamic and brain
      stem monoaminergic fields and olivary nucleus. Double-staining
      immunohistochemistry showed that TH and SPR were colocalized in the SN dopamine
      neurons. Localization of SPR immunoreactive neurons corresponded to monoamine or
      NOS neuronal fields, and also to the areas where no monoamine or NOS neurons were
      located. The results indicate that there might be a BH4 biosynthetic pathway
      where GCH is not involved and that SPR might have some yet unidentified
      function(s) in addition to BH4 biosynthesis.

PMID- 12414108
TI  - Histamine H1 receptors in rat dorsal raphe nucleus: pharmacological
      characterisation and linking to increased neuronal activity.
AB  - In this work we studied the presence of histamine H(1) receptors in the rat
      dorsal raphe nucleus (DRN) and the effect of their activation on the activity of
      presumed serotonergic DRN neurones. [(3)H]-Mepyramine bound to DRN membranes with
      best-fit values of 107+/-13 fmol/mg protein for maximum binding (B(max)) and
      1.2+/-0.4 nM for the equilibrium dissociation constant (K(d)). In DRN slices
      labelled with [(3)H]-inositol and in the presence of 10 mM LiCl, histamine
      stimulated the accumulation of [(3)H]-inositol phosphates ([(3)H]-IPs) with
      maximum effect 172+/-6% of basal and EC(50) 3.2+/-1.3 microM. [(3)H]-IPs
      accumulation induced by 100 microM histamine (162+/-5% of basal) was markedly,
      but not fully blocked by the selective H(1) antagonist mepyramine (300 nM; 64+/
      6% inhibition). The simultaneous addition of mepyramine and the selective H(2)
      antagonist ranitidine (10 microM) abolished histamine-induced [(3)H]-IPs
      accumulation. The presence of H(2) receptors was confirmed by [(3)H]-tiotidine
      binding and by the determination of histamine-induced [(3)H]-cyclic AMP
      formation. Extracellular single-unit recording in brain stem slices showed that
      the exposure to histamine resulted in a marked increase in the firing rate of DRN
      presumed serotonergic neurones (471+/-10% of basal), that was dependent on the
      concentration of the agonist (EC(50) 4.5+/-0.3 microM). The action of histamine
      was not affected by the H(2) antagonist tiotidine (2 microM) but was fully
      prevented by 1 microM mepyramine. Taken together, our results indicate that
      histamine modulates the firing of DRN presumed serotonergic neurones through the
      activation of H(1) receptors coupled to phosphonositide hydrolysis.

PMID- 12414109
TI  - Effects of the calcium antagonist nifedipine on the afferent impulse activity of
      isolated cat muscle spindles.
AB  - The impulse activity of muscle spindles isolated from the cat tenuissimus muscle
      was investigated under varying concentrations of the L-type calcium channel
      blocker nifedipine. At a concentration of 25 microM nifedipine impulse activity
      was clearly diminished in both primary and secondary endings. However, low
      concentrations of the drug (5-10 microM) exerted unexpected excitatory effects.
      The dynamic properties of primary endings in particular were augmented; those of
      secondary endings were also increased, although only slightly. A detailed
      analysis of the afferent discharge patterns obtained under ramp-and-hold
      stretches yielded the following effects of 10 microM nifedipine. (1) The initial
      burst at the beginning of the ramp phase of a stretch was increased in primary
      endings; (2) the peak dynamic discharge frequency at the end of the ramp phase
      was considerably increased in most primary endings; (3) the sensitivity of the
      peak dynamic discharge value to varying amplitudes and velocities of stretch was
      significantly enhanced in primary endings, and also increased, although only
      slightly, in secondary endings; (4) the rise in the discharge frequency during
      the ramp phase of a stretch was augmented in both types of ending, the effect
      being again stronger in primary endings; (5) the fast adaptive decay of the
      impulse frequency following the ramp phase of a ramp-and-hold stretch was
      significantly increased in primary endings, but remained unaffected in secondary
      endings. The enhanced dynamic properties of primary endings were also observed
      under small sinusoidal stretch stimuli (10 microm, 40 Hz), where nifedipine
      induced a significant shift in the position of the 1:1 driven action potentials
      toward smaller phase values. In view of an increase in tension in the isolated
      muscle spindle and an increased initial burst in primary endings in the presence
      of nifedipine, it is suggested that the drug facilitates the attachment of cross
      bridges in the poles of the intrafusal muscle fibers. The increase in the dynamic
      properties of primary endings points to the possibility that the drug
      preferentially affects the nuclear bag(1) fiber. The inhibitory effect on the
      afferent discharge rate at high doses of the drug is interpreted as the
      consequence of a calcium channel block in the membranes of the sensory endings.
      The membrane potential of sensory endings appears to be highly dependent on
      sustained Ca(2+) conductance.

PMID- 12414110
TI  - Delayed kindling epileptogenesis and increased neurogenesis in adult rats housed
      in an enriched environment.
AB  - Environmental risk factors such as stressful experiences have long been
      recognized to affect seizure susceptibility, but little attention has been paid
      to the potential effects of improving housing conditions. In this study, we
      investigated the influence of an enriched environment on epileptogenesis.
      Epileptic susceptibility was assessed in animals housed in an enriched
      environment either before and during (group I) or only during (group II) a
      kindling procedure and in animals placed in isolated conditions (group III). The
      kindling paradigm provides a reliable assessment of the capacity to develop
      seizures following repeated daily low-frequency electrical stimulations. As both
      enriched environment and seizures are known to interfere with hippocampal
      neurogenesis, the number of newly generated dentate cells was assessed before and
      after the kindling procedure to investigate in more detail the relationship
      between epileptogenesis and neurogenesis. We found that susceptibility to
      developing epilepsy differed in animals housed in complex enriched environments
      and in those housed in isolated conditions. Kindling epileptogenesis occurred
      significantly later in animals housed in enriched conditions throughout the
      procedure (group I) than in animals from groups II and III. We also demonstrated
      that cells generated during kindling survived for at least 42 days and that these
      cells were more numerous on both sides of the brain following environmental
      enrichment than in rats housed in isolated conditions. As similar values were
      obtained regardless of the duration of the period of enrichment, these cellular
      changes may not play a major role in delaying kindling development. We suggest
      that the increase response in neurogenesis following seizures may be an
      adaptative rather an epileptogenic response.

PMID- 12414111
TI  - Neuronal differentiation of adult rat hippocampus-derived neural stem cells
      transplanted into embryonic rat explanted retinas with retinoic acid
      pretreatment.
AB  - The purpose of this study was to evaluate the effects of the retinal environment
      and retinoic acid (RA) pretreatment on the differentiation of transplanted adult
      rat hippocampus-derived neural stem cells (AHSCs). AHSCs were transplanted into
      embryonic (E18) or neonatal (P6) rat retinal explants and the mixture was
      cultured for 2 weeks. Other AHSCs were stimulated by 0.5 microM all-trans RA for
      6 days before transplantation. Immunofluorescent double staining showed that a
      larger number of AHSCs became beta-tubulin III-positive neurons in the E18 than
      in P6 retinas. In addition, many AHSCs became MAP2ab-positive and MAP5-positive
      neurons following RA pretreatment and transplantation. Only a few AHSCs became
      HPC-1-, calbindin-, PKC- or rhodopsin-positive cells under these conditions. We
      conclude that the microenvironment supplied by embryonic retinas is conductive to
      neuronal differentiation in general. RA stimulation before transplantation was
      also effective in stimulating differentiation.

PMID- 12414112
TI  - Acute hypoxic hypoxia alters GABA(A) receptor modulation by allopregnanolone and
      pentobarbital in embryonic chick optic lobe.
AB  - Using a previously developed model of acute normobaric hypoxic hypoxia on chick
      embryos, here we studied at embryonic day 12 the in vitro effect of two positive
      allosteric modulators of GABA binding, the barbiturate sodium pentobarbital and
      the neurosteroid allopregnanolone. In both cases an increase in E(max) values in
      membranes obtained from hypoxic embryos was observed. Studies of GABA-gated
      chloride influx showed that there were no differences in maximal chloride uptake
      between hypoxic and control membranes. We have already demonstrated that maximal
      density of GABA binding sites was decreased after hypoxia, suggesting that each
      of the remaining GABA(A) receptors display a greater chloride flux than controls.
      To further characterize GABA(A) receptor alterations, GABA-gated chloride influx
      modulated by the above barbiturate and neurosteroid was determined, finding that
      E(max) values were increased 60% and 42%, respectively. The increase in Cl(-)
      influx per receptor subsequent to hypoxic trauma, and the enhancement in the
      modulatory properties studied, may mediate neuronal damage by potential changes
      in subunit interaction at the GABA(A) receptor level.

PMID- 12414113
TI  - Neurotoxic effects of the human immunodeficiency virus type-1 transcription
      factor Tat require function of a polyamine sensitive-site on the N-methyl-D
      aspartate receptor.
AB  - Human immunodeficiency virus type-I (HIV-1) infection is often associated with
      neuronal loss in cortical and subcortical regions that may manifest as motor
      dysfunction and dementia. The function of the HIV-1 transcription protein Tat and
      subsequent activation of N-methyl-D-aspartate receptors (NMDAr) have been
      implicated in this form of neurodegeneration. However, it is unclear if Tat
      interacts directly with the NMDAr and the role of specific NMDAr subunit
      composition in mediating effects of Tat is also unclear. The present studies
      examined the ability of HIV-1 Tat1-72 protein (10 pM-1.0 microM) to displace
      [3H]MK-801 binding and to attenuate spermidine-induced potentiation of this
      binding in rat brain homogenate comprised of cerebellum, hippocampus, and
      cerebral cortex. The role of NMDAr polyamine-site function in the neurotoxic
      effects of Tat was determined using organotypic hippocampal slice cultures.
      Binding of [3H]MK-801 in adult rat brain homogenate was not reduced by Tat at
      concentrations below 1 microM. Tat potently inhibited the potentiation of [3H]MK
      801 binding produced by co-exposure of membranes to the NMDAr co-agonist
      spermidine (IC(50)=3.74 nM). In hippocampal explants, Tat produced neurotoxicity
      in the CA3 and CA1 pyramidal cell layers, as well as in the dentate gyrus, that
      was significantly reduced by co-exposure to MK-801 (20 microM) and the NMDAr
      polyamine-site antagonist arcaine (10 microM). Exposure to the HIV-1 Tat deletion
      mutant (Tatdelta31-61) did not produce neurotoxicity in hippocampal explants.
      These data suggest that the neurotoxic effects of HIV-1 Tat are mediated, in
      part, by direct interactions with a polyamine-sensitive site on the NMDAr that
      positively modulates the function of this receptor.

PMID- 12414114
TI  - Induction of homosynaptic long-term depression in entorhinal cortex.
AB  - Prolonged low frequency stimulation (1 Hz, 15 min) induced significant long-term
      depression (LTD) in hippocampal CA1 region and superficial, but not deep, layers
      of rat medial entorhinal cortex (EC) in vitro. In the presence of D-AP5,
      significant LTD was induced in EC superficial layers, but not in CA1 or EC deep
      layers. These results show differences in characteristics of LTD induction across
      CA1, EC superficial layers, and EC deep layers.

PMID- 12414115
TI  - Blood-brain barrier integrity is unaltered in human brain cortex with diabetes
      mellitus.
AB  - Diabetes-related cognitive dysfunction has been recognized for many years in
      humans, but the pathogenesis of this condition is poorly understood. Evidence
      from animal studies suggests that altered function of the blood-brain barrier
      (BBB) could be a potential cause contributing to this disease. This study aimed
      to investigate whether the permeability of the BBB is affected in the brains of
      persons with diabetes mellitus (DM). On postmortem prefrontal and temporal cortex
      of diabetic patients and controls, immunohistochemical stainings were carried out
      using specific antibodies against three proteins (PAL-E, IgG and albumin), which
      are considered as markers for the vascular permeability status of the BBB. Rare
      or no PAL-E staining was found in the capillaries of the prefrontal and temporal
      cortex parenchyma, in both DM and control materials. IgG and albumin were
      localized in and directly around blood vessel walls in the prefrontal and
      temporal cortex. No obvious differences in the staining pattern of IgG and
      albumin were observed between brain samples of persons with DM and controls. This
      study suggests that the BBB in diabetic patients is well maintained.

PMID- 12414116
TI  - Enhanced phosphorylation of PTEN in rat brain after transient middle cerebral
      artery occlusion.
AB  - A phosphatase PTEN (phosphatase and tensin homologue deleted on chromosome 10) is
      a tumor suppressor gene that suppresses cell growth, inhibits cell migration, and
      induces apoptosis. Phosphorylated form of PTEN (p-PTEN) is a key survival factor
      relating PI3K-Akt pathway and their downstream effectors. A spatiotemporal
      profiles of PTEN and p-PTEN expression were immunohistochemically examined after
      90 min of transient middle cerebral artery occlusion in rats. In the ischemic
      core, PTEN progressively decreased by 3 days, whereas a rapid but transient
      increase of p-PTEN was found with a peak at 1 h after the reperfusion. In
      contrast, in the ischemic penumbra, PTEN showed a minor change and a gradual but
      sustained p-PTEN expression was observed in the ischemic penumbra with a peak at
      12 h. In addition, the balance of population among strongly, moderately, and
      weakly stained cells was different between the ischemic core and penumbra at
      their peak time points. These results suggest an important role of p-PTEN for
      cell survival after ischemia as an upstream regulator for PI3K-Akt.

PMID- 12414117
TI  - Tacrine attenuates hydrogen peroxide-induced apoptosis by regulating expression
      of apoptosis-related genes in rat PC12 cells.
AB  - The present studies investigated the effects of tacrine, a selective
      acetylcholinesterase (AChE) inhibitor and promising anti-dementia agent, on
      hydrogen peroxide (H(2)O(2))-induced apoptosis and the expression of apoptosis
      related genes in rat pheochromocytoma line PC12 cells. Transient exposure of the
      cells to H(2)O(2) (100 microM) triggered typical apoptosis as evidenced by
      chromatin condensation, nuclei fragmentation and DNA laddering. RT-PCR studies
      showed upregulated p53 and bax mRNA levels with H(2)O(2) treatment. The results
      were further confirmed at protein levels by immunocytochemistry with specific
      antibodies. Preincubation with tacrine significantly attenuated H(2)O(2)-induced
      injury, prevented the cells from apoptosis and attenuated H(2)O(2)-induced
      overexpression of bax and p53. The present findings suggest that tacrine exert
      significant protection against H(2)O(2)-induced apoptosis possibly through
      inhibiting expression of pro-apoptosis genes.

PMID- 12414118
TI  - Hypoxia induces nitric oxide production in mouse microglia via p38 mitogen
      activated protein kinase pathway.
AB  - In vitro exposure of microglial cells to hypoxia induces cellular activation.
      Also, in vivo studies of glial activation following ischemic hypoxia have shown
      that neuronal cell death is followed by microglial activation. Thus, it is likely
      that toxic inflammatory mediators produced by activated microglial cells under
      hypoxic conditions may exacerbate neuronal injury following cerebral ischemia.
      Nitric oxide (NO), which is known to be produced by activated microglia, may
      participate in this process. In the current work, we sought to determine whether
      and how the production of NO and the expression of inducible NO synthase (iNOS)
      are triggered by hypoxia in microglial cells. Exposure of established microglial
      cell lines as well as primary mouse microglial cultures to mild hypoxia (8 h)
      followed by reoxygenation (24 h) induced the production of NO and TNFalpha,
      indicating that hypoxia could lead to the inflammatory activation of microglia.
      Hypoxic induction of NO was accompanied by iNOS induction. Moreover, hypoxia
      induced the activation of p38 MAPK, but not ERK or JNK/SAPK, in BV-2 mouse
      microglial cells. SB203580, a specific inhibitor of p38 MAPK, blocked the hypoxic
      induction of NO and iNOS. Taken together, our results indicated that hypoxia
      could induce inflammatory activation of microglia, and the hypoxic induction of
      NO production in microglia is mediated through p38 MAPK pathway. Thus, during
      cerebral ischemia, hypoxia may not only directly damage neurons, but may also
      promote neuronal injury indirectly via microglial activation.

PMID- 12414119
TI  - Vanilloid receptor subtype-1 (VR1) is specifically localized to taste papillae.
AB  - Pungent sensation of hot peppers is thought to be mediated by vanilloid receptor
      subtype-1 (VR1), which can be activated by capsaicin, but there is little
      information regarding its histological localization in the tongue. We examined
      the immunohistochemical distribution of VR1 in the rat tongue. Intensely labeled
      VR1-immunoreactive (VR1-IR) fibers were concentrated in the circumvallate,
      foliate, and fungiform papillae, while sparse VR1-IR fibers were scattered
      throughout the tongue. VR1-positive taste-bud cells were not observed. Many VR1
      positive nerve fibers surrounded the furrows of the circumvallate and foliate
      papillae, forming plexuses. Some of these VR1-positive fibers penetrated the
      apical epithelium and the trench wall epithelium, while a few of them entered
      taste buds. These VR1 distribution patterns resembled those of substance P (SP)
      and the calcitonin gene-related peptide (CGRP). Double-labeling experiments
      revealed that most of the VR1-immunoreactivity coexisted with SP- or CGRP
      immunoreactivity in the nerve terminals in the circumvallate and foliate
      papillae. On the other hand, in the fungiform papillae, most of the VR1-IR fibers
      were positive for SP, but fewer were also positive for CGRP. Although VR1
      immunoreactivity was not observed in taste-bud cells, our findings that a large
      number of VR1-IR fibers concentrated in the taste papillae suggest that capsaicin
      easily reaches the VR1 nerve terminals because of its lipophilic nature.

PMID- 12414120
TI  - Expression of inorganic phosphate/vesicular glutamate transporters (BNPI/VGLUT1
      and DNPI/VGLUT2) in the cerebellum and precerebellar nuclei of the rat.
AB  - Expression of inorganic phosphate/vesicular glutamate transporters (BNPI/VGLUT1
      and DNPI/VGLUT2) was studied in the cerebellum and precerebellar nuclei of rats
      using immunohistochemistry and in situ hybridization. DNPI/VGLUT2-stained mossy
      fibers were principally seen in the vermis (lobules I and VIII-X) and flocculus,
      whereas BNPI/VGLUT1-stained mossy fibers were localized throughout the cortex.
      Some vermal and floccular mossy fibers were stained for both transporters. High
      levels of DNPI/VGLUT2 mRNA hybridization signals were demonstrated in many
      neurons throughout the vestibular nuclear complex as well as the lateral
      reticular, external cuneate, inferior olivary and deep cerebellar nuclei.
      Significant BNPI/VGLUT1 mRNA signals were demonstrated in the lateral reticular
      nucleus and vestibular nuclear complex but not in the inferior olivary nucleus,
      indicating that climbing fibers have DNPI/VGLUT2 only. These results show that
      DNPI/VGLUT2 is expressed preferentially to vestibulo-, reticulo- and
      cuneocerebellar neurons, some of which also possess BNPI/VGLUT1, suggesting some
      differential and co-operative functions between DNPI/VGLUT2 and BNPI/VGLUT1 in
      the cerebellum.

PMID- 12414121
TI  - Identification of GFR alpha-2 isoforms in myenteric plexus of postnatal and adult
      rat intestine.
AB  - Glial cell line-derived neurotrophic factor family receptor alpha-2 (GFR alpha-2)
      is a GPI-linked receptor that preferentially binds neurturin (NTN), a member of
      the glial cell line-derived neurotrophic factor (GDNF) family. Three splice
      isoforms of GFR alpha-2 have been identified previously in mouse tissues, but the
      occurrence of splice isoforms in rats has not been described. The aim of this
      study was therefore to identify GFR alpha-2 splice isoforms in rat tissues using
      reverse transcription-polymerase chain reaction (RT-PCR) and gene cloning. Three
      isoforms were identified and sequenced, and named GFR alpha-2(a), (b) and (c),
      according to the nomenclature used for the previously identified mouse isoforms.
      The GFR alpha-2(a) and (b) isoforms were identical to those previously described
      in mice. The GFR alpha-2(c) isoform was novel. Sequences for GFR alpha-2(b) and
      (c) were deposited in the GenBank database (accession numbers GI: 16797788 and
      16797786, respectively). All three isoforms were expressed in the brain, kidney,
      and intestine of both postnatal and adult rats.

PMID- 12414122
TI  - Kainic acid induces leukemia inhibitory factor mRNA expression in the rat brain:
      differences in the time course of mRNA expression between the dentate gyrus and
      hippocampal CA1/CA3 subfields.
AB  - Leukemia inhibitory factor (LIF) is a pluripotent cytokine which affects the
      survival and differentiation of various types of cells both in the hematopoietic
      and nervous systems. In this study, the time course and localization of LIF mRNA
      expression following kainic acid-induced seizures were examined by northern blot
      analyses and in situ hybridization. Northern blot analyses demonstrated that
      intraperitoneal injection of kainic acid at a convulsive dose induced LIF mRNA
      expression intensely in the hippocampus and moderately to weakly in the cerebral
      cortex, thalamus and hypothalamus. The expression peaked at 8-24 h after the
      injection in the hippocampus and cerebral cortex and at 8 h in the thalamus and
      hypothalamus. In situ hybridization revealed different time courses of LIF mRNA
      expression depending on the area of the hippocampus; that is, the expression
      peaked at 10 h in the granule cell layer of the dentate gyrus, then at 12 h in
      the polymorph and molecular layers of the dentate gyrus, and finally at 12-24 h
      in the strata oriens and radiatum of the CA1 and CA3 subfields. It is worth
      noting that the expression of LIF mRNA was intense in the dentate gyrus, the
      region where neurogenesis and aberrant network reorganization have been shown to
      be induced by seizures. The upregulation of LIF mRNA expression in the dentate
      granule cell layer followed by that in the dentate polymorph and molecular layers
      may be involved in activity-dependent neurogenesis in the granule cell layer and
      ectopic migration of granule cells to the polymorph and molecular layers in the
      dentate gyrus.

PMID- 12414123
TI  - Neural membrane protein 35/Lifeguard is localized at postsynaptic sites and in
      dendrites.
AB  - We have previously identified and characterized a cDNA coding for neural membrane
      protein 35 (NMP35). We showed that NMP35 mRNA is predominantly expressed in the
      adult CNS with a neuronal expression pattern. Functional analysis indicates that
      the human homologue of NMP35, Lifeguard, plays a role in Fas-mediated cell death.
      In this study we used affinity-purified antibodies raised against the putative
      cytoplasmic N-terminal domain of NMP35 to determine its precise subcellular
      localization in the adult CNS. NMP35 protein is widely expressed throughout the
      brain and spinal cord, most prominently in dendrites of several neuronal cell
      types and in the surrounding neuropil. Immunofluorescence confocal microscopy
      reveals colocalization of NMP35 with the glutamate receptor GluR2 and adjacent
      localization to the presynaptic vesicle protein synaptophysin. These data suggest
      that NMP35 may be localized to the postsynaptic membrane. Immunoelectron
      microscopy with NMP35 antibodies confirms the expression of the protein in
      dendritic processes and in a subset of synapses at the postsynaptic membrane and
      density. These findings suggest a role for NMP35 in synapses of the adult central
      nervous system.

PMID- 12414124
TI  - Induction of TGF-beta-inducible gene-h3 (betaig-h3) by TGF-beta1 in astrocytes:
      implications for astrocyte response to brain injury.
AB  - Transforming growth factor (TGF)-beta-inducible gene-h3 (betaig-h3) product is a
      secreted protein that is induced by TGF-beta in several cell types and implicated
      in various tissue pathologies. The aims of this study were to determine the
      effect of TGF-beta1 on betaig-h3 expression in cultured astrocytes and to examine
      whether betaig-h3 is expressed in the brain after traumatic injury. The results
      showed that betaig-h3 mRNA and protein increased in response to TGF-beta1 in U87
      human astrocytoma cells and mouse cortical astrocytes. Treatment with other
      cytokines, including tumor necrosis factor-alpha and fibroblast growth factor-2,
      did not enhance the expression of betaig-h3 in astrocytes. betaig-h3 was
      significantly expressed in reactive astrocytes at the site of a stab wound in the
      cerebral cortex of adult rats. These results provide an insight into
      understanding a novel role for betaig-h3 protein in the response of astrocytes to
      brain injury.

PMID- 12414125
TI  - Cloning of rat ARHGAP4/C1, a RhoGAP family member expressed in the nervous system
      that colocalizes with the Golgi complex and microtubules.
AB  - The Rho GTPase family of intracellular molecular switches control multiple
      cellular functions via the regulation of the actin cytoskeleton. Increasing
      evidence implicates a critical involvement of these molecules in the nervous
      system, particularly during neuronal migration and polarity, axon and growth cone
      guidance, dendritic arborization and synaptic formation. However, the molecules
      regulating Rho GTPase activities in the nervous system are less known. Here, we
      present the cloning of rat ARHGAP4, a member of the Rho GTPase activating protein
      family, and also demonstrate its close linkage to the vasopressin 2 receptor
      gene. In vitro, recombinant ARHGAP4 stimulated the GTPase activity of three
      members of Rho GTPases, Rac1, Cdc42 and RhoA. ARHGAP4 mRNA expression was
      observed in multiple tissues with marked expression throughout the developing and
      adult nervous systems. On closer analysis of protein levels, ARHGAP4 was
      significantly restricted to specific regions in the nervous system. These
      included the stratum lucidem in the CA3 area of the hippocampus, neuronal fibers
      in the ventral region of the brainstem and striatum, and in the cerebellar
      granule cells. Subcellularly, endogenous ARHGAP4 expression localized to the
      Golgi complex and could redistribute to the microtubules, for example during
      mitosis. In addition, distinct protein expression was observed in the tips of
      differentiating neurites of PC12 cells. Collectively, these results demonstrate
      that ARHGAP4 is more widely expressed than previously thought but potentially
      possesses specialized activity in regulating members of the Rho GTPase family in
      specific cellular compartments of the nervous system.

PMID- 12414126
TI  - Synergistic interaction of estradiol and insulin-like growth factor-I in the
      activation of PI3K/Akt signaling in the adult rat hypothalamus.
AB  - Estradiol and insulin-like growth factor-I (IGF-I) interact in the hypothalamus
      to regulate neuronal function, synaptic plasticity and neuroendocrine events.
      However, the molecular mechanisms involved in these interactions are still
      unknown. In the present study, the effect of estradiol on the signaling pathways
      of IGF-I receptor has been assessed in the hypothalamus of young adult
      ovariectomized rats, using specific antibodies for the phosphorylated forms of
      extracellular-signal regulated kinase (ERK) 1 and ERK2 and Akt/protein kinase B
      (Akt/PKB). Estradiol treatment resulted, between 6 and 24 h after systemic
      administration, in dose-dependent effects on the phosphorylation of ERK and
      Akt/PKB. Estradiol did not modify the level of ERK phosphorylation induced by
      intracerebroventricular administration of IGF-I. However, both hormones had a
      synergistic effect on the phosphorylation of Akt/PKB. These findings suggest that
      estrogen effects in the hypothalamus may be mediated in part by the activation of
      the signaling pathways of the IGF-I receptor.

PMID- 12414128
TI  - A short history of brucellosis.

PMID- 12414129
TI  - The Animal and Plant Health Inspection Service (APHIS) brucellosis eradication
      program in the United States.
AB  - Efforts to eradicate brucellosis caused by Brucella abortus in the United States
      began in 1934 as part of an economic recovery program to reduce the cattle
      population because of the Great Depression and concurrent severe drought
      conditions. A number of states saw this as an opportunity to reduce the level of
      brucellosis, which was the most significant livestock disease problem in the US
      at the time. In 1934 and 1935, the reactor rate in adult cattle tested was 11.5%.
      In 1954, the magnitude of the brucellosis problem in the United States in terms
      of economics to the cattle industry and human health prompted Congress to
      appropriate funds for a comprehensive national effort to eradicate brucellosis.
      The brucellosis eradication program was designed as a cooperative effort between
      the federal government, the states, and livestock producers. As the science and
      technology of brucellosis has developed over the years through research and
      experience, the eradication program has been modified many times. As of 31
      December 2000, there were no affected cattle herds in the United States. This was
      the first time in the history of the brucellosis program that the United States
      had no known brucellosis affected herds. However, brucellosis has a variable,
      sometimes quite lengthy incubation period, so it is expected that additional
      affected herds will be disclosed. It is likely that additional affected herds
      will be disclosed before brucellosis is finally eradicated from cattle. Animal
      health officials remain prepared to aggressively pursue any newly disclosed
      affected herds to eliminate the disease as quickly as possible. The State-Federal
      Brucellosis Eradication Program has made tremendous progress since its inception.
      In an eradication program, it is critically important to recognize that, despite
      all the tools that are available to eliminate the disease, an effective
      surveillance system is the critical first step that must be in place in order to
      be successful. It is imperative, not only to be able to find the disease and
      eliminate it, but to find it before it spreads to susceptible herds. When
      brucellosis can be identified, contained, and eliminated before spread occurs,
      eradication can be achieved.

PMID- 12414130
TI  - Brucellosis in Mexico: current status and trends.
AB  - Traditionally, Mexico has been recognized as endemic with brucellosis. The
      improvements in diagnostics techniques and vaccination strategies and the
      enforcement of a national eradication policy have contributed significantly to
      making progress in the control of brucellosis. The current status of brucellosis
      and its risk factors, in the different production species as well as in human
      population is reviewed. Also the trends in control and eventual eradication
      strategies and perspectives for the near future of Mexico are presented.

PMID- 12414131
TI  - Brucellosis in Central America.
AB  - Brucellosis is a disease of domestic animals and humans in Central America (CA).
      Bovine and swine brucellosis caused by Brucella abortus and Brucella suis,
      respectively, have been identified in all CA countries, while ovine and caprine
      brucellosis caused by Brucella melitensis has been detected in Guatemala. The
      prevalence of bovine brucellosis is estimated between 4 and 8%, with higher
      prevalence in dairy herds, with losses calculated at 25 million US dollars per
      year. National Control Programs based in calf vaccination and removal of the
      reactors have had little impact in the control of brucellosis in CA. In a region
      where experimentation with new vaccines is not affordable, unrestricted adult
      vaccination by the conjunctival route with S19 is recommended. This strategy is
      expected to reduce the prevalence and density of the bacteria to numbers where
      "clean" vaccination would be possible. Thereafter, serological identification and
      elimination of the reactors could be initiated under more favorable conditions of
      herd infection.

PMID- 12414132
TI  - Brucellosis in Venezuela.
AB  - Brucellosis is a public health problem in Venezuela and affects large numbers of
      animals. The most important biovar in the country is Brucella abortus. In cattle
      and buffalo it causes high rates of abortions in females and infertility in
      males; it is transmissible to occupationally exposed humans. In 1968, an official
      program was set up for the control and eradication of the disease and it is still
      in place. Amongst the control provisions, this program provides for the
      vaccination of female calves with strain 19 and the slaughtering of positive
      reactors following the official diagnosis (rapid agglutination in plate test).
      According to the official reports, the positive reactors ranged from 0.8 to 1.2%
      in the past few years. These values do not corroborate reports showing an average
      positive rate of 10.5% and even higher values in some areas of the country. The
      government is working to approve a new resolution that will replace the rapid
      agglutination in plate test with the Card Test, the use of 2-Mercaptoetanol,
      fixation of complement and competitive ELISA as confirmatory tests. In addition,
      there will be an obligatory vaccination with B. abortus strain 19 or B. abortus
      RB51 of all female calves between 3- and 8-month-old and a recommended
      revaccination at 10-15-month-old and adult cows in high prevalence areas. These
      measures should allow help to reduce the prevalence of the disease in cattle
      herds and thus minimize the risk for human populations.

PMID- 12414133
TI  - Eradication of bovine brucellosis in the 10th Region de Los Lagos, Chile.
AB  - The process of Bovine Brucellosis Eradication that began in 1996 in the 10th
      Region de Los Lagos of Chile will be reviewed. The region comprises the most
      important dairy area of the country and it has the largest concentration of
      brucellosis infected herds. Based on the information gathered by an
      epidemiological surveillance system, the results of the eradication process for
      the years 1996 till 2001 are presented as rates of Milk Ring Test (MRT) positive
      dairies, rates of brucellosis reactors (bovines) in livestock markets and
      slaughterhouses, and the annual incidence and prevalence of brucellosis infected
      herds. During the period the rates of positive dairies, bovine reactors in
      livestock markets and slaughterhouses, and the annual incidence and prevalence of
      infected herds have experienced a decrease, while the rate of bovine reactors in
      slaughterhouses has remained stable. Data on the preventive measures taken, such
      as vaccination of female bovines and Certification of Brucellosis Free Herds, are
      also shown. The surveillance system has allowed the detection of infected herds,
      while the measures of prevention and cleaning of infected herds have allowed a
      reduction in the incidence and prevalence of the infection by Brucella abortus.

PMID- 12414134
TI  - Brucellosis in Brazil.
AB  - This paper reviews the epidemiology of bovine, swine, ovine, caprine, and canine
      brucellosis in Brazil. The zoonotic aspects of Brucella infection in Brazil is
      also discussed. Emphasis is given to the new program for the control of
      brucellosis in cattle and buffaloes that is likely to provide important insights
      into the prospects and strategies for controlling brucellosis in developing
      countries.

PMID- 12414135
TI  - Brucellosis: a short review of the disease situation in Paraguay.
AB  - A short review of the brucellosis situation, its control and eradication programs
      are presented. Data from over 1.2 million samples collected from more than 50,718
      groups of cattle over a period of over 20 years (1979-2000) illustrates that over
      the last few years the number of individual reactors remain constant at around 3
      4%. The percentage of reactive groups of animals decreased over these years,
      reflecting a better disease management and possibly an improved general
      education, handling of information on the immune (vaccination) status of animals
      and testing practices. Reported zoonotic cases are presented, as well as control
      and eradication programs, including utilization of vaccines.

PMID- 12414136
TI  - Brucellosis in Argentina.
AB  - Brucellosis has been recognized in Argentina since the 19th century. Several
      studies demonstrated the presence of the disease in most of the domestic species.
      Actually, the estimate of prevalence is that between 10 and 13% of the farm
      animals are infected with bovine brucellosis with an individual rate of 4-5%. The
      annual economical losses have been estimated at 60,000,000 US dollars. The
      control of bovine brucellosis began in 1932 and successive resolutions have been
      issued since then. The current resolution indicates that B. abortus S19 is
      mandatory in female calves between 3 and 8 months of age. The vaccine strain B.
      abortus RB51 was provisionally approved but only for cattle older than 10 months
      of age. The brucellosis control program consists principally of test and
      slaughter. This methodology has been successful mainly in the dairy farms that
      have the incentive due to increased pricing because of obtaining a low prevalence
      of the disease. Brucellosis has been found in porcine, caprine, ovine and canine
      species. All Brucella species have been found in the country. Human brucellosis
      is an important disease and a national coordinated diagnostic net has been formed
      to better control the disease in man.

PMID- 12414137
TI  - Incidence and control of brucellosis in the Near East region.
AB  - In countries of the Near East region, brucellosis was reported in almost all
      domestic animals, particularly cattle, sheep and goats. Brucellosis in camels has
      been reported in Saudi Arabia, Kuwait, Oman, Iraq, Iran, Sudan, Egypt, Libya and
      Somalia. It has been reported even in racing camels in the United Arab Emirates.
      In Egypt, brucellosis has been reported also in buffaloes, equines and swine.
      Brucella melitensis biovar 3 is the most commonly isolated species from animals
      in Egypt, Jordan, Israel, Tunisia and Turkey. B. melitensis biovar 2 was reported
      in Turkey and Saudi Arabia, and B. melitensis biovar 1 in Libya, Oman and Israel.
      B. abortus biovar 1 was reported in Egypt, biovar 2 in Iran, biovar 3 in Iran and
      Turkey, and biovar 6 in Sudan. The countries with the highest incidence of human
      brucellosis are Saudi Arabia, Iran, Palestinian Authority, Syria, Jordan and
      Oman. Bahrain is reported to have zero incidence. Most human cases are caused by
      B. melitensis, particularly biovar 3. However, B. abortus has been responsible
      for an increasing number of cases in recent years, e.g. in Yemen, where B.
      abortus was identified in 45 cases and B. melitensis in 7 cases out of 330
      cultures performed in 1995. Concerning control of brucellosis in animals, there
      is a controversy on the choice of policy. In some countries, the test and
      slaughter policy together with the vaccination of young females is adopted, in
      others, particularly with regard to sheep and goats; mass vaccination has been
      recently started. The most commonly used vaccines are B. abortus S19 and B.
      melitensis Rev.1 vaccines. B. abortus RB51 vaccine is used in some countries on
      small scale. Vaccination is limited to cattle and small ruminants.

PMID- 12414138
TI  - Brucellosis in sub-Saharan Africa: epidemiology, control and impact.
AB  - Brucellosis is an important disease among livestock and people in sub-Saharan
      Africa. In general, the incidence is the highest in pastoral production systems
      and decreases as herd size and size of landholding decreases. The prevalence of
      risk factors for infections are best understood for bovine brucellosis and to a
      lesser extent for ovine and caprine brucellosis. The occurrence and epidemiology
      of brucellosis in pigs is poorly understood. This species bias is also reflected
      in control activities. As with other public-sector animal health services, the
      surveillance and control of brucellosis in sub-Saharan Africa is rarely
      implemented outside southern Africa. Brucellosis is even more ignored in humans
      and most cases go undiagnosed and untreated, leading to considerable suffering
      for those affected. Decision-making to determine the importance of brucellosis
      control relative to other public concerns and what brucellosis control strategies
      should be applied is urgently required. A strategy for how brucellosis decision
      making might be considered and applied in future is outlined.

PMID- 12414139
TI  - Brucellosis in the European Union and Norway at the turn of the twenty-first
      century.
AB  - Control and eradication programs of brucellosis in cattle, sheep, goats and pigs
      have been more or less successfully implemented within the Member States (MS) of
      the European Union (EU) and Norway after Word War II. As a result, the
      epidemiological situation of animal brucellosis is extremely diverse among
      different MS or regions within a MS and among the different animal species. Some
      MS, mainly North European countries, and Norway are declared "officially bovine
      brucellosis free" and/or "officially ovine and caprine (Brucella melitensis)
      free". The situation is less favorable in Southern European countries,
      particularly as far as sheep and goat brucellosis are concerned. This situation
      has important zoonotic consequences as reflected in the number of human
      brucellosis cases due to B. melitensis that are still encountered in those
      countries. Brucellosis in swine has re-emerged as a result of spillover from the
      wild boar brucellosis (Brucella suis biovar 2) reservoir, particularly in outdoor
      reared pigs. Besides the actual challenge to eradicate brucellosis, further
      issues have to be addressed: (1) the management of false positive serological
      results that occur in the course of brucellosis testing, particularly in cattle;
      (2) the impact of wildlife brucellosis, particularly wild boar brucellosis in
      domestic animals; and (3) the importance of B. melitensis infection in cattle
      that are in contact with infected sheep.

PMID- 12414140
TI  - An overview of the epidemiology and epizootology of brucellosis in selected
      countries of Central and Southeast Europe.
AB  - The objective of this paper is to give an overview of the epidemiologic and
      epizootic status of brucellosis in selected countries of Central and Southeast
      Europe (Balkan region). Based on dimension of the disease problem, there is a
      need to establish collaboration in the eradication and prevention of brucellosis
      between all countries in the region. Although there were no readily accessible
      data concerning epidemiology and epizootology of brucellosis in these countries,
      the limited official and published data were analyzed. The incidence of
      brucellosis caused by Brucella melitensis in sheep, goats and humans is a very
      significant problem in Macedonia and Greece. In Greece, cattle are also affected
      either by B. melitensis or B. abortus. The disease is an endemic problem in some
      regions of Yugoslavia and includes B. suis biovar 2 in pigs and in Croatia, B.
      melitensis in sheep, goats and human is found occasionally. No problem appears to
      exist with brucellosis in Bulgaria. Financial well-supported brucellosis control
      programs of the European Union that will include all countries, regardless of the
      magnitude of brucellosis incidence, are needed for eradication and control of
      brucellosis.

PMID- 12414141
TI  - An epidemiological and surveillance overview of brucellosis in Romania.
AB  - This article reports epidemiological investigations on the occurrence of
      brucellosis in Romania. Like in other former communist countries, data concerning
      epidemiology of brucellosis and published articles are very few. The epidemiology
      and control of brucellosis in Romania was analyzed using data made available by
      the Office International des Epizooties and Veterinary Service of Romania.
      Romania, like many other developed countries, has eradicated Brucella abortus
      from cattle since 1969. Brucellosis caused by Brucella melitensis has never been
      reported. The incidence of brucellosis in swine and sheep is very rare but still
      there are a few outbreaks in some regions. In 2000, the number of cases was 47 in
      swine and 270 cases in sheep. Vaccination against brucellosis is prohibited in
      Romania.

PMID- 12414142
TI  - Epidemiology and control of brucellosis in China.
AB  - The paper describes the history and evolvement of brucellosis in China. It
      presents the variation of epidemic situation, epidemiological characteristics,
      application of vaccines and control in brief. Before 1980s, human and animal
      brucellosis was quite severe; during 1980s, the incidence of human and animal
      brucellosis was relatively low, and seemed to decrease during the decade. During
      1990s, there were no obvious changes in the incidence of animal brucellosis, but
      the incidence of human brucellosis increased, especially from 1995 to 2001. There
      are not only some common characteristics but also some differences in brucellosis
      epidemiology relative to that reported in the rest of the world. For the entire
      country, B. melitensis was the predominant strain associated with outbreaks, and
      the epidemic peak is from February to June. Several Brucella vaccines have been
      used in China for prevention and control of brucellosis. such as B. abortus 104 M
      in humans, B. suis S2 in animals. The introduction of comprehensive measures has
      allowed great progress in the prevention and control of brucellosis in China.
      Surveillance points were set-up countrywide to estimate the epidemic situation.
      In addition, we discussed the new characteristics of brucellosis in China, the
      influence of the El Nino phenomenon on brucellosis epidemic situation, the
      phenomenon of antigenic interference between Brucella species and some
      disadvantages of live Brucella vaccines.

PMID- 12414143
TI  - Epidemiology, zoonotic aspects, vaccination and control/eradication of
      brucellosis in India.
AB  - In India, brucellosis was first recognised in 1942 and is now endemic throughout
      the country. The disease is reported in cattle, buffalo, sheep, goats, pigs, dogs
      and humans. B. abortus biotype-1 in cattle and buffaloes and B. melitensis
      biotype-1 in sheep, goats and man are the predominant infective biotypes. The
      long-term serological studies have indicated that 5% of cattle and 3% of
      buffaloes are infected with brucellosis. Economic losses due to brucellosis in
      livestock are considerable in an agrarian country like India. There is no
      organised and effective brucellosis control programme in the country. With the
      indigenous development of serum and milk based ELISA kits, the population survey
      of the disease has been undertaken on a large scale in several states and plans
      for the control of the disease through calf-hood vaccination are being worked
      out. An innovative approach--Bovine Brucellosis Progressive Control Programme
      (BBPCP) is targeted to overcome the basic problems of ban on cow slaughter,
      distress sale of animals following the positive serological diagnosis of
      brucellosis and absence of a disease control strategy. The work plan for the
      implementation of BBPCP is presented.

PMID- 12414144
TI  - Incidence of brucellosis in Sri Lanka: an overview.
AB  - Infection by Brucella abortus seems to be a major cause of abortions among cattle
      and buffaloes in Sri Lanka. The incidence of this disease is more prominent among
      the animals in the Dry zone of the country raised under extensive management
      systems. The present low incidence of this disease and the small size of the
      country may facilitate launching of an effective disease control scheme. The milk
      ring test (MRT) has proven to be usable in testing milk for the infection at farm
      level. An ELISA technique could be employed to test the seroprevalence of
      infection among MRT-positive animals. A program to purchase the diseased animals
      by the state for slaughter, and a countrywide vaccination program with B. abortus
      strain RB51 would enable the country's livestock industry to eventually eradicate
      this disease.

PMID- 12414145
TI  - Brucella evolution and taxonomy.
AB  - The genus Brucella contains alpha-Proteobacteria adapted to intracellular life
      within cells of a variety of mammals. Controversy has arisen concerning Brucella
      internal taxonomy, and it has been proposed that the DNA-DNA hybridization-based
      genomospecies concept be applied to the genus. According to this view, only one
      species, Brucella melitensis, should be recognized, and the classical species
      should be considered as biovars (B. melitensis biovar melitensis; B. melitensis
      biovar abortus; etc.). However, a critical reappraisal of the species concept, a
      review of the population structure of bacteria and the analysis of Brucella
      genetic diversity by methods other than DNA-DNA hybridization show that there are
      no scientific grounds to apply the genomospecies concept to this genus. On the
      other hand, an enlarged biological species concept allows the definition of
      Brucella species that are consistent with molecular analyses and support the
      taxonomical standing of most classical species. Both the host range as a long
      recognized biological criterion and the presence of species-specific markers in
      outer membrane protein genes and in other genes show that B. melitensis, B.
      abortus, B. ovis, B. canis and B. neotomae are not mere pathovars (or
      nomenspecies) but biologically meaningful species. The status of B. suis is,
      however, less clear. These approaches should be useful to define species for the
      marine mammal Brucella isolates, as illustrated by the grouping of the isolates
      from pinnipeds or from cetaceans by omp2 gene analysis. It is shown that a
      correct Brucella species definition is important to understand the evolution of
      the genus.

PMID- 12414146
TI  - Major outer membrane proteins of Brucella spp.: past, present and future.
AB  - The major outer membrane proteins (OMPs) of Brucella spp. were initially
      identified in the early 1980s and characterised as potential immunogenic and
      protective antigens. They were classified according to their apparent molecular
      mass as 36-38 kDa OMPs or group 2 porin proteins and 31-34 and 25-27 kDa OMPs
      which belong to the group 3 proteins. The genes encoding the group 2 porin
      proteins were identified in the late 1980s and consist of two genes, omp2a and
      omp2b, which are closely linked in the Brucella genome, and which share a great
      degree of identity (>85%). In the 1990s, two genes were identified coding for the
      group 3 proteins and were named omp25 and omp31. The predicted amino acid
      sequences of omp25 and omp31 share 34% identity. The recent release of the genome
      sequence of B. melitensis 16 M has revealed the presence of five additional gene
      products homologous to Omp25 and Omp31. The use of recombinant protein technology
      and monoclonal antibodies (MAbs) has shown that the major OMPs appear to be of
      little relevance as antigens in smooth (S) B. abortus or B. melitensis infections
      i.e. low or no protective activity in the mouse model of infection and low or no
      immunogenicity during host infection. However, group 3 proteins, in particular
      Omp31, appear as immunodominant antigen in the course of rough (R) B. ovis
      infection in rams and as important protective antigen in the B. ovis mouse model
      of infection. The major OMP genes display diversity and specific markers have
      been identified for Brucella species, biovars, and strains, including the recent
      marine mammal Brucella isolates for which new species names have been proposed.
      Recently, Omp25 has been shown to be involved in virulence of B. melitensis, B.
      abortus and B. ovis. Mutants lacking Omp25 are indeed attenuated in animal models
      of infection, and moreover provide levels of protection similar or better than
      currently used attenuated vaccine strain B. melitensis Rev.1. Therefore, these
      mutant strains appear interesting vaccine candidates for the future. The other
      group 3 proteins identified in the genome merit also further investigation
      related to the development of new vaccines.

PMID- 12414147
TI  - Sugar metabolism by Brucellae.
AB  - The metabolic capabilities of the species of Brucella were originally of interest
      as a means of distinguishing them from each other and from other genera. Certain
      unusual characteristics, especially erythritol utilization, were studied in the
      hopes they would shed light on the pathogenicity. With the advent of modern
      genetic methods and genomic sequencing, it is now possible to get a good idea of
      the total capabilities of the organism and to do tests to confirm these
      deductions. Brucella appears to be a fairly normal member of the alpha
      proteobacteria, but with some differences. A few questions remain, such as
      whether Brucella uses the Entner-Doudoroff pathway. Some of the genes in
      carbohydrate utilization have been shown to be important in virulence.

PMID- 12414148
TI  - The myth of Brucella L-forms and possible involvement of Brucella penicillin
      binding proteins (PBPs) in pathogenicity.
AB  - Brucella spp. L-forms have been proposed to be stationary phase organisms in the
      evolution of new variants and enduring entities in the host in complicated cases
      of brucellosis and during latent brucellosis. In vitro formation of Brucella L
      forms has been achieved by treating the cells with sub-lethal doses of
      penicillin. Interestingly, Brucella spp. have classified during the evolution
      into two groups, penicillin susceptible or penicillin resistant, yet both types
      grow on 20 microg/ml of methicillin. Strains proven susceptible to penicillin
      grew in the presence of methicillin as L-forms as demonstrated by light and
      electron microscopy. In addition, the B. melitensis vaccine strain Rev.1, a
      penicillin susceptible organism, responded to sheep serum by development of L
      form-like structures unlike wild type, strain 16M. The two strains grew normally
      in sheep macrophages. We propose, for the first time, a model that associates
      Brucella pathogenicity with the structure and activity of two of their penicillin
      binding proteins (PBPs). According to the model, PBP1 has evolved as the major
      cell wall synthesizing enzyme of the genus, capable of responding to host serum
      growth factor(s) necessary for Brucella survival in the host. This property is
      associated with high avidity to beta-lactam antibiotics. PBP2 complements the
      activity of PBP1. New beta-lactam antibiotics and improved vaccines might be
      developed based on this property.

PMID- 12414149
TI  - Brucella intracellular life: from invasion to intracellular replication.
AB  - Brucella organisms are pathogens that ultimate goal is to propagate in their
      preferred niche, the cell. Upon cell contact the bacteria is internalized via
      receptor molecules by activating small GTPases of the Rho subfamily and by a
      moderate recruitment of actin filaments. Once inside cells, Brucella localizes in
      early phagosomes, where it avoids fusion with late endosomes and lysosomes. These
      early events require the control of Rab small GTPases, and cytokines such as the
      G-CSF. Then, the bacterium redirects its trafficking to autophagosomes and
      finally reaches the endoplasmic reticulum, where it extensively replicates. Some
      of the bacterial molecular determinants involved in the internalization and early
      events after ingestion are controlled by the BvrS/BvrR two component regulatory
      system, whereas the intracellular trafficking beyond this early compartments are
      controlled by the VirB type IV secretion system. Once inside the endoplasmic
      reticulum, Brucella extensively replicates without restricting basic cellular
      functions or inducing obvious damage to cells. The integrity of Brucella LPS on
      the bacterial surface is one of the required factors for Brucella intracellular
      survival, and therefore for virulence.

PMID- 12414150
TI  - The intramacrophagic environment of Brucella suis and bacterial response.
AB  - Phagocytes have developed various antimicrobial defense mechanisms to eliminate
      pathogens. They comprise the oxidative burst, acidification of phagosomes, or
      fusion of phagosomes with lysosomes. Facultative intracellular bacteria, in
      return, have developed strategies counteracting the host cell defense, resulting
      in intramacrophagic survival. Until lately, only very little was known about the
      phagosomal compartment containing Brucella spp., the environmental conditions the
      bacteria encounter, and the pathogen's stress response. Recently, we have
      determined that the phagosomes acidify rapidly to a pH of 4.0-4.5 following
      infection, but this early acidification is crucial for intracellular replication
      as neutralization results in bacterial elimination. A vacuolar proton-ATPase is
      responsible for this phenomenon that is not linked to phagosome-lysosome fusion.
      On the contrary, in vitro reconstitution assays revealed association only between
      phagosomes containing killed B. suis and lysosomes, describing the absence of
      phagolysosome fusion due to specific recognition inhibition for live bacteria.
      Further evidence for the necessity of an intact, acidic phagosome as a
      predominant niche of brucellae in macrophages was obtained with a strain of B.
      suis secreting listeriolysin. It partially disrupts the phagosomal membranes and
      fails to multiply intracellularly. How does B. suis adapt to this environment? We
      have identified and studied a series of genes that are involved in this process
      of adaptation. The bacterial heat shock protein and chaperone DnaK is induced in
      phagocytes and it is essential for intracellular multiplication. A low-level,
      constitutive expression of dnaK following promoter exchange does not restore
      intramacrophagic survival. Another chaperone and heat shock protein, ClpB,
      belonging to the family of ClpATPases, is important for the resistance of B. suis
      to several in vitro stresses, but does not contribute to intramacrophagic
      survival of the pathogen. Additional bacterial genes specifically induced within
      the phagocyte were identified by an intramacrophagic screen of random promoter
      fusions to the reporter gene gfp. A large majority of these genes are encoding
      proteins involved in transport of nutrients (sugars, amino acids), or cofactors,
      such as nickel. Analysis of the intracellular gene activation reveals that low
      oxygen tension is encountered by B. suis. Altogether, these results suggest three
      major stress conditions encountered by brucellae in the phagosome: acid stress,
      starvation and low oxygen tension.

PMID- 12414151
TI  - Discovery of Brucella virulence mechanisms using mutational analysis.
AB  - This overview is written with the aim of providing an introduction to and
      historical perspective on naturally occurring and experimentally derived Brucella
      mutants. Spontaneous or naturally occurring mutants have proven of value over the
      last century in combating animal brucellosis. The most effective of these, S19,
      Rev-1 and RB51 have been used as vaccines in animals, but have drawbacks that
      have limited their effectiveness in some hosts including humans. The spontaneous
      appearance of these mutants has never been genetically characterized, but is now
      possible with the advent of genome sequencing. However, it is possible that these
      strains contain multiple genetic changes and identifying the relevant defects may
      be exceedingly difficult. Despite early sequencing initiatives Brucella virulence
      remains unresolved and a limited number of molecular systems have been identified
      that specifically enhance growth in host cells, the so-called virulence genes.
      Instead, the Brucella appear to have preserved a plethora of metabolic functions
      from their ancestors that enhance growth and survival in specific or varied
      environments, some of which are even duplicated. Direct and controlled
      mutagenesis of Brucella remains a valuable experimental approach to characterize
      the role of these genes in survival and virulence.

PMID- 12414152
TI  - Fun stories about Brucella: the "furtive nasty bug".
AB  - Although Brucella is responsible for one of the major worldwide zoonosis, our
      understanding of its pathogenesis remains in its infancy. In this paper, we
      summarize some of the research in progress in our laboratory that we think could
      contribute to a better understanding of the Brucella molecular virulence
      mechanisms and their regulation.

PMID- 12414153
TI  - Regulation of Brucella virulence by the two-component system BvrR/BvrS.
AB  - The Brucella BvrR/BvrS two-component regulatory system is highly similar to the
      regulatory and sensory proteins of Sinorhizobium and Agrobacterium necessary for
      endosymbiosis and pathogenicity in plants, and very similar to a putative system
      present in the animal pathogen Bartonella. Mutations in the bvrR or bvrS genes
      hamper the penetration of B. abortus in non-phagocytic cells and impairs
      intracellular trafficking and virulence. In contrast to virulent Brucella,
      BvrR/BvrS mutants do not recruit small GTPases of the Rho subfamily required for
      actin polymerization and penetration to cells. Dysfunction of the BvrR/BvrS
      system alters the outer membrane permeability, the expression of several group 3
      outer membrane proteins and the pattern of lipid A acylation. Constructs of
      virulent B. abortus chimeras containing heterologous LPS from the bvrS(-) mutant
      demonstrated an altered permeability to cationic peptides similar to that of the
      BvrR/BvrS mutants. We hypothesize that the Brucella BvrR/BvrS is a system devoted
      to the homeostasis of the outer membrane and, therefore in the interface for cell
      invasion and mounting the required structures for intracellular parasitism.

PMID- 12414154
TI  - Type IV secretion and Brucella virulence.
AB  - The type IV secretion system, encoded by the virB region, is a key virulence
      factor for Brucella. The 12 genes of the region form an operon that is
      specifically induced by phagosome acidification in cells after phagocytosis. We
      speculate that the system serves to secrete unknown effector molecules, which
      allow Brucella to pervert the host cell endosomal pathways and to create a novel
      intracellular compartment in which it can replicate.

PMID- 12414155
TI  - Seeking a niche: putative contributions of the hfq and bacA gene products to the
      successful adaptation of the brucellae to their intracellular home.
AB  - Long-term residence of the brucellae in the phagosomal compartment of host
      macrophages is essential to their ability to produce disease in both natural and
      experimental hosts. Correspondingly, the Brucella spp. appear to be well adapted
      to resist the multiple environmental stresses they encounter in their
      intracellular home. This brief review will focus on the contributions of the hfq
      and bacA gene products to this adaptation. Studies with Brucella hfq mutants
      suggest that stationary phase physiology is critical for successful long-term
      residence in host macrophages. Analysis of Brucella bacA mutants, on the other
      hand, reveal very striking parallels between the strategies employed by the
      rhizobia to establish and maintain protracted intracellular residence in their
      plant host and those used by the brucellae during their long-term survival in the
      phagosomal compartment of host macrophages.

PMID- 12414156
TI  - Immune response overview.
AB  - A short synopsis of the history of identification of the protective cellular
      immune response to Brucella is given along with indication of the current major
      research focuses in this area. Finally, critical areas of research for the future
      are suggested.

PMID- 12414157
TI  - Fundamentals of host immune response against Brucella abortus: what the mouse
      model has revealed about control of infection.
AB  - The studies reviewed here evaluated the role cellular immune system components
      play in control of brucellosis by conducting comparative studies with brucella
      resistant C57BL/10 or C57BL/6 mice and susceptible BALB/c mice. We have shown by
      both in vitro and in vivo studies that activation of macrophages with interferon
      gamma (IFN-gamma) is an important factor for control of infection with B. abortus
      in the mouse model and that the mechanism of anti-brucella activity largely
      involved reactive oxygen intermediates. Differences in control of the organism by
      resistant and susceptible mice was not related to inherent differences in the
      ability of their macrophages to control infection either with or without IFN
      gamma activation nor was it attributable to NK cells since we found no role for
      them in control of brucellosis in either mouse strain. However, relative
      resistance to brucellosis did correlate with increased production of IFN-gamma by
      CD4 T cells during the first weeks after infection while IL-10 contributed to
      susceptibility in BALB/c mice. Moreover, by 3 weeks post-infection splenocytes
      from the susceptible BALB/c mice failed to produce IFN-gamma and relied on TNF
      alpha as well as CD8 T cells to control infection until the end of the plateau
      phase around 6 weeks post-infection when IFN-gamma production resumed and
      clearance began. In contrast, IFN-gamma was crucial for control throughout the
      infection in the more resistant C57BL/6 mice and the mice died in its absence by
      6 weeks post-infection compared to 12 weeks for the more susceptible mice that
      relied on additional mechanisms of control. In contrast to the IFN-gamma knock
      out mice, both beta2 microglobulin knock-out C57BL/6 mice, which do not express
      conventional MHC class I molecules and thus cannot present antigen to CD8 T
      cells, or perforin knock-out C57BL/6 mice, which have no T cell cytotoxic
      activity, controlled and cleared the infection as well as normal C57BL/6 mice.
      The hiatus of IFN-gamma production in BALB/c mice correlated with very high
      levels of total IL-12 and it was postulated that the lack of IFN-gamma was a
      consequence of p40 homodimer blocking activity. However, reduction of p40 IL-12
      in vivo through administration of indomethacin reduced the infection without a
      concomitant measurable increase in IFN-gamma. Current studies are aimed at
      elucidating the mechanism of the IFN-gamma hiatus.

PMID- 12414158
TI  - The innate immune response against Brucella in humans.
AB  - Pathogens have developed different strategies to survive and multiply within
      their host. Among them is the ability to control phagocyte apoptosis while
      another is to affect the expression of cytokines which is necessary for a normal
      protective function of the immune response. To establish themselves and cause
      chronic disease in humans and animals, Brucella spp. invade and proliferate
      within monocytic phagocytes. We have established that in humans, Brucella suis
      impairs the apoptosis of monocytes and macrophages, thus preventing its host cell
      elimination. In mice, which are not naturally colonized by the bacteria, Brucella
      infection results in Type1 (Th1) cellular immune response which promotes a
      clearance of the bacterial organism. The development of this response is under
      the control of major cytokines like TNF-alpha, IFN-gamma and IL-12 produced at
      the onset of infection. We have observed that in humans, B. suis-infected
      macrophages which produce IL-1, IL-6, IL-10 and several chemokines including IL
      8, do not secrete TNF-alpha. By constructing null mutants, we demonstrated that
      this inhibition involves the outer membrane protein Omp25 of Brucella, however
      the mechanism regulating the inhibition has not yet been clearly defined. It is
      likely that the Omp25-induced effect on TNF-alpha production assists bacterial
      evasion of antimicrobial defences at different levels. Firstly, by preventing the
      autocrine activation of macrophages thus inhibiting innate immunity and secondly
      by impairing the production of IL-12 and the development of a Th1 type specific
      immunity. In addition to the central role of the macrophage in Brucella
      infection, others cells of the innate immune response are recruited and
      influenced by the interactions between bacteria and host. For instance, human
      Vgamma9Vdelta2 T-cells play an important role in the early response to infection
      with intracellular pathogens. Evidence has been presented that their number
      dramatically increased in the peripheral blood of patients with acute
      brucellosis. We have shown that human Vgamma9Vdelta2 T-cells can be specifically
      activated by non-peptidic low molecular weight compound(s) from B. suis lysate or
      by soluble factors produced by B. suis-infected macrophages. Under these
      conditions, they produce TNF-alpha and IFN-gamma and reduce the bacterial
      multiplication inside infected autologous macrophages. This impairment of B. suis
      multiplication is due to both soluble factors released from activated gammadeltaT
      cells (including TNF-alpha and IFN-gamma) and to a contact-dependent cytotoxicity
      directed against the infected cells. The interactions between the bacteria and
      these cells can counteract the intramacrophagic development of the bacteria and
      finally influence the further development of the host defense. We hypothesize
      that the chronicity or the elimination of the infection will depend on the
      balance between contradictory effects induced by the bacteria which favor either
      the host or the pathogen. Moreover, the interrelationship between the different
      cells must be taken into account in the analysis of the virulence of the bacteria
      and in the development of in vitro models of human macrophage infection.

PMID- 12414159
TI  - Bovine T lymphocyte responses to Brucella abortus.
AB  - The long-held paradigm of T lymphocyte-mediated activation of mononuclear
      phagocytes (Mo) as the major mechanism of protection against facultative
      intracellular pathogens such as Brucella has been modified to include killing of
      infected Mo by various subsets of T lymphocytes. Remnants of killed infected
      cells are phagocytosed by immunologically-activated Mo, which are much more
      efficient at killing such pathogens. Most of the detailed information regarding
      immunity in general and that of brucellosis specifically has been obtained using
      murine infection models rather than in cattle. However, there has been
      considerable definition of cellular phenotypes, cytokines and functional
      characteristics of T lymphocytes in cattle over the last decade. This was mainly
      due to development of monoclonal antibodies against cell surface markers and
      application of molecular cloning and polymerase chain reaction (PCR) for
      isolation, characterization and detection of genes encoding bovine cytokines.
      This review discusses cellular and molecular immunity in bovine brucellosis as
      pertains to T lymphocyte interactions with the Mo. Although current knowledge
      directly obtained from brucellosis immunity studies in the bovine host is limited
      and incomplete, the many parallels between the bovine and murine immune systems
      allow for some extrapolation in the description of bovine host defense
      mechanisms. Direct information from studies with immunized cattle supports the
      concepts of coordinate activation of uninfected Mo and killing of Brucella
      infected Mo by antigen-specific T lymphocytes as major mechanisms of host defense
      in bovine brucellosis. There also appears to be a bias in the T lymphocyte
      compartment towards recognition of particular bacterial stress proteins following
      immunization with live Brucella vaccines.

PMID- 12414160
TI  - Molecular and cellular interactions between Brucella abortus antigens and host
      immune responses.
AB  - Host protection against Brucella abortus, is thought to be mediated primarily by
      a Th1 type immune response. Unfortunately, only few specific bacterial antigens
      involved in stimulating protective cellular immunity against Brucella are known.
      Therefore, identifying bacterial proteins that induce a T-lymphocyte mediated
      response is critical to determine Brucella immunity. Several library screening
      methods are discussed that have been used to identify Brucella proteins that
      stimulate T lymphocytes including cellular immunoblotting, Escherichia coli
      expressed Brucella proteins, green fluorescence reporter systems, and signature
      tagged mutagenesis. Future studies would likely examine how bacterial proteins
      expressed within host cells aid pathogen survival and/or induce host responses.
      Some of these newly identified bacterial gene products may serve as antigens to
      activate a protective host immune response. Also, identifying Brucella proteins
      expressed at particular times during infection will also yield insights into
      Brucella pathogenesis.

PMID- 12414161
TI  - Characterization of the caprine model for ruminant brucellosis.
AB  - The relationship between man, the goat, and brucellosis is historical. Today
      Brucella melitensis and Brucella abortus pose a serious economic and public
      health threat in many countries throughout the world. Infection of pregnant goats
      and sheep with B. melitensis results in abortion during the third trimester of
      pregnancy. Although nearly eradicated in the US, bovine brucellosis is still a
      problem in many countries and the potential for re-infection of domestic stock
      from wildlife reservoirs in this country is a regulatory nightmare. Humans
      infected with this pathogen develop undulant fever, which is characterized by
      pyrexia, arthritis, osteomyelitis, and spondylitis. Although available for both
      organisms, currently available vaccines have problems ranging from false positive
      serological reactions to limited efficacy in different animal species. With the
      continued need for new and better vaccines, we have further developed a goat
      model system to test new genetically derived strains of B. melitensis and B.
      abortus for virulence as measured by colonization of maternal and fetal tissues,
      vaccine safety, and vaccine efficacy.

PMID- 12414162
TI  - Diagnostic strategies used for the identification of Brucella.

PMID- 12414163
TI  - PCR as a diagnostic tool for brucellosis.
AB  - Numerous PCR-based assays have been developed for the identification of Brucella
      to improve diagnostic capabilities. Collectively, the repertoire of assays
      addresses several aspects of the diagnostic process. For some purposes, the
      simple identification of Brucella is adequate (e.g. diagnosis of human
      brucellosis or contamination of food products). In these cases, a genus-specific
      PCR assay is sufficient. Genus-specific assays tend to be simple, robust, and
      somewhat permissive of environmental influences. The main genetic targets
      utilized for these applications are the Brucella BCSP31 gene and the 16S-23S rRNA
      operon. Other instances require identification of the Brucella species involved.
      For example, most government-sponsored brucellosis eradication programs include
      regulations that stipulate a species-specific response. For epidemiological trace
      back, strain-specific identification is helpful. Typically, differential PCR
      based assays tend to be more complex and consequently more difficult to perform.
      Several strategies have been explored to differentiate among Brucella species and
      strains, including locus specific multiplexing (e.g. AMOS-PCR based on IS711),
      PCR-RFLP (e.g. the omp2 locus), arbitrary-primed PCR, and ERIC-PCR to name a few.
      This paper reviews some of the major advancements in molecular diagnostics for
      Brucella including the development of procedures designed for the direct analysis
      of a variety of clinical samples. While the progress to date is impressive, there
      is still room for improvement.

PMID- 12414164
TI  - Diagnosis of brucellosis by serology.
AB  - Serological diagnosis of brucellosis began more than 100 years ago with a simple
      agglutination test. It was realized that this type of test was susceptible to
      false positive reactions resulting from, for instance, exposure to cross reacting
      microorganisms. It was also realized that this test format was inexpensive,
      simple and could be rapid, although results were subjectively scored. Therefore,
      a number of modifications were developed along with other types of tests. This
      served two purposes: one was to establish a rapid screening test with high
      sensitivity and perhaps less specificity and a confirmatory test, usually more
      complicated but also more specific, to be used on sera that reacted positively in
      screening tests. This led to another problem: if a panel of tests were performed
      and they did not all agree, which interpretation was correct? This problem was
      further compounded by the extensive use of a vaccine which gave rise to an
      antibody response similar to that resulting from field infection. This led to the
      development of an assay that could distinguish vaccinal antibody, starting with
      precipitin tests. These tests did not perform well, giving rise to the
      development of primary binding assays. These assays, including the competitive
      enzyme immunoassay and the fluorescence polarization assay are at the apex of
      current development, providing high sensitivity and specificity as well as speed
      and mobility in the case of the fluorescence polarization assay.

PMID- 12414165
TI  - How to substantiate eradication of bovine brucellosis when aspecific serological
      reactions occur in the course of brucellosis testing.
AB  - Collaborative work was financed by the EU to develop and assess new diagnostic
      tools that can differentiate between bovine brucellosis and bovine infections due
      to Yersinia enterocolitica O:9 either in conjunction with, or as an alternative
      to, the classical serological, bacteriological or allergic skin tests. Sixteen
      heifers were experimentally infected with Brucella abortus biovar 1 (five
      heifers), Brucella suis biovar 2 (two heifers), Y. enterocolitica O:9 (six
      heifers) and Y. enterocolitica O:3 (three heifers). Four heifers, naturally
      infected with Y. enterocolitica O:9 that presented aspecific brucellosis
      serological reactions were also included in the experiment. A self-limited
      infection was induced in cattle by B. suis biovar 2. All the brucellosis
      serological tests used, i.e. the slow agglutination test (SAW), the Rose Bengal
      test (RB), the complement fixation test (CFT), indirect and competitive ELISA's,
      lacked specificity when used to analyze sera from Y. enterocolitica O:9 infected
      animals. A Yersinia outer membrane proteins (YOPs)-ELISA was also used and
      although the test is able to detect a Yersinia group infection, it provided no
      evidence of whether or not there is a possible brucellosis infection when dual
      infections are present. The brucellergen IFN-gamma test showed a lack of
      specificity also. The only test that was proven to be specific is the
      brucellergen skin test. All brucellosis serological tests, except the indirect
      ELISA, were limited in their ability to detect B. abortus persistently infected
      animals. Based on these experimental studies, a strategy was implemented as part
      of the year 2001 Belgian Brucellosis Eradication Program to substantiate the
      eradication of bovine brucellosis. Epidemiological inquiries have identified risk
      factors associated with aspecific serological reactions, possible transmission
      and infection of cattle by B. suis biovar 2 from infected wild boars; and both
      legal and administrative measures taken by the veterinary services. No cases of
      bovine brucellosis have been confirmed in Belgium since March 2000.

PMID- 12414166
TI  - Brucellosis vaccines: past, present and future.
AB  - The first effective Brucella vaccine was based on live Brucella abortus strain
      19, a laboratory-derived strain attenuated by an unknown process during
      subculture. This induces reasonable protection against B. abortus, but at the
      expense of persistent serological responses. A similar problem occurs with the B.
      melitensis Rev.1 strain that is still the most effective vaccine against caprine
      and ovine brucellosis. Vaccines based on killed cells of virulent strains
      administered with adjuvant induced significant protection but also unacceptable
      levels of antibodies interfering with diagnostic tests. Attempts were made to
      circumvent this problem by using a live rough strain B. abortus 45/20, but this
      reverted to virulence in vivo. Use of killed cells of this strain in adjuvant met
      with moderate success but batch to batch variation in reactogenicity and
      agglutinogenicity limited application. This problem has been overcome by the
      development of the rifampicin-resistant mutant B. abortus RB51 strain. This
      strain has proved safe and effective in the field against bovine brucellosis and
      exhibits negligible interference with diagnostic serology. Attempts are being
      made to develop defined rough mutant vaccine strains that would be more effective
      against B. melitensis and B. suis. Various studies have examined cell-free native
      and recombinant proteins as candidate protective antigens, with or without
      adjuvants. Limited success has been obtained with these or with DNA vaccines
      encoding known protective antigens in experimental models and further work is
      indicated.

PMID- 12414167
TI  - Control of small ruminant brucellosis by use of Brucella melitensis Rev.1
      vaccine: laboratory aspects and field observations.
AB  - Brucellosis vaccines are essential elements in control programs. Since first
      developed in the mid-1950s, the Brucella melitensis vaccine strain Rev.1 has been
      used worldwide and its significant value in protecting sheep and goats in endemic
      areas recognized. This review provides historical background on the development
      of the vaccine, its use and field complications arising in Israel following
      changes in the strain's pathogenicity. The urgent need for resolving cases of
      vaccine strain excretion in the milk, horizontal transfer and a unique case of
      human infection has led to identification of an atypical B. melitensis biovar 1
      strain that resembles strain Rev.1 in susceptibility to penicillin and dyes. An
      omp2 based PCR method has been developed that traced the lineage of Israeli B.
      melitensis biovar 1 strains. This locus serves as an epidemiological tag for the
      Rev.1 vaccine strain. Despite the rapid development of new approaches in the
      field of vaccination, it is anticipated that in the near future the Rev.1 vaccine
      would remain the only accepted vaccine in national control programs.

PMID- 12414168
TI  - Brucella abortus RB51: enhancing vaccine efficacy and developing multivalent
      vaccines.
AB  - Brucella abortus vaccine strain RB51 is an attenuated, stable rough mutant that
      is being used in many countries to control bovine brucellosis. Our earlier study
      demonstrated that the protective efficacy of strain RB51 can be significantly
      enhanced by overexpressing Cu-Zn superoxide dismutase (SOD), a homologous
      protective antigen. We have also previously demonstrated that strain RB51 can be
      engineered to express heterologous proteins and mice vaccinated with such
      recombinant RB51 strains develop a strong Th1 type of immune response to the
      foreign proteins. The present study is aimed at combining these two
      characteristics to generate new recombinant RB51 vaccines with enhanced abilities
      to protect against brucellosis and simultaneously able to protect against
      infections by Mycobacterium spp. We constructed two recombinant RB51 strains,
      RB51SOD/85A which overexpresses SOD with simultaneous expression of the 85A, a
      protective protein of Mycobacterium spp., and RB51ESAT which expresses ESAT-6,
      another protective protein of M. bovis, as a fusion protein with the signal
      sequence and few additional amino terminal amino acids of SOD. Mice vaccinated
      with these recombinant strains developed specific immune responses to the
      mycobacterial proteins and significantly enhanced protection against Brucella
      challenge compared to the mice vaccinated with strain RB51 alone.

PMID- 12414169
TI  - Brucella vaccines in wildlife.
AB  - Brucellosis has been known to exist in populations of wildlife since the early
      part of the 20th century. At the beginning of this century in the US, Brucella
      abortus is a problem in elk and bison in the Greater Yellowstone Area, B. suis is
      prevalent in millions of feral swine in most of the southern states, and
      caribou/reindeer in Alaska are infected with B. suis biovar 4. Brucellosis has
      been virtually eliminated in domestic livestock in the US after decades of
      expensive governmental disease prevention, control and eradication programs. Now
      the most likely source of transmission of brucellosis to humans, and the risk of
      reintroduction of brucellosis into livestock is from infected populations of free
      ranging wildlife. Brucellosis was eradicated from livestock through a combination
      of testing, vaccination, and removal of infected animals. The use of vaccines to
      control brucellosis in populations of wildlife and therefore reducing the risk of
      transmission to humans and livestock has been proposed in several instances. This
      manuscript reviews research on the use of Brucella vaccines in species of
      wildlife with emphasis on safety and efficacy.

PMID- 12414170
TI  - Paradigm shifts in vaccine development: lessons learned about antigenicity,
      pathogenicity and virulence of Brucellae.
AB  - As part of a program to support the USDA Animal Plant Health Inspection Service
      Bovine Brucellosis Eradication Program, the Brucellosis Research Unit of the
      National Animal Disease Center (NADC) sought to develop a bovine brucellosis
      vaccine that would allow vaccinated animals to be distinguished from virulent
      field infected animals. In order to meet that goal, several avenues of research
      were undertaken to construct and test candidate vaccines, including Brucella
      abortus RB51. In early vaccine development studies, a subunit preparation
      obtained by extracting B. abortus with salts was studied as a candidate subunit
      vaccine. Later, molecular biological techniques were used both to clone genes
      encoding products found in the salt extract (BCSP31 and Cu-Zn SOD) and genes
      encoding proteins of B. abortus that were antigenic (HtrA) or possibly essential
      (two-component systems) for full virulence of B. abortus. In vitro systems using
      mammalian cells lines such as HeLa and macrophage-related were used along with
      the mouse model and host animal models. Results obtained at NADC and in other
      Brucellosis research laboratories, using survival in mammalian cell lines and the
      mouse model to access pathogenicity and virulence of genetically engineered
      strains, do not necessarily identify loci that are essential for full virulence
      or pathogenicity in the natural host, the bovine. Studies at NADC and other
      brucellosis laboratories showed that antigenicity was not a predictor of the
      effectiveness of a protein as a subunit vaccine.

PMID- 12414171
TI  - The pathology of brucellosis reflects the outcome of the battle between the host
      genome and the Brucella genome.
AB  - The successful co-existence of each Brucella spp. with its preferred host is the
      outcome of ancient co-evolutionary relationships and selection pressures that
      often result in a stalemate where the pathogen has evolved to survive within the
      biological systems of the host, and the host has evolved innate and acquired
      immune systems which allow controlled survival of infection by the pathogen,
      ultimately supporting the survival of the host-pathogen system. In general,
      Brucella spp. have evolved a similar fundamental pathogenesis of facultative
      intracellular parasitism though the predominant route of natural exposure varies
      from oropharynx to genital tract, as does the preferred tissue and cellular
      tropism, e.g. non-professional placental trophoblasts, fetal lung, professional
      macrophages of reticulendothelial system, and the male and female reproductive
      tracts. The morphogenesis of the pyogranulomatous lesions stimulated by Brucella
      reflects the nature of the persistent parasitism, i.e. genome versus genome. The
      question is, how can this perplexing array of survival mechanisms be unraveled?
      Fortunately, the integration of real-time image analysis, cell biology, genome
      wide analysis, proteomics and bioinformatics holds the most promise ever for the
      global analysis of the Brucella infectious process and the host:pathogen
      interface leading to a clearer understanding of the interactions of these
      biological systems. These discoveries will be expected to provide a frameshift in
      rationales for interrupting and/or controlling brucellosis at host and/or
      pathogen levels.

PMID- 12414172
TI  - A review of Brucella sp. infection of sea mammals with particular emphasis on
      isolates from Scotland.
AB  - Brucellae recovered from sea mammals were first reported in 1994. In the years
      since both culture and serological analysis have demonstrated that the infection
      occurs in a wide range of species of marine mammals inhabiting a vast amount of
      the world's oceans. Molecular studies have demonstrated that the isolates differ
      from those found amongst terrestrial animals and also distinguish between strains
      which have seals and cetaceans as their preferred hosts. At the phenotypic level
      seal and cetacean strains can also be differed with respect to their CO(2)
      requirement, primary growth on Farrells medium and metabolic activity on
      galactose. Two new species B. cetaceae and B. pinnipediae have been proposed as a
      result. This paper provides a review of Brucella in sea mammals and updates
      findings from the study of sea mammals from around the coast of Scotland.

PMID- 12414173
TI  - The Brucella genome at the beginning of the post-genomic era.
AB  - The year 2002 began with the publication of the first complete genome sequence
      for a Brucella species, that of the two replicons of B. melitensis 16M. Hopefully
      in 2002, the complete genome of B. suis 1330, and, perhaps, a B. abortus strain
      will be published. This is the culmination of over 30 years investigation of the
      composition, structure, organisation and evolution of the Brucella genome.
      Brucella research must now adapt to the new challenges of the post-genomic era.

PMID- 12414174
TI  - The genome of Brucella melitensis.
AB  - The genome of Brucella melitensis strain 16M was sequenced and contained
      3,294,931 bp distributed over two circular chromosomes. Chromosome I was composed
      of 2,117,144 bp and chromosome II has 1,177,787 bp. A total of 3,198 ORFs were
      predicted. The origins of replication of the chromosomes are similar to each
      other and to those of other alpha-proteobacteria. Housekeeping genes such as
      those that encode for DNA replication, protein synthesis, core metabolism, and
      cell-wall biosynthesis were found on both chromosomes. Genes encoding adhesins,
      invasins, and hemolysins were also identified.

PMID- 12414175
TI  - Brucella proteomes--a review.
AB  - The proteomes of selected Brucella spp. have been extensively analyzed by
      utilizing current proteomic technology involving 2-DE and MALDI-MS. In Brucella
      melitensis, more than 500 proteins were identified. The rapid and large-scale
      identification of proteins in this organism was accomplished by using the
      annotated B. melitensis genome which is now available in the GenBank. Coupled
      with new and powerful tools for data analysis, differentially expressed proteins
      were identified and categorized into several classes. A global overview of
      protein expression patterns emerged, thereby facilitating the simultaneous
      analysis of different metabolic pathways in B. melitensis. Such a global
      characterization would not have been possible by using time consuming and
      traditional biochemical approaches. The era of post-genomic technology offers new
      and exciting opportunities to understand the complete biology of different
      Brucella species.

PMID- 12414176
TI  - Does activation-induced deaminase initiate antibody diversification by DNA
      deamination?

PMID- 12414177
TI  - Patterns in spontaneous mutation revealed by human-baboon sequence comparison.
AB  - We have analyzed the alignment of a long homologous region of the human and
      baboon genomes (approximately 1.5 Mb). We show that the frequency of gaps between
      aligned segments decreases slowly with gap length, indicating that several
      successive nucleotides are often deleted or inserted in one event. By contrast,
      runs of consecutive mismatches decrease rapidly in frequency with increasing
      length, following an exponential distribution, indicating that nucleotides are
      mostly substituted one at a time. Nucleotide substitutions are clumped at the
      scales of <10 and 1000-10,000 nucleotides, but show almost no aggregation at the
      scales of <10-100 and over approximately 50,000 nucleotides. Apparently, two
      rather different factors make the substitution rate not exactly uniform along the
      DNA sequence. Comparison of regions of very similar genomes that are
      approximately selectively neutral makes it possible to study spontaneous mutation
      at a new level of resolution.

PMID- 12414178
TI  - Efficient capture of unique sequences from eukaryotic genomes.
AB  - Cot-based cloning and sequencing (CBCS), a synthesis of Cot analysis, DNA cloning
      and high-throughput sequencing, promises to accelerate the study of eukaryotic
      genomes. In particular, CBCS will (1) permit efficient gene discovery in species
      with substantial quantities of repetitive DNA, (2) allow the sequence complexity
      (i.e. all the unique sequence information) of large genomes to be elucidated at a
      fraction of the cost of shotgun sequencing, and (3) enhance genome sequencing
      efforts by facilitating capture of low-copy sequences not secured by EST
      sequencing. CBCS should accelerate comparative genomics research, especially in
      large genomes such as those of many crops.

PMID- 12414181
TI  - Mismatch repair and mutational bias in microsatellite DNA.

PMID- 12414182
TI  - A roadmap of the mouse genome.

PMID- 12414184
TI  - Genotype-phenotype mapping: genes as computer programs.
AB  - The effects of genes on phenotype are mediated by processes that are typically
      unknown but whose determination is desirable. The conversion from gene to
      phenotype is not a simple function of individual genes, but involves the complex
      interactions of many genes; it is what is known as a nonlinear mapping problem. A
      computational method called genetic programming allows the representation of
      candidate nonlinear mappings in several possible trees. To find the best model,
      the trees are 'evolved' by processes akin to mutation and recombination, and the
      trees that more closely represent the actual data are preferentially selected.
      The result is an improved tree of rules that represent the nonlinear mapping
      directly. In this way, the encoding of cellular and higher-order activities by
      genes is seen as directly analogous to computer programs. This analogy is of
      utility in biological genetics and in problems of genotype-phenotype mapping.

PMID- 12414185
TI  - Evidence for population growth in humans is confounded by fine-scale population
      structure.
AB  - Although many studies have reported human polymorphism data, there has been no
      analysis of the effect of sampling design on the patterns of variability
      recovered. Here, we consider which factors affect a summary of the allele
      frequency spectrum. The most important variable to emerge from our analysis is
      the number of ethnicities sampled: studies that sequence individuals from more
      ethnicities recover more rare alleles. These observations are consistent with
      fine-scale geographic differentiation as well as population growth. They suggest
      that the geographic sampling strategy should be considered carefully, especially
      when the aim is to infer the demographic history of humans.

PMID- 12414186
TI  - Planar cell polarization: do the same mechanisms regulate Drosophila tissue
      polarity and vertebrate gastrulation?
AB  - Many types of cell show different aspects of polarization. Epithelial cells
      display a ubiquitous apical-basolateral polarity but often are also polarized in
      the plane of the epithelium - a feature referred to as 'planar cell polarity'
      (PCP). In Drosophila all adult epithelial cuticular structures are polarized
      within the plane, whereas in vertebrates examples of PCP include aspects of skin
      development, features of the inner ear epithelium, and the morphology and
      behavior of mesenchymal cells undergoing the morphogenetic movement called
      'convergent extension'. Recent advances in the study of PCP establishment are
      beginning to unravel the molecular mechanisms that underlie this aspect of cell
      and tissue differentiation. Here I discuss new developments in our molecular
      understanding of PCP in Drosophila and compare them towhat is known about the
      regulation of convergent extension in vertebrates.

PMID- 12414188
TI  - Recycled plastids: a 'green movement' in eukaryotic evolution.
AB  - Secondary endosymbiosis is the process that drives the spread of plastids
      (chloroplasts) from one eukaryote to another. The number of times that this has
      occurred and the kinds of cells involved are now becoming clear. Reconstructions
      of plastid history using molecular data suggest that secondary endosymbiosis is
      very rare and that perhaps as few as three endosymbioses have resulted in a large
      proportion of algal diversity. The significance of these events extends beyond
      photosynthesis, however, because non-photosynthetic organisms such as ciliates
      appear to have evolved from photosynthetic ancestors and could still harbor
      plastid-derived genes or relict plastids.

PMID- 12414187
TI  - Translational repressors in Drosophila.
AB  - Translational regulation is an important aspect of gene regulation, particularly
      during early development of the fruit fly embryo when transcriptional mechanisms
      are untenable. Study of pattern formation and dosage compensation has identified
      several repressors that bind discrete sites in the untranslated portions of
      target mRNAs. These repressors do not work in isolation - each binds multiple
      sites in the appropriate mRNA, and the resulting RNA-protein complexes appear to
      recruit co-repressors by a variety of mechanisms.

PMID- 12414189
TI  - PaJaMas in Paris.
AB  - This is a personal reminiscence of what happened in one year, nearly 50 years
      ago, when I spent a sabbatical year at The Pasteur Institute in Paris. The year
      was fascinating, for I met and worked with Jacques Monod and Francois Jacob, a
      collaboration that culminated in the famous PaJaMa experiment.

PMID- 12414190
TI  - Molecular drive.

PMID- 12414194
TI  - How safe is GM food?

PMID- 12414191
TI  - The meaning of it all: web-based resources for large-scale functional annotation
      and visualization of DNA microarray data.
AB  - The vast amount of unstructured data emerging from the various genome projects
      has led to the development of a number of web-based tools designed to annotate
      genes with biological information. Here we discuss a selection of these tools
      with regards to their scope, limitations and ease of use.

PMID- 12414195
TI  - Coils or clips in subarachnoid haemorrhage?

PMID- 12414196
TI  - Electrode positioning for cardioversion of atrial fibrillation.

PMID- 12414197
TI  - Focused multidisciplinary services for young people with disabilities.

PMID- 12414198
TI  - Glucocorticoid and beta-adrenoceptor agonist interactions in asthma.

PMID- 12414199
TI  - Can transnational research be ethical in the developing world?

PMID- 12414200
TI  - International Subarachnoid Aneurysm Trial (ISAT) of neurosurgical clipping versus
      endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a
      randomised trial.
AB  - BACKGROUND: Endovascular detachable coil treatment is being increasingly used as
      an alternative to craniotomy and clipping for some ruptured intracranial
      aneurysms, although the relative benefits of these two approaches have yet to be
      established. We undertook a randomised, multicentre trial to compare the safety
      and efficacy of endovascular coiling with standard neurosurgical clipping for
      such aneurysms judged to be suitable for both treatments. METHODS: We enrolled
      2143 patients with ruptured intracranial aneurysms and randomly assigned them to
      neurosurgical clipping (n=1070) or endovascular treatment by detachable platinum
      coils (n=1073). Clinical outcomes were assessed at 2 months and at 1 year with
      interim ascertainment of rebleeds and death. The primary outcome was the
      proportion of patients with a modified Rankin scale score of 3-6 (dependency or
      death) at 1 year. Trial recruitment was stopped by the steering committee after a
      planned interim analysis. Analysis was per protocol. FINDINGS: 190 of 801 (23.7%)
      patients allocated endovascular treatment were dependent or dead at 1 year
      compared with 243 of 793 (30.6%) allocated neurosurgical treatment (p=0.0019).
      The relative and absolute risk reductions in dependency or death after allocation
      to an endovascular versus neurosurgical treatment were 22.6% (95% CI 8.9-34.2)
      and 6.9% (2.5-11.3), respectively. The risk of rebleeding from the ruptured
      aneurysm after 1 year was two per 1276 and zero per 1081 patient-years for
      patients allocated endovascular and neurosurgical treatment, respectively.
      INTERPRETATION: In patients with a ruptured intracranial aneurysm, for which
      endovascular coiling and neurosurgical clipping are therapeutic options, the
      outcome in terms of survival free of disability at 1 year is significantly better
      with endovascular coiling. The data available to date suggest that the long-term
      risks of further bleeding from the treated aneurysm are low with either therapy,
      although somewhat more frequent with endovascular coiling.

PMID- 12414201
TI  - Anterior-posterior versus anterior-lateral electrode positions for external
      cardioversion of atrial fibrillation: a randomised trial.
AB  - BACKGROUND: External cardioversion is a readily available treatment for
      persistent atrial fibrillation. Although anatomical and electrophysiological
      considerations suggest that an anterior-posterior electrode position should
      create a more homogeneous shock-field gradient throughout the atria than an
      anterior-lateral position, both electrode positions are equally recommended for
      external cardioversion in current guidelines. We undertook a randomised trial
      comparing the two positions with the endpoint of successful cardioversion.
      METHODS: 108 consecutive patients (mean age 60 years [SD 16]) with persistent
      atrial fibrillation (median duration 5 months, range 0.1-120) underwent elective
      external cardioversion by a standardised step-up protocol with increasing shock
      strengths (50-360 J). Electrode positions were randomly assigned as anterior
      lateral or anterior-posterior. If sinus rhythm was not achieved with 360 J
      energy, a single cross-over shock (360 J) was applied with the other electrode
      configuration. A planned interim analysis was done after these patients had been
      recruited; it was by intention to treat. FINDINGS: Cardioversion was successful
      in a higher proportion of the anterior-posterior than the anterior-lateral group
      (50 of 52 [96%] vs 44 of 56 [78%], difference 23.7% (95% CI 9.1-37.8, p=0.009).
      Cross-over from the anterior-lateral to the anterior-posterior electrode position
      was successful in eight of 12 patients, whereas cross-over in the other direction
      was not successful (two patients). After cross-over, cardioversion was successful
      in 102 of 108 randomised patients (94%). INTERPRETATION: An anterior-posterior
      electrode position is more effective than the anterior-lateral position for
      external cardioversion of persistent atrial fibrillation. These results should be
      considered in clinical practice, for the design of defibrillation electrode pads,
      and when guidelines for cardioversion of atrial fibrillation are updated.

PMID- 12414202
TI  - Team approach versus ad hoc health services for young people with physical
      disabilities: a retrospective cohort study.
AB  - BACKGROUND: Young people with physical disabilities often have difficulty
      attaining independence in adult life and consequently need lifelong support from
      parents and from health-care and social-care services. There are concerns about
      the organisation and cost-effectiveness of such services and their ability to
      meet the independence training and serious health needs of these young people.
      Our aim was to compare a young adult team (YAT) approach with the ad hoc service
      approach in four locations in England, in terms of their ability to enhance the
      participation in society of these young people and their cost. METHODS: We did a
      retrospective cohort study, in which we interviewed 254 physically disabled young
      people. 124 healthy controls were given a questionnaire. We interviewed with
      standardised measures and used logistic regression analysis to test for effects
      of ad hoc and YAT services. The Mantel-Haenszel chi2 statistic was used to test
      for differences in resource use between areas in which the YAT and ad hoc
      services were available. FINDINGS: The absence of pain, fatigue, and stress
      increased the odds of participation two-fold to four-fold. After adjustment for
      these factors, young people cared for by multidisciplinary YAT teams were 2.54
      times (95% CI 1.30-4.98) more likely than those who used ad hoc services to
      participate in society. Resource use did not differ between the two service
      types. INTERPRETATION: A YAT approach costs no more to implement than an ad hoc
      approach, and is more likely to enhance participation in society of young people
      with physical disabilities.

PMID- 12414203
TI  - Herpes encephalitis.

PMID- 12414204
TI  - Diagnosis of adult tuberculous meningitis by use of clinical and laboratory
      features.
AB  - BACKGROUND: The diagnosis of tuberculous meningitis is difficult. Discrimination
      of cases from those of bacterial meningitis by clinical features alone is often
      impossible, and current laboratory methods remain inadequate or inaccessible in
      developing countries. We aimed to create a simple diagnostic aid for tuberculous
      meningitis in adults on the basis of clinical and basic laboratory features.
      METHODS: We compared the clinical and laboratory features on admission of 251
      adults at an infectious disease hospital in Vietnam who satisfied diagnostic
      criteria for tuberculous (n=143) or bacterial (n=108) meningitis. Features
      independently predictive of tuberculous meningitis were modelled by multivariate
      logistic regression to create a diagnostic rule, and by a classification-tree
      method. The performance of both diagnostic aids was assessed by resubstitution
      and prospective test data methods. FINDINGS: Five features were predictive of a
      diagnosis of tuberculous meningitis: age, length of history, white-blood-cell
      count, total cerebrospinal fluid white-cell count, and cerebrospinal fluid
      neutrophil proportion. A diagnostic rule developed from these features was 97%
      sensitive and 91% specific by resubstitution, and 86% sensitive and 79% specific
      when applied prospectively to a further 42 adults with tuberculous meningitis,
      and 33 with bacterial meningitis. The corresponding values for the classification
      tree were 99% and 93% by resubstitution, and 88% and 70% with prospective test
      data. INTERPRETATION: This study suggests that simple clinical and laboratory
      data can help in the diagnosis of adults with tuberculous meningitis. Although
      the usefulness of the diagnostic rule will vary depending on the prevalence of
      tuberculosis and HIV-1 infection, we suggest it be applied to adults with
      meningitis and a low cerebrospinal fluid glucose, particularly in settings with
      limited microbiological resources.

PMID- 12414205
TI  - Interaction between glucocorticoids and beta2 agonists on bronchial airway smooth
      muscle cells through synchronised cellular signalling.
AB  - BACKGROUND: Increased airway smooth muscle bulk is a pathological feature of
      asthma. Asthma is well controlled by the combined inhalation of glucocorticoids
      and beta2-adrenoceptor agonists. The basic molecular mechanism of the interaction
      of the two drugs on proliferation of airway smooth muscle cells is yet to be
      identified. Our aim was to elucidate how glucocorticoids and beta2 agonists
      affect the growth of human bronchial airway smooth muscle cells. METHODS: We
      assessed the effect of formoterol and budesonide on the activation and function
      of transcription factors by immunohistochemistry, western blotting, DNA mobility
      shift assay, and a luciferase reporter gene assay. The effect of the drugs and
      the involvement of specific transcription factors on cell proliferation was
      ascertained by direct cell count and confirmed by thymidine incorporation.
      FINDINGS: Both classes of drugs (10(-8) mol/L) activated C/EBP-alpha and the
      glucocorticoid receptor with different kinetic profiles, and inhibited
      proliferation. The combination of lower doses of drugs (10(-12) to 10(-9) mol/L)
      resulted in a synchronised activation of the transcription factors and an
      enhanced antiproliferative effect. The action of the drugs alone or in
      combination on transcription-factor activity and proliferation was suppressed by
      either depletion of C/EBP-alpha or in the presence of a glucocorticoid-receptor
      blocker. INTERPRETATION: Our findings could provide one explanation for the
      interaction of beta2 agonists and glucocorticoids at a molecular level, and
      indicate that the concentration of inhaled glucocorticoids can be reduced when
      combined with beta2 agonists, minimising the side-effects of the drugs.

PMID- 12414206
TI  - Arthritis and anorexia?

PMID- 12414207
TI  - Comprehension during informed consent in a less-developed country.
AB  - Few practical guidelines exist on how to ensure that research participants in
      less-developed countries understand the consent form before enrollment. In a
      study of HIV-1 transmission in Haiti, participants were required to pass an oral
      examination on the contents of the consent form with a passing score of 12/15
      (80%) before enrollment. 15 individuals were given information during a single
      meeting with a physician, and three (20%) passed. 30 subsequent volunteers were
      given information by a counsellor during three meetings, and 24 (80%) passed.
      Formal assessment of research participants' comprehension of the consent form
      should be considered as a routine step in the informed consent process in less
      developed countries.

PMID- 12414209
TI  - UN food agency redoubles call for African aid.

PMID- 12414208
TI  - Compulsions, Parkinson's disease, and stimulation.
AB  - Pathophysiological models suggest that obsessive compulsive disorder (OCD) might
      be associated with dysfunctions in cortico-striato-pallido-thalamo-cortical
      neuronal circuits. We implanted subthalamic electrodes to alleviate parkinsonian
      symptoms in two patients who had Parkinson's disease and a history of severe OCD.
      Parkinsonian disability improved postoperatively in both patients, and 2 weeks
      after the procedure, their compulsions had disappeared and obsessive symptoms
      improved (58% improvement for patient 1 on the Yale-Brown obsessive compulsive
      scale, 64% for patient 2). The improvements in these two patients suggest that
      high-frequency stimulation could improve function in the subcortical-limbic
      circuitry in patients with severe OCD.

PMID- 12414210
TI  - Detergent-lentiviral combination gives gene therapy hope for cystic fibrosis.

PMID- 12414213
TI  - Mechanism of macular degeneration starts to appear.

PMID- 12414214
TI  - UK starts long-overdue reform to social services.

PMID- 12414215
TI  - Polygraph fails scientific review in the USA.

PMID- 12414217
TI  - UK think-tank asks government to reprioritise health research.

PMID- 12414218
TI  - Argentine doctors face more litigation from desperate patients.

PMID- 12414220
TI  - Global Fund money won't increase health spending, says Uganda.

PMID- 12414219
TI  - Netherlands uncovers AIDS drugs trade fraud.

PMID- 12414222
TI  - More funds for AIDS in Africa.

PMID- 12414223
TI  - Asthma.
AB  - Asthma is one of the commonest chronic diseases of affluent societies. The
      striking increase in prevalence of asthma over recent decades and the rarity of
      this disease in less affluent populations confirms the importance of
      environmental factors in the cause of asthma--although which environmental
      factors are responsible is still not clear. Family studies show that genetic
      factors are also important in determining individual susceptibility to asthma,
      with results of genetic studies suggesting that there are many genes with
      moderate effects rather than a few major genes. Asthmatic airways show
      inflammation and remodelling, with CD4+ helper cells, mast cells, and eosinophils
      characterising the inflammatory response. Inhaled corticosteroids remain the
      cornerstone of treatment with the addition of long-acting beta agonists as the
      next step if symptoms continue. Leukotriene antagonists, the only new drugs to
      reach the market in the past decade, have modest effects. However, a better
      understanding of the mechanisms underlying asthma and the genetic and
      environmental factors that predispose individuals to asthma should lead to better
      preventative strategies and new therapeutic approaches.

PMID- 12414224
TI  - Series of errors.

PMID- 12414225
TI  - Accumulation of mitochondrial DNA mutations in ageing, cancer, and mitochondrial
      disease: is there a common mechanism?
AB  - In man, cells accumulate somatic mutations of mitochondrial DNA (mtDNA) as part
      of normal ageing. Although the overall concentration of mutant mtDNA is low in
      tissue as a whole, very high numbers of various mtDNA mutations develop in
      individual cells within the same person, which causes age-associated
      mitochondrial dysfunction. Some tumours contain high numbers of mtDNA mutations
      that are not present in healthy tissues from the same individual. The proportion
      of mutant mtDNA also rises in patients with progressive neurological disease due
      to inherited mtDNA mutations. This increase parallels the relentless clinical
      progression seen in these disorders. Mathematical models suggest that the same
      basic cellular mechanisms are responsible for the amplification of mutant mtDNA
      in ageing, in tumours, and in mtDNA disease. The accumulation of cells that
      contain high levels of mutant mtDNA may be an inevitable result of the normal
      mechanisms that maintain cellular concentrations of mtDNA.

PMID- 12414226
TI  - Reporting of ethical issues in publications of medical research.
AB  - Clinical investigators rarely describe the rationale for ethically controversial
      features of study design or procedures instituted to enhance the protection of
      patients taking part in research, or how they ensured informed consent. We
      recommend a policy of extensive reporting of pertinent ethical issues to promote
      public accountability for clinical research. Guidelines are presented, and
      possible objections to this recommended policy are addressed.

PMID- 12414228
TI  - The magpie trial.

PMID- 12414227
TI  - The magpie trial.

PMID- 12414229
TI  - The magpie trial.

PMID- 12414231
TI  - The magpie trial.

PMID- 12414232
TI  - The magpie trial.

PMID- 12414233
TI  - Investing in health in a world that lacks implementation capacity.

PMID- 12414234
TI  - Cholinesterase inhibitors for Alzheimer's disease.

PMID- 12414236
TI  - Use and ownership of hearing aids in elderly people.

PMID- 12414237
TI  - Use and ownership of hearing aids in elderly people.

PMID- 12414238
TI  - Interferon-gamma responses to mycobacterial antigens in Heaf-positive children.

PMID- 12414239
TI  - Full routine examination of patients.

PMID- 12414240
TI  - Interferon-gamma responses to mycobacterial antigens in Heaf-positive children.

PMID- 12414241
TI  - Ethics of placental blood collection and storage.

PMID- 12414242
TI  - Quality of referral letters.

PMID- 12414243
TI  - Safety concerns about kava not unique.

PMID- 12414244
TI  - Teaching of creationism in schools.

PMID- 12414248
TI  - Typhomalaria.

PMID- 12414252
TI  - A robust method for extraction and automatic segmentation of brain images.
AB  - A new protocol is introduced for brain extraction and automatic tissue
      segmentation of MR images. For the brain extraction algorithm, proton density and
      T2-weighted images are used to generate a brain mask encompassing the full
      intracranial cavity. Segmentation of brain tissues into gray matter (GM), white
      matter (WM), and cerebral spinal fluid (CSF) is accomplished on a T1-weighted
      image after applying the brain mask. The fully automatic segmentation algorithm
      is histogram-based and uses the Expectation Maximization algorithm to model a
      four-Gaussian mixture for both global and local histograms. The means of the
      local Gaussians for GM, WM, and CSF are used to set local thresholds for tissue
      classification. Reproducibility of the extraction procedure was excellent, with
      average variation in intracranial capacity (TIC) of 0.13 and 0.66% TIC in 12
      healthy normal and 33 Alzheimer brains, respectively. Repeatability of the
      segmentation algorithm, tested on healthy normal images, indicated scan-rescan
      differences in global tissue volumes of less than 0.30% TIC. Reproducibility at
      the regional level was established by comparing segmentation results within the
      12 major Talairach subdivisions. Accuracy of the algorithm was tested on a
      digital brain phantom, and errors were less than 1% of the phantom volume.
      Maximal Type I and Type II classification errors were low, ranging between 2.2
      and 4.3% of phantom volume. The algorithm was also insensitive to variation in
      parameter initialization values. The protocol is robust, fast, and its success in
      segmenting normal as well as diseased brains makes it an attractive clinical
      application.

PMID- 12414253
TI  - N400-like magnetoencephalography responses modulated by semantic context, word
      frequency, and lexical class in sentences.
AB  - Words have been found to elicit a negative potential at the scalp peaking at
      approximately 400 ms that is strongly modulated by semantic context. The current
      study used whole-head magnetoencephalography (MEG) as male subjects read
      sentences ending with semantically congruous or incongruous words. Compared with
      congruous words, sentence-terminal incongruous words consistently evoked a large
      magnetic field over the left hemisphere, peaking at approximately 450 ms. Source
      modeling at this latency with conventional equivalent current dipoles (ECDs)
      placed the N400 m generator in or near the left superior temporal sulcus. A
      distributed solution constrained to the cortical surface suggested a sequence of
      differential activation, beginning in Wernicke's area at approximately 250 ms,
      spreading to anterior temporal sites at approximately 270 ms, to Broca's area by
      approximately 300 ms, to dorsolateral prefrontal cortices by approximately 320
      ms, and to anterior orbital and frontopolar cortices by approximately 370 ms.
      Differential activity was exclusively left-sided until >370 ms, and then involved
      right anterior temporal and orbital cortices. At the peak of the N400 m,
      activation in the left hemisphere was estimated to be widespread in the anterior
      temporal, perisylvian, orbital, frontopolar, and dorsolateral prefrontal
      cortices. In the right hemisphere, the orbital, as well as, weakly, the right
      anterior temporal cortices were activated. Similar but weaker field patterns were
      evoked by intermediate words in the sentences, especially to low-frequency words
      occurring in early sentence positions where there is little preceding context.
      The locations of the N400 m sources identified with the distributed solution
      correspond well with those previously demonstrated with direct intracranial
      recordings, and suggested by functional magnetic resonance imaging (fMRI). These
      results help identify a distributed cortical network that supports online
      semantic processing.

PMID- 12414254
TI  - Linking physics with physiology in TMS: a sphere field model to determine the
      cortical stimulation site in TMS.
AB  - A fundamental problem of transcranial magnetic stimulation (TMS) is determining
      the site and size of the stimulated cortical area. In the motor system, the most
      common procedure for this is motor mapping. The obtained two-dimensional
      distribution of coil positions with associated muscle responses is used to
      calculate a center of gravity on the skull. However, even in motor mapping the
      exact stimulation site on the cortex is not known and only rough estimates of its
      size are possible. We report a new method which combines physiological
      measurements with a physical model used to predict the electric field induced by
      the TMS coil. In four subjects motor responses in a small hand muscle were mapped
      with 9-13 stimulation sites at the head perpendicular to the central sulcus in
      order to keep the induced current direction constant in a given cortical region
      of interest. Input-output functions from these head locations were used to
      determine stimulator intensities that elicit half-maximal muscle responses. Based
      on these stimulator intensities the field distribution on the individual cortical
      surface was calculated as rendered from anatomical MR data. The region on the
      cortical surface in which the different stimulation sites produced the same
      electric field strength (minimal variance, 4.2 +/- 0.8%.) was determined as the
      most likely stimulation site on the cortex. In all subjects, it was located at
      the lateral part of the hand knob in the motor cortex. Comparisons of model
      calculations with the solutions obtained in this manner reveal that the
      stimulated cortex area innervating the target muscle is substantially smaller
      than the size of the electric field induced by the coil. Our results help to
      resolve fundamental questions raised by motor mapping studies as well as motor
      threshold measurements.

PMID- 12414255
TI  - A framework for callosal fiber distribution analysis.
AB  - This paper presents a framework for analyzing the spatial distribution of neural
      fibers in the brain, with emphasis on interhemispheric fiber bundles crossing
      through the corpus callosum. The proposed approach combines methodologies for
      fiber tracking and spatial normalization and is applied on diffusion tensor
      images and standard magnetic resonance images.

PMID- 12414256
TI  - Is it tonotopy after all?
AB  - In this functional MRI study the frequency-dependent localization of acoustically
      evoked BOLD responses within the human auditory cortex was investigated. A
      blocked design was employed, consisting of periods of tonal stimulation (random
      frequency modulations with center frequencies 0.25, 0.5, 4.0, and 8.0 kHz) and
      resting periods during which only the ambient scanner noise was audible. Multiple
      frequency-dependent activation sites were reliably demonstrated on the surface of
      the auditory cortex. The individual gyral pattern of the superior temporal plane
      (STP), especially the anatomy of Heschl's gyrus (HG), was found to be the major
      source of interindividual variability. Considering this variability by tracking
      the frequency responsiveness to the four stimulus frequencies along individual
      Heschl's gyri yielded medio-lateral gradients of responsiveness to high
      frequencies medially and low frequencies laterally. It is, however, argued that
      with regard to the results of electrophysiological and cytoarchitectonical
      studies in humans and in nonhuman primates, the multiple frequency-dependent
      activation sites found in the present study as well as in other recent fMRI
      investigations are no direct indication of tonotopic organization of
      cytoarchitectonical areas. An alternative interpretation is that the activation
      sites correspond to different cortical fields, the topological organization of
      which cannot be resolved with the current spatial resolution of fMRI. In this
      notion, the detected frequency selectivity of different cortical areas arises
      from an excess of neurons engaged in the processing of different acoustic
      features, which are associated with different frequency bands. Differences in the
      response properties of medial compared to lateral and frontal compared to
      occipital portions of HG strongly support this notion.

PMID- 12414257
TI  - A model of the coupling between brain electrical activity, metabolism, and
      hemodynamics: application to the interpretation of functional neuroimaging.
AB  - In order to improve the interpretation of functional neuroimaging data, we
      implemented a mathematical model of the coupling between membrane ionic currents,
      energy metabolism (i.e., ATP regeneration via phosphocreatine buffer effect,
      glycolysis, and mitochondrial respiration), blood-brain barrier exchanges, and
      hemodynamics. Various hypotheses were tested for the variation of the cerebral
      metabolic rate of oxygen (CMRO(2)): (H1) the CMRO(2) remains at its baseline
      level; (H2) the CMRO(2) is enhanced as soon as the cerebral blood flow (CBF)
      increases; (H3) the CMRO(2) increase depends on intracellular oxygen and pyruvate
      concentrations, and intracellular ATP/ADP ratio; (H4) in addition to hypothesis
      H3, the CMRO(2) progressively increases, due to the action of a second messenger.
      A good agreement with experimental data from magnetic resonance imaging and
      spectroscopy (MRI and MRS) was obtained when we simulated sustained and
      repetitive activation protocols using hypotheses (H3) or (H4), rather than
      hypotheses (H1) or (H2). Furthermore, by studying the effect of the variation of
      some physiologically important parameters on the time course of the modeled blood
      oxygenation-level-dependent (BOLD) signal, we were able to formulate hypotheses
      about the physiological or biochemical significance of functional magnetic
      resonance data, especially the poststimulus undershoot and the baseline drift.

PMID- 12414258
TI  - The BOLD response to interictal epileptiform discharges.
AB  - We studied single-event and average BOLD responses to EEG interictal epileptic
      discharges (IEDs) in four patients with focal epilepsy, using continuous EEG-fMRI
      during 80-min sessions. The detection of activated areas was performed by
      comparing the BOLD signal at each voxel to a model of the expected signal. Since
      little is known about the BOLD response to IEDs, we modeled it with the response
      to brief auditory events (G. H., NeuroImage 9, 416-429). For each activated area,
      we then obtained the time course of the BOLD signal for the complete session and
      computed the actual average hemodynamic response function (HRF) to IEDs. In two
      of four patients, we observed clear BOLD responses to single IEDs. The average
      response was composed of a positive lobe peaking between 6 and 7 s in all
      patients and a negative undershoot in three patients. There were important
      variations in amplitude and shape between average HRFs across patients. The
      average HRF presented a wider positive lobe than the Glover model in three
      patients and a longer undershoot in two. There was a remarkable similarity in the
      shape of the HRF across areas for patients presenting multiple activation sites.
      There was no clear correlation between the amplitude of individual BOLD responses
      and the amplitude of the corresponding EEG spike. The possibility of a longer HRF
      could be used to improve statistical detection of activation in simultaneous EEG
      fMRI. The variability in average HRFs across patients could reflect in part
      different pathophysiological mechanisms.

PMID- 12414259
TI  - Statistical parametric mapping of (99m)Tc-HMPAO-SPECT images for the diagnosis of
      Alzheimer's disease: normalizing to cerebellar tracer uptake.
AB  - BACKGROUND: For a quantitative comparison of images obtained during (99m)Tc
      hexamethylpropylene amine oxime (HMPAO) single-photon emission computed
      tomography (SPECT), brain activity values are usually normalized to a reference
      region. In studies of Alzheimer-type dementia (ATD), the cerebellum is often used
      as a reference region, assuming that it is spared any major pathological
      involvement. Statistical parametric mapping (SPM) may enhance the evaluation of
      SPECT scans in ATD patients. However, current SPM software only allows scaling to
      average whole brain activity (i.e., global normalization). The aim of this study
      was to develop an easily applied, objective, and reproducible method for
      determining average cerebellar tracer uptake so that images can be scaled
      specifically to cerebellar activity prior to the performance of SPM analysis. We
      also investigated whether cerebellar normalization increases the sensitivity and
      specificity of SPM analysis of ATD patients compared with global normalization.
      METHODS: Image files were taken from a parallel study investigating the use of
      SPECT as a diagnostic tool for early onset of ATD. Two methods for determining
      cerebellar activity were developed: one manually, using templates, the other
      automated, using specified coordinates entered into a Matlab routine. Group
      comparison of ATD patients versus controls (= healthy volunteers and depressed
      patients) was performed on a voxel-by-voxel basis using SPM 96 on Windows 95.
      Receiver operator characteristics (ROC) were computed for 20 student raters
      examining patient and control scans with and without single-subject SPMs.
      RESULTS: The reduction of cerebral blood flow in the group of ATD patients
      appeared 1.7 times greater in spatial extent when the tracer uptake was
      normalized to cerebellum rather than to average whole brain activity. Computing
      the reverse contrast (reductions in the control group compared with ATD patients)
      produced clusters of significance in globally normalized images which were not
      manifest after normalizing to cerebellum. This is consistent with the notion that
      the cerebellum is spared in ATD. Analysis of the area under the ROC curve showed
      that cerebellar-normalized SPM produced significantly improved accuracy over
      perfusion scans alone. CONCLUSION: An easily applied, objective, reproducible
      method was developed for normalizing images to cerebellum prior to the
      performance of SPM analysis. Cerebellar normalization produced more extensive
      abnormalities in SPM analyses of ATD patients than global normalization.
      Furthermore, cerebellar normalization produced marginally more accurate
      diagnostic results in single-scan SPM analysis of ATD patients than did global
      normalization.

PMID- 12414260
TI  - The importance of distributed sampling in blocked functional magnetic resonance
      imaging designs.
AB  - In this study we demonstrate the importance of distributed sampling of
      peristimulus time in blocked design fMRI studies. Distributed sampling ensures
      all the components of an event-related hemodynamic response are sampled and
      avoids the bias incurred when stimulus presentation is time-locked to data
      acquisition. We found that differences in the temporal offset between stimulus
      presentation and data acquisition had a significant effect on some language
      related activations. These effects, induced by simply shifting stimulus
      presentation by a fraction of the interscan interval, suggest that fixed sampling
      does indeed bias estimated responses, even in blocked designs.

PMID- 12414261
TI  - The human prefrontal and parietal association cortices are involved in NO-GO
      performances: an event-related fMRI study.
AB  - One of the important roles of the prefrontal cortex is inhibition of movement. We
      applied an event-related functional magnetic resonance imaging (fMRI) technique
      to observe changes in fMRI signals of the entire brain during a GO/NO-GO task to
      identify the functional fields activated in relation to the NO-GO decision.
      Eleven normal subjects participated in the study, which consisted of a random
      series of 30 GO and 30 NO-GO trials. The subjects were instructed to press a
      mouse button immediately after the GO signal was presented. However, they were
      instructed not to move when the NO-GO signal was presented. We detected
      significant changes in MR signals in relation to the preparation phases, GO
      responses, and NO-GO responses. The activation fields related to the NO-GO
      responses were located in the bilateral middle frontal cortices, left dorsal
      premotor area, left posterior intraparietal cortices, and right occipitotemporal
      area. The fields of activation in relation to the GO responses were found in the
      left primary sensorimotor, right cerebellar anterior lobule, bilateral thalamus,
      and the area from the anterior cingulate to the supplementary motor area (SMA).
      Brain activations related to the preparation phases were identified in the left
      dorsal premotor, left lateral occipital, right ventral premotor, right fusiform,
      and the area from the anterior cingulate to the SMA. The results indicate that
      brain networks consisting of the bilateral prefrontal, intraparietal, and
      occipitotemporal cortices may play an important role in executing a NO-GO
      response.

PMID- 12414262
TI  - Functional magnetic resonance imaging evidence for a representation of the ear in
      human primary somatosensory cortex: comparison with magnetoencephalography study.
AB  - Our previous study (T. Nihashi et al., 2001, Neuro- Image 13: 295-304), using
      magnetoencephalography (MEG), revealed somatotopy of the ear in the human primary
      somatosensory cortex (SI); that is, the signals following stimulation of the ear
      reach both the neck and face areas of the SI. However, since this was the first
      report on somatotopy of the ear in humans, we performed an fMRI activation study
      to confirm the somatotopic representation, and compared the electrical activity
      by MEG and the cerebral blood flow change by fMRI. We studied eight healthy
      subjects using 3-T MRI. We stimulated three parts of the left ear: the helix, the
      lobulus, and the tragus. First, we identified the location of the ear area in the
      SI based on our previous MEG study, in which equivalent current dipoles (ECDs)
      were located in the neck and/or face areas of the SI. Then, we determined the
      search volume as a sphere with a 15-mm radius, which was placed in the neck
      and/or face area. We analyzed whether or not fMRI activation occurred inside such
      spheres. Stimulation of the helix activated the neck area of the SI in four of
      eight subjects, and both the neck and face areas in two. No activation was
      observed in two subjects. Stimulation of the lobulus activated the neck area in
      one subject, the face area in two, both in four, and neither in one. Stimulation
      of the tragus activated the face in four, both in three, and neither in one.
      These fMRI findings confirm the result of MEG that the representation of the ear
      in the SI is separated into neck and face areas.

PMID- 12414263
TI  - Multidimensional scaling of integrated neurocognitive function and schizophrenia
      as a disconnexion disorder.
AB  - Multidimensional scaling (MDS) is a multivariate statistical technique that can
      be used to define subsystems of functionally connected brain regions based on the
      analysis of functional magnetic resonance imaging (fMRI) data. Here we introduce
      three-way multidimensional scaling as a method for the analysis of a group of
      fMRI data, which yields both a generic interregional configuration in low
      dimensional space and a measure of each individual's deviation from the generic
      configuration. The distance between two generic interregional configurations
      obtained by MDS of two groups of data can be minimized by generalized Procrustes
      analysis, and the probability under the null hypothesis (that the two groups are
      sampled from the same population) of any residual group difference in
      interregional configurations can be assessed by a permutation test. These methods
      are developed and applied to activated fMRI time series acquired from 19 patients
      with schizophrenia and 20 normal comparison subjects during the performance of a
      semantic categorization and subvocal rehearsal task. The first three scaling
      dimensions are interpretable in terms of the major anatomical or functional
      subsystems of the activated system: "left-right," "input processing-other," and
      "subvocal output-other". We found no significant global or local differences
      between groups in interregional configurations in this 3D space. However, there
      was significantly greater variability of interregional configurations within the
      group of patients with schizophrenia. The implications for schizophrenia as a
      disconnexion disorder are discussed.

PMID- 12414264
TI  - Optical imaging of intrinsic signals induced by peripheral nerve stimulation in
      the in vivo rat spinal cord.
AB  - We examined neural response patterns evoked by peripheral nerve stimulation in in
      vivo rat spinal cords using an intrinsic optical imaging technique to monitor
      neural activity. Adult rats were anesthetized by urethane, and laminectomy was
      performed between C5 and Th1 to expose the dorsal surface of the cervical spinal
      cord. The median, ulnar, and radial nerves were dissected, and bipolar electrodes
      were implanted in the forelimb. Changes in optical reflectance were recorded from
      the dorsal cervical spinal cord in response to simultaneous stimulation of the
      median and ulnar nerves using a differential video acquisition system. In the
      region of the cervical spinal cord, intrinsic optical signals were detected
      between C5 and Th1 at wavelengths of 605, 630, 730, 750, and 850 nm: the image
      with the largest signal intensity and highest contrast was obtained at 605 nm.
      The signal intensity and response area expanded with an increase in the
      stimulation intensity and varied with the depth of the focal plane of the
      macroscope. The intrinsic optical response was mostly eliminated by Cd(2+),
      suggesting that the detected signals were mainly mediated by postsynaptic
      mechanisms activated by sensory nerve fibers. Furthermore, we succeeded in
      imaging neural activity evoked by individual peripheral nerve stimulation. We
      found that the response areas related to each peripheral nerve exhibited
      different spatial distribution patterns and that there were animal-to-animal
      variations in the evoked neural responses in the spinal cord. The results
      obtained in this study confirmed that intrinsic optical imaging is a very useful
      technique for acquiring fine functional maps of the in vivo spinal cord.

PMID- 12414265
TI  - Brain regions involved in fatigue sensation: reduced acetylcarnitine uptake into
      the brain.
AB  - Fatigue is an indispensable sense for ordering rest. However, the neuronal and
      molecular mechanisms of fatigue remain unclear. Chronic fatigue syndrome (CFS)
      with long-lasting fatigue sensation seems to be a good model for studying these
      mechanisms underlying fatigue sensation. Recently, we found that most patients
      with CFS showed a low level of serum acetylcarnitine, which well correlated with
      the rating score of fatigue, and that a considerable amount of acetyl moiety of
      serum acetylcarnitine is taken up into the brain. Here we show by metabolite
      analysis of the mouse brain that an acetyl moiety taken up into the brain through
      acetylcarnitine is mainly utilized for the biosynthesis of glutamate. When we
      studied the cerebral uptake of acetylcarnitine by using [2-(11)C]acetyl-L
      carnitine in 8 patients with CFS and in 8 normal age- and sex-matched controls, a
      significant decrease was found in several regions of the brains of the patient
      group, namely, in the prefrontal (Brodmann's area 9/46d) and temporal (BA21 and
      41) cortices, anterior cingulate (BA24 and 33), and cerebellum. These findings
      suggest that the levels of biosynthesis of neurotransmitters through
      acetylcarnitine might be reduced in some brain regions of chronic fatigue
      patients and that this abnormality might be one of the keys to unveiling the
      mechanisms of the chronic fatigue sensation.

PMID- 12414266
TI  - A role for top-down attentional orienting during interference between global and
      local aspects of hierarchical stimuli.
AB  - Various models of selective attention propose that greater attention is allocated
      toward target stimuli when conflicting distracters make selection more difficult,
      but compelling evidence to support this view is scarce. In the present
      experiment, 15 participants performed a cued global/local selective attention
      task while brain activity was recorded with event-related functional magnetic
      resonance imaging. The presence of conflicting versus nonconflicting distracters
      during target processing activated regions of frontal, parietal, and visual
      cortices that were also activated when participants oriented attention in
      response to global- and local-task cues. These findings support models in which
      conflict between target and distracter stimuli is resolved by more selectively
      focusing attention upon target stimuli.

PMID- 12414267
TI  - Time-coherent expansion of MEG/EEG cortical sources.
AB  - In this study we estimated the spatial extent of cortical areas of time-coherent
      activity using the inverse problem in magneto/electroencephalography (MEEG). The
      model discussed here uses classical regularization tools in order to force the
      inverse solution to be piecewise coherent. First, the cortex was seeded by focal
      dipolar sources. Then, a time-coherent expansion (TCE) onto the cortical surface
      was performed in order to obtain surface source models composed of patches with
      uniform current density. Patches represent extended cortical regions with one
      single time course per active area. Results obtained from synthetic data show
      that using the TCE method is relevant even with a low signal-to-noise ratio,
      although the final estimation is often slightly biased. We applied the TCE method
      to evoked magnetic fields obtained after electrical stimulation of fingers in
      order to estimate the somatotopic cortical maps of the primary somatosensory
      cortex.

PMID- 12414268
TI  - Hemispheric asymmetry in global/local processing: effects of stimulus position
      and spatial frequency.
AB  - We examined the neural mechanisms of functional asymmetry between hemispheres in
      the processing of global and local information of hierarchical stimuli by
      measuring hemodynamic responses with functional magnetic resonance imaging
      (fMRI). In a selective attention task, subjects responded to targets at the
      global or local level of compound letters that were (1) broadband in spatial
      frequency spectrum and presented at fixation; (2) broadband and presented
      randomly to the left or the right of fixation; or (3) contrast balanced (CB) to
      remove low spatial frequencies (SFs) and presented at fixation. Central broadband
      stimuli induced stronger activation in the right middle occipital cortex under
      global relative to local attention conditions but in the left inferior occipital
      cortex, stronger activation was induced under local relative to global attention
      conditions. The asymmetry over the occipital cortex was weakened by unilateral
      presentation and by contrast balancing. The results indicate that the
      lateralization of global and local processing is modulated by the position and SF
      spectrum of the compound stimuli. The global attention also produced stronger
      activation over the medial occipital cortex relative to the local attention under
      all the stimulus conditions. The nature of these effects is discussed.

PMID- 12414269
TI  - Human cortical dynamics determined by speech fundamental frequency.
AB  - Evidence for speech-specific brain processes has been searched for through the
      manipulation of formant frequencies which mediate phonetic content and which are,
      in evolutionary terms, relatively "new" aspects of speech. Here we used whole
      head magnetoencephalography and advanced stimulus reproduction methodology to
      examine the contribution of the fundamental frequency F0 and its harmonic integer
      multiples in cortical processing. The subjects were presented with a vowel, a
      frequency-matched counterpart of the vowel lacking in phonetic contents, and a
      pure tone. The F0 of the stimuli was set at that of a typical male (i.e., 100
      Hz), female (200 Hz), or infant (270 Hz) speaker. We found that speech sounds,
      both with and without phonetic content, elicited the N1m response in human
      auditory cortex at a constant latency of 120 ms, whereas pure tones matching the
      speech sounds in frequency, intensity, and duration gave rise to N1m responses
      whose latency varied between 120 and 160 ms. Thus, it seems that the fundamental
      frequency F0 and its harmonics determine the temporal dynamics of speech
      processing in human auditory cortex and that speech specificity arises out of
      cortical sensitivity to the complex acoustic structure determined by the human
      sound production apparatus.

PMID- 12414270
TI  - Neural correlates of artificial grammar learning.
AB  - Artificial grammar learning (AGL) is a form of nondeclarative memory that
      involves the nonconscious acquisition of abstract rules. While data from amnesic
      patients indicate that AGL does not depend on the medial temporal lobe, the
      neural basis of this type of memory is unknown and was therefore examined using
      event-related fMRI. Prior to scanning, participants studied letter strings
      constructed according to an artificial grammar. Participants then made
      grammaticality judgments about novel grammatical and nongrammatical strings while
      fMRI data were collected. The participants successfully acquired knowledge of the
      grammar, as evidenced by correct identification of the grammatical letter strings
      (57.4% correct; SE 1.9). During grammaticality judgments, widespread increases in
      activity were observed throughout the occipital, posterior temporal, parietal,
      and prefrontal cortical areas, reflecting the cognitive demands of the task. More
      specific analyses contrasting grammatical and nongrammatical strings identified
      greater activity in left superior occipital cortex and the right fusiform gyrus
      for grammatical stimuli. Increased activity was also observed in the left
      superior occipital and left angular gyrus for correct responses compared to
      incorrect. Comparing activity during grammaticality judgments versus a matched
      recognition control task again identified greater activation in the left angular
      gyrus. The network of areas exhibiting increased activity for grammatical stimuli
      appears to have more in common with studies examining word-form processing or
      mental calculation than the fluency effects previously reported for
      nondeclarative memory tasks such as priming and visual categorization. These
      results suggest that a novel nondeclarative memory mechanism supporting AGL
      exists in the left superior occipital and inferior parietal cortex.

PMID- 12414271
TI  - Brain activation during smooth-pursuit eye movements.
AB  - A potential application of studying eye movements with functional MRI (fMRI) is
      to examine patient populations with known eye movement dysfunction, but the
      reliability with which normal subjects demonstrate activity in specific brain
      regions has not been established. To date, fMRI studies of smooth-pursuit eye
      movements have used relatively small numbers of subjects and have been restricted
      to fixed-effects analyses. We extend these studies to whole brain imaging at 1.5
      T, properly accounting for intersubject variation using random effects analysis.
      Smooth-pursuit eye movements elicited activation consistently in dorsal cortical
      eye fields and cerebellum. Subcortical activation was greatly attenuated, but not
      eliminated, with the random-effects second-level analysis. In addition, session
      dependent changes in activation were greater in some regions than others and may
      indicate areas of brain, such as the supplementary eye fields, that are sensitive
      to attentional modulation of eye movements.

PMID- 12414272
TI  - Cortical deactivation induced by visual stimulation in human slow-wave sleep.
AB  - It has previously been demonstrated that sleeping and sedated young children
      respond with a paradoxical decrease in the blood oxygenation level-dependent
      (BOLD) functional magnetic resonance imaging (fMRI) signal in the rostro-medial
      occipital visual cortex during visual stimulation. It is unresolved whether this
      negative BOLD response pattern is of developmental neurobiological origin
      particular to a given age or to a general effect of sleep or sedative drugs. To
      further elucidate this issue, we used fMRI and positron emission tomography (PET)
      to study the brain activation pattern during visual stimulation in spontaneously
      sleeping adult volunteers. In five sleeping volunteers fMRI studies confirmed a
      robust signal decrease during stimulation in the rostro-medial occipital cortex.
      A similar relative decrease at the same location was found during visual
      stimulation and polysomnographically verified slow-wave sleep in a separate group
      of six subjects using H(2)(15)O PET measures of the regional cerebral blood flow
      (rCBF). This decrease was more rostro-dorsal compared to the relative rCBF
      increase along the calcarine sulcus found during visual stimulation in the awake
      state. This study reconfirms the previously described paradoxical stimulation
      correlated negative BOLD signal change in the rostro-medial occipital cortex,
      expanding this response mode to an age spectrum ranging from the newborn to the
      adult. Further, the use of complementary brain mapping techniques suggests that
      this decrease was secondary to a relative rCBF decrease. Possible mechanisms for
      the paradoxical response pattern during sleep include an active inhibition of the
      visual cortex or a disruption of an energy-consuming process.

PMID- 12414273
TI  - Role of operculoinsular cortices in human pain processing: converging evidence
      from PET, fMRI, dipole modeling, and intracerebral recordings of evoked
      potentials.
AB  - Insular and SII cortices have been consistently shown by PET, fMRI, EPs, and MEG
      techniques to be activated bilaterally by a nociceptive stimulation. The aim of
      the present study was to refer to, and to compare within a common stereotactic
      space, the nociceptive responses obtained in humans by (i) PET, (ii) fMRI, (iii)
      dipole modeling of scalp LEPs, and (iv) intracerebral recordings of LEPs. PET,
      fMRI, and scalp LEPs were obtained from normal subjects during thermal pain.
      Operculoinsular LEPs were obtained from 13 patients using deep brain electrodes
      implanted for presurgical evaluation of drug-resistant epilepsy. Whatever the
      technique, we obtained responses which were located bilaterally in the insular
      and SII cortices. In electrophysiological responses (LEPs) the SII insular
      contribution peaked between 150 and 250 ms poststimulus and corresponded to the
      earliest portions of the whole cerebral response. Group analysis of PET and fMRI
      data showed highly consistent responses contralateral to stimulation. On single
      subject analysis, LEPs and fMRI activations were concentrated in relatively
      restricted volumes even though spatial sampling was quite different for both
      techniques. Despite our multimodal approach, however, it was not possible to
      separate insular from SII activities. Individual variations in the anatomy and
      function of SII and insular cortices may explain this limitation. This multimodal
      study provides, however, cross-validated spatial and temporal information on the
      pain-related processes occurring in the operculoinsular region, which thus
      appears as a major site for the early cortical pain encoding in the human brain.

PMID- 12414274
TI  - Spatiotemporal imaging of electrical activity related to attention to
      somatosensory stimulation.
AB  - The aim of the present study was to localize the effects of spatial attention on
      somatosensory stimulation in EEG. Median and tibial nerve were stimulated at all
      four limbs in a random order. Subjects were instructed to count the events on
      either the right median or the right tibial nerve. Attention-induced changes in
      the somatosensory evoked potentials (SEP) were revealed by subtracting the median
      nerve SEPs recorded while subjects attended to stimuli applied to the tibial
      nerve from those obtained during attention to the stimulated hand. In a current
      density reconstruction approach source maxima in the time range from 30 to 260 ms
      after median nerve stimulation were localized and the time courses of activation
      were elaborated by dipole modeling. Six regions were identified which contribute
      significant source activity related to selective spatial attention: contralateral
      postcentral gyrus (Brodman area (BA) 3), contralateral mesial frontal gyrus (BA
      6), right posterior parietal cortex (BA 7), anterior cingulate gyrus (BA 32), and
      bilateral middle temporal gyrus (BA 21). Activation started at the right
      posterior parietal cortex, followed by the contralateral middle temporal gyrus,
      probably representing SII activity, and the middle frontal and anterior cingulate
      gyrus. Similar regions of source activation were revealed by tibial nerve SEP,
      but the effect was less pronounced and restricted almost entirely to activation
      of the contralateral postcentral gyrus (BA 3), anterior cingulate gyrus (BA 32),
      and ipsilateral middle temporal gyrus (BA 21). Our data provide evidence for a
      spatially separated frontal generator within the anterior cingulum, dependent on
      selective attention in the somatosensory modality.

PMID- 12414275
TI  - Single-shot interleaved z-shim EPI with optimized compensation for signal losses
      due to susceptibility-induced field inhomogeneity at 3 T.
AB  - A new single-shot echo-planar imaging (EPI) sequence with interleaved z-shim and
      optimized compensation for susceptibility-induced signal loss is proposed in this
      paper. Experiments on human brain demonstrated that the new method is able to
      regain signal dropout in brain areas with severe susceptibility-induced local
      gradients, while its image acquisition speed is comparable to that of
      conventional single-shot EPI techniques. Significant signal-to-noise ratio
      improvements were demonstrated in the ventral prefrontal and lateral temporal
      lobes with the new technique compared to a conventional EPI. Brain activation
      experiments with a bilateral finger-tapping task were performed with
      intentionally introduced local gradients near the left sensorimotor cortex, by a
      small gadolinium (Gd)-doped bottle placed on the left side of the head. The
      results of the functional experiments showed that the interleaved z-shim EPI
      sequence effectively recovered the signal loss caused by the Gd-doped bottle and
      reliably detected activation signals in bilateral sensorimotor regions, while the
      activation signals on the left side diminished considerably in a conventional EPI
      technique. The new technique, with the capability of reducing susceptibility
      artifacts and rapid scanning speed, may be particularly useful for event-related
      functional MRI experiments in the base of the brain, which are of great
      importance in neuropsychiatric studies.

PMID- 12414276
TI  - Hippocampal head size associated with verbal memory performance in nondemented
      elderly.
AB  - The hippocampus plays a crucial role in the consolidation of memory.
      Anatomically, the hippocampal head, body, and tail are connected to separate
      regions of the entorhinal cortex, which conveys processed information from the
      association cortices to the hippocampus. Little is known, however, about the
      functional segregation along its longitudinal axis. In the present study, we
      investigated whether the hippocampal head, body, or tail is selectively involved
      in verbal memory performance. A total of 511 nondemented participants, aged 60-90
      years, underwent a three-dimensional HASTE brain scan in a 1.5-T MRI unit.
      Hippocampal volumes were measured by manual tracing on coronal slices.
      Segmentation was performed in anterior-posterior direction on the basis of
      predefined cutoffs allocating 35, 45, and 20% of slices to the head, body, and
      tail, respectively. Memory performance was assessed by a 15-word learning test
      including tasks of immediate and delayed recall. To analyze the association
      between head, body, and tail volumes and memory performance, we used multiple
      linear regression, adjusting for age, sex, education, and midsagittal area as a
      proxy for intracranial volume. Participants with larger hippocampal heads scored
      significantly higher in the memory test, most notably in delayed recall (0.41
      word per SD increase in left hippocampal head (95% CI (0.16, 0.67)), 0.33 word
      per SD increase in right hippocampal head (95% CI 0.06, 0.59)). Our data suggest
      selective involvement of the hippocampal head in verbal memory, and add to recent
      findings of functional segregation along the longitudinal axis of the
      hippocampus.

PMID- 12414277
TI  - Topographic organization of the human primary and secondary somatosensory
      cortices: comparison of fMRI and MEG findings.
AB  - We studied MEG and fMRI responses to electric median and tibial nerve stimulation
      in five healthy volunteers. The aim was to compare the results with those of a
      previous study using only fMRI on the primary and secondary somatosensory
      cortices in which the somatotopic organization of SII was observed with fMRI. In
      the present work we focus on the comparison between fMRI activation and MEG
      equivalent current dipole (ECD) localizations in the SII area. The somatotopic
      organization of SII was confirmed by MEG, with the upper limb areas located more
      anteriorly and more inferiorly than the lower limb areas. In addition a
      substantial consistency of the ECD locations with the areas of fMRI activation
      was observed, with an average mismatch of about 1 cm. MEG ECDs and fMRI
      activation areas showed comparable differences in SI.

PMID- 12414278
TI  - Human vestibular cortex as identified with caloric stimulation in functional
      magnetic resonance imaging.
AB  - Anatomic and electrophysiological studies in monkeys have yielded a detailed map
      of cortex areas receiving vestibular afferents. In contrast, comparatively little
      is known about the cortical representation of the human vestibular system. In
      this study we applied caloric stimulation and fMRI to further characterize human
      cortical vestibular areas and to test for hemispheric dominance of vestibular
      information processing. For caloric vestibular stimulation we used cold nitrogen
      to avoid susceptibility artifacts induced by water calorics. Right and left side
      vestibular stimulation was repetitively performed inducing a nystagmus for at
      least 90 s after the end of the stimulation in all subjects. Only the first 60 s
      of this nystagmus period was included for statistical analysis and compared with
      the baseline condition. Activation maps revealed a cortical network with right
      hemispheric dominance, which in all subjects comprised the temporoparietal
      junction extending into the posterior insula and, furthermore, the anterior
      insula, pre- and postcentral gyrus, areas in the parietal lobe, the ventrolateral
      portion of the occipital lobe, and the inferior frontal gyrus extending into the
      inferior part of the precentral sulcus. In conclusion, caloric stimulation in
      fMRI reveals a widespread cortical network involved in vestibular signal
      processing corresponding to the findings from animal experiments and previous
      functional imaging studies in humans. Furthermore, this study demonstrates a
      strong right hemispheric dominance of vestibular cortex areas regardless of the
      stimulated side, consistent with the current view of a rightward asymmetrical
      cortical network for spatial orientation.

PMID- 12414279
TI  - Aging gracefully: compensatory brain activity in high-performing older adults.
AB  - Whereas some older adults show significant cognitive deficits, others perform as
      well as young adults. We investigated the neural basis of these different aging
      patterns using positron emission tomography (PET). In PET and functional MRI
      (fMRI) studies, prefrontal cortex (PFC) activity tends to be less asymmetric in
      older than in younger adults (Hemispheric Asymmetry Reduction in Old Adults or
      HAROLD). This change may help counteract age-related neurocognitive decline
      (compensation hypothesis) or it may reflect an age-related difficulty in
      recruiting specialized neural mechanisms (dedifferentiation hypothesis). To
      compare these two hypotheses, we measured PFC activity in younger adults, low
      performing older adults, and high-performing older adults during recall and
      source memory of recently studied words. Compared to recall, source memory was
      associated with right PFC activations in younger adults. Low-performing older
      adults recruited similar right PFC regions as young adults, but high-performing
      older adults engaged PFC regions bilaterally. Thus, consistent with the
      compensation hypothesis and inconsistent with the dedifferentiation hypothesis, a
      hemispheric asymmetry reduction was found in high-performing but not in low
      performing older adults. The results suggest that low-performing older adults
      recruited a similar network as young adults but used it inefficiently, whereas
      high-performing older adults counteracted age-related neural decline through a
      plastic reorganization of neurocognitive networks.

PMID- 12414280
TI  - Functional imaging of visuospatial processing in Alzheimer's disease.
AB  - Alzheimer's disease (AD) is known to cause a variety of disturbances of higher
      visual functions that are closely related to the neuropathological changes.
      Visual association areas are more affected than primary visual cortex.
      Additionally, there is evidence from neuropsychological and imaging studies
      during rest or passive visual stimulation that the occipitotemporal pathway is
      less affected than the parietal pathway. Our goal was to investigate functional
      activation patterns during active visuospatial processing in AD patients and the
      impact of local cerebral atrophy on the strength of functional activation.
      Fourteen AD patients and fourteen age-matched controls were measured with
      functional magnetic resonance imaging (fMRI) while they performed an angle
      discrimination task. Both groups revealed overlapping networks engaged in angle
      discrimination including the superior parietal lobule (SPL), frontal and
      occipitotemporal (OTC) cortical regions, primary visual cortex, basal ganglia,
      and thalamus. The most pronounced differences between the two groups were found
      in the SPL (more activity in controls) and OTC (more activity in patients). The
      differences in functional activation between the AD patients and controls were
      partly explained by the differences in individual SPL atrophy. These results
      indicate that parietal dysfunction in mild to moderate AD is compensated by
      recruitment of the ventral visual pathway. We furthermore suggest that local
      cerebral atrophy should be considered as a covariate in functional imaging
      studies of neurodegenerative disorders.

PMID- 12414281
TI  - A spatio-temporal regression model for the analysis of functional MRI data.
AB  - The standard method for analyzing functional magnetic resonance imaging (fMRI)
      data applies the general linear model to the time series of each voxel
      separately. Such a voxelwise approach, however, does not consider the spatial
      autocorrelation between neighboring voxels in its model formulation and parameter
      estimation. We propose a spatio-temporal regression analysis for detecting
      activation in fMRI data. Its main features are that (1) each voxel has a
      regression model that involves the time series of the neighboring voxels together
      with its own, (2) the regression coefficient assigned to the center voxel is
      estimated so that the time series of these multiple voxels will best fit the
      model, (3) a generalized least squares (GLS) method was employed instead of the
      ordinary least squares (OLS) to put intrinsic autocorrelation structures into the
      model, and (4) the underlying spatial and temporal correlation structures are
      modeled using a separable model which expresses the combined correlation
      structures as a product of the two. We evaluated the statistical power of our
      model in comparison with voxelwise OLS/GLS models and a multivoxel OLS model. Our
      model's power to detect clustered activation was higher than that of the two
      voxelwise models and comparable to that of the multivoxel OLS. We examined the
      usefulness and goodness of fit of our model using real experimental data. Our
      model successfully detected neural activity in expected brain regions and
      realized better fit than the other models. These results suggest that our spatio
      temporal regression model can serve as a reliable analysis suited for the nature
      of fMRI data.

PMID- 12414282
TI  - Dysmyelination revealed through MRI as increased radial (but unchanged axial)
      diffusion of water.
AB  - Myelin loss and axonal damage are both observed in white matter injuries. Each
      may have significant impact on the long-term disability of patients. Currently,
      there does not exist a noninvasive biological marker that enables differentiation
      between myelin and axonal injury. We describe herein the use of magnetic
      resonance diffusion tensor imaging (DTI) to quantify the effect of dysmyelination
      on water directional diffusivities in brains of shiverer mice in vivo. The
      principal diffusion eigenvalues of eight axonal fiber tracts that can be
      identified with certainty on DTI maps were measured. The water diffusivity
      perpendicular to axonal fiber tracts, lambda(perpendicular), was significantly
      higher in shiverer mice compared with age-matched controls, reflecting the lack
      of myelin and the increased freedom of cross-fiber diffusion in white matter. The
      water diffusivity parallel to axonal fiber tracts, lambda(parallel), was not
      different, which is consistent with the presence of intact axons. It is clear
      that dysmyelination alone does not impact lambda(parallel). The presence of
      intact axons in the setting of incomplete myelination was confirmed by electron
      microscopy. Although further validation is still needed, our finding suggests
      that changes in lambda(perpendicular) and lambda(parallel) may potentially be
      used to differentiate myelin loss versus axonal injury.

PMID- 12414283
TI  - Event-related functional MRI study on central representation of acute muscle pain
      induced by electrical stimulation.
AB  - Although pathological muscle pain involves a significantly larger population than
      any other pain condition, the central mechanisms are less explored than those of
      cutaneous pain. The aims of the study were to establish the pain matrix for
      muscle pain in the full head volume and, further, to explore the possibility of a
      functional segregation to nonpainful and painful stimuli within the area of the
      parasylvian cortex corresponding to the secondary somatosensory area.
      Additionally, we speculate that a randomization of nonpainful and painful stimuli
      may target specific structures related to stimulus salience. We used event
      related functional magnetic resonance imaging (MRI) and the high sensitivity of
      the 3-T MRI scanner to study the central processing of acute muscle pain induced
      by intramuscular electrostimulation. Brief nonpainful and painful stimuli (1-ms
      duration, interstimulus interval = 12 s) were randomly applied to the left
      abductor pollicis brevis of 10 subjects. The data disclose a pain matrix for
      muscle pain similar to that for cutaneous pain. Individual analysis suggests
      separate representations within the area bounded by the upper bank of the Sylvian
      fissure (SF) and the circular sulcus of insula (CSI). Nonpainful stimulation
      activated the superficial parietal operculum adjoining the SF, while the painful
      condition additionally targeted the deeper parietal operculum bordering the CSI.
      Randomization of stimuli of different intensities likely introduces cognitive
      components that engage neural substrates servicing the appreciation of stimulus
      salience in the context of affect-laden pain imposition.

PMID- 12414284
TI  - Functional organization of primary somatosensory cortex depends on the focus of
      attention.
AB  - We used magnetic source imaging in human subjects to reveal within-subject
      variations of the homuncular hand representation within the primary somatosensory
      cortex modulated by attention. In one condition subjects were trained to detect
      sequential leftward or rightward stimulus motion across the fingers of the left
      hand ("hand" condition) and in a different condition to detect stimulus motion at
      a specific finger on this hand ("finger" condition). Afferent input was
      controlled by applying exactly the same stimulus pattern to the digits in the two
      tasks. Segregation of the somatotopic hand representation (an increase in the
      distance between the representations of digits 2 and 5) was observed, commencing
      with the onset of practice, in the finger relative to the hand condition.
      Subsequent training in the hand and finger conditions with feedback for
      correctness did not modify segregation, indicating that segregation was a task
      effect and not a training effect. These findings indicate that the hand
      representation within the primary somatosensory cortex is not statically fixed
      but is dynamically modulated by top-down mechanisms to support task requirements.
      A greater capacity for modulation of the functional cortical organization was
      positively correlated with superior learning and task performance.

PMID- 12414285
TI  - Effective connectivity and intersubject variability: using a multisubject network
      to test differences and commonalities.
AB  - This article is about intersubject variability in the functional integration of
      activity in different brain regions. Previous studies of functional and effective
      connectivity have dealt with intersubject variability by analyzing data from
      different subjects separately or pretending the data came from the same subject.
      These approaches do not allow one to test for differences among subjects. The aim
      of this work was to illustrate how differences in connectivity among subjects can
      be addressed explicitly using structural equation modeling. This is enabled by
      constructing a multisubject network that comprises m regions of interest for each
      of the n subjects studied, resulting in a total of m x n nodes. Constructing a
      network of regions from different subjects may seem counterintuitive but embodies
      two key advantages. First, it allows one to test directly for differences among
      subjects by comparing models that do and do not allow a particular connectivity
      parameter to vary over subjects. Second, a multisubject network provides
      additional degrees of freedom to estimate the model's free parameters. Any
      neurobiological hypothesis normally addressed by single-subject or group analyses
      can still be tested, but with greater sensitivity. The common influence of
      experimental variables is modeled by connecting a virtual node, whose time course
      reflects stimulus onsets, to the sensory or "input" region in all subjects.
      Further experimental changes in task or cognitive set enter through modulation of
      the connections. This approach allows one to model both endogenous (or intrinsic)
      variance and exogenous effects induced by experimental design. We present a
      functional magnetic resonance imaging study that uses a multisubject network to
      investigate intersubject variability in functional integration in the context of
      single word and pseudoword reading. We tested whether the effect of word type on
      the reading-related coupling differed significantly among subjects. Our results
      showed that a number of forward and backward connections were stronger for
      reading pseudowords than words, and, in one case, connectivity showed significant
      intersubject variability. The discussion focuses on the implications of our
      findings and on further applications of the multisubject network analysis.

PMID- 12414286
TI  - In vivo serotonin 5HT(2A) receptor binding and personality traits in healthy
      subjects: a positron emission tomography study.
AB  - Using positron emission tomography (PET) and [(11)C]raclopride, an association
      between striatal D(2) dopamine receptors and emotional detachment has been
      recently reported. Several laboratory findings indicate a link between the
      serotoninergic system and harm avoidance. In this study we investigated, in a
      group of healthy volunteers, the relationship between the in vivo binding of 3
      (2'-[(18)F]fluoroethyl)spiperone ([(18)F]FESP) to cortical 5HT(2) and striatal
      D(2) receptors and three personality dimensions, i.e., "novelty seeking," "reward
      dependence," and "harm avoidance." Eleven healthy volunteers were evaluated by
      means of the Tridimensional personality Questionnaire (C. R., Arch. Gen.
      Psychiatry 44: 573-588.) and underwent a PET scan with [(18)F]FESP. Harm
      avoidance showed a significant inverse correlation with [(18)F]FESP binding in
      the cerebral cortex, particularly in the frontal cortex (R(2) = -0.709, P =
      0.0145) and left parietal cortex (R = -0.629, P = 0.038) but not in the basal
      ganglia (r = -0.176, P = 0.651). Similar results were obtained using SPM at a P
      threshold of 0.05. No significant correlation was observed with novelty seeking
      or reward dependence. In the cerebral cortex, high values of [(18)F]FESP binding
      values are associated with a high tendency to avoid danger, indicating
      involvement of the serotoninergic system and, in particular, 5HT(2A) receptors,
      in this trait of personality. The results of this as well as of previous studies
      on personality dimensions indicate the existence of a relationship between
      behavioral and neurobiological factors. In addition these results support the
      concept that the variability of PET data may be explained by neurochemical
      differences related to the prevalence of specific personality traits.

PMID- 12414287
TI  - Syntactic processing modulates the theta rhythm of the human EEG.
AB  - Changes in oscillatory brain dynamics can be studied by means of induced band
      power (IBP) analyses, which quantify event-related changes in amplitude of
      frequency-specific EEG rhythms. Such analyses capture EEG phenomena that are not
      part of traditional event-related potential measures. The present study
      investigated whether IBP changes in the delta, theta, and alpha frequency ranges
      are sensitive to syntactic violations in sentences. Subjects read sentences that
      either were correct or contained a syntactic violation. The violations were
      either grammatical gender agreement violations, where a prenominal adjective was
      not appropriately inflected for the head noun's gender, or number agreement
      violations, in which a plural quantifier was combined with a singular head noun.
      IBP changes of the concurrently measured EEG were computed in five frequency
      bands of 2-Hz width, individually adjusted on the basis of subjects' alpha peak,
      ranging approximately from 2 to 12 Hz. Words constituting a syntactic violation
      elicited larger increases in theta power than the same words in a correct
      sentence context, in an interval of 300-500 ms after word onset. Of all the
      frequency bands studied, this was true for the theta frequency band only. The
      scalp topography of this effect was different for different violations: following
      number violations a left-hemispheric dominance was found, whereas gender
      violations elicited a right-hemisphere dominance of the theta power increase.
      Possible interpretations of this effect are considered in closing.

PMID- 12414288
TI  - Early parallel processing of auditory word and voice information.
AB  - The present study investigates the relationship of linguistic (phonetic) and
      extralinguistic (voice) information in preattentive auditory processing. We
      provide neurophysiological data, which show for the first time that both kinds of
      information are processed in parallel at an early preattentive stage. In order to
      establish the temporal and spatial organization of the underlying neuronal
      processes, we studied the conjunction of voice and word deviations in a mismatch
      negativity experiment, whereby the listener's brain responses were collected
      using magnetoencephalography. The stimuli consisted of single spoken words,
      whereby the deviants manifested a change of the word, of the voice, or both word
      and voice simultaneously (combined). First, we identified the N100m (overlain by
      mismatch field, MMF) and localized its generators, analyzing N100 m/MMF latency,
      dipole localization, and dipole strength. While the responses evoked by deviant
      stimuli were more anterior than the standard, localization differences between
      the deviants could not be shown. The dipole strength was larger for deviants than
      the standard stimulus, but again, no differences between the deviants could be
      established. There was no difference in the hemispheric lateralization of the
      responses. However, a difference between the deviants was observed in the
      latencies. The N100 m/MMF revealed a significantly shorter and less variant
      latency for the combined stimulus compared to all other experimental conditions.
      The data suggest an integral parallel processing model, which describes the early
      extraction of phonetic and voice information from the speech signal as parallel
      and contingent processes.

PMID- 12414289
TI  - Sexual dimorphism in the corpus callosum: a characterization of local size
      variations and a classification driven approach to morphometry.
AB  - We present two complementary quantitative approaches to the problem of
      characterizing morphometric variations between two distinct populations. The case
      presented focuses solely on local size variations, but the general method can
      easily be applied to other scalar morphometric quantities. The first method uses
      a statistical parametric map (SPM) to ascertain a P value, which indicates
      whether any statistically significant differences exist between the populations.
      The second method focuses on finding the best single measurement which can be
      used for classifying the two populations. For our case study midsagittal cross
      sections of the corpora callosa from a population of normal males and females are
      nonrigidly registered (spatially normalized) to an atlas. The resulting
      deformations are then used to ascertain (i) whether there are any statistically
      significant differences between the populations and (ii) whether these
      differences allow one to perform classification. We make use of the Jacobian of
      the deformation field and normalize it to account for overall volume changes
      allowing us to focus on differences which are more related to morphometry than
      scale. From the (SPM) approach to the problem we find evidence of statistically
      significant differences in the morphology between the populations. Using a linear
      discriminant function we find that these differences do not appear to be useful
      for classification. Thus, this dataset provides an example of how statistically
      significant effects may not be of much diagnostic value. They may be of interest
      to the research community, but of little value to the clinician.

PMID- 12414290
TI  - Parietal magnetic stimulation delays visuomotor mental rotation at increased
      processing demands.
AB  - Visuomotor rotation (VMR) is a variant of the classic mental rotation paradigm.
      Subjects perform a center-out arm reaching movement, with the instruction to
      point clockwise or anticlockwise away from the direction of a reaction signal by
      a prespecified amount. Like classic mental rotation (MR) tasks, there is a linear
      relationship between reaction time (RT) and required angle of rotation (angular
      disparity). Although functional imaging studies have consistently demonstrated
      parietal activations centered around the intraparietal sulcus during MR tasks,
      the involvement of parietal cortex in VMR has not been investigated. The aim of
      the present experiments was to test in human subjects whether VMR also involves
      activity in parietal areas. We used short trains of transcranial magnetic
      stimulation (TMS) to produce a temporary "virtual lesion" of the posterior
      parietal cortex (PPC) around the intraparietal sulcus during the reaction period
      of a VMR task. Four pulses of 20-Hz rTMS were applied to the left PPC, right PPC,
      or vertex (control condition) 100 ms after the presentation of an instruction
      cue. Reaction times (RTs) were evenly prolonged by right or left parietal TMS
      compared with vertex stimulation, but only for large angles of rotation, and
      without affecting the spatial accuracy of the final response. A control
      experiment showed that parietal rTMS did not impair visual perception or the
      ability to judge the size of visual angles. The data thus provide evidence for
      bilateral involvement of the PPC in VMR that increases with processing demands.

PMID- 12414291
TI  - Noise reduction in BOLD-based fMRI using component analysis.
AB  - Principle Component Analysis (PCA) and Independent Component Analysis (ICA) were
      used to decompose the fMRI time series signal and separate the BOLD signal change
      from the structured and random noise. Rather than using component analysis to
      identify spatial patterns of activation and noise, the approach we took was to
      identify PCA or ICA components contributing primarily to the noise. These noise
      components were identified using an unsupervised algorithm that examines the
      Fourier decomposition of each component time series. Noise components were then
      removed before subsequent reconstruction of the time series data. The BOLD
      contrast sensitivity (CS(BOLD)), defined as the ability to detect a BOLD signal
      change in the presence of physiological and scanner noise, was then calculated
      for all voxels. There was an increase in CS(BOLD) values of activated voxels
      after noise reduction as a result of decreased image-to-image variability in the
      time series of each voxel. A comparison of PCA and ICA revealed significant
      differences in their treatment of both structured and random noise. ICA proved
      better for isolation and removal of structured noise, while PCA was superior for
      isolation and removal of random noise. This provides a framework for using and
      evaluating component analysis techniques for noise reduction in fMRI.

PMID- 12414292
TI  - Effects of word form on brain processing of written Chinese.
AB  - Both logographic characters and alphabetic pinyins can be used to write words in
      Chinese. Here we use fMRI to address the question of whether the written form
      affects brain processing of a word. Fifteen healthy, right-handed, native Chinese
      reading volunteers participated in our study and were asked to read silently
      either Chinese characters (8 subjects) or pinyins (7 subjects). The stimulus
      presentation rate was varied for both tasks to allow us to identify brain regions
      with word-load-dependent activation. Rate effects (fast minus slow presentations)
      for Chinese character reading were observed in striate and extrastriate visual
      cortex, superior parietal lobule, left posterior middle temporal gyrus, bilateral
      inferior temporal gyri, and bilateral superior frontal gyri. Rate effects for
      pinyin reading were observed in bilateral fusiform, lingual, and middle occipital
      gyri, bilateral superior parietal lobule/precuneus, left inferior parietal
      lobule, bilateral inferior temporal gyrus, left middle temporal gyrus, and left
      superior temporal gyrus. These results demonstrate that common regions of the
      brain are involved in reading both Chinese characters and pinyins, activated
      apparently independently of the surface form of the word. There also appear to be
      brain regions in which activation is dependent on word form. However, it is
      unlikely that these are entirely specific for a given word form; their activation
      more likely reflects relative functional specializations within broader networks
      for processing written language.

PMID- 12414293
TI  - The neural basis for categorization in semantic memory.
AB  - We asked young adults to categorize written object descriptions into one of two
      categories, based on a rule or on overall similarity, while we monitored regional
      brain activity with functional magnetic resonance imaging (fMRI). We found
      significantly greater recruitment of left dorsolateral prefrontal cortex for rule
      based categorization in direct comparison with similarity-based categorization.
      Recruitment of right ventral frontal cortex and thalamus was uniquely associated
      with rule-based categorization as well. These observations lend support to the
      claim that executive functions such as working memory, inhibitory control, and
      selective attention contribute to rule-based categorization. Right inferior
      parietal activation was uniquely associated with similarity-based categorization.
      This region may play an important role in overall feature configuration that is
      important for this form of categorization. We found other brain regions recruited
      for both rule-based and similarity-based categorization: Anterior cingulate
      cortex may support the implementation of executive functions during situations
      with competing response alternatives; and left inferior parietal cortex may be
      related to the integration of feature knowledge about objects represented in
      modality-specific association cortices. We also administered a degraded
      similarity condition where the task of categorizing a written object description
      was made more difficult by perceptually degrading the stimulus materials. The
      degraded condition and the rule-based condition, but not the similarity-based
      condition, were associated with caudate activation. The caudate may support
      resource demands that are not specific for a particular categorization process.
      These findings associate partially distinct large-scale neural networks with
      different forms of categorization in semantic memory.

PMID- 12414294
TI  - Dissociable contributions of prefrontal and parietal cortices to response
      selection.
AB  - The ability to select between possible responses to a given situation is central
      to human cognition. The goal of this study was to distinguish between brain areas
      representing candidate responses and areas selecting between competing response
      alternatives. Event-related fMRI data were acquired while 10 healthy adults
      performed a task used to examine response competition: the Eriksen flanker task.
      Left parietal cortex was activated by either of two manipulations that increased
      the need to maintain a representation of possible responses. In contrast, lateral
      prefrontal and rostral anterior cingulate cortices were specifically engaged by
      the need to select among competing response alternatives. These findings support
      the idea that parietal cortex is involved in activating possible responses on the
      basis of learned stimulus-response associations, and that prefrontal cortex is
      recruited when there is a need to select between competing responses.

PMID- 12414295
TI  - Magnetization transfer measurements of brain structures in patients with multiple
      system atrophy.
AB  - To determine whether magnetization transfer imaging (MTI) demonstrates
      abnormalities in the brain structures of patients with multiple system atrophy
      (MSA), we examined 12 patients with clinically probable MSA and 11 control
      subjects. We calculated magnetization transfer ratios (MTRs) using region of
      interest analysis from MTI and assessed abnormal signal changes on T2-weighted
      images. MTRs of the base of the pons, middle cerebellar peduncle, putamen, and
      white matter of the precentral gyrus were significantly lower in the MSA patients
      than in the controls. Abnormal signal changes on T2-weighted images were observed
      in the base of the pons (n = 6), middle cerebellar peduncle (n = 7), and putamen
      (n = 7). MTRs of regions with abnormal signals were significantly lower than
      those of regions without abnormal signals and those in the controls. Even the
      MTRs of the regions without abnormal signals were lower than those in the
      controls. MTRs of the pyramidal tract, including white matter of the precentral
      gyrus, posterior limb of the internal capsule, cerebral peduncle, and base of the
      pons, were significantly lower in patients with pyramidal tract sign (n = 7) than
      in the controls. Patients with asymmetrical parkinsonism (n = 5) showed
      significantly lower MTRs in the putamen contralateral to the predominant side of
      parkinsonian symptoms than the ipsilateral side, although asymmetry of abnormal
      signal changes on T2-weighted images was not evident in more than half of those
      patients. This study showed that MTI demonstrates abnormalities in the brains of
      patients with MSA that seem to reflect underlying pathological changes and that
      the pathological changes detected by MTI seem to give rise to clinical symptoms.
      This study also showed that the abnormalities are detected more sensitively and
      over a larger area by MTI than by conventional magnetic resonance imaging.

PMID- 12414296
TI  - Spanish language mapping using MEG: a validation study.
AB  - The purpose of the present study was to compare magnetoencephalography (MEG) data
      with the results of the intracarotid amytal procedure (IAP). Twenty-one native
      Spanish-speaking patients with intractable epilepsy underwent MEG language
      mapping. A subset of 8 patients also underwent an IAP. With the exception of 2
      patients who showed right hemisphere dominance, all other patients showed left
      hemisphere dominance for language on the MEG recording. The IAP findings were
      consistent with MEG results in 7 patients. The eighth patient who, according to
      the MEG data, had probable right hemisphere dominance for language did not show
      clear hemispheric specialization for language on the IAP and suffered a transient
      global aphasia following a right temporal lobotomy. These results suggests that
      MEG-based language mapping can play an important role in presurgical clinical
      evaluation.

PMID- 12414297
TI  - Automated histogram-based brain segmentation in T1-weighted three-dimensional
      magnetic resonance head images.
AB  - Current semiautomated magnetic resonance (MR)-based brain segmentation and volume
      measurement methods are complex and not sufficiently accurate for certain
      applications. We have developed a simpler, more accurate automated algorithm for
      whole-brain segmentation and volume measurement in T(1)-weighted, three
      dimensional MR images. This histogram-based brain segmentation (HBRS) algorithm
      is based on histograms and simple morphological operations. The algorithm's three
      steps are foreground/background thresholding, disconnection of brain from skull,
      and removal of residue fragments (sinus, cerebrospinal fluid, dura, and marrow).
      Brain volume was measured by counting the number of brain voxels. Accuracy was
      determined by applying HBRS to both simulated and real MR data. Comparing the
      brain volume rendered by HBRS with the volume on which the simulation is based,
      the average error was 1.38%. By applying HBRS to 20 normal MR data sets
      downloaded from the Internet Brain Segmentation Repository and comparing them
      with expert segmented data, the average Jaccard similarity was 0.963 and the
      kappa index was 0.981. The reproducibility of brain volume measurements was
      assessed by comparing data from two sessions (four total data sets) with human
      volunteers. Intrasession variability of brain volumes for sessions 1 and 2 was
      0.55 +/- 0.56 and 0.74 +/- 0.56%, respectively; the mean difference between the
      two sessions was 0.60 +/- 0.46%. These results show that the HBRS algorithm is a
      simple, fast, and accurate method to determine brain volume with high
      reproducibility. This algorithm may be applied to various research and clinical
      investigations in which brain segmentation and volume measurement involving MRI
      data are needed.

PMID- 12414298
TI  - What does the frontomedian cortex contribute to language processing: coherence or
      theory of mind?
AB  - The frontomedian cortex (FMC) has been shown to be important for coherence
      processes in language comprehension, i.e., for establishing the pragmatic
      connection between successively presented sentences. The same brain region has a
      role during theory-of-mind processes, i.e., during the attribution of other
      people's actions to their motivations, beliefs, or emotions. In this study, we
      used event-related functional magnetic resonance imaging at 3 T to disentangle
      the relative contributions of the FMC to theory-of-mind (ToM) and coherence
      processes, respectively. The BOLD response of nine participants was recorded
      while they listened to pragmatically coherent or unrelated sentence pairs. Using
      a logic instruction for inanimate sentence pairs, ToM processing was discouraged
      during the first part of the experiment. Using explicit ToM instructions for
      sentence pairs mentioning human protagonists, ToM processing was induced during
      the second part. In three of the resulting four conditions a significant increase
      in the BOLD response was observed in FMC: when ToM instructions were given, both
      coherent and incoherent trials elicited frontomedian activation, in replication
      of previous results showing involvement of the FMC during ToM tasks. When logic
      instructions were given, the coherent trials, but not the incoherent trials,
      activated the FMC. These results clearly show that the FMC plays a role in
      coherence processes even in the absence of concomitant ToM processes. The
      findings support the view of this cortex having a domain-independent
      functionality related to volitional aspects of the initiation and maintenance of
      nonautomatic cognitive processes.

PMID- 12414299
TI  - Voxel-based morphometry reveals increased gray matter density in Broca's area in
      male symphony orchestra musicians.
AB  - Broca's area is a major neuroanatomical substrate for spoken language and various
      musically relevant abilities, including visuospatial and audiospatial
      localization. Sight reading is a musician-specific visuospatial analysis task,
      and spatial ability is known to be amenable to training effects. Musicians have
      been reported to perform significantly better than nonmusicians on spatial
      ability tests, which is supported by our findings with the Benton judgement of
      line orientation (JOL) test (P < 0.001). We hypothesised that use-dependent
      adaptation would lead to increased gray matter density in Broca's area in
      musicians. Voxel-based morphometry (VBM) and stereological analyses were applied
      to high-resolution 3D MR images in male orchestral musicians (n = 26) and sex,
      handedness, and IQ-matched nonmusicians (n = 26). The wide age range (26 to 66
      years) of volunteers permitted a secondary analysis of age-related effects. VBM
      with small volume correction (SVC) revealed a significant (P = 0.002) region of
      increased gray matter in Broca's area in the left inferior frontal gyrus in
      musicians. We observed significant age-related volume reductions in cerebral
      hemispheres, dorsolateral prefrontal cortex subfields bilaterally and gray matter
      density in the left inferior frontal gyrus in controls but not musicians; a
      positive correlation between JOL test score and age in musicians but not
      controls; a positive correlation between years of playing and the volume of gray
      matter in a significant region identified by VBM in under-50-year-old musicians.
      We suggest that orchestral musical performance promotes use-dependent retention,
      and possibly expansion, of gray matter involving Broca's area and that this
      provides further support for shared neural substrates underpinning expressive
      output in music and language.

PMID- 12414300
TI  - Motor imagery in mental rotation: an fMRI study.
AB  - Twelve right-handed men performed two mental rotation tasks and two control tasks
      while whole-head functional magnetic resonance imaging was applied. Mental
      rotation tasks implied the comparison of different sorts of stimulus pairs, viz.
      pictures of hands and pictures of tools, which were either identical or mirror
      images and which were rotated in the plane of the picture. Control tasks were
      equal except that stimuli pairs were not rotated. Reaction time profiles were
      consistent with those found in previous research. Imaging data replicate classic
      areas of activation in mental rotation for hands and tools (bilateral superior
      parietal lobule and visual extrastriate cortex) but show an important difference
      in premotor area activation: pairs of hands engender bilateral premotor
      activation while pairs of tools elicit only left premotor brain activation. The
      results suggest that participants imagined moving both their hands in the hand
      condition, while imagining manipulating objects with their hand of preference
      (right hand) in the tool condition. The covert actions of motor imagery appear to
      mimic the "natural way" in which a person would manipulate the object in reality,
      and the activation of cortical regions during mental rotation seems at least in
      part determined by an intrinsic process that depends on the afforded actions
      elicited by the kind of stimuli presented.

PMID- 12414301
TI  - Lateral temporal hyperperfusion in postictal psychosis assessed by 99mTc-HMPAO
      SPECT.
AB  - Postictal psychosis is a rare complication of epileptic seizure characterized by
      reversible psychotic symptoms after flurries of seizure attack. It has been
      attributed to a phenomenon similar to Todd's paralysis without definitive proof.
      We studied regional cerebral blood flow (rCBF) of six patients with postictal
      psychosis by (99m)Tc-HMPAO SPECT scan. Baseline rCBF was compared with the rCBF
      during postictal psychosis. An asymmetry index (ASI) was calculated as 200 x
      [(ipsilateral ROI count density - contralateral ROI count density)/(ipsilateral
      ROI count density + contralateral ROI count density)] %. Significant differences
      could be found between ASIs during postictal psychosis and interictal state SPECT
      scan over the lateral temporal neocortex region (P = 0.017). Although
      hyperperfusion abnormality in SPECT can be found in Todd's paralysis, such
      findings are more commonly found in cerebral hyperactivity conditions. Taking
      into account the clinical characteristics of postictal psychosis, namely a
      preceding lucid interval and crescendo-decrescendo clinical course, these may be
      an alternative psychopathogenic mechanism for the development of postictal
      psychosis.

PMID- 12414302
TI  - Relationships among brain metabolites, cognitive function, and viral loads in
      antiretroviral-naive HIV patients.
AB  - This study aims to determine the relationship among cerebral metabolite
      concentrations (on proton magnetic resonance spectroscopy or (1)H MRS), cognitive
      function, and clinical variables (CD4, plasma and CSF viral loads, and lipids) in
      antiretroviral medication-nai;ve HIV patients. We hypothesized that the probable
      glial markers myo-inositol [MI] and choline compounds [CHO] would correlate with
      cognitive function, CD4 count, and viral loads, but not with serum lipids. Forty
      five antiretroviral-drug-nai;ve HIV patients and 25 control subjects were
      evaluated. Frontal lobe [MI], [CHO], and total creatine [CR] were elevated, while
      basal ganglia [CR] were decreased, with increasing dementia severity. As a group,
      HIV patients showed slowing on fine motor (Grooved Pegboard) and psychomotor
      function (Trails A & B), and deficits on executive function (Stroop tasks). Lower
      CD4 counts and elevated plasma viral loads were associated with elevated frontal
      white matter [MI], which in turn correlated with the Stroop tasks. These findings
      suggest that systemic factors (resulting from suppressed immune function and
      higher plasma viral load) may lead to glial proliferation (elevated [MI], [CHO],
      and [CR]) in the frontal white matter, which in turn may contribute to deficits
      on executive function in HIV. Studying antiretroviral-nai;ve patients minimized
      the confounding effects of antiretroviral treatment on the clinical, MRS, and
      neuropsychological variables, and allowed for a more accurate assessment of the
      relationships among these measurements. Metabolite concentrations, rather than
      metabolite ratios, should be measured since [CR], a commonly used reference for
      metabolite ratios, varies with disease severity in both frontal lobe and basal
      ganglia.

PMID- 12414303
TI  - Optical scatter imaging detects mitochondrial swelling in living tissue slices.
AB  - Mitochondrial swelling is observed in neuronal injury and is a key event in many
      pathways to cell death. Currently, there is no technique for directly measuring
      mitochondrial size changes within living tissue slices with a field of view of
      several millimeters. In this paper, we test our hypothesis that Mie light-scatter
      theory can be used to study mitochondrial swelling in living tissue sections.
      Using a unique dual-angle scatter ratio (DASR) optical imaging system previously
      demonstrated to be sensitive to latex particle size changes and N-methyl-D
      aspartate (NMDA) treatment of hippocampal slices, we studied mitochondrial
      swelling induced by 500 microM NMDA treatment of hippocampal slices. We observed
      a strong (R(2) = 0.73) and significant (P < 0.000005) correlation between the
      electron microscopy-determined diameters of swollen, intact mitochondria and the
      DASR imaging. We examined the robustness of the technique by evaluating the
      correlation between the dual-angle scatter ratio and the diameter of the
      dendrites, observed to swell, in NMDA-treated slices and found no correlation
      (R(2) = 0.06). The advantage of DASR imaging over electron microscopy or other
      methods of studying mitochondrial swelling is the sensitivity of DASR imaging to
      mitochondrial swelling over a large field of view (>9 mm(2)) in an intact tissue
      slice. This novel technique may allow for the study of regional changes in
      mitochondrial swelling and recovery as sequential events within a single
      specimen. This technique will eventually be useful in studying the efficacy of
      stroke and other disease therapies targeting mitochondrial swelling.

PMID- 12414304
TI  - The neural basis of intrusions in free recall and cued recall: a PET study in
      Alzheimer's disease.
AB  - This study was designed to map in Alzheimer's disease patients the correlations
      between resting-state brain glucose utilization measured by PET and the number of
      intrusions obtained by means of a specially designed episodic memory test
      separately in free recall and in cued recall. SPM revealed significant negative
      correlations between the number of intrusions in free recall and the metabolism
      of the right superior frontal gyrus. For the intrusions in cued recall, the
      negative correlations concerned the left rhinal cortex. Our findings suggest that
      intrusions in free recall reflect perturbations in strategic processes and that
      intrusions in cued recall are triggered by the cue in a relatively automatic
      manner. Frontal dysfunction would be responsible for the former and rhinal
      dysfunction for the latter.

PMID- 12414305
TI  - Molecular phylogenetics of the Diprotodontia (kangaroos, wombats, koala, possums,
      and allies).
AB  - Mitochondrial ND2 sequences were used to investigate the phylogenetic
      relationships amongst 31 diprotodontid marsupials (kangaroos, wombats, koala,
      possums, and allies). ND2 sequences were analyzed separately and in conjunction
      with available 12S rDNA sequences for 22 diprotodontid taxa. Phylogenetic
      analyses consistently identified monophyly for the Burramyoidea, Phalangeroidea,
      Petauroidea, Tarsipedoidea, Macropodoidea, and the Vombatiformes. Like previous
      molecular and morphological studies, relationships between the super-families
      were less well resolved. Inconsistency between taxonomic rank and genetic
      distance was identified amongst the diprotodontids.

PMID- 12414306
TI  - Phylogenetic relationships within the Phyllopoda (Crustacea, Branchiopoda) based
      on mitochondrial and nuclear markers.
AB  - For several decades the relationships within the Branchiopoda (Anostraca +
      Phyllopoda) have been a matter of controversy. Interpretations of plesiomorphic
      or apomorphic character states are a difficult venture, in particular in the
      Phyllopoda. We explore the relationships within the Phyllopoda at the level of
      nucleotid comparisons of the two genes 12S rDNA (mitochondrial) and EF1alpha
      (nuclear), and at a higher molecular level based on introns found in the gene
      EF1alpha. Within the Phyllopoda our explorations show further evidence for a non
      monophyletic Conchostraca (Spinicaudata + Cyclestherida + Laevicaudata). The
      monotypic Cyclestherida is more closely related to the Cladocera, both together
      forming the Cladoceromorpha. The Spinicaudata (Leptestheriidae, Limnadiidae, and
      Cyzicidae) is well supported. Spinicaudata and Cladoceromorpha form a monophylum.
      The position of the Laevicaudata remains unclear but we find neither support for
      a sister group relationship to the Spinicaudata nor for a close relationship of
      Laevicaudata and Cladocera. Within the Cladocera, we favour the Gymnomera concept
      with the monotypic Haplopoda being the sister group to the monophyletic
      Onychopoda. The Ctenopoda seems to be the sister group to the Gymnomera, which
      contradicts the common view of a more basal position of the Ctenopoda.

PMID- 12414307
TI  - Phylogenetic and biogeographic relationships of the mouse opossum Thylamys
      (Didelphimorphia, Didelphidae) in southern South America.
AB  - Nucleotide sequence data from the mitochondrial cytochrome b gene were used to
      evaluate the phylogenetic relationships among mouse opossum species of the genus
      Thylamys. Based on approximately 1000 bp in five of the six species of the genus
      and including different localities for some of the species, we concluded that T.
      macrura from the subtropical forests of eastern Paraguay is the most primitive
      taxon. Subsequent radiation of the genus is explained mainly via founder effect
      speciation. This evolutionary scenario would account for the speciation of T.
      pusilla, T. venusta, T. pallidior, and T. elegans in the Chaco, southern Bolivia
      and northern Argentina, the Andean Altiplano, the Coastal Desert of Chile, and
      coastal Peru, respectively. Calibration of a molecular clock set the Pleistocene
      as the period for the differentiation of Thylamys species. The molecular results
      confirm the strong genetic connection between populations that inhabit the "pre
      cordillera" of northern Chile (T. pallidior) and the canyons that run through the
      Atacama Desert to the lowlands in northern Chile. Our results confirm the
      occurrence of two Thylamys species in Chile, T. pallidior and T. elegans, within
      and south to the Atacama Desert, respectively.

PMID- 12414308
TI  - Evolutionary patterns of the gypsy and bilbo retrotransposon families in the
      Drosophila species of the obscura group.
AB  - We analyse in this paper the evolutionary patterns of two types of Drosophila
      retrotransposons, gypsy (a virus-like element), and bilbo (a LINE-like element),
      in host species from the Drosophila and Scaptomyza genus. Phylogenetic analysis
      of the retrotransposon sequences amplified by PCR, revealed concordance with the
      phylogeny of the Drosophila host species from the obscura group, which is
      consistent with vertical transmission during differentiation of the species.
      However, in the species outside of the obscura group, horizontal transmission can
      be considered. The amplified sequences that presented intact open reading frames
      were used in an analysis of the evolutionary constraints on the amino acid
      sequences. The analysed sequences seem to be functional, and the selective
      constraints are evidenced, especially when sequences from distant species are
      compared. Comparison of the evolutionary rates of both retrotransposons in the
      same species, suggests that bilbo seems to evolve more rapidly than gypsy.

PMID- 12414309
TI  - A molecular phylogeny of African kestrels with reference to divergence across the
      Indian Ocean.
AB  - In this paper we examine the evolutionary relationships of kestrels from mainland
      Africa, Indian Ocean islands and related areas. We construct a molecular
      phylogeny of African kestrels, using approximately 1.0 kb of mitochondrial
      cytochrome b sequence. Our molecular results support an Old World origin for
      typical kestrels and an ancient divergence of kestrels into the New World, and
      indicate a more recent radiation of kestrels from Africa via Madagascar towards
      Mauritius and the Seychelles. Phylogenetic placement of the Australian kestrel
      suggests a recent origin from African kestrel stock. We compare evolutionary
      relationships based on kestrel plumage pattern and morphology to our molecular
      results for the African and Indian Ocean kestrels, and reveal some consistency
      with the different island forms. We apply a range of published avian cytochrome b
      substitution rates to our data, as an alternative to internal calibration of a
      molecular clock arising from incomplete paleontological information. We align
      these divergence estimates to the geological history of Indian Ocean island
      formation inferred from potassium-argon dating methods. The arrival of kestrels
      on Mauritius appears consistent with the cessation of volcanic activity on
      Mauritius. The estimated time and route of divergence of the Seychelles kestrel
      from Madagascar may be compatible with the emergence of smaller islands during
      Pleistocene sea level fluctuations.

PMID- 12414310
TI  - Phylogenetics of Australian Acacia thrips: the evolution of behaviour and
      ecology.
AB  - The species of thrips found on Acacia constitute a major component of the
      Australian thrips fauna, with at least 235 species in more than 30 genera, many
      of these being in the process of description as new. These thrips exhibit social
      behaviours, ranging from solitary and colonial species to a variety of more
      complex social organisations. Furthermore, the domiciliary habits of these
      species include domicile construction, gall induction, and opportunistic use of
      abandoned galls and domiciles. This suite of thrips also includes a variety of
      inquiline and kleptoparasitic taxa. To understand how these various traits have
      evolved and interact in this diverse group, we have reconstructed a phylogeny for
      42 species of thrips associated with Acacia around Australia. We obtained DNA
      sequence data from two nuclear genes (Elongation Factor-1alpha and wingless) and
      one mitochondrial gene (cytochrome oxidase I) and analysed these using maximum
      parsimony and maximum likelihood methods. A phylogeny resulting from such
      analysis allows inference of evolutionary transitions in domiciliary habits,
      social organisations, and parasitic behaviours. Gall induction and parasitic
      behaviour are postulated to each have a single origin, with no losses of either
      trait. Once parasitism evolved a remarkable radiation followed that allowed
      exploitation of very diverse hosts. Our data do not allow hypotheses of single
      versus multiple origins of domicile building to be resolved while opportunistic
      gall use appears to have arisen several times.

PMID- 12414311
TI  - Inter- and intraspecific evolutionary relationships of the rice frog Rana
      limnocharis and the allied species R. cancrivora inferred from crossing
      experiments and mitochondrial DNA sequences of the 12S and 16S rRNA genes.
AB  - The rice frog Rana limnocharis is widely distributed in Southeast Asia and the
      rest of the Asian region extending from India to Japan. In Japan, the Sakishima
      island populations of this species were regarded as a distinct species based on
      morphological and genetic divergences. The main purposes of this study were to
      confirm the presence of intraspecific reproductively isolating mechanisms in the
      Sakishima-island populations of R. limnocharis, and to clarify molecular inter-
      and intraspecific relationships of R. limnocharis and an allied species, Rana
      cancrivora. The hybridization experiments revealed that there were no
      reproductively isolating mechanisms between the Sakishima-island populations and
      other populations of R. limnocharis. The molecular evolutionary relationships
      were investigated by analyzing nucleotide sequences of the mitochondrial 12S and
      16S rRNA genes using 12 populations of R. limnocharis from Japan and Taiwan, and
      two populations of R. cancrivora from Thailand and the Philippines. The
      phylogenetic trees constructed by the NJ method showed that the two populations
      of R. cancrivora were clearly separated from the 12 populations of R.
      limnocharis, and that the 12 populations of R. limnocharis were broadly divided
      into three clades; the first comprising eight populations from the main islands
      of Japan, the second comprising the Sakishima-island populations, and the third
      comprising the Okinawa-island and Taiwan populations. Interestingly, the Okinawa
      island and Taiwan populations of R. limnocharis showed a close relationship that
      possibly reflected a secondary contact between the two populations. Based on the
      present crossing experiments and molecular data, it seems reasonable to regard
      the Sakishima-island populations as a single subspecies of R. limnocharis.

PMID- 12414312
TI  - Phylogenetic relationships of Empetraceae inferred from sequences of chloroplast
      gene matK and nuclear ribosomal DNA ITS region.
AB  - We used sequences of nrDNA ITS and chloroplast gene matK to evaluate the
      monophyly of Empetrum and Corema and to examine phylogenetic relationships of the
      Empetraceae. Sequences of these two DNA markers were obtained for 11 plant
      samples, representing species of Empetrum from both the Southern and Northern
      Hemispheres, species and subspecies of Corema, and the monotypic Ceratiola.
      Sequences of four species of Rhododendron were used for rooting purposes. Our
      results show that species of Empetrum form a clade sister to the clade containing
      both Corema and Ceratiola. These two clades are strongly supported in both the
      matK and ITS trees, suggesting that Ceratiola is more closely related to Corema
      than to Empetrum, and is not of a hybrid origin between the ancestors of the
      latter two genera. In the matK tree, Corema conradii is more closely related to
      Ceratiola than to Corema album and C. album subsp. azoricum, whereas in the ITS
      tree, Ceratiola is allied with Corema album and C. album subsp. azoricum. This
      suggests that C. conradii might be a hybrid between ancestral populations of
      Ceratiola and C. album. The monophyly of Empetrum rejects the hypothesis of its
      independent origin in the two Hemispheres. Our trees also suggest the fact that
      the modern amphitropical distribution of Empetrum is the result of long distance
      dispersal, not of the vicarious events.

PMID- 12414313
TI  - Cryptic lineages in a small frog: the post-glacial history of the spring peeper,
      Pseudacris crucifer (Anura: Hylidae).
AB  - The spring peeper (Pseudacris crucifer) is believed to have been a primary
      herpetological invader of eastern North America following the most recent period
      of glacial retreat. We examined the phylogeographic pattern and population
      structure of P. crucifer to determine whether the distribution of haplotypic
      variants reflect post-Pleistocene recolonization dynamics. A number of
      geographically isolated evolutionary lineages were supported by both maximum
      parsimony and neighbor-joining analyses, and by coalescence approaches applied to
      mtDNA. South-western Ontario represents a high level of genotypic diversity (pi)
      due to the presence of two divergent lineages. The geographic distribution of
      these lineages are interpreted as reflecting post-glacial recolonization dynamics
      from separate, isolated refugia during the late Pleistocene that have come into
      secondary contact in SW Ontario. The phylogenetic placement of haplotypes from
      the range of P. crucifer bartramiana (Florida and South Carolina) does not allow
      for monophyly of P. crucifer crucifer, and therefore the bartramiana subspecies
      designation does not reflect a separate evolutionary lineage.

PMID- 12414314
TI  - Evolution of the human killer cell inhibitory receptor family.
AB  - Phylogenetic analysis of different domains of human natural killer cell
      inhibitory receptors (KIR) implicated both intragenic duplication and deletion of
      exons and interlocus recombination in the evolution of these receptors. In
      phylogenies of the extracellular immunoglobulin (Ig) superfamily C2-set domains
      and of the pre-membrane (PM) domain, KIR receptors having two C2-set domains and
      those having three such domains tended to form separate clusters. However, the
      phylogenies of the transmembrane (TM) and cytoplasmic (CYT) domains showed quite
      different topologies, suggesting that major sites of interlocus recombination
      have been between exon 6 (encoding PM) and exon 7 (encoding TM) and between exon
      7 and exons 8-9 (encoding CYT). Examination of the pattern of nucleotide
      substitution in the exons encoding Ig C2-set domains supported the hypothesis
      that positive Darwinian selection has acted to diversify the residues within
      these domains that are involved in contact with class I MHC molecules.

PMID- 12414315
TI  - Radiation in the Cape flora and the phylogeny of peacock irises Moraea
      (Iridaceae) based on four plastid DNA regions.
AB  - Phylogenetic analyses of four plastid DNA regions, the rbcL exon, trnL intron,
      trnL-trnF intergenic spacer, and rps16 intron from each of 73 species in the
      African genus Moraea (Iridaceae: Irideae) including accessions of all major
      species clusters in the genus, show Moraea to be paraphyletic when Barnardiella,
      Galaxia, Hexaglottis, Homeria (all southern African), and Gynandriris (Eurasian
      as well) were recognized as separate genera. There are several small, isolated
      species clusters at the basal nodes of the tree that are all restricted to the
      winter-rainfall zone of southern Africa (the Greater Cape floral kingdom) and a
      few, highly derived, large species groups that have radiated extensively within
      the winter-rainfall zone. Mapping of floral traits shows that an Iris-type flower
      is ancestral in Moraea. Floral changes are associated with shifts in pollination
      systems, either from passive pollen deposition on long-tongued bees foraging for
      nectar to active pollen collection by female bees foraging for pollen, fly, or
      hopliine scarab beetle pollination. Dating the nodes of the phylogenetic tree
      using non-parametric rate smoothing with a calibration point derived from broad
      dating of the angiosperms indicates that the divergence between Moraea and its
      sister genus Ferraria occurred about 25 mya in the early Miocene. The early
      radiation of Moraea took place against a background of aridification and the
      spread of open habitats, such as desert, shrubland, and fynbos.

PMID- 12414316
TI  - Phylogenetic relationships of the dwarf boas and a comparison of Bayesian and
      bootstrap measures of phylogenetic support.
AB  - Four New World genera of dwarf boas (Exiliboa, Trachyboa, Tropidophis, and
      Ungaliophis) have been placed by many systematists in a single group
      (traditionally called Tropidophiidae). However, the monophyly of this group has
      been questioned in several studies. Moreover, the overall relationships among
      basal snake lineages, including the placement of the dwarf boas, are poorly
      understood. We obtained mtDNA sequence data for 12S, 16S, and intervening tRNA
      val genes from 23 species of snakes representing most major snake lineages,
      including all four genera of New World dwarf boas. We then examined the
      phylogenetic position of these species by estimating the phylogeny of the basal
      snakes. Our phylogenetic analysis suggests that New World dwarf boas are not
      monophyletic. Instead, we find Exiliboa and Ungaliophis to be most closely
      related to sand boas (Erycinae), boas (Boinae), and advanced snakes
      (Caenophidea), whereas Tropidophis and Trachyboa form an independent clade that
      separated relatively early in snake radiation. Our estimate of snake phylogeny
      differs significantly in other ways from some previous estimates of snake
      phylogeny. For instance, pythons do not cluster with boas and sand boas, but
      instead show a strong relationship with Loxocemus and Xenopeltis. Additionally,
      uropeltids cluster strongly with Cylindrophis, and together are embedded in what
      has previously been considered the macrostomatan radiation. These relationships
      are supported by both bootstrapping (parametric and nonparametric approaches) and
      Bayesian analysis, although Bayesian support values are consistently higher than
      those obtained from nonparametric bootstrapping. Simulations show that Bayesian
      support values represent much better estimates of phylogenetic accuracy than do
      nonparametric bootstrap support values, at least under the conditions of our
      study.

PMID- 12414317
TI  - Mitochondrial DNA variation among host races of Eurosta solidaginis Fitch
      (Diptera: Tephritidae).
AB  - Eurosta solidaginis Fitch (Diptera: Tephritidae) induces galls on two species of
      goldenrod, Solidago (Compositae), in the northern regions of the United States.
      Recent studies have demonstrated that E. solidaginis is comprised of two host
      races that differ in adult emergence times, mate preference, and host preference.
      However, it is not known how much genetic variation, if any, exists among E.
      solidaginis host-associated populations west of Minnesota where the two host
      races occur in sympatry. Sequencing analysis was used to characterize two
      mitochondrial gene fragments: (1) NADH1 dehydrogenase (ND1: 539 bp) and (2)
      cytochrome oxidase II + tRNA(Lys) + tRNA(Asp) (CO2KD: 396 bp) from sympatric,
      host-associated populations of E. solidaginis in North Dakota. Our results
      indicated that two genetically distinct lineages exist among E. solidaginis in
      North Dakota that correspond with host-plant association.

PMID- 12414318
TI  - Hypochlorous acid-induced oxidative damage of human red blood cells: effects of
      tert-butyl hydroperoxide and nitrite on the HOCl reaction with erythrocytes.
AB  - Hypochlorous acid, one of the most powerful biological oxidants, is believed to
      be important in the pathogenesis of some diseases. The purpose of this study was
      to further characterise the membrane and intracellular events which resulted in
      HOCl-induced oxidative impairments and haemolysis of human erythrocytes and
      interaction of different oxidative agents, which accumulated during respiratory
      burst, in the process of RBS oxidation. The sequence of cellular events after red
      blood cell exposure to HOCl: cell morphological transformations, oxidation of
      cellular constituents, enzyme modifications, and haemolysis have been evaluated.
      It was shown that HOCl-treated cells underwent colloid-osmotic haemolysis,
      preceded by rapid morphological transformations and membrane structural
      transitions. The activation energy of the process of haemolysis (after removal of
      the excess of oxidative agent) was estimated to be 146+/-22 kJ/mol at
      temperatures above the break point of Arrhenius plot (31-32 degrees C). This
      value corresponds to the activation energy of the process of protein
      denaturation. Modification of erythrocytes by HOCl inhibited membrane
      acetylcholinesterase (uncompetitive type of inhibition), depleted intracellular
      glutathione, activated intracellular glutathione peroxidase, but did not induce
      membrane lipid peroxidation. The presence of other oxidants, nitrite or tert
      butyl hydroperoxide (t-BHP), promoted the oxidative damage induced by HOCl and
      led to new oxidative reactions.

PMID- 12414319
TI  - The influence of promoter and of electrode material on the cyclic voltammetry of
      Pisum sativum plastocyanin.
AB  - The reversible cyclic voltammetry of pea plastocyanin (Pisum sativum) was studied
      with a wide range of electrodes: edge-oriented pyrolytic graphite (PGE), glassy
      carbon (GCE), gold (Au) and platinum (Pt) electrodes. Plastocyanin was coated
      onto the electrode surface by exploiting the electrostatic interaction between
      the negatively charged protein and a wide range of positively charged promoters.
      The effect of the redox response with an extended range of promoters, including
      poly-L-lysine, polymyxin B, neomycin, tobramycin, geneticin, spermine and
      spermidine, were included in this study. The resulting cyclic voltammograms
      reveal that the observed midpoint potential for plastocyanin can be shifted
      significantly depending on the choice of promoter. The stability of the
      negatively charged plastocyanin-promoter layer on an electrode was gauged by the
      rate of bulk diffusion of the protein from the immobilised film into the
      solution. Reversible cyclic voltammograms were obtained using edge-oriented
      pyrolytic graphite (PGE) and glassy carbon electrodes (GCE) with all promoters;
      however, platinum and gold electrodes were unable to sustain a defined redox
      response. The combination of pyrolytic graphite electrode/poly-L
      lysine/plastocyanin was found to be the most stable combination, with a redox
      response which remained well defined in solution for more than 1 h at pH 7.0. The
      midpoint potentials obtained in this manner differed between the two graphite
      electrodes PGE and GCE using poly-L-lysine as the promoter. This effect was in
      addition to the expected pH dependence of the midpoint potential for plastocyanin
      and the results indicated that the pK(a) for plastocyanin on PGE was 4.94
      compared to that on GCE of 4.66. It is concluded that both the electrode material
      and the nature of the promoter can influence the position of the redox potentials
      for proteins measured in vitro. This study extends the range of biogenic
      promoters used in combination with electrode materials. Thus, we can begin to
      develop a more comprehensive understanding of electrode-protein interactions and
      draw conclusions as to metalloprotein function, in vivo. To support these
      studies, we have sought information as to the nature of the
      electrode/promoter/protein interaction using scanning tunneling microscopy (STM)
      to study both the promoter and the plastocyanin protein on a gold surface.

PMID- 12414320
TI  - Voltammetric monitoring of laccase-catalysed mediated reactions.
AB  - Six different compounds capable of mediating laccase-catalysed reactions have
      been tested by cyclic voltammetry. They exhibited quasi-reversible electrodic
      behaviour with formal redox potentials ranging from 150 to 800 mV (E(0)' vs.
      SCE). The immersion of a laccase-coated glassy carbon electrode (GCE) in mediator
      solutions generated large cathodic catalytic currents easily recorded by cyclic
      voltammetry at low-potential scan rates. This current showed two well-defined pH
      profiles, which correlated with the variation of the mediator redox potentials at
      the pH range tested. The relevant effect of temperature on the activity of
      laccase has been assessed here. Likewise, it was shown that the current record
      varied with the substrate concentration. This trend fitted Michaelis-Menten
      kinetics, which allowed us to give an estimation of the affinity of the fungal
      laccase for the different mediators.

PMID- 12414321
TI  - Hypochlorous acid-induced membrane pore formation in red blood cells.
AB  - The hyperproduction of hypochlorous acid (HOCl), an extremely toxic biological
      oxidant generated by neutrophils and monocytes, is involved in the pathogenesis
      of many diseases. In these studies, we attempted to determine the membrane and
      cellular events associated with HOCl-induced erythrocyte impairment and
      haemolysis. In vitro human erythrocyte exposure to HOCl (0.1-1.0 mM) resulted in
      rapid oxidation of reduced glutathione, an increase in cell osmotic fragility and
      the formation of transient membrane pores. The process of glutathione oxidation
      depended on the [oxidant]/[cell number] ratio. The HOCl-induced haemolysis
      observed was apparently mediated by pore formation and altered membrane
      electrolyte permeability. The estimated pore radius was approximately 0.7 nm and
      the average number per cell was 0.01. The rate constant of HOCl-produced
      haemolysis depended on pH. There were significant differences in haemolysis of
      HOCl-treated erythrocytes which had maximal stability at pH 7.2-7.3.

PMID- 12414322
TI  - Cellular toxicity induced by different pH levels on the R3230AC rat mammary
      tumour cell line. An in vitro model for investigation of the tumour destructive
      properties of electrochemical treatment of tumours.
AB  - INTRODUCTION: The aim of this study was to evaluate the cellular toxicity of
      different pH levels on the R3230AC mammary tumour cell line (clone-D) in vitro
      and to determine in what way the pH affects the tumour cells. The results could
      be used to interpret the cell damaging effects seen in electrochemical treatment
      of tumours (EChT), where pH alteration in tissue is the major event. METHODS:
      Tumour cells were treated with pH 3.5, 5, 7, 9, 10 and 11 for 10, 20 or 30 min,
      respectively, followed by studies with the viability assay 3-(4,5-dimethylthiazol
      2-yl)-2,5,-diphenyl tetrazolium bromide (methyltetrazolium (MTT)), morphological
      observation in phase contrast microscope (PCM) and light microscope, nucleotide
      analogue incorporation (BrdU; 5-Brdmo-2'-deoxyuridine), Caspase-3 activity
      measurement and detection of DNA fragmentation by an agarose gel electrophoresis.
      RESULTS: In the viability assay, it was found that different pH levels had
      cytotoxic effects; these effects were dependent on the pH value and on the time
      of exposure at a given pH. Morphologically, cells in pH 3.5 and 5 had shrunk,
      were rounded and had condensed chromatin, whereas prominent cell swelling and
      nuclear expansion were seen in the pH 9- and 10-treated cells. Gross cytolysis
      was found in pH 11. A BrdU incorporation assay indicated that proliferation rate
      is inhibited markedly both with decreasing and increasing pH. Significant Caspase
      3 activity was found in pH 3.5 and 5 groups. Caspase-3 levels for the alkaline
      exposure were equal or below the normal control. DNA ladder formation, a
      characteristic of apoptosis, was only visualised in the treatment of pH 3.5 for
      30 min. CONCLUSIONS: pH changes inhibit cell proliferation and decrease cell
      viability. The pathway of killing tumour cell in low pH probably has at least two
      directions: apoptosis and cell necrosis, whereas high pH results in only cell
      necrosis. The study suggests that low pH environment can induce apoptosis in
      unphysiological condition comparable with tissue pH at EChT. In addition, it
      seems that R3230AC mammary tumour cells are more tolerant to high pH than to
      acidic changes. This supports the theory that anodic EChT should be more
      efficient than cathodic.

PMID- 12414323
TI  - The complex dielectric spectrum of heart tissue during ischemia.
AB  - INTRODUCTION: Because of the variety of tissue structures, the interpretation of
      the passive complex dielectric permittivity spectrum epsilon (omega) of the heart
      is still a problem. The aim of this work was to correlate epsilon (omega) of
      heart tissue with physical processes on cellular level. METHODS: epsilon (omega)
      of canine hearts was continuously measured in the range from 10 Hz to 400 MHz
      during cardioplegic perfusion and during following ischemia. Cardioplegic
      perfusion was performed with HTK (Custodiol) without or with heptanol, in order
      to produce electrical cell uncoupling via the closure of gap junctions. To
      analyse epsilon (omega), we present two heart models which consider cell shape,
      electrical cell coupling, and dielectric polarisation of cell membranes and
      membranes of intracellular structures. RESULTS: epsilon (omega) of heart tissue
      shows an alpha-, beta-, and gamma-dispersion. epsilon (omega) remains unchanged
      during cardioplegic perfusion with HTK, but if heptanol is added, there is an
      immediate decrease in the region of alpha-dispersion and an increase in the low
      frequency part of beta-dispersion. Similar changes are observed during ischemia
      following HTK perfusion without heptanol; additionally, the beta-dispersion
      shifts to higher frequencies. Using our models, we obtain analogue changes of
      epsilon (omega) by fitting model parameters which describe water content, water
      distribution, extra- and intracellular conductivity, and gap junction resistance.
      DISCUSSION: Changes of these tissue properties as calculated by our models based
      on the measurement of epsilon (omega) are consistent with intraischemic changes
      of heart tissue known from immunohistochemical, biochemical, and histological
      investigations. The next step will be to use our models for the prognosis of
      irreversible tissue damage.

PMID- 12414324
TI  - Study of catalase electrode for organic peroxides assays.
AB  - The catalytic activity of immobilized catalase (EC 1.11.1.6) for two model
      peroxide compounds (dibenzoyl peroxide and 3-chloroperoxibenzoic acid) in a non
      aqueous medium was used to prepare an organic-phase enzyme electrode (OPEE). The
      enzyme was immobilized within a polymeric film on spectrographic graphite. The
      amperometric signal of the enzyme electrode in substrate solutions was found to
      be due to the reduction of oxygen generated in the enzyme layer. The electrode
      response is proportional to peroxide concentrations up to about 40 microM within
      the potential range from -450 to -650 mV (vs. Ag/AgCl), and the response time is
      at most 90 s. The enzyme electrode retains about 35% of its initial activity
      after a 3-week storage at room temperature.

PMID- 12414325
TI  - Two types of kinetics of membrane potential of water plant leaves illuminated by
      ultraviolet light.
AB  - The effects of ultraviolet-B (UV-B) radiation on plasma membrane of water plant
      (Elodea canadensis, Vallisneria spiralis) cells were investigated by using
      microelectrode methods. A fast and reversible depolarization of membrane
      potential occurs initially during exposure of leaf cells to UV on a white light
      background, after which a slow phase of depolarization sets in. On action series,
      UV is pulsed for 15 s, with dark interval of 3 min, no monotonous response of
      systems on the UV excitation is observed. The action spectrum of the fast UV
      response lies in the interval of 300-330 nm and that of the slow phase-in the
      interval of 280-300 nm. The input impedance of membranes remains unchanged during
      the period of exposure. It is concluded that the H(+)-extruding complex of plant
      cell plasma membranes really consists of two types of interrelated electronic
      H(+)-pumps: an H(+)-pump of redox-active nature and the H(+)-pump of the H(+)
      ATPase enzyme complex. Clearly, during the exposure of leaf cells to UV light,
      initially, the H(+)-pump of redox-active nature and then H(+)-ATPase are
      inhibited. It is proposed that the initial chromophore of UV-B light on plasma
      membrane can be one of the components of H(+)-pump of redox-active nature. It is
      probably the molecular of quinone.

PMID- 12414326
TI  - Interrelation between hydration and interheadgroup interaction in phospholipids.
AB  - The stability and the ionic conductivity of biological membranes and of lipid
      bilayers depend on their hydration. A small number of water molecules adhere
      strongly to the different residues of the lipid headgroups and are oriented by
      them. An additional number of water molecules adhere more weakly, preserving
      their freedom of rotation, but are essential for bestowing the thermodynamic
      properties of hydrated bilayers and of biological membranes. Around six water
      molecules are attached so strongly to the headgroups of different phospholipids
      (PL) that they are rendered unfreezable, or their freezing is extended over such
      a wide range of temperatures that it cannot be detected by differential scanning
      calorimetry (DSC). If cholesterol is added to the PL above the concentration at
      which phase separation of the cholesterol phase occurs, the number of unfreezable
      water molecules per PL increases, indicating that the PL molecules on the border
      line between the two phases attach nearly twice as many water molecules as those
      in the middle of the phase. The orientation of about seven or eight water
      molecules attached to PL headgroups (seven to phosphatidyl serine (PS)) can be
      detected by polarized FTIR. The dichroic ratio of the successively adhering water
      molecules to the headgroup of PS fluctuates between 2.6 and 2.9, with the
      cumulative value of about 2.8 for the seven water molecules adhering to the
      headgroup of PS. In addition, in this case, the number of water molecules
      oriented by PL molecule residues on the border line of the two phases is much
      larger ( approximately 13 for PS). Interaction between two opposite negatively
      charged layers containing PS approaching each other may lead, after correlated
      electrostatic attraction, to change in the conformation of the headgroups with
      concomitant dehydration. This process is enhanced by Ca(+) and by Li(+), but it
      may also occur with Na(+) and K(+) as counter-ions if the layers are mutually
      aligned. This process may be important in the fusion mechanism of biological
      membranes, and its molecular modeling has been carried out.

PMID- 12414327
TI  - A study on Cu2Co2SOD and Co2Co2SOD by voltammetry and thin-layer
      spectroelectrochemistry.
AB  - The electrochemistry of Co(2)Co(2)SOD and Cu(2)Co(2)SOD on a pyrolytic graphite
      electrode (PGE) without using mediators was investigated by cyclic voltammetry
      (CV) and differential pulse voltammetry (DPV). The reversible and quasi
      reversible voltammetric responses were observed for Co(2)Co(2)SOD and
      Cu(2)Co(2)SOD, respectively. Their formal redox potentials and electron numbers
      involved in electrode reactions were obtained, and are in agreement with those by
      spectroelectrochemistry (SEC).

PMID- 12414328
TI  - Introduction. The management of erectile dysfunction (ED).

PMID- 12414329
TI  - Phosphodiesterase type 5 as a pharmacologic target in erectile dysfunction.
AB  - The scientific rationale of pharmacologically inhibiting phosphodiesterase type 5
      (PDE5) in the treatment of erectile dysfunction (ED) is reviewed. Published
      literature on the nitric oxide-cyclic guanosine monophosphate (cGMP) pathway for
      penile erection and on PDE5 inhibition using sildenafil as the model for
      pharmacologic PDE5 inhibition are assessed. The key second messenger in the
      mediation of penile erection is cGMP. PDE5 is the predominant PDE in the corpus
      cavernosum, and cGMP is its primary substrate. Therefore, in men with ED,
      elevation of cGMP in corpus cavernosal tissue via selective inhibition of cGMP
      specific PDE5 is a means of improving erectile function at minimal risk of
      adverse events. This approach is validated by the clinical efficacy and safety of
      sildenafil, the pioneering drug for selective PDE5 inhibitor therapy for ED.
      Sildenafil exhibits inhibitory potency against PDE5 and a 10-fold lower dose
      related inhibitory potency against rod outer segment PDE6, the predominant PDE in
      the phototransduction cascade in rods. Thus, its pharmacologic profile is
      predictable, with close correlation between pharmacodynamic and pharmacokinetic
      properties. Clinically, sildenafil improves erectile function in a large
      percentage of men with ED. The most common adverse events are due to PDE5
      inhibition in vascular and visceral smooth muscle; similar adverse events are
      expected during therapeutic use of all PDE5 inhibitors. As free sildenafil plasma
      concentrations approach concentrations sufficient to inhibit retinal PDE6,
      usually at higher therapeutic doses, transient, reversible visual adverse events
      can occur, albeit infrequently. Selective inhibition of PDE5 is a rational
      therapeutic approach in ED, as proved by the clinical success of sildenafil.

PMID- 12414330
TI  - The efficacy of sildenafil citrate (Viagra) in clinical populations: an update.
AB  - Although certain risk factors are known to be associated with erectile
      dysfunction (ED), the demographic and ED characteristics of the population of men
      with ED are quite diverse. We examined results from randomized trials of
      sildenafil citrate (Viagra) to ascertain if efficacy differed across various
      subgroups of men with ED. In addition, we reviewed findings from long-term
      extension studies and published accounts of sildenafil use in clinical practice
      to determine if effectiveness is maintained with long-term sildenafil treatment
      and to determine if effectiveness in the clinic practice setting is consistent
      with that reported in clinical trials. Data were pooled from 11 double-blind,
      placebo-controlled, flexible-dose (taken as needed) studies to assess efficacy (N
      = 2667) of sildenafil in men (aged 23 to 89 years) with ED of broad-spectrum
      etiology who were not receiving concomitant nitrate therapy. Efficacy evaluations
      included the International Index of Erectile Function, a global efficacy question
      ("Did treatment improve your erections?"), and a patient-recorded event log of
      sexual activity. Significantly improved erectile function was demonstrated for
      sildenafil compared with placebo for all efficacy parameters analyzed (P <0.02 to
      0.0001), regardless of patient age, race, body mass index, ED etiology, ED
      severity, ED duration, or the presence of various comorbidities. Long-term
      effectiveness was assessed in 3 open-label extension studies. Of those who
      continued long-term therapy (1 to 3 years) with sildenafil, >95% of patients
      reported that they were satisfied with the effect of treatment on their
      erections, and that treatment had improved their ability to engage in sexual
      activity. Findings from published accounts of sildenafil use in the clinical
      practice setting further demonstrated that sildenafil is an effective treatment
      for a wide range of patients with ED.

PMID- 12414331
TI  - Achieving treatment optimization with sildenafil citrate (Viagra) in patients
      with erectile dysfunction.
AB  - Since its approval in 1998, sildenafil citrate (Viagra) has been shown to be
      efficacious in >100 clinical trials involving >8000 men with erectile dysfunction
      (ED). In clinical practice, however, many men do not continue long-term use of
      sildenafil for a variety of reasons; thus, 6 different aspects of optimizing
      treatment with sildenafil are described here. (1) Intercourse success rates,
      considered a reflection of real-world effectiveness, were assessed in 1276
      patients with ED. Results indicated that the cumulative probability of achieving
      intercourse success with sildenafil increased with the number of attempts,
      reaching a plateau after approximately 8 attempts. (2) A comprehensive disease
      management approach that included a medical history, physical examination,
      educational material about ED, modifications of risk factors/lifestyle changes,
      and counseling resulted in successful intercourse in 74% of 111 patients taking
      sildenafil. (3) A survey conducted among primary care physicians revealed that
      almost 50% did not routinely question their patients about ED symptoms, although
      it is known that most patients would prefer their physician to take the
      initiative. (4) Overall, 55% of 137 men who were previously not successful with
      sildenafil became successful after reeducation and counseling, which included
      information on patient and partner expectations, how to properly take the drug,
      titration to maximum dose, and a minimum trial of 8 attempts for efficacy
      assessment. (5) Many men with ED have underlying comorbidities or take multiple
      medications that are risk factors for ED. Controlling these risk factors in 521
      men from a multispecialty clinic led to an overall intercourse success rate of
      82%; patients with multiple risk factors were less likely to have intercourse
      success than men with only 1 risk factor. (6) Finally, treatment satisfaction is
      a pivotal factor in maintaining long-term ED therapy. In an open-label trial, 82%
      of 443 subjects reported treatment satisfaction with sildenafil. In summary,
      these findings highlight how important it is for physicians to take a more
      comprehensive, proactive approach when treating men with ED, including control of
      risk factors, instructions on how to properly take the drug, partner involvement,
      and follow-up visits. Using these recommended measures, most men with ED,
      including those whose treatment was previously unsuccessful, can be treated
      successfully with sildenafil.

PMID- 12414332
TI  - Efficacy and safety of sildenafil citrate (Viagra) in black and Hispanic American
      men.
AB  - The objective of this study was to assess the efficacy and safety of sildenafil
      citrate (Viagra) in black American and Hispanic American men with erectile
      dysfunction (ED) of broad-spectrum etiology. A total of 246 black American and
      197 Hispanic American men were randomized to sildenafil (50 mg, adjustable to 25
      mg or 100 mg, depending on efficacy and tolerability; n = 124 and n = 99,
      respectively) or matching placebo (n = 122 and n = 98, respectively). After 6
      weeks, patients were given the option of switching to the other blinded treatment
      for the following 6 weeks. The 12 weeks of double-blind treatment were followed
      by 12 weeks of open-label extension. Despite differences in prevalence of
      hypertension, diabetes mellitus, hyperlipidemia, and use of concomitant
      antihypertensive agents between the 2 study groups, sildenafil was efficacious
      and well tolerated. After 6 weeks, scores for questions 3 and 4 from the
      International Index of Erectile Function (IIEF) were significantly higher among
      sildenafil-treated black and Hispanic patients than in placebo-treated patients.
      In addition, compared with placebo, a significantly larger proportion of
      sildenafil patients reported improved erections and improved ability to have
      sexual intercourse. When efficacy results were stratified by ED severity or
      number of risk factors, scores for IIEF questions 3 and 4 were lower in men with
      severe ED versus mild-to-moderate ED. Similarly, the percentage of patients
      reporting improved erections decreased with ED severity and number of risk
      factors. The proportion of patients switching to the other treatment after 6
      weeks was significantly higher in the placebo group (71% to 85%) than in the
      sildenafil group (27% to 28%). The most common adverse events included headache
      and vasodilation, which were mild to moderate in nature and were comparable
      between groups. These data demonstrate that despite differences in prevalence
      rates of comorbidities, efficacy and safety of sildenafil is maintained across
      different ethnic groups.

PMID- 12414333
TI  - Efficacy and safety of sildenafil citrate (Viagra) in men with erectile
      dysfunction and spinal cord injury: a review.
AB  - Spinal cord injury (SCI) affects a substantial number of men who are young,
      active, and otherwise healthy. Erectile dysfunction (ED) is a common consequence
      of SCI. Since its approval, sildenafil citrate (Viagra) has been shown to
      effectively treat ED of various etiologies. We review the evidence for the
      efficacy and safety of sildenafil treatment of ED in men with SCI. A literature
      search identified 2 randomized controlled trials and 4 prospective case series
      that evaluated sildenafil treatment for ED from SCI. Efficacy was evaluated using
      an assessment of global efficacy and a more specific assessment of erectile
      function. For general efficacy, the proportion of patients who reported improved
      erections and ability to have intercourse was as high as 94%. Up to 72% of
      intercourse attempts were successful. For measures of erectile function, 5 of the
      6 studies showed statistically significant improvements among sildenafil-treated
      versus placebo-treated patients. Erectile response rates were generally higher in
      patients with incomplete versus complete SCI and in patients with upper versus
      lower motor neuron lesions. Nevertheless, a substantial proportion of patients
      with complete lesions, regardless of level or lower motor neuron lesions, also
      benefited from sildenafil. Sildenafil was well tolerated. Incidence rates and
      types of adverse events that occurred in these studies were similar to those
      published previously. Symptoms of autonomic dysreflexia were not reported in any
      study. Existing evidence suggests that oral sildenafil is a highly effective and
      well-tolerated treatment for ED associated with SCI.

PMID- 12414334
TI  - Depression, antidepressant therapies, and erectile dysfunction: clinical trials
      of sildenafil citrate (Viagra) in treated and untreated patients with depression.
AB  - Erectile dysfunction (ED) and depression are highly prevalent conditions and
      frequently occur concomitantly in predisposed individuals. Men with ED and
      depression are also likely to have other comorbid conditions, including diabetes,
      hypertension, and heart disease. Because ED is also a common adverse effect of
      some medications for these conditions, patients are frequently noncompliant with
      treatment. Sildenafil citrate (Viagra) is effective in treating ED of a broad
      range of etiologies, suggesting that it may be equally beneficial in patients
      with ED that is associated with depressive symptoms and in those with ED
      resulting from serotonergic reuptake inhibitor (SRI) antidepressant treatment. We
      review the results of 3 randomized, placebo-controlled trials and a retrospective
      analysis of data pooled from 10 clinical trials that examine the efficacy of
      sildenafil in treating ED associated with depression and as an adverse effect of
      SRI treatment. The results suggest that sildenafil is efficacious as a first-line
      treatment for ED in men with untreated minor depression, in men with ED that is
      refractory to successful SRI treatment of depression, and in those whose
      depression was successfully treated but who developed ED as a consequence of SRI
      treatment. Given the complex interrelations among ED, depression, and other
      comorbid conditions, the key to proper management is a comprehensive evaluation,
      including sexual function, and an accurate differential diagnosis.

PMID- 12414335
TI  - A 4-year update on the safety of sildenafil citrate (Viagra).
AB  - Clinical studies have demonstrated that sildenafil citrate (Viagra) is an
      effective and well-tolerated oral treatment for erectile dysfunction. Despite its
      established safety profile, concern about its cardiovascular safety persists
      among some physicians and the general public. This concern has stemmed primarily
      from sporadic reports of adverse events published in the literature and
      sensationalized by the media. However, the only absolute contraindication for
      sildenafil is concurrent use of nitrates. Because sildenafil has been on the
      market for 4 years and under clinical investigation for even longer, we can now
      evaluate its long-term safety in men who have been taking the drug for several
      years. We review this issue from 3 perspectives. First, we reassess the overall
      safety profile of sildenafil by reviewing the initial controlled clinical trials
      and open-label studies. We present new data from patients who have been exposed
      to sildenafil for up to 4.5 years. We also evaluate the results from independent
      postmarketing studies. Second, we review the cardiovascular-specific results from
      the clinical trials, long-term extension, and postmarketing studies. Lastly, we
      review the specific effects on the visual system based on findings from studies
      conducted during drug development and post marketing.

PMID- 12414336
TI  - Platelet transfusion.

PMID- 12414337
TI  - Desmopressin in the treatment of patients with defects of platelet function.

PMID- 12414338
TI  - Advances in the pathogenesis and treatment of idiopathic thrombocytopenic
      purpura.

PMID- 12414339
TI  - Combining better quality of life with reduced costs in patients with multiple
      myeloma.

PMID- 12414340
TI  - Continuous medical education accreditation and the auspices of the Italian
      Society of Hematology.

PMID- 12414341
TI  - Minimal residual disease monitoring in adult T-cell acute lymphoblastic leukemia:
      a molecular based approach using T-cell receptor G and D gene rearrangements.
AB  - BACKGROUND AND OBJECTIVES: Minimal residual disease (MRD) is important in the
      measurement of response to treatment in childhood B- and T-cell acute
      lymphoblastic leukemia (ALL) and in adult B-cell ALL. Little is known about MRD
      evaluation in adult T-cell ALL. This study aimed to determine the prognostic
      significance of MRD measurements in adult T-cell ALL. DESIGN AND METHODS: T-cell
      receptor (TCR) gamma (G) and TCR delta (D) gene analyses were carried out at
      presentation in 49 patients with de novo T-ALL using a polymerase chain reaction
      (PCR) approach. In 26 of the patients bone marrow (BM) samples were collected at
      sequential time points (0-2, 3-5, 6-9, 10-24 months) after diagnosis for MRD
      investigation. The relationship between MRD status and clinical outcome was
      investigated and correlated with age, gender and white blood cell count at
      presentation. RESULTS: TCRG clonal gene rearrangements were found in 40 patients
      (82%). Eleven patients showed TCRD rearrangements (22%), in one of them as the
      sole molecular marker. V(gamma)I family rearrangements predominated (45 of 65
      alleles) together with V(delta)1-J(delta)1/2 (9 of 13 alleles). Continuous
      clinical remission (CCR) occurred in 17 patients while nine patients relapsed.
      MRD analysis showed that negative tests during the first 6 months post-induction,
      and persisting negative MRD after induction were the best predictors of CCR. A
      positive test after 5 months was better at predicting relapse. In only four of
      seven patients was relapse preceded by a positive test the 5 months preceding
      relapse. INTERPRETATION AND CONCLUSIONS: Overall the ability of positive and
      negative tests to predict relapse or CCR was weaker in this cohort of adult T-ALL
      patients than in T- and B-lineage childhood ALL and B-lineage adult ALL. TCRG and
      TCRD gene analysis provides a clonal marker in the majority of adult T-ALL. These
      results suggest that caution should be taken in using MRD data based on TCR gene
      rearrangements to predict prognosis in adult T-ALL. Biological reasons may
      underlie differences between the performance of MRD tests in B- and T-lineage
      ALL. Further studies in a larger cohort of patients are needed to determine the
      exact role that MRD determination has in the management of T-ALL in adults.

PMID- 12414342
TI  - CD56 and PGP expression in acute myeloid leukemia: impact on clinical outcome.
AB  - BACKGROUND AND OBJECTIVES: Overexpression of P-glycoprotein (PGP), a multidrug
      related (MDR) protein, is one of the most important factors responsible for
      reduced drug sensitivity in acute myeloid leukemia (AML). Recently, we
      demonstrated that the presence of CD56 antigen, an isoform of the neural adhesion
      molecule, in AML cells is a negative independent prognostic factor for the
      achievement of complete remission (CR) and correlates with shorter survival.
      Since in our previous report we observed a more frequent PGP expression in CD56+
      patients, we hypothesized that the reduced response to chemotherapy in this group
      of patients was due to increased PGP-mediated drug efflux. To confirm this
      hypothesis in this study PGP and CD56 expression on AML cells was correlated with
      other clinical and biological features and treatment response. DESIGN AND
      METHODS: Immunophenotypic analysis, including evaluation of CD56 and PGP
      expression, was performed using multiparameter flow cytometry on fresh and/or
      cryopreserved blast cells, obtained after informed consent, from bone marrow
      and/or peripheral blood of 143 consecutive newly diagnosed AML cases at the time
      of diagnosis. Samples expressing CD56 in at least 15% or more cells were
      considered as positive (CD56+). PGP expression was expressed as a mean
      fluorescence index (MFI) i.e. as the ratio of sample mean fluorescence channel
      and the isotypic control mean fluorescence channel. RESULTS: Overall results
      showed that 67/143 cases were PGP-/CD56-, 23/143 were PGP+ /CD56+, 40/143 were
      PGP+/CD56- and the remaining 13/143 were PGP-/CD56+. CD56+ and PGP+ on AML cells
      significantly reduced the CR rate (83% in the PGP-/CD56- group vs 60% in the PGP
      /CD56+ group, 46% in the PGP+/CD56- group and 58% in the PGP+/CD56+ group, p =
      0.002). In addition we observed a significantly higher proportion of total
      failures in patients expressing PGP or CD56 compared to in the group not
      expressing either (73% vs 27%, respectively; p = 0.0001). CD56 and PGP
      overexpression influenced the overall survival: in fact, the median survival of
      CD56+ and PGP+ patients ranged from 10 to 23 months, while the actuarial survival
      of CD56-/PGP- patients at 5 years is 52% (p = 0.023). INTERPRETATION AND
      CONCLUSIONS: Our data underline the independent negative prognostic role of PGP
      and CD56 expression in acute myeloid leukemia. Since the mechanism by which CD56
      reduces drug sensitivity is still unknown, further investigations are required.

PMID- 12414343
TI  - p53 and mdm2 in mantle cell lymphoma in leukemic phase.
AB  - BACKGROUND AND OBJECTIVES: In mantle cell lymphoma (MCL), abnormalities
      additional to t(11;14) including those affecting genes involved in the p53
      pathway, are important for disease development and progression. This study aimed
      to assess the frequency, relationship and impact of p53 abnormalities and those
      of its inhibitor mdm2 in blastoid and non-blastoid MCL in leukemic phase. DESIGN
      AND METHODS: Isolated blood lymphocytes from 21 patients with MCL in leukemic
      phase, characterized by the presence of t(11;14), were analyzed by flow cytometry
      and by fluorescent in situ hybridization in order to investigate whether there is
      a correlation between overexpression and deletion of p53, overexpression of mdm2
      and gain of chromosome 12. Results were also correlated with morphologic
      subtypes, proliferative activity assessed by expression of Ki67 and clinical
      outcome. RESULTS: Cells from 2/21 (10%) and 7/21 (33%) patients overexpressed p53
      and mdm2, respectively. No single case expressed both proteins. Ten out of 19
      (53%) patients had a hemizygous loss of 17p (p53) including the 2 patients (11%)
      overexpressing p53. Gains of chromosome 12 (mdm2) were found in only 2 cases with
      expression of mdm2 in one of them. Overall, p53 deletion and/or overexpression of
      mdm2 was found in 71% of cases. Ten of 19 patients had a blastoid MCL, including
      all 5 patients who were Ki67 positive, 6 of the 7 patients expressing mdm2 and
      one of the 2 patients expressing p53. There was no correlation between p53
      deletion and morphologic subtypes. All patients with blastoid MCL have died after
      a median time of 25 months. INTERPRETATION AND CONCLUSIONS: In MCL in leukemic
      phase there is a high frequency of p53 deletion and/or overexpression of mdm2. In
      contrast, over expression of p53 is relatively rare. Overexpression of mdm2 is
      seen predominantly in blastoid MCL, the latter being characterized by a short
      median survival, and seems unrelated to a numerical gain of chromosome 12. It
      does not reflect a high proliferative rate but might indicate an alternative
      mechanism of inactivating p53 in prognostically adverse types of MCL.

PMID- 12414344
TI  - Lymphomatous superficial lymph nodes: limitations of physical examination for
      accurate staging and response assessment.
AB  - BACKGROUND AND OBJECTIVES: Superficial lymph nodes in lymphoma management are
      usually evaluated by physical examination. However the accuracy of this
      assessment has not been thoroughly tested and so it remains debated whether
      physical examination can meet the international requirements for clinical
      evaluation and response assessment. DESIGN AND METHODS: Palpatory size estimates
      of lymph nodes in 97 lymphoma patients were separately compared with
      ultrasonographic (US) measurements in cervical, supraclavicular, axillary and
      inguinal regions. Comparisons were made between the products of lymph node cross
      sectional diameters, whose changes are critical to assess response. Statistical
      analysis was carried out by simple linear regression, in which the palpatory
      estimate was entered as the mean of the measurements separately taken by two
      different clinicians and the dependent variable was the US measurement. RESULTS:
      Physical examination tended to underestimate the lymph node size in all regions
      but appeared to be closely related to US measurements. However, while R2 was very
      high for cervical and inguinal lymph nodes (0.902 and 0.802, respectively), it
      was disappointingly low for lymph nodes in supraclavicular and axillary regions
      (0.529 and 0.368, respectively). INTERPRETATION AND CONCLUSIONS: This indicates
      that, with the current response criteria, pre- and post-treatment evaluation of
      cervical and inguinal lymph nodes makes substantial errors in 20-30% of cases
      when left to physical examination alone. Errors are even more numerous in
      supraclavicular and axillary regions. Thus, physical evaluation of superficial
      lymph nodes should be integrated by US or other imaging techniques for accurate
      fulfilment of the current standardized guidelines for response assessment.

PMID- 12414345
TI  - Fluorescent polymerase chain reaction and capillary electrophoresis for IgH
      rearrangement and minimal residual disease evaluation in multiple myeloma.
AB  - BACKGROUND AND OBJECTIVES: Several polymerase chain reaction (PCR)-based
      techniques for tracking minimal residual disease (MRD) in B-lymphoproliferative
      disorders have been recently proposed. These procedures show significant
      variation in sensitivity and specificity. We describe an alternative assay based
      on fluorescent PCR combined with capillary electrophoresis and GeneScan analysis,
      to identify the monoclonal immunoglobulin heavy chain (IgH) rearrangement in
      multiple myeloma (MM) and to provide a semi-quantitative evaluation of MRD by
      limiting dilutions. DESIGN AND METHODS: Different sets of family specific primers
      derived from the leader region and from the framework-1 of IgH were used, with a
      unique reverse fluorescent primer JH. The malignant clone was identified by
      GeneScan and sequenced. Two tumor primers, mapping in the complementarity
      determining regions CDRII and CDRIII, were designed for each patient. A
      comparison between the nested-PCR approach and direct fluorescent PCR was
      performed for three patients in complete clinical remission after autologous or
      allogeneic bone marrow transplantation. RESULTS: Thirty-six consecutive patients
      with MM were screened and monoclonality was identified in about 70% of the cases.
      Molecular MRD evaluation was performed in 18 patients using tumor primers. This
      method allowed identification of 1 neoplastic cell among 10(4)-10(6) normal
      cells. In three cases, negative by nested-PCR and agarose gel electrophoresis,
      gene scanning showed persistence of the neoplastic clone, despite the negativity
      of the immunofixation. INTERPRETATION AND CONCLUSIONS: Capillary electrophoresis
      of fluorescent fragments with gene scanning provides a simple, rapid and
      reproducible method to detect IgH rearrangement and to evaluate MRD. Furthermore,
      the sensitivity reached is up to 1 log higher than that of the conventional
      approach with nested-PCR, even though two steps of specificity are maintained.

PMID- 12414346
TI  - Modification of actin, myosin and tubulin distribution during cytoplasmic granule
      movements associated with platelet adhesion.
AB  - BACKGROUND AND OBJECTIVES: Cytoskeletal elements determine the changes in
      platelet cell shape which occur during adhesion, aggregation and release of
      granular contents as part of the activation process. The aim of this study was to
      characterize the changes in the distribution of actin filaments, myosin and
      tubulin molecules during several stages of platelet adhesion to glass and their
      association with granule displacement, as assessed by confocal microscopy. DESIGN
      AND METHODS: Platelets obtained from healthy donors were adhered to glass and
      cytoskeleton distribution was characterized and correlated to changes of cell
      shape and intracellular granule displacement by immunofluorescence assays and
      phase contrast microscopy. Treatment with specific cytoskeleton inhibitors such
      as cytochalasin D, butanedione monoxime and colchicine were used before and after
      the adhesion process. The spatial distribution of the cytoskeleton in association
      with cytoplasmic granules was analyzed in both confocal microscopy projections
      and three-dimensional images obtained by merging the respective projections.
      RESULTS: Our experiments revealed that as platelets contact the substrate, a
      sequential and simultaneous rearrangement of actin filaments, myosin and tubulin
      molecules occurred and this was related to cell shape, as well as to movements of
      cytoplasmic granules. Treatment of platelets with cytoskeleton inhibitors,
      modified not only the target molecule but also other cytoskeletal components with
      consequent alterations in the studied platelet functions. INTERPRETATION AND
      CONCLUSIONS: During platelet adhesion to glass and granule displacement, a close
      spatial and functional relation between actin filaments, myosin molecules and
      microtubules was observed suggesting that these different cytoskeleton components
      interact in supporting the platelet functions here studied.

PMID- 12414348
TI  - Splenectomy after portal thrombosis in patients with polycythemia vera and
      essential thrombocythemia.
AB  - BACKGROUND AND OBJECTIVES: Polycythemia vera (PV) and essential thrombocythemia
      (ET) are two rare acquired myeloproliferative disorders (MPD) with frequent
      thrombotic and hemorrhagic complications. The occurrence of thrombosis in unusual
      sites, e.g. splanchnic vasculature, is a severe complication of these diseases.
      We describe a single-institution experience in patients with ET and PV, diagnosed
      in agreement with the Polycthemia Vera Study Group criteria, with portal vein
      thrombosis who did or did not undergo splenectomy. DESIGN AND METHODS: The
      medical records and the follow-up outcome of 16 MPD patients with portal
      thrombosis who underwent splenectomy (group A1) and 16 who did not (group A2)
      were evaluated. Their median follow-up was, respectively, 13.45 and 10.49 years.
      The overall survival of these patients was compared with that of a population of
      32 patients with MPD and no portal thrombosis (group B) matched for sex, age,
      diagnosis and duration of follow-up. RESULTS: In group A1, 2 patients developed
      deep vein thrombosis, 1 patient had a surgical hemorrhage and 2 patients died
      early, one from acute infection, the other from bone marrow aplasia. Among the
      survivors, one male had a deep vein thrombosis and 1 developed a new portal
      thrombosis. Four patients died during the follow-up (median 9.48 years, range
      3.17-25.1; 1 stroke, 2 gastrointestinal bleedings, 1 leukemic conversion). No
      difference was observed in the incidence of thrombotic or hemorrhagic
      complications or in the rate of deaths when group A1 was compared to the other
      groups. The use of antiplatelets drugs was statistically increased in group A1
      after splenectomy, because portal vein thrombosis induced per se an increased use
      of therapeutic agents. No statistical difference was observed in overall survival
      between the different groups. INTERPRETATION AND CONCLUSIONS: 1) Bleeding and
      thrombosis are the leading causes of morbidity and mortality in ET and PV
      patients with portal vein thrombosis both with or without splenectomy. 2) Portal
      vein thrombosis, and sometimes splenectomy, requires increased use of drugs which
      may enhance the risk of leukemic transformation. In spite of this, the patients
      who survive the first post-splenectomy period may have a long and safe life.

PMID- 12414347
TI  - Efficacy of Helicobacter pylori eradication in raising platelet count in adult
      patients with idiopathic thrombocytopenic purpura.
AB  - BACKGROUND AND OBJECTIVES: There are data consistent with an association between
      idiopathic thrombocytopenic purpura (ITP) and Helicobacter pylori (HP) infection.
      In addition, a significant increase of platelet count following HP eradication
      has been reported in a proportion of ITP patients. We describe here our
      experience on the efficacy of anti-HP treatment in ITP patients. DESIGN AND
      METHODS: Between December 1998 and May 2001 sixteen adult patients with ITP and
      documented HP infection were treated with standard antibiotic therapy for HP
      eradication (amoxicillin and clarithromycin plus pantoprazole combination). Of
      these patients, 7 had untreated ITP with mild/moderate thrombocytopenia (median
      platelet count 70x10(9)/L, range 41-91), 5 had relapsed following a previous
      steroid treatment (median platelet count 39x10(9)/L, range 30-90) and 4 were
      refractory to steroids (median platelet count 18.5x10(9)/L, range 9-30). RESULTS:
      An improvement of platelet count was observed in 11/15 patients (73.3%) who
      achieved HP eradication. The difference between the mean platelet count SD before
      and after HP eradication was statistically significant (51.6 28.2x10(9)/L vs.
      143.3 131.1x10(9)/L; p=0.01). Complete or partial responses were obtained in
      11/16 treated patients (68.7%). This result still persisted after a median follow
      up of 11.7 months. INTERPRETATION AND CONCLUSIONS: Our data confirm the efficacy
      of Helicobacter pylori eradication in increasing platelet count in adult ITP
      patients.

PMID- 12414349
TI  - Pharmacogenetics of acenocoumarol: cytochrome P450 CYP2C9 polymorphisms influence
      dose requirements and stability of anticoagulation.
AB  - BACKGROUND AND OBJECTIVES: Cytochrome P4502C9 (CYP2C9) is the main enzyme
      implicated in coumarinic metabolism. Variant alleles, CYP2C9*2 and CYP2C9*3, have
      been related to decreased enzymatic activity, but their clinical relevance in
      acenocoumarol metabolism has not been established. We investigated CYP2C9
      polymorphisms in relation to acenocoumarol dose requirement, stability of
      anticoagulation and bleeding. DESIGN AND METHODS: CYP2C9 genotyping was performed
      in 325 acenocoumarol-treated patients (INR target between 2.0 and 3.0) and in an
      additional group of 84 patients with repeated bleeding. RESULTS: Patients with
      the wild-type CYP2C9*1/*1 genotype (n=169) required a higher maintenance dose of
      acenocoumarol (17.1 8.7 mg/week) than did patients with the CYP2C9*2 (14.6 6.4
      mg/week, p<0.05, N=97) or the CYP2C9*3 allele (11.2 6.2 mg/week, p<0.001, n=59).
      Out of 170 patients requiring a low-dose of acenocoumarol (<or= 2 mg/day), 27.1%
      carried the CYP2C9*3 allele, while among the patients requiring higher doses,
      8.4% had CYP2C9*3 (OR=4.77, 95% CI = 2.40-9.48, p<0.001 vs. 2C9*1/*1 patients).
      In the multivariate analysis, independent predictive variables for low-dose
      acenocoumarol requirements were age >70 years (OR=3.73, 95%CI=2.29-6.08,
      p<0.001), and the CYP2C9*3 allele (OR=4.75, 95%CI=2.36-9.55, p <0.001). Carriers
      of CYP2C9*3 spent less time within the therapeutic range (64.7 23.1%) than did
      patients with the CYP2C9*1/*1 genotype (75.1 22.0%, p<0.01), and more frequently
      had an INR >4.5 at the initiation of treatment (43.9% vs.11.6%, p<0.001), but did
      not show repeated bleeding more frequently (19.0% vs.15.5%, p=NS). INTERPRETATION
      AND CONCLUSIONS: CYP2C9*3 is related to lower acenocoumarol dose requirements, a
      higher frequency of over-anticoagulation at the initiation of therapy and an
      unstable anticoagulant response.

PMID- 12414350
TI  - Feasibility of a mixed inpatient-outpatient model of peripheral blood stem cell
      transplantation for multiple myeloma.
AB  - BACKGROUND AND OBJECTIVES: A progressively growing number of peripheral blood
      stem cell transplants (PBSCTs) are being performed in patients with newly
      diagnosed multiple myeloma (MM) since they are ever more frequently being offered
      as up-front therapy. Furthermore, there are considerable concerns regarding the
      appropriate use of health care resources in order to reduce costs associated with
      PBSCT. One of the strategies attempted to reach this goal is outpatient-based
      PBSCT. DESIGN AND METHODS: The aim of this study was to analyze the feasibility
      of a mixed inpatient-outpatient model (MIOM) for MM patients receiving high-dose
      melphalan, and homogeneously undergoing autologous PBSCT, antimicrobial and
      antiviral prophylaxis and post-transplant growth factor treatment. Furthermore,
      we retrospectively compared results of the MIOM with those of the traditional
      total inpatient model (TIM). RESULTS: MIOM was applied for 60 transplants in a
      total of 29 MM patients. Results were compared with retrospective data concerning
      the traditional TIM for 40 transplants (27 MM patients). MIOM cases were older
      than TIM ones (55.3 6.3 years vs 49.6 9.2 years, p=0.01), but were comparable for
      sex and disease status. Granulocyte recovery time was shorter in the MIOM group
      (9.0 0.7 vs 9.7 1.2 days, p=0.004), while a similar number of stem cells were
      infused. There was no difference in platelet engraftment. The number of episodes
      and duration of grade II-IV mucositis were similar in both groups. Fever occurred
      in fewer MIOM cases (25% v 51.6%, p=0.02), while its duration was similar. In
      multivariate analysis, mucositis (grades II-IV) was the sole independent
      predictor of fever development (p=0.002). Half of the MIOM cases never required
      re-admission, 26 were re-admitted (median hospital stay 9 days) and 4 cases were
      not discharged (median hospital stay 15 days). The median time to discharge of
      TIM cases was 20 days. Non-hematologic toxicities were low in both groups.
      INTERPRETATION AND CONCLUSIONS: Since outpatient management and liberal
      hospitalization criteria have resulted in safe conduct of MIOM transplants, this
      program can be safely offered to MM patients.

PMID- 12414351
TI  - Hepatitis C virus infection in a hematology ward: evidence for nosocomial
      transmission and impact on hematologic disease outcome.
AB  - BACKGROUND AND OBJECTIVES: Hepatitis C virus (HCV) infection is frequent among
      patients with hematologic malignancies and unapparent routes of infection may be
      important in this setting. Moreover, the impact of this infection on the outcome
      of the hematologic disease needs to be better defined. DESIGN AND METHODS: To
      define sources and clinical courses of HCV infection, an epidemiologic study was
      performed on 13 patients newly admitted over one year who showed transaminase
      elevation and anti-HCV seroconversion. The investigation, started in August 1998,
      included laboratory tests and molecular analysis of virus isolates, and was
      extended to staff and blood donors. Clinical, hematologic and serologic
      surveillance of all infected patients were part of the subsequent follow-up study
      which started in September 1998 and was completed in December 2001. RESULTS: Anti
      HCV seroconversion was observed in 13 of 294 patients (4.4%), admitted to the
      unit from August 1997 and August 1998; 11 of the seroconverted cases had central
      catheters, 12 received transfusions. Transmission via blood derivatives and staff
      was ruled out. All patients were infected by genotype 1b and 11 harbored the same
      viral variant. HCV infection did not influence the course of the underlying
      disease or the use of specific therapies. Forty months after the outbreak, five
      patients are alive (one after autologous and one after allogeneic stem cell
      transplantation), while eight have died, seven of hematologic disease, and one of
      cardiac failure. None died of liver disease. INTERPRETATION AND CONCLUSIONS: The
      molecular data suggest a patient-to-patient nosocomial HCV transmission. After
      having analyzed all the possible routes of transmission, a series of preventive
      measures were adopted: search for HCV RNA in newly admitted patients, protection
      of mucosae and isolation of patients during neutropenic phases, and avoidance of
      multidose vials. As regards the impact of HCV infection on the outcome of the
      hematologic diseases, changes in the scheduled therapy, including stem cell
      transplantation, were not required.

PMID- 12414352
TI  - Prediction of response and other improvements on the limitations of recombinant
      human erythropoietin therapy in anemic cancer patients.
AB  - BACKGROUND AND OBJECTIVES: The majority of cancer patients suffer from chronic
      anemia. While recombinant human erythropoietin (rHuEPO) offers many of the
      advantages of blood transfusions, response rates to this treatment are variable
      and in some trials a large proportion of patients (30 50%) did not respond. This
      failure may be due to factors related to the underlying disease, the chemotherapy
      given or functional iron deficiency. An accurate means of predicting response to
      rHuEPO would be beneficial to both healthcare providers and patients. EVIDENCE
      AND INFORMATION SOURCES: Data were identified by searches of the published
      literature, including PubMed, references from relevant reviews, and abstracts
      presented at recent international oncology and hematology meetings. Only papers
      in English published between 1990 and 2002 were included. References were
      selected according to direct relevance to the topic discussed and availability.
      STATE OF THE ART: The best algorithms for predicting response appear to be those
      combining an assessment of the adequacy of endogenous erythropoietin production
      together with some early indicators of erythropoietic marrow response. Further
      characterization of the dose-response relationship of erythropoietic agents may
      allow better understanding of ways in which response may be enhanced. Adequate
      iron availability could also contribute to better response rates. PERSPECTIVES:
      Further characterization of the predictors of response for current and upcoming
      erythropoietic agents may enhance the management of anemia associated with
      cancer, and provide more convenient, effective, and flexible therapy.

PMID- 12414353
TI  - Functional maturation of myeloid cells during in vitro differentiation from human
      cord blood CD34+ cells.
AB  - CD34+ cells purified from human cord blood were expanded in the presence of
      several cytokines. The cultured cells were assayed for myeloid effector
      functions, including phagocytic activity, respiratory burst and microbicidal
      activity. The results showed that phagocytic activity was observed as early as
      day 6, irrespective of the type of cytokines used. By contrast, respiratory burst
      and microbicidal activity peaked on day 15 and were dependent on the type of
      cytokines used. In particular, granulocyte-colony stimulating factor and
      interleukin-6 markedly enhanced respiratory burst and microbicidal activity.

PMID- 12414354
TI  - Human herpesvirus 7 infection impairs the survival/differentiation of
      megakaryocytic cells.
AB  - In vitro infection of CD61+ megakaryocytic cells with human herpesvirus-7 (HHV-7)
      induced a drastic increase of apoptosis. Moreover, cells surviving HHV-7
      cytotoxicity showed enhanced megakaryocytic maturation with respect to control
      cultures. These data suggest that HHV-7 reactivation in the bone marrow of HIV-1
      infected individuals may contribute to impair megakaryocytopoiesis.

PMID- 12414355
TI  - Complete remission induced by high dose erythropoietin and granulocyte colony
      stimulating factor in acute erythroleukemia (AML-M6 with maturation).
AB  - Alternative therapeutic approaches with low dose chemotherapy and differentiative
      maturative treatment by growth factors are under consideration for elderly
      patients with acute leukemia. Two patients with AML-M6 with maturation, one
      refractory to standard chemotherapy and the other ineligible for cytoxic
      treatment, obtained complete remission from leukemia using high dose recombinant
      erythropoietin and granulocyte colony-stimulating factor.

PMID- 12414356
TI  - A dexamethasone, vinblastine, cyclophosphamide, etoposide, methotrexate and
      bleomycin (D-VICEMB) protocol as first-line treatment of patients aged 70 years
      or older affected by intermediate/high grade non-Hodgkin's lymphoma.
AB  - We treated 30 consecutive untreated patients aged > 70 years with advanced
      aggressive non-Hodgkin's lymphoma with 6 courses of cyclophosphamide,
      mitoxantrone, etoposide, bleomycin, vinblastine and dexamethasone (D-VICEMB). The
      global response was 93%. The 6-year overall survival and progression-free
      survival were 50%, and disease-free survival was 63%.

PMID- 12414357
TI  - Combined treatment with anti-CD20 (rituximab) and CHOP in relapsed advanced-stage
      follicular lymphomas.
AB  - We studied the safety and efficacy of combined treatment with rituximab plus CHOP
      in 16 patients with relapsed advanced-stage follicular lymphomas. The intent-to
      treat overall response rate (ORR) was 88%, 75% complete remissions (CR) and 13%
      partial remissions (PR). At a median follow-up of 18 months, 63% of the patients
      are alive (50% CR). The combination of rituximab and CHOP in relapsed advanced
      stage follicular lymphomas achieves high ORRs and CRs, with low toxicity except
      for in previously autografted patients.

PMID- 12414358
TI  - Levels of tissue factor pathway inhibitor in lupus patients correlate with lupus
      activity and endothelial damage markers.
AB  - Tissue factor (TF) is a low molecular weight glycoprotein considered a major
      regulator of coagulation.1 Tissue factor pathway inhibitor (TFPI) appears to play
      a primary role in regulating TF-induced coagulation, as it is a potent inhibitor
      of activated factor VII/TF complexes. TFPI is expressed by the endothelium under
      normal physiologic conditions. The plasma concentration of TFPI is low, and only
      small amounts circulate in plasma as full-length molecule (free-TFPI).

PMID- 12414359
TI  - Guillain-Barre' syndrome following Varicella zoster reactivation in Chronic
      Lymphocytic Leukemia treated with fludarabine.

PMID- 12414360
TI  - Favorable effect of splenectomy over a five year follow-up in a patient with Aase
      Smith syndrome.

PMID- 12414361
TI  - A CD4+ V(beta)13.6+ CD56+ large granular lymphocyte expansion with decreased
      expression of CD95 and an indolent clinical course.

PMID- 12414362
TI  - Hypopituitarism in a patient with intravascular lymphomatosis.

PMID- 12414363
TI  - Four globin gene defects in a healthy child.

PMID- 12414364
TI  - Low-dose epirubicin in combination with cyclophosphamide, vinblastine and
      prednisone (mini-CEOP) for the treatment of aggressive non-Hodgkin's lymphoma in
      elderly patients.

PMID- 12414365
TI  - Canopy processes research.
AB  - The forest canopy regulates the exchange of carbon, water and energy between the
      ecosystem and the atmosphere, and provides a habitat for a wide variety of
      species. Understanding canopy processes is important for modeling forest
      production and carbon sequestration, and for predicting the effects of global
      changes in climate and atmospheric chemistry on the functioning of forest
      ecosystems. The Canopy Processes Working Group of the International Union of
      Forest Research Organizations has provided a forum for researchers working on
      forest canopies for nearly 20 years, principally through international meetings
      held every 2-3 years. In this paper, I review the history of the Canopy Processes
      Group, show how the research focus has changed and broadened, and provide a brief
      overview of some of the problems that remain to be solved. These include the
      topic of our 2001 meeting (Linking the Complexity of Forest Canopies to Ecosystem
      and Landscape Function), integration of canopy and respiratory processes, carbon
      allocation, physiological changes with tree age, predicting the response of
      forests to global change, understanding the genetic control of canopy structure
      and function, and scaling ecophysiological processes and modeling. Determining
      how forests will respond to global change and understanding the physiology of
      forest production will require increased attention to canopy processes and an
      increased focus on the interactions of canopy processes with other components of
      the ecosystem.

PMID- 12414366
TI  - Universal scaling in tree and vascular plant allometry: toward a general
      quantitative theory linking plant form and function from cells to ecosystems.
AB  - A general theory of allometric scaling that predicts how the proportions of
      vascular plants and the characteristics of plant communities change or scale with
      plant size is outlined. The theory rests, in part, on the assumptions of (1)
      minimal energy dissipation in the transport of fluid through space-filling,
      fractal-like, branching vascular networks; and (2) the absence of scaling with
      plant size in the anatomical and physiological attributes of leaves and xylem.
      The theory shows how the scaling of metabolism with plant size is central to the
      scaling of whole-plant form and function. It is shown how allometric constraints
      influence plant populations and, potentially, processes in plant evolution.
      Rapidly accumulating evidence in support of the general allometric model is
      reviewed and new evidence is presented. Current work supports the notion that
      scaling of how plants utilize space and resources is central to the development
      of a general synthetic and quantitative theory of plant form, function, ecology
      and diversity.

PMID- 12414367
TI  - How the environment, canopy structure and canopy physiological functioning
      influence carbon, water and energy fluxes of a temperate broad-leaved deciduous
      forest--an assessment with the biophysical model CANOAK.
AB  - This paper focuses on how canopy structure, its physiological functioning and the
      environment interact to control and drive the exchange of carbon dioxide (CO2)
      and water vapor between a temperate forest stand and the atmosphere. First, we
      present an overview of how temporal and spatial variations in canopy structure
      (e.g., leaf area index, species, leaf inclination angles, leaf clumping) and
      physiological functioning (e.g., maximal stomatal conductance, photosynthetic
      capacity) modulate CO2 and water vapor fluxes. Then, with the biophysical model
      CANOAK, we quantify the effects of leaf dimension and thickness, vertical
      variations in leaf area and photosynthetic capacity, leaf clumping, leaf
      inclination angles, photosynthetic capacity, stomatal conductance and weather on
      the annual sums of CO2, water vapor and sensible heat exchange. Finally, we
      discuss how much detail is needed in a model to predict fluxes of CO2 and water
      vapor with acceptable fidelity.

PMID- 12414368
TI  - Carbon exchange of an old-growth eastern hemlock (Tsuga canadensis) forest in
      central New England.
AB  - Carbon (C) exchange of an approximately 200-year-old eastern hemlock (Tsuga
      canadensis L.) forest in central Massachusetts, USA, was estimated from mid
      October 2000 through October 2001 based on eddy covariance measurements and
      statistical modeling from microclimatic data. Measurements were made in 68% of
      the hours during the year of study, with > 50% coverage in all months except
      December and August. Data were filtered by wind direction and atmospheric
      turbulence to remove invalid measurements. Analysis of filtered data showed that
      photosynthetically active radiation (PAR) was significant in predicting C
      exchange, except during the winter. Daily minimum air temperature affected C
      exchange in autumn and winter, whereas time of day, water vapor pressure deficit
      and air temperature had significant effects on C storage in spring, summer and
      fall. Most C storage in the stand occurred in April through July and in October
      2001, with maximum rates in April and May. Persistent cold weather prevented C
      storage in December through March. In early spring 2001, C uptake was sensitive
      to nocturnal frost: daily minimum air temperatures below 0 degrees C reduced C
      fixation, and minima below -5 degrees C caused its virtual cessation. Soil
      temperature was a poor predictor of C balance during this period. In August, high
      soil and air temperatures (averaging 16.7 and 21.1 degrees C, respectively) drove
      high ecosystem respiration, which approximately balanced C uptake. These patterns
      show potential for stimulated C storage in hemlock forests in a warmer climate
      with fewer spring and autumn frosts, but reduced C storage during warmer summers.
      Estimated annual C storage was 3.0 Mg ha(-1), which is higher than for younger
      coniferous and deciduous forests during earlier years in the northeastern USA.
      Long-term data are needed to determine if the estimated high C storage in this
      hemlock forest is a result of interannual climate variation or an effect of
      forest composition.

PMID- 12414369
TI  - Branch growth and gas exchange in 13-year-old loblolly pine (Pinus taeda) trees
      in response to elevated carbon dioxide concentration and fertilization.
AB  - We used whole-tree, open-top chambers to expose 13-year-old loblolly pine (Pinus
      taeda L.) trees, growing in soil with high or low nutrient availability, to
      either ambient or elevated (ambient + 200 micromol mol-1) carbon dioxide
      concentration ([CO2]) for 28 months. Branch growth and morphology, foliar
      chemistry and gas exchange characteristics were measured periodically in the
      upper, middle and lower crown during the 2 years of exposure. Fertilization and
      elevated [CO2] increased branch leaf area by 38 and 13%, respectively, and the
      combined effects were additive. Fertilization and elevated [CO2] differentially
      altered needle lengths, number of fascicles and flush length such that flush
      density (leaf area/flush length) increased with improved nutrition but decreased
      in response to elevated [CO2]. These results suggest that changes in nitrogen
      availability and atmospheric [CO2] may alter canopy structure, resulting in
      greater foliage retention and deeper crowns in loblolly pine forests.
      Fertilization increased foliar nitrogen concentration (N(M)), but had no
      consistent effect on foliar leaf mass (W(A)) or light-saturated net
      photosynthesis (A(sat)). However, the correlation between A(sat) and leaf
      nitrogen per unit area (N(A) = W(A)N(M)) ranged from strong to weak depending on
      the time of year, possibly reflecting seasonal shifts in the form and pools of
      leaf nitrogen. Elevated [CO2] had no effect on W(A), N(M) or N(A), but increased
      A(sat) on average by 82%. Elevated [CO2] also increased photosynthetic quantum
      efficiency and lowered the light compensation point, but had no effect on the
      photosynthetic response to intercellular [CO2], hence there was no acclimation to
      elevated [CO2]. Daily photosynthetic photon flux density at the upper, middle and
      lower canopy position was 60, 54 and 33%, respectively, of full sun incident to
      the top of the canopy. Despite the relatively high light penetration, W(A), N(A),
      A(sat) and R(d) decreased with crown depth. Although growth enhancement in
      response to elevated [CO2] was dependent on fertilization, [CO2] by fertilization
      interactions and treatment by canopy position interactions generally had little
      effect on the physiological parameters measured.

PMID- 12414370
TI  - Hydraulic redistribution of soil water during summer drought in two contrasting
      Pacific Northwest coniferous forests.
AB  - The magnitude of hydraulic redistribution of soil water by roots and its impact
      on soil water balance were estimated by monitoring time courses of soil water
      status at multiple depths and root sap flow under drought conditions in a dry
      ponderosa pine (Pinus ponderosa Dougl. ex Laws) ecosystem and in a moist Douglas
      fir (Pseudotsuga menziesii (Mirb.) Franco) ecosystem. The fate of deuterated
      water applied to small plots to create a strong horizontal soil water potential
      gradient was also monitored to assess the potential for horizontal redistribution
      of water and utilization of redistributed water by co-occurring shallow-rooted
      plants. In a 20-year-old Douglas-fir stand, approximately 28% of the water
      removed daily from the upper 2 m of soil was replaced by nocturnal hydraulic
      redistribution during late August. In an old-growth ponderosa pine stand,
      approximately 35% of the total daily water utilization from the upper 2 m of soil
      appeared to be replaced by hydraulic redistribution during July and August. By
      late September, hydraulic redistribution in the ponderosa pine stand was no
      longer apparent, even though total water use from the upper 2 m of soil was
      nearly identical to that observed earlier. Based on these results, hydraulic
      redistribution would allow 21 and 16 additional days of stored water to remain in
      the upper soil horizons in the ponderosa pine and Douglas-fir stands,
      respectively, after a 60-day drought. At both sites, localized applications of
      deuterated water induced strong reversal of root sap flow and caused soil water
      content to cease declining or even temporarily increase at locations too distant
      from the site of water application to have been influenced by movement of water
      through the soil without facilitation by roots. Xylem water deuterium values of
      ponderosa pine seedlings suggested utilization of redistributed water. Therefore,
      hydraulic redistribution may enhance seedling survival and maintain overstory
      transpiration during summer drought. These first approximations of the extent of
      hydraulic redistribution in these ecosystems suggest that it is likely to be an
      important process in both wet and dry forests of the Pacific Northwest.

PMID- 12414371
TI  - When branch autonomy fails: Milton's Law of resource availability and allocation.
AB  - The branch autonomy principle states that the critical characteristics of a
      branch's carbohydrate economy (photosynthesis, respiration, growth, etc.) are
      largely independent of the tree to which the branch is attached, as long as light
      is the primary factor limiting photosynthesis and growth. However, this may not
      be generally true because in the spring, photosynthates are translocated from a
      tree stem into branches, and the amount of photosynthate available for
      translocation should be a function of the tree's canopy status. And the
      correlative inhibition principle states that a branch's priority for allocation
      of carbon and other resources is controlled not only by its own environment, but
      also by its position relative to other branches on the same tree. A study of the
      lower limit of branch growth and survival in trees of different sizes shows that
      the latter principle is more important: even though dominant trees have more
      resources to allocate, branches on suppressed trees are able to grow and produce
      new foliage at solar irradiances where branches on dominant trees die. Thus
      branches are sufficiently interdependent that a positive carbon budget by itself
      does not ensure branch survival; branch position relative to other branches on
      the same tree is also important. Other findings indicate that this result is
      quite general: regardless of the stress involved, a stressed branch on a tree
      where all other branches are also stressed does better than a similarly stressed
      branch on a tree where some branches are relatively unstressed. Although branch
      autonomy is an important and useful principle, it is not an absolute rule
      governing branch growth.

PMID- 12414372
TI  - Midday stomatal closure in Norway spruce--reactions in the upper and lower crown.
AB  - We used local microclimatic conditions and twig sap flow rates to interpret
      midday stomatal closure in the canopies of two 250-year-old Norway spruce (Picea
      abies (L.) Karst.) trees at a subalpine site in the Swiss Alps (1,650 m a.s.l.).
      Both trees showed midday stomatal closure on most clear summer days, despite the
      permanently wet soil. We used a modified Penman-Monteith formula to simulate
      potential transpiration of single twigs (ET(T)) based on high-resolution temporal
      and spatial microclimate data obtained both inside and outside the crowns.
      Comparison of calculated ET(T) values and measured twig sap flow rates enabled us
      to pinpoint the occurrence of midday stomatal closure and the microclimatic
      conditions present at that time. We found that vapor pressure deficit (and for
      upper-crown twigs, ET(T)) largely explained the timing of initial midday stomatal
      closure but gave no explanation for the different patterns of stomatal behavior
      after initial closure in upper- and lower-crown twigs. After the initial stomatal
      closure, upper-crown twigs maintained high transpiration rates by continuously
      regulating stomatal aperture, whereas stomatal aperture decreased rapidly in
      lower-crown twigs and did not increase later in the day. Midday stomatal closure
      in lower-crown twigs occurred on average 1 h later than in upper-crown twigs.
      However, the microclimate at the time of initial stomatal closure was similar at
      both crown locations except that lower-crown twigs received significantly less
      solar radiation than upper-crown twigs both at the time of initial stomatal
      closure and afterwards. High rates of sap flow in twigs did not always lead to
      stomatal closure and therefore could not explain the phenomenon. We conclude that
      stomatal conductance can be modeled accurately only when both local microclimatic
      conditions and tree water status are known. Further, we hypothesize that both the
      quantity and quality of light play an important role in the reopening of closed
      stomata during the day.

PMID- 12414373
TI  - Leaf chemical changes induced in Populus trichocarpa by enhanced UV-B radiation
      and concomitant effects on herbivory by Chrysomela scripta (Coleoptera:
      Chrysomelidae).
AB  - To assess the potential impact of enhanced ultraviolet-B (UV-B) radiation over
      two trophic levels, we monitored key leaf chemical constituents and related
      changes in their concentration to dietary preference and performance of a
      specialist insect herbivore. Ramets of Populus trichocarpa Torr. & Gray (black
      cottonwood) were subjected to near zero (0X), ambient (1X) or twice ambient (2X)
      doses of biologically effective UV-B radiation (UV-B(BE)) in a randomized block
      design using either a square-wave (greenhouse) or a modulated (field) lamp
      system. After a 3-month treatment period, apparent photosynthesis was determined
      in situ and plants were harvested for biomass determination. Leaf subsamples were
      analyzed for nitrogen, sulfur, chlorophylls, UV-absorbing compounds and protein
      precipitable tannins. Effects of changes in these constituents on feeding by
      Chrysomela scripta Fab. (cottonwood leaf beetle) were determined by (1) adult
      feeding preference trials and (2) larval growth rate trials. Enhanced UV-B(BE)
      radiation had minimal effects on photosynthesis, growth, leaf area and biomass
      distribution. In the greenhouse study, concentrations of foliar nitrogen and
      chlorophylls increased, but tannins decreased slightly in young leaves exposed to
      enhanced UV-B(BE) radiation. There were no significant effects on these
      parameters in the field study. The concentration of methanol-extractable foliar
      phenolics increased in plants grown with enhanced UV-B(BE) radiation in both the
      greenhouse and field studies. In feeding preference trials, adult C. scripta
      chose 2X-treated tissue almost twice as often as 1X-treated tissue in both
      greenhouse and field studies, but differences were not statistically significant
      (P = 0.12). In the field study, first instar larvae grown to adult eclosion on 2X
      treated leaves had a significant (P < 0.001) reduction in consumption efficiency
      compared with larvae grown on 1X-treated leaves. We conclude that effects of
      enhanced UV-B(BE) radiation at the molecular-photochemical level can elicit
      significant responses at higher trophic levels that may ultimately affect forest
      canopy structure, plant competitive interactions and ecosystem-level processes.

PMID- 12414374
TI  - Structural differences and functional similarities between two sugar maple (Acer
      saccharum) stands.
AB  - The spatially inexplicit or functional multilayer models used to predict canopy
      transpiration or photosynthesis are based on the assumption that closed stands
      show less functional variability than structural variability, because foliage
      tends to arrange itself in space to optimize the capture of light. To validate
      this assumption, we compared the structural and functional properties, and the
      measured and modeled transpiration fluxes of two sugar maple (Acer saccharum
      Marsh.) stands of comparable leaf mass but differing in height and diameter
      distributions. One stand was characterized by a well-developed single-layer
      canopy, whereas the other stand had a multilayered canopy and a stem diameter
      distribution of the classical inverse-J shape. Stand differences in height and
      diameter distribution, and canopy gap fraction, were highly significant. There
      were minor but significant differences in leaf mass and leaf mass per unit leaf
      area (LMA) distributions. We found no differences in tree-level relationships
      between basal area and either transpiration flux or sapwood area. We compared
      measurements of stand transpiration with transpiration estimates obtained from a
      multilayer gas exchange model, in which only the nonspatial inputs, leaf area
      index and LMA frequency distribution described stand structure. For both stands,
      modeled values of daily transpiration closely followed measured values (r(2) =
      0.94). These results support use of the nonspatially explicit approach to
      estimating canopy gas exchange, especially if the intent is to scale-up to larger
      portions of the landscape.

PMID- 12414375
TI  - Leaf respiration at different canopy positions in sweetgum (Liquidambar
      styraciflua) grown in ambient and elevated concentrations of carbon dioxide in
      the field.
AB  - Trees exposed to elevated CO2 partial pressure ([CO2]) generally show increased
      rates of photosynthesis and growth, but effects on leaf respiration are more
      variable. The causes of this variable response are unresolved. We grew 12-year
      old sweetgum trees (Liquidambar styraciflua L.) in a Free-Air CO2 Enrichment
      (FACE) facility in ambient [CO2] (37/44 Pa daytime/nighttime) and elevated [CO2]
      (57/65 Pa daytime/nighttime) in native soil at Oak Ridge National Environmental
      Research Park. Nighttime respiration (R(N)) was measured on leaves in the upper
      and lower canopy in the second (1999) and third (2000) growing seasons of CO2
      fumigation. Leaf respiration in the light (R(L)) was estimated by the technique
      of Brooks and Farquhar (1985) in the upper canopy during the third growing
      season. There were no significant short-term effects of elevated [CO2] on R(N) or
      long-term effects on R(N) or R(L), when expressed on an area, mass or nitrogen
      (N) basis. Upper-canopy leaves had 54% higher R(N) (area basis) than lower-canopy
      leaves, but this relationship was unaffected by CO2 growth treatment. In August
      2000, R(L) was about 40% of R(N) in the upper canopy. Elevated [CO(2)]
      significantly increased the number of leaf mitochondria (62%), leaf mass per unit
      area (LMA; 9%), and leaf starch (31%) compared with leaves in ambient [CO(2)].
      Upper-canopy leaves had a significantly higher number of mitochondria (73%), N
      (53%), LMA (38%), sugar (117%) and starch (23%) than lower-canopy leaves. Growth
      in elevated [CO2] did not affect the relationships (i.e., intercept and slope)
      between R(N) and the measured leaf characteristics. Although no factor explained
      more than 45% of the variation in R(N), leaf N and LMA were the best predictors
      for R(N). Therefore, the response of RN to CO2 treatment and canopy position was
      largely dependent on the magnitude of the effect of elevated [CO2] or canopy
      position on these characteristics. Because elevated [CO2] had little or no effect
      on N or LMA, there was no effect on R(N). Canopy position had large effects on
      these leaf characteristics, however, such that upper-canopy leaves exhibited
      higher R(N) than lower-canopy leaves. We conclude that elevated [CO2] does not
      directly impact leaf respiration in sweetgum and that barring changes in leaf
      nitrogen or leaf chemical composition, long-term effects of elevated [CO2] on
      respiration in this species will be minimal.

PMID- 12414376
TI  - Shoot structure and growth along a vertical profile within a Populus-Tilia
      canopy.
AB  - We investigated shoot growth patterns and their relationship to the canopy
      radiation environment and the distribution of leaf photosynthetic production in a
      27-m-tall stand of light-demanding Populus tremula L. and shade-tolerant Tilia
      cordata Mill. The species formed two distinct layers in the leaf canopy and
      showed different responses in branch architecture to the canopy light gradient.
      In P. tremula, shoot bifurcation decreased rapidly with decreasing light, and
      leaf display allowed capture of multidirectional light. In contrast, leaf display
      in T. cordata was limited to efficient interception of unidirectional light, and
      shoot growth and branching pattern facilitated relatively rapid expansion into
      potentially unoccupied space even in the low light of the lower canopy. At the
      canopy level, T. cordata had higher photosynthetic light-use efficiency than P.
      tremula, whereas P. tremula had higher nitrogen-use efficiency than T. cordata.
      However, at the individual leaf level, both species had similar efficiencies
      under comparable light conditions. Production of new leaf area in the canopy
      followed the pattern of photosynthetic production. However, the species differed
      substantially in extension growth and space-filling strategy. Light-demanding P.
      tremula expanded into new space with a few long shoots, with shoot length
      strongly dependent on photosynthetic photon flux density (PPFD). Production of
      new leaf area and extension growth were largely uncoupled in this species because
      short shoots, which do not contribute to extension growth, produced many new
      leaves. Thus, in P. tremula, the growth pattern was strongly directed toward the
      top of the canopy. In contrast, in shade-tolerant T. cordata, shoot growth was
      weakly related to PPFD and more was invested in long shoot growth on a leaf area
      basis compared with P. tremula. However, this extension growth was not directed
      and may serve as a passive means of avoiding self-shading. This study supports
      the hypothesis that, for a particular species, allocation patterns and crown
      architecture contribute as much to shade tolerance as leaf-level photosynthetic
      acclimation.

PMID- 12414377
TI  - Plant ecophysiology and forest response to global change.
AB  - There are many ways of studying forest responses to global change. Most current
      national and international programs focus on net gas exchange of the terrestrial
      biosphere and are typically interdisciplinary, multi-scale projects. Key
      objectives of these programs are surprisingly similar to those of classical plant
      ecophysiology studies, i.e., to explore functional relationships of plant or
      plant community responses to environmental change. Thus, common research
      questions that link plant ecophysiology to ecosystem functioning can be
      identified for both research communities, promising complementarity and synergism
      for joint research projects. Although some well-established ecophysiological
      relationships, such as light responses or stomatal limitations of photosynthetic
      gas exchange, are currently employed in many ecosystem-scale net flux studies for
      gap-filling or modeling, only 14% (n = 27) of all eddy covariance flux studies in
      forests (n = 196; published between 1992 and April 2002) include plant
      ecophysiological measurements (n = 24) or biomass and growth estimates (n = 8).
      Generally, emphasis is on CO2 exchange measurements at various scales (foliage,
      shoots, branches; n = 14) and water relations measurements (n = 11). These
      measurements do not fully support the typical parameterization of stand and
      regional models, which often need information on canopy architecture and nitrogen
      nutrition. By means of a complementary research approach, valuable information
      can be acquired that is unobtainable by means of a single approach. This
      additional information is important for the identification of underlying biotic
      and environmental drivers, for the regulation of net ecosystem fluxes and their
      partitioning, and the independent validation of measured net ecosystem fluxes.
      Thus, combining micrometeorology and ecophysiology at flux sites is strongly
      recommended for ecosystem functioning studies.

PMID- 12414378
TI  - Fertilization has little effect on light-interception efficiency of Picea abies
      shoots.
AB  - We investigated effects of nutrient availability on shoot structure and light
      interception efficiency based on data from control (C) and irrigated + fertilized
      (IL) trees of Norway spruce (Picea abies (L.) Karst.). The sampling of 1-year-old
      shoots was designed to cover the variation in canopy exposure within the live
      crown zone, where current-year shoots were still found. Canopy openness was used
      as a measure of light availability at the shoot's position. Openness values for
      the sample shoots ranged from 0.02 to 0.77 on the IL plot, and from 0.10 to 0.96
      on the C plot. Among needle dimensions, needle width increased most with canopy
      openness. At fixed canopy openness, needle width was larger, and the ratio of
      needle thickness to width was smaller in IL trees than in C trees. Specific
      needle area (SNA) and the ratio of shoot silhouette area to total needle area
      (STAR) decreased with canopy openness, so that the combined effect was a
      threefold decrease in the ratio of shoot silhouette area to unit dry mass (SMR =
      STAR x SNA) along the studied range of openness values. This means that the light
      interception efficiency of shoots per unit needle dry mass was three times higher
      for the most shaded shoots than for sun shoots. A test of the effect of
      fertilization on the relationships of SNA, STAR and SMR indicated statistically
      significant differences in both slope and intercept for SNA and STAR, and in the
      intercept for SMR. However, the differences partly cancelled each other so that,
      at medium values of canopy openness, differences between treatments in predicted
      SNA, STAR and SMR were small. At 0.5 canopy openness, predicted STAR of IL shoots
      was 6.1% larger than STAR of C shoots, but SMR of IL shoots was 10% smaller than
      that of C shoots. The results suggest that light-interception efficiency per unit
      needle area or mass of the shoots is not greatly affected by fertilization.

PMID- 12414379
TI  - The influence of the forest canopy on nutrient cycling.
AB  - Rates of key soil processes involved in recycling of nutrients in forests are
      governed by temperature and moisture conditions and by the chemical and physical
      nature of the litter. The forest canopy influences all of these factors and thus
      has a large influence on nutrient cycling. The increased availability of
      nutrients in soil in clearcuts illustrates how the canopy retains nutrients
      (especially N) on site, both by storing nutrients in foliage and through the
      steady input of available C in litter. The idea that faster decomposition is
      responsible for the flush of nitrate in clearcuts has not been supported by
      experimental evidence. Soil N availability increases in canopy gaps as small as
      0.1 ha, so natural disturbances or partial harvesting practices that increase the
      complexity of the canopy by creating gaps will similarly increase the spatial
      variability in soil N cycling and availability within the forest. Canopy
      characteristics affect the amount and composition of leaf litter produced, which
      largely determines the amount of nutrients to be recycled and the resulting
      nutrient availability. Although effects of tree species on soil nutrient
      availability were thought to be brought about largely through differences in the
      decomposition rate of their foliar litter, recent studies indicate that the
      effect of tree species can be better predicted from the mass and nutrient content
      of litter produced, hence total nutrient return, than from litter decay rate. The
      greater canopy complexity in mixed species forests creates similar heterogeneity
      in nutritional characteristics of the forest floor. Site differences in slope
      position, parent material and soil texture lead to variation in species
      composition and productivity of forests, and thus in the nature and amount of
      litter produced. Through this positive feedback, the canopy accentuates inherent
      differences in site fertility.

PMID- 12414381
TI  - Second primary tumors in hereditary retinoblastoma.

PMID- 12414383
TI  - LASIK and dry eye.

PMID- 12414384
TI  - Disc excavation in dominant optic atrophy.

PMID- 12414385
TI  - LASIK and dry eye.

PMID- 12414388
TI  - The "statistical significance = P < or = 0.05" trap.

PMID- 12414389
TI  - Scleral buckle and corneal ectasia after LASIK.

PMID- 12414390
TI  - Prevention of bag-fixated IOL dislocation in pseudoexfoliation.

PMID- 12414392
TI  - Ocular whipple's disease.

PMID- 12414394
TI  - PRK retreatments after regressed myopic LASIK.

PMID- 12414395
TI  - Tacrolimus (FK506) for high-risk corneal and limbal grafts.

PMID- 12414397
TI  - Retrobulbar and peribulbar regional anesthesia.

PMID- 12414398
TI  - 56,000 ways to treat glaucoma.

PMID- 12414399
TI  - Effects of daily and overnight wear of a novel hyper oxygen-transmissible soft
      contact lens on bacterial binding and corneal epithelium: a 13-month clinical
      trial.
AB  - OBJECTIVE: To test prospectively a new biologic rationale for an advanced hyper
      oxygen-transmissible lens (HOTL) providing prospects for safer daily (DW) or
      extended (EW) contact lens wear. DESIGN: Prospective, randomized, double-masked,
      single-center, 13-month clinical trial. PARTICIPANTS: One hundred sixty-eight
      patients completed the DW study (1 month): control lens (n = 70); HOTL (n = 98).
      One hundred thirty-six patients finished 1 year of EW: controls (n = 56), HOTL (n
      = 25, 6 nights; n = 55, 30 nights). TESTING: Irrigation chamber to collect
      corneal surface cells, confocal microscopy, tear collection at baseline, 2, and
      4, weeks of DW, and 24 hours, 1, 3, 6, 9, and 12 months of EW. MAIN OUTCOME
      MEASURES: (1) Pseudomonas aeruginosa (PA) binding to exfoliated corneal surface
      cells; (2) central epithelial thickness (CET); (3) superficial cell area (SCA);
      (4) epithelial surface cell exfoliation (DESQ); and (5) tear lactate
      dehydrogenase (LDH). RESULTS: Daily wear with control lens increased PA binding
      from 5.90 +/- 2.60 to 7.81 +/- 3.04 bacteria per cell (P < 0.01); HOTL wear
      increased PA binding significantly less (5.31 +/- 1.87-5.98 +/- 2.26; P < 0.01).
      Daily wear produced no significant changes in CET or SCA. Significant decreases
      in DESQ were seen with both lenses with no significant intergroup differences.
      Tear LDH increased significantly in DW with HOTL wear versus control (P =
      0.0017), but not after 1 month of subsequent EW (P = 0.533). One to 3 months of
      EW with control lens showed significantly higher PA binding than HOTL wear (P <
      0.01); binding adaptively decreased thereafter, returning to baseline at 9 to 12
      months. Lens EW produced significantly enlarged SCA, thinning of CET (except 6
      night HOTL wear), and decreased DESQ (P < 0.01). Some adaptive recovery was seen
      with CET and DESQ, but not SCA; importantly, the data indicated no significant
      difference between 6- or 30-night EW for all outcomes. CONCLUSIONS: Hyper oxygen
      transmissible lens wear (DW or EW) produced significantly decreased PA binding
      compared with control lens wear, with no significant difference in wearing
      schedule (6 nights vs. 30 nights); additionally, there was a remarkable and
      unexpected adaptive recovery in the first 6 months of all soft lens wear, with a
      return to baseline PA binding levels and partial recovery for the other outcomes
      except SCA at 1 year. These results suggest that HOTL use should result in a
      decrease in the incidence of and risk(s) for lens-related microbial keratitis and
      that further epidemiologic studies should consider time in adapted EW in future
      risk and incidence analyses.

PMID- 12414400
TI  - Anterior ciliary sclerotomy for treatment of presbyopia: a prospective controlled
      study.
AB  - PURPOSE: To examine the safety and efficacy of anterior ciliary sclerotomy to
      restore accommodation in the presbyopic eye. DESIGN: Prospective nonrandomized
      comparative single-center clinical trial. PARTICIPANTS: Nine presbyopic subjects
      with no prior ocular surgery except corneal refractive procedures were enrolled.
      METHODS: One eye from each subject was chosen, in consultation with the patient,
      to undergo anterior ciliary sclerotomy. The contralateral eye of each subject
      served as a control. Examinations were performed preoperatively, and at 1 day, 1
      week, 1 month, and 6 months after surgery. MAIN OUTCOME MEASURES: (1)
      Accommodative amplitude, measured by two methods, (2) Jaeger reading vision at 14
      inches wearing best distance correction, (3) manifest refraction, (4) assessment
      of operative complications. RESULTS: For the nine study eyes, there was no
      statistically significant change between the average accommodative amplitude at
      the preoperative visit (1.11 diopter [D]) and the 1-month postoperative visit
      (1.19 D, P = 0.55) nor at the 6-month postoperative visit (1.31 D, P = 0.21) in
      the study eyes. There was no significant difference between the study and control
      eyes' change in accommodative amplitude at 6 months (P = 0.43). Logarithm of the
      minimum angle of resolution equivalent of Jaeger reading vision in the study eyes
      at 14 inches wearing best distance correction showed no statistically significant
      change from the preoperative visit (0.53 [20/70]) at the 1-month postoperative
      visit (0.41 [20/50], P = 0.07) or at the 6-month postoperative visit (0.48
      [20/60], P = 0.22). There was no significant change in manifest refraction
      spherical equivalent in the study eyes at 1 and 6 months postoperatively. One eye
      experienced a perforation of the anterior chamber during surgery. A second eye
      experienced mild postoperative anterior segment ischemia manifested by sectoral
      iris akinesis. CONCLUSIONS: Anterior ciliary sclerotomy does not restore
      accommodation in presbyopic eyes and can cause significant complications.

PMID- 12414402
TI  - Conductive keratoplasty for the correction of low to moderate hyperopia: U.S.
      clinical trial 1-year results on 355 eyes.
AB  - OBJECTIVE: To document the 1-year safety, efficacy, and stability results of 355
      eyes treated in the multicenter study of conductive keratoplasty (CK) used to
      correct low to moderate hyperopia. DESIGN: Nonrandomized comparative (self
      controlled) trial. PARTICIPANTS: Twenty surgeons at 13 centers performed CK on
      the eyes of all patients enrolled in a multicenter, 2-year, U.S. phase III
      clinical trial. Treated eyes had +0.75 to +3.00 diopters (D) of hyperopia and <
      or =0.75 D of cylinder. Patients were 40 years of age or older. INTERVENTION: Low
      energy, high-frequency current was applied directly into the peripheral corneal
      stroma through a delivery tip inserted at 8 to 32 treatment spots. The number of
      treatment spots was increased for increasing levels of hyperopia, but the amount
      of radiofrequency energy remained constant. Emmetropia was intended. All eyes
      were treated once (there were no retreatments). MAIN OUTCOME MEASURES: Data from
      355 eyes with 1 year of follow-up were analyzed for safety and stability, and
      data from 318 eyes were analyzed for efficacy and predictability, as well as
      stability and safety. All patients reported on satisfaction and quality of vision
      after surgery. RESULTS: At 1 year, uncorrected visual acuity was < or =20/20 in
      56%, < or =20/25 in 75%, and < or =20/40 in 92% of eyes. The manifest refractive
      spherical equivalent refraction was within 0.50 D in 63%, within +/-1.00 D in
      89%, and within +/-2.00 D in 99%. Seven of 355 eyes lost 2 lines of best
      spectacle-corrected visual acuity at 1 year, but no eye lost >2 lines. One eye of
      355 had induced cylinder of >2.00 D. The cycloplegic refractive spherical
      equivalent changed a mean of 0.25 +/- 0.50 D between months 3 and 6, 0.11 +/-
      0.41 D between months 6 and 9, and 0.11 +/- 0.35 D between months 9 and 12.
      Refractive stability seemed to be attained by 6 months and remained stable
      through 12 months. Histology and confocal microscopy showed deep penetration of
      the treatment into the stroma. Endothelial cell counts were not changed by the
      treatment. CONCLUSIONS: CK seems to be safe, effective, and stable for correcting
      low to moderate spherical hyperopia in patients 40 years old or older. Treatment
      penetration is deep and cylindrical in shape, and it does not damage the corneal
      endothelium. Uncorrected visual acuity, predictability, and stability are as good
      as or better than those obtained with other techniques used to correct hyperopia.

PMID- 12414404
TI  - Posterior corneal topographic changes after retreatment LASIK.
AB  - PURPOSE: To evaluate posterior corneal topographic changes after retreatment
      after myopic laser in situ keratomileusis (repeat LASIK). DESIGN: Retrospective
      nonrandomized comparative self-controlled trial. PARTICIPANTS: Thirty-three eyes
      of 23 patients who underwent repeat LASIK for residual myopia. INTERVENTION:
      Retreatments were performed. Slit-scanning corneal topography was performed
      before and at 1, 3, and 6 months after repeat LASIK. MAIN OUTCOME MEASURES:
      Posterior corneal topographic changes before and after repeat LASIK were
      correlated with central corneal pachymetry (preoperatively, before repeat LASIK,
      after repeat LASIK), residual bed thickness (RBT) and ablation depth (after
      primary laser in situ keratomileusis (LASIK) and repeat LASIK). On the basis of
      the amount of posterior corneal elevation after repeat LASIK, the eyes were
      divided into two groups: group 1 (>66 micro m) and group 2 (< or =66 micro m).
      Student's t test/Mann-Whitney rank-sum test was used to determine the significant
      difference of mean level of each variable between the two groups. RESULTS: After
      primary LASIK, an increase in posterior corneal elevation had significant
      positive correlation with attempted correction (P = 0.02), ablation depth (P =
      0.008), and significant negative correlation with preoperative central pachymetry
      (P = 0.0003), RBT (P = 0.0003), and postoperative central pachymetry (P =
      0.00008). After repeat LASIK, the mean increase in posterior corneal elevation
      had significant negative correlation with preoperative central pachymetry (P =
      0.03). However, its correlation with the ablation depth (P = 0.43) during repeat
      LASIK and RBT after repeat LASIK (P = 0.11) was statistically insignificant. On
      multiple linear regression analysis, the attempted correction (P < 0.01) and RBT
      after primary LASIK (P < 0.001) were two independent significant determinants of
      an increase in posterior corneal elevation after primary LASIK. However, for
      increase in posterior corneal elevation after repeat LASIK, preoperative central
      pachymetry (P < 0.01) and posterior corneal elevation increase after primary
      LASIK (P < 0.05) were the two significant determinants. Compared with group 2,
      group 1 had significantly high values of posterior corneal elevation both after
      primary LASIK (P = 0.0037) and after repeat LASIK (P = 0.0000). This group also
      had significantly low values of central pachymetry preoperatively (P = 0.0003)
      and after primary LASIK (P = 0.0001) and repeat LASIK (P = 0.0001) surgeries. The
      mean RBT after primary LASIK (P = 0.0006) and after repeat LASIK (P = 0.001) was
      also lower in group 1. CONCLUSIONS: Posterior corneal elevation increases after
      repeat LASIK. Eyes with an increase in posterior corneal elevation after primary
      LASIK and with thinner cornea are more predisposed.

PMID- 12414405
TI  - Wavefront aberrations measured with Hartmann-Shack sensor in patients with
      keratoconus.
AB  - OBJECTIVE: To compare the ocular wavefront aberrations of normal and keratoconic
      eyes and to describe the characteristics of the higher-order aberrations in eyes
      with keratoconus. DESIGN: Prospective case control and observational study.
      PARTICIPANTS: Thirty-five keratoconic eyes and thirty-eight normal controls.
      METHODS: Higher-order aberrations in refraction were measured with a wavefront
      sensor, and those aberrations resulting from the cornea were evaluated by
      videokeratographic data. MAIN OUTCOME MEASURES: Coma-like (S(3 + 5)), spherical
      like (S(4 + 6)), and total (S(3 + 4 + 5 + 6)) higher-order aberrations in both
      refraction and the cornea. RESULTS: The mean +/- standard deviation of S(3 + 5)
      (1.88 +/- 1.16), S(4 + 6) (0.70 +/- 0.55), and S(3 + 4 + 5 + 6) (2.03 +/- 1.23)
      in refraction (6-mm diameter, root mean square, micro m) were significantly
      higher in the keratoconic eyes than in normal controls (0.26 +/- 0.10, 0.19 +/-
      0.10, 0.34 +/- 0.11, respectively; Mann-Whitney U test, P = 0.001). Coma-like
      aberrations were 2.32 times larger than spherical-like aberrations in keratoconic
      eyes. CONCLUSIONS: The increase of ocular higher-order aberrations in keratoconic
      eyes results from an increase of corneal higher-order aberrations. Coma-like
      aberrations were dominant compared with spherical-like aberrations in keratoconic
      eyes. Wavefront sensing will enable us not only to evaluate the quality of vision
      but also to differentiate keratoconic eyes from normal eyes by analyzing the
      characteristics of the higher-order aberrations.

PMID- 12414406
TI  - Idiopathic limbal stem cell deficiency.
AB  - PURPOSE: To describe and to characterize the clinical findings and prognosis of
      patients with idiopathic limbal stem cell deficiency (LSCD). DESIGN:
      Retrospective case series. PARTICIPANTS/METHODS: We reviewed records from seven
      patients whose LSCD had been diagnosed clinically and confirmed by impression
      cytology and in whom the cause of LSCD was never identified. A detailed history,
      clinical records, and results of slit-lamp biomicroscopy, photography, vital
      staining, and impression cytology were evaluated. RESULTS: Six of seven patients
      (86%) were women, indicating a female predominance. Two patients were from the
      same family, whereas one other had a positive family history. Severe photophobia
      was noted in all patients and reduced vision in three patients. The main clinical
      findings included superficial vascularization, worse in the superior followed by
      the inferior and nasal cornea. The limbal regions showed a loss of limbal
      palisades of Vogt, and the adjacent peripheral cornea revealed an irregular and
      hazy epithelium with positive late fluorescein staining and the presence of
      conjunctival goblet cells by impression cytology. LSCD was bilateral in all
      patients but asymmetric in four. During a mean follow-up of 6.1+/- 3.8 years, the
      visual acuity decreased in both eyes of one patient after cataract extraction and
      in both eyes of two other patients without surgery. The process of
      conjunctivalization advanced in four patients (57%) and remained stable in three
      (43%) without surgical intervention. CONCLUSIONS: Idiopathic LSCD is a rare and
      as yet poorly recognized clinical entity, and the findings reported herein may
      help explore how progressive loss of limbal stem cells occurs. Correct diagnosis
      of idiopathic LSCD is important so that the patient will not be subjected to
      unnecessary surgeries, which may actually severely worsen the clinical course.

PMID- 12414407
TI  - Autologous limbal grafting combined with deep lamellar keratoplasty in unilateral
      eye with severe chemical or thermal burn at late stage.
AB  - PURPOSE: To evaluate the efficacy of autologous limbal transplantation (ALT)
      combined with deep lamellar keratoplasty (DLK) for ocular surface reconstruction
      and corneal clarity recovery in eyes with severe late-stage chemical or thermal
      burns. DESIGN: Retrospective, noncomparative, interventional case series.
      PARTICIPANTS: Thirty-nine eyes of 39 patients with a history of severe chemical
      or thermal burns over 6 months (mean, 47 +/- 28.7 months) exhibiting corneal
      vascularization, conjunctivalization, and heavy corneal scarring were treated at
      two university hospitals. METHODS: Surgical procedures included excising
      epibulbar fibrous tissue, clearing the fibrovascular membrane over the cornea,
      deep removal of corneal stroma 7.5 to 8.0 mm in diameter, exposing Descemet's
      membrane in the pupillary area, grafting a corneal button, transplanting
      autologous limbal and conjunctival epithelial grafts, and making a temporary
      tarsorrhaphy. MAIN OUTCOME MEASURES: Integrity of ocular surface recovery,
      postoperative corneal epithelial stability, optical corneal clarity, and best
      corrected visual acuity were the outcome measurements. RESULTS: Thirty-four of 39
      eyes that received ALT combined with DLK met the criteria of the study. Of 34
      operated eyes, full corneal epithelialization was achieved in 19 eyes (55.9%)
      within 5 days and in 32 eyes (94.1%) within 7 days after surgery. Delayed
      epithelial healing occurred in two eyes (5.9%). The reconstructed corneal surface
      remained stable, and the renewed epithelium was characterized cytologically by
      nonkeratinized squamous cells without goblet cells. After surgery in 11 of 34
      eyes, fluid was identified between Descemet's membrane and the donor corneal
      graft, resulting in a pseudochamber that completely resolved in 10 eyes within 30
      days. In one patient, a persistent pseudochamber was present for 28 months. After
      surgery, transparent cornea especially in the pupillary area was accomplished in
      29 eyes, whereas mild cornea clouding, nebulomacular corneal opacity, and heavy
      corneal scarring were observed, respectively, in three eyes. In addition, corneal
      endothelial decompensation was identified in two eyes and demonstrated persistent
      corneal epithelial and stromal edema. Remarkable improvement of postoperative
      vision was achieved in 30 eyes. Four eyes without postoperative improvement in
      vision were regrafted by penetrating keratoplasty at least 6 months after the
      original ALT and DLK surgery. CONCLUSIONS: Autologous limbal grafting combined
      with DLK simultaneously can restore a normal and stable ocular surface, create
      clear central cornea, and remarkably enhance visual acuity after severe chemical
      or thermal burns.

PMID- 12414408
TI  - Videokeratography findings in children with vernal keratoconjunctivitis versus
      those of healthy children.
AB  - PURPOSE: To determine videokeratographic topography of eyes with vernal
      keratoconjunctivitis (VKC) and to assess whether the severity of the VKC is
      related to the presence of changes compatible with keratoconus. PARTICIPANTS:
      Seventy-six persons aged 6 to 21 years: 40 patients with VKC and 36 healthy
      controls. DESIGN: A comparative, observational case series. METHODS: We examined
      76 persons, of whom 40 were patients with VKC and 36 were control subjects, and
      compared the outcomes of videokeratography (VKG) patterns (EyeSys Laboratories,
      Houston, TX), numerical corneal indices, and spherical equivalent refraction.
      MAIN OUTCOME MEASURES: Corneal topographic patterns, corneal numeric indices, and
      corneal mirror imagery. RESULTS: We found many more abnormal patterns on VKG
      among the VKC patients than expected when compared with 'normal' eyes (P = 0.02
      for the right eye and P = 0.001 for the left eye). Videokeratography allowed us
      to define a subgroup of patients with infraclinical keratoconus. A trend of
      superior corneal steepening ('superior keratoconus') was also found. CONCLUSIONS:
      Vernal keratoconjunctivitis patients have more abnormal corneal topographic
      patterns than non VKC controls. Videokeratography may help decide how to follow
      up and treat a presumed self-limiting disease.

PMID- 12414409
TI  - Trehalose eye drops in the treatment of dry eye syndrome.
AB  - OBJECTIVE: Trehalose can protect human corneal epithelial cells in culture from
      death from desiccation. This study was designed to test the efficacy and safety
      of trehalose eyedrops in the treatment of moderate to severe dry eye syndrome.
      DESIGN: A randomized, double-masked, dose-ranging, fellow eye-controlled clinical
      trial. PARTICIPANTS: Thirty-four patients with moderate to severe dry eye
      syndrome. METHODS: The patients used either 100 or 200 mM trehalose dissolved in
      saline six times daily in one eye and control saline in the other eye for 4
      weeks. MAIN OUTCOME MEASURES: Symptoms and signs in both eyes were recorded
      separately at baseline, 2 weeks, and 4 weeks. RESULTS: Fluorescein and rose
      bengal staining scores of the ocular surface improved at both 2 weeks and 4 weeks
      in the eyes with 100 and 200 mM trehalose, compared with eyes with control saline
      (P = 0.0030 to P < 0.0001, respectively, Mann-Whitney U test). Tear film breakup
      time became significantly longer at 2 weeks and 4 weeks with 100 mM trehalose (P
      = 0.0024 and P < 0.0001, respectively), but not with 200 mM trehalose. No adverse
      effect attributable to trehalose solution was noted. CONCLUSIONS: Trehalose
      solution was an effective and safe eyedrop for the treatment of moderate to
      severe dry eye syndrome in this group of patients.

PMID- 12414410
TI  - Low-concentration homogenized castor oil eye drops for noninflamed obstructive
      meibomian gland dysfunction.
AB  - OBJECTIVE: We developed low-concentration homogenized castor oil eye drops for
      the treatment of patients with noninflamed obstructive meibomian gland
      dysfunction (MGD), a major cause of lipid-deficiency dry eye, and assessed the
      safety, stability, and efficacy of the eye drops. DESIGN: Randomized, double
      masked, placebo-controlled crossover clinical trial. PARTICIPANTS: Forty eyes of
      20 patients with noninflamed MGD. METHODS: After a preliminary study of eye drops
      containing castor oil, 2% castor oil and 5% polyoxyethylene castor oil
      (emulsifier) were mixed to formulate homogenized oil eye drops. The patients were
      assigned randomly to receive oil eye drops or placebo six times daily for 2
      periods of 2 weeks each. MAIN OUTCOME MEASURES: At the end of each treatment
      period, we assessed symptoms, tear interference grade, tear evaporation,
      fluorescein and rose bengal scores, tear break-up time (BUT), and meibomian gland
      orifice obstruction. Safety and stability tests were also performed. RESULTS:
      Symptom scores, tear interference grade, tear evaporation test results, rose
      bengal scores, tear BUT, and orifice obstruction scores after the oil eye drop
      period showed significant improvement compared with the results after the placebo
      period. No complications attributable to the eye drops were observed. The oil eye
      drops were stable when stored at 4 degrees C. CONCLUSIONS: The results indicate
      that castor oil eye drops are effective and safe in the treatment of MGD. The
      possible mechanisms of this treatment are improvement of tear stability as a
      result of lipid spreading, ease of meibum expression, prevention of tear
      evaporation, and the lubricating effect of the oil eye drops.

PMID- 12414411
TI  - Prospective randomized comparison of 3-day versus 1-hour preoperative ofloxacin
      prophylaxis for cataract surgery.
AB  - PURPOSE: To determine the efficacy of reducing conjunctival bacterial flora with
      topical ofloxacin when given for 3 days compared with 1 hour before surgery.
      DESIGN: Prospective, randomized, controlled trial. PARTICIPANTS: Ninety-two eyes
      from 89 patients were randomized to a control group (48 eyes) or study group (44
      eyes). METHODS: All patients from both groups received topical ofloxacin 0.3% 1
      hour before surgery and a 5% povidone iodine scrub of the periorbital area before
      surgery. The patients in the study group received additional ofloxacin four times
      daily for 3 days before surgery. MAIN OUTCOME MEASURES: Conjunctival cultures
      were obtained at five separate time points and were inoculated in solid and
      liquid culture media. The presence of bacteria was determined, quantified, and
      identified. RESULTS: Forty-two percent of eyes in the control group had positive
      conjunctival culture immediately before surgery, compared with 19% of eyes in the
      study group (P < 0.05). Immediately after surgery, 34% and 14% of eyes had
      positive cultures in the control and study groups, respectively (P < 0.05).
      Quantitatively, fewer bacteria were isolated from eyes in the study group
      compared with those in the control group for culture samples that were obtained
      both before povidone iodine scrub and at the conclusion of surgery (P </= 0.05).
      CONCLUSIONS: The application of topical ofloxacin for 3 days before surgery
      appears to be more effective in eliminating bacteria from the conjunctiva than an
      application of ofloxacin 1 hour before surgery.

PMID- 12414413
TI  - Hydrophilic acrylic intraocular lens optic and haptics opacification in a
      diabetic patient: bilateral case report and clinicopathologic correlation.
AB  - OBJECTIVE: To report clinicopathologic and ultrastructural features of two
      opacified single-piece hydrophilic acrylic intraocular lenses (IOLs) explanted
      from a diabetic patient. DESIGN: Interventional case report with
      clinicopathologic correlation. SETTING: A 64-year-old white female underwent
      phacoemulsification and implantation of a single-piece hydrophilic acrylic lens
      (SC60B-OUV; Medical Developmental Research, Inc., Clear Water, FL) in October
      1998 in the left eye and in July 1999 in the right eye. The best-corrected visual
      acuity after surgery was 20/60 in the left eye and 20/50 in the right eye. The
      patient had a marked decrease in visual acuity in June 2000 as a result of a
      milky, white opalescence of both lenses. Intraocular lens explantation and
      exchange was performed in both eyes and the explanted IOLs were submitted to our
      center for detailed pathologic, histochemical, and ultrastructural evaluation.
      They were stained with alizarin red and the von Kossa method for calcium, and
      also underwent scanning electron microscopy and energy dispersive radiograph
      spectroscopy to ascertain the nature of the deposits leading to opacification.
      MAIN OUTCOME MEASURES: Documentation of calcium deposits confirmed by
      histochemical stains and surface analyses. RESULTS: Opacification of the IOL was
      found to be the cause of decreased visual acuity. The opacification involved both
      the IOL optic and the haptics in the left eye and was confined to the IOL optic
      in the right eye. Histochemical and ultrastructural analyses revealed that the
      opacity was caused by deposition of calcium and phosphate within the lens optic
      and haptics. CONCLUSIONS: There are two features that distinguish this case from
      those reported earlier. This is the first clinicopathologic report of lens
      opacification that has involved completely the lens optic and the haptics.
      Second, these two explanted IOLs document the first bilateral case. This process
      of intraoptic and haptic opacification represents dystrophic calcification of
      unknown cause. Diabetic patients appear to be more severely and more often
      affected by lens opacification. Long-term follow-up of diabetic patients
      implanted with this IOL design should be maintained by surgeons and
      manufacturers.

PMID- 12414414
TI  - Incidence of age-related cataract over a 10-year interval: the Beaver Dam Eye
      Study.
AB  - OBJECTIVE OR PURPOSE: To describe the cumulative incidence of age-related
      cataracts and cataract surgery over a 10-year interval. DESIGN: Prospective
      epidemiologic study. PARTICIPANTS: Persons 43 to 86 years of age participating in
      the Beaver Dam Eye Study (n = 4926 at baseline, 2764 for baseline, 5-year and 10
      year follow-ups). METHODS: Questionnaires and examinations were performed
      according to standardized protocols in a clinic setting in the town of Beaver
      Dam, Wisconsin. Lens photographs were obtained with specially modified cameras
      and were graded according to codified rules by trained graders. MAIN OUTCOME
      MEASURES: Nuclear, cortical, and posterior subcapsular cataracts and cataract
      surgery. RESULTS: In right eyes, incident nuclear cataract occurred in 19.4%,
      cortical cataract in 17.4%, posterior subcapsular cataract in 6.1%, and cataract
      surgery in 10.8%. Incidence increased for all end points with age. Women had
      significantly higher incidences of nuclear cataract and cataract surgery than
      men. Time trends seem to be influencing the incidence of cataract surgery.
      CONCLUSIONS: Age-related cataracts are common events in aging. Age-specific
      cataract surgery incidence seems to be increasing.

PMID- 12414415
TI  - Prevalence of lens opacity in Chinese residents of Singapore: the tanjong pagar
      survey.
AB  - OBJECTIVE: To determine the prevalence of lens opacity among Chinese residents of
      Singapore. DESIGN: Population-based, cross-sectional survey. PARTICIPANTS:
      Chinese men and women aged 40 years or more in Singapore. METHODS: A stratified,
      clustered, random sampling method, with more weights given to the older age
      groups, was used to initially select 2000 Chinese persons aged 40 to 79 years
      from the 1996 electoral register in the Tanjong Pagar district in Singapore.
      Eligible subjects (n = 1717) were invited for a comprehensive ocular examination
      at a centralized clinic, after which nonrespondents were examined in their homes
      with portable instruments. MAIN OUTCOME MEASURES: Lens opacity, as determined
      clinically at the slit lamp using a modification of the Lens Opacity
      Classification System III. Prevalence rates were age adjusted to the 1997
      Singapore census population. RESULTS: Of the 1232 persons examined (71.8%), 1206
      (70.2%) provided lens data for this analysis. The age-adjusted prevalence of any
      cataract surgery was 5.1% (95% confidence interval [CI], 3.6, 6.5), with similar
      rates between men and women. The age-adjusted prevalence of specific types of
      lens opacity was 22.6% (95% CI, 19.8, 25.4) for any nuclear opacity, 23.9% (95%
      CI, 21.0, 26.8) for any cortical opacity, and 7.0% (95% CI, 5.3, 8.8) for any
      posterior subcapsular opacity. The overall age-adjusted prevalence of any
      cataract or cataract surgery was 34.7% (95% CI, 31.5, 38.0), increasing from 7.0%
      in those 40 to 49 years and to 94.3% in those 70 years and older (P < 0.001, test
      for trend for age). When the prevalence of distinct types of lens opacity in an
      eye was considered, the most common was mixed (age-adjusted prevalence, 11.5%,
      based on right eye data), followed by nuclear only (9.7%), cortical only (8.3%),
      and posterior subcapsular only (0.6%). For all cataract types, the prevalence was
      similar in men and women and was higher in persons examined at their homes than
      in those examined at the study clinic. CONCLUSIONS: These population-based data
      suggest that cataract is common among adult Chinese residents in Singapore,
      despite ready access to cataract surgical services. Persons accepting the offer
      of free eye examinations were less likely to have cataract than those who did not
      take up this offer.

PMID- 12414416
TI  - Component dependent risk factors for ocular parameters in Singapore Chinese
      children.
AB  - OBJECTIVE: To examine the risk factors for variations in ocular biometry
      parameters in Singapore Chinese children, a population with a known high
      prevalence rate of myopia at an early age. DESIGN: Cross-sectional study.
      PARTICIPANTS: Children aged 7 to 9 years (n = 1453) from three schools in
      Singapore. METHODS: The children underwent A scan biometry and cycloplegic
      autorefraction measurements. Questions were asked regarding number of books read
      per week, night lighting, and parental myopia. MAIN OUTCOME MEASURES: Axial
      length, vitreous chamber depth, lens thickness, anterior chamber depth,
      refraction, and corneal curvature radius measurements were made. RESULTS: After
      controlling for several factors, the axial lengths were found to be longer and
      vitreous chambers deeper in children who were older, male, read more than two
      books per week, or taller, and those who had at least one parent who was myopic.
      In these models, children who read more than two books per week had axial lengths
      that were 0.17 mm longer and vitreous chambers that were 0.15 mm deeper compared
      with children who read two or fewer books per week. Anterior chambers were deeper
      in males and taller children, whereas corneal curvature was steeper in female,
      older, and shorter children. CONCLUSIONS: Increases of axial length and vitreous
      cavity depth were associated with older age, being male, reading more than two
      books per week, increased height, and parental history of myopia. Of these risk
      factors, however, neither reading nor parental myopia history were associated
      with values for anterior chamber depth, corneal curvature, or lens thickness.
      These findings confirm that conventional risk factors for myopia associated with
      the vitreous cavity, but suggest that anterior segment parameters such as corneal
      curvature and lens thickness may be subject to unrelated postnatal growth control
      mechanisms.

PMID- 12414417
TI  - Myopia and advanced-stage open-angle glaucoma.
AB  - OBJECTIVE: To investigate the effect of myopic refraction on the central visual
      field in patients with advanced open-angle glaucoma (OAG). DESIGN: Multicenter
      cross-sectional study. PARTICIPANTS: Three hundred thirteen OAG eyes (176 eyes of
      176 primary open-angle glaucoma [POAG] patients and 137 eyes of 137 normal
      tension glaucoma [NTG] patients) with clear ocular media and a mean deviation
      (MD) <-15 dB. Patients with a recorded maximum intraocular pressure (IOP) of 22
      mmHg or greater were classified as POAG, and those with an IOP of 21 mmHg or less
      were classified as NTG. METHODS: Multiple regression analysis was used to study
      the influence of refraction on 12 central test points of the C30-2 Humphrey
      program, and the differences in visual field defects between POAG and NTG eyes
      were examined using logistic discriminant analysis. In the multiple regression
      analysis, total deviation (TD) of the 12 test points was graded and used as the
      dependent variable, and MD and the spherical equivalent refraction were the
      explanatory variables. In the logistic discrimination analysis, TD, MD, and
      refraction were covariants that determined the OAG subtypes. MAIN OUTCOME
      MEASURES: TD values of the 12 central test points (C30-2 program). RESULTS:
      Higher myopic refraction was significantly associated with more damage at a point
      just temporal and inferior to the fixation point in POAG eyes, whereas it was
      significantly associated with less damage at test points just temporal and
      superior to the fixation point in NTG eyes. After correcting for the influence of
      refraction, POAG eyes had significantly more damage at a test point just temporal
      and inferior to the fixation point, whereas NTG eyes had significantly more
      damage at those test points nasal and inferior to the fixation point.
      CONCLUSIONS: High myopia constitutes a threat to the remaining lower cecocentral
      visual field and is one of the factors that interfere with the quality of vision
      in advanced OAG with high IOP but not low IOP.

PMID- 12414418
TI  - Inter-eye differences in chronic open-angle glaucoma patients with unilateral
      disc hemorrhages.
AB  - OBJECTIVE: Flame-shaped optic disc hemorrhages are a hallmark of glaucomatous
      optic neuropathy. The purpose of this study was to evaluate which parameters
      differ between companion eyes with and without an optic disc hemorrhage in
      patients with chronic open-angle glaucoma. DESIGN: Comparative (companion eye)
      observational case series. PATIENTS: The study included 99 white patients with
      bilateral chronic open-angle glaucoma and unilateral flame-shaped optic disc
      hemorrhages. METHODS: All patients underwent qualitative and morphometric
      evaluation of color stereo optic disc photographs. MAIN OUTCOME MEASURES: Size
      and shape of the optic disc, neuroretinal rim and parapapillary atrophy, diameter
      of the retinal vessels, intraocular pressure measurements, and both mean value
      and loss variance value of the visual field examination. RESULTS: In an
      intraindividual inter-eye comparison, the eyes with disc hemorrhages and the
      contralateral eyes without disc bleeding did not vary significantly (P > 0.20) in
      size and shape of the optic disc and neuroretinal rim, optic cup depth, size of
      alpha and beta zone of parapapillary atrophy, retinal vessel diameter,
      intraocular pressure measurements, refractive error, and perimetric indices.
      CONCLUSIONS: In bilateral chronic open-angle glaucoma, the development of
      unilateral optic disc hemorrhages does not depend on inter-eye differences in
      size and shape of the optic disc, neuroretinal rim and parapapillary atrophy,
      diameter of the retinal vessels, intraocular pressure measurements, or visual
      field loss.

PMID- 12414419
TI  - Full-threshold versus Swedish Interactive Threshold Algorithm (SITA) in normal
      individuals undergoing automated perimetry for the first time.
AB  - PURPOSE: To compare the full-threshold (FT) and Swedish Interactive Threshold
      Algorithm standard (SS) strategies in normal individuals undergoing automated
      perimetry for the first time. DESIGN: Randomized, comparative, observational case
      series. PARTICIPANTS: Eighty perimetrically naive normal individuals. METHODS:
      All individuals underwent computerized visual field examinations (30-2, Humphrey
      750, Humphrey-Zeiss, Dublin, CA) with both FT and SS strategies. One eye of each
      individual was tested. Test order between strategies was randomized. MAIN OUTCOME
      MEASURES: The following variables were compared: test time, foveal threshold,
      fixation losses, false-positive and false-negative errors, mean deviation,
      pattern standard deviation, glaucoma hemifield test, and number of depressed
      points deviating at P < 5%, P < 2%, P < 1%, and P < 0.5% on the total and pattern
      deviation probability maps. Initially, we compared the results of all FT and SS
      tests, regardless of the order in which they were applied. Next, patients
      undergoing SS as the first examination were compared with those undergoing FT as
      the first test. Finally, the SS and FT results obtained in the second test were
      compared. Anderson's criteria were applied to define abnormal examinations,
      allowing for the calculation of the specificity of the SS and FT strategies.
      RESULTS: When the results of all FT and SS tests were analyzed, the number of
      significantly depressed points deviating at P < 5%, P < 2%, and P < 1% on the
      pattern deviation probability maps was higher with the SS strategy (P < 0.05);
      the specificity was 50% for SS and 72.5% for FT (P < 0.01). When only first
      examinations were compared, the number of significantly depressed points
      deviating at P < 5%, P < 2%, and P < 1% on both the total and pattern deviation
      probability maps was higher with the SS strategy (P < 0.05); the specificity was
      38.1% and 63.2% for the SS and FT strategies, respectively (P = 0.04). When only
      the second examinations were compared, there were no significant differences
      either between the number of depressed points or between the specificities of
      both strategies (73.7% for SS and 71.4% for FT) (P = 0.98). CONCLUSIONS: Normal
      individuals with no perimetric experience may present more significantly
      depressed points on the pattern deviation probability map when the SS strategy is
      used, reducing the test specificity in comparison with FT. These findings are
      probably due to a lower interindividual variability observed with SS. However,
      these differences disappeared in a second examination, suggesting that both
      strategies perform similarly in perimetrically experienced individuals.

PMID- 12414421
TI  - Correlation of visual field progression between eyes in patients with open-angle
      glaucoma.
AB  - PURPOSE: To investigate the correlation of visual field progression between eyes
      in patients with chronic forms of open-angle glaucoma (OAG) and to determine risk
      factors for progression. DESIGN: Retrospective observational case series.
      PARTICIPANTS: One hundred fifty-two patients seen between April and November 2000
      undergoing bilateral treatment for at least 2 years for OAG and who were followed
      with standard automated perimetry at the University of Washington Medical Center
      Eye Clinic. METHODS: Visual field progression was defined using criteria modified
      from Anderson and Advanced Glaucoma Intervention Study (AGIS) scoring.
      Progression from a normal to an abnormal visual field required abnormality of two
      of three criteria (glaucoma hemifield test, corrected pattern standard deviation,
      and total deviation plot abnormality) on at least two consecutive fields. For
      abnormal visual fields, criteria for progression were modified from Anderson and
      were based on worsening observed at three adjacent points on the total deviation
      plot on at least two consecutive fields. Another definition of progression was a
      change in AGIS score of four or more points. MAIN OUTCOME MEASURES: Visual field
      progression. RESULTS: The mean follow-up period was 7.5 +/- 3.6 years. Fifty-four
      patients (35.5%) showed progression of the more severely affected of the two eyes
      (worse eye), and 37 patients (24.3%) had progression in the less affected fellow
      (better) eye. Among these patients, 24 (15.8%) had bilateral progression (44% and
      65% of worse and better eyes with progression, respectively). The between-eye
      correlation for progression was statistically significant (chi-square with Yates'
      continuity correction; chi = 16.7, P = 0.00004; R = 0.348, P = 0.00001). The
      Kaplan-Meier estimates at 10 years for progression in the worse eye, the better
      eye, and both eyes was 44%, 33%, and 21%, respectively. CONCLUSIONS: Between-eye
      correlation of visual field progression in patients with chronic OAG was
      statistically and clinically significant. Patient-specific factors may play an
      important role in visual field progression in OAG. Documented progression of
      visual field loss in one eye may prompt the physician to consider reducing the
      target intraocular pressure in both eyes.

PMID- 12414422
TI  - The aftermath of orbital radiotherapy for graves' ophthalmopathy.
AB  - OBJECTIVE: To determine whether long-term improvement could be observed after
      orbital radiotherapy for Graves' disease; in addition, to evaluate ancillary
      treatments needed for those who have received radiotherapy, to search for late
      emerging adverse consequences of radiotherapy, and to relate orbital changes to
      serum levels of thyroid-stimulating immunoglobulin (TSI). DESIGN: Three-year
      follow-up of noncomparative interventional case series. PARTICIPANTS: Forty-two
      patients. INTERVENTION: All patients had received orbital radiotherapy within 6
      months of study entry. Twelve months after study entry, patients were free to
      select any additional treatment for their ophthalmopathy. MAIN OUTCOME MEASURES:
      Need for surgery, steroid therapy, volume of extraocular muscles and fat,
      proptosis, area of diplopia fields and range of extraocular muscle motion, volume
      changes after decompression and correlations of eye findings with serum TSI
      levels, retinal status. RESULTS: Half of the patients elected to have a surgical
      procedure on their eyes or orbits. Among patients who were not decompressed, we
      found only slight improvement in some of the main outcome measures. TSI did not
      positively correlate with baseline status or with any observed change in major
      outcome measures. After orbital decompression, the volumes of both muscle and fat
      increase, but bony orbital volume increases more and proptosis diminishes.
      Retinal microvascular abnormalities consistent with radiation retinopathy
      developed de novo in five eyes of three patients within 3 years of radiation
      therapy. CONCLUSIONS: In this 3-year uncontrolled follow-up phase, limited
      evidence for a clinically significant improvement was observed, which may be the
      result of treatment or of natural remission. In either case, the changes are of
      little clinical significance. Because it is neither effective nor innocuous,
      radiotherapy does not seem to be indicated for treatment of mild to moderate
      ophthalmopathy.

PMID- 12414423
TI  - Success of balloon catheter dilatation as a primary or secondary procedure for
      congenital nasolacrimal duct obstruction.
AB  - PURPOSE: To determine the efficacy of lacrimal balloon catheter dilatation in
      treating congenital nasolacrimal duct obstruction (CNLDO) as a primary procedure
      in children more than 18 months of age and in children who have failed lacrimal
      probing or silicone intubation. DESIGN: Retrospective, interventional case
      series. PARTICIPANTS: Fifty-nine patients, ranging in age from 15 months to 9
      years (mean, 35.6 months), with 73 lacrimal systems diagnosed with CNLDO who
      underwent nasolacrimal balloon catheter dilatation. Thirty-four lacrimal systems
      (46.5%) had no previous procedures, whereas 39 lacrimal systems (53.5%) had
      failed probing, silicone intubation, or both. INTERVENTION: Balloon catheter
      dilatation was performed following standard protocol, with a simplified regimen
      in most patients. MAIN OUTCOME MEASURES: Clinical patency of the nasolacrimal
      duct after balloon dilatation was the main outcome measure and was defined as
      complete resolution of signs and symptoms (crusting, discharge, and increased
      tear meniscus). Age, inferior turbinate infracture, and Downe's syndrome as
      related to the main outcome measure were also analyzed. RESULTS: Overall, 56 of
      the 73 lacrimal systems (76.7%) had complete resolution of symptoms. Twenty-seven
      of all 34 primary balloon catheter dilatations (79.4%) remained clinically
      patent, whereas 29 of all 39 secondary balloon catheter dilatations (74.4%)
      remained clinically patent after surgery (P = 0.8165). Thirty-nine of 47 lacrimal
      systems (82.9%) in children older than 24 months remained clinically patent,
      whereas 17 of 26 lacrimal systems (65.4%) in children younger than 24 months
      remained clinically patent (P = 0.1573). The mean age of patients with successful
      outcomes was 37 months, whereas the mean age of patients with failed balloon
      catheter dilatations was 32 months (P = 0.3924). In the secondary procedure
      group, analysis showed that the mean age of success (32 months) was greater than
      the mean age of failure (18 months; P = 0.0491). Within the secondary group, 16
      of 17 lacrimal systems (94.1%) older than 24 months were successful, whereas 13
      of 22 lacrimal systems (59.1%) younger than 24 months were successful (P =
      0.0344). CONCLUSIONS: Balloon catheter dilatation is an effective treatment for
      congenital nasolacrimal duct obstruction. In particular, balloon catheter
      dilatation in older children who failed previous probing is highly successful.

PMID- 12414424
TI  - Transconjunctival lower eyelid involutional entropion repair: long-term follow-up
      and efficacy.
AB  - OBJECTIVE: To evaluate the safety and long-term efficacy of a modified
      transconjunctival involutional lower eyelid entropion repair. DESIGN:
      Retrospective, noncomparative case series and survey. PARTICIPANTS: Eighty-nine
      consecutive patients with involutional entropion (114 eyelids). METHODS: Modified
      transconjunctival involutional lower eyelid entropion repair technique was
      performed on 114 eyelids of 89 consecutive patients over a 7-year period. All
      cases had a minimum of 3 months of initial office follow-up, with extended follow
      up obtained via standardized telephone interviews. MAIN OUTCOME MEASURES:
      Surgical success and entropion recurrence. RESULTS: Surgery was completed
      successfully with no complications in all 114 cases. All cases demonstrated
      correction of entropion at the 3-month office follow-up. Long-term follow-up
      (mean, 38.3 months; range, 4-85 months) was obtained in 75% of cases. Recurrence
      was noted in only one patient (two eyelids [2%]). CONCLUSIONS: Modified
      transconjunctival lower eyelid entropion repair is a time-efficient, safe, and
      efficacious technique. In contrast to a recent report using another
      transconjunctival technique, we found a relatively low rate of recurrence on
      extended follow-up.

PMID- 12414426
TI  - Injectable hydroxyapatite paste as an option for ocular implantation after
      evisceration.
AB  - OBJECTIVE: To investigate the feasibility of small incision evisceration with an
      injectable ocular implant that is biocompatible and preserves globe size. DESIGN:
      Experimental animal study. METHODS: The axial length of the eyes of 12 rabbits
      was determined by ultrasound before surgery. Subsequently, 12 eyes of 12 separate
      rabbits were eviscerated and injected with hydroxyapatite (HA) paste (BoneSource;
      Stryker Leibinger, Kalamazoo, MI). Three rabbits each were killed at 2 weeks, 6
      weeks, 3 months, and 6 months after evisceration, and measurements of globe size
      were compared with measurements of the fellow eye. Histologic examination of the
      eviscerated eyes was performed. MAIN OUTCOME MEASURES: The axial length and
      lateral globe measurements of the eviscerated eye were compared with the fellow
      eye. The eviscerated eye was examined histologically and the degree of
      inflammation, vascularization, and ossification was noted for each period of
      observation. RESULTS: The mean preoperative difference in axial length between
      the control (fellow eyes) and the subsequently eviscerated eyes was 0.15 +/- 0.04
      mm (mean +/- standard error of mean). The average axial and lateral globe
      measurements of the operated eye were 0.8 +/- 0.4 mm less than the fellow eye 2
      weeks after surgery, and this difference increased to 3.1 +/- 0.7 mm 6 months
      after surgery. Histologic examination showed a decrease in granulomatous
      inflammation and an increase in vascularization of the implanted HA over the time
      of observation with early osseous metaplasia. CONCLUSIONS: Small incision
      evisceration is possible with ocular volume replacement with an injectable
      orbital implant. Injectable HA paste shows promise as an option for implantation
      after eye evisceration; however, further studies are required to establish the
      stability of this material for this application.

PMID- 12414425
TI  - Conservative management of necrotizing fasciitis of the eyelids.
AB  - OBJECTIVE: To describe the management of patients with necrotizing fasciitis of
      the eyelids. DESIGN: Retrospective, noncomparative interventional case series.
      PARTICIPANTS: Seven patients with necrotizing fasciitis limited to the eyelids.
      METHODS: Retrospective review of the charts and photographs of seven patients
      with necrotizing fasciitis limited to the eyelids. MAIN OUTCOME MEASURES: Eyelid
      function and appearance, mortality, and morbidity. RESULTS: Seven of seven
      patients had good eyelid function and adequate appearance without reconstruction
      after healing. No deaths occurred. CONCLUSIONS: Eyelid necrosis due to
      necrotizing fasciitis can be a devastating condition. The morbidity and mortality
      of selected cases are reduced with prompt and appropriate antimicrobial therapy
      and nonaggressive debridement of necrotic tissue after autodemarcation of the
      necrotic zone.

PMID- 12414427
TI  - Topical mitomycin-C for pagetoid invasion of the conjunctiva by eyelid sebaceous
      gland carcinoma.
AB  - PURPOSE: To evaluate the efficacy of topical mitomycin-C for pagetoid invasion of
      the conjunctiva by sebaceous gland carcinoma. DESIGN: Prospective noncomparative
      consecutive interventional case series. INTERVENTION: All patients received
      topical 0.04% mitomycin-C four times daily for 1 week followed by 1 week off
      medication. The treatment cycles were repeated until resolution of the
      conjunctival malignancy was clinically evident. PARTICIPANTS: Four patients with
      histopathologically proven intraepithelial (pagetoid) invasion of the conjunctiva
      by sebaceous gland carcinoma were managed with this regimen. RESULTS: The mean
      patient age was 78 years. Before treatment, the main tumor site included the
      upper eyelid in two cases and the lower eyelid in two cases. Previous resection
      of the tumor had been performed elsewhere in three cases over the prior 6 years.
      At the time of our examination, map biopsies confirmed pagetoid invasion
      involving 25% to 90% of the conjunctival surface, with bulbar, forniceal, and
      tarsal conjunctival involvement in all four cases and corneal extension in one
      case. There was no evidence of deep tumor within the conjunctival stroma or
      tarsus in any case. After treatment, medication intolerance and early
      discontinuation occurred in one patient, and continued tumor progression was
      documented. Of the remaining three patients, chemotherapy was used for a mean of
      four cycles with complete resolution of the pagetoid invasion, confirmed
      histopathologically in two cases, and without recurrence in all three cases over
      12 months (mean) follow-up. The medication caused moderate temporary local
      irritation but no serious intraocular or extraocular complications. CONCLUSIONS:
      Preliminary evidence suggests that topical mitomycin-C is effective treatment for
      pagetoid invasion of the conjunctiva by sebaceous gland carcinoma. Longer follow
      up is necessary to assess the duration of tumor control.

PMID- 12414428
TI  - Adult wilms' tumor metastatic to the choroid of the eye.
AB  - BACKGROUND: Ocular manifestations of Wilms' tumor are rare, particularly in
      adults. We present the first reported case of a choroidal metastasis resulting
      from Wilms' tumor. DESIGN: Case report. PARTICIPANT: A 37-year-old white male
      with an adult-onset biopsy-proven Wilms' tumor with multiorgan metastatic
      disease. RESULTS: We report a unique case of uveal metastasis presumed from a
      Wilms' tumor. The patient's history included a primary Wilms' tumor with known
      disseminated metastasis, orbital pain, metamorphopsia, and decreased vision.
      Ophthalmoscopy revealed a unifocal choroidal tumor in the inferotemporal quadrant
      of the right eye. Ultrasonographic measurements of the tumor were 4.9 mm in
      apical height and 15 x 13 mm in basal diameter. Unusual ultrasound findings
      included echodense stromal opacities and retrobulbar edema. Fluorescein
      angiography revealed double circulation and late intratumoral fluorescence.
      CONCLUSIONS: This is the first reported case of a choroidal metastasis by a
      Wilms' tumor.

PMID- 12414429
TI  - Rhegmatogenous retinal detachment after transscleral local resection of choroidal
      melanoma.
AB  - OBJECTIVE: To report on the incidence and outcome of rhegmatogenous retinal
      detachment after transscleral local resection of choroidal melanoma. DESIGN:
      Prospective, noncomparative, interventional case series. PARTICIPANTS: One
      hundred fifty-six patients with choroidal melanoma treated by transscleral local
      resection between January 1993 and June 2000. INTERVENTION: Transscleral
      choroidectomy or cyclochoroidectomy for uveal melanoma, with ocular decompression
      by single-port pars plana vitrectomy and, in most patients, adjunctive ruthenium
      plaque radiotherapy. MAIN OUTCOME MEASURES: Incidence of rhegmatogenous retinal
      detachment according to predictive factors and outcomes reported in terms of
      anatomic success, visual acuity, and ocular conservation. RESULTS: Rhegmatogenous
      retinal detachment occurred in 28 (18%) eyes and was significantly more common in
      patients with thick tumors (Cox univariate analysis, P = 0.001) and in males (Cox
      univariate analysis, P = 0.013), with posterior tumor extension being of
      borderline significance (Cox univariate analysis, P = 0.069). Surgical treatment
      of the retinal detachment was performed in 25 patients; it was undertaken at our
      center in 22 patients and at the referring hospital in 3 patients. Anatomic
      success was achieved in 21 (84%) of these 25 patients, with 7 eyes retaining
      counting fingers vision, and 3 eyes seeing 6/60 or better. Ten eyes treated for
      retinal detachment were enucleated because of recurrent tumor (four eyes),
      retinal detachment (three eyes), wound dehiscence (one eye), phthisis (one eye),
      and poor visual acuity (one eye). Eleven eyes known to have a retinal tear
      underwent prophylactic vitreoretinal surgery at the end of the local resection,
      with only one (9%) of these subsequently developing retinal detachment.
      CONCLUSIONS: Rhegmatogenous retinal detachment after transscleral choroidectomy
      or cyclochoroidectomy for uveal melanoma is a serious complication requiring
      early vitreoretinal surgery.

PMID- 12414431
TI  - Lymphoma-associated retinopathy.
AB  - OBJECTIVE: To describe the clinical, electrophysiologic, and serologic findings
      in a patient with retinal degeneration associated with Hodgkin's lymphoma.
      DESIGN: Case report with ancillary immunohistochemical studies. METHODS: A 24
      year-old woman experienced night blindness and fundus abnormalities 1 week after
      initiation of chemotherapy for Hodgkin's lymphoma. Visual fields and full-field
      electroretinograms (ERGs) were monitored over a 10-year period. Serum antibodies
      were studied on Western blot reactions on a solubilized extract of bovine retina.
      Serum antibodies were also evaluated through indirect immunohistochemistry on
      rhesus monkey retina. RESULTS: Visual field and ERG amplitudes, initially
      abnormal, became reduced further over 10 years. Serum antibodies were identified
      that reacted to a retinal protein or proteins approximating 65 kd; these
      antibodies showed immunologic activity against photoreceptors. CONCLUSIONS: A
      progressive paraneoplastic retinopathy can occur in association with Hodgkin's
      lymphoma. The pathogenesis of the retinal degeneration appears to be related to a
      serum antibody that is reacting to a retinal protein or proteins of approximately
      65 kd.

PMID- 12414430
TI  - Massive mycobacterial choroiditis during highly active antiretroviral therapy:
      another immune-recovery uveitis?
AB  - PURPOSE: To describe the ocular presentation of disseminated mycobacterial
      disease occurring during immune-recovery in a patient with acquired immune
      deficiency syndrome (AIDS). STUDY DESIGN: Case report and literature review.
      PARTICIPANTS: A 41-year-old AIDS patient with a prior diagnosis of
      cytomegalovirus retinitis. METHODS: The patient developed progressive, bilateral
      multifocal choroiditis with panuveitis 2 months after beginning and responding to
      highly active antiretroviral therapy. His left eye became blind and painful and
      was enucleated. Pathologic examination revealed massive choroiditis with well
      formed, discrete granulomas and multiple intracellular and extracellular acid
      fast organisms within the choroidal granulomas. Culture and polymerase chain
      reaction of vitreous specimens revealed Mycobacterium avium complex (MAC).
      RESULTS: Empiric, and later sensitivity-guided, local and systemic antibiotic
      therapy was used to treat the remaining right eye, but it continued to
      deteriorate. Despite medical therapy, three vitrectomies and repeated
      intravitreal injections of amikacin, a total retinal detachment ensued. One week
      after the third vitrectomy, the patient died from mesenteric artery thrombosis in
      the setting of disseminated mycobacterial disease. CONCLUSIONS: This is the first
      report of ocular inflammation as the presenting finding in the recently
      recognized syndrome of immune-recovery MAC disease. Pathogenesis of this entity
      is related to an enhanced immune response to a prior, subclinical, disseminated
      infection. The formation of discrete granulomas, normally absent in MAC
      infections in AIDS, reflects this mechanism.

PMID- 12414432
TI  - Patchy ischemic retinal whitening in acute central retinal vein occlusion.
AB  - OBJECTIVE: To describe a new fundus abnormality in nonischemic central retinal
      vein occlusion and its pathophysiologic basis. DESIGN: Retrospective,
      observational case series. PARTICIPANTS: Eleven consecutive patients from a
      community-based retina referral practice who had central retinal vein occlusion
      (CRVO) and patchy ischemic retinal whitening (PIRW) and 225 consecutive patients
      from the same practice with CRVO and no PIRW. RESULTS: Patchy ischemic retinal
      whitening occurs in younger patients with nonischemic CRVO (P < 0.0003) and is
      associated with better visual outcomes than without PIRW (P = 0.0201). Patchy
      ischemic retinal whitening has a perivenular distribution in the macula, has no
      fluorescein angiographic correlate in milder cases, can occur before any retinal
      hemorrhages or macular edema, and resolves in 2 to 4 weeks. Cilioretinal
      arteriolar insufficiency is a common finding associated with PIRW (5/11 cases).
      The laboratory evaluation of patients with PIRW is generally normal. CONCLUSIONS:
      Patchy ischemic retinal whitening is a useful fundus sign of nonischemic CRVO
      that can precede other signs. Familiarity with this sign and its correlates will
      allow accurate diagnosis and counseling of affected patients.

PMID- 12414433
TI  - Association of preoperative photoreceptor displacement and improved central
      scotoma after idiopathic macular hole surgery.
AB  - OBJECTIVE: To investigate the relationship between preoperative photoreceptor
      displacement and postoperative scotoma after unilateral idiopathic macular hole
      surgery. DESIGN: Prospective nonrandomized comparative self-controlled trial.
      PARTICIPANTS: Twenty patients who underwent successful surgery for unilateral
      idiopathic macular hole participated in the study. METHODS: Kinetic perimetry
      using red and green filter glasses, black binocular fixation targets, and red and
      green selective monocular stimuli was performed preoperatively. Scanning laser
      ophthalmoscope (SLO) microperimetry was performed preoperatively and
      postoperatively. RESULTS: Sixteen patients had photoreceptor displacement
      preoperatively. In preoperative SLO microperimetry, all eyes with a macular hole
      had a scotoma; postoperatively, 12 of 16 had no scotoma. All four eyes with no
      preoperative photoreceptor displacement were noted to have a postoperative
      scotoma. The prevalence of postoperative scotoma in patients with preoperative
      photoreceptor displacement (4 of 16; 25%) was significantly lower than that in
      patients without preoperative photoreceptor displacement (4 of 4; 100%) (P =
      0.03). CONCLUSIONS: The presence or absence of photoreceptor displacement
      preoperatively should affect postsurgical visual function. Photoreceptor damage
      may occur in eyes without photoreceptor displacement preoperatively, resulting in
      scotoma postoperatively.

PMID- 12414434
TI  - Detection of drusen in the fellow eye of Japanese patients with age-related
      macular degeneration using scanning laser ophthalmoscopy.
AB  - OBJECTIVE: To study the prevalence of drusen in the fellow eye of Japanese
      patients with age-related macular degeneration (AMD). DESIGN: Retrospective,
      cross-sectional study. PARTICIPANTS: Seventeen eyes of 17 Japanese patients with
      unilateral AMD. MAIN OUTCOME MEASURES: To compare the frequency of drusen based
      on photography and scanning laser ophthalmoscopy with confocal and ring apertures
      and a diode laser (780 nm). RESULTS: Using the scanning laser ophthalmoscope
      (SLO) with a ring aperture, drusen were detected clearly as in topographic
      imaging. In the fellow eyes of the study patients with AMD, photography showed
      drusen in 10 cases (58.8%); however, SLO imaging detected drusen in 15 cases
      (88.2%). The number of drusen detected using SLO imaging was significantly
      greater than when using photography (P < 0.05). CONCLUSIONS: Scanning laser
      ophthalmoscope imaging is superior to photography for detecting drusen in the
      fellow eyes of Japanese patients with unilateral AMD. The prevalence of drusen in
      the fellow eye of Japanese patients with AMD is much higher than previously
      speculated.

PMID- 12414435
TI  - Excitatory and inhibitory effects of tricaine (MS-222) on fictive breathing in
      isolated bullfrog brain stem.
AB  - This study examined the direct effects of tricaine methanesulfonate (MS-222), a
      sodium-channel blocking local anesthetic, on respiratory motor output using an in
      vitro brain stem preparation of adult North American bullfrogs (Rana
      catesbeiana). Bullfrogs were anesthetized with halothane, and the brain stem was
      removed and superfused with artificial cerebrospinal fluid containing MS-222 at
      concentrations ranging from 0.1 to 1,000 micro M. At the lowest concentration of
      MS-222, respiratory frequency (fR) increased significantly (P < 0.05), but at
      higher concentrations, fR progressively decreased and was abolished in all
      preparations at 1,000 micro M (P < 0.01). Respiratory burst amplitude and burst
      duration were not affected by MS-222. The frequency of nonrespiratory neural
      activity did not significantly change with the addition of MS-222 below 1,000
      micro M. These data indicate that MS-222 has a significant, direct effect on
      respiratory motor output from the central nervous system, producing both
      excitation and inhibition of fictive breathing. The results are consistent with
      other studies demonstrating that low concentrations of anesthetics generally
      cause excitation followed by depression at higher concentrations. Although the
      mechanisms underlying the excitatory effects of MS-222 in this study are unclear,
      they may include increased excitatory neurotransmission and/or disinhibition of
      inputs to the respiratory central pattern generator.

PMID- 12414436
TI  - PACAP release from the canine adrenal gland in vivo: its functional role in
      severe hypotension.
AB  - This study was to investigate if endogenous pituitary adenylate cyclase
      activating polypeptide (PACAP) can be released during direct splanchnic nerve
      stimulation in vivo and to determine whether PACAP in the adrenal gland can
      modulate the medullary response to sympathoadrenal reflex. The output of adrenal
      catecholamine and PACAP-38-like immunoreactivity (PACAP-38-ir) increased in a
      frequency-dependent manner after direct splanchnic nerve stimulation (0.2-20 Hz).
      Both responses were highly reproducible, and PACAP-38-ir output closely
      correlated with catecholamine output. Sodium nitroprusside (SNP; 0.1 mg/kg iv
      bolus) caused a severe hypotension resulting in marked increases in catecholamine
      secretion. In the presence of local PACAP-27 (125 ng), the maximum catecholamine
      response to SNP was significantly potentiated in a synergistic manner compared
      with that obtained in the group receiving SNP or PACAP-27 alone. The study
      indicates that endogenous PACAP-38 can be released particularly when the
      sympathoadrenal system is highly activated and that the local exogenous PACAP-27
      enhanced the reflex-induced catecholamine release, suggesting collectively a
      facilitating role of PACAP as neuromodulator in the sympathoadrenal function in
      vivo.

PMID- 12414437
TI  - Effects of peripheral CCK receptor blockade on feeding responses to duodenal
      nutrient infusions in rats.
AB  - Type A cholecystokinin receptor (CCKAR) antagonists differing in blood-brain
      barrier permeability were used to test the hypothesis that duodenal delivery of
      protein, carbohydrate, and fat produces satiety in part by an essential CCK
      action at CCKARs located peripheral to the blood-brain barrier. Fasted rats with
      open gastric fistulas received devazepide (1 mg/kg iv) or A-70104 (700 nmol. kg(
      1). h(-1) iv) and either a 30-min intravenous infusion of CCK-8 (10 nmol. kg(-1).
      h(-1)) or duodenal infusion of peptone, maltose, or Intralipid beginning 10 min
      before 30-min access to 15% sucrose. Devazepide penetrates the blood-brain
      barrier; A-70104, the dicyclohexylammonium salt of Nalpha-3-quinolinoyl-d-Glu-N,N
      dipentylamide, does not. CCK-8 inhibited sham feeding by approximately 50%, and
      both A-70104 and devazepide abolished this response. Duodenal infusion of each of
      the macronutrients dose dependently inhibited sham feeding. A-70104 and
      devazepide attenuated inhibitory responses to each macronutrient. Thus endogenous
      CCK appears to act in part at CCKARs peripheral to the blood-brain barrier to
      inhibit food intake.

PMID- 12414438
TI  - Subcellular localization of Pseudomonas pyocyanin cytotoxicity in human lung
      epithelial cells.
AB  - The Pseudomonas aeruginosa secretory product pyocyanin damages lung epithelium,
      likely due to redox cycling of pyocyanin and resultant superoxide and H(2)O(2)
      generation. Subcellular site(s) of pyocyanin redox cycling and toxicity have not
      been well studied. Therefore, pyocyanin's effects on subcellular parameters in
      the A549 human type II alveolar epithelial cell line were examined. Confocal and
      electron microscopy studies suggested mitochondrial redox cycling of pyocyanin
      and extracellular H(2)O(2) release, respectively. Pyocyanin decreased
      mitochondrial and cytoplasmic aconitase activity, ATP levels, cellular reduction
      of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide, and
      mitochondrial membrane potential. These effects were transient at low pyocyanin
      concentrations and were linked to apparent cell-mediated metabolism of pyocyanin.
      Overexpression of MnSOD, but not CuZnSOD or catalase, protected cellular
      aconitase, but not ATP, from pyocyanin-mediated depletion. This suggests that
      loss of aconitase activity is not responsible for ATP depletion. How pyocyanin
      leads to ATP depletion, the mechanism of cellular metabolism of pyocyanin, and
      the impact of mitochondrial pyocyanin redox cycling on other cellular events are
      important areas for future study.

PMID- 12414439
TI  - Left ventricular geometry immediately following defibrillation: shock-induced
      relaxation.
AB  - A previous two-dimensional (2D) ultrasound study suggested that there is
      relaxation of the myocardium after defibrillation. The 2D study could not measure
      activity occurring within the first 33 ms after the shock, a period that may be
      critical for discriminating between shock- and excitation-induced relaxation. The
      objective of our study was to determine the left ventricular (LV) geometry during
      the first 33 ms after defibrillation. Biphasic defibrillation shocks were
      delivered 5-50 s after the induction of ventricular fibrillation in each of the
      seven dogs. One-dimensional, short-axis ultrasound images of the LV cavity were
      acquired at a rate of 250 samples/s. The LV cavity diameter was computed from 32
      ms before to 32 ms after the shock. Preshock and postshock percent changes in LV
      diameter were analyzed as a function of time with the use of regression analysis.
      The normalized mean pre- and postshock slopes (0.2 +/- 2.2 and 3.3 +/- 7.9% per
      10 ms) were significantly different (P < 0.01). The postshock slope was positive
      (P < 0.005). Our results confirm that the bulk of the myocardium is relaxing
      immediately after defibrillation.

PMID- 12414440
TI  - Mechanisms underlying ischemic diastolic dysfunction: relation between rigor,
      calcium homeostasis, and relaxation rate.
AB  - Increased diastolic chamber stiffness (upward arrow DCS) during ischemia may
      result from increased diastolic calcium, rigor, or reduced velocity of
      relaxation. We tested these potential mechanisms during severe ischemia in
      isolated red blood cell-perfused isovolumic rabbit hearts. Ischemia (coronary
      flow reduced 83%) reduced left ventricular (LV) contractility by 70%, which then
      remained stable. DCS progressively increased. When LV end-diastolic pressure had
      increased 5 mmHg, myofilament calcium responsiveness was altered with 50 mmol/l
      NH(4)Cl or 10 mmol/l butanedione monoxime. These affected contractility (i.e., a
      calcium-mediated force) but not upward arrow DCS. Second, quick length changes
      reversed upward arrow DCS, supporting a rigor mechanism. Third, ischemia
      increased the time constant of isovolumic pressure decline from 47 +/- 3 to 58 +/
      3 ms (P < 0.02) but concomitantly abbreviated the contraction-relaxation cycle,
      i.e., pressure dissipation occurred earlier without diastolic tetanization.
      Finally, to assess any link between rate of relaxation and upward arrow DCS,
      hearts were exposed to 10 mmol/l calcium. Calcium doubled contractility and
      accelerated relaxation velocity, but without affecting upward arrow DCS. Thus
      upward arrow DCS developed during ischemia despite severely reduced contractility
      via a rigor (and not calcium mediated) mechanism. Calcium resequestration
      capacity was preserved, and reduced relaxation velocity was not linked to upward
      arrow DCS.

PMID- 12414441
TI  - Border zone geometry increases wall stress after myocardial infarction: contrast
      echocardiographic assessment.
AB  - After myocardial infarction (MI), the border zone expands chronically, causing
      ventricular dilatation and congestive heart failure (CHF). In an ovine model (n =
      4) of anteroapical MI that results in CHF, contrast echocardiography was used to
      image short-axis left ventricular (LV) cross sections and identify border zone
      myocardium before and after coronary artery ligation. In the border zone at end
      systole, the LV endocardial curvature (K) decreased from 0.86 +/- 0.33 cm(-1) at
      baseline to 0.35 +/- 0.19 cm(-1) at 1 h (P < 0.05), corresponding to a mean
      decrease of 55%. Also in the border zone, the wall thickness (h) decreased from
      1.14 +/- 0.26 cm at baseline to 1.01 +/- 0.25 cm at 1 h (P < 0.05), corresponding
      to a mean decrease of 11%. By Laplace's law, wall stress is inversely
      proportional to the product K. h. Therefore, a 55% decrease in K results in a
      122% increase in circumferential stress; a 11% decrease in h results in a 12%
      increase in circumferential stress. These findings indicate that after MI,
      geometric changes cause increased dynamic wall stress, which likely contributes
      to border zone expansion and remodeling.

PMID- 12414443
TI  - Estimation of preload recruitable stroke work relationship by a single-beat
      technique in humans.
AB  - The slope of the preload recruitable stroke work relationship (M(w)) is a highly
      linear, load-insensitive contractile index. To investigate whether M(w) can be
      determined from a single steady-state beat, 45 patients were studied during
      cardiac catheterization. Single-beat M(w) (SBM(w)) was calculated directly from
      the baseline stroke work and baseline left ventricular (LV) end-diastolic volume
      (EDV(B)), and the volume-axis intercept (V(w)) was estimated as k x EDV(B) + (k -
      1) x LV(wall), where k is the ratio of the epicardial shell volumes corresponding
      to V(w) and EDV(B) and LV(wall) is the wall volume. The mean of individual k
      values was 0.72 +/- 0.04, which correlated with LV mass significantly (r = 0.60,
      P < 0.001). SBM(w) calculated from a constant k of 0.7 predicted M(w) well (r =
      0.88, P < 0.0001), and the prediction improved slightly when k was estimated from
      individual LV mass (r = 0.93, P < 0.0001). Subgroup analyses revealed that the
      single-beat technique also worked in patients with small or large LV mass or
      volume or with regional wall motion abnormalities. The absolute change in SBM(w)
      after dobutamine infusion also correlated with that in M(w). In conclusion, M(w)
      can be estimated from a steady-state beat without alteration of preload.

PMID- 12414442
TI  - DITPA stimulates bFGF, VEGF, angiopoietin, and Tie-2 and facilitates coronary
      arteriolar growth.
AB  - Previous studies from our laboratory and those of others have shown thyroxine to
      be a stimulator of coronary microvascular growth. The present study tested the
      hypothesis that 3,5-diiodothyropropionic acid (DITPA), a thyroid hormone analog
      with inotropic but not chronotopic characteristics, is angiogenic in the
      nonischemic heart. Daily injections (3.75 mg/kg sc) of DITPA to Sprague-Dawley
      rats affected protein increases in vascular endothelial growth factor
      (VEGF)(164), VEGF(188,) basic fibroblast growth factor (bFGF) (FGF-2),
      angiopoietin-1, and Tie-2 during the first few days of treatment. After 3 wk of
      treatment, arteriolar length density and the relative number of terminal
      arterioles (<10 microm diameter) increased in the left ventricle as determined by
      image analysis of perfuse-fixed hearts. These findings occurred in hearts that
      did not undergo changes in mass nor in increases in capillary length density. We
      conclude that DITPA, which is known to improve ventricular function after
      infarction, is angiogenic in normal nonischemic hearts.

PMID- 12414444
TI  - Increasing myocardial contraction and blood pressure in C57BL/6 mice during early
      postnatal development.
AB  - Knowledge of the developmental changes of cardiovascular parameters in the
      genetic background of a mouse strain is important for understanding phenotypic
      changes in transgenic or knockout mouse models for heart disease. We studied
      arterial blood pressure and myocardial contractility in mice of the common
      background strain C57BL/6, aged 21 days [postnatal day 21 (P21)] to 580 days.
      Heart rate increased during maturation from 396 beats/min at P21 to 551 beats/min
      at postnatal day 50 (P50), and mean arterial blood pressure increased in parallel
      from 86 to 110 mmHg and remained constant afterward. Echocardiographically
      determined left ventricular myocardial wall dimensions (R = 0.79, P < 0.0001) and
      left ventricular mass calculated using the area-length algorithm correlated
      strongly with histomorphometrical measurements (R = 0.93, P < 0.001). Sarcomere
      shortening records from isolated ventricular myocytes used as a measure for
      myocardial contractility revealed a negative shortening-frequency relation under
      a pacing frequency of 2 Hz and a positive relation above 2 Hz. Shortening
      amplitudes recorded from P21 myocytes were smaller, and the shortening-frequency
      relation was less steep than in adult myocytes. A stimulation pause was followed
      by a negative "staircase" at pacing frequency of < or =6 Hz and a positive
      staircase at > or =6 Hz. P21 myocytes developed positive staircases at 8 and 10
      Hz, and adult myocytes also developed them at 6 Hz. Blood pressure increase
      during maturation until P50 may originate from increasing single cardiomyocyte
      contractility.

PMID- 12414446
TI  - Alterations in mitochondrial function in a mouse model of hypertrophic
      cardiomyopathy.
AB  - Familial hypertrophic cardiomyopathy (HCM) is an autosomal dominant disease
      characterized by varying degrees of ventricular hypertrophy and myofibrillar
      disarray. Mutations in cardiac contractile proteins cause HCM. However, there is
      an unexplained wide variability in the clinical phenotype, and it is likely that
      there are multiple contributing factors. Because mitochondrial dysfunction has
      been described in heart disease, we tested the hypothesis that mitochondrial
      dysfunction contributes to the varying HCM phenotypes. Mitochondrial function was
      assessed in two transgenic models of HCM: mice with a mutant myosin heavy chain
      gene (MyHC) or with a mutant cardiac troponin T (R92Q) gene. Despite
      mitochondrial ultrastructural abnormalities in both models, the rate of state 3
      respiration was significantly decreased only in the mutant MyHC mice by
      approximately 23%. Notably, this decrease in state 3 respiration preceded
      hemodynamic dysfunction. The maximum activity of alpha-ketogutarate dehydrogenase
      as assayed in isolated disrupted mitochondria was decreased by 28% compared with
      isolated control mitochondria. In addition, complexes I and IV were decreased in
      mutant MyHC transgenic mice. Inhibition of beta-adrenergic receptor kinase, which
      is elevated in mutant MyHC mouse hearts, can prevent mitochondrial respiratory
      impairment in mutant MyHC mice. Thus our results suggest that mitochondria may
      contribute to the hemodynamic dysfunction seen in some forms of HCM and offer a
      plausible mechanism responsible for some of the heterogeneity of the disease
      phenotypes.

PMID- 12414445
TI  - Role of serotonin in thromboxane A2-induced coronary chemoreflex.
AB  - We reported previously that the thromboxane A(2) (TxA(2)) mimetic U-46619
      stimulates cardiac vagal afferent nerves, eliciting a reflex decrease in heart
      rate (HR) and arterial blood pressure (ABP). The present experiments were
      designed to test the hypothesis that TxA(2) evokes these changes via the release
      of serotonin [5-hydroxytryptamine (5-HT)] and activation of the 5-HT(3) receptor.
      Injections of the 5-HT(3) antagonist tropisetron (1 mg of 3-tropanyl-indole-3
      carboxylate or ICS-205-930) attenuated the decreases in HR and ABP induced by
      left atrial injections of U-46619 (20 microg). Tropisetron administration also
      eliminated the U-46619-induced increase in impulse frequency in a majority of
      cardiac, vagal afferent units tested. Measurement of serum 5-HT levels revealed
      an elevation in serum 5-HT levels after U-46619 injection in those rabbits that
      displayed a significant HR change following injection of U-46619. These results
      indicate that although other factors may also contribute to these reflex
      responses, the release of 5-HT and stimulation of the 5-HT(3) receptor plays a
      significant role in coronary reflexes induced by TxA(2).

PMID- 12414447
TI  - Echocardiographic measurement of cardiac output in rats.
AB  - The systematic evaluation of different transthoracic echocardiographic (TTE)
      methods to determine cardiac output (CO) and the effect of changes in
      intravascular volume on echocardiographically determined indexes of
      cardiovascular structure in the rat has not been documented. With the use of 11
      Wistar rats, simultaneous echocardiographic and thermodilution measurements of CO
      were compared at baseline and after blood withdrawal or transfusion at 43
      different levels of intravascular volume and using 10 different echocardiographic
      approaches. The best correlation (r = 0.93; P < 0.0001), least bias (-3 ml/min),
      and best precision (16 ml/min) between thermodilution and echocardiographic
      methods were obtained at the level of aortic annulus using pulsed Doppler. In
      conclusion, CO could be accurately assessed in rats using TTE and pulsed Doppler
      at the level of the aortic annulus. This annulus was demonstrated to remain
      stable, but pulmonary annulus, thoracic aorta, mitral valve, and left ventricular
      diameters were found to be more modifiable during volumic changes.

PMID- 12414448
TI  - Ischemic preconditioning alters real-time measure of O2 radicals in intact hearts
      with ischemia and reperfusion.
AB  - Reactive oxygen species (ROS) are believed to be involved in triggering cardiac
      ischemic preconditioning (IPC). Decreased formation of ROS on reperfusion after
      prolonged ischemia may in part underlie protection by IPC. In heart models, these
      contentions have been based either on the effect of ROS scavengers to abrogate
      IPC-induced preservation or on a measurement of oxidation products on
      reperfusion. Using spectrophotofluorometry at the left ventricular wall and the
      fluorescent probe dihydroethidium (DHE), we measured intracellular ROS superoxide
      (O(2)(-).) continuously in isolated guinea pig heart and tested the effect of IPC
      and the O(2)(-). scavenger manganese(III) tetrakis (4-benzoic acid) porphyrin
      chloride (MnTBAP) on O(2)(-). formation throughout the phases of preconditioning
      (PC), 30-min ischemia and 60-min reperfusion (I/R). IPC was evidenced by improved
      contractile function and reduced infarction; MnTBAP abrogated these effects.
      Brief PC pulses increased O(2)(-). during the ischemic but not the reperfusion
      phase. O(2)(-). increased by 35% within 1 min of ischemia, increased further to
      95% after 20 min of ischemia, and decreased slowly on reperfusion. In the IPC
      group, O(2)(-). was not elevated over 35% during index ischemia and was not
      increased at all on reperfusion; these effects were abrogated by MnTBAP. Our
      results directly demonstrate how intracellular ROS increase in intact hearts
      during IPC and I/R and clarify the role of ROS in triggering and mediating IPC.

PMID- 12414451
TI  - Quality in emergency medicine: an introduction.

PMID- 12414449
TI  - Fas pathway is a critical mediator of cardiac myocyte death and MI during
      ischemia-reperfusion in vivo.
AB  - Fas is a widely expressed cell surface receptor that can initiate apoptosis when
      activated by its ligand (FasL). Whereas Fas abundance on cardiac myocytes
      increases in response to multiple pathological stimuli, direct evidence
      supporting its role in the pathogenesis of heart disease is lacking. Moreover,
      controversy exists even as to whether Fas activation induces apoptosis in cardiac
      myocytes. In this study, we show that adenoviral overexpression of FasL, but not
      beta-galactosidase, results in marked apoptosis both in cultures of primary
      neonatal cardiac myocytes and in the myocardium of intact adult rats. Myocyte
      killing by FasL is a specific event, because it does not occur in lpr
      (lymphoproliferative) mice that lack functional Fas. To assess the contribution
      of the Fas pathway to myocardial infarction (MI) in vivo, lpr mice were subjected
      to 30 min of ischemia followed by 24 h of reperfusion. Compared with wild-type
      mice, lpr mice exhibited infarcts that were 62.3% smaller with 63.8% less myocyte
      apoptosis. These data provide direct evidence that activation of Fas can induce
      apoptosis in cardiac myocytes and that Fas is a critical mediator of MI due to
      ischemia-reperfusion in vivo.

PMID- 12414452
TI  - The elusive nature of quality.

PMID- 12414453
TI  - Things my data never told me.

PMID- 12414454
TI  - "Crossing the Quality Chasm" in emergency medicine.

PMID- 12414455
TI  - The emerging imperative for health care quality improvement.
AB  - There are widespread and growing concerns about the variable and too often
      inadequate quality of health care in the United States. As a result, health care
      quality is being questioned and subjected to scrutiny as never before. Awareness
      of the quality deficits, combined with rising health care expenditures and
      changing attitudes of payers and consumers, has given rise to a nascent but
      growing quality improvement movement. Multiple barriers must be surmounted by
      this movement, but substantive work is under way on all fronts. Emergency
      medicine will definitely be affected by the quality improvement movement and
      should quickly move forward to define and establish performance measures for high
      quality emergency care in an era when chronic disease dominates the agenda.
      Emergency medicine should also aggressively work to operationalize a culture of
      quality to minimize medical errors, to practice evidence-based medicine, to
      translate research results into clinical practice in a timely manner, and to
      establish accountability mechanisms for quality improvement and clinical
      excellence.

PMID- 12414456
TI  - Quality in clinical practice.
AB  - This paper reports the proceedings of the discussion panel assigned to look at
      clinical aspects of quality in emergency medicine. One of the seven stated
      objectives of the Academic Emergency Medicine consensus conference on quality in
      emergency medicine was to educate emergency physicians regarding quality measures
      and quality improvement as essential aspects of the practice of emergency
      medicine. Another topic of interest was a discussion of the value of information
      technology in facilitating quality care in the clinical practice of emergency
      medicine. It is important to note that this is not intended to be a comprehensive
      review of this extensive topic, but instead is designed to report the discussion
      that occurred at this session of the consensus conference.

PMID- 12414457
TI  - Measuring and improving quality in emergency medicine.
AB  - The findings are presented of a consensus committee created to address the
      measuring and improving of quality in emergency medicine. The objective of the
      committee was to critically evaluate how quality in emergency medicine can be
      measured and how quality improvement projects can positively affect the care of
      emergency patients. Medical quality is defined as "the care health professionals
      would want to receive if they got sick." The literature of quality improvement in
      emergency medicine is reviewed and analyzed. A summary list of measures of
      quality is included with four categories: condition-specific diseases, diagnostic
      syndromes, tasks/procedures, and department efficiency/efficacy. Methods and
      tools for quantifying these measures are examined as well as their accuracy in
      assessing quality and adjusting for differences in environment, and patient
      populations. Successful strategies for changing physician behavior are detailed
      as well as barriers to change. Examples are given of successful quality
      improvement efforts. Also examined is how to address the emergency care needs of
      vulnerable populations such as older persons, women, those without health
      insurance, and ethnic minorities.

PMID- 12414458
TI  - Quality and education.
AB  - Juxtaposing quality with education in emergency medicine (EM) generates two
      distinct issues: 1) the quality of education in EM, and 2) educating about
      quality in EM. There is considerable overlap between the two, and neither should
      be considered without the other. This paper focuses on education about quality in
      EM, with some discussion of the quality of EM education. Despite its apparent
      importance, there is a relative paucity of research on this topic.

PMID- 12414459
TI  - Researching quality in emergency medicine.
AB  - Research aimed at promoting quality of medical care must be quality research.
      This paper addresses issues of study design that can affect the validity of such
      research. The authors draw on previous research about medical errors-recognizing
      that issues of study design pertaining to medical errors apply to other research
      on quality of care and, indeed, to clinical research in general. The November
      2000 Special Issue of Academic Emergency Medicine addressed medical errors in
      emergency medicine. In that issue, Kyriacou and Coben described three categories
      of research on medical errors: 1) research aimed at describing the magnitude of
      the problem; 2) research identifying causal factors for medical errors; and 3)
      research evaluating interventions aimed at improving quality of care. These three
      categories correspond to research methodologies that are, respectively, 1)
      descriptive; 2) qualitative; and 3) analytic. This article discusses challenges
      to the validity of each type of research and suggests some possible solutions to
      these problems. In addition, the article reviews projects that illustrate
      important issues in research quality. Three research projects are discussed: 1) a
      published project evaluating an intervention aimed at improving quality; 2) a
      quality improvement project that is transformed into a research project; and 3) a
      quality monitoring research project that exemplifies how a statistical technique
      borrowed from industry can offer a unique solution to quality challenges in
      medicine. Each of these projects demonstrates some of the challenges in
      researching quality and their solutions.

PMID- 12414460
TI  - Designing a research agenda to improve the quality of emergency care.
AB  - A systematic approach to develop a research agenda for improving the quality of
      emergency care is presented. This approach is based on the six domains of quality
      outlined by the Institute of Medicine (effective, timely, efficient, safe,
      patient-centered, and equitable care) and a sequence of four research steps
      (evidence, synthesis, assessment, and intervention). Examples related to the care
      of patients with acute myocardial infarction are used to illustrate the proposed
      approach. Examples of other emergency medicine research topics relevant to the
      Institute of Medicine quality domains are also presented. Research to improve the
      quality of emergency care can benefit from a more systematic consideration of the
      domains of quality and the research steps necessary to generate evidence and
      inform quality improvement efforts in practice.

PMID- 12414461
TI  - The development of indicators to measure the quality of clinical care in
      emergency departments following a modified-delphi approach.
AB  - OBJECTIVE: To develop and apply a systematic approach to identify and define
      valid, relevant, and feasible measures of emergency department (ED) clinical
      performance. METHODS: An extensive literature review was conducted to identify
      clinical conditions frequently treated in most EDs, and clinically relevant
      outcomes to evaluate these conditions. Based on this review, a set of condition
      outcome pairs was defined. An expert panel was convened and a Modified-Delphi
      process was used to identify specific condition-outcome pairs where the panel
      felt there was a link between quality of care for the condition and a specific
      outcome. Next, for highly rated condition-outcome pairs, specific measurable
      indicators were identified in the literature. The panelists rated these
      indicators on their relevance to ED performance and need for risk adjustment. The
      feasibility of calculating these indicators was determined by applying them to a
      routinely collected data set. RESULTS: Thirteen clinical conditions and eight
      quality-of-care outcomes (mortality, morbidity, admissions, recurrent visits,
      follow-up with primary care, length of stay, diagnostics, and resource use) were
      identified from the literature (104 pairs). The panel selected 21 condition
      outcome pairs, representing eight of 13 clinical conditions. Then, the panel
      selected 29 specific clinical indicators, representing the condition-outcome
      pairs, to measure ED performance. It was possible to calculate eight of these
      indicators, covering five clinical conditions, using a routinely collected data
      set. CONCLUSIONS: Using a Modified-Delphi process, it was possible to identify a
      series of condition-outcome pairs that panelists felt were potentially related to
      ED quality of care, then define specific indicators for many of these condition
      outcome pairs. Some indicators could be measured using an existing data set. The
      development of sound clinical performance indicators for the ED is possible, but
      the feasibility of measuring them will be dependent on the availability and
      accessibility of high-quality data.

PMID- 12414462
TI  - The emergency department as usual source of medical care: estimates from the 1998
      National Health Interview Survey.
AB  - In emergency medicine, there is an ongoing debate regarding patients who use the
      emergency department (ED) as their usual source of medical care-an arguably
      costly and inefficient pattern of utilization. However, there are few accurate
      national data on the prevalence of such usage. This analysis uses the 1998
      National Health Interview Survey to estimate the number of Americans who name the
      ED as their usual source of care, and compares their characteristics with those
      who have a usual source of care other than the ED. Poverty, lack of insurance,
      younger age, male gender, and minority race or ethnicity predicted identifying
      the ED as the usual source of care.

PMID- 12414463
TI  - Improving the care of patients with non-ST-elevation acute coronary syndromes in
      the emergency department: the CRUSADE initiative.
AB  - Although acute coronary syndromes (ACS) represent a well-recognized source of
      morbidity and mortality for patients with cardiovascular disease, evidence-based
      therapies shown to improve outcomes for ACS are frequently underused in
      appropriate patients, especially in the emergency department (ED). Despite
      dissemination of expert recommendations from the American College of
      Cardiology/American Heart Association (ACC/AHA) and ED-focused recapitulation of
      them in the emergency medicine literature, significant barriers continue to limit
      the adoption of guidelines in clinical practice and appear to hinder the use of
      beneficial therapies and interventions in the ED. Unique and creative approaches
      are therefore needed to stimulate better adherence to practice guidelines and
      improve the quality of care for patients with non-ST-elevation myocardial
      infarction (NSTE) ACS. The CRUSADE (Can Rapid Risk Stratification of Unstable
      Angina Patients Suppress ADverse Outcomes with Early Implementation of the
      ACC/AHA Guidelines) quality improvement and educational initiative provides an
      innovative and multifaceted approach to the education of emergency physicians and
      cardiologists in the care of patients with NSTE ACS. The CRUSADE initiative is a
      multidisciplinary cooperative effort involving over 400 EDs and medical centers.
      It includes an ACS registry designed to characterize demographic patterns and
      risk stratification results in patients who meet diagnostic criteria for high
      risk NSTE ACS. It also measures the use of ED treatment modalities including
      aspirin, heparin, beta-blockers, and platelet inhibitors as recommended in the
      ACC/AHA guidelines. The results of a given institution's treatment patterns will
      be reported back to the practitioners, with comparisons with national norms.
      These reports can be used as quality improvement tools to improve care at
      participating institutions. Beyond a static registry, these reports are coupled
      with educational efforts by the CRUSADE steering committee, scientific
      publications of risk stratification practice and success, as well as ED patterns
      of care, and tailored educational interventions, to reinforce compliance with the
      ACC/AHA guidelines. This initiative represents a truly innovative approach to
      improving care for ACS patients in the ED as well as on the cardiology service.
      This article describes the CRUSADE initiative and its implications for the
      practicing emergency physician. It is the intent of CRUSADE to improve patient
      care in the ED by tracking and encouraging compliance with evidence-based
      guidelines for the evaluation and management of NSTE ACS.

PMID- 12414464
TI  - Medical errors-what and when: what do patients want to know?
AB  - OBJECTIVES: 1) To determine how and when emergency department (ED) patients and
      their families wish to learn of health care errors. 2) To assess the error
      threshold this population believes should trigger reporting to government
      agencies, state medical boards, and hospital patient safety committees. 3) To
      evaluate the role patients and families believe medical educators should play in
      this process. METHODS: A 12-item survey was administered to a convenience sample
      of ED patients and families during evaluation in a tertiary care academic ED.
      Results were tabulated and data were reported as percentages. Statistical
      significance was analyzed using the chi-square test. RESULTS: 258 surveys were
      returned (80%). A majority of respondents wished to be informed immediately of
      any medical error (76%) and to have full disclosure of the error's extent (88%).
      An overwhelming majority of respondents endorse reporting of errors to government
      agencies (92%), state medical boards (97%), and hospital committees (99%). Most
      respondents believe medical educators should focus on teaching students to be
      honest and compassionate (38%) or on how to tell patients about mistakes (25%).
      The frequency of hospital admission or physician visits per year had no impact on
      any response pattern (ns with chi(2) test). CONCLUSIONS: Regardless of health
      care utilization, a majority of respondents want full disclosure of medical error
      and wish to be informed of error immediately upon its detection. Respondents
      support reporting of errors to government agencies, the state medical board, and
      hospital committees focused on patient safety. Teaching physicians error
      disclosure techniques, honesty, and compassion were endorsed as a priority for
      educators who teach error management.

PMID- 12414465
TI  - Drug interactions in at-risk emergency department patients.
AB  - OBJECTIVES: Many emergency department (ED) patients are at risk for drug
      interactions (DIs) because they are elders, and/or they have chronic illnesses
      requiring treatment with multiple medications. In the ED, medications may be
      added to complex treatment regimens without the benefit of screening for DIs.
      Emergency physicians may therefore cause DIs, or miss the opportunity to
      intervene against a pre-existing DI. Prior studies are contradictory regarding
      whether DIs are more likely to be due to medications administered or prescribed
      in the ED or medications prescribed elsewhere. Screening for DIs using computer
      software, such as that done by retail pharmacies, is now a standard of practice,
      and is done more frequently than when these other DI studies were reported during
      the previous decade. The authors monitored DIs among a focused, at-risk
      outpatient ED population, to test the hypothesis that ED-induced DIs have become
      the most common DIs in this population-at-risk. METHODS: A retrospective
      convenience sample of 200 at-risk patients seen at a tertiary teaching hospital
      on selected dates of service was analyzed. Eligible patients were ED outpatients
      aged 60 years or more taking three or more medications, or any age taking five or
      more medications. Micromedex Drug-Reax software identified DIs. DIs had to
      represent "major" or "minor" severity, and have "excellent" or "good" literature
      documentation, to be scored as positive. Pre-existing versus ED-induced DIs were
      compared by chi-square. DIs were stratified by patient age and by number and type
      of medications taken. RESULTS: The 200 outpatients (125 female, 75 male) had a
      mean age (+/-SD) of 64.5 (+/-17.6) years and were taking an average of 7.2
      medications. Seventy-nine pre-existing DIs were noted, occurring in 50 of the 200
      patients studied. One hundred forty patients received a new medication during
      their ED visit. Seven new DIs (one in each of seven patients) occurred among
      these 140 patients. DIs were less frequently caused by medications added during
      the ED visit (chi(2) = 22.2, p < 0.001). Digoxin and warfarin were the sources of
      the greatest number of DIs. CONCLUSIONS: ED outpatients in the at-risk group
      frequently present with pre-existing DIs. Medications initiated in the ED are a
      less frequent cause of DI in this group. Medication screening during an ED visit
      could complement the role of outpatient pharmacies and potentially improve ED
      patient safety. DIs are most frequently due to digoxin and warfarin in these
      patients.

PMID- 12414466
TI  - The effect of computer-assisted prescription writing on emergency department
      prescription errors.
AB  - OBJECTIVE: To determine whether computer-assisted prescription writing reduces
      the frequency of prescription errors in the emergency department (ED). METHODS: A
      pre-post retrospective analysis was used to compare errors between handwritten
      (HW) and computer-assisted (CA) ED prescriptions. Prescriptions were reviewed for
      pharmacist clarifications. A clarification was defined as an error if missing
      information, incorrect information, incorrect dose, non-formulary medication, or
      illegibility was the reason for clarification. The HW and CA error rates were
      compared using odds ratios (ORs) with 95% confidence intervals (95% CIs).
      RESULTS: During the pre-intervention period, there were 7,036 patient visits with
      2,326 HW ED prescriptions filled for 1,459 patients. There were 91
      clarifications, with a rate of 3.9%. There were 54 HW errors, for an error rate
      of 2.3%. During the post-intervention period, there were 7,845 patient visits
      with 1,594 CA prescriptions filled for 1,056 patients. There were 13
      clarifications, with a clarification rate of 0.8%, and 11 errors, for a CA error
      rate of 0.7%. The CA prescriptions were substantially less likely to contain an
      error [OR 0.31 (95% CI = 0.10 to 0.36)] or to require pharmacist clarification
      [OR 0.19 (95% CI = 0.10 to 0.36)] than were the HW prescriptions. CONCLUSIONS:
      Computer-assisted prescriptions were more than three times less likely to contain
      errors and five times less likely to require pharmacist clarification than
      handwritten prescriptions.

PMID- 12414467
TI  - Measuring the quality of hospital-based domestic violence programs.
AB  - OBJECTIVE: To obtain consensus among a panel of experts on performance measures
      useful for evaluating the quality of hospital-based domestic violence (DV)
      programs. METHODS: The Delphi process of consensus development was used with a
      panel of 18 experts including DV researchers, program planners, and advocates.
      Three rounds were conducted over a period of six months, with each round
      involving the completion of a written questionnaire. Panelists were instructed to
      concentrate on structure and process measures of DV program performance. Health
      outcome measures were not considered. During each round, panelists rated (scale
      of 1-5) their level of agreement with each measure, in terms of the measure's
      usefulness for evaluating hospital-based DV programs. Data were entered into SPSS
      on a personal computer and frequency distributions, measures of central tendency,
      and variance were computed for each measure. Consensus development was defined as
      a reduction in the item-specific variance from one round to the next. RESULTS: A
      total of 37 performance measures were agreed upon. These measures fell within
      nine different domains of DV program activities, including: Policies and
      Procedures, Hospital Physical Environment, Hospital Cultural Environment,
      Training of Providers, Screening and Safety Assessment, Documentation,
      Intervention Services, Evaluation Activities, and Collaboration. CONCLUSIONS: A
      number of measures have been identified as useful for evaluating hospital-based
      DV programs. Use of these measures should assist researchers, program planners,
      and administrators in assessing the quality of hospital-based DV programs.

PMID- 12414468
TI  - Achieving quality in clinical decision making: cognitive strategies and detection
      of bias.
AB  - Clinical decision making is a cornerstone of high-quality care in emergency
      medicine. The density of decision making is unusually high in this unique milieu,
      and a combination of strategies has necessarily evolved to manage the load. In
      addition to the traditional hypothetico-deductive method, emergency physicians
      use several other approaches, principal among which are heuristics. These
      cognitive short-cutting strategies are especially adaptive under the time and
      resource limitations that prevail in many emergency departments (EDs), but
      occasionally they fail. When they do, we refer to them as cognitive errors. They
      are costly but highly preventable. It is important that emergency physicians be
      aware of the nature and extent of these heuristics and biases, or cognitive
      dispositions to respond (CDRs). Thirty are catalogued in this article, together
      with descriptions of their properties as well as the impact they have on clinical
      decision making in the ED. Strategies are delineated in each case, to minimize
      their occurrence. Detection and recognition of these cognitive phenomena are a
      first step in achieving cognitive de-biasing to improve clinical decision making
      in the ED.

PMID- 12414469
TI  - The effects of the absence of emergency medicine residents in an academic
      emergency department.
AB  - OBJECTIVE: What are the quality effects of an emergency medicine (EM) residency,
      and the associated 24/7 supervision of residents by faculty, in an academic
      emergency department (ED)? The authors evaluated activity and quality indicators
      when there were no EM residents present. The hypothesis of the study was that
      there was no difference between the patient care provided by faculty supervising
      EM residents and that with an alternative model without EM residents
      (AbsenceEMResident). METHODS: To support the weekly residency educational program
      (Thursday), EM residents are not scheduled clinically for a 24-hour period
      (ConfDay). Emergency medicine resident coverage (mean 62.7 hours) was replaced
      with incremental faculty and mid-level providers (mean 41.0 hours). This study
      was limited to adult patients (22,527 visits of 39,190 ED total) for six months
      (January-June 2001) and compared indicators for ConfDay (n = 23) with all other
      days (NotConfDay, n = 158). RESULTS: Comparing ConfDay (2,842 visits) with
      NotConfDay (19,685 visits), there was no difference in mean daily visits,
      inpatient admissions, intensive care unit admissions, or emergency medical
      services arrivals. ConfDay decision-to-admit time (333 vs. 313 min, p = 0.03) and
      length of stay for admissions (490 vs. 445 min, p = 0.000) were longer, with no
      difference for treat/release patients. There was no difference in the numbers of
      laboratory or radiology tests, consultations, unscheduled return visits, or
      patient satisfaction. CONCLUSION: During the study period, there was no
      measurable difference for most of the quality indicators studied. The
      AbsenceEMResident model is less efficient in admitting patients. Faculty
      supervision results in the same number of laboratory and radiology tests and
      consultations. Other specialties may consider this model if off-hours care
      becomes a concern.

PMID- 12414471
TI  - Getting Ahead of the Curve: the ACGME Best Practices/Core Competencies.
      Proceedings of the Council of Emergency Medicine Residency Directors (CORD) 2002
      Consensus Conference.

PMID- 12414472
TI  - The ACGME core competencies: getting ahead of the curve.

PMID- 12414473
TI  - The ACGME general competencies challenge--perspective of the Council of Emergency
      Medicine Residency Directors.

PMID- 12414474
TI  - Estimating the impact of a competencies-based system of education and evaluation:
      the perspective of the American Board of Emergency Medicine.

PMID- 12414475
TI  - The quiet revolution in postgraduate training.

PMID- 12414476
TI  - Patient care competency in emergency medicine graduate medical education: results
      of a consensus group on patient care.
AB  - "Patient Care" is the first listed core competency of the six new core
      competencies recently formulated by the Accreditation Council for Graduate
      Medical Education (ACGME) and, arguably, the most important. To assist emergency
      medicine (EM) program directors in incorporating and assessing this competency,
      the Council of Emergency Medicine Residency Directors (CORD-EM) held a consensus
      conference in March 2002. Definitions of this competency were generated that are
      specific for the training of practitioners in EM. These built upon the ACGME base
      definition, but include elements unique to or critically important in EM. In
      addition, all of the ACGME assessment tools were examined and prioritized for use
      in assessing the competency of EM residents in the area of patient care.
      Suggestions for an implementation process are also described.

PMID- 12414477
TI  - Application of the medical knowledge general competency to emergency medicine.
AB  - In February 1999, the Accreditation Council for Graduate Medical Education
      (ACGME) identified six general competencies as the basic educational goals
      required by all training programs for their residents. This places emphasis on
      educational outcome assessment in residency programs and in the accreditation
      process. A concomitant goal is to have increasingly valid, reliable assessments
      of the ability of a resident physician to provide safe, evidenced-based,
      humanistic medical care to their patients. To better define these competencies
      for the specialty of emergency medicine (EM), the Council of Emergency Medicine
      Residency Directors (CORD-EM) held a consensus conference in March 2002. This
      article reports the results of the Consensus Group for the core competency area
      of medical knowledge. This competency is already being well addressed in
      residency programs, but there has been inadequate documentation of a resident's
      knowledge base. The Consensus Group focused on many assessment methods to
      determine those having the best potential for use in EM programs. Assessment
      methods felt to be most appropriate for assessment of the medical knowledge base
      of a resident are presented, as are practical suggestions for incorporating these
      into EM programs.

PMID- 12414478
TI  - Definitions and competencies for practice-based learning and improvement.
AB  - The Outcome Project is a long-term initiative by which the Accreditation Council
      for Graduate Medical Education (ACGME) is increasing emphasis on educational
      outcomes in the evaluation of residency programs. The ACGME initiated the Outcome
      Project to "ensure and improve the quality of graduate medical education." In
      order to assist program directors in emergency medicine (EM) to begin complying
      with components of the ACGME Outcome Project, the Council of Residency Directors
      in Emergency Medicine (CORD-EM) convened a consensus conference in March 2002 in
      conjunction with several other EM organizations. The working group for the
      competency of Practice-based Learning and Improvement (PBL) defined the
      components of PBL as: 1) analyze and assess practice experience and perform
      practice-based improvement; 2) locate, appraise, and utilize scientific evidence
      related to the patient's health problems and the larger population from which
      they are drawn; 3) apply knowledge of study design and statistical methods to
      critically appraise the medical literature; 4) utilize information technology to
      enhance personal education and improve patient care; and 5) facilitate the
      learning of students, colleagues, and other health care professionals in EM
      principles and practice. Establishing resident portfolios is a preferred method
      to chronicle resident competence in PBL. Traditional global evaluation of
      resident performance is de-emphasized. Checklist evaluation is appropriate for
      assessing any competency that can be broken down into specific behaviors or
      actions. 360-degree evaluation may be used to assess teamwork, communication
      skills, management skills, and clinical decision making. Chart-stimulated recall
      and record review are additional evaluation methods that can be used to assess
      resident competency in PBL. Simulations and models, such as computer-based
      scenarios, may be ideal for low-frequency but critical procedures.

PMID- 12414479
TI  - Defining and evaluating professionalism: a core competency for graduate emergency
      medicine education.
AB  - Professionalism, long a consideration for physicians and their patients, is
      coming to the forefront as an essential element of graduate medical education as
      one of the six new core competency requirements of the Accreditation Council for
      Graduate Medical Education (ACGME). Professionalism is also integral to the
      widely endorsed Model of the Clinical Practice of Emergency Medicine (Model).
      Program directors have now been charged with implementing the new core
      competencies in training programs and to assess the acquisition of these
      competencies in their trainees. To assist emergency medicine (EM) program
      directors in this endeavor, the Council of Emergency Medicine Residency Directors
      (CORD-EM) held a consensus conference in March 2002. A focused Consensus Group
      addressed the specific core competency of professionalism during the course of
      this conference, and the results are highlighted in this article. The definition
      and curricular requirements relating to professionalism are highlighted, specific
      techniques for evaluating this core competency in EM are reviewed, and
      recommendations are provided regarding the most appropriate assessment method for
      EM programs.

PMID- 12414480
TI  - Assessment of communication and interpersonal skills competencies.
AB  - Excellent communication and interpersonal (C-IP) skills are a universal
      requirement for a well-rounded emergency physician. This requirement for C-IP
      skill excellence is a direct outgrowth of the expectations of our patients and a
      prerequisite to working in the increasingly complex emergency department
      environment. Directed education and assessment of C-IP skills are critical
      components of all emergency medicine (EM) training programs and now are a
      requirement of the Accreditation Council for Graduate Medical Education (ACGME)
      Outcome Project. In keeping with its mission to improve the quality of EM
      education and in response to the ACGME Outcome Project, the Council of Emergency
      Medicine Residency Directors (CORD-EM) hosted a consensus conference focusing on
      the application of the six core competencies to EM. The objective of this article
      is to report the results of this consensus conference as it relates to the C-IP
      competency. There were four primary goals: 1) define the C-IP skills competency
      for EM, 2) define the assessment methods currently used in other specialties, 3)
      identify the methods suggested by the ACGME for use in C-IP skills, and 4)
      analyze the applicability of these assessment techniques to EM. Ten specific
      communication competencies are defined for EM. Assessment techniques for
      evaluation of these C-IP competencies and a timeline for implementation are also
      defined. Standardized patients and direct observation were identified as the
      criterion standard assessment methods of C-IP skills; however, other methods for
      assessment are also discussed.

PMID- 12414481
TI  - Systems-based practice: the sixth core competency.
AB  - Systems-Based Practice (SBP) is the sixth competency defined by the Accreditation
      Council for Graduate Medical Education (ACGME) Outcome Project. Specifically, SBP
      requires "Residents [to] demonstrate an awareness of and responsiveness to the
      larger context and system of health care and the ability to effectively call on
      system resources to provide care that is of optimal value." This competency can
      be divided into four subcompetencies, all of which are integral to training
      emergency medicine (EM) physicians: resources, providers, and systems; cost
      appropriate care; delivery systems; and patient advocacy. In March 2002, the
      Council of Emergency Medicine Residency Directors (CORD-EM) convened a consensus
      conference to assist residency directors in modifying the SBP competency specific
      for EM. The Consensus Group modified the broad ACGME definition for SBP into EM
      specific goals and objectives for residency training in SBP. The primary
      assessment methods from the Toolbox of Assessment Methods were also identified
      for SBP. They are direct observation, global ratings, 360-degree evaluations,
      portfolio assessment, and testing by both oral and written exams. The physician
      tasks from the Model of the Clinical Practice of Emergency Medicine that are most
      relevant to SBP are out-of-hospital care, modifying factors, legal/professional
      issues, diagnostic studies, consultation and disposition, prevention and
      education, multitasking, and team management. Suggested EM residency curriculum
      components for SBP are already in place in most residency programs, so no
      additional resources would be required for their implementation. These include:
      emergency medical services and administrative rotations, directed reading,
      various interdisciplinary and hospital committee participation, continuous
      quality improvement project participation, evidence-based medicine instruction,
      and various didactic experiences, including follow-up, interdisciplinary, and
      case conferences. With appropriate integration and evaluation of this competency
      into training programs, it is likely that future generations of physicians and
      patients will reap the benefits of an educational system that is based on well
      defined outcomes and a more systemic view of health care.

PMID- 12414482
TI  - Assessing the ACGME general competencies: general considerations and assessment
      methods.
AB  - The Accreditation Council for Graduate Medical Education's (ACGME's) general
      competency and outcome assessment initiative (i.e., the ACGME Outcome Project) is
      an effort to enhance residency education and accreditation effectiveness by
      increasing emphasis on educational outcomes. The Project is also a response to
      concerns about new graduates' ability to meet the demands of today's practice
      environment. The competencies emphasize learning in new domains (e.g., Practice
      Based Learning and Improvement and Systems-Based Practice) and more traditional
      ones (e.g., Patient Care and Medical Knowledge). Outcome assessment will provide
      evidence of residency program educational effectiveness and information to guide
      improvement. This paper discusses the development and implementations of
      assessment methods appropriate to evaluate the performance of residents in each
      of the core competencies.

PMID- 12414483
TI  - Clinical assessment in emergency medicine.
AB  - The Accreditation Council for Graduate Medical Education (ACGME) has challenged
      all residencies with a new paradigm-to teach and evaluate residents based on six
      core competencies. One of these core competencies is clinical assessment.
      Standardized patients and direct observation are the most promising for emergency
      medicine educators to use to assess this competency. There is much room for
      research and national standardization of methods.

PMID- 12414484
TI  - The use of simulation for emergency medicine resident assessment.
AB  - Simulations are exercises designed to mimic real-life situations in which
      learners are given the opportunity to reason through a clinical problem and make
      critical decisions without the potential of harming actual patients. Simulation,
      using a variety of formats, is useful for assessing the core competencies
      particularly patient care (decision making, prioritizing, procedural skills),
      interpersonal skills (team leadership, communication), and systems-based practice
      (team structure and utilization, resource use). High-fidelity computerized human
      simulators are a relatively new tool for use in medical simulation. These
      realistic mannequins mimic physical findings including respiratory rate, breath
      sounds, central and peripheral pulses, murmurs, and pupil reactivity. They
      generate an electrocardiographic (ECG) waveform, cardiac indices, and oxygen
      saturation that can be viewed on standard cardiac monitoring equipment and can be
      programmed to respond physiologically to medications and invasive procedures. The
      use of human simulators to reproduce life-threatening situations will be
      especially useful in assessing the clinical competence of emergency medicine
      physicians. Operational definitions of competence and tools with which to
      evaluate performance must first be developed. Standardization of scenarios and
      evaluation tools will permit assessment of the reproducibility of scenarios and
      the reliability and validity of the tools used to measure competence.

PMID- 12414485
TI  - 360-degree feedback: possibilities for assessment of the ACGME core competencies
      for emergency medicine residents.
AB  - The Accreditation Council for Graduate Medical Education (ACGME) has challenged
      residency programs to provide documentation via outcomes assessment that all
      residents have successfully mastered the six core competencies. A variety of
      assessment "tools" has been identified by the ACGME for outcomes assessment
      determination. Although rarely cited in the medical literature, 360-degree
      feedback is currently in widespread use in the business sector. This tool
      provides timely, consolidated feedback from sources in the resident's sphere of
      influence (emergency medicine faculty, emergency medicine residents, off-service
      residents and faculty, nurses, ancillary personnel, patients, out-of-hospital
      care providers, and a self-assessment). This is a significant deviation from both
      the peer review process and the resident review process that almost exclusively
      use physicians as raters. Because of its relative lack of development,
      utilization, and validation as a method of resident assessment in graduate
      medical education, a great opportunity exists to develop the 360-degree feedback
      tool for resident assessment.

PMID- 12414486
TI  - Portfolios: possibilities for addressing emergency medicine resident
      competencies.
AB  - Portfolios are an innovative approach to evaluate the competency of emergency
      medicine residents. Three key characteristics add to their attractiveness. First,
      portfolios draw from the resident's actual work. Second, they require self
      reflection on the part of the resident. Third, they are inherently practice-based
      learning since residents must review and consider their practice in order to
      begin the portfolio. This paper illustrates five different applications of
      portfolios. First, portfolios are applied to evaluating specific competencies as
      part of the training of emergency physicians. While evaluating specific
      competencies, the portfolio captures aspects of the general competencies. Second,
      the article illustrates using portfolios as a way to address a specific residency
      review committee (RRC) requirement such as follow-ups. Third is a description of
      how portfolios can be used to evaluate resident conferences capturing the
      competency of practice-based learning and possibly other competencies such as
      medical knowledge and patient care. Fourth, the authors of the article designed a
      portfolio as a way to demonstrate clinical competence. Fifth, they elaborate as
      to how a continuous quality improvement project could be cast within the
      portfolio framework. They provide some guidance concerning issues to address when
      designing the portfolios. Portfolios are carefully structured and not haphazard
      collections of materials. Following criteria is important in maintaining the
      validity of the portfolio as well as contributing to reliability. The portfolios
      can enhance the relationship between faculty and residents since faculty will
      suggest cases, discuss anomalies, and interact with the residents around the
      portfolio. The authors believe that in general portfolios can cover many of the
      general competencies specified by the ACGME while still focusing on issues
      important to emergency medicine. The authors believe that portfolios provide an
      approach to evaluation commensurate with the self-evaluation skills they would
      like to develop in their residents.

PMID- 12414487
TI  - Human simulation in emergency medicine training: a model curriculum.
AB  - The authors propose a three-year curriculum for emergency medicine residents
      using human simulation both to teach and to assess the Accreditation Council for
      Graduate Medical Education (ACGME) core competencies. Human simulation refers to
      a variety of technologies that allow residents to work through realistic patient
      problems so as to allow them to make mistakes, learn, and be evaluated without
      exposing a real patient to risk. This curriculum incorporates 15 simulated
      patient encounters with gradually increasing difficulty, complexity, and realism
      into a three-year emergency medicine residency. The core competencies are
      incorporated into each case, focusing on the areas of patient care, interpersonal
      skills and communication, professionalism, and practice based learning and
      improvement. Because of the limitations of current assessment tools, the
      demonstration of resident competence is used only for formative evaluations.
      Limitations of this proposal and difficulties in implementation are discussed,
      along with a description of the organization and initiation of the simulation
      program.

PMID- 12414488
TI  - Evaluation of the educational effectiveness of a virtual reality intravenous
      insertion simulator.
AB  - OBJECTIVE: To evaluate construct and content validity as well as learners'
      perceptions of CathSim, a virtual reality intravenous (IV) insertion simulator.
      METHODS: A prospective cohort study design was employed to determine construct
      validity, and a participant survey was used to ascertain content validity as well
      as user perceptions of CathSim. Forty-one attendings, residents, and medical
      students in emergency medicine and anesthesia attempted five simulated IV
      insertions on CathSim. Subject performances were scored by the computer, and
      subject perceptions of the simulator were measured using a Likert scale
      questionnaire (1 = worst rating; 5 = best rating). The subjects were divided into
      three groups (novices, intermediates, and experts) based on previous IV
      experience. To determine construct validity, performances of the three groups
      were compared using one-way analysis of variance (ANOVA). To determine content
      validity, the experts' perceptions of the simulator's realism and usefulness were
      assessed. Study subjects' perceptions of the simulator's ease of use and overall
      appeal were analyzed. RESULTS: The experts scored better than the others in five
      of nine scoring parameters (p < 0.05). The experts rated the realism of CathSim's
      four major simulation components at 3.85, 3.46, 3.69, and 3.46; the overall
      realism of CathSim at 2.93; and its utility for medical student training at 4.57.
      The simulator's ease of use was rated at 2.34 by all subjects. Novices reported a
      score of 4.59 regarding their likelihood to use the simulator. CONCLUSIONS:
      CathSim demonstrated construct validity in five of nine internal scoring
      parameters and was judged to be adequately realistic and highly useful for
      medical student training. Despite being difficult to learn to use, it remained
      appealing to the users, especially the novices.

PMID- 12414489
TI  - The use of standardized patients within a procedural competency model to teach
      death disclosure.
AB  - OBJECTIVE: To design, implement, and evaluate a multi-dimensional,
      interdisciplinary, educational training module that enables residents to deliver
      an effective and empathic death disclosure in the emergency setting. The
      Accreditation Council for Graduate Medical Education (ACGME) "Toolbox of
      Assessment Methods" to assess competency was adopted as the foundation of this
      project. METHODS: Sixteen emergency medicine residents, eight postgraduate year 1
      (PGY-1) and eight PGY-2, underwent a one-day training and evaluation exercise.
      The exercise consisted of: 1) a large-group didactic session, 2) a small-group
      didactic session, and 3) two standardized patient (SP) examinations. Changes in
      comfort levels, training helpfulness, and competency were measured. Inter-rater
      agreement between evaluators was examined. RESULTS: Trainees reported improvement
      in comfort levels and high levels of satisfaction regarding the helpfulness of
      the training. Good interrater agreement was obtained regarding resident
      competency to perform a death disclosure between the faculty and SP evaluators
      [kappa 0.61; 95% confidence interval (95% CI) = 0.33 to 0.88]. However, overall
      agreement among raters was poor (kappa 0.16; standard error = 0.26). This poor
      agreement reflected a lack of agreement between resident and SP evaluators (kappa
      0.08; 95% CI = 0.16 to 0.33) and resident and faculty evaluators (kappa -0.02;
      95% CI = 0.30 to 0.26). CONCLUSIONS: This project used the ACGME "Toolbox of
      Assessment Methods" to evaluate the competency of emergency medicine trainees to
      perform an effective and empathic death disclosure. The finding of inconsistent
      competency assessments by resident self-evaluators compared with those
      assessments made by faculty and standardized patients have important implications
      in future curricular design.

PMID- 12414491
TI  - Using standardized oral examinations to evaluate general competencies.
AB  - Emergency medicine residency programs are required by the Accreditation Council
      for Graduate Medical Education (ACGME) to formally evaluate each resident with
      oral and written examinations. The Michigan State University Emergency Medicine
      Residency Program in Lansing conducts monthly standardized oral examinations
      (SOEs) as part of each resident's evaluation. Recently, the ACGME has advanced
      six areas, termed "general competencies," that should be acquired during graduate
      medical education. According to the ACGME, these competencies should be included
      in the educational process of all residency programs. In promulgating these
      competencies, the ACGME did not provide examples of core content, strategies for
      implementation, or methods of evaluation; rather, individual residency programs
      are required to develop their own methods. The authors describe a modification of
      an existing SOE strategy that assesses residents' knowledge, skills, experiences,
      and attitudes as reflected in the general competencies.

PMID- 12414492
TI  - Direct observation for assessing emergency medicine core competencies:
      interpersonal skills.
AB  - The American Board of Medical Specialties described six core competencies
      considered essential elements of medical practice: patient care, medical
      knowledge, practice-based learning and improvement, interpersonal and
      communication skills, professionalism, and systems-based practice. In response,
      the Accreditation Council for Graduate Medical Education (ACGME) mandated that
      all residency programs assess trainees for the newly defined core competencies.
      Despite the mandate for including these six competencies in residency training,
      neither a specific curriculum nor a method to assess the outlined objectives has
      been developed by the ACGME. Instead, it is up to individual residency programs
      to document how they plan to incorporate and assess the core competencies in
      their programs. This article describes the potential use of direct observation to
      assess resident performance in the interpersonal skills core competency.

PMID- 12414493
TI  - Protected clinical teaching time and a bedside clinical evaluation instrument in
      an emergency medicine training program.
AB  - In a process that has evolved over the last four years, the Emory University
      Emergency Medicine Education Committee has developed an "academic attending"
      teaching shift incorporating a formatted lecture series with a clinical
      evaluation exercise (CEE). The program structures the approach to clinical
      teaching at the bedside, provides an objective clinical evaluation tool specific
      to emergency medicine residents, and provides targeted learning for medical
      students and residents rotating in the emergency department (ED). The CEE
      instrument was designed to be quick and efficient, satisfy requirements of
      assessment of the Accreditation Council for Graduate Medical Education (ACGME)
      general competencies, and incorporate the language of the "Model of the Clinical
      Practice of Emergency Medicine." The original program called for unstructured
      bedside teaching three days a week, by faculty freed from clinical duties,
      combined with a limited series of introductory emergency medicine lectures. The
      program proved more successful when concentrated in a once weekly structured
      educational program. The prepared, repeating lecture series has been expanded to
      include many of the most common ED presenting chief complaints and has
      significantly advanced a curriculum for medical students and visiting interns. A
      CEE was developed to evaluate and provide immediate feedback to residents on many
      of the core ACGME competencies. The CEE has been successfully used to structure
      the bedside educational encounter. This dedicated non-clinical "teaching" shift
      appears effective in meeting the educational goals of the authors' academic ED.
      This is a description of the program and its evolution; the program has not been
      formally evaluated.

PMID- 12414494
TI  - Evaluating systems-based practice in emergency medicine.
AB  - The Accreditation Council for Graduate Medical Education has required that
      training programs initiate an evaluation process to assess resident acquisition
      of the newly promulgated general competencies (GCs). Certain GCs (e.g., systems
      based practice, problem-based learning and improvement) are somewhat more
      challenging to define and measure than others. Systems-based practice essentially
      captures the interactions of the emergency medicine resident that expand beyond
      isolated contact with the patient. Evaluating these various interactions is
      readily accomplished using a detailed ordinal evaluation form that measures
      commonly occurring easily identified actions. Examples of measurable items and
      the method by which they can be integrated into an evaluation device are
      presented.

PMID- 12414495
TI  - An approach to fulfilling the systems-based practice competency requirement.
AB  - The Accreditation Council for Graduate Medical Education (ACGME)-identified core
      competency of systems-based practice requires the demonstration of an awareness
      of the larger context and system of health care, and the ability to call on
      system resources to provide optimum care. This article describes an approach to
      teaching and fulfilling the requirement of this core competency in an emergency
      medicine residency. Beginning residents are oriented to community resources that
      are important to the larger context of care outside the emergency department.
      Each resident completes a community project during his or her residency. Readings
      and discussions concerning community-oriented medical care and the literature of
      research and injury prevention in emergency medicine precede the project
      development. Several projects are described in detail. Such projects help to
      teach not only awareness of the community resources of the greater context of
      medical practice outside the emergency department, but also how to use those
      resources. Projects could be a main component of a resident portfolio. This
      approach to teaching the core competency of systems-based practice is proposed as
      an innovative and substantial contribution toward satisfying the requirement of
      the core competency.

PMID- 12414496
TI  - Teaching communications and professionalism through writing and humanities:
      reflections of ten years of experience.
AB  - Both professionalism and interpersonal communication are core competencies for
      emergency medicine residents as well as residents from other specialties. The
      authors describe a weekly, small-group seminar lasting one year for emergency
      medicine residents that incorporates didactic materials, case studies, narrative
      expression (stories and poems), and small-group discussion. Examples of cases and
      narrative expressions are provided and a rationale for utilizing the format is
      explained. A theoretical model for evaluation measures is also included.

PMID- 12414499
TI  - First steps in unraveling the genotype of enteropathy-type T-cell lymphoma.

PMID- 12414500
TI  - Gene expression studies on soft tissue tumors.

PMID- 12414501
TI  - ADAM12 alleviates the skeletal muscle pathology in mdx dystrophic mice.
AB  - Muscular dystrophy is characterized by muscle degeneration and insufficient
      regeneration and replacement of muscle fibers by connective tissue. New
      therapeutic strategies directed toward various forms of muscular dystrophy are
      needed to preserve muscle mass and promote regeneration. In this study we
      examined the role of the transmembrane ADAM12, a disintegrin and metalloprotease,
      which is normally associated with development and regeneration of skeletal
      muscle. We demonstrate that ADAM12 overexpression in the dystrophin-deficient mdx
      mice alleviated the muscle pathology in these animals, as evidenced by less
      muscle cell necrosis and inflammation, lower levels of serum creatine kinase, and
      less uptake of Evans Blue dye into muscle fibers. These studies demonstrate that
      ADAM12 directly or indirectly contributes to muscle cell regeneration, stability,
      and survival.

PMID- 12414502
TI  - Telomere shortening is nearly universal in pancreatic intraepithelial neoplasia.
AB  - A multistep model of carcinogenesis has recently been proposed for pancreatic
      ductal adenocarcinomas. In this model, noninvasive precursor lesions in the
      pancreatic ductules accumulate genetic alterations in cancer-associated genes
      eventually leading to the development of an invasive cancer. The nomenclature for
      these precursor lesions has been standardized as pancreatic intraepithelial
      neoplasia or PanIN. Despite the substantial advances made in understanding the
      biology of invasive pancreatic adenocarcinomas, little is known about the
      initiating genetic events in the pancreatic ductal epithelium that facilitates
      its progression to cancer. Telomeres are distinctive structures at the ends of
      chromosomes that protect against chromosomal breakage-fusion-bridge cycles in
      dividing cells. Critically shortened telomeres can cause chromosomal instability,
      a sine qua non of most human epithelial cancers. Although evidence for telomeric
      dysfunction has been demonstrated in invasive pancreatic cancer, the onset of
      this phenomenon has not been elucidated in the context of noninvasive precursor
      lesions. We used a recently described in situ hybridization technique in archival
      samples (Meeker AK, Gage WR, Hicks JL, Simon I, Coffman JR, Platz EA, March GE,
      De Marzo AM: Telomere length assessment in human archival tissues: combined
      telomere fluorescence in situ hybridization and immunostaining. American Journal
      of Pathology 2002, 160:1259-1268) for assessment of telomere length in tissue
      microarrays containing a variety of noninvasive pancreatic ductal lesions. These
      included 82 PanIN lesions of all histological grades (24 PanIN-1A, 23 PanIN-1B,
      24 PanIN-2, and 11 PanIN-3) that were selected from pancreatectomy specimens for
      either adenocarcinoma or chronic pancreatitis. Telomere fluorescence intensities
      in PanIN lesions were compared with adjacent normal pancreatic ductal epithelium
      and acini (62 of 82 lesions, 76%), or with stromal fibroblasts and islets of
      Langerhans (20 of 82 lesions, 24%). Telomere signals were strikingly reduced in
      79 (96%) of 82 PanINs compared to adjacent normal structures. Notably, even PanIN
      1A, the earliest putative precursor lesion, demonstrated a dramatic reduction of
      telomere fluorescence intensity in 21 (91%) of 23 foci examined. In chronic
      pancreatitis, reduction of telomere signal was observed in all PanIN lesions,
      whereas atrophic and inflammatory ductal lesions retained normal telomere length.
      Telomere fluorescence intensity in PanIN lesions did not correlate with
      proliferation measured by quantitative Ki-67-labeling index or topoisomerase
      IIalpha expression. Thus, telomere shortening is by far the most common early
      genetic abnormality recognized to date in the progression model of pancreatic
      adenocarcinomas. Telomeres may be an essential gatekeeper for maintaining
      chromosomal integrity, and thus, normal cellular physiology in pancreatic ductal
      epithelium. A critical shortening of telomere length in PanINs may predispose
      these noninvasive ductal lesions to accumulate progressive chromosomal
      abnormalities and to develop toward the stage of invasive carcinoma.

PMID- 12414503
TI  - Genome-wide appraisal of thyroid cancer progression.
AB  - Several lines of evidence suggest that follicular cell-derived thyroid cancers
      represent a continuum of disease that progresses from the highly curable well
      differentiated thyroid cancers to the universally fatal anaplastic cancers.
      However, the genetic mechanisms underlying thyroid cancer progression remain ill
      defined. We compared the molecular-cytogenetic profiles derived from comparative
      genomic hybridization (CGH) analysis of major histological variants of thyroid
      cancer to define genetic variables associated with progression. Overall, a
      sequential increase in chromosomal complexity was observed from well
      differentiated papillary thyroid cancer to poorly differentiated and anaplastic
      carcinomas, both in terms of the presence of CGH detectable abnormalities (P =
      0.003) and the median number of abnormalities per case (P < 0.001). The presence
      of multiple abnormalities common to all thyroid cancer variants, including gains
      of 5p15, 5q11-13, 19p, and 19q and loss of 8p, suggests that these tumors are
      derived from a common genetic pathway. Gains of 1p34-36, 6p21, 9q34, 17q25, and
      20q and losses of 1p11-p31, 2q32-33, 4q11-13, 6q21, and 13q21-31 may represent
      secondary events in progression, as they were only detected in poorly
      differentiated and anaplastic carcinomas. Finally, recurrent gains at 3p13-14 and
      11q13, and loss of 5q11-31 were unique to anaplastic carcinomas, suggesting they
      may be markers for anaplastic transformation. Our data suggests that the
      development of chromosomal instability underlies the progression to more
      aggressive phenotypes of thyroid cancer and sheds light on the possible genomic
      aberrations that may be selected for during this process.

PMID- 12414504
TI  - Software tools for high-throughput analysis and archiving of immunohistochemistry
      staining data obtained with tissue microarrays.
AB  - The creation of tissue microarrays (TMAs) allows for the rapid
      immunohistochemical analysis of thousands of tissue samples, with numerous
      different antibodies per sample. This technical development has created a need
      for tools to aid in the analysis and archival storage of the large amounts of
      data generated. We have developed a comprehensive system for high-throughput
      analysis and storage of TMA immunostaining data, using a combination of
      commercially available systems and novel software applications developed in our
      laboratory specifically for this purpose. Staining results are recorded directly
      into an Excel worksheet and are reformatted by a novel program (TMA-Deconvoluter)
      into a format suitable for hierarchical clustering analysis or other statistical
      analysis. Hierarchical clustering analysis is a powerful means of assessing
      relatedness within groups of tumors, based on their immunostaining with a panel
      of antibodies. Other analyses, such as generation of survival curves,
      construction of Cox regression models, or assessment of intra- or interobserver
      variation, can also be done readily on the reformatted data. Finally, the
      immunoprofile of a specific case can be rapidly retrieved from the archives and
      reviewed through the use of Stainfinder, a novel web-based program that creates a
      direct link between the clustered data and a digital image database. An on-line
      demonstration of this system is available at http://genome
      www.stanford.edu/TMA/explore.shtml.

PMID- 12414505
TI  - Isolation of living neurons from human elderly brains using the immunomagnetic
      sorting DNA-linker system.
AB  - Isolation and culture of mature neurons from affected brain regions during
      diseased states provide a well-suited in vitro model system to study age-related
      neurodegeneration under dynamic conditions at cellular levels. We have developed
      a novel technique to isolate living neurons from rapidly autopsied human elderly
      brains, and have succeeded in keeping them alive in vitro. Specifically, the
      parietal cortex blocks were fractionated by density gradients and further
      enriched for neurons by an immunomagnetic sorting DNA-linker technique. The
      postmortem interval averaged 2.6 hours. After isolation and purification of
      neurons using this technology, the cells were maintained in vitro for 2 weeks.
      Our evaluation revealed that 80% of the isolated cells were neurons and they
      exhibited neurotransmitter phenotypes (glutamate and gamma-aminobutyric acid) as
      well as glutamate receptors. Studies on cell viability and calcium influx suggest
      that these isolated living cortical neurons still retain their typical neuronal
      functions. Our present study demonstrates that neurons isolated from human
      elderly brain autopsies can survive in vitro and maintain their functional
      properties. Our study has opened an opportunity to apply such neurons to dynamic
      pharmacological studies of neurological disorders at the single-cell level.

PMID- 12414506
TI  - A role for caspase-1 and -3 in the pathology of experimental allergic
      encephalomyelitis : inflammation versus degeneration.
AB  - Axonal loss, already present in the acute and first relapse phases of
      experimental allergic encephalomyelitis (EAE) in the ABH mouse, only becomes
      apparent in the third relapse in the interleukin-12 model of relapsing EAE in the
      Lewis rat. Caspase-1 immunostaining in the spinal cord of Lewis rats was mainly
      localized to inflammatory cuffs with the greatest proportion of active caspase-1
      positive cells detected during the first and second relapses, correlating with
      enzyme activity and protein on Western blots. However, in the spinal cord of ABH
      mice during acute EAE, caspase-1 immunostaining was localized both on
      inflammatory and neuronal cells, again correlating with enzyme activity and
      protein production. In contrast, caspase-3 expression in the spinal cord of Lewis
      rats did not increase significantly until the third relapse when inflammatory and
      neuronal cells and axons became positive in line with a significant increase in
      caspase activity. In ABH mice active caspase-3 was already immunolocalized on
      axons and apoptotic neurons in the spinal cord during the acute stage of EAE.
      Because caspase-3 is a downstream cell death signal it may be possible to reduce
      apoptosis by selectively blocking caspase-3 and therefore provide a therapeutic
      target for EAE and potentially, multiple sclerosis.

PMID- 12414507
TI  - Expression profiling of synovial sarcoma by cDNA microarrays: association of
      ERBB2, IGFBP2, and ELF3 with epithelial differentiation.
AB  - Synovial sarcoma is an aggressive spindle cell sarcoma with two major
      histological subtypes, biphasic and monophasic, defined respectively by the
      presence or absence of areas of glandular epithelial differentiation. It is
      characterized by a specific chromosomal translocation, t(X;18)(p11.2;q11.2),
      which juxtaposes the SYT gene on chromosome 18 to either the SSX1 or the SSX2
      gene on chromosome X. The chimeric SYT-SSX products are thought to function as
      transcriptional proteins that deregulate gene expression, thereby providing a
      putative oncogenic stimulus. We investigated the pattern of gene expression in
      synovial sarcoma using cDNA microarrays containing 6548 sequence-verified human
      cDNAs. A tissue microarray containing 37 synovial sarcoma samples verified to
      bear the SYT-SSX fusion was constructed for complementary analyses. Gene
      expression analyses were performed on individual tumor samples; 14 synovial
      sarcomas, 4 malignant fibrous histiocytomas, and 1 fibrosarcoma. Statistical
      analysis showed a distinct expression profile for the group of synovial sarcomas
      as compared to the other soft tissue sarcomas, which included variably high
      expression of ERBB2, IGFBP2, and IGF2 in the synovial sarcomas.
      Immunohistochemical analysis of protein expression in tissue microarrays of 37
      synovial sarcomas demonstrated strong expression of ERBB2 and IGFBP2 in the
      glandular epithelial component of biphasic tumors and in solid epithelioid areas
      of some monophasic tumors. Fluorescence in situ hybridization analysis indicated
      that the ERBB2 overexpression was not because of gene amplification.
      Differentially expressed genes were also found in a comparison of the expression
      profiles of the biphasic and monophasic histological subgroups of synovial
      sarcoma, notably several keratin genes, and ELF3, an epithelial-specific
      transcription factor gene. Finally, we also noted differential overexpression of
      several neural- or neuroectodermal-associated genes in synovial sarcomas relative
      to the comparison sarcoma group, including OLFM1, TLE2, CNTNAP1, and DRPLA. Our
      high-throughput studies of gene expression patterns, complemented by tissue
      microarray studies, confirm the distinctive expression profile of synovial
      sarcoma, provide leads for the study of glandular morphogenesis in this tumor,
      and identify a new potential therapeutic target, ERBB2, in a subset of cases.

PMID- 12414508
TI  - Up-regulation of connexin43 in glomerular podocytes in response to injury.
AB  - Podocyte injury or podocyte loss in the renal glomerulus has been proposed as the
      crucial mechanism in the development of focal segmental glomerulosclerosis.
      However, it is poorly understood how podocytes respond to injury. In this study,
      glomerular expression of connexin43 (Cx43) gap junction protein was examined at
      both protein and transcript levels in an experimental model of podocyte injury,
      puromycin aminonucleoside (PAN) nephrosis. A striking increase in the number of
      immunoreactive dots with anti-Cx43 antibody was demonstrated along the glomerular
      capillary wall in the early to nephrotic stage of PAN nephrosis. The conspicuous
      change was not detected in the other areas including the mesangium and Bowman's
      capsule. Immunoelectron microscopy showed that the immunogold particles for Cx43
      along the capillary wall were localized predominantly at the cell-cell contact
      sites of podocytes. Consistently, Western blotting and ribonuclease protection
      assay revealed a distinct increase of Cx43 protein, phosphorylation, and
      transcript in glomeruli during PAN nephrosis. The changes were detected by 6
      hours after PAN injection. These findings indicate that the increase of Cx43
      expression is one of the earliest responses that have ever been reported in
      podocyte injury. To show the presence of functional gap junctional intercellular
      communication (GJIC) in podocytes, GJIC was assessed in podocytes in the primary
      culture by transfer of fluorescent dye, Lucifer yellow, after a single-cell
      microinjection. Diffusion of the dye into adjacent cells was observed frequently
      in the cultured podocytes, but scarcely in cultured parietal epithelial cells of
      Bowman's capsule, which was compatible with their Cx43 staining. Thus, it is
      concluded that Cx43-mediated GJIC is present between podocytes, suggesting that
      podocytes may respond to injury as an integrated epithelium on a glomerulus
      rather than individually as a separate cell.

PMID- 12414509
TI  - Intercellular adhesion molecule-1 and L-selectin regulate bleomycin-induced lung
      fibrosis.
AB  - The development of bleomycin-induced lung injury, a model of pulmonary fibrosis,
      results from inflammatory cell infiltration, a process highly regulated by the
      expression of multiple adhesion molecules. At present, the identity and role of
      the adhesion molecules involved in the fibrotic process are unknown. Therefore,
      bleomycin-induced pulmonary fibrosis was examined in mice lacking L-selectin (L
      selectin(-/-)) expression, intercellular adhesion molecule-1 (ICAM-1) expression,
      or both. After 16 days of intratracheal bleomycin challenge, collagen deposition
      was inhibited in both L-selectin(-/-) and ICAM-1(-/-) mice when compared with
      wild-type littermates. Interestingly, collagen deposition was virtually
      eliminated in L-selectin/ICAM-1(-/-) mice relative to either the L-selectin(-/-)
      or ICAM-1(-/-) mice. Decreased pulmonary fibrosis was associated with reduced
      accumulation of leukocytes, including neutrophils and lymphocytes. Decreased mRNA
      expression of proinflammatory cytokines and transforming growth factor (TGF)
      beta1 paralleled the inhibition of collagen deposition. The present study
      indicates that L-selectin and ICAM-1 play a critical role in pulmonary fibrosis
      by mediating the accumulation of leukocytes, which regulate the production of
      proinflammatory cytokines and TGF-beta1. This suggests that these adhesion
      molecules are potential therapeutic targets for inhibiting human pulmonary
      fibrosis.

PMID- 12414510
TI  - Proliferation, but not apoptosis, is associated with distinct beta-catenin
      expression patterns in non-small-cell lung carcinomas: relationship with
      adenomatous polyposis coli and G(1)-to S-phase cell-cycle regulators.
AB  - beta-catenin (beta-cat) is a versatile component of homotypic cell adhesion and
      signaling. Its subcellular localization and cytoplasmic levels are tightly
      regulated by the adenomatous polyposis coli (APC) protein. Mutations in beta-cat
      (exon 3) or APC (MCR) result in beta-cat aberrant overexpression that is
      associated with its nuclear accumulation and improper gene activation. Data from
      experimental models have shown that beta-cat overexpression has a multitude of
      effects on cell-cycle behavior. In many of these aspects its function depends on
      major G(1) phase regulators. To the best of our knowledge, most of these issues
      have never been addressed concurrently in tumors. For this reason we investigated
      in a panel of 92 non-small-cell lung carcinomas, beta-cat and APC expression, and
      their relationship with cell-cycle kinetics (PI and AI) and ploidy status.
      Moreover, the above correlations were examined in relation to the main G(1)/S
      phase checkpoint regulators. Four beta-cat immunohistochemical expression
      patterns [membranous (11.1%), membranous-cytoplasmic (54.3%), cytoplasmic (9.9%),
      cytoplasmic-nuclear (24.7%)] and three APC immunohistochemical expression
      patterns [cytoplasmic (37.7%), cytoplasmic-nuclear (58%), nuclear (4.3%)] were
      observed, which were further confirmed by Western blot analysis on subcellular
      fractions in representative samples. The frequent presence of beta-cat in the
      cytoplasm is an indication of aberrant expression, whereas membranous and nuclear
      localization were inversely related. Absence of mutations in beta-cat (exon 3)
      and APC (MCR) suggest that beta-cat destruction mechanisms may be functional.
      However, expression analysis revealed attenuated levels for APC, indicating a
      residual ability to degrade beta-cat. Decreased levels were associated with loss
      of heterozygosity at the APC region in 24% of the cases suggesting that
      additional silencing mechanisms may be involved. Interestingly, the 90-kd APC
      isoform associated with apoptosis, was found to be the predominant isoform in
      normal and cancerous lung tissues. The most important finding in our study, was
      the correlation of nuclear beta-cat immunohistochemical localization with
      increased proliferation, overexpression of E2F1 and MDM2, aberrant p53, and low
      expression of p27(KIP), providing for the first time in vivo evidence that beta
      cat-associated proliferation correlates with release of E2F1 activity and loss of
      p53- and p27(KIP)-dependent cell-cycle checkpoints. Loss of these checkpoints is
      accompanied by low levels of APC, which possibly reflects a diminished ability to
      degrade beta-cat. Taken together our data indicate that cases with nuclear beta
      cat immunohistochemical expression represent a subset of non-small-cell lung
      carcinomas that have gained an increased proliferation advantage in contrast to
      the other beta-cat immunohistochemical expression profiles.

PMID- 12414511
TI  - Chromosomal gains at 9q characterize enteropathy-type T-cell lymphoma.
AB  - Genetic alterations in enteropathy-type T-cell lymphoma (ETL) are unknown so far.
      In this series, 38 cases of ETL were analyzed by comparative genomic
      hybridization (CGH). CGH revealed chromosomal imbalances in 87% of cases
      analyzed, with recurrent gains of genetic material involving chromosomes 9q (in
      58% of cases), 7q (24%), 5q (18%), and 1q (16%). Recurrent losses of genetic
      material occurred on chromosomes 8p and 13q (24% each), and 9p (18%). In this
      first systematic genetic study on ETL, chromosomal gains on 9q (minimal
      overlapping region 9q33-q34) were found to be highly characteristic of ETL.
      Fluorescence in situ hybridization analysis on four cases of ETL, using a probe
      for 9q34, indicated frequent and multiple gains of chromosomal material at 9q34
      (up to nine signals per case). Among 16 patients with ETL who survived initial
      disease presentation, patients with more than three chromosomal gains or losses
      (n = 11) followed a worse clinical course than those with three or less
      imbalances (n = 5). The observation of similar genetic alterations in ETL and in
      primary gastric (n = 4) and colonic (n = 1) T-cell lymphoma, not otherwise
      specified, is suggestive of a genetic relationship of gastrointestinal T-cell
      lymphomas at either localization.

PMID- 12414512
TI  - Up-regulated caveolin-1 accentuates the metastasis capability of lung
      adenocarcinoma by inducing filopodia formation.
AB  - Caveolin-1, a 21- to 24-kd integral membrane protein, is primarily implicated as
      a tumor suppressor gene. Transformed cells normally contain reduced or no
      caveolin-1. Re-expression of caveolin-1 is found in advanced human and mouse
      prostate adenocarcinomas. To explore its potential role in tumorigenesis and
      tumor progression of human lung cancers, we used the well-characterized cell line
      (CL) series of lung adenocarcinoma cells with increasing cellular invasiveness to
      show that expression of caveolin-1 mRNA and protein was up-regulated with
      enhanced invasion/metastatic capability of CL cells. Reintroducing the caveolin-1
      gene into the less invasive, caveolin-1-negative CL cells enhanced their invasive
      capability at least by twofold, as revealed by an in vitro chamber invasion
      assay. Thus, a correlation exists for both constitutive and induced expression of
      caveolin-1 in CL cells. Immunohistochemical examination of caveolin-1 was
      performed in 95 specimens obtained retrospectively from patients who had lung
      adenocarcinoma either with (35 patients) or without (60 patients) ipsilateral
      hilar/peribronchial tumor-metastasized lymph nodes. Caveolin-1 immunoreactivity
      was either totally absent or just barely detectable in a few lung adenocarcinoma
      cells from cases diagnosed as lung adenocarcinoma without regional lymph node
      metastasis. In contrast, increased caveolin-1 immunoreactivity both in number and
      intensity was detected in primary lung adenocarcinoma cells as well as in cancer
      cells that metastasized to regional lymph nodes from the cases diagnosed as
      advanced lung adenocarcinoma with nodal metastases. Multivariate analysis
      considering caveolin-1 immunoreactivity in addition to the established prognostic
      parameters such as pT stage, pN in these patients confirmed that caveolin-1 is an
      independent functional predictor of poor survival. We further revealed that up
      regulated caveolin-1 in CL cells is necessary for mediating filopodia formation,
      which may enhance the invasive ability of lung adenocarcinoma cells.

PMID- 12414513
TI  - Expression and regulation of CD97 in colorectal carcinoma cell lines and tumor
      tissues.
AB  - The expression of CD97, a member of the EGF-TM7 family with adhesive properties,
      is proportional to the aggressiveness and lymph node involvement in thyroid
      tumors. CD97 has never been systematically investigated in other tumors. First,
      we examined colorectal carcinoma cell lines (n = 18) for CD97 expression and
      regulation. All cell lines were CD97-positive. The level of CD97 in each line
      correlated with migration and invasion in vitro. This result was confirmed in
      CD97-inducible Tet-off HT1080 cells. Transforming growth factor-beta, which
      inhibits proliferation in transforming growth factor-beta-sensitive LS513 and
      LS1034 cells, down-regulated CD97 in these cell lines. Examining CD97 during
      sodium butyrate-induced cell differentiation of Caco-2 cells, we could
      demonstrate a CD97-decreasing effect. Second, we screened 81 colorectal
      adenocarcinomas by immunohistology for expression of CD97. Normal colorectal
      epithelium is CD97-negative. Seventy-five of 81 of the carcinomas expressed CD97.
      The strongest staining for CD97 occurred in scattered tumor cells at the invasion
      front compared to cells located within solid tumor formations of the same tumor.
      Carcinomas with more strongly CD97-stained scattered tumor cells showed a poorer
      clinical stage as well as increased lymph vessel invasion compared to cases with
      uniform CD97 staining. In summary, CD97 expression correlates with
      dedifferentiation, migration, and invasion in colorectal tumor cell lines.
      Moreover, more strongly CD97-stained tumor cells at the invasion front of
      colorectal carcinomas indicate the involvement of the molecule in tumor migration
      and invasion.

PMID- 12414514
TI  - Constitutive retinal CD200 expression regulates resident microglia and activation
      state of inflammatory cells during experimental autoimmune uveoretinitis.
AB  - Recent evidence supports the notion that tissue OX2 (CD200) constitutively
      provides down-regulatory signals to myeloid-lineage cells via CD200-receptor
      (CD200R). Thus, mice lacking CD200 (CD200(-/-)) show increased susceptibility to
      and accelerated onset of tissue-specific autoimmunity. In the retina there is
      extensive expression of CD200 on neurons and retinal vascular endothelium. We
      show here that retinal microglia in CD200(-/-) mice display normal morphology,
      but unlike microglia from wild-type CD200(+/+) mice are present in increased
      numbers and most significantly, express inducible nitric oxide synthase (NOS2), a
      macrophage activation marker. Onset and severity of uveitogenic peptide (1-20) of
      interphotoreceptor retinoid-binding protein-induced experimental autoimmune
      uveoretinitis is accelerated in CD200(-/-) mice and although tissue destruction
      appears no greater than seen in CD200(+/+) mice, there is continued increased
      ganglion and photoreceptor cell apoptosis. Myeloid cell infiltrate was increased
      in CD200(-/-) mice during experimental autoimmune uveoretinitis, although NOS2
      expression was not heightened. The results indicate that the CD200:CD200R axis
      regulates retinal microglial activation. In CD200(-/-) mice the release of
      suppression of tonic macrophage activation, supported by increased NOS2
      expression in the CD200(-/-) steady state accelerates disease onset but without
      any demonstration of increased target organ/tissue destruction.

PMID- 12414515
TI  - Immunosuppressive treatment protects against angiotensin II-induced renal damage.
AB  - Angiotensin (Ang) II promotes renal infiltration by immunocompetent cells in
      double-transgenic rats (dTGRs) harboring both human renin and angiotensinogen
      genes. To elucidate disease mechanisms, we investigated whether or not
      dexamethasone (DEXA) immunosuppression ameliorates renal damage. Untreated dTGRs
      developed hypertension, renal damage, and 50% mortality at 7 weeks. DEXA reduced
      albuminuria, renal fibrosis, vascular reactive oxygen stress, and prevented
      mortality, independent of blood pressure. In dTGR kidneys, p22phox immunostaining
      co-localized with macrophages and partially with T cells. dTGR dendritic cells
      expressed major histocompatibility complex II and CD86, indicating maturation.
      DEXA suppressed major histocompatibility complex II+, CD86+, dendritic, and T
      cell infiltration. In additional experiments, we treated dTGRs with mycophenolate
      mofetil to inhibit T- and B-cell proliferation. Reno-protective actions of
      mycophenolate mofetil and its effect on dendritic and T cells were similar to
      those obtained with DEXA. We next investigated whether or not Ang II directly
      promotes dendritic cell maturation in vitro. Ang II did not alter CD80, CD83, and
      MHC II expression, but increased CCR7 expression and cell migration. To explore
      the role of tumor necrosis factor (TNF)-alpha on dendritic cell maturation in
      vivo, we treated dTGRs with the soluble TNF-alpha receptor etanercept. This
      treatment had no effect on blood pressure, but decreased albuminuria, nuclear
      factor-kappaB activation, and infiltration of all immunocompetent cells. These
      data suggest that immunosuppression prevents dendritic cell maturation and T-cell
      infiltration in a nonimmune model of Ang II-induced renal damage. Ang II induces
      dendritic migration directly, whereas in vivo TNF-alpha is involved in dendritic
      cell infiltration and maturation. Thus, Ang II may initiate events leading to
      innate and acquired immune response.

PMID- 12414516
TI  - Differentiation between high- and low-grade astrocytoma using a human recombinant
      antibody to the extra domain-B of fibronectin.
AB  - Different fibronectin (FN) isoforms are generated by the alternative splicing of
      the primary FN transcript. We previously demonstrated that the isoform containing
      the extra domain B sequence of fibronectin (B-FN), a complete type-III-homology
      repeat, is a marker of angiogenesis that accumulates around neovasculature only
      during angiogenic processes. We produced a single-chain human recombinant
      antibody (scFv), L19, which reacts specifically with B-FN and selectively targets
      tumor vasculature in vivo. We used this scFv and an antibody against a pan
      endothelial marker (Factor VIII) in a double-staining procedure on specimens of
      low- and high-grade astrocytomas to determine the percentage of B-FN-positive
      vessels, (denominating the resulting value angiogenic index [AI]). Compared to
      vascular density and proliferative activity (evaluated using antibodies to Factor
      VIII and Ki67, respectively), AI correlated better with tumor grade (1.6 +/- 2.6%
      and 92.0 +/- 8.7% of B-FN-positive vessels in low- and high-grade astrocytomas,
      respectively) and was a more precise diagnostic tool than either of the two
      conventional methods. In fact, discriminating analysis using these three
      parameters showed that only AI accurately classified 100% of the cases studied,
      compared to 64% and 89% correctly diagnosed by vascular density and of
      proliferating cells, respectively.

PMID- 12414517
TI  - Involvement of the mural thrombus as a site of protease release and activation in
      human aortic aneurysms.
AB  - Acquired abdominal aortic aneurysms are usually associated with a mural thrombus
      through which blood continues to flow. Some early data suggest that aneurysmal
      evolution correlates with the biological activity of the thrombus. Our hypothesis
      was therefore that the thrombus could adsorb blood components and store, release,
      and participate in the activation of proteases involved in aneurysmal evolution.
      For this purpose, we have explored both the metalloproteinase and fibrinolytic
      systems in the thrombus and the wall of human aneurysms. We have first
      investigated blood clot formation and lysis in vitro. Spontaneous clotting
      induces a release of promatrix metalloproteinase (pro-MMP)-9 into the serum that
      was fourfold higher than in paired control plasma (P < 0.001). Fibrinolysis
      progressively released more MMP-9 in a time-dependent manner (P < 0.01). After
      selective isolation, we demonstrated that polymorphonuclear leukocytes are the
      main source of MMP-9 release during clot formation. Protease content was then
      analyzed in 35 mural thrombi and walls of human abdominal aortic aneurysms
      sampled during surgical repair. In 15 aneurysms, the liquid phase at the
      interface between the thrombus and the wall was sampled separately. Both thrombus
      and wall contained MMP-2 and MMP-9 but the ratio MMP-9/MMP-2 was higher in the
      thrombus than in the wall. The liquid interface also contained active MMP-9.
      Immunohistochemistry of the thrombus confirmed these findings, showing the
      presence of polymorphonuclear leukocytes at the luminal pole of the thrombus, co
      localizing with MMP-9 storage. In contrast, MMP-3 and MMP-7 were only present in
      the aneurysmal wall. Plasminogen was present in the mural thrombus but plasmin
      activity was present in both thrombus and wall. In the liquid interface, plasmin
      alpha(2)-anti-plasmin complexes were detected demonstrating in vivo the
      activation of plasminogen. In contrast, u-PA and t-PA were detectable only in the
      wall, suggesting that plasminogen present in the thrombus could be activated by
      factors secreted by the arterial wall. This was demonstrated in vitro, in which
      co-incubation of thrombus and wall extracts generated plasmin in the presence of
      a fibrin matrix and activated MMPs. In conclusion, our study strongly suggests
      that the mural thrombus, by trapping polymorphonuclear leukocytes and adsorbing
      plasma components could act as a source of proteases in aneurysms that may play a
      critical role in enlargement and rupture.

PMID- 12414518
TI  - Tau assembly in inducible transfectants expressing wild-type or FTDP-17 tau.
AB  - Conditional expression systems for 4-repeat wild-type (WT) tau or the
      corresponding mutants V337M and R406W were established in human neuroglioma H4
      cells to study the effect of tau mutations on the physicochemical properties of
      tau, and to develop a cellular model for the formation of filamentous tau
      characteristic of frontotemporal dementia with parkinsonism linked to chromosome
      17 (FTDP-17) and Alzheimer's disease. Upon induction tau expression increased,
      reaching maximal levels at 5 to 7 days. WT tau was phosphorylated at amino acids
      T181, S202/T205, T231, and S396/S404. The R406W mutation decreased tau
      phosphorylation at each of these sites as did the V337M mutation except for
      S396/S404 sites that increased. Most tau in postnuclear cell lysates was
      recovered in the supernatant fraction after centrifugation at 200,000 x g. The
      amount of tau in the pellet fraction increased more in mutant transfectants
      compared to WT when the induction was extended beyond 5 days. This particulate
      tau could be partially extracted with salt, Triton X-100, or sarkosyl. Of the
      transfectants, R406W had the highest proportion of sarkosyl-insoluble tau by day
      7. This insoluble fraction was thioflavin S-positive and contained 15- to 5-nm
      wide filaments with tau immunoreactivities. The R406W filaments were more
      abundant than those detected in similar preparations from WT or V337M
      transfectants. At the light microscopy level, most tau was found with
      microtubules, or diffusely distributed in the cytoplasm, but none of this
      appeared thioflavin S-positive. The results suggest that conditional tau
      transfectants are in a pretangle stage making them an attractive model system for
      studying intracellular tangle accumulation and for testing potential therapeutic
      agents as inhibitors for tau aggregation.

PMID- 12414519
TI  - Smad4 overexpression causes germ cell ablation and leydig cell hyperplasia in
      transgenic mice.
AB  - Members of the transforming growth factor-beta (TGF-beta) superfamily play a
      variety of important roles in testicular development and function. The tumor
      suppressor gene, Smad4, is a common mediator of TGF-beta, activin, and bone
      morphogenetic protein-mediated signaling pathways. To investigate the role of the
      Smad4 gene during testicular development and function, transgenic mice were
      generated using a Flag-tagged Smad4 gene driven by 180-bp fragment of the
      Mullerian inhibiting substance upstream promoter sequence. Three Smad4 transgenic
      founders (A, B, and G) were detected by Southern blot analysis; line B showed the
      highest expression of the Smad4 transgene and was further studied. The fertility
      in F1 generation (B) and F2 generation (BB) of the Smad4 transgenic mice was not
      impaired. However, in the F3 generation (B2x) all animals were impacted by the
      overexpression of the Smad4 transgene and two kinds of phenotypes were observed.
      In one group animals were completely infertile, while in the other group animals
      were fertile and sired the normal number of pups/litter. These groups are
      designated as infertile and fertile in the text. Histological evaluation of the
      testes from the infertile group showed variable degrees of Leydig cell
      hyperplasia, apoptosis of germ cells, spermatogenic arrest, seminiferous tubule
      degeneration, and infertility. In the fertile group, there was no apparent change
      in the histology of the testis except for a slight increase in the number of
      Leydig cells. Serum follicle-stimulating hormone levels in the adult animals of
      both groups of Smad4 transgenic male mice were not significantly different from
      normal littermates; however, testosterone levels in both groups were
      significantly (P < 0.05) increased. These results suggest that overexpression of
      Smad4 leads to testicular abnormalities and infertility supporting the hypothesis
      that the TGF-beta signaling pathways are carefully orchestrated during testicular
      development. In the absence of normal levels of Smad4 testicular function is
      compromised.

PMID- 12414520
TI  - Sporadic fundic gland polyps with epithelial dysplasia : evidence for
      preferential targeting for mutations in the adenomatous polyposis coli gene.
AB  - Gastric fundic gland polyps (FGPs) occur in two distinct clinicopathological
      scenarios: sporadic and familial adenomatous polyposis (FAP) associated. FAP
      associated FGPs arise through somatic second hit alterations of the adenomatous
      polyposis coli (APC) gene and frequently demonstrate epithelial dysplasia (Am J
      Pathol 2000, 157:747-754). Sporadic FGPs, in contrast, tend to contain beta
      catenin gene mutations and only infrequently show dysplasia (Am J Pathol 2001,
      158:1005-1010). However, sporadic FGPs with dysplasia have not been previously
      investigated. We studied 13 sporadic FGPs with surface/foveolar low-grade
      dysplasia or changes indefinite for dysplasia for alterations in the APC/beta
      catenin pathway, using chromosome 5q allelic loss assays and direct DNA
      sequencing of the mutation cluster region in exon 15 of APC and the
      phosphorylation region in exon 3 of beta-catenin. In addition, to evaluate for
      possible additional genetic alterations in FGPs, all cases were evaluated for
      microsatellite instability using fluorescent-based amplification of a standard
      panel of five microsatellite markers. Alterations in APC were present in seven
      (53.8%) FGPs, including two cases with bi-allelic APC inactivation (truncating
      intragenic mutation plus 5q allelic loss), two cases with APC mutation only, and
      three cases with 5q allelic loss only. In contrast, only two (15.4%) FGPs
      contained stabilizing beta-catenin mutations. All 13 FGPs were microsatellite
      stable. These results indicate that sporadic FGPs with dysplasia/indefinite for
      dysplasia are molecularly similar to FAP-associated FGPs, and are dissimilar to
      the more common sporadic nondysplastic FGPs. Mutations in APC and beta-catenin,
      despite occurring in the same genetic pathway, show differing biological
      properties, a phenomenon that has previously been demonstrated in colorectal
      neoplasms. The lack of microsatellite instability in FGPs in this study and of K
      ras mutations in a previous study suggests that secondary genetic alterations are
      rare in both dysplastic and nondysplastic FGPs.

PMID- 12414521
TI  - Changes in differential gene expression because of warm ischemia time of radical
      prostatectomy specimens.
AB  - The expression of thousands of genes can be monitored simultaneously using cDNA
      microarray technology. This technology is being used to understand the complexity
      of human disease. One significant technical concern regards potential alterations
      in gene expression because of the effect of tissue ischemia. This study evaluates
      the increase in the differential gene expression because of tissue processing
      time. To evaluate differential gene expression because of ischemia time, prostate
      samples were divided into five time points (0, 0.5, 1, 3, and 5 hours). Each time
      point consisted of a homogeneous mixture of 12 to 15 prostate tissue cubes (5
      mm(3)). These tissues were maintained at room temperature until at the assigned
      time point the tissue was placed in OCT, flash frozen in liquid nitrogen, and
      stored at -80 degrees C until RNA extraction. RNA from each time point was
      hybridized against an aliquot of 0 time point RNA from the same prostate. Four
      prostate glands were used in parallel studies. M-A plots were graphed to compare
      variability between time point sample hybridizations. Statistical Analysis of
      Microarray software was used to identify genes overexpressed at the 1-hour time
      point versus the 0-hour time with statistically significance. Microarray analysis
      revealed only a small percentage of genes (<0.6%) from more than 9000 to
      demonstrate overexpression at the 1-hour time point. Among the 41 statistically
      significant named overexpressed genes at the 1-hour time point were early growth
      response 1 (EGR1), jun B proto-oncogene (jun B), jun D proto-oncogene (jun D),
      and activating transcription factor 3 (ATF3). Genes previously associated with
      prostate cancer did not have significantly altered expression with ischemia time.
      Increased EGR1 protein expression was confirmed by Western blot analysis.
      Microarray technology has opened the possibility of evaluating the expression of
      a multitude of genes simultaneously, however, the interpretation of this complex
      data needs to be assessed circumspectly using refined statistical methods.
      Because RNA expression represents the tissue response to insults such as
      ischemia, and is also sensitive to degradation, investigators need be mindful of
      confounding artifacts secondary to tissue processing. All attempts should be made
      to process tissue rapidly to ensure that the microarray gene profile accurately
      represents the state of the cells and confirmatory studies should be performed
      using alternative methods (eg, Northern blot analysis, Western blot,
      immunohistochemistry).

PMID- 12414522
TI  - Guanylate-binding protein-1 expression is selectively induced by inflammatory
      cytokines and is an activation marker of endothelial cells during inflammatory
      diseases.
AB  - During angiogenesis and inflammatory processes, endothelial cells acquire
      different activation phenotypes, whose identification may help in understanding
      the complex network of angiogenic and inflammatory interactions in vivo. To this
      goal we investigated the expression of the human guanylate-binding protein (GBP)
      1 that is highly induced by inflammatory cytokines (ICs) and, therefore, may
      characterize IC-activated cells. Using a new rat monoclonal antibody raised
      against GBP-1, we show that GBP-1 is a cytoplasmic protein and that its
      expression in endothelial cells is selectively induced by interferon-gamma,
      interleukin-1alpha, interleukin-1beta, or tumor necrosis factor-alpha, but not by
      other cytokines, chemokines, or growth factors. Moreover, we found that GBP-1
      expression is highly associated with vascular endothelial cells as confirmed by
      the simultaneous detection of GBP-1 and the endothelial cell-associated marker
      CD31 in a broad range of human tissues. Notably, GBP-1 expression was
      undetectable in the skin, but it was highly induced in vessels of skin diseases
      with a high-inflammatory component including psoriasis, adverse drug reactions,
      and Kaposi's sarcoma. These results indicate that GBP-1 is a novel cellular
      activation marker that characterizes the IC-activated phenotype of endothelial
      cells.

PMID- 12414523
TI  - Gene transfer of human hepatocyte growth factor into rat skin wounds mediated by
      liposomes coated with the sendai virus (hemagglutinating virus of Japan).
AB  - Hepatocyte growth factor (HGF) regulates cell growth, cell motility, and
      morphogenesis in various types of cells, including epithelial and endothelial
      cells, indicating that it probably promotes epithelial repair and
      neovascularization during wound healing. To better understand the effects of HGF
      on wound healing, we performed human HGF-gene transfer into skin wounds in rats.
      The rat HGF mRNA levels, and human and rat HGF protein concentrations in the
      wounds in HGF gene-transfer rats were significantly elevated at 3 days, 3 to 14
      days, and 3 and 14 days after gene transfer, respectively. An expression of human
      HGF mRNA and protein was revealed in squamous cells in the epidermis, in
      endothelial cells and smooth muscle cells in blood vessels, and in fibroblasts in
      granulation tissues at 3, 7, and 14 days after gene transfer in HGF gene-transfer
      rats. The wound lesion area in HGF gene-transfer rats was significantly less than
      that in control rats from 3 to 7 days after gene transfer. The re
      epithelialization rate, microvessel counts in granulation tissues, proliferating
      cell nuclear antigen index of fibroblasts in granulation tissues, and the
      proliferating cell nuclear antigen index in the epidermis of HGF gene-transfer
      rats were significantly increased at 3 and 7 days after gene transfer.
      Semiquantitative reverse transcriptase-polymerase chain reaction revealed that
      the expression levels of transforming growth factor-beta1 and Colalpha2(I) mRNAs
      in the wounds of HGF gene-transfer rats were significantly decreased at 7 and 14
      days, respectively. The hydroxyproline concentration in the wound was
      significantly less in HGF gene-transfer rats than in control rats at 3 days after
      gene transfer. These results suggest that HGF gene transfer into a skin wound may
      aid re-epithelialization and neovascularization in the early phase of wound
      healing, and that HGF may play a role in modulating cutaneous wound healing.

PMID- 12414524
TI  - Aldosterone-induced inflammation in the rat heart : role of oxidative stress.
AB  - Heart failure and hypertension have each been linked to an induction of oxidative
      stress transduced by neurohormones, such as angiotensin II and catecholamines.
      Herein, we hypothesized that aldosterone (ALDO) likewise induces oxidative stress
      and accounts for a proinflammatory/fibrogenic phenotype that appears at vascular
      and nonvascular sites of injury found in both right and left ventricles in
      response to ALDO/salt treatment and that would be sustained with chronic
      treatment. Uninephrectomized rats received ALDO (0.75 micro g/hour) together with
      1% dietary NaCl, for 3, 4, or 5 weeks. Other groups received this regimen in
      combination with an ALDO receptor antagonist, spironolactone (200 mg/kg p.o.
      daily), or an antioxidant, either pyrrolidine dithiocarbamate (PDTC) (200 mg/kg
      s.c. daily) or N-acetylcysteine (NAC) (200 mg/kg i.p. daily). Unoperated and
      untreated age- and gender-matched rats served as controls. We monitored spatial
      and temporal responses in molecular and cellular events using serial, coronal
      sections of right and left ventricles. Our studies included: assessment of
      systolic blood pressure; immunohistochemical detection of NADPH oxidase
      expression and activity; analysis of redox-sensitive nuclear factor-kappaB
      activation; in situ localization of intercellular adhesion molecule-1, monocyte
      chemoattractant protein-1, and tumor necrosis factor-alpha mRNA expression;
      monitoring cell growth and infiltration of macrophages and T cells; and analysis
      of the appearance and quantity of fibrous tissue accumulation. At week 3 of
      ALDO/salt treatment and comparable to controls, there was no evidence of
      oxidative stress or pathological findings in the heart. However, at weeks 4 and 5
      of treatment, increased gp91(phox) and 3-nitrotyrosine expression and persistent
      activation of RelA were found in endothelial cells and inflammatory cells that
      appeared in the perivascular space of intramural coronary arteries and at sites
      of lost cardiomyocytes in both ventricles. Coincident in time and space with
      these events was increased mRNA expression of intercellular adhesion molecule-1,
      monocyte chemoattractant protein-1, and tumor necrosis factor-alpha. Macrophages,
      lymphocytes, and proliferating endothelial and vascular smooth muscle cells and
      fibroblast-like cells were seen at each of these sites, together with an
      accumulation of fibrillar collagen, or fibrosis, as evidenced by a significant
      increase in ventricular collagen volume fraction. Co-treatment with
      spironolactone, PDTC, or NAC attenuated these molecular and cellular responses as
      well as the appearance of fibrosis at vascular and nonvascular sites of injury.
      Furthermore, elevated systolic blood pressure in ALDO-treated rats was partially
      suppressed by spironolactone or either antioxidant. Thus, chronic ALDO/salt
      treatment is accompanied by a time-dependent sustained activation of NADPH
      oxidase with 3-nitrotyrosine generation and nuclear factor-kappaB activation
      expressed by endothelial cells and inflammatory cells. This leads to a
      proinflammatory/fibrogenic phenotype involving vascular and nonvascular sites of
      injury found, respectively, in both normotensive and hypertensive right and left
      ventricles. Spionolactone, PDTC, and NAC each attenuated these responses
      suggesting ALDO/salt induction of oxidative/nitrosative stress is responsible for
      the appearance of this proinflammatory phenotype.

PMID- 12414525
TI  - Fas and fas ligand are up-regulated in pulmonary edema fluid and lung tissue of
      patients with acute lung injury and the acute respiratory distress syndrome.
AB  - Apoptosis mediated by Fas/Fas ligand (FasL) interaction has been implicated in
      human disease processes, including pulmonary disorders. However, the role of the
      Fas/FasL system in acute lung injury (ALI) and in the acute respiratory distress
      syndrome (ARDS) is poorly defined. Accordingly, we investigated both the soluble
      and cellular expression of the Fas/FasL system in patients with ALI or ARDS. The
      major findings are summarized as follows. First, the soluble expression of the
      Fas/FasL system was assessed in undiluted pulmonary edema fluid and simultaneous
      plasma. Pulmonary edema fluid obtained from patients with ALI or ARDS (n = 51)
      had significantly higher concentrations of both soluble Fas (27 ng/ml; median; P
      < 0.05) and soluble FasL (0.125 ng/ml; P < 0.05) compared to control patients
      with hydrostatic pulmonary edema (n = 40; soluble Fas, 12 ng/ml; soluble FasL,
      0.080 ng/ml). In addition, the concentrations of both soluble Fas and soluble
      FasL were significantly higher in the pulmonary edema fluid of the patients with
      ALI or ARDS compared to simultaneous plasma samples (soluble Fas, 16 ng/ml;
      soluble FasL, 0.058 ng/ml; P < 0.05), indicating local release in the lung.
      Higher soluble Fas concentrations were associated with worse clinical outcomes.
      Second, cellular expression of the Fas/FasL system was assessed by
      semiquantitative immunofluorescence microscopy in lung tissue obtained at autopsy
      from a different set of patients. Both Fas and FasL were immunolocalized to a
      greater extent in the patients who died with ALI or ARDS (n = 10) than in the
      patients who died without pulmonary disease (n = 10). Both proteins were co
      expressed by epithelial cells that lined the alveolar walls, as well as by
      inflammatory cells and sloughed epithelial cells that were located in the air
      spaces. Semiquantitative immunohistochemistry showed that markers of apoptosis
      (terminal dUTP nick-end labeling, caspase-3, Bax, and p53) were more prevalent in
      alveolar wall cells from the patients who died with ALI or ARDS compared to the
      patients who died without pulmonary disease. These findings indicate that
      alveolar epithelial injury in humans with ALI or ARDS is in part associated with
      local up-regulation of the Fas/FasL system and activation of the apoptotic
      cascade in the epithelial cells that line the alveolar air spaces.

PMID- 12414526
TI  - Specific role of interleukin-1 in hepatic neutrophil recruitment after
      ischemia/reperfusion.
AB  - Hepatic ischemia/reperfusion injury is caused primarily by the products of
      neutrophils recruited into the liver after reperfusion. The mediators responsible
      for the development of this inflammatory response are thought to be tumor
      necrosis factor-alpha and interleukin (IL)-1. Although there is abundant evidence
      to support a role for tumor necrosis factor-alpha, much less is known about the
      function of IL-1 in this injury. In the present studies, we investigated whether
      IL-1 was a critical mediator for the induction of liver inflammation after
      ischemia/reperfusion. Wild-type and IL-1 receptor I-knockout (IL-1RI(-/-)) mice
      were exposed to 90 minutes of partial hepatic ischemia and up to 24 hours of
      reperfusion. In wild-type mice, IL-1beta expression was maximal after ischemia
      and 8 hours of reperfusion. At the same time, both wild-type and IL-1RI(-/-) mice
      had severe liver injury as assessed by serum alanine aminotransferase levels and
      hepatic histopathology. However, IL-1RI(-/-) mice had significantly less
      neutrophil accumulation in liver tissues as measured by liver myeloperoxidase
      content and histology. The reduction in hepatic neutrophil recruitment in IL-1RI(
      /-) mice was associated with decreased activation of the transcription factor,
      nuclear factor-kappaB, and reduced expression of the CXC chemokine, macrophage
      inflammatory protein-2. These data suggest that IL-1 functions to augment
      neutrophil accumulation, but does not play an essential role in this response.

PMID- 12414527
TI  - Aging accelerates endotoxin-induced thrombosis : increased responses of
      plasminogen activator inhibitor-1 and lipopolysaccharide signaling with aging.
AB  - Although older subjects are susceptible to thrombosis under septic conditions,
      the underlying molecular mechanisms have not been fully elucidated. Since
      elevated plasminogen activator inhibitor-1 (PAI-1) primarily contributes to
      endotoxin-induced thrombosis, we first compared the induction of PAI-1 by
      lipopolysaccharide (LPS) between young and aged mice. The higher induction of PAI
      1 antigen and mRNA with increased renal glomerular fibrin deposition was observed
      in LPS-treated aged mice compared to young mice. In situ hybridization analysis
      showed that the aging-associated induction of PAI-1 mRNA by LPS was pronounced in
      hepatocytes and in renal glomerular cells. The increased magnitude of the
      response of aged mice to lower doses of LPS was observed in terms of renal
      glomerular fibrin deposition and PAI-1 mRNA induction in the tissues.
      Furthermore, older PAI-1 deficient mice treated with LPS developed much less
      fibrin deposition in kidneys. Importantly, a larger induction of receptor
      molecules for LPS (eg, CD14 and Toll-like receptor 4) was demonstrated in LPS
      treated aged mice as compared with young mice. The enhanced LPS signaling in aged
      mice was also demonstrated by the marked induction of nuclear factor-kappaB in
      the tissues after endotoxin treatment. As a consequence, increases in an
      inflammatory cytokine, tumor necrosis factor-alpha, were pronounced in plasma and
      tissues of LPS-treated aged mice. These results emphasize the key role played by
      PAI-1 in aging-associated deterioration in this thrombosis model, and suggest
      that the hyperresponse of PAI-1 gene to LPS results from the enhanced LPS
      signaling and the subsequent inflammatory response in aged mice.

PMID- 12414528
TI  - Trapping of misdirected dendritic cells in the granulomatous lesions of giant
      cell arteritis.
AB  - Immature dendritic cells (DCs) are scattered throughout peripheral tissues and
      act as sentinels that sample the antigenic environment. After activation, they
      modify their chemokine receptor profile and migrate toward lymphoid tissues. On
      arrival, they have matured into chemokine-producing DCs that express co
      stimulatory molecules and can prime naive T cells. Normal temporal arteries
      contain immature DCs that are located at the media-adventitia border. In temporal
      arteries affected by giant cell arteritis, DCs are highly enriched and activated
      and have matured into fully differentiated cells producing the chemokines, CCL18,
      CCL19, and CCL21. In keeping with their advanced maturation, DCs in the
      granulomatous lesions possess the chemokine receptor, CCR7. CCR7 binds CCL19 and
      CCL21, causing the highly activated DCs to be trapped in the peripheral tissue
      site. The co-stimulatory molecule, CD86, which is critical for DC/T-cell
      interaction, is expressed by a subset of DCs captured in the arterial wall. DC/T
      cell interaction does not involve interleukin-12; transcripts for interleukin-12
      p40 are absent in the vasculitic infiltrates. We propose that differentiation of
      DCs and the autocrine and paracrine actions of chemokines in granulomatous
      lesions misdirect DCs away from their usual journey to lymphoid organs and are
      critical in maintaining T-cell activation and granuloma formation in giant cell
      arteritis.

PMID- 12414529
TI  - Identification of genes involved in resistance to interferon-alpha in cutaneous T
      cell lymphoma.
AB  - Interferon-alpha therapy has been shown to be active in the treatment of mycosis
      fungoides although the individual response to this therapy is unpredictable and
      dependent on essentially unknown factors. In an effort to better understand the
      molecular mechanisms of interferon-alpha resistance we have developed an
      interferon-alpha resistant variant from a sensitive cutaneous T-cell lymphoma
      cell line. We have performed expression analysis to detect genes differentially
      expressed between both variants using a cDNA microarray including 6386 cancer
      implicated genes. The experiments showed that resistance to interferon-alpha is
      consistently associated with changes in the expression of a set of 39 genes,
      involved in signal transduction, apoptosis, transcription regulation, and cell
      growth. Additional studies performed confirm that STAT1 and STAT3 expression and
      interferon-alpha induction and activation are not altered between both variants.
      The gene MAL, highly overexpressed by resistant cells, was also found to be
      expressed by tumoral cells in a series of cutaneous T-cell lymphoma patients
      treated with interferon-alpha and/or photochemotherapy. MAL expression was
      associated with longer time to complete remission. Time-course experiments of the
      sensitive and resistant cells showed a differential expression of a subset of
      genes involved in interferon-response (1 to 4 hours), cell growth and apoptosis
      (24 to 48 hours.), and signal transduction.

PMID- 12414530
TI  - Role of changes in tissular nucleotides on the development of apoptosis during
      ischemia/reperfusion in rat small bowel.
AB  - The aim of this study was to evaluate whether xanthine and adenosine, substances
      modified proportionally to the duration of ischemia, can determine cell demise
      (apoptosis/necrosis) during intestinal ischemia/reperfusion (I/R) and to
      determine the role of nitric oxide (NO) during this process. The following
      experimental groups were studied: I, cold ischemia; I+X, effect of xanthine; I+T,
      effect of adenosine (blocking its receptor by theophylline); I+A, effect of
      excess adenosine; I+T+X, effect of xanthine alone, and I+T+ spermine NONOate
      (NONOs), I+A+NONOs, I+X+NONOs, role of NO. DNA fragmentation, xanthine/adenosine
      levels, caspase-3 activity, NO generation, and histological analysis were
      measured in tissue samples. The rats treated with xanthine or adenosine showed
      increased levels of caspase-3 activity and DNA fragmentation. In contrast,
      theophylline-treated rats showed decreased levels of DNA fragmentation and tended
      to show lower mean values of caspase-3 activity. Administration of xanthine or
      NONOs to theophylline-treated rats reversed these effects. The results of
      histological evaluation were in agreement with these previous results. In
      conclusion, the present study indicates that xanthine and adenosine induced an
      apoptotic response during cold ischemic preservation of rat small intestine. In
      particular, the action of adenosine on apoptotic events was mediated by NO. We
      consider that identification of the role of these factors may help to define the
      best conditions of tissue preservation before intestinal transplantation.

PMID- 12414531
TI  - Generation of C5a by phagocytic cells.
AB  - The complement activation product, C5a, is a powerful phlogistic factor. Using
      antibodies to detect human or rat C5a, incubation at pH 7.4 of human blood
      neutrophils or rat alveolar macrophages (AMs) with C5 in the presence of phorbol
      12-myristate 13-acetate (PMA) led to generation of C5a. Rat AMs activated with
      lipopolysaccharide also generated C5a from C5. With activated neutrophils,
      extensive cleavage of C5 occurred, whereas activated macrophages had much more
      selective proteolytic activity for C5. Peripheral blood human or rat mononuclear
      cells and rat alveolar epithelial cells when stimulated with phorbol ester all
      failed to demonstrate an ability to cleave C5, suggesting a specificity of C5
      cleavage by phagocytic cells. With rat AMs, C5a generation was time-dependent and
      was blocked if AMs were pretreated with inhibitors of transcription or protein
      synthesis (actinomycin D or cycloheximide). Similar treatment of activated human
      polymorphonuclear leukocytes only partially reduced C5a generation after addition
      of C5. C5a generated by activated AMs was biologically (chemotactically) active.
      This generation was sensitive to serine protease inhibitors but not to other
      classes of inhibitors. These data indicate that phagocytic cells, especially lung
      macrophages, can generate C5a from C5. In the context of the lung, this may
      represent an important C5a-generating pathway that is independent of the plasma
      complement system.

PMID- 12414532
TI  - Comparative genomic hybridization pattern distinguishes T-cell/histiocyte-rich B
      cell lymphoma from nodular lymphocyte predominance Hodgkin's lymphoma.
AB  - Several lines of evidences suggest that T cell/histiocyte-rich B-cell lymphoma
      (T/HRBCL) represents an aggressive variant of the clinically indolent entity
      nodular lymphocyte predominance Hodgkin's lymphoma (LPHL). Still, this view has
      not yet been supported by firm genetic evidence. In this study, we analyzed 17
      T/HRBCL cases using comparative genomic hybridization (CGH) combined with
      microdissection of single CD20+ neoplastic cells and DNA amplification by
      degenerate oligonucleotide primed-polymerase chain reaction, an approach we
      previously used in LPHL. Genomic imbalances were detected in all cases (in total,
      80 changes). The most common imbalances included gain of Xq, 4q13q28, Xp21p11,
      and 18q21, and loss of 17p. Of note, a partial gain of 4q, a rare change in
      lymphoma, is also among the genomic imbalances most frequently encountered in
      LPHL. On the other hand, the CGH profiles of T/HRBCL and LPHL showed several
      distinct features, in particular with respect to the number of genomic imbalances
      (average of 4.7 in T/HRBCL versus 10.8 in LPHL) and their distribution (usually 1
      to 5 in T/HRBCL versus 6 to 22 in LPHL). Altogether, our CGH findings of shared
      as well as distinctive cytogenetic features in both diseases suggest that T/HRBCL
      constitutes a separate lymphoma entity, possibly originating from the same
      precursor cell as LPHL.

PMID- 12414533
TI  - Intraneuronal Alzheimer abeta42 accumulates in multivesicular bodies and is
      associated with synaptic pathology.
AB  - A central question in Alzheimer's disease concerns the mechanism by which beta
      amyloid contributes to neuropathology, and in particular whether intracellular
      versus extracellular beta-amyloid plays a critical role. Alzheimer transgenic
      mouse studies demonstrate brain dysfunction, as beta-amyloid levels rise, months
      before the appearance of beta-amyloid plaques. We have now used immunoelectron
      microscopy to determine the subcellular site of neuronal beta-amyloid in normal
      and Alzheimer brains, and in brains from Alzheimer transgenic mice. We report
      that beta-amyloid 42 localized predominantly to multivesicular bodies of neurons
      in normal mouse, rat, and human brain. In transgenic mice and human Alzheimer
      brain, intraneuronal beta-amyloid 42 increased with aging and beta-amyloid 42
      accumulated in multivesicular bodies within presynaptic and especially
      postsynaptic compartments. This accumulation was associated with abnormal
      synaptic morphology, before beta-amyloid plaque pathology, suggesting that
      intracellular accumulation of beta-amyloid plays a crucial role in Alzheimer's
      disease.

PMID- 12414534
TI  - Differential expression of the epithelial-mesenchymal transition regulators
      snail, SIP1, and twist in gastric cancer.
AB  - Epithelial-mesenchymal transition (EMT) involving down-regulation of E-cadherin
      is thought to play a fundamental role during early steps of invasion and
      metastasis of carcinoma cells. The aim of our study was to elucidate the role of
      EMT regulators Snail, SIP1 (both are direct repressors of E-cadherin), and Twist
      (an activator of N-cadherin during Drosophila embryogenesis), in primary human
      gastric cancers. Expression of Snail, SIP1, and Twist was analyzed in 48 gastric
      carcinomas by real-time quantitative RT-PCR in paraffin-embedded and formalin
      fixed tissues. The changes of expression levels of these genes in malignant
      tissues compared to matched non-tumorous tissues were correlated with the
      expression of E- and N-cadherin. From 28 diffuse-type gastric carcinomas analyzed
      reduced E-cadherin expression was detected in 11 (39%) cases compared to non
      tumorous tissues. Up-regulated Snail could be found in 6 cases with reduced or
      negative E-cadherin expression. However, there was no correlation to increased
      SIP1 expression. Interestingly, we could detect abnormal expression of N-cadherin
      mRNA in 6 cases, which was correlated with Twist overexpression in 4 cases. From
      20 intestinal-type gastric cancer samples reduced E-cadherin expression was found
      in 12 (60%) cases, which was correlated to up-regulation of SIP1, since 10 of
      these 12 cases showed elevated mRNA levels, whereas Snail, Twist, and N-cadherin
      were not up-regulated. We present the first study investigating the role of EMT
      regulators in human gastric cancer and provide evidence that an increase in Snail
      mRNA expression is associated with down-regulation of E-cadherin in diffuse-type
      gastric cancer. We detected abnormally positive or increased N-cadherin mRNA
      levels in the same tumors, probably due to overexpression of Twist. SIP1
      overexpression could not be linked to down-regulated E-cadherin in diffuse-type
      tumors, but was found to be involved in the pathogenesis of intestinal-type
      gastric carcinoma. We conclude that EMT regulators play different roles in
      gastric carcinogenesis depending on the histological subtype.

PMID- 12414535
TI  - Heparin inhibits phosphorylation and autonomous activity of Ca(2+)/calmodulin
      dependent protein kinase II in vascular smooth muscle cells.
AB  - Vascular smooth muscle cell (VSMC) hyperproliferation is a characteristic feature
      of both atherosclerosis and restenosis seen after vascular surgery. A number of
      studies have shown that heparin inhibits VSMC proliferation in vivo and in
      culture. To test our hypothesis that heparin mediates its antiproliferative
      effect by altering Ca(2+) regulated pathways involved in mitogenic signaling in
      VSMC, we analyzed the effect of heparin on multifunctional Ca(2+)/calmodulin
      dependent protein kinase II (CaM kinase II) which is abundantly expressed in
      VSMC. Using activity assays, radioactive labeling, and immunoprecipitation it was
      found that heparin inhibits the overall phosphorylation of the delta-subunit of
      CaM kinase II which is consistent with inhibition of autophosphorylation
      dependent, Ca(2+)/calmodulin-independent CaM kinase II activity. This effect was
      less evident in heparin-resistant cells, consistent with a role for CaM kinase II
      in mediating the antiproliferative effect of heparin. Finally, the effects of
      pharmacological inhibitors of phosphatases like okadaic acid, calyculin, and
      tautomycin suggest that heparin inhibits CaM kinase II phosphorylation by
      activating protein phosphatases 1 and 2A. These findings support the hypothesis
      that alterations in calcium-mediated mitogenic signaling pathways may be involved
      in the antiproliferative mechanism of action of heparin.

PMID- 12414536
TI  - Induction of intestinal inflammation in mouse by activation of proteinase
      activated receptor-2.
AB  - Proteinase-activated receptor (PAR)-2, a G-protein-coupled receptor for trypsin
      and mast cell tryptase, is highly expressed in the intestine. Luminal trypsin and
      tryptase are elevated in the colon of inflammatory bowel disease patients. We
      hypothesized that luminal proteinases activate PAR-2 and induce colonic
      inflammation. Mice received intracolonically PAR-2 agonists (trypsin, tryptase,
      and a selective PAR-2-activating peptide) or control drugs (boiled enzymes,
      inactive peptide) and inflammatory parameters were followed at various times
      after this treatment. Colonic administration of PAR-2 agonists up-regulated PAR-2
      expression and induced an inflammatory reaction characterized by granulocyte
      infiltration, increased wall thickness, tissue damage, and elevated T-helper cell
      type 1 cytokine. The inflammation was maximal between 4 and 6 hours and was
      resolved 48 hours after the intracolonic administration. PAR-2 activation also
      increased paracellular permeability of the colon and induced bacterial trans
      location into peritoneal organs. These proinflammatory and pathophysiological
      changes observed in wild-type mice were not detected in PAR-2-deficient mice.
      Luminal proteinases activate PAR-2 in the mouse colon to induce inflammation and
      disrupt the integrity of the intestinal barrier. Because trypsin and tryptase are
      found at high levels in the colon lumen of patients with Crohn's disease or
      ulcerative colitis, our data may bear directly on the pathophysiology of human
      inflammatory bowel diseases.

PMID- 12414537
TI  - Vascular endothelial growth factor immunoneutralization plus Paclitaxel markedly
      reduces tumor burden and ascites in athymic mouse model of ovarian cancer.
AB  - Ovarian cancer is characterized by rapid growth of solid intraperitoneal tumors
      and production of large volumes of ascites. Our previous studies of
      intraperitoneal ovarian carcinoma in an athymic mouse model demonstrated that a
      monoclonal antibody (mAb) to human vascular endothelial growth factor (VEGF)
      could prevent ascites formation. Although ascites was almost completely
      inhibited, tumor burden was variably reduced. To develop more effective therapy,
      we assessed the combination of a human VEGF mAb plus paclitaxel. Four groups of
      female athymic nude mice were inoculated intraperitoneally with OVCAR3 cells. Two
      weeks after inoculation, one group was treated with a human VEGF mAb
      intraperitoneally twice weekly plus paclitaxel intraperitoneally three times
      weekly for 6 weeks. The second group was treated with VEGF mAb alone. The third
      group was treated with paclitaxel alone. The remaining group was treated with
      vehicle only. Tumor burden in the VEGF mAb plus paclitaxel and paclitaxel alone
      groups was reduced by 83.3% and 85.7% and 58.5% and 59.5%, respectively, in two
      separate experiments, compared to controls. VEGF mAb alone caused no significant
      decrease in tumor burden, nor did treatment of mice inoculated intraperitoneally
      with HEY-A8 cells, a non-VEGF-secreting ovarian cell line. Virtually no ascites
      developed in the combined treatment group or the group treated with VEGF mAb
      alone. Paclitaxel alone reduced ascites slightly, but not significantly.
      Morphological studies demonstrated that VEGF immunoneutralization enhanced
      paclitaxel-induced apoptosis in these human ovarian cancers. Thus, combination
      therapy with inhibitors of VEGF plus paclitaxel may be an effective way to
      markedly reduce tumor growth and ascites in ovarian carcinoma.

PMID- 12414538
TI  - An ethyl-nitrosourea-induced point mutation in phex causes exon skipping, x
      linked hypophosphatemia, and rickets.
AB  - We describe the clinical, genetic, biochemical, and molecular characterization of
      a mouse that arose in the first generation (G(1)) of a random mutagenesis screen
      with the chemical mutagen ethyl-nitrosourea. The mouse was observed to have
      skeletal abnormalities inherited with an X-linked dominant pattern of
      inheritance. The causative mutation, named Skeletal abnormality 1 (Ska1), was
      shown to be a single base pair mutation in a splice donor site immediately
      following exon 8 of the Phex (phosphate-regulating gene with homologies to
      endopeptidases located on the X-chromosome) gene. This point mutation caused
      skipping of exon 8 from Phex mRNA, hypophosphatemia, and features of rickets.
      This experimentally induced phenotype mirrors the human condition X-linked
      hypophosphatemia; directly confirms the role of Phex in phosphate homeostasis,
      normal skeletal development, and rickets; and illustrates the power of
      mutagenesis in exploring animal models of human disease.

PMID- 12414539
TI  - Evidence for early cytotoxic aggregates in transgenic mice for human
      transthyretin Leu55Pro.
AB  - Familial amyloidotic polyneuropathy (FAP) is a lethal autosomal dominant disorder
      characterized by systemic extracellular deposition of transthyretin (TTR) amyloid
      fibrils. Several groups have generated transgenic mice carrying human TTR
      Val30Met, the most common mutation in FAP. To study amyloidogenicity and
      cytotoxicity of different TTRs, we produced transgenic mice expressing human TTR
      Leu55Pro, one of the most aggressive FAP-related mutations. TTR deposition and
      presence of amyloid fibrils was investigated and compared to animals carrying the
      human TTR Val30Met gene kept under the same conditions. Deposition in a C57BL/6J
      background (TTR-Leu55Pro mice) and in a TTR-null background [TTR-Leu55Pro X TTR
      knockout (KO) mice] was compared. Animals in a C57BL/6J background presented
      early (1 to 3 months) nonfibrillar TTR deposition but amyloid was absent. In a
      TTR-null background, presence of amyloid fibrils was detected starting at 4 to 8
      months with a particular involvement of the gastrointestinal tract and skin. This
      data suggested that TTR homotetramers are more prone to fibril formation than TTR
      murine wild-type/human mutant heterotetramers. The nature of the deposited
      material was further investigated by immunocytochemistry. Both amorphous
      aggregates and small TTR fibrils were present in TTR-Leu55Pro X TTR-KO
      transgenics. We observed that these TTR deposits mimic the toxic effect of TTR
      deposits in FAP: animals with TTR deposition, present approximately twofold
      increased levels of nitrotyrosine in sites related to deposition. The TTR
      Leu55Pro X TTR-KO mice here described are an important tool for the dual purpose
      of investigating factors involved in amyloidogenesis and in cytotoxicity of
      deposited TTR.

PMID- 12414540
TI  - New approaches to the biology of melanoma: a workshop of the National Institutes
      of Health Pathology B Study Section.

PMID- 12414541
TI  - The Royal College of Physicians report on alcohol: guidelines for managing
      Wernicke's encephalopathy in the accident and Emergency Department.
AB  - The Royal College of Physicians (London) recently published its latest report on
      alcohol misuse entitled 'Alcohol - Can the NHS Afford It?'. Part of this
      document, encompassing our views, has made specific recommendations for the
      management of patients in the Accident and Emergency (A&E) Department who may
      possibly have, or are at risk of developing, Wernicke's encephalopathy. Patients
      showing evidence of chronic alcohol misuse and suspected of having a poor diet
      should be treated at the outset with B vitamins intravenously or intramuscularly,
      especially when the clinical signs are initially masked by drunkenness at
      presentation to the A&E Department. This commentary offers a review of the
      scientific foundations on which these recommendations have been made.

PMID- 12414542
TI  - Neurochemical markers of alcoholism vulnerability in humans.
AB  - This review considers several neurochemical characteristics or trait markers that
      may be related to a genetic vulnerability to alcoholism. These potential
      neurochemical markers of alcoholism vulnerability include indices of activity of
      five neurotransmitter systems, namely gamma-aminobutyric acid, serotonin,
      dopamine, noradrenaline and beta-endorphin. This review evaluates whether
      potential abnormalities in these neurochemical indices, as assessed in alcoholics
      and in the children of alcoholics, meet three criteria for the identification of
      a vulnerability marker of alcoholism: (1). heritable; (2). associated with
      alcoholism in the general population; (3). state independent. It is concluded
      that, at present, indices of increased baseline activity of the serotonin
      transporter in platelets and of increased responsiveness of the pituitary beta
      endorphin system may fulfil each of these three criteria. Additional research
      efforts should be devoted to the evaluation of trait marker properties of
      neurochemical indices in individuals at high risk for alcoholism.

PMID- 12414543
TI  - Phosphotidylethanol mimics ethanol modulation of p42/44 mitogen-activated protein
      kinase signalling in hepatocytes.
AB  - AIMS: Although long-term exposure of hepatocytes to ethanol results in agonist
      selective potentiation of p42/44 mitogen-activated protein kinase (MAPK)
      activation, mediators of this effect of ethanol are not known. METHODS: We
      examined the role of phosphatidylethanol (PEth), a novel phospholipid formed
      exclusively in the presence of ethanol. RESULTS: PEth accumulated in primary
      cultures of rat hepatocytes treated with ethanol. Exogenously added PEth
      potentiated angiotensin II-stimulated p42/44 MAPK similarly to that observed with
      ethanol treatment of cells for 24 h, a condition where PEth accumulates. PEth
      levels remained elevated 2 h after ethanol removal subsequent to a 24-h exposure,
      and the potentiating effects of ethanol were also present. PEth did not
      potentiate p42/44 MAPK activation by either epidermal growth factor or
      vasopressin, thus further mimicking the known agonist selectivity for this
      ethanol effect. CONCLUSIONS: These results offer a novel role for PEth as a
      mediator in the ethanol modulation of p42/44 MAPK cascade in hepatocytes.

PMID- 12414544
TI  - Blockade of gamma-aminobutyric acid receptors does not modify the inhibiton of
      ethanol intake induced by Hypericum perforatum in rats.
AB  - AIMS: Recent studies have shown that Hypericum perforatum extracts (HPE) inhibit
      ethanol intake in alcohol-preferring rats, but their mechanism of action is still
      unknown. HPE have been shown to bind at gamma-aminobutyric acid (GABA)(A) and
      GABA(B) receptors, to inhibit GABA reuptake, to evoke GABA release from
      synaptosomes and to exert an anxiolytic effect that is blocked by the
      benzodiazepine antagonist flumazenil. Since GABA-ergic mechanisms are known to
      influence ethanol intake, the present study was aimed at investigating whether
      they might mediate the effect of a CO2 Hypericum extract (HPCO2) on ethanol
      intake in genetically selected Marchigian Sardinian alcohol-preferring (msP)
      rats. METHODS: The GABA(A) receptor antagonist bicuculline and the GABA(B)
      receptor antagonists CGP-36742 and phaclofen were tested versus the effect of
      HPCO2 on ethanol intake. RESULTS: The results of the present study confirm that
      HPCO2, given by intragastric injection, markedly reduces ethanol intake in msP
      rats and its effect is behaviourally selective, since the same doses which
      inhibited ethanol intake did not modify the simultaneous intake of food or water.
      The GABA(A) receptor antagonist bicuculline, given by intraperitoneal (i.p.)
      injection at a dose of 2 mg/kg, which effectively antagonizes the effects of
      GABA(A) receptor agonists, did not modify the effect of HPCO2, 15 or 125 mg/kg.
      The GABA(B) receptor antagonists CGP-36742, given by i.p. injection at a dose of
      100 mg/kg, and phaclofen, given by intracerebroventricular injection at a dose of
      25 micro g/rat, did not modify the inhibitory effect on alcohol intake induced by
      HPCO2, 15 or 125 mg/kg. The same doses of the two GABA(B) receptor antagonists
      induced a pronounced reduction of the effect of the GABA(B) receptor agonist
      bacoflen, given by i.p. injection at a dose of 5 mg/kg. CONCLUSIONS: These
      findings suggest that the inhibitory effects of HPE on ethanol intake are not
      mediated by GABA agonist actions.

PMID- 12414545
TI  - Pairings of ethanol sipper with food induces Pavlovian autoshaping of ethanol
      drinking in rats: evidence of long-term retention and effects of sipper duration.
AB  - AIMS: This study asks if repeated Pavlovian pairings of a sipper tube
      (conditioned stimulus, CS) with food (unconditioned stimulus, US) will induce
      Pavlovian autoshaping conditioned responses (CRs), consisting of drinking of
      either 6% ethanol or water from the sipper CS. This study also tests predictions
      derived from the autoshaping model by asking if sipper CS-directed drinking will
      be retained, despite the absence of training for several weeks, and, in addition,
      if drinking rate is a negative function of sipper CS duration. METHODS:
      Autoshaping procedures, conducted in two daily sessions, consisted of the brief
      insertion of the sipper tube CS followed by the response-independent presentation
      of food US. For the Ethanol group (n = 8), the sipper CS contained 6% ethanol,
      whereas for the Water group (n = 8), the sipper CS contained tap water. Saccharin
      fading procedures were employed, whereas for both groups, during days 1-19, the
      sipper CS contained 0.1% saccharin, and thereafter across training days the
      concentration of saccharin was gradually reduced (0.07, 0.035, 0.0%). Following
      elimination of saccharin, both groups were maintained in their home cages during
      a 27-day retention interval, and then re-evaluated for autoshaping of drinking of
      unsweetened ethanol and water. Thereafter, across days, the duration of access to
      the sipper CS (5.0, 7.5, 10.0, 15.0 s) during each autoshaping trial was
      increased. RESULTS: Both groups increased drinking across the first 19 days of
      training with sipper CS-food US pairings, and, at 0.0% saccharin, the Ethanol
      group consumed 14.76 ml of 6% ethanol per day, resulting in a daily ethanol
      consumption of 2.77 g/kg. For both groups, daily levels of drinking before and
      after the 27-day retention interval were comparable, attesting to the durability
      of the acquired drinking effects. At each CS duration, the Ethanol group consumed
      more millilitres of fluid per day than did the Water group, and for the Ethanol
      group, peak drinking of 24.0 ml of 6% ethanol per day was observed at the 10 s CS
      duration. For both groups, drinking rate (millilitres of fluid consumed per
      second of CS duration), was a declining monotonic function of CS duration,
      resulting in a daily ethanol consumption of approximately 4.2 g/kg for the
      Ethanol group. CONCLUSIONS: These data reveal that these sipper CS-food US
      autoshaping procedures induce drinking in rats that is durable and negatively
      related to increasing CS duration. The effects of both variables are consistent
      with the hypothesis that drinking from the sipper CS is a Pavlovian autoshaping
      CR. Autoshaping of drinking in the Water group is observed despite the absence of
      water deprivation, and even more fluid is consumed by the Ethanol group than by
      the Water group. The high volumes of ethanol consumed during brief daily sessions
      suggest that Pavlovian autoshaping procedures may provide an animal learning
      model of binge drinking.

PMID- 12414546
TI  - Ethanol modulates coronary permeability to macromolecules in murine AIDS.
AB  - BACKGROUND AND AIMS: The cardiovascular complications of AIDS are serious.
      However, the underlying mechanisms are unclear. Less is known about how ethanol
      affects the coronary microcirculation in individuals with AIDS. The aim of this
      study was to assess the integrity of the coronary microcirculation in murine AIDS
      mice in the presence or absence of chronic ethanol consumption. METHODS: Four
      groups were studied: control, murine AIDS, ethanol and ethanol plus murine AIDS.
      Mouse hearts were prepared for direct visualization of the coronary
      microcirculation and quantification of trans-coronary macromolecular leakage.
      Hearts were isolated and perfused with diluted rat blood containing fluorescein
      isothiocyanate-albumin (FITC-BSA). Coronary vessels were observed using
      intravital fluorescence microscopy after 5, 15 and 25 min of perfusion. The mean
      luminosity of outside/inside coronary vessels (O/I ratio) was used to quantify
      FITC-BSA leakage. RESULTS: We found that the mean O/I ratio for the murine AIDS
      group was significantly greater than in the control group and also significantly
      increased during the perfusion period. Chronic ethanol consumption did not alter
      coronary permeability to macromolecules, but improved the coronary haemodynamics
      in murine AIDS. CONCLUSIONS: These findings suggest that murine AIDS impairs the
      structural and functional coronary endothelium, and moderate ethanol consumption
      modulates the function of the coronary microcirculation.

PMID- 12414547
TI  - Phosphatidylethanolamine N-methyltransferase activity is increased in rat
      intestinal brush-border membrane by chronic ethanol ingestion.
AB  - AIMS: Phosphatidylethanolamine N-methyltransferase (PEMT) catalyses the synthesis
      of phosphatidylcholine from phosphatidylethanolamine. The aim of this study was
      to evaluate the effect of chronic ethanol ingestion on PEMT activity in the
      jejunal brush-border membrane (BBM) of adequately nourished rats. METHODS: For
      this purpose, rats were fed a liquid diet containing ethanol [ethanol-fed group
      (EFG)] or an isocaloric liquid diet without ethanol [pair-fed group (PFG)] for 4
      weeks. Diet ingestion, body weight, nitrogen balance and urinary creatinine
      excretion were monitored during the experimental period, and serum transferrin
      levels were determined at the end. BBM was isolated for the determination of PEMT
      activity. RESULTS: PEMT activity was significantly increased in the jejunal BBM
      of the EFG. Nutritional parameters, however, did not differ between groups.
      CONCLUSIONS: The increase in PEMT activity may be attributed exclusively to
      chronic ethanol ingestion, since a major nutritional deficit was excluded.

PMID- 12414548
TI  - Platelet monoamine oxidase B activity as a state marker for alcoholism: trend
      over time during withdrawal and influence of smoking and gender.
AB  - AIMS AND METHODS: The present study evaluated time-related changes in platelet
      monoamine oxidase B (MAO-B) activity in an Italian cohort of alcohol-dependent
      subjects (n = 98) during early abstinence, and the effect of potential
      confounding factors, such as gender and smoking status, on the temporal trend of
      the enzyme activity. RESULTS: While still under the influence of ethanol (time
      point T1), the mean value of platelet MAO-B activity in alcoholics was 6.4 +/-
      3.1 nmol/mg of protein/h. This increased by >40% (to 9.3 +/- 4.4 nmol/mg of
      protein/h) after 8 days of withdrawal (T2), and remained stable thereafter (T3
      and T4: 15 and 22 days of abstinence, respectively). In a cohort of 138 healthy
      subjects, MAO activity levels averaged 9.9 +/- 0.9 nmol/mg of protein/h. In the
      group of alcoholic patients, alcohol intake cessation was confirmed by the
      progressive decrease of serum % carbohydrate-deficient transferrin (CDT), which
      was pathologically above the reference limits (6%) at T1 (7.8 +/- 3.3%), declined
      to 6.6 +/- 2.1% at T2 and reached physiological values at T3 and T4. In a
      subgroup of cirrhotic alcoholics, %CDT did not decrease over time, while MAO
      activity rose after the first week of abstinence, without further change at T3
      and T4. During early withdrawal, neither gender nor tobacco smoking affected the
      temporal pattern of MAO activity. CONCLUSIONS: MAO-B can be regarded as a state
      marker of alcohol consumption. The temporal pattern of platelet MAO-B activity
      may be used for the diagnostic assessment of alcoholism and early abstinence,
      regardless of gender and smoking status.

PMID- 12414549
TI  - Accuracy of quantity-frequency and graduated frequency questionnaires in
      measuring alcohol intake: comparison with daily diary and commonly used
      laboratory markers.
AB  - AIMS: To ascertain the accuracy of a quantity-frequency questionnaire (QF) and a
      graduated frequency questionnaire (GF) as methods of obtaining self-reported
      alcohol intake in relation to a daily diary and biochemical tests. METHODS: QF
      and GF data were obtained before and after a 1-month daily diary on alcohol
      intake in a sample of 52 volunteers aged 20-63 years, of whom 43 were female. A
      blood sample to measure serum aspartate aminotransferase (ASAT), alanine
      aminotransferase (ALAT), gamma-glutamyltransferase (GGT) and % carbohydrate
      deficient transferrin (CDT) was obtained at the outset. RESULTS: Both QF and GF
      correlated closely with daily diary intake (r > 0.90). Compared with a daily
      diary, the mean QF intake was slightly lower, whereas the mean GF intake was 2
      fold. The apparent overestimation by GF was independent of the actual consumption
      level. Self-reported alcohol intake by each method correlated closely with serum
      ASAT, ALAT and GGT (r = 0.41-0.67) but not with CDT. CONCLUSIONS: In adults
      motivated to recall alcohol intake, both QF and GF classify individuals in the
      correct rank order, but GF probably overestimates actual alcohol consumption.

PMID- 12414550
TI  - Platelet monoamine oxidase B in family history positive and family history
      negative type 1 alcohol-dependent subjects.
AB  - AIMS AND METHODS: In the present study platelet monoamine oxidase B (MAO-B)
      activity was investigated in 76 male type 1 alcohol-dependent subjects with and
      without a family history of alcoholism. RESULTS: Platelet MAO-B activity did not
      differ between family history positive (FHP) and family history negative alcohol
      dependent subjects. The smoking status of the subjects was registered and there
      was still no difference between the groups when possible effects of smoking were
      taken into account. It should, however, be noted that platelet MAO-B activity was
      lower in alcohol-dependent subjects with three or four alcohol-dependent first
      degree relatives. CONCLUSIONS: Although this latter finding should be interpreted
      with caution due to the small number of subjects, it cannot be excluded that FHP
      alcohol-dependent subjects with a large number of alcohol-dependent first-degree
      relatives may have lower platelet MAO-B activity.

PMID- 12414551
TI  - Alcohol-attributable mortality in a high per capita consumption country --
      Germany.
AB  - AIMS: Little is known about age and gender distributions in alcohol-attributable
      mortality (AAM). The aim of this paper is to describe age and gender in AAM in a
      high per capita consumption country. METHODS: The AAM was determined using
      national mortality statistics and data on the prevalence of alcohol risk drinking
      from Germany. According to this approach, alcohol-attributable fractions (AF) of
      causes of death are estimated. RESULTS: In males, as well as females, more than
      70% of the AAM cases are due to alcohol consumption as well as smoking. The
      mortality rates are highest in the age range 35-64 years with 25% of the total
      mortality in males, and 13% in females. The median age at death in AAM
      exclusively based on alcohol is 15 years below the median age at death in the
      male and 24 years below that in the female population. CONCLUSIONS: Early
      intervention should be stressed.

PMID- 12414553
TI  - Audit-3 and audit-4: effectiveness of two short forms of the alcohol use
      disorders identification test.
AB  - AIMS: To identify suitable short versions of the Alcohol Use Disorders
      Identification Test (AUDIT) and to evaluate their effectiveness as screening
      tests for 'risky drinking' among men and women in primary health care (PHC)
      settings. METHODS: A total of 255 patients attending five PHC centres in
      Catalonia (Spain) were interviewed by clinicians regarding health status and
      drinking pattern. Patients also completed the AUDIT. Clinicians' diagnosis of
      risky drinking was used as a gold standard to evaluate the effectiveness of three
      forms of AUDIT. RESULTS: AUDIT-3 and AUDIT-4 performed similarly to AUDIT-10 in
      detecting risky drinking and had equivalent receiver operating characteristics
      curves and their areas under the curve. CONCLUSIONS: Both short forms of AUDIT
      seem to be as effective as the full AUDIT for detecting risky drinking among men
      and women in PHC settings.

PMID- 12414552
TI  - Long-term abstinent alcoholics have a blunted blood glucose response to 2-Deoxy-d
      glucose.
AB  - AIMS: In this study we explored the relationship between alcohol and carbohydrate
      consumption in long-term abstinent alcoholics. METHODS: We employed an
      established laboratory paradigm which allowed us to stimulate and measure dietary
      intake. 2-Deoxy-d-glucose (2-DG) is a glucose analogue that causes an
      intracellular energy deprivation resulting in exaggerated food consumption and a
      compensatory metabolic response to raise blood glucose. Using a double-blind
      design, we gave an infusion of 25 mg/kg 2-DG or placebo to 20 long-term abstinent
      alcoholics and 19 healthy volunteers. RESULTS: There were no baseline differences
      in any dietary, behavioural or biochemical variables. As expected, 2-DG increased
      caloric consumption and blood glucose levels in a time-dependent fashion. There
      were no differences in food consumption between the alcoholics and the healthy
      volunteers following the 2-DG stimulus. However, the alcoholic group had a
      significantly blunted response in blood glucose. CONCLUSIONS: The origin of this
      atypical blood glucose response may antedate the onset of alcoholism, or it may
      be secondary to alcohol-related damage that persists beyond 6 months. Previous
      accounts of increased sweet consumption in alcoholics were not substantiated,
      although they may be present in the peri-withdrawal period.

PMID- 12414554
TI  - Platelet monoamine oxidase activity in alcoholism subtypes: relationship to
      personality traits and executive functions.
AB  - AIMS: The purpose of the present study was to compare alcoholic subtypes (type 1
      versus type 2) with regard to platelet monoamine oxidase (MAO) activity. A
      possible relationship between enzyme activity, personality traits and executive
      functions was also investigated. METHODS: Seventeen type 1 and 16 type 2 in
      patient male chronic alcoholic patients and 17 healthy male volunteers were
      included in the study. The personality traits were investigated by the Minnesota
      Multiphasic Personality Inventory-2 (MMPI-2). Executive functions were assessed
      by the Wisconsin Card Sorting Test (WCST). RESULTS: When compared to the healthy
      subjects, platelet MAO activity was reduced in both alcoholic groups. The enzyme
      activity of the type 2 group was significantly lower than that of type 1
      patients. Both groups of alcoholic patients also displayed impairment in
      executive functions. The comparison of the MMPI-2 scores of the study groups
      revealed that type 2 alcoholics had more severe psychopathology. CONCLUSIONS: The
      results support previous evidence suggesting that platelet MAO activity is a
      useful biochemical measure for the subtyping of alcoholics.

PMID- 12414555
TI  - Alcohol use and cultural change in an indigenous population: a case study from
      Venezuela.
AB  - AIMS: To explore the historical and cultural context of problem drinking in a
      Latin American indigenous population and identify possible areas for
      intervention. METHODS: Focus group discussions. RESULTS: Participants reported
      that prior to 1945, binge drinking and fighting were part of cultural festivals
      held several times each year. Alcohol was brewed in limited quantities by
      specially qualified individuals. Limited family violence and injuries resulted.
      Increasing contact with Western civilization resulted in year-round access to
      large supplies of commercial alcohol and exposure to alcohol-misusing role
      models. Increased heavy drinking and decreases in subsistence farming resulted in
      escalation of problems, including hunger, serious injury, family violence,
      divorce and legal problems. Communities are beginning to regain control by
      prohibiting sale of alcohol in villages, sponsoring alcohol-free celebrations,
      and increasing involvement in religious activities. CONCLUSIONS: Though alcohol
      may cause devastating consequences in cultures in transition, studies of
      community responses may identify useful strategies for reducing alcohol-related
      harm.

PMID- 12414556
TI  - Anxiety as a predictor of relapse in detoxified alcohol-dependent patients.
AB  - AIMS: To evaluate the impact of mood, affect, and personality on predicting
      relapse in detoxified alcohol-dependent patients to uncontrolled drinking during
      a 1-year treatment study. METHODS: A total of 521 patients with a DSM-III-R
      diagnosis of alcohol dependence, excluding those with major depressive disorder,
      took part in a European multicentre study (11 centres in the United Kingdom,
      Irish Republic, Switzerland, and Austria). Depressive symptoms were assessed
      using the Hamilton Depression Scale, whereas symptoms of anxiety were measured
      using the 'STAI-X2' of the self-rating scale State-Trait Anxiety Inventory and
      personality traits were measured by the Tridimensional Personality Questionnaire.
      RESULTS: High anxiety as a stable trait, and personality traits such as high
      novelty seeking and low harm avoidance covering exploratory excitability,
      impulsiveness, extravagance, disorderliness and uninhibited optimism, predicted
      relapse. CONCLUSIONS: These measures could have a direct clinical application for
      predicting relapse to uncontrolled drinking in male and female detoxified alcohol
      dependent patients. The findings indicate the importance of additional
      therapeutic treatment.

PMID- 12414557
TI  - Paternal alcohol exposure and Turner syndrome.
AB  - AIMS: Turner syndrome (TS) is a sex chromosome aneuploidy that occurs as a result
      of a non-disjunctional error in meiosis I or anaphase lag; however, the aetiology
      of this disorder remains unknown. Anecdotal evidence suggests that paternal
      alcoholism may play an unidentified role in the aetiology of TS. Accordingly, the
      primary objective of this study was to determine the potential association
      between paternal alcohol exposure and TS. METHODS: The questionnaire was designed
      to solicit information about the parents' health and lifestyle habits occurring 1
      year prior to and throughout the pregnancy of their daughter with TS. Alcohol
      dependence was assessed by the Brief Michigan Alcohol Screening Test (BMAST). The
      study population was solicited from the Turner's Syndrome Society of Canada and
      included any parent(s) having a child with TS who was of any age. Two hundred and
      twelve families completed and returned the survey. RESULTS: This provided a
      response rate of 86.5%. Six of the fathers (3.6%; n = 166) and six of the mothers
      (3.6%; n = 165) had scores of 5 or more on the BMAST (scores of 5+ are considered
      to be in the 'alcoholic range'). This is considerably lower than the population
      norm of 9.5%. CONCLUSIONS: Our study has suggested there is no association
      between paternal or maternal alcohol consumption and TS.

PMID- 12414558
TI  - Wine consumption is not associated with a decreased risk of alcoholic cirrhosis
      in heavy drinkers.
AB  - AIMS: While it was thought that all alcoholic beverages share a similar liver
      toxicity when drunk at a high level, recent epidemiological surveys have
      suggested that wine drinking might decrease the risk of alcoholic cirrhosis in
      heavy drinkers. Therefore, we performed a study aiming to analyse the type and
      the intake levels of alcoholic beverages in heavy drinkers according to the
      severity of the liver disease. METHODS: This is a case-control study enrolling 42
      cirrhotic and 60 non-cirrhotic patients. Liver status was assessed using
      clinical, biological, histological and ultrasonographic procedures. Alcohol
      consumption was recorded using the Lifetime Drinking History method. RESULTS: We
      did not find any significant differences in total alcohol consumption between
      cases and controls and, moreover, in our series, the relative percentage of pure
      alcohol drunk in wine was significantly higher in cirrhotic, than in non
      cirrhotic, patients. CONCLUSIONS: Our results confirm that the absence of a link
      between the type of alcoholic beverage and the occurrence of cirrhosis is still
      valid.

PMID- 12414562
TI  - Morphogenesis and organogenesis in the regenerating planktotrophic larvae of
      asteroids and echinoids.
AB  - In a previous study, we described complete body regeneration (with organogenesis)
      following surgical bisection in the planktotrophic larvae of the asteroids Luidia
      foliolata and Pisaster ochraceus. Here we present further detailed observations
      of these unique regenerative processes not presented in the previous paper.
      Furthermore, we describe for the first time complete regeneration following
      surgical bisection of planktotrophic larvae of the regular echinoid Lytechinus
      variegatus and the irregular echinoid Dendraster excentricus. Larvae of both
      asteroids and echinoids displayed a capacity for rapid regeneration regardless of
      their developmental stage. Within 48 h after bisection, aggregations of
      mesenchyme cells with pseudopodia were observed at the site of surgical
      bisection. These cellular aggregations were similar in appearance to the
      mesenchymal blastemas that form in adult echinoderms prior to their arm
      regeneration, and to those described in other deuterostomes that undergo
      regeneration. When asteroid larvae were surgically bisected in the early stages
      of their development, clusters of mesenchyme cells developed into completely new
      pairs of coelomic pouches located anterior to the newly regenerated digestive
      tract. This indicates that cell fate in regenerating asteroid larvae remains
      indeterminate during early development. In the larvae of P. ochraceus, regardless
      of the developmental stage at the time of bisection, both the anterior and
      posterior portions regenerated all their missing organs and tissues. However, the
      larvae of L. foliolata displayed differential regenerative capacity in bisected
      larval halves at the late bipinnaria stage. The differences observed may be due
      to differences in larval development (L. foliolata has no brachiolaria stage),
      and may have evolutionary implications. In the regular echinoid L. variegatus,
      both larval portions regenerated into morphologically and functionally normal
      larvae that were indistinguishable from non-bisected control larvae. The
      regenerative processes were similar to those we observed in planktotrophic
      asteroid larvae. Regenerating larvae readily metamorphosed into normal juveniles.
      In the irregular echinoid D. excentricus, posterior portions of larvae completed
      regeneration and metamorphosis, but anterior portions regenerated only partially
      during the 2-week study. Our observations confirm that asteroid and echinoid
      larvae provide excellent models for studies of regeneration in deuterostomes.

PMID- 12414563
TI  - Spermiogenesis and modified sperm morphology in the "seepworm" Methanoaricia
      dendrobranchiata (Polychaeta: Orbiniidae) from a methane seep environment in the
      Gulf of Mexico: implications for fertilization biology.
AB  - Spermatogenesis and mature sperm morphology have been described along with
      limited observations of the ovary in Methanoaricia dendrobranchiata, an orbiniid
      polychaete associated with dense populations of the mussel Bathymodiolus
      childressi at brine pools on the Louisiana slope, Gulf of Mexico. The species is
      gonochoric with gonads serially repeated in numerous segments and each associated
      with a nexus of blood vessels at the base of the parapodia. In the female,
      synchronous, intraovarian egg development occurs with the release from the ovary
      of large, yolky eggs into the coelom at first meiotic metaphase. Sperm develop in
      the coelom as free-floating, plasmodial clones interconnected via an anuclear
      cytophore. At the end of spermiogenesis, mature spermatozoa float freely in the
      coelom. The mature spermatozoon differs significantly from that of shallow-water
      orbiniid species by possessing an elongated nucleus and a greatly elongated and
      curved acrosome reaching 19.5 microm in length. The spermatozoon resembles an ent
      aquasperm and may not fertilize the eggs directly in seawater in the classical
      manner. We hypothesize that the unusual spermatozoon morphology in this species
      has evolved due to the hypoxic environment in which the adults live and that
      fertilization biology is likely modified in some way to minimize sperm exposure
      to high levels of hydrogen sulfide. An analysis of life-history features in
      shallow-water orbiniids is used to infer reproductive features in M.
      dendrobranchiata that could not be directly documented.

PMID- 12414564
TI  - Swimming behavior of the nudibranch Melibe leonina.
AB  - Swimming in the nudibranch Melibe leonina consists of five types of movements
      that occur in the following sequence: (1) withdrawal, (2) lateral flattening, (3)
      a series of lateral flexions, (4) unrolling and swinging, and (5) termination.
      Melibe swims spontaneously, as well as in response to different types of aversive
      stimuli. In this study, swimming was elicited by contact with the tube feet of
      the predatory sea star Pycnopodia helianthoides, pinching with forceps, or
      application of a 1 M KCl solution. During an episode of swimming, the duration of
      swim cycles (2.7 +/- 0.2 s [mean +/- SEM], n = 29) and the amplitude of lateral
      flexions remained relatively constant. However, the latency between the
      application of a stimulus and initiation of swimming was more variable, as was
      the duration of an episode of swimming. For example, when touched with a single
      tube foot from a sea star (n = 32), the latency to swim was 7.0 +/- 2.4 s, and
      swimming continued for 53.7 +/- 9.4 s, whereas application of KCl resulted in a
      longer latency to swim (22.3 +/- 4.5 s) and more prolonged swimming episodes
      (174.9 +/- 32.1 s). Swimming individuals tended to move in a direction
      perpendicular to the long axis of the foot, which propelled them laterally when
      they were oriented with the oral hood toward the surface of the water. The
      results of this study indicate that swimming in Melibe, like that in several
      other molluscs, is a stereotyped fixed action pattern that can be reliably
      elicited in the laboratory. These characteristics, along with the large
      identifiable neurons typical of many molluscs, make swimming in this nudibranch
      amenable to neuroethological analyses.

PMID- 12414565
TI  - Neural correlates of swimming behavior in Melibe leonina.
AB  - The nudibranch Melibe leonina swims by rhythmically bending from side to side at
      a frequency of 1 cycle every 2-4 s. The objective of this study was to locate
      putative swim motoneurons (pSMNs) that drive these lateral flexions and determine
      if swimming in this species is produced by a swim central pattern generator
      (sCPG). In the first set of experiments, intracellular recordings were obtained
      from pSMNs in semi-intact, swimming animals. About 10-14 pSMNs were identified on
      the dorsal surface of each pedal ganglion and 4-7 on the ventral side. In
      general, the pSMNs in a given pedal ganglion fired synchronously and caused the
      animal to flex in that direction, whereas the pSMNs in the opposite pedal
      ganglion fired in anti-phase. When swimming stopped, so did rhythmic pSMN
      bursting; when swimming commenced, pSMNs resumed bursting. In the second series
      of experiments, intracellular recordings were obtained from pSMNs in isolated
      brains that spontaneously expressed the swim motor program. The pattern of
      activity recorded from pSMNs in isolated brains was very similar to the bursting
      pattern obtained from the same pSMNs in semi-intact animals, indicating that the
      sCPG can produce the swim rhythm in the absence of sensory feedback. Exposing the
      brain to light or cutting the pedal-pedal connectives inhibited fictive swimming
      in the isolated brain. The pSMNs do not appear to participate in the sCPG.
      Rather, they received rhythmic excitatory and inhibitory synaptic input from
      interneurons that probably comprise the sCPG circuit.

PMID- 12414566
TI  - Clade perseverance from Mesozoic to present: a multidisciplinary approach to
      interpretation of pattern and process.
AB  - Two clades of marine bryozoans, cyclostomes and cheilostomes, exemplify the
      benefits of applying a multidisciplinary approach to the interpretation of long
      term evolutionary patterns. The cyclostome bryozoans were dominant in the
      Mesozoic; since that era, they have decreased in absolute terms and the
      cheilostomes have come to exceed them in both abundance and diversity. Many
      studies of living assemblages of the encrusting members of these two clades
      indicate that cheilostomes are superior space competitors, but paleontological
      studies suggest that competition between the two taxa has not been escalating
      over geological time. Both clades occur throughout the world's oceans and seas,
      and recent work in the geographical extremes has shown that the relative success
      of the clades varies markedly from place to place. In this study, the importance
      of differential patterns of recruitment and cumulative space occupation in the
      two clades was evaluated over four years and in two environments, one temperate
      and one polar. In both of these environments, peaks of recruitment and space
      occupation by the two clades were out of phase. The different strategies and
      outcomes of spatial competition are examined, largely using data from the
      literature. Only recently has it been realized that tied outcomes of competition
      are stable alternative results and not simply transitory phases. Many competitive
      encounters involving cyclostomes result in ties, implying that their strategy is
      based on persistence rather than dominance. When different indices and models are
      used to analyze competition data from the two clades, the interpretation varies
      markedly with methodology. The differences in patterns of recruitment, space
      occupation, and spatial competition have influenced both our understanding of how
      the two clades have persisted alongside each other and our perception of
      cheilostome superiority. Analysis of fluid dynamics has shown that small
      differences in the mechanical structure of typical members of each clade lead to
      fundamental differences in water movement. For animals that rely on water motion
      for transport of nutritional and excretory elements (suspension feeders), small
      changes in current velocity and direction can have a major impact. Preliminary
      chemical analysis of the excurrent stream leaving cheilostome colonies has shown
      it to be laden with excretory products, which can interfere and mix with a
      neighbor's feeding currents. Clearly, spatial competition involves more than a
      simple mechanical "showdown."

PMID- 12414567
TI  - Relative strengths of competition for space and food in a sessile filter feeder.
AB  - Previous workers have demonstrated that sessile filter feeders compete for food
      and space, but little is known about the relative strengths of these two
      processes. To determine this, the density and position of barnacles (Balanus
      improvisus) in a unidirectional current were manipulated to alter the amount of
      competition for space and food, respectively. Results indicated that competition
      for space significantly reduced growth, and marginally reduced survivorship.
      Competition for food was also detected, but only among uncrowded individuals;
      thus, it appears to be the weaker of the two interactions. However, under crowded
      conditions, downstream individuals actually grew more than those upstream. The
      most likely explanation for this result is that downstream individuals fed more
      efficiently because they were not exposed to the full force of the current. The
      results also suggest that since natural densities started high but continually
      decreased throughout the study, barnacles undergo an ontogenetic shift in the
      relative importance of these processes.

PMID- 12414569
TI  - Physiological effects of tricaine on the supramedullary/dorsal neurons of the
      cunner, Tautogolabrus adspersus.

PMID- 12414570
TI  - Gene expression in the squid giant axon: neurotransmitter modulation of RNA
      transfer from periaxonal glia to the axon.

PMID- 12414571
TI  - Perchlorate prevents sodium channel gating and sodium protects in the squid giant
      axon.

PMID- 12414572
TI  - Blockade of an inward sodium current facilitates pharmacological study of hemi
      gap-junctional currents in Xenopus oocytes.

PMID- 12414573
TI  - Cl(-) and glutamate(-) competition for a volume-regulated anion channel.

PMID- 12414574
TI  - Preliminary evidence for interpulse interval selectivity of cells in the torus
      semicircularis of the oyster toadfish (Opsanus tau).

PMID- 12414575
TI  - Effects of a sensory block on calexcitin levels in the photoreceptors of
      Hermissenda crassicornis.

PMID- 12414576
TI  - A novel turtle retinal preparation for simultaneously measuring light-induced
      electrical activity and changes in metabolite levels.

PMID- 12414577
TI  - Zinc chelation enhances the zebrafish retinal ERG b-wave.

PMID- 12414578
TI  - Immunohistochemical demonstration of a lipopolysaccharide in the cell wall of a
      eukaryote, the green alga, Chlorella.

PMID- 12414579
TI  - Rapid visualization of microtubules in blood cells and other cell types in marine
      model organisms.

PMID- 12414580
TI  - Ca(2+) effects on myosin-II-mediated contraction of pseudo-contractile rings and
      transport of vesicles in extracts of clam oocytes.

PMID- 12414581
TI  - GTPase rho is involved in myosin-II-mediated contraction of pseudo-contractile
      rings and transport of vesicles in extracts of clam oocytes.

PMID- 12414582
TI  - Globular tail fragment of myosin-V displaces vesicle-associated motor and blocks
      vesicle transport in squid nerve cell extracts.

PMID- 12414583
TI  - Peroxisomal catalase in extrusion apparatus posterior vacuole of microsporidian
      spores.

PMID- 12414584
TI  - A metronome-like control of the calcium signal leading to nuclear envelope
      breakdown and mitosis in sand dollar (Echinaracnius parma) cells.

PMID- 12414585
TI  - Culture method for in vitro fertilization to hatching of the squid, Loligo
      pealeii.

PMID- 12414586
TI  - mRNAs located in Squalus acanthias (spiny dogfish) oligodendrocyte processes.

PMID- 12414588
TI  - Early neurogenesis in the horseshoe crab Limulus polyphemus and its implication
      for arthropod relationships.

PMID- 12414587
TI  - SEM comparison of severed ends of giant axons isolated from squid (Loligo
      pealeii) and crayfish (Procambarus clarkii).

PMID- 12414589
TI  - Development of the lateral eye of juvenile Limulus.

PMID- 12414590
TI  - Visual behavior of juvenile Limulus in their natural habitat and in captivity.

PMID- 12414591
TI  - Effects of individual size on pairing in horseshoe crabs.

PMID- 12414592
TI  - Circadian rhythms in locomotor activity of juvenile horseshoe crabs.

PMID- 12414593
TI  - Stable isotopic evidence for changing nutritional sources of juvenile horseshoe
      crabs.

PMID- 12414594
TI  - Acetylcholine mediates excitatory input to chromatophore motoneurons in the
      squid, Loligo pealeii.

PMID- 12414595
TI  - Cuttlefish body patterns as a behavioral assay to determine polarization
      perception.

PMID- 12414596
TI  - Tracking behavior of busyconinae whelks.

PMID- 12414598
TI  - Error-driven motor learning in fish.

PMID- 12414597
TI  - Central pathways mediating oculomotor reflexes in an elasmobranch, Scyliorhinus
      canicula.

PMID- 12414599
TI  - Social interaction and distribution of female zebrafish (Danio rerio) in a large
      aquarium.

PMID- 12414600
TI  - Caranx latus (carangidae) chooses dock pilings to attack silverside schools: a
      tactic to interfere with stereotyped escape behavior of prey?

PMID- 12414601
TI  - Molecular approaches to understanding population dynamics of the toxic
      dinoflagellate Alexandrium fundyense.

PMID- 12414602
TI  - Pelagic larval duration of the Caribbean wrasse, Thalassoma bifasciatum.

PMID- 12414603
TI  - Estuarine-open-water comparison of fish community structure in eelgrass (Zostera
      marina L.) habitats of Cape Cod.

PMID- 12414604
TI  - Influence of epiphytic algal coverage on fish predation rates in simulated
      eelgrass habitats.

PMID- 12414605
TI  - Effects of haying on salt-marsh surface invertebrates.

PMID- 12414606
TI  - Bacterioplankton community composition in flowing waters of the Ipswich River
      watershed.

PMID- 12414607
TI  - Reconstruction of historical land cover in the Ipswich watershed.

PMID- 12414608
TI  - Dissolved iron cycling in the subterranean estuary of a coastal bay: Waquoit Bay,
      Massachusetts.

PMID- 12414609
TI  - Nutrient and freshwater inputs from sewage effluent discharge alter benthic algal
      and infaunal communities in a tidal salt marsh creek.

PMID- 12414610
TI  - Tidal flushing of ammonium from intertidal salt marsh sediments: the relative
      importance of adsorbed ammonium.

PMID- 12414611
TI  - Effects of varying salinity on phytoplankton growth in a low-salinity coastal
      pond under two nutrient conditions.

PMID- 12414612
TI  - Nutrient limitation of phytoplankton growth in Vineyard Sound and Oyster Pond,
      Falmouth, Massachusetts.

PMID- 12414613
TI  - Response of shrimp populations to land-derived nitrogen in Waquoit Bay,
      Massachusetts.

PMID- 12414614
TI  - A three-year retrospective study of abdominal tumors in zebrafish maintained in
      an aquatic laboratory animal facility.

PMID- 12414615
TI  - Microbial analysis of ozone disinfection in a recirculating seawater system.

PMID- 12414617
TI  - Mutation in the ATP-binding pocket of the ABL kinase domain in an STI571
      resistant BCR/ABL-positive cell line.
AB  - The major mechanism of action of STI571 is a competitive interference with the
      ATP-binding site of the Bcr/Abl tyrosine kinase. In the BCR/ABL-positive cell
      line KBM5, we studied cellular events associated with the in vitro acquisition of
      resistance to STI571. The emergence of the STI571-resistant phenotype was
      accompanied by only a marginal increase in the number of copies of the BCR/ABL
      gene and its level of expression. The activity of the Bcr/Abl kinase (level of
      autophosphorylation) in resistant cells was, however, incompletely inhibited by
      STI571, and the acquisition of the high degree of resistance was associated with
      a single-point mutation leading to a substitution of a threonine-to-isoleucine at
      position 315 of Abl. In the resistant KBM5-STI571(R1.0) cells, 20% of the BCR/ABL
      transcripts and 10% of BCR/ABL gene copies on the DNA level were mutated. The
      mutation was present in all 10 STI571-resistant clones derived from low density
      clonogenic assay, confirming its presence in all colony-forming cells but only in
      a fraction of the BCR/ABL gene copies in each cell. The contribution of this
      mutation to STI571-resistant phenotype remains unknown. Preliminary data showing
      partial reversibility of resistance in these cells suggest that resistance may be
      multifactorial. No other mutations were identified in the kinase domain of the
      BCR/ABL gene.

PMID- 12414618
TI  - Identification from public data of molecular markers of adenocarcinoma
      characteristic of the site of origin.
AB  - Patients presenting with metastatic adenocarcinoma of unknown origin are a common
      clinical problem. Their optimal management and therapy are facilitated by
      identification of the primary site, yet histologically these tumors are almost
      identical. Better tumor markers are needed to enable the assignment of metastases
      to likely sites of origin. In this study, hierarchical clustering of public
      serial analysis of gene expression data showed that adenocarcinomas and their
      metastases cluster according to their site of origin. A novel bioinformatic
      approach was developed to exploit the differences between these clusters, using
      diverse sources: public expression data from serial analysis of gene expression
      and digital differential display; and the published literature, including
      microarray studies. Sixty-one candidate tumor markers with expression predicted
      to be characteristic of the site of origin were identified. Eleven genes were
      tested by reverse transcription-PCR in primary adenocarcinomas from a range of
      sites, and seven (64%) were site-restricted. Analysis of public gene expression
      data sets is a powerful method for the identification of clinically relevant
      tumor markers.

PMID- 12414619
TI  - Novel detection and differential utilization of a c-myc transcriptional block in
      colon cancer chemoprevention.
AB  - Mutations in the adenomatous polyposis coli (APC) gene, which initiate almost all
      human colon cancers, directly target the proto-oncogene, c-myc, by elevating beta
      catenin/T-cell factor (TCF) signaling. We have shown that agents ascribed
      chemopreventive activity for colon cancer in fact also stimulate beta-catenin/TCF
      activity in vitro. Their effects on c-myc transcription were assayed using a
      novel variant of fluorescence in situ hybridization that detects c-myc
      transcription sites in intact nuclei. Increased transcriptional initiation of c
      myc induced by the short-chain fatty acid, butyrate, consistent with elevated
      beta-catenin/TCF activity, was efficiently abrogated by a block to
      transcriptional elongation, resulting in decreased c-myc expression. 1alpha,25
      Dihydroxyvitamin D(3) also induced transcriptional blockage. In contrast, the
      nonsteroidal anti-inflammatory drug, sulindac, increased c-myc expression, an
      effect attributable at least in part to its failure to induce transcriptional
      blockage. We have described a novel approach for evaluating the effects of
      chemopreventive agents on the expression of a gene critical in colonic
      tumorigenesis.

PMID- 12414620
TI  - Morphological and molecular heterogeneity within nonmicrosatellite instability
      high colorectal cancer.
AB  - Colorectal cancer (CRC) has traditionally been classified into two groups:
      microsatellite stable/low-level instability (MSS/MSI-L) and high-level MSI (MSI
      H) groups on the basis of multiple molecular and clinicopathologic criteria.
      Using methylated in tumor (MINT) markers 1, 2, 12, and 31, we stratified 77
      primary CRCs into three groups: MINT++ (>2), MINT+ (1-2), and MINT- (0 markers
      methylated). The MSS/MSI-L/MINT++ group was indistinguishable from the MSI
      H/MINT++ group with respect to methylation of p16(INK4a), p14(ARF), and RIZ1, and
      multiple morphological features. The only significant difference between MSI-H
      and non-MSI-H MINT++ cancers was the higher frequency of K-ras mutation (P <
      0.004) and lower frequency of hMLH1 methylation (P < 0.001) in the latter. These
      data demonstrate that the separation of CRC into two nonoverlapping groups (MSI-H
      versus MSS/MSI-L) is a misleading oversimplification.

PMID- 12414621
TI  - Alendronate inhibits lysophosphatidic acid-induced migration of human ovarian
      cancer cells by attenuating the activation of rho.
AB  - Alendronate, a nitrogen-containing bisphosphonate, is a potent inhibitor of bone
      resorption used for the treatment and prevention of osteoporosis. Recent findings
      suggest that alendronate and other nitrogen-containing bisphosphonates inhibit
      the mevalonate pathway and thereby inhibit the synthesis of products derived from
      this metabolite. This, in turn, prevents the prenylation of a number of small
      GTPases, which regulate cell growth, motility, and invasion. We studied the
      effect of alendronate on in vitro migration of human ovarian cancer cells.
      Lysophosphatidic acid (LPA) induced a dose-dependent increase of migration of
      cancer cells by promoting Rho/Rho-associated kinase signaling. The induction of
      cancer cell migration by LPA was inhibited by the addition of alendronate in a
      dose-dependent manner. Treatment of ovarian cancer cells with alendronate
      resulted in inactivation of Rho, changes of cell morphology, loss of stress fiber
      formation, and focal adhesion assembly, and the suppression of phosphorylation of
      myosin light chain and tyrosine phosphorylation of focal adhesion proteins, which
      are essential processes for cell migration. The effects of alendronate on cancer
      cells were prevented by the addition of geranylgeranyol, which is the metabolic
      intermediate of the mevalonate pathway. These results suggest that alendronate
      inhibits Rho activation by preventing geranylgeranylation, which results in
      inhibition of LPA-induced migration of human ovarian cancer cells.

PMID- 12414622
TI  - Inhibition of transforming growth factor-beta activity decreases angiogenesis in
      a human prostate cancer-reactive stroma xenograft model.
AB  - We have shown previously that reactive stroma promotes angiogenesis and growth of
      LNCaP human prostate tumors in the differential reactive stroma xenograft model.
      Regulators of reactive stroma are not known, but transforming growth factor (TGF)
      beta1 is a likely candidate. Three-way differential reactive stroma tumors were
      generated in the presence of TGF-beta1 latency-associated peptide (LAP) or TGF
      beta1 neutralizing antibody. Tumors treated with either of those TGF-beta
      inhibitors exhibited a reduction in blood vessels, and blood lakes were observed
      in some areas. The microvessel density of LAP-treated tumors was decreased 3.5
      fold relative to control tumors. Moreover, the average wet-weight of LAP-treated
      tumors was reduced 46% compared with control tumors. The results of this study
      suggest that TGF-beta regulates reactive stroma and its ability to promote
      angiogenesis and tumor growth.

PMID- 12414623
TI  - Functional alterations of human exonuclease 1 mutants identified in atypical
      hereditary nonpolyposis colorectal cancer syndrome.
AB  - Hereditary Nonpolyposis Colorectal Cancer (HNPCC) is a genetically heterogeneous
      disorder caused by germ-line mutations in one of several DNA mismatch repair
      (MMR) genes, most commonly in hMSH2 and hMLH1. Human exonuclease 1 (hExo1)
      possesses both 5'exonuclease and flap endonuclease activities and plays a role in
      DNA repair, recombination, and replication. The enzyme interacts with MMR
      proteins, hMsh2, hMlh1, and hMsh3. Recently, eight missense mutations in hEXO1
      were identified in atypical HNPCC patients, who have been screened to be negative
      for hMSH2, hMLH1, and hMSH6 mutations. To address the question of whether these
      mutations cause susceptibility to HNPCC, in vitro nuclease activity and protein
      protein interaction assays were performed in this study. We found that two
      mutants, E109K and L410R, lost their exonuclease activities while retaining their
      capacity to bind to the DNA substrate. Three other mutants, P640S, G759E, and
      P770L, displayed a reduced capacity to interact with hMsh2. The combination of
      these three point mutations leads to the binding capacity with hMsh2 to nearly
      zero. Evidence made available in this study sheds light on the pathogenesis of
      HNPCC, perhaps initiated by an additional MMR gene, hEXO1.

PMID- 12414624
TI  - Ku affects the CHK1-dependent G(2) checkpoint after ionizing radiation.
AB  - There are two major pathways for repairing DNA double strand breaks in mammalian
      cells: nonhomologous end joining (NHEJ) and homologous recombination repair
      (HRR). The nonhomologous end joining repair is deficient in cells without Ku,
      whereas HRR is highly efficient in such cells compared with their wild-type
      counterparts. The mechanism remains unclear. We reported previously that Ku80(-/
      ) cells show a stronger ATM-dependent S-phase checkpoint response than Ku80(+/+)
      cells after ionizing radiation (IR; X-Y. Zhou et al., Oncogene, 21:6377-6381,
      2002). We report in this study that Ku80(-/-) cells also show a much stronger
      G(2) accumulation than Ku80(+/+) cells after IR. The stronger G(2) checkpoint
      response in Ku80(-/-) cells is ATM independent but is accompanied with a higher
      activity of CHK1 kinase. Treatment with Chk1 antisense oligonucleotide abolishes
      the stronger G(2) checkpoint response and sensitizes Ku80(-/-) cells to IR. These
      data indicate that the stronger G(2) checkpoint response shown in Ku80(-/-) cells
      is CHK1 dependent and suggest that the CHK1-dependent checkpoint response
      contributes to the highly efficient HRR in such cells.

PMID- 12414625
TI  - Constitutive activation of insulin receptor substrate 1 is a frequent event in
      human tumors: therapeutic implications.
AB  - Insulin receptor substrate 1 (IRS-1) is a major substrate of insulin, insulin
      like growth factors, and cytokine signaling and plays an important role in
      mediating apoptosis, cell differentiation, and cell transformation. We found that
      IRS-1 is constitutively activated in a variety of solid tumors, including breast
      cancers, leiomyomas, Wilms' tumors, rhabdomyosarcomas, liposarcomas,
      leiomyosarcomas, and adrenal cortical carcinomas. Blocking the constitutively
      activated IRS-1 signaling in breast cancer cells with a dominant-negative IRS-1,
      an IRS-1 with all 18 potential tyrosine-phosphorylation sites replaced by
      phenylalanines (F18), dramatically reduced cancer cell growth. Breast cancer
      cells that expressed F18 also formed smaller and far fewer colonies in soft agar
      culture than did the cells that did not express F18. These studies suggest that
      constitutive IRS-1 activation is a common phenomenon in tumors and that activated
      IRS-1 may present an attractive therapeutic target.

PMID- 12414626
TI  - Activation of mitogen-activated protein kinase pathway by the antiandrogen
      hydroxyflutamide in androgen receptor-negative prostate cancer cells.
AB  - Whereas hydroxyflutamide (HF) has been used as an antiandrogen to block androgen
      stimulated prostate tumor growth, the antiandrogen withdrawal syndrome that
      allows antiandrogens to stimulate prostate tumor growth still occurs in many
      patients treated with androgen ablation therapy. This was previously explained by
      mutations in the androgen receptor (AR) and/or modulation from AR coregulators,
      so that HF becomes an AR agonist. Using immunohistochemical analysis, we analyzed
      four prostate cancer patients undergoing androgen ablation therapy with flutamide
      and compared their phospho-extracellular signal-regulated kinase 1/2 levels in
      prostate cancer biopsies before receiving HF and after experiencing disease
      progression while taking HF. We found a significant increase of activated mitogen
      activated protein (MAP) kinase in prostate tumors from patients receiving HF
      during androgen ablation therapy. In vitro studies showed that HF induced a rapid
      activation of the Ras/MAP kinase pathway in human prostate cancer DU145 cells
      which lack the AR, as well as in PC-3AR2 and CWR22 cells which express the AR.
      Cycloheximide failed to inhibit this activation, but both AG1478, an inhibitor of
      the epidermal growth factor receptor (EGF-R), and an EGF-R-neutralizing antibody
      blocked this HF-mediated activation of MAP kinase, which suggests that the
      activation of Ras/MAP kinase by HF is a membrane-initiated, non-AR-mediated, and
      nongenomic action. The consequence of this activation may result in increasing
      cell proliferation and cyclin D1 expression. This raises a concern for using HF
      in the complete-androgen-ablation therapy in prostate cancer treatment and
      provides a possible pathway that might contribute to the HF withdrawal syndrome.

PMID- 12414627
TI  - Restoration of transforming growth factor Beta signaling by functional expression
      of smad4 induces anoikis.
AB  - Smad proteins transduce signals carried by the transforming growth factor beta
      (TGF-beta) cytokine superfamily from receptor serine/threonine kinases at the
      cell surface to the nucleus, thereby affecting cell proliferation,
      differentiation, as well as pattern formation during early vertebrate
      development. Smad4/DPC4, located at chromosome 18q21, was identified as a
      candidate tumor suppressor gene that is inactivated in nearly half of all
      pancreatic carcinomas. For functional characterization of Smad4, a recombinant
      adenovirus encoding Smad4 (Ad-Smad4) was generated. When Smad4 was expressed in
      Smad4-null breast carcinoma cell line MDA-MB-468 using the recombinant
      adenovirus, TGF-beta signaling was restored as determined by TGF-beta-dependent
      activity of plasminogen activator inhibitor 1 promoter and p21 expression.
      Infection with Ad-Smad4 in the presence of TGF-beta1 also resulted in an altered
      cell morphology that coincided with enhanced beta1 integrin expression and
      reduced efficiency of colony formation in soft agar. In agreement with increased
      p21 expression, Smad4-expressing cells showed modest reduction in S phase.
      However, Smad4 expression did not lead to induction of apoptosis under normal
      culture conditions. Interestingly, when Smad4-expressing cells were detached and
      incubated in suspension, they underwent rapid apoptosis in a TGF-beta-dependent
      manner. Induction of apoptosis caused by loss of anchorage is known as anoikis.
      Anoikis is believed to prevent colonization elsewhere of detached cells.
      Additional characterization revealed an increase in the level of focal adhesion
      kinase 2 (or Pyk2) and activation of caspases 2, 3, 6, and 8 during anoikis
      because of Smad4 expression and restoration of TGF-beta signaling. Because
      resistance to anoikis in tumor cells is thought to contribute to metastasis, our
      data suggest a functional basis for the strong correlation between defects in
      Smad4 and development of malignancy.

PMID- 12414628
TI  - Mutations in tetranucleotide repeats following DNA damage depend on repeat
      sequence and carcinogenic agent.
AB  - Sporadic microsatellite mutations are frequently observed in lung, bladder, and
      head and neck tumors with intact DNA mismatch repair. AAAG tetranucleotide
      repeats appear to be especially prone to the accumulation of these mutations. We
      hypothesized that occurrences of microsatellite mutations in these cancers may be
      linked to DNA damage caused by exposure to carcinogens in tobacco smoke. To test
      this hypothesis, we developed a model system based on reactivation of green
      fluorescent protein (GFP) in which a plasmid vector carries a microsatellite
      repeat that places the GFP sequence out of frame for protein translation. In this
      reporter system, DNA slippage mutations can restore the GFP reading frame and
      become detectable by flow cytometry as GFP-positive cells. Pools of stably
      transfected RKO cells were treated at four dose levels each of gamma-irradiation,
      benzo(a)pyrene diol epoxide, N-methyl-N-nitro-N-nitrosoguanidine (MNNG), t-butyl
      hydrogen peroxide, and UV irradiation and assayed for GFP-positive cells 48 h
      later. We studied the microsatellite repeats AAAG, ATAG, CAGT, and CA, as well as
      a control sequence lacking any repetitive elements. A log-linear regression
      approach was used to discriminate between the effects of repeat unit and dose for
      each agent. A statistically significant increase in GFP-positive cells was found
      with increasing dose with all agents, although repeat unit-specific response
      patterns were only observed with MNNG, t-butyl hydrogen peroxide, and UV
      irradiation. With MNNG, significant differences in response were observed between
      dinucleotide and tetranucleotide repeat units. The effects of UV irradiation were
      consistent with the predicted number of pyrimidine dimers/repeat unit, with
      higher GFP activation in repeats that had large numbers of adjacent pyrimidines.
      We found no evidence to indicate that the AAAG repeat responded to any of the DNA
      damaging agents with higher levels of GFP activation than other repeat units.
      These results provide evidence that DNA damage can induce slippage mutations and
      increase mutation rates in repeated sequences and that there are sequence
      specific responses to different types of DNA damage. Our results are compatible
      with the hypothesis that sporadic microsatellite mutations in human cancer may
      reflect DNA damage caused by carcinogen exposure.

PMID- 12414629
TI  - Induction of a low level of microsatellite instability by overexpression of DNA
      polymerase Beta.
AB  - Microsatellite instability (MSI) is the condition in which high rates of
      frameshift mutations are observed in short tandem repeat sequences. Mutations in
      sequences of this type in coding regions of cancer-related genes can contribute
      to the development of cancer. Although defects in mismatch repair are usually
      responsible for high levels of MSI, low levels of MSI have been observed in some
      cancers with no known mismatch repair defects. We have investigated whether
      overexpression of an error-prone polymerase, polbeta, is sufficient to induce MSI
      in the presence of mismatch repair. Because overexpression of polbeta has been
      observed in several types of cancer, we hypothesized that polbeta overexpression
      might increase genetic instability and, thus, contribute to carcinogenesis.
      Microsatellite mutation rate analyses were conducted using a drug-resistance
      reversion assay, where G(17) or A(17) microsatellites were inserted into a
      plasmid upstream of a neomycin-resistance gene (neo), such that the neo gene was
      shifted out of frame. When frameshift mutations occur in the microsatellite, the
      neo gene can be restored, allowing for selection of revertants in G418.
      Microsatellite-containing plasmids were transfected into telomerase-immortalized
      normal human fibroblasts (hTERT-1604), where they integrated into the nuclear
      genome. polbeta-expressing episomal vectors or empty control vectors were then
      introduced for analysis of the effect of polbeta overexpression on these
      microsatellites. Mutation rates were determined by fluctuation analysis. Mutation
      rates in G(17) repeats were elevated for the polbeta transfectants at all levels
      of overexpression ( approximately 2-fold to >100-fold compared with vector-only
      controls), with up to a 3-fold increase in mutation rates compared with the
      vector-only controls in cells with the highest expression. A similar magnitude of
      elevation in mutation rates was observed for A(17) microsatellites. No difference
      was observed between vector-only controls and nontransfected cells in either
      microsatellite sequence. Cells with high polbeta expression showed an
      approximately 1.5-fold increase in population doubling time and a 2-fold
      reduction in mitotic index compared with controls. Cells with both modest and
      high elevations in microsatellite mutation rates had these altered growth
      properties. These results suggest that polbeta overexpression may affect cell
      cycle progression and increase genetic instability.

PMID- 12414630
TI  - Mesothelial cell transformation requires increased AP-1 binding activity and ERK
      dependent Fra-1 expression.
AB  - Mesothelioma is a unique and insidious tumor associated historically with
      occupational exposure to asbestos. The transcription factor, activator protein-1
      (AP-1) is a major target of asbestos-induced signaling pathways. Here, we
      demonstrate that asbestos-induced mesothelial cell transformation is linked to
      increases in AP-1 DNA binding complexes and the AP-1 component, Fra-1. AP-1
      binding to DNA was increased dramatically in mesothelioma cell lines in
      comparison to isolated rat pleural mesothelial (RPM) cells. Elevated levels of AP
      1 complexes, including significant increases in c-Jun, JunB and Fra-1, were found
      in asbestos-exposed RPM cells, but only Fra-1 expression was significantly
      increased and protracted in both asbestos-exposed RPM cells and mesothelioma cell
      lines. Asbestos-induced Fra-1 expression in RPM cells was dependent on
      stimulation of the extracellular signal-regulated kinases (ERKs 1/2). Inhibition
      of ERK phosphorylation or transfection with dominant-negative fra-1 constructs
      reversed the transformed phenotype of mesothelioma cells and anchorage
      independent growth in soft agar. In summary, we demonstrate that ERK-dependent
      Fra-1 is elevated in AP-1 complexes in response to asbestos fibers and is
      critical to the transformation of mesothelial cells.

PMID- 12414631
TI  - Hepatic arterial infusion of a replication-selective oncolytic adenovirus
      (dl1520): phase II viral, immunologic, and clinical endpoints.
AB  - Replication-selective oncolytic adenoviruses are being developed for the
      treatment of cancer, but the safety and feasibility of repeated adenovirus
      delivery to tumors via the bloodstream was unknown, particularly in light of a
      patient death after hepatic artery infusion of a replication-defective adenovirus
      vector. We performed a Phase II trial of an oncolytic replication-selective
      adenovirus (dl1520, also known as Onyx-015) administered by hepatic artery
      infusion in patients with gastrointestinal carcinoma metastatic to the liver (n =
      27). dl1520 was infused into the hepatic artery (2 x 10(12) particles) on days 1
      and 8 as a single agent, and thereafter starting on day 22 in combination with
      i.v. 5-fluorouracil and leucovorin every 28 days. Repeated viral infusions were
      feasible, and no deaths occurred on study; reversible grade 3/4
      hyperbilirubinemia occurred in 2 patients. Systemic inflammatory cytokine
      responses varied greatly between patients and even between cycles within a given
      patient. Proinflammatory cytokines [e.g., tumor necrosis factor, IFN-gamma, and
      interleukin (IL) 6] typically rose within 3 h and were followed at 18 h by a rise
      in IL-10. However, in the single patient who suffered a severe but reversible
      systemic inflammatory response, a unique cytokine profile was detected: marked
      acute increases of IL-6 (20-fold higher than average for all of the patients) and
      inhibition of IL-10 production. Delayed secondary peaks of viremia were
      reproducibly detected 3-6 days after treatment, even in the presence of high
      level neutralizing antibody titers and antiviral cytokines. Mathematical modeling
      was used to calculate the number of virus particles produced and shed into the
      blood with each replication cycle. The combination of virotherapy and
      chemotherapy had antitumoral activity in some chemotherapy-resistant colorectal
      tumors. The intra-arterial infusion of oncolytic adenoviruses warrants additional
      study.

PMID- 12414632
TI  - Double blockade of cell cycle at g(1)-s transition and m phase by 3-iodoacetamido
      benzoyl ethyl ester, a new type of tubulin ligand.
AB  - 3-Iodoacetamido benzoyl ethyl ester (3-IAABE) is a new compound synthesized in
      our laboratory. The primary action of 3-IAABE is to inhibit microtubule assembly
      by interacting with -SH groups on tubulin. In contrast to other known microtubule
      disrupters, 3-IAABE caused a double blockade in the cell cycle at G(1)-S
      transition and in M phase. The blockade was determined by cell cycle analysis and
      chromosome distribution. Kinase activities of cyclin E and cyclin-dependent
      kinase 2 responsible for the G(1)-S transition were increased, as were the
      activities of mitotic cyclin B and cdc2. 3-IAABE treatment also increased p53
      expression and dephosphorylated (or activated) retinoblastoma protein.
      Investigation of the signal transduction pathway showed that 3-IAABE induced bcl
      2 phosphorylation, followed by activation of caspase-9, -3, and -6, but not
      caspase-8. DNA fragmentation factor and poly(ADP-ribose) polymerase, the
      downstream substrates of caspase-3 and -6, were cleaved after 3 h of exposure to
      3-IAABE, followed by DNA fragmentation. Pretreatment of the cells with inhibitors
      of caspase-9, -3, or -6, respectively, inhibited the cleavage of DNA
      fragmentation factor and poly(ADP-ribose) polymerase and thus inhibited the onset
      of apoptosis. 3-IAABE showed antitumor activities in the panel of 60 National
      Cancer Institute human tumor cell lines with total growth inhibition in the range
      of 0.22-4.3 micro M for solid tumor lines and 0.025-0.22 micro M for
      leukemia/lymphoma cell lines. The 3-IAABU total growth inhibition of
      phytohemagglutinin-stimulated healthy human lymphocytes was 450-fold greater than
      that of leukemic cells. 3-IAABE significantly inhibited the growth of human
      hepatocarcinoma (BEL-7402) in nude mice by 72% in tumor volume, more strongly
      than did vincristine (43 percent inhibition). Besides being a novel lead for the
      design of new anticancer tubulin ligands, the activity of 3-IAABE in the cell
      cycle may also help us to understand the molecular pharmacology of microtubule
      active drugs.

PMID- 12414633
TI  - Enzyme-activated Prodrug Therapy Enhances Tumor-specific Replication of
      Adenovirus Vectors.
AB  - Adenoviruses (Ads) that selectively replicate in tumor cells have shown promising
      preliminary results in clinical trials, especially in combination with
      chemotherapy. Here, we describe a system that combines the antitumor synergy of
      Ads and chemotherapeutic agents with the benefits of enzyme-activated prodrug
      therapy. In this system, a functional transgene expression cassette is created by
      homologous recombination during adenoviral DNA replication. Transgene expression
      is strictly dependent on viral DNA replication, which in turn is tumor specific.
      We constructed replication-activated Ad vectors to express a secreted form of
      beta-glucuronidase and a cytosine deaminase/uracil phosphoribosyltransferase,
      which activate the prodrugs 9-aminocamptothecin glucuronide to 9
      aminocamptothecin and 5-fluorocytosine to 5-fluorouracil (5-FU) and further to 5
      fluoro-UMP, respectively. We demonstrated replication-dependent transgene
      expression, prodrug activation, and induction of tumor cell toxicity by secreted
      beta-glucuronidase and cytosine deaminase/uracil phosphoribosyltransferase.
      Furthermore, exposure of cells to activated prodrug or drug at subtoxic
      concentrations enhanced viral DNA replication. Characteristically, these agents
      induced changes in the cell cycle status of exposed cells (G(2) arrest), which
      closely resembled the effect of wild-type Ad infection, and are thought to be
      favorable for viral replication. We tested a number of cytostatic drugs
      (camptothecin, etoposide, daunorubicin, cisplatin, 5-fluorouracil, hydroxyurea,
      Taxol, and actinomycin D) for their effect on viral DNA replication and found
      considerable differences between individual agents. Finally, we show that the
      combination of viral and prodrug therapy enhances viral replication and spread in
      liver metastases derived from human colon carcinoma or cervical carcinoma in a
      mouse model. Our data indicate that specific vector/drug combinations tailored to
      be synergistic may have the potential to improve the potency of either
      therapeutic approach. These data also provide a new rationale for expressing
      prodrug-activating enzymes from conditionally replicating Ads.

PMID- 12414634
TI  - Gene transfer in ovarian cancer cells: a comparison between retroviral and
      lentiviral vectors.
AB  - Local gene therapy could be a therapeutic option for ovarian carcinoma, a life
      threatening malignancy, because of disease containment within the peritoneal
      cavity in most patients. Lentiviral vectors, which are potentially capable of
      stable transgene expression, may be useful to vehicle therapeutic molecules
      requiring long-term production in these tumors. To investigate this concept, we
      used lentiviral vectors to deliver the enhanced green fluorescent protein (EGFP)
      gene to ovarian cancer cells. Their efficiency of gene transfer was compared with
      that of a retroviral vector carrying the same envelope. In vitro, both vectors
      infected ovarian cancer cells with comparable efficiency under standard culture
      conditions; however, the lentiviral vector was much more efficient in transducing
      growth-arrested cells when compared with the retroviral vector. Gene transfer was
      fully neutralized by an anti-VSV-G antibody, and in vitro stability was similar.
      In vivo, the lentiviral vector delivered the transgene 10-fold more efficiently
      to ovarian cancer cells growing i.p. in SCID mice, as evaluated by real-time PCR
      analysis of the tumors. Confocal microscopy analysis of tumor sections showed a
      dramatic difference at the level of transgene expression, because abundant
      EGFP(+) cells were detected only in mice receiving the lentiviral vector.
      Quantitative analysis by flow cytometry confirmed this and indicated 0.05 and
      5.6% EGFP(+) tumor cells after administration of the retroviral and lentiviral
      vector, respectively. Injection of ex vivo transduced tumor cells, sorted for
      EGFP expression, indicated that the lentiviral vector was considerably more
      resistant to in vivo silencing in comparison with the retroviral vector. Finally,
      multiple administrations of a murine IFN-alpha(1)-lentiviral vector to ovarian
      carcinoma-bearing mice significantly prolonged the animals' survival, indicating
      the therapeutic efficacy of this approach. These findings indicate that
      lentiviral vectors deserve attention in the design of future gene therapy
      approaches to ovarian cancer aimed at achieving long-term expression of
      therapeutic genes.

PMID- 12414635
TI  - MS-27-275, an inhibitor of histone deacetylase, has marked in vitro and in vivo
      antitumor activity against pediatric solid tumors.
AB  - The antitumor efficacy of the synthetic benzamide derivative MS-27-275 (MS-275),
      an inhibitor of histone deacetylation [T. Suzuki et al., J. Med. Chem., 42: 3001
      3003, 1999], was evaluated in a series of pediatric solid tumor cell lines,
      including neuroblastoma, rhabdomyosarcoma, Ewing's sarcoma (EWS), retinoblastoma,
      medulloblastoma, undifferentiated sarcoma (US), osteosarcoma, and malignant
      rhabdoid tumors. Treatment with MS-275 results in an increase in acetylation of
      histones within 4 h of drug exposure. The cell lines were treated with various
      concentrations of MS-275 for 3 days and incubated with [(3)H]thymidine for 20 h
      before cell harvest. MS-275 inhibited [(3)H]thymidine uptake in a dose-dependent
      manner in all tumor cell lines examined. The IC(50) ranged from 50 nm in the D283
      medulloblastoma cell line to 1.3 micro M in the US. A common feature of MS-275
      treatment of pediatric tumor cell lines was induction of p21mRNA. However, the
      effects on cell cycle were diverse because in some cases MS-275 induced an
      increase in G(1) or G(2), whereas in others, there was an induction of apoptosis.
      In EWS, the EWS/fli chimeric transcription factor created by the t(11;22)
      suppresses transforming growth factor (TGF) betaRII transcription, however, MS
      275 was able to induce an increase in TGF-betaRII mRNA and restore TGF-beta
      signaling. Using xenograft orthotopic models of US, EWS, and neuroblastoma, we
      find that the growth of established tumors is inhibited in mice treated with MS
      275.

PMID- 12414636
TI  - Sulfonamide derivative, E7820, is a unique angiogenesis inhibitor suppressing an
      expression of integrin alpha2 subunit on endothelium.
AB  - In the process of angiogenesis, endothelial adhesion molecules play a significant
      role in vascular morphogenesis, in coordination with angiogenic factor signaling.
      Here we report that a novel angiogenesis inhibitor, E7820 (an aromatic
      sulfonamide derivative), inhibited in vitro proliferation and tube formation of
      human umbilical vascular endothelial cell (HUVEC). E7820 decreased integrin
      alpha2, 3, 5, and beta1 in confluent culture of HUVEC, and integrin alpha2 was
      initially suppressed in mRNA level, followed by decrement of integrins alpha3, 5,
      and beta1. The inhibition of integrin alpha2 expression in HUVEC showed dose
      dependence but did not alter the level of CD31. Up-regulation of integrin alpha2
      by phorbol 12-myristate 13-acetate abrogated the inhibitory effect of E7820 on
      tube formation within type I collagen gel, whereas addition of antibody against
      integrin alpha2 canceled the phorbol 12-myristate 13-acetate effect. These
      results suggest that E7820 inhibited tube formation through the suppression of
      integrin alpha2. Oral administration of E7820 remarkably resulted in inhibition
      of tumor-induced angiogenesis in mouse dorsal air sac model, and tumor growth of
      human colorectal tumor cell lines (WiDr and LoVo) was inhibited in
      xenotransplanted model in mice. This is the first time that a small molecule has
      been shown to modulate integrins, and this finding may provide the basis for a
      new approach to antiangiogenic therapy through the suppression of integrin alpha2
      on endothelium.

PMID- 12414637
TI  - Antitumor effect of in vivo somatostatin receptor subtype 2 gene transfer in
      primary and metastatic pancreatic cancer models.
AB  - Our previous studies conducted in pancreatic cancer models established in nude
      mice and hamsters revealed that cloned somatostatin receptor subtype 2 (sst2)
      gene expression induced both antioncogenic and local antitumor bystander effects
      in vivo. In the present study, in vivo gene transfer of sst2 was investigated in
      two transplantable models of primary and metastatic pancreatic carcinoma
      developed in hamsters. LacZ reporter or mouse sst2 genes were expressed by means
      of two different delivery agents: an adenoviral vector and a synthetic
      polycationic carrier [linear polyethylenimine (PEI)]. sst2 was injected into
      either exponentially growing pancreatic primary tumors or hepatic metastases, and
      then transgene expression and tumor progression were investigated 5-6 days after
      gene transfer. Molecular mechanisms involved in the inhibition of tumor growth
      were also analyzed. Both adenovirus- and PEI-mediated in vivo gene transfer in
      primary pancreatic tumors induced an increase of beta-galactosidase activity and
      expression of sst2 transgene nRNA (100% and 86% of tumors for adenovirus and PEI
      vector, respectively). Adenoviral vector-based sst2 gene transfer resulted in
      significant reduction of pancreatic tumor growth (P < 0.05). Using PEI vector,
      both pancreatic primary tumor growth and metastatic tumor growth were also
      significantly slackened as compared with both LacZ-treated and untreated control
      groups (P < 0.02). Moreover, the proliferative index decreased significantly (P <
      0.005), whereas apoptosis increased (P < 0.005) in tumors transferred with sst2
      gene. The increase of apoptosis correlated with an activation of the caspase-3
      and poly(ADP-ribose) polymerase pathways. We concluded that in both primary and
      metastatic pancreatic cancer models, the synthetic gene delivery system can
      achieve in vivo sst2 gene transfer and results in a significant antitumor effect
      characterized by an increase of apoptosis and an inhibition of cell
      proliferation. This new strategy of gene therapy allows the restoration of
      expression of an antioncogenic molecule and could be promising for the treatment
      of advanced pancreatic cancer.

PMID- 12414638
TI  - Increased exposure of anionic phospholipids on the surface of tumor blood
      vessels.
AB  - Anionic phospholipids are largely absent from the external leaflet of the plasma
      membrane of mammalian cells under normal conditions. Exposure of
      phosphatidylserine on the cell surface occurs during apoptosis, necrosis, cell
      injury, cell activation, and malignant transformation. In the present study, we
      determined whether anionic phospholipids become exposed on tumor vasculature. A
      monoclonal antibody, 9D2, which specifically recognizes anionic phospholipids,
      was injected into mice bearing a variety of orthotopic or ectopic tumors. Other
      mice received annexin V, a natural ligand that binds to anionic phospholipids.
      Both 9D2 and annexin V specifically localized to vascular endothelium in all of
      the tumors, and also to tumor cells in and around regions of necrosis. Between 15
      and 40% of endothelial cells in tumor vessels were stained. No localization was
      detected on normal endothelium. Various factors and tumor-associated conditions
      known to be present in the tumor microenvironment were examined for their ability
      to cause exposure of anionic phospholipids in cultured endothelial cells, as
      judged by 9D2 and annexin V binding. Hypoxia/reoxygenation, acidity, thrombin,
      and inflammatory cytokines all induced exposure of anionic phospholipids.
      Hydrogen peroxide was also a strong inducer. Combined treatment with inflammatory
      cytokines and hypoxia/reoxygenation had greater than additive effects. Possibly,
      injury and activation of tumor endothelium by cytokines and reactive oxygen
      species induce exposure of anionic phospholipids, most likely phosphatidylserine.
      Anionic phospholipids on tumor vessels could potentially provide markers for
      tumor vessel targeting and imaging.

PMID- 12414639
TI  - Inhibitors of mTOR reverse doxorubicin resistance conferred by PTEN status in
      prostate cancer cells.
AB  - Phosphatase and tensin homologue deleted from chromosome 10 (PTEN) is a lipid
      phosphatase with putative tumor suppressing abilities, which is frequently
      mutated in prostate cancer. Loss of PTEN leads to constitutive activation of the
      phosphatidylinositol 3'-kinase/serine-threonine kinase (Akt) signal transduction
      pathway and has been associated with resistance to chemotherapy. This study aimed
      to determine the effects of PTEN status and treatment with rapamycin, an
      inhibitor of mTOR, in the response of prostate cancer cell lines to doxorubicin.
      The DU-145 PTEN-positive cell line was significantly more susceptible to the
      antiproliferative effects of doxorubicin as compared with the PTEN-negative PC-3
      cell line. Transfection of PTEN into the PC3 cells decreased the activation of
      Akt and the downstream mTOR-regulated 70-kDa S6 (p70(s6k)) kinase and reversed
      the resistance to doxorubicin in these cells, indicating that changes in PTEN
      status/Akt activation modulate the cellular response to doxorubicin. Treatment of
      PC-3 PTEN-negative cells with rapamycin inhibited 70-kDa S6 kinase and increased
      the proliferative response of these cells to doxorubicin, so that it was
      comparable with the responses of PTEN-positive DU-145 cells and the PC-3
      transfected cells. Furthermore, treatment of mice bearing the PTEN-negative PC-3
      prostate cancer xenografts with CCI-779, an ester of rapamycin in clinical
      development combined with doxorubicin, inhibited the growth of the doxorubicin
      resistant PC-3 tumors confirming the observations in vitro. Thus, rapamycin and
      CCI-779, by interacting with downstream intermediates in the phosphatidylinositol
      3'-kinase/Akt signaling pathway, reverse the resistance to doxorubicin conferred
      by PTEN mutation/Akt activation. These results provide the rationale to explore
      in clinical trials whether these agents increase the response to chemotherapy of
      patients with PTEN-negative/Akt active cancers.

PMID- 12414640
TI  - Tumor targeting with radiolabeled alpha(v)beta(3) integrin binding peptides in a
      nude mouse model.
AB  - The alpha(v)beta(3) integrin is expressed on proliferating endothelial cells such
      as those present in growing tumors, as well as on tumor cells of various origin.
      Tumor-induced angiogenesis can be blocked in vivo by antagonizing the
      alpha(v)beta(3) integrin with small peptides containing the Arg-Gly-Asp (RGD)
      amino acid sequence. This tripeptidic sequence, naturally present in
      extracellular matrix proteins, is the primary binding site of the alpha(v)beta(3)
      integrin. Because of selective expression of alpha(v)beta(3) integrin in tumors,
      radiolabeled RGD peptides are attractive candidates for alpha(v)beta(3) integrin
      targeting in tumors. We studied the in vivo behavior of the radiolabeled dimeric
      RGD peptide E-[c(RGDfK)](2) in the NIH:OVCAR-3 s.c. ovarian carcinoma xenograft
      model in BALB/c nude mice. Conjugation of the 1,4,7,10-tetraazadodecane
      N,N',N",N"'-tetraacetic acid (DOTA) and hydrazinonicotinamide (HYNIC) chelators
      enabled efficient radiolabeling with (111)In/(90)Y and (99m)Tc, respectively. The
      radiolabeled peptide was rapidly excreted renally. Uptake in nontarget organs
      such as liver and spleen was considerable. Tumor uptake peaked at 7.5% injected
      dose (ID)/g ((111)In-DOTA-E-[c(RGDfK)](2)) or 6.0%ID/g ((99m)Tc-HYNIC-E
      [c(RGDfK)](2)) at 2 and 1 h postinjection, respectively. Integrin alpha(v)beta(3)
      receptor binding specificity was demonstrated by reduced tumor uptake after
      injection of the scrambled control peptide (111)In-DOTA-E-[c(RDKfD)](2)
      (0.28%ID/g at 2 h p.i.) and after coinjection of excess nonradioactive (115)In
      DOTA-E-[c(RGDfK)](2) (0.22%ID/g at 2 h p.i.). A single injection of (90)Y-DOTA-E
      [c(RGDfK)](2) at the maximum-tolerated dose (37 MBq) in mice with small s.c.
      tumors caused a significant growth delay as compared with mice treated with 37
      MBq (90)Y-labeled scrambled peptide or untreated mice (median survival of 54
      versus 33.5 versus 19 days, respectively). In conclusion, the radiolabeled RGD
      peptides (111)In-DOTA-E-[c(RGDfK)](2) and (99m)Tc-HYNIC-E-[c(RGDfK)](2)
      demonstrated high and specific tumor uptake in a human tumor xenograft. Injection
      of (90)Y-DOTA-E-[c(RGDfK)](2) induced a significant delay in tumor growth.
      Potentially, these peptides can be used for peptide receptor radionuclide imaging
      as well as therapy.

PMID- 12414641
TI  - Defibrotide in combination with granulocyte colony-stimulating factor
      significantly enhances the mobilization of primitive and committed peripheral
      blood progenitor cells in mice.
AB  - Defibrotide is a polydeoxyribonucleotide, which significantly reduces the
      expression of adhesion molecules on endothelial cells. We investigated the
      activity of Defibrotide alone or in combination with recombinant human
      granulocyte colony-stimulating factor (rhG-CSF) to mobilize peripheral blood
      progenitor cells (PBPCs) in BALB/c mice. A 5-day treatment with Defibrotide alone
      (1-15 mg/mouse/day) had no effect on WBC counts, frequencies and absolute numbers
      of total circulating colony-forming cells (CFCs), i.e., granulocyte-macrophage
      colony-forming units, erythroid burst-forming units, and multilineage colony
      forming units. As compared with mock-injected mice, administration of rhG-CSF
      alone (5 micro g/mouse/day) for 5 days significantly (P < or = 0.0001) increased
      WBC counts, CFC frequencies, and CFC absolute numbers by 2-, 13-, and 27-fold,
      respectively. As compared with control mice, the combined administration of
      Defibrotide (15 mg/mouse/day) and rhG-CSF significantly (P < or = 0.0001)
      increased WBC counts, frequencies and absolute numbers of CFCs by 4-, 38-, and
      119-fold, respectively. As compared with rhG-CSF alone, administration of
      Defibrotide plus rhG-CSF resulted in a significant increase (P < or = 0.001) of
      the frequency of circulating long-term culture-initiating cells. In addition,
      transplantation of 2 x 10(5) rhG-CSF- or Defibrotide/rhG-CSF-mobilized
      mononuclear cells rescued 43% and 71% of recipient mice, respectively.
      Experiments of CFC homing performed in lethally irradiated or nonirradiated
      recipients showed that marrow homing of transplanted PBPCs was reduced by 3-fold
      in Defibrotide-treated animals as compared with mock-injected mice (P < or =
      0.001), suggesting that the mobilizing effect of Defibrotide might be because of
      an effect on PBPC trafficking. In conclusion, our data demonstrate that
      Defibrotide synergizes with rhG-CSF and significantly increases the mobilization
      of a broad spectrum of PBPCs, including primitive and committed progenitor cells.
      These data might have relevant implications for autologous and allogeneic
      anticancer therapy in humans.

PMID- 12414642
TI  - Low systemic exposure of oral docetaxel in mice resulting from extensive first
      pass metabolism is boosted by ritonavir.
AB  - P-glycoprotein seems to be the most important factor limiting the oral absorption
      of paclitaxel. We have now explored the mechanisms responsible for the low oral
      bioavailability of docetaxel, a structurally related taxane drug. The recovery of
      33% of oxidative metabolites and only 39% of unchanged drug in the feces of FVB
      wild-type mice receiving 10 mg/kg of oral docetaxel indicates that the major part
      of the oral dose has been absorbed. The feces and bile of mice receiving 10 mg/kg
      of i.v. docetaxel contained large amounts of metabolites and only minor
      quantities of unchanged drug, highlighting the importance of metabolism as an
      elimination route for this drug. In wild-type and P-glycoprotein knockout mice,
      dose escalation of p.o. administered docetaxel from 10 to 30 mg/kg resulted in a
      more than proportional increase in plasma levels, which suggested saturation of
      first-pass metabolism. Moreover, coadministration of 12.5 mg/kg of the HIV
      protease inhibitor ritonavir, also a strong inhibitor of cytochrome P4503A4 with
      only minor P-glycoprotein inhibiting properties, increased the plasma levels
      after oral docetaxel by 50-fold. In vitro transport studies across monolayers of
      LLC-PK1 cells (parental and transduced with MDR1 or Mdr1a) suggested that
      docetaxel is a weaker substrate for P-glycoprotein than paclitaxel is. In
      conclusion, docetaxel is well absorbed from the gut lumen in mice despite the
      presence of P-glycoprotein in the gut wall. Subsequent first-pass extraction is
      the most important factor determining its low bioavailability. The inhibition of
      docetaxel metabolism by ritonavir provides an interesting strategy to improve the
      systemic exposure of oral docetaxel.

PMID- 12414643
TI  - Conditionally replicative adenovirus expressing p53 exhibits enhanced oncolytic
      potency.
AB  - Conditionally replicative adenoviruses (CRAds) hold promise as anticancer agents.
      Their potency depends on their replication efficiency in cancer cells and their
      capacity to destroy these cells by oncolysis. In this regard, a critical
      determinant is the capacity of CRAds to induce cell death at late stages of
      infection to release their progeny. One of the cell death pathways that are
      exploited by adenoviruses involves the tumor suppressor protein p53.
      Unfortunately, many cancer cells have a nonfunctional p53 pathway and thus do not
      effectively support CRAd-induced cell death. We hypothesized that restoration of
      the p53-dependent cell death pathway in cancer cells would promote CRAd-induced
      cell lysis. Exogenous expression of p53 in human cancer cells during adenovirus
      replication accelerated cell death by several days and augmented early virus
      progeny release. The p53-enhanced oncolysis occurred independent of E1A binding
      to pRb and independent of E3 functions. On the basis of these findings, we
      constructed a new CRAd, AdDelta24-p53. This virus expressed functional p53 while
      replicating in cancer cells. Most importantly, AdDelta24-p53 exhibited enhanced
      oncolytic potency on 80% of tested human cancer cell lines of various tissue
      origins and with different p53 status. CRAd potency was increased up to >100-fold
      by p53 expression. We conclude that CRAds expressing p53 are promising new agents
      for more effective treatment of many human cancers.

PMID- 12414644
TI  - Characterization of the drug resistance and transport properties of multidrug
      resistance protein 6 (MRP6, ABCC6).
AB  - Mutations in human multidrug resistance protein 6 (MRP6, ABCC6), a member of the
      MRP family of drug efflux pumps, are the genetic basis of Pseudoxanthoma
      elasticum, a disease that affects elastin fibers in the skin, retina, and blood
      vessels. However, little is known about the functional characteristics of the
      protein, including its potential activity as a resistance factor for anticancer
      agents. Here, we report the results of investigations of the in vitro transport
      properties and drug resistance activity of MRP6. Using membrane vesicles prepared
      from Chinese hamster ovary cells transfected with MRP6 expression vector, it is
      shown that expression of MRP6 is specifically associated with the MgATP-dependent
      transport of the glutathione S-conjugates leukotriene C(4) and S-(2, 4
      dinitrophenyl)glutathione and the cyclopentapeptide BQ123 but not glucuronate
      conjugates such as 17beta-estradiol 17-(beta-D-glucuronide). Analysis of the drug
      sensitivity of MRP6-transfected cells revealed low levels of resistance to
      several natural product agents, including etoposide, teniposide, doxorubicin, and
      daunorubicin. These results indicate that MRP6 is a glutathione conjugate pump
      that is able to confer low levels of resistance to certain anticancer agents.

PMID- 12414645
TI  - Major histocompatibility complex class I-related chain A and UL16-binding protein
      expression on tumor cell lines of different histotypes: analysis of tumor
      susceptibility to NKG2D-dependent natural killer cell cytotoxicity.
AB  - NKG2D, together with NKp46 and NKp30, represents a major triggering receptor
      involved in the induction of cytotoxicity by both resting and activated human
      natural killer cells. In this study, we analyzed the expression and the
      functional relevance of MHC class I-related chain A (MICA) and UL16 binding
      protein (ULBP), the major cellular ligands for human NKG2D, in human tumor cell
      lines of different histological origin. We show that MICA and ULBP are frequently
      coexpressed by carcinoma cell lines, whereas MICA is expressed more frequently
      than ULBP by melanoma cell lines. Interestingly, the MICA(-) ULBP(+) phenotype
      was detected in most T cell leukemia cell lines, whereas the MICA(-) ULBP(-)
      phenotype characterized all acute myeloid leukemia and most B-cell lymphoma cell
      lines analyzed. These results, together with functional experiments, based on
      monoclonal antibody-mediated blocking of either NKG2D or its ligands, showed that
      killing of certain MICA(-) cell tumors is at least in part NKG2D dependent.
      Indeed, leukemic T cells as well as certain B-cell lymphomas were killed in a
      NKG2D-dependent fashion upon recognition of ULBP molecules. Moreover, ULBP could
      induce NKG2D-mediated NK cell triggering also in tumors coexpressing MICA. Our
      data suggest that the involvement of NKG2D in natural killer cell-mediated
      cytotoxicity strictly correlates with the expression and the surface density of
      MICA and ULBP on target cell tumors of different histotypes.

PMID- 12414646
TI  - Antitumor efficacy of wild-type p53-specific CD4(+) T-helper cells.
AB  - Overexpression of p53 is found in approximately 50% of human cancers, making it
      an attractive target antigen for immunotherapy of cancer. Research in this area
      has thus far primarily focused on p53-specific CTLs. Although these CTLs were
      shown to be highly effective against p53-overexpressing tumors in vivo,
      immunological tolerance seems to strongly restrict the spectrum of the p53
      specific CTL repertoire in p53(+/+) subjects. In view of the emerging role of
      CD4(+) Th (Th) cells in the antitumor response, we investigated the specificity
      and antitumor efficacy of the p53-specific Th response in mice. Our data show
      that high affinity Th cells against the naturally processed epitope p53(108-122)
      can be elicited in both p53(-/-) and p53(+/+) mice, indicating that the p53
      specific T-cell response is not affected by tolerance at the Th level.
      Furthermore, p53(108-122)-specific Th cells were effective in enabling p53
      specific CTLs to control the growth of p53-overexpressing tumors in vivo.
      Therefore, exploitation of the p53-specific Th response appears to be a highly
      useful aspect of immunotherapeutic strategies against cancers.

PMID- 12414647
TI  - Loss of Brca2 and p53 synergistically promotes genomic instability and
      deregulation of T-cell apoptosis.
AB  - BRCA2 is a breast cancer susceptibility gene of which the product is thought to
      be involved in monitoring genome integrity and cell cycle progression. Brca2-null
      mice have a defect in embryonic cellular proliferation and die in utero. Here we
      report the generation of T-cell lineage-specific Brca2-deficient (tBrca2(-/-))
      mice using the Cre-loxP system. Mice with a flanked by loxP allele of Brca2 were
      crossed to transgenic mice bearing Cre recombinase driven by the T cell-specific
      promoter Lck. Thymic cellularity and distribution of subset populations were
      normal in tBrca2(-/-) mutants. Thymocytes from tBrca2(-/-) mice underwent normal
      apoptosis in response to a variety of stimuli, and activated tBrca2(-/-) T cells
      had normal proliferative capacity. tBrca2(-/-) T cells were more likely than wild
      type cells to undergo spontaneous apoptosis, but apoptosed normally in response
      to restimulation or DNA-damaging stress signals. Examination of metaphase spreads
      of tBrca2(-/-) T cells revealed that the chromosomes often exhibited aberrations
      such as breaks and tri-radial structures. The level of chromosomal abnormalities
      was enhanced in T cells from tBrca2(-/-); p53(-/-) double-mutant mice. However,
      tBrca2(-/-); p53(-/-) T cells did not show the enhanced level of spontaneous
      apoptosis demonstrated by tBrca2(-/-) T cells, a difference that likely accounts
      for an increase in cell number and (3)[H]thymidine incorporation of double-mutant
      T cells in culture compared with either single mutant. Despite this increased T
      cell number, the onset of T-cell lymphomas was only marginally accelerated in
      tBrca2(-/-); p53(-/-) mice compared with p53(-/-) mice. Our results support a
      role for Brca2 in repairing spontaneous DNA lesions, and suggest that loss of
      Brca2 enhances the susceptibility of mouse T-lineage cells to chromosomal
      aberrations and deregulation of apoptosis in the absence of p53.

PMID- 12414648
TI  - Genetic aberrations defined by comparative genomic hybridization distinguish long
      term from typical survivors of glioblastoma.
AB  - Glioblastoma (GBM) remains a highly lethal neoplasm, refractory to current
      therapies. The molecular genetic aberrations most closely related to clinical
      aggressiveness in GBM have been difficult to identify, perhaps due in part to the
      short survival range observed in cohorts of GBM patients. To address this, we
      characterized 39 tumors from rare patients (2-5% of all GBM cases) who
      experienced long-term survival (>3 years) using comparative genomic hybridization
      as a genome-wide screen. We then compared the frequency and type of aberrations
      with those in tumors from 24 typical or short-term survivors [STSs (<1.5 years)].
      Losses of 9p and 10 and simple gains of chromosome 7 showed at least trends
      toward increased frequency in the STS group. Additional aberrations, including
      loss of 6q and gains of 19q and 20q, were significantly more frequent in the STS
      group. The presence of 19q loss was exclusive to the long-term survivor (LTS)
      group. Multivariate analyses indicated that 6q loss, 10q loss, and 19q gain were
      associated with short-term survival (all P < 0.01). The combination of any two of
      these three aberrations was seen in 16 of 24 STSs but only 1 of 39 LTSs. This
      comparison of rare LTSs with STSs (typical GBM survivors) identified 6q loss, 10q
      loss, and 19q gain, particularly when two or more of these were present, as most
      closely associated with aggressive clinical behavior in GBM. Loss of 19q may be a
      marker of long-term survival.

PMID- 12414649
TI  - Amplicon mapping and transcriptional analysis pinpoint cyclin L as a candidate
      oncogene in head and neck cancer.
AB  - DNA gains targeting the 3q chromosome are common in head and neck squamous cell
      carcinomas, as well as in lung, ovarian, and cervical cancer. Several candidate
      oncogenes located on 3q were proposed, i.e., PIK3CA, p63, and eIF-5A2. However,
      none of these genes was found included in a narrow high-level amplification.
      Recently, microarray-based comparative genomic hybridization (array CGH) was
      developed for high-resolution screening of deletions and amplifications in tumor
      genomes. In this study, by microarray-based comparative genomic hybridization, we
      found a narrow 3q25.3 high-level amplification in a head and neck cancer cell
      line. We precisely delimited the 3-Mb length-amplified segment by
      semiquantitative PCR and measured the transcriptional level of every gene (RefSeq
      full-length mRNA) located inside this segment by cDNA microarray and quantitative
      reverse transcription-PCR. Four genes were overexpressed in three head and neck
      cancer cell lines with increased DNA copy number, compared with a control tongue
      cell line. We extended the transcriptional analysis of these four genes to 20
      head and neck squamous cell carcinomas. Only one gene, cyclin L (ania-6a), is
      commonly overexpressed in primary tumors compared with corresponding normal
      tissues. This cyclin was previously pinpointed as a candidate for a role in
      promoting cell cycle entry. Thus, we propose cyclin L as a candidate oncogene in
      head and neck cancer.

PMID- 12414650
TI  - Genomic and expression analysis of the 12p11-p12 amplicon using EST arrays
      identifies two novel amplified and overexpressed genes.
AB  - We performed parallel array comparative genomic hybridization and array
      expression analysis of the 12p11-p12 amplicon in human testicular seminomas and
      an ovarian carcinoma cell line using an expressed sequence tags (ESTs) array
      spotted with 8254 ESTs. The data were normalized using a robust statistical
      modeling and the significance inferred from the local SD. We identified two ESTs
      within the chromosomal amplicon that were amplified and overexpressed in > or =75
      100 percent of analyzed tumors with the 12p11-p12 amplicon. These sequences,
      belonging to coding regions of two novel genes designated here as GCT1 and GCT2,
      were broadly expressed in a panel of human tissues, including testis and ovary.
      GCT1 and GCT2 were overexpressed in 92 and 71 percent, respectively, of a panel
      of seminomas tested. Combined array comparative genomic hybridization and array
      expression analysis is a valid approach for gene discovery in large chromosomal
      amplicons.

PMID- 12414651
TI  - Characterization of t(3;6)(q27;p21) breakpoints in B-cell non-Hodgkin's lymphoma
      and construction of the histone H4/BCL6 fusion gene, leading to altered
      expression of Bcl-6.
AB  - A recurrent translocation, t(3;6)(q27;p21), in non-Hodgkin's lymphoma results in
      fusion of BCL6 with a particular histone H4 gene on 6p21. We cloned five H4/BCL6
      junctions from both der(3) and der(6) chromosomes. The breakpoints on H4 were
      distributed within the single exon or close to the terminal palindrome, and those
      on BCL6 were localized within or close to the translocation hypercluster.
      Deletions or duplications of variable numbers of nucleotides were identified at
      the junctions. A total of eight single nucleotide alterations were introduced
      into the translocation/mutation cluster of BCL6, whereas four single nucleotide
      substitutions were identified within a 360-bp region of H4. Thus, the somatic
      hypermutation mechanism is likely to target H4, resulting in a predisposition to
      the development of translocation with BCL6. Lymphoma cells carrying H4/BCL6
      produced fusion transcripts containing both H4 and BCL6 messages; however, the
      cells expressed only moderate levels of BCL6 mRNA. We constructed expression
      plasmids that mimicked the H4/BCL6 fusion gene and transiently introduced them
      into COS-7 cells. H4/BCL6-transfected cells expressed markedly higher levels of
      Bcl-6 protein than cells transfected with a plasmid carrying BCL6 driven by its
      normal promoter and displayed bright nuclear staining with a characteristic
      punctate pattern with an anti-Bcl-6 antibody. Deletion analyses revealed that the
      high-level Bcl-6 expression was promoted by the H4 regulatory sequences. The
      levels of expression of activating transcription factor 3, prefoldin 4, and
      retinoblastoma-binding protein 7 significantly increased in accordance with that
      of BCL6, suggesting that Bcl-6 may act as a transcriptional activator. Our study
      suggested that t(3;6)(q27;p21) leads to BCL6 overexpression; however, the high
      level BCL6 expression may not be required to maintain the malignant phenotype of
      lymphoma cells.

PMID- 12414652
TI  - Down-regulation of p300/CBP histone acetyltransferase activates a senescence
      checkpoint in human melanocytes.
AB  - The histone acetyltransferases p300 and cAMP-responsive element-binding protein
      binding protein (CBP) are required for the execution of critical biological
      functions such as proliferation, differentiation, and apoptosis. Both proteins
      are believed to regulate the activity of a large number of general and cell
      specific transcription factors. Here we demonstrate a dramatic decrease in the
      total cellular levels of p300 and CBP with increasing population doublings of
      human normal melanocytes. We show that one consequence of p300 depletion is
      transcriptional down-regulation of the cyclin E gene, caused by deacetylation of
      histones at its promoter. The cyclin E promoter was activated by p300 and the
      histone deacetylase inhibitor trichostatin A. Conversely, the cyclin E promoter
      was repressed by wild-type Retinoblastoma tumor suppressor p105 protein (pRB) and
      by a dominant negative p300 mutant (DN p300) that lacks histone acetyltransferase
      activity. We also provide evidence of the alternative recruitment of p300 and
      histone deacetylase 1 to the cyclin E promoter in proliferating and senescent
      melanocytes, respectively. The biological significance of these results was
      established by showing that block of p300 activity by overexpression of DN p300
      or by Lys-CoA, a specific chemical inhibitor of p300, resulted in growth
      inhibition, down-regulation of cyclin E, and activation of the senescence
      associated beta-galactosidase marker in human melanocytes and melanoma cells.
      Together, these results provide evidence for the essential role of p300 in the
      regulation of proliferation and senescence in cells from melanocytic origin.

PMID- 12414653
TI  - Impact of DNA amplification on gene expression patterns in breast cancer.
AB  - Genetic changes underlie tumor progression and may lead to cancer-specific
      expression of critical genes. Over 1100 publications have described the use of
      comparative genomic hybridization (CGH) to analyze the pattern of copy number
      alterations in cancer, but very few of the genes affected are known. Here, we
      performed high-resolution CGH analysis on cDNA microarrays in breast cancer and
      directly compared copy number and mRNA expression levels of 13,824 genes to
      quantitate the impact of genomic changes on gene expression. We identified and
      mapped the boundaries of 24 independent amplicons, ranging in size from 0.2 to 12
      Mb. Throughout the genome, both high- and low-level copy number changes had a
      substantial impact on gene expression, with 44% of the highly amplified genes
      showing overexpression and 10.5% of the highly overexpressed genes being
      amplified. Statistical analysis with random permutation tests identified 270
      genes whose expression levels across 14 samples were systematically attributable
      to gene amplification. These included most previously described amplified genes
      in breast cancer and many novel targets for genomic alterations, including the
      HOXB7 gene, the presence of which in a novel amplicon at 17q21.3 was validated in
      10.2% of primary breast cancers and associated with poor patient prognosis. In
      conclusion, CGH on cDNA microarrays revealed hundreds of novel genes whose
      overexpression is attributable to gene amplification. These genes may provide
      insights to the clonal evolution and progression of breast cancer and highlight
      promising therapeutic targets.

PMID- 12414654
TI  - Gene expression after treatment with hydrogen peroxide, menadione, or t-butyl
      hydroperoxide in breast cancer cells.
AB  - Global gene expression patterns in breast cancer cells after treatment with
      oxidants (hydrogen peroxide, menadione, and t-butyl hydroperoxide) were
      investigated in three replicate experiments. RNA collected after treatment (at 1,
      3, 7, and 24 h) rather than after a single time point, enabled an analysis of
      gene expression patterns. Using a 17,000 microarray, template-based clustering
      and multidimensional scaling analysis of the gene expression over the entire time
      course identified 421 genes as being either up- or down-regulated by the three
      oxidants. In contrast, only 127 genes were identified for any single time point
      and a 2-fold change criteria. Surprisingly, the patterns of gene induction were
      highly similar among the three oxidants; however, differences were observed,
      particularly with respect to p53, IL-6, and heat-shock related genes. Replicate
      experiments increased the statistical confidence of the study, whereas changes in
      gene expression patterns over a time course demonstrated significant additional
      information versus a single time point. Analyzing the three oxidants
      simultaneously by template cluster analysis identified genes that heretofore have
      not been associated with oxidative stress.

PMID- 12414655
TI  - Characterization of epithelial senescence by serial analysis of gene expression:
      identification of genes potentially involved in prostate cancer.
AB  - Evasion of cellular senescence is required for the immortal phenotype of tumor
      cells. The tumor suppressor genes p16(INK4A), pRb, and p53 have been implicated
      in the induction of cellular senescence. To identify additional genes and
      pathways involved in the regulation of senescence in prostate epithelial cells
      (PrECs), we performed serial analysis of gene expression (SAGE). The gene
      expression pattern of human PrECs arrested because of senescence was compared
      with the pattern of early passage cells arrested because of confluence. A total
      of 144,137 SAGE tags representing 25,645 unique mRNA species was collected and
      analyzed: 157 mRNAs (70 with known function) were up-regulated and 116 (65 with
      known function) were down-regulated significantly in senescent PrECs (P < 0.05;
      fold difference >2.5). The differential regulation of an exemplary set of genes
      during senescence was confirmed by quantitative real-time PCR in PrECs derived
      from three different donors. The results presented here provide the molecular
      basis of the characteristic changes in morphology and proliferation observed in
      senescent PrECs. Furthermore, the differentially expressed genes identified in
      this report will be instrumental in the further analysis of cellular senescence
      in PrECs and may lead to the identification of tumor suppressor genes and proto
      oncogenes involved in the development of prostate cancer.

PMID- 12414656
TI  - Clustered DNA damage leads to complex genetic changes in irradiated human cells.
AB  - Densely ionizing radiations interact with DNA to cause heavily clustered sites of
      damage that are difficult to repair correctly. We have been able to determine for
      the first time the breakpoints of several very large deletions induced by densely
      ionizing radiation in diploid human cells and show that damage clustering is
      reflected in the complexity of mutations. Intra- and interchromosomal insertions
      and inversions occur at the sites of some large deletions. Short sequence repeats
      are commonly found at the breakpoints, showing that microhomologies help patch
      damage sites. We suggest that novel fragments found in complex rearrangements
      derive from other sites of radiation damage in the same cell. These transmissible
      molecular changes are echoed by visible chromosome rearrangements many days after
      irradiation and are likely to contribute significantly to the carcinogenic
      properties of densely ionizing radiations.

PMID- 12414657
TI  - Secreted protein acidic and rich in cysteine promotes glioma invasion and delays
      tumor growth in vivo.
AB  - Secreted protein acidic and rich in cysteine (SPARC) is highly expressed in human
      astrocytomas, grades II-IV. We demonstrated previously that SPARC promotes
      invasion in vitro using the U87MG-derived clone U87T2 and U87T2-derived SPARC
      transfected clones, A2b2, A2bi, and C2a4, in the spheroid confrontation assay.
      Additional in vitro studies demonstrated that SPARC delays growth, increases
      attachment, and modulates migration of tumor cells in extracellular matrix
      specific and concentration-dependent manners. Therefore, we propose that SPARC
      functionally contributes to brain tumor invasion and delays tumor growth in vivo,
      and that the effects of SPARC are related to the level of SPARC secreted into the
      extracellular matrix. To test these hypotheses, we stereotactically injected
      these clones into nude rat brains (six animals were injected per clone). Animals
      were sacrificed on day 7 to assess growth and invasion for all clones at the same
      time in tumor development. To determine whether SPARC delayed but did not inhibit
      growth, rats were injected with U87T2 or clone A2b2, and the animals were
      sacrificed on days 9 (U87T2) and 20 (A2b2), when the animals demonstrated
      neurological deficit. Brains were removed, fixed, photographed, paraffin
      embedded, and sectioned. Sections were then serially stained with H&E for
      morphological assessment of invasion and to measure tumor volume,
      immunohistochemically stained to visualize SPARC, subjected to in situ
      hybridization with the human AluII DNA-binding probe to identify human cells, and
      immunohistochemically stained with MIB-1 to measure proliferation index. The
      results demonstrate that SPARC promotes invasion in vivo at day 7. Both the low
      (A2bi) and the high (A2b2) SPARC-secreting clones produced invasive tumors,
      invading with fingerlike projections and satellite masses into adjacent brain, as
      well as along the corpus collosum. The intermediate SPARC secreting clone (C2a4)
      primarily migrated as a bulk tumor along the corpus collosum. SPARC significantly
      decreased tumor growth at day 7, as measured both by adjusted MIB-1 proliferation
      indices (U87T2 = 95.3 +/- 1.4 versus A2bi = 73.4 +/- 4.0, A2b2 = 30.8 +/- 6.7 and
      C2a4 = 15.7 +/- 13.0) and tumor volumes (U87T2 = 13.4 +/- 0.6 mm(3) versus A2bi =
      4.5 +/- 0.6 mm(3), A2b2 = 1.1 +/- 0.1 mm(3), and C2a4 = 0.4 +/- 0.1 mm(3)).
      Furthermore, SPARC delayed but did not inhibit tumor growth. The patterns of
      invasion and the extent of growth delay correlated with the level of SPARC
      expression. We propose that the ability of SPARC to promote invasion depends on
      the level of its secretion and the resultant modulation of the level of adherence
      and motility induced. This demonstration that SPARC functionally contributes to
      brain tumor invasion in vivo suggests that SPARC is a candidate therapeutic
      target for the design of therapies directed toward inhibition of the invasive
      phenotype.

PMID- 12414658
TI  - Single cell behavior in metastatic primary mammary tumors correlated with gene
      expression patterns revealed by molecular profiling.
AB  - We have developed animal models of breast cancer that allow the direct
      examination of the behavior of individual green fluorescent protein-expressing
      carcinoma cells in live nonmetastatic and metastatic primary tumors in situ. We
      have combined this model with multiphoton microscopy to image differences in cell
      behavior within the primary tumor. Differences in cell behavior between
      nonmetastatic and metastatic cells in culture and within live primary tumors were
      correlated with results from cDNA microarray analyses to identify potentially
      important genetic determinants for breast cancer invasion and metastasis. Using
      multiphoton microscopy, we found five major differences in carcinoma cell
      behavior between the nonmetastatic and metastatic primary breast tumors involving
      extracellular matrix, cell motility, and chemotaxis. Behavioral differences were
      correlated with seven categories of molecules that were differentially expressed
      and related to these behaviors. We have found that extracellular matrix
      composition, actin nucleation factors, molecules involved in mechanical stability
      and survival, and cell polarity and chemotaxis showed large and consistent
      differences in gene expression. We conclude that aligning cell behavior in vivo
      with patterns of gene expression can lead to new insights into the
      microenvironment of carcinoma cells in the primary tumor and the molecular
      mechanisms behind cell behavior.

PMID- 12414659
TI  - Roles of cell adhesion molecules in tumor angiogenesis induced by
      cotransplantation of cancer and endothelial cells to nude rats.
AB  - Roles of cell adhesion molecules mediating the interaction of cancer and
      endothelial cells in tumor angiogenesis were investigated using new in vitro and
      in vivo model systems with a cultured murine endothelial cell line (F-2) and
      human cultured epidermoid cancer cells (A431). The A431 cells exhibited typical
      in vitro cell adhesion to the endothelial F-2 cells. The initial step of adhesion
      was mediated by sialyl Lewis(x) (Le(x)) and sialyl Le(a), the carbohydrate
      determinants expressed on the cancer cells, and E-selectin expressed
      constitutively on F-2 cells. Prolonged culture led to the implantation of cancer
      cells into the monolayer of the F-2 cells, which was mediated mainly by
      alpha(3)beta(1)-integrin. F-2 cells cultured on Matrigel showed evident tube
      formation, and coculture of F-2 cells with A431 cells led to the formation of
      A431 cell nests constantly surrounded by tube-like networks consisting of F-2
      cells. This in vitro morphogenesis was inhibited by the addition of anti-sialyl
      Le(x)/Le(a) or anti-beta(1)-integrin antibodies, which led to the formation of
      cancer cell aggregates that were independent from the F-2 cell networks. This in
      vitro morphological appearance was exactly reproduced in the in vivo tumors,
      which were formed when the mixture of A431 and F-2 cells at the ratio of 10:1
      were cotransplanted s.c. into the back of nude rats. The tumors of A431
      supplemented with F-2 cells were profoundly vascularized throughout by the
      tubular structures formed by F-2 cells, the lumen of which contained the host rat
      blood cells. The tumor mass thus formed was an average 5.8-fold as large as
      control A431 tumors that were grown without F-2 cells. The co-injection of anti
      Le(x)/Le(a) or anti-beta(1)-integrin antibodies produced a marked reduction in
      the size of A431 tumors, which were not vascularized and accompanied an
      independent tiny remnant clump of F-2 cells. The size of these A431 tumors did
      not differ significantly from those of control A431 tumors raised without F-2
      cells. These results indicate that the interaction of tumor cells and endothelial
      cells in orderly tumor angiomorphogenesis is highly dependent on the action of
      cell adhesion molecules mediating the adhesion of cancer cells to endothelial
      cells, inhibition of which remarkably retards tumor growth and angiogenesis.

PMID- 12414660
TI  - Bcl-2 determines susceptibility to induction of lung cancer by oncogenic CRaf.
AB  - The efficiency of tumor induction by oncogenes is influenced by modifier genes
      that determine individual susceptibility. We have used a transgenic mouse model
      to examine the role of a candidate susceptibility gene, bcl-2, for development of
      Raf oncogene-induced lung adenomas. Loss of bcl-2 greatly retarded tumor
      development without affecting tumor phenotype. Tumor tissues from bcl-2 positive
      and negative mice were compared for the fraction of S phase cells by staining for
      proliferating cell nuclear antigen and for the fraction of apoptotic cells by
      terminal deoxynucleotidyl transferase-mediated nick end labeling assay. The data
      indicate that the increased tumor latency in the absence of bcl-2 results
      primarily from an increased apoptotic rate but also involves a decrease in tumor
      cell proliferation. Both effects can be rescued by breeding with H2K-bcl-2
      transgenic mice demonstrating that loss of bcl-2 was the major genetic factor
      determining tumor resistance. These findings suggest that bcl-2 is a major
      susceptibility gene for development of lung cancer in mice and perhaps in humans.

PMID- 12414662
TI  - Extracellular membrane vesicles from tumor cells promote angiogenesis via
      sphingomyelin.
AB  - Actively growing tumor cells shed membrane vesicles into the extracellular milieu
      both in vivo and in vitro. Extracellular membrane vesicles from tumor cells
      contain most surface antigens and proteases present on these cells. They
      facilitate the escape of tumors from immune surveillance and promote tumor cell
      invasion. Here, we demonstrate that tumor membrane vesicles stimulate an
      additional important activity for tumor growth and metastasis by promoting
      endothelial cell migration, invasion, and tube formation, and inducing in vivo
      neovascularization. Our data show that tumor vesicles are one of the multiple
      effectors involved in tumor-induced angiogenesis. Heat-treated vesicles and lipid
      extracts from the vesicles also induce endothelial cell migration and in vivo
      angiogenesis. We identify sphingomyelin as the active component for vesicle
      induced endothelial cell migration, tube formation, and neovascularization.
      Together with previously reported results, our data demonstrate that shed tumor
      vesicles play multiple roles in tumor growth and metastasis by promoting
      angiogenesis, tumor invasion, and immune escape.

PMID- 12414661
TI  - Regulation of cellular proliferation, cytoskeletal function, and signal
      transduction through CXCR4 and c-Kit in small cell lung cancer cells.
AB  - The regulation of biological functions including cell growth, viability,
      migration, and adhesion of small cell lung cancer (SCLC) cells depends largely on
      the autocrine or paracrine stimulation of growth factor receptors and chemokine
      receptors. Stem cell factor (SCF) and its receptor c-Kit have been identified as
      important regulators of SCLC viability and are coexpressed in approximately 40
      70% of SCLC specimens. In vitro, the inhibition of c-Kit tyrosine kinase activity
      by the small molecule tyrosine kinase inhibitor STI571 (Gleevec) abrogates cell
      growth. We have investigated the role of c-Kit and chemokine receptors in the
      regulation of cell migration and adhesion of SCLC cells. CXCR4, the chemokine
      receptor for stromal cell-derived factor-1alpha (SDF-1alpha), was found to be the
      major chemokine receptor commonly expressed in all of the 10 SCLC cell lines
      tested. SCF and SDF-1alpha increased cellular proliferation over a course of 72 h
      in both the c-Kit- and the CXCR4-positive NCI-H69 SCLC cell line. Recently, SDF
      1alpha and CXCR4 have been shown to be important regulators of migration and
      metastasis in breast and ovarian cancer. We found that SDF-1alpha dramatically
      increased cell motility and adhesion in CXCR4-expressing NCI-H446 SCLC cells. In
      addition, SDF-1alpha altered cell morphology with increased formation of
      filopodia and neurite-like projections. In NCI-H69 SCLC cells, SCF and SDF-1alpha
      cooperatively induced morphological changes and activated downstream signaling
      pathways. Treatment of NCI-H69 cells with STI571 specifically inhibited the c-Kit
      signaling events of Akt and p70 S6 kinase, whereas SDF-1alpha-mediated activation
      of Akt or p70 S6 kinase was normal. In contrast, the phosphatidylinositol 3
      kinase inhibitor, LY294002, prevented these cells from adhering and completely
      blocked SCF- and/or SDF-1alpha-induced Akt or p70 S6 kinase phosphorylation.
      These results demonstrate that the CXCR4 receptor is functionally expressed in
      SCLC cells and may, therefore, be involved in the pathogenesis of SCLC in vivo.
      Inhibition of both the CXCR4 and the c-Kit downstream events could be a promising
      therapeutic approach in SCLC.

PMID- 12414663
TI  - PTEN suppresses hyaluronic acid-induced matrix metalloproteinase-9 expression in
      U87MG glioblastoma cells through focal adhesion kinase dephosphorylation.
AB  - Glioblastoma is a severe type of primary brain tumor and its invasion is strongly
      correlated with the secretion of matrix metalloproteinases (MMPs). To investigate
      a role of PTEN, a tumor suppressor gene, in the regulation of hyaluronic acid
      (HA)-induced invasion of glioma cells, we examined the secretion of MMP-9 in
      various glioma cells with or without a functional PTEN gene. The secretion of MMP
      9 in glioma cells lacking functional PTEN (U87MG, U251MG, and U373MG) was induced
      by HA, although not in wildtype (wt)-PTEN-harboring cells (LN229, LN18, and
      LN428). In addition, stable expression of wt-PTEN into U87MG cells significantly
      decreased the secretion of HA-induced MMP-9 and basal levels of MMP-2, inhibiting
      the activation of focal adhesion kinase and extracellular signal-regulated kinase
      1/2, whereas the secretion levels of the tissue inhibitor of metalloproteinase-1
      and -2 were increased, finally resulting in the inhibition of invasion by HA in
      vitro. Ectopic expressions of adenoviral (Ad)-wt-PTEN and -lipid phosphatase
      deficient (G129E)-PTEN, but not both protein and -lipid phosphatase-deficient
      (C124S)-PTEN, reduced MMP-9 secretion and invasion by HA. These results were also
      confirmed by expressions of Ad-wt-PTEN and Ad-G129E-PTEN in other glioblastoma
      cells lacking functional PTEN, U251MG, and U373MG. These findings strongly
      suggest the possibility that PTEN may block HA-induced MMP-9 secretion and
      invasion through its protein phosphatase activity.

PMID- 12414664
TI  - Cyclooxygenase-2 overexpression reduces apoptotic susceptibility by inhibiting
      the cytochrome c-dependent apoptotic pathway in human colon cancer cells.
AB  - The cyclooxygenase-2 (COX-2) gene encodes an inducible enzyme that converts
      arachidonic acid to prostaglandins and is up-regulated in colorectal neoplasms.
      Evidence indicates that COX-2 may regulate apoptosis and can influence the
      malignant phenotype. Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit COX
      enzymes and induce apoptosis in colorectal cancer cell lines, which may
      contribute to their antitumor effects. To determine whether forced COX-2
      expression modulates susceptibility to drug-induced apoptosis, HCT-15 colon
      carcinoma cells were stably transfected with the COX-2 cDNA, and two clones
      overexpressing COX-2 were isolated. Selective COX-2 (NS398) and nonselective
      (sulindac sulfide) COX inhibitors, as well as 5-fluorouracil (5-FU), induced
      apoptosis (terminal deoxynucleotidyl transferase-mediated nick end labeling in a
      dosage-dependent manner. Forced COX-2 expression significantly attenuated
      induction of apoptosis by all three of the drugs compared with parental HCT-15
      cells. NSAIDs and 5-FU induced the mitochondrial release of cytochrome c as well
      as caspase-3 and -9 activation, and to a much lesser extent, caspase-8. COX-2
      overexpressing cells showed reduced cytochrome c and caspase activation, relative
      to parental cells. A specific inhibitor of caspase-3 restored cell survival after
      drug treatment. COX-2 transfectants were found to overexpress the antiapoptotic
      Bcl-2 mRNA and protein relative to parental cells. In conclusion, forced COX-2
      expression significantly attenuates apoptosis induction by NSAIDs and 5-FU
      through predominant inhibition of the cytochrome c-dependent apoptotic pathway.
      COX-2-mediated up-regulation of Bcl-2 suggests a potential mechanism for reduced
      apoptotic susceptibility.

PMID- 12414665
TI  - Lysophosphatidic acid-induced squamous cell carcinoma cell proliferation and
      motility involves epidermal growth factor receptor signal transactivation.
AB  - Transactivation of the epidermal growth factor receptor (EGFR) represents the
      paradigm for cross-talk between G protein-coupled receptors (GPCRs) and receptor
      tyrosine kinase signaling pathways. In a variety of squamous cell carcinoma cell
      lines of the head and neck (HNSCCs), we found that treatment with the GPCR
      agonists lysophosphatidic acid (LPA), bradykinin, thrombin, and carbachol results
      in rapid tyrosine phosphorylation of the EGFR. In these tumor cells, signal
      transactivation of the EGFR and the oncoprotein HER2/neu is critically dependent
      on metalloprotease activity. Using the metalloprotease inhibitor batimastat, the
      EGFR-specific tyrphostin AG1478, and a dominant-negative EGFR mutant, we show
      that in HNSCC cell lines, EGFR tyrosine phosphorylation, recruitment of the
      adaptor proteins SHC and Gab1, and activation of the ERK/mitogen-activated
      protein kinase pathway in response to LPA depend both on metalloprotease function
      and EGFR tyrosine kinase activity. Most importantly, critical characteristics of
      HNSCC cell lines such as DNA synthesis, cell cycle progression and tumor cell
      migration are stimulated by LPA and can be abrogated by interfering with EGFR
      signal transmission. Together, our results demonstrate the importance of a
      mechanism that promotes head and neck cancer cell proliferation and motility by
      GPCR ligands involving EGFR transactivation. Our findings suggest that highly
      abundant GPCR ligands such as LPA may function as tumor promoters and
      determinants of HNSCC progression.

PMID- 12414666
TI  - Epstein-barr virus latent membrane protein 1 induces and causes release of
      fibroblast growth factor-2.
AB  - We have shown that the EBV oncoprotein, latent membrane protein 1 (LMP1), induces
      a constellation of tumor-invasiveness factors. Fibroblast growth factor (FGF)-2
      is angiogenic as well mitogenic. Although FGF-2 does not contain a hydrophobic
      signal sequence for secretion, FGF-2 is released extracellularly. However, the
      mechanism by which FGF-2 is released is unclear. Here we show first that LMP1
      induces in epithelial cells the expression of FGF-2 mRNA and protein through both
      LMP1 COOH-terminal activation domains, CTAR 1 and CTAR 2, which can activate
      nuclear factor (NF)-kappaB signaling and also the p38 mitogen-activated protein
      kinase pathway. Coexpression of IkappaBalpha (S32A/S36A), which cannot be
      phosphorylated and prevents NF-kappaB activation, with LMP1 inhibited induction
      of FGF-2 by LMP1, which suggests that LMP1 induces FGF-2 via NF-kappaB signaling.
      Moreover, unlike phorbol 12-myristate 13-acetate LMP1 also induced the release of
      the M(r) 18,000 isoform of FGF-2 protein. Transfection of Ad-AH cells with LMP1
      deletion mutants lacking either CTAR 1 or CTAR 2 also induced the release of the
      protein. Secretion was confirmed in 293 cells, which do not contain detectable
      endogenous FGF-2 protein, cotransfected with FGF-2 and LMP1. Finally, Na(+)/K(+)
      ATPase participates in FGF-2 release, independently of the classical endoplasmic
      reticulum/Golgi pathway. In this study, the release of M(r) 18,000 FGF-2 protein
      was partially suppressed by ouabain, which inhibits the activity of Na(+)/K(+)
      ATPase alpha1 subunit, but not by Brefeldin A, which inhibits the endoplasmic
      reticulum/Golgi-dependent secretory pathway. In contrast, the release of M(r)
      18,000 FGF-2 protein was almost completely inhibited by IkappaBalpha (S32A/S36A).
      These results suggest that FGF-2 release is independently mediated by NF-kappaB
      signaling, not simply a consequence of induction itself. Thus, NF-kappaB
      signaling is involved in induction of expression and release of FGF-2 by LMP1.

PMID- 12414667
TI  - Correspondence re: D. Zimonjic et al., Derivation of human tumor cells in vitro
      without widespread genomic instability. Cancer Res., 61: 8838-8844, 2001.

PMID- 12414668
TI  - Correspondence re: G. Anderson et al., Intrachromosomal genomic instability in
      human sporadic colorectal cancer measured by genome-wide allelotyping and inter
      (simple sequence repeat) PCR. Cancer Res., 61: 8274-8283, 2001.

PMID- 12414669
TI  - Computational simulations of peptide binding to proteins: how scorpions sting K+
      channels.

PMID- 12414670
TI  - Cooperative setting for long-range linkage of Ca(2+) binding and ATP synthesis in
      the Ca(2+) ATPase.
AB  - High-affinity and cooperative binding of two Ca(2+) per ATPase (SERCA) occurs
      within the membrane-bound region of the enzyme. Direct measurements of binding at
      various Ca(2+) concentrations demonstrate that site-directed mutations within
      this region interfere selectively with Ca(2+) occupancy of either one or both
      binding sites and with the cooperative character of the binding isotherms. A
      transition associated with high affinity and cooperative binding of the second
      Ca(2+) and the engagement of N796 and E309 are both required to form a
      phosphoenzyme intermediate with ATP in the forward direction of the cycle and
      also to form ATP from phosphoenzyme intermediate and ADP in the reverse direction
      of the cycle. This transition, defined by equilibrium and kinetic
      characterization of the partial reactions of the enzyme cycle, extends from
      transmembrane helices to the catalytic site through a long-range linkage and is
      the mechanistic device for interconversion of binding and phosphorylation
      potentials.

PMID- 12414671
TI  - A Monte Carlo model reveals independent signaling at central glutamatergic
      synapses.
AB  - We have developed a biophysically realistic model of receptor activation at an
      idealized central glutamatergic synapse that uses Monte Carlo techniques to
      simulate the stochastic nature of transmission following release of a single
      synaptic vesicle. For the a synapse with 80 AMPA and 20 NMDA receptors, a single
      quantum, with 3000 glutamate molecules, opened approximately 3 NMDARs and 20
      AMPARs. The number of open receptors varied directly with the total number of
      receptors, and the fraction of open receptors did not depend on the ratio of co
      localized AMPARs and NMDARs. Variability decreased with increases in either total
      receptor number or quantal size, and differences between the variability of AMPAR
      and NMDAR responses were due solely to unequal numbers of receptors at the
      synapse. Despite NMDARs having a much higher affinity for glutamate than AMPARs,
      quantal release resulted in similar occupancy levels in both receptor types.
      Receptor activation increased with number of transmitter molecules released or
      total receptor number, whereas occupancy levels were only dependent on quantal
      size. Tortuous diffusion spaces reduced the extent of spillover and the
      activation of extrasynaptic receptors. These results support the conclusion that
      signaling is spatially independent within and between central glutamatergic
      synapses.

PMID- 12414672
TI  - A reduced model clarifies the role of feedback loops and time delays in the
      Drosophila circadian oscillator.
AB  - Although several detailed models of molecular processes essential for circadian
      oscillations have been developed, their complexity makes intuitive understanding
      of the oscillation mechanism difficult. The goal of the present study was to
      reduce a previously developed, detailed model to a minimal representation of the
      transcriptional regulation essential for circadian rhythmicity in Drosophila. The
      reduced model contains only two differential equations, each with time delays. A
      negative feedback loop is included, in which PER protein represses per
      transcription by binding the dCLOCK transcription factor. A positive feedback
      loop is also included, in which dCLOCK indirectly enhances its own formation. The
      model simulated circadian oscillations, light entrainment, and a phase-response
      curve with qualitative similarities to experiment. Time delays were found to be
      essential for simulation of circadian oscillations with this model. To examine
      the robustness of the simplified model to fluctuations in molecule numbers, a
      stochastic variant was constructed. Robust circadian oscillations and entrainment
      to light pulses were simulated with fewer than 80 molecules of each gene product
      present on average. Circadian oscillations persisted when the positive feedback
      loop was removed. Moreover, elimination of positive feedback did not decrease the
      robustness of oscillations to stochastic fluctuations or to variations in
      parameter values. Such reduced models can aid understanding of the oscillation
      mechanisms in Drosophila and in other organisms in which feedback regulation of
      transcription may play an important role.

PMID- 12414673
TI  - Fluctuations and randomness of movement of the bead powered by a single kinesin
      molecule in a force-clamped motility assay: Monte Carlo simulations.
AB  - The motility assay of K. Visscher, M. J. Schnitzer, and S. M. Block (Nature,
      400:184-189, 1999) in which the movement of a bead powered by a single kinesin
      motor can be measured is a very useful tool in characterizing the force-dependent
      steps of the mechanochemical cycle of kinesin motors, because in this assay the
      external force applied to the bead can be controlled (clamped) arbitrarily.
      However, because the bead is elastically attached to the motor and the response
      of the clamp is not fast enough to compensate the Brownian motion of the bead,
      interpretation or analysis of the data obtained from the assay is not trivial. In
      a recent paper (Y. Chen and B. Yan, Biophys. Chem. 91:79-91, 2001), we showed how
      to evaluate the mean velocity of the bead and the motor in the motility assay for
      a given mechanochemical cycle. In this paper we extend the study to the
      evaluation of the fluctuation or the randomness of the velocity using a Monte
      Carlo simulation method. Similar to the mean, we found that the randomness of the
      velocity of the motor is also influenced by the parameters that affect the
      dynamic behavior of the bead, such as the viscosity of the medium, the size of
      the bead, the stiffness of the elastic element connecting the bead and the motor,
      etc. The method presented in this paper should be useful in modeling the kinetic
      mechanism of any processive motor (such as conventional kinesin and myosin V)
      based on measured force-clamp motility data.

PMID- 12414674
TI  - Brownian dynamics simulations of the recognition of the scorpion toxin maurotoxin
      with the voltage-gated potassium ion channels.
AB  - The recognition of the scorpion toxin maurotoxin (MTX) by the voltage-gated
      potassium (Kv1) channels, Kv1.1, Kv1.2, and Kv1.3, has been studied by means of
      Brownian dynamics (BD) simulations. All of the 35 available structures of MTX in
      the Protein Data Bank (http://www.rcsb.org/pdb) determined by nuclear magnetic
      resonance were considered during the simulations, which indicated that the
      conformation of MTX significantly affected both the recognition and the binding
      between MTX and the Kv1 channels. Comparing the top five highest-frequency
      structures of MTX binding to the Kv1 channels, we found that the Kv1.2 channel,
      with the highest docking frequencies and the lowest electrostatic interaction
      energies, was the most favorable for MTX binding, whereas Kv1.1 was intermediate,
      and Kv1.3 was the least favorable one. Among the 35 structures of MTX, the 10th
      structure docked into the binding site of the Kv1.2 channel with the highest
      probability and the most favorable electrostatic interactions. From the MTX-Kv1.2
      binding model, we identified the critical residues for the recognition of these
      two proteins through triplet contact analyses. MTX locates around the
      extracellular mouth of the Kv1 channels, making contacts with its beta-sheets.
      Lys23, a conserved amino acid in the scorpion toxins, protrudes into the pore of
      the Kv1.2 channel and forms two hydrogen bonds with the conserved residues
      Gly401(D) and Tyr400(C) and one hydrophobic contact with Gly401(C) of the Kv1.2
      channel. The critical triplet contacts for recognition between MTX and the Kv1.2
      channel are Lys23(MTX)-Asp402(C)(Kv1), Lys27(MTX)-Asp378(D)(Kv1), and Lys30(MTX)
      Asp402(A)(Kv1). In addition, six hydrogen-bonding interactions are formed between
      residues Lys23, Lys27, Lys30, and Tyr32 of MTX and residues Gly401, Tyr400,
      Asp402, Asp378, and Thr406 of Kv1.2. Many of them are formed by side chains of
      residues of MTX and backbone atoms of the Kv1.2 channel. Five hydrophobic
      contacts exist between residues Pro20, Lys23, Lys30 and Tyr32 of MTX and residues
      Asp402, Val404, Gly401, and Arg377 of the Kv1.2 channel. The simulation results
      are in agreement with the previous molecular biology experiments and explain the
      binding phenomena between MTX and Kv1 channels at the molecular level. The
      consistency between the results of the BD simulations and the experimental data
      indicated that our three-dimensional model of the MTX-Kv1.2 channel complex is
      reasonable and can be used in additional biological studies, such as rational
      design of novel therapeutic agents blocking the voltage-gated channels and in
      mutagenesis studies in both the toxins and the Kv1 channels. In particular, both
      the BD simulations and the molecular mechanics refinements indicate that residue
      Asp378 of the Kv1.2 channel is critical for its recognition and binding
      functionality toward MTX. This phenomenon has not been appreciated in the
      previous mutagenesis experiments, indicating this might be a new clue for
      additional functional study of Kv1 channels.

PMID- 12414675
TI  - Molecular dynamics simulation of spontaneous membrane fusion during a cubic
      hexagonal phase transition.
AB  - We report a molecular dynamics simulation of the phase transition of monoolein
      from an inverted cubic phase to an inverted hexagonal phase. The transition
      proceeds via an intermediate structure consisting of water channels in a cubic
      geometry, in agreement with the predictions of the modified stalk theory (Siegel,
      1999). Two mechanisms are identified by which the topology changes during the
      transition. Bilayer fusion proceeds via the formation of trans-monolayer
      contacts, whereas bilayer rupture is observed as a gradual thinning of each
      monolayer.

PMID- 12414676
TI  - Analysis and evaluation of channel models: simulations of alamethicin.
AB  - Alamethicin is an antimicrobial peptide that forms stable channels with well
      defined conductance levels. We have used extended molecular dynamics simulations
      of alamethicin bundles consisting of 4, 5, 6, 7, and 8 helices in a palmitoyl
      oleolyl-phosphatidylcholine bilayer to evaluate and analyze channel models and to
      link the models to the experimentally measured conductance levels. Our results
      suggest that four helices do not form a stable water-filled channel and might not
      even form a stable intermediate. The lowest measurable conductance level is
      likely to correspond to the pentamer. At higher aggregation numbers the bundles
      become less symmetrical. Water properties inside the different-sized bundles are
      similar. The hexamer is the most stable model with a stability comparable with
      simulations based on crystal structures. The simulation was extended from 4 to 20
      ns or several times the mean passage time of an ion. Essential dynamics analyses
      were used to test the hypothesis that correlated motions of the helical bundles
      account for high-frequency noise observed in open channel measurements. In a 20
      ns simulation of a hexameric alamethicin bundle, the main motions are those of
      individual helices, not of the bundle as a whole. A detailed comparison of
      simulations using different methods to treat long-range electrostatic
      interactions (a twin range cutoff, Particle Mesh Ewald, and a twin range cutoff
      combined with a reaction field correction) shows that water orientation inside
      the alamethicin channels is sensitive to the algorithms used. In all cases, water
      ordering due to the protein structure is strong, although the exact profile
      changes somewhat. Adding an extra 4-nm layer of water only changes the water
      ordering slightly in the case of particle mesh Ewald, suggesting that periodicity
      artifacts for this system are not serious.

PMID- 12414677
TI  - Sequence-dependent DNA curvature and flexibility from scanning force microscopy
      images.
AB  - This paper reports a study of the sequence-dependent DNA curvature and
      flexibility based on scanning force microscopy (SFM) images. We used a
      palindromic dimer of a 1878-bp pBR322 fragment and collected a large pool of SFM
      images. The curvature of each imaged chain was measured in modulus and direction.
      It was found that the ensemble curvature modulus does not allow the separation of
      static and dynamic contributions to the curvature, whereas the curvature, when
      its direction in the two dimensions is taken into account, permits the direct
      separation of the intrinsic curvature contributions static and dynamic
      contributions. The palindromic symmetry also acted as an internal gauge of the
      validity of the SFM images statistical analysis. DNA static curvature resulted in
      good agreement with the predicted sequence-dependent intrinsic curvature.
      Furthermore, DNA sequence-dependent flexibility was found to correlate with the
      occurrence of A.T-rich dinucleotide steps along the chain and, in general, with
      the normalized basepair stacking energy distribution.

PMID- 12414678
TI  - Size and structure of spontaneously forming liposomes in lipid/PEG-lipid
      mixtures.
AB  - The optimal size and structure of spontaneous liposomes formed from lipid/polymer
      lipid mixtures was calculated using a molecular mean-field theory. The
      equilibrium properties of the aggregate are obtained by expanding the free energy
      of a symmetric planar bilayer up to fourth order in curvature and composition of
      lipid and polymer. The expansion coefficients are obtained from a molecular
      theory that explicitly accounts for the conformational degrees of freedom of the
      hydrophobic tails of the lipid and of the polymer chains. The polar headgroup
      interactions are treated using the opposing forces model. The onset of stability
      of the symmetric planar film is obtained from the expansion up to quadratic
      order. For unstable planar films the equilibrium size and structure of the
      spherical aggregates is obtained from the second- and fourth-order terms in
      curvature and composition of lipid and polymer. The driving force for the
      formation of spontaneous vesicles is the asymmetric distribution of polymers
      between the inner and outer monolayer. The composition asymmetry between the two
      monolayers in the aggregates is much larger for the polymer component than for
      the lipid, and it depends upon the size of the aggregate. The smaller the
      aggregate, the more asymmetric the distribution of polymer and lipid. The
      tendency of the polymer chains to be tethered on the outer surface of the
      aggregate is very strong, and it limits the range of polymer loading for which
      spherical liposomes are stable. A very small excess of polymer loading causes
      small spherical micelles to be the optimal aggregates. In these cases spontaneous
      liposomes can form as metastable aggregates, showing as a local minima in the
      free energy. Even for metastable aggregates the asymmetric distribution of
      polymers is very large. The elastic constants of the asymmetric bilayer in the
      spherical aggregate are found to be the same as those that are calculated from
      the planar symmetric film. Therefore, the stable structure of the aggregate is
      not needed to determine its mechanical properties. The range of stable liposomes
      is very narrow in the range of molecular weights studied, which include the
      experimental relevant domain of aggregates used in drug delivery. It is found
      that the stability of the spherical aggregates results from a very fine balance
      between the tendency of the polymer chains and lipid tails to pack in an
      asymmetric spherical aggregate and the tendency of the hydrophobic-water
      interface to keep the area per molecule fixed. The changes in free energy per
      molecules that are responsible for liposome formation are very small and are very
      sensitive to detailed molecular properties. The theoretical description of the
      aggregates requires a theory capable of incorporating these detailed molecular
      properties. The findings are discussed in the context of vesicle formation and
      liposome design for drug delivery.

PMID- 12414679
TI  - Spin-lattice relaxation of coupled metal-radical spin-dimers in proteins:
      application to Fe(2+)-cofactor (Q(A)(-.), Q(B)(-.), phi(-.)) dimers in reaction
      centers from photosynthetic bacteria.
AB  - The spin-lattice relaxation times (T(1)) for the reduced quinone acceptors Q(A)(
      .) and Q(B)(-.), and the intermediate pheophytin acceptor phi(-.), were measured
      in native photosynthetic reaction centers (RC) containing a high spin Fe(2+) (S =
      2) and in RCs in which Fe(2+) was replaced by diamagnetic Zn(2+). From these
      data, the contribution of the Fe(2+) to the spin-lattice relaxation of the
      cofactors was determined. To relate the spin-lattice relaxation rate to the spin
      spin interaction between the Fe(2+) and the cofactors, we developed a spin-dimer
      model that takes into account the zero field splitting and the rhombicity of the
      Fe(2+) ion. The relaxation mechanism of the spin-dimer involves a two-phonon
      process that couples the fast relaxing Fe(2+) spin to the cofactor spin. The
      process is analogous to the one proposed by R. Orbach (Proc. R. Soc. A. (Lond.).
      264:458-484) for rare earth ions. The spin-spin interactions are, in general,
      composed of exchange and dipolar contributions. For the spin dimers studied in
      this work the exchange interaction, J(o), is predominant. The values of J(o) for
      Q(A)(-.)Fe(2+), Q(B)(-.)Fe(2+), and phi(-.)Fe(2+) were determined to be (in
      kelvin) -0.58, -0.92, and -1.3 x 10(-3), respectively. The |J(o)| of the various
      cofactors (obtained in this work and those of others) could be fitted with the
      relation exp(-beta(J)d), where d is the distance between cofactor spins and
      beta(J) had a value of (0.66-0.86) A(-1). The relation between J(o) and the
      matrix element |V(ij)|(2) involved in electron transfer rates is discussed.

PMID- 12414680
TI  - A coarse-grained normal mode approach for macromolecules: an efficient
      implementation and application to Ca(2+)-ATPase.
AB  - A block normal mode (BNM) algorithm, originally proposed by Tama et al.,
      (Proteins Struct. Func. Genet. 41:1-7, 2000) was implemented into the simulation
      program CHARMM. The BNM approach projects the hessian matrix into local
      translation/rotation basis vectors and, therefore, dramatically reduces the size
      of the matrix involved in diagonalization. In the current work, by constructing
      the atomic hessian elements required in the projection operation on the fly, the
      memory requirement for the BNM approach has been significantly reduced from that
      of standard normal mode analysis and previous implementation of BNM. As a result,
      low frequency modes, which are of interest in large-scale conformational changes
      of large proteins or protein-nucleic acid complexes, can be readily obtained.
      Comparison of the BNM results with standard normal mode analysis for a number of
      small proteins and nucleic acids indicates that many properties dominated by low
      frequency motions are well reproduced by BNM; these include atomic fluctuations,
      the displacement covariance matrix, vibrational entropies, and involvement
      coefficients for conformational transitions. Preliminary application to a fairly
      large system, Ca(2+)-ATPase (994 residues), is described as an example. The
      structural flexibility of the cytoplasmic domains (especially domain N),
      correlated motions among residues on domain interfaces and displacement patterns
      for the transmembrane helices observed in the BNM results are discussed in
      relation to the function of Ca(2+)-ATPase. The current implementation of the BNM
      approach has paved the way for developing efficient sampling algorithms with
      molecular dynamics or Monte Carlo for studying long-time scale dynamics of
      macromolecules.

PMID- 12414681
TI  - Extent of hydrogen-bond protection in folded proteins: a constraint on packing
      architectures.
AB  - Progressive structuring and ultimately exclusion of water by hydrophobes
      surrounding backbone hydrogen bonds turn the latter into guiding factors of
      protein folding. Here we demonstrate that an arrangement of five hydrophobes
      yields an optimal hydrogen-bond stabilization. This motif is shown to be nearly
      ubiquitous in native folds.

PMID- 12414682
TI  - Depletion-mediated red blood cell aggregation in polymer solutions.
AB  - Polymer-induced red blood cell (RBC) aggregation is of current basic science and
      clinical interest, and a depletion-mediated model for this phenomenon has been
      suggested; to date, however, analytical approaches to this model are lacking. An
      approach is thus described for calculating the interaction energy between RBC in
      polymer solutions. The model combines electrostatic repulsion due to RBC surface
      charge with osmotic attractive forces due to polymer depletion near the RBC
      surface. The effects of polymer concentration and polymer physicochemical
      properties on depletion layer thickness and on polymer penetration into the RBC
      glycocalyx are considered for 40 to 500 kDa dextran and for 18 to 35 kDa poly
      (ethylene glycol). The calculated results are in excellent agreement with
      literature data for cell-cell affinities and with RBC aggregation-polymer
      concentration relations. These findings thus lend strong support to depletion
      interactions as the basis for polymer-induced RBC aggregation and suggest the
      usefulness of this approach for exploring interactions between macromolecules and
      the RBC glycocalyx.

PMID- 12414683
TI  - Electron tomography of frozen-hydrated isolated triad junctions.
AB  - Cryoelectron microscopy and tomography have been applied for the first time to
      isolated, frozen-hydrated skeletal muscle triad junctions (triads) and terminal
      cisternae (TC) vesicles derived from sarcoplasmic reticulum. Isolated triads were
      selected on the basis of their appearance as two spherical TC vesicles attached
      to opposite sides of a flattened vesicle derived from a transverse tubule (TT).
      Foot structures (ryanodine receptors) were resolved within the gap between the TC
      vesicles and TT vesicles, and some residual ordering of the receptors into arrays
      was apparent. Organized dense layers, apparently containing the calcium-binding
      protein calsequestrin, were found in the lumen of TC vesicles underlying the foot
      structures. The lamellar regions did not directly contact the sarcoplasmic
      reticulum membrane, thereby creating an approximately 5-nm-thick zone that
      potentially constitutes a subcompartment for achieving locally elevated [Ca(2+) ]
      in the immediate vicinity of the Ca(2+)-conducting ryanodine receptors. The lumen
      of the TT vesicles contained globular mass densities of unknown origin, some of
      which form cross-bridges that may be responsible for the flattened appearance of
      the transverse tubules when viewed in cross-section. The spatial relationships
      among the TT membrane, ryanodine receptors, and calsequestrin-containing
      assemblage are revealed under conditions that do not use dehydration, heavy-metal
      staining, or chemical fixation, thus exemplifying the potential of cryoelectron
      microscopy and tomography to reveal structural detail of complex subcellular
      structures.

PMID- 12414684
TI  - Hyperosmotically induced volume change and calcium signaling in intervertebral
      disk cells: the role of the actin cytoskeleton.
AB  - Loading of the spine alters the osmotic environment in the intervertebral disk
      (IVD) as interstitial water is expressed from the tissue. Cells from the three
      zones of the IVD, the anulus fibrosus (AF), transition zone (TZ), and nucleus
      pulposus (NP), respond to osmotic stress with altered biosynthesis through a
      pathway that may involve calcium (Ca(2+)) as a second messenger. We examined the
      hypothesis that IVD cells respond to hyperosmotic stress by increasing the
      concentration of intracellular calcium ([Ca(2+)](i)) through a mechanism
      involving F-actin. In response to hyperosmotic stress, control cells from all
      zones decreased in volume and cells from the AF and TZ exhibited [Ca(2+)](i)
      transients, while cells from the NP did not. Extracellular Ca(2+) was necessary
      to initiate [Ca(2+)](i) transients. Stabilization of F-actin with phalloidin
      prevented the Ca(2+) response in AF and TZ cells and decreased the rate of volume
      change in cells from all zones, coupled with an increase in the elastic moduli
      and apparent viscosity. Conversely, actin breakdown with cytochalasin D
      facilitated Ca(2+) signaling while decreasing the elastic moduli and apparent
      viscosity for NP cells. These results suggest that hyperosmotic stress induces
      volume change in IVD cells and may initiate [Ca(2+)](i) transients through an
      actin-dependent mechanism.

PMID- 12414685
TI  - Intracellular Ca(2+) release as irreversible Markov process.
AB  - In striated muscles, intracellular Ca(2+) release is tightly controlled by the
      membrane voltage sensor. Ca(2+) ions are necessary mediators of this control in
      cardiac but not in skeletal muscle, where their role is ill-understood. An
      intrinsic gating oscillation of Ca(2+) release-not involving the voltage sensor
      is demonstrated in frog skeletal muscle fibers under voltage clamp. A Markov
      model of the Ca(2+) release units is shown to reproduce the oscillations, and it
      is demonstrated that for Markov processes to have oscillatory transients, its
      transition rates must violate thermodynamic reversibility. Such irreversibility
      results in permanent cycling of the units through a ring of states, which
      requires a source of free energy. Inhibition of the oscillation by 20 to 40 mM
      EGTA or partial depletion of Ca(2+) in the sarcoplasmic reticulum (SR) identifies
      the SR [Ca(2+)] gradient as the energy source, and indicates a location of the
      critical Ca(2+)-sensing site at distances greater than 35 nm from the open
      channel. These results, which are consistent with a recent demonstration of
      irreversibility in gating of cardiac Ca(2+) sparks, (Wang, S.-Q., L.-S. Song, L.
      Xu, G. Meissner, E. G. Lakatta, E. Rios, M. D. Stern, and H. Cheng. 2002.
      Biophys. J. 83:242-251) exemplify a cell-wide oscillation caused by coupling
      between ion permeation and channel gating.

PMID- 12414686
TI  - SNAREs in opposing bilayers interact in a circular array to form conducting
      pores.
AB  - The process of fusion at the nerve terminal is mediated via a specialized set of
      proteins in the synaptic vesicles and the presynaptic membrane. Three soluble N
      ethylmaleimide-sensitive factor (NSF)-attachment protein receptors (SNAREs) have
      been implicated in membrane fusion. The structure and arrangement of these SNAREs
      associated with lipid bilayers were examined using atomic force microscopy. A
      bilayer electrophysiological setup allowed for measurements of membrane
      conductance and capacitance. Here we demonstrate that the interaction of these
      proteins to form a fusion pore is dependent on the presence of t-SNAREs and v
      SNARE in opposing bilayers. Addition of purified recombinant v-SNARE to a t-SNARE
      reconstituted lipid membrane increased only the size of the globular t-SNARE
      oligomer without influencing the electrical properties of the membrane. However
      when t-SNARE vesicles were added to a v-SNARE membrane, SNAREs assembles in a
      ring pattern and a stepwise increase in capacitance, and increase in conductance
      were observed. Thus, t- and v-SNAREs are required to reside in opposing bilayers
      to allow appropriate t-/v-SNARE interactions leading to membrane fusion.

PMID- 12414687
TI  - Localization of divalent cation-binding site in the pore of a small conductance
      Ca(2+)-activated K(+) channel and its role in determining current-voltage
      relationship.
AB  - In our previous study, we proposed that the inwardly rectifying current-voltage
      (I-V) relationship of small-conductance Ca(2+)-activated K(+) channels (SK(Ca)
      channels) is the result of voltage-dependent blockade of K(+) currents by
      intracellular divalent cations. We expressed a cloned SK(Ca) channel, rSK2, in
      Xenopus oocytes and further characterized the nature of the divalent cation
      binding site by electrophysiological means. Using site-directed substitution of
      hydrophilic residues in K(+)-conducting pathway and subsequent functional
      analysis of mutations, we identified an amino acid residue, Ser-359, in the pore
      forming region of rSK2 critical for the strong rectification of the I-V
      relationship. This residue interacts directly with intracellular divalent cations
      and determines the ionic selectivity. Therefore, we confirmed our proposition by
      localizing the divalent cation-binding site within the conduction pathway of the
      SK(Ca) channel. Because the Ser residue unique for the subfamily of SK(Ca)
      channels is likely to locate closely to the selectivity filter of the channels,
      it may also contribute to other permeation characteristics of SK(Ca) channels.

PMID- 12414688
TI  - Ca(2+)-dependent interaction between FKBP12 and calcineurin regulates activity of
      the Ca(2+) release channel in skeletal muscle.
AB  - Calcineurin is a Ca(2+) and calmodulin-dependent protein phosphatase with diverse
      cellular functions. Here we examined the physical and functional interactions
      between calcineurin and ryanodine receptor (RyR) in a C2C12 cell line derived
      from mouse skeletal muscle. Coimmunoprecipitation experiments revealed that the
      association between RyR and calcineurin exhibits a strong Ca(2+) dependence. This
      association involves a Ca(2+) dependent interaction between calcineurin and FK506
      binding protein (FKBP12), an accessory subunit of RyR. Pretreatment with
      cyclosporin A, an inhibitor of calcineurin, enhanced the caffeine-induced Ca(2+)
      release (CICR) in C2C12 cells. This effect was similar to those of FK506 and
      rapamycin, two drugs known to cause dissociation of FKBP12 from RyR.
      Overexpression of a constitutively active form of calcineurin in C2C12 cells,
      DeltaCnA(391-521) (deletion of the last 131 amino acids from calcineurin),
      resulted in a decrease in CICR. This decrease in CICR activity was partially
      recovered by pretreatment with cyclosporin A. Furthermore, overexpression of an
      endogenous calcineurin inhibitor (cain) or an inactive form of calcineurin
      (DeltaCnA(H101Q)) in C2C12 cells resulted in up-regulation of CICR. Taken
      together, our data suggest that a trimeric-interaction among calcineurin, FKBP12,
      and RyR is important for the regulation of the RyR channel activity and may play
      an important role in the Ca(2+) signaling of muscle contraction and relaxation.

PMID- 12414689
TI  - Catalyzed insertion of proteins into phospholipid membranes: specificity of the
      process.
AB  - The process of insertion of intrinsic proteins into phospholipid membranes
      conjures up the thought of enormous energy barriers but is a routine occurrence
      in cells. Proteinaceous complexes responsible for protein
      targeting/translocation/insertion into membranes have been studied intensively.
      However, the mitochondrial voltage-dependent anion channel (VDAC), can insert
      into phospholipid membranes by an auto-catalytic process called "auto-directed
      insertion." This process results in an oriented insertion of VDAC channels and an
      increase in insertion rate per unit area of 10 orders of magnitude. Here we
      report that VDAC catalyzes the insertion of PorA/C1 and KcsA by increasing their
      calculated insertion rate per unit area by 9 orders of magnitude with no
      detectable effect on the insertion of alpha-hemolysin. This was measured as a
      reduction in the delay before the first insertion of these proteins. Gramicidin
      and PorA/C1 accelerate the calculated insertion rate per unit area of VDAC by 8
      and 9 orders of magnitude, respectively. Only PorA/C1 increases the overall rate
      of VDAC insertion (50-fold) over the self-catalyzed rate. Our results indicate
      that catalyzed insertion of proteins into phospholipid membranes does not arise
      simply from disturbance of the phospholipid membrane because it shows strong
      specificity.

PMID- 12414690
TI  - Mechanosensitivity of N-type calcium channel currents.
AB  - Mechanosensitivity in voltage-gated calcium channels could be an asset to calcium
      signaling in healthy cells or a liability during trauma. Recombinant N-type
      channels expressed in HEK cells revealed a spectrum of mechano-responses. When
      hydrostatic pressure inflated cells under whole-cell clamp, capacitance was
      unchanged, but peak current reversibly increased ~1.5-fold, correlating with
      inflation, not applied pressure. Additionally, stretch transiently increased the
      open-state inactivation rate, irreversibly increased the closed-state
      inactivation rate, and left-shifted inactivation without affecting the activation
      curve or rate. Irreversible mechano-responses proved to be mechanically
      accelerated components of run-down; they were not evident in cell-attached
      recordings where, however, reversible stretch-induced increases in peak current
      persisted. T-type channels (alpha(1I) subunit only) were mechano-insensitive when
      expressed alone or when coexpressed with N-type channels (alpha(1B) and two
      auxiliary subunits) and costimulated with stretch that augmented N-type current.
      Along with the cell-attached results, this differential effect indicates that N
      type mechanosensitivity did not depend on the recording situation. The
      insensitivity of T-type currents to stretch suggested that N-type mechano
      responses might arise from primary/auxiliary subunit interactions. However, in
      single-channel recordings, N-type currents exhibited reversible stretch-induced
      increases in NP(o) whether the alpha(1B) subunit was expressed alone or with
      auxiliary subunits. These findings set the stage for the molecular dissection of
      calcium current mechanosensitivity.

PMID- 12414691
TI  - Modulation of the gating of unitary cardiac L-type Ca(2+) channels by
      conditioning voltage and divalent ions.
AB  - Although a considerable number of studies have characterized inactivation and
      facilitation of macroscopic L-type Ca(2+) channel currents, the single channel
      properties underlying these important regulatory processes have only rarely been
      examined using Ca(2+) ions. We have compared unitary L-type Ca(2+) channel
      currents recorded with a low concentration of Ca(2+) ions with those recorded
      with Ba(2+) ions to elucidate the ionic dependence of the mechanisms responsible
      for the prepulse-dependent modulation of Ca(2+) channel gating kinetics.
      Conditioning prepulses were applied across a wide range of voltages to examine
      their effects on the subsequent Ca(2+) channel activity, recorded at a constant
      test potential. All recordings were made in the absence of any Ca(2+) channel
      agonists. Moderate-depolarizing prepulses resulted in a decrease in the
      probability of opening of the Ca(2+) channels during subsequent test voltage
      steps (inactivation), the extent of which was more dramatic with Ca(2+) ions than
      Ba(2+) ions. Facilitation, or increase of the average probability of opening with
      strong predepolarization, was due to long-duration mode 2 openings with Ca(2+)
      ions and Ba(2+) ions, despite a decrease in Ca(2+) channel availability
      (inactivation) under these conditions. The degree of both prepulse-induced
      inactivation and facilitation decreased with increasing Ba(2+) ion concentration.
      The time constants (and their proportions) describing the distributions of Ca(2+)
      channel open times (which reflect mode switching) were also prepulse-, and ion
      dependent. These results support the hypothesis that both prior depolarization
      and the nature and concentration of permeant ions modulate the gating properties
      of cardiac L-type Ca(2+) channels.

PMID- 12414692
TI  - Modulation of the conductance of unitary cardiac L-type Ca(2+) channels by
      conditioning voltage and divalent ions.
AB  - The accompanying paper (Josephson, I. R., A. Guia, E. G. Lakatta, and M. D.
      Stern. 2002. Biophys. J. 83:2575-2586) examined the effects of conditioning
      prepulses on the kinetics of unitary L-type Ca(2+) channel currents using Ca(2+)
      and Ba(2+) ions to determine the ionic-dependence of gating mechanisms
      responsible for channel inactivation and facilitation. Here we demonstrate that
      in addition to alterations in gating kinetics, the conductance of single L-type
      Ca(2+) channels was also dependent on the prior conditioning voltage and permeant
      ions. All recordings were made in the absence of any Ca(2+) channel agonists.
      Strongly depolarizing prepulses produced an increased frequency of long-duration
      (mode 2) openings during the test voltage steps. Mode 2 openings also displayed
      >25% larger single channel current amplitude (at 0 mV) than briefer (but well
      resolved) mode 1 openings. The conductance of mode 2 openings was 26 pS for 105
      mM Ba(2+), 18 pS for 5 mM Ba(2+), and 6 pS for 5 mM Ca(2+) ions; these values
      were 70% greater than the conductance of Ca(2+) channel openings of all durations
      (mode 1 and mode 2). Thus, the prepulse-driven shift into mode 2 gating results
      in a longer-lived Ca(2+) channel conformation that, in addition, displays altered
      permeation properties. These results, and those in the accompanying paper,
      support the hypothesis that multiple aspects of single L-type Ca(2+) channel
      behavior (gating kinetics, modal transitions, and ion permeation) are
      interrelated and are modulated by the magnitude of the conditioning
      depolarization and the nature and concentration of the ions permeating the
      channel.

PMID- 12414694
TI  - Beta-amyloid 25 to 35 is intercalated in anionic and zwitterionic lipid membranes
      to different extents.
AB  - Neuronal plasma membranes are thought to be the primary target of the neurotoxic
      beta-amyloid peptides (Abeta) in the pathogenesis of the Alzheimer's disease.
      Histologically, Abeta peptides are observed as extracellular macroscopic senile
      plaques, and most biophysical techniques have indicated the presence of Abeta
      close to the lipid headgroup region but not in the core of the membrane bilayers.
      The focus of this study is an investigation of the interaction between Abeta and
      lipid bilayers from a structural point of view. Neutron diffraction with the use
      of selectively deuterated amino acids has allowed us to determine unambiguously
      the position of the neurotoxic fragment Abeta (25-35) in the membrane. Two
      populations of the peptide are detected, one in the aqueous vicinity of the
      membrane surface and the second inside the hydrophobic core of the lipid
      membrane. The location of the C terminus was studied in two different lipid
      compositions and was found to be dependent on the surface charge of the membrane.
      The localization of beta-amyloid peptides in cell membranes will offer new
      insights on their mechanism in the neurodegenerative process associated with
      Alzheimer's disease and might provide clues for therapeutic developments.

PMID- 12414693
TI  - Modeling the structure of agitoxin in complex with the Shaker K+ channel: a
      computational approach based on experimental distance restraints extracted from
      thermodynamic mutant cycles.
AB  - Computational methods are used to determine the three-dimensional structure of
      the Agitoxin (AgTx2)-Shaker complex. In a first stage, a large number of models
      of the complex are generated using high temperature molecular dynamics,
      accounting for side chain flexibility with distance restraints deduced from
      thermodynamic analysis of double mutant cycles. Four plausible binding mode
      candidates are found using this procedure. In a second stage, the quality and
      validity of the resulting complexes is assessed by examining the stability of the
      binding modes during molecular dynamics simulations with explicit water molecules
      and by calculating the binding free energies of mutant proteins using a continuum
      solvent representation and comparing with experimental data. The docking protocol
      and the continuum solvent model are validated using the Barstar-Barnase and the
      lysozyme-antibody D1.2 complexes, for which there are high-resolution structures
      as well as double mutant data. This combination of computational methods permits
      the identification of two possible structural models of AgTx2 in complex with the
      Shaker K+ channel, additional structural analysis providing further evidence in
      favor of a single model. In this final complex, the toxin is bound to the
      extracellular entrance of the channel along the pore axis via a combination of
      hydrophobic, hydrogen bonding, and electrostatic interactions. The magnitude of
      the buried solvent accessible area corresponding to the protein-protein contact
      is on the order of 1000 A with roughly similar contributions from each of the
      four subunits. Some side chains of the toxin adopt different conformation than in
      the experimental solution structure, indicating the importance of an induced-fit
      upon the formation of the complex. In particular, the side chain of Lys-27, a
      residue highly conserved among scorpion toxins, points deep into the pore with
      its positively charge amino group positioned at the outer binding site for K+.
      Specific site-directed mutagenesis experiments are suggested to verify and
      confirm the structure of the toxin-channel complex.

PMID- 12414695
TI  - Influence of product phase separation on phospholipase A(2) hydrolysis of
      supported phospholipid bilayers studied by force microscopy.
AB  - In situ atomic force microscopy studies reveal a marked influence of the initial
      presence of hydrolysis products on the hydrolysis of supported phospholipid
      bilayers by phospholipase A(2). By analysis of the nano-scale topography of a
      number of supported bilayers with different initial product concentrations, made
      by Langmuir-Blodgett deposition, we show that small depressions enriched in
      products are efficiently promoting enzyme degradation of the bilayer. These small
      depressions, which are indicative of phase separation, are initially present in
      samples with 75% products. The kinetics of phospholipase A(2) exhibit under
      certain conditions an initial phase of slow hydrolysis, termed the latency phase,
      followed by a marked increase in the hydrolysis rate. The appearance of the phase
      separated bilayer is strikingly similar to that of bilayers at the end of the
      latency phase. By analysis of individual nano-scale defects we illustrate a
      quantitative difference in the growth rates of defects caused by product
      aggregation and other structural defects. This difference shows for the first
      time how the enzyme prefers one type of defect to another.

PMID- 12414696
TI  - Ripples and the formation of anisotropic lipid domains: imaging two-component
      supported double bilayers by atomic force microscopy.
AB  - Direct visualization of the fluid-phase/ordered-phase domain structure in mica
      supported bilayers composed of 1,2-dimyristoyl-sn-glycero-3-phosphocholine/1,2
      distearoyl-sn-glycero-3-phosphocholine mixtures is performed with atomic force
      microscopy. The system studied is a double bilayer supported on a mica surface in
      which the top bilayer (which is not in direct contact with the mica) is
      visualized as a function of temperature. Because the top bilayer is not as
      restricted by the interactions with the surface as single supported bilayers, its
      behavior is more similar to a free-standing bilayer. Intriguing straight-edged
      anisotropic fluid-phase domains were observed in the fluid-phase/ordered-phase
      coexistence temperature range, which resemble the fluid-phase/ordered-phase
      domain patterns observed in giant unilamellar vesicles composed of such
      phospholipid mixtures. With the high resolution provided by atomic force
      microscopy, we investigated the origin of these anisotropic lipid domain
      patterns, and found that ripple phase formation is directly responsible for the
      anisotropic nature of these domains. The nucleation and growth of fluid-phase
      domains are found to be directed by the presence of ripples. In particular, the
      fluid-phase domains elongate parallel to the ripples. The results show that
      ripple phase formation may have implications for domain formation in biological
      systems.

PMID- 12414698
TI  - Measuring pKa of activation and pKi of inactivation for influenza hemagglutinin
      from kinetics of membrane fusion of virions and of HA expressing cells.
AB  - The data for the pH dependence of lipid mixing between influenza virus (A/PR/8/34
      strain) and fluorescently labeled liposomes containing gangliosides has been
      analyzed using a comprehensive mass action kinetic model for hemaglutinin (HA)
      mediated fusion. Quantitative results obtained about the architecture of HA
      mediated membrane fusion site from this analysis are in agreement with the
      previously reported results from analyses of data for HA-expressing cells fusing
      with various target membranes. Of the eight or more HAs forming a fusogenic
      aggregate, only two have to undergo the "essential" conformational change needed
      to initiate fusion. The mass action kinetic model has been extended to allow the
      analysis of the pKa for HA activation and pKi for HA inactivation. Inactivation
      and activation of HA following protonation were investigated for various
      experimental systems involving different strains of HA (A/PR/8/34, X:31,
      A/Japan). We find that the pKa for the final protonation site on each monomer of
      the trimer molecule is 5.6 to 5.7, irrespective of the strain. We also find that
      the pKi for the PR/8 strain is 4.8 to 4.9. The inactivation rate constants for
      HA, measured from experiments done with PR/8 virions fusing with liposomes and
      X:31 HA-expressing cells fusing with red blood cells, were both found to be of
      the order of 10(-4) s(-1). This number appears to be the minimal rate for HA's
      essential conformational change at low HA surface density. At high HA surface
      densities, we find evidence for cooperativity in the conformational change, as
      suggested by other studies.

PMID- 12414697
TI  - Lipid intermediates in membrane fusion: formation, structure, and decay of
      hemifusion diaphragm.
AB  - Lipid bilayer fusion is thought to involve formation of a local hemifusion
      connection, referred to as a fusion stalk. The subsequent fusion stages leading
      to the opening of a fusion pore remain unknown. The earliest fusion pore could
      represent a bilayer connection between the membranes and could be formed directly
      from the stalk. Alternatively, fusion pore can form in a single bilayer, referred
      to as hemifusion diaphragm (HD), generated by stalk expansion. To analyze the
      plausibility of stalk expansion, we studied the pathway of hemifusion
      theoretically, using a recently developed elastic model. We show that the stalk
      has a tendency to expand into an HD for lipids with sufficiently negative
      spontaneous splay, (~)J(s)< 0. For different experimentally relevant membrane
      configurations we find two characteristic values of the spontaneous splay.
      (~)J*(s) and (~)J**(s), determining HD dimension. The HD is predicted to have a
      finite equilibrium radius provided that the spontaneous splay is in the range
      (~)J**(s)< (~)J(s)<(~)J*(s), and to expand infinitely for (~)J(s)<(~)J**(s). In
      the case of common lipids, which do not fuse spontaneously, an HD forms only
      under action of an external force pulling the diaphragm rim apart. We calculate
      the dependence of the HD radius on this force. To address the mechanism of fusion
      pore formation, we analyze the distribution of the lateral tension emerging in
      the HD due to the establishment of lateral equilibrium between the deformed and
      relaxed portions of lipid monolayers. We show that this tension concentrates
      along the HD rim and reaches high values sufficient to rupture the bilayer and
      form the fusion pore. Our analysis supports the hypothesis that transition from a
      hemifusion to a fusion pore involves radial expansion of the stalk.

PMID- 12414699
TI  - Cation modulation of bicelle size and magnetic alignment as revealed by solid
      state NMR and electron microscopy.
AB  - The influence of salts (KCl, NaCl, CaCl(2), and MgCl(2)) on bicelles (bilayered
      micelles) made of dimyristoylphosphatidylcholine (DMPC, molar fraction X = 78%)
      and dicaproylphosphatidylcholine (DCPC) was investigated by solid-state (31)P-
      and (2)H NMR as well as by freeze-fracture electron microscopy. Sizes were
      determined from (2)H- and (31)P NMR on the basis of a model that incorporated a
      planar bilayer and a (half-torus) curved rim representing the DMPC and DCPC
      regions of the bicelle, respectively. Good agreement was shown with sizes
      determined independently from freeze-fracture electron microscopy images. In the
      presence of K(+) and Na(+), bicelles have diameters of approximately 300 A while
      in the presence of Ca(2+) and Mg(2+); their diameter increases to approximately
      500 A. Bicelle magnetic alignment is considerably improved by the presence of
      salts. The optimum salt concentration for such an effect ranges from 50 to 200
      mM. Bicelles are magnetically aligned for temperatures roughly ranging from 30
      degrees C to 40 degrees C with monovalent cations; this range is slightly
      extended in the presence of divalent salts. In this temperature range, the
      dynamics of the long-chain hydrocarbon region of the bicelle (leading to a
      bicelle thickness of 38 A) and of water is about the same independently of cation
      nature and concentration. However, at higher temperatures, considerable
      differences in water dynamics are observed between systems with monovalent and
      divalent cations. In these conditions, the system consists of a mixture of
      micelles and extended bilayers, which show residual macroscopic alignment in the
      magnetic field.

PMID- 12414700
TI  - Translational diffusion of individual class II MHC membrane proteins in cells.
AB  - Single-molecule epifluorescence microscopy was used to observe the translational
      motion of GPI-linked and native I-E(k) class II MHC membrane proteins in the
      plasma membrane of CHO cells. The purpose of the study was to look for deviations
      from Brownian diffusion that might arise from barriers to this motion. Detergent
      extraction had suggested that these proteins may be confined to lipid
      microdomains in the plasma membrane. The individual I-E(k) proteins were
      visualized with a Cy5-labeled peptide that binds to a specific extracytoplasmic
      site common to both proteins. Single-molecule trajectories were used to compute a
      radial distribution of displacements, yielding average diffusion coefficients
      equal to 0.22 (GPI-linked I-E(k)) and 0.18 microm(2)/s (native I-E(k)). The
      relative diffusion of pairs of proteins was also studied for intermolecular
      separations in the range 0.3-1.0 microm, to distinguish between free diffusion of
      a protein molecule and diffusion of proteins restricted to a rapidly diffusing
      small domain. Both analyses show that motion is predominantly Brownian. This
      study finds no strong evidence for significant confinement of either GPI-linked
      or native I-E(k) in the plasma membrane of CHO cells.

PMID- 12414701
TI  - Triton promotes domain formation in lipid raft mixtures.
AB  - Biological membranes are supposed to contain functional domains (lipid rafts)
      made up in particular of sphingomyelin and cholesterol, glycolipids, and certain
      proteins. It is often assumed that the application of the detergent Triton at 4
      degrees C allows the isolation of these rafts as a detergent-resistant membrane
      fraction. The current study aims to clarify whether and how Triton changes the
      domain properties. To this end, temperature-dependent transitions in vesicles of
      an equimolar mixture of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, egg
      sphingomyelin, and cholesterol were monitored at different Triton concentrations
      by differential scanning calorimetry and pressure perturbation calorimetry.
      Transitions initiated by the addition of Triton to the lipid mixture were studied
      by isothermal titration calorimetry, and the structure was investigated by (31)P
      NMR. The results are discussed in terms of liquid-disordered (ld) and -ordered
      (lo) bilayer and micellar (mic) phases, and the typical sequence encountered with
      increasing Triton content or decreasing temperature is ld, ld + lo, ld + lo +
      mic, and lo + mic. That means that addition of Triton may create ordered domains
      in a homogeneous fluid membrane, which are, in turn, Triton resistant upon
      subsequent membrane solubilization. Hence, detergent-resistant membranes should
      not be assumed to resemble biological rafts in size, structure, composition, or
      even existence. Functional rafts may not be steady phenomena; they might form,
      grow, cluster or break up, shrink, and vanish according to functional
      requirements, regulated by rather subtle changes in the activity of membrane
      disordering or ordering compounds.

PMID- 12414702
TI  - Lateral diffusion of cholesterol and dimyristoylphosphatidylcholine in a lipid
      bilayer measured by pulsed field gradient NMR spectroscopy.
AB  - The pulsed field gradient NMR method for measuring self-diffusion has been used
      for a direct determination of the lateral diffusion coefficient of cholesterol,
      fluorine labeled at the 6-position, for an oriented lamellar liquid-crystalline
      phase of dimyristoylphosphatidylcholine (DMPC)/cholesterol/water. It is found
      that the diffusion coefficients of DMPC and cholesterol are equal over a large
      temperature interval. The apparent energy of activation for the diffusion process
      (58 kJ/mol) is about the same as for a lamellar phase of DMPC/water, whereas the
      phospholipid lateral diffusion coefficient is approximately four times smaller in
      the presence of cholesterol.

PMID- 12414703
TI  - Mechanics of F-actin characterized with microfabricated cantilevers.
AB  - In this report we characterized the longitudinal elasticity of single actin
      filaments manipulated by novel silicon-nitride microfabricated levers. Single
      actin filaments were stretched from zero tension to maximal physiological
      tension, P(0). The obtained length-tension relation was nonlinear in the low
      tension range (0-50 pN) with a resultant strain of approximately 0.4-0.6% and
      then became linear at moderate to high tensions (approximately 50-230 pN). In
      this region, the stretching stiffness of a single rhodamine-phalloidin-labeled, 1
      microm-long F-actin is 34.5 +/- 3.5 pN/nm. Such a length-tension relation could
      be characterized by an entropic-enthalpic worm-like chain model, which ascribes
      most of the energy consumed in the nonlinear portion to overcoming thermal
      undulations arising from the filament's interaction with surrounding solution and
      the linear portion to the intrinsic stretching elasticity. By fitting the
      experimental data with such a worm-like chain model, an estimation of persistence
      length of approximately 8.75 microm was derived. These results suggest that F
      actin is more compliant than previously thought and that thin filament compliance
      may account for a substantial fraction of the sarcomere's elasticity.

PMID- 12414704
TI  - Crystal structure of the C-terminal half of tropomodulin and structural basis of
      actin filament pointed-end capping.
AB  - Tropomodulin is the unique pointed-end capping protein of the actin-tropomyosin
      filament. By blocking elongation and depolymerization, tropomodulin regulates the
      architecture and the dynamics of the filament. Here we report the crystal
      structure at 1.45-A resolution of the C-terminal half of tropomodulin (C20), the
      actin-binding moiety of tropomodulin. C20 is a leucine-rich repeat domain, and
      this is the first actin-associated protein with a leucine-rich repeat. Binding
      assays suggested that C20 also interacts with the N-terminal fragment, M1-M2-M3,
      of nebulin. Based on the crystal structure, we propose a model for C20 docking to
      the actin subunit at the pointed end. Although speculative, the model is
      consistent with the idea that a tropomodulin molecule competes with an actin
      subunit for a pointed end. The model also suggests that interactions with
      tropomyosin, actin, and nebulin are all possible sources of influences on the
      dynamic properties of pointed-end capping by tropomodulin.

PMID- 12414705
TI  - Thin filament regulation and ionic interactions between the N-terminal region in
      actin and troponin.
AB  - The N-terminal region in actin has been shown to interact with both myosin and
      troponin (Tn) during the cross-bridge cycle and in regulation. To study the role
      of this region in regulation, we used yeast actin mutants with increased and
      decreased numbers of acidic residues. The mutants included D24A/D25A, with
      Asp(24) and Asp(25) replaced with alanines; DNEQ, with the substitution of Asp(2)
      and Glu(4) with their amide analogs; and 4Ac, with Glu(3) and Asp(4) inserted in
      lieu of Ser(3). In the in vitro motility assay, using reconstituted regulated
      thin filaments, the sliding speeds of DNEQ, D24A/D25A, and 4Ac were similar at
      all pCa values. Thus, Ca(2+)-sensitivity of the thin filaments and the inhibitory
      function of TnI appear to be insensitive to changes in charge (+/-2) at the N
      terminus of actin, suggesting little, if any, role of that actin region in
      regulation. A Ca(2+)-independent conformational change in that region was
      detected upon troponin binding to actin-Tm via an increase in the fluorescence of
      a pyrene probe attached to another yeast actin mutant that we used (Cys(1)).

PMID- 12414706
TI  - Conformational dynamics of the SH1-SH2 helix in the transition states of myosin
      subfragment-1.
AB  - The alpha-helix containing the thiols, SH1 (Cys-707) and SH2 (Cys-697), has been
      proposed to be one of the structural elements responsible for the transduction of
      conformational changes in the myosin head (subfragment-1 (S1)). Previous studies,
      using a method that isolated and measured the rate of the SH1-SH2 cross-linking
      step, showed that this helix undergoes ligand-induced conformational changes.
      However, because of long incubation times required for the formation of the
      transition state complexes (S1.ADP.BeF(x), S1.ADP.AlF(4)-, and S1.ADP.V(i)), this
      method could not be used to determine the cross-linking rate constants for such
      states. In this study, kinetic data from the SH1-SH2 cross-linking reaction were
      analyzed by computational methods to extract rate constants for the two-step
      mechanism. For S1.ADP.BeF(x), the results obtained were similar to those for
      S1.ATPgammaS. For reactions involving S1.ADP.AlF(4)- and S1.ADP.V(i), the first
      step (SH1 modification) is rate limiting; consequently, only lower limits could
      be established for the rate constants of the cross-linking step. Nevertheless,
      these results show that the cross-linking rate constants in the transition state
      complexes are increased at least 20-fold for all the reagents, including the
      shortest one, compared with nucleotide-free S1. Thus, the SH1-SH2 helix appears
      to be destabilized in the post-hydrolysis state.

PMID- 12414707
TI  - The structure of Ca(2+) release units in arthropod body muscle indicates an
      indirect mechanism for excitation-contraction coupling.
AB  - The relative disposition of ryanodine receptors (RyRs) and L-type Ca(2+) channels
      was examined in body muscles from three arthropods. In all muscles the
      disposition of ryanodine receptors in the junctional gap between apposed SR and T
      tubule elements is highly ordered. By contrast, the junctional membrane of the T
      tubule is occupied by distinctive large particles that are clustered within the
      small junctional domain, but show no order in their arrangement. We propose that
      the large particles of the junctional T tubules represent L-type Ca(2+) channels
      involved in excitation-contraction (e-c) coupling, based on their similarity in
      size and location with the L-type Ca(2+) channels or dihydropyridine receptors
      (DHPRs) of skeletal and cardiac muscle. The random arrangement of DHPRs in
      arthropod body muscles indicates that there is no close link between them and
      RyRs. This matches the architecture of vertebrate cardiac muscle and is in
      keeping with the similarity in e-c coupling mechanisms in cardiac and
      invertebrate striated muscles.

PMID- 12414708
TI  - Structure and interactions of the carboxyl terminus of striated muscle alpha
      tropomyosin: it is important to be flexible.
AB  - Tropomyosin (TM) binds to and regulates the actin filament. We used circular
      dichroism and heteronuclear NMR to investigate the secondary structure and
      interactions of the C terminus of striated muscle alpha-TM, a major functional
      determinant, using a model peptide, TM9a(251-284). The (1)H(alpha) and
      (13)C(alpha) chemical shift displacements show that residues 252 to 277 are alpha
      helical but residues 278 to 284 are nonhelical and mobile. The (1)H(N) and (13)C'
      displacements suggest that residues 257 to 269 form a coiled coil. Formation of
      an "overlap" binary complex with a 33-residue N-terminal chimeric peptide
      containing residues 1 to 14 of alpha-TM perturbs the (1)H(N) and (15)N resonances
      of residues 274 to 284. Addition of a fragment of troponin T, TnT(70-170), to the
      binary complex perturbs most of the (1)H(N)-(15)N cross-peaks. In addition, there
      are many new cross-peaks, showing that the binding is asymmetric. Q263, in a
      proposed troponin T binding site, shows two sets of side-chain (15)N-(1)H cross
      peaks, indicating conformational flexibility. The conformational equilibrium of
      the side chain changes upon formation of the binary and ternary complexes.
      Replacing Q263 with leucine greatly increases the stability of TM9a(251-284) and
      reduces its ability to form the binary and ternary complexes, showing that
      conformational flexibility is crucial for the binding functions of the C
      terminus.

PMID- 12414709
TI  - Calcium binding to calmodulin mutants monitored by domain-specific intrinsic
      phenylalanine and tyrosine fluorescence.
AB  - Cooperative calcium binding to the two homologous domains of calmodulin (CaM)
      induces conformational changes that regulate its association with and activation
      of numerous cellular target proteins. Calcium binding to the pair of high
      affinity sites (III and IV in the C-domain) can be monitored by observing calcium
      dependent changes in intrinsic tyrosine fluorescence intensity
      (lambda(ex)/lambda(em) of 277/320 nm). However, calcium binding to the low
      affinity sites (I and II in the N-domain) is more difficult to measure with
      optical spectroscopy because that domain of CaM does not contain tryptophan or
      tyrosine. We recently demonstrated that calcium-dependent changes in intrinsic
      phenylalanine fluorescence (lambda(ex)/lambda(em) of 250/280 nm) of an N-domain
      fragment of CaM reflect occupancy of sites I and II (VanScyoc, W. S., and M. A.
      Shea, 2001, Protein Sci. 10:1758-1768). Using steady-state and time-resolved
      fluorescence methods, we now show that these excitation and emission wavelength
      pairs for phenylalanine and tyrosine fluorescence can be used to monitor
      equilibrium calcium titrations of the individual domains in full-length CaM.
      Calcium-dependent changes in phenylalanine fluorescence specifically indicate ion
      occupancy of sites I and II in the N-domain because phenylalanine residues in the
      C-domain are nonemissive. Tyrosine emission from the C-domain does not interfere
      with phenylalanine fluorescence signals from the N-domain. This is the first
      demonstration that intrinsic fluorescence may be used to monitor calcium binding
      to each domain of CaM. In this way, we also evaluated how mutations of two
      residues (Arg74 and Arg90) located between sites II and III can alter the calcium
      binding properties of each of the domains. The mutation R74A caused an increase
      in the calcium affinity of sites I and II in the N-domain. The mutation R90A
      caused an increase in calcium affinity of sites III and IV in the C-domain
      whereas R90G caused an increase in calcium affinity of sites in both domains.
      This approach holds promise for exploring the linked energetics of calcium
      binding and target recognition.

PMID- 12414710
TI  - Analysis of protein sequence/structure similarity relationships.
AB  - Current analyses of protein sequence/structure relationships have focused on
      expected similarity relationships for structurally similar proteins. To survey
      and explore the basis of these relationships, we present a general
      sequence/structure map that covers all combinations of similarity/dissimilarity
      relationships and provide novel energetic analyses of these relationships. To aid
      our analysis, we divide protein relationships into four categories:
      expected/unexpected similarity (S and S(?)) and expected/unexpected dissimilarity
      (D and D(?)) relationships. In the expected similarity region S, we show that
      trends in the sequence/structure relation can be derived based on the requirement
      of protein stability and the energetics of sequence and structural changes.
      Specifically, we derive a formula relating sequence and structural deviations to
      a parameter characterizing protein stiffness; the formula fits the data
      reasonably well. We suggest that the absence of data in region S(?) (high
      structural but low sequence similarity) is due to unfavorable energetics. In
      contrast to region S, region D(?) (high sequence but low structural similarity)
      is well-represented by proteins that can accommodate large structural changes.
      Our analyses indicate that there are several categories of similarity
      relationships and that protein energetics provide a basis for understanding these
      relationships.

PMID- 12414711
TI  - Dynamic transition associated with the thermal denaturation of a small Beta
      protein.
AB  - We studied the temperature dependence of the picosecond internal dynamics of an
      all-beta protein, neocarzinostatin, by incoherent quasielastic neutron
      scattering. Measurements were made between 20 degrees C and 71 degrees C in heavy
      water solution. At 20 degrees C, only 33% of the nonexchanged hydrogen atoms show
      detectable dynamics, a number very close to the fraction of protons involved in
      the side chains of random coil structures, therefore suggesting a rigid structure
      in which the only detectable diffusive movements are those involving the side
      chains of random coil structures. At 61.8 degrees C, although the protein
      structure is still native, slight dynamic changes are detected that could reflect
      enhanced backbone and beta-sheet side-chain motions at this higher temperature.
      Conversely, all internal dynamics parameters (amplitude of diffusive motions,
      fraction of immobile scatterers, mean-squared vibration amplitude) rapidly change
      during heat-induced unfolding, indicating a major loss of rigidity of the beta
      sandwich structure. The number of protons with diffusive motion increases
      markedly, whereas the volume occupied by the diffusive motion of protons is
      reduced. At the half-transition temperature (T = 71 degrees C) most of backbone
      and beta-sheet side-chain hydrogen atoms are involved in picosecond dynamics.

PMID- 12414712
TI  - Numerical study of the entropy loss of dimerization and the folding
      thermodynamics of the GCN4 leucine zipper.
AB  - A lattice-based model of a protein and the Monte Carlo simulation method are used
      to calculate the entropy loss of dimerization of the GCN4 leucine zipper. In the
      representation used, a protein is a sequence of interaction centers arranged on a
      cubic lattice, with effective interaction potentials that are both of physical
      and statistical nature. The Monte Carlo simulation method is then used to sample
      the partition functions of both the monomer and dimer forms as a function of
      temperature. A method is described to estimate the entropy loss upon
      dimerization, a quantity that enters the free energy difference between monomer
      and dimer, and the corresponding dimerization reaction constant. As expected, but
      contrary to previous numerical studies, we find that the entropy loss of
      dimerization is a strong function of energy (or temperature), except in the limit
      of large energies in which the motion of the two dimer chains becomes largely
      uncorrelated. At the monomer-dimer transition temperature we find that the
      entropy loss of dimerization is approximately five times smaller than the value
      that would result from ideal gas statistics, a result that is qualitatively
      consistent with a recent experimental determination of the entropy loss of
      dimerization of a synthetic peptide that also forms a two-stranded alpha-helical
      coiled coil.

PMID- 12414714
TI  - Excluded volume effect within the continuous model for the fluorescence energy
      transfer.
AB  - We consider and discuss the transfer of electronic energy between donor and
      acceptor molecules, both continuously distributed in an infinite space. In
      particular, the ensemble-average fluorescence intensity decay for the donor was
      calculated, taking into account the excluded volume. The latter may be associated
      either with finite molecular size or any other spatial restrictions, which are
      imposed on fluorophore distribution by a superstructure. Results show that in a
      system using excluded volume, the time dependence in donor decay is more complex
      compared to that predicted by a simplified stretched exponential model. We
      identify a crossover between two distinct time regimes in the refined decay and
      demonstrate its correlation with two competing parameters: r(m), which
      characterizes the minimal distance between interacting molecules, and R(0), which
      is related to the strength of the molecular interactions. In this context, the
      "apparent dimensionality" of the energy transfer recovered from the stretched
      exponential model ignores the crossover, and may be quite misleading. Basic
      theoretical considerations to that end are provided.

PMID- 12414713
TI  - (13)C-(1)H NMR relaxation and fluorescence anisotropy decay study of tyrosine
      dynamics in motilin.
AB  - Tyrosine ring dynamics of the gastrointestinal hormone motilin was studied using
      two independent physical methods: fluorescence polarization anisotropy decay and
      NMR relaxation. Motilin, a 22-residue peptide, was selectively (13)C labeled in
      the ring epsilon-carbons of the single tyrosine residue. To eliminate effects of
      differences in peptide concentration, the same motilin sample was used in both
      experiments. NMR relaxation rates of the tyrosine ring C(epsilon)-H(epsilon)
      vectors, measured at four magnetic field strengths (9.4, 11.7, 14.1, and 18.8
      Tesla) were used to map the spectral density function. When the data were
      analyzed using dynamic models with the same number of components, the dynamic
      parameters from NMR and fluorescence are in excellent agreement. However, the
      estimated rotational correlation times depend on the choice of dynamic model. The
      correlation times estimated from the two-component model-free approach and the
      three-component models were significantly different (1.7 ns and 2.2 ns,
      respectively). Various earlier studies of protein dynamics by NMR and
      fluorescence were compared. The rotational correlation times estimated by NMR for
      samples with high protein concentration were on average 18% longer for folded
      monomeric proteins than the corresponding times estimated by fluorescence
      polarization anisotropy decay, after correction for differences in viscosity due
      to temperature and D(2)O/H(2)O ratio.

PMID- 12414715
TI  - Solid-state NMR determination of sugar ring pucker in (13)C-labeled 2'
      deoxynucleosides.
AB  - The H3'-C3'-C4'-H4' torsional angles of two microcrystalline 2'-deoxynucleosides,
      thymidine and 2'-deoxycytidine.HCl, doubly (13)C-labeled at the C3' and C4'
      positions of the sugar ring, have been measured by solid-state magic-angle
      spinning nuclear magnetic resonance (NMR). A double-quantum heteronuclear local
      field experiment with frequency-switched Lee-Goldberg homonuclear decoupling was
      used. The H3'-C3'-C4'-H4' torsional angles were obtained by comparing the
      experimental curves with numerical simulations, including the two (13)C nuclei,
      the directly bonded (1)H nuclei, and five remote protons. The H3'-C3'-C4'-H4'
      angles were converted into sugar pucker angles and compared with crystallographic
      data. The delta torsional angles determined by solid-state NMR and x-ray
      crystallography agree within experimental error. Evidence is also obtained that
      the proton positions may be unreliable in the x-ray structures. This work
      confirms that double-quantum solid-state NMR is a feasible tool for studying
      sugar pucker conformations in macromolecular complexes that are unsuitable for
      solution NMR or crystallography.

PMID- 12414716
TI  - Comparative study of tyrosine radicals in hemoglobin and myoglobins treated with
      hydrogen peroxide.
AB  - The reactions of hydrogen peroxide with human methemoglobin, sperm whale
      metmyoglobin, and horse heart metmyoglobin were studied by electron paramagnetic
      resonance (EPR) spectroscopy at 10 K and room temperature. The singlet EPR
      signal, one of the three signals seen in these systems at 10 K, is characterized
      by a poorly resolved, but still detectable, hyperfine structure that can be used
      to assign it to a tyrosyl radical. The singlet is detectable as a quintet at room
      temperature in methemoglobin with identical spectral features to those of the
      well characterized tyrosyl radical in photosystem II. Hyperfine splitting
      constants found for Tyr radicals were used to find the rotation angle of the
      phenoxyl group. Analysis of these angles in the crystal structures suggests that
      the radical resides on Tyr151 in sperm whale myoglobin, Tyr133 in soybean
      leghemoglobin, and either alphaTyr42, betaTyr35, or betaTyr130 in hemoglobin. In
      the sperm whale metmyoglobin Tyr103Phe mutant, there is no detectable tyrosyl
      radical present. Yet the rotation angle of Tyr103 (134 degrees) is too large to
      account for the observed EPR spectrum in the wild type. Tyr103 is the closest to
      the heme. We suggest that Tyr103 is the initial site of the radical, which then
      rapidly migrates to Tyr151.

PMID- 12414717
TI  - Importance of intracellular water apparent diffusion to the measurement of
      membrane permeability.
AB  - The exchange of water across biological membranes is of fundamental significance
      to both animal and plant physiology. Diffusional membrane permeability (P(d)) for
      the Xenopus oocyte, an important model system for water channel investigation, is
      typically calculated from intracellular water pre-exchange lifetime, cell volume,
      and cell surface area. There is debate, however, whether intracellular water
      motion affects water lifetime, and thereby P(d). Mathematical modeling of water
      transport is problematic because the intracellular water diffusion rate constant
      (D) for cells is usually unknown. The measured permeability may be referred to as
      the apparent diffusional permeability, P, to acknowledge this potential error.
      Herein, we show that magnetic resonance (MR) spectroscopy can be used to measure
      oocyte water exchange with greater temporal resolution and higher signal-to-noise
      ratio than other methods. MR imaging can be used to assess both oocyte geometry
      and intracellular water diffusion for the same single cells. MR imaging is used
      to confirm the dependence of intracellular water lifetime on intracellular
      diffusion. A model is presented to relate intracellular lifetime to true membrane
      diffusional permeability. True water diffusional permeability (2.7 +/- 0.4
      microm/s) is shown to be 39 +/- 6% greater than apparent diffusional permeability
      for 8 oocytes. This discrepancy increases with cell size and permeability (such
      as after water channel expression) and decreases with increasing intracellular
      water D.

PMID- 12414718
TI  - Characterization of a new caged proton capable of inducing large pH jumps.
AB  - A new caged proton, 1-(2-nitrophenyl)ethyl sulfate (caged sulfate), is
      characterized by infrared spectroscopy and compared with a known caged, proton 2
      hydroxyphenyl 1-(2-nitrophenyl)ethyl phosphate (caged HPP). In contrast to caged
      HPP, caged sulfate can induce large pH jumps and protonate groups that have pK
      values as low as 2.2. The photolysis mechanism of caged sulfate is analogous to
      that of P(3)-[1-(2-nitrophenyl)ethyl] ATP (caged ATP), and the photolysis
      efficiency is similar. The utility of this new caged compound for biological
      studies was demonstrated by its ability to drive the acid-induced conformational
      change of metmyoglobin. This transition from the native conformation to a
      partially unfolded form takes place near pH 4 and was monitored by near-UV
      absorption spectroscopy.

PMID- 12414719
TI  - Laminar-flow fluid mixer for fast fluorescence kinetics studies.
AB  - The ability to mix aqueous liquids on microsecond time scales, while consuming
      minimal amounts of sample and maintaining UV-visible optical access to the mixing
      region, is highly desirable for a range of biophysical studies of fast protein
      and nucleic acid interactions and folding. We have constructed a laminar coaxial
      jet mixer that allows the measurement of UV-excited fluorescence from nanoliter
      and microliter quantities of material, mixed at microsecond rates. The mixer
      injects a narrow cylindrical stream (radius a < 1 microm) of fluorescent sample
      into a larger flow of diluting buffer that moves through a capillary (100 microm
      i.d.) at a speed approximately 20 cm/s, under laminar flow conditions (Re
      approximately equal to 14). Construction from a fused silica capillary allows the
      laser excitation (at 266 nm) and detection (at 350 nm) of tryptophan fluorescence
      at reasonably low working concentrations, without interference from background
      fluorescence. Using this mixer we have measured sub-millisecond fluorescence
      quenching kinetics while consuming fluorescent sample at rates no greater than 6
      nl/s. Consumption of the diluting buffer is also very modest (approximately 1-3
      microl/s) in comparison with other rapid mixer designs.

PMID- 12414720
TI  - CD45: a critical regulator of signaling thresholds in immune cells.
AB  - Regulation of tyrosine phosphorylation is a critical control point for
      integration of environmental signals into cellular responses. This regulation is
      mediated by the reciprocal actions of protein tyrosine kinases and phosphatases.
      CD45, the first and prototypic receptor-like protein tyrosine phosphatase, is
      expressed on all nucleated hematopoietic cells and plays a central role in this
      process. Studies of CD45 mutant cell lines, CD45-deficient mice, and CD45
      deficient humans initially demonstrated the essential role of CD45 in antigen
      receptor signal transduction and lymphocyte development. It is now known that
      CD45 also modulates signals emanating from integrin and cytokine receptors.
      Recent work has focused on regulation of CD45 expression and alternative
      splicing, isoform-specific differences in signal transduction, and regulation of
      phosphatase activity. From these studies, a model is emerging in which CD45
      affects cellular responses by controlling the relative threshold of sensitivity
      to external stimuli. Perturbation of this function may contribute to
      autoimmunity, immunodeficiency, and malignancy. Moreover, recent advances suggest
      that modulation of CD45 function can have therapeutic benefit in many disease
      states.

PMID- 12414721
TI  - Control of apoptosis in the immune system: Bcl-2, BH3-only proteins and more.
AB  - Apoptotic cell death plays a critical role in the development and functioning of
      the immune system. During differentiation, apoptosis weeds out lymphocytes
      lacking useful antigen receptors and those expressing dangerous ones. Lymphocyte
      death is also involved in limiting the magnitude and duration of immune responses
      to infection. In this review, we describe the role of the Bcl-2 protein family,
      and to a lesser extent that of death receptors (members of the tumor necrosis
      factor receptor family with a death domain), in the control of lymphoid and
      myeloid cell survival. We also consider the pathogenic consequences of failure of
      apoptosis in the immune system.

PMID- 12414722
TI  - Positive and negative selection of T cells.
AB  - A functional immune system requires the selection of T lymphocytes expressing
      receptors that are major histocompatibility complex restricted but tolerant to
      self-antigens. This selection occurs predominantly in the thymus, where
      lymphocyte precursors first assemble a surface receptor. In this review we
      summarize the current state of the field regarding the natural ligands and
      molecular factors required for positive and negative selection and discuss a
      model for how these disparate outcomes can be signaled via the same receptor. We
      also discuss emerging data on the selection of regulatory T cells. Such cells
      require a high-affinity interaction with self-antigens, yet differentiate into
      regulatory cells instead of being eliminated.

PMID- 12414723
TI  - CD8 T cell responses to infectious pathogens.
AB  - CD8 T cells respond to viral infections but also participate in defense against
      bacterial and protozoal infections. In the last few years, as new methods to
      accurately quantify and characterize pathogen-specific CD8 T cells have become
      available, our understanding of in vivo T cell responses has increased
      dramatically. Pathogen-specific T cells, once thought to be quite rare following
      infection, are now known to be present at very high frequencies, particularly in
      peripheral, nonlymphoid tissues. With the ability to visualize in vivo CD8 T cell
      responses has come the recognition that T cell expansion is programmed and, to a
      great extent, independent of antigen concentrations. Comparison of CD8 T cell
      responses to different pathogens also highlights the intricate relationship
      between microbially induced innate inflammatory responses and the kinetics,
      magnitude, and character of long-term T cell responses. This review describes
      recent progress in some of the major murine models of CD8 T cell-mediated
      immunity to viral, bacterial, and protozoal infection.

PMID- 12414724
TI  - The Argonaute family: tentacles that reach into RNAi, developmental control, stem
      cell maintenance, and tumorigenesis.

PMID- 12414725
TI  - Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened.
AB  - The steroidal alkaloid cyclopamine has both teratogenic and antitumor activities
      arising from its ability to specifically block cellular responses to vertebrate
      Hedgehog signaling. We show here, using photoaffinity and fluorescent
      derivatives, that this inhibitory effect is mediated by direct binding of
      cyclopamine to the heptahelical bundle of Smoothened (Smo). Cyclopamine also can
      reverse the retention of partially misfolded Smo in the endoplasmic reticulum,
      presumably through binding-mediated effects on protein conformation. These
      observations reveal the mechanism of cyclopamine's teratogenic and antitumor
      activities and further suggest a role for small molecules in the physiological
      regulation of Smo.

PMID- 12414726
TI  - Activin type IIA and IIB receptors mediate Gdf11 signaling in axial vertebral
      patterning.
AB  - Vertebral bodies are segmented along the anteroposterior (AP) body axis, and the
      segmental identity of the vertebrae is determined by the unique expression
      pattern of multiple Hox genes. Recent studies have demonstrated that a
      transforming growth factor beta (TGF-beta) family protein, Gdf11 (growth and
      differentiation factor 11), and the activin type II receptor, ActRIIB, are
      involved in controlling the spatiotemporal expression of multiple Hox genes along
      the AP axis, and that the disruption of each of these genes causes anterior
      transformation of the vertebrae. Skeletal defects are more severe in Gdf11-null
      mice than in ActRIIB-null mice, however, leaving it uncertain whether Gdf11
      signals via ActRIIB. Here we demonstrate using genetic and biochemical studies
      that ActRIIB and its subfamily receptor, ActRIIA, cooperatively mediate the Gdf11
      signal in patterning the axial vertebrae, and that Gdf11 binds to both ActRIIA
      and ActRIIB, and induces phosphorylation of Smad2. In addition, we also show that
      these two receptors can functionally compensate for one another to mediate
      signaling of another TGF-beta ligand, nodal, during left-right patterning and the
      development of anterior head structure.

PMID- 12414727
TI  - A novel mitochondrial protein, Tar1p, is encoded on the antisense strand of the
      nuclear 25S rDNA.
AB  - In eukaryotes, it is widely assumed that genes coding for proteins and structural
      RNAs do not overlap. Using a transposon-tagging strategy to globally analyze the
      Saccharomyces cerevisiae genome for expressed genes, we identified multiple
      insertions in an open reading frame that is contained fully within and
      transcribed antisense to the 25S rRNA gene in the nuclear rDNA repeat region on
      Chromosome XII. Expression of this gene, TAR1 (Transcript Antisense to Ribosomal
      RNA), can be detected at the RNA and protein levels, and the primary sequence of
      the corresponding 124-amino-acid protein is conserved in several yeast species.
      Tar1p was found to localize to mitochondria, and overexpression of the protein
      suppresses the respiration-deficient petite phenotype of a point mutation in
      mitochondrial RNA polymerase that affects mitochondrial gene expression and mtDNA
      stability. These findings indicate that coding information for protein and
      structural RNAs can overlap, raising issues regarding the coevolution of such
      complex genes, and also suggest that rDNA transcription and mitochondrial
      function are coordinately regulated in eukaryotic cells.

PMID- 12414728
TI  - Intron status and 3'-end formation control cotranscriptional export of mRNA.
AB  - Messenger RNA export factors are recruited to genes in a transcription-dependent
      manner. To ascertain the mechanism of this process, we show that RNA polymerase
      II transcription is sufficient to recruit the Saccharomyces cerevisiae hnRNP
      protein Npl3 to a gene independent of RNA sequence. In contrast, the
      cotranscriptional recruitment of the RNA-binding protein Yra1 is dependent on pre
      mRNA processing. Yra1 associates with introns of intron-containing genes in a
      splicing-dependent manner. Conversely, Yra1 recruitment to genes without introns
      is not dependent on splicing. Finally, 3'-end formation is required for Yra1
      recruitment to genes regardless of intron status.

PMID- 12414729
TI  - Strand pairing by Rad54 and Rad51 is enhanced by chromatin.
AB  - We investigated the role of chromatin in the catalysis of homologous strand
      pairing by Rad54 and Rad51. Rad54 is related to the ATPase subunits of chromatin
      remodeling factors, whereas Rad51 is related to bacterial RecA. In the absence of
      superhelical tension, we found that the efficiency of strand pairing with
      chromatin is >100-fold higher than that with naked DNA. In addition, we observed
      that Rad54 and Rad51 function cooperatively in the ATP-dependent remodeling of
      chromatin. These findings indicate that Rad54 and Rad51 have evolved to function
      with chromatin, the natural substrate, rather than with naked DNA.

PMID- 12414730
TI  - Activator recruitment by the general transcription machinery: X-ray structural
      analysis of the Oct-1 POU domain/human U1 octamer/SNAP190 peptide ternary
      complex.
AB  - Transcriptional activation of the human U1 snRNA genes is dependent on a
      noncanonical octamer element contained within an upstream enhancer. The U1
      octamer only weakly recruits the Oct-1 POU domain, although recruitment is
      stimulated by a peptide containing the Oct-1-binding domain of SNAP190.
      Structural analysis of the Oct-1 POU domain/U1 octamer/SNAP190 peptide complex
      revealed that SNAP190 makes extensive protein contacts with the Oct-1 POU
      specific domain and with the DNA phosphate backbone within the enhancer. Although
      SNAP190 and OCA-B both interact with the Oct-1 POU domain through the same Oct-1
      interface, a single nucleotide within the U1 octamer ablates OCA-B recruitment
      without compromising activator recruitment by SNAP190.

PMID- 12414731
TI  - 5' exon interactions within the human spliceosome establish a framework for exon
      junction complex structure and assembly.
AB  - A general consequence of pre-mRNA splicing is the stable deposition of several
      proteins 20-24 nucleotides (nt) upstream of exon-exon junctions on spliced mRNAs.
      This exon junction complex (EJC) contains factors involved in mRNA export,
      cytoplasmic localization, and nonsense-mediated mRNA decay. Here we probed the
      mechanism and timing of EJC assembly. Over the course of splicing, the 5' exon is
      subject to numerous dynamic protein-RNA interactions involving at least nine
      distinct polypeptides. Within the fully assembled spliceosome, these interactions
      afford protection to the last 25-27 nt of the 5' exon intermediate. Coincident
      with exon ligation, interactions at the 3' end of the 5' exon disappear, and new
      species associate with position -24. Mass spectrometry and Western blotting of
      purified H, C, and mRNP complexes revealed that at least one EJC component,
      REF/Aly, can interact with pre-mRNA prior to spliceosome assembly, whereas Y14,
      Magoh, RNPS1, UAP56, and SRm160 are found in intermediate-containing
      spliceosomes. Upon exon ligation, association of RNPS1, UAP56, and SRm160 is
      destabilized. In contrast, REF/Aly, Y14, and Magoh remain stably bound to spliced
      mRNA, indicating that these three proteins are components of the EJC core.

PMID- 12414732
TI  - Promoter proximal splice sites enhance transcription.
AB  - Reconstruction of a gene with its introns removed results in reduced levels of
      cytoplasmic mRNA. This is partly explained by introns promoting the export of
      mRNA through coupling splicing to nuclear export processes. However, we show here
      that splicing signals can have a direct role in enhancing gene transcription.
      Removal of promoter proximal splice signals from a mammalian gene or the excision
      of introns from two different yeast genes results in a marked reduction in levels
      of nascent transcription, based on both nuclear run-on and direct image analysis.
      This further establishes that mRNA processing and transcription are tightly
      coupled mechanisms.

PMID- 12414734
TI  - The transcription factor Sox9 has essential roles in successive steps of the
      chondrocyte differentiation pathway and is required for expression of Sox5 and
      Sox6.
AB  - To examine whether the transcription factor Sox9 has an essential role during the
      sequential steps of chondrocyte differentiation, we have used the Cre/loxP
      recombination system to generate mouse embryos in which either Sox9 is missing
      from undifferentiated mesenchymal cells of limb buds or the Sox9 gene is
      inactivated after chondrogenic mesenchymal condensations. Inactivation of Sox9 in
      limb buds before mesenchymal condensations resulted in a complete absence of both
      cartilage and bone, but markers for the different axes of limb development showed
      a normal pattern of expression. Apoptotic domains within the developing limbs
      were expanded, suggesting that Sox9 suppresses apoptosis. Expression of Sox5 and
      Sox6, two other Sox genes involved in chondrogenesis, was no longer detected.
      Moreover, expression of Runx2, a transcription factor needed for osteoblast
      differentiation, was also abolished. Embryos, in which Sox9 was deleted after
      mesenchymal condensations, exhibited a severe generalized chondrodysplasia,
      similar to that in Sox5; Sox6 double-null mutant mice. Most cells were arrested
      as condensed mesenchymal cells and did not undergo overt differentiation into
      chondrocytes. Furthermore, chondrocyte proliferation was severely inhibited and
      joint formation was defective. Although Indian hedgehog, Patched1, parathyroid
      hormone-related peptide (Pthrp), and Pth/Pthrp receptor were expressed, their
      expression was down-regulated. Our experiments further suggested that Sox9 is
      also needed to prevent conversion of proliferating chondrocytes into hypertrophic
      chondrocytes. We conclude that Sox9 is required during sequential steps of the
      chondrocyte differentiation pathway.

PMID- 12414735
TI  - Signaling pathways and physiological functions of Drosophila melanogaster
      FMRFamide-related peptides.
AB  - FMRFamide-related peptides (FaRPs) contain a C-terminal RFamide but unique N
      terminal extensions. They are expressed throughout the animal kingdom and affect
      numerous biological activities. Like other animal species, Drosophila
      melanogaster contains multiple genes that encode different FaRPs. The ease of
      genetic manipulations, the availability of genomic sequence data, the existence
      of established bioassays, and its short lifespan make D. melanogaster a versatile
      experimental organism in which to investigate peptide processing, functions, and
      signal transduction pathways. Here, the structures, precursor organizations,
      distributions, and activities of FaRPs encoded by D. melanogaster FMRFamide
      (dFMRFamide), myosuppressin (Dms), and sulfakinin (Dsk) genes are reviewed, and
      predictions are made on their signaling pathways and biological functions.

PMID- 12414736
TI  - Communication with substrate-borne signals in small plant-dwelling insects.
AB  - Vibratory signals of plant-dwelling insects, such as land bugs of the families
      Cydnidae and Pentatomidae, are produced mainly by stridulation and/or vibration
      of some body part. Signals emitted by the vibratory mechanisms have low-frequency
      characteristics with a relatively narrow frequency peak dominant around 100 Hz
      and differently expressed frequency modulation and higher harmonics. Such
      spectral characteristics are well tuned to the transmission properties of plants,
      and the low attenuation enables long-range communication on the same plant under
      standing wave conditions. Frequencies of stridulatory signals extend up to 10
      kHz. In some groups, vibratory and stridulatory mechanisms may be used
      simultaneously to produce broadband signals. The subgenual organ, joint
      chordotonal organs, campaniform sensilla and mechanoreceptors, such as the
      Johnston's organ in antennae, are used to detect these vibratory signals. Species
      specific songs facilitate mate location and recognition, and less species
      specific signals provide information about enemies or rival mates.

PMID- 12414737
TI  - Contact chemoreception in feeding by phytophagous insects.
AB  - Gustatory receptors associated with feeding in phytophagous insects are broadly
      categorized as phagostimulatory or deterrent. No phytophagous insect is known
      that tastes all its essential nutrients, and the ability to discriminate between
      nutrients is limited. The insects acquire a nutritional balance largely
      "adventitiously" because leaves have an appropriate chemical composition. Sugars
      are the most important phagostimulants. Plant secondary compounds are most often
      deterrent but stimulate phagostimulatory cells if they serve as host-indicating
      sign stimuli, or if they are sequestered for defense or used as pheromone
      precursors. The stimulating effects of chemicals are greatly affected by other
      chemicals in mixtures like those to which the sensilla are normally exposed. Host
      plant selection depends on the balance of phagostimulatory and deterrent inputs
      with, in some oligophagous and monophagous species, a dominating role of a host
      related chemical. Evolution of phytophagy has probably involved a change in
      emphasis in the gustatory system, not fundamentally new developments. The precise
      role of the gustatory systems remains unclear. In grasshoppers, it probably
      governs food selection and the amounts eaten, but in caterpillars there is some
      evidence that central feedbacks are also involved in regulating the amount eaten.

PMID- 12414733
TI  - A bulged stem tethers Est1p to telomerase RNA in budding yeast.
AB  - It is well established that the template for telomeric DNA synthesis is provided
      by the RNA subunit of telomerase; however, the additional functions provided by
      most of the rest of the RNA (>1000 nucleotides in budding yeast) are largely
      unknown. By alignment of telomerase RNAs of Saccharomyces cerevisiae and six
      Kluyveromyces species followed by mutagenesis of the S. cerevisiae RNA, we found
      a conserved region that is essential for telomere maintenance. Phylogenetic
      analysis and computer folding revealed that this region is conserved not only in
      primary nucleotide sequence but also in secondary structure. A common bulged-stem
      structure was predicted in all seven yeast species. Mutational analysis showed
      the structure to be essential for telomerase function. Suppression of bulged-stem
      mutant phenotypes by overexpression of Est1p and loss of co-immunoprecipitation
      of the mutant RNAs with Est1p indicated that this bulged stem is necessary for
      association of Est1p, a telomerase regulatory subunit. Est1p in yeast extract
      bound specifically to a small RNA containing the bulged stem, suggesting a direct
      interaction. We propose that this RNA structure links the enzymatic core of
      telomerase with Est1p, thereby allowing Est1p to recruit or activate telomerase
      at the telomere.

PMID- 12414738
TI  - Belowground herbivory by insects: influence on plants and aboveground herbivores.
AB  - Investigations of plant-herbivore interactions continue to be popular; however, a
      bias neglecting root feeders may limit our ability to understand how herbivores
      shape plant life histories. Root feeders can cause dramatic plant population
      declines, often associated with secondary stress factors such as drought or
      grazing. These severe impacts resulted in substantial interest in root feeders as
      agricultural pests and increasingly as biological weed control agents,
      particularly in North America. Despite logistical difficulties, establishment
      rates in biocontrol programs are equal or exceed those of aboveground herbivores
      (67.2% for aboveground herbivores, 77.5% for belowground herbivores) and root
      feeders are more likely to contribute to control (53.7% versus 33.6%). Models
      predicting root feeders would be negatively affected by competitively superior
      aboveground herbivores may be limited to early successional habitats or
      generalist root feeders attacking annual plants. In later successional habitats,
      root feeders become more abundant and appear to be the more potent force in
      driving plant performance and plant community composition. Aboveground
      herbivores, even at high population levels, were unable to prevent buildup of
      root herbivore populations and the resulting population collapse of their host
      plants. Significant information gaps exist about the impact of root feeders on
      plant physiology and secondary chemistry and their importance in natural areas,
      particularly in the tropics.

PMID- 12414739
TI  - Manipulation of medically important insect vectors by their parasites.
AB  - Many of the most harmful parasitic diseases are transmitted by blood-feeding
      insect vectors. During this stage of their life cycles, selection pressures favor
      parasites that can manipulate their vectors to enhance transmission. Strategies
      may include increasing the amount of contact between vector and host, reducing
      vector reproductive output and consequently altering vector resource management
      to increase available nutrient reserves, and increasing vector longevity.
      Manipulation of these life-history traits may be more beneficial at some phase of
      the parasite's developmental process than at others. This review examines
      empirical, experimental, and field-based evidence to evaluate examples of changes
      in vector behavior and physiology that might be construed to be manipulative.
      Examples are mainly drawn from malaria-infected mosquitoes, Leishmania-infected
      sandflies, and Trypanosoma-infected tsetse flies.

PMID- 12414740
TI  - The ascendancy of Amblyomma americanum as a vector of pathogens affecting humans
      in the United States.
AB  - Until the 1990s, Amblyomma americanum was regarded primarily as a nuisance
      species, but a tick of minor importance as a vector of zoonotic pathogens
      affecting humans. With the recent discoveries of Ehrlichia chaffeensis, Ehrlichia
      ewingii, and "Borrelia lonestari," the public health relevance of lone star ticks
      is no longer in question. During the next 25 years, the number of cases of human
      disease caused by A. americanum-associated pathogens will probably increase.
      Based on current trajectories and historic precedents, the increase will be
      primarily driven by biological and environmental factors that alter the
      geographic distribution and intensity of transmission of zoonotic pathogens.
      Sociologic and demographic changes that influence the likelihood of highly
      susceptible humans coming into contact with infected lone star ticks, in addition
      to advances in diagnostic capabilities and national surveillance efforts, will
      also contribute to the anticipated increase in the number of recognized cases of
      disease.

PMID- 12414741
TI  - The genome sequence and evolution of baculoviruses.
AB  - Comparative analysis of the complete genome sequences of 13 baculoviruses
      revealed a core set of 30 genes, 20 of which have known functions. Phylogenetic
      analyses of these 30 genes yielded a tree with 4 major groups: the genus
      Granulovirus (GVs), the group I and II lepidopteran nucleopolyhedroviruses
      (NPVs), and the dipteran NPV, CuniNPV. These major divisions within the family
      Baculoviridae were also supported by phylogenies based on gene content and gene
      order. Gene content mapping has revealed the patterns of gene acquisitions and
      losses that have taken place during baculovirus evolution, and it has highlighted
      the fluid nature of baculovirus genomes. The identification of shared protein
      phylogenetic profiles provided evidence for two putative DNA repair systems and
      for viral proteins specific for infection of lymantrid hosts. Examination of gene
      order conservation revealed a core gene cluster of four genes, helicase, lef-5,
      ac96, and 38K(ac98), whose relative positions are conserved in all baculovirus
      genomes.

PMID- 12414742
TI  - Cytokines in the pathogenesis of and protection against malaria.

PMID- 12414743
TI  - Jaks, STATs, Cytokines, and Sepsis.

PMID- 12414745
TI  - Phagocytosis and killing of bacteria by professional phagocytes and dendritic
      cells.
AB  - Dendritic cells (DC) represent a class of professional antigen-presenting cells
      whose primary function is to alert the immune system, not to clear invading
      microorganisms. The objective of our study was to compare the abilities of
      polymorphonuclear neutrophilic leukocytes (PMN), monocytes, monocyte-derived
      macrophages (MDM), monocyte-derived immature DC (imDC), and mature DC (maDC) to
      ingest and destroy Staphylococcus aureus and Escherichia coli. Acridine orange
      staining and fluorescence microscopy demonstrated that MDM, followed by
      monocytes, imDC, and PMN, internalized bacteria well but that maDC exhibited less
      pronounced phagocytic activity. PMN, monocytes, and MDM exhibited a much higher
      capacity to kill ingested bacteria than both imDC and maDC. In summary, these
      data are in agreement with the generally accepted idea that different types of
      leukocytes fulfill specialized tasks in antigen presentation and killing of
      pathogens.

PMID- 12414744
TI  - Immune responses to bile-tolerant helicobacter species in patients with chronic
      liver diseases, a randomized population group, and healthy blood donors.
AB  - Bile-tolerant Helicobacter species such as Helicobacter pullorum, Helicobacter
      bilis, and Helicobacter hepaticus are associated with hepatic disorders in
      animals and may be involved in the pathogenesis of chronic liver diseases (CLD)
      in humans. Antibody responses to cell surface proteins of H. pullorum, H. bilis,
      and H. hepaticus in serum samples from patients with CLD, a randomized population
      group, and healthy blood donors were evaluated by using enzyme linked
      immunosorbent assay (ELISA). The results were compared with the antibody
      responses to Helicobacter pylori. For analysis of a possible cross-reactivity
      between bile-tolerant Helicobacter species and H. pylori, sera from a
      subpopulation of each group were absorbed with a whole-cell extract of H. pylori
      and retested by ELISA. Results before absorption showed that the mean value of
      the ELISA units for H. pullorum was significantly higher in patients with CLD
      than in healthy blood donors (P = 0.01). Antibody reactivity to cell surface
      protein of H. hepaticus was also significantly higher in the CLD patients than in
      the healthy blood donors and the population group (P = 0.005 and P = 0.002,
      respectively). Following the absorption, antibody responses to H. pullorum
      decreased significantly in all three groups (P = 0.0001 for CLD patients, P =
      0.0005 for the population group, and P < 0.0001 for the blood donors), indicating
      that cross-reactivity between H. pylori and other Helicobacter spp. occurs. The
      antibody responses to H. hepaticus and H. bilis in CLD patients remained high
      following absorption experiments compared to ELISA results before absorption. The
      significance of this finding requires further investigations.

PMID- 12414746
TI  - Change of mouse CD5(+) B1 cells to a macrophage-like morphology induced by gamma
      interferon and inhibited by interleukin-4.
AB  - The in vitro effects of gamma interferon (IFN-gamma) on the mouse CD5(+) B1-cell
      line, TH2.52, a hybridoma between mouse B lymphoma and mouse splenic B cells that
      expresses a series of B1 markers, were investigated. A significant number of
      macrophage-like cells appeared in the cultures of TH2.52 cells exposed to IFN
      gamma, these adhering to plastic dishes and exhibiting phagocytic activity.
      Positive for esterase staining, the macrophage-like cells returned to the
      original TH2.52 morphology upon removal of IFN-gamma. The change was prevented by
      treatment with SB202190, an inhibitor of p38 mitogen-activated protein (MAP)
      kinase and by transfection of a p38 MAP kinase dominant-negative mutant. Further,
      interleukin-4 (IL-4) inhibited IFN-gamma-induced phosphorylation of p38 MAP
      kinase and the appearance of macrophage-like cells. IFN-gamma and IL-4 exhibited
      contradictory actions on morphological change of CD5(+) B1 cells into macrophage
      like cells. Differential regulation of CD5(+) B1 cells by IFN-gamma, a Th1
      cytokine, and IL-4, a Th2 cytokine, may have clear immunological significance.

PMID- 12414747
TI  - Lipoarabinomannan-induced cell signaling involves ceramide and mitogen-activated
      protein kinase.
AB  - Lipoarabinomannan (LAM) is a major cell wall-associated lipoglycan, produced in
      large amounts (15 mg/g of bacteria) in different species of mycobacteria. Our
      laboratory has previously reported that LAM from Mycobacterium smegmatis exerts
      its cytotoxic activity via inhibition of protein kinase C, a key signaling
      molecule inside the mononuclear cells (S. Ghosh, S. Pal, S. Das, S. K. Dasgupta,
      and S. Majumdar, FEMS Immunol. Med. Microbiol. 21:181-188, 1998). In this study
      we report that LAM from Mycobacterium tuberculosis induces a signal transduction
      pathway in favor of survivability of the host cells via the generation of
      ceramide, a novel second messenger. The endogenous ceramide level in mononuclear
      cells was found to be enhanced during LAM treatment. The effects of LAM on
      protein tyrosine phosphorylation in human peripheral blood mononuclear cells were
      examined. LAM enhanced the tyrosine phosphorylation of p42 mitogen-activated
      protein kinase and phosphoinositol 3-kinase (PI3 kinase) and dephosphorylation of
      stress-activated protein kinase. LAM-induced phosphorylation of p42
      (extracellular signal-regulated kinase 2) was further enhanced by wortmannin, a
      PI3 kinase inhibitor. To examine whether these effects are due to elevation of
      endogenous ceramide, we exposed the cells to cell-permeative C(2)-ceramide
      exogenously and studied the activities of different protein kinases. Fluorescence
      activated cell sorter analysis and morphological studies showed that LAM induces
      cell survival. Therefore, these results suggest the ability of LAM to induce
      ceramide in the altered signaling pathway and help in cell survival.

PMID- 12414748
TI  - Nucleocapsid protein-based enzyme-linked immunosorbent assay for detection and
      differentiation of antibodies against European and North American porcine
      reproductive and respiratory syndrome virus.
AB  - Two types of porcine reproductive and respiratory syndrome virus (PRRSV) have
      been reported, the European type (EU PRRSV) and the North American type (US
      PRRSV). We developed a dual enzyme-linked immunosorbent assay (ELISA) for the
      simultaneous detection and differentiation of serum antibodies directed against
      either of the two PRRSV types. This tandem PRRS ELISA is based on affinity
      purified recombinant nucleocapsid protein expressed in Escherichia coli.
      Sensitivity and specificity were assessed by using the IDEXX HerdChek PRRS ELISA
      and the indirect immunofluorescence assay as reference tests. A total of 1571
      sera originating from the United States, Europe, and two PRRS-free countries,
      i.e., Switzerland and New Zealand, were used for validation of the tandem PRRS
      ELISA. The new test performed at least as well as the reference tests in regard
      to sensitivity (0.94 for the US PRRS ELISA and 0.93 for the EU PRRS ELISA) and
      specificity (0.96 for the US PRRS ELISA and 0.99 for the EU PRRS ELISA). Positive
      sera were correctly differentiated in 582 of 591 cases, indicating a high
      differentiation capability of this dual ELISA. The robustness and repeatability
      of the test were assessed and found to be appropriate for diagnostic
      applications. Taken together, the data indicate that the tandem PRRS ELISA
      described here is the first differentiation ELISA for PRRSV serology based on
      recombinant antigen. It is convenient with respect to antigen production, and it
      is reliable, economical, and highly sensitive and specific. Thus, it is
      considered to be a powerful tool for routine diagnostics, epidemiological
      surveys, and outbreak investigations.

PMID- 12414749
TI  - In vitro and in vivo detection of Mx gene products in bovine cells following
      stimulation with alpha/beta interferon and viruses.
AB  - This study focused on products of the bovine Mx1 gene as specific markers for
      acute viral infections. The rationale for this is the fact that viral infections
      are commonly paralleled by the synthesis, release, and remote action of
      alpha/beta interferons (IFN-alpha/beta). Released IFN-alpha/beta act through
      specific receptors present on nucleated cells to transduce signals for the
      transcription of numerous IFN-regulated genes, such as the ones for double
      stranded-RNA-dependent protein kinase, 2'-5'-oligoadenylate synthetase, or the Mx
      proteins. In this study, cultured MDBK cells and bovine white blood cells (WBC)
      were treated with recombinant IFN-alpha or infected with either bovine
      herpesvirus 1 (BHV-1) or bovine rotavirus (BRV). Treatment of cultured cells with
      IFN-alpha was followed within 4 h by a time- and dose-dependent accumulation of
      intracytoplasmic Mx protein as revealed by immunostaining and Western blot
      immunoassay. This was preceded by a distinct rise of Mx mRNA in similarly treated
      cells, as revealed by a newly established quantitative TaqMan PCR technique. The
      two viruses displayed a cell-dependent in vitro ability to induce Mx proteins,
      which was limited to bovine WBC with BHV-1 and to MDBK cells with BRV. The
      established methods were successfully used to show that infection of calves with
      a noncytopathic strain of bovine viral diarrhea virus, a pestivirus, was followed
      within 2 days postinfection by strong expression of both Mx mRNA and Mx proteins
      in WBC.

PMID- 12414750
TI  - Expression in bacteria of the gene encoding the gp43 antigen of paracoccidioides
      brasiliensis: immunological reactivity of the recombinant fusion proteins.
AB  - gp43 is the major diagnostic antigen of Paracoccidioides brasiliensis, the agent
      of paracoccidioidomycosis (PCM) in humans. In the present study, cDNA of the gp43
      gene (PbGP43) was obtained by reverse transcriptase PCR, inserted into a pGEX
      vector in frame with the glutathione S-transferase (GST) gene, and expressed in
      Escherichia coli as inclusion bodies. Immunoblotting showed that all sera from
      patients with chronic pulmonary and acute lymphatic forms of PCM reacted with the
      recombinant fusion protein of the mature gp43 (381 amino acids). Reactivity with
      fusion proteins containing subfragments of the N-terminal, internal, or C
      terminal regions occurred eventually, and the C-terminal region was the most
      antigenic. Lack of reactivity with the subfragments may be due to the
      conformational nature of the gp43 epitopes. Sera from patients with
      aspergillosis, candidiasis, and histoplasmosis did not react with the gp43-GST
      fusion protein. Our results suggest that recombinant gp43 corresponding to the
      processed antigen can be a useful tool in the diagnosis of PCM.

PMID- 12414751
TI  - Tumor necrosis factor gene polymorphisms, leukocyte function, and sepsis
      susceptibility in blunt trauma patients.
AB  - The tumor necrosis factor alpha (TNF-alpha) -308 G/A and TNF-beta NcO1
      polymorphisms have been described to be associated with an increased risk for
      sepsis in critically ill patients. Functional consequences associated with these
      polymorphisms remain unclear. We compared the genotype distribution of these TNF
      polymorphisms with susceptibility to severe sepsis and leukocyte function in
      blunt trauma patients (n = 70; mean injury severity score, 24 points [range, 4 to
      57). Severe sepsis was defined according to the American College of Chest
      Physicians-Society of Critical Care Medicine consensus conference criteria.
      Genotyping for the NcO1 polymorphism (alleles TNFB1 and TNFB2) was performed by
      PCR and digestion of the products with NcO1, and that for the TNF-alpha -308 G/A
      polymorphism (alleles TNF1 and TNF2) was performed by real-time PCR. Leukocyte
      function was assessed by measurement of the production of endotoxin-induced
      cytokines (TNF-alpha, interleukin-6 [IL-6], and IL-8) in whole blood. TNF-alpha,
      IL-6, and IL-8 were determined by enzyme-linked immunosorbent assay. For the
      genotypes of the TNF-alpha -308 G/A polymorphism, differences in the frequency of
      development of severe sepsis were not detectable. Patients developing severe
      sepsis after trauma were significantly more likely to possess a homozygous
      genotype of the TNF-beta NcO1 polymorphism. Compared with heterozygotes, the odds
      ratio for the TNFB2/B2 genotype for the development of severe posttraumatic
      sepsis was 11 (P = 0.01), and that for the TNFB1/B1 genotype was 13 (P = 0.014).
      TNF-alpha -308:TNF-beta NcO1 haplotype analysis showed that the TNFB2:TNF2
      haplotype is significantly negatively associated with development of severe
      sepsis. Patients homozygous for the TNFB1 or TNFB2 allele showed a persistently
      higher cytokine-producing capacity during at least 4 to 8 days after trauma than
      the heterozygotes. In patients homozygous for the TNF1 allele, a higher TNF-alpha
      and IL-8-producing capacity was found only at day 1 after trauma. Although the
      TNF-beta NcO1 polymorphism appears to be less likely to be causative for
      development of severe sepsis after trauma, it is thus far the only genetic marker
      identified which can be used as a relevant risk estimate for severe sepsis in
      trauma patients immediately after the injury.

PMID- 12414752
TI  - Nef protein of human immunodeficiency virus and lipopolysaccharide induce
      expression of CD14 on human monocytes through differential utilization of
      interleukin-10.
AB  - We investigated the expression of membrane-bound CD14 (mCD14) on monocytes and
      soluble CD14 (sCD14) released into the culture supernatants of peripheral blood
      lymphocytes (PBMC) from human immunodeficiency virus (HIV)-infected individuals.
      Monocytes from HIV-positive individuals exhibited both enhanced mCD14 expression
      and sCD14 production in the PBMC culture supernatants compared to the levels of
      mCD14 and sCD14 in HIV-negative individuals. This enhanced mCD14 expression and
      sCD14 production in HIV-infected individuals may be due to the effects of
      cytokines, the bacterial product lipopolysaccharide (LPS), and/or the HIV
      regulatory antigens Tat and Nef. Interleukin-10 (IL-10), an immunoregulatory
      cytokine, as well as LPS enhanced mCD14 expression and the release of sCD14 in
      the culture supernatants. HIV-Nef, unlike Tat, enhanced mCD14 expression on
      monocytes but did not induce the release of sCD14 into the culture supernatants.
      Studies conducted to investigate the mechanism underlying HIV-Nef-induced mCD14
      expression revealed that HIV-Nef upregulated mCD14 expression via a mechanism
      that does not involve endogenously produced IL-10. In contrast, LPS upregulated
      the expression of mCD14 and increased the release of sCD14 via a mechanism that
      involves, at least in part, endogenously produced IL-10. Furthermore,
      dexamethasone, an anti-inflammatory and immunosuppressive agent, inhibited HIV
      Nef-induced CD14 expression in an IL-10-independent manner. In contrast,
      dexamethasone inhibited IL-10-dependent LPS-induced CD14 expression by
      interfering with IL-10-induced signals but not by blocking IL-10 production.
      These results suggest that HIV-Nef and IL-10 constitute biologically important
      modulators of CD14 expression which may influence immunobiological responses to
      bacterial infections in HIV disease.

PMID- 12414753
TI  - Detection of DNA of lymphotropic herpesviruses in plasma of human
      immunodeficiency virus-infected patients: frequency and clinical significance.
AB  - The frequency and clinical significance of detection of DNA of cytomegalovirus
      (CMV), Epstein-Barr virus (EBV), human herpesvirus 6 (HHV-6), HHV-7, and HHV-8 in
      plasma were investigated by PCR. The plasma was obtained from 120 selected human
      immunodeficiency virus (HIV)-infected patients, of whom 75 had AIDS-related
      manifestations, 32 had primary HIV infection (PHI), and 13 had asymptomatic
      infections. Nested PCR analysis revealed that none of the lymphotropic
      herpesviruses tested were found in patients with PHI, in asymptomatic HIV
      positive individuals, or in HIV-negative controls. By contrast, DNA of one or
      more of the viruses was found in 42 (56%) of 75 patients with AIDS-related
      manifestations, including CMV disease (CMV-D) or AIDS-related tumors. The
      presence of CMV DNA in plasma was significantly associated with CMV-D (P <
      0.001). By contrast, EBV detection was not significantly associated with AIDS
      related lymphomas (P = 0.31). Interestingly, the presence of HHV-8 DNA in plasma
      was significantly associated with Kaposi's sarcoma (KS) disease (P < 0.001) and
      with the clinical status of KS patients (P < 0.001). CMV (primarily), EBV, and
      HHV-8 were the viruses most commonly reactivated in the context of severe
      immunosuppression (P < 0.05). In contrast, HHV-6 and HHV-7 infections were
      infrequent at any stage of disease. In conclusion, plasma PCR was confirmed to be
      useful in the diagnosis of CMV-D but not in that of tumors or other conditions
      possibly associated with EBV, HHV-6, and HHV-7. Our findings support the
      hypothesis of a direct involvement of HHV-8 replication in KS pathogenesis, thus
      emphasizing the usefulness of sensitive and specific diagnostic tests to monitor
      HHV-8 infection.

PMID- 12414754
TI  - Cytokine profiles in peripheral blood mononuclear cells and lymph node cells from
      piglets infected in utero with porcine reproductive and respiratory syndrome
      virus.
AB  - The aim of the present study was to investigate at 2, 4, and 6 weeks after birth
      cytokine expression by peripheral blood mononuclear cells and bronchial lymph
      node cells from piglets infected in utero with porcine reproductive and
      respiratory syndrome virus (PRRSV). Technically, by flow cytometry we were able
      to measure gamma interferon (gamma-IFN), tumor necrosis factor alpha (TNF-alpha),
      interleukin-4 (IL-4), and IL-8 levels. In general, we found increases in the
      percentages of IL-4-, gamma-IFN-, and TNF-alpha-producing lymphocytes in the
      infected piglets compared to the percentages in the uninfected control animals,
      while there was a decrease in the percentage of IL-8-producing monocytes. We
      believe that these findings reflect a general lymphocyte activation stage that is
      created due to the infection and that occurs in combination with impairment of
      the monocyte function, possibly due to the ongoing viral replication in these
      cells. Single-cell bronchial lymph node preparations exhibited very much the same
      cytokine profiles as peripheral blood mononuclear cells except for a lack of IL-8
      production. When the levels of the individual cytokines in the three groups of
      PRRSV-infected piglets were compared, the levels of cytokine expression at 4
      weeks diverged from those at 2 and 6 weeks, in that there was a significant
      decrease in the numbers of lymphocytes producing gamma-IFN and TNF-alpha. This
      tendency was also observed among blood monocytes and lymph node macrophages.
      Possible reasons for this temporary immunosuppression in the piglets at 4 weeks
      are discussed.

PMID- 12414755
TI  - Use of coefficient of variation in assessing variability of quantitative assays.
AB  - We have derived the mathematical relationship between the coefficient of
      variation associated with repeated measurements from quantitative assays and the
      expected fraction of pairs of those measurements that differ by at least some
      given factor, i.e., the expected frequency of disparate results that are due to
      assay variability rather than true differences. Knowledge of this frequency helps
      determine what magnitudes of differences can be expected by chance alone when the
      particular coefficient of variation is in effect. This frequency is an
      operational index of variability in the sense that it indicates the probability
      of observing a particular disparity between two measurements under the assumption
      that they measure the same quantity. Thus the frequency or probability becomes
      the basis for assessing if an assay is sufficiently precise. This assessment also
      provides a standard for determining if two assay results for the same subject,
      separated by an intervention such as vaccination or infection, differ by more
      than expected from the variation of the assay, thus indicating an intervention
      effect. Data from an international collaborative study are used to illustrate the
      application of this proposed interpretation of the coefficient of variation, and
      they also provide support for the assumptions used in the mathematical
      derivation.

PMID- 12414756
TI  - Adjuvant activity of emulsan, a secreted lipopolysaccharide from acinetobacter
      calcoaceticus.
AB  - Several promising adjuvant candidates have been studied over the past 75 years;
      however, only alum is currently approved for human use. The complex acylated
      polysaccharide emulsan, secreted from Acinetobacter calcoaceticus, represents a
      new candidate. Unique features of this family of polymers are their amenability
      to structural tailoring and their emulsification behavior. We demonstrate that
      emulsan activates macrophages in a dose-dependent manner. This activation is
      dependent on the presence of the fatty acid side chains that decorate the
      polysaccharide backbone, and, furthermore, the level of activation can be
      affected by changes in the chemical characteristics of emulsan structural
      variants. One emulsan variant was examined in a classical hapten carrier
      immunization protocol and demonstrated significant adjuvant activity as
      determined by hapten-specific antibody titers. This immune response was
      characterized by a high immunoglobulin G2a titer, consistent with a Th1 response.
      The significant immunopotentiation demonstrated by this complex polymer
      establishes emulsan as an exciting new candidate adjuvant. Furthermore, by
      manipulating the chemical structure of this compound, we can explore the physical
      basis of pattern recognition receptors and macrophage activation.

PMID- 12414757
TI  - Quantitative fluorescence measures for determination of intracellular perforin
      content.
AB  - We present methodologic details and operating characteristics of a procedure with
      whole blood for the quantitative assessment of intracellular perforin within
      distinct lymphocyte subsets. Using this method, we analyzed 20 healthy controls
      and 2 individuals with an inherited deficiency of perforin. The mean +/- standard
      deviation perforin contents of natural killer (NK) cells and cytotoxic T cells of
      healthy controls were 3561 +/- 1157 and 500 +/- 779 relative number of molecules
      (rMol) of antiperforin antibody bound per cell, respectively. The NK cell
      perforin contents of individuals with heterozygous and homozygous perforin
      deficiency (familial hemophagocytic lymphohistiocytosis) were 2260 and 212 rMol
      of antiperforin antibodies per NK cell. While the homozygous deficiency was found
      to be associated with negligible antiperforin binding, the heterozygous condition
      was associated with a level of perforin binding that was below the 15th
      percentile for healthy individuals. Because 83% of this subject's NK cells were
      shown to bind to antiperforin antibodies by conventional flow cytometry (relative
      to the normal range of 81% +/- 25%), quantitative cytometry may be more sensitive
      than conventional cytometric methods in identifying cytolytic defects.

PMID- 12414758
TI  - Streptokinase promotes development of dipeptidyl peptidase IV (CD26)
      autoantibodies after fibrinolytic therapy in myocardial infarction patients.
AB  - Dipeptidyl peptidase IV (DPP IV) (CD26) plays a critical role in the modulation
      and expression of autoimmune and inflammatory diseases. We recently reported that
      sera from patients with rheumatoid arthritis and systemic lupus erythematosus
      contained low levels of DPP IV and high titers of anti-DPP IV autoantibodies of
      the immunoglobulin A (IgA) and IgG classes and found a correlation between the
      low circulating levels of DPP IV and the high titers of anti-DPP IV
      autoantibodies of the IgA class. Since streptokinase (SK) is a potent immunogen
      and binds to DPP IV, we speculated that patients with autoimmune diseases showed
      higher DPP IV autoantibody levels than healthy controls as a consequence of an
      abnormal immune stimulation triggered by SK released during streptococcal
      infections. We assessed this hypothesis in a group of patients suffering from
      acute myocardial infarction, without a chronic autoimmune disease, who received
      SK as part of therapeutic thrombolysis. Concomitant with the appearance of anti
      SK antibodies, these patients developed anti-DPP IV autoantibodies. These
      autoantibodies bind to DPP IV in the region which is also recognized by SK,
      suggesting that an SK-induced immune response is responsible for the appearance
      of DPP IV autoantibodies. Furthermore, we determined a correlation between high
      titers of DPP IV autoantibodies and an augmented clearance of the enzyme from the
      circulation. Serum levels of the inflammatory cytokines tumor necrosis factor
      alpha (TNF-alpha) and interleukin 6 (IL-6) increased significantly after 30 days
      of SK administration, while the levels of soluble IL-2 receptor remained
      unchanged during the same period, suggesting a correlation between the lower
      levels of circulating DPP IV and higher levels of TNF-alpha and IL-6 in serum in
      these patients.

PMID- 12414759
TI  - Immunomodulatory effects of CpG oligodeoxynucleotides on established th2
      responses.
AB  - CpG oligodeoxynucleotides (CpG ODNs) are known to induce type 1 T-helper-cell
      (Th1) responses. We have previously demonstrated that CpG ODNs administered
      during sensitization prevent Th2-mediated eosinophilic airway inflammation in
      vivo. We also reported that key Th1 cytokines, gamma interferon (IFN-gamma) and
      interleukin 12 (IL-12), are not necessary for this protection. Recent in vivo
      data suggest that CpG ODNs might also reverse established pulmonary eosinophilia.
      In order to clarify how CpG ODNs can inhibit established Th2 responses, we
      evaluated the cytokine production from splenocytes from antigen- and alum
      immunized mice. Restimulation with antigen induced IL-5, which was clearly
      inhibited by coculture with CpG ODNs in a concentration-dependent manner. CpG
      ODNs also induced IFN-gamma, but in a concentration-independent manner. The
      inhibition of IL-5 production was not mediated through natural killer cells or
      via CD8(+) T lymphocytes. Although IFN-gamma plays an important role in
      inhibition of antigen-induced IL-5 production by CpG ODNs, IFN-gamma was not the
      sole factor in IL-5 inhibition. CpG ODNs also induced IL-10, and this induction
      correlated well with IL-5 inhibition. Elimination of IL-10 reduced the anti-IL-5
      effect of CpG ODNs, although incompletely. This may be because IFN-gamma, induced
      by CpG ODNs, is also inhibited by IL-10, serving as a homeostatic mechanism for
      the Th1-Th2 balance. Overproduction of IFN-gamma was downregulated by CpG ODN
      induced IL-10 via modulation of IL-12 production. These data suggest that CpG
      ODNs may inhibit established Th2 immune responses through IFN-gamma and IL-10
      production, the latter serving to regulate excessive Th1 bias. These properties
      of CpG ODNs might be a useful feature in the development of immunotherapy
      adjuvants against allergic diseases such as asthma.

PMID- 12414760
TI  - Identification of pulmonary T-lymphocyte and serum antibody isotype responses
      associated with protection against Rhodococcus equi.
AB  - Rhodococcus equi infects and causes pneumonia in foals between 2 and 4 months of
      age but does not induce disease in immunocompetent adults, which are immune and
      remain clinically normal upon challenge. Understanding the protective response
      against R. equi in adult horses is important in the development of vaccine
      strategies, since those mechanisms likely reflect the protective phenotype that
      an effective vaccine would generate in the foal. Twelve adult horses were
      challenged with virulent R. equi and shown to be protected against clinical
      disease. Stimulation of cells obtained from bronchoalveolar lavage fluid with
      either R. equi or the vaccine candidate protein VapA resulted in significant
      proliferation and a significant increase in the level of gamma interferon (IFN
      gamma) expression by day 7 postchallenge. The levels of interleukin-4 expression
      were also increased at day 7 postchallenge; however, this increase was not
      antigen specific. Anamnestic increases in the levels of binding to R. equi and
      VapA of all immunoglobulin G (IgG) antibody isotypes [IgGa, IgGb, IgG(T)]
      examined were detected postchallenge. The levels of R. equi- and VapA-specific
      IgGa and IgGb antibodies, the IgG isotypes that preferentially opsonize and fix
      complement in horses, were dramatically enhanced postchallenge. The antigen
      specific proliferation of bronchoalveolar lavage fluid cells, the levels of IFN
      gamma expression by these cells, and the anamnestic increases in the levels of
      opsonizing IgG isotypes are consistent with stimulation of a memory response in
      immune adult horses and represent correlates for vaccine development in foals.

PMID- 12414761
TI  - Unique epitope of bovine immunodeficiency virus gag protein spans the cleavage
      site between p16(MA) and p2L.
AB  - Bovine immunodeficiency virus (BIV) and Jembrana disease virus (JDV) are closely
      related bovine lentiviruses that are difficult to distinguish by presently
      available diagnostic methods. Recently, in our laboratory, a monoclonal antibody
      (MAb; MAb 10H1) against the BIV Gag protein identified a differential epitope,
      located at the 6.4-kDa N terminus of a 29-kDa Gag capsid protein, which was
      absent in JDV. To define the essential amino acids of the epitope, a series of
      primers within the 163 bp of DNA corresponding to the 6.4-kDa protein were
      designed. The full-length 163-bp DNA fragment and the smaller DNA fragments with
      deletions were amplified by PCR and then cloned into pQE32 vectors for protein
      expression studies. The expressed proteins were analyzed with MAb 10H1 by Western
      blotting. The differential epitope has been narrowed to a 26-amino-acid region
      (R121 to R146), which includes 6 residues of p16(MA) (where MA represents the
      matrix protein) and 20 residues of p2L. A synthetic peptide corresponding to the
      putative 26-amino-acid epitope blocked MAb 10H1 binding to the expressed peptide.
      These experiments revealed that the epitope spans the cleavage site between
      p16(MA) and p2L and presumably will be valuable in distinguishing the two
      viruses.

PMID- 12414763
TI  - Celiac disease and immunoglobulin a deficiency: how effective are the serological
      methods of diagnosis?
AB  - Immunoglobulin A (IgA) deficiency is 10 to 15 times more common in patients with
      celiac disease (CD) than in healthy subjects. Serological tests have become the
      preferred methods of diagnosing CD in both symptomatic and asymptomatic patients.
      However, commercially available serological methods are limited in that they
      detect only the IgA isotype of antibodies (with the exception of IgG gliadin
      assays); hence, IgA-deficient patients with CD may yield false-negative serology.
      Fifteen pediatric patients with CD and 10 IgA-deficient pediatric patients
      without CD were examined for IgA and IgG antibodies to endomysium, gliadin, and
      tissue transglutaminase. Twenty-five specimens from patients with IgA deficiency
      were examined. Fifteen were from patients with CD, and 10 were patients without
      CD. All 15 IgA-deficient patients with CD were positive for endomysium antibodies
      of the IgG isotype and for IgG gliadin antibodies. All but one of the IgA
      deficient patients with CD were also positive for IgG tissue transglutaminase
      antibodies. None of the IgA-deficient patients without CD were positive for any
      of the antibody markers. All the specimens examined were also negative for IgA
      specific antibodies to endomysium, gliadin, and tissue transglutaminase. IgG
      specific antibody tests for endomysium, gliadin, and tissue transglutaminase are
      useful for the identification of IgA-deficient patients with CD. IgG antibody
      tests along with tests routinely being used in clinical laboratories can reliably
      detect all active patients with CD. In addition, the levels of these CD-specific
      IgG antibodies could be used to monitor patient dietary compliance.

PMID- 12414764
TI  - Conformational dependence and conservation of an immunodominant epitope within
      the babesia equi erythrocyte-stage surface protein equi merozoite antigen 1.
AB  - Equi merozoite antigen 1 (EMA-1) is an immunodominant Babesia equi erythrocyte
      stage surface protein. A competitive enzyme-linked immunosorbent assay (ELISA),
      based on inhibition of monoclonal antibody (MAb) 36/133.97 binding to recombinant
      EMA-1 by equine anti-B. equi antibodies, detects horses infected with strains
      present throughout the world. The objectives of this study were to define the
      epitope bound by MAb 36/133.97 and quantify the amino acid conservation of EMA-1,
      including the region containing the epitope bound by MAb 36/133.97. The alignment
      of the deduced amino acid sequence of full-length EMA-1 (Florida isolate) with 15
      EMA-1 sequences from geographically distinct isolates showed 82.8 to 99.6%
      identities (median, 98.5%) and 90.5 to 99.6% similarities (median, 98.9%) between
      sequences. Full-length and truncated recombinant EMA-1 proteins were expressed
      and tested for their reactivities with MAb 36/133.97. Binding required the
      presence of amino acids on both N- and C-terminal regions of a truncated peptide
      (EMA-1.2) containing amino acids 1 to 98 of EMA-1. This result indicated that the
      epitope defined by MAb 36/133.97 is dependent on conformation. Sera from
      persistently infected horses inhibited the binding of MAb 36/133.97 to EMA-1.2 in
      a competitive ELISA, indicating that equine antibodies which inhibit binding of
      MAb 36/133.97 also recognize epitopes in the same region (the first 98 residues).
      Within this region, the deduced amino acid sequences had 85.7 to 100% identities
      (median, 99.0%), with similarities of 94.9 to 100% (median, 100%). Therefore, the
      region which binds to both MAb 36/133.97 and inhibiting equine antibodies has a
      median amino acid identity of 99.0% and a similarity of 100%. These data provide
      a molecular basis for the use of both EMA-1 and MAb 36/133.97 for the detection
      of antibodies against B. equi.

PMID- 12414762
TI  - NK cells mediate increase of phagocytic activity but not of proinflammatory
      cytokine (interleukin-6 [IL-6], tumor necrosis factor alpha, and IL-12)
      production elicited in splenic macrophages by tilorone treatment of mice during
      acute systemic candidiasis.
AB  - The participation of NK cells in the activation of splenic macrophages or in
      resistance to systemic candidiasis is still a matter of debate. We had previously
      reported that there is a correlation between natural killer cell activation and
      resistance to systemic candidiasis. In those experiments we had used tilorone to
      boost NK cell activity in mice. Here we show a mechanism elicited by tilorone in
      splenic macrophages which could explain their effect on mouse survival during
      acute disseminated Candida albicans infection. The results demonstrate that
      tilorone treatment elicits, by a direct effect, the production of proinflammatory
      cytokines (interleukin-6 [IL-6], tumor necrosis factor alpha [TNF-alpha], and IL
      12) by splenic macrophages. In addition, it increases the capacity of splenic
      macrophages to phagocytize C. albicans through activation of NK cells. We also
      demonstrate that the presence of NK cells is essential for maintaining a basal
      level of phagocytic activity, which characterizes splenic macrophages of naive
      control mice. The results demonstrate that it is possible to identify two
      phenotypically and functionally peculiar cell populations among splenic
      macrophages: (i). cells of the "stimulator/secretor phenotype," which show high
      levels of major histocompatibility complex (MHC) class II surface expression, are
      poorly phagocytic, and synthesize the proinflammatory cytokines IL-6, TNF-alpha,
      and IL-12, and (ii). cells of the "phagocytic phenotype," which express low
      levels of MHC class II molecules, are highly phagocytic, and do not secrete
      proinflammatory cytokines.

PMID- 12414765
TI  - Primary role of interleukin-1 alpha and interleukin-1 beta in lipopolysaccharide
      induced hypoglycemia in mice.
AB  - Within a few hours of its injection into mice, lipopolysaccharide (LPS) induces
      hypoglycemia and the production of various cytokines. We previously found that
      interleukin-1 alpha (IL-1 alpha), IL-1 beta, and tumor necrosis factor alpha (TNF
      alpha) induce hypoglycemia and that the minimum effective dose of IL-1 alpha or
      IL-1 beta is about 1/1000 that of TNF-alpha. In the present study, we examined
      the contribution made by IL-1 to the hypoglycemic action of LPS. Nine other
      cytokines tested were all inactive at inducing hypoglycemia. LPS produced
      hypoglycemia in mice deficient in either IL-1 alpha or IL-1 beta but not in mice
      deficient in both cytokines (IL-1 alpha and -1 beta knockout [IL-1 alpha/beta KO]
      mice). IL-1 alpha, IL-1 beta, and TNF-alpha induced hypoglycemia in IL-1
      alpha/beta KO mice, as they did in normal control mice. The LPS-induced elevation
      of serum cortisol was weaker in IL-1 alpha/beta KO mice than in control mice,
      and, in the latter, serum cortisol was markedly raised while blood glucose was
      declining. IL-1 alpha decreased blood glucose both in NOD mice (which have
      impaired insulin production) and in KK-Ay mice (insulin resistant). These results
      suggest that (i). cortisol may not be involved in mediating the resistance of IL
      1 alpha/beta KO mice to the hypoglycemic action of LPS, (ii). as a mediator, IL-1
      is a prerequisite for the hypoglycemic action of LPS, (iii). IL-1 alpha and IL-1
      beta perform mutual compensation, and (iv). IL-1 plays a role as the primary
      stimulator of the many anabolic reactions required for the elaboration of immune
      responses against infection.

PMID- 12414766
TI  - Responses of endoscopy patients in Ladakh, India, to Helicobacter pylori whole
      cell and Cag A antigens.
AB  - Although Helicobacter pylori is a cosmopolitan colonizer of the human stomach,
      the responses among persons in remote populations from whom H. pylori was
      cultured have not been studied. We report on studies of 189 persons in the Ladakh
      region of India in whom serum immunoglobulin G responses to H. pylori whole-cell
      and Cag A antigens were measured. H. pylori was isolated from 68 of these
      patients. An H. pylori whole-cell antigen derived from Ladakhi strains
      outperformed a similar antigen from U.S. strains, as determined by antigen
      specific enzyme-linked immunosorbent assays. In total, 95% of the population was
      seropositive, including individuals responding only to the Cag A antigen.
      Correlation with culture results showed that these were true positives and,
      therefore, that the H. pylori whole-cell serology was falsely negative in some
      cases. In addition to establishing a collection of H. pylori isolates from a
      remote area in the world, we show that use of H. pylori whole-cell and Cag A
      serology together increases the sensitivity for the detection of colonization.

PMID- 12414767
TI  - Evaluation of immunomodulatory effects of lactic acid bacteria in turbot
      (Scophthalmus maximus).
AB  - In the present work, the effects of several lactic acid bacteria on the immune
      response of turbot (Scophthalmus maximus) macrophages have been studied both in
      vitro and in vivo. Out of six lactic acid bacterial strains tested, only heat
      killed Lactococcus lactis significantly increased the turbot head kidney
      macrophage chemiluminescent (CL) response after 24 h of incubation. Nitric oxide
      (NO) was also significantly enhanced by this bacterium after 72 h of incubation
      with either viable (10(3) and 10(6) cells/ml) or heat-killed (10(6) cells/ml)
      bacteria. Viable Leuconostoc mesenteroides (10(6) cells/ml) was also capable of
      significantly increasing NO production. Since L. lactis proved to be the strain
      with more effects on the host immune function, further in vivo and in vitro
      experiments were conducted with this bacterium. The in vitro capacity of L.
      lactis to adhere to turbot intestinal mucus was positively confirmed. When orally
      administered, L. lactis significantly increased the macrophage CL response and
      the serum NO concentration after 7 days of daily administration. The
      antibacterial effect of the extracellular products from the six LAB strains
      against the fish-pathogenic bacterium Vibrio anguillarum was also demonstrated in
      vitro.

PMID- 12414769
TI  - Antimicrobial susceptibilities and serotype distribution of Streptococcus
      pneumoniae isolates from a Low socioeconomic area in Lima, Peru.
AB  - Streptococcus pneumoniae isolates were obtained from nasopharyngeal swabs taken
      from children living in a low socioeconomic area of Lima, Peru, to determine the
      rates of antimicrobial resistance and serotype distribution. A total of 146
      nasopharyngeal isolates were collected from children from 3 to 38 months of age.
      Twenty-one clinical laboratory isolates from both sterile and nonsterile sites
      were obtained from a local hospital. Isolates with reduced susceptibilities to
      penicillin represented 15.1 and 42.9% of the nasopharyngeal and clinical
      isolates, respectively. For neither group of isolates did penicillin MICs exceed
      1.5 micro g/ml, indicating only intermediate resistance. Thirty-two different
      serotypes were identified from the 146 nasopharyngeal isolates. The serotypes of
      the clinical isolates were represented among those 32 types. Isolates with
      reduced susceptibility to multiple antimicrobial agents were present in both
      settings. These findings indicate some of the highest rates of antimicrobial
      resistance in the region as well as a slightly different serotype distribution
      pattern from those of other South American countries. The 7-valent conjugate
      pneumococcal vaccines would only have a limited effect, providing coverage for
      about half of all isolates. Increasing rates of resistance in Peru necessitate an
      awareness of antimicrobial treatment practices and vaccination strategies.

PMID- 12414768
TI  - Patterns of cytokines and soluble cellular receptors in the sera of children with
      acute chagas' disease.
AB  - Cytokines and soluble cellular receptors are involved in inflammatory processes
      and probably in the pathogenesis of parasite and bacterial diseases. In a
      previous study, we reported increased levels of soluble receptors of interleukin
      2 (sIL2-R) in children with acute Chagas' disease, one of the main parasitic
      infections that is endemic in Latin America. We sought to analyze the pattern of
      different cytokines and soluble receptors in the sera of children with chagasic
      infection. Children with acute and indeterminate stages of Chagas' disease, as
      well as nonchagasic children, were studied. Sera were assayed by enzyme-linked
      immunosorbent assay to measure the levels of tumor necrosis factor alpha (TNF
      alpha), IL-6, IL-2, IL-8, IL-12, sIL-2R, and the soluble receptors of CD8 and CD4
      (sCD8 and sCD4). sIL-2R and sCD8 showed the highest levels in serum in acutely
      infected children, decreasing after specific antiparasite therapy. Chronic
      children showed a pattern similar to the one of nonchagasic children. Although
      they were not statistically significant, TNF-alpha, IL-6, and sCD4 showed a
      tendency to reach high levels in the acutely infected group, whereas IL-2, IL-8,
      and IL-12 did not reveal changes with respect to the noninfected children. In
      summary, we report here the patterns of cytokines and soluble receptors in in the
      sera of children infected with Trypanosoma cruzi; we found significantly
      increased levels of sIL-2R and sCD8 in acute infection that decreased after
      therapy, and high levels of TNF-alpha, IL-6, and sCD4 in some of the acute
      patients. The measurement of sIL-2R and sCD8 may provide a useful tool in the
      follow-up of children with Chagas' disease.

PMID- 12414770
TI  - Comparative study of the presence of Chlamydia pneumoniae in cerebrospinal fluid
      of Patients with clinically definite and monosymptomatic multiple sclerosis.
AB  - There is considerable controversy concerning the evidence for the presence of
      Chlamydia pneumoniae in the cerebrospinal fluid (CSF) of both multiple sclerosis
      (MS) patients and patients with other neurological diseases (OND). In order to
      clarify this issue, the laboratories at Vanderbilt University Medical Center
      (VUMC) and the University of South Florida (USF) examined the reproducibility of
      their respective PCR assays for the detection of C. pneumoniae DNA in the CSF of
      a common group of MS patients and OND controls. The two laboratories used
      different DNA extraction and PCR techniques in order to determine the prevalence
      of the C. pneumoniae genome in both monosymptomatic and clinically definite MS
      patients as well as in OND controls. In clinically definite MS patients, the VUMC
      and USF detection rates were 72 and 61%, respectively, and in patients with
      monosymptomatic MS, the VUMC and USF detection rates were 41 and 54%,
      respectively. The PCR signal was positive for 7% of the OND controls at VUMC and
      for 16% at USF. These studies confirm our previous reports concerning the high
      prevalence of C. pneumoniae in the CSF of MS patients. The presence of C.
      pneumoniae in patients with monosymptomatic MS would also suggest that infection
      with the organism occurs early in the course of the disease.

PMID- 12414771
TI  - Efficiency of reconstitution of immunoglobulin g from blood specimens dried on
      filter paper and utility in herpes simplex virus type-specific serology
      screening.
AB  - The performance of studies using sera from remote locations is greatly
      facilitated if whole-blood samples dried on filter paper are shown to be
      compatible with the serologic assay being employed. Since dried blood samples do
      not require immediate refrigeration, occupy little space, and are easily
      transported, they may be used for evaluating the seroprevalence of herpes simplex
      virus type 1 (HSV-1) and HSV-2 in geographic locations where laboratory resources
      are limited. We evaluated the utility of dried blood samples for the detection of
      type-specific HSV antibodies. The efficiency of using immunoglobulin G (IgG)
      eluted from dried blood samples was found to be consistent with measurement of
      IgG concentrations in most corresponding serum samples. The ratio of the mean IgG
      concentration for all dried blood samples to the mean IgG concentration for the
      corresponding sera was 1:29. When the 1:29 ratio was applied to each of the 22
      pairs of samples, there was a deviation of less than 15% between concentrations
      in the dried blood sample and in the corresponding serum sample in 19 of the
      pairs. No positive or negative bias was detected for the IgG eluted from dried
      blood. The presence of HSV-1 and HSV-2 antibodies was determined in the paired
      dried blood and serum samples, and no differences in the HSV serostatuses were
      detected for 43 of the 44 pairs. One pair's serostatus varied, with the serum
      sample being weakly positive for HSV-1 and the dried blood sample results being
      equivocal. The detection of HSV antibodies was generally consistent for dried
      blood samples stored frozen for over 1 year or at room temperature for 30 days,
      although decreased reactivities were found in a few samples.

PMID- 12414772
TI  - Characterization of Toxoplasma gondii SAG2 expressed in insect cells by
      recombinant baculovirus and evaluation of its diagnostic potential in an enzyme
      linked immunosorbent assay.
AB  - A baculovirus carrying the SAG2 gene of Toxoplasma gondii was constructed, and
      recombinant SAG2 protein (S-rSAG2) was expressed in insect cells. S-rSAG2 was
      recognized by sera from cats and pigs infected with T. gondii. Mice immunized
      with S-rSAG2 produced high titers of specific immunoglobulin G2a (IgG2a) and IgG1
      antibodies. In an indirect fluorescent antibody test, all mouse antisera against
      S-rSAG2 reacted strongly to the natural parasites, but those against rSAG2
      expressed in Escherichia coli (E-rSAG2) only showed very weak reaction, although
      no markedly difference was found in the reaction to denatured antigen, T. gondii
      lysate, in Western blot analysis. The results suggest that S-rSAG2 is better than
      E-rSAG2 in both antigenicity and immunogenicity. Enzyme-linked immunosorbent
      assay (ELISA) with S-rSAG2 could differentiate clearly between sera from 30
      specific-pathogen-free cats and 4 experimentally infected cats. Serum samples
      from domestic cats in Japan were tested by the ELISA and compared with a latex
      agglutination test (LAT) and ELISA with E-rSAG2. Of 187 samples, all 35 LAT
      positive sera had strong reactions to S-rSAG2 and E-rSAG2. Of the 152 LAT
      negative sera, 18 were positive in the ELISA with S-rSAG2, whereas only 2 were
      positive in the ELISA with E-rSAG2. Although there were significant correlations
      among the three methods, the ELISA with S-rSAG2 was more sensitive than the
      others, which could be attributed to the fact that S-rSAG2 shares some common
      conformational structure with the native antigen. The results suggest that S
      rSAG2 would be a useful reagent for the detection of T. gondii infection in cats.

PMID- 12414773
TI  - Humoral immune response associated with lyme borreliosis in nonhuman primates:
      analysis by immunoblotting and enzyme-linked immunosorbent assay with sonicates
      or recombinant proteins.
AB  - The immune response to Borrelia burgdorferi, the causative agent of Lyme disease,
      is complex. We studied the immunoglobulin M (IgM) and IgG antibody response to
      N40Br, a sensu stricto strain, in the rhesus macaque(nonhuman primate [NHP])
      model of infection to identify the spirochetal protein targets of specific
      antibody. Antigens used in enzyme-linked immunosorbent assays were whole-cell
      sonicates of the spirochete and recombinant proteins of B. burgdorferi.
      Immunoblotting with a commercially available strip and subsequent quantitative
      densitometry of the bands were also used. Sera from four different groups of NHPs
      were used: immunocompetent, transiently immunosuppressed, extended
      immunosuppressed, and uninfected. In immunocompetent and transiently
      immunosuppressed NHPs, there was a strong IgM and IgG response. Major proteins
      for the early IgM response were P39 and P41 and recombinant BmpA and OspC. Major
      proteins for the later IgG response were P39, P41, P18, P60, P66, and recombinant
      BmpA and DbpA. There was no significant response in the NHPs to recombinant OspA
      or to Arp, a 37-kDa protein that elicits an antibody response during infection in
      mice. Most antibody responses, except for that to DbpA, were markedly diminished
      by prolonged dexamethasone treatment. This study supports the hypothesis that
      recombinant proteins may provide a useful adjunct to current diagnostic testing
      for Lyme borreliosis.

PMID- 12414774
TI  - Fluorescence polarization assay for detection of Brucella abortus antibodies in
      bulk tank bovine milk samples.
AB  - A simple, rapid, inexpensive fluorescence polarization assay for the detection of
      antibodies to Brucella abortus in bulk tank milk samples at the farm level or at
      dairies with a sensitivity and specificity of 100 and 95.9%, respectively, is
      described. The assay detects antibodies to B. abortus in 15 min by testing
      undiluted whey produced by chemical and physical manipulation of milk from bulk
      tanks. This sampling is noninvasive and therefore costs less and is less
      stressful than blood-based tests. The assay is specific and can detect antibodies
      at levels below that of the indirect enzyme immunoassay for milk and the
      fluorescence polarization assay for individual milk samples. Use of this test
      would make programs for surveillance of dairy animals and eradication of B.
      abortus more cost-effective.

PMID- 12414775
TI  - Leishmania major-like antigen for specific and sensitive serodiagnosis of human
      and canine visceral leishmaniasis.
AB  - An antigen (LMS) prepared from Leishmania major-like promastigotes was used in an
      enzyme-linked immunosorbent assay (ELISA) for the diagnosis of human and dog
      visceral leishmaniasis. The results were compared with those from the indirect
      immunofluorescent antibody test (IFAT). A total of 1822 canine sera were tested,
      including sera from dogs with visceral leishmaniasis, transmissible venereal
      tumors, ehrlichiosis, rickettsiosis, or Chagas' disease and sera from healthy
      dogs. The antigen was also tested with 227 samples of human sera, including sera
      from patients with visceral, cutaneous, or diffuse cutaneous leishmaniasis and
      from noninfected individuals, as well as sera from patients with Chagas' disease,
      toxoplasmosis, rickettsiosis, hepatitis B, schistosomiasis, ascaridiasis,
      malaria, rheumatoid factor, leprosy and rheumatoid factor, tuberculosis, or
      leprosy. All dogs and all human patients had a clinical and/or serological and/or
      parasitological diagnosis. For detecting antibodies in sera from dogs with
      leishmaniasis, the antigen showed a sensitivity of 98%, specificity of 95%, and
      concordance of 93% and when used for detecting antibodies in human sera presented
      a sensitivity of 92%, specificity of 100%, and concordance of 92%. Comparison
      between ELISA and IFAT demonstrated that ELISA using the LMS antigen yielded more
      reliable results than IFAT. The LMS antigen displayed no cross-reactivity with
      sera from patients or dogs that had any of the other diseases tested.

PMID- 12414776
TI  - Interpretation of a commercial bovine paratuberculosis enzyme-linked
      immunosorbent assay by using likelihood ratios.
AB  - Evidence-based medicine encourages the use of quantitative diagnostic test
      results to estimate the probability of a particular diagnosis. Likelihood ratios
      (LRs) are among the best tools for maximizing the diagnostic information gained
      from diagnostic assays that provide results on a continuous scale. They provide
      the odds that an animal with a particular test result actually has the disease in
      question based on the magnitude of the test result. A commercial enzyme-linked
      immunosorbent assay (ELISA) was used to test sera from 143 dairy cattle infected
      with Mycobacterium paratuberculosis and 2974 cattle free of this infection. This
      assay transforms ELISA reader optical density values into sample-to-positive
      (S/P) ratios. The LR was calculated for S/P results from 0.00 to 1.00 at 0.05-S/P
      unit intervals. LRs were directly but not linearly correlated with ELISA S/P
      ratios (r(2) = 0.94). The mathematical function describing the relationship
      between the ELISA S/P ratio and the LR was LR = 265 x (S/P value)(2.03). LRs were
      also directly related to the frequency of animals testing positive for
      paratuberculosis by fecal culture and other serologic tests. Based on these LRs,
      guidelines for interpretation and application of this ELISA for the diagnosis and
      control of paratuberculosis in dairy cattle herds are recommended.

PMID- 12414778
TI  - Defibrination of blood plasma for use in serological tests for syphilis.
AB  - Syphilitic plasma can be salvaged from discarded blood donations and converted to
      serum by defibrination. Sixty-nine units of plasma were treated with a stock
      solution of 100 U of thrombin per ml in 1 M calcium chloride and then with a 10%
      (wt/vol) solution of kaolin. Fibrinogen concentrations detected in initial plasma
      samples ranged from 94 to 4970 mg/liter (mean, 2532 mg/liter) for samples that
      were reactive by the rapid plasma reagin circle card test (RPR) and from 314 to
      2742 mg/liter (mean 1528 mg/liter) for samples that were not reactive by the RPR.
      The treated samples showed no measurable fibrinogen remaining after the
      defibrination process. In the nontreponemal RPR for syphilis, 86% of the treated
      plasma samples retained the same endpoint titer as that of the initial plasma
      sample. When the Treponema pallidum passive-particle-agglutination test was used,
      98% retained the same reactivity. In the Captia Syphilis-G enzyme immunoassay,
      89% of the treated samples demonstrated no change in reactivity index, and in the
      fluorescent treponemal antibody absorption test, 96% showed no reduction in
      fluorescence. Human sera containing antibodies to syphilis are used at the
      Centers for Disease Control and Prevention for the preparation of reference
      controls or as samples for proficiency testing. Finding reactive sera is becoming
      more difficult due to the general decline of syphilis cases in the United States.
      The decreasing availability of these sera can be alleviated by salvaging plasma
      and converting it to serum.

PMID- 12414777
TI  - Concentrations of cytokines, soluble interleukin-2 receptor, and soluble CD30 in
      sera of patients with hepatitis B virus infection during acute and convalescent
      phases.
AB  - The immunoregulatory roles of interleukin-2 (IL-2), IL-4, IL-10, gamma interferon
      (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), the soluble form of the IL
      2 receptor (sIL-2R), and the soluble form of CD30 (sCD30) were evaluated in
      patients with hepatitis B virus (HBV) infection. Two groups of subjects were
      studied: 15 healthy individuals without hepatitis antecedents and 15 patients
      with HBV infection. Blood samples were taken during the acute and convalescent
      phases. The analysis of the samples was done by the enzyme-linked immunosorbent
      assay technique. IFN-gamma and TNF-alpha levels decreased in the convalescent
      phase. IL-10, IL-2, and sIL-2R levels increased in the acute and convalescent
      phases, while sCD30 levels increased during the acute phase. The IL-4
      concentrations decreased in both phases. During the acute phase, IFN-gamma and
      TNF-alpha induced increases in IL-2, sIL-2R, IL-10, and sCD30 levels in serum,
      which allowed the development of immunity characterized by the nonreactivity of
      the HBV surface antigen, the onset of antibodies to the HBV surface antigen (anti
      HBs), and normal alanine aminotransferase levels during the convalescent phase.
      Increased IL-2 levels during the acute phase would stimulate the activities of NK
      cells and CD8(+) lymphocytes, which are responsible for viral clearing. The
      raised sIL-2R levels reveal activation of T lymphocytes and control of the IL-2
      dependent immune response. The sCD30 increment during the acute phase reflects
      the greater activation of the Th2 cellular phenotype. Its decrease in the
      convalescent phase points out the decrease in the level of HBV replication. The
      increase in IL-10 levels could result in a decrease in IL-4 levels and modulate
      IFN-gamma and TNF-alpha levels during both phases of disease, allowing the
      maintenance of anti-HBs concentrations.

PMID- 12414779
TI  - Use of a single monoclonal antibody to determine the susceptibilities of herpes
      simplex virus type 1 and type 2 clinical isolates to acyclovir.
AB  - This report describes a flow cytometry drug susceptibility assay that uses a
      single fluorochrome-labeled monoclonal antibody to determine the acyclovir
      susceptibilities of herpes simplex virus (HSV) type 1 or type 2 clinical
      isolates. This assay yields 50% effective doses (drug concentrations that reduce
      the number of antigen-positive cells by 50%) for HSV clinical isolates that are
      equivalent to those obtained with the plaque reduction assay.

PMID- 12414780
TI  - Differential immune response to the variable surface loop antigen of P66 of
      Borrelia burgdorferi sensu lato species in geographically diverse populations of
      lyme borreliosis patients.
AB  - We have studied the immune response to a variable surface-exposed loop region of
      the P66 outer membrane protein from Borrelia burgdorferi sensu lato by using an
      enzyme immunoassay. Lyme borreliosis populations found in North America and
      Sweden were preferentially more seroreactive to P66 from their respective
      regional species, namely, B. burgdorferi sensu stricto and B. garinii and B.
      afzelii, respectively.

PMID- 12414781
TI  - Fully automated detection of hepatitis C virus RNA in serum and whole-blood
      samples.
AB  - In this study, we established a fully automated molecular assay for qualitative
      detection of hepatitis C virus (HCV) in serum and whole-blood samples and
      compared it with conventional molecular assays, including manual HCV RNA
      extraction protocols. Whole-blood samples were collected from patients with and
      without chronic HCV infection in EDTA tubes and nucleic acid stabilization tubes
      (NASTs). Prior to HCV RNA extraction, the HCV Internal Control (IC), derived from
      the COBAS AMPLICOR HCV test, version 2.0 (Roche Molecular Diagnostics), was
      added. The new assay was based on an automated extraction protocol on the MagNA
      Pure LC instrument (Roche Applied Science), followed by automated reverse
      transcription, amplification, hybridization, and detection on the Cobas Amplicor
      analyzer (Roche Molecular Diagnostics). The detection limit of the new assay was
      found to be similar to those of conventional molecular assays. In clinical
      samples, 100% agreement between the new assay and conventional methods was
      observed. The introduced amount of IC was detected in 45 of 45 serum samples, 41
      of 45 EDTA tube whole-blood samples, and 43 of 45 NAST whole-blood samples.
      Retesting led to more frequent IC detection. The fully automated molecular assay
      was found to be suitable for detection of HCV RNA in different kinds of sample
      materials. It may be recommended for use in the high-throughput routine molecular
      diagnostic laboratory.

PMID- 12414782
TI  - Prophylactic effect of mycobacterium bovis BCG vaccination against osteomyelitis
      in children with Mycobacterium ulcerans disease (Buruli Ulcer).
AB  - Mycobacterium ulcerans disease, or Buruli ulcer (BU), causes significant
      morbidity in West Africa. In 233 consecutive, laboratory-confirmed samples from
      BU patients in Benin whose Mycobacterium bovis BCG scar status was known, 130
      children (<15 years old) and 75 adults had a neonatal BCG vaccination scar. Of
      130 children with BCG scars, 10 (7.7%) had osteomyelitis, while 3 of 9 children
      without BCG scars (33.3%) had osteomyelitis. Our observations support the
      conclusion that having a BCG vaccination scar provides significant protection
      against M. ulcerans osteomyelitis in children with BU disease.

PMID- 12414783
TI  - In vitro detection of apoptosis in monocytes/macrophages infected with human
      coronavirus.
AB  - Human coronavirus (HCoV) strain 229E infection, but not HCoV strain OC43
      infection, of monocytes/macrophages from healthy donors and patients with
      multiple sclerosis in remission resulted in increased apoptosis, as measured by
      DNA changes and annexin V staining. Apoptosis correlated with the differential
      release of infectious virus. HCoV strain 229E titers were 10(3.5) to 10(6) 50%
      tissue culture-infective doses (TCID(50))/ml, and HCoV strain OC43 titers were
      only 10(1.2) to 10(2.7) TCID(50)/ml.

PMID- 12414784
TI  - Dichotomal effect of the coumadin derivative warfarin on inflammatory signal
      transduction.
AB  - Warfarin, a widely prescribed drug for preventing thrombosis, is thought to act
      solely through inhibition of vitamin K-dependent coagulation factors. Low
      concentrations of warfarin inhibit interleukin-6 production and phosphorylation
      of I-kappa B but not activation of p38 mitogen-activated protein kinase. Thus,
      warfarin inhibits inflammatory signal transduction, and this may contribute to
      clinical effects of warfarin.

PMID- 12414785
TI  - Coombs antiglobulin test using Brucella abortus 99 as antigen to detect
      incomplete antibodies induced by B abortus RB51 vaccine in cattle.
AB  - This study showed that vaccination of cattle with Brucella abortus rough strain
      RB51 induces incomplete antibodies that can be detectable by a Coombs
      antiglobulin test using the B. abortus 99 smooth strain.

PMID- 12414786
TI  - Low specificity of an immunochromatographic serological assay for diagnosis of
      dengue Fever in travelers returning with malaria.

PMID- 12414787
TI  - Interleukin-8 (IL-8) preferable to IL-6 as a marker for clinical infection.

PMID- 12414788
TI  - Journey of a late blooming biochemical neuroscientist.

PMID- 12414789
TI  - The production of 53-55-kDa isoforms is not required for rat L-histidine
      decarboxylase activity.
AB  - Post-translational processing of the histamine-producing enzyme, L-histidine
      decarboxylase (HDC), leads to the formation of multiple carboxyl-truncated
      isoforms. Nevertheless, it has been widely reported that the mature catalytically
      active dimer is dependent specifically on the production of carboxyl-truncated 53
      55-kDa monomers. Here we use transiently transfected COS-7 cells to study the
      properties of carboxyl-truncated rat HDC isoforms in the 52-58-kDa size range.
      Amino acid sequences important for the production of a 55-kDa HDC isoform were
      identified by successive truncations through amino acids 502, 503, and 504.
      Mutating this sequence in the full-length protein prevented the production of 55
      kDa HDC but did not affect enzymatic activity. Further truncations to amino acid
      472 generated an inactive 53-kDa HDC isoform that was degraded by the proteasome
      pathway. These results suggested that processed isoforms, apart from 53-55-kDa
      ones, contribute toward histamine biosynthesis in vivo. This was confirmed in
      physiological studies where regulated increases in HDC activity were associated
      with the expression of isoforms that were greater than 55 kDa in size. We provide
      evidence to show that regulation of HDC expression can be achieved by the
      differential production or differential stabilization of multiple enzyme
      isoforms.

PMID- 12414790
TI  - Protein-tyrosine phosphatase-1B (PTP1B) mediates the anti-migratory actions of
      Sprouty.
AB  - Mammalian Sprouty proteins have been shown to inhibit the proliferation and
      migration of cells in response to growth factors and serum. In this
      communication, using HeLa cells, we have examined the possibility that human
      Sprouty 2 (hSPRY2) mediates its anti-migratory actions by modulating the activity
      or intracellular localization of protein-tyrosine phosphatases. In HeLa cells,
      overexpression of hSPRY2 resulted in an increase in protein-tyrosine phosphatase
      (PTP1B) amount and activity in the soluble (100,000 x g) fraction of cells
      without an increase in total amount of cellular PTP1B. This increase in the
      soluble form of PTP1B was accompanied by a decrease in the amount of the enzyme
      in the particulate fraction. The amounts of PTP-PEST or PTP1D in the soluble
      fractions were not altered. Consistent with an increase in soluble PTP1B amount
      and activity, the tyrosine phosphorylation of cellular proteins and p130(Cas) was
      decreased in hSPRY2-expressing cells. In control cells, overexpression of wild
      type (WT) PTP1B, but not its C215S catalytically inactive mutant mimicked the
      actions of hSPRY2 on tyrosine phosphorylation of cellular proteins and migration.
      On the other hand, in hSPRY2-expressing cells, the C215S mutant, but not WT
      PTP1B, increased tyrosine phosphorylation of cellular proteins and attenuated the
      anti-migratory actions of hSPRY2. Interestingly, neither WT nor C215S mutant
      forms of PTP1B modulated the anti-mitogenic actions of hSPRY2. Therefore, we
      conclude that an increase in soluble PTP1B activity contributes to the anti
      migratory, but not anti-mitogenic, actions of hSPRY2.

PMID- 12414791
TI  - Antidiabetic action of a liver x receptor agonist mediated by inhibition of
      hepatic gluconeogenesis.
AB  - The oxysterol receptors LXR (liver X receptor)-alpha and LXRbeta are nuclear
      receptors that play a key role in regulation of cholesterol and fatty acid
      metabolism. We found that LXRs also play a significant role in glucose
      metabolism. Treatment of diabetic rodents with the LXR agonist, T0901317,
      resulted in dramatic reduction of plasma glucose. In insulin-resistant Zucker
      (fa/fa) rats, T0901317 significantly improved insulin sensitivity. Activation of
      LXR did not induce robust adipogenesis but rather inhibited the expression of
      several genes involved in hepatic gluconeogenesis, including phosphoenolpyruvate
      carboxykinase (PEPCK). Hepatic glucose output was dramatically reduced as a
      result of this regulation. Nuclear run-on studies indicated that transcriptional
      repression was primarily responsible for the inhibition of PEPCK by the LXR
      agonist. In addition, we show that the regulation of the liver gluconeogenic
      pathway by LXR agonists was a direct effect on hepatocytes. These data not only
      suggest that LXRs are novel targets for diabetes but also reveal an unanticipated
      role for these receptors, further linking lipid and glucose metabolism.

PMID- 12414792
TI  - Cyclic GMP-dependent protein kinase regulates the expression of thioredoxin and
      thioredoxin peroxidase-1 during hormesis in response to oxidative stress-induced
      apoptosis.
AB  - Human neuroblastoma cells, SH-SY5Y, contain relatively low levels of thioredoxin
      (Trx); thus, they serve favorably as a model for studying oxidative stress
      induced apoptosis (Andoh, T., Chock, P. B., and Chiueh, C. C. (2001) J. Biol.
      Chem. 277, 9655-9660). When these neurotrophic cells were subjected to nonlethal
      2-h serum deprivation, their neuronal nitric oxide synthase and Trx were up
      regulated, and the cells became more tolerant of oxidative stress, indicating
      that NO may protect cells from serum deprivation-induced apoptosis. Here, the
      mechanism by which NO exerts its protective effects was investigated. Our results
      reveal that in SH-SY5Y cells, NO inhibits apoptosis through its ability to
      activate guanylate cyclase, which in turn activates the cGMP-dependent protein
      kinase (PKG). The activated PKG is required to protect cells from lipid
      peroxidation and apoptosis, to inhibit caspase-9 and caspase-3 activation, and to
      elevate the levels of Trx peroxidase-1 and Trx, which subsequently induces the
      expression of Bcl-2. Furthermore, active PKG promotes the elevation of c-Jun,
      phosphorylated MAPK/ERK1/2, and c-Myc, consistent with the notion that PKG
      enhances the expression of Trx through its c-Myc-, AP-1-, and PEA3-binding
      motifs. Elevation of Trx and Trx peroxidase-1 and Mn(II)-superoxide dismutase
      would reduce H(2)O(2) and O(2)(), respectively. Thus, the cytoprotective effect
      of NO in SH-SY5Y cells appears to proceed via the PKG-mediated pathway, and S
      nitrosylation of caspases plays a minimal role.

PMID- 12414793
TI  - Steroid responsiveness of renal epithelial cells. Dissociation of transrepression
      and transactivation.
AB  - Glucocorticoids modulate cellular and inflammatory responses via stimulation or
      inhibition of gene transcription. Inhibition of cytokine gene expression is
      mediated via repression of transcription factors, including NF-kappaB. Previously
      we have shown that cytokine production by renal epithelial cells is insensitive
      to the inhibitory action of dexamethasone. In this study we demonstrate that
      dexamethasone is unable to inhibit NF-kappaB activation in the renal epithelial
      cell line HK-2, as measured by IkappaB-alpha degradation and DNA binding
      activity. Transfection of an NF-kappaB-inducible reporter gene demonstrated that
      non-stimulated HK-2 cells contain a high level of constitutively active NF-kappaB
      compared with the steroid-sensitive airway epithelial cell line A549, which was
      not blocked by dexamethasone. Expression and nuclear translocation of the
      glucocorticoid receptor (GR) was comparable in both cell types. In HK-2 cells,
      dexamethasone stimulated expression of two glucocorticoid-responsive genes,
      beta(2)-adrenoreceptors and angiotensinogen. The capacity of GR to transactivate
      the native angiotensinogen glucocorticoid-responsive element (GRE) using
      chromatin-IP was not impaired. Moreover, dexamethasone activation of a GRE-driven
      reporter construct appeared to be equally effective, although less sensitive
      compared with A549 cells. In conclusion, we provide evidence that glucocorticoids
      are unable to repress the activity of NF-kappaB in renal epithelial cells in the
      presence of an intact stimulatory pathway.

PMID- 12414794
TI  - ATF1 phosphorylation by the ERK MAPK pathway is required for epidermal growth
      factor-induced c-jun expression.
AB  - Epidermal growth factor induction of c-jun expression requires ATF1 and MEF2
      sites in the c-jun promoter. We find that activation of the c-jun promoter
      through the ATF1 site requires phosphorylation of ATF1 at serine 63. A serine 63
      to alanine mutation of ATF1 acts to block epidermal growth factor (EGF) induction
      of a transfected c-jun gene. ATF1 can be phosphorylated by mitogen- and stress
      activated protein kinase 1 (MSK1), which is activated by EGF and ERK1/2. Kinase
      dead MSK1 mutants blocked EGF induction of a transfected c-jun gene suggesting
      that MSK1 or a similar family member is required for induced c-jun expression.
      Use of the MEK1 inhibitor U0126 and dominant negative MEK1 further showed that
      MSK1 activation and c-jun induction require the ERK pathway. In contrast, a JNK
      inhibitor blocked EGF induction of c-jun expression but not ATF1 phosphorylation.
      These results show that the two MAPK pathways, ERK and JNK, are required for EGF
      induced c-jun expression and that the ERK pathway acts through downstream
      phosphorylation of ATF1.

PMID- 12414795
TI  - The genome-wide transcriptional responses of Saccharomyces cerevisiae grown on
      glucose in aerobic chemostat cultures limited for carbon, nitrogen, phosphorus,
      or sulfur.
AB  - Profiles of genome-wide transcriptional events for a given environmental
      condition can be of importance in the diagnosis of poorly defined environments.
      To identify clusters of genes constituting such diagnostic profiles, we
      characterized the specific transcriptional responses of Saccharomyces cerevisiae
      to growth limitation by carbon, nitrogen, phosphorus, or sulfur. Microarray
      experiments were performed using cells growing in steady-state conditions in
      chemostat cultures at the same dilution rate. This enabled us to study the
      effects of one particular limitation while other growth parameters (pH,
      temperature, dissolved oxygen tension) remained constant. Furthermore, the
      composition of the media fed to the cultures was altered so that the
      concentrations of excess nutrients were comparable between experimental
      conditions. In total, 1881 transcripts (31% of the annotated genome) were
      significantly changed between at least two growth conditions. Of those, 484 were
      significantly higher or lower in one limitation only. The functional annotations
      of these genes indicated cellular metabolism was altered to meet the growth
      requirements for nutrient-limited growth. Furthermore, we identified responses
      for several active transcription factors with a role in nutrient assimilation.
      Finally, 51 genes were identified that showed 10-fold higher or lower expression
      in a single condition only. The transcription of these genes can be used as
      indicators for the characterization of nutrient-limited growth conditions and
      provide information for metabolic engineering strategies.

PMID- 12414796
TI  - Contribution of glycine 146 to a conserved folding module affecting stability and
      refolding of human glutathione transferase p1-1.
AB  - In human glutathione transferase P1-1 (hGSTP1-1) position 146 is occupied by a
      glycine residue, which is located in a bend of a long loop that together with the
      alpha6-helix forms a substructure (GST motif II) maintained in all soluble GSTs.
      In the present study G146A and G146V mutants were generated by site-directed
      mutagenesis in order to investigate the function played by this conserved residue
      in folding and stability of hGSTP1-1. Crystallographic analysis of the G146V
      variant, expressed at the permissive temperature of 25 degrees C, indicates that
      the mutation causes a substantial change of the backbone conformation because of
      steric hindrance. Stability measurements indicate that this mutant is inactivated
      at a temperature as low as 32 degrees C. The structure of the G146A mutant is
      identical to that of the wild type with the mutated residue having main-chain
      bond angles in a high energy region of the Ramachandran plot. However even this
      Gly --> Ala substitution inactivates the enzyme at 37 degrees C. Thermodynamic
      analysis of all variants confirms, together with previous findings, the critical
      role played by GST motif II for overall protein stability. Analysis of
      reactivation in vitro indicates that any mutation of Gly-146 alters the folding
      pathway by favoring aggregation at 37 degrees C. It is hypothesized that the GST
      motif II is involved in the nucleation mechanism of the protein and that the
      substitution of Gly-146 alters this transient substructure. Gly-146 is part of
      the buried local sequence GXXh(T/S)XXDh (X is any residue and h is a hydrophobic
      residue), conserved in all GSTs and related proteins that seems to behave as a
      characteristic structural module important for protein folding and stability.

PMID- 12414797
TI  - A site in the fourth membrane-associated domain of the N-methyl-D-aspartate
      receptor regulates desensitization and ion channel gating.
AB  - The N-methyl-d-aspartate (NMDA) receptor has four membrane-associated domains,
      three of which are membrane-spanning (M1, M3, and M4) and one of which is a re
      entrant pore loop (M2). The M1-M3 domains have been demonstrated to influence the
      function of the ion channel, but a similar role for the M4 domain has not been
      reported. We have identified a methionine residue (Met(823)) in the M4 domain of
      the NR2A subunit that regulates desensitization and ion channel gating. A
      tryptophan substitution at this site did not alter the EC(50) for glycine or the
      peak NMDA EC(50) but decreased the steady-state NMDA EC(50) and markedly
      increased apparent desensitization, mean open time, and peak current density.
      Results of rapid solution exchange experiments revealed that changes in
      microscopic desensitization rates and closing rates could account for the changes
      in macroscopic desensitization, steady-state NMDA EC(50), and current density.
      Other amino acid substitutions at this site could increase or decrease the rate
      of desensitization and mean open time of the ion channel. Both mean open time and
      desensitization were dependent primarily upon the hydrophobic character of the
      amino acid at the position. These results demonstrate an important role for
      hydrophobic interactions at Met(823) in regulation of NMDA receptor function.

PMID- 12414798
TI  - Storage and release of ATP from astrocytes in culture.
AB  - ATP is released from astrocytes and is involved in the propagation of calcium
      waves among them. Neuronal ATP secretion is quantal and calcium-dependent, but it
      has been suggested that ATP release from astrocytes may not be vesicular. Here we
      report that, besides the described basal ATP release facilitated by exposure to
      calcium-free medium, astrocytes release purine under conditions of elevated
      calcium. The evoked release was not affected by the gap-junction blockers
      anandamide and flufenamic acid, thus excluding purine efflux through connexin
      hemichannels. Sucrose-gradient analysis revealed that a fraction of ATP is stored
      in secretory granules, where it is accumulated down an electrochemical proton
      gradient sensitive to the v-ATPase inhibitor bafilomycin A(1). ATP release was
      partially sensitive to tetanus neurotoxin, whereas glutamate release from the
      same intoxicated astrocytes was almost completely impaired. Finally, the
      activation of metabotropic glutamate receptors, which strongly evokes glutamate
      release, was only slightly effective in promoting purine secretion. These data
      indicate that astrocytes concentrate ATP in granules and may release it via a
      regulated secretion pathway. They also suggest that ATP-storing vesicles may be
      distinct from glutamate-containing vesicles, thus opening up the possibility that
      their exocytosis is regulated differently.

PMID- 12414799
TI  - Characterization of the necrotic protein that regulates the Toll-mediated immune
      response in Drosophila.
AB  - Necrotic (Nec) is an important component of the proteolytic cascade that
      activates the Toll-mediated immune response in Drosophila. The Nec protein is a
      member of the serpin (SERine Protease INhibitor) superfamily and is thought to
      regulate the cascade by inhibiting the serine protease Persephone. Nec was
      expressed in Escherichia coli, and the purified protein folded to the active
      native conformation required for protease inhibitory activity. Biochemical
      analysis showed that Nec had a broad inhibitory specificity and inhibited
      elastase, thrombin, and chymotrypsin-like proteases. It did not inhibit trypsin
      or kallikrein. These data show that Necrotic is likely to inhibit a wide range of
      proteases in Drosophila and that Nec has the specificity requirements to act as
      the physiological inhibitor of Persephone in vivo.

PMID- 12414800
TI  - Resolution of the V1 ATPase from Manduca sexta into subcomplexes and
      visualization of an ATPase-active A3B3EG complex by electron microscopy.
AB  - The effect of the ATPase activity of Manduca sexta V(1) ATPase by the amphipathic
      detergent lauryldimethylamine oxide (LDAO) and the relationship of these
      activities to the subunit composition of V(1) were studied. The V(1) was highly
      activated in the presence of 0.04-0.06% LDAO combined with release of the
      subunits H, C, and F from the enzyme. Increase of LDAO concentration to 0.1-0.2%
      caused the characterized subcomplexes A(3)B(3)HEGF and A(3)B(3)EG with a
      remaining ATPase activity of 52 and 65%, respectively. The hydrolytic-active
      A(3)B(3)EG subcomplex has been visualized by electron microscopy showing six
      major masses of density in a pseudo-hexagonal arrangement surrounding a seventh
      mass. The compositions of the various subcomplexes and fragments of V(1) provide
      an organization of the subunits in the enzyme in the framework of the known three
      dimensional reconstruction of the V(1) ATPase from M. sexta (Radermacher, M.,
      Ruiz, T., Wieczorek, H., and Gruber, G. (2001) J. Struct. Biol. 135, 26-37).

PMID- 12414801
TI  - ESE-1, an enterocyte-specific Ets transcription factor, regulates MIP-3alpha gene
      expression in Caco-2 human colonic epithelial cells.
AB  - We have previously shown that colonic epithelial cells are a major site of MIP
      3alpha production in human colon and that enterocyte MIP-3alpha protein levels
      are elevated in inflammatory bowel disease. The aim of this study was to
      determine the molecular mechanisms regulating MIP-3alpha gene transcription in
      Caco-2 intestinal epithelial cells. We show that a kappaB element at nucleotides 
      82 to -93 of the MIP-3alpha promoter binds p50/p65 NF-kappaB heterodimers and is
      a major regulator of basal and interleukin-1beta (IL-1beta)-mediated gene
      activation. Scanning mutagenesis of the MIP-3alpha 5'-flanking region also
      identified two additional binding elements: Site X (nucleotides -63 to -69) and
      Site Y (nucleotides -143 to -154). Site X (CGCCTTC) bound Sp1 and regulated basal
      MIP-3alpha gene transcription. Overexpression of Sp1 increased basal luciferase
      activity, whereas, substitutions in the Sp1 element significantly reduced
      reporter activity. In contrast, Site Y (AAGCAGGAAGTT) regulated both basal and
      cytokine-induced gene activation and bound the Ets nuclear factor ESE-1.
      Substitutions in the Site Y element markedly reduced inducible MIP-3alpha
      reporter activity. Conversely, overexpression of ESE-1 significantly up-regulated
      MIP-3alpha luciferase levels. Taken together, our findings demonstrate that co
      ordinate activation and binding of ESE-1, Sp1, and NF-kappaB to the MIP-3alpha
      promoter is required for maximal gene expression by cytokine-stimulated Caco-2
      human intestinal epithelial cells.

PMID- 12414802
TI  - Structure-function analysis of the prosegment of the proprotein convertase PC5A.
AB  - To investigate if some residues within the prosegment of PC5A are important for
      its optimal proteolytic function, various PC5A mutants were cellularly expressed,
      and their processing activities were compared using pro-vascular endothelial
      growth factor C (pro-VEGF-C) as a substrate. Although wild type PC5A almost
      completely processes pro-VEGF-C, a prosegment deletion as well as both P1 mutants
      of the primary (R116A) and secondary (R84A) autocatalytic cleavage sites are
      inactive. The in vitro inhibitory potency of various decapeptides mimicking the C
      terminal sequence of PC5 prosegment (pPC5) revealed that the native
      (107)QQVVKKRTKR(116) peptide is a nanomolar inhibitor, whereas its P6 mutant
      K111H is more selective toward PC5A than Furin. In vitro activity assays using
      the bacterially expressed pPC5 and its mutants revealed them to be very potent
      nanomolar inhibitors (IC(50)) and only approximately 6-fold more selective
      inhibitors of PC5A versus Furin. Expression of the preprosegment of PC5 (ppPC5)
      and its mutants in Chinese hamster ovary FD11 cells overexpressing pro-VEGF-C
      with either PC5A or Furin showed them to be as good inhibitors of PC5A as the
      serpin alpha1-antitrypsin Portland (alpha1-PDX), ppFurin, or ppPACE4 but less
      potent toward overexpressed Furin. In conclusion, cleavages of the prosegment of
      PC5A at both Arg(116) and Arg(84) are required for PC5A cellular activity, and
      ppPC5 is a very potent but modestly selective cellular inhibitor of PC5A.

PMID- 12414803
TI  - Rosiglitazone and retinoic acid induce uncoupling protein-1 (UCP-1) in a p38
      mitogen-activated protein kinase-dependent manner in fetal primary brown
      adipocytes.
AB  - Brown adipose tissue expresses the thermogenic uncoupling protein-1 (UCP-1),
      which is positively regulated by peroxisome proliferator-activated receptor
      (PPAR) agonists and retinoids through the activation of the heterodimers
      PPAR/retinoid X receptor (RXR) and retinoic acid receptor (RAR)/RXR and binding
      to specific elements in the ucp-1 enhancer. In this study we show that in fetal
      rat brown adipocyte primary cultures the PPARgamma agonist rosiglitazone (Rosi),
      as well as retinoic acids 9-cis-retinoic acid and all-trans-retinoic acid also
      have "extragenic" effects and induce p44/p42 and p38 mitogen-activated protein
      kinase (p38MAPK) activation. The latter is involved in UCP-1 gene expression,
      because inhibition of p38MAPK activity with PD169316 impairs the ability of Rosi
      and retinoids for UCP-1 induction. The inhibitory effects of PD169316 are
      mimicked by the antioxidant GSH, suggesting a role for reactive oxygenated
      species (ROS) generation in the increase of UCP-1 expression in response either
      to Rosi or 9-cis-retinoic acid. Thus, we propose that Rosi and retinoids act as
      PPAR/RXR and RAR/RXR agonists and also activate p38MAPK. These two coordinated
      actions could result in a high increase of transcriptional activity on the ucp-1
      enhancer and hence on thermogenesis. PPARalpha and gamma agonists but not
      retinoids also increase UCP-3 expression in fetal brown adipocytes. However, the
      regulation of UCP-3, which is not involved in thermogenesis, seems to differ from
      UCP-1 given the fact that is not affected by p38MAPK inhibition.

PMID- 12414804
TI  - Peroxynitrite protects neurons against nitric oxide-mediated apoptosis. A key
      role for glucose-6-phosphate dehydrogenase activity in neuroprotection.
AB  - Peroxynitrite is thought to be a nitric oxide-derived neurotoxic effector
      molecule involved in the disruption of key energy-related metabolic targets. To
      assess the consequences of such interference in cellular glucose metabolism and
      viability, we studied the possible modulatory role played by peroxynitrite in
      glucose oxidation in neurons and astrocytes in primary culture. Here, we report
      that peroxynitrite triggered rapid stimulation of pentose phosphate pathway (PPP)
      activity and the accumulation of NADPH, an essential cofactor for glutathione
      regeneration. In contrast to peroxynitrite, nitric oxide elicited NADPH
      depletion, glutathione oxidation, and apoptotic cell death in neurons, but not in
      astrocytes. These events were noticeably counteracted by pretreatment of neurons
      with peroxynitrite. In an attempt to elucidate the mechanism responsible for this
      PPP stimulation and neuroprotection, we found evidence consistent with both
      exogenous and endogenous peroxynitrite-mediated activation of glucose-6-phosphate
      dehydrogenase (G6PD), an enzyme that catalyzes the first rate-limiting step in
      the PPP. Moreover, functional overexpression of the G6PD gene in stably
      transformed PC12 cells induced NADPH accumulation and offered remarkable
      resistance against nitric oxide-mediated apoptosis, whereas G6PD gene-targeted
      antisense inhibition depleted NADPH levels and exacerbated cellular
      vulnerability. In light of these results, we suggest that G6PD activation
      represents a novel role for peroxynitrite in neuroprotection against nitric oxide
      mediated apoptosis.

PMID- 12414805
TI  - Secretory granule-mediated co-secretion of L-glutamate and glucagon triggers
      glutamatergic signal transmission in islets of Langerhans.
AB  - L-Glutamate is believed to function as an intercellular transmitter in the islets
      of Langerhans. However, critical issues, i.e. where, when and how L-glutamate
      appears, and what happens upon stimulation of glutamate receptors in the islets,
      remain unresolved. Vesicular glutamate transporter 2 (VGLUT2), an isoform of the
      vesicular glutamate transporter essential for neuronal storage of L-glutamate, is
      expressed in alpha cells (Hayashi, M., Otsuka, M., Morimoto, R., Hirota, S.,
      Yatsushiro, S., Takeda, J., Yamamoto, A., and Moriyama, Y. (2001) J. Biol. Chem.
      276, 43400-43406). Here we show that VGLUT2 is specifically localized in glucagon
      containing secretory granules but not in synaptic-like microvesicles in alpha TC6
      cells, clonal alpha cells, and islet alpha cells. VGLUT1, another VGLUT isoform,
      is also expressed and localized in secretory granules in alpha cells. Low glucose
      conditions triggered co-secretion of stoichiometric amounts of L-glutamate and
      glucagon from alpha TC6 cells and isolated islets, which is dependent on
      temperature and Ca(2+) and inhibited by phentolamine. Similar co-secretion of L
      glutamate and glucagon from islets was observed upon stimulation of beta
      adrenergic receptors with isoproterenol. Under low glucose conditions,
      stimulation of glutamate receptors facilitates secretion of gamma-aminobutyric
      acid from MIN6 m9, clonal beta cells, and isolated islets. These results indicate
      that co-secretion of L-glutamate and glucagon from alpha cells under low glucose
      conditions triggers GABA secretion from beta cells and defines the mode of action
      of L-glutamate as a regulatory molecule for the endocrine function. To our
      knowledge, this is the first example of secretory granule-mediated glutamatergic
      signal transmission.

PMID- 12414806
TI  - Identification and functional characterization of the novel BM-motif in the
      murine phosphoadenosine phosphosulfate (PAPS) synthetase.
AB  - PAPS synthetase (SK) catalyzes the two sequential reactions of phosphoadenosine
      phosphosulfate (PAPS) synthesis. A functional motif in the kinase domain of mouse
      SK, designated the BM-motif ((86) LDGDNhRxhh(N/S)(K/R)(97)), was defined in the
      course of identifying the brachymorphic (bm) defect. Sequence comparison and the
      secondary structure predicted for APS kinase suggest that the BM-motif consists
      of a DGD-turn sequence flanked by other conserved residues. Mutational analysis
      of the DGD-turn revealed that a flexible and neutral amino acid is preferred at
      residue 88, that negatively charged residues are strictly required at positions
      87 and 89, and that the active site is rigid. The reduction in kinase activity
      for all DGD-turn mutants, except G88A, was much less severe than the reduction in
      overall activity, indicating that the BM-motif may also be playing a role in
      adenosine phosphosulfate (APS) channeling. Two switch mutations, LD86DL and
      DN89ND, designed to test the positional constraints of Asp(87) and Asp(89),
      exhibited complete loss of both kinase and overall activities, while LD86DL also
      exhibited a significant (60%) loss of reverse sulfurylase activity, suggesting
      that this peptide region is interacting with the sulfurylase domain as well as
      functioning in the kinase reaction. Other residues targeted for mutational
      analysis were the highly conserved flanking Asn(90), Arg(92), and Lys(97). N90A
      resulted in a partial (30%) loss in kinase and overall activities, R92A exhibited
      total loss of kinase and overall activities, and K97A had no effect on any of the
      three activities. The complexity of the bifunctional SK in catalyzing the kinase
      reaction and channeling APS is illustrated by the strict requirements of this
      novel structural motif in the kinase active site.

PMID- 12414807
TI  - AMY-1 interacts with S-AKAP84 and AKAP95 in the cytoplasm and the nucleus,
      respectively, and inhibits cAMP-dependent protein kinase activity by preventing
      binding of its catalytic subunit to A-kinase-anchoring protein (AKAP) complex.
AB  - We have reported that a novel c-Myc-binding protein, AMY-1, binds to cAMP
      dependent protein kinase-anchoring protein 149 (AKAP149) and its splicing
      variant, AKAP84 and is localized in the mitochondria in a complex with RII, a
      regulatory subunit of cAMP-dependent protein kinase (PKA) (Furusawa, M., Ohnishi,
      T., Taira, T., Iguchi-Ariga, S. M. M., and Ariga, H. (2001) J. Biol. Chem. 276,
      36647-36651). In this study, we further found that AMY-1 competitively bound to
      either AKAP95 or AKAP84 in the nucleus and the cytoplasm, respectively, in a
      concentration-dependent manner of either AKAP. Like AKAP84, AMY-1 was found to
      bind to the RII-binding region of AKAP95 in vivo and in vitro and to make a
      ternary complex with RII. It was also found that the formation of the complex of
      AMY-1 with AKAP84/95 and RII prevented a catalytic subunit from binding to this
      AKAP complex, leading to suppression of PKA activity. These findings suggest that
      AMY-1 is an important modulator of PKA.

PMID- 12414808
TI  - A thermally sensitive loop in clostridial glutamate dehydrogenase detected by
      limited proteolysis.
AB  - The structural flexibility and thermostability of glutamate dehydrogenase (GDH)
      from Clostridium symbiosum were examined by limited proteolysis using three
      proteinases with different specificities, trypsin, chymotrypsin, and
      endoproteinase Glu-C. Clostridial GDH resisted proteolysis by any of these
      enzymes at 25 degrees C. Above 30 degrees C, however, GDH became cleavable by
      chymotrypsin, apparently at a single site. SDS-PAGE indicated the formation of
      one large fragment with a molecular mass of approximately 44 kDa and one small
      one of <10 kDa. Proteolysis was accompanied by the loss of enzyme activity, which
      outran peptide cleavage, suggesting a cooperative conformational change.
      Proteolysis was prevented by either of the substrates 2-oxoglutarate or l
      glutamate but not by the coenzymes NAD(+) or NADH. Circular dichroism
      spectroscopy indicated that the protective effects of these ligands resulted from
      fixation of flexible regions of the native structure of the enzyme. Size
      exclusion chromatography and SDS-PAGE studies of chymotrypsin-treated GDH showed
      that the enzyme retained its hexameric structure and all of its proteolytic
      fragments. However, circular dichroism spectroscopy and analytical
      ultracentrifugation showed global conformational changes affecting the overall
      compactness of the protein structure. Chymotrypsin-catalyzed cleavage also
      diminished the thermostability of GDH and the cooperativity of the transition
      between its native and denatured states. N-terminal amino acid sequencing and
      mass spectrometry showed that heat-induced sensitivity to chymotrypsin emerged in
      the loop formed by residues 390-393 that lies between helices alpha(15) and
      alpha(16) in the folded structure of the enzyme.

PMID- 12414809
TI  - Structural divergence of human ghrelin. Identification of multiple ghrelin
      derived molecules produced by post-translational processing.
AB  - Ghrelin, a novel 28-amino acid peptide with an n-octanoyl modification at Ser(3),
      was isolated from rat stomach and found to be an endogenous ligand for the growth
      hormone secretagogue receptor (GHS-R). This octanoyl modification is essential
      for ghrelin-induced GH release. We report here the purification and
      identification of human ghrelin from the stomach, as well as structural analysis
      of the human ghrelin gene and quantitation of changes in plasma ghrelin
      concentration before and after gastrectomy. Human ghrelin was purified from the
      stomach by gel filtration and high performance liquid chromatography, using a
      ghrelin-specific radioimmunoassay and an intracellular calcium influx assay on a
      stable cell line expressing GHS-R to test the fractions. In the course of
      purification, we isolated human ghrelin of the expected size, as well as several
      other ghrelin-derived molecules. Classified into four groups by the type of
      acylation observed at Ser(3); these peptides were found to be non-acylated,
      octanoylated (C8:0), decanoylated (C10:0), and possibly decenoylated (C10:1). All
      peptides found were either 27 or 28 amino acids in length, the former lacking the
      C-terminal Arg(28), and are derived from the same ghrelin precursor through two
      alternative pathways. The major active form of human ghrelin is a 28-amino acid
      peptide octanoylated at Ser(3), as was found for rat ghrelin. Synthetic
      octanoylated and decanoylated ghrelins produce intracellular calcium increases in
      GHS-R-expressing cells and stimulate GH release in rats to a similar degree. Both
      ghrelin and the ghrelin-derived molecules were found to be present in plasma as
      well as stomach tissue. Plasma levels of immunoreactive ghrelin after total
      gastrectomy in three patients were reduced to approximately half of their pre
      gastrectomy values, after which they gradually increased. This suggests that the
      stomach is the major source of circulating ghrelin and that other tissues
      compensate for the loss of ghrelin production after gastrectomy.

PMID- 12414810
TI  - Stromal cell-derived factor-1alpha induces tube-like structure formation of
      endothelial cells through phosphoinositide 3-kinase.
AB  - Stromal cell-derived factor-1alpha (SDF-1alpha) is a CXC chemokine, which induces
      tube formation of endothelial cells. Although SDF-1alpha transduces signals via
      CXC receptor 4 (CXCR4), resulting in activating a panel of downstream signaling
      molecules, such as phosphoinositide 3-kinase (PI3-kinase), little is known about
      the SDF-1alpha-mediated signaling pathways leading to tube formation. Here we
      examined the signal transduction pathway involved in SDF-1alpha-mediated tube
      formation by primary human umbilical endothelial cells and murine brain capillary
      endothelial cell line (IBE (immortalized murine brain capillary endothelial)
      cells). SDF-1alpha stimulated tube formation by IBE cells, which was blocked by
      LY294002 and pertussis toxin, suggesting that PI3-kinase and G(i) protein were
      involved in this process. SDF-1 also stimulated tube formation of human umbilical
      endothelial cells, and the response was LY294002-sensitive. SDF-1alpha activated
      PI3-kinase in IBE cells. In stable IBE cell lines expressing either the mutant
      p85 subunit of PI3-kinase (denoted Deltap85-8 cells), which lacks association
      with the p110 subunit, or kinase-inactive c-Fes (denoted KEFes 5-15 cells), SDF
      1alpha failed to activate PI3-kinase and to stimulate tube formation. SDF-1alpha
      induced tube formation was inhibited by an antibody against murine vascular
      endothelial cadherin. The antibody as well as LY294002 attenuated SDF-1alpha
      mediated compact cell-cell contact, which proceeded to tube formation. Taken
      together, SDF-1alpha induces compact cell-cell contact through PI3-kinase,
      resulting in tube formation of endothelial cells.

PMID- 12414811
TI  - Subunit gamma-green fluorescent protein fusions are functionally incorporated
      into mitochondrial F1F0-ATP synthase, arguing against a rigid cap structure at
      the top of F1.
AB  - We have investigated the question of the presence of a cap structure located at
      the top of the F(1) alpha(3)beta(3) hexamer of the yeast mitochondrial F(1)F(0)
      ATP synthase complex. Specifically, we sought to determine whether the putative
      cap has a rigid structure and occludes the central shaft space formed by the
      alpha(3)beta(3) hexamer or alternatively whether the cap is more flexible
      permitting access to the central shaft space under certain conditions. Thus, we
      sought to establish whether subunit gamma, an essential component of the F(1)
      central stalk housed within the central shaft space and whose N and C termini
      would both lie beneath a putative cap, could be fused at its C terminus to green
      fluorescent protein (GFP) without loss of enzyme function. The GFP moiety serves
      to report on the integrity and location of fusion proteins containing different
      length polypeptide linkers between GFP and subunit gamma, as well as being a
      potential occluding structure in itself. Functional incorporation of subunit
      gamma-GFP fusions into ATP synthase of yeast cells lacking native subunit gamma
      was demonstrated by the ability of intact complexes to hydrolyze ATP and retain
      sensitivity to oligomycin. Our conclusion is that the putative cap structure
      cannot be an inflexible structure, but must be of a more flexible nature
      consistent with the accommodation of subunit gamma-GFP fusions within functional
      ATP synthase complexes.

PMID- 12414812
TI  - Aplidin induces apoptosis in human cancer cells via glutathione depletion and
      sustained activation of the epidermal growth factor receptor, Src, JNK, and p38
      MAPK.
AB  - We report that Aplidin, a novel antitumor agent of marine origin presently
      undergoing Phase II clinical trials, induced growth arrest and apoptosis in human
      MDA-MB-231 breast cancer cells at nanomolar concentrations. Aplidin induced a
      specific cellular stress response program, including sustained activation of the
      epidermal growth factor receptor (EGFR), the non-receptor protein-tyrosine kinase
      Src, and the serine/threonine kinases JNK and p38 MAPK. Aplidin-induced apoptosis
      was only partially blocked by the general caspase inhibitor benzyloxycarbonyl-VAD
      fluoromethyl ketone and was also sensitive to AG1478 (an EGFR inhibitor), PP2 (an
      Src inhibitor), and SB203580 (an inhibitor of JNK and p38 MAPK) in MDA-MB-231
      cells. Supporting a role for EGFR in Aplidin action, EGFR-deficient mouse embryo
      fibroblasts underwent apoptosis upon treatment more slowly than wild-type EGFR
      fibroblasts and also showed delayed JNK and reduced p38 MAPK activation. N
      Acetylcysteine and ebselen (but not other antioxidants such as
      diphenyleneiodonium, Tiron, catalase, ascorbic acid, and vitamin E) reduced EGFR
      activation by Aplidin. N-Acetylcysteine and PP2 also partially inhibited JNK and
      p38 MAPK activation. The intracellular level of GSH affected Aplidin action;
      pretreatment of cells with GSH or N-acetylcysteine inhibited, whereas GSH
      depletion caused, hyperinduction of EGFR, Src, JNK, and p38 MAPK. Remarkably,
      Aplidin also induced apoptosis and activated EGFR, JNK, and p38 MAPK in two cell
      lines (A-498 and ACHN) derived from human renal cancer, a neoplasia that is
      highly refractory to chemotherapy. These data provide a molecular basis for the
      anticancer activity of Aplidin.

PMID- 12414813
TI  - The p75 neurotrophin receptor interacts with multiple MAGE proteins.
AB  - The p75 neurotrophin receptor has been implicated in diverse aspects of
      neurotrophin signaling, but the mechanisms by which its effects are mediated are
      not well understood. Here we identify two MAGE proteins, necdin and MAGE-H1, as
      interactors for the intracellular domain of p75 and show that the interaction is
      enhanced by ligand stimulation. PC12 cells transfected with necdin or MAGE-H1
      exhibit accelerated differentiation in response to nerve growth factor.
      Expression of these two MAGE proteins is predominantly cytoplasmic in PC12 cells,
      and necdin was found to be capable of homodimerization, suggesting that it may
      act as a cytoplasmic adaptor to recruit a signaling complex to p75. These
      findings indicate that diverse MAGE family members can interact with the p75
      receptor and highlight type II MAGE proteins as a potential family of interactors
      for signaling proteins containing type II death domains.

PMID- 12414815
TI  - Screening for microsatellite instability target genes in colorectal cancers.
AB  - BACKGROUND: Defects in the DNA repair system lead to genetic instability because
      replication errors are not corrected. This type of genetic instability is a key
      event in the malignant progression of HNPCC and a subset of sporadic colon
      cancers and mutation rates are particularly high at short repetitive sequences.
      Somatic deletions of coding mononucleotide repeats have been detected, for
      example, in the TGFbetaRII and BAX genes, and recently many novel target genes
      for microsatellite instability (MSI) have been proposed. Novel target genes are
      likely to be discovered in the future. More data should be created on background
      mutation rates in MSI tumours to evaluate mutation rates observed in the
      candidate target genes. METHODS: Mutation rates in 14 neutral intronic repeats
      were evaluated in MSI tumours. Bioinformatic searches combined with keywords
      related to cancer and tumour suppressor or CRC related gene homology were used to
      find new candidate MSI target genes. By comparison of mutation frequencies
      observed in intronic mononucleotide repeats versus exonic coding repeats of
      potential MSI target genes, the significance of the exonic mutations was
      estimated. RESULTS: As expected, the length of an intronic mononucleotide repeat
      correlated positively with the number of slippages for both G/C and A/T repeats
      (p=0.0020 and p=0.0012, respectively). BRCA1, CtBP1, and Rb1 associated CtIP and
      other candidates were found in a bioinformatic search combined with keywords
      related to cancer. Sequencing showed a significantly increased mutation rate in
      the exonic A9 repeat of CtIP (25/109=22.9%) as compared with similar intronic
      repeats (p< or =0.001). CONCLUSIONS: We propose a new candidate MSI target gene
      CtIP to be evaluated in further studies.

PMID- 12414816
TI  - High throughput screening of human subtelomeric DNA for copy number changes using
      multiplex amplifiable probe hybridisation (MAPH).
AB  - BACKGROUND: Subtelomeric regions of the human genome are gene rich, with a high
      level of sequence polymorphism. A number of clinical conditions, including
      learning disability, have been attributed to subtelomeric deletions or
      duplications, but screening for deletion in these regions using conventional
      cytogenetic methods and fluorescence in situ hybridisation (FISH) is laborious.
      Here we report that a new method, multiplex amplifiable probe hybridisation
      (MAPH), can be used to screen for copy number at subtelomeric regions. METHODS:
      We have constructed a set of MAPH probes with each subtelomeric region
      represented at least once, so that one gel lane can assay copy number at all
      chromosome ends in one person. Each probe has been sequenced and, where possible,
      its position relative to the telomere determined by comparison with mapped
      clones. RESULTS: The sensitivity of the probes has been characterised on a series
      of cytogenetically verified positive controls and 83 normal controls were used to
      assess the frequency of polymorphic copy number with no apparent phenotypic
      effect. We have also used MAPH to test a cohort of 37 people selected from males
      referred for fragile X syndrome testing and found six changes that were confirmed
      by dosage PCR. CONCLUSIONS: MAPH can be used to screen subtelomeric regions of
      chromosomes for deletions and duplications before confirmation by FISH or dosage
      PCR. The high throughput nature of this technique allows it to be used for large
      scale screening of subtelomeric copy number, before confirmation by FISH. In
      practice, the availability of a rapid and efficient screen may allow subtelomeric
      analysis to be applied to a wider selection of patients than is currently
      possible using FISH alone.

PMID- 12414817
TI  - Novel ATP6V1B1 and ATP6V0A4 mutations in autosomal recessive distal renal tubular
      acidosis with new evidence for hearing loss.
AB  - Autosomal recessive distal renal tubular acidosis (rdRTA) is characterised by
      severe hyperchloraemic metabolic acidosis in childhood, hypokalaemia, decreased
      urinary calcium solubility, and impaired bone physiology and growth. Two types of
      rdRTA have been differentiated by the presence or absence of sensorineural
      hearing loss, but appear otherwise clinically similar. Recently, we identified
      mutations in genes encoding two different subunits of the renal alpha
      intercalated cell's apical H(+)-ATPase that cause rdRTA. Defects in the B1
      subunit gene ATP6V1B1, and the a4 subunit gene ATP6V0A4, cause rdRTA with
      deafness and with preserved hearing, respectively. We have investigated 26 new
      rdRTA kindreds, of which 23 are consanguineous. Linkage analysis of seven novel
      SNPs and five polymorphic markers in, and tightly linked to, ATP6V1B1 and
      ATP6V0A4 suggested that four families do not link to either locus, providing
      strong evidence for additional genetic heterogeneity. In ATP6V1B1, one novel and
      five previously reported mutations were found in 10 kindreds. In 12 ATP6V0A4
      kindreds, seven of 10 mutations were novel. A further nine novel ATP6V0A4
      mutations were found in "sporadic" cases. The previously reported association
      between ATP6V1B1 defects and severe hearing loss in childhood was maintained.
      However, several patients with ATP6V0A4 mutations have developed hearing loss,
      usually in young adulthood. We show here that ATP6V0A4 is expressed within the
      human inner ear. These findings provide further evidence for genetic
      heterogeneity in rdRTA, extend the spectrum of disease causing mutations in
      ATP6V1B1 and ATP6V0A4, and show ATP6V0A4 expression within the cochlea for the
      first time.

PMID- 12414818
TI  - De novo GLI3 mutation in acrocallosal syndrome: broadening the phenotypic
      spectrum of GLI3 defects and overlap with murine models.
AB  - Acrocallosal syndrome (ACS) is characterised by postaxial polydactyly, hallux
      duplication, macrocephaly, and absence of the corpus callosum, usually with
      severe developmental delay. The condition overlaps with Greig
      cephalopolysyndactyly syndrome (GCPS), an autosomal dominant disorder that
      results from mutations in the GLI3 gene. Here we report a child with agenesis of
      the corpus callosum and severe retardation, both cardinal features of ACS and
      rare in GCPS, who has a mutation in GLI3. Since others have excluded GLI3 in ACS,
      we suggest that ACS may represent a heterogeneous group of disorders that, in
      some cases, may result from a mutation in GLI3 and represent a severe, allelic
      form of GCPS. The finding is important for counselling families with suspected
      ACS.

PMID- 12414819
TI  - Two novel frameshift mutations in NKX2.5 result in novel features including
      visceral inversus and sinus venosus type ASD.

PMID- 12414820
TI  - Childhood onset mitochondrial myopathy and lactic acidosis caused by a stop
      mutation in the mitochondrial cytochrome c oxidase III gene.

PMID- 12414821
TI  - Bar code screening on combed DNA for large rearrangements of the BRCA1 and BRCA2
      genes in French breast cancer families.

PMID- 12414823
TI  - Family history of breast cancer as a determinant of the risk of developing
      endometrial cancer: a nationwide cohort study.

PMID- 12414822
TI  - Identification of novel CLN2 mutations shows Canadian specific NCL2 alleles.

PMID- 12414824
TI  - Genetic testing in hereditary non-polyposis colorectal cancer families with a
      MSH2, MLH1, or MSH6 mutation.

PMID- 12414826
TI  - Promoter polymorphisms in the CD14 receptor gene and their potential association
      with the severity of chronic periodontitis.

PMID- 12414825
TI  - Linkage to 18qter differentiates two clinically overlapping syndromes: congenital
      cataracts-facial dysmorphism-neuropathy (CCFDN) syndrome and Marinesco-Sjogren
      syndrome.

PMID- 12414827
TI  - Protein losing enteropathy-hepatic fibrosis syndrome in Saguenay-Lac St-Jean,
      Quebec is a congenital disorder of glycosylation type Ib.

PMID- 12414828
TI  - Severe digital abnormalities in a patient heterozygous for both a novel missense
      mutation in HOXD13 and a polyalanine tract expansion in HOXA13.

PMID- 12414830
TI  - Hereditary ovarian cancer resulting from a non-ovarian cancer cluster region
      (OCCR) BRCA2 mutation: is the OCCR useful clinically?

PMID- 12414829
TI  - Behavioural complaints in participants who underwent predictive testing for
      Huntington's disease.

PMID- 12414831
TI  - Continuous medical education approaches for clinical genetics: a postal survey of
      general practitioners.

PMID- 12414833
TI  - Monozygotic twins with chromosome 22q11 deletion and discordant phenotypes:
      updates with an epigenetic hypothesis.

PMID- 12414832
TI  - No association between HOXA1 and HOXB1 genes and autism spectrum disorders (ASD).

PMID- 12414834
TI  - Mosaicism for duplication 12q (12q13-->12q21.2) accompanied by a pericentric
      inversion in a dysmorphic female infant.

PMID- 12414835
TI  - Splice mutation 1811+1.6kbA>G causes severe cystic fibrosis with pancreatic
      insufficiency: report of 11 compound heterozygous and two homozygous patients.

PMID- 12414836
TI  - CYS127S (FH-Kairouan) and D245N (FH-Tozeur) mutations in the LDL receptor gene in
      Tunisian families with familial hypercholesterolaemia.

PMID- 12414837
TI  - Clinical review 153: Lipodystrophy in human immunodeficiency virus-infected
      patients.
AB  - Human immunodeficiency virus (HIV) infection is a major global health problem.
      Recently, combination therapy including HIV-1 protease inhibitors (PIs) has
      dramatically improved the long-term survival of HIV-infected patients. However,
      such therapy is associated with a lipodystrophy syndrome characterized by
      selective loss of sc fat from the face and extremities and, in some patients,
      accumulation of fat around the neck, dorsocervical region, abdomen, and trunk.
      Lipodystrophy in HIV-infected patients (LDHIV) is associated with insulin
      resistance and its metabolic complications such as impaired glucose tolerance,
      diabetes, hypertriglyceridemia and low serum high density lipoprotein cholesterol
      levels. PIs appear to be the strongest link to LDHIV; however, fat loss has been
      reported in some patients taking non-PI antiretroviral drugs. Other factors, such
      as duration of HIV infection, age, and gender, may also contribute to the risk of
      development of LDHIV. The molecular basis of LDHIV remains unknown. There is no
      specific therapy for LDHIV. Avoiding weight gain by reducing energy intake and
      increasing physical activity may be beneficial in reducing fat accumulation as
      well as improving metabolic complications. Antihyperglycemic drugs may be used to
      treat diabetes. Management of dyslipidemia may require lipid-lowering drugs;
      however, the safety and efficacy of such intervention require further studies.
      Substitution of PIs with other antiretroviral drugs can mitigate dyslipidemia and
      glucose intolerance, but whether reversal of lipodystrophy occurs remains
      unknown. Future research is needed to discover the biochemical and molecular
      markers of lipodystrophy in HIV patients and develop PIs or other antiretroviral
      agents that are free of metabolic toxicity.

PMID- 12414838
TI  - Advances in diagnosis and treatment of hyperinsulinism in infants and children.

PMID- 12414839
TI  - BPDZ 154 activates adenosine 5'-triphosphate-sensitive potassium channels: in
      vitro studies using rodent insulin-secreting cells and islets isolated from
      patients with hyperinsulinism.
AB  - A novel ATP-sensitive potassium channel (K(ATP)) channel agonist, BPDZ 154 (6,7
      dichloro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide), was
      synthesized, and its effects on insulin-secreting cells were evaluated using
      electrophysiology, (86)Rb(+) and (45)Ca(2+) efflux, and RIA determinations of
      insulin secretion. BPDZ 154, an analog of diazoxide, inhibited both glucose
      induced insulin secretion from isolated perifused islets and the secretion of
      insulin induced by glucose and tolbutamide. These effects were mediated by the
      activation of ATP-sensitive potassium channels because BPDZ 154 induced a
      concentration-dependent increase in channel activity that was inhibited by the
      sulfonylurea tolbutamide and the imidazoline efaroxan. In beta-cells isolated
      from patients with either nontypical hyperinsulinism (preserved K(ATP) channel
      function) or from the control areas of the pancreas of patients with focal
      hyperinsulinism, BPDZ 154 activated K(ATP) channels and was found to be more
      effective and less readily reversible than diazoxide. By contrast, it was not
      possible to activate K(ATP) channels by either diazoxide or BPDZ 154 in beta
      cells from patients with hyperinsulinism as a consequence of defects in K(ATP)
      channel function. In beta-cells isolated from a patient with pancreatic
      insulinoma, K(ATP) channels were readily recorded and modulated by BPDZ 154.
      These data suggest that BPDZ 154 or BPDZ 154-like compounds may have therapeutic
      potential in the treatment of certain forms of hyperinsulinism.

PMID- 12414840
TI  - Adrenal incidentaloma--a modern disease with old complications.

PMID- 12414841
TI  - Patients with subclinical Cushing's syndrome due to adrenal adenoma have
      increased cardiovascular risk.
AB  - Subclinical Cushing's syndrome (SCS) is increasingly being reported in
      incidentally discovered adrenal adenomas; its hallmark is mild autonomous
      cortisol hyperproduction without specific clinical signs of cortisol excess.
      Increased prevalence of hypertension, obesity, and impaired glucose tolerance
      have been described in SCS, but there is no specific study of the risk factors
      for cardiovascular diseases. In this cross-sectional study we assessed the
      cardiovascular profile in 28 consecutive SCS patients (19 women and 9 men; aged
      56 +/- 10.6 yr) compared with 100 controls matched for age, gender, and body mass
      index. Systolic (P < 0.001) and diastolic (P < 0.005) blood pressures were higher
      in patients, as were fasting glucose, insulin, total cholesterol, triglycerides
      (all P < 0.001), and fibrinogen (P < 0.05). Moreover, the insulin resistance
      index was increased in patients as was the waist to hip ratio and mean carotid
      artery intima-media thickness (all P < 0.001). Of the patients, 60.7% had
      arterial hypertension, 71.4% had lipid abnormalities, 28.6% had impaired glucose
      tolerance, 35.7% type 2 diabetes mellitus, and 53.6% had abnormalities in
      hemostatic parameters. Atherosclerotic plaques were more frequent in patients (P
      < 0.0001). Only 4 (14.3%) patients did not have multiple risk factors for
      cardiovascular events. Six (21.3%) had clinical evidence of cardiovascular
      disease; another 11 (39.3%) had cardiovascular abnormalities as revealed by
      ultrasound scanning of carotid arteries and/or electrocardiogram records. These
      results strongly suggest that an increased cardiovascular risk profile, similar
      to that described in overt Cushing's syndrome, is present in SCS subjects. This
      finding supports the concept that chronic mild endogenous cortisol excess may
      have important systemic effects on the human body.

PMID- 12414842
TI  - Channel surfing.

PMID- 12414843
TI  - A mutation in the KCNE3 potassium channel gene is associated with susceptibility
      to thyrotoxic hypokalemic periodic paralysis.
AB  - Hypokalemic Periodic Paralyses comprise diverse diseases characterized by acute
      and reversible attacks of severe muscle weakness, associated with low serum
      potassium. The most common causes are Familial Hypokalemic Periodic Paralysis
      (FHypoKPP), an autosomal dominant disease, and Thyrotoxic Hypokalemic Periodic
      Paralysis (THypoKPP), secondary to thyrotoxicosis. Symptoms of paralysis are
      similar in both diseases, distinguished by thyrotoxicosis present in THypoKPP.
      FHypoKPP is caused by mutations in ionic channel genes calcium (CACN1AS), sodium
      (SCN4A) and potassium (KCNE3). Since both diseases are similar, we tested the
      hypothesis that THypoKPP could carry the same mutations described in FHypoKPP,
      being the paralysis a genetically conditioned complication of thyrotoxicosis. In
      15 patients with THypoKPP, using target-exon PCR, CSGE screening, and direct
      sequencing, we excluded known mutations in CACN1AS and SCN4A genes. On the other
      hand, we were able to identify the R83H mutation in the KCNE3 gene in one
      sporadic case of THypoKPP, a man who had been asymptomatic until developing
      thyrotoxicosis caused by Graves' disease; we confirmed the disease-causing
      mutation in 2 of 3 descendants. R83H was recently found in two FHypoKPP unrelated
      families, in which the mutant decreased outward potassium flux, resulting in a
      more positive resting membrane potential. We, therefore, identified the first
      genetic defect in THypoKPP, a mutation in the KCNE3 gene.

PMID- 12414844
TI  - Ghrelin expression in islet cell tumors: augmented expression of ghrelin in a
      case of glucagonoma with multiple endocrine neoplasm type I.
AB  - Ghrelin is a 28-amino acid peptide that regulates GH release together with GHRH
      and somatostatin. The expression of ghrelin has been detected in the stomach,
      small intestine, hypothalamus, pituitary gland, kidney, placenta, and testis.
      Recently it was reported that ghrelin is present in pancreatic alpha-cells and
      that it stimulates insulin secretion. In this study, we examined the ghrelin
      expression in two cases of glucagonoma and two cases of insulinoma by Northern
      blot analysis and immunohistochemistry. Ghrelin expression was identified in a
      case of glucagonoma associated with multiple endocrine neoplasm type I both by
      Northern blot analysis using total RNA and by immunohistochemistry, although the
      plasma ghrelin level was not elevated. This is the first case of tumor in which
      ghrelin gene expression was detected by Northern blot analysis using total RNA.

PMID- 12414845
TI  - Insulinoma in chronic renal failure: a case report.
AB  - The diagnosis of insulinoma depends on the fulfillment of well-established
      criteria during the 72-h fast. However, these criteria rely on normal renal
      function. Spontaneous hypoglycemia that is not attributable to insulinoma may
      occur in persons with renal failure. We describe herein a patient with renal
      impairment who had undergone renal transplant and had a 20-yr history of
      hypoglycemic symptoms and successful resection of insulinoma. Although the
      results of a 72-h fast were consistent with endogenous hyperinsulinemia, their
      interpretation was complicated in the presence of renal impairment. Fortunately,
      the identification of the tumor, by endoscopic ultrasonograph, led to a correct
      diagnosis. This case seems to be the second report of a patient with insulinoma
      with concomitant renal failure.

PMID- 12414846
TI  - Risk factors for cerebrovascular deaths in patients operated and irradiated for
      pituitary tumors.
AB  - Vascular mortality, especially cerebrovascular disease (CVD), are the most
      pronounced cause of mortality in women with hypopituitarism. In a cohort of 342
      patients operated and irradiated for pituitary tumors, 31 died from CVD (CVD
      patients) between 1952 and 1996. The study assessed whether the radiation
      regimens and duration of symptoms of hypopituitarism before operation differed
      between the 31 CVD patients and the 62 matched patients from the same cohort who
      had not died from CVD (control patients). Furthermore, the infarction/hemorrhage
      ratio, type of clinical stroke syndrome, and time to death after stroke were
      investigated in the CVD patients and in matched controls from the general
      population who had died from CVD (population controls). No significant
      differences in maximum or centrally absorbed dose, maximum or central biological
      equivalent dose, field size, or number of fraction were recorded between CVD and
      control patients. A significant difference in the duration of symptoms of
      hypopituitarism before operation was recorded, but only in women (P = 0.01).
      There were no significant differences in the infarction/hemorrhage ratio (P >
      0.3) of lacunar or posterior circulation syndrome compared with middle cerebral
      artery syndrome with cortical features (P = 0.22) or the proportion of patients
      who died within the first month after stroke onset (60% vs. 59%, respectively)
      between CVD patients and population controls. In conclusion, no significant
      effect on CVD deaths could be detected for any radiation parameter. A long
      history of unsubstituted pituitary insufficiency may be a contributing factor to
      the very high CVD mortality among women. There were no indications of significant
      differences in type of stroke, clinical stroke syndromes, or stroke fatality
      between the CVD patients and the population controls.

PMID- 12414848
TI  - Two years of treatment with recombinant human growth hormone increases bone
      mineral density in men with idiopathic osteoporosis.
AB  - We have investigated the effects of GH treatment on bone turnover, bone size,
      bone mineral density (BMD), and bone mineral content (BMC) in 29 men, 27-62 yr
      old, with idiopathic osteoporosis. The patients were randomly assigned to
      treatment with GH, either as continuous treatment with daily injections of 0.4 mg
      GH/d (group A, n = 14) or as intermittent treatment with 0.8 mg GH/d for 14 d
      every 3 months (group B, n = 15). All patients were treated with GH for 24
      months, with a follow-up period of 12 months, and also received 500 mg calcium
      and 400 U vitamin D3 daily during all 36 months. Fasting morning urine and serum
      samples were obtained for assay of IGF-I, bone markers, and routine laboratory
      tests at baseline, after 1, 12, 24, and 36 months. Body composition, BMD, and BMC
      were determined by dual-energy x-ray absorptiometry at baseline and every 6
      months. After 2 yr, there was an increase in BMD in lumbar spine (by 4.1%) in
      group A, and in total body (by 2.6%) in group A and (by 2.7%) in group B. BMC of
      the total body and lean body mass increased, whereas fat mass decreased in both
      treatment groups. After 36 months, the BMD and BMC in lumbar spine and total body
      had increased further in both groups. We conclude that 2 yr of intermittent or
      continuous treatment with GH in men with idiopathic osteoporosis results in an
      increase in BMD and BMC that is sustained for at least 1 yr post treatment.

PMID- 12414849
TI  - The effect of micronized estradiol on bone turnover and calciotropic hormones in
      older men receiving hormonal suppression therapy for prostate cancer.
AB  - To examine the effect of estradiol (E(2)) without the confounding effect of
      hypothalamic-pituitary feedback, we studied men with prostate cancer in whom
      gonadotropin secretion was suppressed by LH-releasing hormone agonists (LHRH-A).
      Fourteen men over 65 yr of age and receiving established LHRH-A treatment (EST
      group) without bony metastases and 12 men who received LHRH-A as neoadjuvant
      therapy for locally advanced prostate cancer (NEO group) were randomized (double
      blind) to receive either 1 mg/d micronized E(2) (n = 12) or placebo (PL; n = 13)
      for 9 wk. E(2), estrone, testosterone, SHBG, PTH, and 25-hydroxy- and 1,25
      dihydroxyvitamin D levels as well as markers of bone resorption [N- and C
      telopeptide cross-links (NTX and CTX) and deoxypyridinoline] and bone formation
      (bone-specific alkaline phosphatase, osteocalcin, and N-terminal type I collagen)
      were measured before LHRH-A in the NEO group, before [baseline (BL)] and after 9
      wk of E(2) or PL in all patients, and 6 wk after E(2) treatment in the EST group.
      In the NEO group, hormone levels fell 3 wk after the initial LHRH-A injection,
      and deoxypyridinoline increased significantly (P = 0.006). At BL, the EST group
      had higher bone turnover due to the longer duration of LHRH-A treatment. With
      E(2) treatment, E(2) levels rose into the normal male range, and two resorption
      markers decreased significantly from BL by 33% for NTX (P < 0.001) and 28% for
      CTX (P = 0.009). Bone formation markers did not change. PTH increased by 43% from
      BL (P < 0.01) in the E(2) group and decreased 16% from BL in the PL group (P <
      0.01). Ionized calcium did not change in the E(2) group, but increased in the PL
      group by 2.3% (P < 0.01). NTX and CTX increased 6 wk after E(2) withdrawal in the
      EST group. We conclude that E(2) inhibits bone resorption in hypogonadal men
      through a direct skeletal effect that is independent of PTH. Low dose estrogen
      may be an option for the prevention and/or treatment of bone loss in this
      population.

PMID- 12414850
TI  - Effect of discontinuation of estrogen, calcitriol, and the combination of both on
      bone density and bone markers.
AB  - In a 5-yr randomized prospective study we examined the treatment effect of
      estrogen replacement therapy/hormone replacement therapy (ERT/HRT), calcitriol,
      ERT/HRT and calcitriol, or placebo for 3 yr and the effect of discontinuation of
      therapy for 2 more yr on bone mineral density (BMD), calciotropic hormones,
      markers of bone remodeling, and calcium absorption in 489 elderly women. The
      treatment phase of the study was double-blinded. After discontinuing therapy for
      2 yr, there was rapid bone loss in all 3 treatment groups, and most of the
      decrease in BMD occurred in the first year. In the ERT/HRT group, spine BMD
      increased 5.5% in yr 3, decreased 3.2% in yr 4, and decreased 0.7% in yr 5;
      femoral neck BMD increased 3.7% in yr 3, decreased 2.5% in yr 4, and decreased
      0.4% in yr 5; total body BMD increased 2.1% in yr 3, decreased 1.4% in yr 4, and
      decreased 0.6% in yr 5. In the combination group, spine BMD increased 7.1% in yr
      3, decreased 4.3% in yr 4, and decreased 0.3% in yr 5; femoral neck BMD increased
      4.5% in yr 3, decreased 3.0% in yr 4, and decreased 0.01% in yr 5; total body BMD
      increased 2.2% in yr 3, decreased 1.5% in yr 4, and decreased 0.6% in yr 5. In
      the calcitriol group, spine BMD increased 1.8% in yr 3, decreased 1.8% in yr 4,
      and showed no change in yr 5; femoral neck BMD increased 0.2% in yr 3, decreased
      0.2% in yr 4, and decreased 0.6% in yr 5; total body BMD decreased 0.4% in yr 3,
      decreased 0.6% in yr 4, and decreased 0.4% in yr 5. Compared with placebo, all
      treated groups at yr 5 had significantly higher total body BMD; only the
      combination group had significantly higher spine BMD (3.4%; P < 0.001) and total
      hip BMD (2.4%; P < 0.01.) compared with the placebo group. Compared with
      baseline, only spine BMD in the combination group was significantly higher (2.6%;
      P < 0.001) at yr 5. The increase in calcium absorption and the decrease in serum
      PTH levels in the calcitriol groups were reversed after discontinuation of
      treatment, and the decrease in bone markers was reversed in the hormone-treated
      groups. These results suggest that discontinuation of ERT/HRT and/or calcitriol
      therapy in elderly women leads to a decrease in much of the BMD gained on
      treatment; however, in the combination group there was a statistically
      significant residual effect on spine BMD.

PMID- 12414851
TI  - Assessment of nondiagnostic ultrasound-guided fine needle aspirations of thyroid
      nodules.
AB  - Thyroid nodules are common. Evaluation of patients with thyroid nodules typically
      includes fine needle aspiration biopsy (FNA), an approach that has proven to be
      accurate for the detection of thyroid cancer. Although the majority of biopsies
      are adequate for a cytological diagnosis, up to 20% will be insufficient or
      nondiagnostic. Current opinion suggests that such aspirates should be repeated,
      although no systematic study has investigated the usefulness of this approach,
      especially when ultrasound guidance is used to direct the initial FNA. We sought
      to define the predictors and optimal follow-up strategy for initial nondiagnostic
      ultrasound-guided FNAs of thyroid nodules. Data were collected for all patients
      at the Brigham and Women's Hospital Thyroid Nodule Clinic between 1995-2000 who
      underwent ultrasound-guided FNA of a thyroid nodule. All patients with
      nondiagnostic cytology were advised to return for a repeat ultrasound-guided FNA.
      Patient age, gender, nodule size, cystic content, solitary vs. multinodular
      thyroid, and nodule location were documented and evaluated as possible predictors
      of a nondiagnostic biopsy in a multivariable model. The rate of diagnostic
      cytology obtained on repeat ultrasound-guided FNA was calculated. A total of 1128
      patients with 1458 nodules were biopsied over a 6-yr period. A total of 1269
      aspirations (950 patients) were diagnostic, and 189 (178 patients) were
      nondiagnostic. The cystic content of each nodule was the only significant
      independent predictor of nondiagnostic cytology (P < 0.001). The fraction of
      specimens with initial nondiagnostic cytology increased with greater cystic
      content (P < 0.001 for trend). A diagnostic ultrasound-guided FNA was obtained on
      the first repeat biopsy in 63% of nodules and was inversely related to increasing
      cystic content of each nodule (P = 0.03). One hundred and nineteen patients with
      127 nodules returned for follow-up as advised, and malignancy was documented in
      5%. Despite ultrasound-guided FNA, there remains a significant risk of initial
      nondiagnostic cytology, largely predicted by the cystic content of each nodule.
      Repeat aspiration is often successful and should be the standard approach to such
      nodules, given their risk of malignancy.

PMID- 12414852
TI  - Effects of thyroid-stimulating hormone suppression with levothyroxine in reducing
      the volume of solitary thyroid nodules and improving extranodular nonpalpable
      changes: a randomized, double-blind, placebo-controlled trial by the French
      Thyroid Research Group.
AB  - The efficacy of suppressing TSH secretion with levothyroxine (L-T(4)) in reducing
      solitary thyroid nodule growth is still controversial. In this prospective
      multicenter, randomized, double-blind, placebo-controlled trial, 123 patients
      with a single palpable benign nodule were included and randomly allocated to an
      18-month treatment with L-T(4) or placebo. Individual dose was adjusted to allow
      a serum TSH level below 0.3 mIU/liter. Clinical and ultrasonographic nodule
      characteristics were assessed before treatment and 3, 6, 12, and 18 months
      thereafter. The largest mean nodule size assessed on palpation and largest
      volume, assessed by ultrasonography, decreased in the L-T(4) group and increased
      slightly in the placebo group [size, -3.5 +/- 7 mm vs. +0.5 +/- 6 mm (P = 0.006);
      volume, -0.36 +/- 1.71 ml vs. +0.62 +/- 3.67 ml (P = 0.01), respectively]. The
      proportion of clinically relevant volume reduction (> or =50%) rose significantly
      in the L-T(4) group [26.6% vs. 16.9% (P = 0.04)]. The proportion of patients with
      a reduced number of infraclinical additional nodules was significantly higher in
      the L-T(4) group [9.4% vs. 0 (P = 0.04)]. It is concluded from this study that
      suppressive L-T(4) therapy is effective in reducing solitary thyroid nodule
      volume and improving infraclinical extranodular changes.

PMID- 12414853
TI  - Effects of oral dehydroepiandrosterone on bone density in young women with
      anorexia nervosa: a randomized trial.
AB  - Young women with anorexia nervosa (AN) have subnormal levels of
      dehydroepiandrosterone (DHEA) and estrogen that may be mechanistically linked to
      the bone loss seen in this disease. The purpose of this study was to compare the
      effects of a 1-yr course of oral DHEA treatment vs. conventional hormonal
      replacement therapy (HRT) in young women with AN. Sixty-one young women were
      randomly assigned to receive oral DHEA (50 mg/d) or HRT (20 micro g ethinyl
      estradiol/0.1 mg levonorgestrel). Anthropometric, nutrition, and exercise data
      were acquired every 3 months, and bone mineral density (BMD) and body composition
      were measured by dual energy x-ray absorptiometry (DXA) every 6 months over 1 yr.
      Serum samples were obtained for measurements of hormones, proresorptive
      cytokines, and bone formation markers, and urine was collected for determinations
      of bone resorption markers at each visit. In initial analyses, total hip BMD
      increased significantly and similarly (+1.7%) in both groups. Hip BMD increases
      were positively correlated with increases in IGF-I (r = 0.44; P = 0.030) and the
      bone formation marker, bone-specific alkaline phosphatase increased significantly
      only in the DHEA treatment group (P = 0.003). However, both groups gained
      significant amounts of weight over the year of therapy, and after controlling for
      weight gain, no treatment effect was detectable. There was no significant change
      in lumbar BMD in either group. Both bone formation markers, bone-specific
      alkaline phosphatase and osteocalcin, increased transiently at 6-9 months in
      those subjects receiving DHEA compared with the estrogen-treated group (P <
      0.05). Both DHEA and HRT significantly reduced levels of the bone resorption
      markers, urinary N-telopeptides (P < 0.05). There was a positive correlation
      between changes in IGF-I and changes in weight, body fat determined by DXA, and
      estradiol for both groups. In addition, patients receiving DHEA exhibited
      improvement on three validated psychological instruments (Eating Attitudes Test,
      Anorexia Nervosa Subtest, and Spielberger Anxiety Inventory). Both DHEA and HRT
      had similar effects on hip and spinal BMD. Over the year of treatment,
      maintenance of both hip and spinal BMD was seen, but there was no significant
      increase after accounting for weight gain. Compared with HRT, DHEA appeared to
      have anabolic effects, evidenced by the positive correlation between increases in
      hip DXA measurements and IGF-I and significant increases in bone formation
      markers. Both therapies significantly decreased bone resorption. Replicating
      results from studies of the elderly, DHEA resulted in improvements in specific
      psychological parameters in these young women.

PMID- 12414854
TI  - Effect of subcutaneous leptin replacement therapy on bone metabolism in patients
      with generalized lipodystrophy.
AB  - The adipocyte-derived hormone leptin, which plays an important role in energy
      homeostasis, has been suggested to have an influence on bone development and
      remodeling. However, it is not clear from animal studies whether leptin is a
      stimulator or an inhibitor of bone growth. Cross-sectional studies in humans
      suggest that serum leptin levels are positively associated with bone mineral
      density (BMD), but these observations are not consistent, and whether this
      relationship is independent of obesity remains unclear. We therefore examined the
      effect of sc leptin administration on BMD and markers of bone turnover in two
      women, one with congenital generalized lipodystrophy and the other with acquired
      generalized lipodystrophy. Both patients had regular menstrual cycles. At
      baseline, the BMD for both patients, measured at the lumbar spine and total hip,
      was within 1 SD of the peak bone mass. There was no significant change in BMD in
      both patients after 16-18 months of leptin therapy. Similarly, concentrations of
      serum osteocalcin and bone-specific alkaline phosphatase or urinary excretion of
      deoxypyridinoline and N-telopeptides remained unchanged after 6-8 months of
      leptin therapy, suggesting no effects of leptin on osteoblastic or osteoclastic
      activity. Our preliminary data suggest that sc leptin replacement in
      hypoleptinemic patients with generalized lipodystrophy has no effect on the
      mature adult skeleton.

PMID- 12414855
TI  - Circulating levels of interleukin-6 soluble receptor predict rates of bone loss
      in patients with primary hyperparathyroidism.
AB  - It remains unclear whether mild primary hyperparathyroidism results in
      accelerated bone loss, with recent studies reaching different conclusions. This
      could be due to intrinsic differences in disease activity not captured by the
      classical biochemical markers of the disease. Because circulating levels of IL-6
      and IL-6 soluble receptor (IL-6sR) are reportedly elevated in patients with
      hyperparathyroidism, we sought to determine whether measures of this cytokine
      axis could be helpful in determining the risk for bone loss in
      hyperparathyroidism. We prospectively followed 23 patients with
      hyperparathyroidism for 22 +/- 1.5 months and found that baseline circulating
      levels of IL-6sR correlated significantly with rates of bone loss at the total
      femur (r = -0.53, P < 0.01). Furthermore, the combination of a serum IL-6sR in
      the upper tertile (> or=45.6 ng/ml) and IL-6 in the upper half (> or =11.8 pg/ml)
      of values in the whole group defined a subset of patients with a significantly
      greater rate of yearly bone loss at the total femur than the remainder of the
      group (-2.6 +/- 1.3% vs. +0.4 +/- 0.3%, P < 0.05). We conclude that the combined
      measurements of serum IL-6sR and IL-6 may be helpful in identifying patients with
      untreated hyperparathyroidism who are more likely to experience bone loss at the
      total femur.

PMID- 12414856
TI  - Effects of above average summer sun exposure on serum 25-hydroxyvitamin D and
      calcium absorption.
AB  - The purpose of this study was to examine the effects of summer sun exposure on
      serum 25-hydroxyvitamin D [25(OH)D], calcium absorption fraction, and urinary
      calcium excretion. Subjects were 30 healthy men who had just completed a summer
      season of extended outdoor activity (e.g. landscaping, construction work,
      farming, or recreation). Twenty-six subjects completed both visits: after summer
      sun exposure and again approximately 175 d later, after winter sun deprivation.
      We characterized each subject's sun exposure by locale, schedule, and usual
      attire. At both visits we measured serum 25(OH)D, fasting urinary calcium to
      creatinine ratio, and calcium absorption fraction. Median serum 25(OH)D decreased
      from 122 nmol/liter in late summer to 74 nmol/liter in late winter. The median
      seasonal difference of 49 nmol/liter (interquartile range, 29-67) was highly
      significant (P < 0.0001). However, we found only a trivial, nonsignificant
      seasonal difference in calcium absorption fraction and no change in fasting
      urinary calcium to creatinine ratio. Findings from earlier work indicate that our
      subjects' sun exposure was equivalent in 25(OH)D production to extended oral
      dosing with 70 micro g/d vitamin D(3) (interquartile range, 41-96) or,
      equivalently, 2800 IU/d (interquartile range, 1640-3840). Despite this input, at
      the late winter visit, 25(OH)D was less than 50 nmol/liter in 3 subjects and less
      than 75 nmol/liter in 15 subjects.

PMID- 12414858
TI  - Increased circulatory level of biologically active full-length FGF-23 in patients
      with hypophosphatemic rickets/osteomalacia.
AB  - Hypophosphatemic rickets/osteomalacia with inappropriately low serum 1,25
      dihidroxyvitamin D level is commonly observed in X-linked hypophosphatemic
      rickets/osteomalacia, autosomal dominant hypophosphatemic rickets/osteomalacia
      and tumor-induced osteomalacia. Although the involvement of a newly identified
      factor, FGF-23, in the pathogenesis of ADHR and TIO has been suggested, clinical
      evidence indicating the role of FGF-23 has been lacking. We have previously shown
      that FGF-23 is cleaved between Arg(179) and Ser(180), and this processing
      abolished biological activity of FGF-23 to induce hypophosphatemia. Therefore,
      sandwich ELISA for biologically active intact human FGF-23 was developed using
      two kinds of monoclonal antibodies that requires the simultaneous presence of
      both the N-terminal and C-terminal portion of FGF-23. The serum levels of FGF-23
      in healthy adults were measurable and ranged from 8.2 to 54.3 ng/L. In contrast,
      those in a patient with TIO were over 200 ng/L. After the resection of the
      responsible tumor, the elevated FGF-23 level returned to normal level within 1 h.
      The increase of serum concentrations of 1,25-dihidroxyvitamin D and phosphate,
      and the decrease of serum 24,25-dihydroxyvitamin D followed the change of FGF-23.
      In addition, the elevated serum FGF-23 levels were demonstrated in most patients
      with XLH. It is likely that increased serum levels of FGF-23 contributes to the
      development of hypophosphatemia not only in TIO but also in XLH.

PMID- 12414859
TI  - Angiogenesis in human normal and pathologic adrenal cortex.
AB  - The angiogenic phenotype of 13 normal adrenal glands (N), 13 aldosterone
      producing adenomas (APA), 12 cortisol-producing adenomas (CPA), 13 nonfunctioning
      adrenal cortical adenomas (NFA), and 13 adrenal cortical carcinomas (CA) was
      investigated. Intratumoral vascular density was explored by CD34, a marker of
      endothelial cells, and the angiogenic status was investigated by vascular
      endothelial growth factor (VEGF) expression, an important angiogenic factor
      expressed by tumoral cells. Vascular density, quantified as the number of vessels
      per square millimeter, was significantly lower (P < 0.0001) in CA (110.3 +/-
      27.8) than in N (336.6 +/- 14.5), APA (322.8 +/- 19.1), CPA (288.5 +/- 14.3), and
      NFA (274.2 +/- 19.8). VEGF expression, calculated as the percentage of positive
      cells, was significantly greater (P < 0.0001) in CA (85.3 +/- 2.1) than in APA
      (56.5 +/- 7.5), CPA (38.5 +/- 7.0), N (33.1 +/- 6.1), and NFA (0.76 +/- 0.6). In
      APA, a negative relation between CD34 and plasma renin activity (P < 0.0002) and
      a positive association between CD34 and aldosterone levels (P < 0.05) was found.
      In conclusion, the angiogenic phenotype of CA is characterized by VEGF
      overexpression but low vascularization, a finding suggesting a dissociation
      between angiogenic potential and neoangiogenic capabilities of these tumors. The
      lack of VEGF expression in NFA and the close association between angiogenesis and
      functional status in APA also suggest a possible influence of the angiogenic
      phenotype on hormonal secretion of these endocrine tumors.

PMID- 12414861
TI  - Elevating circulating leptin in prepubertal male rhesus monkeys (Macaca mulatta)
      does not elicit precocious gonadotropin-releasing hormone release, assessed
      indirectly.
AB  - The purpose of this study was to examine the hypothesis that the pubertal
      reaugmentation of pulsatile GnRH release in male primates is triggered by a rise
      in circulating leptin concentrations. Agonadal juvenile male rhesus monkeys (n =
      7) were implanted with indwelling venous catheters and housed in specialized
      cages that allow continuous access to the venous circulation. GnRH release was
      monitored indirectly using LH secretion from the in situ pituitary sensitized to
      the LH releasing action of GnRH as a bioassay for the hypothalamic peptide.
      Infusion of recombinant human leptin (5 micro g/kg body weight.h for 16 d
      resulted in a marked square wave increment in circulating leptin concentration
      from approximately 2-20 ng/ml but did not elicit precocious GnRH release. GH
      secretion, however, was stimulated confirming that the heterologous leptin
      preparation was bioactive in the monkey. Parenthetically, recombinant human
      leptin was found to be immunogenic in the monkey and circulating antileptin IgG
      was demonstrable 22-35 d after the initial exposure to the human protein. These
      findings further support the view that circulating leptin is unlikely to provide
      the signal that triggers the onset of puberty in male primates.

PMID- 12414860
TI  - Acute growth hormone administration causes exaggerated increases in plasma
      lactate and glycerol during moderate to high intensity bicycling in trained young
      men.
AB  - We studied the acute effects of a single, sc GH dose on exercise performance and
      metabolism during bicycling. Seven highly trained men [age, 26 +/- 1 yr (mean +/-
      SEM); weight, 77 +/- 3 kg; maximal oxygen uptake, 65 +/- 1 ml O(2).min(-1).kg(
      1)] performed 90 min of bicycling 4 h after receiving 7.5 IU (2.5 mg) GH or
      placebo in a randomized, double-blinded, cross-over design trial. A standardized
      pre-exercise meal was given 2 h before exercise. Blood was sampled at rest and
      during exercise and analyzed for GH, IGF-I, glucose, lactate, insulin, glycerol,
      and nonesterified fatty acids (NEFA). In the placebo trial, all subjects
      completed the exercise protocol without any difficulties. In contrast, two
      subjects were not able to complete the exercise protocol in the GH trial, and one
      subject barely managed to complete the protocol. In addition, GH administration
      resulted in exaggerated increases in plasma lactate concentrations during
      exercise (P < 0.0001). The combined lipolytic effect of GH and exercise,
      evidenced by increased plasma glycerol and serum NEFA concentrations, was 3-fold
      greater than the effect of exercise alone (P < 0.0001), but this increased
      substrate availability did not result in increased whole body fat oxidation
      (indirect calorimetry). Plasma glucose was, on average, 9% higher during exercise
      after GH administration compared with placebo (P < 0.0001). We conclude that a
      single, relevant GH dose causes exaggerated increases in plasma lactate and
      glycerol as well as serum NEFA during 90 min of subsequent bicycling at moderate
      to high intensity. The exaggerated increase in plasma lactate may be associated
      with substantially decreased exercise performance.

PMID- 12414862
TI  - Association studies between microsatellite markers within the gene encoding human
      11beta-hydroxysteroid dehydrogenase type 1 and body mass index, waist to hip
      ratio, and glucocorticoid metabolism.
AB  - Two isozymes of 11beta-hydroxysteroid dehydrogenase (11beta-HSD) interconvert
      active cortisol (F) and inactive cortisone (E). 11beta-HSD1 is an oxo-reductase
      (E to F) expressed in several glucocorticoid target tissues, including liver and
      adipose tissue, where it facilitates glucocorticoid-induced gluconeogenesis and
      adipocyte differentiation, respectively. We have isolated a full-length HSD11B1
      genomic clone; the gene is more than 30 kb in length, not 9 kb in length as
      previously reported, principally due to a large intron 4. Two polymorphic (CA)(n)
      repeats have been characterized within intron 4: a CA(19) repeat 2.7 kb 3' of
      exon 4 and a CA(15) repeat 3 kb 5' of exon 5. The microsatellites, CA(19) and
      CA(15), were PCR amplified using fluorescent primers and were genotyped on an ABI
      377 DNA sequencer from DNA of 413 normal individuals enrolled in the MONICA study
      of cardiovascular risk factors and 557 Danish men (ADIGEN study), of whom 234
      were obese [body mass index (BMI), >/=31 kg/m(2) ] at draft board examination and
      323 were randomly selected controls from the draftee population with BMI below 31
      kg/m(2) (mean +/- SE, 21.7 +/- 0.41). Genotypic data from the normal MONICA
      cohort was compared with gender, 5beta-tetrahydrocortisol+5alpha
      tetrahydrocortisol/tetrahydrocortisone ratio, and waist to hip (W:H) ratio. When
      analyzed by allele length (0, 1, or 2 short alleles) for the CA(19) marker, there
      was a trend toward a higher 5beta-tetrahydrocortisol+5alpha
      tetrahydrocortisol/tetrahydrocortisone ratio (P = 0.058) and an increased W:H
      ratio (2 vs. 0.1 short; P(c) = 0.10) with overrepresentation of short alleles.
      The opposite was true for the CA(15) locus, with longer alleles at this locus
      predicting increased 11beta-HSD1 activity, particularly in females. Genotypic
      data from the ADIGEN case-control population was compared with clinical markers
      of obesity such as BMI and W:H ratio. There was no significant difference in the
      distribution of either microsatellite marker between lean and obese groups.
      Allele distributions were binomial, as seen for the MONICA cohort, and the data
      were split accordingly (zero, one, or two short alleles). No significant
      association was seen between grouped alleles and the clinical parameters. No
      association was observed between HSD11B1 genotype and BMI in either population.
      These data suggest that 11beta-HSD1 is not a major factor in explaining genetic
      susceptibility to obesity per se. However, weak associations between HSD11B1
      genotype, increased 11beta-HSD1 activity, and W:H ratio suggest that polymorphic
      variability at the HSD11B1 locus may influence susceptibility to central obesity
      through enhanced 11beta-HSD1 activity (E to F conversion) in visceral adipose
      tissue.

PMID- 12414863
TI  - Atorvastatin reduces postprandial accumulation and cholesteryl ester transfer
      protein-mediated remodeling of triglyceride-rich lipoprotein subspecies in type
      IIb hyperlipidemia.
AB  - The effect of atorvastatin, at 10 mg or 40 mg for 6 wk, on lipid and lipoprotein
      metabolism during the postprandial phase in subjects (n = 11) displaying type IIB
      hyperlipidemia was evaluated. The postprandial increment in area under the curve
      above baseline concentrations in type IIB subjects was significantly decreased by
      atorvastatin for plasma triglyceride (A10: -42% and A40: -55%, P < 0.01),
      chylomicrons (CMs) (A10: -24% and A40: -40%, P < 0.03) and VLDL-1 (A10: -54% and
      A40: -52%, P < 0.02). Before atorvastatin therapy, postprandial cholesteryl ester
      (CE) transfer from high-density lipoprotein (HDL) to CMs (2.5-fold; P < 0.005),
      very low-density lipoprotein (VLDL)-1 (1.8-fold; P < 0.005), VLDL-2 (1.4-fold; P
      < 0.05), and intermediate-density lipoproteins (1.4-fold; P < 0.05) were
      significantly increased 4 h postprandially. Following statin treatment, the
      postprandial transfer of CE from HDL to triglyceride-rich lipoproteins (TRLs) at
      the 4-h time point was significantly reduced at 10 mg/d (-26%; P < 0.05) and at
      40 mg/d (-24%; P < 0.05), compared with that before treatment. Such postprandial
      increase in CE transferred from HDLs to TRLs arose exclusively from accelerated
      CE transfer from HDLs to CMs (2.5-fold; P < 0.005). In conclusion, atorvastatin
      attenuates the abnormal intravascular remodeling of postprandial TRL particles
      via marked reduction in CE transfer in type IIB hyperlipidemia and diminishes the
      postprandial formation and accumulation of CMs and VLDL-1.

PMID- 12414864
TI  - Longitudinal assessment of serum free testosterone concentration predicts memory
      performance and cognitive status in elderly men.
AB  - Circulating testosterone (T) levels have behavioral and neurological effects in
      both human and nonhuman species. Both T concentrations and neuropsychological
      function decrease substantially with age in men. The purpose of this prospective,
      longitudinal study was to investigate the relationships between age-associated
      decreases in endogenous serum T and free T concentrations and declines in
      neuropsychological performance. Participants were volunteers from the Baltimore
      Longitudinal Study of Aging, aged 50-91 yr at baseline T assessment. Four hundred
      seven men were followed for an average of 10 yr, with assessments of multiple
      cognitive domains and contemporaneous determination of serum total T, SHBG, and a
      free T index (FTI). We administered neuropsychological tests of verbal and visual
      memory, mental status, visuomotor scanning and attention, verbal
      knowledge/language, visuospatial ability, and depressive symptomatology. Higher
      FTI was associated with better scores on visual and verbal memory, visuospatial
      functioning, and visuomotor scanning and a reduced rate of longitudinal decline
      in visual memory. Men classified as hypogonadal had significantly lower scores on
      measures of memory and visuospatial performance and a faster rate of decline in
      visual memory. No relations between total T or the FTI and measures of verbal
      knowledge, mental status, or depressive symptoms were observed. These results
      suggest a possible beneficial relationship between circulating free T
      concentrations and specific domains of cognitive performance in older men.

PMID- 12414865
TI  - The impact of dietary fat composition on serum leptin concentrations in healthy
      nonobese men and women.
AB  - The recently discovered hormone leptin is primarily secreted by adipose tissue
      and serves as an internal signal indicating the size of body fat stores. The aim
      of the present study was to investigate the impact of the dietary fatty acid
      composition on serum leptin concentrations. Therefore, serum leptin levels were
      measured by RIA in healthy nonobese men (n = 30) and women (n = 25). First, all
      participants received a baseline high-fat diet, rich in saturated fat, for 2 wk
      and were then randomly assigned to one of three high-fat dietary treatments,
      which contained refined olive oil (rich in monounsaturated fatty acids, n = 19),
      rapeseed oil [rich in monounsaturated fatty acids and alpha-linolenic acid (18:3n
      3), n = 17], or sunflower oil (rich in n-6-polyunsaturated fatty acids, n = 19)
      as the principal source of fat for 4 wk. On the rapeseed oil diet, serum leptin
      concentrations increased slightly in men [+0.25 ng/ml, T(9) = -2.778, P = 0.021],
      but decreased distinctly in women [-4.70 ng/ml, T(6) = 5.083, P = 0.002]. Both
      the olive oil and the sunflower oil diet did not affect serum leptin
      concentrations. Thus, it is proposed that serum leptin levels were affected by
      the high amount of alpha-linolenic acid in rapeseed oil. However, questions
      remain as to why this diet differently affected serum leptin in men and women.

PMID- 12414866
TI  - Identification of genes associated with the corticotroph phenotype in bronchial
      carcinoid tumors.
AB  - The proopiomelanocortin (POMC) gene is occasionally expressed in nonpituitary
      tumors leading to Cushing's syndrome. Bronchial carcinoid tumors, one of the most
      frequent source for ectopic ACTH secretion, often display numerous features of
      the corticotroph phenotype. To identify new markers of corticotroph
      differentiation in these tumors, we compared the pattern of gene expression in
      ACTH-secreting (ACTH+) and nonsecreting (ACTH-) bronchial carcinoids by
      differential display/RT-PCR. Using groups of ACTH+ and ACTH- tumors, we initially
      selected approximately 300 differentially expressed genes. Fifteen were
      considered differentially expressed after further characterization by RT-PCR on a
      larger series of 8 ACTH+ and 12 ACTH- bronchial carcinoids; 11 were restricted to
      -or overexpressed in--ACTH+ and four in ACTH- tumors. In ACTH+, beside the
      expected POMC gene, we identified cFos, and KIAA1775, a large expressed sequence
      tag encoding a putative protocadherin-related protein. On the other hand, the
      tetraspanin TM4SF5 gene was specifically expressed in ACTH-. Dot blot analysis
      confirmed the specific expression of KIAA1775 in ACTH+ bronchial carcinoids.
      However, the expression of most of the differential genes, including KIAA1775,
      was detected by RT-PCR in pituitary or lung tumors, whether secreting ACTH or
      not, excepted for TM4SF5, which was only detected in some nonendocrine lung
      tumors. Our results show that corticotroph differentiation of bronchial carcinoid
      tumors is accompanied by induction and repression of specific genes. The nature
      of some of these genes, identified here, underlines the importance of cell-cell
      or cell-extracellular matrix interactions in the establishment of neoplastic
      corticotroph phenotype. These genes should help to better characterize ACTH+
      bronchial carcinoids as well as other bronchial carcinoid subtypes.

PMID- 12414867
TI  - Diurnal leptin secretion is intact in male hypogonadotropic hypogonadism and is
      not influenced by exogenous gonadotropins.
AB  - Circulating leptin shows a pulsatile secretory pattern along with a nocturnal
      rise. We have previously shown that circulating leptin concentrations are high in
      males with untreated idiopathic hypogonadotropic hypogonadism (IHH). However,
      circadian leptin secretion in IHH before and after gonadotropin treatment is not
      known. Thus, we studied 14 adult males with IHH who had no history of previous
      hormonal therapy, and 12 age- and body mass index-matched healthy men. Plasma
      leptin concentrations were measured with 1-h intervals for 24 h before and 6
      months after gonadotropin treatment. The 24-h mean leptin concentration showed a
      significant decrease, from 11.78 +/- 1.908 microg/liter at baseline to 10.85 +/-
      1.939 microg/liter after 6 months of therapy (z = 3.107; P = 0.002). Before and
      after treatment, 24-h mean leptin concentrations were also significantly higher
      in the patient group when compared with controls (4.275 +/- 0.711 microg/liter)
      (z = 5.938; P = 0.0001). Hourly leptin levels demonstrated a diurnal pattern in
      hypogonadal patients, a surge in the midday, and a peak just after midnight, and
      this pattern did not differ before and after treatment. We observed a similar
      diurnal pattern in the control subjects too. Leptin levels were negatively and
      significantly correlated with free testosterone and total testosterone levels
      both before (r = -0.656, P = 0.011; and r = -0.639, P = 0.014, respectively) and
      after (r = -0.537, P = 0.048; and r = -0.563, P = 0.036, respectively)
      gonadotropin administration. Our observations suggest that the diurnal rhythm of
      leptin is intact in males with IHH, and short-term gonadotropin treatment does
      not effect its diurnal rhythm. Moreover, testosterone produced under the
      influence of the gonadotropin treatment led to decreases in the leptin levels.

PMID- 12414868
TI  - Vascular reactivity in hypogonadal men is reduced by androgen substitution.
AB  - The effect of testosterone (T) substitution therapy on blood vessel functions in
      relation to cardiovascular disease has not been fully elucidated. In 36 newly
      diagnosed nonsmoking hypogonadal men (37.5 +/- 12.7 yr) endothelium-dependent
      flow-mediated vasodilatation (FMD; decreased in atherosclerosis) of the brachial
      artery was assessed before treatment and after 3 months of T substitution therapy
      (250 mg testosterone enanthate im every 2 wk in 19 men, human chorionic
      gonadotropin sc twice per week in 17 men). Twenty nonsmoking controls matched for
      age, low-density lipoprotein cholesterol (LDL-C), body height, and baseline
      diameter of the artery were selected for repeated measurements from a larger
      eugonadal control group (n = 113). In hypogonadal men, basal FMD (17.9 +/- 4.5%)
      was significantly higher than in the large (11.9 +/- 6.4%) and matched control
      (11.8 +/- 7.1%, both P < 0.001) groups. Grouped multiple linear regression
      analysis revealed a significant negative association of T levels with FMD within
      the hypogonadal range, but no significant association was seen within the
      eugonadal range. During substitution therapy, T levels increased from 5.8 +/- 2.3
      to 17.2 +/- 5.1 nmol/liter and FMD decreased significantly to 8.6 +/- 3.1% (P <
      0.001, analysis for covariance for repeated measurements including matched
      controls). LDL-C and advanced age contributed significantly to decrease FMD (P =
      0.01, P = 0.04, respectively). Because T substitution adversely affects this
      important predictor of atherosclerosis, other contributing factors (such as
      smoking, high blood glucose, and LDL-C) should be eliminated or strictly
      controlled during treatment of hypogonadal men.

PMID- 12414869
TI  - Pubertal and gender-related changes in the sympathoadrenal system in healthy
      children.
AB  - A critical amount of body fat is necessary for the initiation of puberty, and
      leptin, an adipocyte-derived hormone, is necessary for pubertal development. The
      sympathoadrenal system modulates body fat stores and leptin secretion and
      interacts with adrenocortical androgen production, suggesting a possible role in
      sexual maturation. We studied sympathetic nerve and adrenomedullary activity at
      rest in 80 healthy children (ages, 5-17 yr; 37 boys and 43 girls) in relation to
      age, pubertal stage, gender, physical activity, body mass index, and serum levels
      of sex steroids, dehydroepiandrosterone sulfate, cortisol, leptin, and insulin.
      Plasma concentrations of the adrenomedullary hormone, epinephrine (E), and its
      metabolite metanephrine (MN), decreased significantly with advancing puberty and
      were higher in boys than in girls. E and MN correlated significantly and
      inversely with dehydroepiandrosterone sulfate, estradiol, testosterone, leptin,
      and insulin. Plasma norepinephrine, which is primarily derived from sympathetic
      nerve endings, increased significantly with advancing puberty and increasing
      testosterone levels in boys. Stepwise multiple regression analysis revealed that
      E was best predicted by pubertal stage and leptin, and MN by estradiol and
      leptin. Our data suggest that sympathoadrenal hormones may play a role in the
      complex process of sexual maturation. Further studies are needed to investigate a
      possible modulatory role of the adrenal medulla in the body weight-related timing
      of adrenarche and/or gonadarche.

PMID- 12414870
TI  - Abdominal obesity, muscle composition, and insulin resistance in premenopausal
      women.
AB  - The independent relationships between visceral and abdominal sc adipose tissue
      (AT) depots, muscle composition, and insulin sensitivity were examined in 40
      abdominally obese, premenopausal women. Measurements included glucose disposal by
      euglycemic clamp, muscle composition by computed tomography, abdominal and
      nonabdominal (e.g. leg) AT by magnetic resonance imaging and cardiovascular
      fitness. Glucose disposal rates were negatively related to visceral AT mass (r = 
      0.42, P < 0.01). These observations remained significant (P < 0.01) after control
      for nonabdominal and abdominal sc AT, muscle attenuation, and peak oxygen uptake.
      Total, abdominal, or leg sc AT or muscle attenuation was not significantly (P >
      0.10) related to glucose disposal. Subdivision of abdominal sc AT into anterior
      and posterior depots did not alter the observed relationships. Further analysis
      matched two groups of women for abdominal sc AT but with low and high visceral
      AT. Women with high visceral AT had lower glucose disposal rates compared with
      those with low visceral AT (P < 0.05). A similar analysis performed on two groups
      of women matched for visceral AT but high and low abdominal sc AT revealed no
      statistically different values for insulin sensitivity (P > 0.10). In conclusion,
      visceral AT alone is a strong correlate of insulin resistance independent of
      nonabdominal, abdominal sc AT, muscle composition, and cardiovascular fitness.
      Subdivision of abdominal sc AT did not provide additional insight into the
      relationship between abdominal obesity and metabolic risk.

PMID- 12414871
TI  - Concomitant impairment of growth hormone secretion and peripheral sensitivity in
      obese patients with obstructive sleep apnea syndrome.
AB  - To clarify the impairment of the GH/IGF-I axis in obstructive sleep apnea
      syndrome (OSAS), in 13 adult male patients with OSAS (OSA) as well as 15 weight
      matched patients with simple obesity (OB) and 10 normal lean male subjects (NS),
      we studied: 1) the GH response to GHRH (1 micro g/kg iv) plus arginine (30 g iv);
      and 2) the IGF-I and IGF binding protein-3 responses to a very low dose
      recombinant human (rh)GH treatment (5.0 microg/kg sc per day for 4 d). The GH
      response to arginine plus GHRH in OSA was lower than in OB (P < 0.05), which in
      turn was lower than in NS (P < 0.001). Basal IGF-I levels in OSA were lower than
      in OB (P < 0.05), which in turn were lower than in NS (P < 0.03). As opposed to
      OB and NS, in OSA a very low rhGH dose did not affect IGF-I. Adjusting for age
      and basal values, rhGH-induced IGF-I rise in OSA was lower than in OB (P < 0.01).
      IGF binding protein-3, glucose, and insulin levels in the three groups were not
      modified by rhGH. OSA show a more marked impairment of the maximal secretory
      capacity of somatotroph cells together with reduced IGF-I sensitivity to rhGH
      stimulation. These findings suggest that OSAS is connoted by a concomitant
      impairment of GH secretion and sensitivity.

PMID- 12414872
TI  - Long-lasting bone damage detected by dual-energy x-ray absorptiometry, phalangeal
      osteosonogrammetry, and in vitro growth of marrow stromal cells after allogeneic
      stem cell transplantation.
AB  - Bone complications after allogeneic stem cell transplant (allo-SCT) include
      osteoporosis, fractures, and osteonecrosis. We investigated bone abnormalities in
      long-term survivors after busulfan cyclophosphamide-conditioning regimen,
      followed by human leukocyte antigen-identical sibling SCT. Bone density was
      measured by dual-energy x-ray absorptiometry at lumbar spine (LS) and femoral
      neck (FN) and phalangeal osteosonogrammetry (OSG) in 41 patients 1-10 yr after
      allo-SCT. Using colony-forming units-fibroblast (CFU-F) assay, we analyzed the
      repopulating capacity of clonogenic fibroblast progenitors belonging to the
      osteogenic stromal lineage. LS and FN bone mineral density (BMD) and phalangeal
      densitometric values were significantly reduced, compared with 188 healthy
      controls (P < 0.001). Decrease in T-score less than 1 SD was documented in 29%
      and 52% of patients at the LS and FN, respectively. OSG detected densitometric
      values with a T-score less than 1 SD in 68% of transplanted patients. The
      patients examined within the first 3 yr after transplant showed low BMD, which
      remained stable at FN and improved at LS. Phalangeal densitometry was low up to
      10 yr after transplant. CFU-F was found permanently depressed and unable to give
      rise to a confluent stroma. Low serum osteocalcin levels were present throughout
      the whole follow-up period. A significant correlation was found between
      densitometric values detected by both techniques and CFU-F growth in vitro.
      Osteonecrosis was associated with lower FN BMD, and phalangeal densitometry
      correlated inversely with duration of amenorrhea and chronic graft vs. host
      disease requiring long-lasting steroid therapy. In conclusion, dual-energy x-ray
      absorptiometry and phalangeal OSG may provide complementary information on bone
      density after allo-SCT. Prolonged severe impairment of femoral BMD and phalangeal
      densitometry suggest that bone loss may persist for many years after transplant.
      Inability to regenerate a normal number of osteoblastic precursors in the stromal
      stem cell compartment may in part account for severe long-lasting posttransplant
      decrease in bone mass.

PMID- 12414873
TI  - Highly active antiretroviral therapy-induced lipodystrophy has minor effects on
      human immunodeficiency virus-induced changes in lipolysis, but normalizes resting
      energy expenditure.
AB  - Combination antiretroviral therapy for the treatment of human immunodeficiency
      virus type 1-infected patients is associated with development of the
      lipodystrophy syndrome (LD). We previously showed that plasma levels of free
      fatty acids are higher in patients with lipodystrophy. The purpose of this study
      was to evaluate the postabsorptive rate of lipolysis, using [(2)H(5)]glycerol
      infusion, the resting energy expenditure (REE) measured by indirect calorimetry,
      and the responses of both to epinephrine infusion ( approximately 15 ng/kg.min)
      in patients with LD. Results were compared with those obtained in five matched
      human immunodeficiency virus type 1-infected patients. The postabsorptive rate of
      appearance of glycerol did not differ between the two groups. There was no
      difference in the lipolytic response to epinephrine, although the response in the
      LD group was delayed (P < 0.001). The postabsorptive REE adjusted for lean body
      mass was lower and remained lower during epinephrine infusion in the LD group.
      Postabsorptive norepinephrine concentrations were higher and remained elevated
      during epinephrine infusion in the LD group. We conclude that the lipolytic
      response to epinephrine in the LD group was normal, albeit delayed.
      Norepinephrine concentrations were increased in patients with lipodystrophy,
      indicating increased sympathetic activity. Postabsorptive REE was lower in the
      patients with lipodystrophy. Our data suggest that highly active antiretroviral
      therapy-associated lipodystrophy normalizes the REE, but has only minor effects
      on lipolysis as a result of concomitant sympathetic stimulation of adipose
      tissue.

PMID- 12414874
TI  - Rapid potentiation of endothelium-dependent vasodilation by estradiol in
      postmenopausal women is mediated via cyclooxygenase 2.
AB  - Estrogens influence cardiovascular function through direct and indirect effects
      and via genomic and nongenomic mechanisms. The pathways underlying the nongenomic
      mechanisms are not completely understood. Estrogen-induced responses in vascular
      cells have been shown to influence prostaglandins and cyclooxygenase (COX), a key
      enzyme in the production of prostaglandins, with two isoforms, COX-1 and COX-2.
      We investigated the effects of prostaglandins on the acute potentiation by 17beta
      estradiol (E) of acetylcholine (ACh)-mediated vasodilation in the cutaneous
      vasculature. Using a double-blind placebo-controlled design, we assessed skin
      blood flow in 32 healthy, postmenopausal women by laser Doppler velocimetry with
      direct current iontophoresis of ACh and sodium nitroprusside before and after 6
      wk treatment periods with aspirin (a nonspecific COX-1 and COX-2 inhibitor),
      diclofenac (predominantly a COX-2 inhibitor, which also inhibits COX-1),
      celecoxib (a specific COX-2 inhibitor), given at anti-inflammatory doses, or
      placebo. Blood flux values before iontophoresis of ACh did not differ between the
      treatment groups or after E administration, excluding a direct cutaneous
      vasodilator effect of the treatments or of E. Acute E administration enhanced the
      response to ACh after aspirin, diclofenac, and placebo; however, this effect was
      completely abolished with celecoxib treatment (P < 0.05). E had no effect on
      sodium nitroprusside-mediated vasodilation after any of the treatments. We
      conclude that the COX-2 pathway plays a specific role in the rapid E-induced
      potentiation of cholinergic vasodilation in postmenopausal women.

PMID- 12414875
TI  - Pituitary magnetic resonance imaging and function in patients with growth hormone
      deficiency with and without mutations in GHRH-R, GH-1, or PROP-1 genes.
AB  - Pituitary stalk interruption and ectopic posterior lobe on magnetic resonance
      imaging (MRI) are frequently observed in patients with GH deficiency (GHD), but
      their pathogenesis remains controversial. We performed pituitary stimulation
      tests, MRI, and studied GH-1, GHRH receptor (GHRH-R), and Prophet of Pit-1 (PROP
      1) genes in 76 patients with GHD. Of 33 patients with isolated GHD, 4 had GH-1
      deletions and 4 had GHRH-R mutations; of 43 patients with combined pituitary
      hormone deficiency, 1 had PIT-1 and 5 had PROP-1 mutations. Compared with the 62
      patients without mutations, 14 patients with mutations had higher frequency of
      consanguinity (57 vs. 2%, P < 0.001), familial cases (21 vs. 3%, P < 0.05), and
      lower frequency of breech delivery or hypoxemia at birth (0 vs. 39%, P < 0.005).
      On MRI, all patients with mutations had an intact stalk, whereas it was
      interrupted or thin in 74% without mutations (P < 0.001). The posterior pituitary
      lobe was in normal position in 92% of patients with mutations against 13% without
      mutations (P < 0.001). Among patients with combined pituitary hormone deficiency,
      hormonal deficiencies were of pituitary origin in all with PROP-1 and PIT-1
      mutations and suggestive of hypothalamic origin in 81% without mutations.
      Perinatal insults were associated with thin/interrupted pituitary stalk, ectopic
      posterior lobe, and hypothalamic origin of hormonal deficiencies. In contrast, GH
      1, GHRH-R, and PROP-1 mutations were associated with consanguineous parents,
      intact pituitary stalk, normal posterior lobe, and pituitary origin of hormonal
      deficiencies. We conclude that pituitary MRI and hormonal response to stimulation
      tests are useful in selection of patients and candidate genes to elucidate the
      etiological diagnosis of GHD.

PMID- 12414876
TI  - Dynamics of the pituitary-adrenal ensemble in hypocretin-deficient narcoleptic
      humans: blunted basal adrenocorticotropin release and evidence for normal time
      keeping by the master pacemaker.
AB  - Narcolepsy is a sleep disorder caused by disruption of hypocretin (orexin)
      neurotransmission. It has been suggested that anomalous timing by the biological
      clock contributes to the symptomatology. Hypocretins stimulate the pituitary
      adrenal (PA) axis in rodents. We explored whether hypocretin deficiency disrupts
      circadian timing and blunts PA hormone release. We deconvolved 24-h plasma
      profiles of ACTH and cortisol, and determined their circadian rhythm by cosinor
      analysis in seven hypocretin-deficient narcoleptic males and seven matched
      controls. Basal and total ACTH production were blunted in narcoleptics [310 +/-
      86 vs. 760 +/-160 ng/liter.24 h (P = 0.02) and 920 +/- 147 vs. 1460 +/- 220
      ng/liter.24 h (P = 0.04), respectively], whereas pulsatile release did not differ
      between groups. In contrast, basal, pulsatile and total cortisol secretion were
      similar in both groups. The cross-approximate entropy of the joint ACTH/cortisol
      time series was higher in narcoleptics (1.26 +/- 0.07 vs. 1.07 +/- 0.04; P =
      0.04), reflecting reduced secretory process regularity. The acrophases of both
      ACTH and cortisol occurred at similar clock times (approximately 0830 h) in
      patients and controls, which supports the idea that the master pacemaker is
      intact in narcolepsy. The reduced (basal) ACTH secretion and the diminished
      secretory process regularity of the ACTH/cortisol ensemble conjointly suggest
      that hypocretin deficiency induces changes in the interplay between PA hormones.

PMID- 12414877
TI  - Low insulin sensitivity measured by both quantitative insulin sensitivity check
      index and homeostasis model assessment method as a risk factor of increased
      intima-media thickness of the carotid artery.
AB  - The present study evaluated the association of ultrasonographic manifestations of
      carotid atherosclerosis with glucose status, various components of the insulin
      resistance syndrome, and insulin sensitivity measured by a novel quantitative
      insulin sensitivity check index (QUICKI = 1/[log(I0) + log (G0)]). Carotid
      ultrasonographic measurements were performed on 54 diabetic subjects, 97 subjects
      with impaired glucose tolerance and 57 normoglycemic subjects. QUICKI and insulin
      resistance measured by a HOMA (homeostasis model assessment) method had a high
      negative correlation (r = -0.995, P < 0.001). QUICKI was lower in diabetic
      subjects (0.319 +/- 0.022) than in subjects with impaired glucose tolerance
      (0.334 +/- 0.027) or normoglycemia (0.335 +/- 0.022, P = 0.002). There was an
      increasing trend in the mean and maximal intima-media thickness (IMT) of the
      common carotid artery (CCA) with worsening of glucose status. The maximal IMT of
      the CCA correlated inversely with QUICKI (r = -0.158, P = 0.027). The prevalence
      of severe CCA atherosclerosis (maximal IMT of the CCA > or = 1.2 mm) was 41% in
      men and 16% in women (P < 0.001). It was also associated with a long (> or =26
      yr) smoking history. The prevalence of severe CCA atherosclerosis was 11% in the
      highest QUICKI tertile, 36% in the middle tertile, and 33% in the lowest tertile
      (P = 0.002). Systolic blood pressure was higher and high-density lipoprotein
      cholesterol lower in subjects with severe CCA atherosclerosis, compared with
      those without it. In multiple regression analysis, the adjusted odds ratio for
      severe CCA atherosclerosis was 5.7 (95% confidence interval, 2.2-15.1) in
      subjects in the two lowest tertiles of QUICKI, compared with those in the highest
      tertile.

PMID- 12414878
TI  - Metabolic effects of visceral fat accumulation in type 2 diabetes.
AB  - Visceral fat (VF) excess has been associated with decreased peripheral insulin
      sensitivity and has been suggested to contribute to hepatic insulin resistance.
      However, the mechanisms by which VF impacts on hepatic glucose metabolism and the
      quantitative role of VF in glycemic control have not been investigated. In the
      present study 63 type 2 diabetic subjects (age, 55 +/- 1 yr; fasting plasma
      glucose, 5.5-14.4 mmol/liter; hemoglobin A(1c), 6.1-11.7%) underwent measurement
      of 1) fat-free mass ((3)H(2)O technique), 2) sc and visceral abdominal fat area
      (magnetic resonance imaging), 3) insulin sensitivity (euglycemic insulin clamp),
      4) endogenous glucose output ([(3)H]glucose infusion technique), and 5)
      gluconeogenesis ((2)H(2)O method). After adjustment for sex, age, body mass
      index, diabetes duration, ethnicity, and sc fat area, VF area was positively
      related to fasting hyperglycemia (partial r = 0.46; P = 0.001) as well as to
      hemoglobin A(1c) (partial r = 0.50; P = 0.0003). Insulin sensitivity was
      reciprocally related to VF independently of body mass index (partial r = 0.33; P
      = 0.01). In contrast, the relation of basal endogenous glucose output to VF was
      not statistically significant. This lack of association was explained by the fact
      that VF was positively associated with gluconeogenesis flux (confounder-adjusted,
      partial r = 0.45; P = 0.003), but was reciprocally associated with glycogenolysis
      (partial r = 0.31; P < 0.05). We conclude that in patients with established type
      2 diabetes, VF accumulation has a significant negative impact on glycemic control
      through a decrease in peripheral insulin sensitivity and an enhancement of
      gluconeogenesis.

PMID- 12414879
TI  - Characterization of gsp-mediated growth hormone excess in the context of McCune
      Albright syndrome.
AB  - McCune-Albright syndrome (MAS) is a disorder characterized by the triad of cafe
      au-lait skin pigmentation, polyostotic fibrous dysplasia of bone, and
      hyperfunctioning endocrinopathies, including GH excess. The molecular etiology of
      the disease is postzygotic activating mutations of the GNAS1 gene product,
      G(s)alpha. The term gsp oncogene has been assigned to these mutations due to
      their association with certain neoplasms. The aim of this study was to estimate
      the prevalence of GH excess in MAS, characterize the clinical and endocrine
      manifestations, and describe the response to treatment. Fifty-eight patients with
      MAS were screened, and 22 with stigmata of acromegaly and/or elevated GH or IGF-I
      underwent oral glucose tolerance testing. Twelve patients (21%) had GH excess,
      based on failure to suppress serum GH on oral glucose tolerance test, and
      underwent a TRH test, serial GH sampling from 2000-0800 h, and magnetic resonance
      imaging of the sella. We found that vision and hearing deficits were more common
      in patients with GH excess (4 of 12, 33%) than those without (2 of 56, 4%). Of
      interest, patients with a history of precocious puberty and GH excess who had
      reached skeletal maturity achieved normal adult height despite a history of early
      epiphyseal fusion. All 9 patients tested had an increase in serum GH after TRH,
      11 of 12 (92%) had hyperprolactinemia, and all 8 tested had detectable or
      elevated nighttime GH levels. Pituitary adenoma was detected in 4 of 12 (33%)
      patients. All patients with elevated IGF-I levels were treated with cabergoline
      (7 patients), long-acting octreotide (LAO; 8 patients), or a combination of
      cabergoline and LAO (4 patients). In six of the seven patients (86%) treated with
      cabergoline, serum IGF-I decreased, but not to the normal range. In the eight
      patients treated with LAO alone, IGF-I decreased, and, in four, returned to the
      normal range. The remaining 4 patients were treated with a combination of
      cabergoline and LAO. For them, symptoms of GH excess diminished, and IGF-I
      decreased further, but did not enter the normal range. GH excess is common in MAS
      and results in a distinct clinical phenotype characterized by inappropriately
      normal stature, TRH responsiveness, prolactin cosecretion, small or absent
      pituitary tumors, a consistent but inadequate response to treatment with
      cabergoline, and an intermediate response to LAO.

PMID- 12414880
TI  - Apoptosis and proliferation of human testicular somatic and germ cells during
      prepuberty: high rate of testicular growth in newborns mediated by decreased
      apoptosis.
AB  - Programmed cell death and proliferation are evolutionary conserved processes that
      play a major role during normal development and homeostasis. In the testis,
      during the fetal and newborn periods, they might determine final adult size and
      fertility potential. In the present study, we have measured the relative number
      of testicular cells in apoptosis and in active proliferation in the seminiferous
      cords and in the interstitium, at different age periods of prepubertal testicular
      development in humans. Testes from 44 prepubertal subjects without endocrine and
      metabolic abnormalities were collected at necropsy. They were divided in three
      age groups (Gr): Gr 1, newborn (1- to 21-d-old neonates), n = 18, mean (+/-SD)
      age 0.3 +/- 0.23 months; Gr 2, post natal activation (1- to 6-month-old infants),
      n = 13, mean age 3.93 +/- 1.90 months; and Gr 3, early childhood period (1- to <6
      yr-old boys), n = 13, mean age 31.5 +/- 18.9 months. Apoptosis was detected in 5-
      microm tissue sections using a modified terminal deoxynucleotidyl transferase
      mediated dUTP nick end-labeling assay and cell proliferation was assessed by Ki
      67 immunohistochemistry. Evaluation of apoptosis was confirmed by estimation of
      active caspase-3. Mean (+/-SD) testicular weight was 0.38 +/- 0.20, 0.54 +/-
      0.35, and 0.51 +/- 0.11 g in Gr 1, Gr 2, and Gr 3, respectively. In Gr 1, there
      was a significant positive correlation between age and testis weight (P = 0.02).
      Mean (+/-SD) germ cell apoptotic index, AI, (% of apoptotic cells out of total
      cell number) was 15.0 +/- 6.60, 27.0 +/- 8.80 and 33.4 +/- 11.4 in Gr 1, Gr 2,
      and Gr 3, respectively. In Sertoli cells, it was 6.60 +/- 4.07, 22.0 +/- 14.0 and
      27.5 +/- 19.8, respectively. In interstitial cells, it was 10.2 +/- 6.38, 18.0 +/
      6.70 and 25.7 +/- 15.5, respectively. In the three types of cells, AI in Gr 1
      was significantly lower than in Gr 2 or Gr 3 (P < 0.05). Mean (+/-SD) germ cell
      proliferation index, PI, was 18.6 +/- 13.0, 10.0 +/- 6.50 and 10.9 +/- 6.24% in
      Gr 1, Gr 2, and Gr 3, respectively. In Sertoli cells and in interstitial cells PI
      was similar in the three age groups. The PI/AI ratio was used to compare relative
      differences among age groups. The PI/AI ratio of germ cells, Sertoli cells and
      interstitial cells in Gr 1 was significantly higher than in Gr 2 or Gr 3 (P <
      0.05). It is concluded that, in normal subjects, there is a vigorous growth of
      the testis during the newborn period with subsequent stabilization during the
      first years of prepuberty. This cell growth seems to be mainly mediated by
      decreased apoptosis. The factors that modulate apoptosis of testicular cells are
      not known, but it is remarkable that this change takes place before the
      testosterone peak of the post natal gonadal activation of the first trimester of
      life. These changes taking place during the newborn period might be important to
      define testicular function in adults.

PMID- 12414881
TI  - Sex-typed toy play behavior correlates with the degree of prenatal androgen
      exposure assessed by CYP21 genotype in girls with congenital adrenal hyperplasia.
AB  - Previous studies have shown that girls with congenital adrenal hyperplasia (CAH),
      a syndrome resulting in overproduction of adrenal androgens from early fetal
      life, are behaviorally masculinized. We studied play with toys in a structured
      play situation and correlated the results with disease severity, assessed by
      CYP21 genotyping, and age at diagnosis. Girls with CAH played more with masculine
      toys than controls when playing alone. In addition, we could demonstrate a dose
      response relationship between disease severity (i.e. degree of fetal androgen
      exposure) and degree of masculinization of behavior. The presence of a parent did
      not influence the CAH girls to play in a more masculine fashion. Four CAH girls
      with late diagnosis are also described. Three of the four girls played
      exclusively with one of the masculine toys, a constructional toy. Our results
      support the view that prenatal androgen exposure has a direct organizational
      effect on the human brain to determine certain aspects of sex-typed behavior.

PMID- 12414882
TI  - Somatostatin receptor genes are expressed in lymphocytes from retroorbital
      tissues in Graves' disease.
AB  - The radiolabeled somatostatin (SST) analog octreotide accumulates within the
      orbits of active Graves' ophthalmopathy (GO), and octreotide and lanreotide have
      been proposed to treat this disorder. It is still unclear which retroorbital
      cells the SST analogs target. Lymphocytic infiltration of retroorbital tissues is
      a peculiarity of GO, and labeled octreotide could accumulate at specific sites on
      retroorbital-activated lymphocytes. The accumulation of radiolabeled analogs is
      due to the interaction with specific cell surface SST receptors. Five subtypes of
      somatostatin receptors (SST1-5), member of the G protein-coupled, seven
      transmembrane superfamily, are described. It still unknown which SST subtype is
      expressed in retroorbital activated lymphocytes. The aim of this study was to
      evaluate the expression of SST1-5 genes in lymphocytes recovered from
      retroorbital tissues obtained from patients with GO undergoing orbital
      decompression. Cultured phytohemagglutinin-stimulated lymphocytes from
      retroorbital blood samples, drawn during orbital surgery in five patients with GO
      and in two control patients without autoimmune or thyroid diseases and without
      orbital inflammatory conditions, were also studied. RT-PCR of total RNA extracted
      from lymphocytes was performed using primers for SST1-5 and, as internal control,
      for glyceraldehyde-3-phosphate dehydrogenase. All SSTs transcripts were found in
      lymphocytes both from GO retroorbital tissues and blood samples. The levels of
      expression of SST1, -2, and -4 mRNA were higher than those of the SST3 and -5
      transcripts. In the lymphocytes from control subjects, the SST subtypes with high
      affinity for octreotide were barely found. The presence, even if at different
      concentrations, of all SST1-5 receptors in retroorbital lymphocytes from GO shows
      that they are targeted by SST analogs and could explain the effects described in
      GO patients treated with SST analogs.

PMID- 12414884
TI  - Neurosteroid quantification in human brain regions: comparison between
      Alzheimer's and nondemented patients.
AB  - Some neurosteroids have been shown to display beneficial effects on
      neuroprotection in rodents. To investigate the physiopathological significance of
      neurosteroids in Alzheimer's disease (AD), we compared the concentrations of
      pregnenolone, pregnenolone sulfate (PREGS), dehydroepiandrosterone,
      dehydroepiandrosterone sulfate (DHEAS), progesterone, and allopregnanolone,
      measured by gas chromatography-mass spectrometry, in individual brain regions of
      AD patients and aged nondemented controls, including hippocampus, amygdala,
      frontal cortex, striatum, hypothalamus, and cerebellum. A general trend toward
      decreased levels of all steroids was observed in all AD patients' brain regions
      compared with controls: PREGS and DHEAS were significantly lower in the striatum
      and cerebellum, and DHEAS was also significantly reduced in the hypothalamus. A
      significant negative correlation was found between the levels of cortical beta
      amyloid peptides and those of PREGS in the striatum and cerebellum and between
      the levels of phosphorylated tau proteins and DHEAS in the hypothalamus. This
      study provides reference values for steroid concentrations determined by gas
      chromatography-mass spectrometry in various regions of the aged human brain. High
      levels of key proteins implicated in the formation of plaques and neurofibrillary
      tangles were correlated with decreased brain levels of PREGS and DHEAS,
      suggesting a possible neuroprotective role of these neurosteroids in AD.

PMID- 12414883
TI  - Norepinephrine transporter function and autonomic control of metabolism.
AB  - Genetic variability, numerous medications, and some illicit drugs influence
      norepinephrine transporter (NET) function; however, the metabolic consequences of
      NET inhibition are poorly understood. We performed a randomized, double-blind,
      cross-over trial in 15 healthy subjects who ingested 8 mg of the selective NET
      inhibitor reboxetine or placebo. Energy expenditure and substrate oxidation rates
      were determined by indirect calorimetry before and during iv infusion of 0.25,
      0.5, 1, and 2 micro g isoproterenol/min. Adipose tissue metabolism was studied by
      microdialysis before and during local isoproterenol perfusion. At rest, energy
      expenditure and substrate oxidation rates did not differ between reboxetine and
      placebo treatment. At 1 micro g/min isoproterenol, energy expenditure was
      significantly increased in men (+15%) and women (+20%) with both reboxetine and
      placebo treatment. However, carbohydrate oxidation rate was significantly higher
      with reboxetine compared with placebo. Baseline and isoproterenol-stimulated
      adipose tissue blood flow was about 2-fold higher with reboxetine vs. placebo.
      Furthermore, glucose supply and metabolism was significantly increased and lipid
      mobilization much more stimulated in adipose tissue under reboxetine when
      compared with placebo at all isoproterenol concentrations used. We conclude that
      acute NET inhibition increases adipose tissue glucose uptake and metabolism.
      While lipid mobilization is increased, overall lipid oxidation is decreased
      during beta-adrenergic stimulation. This effect cannot be explained by increased
      systemic or adipose tissue norepinephrine concentrations. Instead, NET inhibition
      may sensitize adipose tissue to beta-adrenergic stimulation.

PMID- 12414886
TI  - A whole-genome linkage scan suggests several genomic regions potentially
      containing quantitative trait Loci for osteoporosis.
AB  - Osteoporosis is an important health problem, particularly in the elderly women.
      Bone mineral density (BMD) is a major determinant of osteoporosis. For a sample
      of 53 pedigrees that contain 1249 sibling pairs, 1098 grandparent-grandchildren
      pairs, and 2589 first cousin pairs, we performed a whole- genome linkage scan
      using 380 microsatellite markers to identify genomic regions that may contain
      quantitative trait loci (QTL) of BMD. Each pedigree was ascertained through a
      proband with BMD values belonging to the bottom 10% of the population. We
      conducted two-point and multipoint linkage analyses. Several potentially
      important genomic regions were suggested. For example, the genomic region near
      the marker D10S1651 may contain a QTL for hip BMD variation (with two-point
      analysis LOD score of 1.97 and multipoint analysis LOD score of 2.29). The
      genomic regions near the markers D4S413 and D12S1723 may contain QTLs for spine
      BMD variation (with two-point analysis LOD score of 2.12 and 2.17 and multipoint
      analysis LOD score of 3.08 and 2.96, respectively). The genomic regions
      identified in this and some earlier reports are compared for exploration in
      extension studies with larger samples and/or denser markers for confirmation and
      fine mapping to eventually identify major functional genes involved in
      osteoporosis.

PMID- 12414885
TI  - Effect of gender on counterregulatory responses to euglycemic exercise in type 1
      diabetes.
AB  - A marked sexual dimorphism in neuroendocrine and metabolic responses to moderate,
      prolonged exercise occurs in healthy humans. It is unknown whether similar
      differences occur in type 1 diabetes mellitus (T1DM). Fifteen patients with T1DM
      (7 women and 8 men) were studied during 90 min of euglycemic exercise at 50% of
      the maximum rate of O(2) consumption. Men and women were matched for age,
      glycemic control, duration of diabetes, and exercise fitness, and had no history
      or evidence of autonomic neuropathy. Hypoglycemia was scrupulously avoided during
      the week preceding tests. Exercise was performed under constant infusion of
      regular insulin (1 U/h) and a variable 20% dextrose infusion, as needed to
      maintain euglycemia. At 15-min intervals, neuroendocrine, metabolic (glucose
      kinetics, intermediate metabolism, lipolysis), and cardiovascular responses were
      assessed. Indirect calorimetry was performed during the last 10 min of exercise.
      Plasma glucose and insulin did not differ between genders at baseline or during
      exercise. Key neuroendocrine responses were significantly reduced in women,
      compared with men, during exercise (epinephrine, 360 +/- 104 vs. 666 +/- 126 pM;
      norepinephrine, 2.3 +/- 0.8 vs. 4.1 +/- 1.0 nM; GH, 10 +/- 5 vs. 22 +/- 8 micro
      g/liter). Glucagon, cortisol, and pancreatic polypeptide responses were similar
      between genders. Despite reduced catecholamine responses in women, no gender
      differences were observed in endogenous glucose production (EGP) or exogenous
      glucose infusion rate during exercise. The lipolytic response to exercise (blood
      glycerol), on the other hand, was greater in women than in men. In conclusion, a
      marked sexual dimorphism exists in counterregulatory responses to exercise in
      T1DM, including key neuroendocrine (catecholamine, GH) and metabolic (lipolysis)
      responses. Other responses, including glucagon and EGP, were similar between
      genders, suggesting that the glucagon to insulin ratio may be the primary
      determinant of EGP during moderate intensity exercise in T1DM.

PMID- 12414887
TI  - Aging-related changes in release of growth hormone and luteinizing hormone in
      female rhesus monkeys.
AB  - A decline in somatic function with aging in women is associated with a decrease
      in GH release and a loss of estrogen after menopause. As an initial step to
      establish a monkey model for the neuroendocrine mechanisms underlying somatopause
      and menopause, we have conducted three experiments in unrestrained aged
      (approximately 25.7-yr-old) and young (approximately 5.4-yr-old) female rhesus
      monkeys. GH release was pulsatile, and mean GH release and pulse amplitude were
      significantly lower in aged monkeys than in young monkeys. Injection of GHRH
      alone, GH-releasing peptide-2 alone, or the combination of both induced an
      increase in GH release in both age groups. The mean LH level, pulse amplitude,
      and baseline LH levels were significantly higher in aged animals than in young
      animals. Both estrogen and IGF-I levels were lower in aged than young monkeys.
      These results suggest that in female rhesus monkeys 1) there is a clear decline
      in circulating GH and IGF-I levels with aging; 2) GHRH and GH-releasing peptide-2
      stimulate GH release synergistically; and 3) circulating LH levels increase as
      estrogen decreases with aging. These results indicate that the rhesus monkey is
      an excellent model for studies of the neuroendocrine mechanisms of aging.

PMID- 12414888
TI  - Effects of dietary macronutrient content on glucose metabolism in children.
AB  - Effects of carbohydrate, fat, and fructose intake on substrate and hormone
      concentrations, glucose production, gluconeogenesis, and insulin sensitivity were
      determined in healthy, nonobese prepubertal children (n = 12) and adolescents (n
      = 24) using a cross-over design. In one group (12 prepubertal children and 12
      adolescents), subjects were studied after 7 d of isocaloric, isonitrogenous diets
      providing either 60% carbohydrate and 25% fat [high carbohydrate (H(CHO))/low fat
      (L(F))] or 30% carbohydrate and 55% fat [low carbohydrate (L(CHO))/high fat
      (H(F))], and in a second group (12 adolescents) H(CHO)/L(F) diets containing
      either 40% or 10% fructose was used. All subjects adapted to changes in
      carbohydrate and fat intakes primarily by appropriately adjusting their substrate
      oxidation rates to match the intakes, with only minor changes in parameters of
      glucose metabolism. Changing from a L(CHO)/H(F) to H(CHO)/L(F) diet resulted in
      increased insulin sensitivity (stable labeled iv glucose tolerance test) in
      adolescents [from 3.2 +/- 0.7 x 10(-4) to 5.0 +/- 1.4 x 10(-4) (min(-1))/( micro
      U.ml(-1)) (mean +/- SE)] but not in prepubertal children [9.4 +/- 2.5 x 10(-4) to
      9.9 +/- 1.5 x 10(-4) (min(-1))/( micro U.ml(-1))], whereas beta-cell sensitivity
      was unaffected in both groups. Insulin sensitivity was higher in prepubertal
      children than in adolescents (P < 0.05). The dietary fructose content did not
      affect any measured parameter. We conclude that in the short term, dramatic
      changes in fat and carbohydrate intakes (regardless of fructose content) did not
      adversely affect glucose and lipid metabolism in healthy nonobese children. In
      the adolescents, the high carbohydrate diet resulted in increased insulin
      sensitivity, thus facilitating insulin-mediated glucose uptake.

PMID- 12414889
TI  - Muscle uridine diphosphate-hexosamines do not decrease despite correction of
      hyperglycemia-induced insulin resistance in type 2 diabetes.
AB  - Animal studies suggest that overactivity of the hexosamine pathway, resulting in
      increased UDP-hexosamines [UDP-N-acetylglucosamine (UDP-GlcNAc) and UDP-N
      acetylgalactosamine (UDP-GalNAc)] is an important mechanism by which
      hyperglycemia causes insulin resistance. This study was performed to test this
      hypothesis in patients with type 2 diabetes mellitus (DM). Eight obese patients
      with uncontrolled DM type 2 and severe insulin resistance were treated with iv
      insulin for 28 +/- 6 d aimed at euglycemia. Before and after iv insulin
      treatment, insulin sensitivity was measured using a hyperinsulinemic euglycemic
      clamp, and a muscle biopsy was taken for measurement of UDP-GlcNAc, UDP-GalNAc,
      UDP-glucose, and UDP-galactose levels. Also, isoelectric focusing patterns of
      serum transferrin and the urinary excretion of glycosaminoglycans as measures of
      final products of the hexosamine pathway were examined. After euglycemia, insulin
      resistance improved, as demonstrated by an increase in the glucose infusion rate
      during the clamp from 12.7 +/- 5.6 to 22.4 +/- 8.8 micro mol/kg.min (P < 0.0005)
      and a decrease in insulin requirement from 1.7 +/- 0.9 to 1.1 +/- 0.6 U/kg.d (P <
      0.005), whereas metabolic control improved. Surprisingly, both UDP-GlcNAc, from
      8.81 +/- 1.21 to 12.31 +/- 2.52 nmol/g tissue (P < 0.005), and UDP-GalNAc
      concentrations, from 4.49 +/- 0.85 to 5.89 +/- 1.55 nmol/g tissue (P < 0.05)
      increased. Isoelectric focusing patterns of serum transferrin and excretion of
      glycosaminoglycans were similar before and after euglycemia. In conclusion, after
      amelioration of hyperglycemia- induced insulin resistance, UDP-hexosamines
      increased in skeletal muscle of patients with type 2 DM. These results do not
      support the hypothesis that accumulation of products of the hexosamine pathway
      plays a major role in hyperglycemia-induced insulin resistance.

PMID- 12414890
TI  - Thyroid hormone action is disrupted by bisphenol A as an antagonist.
AB  - Bisphenol A (BPA), a monomer of polycarbonate plastics, has been shown to possess
      estrogenic properties and act as an agonist for the estrogen receptors. Although
      an epidemiologically based investigation has suggested that some chemicals could
      disrupt thyroid function in animals, the effects on thyroid hormone receptors
      (TRs) are unknown. We show here that BPA inhibits TR-mediated transcription by
      acting as an antagonist. In the transient gene expression experiments, BPA
      suppressed transcriptional activity that is stimulated by thyroid hormone (T(3))
      in a dose-dependent manner. The inhibitory effects were observed in the presence
      of physiological concentrations of T(3). In contrast, in the case of negatively
      regulated TSHalpha promoter, BPA activated the gene transcription that is
      suppressed by T(3). To elucidate possible mechanisms of the antagonistic action
      of BPA, the effects on T(3) binding and cofactor interaction with TR were
      examined. The K(i) value for BPA was 200 micro M when assessed by inhibition of
      [(125)I]T(3) binding to rat hepatic nuclear TRs. In a mammalian two-hybrid assay,
      BPA recruited the nuclear corepressor to the TR. These results suggest that BPA
      could displace T(3) from the TR and recruit a transcriptional repressor,
      resulting in gene suppression. This is the first report that BPA can antagonize
      T(3) action at the transcriptional level. BPA may disrupt the function of various
      types of nuclear hormone receptors and their cofactors to disturb our internal
      hormonal environment.

PMID- 12414891
TI  - Elevated glucagon-like peptide-1-(7-36)-amide, but not glucose, associated with
      hyperinsulinemic compensation for fat feeding.
AB  - We previously developed a canine model of central obesity and insulin resistance
      by supplementing the normal chow diet with 2 g cooked bacon grease/kg body
      weight. Dogs fed this fatty diet maintained glucose tolerance with compensatory
      hyperinsulinemia. The signal(s) responsible for this up-regulation of plasma
      insulin is unknown. We hypothesized that meal-derived factors such as glucose,
      fatty acids, or incretin hormones may signal beta-cell compensation in the fat
      fed dog. We fed the same fat-supplemented diet for 12 wk to six dogs and compared
      metabolic responses with seven control dogs fed a normal diet. Fasting and
      stimulated fatty acid and glucose-dependent insulinotropic peptide concentrations
      were not increased by fat feeding, whereas glucose was paradoxically decreased,
      ruling out those three factors as signals for compensatory hyperinsulinemia.
      Fasting plasma glucagon-like peptide-1 (GLP-1) concentration was 2.5-fold higher
      in the fat-fed animals, compared with controls, and 3.4-fold higher after a mixed
      meal. Additionally, expression of the GLP-1 receptor in whole pancreas was
      increased 2.3-fold in the fat-fed dogs. The increase in both circulating GLP-1
      and its target receptor may have increased beta-cell responsiveness to lower
      glucose. Glucose is not the primary cause of hyperinsulinemia in the fat-fed dog.
      Corequisite meal-related signals may be permissive for development of
      hyperinsulinemia.

PMID- 12414893
TI  - Human chorionic gonadotropin (HCG) activates monocytes to produce interleukin-8
      via a different pathway from luteinizing hormone/HCG receptor system.
AB  - To investigate immune-endocrine interactions between the embryo and the mother
      early in pregnancy, we examined the effects of human chorionic gonadotropin (HCG)
      on IL-8 production by peripheral blood mononuclear cells (PBMC). Recombinant HCG
      promoted IL-8 secretion by PBMC derived from nonpregnant women. The induction of
      IL-8 mRNA expression was observed after 30 min of HCG stimulation. Adsorption of
      the HCG with anti-HCG antibodies confirmed the specificity of this effect. The
      translocation of nuclear factor kappaB into the nucleus and subsequent IL-8
      production were observed mainly in monocytes, and IL-8 production was reduced
      when a proteasome inhibitor was added to inactivate nuclear factor kappaB.
      Although fluorescein isothiocyanate-labeled HCG was bound to the majority of
      monocytes, cell surface expression of HCG receptor was hardly detected. IL-8
      production by HCG was not affected by inhibitors of protein kinases A and C. In
      contrast, this stimulation was attenuated by D-mannose, which inhibits binding to
      C-type lectins. The basal IL-8 production by PBMC from women early in pregnancy
      was significantly elevated, compared with that from nonpregnant women. This study
      showed that human monocytes respond to HCG and secrete IL-8 through a pathway
      different from the HCG receptor system, suggesting that this glycoprotein hormone
      can react with not only endocrine cells but also immune cells early in pregnancy,
      probably via primitive systems such as C-type lectins.

PMID- 12414895
TI  - Expression patterns of insulin-like growth factor-binding proteins 1, 2, 3, 5,
      and 6 in the mid-cycle monkey ovary.
AB  - IGFs and IGF-binding proteins (IGFBPs) are thought to play important roles in
      ovarian follicular growth and selection. To elucidate the role of IGFBPs in
      primate ovarian function, we analyzed IGFBP mRNA expression patterns in ovaries
      from mid-cycle rhesus monkeys using in situ hybridization. IGFBP-1 mRNA was
      concentrated in theca-interstitial cells and was present at low levels in
      granulosa cells of atretic follicles. IGFBP-2 mRNA was expressed in the ovarian
      surface epithelium and granulosa cells of all antral follicles, including
      obviously atretic as well as dominant follicles. IGFBP-3 mRNA was localized in
      oocytes and in the ovarian vascular endothelium; this mRNA was also concentrated
      in the superficial cortical stroma in which it was distinctly more abundant in
      the nondominant ovary. Granulosa cells of mature dominant and ovulatory follicles
      selectively expressed IGFBP-5 mRNA. IGFBP-5 mRNA was also widely expressed in the
      ovarian stroma, in which, in contrast to IGFBP-3, it was distinctly more abundant
      in dominant, compared with nondominant, ovary. IGFBP-6 mRNA was present at low
      levels in the ovary interstitium and theca externa and was more abundant in the
      ovary surface epithelium. These novel data reveal distinctive cellular expression
      patterns for IGFBPs 1, 2, 3, 5, and 6 in the nonhuman primate ovary, suggesting
      distinct roles for each binding protein in ovarian function.

PMID- 12414894
TI  - Cyclic mechanical stretch augments prostacyclin production in cultured human
      uterine myometrial cells from pregnant women: possible involvement of up
      regulation of prostacyclin synthase expression.
AB  - Prostacyclin (PGI(2)), a potent smooth muscle relaxant, is a major prostaglandin
      secreted from human myometrium. The concentrations of PGI(2) metabolites in the
      maternal plasma were reported to be elevated during pregnancy, especially in
      labor. To clarify the mechanism in PGI(2) secretion from the myometrium, we first
      investigated the protein expression of cytosolic phospholipase A(2),
      cyclooxygenase (COX)-1, COX-2, and prostacyclin synthase (PGIS) in the human
      uterine myometrium at various gestational ages before labor. To elucidate the
      involvement of labor in the increase in PGI(2) production during labor, we next
      examined the effect of labor-like cyclic mechanical stretch on PGI(2) production
      by cultured human myometrial cells. Pregnancy specifically increased COX-1 and
      PGIS protein expression in the myometrial tissues before labor (P < 0.01 for
      both). Cyclic mechanical stretch augmented PGIS promoter activity, via activation
      of activator protein-1 site, and PGIS mRNA and protein expression in cultured
      human myometrial cells and resulted in a 3.5-fold increase in the concentration
      of 6-keto-prostaglandin F(1alpha), the stable metabolite of PGI(2), in the
      culture medium (P < 0.05). However, stretch did not affect the levels of
      prostaglandin E(2), prostaglandin F(2alpha), or thromboxane A(2) secreted into
      the same culture media. These results suggest that cyclic mechanical stretch
      during labor may contribute to the increase in the PGI(2) concentration in the
      maternal plasma during parturition.

PMID- 12414896
TI  - Mifepristone-induced vaginal bleeding is associated with increased immunostaining
      for cyclooxygenase-2 and decrease in prostaglandin dehydrogenase in luteal phase
      endometrium.
AB  - The mechanism of mifepristone-induced vaginal bleeding and endometrial shedding
      was investigated in 13 women who took 200 mg mifepristone in the midluteal phase
      on d 8 after the onset of the urinary LH surge (LH+8). Endometrial biopsies were
      collected, 6-24 h after mifepristone (group 1, n = 7) or 36-48 h after
      mifepristone (group 2, n = 6), and compared with those from a control group in
      the midluteal phase (n = 7). All women reported vaginal bleeding commencing 36-48
      h after taking mifepristone. Treatment with mifepristone significantly reduced
      serum progesterone levels in all women, when compared with the controls (13.2 nM
      vs. 34.8 nM, P = 0.001). After mifepristone, a significant increase in
      cyclooxygenase-2 immunoreactivity was apparent at 36-48 h (P = 0.0018), whereas
      prostaglandin 15 dehydrogenase enzyme-positive immunostaining declined, to be
      virtually absent by 36-48 h in both glands and in stroma (P < 0.05). There was no
      change in intensity or distribution of staining for steroid receptors after
      mifepristone. The changes in immunostaining for cyclooxygenase-2 and
      prostaglandin 15 dehydrogenase strongly support the hypothesis that an increase
      in the local concentration of prostaglandins in the endometrium is involved in
      the mechanism of bleeding induced by mifepristone in the luteal phase.

PMID- 12414897
TI  - Pregnancy-associated plasma protein A proteolytic activity is associated with the
      human placental trophoblast cell membrane.
AB  - Pregnancy-associated plasma protein-A (PAPP-A) is a product of the placenta and
      decidua and is secreted into the maternal circulation during human pregnancy. It
      recently has been identified as an IGF binding protein (IGFBP)-4 protease.
      Presumed functions at the maternal-fetal interface are to proteolyze IGFBP-4 and
      thus increase IGF bioavailability locally in the placenta, to promote IGF-II
      mediated trophoblast invasion into the maternal decidua, and to modulate IGF
      regulation of steroidogenesis and glucose and amino acid transport in the
      villous. Herein, we have investigated the possibility that IGFBP-4 proteolysis
      may occur on the trophoblast cell membrane, presumably to increase local
      bioavailable IGF for interactions with cognate IGF membrane receptors. Human
      trophoblasts were cultured, trophoblast plasma membranes were isolated and
      solubilized, and IGFBP-4 protease activity and PAPP-A immunoreactivity in the
      solubilized plasma membrane fraction were investigated. IGFBP-4 protease activity
      was detected in solubilized human trophoblast membranes, resulting in cleavage of
      recombinant human IGFBP-4 into 18- and 14-kDa fragments, detected by Western
      immunoblot analysis. This protease activity was dependent on the presence of IGF
      II, and its metal ion dependence was demonstrated by inhibition of the protease
      by the metal chelators, EDTA and EGTA. The presence of PAPP-A in solubilized
      human trophoblast membranes was demonstrated by Western immunoblotting.
      Trophoblast membrane PAPP-A had a relative molecular weight of approximately 200
      kDa and comigrated on (reducing) SDS-PAGE with recombinant human PAPP-A and PAPP
      A secreted into media conditioned by cultured human trophoblasts. IGFBP-4
      protease activity was not detected after immunodepletion of PAPP-A from the
      trophoblast membrane fraction with PAPP-A polyclonal antibodies, suggesting the
      identity of the membrane-derived IGFBP-4 protease as PAPP-A. Immunocytochemistry
      revealed PAPP-A on the cell membrane and in the cytoplasm of human trophoblasts
      in culture. Together, these data demonstrate the presence of an IGF-II- and metal
      dependent IGFBP-4 protease activity in human trophoblast plasma membranes,
      identified as PAPP-A, which is well situated to proteolyze IGFBP-4 at the
      maternal-placental interface to facilitate IGF action at the villous surface
      and/or the invading extravillous cytotrophoblast.

PMID- 12414898
TI  - VHL2C phenotype in a German von Hippel-Lindau family with concurrent VHL germline
      mutations P81S and L188V.
AB  - Von Hippel-Lindau disease (VHL) is a multitumor syndrome that develops on the
      basis of germline mutations in the VHL tumor suppressor gene. Genotype-phenotype
      correlations have helped to stratify the disease into VHL type 1 (without
      pheochromocytoma) and VHL type 2A, 2B, and 2C (with pheochromocytoma). VHL2C is
      characterized by a pheochromocytoma-only phenotype. We report on the P81S
      germline mutation in a German VHL2C family with the previously identified L188V
      mutation. The concurrent P81S mutation was identified by novel screening
      approaches including denaturing HPLC and sequencing. We show the co-segregation
      of these two mutations with the disease and discuss their possible impact on pVHL
      function and phenotype.

PMID- 12414899
TI  - Aminoglycoside pretreatment partially restores the function of truncated V(2)
      vasopressin receptors found in patients with nephrogenic diabetes insipidus.
AB  - By screening patients with X-linked nephrogenic diabetes insipidus (NDI) for
      mutations within the V(2) vasopressin receptor (AVPR2) gene, we have identified
      six novel and two recurrent mutations. Additionally, one patient revealed a
      genomic deletion of 3.2 kb encompassing most of the AVPR2 gene and the last
      exon/3'-region of C1 gene, which is in close proximity to the AVPR2 locus. In
      depth characterization of the mutant AVPR2s by a combination of functional and
      immunological techniques allowed to gain further insight into molecular
      mechanisms leading to the receptor dysfunction. Aiming at the functional
      reconstitution of mutant G protein-coupled receptors, several strategies of
      potential therapeutic usefulness have been tested. Because the functional rescue
      of truncated receptors is most challenging, we addressed this issue by applying
      an aminoglycoside approach. Here, we demonstrate that the misreading capacity of
      the aminoglycoside antibiotic geneticin was sufficient to restore function of
      mutant AVPR2s harboring premature stop codons in an in vitro expression system.

PMID- 12414900
TI  - Association of a single-nucleotide polymorphism of the deleted-in-azoospermia
      like gene with susceptibility to spermatogenic failure.
AB  - Single-strand conformation polymorphism analysis of exon-containing genomic DNA
      segments of the deleted-in-azoospermia-like (DAZL) gene was performed in 160
      infertile Taiwanese men presenting with severe oligozoospermia and nonobstructive
      azoospermia. An A-->G transition at nucleotide 386 in exon 3 was identified. The
      mutation is located within the RNA-recognition motif (aa 32-117) domain of the
      DAZL protein and will lead to Thr54-->Ala change (T54A) of DAZL protein. Analysis
      of cDNA from testicular tissue of infertile carriers showed absence of expression
      for the T54A allele, implying that the allele carrying T54A polymorphism is
      hardly, if ever, expressed. The frequencies of T54A allele in patients and the
      control group were 7.39% and 0.86%, respectively (P = 0.0003). The phenotypes
      varied significantly in cases with heterozygous T54A polymorphism, ranging from
      hypospermatogenesis and maturation arrest to Sertoli cell-only syndrome. A
      combination of DAZ gene deletion and T54A polymorphism did not worsen the
      phenotype. Our findings provide strong evidence for the role of the autosomal
      DAZL gene in human spermatogenesis.

PMID- 12414901
TI  - Wild-type estrogen receptor (ERbeta1) and the splice variant (ERbetacx/beta2) are
      both expressed within the human endometrium throughout the normal menstrual
      cycle.
AB  - Estrogen action is mediated via two subtypes of the estrogen receptor (ER),
      usually referred to as ERalpha and ERbeta. We have previously compared the
      spatial and temporal expressions of ERalpha and ERbeta proteins in human
      endometrium and reported that endothelial cells exclusively express ERbeta. In
      the present study we have extended our investigations to compare the pattern of
      expression of wild-type (ERbeta1) and a newly identified ERbeta variant isoform
      (ERbetacx/beta2) that lacks the ability to bind steroids. mRNAs encoding both
      ERbeta1 and ERbetacx/beta2 receptors were identified in human endometrial
      extracts by RT-PCR. Quantitative TaqMan R-TPCR demonstrated that levels of total
      mRNAs were increased significantly premenstrually as circulating progesterone
      levels declined. ERbeta1 and ERbetacx/beta2 proteins were identified within
      multiple cell types within the endometrium using isotype-specific monoclonal
      antibodies; immunoexpression of ERbetacx/beta2 appeared less intense than that of
      ERbeta1 in endometrial glandular epithelium and endothelial cells.
      Immunoexpression of ERbeta1 appeared unchanged throughout the menstrual cycle. In
      contrast, levels of ERbetacx/beta2-specific immunoreactivity were specifically
      reduced in gland cells within the functional layer, but not in those of the basal
      layer, in the midsecretory phase. It is possible that coexpression of
      ERbetacx/beta2 in cells containing ERbeta1 and/or ERalpha may modulate the
      effects of estrogens on the endometrium.

PMID- 12414902
TI  - Expression of prostaglandin I(2) synthase, but not prostaglandin E synthase,
      changes in myometrium of women at term pregnancy.
AB  - Prostaglandins (PGs) act as potent uterotonins at the time of labor.
      Prostaglandin E synthase (PGES) is responsible for the formation of PGE(2), a
      uterotonin. PGI(2) is synthesized by the prostaglandin I synthase enzyme (PGIS)
      and contributes to relaxation in the lower uterine segment. We examined the
      expression of membrane-bound PGES and PGIS in myometrium from pregnant women
      during preterm and term labor. Tissues were collected from the lower uterine
      segment from preterm no labor, preterm labor, term no labor, and term labor
      patients and used for immunohistochemistry and Western blot analysis using
      specific antibodies. Immunoreactive (ir-) PGES and PGIS proteins were localized
      to the cytoplasm of myocytes of the myometrium and vascular smooth muscle cells.
      Ir-PGES was also detected in vascular endothelial cells. Western blot analyses
      revealed a predominant protein band of 180 kDa, and a second 16-kDa band for ir
      PGES and 56-kDa band for ir-PGIS. There was no significant change in ir-PGES
      protein (180 or 16 kDa) or mRNA levels with preterm or term labor or gestational
      age. There was a significant decrease in PGIS mRNA and protein with advancing
      gestational age. We conclude that the gestational age decrease in the inhibitory
      PGIS is consistent with lessening of its influence in myometrium at the time of
      labor. The lack of change in PGES indicates that alterations at other points
      along the pathway of arachidonic acid metabolism may be of greater importance in
      affecting local changes in PGE(2).

PMID- 12414903
TI  - Production of activins by the human endosalpinx.
AB  - Uterine tubes from 11 premenopausal and 6 postmenopausal women were collected and
      examined for the presence of inhibin, activin, and follistatin in the
      endosalpinx. Immunocytochemistry of tissue from both the isthmic and ampullary
      regions demonstrated clear staining for the beta(A)- and beta(B)-subunits that
      increased in intensity from the isthmus to the ampulla. Staining for follistatin
      showed a similar pattern, but no staining for the alpha-subunit was observed.
      Although staining for the beta(A)-subunit was seen in almost every epithelial
      cell, staining for the beta(B)-subunit was more variable. Western blotting showed
      a band with an apparent molecular mass of 28 kDa (corresponding to the activin
      dimer) and a band of approximately 60 kDa (corresponding to the pro-protein of
      activin). In situ hybridization confirmed the presence of mRNA for the beta(A)-
      and beta(B)-subunits in the endosalpinx. These results indicate that the
      endosalpinx is able to synthesize activin, not inhibin, suggesting that in
      premenopausal women they may have an important role in the biology of the
      developing embryo. The role in postmenopausal women is less certain, but could
      lead to the stimulation of FSH secretion by the pituitary gland or other
      autocrine/paracrine function within the uterine tube.

PMID- 12414905
TI  - Trans-differentiation of prostatic stromal cells leads to decreased glycoprotein
      hormone alpha production.
AB  - Age-related development of benign prostatic hyperplasia is an important health
      issue in developed countries. The histopathogenetic hallmark of this disease is
      the increase in relative and absolute numbers of smooth muscle cells (SMC).
      Glycoprotein hormone alpha-subunit (GPHalpha) is expressed in the human prostate,
      and, because of its structural similarities to other cystine knot growth factors,
      it has been considered to have growth regulatory functions of its own. Primary
      cell cultures allowing for selective cultivation of prostatic epithelial cells,
      fibroblasts, and SMC were established. Directed trans-differentiation and
      cellular homogeneity was pursued by confocal scanning laser microscopy with cell
      type-specific markers. GPHalpha production by these cells was assessed by
      immunofluorimetric assays. Its predominant source was young fibroblasts, whereas
      replicative senescent fibroblasts, SMC, and control fibroblasts from foreskin did
      not produce significant amounts. Functionally, GPHalpha reduced growth of stromal
      cells at concentrations of 10 and 100 nmol/liter as shown by cell viability
      assays. It is concluded that histogenetic reorganization over the adult lifetime,
      guided by endocrine factors like steroid hormones together with senescence of
      fibroblasts, leads to a decreased production of growth inhibitors, such as
      GPHalpha, favoring proliferation and the development of benign prostatic
      hyperplasia.

PMID- 12414904
TI  - Characterization of human chorionic gonadotropin as a novel angiogenic factor.
AB  - Angiogenesis and vascular remodeling are crucial processes in tumor invasion and
      metastasis as well as in embryo implantation and normal development of the
      placenta. We have previously shown that hCG expressed in trophoblast and various
      malignant tumors promotes cellular motility and that uterine endothelium
      expresses hCG/LH receptor in vivo. In this study hCG was proposed to promote
      angiogenesis. A three-dimensional in vitro angiogenesis system consisting of
      uterine microvascular endothelial cells seeded on microcarriers and entrapped in
      a fibrin matrix was used to study the influence of hCG on neovascularization.
      Physiological concentrations of hCG (5-50,000 mU/ml) significantly increased in
      vitro capillary formation (up to 2.5-fold) and migration of endothelial cells in
      a Boyden chamber assay (up to 3.6-fold) in a dose-dependent manner, whereas hCG
      had no effect on cell proliferation. In vivo, hCG induced neovascularization in
      the chicken chorioallantoic membrane assay comparable to the activity of vascular
      endothelial growth factor. hCG-secreting tumors (choriocarcinoma, endometrium,
      and ovarian carcinoma) promoted in vitro neovascularization (up to 3-fold),
      whereas hCG-neutralizing antibody, pertussis toxin (G protein inhibitor), or
      GRGDTP peptide (integrin antagonist), respectively, abolished both tumor- and hCG
      induced capillary sprout formation. Our data indicate a novel function for hCG in
      uterine adaptation to early pregnancy as well as in tumor development and
      underline the importance of hCG as an as yet unrecognized angiogenic factor.

PMID- 12414907
TI  - Transcriptionally targeted retroviral vector for combined suicide and
      immunomodulating gene therapy of thyroid cancer.
AB  - Gene therapy may be an effective approach to thyroid carcinoma refractory to
      conventional treatment. A transcriptionally targeted retroviral vector for gene
      therapy of thyroid carcinomas was generated replacing the viral enhancer with the
      enhancer sequence of the human thyroglobulin (TG) gene, yielding a chimeric long
      terminal repeat. The TG enhancer was used to drive the expression of either a
      reporter gene (beta-galactosidase) or two therapeutic genes, i.e. the prodrug
      activating enzyme thymidine kinase of herpes simplex virus (HSV-TK) and human IL
      2, separated by an internal ribosome entry site. The corresponding vector having
      an unmodified long-terminal repeat was used as control. The targeted vector
      allowed selective transgene expression and cell killing in differentiated thyroid
      tumor cells but not in anaplastic thyroid carcinoma cells and nonthyroid cells,
      as demonstrated by quantitative RT-PCR and cytotoxicity assays. Nude mice
      injected with tumor cells underwent near complete or complete regression of
      tumors transduced with the control vector after ganciclovir treatment. On the
      other hand, infection with the thyroid-specific vector led to regression only of
      TG-expressing tumors. In addition, tumors expressing human IL-2 showed
      significant growth retardation, compared with nontransduced tumors while
      exhibiting signs of necrosis and presence of an inflammatory infiltrate. However,
      HSV-TK/IL-2 plus ganciclovir was significantly more efficient than HSV-TK/IL-2
      alone in eradicating tumor masses. Our results indicate that replacement of viral
      enhancer with TG enhancer confers selectivity of transgene expression in thyroid
      cells. Thus, the combined thyroid-specific expression of two therapeutic genes
      (cytokine and suicide genes), although a safe tumor-targeted treatment, would
      allow an increased anticancer effect.

PMID- 12414908
TI  - PAX3/forkhead homolog in rhabdomyosarcoma oncoprotein activates glucose
      transporter 4 gene expression in vivo and in vitro.
AB  - Increased levels of glucose uptake and increased expression of the glucose
      transporter (GLUT) genes are characteristic features of tumors. In the muscle
      derived tumor alveolar rhabdomyosarcoma (ARMS), a chromosomal translocation
      t(2:13) generates the PAX3/forkhead homolog in rhabdomyosarcoma (FKHR)
      oncoprotein. In muscle tissues, glucose transport is primarily mediated by GLUT4.
      However, the mechanisms that regulate GLUT4 gene expression in tumor tissues are
      largely unknown. Therefore, we evaluated the role of PAX3/FKHR in the regulation
      of GLUT4 gene expression in muscle tumorigenesis. GLUT4 mRNA and protein were
      detected in ARMS-derived human biopsies and in ARMS-derived RH30 myoblasts, which
      both express the PAX3/FKHR chimeric protein, but not in either C2C12 or embryonal
      rhabdomyosarcoma-derived myoblasts. GLUT4 was functionally active in RH30 cells,
      because insulin induced a 1.4-fold stimulation of basal 2-deoxyglucose uptake
      rates. Coexpression of PAX3/FKHR increased basal transcriptional activity from a
      GLUT4 promoter reporter (GLUT4-P) in C2C12, SaOS-2, and Chinese hamster ovary-K1
      cells in a dose-dependent and tissue-specific manner. PAX3/FKHR mutants with
      deletions in either the homeodomain (DeltaHD) or the FKHR-derived activation
      domain (DeltaFKHR), or in which the PAX3-derived paired domain (PD) was point
      mutated (PD-R56L), were unable to activate GLUT4-P. Progressive 5'-deletion
      analysis of GLUT4-P further identified a specific region of the promoter, 
      66/+163 bp, which retained about 65% of the full transactivation effect. EMSA
      studies established that the PAX3/FKHR protein directly and specifically binds to
      this region and to a shorter fragment, -4/+36 bp, that contains potential binding
      sites for HD and PD, but not to a -4/+36-bp fragment whose HD and PD sites have
      been mutated. Thus, the functional interaction of PAX3/FKHR with GLUT4-P appears
      to require all of the functional domains of PAX3/FKHR, as well as a -4/+36-bp
      region within the GLUT4 promoter. Taken together, the data suggest that the GLUT4
      gene is a downstream target of PAX3/FKHR and that GLUT4 is aberrantly
      transactivated by this oncoprotein both in vivo and in vitro.

PMID- 12414909
TI  - Progesterone production and actions in the human central nervous system and
      neurogenic tumors.
AB  - Progesterone has been suggested to be involved in the functions of the nervous
      system, but it has yet to be examined in humans. Progesterone has also been
      postulated to be involved in the biological behavior of various human neurogenic
      tumors via progesterone receptors A and B (PR-A and PR-B). In this study we
      examined the expression of PR and the enzymes responsible for progesterone
      biosynthesis (P450scc, 3betahydroxysteroid dehydrogenase, and steroidogenic acute
      regulatory protein) in human brain. We also examined the distribution of PR
      isoforms in neurogenic tumors using immunohistochemistry and RT-PCR analysis. The
      presence of PR and mRNA for P450scc, 3beta-hydroxysteroid dehydrogenase, and
      steroidogenic acute regulatory protein was detected in human brain. PR isoforms
      were detected in neurogenic tumors. PR-A and PR-B were equally expressed in
      meningiomas, but PR-B was the predominant isoform compared with PR-A in
      astrocytic tumors and Schwannomas. There was a statistically significant inverse
      correlation between PR-A and the proliferation index in meningiomas and
      astrocytic tumors. These findings suggest that progesterone is locally
      synthesized and exerts its actions through PR in the human central nervous
      system, and that progesterone may be involved in regulation of the growth and
      development of neurogenic tumors via PR, especially in the inhibition of tumor
      cell proliferation via PR-A.

PMID- 12414910
TI  - Neither homeostasis model assessment nor quantitative insulin sensitivity check
      index can predict insulin resistance in elderly patients with poorly controlled
      type 2 diabetes mellitus.
AB  - To clarify whether homeostasis model assessment (HOMA IR) and quantitative
      insulin sensitivity check index (QUICKI) may be indicators of insulin resistance
      in elderly patients with type 2 diabetes mellitus, their relationship with the
      glucose infusion rate during the euglycemic hyperinsulinemic clamp study (clamp
      IR) was assessed. This study comprised 56 Japanese patients with type 2 diabetes
      mellitus; of these, 28 were 70 yr of age or older (group 1) and 28 were less than
      70 yr of age (group 2). Their blood sugars were in poor control (fasting plasma
      glucose levels: group 1, 9.0 +/- 2.6 mmol/liter; group 2, 8.9 +/- 2.3 mmol/liter;
      hemoglobin A1c: group 1, 9.5 +/- 2.0%; group 2, 9.2 +/- 1.7%). Log-transformed
      HOMA IR was significantly correlated with the clamp IR in group 2 patients (r = 
      0.51, P < 0.01), but not in group 1 patients (r = -0.28, P = 0.15). There was a
      significant positive correlation between QUICKI and clamp IR in group 2 patients
      (r = 0.50, P < 0.01). However, no significant correlation was observed between
      QUICKI and clamp IR in group 1 patients (r = 0.31, P = 0.12). There was a
      significant correlation between log-transformed HOMA IR (r = -0.37, P < 0.01) or
      QUICKI (r = 0.37, P < 0.01) and clamp IR when both groups were combined. In
      conclusion, neither HOMA IR nor QUICKI should be used as an index of insulin
      resistance in elderly patients with poorly controlled type 2 diabetes mellitus.
      The results of this study suggest the need for developing a new noninvasive
      method for evaluating insulin resistance in those patients.

PMID- 12414911
TI  - Transcriptional expression of genes involved in cell invasion and migration by
      normal and tumoral trophoblast cells.
AB  - Once initiated, invasion of trophoblast cells must be tightly regulated,
      particularly in early pregnancy. The mechanisms necessary for the invasion and
      migration of trophoblast cells are thought to be related to those involved in the
      invasive and metastatic properties of cancer cells. Quantitative PCR was used to
      measure, in trophoblast cells, the transcriptional expression profiles of four
      genes, INSL4, BRMS1, KiSS-1 and KiSS-1R, reported to be implicated in tumor
      invasion and metastasis. Laser capture microdissection and purification of
      trophoblast cells demonstrate that, as already known for INSL4, BRMS1, KiSS-1 and
      KiSS-1R are expressed by the trophoblast subset of placental tissues. Expression
      profiles of these genes studied in early placentas (7-9 weeks, n=55) and term
      placentas (n=11) showed that expression levels of BRMS1 are higher in term than
      in early placentas, while expression levels of KiSS-1R are higher in early than
      in term placentas. Low levels of expression of BRMS1 were observed in normal
      pregnancies, in molar pregnancies and in choriocarcinoma cell lines BeWo, JAR and
      JEG3 while, in striking contrast, the expression levels of INSL4, KiSS-1 and Kiss
      1R were increased in both early placentas and molar pregnancies and were reduced
      in choriocarcinoma cells. These transcriptional expression profiles are in favor
      of a predominant role of INSL4, KiSS-1 and KiSS-1R in the control of the invasive
      and migratory properties of trophoblast cells.

PMID- 12414912
TI  - Endocrine-related resources from the National Institutes of Health.

PMID- 12414914
TI  - Anti-integrin therapy.
AB  - The glycoprotein IIb/IIIa integrin receptor binds fibrinogen and is therefore a
      final common pathway responsible for platelet aggregation. One antibody
      (abciximab) and two synthetic compounds (tirofiban and eptifibatide) are
      clinically available to antagonize the function of this receptor. Several large
      scale studies have documented the benefit of these compounds in acute coronary
      syndromes and during percutaneous interventions. Current data suggest that
      abciximab is the preferred drug in the catheterization laboratory, whereas the
      other compounds reduce risk for patients with unstable angina before coronary
      interventions are performed. The highest benefit is achieved in diabetic patients
      and in patients with elevated troponins. Adverse reactions are rare, and bleeding
      complications are minor when weight-adjusted heparin is given. Oral compounds
      have been associated with excess mortality, precluding their clinical use.

PMID- 12414915
TI  - Genetics and pathophysiology of human obesity.
AB  - Obesity has become a leading public health concern. Over 1 billion people are now
      overweight or obese, and the prevalence of these conditions is rising rapidly.
      Remarkable new insights into the mechanisms that control body weight are
      providing an increasingly detailed framework for a better understanding of
      obesity pathogenesis. Key peripheral signals, such as leptin, insulin, and
      ghrelin, have been linked to hypothalamic neuropeptide systems, and the anatomic
      and functional networks that integrate these systems have begun to be elucidated.
      This article highlights some of these recent findings and their implications for
      the future of obesity treatment.

PMID- 12414916
TI  - Atheroprotective effects of high-density lipoproteins.
AB  - Observational studies provide overwhelming evidence that a low high-density
      lipoprotein (HDL)-cholesterol level increases the risk of coronary events, both
      in healthy subjects and in patients with coronary heart disease. Based on in
      vitro experiments, several mechanistic explanations for the atheroprotective
      function of HDL have been suggested. However, few of these were verified in vivo
      in humans or in experiments with transgenic animals. The HDL functions currently
      most widely held to account for the antiatherogenic effect include participation
      in reverse cholesterol transport, protection against endothelial dysfunction, and
      inhibition of oxidative stress. This review summarizes current views on the
      molecular mechanism underlying these atheroprotective effects of HDL.

PMID- 12414917
TI  - The antiphospholipid syndrome.
AB  - The antiphospholipid (aPL) antibody syndrome is an autoimmune condition in which
      vascular thrombosis and/or recurrent pregnancy losses occur in patients with
      laboratory evidence for antibodies that bind to phospholipids. There have been
      significant advances in the recognition of the role of phospholipid-binding
      cofactors, primarily beta2GPI, as the true immunologic targets of the antibodies.
      Recent evidence suggests that the antibodies disrupt phospholipid-dependent
      anticoagulant mechanisms and/or that aPL antibodies induce the expression of
      procoagulant and proadhesive molecules on endothelial cells. Current diagnosis is
      based on clinical findings and empirically derived tests, such as assays for
      antibodies that bind to phospholipids or putative cofactors and coagulation
      assays that detect inhibition of phospholipid-dependent coagulation reactions.
      Current treatment relies primarily on anticoagulant therapy. Research advances
      are expected to bring mechanistically based diagnostic tests and improved therapy
      that target the roots of the disease process.

PMID- 12414918
TI  - The current status of hematopoietic cell transplantation.
AB  - Hematopoietic cell transplantation is the preferred therapy for a substantial
      proportion of patients with life-threatening diseases of the lymphohematopoietic
      system. Recent advances in donor identification, disease eradication, and
      supportive care measures have broadened the application of transplantation and
      improved outcomes. This article provides a brief review of the major clinical
      principles of transplantation and results achieved to date.

PMID- 12414919
TI  - Open surgical repair versus endovascular therapy for chronic lower-extremity
      occlusive disease.
AB  - Chronic lower-extremity occlusive disease is most often manifested by mild
      symptoms of claudication that can be managed conservatively. When conservative
      therapy fails, endovascular procedures may be effective, particularly if the
      disease extent is minimal. Surgery may be considered for selected patients with
      claudication who fail endovascular therapy or are not candidates for it. Patients
      with more severe symptoms of lower-extremity occlusive disease typically have
      more extensive disease that is treated best with surgery or with a combination of
      surgery and endovascular therapy. Occasionally, endovascular procedures are
      performed on patients with more extensive disease who are poor candidates for
      traditional open surgery because of severe comorbidity. Further advances in
      endovascular technology may improve patency after endovascular procedures in
      these patients.

PMID- 12414920
TI  - Peptides containing cyclin/Cdk-nuclear localization signal motifs derived from
      viral initiator proteins bind to DNA when unphosphorylated.
AB  - A single phosphorylation event at T-antigen residue Thr124 regulates initiation
      of simian virus 40 DNA replication. To explore this regulatory process, a series
      of peptides were synthesized, centered on Thr124. These peptides contain a
      nuclear localization signal (NLS) and a recognition site for cyclin/Cdk kinases.
      When unphosphorylated, the "CDK/NLS" peptides inhibit T-antigen assembly and bind
      non-sequence specifically to DNA. However, these activities are greatly reduced
      upon phosphorylation of Thr124. Similar results were obtained by using peptides
      derived from the CDK/NLS region of bovine papillomavirus E1. Related studies
      indicate that residues in the NLS bind to DNA, whereas those in the CDK motif
      regulate binding. These findings are discussed in terms of the control of T
      antigen double hexamer assembly and initiation of viral replication.

PMID- 12414921
TI  - Frequent reassortments may explain the genetic heterogeneity of rotaviruses:
      analysis of Finnish rotavirus strains.
AB  - The predominant rotavirus electropherotypes (e-types) during 17 epidemic seasons
      (1980 through 1997) in Finland were established, and representative virus
      isolates were studied by nucleotide sequencing and phylogenetic analysis. The
      virus isolates were either P[8]G1 or P[8]G4 types. The G1 and G4 strains formed
      one G1 lineage (VP7-G1-1) and one G4 lineage, respectively. Otherwise, they
      belonged to two P[8] lineages (VP4-P[8]-1 and -2) unrelated to their G types.
      Phylogenetic analysis of partial sequences of all 11 RNA segments obtained from
      the strains also revealed genetic diversity among gene segments other than those
      defining P and G types. With the exception of segments 1, 3, and 10, the
      sequences of the other segments could be assigned to 2 to 4 different genetic
      clusters. The results of this study suggest that, in addition to the RNA segments
      encoding VP4 and VP7, the other RNA segments may segregate independently as well.
      In total, the 9 predominant e-types represented 7 different RNA segment
      combinations when the phylogenetic clusters of their 11 genes were determined.
      The extensive genetic diversity and number of e-types among rotaviruses are best
      explained by frequent genetic reassortment.

PMID- 12414922
TI  - Amino acid residues in the carboxy-terminal region of cottontail rabbit
      papillomavirus E6 influence spontaneous regression of cutaneous papillomas.
AB  - Previous studies have identified two different strains of cottontail rabbit
      papillomavirus (CRPV) that differ by approximately 5% in base pair sequence and
      that perform quite differently when used to challenge New Zealand White (NZW)
      rabbit skin. One strain caused persistent lesions (progressor strain), and the
      other induced papillomas that spontaneously regressed (regressor strain) at high
      frequencies (J. Salmon, M. Nonnenmacher, S. Caze, P. Flamant, O. Croissant, G.
      Orth, and F. Breitburd, J. Virol. 74:10766-10777, 2000; J. Salmon, N. Ramoz, P.
      Cassonnet, G. Orth, and F. Breitburd, Virology 235:228-234, 1997). We generated a
      panel of CRPV genomes that contained chimeric and mutant progressor and regressor
      strain E6 genes and assessed the outcome upon infection of both outbred and
      EIII/JC inbred NZW rabbits. The carboxy-terminal 77-amino-acid region of the
      regressor CRPV strain E6, which contained 15 amino acid residues that are
      different from those of the equivalent region of the persistent CRPV strain E6,
      played a dominant role in the conversion of the persistent CRPV strain to one
      showing high rates of spontaneous regressions. In addition, a single amino acid
      change (G252E) in the E6 protein of the CRPV progressor strain led to high
      frequencies of spontaneous regressions in inbred rabbits. These observations
      imply that small changes in the amino acid sequences of papillomavirus proteins
      can dramatically impact the outcome of natural host immune responses to these
      viral infections. The data imply that intrastrain differences between separate
      isolates of a single papillomavirus type (such as human papillomavirus type 16)
      may contribute to a collective variability in host immune responses in outbred
      human populations.

PMID- 12414923
TI  - Inhibition of polyomavirus ori-dependent DNA replication by mSin3B.
AB  - When tethered in cis to DNA, the transcriptional corepressor mSin3B inhibits
      polyomavirus (Py) ori-dependent DNA replication in vivo. Histone deacetylases
      (HDACs) appear not to be involved, since tethering class I and class II HDACs in
      cis does not inhibit replication and treating the cells with trichostatin A does
      not specifically relieve inhibition by mSin3B. However, the mSin3B L59P mutation
      that impairs mSin3B interaction with N-CoR/SMRT abrogates inhibition of
      replication, suggesting the involvement of N-CoR/SMRT. Py large T antigen
      interacts with mSin3B, suggesting an HDAC-independent mechanism by which mSin3B
      inhibits DNA replication.

PMID- 12414924
TI  - Receptor-induced conformational changes of murine coronavirus spike protein.
AB  - Although murine coronavirus mouse hepatitis virus (MHV) enters cells by virus
      cell membrane fusion triggered by its spike (S) protein, it is not well known how
      the S protein participates in fusion events. We reported that the soluble form of
      MHV receptor (soMHVR) transformed a nonfusogenic S protein into a fusogenic one
      (F. Taguchi and S. Matsuyama, J. Virol. 76:950-958, 2002). In the present study,
      we demonstrate that soMHVR induces the conformational changes of the S protein,
      as shown by the proteinase digestion test. A cl-2 mutant, srr7, of the MHV JHM
      virus (JHMV) was digested with proteinase K after treatment with soMHVR, and the
      resultant S protein was analyzed by Western blotting using monoclonal antibody
      (MAb) 10G, specific for the membrane-anchored S2 subunit. A 58-kDa fragment,
      encompassing the two heptad repeats in S2, was detected when srr7 was digested
      after soMHVR treatment, while no band was seen when the virus was untreated. The
      appearance of the proteinase-resistant fragment was dependent on the temperature
      and time of srr7 incubation with soMHVR and also on the concentration of soMHVR.
      Coimmunoprecipitation indicated that the direct binding of soMHVR to srr7 S
      protein induced these conformational changes; this was also suggested by the
      inhibition of the changes following pretreatment of soMHVR with anti-MHVR MAb
      CC1. soMHVR induced conformational changes of the S proteins of wild-type (wt)
      JHMV cl-2, as well as revertants from srr7, srr7A and srr7B; however, a major
      proportion of these S proteins were resistant to proteinase K even without soMHVR
      treatment. The implications of this proteinase-resistant fraction are discussed.
      This is the first report on receptor-induced conformational changes of the
      membrane-anchored fragment of the coronavirus S protein.

PMID- 12414925
TI  - Capture and transfer of simian immunodeficiency virus by macaque dendritic cells
      is enhanced by DC-SIGN.
AB  - Dendritic cells (DCs) are among the first cells encountered by human and simian
      immunodeficiency virus (HIV and SIV) following mucosal infection. Because these
      cells efficiently capture and transmit virus to T cells, they may play a major
      role in mediating HIV and SIV infection. Recently, a C-type lectin protein
      present on DCs, DC-specific ICAM-3-grabbing nonintegrin (DC-SIGN), was shown to
      efficiently bind and present HIV and SIV to CD4(+), coreceptor-positive cells in
      trans. However, the significance of DC-SIGN for virus transmission and
      pathogenesis in vivo remains unclear. Because SIV infection of macaques may
      represent the best model to study the importance of DC-SIGN in HIV infection, we
      cloned and characterized pig-tailed macaque DC-SIGN and generated monoclonal
      antibodies (MAbs) against it. We demonstrate that, like human DC-SIGN, pig-tailed
      macaque DC-SIGN (ptDC-SIGN) is expressed on DCs and macrophages but not on
      monocytes, T cells, or B cells. Moderate levels of ptDC-SIGN expression were
      detected on the surface of DCs, and low-level expression was found on
      macrophages. Additionally, we show that ptDC-SIGN efficiently binds and transmits
      replication-competent SIVmne variants to CD4(+), coreceptor-positive cells.
      Moreover, transmission of virus between pig-tailed macaque DCs and CD4(+) T cells
      is largely ptDC-SIGN dependent. Interestingly, MAbs directed against ptDC-SIGN
      vary in the capacity to block transmission of different SIVmne variants. These
      data demonstrate that ptDC-SIGN plays a central role in transmitting virus from
      macaque DCs to T cells, and they suggest that SIVmne variants may differ in their
      interactions with ptDC-SIGN. Thus, SIVmne infection of pig-tailed macaques may
      provide an opportunity to investigate the significance of DC-SIGN in primate
      lentiviral infections.

PMID- 12414926
TI  - Comparison of molecular and biological characteristics of a modified live porcine
      reproductive and respiratory syndrome virus (PRRSV) vaccine (ingelvac PRRS MLV),
      the parent strain of the vaccine (ATCC VR2332), ATCC VR2385, and two recent field
      isolates of PRRSV.
AB  - The objectives of this study were to compare the molecular and biological
      characteristics of recent porcine reproductive and respiratory syndrome virus
      (PRRSV) field isolates to those of a modified live virus (MLV) PRRS vaccine and
      its parent strain. One hundred seventeen, 4-week-old pigs were randomly assigned
      to six groups. Group 1 (n = 20) served as sham-inoculated negative controls,
      group 2 (n = 19) was inoculated with Ingelvac PRRS MLV vaccine, group 3 (n = 20)
      was inoculated with the parent strain of the vaccine (ATCC VR2332), group 4 (n =
      19) was inoculated with vaccine-like PRRSV field isolate 98-38803, group 5 (n =
      19) was inoculated with PRRSV field isolate 98-37120, and group 6 (n = 20) was
      inoculated with known high-virulence PRRSV isolate ATCC VR2385. The levels of
      severity of gross lung lesions (0 to 100%) among the groups were significantly
      different at both 10 (P < 0.0001) and 28 days postinoculation (p.i.) (P = 0.002).
      At 10 days p.i., VR2332 (26.5% +/- 4.64%) and VR2385 (36.4% +/- 6.51%) induced
      gross lesions of significantly greater severity than 98-38803 (0.0% +/- 0.0%), 98
      37120 (0.8% +/- 0.42%), Ingelvac PRRS MLV (0.9% +/- 0.46%), and negative controls
      (2.3% +/- 1.26%). At 28 days p.i., 98-37120 (17.2% +/- 6.51%) induced gross
      lesions of significantly greater severity than any of the other viruses. Analyses
      of the microscopic-interstitial-pneumonia-lesion scores (0 to 6) revealed that
      VR2332 (2.9 +/- 0.23) and VR2385 (3.1 +/- 0.35) induced significantly more severe
      lesions at 10 days p.i. At 28 days p.i., VR2385 (2.5 +/- 0.27), VR2332 (2.3 +/-
      0.21), 98-38803 (2.6 +/- 0.29), and 98-37120 (3.0 +/- 0.41) induced significantly
      more severe lesions than Ingelvac PRRS MLV (0.7 +/- 0.17) and controls (0.7 +/-
      0.15). The molecular analyses and biological characterizations suggest that the
      vaccine-like isolate 98-38803 (99.5% amino acid homology based on the ORF5 gene)
      induces microscopic pneumonia lesions similar in type to, but different in
      severity and time of onset from, those observed with virulent strains VR2385 and
      the parent strain of the vaccine. Our data strongly suggest that isolate 98-38803
      is a derivative of Ingelvac PRRS MLV and that the isolate is pneumovirulent.

PMID- 12414927
TI  - Palmitoylation of the murine leukemia virus envelope protein is critical for
      lipid raft association and surface expression.
AB  - To investigate the association of the murine leukemia virus (MuLV) Env protein
      with lipid rafts, we compared wild-type and palmitoylation-deficient mutant Env
      proteins by using extraction with the mild detergent Triton X-100 (TX-100)
      followed by a sucrose gradient flotation assay. We found that the wild-type MuLV
      Env protein was resistant to ice-cold TX-100 treatment and floated to the top of
      the gradients. In contrast, we observed that the palmitoylation-deficient mutant
      Env protein was mostly soluble when extracted by ice-cold TX-100 and stayed at
      the bottom of the gradients. Both the wild-type and mutant Env proteins were
      found to be soluble when treated with methyl-beta-cyclodextrin before extraction
      with ice-cold TX-100 or when treated with ice-cold octyl-beta-glucoside instead
      of TX-100. These results indicate that the MuLV Env protein is associated with
      lipid rafts and that palmitoylation of the Env protein is critical for lipid raft
      association. Although the palmitoylation-deficient Env mutant was synthesized at
      a level similar to that of the wild-type Env, it was found to be expressed at
      reduced levels on the cell surface. We observed syncytium formation activity with
      both the wild-type and mutant Env proteins, indicating that palmitoylation or
      raft association is not required for MuLV viral fusion activity.

PMID- 12414928
TI  - RNA incorporation is critical for retroviral particle integrity after cell
      membrane assembly of Gag complexes.
AB  - The nucleocapsid (NC) domain of retroviruses plays a critical role in specific
      viral RNA packaging and virus assembly. RNA is thought to facilitate viral
      particle assembly, but the results described here with NC mutants indicate that
      it also plays a critical role in particle integrity. We investigated the assembly
      and integrity of particles produced by the human immunodeficiency virus type 1 M1
      2/BR mutant virus, in which 10 of the 13 positive residues of NC have been
      replaced with alanines and incorporation of viral genomic RNA is virtually
      abolished. We found that the mutations in the basic residues of NC did not
      disrupt Gag assembly at the cell membrane. The mutant Gag protein can assemble
      efficiently at the cell membrane, and viral proteins are detected outside the
      cell as efficiently as they are for the wild type. However, only approximately
      10% of the Gag molecules present in the supernatant of this mutant sediment at
      the correct density for a retroviral particle. The reduction of positive charge
      in the NC basic domain of the M1-2/BR virus adversely affects both the specific
      and nonspecific RNA binding properties of NC, and thus the assembled Gag
      polyprotein does not bind significant amounts of viral or cellular RNA. We found
      a direct correlation between the percentage of Gag associated with sedimented
      particles and the amount of incorporated RNA. We conclude that RNA binding by
      Gag, whether the RNA is viral or not, is critical to retroviral particle
      integrity after cell membrane assembly and is less important for Gag-Gag
      interactions during particle assembly and release.

PMID- 12414929
TI  - Mapping of functional regions in the amino-terminal portion of the herpes simplex
      virus ICP27 regulatory protein: importance of the leucine-rich nuclear export
      signal and RGG Box RNA-binding domain.
AB  - Infected-cell protein 27 (ICP27) is an essential herpes simplex virus type 1 (HSV
      1) regulatory protein that activates a subset of viral delayed-early and late
      genes, at least in part through posttranscriptional mechanisms. Previous studies
      have shown that the amino (N)-terminal half of the protein contains important
      functional regions, including a leucine-rich nuclear export signal (NES).
      However, to date, the phenotype of an HSV-1 ICP27 NES mutant has not been
      reported. In this study, we engineered and characterized dLeu, an HSV-1 deletion
      mutant that specifically lacks ICP27's NES (amino acids 6 to 19). The phenotype
      of dLeu was analyzed alongside those of eight other ICP27 N-terminal deletion
      mutants. We found that in Vero cells, dLeu displays modest defects in viral gene
      expression and an approximately 100-fold reduction in the production of viral
      progeny. Unlike wild-type (WT) ICP27, which exhibits a cytoplasmic distribution
      in addition to its predominant nuclear localization, dLeu ICP27 is highly
      restricted to the cell nucleus. This strongly suggests that the N-terminal
      leucine-rich sequence functions as an NES during viral infection. Our analysis of
      dLeu and the other mutants has enabled us to genetically define the regions in
      the N-terminal 200 residues of ICP27 which are required for efficient viral
      growth in Vero cells. Only two regions appear to be important: (i) the leucine
      rich NES and (ii) the RGG box RNA-binding domain, encoded by residues 139 to 153.
      A virus lacking the RGG box-encoding sequence, d4-5, has a phenotype similar to
      that of dLeu in that it displays modest defects in viral gene expression and
      grows poorly. Interestingly, deletion of both the NES and RGG box, as well as the
      sequences in between, is lethal. The resulting virus, d1-5, displays severe
      defects in viral gene expression and DNA synthesis and is unable to produce
      significant amounts of infectious progeny. Therefore, the N-terminal portion of
      ICP27 contains at least two functional domains which collectively are absolutely
      essential for viral infection.

PMID- 12414930
TI  - The Kaposi's sarcoma-associated herpesvirus K12 transcript from a primary
      effusion lymphoma contains complex repeat elements, is spliced, and initiates
      from a novel promoter.
AB  - Kaposi's sarcoma-associated herpesvirus (KSHV) latently infects KS tumors,
      primary effusion lymphomas (PELs), and PEL cell lines. K12 (T0.7) is the most
      abundant transcript expressed in latent KSHV infection. We characterize here the
      K12 transcript from a PEL tumor prior to passage in cell culture. The PEL tumor
      KSHV K12 transcript contained additional complex nucleotide repeat elements
      compared to the previously described K12 message of the BCBL-1 PEL cell line. The
      PEL tumor lacked kaposin B, the predominant BCBL-1 K12 protein product, but
      encoded kaposins A and C. The K12 transcript was spliced and the splicing event
      occurred in all KSHV isolates tested. The 5' end of the K12 transcript was mapped
      by 5' RACE (rapid amplification of cDNA ends) and S1 nuclease protection assays
      and was at the site of an active promoter. This work demonstrates that the K12
      transcript contains variable, complex repeat elements, is spliced and is
      expressed from a novel KSHV promoter.

PMID- 12414931
TI  - Mapping the encapsidation determinants of feline immunodeficiency virus.
AB  - Encapsidation of retroviral RNA involves specific interactions between viral
      proteins and cis-acting genomic RNA sequences. Human immunodeficiency virus type
      1 (HIV-1) RNA encapsidation determinants appear to be more complex and dispersed
      than those of murine retroviruses. Feline lentiviral (feline immunodeficiency
      virus [FIV]) encapsidation has not been studied. To gain comparative insight into
      lentiviral encapsidation and to optimize FIV-based vectors, we used RNase
      protection assays of cellular and virion RNAs to determine packaging efficiencies
      of FIV deletion mutants, and we studied replicative phenotypes of mutant viruses.
      Unlike the case for other mammalian retroviruses, the sequences between the major
      splice donor (MSD) and the start codon of gag contribute negligibly to FIV
      encapsidation. Moreover, molecular clones having deletions in this region were
      replication competent. In contrast, sequences upstream of the MSD were important
      for encapsidation, and deletion of the U5 element markedly reduced genomic RNA
      packaging. The contribution of gag sequences to packaging was systematically
      investigated with subgenomic FIV vectors containing variable portions of the gag
      open reading frame, with all virion proteins supplied in trans. When no gag
      sequence was present, packaging was abolished and marker gene transduction was
      absent. Inclusion of the first 144 nucleotides (nt) of gag increased vector
      encapsidation to detectable levels, while inclusion of the first 311 nt increased
      it to nearly wild-type levels and resulted in high-titer FIV vectors. However,
      the identified proximal gag sequence is necessary but not sufficient, since viral
      mRNAs that contain all coding regions, with or without as much as 119 nt of
      adjacent upstream 5' leader, were excluded from encapsidation. The results
      identify a mechanism whereby FIV can encapsidate its genomic mRNA in preference
      to subgenomic mRNAs.

PMID- 12414932
TI  - Poly(ADP-ribose) polymerase 1 is not strictly required for infection of murine
      cells by retroviruses.
AB  - The DNA-breaking and -joining steps initiating retroviral integration are well
      understood, but the later steps, thought to be carried out by cellular DNA repair
      enzymes, have not been fully characterized. Poly(ADP-ribose) polymerase 1 (PARP
      1) has been proposed to play a role late during retroviral integration, because
      infection by human immunodeficiency virus (HIV)-based vectors was reported to be
      strongly inhibited in PARP-1-deficient fibroblasts. PARP-1, a nuclear enzyme,
      binds tightly to nicked DNA and synthesizes poly(ADP-ribose) as an early response
      to DNA damage. To investigate the role of PARP-1 in retroviral integration, we
      infected wild-type and PARP-1-deficient mouse embryonic fibroblasts (MEFs)
      separately with two HIV type 1-derived, vesicular stomatitis virus G-pseudotyped
      lentivirus vectors. Surprisingly, infection of both wild-type and PARP-1
      deficient cells was observed with both vectors. Marker gene transduction and
      provirus formation by one vector was reduced by 45 to 75% compared to the wild
      type, but the other vector was unaffected by the PARP-1 mutant. In addition, PARP
      1-deficient MEFs infected with Moloney murine leukemia virus showed no decrease
      in virus output after infection compared to the wild type. We conclude that PARP
      1 cannot be strictly required for retroviral infection because replication steps,
      including integration, can proceed efficiently in its absence.

PMID- 12414933
TI  - Neonates mount robust and protective adult-like CD8(+)-T-cell responses to DNA
      vaccines.
AB  - Neonates are thought to mount less vigorous adaptive immune responses than adults
      to antigens and infectious agents. This concept has led to a delay in the
      administration of many currently available vaccines until late infancy or early
      childhood. It has recently been shown that vaccines composed of plasmid DNA can
      induce both humoral and cell-mediated antimicrobial immunity when administered
      within hours of birth. In most of these studies, immune responses were measured
      weeks or months after the initial vaccination, and it is therefore questionable
      whether the observed responses were actually the result of priming of splenocytes
      within the neonatal period. Here we show that DNA vaccination at birth results in
      the rapid induction of antigen-specific CD8(+) T cells within neonatal life.
      Analyses of T-cell effector functions critical for the resolution of many viral
      infections revealed that neonatal and adult CD8(+) T cells produce similar arrays
      of cytokines. Furthermore, the avidities of neonatal and adult CD8(+) T cells for
      peptide and the rapidity with which they upregulate cytokine production after
      recall encounters with antigen are similar. Protective immunity against the
      arenavirus lymphocytic choriomeningitis virus, which is mediated by CD8(+)
      cytotoxic T cells, is also rapidly acquired within the neonatal period.
      Collectively these data imply that, at least in the case of CD8(+) T cells,
      neonates are not as immunodeficient as previously supposed and that DNA vaccines
      may be an effective and safe means of providing critical cell-mediated antiviral
      immunity extremely early in life.

PMID- 12414934
TI  - Hepatitis A virus inhibits cellular antiviral defense mechanisms induced by
      double-stranded RNA.
AB  - The consequences of a hepatitis A virus (HAV) infection on cell-based antiviral
      responses and the interactions between virus and host cells resulting in
      persistent infections are poorly understood. In this report, we show that HAV
      does inhibit double-stranded (dsRNA)-induced beta interferon (IFN-beta) gene
      expression by influencing the IFN-beta enhanceosome, as well as dsRNA-induced
      apoptosis, which suggests that both effects may be connected by shared viral
      and/or cellular factors. This ability of HAV, which preserves the sites of virus
      production for a longer time, may allow the virus to establish an infection and
      may be the presupposition for setting up persistent infections. Our results
      suggest that the inhibitory effect of HAV on the cellular defense mechanisms
      might not be sufficient to completely prevent the antiviral reactions, which may
      be induced by accumulating viral dsRNA, at a later stage of infection. However,
      HAV seems to counteract this situation by downregulation of viral replication and
      in the following production of viral dsRNA. This ability of noncytopathogenic HAV
      acts dominantly on cytopathogenic HAV in trans. The downregulation might ensure
      the moderate replication which seems necessary for inhibition of the antiviral
      mechanisms by HAV and therefore for the persistent state of the HAV infection.

PMID- 12414935
TI  - Recombinant respiratory syncytial virus with the G and F genes shifted to the
      promoter-proximal positions.
AB  - The genome of human respiratory syncytial virus (RSV) encodes 10 mRNAs and 11
      proteins in the order 3'-NS1-NS2-N-P-M-SH-G-F-M2-1/M2-2-L-5'. The G and F
      glycoproteins are the major RSV neutralization and protective antigens. It seems
      likely that a high level of expression of G and F would be desirable for a live
      RSV vaccine. For mononegaviruses, the gene order is a major factor controlling
      the level of mRNA and protein expression due to the polar gradient of sequential
      transcription. In order to increase the expression of G and F, recombinant RSVs
      based on strain A2 were constructed in which the G or F gene was shifted from the
      sixth or seventh position (in a genome lacking the SH gene), respectively, to the
      first position (rRSV-G1/DeltaSH and rRSV-F1/DeltaSH, respectively). Another virus
      was made in which G and F were shifted together to the first and second
      positions, respectively (rRSV-G1F2/DeltaSH). Shifting one or two genes to the
      promoter-proximal position resulted in increased mRNA and protein expression of
      the shifted genes, with G and F expression increased up to 2.4-and 7.8-fold,
      respectively, at the mRNA level and approximately 2.5-fold at the protein level,
      compared to the parental virus. Interestingly, the transcription of downstream
      genes was not greatly affected even though shifting G or F, or G and F together,
      had the consequence of moving the block of genes NS1-NS2-N-P-M-(G) one or two
      positions further from the promoter. The efficiency of replication of the gene
      shift viruses in vitro was increased up to 10-fold. However, their efficiency of
      replication in the lower respiratory tracts of mice was statistically
      indistinguishable from that of the parental virus. In the upper respiratory
      tract, replication was slightly reduced on some days for viruses in which G was
      in the first position. The magnitude of the G-specific antibody response to the
      gene shift viruses was similar to that to the parental virus, whereas the F
      specific response was increased up to fourfold, although this was not reflected
      in an increase of the neutralizing activity. Thus, shifting the G and F genes to
      the promoter-proximal position increased virus replication in vitro, had little
      effect on replication in the mouse, and increased the antigen-specific
      immunogenicity of the virus beyond that of parental RSV.

PMID- 12414936
TI  - Relationship between autophosphorylation and phosphorylation of exogenous
      substrates by the human cytomegalovirus UL97 protein kinase.
AB  - Human cytomegalovirus encodes an unusual protein kinase, UL97, which is a member
      of the HvU(L) family of protein kinases encoded by diverse herpesviruses. UL97 is
      able to autophosphorylate and to phosphorylate certain exogenous substrates,
      including nucleoside analogs such as ganciclovir. It has previously been
      concluded that phosphorylation of UL97 is essential for its phosphorylation of
      ganciclovir. We examined the relationship between autophosphorylation of UL97 and
      its activity on exogenous substrates. Glutathione S-transferase-UL97 fusion
      protein purified from insect cells was found to be already partially
      phosphorylated, but neither extensive autophosphorylation nor phosphatase
      treatment meaningfully altered the time course of its phosphorylation of the
      exogenous substrate, histone H2B. Sequencing and mass spectrometric analyses of
      (32)P-labeled tryptic peptides of the UL97 fusion protein identified nine sites
      of autophosphorylation, all within the first 200 residues of the protein, outside
      of conserved protein kinase subdomains. A peptide corresponding to the N-terminal
      UL97 segment that was most extensively autophosphorylated was readily
      phosphorylated by UL97, confirming that fusion protein sequences are not required
      for phosphorylation at this site. Deletion mutants lacking at least the first 239
      residues exhibited drastically reduced autophosphorylation (<5%) but retained
      near-wild-type H2B phosphorylation activity. Baculoviruses expressing these
      mutants efficiently directed the phosphorylation of ganciclovir in insect cells.
      Taken together, these results identify the autophosphorylation sites of a
      herpesvirus protein kinase and show that autophosphorylation of UL97 is not
      required for phosphorylation of exogenous substrates.

PMID- 12414938
TI  - Differential regulation of the inhibitor of apoptosis ch-IAP1 by v-rel and the
      proto-oncogene c-rel.
AB  - The v-rel oncogene encoded by reticuloendotheliosis virus is the acutely
      transforming member of the Rel/NF-kappaB family of transcription factors. v-Rel
      is a truncated and mutated form of c-Rel and transforms cells by inducing the
      aberrant expression of genes regulated by Rel/NF-kappaB proteins. The expression
      of ch-IAP1, a member of the inhibitor-of-apoptosis family, is highly elevated in
      cells expressing v-Rel and contributes to the immortalization of cells
      transformed by this oncoprotein. In this study we demonstrate that the elevated
      expression of ch-IAP1 in v-Rel-expressing cells is due to an increased rate of
      transcription. The ch-IAP1 promoter was isolated, and four Rel/NF-kappaB binding
      sites were identified upstream of the transcription start site. Two kappaB sites
      proximal to the transcription start site were required for v-Rel to activate the
      ch-IAP1 promoter. While c-Rel also utilized these sites, a third more-distal
      kappaB site was required for its full activation of the ch-IAP1 promoter.
      Differences in the transactivation domains of v-Rel and c-Rel are responsible for
      their different abilities to utilize these sites and account for their
      differential activation of the ch-IAP1 promoter. Although c-Rel was a more potent
      activator of the ch-IAP1 promoter than v-Rel in transient reporter assays, cells
      stably overexpressing c-Rel failed to maintain high levels of ch-IAP1 expression.
      The reduction of ch-IAP1 expression in these cells correlated with the efficient
      regulation of c-Rel by IkappaBalpha. The ability of v-Rel to escape IkappaBalpha
      regulation allows for the gradual and sustained elevation of ch-IAP1 expression
      directly contributing to the transforming properties of v-Rel.

PMID- 12414937
TI  - Virus population homogenization following acute human immunodeficiency virus type
      1 infection.
AB  - Understanding the properties of human immunodeficiency virus type 1 (HIV-1)
      variants capable of establishing infection is critical to the development of a
      vaccine against AIDS. Previous studies of men have shown that the HIV-1 env gene
      is homogeneous early in infection, leading to the suggestion that infection is
      established by a single transmitted variant. However, we report here that all of
      eight homosexual men evaluated beginning 3.7 to 9 weeks following onset of
      symptoms of acute infection harbored diverse virus populations in their blood,
      with median genetic distances averaging 1.08% in the env C2V5 region and 0.81% in
      the gag p17 gene. Within another 4.7 to 11 weeks, the variant lineage in env
      became more homogeneous, while gag sequences continued to diversify. Thus, the
      homogenization that has been reported to characterize acute infection is actually
      preceded by the replication of multiple virus variants. This early selective
      process focuses on viral properties within Env but not Gag p17. Hence, the viral
      homogeneity observed early in HIV-1 infection results from a selective process
      that occurs during the establishment of infection.

PMID- 12414939
TI  - Characterization of RNA determinants recognized by the arginine- and proline-rich
      region of Us11, a herpes simplex virus type 1-encoded double-stranded RNA binding
      protein that prevents PKR activation.
AB  - The herpes simplex virus Us11 gene product inhibits activation of the cellular
      PKR kinase and associates with a limited number of unrelated viral and cellular
      RNA molecules via a carboxyl-terminal 68-amino-acid segment rich in arginine and
      proline. To characterize the determinants underlying the recognition of an RNA
      target by Us11, we employed an in vitro selection technique to isolate RNA
      ligands that bind Us11 with high affinity from a population of molecules
      containing an internal randomized segment. Binding of Us11 to these RNA ligands
      is specific and appears to occur preferentially on conformational isoforms that
      possess a higher-order structure. While the addition of unlabeled poly(I. C)
      reduced binding of Us11 to a selected radiolabeled RNA, single-stranded
      homopolymers were not effective competitors. Us11 directly associates with
      poly(I. C), and inclusion of an unlabeled selected RNA in the reaction reduces
      poly(I. C) binding, while single-stranded RNA homopolymers have no effect.
      Finally, Us11 binds to defined, double-stranded RNA (dsRNA) molecules that
      exhibit greater sequence complexity. Binding to these dsRNA perfect duplexes
      displays a striking dependence on length, as 39-bp or shorter duplexes do not
      bind efficiently. Furthermore, this interaction is specific for dsRNA as opposed
      to dsDNA, implying that the Us11 RNA binding domain can distinguish nucleic acid
      duplexes containing 2' hydroxyl groups from those that do not. These results
      establish that Us11 is a dsRNA binding protein. The arginine- and proline-rich
      Us11 RNA binding domain is unrelated to known dsRNA binding elements and thus
      constitutes a unique recognition motif that interacts with dsRNA. The ability of
      Us11 to bind dsRNA may be important for inhibiting activation of the cellular PKR
      kinase in response to dsRNA.

PMID- 12414940
TI  - An efficient and versatile mammalian viral vector system for major
      histocompatibility complex class I/peptide complexes.
AB  - We report a Sendai virus (SeV) vector system for expression of major
      histocompatibility complex (MHC) class I/peptide complexes. We cloned the
      extracellular domain of a human MHC class I heavy chain, HLA-A*2402, and human
      beta-2 microglobulin (beta2m) fused with HLA-A*2402-restricted human
      immunodeficiency virus type 1 (HIV-1) cytotoxic T-lymphocyte (CTL) epitopes (e
      beta2m) in separate SeV vectors. When we coinfected nonhuman mammalian cells with
      the SeVs, naturally folded human MHC class I/peptide complexes were secreted in
      the culture supernatants. Biotin binding peptide sequences on the C terminus of
      the heavy chain were used to tetramerize the complexes. These tetramers made in
      the SeV system recognized specific CD8-positive T cells in peripheral blood
      mononuclear cells of HIV-1-positive patients with a specificity and sensitivity
      similar to those of MHC class I tetramers made in an Escherichia coli system.
      Solo infection of e-beta2m/SeV produced soluble e-beta2m in the culture
      supernatant, and cells pulsed with the soluble protein were recognized by
      specific CTLs. Furthermore, when cells were infected with e-beta2m/SeV, these
      cells were recognized by the specific CTLs more efficiently than the protein
      pulse per se. SeV is nonpathogenic for humans, can transduce foreign genes into
      nondividing cells, and may be useful for immunotherapy to enhance antigen
      specific immune responses. Our system can be used not only to detect but also to
      stimulate antigen-specific cellular immune responses.

PMID- 12414941
TI  - Cell proteins TIA-1 and TIAR interact with the 3' stem-loop of the West Nile
      virus complementary minus-strand RNA and facilitate virus replication.
AB  - It was reported previously that four baby hamster kidney (BHK) proteins with
      molecular masses of 108, 60, 50, and 42 kDa bind specifically to the 3'-terminal
      stem-loop of the West Nile virus minus-stand RNA [WNV 3'(-) SL RNA] (P. Y. Shi,
      W. Li, and M. A. Brinton, J. Virol. 70:6278-6287, 1996). In this study, p42 was
      purified using an RNA affinity column and identified as TIAR by peptide
      sequencing. A 42-kDa UV-cross-linked viral RNA-cell protein complex formed in BHK
      cytoplasmic extracts incubated with the WNV 3'(-) SL RNA was immunoprecipitated
      by anti-TIAR antibody. Both TIAR and the closely related protein TIA-1 are
      members of the RNA recognition motif (RRM) family of RNA binding proteins. TIA-1
      also binds to the WNV 3'(-) SL RNA. The specificity of these viral RNA-cell
      protein interactions was demonstrated using recombinant proteins in competition
      gel mobility shift assays. The binding site for the WNV 3'(-) SL RNA was mapped
      to RRM2 on both TIAR and TIA-1. However, the dissociation constant (K(d)) for the
      interaction between TIAR RRM2 and the WNV 3'(-) SL RNA was 1.5 x 10(-8), while
      that for TIA-1 RRM2 was 1.12 x 10(-7). WNV growth was less efficient in murine
      TIAR knockout cell lines than in control cells. This effect was not observed for
      two other types of RNA viruses or two types of DNA viruses. Reconstitution of the
      TIAR knockout cells with TIAR increased the efficiency of WNV growth, but neither
      the level of TIAR nor WNV replication was as high as in control cells. These data
      suggest a functional role for TIAR and possibly also for TIA-1 during WNV
      replication.

PMID- 12414942
TI  - Cell-free replication of the hepatitis C virus subgenomic replicon.
AB  - The hepatitis C virus (HCV) contains a plus-strand RNA genome. The 5' noncoding
      region (NCR) of the viral genome functions as an internal ribosome entry site,
      and its unique 3' NCR is required for the assembly of the replication complex
      during initiation of HCV RNA replication. Lohmann et al. (V. Lohmann, F. Korner,
      J.-O. Koch, U. Herian, L. Theilman, and R. Batenschlager, Science 285:110-113,
      1999) developed a subgenomic HCV replicon system, which represents an important
      tool in studying HCV replication in cultured cells. In this study, we describe a
      cell-free replication system that utilizes cytoplasmic lysates prepared from Huh
      7 cells harboring the HCV subgenomic replicons. These lysates, which contain
      ribonucleoprotein complexes associated with cellular membranes, were capable of
      incorporating [alpha(32)P]CTP into newly synthesized RNA from subgenomic
      replicons in vitro. Replicative forms (RFs) and replicative intermediates (RIs)
      were synthesized from the endogenous HCV RNA templates. Consistent with previous
      observations, RFs were found to be resistant to RNase A digestion, whereas RIs
      were sensitive to RNase treatment. The radiolabeled HCV RF-RI complexes contained
      both minus and plus strands and were specific to the lysates derived from
      replicon-expressing cells. The availability of a cell-free replication system
      offers opportunities to probe the mechanism(s) of HCV replication. It also
      provides a novel assay for potential therapeutic agents.

PMID- 12414944
TI  - Addition of six-His-tagged peptide to the C terminus of adeno-associated virus
      VP3 does not affect viral tropism or production.
AB  - Production of large quantities of recombinant adeno-associated virus (AAV) is
      difficult and not cost-effective. To overcome this problem, we have explored the
      feasibility of creating a recombinant AAV encoding a 6xHis tag on the VP3 capsid
      protein. We generated a plasmid vector containing a six-His (6xHis)-tagged AAV
      VP3. A second plasmid vector was generated that contained the full-length AAV
      capsid capable of producing VP1 and VP2, but not VP3 due to a mutation at
      position 2809 that encodes the start codon for VP3. These plasmids, necessary for
      production of AAV, were transfected into 293 cells to generate a 6xHis-tagged
      VP3mutant recombinant AAV. The 6xHis-tagged VP3 did not affect the formation of
      AAV virus, and the physical properties of the 6xHis-modified AAV were equivalent
      to those of wild-type particles. The 6xHis-tagged AAV did not affect the
      production titer of recombinant AAV and could be used to purify the recombinant
      AAV using an Ni-nitrilotriacetic acid column. Addition of the 6xHis tag did not
      alter the viral tropism compared to wild-type AAV. These observations demonstrate
      the feasibility of producing high-titer AAV containing a 6xHis-tagged AAV VP3
      capsid protein and to utilize the 6xHis-tagged VP3 capsid to achieve high
      affinity purification of this recombinant AAV.

PMID- 12414943
TI  - Distinct poly(rC) binding protein KH domain determinants for poliovirus
      translation initiation and viral RNA replication.
AB  - The limited coding capacity of picornavirus genomic RNAs necessitates utilization
      of host cell factors in the completion of an infectious cycle. One host protein
      that plays a role in both translation initiation and viral RNA synthesis is
      poly(rC) binding protein 2 (PCBP2). For picornavirus RNAs containing type I
      internal ribosome entry site (IRES) elements, PCBP2 binds the major stem-loop
      structure (stem-loop IV) in the IRES and is essential for translation initiation.
      Additionally, the binding of PCBP2 to the 5'-terminal stem-loop structure (stem
      loop I or cloverleaf) in concert with viral protein 3CD is required for
      initiation of RNA synthesis directed by poliovirus replication complexes. PCBP1,
      a highly homologous isoform of PCBP2, binds to poliovirus stem-loop I with an
      affinity similar to that of PCBP2; however, PCBP1 has reduced affinity for stem
      loop IV. Using a dicistronic poliovirus RNA, we were able to functionally
      uncouple translation and RNA replication in PCBP-depleted extracts. Our results
      demonstrate that PCBP1 rescues RNA replication but is not able to rescue
      translation initiation. We have also generated mutated versions of PCBP2
      containing site-directed lesions in each of the three RNA-binding domains.
      Specific defects in RNA binding to either stem-loop I and/or stem-loop IV suggest
      that these domains may have differential functions in translation and RNA
      replication. These predictions were confirmed in functional assays that allow
      separation of RNA replication activities from translation. Our data have
      implications for differential picornavirus template utilization during viral
      translation and RNA replication and suggest that specific PCBP2 domains may have
      distinct roles in these activities.

PMID- 12414945
TI  - Baculovirus lef-12 is not required for viral replication.
AB  - The baculovirus lef-12 (orf41) gene is required for transient expression of
      baculovirus late genes. To analyze the role of LEF-12 in the context of infected
      cells, two mutant viruses were constructed. Both mutants were viable in
      Trichoplusia ni High 5 and Spodoptera frugiperda Sf9 cells. Single-step growth
      curves, however, indicated that virus yields were reduced approximately fivefold
      in the absence of LEF-12. Pulse-labeling of infected cells revealed that LEF-12
      mutant viruses entered the late phase and synthesized late proteins at levels
      equivalent to or only twofold lower than those of wild-type virus-infected cells.
      Western blot analyses confirmed that LEF-12 was not synthesized in cells infected
      with mutant virus. In wild-type virus-infected cells, LEF-12 was not detected
      until 18 h postinfection, and accumulation of LEF-12 peaked at 24 to 36 h
      postinfection. Primer extension mapping revealed that lef-12 mRNA was synthesized
      by 12 h postinfection and peaked between 18 and 24 h postinfection. Furthermore,
      synthesis of lef-12 mRNA and LEF-12 protein were inhibited by the addition of
      aphidicolin, indicating that lef-12 is expressed after DNA replication.

PMID- 12414946
TI  - Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) replication and
      transcription factor activates the K9 (vIRF) gene through two distinct cis
      elements by a non-DNA-binding mechanism.
AB  - The replication and transcription activator (RTA) of Kaposi's sarcoma-associated
      herpesvirus (KSHV), or human herpesvirus 8, a homologue of Epstein-Barr virus
      BRLF1 or Rta, is a strong transactivator and inducer of lytic replication. RTA
      acting alone can induce lytic replication of KSHV in infected cell lines that
      originated from primary effusion lymphomas, leading to virus production. During
      the lytic replication process, RTA activates many kinds of genes, including
      polyadenylated nuclear RNA, K8, K9 (vIRF), ORF57, and so on. We focused here on
      the mechanism of how RTA upregulates the K9 (vIRF) promoter and identified two
      independent cis-acting elements in the K9 (vIRF) promoter that responded to RTA.
      These elements were finally confined to the sequence 5'-TCTGGGACAGTC-3' in
      responsive element (RE) I-2B and the sequence 5'-GTACTTAAAATA-3' in RE IIC-2,
      both of which did not share sequence homology. Multiple factors bound
      specifically with these elements, and their binding was correlated with the RTA
      responsive activity. Electrophoretic mobility shift assay with nuclear extract
      from infected cells and the N-terminal part of RTA expressed in Escherichia coli,
      however, did not show that RTA interacted directly with these elements, in
      contrast to the RTA responsive elements in the PAN/K12 promoter region, the
      ORF57/K8 promoter region. Thus, it was likely that RTA could transactivate
      several kinds of unique cis elements without directly binding to the responsive
      elements, probably through cooperation with other DNA-binding factors.

PMID- 12414947
TI  - Complete genomic sequence of an Epstein-Barr virus-related herpesvirus naturally
      infecting a new world primate: a defining point in the evolution of oncogenic
      lymphocryptoviruses.
AB  - Callitrichine herpesvirus 3 (CalHV-3) was isolated from a B-cell lymphoma arising
      spontaneously in the New World primate Callithrix jacchus, the common marmoset.
      Partial genomic sequence analysis definitively identified CalHV-3 as a member of
      the Epstein-Barr virus (EBV)-related lymphocryptovirus (LCV) genus and extended
      the known host range of LCVs beyond humans and Old World nonhuman primates. We
      have now completed the first genomic sequence of an LCV infecting a New World
      primate by describing the unique short region, the major internal repeat, and a
      portion of the unique long region. This portion of the genome contains the
      putative latent origin of replication and 13 additional open reading frames
      (ORFs), 5 of which show no homology to any viral or cell genes. One of the novel
      genes, C5, is a positional homologue for the transformation-essential EBV gene
      EBNA-2. The marmoset LCV genome is also notable for the absence of viral
      interleukin-10 and small nonpolyadenylated RNA homologues. Marmoset LCV
      transcripts encoding putative latent infection nuclear proteins have a common
      leader sequence that is spliced from the major internal repeat in a manner
      similar to that of the EBV EBNA-LP, suggesting strong conservation of a common
      promoter and splicing of these latent infection mRNAs. An EBV LMP2A-like spliced
      transcript crossing the terminal repeats encodes a unique ORF, C7, with multiple
      transmembrane domains and tyrosine kinase phosphorylation sites functionally
      reminiscent of EBV LMP2A. However, the carboxy-terminal location of the candidate
      phosphotyrosine residues is more reminiscent of the Kaposi's sarcoma-associated
      herpesvirus K15 gene and provides potential evidence of an evolutionary
      transition from rhadinoviruses to lymphocryptoviruses. The unusual gene
      repertoire of the marmoset LCV differentiates ancestral viral genes likely
      present in an LCV progenitor from viral genes acquired later as primates and LCV
      coevolved, providing a defining point in the evolution of oncogenic LCVs.

PMID- 12414948
TI  - Replication advantage and host factor-independent phenotypes attributable to a
      common naturally occurring capsid mutation (I97L) in human hepatitis B virus.
AB  - Mutations of human hepatitis B virus (HBV) occur frequently within the capsid
      (core) protein in natural infections. The most frequent mutation of the core
      protein in HBV from Southeast Asia occurs at amino acid 97, changing an
      isoleucine (I) to a leucine (L). In our systematic study of virus-host
      interactions, we have examined the replication efficiency of a site-directed
      mutant, I97L, and its parental wild-type HBV in several different hepatoma cell
      lines. Interestingly, we found that this capsid variant replicated in human Huh7
      hepatoma cells approximately 4.8-fold better than its parental wild-type HBV. A
      similar phenomenon was observed in another hepatoma cell line, J3. In addition,
      the level of encapsidated RNA pregenome in mutant I97L was about 5.7-fold higher
      than that of the wild-type HBV in Huh7 cells. Unlike Huh7 cells, no significant
      difference in viral DNA replication between the same I97L mutant and its parental
      wild-type HBV was observed in HepG2, a human hepatoblastoma cell line. This
      finding of a profound replication advantage for mutant I97L in Huh7 and J3 cells
      but not in HepG2 cells may have important implications for the emergence of this
      mutant in chronic HBV carriers. We speculate here that the mutation confers a
      host factor-independent growth advantage for the survival of HBV variants in
      gradually dedifferentiating hepatocytes and thus helps prolong viral persistence.

PMID- 12414949
TI  - Wild-type levels of nuclear localization and human immunodeficiency virus type 1
      replication in the absence of the central DNA flap.
AB  - Numerous factors have been implicated in the nuclear localization of retroviral
      preintegration complexes. Whereas sequences in human immunodeficiency virus type
      1 (HIV-1) matrix, Vpr, and integrase proteins were initially reported to function
      specifically in nondividing cells, other recently identified sequences apparently
      function in dividing cells as well. One of these, the central DNA flap formed
      during reverse transcription, is specific to lentiviruses. It was previously
      reported that flap-negative (F(-)) HIV-1(LAI) was completely defective for viral
      spread in the MT-4 T-cell line, yet F(-) HIV-1 vectors were only 2- to 10-fold
      defective in various single-round transduction assays. To address these different
      findings, we analyzed the infectivity and nuclear localization phenotypes of two
      highly related T-cell-tropic strains, HIV-1(NL4-3) and a derivative of HIV
      1(HXBc2) deficient for both Vpr and Nef. In stark contrast to the previous
      report, F(-) derivatives of both strains replicated efficiently in MT-4 cells. F(
      ) HIV-1(NL4-3) also spread like wild-type HIV-1(NL4-3) in infected Jurkat and
      primary T-cell cultures. In contrast, F(-) HIV-1(HXBc2) was replication defective
      in primary T cells. Results of real-time quantitative PCR assays, however,
      indicated that F(-) HIV-1(HXBc2) entered primary T-cell nuclei as efficiently as
      its wild-type counterpart. Thus, the F(-) HIV-1(HXBc2) growth defect did not
      appear to correlate with defective nuclear import. Consistent with this
      observation, wild-type nef restored replication to F(-) HIV-1(HXBc2) in primary T
      cells. Our results indicate that the central DNA flap does not play a major role
      in either preintegration complex nuclear import or HIV-1 replication in a variety
      of cell types.

PMID- 12414950
TI  - Reassessment of the roles of integrase and the central DNA flap in human
      immunodeficiency virus type 1 nuclear import.
AB  - Human immunodeficiency virus type 1 (HIV-1) can infect nondividing cells
      productively because the nuclear import of viral nucleic acids occurs in the
      absence of cell division. A number of viral factors that are present in HIV-1
      preintegration complexes (PICs) have been assigned functions in nuclear import,
      including an essential valine at position 165 in integrase (IN-V165) and the
      central polypurine tract (cPPT). In this article, we report a comparison of the
      replication and infection characteristics of viruses with disruptions in the cPPT
      and IN-V165. We found that viruses with cPPT mutations still replicated
      productively in both dividing and nondividing cells, while viruses with a
      mutation at IN-V165 did not. Direct observation of the subcellular localization
      of HIV-1 cDNAs by fluorescence in situ hybridization revealed that cDNAs
      synthesized by both mutant viruses were readily detected in the nucleus. Thus,
      neither the cPPT nor the valine residue at position 165 of integrase is essential
      for the nuclear import of HIV-1 PICs.

PMID- 12414951
TI  - Toward testing the hypothesis that group B coxsackieviruses (CVB) trigger insulin
      dependent diabetes: inoculating nonobese diabetic mice with CVB markedly lowers
      diabetes incidence.
AB  - Insulin-dependent (type 1) diabetes mellitus (T1D) onset is mediated by
      individual human genetics as well as undefined environmental influences such as
      viral infections. The group B coxsackieviruses (CVB) are commonly named as
      putative T1D-inducing agents. We studied CVB replication in nonobese diabetic
      (NOD) mice to assess how infection by diverse CVB strains affected T1D incidence
      in a model of human T1D. Inoculation of 4- or 8-week-old NOD mice with any of
      nine different CVB strains significantly reduced the incidence of T1D by 2- to 10
      fold over a 10-month period relative to T1D incidences in mock-infected control
      mice. Greater protection was conferred by more-pathogenic CVB strains relative to
      less-virulent or avirulent strains. Two CVB3 strains were employed to further
      explore the relationship of CVB virulence phenotypes to T1D onset and incidence:
      a pathogenic strain (CVB3/M) and a nonvirulent strain (CVB3/GA). CVB3/M
      replicated to four- to fivefold-higher titers than CVB3/GA in the pancreas and
      induced widespread pancreatitis, whereas CVB3/GA induced no pancreatitis.
      Apoptotic nuclei were detected by TUNEL (terminal deoxynucleotidyltransferase
      mediated dUTP-biotin nick end labeling) assay in CVB3/M-infected pancreata but
      not in CVB3/GA-infected pancreata. In situ hybridization detected CVB3 RNA in
      acinar tissue but not in pancreatic islets. Although islets demonstrated
      inflammatory infiltrates in CVB3-protected mice, insulin remained detectable by
      immunohistochemistry in these islets but not in those from diabetic mice. Enzyme
      linked immunosorbent assay-based examination of murine sera for immunoglobulin G1
      (IgG1) and IgG2a immunoreactivity against diabetic autoantigens insulin and HSP60
      revealed no statistically significant relationship between CVB3-protected mice or
      diabetic mice and specific autoimmunity. However, when pooled sera from CVB3/M
      protected mice were used to probe a Western blot of pancreatic proteins, numerous
      proteins were detected, whereas only one band was detected by sera from CVB3/GA
      protected mice. No proteins were detected by sera from diabetic or normal mice.
      Cumulatively, these data do not support the hypothesis that CVB are causative
      agents of T1D. To the contrary, CVB infections provide significant protection
      from T1D onset in NOD mice. Possible mechanisms by which this virus-induced
      protection may occur are discussed.

PMID- 12414952
TI  - Characterization of a novel murine retrovirus mixture that facilitates
      hematopoiesis.
AB  - A new virus previously arose in BALB/c females mated repeatedly to C57BL/6 (B6)
      males and then injected with fixed, activated B6 male spleen cells (V. S. Ter
      Grigorov, O. Krifuks, E. Liubashevsky, A. Nyska, Z. Trainin, and V. Toder, Nat.
      Med. 3:37-41, 1997). In the present study, BALB/cJ mice inoculated with virus
      containing plasma from affected mice developed splenomegaly, which was caused by
      increased numbers of Sca-1(+) Lin(-) hematopoietic stem cells (HSC) and their
      differentiated progeny. Biological and molecular analyses of a new virus revealed
      a mixture of murine leukemia viruses (MuLVs). These MuLVs comprised ecotropic and
      mink lung cell focus-forming (MCF) virus classes and are termed Rauscher-like
      MuLVs because they bear numerous similarities to the ecotropic and MCF viruses of
      the Rauscher MuLV complex but do not include a spleen focus-forming virus. The
      ecotropic virus component alone transferred some disease characteristics, while
      MCF virus alone did not. Thus, we have described a novel virus mixture, termed
      Rauscher-like MuLV, that causes an increase in hematopoiesis due to activation of
      pluripotent HSC. Experiments using mice and a protocol that replicated the
      pregnancy and immunization strategy of the original experiment demonstrated that
      endogenous BALB/c mouse ecotropic and xenotropic MuLVs are activated by these
      treatments. Emv1 was expressed in the spleens of multiparous mice but not in
      those of virgin mice, and Bxv1Emv1-pseudotyped MuLVs were recovered following
      injection of fixed, activated B6 cells. Thus, multiple pregnancies and
      allostimuli appear to have provided the signals required for activation of and
      recombination among endogenous viruses and could have resulted in generation of
      the Rauscher-like MuLV mixture.

PMID- 12414953
TI  - Antigenic properties of the human immunodeficiency virus transmembrane
      glycoprotein during cell-cell fusion.
AB  - Human immunodeficiency virus (HIV) entry is triggered by interactions between a
      pair of heptad repeats in the gp41 ectodomain, which convert a prehairpin gp41
      trimer into a fusogenic three-hairpin bundle. Here we examined the disposition
      and antigenic nature of these structures during the HIV-mediated fusion of HeLa
      cells expressing either HIV(HXB2) envelope (Env cells) or CXCR4 and CD4 (target
      cells). Cell-cell fusion, indicated by cytoplasmic dye transfer, was allowed to
      progress for various lengths of time and then arrested. Fusion intermediates were
      then examined for reactivity with various monoclonal antibodies (MAbs) against
      immunogenic cluster I and cluster II epitopes in the gp41 ectodomain. All of
      these MAbs produced similar staining patterns indicative of reactivity with
      prehairpin gp41 intermediates or related structures. MAb staining was seen on Env
      cells only upon exposure to soluble CD4, CD4-positive, coreceptor-negative cells,
      or stromal cell-derived factor-treated target cells. In the fusion system, the
      MAbs reacted with the interfaces of attached Env and target cells within 10 min
      of coculture. MAb reactivity colocalized with the formation of gp120-CD4
      coreceptor tricomplexes after longer periods of coculture, although reactivity
      was absent on cells exhibiting cytoplasmic dye transfer. Notably, the MAbs were
      unable to inhibit fusion even when allowed to react with soluble-CD4-triggered or
      temperature-arrested antigens prior to initiation of the fusion process. In
      comparison, a broadly neutralizing antibody, 2F5, which recognizes gp41 antigens
      in the HIV envelope spike, was immunoreactive with free Env cells and Env-target
      cell clusters but not with fused cells. Notably, exposure of the 2F5 epitope
      required temperature-dependent elements of the HIV envelope structure, as MAb
      binding occurred only above 19 degrees C. Overall, these results demonstrate that
      immunogenic epitopes, both neutralizing and nonneutralizing, are accessible on
      gp41 antigens prior to membrane fusion. The 2F5 epitope appears to depend on
      temperature-dependent elements on prefusion antigens, whereas cluster I and
      cluster II epitopes are displayed by transient gp41 structures. Such findings
      have important implications for HIV vaccine approaches based on gp41
      intermediates.

PMID- 12414954
TI  - Cell cycle arrest by human cytomegalovirus 86-kDa IE2 protein resembles premature
      senescence.
AB  - Primary human embryo lung fibroblasts and adult diploid fibroblasts infected by
      the human cytomegalovirus (HCMV) display beta-galactosidase (beta-Gal) activity
      at neutral pH (senescence-associated beta-Gal [SA-beta-Gal] activity) and
      overexpression of the plasminogen activator inhibitor type 1 (PAI-1) gene, two
      widely recognized markers of the process designated premature cell senescence.
      This activity is higher when cells are serum starved for 48 h before infection, a
      process that speeds and facilitates HCMV infection but that is insufficient by
      itself to induce senescence. Fibroblasts infected by HCMV do not incorporate
      bromodeoxyuridine, a prerequisite for the formal definition of senescence. At the
      molecular level, cells infected by HCMV, beside the accumulation of large amounts
      of the cell cycle regulators p53 and pRb, the latter in its hyperphosphorylated
      form, display a strong induction of the cyclin-dependent kinase inhibitor (cdki)
      p16(INK4a), a direct effector of the senescence phenotype in fibroblasts, and a
      decrease of the cdki p21(CIP1/WAF). Finally, a replicative senescence state in
      the early phases of infection significantly increased the number of cells
      permissive to virus infection and enhanced HCMV replication. HCMV infection
      assays carried out in the presence of phosphonoformic acid, which inhibits the
      virus DNA polymerase and the expression of downstream genes, indicated that
      immediate-early and/or early (alpha) genes are sufficient for the induction of SA
      beta-Gal activity. When baculovirus vectors expressing HCMV IE1-72 or IE2-86
      proteins were inoculated into fibroblasts, the increase of p16(INK4a) (observed
      predominantly with IE2-86) was similar to that observed with the whole virus, as
      was the induction of SA-beta-Gal activity, suggesting that the viral IE2 gene
      leads infected cells into senescence. Altogether our results demonstrate for the
      first time that HCMV, after arresting the cell cycle and inhibiting apoptosis,
      triggers the cellular senescence program, probably through the p16(INK4a) and p53
      pathways.

PMID- 12414955
TI  - Noninvasive bioluminescence imaging of herpes simplex virus type 1 infection and
      therapy in living mice.
AB  - Mouse models of herpes simplex virus type 1 (HSV-1) infection provide significant
      insights into viral and host genes that regulate disease pathogenesis, but
      conventional methods to determine the full extent of viral spread and replication
      typically require the sacrifice of infected animals. To develop a noninvasive
      method for detecting HSV-1 in living mice, we used a strain KOS HSV-1 recombinant
      that expresses firefly (Photinus pyralis) and Renilla (Renilla reniformis)
      luciferase reporter proteins and monitored infection with a cooled charge-coupled
      device camera. Viral infection in mouse footpads, peritoneal cavity, brain, and
      eyes could be detected by bioluminescence imaging of firefly luciferase. The
      activity of Renilla luciferase could be imaged after direct administration of
      substrate to infected eyes but not following the systemic delivery of substrate.
      The magnitude of bioluminescence from firefly luciferase measured in vivo
      correlated directly with input titers of recombinant virus used for infection.
      Treatment of infected mice with valacyclovir, a potent inhibitor of HSV-1
      replication, produced dose-dependent decreases in firefly luciferase activity
      that correlated with changes in viral titers. These data demonstrate that
      bioluminescence imaging can be used for noninvasive, real-time monitoring of HSV
      1 infection and therapy in living mice.

PMID- 12414956
TI  - The human papillomavirus type 16 E5 protein impairs TRAIL- and FasL-mediated
      apoptosis in HaCaT cells by different mechanisms.
AB  - The effect of the human papillomavirus type 16 (HPV-16) E5 protein on apoptosis
      was investigated by using the polyclonal HaCaT-cell lines stably transfected
      either with E5 (HaCaT/E5) or the empty vector (HaCaT/pMSG) as reference.
      Apoptosis was triggered either by Fas ligand (FasL) or by tumor necrosis factor
      related apoptosis-inducing ligand (TRAIL) and was monitored by detection of
      cleavage of procaspase-8 and procaspase-3, as well as their substrate poly(ADP
      ribose) polymerase (PARP). In contrast to the HaCaT/pMSG control cells we found
      that apoptosis induced by either of the two ligands is strongly suppressed in the
      E5-expressing keratinocytes. Fas expression is reduced by about a factor of two
      in HaCaT/E5 cells, which could be part of the mechanisms that protect the cells
      from FasL-induced apoptosis. For the TRAIL receptors, no such downregulation was
      observed. Here, E5 impairs the formation of the death-inducing signaling complex
      triggered by TRAIL. Apparently, E5 employs different mechanisms to inhibit death
      receptor signaling. This effect is not restricted to HaCaT/E5 cells since we
      found that the mouse fibroblast cell line A31-E5 is protected from TRAIL-induced
      apoptosis, as well but not the E5-lacking control cells A31-Neo. However, no such
      protection was observed upon FasL-induced apoptosis. Presumably, some of the
      antiapoptotic mechanisms employed by E5 of the human pathogenic HPV-16 are cell
      type specific. We propose that inhibition of ligand-mediated apoptosis in human
      keratinocytes is a primary function of the HPV-16 E5 protein needed to prevent
      apoptosis at early stages of viral infection.

PMID- 12414957
TI  - Direct binding of human immunodeficiency virus type 1 Nef to the major
      histocompatibility complex class I (MHC-I) cytoplasmic tail disrupts MHC-I
      trafficking.
AB  - Nef, an essential pathogenic determinant for human immunodeficiency virus type 1,
      has multiple functions that include disruption of major histocompatibility
      complex class I molecules (MHC-I) and CD4 and CD28 cell surface expression. The
      effects of Nef on MHC-I have been shown to protect infected cells from cytotoxic
      T-lymphocyte recognition by downmodulation of a subset of MHC-I (HLA-A and -B).
      The remaining HLA-C and -E molecules prevent recognition by natural killer (NK)
      cells, which would otherwise lyse cells expressing small amounts of MHC-I.
      Specific amino acid residues in the MHC-I cytoplasmic tail confer sensitivity to
      Nef, but their function is unknown. Here we show that purified Nef binds directly
      to the HLA-A2 cytoplasmic tail in vitro and that Nef forms complexes with MHC-I
      that can be isolated from human cells. The interaction between Nef and MHC-I
      appears to be weak, indicating that it may be transient or stabilized by other
      factors. Supporting the fact that these molecules interact in vivo, we found that
      Nef colocalizes with HLA-A2 molecules in a perinuclear distribution inside cells.
      In addition, we demonstrated that Nef fails to bind the HLA-E tail and also fails
      to bind HLA-A2 tails with deletions of amino acids necessary for MHC-I
      downmodulation. These data provide an explanation for differential downmodulation
      of MHC-I allotypes by Nef. In addition, they provide the first direct evidence
      indicating that Nef functions as an adaptor molecule able to link MHC-I to
      cellular trafficking proteins.

PMID- 12414958
TI  - Suppression of tetradecanoyl phorbol acetate-induced lytic reactivation of
      Kaposi's sarcoma-associated herpesvirus by K1 signal transduction.
AB  - The K1 protein of Kaposi's sarcoma-associated herpesvirus (KSHV) contains an
      immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic region
      and elicits cellular signal transduction through this motif. To investigate the
      role of K1 signal transduction in KSHV replication, we expressed full-length K1
      and CD8-K1 chimeras in BCBL1 cells. Unlike its strong signaling activity in
      uninfected B lymphocytes, K1 did not induce intracellular calcium mobilization or
      NF-AT activation at detectable levels in KSHV-infected BCBL1 cells. Instead, K1
      signaling dramatically suppressed KSHV lytic reactivation induced by
      tetradecanoyl phorbol acetate (TPA) stimulation, but not by ORF50 ectopic
      expression. Mutational analysis showed that the cytoplasmic ITAM sequence of K1
      was required for this suppression. Viral microarray and immunoblot analyses
      demonstrated that K1 signaling suppressed the TPA-mediated increase in the
      expression of a large subset of viral lytic genes in KSHV-infected BCBL1 cells.
      Furthermore, electrophoretic mobility shift assays demonstrated that TPA-induced
      activation of AP-1, NF-kappaB, and Oct-1 activities was severely diminished in
      BCBL1 cells expressing the K1 cytoplasmic domain. The reduced activities of these
      transcription factors may confer the observed reduction in viral lytic gene
      expression. These results demonstrate that K1-mediated signal transduction in
      KSHV-infected cells is profoundly different from that in KSHV-negative cells.
      Furthermore, K1 signal transduction efficiently suppresses TPA-mediated viral
      reactivation in an ITAM-dependent manner, and this suppression may contribute to
      the establishment and/or maintenance of KSHV latency in vivo.

PMID- 12414959
TI  - Characterization of the Golgi retention motif of Rift Valley fever virus G(N)
      glycoprotein.
AB  - As Rift Valley fever (RVF) virus, and probably all members of the family
      Bunyaviridae, matures in the Golgi apparatus, the targeting of the virus
      glycoproteins to the Golgi apparatus plays a pivotal role in the virus
      replication cycle. No consensus Golgi localization motif appears to be shared
      among the glycoproteins of these viruses. The viruses of the family Bunyaviridae
      synthesize their glycoproteins, G(N) and G(C), as a polyprotein. The Golgi
      localization signal of RVF virus has been shown to reside within the G(N) protein
      by use of a plasmid-based transient expression system to synthesize individual
      G(N) and G(C) proteins. While the distribution of individually expressed G(N)
      significantly overlaps with cellular Golgi proteins such as beta-COP and GS-28,
      G(C) expressed in the absence of G(N) localizes to the endoplasmic reticulum.
      Further analysis of expressed G(N) truncated proteins and green fluorescent
      protein/G(N) chimeric proteins demonstrated that the RVF virus Golgi localization
      signal mapped to a 48-amino-acid region of G(N) encompassing the 20-amino-acid
      transmembrane domain and the adjacent 28 amino acids of the cytosolic tail.

PMID- 12414960
TI  - The hydrophilic amino-terminal arm of reovirus core shell protein lambda1 is
      dispensable for particle assembly.
AB  - The reovirus core particle is a molecular machine that mediates synthesis,
      capping, and export of the viral plus strand RNA transcripts. Its assembly and
      structure-function relationships remain to be well understood. Following the lead
      of previous studies with other Reoviridae family members, most notably
      orbiviruses and rotaviruses, we used recombinant baculoviruses to coexpress
      reovirus core proteins lambda1, lambda2, and sigma2 in insect cells. The
      resulting core-like particles (CLPs) were purified and characterized. They were
      found to be similar to cores with regard to their sizes, morphologies, and
      protein compositions. Like cores, they could also be coated in vitro with the two
      major outer-capsid proteins, micro 1 and sigma3, to produce virion-like
      particles. Coexpression of core shell protein lambda1 and core nodule protein
      sigma2 was sufficient to yield CLPs that could withstand purification, whereas
      expression of lambda1 alone was not, indicating a required role for sigma2 as a
      previous study also suggested. In addition, CLPs that lacked lambda2 (formed from
      lambda1 and sigma2 only) could not be coated with micro 1 and sigma3, indicating
      a required role for lambda2 in the assembly of these outer-capsid proteins into
      particles. To extend the use of this system for understanding the core and its
      assembly, we addressed the hypothesis that the hydrophilic amino-terminal region
      of lambda1, which adopts an extended arm-like conformation around each threefold
      axis in the reovirus core crystal structure, plays an important role in
      assembling the core shell. Using a series of lambda1 deletion mutants, we showed
      that the amino-terminal 230 residues of lambda1, including its zinc finger, are
      dispensable for CLP assembly. Residues in the 231-to-259 region of lambda1,
      however, were required. The core crystal structure suggests that residues in the
      231-to-259 region are necessary because they affect the interaction of lambda1
      with the threefold and/or fivefold copies of sigma2. An effective system for
      studies of reovirus core structure, assembly, and functions is hereby
      established.

PMID- 12414961
TI  - Borna disease virus accelerates inflammation and disease associated with
      transgenic expression of interleukin-12 in the central nervous system.
AB  - Targeted expression of biologically active interleukin-12 (IL-12) in astrocytes
      of the central nervous system (CNS) results in spontaneous neuroimmunological
      disease of aged mice. Borna disease virus (BDV) can readily multiply in the mouse
      CNS but does not trigger disease in most strains. Here we show that a large
      percentage of IL-12 transgenic mice developed severe ataxia within 5 to 10 weeks
      after infection with BDV. By contrast, no disease developed in mock-infected IL
      12 transgenic and wild-type mice until 4 months of age. Neurological symptoms
      were rare in infected wild-type animals, and if they occurred, these were milder
      and appeared later. Histological analyses showed that the cerebellum of infected
      IL-12 transgenic mice, which is the brain region with strongest transgene
      expression, contained large numbers of CD4(+) and CD8(+) T cells as well as lower
      numbers of B cells, whereas other parts of the CNS showed only mild infiltration
      by lymphocytes. The cerebellum of diseased mice further showed severe
      astrogliosis, calcifications and signs of neurodegeneration. BDV antigen and
      nucleic acids were present in lower amounts in the inflamed cerebellum of
      infected transgenic mice than in the noninflamed cerebellum of infected wild-type
      littermates, suggesting that IL-12 or IL-12-induced cytokines exhibited antiviral
      activity. We propose that BDV infection accelerates the frequency by which immune
      cells such as lymphocytes and NK cells enter the CNS and then respond to IL-12
      present in the local milieu causing disease. Our results illustrate that
      infection of the CNS with a virus that is benign in certain hosts can be harmful
      in such normally disease-resistant hosts if the tissue is unfavorably
      preconditioned by proinflammatory cytokines.

PMID- 12414962
TI  - Regulation of indoleamine 2,3-dioxygenase expression in simian immunodeficiency
      virus-infected monkey brains.
AB  - The human immunodeficiency virus type 1-associated cognitive-motor disorder,
      including the AIDS dementia complex, is characterized by brain functional
      abnormalities that are associated with injury initiated by viral infection of the
      brain. Indoleamine 2,3-dioxygenase (IDO), the first and rate-limiting enzyme in
      tryptophan catabolism in extrahepatic tissues, can lead to neurotoxicity through
      the generation of quinolinic acid and immunosuppression and can alter brain
      chemistry via depletion of tryptophan. Using the simian immunodeficiency virus
      (SIV)-infected rhesus macaque model of AIDS, we demonstrate that cells of the
      macrophage lineage are the main source for expression of IDO in the SIV-infected
      monkey brain. Animals with SIV encephalitis have the highest levels of IDO mRNA,
      and the level of IDO correlates with gamma interferon (IFN-gamma) and viral load
      levels. In vitro studies on mouse microglia reveal that IFN-gamma is the primary
      inducer of IDO expression. These findings demonstrate the link between IDO
      expression, IFN-gamma levels, and brain pathology signs observed in neuro-AIDS.

PMID- 12414963
TI  - Virus replication and cytokine production in dengue virus-infected human B
      lymphocytes.
AB  - Dengue virus (DV) replication, antibody-enhanced viral infection, and cytokine
      responses of human primary B lymphocytes (cells) were characterized and compared
      with those of monocytes. The presence of a replication template (negative-strand
      RNA intermediate), viral antigens including core and nonstructural proteins, and
      increasing amounts of virus with time postinfection indicated that DV actively
      replicated in B cells. Virus infection also induced B cells to produce
      interleukin-6 and tumor necrosis factor alpha, which have been previously
      implicated in virus pathogenesis. In addition, a heterologous antibody was able
      to enhance both virus and cytokine production in B cells. Furthermore, the levels
      of virus replication, antibody-enhanced virus replication, and cytokine responses
      observed in B cells were not statistically different from those in monocytes.
      These results suggest that B cells may play an important role in DV pathogenesis.

PMID- 12414964
TI  - An antibody to the putative aphid recognition site on cucumber mosaic virus
      recognizes pentons but not hexons.
AB  - Cucumber mosaic virus (CMV), the type member of the genus Cucumovirus (family
      Bromoviridae), is transmitted by aphids in a nonpersistent manner. Mutagenesis
      experiments identified the betaH-betaI loop of the capsid subunit as a potential
      key motif responsible for interactions with the insect vector. To further examine
      the functional characteristics of this motif, we generated monoclonal antibodies
      that bound to native virions but not to betaH-betaI mutants. Fab fragments from
      these antibodies were complexed with wild-type CMV and the virus-Fab structure
      was determined to 12-A resolution by using electron cryomicroscopy and image
      reconstruction techniques. The electron density attributed to the bound antibody
      has a turret-like appearance and protrudes from each of the 12 fivefold axes of
      the icosahedral virus. Thus, the antibody binds only to the pentameric clusters
      (pentons) of A subunits of the T=3 quasisymmetric virus and does not appear to
      bind to any of the B and C subunits that occur as hexameric clusters (hexons) at
      the threefold (quasi-sixfold) axes. Modeling and electron density comparisons
      were used to analyze the paratope-epitope interface and demonstrated that the
      antibody binds to three betaH-betaI loops in three adjacent A subunits in each
      penton. This antibody can discriminate between A and B/C subunits even though the
      betaH-betaI loop adopts the same structure in all 180 capsid subunits and is
      therefore recognizing differences in subunit arrangements. Antibodies with such
      character have potential use as probes of viral assembly. Our results may provide
      an additional rationale for designing synthetic vaccines by using symmetrical
      viral particles.

PMID- 12414965
TI  - Processing and degradation of exogenous prion protein by CD11c(+) myeloid
      dendritic cells in vitro.
AB  - The immune system plays an important role in facilitating the spread of prion
      infections from the periphery to the central nervous system. CD11c(+) myeloid
      dendritic cells (DC) could, due to their subepithelial location and their
      migratory capacity, be early targets for prion infection and contribute to the
      spread of infection. In order to analyze mechanisms by which these cells may
      affect prion propagation, we studied in vitro the effect of exposing such DC to
      scrapie-infected GT1-1 cells, which produce the scrapie prion protein PrP(Sc). In
      this system, the DC efficiently engulfed the infected GT1-1 cells. Unexpectedly,
      PrP(Sc), which is generally resistant to protease digestion, was processed and
      rapidly degraded. Based on this observation we speculate that CD11c(+) DC may
      play a dual role in prion infections: on one hand they may facilitate
      neuroinvasion by transfer of the infectious agent as suggested from in vivo
      studies, but on the other hand they may protect against the infection by causing
      an efficient degradation of PrP(Sc). Thus, the migrating and highly proteolytic
      CD11c(+) myeloid DC may affect the balance between propagation and clearance of
      PrP(Sc) in the organism.

PMID- 12414966
TI  - Saccharomyces cerevisiae is permissive for replication of bovine papillomavirus
      type 1.
AB  - We recently demonstrated that Saccharomyces cerevisiae protoplasts can take up
      bovine papillomavirus type 1 (BPV1) virions and that viral episomal DNA is
      replicated after uptake. Here we demonstrate that BPV virus-like particles are
      assembled in infected S. cerevisiae cultures from newly synthesized capsid
      proteins and also package newly synthesized DNA, including full-length and
      truncated viral DNA and S. cerevisiae-derived DNA. Virus particles prepared in S.
      cerevisiae are able to convey packaged DNA to Cos1 cells and to transform C127
      cells. Infectivity was blocked by antisera to BPV1 L1 but not antisera to BPV1
      E4. We conclude that S. cerevisiae is permissive for the replication of BPV1
      virus.

PMID- 12414967
TI  - Antibody epitopes on the neuraminidase of a recent H3N2 influenza virus
      (A/Memphis/31/98).
AB  - We have characterized monoclonal antibodies raised against the neuraminidase (NA)
      of a Sydney-like influenza virus (A/Memphis/31/98, H3N2) in a reassortant virus
      A/NWS/33(HA)-A/Mem/31/98(NA) (H1N2) and nine escape mutants selected by these
      monoclonal antibodies. Five of the antibodies use the same heavy chain VDJ genes
      and may not be independent. Another antibody, Mem5, uses the same V(H) and J
      genes with a different D gene and different isotype. Sequence changes in escape
      mutants selected by these antibodies occur in two loops of the NA, at amino acid
      198, 199, 220, or 221. These amino acids are located on the opposite side of the
      NA monomer to the major epitopes found in N9 and early N2 NAs. Escape mutants
      with a change at 198 have reduced NA activity compared to the wild-type virus.
      Asp198 points toward the substrate binding pocket, and we had previously found
      that a site-directed mutation of this amino acid resulted in a loss of enzyme
      activity (M. R. Lentz, R. G. Webster, and G. M. Air, Biochemistry 26:5351-5358,
      1987). Mutations at residue 199, 220, or 221 did not alter the NA activity
      significantly compared to that of wild-type NA. A 3.5-A structure of Mem5 Fab
      complexed with the Mem/98 NA shows that the Mem5 antibody binds at the sites of
      escape mutation selected by the other antibodies.

PMID- 12414968
TI  - Identification of six Autographa californica multicapsid nucleopolyhedrovirus
      early genes that mediate nuclear localization of G-actin.
AB  - Nuclear filamentous actin (F-actin) is required for nucleopolyhedrovirus (NPV)
      progeny production in NPV-infected, cultured lepidopteran cells. We have
      determined that monomeric G-actin is localized within the nuclei of host cells
      during the early stage of infection by Autographa californica multicapsid
      nucleopolyhedrovirus (AcMNPV). With a library of cloned AcMNPV genomic fragments,
      along with a plasmid engineered to express enhanced green fluorescent protein
      Bombyx mori G-actin in transient transfection experiments, we identified six
      AcMNPV early genes that mediate nuclear localization of G-actin in TN-368 cells:
      ie-1, pe38, he65, Ac004, Ac102, and Ac152. Within this subset, ie-1 and pe38
      encode immediate-early transcriptional transactivators, he65 encodes a delayed
      early product, and the products encoded by Ac004, Ac102, and Ac152 have not been
      characterized. We found that when driven by foreign promoters, ie-1, pe38, and
      Ac004 had to be expressed prior to Ac102 or he65 for nuclear G-actin to
      accumulate and that expression of Ac152 was no longer required. These results and
      others suggested that the product of Ac152 was a transactivator (directly or
      indirectly) of both Ac102 and he65 and that recruitment of G-actin to the nucleus
      was a temporally regulated process. Determining the functions of each of the six
      AcMNPV gene products with respect to our assay should provide valuable clues to
      basic cellular mechanisms of actin regulation and how AcMNPV infection affects
      them.

PMID- 12414969
TI  - Mutant human cytomegalovirus lacking the immediate-early TRS1 coding region
      exhibits a late defect.
AB  - The human cytomegalovirus IRS1 and TRS1 open reading frames encode immediate
      early proteins with identical N-terminal domains and divergent C-terminal
      regions. Both proteins have been shown previously to activate reporter genes in
      transfection assays in cooperation with other viral gene products. We have
      constructed two viruses carrying substitution mutations within either the IRS1 or
      TRS1 open reading frame. ADsubIRS1 failed to produce the related IRS1 and
      IRS1(263) proteins, but it replicated with normal kinetics to produce a wild-type
      yield in human fibroblasts. The addition in trans of the IRS1(263) protein, which
      antagonizes the ability of IRS1 and TRS1 proteins to activate reporter genes, did
      not inhibit the growth of the mutant virus. ADsubTRS1 failed to produce the TRS1
      protein, and it generated an approximately 200-fold-reduced yield of infectious
      virus in comparison to its wild-type parent. Viral DNA accumulated normally, as
      did a set of viral mRNAs that were monitored in ADsubTRS1-infected cells.
      However, two tegument proteins were partially mislocalized and infectious virus
      particles did not accumulate to normal levels within ADsubTRS1-infected cells.
      Further, infectious ADsubTRS1 particles sedimented abnormally in a glycerol
      tartrate gradient, indicating that the structure of the mutant particles is
      aberrant. Our analysis of the ADsubTRS1 phenotype indicates that the TRS1 protein
      is required, either directly or indirectly, for efficient assembly of virus
      particles.

PMID- 12414970
TI  - The membrane-proximal domain of vesicular stomatitis virus G protein functions as
      a membrane fusion potentiator and can induce hemifusion.
AB  - Recently we showed that the membrane-proximal stem region of the vesicular
      stomatitis virus (VSV) G protein ectodomain (G stem [GS]), together with the
      transmembrane and cytoplasmic domains, was sufficient to mediate efficient VSV
      budding (C. S. Robison and M. A. Whitt, J. Virol. 74:2239-2246, 2000). Here, we
      show that GS can also potentiate the membrane fusion activity of heterologous
      viral fusion proteins when GS is coexpressed with those proteins. For some fusion
      proteins, there was as much as a 40-fold increase in syncytium formation when GS
      was coexpressed compared to that seen when the fusion protein was expressed
      alone. Fusion potentiation by GS was not protein specific, since it occurred with
      both pH-dependent as well as pH-independent fusion proteins. Using a recombinant
      vesicular stomatitis virus encoding GS that contained an N-terminal hemagglutinin
      (HA) tag (GS(HA) virus), we found that the GS(HA) virus bound to cells as well as
      the wild-type virus did at pH 7.0; however, the GS(HA) virus was noninfectious.
      Analysis of cells expressing GS(HA) in a three-color membrane fusion assay
      revealed that GS(HA) could induce lipid mixing but not cytoplasmic mixing,
      indicating that GS can induce hemifusion. Treatment of GS(HA) virus-bound cells
      with the membrane-destabilizing drug chlorpromazine rescued the hemifusion block
      and allowed entry and subsequent replication of GS(HA) virus, demonstrating that
      GS-mediated hemifusion was a functional intermediate in the membrane fusion
      pathway. Using a series of truncation mutants, we also determined that only 14
      residues of GS, together with the VSV G transmembrane and cytoplasmic tail, were
      sufficient for fusion potentiation. To our knowledge, this is the first report
      which shows that a small domain of one viral glycoprotein can promote the fusion
      activity of other, unrelated viral glycoproteins.

PMID- 12414971
TI  - The p23 protein of hibiscus chlorotic ringspot virus is indispensable for host
      specific replication.
AB  - Hibiscus chlorotic ringspot virus (HCRSV) possesses a novel open reading frame
      (ORF) which encodes a putative 23-kDa protein (p23). We report here the in vivo
      detection of p23 and demonstrate its essential role in viral replication. The
      expression of p23 could be detected in protein extracts from transfected kenaf
      (Hibiscus cannabinus L.) protoplasts and in HCRSV-infected leaves. Further,
      direct immunoblotting of infected kenaf leaves also showed the presence of p23,
      and transient expression in onion and kenaf cells demonstrated that the protein
      is distributed throughout the cell. Site-directed mutagenesis showed that
      mutations introduced into the ORF of p23 abolished viral replication in kenaf
      protoplasts and plants but not in Chenopodium quinoa L. The loss of function of
      the p23 mutant M23/S33-1 could be complemented in trans upon the induced
      expression of p23 from an infiltrated construct bearing the ORF (pCam23).
      Altogether, these results demonstrate that p23 is a bona fide HCRSV protein that
      is expressed in vivo and suggest that p23 is indispensable for the host-specific
      replication of HCRSV. In addition, we show that p23 does not bind nucleic acids
      in vitro and does not act as a suppressor of posttranscriptional gene silencing
      in transgenic tobacco carrying a green fluorescent protein.

PMID- 12414972
TI  - Covariation in the capsid protein of hibiscus chlorotic ringspot virus induced by
      serial passaging in a host that restricts movement leads to avirulence in its
      systemic host.
AB  - Hibiscus chlorotic ringspot virus (HCRSV) from naturally infected Hibiscus rosa
      sinensis L. loses virulence in its experimental systemic host Hibiscus cannabinus
      L. (kenaf) after serial passages in a local lesion host Chenopodium quinoa. Here
      we report the genetic changes responsible for the loss of virulence at the
      molecular level. A remarkable covariation of eight site-specific amino acids was
      found in the HCRSV capsid protein (CP) after serial passages in C. quinoa:
      Val(49)-->Ile, Ile(95)-->Val, Lys(270)-->Arg, Gly(272)-->Asp, Tyr(274)-->His,
      Ala(311)-->Asp, Asp(334)-->Ala, and Ala(335)-->Thr. Covariation of at least three
      of the eight amino acids, Val(49), Ile(95), and Lys(270), caused the virus to
      become avirulent in kenaf. Interestingly, the nature of the covariation was
      consistent and reproducible at each serial passage. These data indicate that the
      nonsynonymous substitutions of amino acids in the HCRSV CP after serial passages
      in C. quinoa are not likely to be random events but may be due to host-associated
      positive selection or accelerated genetic drift. The observed interdependence
      among the three amino acids leading to avirulence in kenaf may have implications
      for structural or functional relationships in this virus-host interaction.

PMID- 12414973
TI  - Generation of hepatitis C virus-like particles by use of a recombinant vesicular
      stomatitis virus vector.
AB  - Hepatitis C virus (HCV), a major etiologic agent of hepatocellular carcinoma,
      presently infects approximately 400 million people worldwide, making the
      development of protective measures against HCV infection a key objective. Here we
      have generated a recombinant vesicular stomatitis virus (VSV), which expresses
      the HCV structural proteins, by inserting the contiguous Core, E1, and E2 coding
      region of HCV into the VSV genome. Recombinant VSV expressing HCV Core, E1, and
      E2 (VSV-HCV-C/E1/E2) grew to high titers in vitro and efficiently expressed the
      incorporated HCV gene product, which became fully processed into the individual
      HCV structural proteins. Biochemical and biophysical analysis indicated that the
      HCV Core, E1, and E2 proteins assembled to form HCV-like particles (HCV-LPs)
      possessing properties similar to the ultrastructural properties of HCV virions.
      Mice immunized with VSV-HCV-C/E1/E2 generated cell-mediated immune responses to
      all of the HCV structural proteins, and humoral responses, particularly to E2,
      were also readily evident. Our data collectively indicate that engineered VSVs
      expressing HCV Core, E1, and E2 and/or HCV-LPs represent useful tools in vaccine
      and immunotherapeutic strategies designed to address HCV infection.

PMID- 12414974
TI  - Binding of Norwalk virus-like particles to ABH histo-blood group antigens is
      blocked by antisera from infected human volunteers or experimentally vaccinated
      mice.
AB  - Attachment of Norwalk (NV), Snow Mountain (SMV), and Hawaii (HV) virus-like
      particles (VLPs) to specific ABH histo-blood group antigens was investigated by
      using human saliva and synthetic biotinylated carbohydrates. The three distinct
      Norwalk-like viruses (NLVs) have various capacities for binding ABH histo-blood
      group antigens, suggesting that different mechanisms for NLV attachment likely
      exist. Importantly, antisera from NV-infected human volunteers, as well as from
      mice inoculated with packaged Venezuelan equine encephalitis virus replicons
      expressing NV VLPs, blocked the ability of NV VLPs to bind synthetic H type 1,
      Le(b), and H type 3, suggesting a potential mechanism for antibody-mediated
      neutralization of NV.

PMID- 12414975
TI  - Viral evolution during structured treatment interruptions in chronically human
      immunodeficiency virus-infected individuals.
AB  - We analyzed the evolution of the human immunodeficiency virus type 1 (HIV-1) env
      gene in 12 chronically infected individuals who underwent structured treatment
      interruptions (STIs). Analyses of length variation and of clonal sequences
      demonstrated highly unpredictable evolution, which may limit the strengthening of
      HIV-specific immune responses by STIs because of the variability in exposure to
      viral antigens.

PMID- 12414976
TI  - Targeted derepression of the human immunodeficiency virus type 1 long terminal
      repeat by pyrrole-imidazole polyamides.
AB  - The host factor LSF represses the human immunodeficiency virus type 1 long
      terminal repeat (LTR) by mediating recruitment of histone deacetylase. We show
      that pyrrole-imidazole polyamides targeted to the LTR can specifically block LSF
      binding both in vitro and within cells via direct access to chromatin, resulting
      in increased LTR expression.

PMID- 12414977
TI  - Mucosal immunization with live recombinant bovine respiratory syncytial virus
      (BRSV) and recombinant BRSV lacking the envelope glycoprotein G protects against
      challenge with wild-type BRSV.
AB  - Recombinant bovine respiratory syncytial virus (rBRSV) and an rBRSV deletion
      mutant lacking the G gene (rBRSVDeltaG) were characterized in calves with respect
      to replication competence, attenuation, and protective efficacy as live
      attenuated BRSV vaccines. Both recombinant viruses were safe and induced
      protection against a BRSV challenge infection. rBRSV replicated efficiently in
      the upper respiratory tract. Intranasal immunization with rBRSVDeltaG led to
      infection but not to mucosal virus replication. Neutralizing antibodies were
      induced by rBRSV and rBRSVDeltaG. Thus, the BRSV attachment glycoprotein G seems
      to be dispensable in vaccinating calves against BRSV.

PMID- 12414978
TI  - T-cell receptor:CD3 down-regulation is a selected in vivo function of simian
      immunodeficiency virus Nef but is not sufficient for effective viral replication
      in rhesus macaques.
AB  - We investigated the function of severely truncated simian immunodeficiency virus
      (SIV) Nef proteins (tNef) in vitro and in vivo. These variants emerged in rhesus
      monkeys infected with SIVmac239 containing a 152-bp deletion in the nef-unique
      region and have been suggested to enhance SIV virulence (E. T. Sawai, M. S.
      Hamza, M. Ye, K. E. Shaw, and P. A. Luciw, J. Virol. 74:2038-2045, 2000). We
      found that the tNef proteins were unable to down-regulate the cell surface
      expression of major histocompatibility complex class I proteins, CD4, and CD28
      and neither stimulated SIV replication nor enhanced virion infectivity. The tNef
      proteins did efficiently down-regulate T-cell receptor (TCR):CD3 cell surface
      expression. Nevertheless, the SIVmac239 tnef variants were strongly attenuated in
      six infected juvenile rhesus macaques. Thus, while the ability of SIV Nef to down
      modulate TCR:CD3 cell surface expression apparently confers a selective advantage
      in vivo, it is insufficient for efficient viral replication in infected macaques.
      Additional mutations elsewhere in SIVmac239 tnef genomes are required for a
      virulent phenotype.

PMID- 12414979
TI  - Comparison of abnormal prion protein glycoform patterns from transmissible
      spongiform encephalopathy agent-infected deer, elk, sheep, and cattle.
AB  - Analysis of abnormal prion protein glycoform patterns from chronic wasting
      disease (CWD)-affected deer and elk, scrapie-affected sheep and cattle, and
      cattle with bovine spongiform encephalopathy failed to identify patterns capable
      of reliably distinguishing these transmissible spongiform encephalopathy
      diseases. However, PrP-res patterns sometimes differed among individual animals,
      suggesting infection by different or multiple CWD strains in some species.

PMID- 12414980
TI  - Host range and receptor binding properties of vectors bearing feline leukemia
      virus subgroup B envelopes can be modulated by envelope sequences outside of the
      receptor binding domain.
AB  - To evaluate host range differences between two different strains of feline
      leukemia virus subgroup B (FeLV-B), we compared the binding and infectivity
      patterns of retrovirus vectors bearing either FeLV-B-90Z or FeLV-B-GA envelopes.
      We report here that the ability of these envelopes to utilize different Pit1
      orthologs is mediated primarily by the receptor binding domain; however, in the
      case of FeLV-B-90Z, the C terminus also contributes to the recognition of certain
      Pit1 orthologs.

PMID- 12414981
TI  - Regulatory mechanisms by which barrier-to-autointegration factor blocks
      autointegration and stimulates intermolecular integration of Moloney murine
      leukemia virus preintegration complexes.
AB  - Retroviral integration is mediated by a preintegration complex (PIC) which
      contains the viral DNA made by reverse transcription together with associated
      protein factors. Prior to association with target DNA, the PIC must avoid
      suicidal intramolecular integration of its viral DNA (autointegration). We have
      demonstrated that barrier-to-autointegration factor (BAF) blocks the
      autointegration of Moloney murine leukemia virus (MoMLV) PICs in vitro. In this
      study, we show that BAF is an authentic component of MoMLV. Analysis of the
      sedimentation properties of initial, salt-stripped, and BAF-reconstituted PICs
      reveals that the viral DNA within the PIC is reversibly compacted by BAF,
      consistent with the functional role of BAF in protecting the viral DNA from
      autointegration. Furthermore, we find that BAF can promote the association of
      PICs with target DNA. Thus, our data suggest that BAF plays critical roles in
      promoting preferential intermolecular integration by both blocking
      autointegration and stimulating the capture of target DNA.

PMID- 12414982
TI  - RNA structure and packaging signals in the 5' leader region of the human
      immunodeficiency virus type 1 genome.
AB  - The leader region of the human immunodeficiency virus type 1 (HIV-1) genome has a
      highly folded structure, comprising at least two RNA stem-loops [the
      transactivation response (TAR) and poly(A) hairpins] near its 5' end and four
      others (SL1 to SL4) downstream. Each of these stem-loops contributes to the
      function of the HIV-1 packaging signal, which efficiently targets genomic RNA
      into nascent virions. The central 140-base region of the leader, which includes
      the U5 and primer binding site (PBS) sequences, is also believed to adopt a
      complex structure, but the nature of this structure and its possible role in RNA
      packaging have not been extensively explored. Here we report a mutational
      analysis identifying at least three separate loci within the U5-PBS region which,
      when mutated, impair both HIV-1 packaging specificity and infectivity in a single
      round proviral assay. In common with those of all previously described packaging
      signals in the leader, the function of one of these loci appeared to depend on
      secondary structure rather than on sequence alone. By contrast, the activity of
      the other two loci did not correlate with any predicted conformations. Moreover,
      unlike SL1 to SL4, the TAR, poly(A), and U5-PBS hairpins were not bound with high
      affinity by the nucleocapsid portion of the HIV-1 Gag protein in vitro, implying
      that they contribute to packaging through a mechanism distinct from that of SL1
      to SL4. Our findings confirm the existence and importance of secondary structure
      around the PBS and demonstrate that functional packaging signals are distributed
      across the entire HIV-1 leader.

PMID- 12414983
TI  - Compromised influenza virus-specific CD8(+)-T-cell memory in CD4(+)-T-cell
      deficient mice.
AB  - The primary influenza A virus-specific CD8(+)-T-cell responses measured by
      tetramer staining of spleen, lymph node, and bronchoalveolar lavage (BAL)
      lymphocyte populations were similar in magnitude for conventional I-A(b+/+) and
      CD4(+)-T-cell-deficient I-A(b-/-) mice. Comparable levels of virus-specific
      cytotoxic-T-lymphocyte activity were detected in the inflammatory exudate
      recovered by BAL following challenge. However, both the size of the memory T-cell
      pool and the magnitude of the recall response in the lymphoid tissues (but not
      the BAL specimens) were significantly diminished in mice lacking the CD4(+)
      subset. Also, the rate of virus elimination from the infected respiratory tract
      slowed at low virus loads following challenge of naive and previously immunized I
      A(b-/-) mice. Thus, though the capacity to mediate the CD8(+)-T-cell effector
      function is broadly preserved in the absence of concurrent CD4(+)-T-cell help,
      both the maintenance and recall of memory are compromised and the clearance of
      residual virus is delayed. These findings are consistent with mathematical models
      that predict virus-host dynamics in this, and other, models of infection.

PMID- 12414984
TI  - Involvement of apolipoprotein E in the hematogenous route of herpes simplex virus
      type 1 to the central nervous system.
AB  - Apolipoprotein E (ApoE), a constituent of the lipoproteins, may be relevant in
      herpes simplex virus type 1 (HSV-1) infection of the central nervous system
      (CNS), since HSV-1 binds to human serum ApoE lipoproteins. This study
      demonstrates the involvement of ApoE in the hematogenous route of HSV-1 to the
      CNS.

PMID- 12414985
TI  - Inhibition of hepatitis delta virus RNA editing by short inhibitory RNA-mediated
      knockdown of ADAR1 but not ADAR2 expression.
AB  - Hepatitis delta virus (HDV) requires host RNA editing at the viral RNA amber/W
      site. Of the two host genes responsible for RNA editing via deamination of
      adenosines in double-stranded RNAs, short inhibitory RNA-mediated knockdown of
      host ADAR1 expression but not that of ADAR2 led to decreased HDV amber/W editing
      and virus production. Despite substantial sequence and structural variation among
      the amber/W sites of the three HDV genotypes, ADAR1a was primarily responsible
      for editing all three. We conclude that ADAR1 is primarily responsible for
      editing HDV RNA at the amber/W site during HDV infection.

PMID- 12414986
TI  - Hedgehogs tryst with the cell cycle.
AB  - Hedgehog proteins play an essential role during pattern formation in animal
      development and, increasingly, much of our appreciation of their modes of action
      is emanating from studies of their signalling mechanisms at the cellular level.
      Recent work has provided insights into how Hedgehog controls the cell cycle in a
      variety of circumstances. The data suggest that this influence may be direct and
      operates through interaction of the signalling pathway with cell cycle regulators
      at multiple points within the cell cycle. These new findings have profound
      implications in the context of clinical conditions - especially cancers - that
      arise from de-regulated cell proliferation in response to aberrant Hedgehog
      signalling activity.

PMID- 12414987
TI  - Move over protein kinase C, you've got company: alternative cellular effectors of
      diacylglycerol and phorbol esters.
AB  - Diacylglycerol is an essential second messenger in mammalian cells. The most
      prominent intracellular targets of diacylglycerol and of the functionally
      analogous phorbol esters belong to the protein kinase C (PKC) family. However, at
      least five alternative types of high-affinity diacylglycerol/phorbol-ester
      receptor are known: chimaerins, protein kinase D, RasGRPs, Munc13s and DAG kinase
      gamma. Recent evidence indicates that these have functional roles in
      diacylglycerol second messenger signalling in vivo and that several cellular
      processes depend on these targets rather than protein kinase C isozymes. These
      findings contradict the still prevalent view according to which all
      diacylglycerol/phorbol-ester effects are caused by the activation of protein
      kinase C isozymes. RasGRP1 (in Ras/Raf/MEK/ERK signalling) and Munc13-1 (in
      neurotransmitter secretion) are examples of non-PKC diacylglycerol/phorbol-ester
      receptors that mediate diacylglycerol and phorbol-ester effects originally
      thought to be caused by PKC isozymes. In the future, pharmacological studies on
      PKC must be complemented with alternative experimental approaches to allow the
      separation of PKC-mediated effects from those caused by alternative targets of
      the diacylglycerol second messenger pathway. The examples of RasGRP1 and Munc13-1
      show that detailed genetic analyses of C(1)-domain-containing non-PKC
      diacylglycerol/phorbol-ester receptors in mammals are ideally suited to achieve
      this goal.

PMID- 12414988
TI  - Localisation of human DNA polymerase kappa to replication foci.
AB  - The replication of the undamaged genomic DNA requires error-free DNA polymerases
      delta and epsilon as part of a protein complex that acts continuously along the
      double helix. In contrast, when the genomic structure is perturbed, DNA
      replication needs to function more flexibly to bypass DNA distortions. It has
      been proposed that the newly discovered error prone DNA polymerases play a role
      in the replication of irregular structure. Here we report that one of them, the
      human Polkappa, is mostly localised uniformly in the nucleus of undamaged cells,
      but could be also concentrated in PCNA-containing replication foci. Following
      treatment with anti-replicative agents, the proportion of foci-containing cells
      was increased. These data suggest that Polkappa may function as part of the
      replication machinery itself and could be recruited when replicative complexes
      are stalled. Mutagenesis experiments also indicated that Polkappa involvement may
      affect the accuracy of DNA replication. The results are discussed within the
      context of the oncogenic process since Polkappa has been found as overexpressed
      in some cancers.

PMID- 12414989
TI  - Retinoids induce lumen morphogenesis in mammary epithelial cells.
AB  - Lumen formation is a fundamental step in the development of the structural and
      functional units of glandular organs, such as alveoli and ducts. In an attempt to
      elucidate the molecular signals that govern this morphogenetic event, we set up
      an in vitro system in which cloned mammary epithelial cells grown in collagen
      gels under serum-free conditions form solid, lumen-less colonies. Addition of as
      little as 0.1% donor calf serum (DCS) was sufficient to induce the formation of a
      central cavity. Among a number of serum constituents analyzed, retinol was found
      to mimic the effect of DCS in inducing lumen morphogenesis. Since the biological
      activities of retinol are largely dependent on its conversion to all-trans
      retinoic acid (RA), we examined in more detail the effect of RA on lumen
      formation. RA induced the formation of lumen-containing colonies (cysts) in a
      concentration- and time-dependent manner, a half-maximal effect after 9 days of
      culture being observed with 100 pM RA. The pleiotropic effects of retinoids are
      mediated by nuclear retinoic acid receptors (RARs; alpha, beta and gamma) and
      retinoid X receptors (RXRs; alpha, beta and gamma). To identify the signaling
      pathway involved in RA-induced lumen formation, we used receptor-specific
      synthetic retinoids. TTNPB, a selective RAR agonist, promoted lumen
      morphogenesis, whereas RXR-selective ligands lacked this activity. Lumen
      formation was also induced at picomolar concentrations by Am-580, a synthetic
      retinoid that selectively binds the RARalpha receptor subtype. Moreover, co
      addition of Ro 41-5253, an antagonist of RARalpha, abrogated the lumen-inducing
      activity of both RA and DCS, indicating that this biological response is mediated
      through an RARalpha-dependent signaling pathway. To gain insight into the
      mechanisms underlying RA-induced lumen formation, we assessed the potential role
      of matrix metalloproteinases (MMP). Using gelatin zymography, we observed a dose
      dependent increase in latent and active forms of gelatinase B (MMP-9) upon RA
      treatment. In addition, lumen formation was abrogated by addition of the
      synthetic MMP inhibitor BB94, indicating that this morphogenetic process is
      likely to require MMP activity. Collectively, our results provide evidence that
      RA promotes lumen formation by mammary epithelial cells in vitro and suggest that
      it plays a similar role during mammary gland development in vivo.

PMID- 12414990
TI  - A developmentally regulated ARF-like 5 protein (ARL5), localized to nuclei and
      nucleoli, interacts with heterochromatin protein 1.
AB  - ARF-like proteins (ARLs) are distinct group of members of the ARF family of Ras
      related GTPases. Although ARLs are very similar in primary structure to ARFs,
      their functions remain unclear. We cloned mouse (m) and human (h) ARL5 cDNAs to
      characterize the protein products and their molecular properties. mARL5 mRNA was
      more abundant in liver than in other adult tissues tested. mARL5, similar to
      mARL4, was developmentally regulated and localized to nuclei. hARL5 interacted
      with importin-alpha through its C-terminal bipartite nuclear localization signal.
      When expressed in COS-7 cells, mutant hARL5(T35N), which is predicted to be GDP
      bound, was concentrated in nucleoli. The N-terminus of hARL5, like that of ARF,
      was myristoylated. Yeast two-hybrid screening and in vitro protein-interaction
      assays showed that hARL5(Q80L), predicted to be GTP bound, interacted with
      heterochromatin protein 1alpha (HP1alpha), which is known to be associated with
      telomeres as well as with heterochromatin, and acted as a transcriptional
      suppressor in mammalian cells. The interaction was reproduced in COS cells, where
      hARL5(Q80L) was co-immunoprecipitated with HP1alpha. hARL5 interaction with
      HP1alpha was dependent on the nucleotide bound, and required the MIR-like motif.
      Moreover, hARL5(Q80L), but not hARL5 lacking the MIR-like motif, was partly co
      localized with overexpressed HP1alpha. Our findings suggest that developmentally
      regulated ARL5, with its distinctive nuclear/nucleolar localization and
      interaction with HP1alpha, may play a role(s) in nuclear dynamics and/or
      signaling cascades during embryonic development.

PMID- 12414991
TI  - Drosophila syntaxin 16 is a Q-SNARE implicated in Golgi dynamics.
AB  - SNARE isoforms appear to regulate specific intracellular membrane trafficking
      steps. To identify new SNARE proteins in Drosophila melanogaster we used a yeast
      two-hybrid screen to search for proteins that interact with SNAP. Here we report
      the identification of the Drosophila homologue of syntaxin 16. dsyntaxin 16 binds
      SNAP in a concentration-dependent fashion and genetically interacts with NSF2.
      Like its mammalian homologue, dsyntaxin 16 is ubiquitously expressed and appears
      to be localized to the Golgi apparatus. In addition, membranes containing
      dsyntaxin 16 become aggregated upon Brefeldin A treatment and are dispersed
      during meiosis. Inhibition of dsyntaxin 16 function by overexpression of
      truncated forms in cultured Schneider cells indicates that dsyntaxin 16 may
      selectively regulate Golgi dynamics.

PMID- 12414992
TI  - The scaffolding domain of caveolin 2 is responsible for its Golgi localization in
      Caco-2 cells.
AB  - In this work, we showed that in Caco-2 cells, a polarized cell line derived from
      human colon cancer that does not express caveolin 1 (Cav-1), there was no
      detectable expression of caveolin 2 (Cav-2). When Cav-2 was reintroduced in these
      cells, it accumulated in the Golgi complex. A chimera, in which the scaffolding
      domain of Cav-1 was replaced by the one from Cav-2, induced a prominent Golgi
      staining of Cav-1, strongly indicating that this domain was responsible for the
      accumulation of Cav-2 in the Golgi complex. Cav-2 was able to interact with Cav-1
      in the Golgi complex but this interaction was not sufficient to export it from
      this compartment. Several chimeras between Cav-1 and 2 were used to show that
      surface expression of caveolin was necessary but not sufficient to promote
      caveolae formation. Interestingly, levels of incorporation of the chimeras into
      Triton insoluble rafts correlated with their ability to trigger caveolae
      formation raising the possibility that a critical concentration of caveolins to
      discrete domains of the plasma membrane might be necessary for caveolae
      formation.

PMID- 12414993
TI  - Transient association of titin and myosin with microtubules in nascent myofibrils
      directed by the MURF2 RING-finger protein.
AB  - Assembly of muscle sarcomeres is a complex dynamic process and involves a large
      number of proteins. A growing number of these have regulatory functions and are
      transiently present in the myofibril. We show here that the novel tubulin
      associated RING/B-box protein MURF2 associates transiently with microtubules,
      myosin and titin during sarcomere assembly. During sarcomere assembly, MURF2
      first associates with microtubules at the exclusion of tyrosinated tubulin. Then,
      MURF2-labelled microtubules associate transiently with sarcomeric myosin and
      later with A-band titin when non-striated myofibrils differentiate into mature
      sarcomeres. Finally, MURF2 labelled microtubules disappear from the sarcomere
      after the incorporation of myosin filaments and the elongation of titin. This
      suggests that the incorporation of myosin into nascent sarcomeres and the
      elongation of titin require an active, microtubule-dependent transport process
      and that MURF2-associated microtubules play a role in the alignment and extension
      of nascent sarcomeres. MURF2 is expressed in at least four isoforms, of which a
      27 kDa isoform is cardiac specific. A C-terminal isoform is generated by
      alternative reading frame use, a novelty in muscle proteins. In mature cardiac
      sarcomeres, endogenous MURF2 can associate with the M-band, and is translocated
      to the nucleus. MURF2 can therefore act as a transient adaptor between
      microtubules, titin and nascent myosin filaments, as well as being involved in
      signalling from the sarcomere to the nucleus.

PMID- 12414994
TI  - Inactivation of Galpha(z) causes disassembly of the Golgi apparatus.
AB  - We showed previously that overexpression of the alpha subunit of G(z) or G(i2)
      suppresses nordihydroguaiaretic acid-induced Golgi disassembly. To determine
      whether the active form of Galpha is required to maintain the structure of the
      Golgi apparatus, we examined the effects of a series of Galpha GAPs, regulators
      of G protein signaling (RGS) proteins, on the Golgi structure. Expression of
      RGSZ1 or RGSZ2, both of which exhibit high selectivity for Galpha(z), markedly
      induced dispersal of the Golgi apparatus, whereas expression of RGS proteins that
      are rather selective for Galpha(q) or other Galpha(i) species did not. A mutated
      RGSZ1, which is deficient in the interaction with Galpha(z), did not induce Golgi
      disassembly. These results suggest that the active form of Galpha(z), but not
      Galpha(i2), is crucial for maintenance of the structure of the Golgi apparatus.
      Consistent with this idea, Golgi disruption also took place in cells transfected
      with a dominant-negative Galpha(z) mutant. Although previous studies showed that
      the expression of Galpha(z) is confined to neuronal cells and platelets,
      immunofluorescence and mRNA expression analyses revealed that it is also
      expressed, albeit at low levels, in non-neuronal cells, and is located in the
      Golgi apparatus. These results taken together suggest a general regulatory role
      for Galpha(z) in the control of the Golgi structure.

PMID- 12414995
TI  - Signalling by glial cell line-derived neurotrophic factor (GDNF) requires heparan
      sulphate glycosaminoglycan.
AB  - Glial cell line-derived neurotrophic factor, GDNF, is vital to the development
      and maintenance of neural tissues; it promotes survival of sympathetic,
      parasympathetic and spinal motor neurons during development, protects midbrain
      dopaminergic neurons from apoptosis well enough to be a promising treatment for
      Parkinson's disease, and controls renal and testicular development. Understanding
      how GDNF interacts with its target cells is therefore a priority in several
      fields. Here we show that GDNF requires glycosaminoglycans as well as the already
      known components of its receptor complex, c-Ret and GFRalpha-1. Without
      glycosaminoglcyans, specifically heparan sulphate, c-Ret phosphorylation fails
      and GDNF cannot induce axonogenesis in neurons, in PC-12 cells, or scatter of
      epithelial cells. Furthermore, exogenous heparan sulphate inhibits rather than
      assists GDNF signalling. The involvement of heparan sulphates in GDNF signalling
      raises the possibility that modulation of heparan expression may modulate
      signalling by GDNF in vivo.

PMID- 12414996
TI  - E-cadherin-mediated interactions of thymic epithelial cells with CD103+
      thymocytes lead to enhanced thymocyte cell proliferation.
AB  - Cadherins are a family of cell adhesion molecules that mainly mediate homotypic
      homophilic interactions, but for E-cadherin, heterophilic interactions with the
      integrin alpha(E)(CD103)beta(7) have also been reported. In the human thymus,
      where thymocytes develop in close contact with thymic stromal cells, E-cadherin
      expression was detected on thymic epithelial cells. By immunofluorescence
      staining, the strongest expression of E-cadherin was observed on medullary thymic
      epithelial cells. These cells also express cytosolic catenins, which are
      necessary to form functional cadherin-catenin complexes. Regardless of their
      developmental stage, human thymocytes do not express E-cadherin, indicating that
      homophilic interactions cannot occur. Flow cytometric analysis revealed that the
      E-cadherin ligand CD103 is expressed on subpopulations of the early CD4(-) CD8(-)
      double-negative and of the more mature CD8(+) single-positive thymocytes. Using
      an in vitro cell adhesion assay, double-negative and CD8(+) single-positive
      thymocytes adhered strongly to isolated thymic epithelial cells. These adhesive
      interactions could be inhibited by antibodies against E-cadherin or CD103. CD8(+)
      thymocytes showed a proliferative response when incubated with thymic epithelial
      cells. This mitogenic effect was inhibited by antibodies against CD103, which
      strongly indicates a direct involvement of the adhesive ligand pair CD103-E
      cadherin in human thymocyte cell proliferation.

PMID- 12414997
TI  - Defects in keratinocyte activation during wound healing in the syndecan-1
      deficient mouse.
AB  - Mice lacking syndecan-1 are viable, fertile and have morphologically normal skin,
      hair and ocular surface epithelia. While studying the response of these mice to
      corneal epithelial and skin wounding, we identified defects in epithelial cell
      proliferation and regulation of integrin expression. mRNA profiling of corneal
      epithelial tissues obtained from wild-type and syndecan-1(-/-) mice suggest that
      these defects result from differences in overall gene transcription. In the
      cornea, syndecan-1(-/-) epithelial cells migrate more slowly, show reduced
      localization of alpha9 integrin during closure of wounds and fail to increase
      their proliferation rate 24 hours after wounding. In the skin, we did not
      document a migration defect after full thickness wounds but did observe cell
      proliferation delays and reduced localization of alpha9 integrin in the syndecan
      1(-/-) epidermis after dermabrasion. Despite increased cell proliferation rates
      in the uninjured syndecan-1(-/-) epidermis and the corneal epithelium,
      morphologically normal epithelial thickness is maintained prior to injury;
      however, wounding is accompanied by prolonged hypoplasia in both tissues.
      Analyses of integrin protein levels in extracts from full thickness skin,
      revealed increased levels of alpha3 and alpha9 integrins both prior to injury and
      after hair removal in syndecan-1(-/-) mice but no increase 2 days after
      dermabrasion. These data for the first time show involvement of alpha9 integrin
      in skin wound healing and demonstrate essential roles for syndecan-1 in mediating
      cell proliferation and regulation of integrin expression in normal and wounded
      epithelial tissues.

PMID- 12414998
TI  - Nuclear localisation of cytosolic phospholipase A2-alpha in the EA.hy.926 human
      endothelial cell line is proliferation dependent and modulated by
      phosphorylation.
AB  - Cytosolic phospholipase A(2)-alpha (cPLA(2)-alpha) is a calcium-sensitive enzyme
      involved in receptor-mediated eicosanoid production. In resting cells, cPLA(2)
      alpha is present in the cytosol and nucleus and translocates to membranes via its
      calcium-dependent lipid-binding (CaLB) domain following stimulation. cPLA(2)
      alpha is also regulated by phosphorylation on several residues, which results in
      enhanced arachidonic acid release. Little is known about the factors controlling
      the nuclear localisation of cPLA(2)-alpha. Here the nuclear localisation of
      cPLA(2)-alpha in the EA.hy.926 human endothelial cell line was investigated.
      Nuclear localisation was dependent on proliferation, with subconfluent cells
      containing higher levels of nuclear cPLA(2)-alpha than contact-inhibited
      confluent or serum-starved cells. The broad-range protein kinase inhibitor
      staurosporine caused a decrease in the nuclear level of cPLA(2)-alpha, whereas
      the protein phosphatase inhibitor okadaic acid increased the level of nuclear
      cPLA(2)-alpha. Using inhibitors for specific mitogen-activated protein (MAP)
      kinases, both p42/44(MAPK) and p38(MAPK) were shown to be important in modulating
      nuclear localisation. Finally, inhibition of nuclear import and export using
      Agaricus bisporus lectin and leptomycin B, respectively, demonstrated that
      cPLA(2)-alpha contains functional nuclear localisation and export signals. Thus
      we have identified a novel mode of regulation of cPLA(2)-alpha. This, together
      with the increasing body of evidence supporting the role of nuclear lipid second
      messengers in gene expression and proliferation, may have important implications
      for controlling the growth of endothelial cells in angiogenesis and tumour
      progression.

PMID- 12414999
TI  - Retinal pigment epithelial cells exhibit unique expression and localization of
      plasma membrane syntaxins which may contribute to their trafficking phenotype.
AB  - The SNARE membrane fusion machinery controls the fusion of transport vesicles
      with the apical and basolateral plasma-membrane domains of epithelial cells and
      is implicated in the specificity of polarized trafficking. To test the hypothesis
      that differential expression and localization of SNAREs may be a mechanism that
      contributes to cell-type-specific polarity of different proteins, we studied the
      expression and distribution of plasma-membrane SNAREs in the retinal pigment
      epithelium (RPE), an epithelium in which the targeting and steady-state polarity
      of several plasma membrane proteins differs from most other epithelia. We show
      here that retinal pigment epithelial cells both in vitro and in vivo differ
      significantly from MDCK cells and other epithelial cells in their complement of
      expressed t-SNAREs that are known - or suggested - to be involved in plasma
      membrane trafficking. Retinal pigment epithelial cells lack expression of the
      normally apical-specific syntaxin 3. Instead, they express syntaxins 1A and 1B,
      which are normally restricted to neurons and neuroendocrine cells, on their
      apical plasma membrane. The polarity of syntaxin 2 is reversed in retinal pigment
      epithelial cells, and it localizes to a narrow band on the lateral plasma
      membrane adjacent to the tight junctions. In addition, syntaxin 4 and the v-SNARE
      endobrevin/VAMP-8 localize to this sub-tight junctional domain, which suggests
      that this is a region of preferred vesicle exocytosis. Altogether, these data
      suggest that the unique polarity of many retinal pigment epithelial proteins
      results from differential expression and distribution of SNAREs at the plasma
      membrane. We propose that regulation of the expression and subcellular
      localization of plasma membrane SNAREs may be a general mechanism that
      contributes to the establishment of distinct sorting phenotypes among epithelial
      cell types.

PMID- 12415000
TI  - Phosphorylation activates Chk1 and is required for checkpoint-mediated cell cycle
      arrest.
AB  - In the fission yeast Schizosaccharomyces pombe, the protein kinase Chk1 has an
      essential role in transducing a delay signal to the cell cycle machinery in the
      presence of DNA damage. Fission yeast cells lacking the chk1 gene do not delay
      progression of the cell cycle in response to damage and are thus sensitive to DNA
      damaging agents. We have previously shown that Chk1 is phosphorylated following
      DNA damage induced by a variety of agents and that this is dependent on the
      integrity of the DNA damage checkpoint pathway, including Rad3, the ATR homolog.
      Through a combination of mutagenesis and phospho-specific antibodies, we have
      shown that serine at position 345 (S345) is phosphorylated in vivo in response to
      DNA damage, and that S345 phosphorylation is required for an intact checkpoint
      response. We have developed a kinase assay for Chk1, and have shown that basal
      Chk1 kinase activity is increased in response to DNA damage and that this
      increase, but not the basal activity, is dependent on S345. Furthermore, we show
      that S345 phosphorylation is required for Chk1 to associate with Rad24, a 14-3-3
      protein, upon DNA damage. These results are consistent with a model whereby Chk1
      phosphorylation results in increased Chk1 kinase activity that is necessary for
      both checkpoint delay and cellular survival following damage to the genome. These
      data are similar to observations made in mammalian cells and Xenopus oocyte
      extracts, suggesting that mechanisms leading to Chk1 activation have been
      conserved in evolution.

PMID- 12415001
TI  - The CBEL glycoprotein of Phytophthora parasitica var-nicotianae is involved in
      cell wall deposition and adhesion to cellulosic substrates.
AB  - The cell wall of the oomycete plant pathogen Phytophthora parasitica var.
      nicotianae contains a protein called CBEL that shows cellulose-binding (CB),
      elicitor (E) of defense in plants and lectin-like (L) activities. The biological
      role of this molecule in Phytophthora was investigated by generating transgenic
      strains suppressed in CBEL expression. Phenotypic characterization of these
      strains showed that they were severely impaired in adhesion to a cellophane
      membrane, differentiation of lobed structures in contact with cellophane, and
      formation of branched aggregating hyphae on cellophane and on flax cellulose
      fibres. Infection assays revealed that the strains suppressed in CBEL expression
      were not greatly affected in pathogenicity and formed branched aggregating hyphae
      in contact with the roots of the host plant, thereby indicating that CBEL is
      involved in the perception of cellulose rather than in the morphogenesis of
      hyphal aggregates. Interestingly, the absence of CBEL was correlated with
      abnormal formation of papillae-like cell wall thickenings in vitro, suggesting
      that CBEL is involved in cell wall deposition in Phytophthora. Reverse genetics
      in oomycetes has long been hampered by their diploid nature and difficulties in
      transformation and regeneration. The gene inactivation approach reported in this
      work provides the first direct evidence for intrinsic functions of an elicitor
      and cell wall protein in oomycetes.

PMID- 12415003
TI  - beta-Catenin is not required for proliferation and differentiation of epidermal
      mouse keratinocytes.
AB  - Despite the pivotal role of beta-catenin in a variety of biological processes,
      conditional beta-catenin gene ablation in the skin of transgenic mice failed to
      affect interfollicular epidermal morphogenesis. We elucidated the molecular
      mechanisms underlying this phenomenon. Long-term cultures of homozygous,
      heterozygous and beta-catenin-null mutant keratinocytes were established to
      demonstrate that epidermal keratinocyte proliferation, cell cycle progression and
      cyclin D1 expression occur independently of beta-catenin and correlate with
      repression of transcription from Tcf/Lef-responsive promoters. Moreover, during
      differentiation, beta-catenin-null cells assemble normal intercellular adhesion
      junctions owing to the substitution of beta-catenin with plakoglobin, whereas the
      expression of the other adhesion components remains unaffected. Taken together,
      our results demonstrate that epidermal proliferation and adhesion are independent
      of beta-catenin.

PMID- 12415002
TI  - Stem-loop binding protein accumulates during oocyte maturation and is not cell
      cycle-regulated in the early mouse embryo.
AB  - The stem-loop binding protein (SLBP) binds to the 3' end of histone mRNA and
      participates in 3'-processing of the newly synthesized transcripts, which
      protects them from degradation, and probably also promotes their translation. In
      proliferating cells, translation of SLBP mRNA begins at G1/S and the protein is
      degraded following DNA replication. These post-transcriptional mechanisms closely
      couple SLBP expression to S-phase of the cell cycle, and play a key role in
      restricting synthesis of replication-dependent histones to S-phase. In contrast
      to somatic cells, replication-dependent histone mRNAs accumulate and are
      translated independently of DNA replication in oocytes and early embryos. We
      report here that SLBP expression and activity also differ in mouse oocytes and
      early embryos compared with somatic cells. SLBP is present in oocytes that are
      arrested at prophase of G2/M, where it is concentrated in the nucleus. Upon entry
      into M-phase of meiotic maturation, SLBP begins to accumulate rapidly, reaching a
      very high level in mature oocytes arrested at metaphase II. Following
      fertilization, SLBP remains abundant in the nucleus and the cytoplasm throughout
      the first cell cycle, including both G1 and G2 phases. It declines during the
      second and third cell cycles, reaching a relatively low level by the late 4-cell
      stage. SLBP can bind the histone mRNA-stem-loop at all stages of the cell cycle
      in oocytes and early embryos, and it is the only stem-loop binding activity
      detectable in these cells. We also report that SLBP becomes phosphorylated
      rapidly following entry into M-phase of meiotic maturation through a mechanism
      that is sensitive to roscovitine, an inhibitor of cyclin-dependent kinases. SLBP
      is rapidly dephosphorylated following fertilization or parthenogenetic
      activation, and becomes newly phosphorylated at M-phase of mitosis.
      Phosphorylation does not affect its stem-loop binding activity. These results
      establish that, in contrast to Xenopus, mouse oocytes and embryos contain a
      single SLBP. Expression of SLBP is uncoupled from S-phase in oocytes and early
      embryos, which indicates that the mechanisms that impose cell-cycle-regulated
      expression of SLBP in somatic cells do not operate in oocytes or during the first
      embryonic cell cycle. This distinctive pattern of SLBP expression may be required
      for accumulation of histone proteins required for sperm chromatin remodelling and
      assembly of newly synthesized embryonic DNA into chromatin.

PMID- 12415004
TI  - The architecture of interphase chromosomes and gene positioning are altered by
      changes in DNA methylation and histone acetylation.
AB  - Wheat nuclei have a remarkably well defined interphase organisation, and we have
      made use of this to determine the relationship between interphase chromosome
      organisation, the positioning of specific transgenes and induced changes in DNA
      methylation and histone acetylation, using in situ hybridisation and confocal 3D
      imaging. After germinating seeds either in the presence of 5-Azacytidine (5-AC),
      which leads to DNA hypomethylation, or trichostatin A (TSA), which results in
      histone hyperacetylation, the architecture of the interphase chromosome arms
      changes significantly even though the overall Rabl configuration is maintained.
      This suggests that specific chromosome segments are remodelled by these
      treatments but that there is a strong link of both centromeres and telomeres to
      the nuclear envelope. In lines carrying multiple transgene integrations at widely
      separated sites, we show that the multiple transgenes, which are usually
      colocalised during interphase, are dispersed after 5-AC or TSA treatment and that
      there is an increase in transgene activity. This suggests that the
      colocalisation/dispersion of the transgenes may be a function of specific
      interphase chromosome organisation and that these lines containing multiple
      transgene copies may all be partially transcriptionally repressed.

PMID- 12415005
TI  - Loss of Rb overrides the requirement for ERK activity for cell proliferation.
AB  - The Ras GTPase is a critical transducer of mitogenic signals ultimately leading
      to inactivation of the retinoblastoma (Rb) protein, but the molecular basis
      underlying Ras-dependent control of cell cycle kinetics remains to a great extent
      unknown. In an effort to further elucidate the role of Ras activation in cell
      cycle control, we have studied the role of the downstream Mek-ERK pathway in
      facilitating exit from the quiescent G0 state and passage through the G1/S
      transition. We have adopted a genetic approach in combination with U0126, an
      inhibitor of Mek activation to study the role of Mek in cell cycle progression.
      Here we report that whereas wild-type (Wt) mouse embryo fibroblasts (MEFs) depend
      on ERK activation to enter the cell cycle, Rb-deficient (Rb(-/-)) MEFs have a
      reduced requirement for ERK signalling. Indeed in the presence of U0126 we found
      that Rb-null MEFs can exit G0, make the G1/S transition and proliferate. Analysis
      of Rb-deficient tumour cell lines also revealed a reduced requirement for ERK
      signalling in asynchronous growth. We discuss the molecular mechanism that may
      underlie this escape from MAP kinase signalling.

PMID- 12415006
TI  - Differentiation plasticity of chondrocytes derived from mouse embryonic stem
      cells.
AB  - Evidence exists that cells of mesenchymal origin show a differentiation
      plasticity that depends on their differentiation state. We used in vitro
      differentiation of embryonic stem cells through embryoid bodies as a model to
      analyze chondrogenic and osteogenic differentiation because embryonic stem cells
      recapitulate early embryonic developmental phases during in vitro
      differentiation. Here, we show that embryonic stem cells differentiate into
      chondrocytes, which progressively develop into hypertrophic and calcifying cells.
      At a terminal differentiation stage, cells expressing an osteoblast-like
      phenotype appeared either by transdifferentiation from hypertrophic chondrocytes
      or directly from osteoblast precursor cells. Chondrocytes isolated from embryoid
      bodies initially dedifferentiated in culture but later re-expressed
      characteristics of mature chondrocytes. The process of redifferentiation was
      completely inhibited by transforming growth factor beta3. In clonal cultures of
      chondrocytes isolated from embryoid bodies, additional mesenchymal cell types
      expressing adipogenic properties were observed, which suggests that the
      subcultured chondrocytes indeed exhibit a certain differentiation plasticity. The
      clonal analysis confirmed that the chondrogenic cells change their developmental
      fate at least into the adipogenic lineage. In conclusion, we show that
      chondrocytic cells are able to transdifferentiate into other mesenchymal cells
      such as osteogenic and adipogenic cell types. These findings further strengthen
      the view that standardized selection strategies will be necessary to obtain
      defined cell populations for therapeutic applications.

PMID- 12415007
TI  - The small GTPase Rho3 and the diaphanous/formin For3 function in polarized cell
      growth in fission yeast.
AB  - We identified a novel Rho gene rho3(+) and studied its interaction with
      diaphanous/formin for3(+) in the fission yeast Schizosaccharomyces pombe. Both
      rho3 null cells and for3 null cells showed defects in organization of not only
      actin cytoskeleton but also cytoplasmic microtubules (MTs). rho3 for3 double null
      cells had defects that were more severe than each single null cell: polarized
      growth was deficient in the double null cells. Function of For3 needed the highly
      conserved FH1 and FH2 domains, an N-terminal region containing a Rho-binding
      domain, and the C-terminal region. For3 bound to active forms of both Rho3 and
      Cdc42 but not to that of Rho1. For3 was localized as dots to the ends of
      interphase cells and to the mid-region in dividing cells. This localization was
      probably dependent on its interaction with Rho proteins. Overexpression of For3
      produced huge swollen cells containing depolarized F-actin patches and thick
      cytoplasmic MT bundles. In addition, overexpression of a constitutively active
      Rho3Q71L induced a strong defect in cytokinesis. In conclusion, we propose that
      the Rho3-For3 signaling system functions in the polarized cell growth of fission
      yeast by controlling both actin cytoskeleton and MTs.

PMID- 12415008
TI  - Integrin alpha8beta1 mediates adhesion to LAP-TGFbeta1.
AB  - The development of fibrosis is a common response to a variety of injuries and
      results in the net accumulation of matrix proteins and impairment of normal organ
      function. We previously reported that the integrin alpha8beta1 is expressed by
      alveolar interstitial cells in normal lung and is upregulated during the
      development of fibrosis. TGFbeta1 is an important mediator of the inflammatory
      response in pulmonary fibrosis. TGFbeta1 is secreted as a latent protein that is
      non-covalently associated with latency-associated peptide (LAP) and requires
      activation to exert its effects. LAP-TGFbeta1 and LAP-TGFbeta3 contain the
      tripeptide sequence, arginine-glycine-aspartic acid (RGD), a known integrin
      recognition motif. The integrin alpha8beta1 binds to several ligands such as
      fibronectin and vitronectin through the RGD sequence. Recent reports demonstrate
      that the integrins alphavbeta1, alphavbeta6 and alphavbeta8 adhere to LAP
      TGFbeta1 through the RGD site. Therefore, we asked whether LAP-TGFbeta1 might be
      a ligand for alpha8beta1 and whether this may be important in the development of
      fibrosis. We found that cell lines transfected with alpha8 subunit were able to
      spread on and adhere to recombinant LAP-TGFbeta1 significantly better than mock
      transfected cell lines. alpha8-transfected cells were also able to adhere to LAP
      TGFbeta3 significantly better than mock transfected cells. Adhesion to LAP
      TGFbeta1 was enhanced by activation of alpha8beta1 by Mn(2+), or 8A2, an integrin
      beta1 activating antibody. Furthermore, cell adhesion was abolished when we used
      a recombinant LAP-TGFbeta1 protein in which the RGD site was mutated to RGE.
      alpha8beta1 binding to LAP-TGFbeta1 increased cell proliferation and
      phosphorylation of FAK and ERK, but did not activate of TGFbeta1. These data
      strongly suggest that LAP-TGFbeta1 is a ligand of alpha8beta1 and interaction of
      alpha8beta1 with LAP-TGFbeta1 may influence cell behavior.

PMID- 12415009
TI  - Spatial regulation of actin dynamics: a tropomyosin-free, actin-rich compartment
      at the leading edge.
AB  - Rapid polymerization of a network of short, branched actin filaments takes place
      at the leading edge of migrating cells, a compartment enriched in activators of
      actin polymerization such as the Arp2/3 complex and cofilin. Actin filaments
      elsewhere in the cell are long and unbranched. Results reported here show that
      the presence or absence of tropomyosin in these different actin-containing
      regions helps establish functionally distinct actin-containing compartments in
      the cell. Tropomyosin, an inhibitor of the Arp2/3 complex and cofilin function,
      was localized in relation to actin filaments, the Arp2/3 complex, and free barbed
      ends of actin filaments in MTLn3 cells, which rapidly extend flat lamellipodia
      following EGF stimulation. All tropomyosin isoforms examined using indirect
      immunofluorescence were relatively absent from the dynamic leading edge
      compartment, but did colocalize with actin structures deeper in the lamellipodium
      and in stress fibers. An in vitro light microscopy assay revealed that
      tropomyosin protects actin filaments from cofilin severing. The results suggest
      that tropomyosin-free actin filaments under the membrane can participate in
      rapid, dynamic processes that depend on interactions between the activities of
      the Arp2/3 complex and ADF/cofilin that tropomyosin inhibits elsewhere in the
      cell.

PMID- 12415010
TI  - RNA trafficking and stabilization elements associate with multiple brain
      proteins.
AB  - Two of the best understood somatic cell mRNA cytoplasmic trafficking elements are
      those governing localization of beta-actin and myelin basic protein mRNAs. These
      cis-acting elements bind the trans-acting factors fibroblast ZBP-1 and hnRNP A2,
      respectively. It is not known whether these elements fulfil other roles in mRNA
      metabolism. To address this question we have used Edman sequencing and western
      blotting to identify six rat brain proteins that bind the beta-actin element
      (zipcode). All are known RNA-binding proteins and differ from ZBP-1. Comparison
      with proteins that bind the hnRNP A2 and AU-rich response elements, A2RE/A2RE11
      and AURE, showed that AURE and zipcode bind a similar set of proteins that does
      not overlap with those that bind A2RE11. The zipcode-binding protein, KSRP, and
      hnRNP A2 were selected for further study and were shown by confocal
      immunofluorescence microscopy to have similar distributions in the central
      nervous system, but they were found in largely separate locations in cell nuclei.
      In the cytoplasm of cultured oligodendrocytes they were segregated into separate
      populations of cytoplasmic granules. We conclude that not only may there be
      families of trans-acting factors for the same cis-acting element, which are
      presumably required at different stages of mRNA processing and metabolism, but
      independent factors may also target different and multiple RNAs in the same cell.

PMID- 12415011
TI  - Caspase-dependent initiation of apoptosis and necrosis by the Fas receptor in
      lymphoid cells: onset of necrosis is associated with delayed ceramide increase.
AB  - Engagement of the Fas receptor promotes apoptosis by activation of caspases. In
      addition, alterations in plasma membrane lipid orientation and intracellular
      ceramide levels are often observed. In A20 B-lymphoma cells, FasL-induced cell
      death and phosphatidylserine (PS) externalization were completely prevented by
      the generic caspase inhibitor z-VAD-fmk. By contrast, the caspase-3 inhibitor Ac
      DEVD-cho only partially restored cell viability and had no effect on surface
      exposure of PS. Flow cytometric analysis after FasL treatment identified two
      populations of dead cells. In one, death was dependent on caspase-3 and
      paralleled by DNA fragmentation and cell shrinkage. In the second, death occurred
      in the absence of caspase-3 activity and apoptotic features but was also blocked
      by zVAD-fmk. By morphological criteria these were identified as apoptotic and
      necrotic cells, respectively. Using fluorescent substrates, caspase-3 activity
      was detected only in the apoptotic cell population, whereas caspase-8 activity
      was detected in both. Both forms of caspase-8-dependent cell death were also
      detected downstream of Fas in Jurkat T-cells, where Fas-dependent PS
      externalization and delayed ceramide production, which is similar to results
      shown here in A20 cells, have been reported. However, for Raji B-cells, lacking
      lipid scrambling and ceramide production in response to Fas activation, only
      apoptosis was detected. Short-chain C2- or C6-ceramides, but not the respective
      inactive dihydro compounds or treatment with bacterial sphingomyelinase, induced
      predominantly necrotic rather than apoptotic cell death in A20 B-, Raji B- and
      Jurkat T-cells. Thus, delayed elevation of ceramide is proposed to promote
      necrosis in those Fas-stimulated cells where caspase-8 activation was
      insufficient to trigger caspase-3-dependent apoptosis.

PMID- 12415012
TI  - Chromosomal association of Ran during meiotic and mitotic divisions.
AB  - Recent studies in Xenopus egg extracts indicate that the small G protein Ran has
      a central role in spindle assembly and nuclear envelope reformation. We
      determined Ran localization and dynamics in cells during M phase. By
      immunofluorescence, Ran is accumulated on the chromosomes of meiosis-II-arrested
      Xenopus eggs. In living cells, fluorescently labeled Ran associated with the
      chromosomes in Xenopus and remained associated during anaphase when eggs were
      artificially activated. Fluorescent Ran associated with chromosomes in mouse
      eggs, during meiotic maturation and early embryonic divisions in starfish, and to
      a lesser degree during mitosis of a cultured mammalian cell line. Chromosomal Ran
      undergoes constant flux. From photobleach experiments in immature starfish
      oocytes, chromosomal Ran has a k(off) of approximately 0.06 second(-1), and
      binding analysis suggests that there is a single major site. The chromosomal
      interactions may serve to keep Ran-GTP in the vicinity of the chromosomes for
      spindle assembly and nuclear envelope reformation.

PMID- 12415013
TI  - The postsynaptic density and dendritic raft localization of PSD-Zip70, which
      contains an N-myristoylation sequence and leucine-zipper motifs.
AB  - The postsynaptic site of the excitatory synapse, which is composed of the
      postsynaptic density (PSD) attached to the postsynaptic membrane, is a center for
      synaptic plasticity. To reveal the molecular organization and functional
      regulation of the postsynaptic site, we cloned a 70 kDa protein that is
      concentrated in PSDs using a monoclonal antibody against the PSD. This protein,
      named PSD-Zip70, is highly homologous to the human FEZ1/LZTS1 gene product. PSD
      Zip70 contains an N-myristoylation consensus sequence, a polybasic cluster in the
      N-terminal region and four leucine-zipper motifs in the C-terminal region. Light
      and electron microscopy showed that this protein was localized to the dendritic
      spines, especially in the PSD and the postsynaptic membrane. Fractionation of the
      synaptic plasma membrane demonstrated that PSD-Zip70 was localized to the PSD and
      the dendritic raft. In Madin-Darby canine kidney (MDCK) cells, exogenous PSD
      Zip70 was targeted to the apical plasma membrane of microvilli, and its N
      myristoylation was necessary for this targeting. In hippocampal neurons, N
      myristoylation was also required for the membrane localization and the C-terminal
      region was critically involved in the synaptic targeting. These results suggest
      that PSD-Zip70 may be involved in the dynamic properties of the structure and
      function of the postsynaptic site.

PMID- 12415014
TI  - The centrosome is a dynamic structure that ejects PCM flares.
AB  - The Drosophila Centrosomin (Cnn) protein is an essential core component of
      centrosomes in the early embryo. We have expressed a Cnn-GFP fusion construct in
      cleavage stage embryos, which rescues the maternal effect lethality of cnn mutant
      animals. The localization patterns seen with GFP-Cnn are identical to the
      patterns we see by immunofluorescent staining with anti-Cnn antibodies. Live
      imaging of centrosomes with Cnn-GFP reveals surprisingly dynamic features of the
      centrosome. Extracentrosomal particles of Cnn move radially from the centrosome
      and frequently change their direction. D-TACC colocalized with Cnn at these
      particles. We have named these extrusions 'flares'. Flares are dependent on
      microtubules, since disruption of the microtubule array severs the movement of
      these particles. Movement of flare particles is cleavage-cycle-dependent and
      appears to be attributed mostly to their association with dynamic astral
      microtubules. Flare activity decreases at metaphase, then increases at telophase
      and remains at this higher level of activity until the next metaphase. Flares
      appear to be similar to vertebrate PCM-1-containing 'centriolar satellites' in
      their behavior. By injecting rhodamine-actin, we observed that flares extend no
      farther than the actin cage. Additionally, disruption of the microfilament array
      increased the extent of flare movement. These observations indicate that
      centrosomes eject particles of Cnn-containing pericentriolar material that move
      on dynamic astral microtubules at a rate that varies with the cell cycle. We
      propose that flare particles play a role in organizing the actin cytoskeleton
      during syncytial cleavage.

PMID- 12415016
TI  - Disorders of water metabolism in children: hyponatremia and hypernatremia.

PMID- 12415017
TI  - Group B streptococcal infections.

PMID- 12415018
TI  - Delinquent behavior.

PMID- 12415019
TI  - Index of suspicion.

PMID- 12415020
TI  - Question from the clinician: levalbuterol in managing pediatric asthma.

PMID- 12415021
TI  - Projected cost-effectiveness of statewide universal newborn hearing screening.
AB  - OBJECTIVES: Early identification of hearing impairment may improve language
      outcomes and subsequent school and occupational performance of the deaf.
      Universal newborn hearing screening (UNHS), currently mandated by 32 states, can
      reduce the median age of identification of hearing impairment from 12 to 18
      months to 6 months or less. However, because false-negative tests must be
      minimized, the prevalence of congenital deafness is low, and screening tests are
      imperfect, UNHS results in many false-positive results and has a low positive
      predictive value (PPV). The objective of this study was to evaluate UNHS and
      selective screening in terms of both short- and long-term benefits, harms, and
      financial costs and to identify steps in the screening process that could be
      improved to increase cost-effectiveness. METHODS: The cost-effectiveness
      analysis, conducted from the societal perspective, compared the projected
      outcomes of 1) no newborn hearing screening, 2) selective newborn hearing
      screening, and 3) UNHS for a hypothetical state birth cohort of 80 000 infants.
      Probability and cost estimates for the decision model were obtained from
      published studies, expert opinion, and national and state sources. The main
      outcomes were incremental cost per infant whose deafness was diagnosed by 6
      months, which included only the cost of screening and diagnostic evaluation; and
      incremental cost per deaf child with normal language, which also included the
      costs of medical care, education and assistive devices, and lost productivity
      over the lifetime of the deaf individual. RESULTS: Selective screening identified
      62 of the 128 deaf infants in the birth cohort, referred 0.18% of all infants for
      diagnostic evaluation, and had a PPV of 43%. UNHS identified 116 of the 128 deaf
      infants, referred 1.6% of all infants, and had a PPV of 8.8%. Our model simulated
      real-world conditions in which some infants whose deafness is identified at
      screening do not receive a definitive diagnosis of being deaf before 6 months;
      and a portion of deaf and hard-of-hearing infants who 1) have false-negative
      screening test results, 2) are not screened, or 3) fail the hearing screen but
      are not immediately followed up with diagnostic evaluation nonetheless receive a
      diagnosis by 6 months of age. In the absence of newborn hearing screening,
      approximately 30 deaf infants were identified by 6 months of age by passive
      detection alone at a cost of $69 000. The selective screening protocol, when
      compared with no newborn hearing screening, resulted in an additional 36 infants
      whose deafness was diagnosed by 6 months at an additional cost of approximately
      $600 000, yielding an incremental cost-effectiveness of approximately $16 000 per
      additional infant whose deafness was diagnosed by 6 months. Compared with
      selective screening, the UNHS protocol resulted in 33 additional infants whose
      deafness was diagnosed by 6 months of age at an additional cost of approximately
      $1.5 million, yielding an incremental cost-effectiveness of approximately $44 000
      per additional infant whose deafness was diagnosed by 6 months of age. Increasing
      the rate of follow-up to diagnostic evaluation from the base-case estimate of 77%
      to 100% decreased the incremental cost of UNHS to $38 000 per additional infant
      whose deafness was diagnosed by 6 months. Under the base-case assumptions about
      lifetime savings that result from normal language with early intervention, UNHS
      resulted in normal language achievement for more deaf children and was cost
      saving in the long term compared with both selective screening and no screening.
      CONCLUSIONS: The short-term cost-effectiveness of UNHS is comparable to the cost
      per case diagnosed of other newborn screening programs and could be improved by
      increasing the rate of follow-up to diagnostic evaluation after positive
      screening test results. If early identification results in improved language
      abilities, lower educational and vocational costs, and increased lifetime
      productivity, then UNHS has the potential for long-term cost savings compared
      with selective hearing screening and no screening. To understand the actual long
      term economic effects of UNHS, better evidence is needed regarding the impact of
      early intervention on language outcomes and subsequent changes in educational
      costs and lifetime productivity.

PMID- 12415022
TI  - Caller satisfaction with after-hours telephone advice: nurse advice service
      versus on-call pediatricians.
AB  - OBJECTIVE: To compare caller satisfaction with after-hours medical advice
      provided by a for-profit nurse advice service with advice provided by on-call
      pediatricians. METHODS: The study setting was the general pediatrics faculty
      practice of an urban university medical center. Participants were parents or
      guardians of a population of approximately 6000 children calling for after-hours
      medical advice over a 10-month period from January 18 to November 20, 2000. After
      hours medical advice calls were randomized to either a nurse advice service or
      the on-call pediatrician. Caller satisfaction and subsequent health care
      utilization were measured by a telephone survey of callers and review of all
      health care visits within 3 days of the initial telephone advice call. RESULTS:
      Five hundred sixty-six (48%) callers were enrolled in the on-call pediatrician
      group, and 616 (52%) were enrolled in the advice nurse group. Caller satisfaction
      was rated as very good or excellent significantly more often for the on-call
      pediatrician than for the nurse advice service as follows: telephone call overall
      (68.5% vs 55.0%; 95% confidence interval [CI] of difference: 8.0%-19.0%),
      thoroughness and competence of the person they spoke with (74.0% vs 59.1%; 95% CI
      of difference: 9.6%-20.2%), courtesy and friendliness of the person they spoke
      with (77.4% vs 73.9%; 95% CI of difference: -1.4%-8.4%), length of time spent
      waiting (70.8% vs 60.1%; 95% CI of difference: 5.4%-16.2%), time spent talking
      with the on-call pediatrician or advice nurse (68.2% vs 52.4%; 95% CI of
      difference: 10.2%-21.3%), and the medical advice given (68.6% vs 53.9%; 95% CI of
      difference: 9.2%-20.1%). Compliance with the advice given was significantly
      higher for office care in the on-call pediatrician group (51.5% vs 29.6%; 95% CI
      of difference: 8.9%-34.2%). Repeat calls for advice were significantly more
      frequent for the nurse advice service, both within 4 hours (13.0% vs 4.8%; 95% CI
      of difference: 5.0%-11.4%), and within 72 hours (23.4% vs 13.3%; 95% CI of
      difference: 5.8%-14.5%). CONCLUSION: Callers were less satisfied with medical
      advice provided by a nurse advice service compared with the traditional on-call
      pediatrician. The lower satisfaction was associated with somewhat poorer
      compliance with recommended triage dispositions and more frequent repeat calls
      for medical advice.

PMID- 12415023
TI  - Lead and mercury in breast milk.
AB  - OBJECTIVE: Heavy metals are potentially toxic substances, especially for the
      susceptible infant. Exposure to mercury (Hg) and lead (Pb) may result in
      neurotoxic and nephrotoxic impairment and in anemia. Previous data on breast milk
      Pb and Hg contents are sparse or missing for the Austrian population. No
      evaluations of the influence of mothers' lifestyles on Pb and Hg levels in breast
      milk are available. METHODS: Five- to 10-mL individual samples of breast milk
      were provided from healthy mothers in Vienna (urban; n = 59), Linz (industrial; n
      = 47), and Tulln (rural; n = 59). A questionnaire about area of residence,
      maternal nutrition, smoking habits, and dental fillings was filled out by the
      lactating mothers. Milk samples and infant formulas were lyophilized, wet-ashed
      with nitric acid (65%), and analyzed with atomic absorption spectrophotometry.
      Spiked skim milk powder was used as reference material. Statistical analysis
      included the Kruskal-Wallis test and multiple robust regression analysis.
      RESULTS: Breast milk showed low Hg and Pb concentrations (Hg: 1.59 +/- 1.21 1g/l,
      n = 116; Pb: 1.63 +/- 1.66 6g/l, n = 138). Eight percent of the breast milk
      samples marginally exceeded the screening level of 3.5 micro g/L for Hg. Austrian
      Pb values declined strongly during the last 20 years. Bivariate comparison
      revealed that the factors significantly related to metal levels in breast milk
      were area of residence (Hg, Pb), prematurity (Hg), consumption of fish (Pb) and
      cereals (Hg), vitamin supplementation (Hg), and smoking (Pb). The Hg and Pb
      contents of cow milk and infant formulas were far below respective guideline
      values. CONCLUSIONS: Neither Hg nor Pb concentrations exceeded critical levels.
      There are no reports on infants harmed by the intake of milk from unexposed
      mothers. We conclude that even theoretical risks from current Hg or Pb levels for
      the breastfed infant of a healthy mother can be ruled out.

PMID- 12415024
TI  - Cardiorespiratory stability of premature and term infants carried in infant
      slings.
AB  - OBJECTIVE: Parents in industrialized societies make increasing use of infant
      slings to carry their infants. This study was conducted to determine whether
      infants who are carried in slings are at risk of experiencing clinically relevant
      changes in cardiorespiratory measurements. METHODS: In a 3-period crossover
      trial, 24 preterm and 12 term newborns were continually monitored while being
      carried horizontally or vertically in a sling or lying in a pram. Oxygen
      saturation, heart rate, nasal airflow, abdominal breathing, and movements were
      recorded. RESULTS: Infants who were carried in slings were not at risk of
      clinically relevant changes of oxygen saturation or heart rate. The 90%
      confidence interval of oxygen saturation in both infant sling positions remained
      within a +/-2% interval around the average oxygen saturation in the pram.
      However, a significant decrease of oxygen saturation was observed while infants
      were carried in a sling with a mean oxygen saturation of 96.3% (standard
      deviation [SD]: 1.8) in the vertical and 96.1% (SD: 2.0) in the horizontal sling
      position compared with the mean oxygen saturation in the pram (97.1%; SD: 1.5).
      The degree and the incidence of desaturations and bradycardia did not change
      while the infants were carried. Both types of episodes were seen only in preterm
      infants. CONCLUSION: The use of carrying slings is not associated with an
      increased risk of clinically relevant cardiorespiratory changes in term and
      preterm infants.

PMID- 12415025
TI  - Effect of supplemental oxygen on sleep architecture and cardiorespiratory events
      in preterm infants.
AB  - OBJECTIVE: To investigate the effect of low-flow supplemental oxygen (SupOx) on
      sleep architecture and cardiorespiratory events in asymptomatic preterm infants.
      METHODS: An overnight polysomnographic evaluation was conducted prospectively in
      23 premature infants who were born at 30.0 +/- 3.2 (standard deviation) weeks'
      gestational age and studied at 38.1 +/- 4.4 weeks' postconceptional age. Infants
      were free of any adverse events, including cardiorespiratory monitor alarms in
      the nursery for at least 1 week before the study. Infants received room air (RA)
      or SupOx via nasal cannula at 0.25 L/min. RESULTS: Quiet sleep density was
      increased during SupOx (33.3 +/- 10.8% vs 26.6 +/- 10.0% total sleep time [TST]
      in RA), and a reciprocal decrease in active sleep density was observed (61.5 +/-
      11.1% vs 68.4 +/- 9.9% TST in RA). No differences in sleep efficiency emerged
      (69.7 +/- 10.6% SupOx vs 69.7 +/- 8.8% RA). SupOx elicited significant decreases
      in apnea index (3.8 +/- 2.4 events/h vs 11.1 +/- 6.4 events/h in RA) and in the
      percentage of time spent in periodic breathing (1.8 +/- 2.9% vs 6.7 +/- 8.9% in
      RA). In addition, SupOx decreased the frequency of bradycardic events (0.3 +/-
      0.8 events vs 2.5 +/- 0.03 events in RA) and improved overall oxygen saturation
      (98.7 +/- 1.1% vs 96.4 +/- 2.2%). No changes in alveolar ventilation, as derived
      from end-tidal CO2 measurements, was detected (38.6 +/- 5.8 mm Hg in SupOx vs
      38.4 +/- 5.4 mm Hg in RA). CONCLUSIONS: Asymptomatic preterm infants exhibit
      frequent and potentially clinically adverse cardiorespiratory events when
      assessed in the sleep laboratory. Administration of SupOx to these infants is
      associated with an increase in the overall duration and percentage TST spent in
      quiet sleep with reciprocal changes in active sleep. In addition, improvement in
      respiratory stability is observed with the use of low-flow SupOx, as evidenced by
      a decrease in apnea, periodic breathing, and bradycardia, without adverse effects
      on alveolar ventilation.

PMID- 12415026
TI  - Short-term growth hormone treatment in girls with Turner syndrome decreases fat
      mass and insulin sensitivity: a randomized, double-blind, placebo-controlled,
      crossover study.
AB  - BACKGROUND: Most girls with Turner syndrome (TS) receive growth hormone (GH)
      treatment during childhood and adolescence, but controlled data on the effects on
      body composition and glucose metabolism are lacking. OBJECTIVE: To study the
      effects of GH treatment on insulin sensitivity, glucose metabolism, bone
      turnover, and body composition. METHODS: A randomized, placebo-controlled,
      crossover study was conducted with girls with TS. All girls with TS were treated
      with GH 0.1 IU/kg/d subcutaneously at bedtime or with placebo for 2 months and
      studied at the end of each period. Control subjects were studied once without
      treatment. Twelve girls with TS, aged 9.5 to 14.8 years (median: 12.9 years) and
      16 age-matched control subjects (10.3-16.0 years; median: 12.1 years) were
      studied. Twenty-four-hour sampling of blood was performed; GH, insulin-like
      growth factor I (IGF-I), IGF binding proteins (IGFBPs), insulin, glucose, and
      lipolytic and gluconeogenic precursors were assayed, followed by an oral glucose
      tolerance test. Body composition was evaluated by dual-energy x-ray
      absorptiometry scanning and body mass index (BMI). Fasting bone markers were
      measured. RESULTS: Height was reduced in TS as compared with control subjects. In
      the placebo situation, 24-hour integrated GH as well as IGF-I was significantly
      reduced in girls with TS compared with control subjects. Controlling for
      differences in lean body mass (LBM; or fat mass [FM]) and sexual development did
      not explain the difference in 24-hour integrated GH. Differences in sexual
      development, BMI, FM, insulin sensitivity, and IGFBP-3 could explain the
      difference in IGF-I between TS and control subjects. Carbohydrate metabolism in
      TS was comparable with control subjects. GH treatment induced insulin resistance,
      with increments in fasting glucose and insulin, as well as 24-hour insulin.
      Circulating levels of lipid and gluconeogenic substrates were comparable in TS
      and control subjects and unchanged in response to treatment. Bone markers
      increased in response to GH. Total FM was increased in girls with TS, accounted
      for by an increased FM in the arms and trunk, whereas LBM was decreased.
      Especially LBM in the legs was decreased. Overall, bone mineral content was
      diminished. Treatment with GH reduced FM in TS, especially in the arms and legs,
      and likewise increased total LBM, primarily in the trunk. CONCLUSION: This study
      documented evidence of impaired GH secretion and action, disproportionate body
      composition, but a normal carbohydrate metabolism in girls with TS. Short-term GH
      administration was associated with favorable changes in body composition but also
      with relative impairment of glucose tolerance and insulin sensitivity. We
      recommend that glucose metabolism be monitored carefully during long-term GH
      treatment in these patients.

PMID- 12415027
TI  - Secondary sexual characteristics in children with cerebral palsy and moderate to
      severe motor impairment: a cross-sectional survey.
AB  - OBJECTIVES: To compare the development of secondary sexual characteristics in
      children with cerebral palsy (CP) of moderate to severe motor impairment to
      children in the general population and to relate their sexual maturation to a
      measure of their body fat. METHODS: A multicenter, cross-sectional survey of 207
      children who were 3 to 18 years of age and had CP of moderate to severe motor
      impairment (Gross Motor Functional Classification System [GMFCS] levels 3, 4, and
      5) was conducted at 6 geographic sites; attempts were made to identify all
      eligible children through multiple methods and enroll them in the study. Trained
      research assistants performed anthropometric measurements, including subscapular
      skinfold thickness, determined GMFCS level, and assessed sexual maturation by
      Tanner stage. Secondary sexual characteristics were compared with the general
      population of children using cross-sectional surveys of the American Academy of
      Pediatrics Pediatric Research in Office Settings network and of the National
      Center for Health Statistics National Health and Nutrition Examination Survey
      (NHANES) III. Girls were classified as having begun puberty when they were at
      Tanner stage 2 or greater for pubic hair and breast development and to have
      completed puberty when they were at Tanner stage 4 or greater for pubic hair and
      breast development. Boys were classified as having begun puberty when they were
      at Tanner stage 2 or greater for pubic hair and genital development and to have
      completed puberty when they were at Tanner stage 4 or greater for pubic hair and
      genital development. RESULTS: The mean age (standard deviation) of subjects was
      9.6 (4.6) years. Of the 207 subjects, 71% were white, 21% were black, and 8% were
      of other races; 59% were boys, and 41% were girls. Girls with CP (n = 84) entered
      puberty earlier than did boys with CP (n = 123). In contrast, girls with CP
      tended to complete puberty later than did boys with CP. Black boys and girls with
      CP (n = 43) entered puberty earlier than did white boys and girls with CP (n =
      147). No difference between races was found in completion of puberty. Only for
      white children with CP were there a sufficient number of subjects for comparisons
      of sexual maturation to race-matched children in the general population, using
      data from the American Academy of Pediatrics Pediatric Research in Office
      Settings network and the NHANES III study. White girls with CP initiated pubic
      hair development (Tanner stage 2 or greater) earlier than in the general
      population, but the age of onset of breast development was similar to the general
      population, although the age distribution was different. A greater proportion of
      white girls with CP had early onset of breast development (Tanner stage 2 or
      greater), and a greater proportion had delayed onset of breast development than
      in the general population. White girls with CP completed breast development later
      than in the general population but not pubic hair development. For white boys
      ages 8 to 18 years with CP (n = 75), pubic hair and genital development both
      began earlier than in the general population, but genital development was
      completed later. The estimated median age of menarche for white girls with CP was
      14.0 years, which was 1.3 years later (95% confidence interval: 0.7-2.3) than for
      the general population (estimated median age: 12.8 years; NHANES III).
      Relationships between sexual maturation and nutritional state, as assessed by
      subscapular skinfold thickness z score, were determined separately in white boys
      and in white girls with CP, between the ages of 8 and 18 years. For white girls
      with CP, more advanced sexual maturation was associated with more body fat,
      adjusting for age and GMFCS level (Spearman partial correlation: 0.41). In
      contrast, for white boys with CP, the opposite relationship pertained: more
      advanced sexual maturation was associated with less body fat (-0.29).
      CONCLUSIONS: The pattern of sexual maturation in children with CP of moderate to
      severe motor impairment differs from that of children in the general population.
      Puberty begins earlier but ends later in white children with CP, compared with
      white children in the general population. In addition, menarche occurs later in
      white girls with CP. More advanced sexual maturation was associated with more
      body fat in girls but less body fat in boys.

PMID- 12415028
TI  - Is obesity associated with early sexual maturation? A comparison of the
      association in American boys versus girls.
AB  - BACKGROUND: Increasing evidence suggests a close association between early sexual
      maturation (SM) and obesity in girls and female adults. Earlier maturing girls
      are more likely to be obese than nonearly maturers. However, limited research has
      been conducted in boys. OBJECTIVE: To examine the influence of early SM on
      fatness in boys and compare it with girls, and to test the hypothesis that the
      associations differ by gender because of the differences in growth and SM
      patterns in boys and girls. STUDY DESIGN: Cross-sectional study. SUBJECTS: One
      thousand five hundred one girls and 1520 boys (aged 8-14 years) who participated
      in the Third National Health and Nutrition Examination Survey survey (1988-1994)
      and had complete anthropometry (weight, height, skinfold thickness) and SM data.
      METHODS: Based on each individual's age and SM status (Tanner stages: genitalia
      stages for boys and breast stages for girls), the subjects were classified as: 1)
      early maturers (those who reached a certain Tanner stage earlier than the median
      age for that stage), and 2) the others (average and later maturers). Overweight
      was defined as a body mass index (BMI) > or =85th percentile, and obesity > or
      =95th percentile. Logistic regression analysis was to test how early maturation
      affected the risks for overweight and obese. Using multiple linear regression
      models, the associations between fatness (BMI and skinfold thickness) and SM were
      systematically examined. Covariates including age, ethnicity, residence, family
      income, energy intake, and physical activity were adjusted. RESULTS: Early SM was
      positively associated with overweight and obesity in girls, but the associations
      were reverse for boys. The prevalence of overweight in early maturers versus the
      others was 22.6% versus 31.6% in boys and 34.4% versus 23.2% in girls; the
      figures for obesity were 6.7% versus 14.8% and 15.6% versus 8.1%, respectively.
      Odd ratios and 95% confidence intervals for obesity were 0.4 (0.2, 0.8) for boys
      and 2.0 (1.1, 3.5) for girls, and covariates were adjusted. Most significant
      differences in overweight and obesity among ethnic groups disappeared after
      controlling for SM. Fatness (BMI and skinfold thickness) was associated with SM
      stages and with early maturation in boys and girls, but the associations were in
      opposite directions. Compared with their counterparts, early maturing boys were
      thinner, whereas early maturing girls were fatter. CONCLUSIONS: Obesity is
      associated with sexual maturation in both boys and girls, but the association
      differs. There is positive association in girls, but a negative one in boys.
      Maturation status should be taken into consideration when assessing child and
      adolescent obesity.

PMID- 12415030
TI  - Discrepancies between direct and indirect blood pressure measurements using
      various recommendations for arm cuff selection.
AB  - OBJECTIVE: The current recommendation for choosing an appropriate size cuff for
      measuring blood pressure (BP) is a bladder width to equal 40% of the upper arm
      circumference (UAC). However, most physicians use the older two-thirds or three
      fourths upper arm length (UAL) recommendations to choose a cuff. The aim of this
      study was to verify the disparity in cuff size by using two-thirds UAL, three
      fourths UAL, and 40% UAC criteria for cuff selection and to compare the
      indirectly measured BP by these criteria with directly measured radial intra
      arterial BP. METHODS: A prospective, cross-sectional, observational study was
      conducted in 65 hemodynamically stable patients, aged 5 days to 22 years. Direct
      BP measurements were obtained from a radial intra-arterial catheter. Indirect BP
      measurements were taken from the same arm as the arterial catheter with a mercury
      sphygmomanometer and standard-size arm cuffs. UAL and UAC of each patient were
      measured, and the 3 cuffs closest to two-thirds and three-fourths UAL and 40% UAC
      were used. For each cuff, 3 direct and 3 indirect BP measurements were taken.
      Student t test was used to compare mean systolic and diastolic BP for direct and
      indirect measurements. RESULTS: A total of 172 observations were recorded,
      including 56 by two-thirds UAL, 55 by three-fourths UAL, and 61 by 40% UAC
      criteria. There was no significant difference between the means of the ideal cuff
      size by 40% UAC criterion and the actual cuffs used from the available standard
      cuffs. However, because of an unavailability of the larger cuffs for UAL
      criteria, the actual cuffs used were significantly smaller than ideal. Comparison
      of direct and indirect BP measurements revealed no significant difference in
      systolic BP when the latter was obtained by 40% UAC criterion. However, the
      difference in diastolic BP was significant. With available cuffs, a significant
      difference in systolic as well as diastolic BP was seen with both UAL criteria.
      CONCLUSIONS: Practitioners are likely to use significantly larger arm cuffs when
      following the two-thirds and three-fourths UAL criteria than when following the
      40% UAC criterion. Of the 3 criteria for cuff selection, systolic BP by 40% UAC
      criterion most accurately reflects directly measured radial arterial pressure.
      However, the 40% UAC cuff significantly overestimates the diastolic pressure.
      Using available cuffs for indirect measurements by two-thirds and three-quarters
      UAL criteria significantly underestimates systolic as well as diastolic BP when
      compared with radial intra-arterial BP.

PMID- 12415029
TI  - National estimates of the timing of sexual maturation and racial differences
      among US children.
AB  - OBJECTIVE: To provide clinically meaningful, normative reference data that
      describe the timing of sexual maturity indicators among a national sample of US
      children and to determine the degree of racial/ethnic differences in these
      estimates for each maturity indicator. METHODS: Tanner staging assessment of
      sexual maturity indicators was recorded from 4263 non-Hispanic white, black, and
      Mexican American girls and boys aged 8.00 to 19.00 years as part of the Third
      National Health and Nutrition Examination Survey (NHANES III) conducted between
      1988 and 1994. NHANES III followed a complex, stratified, multistage probability
      cluster design. SUDAAN was used to calculate the mean age and standard error for
      each maturity stage and the proportion of entry into a maturity stage and to
      incorporate the sampling weight and design effects of the NHANES III complex
      sampling design. Probit analysis and median age at entry into a maturity stage
      and its fiducial limits were calculated using SAS 8.2. RESULTS: Reference data
      for age at entry for maturity stages are presented in tabular and graphical
      format. Non-Hispanic black girls had an earlier sexual development for pubic hair
      and breast development either by median age at entry for a stage or for the mean
      age for a stage than Mexican American or non-Hispanic white girls. There were few
      to no significant differences between the Mexican American and non-Hispanic white
      girls. Non-Hispanic black boys also had earlier median and mean ages for sexual
      maturity stages than the non-Hispanic white and Mexican American boys.
      CONCLUSION: Non-Hispanic black girls and boys mature early, but US children
      completed their sexual development at approximately the same ages. The present
      reference data for the timing of sexual maturation are recommended for the
      interpretation of assessments of sexual maturity in US children.

PMID- 12415031
TI  - Time lag to diagnosis of stroke in children.
AB  - OBJECTIVE: Strokes occur rarely in children, and the causes are different from
      those in adults. Frequently, more than 1 cause is found. The consequences are
      lifelong significant disability in a majority of cases. Children who are younger
      than 18 years have not been included in therapeutic trials of thrombolytic or
      neuroprotective agents. We evaluated whether children who receive a diagnosis of
      stroke meet a major inclusion criterion for such trials, namely time to diagnosis
      of <3 to 6 hours. METHODS: Prospective documentation and retrospective chart
      review was conducted of children who were 0 to 18 years and carried a diagnosis
      of stroke during the last 2 years in the hospital database, including children
      who presented with either ischemic or hemorrhagic strokes. RESULTS: Forty-seven
      events were encountered in 41 children. Twelve neonates with stroke, diagnosed in
      the neonatal period, were excluded from the subsequent analysis. In the remaining
      29 children, the mean age at presentation was 8.67 years. Accurate time records
      were available in 24 children. In this group, 28 events were recorded. Time from
      clinical onset to first medical contact averaged 28.5 hours, and the time to
      diagnosis of stroke averaged 35.7 hours. We subsequently separated between
      children with ischemic (21 documented events) and hemorrhagic strokes (7
      documented events), because the presentation and the intervention options are
      different. CONCLUSIONS: Stroke in children is rarely diagnosed in the time frame
      of 3 to 6 hours. Given the causes and outcome of stroke in children, this age
      group might benefit from thrombolysis and from neuroprotective therapy, yet the
      long delay in diagnosis in this age group excludes most cases from being
      considered for such treatments. This situation should encourage attempts to
      increase public and professional awareness of stroke in children and of the
      potential value of early diagnosis and treatment, preferably by broadening
      current educational efforts to all age groups.

PMID- 12415032
TI  - Hepatitis B vaccination among adolescents in 3 large health maintenance
      organizations.
AB  - OBJECTIVE: In 1995, the Advisory Committee on Immunization Practices (ACIP)
      recommended routine hepatitis B (HB) vaccination of all unvaccinated 11- to 12
      year-old adolescents. Little is known about the implementation of these
      recommendations in a managed care setting. The objective of this study was to
      determine the impact of ACIP recommendations on HB vaccination among adolescents
      in 3 managed care settings. METHODS: We assessed HB vaccination coverage among
      adolescents who were enrolled in 3 large health maintenance organizations (HMOs)
      and who turned 13 years old after the 1995 ACIP recommendations. Children who
      were 8 to 10 years of age during May 1993 and were continuously enrolled through
      December 1998 were eligible. We used the HMOs' computerized immunization tracking
      system to collect HB vaccination dates. The percentage of adolescents who
      received 3 doses of HB vaccine was determined. RESULTS: In HMOs A, B, and C,
      coverage levels for 3 doses of HB vaccine were 43.4%, 65.5%, and 25.7%,
      respectively, among 13-year-olds in 1998 compared with 26.1%, 50.4%, and 5.5%
      among 13-year-olds in 1996. Between the ages of 11 and 13 years, coverage rates
      among adolescents aged 13 in 1998 rose more than the coverage among adolescents
      aged 13 in 1996. The proportion of 13-year-olds in 1998 who received the first
      dose of HB vaccine by December 1998 was much higher at 89.6%, 65.2%, and 56.6% in
      HMOs A, B, and C, respectively, compared with the proportion who completed the 3
      dose series (43.4%, 65.5%, and 25.7%, respectively). CONCLUSIONS: After the 1995
      ACIP recommendations, HB vaccination coverage levels among 13-year-olds increased
      in each of the HMOs, suggesting adherence with national recommendations.
      Differences among the 3 HMOs may reflect differences in internal policies. More
      effective strategies may be needed to achieve the Healthy People 2010 goal of 90%
      vaccination coverage rates among adolescents.

PMID- 12415033
TI  - Timeliness of childhood immunizations.
AB  - OBJECTIVE: To examine the timeliness of vaccine administration among infants and
      young children in the United States. METHODS: We analyzed age at receipt of
      vaccines among 16 211 children aged 24 to 35 months in the 2000 National
      Immunization Survey and examined receipt at the recommended time of each dose and
      selected vaccination series, as well as receipt at 4 additional time frames:
      acceptably early, late, never by 24 months, and too early to be considered valid.
      We also examined the relationship between timeliness of vaccinations and
      characteristics of the child, mother, and immunization provider, using
      multivariate logistic regression. RESULTS: Only 9% of children received all
      recommended vaccines at the recommended ages. The rates varied significantly by
      antigen, ranging from 24% for all Haemophilus influenzae type b doses to 75% for
      all hepatitis B doses as recommended. Overall, 55% of children did not receive
      all recommended doses by 24 months of age, and 8% of children received at least 1
      vaccination dose too early to be considered valid. Factors associated with not
      receiving all vaccines as recommended were having more children in the household,
      mothers younger than 30 years, use of public providers, and multiple vaccination
      providers. CONCLUSIONS: By 24 months of age, 9 of 10 children received at least 1
      vaccine outside the recommended age ranges. High vaccination status of children
      at 24 months of age does not reflect the reality that many vaccinations are not
      given at the appropriate ages. Timeliness of vaccination is critical to prevent
      disease outbreaks, protect children through their first 2 years of life, and
      minimize the need to repeat doses.

PMID- 12415034
TI  - Effect of Child Health Insurance Plan enrollment on the utilization of health
      care services by children using a public safety net system.
AB  - OBJECTIVE: To examine differences in health care services utilization between
      children who are enrolled in the Child Health Insurance Plan (CHIP) and uninsured
      children and between children before and during their enrollment period in CHIP.
      METHODS: Denver County CHIP enrollment data from 1998 through 2000 were merged
      with Denver Health utilization data from 1998 through 2000 to determine
      utilization rates for CHIP-enrolled children at Denver Health (n = 2005). The
      first method compared the rates of CHIP-enrolled children with those of uninsured
      children (n = 20 374) during the same time period. The second method compared the
      utilization of services for children enrolled in CHIP during 1999 before CHIP
      enrollment (n = 748) and during CHIP enrollment (n = 757). The outcomes measured
      include emergency, urgent care, specialty care, well-child care, dental visits,
      and immunizations. RESULTS: For the first method, CHIP children were more likely
      to have well-child care, dental, and specialty visits and the recommended
      immunizations than uninsured children. They were less likely to have an emergency
      care visit than uninsured children. For the second method, before enrolling in
      CHIP, children had fewer outpatient visits and were less likely to have a well
      child care visit than during their enrollment span in CHIP. There was not a
      significant difference before and during enrollment for the other outcome
      measures for these children. CONCLUSIONS: These results indicate that children
      who are enrolled in CHIP are more likely to receive preventive care services and
      less likely to use emergency care than uninsured children, even within a safety
      net institution, emphasizing the benefits of public insurance programs for
      children.

PMID- 12415035
TI  - Asthma management and environmental tobacco smoke exposure reduction in Latino
      children: a controlled trial.
AB  - OBJECTIVES: This study tested the efficacy of coaching to reduce environmental
      tobacco smoke (ETS) exposure among asthmatic Latino children. DESIGN: After
      asthma management education, families were randomly assigned to no additional
      service (control condition) or to coaching for ETS exposure reduction
      (experimental condition). SETTING: The study was conducted in San Diego,
      California. PARTICIPANTS: Two hundred four Latino children (ages 3-17 years) with
      asthma participated. INTERVENTION: Approximately 1.5 hours of asthma management
      education was provided; experimental families also obtained 7 coaching sessions (
      approximately 45 minutes each) to reduce ETS exposure. OUTCOME MEASURES: Reported
      ETS exposure and children's urine cotinine were measured. RESULTS: Parents in the
      coached condition reported their children exposed to significantly fewer
      cigarettes than parents of control children by 4 months (postcoaching). Reported
      prevalence of exposed children decreased to 52% for the coached families, but
      only to 69% for controls. By month 4, mean cotinine levels decreased among
      coached and increased among control children. Cotinine prevalence decreased from
      54% to 40% among coached families, while it increased from 43% to 49% among
      controls. However, cotinine levels decreased among controls to the same level
      achieved by coached families by the 13-month follow-up. CONCLUSIONS: Asthma
      management education plus coaching can reduce ETS exposure more than expected
      from education alone, and decreases in the coached condition may be sustained for
      about a year. The delayed decrease in cotinine among controls is discussed.

PMID- 12415036
TI  - Neurologic disorders after measles-mumps-rubella vaccination.
AB  - OBJECTIVE: The possibility of adverse neurologic events has fueled much concern
      about the safety of measles-mumps-rubella (MMR) vaccinations. The available
      evidence concerning several of the postulated complications is controversial. The
      aim of this study was to assess whether an association prevails between MMR
      vaccination and encephalitis, aseptic meningitis, and autism. METHODS: A
      retrospective study based on linkage of individual MMR vaccination data with a
      hospital discharge register was conducted among 535 544 1- to 7-year-old children
      who were vaccinated between November 1982 and June 1986 in Finland. For
      encephalitis and aseptic meningitis, the numbers of events observed within a 3
      month risk interval after vaccination were compared with the expected numbers
      estimated on the basis of occurrence of encephalitis and aseptic meningitis
      during the subsequent 3-month intervals. Changes in the overall number of
      hospitalizations for autism after vaccination throughout the study period were
      searched for. In addition, hospitalizations because of inflammatory bowel
      diseases were checked for the children with autism. RESULTS: Of the 535 544
      children who were vaccinated, 199 were hospitalized for encephalitis, 161 for
      aseptic meningitis, and 352 for autistic disorders. In 9 children with
      encephalitis and 10 with meningitis, the disease developed within 3 months of
      vaccination, revealing no increased occurrence within this designated risk
      period. We detected no clustering of hospitalizations for autism after
      vaccination. None of the autistic children made hospital visits for inflammatory
      bowel diseases. CONCLUSIONS: We did not identify any association between MMR
      vaccination and encephalitis, aseptic meningitis, or autism.

PMID- 12415037
TI  - The efficacy of noncontact oxygen delivery methods.
AB  - OBJECTIVES: "Wafting" oxygen is a possible strategy to deliver oxygen to a
      patient who may not tolerate delivery systems that involve contact on the face.
      We wished to assess the concentration of oxygen delivered to the patient with
      various methods of "wafting" oxygen. DESIGN: Three methods of wafting oxygen were
      examined: an infant resuscitator bag, a standard pediatric Hudson RCI face mask,
      and a piece of standard green oxygen tubing. Contour lines for oxygen
      concentrations of 30% to 70% in 10% intervals were found with a Teledyne oxygen
      meter, at an oxygen flow rate of 5 L/min and 10 L/min. Experimental conditions
      simulated an infant in a cot in a pediatric ward. RESULTS: The resuscitator bag
      can not be recommended for wafting oxygen delivery, as the flow-back valve may
      close and result in insignificant levels of oxygen delivery. Oxygen tubing gave a
      useable area too narrow for use with an active patient, with 30% oxygen
      concentration being available in an area with width of only 18 cm. This is,
      however, a suitable method in short-term attended administration, either during
      feeding, or in the situation of a neonatal resuscitation. The standard pediatric
      Hudson RCI face mask, at a flow rate of 10 L/min, delivers 30% oxygen to an area
      35 cm wide and 32 cm from the top of the mask. At 10 L/min, 40% oxygen is
      delivered to an area 16 cm wide and 14 cm from the top of the mask. This is an
      area large enough to be usable in the infant who will not tolerate other methods
      of oxygen delivery. The contour lines are presented graphically. CONCLUSIONS:
      Although wafting can never replace conventional methods of oxygen delivery to
      children, if these have failed, a standard pediatric oxygen mask can give
      significant oxygen therapy without irritating the patient. Care should be taken
      to place the mask in the area described (ie, opposite the chest) to give the
      maximum benefit. Short-term administration can be appropriate with standard
      oxygen tubing aimed at the airway.

PMID- 12415038
TI  - Crotaline Fab antivenom for the treatment of children with rattlesnake
      envenomation.
AB  - OBJECTIVE: There is little data regarding safety or efficacy of Crotalinae
      polyvalent immune Fab (ovine) antivenom (crotaline Fab) in pediatric patients.
      Our objective was to provide the first information regarding safety and
      effectiveness of this new drug in children. METHODS: Data were collected
      prospectively and retrospectively for all consecutive pediatric patients bitten
      by rattlesnakes and treated at 2 urban hospitals during 2001. Cases were included
      if there were signs of envenomation at presentation, patient age was 13 years or
      less, and there was administration of crotaline Fab. Cases were excluded if
      antivenin (Crotalidae) polyvalent (equine origin, the conventional antivenom) was
      given. Primary outcome variables were snakebite severity scores throughout the
      course of therapy, number of vials of crotaline Fab administered, occurrence of
      allergic reactions, adjunct surgical therapy, and the presence of permanent
      sequelae or serum sickness identified at follow-up. RESULTS: In the 12 cases
      studied, ages ranged from 14 months to 13 years (mean: 6.9; standard deviation:
      4.2). Presentation snakebite severity scores ranged from 2 to 9 (mean: 5.3;
      standard deviation: 2.3). Total crotaline Fab doses ranged from 4 to 22 vials
      (mean: 12.7; standard deviation: 5.4). Initial control of symptoms was achieved
      with 4 to 16 vials (mean: 7.7; standard deviation: 3.7), and severity scores
      stabilized or improved within 24 hours in all patients. Recurrence of local
      swelling occurred in 1 case despite scheduled repeat doses of antivenom. No cases
      required surgical intervention, and no permanent sequelae were identified. No
      immediate or delayed hypersensitivity reactions occurred. CONCLUSION: In this
      group of pediatric patients treated for rattlesnake envenomation, crotaline Fab
      antivenom was safe and seemed to be effective.

PMID- 12415039
TI  - Gastroesophageal reflux and cow milk allergy: is there a link?
AB  - Gastroesophageal reflux (GER) and cow milk allergy (CMA) occur frequently in
      infants younger than 1 year. In recent years, the relation between these 2
      entities has been investigated and some important conclusions have been reached:
      in up to half of the cases of GER in infants younger than 1 year, there may be an
      association with CMA. In a high proportion of cases, GER is not only CMA
      associated but also CMA induced. The frequency of this association should induce
      pediatricians to screen for possible concomitant CMA in all infants who have GER
      and are younger than 1 year. With the exception of some patients with mild
      typical CMA manifestations (diarrhea, dermatitis, or rhinitis), the symptoms of
      GER associated with CMA are the same as those observed in primary GER.
      Immunologic tests and esophageal pH monitoring (with a typical pH pattern
      characterized by a progressive, slow decrease in esophageal pH between feedings)
      may be helpful if an association between GER and CMA is suspected, although the
      clinical response to an elimination diet and challenge is the only clue to the
      diagnosis. This article reviews the main features of GER and CMA, focusing on the
      aspects in common and the discrepancies between both conditions.

PMID- 12415040
TI  - Munchausen by proxy defined.

PMID- 12415041
TI  - Pediatrics by the book: pediatricians and literacy promotion.

PMID- 12415042
TI  - Childhood obesity: a new pandemic of the new millennium.

PMID- 12415043
TI  - Parental separation and divorce: can we provide an ounce of prevention?

PMID- 12415044
TI  - The 2002 Hospital Infection Control Practices Advisory Committee Centers for
      Disease Control and Prevention guideline for prevention of intravascular device
      related infection.

PMID- 12415045
TI  - Loffler's endocarditis presenting in 2 children as fever with eosinophilia.
AB  - Hypereosinophilic syndromes are defined by the presence of peripheral and bone
      marrow eosinophilia and by the infiltration of multiple organs by mature
      eosinophilic cells. Loffler's endocarditis is a condition in which mature
      eosinophils infiltrate and damage the endocardium and myocardium. Male adults who
      live in the tropics are the population predominantly affected by this condition.
      Typical clinical features include weight loss, fever, cough, rash, and congestive
      heart failure. In this article, we report the typical presentation of an unusual
      illness that occurred in 2 pediatric patients in different geographic locations.
      In addition, we believe that these are the youngest patients with Loffler's
      endocarditis reported.

PMID- 12415046
TI  - Helping children and families deal with divorce and separation.
AB  - More than 1 million children each year experience their parents' divorce. For
      these children and their parents, this process can be emotionally traumatic from
      the beginning of parental disagreement and rancor, through the divorce, and often
      for many years thereafter. Pediatricians are encouraged to be aware of behavioral
      changes in their patients that might be signals of family dysfunction so they can
      help parents and children understand and deal more positively with the issue. Age
      appropriate explanation and counseling is important so children realize that they
      are not the cause of, and cannot be the cure for, the divorce. Pediatricians can
      offer families guidance in dealing with their children through the troubled time
      as well as appropriate lists of reading material and, if indicated, can refer
      them to professionals with expertise in the emotional, social, and legal aspects
      of divorce and its aftermath.

PMID- 12415047
TI  - Perinatal care at the threshold of viability.
AB  - In the United States, an increase in the number of births of extremely preterm
      infants and in their survival potential has occurred over the last decade.
      Determining the survival prognosis for the infant of a pregnancy with threatened
      preterm delivery between 22 and 25 completed weeks of gestation remains
      problematic. Many physicians and families encounter the difficulty of making
      decisions regarding the institution and continuation of life support for an
      infant born within this threshold period. This report addresses the process of
      counseling, assisting, and supporting families faced with the dilemma of an
      extremely preterm delivery.

PMID- 12415048
TI  - Lumbar punctures and meningitis.

PMID- 12415049
TI  - Lumbar punctures and meningitis.

PMID- 12415050
TI  - Inhaled steroids and asthma.

PMID- 12415051
TI  - Silicon, silicone, and breast implants.

PMID- 12415052
TI  - Residency education, billing practices, and compliance issues.

PMID- 12415053
TI  - Effect of AAP statement regarding postnatal corticosteroids on ongoing and future
      randomized, controlled trials.

PMID- 12415054
TI  - 33 272 infants, 7-year follow-up: total serum bilirubin, transfusions reexamined.

PMID- 12415055
TI  - Breastfeeding decisions.

PMID- 12415056
TI  - Concern about Fetus and Newborn Committee statement on corticosteroid use.

PMID- 12415057
TI  - Guidelines for the prevention of intravascular catheter-related infections. The
      Hospital Infection Control Practices Advisory Committee, Center for Disease
      Control and Prevention, U.S.
AB  - These guidelines have been developed for practitioners who insert catheters and
      for persons responsible for surveillance and control of infections in hospital,
      outpatient, and home health-care settings. This report was prepared by a working
      group comprising members from professional organizations representing the
      disciplines of critical care medicine, infectious diseases, health-care infection
      control, surgery, anesthesiology, interventional radiology, pulmonary medicine,
      pediatric medicine, and nursing. The working group was led by the Society of
      Critical Care Medicine (SCCM), in collaboration with the Infectious Disease
      Society of America (IDSA), Society for Healthcare Epidemiology of America (SHEA),
      Surgical Infection Society (SIS), American College of Chest Physicians (ACCP),
      American Thoracic Society (ATS), American Society of Critical Care
      Anesthesiologists (ASCCA), Association for Professionals in Infection Control and
      Epidemiology (APIC), Infusion Nurses Society (INS), Oncology Nursing Society
      (ONS), Society of Cardiovascular and Interventional Radiology (SCVIR), American
      Academy of Pediatrics (AAP), and the Healthcare Infection Control Practices
      Advisory Committee (HICPAC) of the Centers for Disease Control and Prevention
      (CDC) and is intended to replace the Guideline for Prevention of Intravascular
      Device-Related Infections published in 1996. These guidelines are intended to
      provide evidence-based recommendations for preventing catheter-related
      infections. Major areas of emphasis include 1) educating and training health-care
      providers who insert and maintain catheters; 2) using maximal sterile barrier
      precautions during central venous catheter insertion; 3) using a 2% chlorhexidine
      preparation for skin antisepsis; 4) avoiding routine replacement of central
      venous catheters as a strategy to prevent infection; and 5) using
      antiseptic/antibiotic impregnated short-term central venous catheters if the rate
      of infection is high despite adherence to other strategies (ie, education and
      training, maximal sterile barrier precautions, and 2% chlorhexidine for skin
      antisepsis). These guidelines also identify performance indicators that can be
      used locally by health-care institutions or organizations to monitor their
      success in implementing these evidence-based recommendations.

PMID- 12415058
TI  - Unlicensed and off-label drug use in an Australian neonatal intensive care unit.
AB  - OBJECTIVES: To determine the extent of unlicensed and off-label drugs prescribed
      in the level 3 neonatal intensive care unit (NICU) at the Royal Women's Hospital,
      Melbourne, Australia. METHODS: A prospective cohort study was conducted of all
      infants who were admitted to the NICU during a 10-week period. Each drug
      prescribed was evaluated in relation to the licensed approved uses to determine
      whether the drug was administered in a licensed manner or was unlicensed or used
      in an off-label manner. RESULTS: There were a total of 101 admissions involving
      97 infants. A total of 1442 prescriptions were administered; 42% were licensed,
      11% were unlicensed, and 47% were off-label. Twenty-one percent were off-label
      for 2 or more reasons. Eighty percent of infants received either an unlicensed or
      an off-label prescription or both; this proportion rose to 93% of extremely low
      birth weight infants. CONCLUSIONS: This is the largest study performed of
      unlicensed and off-label drug use in the NICU. This practice remains widespread
      despite clear recommendations to improve this undesirable situation. The
      attendant risks to infants and prescribers remain. It is time for legislation to
      be introduced to govern this area.

PMID- 12415059
TI  - Reported adverse drug events in infants and children under 2 years of age.
AB  - OBJECTIVE: To characterize risks to infants and young children from drugs and
      biological products that were identified in spontaneous adverse event reports
      submitted to the US Food and Drug Administration. METHODS: Of >500 000 MedWatch
      adverse event reports received by the Food and Drug Administration from November
      1997 through December 2000, we identified 7111 reports about infants and children
      younger than age 2. The reports were analyzed for health outcome (eg, death,
      hospitalization, congenital anomaly), principal suspect drug, and whether the
      route of drug exposure was direct administration or through the mother in the
      perinatal period. RESULTS: Drug therapy was associated with an average of 243
      reported deaths annually over the 38-month study period, with 100 (41%) occurring
      during the first month of life and 204 (84%) during the first year. In 1432 (24%)
      reported adverse event cases of all levels of severity, exposure to the drug was
      from the mother during pregnancy, delivery, or lactation. Although 1902 different
      drugs, biological products, and other chemicals were identified in the reports,
      only 17 drugs or biological products were a suspect in 54% of all serious and
      fatal adverse events in drugs administered directly. CONCLUSION: Adverse
      reactions to drug therapy are a significant cause of death and injury in infants
      and children under 2 years of age. Drugs administered to the mother in the
      perinatal period constituted a major route of exposure to adverse drug advents.
      These results underscore the need for additional drug testing in the youngest
      pediatric patients and for carefully weighing the risks versus benefits of
      medication.

PMID- 12415060
TI  - Obesity development during adolescence in a biracial cohort: the NHLBI Growth and
      Health Study.
AB  - OBJECTIVE: The National Heart, Lung, and Blood Institute Growth and Health Study
      (NGHS) is a 10-year study to investigate the development of obesity in black and
      white girls during adolescence and its environmental and psychosocial correlates.
      The purpose of this report was to examine changes in the annual prevalence rates
      of overweight and obesity in the NGHS cohort from ages 9 to 19 years.
      PARTICIPANTS AND SETTING: A total of 2379 black and white girls, aged 9 to 10
      years, were recruited from schools in Richmond, California, and Cincinnati, Ohio,
      and from families enrolled in a health maintenance organization in the
      Washington, DC area. Participant eligibility was limited to girls and their
      parents who declared themselves as being either black or white and who lived in
      racially concordant households. DESIGN AND STATISTICAL ANALYSIS: The NGHS is a
      multicenter prospective study of a biracial cohort followed annually from ages 9
      to 10 years through 18 to 19 years. The prevalence of overweight and obesity was
      based on age-specific > or =85th and > or =95th percentile values, respectively,
      for body mass index based on the 1960-1965 National Health Examination Survey
      reference population. MAIN OUTCOME MEASURES: The main outcome measures were body
      mass index (weight in kilograms divided by height in meters, squared) and
      proportions of girls who were "overweight" and "obese" by age and race. RESULTS:
      The prevalence of overweight was 37% higher in blacks as compared with whites
      (30.6% vs 22.4%) even by age 9. The rate of overweight almost doubled in both
      groups during the 10-year period. By age 19, the rate of overweight was 56.9% in
      black and 41.3%, in white girls. The prevalence of obesity was 17.7% in black and
      7.7% in white girls at 9 years old, and the rates also doubled during the study
      period. CONCLUSIONS: The doubling in the prevalence of overweight and obesity
      during adolescence in black and white NGHS girls was surprising. By age 19, more
      than half of black girls were overweight and more than one third were obese.
      Almost half of white girls were overweight and almost 1 of 5 girls were obese.
      These findings should sound an alarm for all primary care physicians and public
      health professionals to take heed of what is happening to our youth.

PMID- 12415061
TI  - Omalizumab improves asthma-related quality of life in children with allergic
      asthma.
AB  - BACKGROUND AND OBJECTIVE: Omalizumab is a recombinant, humanized, monoclonal anti
      immunoglobulin E (IgE) antibody, developed for the treatment of IgE-mediated
      diseases. In children with allergic asthma, it was shown to reduce the
      requirement for inhaled corticosteroids while protecting against disease
      exacerbation. Here we report the effects of treatment with omalizumab on asthma
      related quality of life (AQoL) in children with allergic asthma. METHODS: This
      evaluation was part of a previously reported 28-week, randomized, double-blind,
      placebo-controlled study to assess the efficacy, safety, and tolerability of
      omalizumab (at least 0.016 mg/kg/IgE [IU/mL] per 4 weeks) in children with
      allergic asthma who were well controlled on daily treatment with inhaled
      corticosteroids. Dosage of beclomethasone dipropionate was kept constant for 16
      weeks (steroid-stable phase), then reduced over 8 weeks to the minimum effective
      dose (steroid-reduction phase). This dose was then maintained for the final 4
      weeks. The Pediatric Asthma Quality of Life Questionnaire (PAQLQ) was
      administered at baseline, week 16, and week 28. RESULTS: Baseline demographics,
      PAQLQ scores, and other data were comparable for the 2 treatment groups. At the
      end of the steroid-reduction phase, patients in the omalizumab-treated group
      reported significant improvements in the "activities" and "symptoms" domain
      scores as well as overall AQoL compared with placebo. More patients in the
      omalizumab group achieved clinically relevant (> or =0.5) changes in PAQLQ scores
      during the course of the study, and this difference was significant for
      activities and overall AQoL. CONCLUSION: Omalizumab improves AQoL in children
      with allergic asthma.

PMID- 12415062
TI  - Marked dyslipidemia in human immunodeficiency virus-infected children on protease
      inhibitor-containing antiretroviral therapy.
AB  - OBJECTIVE: To assess the effects of antiretroviral combination therapy that
      contains protease inhibitor (PI) on carbohydrate and lipid metabolism in human
      immunodeficiency virus (HIV)-infected children. METHODS: A cross-sectional,
      descriptive clinical study was conducted in an outpatient clinic. Thirty-seven
      HIV-infected children who ranged from 1 to 17 years of age received nucleoside
      reverse transcriptase inhibitor treatment together with PI (PI group, n = 25) or
      without PI (non-PI group, n = 12). Age, gender, weight, length, CD4 cell count,
      and viral load did not differ between groups. Nonfasting total cholesterol,
      triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein (LDL)
      cholesterol, glucose, lactate, and blood gases were determined. In addition, c
      peptide, insulin, hemoglobin A1c, free fatty acids, lipoprotein a, and
      apolipoproteins A1 and B were evaluated after fasting. PI and non-PI group values
      were compared with normal values taken from healthy children. RESULTS: In
      nonfasting and fasting conditions, children of the PI group had higher total
      cholesterol (fasting PI group: 235 +/- 71 mg/dL; non-PI group: 176 +/- 25 mg/dL,
      mean +/- standard deviation), triglycerides (156 +/- 89 vs 87 +/- 31 mg/dL), and
      LDL cholesterol levels (159 +/- 58 vs 113 +/- 23 mg/dL) compared with the non-PI
      group. High-density lipoprotein cholesterol and apolipoprotein A1 levels did not
      differ in both groups; there was a trend toward higher apolipoprotein B levels in
      the PI group. After fasting, 8 (47%) of 17 patients in the PI group presented
      with hypercholesterolemia as a result of an increase of LDL cholesterol and 11
      (65%) had hypertriglyceridemia. It is interesting that the non-PI group showed no
      pathologic deviations. Compared with normal values, lipoprotein a and free fatty
      acids were increased in the PI and non-PI groups. Glucose, lactate, blood gases,
      c-peptide, insulin, and hemoglobin A1c were normal in both groups. CONCLUSION: PI
      containing antiretroviral treatment of HIV-infected children was associated with
      hypercholesterolemia, hypertriglyceridemia, and an increase of LDL cholesterol.
      The long-term complications of dyslipidemia are of major concern in the growing
      HIV-infected child.

PMID- 12415063
TI  - Gang involvement and the health of African American female adolescents.
AB  - OBJECTIVE: To examine the association between gang involvement and female
      adolescents' health. METHODS: African American adolescent females (N = 522)
      completed a survey that assessed their history of gang involvement and health
      behaviors and provided specimens that were analyzed for marijuana use and
      sexually transmitted diseases. RESULTS: In logistic regression analyses,
      adolescents with a history of gang involvement were more likely to have been
      expelled from school (odds ratio [OR]: 3.6), be a binge drinker (OR: 3.3), have a
      positive toxicologic test for marijuana (OR: 2.6), have been in 3 or more fights
      in the past 6 months (OR: 3.8), have a nonmonogamous partner (OR: 2.4), and test
      positive for Trichomonas vaginalis (OR: 2.2) and Neisseria gonorrhoeae (OR: 3.6).
      CONCLUSION: This study extends the current research on risk behaviors associated
      with gang involvement to include biological markers for substance use and sexual
      health outcomes, namely, marijuana use and sexually transmitted diseases.

PMID- 12415064
TI  - Reducing geographic, racial, and ethnic disparities in childhood immunization
      rates by using reminder/recall interventions in urban primary care practices.
AB  - CONTEXT: An overarching national health goal of Healthy People 2010 is to
      eliminate disparities in leading health care indicators including immunizations.
      Disparities in US childhood immunization rates persist, with inner-city, black,
      and Hispanic children having lower rates. Although practice or clinic-based
      interventions, such as patient reminder/recall systems, have been found to
      improve immunization rates in specific settings, there is little evidence that
      those site-based interventions can reduce disparities in immunization rates at
      the community level. OBJECTIVE: To assess the effect of a community-wide
      reminder, recall, and outreach (RRO) system for childhood immunizations on known
      disparities in immunization rates between inner-city versus suburban populations
      and among white, black, and Hispanic children within an entire county. SETTING:
      Monroe County, New York (birth cohort: 10 000, total population: 750 000), which
      includes the city of Rochester. Three geographic regions within the county were
      compared: the inner city of Rochester, which contains the greatest concentration
      of poverty (among 2-year-old children, 64% have Medicaid); the rest of the city
      of Rochester (38% have Medicaid); and the suburbs of the county (8% have
      Medicaid). INTERVENTIONS: An RRO system was implemented in 8 city practices in
      1995 (covering 64% of inner-city children) and was expanded to 10 city practices
      by 1999 (covering 74% of inner-city children, 61% of rest-of-city children, and
      9% of suburban children). The RRO intervention involved lay community-based
      outreach workers who were assigned to city practices to track immunization rates
      of all 0- to 2-year-olds, and to provide a staged intervention with increasing
      intensity depending on the degree to which children were behind in immunizations
      (tracking for all children, mail, or telephone reminders for most children,
      assistance with transportation or scheduling for some children, and home visits
      for 5% of children who were most behind in immunizations and who faced complex
      barriers). STUDY PARTICIPANTS: Three separate cohorts of 0- to 2-year-old
      children were assessed-those residing in the county in 1993, 1996, and 1999.
      STUDY DESIGN: Immunization rates were measured for each geographic region in
      Monroe County at 3 time periods: before the implementation of a systematic RRO
      system (1993), during early phases of implementation of the RRO system (1996),
      and after implementation of the RRO system in 10 city practices (1999).
      Immunization rates were compared for children living in the 3 geographic regions,
      and for white, black, and Hispanic children. Immunization rates were measured by
      the same methodology in each of the 3 time periods. A denominator of children was
      obtained by merging patient lists from the practice files of most pediatric and
      family medicine practices in the county (covering 85% to 89% of county children).
      A random sample of children (>500 from the suburbs and >1200 from the city for
      each sampling period) was then selected for medical chart review at practices to
      determine demographic characteristics (including race and ethnicity) and
      immunization rates. City children were oversampled to allow detection of effects
      by geographic region and race. Rates for the 3 geographic regions and for the
      entire county were determined using Stata to adjust for the clustered sampling.
      MAIN OUTCOME MEASURES: Immunization rates at 12 and 24 months for recommended
      vaccines (4 diphtheria-tetanus-pertussis:3 polio:1 measles-mumps-rubella: > or =1
      Haemophilus influenzae type b on or after 12 months of age). RESULTS: DISPARITIES
      BY GEOGRAPHIC REGION: Baseline immunization rates (1993) for 24-month-olds were
      as follows: inner city (55%), rest of city (64%), and suburbs (73%), with an 18%
      difference in rates between the inner city and suburbs. By 1996, immunization
      rates rose faster in the inner city (+21% points) than in the suburbs (+14%
      points) so that the difference in rates between the inner city and suburbs had
      narrowed to 11%. In 1999, rates were similar across geographic regions: inner
      city (84%), rest of city (81%), and suburbs (88%), with a 4% difference between
      the inner city and suburbs. DISPARITIES BY RACE AND ETHNICITY: Immunization rates
      were available in 1996 and 1999 by race and ethnicity. Twenty-four-month
      immunization rates in 1996 showed disparities: white (89%), black (76%), and
      Hispanic (74%), with a 13% difference between rates for white and black children
      and a 15% difference between white and Hispanic children. In 1999, rates were
      similar across the groups: white (88%), black (81%), and Hispanic (87%), with a
      7% difference between rates for white and black children, and a 1% difference
      between white and Hispanic children. CONCLUSIONS: A community-wide intervention
      of patient RRO raised childhood immunization rates in the inner city of Rochester
      and was associated with marked reductions in disparities in immunization rates
      between inner-city and suburban children and among racial and ethnic minority
      populations. By targeting a relatively manageable number of primary care
      practices that serve city children and using an effective strategy to increase
      immunization rates in each practice, it is possible to eliminate disparities in
      immunizations for vulnerable children.

PMID- 12415065
TI  - Effect of an educational intervention about breastfeeding on the knowledge,
      confidence, and behaviors of pediatric resident physicians.
AB  - OBJECTIVE: Breastfeeding is the preferred nutrition for infants, but many
      pediatricians report inadequate training to advise mothers who breastfeed. This
      study was designed to examine the effect of an educational intervention on
      pediatric residents' knowledge about breastfeeding, their confidence in
      addressing lactation issues, and their management skills during clinical
      encounters with breastfeeding mothers. DESIGN: An interactive multimedia
      curricular intervention was designed for pediatric residents to increase their
      knowledge about common lactation issues. The residents completed questionnaires
      before and after the intervention to measure knowledge and confidence. Resident
      behaviors in the clinical setting were measured before and after the intervention
      using telephone surveys of breastfeeding mothers after a clinic visit with a
      pediatric resident. RESULTS: Forty-nine pediatric residents participated in the
      study. Mean knowledge scores increased from 69% before the intervention to 80%
      after the intervention. Significant increases in knowledge included advising
      mothers about low milk supply, mastitis, abscess, or using medication, and in
      recognizing the benefit of the decreased risk of maternal cancer. Management
      skills with breastfeeding mothers and infants in the clinical setting improved
      significantly. Before the intervention residents performed an acceptable number
      of behaviors 22% of the time, while after the intervention their performance was
      acceptable 65% of the time. Particular behaviors that showed significant
      improvement after the intervention included discussing signs of breastfeeding
      adequacy with the mother and correct management of lactation problems.
      CONCLUSIONS: These results indicate that not only breastfeeding knowledge and
      confidence, but most importantly clinical behaviors of pediatric residents can be
      enhanced through innovative educational opportunities. Appropriate counseling for
      breastfeeding mothers by pediatricians might contribute to an increase in the
      duration of breastfeeding.

PMID- 12415066
TI  - Impact of mandatory helmet legislation on bicycle-related head injuries in
      children: a population-based study.
AB  - OBJECTIVE: Childhood bicycle-related head injuries can be prevented through the
      use of helmets. Although helmet legislation has proved to be a successful
      strategy for the adoption of helmets, its effect on the rates of head injury is
      uncertain. In Canada, 4 provinces have such legislation. The objective of this
      study was to measure the impact of helmet legislation on bicycle-related head
      injuries in Canadian children. METHODS: Routinely collected data from the
      Canadian Institute for Health Information identified all Canadian children (5-19
      years) who were hospitalized for bicycling-related injuries from 1994-1998.
      Children were categorized as head or other injury on the basis of International
      Classification of Diseases, Ninth Revision, codes. Rates of head injuries and
      other injuries were compared over time in provinces that adopted legislation and
      those that did not. RESULTS: Of the 9650 children who were hospitalized because
      of a bicycle-related injury, 3426 sustained injuries to the head and face and the
      remaining 6224 had other injuries. The bicycle-related head injury rate declined
      significantly (45% reduction) in provinces where legislation had been adopted
      compared with provinces and territories that did not adopt legislation (27%
      reduction). CONCLUSION: This country-wide study compared rates of head injury in
      regions with and without mandatory helmet legislation. Comparing head injuries
      with other non-head-injured children controlled for potential differences in
      children's cycling habits. The strong protective association between helmet
      legislation and head injuries supports the adoption of helmet legislation as an
      effective tool in the prevention of childhood bicycle-related head injuries.

PMID- 12415067
TI  - Child safety seat knowledge among parents utilizing emergency services in a level
      I trauma center in Southern California.
AB  - OBJECTIVE: To determine the level of child safety seat (CSS) and airbag safety
      knowledge in parents who utilize emergency care services for their children and
      to determine factors that influence knowledge of safe transportation of children.
      METHODS: A prospective survey study was conducted in a 42 000-visit-per-year
      Level I trauma center and emergency department (ED) in Southern California from
      May through October 2000. Subjects were parents of ED-registered children (< or
      =6 years). Research assistants administered the survey in the subject's native
      language. Parent knowledge of age-appropriate restraint use and airbag safety was
      collected. RESULTS: Six hundred fifty-five subjects were enrolled. Most parents
      (97%) reported a regular source of pediatric medical care, and 57% had a previous
      ED visit. Eighty-six percent reported owning a CSS or booster seat. Eighty-one
      percent were aware that infants in rear-facing CSSs should never be placed in
      front of an airbag. Only 46% knew that a child weighing 40 to 60 lb should travel
      in a booster seat, and 59% knew that the State law required CSS use for children
      up to 4 years and weighing up to 40 lb. When knowledge scores were examined by
      ethnicity, fluency in English, income, and years of education, fluency was found
      to have the greatest influence on both CSS and airbag knowledge. CONCLUSIONS:
      Although nearly all of our subjects admitted that their children had a regular
      source of care, many parents showed evidence of lack of knowledge of CSS and
      airbag safety. Furthermore, many parents were not familiar with the state law
      regarding child restraints. Our findings suggest that parents of small children
      who utilize emergency care services could benefit from child passenger safety
      education during their ED visit and that non-English media and materials may be
      important to reaching this population.

PMID- 12415068
TI  - Incidence and description of stroller-related injuries to children.
AB  - OBJECTIVE: To describe the incidence, circumstances, and types of stroller
      related injuries among US children. DESIGN: Retrospective review of data for
      children 3 years old and younger from the National Electronic Injury Surveillance
      System of the United States Consumer Product Safety Commission for 1994-1998.
      RESULTS: There were an estimated 64 373 stroller-related injuries (95% confidence
      interval [CI]: 49 223-79 514) to children 3 years old and younger treated in
      hospital emergency departments in the United States during the 5-year study
      period. The median age at the time of the injury was 11 months; 51% were males.
      The annual rate of injury among children <1 year old was 184.4 per 100 000.
      Seventy-six percent of injuries resulted from a fall from the stroller. A motor
      vehicle was involved in <1% of cases. Most injuries involved the head (44%) or
      face (43%). Injury diagnoses included contusions or abrasions (38%), lacerations
      (24%), closed head injury (22%), and extremity fractures (3%). Two percent of
      injured children, an estimated 992 (95% CI: 428-1556), were admitted to the
      hospital during the study period, an annual admission rate of 1.3 per 100 000.
      Seventy percent of admissions were for head trauma. CONCLUSIONS: Injuries related
      to strollers are common, particularly among children in the first year of life.
      They often result from falls from the stroller. The data suggest that restraint
      use would prevent many stroller-related injuries.

PMID- 12415069
TI  - Ankyloglossia: assessment, incidence, and effect of frenuloplasty on the
      breastfeeding dyad.
AB  - OBJECTIVE: Ankyloglossia in breastfeeding infants can cause ineffective latch,
      inadequate milk transfer, and maternal nipple pain, resulting in untimely
      weaning. The question of whether the performance of a frenuloplasty benefits the
      breastfeeding dyad in such a situation remains controversial. We wished to 1)
      define significant ankyloglossia, 2) determine the incidence in breastfeeding
      infants, and 3) measure the effectiveness of the frenuloplasty procedure with
      respect to solving specific breastfeeding problems in mother-infant dyads who
      served as their own controls. METHODS: We examined 2763 breastfeeding inpatient
      infants and 273 outpatient infants with breastfeeding problems for possible
      ankyloglossia and assessed each infant with ankyloglossia, using the Hazelbaker
      Assessment Tool for Lingual Frenulum Function. We then observed each dyad while
      breastfeeding. When latch problems were seen, we asked the mother to describe the
      sensation and quality of the suck at the breast. When pain was described, we
      asked the mother to grade her pain on a scale of 1 to 10. When lingual function
      was impaired, we discussed the frenuloplasty procedure with the parent(s) and
      obtained informed consent. After the procedure, the infants were returned to
      their mothers for breastfeeding. Infant latch and maternal nipple pain were
      reassessed at this time. RESULTS: Ankyloglossia was diagnosed in 88 (3.2%) of the
      inpatients and in 35 (12.8%) of the outpatients. Mean Hazelbaker scores were
      similar for the presenting symptoms of poor latch and nipple pain. Median infant
      age (25th and 75th percentiles) at presentation was lower for poor latch than for
      nipple pain: 1.2 days (0.7, 2.0) versus 2.0 days (1.0, 12.0), respectively. All
      frenuloplasties were performed without incident. Latch improved in all cases, and
      maternal pain levels fell significantly after the procedure: 6.9 +/- 2.31 down to
      1.2 +/- 1.52. CONCLUSION: Ankyloglossia is a relatively common finding in the
      newborn population and represents a significant proportion of breastfeeding
      problems. Poor infant latch and maternal nipple pain are frequently associated
      with this finding. Careful assessment of the lingual function, followed by
      frenuloplasty when indicated, seems to be a successful approach to the
      facilitation of breastfeeding in the presence of significant ankyloglossia.

PMID- 12415070
TI  - The triple risk hypotheses in sudden infant death syndrome.
AB  - Sudden infant death syndrome (SIDS) victims were regarded as normal as a matter
      of definition (Beckwith 1970) until 1952 when Kinney and colleagues argued for
      elimination of the clause, "unexpected by history." They argued that "not all
      SIDS victims were normal," and referred to their hypothesis that SIDS results
      from brain abnormalities, which they postulated "to originate in utero and lead
      to sudden death during a vulnerable postnatal period." Bergman (1970) argued that
      SIDS did not depend on any "single characteristic that ordains a infant for
      death," but on an interaction of risk factors with variable probabilities.
      Wedgwood (1972) agreed and grouped risk factors into the first "triple risk
      hypothesis" consisting of general vulnerability, age-specific risks, and
      precipitating factors. Raring (1975), based on a bell-shaped curve of age of
      death (log-transformed), concluded that SIDS was a random process with
      multifactorial causation. Rognum and Saugstad (1993) developed a "fatal triangle"
      in 1993, with groupings similar to those of Wedgwood, but included mucosal
      immunity under a vulnerable developmental stage of the infant. Filiano and Kinney
      (1994) presented the best known triple risk hypothesis and emphasized prenatal
      injury of the brainstem. They added a qualifier, "in at least a subset of SIDS,"
      but, the National Institute of Child Health and Development SIDS Strategic Plan
      2000, quoting Kinney's work, states unequivocally that "SIDS is a developmental
      disorder. Its origins are during fetal development." Except for the emphasis on
      prenatal origin, all 3 triple risk hypotheses are similar. Interest in the
      brainstem of SIDS victims began with Naeye's 1976 report of astrogliosis in 50%
      of all victims. He concluded that these changes were caused by hypoxia and were
      not the cause of SIDS. He noted an absence of astrogliosis in some older SIDS
      victims, compatible with a single, terminal episode of hypoxia without previous
      hypoxic episodes, prenatal or postnatal. Kinney and colleagues (1983) reported
      gliosis in 22% of their SIDS victims. Subsequently, they instituted studies of
      neurotransmitter systems in the brainstem, particularly the muscarinic (1995) and
      serotenergic systems (2001). The major issue is when did the brainstem
      abnormalities, astrogliosis, or neurotransmitter changes occur and whether either
      is specific to SIDS. There is no published method known to us of determining the
      time of origin of these markers except that the injury causing astrogliosis must
      have occurred at least 4 days before death (Del Bigio and Becker, 1994). Because
      the changes in neurotransmitter systems found in the arcuate nucleus in SIDS
      victims were also found in the chronic controls with known hypoxia, specificity
      of these markers for SIDS has not been established. It seems likely that the
      "acute control" group of Kinney et al (1995) died too quickly to develop gliosis
      or severe depletion of the neurotransmitter systems. We can conclude that the
      acute controls had no previous episodes of severe hypoxia, unlike SIDS or their
      "chronic controls." Although the average muscarinic cholinergic receptor level in
      the SIDS victim was significantly less than in the acute controls, the difference
      was only 27%, and only 21 of 41 SIDS victims had values below the mean of the
      acute controls. The study of the medullary serotonergic network by Kinney et al
      (2001) revealed greater reductions in the SIDS victims than in acute controls,
      but the questions of cause versus effect of the abnormalities, and whether they
      occurred prenatally or postnatally, remain unanswered. Hypoplasia of the arcuate
      nucleus was stated to occur in 5% of their SIDS cases by Kinney et al (2001), but
      this is a "primary developmental defect" according to Matturri et al (2002) with
      a larger series, many of whom were stillbirths. These cases should not be
      included under the rubric of SIDS, by definition. There are difficulties with
      Filiano and Kinney's (1994) explanation of the age at death distribution of SIDS.
      They postulate that the period between 1 and 6 months represents an unstable time
      for virtually all physiologic systems. However, this period demonstrates much
      less instability than does the neonatal period, when most deaths from congenital
      defects and severe maternal anemia occur. We present data for infants born to
      mothers who were likely to have suffered severe anemia as a consequence of
      placenta previa, abruptio placentae, and excessive bleeding during pregnancy;
      these infants presumably are at increased risk of hypoxia and brainstem injury.
      The total neonatal mortality rate in these 3 groups of infants is 4 times greater
      than the respective postneonatal mortality, and in the postneonatal period the
      non-SIDS mortality rate is between 14 and 22 times greater than the postneonatal
      SIDS rate in these 3 groups. A preponderance of deaths in the neonatal period is
      also found for congenital anomalies, a category that logically should include
      infants who experienced prenatal hypoxia or ischemia; this distribution of age of
      death is very different from that for SIDS, which mostly spares the first month
      and peaks between 2 and 3 months of age. Finally, evidence inconsistent with
      prenatal injury as a frequent cause of SIDS comes from prospective studies of
      ventilatory control in neonates who subsequently died of SIDS; no significant
      respiratory abnormalities in these infants have been found (Waggener et al 1990;
      Schectman et al 1991). We conclude that none of the triple risk hypotheses
      presented so far have significantly improved our understanding of the cause of
      SIDS. Bergman's and Raring's concepts of multifactorial causation with
      interaction of risk factors with variable probabilities is less restrictive and
      more in keeping with the large number of demonstrated risk factors and their
      varying prevalence. If prenatal hypoxic damage of the brainstem occurred, it
      seems likely that the infant so afflicted would be at risk for SIDS, but it is
      even more likely that their death would occur in the neonatal period, as we have
      demonstrated in infants who have known maternal risk factors that involve severe
      anemia. This is in contrast to the delay until the postneonatal period of most
      SIDS deaths. A categorical statement that the origin of SIDS is prenatal is
      unwarranted by the evidence. Brainstem abnormalities have not been shown to cause
      SIDS, but are more likely a nonspecific effect of hypoxia.

PMID- 12415071
TI  - Candida (amphotericin-sensitive) lens abscess associated with decreasing arterial
      blood flow in a very low birth weight preterm infant.
AB  - In this report, we review the case of a candidal lens abscess in a premature
      infant girl who was 28 weeks' gestational age at birth. The culture obtained from
      the lens abscess grew Candida albicans sensitive to amphotericin B but resistant
      to flucytosine. This case is unique in that the infant developed a fungal lens
      cataract at 34 weeks' postconceptional age during the last week of a 30-day
      course of amphotericin B. The embryonic hyaloid artery system, which perfuses the
      developing lens, regresses between 29 and 32 weeks of gestation; thus, the
      mechanism for an infection of the lens may be inoculation of the lens by Candida
      before hyaloid artery system regression, followed by developmental loss of this
      blood supply, which makes the lens inaccessible to antimicrobial penetration.
      Candidal endophthalmitis with lens abscess is an uncommon morbidity that requires
      prompt recognition and surgical intervention for effective management.

PMID- 12415072
TI  - Community contexts of human welfare.
AB  - This chapter identifies "context minimization error" as the tendency to ignore
      the impact of enduring neighborhood and community contexts on human behavior. The
      error has adverse consequences for understanding psychological processes and
      efforts at social change. The chapter describes a series of theoretical models of
      how neighborhoods and community settings are associated with various aspects of
      human welfare and reviews evidence of associations of contexts with health,
      psychological distress, risky behaviors, psychological attitudes, and child
      development. It suggests that many psychological processes may play out
      differently in different contexts and that contextual factors interact with
      sociocultural characteristics of individuals in predicting outcomes. People, in
      turn, can shape community contexts. A more sophisticated understanding of the
      effects of contexts depends on more sophisticated approaches to assessing them.

PMID- 12415073
TI  - Interdependence, interaction, and relationships.
AB  - Interdependence theory presents a logical analysis of the structure of
      interpersonal situations, offering a conceptual framework in which
      interdependence situations can be analyzed in terms of six dimensions. Specific
      situations present specific problems and opportunities, logically implying the
      relevance of specific motives and permitting their expression. Via the concept of
      transformation, the theory explains how interaction is shaped by broader
      considerations such as long-term goals and concern for a partner's welfare. The
      theory illuminates our understanding of social-cognitive processes that are of
      longstanding interest to psychologists such as cognition and affect, attribution,
      and self-presentation. The theory also explains adaptation to repeatedly
      encountered interdependence patterns, as well as the embodiment of such
      adaptations in interpersonal dispositions, relationship-specific motives, and
      social norms.

PMID- 12415074
TI  - Facial and vocal expressions of emotion.
AB  - A flurry of theoretical and empirical work concerning the production of and
      response to facial and vocal expressions has occurred in the past decade. That
      emotional expressions express emotions is a tautology but may not be a fact.
      Debates have centered on universality, the nature of emotion, and the link
      between emotions and expressions. Modern evolutionary theory is informing more
      models, emphasizing that expressions are directed at a receiver, that the
      interests of sender and receiver can conflict, that there are many determinants
      of sending an expression in addition to emotion, that expressions influence the
      receiver in a variety of ways, and that the receiver's response is more than
      simply decoding a message.

PMID- 12415076
TI  - Cultural pathways through universal development.
AB  - We focus our review on three universal tasks of human development: relationship
      formation, knowledge acquisition, and the balance between autonomy and
      relatedness at adolescence. We present evidence that each task can be addressed
      through two deeply different cultural pathways through development: the pathways
      of independence and interdependence. Whereas core theories in developmental
      psychology are universalistic in their intentions, they in fact presuppose the
      independent pathway of development. Because the independent pathway is therefore
      well-known in psychology, we focus a large part of our review on empirically
      documenting the alternative, interdependent pathway for each developmental task.
      We also present three theoretical approaches to culture and development: the
      ecocultural, the sociohistorical, and the cultural values approach. We argue that
      an understanding of cultural pathways through human development requires all
      three approaches. We review evidence linking values (cultural values approach),
      ecological conditions (ecocultural approach), and socialization practices
      (sociohistorical approach) to cultural pathways through universal developmental
      tasks.

PMID- 12415075
TI  - Operant conditioning.
AB  - Operant behavior is behavior "controlled" by its consequences. In practice,
      operant conditioning is the study of reversible behavior maintained by
      reinforcement schedules. We review empirical studies and theoretical approaches
      to two large classes of operant behavior: interval timing and choice. We discuss
      cognitive versus behavioral approaches to timing, the "gap" experiment and its
      implications, proportional timing and Weber's law, temporal dynamics and linear
      waiting, and the problem of simple chain-interval schedules. We review the long
      history of research on operant choice: the matching law, its extensions and
      problems, concurrent chain schedules, and self-control. We point out how linear
      waiting may be involved in timing, choice, and reinforcement schedules generally.
      There are prospects for a unified approach to all these areas.

PMID- 12415077
TI  - Impact of the European Convention on Human Rights on medical law.

PMID- 12415078
TI  - Diagnosis and treatment of viral encephalitis.
AB  - Acute encephalitis constitutes a medical emergency. In most cases, the presence
      of focal neurological signs and focal seizures will distinguish encephalitis from
      encephalopathy. Acute disseminated encephalomyelitis is a non-infective
      inflammatory encephalitis that may require to be treated with steroids. Acute
      infective encephalitis is usually viral. Herpes simplex encephalitis (HSE) is the
      commonest sporadic acute viral encephalitis in the Western world. Magnetic
      resonance imaging of brain is the investigation of choice in HSE and the
      diagnosis may be confirmed by the polymerase chain reaction test for the virus in
      the cerebrospinal fluid. In this article, we review the diagnosis,
      investigations, and management of acute encephalitis. With few exceptions (for
      example, aciclovir for HSE), no specific therapy is available for most forms of
      viral encephalitis. Mortality and morbidity may be high and long term sequelae
      are known among survivors. The emergence of unusual forms of zoonotic
      encephalitis has posed an important public health problem. Vaccination and vector
      control measures are useful preventive strategies in certain arboviral and
      zoonotic encephalitis. However, we need better antiviral therapy to meet the
      challenge of acute viral encephalitis more effectively.

PMID- 12415080
TI  - Prostate cancer.
AB  - It is a paradigm in cancer treatment that early detection and treatment improves
      survival. However, although screening measures lead to a higher rate of
      detection, for small bulk localised prostate cancer it remains unclear whether
      early detection and early treatment will lead to an overall decrease in
      mortality. The management options include surveillance, radiotherapy, and radical
      prostatectomy but there is no evidence base to evaluate the benefits of each
      approach. Advanced prostate cancer is managed by hormonal therapy. There have
      been major changes in treatment over the last two decades with the use of more
      humane treatment and developments in both chemotherapy and radiation. In this
      article we review the natural history and management of prostate cancer.

PMID- 12415079
TI  - Epidermal growth factor receptor and bladder cancer.
AB  - Muscle-invasive bladder cancer is a disease which causes significant morbidity
      and mortality. The two main forms of treatment for this disease include radical
      cystectomy and radical radiotherapy, but five year survival after treatment
      remains low at 40%. Many clinical and molecular risk factors have been shown to
      be associated with poor prognosis. One such factor is the expression of epidermal
      growth factor receptor (EGFR), which is overexpressed by many epithelial tumours,
      including bladder cancers. There are several methods of inhibiting the activity
      of EGFR and it may be that use of an anti-EGFR therapy, in combination with more
      conventional treatment, provides a method of improving the prognosis for muscle
      invasive bladder cancer.

PMID- 12415081
TI  - Nocturnal leg cramps in older people.
AB  - Nocturnal leg cramps are common in older people. Such cramps are associated with
      many common diseases and medications. Physiological methods may be useful for
      preventing cramps in some people, but there have been no controlled trials of
      these approaches. Quinine is moderately effective in preventing nocturnal leg
      cramps. However, there are concerns about the risk/benefit ratio with this drug.
      In patients with severe symptoms, a trial of 4-6 weeks' treatment with quinine is
      probably still justified, but the efficacy of treatment should be monitored, for
      example using a sleep and cramp diary.

PMID- 12415083
TI  - Current concepts for the management of systemic lupus erythematosus in adults: a
      therapeutic challenge.
AB  - Systemic lupus erythematosus (SLE) is a chronic, autoimmune rheumatic disease
      with many clinical presentations typically affecting women of childbearing age.
      The successful therapy of SLE depends upon treating both symptoms and the
      underlying inflammation. Both non-pharmacological as well as pharmacological
      therapies are invariably required. Non-pharmacological therapy includes avoiding
      over-exposure to sunlight with the use of adequate sunscreen protection, avoiding
      "live" vaccination if on immunosuppressive agents, adherence to a diet low in
      saturated fat and high in fish oil, stress avoidance, and smoking cessation.
      Pharmacological measures revolve around four main classes of drugs: non-steroidal
      anti-inflammatory drugs, antimalarials, corticosteroids, and cytotoxic agents.
      Cyclophosphamide and azathioprine are the two most commonly used cytotoxic agents
      and these in combination with corticosteroids need to be employed early if there
      is major organ involvement to prevent or minimise irreversible damage. The
      potential side effects of corticosteroids and cytotoxic agents need constant
      consideration. The rapid developments in biotechnology of recent years may soon
      lead to new and more specific therapies for patients with SLE.

PMID- 12415084
TI  - Surveillance of surgical training by detailed electronic registration of logical
      components.
AB  - OBJECTIVE: To obtain detailed information about the degree of surgical trainee
      supervision and delegation of procedures in a subspecialised department. DESIGN:
      Operative procedures and their logical components were recorded in a database
      constructed in Microsoft Access. Information about operating surgeon and
      assistants and their grade was registered prospectively over 12 months. SUBJECTS
      AND METHODS: A total of 1250 intermediate or major procedures were performed by
      eight consultants, one staff specialist, four senior registrars, three specialist
      registrars, and five registrars. MAIN MEASURE: Number of components performed by
      surgeons in each grade and the degree of supervision and delegation. RESULTS:
      Eight hundred and eighty five of the operations were elective, while 365 were
      done as emergency procedures. Emergency procedures were far more often done by
      surgeons in training than by a staff surgeon, while the opposite was true for
      elective operations. Out of 323 elective operations done by surgeons in training,
      189 were done under supervision (58.5%), while 119 out of 276 emergency
      operations done by surgeons in training were supervised (43.1%; p=0.0002). One
      hundred and twenty eight of 638 (20%) open abdominal operations were done by the
      most junior surgeons, and yet they closed 36% of all abdominal wounds. Although
      the most junior surgeons only served as operating surgeons in 39 of 334 bowel
      operations (12%), they constructed 24% of all stomas, and 20% of all anastomoses.
      Registrars and specialist registrars never constructed stomas or anastomoses
      without supervision. CONCLUSION: Detailed information about individual and
      general training and supervision was achieved by a simple registration.
      Significant additional information was obtained about the extent of delegation of
      components compared with standard registration of operative procedures.

PMID- 12415085
TI  - Use of complementary therapies and non-prescribed medication in patients with
      Parkinson's disease.
AB  - Patients with Parkinson's disease resort to complementary therapy and non
      prescribed medication in the hope of improving their quality of life. In the US
      40% of patients with Parkinson's disease reported the use of at least one form of
      complementary therapy for Parkinson's disease. Data for the UK are limited. A
      structured questionnaire was administered to consecutive patients attending a
      Parkinson's disease clinic. Patients were excluded if they were cognitively
      impaired, if they were living in an institution, or if they declined to take
      part. The participants were asked about current and previous use of complementary
      therapy in general and Parkinson's disease in particular and were presented with
      an extensive list of complementary therapies and non-prescribed medications. The
      response rate was 90% and 80 patients met the inclusion criteria. Fifty four per
      cent (n=44) reported the use of at least one form of complementary therapy or non
      prescribed medication either for Parkinson's disease or for some other
      indication, of whom 31 (38.7% of the total sample) used it solely for the
      treatment of Parkinson's disease. The most commonly used complementary therapies
      for Parkinson's disease were massage (n=9) and aromatherapy (n=8). Non-prescribed
      medication was mainly used for indications other than Parkinson's disease and the
      commonest drugs used were simple analgesics (n=7), cod liver oil (n=5), and
      multivitamins (n=4). The use of complementary therapy for Parkinson's disease
      correlated significantly (Pearson's r=0.44, p=0.01) with a younger age at
      diagnosis of Parkinson's disease. Comorbidity correlated significantly with
      complementary therapy use for indications other than Parkinson's disease
      (Pearson's r=0.29, p= 0.01). The use of complementary therapy for Parkinson's
      disease in this UK based clinic closely mimics that in the US. Non
      pharmacological complementary therapy is mainly used for Parkinson's disease,
      while non-prescribed medication is more commonly used for other indications.

PMID- 12415086
TI  - Does patient knowledge affect the colorectal cancer risk in ulcerative colitis?
AB  - OBJECTIVES: Formal efforts to improve patient education are associated with fewer
      disease complications in a number of conditions. The possible relationship
      between knowledge about ulcerative colitis and its cancer risk, and the
      development of colorectal cancer using a previously developed and validated
      instrument-the Crohn's and colitis knowledge (CCKNOW) score-were investigated.
      METHODS: The 24 item CCKNOW questionnaire was mailed to patients known to have
      developed colorectal cancer as a complication of ulcerative colitis (cases) and
      to colitics from the Leicestershire inflammatory bowel disease patient database
      who had not developed cancer (controls). RESULTS: The mean (SD) CCKNOW scores for
      cases was 8.21 (3.02) and for controls was 8.27 (4.3). These scores did not
      differ significantly between cases and controls (difference 0.06, 95% confidence
      interval (CI) -1.7 to 1.5, p=0.9). There were four times as many members of the
      National Association of Crohn's and Colitis (NACC) in the control group compared
      with the cancer group and patients who are members of NACC achieve statistically
      significantly higher scores than non-members (11.6 v 7.8, p=0.05, 95% CI -0.1 to
      7.6). However, after adjusting for NACC membership, the CCKNOW score did not
      appear to be associated with having developed cancer (odds ratio 1.04, 95% CI
      0.92 to 1.18, p=0.5). CONCLUSIONS: The CCKNOW scores were comparable in cases and
      controls. Thus, in a retrospective study, no evidence has been demonstrated of an
      association between patient knowledge and the risk of developing colorectal
      cancer in patients with ulcerative colitis. However, knowledge may have been
      increased in cases as a direct result of having had colorectal cancer as a
      complication of ulcerative colitis.

PMID- 12415087
TI  - Wallenberg's lateral medullary syndrome.

PMID- 12415088
TI  - An unusual epistaxis.
AB  - The case of a man who presented complaining of epistaxis is reported. He had
      coarctation repair 18 years previously. Subsequent investigation revealed an
      aortobronchial fistula resulting from false aneurysm formation distal to the
      original vessel anastamosis. This was repaired at surgery, the patient suffering
      a minor stroke, before rehabilitation and good recovery.

PMID- 12415089
TI  - Bronchiolitis obliterans and organising pneumonia caused by carbamazepine and
      mimicking community acquired pneumonia.
AB  - Bronchiolitis obliterans and organising pneumonia (BOOP) presents with fever,
      dyspnoea, and other features that may be mistaken for pneumonia. Treatment is,
      however, very different, requiring corticosteroids. A man was admitted as an
      emergency with fever, dyspnoea, and non-productive cough. The chest radiograph
      showed consolidation which, despite antibiotics, progressed to become bilateral.
      BOOP was considered, and confirmed by transbronchial biopsy. The response to oral
      prednisolone was rapid with complete resolution of symptoms and radiographic
      consolidation within three weeks. The cause of BOOP is often never found; it is
      believed, however, that in this instance it occurred as a result of carbamazepine
      therapy started seven weeks earlier.

PMID- 12415090
TI  - Possible functional regression of insulinoma with prolonged octreotide.
AB  - A 75 year old woman was treated for over three years with the somatostatin
      analogue, octreotide for an insulinoma. She had presented in a hypoglycaemic
      coma. C-peptide and insulin concentrations were both raised and an area of
      increased vascularity within the pancreas was shown by angiography. No lesion was
      found at laparotomy and no resection was performed. After over three years of
      octreotide treatment it was withdrawn for a week. Her insulin and C-peptide
      concentrations were greatly reduced at this time and remained so.

PMID- 12415091
TI  - How safe is blood sampling? Anterior interosseus nerve injury by venepuncture.
AB  - All invasive procedures carry some degree of risk of damage to the normal
      structures in the proximity of the region where the procedure is performed. The
      risk is, however, minimal for venous cannulation. A case is reported of an injury
      to the anterior interosseus nerve sustained during venepunture for routine blood
      sampling at the cubital fossa.

PMID- 12415092
TI  - An interesting case of small bowel obstruction.

PMID- 12415093
TI  - Terminal ileal stricture.

PMID- 12415094
TI  - Iatrogenic groin pain.

PMID- 12415095
TI  - Spinal tumour with raised intracranial pressure.

PMID- 12415097
TI  - A man with a chest mass.

PMID- 12415098
TI  - A smoker with an apical mass.

PMID- 12415101
TI  - Lung nodules in a silver polisher.

PMID- 12415108
TI  - Estrogen receptor-interacting protein that modulates its nongenomic activity
      crosstalk with Src/Erk phosphorylation cascade.
AB  - Numerous studies have demonstrated that estrogens induce rapid and transient
      activation of the Src/Erk phosphorylation cascade. Activation of this cascade
      triggers vital cellular functions including cell proliferation and
      differentiation. However, the details of the molecular mechanism of this process
      remain to be elucidated. We have identified a previously uncharacterized nuclear
      receptor-interacting protein designated as modulator of nongenomic activity of
      estrogen receptor (MNAR). Here we show that MNAR modulates estrogen-receptor (ER)
      interaction with members of the Src family of tyrosine kinases, which leads to a
      stimulation of Src enzymatic activity and activation of Erk1 and Erk2 kinases. We
      also show that MNAR, through activation of the Src/Erk phosphorylation cascade,
      affects ER transcriptional activity and ultimately ER-mediated gene expression.
      These data reveal that MNAR mediates the crosstalk between two important classes
      of signal transducing molecules and suggest that ER "genomic" and "nongenomic"
      activities are interrelated.

PMID- 12415110
TI  - Quantifying signaling-induced reorientation of T cell receptors during
      immunological synapse formation.
AB  - Productive T cell recognition of antigen-presenting cells (APCs) is normally
      accompanied by the formation of a cell-cell contact called the "immunological
      synapse." Our understanding of the steps leading up to this formation has been
      limited by the absence of tools for analyzing 3D surfaces and surface
      distributions as they change over time. Here we use a 3D fluorescence
      quantitation method to show that T cell receptors are recruited in bulk within
      the first minute after the onset of activation and with velocities ranging from
      0.04 to 0.1 microm/s; a speed significantly greater than unrestricted diffusion.
      Our method reveals a second feature of this reorientation: a conformational
      change as the T cell pushes more total membrane into the interface creating a
      larger contact area for additional receptors. Analysis of individual T cell
      receptor velocities using a single-particle tracking method confirms our velocity
      measurement. This method should permit the quantitation of other dynamic membrane
      events and the associated movement of cell-surface molecules.

PMID- 12415109
TI  - Gene expression comparison of biopsies from Duchenne muscular dystrophy (DMD) and
      normal skeletal muscle.
AB  - The primary cause of Duchenne muscular dystrophy (DMD) is a mutation in the
      dystrophin gene leading to the absence of the corresponding RNA transcript and
      protein. Absence of dystrophin leads to disruption of the dystrophin-associated
      protein complex and substantial changes in skeletal muscle pathology. Although
      the histological pathology of dystrophic tissue has been well documented, the
      underlying molecular pathways remain poorly understood. To examine the pathogenic
      pathways and identify new or modifying factors involved in muscular dystrophy,
      expression microarrays were used to compare individual gene expression profiles
      of skeletal muscle biopsies from 12 DMD patients and 12 unaffected control
      patients. Two separate statistical analysis methods were used to interpret the
      resulting data: t test analysis to determine the statistical significance of
      differential expression and geometric fold change analysis to determine the
      extent of differential expression. These analyses identified 105 genes that
      differ significantly in expression level between unaffected and DMD muscle. Many
      of the differentially expressed genes reflect changes in histological pathology.
      For instance, immune response signals and extracellular matrix genes are
      overexpressed in DMD muscle, an indication of the infiltration of inflammatory
      cells and connective tissue. Significantly more genes are overexpressed than are
      underexpressed in dystrophic muscle, with dystrophin underexpressed, whereas
      other genes encoding muscle structure and regeneration processes are
      overexpressed, reflecting the regenerative nature of the disease.

PMID- 12415111
TI  - Altered kinetics and benzodiazepine sensitivity of a GABAA receptor subunit
      mutation [gamma 2(R43Q)] found in human epilepsy.
AB  - The gamma-aminobutyric acid type A (GABA(A)) receptor mediates fast inhibitory
      synaptic transmission in the CNS. Dysfunction of the GABA(A) receptor would be
      expected to cause neuronal hyperexcitability, a phenomenon linked with
      epileptogenesis. We have investigated the functional consequences of an arginine
      to-glutamine mutation at position 43 within the GABA(A) gamma(2)-subunit found in
      a family with childhood absence epilepsy and febrile seizures. Rapid-application
      experiments performed on receptors expressed in HEK-293 cells demonstrated that
      the mutation slows GABA(A) receptor deactivation and increases the rate of
      desensitization, resulting in an accumulation of desensitized receptors during
      repeated, short applications. In Xenopus laevis oocytes, two-electrode voltage
      clamp analysis of steady-state currents obtained from alpha(1)beta(2)gamma(2) or
      alpha(1)beta(2)gamma(2)(R43Q) receptors did not reveal any differences in GABA
      sensitivity. However, differences in the benzodiazepine pharmacology of mutant
      receptors were apparent. Mutant receptors expressed in oocytes displayed reduced
      sensitivity to diazepam and flunitrazepam but not the imidazopyridine zolpidem.
      These results provide evidence of impaired GABA(A) receptor function that could
      decrease the efficacy of transmission at inhibitory synapses, possibly generating
      a hyperexcitable neuronal state in thalamocortical networks of epileptic patients
      possessing the mutant subunit.

PMID- 12415112
TI  - Multistage carcinogenesis and the incidence of colorectal cancer.
AB  - We use general multistage models to fit the age-specific incidence of colorectal
      cancers in the Surveillance, Epidemiology, and End Results registry, which covers
      approximately 10% of the U.S. population, while simultaneously adjusting for
      birth cohort and calendar year effects. The incidence of colorectal cancers in
      the Surveillance, Epidemiology, and End Results registry is most consistent with
      a model positing two rare events followed by a high-frequency event in the
      conversion of a normal stem cell into an initiated cell that expands clonally to
      give rise to an adenomatous polyp. Only one more rare event appears to be
      necessary for malignant transformation. The two rare events involved in
      initiation are interpreted to represent the homozygous loss of adenomatous
      polyposis coli gene function. The subsequent transition of a preinitiated stem
      cell into an initiated cell capable of clonal expansion via symmetric division is
      predicted to occur with a frequency too high for a mutational event but may
      reflect a positional effect in colonic crypts. Our results suggest it is not
      necessary to invoke genomic instability to explain colorectal cancer incidence
      rates in human populations. Temporal trends in the incidence of colon cancer
      appear to be dominated by calendar year effects. The model also predicts that
      interventions, such as administration of nonsteroidal anti-inflammatory drugs,
      designed to decrease the growth rate of adenomatous polyps, are very efficient at
      lowering colon cancer risk substantially, even when begun later in life. By
      contrast, interventions that decrease the rate of mutations at the adenomatous
      polyposis coli locus are much less effective in reducing the risk of colon
      cancer.

PMID- 12415114
TI  - Combining mapping and arraying: An approach to candidate gene identification.
AB  - A combination of quantitative trait locus (QTL) mapping and microarray analysis
      was developed and used to identify 34 candidate genes for ovariole number, a
      quantitative trait, in Drosophila melanogaster. Ovariole number is related to
      evolutionary fitness, which has been extensively studied, but for which few a
      priori candidate genes exist. A set of recombinant inbred lines were assayed for
      ovariole number, and QTL analyses for this trait identified 5,286 positional
      candidate loci. Forty deletions spanning the QTL were employed to further refine
      the map position of genes contributing to variation in this trait between
      parental lines, with six deficiencies showing significant effects and reducing
      the number of positional candidates to 548. Parental lines were then assayed for
      expression differences by using Affymetrix microarray technology, and ANOVA was
      used to identify differentially expressed genes in these deletions. Thirty-four
      genes were identified that showed evidence for differential expression between
      the parental lines, one of which was significant even after a conservative
      Bonferroni correction. The list of potential candidates includes 5 genes for
      which previous annotations did not exist, and therefore would have been unlikely
      choices for follow-up from mapping studies alone. The use of microarray
      technology in this context allows an efficient, objective, quantitative
      evaluation of genes in the QTL and has the potential to reduce the overall effort
      needed in identifying genes causally associated with quantitative traits of
      interest.

PMID- 12415113
TI  - Site-specific translocation and evidence of postnatal origin of the t(1;19) E2A
      PBX1 fusion in childhood acute lymphoblastic leukemia.
AB  - The t(1;19) translocation yields a fusion between E2A and PBX1 genes and occurs
      in 5% of acute lymphoblastic leukemia in children and adults. We used chromosomal
      translocations and Ig heavy chain (IGH)/T cell antigen receptor (TCR)
      rearrangements to develop an understanding of the etiology and natural history of
      this subtype of leukemia. We sequenced the genomic fusion between E2A and PBX1 in
      22 preB acute lymphoblastic leukemias and two cell lines. The prenatal origin of
      the leukemia was assessed in 15 pediatric patients by screening for the
      clonotypic E2A-PBX1 translocation in neonatal blood spots, or Guthrie cards,
      obtained from the children at the time of birth. Two patients were determined to
      be weakly positive for the fusion at the time of birth, in contrast to previously
      studied childhood leukemia fusions, t(12;21), t(8;21), and t(4;11), which were
      predominantly prenatal. The presence of extensive N-nucleotides at the point of
      fusion in the E2A-PBX1 translocation as well as specific characteristics of the
      IGH/TCR rearrangements provided additional evidence for a postnatal, preB cell
      origin. Intriguingly, 16 of 24 breakpoints on the 3.2-kb E2A intron 14 were
      located within 5 bp, providing evidence for a site-specific recombination
      mechanism. Breakpoints on the 232-kb PBX1 intron 1 were more dispersed but highly
      clustered proximal to exon 2. In sum, the translocation breakpoints displayed
      evidence of unique temporal, ontological, and mechanistic formation than the
      previously analyzed pediatric leukemia translocation breakpoints and emphasize
      the need to differentiate cytogenetic and molecular subgroups for studies of
      leukemia causality.

PMID- 12415115
TI  - Identification of E2A target genes in B lymphocyte development by using a gene
      tagging-based chromatin immunoprecipitation system.
AB  - The transcription factors encoded by the E2A gene are known to be essential for B
      lymphocyte development, and ectopic expression or gene inactivation studies have
      revealed several potential lineage-specific E2A target genes. However, it remains
      unknown whether these target genes are directly regulated by E2A at the
      transcriptional level. We therefore generated mice carrying an affinity-tagged
      E2A knock-in allele to provide a system for the direct elucidation of E2A target
      genes based on E2A binding to target regulatory regions. Abelson-transformed pre
      B cell lines derived from these mice were used in chromatin immunoprecipitation
      experiments to identify regulatory sequences bound by E2A in the context of an
      early B lymphocyte environment. Significant E2A binding was detected at the
      promoters and enhancers of several essential B-lineage genes, including the
      Igkappa intronic and 3' enhancers, lambda5 and VpreB surrogate light chain
      promoters, the EBF locus promoter region, and the mb-1 (Igalpha) promoter. Low
      levels of E2A binding were observed at several other lymphoid-restricted
      regulatory regions including the Ig heavy chain (IgH) intronic enhancer, the IgH
      3' enhancers hs3b/hs4, the RAG-2 enhancer, and the 5' regions of the B29 and TdT
      loci. An E2A target gene, the predicted butyrophilin-like gene NG9 (BTL-II), was
      also identified by using a chromatin immunoprecipitation-based cloning strategy.
      In summary, our studies have provided evidence that E2A is directly involved in
      the transcriptional regulation of a number of early B-lineage genes.

PMID- 12415116
TI  - Analysis of optimality in natural and perturbed metabolic networks.
AB  - An important goal of whole-cell computational modeling is to integrate detailed
      biochemical information with biological intuition to produce testable
      predictions. Based on the premise that prokaryotes such as Escherichia coli have
      maximized their growth performance along evolution, flux balance analysis (FBA)
      predicts metabolic flux distributions at steady state by using linear
      programming. Corroborating earlier results, we show that recent intracellular
      flux data for wild-type E. coli JM101 display excellent agreement with FBA
      predictions. Although the assumption of optimality for a wild-type bacterium is
      justifiable, the same argument may not be valid for genetically engineered
      knockouts or other bacterial strains that were not exposed to long-term
      evolutionary pressure. We address this point by introducing the method of
      minimization of metabolic adjustment (MOMA), whereby we test the hypothesis that
      knockout metabolic fluxes undergo a minimal redistribution with respect to the
      flux configuration of the wild type. MOMA employs quadratic programming to
      identify a point in flux space, which is closest to the wild-type point,
      compatibly with the gene deletion constraint. Comparing MOMA and FBA predictions
      to experimental flux data for E. coli pyruvate kinase mutant PB25, we find that
      MOMA displays a significantly higher correlation than FBA. Our method is further
      supported by experimental data for E. coli knockout growth rates. It can
      therefore be used for predicting the behavior of perturbed metabolic networks,
      whose growth performance is in general suboptimal. MOMA and its possible future
      extensions may be useful in understanding the evolutionary optimization of
      metabolism.

PMID- 12415117
TI  - Caspase activation and neuroprotection in caspase-3- deficient mice after in vivo
      cerebral ischemia and in vitro oxygen glucose deprivation.
AB  - Caspase-3 is a major cell death effector protease in the adult and neonatal
      nervous system. We found a greater number and higher density of cells in the
      cortex of caspase-3(-/-) adult mice, consistent with a defect in developmental
      cell death. Caspase-3(-/-) mice were also more resistant to ischemic stress both
      in vivo and in vitro. After 2 h of ischemia and 48 h of reperfusion, cortical
      infarct volume was reduced by 55%, and the density of terminal
      deoxynucleotidyltransferase-mediated dUTP nick end labeling-positive cells was
      decreased by 36% compared with wild type. When subjected to oxygen-glucose
      deprivation (2 h), cortical neurons cultured from mice deficient in caspase-3
      expression were also more resistant to cell death by 59%. Mutant brains showed
      caspase-specific poly(ADP-ribose) polymerase cleavage product (85-kDa fragment)
      in vivo and in vitro, suggesting redundant mechanisms and persistence of caspase
      mediated cell death. In the present study, we found that caspase-8 mediated
      poly(ADP-ribose) polymerase cleavage in caspase-3(-/-) neurons in vivo and in
      vitro. In addition, mutant neurons showed no evidence of compensatory activation
      by caspase-6 or caspase-7 after ischemia. Taken together, these data extend the
      pharmacological evidence supporting an important role for caspase-3 and caspase-8
      as cell death mediators in mammalian cortex and indicate the potential advantages
      of targeting more than a single caspase family member to treat ischemic cell
      injury.

PMID- 12415118
TI  - Time-lapse imaging of a dynamic phosphorylation-dependent protein-protein
      interaction in mammalian cells.
AB  - The ability to make sensitive measurements of protein-protein interaction
      kinetics in single neurons is critical for understanding the molecular and
      cellular basis of neuronal function. We have developed a reporter technology
      based on the differential induction of Escherichia coli TEM-1 beta-lactamase
      (Bla) enzymatic activity that can function as a sensor of the interaction state
      of two target proteins within single neurons in vivo. To modulate Bla enzymatic
      activity, we first split the enzyme into two separate, complementary protein
      fragments that we identified by using a functional screening approach based on
      circular permutation of the Bla enzyme. The split enzyme was then brought
      together by the phosphorylation-dependent association of the kinase inducible
      domain of the cAMP response element binding protein (CREB) and the KIX domain of
      the CREB binding protein. Using an intracellular substrate whose fluorescence
      spectrum changes after hydrolysis by Bla, we performed time-lapse ratiometric
      imaging measurements of Bla enzymatic induction after association of the CREB and
      CREB binding protein interaction domains. This approach permits direct imaging of
      protein-protein interactions in single cells with high signal discrimination.

PMID- 12415119
TI  - Down-regulation of parkin protein in transient focal cerebral ischemia: A link
      between stroke and degenerative disease?
AB  - Ubiquitylated protein aggregates are characteristic features of neurodegenerative
      disorders that are also found in acute pathological states of the brain such as
      stroke. Many of the proteins connected to neurodegenerative diseases play a role
      in the ubiquitin-proteasomal pathway. Mutation of one of these proteins, the E3
      ubiquitin ligase parkin, is the cause of autosomal recessive juvenile Parkinson's
      disease. Here we show that transient focal cerebral ischemia of 1-h duration
      induces marked depletion of parkin protein levels, to 60%, 36%, 33%, and 25% of
      controls after 1, 3, 6, and 24 h of reperfusion, but that ischemia does not cause
      lower protein levels of E2 ubiquitin-conjugating enzymes Ubc6, Ubc7, or Ubc9.
      After 3 h of reperfusion, when parkin protein levels were already reduced to <40%
      of control, ATP levels were almost completely recovered from ischemia and we did
      not observe DNA fragmentation, suggesting that parkin depletion preceded
      development of neuronal cell death. Up-regulation of the expression of parkin has
      been shown to protect cells from injury induced by endoplasmic reticulum (ER)
      dysfunction, and this form of cellular stress is also triggered by transient
      cerebral ischemia. However, in contrast to observations in neuroblastoma cells,
      we saw no up-regulation of parkin expression in primary neuronal cell cultures
      after induction of ER dysfunction. Our data thus suggest that ischemia-induced
      depletion of parkin protein may contribute to the pathological process resulting
      in cell injury by increasing the sensitivity of neurons to ER dysfunction and the
      aggregation of ubiquitylated proteins during the reperfusion period.

PMID- 12415121
TI  - Progress toward clinical application of the nitric oxide-releasing
      diazeniumdiolates.
AB  - Diazeniumdiolates, compounds of structure R(1)R(2)NN(O)=NOR(3), which have also
      been called NONOates, have proven useful for treating an increasing diversity of
      medical disorders in relevant animal models. Here, I review the chemical features
      that make them such excellent starting points for designing materials capable of
      targeting reliable and controllable fluxes of bioactive NO for in vitro and in
      vivo applications. This is followed by a consideration of recent proof-of-concept
      studies that underscore what I believe to be the substantial clinical promise of
      such materials. Examples covered include progress toward inhibiting restenosis
      after angioplasty, preparing thromboresistant medical devices, reversing
      vasospasm, and relieving pulmonary hypertension. Together with a very recent
      report describing the beneficial effects of diazeniumdiolate therapy in a patient
      with acute respiratory distress syndrome, the results of the animal experiments
      support the prediction that a broad selection of problems in clinical medicine
      can be solved by judiciously mining the enormous variety of possible
      R(1)R(2)NN(O)=NOR(3) structures.

PMID- 12415120
TI  - Reactivation of a complex retrovirus is controlled by a molecular switch and is
      inhibited by a viral protein.
AB  - Spumaviruses, commonly called foamy viruses (FV), are complex retroviruses that
      establish lifelong persistent infections without any accompanying pathologies. In
      tissue culture, cells can be either lytically or latently infected, depending on
      cell type. Regulation of FV replication is controlled by two promoters: the LTR
      and a second promoter within the env gene termed the internal promoter (IP). The
      IP directs expression of the transcriptional activator, Tas, and a second
      accessory protein, Bet, whose function has been elusive. In this study, we report
      that expression of exogenous Tas is sufficient to initiate a switch from latent
      to lytic replication. We also show that treatment with the phorbol ester phorbol
      12-myristate 13-acetate (PMA) can lead to an increase in transcription from the
      IP, and that Bet protein expression abrogates this effect. Finally, we
      demonstrate that Bet expression severely limits the ability of PMA to activate
      transcription of latent FV genomes, and that replication of a Bet(-) virus is
      more easily activated than wild-type FV. Taken together, these data suggest that
      viral transcription is regulated by a sensitive switch, and that Bet functions as
      a negative regulator of basal IP activity.

PMID- 12415122
TI  - The Caenorhabditis elegans dopaminergic system: opportunities for insights into
      dopamine transport and neurodegeneration.
AB  - The neurotransmitter dopamine (DA) plays a central role in the coordination of
      movement, attention, and the recognition of reward. Loss of DA from the basal
      ganglia, as a consequence of degeneration of neurons in the substantia nigra,
      triggers postural instability and Parkinson's disease (PD). DA transporters
      (DATs) regulate synaptic DA availability and provide a conduit for the uptake of
      DA mimetic neurotoxins, which can be used to evoke neuronal death and Parkinson
      like syndrome. Recently, we have explored the sensitivity of DA neurons in the
      nematode Caenorhabditis elegans to the Parkinsonian-inducing neurotoxin 6
      hydroxydopamine (6-OHDA) and found striking similarities, including DAT
      dependence, to neurodegeneration observed in mammalian models. In this review, we
      present our findings in the context of molecular and behavioral dimensions of DA
      signaling in C. elegans with an eye toward opportunities for uncovering DAT
      mutants, DAT regulators, and components of toxin-mediated cell death.

PMID- 12415123
TI  - The role of drug transporters at the blood-brain barrier.
AB  - The blood-brain barrier (BBB) is a dynamic interface between the blood and the
      brain. It eliminates (toxic) substances from the endothelial compartment and
      supplies the brain with nutrients and other (endogenous) compounds. It can be
      considered as an organ protecting the brain and regulating its homeostasis. Until
      now, many transport systems have been discovered that play an important role in
      maintaining BBB integrity and brain homeostasis. In this review, we focus on the
      role of carrier- and receptor-mediated transport systems (CMT, RMT) at the BBB.
      These include CMT systems, such as P-glycoprotein, multidrug-resistance proteins
      1-7, nucleoside transporters, organic anion transporters, and large amino-acid
      transporters; RMT systems, such as the transferrin-1 and -2 receptors; and the
      scavenger receptors SB-AI and SB-BI.

PMID- 12415124
TI  - Challenging dogma: thresholds for genotoxic carcinogens? The case of vinyl
      acetate.
AB  - Although many questions remain unanswered, the general principle of the sequence
      of events leading to cancer after exposure to genotoxic carcinogens has become
      increasingly clear. This helps to understand the parameters that influence the
      shape of the dose-effect curve for carcinogenesis, including metabolic activation
      and inactivation of carcinogens, DNA repair, cell cycle control, apoptosis, and
      control by the immune system. A linear dose-response relationship with no
      observable threshold seems to be a conservative but adequate description for the
      carcinogenic activity of many genotoxic carcinogens, such as aflatoxin B1, the
      tobacco-specific nitrosoketone NNK, and probably N,N-diethylnitrosamine. However,
      extrapolation models connecting the high-level risk to the zero intercept have
      clearly resulted in overestimations of risk. Vinyl acetate is an example that is
      discussed extensively in this review. At extremely high and toxic doses, vinyl
      acetate is carcinogenic in rats and mice and causes chromosomal aberrations. In
      tissues of contact, vinyl acetate is converted to acetic acid and acetaldehyde.
      Only when threshold levels are achieved do critical steps in the mechanism
      ultimately leading to cancer become active, namely pH reduction in exposed cells
      of more than 0.15 units leading to cytotoxicity, damage to DNA, and regenerative
      proliferation. Consistent with the known exposure to endogenous acetic acid and
      acetaldehyde, tissues sustain a certain level of exposure without adverse
      effects. Physiological modeling shows that the conditions necessary for
      carcinogenesis are in place only when threshold levels of vinyl acetate are
      exceeded. The example of vinyl acetate underlines the importance of toxicological
      research that unequivocally identifies genotoxic carcinogens acting through a
      threshold process.

PMID- 12415125
TI  - Alzheimer's disease: molecular understanding predicts amyloid-based therapeutics.
AB  - Degenerative diseases of the brain were long considered among the most obscure
      and intractable of human maladies. However, recent advances in understanding
      their mechanisms have brought us to the verge of potential disease-modifying
      agents. This progress is perhaps best exemplified by the case of Alzheimer's
      disease. The application of molecular pathology and genetics has led to the
      recognition that the four genes implicated to date in familial Alzheimer's
      disease all chronically elevate cerebral levels of the amyloid beta-protein
      (Abeta). Accordingly, small molecule inhibitors of the beta- and gamma
      secretases, the proteases that generate Abeta from its precursor, are under
      active development, and some have shown in vivo efficacy in mouse models. An
      alternative approach, active or passive immunization against Abeta, has received
      extensive pre-clinical validation in mice, but an effective preparation free of
      significant side effects in humans is still awaited. Several other potential
      therapies are also reviewed here. If one or more of these varied approaches is
      ultimately proven to slow or prevent dementia, Alzheimer's disease will become a
      salient example of the successful application of reductionist biology to the most
      complex of organs, the human cerebral cortex.

PMID- 12415128
TI  - The experience of dying: an ethnographic nursing home study.
AB  - PURPOSE: This article reviews the literature on "The Experience of Dying" and
      presents data from a larger, ongoing study of an ethnography of dying in nursing
      homes. The purpose of the ethnographic study was to investigate the process of
      providing end-of-life care to residents who were dying in nursing homes. DESIGN
      AND METHODS: Participant observation, in-depth interviews, and event analysis
      were used to obtain data in three nursing facilities. RESULTS: The review of the
      literature disclosed that research on the experience of dying is limited; most of
      the studies have been conducted in acute care hospitals among people who were
      dying of cancer. The ethnographic study found that lack of attention to cultural
      needs, cognitive status, inadequate staffing, and inappropriate and inadequate
      communication between health care providers and nursing home residents and their
      families were the predominant factors that influenced the experience of dying.
      IMPLICATIONS: Future research is needed on: The experience of dying for patients
      with dementia, for people in a comatose state, and for non-English speaking
      patients; symptom management; health care provider/patient-family interaction;
      the burden of caregiving for families; and the consequences of the constraints
      within our health care system for people who are dying in various settings.

PMID- 12415129
TI  - A commentary: the role of religion and spirituality at the end of life.

PMID- 12415130
TI  - A biopsychosocial-spiritual model for the care of patients at the end of life.
AB  - PURPOSE: This article presents a model for research and practice that expands on
      the biopsychosocial model to include the spiritual concerns of patients. DESIGNS
      AND METHODS: Literature review and philosophical inquiry were used. RESULTS: The
      healing professions should serve the needs of patients as whole persons. Persons
      can be considered beings-in-relationship, and illness can be considered a
      disruption in biological relationships that in turn affects all the other
      relational aspects of a person. Spirituality concerns a person's relationship
      with transcendence. Therefore, genuinely holistic health care must address the
      totality of the patient's relational existence-physical, psychological, social,
      and spiritual. The literature suggests that many patients would like health
      professionals to attend to their spiritual needs, but health professionals must
      be morally cautious and eschew proselytizing in any form. Four general domains
      for measuring various aspects of spirituality are distinguished: religiosity,
      religious coping and support, spiritual well-being, and spiritual need. A
      framework for understanding the interactions between these domains is presented.
      Available instruments are reviewed and critiqued. An agenda for research in the
      spiritual aspects of illness and care at the end of life is proposed.
      IMPLICATIONS: Spiritual concerns are important to many patients, particularly at
      the end of life. Much work remains to be done in understanding the spiritual
      aspects of patient care and how to address spirituality in research and practice.

PMID- 12415131
TI  - A commentary: hospital experience and meaning at the end of life.

PMID- 12415132
TI  - What is known about the economics of end-of-life care for medicare beneficiaries?
AB  - PURPOSE: This article reviews the state of science on the economics of end-of
      life care for Medicare beneficiaries and outlines the research needed to fill
      gaps in that literature. DESIGNS AND METHODS: Searches of the medical, health
      services, and economics literature were conducted. Key topics examined were
      studies of spending on end-of-life care and financial, organizational, and
      nonfinancial barriers to high-quality end-of-life care. RESULTS: Studies have
      documented poor quality of care, dissatisfaction with care, and limitations in
      the coverage of end-of-life care for Medicare beneficiaries. However, critical
      gaps in our knowledge about how to design a better end-of-life care system for
      Medicare beneficiaries remain. IMPLICATIONS: Further research on how treatment
      decisions at the end of life are made and prospective studies of costs,
      satisfaction, and outcomes are needed.

PMID- 12415133
TI  - A commentary: social and cultural determinants of end-of-life care for elderly
      persons.

PMID- 12415134
TI  - What impact do setting and transitions have on the quality of life at the end of
      life and the quality of the dying process?
AB  - PURPOSE: The aim of this article was to identify major research needs related to
      quality of life at the end of life and quality of the dying process for
      vulnerable older people at home, in assisted living facilities, in skilled
      nursing facilities, and in prisons. DESIGN AND METHODS: Review and analysis of
      the literature was used. RESULTS: The science is generally weak in relationship
      to what is known about quality of life at the end of life and quality of dying
      for vulnerable older adults in different settings. Few studies address actively
      dying patients and the reasons for transfers between home and other settings.
      Existing studies are primarily anecdotal, descriptive, have small samples, and
      involve a single setting. Participant decisional capacity is a barrier to
      conducting research in these settings. IMPLICATIONS: Research recommendations for
      each setting and across settings are provided. The National Institutes of Health
      should clarify criteria for enrollment of persons with diminished, fluctuating,
      and absent decisional capacity in research.

PMID- 12415135
TI  - A commentary: where to live while dying.

PMID- 12415136
TI  - Measurement of quality of care and quality of life at the end of life.
AB  - PURPOSE: Consumers and providers demand better indicators for quality of care and
      quality of life at the end of life. This article presents recommendations for
      advancing the science of measurement at end of life. DESIGN AND METHODS: The
      authors reviewed the extant literature and applied the Institute of Medicine's
      conceptual framework for national health care quality to end-of-life care and
      research. RESULTS: Ten recommendations were developed, charting a course for
      research that will improve the quality of care delivered and, consequently, the
      quality of life experienced at life's end. IMPLICATIONS: Measurement bridges the
      conceptual and operational levels of scientific research, clinical care, and
      quality improvement. Although a large amount of psychometric groundwork has been
      laid in the field of end-of-life research, the next wave of studies will ideally
      take measurement at end of life to a higher level of rigor and precision.

PMID- 12415137
TI  - A commentary: cross-cultural quality-of-life assessment at the end of life.

PMID- 12415138
TI  - Research design in end-of-life research: state of science.
AB  - PURPOSE: The volume of research on end-of-life care, death, and dying has
      exploded during the past decade. This article reviews the conceptual and
      methodological adequacy of end-of-life research to date, focusing on limitations
      of research to date and ways of improving future research. DESIGN AND METHODS: A
      systematic search was conducted to identify the base of end-of-life research.
      Approximately 400 empirical articles were identified and are the basis of this
      review. RESULTS: Although much has been learned from research to date,
      limitations in the knowledge base are substantial. The most fundamental problems
      identified are conceptual and include failure to define dying; neglect of the
      distinctions among quality of life, quality of death, and quality of end-of-life
      care. Methodologically, the single greatest problem is the lack of longitudinal
      studies that cover more than the time period immediately before death.
      IMPLICATIONS: Gaps in the research base include insufficient attention to
      psychological and spiritual issues, the prevalence of psychiatric disorder and
      the effectiveness of the treatment of such disorders among dying persons,
      provider and health system variables, social and cultural diversity, and the
      effects of comorbidity on trajectories of dying.

PMID- 12415139
TI  - Commentary on "Research Design in End-of-Life Research: State of Science".

PMID- 12415140
TI  - What's end of life got to do with it? Research ethics with populations at life's
      end.
AB  - PURPOSE: This study addressed key concerns that gave rise to the question of
      whether special guidelines were needed to monitor research at the end of life.
      DESIGN AND METHODS: Summary of established ethical and legal guidelines that
      govern the conduct of research with human subjects, with discussion of issues
      relevant to populations at life's end. Discussion of whether special guidelines
      are indicated focuses on four questions concerning: (a). time periods; (b).
      methods and approaches; (c). informed consent; and (d). obligations of
      researchers. RESULTS: Although research involving patients at end of life does
      present important ethical and moral challenges to researchers and should be
      scrutinized carefully by institutional review boards (IRBs), special guidelines
      are not required. IMPLICATIONS: Closer examination of the dimensions discussed
      will enhance the research endeavor and model the qualities for which end-of-life
      research should become known.

PMID- 12415141
TI  - A commentary-institutional review board approval and beyond: proactive steps to
      improve ethics and quality in end-of-life research.

PMID- 12415142
TI  - "Choice" in end-of-life decision making: researching fact or fiction?
AB  - PURPOSE: The contribution of bioethics to clinical care at the end of life (EOL)
      deserves critical scrutiny. We argue that researchers have rarely questioned the
      normative power of autonomy-based bioethics practices. Research on the ethical
      dimensions of EOL decision making has focused on an idealized discourse of
      patient "choice" that requires patients to embrace their dying to receive
      excellent palliative care. DESIGN AND METHODS: Our critique is based on a
      comprehensive review of empirical research exploring bioethics practices at the
      EOL. In addition we will provide a brief review of our own ethnographic,
      longitudinal study of the decision-making experience of dying patients, their
      families, and their health care providers. RESULTS: There is little or no
      empirical evidence to support the autonomy paradigm of patient "choice" in EOL
      decision making. What we found is that (a). prognostication at the EOL is
      problematic and resisted; (b). shared decision making is illusory, patients often
      resist advance care planning and hold other values more important than autonomy,
      and system characteristics are more determinative of EOL care than patient
      preferences; and (c). the incommensurability of medical and lay knowledge and
      values and the multifaceted and processual nature of patient and family decision
      making are at odds with the current EOL approach toward advance care planning.
      IMPLICATIONS: It is exceedingly difficult to identify, study, and critique
      normative assumptions without creating them, reproducing them, or obliterating
      them in the process. However, a fuller account of the morally significant domains
      of end-of-life care is needed. Researchers and policy makers should heed what we
      have learned from empirical research on EOL care to develop more sensitive and
      supportive programs for care of the dying.

PMID- 12415143
TI  - A commentary-putting autonomy in its place: developing effective guidelines.

PMID- 12415145
TI  - Implications of the tobacco industry documents for public health and policy.
AB  - The release of previously secret internal tobacco industry documents has given
      the public health community unprecedented insight into the industry's motives,
      strategies, tactics, and data. The documents provide information that is not
      available from any other source and describe the history of industry activities
      over the past 50 years. The documents show that the tobacco industry has been
      engaged in deceiving policy makers and the public for decades. This paper begins
      with a brief history of the tobacco industry documents and describes the
      methodological challenges related to locating and analyzing an enormous number of
      poorly indexed documents. It provides an overview of selected important findings
      of document research conducted to date, including analyses of industry documents
      on nicotine and addiction, product design, marketing and promotion, passive
      smoke, and internal activities. The paper concludes with a discussion of the
      implications of tobacco document research for public health and the application
      of such research to fields other than tobacco control.

PMID- 12415146
TI  - Will a healthy lifestyle help prevent Alzheimer's disease?
AB  - Alzheimer's disease (AD) appears to resemble other chronic diseases, whereby a
      myriad of interconnected factors, including those associated with lifestyle, are
      involved in disease development. In this paper, we examine accepted and proposed
      risk factors for AD and explore health behaviors, including diet, exercise,
      prevention of injury, and cognitive stimulation, that may help prevent AD.
      Adherence to a healthy lifestyle may directly protect against AD or may prevent
      diseases associated with AD, such as vascular disease and diabetes. A healthy
      lifestyle to prevent AD may be important throughout life rather than after
      disease manifestation and may be particularly relevant if other factors, such as
      genetic predisposition, also increase risk of AD. If changes in lifestyle can
      help prevent AD by reducing modifiable risk factors, this knowledge can aid
      individuals who wish to take action to protect themselves and their families from
      the disease.

PMID- 12415147
TI  - Management of chronic disease by patients.
AB  - Chronic conditions dominate health care in most parts of the world, including the
      United States. Management of a disease by the patient is central to control of
      its effects. A wide range of influences in the person's social and physical
      environments enhance or impede management efforts. Interventions to improve
      management by patients can produce positive outcomes including better monitoring
      of a condition, fewer symptoms, enhanced physical and psychosocial functioning,
      and reduced health care use. Successful programs have been theory based. Self
      regulation is a promising framework for the development of interventions.
      Nonetheless, serious gaps in understanding and improving disease management by
      patients remain because of an emphasis on clinical settings for program delivery,
      neglect of the factors beyond patient behavior that enable or deter effective
      management, limitations of study designs in much work to date, reliance on short
      term rather than long-term assessments, and failure to evaluate the independent
      contribution of various program components.

PMID- 12415148
TI  - The iron phosphate NaZnFe2 PO43.
AB  - Crystals of sodium zinc diiron(III) triphosphate, NaZnFe(2)(PO(4))(3), have been
      synthesized and structurally characterized by single-crystal X-ray diffraction.
      The compound features a new structural type built up from ZnO(6) octahedra,
      FeO(6) octahedra and FeO(4) tetrahedra, linked together via the corners and edges
      of PO(4) tetrahedra to form a three-dimensional framework, with tunnels running
      along [100]. Within these tunnels, Na(+) cations occupy a highly distorted cubic
      site.

PMID- 12415149
TI  - Nonasodium decatungstodysprosate pentatriacontahydrate.
AB  - In the crystal structure of the title compound, Na(9)[Dy(W(5)O(18))(2)].35H(2)O,
      the complex anion has approximate D(4d) symmetry, with Dy-O and W-O distances in
      the ranges 2.355 (6)-2.405 (6) and 1.715 (7)-2.369 (5) A, respectively.

PMID- 12415150
TI  - Zn location in the W-type hexagonal ferrite SrZnCoFe16O27.
AB  - The title compound, SrZnCoFe(16)O(27) (ZnCo-W), strontium zinc cobalt
      hexadecairon oxide, crystallizes in space group P6(3)/mmc, with the Sr atom at a
      site with -6 m 2 symmetry and Zn(2+) located at two tetrahedral sites (4e and 4f,
      each with 3m symmetry) of the spinel blocks. The Zn occupancy is 36% on equipoint
      4e and 14% on 4f. The enrichment of diamagnetic ions on one of seven sublattices
      is thought to be responsible for the high temperature dependence of the
      saturation magnetization.

PMID- 12415151
TI  - The intermetallic compound Mg21Zn25.
AB  - The crystal structure of the intermetallic compound henicosamagnesium
      pentacosazinc, Mg(21)Zn(25), has been determined by single-crystal X-ray
      diffraction. It is isomorphous with Zr(21)Re(25) and deviates slightly from the
      rules that define the Frank-Kasper phases.

PMID- 12415152
TI  - The iron phosphate K3Fe5 PO4 6.
AB  - The crystal structure of tripotassium pentairon hexaphosphate has been determined
      by single-crystal X-ray diffraction. The structure contains one Fe atom on a
      center of symmetry, one K, two Fe and two P atoms on twofold axes, and one Fe,
      two P and one K atom in general positions. The K(3)Fe(5)(PO(4))(6) structure
      consists of a complex three-dimensional framework of corner-sharing between iron
      polyhedra, and corner- and edge-sharing between PO(4) tetrahedra and iron
      polyhedra (FeO(5) and FeO(6)). This linkage between iron and phosphorus forms
      intersecting channels containing the K atoms.

PMID- 12415153
TI  - LiNa2AlF6: a powder structure solution.
AB  - Lithium sodium aluminium fluoride was obtained as a white powder by melting a
      stoichiometric mixture of AlF(3), NaF and LiF at 1223 K, and then cooling to 923
      K and sintering at this temperature for 4 h. The ab initio crystal structure
      determination was carried out using X-ray powder diffraction techniques. The
      monoclinic structure of LiNa(2)AlF(6) can be related to cubic elpasolite. The Li
      and Al atoms lie on inversion centres. The main octahedral AlF(6) structural
      elements are not deformed, but are rotated slightly with respect to the unit-cell
      axes. The Li atoms have octahedral coordinations, whereas the Na atoms have cubo
      octahedral coordinations. The Na coordination polyhedron is distorted in
      comparison with that of elpasolite.

PMID- 12415154
TI  - Dichloro[N-[3-(eta5-cyclopentadienyl)propyl]-4-toluenesulfonamido
      kappa2N,O]titanium(IV).
AB  - The title compound, [Ti(C(15)H(17)NO(2)S)Cl(2)], has a Ti atom bound to the N and
      O atoms of a p-toluenesulfonamide ligand, which is tethered by a three-carbon
      chain to a eta(5)-cyclopentadienyl group. The distorted square-pyramidal geometry
      is completed by two Cl atoms. The Ti-N bond length of 2.0375 (13) A is longer
      than that in related compounds, the N atom having asymmetric trigonal-planar
      geometry. Conformational strain relief is noted when compared with ethyl-tethered
      compounds.

PMID- 12415155
TI  - A ternary complex of aqua(18-crown-6)bis(o-nitrophenolato)barium(II), the
      triaqua(18-crown-6)(o-nitrophenolato)barium(II) cation and the o-nitrophenolate
      anion.
AB  - In the title compound [systematic name: triaqua(1,4,7,10,13,16
      hexaoxacyclooctadecane-kappa(6)O)(2-nitrophenolato-kappaO)barium(II)
      aqua(1,4,7,10,13,16-hexaoxacyclooctadecane-kappa(6)O)bis(2-nitrophenolato
      kappa(2)O,O')barium(II)-2-nitrophenolate (1/1/1)],
      [Ba(C(12)H(24)O(6))(C(6)H(4)NO(3))(H(2)O)(3)][Ba(C(12)H(24)O(6))(C(6)H(4)NO(3))(2
      (H(2)O)](C(6)H(4)NO(3)), the two Ba(II) atoms encapsulated by the 18-crown-6
      rings have different coordinations. Although both Ba(II) atoms are coordinated to
      the six O atoms of the crowns, in the neutral moiety, the Ba(II) atom is
      coordinated to one terminal O atom from a water molecule, two phenolate O atoms
      and two nitro-group O atoms, while in the cationic moiety, the Ba(II) atom is
      coordinated to three terminal O atoms from water molecules and one phenolate O
      atom. Both the crowns are eclipsed and translated along the b direction. In the
      asymmetric unit, the three components are interconnected by four O-H.O
      interactions. The packing is stabilized by two intermolecular C-H.O interactions
      and by one O-H.O interaction.

PMID- 12415156
TI  - Di-mu-sulfido-bis[diaqua(18-crown-6)barium(II)]-saccharin (1/2).
AB  - The molecule of the title compound [systematic name: di-mu-sulfido
      bis[diaqua(1,4,7,10,13,16-hexaoxacyclooctadecane-kappa(6)O)barium(II)] bis[1,2
      benzisothiazol-3(2H)-one 1,1-dioxide]],
      [Ba(2)S(2)(C(12)H(24)O(6))(2)(H(2)O)(4)](C(7)H(5)NO(3)S)(2), lies on an inversion
      centre. The Ba(II) atom encapsulated by the 18-crown-6 ring is coordinated by the
      six O atoms of the crown, two water O atoms and two bridging S atoms. The four
      membered ring composed of the Ba(II) atoms and the bridging S atoms makes a
      dihedral angle of 67.1 (1) degrees with the crown-ether ring. The aromatic ring
      system of the saccharin moiety is essentially planar. The packing is built up
      from layers of the molecules and is stabilized by three intermolecular O-H.O
      hydrogen bonds.

PMID- 12415157
TI  - The new thioantimonate(V) (C3H10N)[NiSbS4(C6H18N4)].
AB  - Turquoise crystals of the title salt, propylammonium di-mu-thio-1:2 kappa(4)S
      dithio-2 kappa(2)S-tris(2-aminoethyl)amine-1 kappa(4)N-antimony(V)nickel(II),
      (C(3)H(10)N)[NiSbS(4)(C(6)H(18)N(4))] or [PAH][Ni(tren)SbS(4)] [where tren is
      tris(2-aminoethyl)amine and PA is propylamine], were synthesized under
      solvothermal conditions by reacting [Ni(tren)(2)]Cl(2), Sb and S in a solution of
      PA. The Ni(II) ion is octahedrally surrounded by four N atoms of the tetradentate
      tren molecule and by two S atoms of the tetrahedral [Sb(V)S(4)](3-) anion, thus
      forming the anionic [Ni(tren)SbS(4)](-) part of the compound. Charge balance is
      achieved through the PAH(+) cation. An extended intermolecular hydrogen-bonding
      network is observed between the anion and the cation.

PMID- 12415158
TI  - Bis[trans-dibromo(2,2-dimethylpropane-1,3-diamine-kappa2N,N')chromium(III)]
      dibromide hydrogen perchlorate hexahydrate.
AB  - In the title compound, [CrBr(2)(C(5)H(14)N(2))(2)](2)Br(2).HClO(4).6H(2)O, there
      are two independent Cr(III) complex cations which are conformational isomers of
      each other. The Cr atoms lie respectively on a center of symmetry and on a mirror
      plane and have octahedral environments, coordinated by the N atoms of two 2,2
      dimethylpropane-1,3-diamine ligands and by two Br atoms in trans positions. The
      Cr-N and Cr-Br bond lengths are in the ranges 2.078 (3)-2.089 (3) and 2.4495 (9)
      2.5017 (9) A, respectively. The crystal structure consists of two Cr(III) complex
      cations, two Br(-) anions, a (ClO(4))(-) anion and an [H(13)O(6)](+) hydrogen
      bonded cluster cation.

PMID- 12415159
TI  - (Acetonitrile)[2,6-bis(pyrazol-1-yl)pyridine](isonicotinamide)copper(II)
      tetrafluoroborate-acetonitrile (1/2/2).
AB  - Molecules of the title compound,
      [Cu(C(2)H(3)N)(C(11)H(9)N(5))(C(6)H(6)N(2)O)](BF(4))(2).2C(2)H(3)N, comprise
      (acetonitrile)[2,6-bis(pyrazol-1-yl)pyridine](isonicotinamide)copper(II) cations,
      tetrafluoroborate anions and lattice acetonitrile molecules. The cations have
      distorted square-pyramidal geometries in which the N(3)-donor, viz. 2,6
      bis(pyrazol-1-yl)pyridine, and the N-donor, viz. the isonicotinamide ligand,
      occupy the four basal positions, with the coordinated acetonitrile N-donor atom
      occupying the apical position. Pairs of cations are linked by N-H.F hydrogen
      bonds through tetrafluoroborate anions, forming centrosymmetric dimers, which are
      further linked by C-H.O hydrogen bonds into two-dimensional undulating sheets,
      three of which interpenetrate to generate a two-dimensional network.

PMID- 12415160
TI  - (R)-Di-mu-acetato-kappa 2 O:O'-bis[[2-(1-aminoethyl)phenyl-kappa 2
      C1,N]palladium(II)], (R)-di-mu-chloro-bis[[2-(1-aminoethyl)phenyl-kappa 2
      C1,N]palladium(II)] and [SP-4-4]-(R)-[2-(1-aminoethyl)phenyl-kappa 2
      C1,N]chloro(pyridine-kappa N)palladium(II).
AB  - The title complexes, [Pd(2)(C(8)H(10)N)(2)(C(2)H(3)O(2))(2)], (I),
      [Pd(2)(C(8)H(10)N)(2)Cl(2)], (II), and [Pd(C(8)H(10)N)Cl(C(5)H(5)N)], (III),
      respectively, have been prepared as intermediates and the final product of a
      cyclopalladation reaction sequence, and their structures studied by single
      crystal X-ray diffraction. Complexes (I) and (II) represent the first
      structurally characterized dinuclear cyclopalladation products of primary amines.
      For (I) and (III), pseudosymmetry relates two independent molecules in the
      asymmetric unit.

PMID- 12415161
TI  - Aqua(phthalocyaninato)magnesium.
AB  - The title compound, [Mg(C(32)H(16)N(8))(H(2)O)], crystallizes with two
      MgPc(H(2)O) molecules (Pc is phthalocyaninate) in the asymmetric unit. The
      geometries of the two molecules are very similar, with the Mg atoms each 4+1
      coordinated by four isoindole N atoms at the base and by the O atom of the water
      molecule. The Mg atoms are displaced by 0.447 (1) and 0.468 (1) A from the basal
      coordination planes towards the water O atoms. O-H.N hydrogen bonds form dimers
      stacked along the b axis in a herring-bone fashion.

PMID- 12415162
TI  - A new optically pure half-sandwich Cp-Ru diphosphine complex with a chiral metal
      centre, (S)-Ru(eta 5-C5H5)(EPHOS)Cl [EPHOS is (+)-(1R,2S)-2
      [(diphenylphosphino)methylamino]-1-phenylpropyl diphenylphosphinite].
AB  - The crystal structure of the title compound, chloro(eta(5)
      cyclopentadienyl)[(1R,2S)-2-[(diphenylphosphino)methylamino]-1-phenylpropyl
      diphenylphosphinite-kappa(2)P,P']ruthenium(II),
      [Ru(C(5)H(5))Cl(C(34)H(33)NOP(2))], is reported. The pseudo-octahedral complex is
      chiral and the configuration at the Ru atom is S. The seven-membered metallacycle
      adopts a boat-like conformation.

PMID- 12415163
TI  - Aqua(dipicolinato-kappa 3 O2,N,O6)(1,10-phenanthroline-kappa 2N,N')manganese(II)
      monohydrate.
AB  - In the title compound [systematic name: aqua(1,10-phenanthroline
      kappa(2)N,N')(pyridine-2,6-dicarboxylato-kappa(3)O(2),N,O(6))manganese(II)
      monohydrate, [Mn(C(7)H(3)NO(4))(C(12)H(8)N(2))(H(2)O)].H(2)O, the manganese(II)
      centre is surrounded by one bidentate phenanthroline ligand [Mn-N = 2.248 (3) and
      2.278 (3) A], one tridentate dipicolinate ligand [Mn-N = 2.179 (3) A, and Mn-O =
      2.237 (2) and 2.266 (2) A] and one water molecule [Mn-O = 2.117 (3) A], and it
      exhibits a strongly distorted octahedral geometry, with trans angles ranging from
      144.12 (9) to 158.88 (11) degrees. Extensive intermolecular hydrogen-bonding
      interactions involving coordinated and uncoordinated water molecules and the
      carboxyl O atoms of the dipicolinate ligand, as well as a stacking interaction
      involving the phenanthroline rings, are observed in the crystal structure.

PMID- 12415164
TI  - Dihydro[2.2.2]cryptand di-mu-hydroxo-bis[bis(nitrato-kappa
      2O,O')dioxouranium(VI)] monohydrate.
AB  - In the title dinuclear uranyl complex,
      (C(18)H(38)N(2)O(6))[(UO(2))(2)(NO(3))(4)(OH)(2)].H(2)O, each pair of uranyl ions
      in the two independent centrosymmetric dianionic dimers is bridged by the two
      hydroxide ions, with the nitrate ions ensuring equatorial hexagonal coordination.
      The dihydro[2.2.2]cryptand (4,7,13,16,21,24-hexaoxa-1,10
      diazabicyclo[8.8.8]hexacosane) dication presents an 'in-in' conformation (endo
      protonation) and it is hydrogen bonded to the hydroxide ions, either directly or
      via a water molecule, resulting in the formation of linear hydrogen-bonded
      polymers.

PMID- 12415165
TI  - Derivatives of substituted 3-trichlorogermylpropionic acid.
AB  - The central Ge atoms in the structures of 3-(2-fluorophenyl)-3
      (triphenylgermyl)propionic acid, [Ge(C(6)H(5))(3)(C(9)H(8)FO(2))], 3-(2-tolyl)-3
      (tri-4-tolylgermyl)propionic acid, [Ge(C(7)H(7))(3)(C(10)H(11)O(2))], and 3-(4
      tolyl)-3-(tribenzylgermyl)propionic acid, [Ge(C(7)H(7))(3)(C(10)H(11)O(2))], are
      four-coordinate with slightly distorted tetrahedral geometry. The Ge-Csp(3)
      distances [1.970 (3)-1.997 (3) A] are significantly longer than the Ge
      C(aromatic) distances [1.940 (3)-1.959 (2) A]. In all three structures, the
      molecules form dimeric pairs about inversion centres through strong hydrogen
      bonding interactions between carboxylic acid groups.

PMID- 12415166
TI  - O- and m-Benzenedicarbaldehyde.
AB  - o-Benzenedicarbaldehyde (systematic name: benzene-1,2-dicarbaldehyde),
      C(8)H(6)O(2), exhibits a weak intramolecular hydrogen bond between an aldehyde H
      atom and the O atom of the adjacent aldehyde group, with a C.O distance of 2.852
      (2) A. m-Benzenedicarbaldehyde (systematic name: benzene-1,3-dicarbaldehyde),
      C(8)H(6)O(2), occurs as two different isomorphs. In all three crystals, there are
      intermolecular C-H.O contacts involving both aldehyde and ring H atoms.

PMID- 12415168
TI  - 1-(2-Pyridyl) ethan-1-one 8-quinolylhydrazone and 1-(1H-pyrrol-2-yl) ethan-1-one
      8-quinolylhydrazone.
AB  - The structures of the title compounds, C(16)H(14)N(4), (I), and C(15)H(14)N(4),
      (II), respectively, have been determined, and their molecular packing
      arrangements compared. Both are essentially flat molecules, with respective
      dihedral angles between the quinoline and heterocyclic rings of 19.0 (1) and 8.5
      (2) degrees. The pyridyl derivative, (I), packs in a P2(1)/c unit cell, while in
      the pyrrolyl compound, (II), the molecules pack in Pca2(1) and form a crinkled
      ribbon arrangement through the association of pyrrole NH groups with the
      quinoline N atoms.

PMID- 12415167
TI  - 3,6-Di(thiophen-2-yl)pyridazine.
AB  - Molecules of the title compound, C(12)H(8)N(2)S(2), which are effectively planar,
      have all four heteroatoms on the same side but do not have twofold symmetry.

PMID- 12415169
TI  - Structural motifs in acetoacetanilides: the effect of a fluorine substituent.
AB  - The structures of three fluoro-substituted acetoacetanilides, namely 2'-, 3'- and
      4'-fluoroacetoacetanilide, all C(10)H(10)FNO(2), are presented and discussed. We
      observe a planar structure with intramolecular hydrogen bonding when the F atom
      is in the ortho position of the aromatic ring, and a twisted structure with
      intermolecular hydrogen bonding when the F atom is in the meta or para positions.
      It can be predicted which of these two structural motifs will be adopted by
      considering the position of any aromatic substituents. In this regard, fluorine
      appears to mimic the steric effect of a larger substituent, which we attribute to
      its high electronegativity.

PMID- 12415170
TI  - (+/-)-6-tert-butyl-8-hydroxymethyl-2-phenyl-4H-1,3-benzodioxin and 2,2,2',2',6,6'
      hexamethyl-8,8'-methylenebis(4H-1,3-benzodioxin).
AB  - Two compounds containing 1,3-benzodioxin groups are reported, namely (+/-)-6-tert
      butyl-8-hydroxymethyl-2-phenyl-4H-1,3-benzodioxin, C(19)H(22)O(3), (I), and
      2,2,2',2',6,6'-hexamethyl-8,8'-methylenebis(4H-1,3-benzodioxin), C(23)H(28)O(4),
      (II). The hydroxy groups of neighbouring molecules in (I) are hydrogen bonded to
      each other, giving rise to double-row chains. The molecule in (II) adopts a
      'butterfly' conformation, with the O atoms in distal positions. In both
      compounds, the dioxin rings are in distorted half-chair conformations.

PMID- 12415171
TI  - Di-2-pyridyl ketone N4,N4-(butane-1,4-diyl)thiosemicarbazone.
AB  - The title compound, C(16)H(17)N(5)S, is in the thione form and crystallizes with
      two independent molecules in the asymmetric unit. In both molecules, the
      pentamethyleneimine five-membered ring adopts an envelope conformation, and in
      one of the molecules this ring shows positional disorder. The thione S and
      hydrazine N atoms are in the Z configuration with respect to the C-N bond.

PMID- 12415172
TI  - 2-Amino-4,6-dimethoxy-5-nitrosopyrimidine-water (4/3): seven independent
      molecular components are linked into a three-dimensional framework by six three
      centre and eight two-centre hydrogen bonds.
AB  - In the title compound, 4C(6)H(8)N(4)O(3).3H(2)O, the pyrimidine molecules all
      exhibit a polarized molecular electronic structure; the seven-component
      asymmetric unit can be selected as a closed cyclic aggregate and the linking of
      these aggregates can be analysed in terms of translational chain motifs running
      parallel to [110], [210] and [011], which combine to generate a single three
      dimensional framework.

PMID- 12415173
TI  - Glycinium trifluoroacetate.
AB  - In the title compound, C(2)H(6)NO(2)(+).C(2)F(3)O(2)(-), the main N-C-COOH
      skeleton of the glycinium cation is almost perfectly planar. The trifluoroacetate
      anion has a staggered conformation with typical bond distances and angles. The
      CF(3) group is slightly disordered. The structure is stabilized by an extensive
      network of strong O-H.O hydrogen bonds and weaker N-H.O bonds.

PMID- 12415174
TI  - (S)-trans-cyclohexane-1,2-dicarboximide.
AB  - The molecule of the title compound, C(8)H(11)NO(2), contains a strained bicyclic
      system with a significantly twisted imide chromophore. The five-membered ring
      fragment containing the imide function is strongly puckered and adopts a half
      chair conformation. The six-membered ring has a slightly distorted chair
      conformation. The molecules are joined by strong N-H.O and weak C-H.O hydrogen
      bonds into infinite chains.

PMID- 12415175
TI  - Hydrogen-bonded 1,2-bis(4-pyridyl)ethylene and maleic acid.
AB  - The title compound (systematic name: 4,4'-ethylenedipyridinium dimaleate),
      C(12)H(12)N(2)(2+).2C(4)H(3)O(4)(-), is a 1:2 adduct of 1,2-bis(4
      pyridyl)ethylene (BPE) and maleic acid (MA). The interaction between the two
      components in the molecular complex is due to intermolecular hydrogen bonding via
      an N(+)-H.O(-) hydrogen bond.

PMID- 12415176
TI  - Secondary interactions in N-(chloromethyl)pyridinium chlorides (n = 2, 3, 4).
AB  - In the isomeric title compounds, viz. 2-, 3- and 4-(chloromethyl)pyridinium
      chloride, C(6)H(7)ClN(+).Cl(-), the secondary interactions have been established
      as follows. Classical N-H.Cl(-) hydrogen bonds are observed in the 2- and 3
      isomers, whereas the 4-isomer forms inversion-symmetric N-H(.Cl(-).)(2)H-N dimers
      involving three-centre hydrogen bonds. Short Cl.Cl contacts are formed in both
      the 2-isomer (C-Cl.Cl(-), approximately linear at the central Cl) and the 4
      isomer (C-Cl.Cl-C, angles at Cl of ca 75 degrees ). Additionally, each compound
      displays contacts of the form C-H.Cl, mainly to the Cl(-) anion. The net effect
      is to create either a layer structure (3-isomer) or a three-dimensional packing
      with easily identifiable layer substructures (2- and 4-isomers).

PMID- 12415177
TI  - 10-Methyl- and 9,10-dimethylacridinium methyl sulfate.
AB  - The title compounds, C(14)H(12)N(+).CH(3)O(4)S(-), (I), and
      C(15)H(14)N(+).CH(3)O(4)S(-), (II), respectively, crystallize with the planar 10
      methylacridinium or 9,10-dimethylacridinium cations arranged in layers, parallel
      to the twofold axis in (I) and perpendicular to the 2(1) axis in (II). Adjacent
      cations in both compounds are packed in a 'head-to-tail' manner. The methyl
      sulfate anion only exhibits planar symmetry in (II). The cations and anions are
      linked through C-H.O interactions involving three O atoms of the anion, six
      acridine H atoms and the CH(3) group on the N atom in (I), and the four O atoms
      of the anion, three acridine H atoms and the carbon-bound CH(3) group in (II).
      The methyl sulfate anions are oriented differently in the two compounds relative
      to the cations, being nearly perpendicular in (I) but parallel in (II).
      Electrostatic interaction between the ions and the network of C-H.O interactions
      leads to relatively compact crystal lattices in both structures.

PMID- 12415178
TI  - Neutron powder-profile study of chlorofluoromethane.
AB  - The crystal structure of chlorofluoromethane, CH(2)ClF, has been determined at
      100 and 30 K using indexing, packing considerations and Rietveld refinement of
      neutron powder profiles. There is only one phase, in monoclinic space group P2(1)
      and with two molecules in the unit cell occupying general positions. The
      structure has close packing in several directions and there are weak hydrogen
      bonds forming zigzag chains.

PMID- 12415179
TI  - Hexamethylenetetramine-4-nitrocatechol-water (1/2/1).
AB  - In the title adduct, 1,3,5,7-tetraazatricyclo[3.3.1.1(3,7)]decane-4-nitrobenzene
      1,2-diol-water (1/2/1), C(6)H(12)N(4).2C(6)H(5)NO(4).H(2)O, the
      hexamethylenetetramine molecule acts as an acceptor of intermolecular O-H.N
      hydrogen-bonding interactions from the water molecule and the hydroxy groups of
      one of the two symmetry-independent 4-nitrocatechol molecules. The structure is
      built from molecular layers which are stabilized by three intermolecular O-H.O,
      two intermolecular O-H.N and four intermolecular C-H.O hydrogen bonds. The layers
      are further interconnected by one additional intermolecular O-H.N and two
      intermolecular C-H.O hydrogen bonds.

PMID- 12415180
TI  - 9,9-Dimethoxy-7,11-diphenyl-2,4-diazaspiro[5.5]undecane-1,3,5-trione monohydrate.
AB  - Due to steric repulsions, the cyclohexane ring in the title compound,
      C(23)H(24)N(2)O(5).H(2)O, shows some bond-length abnormalities and adopts a chair
      conformation. The pyrimidine and cyclohexane rings are approximately
      perpendicular to each other, and the phenyl rings are equatorial. C-H.pi and N
      H.O intermolecular interactions, as well as C-H.O inter- and intramolecular
      interactions, occur between the molecules. In addition to van der Waals
      interactions, the water molecule interacts with the pyrimidinetrione ring to
      stabilize the structure.

PMID- 12415181
TI  - 2',3'-Dehydrosalannol.
AB  - The title compound, methyl (2aS,3R,5R,5aS,6S,6aS,8R,9aS,10aR,10bR,10cS)-8-(3
      furyl)-2a,4,5,5a,6,6a,8,9,9a,10a,10b,10c-dodecahydro-3-hydroxy-2a,5a,6a,7
      tetramethyl-5-(3-methylbut-2-enoyloxy)-2H,3H
      cyclopenta[4',5']furo[2',3':6,5]benzo[cd]isobenzofuran-6-acetate, C(32)H(42)O(8),
      was isolated from uncrushed green leaves of Azadirachta indica A. Juss (neem) and
      has been found to possess antifeedant activity against Spodptera litura. The
      conformations of the functional groups are similar to those of 3
      desacetylsalannin, which was isolated from neem kernels. The molecules are linked
      into chains by intermolecular O-H.O hydrogen bonds.

PMID- 12415182
TI  - A new polymorph of cis-transoid-cis-dicyclohexano-18-crown-6.
AB  - A new orthorhombic polymorphic modification of the title compound (alternative
      name: cis-transoid-cis-2,5,8,15,18,21-hexaoxatricyclo[20.4.0.0(9,14)]hexacosane),
      C(20)H(36)O(6), has been found and is compared with the previously known
      monoclinic modification. In the structures of the two polymorphs, the crown-ether
      molecules are centrosymmetric and reveal essentially the same molecular shape but
      different packing motifs.

PMID- 12415183
TI  - Hydrogen-bonding and C-H...pi interactions in ethyl 4-acetyl-5-methyl-3-phenyl-1H
      pyrrole-2-carboxylate monohydrate.
AB  - In the title compound, C(16)H(17)NO(3).H(2)O, the pyrrole ring is distorted
      slightly from ideal C(2v) symmetry. Three strong hydrogen bonds link the
      substituted pyrrole and water molecules to form infinite chains, in which the
      hydrogen bonds form rings and chain patterns. Two intermolecular C-H.pi
      interactions maintain the internal cohesion between these chains. The molecular
      structure differs slightly from that of the isolated molecule calculated by ab
      initio quantum-mechanical calculations. In the latter model, the non-H
      substituent atoms share the plane of the pyrrole ring, except for the phenyl
      group, which lies almost perpendicular to this plane.

PMID- 12415184
TI  - 7-Methoxy-1H-indazole, a new inhibitor of neuronal nitric oxide synthase.
AB  - The crystal structure of 7-methoxy-1H-indazole, C(8)H(8)N(2)O, an inhibitor of
      nitric oxide synthase, shows that the methoxy group lies in the plane of the
      indazole system with its methyl group located trans to the indazole N-H group.
      The crystal packing consists principally of hydrogen-bonded trimers.
      Intermolecular hydrogen-bonding interactions are formed between the indazole N
      atoms, with the N-H group as a hydrogen-bond donor and the remaining N atom as an
      acceptor.

PMID- 12415185
TI  - 2-Aminopyridinium-succinate-succinic acid (2/1/1).
AB  - In the title compound, 2C(5)H(7)N(2)(+).C(4)H(4)O(4)(2-).C(4)H(6)O(4), cyclic
      eight-membered hydrogen-bonded rings exist involving 2-aminopyridinium and
      succinate ions. The succinic acid and succinate moieties lie on inversion
      centres. Succinic acid molecules and succinate ions are linked into zigzag chains
      by O-H.O hydrogen bonds, with O.O distances of 2.6005 (16) A.

PMID- 12415186
TI  - Alterations of cell cycle-regulatory genes in prostate cancer.
AB  - Deregulated proliferation is one of the main events in neoplastic transformation,
      and this has prompted increased attention being given to the understanding of the
      mechanisms involved in cell cycle regulation and its alterations. The
      'retinoblastoma pathway', a key effector controlling G1-S phase transition,
      includes several oncogenes and tumour suppressor genes which display a wide range
      of abnormalities with potential usefulness as markers of evolution or treatment
      response in prostate cancer. Among these, the existence of p53 mutations seems to
      predict resistance to radiotherapy or systemic treatment, and p16 overexpression
      or p27 downregulation seems to serve as markers of poor evolution. The well
      established existence of a critical hormonal role in prostate carcinogenesis
      coupled with the relationship of androgenic activity and regulation of several
      cell cycle modulators forces cell cycle control in the prostate to be envisioned
      as a highly complex steroid-influenced system, which will undoubtedly have
      critical implications in the future management of prostate cancer patients.

PMID- 12415187
TI  - Expression of CD34 in pulmonary endothelial cells in vivo.
AB  - OBJECTIVES: The morphological phenotype of endothelial cells (EC) is specific for
      individual types of vessels. There are, however, no studies on the phenotypical
      diversity of EC in human lung tissue. The influences exerted by physiological
      factors (e.g. age, sex) or pathological factors (e.g. pulmonary hypertension) on
      EC have not been ascertained up to now. METHODS: In order to determine the
      influence of pulmonary hypertension (PH), age and sex on EC, we localized the
      expression of the endothelial marker CD34 immunohistologically by light
      microscopy and laser scanning microscopy in lung tissue specimens from children
      and adults. RESULTS: Capillary EC showed a stronger staining reaction than EC in
      arteries, veins, arterioles or venules. The staining intensity increased with age
      in veins and arteries and decreased with age in venules, arterioles and
      capillaries. Sex exerted no statistically significant influence. CD34 was
      generally more strongly expressed in specimens with PH than in those without.
      CONCLUSION: The study demonstrates for the first time that (1) CD34 is
      heterogeneously expressed by human pulmonary EC, and (2) the
      physiological/pathophysiological factors age/PH influence CD34 expression. Hence
      a correlation between CD34 expression and its role as adhesion molecule and a
      link between CD34 expression and maturation are subject of discussion.

PMID- 12415188
TI  - Possible involvement of toll-like receptor 4 in endothelial cell activation of
      larger vessels in response to lipopolysaccharide.
AB  - Toll-like receptors (TLRs) serve as recognition and signaling elements for
      bacterial substances. To examine the role of TLRs in endothelial cells of larger
      vessels in lipopolysaccharide (LPS)-induced signaling, the expression and
      function of TLRs in human umbilical vein endothelial cells (HUVEC) were analyzed.
      A high level of TLR4 mRNA expression was found in HUVEC, human peripheral blood
      mononuclear cells (PBMC) and human monocyte cell line THP-1 cells. Little or no
      TLR2 mRNA expression was observed in HUVEC. In contrast, strong TLR2 mRNA
      expression was observed in PBMC and THP-1 cells. Moderate and high levels of TLR1
      mRNA expression were found in HUVEC, PBMC and THP-1 cells, respectively. TLR3
      mRNA expression was moderate in PBMC but weak in HUVEC and THP-1 cells. Little or
      no TLR5 and RP105 mRNA expression was observed in HUVEC, whereas a moderate level
      was detected in PBMC and THP-1 cells. The LPS-induced E-selectin expression in
      HUVEC was significantly inhibited by pretreatment with an anti-TLR4 mAb.
      Preincubation of HUVEC with an anti- TLR4 mAb significantly reduced the LPS
      induced IL-6 production. LPS induced E-selectin and IL-6 production by HUVEC only
      in the presence of human serum, suggesting the involvement of soluble CD14. Anti
      CD14 mAb strongly inhibited the LPS-induced E-selectin and IL-6 production by
      HUVEC. The inhibition with the concomitant treatment with anti-TLR4 and anti-CD14
      mAbs was stronger than that with anti-CD14 mAb only, although it was slight.
      These results show that TLR4 in the presence of soluble CD14 plays a major role
      in the signaling of LPS in endothelial cells of larger vessels.

PMID- 12415189
TI  - Effects upon bone metabolism following total hip and total knee arthroplasty.
AB  - OBJECTIVE: In a prospective study we evaluated the course of markers for bone
      formation and bone resorption in patients undergoing elective total hip and total
      knee arthroplasty due to osteoarthritis. The aim was to evaluate which changes in
      bone metabolism take place in the immediate postoperative course following
      arthroplasty. METHODS: Serum and urine samples were obtained preoperatively and
      in the postoperative course from patients undergoing total arthroplasty over a 90
      or 180-day period. The study included a total of 63 patients with cemented hip
      prostheses (n = 20), uncemented hip prostheses (n = 23) and cemented knee
      prostheses (n = 20). Different biochemical markers of bone metabolism were
      assessed including the serum markers bone-specific alkaline phosphatase, and
      carboxyterminal propeptide of type I procollagen, and the urine markers n
      telopeptide (NTx) and deoxypyridinoline (DPD). RESULTS: For all four markers,
      there were changes over time which were statistically significant. Markers
      indicating bone formation were slightly elevated after a 3-month period. In
      contrast, the two markers indicating bone resorption were back to normal after a
      6-month period. There were differences between the groups with cemented and
      uncemented total hip arthroplasty in the postoperative course with higher values
      of the markers indicating bone resorption in the cemented group. However, these
      differences were not statistically significant. CONCLUSIONS: Our results indicate
      that the two markers of bone resorption, NTx and DPD, are elevated during the
      first 6 months after hip and knee arthroplasty. Therefore, during this period
      they cannot be used as a marker for aseptic loosening. However, if these two
      markers are still elevated after this period, they may reflect an impaired bone
      metabolism. Further studies are required to assess the potential value of these
      markers for the diagnosis of aseptic loosening.

PMID- 12415190
TI  - Identification of germline mutation of PTEN gene and analysis of apoptosis
      resistance of the lymphocytes in a patient with Cowden disease.
AB  - Mutations of the tumor suppressor gene PTEN have been reported in patients with
      Cowden disease (CD) and in several malignant tumors. We analyzed a germline
      mutation of the PTEN gene in a patient with CD and identified a 4-bp deletion in
      exon 8 of the PTEN gene. The same germline mutation was detected in 3 members of
      her family. The mutated gene was predicted to encode a C-terminal truncated PTEN
      protein. Immunoblotting analysis revealed that the expression level of the wild
      type PTEN protein in the patient's lymphocytes was reduced to almost half the
      level of the control lymphocytes, and the predicted truncated mutant PTEN could
      not be detected. Since PTEN is known to function as a negative regulator of the
      phosphatidylinositol-3-kinase signal pathway that promotes cell survival, the
      patient's lymphocytes were tested for the resistance against the apoptotic
      stimulus. It was shown that the patient's lymphocytes were more resistant to
      apoptosis induced by calcium ionophore than the healthy control lymphocytes.
      These results indicate that the germline mutation of the PTEN gene and the
      consequent loss of heterozygous expression may lead to an increase in the
      survival potential of cells, thereby elucidating a role of PTEN in the
      pathogenesis of tumor generation and hyperplasia of lymphoid tissue in CD.

PMID- 12415191
TI  - Induction of hRAD9 is required for G2/M checkpoint signal transduction in gastric
      cancer cells.
AB  - DNA damage triggers the activation of checkpoints that delay cell cycle
      progression to allow for DNA repair. Loss of G2 checkpoints provides a growth
      advantage for tumor cells undergoing aberrant mitosis. However, the precise
      mechanisms of G2 checkpoints acting in gastric cancer are unknown. Here, we
      analyzed the G2 checkpoint function in two gastric cancer cells, MKN-28 cells
      containing a mutant p53 gene and MKN-45 cells which have wild-type p53. Two
      agents damaging DNA, camptothecin (CPT) or ultraviolet light (UV), were utilized
      to trigger a G2 phase cell cycle checkpoint response in these tumor cells. Both
      CPT and UV inhibited the growth of MKN-45 cells, whereas they did not affect the
      growth of MKN-28 cells. CPT induced cell cycle arrest at the G2/M phase and
      enhanced the expression of human RAD9 (hRAD9) in MKN-45 cells. In addition, hRAD9
      showed perinuclear staining and similar localization with Bcl-2 in MKN-45 cells
      but not in MKN-28 cells after having applied CPT or UV light. These results
      suggest that besides p53 activity, the induction of hRAD9 is required for G2/M
      checkpoint signal transduction in gastric cancer cells.

PMID- 12415192
TI  - CD156 transgenic mice. Different responses between inflammatory types.
AB  - CD156 (ADAM8) is part of the ADAM family of proteins with the catalytic site
      consensus sequence of metalloprotease and disintegrins. To examine the role of
      CD156 in vivo, we generated mutant CD156 (eCD156) transgenic mice expressing the
      ectodomain of CD156 under the control of the alpha1-antitrypsin (AT) promoter.
      One of the transgenic mice designated ATMS2-TG18 expressed a 1.84 kb mRNA which
      was predicted to be a truncated CD156. The expression of the transgenic CD156
      mRNA in ATMS2-TG18 mice was abundant in the liver and slight in kidney.
      Turpentine oil (TO) and lipopolysaccharide (LPS) markedly upregulated the
      expression. Soluble CD156 (sCD156) was produced constitutively, and increased
      after the treatment with TO. Casein-induced peritoneal leukocyte infiltration was
      significantly less extensive in ATMS2-TG18 than non-transgenic mice. The
      expression of L-selectin in neutrophils (PMN) from peripheral blood leukocytes
      (PBL) was more strongly downregulated in ATMS2-TG18 than non-transgenic mice,
      suggesting that L-selectin in PMN from ATMS2-TG18 mice was shed by sCD156. In
      contrast, oxazolone (Ox)-induced contact hypersensitivity reactions (CHR) were
      more marked in ATMS2-TG18 than non-transgenic mice. The expression of E-selectin
      mRNA was detected in inflammatory skin sites from ATMS2-TG18, but not non
      transgenic mice, suggesting that sCD156 may activate the endothelial cells and
      lead to the upregulation of E-selectin. These results suggest that CD156
      regulates leukocyte infiltration directly or indirectly.

PMID- 12415193
TI  - Preclinical development of a vaccine 'against smoking'.
AB  - BACKGROUND: Nicotine is the main culprit for dependence on tobacco-containing
      products, which in turn are a major etiologic factor for cardiovascular diseases
      and cancer. This publication describes a vaccine, which elicits antibodies
      against nicotine. The antibodies in the blood stream intercept the nicotine
      molecule on its way to its receptors and greatly diminish the nicotine influx to
      the brain shortly after smoking. METHODS: The nicotine molecule is chemically
      linked to cholera toxin B as a carrier protein in order to induce antibodies. The
      potential to elicit antibodies after subcutaneous as well as intranasal
      immunization is evaluated. In order to simulate realistic conditions, nicotine
      pumps delivering the nicotine equivalent of 5 packages of cigarettes for 4 weeks
      are implanted into the mice 1 week prior to vaccination. The protective effect of
      the vaccine is measured 5 weeks after vaccination by comparing the influx of
      radiolabeled nicotine in the brains of vaccinated and non-vaccinated animals 5
      min after challenge with the nicotine equivalent of 2 cigarettes. RESULTS: The
      polyclonal antibodies induced by the vaccine show a mean avidity of 1.8 x 10(7)
      l/Mol. Subcutaneous immunization elicits high antibody levels of the IgG class,
      and significant IgA antibody levels in the saliva of vaccinated mice can be found
      after intranasal vaccination. The protective effect also in the animals with
      implanted nicotine pumps is significant: less than 10% of radiolabeled nicotine
      found in the brains of non-vaccinated animals can be found in the brains of
      vaccinated animals. CONCLUSIONS: These data provide credible evidence that a
      vaccine can break the vicious circle between smoking and instant gratification by
      intercepting the nicotine molecule. Astonishingly, there is no sign of exhaustion
      of specific antibodies even under extreme conditions, which makes it highly
      unlikely that a smoker can overcome the protective effect of the vaccine by
      smoking more. Finally, the high titers of specific antibodies after 1 year let us
      hope that booster vaccinations are probably only necessary in intervals of years.

PMID- 12415194
TI  - Smoking cessation intervention in clinical practice.
AB  - Physicians are in a unique position to advise smokers to quit because of their
      ability to integrate the various aspects of nicotine dependence. This review
      provides an overview on interventions with smokers presenting in a primary care
      setting. Strategies used for smoking cessation counseling differ according to
      patient's readiness to quit. For smokers who do not intent to quit smoking,
      physicians should inform and sensitize patients about tobacco use and cessation,
      especially by personalizing benefits to quit and challenging smokers' beliefs.
      For smokers who are insecure, physicians should use motivational strategies, such
      as discussing barriers to cessation and their solutions. For smokers ready to
      quit, the physician should show strong support, help set a quitting date,
      prescribe pharmaceutical therapies for nicotine dependence, such as replacement
      therapy and/or bupropion, with instructions for use, and suggest behavioral
      strategies to prevent relapse.

PMID- 12415195
TI  - Prognostic factors for patients with microsurgically resected brain metastases.
AB  - BACKGROUND: With the advent of new therapies for metastatic carcinoma to the
      brain, patterns of intracranial disease and factors influencing survival become
      important considerations when examining treatment options. This study was
      conducted at a single institution to determine prognostic factors for tumor
      response and patient survival after microsurgical resection of brain metastases.
      PATIENTS AND METHODS: 187 consecutive patients who underwent microsurgical
      resection of brain metastases between July 1989 and September 1996 were
      retrospectively reviewed and statistically analyzed. The primary cancers included
      lung cancer (85), gastrointestinal cancer (20), renal cell cancer (19), breast
      cancer (17), malignant melanoma (8) and 38 cases of various other carcinomas or
      of unknown primary site. 111 patients received whole-brain radiation therapy
      (WBRT) with a mean dose of 32 Gy after tumor resection. The influence of number,
      size, and localization of brain metastases as well as histology of the primary
      tumor, preoperative performance status, presence of extracranial systemic
      disease, time course and adjuvant radiation therapy were statistically evaluated
      (uni- and multivariate) as prognostic factors for survival. RESULTS: Early
      postoperative Karnofsky score was improved in 59%, unchanged in 32% and worse in
      9% of patients. Median survival time (MST) was 9.8 months (range 1 day-5.3
      years). The most important parameter showing a significant influence on survival
      time was the histology of the primary tumor, with prediction of a bad outcome
      especially for patients with metastases from renal-cell cancer and malignant
      melanomas. Patients with breast cancer showed longer survival than patients with
      other primary cancers. Furthermore, survival varied significantly depending on
      location of brain metastases, performance status at time of craniotomy and
      duration of symptoms. None of the other studied variables gained prognostic
      significance. CONCLUSION: Microsurgical resection of one or more brain metastases
      followed by WBRT still is a useful and efficient treatment in a carefully
      selected patient group to prolong median survival and improve or stabilize the
      performance status. Among the factors determining the survival times in this
      patient group, histology of the primary tumor is most important, together with
      preoperative Karnofsky score, location of metastasis and preoperative duration of
      symptoms.

PMID- 12415196
TI  - Adjuvant chemotherapy in stage III colon cancer with 5-fluorouracil and
      levamisole versus 5-fluorouracil and leucovorin.
AB  - BACKGROUND: Adjuvant chemotherapy for colon cancer has been established during
      the past decade. From 1990 until recently treatment with 5- fluorouracil (5-FU)
      and levamisole (LEV) lasting 12 months was recommended as standard treatment. At
      the initiation of this study in 1993 improvement of adjuvant therapy was expected
      by the modulation of 5-FU with folinic acid (FA). Therefore, we decided to
      perform a prospective randomized multicenter trial to compare standard 5-FU/LEV
      to 5-FU/FA for either 6 or 12 months. PATIENTS AND METHODS: Patients with stage
      III colon cancer after curative en bloc resection were randomized in 3 treatment
      groups: arm A (5-FU/LEV, weekly, 12 months), arm B (5-FU/FA, days 1-5, every 4
      weeks, 12 months) and arm C (like B, 6 months). RESULTS: Between March 1993 and
      November 1997, 180 patients were randomized into the study, 155 were eligible for
      further evaluation. The interim analysis in November 2000 showed no significant
      difference for recurrence and disease-free survival in arm B and C, therefore the
      data from both 5-FU/FA treatment arms (B+C) were combined for comparison with 5
      FU/LEV-treatment (A). Most pronounced toxicity in all treatment arms was mild
      nausea, loss of appetite and leukopenia. A tendency for more diarrhea and
      stomatitis was observed in arm B+C. After a median follow-up of 36.2 months no
      significant difference was seen for disease free survival (p = 0.9) and overall
      survival (p = 1.0). 3-year recurrence rates were 39.6% in arm A and 39.1% in arm
      B+C, 3-year survival rates amounted to 74.1% in arm A and 74.9% in arm B+C.
      CONCLUSION: Only a limited number of patients could be recruited in this study.
      The observed data support the results of other studies, which concluded that 6
      months (or 12 months) treatment with 5-FU/FA is equivalent to 12 months treatment
      with 5-FU/LEV. Therefore the 6 months treatment with 5-FU/FA can be supported as
      standard for adjuvant therapy of stage III colon cancer.

PMID- 12415197
TI  - p16 Expression in squamous carcinomas of the tongue.
AB  - BACKGROUND: 81 patients with tongue carcinomas were studied to determine: 1). the
      proportion of carcinomas with altered p16 expression; 2). whether loss of p16 is
      an early carcinogenic event; 3). whether p16 expression alterations influence the
      prognosis. METHODS: 50/81 cases could be analysed by immunohistochemistry.
      RESULTS: Tumours were p16- in 32% (16/50) and p16+ in 68% (34/50) of patients;
      32.3% (11/34) of p16+ tumours presented 1-10% of tumour cells as positive, 14.7%
      (5/34) 11-40% as positive, and 59.2% (18/34) presented 41-100% of tumour cells as
      positive. Adjacent nontumoural epithelium (ANTE) was available in 33 of the 50
      immunohistochemically analysed specimens. ANTE was normal in 25 cases and
      dysplastic in 8 cases. In normal ANTE, p16 expression was positive in 16% (4/25)
      and negative in 84% (21/25) of cases. p16 expression was negative in all
      dysplastic ANTE samples (8/8). CONCLUSIONS: Changes in p16 expression are
      frequent in tongue cancer and can be detected at very early stages of
      carcinogenesis. Nevertheless, in our study neither the absence nor the degree of
      p16 expression influenced the survival of patients.

PMID- 12415198
TI  - Radiation recall dermatitis from docetaxel.
AB  - BACKGROUND: Experiences with inflammatory skin reactions after treatment with
      docetaxel and prior exposure to radiotherapy like a recall phenomenon are very
      rare. We present the case of an uncommon and severe skin reaction after docetaxel
      application and prior radiotherapy. PATIENT AND METHODS: A 40-year-old female was
      treated with an upper body irradiation with electrons because of relapsed breast
      cancer. In addition, because of metastases of brain and bone she received
      radiotherapy on the whole brain and the left pelvis. One week after radiotherapy
      weekly chemotherapy with docetaxel was started. RESULTS: Radiotherapy was well
      tolerated. There was a cutaneous erythema RTOG grade 1. After second application
      of docetaxel the patient developed a severe skin erythema, after fourth
      application confluent desquamations exactly demarcated the previously irradiated
      skin area. After discontinuation of docetaxel and after antiinflammatory
      treatment the skin reactions improved rapidly. CONCLUSION: In our opinion the
      severe skin reaction was clearly associated with the application of docetaxel
      like a recall phenomenon after previous radiotherapy. In case of severe skin
      reaction after this therapy it is important to know the possibility of recall
      phenomenon.

PMID- 12415199
TI  - Pseudo-meigs syndrome: uterine leiomyoma with bladder attachment associated with
      ascites and hydrothorax - a rare case of a rare syndrome.
AB  - INTRODUCTION: Pseudo-Meigs syndrome is a rare syndrome with pelvic tumors (not
      ovarian fibromas), which is combined with ascites and hydrothorax. Up to now 23
      cases of pseudo-Meigs syndrome associated with uterine leiomyomas are described.
      We present a further case of a young woman with pseudo-Meigs syndrome combined
      with bladder attachment and elevated CA-125. CASE REPORT: A 27- year-old woman
      complained about increasing abdominal volume for about 2 months. Clinical results
      showed a normal sized uterus with a pedunculated leiomyoma, ascites, and a small
      pleural effusion. CA-125 levels were approximately more than 50 times higher than
      normal range. An explorative laparotomy revealed a leiomyoma and ascites. The
      myoma was attached to the posterior wall of the bladder; the rest of the uterus
      and both adnexae were normal. An organ-preserving operation was performed. Three
      months afterwards the patient presented normal clinical and sonographical
      findings and normal CA-125 serum levels. DISCUSSION: Uterine leiomyoma is only
      rarely associated with ascites and hydrothorax. Our case is the 24th in
      literature. Like other authors we could show elevated CA-125 serum levels. Cases
      of pseudo-Meigs syndrome with penduculated myomas and tight adhesions of
      neighbouring structures have been described frequently. In our case the bladder
      was tightly attached, and the vascularisation seemed to come from the uterus and
      the bladder. This atypical double supply might be in etiological context with the
      ascites. Pseudo- Meigs syndrome should be considered as a rare differential
      diagnosis for ascites and pleural effusions.

PMID- 12415200
TI  - Towards defining specific antigens for cutaneous lymphomas.
AB  - Cutaneous lymphomas (CLs) are a heterogeneous group of malignancies of T-cell
      (cutaneous T-cell lymphoma, CTCL) or B-cell (cutaneous B-cell lymphoma, CBCL)
      origin with primary manifestation in the skin. CLs are difficult to treat in
      their advanced stages, especially as there is no curative treatment available.
      Immunological therapies might be a promising alternative, but the prerequisite
      for such strategies is the knowledge of tumor-specific antigens. This paper is
      reviewing the methods used today for identifying such antigens with special
      respect to CLs. The most successful strategies for the discovery of new tumor
      antigens include the cytotoxic T-cell approach using either genetic or
      biochemical tools, or synthetic peptide libraries leading to so-called mimotopes.
      A second strategy utilizes antibodies for screening recombinant libraries: either
      monoclonal antibodies generated against tumor cells or the so-called SEREX
      approach using antibodies of the patient's serum. Especially the antibody-based
      strategies led to several new antigens expressed in CTCL. Finally, already known
      tumor antigens have been evaluated as possible targets for CLs. A growing list of
      tumor antigens can be summarized for CLs, especially CTCL, which include cTAGE-1,
      SCP-1, GBP-TA, several mimotopes, SC5, LAGE-1, and NY-ESO-1, as well as the GAGE
      and MAGE-A groups. Perspectives on basis of the present knowledge are discussed.

PMID- 12415201
TI  - Dendritic cells as adjuvants in antitumor immune therapy.
AB  - While there has been considerable progress in the development of techniques to
      identify tumor-associated antigens, the traditional methods for delivering these
      antigens in the context of a tumor vaccine are, in many cases, crude and
      inadequate. Most adjuvants that are in principle available for such a vaccine
      have been discovered empirically and their mechanism of immune-stimulatory action
      is poorly understood. In addition, preclinical studies suggest that most of the
      conventional adjuvants often fail to elicit activation of both the humoral and
      the cellular arm of the immune system. Among other reasons, these findings have
      led to the application of dendritic cells (DCs) as adjuvants. In such experiments
      DCs were pulsed in vitro with tumor antigens which, upon in vivo application,
      caused tumor rejection in experimental mouse tumor systems, and such preparations
      indeed increased antitumor immunity in cancer patients. Recent advances in the
      understanding of the function of DCs and their first clinical applications in
      antitumor immune therapy are described.

PMID- 12415202
TI  - Heat-shock protein 90: potential involvement in the pathogenesis of malignancy
      and pharmacological intervention.
AB  - Heat-shock protein 90 (Hsp90) is an essential, cytosolic protein. Its
      overexpression in a wide variety of malignant tumors makes it a candidate target
      for pharmacological intervention. The association with Hsp90 stabilizes key
      regulatory proteins like Fak, Bcr-Abl, ErbB2, mutant p53 and Raf-1. The
      disruption of these heterocomplexes by Hsp90 inhibitors causes the rapid
      degradation of Hsp90-client proteins by the proteasome. Benzoquinone ansamycins
      were the first group of compounds for which interference with Hsp90 function was
      shown to be the major mechanism of action. They are in the early phase of
      clinical development. Radicicol and its derivatives are functional analogues of
      benzoquinone ansamycins without structural similarity. Flavonoids and stresgenin
      B share the ability to suppress heat-shock protein synthesis. Recently, it became
      apparent that coumarin antibiotics, cisplatin and paclitaxel also bind to Hsp90.
      The clinical value of the newly characterized agents with activity towards Hsp90
      remains to be determined.

PMID- 12415204
TI  - Surgery of brain metastases - pro and contra.
AB  - CONCLUSION: Surgery should be considered whenever possible. This means that the
      patient has to be in good clinical condition (Karnofsky performance score > 70),
      the extracerebral metastases should be stable, the number of cerebral lesions
      should not exceed more than 3 seedings, and the age of the patient should be
      below 70 years. Since brain metastases are usually well circumscribed, complete
      extirpation seems to be possible. Postoperative MRI should be demanded in order
      to confirm complete extirpation. Additional radiotherapy is indicated in case of
      subtotal resection of a single lesion and in multiple lesions. In single brain
      metastasis a prospective randomized trial is necessary to prove whether
      conventional radiotherapy is essential after surgery in the primary treatment of
      the tumors or can be delayed until cerebral lesions recur. Radiosurgery is an
      alternative to surgery in the treatment of metastasis.

PMID- 12415203
TI  - Chemotherapy for breast cancer brain metastases.
AB  - Breast cancer is the second most common cause of brain metastases, and 10-15% of
      patients develop clinically overt central nervous system disease. Radiotherapy is
      the standard treatment for patients with brain metastases. Surgical resection
      should be considered in patients with isolated brain metastasis and no
      extracranial disease. The role of chemotherapy in breast cancer brain metastases
      is not clearly defined; the results of the 8 trials found in the literature are
      reported. Most experience has been gained with the CMF (cyclophosphamide,
      methotrexate and fluorouracil) and PE (cisplatin and etoposide) regimens; here
      the median survival of 6 months is similar to radiotherapy. The blood-brain
      barrier, maintained by tight endothelial junctions and active transport
      mechanisms, is a major reason for the lower activity of most chemotherapeutic
      agents compared to other sites of metastatic disease. Most substances with good
      penetration of the blood-brain barrier have limited activity against breast
      cancer and some of the most active substances in breast cancer - including
      doxorubicine, the taxanes and trastuzumab - appear not to reach the central
      nervous system in sufficient concentrations. Approaches to overcome the blood
      brain barrier are still experimental, and more research is clearly needed to
      identify chemotherapeutic agents both active in breast cancer and with good
      penetration of the blood-brain barrier. With the exception of patients with
      resectable brain metastases, danger of cranial herniation or poor general
      condition, chemotherapy should be offered to breast cancer patients with brain
      metastases that have progressive extracranial metastatic disease or relapse after
      radiotherapy.

PMID- 12415205
TI  - [Concept for an integrated gyneco-oncologic management. Center for Comprehensive
      Gynecology]].

PMID- 12415206
TI  - [Causes of failure in open cavity mastoidectomy].
AB  - OBJECTIVES: We assessed the causes of failure in patients who underwent open
      cavity mastoidectomy. PATIENTS AND METHODS: Of sixty-three patients who had
      undergone open cavity mastoidectomy for chronic otitis media, 11 patients (7
      females, 4 males; mean age 35.2 years; range 8 to 59 years) required revision
      mastoidectomy. Membrane repair was accomplished with the use of temporal muscle
      fascia and tragal cartilage; ossicular reconstruction was performed by the
      interposition of incus and TORP. The mean follow-up was 13.1 months (range 6
      months to 2 years). RESULTS: The involved ear was the right in seven and the left
      in four patients. None of the patients, but one with nasal allergy had any immune
      or systemic diseases. In all patients cavity epithelialization was completed in a
      mean of 1.6 months (range 1 to 3 months). The indications for revision included
      residual cholesteatoma in three patients, inadequate meatoplasty and lowering of
      the facial ridge in four patients, patent tuba and serous discharge in two
      patients, and tympanic membrane perforation and granulation tissue in the
      hypotympanum and mastoid apex in two patients. CONCLUSION: The incidence of
      revision mastoidectomy may be decreased when a safe open cavity is obtained
      through lowering the facial bridge down to the level of the facial nerve,
      adequate meatoplasty, and by a complete exenteration of all the mastoid cells.

PMID- 12415208
TI  - [A review of antrochoanal polyps in 14 cases].
AB  - OBJECTIVES: We evaluated the clinical results of surgical treatment for
      antrochoanal polyps. PATIENTS AND METHODS: The study included 14 patients (9
      males, 5 females; mean age 23 years; range 7 to 48 years). Skin prick test was
      performed and specific IgE responses were determined. Treatment involved
      endoscopic sinus surgery in 13 patients, and polypectomy combined with Caldwell
      Luc operation in one patient. Follow-up examinations were performed in the
      postoperative first and sixth months. RESULTS: The polyps originated from the
      right (n=8) and from the left (n=6) maxillary sinuses. Nasal obstruction was
      found in all cases, with accompanying nasal discharge, sneezing, and postnasal
      discharge in four; snoring and mouth breathing during sleep in five patients, and
      sore throat and rhinorrhea in one patient. Allergy was determined in three
      patients. Computed tomography showed coexistent sinus diseases in nine patients.
      During surgery, the precise origin of the polyp was detected in four cases; being
      in the lateral wall in two, and in the posterior wall in two patients.
      Complications were minor hemorrhage in two cases, and synechia in three.
      Recurrence was observed in two patients. CONCLUSION: Endoscopic sinus surgery
      proved an ideal approach for antrochoanal polyps as it enables complete removal
      of the antral portion of the polyp, and simultaneous intervention to other sinus
      diseases.

PMID- 12415207
TI  - [The incidence of allergic rhinitis in children with otitis media with effusion].
AB  - OBJECTIVES: Many factors have been implicated in the etiopathogenesis of otitis
      media with effusion (OME). In this study, we investigated the role of allergy and
      the incidence of allergic rhinitis in patients with OME. PATIENTS AND METHODS:
      The study included 22 children (17 boys, 5 girls; mean age 7.8 years; range 2 to
      12 years) with OME confirmed by findings of physical examination and
      tympanometry. Patients with high IgE levels and symptoms of allergic rhinitis
      were further investigated by skin prick tests and nasal smears. The results were
      compared with those of an age- and sex-matched control group (13 boys, 8 girls;
      mean age 7.8 years) with no symptoms of otolaryngological diseases. RESULTS:
      Symptoms of rhinitis, serum IgE levels, prick test and nasal smear findings
      suggested a diagnosis of allergic rhinitis in five children with OME (23%), and
      in one child (4.8%) in the control group. However, this difference did not reach
      significance (p>0.05). CONCLUSION: Identification and appropriate treatment of
      allergic rhinitis in patients with OME may increase the success rate of OME
      treatment.

PMID- 12415209
TI  - [The efficacy of laser-assisted uvulopalatoplasty in the treatment of snoring and
      obstructive sleep apnea].
AB  - OBJECTIVES: We evaluated the efficacy of laser-assisted uvulopalatoplasty in the
      treatment of snoring and obstructive sleep apnea syndrome (OSAS). PATIENTS AND
      METHODS: Laser-assisted uvulopalatoplasty was performed in 34 patients (30 males,
      4 females; mean age 45.7 years; range 17 to 70 years) with simple snoring and
      mild OSAS. The patients were evaluated preoperatively and in the first and sixth
      months postoperatively with the use of the Epworth sleepiness scale,
      polysomnography, and snoring scores. A questionnaire was administered to assess
      patient satisfaction. RESULTS: All patients had decreased snoring. The quality of
      sleep increased in 79%. The clinical improvement seen in the first month
      continued through the sixth postoperative month. Satisfaction rates for the
      patients and their families were 88% and 85%, respectively. Significant decreases
      were found in the Epworth sleepiness scale (p=0.000) and visual snoring scores
      (p<0.001). In addition, postoperative desaturation indices decreased and minimal
      desaturation levels increased. However, no significant decreases occurred in the
      apnea/hypopnea index. No complications were encountered during and after
      operation. CONCLUSION: Laser-assisted uvulopalatoplasty has high efficacy in the
      treatment of snoring and mild OSAS, with such additional advantages as ease, low
      complication rate, and no need for hospitalization.

PMID- 12415210
TI  - [Primary carcinoma of the subglottic larynx].
AB  - OBJECTIVES: Primary carcinoma of the subglottic larynx is very rare. This study
      was designed to evaluate patients who were treated for primary carcinoma of the
      subglottic larynx. PATIENTS AND METHODS: The study included 15 patients (14 men,
      1 woman; mean age 62.8 years; range 45 to 95 years) with primary subglottic
      carcinoma. Correlations of different clinical parameters with three-year survival
      rate and Kaplan-Meier survival analysis were investigated. RESULTS: On
      presentation, two patients (14%) had T1, five patients (33%) had T2, three
      patients (20%) had T3, and five patients (33%) had T4 tumors. The overall three
      year survival rate was 73.4% (11/15). The median survival calculated by the
      Kaplan-Meier method was 45 months. No significant differences were found between
      the survival rates of patients with and without extralaryngeal extension.
      CONCLUSION: Although primary subglottic cancer is locally aggressive with high
      tendency to extend to the extralaryngeal compartment at the time of diagnosis,
      high survival rates can be expected when appropriate treatment modalities are
      selected.

PMID- 12415211
TI  - [Comparison of magnetic resonance imaging findings with postoperative
      histopathologic results in laryngeal cancers].
AB  - OBJECTIVES: We compared the findings of magnetic resonance imaging (MRI) with
      histopathologic results in laryngeal cancer. PATIENTS AND METHODS: Twenty-five
      patients (24 males, 1 female; mean age 58 years; range 24 to 80 years) were
      evaluated preoperatively by MRI with regard to involvement of the thyroid
      cartilage, anterior commissure, vocal cords, sinus pyriformis, subglottic region,
      and prelaryngeal soft tissues. The findings were compared with those of
      histopathologic examination. RESULTS: The highest accuracy was found in the
      detection of invasion to the prelaryngeal soft tissue (92%). The accuracy of MRI
      was 84% for the anterior commissure, 80% for vocal cords, 76% for the thyroid
      cartilage, and 72% for sinus pyriformis and the subglottic region. CONCLUSION:
      Magnetic resonance imaging proved to be useful in the preoperative evaluation of
      laryngeal cancers.

PMID- 12415212
TI  - [Results of open structure rhinoplasty].
AB  - OBJECTIVES: This study aimed to evaluate the techniques used in open structure
      rhinoplasty operations, together with a presentation of our results and
      experience. PATIENTS AND METHODS: The study included 122 patients (64 males, 58
      females; mean age 27 years; range 17 to 48 years) who underwent open structure
      rhinoplasty. Of these, 72.9% had primary, 9% had revision surgeries; 18% had
      traumatic deformities. The mean follow-up period was 18 months (range 3 to 24
      months). RESULTS: We did not encounter transcolumellar scar formation or flap
      necrosis in any of the cases. In five cases (4%), edema and hyperemia were
      detected in the columellar skin in the early postoperative period. Resorption of
      the tip graft developed in one (0.8%) of the patients in whom auricular cartilage
      grafts were used. A year after surgery, one patient (0.8%) presented with
      granulation tissue formation in the nasal vestibule, secondary to the use of
      nylon suture material. Axial deviation was seen in the early postoperative period
      in two patients (1.6%). Five patients (4%) required revision surgery. CONCLUSION:
      Open structure rhinoplasty gives excellent results when employed on proper
      indications and by experienced surgeons.

PMID- 12415213
TI  - [A case of natural killer T-cell lymphoma in the nasal cavity].
AB  - CD56 positive natural killer T cell lymphoma is characterized by destructive
      lesions in the nasal cavity and nasopharynx. Severe tissue necrosis makes
      histopathologic diagnosis difficult, generally necessitating multiple biopsies. A
      thirty-three-year-old male patient presented with complaints of nasal
      obstruction, hemorrhagic discharge of fetid odor, and rhinolalia.
      Immunohistochemical studies on biopsy specimens obtained from the lesion in the
      nasal septum and posterior nasal cavity revealed CD56 positive natural killer T
      cell lymphoma. The patient was treated with eight courses of combination
      chemotherapy, since then he has been in remission for more than 1.5 years.

PMID- 12415214
TI  - [ENT examination in SCUBA divers and ENT pathologies restricting diving].
AB  - SCUBA diving can be safely performed if a careful pre-dive examination regarding
      the medical standards of diving is performed, and if all necessary precautions
      are taken with attention being paid to the potential risks of diving. The most
      frequent medical problems arising from SCUBA diving fall into the otolaryngology
      discipline; thus, candidates should be examined in terms of ENT disorders that
      may prevent them from diving. This article aims to review particular aspects of
      ENT examination, investigation methods, and criteria for candidates

PMID- 12415215
TI  - Salivary gland tumours in a Mexican sample. A retrospective study.
AB  - Salivary gland tumours are an important part of the Oral and Maxillofacial
      Pathology, unfortunately, only few studies on these tumours have been done in
      Latin-American population. The aim of this study was to compare demographic data
      on salivary gland tumours in a Mexican sample with those previously published
      from Latin American and non-Latin American countries. All cases of salivary gland
      tumours or lesions diagnosed in our service were reviewed. Of the reviewed
      cases,67 were confirmed as salivary gland tumours. Out of these 64.2% were benign
      neoplasms, 35.8% were malignant and a slight female predominance (56.7%) was
      found. The most common location was palate followed by lips and floor of the
      mouth. Mean age for benign tumours was 40.6 years with female predominance
      (60.5%). Mean age for malignant tumours was 41 years and female predominance was
      found again. Palate followed by retromolar area were the usual locations.
      Pleomorphic adenoma (58.2%), mucoepidermoid carcinoma (17.9%) and adenoid cystic
      carcinoma (11.9%) were the more frequent neoplasms. All retromolar cases were
      malignant and all submandibular gland tumours were benign. We found a high
      proportion of salivary gland neoplasms in children. Our results showed that
      differences of the studied tumours among our sample and previously reported
      series exist. These differences can be related to race and geographical location.

PMID- 12415216
TI  - Malignant transformation in odontogenic keratocysts. Case report.
AB  - Squamous cell carcinoma arising in the epithelial lining of an odontogenic
      keratocyst is a rare finding. Up to now, only 12 cases have been reported in the
      literature. The present work reports a new case diagnosed in a 70 year old man.
      The clinical, radiographic, and histopathological findings and the treatment are
      described.

PMID- 12415217
TI  - PCNA in palate and tongue mucosal dysplastic lesions induced by topically applied
      4NQO in desalivated rat.
AB  - OBJECTIVES: Saliva has been suggested to have a protective role against
      carcinogens in the oral cavity in animals. Water-soluble 4NQO is a suitable
      carcinogen to use in examining the role of saliva in oral cancer. The purpose of
      this study was to follow the changes induced by the carcinogen at the molecular
      level, as well as the effect of lack of saliva on these changes. MATERIALS AND
      METHODS: Topical application to the palate of a 0.5% 4NQO solution dissolved in
      glycol was used for 4 months to induce malignant transformation in a desalivated
      rat model. Histomorphometric analysis of proliferating cell nuclear antigen
      (PCNA), a cell cycle regulator and a proliferation marker, was performed.
      RESULTS: Manifestation of PCNA significantly increased as the observed histologic
      changes progressed from hyperkeratosis, to mild or moderate dysplasia, severe
      dysplasia and squamous cell carcinoma. Differences in manifestation of PCNA among
      the diagnostic groups was significant (p< 0.05). In the desalivated group, PCNA
      expression was significantly higher than in control and normal groups, in both
      tongue and palate after 2 and 4 months (p< 0.05). CONCLUSIONS: An unknown
      component of saliva has a temporary anti-carcinogenic protective effect, which
      can both delay and decrease the level of proliferation induced by the carcinogen
      4NQO. The specific salivary component and the mechanism by which this protective
      effect is rendered are yet to be discovered.

PMID- 12415218
TI  - Dentistry and self-medication: a current challenge.
AB  - The classical definition of self-medication is "the taking of drugs, herbs or
      home remedies on one's own initiative, or on the advice of another person,
      without consulting a doctor". Used as a solution to the wide range of complaints
      and minor health problems which may appear over a lifetime, it can be the result
      of an individual choice or by the influence of a family who is well informed
      about which techniques and drugs are safe and useful. This paper reviews the
      concept of self-medication, placing particular emphasis on the common self
      medication errors within dentistry and their negative consequences in terms of
      systemic disease. Used in a responsible way self-medication is desirable because,
      as an independent search for a drug treatment, it can complement the work of
      health professionals. Furthermore, it represents a self affirming, independent
      attitude on the part of patients. Information, therapeutic advice and education
      are argued to be the basic elements underlying responsible self-medication.

PMID- 12415219
TI  - Antibiotic prophylaxis in dental patients with body prostheses.
AB  - Antibiotic administration before performing dental treatments, with the purpose
      of preventing the possible risks associated with bacteremia, has received much
      support but also considerable criticism. Advances in surgery have led dental
      professionals to deal with patients carrying body prostheses of different kinds -
      thus giving rise to situations in relation to dental management that require
      careful evaluation. In this context, when deciding whether or not to provide
      antibiotic prophylaxis, the dental professional must also be able to adequately
      assess other aspects such as oral status, the dental treatment required, the type
      of body implant involved, the potential risk of infection in relation to the
      prosthesis, associated secondary pathologies, the type of antibiotic indicated
      and its spectrum of action, as well as the dosage, side effects and economical
      cost of the antibiotic administered.

PMID- 12415220
TI  - Relation of patient and surgical variables to postoperative pain and inflammation
      in the extraction of third molars.
AB  - OBJECTIVES: An analysis is made of the influence of patient and surgical
      variables upon the postoperative pain and swelling normally associated with third
      molar extractions. STUDY DESIGN: The following patient variables were considered
      in a series of 150 individuals subjected to third molar extraction: sex, age, and
      dimensions of neurotic personality trait and extroversion (based on the Eysenck
      Personality Inventory, EPI). The corresponding surgical intervention parameters
      were: duration, ostectomy degree, dental sectioning and number of sutures. Pain
      was scored on a visual analog scale (VAS) 0, 8, 24, 43 and 48 hours after
      surgery, while inflammation was rated by means of a verbal response scale (VRS)
      48 hours after extraction. RESULTS: Multivariate analysis showed postextraction
      pain to be mainly related to patient age and the number of sutures on the day of
      the operation, and to swelling over the subsequent days. A less important
      relation was observed with patient sex and the dimensions of neuroticism and
      extroversion. CONCLUSIONS: In conclusion, older patients and those subjected to
      extractions involving a greater number of sutures refer the most intense pain. In
      turn, patients with increased intensity pain also present greater inflammation.

PMID- 12415221
TI  - Primary intraosseous carcinoma arising in a mandibular cyst.
AB  - Although primary intraosseous carcinoma of the mandible is an uncommon lesion,
      they may not be as rare as generally believed. These tumours may, in theory,
      arise de novo from odontogenic remnants or from the malignant transformation of
      the lining of odontogenic cysts or tumours. Diagnosis based on histology and
      radiology is difficult. The prognosis is more favorable when PIOCs arise from
      odontogenic cysts. These tumors are locally aggressive and metastasize to
      regional nodes. The case study of a 70 year-old man with a primary intraosseous
      squamous carcinoma arising from a mandibular cyst is given.

PMID- 12415222
TI  - Do ambulatory-use Platelet-Rich Plasma (PRP) concentrates present risks?
AB  - Platelet-Rich Plasma (PRP) concentrates have been widely used in the past decade
      as a complement to tissue regeneration procedures. The authors who have
      clinically used PRP refer no risk of infection, disease transmission, or
      undesirable effects. Nevertheless, there have been reports on the over-expression
      of growth factors (GFs) and their receptors related to tumour and dysplastic
      tissues. This has led to evaluation of the possible coincidences between
      carcinogenesis and the mitogenic pathways employed by GFs. The present study
      provides a review of the literature on the possible effects of the therapeutic
      uses of GFs (including PRP) in relation to carcinogenesis, their influence upon
      tissues with epithelial dysplasia or oral carcinoma, and their relation to tumour
      growth and infiltration.

PMID- 12415223
TI  - Salivary Gland Epithelial- Myoepithelial Carcinoma: behaviour, diagnosis and
      treatment.
AB  - Across the whole spectrum of the tumoral pathology in the maxillo-facial and
      cervical areas, we can find those tumours where the aetieology is in the salivary
      glands. The tumours in the salivary glands are subdivided in benign and malignant
      tumours whenever this theorical subdivision is possible. The Epithelial
      Myoepithelial Carcinoma represents about the 1% of the malignant neoplasms in the
      salivary glands and also affect other anatomical areas where there are glands:
      lung, kidney, uterus and so on. We start from a clinical case of a Epithelial
      Myoepithelial of salivary minor gland carcinoma doing a bibliographic review of
      this unusual histological lineage. So we present a case of Epithelial
      Myoepithelial Carcinoma of a minor salivary gland in the right cheek. We'll
      review the clinical and histological features of this uncommon tumour. And we'll
      discuss about the best way for diagnosis, treatment and the differential
      diagnosis to similar clinical injuries.

PMID- 12415224
TI  - Left ventricular shape assessment: a new simple diagnostic tool in stress
      echocardiography.
AB  - OBJECTIVE: Knowing that ventricular shape can be distorted by ischemia, we
      conducted this retrospective study to evaluate the value of left ventricular
      shape assessment as a diagnostic tool in stress echocardiography. METHODS: Forty
      studies (normal and abnormal dobutamine or exercise tests) were analyzed. All
      patients had normal systolic function at baseline. Endocardial borders were
      traced in diastole, in systole, at rest, and at peak stress. The endocardial
      border tracings (without corresponding video images) were presented to a blinded
      observer. Normal shape was defined as "rectangular or circular in parasternal
      long- and short-axis views, respectively, and triangular in the apical view." On
      the basis of those simple criteria for normal ventricular shape, the tracings
      were classified as normal or abnormal (ischemia) and results were compared with
      the wall-motion analysis of video images. RESULTS: Sensitivity, specificity, and
      positive and negative predictive values for shape abnormalities were 95%. Thirty
      eight of the 40 studies were accurately classified without looking at the video
      tapes of the studies. CONCLUSIONS: Visual evaluation of ventricular shape can be
      very helpful in stress echocardiography. It can be easily accomplished even by
      someone with limited experience in this technique.

PMID- 12415225
TI  - Exercise echocardiography and thallium-201 single-photon emission computed
      tomography stress test for 5- and 10-year prognosis of mortality and specific
      cardiac events.
AB  - Limited data suggest that stress myocardial perfusion imaging and stress
      echocardiography have similar prognostic value for composite cardiac events.
      However, it is not known whether exercise echocardiography and stress thallium
      are similar in their prediction of specific cardiac events, eg, death, sudden
      death, myocardial infarction, unstable angina, and congestive heart failure. A
      total of 206 patients undergoing stress echocardiography and thallium-201 single
      photon emission computed tomography imaging during the same exercise test were
      followed-up for 5 and 10 years. Multivariate Cox regression analyses
      incorporating clinical, exercise stress test, echocardiographic, and nuclear
      imaging parameters were used to predict mortality and specific cardiac events. A
      moderate to large amount of ischemia (> or =4 segments on the basis of a 16
      segment model) by exercise stress echocardiography was the strongest predictor of
      overall mortality (relative risk [RR] 6.2; P <.0001), cardiac death (RR 17.6; P
      =.01), congestive heart failure (RR 17.4; P =.0005) or sudden death (RR 26.8; P
      =.003), whereas a moderate to large fixed defect (> or =2 segments on the basis
      of a 6-segment model) by nuclear imaging was the strongest predictor of
      myocardial infarction (RR 8.1; P =.0002) or unstable angina (RR 3.0; P =.005) at
      5 years. The heterogeneity in the prediction of these specific cardiac events by
      these 2 modalities was similarly observed at 10 years. The extent of ischemia by
      stress echocardiography is a better predictor of overall mortality, cardiac
      death, congestive heart failure, or sudden death, whereas the extent of a fixed
      defect by nuclear imaging is a better predictor of myocardial infarction or
      unstable angina.

PMID- 12415227
TI  - Prognostic implication of ergonovine echocardiography in patients with near
      normal coronary angiogram or negative stress test for significant fixed stenosis.
AB  - OBJECTIVES: The goal of this study was to assess the prognostic value of
      ergonovine echocardiography (Erg Echo) for diagnosis of coronary vasospasm (CVS)
      in patients without significant fixed coronary stenosis. MATERIAL AND METHODS:
      Medical records of 650 patients who underwent Erg Echo were reviewed. Before Erg
      Echo, absence of significant fixed coronary stenosis was confirmed by invasive
      coronary angiography (CAG) in 316 patients (49%) or by noninvasive confirmation
      of negative treadmill or normal myocardial perfusion scan in 334 patients (51%).
      The cardiac events after Erg Echo were tabulated and these included cardiac
      death, myocardial infarction (MI), readmission due to intractable chest pain.
      RESULTS: The average age was 54 +/- 10 years, with 223 women and 427 men. Erg
      Echo was positive in 237 patients (36%), for whom long-acting calcium channel
      blocker and nitrates were prescribed. During follow-up (46 +/- 23 months),
      cardiac events developed in 13% (30 of 237) of the positive Erg Echo group and 3%
      (14 of 413) of the negative Erg Echo group (P <.001). Incidence of cardiac death
      was higher in the positive Erg Echo group (3.4% vs 0.7%, P =.022). The 5-year
      survival rate (93% +/- 3% vs 99% +/- 1%, P =.013) and event-free survival rate
      (94% +/- 2% vs 77% +/- 6%, P <.001) were significantly lower in the positive Erg
      Echo group. Smoking (hazards ratio 6.3; 95% CI 1.7-23.5) and multivessel spasm
      (hazards ratio 37.2, 95% CI, 8.1 to 170.4) were independent factors associated
      with cardiac death and/or MI. CONCLUSION: Erg Echo for noninvasive diagnosis of
      CVS in the differential diagnosis of chest pain provides useful prognostic
      information for patients without significant fixed coronary stenosis and can play
      a role as a cost-effective diagnostic strategy in these selected patients.

PMID- 12415226
TI  - Economic impact of contrast stress echocardiography on the diagnosis and initial
      treatment of patients with suspected coronary artery disease.
AB  - OBJECTIVE: To estimate the impact of contrast stress echocardiography on resource
      use in the treatment of patients with suspected coronary artery disease (CAD).
      METHODS: Fifty-nine patients with suspected CAD underwent nuclear perfusion
      imaging and contrast echocardiography examination. Further treatment was planned
      after each test and a final treatment was recommended after reviewing the results
      of both examinations. Medical resources and productivity losses were then
      collected for a 3-month follow-up period. RESULTS: Diagnosis was possible in
      96.6% of patients with nuclear perfusion imaging and 93.2% with contrast
      echocardiography, resulting in a cost per successful diagnosis of $637 (Can) and
      $476 (Can), respectively. For the majority of patients (74%), both tests provided
      the same result, but for 12 patients nuclear imaging suggested abnormal
      perfusion, whereas contrast echocardiography indicated normal function and for 2
      patients it was the opposite situation. Per-patient costs for the total patient
      population decreased from $316 (Can) after nuclear perfusion imaging to $250
      (Can) when results from both tests were known. Three-month follow-up societal
      costs were $441 (Can) per patient, with hospitalization contributing 58% of this
      total cost. CONCLUSION: Contrast echocardiography has a similar success rate to
      nuclear perfusion imaging in diagnosing CAD, but has a 28% lower cost and has the
      potential of additional cost savings through the elimination of further
      diagnostic tests.

PMID- 12415228
TI  - Doppler tissue echocardiographic features of cardiac amyloidosis.
AB  - The purpose of the study was to assess whether quantification of myocardial
      involvement by Doppler tissue echocardiography (DTE) enhances the accuracy of
      echocardiographic characterization of cardiac amyloidosis (CA). A group of 36
      patients with CA (mean age 58 +/- 13 years; 22 male) and 40 age-matched control
      patients were studied. Patients with CA were divided into CA-1 subgroup with
      nonrestrictive (n = 22) and CA-2 with restrictive left ventricular (LV) filling
      pattern (n = 14). Peak lateral and medial mitral annulus velocities by pulsed
      wave DTE were measured in systole, early diastole, and late diastole. Using color
      M-mode DTE of the LV posterior wall, mean myocardial velocities (MMV) and
      myocardial velocity gradient (MVG) were measured during ventricular ejection,
      early and late isovolumic relaxation (IVR), rapid ventricular filling, and atrial
      contraction. In both CA-1 and CA-2 groups, mitral annulus velocities, MMV, and
      all MVG were lower than those measured in control patients, with the exception of
      peak late diastolic annulus velocities at lateral side and MMV in atrial
      contraction. MVGs in both early IVR and rapid ventricular filling were lower in
      the CA-1 as compared with the CA-2 group. Late IVR-MVG was negative in control
      patients and positive in patients with CA indicating a faster movement of the
      subendocardium rather than the subepicardium during late IVR in patients with CA
      (0.88 +/- 0.50 s(-1) vs -0.40 +/- 1.59 s(-1); P <.001). The following parameters:
      peak early diastolic annulus velocities at lateral side < or = -12 cm/s, peak
      early diastolic annulus velocities at medial side < or = -10 cm/s, early IVR-MMV
      < or = -2.5 cm/s, early IVR-MVG < or = -0.7 s(-1), and late IVR-MVG > or = 0.5 s(
      1) differentiated patients with CA from control patients with an overall accuracy
      of 0.82, 0.83, 0.81, 0.87, and 0.81, respectively. In patients with CA, reduction
      in early IVR-MMV was independent of patients' age and LV mass. DTE indices proved
      helpful in differentiating patients with CA from control patients including those
      patients with CA who had borderline conventional echocardiographic features and
      nonrestrictive LV filling pattern.

PMID- 12415230
TI  - Evaluation of shunt flow by multiplane transesophageal echocardiography in adult
      patients with isolated patent ductus arteriosus.
AB  - The role of multiplane (M) transesophageal echocardiography (TEE) in the
      diagnosis of isolated patent ductus arteriosus (PDA) in adults and its
      effectiveness in the assessment of the pulmonary to systemic flow ratio were
      evaluated and compared with those obtained from cardiac catheterization
      examination. Eleven consecutive patients, ranging from 17 to 56 years old (mean
      of 29.5 +/- 12.0), with clinically suspected PDA were subjects of this study. A
      complete transthoracic echocardiographic study was performed in each patient
      before MTEE. MTEE with Doppler color flow mapping showed clear visualization of a
      ductal structure between the descending aorta and pulmonary artery with a
      continuous turbulent mosaic flow suggestive of PDA in all 11 patients. The
      pulmonary/systemic flow and vascular resistance ratios obtained by
      echocardiography and cardiac catheterization correlated well (r = 0.8732, P
      =.0004; r = 0.623, P =.04, respectively). This study demonstrated that MTEE
      combined with transthoracic echocardiography examination is an accurate
      noninvasive means in the diagnosis of PDA and assessment of the pulmonary to
      systemic flow and vascular resistance ratios in adult patients.

PMID- 12415229
TI  - Diastolic alterations in infants exposed to intrauterine cocaine: a follow-up
      study by color kinesis.
AB  - BACKGROUND: During the first 48 hours of life, newborn infants exposed to cocaine
      in utero have left ventricular diastolic segmental abnormalities. It is unknown
      whether these abnormalities are transient because of short-term effects or
      persist in older infants, possibly reflecting a teratogenic effect of cocaine.
      METHODS: This study prospectively evaluated global and segmental systolic and
      diastolic cardiac parameters by color kinesis. The patients were 2- to 6-month
      old infants who were exposed to cocaine in utero (N = 56). Their data were
      compared with normal control patients with no intrauterine drug exposure (N = 60)
      and newborns exposed to drugs other than cocaine (N = 72). RESULTS: At the age of
      2 to 6 months, there was no significant difference in the measured color kinesis
      parameters among the cocaine-exposed and the 2 control groups (infants prenatally
      exposed to other drugs and no drugs). Infants exposed to heavy cocaine
      prenatally, as compared with the noncocaine-exposed group, had a significant (P
      =.007) increase in septal fractional area change during left ventricular filling.
      CONCLUSIONS: At 2 to 6 months of age, infants have recovered from initial left
      ventricular diastolic segmental alterations seen in the first 48 hours of life
      except for the septal wall in the heavily cocaine-exposed group.

PMID- 12415231
TI  - Usefulness and limits of transthoracic echocardiography in the evaluation of
      patients with primary and chronic thromboembolic pulmonary hypertension.
AB  - The aim of the study was to evaluate the potential usefulness of transthoracic
      echocardiography in differentiating patients with primary or chronic
      thromboembolic pulmonary hypertension and to define the capability of
      echocardiography to assess right-heart performance in such patients. Right-heart
      catheterization and ultrasound examination were performed in 111 patients with
      chronic thromboembolic pulmonary hypertension and in 31 patients with primary
      pulmonary hypertension. All echocardiographic and Doppler parameters were similar
      in primary and chronic thromboembolic pulmonary hypertension. A significant
      correlation was found between the tricuspid annular plane systolic excursion and
      the right ventricular fractional area change and thermodilution-derived right
      ventricular ejection fraction (P <.001 for both). Furthermore, different patterns
      of the pulsed Doppler flow velocity curve into the superior vena cava were
      associated with different right-heart hemodynamic profiles. In conclusion, in
      patients with chronic pulmonary hypertension transthoracic echocardiography
      portends meaningful information on the capability of the right heart to confront
      the increased afterload but it does not permit etiologic differentiation.

PMID- 12415232
TI  - Continuous recording of pulmonary artery diastolic pressure and cardiac output
      using a novel ultrasound transducer.
AB  - BACKGROUND: The feasibility of hands-free transthoracic continuous determination
      of pulmonary artery (PA) diastolic pressure (PAD) and cardiac output (CO) by
      Doppler ultrasound has not been previously demonstrated. We developed a 2.5-MHz
      spherical transducer mounted in an external housing to permit steering in 360
      degrees (Contison). The external housing was attached to the chest wall using an
      adhesive patch. METHODS AND RESULTS: Fifty patients in the coronary care
      department who had PA catheters had Doppler ultrasound studies. The 2.5-MHz
      spherical transducer was placed at the left sternal border to permit imaging of
      the pulmonic valve and was attached to a commercial ultrasound machine. The PA
      was imaged and its diameter measured. The pulmonary flow velocity signal was
      recorded and the time velocity integral obtained. The CO was calculated as: CO =
      time velocity integral of the PA systolic flow velocity signal x pi diameter(2)
      divided by 4 x heart rate. The pulmonary regurgitation signal was then recorded
      and the end-diastolic velocity of the regurgitant signal was measured. Right
      atrial pressure was assessed from the jugular venous pressure or from the size
      and pulsatility of the inferior vena cava. The PADP was calculated as: PADP = 4
      end-diastolic velocity of the regurgitant signal(2) + right atrial pressure. The
      CO, PADP, and pulmonary wedge pressure were recorded from the PA catheter
      immediately after the ultrasound studies. Serial data were obtained every half
      hour or 1 hour up to a maximum of 5 hours. Adequate Doppler signals were obtained
      in 43 patients. RESULTS: There was a good correlation between the PADP by Doppler
      versus PA catheter (r = 0.90, standard error of the estimate = 3.3 mm Hg); PADP
      by Doppler versus PA wedge pressure (r = 0.88, standard error of the estimate =
      3.7 mm Hg); and CO by Doppler versus PA catheter (r = 0.92, standard error of the
      estimate = 0.7 L/min). CONCLUSION: The 2.5-MHz spherical transducer permitted
      accurate assessment of CO and PAD. This transducer could be of potential value in
      monitoring patients in the intensive care setting.

PMID- 12415233
TI  - Epicardial ultrasound guidance of coronary catheter placement in an experimental
      animal model.
AB  - We evaluated epicardial ultrasonography with a 10-MHz transducer for coronary
      catheter guidance in 18 normal pigs. A modified long-axis view of the aortic root
      was used to direct a coronary catheter into the root, and then with a short-axis
      view of the aortic root, the catheter tip was placed selectively into either the
      right or the left main coronary artery. Subsequently, with modified coronary
      views, an angioplasty infusion catheter was guided with precision to the exact
      location desired in the coronary artery. Position was confirmed by direct
      visualization and palpation of the epicardial vessels, and the procedure was
      completed within 5 to 15 minutes without complication. Epicardial ultrasonography
      is a suitable alternative to fluoroscopy for guidance of coronary catheter
      placement in an open-chest experimental model.

PMID- 12415234
TI  - Detection of calcium deposits on heart valve leaflets by vibro-acoustography: an
      in vitro study.
AB  - The presence of calcium deposits on heart valve leaflets constitutes a clinically
      significant diagnostic indication. A novel method for imaging and detecting
      calcium deposits on tissue heart valves is presented. The method, called vibro
      acoustography, uses the radiation force of ultrasound to vibrate the tissue at
      low (kHz) frequency and records the resulting acoustic response to produce images
      that are related to the hardness of the tissue. The method is tested on excised
      human heart valve tissues. Resulting images clearly show calcium deposits with
      high contrast and are in agreement with the corresponding radiographs of the
      specimens.

PMID- 12415235
TI  - Safety of transesophageal echocardiography in patients who are obese.
AB  - Patients with obesity tend to have a higher incidence of hypertension, coronary
      artery disease, and sleep apnea, conditions that could potentially predispose to
      complications during transesophageal echocardiography (TEE). In addition,
      patients who are obese are more likely to have oxygen desaturation during upper
      gastrointestinal endoscopy. However, the safety of TEE in a large cohort of
      patients with obesity has not been reported. Thus, the safety of TEE in 341
      patients who were obese (body mass index >/= 27.5 kg/m(2), mean 41.0 +/- 10.3)
      and in 323 control patients who were not obese was compared. Minor complications
      (ie, complications of a transient duration and requiring no or only simple
      intervention) occurred with equal frequency in the control and obese groups
      (16.5% vs 16.7%, P = not significant). Transient oxygen desaturation did not
      differ between the control versus obese group (2.5% vs 3.8%, P = not
      significant), but was more common (6.7%) in a subgroup (n = 150) of patients who
      were morbidly obese as compared with control patients (P <.05). Transient
      hypotension was observed in 3.5% of the obese group compared with 7.4% in the
      control group (P <.05). However, transient hypertension was noted in 10.6% of the
      patients who were obese compared with 6.5% in the control group (P =.072). A
      major complication occurred in 2 patients with obesity, one who required
      vasopressor medication for persistent hypotension and another needing
      pharmacologic rate control of atrial fibrillation. One patient in the control
      group had provoked supraventricular tachycardia and angina. No deaths occurred in
      either group. Subjective tolerance for the procedure was similar (P = not
      significant) in both groups with 84% of patients with obesity having good to
      excellent tolerance compared with 88% in that of the control group. Thus, TEE can
      be safely performed in patients who are obese.

PMID- 12415236
TI  - Safety of dobutamine stress echocardiography in patients with unruptured
      intracranial aneurysms.
AB  - Dobutamine stress echocardiography has been increasingly used for the
      preoperative assessment of patients who undergo major vascular surgery. The
      safety of this modality has been well documented in various patient subgroups,
      including patients with aneurysms of the aorta. No previous reports, however,
      have addressed the safety of this form of stress testing in patients with
      unruptured intracranial aneurysms. After reviewing the experience of 2
      institutions, we identified 40 patients who underwent dobutamine stress
      echocardiography while harboring at least 1 unruptured intracranial aneurysm, and
      found no evidence of aneurysm instability in relation to the dobutamine infusion.
      Although vasodilator stress modalities should intuitively be the non-exercise
      stress technique of choice in these patients, stress echocardiography with the
      use of dobutamine appears to be safe and represents an acceptable option when
      used for diagnostic purposes or preoperative risk stratification in this patient
      population.

PMID- 12415237
TI  - Painful left bundle branch block detected during dobutamine stress
      echocardiography.
AB  - We report on the observation, in a 50-year-old woman undergoing dobutamine stress
      echocardiography, of the simultaneous onset of complete left bundle branch block
      and anginal chest pain, unaccompanied by any abnormality of left ventricular
      segmental contraction or wall thickening. Further etiologic investigations, in
      particular for coronary artery disease, proved negative. This observation is
      discussed in the context of a literature review.

PMID- 12415238
TI  - Aortic dissection with aorto-left atrial fistula formation soon after aortic
      valve replacement: A lethal complication diagnosed by transthoracic and
      transesophageal echocardiography.
AB  - Fistulas between the aorta and left atrium are a rare manifestation of aortic
      dissection and are infrequently diagnosed premortem. We report the case of a 70
      year-old man who exhibited this condition soon after aortic valve replacement and
      eventually died from rapidly developing refractory congestive heart failure. The
      diagnosis was indicated by transthoracic echocardiography and was ultimately made
      with transesophageal echocardiography and color flow Doppler imaging.
      Transesophageal echocardiography is the procedure of choice for establishing the
      correct diagnosis and leading to prompt surgical repair of this lethal condition.

PMID- 12415239
TI  - Severe aortic and mitral calcification in identical twin boys.
AB  - Identical twin boys presented with exercise-induced syncope. Echocardiographic
      examination revealed severe calcification at aortic valves, mitral anterior
      leaflets, and mitral annuli in both patients. In addition, basal interventricular
      septum was also involved in 1 patient. Doppler evaluation demonstrated severe
      aortic stenosis with a peak gradient of 112 and 118 mm Hg in both patients.
      Moderate mitral stenosis was also detected in one of them. Patients underwent
      operation for valve replacement.

PMID- 12415241
TI  - Paradoxical embolism to the left main coronary artery: visualization by
      transesophageal echocardiography.
AB  - A case of myocardial infarction is described with transesophageal
      echocardiography visualization of left main coronary artery thrombus arising from
      paradoxical embolism of mobile venous thrombus by patent foramen ovale.

PMID- 12415240
TI  - Generalized tetany: an unusual complication during dobutamine stress
      echocardiography.
AB  - Dobutamine stress echocardiography is a frequently used noninvasive method for
      the evaluation of inducible myocardial ischemia, myocardial viability, and
      preoperative cardiac risk. Although its clinical safety has been validated, side
      effects and complications especially with the coadministration of atropine can
      occur. We report a case of generalized tetany in a 49-year-old woman undergoing
      dobutamine stress echocardiography.

PMID- 12415242
TI  - Assessment of the vascularity of a left ventricular mass using myocardial
      contrast echocardiography.
AB  - In addition to a thrombus, an intracardiac mass lesion can represent a primary
      cardiac tumor, or a metastatic lesion to the heart. The echocardiographic
      appearance and location of the mass, as well as the associated clinical scenario
      provide useful clues regarding cause, but these echocardiographic features alone
      may not always be diagnostic. Because most benign cardiac tumors are relatively
      avascular, the vascularity of a mass may be a feature that can help differentiate
      benign from malignant tumors. We present a case of a patient with a history of
      malignant melanoma who was found incidentally to have a cardiac mass on
      echocardiography. Contrast echocardiography (CE) was used to evaluate the
      vascularity of the mass. This case is compared with another patient with an
      apical thrombus, which represents an "avascular" intracardiac structure.

PMID- 12415243
TI  - Intercoronary blood flow detected by color flow Doppler mapping is a well-known
      marker for anomalous origin of a coronary artery from the pulmonary trunk.

PMID- 12415245
TI  - Designing peptide receptor agonists and antagonists.
AB  - The most ubiquitous mode for controlling and modulating cellular function,
      intercellular communication, immune response and information-transduction
      pathways is through peptide-protein non-covalent interactions. Hormones,
      neurotransmitters, antigens, cytokines and growth factors represent key classes
      of such peptide ligands. These ligands might either be processed fragments of
      larger precursor proteins or surface segments of larger proteins. Although there
      are numerous exceptions, such as insulin, oxytocin and calcitonin, most ligands
      are not used directly as drugs, and often the most useful ligands for therapy
      would be analogues that act as antagonists of the native ligands. A search for
      systematic structure-based or ligand-based approaches to designing such ligands
      has been an important concern. Today, a robust strategy has been developed for
      the design of peptides as drugs, drug candidates and biological tools. This
      strategy includes structural, conformational, dynamic and topographical
      considerations.

PMID- 12415246
TI  - Therapeutic strategies for Alzheimer's disease.
AB  - Alzheimer's disease is a progressive and ultimately fatal neurological disorder
      for which there is no effective treatment at present. The disease is
      characterized pathologically by cerebral plaques that contain the amyloid-beta
      peptide and thread-like neuronal structures composed of the microtubule
      associated protein TAU. Both amyloid-beta and TAU are thought to be crucial to
      pathogenesis, but compelling evidence supports amyloid-beta as the 'prime mover'.
      The main efforts for developing therapeutics are therefore focused on preventing
      amyloid-beta production, aggregation or downstream neurotoxic events. The
      progress of these and other approaches raises the hope that effective agents for
      the prevention and treatment of Alzheimer's disease will be available in the near
      future.

PMID- 12415247
TI  - Hepatitis C therapeutics: current status and emerging strategies.
AB  - Chronic infection with hepatitis C virus (HCV) is an emerging global epidemic.
      The development of effective HCV antiviral therapeutics continues to be a
      daunting challenge owing to the absence of adequate animal models and tissue
      culture systems for analysis and propagation of the virus. Despite these
      obstacles, inhibitors of the replicative elements of HCV, immune modulators and
      non-specific hepatoprotective agents are being pursued and exciting progress has
      been made. Successful therapeutic intervention of HCV will probably require
      combination approaches and new approaches, including host drug discovery targets.

PMID- 12415248
TI  - Integration of virtual and high-throughput screening.
AB  - High-throughput and virtual screening are important components of modern drug
      discovery research. Typically, these screening technologies are considered
      distinct approaches, as one is experimental and the other is theoretical in
      nature. However, given their similar tasks and goals, these approaches are much
      more complementary to each other than often thought. Various statistical,
      informatics and filtering methods have recently been introduced to foster the
      integration of experimental and in silico screening and maximize their output in
      drug discovery. Although many of these ideas and efforts have not yet proceeded
      much beyond the conceptual level, there are several success stories and good
      indications that early-stage drug discovery will benefit greatly from a more
      unified and knowledge-based approach to biological screening, despite the many
      technical advances towards even higher throughput that are made in the screening
      arena.

PMID- 12415249
TI  - The future challenges facing the development of new antimicrobial drugs.
AB  - The emergence of resistance to antibacterial agents is a pressing concern for
      human health. New drugs to combat this problem are therefore in great demand, but
      as past experience indicates, the time for resistance to new drugs to develop is
      often short. Conventionally, antibacterial drugs have been developed on the basis
      of their ability to inhibit bacterial multiplication, and this remains at the
      core of most approaches to discover new antibacterial drugs. Here, we focus
      primarily on an alternative novel strategy for antibacterial drug development
      that could potentially alleviate the current situation of drug resistance-
      targeting non-multiplying latent bacteria, which prolong the duration of
      antimicrobial chemotherapy and so might increase the rate of development of
      resistance.

PMID- 12415250
TI  - Hepatitis C virus replicons: potential role for drug development.
AB  - The development of causal therapies depends on the availability of systems to
      determine the inhibitory capacity of a compound. As viruses are obligate
      intracellular parasites, the efficacy of an antiviral drug is usually evaluated
      in a cell-culture system. Unfortunately, the hepatitis C virus, the principal
      causative agent of acute and chronic liver disease, cannot be propagated
      efficiently in the laboratory. However, the recent development of a replicon
      system opens up an encouraging possibility for drug discovery.

PMID- 12415251
TI  - Drug advertising: the right or wrong prescription for our ailments?
AB  - As the cost of health care--particularly prescription drugs--is rising at a rate
      that has not been seen in a decade, the United States finds itself once again
      searching for new solutions to what has, until now, been an intractable problem.
      Drug advertising, which has almost become part of the social fabric in the United
      States, is an appealing and visible target. Critics point to pharmaceutical
      companies boosting profits by pitching pills, whereas advocates talk of
      empowering patients with information. With a topic that is so dominated by money
      and politics, it is sometimes hard to tell who is correct.

PMID- 12415252
TI  - Centrosome aberrations: cause or consequence of cancer progression?

PMID- 12415253
TI  - Vascular and haematopoietic stem cells: novel targets for anti-angiogenesis
      therapy?

PMID- 12415254
TI  - The pathogenesis of pituitary tumours.

PMID- 12415255
TI  - New aspects of natural-killer-cell surveillance and therapy of cancer.

PMID- 12415256
TI  - Cachexia in cancer patients.

PMID- 12415257
TI  - Quality of life: a new perspective for cancer patients.

PMID- 12415258
TI  - Telomere maintenance and cancer -- look, no telomerase.

PMID- 12415259
TI  - Beta cells are responsible for CXCR3-mediated T-cell infiltration in insulitis.
AB  - T cell-mediated loss of insulin-secreting beta cells in the islets of Langerhans
      is the hallmark of type 1 diabetes. The molecular basis for the directed
      migration of autoreactive T cells leading to insulitis is presently unknown. Here
      we demonstrate that in response to inflammation, beta cells secrete the
      chemokines CXC ligand 10 and CXC ligand 9, which specifically attract T-effector
      cells via the CXC chemokine receptor 3. In mice deficient for this receptor, the
      onset of type 1 diabetes is substantially delayed. Thus, in the absence of known
      etiological agents, CXC receptor 3 represents a novel target for therapeutic
      interference early in type 1 diabetes.

PMID- 12415260
TI  - Serum insulin-like growth factor I regulates brain amyloid-beta levels.
AB  - Levels of insulin-like growth factor I (IGF-I), a neuroprotective hormone,
      decrease in serum during aging, whereas amyloid-beta (Abeta), which is involved
      in the pathogenesis of Alzheimer disease, accumulates in the brain. High brain
      Abeta levels are found at an early age in mutant mice with low circulating IGF-I,
      and Abeta burden can be reduced in aging rats by increasing serum IGF-I. This
      opposing relationship between serum IGF-I and brain Abeta levels reflects the
      ability of IGF-I to induce clearance of brain Abeta, probably by enhancing
      transport of Abeta carrier proteins such as albumin and transthyretin into the
      brain. This effect is antagonized by tumor necrosis factor-alpha, a pro
      inflammatory cytokine putatively involved in dementia and aging. Because IGF-I
      treatment of mice overexpressing mutant amyloid markedly reduces their brain
      Abeta burden, we consider that circulating IGF-I is a physiological regulator of
      brain amyloid levels with therapeutic potential.

PMID- 12415261
TI  - A DNA vaccine against VEGF receptor 2 prevents effective angiogenesis and
      inhibits tumor growth.
AB  - Tumor cells are elusive targets for immunotherapy due to their heterogeneity and
      genetic instability. Here we describe a novel, oral DNA vaccine that targets
      stable, proliferating endothelial cells in the tumor vasculature rather than
      tumor cells. Targeting occurs through upregulated vascular-endothelial growth
      factor receptor 2 (FLK-1) of proliferating endothelial cells in the tumor
      vasculature. This vaccine effectively protected mice from lethal challenges with
      melanoma, colon carcinoma and lung carcinoma cells and reduced growth of
      established metastases in a therapeutic setting. CTL-mediated killing of
      endothelial cells indicated breaking of peripheral immune tolerance against this
      self antigen, resulting in markedly reduced dissemination of spontaneous and
      experimental pulmonary metastases. Angiogenesis in the tumor vasculature was
      suppressed without impairment of fertility, neuromuscular performance or
      hematopoiesis, albeit with a slight delay in wound healing. Our strategy
      circumvents problems in targeting of genetically unstable tumor cells. This
      approach may provide a new strategy for the rational design of cancer therapies.

PMID- 12415262
TI  - Induction of angiogenesis in a mouse model using engineered transcription
      factors.
AB  - The relationship between the structure of zinc-finger protein (ZFP) transcription
      factors and DNA sequence binding specificity has been extensively studied.
      Advances in this field have made it possible to design ZFPs de novo that will
      bind to specific targeted DNA sequences. It has been proposed that such designed
      ZFPs may eventually be useful in gene therapy. A principal advantage of this
      approach is that activation of an endogenous gene ensures expression of the
      natural array of splice variants. Preliminary studies in tissue culture have
      validated the feasibility of this approach. The studies reported here were
      intended to test whether engineered transcription factors are effective in a
      whole-organism model. ZFPs were designed to regulate the endogenous gene encoding
      vascular endothelial growth factor-A (Vegfa). Expression of these new ZFPs in
      vivo led to induced expression of the protein VEGF-A, stimulation of angiogenesis
      and acceleration of experimental wound healing. In addition, the neovasculature
      resulting from ZFP-induced expression of Vegfa was not hyperpermeable as was that
      produced by expression of murine Vegfa(164) cDNA. These data establish, for the
      first time, that specifically designed transcription factors can regulate an
      endogenous gene in vivo and evoke a potentially therapeutic biophysiologic
      effect.

PMID- 12415263
TI  - Identification of diversified genes that contain immunoglobulin-like variable
      regions in a protochordate.
AB  - The evolutionary origin of adaptive immune receptors is not understood below the
      phylogenetic level of the jawed vertebrates. We describe here a strategy for the
      selective cloning of cDNAs encoding secreted or transmembrane proteins that uses
      a bacterial plasmid (Amptrap) with a defective beta-lactamase gene. This method
      requires knowledge of only a single target motif that corresponds to as few as
      three amino acids; it was validated with major histocompatibility complex genes
      from a cartilaginous fish. Using this approach, we identified families of genes
      encoding secreted proteins with two diversified immunoglobulin-like variable (V)
      domains and a chitin-binding domain in amphioxus, a protochordate. Thus,
      multigenic families encoding diversified V regions exist in a species lacking an
      adaptive immune response.

PMID- 12415264
TI  - CD1-dependent dendritic cell instruction.
AB  - Both microbial products and T cell factors influence dendritic cell (DC)
      maturation. However, it is not known which T cells are capable of interacting
      with DCs at the initiation of adaptive immunity, when foreign antigen-specific T
      cells are rare. We show here that self-reactive CD1-restricted T cells can
      promote DC maturation by recognizing CD1 in the absence of foreign antigens. T
      cell recognition of all four CD1 isoforms can trigger DC maturation, but their
      distinct mechanisms of costimulation lead to profound differences in concomitant
      interleukin 12 p70 production. Distinct CD1-reactive T cells may thus
      differentially direct DC development early in the immune response, thereby
      controlling subsequent polarization of acquired immunity.

PMID- 12415266
TI  - Dominant transplantation tolerance impairs CD8+ T cell function but not
      expansion.
AB  - Alloreactive CD8+ T cells may persist in animals made tolerant of transplanted
      tissues; their function is controlled through continuous censorship by regulatory
      CD4+ T cells. We sought to establish the stage at which such censorship operates.
      We found that monospecific CD8+ T cells introduced into tolerant animals
      responded to the tolerated tissue antigen as if they had received CD4+ T cell
      "help": they proliferated and accumulated normally. However, they did show
      compromised graft rejection, interferon-gamma production and cell-mediated
      cytotoxicity. These findings suggest that tolerance mediated by regulatory T
      cells acts by censoring immune effector functions rather than by limiting the
      induction of T cell responses.

PMID- 12415265
TI  - Langerhans cells renew in the skin throughout life under steady-state conditions.
AB  - Langerhans cells (LCs) are bone marrow (BM)-derived epidermal dendritic cells
      (DCs) that represent a critical immunologic barrier to the external environment,
      but little is known about their life cycle. Here, we show that in lethally
      irradiated mice that had received BM transplants, LCs of host origin remained for
      at least 18 months, whereas DCs in other organs were almost completely replaced
      by donor cells within 2 months. In parabiotic mice with separate organs, but a
      shared blood circulation, there was no mixing of LCs. However, in skin exposed to
      ultraviolet light, LCs rapidly disappeared and were replaced by circulating LC
      precursors within 2 weeks. The recruitment of new LCs was dependent on their
      expression of the CCR2 chemokine receptor and on the secretion of CCR2-binding
      chemokines by inflamed skin. These data indicate that under steady-state
      conditions, LCs are maintained locally, but inflammatory changes in the skin
      result in their replacement by blood-borne LC progenitors.

PMID- 12415267
TI  - c-Cbl and Cbl-b regulate T cell responsiveness by promoting ligand-induced TCR
      down-modulation.
AB  - How Cbl family proteins regulate T cell responses is unclear. We found that c-Cbl
      Cbl-b double knock-out (dKO) T cells became hyperresponsive upon anti-CD3
      stimulation, even though the major T cell antigen receptor (TCR) signaling
      pathways were not enhanced. The dKO T cells did not down-modulate surface TCR
      after ligand engagement, which resulted in sustained TCR signaling. However,
      these cells showed normal ligand-independent TCR internalization, and trafficking
      of internalized TCR to the lysosome compartment after ligand engagement was
      reduced. These findings show that Cbl family proteins negatively regulate T cell
      activation by promoting clearance of engaged TCR from the cell surface, a process
      that is apparently essential for the termination of TCR signals.

PMID- 12415268
TI  - Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia.
AB  - Chuvash polycythemia is an autosomal recessive disorder that is endemic to the
      mid-Volga River region. We previously mapped the locus associated with Chuvash
      polycythemia to chromosome 3p25. The gene associated with von Hippel-Lindau
      syndrome, VHL, maps to this region, and homozygosity with respect to a C-->T
      missense mutation in VHL, causing an arginine-to-tryptophan change at amino-acid
      residue 200 (Arg200Trp), was identified in all individuals affected with Chuvash
      polycythemia. The protein VHL modulates the ubiquitination and subsequent
      destruction of hypoxia-inducible factor 1, subunit alpha (HIF1alpha). Our data
      indicate that the Arg200Trp substitution impairs the interaction of VHL with
      HIF1alpha, reducing the rate of degradation of HIF1alpha and resulting in
      increased expression of downstream target genes including EPO (encoding
      erythropoietin), SLC2A1 (also known as GLUT1, encoding solute carrier family 2
      (facilitated glucose transporter), member 1), TF (encoding transferrin), TFRC
      (encoding transferrin receptor (p90, CD71)) and VEGF (encoding vascular
      endothelial growth factor).

PMID- 12415269
TI  - RNASEL Arg462Gln variant is implicated in up to 13% of prostate cancer cases.
AB  - RNASEL (encoding ribonuclease L) has recently been proposed as a candidate for
      the hereditary prostate cancer (HPC1) gene. We determined that the RNASEL variant
      Arg462Gln has three times less enzymatic activity than the wildtype and is
      significantly associated with prostate cancer risk (P = 0.007). At least one copy
      of the mutated allele that causes this substitution is carried by nearly 60% of
      the men in our study. Men that are heterozygous with respect to the mutated
      allele have 50% greater risk of prostate cancer than non-carriers, and
      homozygotes have more than double the risk.

PMID- 12415270
TI  - A mouse model of human L1 retrotransposition.
AB  - The L1 retrotransposon has had an immense impact on the size and structure of the
      human genome through a variety of mechanisms, including insertional mutagenesis.
      To study retrotransposition in a living organism, we created a mouse model of
      human L1 retrotransposition. Here we show that L1 elements can retrotranspose in
      male germ cells, and that expression of a human L1 element under the control of
      its endogenous promoter is restricted to testis and ovary. In the mouse line with
      the highest level of L1 expression, we found two de novo L1 insertions in 135
      offspring. Both insertions were structurally indistinguishable from natural
      endogenous insertions. This suggests that an individual L1 element can have
      substantial mutagenic potential. In addition to providing a valuable in vivo
      model of retrotransposition in mammals, these mice are an important step in the
      development of a new random mutagenesis system.

PMID- 12415271
TI  - A myogenic differentiation checkpoint activated by genotoxic stress.
AB  - Cell-cycle checkpoints help to protect the genomes of proliferating cells under
      genotoxic stress. In multicellular organisms, cell proliferation is often
      directed toward differentiation during development and throughout adult
      homeostasis. To prevent the formation of differentiated cells with genetic
      instability, we hypothesized that genotoxic stress may trigger a differentiation
      checkpoint. Here we show that exposure to genotoxic agents causes a reversible
      inhibition of myogenic differentiation. Muscle-specific gene expression is
      suppressed by DNA-damaging agents if applied prior to differentiation induction
      but not after the differentiation program is established. The myogenic
      determination factor, MyoD (encoded by Myod1), is a target of the differentiation
      checkpoint in myoblasts. The inhibition of MyoD by DNA damage requires a
      functional c-Abl tyrosine kinase (encoded by Abl1), but occurs in cells deficient
      for p53 (transformation-related protein 53, encoded by Trp53) or c-Jun (encoded
      by the oncogene Jun). These results support the idea that genotoxic stress can
      regulate differentiation, and identify a new biological function for DNA damage
      activated signaling network.

PMID- 12415272
TI  - Mutations in PHF6 are associated with Borjeson-Forssman-Lehmann syndrome.
AB  - Borjeson-Forssman-Lehmann syndrome (BFLS; OMIM 301900) is characterized by
      moderate to severe mental retardation, epilepsy, hypogonadism, hypometabolism,
      obesity with marked gynecomastia, swelling of subcutaneous tissue of the face,
      narrow palpebral fissure and large but not deformed ears. Previously, the gene
      associated with BFLS was localized to 17 Mb in Xq26-q27 (refs 2-4). We have
      reduced this interval to roughly 9 Mb containing more than 62 genes. Among these,
      a novel, widely expressed zinc-finger (plant homeodomain (PHD)-like finger) gene
      (PHF6) had eight different missense and truncation mutations in seven familial
      and two sporadic cases of BFLS. Transient transfection studies with PHF6 tagged
      with green fluorescent protein (GFP) showed diffuse nuclear staining with
      prominent nucleolar accumulation. Such localization, and the presence of two PHD
      like zinc fingers, is suggestive of a role for PHF6 in transcription.

PMID- 12415273
TI  - Of man in mice.

PMID- 12415276
TI  - Nematodes net Nobel.

PMID- 12415277
TI  - Synaptic vesicle retrieval: still time for a kiss.

PMID- 12415278
TI  - Wnt signalling sees spots.

PMID- 12415279
TI  - Drosophila, actin and videotape -- new insights in wound healing.

PMID- 12415280
TI  - Pin-ning down p53 function.

PMID- 12415281
TI  - Integrins as developmental switches.

PMID- 12415282
TI  - Chk2 leaves the PML depot.

PMID- 12415283
TI  - Polar exploration.

PMID- 12415285
TI  - Hopeful monsters and morphogens at the beach.
AB  - The Santa Cruz Developmental Biology Conference (August 15-19, 2002) provided the
      latest insights into how a single cell is transformed into a complex organism.
      Organisms that flower, slither, walk and fly continue to provide new insights
      into the cell biological and molecular mechanisms that control cell movement,
      signalling pathways and post-transcriptional regulation; hopeful monsters sit at
      our doorstep to provide new insight into evolutionary change and human disease.

PMID- 12415286
TI  - The cellular and molecular basis of store-operated calcium entry.
AB  - The impact of calcium signalling on so many areas of cell biology reflects the
      crucial role of calcium signals in the control of diverse cellular functions.
      Despite the precision with which spatial and temporal details of calcium signals
      have been resolved, a fundamental aspect of the generation of calcium signals --
      the activation of 'store-operated channels' (SOCs) -- remains a molecular and
      mechanistic mystery. Here we review new insights into the exchange of signals
      between the endoplasmic reticulum (ER) and plasma membrane that result in
      activation of calcium entry channels mediating crucial long-term calcium signals.

PMID- 12415287
TI  - Boosting heterologous protein production in transgenic dicotyledonous seeds using
      Phaseolus vulgaris regulatory sequences.
AB  - Over the past decade, several high value proteins have been produced in different
      transgenic plant tissues such as leaves, tubers, and seeds. Despite recent
      advances, many heterologous proteins accumulate to low concentrations, and the
      optimization of expression cassettes to make in planta production and
      purification economically feasible remains critical. Here, the regulatory
      sequences of the seed storage protein gene arcelin 5-I (arc5-I) of common bean
      (Phaseolus vulgaris) were evaluated for producing heterologous proteins in
      dicotyledonous seeds. The murine single chain variable fragment (scFv) G4 (ref.
      4) was chosen as model protein because of the current industrial interest in
      producing antibodies and derived fragments in crops. In transgenic Arabidopsis
      thaliana seed stocks, the scFv under control of the 35S promoter of the
      cauliflower mosaic virus (CaMV) accumulated to approximately 1% of total soluble
      protein (TSP). However, a set of seed storage promoter constructs boosted the
      scFv accumulation to exceptionally high concentrations, reaching no less than
      36.5% of TSP in homozygous seeds. Even at these high concentrations, the scFv
      proteins had antigen-binding activity and affinity similar to those produced in
      Escherichia coli. The feasibility of heterologous protein production under
      control of arc5-I regulatory sequences was also demonstrated in Phaseolus
      acutifolius, a promising crop for large scale production.

PMID- 12415288
TI  - Dual-specific T cells combine proliferation and antitumor activity.
AB  - An effective immune response against cancer requires the activation and expansion
      of specific T cells. Tumor antigens, however, are generally poor immunogens. To
      achieve expansion of tumor-reactive T cells in vivo, we used a strategy of
      generating dual-specific T cells that could respond to a powerful immunogen while
      also possessing tumor reactivity. We generated dual-specific T cells by genetic
      modification of alloreactive T cells with a chimeric receptor recognizing folate
      binding protein, an ovarian cancer-associated antigen. Mouse dual-specific T
      cells responded in vitro to both allogeneic antigen and tumor cells expressing
      folate-binding protein, and expanded in number in vivo in response to
      immunization with allogeneic cells. Most importantly, the combination of dual
      specific T cells and immunization had an antitumor effect in vivo. We also
      generated human dual-specific T cells and characterized the dual-specific nature
      of individual clones. Assigning the tasks of expansion and tumor reactivity to
      different receptors within the same lymphocyte may help to overcome the problem
      of poor immunogenicity of tumor antigens.

PMID- 12415289
TI  - Structural basis for oligosaccharide-mediated adhesion of Pseudomonas aeruginosa
      in the lungs of cystic fibrosis patients.
AB  - Pseudomonas aeruginosa galactose- and fucose-binding lectins (PA-IL and PA-IIL)
      contribute to the virulence of this pathogenic bacterium, which is a major cause
      of morbidity and mortality in cystic fibrosis patients. The crystal structure of
      PA-IIL in complex with fucose reveals a tetrameric structure. Each monomer
      displays a nine-stranded, antiparallel b-sandwich arrangement and contains two
      close calcium cations that mediate the binding of fucose in a recognition mode
      unique among carbohydrate-protein interactions. Experimental binding studies,
      together with theoretical docking of fucose-containing oligosaccharides, are
      consistent with the assumption that antigens of the Lewis a (Le(a)) series may be
      the preferred ligands of this lectin. Precise knowledge of the lectin-binding
      site should allow a better design of new antibacterial-adhesion prophylactics.

PMID- 12415290
TI  - Identification and analysis of a bottleneck in PCB biodegradation.
AB  - The microbial degradation of polychlorinated biphenyls (PCBs) provides the
      potential to destroy these widespread, toxic and persistent environmental
      pollutants. For example, the four-step upper bph pathway transforms some of the
      more than 100 different PCBs found in commercial mixtures and is being engineered
      for more effective PCB degradation. In the critical third step of this pathway,
      2,3-dihydroxybiphenyl (DHB) 1,2-dioxygenase (DHBD; EC 1.13.11.39) catalyzes
      aromatic ring cleavage. Here we demonstrate that ortho-chlorinated PCB
      metabolites strongly inhibit DHBD, promote its suicide inactivation and interfere
      with the degradation of other compounds. For example, k(cat)(app) for 2',6'-diCl
      DHB was reduced by a factor of approximately 7,000 relative to DHB, and it bound
      with sufficient affinity to competitively inhibit DHB cleavage at nanomolar
      concentrations. Crystal structures of two complexes of DHBD with ortho
      chlorinated metabolites at 1.7 A resolution reveal an explanation for these
      phenomena, which have important implications for bioremediation strategies.

PMID- 12415291
TI  - Structural basis for uracil recognition by archaeal family B DNA polymerases.
AB  - Deamination of cytosine to uracil in a G-C base pair is a major promutagenic
      event, generating G-C-->A-T mutations if not repaired before DNA replication.
      Archaeal family B DNA polymerases are uniquely able to recognize unrepaired
      uracil in a template strand and stall polymerization upstream of the lesion,
      thereby preventing the irreversible fixation of an A-T mutation. We have now
      identified a 'pocket' in the N-terminal domains of archaeal DNA polymerases that
      is positioned to interact with the template strand and provide this ability. The
      structure of this pocket provides interacting groups that discriminate uracil
      from the four normal DNA bases (including thymine). These groups are conserved in
      archaeal polymerases but absent from homologous viral polymerases that are unable
      to recognize uracil. Using site-directed mutagenesis, we have confirmed the
      biological role of this pocket and have engineered specific mutations in the Pfu
      polymerase that confer the ability to read through template-strand uracils and
      carry out PCR with dUTP in place of dTTP.

PMID- 12415292
TI  - Retinoid signalling in the development of the central nervous system.

PMID- 12415293
TI  - Ubiquitin and the synapse.

PMID- 12415294
TI  - Calcium dyshomeostasis and intracellular signalling in Alzheimer's disease.

PMID- 12415295
TI  - Calcium-dependent inactivation of neuronal calcium channels.

PMID- 12415296
TI  - Olfactory network dynamics and the coding of multidimensional signals.

PMID- 12415297
TI  - The molecular organization of cerebellar long-term depression.

PMID- 12415298
TI  - Neural worlds and real worlds.

PMID- 12415299
TI  - Intraflagellar transport.
AB  - Eukaryotic cilia and flagella, including primary cilia and sensory cilia, are
      highly conserved organelles that project from the surfaces of many cells. The
      assembly and maintenance of these nearly ubiquitous structures are dependent on a
      transport system--known as 'intraflagellar transport' (IFT)--which moves non
      membrane-bound particles from the cell body out to the tip of the cilium or
      flagellum, and then returns them to the cell body. Recent results indicate that
      defects in IFT might be a primary cause of some human diseases.

PMID- 12415300
TI  - Motors and switches: AAA+ machines within the replisome.
AB  - Clamp loaders are required to load the ring-shaped clamps that tether replicative
      DNA polymerases onto DNA. Recently solved crystal structures, along with a series
      of biochemical studies, have provided a detailed understanding of the clamp
      loading reaction. In particular, studies of the Escherichia coli clamp loader--an
      AAA+ machine--have provided insights into the architecture of clamp loaders from
      eukaryotes, bacteriophage T4 and archaea. Other AAA+ proteins are also involved
      in the initiation of DNA replication, and studies of the E. coli clamp loader
      indicate mechanisms by which these proteins might function.

PMID- 12415301
TI  - Formation and transfer of disulphide bonds in living cells.
AB  - Protein disulphide bonds are formed in the endoplasmic reticulum of eukaryotic
      cells and the periplasmic space of prokaryotic cells. The main pathways that
      catalyse the formation of protein disulphide bonds in prokaryotes and eukaryotes
      are remarkably similar, and they share several mechanistic features. The recent
      identification of new redox-active proteins in humans and yeast that
      mechanistically parallel the more established redox-active enzymes indicates that
      there might be further uncharacterized redox pathways throughout the cell.

PMID- 12415302
TI  - Lamins: building blocks or regulators of gene expression?
AB  - Intermediate filament (IF) proteins are the building blocks of cytoskeletal
      filaments, the main function of which is to maintain cell shape and integrity.
      The lamins are thought to be the evolutionary progenitors of IF proteins and they
      have profound influences on both nuclear structure and function. These influences
      require the lamins to have dynamic properties and dual identities--as building
      blocks and transcriptional regulators. Which one of these identities underlies a
      myriad of genetic diseases is a topic of intense debate.

PMID- 12415303
TI  - Recombinational repair and restart of damaged replication forks.
AB  - Genome duplication necessarily involves the replication of imperfect DNA
      templates and, if left to their own devices, replication complexes regularly run
      into problems. The details of how cells overcome these replicative 'hiccups' are
      beginning to emerge, revealing a complex interplay between DNA replication,
      recombination and repair that ensures faithful passage of the genetic material
      from one generation to the next.

PMID- 12415304
TI  - George Emil Palade: charismatic virtuoso of cell biology.
AB  - George Palade has created, shared and passed on a multidisciplinary view of the
      functional organization, biogenesis and dynamics of organelles. His open
      mindedness and tenacity, along with his rigour and sense of intellectual
      elegance, have been remarkable. This focus on the logic of organelles defined a
      crucial turning point in biomedical science. The following article sketches
      Palade's research, as part of a larger community that flourished after the Second
      World War.

PMID- 12415305
TI  - The significance of molecular slips in transport systems.
AB  - The advantage of precision in biological processes is obvious; however, in many
      cases, deviations from the faithful mechanisms occur. Here, we discuss how in
      built operating imperfections in transport systems can actually benefit a cell.

PMID- 12415306
TI  - Lymphocide: cytokines and the control of lymphoid homeostasis.
AB  - In a human, about 10(11) excess peripheral lymphocytes die every day. This death
      process maintains a constant lymphocyte population size in the face of a
      continuous influx of new lymphocytes and the homeostatic proliferation of old
      ones. Death is triggered when a lymphocyte fails to acquire signals from survival
      factors, the availability of which, therefore, determines the size of the pool of
      lymphocytes. A lymphocyte acquires survival signals through receptors for
      cytokines, antigens, hormones and probably other extracellular factors. Here, we
      discuss current concepts of the intracellular signalling pathways for survival
      versus death that establish cytokine-regulated lymphocyte homeostasis.

PMID- 12415307
TI  - Antigens and immunoevasins: opponents in cytomegalovirus immune surveillance.
AB  - CD8+ T cells are the main effector cells for the immune control of
      cytomegaloviruses. To subvert this control, human and mouse cytomegaloviruses
      each encode a set of immune-evasion proteins, referred to here as immunoevasins,
      which interfere specifically with the MHC class I pathway of antigen processing
      and presentation. Although the concerted action of immunoevasins prevents the
      presentation of certain viral peptides, other viral peptides escape this blockade
      conditionally or constitutively and thereby provide the molecular basis of immune
      surveillance by CD8+ T cells. The definition of viral antigenic peptides that are
      presented despite the presence of immunoevasins adds a further dimension to the
      prediction of protective epitopes for use in vaccines.

PMID- 12415308
TI  - The immunology of susceptibility and resistance to Leishmania major in mice.
AB  - Established models of T-helper-2-cell dominance in BALB/c mice infected with
      Leishmania major -- involving the early production of interleukin-4 by a small
      subset of Leishmania-specific CD4+ T cells -- have been refined by accumulating
      evidence that this response is not sufficient and, under some circumstances, not
      required to promote susceptibility. In addition, more recent studies in L. major
      resistant mice have revealed complexities in the mechanisms responsible for
      acquired immunity, which necessitate the redesign of vaccines against Leishmania
      and other pathogens that require sustained cell-mediated immune responses.

PMID- 12415309
TI  - Stem cell medicine encounters the immune system.
AB  - Recent progress in deriving human embryonic stem (hES) cells and defining their
      capacity to differentiate has inspired hope that they could become a source of
      replacement cells for damaged or diseased tissues. We review the immunological
      barriers to transplanting hES cells and consider several potential solutions,
      including stem-cell banking, modification of the immunogenicity of donor cells
      and induction of tolerance to the graft. We evaluate the probable efficacy of
      these approaches with a view to facilitating the use of hES cells in clinical
      practice.

PMID- 12415310
TI  - Two-photon tissue imaging: seeing the immune system in a fresh light.
AB  - Many lymphocyte functions, such as antigen recognition, take place deep in
      densely populated lymphoid organs. Because direct in vivo observation was not
      possible, the dynamics of immune-cell interactions have been inferred or
      extrapolated from in vitro studies. Two-photon fluorescence excitation uses
      extremely brief (<1 picosecond) and intense pulses of light to 'see' directly
      into living tissues, to a greater depth and with less phototoxicity than
      conventional imaging methods. Two-photon microscopy, in combination with newly
      developed indicator molecules, promises to extend single-cell approaches to the
      in vivo setting and to reveal in detail the cellular collaborations that underlie
      the immune response.

PMID- 12415311
TI  - Opinion: Interpretation of the complexity of innate immune responses by
      functional genomics.
AB  - Understanding how the immune system is regulated and responds to pathogens will
      require whole-system approaches, because the study of single immunological
      parameters has, so far, been unable to unlock immune-system complexity. Global
      transcription analysis using microarray technologies provides a new approach to
      the description of complex biological phenomena. Here, we discuss insights into
      innate immunity that have been provided by genome-wide approaches and their
      impact on the interpretation of immune-system complexity.

PMID- 12415312
TI  - A positive look at double-negative thymocytes.
AB  - In some respects, our understanding of the cellular and molecular aspects of
      early T-cell differentiation is lagging behind that of B cells. Papers describing
      gene-knockout and reporter-transgenic mice in which thymocyte development is
      affected are often difficult to interpret. Progress in this field will be
      hampered unless a more detailed phenotypic and molecular analysis of progenitor
      thymocytes at the single-cell level is carried out.

PMID- 12415313
TI  - Splitting pairs: the diverging fates of duplicated genes.
AB  - Many genes are members of large families that have arisen during evolution
      through gene duplication events. Our increasing understanding of gene
      organization at the scale of whole genomes is revealing further evidence for the
      extensive retention of genes that arise during duplication events of various
      types. Duplication is thought to be an important means of providing a substrate
      on which evolution can work. An understanding of gene duplication and its
      resolution is crucial for revealing mechanisms of genetic redundancy. Here, we
      consider both the theoretical framework and the experimental evidence to explain
      the preservation of duplicated genes.

PMID- 12415314
TI  - The origin and evolution of model organisms.
AB  - The phylogeny and timescale of life are becoming better understood as the
      analysis of genomic data from model organisms continues to grow. As a result,
      discoveries are being made about the early history of life and the origin and
      development of complex multicellular life. This emerging comparative framework
      and the emphasis on historical patterns is helping to bridge barriers among
      organism-based research communities.

PMID- 12415315
TI  - Genome evolution in bacterial endosymbionts of insects.
AB  - Many insect species rely on intracellular bacterial symbionts for their viability
      and fecundity. Large-scale DNA-sequence analyses are revealing the forces that
      shape the evolution of these bacterial associates and the genetic basis of their
      specialization to an intracellular lifestyle. The full genome sequences of two
      obligate mutualists, Buchnera aphidicola of aphids and Wigglesworthia glossinidia
      of tsetse flies, reveal substantial gene loss and an integration of host and
      symbiont metabolic functions. Further genomic comparisons should reveal the
      generality of these features among bacterial mutualists and the extent to which
      they are shared with other intracellular bacteria, including obligate pathogens.

PMID- 12415316
TI  - DNA Pooling: a tool for large-scale association studies.
AB  - DNA pooling is a practical way to reduce the cost of large-scale association
      studies to identify susceptibility loci for common diseases. Pooling allows
      allele frequencies in groups of individuals to be measured using far fewer PCR
      reactions and genotyping assays than are used when genotyping individuals. Here,
      we discuss recent developments in quantitative genotyping assays and in the
      design and analysis of pooling studies. Sophisticated pooling designs are being
      developed that can take account of hidden population stratification, confounders
      and inter-loci interactions, and that allow the analysis of haplotypes.

PMID- 12415317
TI  - Classical twin studies and beyond.
AB  - Twin studies have been a valuable source of information about the genetic basis
      of complex traits. To maximize the potential of twin studies, large, worldwide
      registers of data on twins and their relatives have been established. Here, we
      provide an overview of the current resources for twin research. These can be used
      to obtain insights into the genetic epidemiology of complex traits and diseases,
      to study the interaction of genotype with sex, age and lifestyle factors, and to
      study the causes of co-morbidity between traits and diseases. Because of their
      design, these registers offer unique opportunities for selected sampling for
      quantitative trait loci linkage and association studies.

PMID- 12415318
TI  - A fortunate choice: the history of Arabidopsis as a model plant.
AB  - During the past 20 years, the flowering plant Arabidopsis thaliana has been
      adopted as a model organism by thousands of biologists. This community has
      developed important tools, resources and experimental approaches that have
      greatly stimulated plant biological research. Here, we review some of the key
      events that led to the uptake of Arabidopsis as a model plant and to the growth
      of the Arabidopsis community.

PMID- 12415319
TI  - Conrad Hal Waddington: the last Renaissance biologist?
AB  - Conrad Hal Waddington was a leading embryologist and geneticist from the 1930s to
      the 1950s. He is remembered mainly for his concepts of the 'epigenetic landscape'
      and 'genetic assimilation'. This article reviews his life and work, and enquires
      to what extent his ideas are relevant tools for understanding the biological
      problems of today.

PMID- 12415320
TI  - Science and humanism: the twin pillars of medicine.

PMID- 12415321
TI  - Pathogenesis and prediction of diabetes mellitus: lessons from integrative
      physiology.
AB  - The molecular revolution in biology is providing an exponentially increasing body
      of data regarding subcellular events in normal and pathological conditions. The
      task of integrating even a small part of this deluge of information is a
      formidable challenge. Many integrative regulatory principles are still unknown.
      The present article argues that important principles may be discovered by the
      repetitive experimental testing of simple isomorphic computer or mathematical
      models of biological regulation. The system regulating the blood glucose is used
      as an example. Implicit in a  minimal model,  postulated more than 20 years ago,
      were specific but untested assumptions. These assumptions, which were tested over
      the ensuing decades, have enriched our understanding of metabolic regulation and
      the causes of diabetes. Currently accepted concepts emerging from modeling
      include: (a) the importance of sluggish insulin transport across the capillary
      endothelium in stimulation of glucose uptake; (b) the  single gateway  concept,
      that insulin transport across endothelium of adipose tissue suppresses free fatty
      acids, which act in turn to reduce endogenous glucose production by the liver;
      (c) the importance of the single gateway mechanism in the metabolic syndrome,
      whereby increased fat in the abdominal compartment relates to insulin resistance
      and risk for type 2 diabetes; and (d) the hyperbolic relationship between insulin
      action and insulin secretion, which provides an accurate prediction of diabetes
      risk. It is hoped that the experience with the metabolic system will provide a
      metaphor for other regulatory systems less subjected to critical quantitative
      analysis. Such analysis may well lead to analogous conceptual understanding of
      other important integrated biological systems, and provide approaches for early
      intervention in the pathogenic process of other chronic and devastating diseases.

PMID- 12415322
TI  - The small world of global health.
AB  - This article is based on the Solomon Berson lecture, delivered by Dr. Koplan in
      January 2000. In his remarks, Dr. Koplan discussed the current status of global
      health and projected trends in three categories: communicable diseases, risk
      factors for disease, and selected diseases and health conditions. Reflecting on
      differences in health issues in the 30 years since he left Mount Sinai, Dr.
      Koplan pointed out that the health problems of developed and developing nations
      are strikingly similar now   which also means they are amenable to similar
      interventions.

PMID- 12415323
TI  - Role of stathmin in the regulation of the mitotic spindle: potential applications
      in cancer therapy.
AB  - Stathmin is a member of a novel class of microtubule-destabilizing proteins that
      regulate the dynamics of microtubule polymerization and depolymerization.
      Stathmin promotes microtubule depolymerization during interphase and late
      mitosis. This microtubule depolymerizing activity of stathmin is regulated by
      changes in its level of phosphorylation that occur during cell cycle progression.
      These modifications allow it to play a critical role in the regulation of the
      dynamic equilibrium of microtubules during different phases of the cell cycle.
      Stathmin is expressed at high levels in a wide variety of human cancers.
      Inhibition of stathmin expression in malignant cells interferes with their
      orderly progression through the cell cycle and abrogates their transformed
      phenotype. Thus, stathmin provides an attractive molecular target for disrupting
      the mitotic apparatus and arresting the growth of malignant cells. In this
      review, we describe the current understanding of the role of stathmin in the
      regulation of the mitotic spindle and discuss its potential as a therapeutic
      target of cancer therapy.

PMID- 12415324
TI  - Interesting clinical case studies involving secondary causes of hypertension.
AB  - While essential hypertension is very prevalent, secondary hypertension does occur
      in clinical practice with sufficient frequency to warrant special attention being
      given to those patients with severe hypertension who do not respond to standard
      treatments. The evaluation, diagnosis and treatment of secondary hypertension
      pose interesting challenges to the physician. In this article, three patients are
      described with different secondary causes of hypertension.

PMID- 12415325
TI  - Genetics and education: the ethics of shaping human identity.
AB  - This paper suggests an analogy between education and genetic interventions as
      means of shaping the identity of children and future adults. It proposes to look
      at issues discussed in the philosophy of education as a possible source of
      insight for ethical guidelines regarding future genetic interventions. The paper
      focuses on situations of conflict between parents and state regarding the
      authority to determine the child s best interests. It describes the current
      formulation of the conflict in the literature as lacking the crucial element of
      the child s right to a cultural identity. It argues that this element is a
      necessary component in an ethical analysis of the child s best interests in a
      multicultural, liberal society which respects diversity. The paper therefore
      proposes a better model for the moral evaluation of identity-shaping decisions
      and offers some implications of this model for genetics.

PMID- 12415326
TI  - The doctor's defense.
AB  - The paper takes as its point of departure a relatively recent case which
      attracted publicity in Britain, concerning a doctor charged with (but acquitted
      of) the murder of his terminally ill patient, and critically examines the
      criminal law of England and Wales relating to homicide in the context of medical
      practice. While similar issues obviously arise in many other countries, no
      comparative study is attempted in the paper. However, the arguments which have
      been presented are of more than local interest. From an analysis of this case and
      others, it appears that there is in common law something which can be called  the
      doctor s defense.  It holds that a doctor may, when caring for a patient who is
      suffering great pain, lawfully administer pain-killing drugs, despite the fact
      that, as the doctor well knows, one certain or highly probable consequence will
      be to shorten the patient s life. Current justifications for this defense are
      either incoherent or too weak. Some require that different conceptions of 
      intention  be deployed, depending on whether the agent is a doctor or not. Others
      rely on the philosophically controversial doctrine of double effect. Still others
      invoke an implausible notion of minimal causation. All these justifications apply
      readily enough to morally and factually easy cases, but fail in hard cases where
      the need for some justification is most pressing. These justifications seem
      incapable of providing adequate guidance to prosecutors or trial judges. Absent
      principled and transparent justification, the English criminal justice system
      exhibits different outcomes on what appear to be broadly similar facts. It is
      disturbing that the law is uncertain and incapable of giving adequate guidance. A
      doctor, compelled by conscience to intervene to end a person s life, should
      certainly be ready and willing to face rigorous legal scrutiny, but the law
      applied should not be arbitrary and random, nor should the outcome turn solely or
      chiefly on prosecutorial discretion or the predilections of the trial judge. The
      hope is to find a better rationale for the doctor s defense through an analysis
      of professional ethics and the concept of a recourse role.

PMID- 12415327
TI  - Is HIV infection a risk factor for complications of surgery?
AB  - BACKGROUND: The literature is inconsistent as to whether HIV-infected patients
      have higher rates of surgical complication rates than HIV-uninfected patients.
      This inconsistency reflects the failure to control for confounding variables in
      many of the previous studies. METHODS: A retrospective cohort study of records of
      HIV-infected individuals who underwent surgical procedures between 1990 and 1995
      was matched with the records of HIV-uninfected control patients. We performed a
      logistic regression analysis to determine the independent effects of HIV
      infection and other potential risk factors for surgical complications. RESULTS:
      The crude rates of death and infectious and hematologic complications were higher
      among HIV-infected patients than among uninfected patients. Although the crude
      risk of having any complication was higher among the HIV-infected (odds ratio
      [OR]=2.47, p=0.015), the adjusted risk was not (OR=0.72 [p<0.613]). Variables
      significantly associated with complications were American Society of
      Anesthesiology (ASA) risk class (OR=2.7), age (OR=1.06 per year), and weight
      (OR=0.96 per kg). CONCLUSIONS: HIV sero-status was not found to be an independent
      risk factor for complications of surgery. The most important risk factor for
      complication of surgery in HIV-infected patients is ASA risk class.

PMID- 12415328
TI  - Choriocarcinoma in a patient with human immunodeficiency virus: case presentation
      and review of the literature.
AB  - A 26-year-old woman with choriocarcinoma and acquired immunodeficiency syndrome
      initially presented with hydatidiform mole and was treated with dilation and
      curettage. Because of persistent elevation of serum beta human chorionic
      gonadotropin, the patient was treated with combination chemotherapy with
      etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine (EMACO)
      for high-risk gestational trophoblastic tumor. The patient s initial stage was
      IIc. The serum beta human chorionic gonadotropin level returned to normal.
      Fourteen months later, the gonadotropin level again increased. The patient was
      treated with uterine curettage followed by vaginal hysterectomy. Despite further
      chemotherapy (with methotrexate and leucovorin, then oral etoposide), she died
      following metastasis of the tumor to the brain. Only four other cases of human
      immunodeficiency virus (HIV) infection with choriocarcinoma have been reported.
      There is no evidence to date that gestational trophoblastic disease is more
      prevalent in patients with acquired immunodeficiency syndrome. HIV infection and
      other immunodeficiency states, however, can influence the course of treatment and
      outcome in these patients. The low CD4 count in HIV infection may lead to a poor
      outcome despite chemotherapy.

PMID- 12415329
TI  - Coronary artery disease in women: a review of emerging cardiovascular risk
      factors.
AB  - Coronary heart disease is the leading cause of death and disability in both men
      and women in industrial nations. From 1988 to 1998, the death rate from coronary
      heart disease actually declined 26.3%, resulting to some extent from the
      recognition and treatment of modifiable risk factors. The clinical observation
      that traditional risk factors for atherosclerosis cannot account for all patients
      who develop coronary heart disease or stroke has stimulated interest in
      reevaluating these factors and considering other determinants of pathogenesis.
      Our understanding of atherogenesis has evolved from a focus on lipid deposition
      within the arterial wall causing obstruction to the broader view of an
      inflammatory process which involves specific cellular and molecular responses to
      endothelial dysfunction. As a consequence,  emerging  cardiovascular risk factors
      and preventive strategies have been proposed. For example, there is an increasing
      understanding of the pathology of hypercholesterolemia and the benefits of lipid
      lowering medications (specifically statins), the role of oxidative stress, and
      antioxidant, homocysteine, and hypercoagulable states. This review examines the
      data for these and other emerging risk factors, with specific attention to gender
      differences.

PMID- 12415330
TI  - Nocardiosis presenting as an anterior mediastinal mass in a patient with
      sarcoidosis.
AB  - We report a patient with tissue-proven sarcoidosis receiving adrenocorticosteroid
      medication, who developed an enlarging mediastinal mass. Transcutaneous needle
      biopsy of the mass yielded pus which grew Nocardia asteroides on culture. Pleural
      effusion, bronchoesophageal fistula and brain nocardia metastases occurred. All
      evidence of active infection cleared with sulfa therapy. An enlarging mass in a
      patient with sarcoidosis unresponsive to corticosteroid therapy should provoke
      studies for other causes of mediastinal disease, including opportunistic
      infections.

PMID- 12415331
TI  - Molecular dynamics studies on the aggregation of Y-shaped fluoroalkanes.
AB  - Molecular dynamics (MD) calculations have been performed on the aggregation of
      clusters with up to 128 Y-shaped perfluoroalkylated molecules of the type
      C10F20[C7H15]2 (Y-A/128) and C10H20[C7F15]2 (Y-B/128) as well as mixed clusters
      (Y-A/64+Y-B/64) using the AMBER 5 program. The effect of the segregation tendency
      of the chemically different parts and the influence of the steric repulsion due
      to the wedge shape of the molecules on the structure formation have been studied.
      The results have been analyzed by snapshots, radial atom pair distribution
      functions, orientational correlation functions as well as diffusion coefficients
      and are compared with the corresponding findings on clusters of alkanes and
      perfluoroalkanes. Electronic supplementary material to this paper can be obtained
      by using the Springer LINK server located at
      http://dx.doi.org/10.1007/s008940020092y.

PMID- 12415332
TI  - Evaluation of overlap integrals with integer and noninteger n Slater-type
      orbitals using auxiliary functions.
AB  - The series expansion formulae are derived for the overlap integrals with
      arbitrary integer n and noninteger n* Slater-type orbitals (ISTOs and NISTOs) in
      terms of a product of well-known auxiliary functions A(sigma) and B (k). The
      series becomes an ordinary closed expression when both principal quantum numbers
      n* and n'* of orbitals are integer n*= n and n'*= n'. These formulae are
      especially useful for the calculation of overlap integrals for large quantum
      numbers. Accuracy of the results is satisfactory for values of integer and
      noninteger quantum numbers up to n= n'=60, n*= n'*<33 and for arbitrary values of
      screening constants of orbitals and internuclear distances.

PMID- 12415333
TI  - QSPR models based on molecular mechanics and quantum chemical calculations. 1.
      Construction of Boltzmann-averaged descriptors for alkanes, alcohols, diols,
      ethers and cyclic compounds.
AB  - Values for nine descriptors for QSPR (quantitative structure-property
      relationships) modeling of physical properties of 96 alkanes, alcohols, ethers,
      diols, triols and cyclic alkanes and alcohols in conjunction with the program
      Codessa are presented. The descriptors are Boltzmann-averaged by selection of the
      most relevant conformers out of a set of possible molecular conformers generated
      by a systematic scheme presented in this paper. Six of these descriptors are
      calculated with molecular mechanics and three with quantum chemical methods.
      Especially interesting descriptors are the relative van der Waals energies and
      the molecular polarizabilities, which correlate very well with boiling points.
      Five more simple descriptors that only depend on the molecular constitutional
      formula are also discussed briefly.

PMID- 12415335
TI  - Endoscopic mucosal resection for advanced non-polypoid colorectal adenoma and
      early stage carcinoma.
AB  - PURPOSE: Endoscopic mucosal resection (EMR) techniques were evaluated in the
      treatment of flat and sessile colorectal neoplasm. PATIENTS AND METHODS: Fifty
      seven patients (32 female, 25 male) with non-polypoid colorectal lesions (n = 71,
      size >or= 10 mm) were included in the study. Tumor location, shape, size, and
      depth (in malignant lesions) were determined by endoscopy and endoscopic
      ultrasound. EMR was performed using snare resection, endoscopic aspiration
      mucosectomy, or EMR using a cap-fitted endoscope. RESULTS: Lesion size ranged
      from 10 to 50 mm. Complete resection was achieved in 59 of 61 benign and 6 of 8
      malignant tumors. Thirty-five tumors were excised in one segment and 34 tumors in
      piecemeal technique. Pathological examination of neoplasm treated by EMR showed
      adenoma in 61 and early-stage carcinoma in 8 cases. Because of the non-lifting
      sign, 2 of 71 tumors were not treated endoscopically and referred to surgical
      resection revealing a T2 adenocarcinoma in both cases. Resection was incomplete
      in 2 of 61 adenomas with histological positive resection margin. Complications
      occurred in 2 patients, with 1 bleeding treated endoscopically and 1 perforation
      treated by surgery. Local recurrence was observed in 2 of 59 completely resected
      adenomas and in none of 6 early-stage carcinomas during a mean follow-up of 18
      months (range 6 to 30 months). CONCLUSION: Advanced non-polypoid colorectal
      adenomas and early-stage carcinomas can be safely and effectively resected by
      endoscopic mucosal resection.

PMID- 12415334
TI  - A cost--utility analysis of treatment options for inguinal hernia in 1,513,008
      adult patients.
AB  - BACKGROUND: The controversial issue of the cost-effectiveness of laparoscopic
      inguinal hernia repair is examined, employing a decision analytic method.
      MATERIALS AND METHODS: The NSAS, NHDS (National Center for Health Statistics),
      HCUP-NIS (Agency for Healthcare Research and Quality) databases and 51 randomized
      controlled trials were analyzed. The study group constituted of a total of
      1,513,008 hernia repairs. Projection of the clinical, economic, and quality-of
      life outcomes expected from the different treatment options was done by using a
      Markov Monte Carlo decision model. Two logistic regression models were used to
      predict the probability of hospital admission after an ambulatory procedure and
      the probability of death after inguinal hernia repair. Four treatment strategies
      were modeled: (1) laparoscopic repair (LR), (2) open mesh (OM), (3) open non-mesh
      (ONM), and (4) expectant management. Costs were expressed in US dollars and
      effectiveness in quality-adjusted life years (QALYs). The main outcome measures
      were the average and the incremental cost-effectiveness (ICER) ratios. RESULTS:
      Compared to the expectant management, the incremental cost per QALY gained was
      605 dollars (4086 dollars, 9.04 QALYs) for LR, 697 dollars (4290 dollars, 8.975
      QALYs) for OM, and 1711 dollars (6200 dollars, 8.546 QALYs) for ONM. In
      sensitivity analysis the two major components that affect the cost-effectiveness
      ratio of the different types of repair were the ambulatory facility cost and the
      recurrence rate. At a LR ambulatory facility cost of 5526 dollars the ICER of LR
      compared to OM surpasses the threshold of 50,000 dollars/QALY. CONCLUSIONS: On
      the basis of our assumptions this mathematical model shows that from a societal
      perspective laparoscopic approach can be a cost-effective treatment option for
      inguinal hernia repair.

PMID- 12415336
TI  - Renal hemodynamics during carbon dioxide pneumoperitoneum: an experimental study
      in pigs.
AB  - BACKGROUND: Laparoscopic living donor nephrectomy is increasingly being
      performed, although the effects of carbon dioxide pneumoperitoneum (CO2 PP) on
      renal function and hemodynamics and the levels of vasopressin are not well
      studied. METHODS: Renal blood flow, renal venous pressure, urine output, and
      vasopressin concentrations in renal venous blood were measured in pigs subjected
      to 12 mmHg of CO2 PP for 150 min. RESULTS: Renal blood flow was decreased at
      induction of PP and increased during the first 30 min after exsufflation. Renal
      venous pressure was increased during PP. There was indirect evidence of a
      decrease in urine output during PP. No changes in renal venous vasopressin
      concentrations were seen. CONCLUSION: A CO2 PP of 12 mmHg causes changes in renal
      hemodynamics and urine output. No changes in vasopressin levels were seen in this
      pig model, suggesting that other explanations for the observed changes must be
      sought.

PMID- 12415337
TI  - Laparoscopic-assisted vaginal hysterectomy with lateral transsection of the
      uterine vessels.
AB  - BACKGROUND: Increased safety and diminished blood loss are achieved through
      laparoscopic-assisted vaginal hysterectomy by selective coagulation and
      transsection of the uterine vessels at their origin. METHODS: Three laparoscopic
      steps are performed: coagulation and transsection of the round ligament, of the
      uterine artery at its origin, and of the fallopian tube and ovarian ligament or
      (in BSO) the infundibulopelvic ligament. The uterine vessels are identified from
      the pararectal space and, following the internal liliac artery, and the ureter.
      Hysterectomy is completed transvaginally. RESULTS: Two hundred and sixty-seven
      patients underwent this procedure. Mean operation time was 121 min, and
      hemoglobin decreased to 0.6 g/dl by postoperative day 3. It took 8.4 min on
      average to identify and coagulate the uterine artery. CONCLUSIONS: Lateral
      transsection of the uterine vessels is safe and blood sparing and can be used in
      patients in whom blood loss must be minimized.

PMID- 12415338
TI  - Day-case laparoscopic hernia repair in a single unit.
AB  - BACKGROUND: Laparoscopic groin hernia repair has been shown to be a safe, well
      tolerated procedure. Here, we report a series of patients who underwent
      laparoscopic transabdominal preperitoneal (TAPP) mesh repair as day cases.
      RESULTS: We performed 984 repairs on 769 patients, 218 had bilateral repairs.
      Mean operating time was 25 min for unilateral and 38 min for bilateral repairs.
      Three were converted, and 39 required admission. Five were readmitted more than
      48 h postoperatively. Three required reoperation for small bowel obstruction from
      herniation through a peritoneal defect. Only 57% of patients required analgesia
      for a mean of 1.9 days after discharge. Recovery times were similar for
      unilateral and bilateral herniae. Eight hernias have recurred to date.
      CONCLUSIONS: Laparoscopic hernia repair is suitable for day-case surgery for
      unilateral, bilateral, and recurrent herniae. TAPP repair allows inspection of
      the contralateral groin, with repair of defects as necessary.

PMID- 12415340
TI  - Neuroblastoma.

PMID- 12415341
TI  - Outcome of infants with neuroblastoma detected by mass screening and surgically
      treated in Shiga Prefecture, Japan: what is the role of surgery?
AB  - To investigate retrospectively the clinical and biological features that
      influence the outcome of infants with neuroblastoma (NB) detected by mass
      screening (NBMS), and to construct surgical strategies to deal with NBMS, 20
      infants diagnosed as having either NB or ganglioneuroblastoma (GNB) between 1986
      and 1998 were enrolled in a study. They comprised 15 boys and 5 girls ranging in
      age from 7 to 14 months. The following factors were analyzed by multivariate
      analysis: age, stage according to the Japanese staging system at the time of
      diagnosis, site of the primary tumor, histologic findings, preoperative urinary
      vanillylmandelic acid (VMA) and homovanillic acid (HVA) levels, VMA/HVA ratio,
      lactate dehydrogenase, neuron-specific enolase, Shimada's histologic
      classification, amplification of the N- myc oncogene by Southern blot analysis,
      nuclear content, and chromosomal abnormality. The 2-year survival was 95.0%
      (19/20). The site of the primary tumor was the adrenal gland in 12 cases,
      retroperitoneum in 6, and retrothoracic space in 2. Four infants had stage I, 6
      stage II, 3 stage III, 3 stage IVB, and 4 stage IV disease. Complete resection
      was achieved in all cases except for 1 retroperitoneal GNB. Histologic
      examination showed that 8 patients had NB. Of the 12 GNBs, 8 were poorly
      differentiated and 1 was well-differentiated. Only 1 of the 14 examined tumors
      showed amplification of N- myc (20 copies). The infant with N- myc-positive NB
      (stage II) died 23 months after surgery in spite of aggressive postoperative
      chemotherapy. Multivariate analysis revealed the plasma NSE level to be a
      significant predictor of survival (p < 0.0143). This suggests that N- myc
      amplification and plasma NSE level could be closely related to the survival of
      infants with NBMS. The N- myc-positive NB case implies that even in locoregional
      NB detected by NBMS, surgical excision should play a central role in the
      diagnosis of its oncogenic characteristics and indicate any subsequent therapy.

PMID- 12415342
TI  - The role of the pathologist in the management of neuroblastoma.
AB  - The role of the pathologist in the management of neuroblastoma, in the context of
      the team approach to these lesions, is discussed. The importance of the provision
      of fresh material is stressed, and the prognostic importance of histology and
      ancillary tests is noted. Participation by the team in a children's cancer study
      group is a vital component of current and future treatment methods.

PMID- 12415343
TI  - Perspectives on neuroblastoma.

PMID- 12415344
TI  - Neonatal tumours: a single-centre experience.
AB  - Solid tumours are uncommon in the neonatal period. We present our experience of
      managing neonatal tumours in a tertiary reference centre to study the incidence,
      pathology and types, efficacy of treatment, and impact of antenatal diagnosis on
      the management in our practice in a retrospective study of case-notes and
      pathology reports. Eighty-three neonates with solid tumours were seen over a 45
      year period (1955-1999); 62 (74%) presented at birth. Only 11 were diagnosed
      antenatally. Teratomas were the commonest type (n = 33, 40%) followed by
      neuroblastomas (NB) (14), renal (13), soft-tissue (10), hepatic (4), and
      miscellaneous tumours (2). Twenty-three (28%) were malignant, 50% of these being
      NBs. Surgery remains the mainstay of treatment. Chemotherapy has also become
      safer. Therapeutic complications were responsible for 50% of deaths before 1986;
      from 1986 onwards, there has been no therapy-related mortality. Only one-third of
      the recent cases were diagnosed antenatally. Counseling the family and in-utero
      transfer is the best option. In our limited series, there was no significant
      difference in management and outcome in the antenatally-diagnosed cases. The
      small numbers of neonatal tumours seen by individual centres underline the need
      for an international effort to optimise therapy and improve understanding of
      these tumours.

PMID- 12415345
TI  - Plastic particle migration during intravenous infusion assisted by a peristaltic
      finger pump in an animal model.
AB  - The contamination of intravenously administered fluid with foreign material has
      always been of major concern, but the in-vivo impact of silicone embolisation
      from administration of fluid via a peristaltic finger pump (PFP) has not
      previously been assessed. To determine whether silicone particles enter the lungs
      and to review the histological response, 10 rabbits received an IV infusion of
      0.9% saline at 10 ml/kg per hour over a 72-h period, via an IVAC 591 PFP. The
      lungs were analysed for silicone particles with scanning electron microscopy
      (SEM) and energy-dispersive X-ray analysis (EDXA). These results were compared
      with a control group of non-infused animals. Silicone particles were found in 8
      of 10 animals in the experimental group and in 2 of 9 control animals, indicating
      that silicone particles are dislodged during pump-assisted IV infusions. The
      difference between the control and infused animals was statistically significant
      using Fisher's exact test (P = 0.023). However, silicone plastic particles in
      control animals suggest that there is also environmental exposure to silicone in
      addition to those particles that come from a therapeutic source. The additional
      finding of elemental silicon (which is one of the constituents of silicone
      plastic) in both infused and control animals in which silicone plastic was not
      found indicates that not all elemental silicon in animals reflects the presence
      of silicone plastic. The clinical significance of each of these two findings is
      yet to be determined.

PMID- 12415346
TI  - Demonstration of nitrergic and cholinergic innervation in whole-mount
      preparations of rabbit, pig, and human upper urinary tract.
AB  - To investigate the distribution of nitrergic and cholinergic innervation in
      rabbit, pig, and human upper urinary tract, (UUT) whole-mount preparations and
      frozen sections were stained with nicotinamide adenine dinucleotide phosphate
      (NADPH)-diaphorase and acetylcholinesterase (AChE) histochemistry. NADPH
      diaphorase and AChE staining demonstrated two neuronal plexuses in the submucous
      and muscular layer of the UUT in all three species. The presence of nitrergic and
      cholinergic neuronal networks in the normal UUT suggests that autonomic
      innervation may play an important role in the transmission of ureteral
      peristalsis.

PMID- 12415347
TI  - Embryogenesis of tracheo esophageal anomalies: a review.
AB  - The embryology of the normal esophagus and trachea is controversial. There are
      two main opinions regarding the role played by the tracheoesophageal (TE) septum.
      Similar controversy exists in explaining the embryology of anomalous TE
      development, mainly due to a lack of embryos demonstrating these anomalies at
      critical stages during development. Proposed theories can be divided into four
      main groups: intraembryonic pressure; epithelial occlusion; differential growth;
      and vascular occlusion. More recently, a new theory has been described based on
      analysis of anomalous TE development in adriamycin (doxorubicin)-exposed rat
      embryos. Impaired tracheal development, with the foregut developing into the
      trachea rather than the esophagus and associated with development of a dorsal
      pouch from the upper part of the foregut, gave rise to esophageal atresia with
      distal TE fistula. On the other hand, development of a ventral upper foregut
      pouch led to tracheal atresia. A laryngotracheo-esophageal cleft may result if no
      upper foregut pouches develop, with differentiation of the ventral half of the
      foregut into trachea and the dorsal half into esophagus. This review describes
      the basic theories of normal and abnormal TE development in mammalian embryos and
      presents new data related to this abnormality.

PMID- 12415348
TI  - Experimental abdominal wall defect repaired with acellular matrix.
AB  - In the surgical repair of congenital abdominal-wall defects (AWD), the ready
      availability of a non-immunogenic and non-prosthetic biomaterial that could guide
      the regeneration of normal tissue is a fascinating possibility. Biomaterials are
      already in use, but in our experience, an acellular matrix (ACM) can stimulate
      exact regeneration of the absent tissue. We explored the possibility of using an
      ACM to repair a muscular AWD in an animal model. Male New Zealand white rabbits
      (3-4 kg, n = 18) were anesthetized and the abdominal wall was shaved and
      scrubbed; a vertical incision was made in the left lower quadrant and a large
      patch of external-oblique muscle was resected (3 x 3 cm). The animals underwent
      reconstruction with homologous diaphragm acellular matrix (HDAM) grafts that were
      previously prepared using a detergent enzymatic method. The patches were
      evaluated histologically at 9 (n = 6), 40 (n = 6), and 90 (n = 6) days post
      surgery in each group; moreover, 90 days post-surgery an electromyogram (EMG) (n
      = 6) of the implanted matrix was recorded. Histologic analysis demonstrated that
      the HDAM supported fibroblast migration, deposition of newly-formed collagen, and
      neovascularization. No signs of necrosis, or evidence of skeletal-muscle-cell
      ingrowth were detected. The EMG revealed minimum muscular electrophysiologic
      activity, probably due to muscle underlying the patch. The HDAM we employed was
      thus not able to produce reconstruction of the skeletal muscle, and was
      progressively remodeled into fibrous tissue. Since the ultimate reason for
      failure of muscle regeneration is a lack of myogenesis, future studies will use
      ACMs preconditioned by various regulators of myoblast proliferation and
      differentiation.

PMID- 12415349
TI  - Effects of supplemental L-arginine on the intestinal adaptive response after
      massive small-bowel resection in rats.
AB  - To evaluate whether L-arginine methyl ester (L-Arg) can improve the structure of
      the small intestine and enhance adaptation in an experimental model of short
      bowel syndrome (SBS), 40 Sprague-Dawley rats were divided randomly into four
      groups of 10 each. In one group only a laparotomy was performed (G1). The
      remaining 30 rats underwent 90% small-bowel resection (SBR) and formed the three
      experimental groups: the SBR/untreated group (G2), the SBR/L-NAME-treated group
      (G3), and the SBR/ L-Arg-treated group (G4). Rats in G2 received no therapeutic
      treatment. Rats in the SBR/L-NAME and SBR/L-Arg treated groups received N-G-nitro
      L-arginine-methyl ester (L-NAME) and L-Arg intraperitoneally for 3 weeks,
      respectively. The animals were weighed daily. All rats underwent a relaparotomy
      on day 21 of the experiment. Remnant small bowel was excised and evaluated for
      villus height and crypt cell mitoses. After the 90% SBR, all animals had from
      diarrhea and weight loss between the 1st and 6th postoperative days (POD). The
      body weight of the SBR/L-Arg group showed significant increases at POD 10 and 21
      in comparison to the SBR/untreated and SBR/L-NAME groups (P < 0.001). The rats
      treated with L-Arg had significantly greater villus height and crypt-cell mitoses
      compared to the other groups (P < 0.0001, P < 0.001). These observations suggest
      that L-Arg treatment increases villus height and crypt-cell mitoses after massive
      SBR and may play a considerable role in the mucosal adaptive response in SBS in
      rats.

PMID- 12415350
TI  - Morphologic changes and lipid peroxidation in renal tissues of young rats
      following intestinal ischemia-reperfusion.
AB  - Intestinal ischemia-reperfusion (IIR) is a complex phenomenon causing local and
      remote tissue destruction, and even multiple-organ failure. To examine the
      hypothesis that IIR affects renal function, 21-day-old male Sprague-Dawley rats
      underwent 45 min superior mesenteric artery occlusion and control rats were
      subjected to a sham laparotomy. After 2 and 24 h and 1 week of reperfusion, blood
      was sampled for urea and the kidneys were harvested for lipid peroxidation and
      histologic examination. Malondialdehyde (MDA) levels as an indicator of lipid
      peroxidation were significantly increased in renal tissue after 2 h of
      reperfusion, and this finding was in accordance with serum urea levels (SU) and
      endothelial injury. However, at 24 h of reperfusion MDA and SU had returned to
      normal. These data were supported by electron-microscopic studies suggesting
      reversibility of the changes. It is concluded that IIR leads to renal injury and
      that free radicals may be responsible for this injury.

PMID- 12415351
TI  - Hospital re-admission in children with non-specific abdominal pain.
AB  - In children with non-specific abdominal pain (NSAP) who were subsequently re
      admitted to hospital with a further episode of pain within 30 days, the
      contribution of active observation to the initial and subsequent admission was
      evaluated and the diagnostic process reviewed. The cohort comprised all children
      with a discharge diagnosis of NSAP admitted to Royal Aberdeen Children's Hospital
      between January 1990 and December 1999. Data were extracted from a computerised
      database. A measure was made of the investigations employed in the children who
      were re-admitted and an arbitrary score produced in an attempt to measure the
      intensity and degree of the diagnostic process. This investigation score was then
      related to both clinical outcome and the need for revision of the original
      diagnosis of NSAP. A total of 1,238 children (675 males, 563 females) were
      admitted with NSAP; 46 (22 males and 24 females, age range 4-14 years) were re
      admitted with further abdominal pain within a 30-day period. The total number of
      re-admission events was 53. In 19 children the subsequent diagnosis was revised.
      Ten of the 46 children underwent an operation; in 31 cases re-admission
      investigations were more detailed and invasive, but contributed to a change in
      diagnosis in only 13. There was no recorded mortality over the study period. In
      children re-admitted with abdominal pain, the subsequent diagnosis thus changed
      from the original in over one-third of cases. Most children undergo more invasive
      and more detailed investigations on re-admission in comparison to the initial
      episode of hospitalisation. The majority, however, continue to be managed
      conservatively. This study endorses the continued use of active observation in
      the management of NSAP in children, and recognises that even intense
      investigation may fail to contribute to a more specific diagnosis.

PMID- 12415352
TI  - The role of transanal endorectal pull-through in the treatment of Hirschsprung's
      disease - a multicenter experience.
AB  - The transanal approach (TAA) is a new technique for surgery of Hirschsprung's
      disease (HD) that was introduced by de la Torre in 1998. The purpose of this
      multicenter study, including experience from three Austrian and one Italian
      departments of peadiatric surgery, was to evaluate the role of this approach in
      HD in 18 children aged 1-72 months. In 14 children the TAA only was performed; in
      3 an additional laparoscopy was performed and in 1 conversion to a laparotomy was
      necessary. One complication (abscess) occurred after laparoscopic-assisted pull
      through. The postoperative recovery was rapid, no severe long-term problems were
      observed. The transanal pull-through technique is generally possible in most
      classic cases of HD with extension of the disease to the sigmoid colon. If
      necessary, it can be combined with laparoscopy. Our preliminary results show that
      the technique is safe, less invasive, and gives excellent cosmetic results, and
      allows rapid recovery. Long-term results are still pending.

PMID- 12415353
TI  - Acetylcholinesterase distribution and refractory constipation - a new criterion
      for diagnosis and management.
AB  - To describe manifestations of acetylcholinesterase (AchE) activity in the bowel
      of patients presenting with refractory constipation and correlate them with
      outcome, rectal biopsy specimens (RBS) from 165 patients who presented with
      refractory constipation between 1988 and 1999 were examined. Age at biopsy ranged
      from 4 days to 17 years; 45 subjects were excluded because they satisfied
      diagnostic criteria for Hirschsprung's disease, intestinal neuronal dysplasia, or
      hypoganglionosis. Thirty-five autopsy subjects were used as controls. All RBS
      were compared and AchE activity was assessed in the lamina propria (LP),
      muscularis mucosae (MM), and around the submucosal vessels (V). Variations in
      AchE distribution were classified as grade I (no AchE-positive nerve fibers in
      the LP or MM), grade II (some positive fibers in the LP or MM), grade III
      (moderate positive fibers in the LP or MM), grade IV (many positive fibers in the
      LP, MM, or V), or grade V (fibrillar, foamy, or amorphous staining for AchE). All
      grade I (11/120) and V (12/120) subjects achieved normal bowel control with
      laxatives alone and all grade II subjects (58/120) did with laxatives and enemas.
      Grade III subjects (34/120) required addition of cisapride. All grade IV subjects
      (5/120) were unresponsive to conservative management and 4/5 were found to have a
      megarectum, which was treated surgically. AchE distribution correlated well with
      eventual outcome and requirement for surgery. AchE distribution could also be
      used to classify bowel motility disorders, and we suggest the term AchE-positive
      disease be used to describe them.

PMID- 12415354
TI  - Paediatric liver transplantation [corrected] in Melbourne: the first 50 patients.
AB  - To report the outcomes of the first 50 paediatric patients who have undergone
      liver transplantation (LT) at the Victorian Liver Transplant Unit, a
      retrospective review of case records was carried out. From December 1988 to
      December 2000, 108 patients 18 years or younger were referred for LT; 50 of these
      underwent a total of 53 transplants. The most common indications were biliary
      atresia (32%), metabolic disease (26%), and acute hepatic necrosis (26%). The
      majority of deaths (6/7) occurred in the 1st week after LT. The actuarial
      survival at 1 year was 88% (95% CI 75% to 94%) and at 10 years 85% (95% CI 71% to
      93%). Survival rates were highest for children aged 3 to 14 years (95%) and
      lowest in those weighing less than 8 kg at the time of LT (66%). All 43 survivors
      are attending age-appropriate activities including kindergarten, school, and
      employment. The survival of patients undergoing LT in this unit compares
      favourably with those recorded by the Australia and New Zealand Transplant
      Registry and is commensurate with that reported by larger paediatric transplant
      programs overseas.

PMID- 12415355
TI  - Biliary dyskinesia in children.
AB  - Biliary dyskinesia (BD) is a well-recognized cause of chronic abdominal pain in
      adults, but is less common in children. We reviewed our experience with the
      diagnosis, treatment, and follow-up in a group of children treated with
      cholecystectomy from March 1995 to October 2000. We identified children with
      chronic upper abdominal pain, normal ultrasonography (US), and delayed
      cholecystokinin (CCK)-stimulated gallbladder emptying (<35%). All other
      diagnostic tests for their abdominal pain were reviewed. Their treatment,
      surgical intervention, and outcome were recorded. During the study period, 74
      cholecystectomies were performed in our institution, 10 (13.5%) of them for BD.
      The duration of symptoms ranged between 1 and 60 months (mean 22). All patients
      had a normal plain abdominal radiograph, normal US, and delayed gallbladder
      ejection fraction (EF). All were treated by elective laparoscopic
      cholecystectomy. Symptoms were completely relieved in all patients during the
      follow-up period, which ranged between 9 and 24 months (mean 12.8).
      Cholecystectom should be considered in children with chronic upper-abdominal pain
      and delayed EF on CCK-HIDA scintigraphy. Laparoscopic cholecystectomy is the
      procedure of choice in these patients.

PMID- 12415356
TI  - The clinical relevance of non-classified dysganglionoses and implications for a
      new grading system.
AB  - In addition to the classified types of dysganglionosis, certain non-classified
      dysganglionoses (NCD) (types 1-4) were introduced by Meier-Ruge in 1992. Clinical
      data on these conditions are limited. Among 134 children with intestinal
      dysganglionoses (ID) treated from 1979 to 1999, 12 were identified to have a NCD.
      Their clinical course is presented. The existence of mild ID (type 1) is
      difficult to demonstrate. Current definitions and data on clinical relevance are
      not convincing. An indication for surgical treatment is not present. Isolated
      hypogenesis of the submucous plexus (SMP) (type 2, n = 8) is clinically a more
      severe kind of intestinal neuronal dysplasia type B and often requires early
      surgical intervention, but not resection. When associated with aganglionosis, its
      recognition is important for surgical strategy, to avoid complicated clinical
      courses, which are frequent if total or nearly-total resection is not performed.
      Hypogenesis of the myenteric plexus (MP) (type 5, n = 1) has received little
      attention so far. The sporadic appearance of heterotopic nerve cells of the SMP
      in the mucosa (type 3, n = 1) is physiologic; clusters of such cells, however,
      are probably of pathologic value, especially in combination with other types of
      ID in the same patient. Heterotopic nerve cells of the MP (type 4, n = 3) in the
      circular and longitudinal muscle layers are highly pathologic. This clearly
      defined type is of major clinical relevance and requires complete resection. A
      severe disturbance of the migration process is the underlying cause. To simplify
      the terminology of IDs, a grading system based on the anatomic structures and
      clinical findings is proposed: innervation disturbances of the mucosa (grade I)
      are of limited clinical significance. Isolated malformations of the SMP (grade
      II) may require an enterostomy, but do not require resection except in certain
      cases associated with distal aganglionosis. Dysganglionosis of the MP (grade III)
      usually exhibits more severe symptoms and resection is indicated, especially with
      associated hypo- or aganglionosis. In aganglionic bowel (grade IV) resection is
      mandatory.

PMID- 12415357
TI  - Lateral sphincteromyotomy in patients with outlet obstruction after surgery for
      Hirschsprung's disease and short-segment disease.
AB  - The results of lateral sphincteromyotomy (LSM) including the external sphincter
      in patients with severe outlet obstruction (OO) and constipation refractory to
      medical treatment after surgery for Hirschsprung's disease (HD) or with short
      segment disease were evaluated. The parents filled out a detailed questionnaire
      on the child's bowel habits prior to surgery and at follow-up 2-26 months after
      surgery. The postoperative questionnaire included a 10-grade visual analog scale
      (VAS) indicating the general effect of LSM on the child's bowel habits: grade 1
      represented no change at all and 10 represented an excellent result with normal
      bowel habits. 15 (65%) of the 23 patients had a VAS score of 7 or more, and 7
      were reported to have normal bowel habits. Patients with a previous Soave
      operation did better compared to patients with short-segment disease (SSD). In 2
      patients (Soave's operation) with scores of 1 and 2, respectively, a
      sigmoidostomy was performed 4 and 6 months after the LSM. High-dose laxatives
      and/or enemas have been used in the 5 patients with scores of 3-5. One patient
      developed a perianal abscess and one experienced minor soiling. LSM including the
      whole sphincter complex thus gave significant symptomatic relief in two-thirds of
      the patients. However, the long-term results are still pending.

PMID- 12415358
TI  - Foregut duplications.
AB  - Twenty-one children were treated for foregut duplications at the Royal Hospital
      for Sick Children over a 42-year period. There were 11 males and 10 females. The
      mean age at diagnosis was 1 year 6 months; antenatal diagnosis was made in 1
      case. Respiratory and gastrointestinal (GI) presentation predominated. The
      diagnosis was made by chest radiograph (10), barium swallow (5), at operation
      (4), and by ultrasound (2). All patients were treated surgically; the mortality
      was 10%. The histology of the epithelial lining of the duplications revealed
      gastric mucosa in 15 cases; in 5 the duplication cyst was lined by more than one
      cell type. Nine patients had other associated congenital anomalies, the majority
      of these were vertebral abnormalities. The size of this series emphasises that
      clinicians should be aware that duplication cysts occur and should be considered
      in a child with unusual respiratory or GI symptoms.

PMID- 12415359
TI  - Retroperitoneoscopic resection of retroperitoneal bronchogenic cysts.
AB  - Two children aged 8 and 15 years underwent excision of retroperitoneal
      bronchogenic cysts (RBC) via a posterior retroperitoneoscopic approach (RPA). The
      operative technique and efficacy of this approach are reviewed. One lesion was
      symptomatic, while the other was an incidental finding on abdominal ultrasound.
      Operating times were 45 and 55 min. One patient was discharged on the day of
      surgery, the other on the 1st postoperative day. Both returned to normal physical
      activities within 1 week of surgery. No complication occurred in either case. To
      our knowledge, this is the first description in the literature of excision of
      this rare lesion via a RPA. We conclude that this is a safe method for resection
      of RBCs that offers several potential advantages compared with the open
      technique.

PMID- 12415360
TI  - Diagnostic and therapeutic approach to multiple endocrine neoplasia type 2B in
      pediatric patients.
AB  - Multiple endocrine neoplasia (MEN) 2B is a hereditary syndrome including
      medullary thyroid carcinoma (MTC), pheochromocytoma, gastrointestinal (GI)
      disorders, marfanoid facies, and multiple ganglioneuromas. MTC is the major cause
      of mortality, and often appears during the 1st decade of life. RET proto-oncogene
      mutations are responsible for MEN 2B. Other RET mutations cause MEN 2A syndrome,
      familial MTC, or Hirschsprung's disease. We studied three MEN 2B patients with
      the aim of delineating the best diagnostic and therapeutic protocol. The gold
      standards for diagnosis are histochemical study of the rectal mucosa and
      molecular analysis of RET, which in familial cases detects MEN 2B at a
      preclinical stage so that early total prophylactic thyroidectomy can be
      performed. In non-familial cases, the diagnosis can be suggested by the presence
      of GI symptoms, ganglioneuromas, and/or the typical facies. The intestinal
      innervation pattern, analyzed with the acetylcholinesterase technique, is
      pathognomonic for MEN 2B. In our protocol a rectal biopsy is, therefore, the
      first measure. The surgical treatment of MEN 2B is total thyroidectomy with
      cervical lymphadenectomy of the central compartment of the neck. When possible,
      this intervention should be performed prophylactically before 1 year of age.

PMID- 12415361
TI  - Sacrococcygeal teratoma.
AB  - This retrospective study details our experience regarding 72 patients with
      sacrococcygeal teratoma treated over a period of 17 years. The sex incidence was
      nearly equal, but there was a high proportion of Altmann type IV tumors. A
      preliminary colostomy before combined abdominosacral excision of large type III
      and IV lesions reduced morbidity. Sixty-six percent of the patients presented
      beyond the neonatal period; 14 had been treated elsewhere for bowel/urinary
      obstruction. Imaging studies included radiography, abdominal ultrasound, computed
      tomography, and magnetic resonance imaging (after 1995). In 60 patients the tumor
      was excised via the sacral route, 11 had a preliminary colostomy, and 1 had a
      vesicostomy. Eight children (5 with malignant lesions) required abdominosacral
      excision. After 1990, serial estimation of serum alpha-fetoprotein (AFP) was used
      to monitor tumor recurrence. There were 34 male and 38 female patients (age range
      3 days-12 years); 47 had benign tumors, of which 42 were excised through the
      sacral route. Three patients underwent a preliminary colostomy and abdominosacral
      excision of the tumor with subsequent colostomy closure. There were 4 deaths in
      this group; no recurrence was seen in the surviving children with benign tumors.
      Twenty-five patients had malignant teratomas. In 18 of these the tumor was
      excised via the sacral route and 5 underwent abdominal-sacral excision. Eight had
      a preliminary colostomy and chemotherapy followed by excision of the residual
      tumor and colostomy closure. None of the initial 14 patients with malignant
      lesions survived beyond 2 years. Of the latter 11 (who received cisplatinum-based
      chemotherapy), 10 were alive 1 year after surgery. One patient is currently on
      preoperative chemotherapy and another developed recurrence of the tumor. The
      overall follow-up ranged from 3 months to 8 years; there has been no complaint of
      functional neurological deficit in any of the patients. As intrapelvic tumors
      tend to have a delayed diagnosis, this can be avoided by performing a rectal
      examination. There should be no recurrence after excision of a benign teratoma.
      Cisplatinum-based chemotherapy has improved the survival of patients with
      malignant tumors.

PMID- 12415362
TI  - Measures to prevent renal impairment after resection of retroperitoneal
      neuroblastoma.
AB  - Postoperative renal impairment has been reported after kidney-preserving
      resection of retroperitoneal neuroblastomas (NB). To avoid renal damage,
      intraoperative procedures include monitoring of central venous pressure (CVP) and
      diuresis, i.v. administration of electrolyte solutions, mannitol, and furosemide,
      and local application of lidocaine to the renal vessels. During the first 5
      postoperative (p.o.) days, CVP, diuresis, body temperature (T), and lactate
      dehydrogenase (LDH) levels were monitored; color Doppler ultrasound (CDUS) was
      also performed on the 7th p.o. day. Simultaneous increases of T (>38.5 degrees )
      and LDH (>1,500 IU/l) and/or reduction of urinary flow (< 1.5 ml/kg.h) were
      indicative of renal damage: in these cases dopamine was administered and CDUS
      performed. If renal blood flow was normal on CDUS, dopamine was administered for
      another 2 days; if a vascular thrombosis was detected, fibrinolytic agents
      (urokinase 4,000 IU/kg bolus and then 4,000 IU/kg.h for 24 h) were utilized.
      Between May 1997 and June 2000, 29 children (9 F, 20 M, aged) 6-72 months (median
      39) affected by grade II inoperable, grade III, and grade IV NB underwent these
      preventive procedures at the time of surgical excision of the mass after
      chemotherapy 23 had an uneventful p.o. course. CDUS at 7 days was normal in 22;
      in 1 (polar resection at operation) it demonstrated a slight reduction of blood
      flow in the renal cortex. For all 23 patients, the CDUS at 3, 6, and 12 months
      was negative. Three patients showed a single altered parameter; the CDUS p.o. and
      during follow-up did not show any alteration. The other 3 patients had two or
      more altered parameters and were treated with dopamine: in 1 the initial CDUS was
      normal, but it later showed moderate hypotrophy; in 2 patients a vascular
      thrombosis was documented. Treatment with urokinase was successful in only 1
      patient who had a normalized CDUS after 3 months. The 2nd child developed renal
      failure and needed hemodyalisis. In our experience, elevation of serum LDH and T
      and/or oliguria were good indicators of renal impairment. CDUS was also useful in
      detecting renal blood flow reduction and artery occlusion. These preliminary
      results show these intra- and postoperative measures to reliably avoid renal
      impairment in these children. Long-term follow-up could confirm the efficacy of
      these methods.

PMID- 12415363
TI  - Duodenal intubation and test for bile - a reliable method to rule out biliary
      atresia.
AB  - Between January 1997 and December 1998, 30 consecutive children with suspected
      biliary atresia (BA) were selected to assess whether duodenal intubation (DI) and
      testing of aspirate for bile would help to rule out BA. Duodenal fluid was
      aspirated every 2 h for 24 h and tested for bile. A HIDA scan was also done in
      all cases. Every patient underwent a peroperative cholangiogram (POC) and liver
      biopsy; a Kasai portoenterostomy was done in indicated cases. In 22 cases all
      three investigations (DI, HIDA scan, POC) suggested BA. In 3 the HIDA scan ruled
      out BA, but DI and POC suggested BA. In 2 other cases, both the HIDA scan and DI
      suggested BA, but POC ruled it out and suggested biliary hypoplasia; in 3 others
      the HIDA scan suggested BA, but DI and POC both, ruled it out. There was no case
      where DI ruled out BA (i.e., showed bile in aspirate) and POC suggested BA. A
      liver biopsy confirmed BA in all proven cases. DI and testing the aspirate for
      bile is a very reliable means to rule out BA if the aspirate tests positive. It
      is an inexpensive, noninvasive, and quick bedside test that may be especially
      useful in developing countries where biliary scintigraphy is not available.

PMID- 12415364
TI  - Spontaneous neonatal gastric perforation.
AB  - Over a 7-year period (1990-1997) spontaneous gastric perforation was diagnosed in
      five neonates. The mean gestational age and birth weight were 33/40 weeks and
      1.83 kg, respectively. All patients presented with severe abdominal distention
      and frank pneumoperitoneum on roentgenograms. All perforations were on the
      anterior wall of the greater curvature and were managed by prompt laparotomy and
      primary closure of the perforation. No gastrostomy was used, however, peritoneal
      drainage was used in all cases. There was no mortality or morbidity. An attempt
      to understand the possible etiology together with a review of the literature is
      presented.

PMID- 12415365
TI  - Marked (24-fold) elevation of peritoneal cavity drainage fluid vascular
      endothelial growth factor after successful "patch, drain, and wait" approach for
      extensive midgut necrosis in a newborn.
AB  - In a current publications, it has been suggested that hypoxia-triggered "good
      angiogenesis" involving hypoxic up-regulation of vascular endothelial growth
      factor (VEGF) molecules, genes, and receptors is likely responsible in a major
      way for the remarkable gut and patient salvage experience associated with use of
      the "patch, drain, and wait" (PD&W) surgical approach to perforated necrotizing
      enterocolitis and midgut volvulus (MGV) with extensive ischemia/necrosis. We
      report a case in which extensive ischemia/necrosis in a newborn with
      gastroschisis (likely MGV-induced) was managed successfully by PD&W with an
      associated marked (24-fold) elevation of VEGF in drainage fluid at 7 days post
      initiation of PD&W.

PMID- 12415366
TI  - Evaluation of dysfunction following reconstruction of an anorectal anomaly.
AB  - To evaluate the utility of anorectal manometry (ARM) and magnetic resonance
      imaging (MRI) with an endocoil in the assessment of dysfunction in children with
      repaired anorectal anomalies (ARA), 15 patients aged 1 to 15 years with repaired
      ARAs and chronic faecal incontinence or constipation were prospectively
      recruited. They underwent clinical assessment using a modified Wingfield score
      (MWS). ARM and MRI with an endocoil and conventional external coil were carried
      out. The results of ARM alone, MRI alone, and a combination of ARM and MRI were
      correlated with the MWS. Manometric internal anal sphincter (IAS) scores
      determined from sphincter length and activity correlated with MWS (r = 0.56, P =
      0.02); manometric scores of rectal peristaltic activity did not. Overall
      manometric score (IAS and rectal scores combined) showed a correlation with MWS
      (r = 0.55, P = 0.02). Endoanal MRI sphincter scores did not correlate with MWS,
      but the presence of a megarectum on MRI did (r = 0.44, P = 0.05). Overall MRI
      score did not correlate with MWS. Minor neurosacral anomalies were shown on MRI
      in 3 children who had poor functional scores. Combined manometric and MRI scores
      showed a correlation with MWS (r = 0.58, P = 0.01). ARM and MRI are potentially
      useful in the assessment of dysfunction of children with repaired ARAs. Both
      modalities require refinement and further assessment in the context of directing
      management.

PMID- 12415367
TI  - Perforation of toxic megacolon in non-typhoid Salmonella enterocolitis spares
      young infants and is immune-mediated.
AB  - Intestinal perforation, a life-threatening complication of toxic megacolon (TM)
      following non-typhoid Salmonella infection, is relatively uncommon in infants
      less than 1 year of age. The situation, also found in typhoid fever, appears to
      be cytokine-mediated. This finding may justify immunotherapy for older children
      with TM associated with non-typhoid Salmonella infection in order to prevent this
      complication.

PMID- 12415368
TI  - Major complications of omphalitis in neonates and infants.
AB  - Omphalitis is a common problem in developing countries, and a wide range of
      complications requiring surgery may occur. We conducted a retrospective review of
      19 neonates and infants treated for major complications of omphalitis: 13 boys
      and 6 girls aged 5-75 days (median 33 days). Five (26%) patients presented with
      spontaneous evisceration of small bowel through the umbilical cicatrix, resulting
      in intestinal gangrene in 1. Necrotizing fasciitis (NF) occurred in 5 (26%)
      patients involving mainly the scrotum, and in 2 involving the penis as well.
      Three (16%) patients had peritonitis, resulting in intra-abdominal abscesses in
      2. Three (16%) had superficial abscesses, 2 (11%) had hepatic abscesses resulting
      in extensive destruction of the left lobe in 1, and 1 (5%) developed an adhesive
      intestinal obstruction. Although Staphylococcus aureus was the most commonly
      cultured organism, many cultures were sterile due to the use of antibiotics
      before presentation. Treatments consisted of repair of the umbilical cicatrix for
      evisceration (and intestinal resection for gangrene), radical debridement for NF,
      drainage and lavage for peritonitis, drainage of superficial abscesses, and lysis
      of adhesions. Broad-spectrum antibiotics were also given. No patient developed
      tetanus. One patient died from peritonitis. There was no death from NF. As
      serious complications may result from omphalitis in neonates and infants, with
      high morbidity and possible mortality, early recognition and prompt treatment are
      necessary for a good outcome.

PMID- 12415369
TI  - Hydatid disease in childhood.
AB  - To review the results of different modalities of treatment of hydatid disease of
      the liver (HDL) in pediatric patients, 31 children treated surgically between
      1990 and 2000 at the departments of general surgery and pediatric surgery,
      Ataturk University School of Medicine, were reviewed retrospectively; 19 were
      male and 12 were female. The mean age was 8.4 years (range 4-12 years). The most
      common complaints were an abdominal mass and right-upper-quadrant pain, which
      were present in 35.5% and 77.4% of cases, respectively. Twenty-five cysts were in
      the right lobe, 2 in the left lobe, and 4 in both lobes; 8 patients had multiple
      hepatic cysts and 5 had coexisting cysts in other organs. Surgical procedures
      were: unroofing plus tube drainage (UTD); capitonnage; omentoplasty; and
      pericystectomy. Of the patients treated by UTD, 2 developed cholangitis and 1
      developed a biliary fistula. Of the patients with capitonnage, 1 developed
      cholangitis. Surgery is still one of treatment modalities for management of HDL.
      Omentoplasty and capitonnage are the most effective modalities for the management
      of the cyst cavity.

PMID- 12415370
TI  - Gastroschisis: a 15-year, single-center experience.
AB  - 70 cases of gastroschisis (GS) were surgically treated at the Pediatric Surgical
      University Clinic, Munster, from 1984 through 1998. The defect occurred more
      frequently in males (44) than females (26). The average birth weight was 2,383 g
      and mean gestational age 36.8 weeks. 9 infants (12.9%) were delivered vaginally
      and the rest (87.1%) by cesarean section; 34 of the 61 (55.7%) cesarean sections
      were done solely for prenatal ultrasonic identification of the abdominal-wall
      defect. 10 infants (14.3%) underwent primary closure; in 19 (27.1%) primary
      closure of the skin was possible, however, a single solvent-dried dura (SDD)
      graft was required for fascial enlargement. The remaining 41 infants (58.6%) had
      extensive defects and required two grafts for optimal closure. 22 patients
      (31.4%) had associated anomalies, the most common being bowel atresias and
      undescended testis. 14 (20%) required secondary laparotomies because of bowel
      associated complications and 1 (1.4%) for a urinary-bladder perforation. 11
      patients (15.7%) had non-bowel-associated complications. The average
      postoperative tracheal intubation time was 3.9 days and the average hospital stay
      was 75.6 days. The overall mortality was 2.8%. No major complications associated
      with SDD implants were encountered; only 4 patients (5.7%) had minor
      complications such as local inflamation and infection and were managed
      conservatively. The present data support the employment of SDD implants as
      acceptable biomaterial for the repair of large GS defects.

PMID- 12415371
TI  - Prenatal ultrasonographic appearance of type IIId (uncorrectable type with cystic
      dilatation) biliary atresia.
AB  - Although prenatal ultrasonographic (US) diagnosis has been reported in biliary
      atresia (BA), most cases are type I (correctable with cystic dilatation). We
      report three prenatal cases of type IIId BA (uncorrectable with cystic
      dilatation). Routine fetal US at 22 to 24 weeks of gestation showed two
      communicating cystic lesions 12 to 16 mm in diameter. On color Doppler US, the
      lesions were separate from the portal vein or hepatic artery. The size did not
      change during the prenatal period in any case. Choledochal cyst (CC) was
      considered the most likely diagnosis, although BA with cystic lesions was also
      considered. After birth, the patients developed acholic stools and prolonged
      neonatal jaundice. Hepatobiliary scintigraphy showed negative passage. Duodenal
      fluid showed a negative or slightly positive Gmelin test. The neonates underwent
      laparotomy at the age of 36, 46, and 32 days, respectively. Intraoperative
      cholangiography showed the gallbladder and slightly-dilated common-bile duct
      without entering the proximal or distal bile ducts in all cases. They were
      classified as type IIId BA and underwent excision of the cystic lesions and
      dissection of the portal bile-duct remnants, followed by hepatic
      portoenterostomy. Case 1 showed persistent jaundice and finally underwent liver
      transplantation (LTx), case 2 became anicteric. Case 3 remained jaundiced and is
      to undergo LTx. In conclusion, type IIId BA may be one of the differential
      diagnoses when a cystic lesion is detected under the hepatic hilum by fetal US.
      However, prenatal diagnosis of BA is still difficult with respect to
      differentiation from a CC or type I BA. Early postnatal diagnosis followed by
      immediate treatment is important, especially in type IIId BA.

PMID- 12415372
TI  - Diagnostic imaging in the follow-up of nonoperative management of splenic trauma
      in children.
AB  - The spleen is the most frequently injured organ in blunt abdominal trauma (BAT).
      Contrast-enhanced computed tomography (CT) is approximately 95% sensitive and
      specific for detection of splenic injury. In children, nonoperative treatment is
      well-established. The basic tenet of such management is an obligatory period of
      rest to prevent recurrent bleeding and allow splenic healing. Splenic
      preservation prevents post-splenectomy sepsis. At our level I trauma center,
      pediatric patients (N=54) with BAT between 1993 and 1998 were retrospectively
      studied. Two (3.7%) died of associated injuries; 2 underwent splenectomy before
      transfer to our hospital. All had been diagnosed with splenic injury by CT. The
      mean age was 11.3 years. The mechanisms of injury were motor vehicle accidents
      (66%), bicycle accidents (26%), and falls (8%). All 50 remaining patients were
      followed by ultrasound (US) after the initial diagnosis by CT. The mean hospital
      stay was 6 days. One patient developed the rare complication of an arterio venous
      (AV) fistula within the damaged spleen; 47 (94%) had normal, homogeneous
      parenchymal echogenicity at healing (including the patient with the AV fistula).
      The remaining 3 demonstrated a visible echogenic scar. Imaging documentation of
      healing blunt splenic trauma should ideally minimize cost and relative risk. Our
      results add further evidence that US is well-suited to the task. No delayed
      complications with this approach were recorded in this series.

PMID- 12415373
TI  - Prenatal ultrasound screening of the urinary tract is useful.
AB  - Fetal uropathies can be identified by obstetric ultrasound (US) examination,
      permitting treatment before their clinical manifestation. To evaluate the
      justification for prenatal US screening for urinary-tract malformations (UTM),
      the outcome of occult UTMs in 23,000 babies born in our hospital between 1992 and
      1998 was examined retrospectively. A prenatal US examination was performed on
      19,400 newborns; 128 (0.7%) had an abnormal urinary tract, leading to surgery in
      38 cases. The overall incidence of UTMs requiring either medical or surgical
      therapy was 0.2% (45:19,400); 3,600 pregnancies were not screened by prenatal US.
      To date, 7 of the newborns have presented with urosepsis (2 with renal
      impairment) and 2 additional case of posterior urethral valves were identified by
      routine postnatal US. The incidence of significant UTMs was similar in both
      groups, but complications occurred in the unscreened group. Prenatal US to detect
      occult UTMs is thus beneficial, fulfilling the criteria for a population
      screening test. We recommend postnatal US urinary-tract screening for newborns
      with no prenatal US examination.

PMID- 12415374
TI  - The incidence and investigation of acute scrotal problems in children.
AB  - The true incidence of the various causes of acute scrotum in children is unclear;
      epididymo-orchitis (EO) is thought to be uncommon. Investigation for underlying
      urological abnormality in children with EO is recommended. To determine the
      incidence of the various pathologies in boys presenting to the emergency
      department with an acute scrotal condition and assess the value of further
      investigation of the urinary tract in a subgroup of boys with EO, a retrospective
      review of 100 consecutive patients admitted with a diagnosis of testicular pain
      was performed. Seventy had torsion of an appendix testis (TAT) and 12 had torsion
      of the testicle (TT). Ten boys were admitted with 11 episodes of EO; 7 had other
      pathologies including incarcerated hernia, varicocoele, and idiopathic scrotal
      oedema. The diagnosis of EO was made at operation in all 11 episodes. Escherichia
      coli was cultured in 4 patients; none were found to have underlying urinary tract
      abnormality. TAT was thus commonest causes of the acute scrotum. EO is not rare
      in infants, the incidence in this study being equal to the of TT. Subsequent
      urological investigation did not disclose any underlying abnormality. However,
      based on the current published literature futher investigation is recommended in
      selected cases.

PMID- 12415375
TI  - Initial surgical treatment as a determinant of bladder dysfunction in posterior
      urethral valves.
AB  - Bladder function in patients with posterior urethral valves (PUV) has an immense
      impact on long-term continence and renal function. Bladder dysfunction was
      corelated with the initial surgical treatment in 67 patients with PUV treated
      between 1985 and 2000. Age at presentation, current age, duration of follow-up,
      initial surgical treatment (diversion or valve fulguration), trends of renal
      function tests, voiding disturbances, and changes in the upper tracts were
      recorded. Urodynamic studies were done in all patients to determine urine flow
      rates, residual volume, maximal cystometric capacity (MCC), bladder compliance,
      involuntary detrusor activity, and pressure-specific bladder volume (PSBV) at 30
      cm water. The patients were divided into three groups depending on the initial
      treatment: fulguration (n = 38), vesicostomy (n = 25), and ureterostomy (n = 4).
      At the time of this study voiding symptoms persisted in 45 patients. Mean percent
      MCC (% MCC) was 62%, 96%, and 100% of normal in the vesicostomy, fulguration, and
      ureterostomy groups, respectively (P = 0.002). Large-capacity bladders were seen
      in 10.9% of patients, mostly in pubertal and post-pubertal boys who were treated
      initially by either fulguration or ureterostomy; vesicostomy adversely affected
      bladder capacity and compliance (P = 0.007). PSBV was decreased in 48% of
      patients in the vesicostomy group and was significantly lower in the other groups
      (P = 0.01). Mean percent PSBV was 75%, 95%, and 96% of normal in the vesicostomy,
      fulguration, and ureterostomy groups, respectively. Uninhibited contractions were
      present in 21 patients (14 in the vesicostomy group) (P = 0.01). The highest
      incidence of upper-tract deterioration was seen with %MCC below 60% of normal (P
      = 0.001). The predominant urodynamic patterns were: (1) fulgurated group: good
      capacity, compliant bladder; (2) vesicostomy group: small-capacity, hyperreflexic
      bladder; and (3) ureterostomy group: good capacity, compliant bladder. Primary
      valve ablation is associated with better bladder function than vesicostomy and
      should be the treatment of choice in PUV. Also, vesicostomy and ureterostomy have
      distinctly different effects on bladder function.

PMID- 12415376
TI  - Congenital posterior urethral obstruction: re-do fulguration.
AB  - In patients with congenital posterior urethral obstruction, transurethral
      fulguration (TUF) is usually the treatment of choice if the patient is in a
      stable condition. However, few papers have described the proportion of patients
      who need further fulguration. We reviewed 83 boys with a congenital obstructive
      posterior urethral membrane (COPUM) to assess the role of re-do fulguration, as
      judged by prospective video recordings. Between December 1990 and March 2000, 83
      boys (aged from newborn to 15 years) underwent cystourethroscopy for
      investigation of a urethral anomaly and were found to have a COPUM. TUF was
      performed endoscopically with a hook diathermy electrode. Two to 3 months later
      boys who had cauterisation had a further urethroscopy and diathermy as required.
      Of the 83 membranous lesions in the posterior urethra, 38 were considered severe,
      20 moderate, and 21 minor. Four patients had inadequate data to be properly
      classified. Eighteen (47.4%) of the 38 patients who had a severe obstructive
      membrane equired further endoscopic intervention to obliterate residual membrane
      elements. As over 45% of patients who had a severe obstructing membrane needed
      further fulguration, it is important to follow patients carefully and to repeat
      the cystourethroscopy.

PMID- 12415377
TI  - Is it possible to create a slit-like meatus without incising the urethral plate?
AB  - A series of hypospadias repairs using the Mathieu and V-incision-sutured (MAVIS)
      technique, aiming to achieve a normal-looking,vertical, slit-like meatus in 32
      patients was reviewed. A Mathieu procedure was performed in 26 patients as a
      primary repair and in 3 as a rescue operation. In another 3 patients who had
      severe proximal hypospadias with failed repair, techniques other than Mathieu's
      were used. Good cosmetic and functional results were achieved in all patients.
      There were no complications such as fistula or stricture formation. The MAVIS
      meatoplasty creates a natural-looking, slit-like glanular meatus in both distal
      and proximal hypospadias, even in complicated cases.

PMID- 12415378
TI  - Polyorchidism revisited.
AB  - Polyorchidism is a rare urogenital anomaly. A review of the literature has
      yielded 99 cases. We add one more report, and guidelines regarding the surgical
      management are suggested.

PMID- 12415379
TI  - Urinary-tract infection affects somatic growth in unilateral symptomatic
      hydronephrosis.
AB  - To assess whether symptomatic unilateral ureteropelvic junction obstruction
      (SUUPJO) affects somatic growth and, if so, the parameters associated with it, 61
      children (54 boys and 7 girls) who underwent pyeloplasty for SUUPJO without any
      other associated urological abnormalities were retrospectively studied. Height
      was compared with standard growth charts and was considered to be affected if it
      was below 2.00 Z-score. Such children were considered group B and the rest group
      A. Mean (+/-SD) age at presentation and mean (+/-SD) split renal function (SRF)
      (%) of the affected kidney were 6.0 +/- 4.0 years and 27.3 +/- 13.2,
      respectively, for the entire group. Somatic growth was affected in 16 (12 boys, 4
      girls) children (26.2%). Urinary tract infection (UTI) was the presenting symptom
      in 11 (69%) and 5 (11%) children in groups B and A, respectively. Impaired
      somatic growth had no association with age at presentation or SRF, but a
      significant association (P < 0.001) was found with UTI. The mean post-surgery
      height percentile (2.92 +/- 4.85) over a mean follow-up of 3.37 +/- 1.86 years
      was significantly (P < 0.005) better compared with pre-surgery height percentile
      (0.67 +/- 0.96) in group B, indicating catch-up growth after surgery. In SUUPJO,
      somatic growth is affected. Presentation with UTI has a significant association,
      and height significantly improves after surgery in these patients.

PMID- 12415380
TI  - The character of variant persistent mullerian-duct structures.
AB  - To categorize variant persistent mullerian-duct derivatives (MDD) in males and
      determine their related clinical presentations for further management, five male
      patients with retained MDDs from abnormal mullerian remnants were studied. They
      comprised one patient with persistent mullerian-duct syndrome, one with
      transverse testicular ectopia, two with mixed gonadal dysgenesis, and one with a
      mullerian-duct cyst. Removal of persistent mullerian-duct structures and
      genitoplasty were done in selected patients. Categorization of patients with
      persistent MDDs permits further understanding of the pathogenesis and facilitates
      the choice of treatment.

PMID- 12415381
TI  - Imaging for endoscopic surgery: new developments applicable to pediatric surgical
      interventions.
AB  - To introduce pediatric surgeons to new developments in imaging that are already
      or soon to become available that permit "in-line" work and three-dimensionality,
      five new approaches to imaging were evaluated in 419 children over a 3-year
      period: (1) Image projection onto the abdomen (n = 4). As opposed to conventional
      video camera positions, with this modality the line of view and the line of work
      are aligned. (2) Image projection onto a plate mounted just above the abdomen (n
      = 280). As in the first approach, screen arrangement position obviates looking up
      at the monitor. (3) A touch screen mounted above the abdomen, enabling the
      surgeon to not only monitor the procedure, but also to control all the equipment
      (n = 128). As with the first two modalities, the line of view is aligned with the
      direction of the work. (4) A three-dimensional (3-D) head display (n = 6). With
      this approach the use of a headset is required. (5) A 3-D screen (n = 1) for
      which, no goggles or headsets are required. The 3-D picture can be appreciated
      from a wide angle of view, and thus can be used by the surgeon and assisting
      team. Direct imaging projection onto the abdominal surface is a visual process
      that at present is too complicated for routine surgery. Projection onto a flat
      plate or touch screen is a major improvement; the surgeon looks and works in the
      same direction. Headsets for 3-D imaging remain heavy and the image is not as
      sharp as that provided by two-dimensional monitors. The most significant
      practical progress was felt to be with the flat 3-D monitor because with this
      equipment, depth perception and ergonomic positioning were both rated as very
      good. New imaging modalities are exciting, albeit still in their early
      developmental stages. The novel imaging provided by a 3-D monitor is most
      promising, because it combines good depth perception with physiologic in-line
      visual-manual coordination. These developments should further facilitate the
      transition from conventional, open techniques to videoscopic approaches.

PMID- 12415382
TI  - Videolaparoscopy of the contralateral internal inguinal ring via the hernia sac
      in children with unilateral inguinal hernia-initial experience in Brazil, with a
      meta-analysis.
AB  - Videolaparoscopy of the contralateral internal inguinal ring (CIIR) via the
      hernia sac was performed in 100 children with a unilateral inguinal hernia (UIH)
      between August 1996 and May 1999. During general anesthesia, after dissection and
      opening of the hernia sac with the patient in the Trendelenburg position, the
      external cannula of a 10-mm trocar was introduced into the peritoneal cavity via
      the hernia sac. The abdomen was insufflated with CO(2) to a maximum pressure of 9
      mmHg. A 10-mm, 30 degrees angled laparoscope attached to a video camera was then
      inserted through the trocar to examine the CIIR. Routine contralateral inguinal
      exploration was performed in the first 10 cases and in all children whose
      videolaparoscopic exam showed an open CIIR. There were no false-positive
      findings. The positive predictive value of the method was 100% for an open CIIR;
      the average time needed to perform the examination was 8.06 min. The frequency of
      an open CIIR was 21% and that of a closed CIIR was 79%. There was no
      statistically significant relationship between the morphology of the CIIR and the
      sex or race of the child. The frequency of an open CIIR was significantly higher
      (34.1%) in children with a left IH, than in those with a right IH (11.8%, chi(2)
      = 5.95, P = 0.0146). The frequency of an open CIIR was significantly higher
      (31.1%) in children aged 4 years or older than in those less than 4 years (12.7%,
      chi(2) = 3.99; P = 0.0456), although the sample was too small to study the
      correlation between the morphology of the CIIR and age. There were no intra- or
      postoperative complications. This method for examining the CIIR is safe,
      efficient and rapid and provides the surgeon with more objective anatomic data
      for the appropriate selection of children with a UIH who will benefit from
      contralateral inguinal exploration for ligature of the contralateral patent
      Processus vaginalis, during the same anesthetic in order to prevent a possible
      subsequent contralateral indirect IH. Our initial experience is presented with a
      meta-analysis.

PMID- 12415383
TI  - Contralateral exploration is not mandatory in unilateral inguinal hernia in
      children: a prospective 6-year study.
AB  - Contralateral exploration (CE) in children with a unilateral inguinal hernia (IH)
      is still controversial. To define the necessity of CE in unilaterally-presenting
      IH, all patients who had been operated upon unilaterally in a 6-year period and
      were followed for 4-10 years had annual evaluations for a contra-lateral IH.
      Comparison of the frequency of different variables was done by chi-square test.
      Of 650 patients aged 1 month-12 years, 521 (3.6%) developed a contralateral IH.
      There was no significant difference in occurrence in the different sex and age
      groups. There was a significant difference in the side of presentation: patients
      who presented with a left-sided hernia had a greater chance of developing a
      contralateral IH (P = 0.006). The finding of a patent processus vaginalis (PPV)
      in the literature is usually present in over 35% of cases, while the occurrence
      of a contralateral hernia is usually seen in less than 15% of cases. In our study
      this rate was also very low (3.6%). Therefore, it seems that most PPVs will close
      or remain asymptomatic and only a few will lead to IHs, so that routine CE does
      not seem justified.

PMID- 12415384
TI  - A clinicopathological study of acute necrotising jejunoileitis.
AB  - We describe a variety of acute necrotizing enteritis that is endemic to the
      Indian subcontinent. During the period 1992-1998, 18 cases of acute jejunoileitis
      (AJI) were managed. Only those in whom the diagnosis was confirmed at laparotomy
      have been included in this study. The most common symptoms were abdominal pain
      (100%), fever (77%), and blood in the stool (100%). A stricture following
      conservative treatment was present in 1 case. The mean age at presentation was
      6.5 years (range 6 months-12 years); the male:female ratio was 1.2:1. All cases
      were seen during May-October. Routine investigations and X-ray films were
      nonspecific. Stool cultures did not show any clostridia, shigella, or salmonella.
      The jejunum was involved most commonly; 28% of patients did not require a bowel
      resection. Only 1 child presented with shock; the mortality was less than 5%.
      Short-bowel syndrome resulted in 1 patient due to extensive disease. The
      histopathologic features that were characteristic of the disease were patchy
      transmural mucosal necrosis extending centrifugally with submucosal edema,
      interstitial hemorrhage, type III hypersensitivity reaction, and extensive
      neovascularization. This type of AJI seen in South/Southeast Asia does not seem
      to be due a to bacterial infective etiology; immune mediation is suggested. The
      milder forms can be confused with dysentery. Mild forms of the disease can be
      managed conservatively, but carry the risk of developing strictures. This disease
      should be suspected in cases of prolonged dysentery during the summer and autumn
      months.

PMID- 12415385
TI  - Cervical thymic cysts.
AB  - Thymic cysts are considered uncommon lesions in the differential diagnosis of
      pediatric neck masses. They usually present in the 1st decade after the age of 2
      years, possibly because the thymus attains its greatest development before
      puberty. They may be found anywhere along the normal descent route of the thymus
      gland from the mandible to the sternal notch; 50% extend into the mediastinum.
      Most patients are asymptomatic, although respiratory complications may occur. A
      review of the operative records in our hospital over the last 10 years revealed
      two cases of cervical thymic cysts (CTC) in a 5- and a 9-year-old boy. Both
      children presented with an atraumatic, painless, enlarging mass in the left side
      of the neck anterior to the sternocleidomastoid muscle. Neither boy had
      respiratory problems or swallowing difficulties. Ultrasound and computed
      tomography showed a lesion consistent with a tentative diagnosis of a branchial
      cyst in one boy and an extensive cystic hygroma in the other. Both lesions were
      approached through a transverse cervical incision and, although closely adherent
      to the internal jugular vein, carotid artery, and vagus nerve, were resected
      completely. There were no postoperative complications and so far there has been
      no recurrence. CTCs are uncommon benign lesions that should be considered in the
      evaluation of neck masses in children. Preoperative diagnosis is unusual and, at
      this time, there is no preoperative radiologic test that can accurately identify
      a neck mass as a CTC. Histologic investigation of the excised specimen showing
      thymic tissue remnants with pathognomonic Hassall's corpuscles and cholesterol
      clefts in the cyst wall is the only definitive diagnosis. Evolution is benign.
      Intact, complete surgical excision remains the treatment of choice.

PMID- 12415386
TI  - Delayed presentation of congenital diaphragmatic hernia.
AB  - The late-presenting congenital diaphragmatic hernia (CDH) represents a
      considerable diagnostic challenge. This study was undertaken to define various
      patterns of delayed presentation and to analyze pitfalls in the diagnosis and
      treatment of these patients. Thirty-three children with CDH were treated between
      1993 and 2000; 15 of these (45.5%) who were diagnosed after the age of 2 months
      14 years, median of 2.5 years are reported. Thirteen had a Bochdalek hernia and 2
      had a Morgagni hernia. The diaphragmatic defect was right-sided in 6 cases and
      left-sided in 9. Five patients presented acutely, 3 with respiratory distress and
      2 with gastrointestinal (GI) obstruction. The remaining 10 presented with chronic
      respiratory or GI complaints. Inappropriate insertion of a chest drain occurred
      in 3 patients misdiagnosed as having pleural effusion (2) and a pneumothorax (1).
      Two patients had previous chest radiographs reported normal. Plain radiographs
      were sufficient to make a definitive diagnosis in only 6 patients; GI contrast
      studies were necessary in the other 9. All patients were treated through an
      abdominal approach with primary closure of the diaphragmatic defect without a
      patch. A distinct hernia sac was present in 6 cases, and associated malrotation
      in 6. All except 1 patient survived the operation with rapid improvement of their
      GI and respiratory symptoms. We conclude that: (1) late-presenting CDH should be
      included in the differential diagnosis of any child with persistent GI or
      respiratory problems associated with an abnormal chest X-ray film; (2)
      nasogastric tube placement must be considered as an early diagnostic or
      therapeutic intervention when the diagnosis is suspected; and (3) GI contrast
      studies should be a part of the diagnostic work-up of these patients.

PMID- 12415387
TI  - Long-term dilatation of caustic strictures of the oesophagus.
AB  - Caustic strictures of the oesophagus (CSO) in children are managed in different
      ways. Our study looks into the results of long-term dilatation of such
      strictures. Of 109 children admitted to our hospital with caustic ingestion, 10
      developed strictures. The dilatations were carried out for periods varying from 9
      months to 4 years. While 3 patients needed surgical treatment, 7 did not and did
      well. The oesophageal perforation rate with dilatations was only 0.47% (2
      perforations from a total of 424 dilatations). Long-term dilatations are
      successful in managing a majority of CSO in children and are associated with
      minimal complications.

PMID- 12415388
TI  - Laparoscopic repair of a congenital diaphragmatic hernia.
AB  - The standard treatment of congenital diaphragmatic hernia is by open operation.
      We have successfully performed a laparoscopic repair in an asymptomatic 2-year
      old child. We recommend this as a safe alternative treatment modality in
      diaphragmatic hernias presenting past infancy. The role of laparoscopic
      correction in the newborn period, however, remains to be determined.

PMID- 12415389
TI  - Unusual epithelium in a subpubic sinus.
AB  - A 5-year-old male presented with the history of whitish discharge from a midline
      sinus opening just above the pubis for 2 months. Attempted radiography of the
      sinus revealed a blind fistula and voiding cystourethrography was normal. The
      fistula was excised deep to the subpubic space without any evidence of connection
      to the lower urinary tract. Pathologic evaluation of the lesion revealed a
      ciliated-columnar lining with stratified-squamous and transitional epithelium. To
      our knowledge, a subpubic sinus with this unique presentation of epithelium has
      not been reported previously.

PMID- 12415390
TI  - Isolated asternia: a case report.

PMID- 12415391
TI  - Necrotizing amebic colitis in a child.
AB  - Necrotizing amebic colitis (NAC) is a rare complication of intestinal amebiasis,
      and only a few cases have been reported in the literature. The outcome of NAC is
      dismal, particularly in children. We encountered a 3-year-old child who presented
      with bloody diarrhea, fever, toxemia, and peritonitis. At laparotomy the whole
      colon was found to be necrotic with several perforations. Histopathology of the
      resected colon showed features of NAC. This is a rare case of survival of a child
      with NAC involving the whole colon.

PMID- 12415392
TI  - Duodenojejunal obstruction by a hemangioma.
AB  - Gastrointestinal obstruction by hemangiomas is exceedingly rare. We report a case
      of a duodenojejunal obstruction caused by a large hemangioma. The patient
      underwent a gastrojejunostomy for relief of the obstruction and has been symptom
      free, although the hemangioma persists.

PMID- 12415393
TI  - Treatment of transient posttraumatic bile-duct stenosis by laparoscopic-assisted
      cholecystotomy.
AB  - A 10-year-old boy developed severe obstructive jaundice following blunt abdominal
      trauma. Endoscopic retrograde cholangiography and magnetic resonance
      cholangiography revealed a stricture of the common bile duct. A cholecystostomy
      tube was inserted under laparoscopic guidance. After temporary bile drainage and
      a cholecystoenteric bypass the patient recovered.

PMID- 12415394
TI  - Retroperitoneal paraganglioma in a child: resection and vena caval
      reconstruction.
AB  - Retroperitoneal paragangliomas (PG) are tumors of neuroectodermal origin rarely
      seen in children. A 10-year-old boy presented with back pain and a palpable mass
      secondary to a large right-sided retrocaval PG inferomedial to the kidney.
      Preoperative chemotherapy and perioperative embolisation were instigated to
      reduce tumor vascularity. En-bloc resection of the inferior vena cava below the
      left renal vein and above the caval bifurcation was achieved. Caval
      reconstruction was completed using a complex autograft of anterior uninvolved
      vena cava and right renal vein. At 4-year follow-up, the child remains tumor-free
      with normal caval flow and patency.

PMID- 12415395
TI  - Traumatic urethral fistula.
AB  - An 11-year-old male was passing urine from an opening on the undersurface of the
      penis as well as from the normal meatal opening. He had passed a calculus per
      urethra 1.5 years previously. Operative intervention revealed it to be a distal
      urethral fistula 1 cm proximal to the original meatus. A double-layered repair
      using local tissue was done, achieving good results.

PMID- 12415396
TI  - Unilateral inguinal ectopic scrotum with covered exstrophy.
AB  - A case of ectopic scrotum located in the right inguinal area and associated with
      covered exstrophy and ipsilateral renal agenesis is described. Initially, repair
      of the exstrophy was performed. Scrotal reconstruction was carried out after 1
      year, during which time the patient developed an inguinal hernia in the ectopic
      scrotum. The literature is reviewed and the scrotal reconstruction procedure is
      discussed.

PMID- 12415397
TI  - Congenital mesenterico-portal (Rex) shunt.
AB  - Congenital anomalies of the portal and umbilical-venous system are rare, with few
      reported cases. We describe a case where the native umbilical vein had acquired
      mesenteric venous outflow to bypass an in-utero portal-vein (PV) obstruction and
      restore normal venous return to the liver. This is analogous to the recently
      described Rex shunt procedure used in some cases of extrahepatic portal
      hypertension due to PV occlusion.

PMID- 12415398
TI  - Treatment of chronic wounds by local delivery of granulocyte-macrophage colony
      stimulating factor in patients with neutrophil dysfunction.
AB  - Chronic wounds are associated with considerable morbidity and prolonged
      hospitalizations. The availability of recombinant growth factors and cytokines
      provides a new modality for treatment of recalcitrant wounds. Granulocyte
      macrophage colony-stimulating factor (GM-CSF), a growth protein for hematopietic
      cells, also enhances neutrophil and monocyte function and promotes keratinocyte
      proliferation. In three patients with inherited disorders associated with
      leukocyte dysfunction and non-healing wounds, topical application of GM-CSF
      resulted in complete wound closure within 1 to 4 weeks. A subcutaneous (s.c.)
      infusion pump for the local s.c. delivery of GM-CSF was also found to enhance
      healing. Local application of GM-CSF may thus promote wound closure in patients
      with impaired wound healing.

PMID- 12415399
TI  - A rare germ-cell tumor site: vaginal endodermal sinus tumor.
AB  - Malignant germ-cell tumors (MGCT) are rare tumors of childhood accounting for
      less than 3% of pediatric malignancies. Endodermal sinus tumor (EST) forms the
      most common histologic subtype of MGCT. The vagina is an extremely rare site for
      GCTs. A 9-month-old female was admitted with a short history of vaginal bleeding,
      a mass protruding from the vagina, and difficulty in passing urine. She was pale,
      the bladder was full, and a mass was palpable anteriorly on rectal examination.
      Ultrasound showed an ovoid, hyperechoic mass posterior to the bladder. A biopsy
      revealed a vaginal EST. The serum alpha-fetoprotein (AFP) was elevated partial
      vaginectomy was done and the tumor was excised in toto. The patient was
      subsequently given six courses of cis-platinum, etoposide, and bleomycin and on
      follow-up continues to be free from disease. EST is the most common GCT in
      children. In females, it is usually encountered in the ovary. EST of the vagina
      is a rare, highly malignant GCT that exclusively involves children less than 3
      years of age. The diagnosis is based on histology and raised AFP. Vaginal EST is
      both locally aggressive and capable of metastasis. Untreated patients have died
      within 2 to 4 months of presentation. Radical surgery leads to a loss of sexual
      and reproductive function. Long-term irradiation has secondary effects of
      sterility, aseptic necrosis of the femoral head, and abnormal growth of the
      pelvic bones. Partial vaginectomy with combination chemotherapy is the most
      recommended line of treatment. The surgery eradicates local tumor cells and makes
      subsequent chemotherapy more effective. Simple tumor excision is not sufficient,
      as residual tumor cells induce early recurrence and make chemotherapy
      ineffective. The serum AFP level is a useful marker for diagnosis and monitoring
      the recurrence of vaginal EST in infants.

PMID- 12415400
TI  - Spontaneous scrotal faecal fistula in infants.
AB  - Two infants aged 29 and 43 days, respectively, presented with a spontaneous
      scrotal faecal fistula from a strangulated inguinal hernia. There was associated
      necrotising fasciitis of the scrotum in both patients, but the testes were
      spared. Resection and anastomosis along with debridement of the scrotal fasciitis
      was successful in both cases. This complication is rare: only three other cases
      have been reported in the world literature. The complication appears to occur
      mainly in developing countries, and is the result of late presentation. The
      principle of early referral and repair of childhood inguinal hernias should
      reduce this complication and the attendant morbidity and mortality.

PMID- 12415401
TI  - Angiomyolipoma with hypertension mimicking a malignant renal tumor.
AB  - A 13-month-old girl with a unilateral renal angiomyolipoma causing severe
      hypertension is reported. The differential diagnosis of renal masses, a review of
      the literature, and the diagnostic algorithm for renal masses used at our center
      are presented.

PMID- 12415402
TI  - Meckel's diverticulum associated with ileal volvulus in a neonate.
AB  - A symptomatic Meckel's diverticulum (MD) may manifest as an intestinal
      obstruction secondary to a volvulus. We describe a case of a meconium-impacted MD
      associated with inflammatory adhesions to adjacent viscera that presented as an
      intestinal obstruction in a 4-h-old infant secondary to an ileal volvulus with
      resultant infarction of the diverticulum and ileal segment.

PMID- 12415403
TI  - Mucosal-lined hemiperineal anomaly possibly caused by antenatal rupture of a
      caudal duplication.
AB  - In a 1-month-old infant with a mucosal-line left hemiperineal defect associated
      with penoscrotal hypospadias, penoscrotal transposition (PST) and an overhanging
      caudal skin-covered soft-tissue flap resembling a caudal appendage, perineal
      anatomy could be restored by excising the mucosa and using the overhanging flap
      to cover the resultant defect. The PST was corrected at the same time. Squamous,
      gastric, small-intestinal, and respiratory epithelia were present histologically
      in the mucosa in addition to adjacent cartilaginous elements. A caudal
      duplication that had ruptured in utero through the hemiperineum could explain the
      anomaly.

PMID- 12415404
TI  - Duodenal atresia with vascular rings and subglottic stenosis.
AB  - This case report of duodenal atresia associated with a vascular ring and
      subglottic stenosis raises some interesting issues of management.

PMID- 12415405
TI  - Hypertrophic pyloric stenosis in utero.
AB  - Hypertrophic pyloric stenosis (HPS) is the most common surgical condition
      producing vomiting in infants. It has been reported as early as the 1st week of
      life. We report an infant with HPS seen on prenatal ultrasound. Although infants
      with HPS usually present between 3 and 5 weeks of life, HPS must be considered as
      part of the differential diagnosis of newborns with non-bilious vomiting.

PMID- 12415406
TI  - Wilms' tumour metastasis to the testis: long-term survival.
AB  - We report the case of a 3-year-old boy with a Wilms' tumour of unfavourable
      histology with metastatic spread to the right testis. Orchiectomy and
      chemotherapy led to disease-free survival for more than 8 years.

PMID- 12415407
TI  - Extrarenal Wilm's tumour - a rare entity.
AB  - A rare case of extrarenal Wilms' tumour (ERWT) that presented as an asymptomatic
      subcutaneous lumbar mass is reported. The diagnosis could only be established
      postoperatively.

PMID- 12415408
TI  - Sporadic aplasia cutis congenita.
AB  - Aplasia cutis congenita (ACC) is a rare group of disorders characterized by the
      focal absence of skin at birth. The majority of cases affect the scalp, but
      involvement of the trunk and extremities has been described. Proposed etiologies
      for ACC include infection, vascular malformations, amniogenesis, and teratogens,
      but no unifying theory has been identified. We present the case of a 1-day-old
      female with large, bilateral posterolateral trunk skin defects noted at birth.
      The prenatal history was significant for maternal diabetes, fetal papyraceus at
      12 weeks' gestation, and a family history of limb defects. The infant was treated
      non-surgically with local wound care and antibiotics, as well as frequent
      dressing changes. The areas of absent skin developed a granulation-tissue layer
      followed by re-epithelialization and mild wound contracture. With early
      identification of the etiology of the lesions and appropriate investigation and
      treatment, including conservative wound management, aplastic lesions can heal
      successfully without affecting growth, but may require cosmetic repair at a later
      stage.

PMID- 12415409
TI  - Autoamputation of a congenital oropharyngeal hairy polyp.
AB  - Hairy polyps or dermoids are rare, benign congenital tumours of the
      oronasopharynx containing elements of both ectodermal and mesodermal origin. They
      occur most commonly in young infants and can cause respiratory distress or
      failure to thrive due to feeding difficulties. Computed tomography, magnetic
      resonance imaging, and barium video fluoroscopy can be useful in delineating the
      origin and extent of these lesions. Treatment usually consists of surgical
      removal. We describe a case of spontaneous resolution of symptoms in an 11-week
      old baby due to autoamputation of the lesion.

PMID- 12415410
TI  - Prenatally closed gastroschisis with midgut atresia.
AB  - Spontaneous prenatal closure of gastroschisis (GS) is rare and usually associated
      with atresia of the midgut. We describe a case of GS diagnosed at 20 weeks'
      gestation that resolved spontaneously in utero. At delivery the infant had an
      ileus. A laparotomy with a jejunocolostomy was performed, but she died at 2
      months of age due to complications of total parenteral nutrition.

PMID- 12415411
TI  - Comparing wound closure using tissue glue versus subcuticular suture for
      pediatric surgical incisions: a prospective, randomised trial.
AB  - Tissue adhesives have gained favour for quicker and painless closure of
      lacerations. To compare the tissue adhesive 2-octylcyanoacrylate with our current
      standard subcuticular suture for closure of surgical incisions in children,
      looking at outcome measures of time efficiency, cosmesis, and wound
      complications, a prospective, randomised, controlled trial was conducted at our
      institution's ambulatory surgery centre. All healthy patients undergoing
      unilateral or bilateral herniotomies were recruited prospectively with informed
      consent and randomly allocated to suture or glue. The exclusion criteria were
      neonates or children with allergy to tissue glue. Time of wound closure was
      measured from the subcutaneous layer to application of the dressing. An
      independent, blinded observer assessed cosmesis at 2 to 3 weeks using a validated
      wound scale ranging from worst (0) to best (6). Parent satisfaction with wound
      appearance was recorded on a 100-mm visual analogue scale (VAS). A total of 59
      patients were recruited into the study with 26 in the glue group and 33 in the
      suture group. There was no difference in mean time of closure (glue 181 +/- 62 s
      vs suture 161 +/- 45 s, P = 0.18). Two patients in each group had a suboptimal
      Hollander wound score of 5 (7.7% glue, 6.1% suture). There was also no difference
      in parent satisfaction (VAS: glue 78 +/- 19 mm vs suture 81 +/- 15 mm, P = 0.68).
      No patient reported any rash, wound infection, or dehiscence. Tissue glue is easy
      to use with no complications and has equivalent cosmetic results, but is not
      faster than a subcuticular suture.

PMID- 12415412
TI  - Computed tomography-guided percutaneous drainage of intra-abdominal abscesses in
      neutropenic children.
AB  - The mortality associated with undrained intra-abdominal abscesses is high.
      Computed tomography-guided percutaneous drainage (CT-PD), a minimally invasive
      technique, allows a drainage catheter to be inserted into fluid collections
      throughout the body with minimal risk. We described two neutropenic patients with
      intra-abdominal abscesses treated with CT-PD after they failed to respond to
      antimicrobial therapy. With this modality, the surgery was successfully avoided
      or delayed. We are of an opinion that CT-PD is an efficient and simple urgent
      radiology procedure.

PMID- 12415413
TI  - A new technique for repair of exstrophy-epispadias complex.
AB  - We report a new method of repair of exstrophy-epispadias complex (EEC) at a
      second stage by using flaps from the skin between the penis and scrotum (the
      clitoris and labia majora in females) used in seven patients. The non-pigmented
      skin between the penis and scrotum in males or a band of skin between the
      clitoris and labia majora in female is mobilized in two flaps, which are rotated
      superiorly. Five patients were treated primarily by this method and two patients
      at the time of secondary reconstruction. There were six boys and one girl. Two
      patients were post-pubertal, one male and one female. Follow-up (6-12 months)
      revealed good cosmetic and functional results. If EEC is repaired in a single
      stage, the entire pelvic diaphragm is visualized from inside and the sphincters
      can be reconstructed around the bladder neck. This procedure gives better
      exposure of attachments of the corporal bodies to the pubic rami, allowing easier
      mobilization. The bulbospongiosus muscle can be reconstructed. A normal
      penoscrotal relation is achieved in male patients. The root of the scrotum, which
      is splayed out and wide, narrows. Rotation of the flaps superiorly normalizes the
      symphyseal area. In female patients the appearance of the mons pubis is
      satisfactory. In post-pubertal children the pubic hair distribution appears
      normal.

PMID- 12415414
TI  - Hypertrophic pyloric stenosis, congenital or not congenital: a critical overview.

PMID- 12415415
TI  - Is spontaneous perforation of the bile duct in children due solely to pancreatico
      biliary maljunction?

PMID- 12415416
TI  - Saccharomyces boulardii: a possible addition to the standard treatment and
      prophylaxis of enterocolitis in Hirschsprung's disease ?

PMID- 12415417
TI  - Transjugular intrahepatic portosystemic shunts in children with biliary atresia.
AB  - PURPOSE: We retrospectively evaluated the technical and long-term clinical
      results of transjugular intrahepatic portosystemic shunts (TIPS) in children with
      portal hypertension and biliary atresia (BA). METHODS: Nine children with BA and
      recurrent bleeding from esophagogastric and/or intestinal varices were treated by
      TIPS at the age of 34-156 months and followed-up in two centers. Different types
      of stents were used. RESULTS: Shunt insertion succeeded in all patients, but in
      two a second procedure was necessary. Seven procedures lasted more than 3 hr,
      mainly due to difficult portal vein puncture. Variceal bleeding ceased in all
      patients; however, 16 reinterventions were performed in eight patients for
      clinical reasons (n = 11) and sonographically suspected restenosis (n = 5). Four
      patients underwent successful liver transplantation 4-51 months after TIPS and
      five are in good clinical conditions 64-75 months after TIPS. CONCLUSION: TIPS in
      children with BA is technically difficult, mainly due to periportal fibrosis and
      small portal veins. Frequency of reinterventions seems to be higher compared with
      adults.

PMID- 12415418
TI  - Why do grafts clot despite access blood flow surveillance?
AB  - PURPOSE: To look in more detail at those grafts that clot despite access blood
      flow (ABF) surveillance and the outcome of radiological thrombectomy in those
      grafts. METHODS: Retrospective review was carried out of all
      polytetrafluoroethylene grafts that clotted from September 1, 1998 to October 30,
      2000. During this period, each graft had ABF measured monthly and was referred
      for prophylactic angioplasty if flow fell below 600 ml/min or by 25%. RESULTS:
      Thirty-one of 62 monitored grafts clotted (0.44 episodes per patient per month).
      Five were surgically thrombectomized and 19 were radiologically thrombectomized.
      The last available ABF prior to graft thrombosis averaged 804 +/- 108 ml/min and
      ranged from 215 to 2497 ml/min. Nine of the 23 grafts failed to trigger either of
      the ABF criteria prior to initial thrombosis. All but one of the 17 grafts
      thrombolysed radiologically showed evidence of significant (>50%) venous
      stenoses, though additional lesions were found in nine. Thrombolysis was
      successful in 14 grafts, with ABF rising from 693 +/- 96 to 941 +/- 135 ml/min (p
      <0.05). Six additional grafts reclotted and were lost (6-month graft survival
      37%). CONCLUSION: (1) A significant proportion (40%) of graft thromboses that
      occur despite ABF surveillance occur in grafts with preserved ABF (>600 ml/min);
      (2) over 70% can be successfully thrombectomized/angioplastied with about 35%
      long-term (6 months) survival.

PMID- 12415419
TI  - A two-species test of the hypothesis that spatial isolation influences microbial
      diversity in soil.
AB  - The hypothesis that spatial isolation is a key determinant of microbial community
      structure in soils was evaluated by examining the competitive dynamics of two
      species growing on a single resource in a uniform sand matrix under varied
      moisture content. One species dominated the community under highly connected,
      saturated treatments, suggesting that these conditions allow competitive
      interactions to structure the community. As moisture content decreased, however,
      the less competitive species became established in the community. This effect was
      most pronounced at a matric water potential of -0.14 MPa where estimates of final
      population density and species fitness were equal. A second but more closely
      related species pair exhibited a similar response to decreasing moisture,
      suggesting that the effects of spatial isolation we observed are not simply a
      species-pair-specific phenomenon. These findings indicate that spatial isolation,
      created by low moisture content, plays an important role in structuring soil
      microbial communities.

PMID- 12415420
TI  - Simultaneous growth on citrate reduces the effects of iron limitation during
      toluene degradation in Pseudomonas.
AB  - Rhizoremediation has been suggested as an attractive bioremediation strategy for
      the effective breakdown of pollutants in soil. The presence of plant root
      exudates such as organic acids, sugars, and amino acids that may serve as carbon
      sources or biosynthetic building blocks and the limited bioavailability of iron
      may influence the degradation of pollutants in the rhizosphere. To test the
      effect of such compounds on hydrocarbon degradation, trace concentrations of
      yeast extract or mixtures of organic acids and amino acids were added to
      continuous cultures of Pseudomonas putida mt2 and P. putida WCS358 (TOL) growing
      on toluene. By addition of these compounds increased growth yields and higher
      specific growth rates on toluene were obtained. The effects of iron limitation on
      the substrate utilization pattern of both strains were tested by growing the
      strains on a mixture of toluene and the readily degradable carbon source citrate
      while the iron concentration was varied. Simultaneous use of both substrates
      under carbon-limited as well as iron-limited conditions was observed. Growth
      yields were less reduced and iron requirement was lower during iron-limited
      growth in the toluene + citrate grown cultures compared to cultures in which
      toluene was used as the sole carbon source. The kinetic properties of the cells
      for toluene degradation were less hampered by the lack of iron when citrate was
      used as an additional carbon source. The results indicate that the availability
      of low concentrations of natural organic compounds, such as produced in the
      rhizosphere, may positively influence the degradative performance of hydrocarbon
      degrading bacteria.

PMID- 12415421
TI  - Identification of dexamethasone-dependent osteoprogenitors in cell populations
      derived from adult human female bone.
AB  - The purpose of this investigation was to establish whether or not dexamethasone
      (Dex)-dependent osteoprogenitors with sufficient proliferative capacity to form a
      colony of bone-forming osteoblasts could be identified in cell populations
      isolated from adult human bone. This question is relevant because of the ongoing
      controversy regarding the effects of dexamethasone on bone formation in humans,
      the clearly different effects of dexamethasone on osteoprogenitor differentiation
      in mouse vs. rat bone cell populations, and the related question of whether
      observations in either rat or mouse systems are applicable to human systems. To
      answer the question, we isolated cell populations from distal femoral cancellous
      bone of 8 female patients with osteoarthritis and quantitated the number of Dex
      dependent osteoprogenitors in these populations by counting the number of
      osteoblastic colonies forming bone (bone nodules) or unmineralized bone matrix
      (osteoid nodules). Dex increased alkaline phosphatase (AP) content in all
      populations, induced bone nodule formation in 2 of the 8 populations, and induced
      formation of AP-positive clusters of cells with osteoblastic morphology in one.
      Treatment with 1,25-dihydroxyvitamin D3 increased osteocalcin (OC) production in
      the nodule forming populations, but not in the non-nodule-forming populations.
      Our results thus establish that Dex-dependent osteoprogenitors with sufficient
      proliferative capacity to form bone or osteoid nodules are present in cell
      populations derived from adult human bone. They also show that frozen primary
      human bone cell populations that have been characterized previously in terms of
      the number of Dex-dependent osteoprogenitors present can be used to further study
      the characteristics of such progenitors.

PMID- 12415423
TI  - Immature uterotrophic assay of estrogenic compounds in rats given diets of
      different phytoestrogen content and the ovarian changes with ICI 182,780 or
      antide.
AB  - To investigate the influence of phyotestrogens in the diet, an immature
      uterotrophic assay of ethinylestradiol, bisphenol A, 4-nonylphenol or genistein
      was performed in rats given the formula MF diet, modified NIH-07 open formula
      diet, or modified NIH-07 phytoestrogen-lowered-diet (study 1). The chemicals were
      administered subcutaneously from 20 days of age for 3 days. Doses of
      ethinylestradiol, bisphenol A, 4-nonylphenol or genistein were 0.06-0.6 micro
      g/kg per day, 1-10 mg/kg per day, 10-100 mg/kg per day or 1-20 mg/kg per day,
      respectively. In another study, an immature uterotrophic assay of genistein and
      ethinylestradiol together with ICI 182,780 or antide was performed to compare the
      ovarian changes with these chemicals (study 2). Doses of genistein or
      ethinylestradiol were 30 mg/kg per day or 0.6 micro g/kg per day, respectively,
      and these chemicals were injected subcutaneously from 20 days of age for 3 days.
      In study 1, there were no essential differences in the uterus weights among the
      various phytoestrogen-content diets. In study 2, the ovary weights in rats given
      genistein were significantly higher than in the controls, whereas the ovary
      weights in rats given ethinylestradiol were lower than in the controls. The ovary
      weights in the ICI 182,780 plus genistein group were significantly higher than in
      the genistein group, but decrease of the ovary weights was detected in the antide
      plus genistein group. There was no significant difference in ovary weights
      between the ICI 182,780 plus ethinylestradiol group and the ethinylestradiol
      group, but decrease of ovary weights was detected in antide plus ethinylestradiol
      group. In a histological examination of the ovary, fluid-filled follicles in the
      genistein group were more numerous than in other groups and increase of granulosa
      cell fragmentation was seen in the ethinylestradiol and other groups with the
      exception of the genistein group. The present findings demonstrate that the
      sensitivity of the immature rat uterotrophic assay is not influenced by the
      relatively low level of phytoestrogen in diets and that the ovarian changes
      occurring with genistein and ethinylestradiol are different.

PMID- 12415424
TI  - Increased expression and decreased activity of cytochrome P450 1A1 in a murine
      model of toluene diisocyanate-induced asthma.
AB  - In the lung, cytochromes P450 (CYP) may be affected by inhaled pollutants. In a
      previous study, we showed that acute inhalation of toluene diisocyanate (TDI), a
      low molecular weight chemical known to cause occupational asthma, decreased
      CYP2B1 expression in rat lung. In the present work, we investigated the effect of
      TDI in a murine model of TDI-induced asthma. Mice were skin-sensitized with TDI
      on 2 consecutive days and challenged intranasally 8 days later. Lung expression
      and activity of CYP were assessed 24 h after the challenge. A significant
      increase in Cyp1a1 protein expression was detected by western blotting in lung
      from mice sensitized and challenged with TDI, whereas no modification of
      expression of other CYP, namely Cyp2b, Cyp2e1 and Cyp3a was observed. Increase in
      Cyp1a1 protein was associated with an increase in Cyp1a1 mRNA, as assessed by
      polymerase chain reaction after reverse transcription of total lung RNA. However,
      a decreased Cyp1a1 activity, as measured by O-deethylation of ethoxyresorufin was
      observed in lung from TDI-sensitized and challenged mice, suggesting that TDI may
      inhibit Cyp1a1 function. In agreement with this hypothesis, in vitro experiments
      conducted on liver microsomes overexpressing Cyp1a1 after treatment of mice with
      3-methylcholanthrene showed that TDI markedly inhibited in a concentration
      dependent manner Cyp1a1 activity. In conclusion, expression of Cyp1a1, known to
      exhibit rather negative functions in the lung, is increased in mice sensitized
      and challenged with TDI. However, this effect is associated with a decreased
      enzyme activity, which might limit the toxicological consequences of increased
      Cyp1a1 expression.

PMID- 12415425
TI  - Fractionation of protein adducts in rats and mice dosed with
      [14C]pentachlorophenol.
AB  - Pentachlorophenol (PCP) induces liver cancer in mice, possibly due to covalent
      binding of PCP metabolites to critical macromolecules. In this work, covalent
      binding was related to PCP biotransformation and specific (cysteinyl) adducts of
      chlorinated quinones in liver and blood of Sprague-Dawley rats and B6C3F1 mice
      dosed with [(14)C]PCP. Using a sequential scheme of scintillation counting along
      with selective cleavage of cysteinyl adducts by Raney nickel, we quantified total
      radiobinding, total covalent binding, non-cysteinyl protein binding, and specific
      protein adducts in liver nuclei (Np), liver cytosol (Cp), hemoglobin (Hb), and
      serum albumin (Alb). Almost all of the radiobinding to Np (>98%) was attributed
      to covalent binding in both rats and mice. Regarding Cp, more covalent binding
      was observed in mice than in rats (100% versus 67%, P=0.015). Very little binding
      was attributed to serum Alb (rats 1.3%, mice 2.6%, P=0.046) or Hb (not detected
      in either species). These results indicate that the liver was the main organ for
      PCP metabolism and that relatively little of the dose of reactive metabolites
      became systemically available. Cysteinyl binding accounted for 76-91% of total
      covalent binding to Np and 68-76% of total covalent binding to Cp. In addition,
      five times more PCP was bioactivated in the livers of mice than in those of rats
      (2.14% of the dose bound to Cp in mice and 0.416% in rats). These results
      reinforce previous studies, suggesting that the liver was a target organ of PCP
      carcinogenicity and that mice were more susceptible to liver damage than rats.
      However, the sum of all quantified adducts accounted for only 7-8% of total
      cysteinyl binding to Np and 2% to Cp, suggesting that other uncharacterized
      binding species may be important to the toxicity of PCP.

PMID- 12415426
TI  - Phenotyping of human glutathione S-transferase hGSTT1-1: a comparison of two ex
      vivo routine procedures.
AB  - The human glutathione S-transferase hGSTT1-1 is characterized by a polymorphism
      displaying three phenotypes: the "non-conjugator" (NC) phenotype expresses no or
      only a residual activity due to a homozygous deletion of the hGSTT1 gene, a
      medium hGSTT1-1 activity can be demonstrated for the "low conjugator" (LC)
      phenotype as the heterozygous bearer of one hGSTT1 allele, and a high hGSTT1-1
      activity is detected for the "high conjugator" (HC) phenotype as the homozygous
      bearer of two hGSTT1 alleles. We have developed a routine ex vivo photometric
      phenotyping procedure based on the determination of bromide release rates from
      the hGSTT1-1-catalyzed glutathione conjugation of the substrate methyl bromide in
      EDTA blood samples under standard conditions (1,000 ppm methyl bromide, 10 min
      incubation). The bromide release rates were standardized to the hemoglobin (Hb)
      value. Twenty-six individuals were phenotyped following the new procedure. Four
      individuals were classified as NCs (24-33 pmol Br(-)/mg Hb per min), 21
      individuals were regarded as LCs (107-206 pmol Br(-)/mg Hb per min) and one
      person of the study group was designated HC (236 pmol Br(-)/mg Hb per min). The
      results were validated by qualitative hGSTT1 genotyping and demonstrated a 100%
      match for conjugators and non-conjugators. A second HPLC phenotyping routine
      procedure based on the formation of S-methylglutathione from methyl chloride in
      erythrocyte lysate incubations (Muller et al. 2001, Arch Toxicol 74:760-767) was
      established and validated by genotyping. The phenotyping results obtained with
      both methods were correlated, resulting in a good correlation with R(2)=0.64
      (y=0.8997x +51.535). Three distinct phenotype clusters for NCs, LCs and HCs,
      consistent with the proposed genetics, were demonstrated. Assay-dependent storage
      experiments revealed an excellent stability of the hGSTT1-1 activity. In
      conclusion, the evaluated methods provide powerful tools for determination of
      hGSTT1-1 activity as a clinical parameter.

PMID- 12415427
TI  - Cytochrome P450 CYP1B1 and catechol O-methyltransferase (COMT) genetic
      polymorphisms and breast cancer susceptibility in a Turkish population.
AB  - Epidemiological studies indicate that most risk factors for breast cancer are
      related to reproductive and hormonal factors. Estrogen has been proposed to
      trigger breast cancer development via an initiating mechanism involving its
      metabolite, catechol estrogen (CE). Because of the important role of cytochrome
      P450 1B1 ( CYP1B1) and catechol O-methyltransferase ( COMT) in mammary estrogen
      and carcinogen metabolism, we examined the CYP1B1 and COMT genes to determine
      whether genetic variations could account for inter-individual differences in
      breast cancer. In this case-control study, we determined CYP1B1 and COMT
      genotypes in 84 breast cancer patients and 103 healthy unrelated women controls
      from a Turkish population. In the case of CYP1B1, we genotyped CYP1B1*3 (L432 V)
      allele. We found that carriers of the CYP1B1*3 allele were more frequent among
      breast cancer patients with adjusted odds ratio (OR) for age, age at menarche,
      age at first full-term pregnancy, body mass index (BMI) and smoking status of
      2.32 (95% confidence interval 1.26-4.25) associated with the allele. However,
      this allele appeared to be a significant factor for susceptibility only in
      patients with a BMI greater than 24 kg/m(2). Menopausal status did not appear to
      affect susceptibility. In the case of COMT, there was no significant difference
      in susceptibility for breast cancer development between patients with low
      activity COMT-L (V158 M) allele and high activity COMT-H allele, and
      susceptibility was not affected by menopausal status, BMI or CYP1B1 genotype. We
      conclude that the CYP1B1* 3 allele appears to be a factor for susceptibility to
      breast cancer in Turkish women especially those with a BMI greater than 24
      kg/m(2).

PMID- 12415428
TI  - Therapeutic efficacy of the adenosine A1 receptor agonist N6-cyclopentyladenosine
      (CPA) against organophosphate intoxication.
AB  - The objective of the present study was to investigate whether reduction of
      central acetylcholine (ACh) accumulation by adenosine receptor agonists could
      serve as a generic treatment against organophosphate (OP) poisoning. The OPs
      studied were tabun ( O-ethyl- N-dimethylphosphoramidocyanidate), sarin
      (isopropylmethylphosphonofluoridate), VX ( O-ethyl- S-2
      diisopropylaminoethylmethylphosphonothiolate) and parathion ( O, O-diethyl- O-(4
      nitrophenyl)phosphorothioate). The efficacy of the adenosine A(1) receptor
      agonist N(6)-cyclopentyladenosine (CPA) against an OP intoxication was examined
      on the basis of the occurrence of clinical symptoms that are directly associated
      with such intoxication. CPA (1-2 mg/kg) effectively attenuated the cholinergic
      symptoms and prevented mortality in lethally tabun- or sarin-intoxicated rats. In
      contrast, CPA (2 mg/kg) proved to be ineffective against VX or parathion
      intoxication. Intracerebral microdialysis studies revealed that survival of sarin
      poisoned and CPA-treated animals coincided with a minor elevation of
      extracellular ACh concentrations in the brain relative to the baseline value,
      whereas an 11-fold increase in transmitter levels was observed in animals not
      treated with CPA. In VX-intoxicated rats, however, the ACh amounts increased 18
      fold, irrespective of treatment with CPA. The striatal acetylcholinesterase
      (AChE) activity following a lethal sarin intoxication was completely abolished in
      the vehicle-treated animals, whereas 10% and 60% AChE activity remained in
      animals treated with 2 mg/kg CPA 1 min after or 2 min prior to the poisoning,
      respectively. In VX-intoxicated animals the AChE activity in the brain was
      strongly reduced (striatum 10%, hippocampus 1%) regardless of the CPA treatment.
      These results demonstrate that CPA is highly effective against tabun or sarin
      poisoning, but fails to protect against VX or parathion. Survival and attenuation
      of clinical signs in tabun- or sarin-poisoned animals are associated with a
      reduction of ACh accumulation and with protection of AChE activity in the brain.

PMID- 12415429
TI  - Effects of 5-day styrene inhalation on serum prolactin and dopamine levels and on
      hypothalamic and striatal catecholamine concentrations in male rats.
AB  - In several studies a hypersecretion of the pituitary hormone prolactin (PRL) in
      styrene-exposed workers has been described. This should cause reproductive
      problems like oligomenorrhea, secondary amenorrhea and reduced fertility [Arfini
      et al. (1987) J Occup Med 29:826-830, Bergamaschi et al. (1996) Neurotoxicology
      17:753-760, Mutti and Smargiassi (1998) Toxicol Ind Health 14:311-323]. Secretion
      of PRL is tonically inhibited by the catecholamine dopamine (DA), which is
      released from hypothalamic neurons. It has been suggested that the activity of
      the enzyme dopamine-beta-hydroxylase (DBH) in the serum is a peripheral marker of
      central dopaminergic function. A slight reduction of such enzymatic activity was
      observed in styrene-exposed workers, which was associated with hypersecretion of
      PRL. To further investigate the putative effects of styrene on PRL release, male
      rats were exposed to styrene vapors (645, 2150 and 6450 mg/m(3)) for 6 h/day on 5
      consecutive days. Animals were killed either directly following the last exposure
      (immediate group) or after a recovery period of 24 h (recovery group). Serum PRL
      and DA levels were measured by radioimmunoassay. Concentrations of catecholamines
      and their metabolites in the striatum and mediobasal hypothalamus (MBH) were
      determined by high performance liquid chromatography with electrochemical
      detection. Neither in the immediate nor in the recovery group were any
      statistically significant changes of serum PRL levels observed. Likewise,
      concentrations of catecholamines and their metabolites in the striatum and MBH
      remained unaffected. We conclude from these data that styrene, even at very high
      concentrations, has no adverse effects on the neuroendocrine mechanisms
      regulating PRL release and DA levels in the brain. With the limitations inherent
      in any animal model, we suggest that our data indicate that styrene also has no
      adverse neuroendocrine effects in humans.

PMID- 12415430
TI  - Inhibitory effect of berberine on tert-butyl hydroperoxide-induced oxidative
      damage in rat liver.
AB  - Berberine, a main protoberberine component of Coptidis Rhizoma, was studied for
      the mechanism of its inhibitory effects on the tert-butyl hydroperoxide (t-BHP)
      induced cytotoxicity and lipid peroxidation in rat liver. In the preliminary
      study, berberine expressed an antioxidant property by its capacity for quenching
      the free radicals of 1,1-diphenyl-2-picrylhydrazyl (DPPH). Further investigations
      were conducted using t-BHP-induced cytotoxicity in rat primary hepatocytes and
      hepatotoxicity in rats to evaluate the antioxidative bioactivity of berberine.
      The results in rat primary hepatocytes demonstrated that berberine, at the
      concentrations of 0.01-1.0 mM, significantly decreased the leakage of lactate
      dehydrogenase (LDH) and alanine aminotransferase (ALT), and the formation of
      malondialdehyde (MDA) induced by 30 min treatment of t-BHP (1.5 mM). Berberine
      also attenuated the t-BHP-induced depletion of glutathione (GSH) and induced a
      high level of DNA repair synthesis. The in vivo study showed that the
      intraperitoneal pretreatment with berberine (0.5 and 5 mg/kg) for 5 days before a
      single dose of t-BHP (0.1 mmol/kg) significantly lowered the serum levels of
      hepatic enzyme markers (ALT and aspartate aminotransferase) and reduced oxidative
      stress in the liver. The histopathological evaluation of the livers revealed that
      berberine reduced the incidence of liver lesions, including hepatocyte swelling,
      leukocyte infiltrations, and necrosis induced by t-BHP. These results lead us to
      speculate that berberine may play a chemopreventive role via reducing oxidative
      stress in living systems.

PMID- 12415431
TI  - Models for assessing the cost-effectiveness of the treatment and prevention of
      osteoporosis.

PMID- 12415432
TI  - The analgesic role of calcitonin following osteoporotic fracture.
AB  - Osteoporosis is a systemic skeletal condition characterized by decreased bone
      strength with consequent increased susceptibility to bone fracture. Fragility
      fractures in osteoporosis are often painful and result in loss of quality of life
      and disability. Salmon calcitonin (SCT) is a natural hormone that may assist in
      the management of osteoporotic patients following fracture by reducing fracture
      risk and decreasing pain. SCT is an antiresorptive agent which has been shown to
      reduce the risk of vertebral fractures (by 36%) in postmenopausal women with
      osteoporosis and previous fractures, with a safety profile comparable to placebo
      over long-term use. Clinical evidence suggests that SCT (with either subcutaneous
      and intranasal delivery) is an analgesic for the acute pain following
      osteoporotic fracture. Pain relief with SCT occurs after 1 week or less of
      treatment. Associated with this pain relief, vertebral fracture patients
      receiving SCT have been observed to have earlier mobilization compared with those
      receiving a placebo. Both preclinical and clinical data suggest a central
      analgesic effect for SCT. The mechanism(s) by which SCT induces pain relief has
      (have) not been conclusively shown. Neither a direct receptor-mediated action nor
      an indirect endorphin-mediated effect can be ruled out.

PMID- 12415433
TI  - The influence of back pain on balance and functional mobility in 65- to 75-year
      old women with osteoporosis.
AB  - To determine whether the presence of back pain and its related disabilities are
      determinants of balance and functional mobility in a group of women with
      osteoporosis, we carried out a cross-sectional analysis of 93 community-dwelling
      women with osteoporosis between the ages of 65 and 75 years old. We assessed
      health history, anthropometrics, self-report of current physical activity level
      and self-report of back pain (intensity and pain-related disabilities). Balance
      was measured by computerized dynamic posturography and functional mobility was
      assessed by timed figure-of-eight test. The prevalence of back pain was high
      (75%) in this cohort of older women with osteoporosis. Age was the major
      determinant of both balance and functional mobility and accounted for 9% and 14%
      of the variance, respectively. After accounting for age, back pain explained an
      additional 9% of the variance in balance and 13% of the variance in functional
      mobility. The high prevalence of back pain demonstrates the importance of pain
      management in the treatment of osteoporosis. Furthermore, the finding of self
      reported back pain as a determinant of both balance and functional mobility
      suggests that this measure may deserve attention when screening women with
      osteoporosis for fracture risk. Prospective studies are needed to determine
      whether pain management will improve balance and functional mobility.

PMID- 12415434
TI  - Age-related changes in parathyroid hormone-related protein and vascular
      endothelial growth factor in human osteoblastic cells.
AB  - Osteogenesis and angiogenesis occur in a coordinated manner in skeletal tissue,
      so that impaired angiogenesis is associated with decreased bone formation in aged
      subjects. However, the interaction between bone endothelium and osteoblastic
      cells is poorly understood. Parathyroid hormone-related protein (PTHrP), a bone
      factor which modulates osteoblastic cell growth and/or differentiation,
      stimulates vascular endothelial growth factor (VEGF), a potent angiogenic factor,
      in primary cultures of human osteoblastic (hOB) cells. In the present study, we
      examined the age-related changes of both factors in these cells. Human OB cells
      were isolated from trabecular bone samples from knee or hip explants obtained
      from 45 osteoarthritic patients: 12 <60 years (21-59 years), 5 women and 7 men,
      and 33 >60 years (61-82 years), 20 women and 13 men. Cell total RNA was isolated,
      and mRNA analysis was performed by reverse transcription-polymerase chain
      reaction. Relative ratios of amplified products with respect to glyceraldehyde-3
      phosphate dehydrogenase were then calculated. PTHrP and VEGF were measured in the
      cell-conditioned medium, after stimulation with (or without) 10 nM
      1,25(OH)(2)D(3) for 72 h, using specific immunoradiometric assay and a
      competitive immunoassay, respectively. A positive correlation was found between
      PTHrP and VEGF (both mRNA and secreted protein), and also between PTHrP mRNA and
      the secreted protein levels, in these cells. PTHrP, both mRNA and protein
      secretion levels, and VEGF secreted values were higher in knee hOB cells than in
      hip hOB cells only in the younger group. In addition, a decrease in the secreted
      levels of these factors occurs with aging only in hOB cells from knee. Treatment
      with 10 nM 1,25(OH)(2)D(3) induced a lower inhibitory response of PTHrP
      secretion, and a higher stimulatory response of secreted VEGF, in hOB cells with
      age. These findings indicate that age-related bone loss in humans is associated
      with a decrease in the osteoblastic secretion of both PTHrP and VEGF in the knee,
      a predominantly trabecular bone. These data might provide a rationale to explain
      the impaired angiogenesis associated with trabecular bone loss in aging.

PMID- 12415435
TI  - Quantitative ultrasound of the calcaneus and falls risk in the institutionalized
      elderly: sex differences and relationship to vitamin D status.
AB  - Very frail older people constitute an increasing proportion of aging populations
      and are likely to contribute substantially to costs due to osteoporosis.
      Quantitative ultrasound (QUS) of the calcaneus is potentially a simple method for
      assessing fracture risk in frail elderly, but there have been few studies of
      male/female differences in QUS or its relationship to falls risk or vitamin D
      status, which is often subnormal in this population. We studied QUS, falls risk
      and serum 25(OH)-vitamin D in subjects living in institutional aged care
      facilities (hostels or nursing homes). The study sample comprised 294 men (mean
      age 81.2 years, range 65-102 years) and 899 women (mean age 86.7 years, range 65
      104 years). Broadband ultrasound attenuation (BUA) and velocity of sound (VOS)
      were higher in men than women by approximately 30% and 2% respectively (
      p<0.0001) and this difference was maintained at all ages. Serum 25(OH)D levels
      were higher in men than women ( p<0.001) but vitamin D deficiency was very common
      in both sexes and serum 25(OH)D was not associated with QUS in either sex. There
      was no significant decline in BUA or VOS with age in men; however, for women BUA
      declined by 2.8-4.7% per decade and VOS by 1% per decade (both p<0.001). Mean BUA
      T-scores were -1.55 and -2.48 at age 90 years in men and women. Quadriceps
      strength and weight but not serum 25(OH)D were significantly associated with BUA.
      These data suggest only minor loss occurs at the calcaneal site in BUA and VOS
      with very old age in either sex.

PMID- 12415436
TI  - Effect of temperature on ultrasonic properties of the calcaneus in situ.
AB  - To assess the dependence of calcaneal quantitative ultrasound (QUS) on foot
      temperature, a series of acoustic measurements were made in five cadaver feet in
      situ (all soft tissues retained) over a temperature range of 25 degrees C to 40
      degrees C in steps of 5 degrees C. An implanted probe was used to measured
      temperature directly in the calcaneus itself. Ultrasound velocity decreased
      linearly with increasing temperature, with a mean thermal coefficient of -2.2
      m/s/ degrees C. In contrast, broadband ultrasonic attenuation (BUA) increased
      with temperature with a mean thermal coefficient of +0.75 dB/MHz/ degrees C. We
      argue that the temperature trends in velocity are likely to be due to the
      influence of fat, present in the bone marrow and in the soft tissues, which has a
      negative thermal coefficient for acoustic velocity. The attenuation trends may
      arise, in part, from greater scattering losses inside the cancellous bone due to
      an increased acoustic impedance mismatch between trabeculae and fatty marrow at
      higher temperatures. These considerations suggest that the greatest temperature
      effects may be expected in patients with a high proportion of fat within the
      measured volume and/or low calcaneal bone density. Given the magnitude of the
      thermal coefficients observed, the clinical impact of temperature-related QUS
      errors is likely to be modest for diagnostic purposes but of greater significance
      in follow-up studies.

PMID- 12415437
TI  - Oral contraceptives and bone mineral density in white and black women in CARDIA.
      Coronary Risk Development in Young Adults.
AB  - To examine whether exposure to oral contraceptives (OCs) is associated with bone
      mineral density (BMD) in young women, we studied, cross-sectionally and
      longitudinally, 216 white and 260 black women enrolled in the Coronary Artery
      Risk Development in Young Adults (CARDIA) study. Spine, hip and whole body BMDs
      were measured by dual-energy X-ray absorptiometry (DXA) when the women were aged
      25-37 years, and whole body BMD was remeasured in 369 of the women 3 years later.
      A comprehensive history of OC use, including dose of ethinyl estradiol (estrogen)
      and duration of use, was determined from an interviewer-administered
      questionnaire. After adjustment for other relevant variables, we found that
      cumulative estrogen from OCs (mg) explained 4.0% of the variation in spine BMD (
      p = 0.024) among white women, but did not explain any of the variance in BMD in
      black women. Cumulative OC estrogen was associated with a decreased risk for low
      bone density (lowest quartile) at the spine, hip and whole body in white women.
      The odds ratios (95% CIs) comparing women in the highest quartile of cumulative
      OC estrogen with those in the lowest quartile were, at the spine: 0.08 (0.02,
      0.46); at the hip: 0.23 (0.06, 0.87); and at the whole body: 0.37 (0.11, 1.26).
      OC exposure was not related to low bone density in black women. OCs did not
      predict longitudinal changes in whole body BMD in either race. These results
      suggest that exposure to the estrogen from OCs during the premenopausal years may
      have a small beneficial effect on the skeleton in white women. Benefit is
      proportional to the cumulative estrogen exposure, suggesting that previous cross
      sectional studies that considered OC use as a dichotomous variable may have
      lacked the power to detect an association.

PMID- 12415438
TI  - Bone loss and recovery in regional migratory osteoporosis.
AB  - Regional migratory osteoporosis (RMO) is a migrating arthralgia of the weight
      bearing joints of the lower limb associated with focal osteoporosis. Little
      information is available on a quantitative assessment of systemic or local
      osteoporosis. In this study, we report three cases of RMO in which spine, hip and
      whole body serial assessments of bone mass have been evaluated to outline their
      extent and time course of changes. Systemic osteoporosis, with a prevalent
      involvement of the mainly trabecular skeletal sites, was present in all the
      patients, with T-scores below -2.5 at both the lumbar spine and femoral neck.
      Bone loss in acute episodes ranged from -75.5% to -14.7% and appeared related to
      the severity of the episode. In acute episodes the demineralizing process
      affected the whole limb from the hemipelvis to the foot: the bone loss ranged
      from -33.6% to -3.5% at sites with prevalent trabecular composition and from 
      19.1% to -1.1% at sites with prevalent cortical composition. Bone recovery was
      complete in one episode out of six. In the other five cases, the average residual
      bone loss was 26% (range 13.9-32.7%). Our observations suggest that RMO occurs in
      subjects with systemic osteoporosis and densitometric assessment may aid in the
      clinical management.

PMID- 12415439
TI  - Effects of raloxifene on fracture severity in postmenopausal women with
      osteoporosis: results from the MORE study. Multiple Outcomes of Raloxifene
      Evaluation.
AB  - Raloxifene reduces the risk of new vertebral fractures, but its effect on the
      severity of these new fractures has not been determined. The MORE (Multiple
      Outcomes of Raloxifene Evaluation) trial studied the effects of placebo,
      raloxifene 60 or 120 mg/day in 7,705 postmenopausal women with osteoporosis.
      Radiologists assessed new vertebral fractures from radiographs and graded the
      fracture severity as normal (no fracture) or mild, moderate or severe. New
      clinical vertebral fractures were defined as new vertebral fractures associated
      with symptoms, such as back pain, and confirmed in radiographs. In the total
      study population, the majority (76.4%) of the women who experienced clinical
      vertebral fractures were diagnosed with new moderate/severe vertebral fractures.
      In turn, women with moderate/severe vertebral fractures in the overall population
      were more likely to experience clinical symptoms suggestive of fracture than were
      women who had new mild-only vertebral fractures. The incidence of new mild-only
      and moderate/severe fractures was the same in women without prevalent vertebral
      fractures, but the incidence of new moderate/severe fractures was 2 to 3 times
      higher than that for new mild-only fractures in women with prevalent vertebral
      fractures. Raloxifene 60 mg/day decreased the risk of at least 1 new
      moderate/severe vertebral fracture by 61% in women without prevalent vertebral
      fractures [RR 0.39 (95% CI 0.17, 0.69)], and by 37% in women with prevalent
      vertebral fractures [RR 0.63 (95% CI 0.49, 0.83)] at 3 years. The risk reductions
      for at least 1 new moderate/severe vertebral fracture were not significantly
      different between the raloxifene doses, in women with and without prevalent
      vertebral fractures. The effects of raloxifene on significantly decreasing the
      risk of new moderate/severe vertebral fractures may explain the risk reduction
      for new painful clinical vertebral fractures observed with raloxifene, and is
      particularly important in postmenopausal women with severe osteoporosis who are
      at higher risk for moderate or severe fractures.

PMID- 12415440
TI  - Position paper of the ESICM Working Group on Nutrition and Metabolism. Metabolic
      basis of nutrition in intensive care unit patients: ten critical questions.
AB  - The metabolic changes associated with critical illness involve several pathways
      acting at different steps of the utilization of nutritive substrates. The
      understanding of the role of these pathways and of their complex regulation has
      led to the development of new strategies for the metabolic and nutritional
      management of critically ill patients, including the development of new products
      for nutritional support. The rationale for changing the profile of nutritional
      support solutions by adding novel substrates is also discussed. This review
      focuses on the metabolic specificities of critically ill patients and also
      includes an analysis of the adequacy of tools to monitor the metabolic status and
      the adequacy of the nutritional support.

PMID- 12415441
TI  - Pyrexia in head-injured patients admitted to intensive care.
AB  - OBJECTIVES: (a) To quantify the occurrence of pyrexia during the first week after
      head injury; (b) to elucidate the relationships between pyrexia and neurological
      severity, length of stay in the ICU, intracranial hypertension, and cerebral
      perfusion pressure (CPP); and (c) to describe the effects of antipyretic therapy
      on temperature, intracranial pressure (ICP) and CPP. DESIGN AND SETTING:
      Multicenter retrospective observational study in three ICUs in the Milan area.
      PATIENTS: 110 patients with traumatic brain injury. MEASUREMENTS AND RESULTS:
      Eighty patients suffered pyrexia, defined as an external temperature higher than
      38 degrees C or internal temperature higher than 38.4 degrees C. Occurrence and
      duration of pyrexia were associated with the degree of neurological impairment
      and with prolonged ICU stay. In patients with normal perimesencephalic cisterns
      the episodes of increased ICP were more frequent in febrile cases. Various
      antipyretic therapies were used in 66 patients. Pharmacological treatment was
      slightly effective (mean temperature reduction 0.58+/-0.7 degrees C) but caused a
      significant drop in CPP (6.5+/-12.5 mmHg). CONCLUSIONS: Pyrexia is extremely
      frequent in the acute phase after head injury. Its incidence is higher in more
      severe cases and is correlated with a longer ICU stay. It may affect ICP, but its
      contribution is difficult to assess when other major causes of increased
      intracranial volume are present. Antipyretic therapy is poorly effective for
      controlling body temperature and may be deleterious for CPP.

PMID- 12415442
TI  - Effects of therapeutic hypothermia on intracranial pressure and outcome in
      patients with severe head injury.
AB  - OBJECTIVE: Therapeutic hypothermia may improve outcome in patients with severe
      head injury, but clinical studies have produced conflicting results. We
      hypothesised that the severe side effects of artificial cooling might have masked
      the positive effects in earlier studies, and we treated a large group of patients
      with severe head injury with hypothermia using a strict protocol to prevent the
      occurrence of cooling-induced side effects. DESIGN: Prospective clinical trial.
      SETTING: University teaching hospital. PATIENTS: Hundred thirty-six consecutive
      patients admitted to our hospital with severe head injury (Glasgow Coma Scale
      (GCS) < or =8). MEASUREMENTS AND RESULTS: Patients included are the 136 patients
      with a GCS of 8 or less on admission in whom intracranial pressure (ICP) remained
      above 20 mmHg in spite of therapy according to a step-up protocol. Those who
      responded to the last step of our protocol (barbiturate coma) constituted the
      control group (n=72). Those who did not respond to barbiturate coma (n=64) were
      treated with moderate hypothermia (32-34 degrees C). Average APACHE II scores
      were higher (28.9+/-14.4 vs 25.2+/-12.1, p<0.01) and average GCS at admission
      slightly lower (5.37+/-1.8 vs 5.9+/-2.1, p<0.05) in the hypothermia group,
      indicating greater severity of illness and more severe neurological injury.
      Predicted mortality was 86% for the hypothermia group versus 80% in controls
      (p<0.01). Actual mortality rates were significantly lower: 62% versus 72%; the
      difference in mortality between hypothermic patients and controls was significant
      (p<0.05). The number of patients with good neurological outcome was also higher
      in the hypothermia group: 15.7% versus 9.7% for hypothermic patients versus
      controls, respectively (p<0.02). These differences were explained almost entirely
      by the subgroup of patients with GCS of 5 or 6 at admission (mortality 52% vs
      76%, p<0.01; good neurological outcome 29% vs 8%, p<0.01). CONCLUSIONS:
      Artificial cooling can significantly improve survival and neurological outcome in
      patients with severe head injury when used in a protocol with great attention to
      the prevention of side effects. Because there is likely to have been bias against
      the hypothermia group in this study, the positive effects of hypothermia might
      even have been underestimated. In addition, our results confirm the value of
      therapeutic hypothermia in treating refractory intracranial hypertension.

PMID- 12415443
TI  - Acute haemodynamic effects of a hypertonic saline/dextran solution in stable
      patients with severe sepsis.
AB  - OBJECTIVE: To study the haemodynamic effects of a hypertonic saline/dextran
      solution compared with a normal saline solution in patients with severe sepsis.
      DESIGN: Prospective double blind and control-randomised study. SETTING: Adult
      intensive care unit in a university hospital. PATIENTS: Twenty-nine patients with
      sepsis with a pulmonary artery occlusion pressure (PAOP) lower than 12 mmHg.
      INTERVENTIONS: Patients were randomised to receive 250 ml of blinded solutions of
      either normal saline (SS group, n=16) or hypertonic saline (NaCl 7.5%)/dextran 70
      8% (HSS group, n=13) solutions. MEASUREMENTS AND RESULTS: Haemodynamic, blood
      gas, and sodium data were collected at the following time points: baseline, 30
      min, 60 min, 120 min, and 180 min. PAOP was higher in the HSS group at 30 min
      (10.7+/-3.2 mmHg vs 6.8+/-3.2 mmHg) and 60 min (10.3+/-3 mmHg vs 7.4+/-2.9 mmHg);
      P<0.05. The cardiac index increased in the HSS group and it was greater than the
      SS group at 30 min (6.5+/-4.7 l min(-1) m(-2) vs 3.8+/-3.4 l min(-1) m(-2)), 60
      min (4.9+/-4.5 l min(-1) m(-2) vs 3.7+/-3.3 l min(-1) m(-2)), and 120 min (5.0+/
      4.3 l min(-1) m(-2) vs 4.1+/-3.4 l min(-1) m(-2)); P<0.05. The stroke volume
      index followed a comparable course and it was higher at 30 min [53.6(39.2-62.8)
      ml m(-2) vs 35.6(31.2-49.2) ml m(-2)] and 60 min [46.8(39.7-56.6) ml m(-2) vs
      33.9(32.2-47.7) ml m(-2)]; P<0.05. Systemic vascular resistance decreased in the
      HSS group and became significantly lower at 30 min (824+/-277 dyne s(-1) cm(-5)
      m(-2) vs 1139+/-245 dyne s(-1) cm(-5) m(-2)), 60 min (921+/-256 dyne s(-1) cm(-5)
      m(-2) vs 1246+/-308 dyne s(-1) cm(-5) m(-2)), and 120 min (925+/-226 dyne s(-1)
      cm(-5) m(-2) vs 1269+/-494 dyne s(-1) cm(-5) m(-2)). Sodium levels increased in
      the HSS group (P=0.056) and were higher than in the SS group at 30 min (145+/-3
      mEq l(-1)vs 137+/-7 mEq l(-1)), 60 min (143+/-4 mEq l(-1) vs 136+/-7 mEq l(-1)),
      120 (142+/-5 mEq l(-1)vs 136+/-7 mEq l(-1)), and 180 min (142+/-5 mEq l(-1) vs
      136+/-8 mEq l(-1)). CONCLUSION: Hypertonic saline/dextran solution may improve
      cardiovascular performance in severe sepsis without significant side effects. The
      haemodynamic effect appears related mainly to a volume effect.

PMID- 12415444
TI  - Effect of the humidification device on the work of breathing during noninvasive
      ventilation.
AB  - OBJECTIVE: Heat and moisture exchangers (HME) increase circuitry deadspace
      compared to heated humidifiers (HH). This study compared the effect of HH and HME
      during noninvasive ventilation (NIV) on arterial blood gases and patient's effort
      assessed by respiratory muscles pressure-time product and by work of breathing
      (WOB). DESIGN AND SETTING: Randomized cross-over study in a medical intensive
      care unit. PATIENTS: Nine patients receiving NIV for moderate to severe acute
      hypercapnic respiratory failure. MEASUREMENTS: HME was randomly compared to HH
      during periods of 20 min. Each device was studied without (ZEEP) and with a PEEP
      of 5 cmH(2)O. At the end of each period arterial blood gases, ventilatory
      parameters, oesophageal and gastric pressures were recorded and indexes of
      patient's effort calculated. RESULTS: Minute ventilation was significantly higher
      with HME than with HH (ZEEP: 15.8+/-3.7 vs. 12.8+/-3.6 l/min) despite a similar
      PaCO(2) (60+/-16 vs. 57+/-16 mmHg). HME was associated with a greater increase in
      WOB (ZEEP: 15.5+/-7.7 vs. 8.4+/-4.5 J/min and PEEP: 11.3+/-5.7 vs. 7.3+/-3.8
      J/min) and indexes of patient effort. NIV with HME failed to decrease WOB
      compared to baseline. Addition of PEEP reduced the level of effort, but similar
      differences between HME and HH were observed. CONCLUSIONS: In patients receiving
      NIV for moderate to severe acute hypercapnic respiratory failure, the use of HME
      lessens the efficacy of NIV in reducing effort compared to HH.

PMID- 12415445
TI  - Comparison of the effects of heat and moisture exchangers and heated humidifiers
      on ventilation and gas exchange during non-invasive ventilation.
AB  - OBJECTIVE: To compare the short-term effects of a heat and moisture exchanger
      (HME) and a heated humidifier (HH) during non-invasive ventilation (NIV). DESIGN:
      Prospective, clinical investigation. SETTING: Intensive care unit of a university
      hospital. PATIENTS: Twenty-four patients with acute respiratory failure (ARF).
      INTERVENTION: Each patient was studied with a HME and a HH in a random order
      during two consecutive 20min periods of NIV. MEASUREMENTS AND RESULTS:
      Respiratory rate (RR), expiratory tidal volume (VTe) and expiratory minute
      ventilation (VE) were measured during the last 5 min of each period and blood
      gases were measured. Mean pressure support and positive end-expiratory pressure
      levels were, respectively, 15+/-4 and 6+/-2 cmH(2)O. VE was significantly greater
      with HME than with HH (14.8+/-4.8 vs 13.2+/-4.3 l/min; p<0.001). This increase in
      VE was the result of a greater RR for HME than for HH (26.5+/-10.6 vs 24.1+/-9.8
      breaths/min; p=0.002), whereas the VT for HME was similar to that for HH (674+/
      156 vs 643+/-148 ml; p=0.09). Arterial partial pressure of carbon dioxide
      (PaCO(2)) was significantly higher with a HME than with a HH (43.4+/-8.9 vs
      40.8+/-8.2 mmHg; p<0.005), without significantly changing oxygenation.
      CONCLUSION: During NIV the increased dead space of a HME can negatively affect
      ventilatory function and gas exchange. The effect of HME dead space may decrease
      efficiency of NIV in patients with ARF.

PMID- 12415446
TI  - Pulmonary gas exchange response to weaning with pressure-support ventilation in
      exacerbated chronic obstructive pulmonary disease patients.
AB  - OBJECTIVE: To assess if pressure-support ventilation (PSV) can improve
      ventilation-perfusion (V(A)/Q) imbalance observed during the transition from
      positive-pressure ventilation to spontaneous breathing in intubated chronic
      obstructive pulmonary disease (COPD) patients during weaning. DESIGN: Prospective
      study. SETTING: Respiratory intensive care unit of a tertiary university
      hospital. PATIENTS: Seven mechanically ventilated COPD male patients (age 68+/-6
      (SD) years; FEV(1) 26+/-6% predicted) during weaning. INTERVENTIONS: Patients
      were studied during three ventilatory modalities: (1) assist-control ventilation
      (ACV), tidal volume (V(T)), 8-10 ml. kg(-1); (2) PSV aimed to match V(T)in ACV,
      15+/-1 cmH(2)O and (3) spontaneous breathing. MEASUREMENTS AND RESULTS: Arterial
      and mixed venous respiratory blood gases, V(A)/Q distributions, hemodynamics and
      breathing pattern were measured. Compared with both ACV and PSV, during
      spontaneous breathing patients exhibited decreases in V(T) (of 43%, p<0.001) and
      increases in respiratory rate (of 79%, p<0.001), PaCO(2) (of 8.5 mmHg, p=0.001),
      cardiac output (of 27%, p<0.001) and mixed venous oxygen tension (of 3.4 mmHg,
      p=0.003), while PaO(2) remained unchanged throughout the study. Except for a
      shift of the pulmonary blood flow distribution to areas with lower V(A)/Q ratios
      (p=0.044) and an increase of dead space (of 25%, p=0.004) during spontaneous
      breathing, no other changes in V(A)/Q distributions occurred. No differences were
      shown between ACV and PSV modalities. CONCLUSION: In COPD patients during
      weaning, PSV avoided V(A)/Q worsening during the transition from positive
      pressure ventilation to spontaneous breathing. Hemodynamics, blood gases or
      V(A)/Q mismatch were no different between ACV and PSV when both modalities
      provided similar levels of ventilatory assistance.

PMID- 12415447
TI  - Value of the plasma protein and hemoglobin concentration in the diagnosis of
      pulmonary edema in scorpion sting patients.
AB  - OBJECTIVE: To investigate the value of measuring total plasma protein and
      hemoglobin concentrations for the diagnosis of pulmonary edema secondary to
      scorpion envenomation. DESIGN AND SETTING: Retrospective study over a 4-year
      period in the medical intensive care unit of a university hospital. PATIENTS: 67
      patients older than 3 years admitted in the intensive care unit for scorpion
      envenomation and stratified into two groups according to the presence of
      pulmonary edema assessed by a medical committee that took into account clinical,
      radiological, and blood gas data at admission and after treatment. Total plasma
      protein and hemoglobin concentrations were analyzed separately. RESULTS: At
      admission all patients with and without pulmonary edema exhibited polypnea and
      tachycardia. The mean plasma protein and hemoglobin concentrations were higher in
      patients with pulmonary edema (74+/-6 and 14.2+/-2.0 g/dl, respectively) than in
      those without pulmonary edema (64+/-6 and 12.3+/-1.4 g/dl). After 24 h plasma
      protein and hemoglobin concentrations decreased in the pulmonary edema group (-11
      and -1.9 g/dl) despite a negative fluid balance (-500 ml). A plasma protein
      concentration of 70 g/l or more predicted the presence of pulmonary edema with a
      sensitivity of 80% a specificity of 96%, a positive predictive value of 97%, and
      negative predictive value of 77%. CONCLUSIONS: In scorpion-envenomed patients
      with cardiorespiratory manifestations high plasma protein and hemoglobin
      concentrations suggest the presence of pulmonary edema.

PMID- 12415448
TI  - Procalcitonin as a prognostic marker in meningococcal disease.
AB  - OBJECTIVE: To assess the prognostic value of procalcitonin levels during the
      clinical course of meningococcal disease in children. DESIGN: A retrospective,
      descriptive study. SETTING: University paediatric intensive care unit. PATIENTS:
      Nine patients with meningococcal sepsis and 55 patients with meningococcal septic
      shock were included in the study, giving a total of 64. MEASUREMENTS AND RESULTS:
      Procalcitonin (PCT), C-reactive protein (CRP), cytokines (IL-6, IL-8 and TNF
      alpha), plasminogen activator inhibitor-1 (PAI-1) and several routine laboratory
      parameters were determined and expressed as medians (ranges). PCT levels on
      hospitalisation were elevated in all children as compared to normal values.
      Median PCT levels on admission were significantly higher in children with septic
      shock than in children with sepsis (270 ng/ml (5.7-672.3) versus 64.4 (20.6
      283.7); p<0.01). When the patients were categorised to severity using the
      Pediatric Risk of Mortality (PRISM) score (group 1: <15 points, group 2: 16-30,
      group 3: >30), the PCT levels were significantly different in the three groups.
      All markers, with the exception of PCT (p=0.056), were significantly different
      between survivors and non-survivors. When the duration of petechiae was taken
      into account, the difference in PCT levels became significant (p=0.04).
      CONCLUSIONS: Procalcitonin levels on admission are related to severity. In the
      case of a short disease history (duration of petechiae), PCT levels are also
      related to mortality. Although PCT levels are elevated in all patients, the
      levels per se do not allow a prediction about survival versus non-survival, this
      is in contrast to other markers and scores (PRISM).

PMID- 12415449
TI  - Soluble L-selectin levels predict survival in sepsis.
AB  - OBJECTIVE: To evaluate serum soluble L-selectin as a prognostic factor for
      survival in patients with sepsis. DESIGN: A prospective study of mortality in
      patients with sepsis whose serum levels of sL-selectin were measured on admission
      to an intensive care unit (ICU) and 4 days later. Follow-up data on mortality
      were obtained from the Danish Central Office of Civil Registration. SETTING: A
      tertiary referral university hospital ICU in Copenhagen. PATIENTS: Sixty-three
      patients meeting the criteria for systemic inflammatory response syndrome (SIRS)
      with a suspected or verified infection in one or more major organs, and 14
      control subjects. MEASUREMENTS AND RESULTS: On admission to the ICU the
      Simplified Acute Physiology Score (SAPS) II was calculated, and relevant
      microbial cultures were performed. Mortality was registered at various follow-up
      points: 7 days after admission, at discharge from hospital, and 3 and 12 months
      after admission. Serum sL-selectin levels were significantly lower in the
      patients than in the controls. Sepsis nonsurvivors had significantly lower levels
      than survivors. Efficiency analysis and receiver operation characteristics showed
      that the ideal cutoff point for sL-selectin as a test for sepsis survival was 470
      ng/ml. The accumulated mortality in patients with subnormal sL-selectin levels on
      admission was significantly increased. No correlation was found between clinical
      or paraclinical markers, including SAPS II and sL-selectin, and no relationship
      to the microbial diagnosis was found. CONCLUSIONS: Serum sL-selectin is a
      predictor of survival in patients with sepsis. Those admitted with low sL
      selectin (<470 ng/ml) are characterized by a high mortality within the subsequent
      12-month period.

PMID- 12415451
TI  - Death of terminally ill patients on a stretcher in the emergency department: a
      French speciality?
AB  - OBJECTIVES: To determine the frequency, modalities of admission and management of
      terminally ill patients who died on a stretcher in an emergency department (ED).
      DESIGN AND SETTING: Retrospective study in an ED of a university hospital.
      METHODS: Current place of residence, modalities of admission in ED, mortality
      probability scores and type of management were extracted for each patient in the
      terminal stage of chronic disease who died on a stretcher in our ED during a
      3year period. RESULTS: Of 159 deaths observed in the ED, 56 (35%) concerned
      terminally ill patients. The illness was a malignancy in 22 cases, a neurological
      disease in 22 cases and a cardiopulmonary disease in 12 cases. Most of the
      patients were referred by their regular doctor. Seventy-two percent of the
      malignancy patients were living at home, 55% of the neurological patients came
      from nursing facilities and 58% of the cardio-respiratory patients came from the
      hospital. In 73%, 83% and 23% of the patients with malignancy, cardiopulmonary
      and neurological diseases, respectively, admission was related to the evolution
      of the chronic disease. Severity of illness on admission was similar whatever the
      disease. Request for compassionate end-of-life care was expressed in only 12.5%.
      At the ED, 91% of patients with neurological diseases received palliative support
      care. Supportive therapy was undertaken in one third of patients with malignancy
      or cardiopulmonary disease. CONCLUSION: An ED may be used as a place for dying
      for some terminally ill patients. This could be related to the legal opposition
      to withdrawal or withholding of life-support therapies as well as the absence of
      guidelines from scientific bodies.

PMID- 12415450
TI  - The Multiple Organ Dysfunction Score (MODS) versus the Sequential Organ Failure
      Assessment (SOFA) score in outcome prediction.
AB  - OBJECTIVE: To compare outcome prediction using the Multiple Organ Dysfunction
      Score (MODS) and the Sequential Organ Failure Assessment (SOFA), two of the
      systems most commonly used to evaluate organ dysfunction in the intensive care
      unit (ICU). DESIGN: Prospective, observational study. SETTING: Thirty-one-bed,
      university hospital ICU. PATIENTS AND PARTICIPANTS: Nine hundred forty-nine ICU
      patients. MEASUREMENTS AND RESULTS: The MODS and the SOFA score were calculated
      on admission and every 48 h until ICU discharge. The Acute Physiology and Chronic
      Health Evaluation (APACHE) II score was calculated on admission. Areas under
      receiver operating characteristic (AUROC) curves were used to compare initial, 48
      h, 96 h, maximum and final scores. Of the 949 patients, 277 died (mortality rate
      29.1%). Shock was observed in 329 patients (mortality rate 55.3%). There were no
      significant differences between the two scores in terms of mortality prediction.
      Outcome prediction of the APACHE II score was similar to the initial MODS and
      SOFA score in all patients, and slightly worse in patients with shock. Using the
      scores' cardiovascular components (CV), outcome prediction was better for the
      SOFA score at all time intervals (initial AUROC SOFA CV 0.750 vs MODS CV 0.694,
      p<0.01; 48 h AUROC SOFA CV 0.732 vs MODS CV 0.675, p<0.01; and final AUROC SOFA
      CV 0.781 vs MODS CV 0.674, p<0.01). The same tendency was observed in patients
      with shock. There were no significant differences in outcome prediction for the
      other five organ systems. CONCLUSIONS: MODS and SOFA are reliable outcome
      predictors. Cardiovascular dysfunction is better related to outcome with the SOFA
      score than with the MODS.

PMID- 12415452
TI  - Duration of life-threatening antecedents prior to intensive care admission.
AB  - OBJECTIVE: To document the characteristics and incidence of serious abnormalities
      in patients prior to admission to intensive care units. DESIGN AND SETTING:
      Prospective follow-up study of all patients admitted to intensive care in three
      acute-care hospitals. PATIENTS: The study population totalled 551 patients
      admitted to intensive care: 90 from the general ward, 239 from operating rooms
      (OR) and 222 from the Emergency Department (ED). MEASUREMENTS AND RESULTS:
      Patients from the general wards had greater severity of illness (APACHE II median
      21) than those from the OR (15) or ED (19). A greater percentage of patients from
      the general wards (47.6%) died than from OR (19.3%) and ED (31.5%). Patients from
      the general wards had a greater number of serious antecedents before admission to
      intensive care 43 (72%) than those from OR 150 (64.4%) or ED 126 (61.8%). Of the
      551 patients 62 had antecedents during the period 8-48 h before admission to
      intensive care, and 53 had antecedents both within 8 and 48 h before their
      admission. The most common antecedents during the 8 h before admission were
      hypotension (n=199), tachycardia (n=73), tachypnoea (n=64), and sudden change in
      level of consciousness (n=42). Concern was expressed in the clinical notes by
      attending staff in 70% of patients admitted from the general wards. CONCLUSIONS:
      In over 60% of patients admitted to intensive care potentially life-threatening
      abnormalities were documented during the 8 h before their admission. This may
      represent a patient population who could benefit from improved resuscitation and
      care at an earlier stage.

PMID- 12415453
TI  - Life-threatening hemorrhage in neonates: management with recombinant activated
      factor VII.
AB  - OBJECTIVE: Massive hemorrhage with shock is a common problem for the intensivist.
      The use of recombinant activated factor VII (rFVIIa), known as efficient
      treatment for hemophilia, has been reported to control severe bleeding episodes
      in critically care patients, but never in preterm neonates. DESIGN: Case report
      (two cases) and review of the literature. SETTING: Neonatal intensive care unit,
      university teaching hospital. PATIENTS: Two preterm neonates with life
      threatening hemorrhages, from the liver and spleen in one patient and from the
      lung in the other. INTERVENTION: Intravenous administration of 150/200 microg/kg
      of rFVIIa (Novoseven, NovoNordisk, Copenhagen, Denmark). MEASUREMENTS AND
      RESULTS: Complete hemostasis 10 min after the second bolus in the two patients.
      CONCLUSION: For the intensivist, the successful use of rFVIIa in these patients
      and others lacking pre-existing coagulopathies points to rFVIIa as a novel
      therapeutic approach for patients presenting with massive life-threatening
      hemorrhage.

PMID- 12415454
TI  - Pressurized bag pump and syringe pump arterial flushing systems: an unrecognized
      hazard in neonates?
AB  - OBJECTIVE: Hand-held flushing of radial arterial lines at 0.5 ml/s in neonates
      can result in retrograde embolization of flush solution into the central arterial
      circulation. We studied flush flow velocities during intermittent arterial line
      purging using a flow regulating device with an infusion bag pump and a syringe
      pump system. MEASUREMENTS AND INTERVENTIONS: In this in vitro experiment we
      simulated flushing of a 24- and a 22-G cannula against a mean arterial pressure
      of 45 mmHg. Fluid flow velocities were gravimetrically measured during flushing
      from an infusion bag system pressurized to 100, 200, and 300 mmHg and from a
      syringe pump flush system after initialization of boluses of 0.5, 1.0, 1.5, 2.0,
      and 2.5 ml. The flow regulating device was opened for 1, 2, and 5 s. RESULTS:
      Both flush systems tested allowed delivery of flush flow velocities exceeding 0.5
      ml/s (e.g., 22-G cannula; bag system, pressure 300 mmHg up to 0.64+/-0.08 ml/s;
      syringe pump, 2 ml bolus up to 0.74+/-0.05 ml/s). In syringe pump systems the
      main determinant of flow velocity was bolus size, in bag pump systems flushing
      time and bag pressure. CONCLUSIONS: Based on data about critical flow velocities
      through an radial arterial cannula in neonates, both tested flushing systems
      carry the risk of exceeding the critical value of 0.5 ml/s. They are likely to
      cause retrograde embolization of flushing solution into the central arterial
      circulation with the associated risk of clot and air embolization. In vivo
      studies should identify margins of safety to minimize the risk of retrograde
      flushing into the central arterial circulation.

PMID- 12415455
TI  - Acute lung injury and acute respiratory distress syndrome at the intensive care
      unit of a general university hospital in Brazil. An epidemiological study using
      the American-European Consensus Criteria.
AB  - OBJECTIVES: To determine: (1) the frequency of acute lung injury (ALI)/acute
      respiratory distress syndrome (ARDS); (2) the mortality associated with these
      syndromes and (3) the influence of risk factors, comorbidities and organ system
      dysfunction in the mortality of ALI patients. DESIGN: Prospective cohort study.
      SETTING: Intensive care unit (ICU) of a general university hospital in Brazil.
      PATIENTS AND PARTICIPANTS: All patients that remained in the ICU for more than 24
      h were evaluated regarding the presence/development of ALI/ARDS according to the
      1994 American-European Consensus Conference. INTERVENTIONS: None. MEASUREMENTS
      AND RESULTS: One thousand three hundred and one patients were studied and
      analyzed regarding mortality, risk factors, comorbidities and organ system
      dysfunction(s). The frequency of ALI was 3.8% (50), of which ARDS was 2.3% (30)
      and ALI/non-ARDS 1.5% (20) (p=0.15). The ICU mortality of patients with ALI was
      44.0%; in ALI/non-ARDS and ARDS patients it was 40.0% and 46.7%, respectively
      (p=0.43). The hospital mortality of ALI patients was 48.0%; in ALI/non-ARDS and
      ARDS patients it was 50.0% and 46.7%, respectively (p=0.21). A multivariate
      analysis demonstrated that renal (ICU and hospital: p=0.002) and hematological
      dysfunction (ICU: p=0.008; hospital: p=0.02) were independently associated with
      ICU and hospital mortality in ALI patients. CONCLUSIONS: (1) The frequency of ALI
      was 3.8%, of which the frequency of ARDS was 2.3% and of ALI/non-ARDS 1.5%; (2)
      The ICU and hospital mortality of ALI patients was 44.0% and 48.0%, respectively;
      mortality rates of ARDS and ALI/non-ARDS did not differ significantly; (3) Renal
      and hematological dysfunction were associated with mortality in ALI patients.

PMID- 12415456
TI  - Conventional coagulation and thromboelastograph parameters and longevity of
      continuous renal replacement circuits.
AB  - OBJECTIVE: To determine the relationship between conventional and
      thromboelastograph (TEG) coagulation parameters and continuous renal replacement
      therapy (CRRT) circuit longevity. DESIGN: Conventional coagulation and TEG
      parameters were measured at the commencement of and during CRRT. Time to circuit
      cessation was measured and only circuits reaching a predetermined rise from
      baseline in the pressure gradient across the haemofilter were diagnosed as
      failing due to clotting. All other circuits were excluded from analysis. SETTING:
      A general critical care unit of a metropolitan tertiary hospital. PATIENTS AND
      PARTICIPANTS: Fourteen consecutive patients requiring CRRT were studied. The CRRT
      technique used was continuous veno-venous haemodialysis. INTERVENTIONS:
      Thromboelastograph measurements were made prior to the commencement of CRRT and
      daily thereafter for each circuit. The international normalised ratio (INR),
      activated partial thromboplastin time (APTT) and platelet numbers were measured
      at commencement and 8 hourly thereafter. Heparin was used for anticoagulation
      unless considered contraindicated. MEASUREMENTS AND RESULTS: Forty-seven circuits
      with a mean (SD) circuit life of 33.0 (30.2) h were entered. Twenty-five circuits
      fulfilled circuit clotting criteria; the mean circuit life was 30.8 (22.1) h.
      Heparin anticoagulation was found to prolong circuit life significantly despite
      adequate mean circuit life, 33.2 (35.7) h, in heparin-free circuits. The starting
      APTT and the TEG variables reaction time (R) and coagulation time (RK) were
      significantly correlated. The starting APTT, starting RK and mean time taken for
      the amplitude to increase from 2 to 20 mm (K) were predictive of circuit life.
      None of these variables predicted which patients would need heparin. CONCLUSION:
      While TEG variables more closely predicted circuit longevity than conventional
      coagulation variables, the clinical benefit of TEG monitoring of anticoagulation
      for CRRT would appear to be minimal.

PMID- 12415457
TI  - A randomized prospective trial of immediate vs. next-day feeding after
      percutaneous endoscopic gastrostomy in intensive care patients.
AB  - OBJECTIVE: To determine the effect of immediate vs. next-day feeding after
      percutaneous endoscopic gastrostomy in intensive care and intermediate care
      patients. DESIGN AND SETTING: A prospective, randomized, controlled trial of the
      clinical outcome in two German hospitals. PATIENTS: The study included 80
      patients: 40 in group 1 who received enteral feeding within 1 h and 40 in group 2
      in whom feeding was started 24 h after percutaneous endoscopic gastrostomy
      feeding. INTERVENTIONS: Patients were fed a polymeric iso-osmolar formula via
      pump 30 ml/h in 20 h on day 1, 70 on day 2, and l00 on day 3. Every 6 h for 72 h
      gastric residue was checked, and the patient was examined by a physician the
      first 3 days. MEASUREMENTS AND RESULTS: Comparing the maximum residual volumes
      for each group for each day as the major end-points, the immediate feeding group
      showed an increase of about 20-50% on each day, which, however, was significant
      only on day 2. Our study also failed to show any significant difference in
      complication rate or either short-term (1-3 days) or long-term (1-30 days)
      mortality. CONCLUSIONS: In acutely ill intensive and intermediate care patients
      immediate enteral feeding via a percutaneous endoscopic gastrostomy tube is as
      safe as next-day feeding.

PMID- 12415458
TI  - Top-down costing: problems in determining staff costs in intensive care medicine.
AB  - OBJECTIVE: To describe the activities carried out by the staff of Italian ICUs
      and to quantify the amount of working time devoted to ICU patients. DESIGN AND
      SETTING: Prospective, observational, multicenter study in 110 ICUs to report the
      non-ICU-related activities performed by ICU staff, together with the time such
      activities require. Of the 110 ICUs 80 participated in the project. MEASUREMENTS
      AND RESULTS: We found substantial variation in the number of activities carried
      out and in the working time allocated to such activities. Considering the
      differences in the number of employees, their salaries, and the amount of time
      spent performing various activities, it was found that the personnel cost for ICU
      activity was 83.4% (range 55-100%) of the total personnel costs. CONCLUSIONS:
      Given the wide variation in the number of activities performed and in the
      proportion of working time spent performing non-ICU related activities, data
      comparing costs between different ICUs should be interpreted with caution.

PMID- 12415460
TI  - Abdominal compartment syndrome and intrahepatic portal venous gas: a possible
      complication of endoscopy.
AB  - OBJECTIVE: We report the first patient to developed abdominal compartment
      syndrome (ACS) with intrahepatic portal venous gas (IHPVG) and pneumatosis
      cystoides intestinalis following emergency upper gastrointestinal endoscopy. CASE
      PRESENTATION: A 53-year-old man underwent an emergency upper gastrointestinal
      endoscopy for suspicion of upper gastrointestinal bleeding. The patient developed
      intra-abdominal hypertension and ACS associated with IHPVG after the endoscopy.
      Although the patient developed severe shock following ACS, he was managed
      conservatively and successfully recovered. CONCLUSIONS: An emergency upper
      gastrointestinal endoscopy may be associated with intra-abdominal hypertension
      and ACS. Our report provides an additional case of a survivor who required no
      surgical intervention for ACS and IHPVG following endoscopy.

PMID- 12415462
TI  - Evaluation of the effect of varying MPEG-2 compression ratios on digital coronary
      angiographic assessment of stenosis severity.
AB  - The purpose of this study is to evaluate the influence of MPEG-2 compression
      scheme on coronary angiography and to search the highest compression ratio at
      which no significant effect to accuracy of assessment of stenosis severity
      occurs. Forty-Four digital cine angiographies were used. Three cardiologists
      participated in a subjective study in which they read both uncompressed images
      and compressed images. Furthermore, an objective study was carried out to measure
      vessel stenosis ratio by using software. The influence of compression was
      evaluated by kappa statistics in case of subjective study and by both systematic
      error and random error in case of objective study. Kappa statistics between
      uncompressed image and compressed image at a ratio of 80:1 was significantly
      lower than that of other compression ratios such as 40:1. Similar results were
      obtained in objective evaluation. In this report, the authors provide the
      baseline for further studies on observer performance for motion images.

PMID- 12415463
TI  - Impact of speech recognition on radiologist productivity.
AB  - A survey was conducted of radiology practices with productivity data from at
      least 3 of the following 4 workflows: film with manual transcription, filmless
      with manual transcription, film with speech recognition, and filmless with speech
      recognition. Two surveys were submitted to candidate sites. The first was used to
      ascertain suitable available data for follow-up. The second survey requested data
      for report turn around times, full-time equivalent (FTE) staffing levels, and
      report volume. Data were collected and stored in a Microsoft Access database and
      statistical analysis performed in Excel. Whereas several metrics were used, the
      normalized figure of reports-per-day/FTE was found to have improved an average of
      1.9 (for filmless with speech recognition) and 2.3 (for film with speech
      recognition) over the film with manual transcription case. Filmless with manual
      transcription was only 1.4 times the value of the all manual case. At the 10%
      confidence level, both filmless with manual transcription and film with speech
      recognition workflows were found to have statistically significant enhanced
      productivity. Insufficient data exist to show if the fully automated workflow
      (filmless with speech recognition) offers benefits over 2 previous semiautomated
      workflows.

PMID- 12415464
TI  - Image annotation with Adobe Photoshop.
AB  - The authors relate the basic steps used to annotate grayscale cross sectional
      images with keyboard characters, arrowheads, and arrows using Adobe Photoshop 6.0
      and 7.0.

PMID- 12415465
TI  - Relational data model for the American College of Radiology Appropriateness
      Criteria.
AB  - This article describes a data model for encoding the American College of
      Radiology Appropriateness Criteria (ACRAC) for selection of diagnostic imaging
      procedures. These guidelines are recognized widely as an authoritative repository
      of "best evidence" concerning appropriate radiology tests for a large number of
      clinical conditions. In its current text document format, the ACRAC is of limited
      utility for electronic use. The data model the authors propose completely encodes
      all attributes and domains of the published guidelines and is suitable for
      translation into any industry standard relational database system. Additionally,
      the authors have added mappings onto commonly used procedure (CPT) and clinical
      problem (ICD) coding systems. When populated with the current ACRAC content, such
      a database could serve as the "master" repository of the guidelines with changes
      and additions made via an interface built with standard database application
      development tools. The database also could be made available for incorporation
      into existing information systems used for order entry, decision support,
      compliance tracking, and health services research at regional and national
      levels.

PMID- 12415466
TI  - The effect of PACS on the time required for technologists to produce radiographic
      images in the emergency department radiology suite.
AB  - The purpose of this study was to evaluate the effect of a switch to a filmless
      image management system on the time required for technologists to produce
      radiographic images in the emergency department (ED) after controlling for exam
      difficulty and a variable workload. Time and motion data were collected on
      patients who had radiographic images taken while being treated in the emergency
      department over the 3 1/2-year period from April 1997 to November 2000. Event
      times and demographic data were obtained from the radiology information system,
      from the hospital information system, from emergency department records, or by
      observation by research coordinators. Multiple least squares regression analysis
      identified several independent predictors of the time required for technologists
      to produce radiographic images. These variables included the level of
      technologist experience, the number of trauma-alert patient arrivals, and whether
      a filmless image management system was used (all P <.05). Our regression model
      explained 22% of the variability in technologist time (R2 Adjusted, 0.22; F =
      24.01; P <.0001). The regression model predicted a time saving of 2 to 3 minutes
      per patient in the elapsed time from notification of a needed examination until
      image availability because of the implementation of PACS, a delay of 4 to 6
      minutes per patient who were imaged by technologists who spent less than 10% of
      their work assignments within the ED, and a delay of 18 to 27 minutes in
      radiology workflow because of the arrival of a trauma alert patient. A filmless
      system decreased the amount of time required to produce radiographs. The arrival
      of a trauma alert patient delayed radiology workflow in the ED. Inexperienced
      technologists require 4 to 6 minutes of additional time per patient to complete
      the same amount of work accomplished by an experienced technologist.

PMID- 12415467
TI  - Legionnaires' disease contracted from patient homes: the coming of the third
      plague?

PMID- 12415468
TI  - Residential water supply as a likely cause of community-acquired Legionnaires'
      disease in an immunocompromised host.
AB  - A 69-year-old man with Sweet's syndrome and myelodysplastic syndrome presented
      with pneumonia and respiratory distress. He had been taking corticosteroids and
      methotrexate. The diagnosis of Legionnaires' disease was established by the
      isolation of Legionella pneumophila serogroup 6 from sputum and a fourfold
      seroconversion of Legionella antibodies to 1:512. Legionella pneumophila
      serogroup 6 was isolated from faucets in two homes owned by the patient. Strains
      of Legionella pneumophila serogroup 6 isolated from the patient's sputum and from
      one home were demonstrated to be genetically identical by pulsed-field gel
      electrophoresis but different from strains found in the other home and in a
      hospital outpatient clinic that he visited. This case illustrates an emerging
      public health issue concerning acquisition of community-acquired Legionnaires'
      disease from the homes of immunocompromised hosts. This is the first such case
      reported in Asia.

PMID- 12415469
TI  - Pan-European study on culture-proven Legionnaires' disease: distribution of
      Legionella pneumophila serogroups and monoclonal subgroups.
AB  - This pan-European study included unrelated strains of Legionella pneumophila
      obtained from 1335 cases of Legionnaires' disease. The isolates were serotyped
      into the serogroups 1 to 15 by monoclonal antibodies (MAb) and/or rabbit
      antisera. Additionally, MAb subgrouping was undertaken for isolates belonging to
      serogroups 1, 4, and 5. Monoclonal types of serogroup 1 were subdivided as
      having, or not having, the virulence-associated epitope recognized by the MAb 3/1
      (Dresden Panel). This epitope is not present on strains belonging to any other
      serogroups. Taking all Legionella incidents together, MAb 3/1-positive cases were
      most frequent (66.8%); 11.7% of the isolates belonged to MAb 3/1-negative
      serogroup 1 subgroups and 21.5% to other serogroups, with serogroups 3 and 6
      predominating. Among all serotypes discriminated in this study, monoclonal
      subtype Philadelphia was the most frequent. If categories of infection were
      considered, the proportion of MAb 3/1-negative strains differed significantly (
      P<0.0005) between community-acquired cases (139/510; 27.3%) and travel-associated
      (42/295; 14.2%) or hospital-acquired infections (176/329; 53.5%). Moreover,
      taking distribution in different European areas into account, the proportion of
      MAb 3/1-negative strains was significantly higher in the Scandinavian region than
      in the Mediterranean countries or the UK for both community-acquired (48.7% vs.
      18.6% or 12.0%; P<0.0005) and nosocomial cases (87.7% vs. 32.6% or 52.6%;
      P</=0.0007).

PMID- 12415470
TI  - Factors promoting colonization by legionellae in residential water distribution
      systems: an environmental case-control survey.
AB  - As part of a case-control study of community-acquired Legionnaires' disease,
      several factors related to residential water distribution systems and public
      drinking water systems were studied in the homes of 124 patients with community
      acquired Legionnaire's disease and in the homes of 354 controls. The presence of
      water reservoirs and hot water tanks was studied in residential systems. Factors
      such as deficient chlorine levels, pipe repairs and other work, water flow
      interruptions, the use of alternative water sources, inadequate cleaning
      operations in public water reservoirs, and the position of the home within the
      public network (and whether this location constituted an endpoint) were studied
      in public water supply systems. Levels of legionellae in domestic water samples
      were also measured. Although the use of water reservoirs and hot water tanks
      promotes colonization by legionellae in residential systems, none of the
      variables studied seems to increase the incidence of community-acquired
      Legionnaires' disease.

PMID- 12415471
TI  - Designation of the European Working Group on Legionella Infection (EWGLI)
      amplified fragment length polymorphism types of Legionella pneumophila serogroup
      1 and results of intercentre proficiency testing Using a standard protocol.
AB  - The utility of amplified fragment length polymorphism (AFLP) analysis as a
      genotyping method for the epidemiological typing of Legionella pneumophila
      serogroup 1 has been previously demonstrated. This study (i). reports
      recommendations for the designation of the European Working Group on Legionella
      Infections (EWGLI) AFLP types, (ii). describes the EWGLI AFLP types identified
      for the 130 strains in the EWGLI culture collection, and (iii). reports the
      results of a newly introduced international programme of proficiency testing.
      Following preliminary analysis of 20 epidemiologically unrelated isolates, 16
      major AFLP types were identified. A coded proficiency panel, comprising 12
      additional isolates representing 9 of these 16 AFLP types, was sent to 17 centres
      in 14 European countries where it was analysed following a previously determined
      standard protocol. The identity of each coded strain (recorded as AFLP type 001
      016 or untypeable) was determined by participants with reference to these 16 AFLP
      types, either visually or using gel analysis software where available, and
      reported to the coordinating centre. Nine of the 12 strains, including an
      epidemiologically related pair and two pairs of unrelated isolates of the same
      type, were correctly identified to the correct AFLP type by all or all but one of
      the participants. Seven laboratories correctly identified all 12 isolates, and a
      further seven laboratories correctly identified 11. Type identification scores
      ranged from 75% (1 centre), 83% (2 centres), and 92% (7 centres) to 100% (7
      centres). The AFLP method as described is robust and rapid and allows the
      genotypic comparison of isolates of Legionella pneumophila between different
      testing centres without the need for exchange of the strains studied.

PMID- 12415472
TI  - Clinical study of an outbreak of Legionnaire's disease in Alcoy, Southeastern
      Spain.
AB  - The aim of this study was to identify the clinical features of Legionnaires'
      disease, sudden outbreaks of which demand a quick and flexible clinical approach,
      particularly with regard to diagnosis and therapy. A prospective and comparative
      study based on a clinical protocol was performed during an outbreak of
      Legionnaires' disease in Alcoy, Spain. The outbreak was environmental in origin,
      linked to cooling towers. Data about epidemiological and clinical features, blood
      chemistry values, radiological and microbiological findings, and characteristics
      related to the clinical course of Legionnaires' disease were obtained for 357
      patients admitted to hospital with community-acquired pneumonia (177 with
      Legionella pneumonia). Patients with Legionnaires' disease were younger (mean
      age, 65.3+/-16.5 years) and more likely to be smokers compared with patients with
      other types of pneumonia (28.8% vs. 11.1%; P<0.01). Moreover, they had not been
      admitted to any hospital because of pneumonia in the previous year. Patients with
      Legionnaires' disease had higher fever, more severe headache, and less
      expectoration as well as lower sodium blood levels (mean, 132.6+/-4.8 mmol/l vs.
      135.7 mmol/l; P<0.01). Radiological studies also showed that fewer patients with
      Legionnaires' disease had pleural effusion (9% vs. 19.4% of those with non-
      Legionella pneumonia). The presence of headache, high fever, hyponatremia, scanty
      or null expectoration, and current cigarette smoking provides physicians with
      important clues for a high suspicion of Legionella pneumonia before the results
      of confirmatory laboratory tests are available.

PMID- 12415473
TI  - Spontaneous resolution of hemophagocytic syndrome associated with acute
      parvovirus B19 infection and concomitant Epstein-Barr virus reactivation in an
      otherwise healthy adult.
AB  - Reported here is the case of a patient who spontaneously recovered from
      hemophagocytic syndrome associated with acute B19 infection and concomitant
      Epstein-Barr virus reactivation. The previously healthy 37-year-old-man was
      hospitalized after 10 days of high fever, arthralgia and arthritis and was
      determined to have hemophagocytic syndrome. Immunoglobulin (Ig) M antibodies to
      Epstein-Barr virus (EBV) capsid antigen, early antigen and parvovirus B19 (B19)
      were found. B19 DNA and low-level EBV DNA were detected in bone marrow, serum and
      peripheral blood mononuclear cells. The patient recovered spontaneously without
      any treatment. Two months later anti-B19 IgG antibodies were detected, while at 9
      month follow-up, anti-B19 IgM antibodies were no longer detectable and B19 DNA
      had disappeared from serum. To the best of our knowledge, this is the first
      report of spontaneous resolution of hemophagocytic syndrome associated with acute
      B19 infection and concomitant EBV reactivation in an otherwise healthy adult.

PMID- 12415474
TI  - Antimicrobial susceptibility profiles of clinically relevant blood culture
      isolates from nine surgical intensive care units, 1996-2000.
AB  - In order to elucidate trends in the incidence and susceptibility profiles of
      causative agents of bacteremia/fungemia in nine surgical intensive care units, a
      total of 744 isolates obtained during a 5-year period (1996-2000) were studied.
      The isolates included 698 bacteria and 46 fungi obtained from 523 positive blood
      cultures, representing 317 episodes of bacteremia/fungemia. Methicillin-resistant
      Staphylococcus aureus accounted for 2.3 episodes per 1000 surgical ICU admissions
      in 1996, 1.6 in 1997, 0.3 in 1998, 0.6 in 1999, and 1.7 in 2000. One Enterococcus
      faecalis (VanA) isolate resistant to both vancomycin and teicoplanin was
      recovered in 1996. Ciprofloxacin resistance in Pseudomonas aeruginosa decreased
      from 36% in 1996 to 20% in 2000, and resistance to third-generation
      cephalosporins decreased from 40% in 1996 to 9% in 2000. In light of differences
      between these results and those found elsewhere, these findings might prove
      useful for making infection control policy decisions in intensive care units.

PMID- 12415475
TI  - Comparison of aerobic standard medium with specific fungal medium for detecting
      fusarium spp in blood cultures.
AB  - In order to compare the performances of a specific fungal medium and a standard
      aerobic medium for detecting growth of Fusarium spp. in blood, simulated blood
      cultures were performed. For lower inocula (10(2) and 10(3) cfu/ml taken
      together), fungal growth was detected significantly earlier using the fungal
      medium. The mean difference in the time to detection between the two media was
      22.33 h at 10(2) cfu/ml, with the maximum difference being achieved for Fusarium
      verticilloides at 37.05 h. These in vitro test results suggest fungal medium
      could be useful for obtaining more rapid blood culture results when evaluating
      patients at risk for invasive infection with Fusarium spp.

PMID- 12415476
TI  - Emerging linezolid-resistant Enterococcus faecalis and Enterococcus faecium
      isolated from two Austrian patients in the same intensive care unit.
AB  - Of two patients in the same intensive care unit who were treated with linezolid,
      one yielded linezolid-resistant Enterococcus faecalis, whereas the other yielded
      linezolid-resistant Enterococcus faecium. In each case, molecular typing
      indicated that the resistant isolates were related to linezolid-susceptible
      isolates from the same patient, but differed from them by the same G2576U
      ribosomal RNA mutation. This is the first clinical case report of emerging
      resistance to linezolid among Enterococcus faecalis and also the first report of
      resistance involving vancomycin-susceptible rather than vancomycin-resistant
      enterococci. The linezolid-resistant isolates showed cross-resistance to the
      experimental oxazolidinone AZD2563, suggesting that oxazolidinone resistance
      might be a class effect.

PMID- 12415477
TI  - Oro-dental bacteria in various atherosclerotic arteries.
AB  - Chlamydia pneumoniae DNA has been detected in at least 40% of all major arteries
      affected by atherosclerosis, but several other microorganisms have also been
      detected. In this study, diseased vessels were evaluated for the presence of the
      DNA of seven oro-dental bacteria and two nonoral bacteria. A polymerase chain
      reaction technique was employed using primer pairs based on 16S rRNA genes. Of 32
      specimens tested, 10 (31.2%) were DNA positive: seven for Actinobacillus
      actinomycetemcomitans and three for Prevotella intermedia. The DNA was found in
      specimens from the aorta and the iliac, internal mammary and coronary arteries.
      Eleven (35.4%) of 31 specimens had been shown previously to be positive for
      Chlamydia pneumoniae DNA. A mixture of chlamydiae and oro-dental bacteria was
      found in three cases. These findings may have implications for antibiotic
      prophylaxis of coronary heart disease if directed solely at Chlamydia pneumoniae.

PMID- 12415478
TI  - Clinical significance of herpes simplex virus in the lower respiratory tract of
      critically ill patients.

PMID- 12415479
TI  - Clinical and diagnostic aspects of relapsing meningoencephalitis due to Brucella
      suis.

PMID- 12415480
TI  - Drug resistance in pulmonary tuberculosis in Istanbul.

PMID- 12415481
TI  - Cystic fibrosis and Chiari type I malformation: autopsy study of two infants with
      a rare association.
AB  - Cystic fibrosis (CF), an epithelial cell transport disorder caused by mutations
      of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, is not
      generally associated with malformations of the central nervous system (CNS). This
      report describes two African-American children who died at less than 2 years of
      age with known Chiari I malformations and were found, unexpectedly at autopsy, to
      have the classic pancreatic and respiratory changes of CF. Both patients had
      suffered from failure to thrive that had been attributed to their CNS
      malformations. One child also had recurrent pneumonia and died with Pseudomonas
      sepsis. Mutational analysis for > 70 common CFTR mutations identified a single
      delta F508 mutation in one patient and a single 3120+1G to A mutation in the
      other. Their second CFTR mutations were not identified. The association of CF
      with Chiari I malformation is not likely to be purely coincidental, as the
      probability of such an occurrence in African-Americans is greater than one in
      7,500,000 patients. It is possible that the CFTR gene may play a previously
      unrecognized role in CNS development. Alternatively, this CNS abnormality may be
      acquired due to the metabolic and electrolyte imbalances that characteristically
      occur in CF.

PMID- 12415482
TI  - Subclavian artery injury, vertebral artery dissection, and arteriovenous fistulae
      following attempt at central line placement.
AB  - Vertebral artery dissection and arteriovenous fistulas are uncommon complications
      of vascular access and angiographic procedures. There are several cases of
      iatrogenic vertebral artery dissection secondary to central line placement
      reported in the literature. Only a few iatrogenic arteriovenous fistulae have
      been reported, but none also involving the dissection of the vertebral artery. In
      each of these cases, the fistulae were treated by direct ligation of the
      fistulous communication. We present an unusual case of an iatrogenic
      arteriovenous fistula and vertebral artery dissection as a result of left
      subclavian central line placement. The left subclavian artery and associated
      fistula were successfully repaired using a self-expanding endovascular graft.

PMID- 12415483
TI  - EEG as a criterion for shunt need in carotid endarterectomy.
AB  - The efficacy of continuous intraoperative electroencephalographic (EEG)
      monitoring as a criterion for selective shunt use during carotid endarterectomy
      is evaluated in a group of 1661 operations in which the EEG was the sole
      criterion for shunt insertion. EEG monitoring is measured by the intraoperative
      stroke rate. Carotid stump pressure measurements were recorded as an additional
      observation in 1517 operations and represent a subset of the study group allowing
      comparison of this technique with EEG. Intraoperative stroke rate for the 1661
      operations in the study group was 0.03% (five strokes). A statistically
      significant increase in intraoperative stroke rate was associated with the
      development of an abnormal EEG (1.1%), contralateral internal carotid artery
      occlusion (1.8%), and the combination of both abnormal EEG and contralateral
      internal carotid occlusion (3.3%). The EEG remained normal in 1295 operations
      including 75 operations with contralateral internal carotid artery occlusion. One
      minor intraoperative stroke (0.08%) which resolved in 1 week occurred in the
      absence of an EEG change with no intraoperative strokes in the 75 operations in
      which the contralateral internal carotid artery was occluded. Intraoperative EEG
      monitoring accurately (99.92%) identified patients who may safely have carotid
      endarterectomy without the need of a shunt.

PMID- 12415484
TI  - Infrarenal aortic rupture secondary to neurofibromatosis.
AB  - Neurofibromatosis is characterized by its cutaneous manifestations. It also is
      manifested by arterial lesions commonly found in arterioles and small arteries
      but rarely in large arteries. We present a patient with type I neurofibromatosis
      with spontaneous rupture of his abdominal aorta. He was found at the time of
      emergency laparotomy to have direct compression of his aorta by retroperitoneal
      neurofibromas and abnormal aortic structural wall integrity.

PMID- 12415485
TI  - Stent-graft repair of the thoracic aorta: short-term results.
AB  - The purpose of this study was to evaluate clinical feasibility and immediate
      outcome of stent-graft repair of the thoracic aorta. From December 1999 to
      January 2001, a total of 14 patients underwent stent-graft repair of the thoracic
      aorta. The underlying etiologies were traumatic rupture of the aortic isthmus in
      four cases, Stanford type B dissection in four, thoracic aortic aneurysm in
      three, penetrating atherosclerotic ulcer in two cases, and postoperative
      aortoesophageal fistula in one case. Stent-graft placement was performed under
      angiographic control in all cases in association with transesophageal echography
      in seven cases. The procedure was performed under emergency conditions in five
      cases. Thirteen patients presented contraindications for surgery. Stent-graft
      placement was successful in all cases. No further surgery has been performed in
      any case. Thus we conclude that endovascular treatment of the thoracic aorta
      using stent grafts is a promising therapeutic modality in patients with
      contraindications for conventional surgical treatment.

PMID- 12415486
TI  - Importance of a arteriography for intraoperative quality control during carotid
      artery surgery.
AB  - The purpose of this study was to determine the impact of intraoperative quality
      control using arteriography on the conduct and immediate outcome of carotid
      artery surgery. This retrospective study included 623 carotid artery repair
      procedures performed between January 1993 and January 2000. There were 427 men
      and 159 women (37 bilateral procedures) with a mean age of 71.6 years. The repair
      technique consisted of conventional endarterectomy alone in 353 cases,
      conventional endarterectomy with patch closure in 95 cases, eversion in 44 cases,
      and vein (n = 105) or prosthetic (n = 26) grafting in 131 cases. Findings of
      intraoperative arteriography, which is used routinely in our department, were
      reviewed and analyzed in all cases. Our findings indicate that intraoperative
      quality control with arteriography is an important part of carotid artery
      surgery. In 11.7% of cases in this study, intraoperative arteriography revealed
      significant defects that are the main cause of postoperative neurological
      complications.

PMID- 12415487
TI  - Incorporating exposure models in probabilistic assessment of the risks of
      premature mortality from particulate matter.
AB  - This paper examines the link between the ambient level of particulate pollution
      and subsequent human health effects and various sources of uncertainty when total
      exposure is taken into consideration. The exposure simulation model statistically
      simulates daily personal total exposure to ambient PM and nonambient PM generated
      from indoor sources. It incorporates outdoor-indoor penetration of PM,
      contributions of PM from indoor sources, and time-activity patterns for target
      groups of the population. The model is illustrated for Los Angeles County using
      recent 1997 monitoring data for both PM(10) and PM(2.5). The results indicate
      that, on average, outdoor-source PM contributes about 20-25% of the total PM
      exposure to Los Angeles County individuals not exposed to environmental tobacco
      smoking (ETS), and about 15% for those who are exposed to ETS. The model computes
      both the fractional contribution of outdoor concentrations to total exposure and
      the effect of exposure uncertainties on the estimated slope of the (linear)
      concentration-response curve in time-series studies for PM health effects. The
      latter considers the effects of measurement and misclassification error on PM
      epidemiological time-series studies. The paper compares the predictions of a
      conventional PM epidemiological model, based solely on ambient concentration
      measurements at a central monitoring station, and an exposure simulation model,
      which considers the quantitative relationship between central-monitoring PM
      concentrations and total individual exposures to particulate matter. The results
      show that the effects of adjusting from outdoor concentrations to personal
      exposures and correcting dose-response bias are nearly equal, so that roughly the
      same premature mortalities associated with short-term exposure to both ambient
      PM(2.5) and PM(10) in Los Angeles County are predicted with both models. The
      uncertainty in the slope of the concentration-response curve in the time-series
      studies is the single most important source of uncertainty in both the ambient-
      and the exposure-health model.

PMID- 12415488
TI  - Investigation of the relation between self-reported food consumption and
      household chemical exposures with urinary levels of selected nonpersistent
      pesticides.
AB  - Concerns about pesticide exposure through food consumption have increased during
      the past several years. The main objective of our study was to determine whether
      we could use data from the Third National Health and Nutrition Examination Survey
      (NHANES III) to detect a relation between self-reported food consumption-
      particularly consumption of fruits, vegetables, and bread products--and urinary
      levels of pesticides or their metabolites in a population of 978 adults living in
      the US. A secondary objective was to investigate whether these urine levels
      differed for people who reported exposure to selected common household chemicals
      including bug or insect spray, weed killer, and mothballs or crystals. We used
      monthly food frequency data from the NHANES III, 1988-1994. Urinary
      pesticide/metabolite levels and information about chemical exposures were taken
      from the Priority Toxicant Reference Range Study (a component of the NHANES III).
      Six pesticides or their metabolites were detected in at least 50% of the sample,
      three of which--1-naphthol (86.4%), pentachlorophenol (62.5%), and 3,5,6
      trichloro-2-pyridinol (82.0%)--were possibly related to food consumption. We were
      unable to detect a relation between self-reported food consumption and their
      urinary levels. This may be due more to the limitations of the datasets than to a
      lack of a relation between food consumption and urine pesticide/metabolite
      levels. We did find that people who reported recently using selected common
      chemicals had higher geometric mean urine pesticide/metabolite levels than did
      people who reported not recently using these chemicals.

PMID- 12415489
TI  - Characterization of dioxin exposure in residents of Chapaevsk, Russia.
AB  - Since 1967, a chemical plant in the town of Chapaevsk (Samara province, Russia)
      has produced large amounts of chlorinated compounds and is suspected to be a
      major source of local environmental dioxin contamination. Dioxins have been
      detected in the local air, soil, drinking water, vegetables, and cow's milk.
      Human exposure to dioxins is suspected as a factor in the deteriorating local
      public health. In an effort to characterize nonoccupational dioxin exposure among
      local residents, during the summer of 1998, 24 volunteers were recruited to
      donate blood and to provide information about their residence, employment,
      demographics, medical history, and dietary habits. Selected polychlorinated
      dibenzodioxins, dibenzofurans, and coplanar biphenyls were measured in blood
      serum samples. The mean concentration of total dioxin World Health Organization
      toxic equivalents (WHO-TEQ(98)) based on polychlorinated dibenzo-para-dioxins
      (PCDDs), polychlorinated dibenzofurans (PCDFs), and coplanar polychlorinated
      biphenyls (PCBs) was 61.2 (range 16.4-168.1) pg/g lipid. Subjects living in close
      proximity to the plant (less than 5 km) had significantly higher dioxin levels
      (mean WHO-TEQ(98), 75.7 pg/g lipid), as compared to subjects living more than 5
      km from the plant (mean WHO-TEQ(98), 44.1 pg/g lipid) (P<0.04). Comparisons of
      the study results with available published data indicate that average blood
      dioxin levels were substantially higher in Chapaevsk residents than in
      nonoccupationally exposed populations of other parts of Russia, Europe, and North
      America. Chronic exposures of such magnitude may have appreciable adverse effects
      on public health.

PMID- 12415490
TI  - Prevalence of exposure to solvents, metals, grain dust, and other hazards among
      farmers in the Agricultural Health Study.
AB  - Exposures to multiple chemical, physical, and biological agents in agricultural
      work environments can result in confounding that may obscure or distort risks
      observed in epidemiologic studies. The Agricultural Health Study (AHS) is a large
      epidemiology study being conducted to investigate health risks among pesticide
      applicators and their families. During enrollment in the AHS, questionnaires were
      administered to over 52,000 licensed pesticide applicators from North Carolina
      and Iowa, who were mostly farmers. Questions about the frequency of various
      farming tasks were used to estimate the prevalence of exposure to solvents (25%),
      metals (68%), grain dusts (65%), diesel exhaust fumes (93%), and other hazards,
      including exposure to pesticides. Most of the farmers in the AHS reported
      performing routine maintenance tasks at least once a month, such as painting
      (63%), welding (64%), and repair of pesticide equipment (58%). The majority of
      farmers (74% in North Carolina; 59% in Iowa) reported holding nonfarm jobs, of
      which the most frequent were construction and transportation. The majority of the
      farmers enrolled in the AHS (55%) also reported that they mixed or applied
      pesticides on 10 or more days per year. The associations between the use of
      pesticides and the frequency with which the farmers in the AHS reported
      performing various types of specific farming activities were assessed to evaluate
      potential confounding. Confounding risk ratios calculated for these activities
      suggest that the magnitude of bias due to confounding is likely to be minimal.

PMID- 12415491
TI  - It's about time: a comparison of Canadian and American time-activity patterns.
AB  - This study compares two North American time-activity data bases: the National
      Human Activity Pattern Survey (NHAPS) of 9386 interviewees in 1992-1994 in the
      continental USA with the Canadian Human Activity Pattern Survey (CHAPS) of 2381
      interviewees in 1996-1997 in four major Canadian cities. Identical surveys and
      methodology were used to collect this data: random sample telephone selection
      within the identified telephone exchanges, computer-assisted telephone
      interviews, overselection of children and weekends in the 24-h recall diary and
      the same interviewers. Very similar response rates were obtained: 63% (NHAPS) and
      64.5% (CHAPS). Results of comparisons by age within major activity and location
      groups suggest activity and location patterns are very similar (most differences
      being less than 1% or 14 min in a 24-h day) with the exception of seasonal
      differences. Canadians spend less time outdoors in winter and less time indoors
      in summer than their U.S. counterparts. When exposure assessments use time of
      year or outdoor/indoor exposure gradients, these differences may result in
      significant differences in exposure assessments. Otherwise, the 24-h time
      activity patterns of North Americans are remarkably similar and use of the
      combined data set for some exposure assessments may be feasible.

PMID- 12415492
TI  - A pilot study of global positioning system/geographical information system
      measurement of residential proximity to agricultural fields and urinary
      organophosphate metabolite concentrations in toddlers.
AB  - This pilot study enrolled 20 children between the ages of 11 and 17 months in
      Imperial County, California to assess children's pesticide exposure and
      residential proximity to agricultural fields. We compared parental self-report of
      residential proximity to agricultural fields to measurements using global
      positioning system/geographical information system (GPS/GIS) technology, and we
      assessed the relationship between residential proximity to agricultural fields
      and a biomarker of organophosphate (OP) pesticide exposure. Questionnaires were
      administered twice, 4 weeks apart, to determine self-reported residential
      proximity to agricultural fields. Urine samples were collected at each contact to
      measure OP metabolites. Actual residential proximity to the closest agricultural
      field and number of fields was within 1 mile to the west were measured using
      GPS/GIS. Self-report of living proximity to agricultural fields agreed with
      GPS/GIS measurement 75% of the time during the initial interview, compared to 66%
      agreement during the second interview. Presence of urinary metabolites suggests
      that OP exposure was ubiquitous: creatinine-adjusted total urinary dimethyl
      values ranged from 1.60 to 516.00 microg/g creatinine, and total diethyl ranged
      from 2.70 to 134.84 microg/g creatinine. No association was found between urinary
      OP metabolites and residential to field proximity. These results suggest that
      initial self-report of living proximity to agricultural fields may be more
      accurate than follow-up self-report. Limitations in this pilot study prevent
      determination of whether self-report is an accurate measure of proximity.

PMID- 12415493
TI  - Correlation of year-to-year magnetic field exposure metrics among children in a
      leukemia survival study.
AB  - The Childhood Leukemia Survival Study is examining the possible association
      between magnetic field exposure and survival of children with newly diagnosed
      acute lymphocytic leukemia (ALL). We report the results of serial 24-h personal
      magnetic field monitoring for 412 US and Canadian children and present the
      correlations between annual values. The mean time-weighted average (TWA) and
      geometric mean (GM) were similar for first, second, and third year measurements
      [TWA: 0.11 microT (n = 412), 0.13 microT (n = 304), and 0.12 microT (n = 134),
      respectively]. There were no consistent differences in mean TWA or GM based on
      age or gender. Significantly lower mean TWA and GM were found for children living
      in rural areas. Higher exposures were noted among children living in urban areas,
      among apartments dwellers, and those living in rental homes. Measurements taken
      during summer months and among children residing in the northeast and Canada also
      tended to be higher. Correlations for most metrics were increased among children
      who had annual measurements performed during the same season. The metric with the
      highest year-to-year correlation was the GM. The lowest correlations were found
      for metrics estimating field intermittency and temporal stability. First to
      second year GMs were well correlated when taken in the same home (Spearman rank
      correlation = 0.70), but a lower correlation (0.44) was noted among residentially
      mobile children. Our findings suggest that summarizing exposure using a single
      measurement of GM can estimate exposures for residentially stable children, but
      is not a good predictor of personal exposures among children who change residence
      during the study interval.

PMID- 12415494
TI  - Stability of Wertheimer-Leeper wire codes as a measure of exposure to residential
      magnetic fields over a 9- to 11-year interval.
AB  - The Wertheimer-Leeper (W-L) wire code is a construct used as a surrogate
      indicator of residential exposure to electromagnetic fields. However, little is
      known about how changes in electrical distribution systems affect wire code
      assignment. The wire code was determined for 150 homes in the Seattle, WA, area
      twice, 9-11 years apart. For each home, the authors evaluated whether the
      electrical configuration around the home and the wire code changed between the
      two time points. The effect of wire code misclassification on observable odds
      ratios was evaluated, given hypothetical true control distributions and two
      different dose-response curves. There was an electrical configuration change for
      77 (51.3%) homes, which resulted in a wire code change for 29 (19.3%) homes.
      Eight (5.3%) other homes had a wire code change due to mapping errors or
      methodological inconsistencies. Misclassification masked the shape of a threshold
      (nonlinear) dose-response curve and changed the slope of a linear dose-response
      curve. Although the wire code detected less than half of electrical configuration
      changes, misclassification of exposure over time may change odds ratios and mask
      possible dose-response relationships.

PMID- 12415497
TI  - Abdominal vascular injuries: a continuing challenge.

PMID- 12415498
TI  - Tc-99 HMPAO cerebral SPECT imaging in brain death patients with complex spinal
      automatism.
AB  - BACKGROUND: The aim of this study is to evaluate the value ofTc-99 HMP AO
      cerebral SPECT imaging to confirm brain death in patients with complex spinal
      automatism. METHODS: Fifteen patients (8 female, 7 male) aged between 1,5-48
      years showing spinal movements within 24-72 hours after brain death were examined
      with Tc-99 HMPAO cerebral SPECT. RESULTS: All patients demonstrated empty skull
      on Tc-99 HMPAO images and no contradictory case was ob- served between standard
      clinical criteria and SPECT study. CONCLUSION: Non-invasive brain SPECT study is
      valuable to diagnose and confirm brain death with spinal automatism in adults and
      children. Key words: Tc-99 HMPAO SPECT, brain death, spinal automatism

PMID- 12415499
TI  - [Massive lower gastrointestinal bleeding in the elderly].
AB  - BACKGROUND: This study was performed to evaluate the results of massive lower
      gastrointestinal bleeding in the elderly patients. METHODS: The data of patients
      older than 60 years with massive lower gastrointestinal bleeding were
      retrospectively analyzed between January 1999 and March 2002. RESULTS: There were
      14 (52%) males and 13 (48%), females with mean age of 70.2 years (range 60 to
      88). Twenty patients were diagnosed with colonoscopy. Angiography was employed in
      six, scintigraphy in three and r- enteroclysis in two patients. Colonic
      diverticulosis was the leading etiologic factor (48%). Mean comorbidity and
      hospital stay were 1.59 and 6.7 days, respectively. Conservative treatment were
      performed in eighteen, band JCC, ligation in three, surgery in five and
      embolization in two patients. Mortality rate was 26%. Mortality was high it in
      patients who had a lower initial diastolic pressure and required more
      transfusions (p:0.006 and p:0.025, respectively ) CONCLUSION: Massive lower
      gastrointestinal system bleeding in the elderly with comorbidities is associated
      with higher rate of mortality. Surgery in these patients has high mortality
      rates. Endoscopic and conservative diagnosis and treatment methods should be the
      first choice in the elderly. Key words: Bleeding, lower gastrointestinal system,
      elderly.

PMID- 12415500
TI  - [Selective approach to the penetrating stab wounds to the abdomen].
AB  - BACKGROUND: To present the results of the selective treatment on the penetrating
      stab wound to the abdomen METHODS: From December 1997 to February 200, 175
      patients had penetrating stab wound injuries to the abdomen. Of the 175 patients,
      61 (34.9%) in Group I were taken to the operating room urgently, 114 (65.1%) in
      Group 11 were treated selectively. RESULTS: It is evident that the rate of
      unnecessary laparotomies (X2=6.7, p=0.03), morbidity rate (X2=15.4, p<O.OO1), and
      hospital stay (F=54, p<O.OOO1 ) in the selectively treated group decrease
      significantly when compared with the non-selective group. CONCLUSION: Selective
      approach to the penetrating stab wounds to the abdomen is a safe method.
      Furthermore, this method obviates most of the unnecessary laparotomies. For this
      reason, morbidity rate and hospitalization decrease significantly. Key words:
      Conservative treatment, unnecessary laparotomy, morbidity, hospital stay.

PMID- 12415501
TI  - [Evaluation of stress factors and burnout in the emergency department staff].
AB  - INTRODUCTION: Burnout has been defined as a syndrome of emotional exhaustion,
      depersonalization, and 1 reduced personal accomplishment. The syndrome have been
      linked to high levels of absenteeism from work among professionals group.
      METHODS: We studied on 22 emergency service and 22 other health staff working at
      our Hospital. We investigated on health workers with burnout symptoms by the
      protocol was self-reported (using a poll). Also we used, Maslach Burnout
      Inventory in order to obtain as valid data as possible to assess the level of
      burnout. RESULT: 45.3% showed high levels of burnout on emotional exhaustion
      subscale, 32.~% on depersonalizaion subscale and 28.1% on personal
      accomplishment. Seven (31.82%) have been determined to be under serious. stress
      based on the investigation in emergency services; where as 2 (9.09%) in other
      health services workers as well (t=1.903; p< 0.05 ). CONCLUSION: Burnout symptoms
      were more likely to occur in the emergency personnel than the other health
      service workers. Sharing experiences with family and friends and with other
      health staff who understand what health staffs do best, prevents burnout
      syndrome. KEYWORDS: Burnout, emergency services, stress.

PMID- 12415502
TI  - [Epidemiologic and clinical features of childhood falls].
AB  - BACKGROUND: Trauma is a leading cause of morbidity and mortality for childhood
      and young adults. Falls are the most common mechanism. for injury children. Aim
      of this study is to determine the epidemiology and clinical features of falls
      among children. METHODS: We retrospectively analysed children under 14 years of
      age sustained from falls admitted to the our emergency service between January
      1997- June 2001. RESULTS: A total of 1039 children were admitted during the study
      period. Fa/ls comprised 38% these admissions, and 47% of falls were from
      balconies.252 patients were male and 141 patients were female. Mean age was 5.23.
      62.3 % of children were under the 5 years old. Major injuries included head
      trauma (57%) extremity trauma ( 16%), and abdominal trauma (11%). Mean ISS score
      was 9.16 and 32% of children had an, 1SS score was 9,16. Overall mortality rate
      was 2.23 %. CONCLUSION: Although falls are the significant cause of childhood
      injury, these injuries are rarely fatal. Most, common type of injury is head
      trauma. ISS, age, and height are significantly associated with mortality. Key
      words: Children, trauma,fa/l, epidemiology, mortality.

PMID- 12415503
TI  - [The levels of serum interleukins in the children with trauma].
AB  - BACKGROUND: We investigated the levels of IL-I, IL-2, IL-4, IL-6, IL-I0 and IL-12
      in serum of the children with trauma and its relation with the severity of
      trauma. METHODS: We included 45 children with moderate or severe multiple trauma
      and 21 healthy children for control group to our study. The serum IL-I, IL-2, IL
      4, IL-6, IL-IO and IL-12 were measured by micro ELISA. RESULTS: We found a
      statistically significant difference between the serum values of IL-l, IL-4, 1 L
      6, IL-I0 in the children with trauma and healthy control group. A similar
      difference was also observed between the control group and the trauma group with
      injury severity score (ISS) 30 and also ISS 32. Serum values of IL-2 and IL-12
      did not show significant difference between the groups.W e detected a positive
      correlation between ISS and IL-l, IL-6, IL-I0 and IL-I2 (respectively r = 0,602,
      p = 0,000; r = 0,391, p = 0,008; r = 0,399, p = 0,007; r = 0,475, p = 0,001 ).
      CONCLUSION: These results point out that serum IL-6, IL-I0, IL-12 and especially
      IL-l has a close relationship with the severity of the tissue damage after
      trauma. Key words: Child, cytokine, ISS, trauma, the severity of trauma

PMID- 12415504
TI  - [Results of conservative treatment of midclavicular fractures].
AB  - BACKGROUND: ln this study, we compare the outcome of conservative management by
      closed reduction and figure of eight bandage in cases of midclavicular fractures
      with previously published results of other treatment methods. METHODS: In our
      department between 1997-2002, 37 cases ofmidclavicular fractures having undergone
      conservative treatment were evaluated. RESULTS: 26 patients (70.2%) were male and
      the remaining 11 (29.8%) female. The average age was 34.3 years (range; 9 to 65).
      The claviclefractures were classified according to the Allman classification and
      all fractures were in group 1. After reduction, a figure of eight bandage was
      applied. The mean follow-up period was 29.8 months (range; 6 to 48). All the
      fractures showed a complete union but one case (2.7%). 1n 16.2% of the cases
      minor cosmetic problems were observed. CONCLUSIONS: We conclude that conservative
      treatment is the preferred method of treatment in cases of mid-clavicular
      fractures, unless there is an absolute indication for surgical therapy. This
      approach is easily applicable, cost effective and has fewer complications. Key
      Words: Midclavicular fracture, conservative treatment, closed reduction,figure of
      eight bandage.

PMID- 12415505
TI  - Results of surgical treatment of intra-articular (ao-c3) distal humeral fractures
      in adults.
AB  - BACKGROUND: The results of intra-articular comminuted distal humeral fractures,
      which have been treated by open reduction and dual plate fixation, are compared
      in this study with previously published results. METHODS: At Uludag University
      Faculty of Medicine Department of Orthopaedics and Traumatology, between 1995 and
      2002, the results of 20 cases were evaluated in patients with intra-articular
      comminuted distal humer- alfractures, who had been treated by open reduction and
      internal jixation. RESULTS: Eleven (55%) cases were male, nine (45%) were female
      and mean age was 40.6 (range; 18 to 76). All fractures were C3 type according to
      AO/ASIF classification. Eight (40%) cases were open fractures and of these, six (
      30% ) were type 3A and 2 ( 1 0% ) were type 3B on the Gustilo-Anderson
      classification. All the fractures were jixed with dual plate after open
      reduction. In 25% ~f the cases, superficial wound infection was observed and in
      5% heterotopic ossification. CONCLUSION: In adult distal humeral. fractures of
      type C3, stabilization by dual plate, following open reduction and early
      commencement of joint movements, has fewer complications and should he the
      preferred method of treatment. Key Words: Distal humeral, fracture, intra
      articular, dual plate. fixation.

PMID- 12415506
TI  - [Pancreatic injuries: analysis of 20 cases].
AB  - BACKGROUND: The aim of this study is to stage pancreatic injury and to assess the
      appropriate surgical approach. Trauma leading to pancreatic injury, factors
      responsible for the mortality and complication rates are evaluated and compared
      with the literature. METHODS: Records of 20 patients with pancreatic injuries
      treated at the Emergency Surgical Unit of Research Hospital between January 1997
      to October 2001 were retrospectively evaluated. RESULTS: In this series 20 per
      cent of the mortality occurred within the first 48 hours. The factor responsible
      for the mortality in these patients was major bleeding; related to major
      vascular, hepatic, splenic, renal or thoracic injuries. Late mortality was seen
      in 3 patients (15 per cent) due to sepsis, respiratory insufficiency or ARDS. ln
      the literature mortality rate is between 5 to 30 per cent and morbidity rate is
      30 to 64 per cent. In this series, these percentages were 35 per cent and 43 per
      cent respectively. CONCLUSION: The surgical therapy should be tailored up to the
      presence of ductal injury and the extent and anatomical localization of the
      injured segment. In principle the control of bleeding and contamination, and
      application of the appropriate surgical treatment can lower the morbidity and
      mortality. Key words: Abdominal trauma, pancreatic injury, pancreatic drainage

PMID- 12415507
TI  - [The factors affecting mortality in complicated emergency cases who were
      transferred to our center after being operated on].
AB  - BACKGROUND: To find out the deficiencies related to education and experience of
      surgeons about the surgical treatment of emergency patients, and to investigate
      their effects on mortality. METHODS: The records of 214 patients, who were
      transferred to our department after being operated with the diagnosis of
      abdominal trauma or acute abdomen in last 7 years, were reviewed. RESULTS: Total
      mortality rate was 34.1%.1t was seen that 14.5% in patients who underwent
      efficient surgical treatment and 42.1 % in patients whose treatment was
      inefficient. CONCLUSION: In centre when intensive care unit does not exist,
      immediately transportation of emergency operated patients with high risk will
      decrease morbidity and mortality rates. Participation of the surgeons who deal
      with emergency surgery to the post graduating courses adapting their experiences
      to the current improvements has also importance. Key words: Abdominal trauma,
      acute abdomen, postoperatively transported patients, mortality, surgery training.

PMID- 12415508
TI  - A rare complication after thyroidectomy: esophageal perforation.
AB  - A 67 year-old woman with recurrent multinodular goiter was admitted for bilateral
      near total thyroidectomy. On the postoperative period, a turbid fluid came from
      suction drain which was due to an esophageal perforation. Esophagoscopy and
      contrast computerized tomography revealed a perforation in the upper third part
      of the esophagus. Following nonoperative treatment by restricting oral intake,
      parenteral administration of antibiotics, and parenteral nutrition for 10 days,
      the patient has recovered and was discharged without any sequela. We discussed
      the cause of perforation according to the possible reasons frequently seen in the
      literature. Among iatrogenic reasons, unsuccessful intubation trials were more
      common than neck surgery. Key words: Esophagus, perforation, surgery, intubation,
      thyroidectomy

PMID- 12415509
TI  - A patient with liver trauma and incomplete behcet s disease.
AB  - Behcet' s Disease (BD ) is a complex multisystemic disease, which is
      characterized by recurrent oral and genital aphteous ulcers and iritis in which
      vasculitis can also be one of the possible clinical manifestations. A thirty
      seven year-old female patient with incomplete BD was admitted to emergency
      service, with intra-abdominal hemorrhage more severe than that would be expected,
      with the degree of related trauma. We decided to manage the patient
      conservatively, observing vital signs, haemogram, computed tomography (CT) and
      angiography instead. Subcapsular hematomas were detected in the right and left
      lobes of the liver. No data was encountered in the literature and textbooks
      referring to liver trauma with BD, except a case of fatal hemobilia. H ere in we
      present a liver trauma case with hemorrhage and hepatic fragility due to
      vasculitis in Behcet' s disease and review the literature. Key words: liver
      trauma, incomplete Behcet' s disease

PMID- 12415510
TI  - [Ischemia of the hand following radial artery catheterization].
AB  - A 26 year old women with a history of drug intoxication was taken to intensive
      care unit and had an ischemic, hand injury due to insufficient collateral low
      after placement of a radial artery catheter. Ischemic hand injury 1 occurred 36
      hours after the cannulation. The patient had fingers gangrene in spite of the
      removal of the catheter, elevation and heating of the hand, systemic
      anticoagulation therapy, stellate ganglion blockade, and peripheral circulatory
      regulator therapy. Any evidence of hand ischemia after radial artery cannulation
      should be aggressively investigated and promptly treated in order to prevent
      morbidity and necrosis of the hand. Key Words: Radial artery cannulation,
      Ischemic hand injury.

PMID- 12415511
TI  - [Reconstruction with vein graft interposition and pedicled muscle flap in a
      patient with above.elbow partial arm amputation].
AB  - It is difficult to decide replantation or revascularization in partial or total
      amputations proximal to the wrist. Important point is the expected functional
      result and/ or protection of sensibility. Crush type partial or total amputations
      have poor prognosis. In addition to the vascular injury there are also broad
      cutaneous and muscular injury which have a potential risk for necrosis and
      infection. And this may threat the patient's life. In this case report, as two
      major nerves seemed intact, arterial reconstruction by a vein graft 22 cm. long
      and protection of important structures such as vein graft, nerves and bone which
      were exposed after debridement was performed by pedicled latissimus dorsi muscle
      flap in an above-elbow partial amputation caused by crush injury, and successful
      result was obtained. Key Words: Major limb amputation, revascularization, vein
      graft, pedicled muscle flap.

PMID- 12415513
TI  - The regulatory pendulum in transfusion medicine.
AB  - Blood banking and the manufacture of blood products have been relatively outside
      the influence of regulatory authorities. Several developments contributed to a
      revision of this environment. The transmission of acquired immunodeficiency
      syndrome by blood products changed the perception of blood product safety and
      also spawned litigation and governmental inquiries. The blood banking industry
      has embraced, with varying degrees of enthusiasm, the principles of systematic
      quality management and good manufacturing practice, which has created a
      substantial subindustry and has contributed to a disproportionate focus on
      product quality. Conventional market forces have also gradually penetrated the
      traditional blood economies. The public and political focus has resulted in
      regulatory and policy efforts being concentrated on inappropriate areas. Several
      of the safety efforts can be arguably described as cost-ineffective while
      diverting attention and resources from more important issues. An improved
      integration into mainstream public health policy and incorporation of objectively
      measured risks into regulatory policy would do much to enhance the quality of the
      transfusion system. This can be achieved if regulators themselves are overseen
      through a process that ensures performance and accountability against objective
      and predefined standards. A further beneficial outcome from this approach could
      be the harmonization of blood safety and policy measures, the need for which is
      being felt increasingly worldwide.

PMID- 12415512
TI  - Molecular analysis of collagen XVIII reveals novel mutations, presence of a third
      isoform, and possible genetic heterogeneity in Knobloch syndrome.
AB  - Knobloch syndrome (KS) is a rare disease characterized by severe ocular
      alterations, including vitreoretinal degeneration associated with retinal
      detachment and occipital scalp defect. The responsible gene, COL18A1, has been
      mapped to 21q22.3, and, on the basis of the analysis of one family, we have
      demonstrated that a mutation affecting only one of the three COL18A1 isoforms
      causes this phenotype. We report here the results of the screening of both the
      entire coding region and the exon-intron boundaries of the COL18A1 gene (which
      includes 43 exons), in eight unrelated patients with KS. Besides 20 polymorphic
      changes, we identified 6 different pathogenic changes in both alleles of five
      unrelated patients with KS (three compound heterozygotes and two homozygotes).
      All are truncating mutations leading to deficiency of one or all collagen XVIII
      isoforms and endostatin. We have verified that, in exon 41, the deletion c3514
      3515delCT, found in three unrelated alleles, is embedded in different haplotypes,
      suggesting that this mutation has occurred more than once. In addition, our
      results provide evidence of nonallelic genetic heterogeneity in KS. We also show
      that the longest human isoform (NC11-728) is expressed in several tissues
      (including the human eye) and that lack of either the short variant or all of the
      collagen XVIII isoforms causes similar phenotypes but that those patients who
      lack all forms present more-severe ocular alterations. Despite the small sample
      size, we found low endostatin plasma levels in those patients with mutations
      leading to deficiency of all isoforms; in addition, it seems that absence of all
      collagen XVIII isoforms causes predisposition to epilepsy.

PMID- 12415514
TI  - Storage of red blood cells: new approaches.
AB  - Longer red blood cell (RBC) storage can improve blood logistics, increase the
      usefulness of autologous blood storage, and reduce donor exposure in neonatal
      intensive care. Better RBC storage can prevent membrane loss and preserve the
      secretion of adenosine 5'-triphosphate (ATP) in response to deformation. Better
      RBC storage may also reduce the formation of proinflammatory membrane breakdown
      products that lead to transfusion-related acute lung injury and the systemic
      inflammatory response syndrome. To improve RBC storage, the authors have
      attempted to maximize the production of ATP by the manipulation of pH and to
      minimize membrane loss through the use of membrane protectants and the
      manipulation of tonicity. Increasing the initial storage pH led to successively
      higher RBC ATP concentrations until pH 7.2 was reached, when the synthesis of 2,3
      diphophoglycerate was initiated at the expense of ATP. Synthesis of ATP could be
      maintained by buffering the fall of pH with increased storage solution volume or
      the addition of bicarbonate. Maintaining RBC ATP turns out to be an important way
      of preventing membrane microvesiculation or blebbing, as does the manipulation of
      tonicity and the addition of mannitol. These experiments show that it is possible
      to store RBC in experimental additive solutions containing only saline, adenine,
      glucose, mannitol, sodium bicarbonate, and disodium phosphate for 11 weeks or
      longer with little loss of membrane and high in vivo recovery.

PMID- 12415515
TI  - The before/after study design in transfusion medicine: methodologic
      considerations.
AB  - To ascertain the effectiveness of an intervention, a randomized controlled trial
      (RCT) is considered the gold standard. An obstacle to conducting an RCT only
      rarely discussed is the universal implementation of an intervention. Universal
      implementation clearly precludes the feasibility of conducting an RCT. Thus, the
      most attractive alternative study design in such instances becomes the
      before/after study. This article describes important methodologic considerations
      in undertaking a before/after evaluation. The methodologic considerations to be
      discussed are (1) threats to internal validity, (2) precision and (3)
      generalizability. Two before/after studies evaluating the potential effectiveness
      of universal leukoreduction serve as examples. Because of the universal
      application of many transfusion interventions, one has to consider carefully the
      methodologic rigor as to which of these interventions are evaluated. We have
      outlined the major methodologic issues one must consider when undertaking a
      before/after study design. When properly conceived, conducted, and analyzed, such
      a before/after study design can yield informative associations.

PMID- 12415516
TI  - Meta-analysis of randomized controlled trials investigating the risk of
      postoperative infection in association with white blood cell-containing
      allogeneic blood transfusion: the effects of the type of transfused red blood
      cell product and surgical setting.
AB  - Previous meta-analyses of the randomized controlled trials (RCTs) investigating
      the association of perioperative allogeneic blood transfusion (ABT) with
      postoperative bacterial infection included studies transfusing either autologous
      or white blood cell (WBC)-reduced allogeneic red blood cells (RBCs) or whole
      blood to the control arm, and they were unable to investigate the type of RBC
      product administered as an explanation for the disagreements among the studies.
      The availability of additional RCTs has permitted investigation of this
      hypothesis in a meta-analysis restricted to RCTs transfusing WBC-reduced
      allogeneic RBCs or whole blood to the control arm. In this analysis, across 5
      RCTs comparing recipients of non-WBC-reduced versus WBC-reduced allogeneic RBCs,
      there was no difference (P > .25) in the risk of postoperative infection between
      recipients of buffy-coat-reduced versus WBC-reduced allogeneic RBCs filtered
      before storage (summary odds ratio [OR] = 1.19; 95% confidence interval [CI],
      0.87-1.63). In contrast, across 3 RCTs, there was an increased (P < .05) risk of
      postoperative infection in recipients of non-buffy-coat-reduced allogeneic RBCs,
      or whole blood, as compared with recipients of WBC-reduced allogeneic RBCs, or
      whole blood, filtered before or after storage (summary OR = 1.77; 95% CI, 1.02
      3.09). Moreover, across 3 RCTs that enrolled patients undergoing open-heart
      surgery, there was an increased (P < .05) risk of postoperative infection in
      recipients of buffy-coat-reduced (compared with WBC-reduced) allogeneic RBCs
      (summary OR = 1.39; 95% CI, 1.08-1.80), but the findings of 5 RCTs that enrolled
      patients having abdominal surgery could not be combined because of extreme
      variation in the results of the studies. RCTs conducted in the setting of open
      heart surgery or transfusing non-buffy-coat-reduced RBCs or whole blood to the
      treatment arm had administered various RBC products to the control arm, however,
      and thus the medical heterogeneity of the studies precludes any conclusion about
      an immunomodulatory (TRIM) effect of ABT mediated by non-buffy-coat-reduced RBC
      products. To determine whether such a deleterious immunomodulatory effect of ABT
      exists, additional RCTs transfusing non-buffy-coat-reduced RBCs to the treatment
      arm should be conducted.

PMID- 12415517
TI  - The value of lookback to understanding blood-borne infectious diseases: the New
      South Wales' HIV experience.
AB  - This article describes the methods used by the New South Wales Division of the
      Australian Red Cross Blood Service (ARCBS-NSW) to conduct human immunodeficiency
      virus (HIV) lookback, assesses the success and limitations of the different
      methods used, and discusses the results obtained. This article shows that an
      important outcome of the HIV lookback undertaken by the ARCBS-NSW was the
      establishment and maintenance of an observational database. This database became
      an integral part of several research projects that contributed significantly to
      understanding factors influencing the rate of progression of HIV to acquired
      immunodeficiency virus and knowledge of HIV pathogenesis in general. This article
      argues that if lookback is extended beyond its original function of identifying
      transfusion-infected recipients and the implicated donors to create and maintain
      a linked register of these recipients and donors, the information obtained in
      such an observational database can be used to describe the natural history of
      transfusion-transmitted infectious diseases and can contribute to the research
      necessary to the understanding of disease pathogenesis.

PMID- 12415518
TI  - Dorsal displacement of the soft palate in 92 horses during high-speed treadmill
      examination (1993-1998).
AB  - OBJECTIVE: To evaluate the occurrence of dorsal displacement of the soft palate
      (DDSP) during high-speed treadmill (HSTM) exercise in racehorses, and determine
      treatment efficacy relative to the endoscopic findings observed during resting
      and HSTM endoscopic examination. STUDY DESIGN: Retrospective study. Animals
      Ninety-two racehorses (74 Thoroughbreds, 18 Standardbreds). METHODS: The
      signalment, history (clinical and race), treatments, and video recordings made
      during resting and HSTM endoscopy were reviewed in 92 racehorses that developed
      DDSP during HSTM exercise. Only horses that completed 3 starts before and after
      HSTM examination were included in performance-outcome analysis. Statistical
      associations were made between the independent variables (the historical findings
      and the resting and HSTM endoscopic findings) and performance outcome. RESULTS:
      Forty-five horses (49%) displaced their palate in an uncomplicated manner,
      whereas the other horses either had another upper-respiratory abnormality in
      association with DDSP (35) or displaced after swallowing (12). Although
      respiratory noise was not recorded during HSTM exercise, only 57 horses (62%)
      that developed DDSP during HSTM examination had a history of abnormal upper
      respiratory noise. For the 45 horses that met the criteria for performance
      outcome analysis, there were no independent variables recorded during resting or
      HSTM endoscopy that had a significant association with performance outcome.
      Treatment for DDSP varied by clinician. Overall, 29 horses (64%) had improved
      average earnings per start after diagnosis and treatment. CONCLUSIONS: Thirty
      five horses (38%) that had DDSP during HSTM endoscopy had no previous history of
      abnormal upper-respiratory noise, and 74 (80%) had no structural abnormalities
      noted on resting endoscopic examination. CLINICAL RELEVANCE: HSTM examination is
      an excellent tool for diagnosis of DDSP and the manner in which it occurs. DDSP
      did not occur similarly in all horses, and was often associated with another
      upper-respiratory abnormality. Thus, it is unlikely that a single treatment can
      be applied effectively for all horses that experience DDSP. Both surgical and
      medical treatments can be beneficial in improving a horse's performance after a
      diagnosis of DDSP is made. Neither resting nor HSTM endoscopic findings were
      clearly prognostic.

PMID- 12415519
TI  - Prognostic indicators for time to ambulation after surgical decompression in
      nonambulatory dogs with acute thoracolumbar disk extrusions: 112 cases.
AB  - OBJECTIVES: To determine prognostic indicators for time to ambulation after
      surgical decompression in nonambulatory dogs with intact pain sensation and acute
      Hansen type-1 disk extrusions. STUDY DESIGN: Retrospective clinical study.
      ANIMALS: One-hundred twelve dogs with Hansen type-I disk extrusions that had
      decompressive hemilaminectomy or dorsal laminectomy. METHODS: All dogs had
      thoracolumbar disk extrusion and were nonambulatory with intact pain sensation at
      admission. Variables considered included age, weight, voluntary motor function at
      time of anesthetic induction, glucocorticoid use, times from onset of
      nonambulatory status to admission and surgical decompression, time in hospital to
      surgical decompression, anesthetic time, surgical time, number of contrast
      injections required to perform a diagnostic myelogram, postoperative pain
      sensation, and postoperative voluntary motor function. Time to ambulation was
      defined as the number of days from surgical decompression until the dog was able
      to stand and take a series of steps without assistance. RESULTS: One-hundred
      seven dogs (96%) were able to ambulate within 3 months. The mean time to
      ambulation was 12.9 days and was significantly shorter if dogs had postoperative
      voluntary motor function (7.9 days v 16.4 days, P <.0001). No other variable had
      a significant association with time to ambulation. CONCLUSIONS: Few perioperative
      variables have prognostic value for return to ambulation. Nonambulatory dogs with
      intact pain sensation and Hansen type-1 disk extrusions in the thoracolumbar
      spine that are treated with surgical decompression have a favorable prognosis.
      CLINICAL RELEVANCE: The presence of postoperative voluntary motor function is a
      favorable prognostic indicator for early return to ambulation.

PMID- 12415520
TI  - Malignant transformation of an aneurysmal bone cyst in a dog.
AB  - OBJECTIVE: To report malignant transformation of an aneurysmal bone cyst in a
      dog. STUDY DESIGN: Case report. SAMPLE POPULATION: Client-owned dog. RESULTS: A 5
      year-old male Labrador retriever was diagnosed with an aneurysmal bone cyst of
      the distal aspect of the right ulna. Surgical curettage resulted in remission of
      clinical signs for 33 months. Because of recurrence of clinical signs, a distal
      ulnar ostectomy was performed. Histopathologic examination of the excised
      specimen revealed a moderately differentiated chondrosarcoma at the level of the
      bone cyst. Limb function was normal for 17 months until a subcutaneous mass,
      determined to be a chondrosarcoma, occurred at the level of the shoulder. A right
      forequarter amputation was performed. CONCLUSIONS: Aneurysmal bone cysts are
      benign but may be transformed into a malignancy after surgical manipulation.
      Complete surgical excision should be attempted where possible. In this case,
      distal ulnar ostectomy was an effective means of preserving limb function and
      preventing local recurrence of chondrosarcoma.

PMID- 12415521
TI  - Pasteurized tumoral autograft as a novel procedure for limb sparing in the dog: A
      clinical report.
AB  - OBJECTIVE: To evaluate use of a pasteurized tumoral autograft prepared from the
      resected primary bone neoplasm for limb sparing in a dog with distal radial
      osteosarcoma (OSA). STUDY DESIGN: Clinical case report. ANIMALS: A 9-year-old
      male Maremma shepherd dog. METHODS: After right distal radial OSA removal, the
      tumoral autograft was pasteurized. The excised bone segment was placed in a
      sterile watertight box containing sterile saline solution preheated to 65 degrees
      C in a water bath. The box was kept immersed in the water bath at 65 degrees C
      for 40 minutes to kill the tumor cells. The autograft was then fixed in the host
      with a plate and screws based on standard AO/ASIF technique for carpal
      arthrodesis. Three doses of cisplatin (70 mg/m(2) intravenously) were
      administered, 3 weeks apart; the initial dose was administered the day after
      surgery. RESULTS: The autograft was incorporated in a manner comparable to an
      allograft, and after 708 days, the metallic implants were removed. A 1-month
      activity restriction as well as spoon splint to protect the leg from a full
      loading were used thereafter. Limb function was fair to good, and the dog remains
      disease free after 56 months. CONCLUSIONS: A pasteurized autograft consisting of
      the resected primary bone neoplasm is a valid alternative to a cortical bone
      allograft for limb sparing in dogs with appendicular OSA in terms of feasibility
      and pattern of healing. CLINICAL RELEVANCE: This procedure can be an alternative
      method of limb sparing when difficulties are encountered in establishing and
      maintaining a canine bone allograft bank.

PMID- 12415522
TI  - Evaluation of the bone injection gun as a method for intraosseous cannula
      placement for fluid therapy in adult dogs.
AB  - OBJECTIVE: To evaluate the Bone Injection Gun (BIG) for placement of intraosseous
      cannulas through impact penetration and compare it with a standard Jamshidi bone
      marrow needle (JBMN) and to compare fluid delivery dynamics through each device.
      STUDY DESIGN: Randomized in vivo study. ANIMALS: Forty-eight mature dogs.
      METHODS: During surgical laboratories, dogs were randomly assigned to 2 groups (n
      = 24), and intraosseous access in the proximal tibial metaphysis was obtained
      using a BIG or JBMN. Variables measured during placement included insertion
      success, time required for placement, and alterations in respiratory rate (RR),
      heart rate (HR), and systolic blood pressure. After placement, maintenance fluids
      were administered to 6 dogs from each group, and fluids were administered under
      pressure to 6 dogs from each group to compare rates of delivery through each
      device. After euthanasia, the tibiae were harvested to evaluate and compare the
      morphologic consequences of needle and cannula placement. RESULTS: Successful
      placement occurred in 20 (83%) dogs for the BIG and 23 (96%) dogs for the JBMN,
      which was not significantly different (P =.3475). Time required for placement was
      significantly less (P =.0024) for the BIG (mean, 22.4 +/- 8.2 seconds) compared
      with the JBMN (mean, 42.0 +/- 28.1 seconds). Significant increases in RR occurred
      in both groups and in the HR for the BIG group, but significant differences were
      not noted between groups. Mean rate of pressurized fluid administration was
      similar for both groups. Two distinct patterns of cortical bone damage occurred,
      but the clinical significance of this observation is uncertain. CONCLUSIONS: The
      BIG provides more rapid access to the intraosseous space for fluid administration
      than the JBMN. CLINICAL RELEVANCE: The BIG is an effective alternative for
      obtaining rapid access to the intraosseous space for emergency fluid and drug
      administration.

PMID- 12415523
TI  - The effect of a porcine-derived small intestinal submucosa product on wounds with
      exposed bone in dogs.
AB  - OBJECTIVE: To determine the effect of a porcine-derived small intestinal
      submucosa product (PSIS) on healing time, epithelialization, angiogenesis,
      contraction, and inflammation of wounds with exposed bone on the distal aspect of
      the limbs of dogs. STUDY DESIGN: Prospective, controlled, experimental study.
      ANIMAL POPULATION: 10 young adult, purpose-bred, male Beagles. METHODS: Small
      wounds with exposed bone were created on the lateral aspect of metatarsal V and
      the medial aspect of metatarsal II on both hindlimbs. Three sheets of PSIS were
      sutured into the wounds of the treated limb, and the other limb served as a
      control. On day 10, punch biopsies of the medial metatarsal wounds were collected
      and were evaluated microscopically after routine hematoxylin and eosin and
      phosphotungstic acid hematoxylin (PTAH) staining. The lateral metatarsal wounds
      were evaluated by planimetry and laser Doppler perfusion imaging on days 7, 14,
      and 21. Time until complete wound healing was also recorded. The level of
      significance was set at P < or =.05 for all statistical analyses. RESULTS: Laser
      Doppler perfusion measurements were significantly higher in control wounds on day
      7, but no differences were noted on days 14 and 21. No significant differences in
      planimetric values, histopathologic appearance, or time until complete wound
      healing were noted among treated and control groups. CONCLUSIONS: No objective
      differences in healing were noted between control wounds and wounds treated with
      PSIS. CLINICAL RELEVANCE: There appears to be no contraindication to the use of
      PSIS on clean wounds with exposed bone on the distal limbs of dogs. However, our
      objective data provides no evidence that this product affects epithelialization,
      contraction, or time to complete healing in wounds with exposed bone.

PMID- 12415524
TI  - Removal of infected canine cemented total hip prostheses using a femoral window
      technique.
AB  - OBJECTIVE: To evaluate a femoral window technique for retrieval of cemented total
      hip prostheses. STUDY DESIGN: Retrospective clinical study. ANIMALS: Twelve dogs
      with infection of a cemented modular total hip prosthesis. METHODS: Implant
      removal was performed by an extended craniolateral approach to the hip and
      proximal femur without trochanteric osteotomy. The femoral cement mantle was
      fragmented and removed with simple orthopedic instrumentation by a lateral
      femoral window that was repaired using cerclage wires. Surgical technique,
      intraoperative and postoperative complications, bacterial culture results,
      histopathologic findings, and completeness of cement removal were recorded.
      Follow-up radiographs were taken 5 to 9 weeks postoperatively. Long-term follow
      up information was obtained by client questionnaire. Functional outcome was
      assessed by scoring ability to stand, sit, walk, run, play, climb stairs, and get
      into a car. RESULTS: Prosthesis retrieval was performed 2 to 41 months after
      implantation (median, 14 months). Complete removal of femoral cement was achieved
      in 10 dogs. A nondisplaced femoral fissure, extending proximally from the window,
      was an intraoperative complication in 2 dogs. Staphylococcus spp was most
      commonly isolated (6 dogs) from interfacial membrane samples. Systemic antibiotic
      therapy, dependent on susceptibility testing, was administered for 3 to 10 weeks
      postoperatively. There was radiographic evidence of osteotomy healing at 5- to 9
      week reassessment. Recurrence of osteomyelitis was not observed. Long-term
      functional outcome was considered mildly abnormal. CONCLUSIONS: The lateral
      window was an effective technique for retrieval of retained femoral cement.
      CLINICAL RELEVANCE: Removal of an infected prosthesis using this technique
      generally resulted in a clinical outcome comparable to that with ab initio
      femoral head and neck excision.

PMID- 12415525
TI  - Survival and prognostic indicators for dogs with intrahepatic portosystemic
      shunts: 32 cases (1990-2000).
AB  - OBJECTIVE: To determine prognostic indicators for short-term outcome and long
      term survival for dogs with intrahepatic portosystemic shunts (IPSS). STUDY
      DESIGN: Retrospective study. ANIMALS: Thirty-two dogs of various breeds. METHODS:
      Clinical data extracted from medical records of dogs with IPSS were reviewed and
      included gender, age at surgery, weight, preoperative packed cell volume (PCV),
      total plasma protein concentration (TP), albumin (ALB), serum activities of
      alanine aminotransferase (ALT) and alkaline phosphatase (ALP), preprandial and
      postprandial bile acid concentrations (pre-BA, post-BA), blood urea nitrogen
      (BUN), glucose concentration, band neutrophils, per-rectal nuclear scintigraphy
      shunt fraction, whether an angiogram was performed, shunt location at surgery,
      whether a partial or complete attenuation of the shunt was performed, rectal
      temperature at the end of surgery, and duration of surgical procedure. Follow-up
      was determined from visits to the veterinary teaching hospital or by telephone
      communications with the owner or referring veterinarian. RESULTS: Median survival
      time was 35.68 months, and 1- and 2-year probabilities of survival were 60% and
      55%, respectively. Body weight, TP, ALB, and BUN were identified as prognostic
      indicators for short-term outcome. PCV and TP were identified as prognostic
      indicators for long-term survival. CONCLUSIONS: PCV and TP were identified as
      prognostic indicators for long-term survival, whereas body weight, TP, ALB, and
      BUN were identified as indicators for short-term outcome in dogs with IPSS. Shunt
      location at surgery did not have any effect on short-term outcome and long-term
      survival. CLINICAL RELEVANCE: Total protein, ALB, BUN, and PCV can be used to
      determine prognosis of dogs with intrahepatic shunt.

PMID- 12415526
TI  - Influence of bolt tightening torque, wire size, and component reuse on wire
      fixation in circular external fixation.
AB  - OBJECTIVES: To evaluate the effects of bolt torque, wire size, and component
      reuse on the ability to maintain wire tension in 3 external skeletal fixation
      systems. STUDY DESIGN: Biomechanical study. METHODS: Yield strength in tension of
      1.0-, 1.2-, 1.5-, and 1.6-mm-diameter wires, and yield strength in torque of
      Hofmann Small Bone Fixation (SBF) cannulated and slotted bolts and IMEX regular
      and miniature bolts were determined on a testing machine. The minimum bolt
      tightening torque needed to prevent wire slippage at clinically recommended wire
      tensions was determined. Components were tested 10 times, and loads at slippage
      were recorded. RESULTS: The IMEX system required a mean of 8 Nm of bolt
      tightening torque to maintain 900 N (1.6-mm wires). The SBF system required a
      mean of 3 Nm bolt torque to maintain 300 N (1.0-mm wires) and 5 Nm to maintain
      600 N (1.2-mm wires). The SBF cannulated bolt required 9 Nm of torque to maintain
      900 N (1.5-mm wires). The SBF slotted bolts could only maintain 800 N before
      yield. The IMEX miniature system required a mean bolt torque of 1.1 Nm to
      maintain 300 N. The cannulated and slotted bolts from both manufacturers failed
      to maintain 70% of initial wire tension after 7 and 4 uses, respectively.
      CONCLUSIONS: The IMEX systems and the SBF system using 1.0- and 1.2-mm wires
      could maintain clinically recommended wire tension safely. Only the IMEX system
      could maintain clinically recommended wire tension safely using 1.5- or 1.6-mm
      wires. CLINICAL RELEVANCE: The SBF system using 1.0- and 1.2-mm wires and the
      IMEX system using all wire sizes can maintain clinically relevant wire tension.
      The SBF system using 1.5-mm wires could not. Cannulated and slotted bolts should
      not be used more than 6 and 3 times, respectively. Nuts should not be reused.

PMID- 12415527
TI  - Epidemiologic evaluation of postoperative wound infection in clean-contaminated
      wounds: A retrospective study of 239 dogs and cats.
AB  - OBJECTIVE: To evaluate risk factors for development of postoperative wound
      infections in clean-contaminated wounds. STUDY DESIGN: Retrospective clinical
      study. SAMPLE POPULATION: Two hundred thirty-nine dogs and cats that had clean
      contaminated surgical procedures. METHODS: Records of animals that had a clean
      contaminated surgical procedure and were prospectively monitored for development
      of postoperative wound infection were reviewed. Prospective data included
      signalment, nutritional status, body weight, duration of surgery, surgical
      procedures, wound classification, surgical site clip time before surgery,
      hypotension during surgery, the presence of an active distant infection,
      endocrinopathy, administration of an immunosuppressive agent, administration of
      antibiotics, and the type of antibiotic used. Additional retrieved data included
      total anesthesia time, temperature variables, blood loss, and suture material
      used. RESULTS: Intact males (P =.008) and animals with concurrent endocrinopathy
      (P =.008) were at a higher risk of development of postoperative wound infection.
      Total surgery time (P =.02) and total anesthesia time (P =.04) were longer in
      animals that developed postoperative wound infection. No other factors were
      statistically significant. CONCLUSIONS: Intact males and animals with a
      concurrent endocrinopathy were at higher risk of postoperative wound infection
      after clean-contaminated surgical procedures. CLINICAL RELEVANCE: Time under
      anesthesia and duration of surgery should be minimized to reduce the risk of
      wound infection in clean-contaminated surgical procedures.

PMID- 12415528
TI  - Comparison of double dynamic compression plating versus two configurations of an
      internal veterinary fixation device: Results of in vitro mechanical testing using
      a bone substitute.
AB  - OBJECTIVE: To compare the mechanical properties of 2 configurations of a
      veterinary fixation system (VFS) for large animal long bones with dynamic
      compression plating (DCP). SAMPLE POPULATION: Eighteen pairs of Canevasit tubes
      (Canevasit; Amsler und Frei, Schinznach Dorf, Switzerland) (length, 170 mm;
      diameter, 47.5 mm; cortex thickness, 10 mm), aligned with a 10-mm gap, and
      stabilized with 2 DCP or 2 VFS implants. METHODS: Three groups (n = 6) were
      compared. Group 1 Canevasit tubes were stabilized with two 10-hole, broad 4.5-mm
      stainless steel DCP applied with both plates centered over the gap, in orthogonal
      planes parallel to the long axis of the tubes and staggered to allow bicortical
      fixation with ten 4.5-mm, 52-mm-long cortex screws each. Group 2 tubes were
      stabilized similarly with 2 VFS implants, each composed of a stainless steel rod
      (length, 167 mm; diameter, 8 mm), and 10 clamps were applied in alternating
      fashion left and right on the rod and fixed bicortically with ten 4.5-mm, 52-mm
      long, cortex screws. Group 3 tubes were stabilized similarly, but using only 6
      clamps/rod. All groups were tested initially in torsion within elastic limits and
      subsequently in 4-point bending, with 1 implant on the tension side, until gap
      closure occurred. RESULTS: None of the constructs failed, but all had plastic
      deformation after 4-point bending. No statistically significant differences were
      found among the 3 groups in torsional stiffness. Double DCP fixation was
      significantly stiffer and stronger in 4-point bending, compared with both
      configurations of double VFS fixation. CONCLUSIONS: The plate design was favored
      in this study. The VFS system may have to be adapted before further tests are
      conducted. Test modalities have to be chosen closer to clinical conditions (real
      bone, cyclic loading, closed gap). CLINICAL RELEVANCE: The veterinary fixation
      system has not yet proven its advantages for large animal long bone fracture
      repair. From the pure mechanical point of view, double DCP is the favored method
      for the treatment mentioned.

PMID- 12415529
TI  - Effects of suture tension and surgical approach during unilateral arytenoid
      lateralization on the rima glottidis in the canine larynx.
AB  - OBJECTIVES: To evaluate the effect of abduction suture tension and cricothyroid
      (CT) joint disarticulation on the area, height, and width of the rima glottidis
      (RG) during unilateral arytenoid lateralization. STUDY DESIGN: Experimental
      study. ANIMALS: Nine canine cadaver larynges. METHODS: Left arytenoid
      lateralization was performed with high or low abduction suture tension. RG area,
      height, and width were measured by computerized planimetric analysis with the
      epiglottis in an open and closed position. The experiment was performed with the
      CT joint intact and disarticulated. The effects of suture tension, CT
      disarticulation, and their interaction on RG area with the epiglottis closed or
      open were evaluated by repeated measures analysis of variance (ANOVA). RESULTS:
      RG area increased by 82% and 129% (P <.0001) with low and high suture tension,
      respectively. The aperture not covered by the epiglottis in a closed position was
      467% larger with high suture tension than with low tension (P <.0001). CT
      disarticulation had no significant effect on RG geometry with either low or high
      suture tension (P =.4970). CONCLUSIONS: Low suture tension increased RG area when
      the epiglottis was in an open position without increasing RG aperture when the
      epiglottis was closed. Suture tension had a significant effect on RG opening when
      the epiglottis was closed. CT disarticulation did not modify the geometry of the
      RG. CLINICAL RELEVANCE: Use of a low-suture tension should be considered during
      arytenoid lateralization because it has the potential to reduce the risk of
      aspiration pneumonia.

PMID- 12415530
TI  - The effect of cranial cruciate ligament insufficiency on caudal cruciate ligament
      morphology: An experimental study in dogs.
AB  - OBJECTIVES: To investigate the effect of cranial cruciate ligament (CrCL)
      insufficiency on morphology of the canine caudal cruciate ligament (CdCL). STUDY
      DESIGN: In vivo experimental study. ANIMALS: Five adult foxhounds. METHODS: Two
      years after CrCL transection, the histologic appearance of CdCLs from CrCL
      deficient and unoperated contralateral control (CrCL-intact) stifle joints were
      evaluated using light and transmission electron microscopy. RESULTS: CdCLs from
      CrCL-deficient joints had extracellular matrix changes, characterized by
      chondroid metaplasia and disruption of cell architecture. Percent of small
      diameter fibrils in CdCLs from CrCL-deficient joints was significantly greater (P
      <.05) than that in CdCLs from CrCL-intact joints. Collagen fibril density in
      CdCLs from CrCL-deficient joints (41.09 +/- 5.39%) tended to be less than that in
      CdCLs from CrCL-intact joints (52.96 +/- 6.92%); however, this difference was not
      significant (P =.056). Mean eccentricity (ratio of minor to major diameters) of
      collagen fibrils was significantly (P <.0001) lower for CdCLs from CrCL-deficient
      joints (0.85 +/- 0.016) when compared with that for CdCLs from CrCL-intact joints
      (0.87 +/- 0.015). CONCLUSIONS: Significant alterations were found in the
      morphology of CdCLs from CrCL-deficient joints. These changes may be associated
      with repetitive microtrauma to the CdCL secondary to instability or enzymatic
      degradation in the hostile synovial environment of an unstable joint. CLINICAL
      RELEVANCE: Regardless of the cause, the switch to a predominantly small-diameter
      collagen fibril profile may reflect compromised material properties of the CdCL.
      This should be taken into account when considering surgical techniques that rely
      on the CdCL to stabilize CrCL-deficient stifles.

PMID- 12415531
TI  - Neuronal nicotinic receptor inhibition for treating mood disorders: preliminary
      controlled evidence with mecamylamine.

PMID- 12415532
TI  - Effects of olanzapine and clozapine upon pulse rate variability.
AB  - Based upon their in vitro receptor binding profiles, the atypical antipsychotics
      clozapine and olanzapine exhibit cholinergic receptor binding of similar potency.
      Data comparing the in vivo anticholinergic effects, however, of these
      neuroleptics upon neurocardiac control are sparse. The goal of this study was to
      compare the in vivo effects of clozapine and olanzapine upon neurocardiac control
      by assessment of the pulse rate variability (PRV) in schizophrenic patients and
      healthy controls. Twenty patients with schizophrenia (according to DSM-III-R
      criteria) treated with either clozapine (100-600 mg/day) or olanzapine (10-20
      mg/day), and ten healthy controls, were recruited into the study. PRV was
      assessed by continuously recording the skin blood volume in the fingertip of the
      second digit under resting conditions and PRV parameters were calculated. When
      significant differences in PRV parameters between the patients and controls were
      detected by Kruskal-Wallis tests, Mann-Whitney tests were used to test for group
      differences between the olanzapine- and clozapine-treated patients. In comparison
      to the healthy controls, the PRV parameters of the clozapine- and olanzapine
      treated schizophrenic patients were significantly reduced. Indeed the reduction
      of PRV was significantly greater in the clozapine-treated group compared to the
      olanzapine-treated group (P<0.05). Compared to the controls, only the clozapine
      treated patients showed a significantly diminished low-frequency (LF)/high
      frequency (HF)-ratio, a PRV parameter reflecting sympatho-vagal balance. The
      significantly greater reductions in PRV parameters of the clozapine-treated
      compared to olanzapine-treated patients may be caused by clozapine's higher
      affinity for alpha(1)-adrenergic receptors in vivo compared with olanzapine. The
      similar LF/HF ratios of the healthy controls and olanzapine-treated patients
      suggests that the sympathetic-parasympathetic modulation of PRV remains
      relatively unchanged even during olanzapine treatment.

PMID- 12415533
TI  - Relation between depression and anxiety in dystonic patients: implications for
      clinical management.
AB  - Past clinical research has identified depression as the most common psychiatric
      disorder associated with cervical dystonia (CD). The purpose of our study is to
      document different patterns of psychopathology, the frequency of psychiatric
      disorders, and possible correlation with the neurological disorder in patients
      with CD. Forty patients with CD were investigated to assess levels of
      psychopathology on two self-rated scales: the Beck Depression Inventory (BDI) and
      Symptom Check List (SCL-90). To determine the presence of psychiatric disorders,
      the patients were evaluated using the standard instrument in the DSM-III-R
      (Structured Clinical Interview Schedule, SCID). A small group of dystonic
      patients (12%) had higher levels of psychopathology, with significant amounts of
      concomitant anxiety and depression on the BDI and SCL-90. SCID criteria for at
      least one psychiatric disorder were fulfilled in 22 patients (55%), including
      both the lifetime and current diagnoses. The most frequent diagnostic categories
      were anxiety (40%) and major depressive disorders (37.5%). In 17 patients
      (42.5%), criteria for at least one lifetime diagnosis were fulfilled prior to the
      onset of CD. Psychiatric evaluation does not indicate one specific disorder
      associated with CD. The presence of anxiety and depression symptoms before and
      during the course of dystonia, without a possible causal relationship, could mean
      that the alteration of a chain of physiological events in the central nervous
      system may not lead to a single clinical picture. The relatively high overall
      lifetime prevalence of anxiety and depressive disorders may indicate the need for
      a broader diagnostic and therapeutic approach to patients with focal dystonia.

PMID- 12415534
TI  - Life events, number of social relationships, and twelve-month naturalistic course
      of major depression in a community sample of women.
AB  - Research suggests that negative life events and social support are associated
      with the course of major depressive episodes. However, the manner in which these
      variables may be specifically interrelated remains unclear. The present study
      compared two models of the relation among life events, number of social
      relationships, and the naturalistic course of major depression in a community
      sample of women. The life event profiles of 32 women were assessed during their
      index episode of major depression (T1) and again 1 year later (T2). Measures
      included the Hamilton Depression Rating Scale, the Beck Depression Inventory, and
      the Life Events and Difficulties Schedule. Data analysis focused on whether life
      events and social relationships were independent predictors of depressive
      symptomatology (i.e., "main effects" model) or whether social relationships
      moderated the influence of life events on the naturalistic course of
      participants' major depressive episodes (i.e., "stress buffering" model). The
      results only partially supported the main effects model and failed to support the
      buffering model of the relation among life events, social relationships, and
      naturalistic depression course. In particular, the present findings indicated
      that number of social relationships was a significantly stronger predictor of
      naturalistic depression course than were life events. These findings suggest that
      insufficient social support is a particularly strong prospective predictor of
      elevated depressive symptomatology. Determining the quality of patients' social
      support networks should be a regular part of clinical assessment, and efforts
      should be made to help depressed patients establish supportive relationships both
      in the therapeutic environment and in their personal lives.

PMID- 12415535
TI  - Interpersonal psychotherapy delivered over the telephone to recurrent
      depressives. A pilot study.
AB  - Rates of recurrent depression peak among women in their childbearing years, yet a
      large number of these women are not treated or do not seek maintenance treatment
      between episodes. Barriers to treatment include time constraints, demands of
      child care, and finances. A method for improving access to treatment of
      depression may be delivery of psychotherapy over the telephone. A 12-week pilot
      controlled clinical trial with random assignment was conducted to test the
      feasibility and efficacy of Interpersonal Psychotherapy delivered over the
      telephone (IPT-T) for depression in women (N=15 IPT-T and N=15 no treatment) with
      a life-time history of recurrent depression and low rates of previous treatment.
      Patients were interviewed at baseline and at 12 weeks by a blind and independent
      clinical evaluator to assess their symptom level and social functioning. IPT-T as
      compared to no treatment was significantly better in lowering symptoms of
      depression as measured by the Hamilton Rating Scale for Depression (p<.02),
      improving global functioning (GAS) (p<.02), and improving work and social
      functioning (p<.03-.05, respectively). These preliminary findings support the
      feasibility and helpfulness of IPT-T in preventing an increase in depressive
      symptoms among women with recurrent depression but current mild to moderately
      levels of depression.

PMID- 12415536
TI  - A cross-national relationship between sugar consumption and major depression?
AB  - We have preliminarily investigated the hypothesis that sugar consumption may
      impact the prevalence of major depression by correlating per capita consumption
      of sugar with the prevalence of major depression. Major depression prevalence
      data (annual rate/100) was obtained from the Cross-National Epidemiology of Major
      Depression and Bipolar Disorder study [Weissman et al., 1996]. Sugar consumption
      data from 1991 was obtained from the Food and Agricultural Organization of the
      United Nations. For the primary analysis, sugar consumption rates (cal/cap/day)
      were correlated with the annual rate of major depression, using the Pearson
      correlation coefficient. For the six countries with available data for the
      primary analysis, there was a highly significant correlation between sugar
      consumption and the annual rate of depression (Pearson correlation 0.948,
      P=0.004). Naturally, a correlation does not necessarily imply etiology. Caveats
      such as the limited number of countries with available data must be considered.
      Although speculative, there are some mechanistic reasons to consider that sugar
      consumption may directly impact the prevalence of major depression. Possible
      relationships between sugar consumption, beta-endorphins, and oxidative stress
      are discussed.

PMID- 12415537
TI  - Naturalistic study of the early psychiatric use of citalopram in the United
      States.
AB  - We obtained information on the efficacy and safety of citalopram in settings that
      resemble actual clinical practice. A total of 1,783 patients participated in this
      open, uncontrolled, naturalistic Phase IV evaluation of citalopram at 447 U.S.
      investigative sites. Participants were selected by guidelines in the citalopram
      package insert using minimal exclusion criteria. Citalopram dosing began at 20
      mg/day and could be titrated to 60 mg/day. Outcomes included the Clinical Global
      Impressions-Improvement scale (CGI-I) and a Patient Global Evaluation. Separate
      analyses were performed on patients with a primary diagnosis of major depressive
      disorder (MDD) (76%) who reported intolerance or nonresponse to previous
      selective serotonin reuptake inhibitors (SSRIs). Patients included tended to have
      treatment-resistant or intolerant, chronic or recurrent, comorbid depression with
      a mean duration of illness of 10 years. At study completion, more than 68% of
      treatment completers were classified as responders (CGI-I score of 1 or 2).
      Endpoint analyses showed response rates of 54% in all patients, 56% in patients
      with MDD, 49% in SSRI nonresponsive patients, and 53% in patients with a history
      of SSRI intolerance. Nausea (9.8%) and headache (7.3%) were the most often
      reported adverse events. Patients with a history of SSRI intolerance had a
      discontinuation rate of 21.8%, whereas those without such a history had a
      discontinuation rate of 13.3%. Citalopram administered at an average dose of 23.6
      mg/day was associated with favorable outcomes and was generally well tolerated.

PMID- 12415538
TI  - Citalopram treatment of paroxetine-intolerant depressed patients.
AB  - We assessed the tolerability and antidepressant response to citalopram in a group
      of patients who could not tolerate a recent trial of paroxetine therapy. Sixty
      one outpatients with major depressive disorder and a confirmed history of
      intolerance to paroxetine (mean final dose: 26.7 mg/day) were switched after at
      least a 1 week washout to citalopram therapy (20 mg/day). During the 6-week, open
      label treatment protocol, citalopram could be titrated up to a maximum dose of 40
      mg/day. Response was evaluated using the Clinical Global Impressions CGI scale,
      the 24-item Hamilton Rating Scale for Depression, and several other measures of
      symptoms and quality of life. Fifty-three patients (87%) completed 6 weeks of
      citalopram therapy (mean intent-to-treat dose: 23.9 mg/day). The specific side
      effects that were reported to be intolerable during the earlier paroxetine trial
      typically recurred only less than 30% of the time during citalopram therapy; only
      6 patients (10%) dropped out because of adverse events. The intent-to-treat CGI
      response rate was 56% at study endpoint; 62% of the completers responded.
      Significant improvement from pretreatment was observed on various symptom
      measures after two weeks of citalopram therapy. Citalopram therapy was well
      tolerated, and more than one half of the patients who began treatment improved
      significantly. Although further work is necessary to assess the relative merits
      of this within-class switching strategy (as compared to other options), these
      data provide further evidence that the various selective serotonin reuptake
      inhibitors do not have interchangeable tolerability profiles.

PMID- 12415539
TI  - Electrospray ionization tandem mass spectrometric study of the aconitines in the
      roots of aconite.
AB  - Fragmentation pathways of aconitine-type alkaloids were investigated by
      electrospray ionization/ion trap multistage tandem mass spectrometry. Low-energy
      collision-induced dissociation of protonated aconitines follows a dominant first
      step, the elimination of the C(8)-substituent as acetic acid or fatty acid in
      MS(2) spectra. Successive losses of 1-4 CH(3)OH molecules, 1-3 H(2)O, CO, benzoic
      acid, and CH(3) or C(2)H(5) (N-substituents) are all fragmentation pathways
      observed in MS(3) and MS(4) spectra. By applying knowledge of these fragmentation
      pathways to the aconitines in the ethanolic extract of aconite roots, all the
      known aconitines were detected and also 23 unknown aconitine-type alkaloids, in
      which the lipo-alkaloids containing residues of 15C, 17C and 19C saturated or
      unsaturated fatty acids were characterized. These odd-carbon-number fatty acid
      substituents have not been reported previously.

PMID- 12415540
TI  - Identification of proteins in human cerebrospinal fluid using liquid-phase
      isoelectric focusing as a prefractionation step followed by two-dimensional gel
      electrophoresis and matrix-assisted laser desorption/ionisation mass
      spectrometry.
AB  - Cerebrospinal fluid (CSF) is in close proximity to the brain and changes in the
      protein composition of CSF may be indicative of altered brain protein expression
      in neurodegenerative disorders. Analysis of brain-specific proteins in CSF is
      complicated by the fact that most CSF proteins are derived from the plasma and
      tend to obscure less abundant proteins. By adopting a prefractionation step prior
      to two-dimensional gel electrophoresis (2-DE), less abundant proteins are
      enriched and can be detected in complex proteomes such as CSF. We have developed
      a method in which liquid-phase isoelectric focusing (IEF) is used to
      prefractionate individual CSF samples; selected IEF fractions are then analysed
      on SYPRO-Ruby-stained 2-D gels, with final protein identification by matrix
      assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI
      TOFMS). To optimise the focusing of the protein spots on the 2-D gel, the
      ampholyte concentration in liquid-phase IEF was minimised and the focusing time
      in the first dimension was increased. When comparing 2-D gels from individual
      prefractionated and unfractionated CSF samples it is evident that individual
      protein spots are larger and contain more protein after prefractionation of CSF.
      Generally, more protein spots were also detected in the 2-D gels from
      prefractionated CSF compared with direct 2-DE separations of CSF. Several
      proteins, including cystatin C, IgM-kappa, hemopexin, acetyl-coenzyme A
      carboxylase-alpha, and alpha-1-acid glycoprotein, were identified in
      prefractionated CSF but not in unfractionated CSF. Low abundant forms of
      posttranslationally modified proteins, e.g. alpha-1-acid glycoprotein and alpha-2
      HS glycoprotein, can be enriched, thus better resolved and detected on the 2-D
      gel. Liquid-phase IEF, as a prefractionation step prior to 2-DE, reduce sample
      complexity, facilitate detection of less abundant protein components, increases
      the protein loads and the protein amount in each gel spot for MALDI-MS analysis.

PMID- 12415541
TI  - Structural determination of hexadecanoic lysophosphatidylcholine regioisomers by
      fast atom bombardment tandem mass spectrometry.
AB  - The structural determination of sn-1 and sn-2 hexadecanoic
      lysophosphatidylcholine (LPC) regioisomers was carried out using fast atom
      bombardment tandem mass spectrometry (FAB-MS/MS). The collision-induced
      dissociation (CID) of protonated and sodiated molecules produced diverse product
      ions due mainly to charge remote fragmentations. Based on the information
      obtained from the CID spectra of protonated and sodiated molecules, sn-1 and sn-2
      hexadecanoic LPC isomers could be discriminated. Especially, the abundance ratio
      of the diagnostic ion pair [m/z 224/226] in the CID spectra of [M + H](+) ions
      was shown to be greatly different. Moreover, the CID-MS/MS spectra of sodium
      adducted molecules for hexadecanoic LPC isomers showed characteristic product
      ions such as [M + Na - 103](+), [M + Na - 85](+), and [M + Na - 59](+), by which
      their regio-specificity can be differentiated.

PMID- 12415542
TI  - Investigation of cytolysin variants by peptide mapping: enhanced protein
      characterization using complementary ionization and mass spectrometric
      techniques.
AB  - Matrix-assisted laser desorption/ionization (MALDI) and electrospray ionization
      (ESI) have been used in conjunction with time-of-flight (TOF) and quadrupole ion
      trap (IT) mass spectrometry, respectively, to analyze various cytolysin proteins
      isolated from the sea anemone Stichodactyla helianthus and digested by the
      protease trypsin. By employing different ionization methods, the subsequent
      changes in ionization selectivity for the peptides in the digested protein
      samples resulted in ion abundance variation reflected in the mass spectra. Upon
      investigation of this variation generated by the two ionization processes, it has
      been shown in this study that enhanced protein coverage (e.g., >95% for cytolysin
      III) can be achieved. Additionally, capillary and microbore reversed-phase high
      performance liquid chromatography (RP-HPLC) coupled with ESI mass spectrometry
      (MS) as well as flow injection analysis by nanoflow ESI-MS afforded the necessary
      limit of detection (LOD) for detailed structural information of the cytolysin
      proteins by tandem mass spectrometry (MS/MS) methods. It can be concluded that
      cytolysins II and III correspond to sticholysins I and II, that "cytolysin I" is
      a mixture of modified forms of cytolysins II and III, and that "cytolysin IV" is
      an incompletely processed precursor of cytolysin III.

PMID- 12415543
TI  - Delta13C and delta18O isotopic composition of CaCO3 measured by continuous flow
      isotope ratio mass spectrometry: statistical evaluation and verification by
      application to Devils Hole core DH-11 calcite.
AB  - A new method was developed to analyze the stable carbon and oxygen isotope ratios
      of small samples (400 +/- 20 micro g) of calcium carbonate. This new method
      streamlines the classical phosphoric acid/calcium carbonate (H(3)PO(4)/CaCO(3))
      reaction method by making use of a recently available Thermoquest-Finnigan
      GasBench II preparation device and a Delta Plus XL continuous flow isotope ratio
      mass spectrometer. Conditions for which the H(3)PO(4)/CaCO(3) reaction produced
      reproducible and accurate results with minimal error had to be determined. When
      the acid/carbonate reaction temperature was kept at 26 degrees C and the reaction
      time was between 24 and 54 h, the precision of the carbon and oxygen isotope
      ratios for pooled samples from three reference standard materials was </=0.1 and
      </=0.2 per mill or per thousand, respectively, although later analysis showed
      that materials from one specific standard required reaction time between 34 and
      54 h for delta(18)O to achieve this level of precision. Aliquot screening methods
      were shown to further minimize the total error. The accuracy and precision of the
      new method were analyzed and confirmed by statistical analysis. The utility of
      the method was verified by analyzing calcite from Devils Hole, Nevada, for which
      isotope-ratio values had previously been obtained by the classical method. Devils
      Hole core DH-11 recently had been re-cut and re-sampled, and isotope-ratio values
      were obtained using the new method. The results were comparable with those
      obtained by the classical method with correlation = +0.96 for both isotope
      ratios. The consistency of the isotopic results is such that an alignment offset
      could be identified in the re-sampled core material, and two cutting errors that
      occurred during re-sampling then were confirmed independently. This result
      indicates that the new method is a viable alternative to the classical reaction
      method. In particular, the new method requires less sample material permitting
      finer resolution and allows automation of some processes resulting in
      considerable time savings.

PMID- 12415544
TI  - Amino acid residue specific stable isotope labeling for quantitative proteomics.
AB  - Various stable isotope labeling (SIL) techniques have recently emerged to improve
      the efficiency and accuracy of protein quantitation by mass spectrometry (MS). We
      have developed a mass-tagging strategy to incorporate stable isotope tagged amino
      acids into cellular proteins in a residue-specific manner during cell growth. In
      this study, we further extend this residue-specific SIL approach to the accurate
      quantitation of protein abundances in different cell populations. For proteins
      whose expression levels are the same in cells grown in the normal and labeled
      media, the relative areas of the normal (light) and labeled (heavy) isotopic
      peaks are linearly correlated with the cells mixing ratios. This approach was
      first used to determine the effect of the zinc-responsive transcription factor
      Zap1 on the yeast proteome. Ten protein spots from a PAGE gel were chosen
      randomly and their differential protein expression levels in wild-type and
      zap1delta cells were readily determined by the isotopic ratio. Methionine
      synthase (Met6) was identified to be up-regulated more than four times in the
      zap1delta mutant strain whereas the expression level of other nine proteins
      remained unchanged. Further, we applied this strategy to study the cellular
      response to radiation in human skin fibroblast cells. Analyzing one protein band
      randomly selected from SDS-PAGE, the expression level of a novel protein was
      found to increase two-fold in response to radiation whereas the expression level
      of a control protein remained unchanged. This strategy is generally applicable
      using any particular type of amino acid as the labeling precursors for accurate
      quantitation of protein relative abundances.

PMID- 12415545
TI  - Structural characterisation of underivatised olive pulp xylo-oligosaccharides by
      mass spectrometry using matrix-assisted laser desorption/ionisation and
      electrospray ionisation.
AB  - Purified olive pulp glucuronoxylans, with a Xyl/GlcA ratio of 7:1, were subjected
      to mild acid hydrolysis and the mixture of oligosaccharides obtained was
      fractionated by size exclusion chromatography. One elution fraction
      representative of low molecular weight oligosaccharides was analysed by mass
      spectrometry using matrix-assisted laser desorption/ionisation (MALDI) and
      electrospray ionisation (ESI) as ionisation methods, in the positive mode. Both
      types of spectra showed cationised molecules [M + Na](+) of xylo-oligosaccharides
      in a range below m/z 1,000. The xylo-oligosaccharide structures identified were
      series of neutral oligosaccharides of xylose (Xyl(n), n = 3-7), of acidic
      oligosaccharides substituted by one glucuronic acid (Xyl(n)GlcA, n = 3-5) and by
      two glucuronic acid residues (Xyl(n)GlcA(2), n = 2 and 3), and also of acidic
      oligosaccharides substituted with one 4-O-methylglucuronic acid residue
      (Xyl(n)meGlcA, n = 2-4). The proposed structures were confirmed by tandem mass
      (MS/MS) spectra obtained using collision induced dissociation of the molecular
      ions. Fragmentation of cationised adducts of neutral Xyl(n) yielded C- and A-type
      fragments, while ammonium adducts mainly yielded B-type fragments. The
      fragmentation of the sodium adducts of acidic oligosaccharides (Xyl(n)meGlcA,
      Xyl(n)GlcA) resulted in the loss of the substituting residue (GlcA or meGlcA) as
      the predominant fragment, while the corresponding ammonium adducts yielded B-type
      fragments.

PMID- 12415546
TI  - Enhanced mass detection of oligonucleotides using reverse-phase high-performance
      liquid chromatography/electrospray ionization ion-trap mass spectrometry.
AB  - A new method providing enhanced sensitivity for the analysis of oligonucleotides
      using an on-line coupled system of reversed-phase high-performance liquid
      chromatography (RP-HPLC) and electrospray ionization ion-trap mass spectrometry
      (ESI-MS) has been developed. The presented method allows the use of the standard
      gradient elution of 0.1 M triethylammonium acetate (TEAA) buffer (adjusted to pH
      7.0 with acetic acid) and acetonitrile that is typically used for the separation
      of oligonucleotides in RP-HPLC. An added feature of this method is the ability to
      combine and mix additional 0.1 M imidazole in acetonitrile after the separation
      column for improved ESI-MS performance. This is similar to the post-column
      reaction method in liquid chromatography (LC) and the liquid sheath flow method
      in LC/ESI-MS, both of which offer the advantage of not compromising the
      chromatographic separation conditions. The application of this new method is
      demonstrated to afford improved sensitivity for the analysis of oligonucleotides
      (20-50 mer) via on-line coupled HPLC/ESI-MS analysis and purification systems.

PMID- 12415547
TI  - Determination of melanotan-II in rat plasma by liquid chromatography/tandem mass
      spectrometry: determination of pharmacokinetic parameters in rat following
      intravenous administration.
AB  - A method is described for the determination of melanotan-II (MT-II), a synthetic
      cyclic heptapeptide analog of alpha-melanocyte-stimulating hormone (alpha-MSH),
      in rat plasma by liquid chromatography/tandem mass spectrometry (LC/MS/MS). The
      analyte is recovered from plasma by solid-phase extraction (SPE) and subsequently
      analyzed by LC/MS/MS. A SPE procedure using OASIS 96-well plates is used for
      extraction of MT-II from rat plasma. Using the described approach a limit of
      quantitation of 5 ng/mL was achieved in rat plasma. This level of sensitivity
      allowed the determination of pharmacokinetic parameters, following intravenous
      administration of MT-II in rat.

PMID- 12415548
TI  - Quantification of volatile compounds in the headspace of aqueous liquids using
      selected ion flow tube mass spectrometry.
AB  - We describe a method by which the concentrations of volatile compounds in the
      headspace of their dilute aqueous solutions in sealed containers can be
      determined using on-line selected ion flow tube mass spectrometry (SIFT-MS).
      Thus, the changing number density of the molecules of the volatile compound in
      the carrier gas of the SIFT-MS instrument is described in terms of its changing
      flow rate as the pressure in the sealed container decreases during the sampling
      procedure. It is shown that the best analytical procedure is to determine the
      mean concentration of the trace gas in the liquid headspace over a given sampling
      time and relate this to the required concentration, which is the initial
      equilibrium concentration established before the pressure in the sealed container
      reduces significantly. To test the validity of this analytical approach, the
      headspace concentrations of acetaldehyde, ethanol and acetone above aqueous
      solutions of known concentrations have been determined. Hence, the Henry's Law
      constants for these compounds have been determined and found to agree with the
      published values. The confirmation of the quality of this sampling methodology
      combined with SIFT-MS for the analysis of volatile compounds in liquid headspace
      paves the way for the rapid analyses of biological liquids such as urine and
      serum for clinical diagnosis and physiological monitoring.

PMID- 12415549
TI  - Chronic treatment with both lithium and sodium valproate may normalize
      phosphoinositol cycle activity in bipolar patients.
AB  - BACKGROUND: It has been proposed that lithium may be clinically effective due to
      its actions on the phosphoinositol second messenger system (PI-cycle). Studies
      have also suggested that untreated manic patients may have raised myo-inositol
      and phosphomonoester (PME) concentrations and also that unmedicated euthymic
      bipolar patients may have lowered PME concentrations. The objective of the
      present study was to test the hypothesis that chronic treatment with either
      lithium or sodium valproate in patients with bipolar mood disorder leads to a
      normalization in the activity of the PI-cycle. METHODS: This study had two parts
      each with different MRS methodology. The first part compared healthy controls (n
      = 19) with euthymic bipolar patients who were taking either lithium (n = 16) or
      sodium valproate (n = 11) using both (1)H-MRS and (31)P-MRS. In the second part
      we examined a separate group of euthymic bipolar disorder patients taking sodium
      valproate (n = 9) and compared these with age and sex-matched healthy controls (n
      = 11) using (1)H-MRS. RESULTS: Both studies showed that there were no differences
      in either myo-inositol or phosphomonoester (PME) concentrations between controls
      and patients taking either medication. CONCLUSIONS: These findings examine two
      key components of the PI-cycle in treated euthymic bipolar (myo-inositol and PME
      concentrations). The results from this study are consistent with the suggestion
      that chronic treatment with either lithium or sodium valproate in bipolar
      patients may normalize PI-cycle functioning.

PMID- 12415550
TI  - The efficacy of reboxetine in the treatment-refractory patients with panic
      disorder: an open label study.
AB  - BACKGROUND AND OBJECTIVE: Selective serotonin reuptake inhibitors (SSRIs) are
      currently the first-line treatment for panic disorder, although up to 30% of
      patients either do not respond to SSRIs or withdraw due to adverse events.
      Reboxetine, a selective norepinephrine reuptake inhibitor (selective NRI), is
      effective in treating depression and may alleviate depression-related anxiety.
      This study aimed to investigate the efficacy of reboxetine in the treatment of
      patients with panic disorder who did not respond to SSRIs. METHOD: In this 6
      week, open-label study, 29 adult outpatients with panic disorder who had
      previously failed to respond to SSRI treatment received reboxetine 2 mg/day,
      titrated to a maximum of 8 mg/day over the first 10 days. Efficacy was assessed
      using the Panic Self-Questionnaire (PSQ), the Hamilton Rating Scale for Anxiety
      (HAM-A), the 17-item Hamilton Rating Scale for Depression (HRSD) and the Global
      Assessment of Functioning (GAF) Scale. RESULTS: The 24 patients who completed the
      study responded well to reboxetine treatment. Significant improvement (p < 0.001)
      was observed in the number of daily panic attacks, and on the scales measuring
      anxiety, depression and functioning. Reboxetine was generally well tolerated.
      Five patients withdrew due to adverse events. CONCLUSIONS: Reboxetine appears to
      be effective in the treatment of SSRI-refractory panic disorder patients and
      warrants further clinical investigation.

PMID- 12415551
TI  - Safety and efficacy of high dose of venlafaxine XL in treatment resistant major
      depression.
AB  - AIM: The aim of the study was to look at efficacy and the safety profile of high
      dose (450-600 mg) venlafaxine XL in five patients with treatment resistant major
      depressive illness. METHODS: Five patients with treatment resistant depression
      were treated with high dose venlafaxine XL. Efficacy was evaluated using the
      Montgomery-Asberg depression rating scale (MADRS), the 21-item Hamilton rating
      scale for depression (HAM-D-21) and the clinical global impressions (CGI) scale.
      Level of functioning was evaluated by social adaptation self-evaluation scale
      (SASS). Body weight, supine pulse and blood pressure were recorded. RESULTS: The
      response rate was based on a 50% decrease in MADRS and HAM-D scores between weeks
      1 and 24. There was a more than 50% decrease in MADRS scores in 3 of 5 patients
      and 4 of 5 patients in HAM-D scores. There was a trend to improvement of SASS
      scores in three of the study patients and in two of them the mean scores were
      within the normal range. Supine pulse and blood pressure remained stable in four
      patients, except in one patient where there was a slight increase although the
      final reading at week 24 was normal. Weight was relatively stable in all three
      patients where it was recorded, but in one patient there was a slight increase
      which may have been due to an atypical neuroleptic the patient was taking at the
      time. CONCLUSION: High dose venlafaxine was safe, well tolerated and effective in
      this small number of severe treatment resistant patients with major depression
      and it also improved social functioning.

PMID- 12415552
TI  - Effects of mirtazapine in patients with post-traumatic stress disorder in Korea:
      a pilot study.
AB  - This study was aimed at testing the efficacy and tolerability of mirtazapine in
      the treatment of Korean patients with chronic post-traumatic stress disorder
      (PTSD). Mirtazapine was administered for 8 weeks using a flexible-dose regime in
      15 Korean patients with PTSD based on the DSM-IV criteria. We evaluated the
      patients at baseline and at weeks 4 and 8 after treatment with the interviewer
      administered structured interview for PTSD (SIP), short PTSD rating interview
      (SPRINT), impact of event scale-revised (IES-R) and the Montgomery Asberg
      depression rating scale (MADRS). Scores on the SIP, SPRINT, IES-R and MADRS had
      significantly reduced after 8 weeks treatment. In this pilot study, mirtazapine
      was found to be effective and well tolerated in the treatment of patients with
      PTSD. This calls for further evaluation of the effect of this drug on subjects
      with PTSD with randomized placebo-controlled studies.

PMID- 12415553
TI  - Clinical and biochemical observations during treatment of depression with
      electroacupuncture: a pilot study.
AB  - Six patients suffering from major depression were treated with
      electroacupuncture. During 4 weeks of treatment, the total CPRS-S-A score
      decreased from 23.8 to 13.4 (p=0.0095). A decrease of neuropeptide Y (NPY) in
      plasma during the first 2 weeks of treatment was noted in five of the patients,
      all being women (p=0.0431). The decrease was negatively correlated with age (rs=
      0.29; p=0.046). The results are in line with a putative antidepressive effect of
      electroacupuncture, along with an influence on NPY in plasma.

PMID- 12415554
TI  - Monitoring the response to rTMS in depression with visual analog scales.
AB  - Visual analog scales (VAS) administered on a daily basis provide a fast and
      reliable method for assessing clinical change during transcranial magnetic
      stimulation (TMS). We treated 40 patients with major depression with TMS and
      assessed their clinical condition with VAS. Response to TMS was defined with the
      Hamilton rating scale for depression and the Global assessment of function scale.
      Nineteen patients of 40 were responders to TMS (when the whole sample was
      considered) whereas 17 of 29 responded when only the non-psychotic patients were
      considered. Patients who eventually responded to TMS demonstrated early changes
      in the VAS scores. We conclude that monitoring with VAS scores can detect early
      response to TMS.

PMID- 12415555
TI  - Combining high and low frequencies in rTMS antidepressive treatment: preliminary
      results.
AB  - The antidepressive potency of repetitive transcranial magnetic stimulation (rTMS)
      seems to depend on variables such as the stimulation placements, different
      frequencies, stimulus intensities, coil shape and interstimulus intervals. The
      aim of this pilot study was to investigate the augmentation properties of rTMS
      combining low and high frequencies. Thirty six depressed medicated in-patients
      were recruited and assigned to three different rTMS treatment modalities as an
      add-on strategy (each n = 12). In group 1 a stimulus intensity of 110% of the
      motor threshold (MT) was used with a frequency of 10 Hz over the left dorsolatero
      prefrontal cortex (DLPC). The right DLPC was stimulated in the same session with
      110% MT at 1 Hz. In group 2 the patients were stimulated only over the left DLPC
      with alternating trains of 110% MT at 10 Hz and trains of 110% MT at 1 Hz in the
      same session. In group 3 the high frequency stimulation over the left DLPC was
      performed as an internal control group. None of the treatment modalities was
      superior but different side effects were observed. These preliminary findings
      suggest that rTMS, at varying frequencies and stimulation placements, evokes
      different psychoactive effects of clinical relevance.

PMID- 12415556
TI  - Quinacrine-induced psychiatric disturbances in a child with common variable
      immunodeficiency and chronic giardiasis.
AB  - Psychiatric disorders due to quinacrine for antiparasitic therapy represent an
      infrequent, but serious, complication. The remarkable course of a 12-year-old boy
      with common variable immunodeficiency who developed severe psychiatric reactions
      following quinacrine therapy for his resistant chronic giardiasis is presented.
      The broad clinical spectrum of quinacrine-associated neuropsychiatric
      disturbances has been emphasized for the clinicians.

PMID- 12415558
TI  - Acute effects of cigarettes in non-deprived smokers on memory, calculation and
      executive functions.
AB  - To determine whether smoking one or two cigarettes daily has effects on cognitive
      functions and the blood nicotine level, we examined 20 smokers and 20 nonsmokers
      as part of a normal daily smoking regimen using psychological tests for memory,
      calculation and association. Subjects underwent Buschke's selective reminding
      test, a mental arithmetic task (multiplication between two digits and one digit)
      and an association task (letter fluency); the duration of each task being 2 min
      under the condition of pre-smoking, one cigarette smoking and two cigarette
      smoking sessions, with an inter-session interval of 50 min. The total recall or
      correct responses were evaluated. The results showed that performance
      deteriorated in the later sessions in the memory task, whereas it improved in the
      later sessions in the calculation and association tasks, with no group (smoker
      nonsmoker) difference, nor interaction between tasks and groups in each task.
      Plasma nicotine increased by 10 ng/ml immediately after smoking a cigarette, and
      14 ng/ml immediately after smoking two cigarettes, but decreased to the pre
      smoking level or slightly higher 10 min after smoking. These findings suggested
      that a daily dose of nicotine had little effect on the performance related to
      memory, calculation and mental association.

PMID- 12415557
TI  - Evidence for a relationship between daily caffeine consumption and accuracy of
      time estimation.
AB  - The present study examined the relationship between regular caffeine consumption
      and time estimation. Sixty participants (aged 18-57 years, mean 24 years)
      completed a 47 s time estimation exercise and questionnaires related to daily
      caffeine consumption and perceptions of time. We hypothesized that the effects of
      caffeine on time estimation would follow a U-shaped pattern such that individuals
      who reported moderate amounts of daily caffeine would be more accurate in their
      perceptions of time than would those who reported high amounts of caffeine intake
      or no daily caffeine consumption. Timing accuracy was computed by dividing
      participant-reported time by actual time (47 s). Timing accuracy followed a U
      shaped curve such that those respondents who reported 'low' daily caffeine
      consumption (< or = 135 mg/day, n = 24) were the most accurate in their time
      estimates (mean= 44.2 s). Individuals who reported no caffeine (mean= 69.3 s; n=
      7) or 'high' daily caffeine consumption (mean=56.2 s; >135 mg/day, n = 28) were
      less accurate in their time estimates [F(2, 56)= 3.34, p< 0.05]. Findings suggest
      that 'low' daily caffeine consumption may enhance time estimation accuracy above
      that of 'high' or no daily caffeine consumption.

PMID- 12415559
TI  - The regulation of mitochondrial physiology by organelle-associated GTP-binding
      proteins.
AB  - Recent studies have shown that GTP-binding proteins can modulate mitochondrial
      membrane fusion and fission. Furthermore, GTP-binding proteins can regulate the
      binding of ribosomes to the mitochondrial membrane and may facilitate the import
      of proteins through contact points between inner and outer mitochondrial
      membranes. Mitochondrial GTP-binding proteins therefore appear to have the
      potential to modulate physiological function of the organelle and may also be
      involved in cellular processes such as cellular transformation. A beginning has
      been made on the characterization of mitochondrial GTP-binding proteins and the
      DNA sequence of one protein has become newly available. Future studies are needed
      to determine whether GTP-binding proteins are interacting with cell signalling
      molecules such as protein kinases in the mitochondria.

PMID- 12415560
TI  - Effects of electromagnetic radiation from a cellular telephone on the oxidant and
      antioxidant levels in rabbits.
AB  - The number of reports on the effects induced by electromagnetic radiation (EMR)
      in various cellular systems is still increasing. Until now no satisfactory
      mechanism has been proposed to explain the biological effects of this radiation.
      Oxygen free radicals may play a role in mechanisms of adverse effects of EMR.
      This study was undertaken to investigate the influence of electromagnetic
      radiation of a digital GSM mobile telephone (900 MHz) on oxidant and antioxidant
      levels in rabbits. Adenosine deaminase, xanthine oxidase, catalase,
      myeloperoxidase, superoxide dismutase (SOD) and glutathione peroxidase activities
      as well as nitric oxide (NO) and malondialdehyde levels were measured in sera and
      brains of EMR-exposed and sham-exposed rabbits. Serum SOD activity increased, and
      serum NO levels decreased in EMR-exposed animals compared to the sham group.
      Other parameters were not changed in either group. This finding may indicate the
      possible role of increased oxidative stress in the pathophysiology of adverse
      effect of EMR. Decreased NO levels may also suggest a probable role of NO in the
      adverse effect.

PMID- 12415561
TI  - Effects of exogenous fatty acids and cholesterol on aminopeptidase activities in
      rat astroglia.
AB  - Several studies have addressed the interaction between fatty acids and lipids
      with central nervous system peptides. Because aminopeptidases (AP) are involved
      in the regulation of neuropeptides, this work studies several AP expressed in
      cultured astroglia, after exogenous addition of oleic and linoleic fatty acids
      and cholesterol to the culture medium. Alanyl-AP, arginyl-AP, cystyl-AP, leucyl
      AP, tyrosyl-AP and pyroglutamyl-AP activities were analysed in whole cells using
      the corresponding aminoacyl-beta-naphthylamides as substrates. Oleic acid
      inhibits alanyl-AP, cystyl-AP and leucyl-AP activities, whereas linoleic acid
      inhibits alanyl-AP, arginyl-AP and tyrosyl-AP activities. Neither oleic acid nor
      linoleic acid modifies pyroglutamyl-AP activity. In contrast, cholesterol
      increases arginyl-AP, cystyl-AP, leucyl-AP, tyrosyl-AP and pyroglutamyl-AP
      activities, although it does not modify alanyl-AP activity. The changes reported
      here suggest that oleic and linoleic fatty acids and cholesterol can modulate
      peptide activities via their degradation route involving aminopeptidases; each of
      them being differentially regulated.

PMID- 12415562
TI  - The effect of quercetin on renal ischemia and reperfusion injury in the rat.
AB  - Renal ischemia-reperfusion injury occurs in many clinical conditions such as
      hypovolemic shock, thromboembolism, injury and after renal transplantation. Under
      these conditions, ROS are considered to be the reason for cellular damage.
      Bioflavonoids have antioxidant and renoprotective properties. We studied the
      effect of quercetin, a bioflavonoid, on ischemia and reperfusion in rats. The
      rats (n = 28) were separated into three groups. Group I was the control group.
      Animals in groups II (IR) and III (IR + Q) underwent 30 min ischemia and 45 min
      reperfusion, respectively. Rats, in group III, also received 50 mg kg(-1)
      quercetin before 45 min of reperfusion. The activities of SOD, CAT, GPx, and
      concentrations of GSH and GSSGR were determined in renal cortex and erythrocytes.
      Also, the levels of MDA in renal cortex and plasma, and XO in renal cortex were
      measured in these groups. The renal cortex XO levels in the IR group were higher
      than that of the control and IR+Q groups (p<0.001). The renal cortex and plasma
      MDA levels in the IR group were also found to be higher than the control and IR+Q
      groups (p<0.01, and p<0.001, respectively). However, a decrease in MAD level of
      the IR+Q group was found in renal cortex and erythrocytes. In addition, SOD, CAT,
      and GPx activities in renal cortex and erythrocytes of quercetin-treated animals
      were enhanced compared to animals of the IR group. Furthermore, there were no
      significant differences in the SOD, CAT, and GPx activities of the control and
      IR+Q group. A reduction of GSH and GSSGR levels in IR and IR+Q groups was
      detected but no significant differences were found between these groups. This
      study stresses that high concentration of ROS leads to renal ischemia and
      reperfusion, and quercetin reduces the renal injury by preventing the oxidative
      stress dependent on ischemia and reperfusion. Quercetin may be used in renal
      transplantation as an antioxidant drug.

PMID- 12415563
TI  - Effects of cod liver oil on tissue antioxidant pathways in normal and
      streptozotocin-diabetic rats.
AB  - Lipid disorders and increased oxidative stress may exacerbate some complications
      of diabetes mellitus. Previous studies have implicated the beneficial effects of
      some antioxidants, omega-3 polyunsaturated fatty acids (PUFAs), eicosapentaenoic
      acid (EPA) and docosahexaenoic acid (DHA) in the protection of cells from the
      destructive effect of increased lipids and lipid peroxidation products. This
      study, therefore, was designed to investigate the effects of cod liver oil (CLO,
      Lysi Ltd. Island), which comprises mainly vitamin A, PUFAs, EPA and DHA. Effects
      were monitored on plasma lipids, lipid peroxidation products (MDA) and the
      activities of antioxidant enzymes, glutathione peroxidase (GSHPx) and catalase in
      heart, liver, kidney and lung of non-diabetic control and streptozotocin (STZ)
      induced-diabetic rats. Two days after STZ-injection (55 mg kg(-1) i.p.), non
      diabetic control and diabetic rats were divided randomly into two groups as
      untreated or treated with CLO (0.5 ml kg(-1) rat per day) for 12 weeks. Plasma
      glucose, triacylglycerol and cholesterol concentrations were significantly
      elevated in 12-week untreated-diabetic animals; CLO treatment almost completely
      prevented these abnormalities in triacylglycerol and cholesterol, but
      hyperglycaemia was partially controlled. CLO also provided better weight gain in
      diabetic animals. In untreated diabetic rats, MDA markedly increased in aorta,
      heart and liver but was not significantly changed in kidney and lung. This was
      accompanied by a significant increase in both GSHPx and catalase enzyme
      activities in aorta, heart, and liver of diabetic rats. In kidney and lung,
      diabetes resulted in reduced catalase while GSHPx was significantly activated. In
      aorta, heart, and liver, diabetes-induced changes in MDA were entirely prevented
      by CLO treatment. In the tissues of CLO-treated diabetic animals, GSHPx activity
      paralleled those of control animals. CLO treatment also caused significant
      improvements in catalase activities in every tissue of diabetic rats, but failed
      to affect MDA and antioxidant activity in control animals. The current study
      suggests that the treatment of diabetic rats with CLO provides better control of
      glucose and lipid metabolism, allows recovery of normal growth rate, prevents
      oxidative/peroxidative stress and ameliorates endogenous antioxidant enzyme
      activities in various tissues. Because CLO contains a plethora of beneficial
      compounds together, its use for the management of diabetes-induced complications
      may provide important advantages.

PMID- 12415564
TI  - Effect of 4-hydroxynonenal, a lipid peroxidation product, on exocytosis in HL-60
      cells.
AB  - Our work analysed the effect of 4-hydroxynonenal (HNE), a chemotactic aldehydic
      end-product of lipid peroxidation, on exocytosis in HL-60 cells. We measured the
      release of beta-glucuronidase, an enzyme of azurophil granules, from the cells
      incubated at 37 degrees C for 10 min in the presence of HNE concentrations
      ranging between 10(-8) and 10(-5) M. The release of lactate dehydrogenase was
      assayed to test cell viability. HNE (1 microM) was able to induce a significant
      and strong stimulation of beta-glucuronidase secretion without leading to
      cytotoxic effects. The finding that HNE could increase the exocytotic secretion
      from HL-60 cells together with its known chemotactic property supports the
      hypothesis that this lipid peroxidation product may play an important role as a
      chemical mediator of inflammation; moreover it is noteworthy that micromolar
      concentrations of HNE have actually been found in exudates from acute and chronic
      inflammations.

PMID- 12415566
TI  - Incorporation of [1-14C]-linoleic acid by LLC-WRC256 tumour cells.
AB  - The incorporation of [(14)C]-linoleic acid (LA) into total lipid fractions was
      higher in LLC-WRC256 cells from the log phase of growth as compared to those of
      the plateau phase. LA was mainly incorporated into the phospholipid (PL) fraction
      of cells during the log phase, whereas in the plateau phase it was mostly taken
      into cholesterol ester. The proportion of radioactivity was higher in
      phosphatidylserine of cells from the log phase, whereas in the plateau phase it
      was higher in phosphatidylcholine. This feature of LA incorporation may be an
      important factor in determining the proliferative capacity of tumour cells.

PMID- 12415565
TI  - CD157, the Janus of CD38 but with a unique personality.
AB  - CD157 is a pleiotropic ectoenzyme which belongs to the CD38 family and to the
      growing number of leukocyte surface molecules known to act independently as both
      receptors and enzymes. A 45-kDa surface structure with a GPI anchor, the CD157
      molecule displays two distinct domains in its extracellular component. The first
      is implicated in the enzymic activities of the molecule and the second features
      adhesion/signalling properties. CD157 shares several characteristics with CD38,
      including a similar amino acid sequence and enzymic functions. Both molecules are
      involved in the metabolism of NAD(+), and the CD157 gene is synthenic on 4p15
      with CD38, with which it also shares a unique genomic organization. Their
      conservation in phylogeny is striking evidence for their relevance in the life
      and death cycle of the cell.

PMID- 12415567
TI  - Oxidant/antioxidant status in blood of patients with malignant breast tumour and
      benign breast disease.
AB  - The aim of this study was to investigate the alterations in lipid peroxidation
      and antioxidant enzyme defences in the blood of patients with malignant breast
      tumour and benign breast disease. Forty patients with malignant breast tumour, 20
      patients with benign breast disease and also 20 healthy control subjects were
      recruited for the study. Malondialdehyde levels in plasma and erythrocytes, and
      the activities of erythrocyte CuZn-superoxide dismutase, catalase, glutathione
      peroxidase and glucose-6-phosphate dehydrogenase were measured. Malondialdehyde
      levels were higher in patients with both benign breast disease and malignant
      breast tumour compared with control subjects. The activities of all antioxidant
      enzymes were higher in patients with malignant breast tumour, while only
      glutathione peroxidase and CuZn-superoxide dismutase activities were higher in
      patients with benign breast disease. Except for glucose-6-phosphate
      dehydrogenase, the antioxidant enzymes studied correlated positively with the
      malondialdehyde levels in patients with malignant breast tumour. On the other
      hand, only glucose-6-phosphate dehydrogenase activity was increased by the level
      of malignancy. The activity increases in erythrocyte antioxidant enzymes may be a
      compensatory upregulation in response to increased oxidative stress especially in
      patients with malignant breast tumour.

PMID- 12415568
TI  - Interleukin-18 enhances HIV-1 production in a human chronically-infected T cell
      line (H9-V).
AB  - Interleukin-18 (IL-18) is a recently identified immunoregulatory cytokine
      expressed by activated macrophages, that induces production of interferon-gamma
      (IFN-gamma) and Th-1 development. Recently some investigators reported
      controversial in vitro data on IL-18 stimulation of HIV-1 replication in several
      cell lines. In the present study the effect of IL-18 on HIV replication in a
      human chronically HIV-1-infected lymphocytic T cell line (H9-V) was investigated.
      HIV-1 replication was determined by an immunoassay method in order to evaluate
      the content of p24 antigen in the cell culture supernatants. Stimulation of H9-V
      cells with IL-18 resulted in increased production of p24, especially at
      concentrations of 0.01 microg ml(-1) and 0.10 microg ml(-1). Moreover a
      significant and persistent IL-18 stimulation of HIV-1 replication was observed at
      a concentration of 0.01 microg ml(-1) during a 7-day period. Pre-treatment of IL
      18 with a specific neutralizing monoclonal antibody significantly reduced HIV-1
      replication. These experiments show that IL-18 promotes the increase of HIV-1
      replication in human chronically-infected lymphocytic T cells and confirm the
      role of IL-18 as a proimflammatory cytokine in stimulating and maintaining HIV-1
      replication during the course of the disease. In a successive set of experiments,
      since one of the main activities of IL-18 is the induction of IFN-gamma, we
      evaluated the effect of this biological modifier on H9-V cells. In particular,
      IFN-gamma shows a significant effect on cell replication and on reduction of CD4
      and CD71 surface expression.

PMID- 12415569
TI  - Agonists of proteinase-activated receptor 2 induce TNF-alpha secretion from
      astrocytoma cells.
AB  - Proteinase-activated receptor 2 (PAR2) is cleaved and activated by trypsin or
      mast cell tryptase, and may play an important role in inflammation. We have
      investigated the potential of PAR2 agonists to modulate TNF-alpha secretion from
      human astrocytoma cell line CCF-STTG1. We found that CCF-STTG1 expresses PAR2 by
      RT-PCR and Western blot analysis. Agonists such as trypsin, the peptide SLIGKV
      NH(2) (corresponding to the PAR2 tethered ligand), or mast cell tryptase directly
      signal to CCF-STTG1 to stimulate secretion of TNF-alpha but do not stimulate in
      the presence of soybean trypsin inhibitor (SBTI) or VKGILS-NH(2) (reverse
      peptide). The secretion of TNF-alpha by trypsin was significantly blocked by
      pretreatment with either 50 microM PD98059 or 1 microM SB203580. Furthermore,
      trypsin stimulated the activation of extracellular signal-regulated kinase (ERK)
      and p38 MAP kinase homologue in CCF-STTG1 without any detectable activation of c
      Jun N-terminal kinase (JNK). These results show that trypsin may induce TNF-alpha
      secretion following activation of ERK and p38 via PAR2 in CCF-STTG1.

PMID- 12415570
TI  - Dietary influence of selenium on the incidence of N-nitrosodiethylamine-induced
      hepatoma with reference to drug and glutathione metabolizing enzymes.
AB  - The dietary administration of selenium (sodium selenite; 4 p.p.m.) daily has been
      found to be highly effective in reducing the incidence of cancer induced by N
      nitrosodiethylamine (DEN) in Wistar strain rats. Selenium treatment either before
      initiation, during initiation and selection/phenobarbital promotion phases of
      hepatocarcinogenesis has been found to be effective in elevating hepatic
      microsomal cytochrome b(5), NADPH-cytochrome C reductase and cytosolic aryl
      hydrocarbon hydroxylase activities to a statistically significant level measured
      either in the hyperplastic nodule or in the surrounding liver tissues compared to
      control animals. Moreover, selenium treatment throughout the study, decreases the
      cytosolic glutathione S-transferase and microsomal UDP-glucuronyl transferase
      activities by a significant degree when compared to control rats. Alterations in
      glutathione metabolizing enzyme activities (glutathione reductase, gamma-glutamyl
      transpeptidase, gamma-glutamylcysteine synthetase and glucose-6-phosphate
      dehydrogenase) were also observed in selenium-treated groups. Our results confirm
      the fact that selenium is particularly protective in limiting the action of DEN
      during the initiation phase of hepatocarcinogenesis.

PMID- 12415571
TI  - Dose-dependent pharmacokinetics and disposition of bisphosphonic prodrug of
      diclofenac based on osteotropic drug delivery system (ODDS).
AB  - Rat pharmacokinetics and in vivo disposition of a novel bisphosphonic prodrug of
      diclofenac (DIC-BP), synthesized with the aim of osteotropic delivery of
      diclofenac, were determined at whole body, organ and cellular levels in a dose
      range 0.32-10mg/kg. With an increase in injected dose, total body clearance was
      decreased while the distribution volume at steady state (V(dss)) was reduced and
      plasma half-life was prolonged. Over 50% of a dose of DIC-BP was selectively
      transported into osseous tissues after intravenous injection into rats at doses
      up to 1mg/kg. As dose increased, the skeletal distribution decreased with hepatic
      and splenic accumulations increasing. The intrahepatic distribution at 10mg/kg
      revealed that liver macrophages play a significant role in hepatic uptake of DIC
      BP. This is consistent with general arguments that bisphosphonates themselves
      cannot distribute in soft tissues, but are taken up by the reticuloendothelial
      system as foreign substances when they form large complexes or aggregate with
      endogenous metals in plasma. Therefore, to optimize the osteotropic delivery of
      diclofenac via a bisphosphonic prodrug, the dosage regimen should be such that
      plasma concentration of DIC-BP is maintained at a level lower than that required
      for precipitate formation of complexes, similar to the usage of other
      bisphosphonates.

PMID- 12415572
TI  - Transporters involved in apical and basolateral uptake of ceftibuten into Caco-2
      cells.
AB  - Ceftibuten uptake from the apical and basolateral side of Caco-2 cells grown on
      transwells was studied. Uptake into the cells showed concentration dependent
      saturation. The apical transporter(s) showed a higher capacity and lower affinity
      for ceftibuten than the basolateral transporter(s). Uptake was inhibited in the
      presence of higher pH and in the presence of 2,4-dinitro phenol (DNP). A proton
      gradient had a greater effect on the apical than on the basolateral transporter.
      Glycyl proline, a dipeptide transport system (PEPT1) substrate, inhibited
      ceftibuten uptake into Caco-2 cells. Benzoic acid, a monocarboxylic acid (MCT)
      transporter substrate also exhibited a strong inhibition of ceftibuten uptake,
      but acetic acid had no effect. Adipic acid inhibited apical uptake of ceftibuten
      but had no effect on the basolateral uptake. None of the inhibitors had a
      significant effect on ceftibuten uptake in absence of a pH gradient. Addition of
      inhibitors in presence of DNP led to a greater decrease in ceftibuten uptake,
      when compared to the effect of DNP alone, indicating a facilitated diffusion
      process. These results indicate that ceftibuten uptake in Caco-2 cells involve
      multiple transport pathways. Apical uptake is mediated by an energy dependent
      carrier-mediated process and an energy independent facilitated diffusion process.
      The apical transport system is different from the basolateral transporter.

PMID- 12415573
TI  - Influence of nonspecific brain and plasma binding on CNS exposure: implications
      for rational drug discovery.
AB  - Relative plasma, brain and cerebrospinal fluid (CSF) exposures and unbound
      fractions in plasma and brain were examined for 18 proprietary compounds in rats.
      The relationship between in vivo brain-to-plasma ratio and in vitro plasma-to
      brain unbound fraction (fu) was examined. In addition, plasma fu and brain fu
      were examined for their relationship to in vivo CSF-to-plasma and CSF-to-brain
      ratios, respectively. Findings were delineated based on the presence or absence
      of active efflux. Finally, the same comparisons were examined in FVB vs. MDR
      1a/1b knockout mice for a selected P-glycoprotein (Pgp) substrate. For the nine
      compounds without indications of active efflux, predictive correlations were
      observed between ratios of brain-to-plasma exposure and plasma-to-brain fu (r(2)
      = 0.98), CSF-to-brain exposure vs. brain fu (r(2) = 0.72), and CSF-to-plasma
      exposure vs. plasma fu (r(2) = 0.82). For the nine compounds with indications of
      active efflux, nonspecific binding data tended to over predict the brain-to
      plasma and CSF-to-plasma exposure ratios. Interestingly, CSF-to-brain exposure
      ratio was consistently under predicted by brain fu for this set. Using a select
      Pgp substrate, it was demonstrated that the brain-to-plasma exposure ratio was
      identical to that predicted by plasma-to-brain fu ratio in MDR 1a/1b knockout
      mice. In FVB mice, plasma-to-brain fu over predicted brain-to-plasma exposure
      ratio to the same degree as the difference in brain-to-plasma exposure ratio
      between MDR 1a/1b and FVB mice. Consistent results were obtained in rats,
      suggesting a similar kinetic behavior between species. These data illustrate how
      an understanding of relative tissue binding (plasma, brain) can allow for a
      quantitative examination of active processes that determine CNS exposure. The
      general applicability of this approach offers advantages over species- and
      mechanism-specific approaches.

PMID- 12415574
TI  - Pharmacokinetics of SB-247083, a potent and selective endothelin(A) receptor
      antagonist, in the rat, dog, and monkey.
AB  - The endothelins (ET) are among the most potent vasoconstrictors identified to
      date, and have been implicated in such diseases as renal failure, pulmonary
      hypertension, atherosclerosis, and congestive heart failure. There is currently
      interest in developing selective antagonists of the ET-A subtype receptor, and
      one such antagonist is SB-247083 ((E)-[1-butyl-5-[2-(2-carboxyphenyl) methoxy-4
      chlorophenyl]-1H-pyrazole-4-yl]-2-[5-methoxydihydrobenzofuran-6-yl]methyl]-2
      propionic acid). This investigation was conducted to evaluate the preclinical
      pharmacokinetics of SB-247083. Clearance of SB-247083 was low to moderate in the
      rat and monkey, and high in the dog. Oral bioavailability of SB-247083
      administered as a solid formulation of the free acid was 24% in the rat, but low
      in the dog (4%) and the monkey (2%). An extensive in vitro salt form and
      formulation screen resulted in the identification of a formulation containing the
      monoarginyl salt with improved dissolution properties. This formulation provided
      a 2- to 4-fold increase in oral bioavailability in each of the preclinical
      species. In the dog, this improvement was reversed by the pre-administration of
      0.1 N HCl to normalize the achlorhydric fasting dog stomach. These data show that
      SB-247083 may have suitable drug properties for progression in development.

PMID- 12415575
TI  - The rewards of taking a hard look at the practice of rheumatology.

PMID- 12415576
TI  - Uveitis associated with juvenile idiopathic arthritis: envisioning the future.

PMID- 12415577
TI  - Measuring disease activity in systemic lupus: progress and problems.

PMID- 12415578
TI  - Early arthritis clinics. Much early arthritis is unclassified.

PMID- 12415579
TI  - Increased expression of arginase II in patients with different forms of
      arthritis. Implications of the regulation of nitric oxide.
AB  - OBJECTIVE: To investigate the expression of arginase isoforms in patients with
      different forms of arthritis and the possible implications of the synthesis of
      nitric oxide (NO). METHODS: Arginase activity was measured in synovial fluid (SF)
      cells from patients with different forms of arthritis, either directly or after
      in vitro stimulation with cytokines. The identity of the isoform expressed was
      confirmed by reverse transcription polymerase chain reaction. We measured both
      arginase activity and NO production in SF macrophages and synovial membrane
      fibroblasts from patients with rheumatoid arthritis (RA). RESULTS: Arginase II
      was the isoform expressed in SF cells. In SF macrophages, dibutyryl-cAMP (dBt
      cAMP), prostaglandin E2 (PGE2), and lipopolysaccharide (LPS) further increased
      the enzyme activity, while NO production was not detected even in the presence of
      Th1-like cytokines. In contrast, synovial membrane fibroblasts from patients with
      RA released NO into the culture media. Moreover, dBt-cAMP, PGE2, and transforming
      growth factor-beta, which induced arginase II, reduced the levels of NO.
      Reciprocally, the induction of NO by Th1 cytokines inhibited arginase activity
      levels. CONCLUSION: Arginase II expression is upregulated in RA and may increase
      cell proliferation by providing L-ornithine, which is the substrate of polyamine
      biosynthesis. In cells where both arginase II and inducible NO synthase activity
      occurs, there is a reciprocal regulation, suggesting that agents that induce
      arginase II in synovial cells could downregulate the levels of NO and divert L
      arginine metabolism toward cell proliferation and/or tissue regeneration.

PMID- 12415580
TI  - Differential expression patterns of secreted frizzled related protein genes in
      synovial cells from patients with arthritis.
AB  - OBJECTIVE: To detect expression of the secreted frizzled related protein (sFRP)
      gene in synovial cells from patients with arthritis. METHODS: Expression of sFRP
      1, 2, 3, 4, and 5 genes was detected in synovial cells from patients with
      rheumatoid arthritis (RA) and osteoarthritis (OA) by semiquantitative reverse
      transcription-polymerase chain reaction (RT-PCR) analysis. To identify synovial
      cell populations expressing sFRP-1, 3, and 4 genes, expression was compared in
      macrophage-rich populations and fibroblast-like cell-rich populations by RT-PCR.
      Levels of expression of these genes were also studied in activated peripheral
      blood mononuclear cells (PBMC) and activated skin fibroblasts. RESULTS:
      Expression of the sFRP-1, 3, and 4 genes was observed in both RA and OA synovial
      cells. sFRP-1 and 4 genes were expressed predominantly in fibroblast-like cell
      rich populations, and the sFRP-3 gene was expressed predominantly in macrophage
      rich populations. Levels of expression of sFRP-3 and 4 genes were elevated in
      activated PBMC and activated skin fibroblasts. CONCLUSION: Our findings suggest
      that sFRP-1, 3, and 4 may play different roles in the pathogenesis of synovitis.

PMID- 12415581
TI  - Antioxidant vitamins and lipid peroxidation in patients with rheumatoid
      arthritis: association with inflammatory markers.
AB  - OBJECTIVE: We evaluated vitamin status in relation to inflammatory markers and
      lipid peroxidation measures in patients with rheumatoid arthritis (RA). METHODS:
      Thirty patients with RA and 30 controls were studied. Lipid profile, vitamin A,
      vitamin E, and inflammatory markers were analyzed in all subjects. Susceptibility
      to low density lipoprotein (LDL) oxidation was evaluated in both groups by
      measuring the kinetics of conjugated dienes induced by hemin. RESULTS: Patients
      and controls had similar lipid profiles, except with LDL cholesterol, which was
      lower in the patients (p < 0.05). Patients had significantly higher plasma levels
      of inflammatory markers with respect to controls (p < 0.01). Plasma levels of
      vitamin A were lower in patients, and similar levels of vitamin E were observed
      in both groups. Oxidative variables, measured as the different phases of
      conjugated diene formation, were similar in patients and controls. We found a
      significant inverse correlation between vitamin A, vitamin E, and secretory type
      II phospholipase A2 in patients. We found a positive correlation between the
      affinity constant of LDL binding to glycosaminoglycans (GAG), Kd-LDL, and the lag
      phase of LDL oxidation (p < 0.05) in patients. CONCLUSION: This report supports
      the hypothesis that chronic inflammation affects antioxidant vitamin levels in
      RA. Combined with the presence of a chronic inflammatory process and high LDL
      affinity for GAG, this may explain the high risk of cardiovascular disease in
      patients with RA.

PMID- 12415582
TI  - Very recent onset arthritis--clinical, laboratory, and radiological findings
      during the first year of disease.
AB  - OBJECTIVE: To describe clinical and radiological findings in patients with very
      early arthritis (< 3 months of symptoms) during one year of observation. METHODS:
      In an Austrian multicenter setting, patients were eligible if they had
      nontraumatic swelling or pain in at least one joint and laboratory signs of
      inflammation [elevated erythrocyte sedimentation rate, C-reactive protein,
      leukocytosis, or rheumatoid factor (RF)] within the last 3 months. Clinical and
      laboratory assessments were performed every 3 months. Radiographs of hands and
      feet were taken at entry and after one year. Treatment decisions were left to the
      discretion of the participating center. RESULTS: In total, 108 patients included
      between 1996 and 2000 had followup investigations during at least one year; 61.1%
      of these patients had rheumatoid arthritis (RA). Over 65% of RA diagnoses were
      made at the first visit. Lag time to referral was significantly longer in
      patients with RA than in patients with other inflammatory joint diseases (median
      8 vs 4 weeks). Disease modifying antirheumatic drugs were started 19 +/- 10 (mean
      +/- SD) weeks after symptom onset in patients with RA. Patients with RA improved
      significantly (by American College of Rheumatology response criteria and the
      Disease Activity Score 28) during the first year. Erosions were present in 12.8%
      of RA patients' initial radiographs, compared to 27.6% after one year. Odds ratio
      to develop new erosions during the first year of RA was 9.7 (95% CI 1.05-89.93)
      in RF+ patients compared to RF- individuals (p < 0.05). CONCLUSION: When early
      referral of patients with arthritis is encouraged, RA can be diagnosed and
      treatment initiated early, with significant clinical response. Moreover, patients
      with RA tend to be referred later than patients with other inflammatory joint
      diseases; RA patients at this very early stage have low frequency of joint
      damage; and RF predicts erosions in the first year.

PMID- 12415583
TI  - A single dose, placebo controlled study of the fully human anti-tumor necrosis
      factor-alpha antibody adalimumab (D2E7) in patients with rheumatoid arthritis.
AB  - OBJECTIVE: To assess the pharmacokinetics, safety profile, and efficacy of the
      fully human anti-tumor necrosis factor-alpha (anti-TNF-alpha) monoclonal antibody
      adalimumab (D2E7) in patients with long-standing, active rheumatoid arthritis
      (RA). METHODS: This was a randomized, double blind, placebo controlled study of
      single intravenous injections of ascending doses (0.5 to 10 mg/kg) of adalimumab
      in 5 cohorts of 24 patients each (18 adalimumab and 6 placebo in all cohorts
      except the 0.5 mg/kg cohort of 17 adalimumab, 7 placebo). A total of 120 patients
      participated (adalimumab 89, placebo 31). The clinical response was measured by
      changes in composite scores defined by the criteria of the European League
      Against Rheumatism (EULAR) and the American College of Rheumatology. RESULTS:
      Single doses of adalimumab showed a rapid onset of clinical effect (24 hours to 1
      week), with peak efficacy at 1 to 2 weeks that was sustained for at least 4 weeks
      and for as long as 3 months in some patients. EULAR response was seen at least
      once during the 4 week period after drug injection in 29% of patients in the
      placebo group as well as in 41%, 78%, 72%, 89%, and 100% in the 0.5, 1, 3, 5, and
      10 mg/kg groups, respectively. No dose related increases in adverse events were
      observed in the adalimumab patients compared with the placebo group. Adalimumab
      systemic drug exposure (AUC0-( )) increased linearly with an increase in dose.
      The mean total serum clearance was 0.012 to 0.017 l/h, and the steady-state
      volume of distribution ranged from 4.7 to 5.5 l. The estimated mean terminal half
      life ranged from 10.0 to 13.6 days for the 5 cohorts, with an overall mean half
      life of 12 days. CONCLUSION: Treatment with the fully human Mab adalimumab was
      safe and well tolerated when administered as a single intravenous injection at
      doses up to 10 mg/kg, and was associated with a clinically significant
      improvement in the signs and symptoms of active RA.

PMID- 12415584
TI  - Bone mineral density in men with rheumatoid arthritis is associated with erosive
      disease and sulfasalazine treatment but not with sex hormones.
AB  - OBJECTIVE: To quantify bone mineral density (BMD) in men with rheumatoid
      arthritis (RA) and to evaluate the influence of various disease-specific and non
      disease-specific variables on bone mass. METHODS: Dual energy x-ray
      absorptiometry was performed in 104 male patients with RA and BMD was measured in
      lumbar spine, femoral neck, trochanter, and Ward's triangle. Inflammatory
      activity, measured as Disease Activity Score including 28 joints (DAS28), degree
      of functional impairment measured with the Health Assessment Questionnaire, and
      sex hormones (bioavailable testosterone, DHEAS, estradiol, and estrone) were
      estimated. Presence of erosions, rheumatoid factor, and current treatment as well
      as body mass index and smoking habits were recorded. Correlations were performed
      with nonparametric tests and multiple regression analyses. RESULTS: BMD was
      reduced in both spine and hip compared to an age matched reference population.
      Erosive disease was the variable with the strongest correlation with BMD.
      Treatment with sulfasalazine correlated positively with BMD at 3 of the 5
      measured bone sites. However, in multivariate analysis significance was sustained
      only in the trochanter region. There were no correlations between the degree of
      inflammation, levels of sex hormones, treatment with corticosteroids, or smoking
      and BMD at any site measured. CONCLUSION: A large proportion of the men with RA
      had reduced bone mass. Sex hormone levels and treatment with corticosteroid did
      not influence BMD, nor did current degree of disease activity. Erosive disease
      was closely correlated with low BMD, whereas sulfasalazine was associated with
      high BMD at least in the trochanter region.

PMID- 12415585
TI  - Detecting radiological changes in rheumatoid arthritis that are considered
      important by clinical experts: influence of reading with or without known
      sequence.
AB  - OBJECTIVE: To evaluate whether knowledge of the chronological sequence influences
      the sensitivity and specificity of the Sharp/van der Heijde (SvH) and
      Larsen/Scott (LS) scoring method to detect clinically important progression of
      joint damage caused by rheumatoid arthritis (RA) in the individual patient and
      assess whether scoring in chronological order leads to better sensitivity at the
      cost of lower specificity. METHODS: For both scoring methods, progression scores
      obtained with (chronological) and without knowledge of the sequence of the films
      (paired) were compared with the judgment of an international expert panel. This
      panel assessed whether progression of joint damage seen on films with 1 year
      intervals was clinically relevant (defined as progression of joint damage that
      would make clinicians change therapy). The applied thresholds for clinical
      relevance were (1) the progression scores with the highest accuracy by receiver
      operating characteristics analyses for the expert opinion, and (2) the smallest
      progression score that can be detected apart from interobserver measurement error
      by the scoring method, i.e., the smallest detectable difference (SDD). RESULTS:
      Progression scores that detected clinically relevant progression most accurately
      (chronological: 3.0 SvH units and 2.0 LS units; paired: 2.5 SvH units and 1.5 LS
      units) were smaller than the SDD (chronological 5.0 SvH units and 5.8 LS units;
      paired 13.8 SvH units and 9.7 LS units). With the SDD as threshold, the
      sensitivity to detect clinically relevant progression increased significantly
      from 20 to 60% for the SvH method and from 23 to 33% for the LS method if the
      sequence of the films was known. The specificity remained good when scoring
      chronologically: 88% for the SvH and 100% for the LS. CONCLUSION: Our results
      suggest that knowing the chronological sequence leads to an increase in detecting
      clinically relevant changes in the patient without serious overestimation of
      nonrelevant differences. Analyzing a clinical trial should be done preferably by
      reading films in chronological order.

PMID- 12415586
TI  - Nodular disease in rheumatoid arthritis: association with cigarette smoking and
      HLA-DRB1/TNF gene interaction.
AB  - OBJECTIVE: To investigate the association of nodular disease in rheumatoid
      arthritis (RA) with smoking, seropositivity, and polymorphisms at HLA-DRB1 and
      TNF loci. METHODS: Consecutive patients with RA (n = 420) attending a hospital
      clinic were examined for the presence of subcutaneous nodules. Rheumatoid factor
      (RF) status and HLA-DRB1 genotype were determined on every patient, and their
      smoking history was recorded. TNFa microsatellite polymorphisms were examined in
      a subgroup of 144 patients. The relationships between smoking, RF status, HLA
      DRB1 genotype, TNFa microsatellite polymorphism, and the presence of nodules were
      examined using chi-square tests and logistic regression analyses. RESULTS:
      Current smokers were more likely to have nodular disease than those who had never
      smoked (OR 1.8, 95% CI 1.0-2.9). An association was also found between RF
      positivity and nodular disease (OR 2.2, 95% CI 1.2-3.8) that remained significant
      after correction for current smoking. A combination of current smoking and
      seropositivity increased the risk of nodular disease (OR 3.9, 95% CI 1.7-9.1).
      Analysis of HLA-DRB1 genotypes in this RA population revealed that only DRB1*0401
      homozygotes were associated with nodular disease, and that this was independent
      of the influence of smoking and seropositivity. Individual TNFa microsatellite
      alleles were not associated with the presence of nodules, but an interactive
      effect was found between the TNF a6 allele and homozygosity for DRB1*0401.
      CONCLUSION: Our data indicate that nodular disease in RA is independently
      associated with current cigarette smoking, seropositivity, and homozygosity for
      HLA-DRB1*0401. The latter association involves a possible interaction with the
      TNF a6 microsatellite allele.

PMID- 12415587
TI  - HLA and cytokine gene polymorphisms in relation to occurrence of palindromic
      rheumatism and its progression to rheumatoid arthritis.
AB  - OBJECTIVE: Palindromic rheumatism (PR) is an episodic arthropathy that may
      precede typical rheumatoid arthritis (RA), although pathogenetic relationships
      between these disorders remain unclear. The predictive value for those
      immunogenetic risk factors implicated in RA for disease progression in PR remains
      to be established. A previous retrospective analysis from our group has
      implicated rheumatoid factor in disease progression. Our objective was to
      determine the contribution of HLA and cytokine gene polymorphisms implicated in
      RA to predisposition to PR and to progression of PR to chronic joint
      inflammation. METHODS: We studied 147 patients with PR seen in a tertiary
      referral center; 87 were selected retrospectively from the period 1986-96 using a
      structured selection process and 60 were selected prospectively in the period
      1997-2001. Comparison groups included 149 patients with RA and 149 ethnically
      matched controls. Typing for HLA-DRB1 alleles and HLA-DRB1-04 subtypes was
      performed following polymerase chain reaction (PCR) amplification using sequence
      specific primers (SSP). Cytokine genotypes were ascertained following PCR-SSP
      with and without digestion with restriction enzymes. Time-adjusted survival
      analysis (Kaplan-Meier) and multivariate logistic regression were used to assess
      the independent contribution of immunogenetic markers in assessing progression of
      PR to chronic joint inflammation. RESULTS: Thirty-one percent of patients
      progressed to connective tissue disease after a mean of 10.6 (retrospective
      group) and 3.9 (prospective group) years. A significantly increased prevalence of
      the shared epitope (SE) allele was noted in patients with PR (65%) versus
      controls (39%) (OR 2.9, 95% CI 1.8-4.6, p < 0.001). This primarily reflected
      increased prevalence of the DRB1-0401 and 0404 and not DRB1-01 alleles. A weak
      contribution to disease susceptibility was also noted with carriage of the IL4
      promoter -590T (OR 1.8, 95% CI 1.1-3.0, p = 0.02) and IL4 intron 3 RP1 (OR 1.7,
      95% CI 1.1-2.9, p = 0.03) alleles. The TNFa +489A allele was associated with RA
      (OR = 2.7, 95% CI 1.5-5.1, p = 0.001) in both SE+ and SE- patients, but not with
      PR. Time-adjusted and multivariate Cox regression analysis revealed that only
      homozygosity for SE alleles was a significant independent risk factor for disease
      progression to chronicity in PR (hazard ratio 2.9, 95% CI 1.2-6.9, p = 0.02).
      However, none of 8 patients homozygous for SE- DRB1 XP4n alleles developed
      chronic disease after 10 years of followup (p = 0.07). CONCLUSION: The
      immunogenetic risk profile for PR resembles that for RA, indicating that PR is
      likely not an independent entity. A significant gene dose effect for SE alleles
      is operative in determining risk for progression from PR to RA.

PMID- 12415588
TI  - Longterm predictors of anxiety and depressed mood in early rheumatoid arthritis:
      a 3 and 5 year followup.
AB  - OBJECTIVE: Heightened levels of anxiety and depressed mood are known to be common
      consequences of rheumatoid arthritis (RA). We examined the role of stress
      vulnerability factors in the longterm course of anxiety and depressed mood in
      patients with early RA. Specifically, the role of personality characteristics
      (neuroticism, extraversion), physical and psychological stressors (clinical
      status, disease influence on daily life, major life events), and coping and
      social support at the time of diagnosis were studied to predict changes in
      anxiety and depressed mood 3 and 5 years later. METHODS: Anxiety and depressed
      mood, predicted from clinical and self-reported assessments of stress
      vulnerability factors at the time of diagnosis in 78 patients with RA were
      assessed again after 3 and 5 years. RESULTS: A worse clinical status, more
      neuroticism, and lower education level at the time of diagnosis were all
      significantly related to increased psychological distress at the 3 and 5 year
      followup. However, the personality characteristics of neuroticism proved to be
      the most consistent and effective predictor of anxiety and depressed mood after 3
      and 5 years, irrespective of initial distress levels, biomedical factors, use of
      medication, and other stressors or vulnerability factors. CONCLUSION: Results
      indicate the prognostic value of personality characteristics for longterm
      susceptibility to distress in patients with early RA, and emphasize the
      importance of paying close attention to factors unrelated to RA when screening
      for patients at risk.

PMID- 12415589
TI  - Connective tissue activation XXXVIII: heparin/heparanase activity of human
      platelets resides in a high molecular weight protein, not in connective tissue
      activating peptide III.
AB  - OBJECTIVE: Connective tissue activating protein-III (CTAP-III), with molecular
      weight 9278 Da and isoforms including CTAP-III des 1-15 (neutrophil activating
      peptide-2, NAP-2) and other amino terminal deletion isoforms, has been isolated
      from human platelets and characterized. Platelets have also been shown to possess
      significant heparin/heparanase activity. We investigated whether human platelet
      heparin/heparanase activity derives from CTAP-III. METHODS: Radial
      immunodiffusion measurement showed substantial amounts of CTAP-III in plasma from
      outdated platelet packs. A convenient method for measurement of
      heparin/heparanase activity is described, and with this method platelet
      associated plasma was investigated for heparin/heparanase activity assayed
      against 3H-heparin and 35S-heparan sulfate. RESULTS: Removal of CTAP-III from
      platelet associated plasma with an immunospecific immunoaffinity column did not
      remove the heparin/heparanase activity from the plasma. Highly purified CTAP-III
      eluted from an immunospecific affinity column lacked heparin/heparanase activity.
      CONCLUSION: Human platelet heparin/heparanase activity resides not in CTAP-III
      but in a protein or proteins with molecular weight >/= 55 kDa.

PMID- 12415590
TI  - Undifferentiated connective tissue disease: analysis of 83 patients with a
      minimum followup of 5 years.
AB  - OBJECTIVE: Undifferentiated connective tissue disease (UCTD) refers to a cluster
      of systemic disorders characterized by a simple clinical and autoantibody
      profile. Previously, we had described a series of 91 patients with UCTD who were
      followed at our unit for a minimum period of one year; here we report the
      extended followup of these patients. METHODS: Of the original 91 patients, 8 were
      lost to followup; the remaining 83, with a minimum followup of 5 years, were
      included in our analysis. RESULTS: During the followup 18 patients developed
      systemic lupus erythematosus (SLE) and one developed Sjogren's syndrome within a
      mean period of 54 months after the onset of the disease (range 17-96 mo). On
      analysis the 18 patients with SLE showed a clinical profile similar to cohorts
      reported in the literature. In one patient the evolution to SLE occurred during
      puerperium, but no other triggering factors were observed in our series. The
      presence of anticardiolipin antibodies and of multiple antibody specificities was
      significantly correlated with the development of SLE (p < 0.05). CONCLUSION: This
      analysis confirms the findings of our one year followup study that UCTD comprises
      a distinct group of mild diseases and that the rate of evolution to defined
      connective tissue diseases is higher during the first years after its onset.
      Patients who maintain an undifferentiated profile during the followup seem to run
      a decreasing risk of developing a defined CTD.

PMID- 12415591
TI  - Organ manifestations influence differently the responsiveness of 2 lupus disease
      activity measures, according to patients' or physicians' evaluations of recent
      lupus activity.
AB  - OBJECTIVE: To determine (1) which organ system manifestations contribute to the
      overall responsiveness of the Systemic Lupus Activity Measure (SLAM, revised 1991
      with minor modifications as SLAM-R) and the Systemic Lupus Erythematosus Disease
      Activity Index (SLEDAI); and (2) whether responsive items differ for physicians
      and patients. METHODS: Blinded data were obtained from repeated visits of 76
      patients in the Study of Methotrexate in Lupus Erythematosus. At each visit,
      physicians and patients reported improvement, no change, or deterioration, and
      physicians then completed SLAM-R and SLEDAI. Items in SLAM-R and SLEDAI were
      grouped by organ system. The generalized estimating equations approach was used
      to measure associations between change in organ system activity and physician or
      patient perception of change in overall disease activity. The outcomes assessed,
      in separate analyses, were improvement and deterioration from the previous visit.
      RESULTS: Seventy-six patients contributed a total of 471 observations. The
      strongest correlates of physician-reported improvement were decreased
      constitutional, gastrointestinal (GI), and musculoskeletal involvement
      (components of SLAM-R), and decreased musculoskeletal (MSK) and central nervous
      system involvement (SLEDAI). Improvement reported by patients was most strongly
      associated with decreases in erythrocyte sedimentation rate and MSK and
      reticuloendothelial activity (SLAM-R), and in MSK activity (SLEDAI). Increased
      integument and MSK subscores (SLAM-R) and serosal and MSK subscores (SLEDAI) were
      associated with overall deterioration reported by physicians. Patient-reported
      deterioration was associated with increased GI subscores (SLAM-R) and with no
      changes in organ system involvement in SLEDAI. CONCLUSION: Organ systems
      associated with reported change in overall SLE activity differed between SLAM-R
      and SLEDAI, between patients and physicians, and between each direction of
      change.

PMID- 12415592
TI  - C4A deficiency and elevated level of immune complexes: the mechanism behind
      increased susceptibility to systemic lupus erythematosus.
AB  - OBJECTIVE: Studies of an Icelandic cohort showed that susceptibility to systemic
      lupus erythematosus (SLE) in individuals with C4A deficiency was increased only
      in the presence of increased concentrations of immune complexes. We investigated
      the interaction of C4A deficiency with elevated concentrations of immune
      complexes in healthy individuals; i.e., how different levels of C4A affected the
      activation of C4 and C3 and subsequent binding of increased immune complex load
      to human red blood cells (RBC). METHODS: Forty-five healthy individuals having
      different levels of C4A were studied, 8 with homozygous C4AQ0, 12 with
      heterozygous C4A deficiency, and 25 with normal C4A. For comparison to the
      complement status present after prolonged disease activity, 5 patients with SLE
      homozygous for C4AQ0 were also studied. RESULTS: The results showed that intact
      immune complex-RBC binding is dependent on the levels of immune complex-bound C3
      fragments, which correlate to the levels of IC-bound C4Ad (R = 0.677, p = 0.02),
      but not on levels of IC-bound total C4d (R = 0.451, p = 0.16). Immune complex
      binding to RBC was also evaluated in increasing immune complex load. C4A
      deficient sera had less ability to bind the increased immune complex load to RBC
      than sera with normal C4A. These results are consistent with the presence of
      increased amounts of poorly opsonized immune complexes in C4A deficiency, leading
      to increased precipitation in tissues and initiation of a self-perpetuating
      cycle. CONCLUSION: Susceptibility to SLE is increased in individuals with C4A
      deficiency as C3 opsonization of immune complexes becomes insufficient at
      elevated immune complex concentrations.

PMID- 12415593
TI  - Interleukin 8 gene polymorphism is associated with increased risk of nephritis in
      cutaneous vasculitis.
AB  - OBJECTIVE: To assess the influence of interleukin-8 (IL-8), epithelial cell
      derived neutrophil-activating peptide (ENA-78), and regulated upon activation
      normal T cell expressed and secreted (RANTES) gene polymorphisms in the
      susceptibility and clinical expression of patients fulfilling classification
      criteria for Henoch-Schonlein purpura (HSP). METHODS: Fifty patients (25 men)
      from Northwest Spain with primary cutaneous vasculitis classified as HSP
      according to proposed criteria were studied. All patients were required to have
      had at least 2 years' followup. Patients and ethnically matched controls were
      genotyped for IL-8, ENA-78, and RANTES gene polymorphisms. RESULTS: No allele or
      genotype differences between patients fulfilling HSP classification criteria and
      controls were observed for any of the chemokines. However, a significantly
      increased frequency of allele A of the IL-8 gene polymorphism was found in
      patients with HSP who developed renal manifestations compared with patients
      without renal involvement (p = 0.02; pcorr = 0.036). Moreover, the genotype
      distribution in HSP patients with and without renal involvement showed
      statistically significant differences (p = 0.02). CONCLUSION: In unselected
      patients with cutaneous vasculitis, carriage of IL-8 allele A influences the
      susceptibility to renal involvement.

PMID- 12415594
TI  - Systemic sclerosis and interstitial lung disease: a pilot study using pulse
      intravenous methylprednisolone and cyclophosphamide to assess the effect on high
      resolution computed tomography scan and lung function.
AB  - OBJECTIVE: To document the effectiveness, including the longterm effect, of a
      course of intravenous (IV) pulses of methylprednisolone (MP) and cyclophosphamide
      (CYC) in patients with scleroderma (SSc) who had evidence of lung inflammation on
      high resolution computer tomographic (HRCT) scan of the chest. METHODS: Fourteen
      consecutive patients with SSc and lung involvement were treated with 6 pulses of
      IV MP (10 mg/kg) and IV CYC (15 mg/kg) given at 3-4 weekly intervals. HRCT scans
      and lung function tests were performed at baseline and after the 6th pulse.
      Further lung function tests were repeated at 12 months and annually thereafter.
      RESULTS: Modified Rodnan skin scores improved significantly by 35% from a median
      baseline score of 17 (IQR 14-26.5) to a posttreatment score of 13 (IQR 10.5-18.5;
      p = 0.0058). HRCT scan scores improved significantly (p = 0.04). Twelve of 13
      patients experienced either improvement or stabilization of the HRCT score.
      Median DLCO and lung volumes remained stable during the first 12 months. After a
      median followup of 26 months (IQR 19-43), 67% of patients experienced
      deterioration in DLCO. Median deterioration was 23% (IQR 44-0.6), with the median
      rate of deterioration of the predicted value of the DLCO/month being 0.87% (IQR
      1.24-0.02). The treatment was safe and well tolerated. CONCLUSION: This IV
      regimen stabilized lung disease in patients with SSc. When treatment was stopped,
      or reduced in intensity, a deterioration in lung function occurred in the
      majority of patients. Rate of deterioration of DLCO may be a useful marker for
      determining the intensity of treatment. These findings have implications for
      treating lung disease and designing clinical trials in patients with SSc.

PMID- 12415595
TI  - Pulmonary hypertension in scleroderma spectrum of disease: lack of bone
      morphogenetic protein receptor 2 mutations.
AB  - OBJECTIVE: To determine whether mutations in the bone morphogenetic protein
      receptor 2 gene (BMPR2), initially reported in primary pulmonary hypertension,
      were present in patients with pulmonary arterial hypertension and scleroderma
      spectrum of disease. Methods. BMPR2 gene mutations were determined using nucleic
      acid sequencing in 24 patients with pulmonary arterial hypertension and
      scleroderma spectrum of disease and in 2 control groups, 96 healthy North
      American individuals and 100 Israeli Ashkenazi Jews. The patients also had
      antinuclear antibody determinations and underwent right heart catheterization.
      RESULTS: One BMPR2 guanine to adenine (G to A) mutation in exon 13 was found in a
      59-year-old Ashkenazi Jewish woman with the limited cutaneous variant, a normal
      chest radiograph, and positive anticentromere and rheumatoid factor
      autoantibodies. However, this mutation is thought to be a polymorphism because
      the same mutation was also found in an ethnically matched healthy Ashkenazi Jew.
      CONCLUSION: Pulmonary arterial hypertension in scleroderma spectrum of disease
      was not associated with heterogeneous germline mutations of BMPR2.

PMID- 12415596
TI  - Presence of hepatitis C virus RNA in the salivary glands of patients with
      Sjogren's syndrome and hepatitis C virus infection.
AB  - OBJECTIVE: To determine whether hepatitis C virus (HCV) RNA could be detected in
      the salivary glands of patients with both a diagnosis of Sjogren's syndrome (SS)
      and HCV infection. METHODS: Five patients with primary SS (European criteria) and
      chronically infected by HCV and 3 controls (one with primary SS without HCV
      infection, another with HCV infection without sicca syndrome, and a third without
      SS and HCV infection) were tested for the presence of HCV-RNA (using reverse
      transcriptase-polymerase chain reaction) in their saliva, serum, and salivary
      glands. RESULTS: In the patient group, HCV-RNA was detected in the serum and
      saliva of all cases and RNA extracted from salivary gland specimens tested
      positive in 3 cases. In the control group, HCV-RNA was not detected in the serum,
      saliva, or salivary glands from subjects without HCV infection. Only the control
      subject with HCV but without sicca syndrome tested positive for the presence of
      HCV-RNA in the serum, saliva, and salivary gland tissue. CONCLUSION: Our results
      showed that HCV may propagate and reside within salivary gland tissue, leading to
      HCV associated sialadenitis or Sjogren's-like syndrome in some cases, a
      phenomenon that does not seem specific. However, a direct role for HCV in the
      physiopathology of certain cases of primary SS is suggested.

PMID- 12415597
TI  - Development of the myositis activities profile--validity and reliability of a
      self-administered questionnaire to assess activity limitations in patients with
      polymyositis/dermatomyositis.
AB  - OBJECTIVE: To develop a disease-specific questionnaire for assessing limitations
      in activities of daily life, the Myositis Activities Profile (MAP), and to
      investigate its validity and reliability. METHODS: Groups of 10, 27, 31, and 17
      patients with polymyositis (PM) or dermatomyositis (DM) participated in different
      parts of the study. In the first draft of the MAP, patients rated their
      difficulty and experienced importance of selected activities from the
      International Classification of Impairments, Disabilities, and Handicaps (ICIDH)
      2 Beta-2 draft. The 37 highest rated activities formed a second draft of the MAP,
      which was analyzed for internal redundancy and consistency. For construct
      validity a third draft was correlated with CPK levels, the Functional Index in
      myositis (FI), the Arthritis Impact Measurement Scales-2 (AIMS2), the Health
      Assessment Questionnaire (HAQ), and subjective global disease impact. Test-retest
      reliability over one week was investigated. RESULTS: There were several expected
      correlations (rs > 0.50) between subscales of the MAP and corresponding subscales
      of the AIMS2, and a 31 item MAP correlated moderately with the HAQ (rs = 0.70)
      and less with the FI (rs = 0.55), subjective global disease impact (rs = 0.43),
      and CPK levels (rs = 0.17). No systematic differences were found between test and
      retest, and weighted kappa coefficients ranged from Kw = 0.56 to 0.77.
      CONCLUSION: The MAP seems to be a valid and reliable method for assessing
      activity limitations in patients with PM and DM.

PMID- 12415598
TI  - Target organ associations in Turkish patients with Behcet's disease: a cross
      sectional study by exploratory factor analysis.
AB  - OBJECTIVE: To look for target organ associations in Turkish patients with
      Behcet's disease (BD). METHODS: We studied target organ associations in 272
      consecutive patients with BD. The occurrence of any of the clinical
      manifestations related to BD within the previous 3 months was sought by history
      questionnaire completed by a rheumatologist and by physical examination. Factor
      analysis was used to analyze the data. RESULTS: Four factors were identified by
      factor analysis of variables oral and genital ulcers, erythema nodosum,
      papulopustular skin lesions, uveitis, superficial and deep vein thrombosis,
      joint, arterial, neurological, and gastrointestinal involvement; the 4 identified
      factors explained 69% of the original information of the matrix. There was an
      association between oral ulcers, genital ulcers, and erythema nodosum (Factor 1);
      and between superficial and deep vein thrombosis (Factor 2). Uveitis was
      identified as a distinct feature, and was negatively associated with erythema
      nodosum (Factor 3) only among the females. There was also an association between
      papulopustular skin lesions and joint involvement (Factor 4). Factors 2 and 3 had
      higher scores in males (p = 0.001 and p = 0.009, respectively) versus females.
      CONCLUSION: We studied clinical features of BD in Turkish patients. The 4 factors
      we identified by factor analysis differ from a previous study from Israel,
      probably due to different methodologies used in the 2 studies. One factor
      described in our study, the association between papulopustular lesions and
      arthritis, supports findings of our recent study. A recognized association
      between superficial and deep vein thrombosis was also confirmed.

PMID- 12415599
TI  - Decreased expression of proliferating cell nuclear antigen is associated with
      dexamethasone inhibition of the proliferation of rat tendon fibroblasts.
AB  - OBJECTIVE: To investigate the effects of dexamethasone (Dex) on the proliferation
      of cultured rat Achilles tendon fibroblasts at concentrations typically used for
      local injection treatment. METHODS: Fibroblasts cultured from rat Achilles
      tendons were treated with Dex at concentrations of 0, 10-4, 3 10-4, and 10-3 M.
      [3H]thymidine incorporation was used to measure the rate of cell proliferation.
      mRNA expression of proliferating cell nuclear antigen (PCNA) and cyclin kinase
      inhibitor p21CIP1 was determined by reverse transcription-polymerase chain
      reaction (RT-PCR). The protein levels of PCNA and p21CIP1 were investigated by
      Western blot analysis. RESULTS: An initial inhibitory effect on tendon fibroblast
      proliferation was observed at a concentration of 10-4 M. Further, a significant
      decline in [3H]thymidine incorporation as a function of Dex concentration was
      noted (p = 0.019). RT-PCR results revealed that PCNA mRNA expression was
      inhibited after Dex treatment. Western blot analysis of PCNA protein also
      revealed Dex downregulation. Gradual declines in the levels of PCNA mRNA
      expression and PCNA protein as a function of Dex concentration were noted. The
      expression of p21CIP1 both at mRNA and the protein levels remained constant.
      CONCLUSION: These results suggest that Dex inhibition of the proliferation of rat
      tendon fibroblasts is associated with a p21CIP1 independent decrease of the PCNA
      gene expression.

PMID- 12415601
TI  - Active ingredient consistency of commercially available glucosamine sulfate
      products.
AB  - OBJECTIVE: To assess the content of active ingredient in over-the-counter (OTC)
      glucosamine sulfate (GLS) preparations. METHODS: We analyzed in a coded, blind
      manner 14 commercially available capsules or tablets of GLS, plus one herbal
      mixture as a control. We used a high performance liquid chromatography system as
      described. RESULTS: The amount of free base varied from 41 to 108% of the mg
      content stated on the label; the amount of glucosamine varied from 59 to 138%
      even when expressed as sulfate. CONCLUSION: If GLS is used as a therapeutic
      agent, it is important that the products conform to a standard in their
      description. The content is probably best expressed in terms of free base.

PMID- 12415600
TI  - Epidemiology of gout: is the incidence rising?
AB  - OBJECTIVE: To determine whether the incidence of gout is higher in 1995-1996
      compared to 1977-1978. METHODS: Using the Rochester Epidemiology Project
      computerized medical record system, all potential cases of acute gout in the city
      of Rochester, Minnesota during the time intervals of 1977-1978 and 1995-1996 were
      identified. The complete medical records of all potential cases were screened and
      all who fulfilled the 1977 American College of Rheumatology proposed criteria for
      gout were included as incidence cases. Demographic data, body mass index,
      clinical presentation, and associated comorbid conditions were abstracted. The
      overall and age-gender adjusted incidence rates from the 2 cohorts were
      calculated and compared. RESULTS: A total of 39 new cases of acute gout were
      identified during the 2 year interval 1977-1978 representing an age and sex
      adjusted annual incidence rate of 45.0/100,000 (95% CI: 30.7, 59.3). For the
      interval 1995-1996, 81 cases were diagnosed, representing an annual incidence
      rate of 62.3/100,000 (95% CI: 48.4, 76.2). There was a greater than 2-fold
      increase in the rate of primary gout (i.e., no history of diuretic exposure) in
      the recent compared to the older time periods (p = 0.002). The incidence of
      secondary, diuretic related gout did not increase over time (p = 0.140).
      CONCLUSION: Our results indicate that the incidence of primary gout has increased
      significantly over the past 20 years. While this increase might be a result of
      improved ascertainment of atypical gout, it may also be related to other, as yet
      unidentified, risk factors.

PMID- 12415602
TI  - Compensatory gait mechanics in patients with unilateral knee arthritis.
AB  - OBJECTIVE: Few studies exist on gait adaptation caused by knee osteoarthritis
      (OA), and those have only explored adaptations of the kinematics and kinetics of
      the knee joint itself. We characterize ankle, knee, hip, and low back mechanical
      energy expenditures (MEE) and compensations (MEC) during gait in patients with
      knee OA. METHODS: Thirteen elderly patients with unilateral knee OA and 10
      matched healthy elderly controls were studied during preferred and paced speed
      gait. Gait speed, step length, and lower extremity and low back joint MEE and MEC
      were compared between groups. RESULTS: Patients with knee OA had lower, but not
      significantly different, walking speed and step length compared to the controls,
      and had significantly different joint kinetic profiles. Patients had reduced
      ankle power at terminal stance, lacked a second positive peak in knee power, and
      had increased power absorption at the hip. Abnormal knee kinematics were
      exaggerated when walking at a paced speed, but hip kinetics normalized among
      patients with OA. CONCLUSION: Reduced ankle plantar-flexion power in patients
      with knee OA was probably due to disrupted transfer of energy through the knee.
      Lack of concentric knee power supports prior studies' conclusions that patients
      with knee OA avoid using their quadriceps to stabilize the knee, probably to
      reduce articular loads. Patients with knee OA increase eccentric hip power due to
      increased hip extension caused by abnormal knee kinematics, potentially
      increasing hip articular forces. This passive mechanism, however, may assist in
      the advancement of the leg into swing phase.

PMID- 12415604
TI  - Health and functional status of twins with chronic regional and widespread pain.
AB  - OBJECTIVE: To examine the independent effects of chronic regional and widespread
      pain syndromes on health and functional status after accounting for comorbid
      chronic fatigue using a co-twin control design. METHODS: We identified 95 twin
      pairs discordant for pain in which one twin had chronic regional or widespread
      pain and the other denied chronic pain. Demographic data, functional and
      psychological status, health behaviors, and symptoms based on the 1994 criteria
      for chronic fatigue syndrome (CFS) were assessed by questionnaire. Psychiatric
      diagnoses were based on structured interview. Random effects regression modeling
      estimated associations between chronic regional and widespread pain and each
      health measure with and without adjustment for CFS. RESULTS: Significant
      differences (p </= 0.05) were found within twin pairs discordant for chronic
      regional and widespread pain, for general health perception, and physical and
      mental health functioning as measured by summary scores from the Short Form-36.
      In addition, differences were observed within pain discordant pairs in
      psychological distress as measured by the General Health Questionnaire as well as
      the number of psychiatric diagnoses. Adjustment for CFS eliminated the
      association between chronic pain and mental health, but the association between
      chronic pain and poor general health, physical functioning, and sleep quality
      persisted (p </= 0.01). Only the intra-pair difference in physical functioning
      distinguished twins with regional vs widespread pain (p </= 0.05). CONCLUSION:
      Both chronic regional and widespread pain exact debilitating effects on perceived
      general health, physical functioning, and sleep quality independent of CFS.
      However, the psychological and psychiatric influence of chronic pain appears
      closely tied to CFS. Research should examine the additive role of CFS-like
      illnesses in patients with chronic pain, and its influence on treatment and
      outcome.

PMID- 12415603
TI  - Barriers to providing adequate rheumatology care: implications from a survey of
      rheumatologists in ontario, Canada.
AB  - OBJECTIVE: To determine what, if any, barriers exist that prevent rheumatologists
      from providing adequate rheumatology care. METHODS: All 158 identified
      rheumatologists in Ontario were sent a self-administered questionnaire and
      followed up by telephone. RESULTS: The response rate was 83%. All but 6
      rheumatologists reported at least one barrier to the provision of service. The 3
      most commonly reported barriers were the cost of drugs for patients (83%),
      billing policies and regulations for consultation and followup visits (72%), and
      long waiting times for patients (61%). Rheumatologists reporting the latter had
      significantly longer waiting times (12 vs 4 wks) for new non-urgent patients,
      although there was no difference for new patients with inflammatory arthritis.
      Nearly three-quarters of respondents had changed the patterns of their practice
      over the last 3 years, with significant increases in the amount of independent
      medical services (e.g., third party billing) and pharmaceutical company work. The
      majority (89%) of responding rheumatologists reported having at least some
      difficulty in making ends meet from rheumatology practice alone and 28% found it
      was not possible. CONCLUSION: These results indicate that the majority of
      rheumatologists face significant barriers to providing adequate care. Given the
      recruitment and service provision concerns in Canada, these barriers to service
      need to be addressed to ensure adequate provision of care.

PMID- 12415605
TI  - Use of complementary and alternative therapies by patients self-reporting
      arthritis or rheumatism: results from a nationwide canadian survey.
AB  - OBJECTIVE: Arthritis or rheumatism (A/R) often leads patients to experiment with
      complementary and alternative medicine (CAM); we investigated the factors
      associated with use of CAM. METHODS: The source of the data is the cross
      sectional household component of the 1996-97 National Population Health Survey of
      the health status and behaviors of Canadians. The survey sample is based on
      66,000 persons aged 20 years and older, representing 21 million adults. Cross
      tabulations were used to estimate the percentage of adults with A/R who used CAM.
      Multivariate logistic regression was used to identify those characteristics
      associated with the use of CAM in the year preceding the survey. RESULTS: In 1996
      97, among the 3.3 million Canadian adults aged 20 years or older who self
      reported arthritis, 22% utilized CAM in the past year. CAM users tended to be
      younger and with higher education and household income. They reported more pain,
      consumed more analgesics, and tended to be more depressed. The coexistence of
      back or bowel disorders, cancer, sinusitis, or food allergies with arthritis was
      also related to CAM use. Moreover, CAM users also used more traditional health
      resources. CONCLUSION: Our results indicate that patients with A/R consulting CAM
      providers self-report more intense symptoms than nonusers and often have other
      chronic conditions. They do not seem to reject the traditional health care
      system, but supplement it with CAM, possibly to fulfill needs insufficiently
      satisfied by traditional health care providers.

PMID- 12415606
TI  - Hepatotoxicity in patients with juvenile idiopathic arthritis receiving longterm
      methotrexate therapy.
AB  - OBJECTIVE: To evaluate hepatotoxicity in patients with juvenile idiopathic
      arthritis (JIA) receiving methotrexate (MTX) therapy with doses of 20-30 mg/m2 of
      body surface area. METHODS: We graded the histology of percutaneous liver
      biopsies from 34 patients with JIA receiving longterm (> 2.4 years) MTX therapy
      at the Rheumatism Foundation Hospital, Heinola, Finland, using the Roenigk
      classification scale. Medical records of the patients with JIA were
      retrospectively analyzed. RESULTS: Of 10 patients with MTX doses >/= 20 mg/m2, 4
      had grade II, 5 had grade I histology, and one specimen with extensive steatosis
      as the only pathologic finding could not be classified. All 24 patients treated
      with low dose MTX had grade I histology. No specimen showed fibrosis or
      cirrhosis. In 2 patients with grade II histology, extensive portal tract
      inflammation resolved when MTX was discontinued for 6 months. CONCLUSION:
      Aggressive medical treatment of JIA with MTX at 20-30 mg/m2 with concomitant
      disease modifying antirheumatic drugs and corticosteroids may contribute to minor
      liver abnormalities that seem to be reversible.

PMID- 12415608
TI  - The influence of heredity for psoriasis on the ILAR classification of juvenile
      idiopathic arthritis.
AB  - OBJECTIVE: To evaluate how heredity for psoriasis influences classification
      according to the International League of Associations for Rheumatology (ILAR).
      Heredity for psoriasis is currently both an exclusion and an inclusion criterion
      for different types of childhood arthritis according to ILAR classification
      criteria. METHODS: Twenty physicians in 5 Nordic countries prospectively
      collected data from the incident cases in their catchment areas over an 18 month
      period beginning July 1, 1997. Clinical and serological data from the first year
      of disease were collected. RESULTS: Of the 321 patients included who could be
      classified according to ILAR criteria for childhood arthritis, 50 (15.6%)
      patients were excluded from 55 classification events and fulfilled criteria for
      "other arthritis 1" i.e., did not fulfill criteria for any of the other
      classification categories, primarily because of heredity for psoriasis. If
      psoriasis in second degree relatives was disregarded as an exclusion criterion,
      only 8.7% of the patients remained in the "other arthritis 1" subgroup. For 20.6%
      of the whole group, heredity for psoriasis in a first or second degree relative
      (or both) and its distribution among arthritis subgroups did not differ except
      for juvenile psoriatic arthritis. CONCLUSION: We suggest that second degree
      heredity for psoriasis be withdrawn as an exclusion criterion from the ILAR
      criteria.

PMID- 12415607
TI  - Early predictors of severe course of uveitis in oligoarticular juvenile
      idiopathic arthritis.
AB  - OBJECTIVE: To determine whether demographic, clinical, and laboratory variables
      at onset of arthritis can predict the development and the severity of anterior
      uveitis (AU) in oligoarticular juvenile idiopathic arthritis (JIA). METHODS: In a
      retrospective study, a cohort of 366 patients with oligoarticular onset JIA from
      3 pediatric rheumatology centers were evaluated. Patients were classified in 3
      groups: severe uveitis (SU) with a mean >/= 2 uveitis relapses/year with
      complications or need for immunosuppressive therapy; mild uveitis (MU) with a
      mean </= 1 uveitis relapse/year with no complications; and no uveitis. Variables
      that were significant with univariate tests or were clinically relevant for each
      outcome underwent multivariate logistic regression analysis. RESULTS: There were
      316 patients available for analyses: 66 in the SU group, 64 in the MU group, and
      186 in the no uveitis group. Multivariate analysis showed the following factors
      to be significant as predictors of AU onset: low age at onset (OR 0.96), a2
      globulin plasma concentration (OR 1.34), and HLA-A19 (OR 2.87), B22 (OR 4.51) and
      DR9 (OR 2.33), while HLA-DR1 conferred protection (OR 0.13). This model was not
      good in predicting which patient would develop uveitis (sensitivity 55%,
      specificity 26%). Time interval between onset of arthritis and the first AU and
      elevated a2-globulin level in the serum were the best predictors of AU severity
      (OR 1.62 and 0.85, respectively). When applied prospectively, the model revealed
      good sensitivity (89.2%), specificity (76.1%), and efficiency (86.3%).
      CONCLUSION: Clinical and laboratory variables measurable at onset of arthritis
      can be used to predict severity of the course of AU in oligoarticular JIA, but
      not its onset. More accurate prediction can shorten or lengthen the intervals
      between ophthalmologic evaluations and can change the therapeutic approach
      undertaken on the basis of expected disease severity.

PMID- 12415609
TI  - Anti-androgen treatment of prostatic carcinoma may be a risk factor for
      development of rheumatoid arthritis.

PMID- 12415610
TI  - Normal radiographs in patients with persistent "hip pain"--value of magnetic
      resonance imaging.

PMID- 12415611
TI  - Gingival hyperplasia associated with cyclosporin A.

PMID- 12415612
TI  - Relationship of length of clinical rotation to achievement of skills necessary
      for clinical management of musculoskeletal disease.

PMID- 12415613
TI  - Intensity and duration of oral anticoagulation in antiphospholipid antibody
      associated thrombosis.

PMID- 12415614
TI  - The Crohn's associated NOD2 3020InsC frameshift mutation does not confer
      susceptibility to ankylosing spondylitis.

PMID- 12415615
TI  - Loss of heterozygosity and microsatellite instability in epithelial hyperplasia
      of the breast.
AB  - We evaluated loss of heterozygosity (LOH) and microsatellite instability (MSI) in
      epithelial hyperplasia of the breast by the PCR method using microsatellite
      markers. Seven loci of 16q, 17p, 17q, and 18q were examined in 35 lesions of
      epithelial hyperplasia observed in non-neoplastic breast tissue of eight breast
      carcinoma cases, and 29 lesions were observed within 19 fibroadenomas. These
      hyperplastic lesions were classified by standard criteria into three groups,
      namely, mild, moderate and atypical ductal hyperplasia (ADH). In the breast
      carcinoma cases, the frequency of loss of heterozygosity was 40% in mild, 50% in
      moderate, and 100% in ADH; while in the fibroadenoma cases, the frequency was 10%
      in mild, 27% in moderate, and 25% in ADH; total frequency of LOH was
      statistically higher in carcinoma cases than in fibroadenoma cases. On the other
      hand, the frequency of microsatellite instability was higher in fibroadenoma
      cases (28%) than in breast carcinoma cases (11%). Furthermore, we analyzed two
      cases of noninvasive ductal carcinoma arising in fibroadenoma, which had various
      types of hyperplasia along with carcinoma in situ, and many hyperplasias showed
      LOH at several of the same markers as carcinoma in situ. From those results, we
      speculated that LOH at these markers is an early event in mammary tumorigenesis,
      and some of the hyperplastic lesions with LOH have precancerous natures.

PMID- 12415616
TI  - Augmentation of apoptosis by the combination of bleomycin with trifluoperazine in
      the presence of mutant p53.
AB  - A variety of anticalmodulin drugs can increase the cytotoxicity of bleomycin, a
      DNA damaging cancer chemotherapeutic. The combination has been shown to produce
      greater than expected DNA damage compared wot what was observed with either drug
      alone. Promising preclinical results led to Phase I and Phase II trials of
      trifluoperazine and bleomycin, which revealed activity in non-Hodgkin's lymphoma.
      Despite the unique activity of the combination, the mechanism underlying the DNA
      damaging effect remained poorly understood. In several systems, DNA damage leads
      to the induction of programmed cell death or apoptosis, which is characterized by
      interoligonucleosomal cleavage of DNA. To determine whether the activity of the
      combination of bleomycin with trifluoperazine was due to induction of apoptosis,
      we exposed L1210 leukemic lymphocytes to bleomycin in the presence or absence of
      trifluoperazine. The combination produced DNA laddering, cellular shrinkage, and
      chromatin condensation typical of programmed cell death. Cell cycle analyses
      revealed a blockade of cells in G2/M, suggesting the presence of mutant p53,
      which was confirmed by immunoanalysis. In addition, L1210 cells were found not to
      overexpress Bcl-2 in the presence or absence of drugs. These results indicate
      that the enhancement of bleomycin induced DNA damage by trifluoperazine is
      mediated, at least in part, through the induction of apoptosis.

PMID- 12415617
TI  - Interleukin-1 alpha increases the cytotoxic activity of etoposide against human
      osteosarcoma cells.
AB  - The recurrence of pulmonary metastases resistant to salvage chemotherapy
      continues to be a major problem in osteosarcoma patients. Our goal is to identify
      novel combinations of biologic response modifiers plus chemotherapeutic agents
      that can be translated into clinical trials. Response rates of relapsed
      osteosarcoma patients to etoposide have been extremely low. The present
      investigation demonstrated that IL-1 alpha dramatically increased the sensitivity
      of MG-63, SAOS-2, and TE-85 osteosarcoma cells to etoposide when the two agents
      were used simultaneously. The cytostatic activity of 1 microM etoposide was
      increased from 35 to 70%, 30 to 65%, and 4 to 90%, respectively, by 5.0 U/ml IL-1
      alpha. Analysis using the colony-forming assay to quantify cytotoxicity showed
      that the percentage of cell survival following exposure to etoposide decreased
      from 0.81 to 0.56, 0.55 to 0.2, and 0.4 to 0.05 when the combination treatment
      was used. Increased sensitivity was not seen when etoposide treatment preceded IL
      1 alpha treatment. IL-1 alpha also increased the sensitivity of these cells to
      doxorubicin but not to cisplatin or topotecan. The mechanism of this enhanced
      activity is independent of p-glycoprotein, drug-uptake, or effects on
      topoisomerase II.

PMID- 12415618
TI  - Modulation of multidrug resistance in human ovarian cancer cell lines by
      inhibition of P-glycoprotein 170 and PKC isoenzymes with antisense
      oligonucleotides.
AB  - Multidrug resistance in human ovarian carcinoma cell lines is caused by the
      expression of several related proteins, namely P-glycoprotein 170 (Pgp-170),
      glutathione S-transferase-pi GST-pi), and thymidylate synthase (TS). These
      proteins seem to be regulated by a common mechanism in which the expression of
      protein kinase C (PKC) is involved. Additionally, the function of Pgp-170 is
      dependent on PKC phosphorylation. However, in ovarian carcinoma cell lines the
      role of different PKC enzymes responsible for resistance is not quite clear. In
      the present study we circumvented resistance in taxol resistant human ovarian
      carcinoma cell lines with antisense oligonucleotides to PKC alpha and PKC beta
      mRNA and compared the effects with those obtained by Pgp-170 antisense
      oligonucleotides. We found a significant inhibition of cell number after
      treatment with Pgp-170 antisense oligonucleotides in combination with taxol.
      Additionally, resistance could be reversed by treatment with taxol and antisense
      oligomers to PKC alpha and PKC beta. This shows that regulatory correlations
      between these proteins exist and that inhibition of the mRNA of PKC alpha and PKC
      beta isoforms and Pgp-170 can reverse multidrug resistance.

PMID- 12415619
TI  - In vivo advantage of combined administration with CPT-11 and 5-fluorouracil in
      rats.
AB  - In vivo effect of a bolus combination with 5-fluorouracil (5-FU) and CPT-11 was
      studied against experimental rat lung cancer, SLC cells. 5-FU and CPT-11, when
      administrated individually, showed dose-dependent inhibition against the tumor
      (ID50, 7.0 mg/kg/day and 16.0 mg/kg/day, respectively). 5-FU synergistically
      enhanced the sensitivity of the tumor cells to CPT-11 and permitted the
      administration of approximately a one-third lower dose of CPT-11 to obtain the
      same inhibition against the tumor cell growth. The ID50 of CPT-11 alone (16.0
      mg/kg/day) was reduced to 4.8 mg/kg/day when combined with 5-FU at 2.5 mg/kg.
      There were no deaths caused by toxicity in the combination group, and for lower
      doses (less than 4 mg/kg/day) of CPT-11 combined with 2.5 mg/kg/day of 5-FU, all
      rats showed less than 10% body weight loss at the end of the experiments. When
      the tumor weights were evaluated by using isoeffect plot analysis, the data
      points resulting from the combination showed a synergistic interaction between
      these agents. There was no significant increase of toxicity as assessed by the
      body weight. The results might support for the use of the combination of 5-FU and
      CPT-11 in cancer chemotherapy.

PMID- 12415620
TI  - Recombinant human interleukin-3 administered concomitantly with chemotherapy in
      patients with relapsed small cell lung cancer.
AB  - Although recombinant human interleukin-3 (rhIL-3) shortens both the duration of
      chemotherapy-induced neutropenia and thrombocytopenia, its effect on nadir counts
      is limited. Concurrent administration of rhIL-3 and chemotherapy may enhance this
      effect. However, simultaneous administration of other hematopoietic growth
      factors and chemotherapy has resulted in enhanced myelosuppression. We
      investigated whether concomitant administration of rhIL-3 and chemotherapy would
      result in enhanced myelosuppression. Twelve patients with relapsed small cell
      lung cancer received vincristine, ifosfamide, mesna, and carboplatin on day 1
      every four weeks. RhIL-3 was administered subcutaneously on days 1-14 during
      cycle 1 at doses of 4 (three patients) or 8 micrograms/kg/day (nine patients).
      During cycle 2 patients received only chemotherapy. No significant difference in
      leukocyte (1.4 +/- 1.0 vs. 0.9 +/- 0.4 x 10(9)/l (mean +/- SD), neutrophil (0.5
      +/- 0.6 vs. 0.2 +/- 0.2 x 10(9)/l), and platelet (64 +/- 60 vs. 38 +/- 58 x
      10(9)/l) nadir counts were demonstrated. The hemoglobin nadir level was
      significantly higher during cycle 1 (6.5 +/- 1.1 vs. 5.5 +/- 0.9 mmol/l, P =
      0.05). Both leukocyte and platelet recovery were significantly enhanced in the
      rhIL-3 cycle. There was no significant difference in chemotherapy postponement or
      platelet transfusions. As a result of severe headaches, rhIL-3 administration was
      discontinued in one patient at 8 micrograms. RhIL-3 during this chemotherapy
      regimen for relapsed small cell lung cancer did not enhance myelotoxicity but did
      improve bone marrow recovery. This observation may increase the application of
      rhIL-3, for instance in combination with other hematopoietic growth factors.

PMID- 12415621
TI  - Parameters affecting the ex vivo cytotoxic drug sensitivity of human
      hematopoietic cells.
AB  - The drug sensitivity of normal cells provides a baseline for determining the
      therapeutic index, and therefore the effectiveness, of cytotoxic drugs, yet
      little is known about the factors that affect normal cell chemosensitivity. Some
      parameters are known to have a profound effect on tumor cell sensitivity. The
      purpose of this study was to determine how cytotoxic drug sensitivity of
      hematopoietic cells isolated from cancer patients was affected by various
      parameters. These included previous chemotherapy (yes or no), sex, age, tumor
      type (leukemias or solid tumors), sample source (blood, bone marrow, serous
      effusions, or tumor biopsies) and predominant cell lineage (lymphoid, myeloid,
      macrophage, or mixed). Mononuclear cells isolated from blood, bone marrow, serous
      effusions, and tumor biopsies were incubated for four days with a median of 16
      drugs. The differential staining cytotoxicity assay, an ex vivo apoptotic drug
      sensitivity test in which cell survival is determined morphologically, was used
      to assess normal hematopoietic and tumor cell response to cytotoxic drugs. One
      hundred forty-six specimens yielded hematopoietic cell chemosensitivity results
      with 3-36 drugs. Compared with tumor cells, there was far less interpatient
      variation in chemosensitivity of hematopoietic cells. Mean hematopoietic cell
      drug sensitivity showed little variation due to previous chemotherapy, sex, age,
      tumor type, and sample source or cell lineage. We therefore concluded that
      cytotoxic drug sensitivity of hematopoietic cells from a variety of sources could
      be used for assessment of therapeutic index. Drug therapeutic index results are a
      valuable tool in identifying novel cytotoxic agents and individually tailored
      chemotherapy regimens.

PMID- 12415622
TI  - Tissue reactions after long-term intracerebral implantation of three different
      types of biodegradable polylactide rods in the rat.
AB  - PURPOSE: To investigate acute and late tissue reactions following intracerebral
      implantation of three different biodegradable DL-polylactids: Resomer R104 + R203
      (1 + 1) (SU48), Resomer R203 (SU49), and DL-polylactid-co-trimethylencarbonat
      (SU50). METHODS: Polylactide (PL) rods and small pieces of silicon (control) were
      stereotactically implanted in the forebrain of 60 Wistar rats. Twenty-eight, 70,
      and 112 days after implantation, five animals of each group (SU48, SU49, SU50,
      control) were sacrificed. Tissue slices of the paraffin-embedded brains were
      stained with hematoxylin and eosin (HE) for histological evaluation. RESULTS:
      Independent from the investigated sample, the site of implantation was visible on
      the brain sections as a clearly demarcated tissue defect surrounded by minimal
      inflammatory cellular reactions. Although not significant, implantation of SU50
      caused the most distinct invasion of foamy macrophages. Despite SU48, which 112
      days after implantation was surrounded by a thin layer of predominantly gliotic
      fibers, demarcation of surrounding brain tissue was of minor degree. DISCUSSION:
      The PL rods investigated in this study caused no significant early and late
      tissue alterations. Both the good biocompatibility of these samples and a high
      flexibility with regard to degradation time and release kinetics allow either
      long protracted drug release or short-term application of substances.

PMID- 12415623
TI  - Antitumoral activity of a new series of 5,6-dihydrobenzo(a)carbazoles.
AB  - The overlapping of three-dimensional structures of 5,6-dihydrobenzo(a)carbazole
      (DHBC) derivatives over the structure of 4-hydroxytamoxifen (4-OH-TAM), by means
      of the MDL CHEMLAB 11.0 computational program, shows a reasonable structural and
      spatial resemblance. This finding raised the hypothesis of their possible
      antitumoral activity, similar to that of tamoxifen (TAM). A number of DHBCs with
      an alkyl chain and a second basic nitrogen as substituent were synthesized in our
      laboratory and their possible antitumoral activity was tested by means of: 1)
      competitive radioligand assays to determine relative drug affinity for the
      estrogen receptor (ER); 2) in vivo studies, giving the synthetic drugs
      subcutaneously (1 mg kg-1 day-1) to Sprague-Dawley rats with N-nitroso-N
      methylurea (NMU)-induced mammary tumors; and 3) in vitro cell proliferation
      experiments employing the soft agar clonogenic technique. Besides, studies on
      toxicity and histopathological analyses of organs and tumors from treated animals
      were performed. Results obtained showed that: 1) relative binding affinities
      (RBA) for the ER were similar to that of TAM; 2) some structures showed
      significant antitumoral activity and induced tumoral regression similar to TAM;
      and 3) these compounds had in vitro inhibitory effect on cell proliferation. Even
      though all the compounds of the series of synthesized DHBCs showed affinity for
      the ER similar to TAM, the results of in vivo experiments confirmed the crucial
      role of hydroxyl groups in the molecule and of the interatomic distance between
      them, similar to that of estradiol, as well as the necessary presence of the
      aminoalkyl chain on the annular N atom. However, the effect of alkyl chain
      enlargement in the nitrogen substituent on the biological activity of those drugs
      is as yet unclear.

PMID- 12415625
TI  - Capacity of murine IL-12 to inhibit the development of primary melanoma tumors
      and to prevent lung metastases in the melanoma-challenged mice.
AB  - Interleukin-12 (IL-12) has the capacity to activate cytotoxic lymphocytes,
      stimulate natural killer cells, induce the production of INF-gamma, and be
      synergistic with IL-2. We have evaluated this cytokine in an experimental model
      for metastatic melanoma that approximates the major clinical stages of metastatic
      dissemination. To develop primary melanoma tumors, mice were injected
      subcutaneously with 5 x 10(5) cells in a volume of 25 microliters into the middle
      of the tail (11). In a month, mice were started to be treated for 4 weeks with
      recombinant murine IL-12 (R mIL-12) at the following doses: 0, 0.5, 2.5, 5.0,
      15.0, and 50 micrograms/kg. Diameters of the primary melanoma tumors were
      measured at weekly intervals. At the end of 13 weeks (9 weeks from the start of
      treatment with R mIL-12), all surviving mice were sacrificed. Pathological
      examination of lung metastases (macroscopy) was done with all dead or sacrificed
      mice. Treatment of mice bearing melanoma at a dose of 300 ng/mouse (15
      micrograms/kg) inhibited development of primary tumors in 40% of mice. The
      primary tumor diameters were significantly lower in the group treated with 300
      ng/mouse (15 micrograms/kg) in comparison to controls. At the end of the
      observation period, groups treated with 0.5, 2.5, 15.0, and 50 micrograms/kg had
      mean primary tumor diameters smaller than the control group. Evaluation of IL-12
      therapy on primary tumor growth, mean diameters of primary tumors, survival rate,
      and development of lung metastases showed that the best results were observed
      using 300 ng/mouse (15 micrograms/kg) R mIL-12.

PMID- 12415624
TI  - Effects of hexadecylphosphocholine on phosphatidylcholine and phosphatidylserine
      metabolism in human lymphoma cells.
AB  - Hexadecylphosphocholine (HePC) belongs to a new group of antineoplastic agents,
      the alkylphosphocholines (APC). HePC shows a broad spectrum of biological effects
      in various cells in vitro and in vivo. It has pronounced antiproliferative
      effects on neoplastic cells. The molecular mechanism by which HePC exerts its
      biological effects is still under investigation. By generating a HePC-resistant
      cell variant of the lymphoma cell line Raji, we established a model to
      investigate which molecular mechanism may be responsible for the
      antiproliferative action of HePC. Here we present data showing that HePC
      substantially interferes with the metabolism of cellular phosphatidylcholine (PC)
      and phosphatidylserine (PS) in the human lymphoma cell line Raji. HePC leads to
      an inhibition of PC synthesis via CDP-choline and as a compensatory mechanism
      enhances the generation of PC via PS indicating that the reduced PC synthesis
      seems to significantly disturb cellular homeostasis. In HePC-resistant Raji
      cells, PC synthesis via CDP-choline is constitutively less active and is not
      further reduced by HePC. Resistant Raji cells do not seem to use the alternative
      pathway of PC synthesis via PS nor can this be induced by HePC. The resistance
      mechanism may therefore be independent of cell membrane metabolism.

PMID- 12415626
TI  - Adenovirus-mediated tissue-specific cytosine deaminase gene therapy for human
      hepatocellular carcinoma with different AFP expression levels.
AB  - To evaluate whether in vitro and in vivo transferring of Escherichia coli
      cytosine deaminase gene to a solid tumor will confer the sensitivity to the
      prodrug 5-fluorocytosine (5FC) on these cells, we constructed two replication
      defective adenovirus vector in which the cytosine deaminase gene was driven by
      CAG promoter (Adex1CACD) and AFP gene 5'-flanking region (Adex1AFPCD),
      respectively. By transferring these two vectors to SMMC7721AFP(-) and HepG2 human
      hepatocellular carcinoma (HCC) cells in vitro, we found that Adex1CACD vector
      could effectively suppress SMMC7721AFP(-) and HepG2 cells growing in the presence
      of 5FC even if the infected cell is less to 20%, while Adex1AFPCD vector only
      conferred HepG2 cells sensitivity to 5FC. When Adex1CACD was directly injected
      into established subcutaneous SMMC7721AFP(-) tumors in nude mice receiving 5FC,
      the tumor growth was inhibited significantly, which was consistent with those in
      vitro results. Furthermore, the Adex1AFPCD plus 5FC suppressed SMMC7721AFP(+)
      tumor growth in vivo, but not SMMC7721AFP(-) tumor. The results suggested that
      the CAG promoter-controlled CD gene could effectively mediate the growth
      inhibition in different kinds of HCC combined with administration of 5FC, and the
      AFP promoter-controlled CD gene could only suppress the HCCs expressing high
      levels of AFP. Therefore, adenovirus-mediated tumor-specific gene transfer may be
      a potential strategy for local control of tumor growth.

PMID- 12415627
TI  - Identification of two distinct intracellular sites that contribute to the
      modulation of multidrug resistance in P388/ADR cells expressing P-glycoprotein.
AB  - Although the ability of chemosensitizers to modulate P-glycoprotein (PGP)-based
      multidrug resistance (MDR) has been extensively studied, relatively little is
      known about the cellular pharmacology of the PGP inhibitors themselves in MDR
      cells. The studies described here have correlated the in vitro accumulation and
      retention properties of verapamil (VRP) in murine P388 (sensitive) and P388/ADR
      (MDR) cells with doxorubicin (DOX) uptake and cytotoxicity modulation
      characteristics in order to better understand VRP-tumor cell interactions that
      give rise to MDR modulation. VRP is rapidly taken up by DOX-sensitive and 
      resistant P388 cells where greater than 50% maximal VRP uptake occurs within 10
      min of initial exposure at 37 degrees C. Whereas chemosensitization and DOX
      uptake in P388/ADR cells increase with increasing VRP concentration until a
      plateau is achieved at approximately 5 microM VRP, cellular modulator levels
      increase proportionally with increasing VPR concentrations beyond 20 microM.
      Subsequent to removal of noncell-associated modulator, VRP levels in both
      sensitive and resistant cells rapidly fall below 10% of those obtained at uptake
      equilibrium. However, a residual amount of VRP remains associated with the cells
      for extended time periods after the cells are washed. Pulse exposures of P388/ADR
      cells to high concentrations of VRP (50-100 microM) are capable of providing
      extended cell-associated VRP levels comparable to those obtained with continuous
      exposure at biologically active VRP concentrations (1-3 microM) and this leads to
      chemosensitization. These results are consistent with the existence of high- and
      low-affinity intracellular VRP pools in P388 MDR cells, both of which can
      contribute to the reversal of drug resistance. It is suggested that these
      properties should be taken into consideration during the design and evaluation of
      preclinical in vivo MDR models where pulsed exposure to high concentrations of
      resistance modulators often occurs. Special attention must be given to whether
      such high concentration pulses are desirable and/or achievable in relevant
      clinical settings.

PMID- 12415628
TI  - p53 expression, growth, and spontaneous metastasis of the human GI 101 breast
      carcinoma in athymic nude mice.
AB  - The human GI 101 breast carcinoma cell lines produces spontaneous metastasis to
      the lungs when xenografted subcutaneously in female athymic nude mice. To
      establish the time-course of tumor growth and distant metastasis to the lungs and
      axillary lymph nodes, 5 mm3 of tumor tissue was implanted in the subaxial region
      of female athymic nude mice. Micrometastases in the lung were first detected 3
      weeks after tumor implantation. The incidence of lung metastasis and the number
      of tumor emboli were correlated with the volume of the primary tumors.
      Ipsilateral axillary lymph node metastasis was observed within 17 weeks,
      indicating that metastasis to the lymph node is a later event. Unlike pulmonary
      micrometastases which were in the form of clusters of four to six tumor cells,
      metastasis to the lymph nodes were in nodules of poorly differentiated and larger
      tumor cells. Immunohistochemistry evaluation of p53 oncoprotein in the primary
      and metastatic tumor cells showed different patterns of subcellular accumulation.
      Cytoplasmic staining was mainly detected in the primary and secondary tumor cells
      disseminated to the lungs. In contrast, nuclear staining was only detected in
      tumor cells infiltrated to the axillary lymph nodes. There was no gain of loss of
      positivity of p53 accumulation (i.e., qualitative measurements) as the tumor grew
      in size. The data indicate that the GI 101 tumor cells could be used as a useful
      model for studying the malignant progression of hormone-independent breast
      cancer, antimetastatic drugs, and early events in tumor metastasis.

PMID- 12415629
TI  - Human chorionic gonadotropin (hCG), the hormone of life and death: a review.

PMID- 12415630
TI  - P-glycoprotein expression by cancer cells affects cell cytotoxicity and cell
      cycle perturbations induced by six chemotherapeutic drugs.
AB  - BACKGROUND: P-glycoprotein (P-gp)-mediated chemoresistance plays an important
      role in drug resistance. METHODS: We investigated if P-gp expression by cancer
      cells affects cell cytotoxicity and cell-cycle perturbations induced by six
      commonly used chemotherapeutic agents (doxorubicin, daunorubicin, mitoxantrone,
      vinblastine, paclitaxel, and colchicine). For this purpose, we used KB cell lines
      as a model and flow cytometric cell viability and drug-induced cell-cycle
      perturbation-based methods. We continuously cultured KB cell lines, in the
      presence of various anticancer agents and measured the cell-cycle kinetics and
      percentage of cell viability by flow cytometry at different time intervals.
      RESULTS: The highly resistant cell line KB V-1 was significantly less susceptible
      to drug cytotoxicity than the sensitive cell line KB 3-1. KB V-1 cells cultured
      with different chemotherapy agents continued cell-cycle progression without any
      significant perturbation of cell compartment distribution. Addition of verapamil,
      by inhibiting P-gp, reversed resistance thereby increasing drug cytotoxicity and
      allowing the appearance of drug induced cell-cycle perturbations. CONCLUSIONS: We
      conclude that P-gp interferes with cell cytotoxicity and cell-cycle perturbations
      induced by anticancer agents. Flow cytometry can be used to conveniently detect P
      gp-mediated chemoresistance by cancer cells as it allows the analysis of cell
      cytotoxicity and cell-cycle modifications after exposure to specific
      chemotherapeutic and reversal agents.

PMID- 12415631
TI  - Lymphocyte activation by granulocyte macrophage-colony stimulating factor in
      human bladder cancer.
AB  - OBJECTIVES: The goal of this study was to investigate the ablative or reductive
      activity of granulocyte macrophage-colony stimulating factor (GM-CSF)
      instillations on transitional cell carcinoma marker lesions as well as its
      ability to increase and/or activate lymphocyte population. METHODS: Eleven
      patients (pts) with newly diagnosed cancer pTa-pT1 were studied. A well-defined
      marker lesion (< or = 0.5 cm) was left after transurethral resection (TUR). All
      pts received eight weekly instillations of 300 micrograms of GM-CSF after which
      cystoscopy with biopsies +/- TUR was repeated. Specimens from adjacent to the
      lesion mucosa were obtained before and after GM-CSF therapy and processed for
      ultrastructural study. RESULTS: The response was complete in six pts (55%), no
      change in two pts (18%), for a total of 73% response, and all pts were free of
      disease after one year. Progression was observed in three pts (27%) with no case
      of muscular invasion. Before treatment, the scarcely detected lymphocytes had
      morphological characteristics of resting cells. After treatment, the most
      impressive finding was the detection of lymphocytes with "hand mirror"
      morphology, suggesting an immunological activation. This finding has not been
      previously described in the bladder mucosa. CONCLUSION: The present study led us
      to speculate on the use of GM-CSF as a new alternative approach in the management
      of TCC through immunomodulation.

PMID- 12415632
TI  - Effect of thalidomide in different tumors in rodents.
AB  - This study investigated the effects of chronic administration of thalidomide on
      three different neoplasms of ectodermic origin in rodents: 1) chemically induced
      tumors of the nervous system of rats by transplacental exposure to
      ethylnitrosourea; 2) transplanted RPMI-1846 melanoma in hamsters and 3)
      transplanted C6 glioblastoma in rats. No effects were seen on thalidomide-treated
      rats on the frequency- and time of tumor development induced by ethylnitrosourea.
      In contrast, a reduction in tumoral growth and mitotic-index was obtained in
      animals treated with thalidomide in transplanted tumors, melanoma and
      glioblastoma, when compared with controls (P < 0.001 and 0.025, respectively).
      These results suggest that, although thalidomide is not a cytotoxic drug for
      neoplastic cells, it might partially inhibit the tumoral growth through any of
      its pharmacological actions; by blockage of cell-surface adhesion receptors
      induction of DNA oxidation, or inhibition of angiogenesis. Further investigations
      on the use of thalidomide perhaps associated to cytotoxic drugs, for treatment of
      ectodermic neoplasms seem guaranteed.

PMID- 12415633
TI  - Use of microdialysis to study platinum anticancer agent pharmacokinetics in
      preclinical models.
AB  - Microdialysis sampling of blood and extracellular fluid (ECF) of living tissue
      offers unique advantages for studying anticancer drug distribution, metabolism,
      and mechanisms of tumor drug resistance. We applied microdialysis sampling in a
      rat model to describe the pharmacokinetics of cisplatin and carboplatin
      simultaneously in blood and several peripheral tissues, including tumor tissue.
      After i.v. bolus drug administration, samples were collected every 10 min for 4-6
      h using microdialysis probes implanted into the jugular vein, kidney, and either
      liver or subcutaneously growing breast tumor tissue in anesthetized Fisher 344
      rats. Analyte concentrations are expressed as absolute extracellular
      concentrations obtained by correction of the data for in vivo recovery. For
      cisplatin, peak renal concentrations (mean, 36.7 and 80.1 micrograms/mL) always
      exceeded peak plasma (8.4 and 13.2 micrograms/mL) and hepatic (6.3 and 10.4
      micrograms/mL) concentrations following 5 and 10 mg/kg doses, respectively. For
      carboplatin, doses of 20 and 30 mg/kg also resulted in high peak renal
      concentrations, which were similar at both dose levels (mean, 87.9 and 89.3
      micrograms/mL). However, at 30 mg/kg peak hepatic carboplatin concentrations were
      increased significantly, resulting in a disproportionate 3.5-fold increase in
      mean AUC at the higher dose level. Tumor cisplatin and carboplatin AUCs were
      similar to that in the circulation, but variable, ranging from 52 to 109% of the
      corresponding plasma AUCs. Microdialysis was determined to be a reliable
      methodology for examining the in vivo disposition of platinum anticancer agents
      in multiple tissue types. Our results revealed expected large renal exposures
      following i.v. administration, and variable tumor exposure with dose. Significant
      increases in hepatic carboplatin exposure with increasing dose suggest a possible
      mechanism for high-dose carboplatin-induced hepatic toxicity.

PMID- 12415635
TI  - Epidemiology of colorectal cancer.
AB  - This review article presents colorectal cancer epidemiology, describing main
      epidemiologic characteristics and the influence of environmental and life style
      risk factors. The most important ideas for primary prevention are listed at the
      end of the article.

PMID- 12415634
TI  - Lack of toxicity of EGFR antisense gene therapy.
AB  - PURPOSE: EGFR is overexpressed in many human cancer cells, including head and
      neck squamous cell carcinoma (HNSCC). We have previously shown that elevated EGFR
      levels in the primary HNSCC tumor are associated with decreased survival.
      Reduction of EGFR tumor expression levels using an antisense EGFR sequence under
      the control of the U6 small nuclear RNA promoter abrogates tumor growth in a head
      and neck xenograft model. In support of a phase I clinical trial of an EGFR
      antisense gene-liposome complex administered to HNSCC patients, we conducted a
      series of studies to evaluate the safety of intralesional injections of EGFR
      liposomal antisense gene therapy in normal mice. METHODS: Three dose tiers were
      examined including the starting DNA-lipid dose for the clinical trial. RESULTS:
      Tissues and blood were harvested from mice treated with the liposome-mediated
      gene therapy and control mice at several time points for analysis. In this dosing
      range, administration of the antisense EGFR DNA-liposome complex had no apparent
      adverse effect on renal, hepatic and hematologic parameters studied. No major
      organ pathologic changes were observed. CONCLUSIONS: These results suggest that
      the toxicity of intralesional EGFR antisense DNA plus liposomes is restricted to
      a self-limited inflammation at the injection site, and may be well-tolerated in
      the clinical setting. EGFR antisense gene therapy was reviewed by the Recombinant
      DNA Advisory Committee and the Food and Drug Administration, and a phase I
      clinical trial is currently underway in patients with advanced HNSCC.

PMID- 12415636
TI  - Influence of bacterial immunomodulators on the induction of specific IGG with
      patients during a peroral hyposensitization therapy.
AB  - Peroral administration of allergen during hyposensitization therapy with allergic
      patients is in comparison with an administration by injection of a wilder
      inductor of specific IgG antibodies. The peroral administration of bacterial
      immunomodulators increases IgG formation significantly. The described experiment
      examines the influence of bacterial immunomodulator Olimunostim on the level of
      specific antibodies during peroral hyposensitization therapy with allergic
      patients.

PMID- 12415637
TI  - Expression of ob gene coding the production of the hormone leptin in hepatocytes
      of liver with steatosis.
AB  - Leptin is a circulating pleiotropic hormone that play an important role in
      appetite control, fat metabolism, regulation of body weight, fetus growth, growth
      and aging of adults and hematopoiesis. It is expressed abundantly and
      specifically in the adipose tissue. A liver cell with developed steatosis
      represents a cell metabolism similar to metabolism of cells of adipose tissue.
      Analyses of serum leptin and free leptin receptor in the serum of patients with
      steatosis showed significant variations from reference limits of normal values.
      However in liver tissue with verified steatosis detection of mRNA gene for leptin
      was not proven. Such expression of ob gene for leptin was not found even in the
      liver tissue without steatosis. With respect to the absence of ob gene
      expression, the direct effect of ob gene expression on other parameters of leptin
      metabolism could not be evaluated. The RT-PCR method with verified specificity
      and satisfying sensitivity was developed. The results obtained from analysis of
      serum leptin and free leptin receptor in the serum are presented and evaluated.
      The used methods were verified and reference limits for Czech population were
      defined in dependence on age and other clinical parameters.

PMID- 12415638
TI  - The cathepsin-D expression in the cyto-invasive stages of coccidia in intestinal
      mucosa of chickens, and the relevance of this proteinase for intracellular
      penetration and spreading of coccidia in host tissues.
AB  - The Cathepsin-D proteinase was demonstrated immunohistochemically in cases of
      intestinal coccidiosis in chickens; its expression concerned almost the cyto
      invasive stages of reproductive cycle of several strains of coccidia (merozoites
      of the II-nd generation and also microgametes). The authors consider Cathepsin-D
      as a potentional "penetration/spreading factor", being significant for
      intracellular invasion and spreading of coccidia into host cells. In diagnostic
      practice, an immunohistochemical demonstration of Cathepsin-D is a relatively
      simple and sensitive method, which brings information on the extent of parasitic
      lesions, and on participation of particular evolutive forms of coccidial life
      cycle; it may also be useful in proving isolated coccidia in the intestinal
      epithelium, poorly recognized in routine HE preparation. Some Cathepsin-D
      protease reactivity in intestinal Cryptosporidiosis is also briefly mentioned.
      The examined cases of cerebral toxoplasmosis and primary acanthamoebic
      meningoencephalitis (PAME) showed in above mentioned methods negative results.

PMID- 12415683
TI  - Characteristic genetic alterations in lung cancer.
AB  - Our understanding of the molecular pathology of lung cancer is advancing rapidly
      with several specific genes and chromosomal regions being identified. Lung cancer
      appears to require many mutations in both dominant and recessive oncogenes before
      they become invasive. Several genetic and epigenetic changes are common to all
      lung cancer histologic types, while others appear to be tumor-type specific. The
      identification of those specific genes undergoing such mutations and the sequence
      of cumulative changes that lead the neoplastic changes for each lung tumor
      histologic type remain to be fully elucidated. Recent findings in normal and
      preneoplastic bronchial epithelium from lung cancer patients and smoker subjects
      suggest that genetic changes may provide in this neoplasm new methods for early
      diagnosis, risk assessment, and for monitoring response to chemoprevention.

PMID- 12415684
TI  - Clinical and biological relevance of recently defined categories of pulmonary
      neoplasia.

PMID- 12415685
TI  - Molecular epidemiology of human cancer risk. Gene-environment interactions and
      p53 mutation spectrum in human lung cancer.
AB  - Molecular epidemiology of cancer risk utilizes knowledge of both the genetic
      changes in cancer and the current hypothesis of chemical carcinogenesis when
      selecting possible markers for individual susceptibility, early disease, and
      biologically significant exposure. Polymorphisms of drug-metabolizing enzymes,
      especially CYP enzymes, and mutations in the p53 tumor-suppressor gene have been
      in the center of interest for the past decade. Both have shown promise, CYP
      polymorphisms as markers for individual susceptibility and p53 mutation spectrum
      at population level for specific exposure. However, it is probable that very few
      markers, if any, are sufficient alone. Future challenges for molecular
      epidemiology in the lung cancer field include pursuing ethically the best
      performance in applying that knowledge, in addition to the development of
      reliable and well-validated markers.

PMID- 12415686
TI  - Neuroendocrine phenotype of small cell lung cancer.
AB  - In conclusion, we have identified several neuroendocrine markers of SCLC and it
      is likely that for a successful screening program a small panel would need to be
      employed. From our studies AVP, CCK-BR, and GRP would be the most appropriate of
      the classical markers, while certain transcription factors such as sNRSF will
      also prove useful. Although SCLC may not originate from neuroendocrine cells,
      these genes appear to be expressed early in disease. The application of
      neuroendocrine markers for screening clinical samples is discussed in detail in
      Chapter 20 of the companion to this volume: Detection of small cell lung cancer
      by RT-PCR for neuropeptides, neuropeptide receptors, or a splice variant of the
      neuron restrictive silencer factor, Coulson, J. M., et al.

PMID- 12415687
TI  - AIDS-associated pulmonary cancers.

PMID- 12415688
TI  - Abrogation of the RB-p16 tumor suppressor pathway in human lung cancer.

PMID- 12415689
TI  - Sensitive detection of hypermethylated p16INK4a alleles in exfoliative tissue
      material.

PMID- 12415690
TI  - Role of receptor tyrosine kinases in lung cancer.
AB  - Receptor tyrosine kinases are important in normal cellular physiology as well in
      the pathogenesis of a variety of tumors, including lung cancer. RTKs are a target
      for novel therapies currently being investigated. In the clinics, EGFR inhibitors
      and c-Kit inhibitors are already being utilized, and c-Met inhibitors are in
      development. Even though the RTK inhibitors provide a novel mechanism, it is
      important to realize that lung cancer etiology is a complex process, and
      eventually standard chemotherapy may need to be used in conjunction with these
      novel therapies to make an important difference in response rates.

PMID- 12415691
TI  - Relationship of EGFR signal-transduction modulation by tyrosine kinase inhibitors
      to chemosensitivity and programmed cell death in lung cancer cell lines.

PMID- 12415692
TI  - Detection of the transcripts and proteins for the transforming growth factor-beta
      isoforms and receptors in mouse lung tumorigenesis using in situ hybridization
      and immunohistochemistry in paraffin-embedded tissue sections.

PMID- 12415693
TI  - Alterations in the expression of insulin-like growth factors and their binding
      proteins in lung cancer.

PMID- 12415694
TI  - Screening of mutations in the ras family of oncogenes by polymerase chain
      reaction-based ligase chain reaction.

PMID- 12415695
TI  - Assays for raf-1 kinase phosphorylation and activity in human small cell lung
      cancer cells.

PMID- 12415696
TI  - gamma-Glutamylcysteine synthetase in lung cancer. Effect on cell viability.

PMID- 12415697
TI  - Localization of cyclooxygenase-2 protein expression in lung cancer specimens by
      immunohistochemical analysis.

PMID- 12415698
TI  - Non-RI protocols for L-myc allelotyping and deletion mapping of chromosome 1p in
      primary lung cancers.

PMID- 12415699
TI  - Intercellular adhesion molecules (ICAM-1, VCAM-1, and LFA-1) in adenocarcinoma of
      lung. Technical aspects.

PMID- 12415700
TI  - MUC1 expression in lung cancer.

PMID- 12415701
TI  - Altered surface markers in lung cancer. Lack of cell-surface Fas/APO-1 expression
      in pulmonary adenocarcinoma may allow escape from immune surveillance.

PMID- 12415702
TI  - Prognostic relevance of angiogenic, proliferative, and apoptotic factors in lung
      carcinomas. A case review.

PMID- 12415703
TI  - Morphological assessment of apoptosis in human lung cells.

PMID- 12415704
TI  - [D-Arg6, D-Trp7,9, NmePhe8]-substance P (6-11) activates JNK and induces
      apoptosis in small cell lung cancer cells via an oxidant-dependent mechanism.

PMID- 12415705
TI  - Isolation of cells entering different programmed cell death pathways using a
      discontinuous Percoll gradient.

PMID- 12415706
TI  - Angiogenesis, metastasis, and lung cancer. An overview.

PMID- 12415707
TI  - Matrix metalloproteinase expression in lung cancer.

PMID- 12415708
TI  - Vascular endothelial growth factor expression in non-small cell lung cancer.

PMID- 12415709
TI  - Regulation of angiostatin mobilization by tumor-derived matrix metalloproteinase
      2.

PMID- 12415710
TI  - In vitro and in vivo assays for the proliferative and vascular permeabilization
      activities of vascular endothelial growth factor (VEGF) and its receptor.

PMID- 12415711
TI  - Detection of telomerase activity in lung cancer tissues.

PMID- 12415712
TI  - Analysis of alterations in a base-excision repair gene in lung cancer.

PMID- 12415713
TI  - Induction of lung cancer by passive smoking in an animal model system.

PMID- 12415714
TI  - Metastatic orthotopic mouse models of lung cancer.

PMID- 12415715
TI  - Lung-specific expression of mutant p53 as mouse model for lung cancer.

PMID- 12415716
TI  - Use of nucleotide excision repair-deficient mice as a model for chemically
      induced lung cancer.

PMID- 12415717
TI  - Nude mouse lung metastases models of osteosarcoma and Ewing's sarcoma for
      evaluating new therapeutic strategies.

PMID- 12415718
TI  - Tumor-specific metastasis to lung using reporter gene-tagged tumor cells.

PMID- 12415719
TI  - Cultures of surgical material from lung cancers. A kinetic approach.

PMID- 12415720
TI  - The hollow fiber assay.

PMID- 12415721
TI  - The potential of latent semantic analysis for machine grading of clinical case
      summaries.
AB  - OBJECTIVE: This paper introduces latent semantic analysis (LSA), a machine
      learning method for representing the meaning of words, sentences, and texts. LSA
      induces a high-dimensional semantic space from reading a very large amount of
      texts. The meaning of words and texts can be represented as vectors in this space
      and hence can be compared automatically and objectively. PSYCHOLOGICAL THEORY: A
      generative theory of the mental lexicon based on LSA is described. The word
      vectors LSA constructs are context free, and each word, irrespective of how many
      meanings or senses it has, is represented by a single vector. However, when a
      word is used in different contexts, context appropriate word senses emerge.
      CURRENT APPLICATIONS: Several applications of LSA to educational software are
      described, involving the ability of LSA to quickly compare the content of texts,
      such as an essay written by a student and a target essay. POTENTIAL MEDICAL
      APPLICATIONS: An LSA-based software tool is sketched for machine grading of
      clinical case summaries written by medical students.

PMID- 12415722
TI  - Patients' and physicians' understanding of health and biomedical concepts:
      relationship to the design of EMR systems.
AB  - OBJECTIVE: The aim of this paper is to examine knowledge organization and
      reasoning strategies involved in physician-patient communication and to consider
      how these are affected by the use of computer tools, in particular, electronic
      medical record (EMR) systems. DESIGN: In the first part of the paper, we
      summarize results from a study in which patients were interviewed before their
      interactions with physicians and where physician-patient interactions were
      recorded and analyzed to evaluate patients' and physicians' understanding of the
      patient problem. We give a detailed presentation of one of such interaction, with
      characterizations of physician and patient models. In a second set of studies,
      the contents of both paper and EMRs were compared and in addition, physician
      patient interactions (involving the use of EMR technology) were video recorded
      and analyzed to assess physicians' information gathering and knowledge
      organization for medical decision-making. RESULTS: Physicians explained the
      patient problems in terms of causal pathophysiological knowledge underlying the
      disease (disease model), whereas patients explained them in terms of narrative
      structures of illness (illness model). The data-driven nature of the traditional
      physician-patient interaction allows physicians to capture the temporal flow of
      events and to document key aspects of the patients' narratives. Use of electronic
      medical records was found to influence the way patient data were gathered,
      resulting in information loss and disruption of temporal sequence of events in
      assessing patient problem. CONCLUSIONS: The physician-patient interview allows
      physicians to capture crucial aspects of the patient's illness model, which are
      necessary for understanding the problem from the patients' perspective. Use of
      computer-based patient record technology may lead to a loss of this relevant
      information. As a consequence, designers of such systems should take into account
      information relevant to the patient comprehension of medical problems, which will
      influence their compliance.

PMID- 12415723
TI  - Representations of health concepts: a cognitive perspective.
AB  - OBJECTIVE: This paper studies the differences between controlled medical
      vocabularies that are designed as external artifacts and the mental concepts that
      are inside users' heads and used by users for reasoning, decision making,
      diagnosis, and treatment. DESIGN: The major theories of concept representations
      developed in cognitive science were reviewed, analyzed, and compared with the
      major controlled medical vocabularies developed in medicine. RESULTS: It was
      found that there are significant mismatches between controlled medical
      vocabularies that are designed as external artifacts and the mental concepts that
      are inside users' heads and used by users for reasoning, decision making,
      diagnosis, and treatment. CONCLUSIONS: Controlled medical vocabularies should be
      designed with systematical considerations of the cognitive structures and
      processes of the users. Without such considerations, the designed vocabularies
      will not be appropriate for people because they are hard to use, although they
      may or may not be appropriate for machine processing.

PMID- 12415724
TI  - Visualization and evaluation of clusters for exploratory analysis of gene
      expression data.
AB  - Clustering algorithms have been shown to be useful to explore large-scale gene
      expression profiles. Visualization and objective evaluation of clusters are two
      important considerations when users are selecting different clustering
      algorithms, but they are often overlooked. The developments of a framework and
      software tools that implement comprehensive data visualization and objective
      measures of cluster quality are crucial. In this paper, we describe a theoretical
      framework and formalizations for consistently developing clustering algorithms. A
      new clustering algorithm was developed within the proposed framework. We
      demonstrate that a theoretically sound principle can be uniformly applied to the
      developments of cluster-optimization function, comprehensive data-visualization
      strategy, and objective cluster-evaluation measures as well as actual
      implementation of the principle. Cluster consistency and quality measures of the
      algorithm are rigorously evaluated against those of popular clustering algorithms
      for gene expression data analysis (K-means and self-organizing maps), in four
      data sets, yielding promising results.

PMID- 12415725
TI  - Archimedes: a new model for simulating health care systems--the mathematical
      formulation.
AB  - This paper designs an object-oriented, continuous-time, full simulation model for
      addressing a wide range of clinical, procedural, administrative, and financial
      decisions in health care at a high level of biological, clinical, and
      administrative detail. The full model has two main parts, which with some
      simplification can be designated "physiology models" and "models of care
      processes." The models of care processes, although highly detailed, are
      mathematically straightforward. However, the mathematics that describes human
      biology, diseases, and the effects of interventions are more difficult. This
      paper describes the mathematical formulation and methods for deriving equations,
      for a variety of different sources of data. Although Archimedes was originally
      designed for health care applications, the formulation, and equations are general
      and can be applied to many natural systems.

PMID- 12415726
TI  - Emerging paradigms of cognition in medical decision-making.
AB  - The limitations of the classical or traditional paradigm of decision research are
      increasingly apparent, even though there has been a substantial body of empirical
      research on medical decision-making over the past 40 years. As decision-support
      technology continues to proliferate in medical settings, it is imperative that
      "basic science" decision research develop a broader-based and more valid
      foundation for the study of medical decision-making as it occurs in the natural
      setting. This paper critically reviews both traditional and recent approaches to
      medical decision making, considering the integration of problem-solving and
      decision-making research paradigms, the role of conceptual knowledge in decision
      making, and the emerging paradigm of naturalistic decision-making. We also
      provide an examination of technology-mediated decision-making. Expanding the
      scope of decision research will better enable us to understand optimal decision
      processes, suitable coping mechanisms under suboptimal conditions, the
      development of expertise in decision-making, and ways in which decision-support
      technology can successfully mediate decision processes.

PMID- 12415727
TI  - Supramolecular Complex Formation in Signaling and Disease. Proceedings of a
      symposium. Santiago, Chile, September 2002.

PMID- 12415728
TI  - Introduction to supramolecular complex formation in cell signaling and disease.

PMID- 12415729
TI  - Lipid rafts: cell surface platforms for T cell signaling.
AB  - The Src family tyrosine kinase Lck is essential for T cell development and T cell
      receptor (TCR) signaling. Lck is post-translationally fatty acylated at its N
      terminus conferring membrane targeting and concentration in plasma membrane lipid
      rafts, which are lipid-based organisational platforms. Confocal fluorescence
      microscopy shows that Lck colocalizes in rafts with GPI-linked proteins, the
      adaptor protein LAT and Ras, but not with non-raft membrane proteins including
      the protein tyrosine phosphatase CD45. The TCR also associates with lipid rafts
      and its cross-linking causes coaggregation of raft-associated proteins including
      Lck, but not of CD45. Cross-linking of either the TCR or rafts strongly induces
      specific tyrosine phosphorylation of the TCR in the rafts. Remarkably, raft
      patching alone induces signalling events analogous to TCR stimulation, with the
      same dependence on expression of key TCR signalling molecules. Our results
      indicate a mechanism whereby TCR engagement promotes aggregation of lipid rafts,
      which facilitates colocalization of signaling proteins including Lck, LAT, and
      the TCR, while excluding CD45, thereby potentiating protein tyrosine
      phosphorylation and downstream signaling. We are currently testing this
      hypothesis as well as using imaging techniques such as fluorescence resonance
      energy transfer (FRET) microscopy to study the dynamics of proteins and lipids in
      lipid rafts in living cells undergoing signaling events. Recent data show that
      the key phosphoinositide PI(4,5)P2 is concentrated in T cell lipid rafts and that
      on stimulation of the cells it is rapidly converted to PI(3,4,5)P3 and
      diacylglycerol within rafts. Thus rafts are hotspots for both protein and lipid
      signalling pathways.

PMID- 12415730
TI  - New insights to the functional role of the T cell-antigen presenting cell
      immunological synapse.
AB  - Three innovative and complementary morphological approaches were employed to
      study the T cell/antigen presenting cell (APC) interaction: (i) high resolution
      three-dimensional confocal microscopy of the T cell-APC contact site; (ii) time
      lapse video recording in living T cells of [Ca2+]I and changes in distribution of
      various GFP fusion proteins with TCR/CD3-zeta complex associated- and other
      signaling components; (iii) measurement of lateral TCR mobility and that of
      recruited signaling components using techniques based on fluorescence recovery
      after photo-bleaching. These approaches were combined with biochemical and
      functional experiments to investigate two principal issues: (A) Recruitment and
      the three-dimensional arrangement of receptors and signaling components at the
      contact site between human CD4+ T lymphocytes and APCs, (B) Structure of the
      immunological synapse formed at the contact site between cytotoxic T lymphocytes
      (CTLs) and target cells. We discuss evidence indicating that TCR engagement and
      triggering can occur in the absence of large-scale molecular segregation into the
      T cell-APC contact site. Taken together our results indicate that although not
      required for TCR engagement and triggering, formation of the IS is important to
      reinforce TCR-mediated signal transduction and achieve full T cell activation.

PMID- 12415731
TI  - Posttranslational protein S-palmitoylation and the compartmentalization of
      signaling molecules in neurons.
AB  - Protein domains play a fundamental role in the spatial and temporal organization
      of intracellular signaling systems. While protein phosphorylation has long been
      known to modify the interactions that underlie this organization, the dynamic
      cycling of lipids should now be included amongst the posttranslational processes
      determining specificity in signal transduction. The characteristics of this
      process are reminiscent of the properties of protein and lipid phosphorylation in
      determining compartmentalization through SH2 or PH domains. Recent studies have
      confirmed the functional importance of protein S-palmitoylation in the
      compartmentalization of signaling molecules that support normal physiological
      function in cell division and apoptosis, and synaptic transmission and neurite
      outgrowth. In neurons, S-palmitoylation and targeting of proteins to rafts are
      regulated differentially in development by a number of processes, including some
      related to synaptogenesis and synaptic plasticity. Alterations in the S
      palmitoylation state of proteins substantially affect their cellular function,
      raising the possibility of new therapeutic targets in cancer and nervous system
      injury and disease.

PMID- 12415732
TI  - Caveolae and caveolae-like membrane domains in cellular signaling and disease:
      identification of downstream targets for the tumor suppressor protein caveolin-1.
AB  - Caveolae are small, flask-shaped invaginations of the plasma membrane present on
      a large number of mammalian cells. Recent results obtained with knock-out mice
      for the gene caveolin-1 demonstrate that expression of caveolin-1 protein is
      essential for caveolae formation in vivo. Caveolae are implicated in a wide
      variety of cellular events including transcytosis, cholesterol trafficking and as
      cellular centers important in coordinating signalling events. Caveolae share this
      role and the property of detergent insolubility with plasma membrane assemblies
      rich in glycosphingolipids and cholesterol, often called lipid rafts, but
      preferably referred to here as caveolae-like membrane domains. Due to such
      widespread presence and usage in cellular function, caveolae and related domains
      are implicated in human diseases, including cancer. In particular, the protein
      caveolin-1 is suggested to function as a tumor suppressor protein. Evidence
      demonstrating such a role for caveolin-1 in human colon carcinoma cells will be
      discussed together with data from microarray experiments seeking to identify
      caveolin-1 target genes responsible for such behavior.

PMID- 12415733
TI  - Caveolin-1-mediated post-transcriptional regulation of inducible nitric oxide
      synthase in human colon carcinoma cells.
AB  - Reactive oxygen species are now widely recognized as important players
      contributing both to cell homeostasis and the development of disease. In this
      respect nitric oxide (NO) is no exception. The discussion here will center on
      regulation of the inducible form of nitric oxide synthase (iNOS) for two reasons.
      First, only iNOS produces micromolar NO concentrations, amounts that are high by
      comparison with the picomolar to nanomolar concentrations resulting from Ca2(+)
      controlled NO production by endothelial eNOS or neuronal nNOS. Second, iNOS is
      not constitutively expressed in cells and regulation of this isoenzyme, in
      contrast to endothelial eNOS or neuronal nNOS, is widely considered to occur at
      the transcriptional level only. In particular, we were interested in the
      possibility that caveolin-1, a protein that functions as a tumor suppressor in
      colon carcinoma cells (Bender et al., 2002; this issue), might regulate iNOS
      activity. Our results provide evidence for the existence of a post
      transcriptional mechanism controlling iNOS protein levels that involves caveolin
      1-dependent sequestration of iNOS within a detergent-insoluble compartment.
      Interestingly, despite the high degree of conservation of the caveolin-1
      scaffolding domain binding motif within all NOS enzymes, the interaction detected
      between caveolin-1 and iNOS in vitro is crucially dependent on presence of a
      caveolin-1 sequence element immediately adjacent to the scaffolding domain. A
      model is presented summarizing the salient aspects of these results. These
      observations are important in the context of tumor biology, since down-regulation
      of caveolin-1 is predicted to promote uncontrolled iNOS activity, genotoxic
      damage and thereby facilitate tumor development in humans.

PMID- 12415734
TI  - Calcium signal compartmentalization.
AB  - Cytosolic calcium signals are produced by suddenly increasing the concentration
      of free calcium ions (Ca2+). This can occur by opening channels permeable to Ca2+
      either in the surface cell membrane or in the membranes of intracellular
      organelles containing high Ca2+ concentrations. Ca2+ signals can control several
      different processes, even in the same cell. In pancreatic acinar cells, for
      example, Ca2+ signals do not only control the normal secretion of digestive
      enzymes, but can also activate autodigestion and programmed cell death. Recent
      technical advances have shown that different patterns of Ca2+ signals can be
      created, in space and time, which allow specific cellular responses to be
      elicited. The mechanisms responsible for Ca2+ signal compartmentalization are now
      largely known and will be described on the basis of recent studies of Ca2+
      transport pathways and their regulation in pancreatic acinar cells. It turns out
      that the Ca2+ handling as well as the structural characteristics of the
      endoplasmic reticulum (ER) and the mitochondria are of particular importance.
      Using a variety of Ca(2+)-sensitive fluorescent probes placed in different sub
      cellular compartments in combination with local uncaging of caged Ca2+, many new
      insights into Ca2+ signal generation, compartmentalization and termination have
      recently been obtained.

PMID- 12415735
TI  - Redox regulation of calcium release in skeletal and cardiac muscle.
AB  - In skeletal and cardiac muscle cells, specific isoforms of the Ryanodine receptor
      channels mediate Ca2+ release from the sarcoplasmic reticulum. These channels are
      highly susceptible to redox modifications, which regulate channel activity. In
      this work, we studied the effects of Ca2+ (endogenous agonist) and Mg2+
      (endogenous inhibitor) on the kinetics of Ca2+ release from sarcoplasmic
      reticulum vesicles isolated from skeletal or cardiac mammalian muscle. Native
      skeletal vesicles exhibited maximal stimulation of release kinetics by 10-20
      microM [Ca2+], whereas in native cardiac vesicles, maximal stimulation of release
      required only 1 microM [Ca2+]. In 10 microM [Ca2+], free [Mg2+] < 0.1 mM produced
      marked inhibition of release from skeletal vesicles but free [Mg2+] < or = 0.8 mM
      did not affect release from cardiac vesicles. Incubation of skeletal or cardiac
      vesicles with the oxidant thimerosal increased their susceptibility to
      stimulation by Ca2+ and decreased the inhibitory effect of Mg2+ in skeletal
      vesicles. Sulfhydryl-reducing agents fully reversed the effects of thimerosal.
      The endogenous redox species, glutathione disulfide and S-nitrosoglutathione,
      also stimulated release from skeletal sarcoplasmic reticulum vesicles. In 10
      microM [Ca2+], 35S-nitrosoglutathione labeled a protein fraction enriched in
      release channels through S-glutathiolation. Free [Mg2+] 1 mM or decreasing free
      [Ca2+] to the nM range prevented this reaction. Possible physiological and
      pathological consequences of redox modification of release channels on Ca2+
      signaling in heart and muscle cells are discussed.

PMID- 12415736
TI  - IP3 dependent Ca2+ signals in muscle cells are involved in regulation of gene
      expression.
AB  - Potassium depolarization of cultured muscle cells was employed to study cellular
      responses linked to calcium signaling. Events occurring after depolarization
      include i) A transient increase of the IP3 mass (2-10s); ii) A slow calcium
      transient (5 to 25s) that propagates as a low concentration wave along the
      myotube showing a distinct calcium transient at the level of cell nuclei. Due to
      the presence of IP3 receptors both in the SR (A-band region) and in the nuclear
      envelope, these two events appear to be related; iii) Phosphorylation of mitogen
      activated kinases (ERK 1/2) and of the transcription factor CREB (30 s-10 min),
      as well as expression of the early genes c-fos, c-jun and egr-1 mRNA (5-15 min).
      Several independent pieces of evidence, including results obtained using
      inhibitors specific for individual steps, allowed us to connect these in a
      sequential manner. As the same type of signaling cascade can be triggered by
      oxidants, neurotransmitters and hormones, the ensemble of results allows us to
      propose a general model to describe signaling events that link membrane
      stimulation to regulation of gene transcription in skeletal muscle cells.

PMID- 12415737
TI  - Molecular interplay between ion channels and the regulation of apoptosis.
AB  - Apoptosis is the programmed and deliberate destruction of specific cells. This
      process occurs during normal development and maintains cellular homeostasis.
      Disruption or malfunction of apoptosis is implicated in diseases like cancer,
      AIDS as well as neurodegenerative disorders. The movement of monovalent ions
      appears to set the stage for the induction of the self-destruction machinery by
      creating an intracellular environment that favors activation and coordinated
      execution of the apoptotic program. Understanding the components and steps
      involved in this intricate process can further our insight to diseases and reveal
      new approaches for therapeutic treatment.

PMID- 12415738
TI  - Ion movements in cell death: from protection to execution.
AB  - Cell death is preceded by severe disruption of inorganic ion homeostasis. Seconds
      to minutes after an injury, calcium, protons, sodium, potassium and chloride are
      exchanged between the cell and its environment. Simultaneously, ions are shifted
      between membrane compartments inside the cell, whereby mitochondria and
      endoplasmic reticulum play a crucial role. Depending of the type and severity of
      injury, two mutually exclusive metastable states can be reached, which predict
      the final outcome. Cells characterized by large increases in cytosolic [Ca2+],
      [Na+] and [Mg2+] swell and die by necrosis; alternatively, cells characterized by
      high [H+] and low [K+], with normal [Na+] and normal to moderate [Ca2+] increases
      die by apoptosis. The levels of these ions represent central determinants in
      signaling events leading to cell death. Their movements are explained
      mechanistically by specific modulation of membrane transport proteins including
      channels, pumps and carriers.

PMID- 12415739
TI  - Non-selective cation channels and oxidative stress-induced cell swelling.
AB  - Necrosis is considered as a non-specific form of cell death that induces tissue
      inflammation and is preceded by cell swelling. This increase in cell volume has
      been ascribed mainly to defective outward pumping of Na+ caused by metabolic
      depletion and/or to increased Na+ influx via membrane transporters. A specific
      mechanism of swelling and necrosis driven by the influx of Na+ through
      nonselective cation channels has been recently proposed (Barros et al., 2001a).
      We have characterized further the properties of the nonselective cation channel
      (NSCC) in HTC cells. The NSCC shows a conductance of approximately 18 pS, is
      equally permeable to Na+ and K+, impermeant to Ca2+, requires high intracellular
      Ca2+ as well as low intracellular ATP for activation and is inhibited by
      flufenamic acid. Hydrogen peroxide induced a significant increase in cell volume
      that was dependent on external Na+. We propose that the NSCC, which is ubiquitous
      though largely inactive in healthy cells, becomes activated under severe
      oxidative stress. The ensuing Na+ influx initiates via positive feedback a series
      of metabolic and electrolytic disturbances, resulting in cell death by necrosis.

PMID- 12415740
TI  - Phospholipid synthesis, diacylglycerol compartmentation, and apoptosis.
AB  - Apoptosis is a means by which organisms dispose of unwanted cells without
      inducing an inflammatory response. Alterations in apoptosis is a common process
      by which cells become cancerous. Paradoxically, many cancer chemotherapeutics
      preferentially kill cancer cells by inducing apoptosis. Diacylglycerol is a lipid
      second messenger that regulates cell growth and apoptosis and is produced during
      signal transduction by hydrolysis of membrane phospholipids. Protein kinase Cs
      are a family of diacyglycerol responsive enzymes that are recruited to cellular
      membranes as a consequence of diacylglycerol production where they phosphorylate
      specific target proteins responsible for regulating cell growth. In this review,
      we will first summarize our current understanding of the role of specific
      proteins kinase C isoforms in the induction of cell growth/apoptosis.
      Subsequently, we will discuss how insights gained in lipid-mediated regulation of
      protein kinase Cs promotes our understanding of the role specific family members
      play in regulating cell growth. Finally, other diacylglycerol binding proteins
      involved in regulating apoptosis will be discussed.

PMID- 12415741
TI  - Signaling triggered by Thy-1 interaction with beta 3 integrin on astrocytes is an
      essential step towards unraveling neuronal Thy-1 function.
AB  - Thy-1 is an abundant neuronal glycoprotein in mammals. Despite such prevalence,
      Thy-1 function remains largely obscure in the absence of a defined ligand.
      Recently described evidence that Thy-1 interacts with beta 3 integrin on
      astrocytes will be discussed. Thy-1 binding to beta 3 integrin triggers tyrosine
      phosphorylation of focal adhesion proteins in astrocytes, thereby promoting focal
      adhesion formation, cell attachment and spreading. Thy-1 has been reported to
      modulate neurite outgrowth by triggering a cellular response in neurons. However,
      our data indicate that Thy-1 can also initiate signaling events that promote
      adhesion of adjacent astrocytes to the underlying surface. Preliminary results
      suggest that morphological changes observed in the actin cytoskeleton of
      astrocytes as a consequence of Thy-1 binding is mediated by small GTPases from
      the Rho family. Our findings argue that Thy-1 functions in a bimodal fashion, as
      a receptor on neuronal cells and as a ligand for beta 3 integrin receptor on
      astrocytes. Since Thy-1 is implicated in the inhibition of neurite outgrowth,
      signaling events in astrocytes are likely to play an important role in this
      process.

PMID- 12415742
TI  - Regulation of Rho family GTPases by cell-cell and cell-matrix adhesion.
AB  - Integrins and cadherins are transmembrane adhesion receptors that are necessary
      for cells to interact with the extracellular matrix or adjacent cells,
      respectively. Integrins and cadherins initiate signaling pathways that modulate
      the activity of Rho family GTPases. The Rho proteins Cdc42, Rac1, and RhoA
      regulate the actin cytoskeleton. Cdc42 and Rac1 are primarily involved in the
      formation of protrusive structures, while RhoA generates myosin-based
      contractility. Here we examine the differential regulation of RhoA, Cdc42, and
      Rac1 by integrin and cadherin signaling. Integrin and cadherin signaling leads to
      a decrease in RhoA activity and activation of Cdc42 and Rac1. When the normal
      RhoA suppression is antagonized or RhoA signaling is increased, cells exhibited
      impaired spreading on the matrix protein fibronectin and decreased cell-cell
      adhesion. Spreading on fibronectin and the formation of cell-cell adhesions is
      decreased in cells expressing dominant negative forms of Cdc42 or Rac1. These
      data demonstrate that integrins and cadherins regulate Rho proteins in a
      comparable manner and lead us to speculate that these changes in Rho protein
      activity participate in a feedback mechanism that promotes further cell-matrix or
      cell-cell interaction, respectively.

PMID- 12415743
TI  - Cytohesins and centaurins control subcellular trafficking of macromolecular
      signaling complexes: regulation by phosphoinositides and ADP-ribosylation
      factors.
AB  - The ADP-ribosylation factor family of small GTP-binding proteins are implicated
      in the regulation of vesicular transport and control of cytoskeletal and cell
      adhesion events. The phosphoinositide 3-kinase, phosphoinositide 4-P 5-kinase and
      phospholipase D signaling pathways are major regulators of ARF signaling
      cascades. Two families of ARF regulatory molecules, the cytohesin ARF-Guanine
      nucleotide Exchange Factors and the centaurin GTPase-Activating Proteins provide
      key targets for the action of these lipids signals. A critical feature of the
      regulation of ARF signaling is coordinated recruitment of exchange factors, ARFs
      and GAPs to appropriate subcellular locations. These complexes drive repetitive
      cycles of ARF activation and membrane association that underlie the processes of
      cell movement as well as endosomal uptake and intracellular redistribution of
      signaling molecules. Cytohesins and centaurins bind specifically to a variety of
      other signaling proteins and these interactions may provide routes for regulated
      recruitment to the sites of ARF activation. Through their ability to control
      endosomal trafficking/recycling of these supramolecular signaling complexes ARF
      and phospholipid signaling pathways may have consequences that reach as far as
      the regulation of gene transcription and control of cell fate.

PMID- 12415744
TI  - Extracellular signals, cell interactions and transcription factors involved in
      the induction of the neural crest cells.
AB  - The neural crest is induced at the border between the neural plate and the
      epidermis. A complex set of signals is required for the specification of the
      crest cells between the epidermis and the neural plate. Here we discuss evidence
      supporting a model for neural crest induction in which different signals
      contribute in a sequential order. First, a gradient of bone morphogenic proteins
      (BMPs) is established in the ectoderm that results in segregation into neural
      plate, neural folds and epidermis at increasing levels of BMP activity. Thus, the
      neural folds are induced at a precise threshold concentration of BMP, but this
      neural fold has an anterior character. In a second step, these anterior neural
      folds are transformed into prospective neural crest by posteriorizing signals due
      to fibroblast growth factor, Wnts and retinoic acid. Finally, the induced cells
      interact to complete neural crest induction by a process that requires
      Notch/Delta signaling. Once neural crest formation has been induced by this
      combination of extracellular and intracellular signals, a cascade of
      transcription factors is activated in these cells that culminates in the ultimate
      steps of neural crest differentiation.

PMID- 12415745
TI  - Wnt signaling: a complex issue.
AB  - The development of tissues and organs in multicellular organisms is controlled by
      the interplay of several signaling pathways that cross-talk to provide positional
      information and induce cell fate specification. Together with other families of
      secreted factors such as TGF beta s, FGFs, Hedgehog and Notch proteins, Wnt
      growth factors are crucially implicated in these processes. Here, we will first
      discuss molecular mechanisms and then consider some biological consequences of
      Wnt signaling.

PMID- 12415746
TI  - T-kininogen inhibits kinin-mediated activation of ERK in endothelial cells.
AB  - Serum levels of T-kininogen increase dramatically as rats approach the end of
      their lifespan. Stable expression of the protein in Balb/c 3T3 fibroblasts leads
      to a dramatic inhibition of cell proliferation, as well as inhibition of the ERK
      signaling pathway. T-kininogen is a potent inhibitor of cysteine proteinases, and
      we have described that the inhibition of ERK activity occurs, at least in part,
      via stabilization of the MAP kinase phosphatase, MKP-1. Since fibroblasts are not
      a physiological target of T-kininogen, we have now purified the protein from rat
      serum, and used it to assess the effect of T-kininogen on endothelial cells.
      Adding purified T-kininogen to EAhy 926 hybridoma cells resulted in inhibition of
      basal ERK activity levels, as estimated using appropriate anti-phospho ERK
      antibodies. Furthermore, exogenously added T-kininogen inhibited the activation
      of the ERK pathway induced by either bradykinin or T-kinin. We conclude that the
      age-related increase in hepatic T-kininogen gene expression and serum levels of
      the protein could have dramatic consequences on endothelial cell physiology, both
      under steady state conditions, and after activation by cell-specific stimuli. Our
      results are consistent with T-kininogen being an important modulator of the
      senescent phenotype in vivo.

PMID- 12415747
TI  - Modulation of nuclear receptor dependent transcription.
AB  - Nuclear receptors comprise a family of transcription factors that regulate gene
      expression in a ligand dependent manner. They can activate or repress target
      genes by binding directly to DNA response elements as homo- or hetero-dimers or
      by binding to other classes of DNA-bound transcription factors. These activities
      have been linked to the formation of complexes with molecules that appear to
      serve as coactivators or corepressors, causing local modification of chromatin
      structure in order to regulate expression of their target genes. Several members
      of nuclear receptor family are directly associated with human malignancies
      including breast cancer, prostate cancer and leukaemia. The pathogenesis of each
      of these diseases is underpinned by the activities of a member of the
      superfamily; estrogen receptor-alpha (ER alpha) in breast cancer, androgen
      receptor (AR) in prostate cancer, and retinoic acid receptor alpha (RAR alpha) in
      acute promyelocytic leukaemia.

PMID- 12415748
TI  - The S6 kinase signaling pathway in the control of development and growth.
AB  - The discussion will focus on the role of the ribosomal protein S6 kinase (S6K)
      signaling pathway in the regulation of cell growth and proliferation. Although
      40S ribosomal protein S6 phosphorylation was first described 25 years ago
      (Gressner and Wool, 1974), it only recently has been implicated in the
      translational up-regulation of mRNAs coding for the components of protein
      synthetic apparatus (Fumagalli and Thomas, 2000). These mRNAs contain an
      oligopyrimidine tract at their 5' transcriptional start site, termed a 5'TOP,
      which has been shown to be essential for their regulation at the translational
      level (Meyuhas et al., 1996). In parallel, a great deal of information has
      accumulated concerning the identification of the signaling pathway and the
      regulatory phosphorylation sites involved in controlling S6K activation (Dufner
      and Thomas, 1999). Despite this knowledge we are only beginning to identify the
      direct upstream elements involved in growth factor-induced kinase activation
      (Dennis et al., 2001; Pullen et al., 1998). Use of the immunosuppressant
      rapamycin, a bacterial macrolide, in conjunction with dominant interfering and
      activated forms of S6K1 has helped to establish the role of this signaling
      cascade in the regulation of growth and proliferation (Dennis and Thomas, 2002).
      In addition, current studies employing the mouse as well as Drosophila
      melanogaster have provided new insights into physiological function of S6K in the
      animal (Montagne et al., 1999; Pende et al., 2000). Loss of dS6K function in
      Drosophila melanogaster demonstrated its paramount importance in development and
      growth control (Montagne et al., 1999), whereas deletion of the S6K1 gene in the
      mouse led to an animal of reduced size and the identification of the S6K1
      homologue, S6K2 (Shima et al., 1998). Such mice are significantly smaller during
      fetal development (Shima et al., 1998) and hypoinsulinemic in the adult,
      conditions known to lead to type 2 diabetes (Pende et al., 2000).

PMID- 12415749
TI  - MMR vaccination: protecting our children.

PMID- 12415750
TI  - Primary care trusts: radical innovation or natural evolution?

PMID- 12415751
TI  - Diet in autism and associated disorders.
AB  - A dietitian discusses the theory that peptides with opioid activity may cause or
      trigger autism. The use of an exclusion diet to treat autism is explained,
      weighing the potential benefits against some of the practical difficulties of
      keeping to a strict exclusion diet. The use of nutritional supplements is
      described. An abnormal gut flora has also been implicated in autism and the use
      of probiotics and prebiotics in improving the integrity of the gut mucosa is also
      discussed.

PMID- 12415752
TI  - Childhood coughs and colds.
AB  - Causes, incidence and management of coughs and colds in children are discussed.
      In most cases consultation with a doctor and antibiotic therapy are unnecessary
      but health visitors and nurses have an important role in reassuring parents and
      advising them on management and relief of symptoms. When symptoms are frequent
      and persistent, the possibility of an underlying cause such as asthma should be
      considered. Parents should be advised to consult their doctor if a young baby
      with a cough or cold seems ill and is reluctant to feed, even if the baby does
      not have a raised temperature.

PMID- 12415753
TI  - Community midwifery in an inner-London district.
AB  - A community midwife describes the challenges and satisfactions of providing good
      care in a deprived, multiracial inner-city area.

PMID- 12415754
TI  - Baby massage: a dialogue of touch.
AB  - The significance and benefits of touch and massage for preterm infants in
      Neonatal Intensive Care Units and in the community are discussed. The article
      emphasises the value of massage in helping parents to bond with their baby and as
      part of family-centred care. A bibliography is included.

PMID- 12415756
TI  - Adult's and children's diets are different.

PMID- 12415755
TI  - School nursing in a Health Action Zone: how the service needs to change.
AB  - This article summarises the findings of a qualitative study carried out between
      January and July 2000. The aims were to examine the public health role of school
      nurses and to find out the views of young people, other agencies and school
      nurses on the school nursing service and how they want it to develop. The study
      was funded by the national Health Action Zone Fellowship Programme. Six
      recommendations to improve the school nursing service are made, based on issues
      raised during focus groups with young people aged 13-14 years, semi-structured
      interviews with stakeholders, and a workshop for school nurses. The
      recommendations are further supported by the findings of a literature review.

PMID- 12415757
TI  - Ethnic diets in a Western world.

PMID- 12415758
TI  - Deprived families: problems and needs.

PMID- 12415759
TI  - Solving feeding problems.

PMID- 12415760
TI  - Inadequate diets: short- and long-term problems.

PMID- 12415761
TI  - Responding when a baby dies.

PMID- 12415762
TI  - Group B streptococcus and the newborn: prevention needs a boost.

PMID- 12415763
TI  - The obesity epidemic.

PMID- 12415764
TI  - Domestic violence: an education programme for hospital staff.
AB  - An assistant director of nursing in an acute hospital describes how she
      identified a need for staff education about domestic violence and set up an
      awareness programme. Nominated nurses from the clinical areas most affected-
      Accident & Emergency, maternity, gynaecology and paediatrics--attended and
      disseminated information to colleagues. The content of the course is described.
      Evaluation showed that participants' knowledge base increased by an estimated
      25%. Junior medical staff now receive one hour's education in domestic violence
      during their A&E rotation. Links were forged with community agencies specialising
      in domestic violence, resulting in a more effective referral system.

PMID- 12415765
TI  - Caring for Bangladeshi children with atopic eczema.
AB  - A clinical nurse specialist discusses the care of Bangladeshi children with
      atopic eczema in the UK, outlining some specific differences in the way the
      condition presents in Asian children. The article also outlines some health
      beliefs and practices among Bangladeshi families which may affect the way they
      regard and manage atopic eczema. Nurses in a multicultural society such as the UK
      have a professional duty to offer appropriate care for all cultural groups and to
      try to ensure effective communication with families whose first language is not
      English.

PMID- 12415766
TI  - Teenage pregnancy and sex education.
AB  - The head of the Government's Teenage Pregnancy Unit at the Department of Health
      discusses the incidence and causes of the UK's high teenage pregnancy rates and
      the risk factors. She outlines current Government strategy and progress towards
      reducing the rate of teenage conceptions. These include initiatives to improve
      sex and relationship education in schools.

PMID- 12415767
TI  - "Let's talk about sex": ideas for sex education in schools.
AB  - A school health nurse describes how he developed sessions on sex education for 14
      15 year olds in the classroom setting, taking students' actual questions as a
      starting point. He compiled an information booklet and, with a colleague, set up
      a website to provide further information for the students and answer individual e
      mailed queries.

PMID- 12415769
TI  - Testicular cancer: seek advice early.
AB  - Men's partners are often the first to notice a common sign of testicular cancer -
      painless swelling or abnormality of the testis or scrotum.  The man should
      consult his GP straightaway, as early diagnosis is critical.

PMID- 12415768
TI  - Head louse and other common infections in schools: head teachers' use of an
      information pack.
AB  - A descriptive study examined head teachers' use of an information pack about
      common childhood infections and its usefulness, particularly for head louse
      infection. The survey covered all 122 schools in one borough in the North West of
      England. Overall response was 73% and 83.3% of head teachers considered the pack
      helpful for teachers and parents. The study highlights schools' wish for
      information and help with common infections, especially head louse infections,
      from the public health and community health services. The authors recommend
      providing such information regularly each term or year for teachers and parents,
      putting head louse infection in context with other common childhood infections.
      Regular education sessions are recommended for head teachers and community health
      professionals involved with head louse infections. These measures should help
      ensure a consistent, evidence-based and up-to-date approach.

PMID- 12415770
TI  - 20% men and 25% women obese by 2005.

PMID- 12415771
TI  - Increasing touch between parents and children with disabilities: preliminary
      results from a new programme.
AB  - Initial findings are presented from a specially devised touch therapy programme
      for parents of children with disabilities. A total of 42 parent children have
      completed the programme. Therapists teach parents simple massage techniques
      during one-hour sessions held once a week for eight weeks. The children had a
      range of disabilities including cerebral palsy, asthma, sensory impairments and
      Down's syndrome. Parents reported improvements in children's muscle tone, joint
      mobility, sleep patterns, bowel movements and response to other forms of therapy,
      e.g. physiotherapy. Parents also reported that they themselves had benefited,
      e.g. by feeling "closer" to their child and less stressed.

PMID- 12415772
TI  - "Midwife's mandarin madness": walking the Great Wall of China for charity.
AB  - The author, a midwife, describes how she accomplished a strenuous, organised trek
      in China to raise funds for the charity The Foundation for the Study of Infant
      Deaths. The experience was a challenge which taught many of the participants more
      about themselves as well as about the country they visited.

PMID- 12415773
TI  - Teething in children and the alleviation of symptoms.
AB  - Teething is a normal process by which an infant begins to cut the first teeth
      (primary dentition). On average, infants begin teething at six months and by the
      age of three years all the first teeth have erupted. A variety of symptoms can
      accompany teething including sensitive and painful gums, mouth ulceration,
      drooling, feeding difficulties, lack of sleep and crying, all of which result in
      a distressed child and anxious parent. Some teething symptoms can be alleviated
      effectively at home with teething aids such as cold teething rings. In addition,
      over-the-counter treatments are available which provide pain relief and are
      mainly in the form of analgesic and anaesthetic gels, some of which also possess
      antiseptic properties. Gels such as those containing choline salicylate can be
      applied direct to the gums specifically to relieve pain and inflammation.

PMID- 12415774
TI  - "Too clean for our own good?": current issues in home hygiene.
AB  - The public is confused by apparently conflicting messages about the need for
      hygiene to prevent food poisoning and other infectious intestinal disease (IID)
      and the hypothesis that the increase in atopic disease may be linked to lack of
      exposure to microbes in early childhood. The consensus of hygiene experts is that
      the public needs to understand what constitutes effective hygiene and how to
      target key household areas. Handwashing is particularly important, as are
      cleanliness and disinfection of food preparation surfaces. The issues are
      discussed and practical tips are given to pass on to families.

PMID- 12415775
TI  - Feeding "fussy" toddlers: some tips to give parents.
AB  - A dietitian offers practical solutions, both nutritional and psychological, for
      encouraging "fussy" toddlers aged 12 months upwards to eat a reasonable diet.

PMID- 12415776
TI  - [Conventional versus laparoscopic surgery in tumors of the colon].

PMID- 12415777
TI  - [Laparoscopic hepatic resection: personal experience with 29 cases].

PMID- 12415778
TI  - [Cryoablation and thermal ablation with radiofrequency in the treatment of
      neoplasms of the liver].

PMID- 12415779
TI  - [Conventional surgery versus laparoscopic surgery. Adrenal pathology].

PMID- 12415780
TI  - [Carcinoma of the pancreas: adjuvant and neoadjuvant treatment].

PMID- 12415781
TI  - [Adjuvant and neoadjuvant treatment of rectal carcinoma].

PMID- 12415782
TI  - [Neoadjuvant chemotherapy of gastric carcinoma].

PMID- 12415783
TI  - [Hepatic intra-arterial chemotherapy in the treatment of non-resectable
      colorectal liver metastasis: personal experience].

PMID- 12415784
TI  - [Isolation regional perfusion].

PMID- 12415785
TI  - [Hyperthermic-antiblastic perfusion in the treatment of tumor of the
      extremities].

PMID- 12415786
TI  - [Therapy of oncologic pain].

PMID- 12415787
TI  - [Treatment of liver metastasis with radiofrequency].

PMID- 12415788
TI  - [Treatment of loco-regional lymph nodes in neoplasms of the head and neck:
      strategies in clinical N+].

PMID- 12415789
TI  - [Treatment of the N0 neck in tumors of the larynx].

PMID- 12415790
TI  - [Treatment of the N0 neck in carcinoma of the larynx].

PMID- 12415791
TI  - [Treatment of loco-regional lymph nodes in breast neoplasms: learning curve and
      clinical application in the study of sentinel lymph nodes].

PMID- 12415792
TI  - [Ductal carcinoma in situ (DCIS): an always present reality; which treatment?
      Role of sentinel lymph node].

PMID- 12415793
TI  - [Treatment of loco-regional lymph nodes in cutaneous melanoma].

PMID- 12415794
TI  - [Systematic lymphadenectomy in cancer of the stomach: rationale and technique].

PMID- 12415795
TI  - [Colorectal neoplasms: the role of loco-regional lymph nodes].

PMID- 12415796
TI  - [The role of lymphadenectomy in the surgical treatment of pancreatic neoplasms].

PMID- 12415797
TI  - [Familiarity and heredity of tumors in function of an early surgical therapeutic
      approach].

PMID- 12415798
TI  - [Psychological support strategies in oncologic surgery].

PMID- 12415799
TI  - [Nursing interventions before and after surgical procedures].

PMID- 12415800
TI  - [Tools and procedures in the management of surgical specimens].

PMID- 12415801
TI  - [Molecular biology in postoperative monitoring].

PMID- 12415803
TI  - [Levels of university training of professional nurses in oncologic surgery].

PMID- 12415802
TI  - [Nursing research in oncologic surgery: state of the art].

PMID- 12415804
TI  - Current treatment of non-small cell lung cancer.

PMID- 12415805
TI  - Pemetrexed: current development and future directions in thoracic cancers.

PMID- 12415806
TI  - Epothilones: a new generation of microtubule-stabilizing compounds.

PMID- 12415807
TI  - Hypoxic active drugs.

PMID- 12415808
TI  - New anti-tubulin agents.

PMID- 12415809
TI  - Oral cytotoxic drugs.

PMID- 12415810
TI  - New platinum derivatives in advanced non-small cell lung cancer.

PMID- 12415811
TI  - New drugs in small cell lung cancer.

PMID- 12415812
TI  - Pharmacogenomics in lung tumors.

PMID- 12415813
TI  - The rational basis of using novel targeted biological agents in non-small cell
      lung cancer.

PMID- 12415814
TI  - Tyrosine kinase signal transduction inhibitors. Clinical trials.

PMID- 12415815
TI  - Second/third/fourth line therapy with tyrosine kinase inhibitors in NSCLC.

PMID- 12415817
TI  - A novel approach to the treatment of bone metastasis.

PMID- 12415816
TI  - Antiangiogenic agents.

PMID- 12415818
TI  - Therapeutic targeting of epidermal growth factor receptor with monoclonal
      antibodies.

PMID- 12415819
TI  - Targeted biological treatments in NSCLC. Farnesyl transferase inhibitors.

PMID- 12415821
TI  - Histone deacetylation inhibitors.

PMID- 12415820
TI  - Antisense oligonucleotides in lung cancer.

PMID- 12415822
TI  - The new drugs and biologics as sensitizers in the treatment of non-small cell
      lung cancer.

PMID- 12415823
TI  - Medical treatment of brain metastases from lung cancer.

PMID- 12415824
TI  - Targeting the epidermal growth factor receptor a new strategy in cancer
      treatment.

PMID- 12415825
TI  - Involvement of FHIT in lung carcinogenesis prospects for future clinical gene
      therapy applications.

PMID- 12415826
TI  - Cancer immunotherapy with MAGE antigens.

PMID- 12415828
TI  - Medical malpractice claims and quality improvement program as viewed by a
      forensic pathologist.
AB  - This is a review article dealing with the half-century evolution of the quality
      assurance program to improve patient care in the United States. The author
      attempted to point out some differences in approach to solving the medical error
      and medical malpractice problems between Japan and the U.S. In the 1970s, an
      increase in the medical malpractice claims resulted in such high premiums for
      medical liability insurance that it threatened the healthcare system in the U.S.
      Urgent legislative remedy, the Medical Injury Compensation Reform Act (MICRA) was
      put into place in the State of California. This act was the beginning of the
      definitive quality improvement in our health care system. It was followed by
      other improvement programs, such as the National Practitioner Data Bank (NPDB)
      for tracking physicians with malpractice judgments or settlements against them,
      or who have problems with the medical licensing Board or other impairments. By
      comparison, in recent years, in Japan, there has been a rash of medical
      malpractice claims, similar to the situation in the U.S. in the 1970's. The two
      pronged approach to maintaining and assuring quality health care are: (1) Set
      standards by inspection and accreditation of hospitals and healthcare facilities
      and (2) by credentialing and peer review program to assure the competency of the
      physicians and other healthcare personnel. Clinical medicine has made a major
      effort in setting up a quality assurance program and so has forensic medicine.
      Similar approaches have been used in both programs. The current emphasis in
      forensic medicine is on inspection and accreditation of the medical examiner and
      coroner's offices by the National Association of Medical Examiners (NAME) and re
      certification for the medical license and specialty board and credentialing and
      peer review activities.

PMID- 12415827
TI  - A new class of anti-cancer drugs: HDAC-inhibitors.

PMID- 12415829
TI  - [Continuous challenges in Japanese forensic toxicology practice: strategy to
      address specific goals].
AB  - In this paper, the status quo of forensic toxicology in Japan and the West is
      surveyed and a strategy to address future goals of Japanese forensic toxicology
      is proposed. Forensic toxicology in the West consists of three main areas--post
      mortem forensic toxicology, human-performance forensic toxicology and forensic
      urine drug testing. In Japan, post-mortem forensic toxicology is practiced in
      university forensic medicine departments while most of the human-performance
      forensic toxicology is carried out in police laboratories. However, at least at
      present, strictly controlled workplace urine drug testing is not being performed,
      despite the abuse of drugs even by uniformed members of the National Defence
      Forces and police. For several years, the author has been introducing Western
      forensic toxicology guidelines and recommendations, translated into Japanese with
      the help of Western forensic toxicologists, to Japanese forensic toxicologists.
      Western forensic toxicology practice is at an advanced stage, whereas Japanese
      practice is in a critical condition and holds many problems awaiting solution, as
      exemplified by the urine drug testing in police laboratories. There is never any
      sample left for re-examination by the defence in all cases, though the initial
      volume of the urine sample available for examination is 30-50 ml. Only one
      organisation carries out everything from sampling to reporting and, in addition,
      the parent drug and its metabolites are not quantified. It is clear that the
      police laboratories do not work within good laboratory practice guidelines, nor
      do they have quality manuals or standard operating procedures manuals. A basic
      change in Japanese forensic toxicology practice is now essential. The author
      strongly recommends that, first of all, Japanese toxicologists should prepare
      forensic toxicology guidelines based on the Western models. The guidelines would
      progress the following objectives for forensic toxicology laboratories: 1) to
      have documented good laboratory practice standards; 2) to have a quality control
      system including a quality manual and standard operating procedures manual; 3) to
      have some degree of compulsion to implement quality assurance both through their
      own internal efforts and by appropriate remedial actions based on the results of
      an external proficiency testing scheme. For forensic toxicologists, the
      implications are that they should be: 1) responsible for ensuring that laboratory
      practices are performed under satisfactory conditions and 2) required to be
      certified as a forensic toxicology specialist in order to prove their forensic
      toxicology ability. For their part, governments should: 1) carry out
      administrative reforms related to forensic toxicology; 2) simplify the procedure
      for obtaining certified reference materials; 3) introduce a strict workplace
      urine drug testing programme for government employees, at least for those related
      to law enforcement. When all of these objectives have been realised, the specific
      goal will be achieved through which Japanese forensic toxicology is able, in
      practice, to fulfill its responsibility to society.

PMID- 12415830
TI  - [Application of the HLA system to forensic medicine--from serology to DNA
      polymorphism].
AB  - HLA antigens are highly polymorphic and therefore considered useful for personal
      identification in forensic medicine. The HLA system was first applied to forensic
      medicine for serological typing and is currently being applied to DNA typing. We
      first applied the HLA system to serological typing for paternity testing.
      Exclusion of paternity was confirmed in 39 of 93 cases. While serological HLA
      typing and other testing yielded consistent results in 37 of these 39 cases,
      exclusion of paternity could be confirmed only by serological HLA typing in 1
      case and only by other testing in 1 case. Even in cases where exclusion could not
      be confirmed, it was possible to increase the probability of paternity.
      Bloodstains with known HLA types were then subjected to lymphocytotoxic
      inhibition tests to detect HLA antigens using one of the following methods: a two
      stage method using an antibody and a bloodstain extract; a one-stage method where
      a bloodstain was allowed to react directly with an antiserum; or a washing method
      where washing was combined with one of the two above methods. Although HLA
      antigen detection was possible using any of these methods, some antisera yielded
      false-positive reactions, which limited the range of usable antisera. With the
      exception of cross-reactions, the washing method eliminated false-positive
      reactions. Antigens were detectable in bloodstains that were left to stand for up
      to 42 days. DNA typing based on the HLA system was investigated by determining DR
      and DQB1 types using the Hot Start PCR-SSP method with various samples of known
      HLA types and tissue samples collected from unidentified corpses. With
      bloodstains, DR typing was possible in all 61 cases, while DQB1 typing was
      possible in 31 of 33 cases. DR typing was possible even when bloodstains had been
      stored for 10 to 20 years. With saliva stains, typing was possible in all cases
      by purifying DNA using a Microcon 100 microconcentrator. With hair samples,
      typing was possible with all hair root samples and about half of hair shaft
      samples. With mixed stains, the detection of minor components was possible even
      at a low mixing ratio of 10:1. With cigarette butts, as was the case with saliva
      stains, typing was possible using purified DNA. Lipstick did not affect the
      results of DNA typing. Although DNA typing was possible in many cases using
      tissue samples collected from unidentified corpses, the results were affected by
      factors such as status of corpse, postmortem interval, postmortem change and
      tissue type. With some aorta samples, for example, typing was possible up to one
      year after death. The results of typing were also fairly favorable using bone
      samples.

PMID- 12415831
TI  - [Medicolegal and compensation scientific approach to automobile accident].
AB  - Multiple injuries are frequently observed over the whole body of traffic victims
      in medico-legal autopsy cases. The assessment of a traffic casualty must include
      not only the victim but also the vehicle and the circumstances of the accident.
      Only consideration of all available data permits a better assessment of the
      mechanism of the crash and causation of injuries. J. M. Thevenet drove the first
      car carried from France to Japan on February 6, 1898. On October 28th, 1905, the
      first death by a road traffic accident occurred in Osaka. We performed a
      retrospective analysis of 279 traffic fatalities examined by medico-legal autopsy
      in Niigata that occurred over a twenty-two-year period from 1980 to 2001. All
      persons who had an ICD-10 code were grouped by 153 pedestrians, 43 pedal
      cyclists, 20 motorcycle riders, 45 car occupants, 11 occupants of pick-up trucks
      or vans, 4 occupants of heavy transport vehicles and 3 others. The average of ISS
      (injury scale score) is 40.7 in pedestrians, 26.7 in pedal cyclists, 32.4 in
      motorcycle riders, 25.1 in car occupants, 16.5 in occupants of pick-up trucks or
      vans, 24.0 in heavy transport vehicles and 69.0 in others. Rib fractures were
      observed in 170 cases (60.9%) and the frequency of other injuries was shown in
      Table 2. Criminal Punishment for drivers involved in 261 traffic accidents
      amounted to 35 sentences of imprisonment (13.4%), 46 suspension of execution of
      sentence (17.6%) and 60 sentence of fine (23.0%). Forty prone pedestrians run
      over by cars showed high ethanol levels in their blood. It was necessary to
      identify the driver of a vehicle in twelve car accidents and simulation with a
      computer is very useful. The average of ISS was 34.0 in ten drivers and 22.0 in
      fourteen fellow passengers. Four sudden natural deaths of drivers at the wheel,
      eight cases of death immediately after and from one day to five months after road
      traffic accidents, nine suicides and one intentional accident are excluded from
      traffic death. Both a medico legal and scientific compensation approach to
      automobile accident is now necessary.

PMID- 12415832
TI  - [Ethanol concentrations in multi-site sampling blood in forensic autopsy cases--a
      retrospective analysis over a period of six years (1994-1999) in Kumamoto
      University].
AB  - Ethanol and n-propanol concentrations in forensic autopsy cases determined in
      Department of Forensic Medicine, Kumamoto University School of Medicine were
      reviewed retrospectively. Out of 388 autopsies in 6 years (1994-1999), ethanol
      was positive in 88 (22.7%) cases. Higher positive rates were observed in bleeding
      and burning cases compared to other cases. Histograms of the blood ethanol
      concentrations in all ethanol positive cases had two peaks at 0.1 mg/ml to 0.5
      mg/ml and 1.5 mg/ml to 2.0 mg/ml ranges, which indicated that not only an
      intermediate but also a weak drunkenness level could be a risk factor of being
      involved in forensic fatalities. There were no differences in mean ethanol
      concentrations in the blood samples of the right, left and whole heart blood
      collected from each victim. The femoral blood, however, was slightly higher than
      those of heart blood. N-Propanol, an indicator for postmortem ethanol production,
      was detected in 14.7% of stomach contents samples as early as 6 to 12 hours of
      post mortem intervals, whereas it was not remarkable in urine and femoral vein
      blood.

PMID- 12415833
TI  - [Usefulness of postmortem dental panoramic X-ray photographs taken using a
      portable radiography apparatus for dental identification].
AB  - Fourteen unidentified human corpses were subjected to personal identification
      between 1999 and 2001. They included 5 drowning victims, three extensively burnt
      bodies, three skeletonized bodies, two highly putrefied bodies, and a body that
      had been run over by a train. Antemortem dental records were available in 12
      cases, and all were positively identified. For 10 of these cases, antemortem
      panoramic X-ray photographs were obtained. For postmortem examination, panoramic
      X-ray photographs were taken using a portable dental panoramic radiography
      apparatus, LPX7007 (ASAHI ROENTGEN, Japan), during autopsy. Comparison of the
      ante- and postmortem panoramic X-ray photographs gave accurate and useful
      information not only about dental treatment but also the anatomical features
      surrounding the upper and lower jaws. This method is not time-consuming and also
      has the advantage of allowing dental treatment to be examined extraorally in
      cases where it is difficult to open the mouth of the corpse.

PMID- 12415835
TI  - [The present situations and problems of endoscopic surgery--diagnosis and
      limitation].

PMID- 12415834
TI  - [Forensic autopsy cases of battered children in Japan (1990-1999)].
AB  - The investigation committee of Japanese Society of Legal Medicine has
      investigated 459 forensic autopsy cases of battered children from 1990-1999. The
      age range was 0-4 years of 381 cases (83%). Of them, the age less than 1 year was
      high as 161 cases (35.1%). The cause of death including head injury was 161 cases
      (35.1%), suffocation caused by nasal blockages 37 cases (8.1%), strangulation 32
      cases (7.0%), and drowning 30 cases (6.5%) was revealed. In case of assailant,
      own mother was 226 cases (49.2%), own father was 73 cases (15.9%) and stepfather
      46 cases (10.0%) were reported. The intention of cruelty was that the body was
      positively assaulted (84.3%) and duration was less than 2 months in 136 cases
      (67%). The nature of cruelty was that beating by other hands (16.8%) in 77 cases
      and pushed away and threw (1.7%) in 8 cases and those complex (7.8%) in 36 cases.
      The motive of cruelty when he assailant was own mother (209 cases) was as fellow:
      1. Mentally abnormal (15.3%), 2. Irresponsibility (14.4%), 3. Victim cries
      (5.7%). When the assailant was own father (63%), the motive of cruelty was as 1.
      Victim cries (12.7%), 2. Lack of love (7.9%), 3. Reassisted attitude (6.3%).
      Reported death in high temperature was in 29 cases (6.3%) and strangulation was
      in 27 cases (5.9%). The homicide was 13% and neither care nor protection
      (neglect) was 2.7%. The physical conditions of battered children were emaciated
      and stunted growth in 128 cases (31.2%). The past history of medical consultation
      to the medical hospital was 32 cases (17.8%). Among the injuries, external
      findings consist of abrasions and bruises were 147 cases (32%) and internal
      findings were 70 cases (16.7%) mainly numerous gastro-intestinal tract injuries
      than liver and lungs. In addition, lung edema (16.8%) in 68 cases, thymus atrophy
      (12.6%) in 51 cases and amalgamation (4.5%) in 18 cases were reported. The injury
      around the anus and genitalia were 13 cases (3.2%). The bone fracture was not
      observed in 368 cases (80.2%) out of 459. Among the intracranial injuries,
      subdural haemastoma or amalgamation were 31.6% (145 cases) out of 459.

PMID- 12415836
TI  - [Indications for and limitations of endoscopic thyroid surgery].
AB  - Endoscopic thyroid surgery has become a common procedure in recent years, mainly
      because of its cosmetic advantages. Generally two methods are used to obtain a
      working space: CO2 insufflation and anterior neck skin lifting. The incision
      sites for approaching the thyroid are the chest wall, mammary areolar area,
      axillary and submandibular area, in addition to the neck. Among the new operative
      devices, the ultrasonically activated scalpel has contributed to the development
      of endoscopic thyroid surgery. Based on our experience of more than 180 cases
      using our original endoscopic method, video-assisted neck surgery(the VANS
      method), we here report the clinical outcome and usefulness of the method. The
      operating time and blood loss in patients with 161 benign thyroid tumors were
      statistically compared between the small-tumor group (n = 138, < 5 cm) and the
      large-tumor group (n = 23, > or = 5 cm). More than 60% of the benign and 7.1% of
      the malignant thyroid tumors were operated on using the VANS method. Near or
      subtotal lobectomy was the most common procedure (64.4%) for benign tumors.
      Malignancy was defined as a papillary carcinoma < 1 cm in diameter. Total
      lobectomy with lymph node clearance was performed for all malignant cases.
      Although the operating time and blood loss were statistically greater in the
      large-tumor group than the small-tumor group, with increased experience it was
      possible to remove tumors of up to 7.4 cm safely. Our findings show that the VANS
      method is feasible, practical, and safe, and has great cosmetic benefits.
      However, it must be remembered that the intrinsic surgical goal of treatment
      should not be compromised in the pursuit of less-invasive surgery. Care must be
      taken to select appropriate patients carefully and to train surgeons sufficiently
      in the techniques required.

PMID- 12415837
TI  - [Endoscopic surgery for breast diseases: the present state of art and outlook for
      the future].
AB  - Endoscopic breast surgery (EBS) is still not in common use today, mainly because
      of the lack of intracavitary operative maneuvers in breast surgery. It has been
      shown, however, that in experienced hands, the therapeutic benefits of EBS
      include not only improved natural esthetic outcomes but also less morbidity with
      faster recovery. Endoscopic partial/total mastectomy, axillary dissection, and
      breast reconstruction can be performed through an axillary incision with an
      additional periareolar incision depending on the situation, as safe alternatives
      to conventional operative procedures for early breast cancer. Furthermore, EBS is
      particularly effective when performing axillary dissection and mobilizing tissue
      flaps for immediate reconstruction. Since EBS requires the creation of a
      dissecting working passage and space, which tends to increase operative
      invasiveness, operating time, and blood loss, in less experienced hands an
      initial period of learning curve adjustment appears to be mandatory. Safety in
      terms of adequate local control must be further evaluated and long-term results
      need to be followed up before EBS can be applied in more advanced-stage breast
      cancer. Instead of being regarded as a competing technology. EBS should be
      welcomed and accepted in combination with conventional methods to nurture and
      further improve the technical aspects of breast cancer surgery. EBS is expected
      to become an indispensable and integral part of breast surgery in the near
      future, especially in an era when informed consent is sought with broader patient
      choice and empowerment models.

PMID- 12415838
TI  - [Video-assisted thoracic surgical lobectomy in conjunction with lymphadenectomy
      for lung cancer].
AB  - Video-assisted thoracic surgery (VATS) has been in widespread use since the
      beginning of the 1990s. The initial indications for VATS were benign lesions of
      the lung, pneumothorax, benign tumors, etc. However, its application was extended
      to resection of lung cancer. We first gained experience with VATS lobectomy in
      September 1992, and also started performing lymphadenectomy using VATS in
      November 1993 after developing instruments for this meticulous operation. The 8
      year survival rate of final stage IA lung cancers following VATS is 97.2%; this
      survival rate is significantly better than that with open thoracotomy. Here we
      report on our 10-year experience with VATS lobectomy, focusing on stage I lung
      cancer.

PMID- 12415839
TI  - [Advantages and limitations in minimally invasive cardiac surgery].
AB  - The introduction of endoscopic technology to cardiovascular surgery was
      significantly delayed compared to abdominal and lung surgery, although it has
      been gradually introduced in this field during the past decade in closure of
      patent ductus arteriosus, repair of the vascular ring, implantation of pacemaker
      leads or AICD, and pericardectomy. Endoscopic technology also started to be used
      in harvesting saphenous vein grafts (SVG) and the left internal thoracic artery
      for coronary artery bypass grafting(CABG) from the mid-1990s. Although complete
      endoscopic surgery has not yet been established in the major field of standard
      cardiovascular surgery, many cardiac surgeons attempt to minimize the size of
      chest wounds with 6- to 8-cm skin incisions, which is called minimally invasive
      cardiac surgery (MICS) or minimally invasive direct coronary artery bypass
      (MIDCAB). Complete endoscopic cardiac surgeries were performed utilizing the Zeus
      system and Da Vinci system at the end of the 20th century. Another method to
      minimize the invasiveness of CABG is to perform it without cardiopulmonary
      bypass, so-called off-pump coronary artery bypass (OPCAB). Currently, less
      invasive procedures are mainly applied for relatively simple cardiac surgeries,
      although these procedures are also potentially effective to avoid postoperative
      cerebral or respiratory complications in high-risk patients. MICS is effective in
      reducing the size of surgical wounds and in decreasing intraoperative blood loss.
      On the other hand, the duration of anesthesia and surgery can be prolonged due to
      technical difficulty, and the risk of unsatisfactory anastomosis or incomplete
      revascularization can also be increased. The cardiopulmonary bypass circuit
      utilized for MICS requires a more complicated system including negative pressure
      venous drainage. The detection of accidental trouble during surgery, which is
      related to the extracorporeal circulation or the MICS procedure itself, can be
      delayed due to the limited surgical view. MICS procedures carry additional risks
      related to the more complicated cardiopulmonary bypass system and small surgical
      wound. We must be deliberate in determining the indications for MICS and obtain
      complete informed consent from patients when we perform MICS, including informing
      them of the additional risks related to the MICS procedure itself and the
      possibility of conversion to standard open-heart surgery.

PMID- 12415840
TI  - [Endoscopic surgery for malignant esophageal disease].
AB  - Endoscopic surgery for benign esophageal disease has been well established and is
      widely performed. On the other hand, endoscopic surgery for malignant esophageal
      disease has not yet been well established. However, we have developed and have
      been performing thoracoscopic esophagectomy with lymphadenectomy for esophageal
      cancer. We introduce here the results of our endoscopic surgery for esophageal
      cancer. In the early period of this surgery, more operative complications
      occurred, such as recurrent nerve palsy, chirothorax, bleeding, etc. However,
      these complications have gradually decreased. The survival rates of patients in
      each pathological stage who underwent this surgery are comparable to those of
      patients who underwent conventional surgery. In conclusion, thoracoscopic
      esophagectomy has become safe and will be acknowledged as the standard procedure
      for the treatment of esophageal cancer.

PMID- 12415842
TI  - [Laparoscopic biliary surgery].
AB  - Laparoscopic cholecystectomy has become the standard treatment for patients with
      symptomatic gallbladder disease. However, there is a substantial proportion of
      patients in whom laparoscopic cholecystectomy cannot be successfully performed,
      and conversion to open surgery is required because of technical difficulties or
      complications. The incidence of bile duct injury has increased in laparoscopic
      cholecystectomy. Meticulous dissection and intraoperative cholangiography could
      significantly reduce the rate of that injury. Laparoscopic cholecystectomy for
      acute cholecystitis is still controversial because of surgical difficulty. In our
      experience, early laparoscopic cholecystectomy is a beneficial option for
      patients with acute cholecystitis, and it may even be safe in the acute stage. A
      better alternative for high-risk early operation and septic cases is percutaneous
      transhepatic gallbladder drainage. The coexistence of gallbladder cancer should
      be ruled out and preoperative diagnosis should be done carefully. Laparoscopic
      management of common bile duct (CBD) stones has many advantages. However it has
      been reported to be demanding and time-consuming to perform, which limits its
      widespread adoption. In our experience with 258 patients, laparoscopic CBD
      exploration was feasible for almost all CBD stones. The technical difficulties
      associated with laparoscopic CBD exploration could be overcome with the
      development of suitable equipment and increased expertise.

PMID- 12415841
TI  - [Laparoscopic surgery for gastroduodenal disease].
AB  - Since 1990, laparoscopic surgery for gastrointestinal disease has been accepted
      worldwide because it is minimally invasive, associated with less pain, and
      results in early recovery. For the surgical management of gastroesophageal reflux
      and perforated peptic ulcer, laparoscopic procedures are recognized as the
      standard. Laparoscopic gastrectomies for cancer have developed since 1991.
      Laparoscopic wedge resection and intragastric mucosal resection are performed for
      the treatment of early gastric cancer without the risk of lymph node metastasis.
      For early gastric cancer with the risk of perigastric lymph node metastasis,
      laparoscopy-assisted Billroth-I gastrectomy with D1 lymph node dissection has
      been successfully performed. Thus, laparoscopic approaches play an important role
      in the management of gastroduodenal disease.

PMID- 12415843
TI  - [Present status and problems of laparoscopic surgery for colorectal cancer,
      especially indications and limitations].
AB  - Ten years have passed since laparoscopic surgery for colorectal cancer was
      performed for the first time in Japan. Health insurance has covered laparoscopic
      surgery for every stage of colorectal cancer since April 2002, indicating that
      this method will become an established operative procedure in the 21st century.
      As lymph node dissection is performed not only in D1 or D1 + alpha but also in D2
      or D3, this method is being used in advanced as well as early cancers. When
      extensive colorectal resection with appropriate lymph node dissection is
      performed in laparoscopic surgery, the laparoscopic mobilization of the colon and
      rectum and lymph node dissection are essential points, which require
      understanding of the anatomic characteristics of the colon and rectum. It is
      generally recognized that there is no difference in D3 lymph node dissection
      except for no. 223 and in lateral lymph node dissection between this method and
      the conventional method. However, this method involves various problems such as
      intraoperative accidents, difficulties in lymph node dissection and rectal
      exfoliation and excision, cost-effect issues, technical problems, port site
      recurrences, and long-term prognosis. The most decisive factor in the future
      development of this method is the concern about long-term prognosis. The results
      of a randomized controlled trial conducted in the USA/Europe will have
      considerable effect in determining the indications for this method. Care should
      be taken not to expand the indications for laparoscopic surgery in the absence of
      skilled techniques.

PMID- 12415844
TI  - [The current state of laparoscopic surgery for abdominal parenchymatous organs].
AB  - Laparoscopic surgery for abdominal parenchymatous organs such as the liver and
      pancreas presents unique technical challenges and anatomic difficulties although
      laparoscopic splenectomy has become the standard procedure in some hospitals. The
      advances in laparoscopic technology have encouraged expert hands to extend the
      procedure to parenchymatous organs. Clinical cases of laparoscopic hepatectomy,
      as well as laparoscopic thermal ablation, for patients with hepatic tumor have
      been increasing recently. The most important considerations for laparoscopic
      hepatectomy are the clinical characteristics of the tumor. Tumors that are
      smaller than 5 cm and located in the lower or left lateral segment are good
      candidates. At present, partial hepatectomy and left lateral segmentectomy are
      appropriate operative procedures. The laparoscopic approach is considered the
      treatment of choice, as it is less invasive in selected patients. Laparoscopic
      pancreatectomy is difficult to evaluate at present because of the scarcity of
      clinical cases. Laparoscopic pancreatectomy is indicated for distal, enucleated
      tumors. Another procedure, pancreatic cystogastrostomy, utilizes an intragastric
      approach. Laproscopic splenectomy will be the standard procedure in patients
      suffering hematologic disease, although it remains controversial in cases of
      splenomegaly due to the possibility of portal hypertension or hematologic
      malignancy. The incidence of conversion to open laparotomy due to uncontrollable
      bleeding is closely related to the technical skill of the surgeon. Safer
      laparoscopic procedures for abdominal parenchymatous organs depends on further
      refinement of endoscopic technology and improved training in endoscopic
      techniques.

PMID- 12415845
TI  - [Endoscopic surgery in children: current status and problems].
AB  - Endoscopic surgery has been established in various surgical conditions in
      children and infants for the past 10 years after pioneering work by experts
      specializing in pediatric endosurgery. These include pull-through for
      Hirschsprung's disease and anorectal malformations, pyloromyotomy, hernia repair,
      and endoscopic surgery for malignancies, malrotation, intussusception, etc.
      Laparoscopic pull-through is now accepted as a standard modality for the
      treatment of Hirschsprung's disease. Advanced endoscopic procedures such as
      esophageal atresia repair or fetal tracheal occlusion have also been performed.
      An efficient system for training is needed to compensate for the small number of
      patients and varieties of specific illness in children.

PMID- 12415846
TI  - [Diagnosis related groups (1). International perspective].

PMID- 12415847
TI  - [Hepatectomy with an additional parasternal incision without thoracotomy].
AB  - A 74-year-old woman was diagnosed with hepatocellular carcinoma in S8 and
      underwent partial hepatectomy. A 5-cm right parasternal skin incision was added
      to the median incision, followed by division of the two costal cartilages, which
      resulted in excellent exposure of the subphrenic portion of the liver including
      the root of hepatic veins. The authors used this access technique in 7 patients
      over the past 12 months, and a satisfactory operative field was achieved in all
      cases. This simple technique without thoracotomy may be useful as an alternative
      access to the liver, especially when fine isolation around the root of the
      hepatic veins is required.

PMID- 12415848
TI  - [Guiding principles for the care and use of animals in the field of physiological
      sciences].

PMID- 12415849
TI  - [Influence of long-term weightlessness on the morphological changes and
      composition of myosin heavy chain molecules in the fast-twitch muscles of the
      mature rats].

PMID- 12415850
TI  - [The influence of severe long-term exercise on the mouse hippocampus].
AB  - To determine whether severe long-term exercise affects on the brain, we
      investigated the mice brain after 12-week treadmill exercise. The mice (ddN,
      male, 25-35 g in body weight) were divided into severe, mild, and non-exercise
      group. Mice in severe groups ran on a treadmill at a speed of 25 m/min for 12
      weeks and mice in mild group ran on a treadmill at a speed of 10 m/min for 12
      weeks. The mice were killed by transcardial perfusion with 0.1 M phosphate
      buffered saline (PBS) followed by ice-cold 4% paraformaldehyde in 0.1 M PB. The
      another sets of mice were fixed by 2.5% glutaraldehyde-2% osmium tetroxide for
      electromicroscope (EM). The brains were serially sectioned in the coronal plane
      at a thickness of 20-microns with a vibratome and then processed for histology,
      by means of hematoxylin-eosin (HE) staining and immunohistochemistry. Fifty % of
      mice in severe exercise showed hyperchromatic and shrunken nerve cells with
      nuclear pyknosis (dark neuron) in the hippocampus, but not in mild exercise and
      non-exercise groups. The immunoreactivity of microtuble associated protein-2 (MAP
      2) decreased, while the heat-shock protein/cognate 70 (HSP/C 70) increased in the
      hippocampus of severe exercise group. Many destroyed mitochondria were observed
      in dark neurons by Electron micrograph. These findings suggested that severe long
      term exercise might damage hippocampal neurons.

PMID- 12415851
TI  - [Development of bile acid therapy; from a choleretic to an immunomodulator, and
      at present time].

PMID- 12415852
TI  - [Hereditary pancreatitis].

PMID- 12415853
TI  - [Non-surgical treatment of pancreatic stones in patients with chronic
      pancreatitis and pain].

PMID- 12415854
TI  - [Clinical study of the combination of small amount of nedaplatin (CDGP)/5-FU with
      radiation for the treatment of esophageal cancer].
AB  - Recently chemoradiotherapy for esophageal cancer has been drawing public
      attention to the issue of quality of life maintenance for patients. Although the
      standard method of chemoradiotherapy is CDDP/5FU, it has been claimed that CDGP
      (a derivative of CDDP) alone is more effective than CDDP for the treatment of
      esophageal cancer due to its low nephro- and digestive toxicity. We used a small
      amount of CDGP/5-FU in combination with radiation instead of CDDP, for the
      treatment of esophageal cancer and performed clinical examination of patients.
      The partial response rate was 80% and the complete response rate was 50%. Major
      side-effects were leukopenia, neutropenia, thrombocytopenia and anemia. Further
      study of dosage and schedule is necessary, however, CDGP/5-FU combined with
      radiation therapy could be used as choices of chemoradiotherapy for esophageal
      cancer in the future.

PMID- 12415855
TI  - [Clinical investigation of perforated duodenal ulcer--with special reference to
      the presence of Helicobacter pylori infection and rate of recurrence].
AB  - Perforated duodenal ulcer was clinically evaluated with respect to Helicobacter
      pylori infection and rate of recurrence in 38 ulcer patients perforated and 154
      patients with non-perforated duodenal ulcer who visited our hospital in past 5
      years and 6 months. The frequency of occurrence of H. pylori-positivity was 42.1%
      in patients with perforated duodenal ulcer, significantly lower than that of
      92.9% in patients with non-perforated lesions. This result suggests that H.
      pylori is hardly involved in the development of perforated duodenal ulcer. The
      rate of recurrence was significantly lower for perforated duodenal ulcer than for
      non-perforated ulcer. In particular, perforated duodenal ulcer did not recur in
      the group on maintenance therapy with H2-recepter antagonists. Maintenance
      therapy using inhibitors of gastric acid secretion seems effective for the
      prevention of recurrence of perforated duodenal ulcer.

PMID- 12415856
TI  - [Intensive therapy for fulminant hepatic failure: importance of co-operation
      between physicians of internal medicine and transplantation surgery].
AB  - We followed up the patients with fulminant hepatic failure who admitted in our
      hospital and investigated clinical problems raised in the patients who underwent
      living-related liver transplantation (LRLT). Among 15 patients with fulminant
      hepatic failure 6 were managed without LRLT and 3 patients survived, and the
      survival rate was 50%. Other 9 patients received LRLT, and 2 of these 9 died with
      their complications after the transplantation. Thus the survival rate by LRLT in
      fulminant hepatic failure was 77.8%. Brain CT scan examination showed severe
      brain edema in a patient and the edema did not improve after LRLT. Another
      patient suffered from development of fungal infection in her lungs after LRLT. We
      suspected the presence of subclinical infection in the preoperation period. The
      recovery from brain edema and the existence of subclinical infection are mostly
      difficult to evaluate but are very important for obtaining a good output. These
      results suggest that LRLT is a promising procedure for treatment of fulminant
      hepatic failure but a close cooperation between physicians of internal medicine
      and transplantation surgery from preoperative management until postoperative
      period is necessary.

PMID- 12415857
TI  - [Twenty-four weeks administration of interferon-alpha for chronic hepatitis B].
AB  - Twenty-four weeks administration of interferon-alpha has been performed to 23
      patients of chronic hepatitis B. As the result, complete or partial responders
      reached to 47.8%, so that it was considered to be effective therapy for chronic
      hepatitis B. By the investigation of behaviors of HBV-DNA, the reduction of HBV
      DNA below 4 x 10(2) copy/ml during the administration of interferon was
      considered to be one essential factor for inducing the effectiveness of
      interferon. Though lamivudine, which has a strong anti-viral effect, has been
      permitted, interferon is still considered as the good indication for relative
      young patients who do not have advanced hepatic fibrosis. As a newly strategy for
      the patients with high titer of HBV-DNA or breakthrough hepatitis, the
      combination therapy of interferon and lamivudine will be expected.

PMID- 12415858
TI  - [A case of colon sm cancer IIa + IIc type converted well differentiated
      adenocarcinoma into signet-ring cell carcinoma].

PMID- 12415859
TI  - [A case of ischemic stricture of the small intestine after acute hypovolemic
      shock caused by MRSA enteritis].

PMID- 12415860
TI  - [A case of superior mesenteric artery syndrome induced by bulimia of anorexia
      nervosa].

PMID- 12415861
TI  - [A case of multiple arteriovenous malformations of the colon with
      gastrointestinal bleeding diagnosed by colonoscopy].

PMID- 12415862
TI  - [Hepatitis C acquired through drug abuse among young generations].

PMID- 12415863
TI  - [A case of gallbladder carcinoma accompanied with occult pancreatobiliary reflux
      in normal pancreaticobiliary junction].

PMID- 12415864
TI  - [A case of mediastinal pancreatic pseudocyst with pleural effusion caused
      obstruction of pancreatic duct by protein plug].

PMID- 12415865
TI  - [A case of pseudocyst pathologically but solid-pseudopapillary tumor clinically].

PMID- 12415866
TI  - [A case of arteriovenous malformation of the jejunum detected by enteroscopy].

PMID- 12415867
TI  - [Treatment of acute poisoning in conformity with position statement].

PMID- 12415868
TI  - [Clinical toxicology and toxicogenomics].

PMID- 12415869
TI  - [Issues association with SBE].

PMID- 12415870
TI  - [Neurotoxicity in sodium azide poisoning].
AB  - The effects of sodium azide administration on the central cholinergic functions
      were investigated utilizing mice to evaluate the neurotoxicity in the acute
      poisoning. Seven oral doses of the toxicant, ranging in dosage from 12.3 to 59.3
      mg/kg, based upon a multiple of 1.3 x 27 mg/kg (an empirical LD50 for mice) or 27
      mg/kg divided by 1.3 to calculate the lower three doses, were administered to
      facilitate the acute signs and to observe behavior. The behavior included
      locomotor activity, rectal temperature and rotarod performance which are
      convenient for the evaluation of central cholinergic involvement even if it may
      be partial, since no behavioral methods to study totally the cholinergic system
      have been known. Measurements of the activities of acetylcholinesterase (AChE)
      and choline acetyltransferase (ChAT), enzymes that hydrolyze and synthesize
      acetylcholine (ACh) and high-affinity choline uptake (HACU), a rate-limiting step
      in the synthesis of ACh, were determined in the presence of various
      concentrations of sodium azide in vitro. Adult (12-15 weeks) female ICR strain
      mice were utilized in this study. Mice were orally given sodium azide in doses
      from 27 to 59.3 mg/kg and appeared sedated within 5 min. Next we observed
      hyperpnea and dyspnea, which were followed by seizure and death for mouse groups
      which received more than 35.1 mg/kg. Oral administration of the sodium azide
      solution produced an increase in locomotor activity for the 12.3 mg/kg group and
      a decrease for the higher doses (ranging from 16.0 to 27.0 mg/kg). The sodium
      azide administration suppressed rectal temperature dose-dependently as well as
      rotarod performance at high doses (20.8 and 27.0 mg/kg). Such behavioral changes
      elicited by sodium azide administration suggest an involvement of the central
      cholinergic system. Sodium azide also caused a measured decrease in the activity
      of AChE, but an increase in the activities of ChAT and HACU, dose-dependently, in
      vitro. From the results obtained from the behavioral and the in vitro
      experiments, we concluded that acute sodium azide poisoning significantly affects
      the central cholinergic system.

PMID- 12415871
TI  - [A case of acute ethanol intoxication with remarkable hyperglycemia by "ume-shu",
      a Japanese apricot liquor made with a large amount of sugar].
AB  - A 19-year-old woman ingested 2.2 L of "umeshu", a Japanese apricot liquor made
      with a large amount of sugar. She was unconscious and in shock. The estimated
      blood ethanol concentration was 607 mg/dl, and the blood glucose level was 576
      mg/dl. Because her respiration and circulation was highly suppressed, blood
      purification was indicated. Continuous hemodiafiltration (CHDF) was performed
      instead of hemodialysis because her hemodynamics was unstable. After CHDF was
      instituted, her blood glucose level reduced to normal range, and her
      consciousness became alert. CHDF was effective in eliminating ethanol and
      stabilizing her hemodynamics within an early stage. Though acute ethanol
      intoxication is known to inhibit glucogenesis, leading to hypoglycemia, marked
      hyperglycemia was seen in this case. Ingestion of a large amount of glucose-rich
      liquor and being in shock seemed to be the causes of hyperglycemia.

PMID- 12415873
TI  - [The opinion poll of the parents who used child resistant package].

PMID- 12415872
TI  - [Relapse of Creosote poisoning: report of a case taking Seirogan tablets].
AB  - A thirty-eight year old man took about 180 tablets of Seirogan. He was
      unconscious and had dyspnea with dark brown urine on admission. He recovered
      gradually after initial treatment. Seirogan contains a phenolic component.
      Symptoms and signs of poisoning are unconsciousness, convulsion, digestive tract
      disorder, pulmonary edema, hepatic failure, renal failure, and miosis. Clinical
      features include dark brown urine. On day 7, he again showed signs of creosote
      poisoning: relapse of unconsciousness and dark colored urine. Plasma
      concentration of phenol determined on the day before the relapse was much higher
      than that expected from the half-life of blood phenol. It is reported that
      Creosote poisoning results in a decrease in the intestinal peristalsis, or
      paralytic ileus. We would like to emphasize that a relapse of Creosote poisoning
      may occur due to possible delayed absorption of the Seirogan tablets.

PMID- 12415874
TI  - [Practical analysis of toxic substances useful for clinical toxicology--3-
      Bromovalerylurea].

PMID- 12415875
TI  - [Investigation and case study of Imidacloprid insecticide caused poisoning].

PMID- 12415876
TI  - Appropriate treatment selection.

PMID- 12415877
TI  - Cementation of porcelain restorations.

PMID- 12415878
TI  - The use of acellular dermal matrix allograft for the elimination of gingival
      melanin pigmentation: case presentation with 2 years of follow-up.
AB  - The most common cause of gingival pigmentation is the deposit of melanin in the
      basal layer of the oral epithelium. The presence of pigmentation does not
      constitute a pathology, and treatments including cryosurgery, Nd:YAG laser,
      gingival grafts, and removal of the epithelium in the pigmented area have been
      described in the literature. This case presentation illustrates the aesthetic
      treatment of bilateral gingival melanin pigmentation. The clinical results
      obtained using an acellular dermal matrix allograft were compared to the
      postoperative results of gingivoplasty in the same patient.

PMID- 12415879
TI  - Aesthetic restoration of a patient with insufficient crown height: maintenance of
      anatomical occlusal function using contemporary porcelain materials.

PMID- 12415880
TI  - Power bleaching--does it work or is it marketing hype?

PMID- 12415881
TI  - Synaesthetic restorations: a psychological perspective for surpassing aesthetic
      dentistry.
AB  - Dentistry is often described as a fusion of art and science. While the scientific
      aspect is well documented, the artistic component is nebulous and often subject
      to interpretation. The use of the word "aesthetic" as a description of artistic
      dentistry is essentially flawed. While it forms part of artistic concepts,
      aesthetics is not the quintessential description of what constitutes art or its
      perception by the human brain. This article redresses this balance by emphasizing
      the artistic nature of dentistry and rationalizing the criteria that constitute
      artistic perception.

PMID- 12415882
TI  - The dental management pyramid: Part 4--Strategic planning.

PMID- 12415883
TI  - Restorative alternatives for the treatment of an impacted canine: surgical and
      prosthetic considerations.
AB  - Impaction occurs more frequently with maxillary canines than with any other tooth
      except maxillary third molars. For functional and aesthetic purposes, impaction
      must be treated in a manner that facilitates recreation of the anatomical
      structures in the canine region. The general treatment of choice is surgical and
      orthodontic restoration of the impacted canine. When this protocol is impossible
      due to anatomical limitations or the patient's indications, alternative
      treatments are necessary. The authors introduce two case presentations in which
      impacted maxillary canine teeth were restored with alternatives to orthodontic
      therapy.

PMID- 12415884
TI  - Immediate provisional implants as abutments for an overdenture in the mandibular
      edentulous jaw: case presentation.
AB  - Based on the need for provisionalization to provide sufficient phonetics,
      adaptation, and function following implant therapy, simultaneous placement of
      immediate provisional implants has evolved to allow abutment positioning
      following initial surgery. This modality allows the patient to be restored with a
      stable, functional, and aesthetic restoration during soft tissue healing prior to
      the removal of the provisional implants. This article presents the clinical
      protocol for treatment of the edentulous mandible using an immediately
      provisionalized implant supported overdenture.

PMID- 12415885
TI  - Potential Salmonella transmission from ornamental fountains.
AB  - Besides the usual food and drinking-water vehicles, there are other routes by
      which Salmonella can be transmitted, especially at outdoor locations. Public
      fountains containing Salmonella offer models of exposure routes beyond those
      usually considered in the context of recreational use. The authors studied the
      bacteriological quality of water sampled from five ornamental fountains in
      Guadalajara, Mexico during two periods of six and of 10 months. Coliform bacteria
      and Escherichia coli were detected in 75 percent and 49 percent of the samples,
      respectively, and various serovars of Salmonella enterica were found in 12.4
      percent of samples. In addition to risks from ingestion of the contaminated
      waters; ornamental fountains may also pose risks to people in the vicinity from
      inhalation of mists.

PMID- 12415886
TI  - Indoor air quality assessment of daycare facilities with carbon dioxide,
      temperature, and humidity as indicators.
AB  - Poor indoor air quality (IAQ) in daycare facilities affects both attending
      children and care providers. Incident rates of upper-respiratory-tract infections
      have been reported to be higher in children who attend daycare. Excessive carbon
      dioxide (CO2) exposure can cause several health effects and even sudden infant
      death. For this study, 26 facilities were randomly selected in a Midwestern
      county of the United States. CO2, room temperature, and relative humidity were
      used as indicators for IAQ and comfort levels. These IAQ parameters were
      continuously monitored for eight hours at each facility by a direct-reading
      instrument that was calibrated before each measurement. More than 50 percent of
      the facilities had an average CO2 level over the American Society of Heating,
      Refrigerating and Air Conditioning Engineers (ASHRAE) standard of 1,000 parts per
      million (ppm). For temperature and relative humidity, respectively, 42.3 percent
      and 15.4 percent of facilities were outside of the ASHRAE-recommended comfort
      zones. The nap-time average CO2 level was about 117 ppm higher than the non-nap
      time level. The increment of the nap-time CO2 level in the sleeping-only room
      over the level in multipurpose rooms was statistically significant (p < .05).
      According to stepwise multiple regression analysis, nap-time CO2 level was
      predicted by CO2 level before occupancy, nap-time average temperature, carbon
      monoxide, and child density (R2 = .83). It is recommended that an appropriate IAQ
      standard for daycare facilities be established and that children should not be
      placed in a completely isolated room during nap time.

PMID- 12415887
TI  - Consensus-based standards development processes--serving the needs of the
      environment and public-health community.

PMID- 12415888
TI  - Lawsuits versus regulations and penalties: implications for health departments.

PMID- 12415889
TI  - Abstracts for scientific articles.

PMID- 12415890
TI  - A handy and useful radiation monitor.

PMID- 12415891
TI  - Controlling moisture in buildings.

PMID- 12415892
TI  - The art of position taking.

PMID- 12415893
TI  - [Disseminated cryptococcosis in patients with AIDS. Clinical, microbiological,
      and immunological analysis of 51 patients].
AB  - In the context of HIV infection, cryptococcal meningitis is the most common
      mycosis threatening the patient's life. We conducted a retrospective evaluation
      to determine the epidemiological, microbiological, immunological and clinical
      characteristics of disseminated cryptococcosis in 51 hospitalised HIV
      seropositive patients. All the individuals (n = 51) presented reactive serology
      for HIV (ELISA and/or Western blot) and none fulfilled strict HAART treatment,
      previous to the opportunistic infection. CD4+ lymphocyte T counts showed levels
      between 361 and 0 cells/microliter (mean = 45). All patients but one had counts
      lower than 100 cells/microliter. Cryptococcosis presented as unique episode in 35
      patients (68.6%) and in 16 as relapse (31.3%). In all of them we detected central
      nervous system involvement. The induction treatment was carried out with
      amphotericin B (AMB), continued with maintenance therapy with fluconazole.
      Lethality rate was 36.7%, slightly superior among patients in relapse (40%)
      compared to those who presented a first episode of the mycosis (35.2%). In those
      individuals for whom data were available, 65.2% of blood cultures, 94.1% of CSF
      cultures and 79.06% of microscopic CSF examination with India ink were positive.
      Titers of Cryptococcus neoformans capsular antigen in CSF > or = 1/1000 were
      found in 36.1% and > or = 1/1000 in 73.6% of serum samples. In conclusion,
      manifestations and severity of disseminated cryptococcosis continue maintaining
      the characteristics of half a decade behind, in those patients who are not
      treated with HAART. Neurological involvement existed in all patients of this
      cohort. Treatment is not able to modify the parameters of mortality seen in
      previous communications. Diagnostic methods applied in this study are in
      accordance with those in the bibliography.

PMID- 12415895
TI  - Nontuberculous mycobacteria in soils of La Pampa province (Argentina).
AB  - The presence of nontuberculous mycobacteria (NTM) was investigated in forty soil
      samples belonging to the four physiographic regions (Eastern, Central, Southern
      and Western) that constitute La Pampa province. The presence of NTM in 67.5% of
      these soil samples was determined. The density of mycobacteria ranged 25-4,500
      mycobacteria g-1 dry soil (mean = 516 CFU g-1). Significant differences were
      found in relation to both the investigated regions (p < 0.01) and the soil pH (r
      = 0.44*) (P = 0.02). The mycobacteria represented less than 0.00001% of the total
      aerobic bacteria found in the soils. Twenty-seven isolated mycobacteria were
      classified according to the culture, biochemical, enzymatic characteristics and
      antibiotic sensitivity. Mycobacterium fortitium was the dominant mycobacterium
      and was detected in 63% of the positive soils. This species showed ability for
      living in sandy to sandy loam soils, within a wide pH range (6.5-9.7) and organic
      matter (4.15-83.63 g kg-1). Two other species were M. phlei (range = 50-4,500 CFU
      g-1) and M. kansasii (range = 50-500 CFU g-1).

PMID- 12415894
TI  - [Outbreak of human leptospirosis after a flood in Reconquista, Santa Fe, 1998].
AB  - Since April of 1998 a high number of leptospirosis cases were detected, coming
      from the area of Reconquista Central Hospital in Santa Fe province. Since January
      of that year a notable increase in rainfall and river levels was observed causing
      inundation. As screening test, macroscopic agglutination (MAT) using 10 serotypes
      of L. interrogans. Among the 122 patients studied 71 were TR positive and 52 were
      also ELISA positive, leptospirosis diagnosis being confirmed in 40 of them. Five
      infecting serogroups were identified: Icterohaemorrhagiae (7/40), Ballum (5/40),
      Sejroe (3/40), Pomona (3/40) and Canicola (2/40). In the remaining cases (20/40),
      co-agglutinins were found at the same titer against two or more serotypes of
      leptospires. Infection prevalence was higher in men and productive age (21 to 40
      years). The clinical symptoms more frequently observed were headache, fever and
      myalgias. All cases occurred after the rains and in the period when the area was
      flooded. Their clinical presentation, time distribution, geographical
      localization and high frequency of contact with the risk factor inundation could
      indicate that, independently of search activities, there was an outbreak.

PMID- 12415896
TI  - [Analysis of aromatic hydrocarbon catabolic genes in strains isolated from soil
      in Patagonia].
AB  - Seven strains belonging to genus Pseudomonas were isolated from an enrichment
      with hydrocarbon mixtures. Tests for enzyme activities showed that five strains
      used predominantly the catabolic meta-pathway for aromatic hydrocarbon
      degradation. Furthermore, the xylE gene which encodes a catechol 2,3-dioxygenase
      was amplified by PCR, and in two strains the nahAc gene, a key enzyme for
      naphthalene catabolism, was also found. The xylE gene might be a good marker to
      identify aromatic hydrocarbon degrading bacteria in soils from Patagonia.

PMID- 12415897
TI  - [Bluetongue: isolation and characterization of the virus and identification of
      vectors in northeastern Argentina].
AB  - To establish if BTV was circulating in Argentina, 94 bovines from the Santo Tome
      and Ituzaingo Departments of Corrientes Province were sampled every 30-60 days
      during 14 months. Red blood cells from those animals that showed seroconvertion
      with a c-ELISA were processed for virus isolation by inoculation in embryonated
      chicken eggs and cell cultures. Cells with CPE were positive by direct and
      indirect immunofluorescence with BTV specific reagents. These samples examined by
      electron microscopy showed virus particles with BTV morphological
      characteristics. Blood samples and tissue culture supernantants were positive by
      RT-PCR technique with primers corresponding to the segment 3 of the BTV genome.
      Haematophagous insects were captured in one farm using light traps and Culicoides
      insignis Lutz was the predominant species detected. This is the first isolation
      of BTV in Argentina from northeastern bovines without any disease symptom.

PMID- 12415898
TI  - Degradation of environmental pollutants by Trametes trogii.
AB  - The ability of the ligninolytic fungus Trametes trogii to degrade in vitro
      different xenobiotics (PCBs, PAHs and dyes) was evaluated. Either 200 ppm of a
      PCB mixture (Aroclor 1150) or 160 ppm of an industrial PAH mixture (10% V/V of
      PAHs, principal components hexaethylbenzene, naphthalene, 1-methyl naphthalene,
      acenaphthylene, anthracene, fluorene and phenanthrene), were added to
      trophophasic and idiophasic cultures growing in a nitrogen limited mineral medium
      (glucose/asparagine) and in a complex medium (malt extract/glucose). Gas-liquid
      chromatography proved that within 7 to 12 d more than 90% of the organopollutants
      added were removed. The decrease in absorbance at 620 nm demonstrated that
      cultures of this fungus were able to transform 80% of the dye Anthraquinone-blue
      (added at a concentration of 50 ppm) in 1.5 h. Enzyme estimations indicated high
      activity of laccase (up to 0.55 U/mL), as well as lower production of manganese
      peroxidase. Laccase activity, detected in all the conditions assayed, could be
      implicated in the degradation of these organopollutants. Considering the results
      obtained, T. trogii seems promising for detoxification.

PMID- 12415899
TI  - [False-positive cultures due to cross contamination in tuberculosis
      laboratories].
AB  - Fifteen episodes of Mycobacterium tuberculosis laboratory cross-contamination
      suspected between 1996 and 2001 at 6 laboratories in Buenos Aires City and
      suburbs were investigated by IS6110 RFLP. Thirteen episodes were confirmed. Even
      though BACTEC 460 produced the highest number of confirmed episodes in a single
      laboratory, the most extended one occurred while employing conventional culture
      procedures in solid medium. The double repetitive element-polymerase chain
      reaction (DRE-PCR) was applied to 8 of these episodes and produced concordant
      results with those of the RFLP. The DRE-PCR appears to be a valuable tool for the
      prompt identification of false positive cultures. The timely rectification of
      defects in laboratory protocols can avert false diagnoses of tuberculosis and
      unnecessary prolonged treatments.

PMID- 12415900
TI  - Characterization of enteroaggregative Escherichia coli strains isolated from
      children with acute diarrhea, in Mendoza, Argentina.
AB  - Enteroaggregative Escherichia coli (EAEC) is an increasingly recognized cause of
      diarrhea in children in developing and developed countries. EAEC is recognized by
      a characteristic aggregative pattern of adherence to human epithelial (HEp-2)
      cells cultured in vitro. This is the gold standard assay. The aggregative
      phenotype is associated with the presence of a 65 MDa plasmid (pAA) that also
      encodes several other putative virulence factors, such as the aggregative
      adherence fimbria I (AAF/I) and the enteroaggregative heat-stable enterotoxin
      (EAST1). The objective of this work was to evaluate the application of PCR
      (polymerase chain reaction) to identify EAEC strains in cases of acute diarrhea.
      A total of 87 E. coli strains, isolated from patients under 2 years of age with
      acute diarrhea in Mendoza, Argentina, were characterized by the reference method
      (HEp-2 assay), and by AAF/I- and EAST1-PCR. PCR sensitivity and specificity in
      comparison with the cell culture assay showed 94.4% sensitivity and 78.26%
      specificity. EAST1- and AAF/I-PCR could be recommended as a screening test,
      applicable to epidemiologic studies.

PMID- 12415901
TI  - [Antimicrobial sensitivity of coagulase-positive staphylococcal strains isolated
      from bovine mastitis in the central dairy catchment area of Argentina ].
AB  - The activity of antimicrobial agents frequently used for treating bovine mastitis
      was determined against 101 coagulase-positive staphylococci isolated from bovine
      mammary secretion. The isolates were obtained from 39 dairy farms located in the
      central dairy area of Argentina. The disk diffusion method was used and the
      following antimicrobial agents were tested: penicillin, ampicillin, oxacillin,
      cephacetrile, penicillin + novobiocin, erythromycin, pirlimycin, novobiocin and
      neomycin. The highest levels of resistance were observed against penicillin and
      ampicillin (47.6%), while the lowest against erythromycin (2%), pirlimycin (4%)
      and neomycin (2.9%). No resistant strains against oxacillin, cephacetrile and
      penicillin + novobiocin were detected.

PMID- 12415902
TI  - National mental health parity bill poised to pass this time around.

PMID- 12415903
TI  - Compensation monitor. For locum tenens physicians, money's not everything--but
      it's not bad.

PMID- 12415904
TI  - Prevent crime from paying: fight managed care fraud.

PMID- 12415905
TI  - How physicians can steer clear of fraud charges.

PMID- 12415906
TI  - It's not the road you take--it's getting there that counts.

PMID- 12415907
TI  - Hospitalists make it look easy.

PMID- 12415908
TI  - Is 34 weeks an acceptable goal for a complicated singleton pregnancy?
AB  - PURPOSE: To examine neonatal risk and associated nursery costs for infants with
      delivery following untreated preterm labor at 34, 35, or 36 weeks' gestation, by
      assessing the incidence of neonatal intensive care unit (NICU) admission,
      respiratory distress syndrome (RDS), and need for ventilatory assistance. DESIGN:
      Infants with preterm birth at 34, 35, or 36 weeks were identified from a database
      of prospectively collected clinical information and pregnancy outcomes of women
      receiving outpatient preterm-labor management services, in addition to routine
      prenatal care. Cases of singleton gestations with delivery related to spontaneous
      preterm labor were analyzed. Data were divided into three groups by gestational
      week at delivery. METHODOLOGY: Descriptive and statistical methods were used to
      compare maternal demographics, pregnancy outcome, and nursery costs. A cost model
      was utilized. PRINCIPAL FINDINGS: 2849 infants were studied. Risk of NICU
      admission decreased by 47.4 percent from weeks 34 to 35 and 41.8 percent from
      weeks 35 to 36. Risk of RDS decreased by 25.4 percent from weeks 34 to 35, and
      40.7 percent from weeks 35 to 36. Mean nursery costs per infant delivering at 34,
      35, and 36 weeks were $11,439 +/- $19,774, $5,796 +/- $11,858, and $3,824 +/-
      $9,135, respectively (p < .001). CONCLUSION: Rates of NICU admission, RDS,
      ventilator use, and nursery-related costs decreased significantly with each week
      gained. The data indicate that benefit is derived in prolonging pregnancy beyond
      34 weeks.

PMID- 12415909
TI  - HMO drug formulary access increases for COX-2s.

PMID- 12415910
TI  - How to--and not to--disclose medical errors to patients.

PMID- 12415911
TI  - Managed care outlook. Survey: '90s boom didn't increase number of covered
      employees.

PMID- 12415912
TI  - Dental implants--isn't it about time?
AB  - Long-term studies indicate that dental implants are the most successful
      restorations fabricated and placed by dentists; however, only 30 percent of the
      dentists in this country restore implants on a regular basis. This article
      provides a six-step process for adding implant restoration to the regular
      services general practitioners provide for patients.

PMID- 12415913
TI  - Enhancing implant esthetics with ideal provisionalization.
AB  - BACKGROUND: Recent literature has increased our understanding of how the osseous
      crest responds to implant placement. Proper pre-prosthetic conditioning of these
      tissues is required to achieve predictable esthetic results in the anterior
      region. CASE DESCRIPTION: The author presents a case of a 38-year-old male with
      traumatic loss of a central incisor replaced with an ITI implant. The case
      demonstrates the fabrication of a provisional temporary crown designed to
      optimize the development of ideal soft tissue form. CLINICAL IMPLICATIONS: The
      difference between implants and teeth in terms of sulcular makeup
      (osseointegration vs. periodontal ligaments and circumferential fibers vs.
      transverse ligamental fibers) requires modification of procedures for temporary
      crown fabrication.

PMID- 12415914
TI  - Early loading with the ITI SLA surface as a predictable, routine procedure.
AB  - BACKGROUND: Historically replacement of missing teeth with dental implants often
      required multiple surgical procedures and long delays between initiating and
      completing treatment. CASE DESCRIPTION: This case describes accelerated implant
      restoration of teeth #29 and #30 on a 67-year-old male with a history of bruxism
      and a failed fixed partial denture. The abutments were connected and final
      restorations were begun 42 days following implant placement surgery. CLINICAL
      IMPLICATIONS: Ideal results following implant placement can be obtained in less
      than 10 weeks.

PMID- 12415915
TI  - Immediate placement/immediate load: a single-tooth case study utilizing the ITI
      dental implant system.
AB  - For the past 35 years, endosseous dental implants have revolutionized the methods
      clinicians use to treat edentulous and partially edentulous patients. Initially
      recommended only to rehabilitate fully edentulous patients utilizing fixed
      prosthetics, endosseous dental implants were then shown to be effective to treat
      partial edentulism. Over the last decade, numerous studies have documented
      successful placement of endosseous dental implants in fresh extraction sites, and
      methods have been developed to provisionalize both full-arch and single-tooth
      implant cases at the time of surgery. This article describes the immediate
      placement/immediate load of a single ITI dental implant.

PMID- 12415916
TI  - Same-day restoration of mandibular single-stage implants.
AB  - The Novum system by Nobel Biocare is a unique approach that delivers a full arch
      definitive restoration in one day on three implants. The pre-operative
      evaluation, surgical protocol, and prosthetic protocol are described, and
      contraindications for this system are discussed. This system of immediately
      loaded implants placed in a single-stage surgery has success rates that compare
      favorably with the classic two-stage approach.

PMID- 12415917
TI  - Implants quickly setting standard of treatment.
AB  - A recent consumer survey reveals surprising results about possible patient
      acceptance of dental implants.  This article examines the differences between
      dentist and patient expectations of successful treatment and the seven
      characteristics of practices that are successful with implant dentistry.  A
      practice management checklist is provided to evaluate a practice's ability to
      meet patient expectations with implant procedures.

PMID- 12415918
TI  - Dental implant jurisprudence: avoiding the legal failures.
AB  - The law measures the quality of dentistry by the "standard of care" as defined by
      the courts.  The ultimate judges of the facts in a malpractice suit are usually
      juries made up mostly of lay people.  Ignorance of the legal requirements for
      dentistry, and specifically dental implants, unnecessarily exposes today's dental
      health care provider to such suits.  However, with a reasonable understanding of
      the legal issues and requirements surrounding the standard of care, a dentist may
      avoid becoming embroiled in a malpractice claim.

PMID- 12415919
TI  - Advancing population health in the Harlem Children's Zone Project.

PMID- 12415920
TI  - Measuring and monitoring quality-of-life in population surveys: still a challenge
      for public health research.

PMID- 12415921
TI  - Sol Levine and Jonathan Mann: we must hope that their influence will persist.

PMID- 12415922
TI  - One of those moments of history: an interview with Jonathan Mann. Interview by
      Anne Brunner.

PMID- 12415923
TI  - At heart of the matter: human rights.

PMID- 12415924
TI  - Defending the vision of public health.

PMID- 12415925
TI  - The history of confounding.
AB  - Confounding is a basic problem of comparability--and therefore has always been
      present in science. Originally a plain English word, it acquired more specific
      meanings in epidemiologic thinking about experimental and non-experimental
      research. The use of the word can be traced to Fisher. The concept was developed
      more fully in social science research, among others by Kish. Landmark
      developments in epidemiology in the second half of the 20th century were by
      Cornfield and by Miettinen. These developments emphasised that reasoning about
      confounding is almost entirely an a priori process that we have to impose upon
      the data and the data-analysis to arrive at a meaningful interpretation. The
      problems of confounding present their old challenges again in recent applications
      to genetic epidemiology.

PMID- 12415926
TI  - Associations among health-related behaviours: sociodemographic variation in
      Finland.
AB  - OBJECTIVES: The study examines sociodemographic variation in associations and co
      occurrence of health behaviours that contribute to multifactorial chronic
      diseases. METHODS: Mantel-Haenszel odds ratios were used to examine pairwise
      associations among smoking, alcohol use, physical activity, and diet across
      categories of sociodemographic characteristics. Breslow-Day test for homogeneity
      was used to test for sociodemographic differences. In addition, co-occurrence of
      each two unhealthy behaviours was examined across sociodemographic groups using
      nationwide population survey data from 26,014 Finnish adults. RESULTS: Most of
      the health behaviours examined were interrelated and sociodemographic differences
      in the associations were few. Differences were inconsistent for all
      sociodemographic characteristics. Variation was observed only in the strength of
      the associations, not in their direction. However, due to unequal distribution of
      the individual behaviours, co-occurrence of unhealthy behaviours varied strongly
      across sociodemographic groups. CONCLUSIONS: Associations between health
      behaviours were relatively similar across sociodemographic groups. Since co
      occurrence of unhealthy behaviours depends on the prevalence of individual
      unhealthy behaviours and the strength of their association, their co-occurrence
      in any particular sociodemographic group was primarily determined by the
      prevalence of individual unhealthy behaviours.

PMID- 12415927
TI  - Socio-economic differences in health risk behaviour and attitudes towards health
      risk behaviour among Slovak adolescents.
AB  - OBJECTIVES: Socio-economic differences in the frequency of smoking, alcohol
      consumption, drug use, physical exercise, and attitudes toward smoking were
      explored in a sample of Slovak adolescents (1,370 boys, 1,246 girls, mean age 15
      years). METHODS: Identification of socio-economic status was based on three
      indicators: the highest educational level of parents, the highest occupational
      class of parents, and the type of school the adolescents attended. RESULTS:
      Health risk behaviour was strongly related to socio-economic status based on all
      three socio-economic indicators, although there were some exceptions mostly
      related to education as indicator of socio-economic status and to alcohol
      consumption experience and drug use experience. The pattern of socio-economic
      differences was unfavourable for lower socio-economic groups of adolescents,
      except for differences in frequency of alcohol consumption among females when
      highest education of parents was used as an indicator of socio-economic status.
      CONCLUSIONS: There are socio-economic differences in health risk behaviour. Lower
      socio-economic groups of adolescents behave risky more frequently than higher
      socio-economic groups of adolescents.

PMID- 12415928
TI  - Psychosocial determinants of smoking in Swiss adolescents with special reference
      to school stress and social capital in schools.
AB  - OBJECTIVES: To identify the major psychosocial determinants of smoking in
      adolescents and the school influence on these determinants. METHODS: Cross
      sectional questionnaire survey in 8th grade (age 14.8 years, n = 459) of 14
      schools. Logistic regression with smoking as the dependent, and psychosocial
      indicators as independent variables. Total climate score for each school computed
      as the sum of scores of five school-related indicators. Linear regression
      analysis on aggregate data (school level), controlling for gender, ethnicity, and
      social class. RESULTS: Five out of 15 tested psychosocial indicators were
      identified as independent protective factors. The prevalence of smoking decreased
      steeply with an increasing number of protective factors. In the regression
      analysis on the aggregate level the mean number of protective factors per school
      and the prevalence of smoking were significantly related to the school climate
      score (R2 = 0.650, p < 0.001, and R2 = 0.456, p < 0.001). CONCLUSIONS: Provided a
      causal interpretation of the cross-sectional statistical associations is correct,
      efforts to improve the general climate in schools appear as a promising strategy
      to enhance individual protective factors. Longitudinal evaluative studies are
      needed to prove the effectiveness of such a strategy.

PMID- 12415929
TI  - [German-language reconstruction of the processes of behavior change according to
      the trans-theoretical model in participants of women's fun run].
AB  - OBJECTIVES: For the first time the German version of the key construct "processes
      of change" for exercise behaviour is presented. Specific aims were to find out
      whether 10 different processes of change can be ascertained and whether the
      processes of change are also organised into a higher level of order. METHODS: The
      data are part of a cross-sectional study. The participants were 1208 women of the
      fun run in Graz in 2000. Exploratory factor analysis and structural equation
      models were conducted to reconstruct the German version of the processes of
      change. RESULTS: 822 women (68%) returned the questionnaire. The variance,
      limited to a 10-factor-solution, was 67.6%. In comparison to the construct
      derived from the theory, subscales show a change of items. The fit-indices of the
      two hierarchical-factor model (NNFI = 0.92, CFI = 0.94) and of the three
      hierarchical-factor model (NNFI = 0.91, CFI = 0.94) show better overall fit than
      the one hierarchical-factor model (NNFI = 0.86, CFI = 0.89). CONCLUSIONS:
      According to the change of items between the subscales in comparison to the
      theory it is recommended to test the German version again in a population-based
      sample. The overall fit indices support the assumption that the 10 processes of
      change follow an hierarchical order.

PMID- 12415930
TI  - [Disparities in dental health among school children in the city of Stuttgart].
AB  - OBJECTIVES: In an ecological study, we investigated differences in dental health
      among children attending elementary schools in Stuttgart. METHODS: We used a
      classification of 67 socially homogeneous districts into seven clusters with
      comparable socio-economic structures. Public health service dentists data of the
      school year 1999/2000 on 16755 children were assigned to the seven clusters.
      RESULTS: 81.7% of children had healthy natural permanent teeth (variation among
      the clusters: 74.6-88.0%). Not children in the poorest areas had the worst
      results but children living in inner-city areas. They were twice as likely not to
      have healthy natural teeth and three times as likely to be in need of dental
      treatment than children living in affluent areas. CONCLUSIONS: Efforts in
      prevention of dental health should be strengthened in nurseries and schools in
      socially deprived areas.

PMID- 12415931
TI  - The SF-36 questionnaire and its usefulness in population studies: results of the
      German Health Interview and Examination Survey 1998.
AB  - OBJECTIVES: To describe the distribution and the relationships of the SF-36
      scales in a representative sample of the German population. METHODS: The German
      National Health Interview and Examination Survey 1998 comprised 7,124
      participants aged 18 to 79 years and included the Short Form 36 Questionnaire (SF
      36). The 1998 findings are compared to those of the first normative German SF-36
      sample from 1994. RESULTS: Older people (> or = 65 years) in particular have
      increased the mean scale values for quality-of-life assessment during the four
      years. The average of all SF-36 scales increases with the social status of the
      individual in all age categories. The representative sample shows a more positive
      subjective assessment of their quality-of-life by East Germans in nearly all
      scales of SF-36, although they do not have a correspondingly better health
      status. The intensity of pain and the number of diseases during the preceding
      year are shown to decrease the life quality scales. Furthermore the General
      Health scale of SF-36 is correlated with the physicians' consultation.
      CONCLUSION: The instrument to assess quality-of-life can generate useful
      information for a wide variety of variables. However, future health-related
      quality-of-life measurements in healthy population should be more sensitive and
      more differentiating than the SF-36 instruments.

PMID- 12415932
TI  - Pitfalls in wrist arthroscopy.
AB  - Arthroscopy of the wrist is a well-established procedure; however complications,
      problems and difficulties are possible. The complication rate is estimated to be
      about 2%, of which equipment failure is probably the most frequent. Injury of the
      overlying tendons, nerves and even the radial artery has also been described. The
      anatomy of certain wrists can cause considerable difficulties in obtaining a
      clear view. The major problem however is the correlation between the clinical and
      radiographic findings, and the arthroscopic findings. There are some
      abnormalities which do not have any significance since most of them can be
      considered as normal ageing phenomena.

PMID- 12415933
TI  - Pseudodystrophy. A conversion disorder mimicking reflex sympathetic dystrophy.
AB  - The authors suggest some criteria by which pseudodystrophy and reflex sympathetic
      dystrophy, although sharing some similar clinical features, can be distinguished
      as two different conditions, each requiring its own approach and management. The
      most important distinction is found on bone scintigraphy. In reflex sympathetic
      dystrophy the bone scan shows a typical increased tracer uptake (at least during
      stages I and II); in pseudodystrophy there is a normal or decreased tracer uptake
      in the affected region. Moreover the vascularization is increased in reflex
      sympathetic dystrophy stage I, whereas in pseudodystrophy hypovascularization is
      found from the beginning. The clinical features, as well as the results of
      technical investigations, psychological evaluation and treatment of 4 patients
      with pseudodystrophy are presented. The importance of distinguishing this
      condition from reflex sympathetic dystrophy is stressed.

PMID- 12415934
TI  - Motorcycle injury and survival: improving outcomes.
AB  - The aim of this study was to examine all motorcycle accident injuries presenting
      in Yorkshire, United Kingdom, and to assess the impact of the introduction of a
      consultant-led trauma team on mortality, 1993-2000. Data were collected on 1239
      patients. Factors independently associated with survival by logistic regression
      were: the presence of abdominal trauma (odds ratio 0.46, 95% confidence interval
      0.31 to 0.68), the presence of chest trauma (OR 0.41, 0.29 to 0.6), the presence
      of head trauma (OR 0.36, 0.30 to 0.45), requirement of a blood transfusion in the
      emergency room (OR 0.88/unit of blood, 0.72 to 1.07), presence of the trauma team
      (OR 0.43, 0.16 to 1.03) and the number of years into the program (OR 1.34/year,
      1.07 to 1.67). The single factor determining improved survival was the time into
      the study. This shows that treatment of motorcycle trauma has improved overall
      with time. We propose that the introduction of uniform treatment protocols and
      improvements in the general standard of care have had a great effect.

PMID- 12415935
TI  - [Surgical management of isolated fractures of the ulnar shaft].
AB  - Between 1997 and 2001, 40 isolated fractures of the shaft of the ulna were
      treated by internal fixation and were followed until healing. The mean age was 27
      years. Twenty six were treated by open reduction and plate fixation (group I),
      and 14 by closed intramedullary pinning (group II). Most complications were
      secondary to technical defects and occurred in the first group, with nonunion in
      7.7% of cases; complications in the second group were minimal. The authors used
      Oestern and Tscherne's criteria for their evaluation; good results were noted in
      86% in the first group, and in 93% in the second. Surgical management of isolated
      ulnar shaft fracture using intramedullary pinning or AO plate fixation (1/2 tube
      or 1/3 tube), appear to provide comparable results, provided the technique was
      correct.

PMID- 12415936
TI  - Do unloading periods affect migration characteristics of cemented femoral
      components? An in vitro evaluation with the Exeter stem.
AB  - Prosthetic migration has been identified as a marker for future revision of
      cemented total hip reconstructions. This could be tested at a pre-clinical stage
      with dynamic loading experiments. The purpose of this study was to assess the
      effects of resting periods, which are a considerable part of the daily activity
      cycle, on the migration characteristics of femoral cemented stems. Ten polished
      Exeter stems were implanted in composite femurs and loaded either with a
      continuous load or a discontinuous load. Continuous loading involved 345,600
      loading cycles at 1 Hz, whereas the discontinuous loading involved loading at 1
      Hz for 2.5 hours and a resting period of 21.5 hours for a period of four days.
      Hence, a total of 36,000 loading cycles were applied to these reconstructions.
      The subsidence patterns of the prostheses were considerably affected by the
      resting periods. The prostheses exhibited a step-wise migration pattern with
      migration steps of about 50 microns after every resting period, whereas the
      continuously loaded prostheses showed a more gradual migration pattern. The final
      subsidence of the specimens when loaded with resting periods was significantly
      less than the subsidence measured without resting periods. However, these
      specimens were loaded with fewer loading cycles. If this was taken into account,
      the discontinuously loaded specimens had a four fold higher average migration per
      loading cycle than the specimens that were loaded continuously. In conclusion,
      the resting periods had a considerable effect on the migration patterns, which
      should be realized when these stems are analyzed with pre-clinical tests.

PMID- 12415937
TI  - Arthroscopic partial lateral meniscectomy long-term results in athletes.
AB  - This is a retrospective case-control study of arthroscopic partial meniscectomy
      for isolated lesions of the lateral meniscus, performed between 1990 and 1995.
      Thirty-one knees were evaluated after an average follow-up of 8 years: 48.4% had
      excellent/good IKDC-scores and 64.5% excellent/good Lysholm scores. The Tegner
      activity score dropped from 7.2 (competitive sports) to 5.7 (recreational
      sports). Fairbank changes were noted in 92.9% of the radiographs. Deterioration
      of results after arthroscopic partial lateral meniscectomy is obvious. The extent
      of the resection is a significant factor.

PMID- 12415938
TI  - Wear pattern of retrieved patellar implants.
AB  - The so-called "papillon" pattern of polyethylene wear of 17 patellar components
      from 5 Kinematic and 12 Total Condylar prostheses, retrieved after an average of
      80 months in situ, was studied. The primary diagnosis was osteoarthritis in all
      cases. Four modes of damage were observed: polishing in 13 cases, delamination in
      12, cold flow in 6 and scratching in 3. The median total area of polyethylene
      damage was 76.5% for polishing, 70.6% for delamination, 35.3% for cold flow and
      17.6% for scratching. The importance of the conformity of the Kinematic patellar
      component in order to decrease contact stresses was confirmed. The average
      contact stresses on the nonconforming total Condylar patellar component (12.9
      kgf/mm2), were significantly higher (p < 0.002) than the average contact stresses
      on the conforming Kinematic patellar component (2.9 kgf/mm2). The area of wear
      was smaller for the nonconforming Total Condylar (357.2 mm2) than for the
      conforming Kinematic patella (439.2 mm2). This difference, however, is not
      statistically significant. The average weight of the patients with a Kinematic
      Knee (74.5 kg) was higher than that of patients with a Total Condylar knee (66
      kg), but the difference was not significant. The high incidence of significant
      wear of the patellar components indicates that a basic deficiency is present in
      the design of patellar implants, and calls for the improvement of two mechanical
      features: adequate thickness of the polyethylene implant and conforming
      articulating surfaces.

PMID- 12415939
TI  - A comparative biomechanical study of the strength of the bony patella following
      dome cut or uniplanar cut in total knee arthroplasty.
AB  - This study was designed to investigate whether there is a difference in the
      strength of the bony patella following preparation either with a dome
      configuration or with a regular uniplanar cut in total knee arthroplasty. For
      each test 4 cadaveric patellae were used. Two of the 4 patellae were prepared
      with a regular uniplanar cut and 2 were prepared into a dome shape with a
      circumferential wall, using a concave reamer. The thickness of each patella after
      preparation was [figure 1 & 2: see text] 15 mm. The tests were performed using an
      impact drop weight apparatus. In the first two tests, which tested the resistance
      of the patella to tensile force and evaluated the strength of the patella by
      impact load while under tension, the soft tissues were torn, with no harm to the
      bony patella. In the third test, which evaluated the resistance of the patella
      without tension against impact load, the force required to fracture the dome
      shaped patella was greater than for the traditional uniplanar cut (500 Kg vs 350
      Kg). Dome shape with circumferential wall preparations of the bony patella in
      total knee arthroplasty were stronger in resisting external impact than the
      conventional uniplanar cut patella. This established the rationale for our use of
      the dome-shaped patella implant with a concave undersurface.

PMID- 12415940
TI  - Polydactyly of the foot. Literature review and case presentations.
AB  - Polydactyly is a fairly common congenital condition of the foot and is
      characterized literally by supernumerary toes (digit or metatarsal). The
      frequency of polydactyly varies widely among populations. It may be an isolated
      condition or part of a congenital syndrome. Polydactyly is generally classified
      into three major groups: medial ray (preaxial), central ray and lateral ray
      (postaxial). The duplication may appear at the distal and middle phalanges or at
      the whole digit and metatarsal. The complexity of the deformity ranges from a
      simple soft-tissue problem to a completely developed accessory ray. Careful
      clinical and radiographic evaluation should be made prior to treatment to achieve
      good functional and cosmetic results. Most cases are treated during childhood
      before walking age. Adult cases are more rare, and surgical management of the
      deformity is still debated. Nevertheless, surgery can be performed at any age as
      in our series with good results.

PMID- 12415941
TI  - [Infectious spondylitis. Study of a series of 151 cases].
AB  - The authors report their findings in a retrospective study of 151 cases of
      infectious spondylitis collected between 1970 and 2000. Diagnosis was based on
      bacteriological or pathological confirmation or on clinical, radiological and
      outcome arguments. Among 151 cases of infectious spondylitis diagnosed and
      treated, 110 were due to tuberculosis and 41 to other causes. There were 82 men
      and 69 women, with a mean age of 42 years. The delay from onset to diagnosis was
      12 months. Risk factors were observed in 21% of the cases. The patients searched
      medical attention because of pain in 85% of cases. The leading causative agents
      in non tuberculous spondylitis were Staphylococcus aureus, followed by Brucella,
      and Salmonella, in this order. The diagnosis was considerably facilitated by the
      imaging techniques used; the most reliable technique was magnetic resonance
      imaging which improved diagnostic performance by detecting early, specific
      changes. A histo-bacteriological diagnosis was obtained by percutaneous
      transpedicular needle biopsy. Globally, 53% of the patients underwent needle
      biopsy, with a success rate of 62%, a figure comparable with those reported in
      other studies. In 35% of the patients, bacteriological confirmation of the
      infection was not obtained and diagnosis was founded on a set of clinical,
      biological and radiological data. Our results are similar to those described in
      the literature. However, in our country tuberculosis is the most frequent cause
      of infectious spondylodiscitis. Two populations are especially susceptible: the
      elderly and the immunodepressed. A specific diagnosis was obtained in 62% of the
      percutaneous transpedicular needle biopsy.

PMID- 12415942
TI  - Gram staining in the diagnosis of acute septic arthritis.
AB  - This study aimed at determining the sensitivity and specificity of Gram staining
      of synovial fluid as a diagnostic tool in acute septic arthritis. A retrospective
      study was made of 22 patients who had arthroscopic lavage following a provisional
      diagnosis of acute septic arthritis of the knee joint. Gram stains and cultures
      of the knee aspirates were compared with the clinical and laboratory parameters,
      to evaluate their usefulness in diagnosing acute arthritis. All patients who had
      septic arthritis had pain, swelling and limitation of movement. CRP was elevated
      in 90% of patients. The incidence of elevated white blood cell count was higher
      in the group of patients with a positive Gram stain study (60%) as compared to
      patients with a negative Gram stain study (33%). Gram staining sensitivity was
      45%. Its specificity was however 100%. Gram staining is an unreliable tool in
      early decision making in patients requiring urgent surgical drainage and washout.

PMID- 12415943
TI  - One-stage elbow interposition arthroplasty with a fasciocutaneous distally
      planned lateral arm flap.
AB  - We report a case of severe posttraumatic ankylosis of the elbow with chronic
      osteomyelitis of the lateral condyle of the humerus. The triple problem of
      restoring elbow mobility, providing for coverage, and controlling infection was
      treated in a one-stage procedure. A distally planned fasciocutaneous lateral arm
      flap was used for elbow interposition arthroplasty. Clinical examination at 27
      months showed restoration of a useful range of elbow motion and good pain relief.

PMID- 12415944
TI  - Isolated avulsion fracture of the coronoid process requiring open reduction in a
      paediatric patient: a case report.
AB  - Coronoid process fractures are reported to occur from avulsion by the brachialis
      muscle or to be associated with elbow dislocations. We report a rare case of
      coronoid process fracture due to avulsion by the anterior bundle of the medial
      collateral ligament rendering the elbow unstable. In children, small fracture
      fragments of the coronoid process (types 1 & 2) are in reality often much larger
      but the actual size is not appreciated radiographically, as the coronoid process
      contains considerable amounts of cartilage. If the fragment is seen to be
      significantly displaced it may have resulted from avulsion by important
      structures such as the medial collateral ligament and open reduction is required
      to stabilise the elbow.

PMID- 12415945
TI  - Non rheumatoid closed rupture of extensor carpi ulnaris tendon. Report of a case
      in a professional athlete.
AB  - A rare case of closed, non-rheumatoid rupture of the extensor carpi ulnaris
      tendon, that occurred in a professional tennis player, is presented. The authors
      describe the diagnostic problems and the treatment. They discuss the anatomical
      particularities of the area, the probable pathological mechanisms that lead to
      the lesion and the best ways of dealing with the problem.

PMID- 12415946
TI  - [Juxtacortical osteosarcoma of the radius in a child].
AB  - The authors report a rare case of juxtacortical osteosarcoma of the radius in a
      child. The diagnosis and treatment were delayed because of misleading and wrongly
      reassuring radiological and histological aspects. The 12-year-old boy was
      admitted for a tumefaction of the proximal extremity of the right radius noticed
      after trauma. Physical examination showed a hard and slightly painful swelling.
      Xrays showed an irregular osseous mass developed from the superior metaphysis of
      the radius and encircling it. MRI showed a juxtacortical tumor with medullary
      involvement. A biopsy concluded to a fracture callus. Ten months later, the tumor
      became painful and homogeneous, regular and well defined on Xrays. A repeat
      biopsy showed juxtacortical osteosarcoma. Enbloc resection of the tumor was done.
      After a follow-up of 2 years, the child is alive without recurrence and
      metastasis and with a satisfactory function of the upper limb.

PMID- 12415947
TI  - [Fifty-year survival of a Judet acrylic prosthesis].
AB  - The first mould arthroplasty was made from glass in 1923 and was inserted in an
      ankylosed hip by Smith-Petersen at the Massachusetts General Hospital. Over the
      next decades, various other materials were used such as Vitallium (cobalt
      chromium alloy), introduced in 1938 and polymethylmethacrylate (PMMA) by the
      Judet brothers in 1950. These prostheses are no longer in use. We report the case
      of a patient with a Judet acrylic prosthesis which has remained in place since
      1951.

PMID- 12415948
TI  - Adamantinoma of the tibia in a nine-year-old child.
AB  - Adamantinoma of the long bones is a rare, low-grade malignancy with a marked
      predilection for the tibia and is usually seen in patients during the second to
      fifth decades of life. Adamantinomas have also been reported in children, but the
      histological pattern in this age group is different from that seen in adults. We
      report a case of adamantinoma of the tibia in a 9-year-old boy. Histologically,
      the lesion was osteofibrous dysplasia with an epithelial component, called
      "differentiated adamantinoma". An osteofibrous dysplasia-like adamantinoma
      (differentiated adamantinoma) may be the precursor lesion of the classic type of
      adamantinoma.

PMID- 12415949
TI  - Elastofibroma dorsi. Report of five cases and review of the literature.
AB  - Five cases of elastofibroma dorsi are described. The location of the lesions
      (bilateral in one case) was typical, in the thoracoscapular region. In the first
      case the diagnosis was established by biopsy; in the remaining cases the
      diagnosis was suspected based on clinical and magnetic resonance imaging findings
      and was confirmed by histopathological study after surgical excision. Although
      these lesions are benign, histological study is advisable to establish a
      differential diagnosis with malignant neoplastic processes.

PMID- 12415950
TI  - [Advice for potential surgeons].

PMID- 12415951
TI  - [Genetic material: instruction manual for the management of disease; breast
      cancer, for example].

PMID- 12415952
TI  - [Euthanasia and assisted suicide. End-of-life options].

PMID- 12415953
TI  - [High-risk human papilloma virus and cervical intraepithelial neoplasia in women
      at 2 hospitals in Mexico City].
AB  - OBJECTIVE: To determine the high risk HPV (HR-HPV) association with Cervical
      Intraepithelial Neoplasia (CIN) in women of two Dysplasia Clinics in Mexico City.
      MATERIAL AND METHODS: Prolective case-control study was done. Women with and
      without security affiliation attended in Instituto Mexicano del Seguro Social
      (Hospital 1) and Hospital General de Mexico (Hospital 2) were included in the
      study. Cases were women with histopathologic diagnosis of CIN and controls were
      women with negative dysplasia in cytologic study (Pap). Information was obtained
      by direct interview. HR-HPV was determined by Hybrid Capture II assay, in
      cervical samples. Bivariate and logistic regression analysis was done. RESULTS:
      One hundred and two cases and 192 controls from Hospital 1 and 89 cases and 66
      controls from Hospital 2 were included. 83.3% and 77.3% of women from Hospital 1
      and 2 respectively were positive to HR-HPV. The association HR-HPV and CIN in
      Hospital 1 was ORa = 40.6, C.I. 95% = 17-96.8; while in Hospital 2 there was not
      association. Age was an effect modifier in the HR-HVP and CIN association, in
      Hospital 1. It was observed a correlation between viral load and CIN degree.
      CONCLUSIONS: The HR-HPV infection frequency in controls and CIN I was higher than
      the reported in other studies. Age was a modifier in the HR-HPV association and
      CIN. In dysplasia clinics without medical referral system of patients is possible
      to observe similar risk factors to cervical cancer.

PMID- 12415954
TI  - Remission of Graves' hyperthyroidism treated with methimazole.
AB  - BACKGROUND: Long-term thionamide treatment is considered one of the main
      resources for Graves' hyperthyroidism. Although a 54.2% remission rate in
      patients so treated in Mexico was previously reported, most articles have shown a
      wide variation over time. In the present article we report the actual remission
      rate of long-term methimazole (MMZ) therapy of Graves' hyperthyroidism in Mexico.
      METHODS: We carried out a retrospective study of long-term MMZ treatment in 80
      patients with Graves' hyperthyroidism with a postreatment follow-up of at least
      twelve months. Remission was considered by clinical as well as biochemical
      criteria. RESULTS: We studied 63 females and 17 males, mean age 37.7 +/- 10.4
      years. Duration of symptoms was 13.3 +/- 20.7 months. Daily MMZ dose: 20.0 +/-
      8.8 mg, treatment duration 16.7 +/- 8.9 months and follow-up was 34.8 +/- 60.3
      months. Fourteen patients (17.5%) are in remission and sixty six relapsed
      (82.5%). Relapse occurred after a mean of an 11.9 +/- 11.8 month follow-up.
      Goiter size was the only statistically significant remission sign whereas age,
      disease duration, MMZ dose, exophthalmos, treatment duration or 1-thyroxine
      concomitant use were not useful predictive factors. CONCLUSIONS: Remission rate
      of long-term MMZ treatment of Graves' hyperthyroidism has substantially decreased
      in Mexico, since the previous report. We suggest that our results may be related
      to an increase of iodine intake or poor treatment, compliance. Goiter size was
      the only remission predictive sign. Due to our low remission rate we suggest
      Graves' disease patients must be selected for this kind of treatment.

PMID- 12415955
TI  - [Post-discharge survival of newborn infants with congenital cardiopathies
      undergoing heart surgery or interventional catheterization].
AB  - OBJECTIVE: To report survival of newborns with congenital heart disease who
      underwent cardiac surgery during neonatal period. DESIGN: Descriptive,
      ambispective. SETTING: Neonatal Intensive Care Unit (NICU), Hospital de
      Pediatria, Centro Medico Nacional Siglo XXI. PATIENTS: We studied 74 newborns
      with congenital heart defects who underwent corrective surgery, palliative
      surgery or interventional techniques and received preoperative and postoperative
      care in NICU. Premature patients with patent ductus arteriosus were excluded.
      RESULTS: The following median values were found: birth weight was 2,862 g,
      gestational age was 39 weeks, onset of symptoms was 1 day, age at surgery was
      14.5 days and postoperative hospital stay was 9 days. Most frequent congenital
      heart defects were single-ventricle, transposition of the great arteries and
      hypoplastic right heart. Fifty percent of surgeries were corrective, 46% were
      palliative and 4% were interventional techniques. Global survival was 51%, for
      curative surgery was 43% and for palliative surgery was 58%. Only 3 patients
      underwent interventional cardiology, 2 of them died (survival 33%). CONCLUSIONS:
      Global survival in newborns who underwent cardiac surgery is lower in comparison
      with other studies. Survival is higher in children with palliative surgery in
      comparison with those who underwent corrective surgery.

PMID- 12415956
TI  - [Obesity and gastroesophageal reflux disease].
AB  - INTRODUCTION: Obesity is a condition that has been associated with
      gastroesophageal reflux disease (GERD), however, a cause-effect relationship has
      not been established. AIM: To analyze current evidence evaluating the
      relationship between obesity and GERD, as well as the impact of hypocaloric diets
      and bariatric surgery in gastroesophageal reflux symptoms. MATERIAL AND METHODS:
      An electronic search in the MEDLINE was performed, looking for information
      published during the past 15 years: Cohort studies, case-control studies, case
      series and case reports, including the following key words: "heartburn",
      "reflux", "gerd", "reflux esophagitis", "obesity", "overweight", "diet",
      "bariatric surgery" were analized. RESULTS: Thirty-one articles were included.
      These studies were classified according to the diagnostic method of GERD (i.e.,
      manometry, 24-hour pH monitoring, esophageal transit, endoscopy) and type of
      bariatric surgery: Adjustable gastric banding (AGB), vertical banded gastroplasty
      (VBG), and Roux-en-Y gastric bypass (RYGB), or anti-reflux procedure.
      CONCLUSIONS: Most studies suggest that obesity is a condition predisposing to the
      development of GERD. However, there are no studies that correlate the degree of
      obesity with the symptoms of reflux. Hypotonic lower esophageal sphincter,
      ineffective esophageal motility and presence of hiatal hernia are the
      pathophysiological mechanisms proposed as inductors of gastroesophageal reflux
      among obese patients. AGB and VBG seem to induce postoperative esophagitis in
      some patients, but RYGB has shown to be effective to control GERD symptoms.
      Overweight and obesity do not seem to affect the results of antireflux surgery.
      The impact of body weight loss on GERD following hypocaloric diets requires
      further investigation.

PMID- 12415957
TI  - [The performance of professors of Medicine as an indicator of the influence of an
      educational training course].
AB  - OBJECTIVE: To compare the educational environments created by the professors who
      attended the Regional Center of Teachers Training to those who did not attend it.
      MATERIAL AND METHODS: An instrument was developed to explore the educational
      environment that every professor creates for students with indirect technique,
      with double statements in accordance to the passive and participative focus of
      the education they approached of the type and frequency of activities carried on
      regularly in the educational process, validated by rounds of experts, with a
      final version of 60 statements and six indicators. The instrument was applied to
      480 residents (students) from the different specialization courses in 10
      hospitals from a Delegation of the Mexican Institute of Social Security
      corresponding to 82 professors evaluated. For the statistic analysis was used Chi
      2 with Yates correction, the odds ratio with confidence intervals and the U of
      Mann Whitney. The Kuder Richardson test was used to determine the instruments
      consistency. RESULTS: There were no significant differences (p > .50) when
      comparing the educational environment created by the professors who attended the
      training courses at the Center and those who did not attend. The odds ratio to
      evaluate if training creates a more participative environment for students was of
      1.84 (IC 0.94-2.92). CONCLUSION: There are limitations in the courses for
      teachers training and that is because a profound change has not been accomplished
      in the graduates to allow a turn in their teaching experience to an education
      that promotes the elaboration of knowledge (participative) by the students, when
      they return to their medical units. It is necessary to reorient the educational
      process.

PMID- 12415958
TI  - [Evaluation of the use of bovine pericardium in non-anatomical lung resections in
      dogs].
AB  - In this study we assessed the usefulness, healing, as well as the integration to
      lung tissue of glutaraldehyde preserved at 0.5% bovine pericardium GPBP and
      lyophilized (GPBPL), after reinforced resection of lung tissue in dogs by
      thoracotomy or thoracoscopy. MATERIAL AND METHODS: GPBP and GPBPL were prepared
      and used to reinforce the suture line of lung resection in 30 mongrel dogs: Group
      I (n = 6): The GPBP were fixed on the lung with 4-0 polypropylene by thoracotomy.
      Group II (n = 6): The resection and fixed of the GPBP were performed with an
      linear stapler by thoracotomy. Group III (n = 6): The resection and fixed of the
      GPBPL were performed with an linear stapler by thoracotomy. Group IV (n = 6): The
      resection and fixed of the GPBP strips were performed with a linear stapler by
      thoracoscopy. Group V: The resection and fixed of the GPBPL strips were performed
      with a linear stapler by thoracoscopy. Clinico-radiological evaluation was done
      until euthanasia of all animals at week 8 postop. Progressive insufflation up to
      40 cm H2O of airway pressure was done to evaluated resistance of the heal in the
      suture line reinforced. Macroscopic, and microscopic examination of the GPBP,
      GPBPL and lung were evaluated. RESULTS: All animals survived the surgical
      procedure and study time (8 weeks). No airleaks were evident at any time during
      the study including the insufflation test. Macroscopic examination of the GPBP
      and GPBPL showed good adaptation to the lung tissue. Microscopically all animals
      presented good healing with deposition of fibrotic tissue layer on the GPBP and
      GPBPL. CONCLUSION: GPBP and GPBPL are an adequate materials to reinforce lung
      staple line, when resection of lung tissue was performed in dogs by thoracotomy
      or thoracoscopy.

PMID- 12415959
TI  - [Telomerase: an enzyme with multiple applications in cancer research].
AB  - The telomerase is a ribonucleoprotein enzyme to which multiple functions have
      been attributed, the most important of these is the maintenance of the telomere
      which is related with cellular immortalization and cancer. 85% of human tumors
      have telomerase activity, that in normal cells goes undetected. These
      characteristics make the telomerase an attractive target for chemotherapy.

PMID- 12415960
TI  - [Multiple drug resistance in Entamoeba histolytica].

PMID- 12415962
TI  - [Thoracoscopy and video-assisted thoracic surgery].

PMID- 12415961
TI  - [Guillain-Barre syndrome: etiology and pathogenesis].
AB  - Guillain-Barre syndrome (GBS) is a reactive, self-limited, monophasic disease
      triggered by a preceding bacterial or viral infection. GBS has also been linked
      to underlying systemic diseases, certain malignancies, surgery, pregnancy, trauma
      severe infection, and tissue transplantation (bone marrow and organs). Although
      its pathogenesis is unclear, it is likely to be a consequence of an immune
      mediated process. Therefore, we believe that GBS results from an aberrant immune
      response that somehow mistakenly attacks the nerve tissue of its host, most
      probably by recognizing a molecular similar epitope mechanism (molecular
      mimicry). Immune reactions against these epitopes result in acute inflammatory
      demyelinating neuropathy or acute axonal forms. GBS has a worldwide distribution
      with an annual incidence of approximately 1.2-8.6 cases per 100,000 people. Both
      genders are at similar risk (but there is a slight male predominance). All ages
      are affected, although the distribution is bimodal. The supporting measures are
      critically important to provide optimal treatment. Immunomodulation with plasma
      exchange and intravenous immunoglobulin treatments shorten the disease course.
      Outcome is generally good, with virtually full recovery in 70-80% of the
      patients. In this review physiopathological aspects and clinical implications of
      GBS are fully discussed.

PMID- 12415963
TI  - [Medicine: science and humanism. Questions and reflections on medical practice].

PMID- 12415964
TI  - [I want to be a surgeon].

PMID- 12415965
TI  - [Breast conservation: safe for early breast cancer].
AB  - Between 1981-1993 581 women with primary breast cancer were treated by breast
      conservation. Their mean age was 56 +/- 12 years and 63% were postmenopausal and
      37% pre- or perimenopausal. The median follow-up time was 56 months. 45% had
      pathological Stage I disease, 49% Stage II, 2.5% Stage III and 3.5% clinical
      Stage I-II disease. 54% of lesions were excised with good margins, 10% with close
      margins (< 0.5 cm), 9% with microscopic residual, 3% with macroscopic residual,
      and in 24% margins were not reported. Adjuvant therapy, consisting of combination
      chemotherapy and/or hormones, was given to 69%. Radiotherapy, usually 50 Gy
      tangential photon irradiation to the whole breast, was given to 564 (97%); an
      electron or photon "boost" to the tumor with a median dose of 17.5 Gy was given
      to 378 (65%). Most of those with positive nodes received 50 Gy to the lymphatic
      drainage system. 1 year after radiotherapy cosmetic results were rated as "good"
      or "excellent" in 80%, "moderate" in 17% and "poor" in 3%. The 5-year actuarial
      survival was 97% in Stage I and 88% in Stage II. 37 patients (6.5%) developed
      breast recurrence; 11 of these (2%) had simultaneous distant metastases. 5 (< 1%)
      developed axillary or supraclavicular lymph node metastases, and 81 (14%)
      developed distant metastases. Most local recurrences were in those younger than
      40, and in those with primary tumors > 1.75 cm. The satisfactory level of local
      control achieved is attributed to the high doses of radiation (up to 75 Gy)
      administered to those with high risk lesions.

PMID- 12415966
TI  - [One-stage surgery for Hirschsprung's disease in children].
AB  - Traditionally Hirschsprung's disease has been treated by 2- or 3-stage
      procedures. During the past 6 years a 1-stage Duhamel procedure without stoma has
      become our treatment of choice for Hirschsprung's disease in neonates and young
      infants. Over a 6-year period, 15 infants and children with colonic
      Hirschsprung's disease were treated with the 1-stage Duhamel retro-rectal pull
      through procedure without a stoma, with the Lester-Martin modification. All
      patients had the usual short segment aganglionosis, but 1 had a long segment
      which included the splenic flexure. Early complications included wound infection
      in 1 and minor rectal bleeding in 3. Late complications included constipation in
      1 and enterocolitis in 4. Long-term functional results were very good in all
      those operated except for 1 with rectal achalasia. We conclude that
      Hirschsprung's disease can be successfully treated with a 1-stage pull-through
      operation, the child usually benefitting from the shorter hospital stay and the
      avoidance of a colostomy.

PMID- 12415967
TI  - [Sensitivity and resistance of Helicobacter pylori to antibiotic treatment].
AB  - Resistance to antibiotics is considered the main reason for failure to eradicate
      Helicobacter pylori (HP). Resistance rates are different in developed and
      developing countries and are not known for Israel. We studied HP resistance rates
      in 40 patients who underwent esophagoduodenoscopy for various indications and
      were found to have gastric HP colonies. Sensitivity was determined by E-test,
      using clarythromycin, amoxycillin, clindamycin, erythromycin and metronidazole.
      The resistance rate for metronidazole was up to 67% but that for clindamycin was
      only 10%. HP was very sensitive to both macrolide antibiotics, erythromycin and
      clarythromycin.

PMID- 12415968
TI  - [Computerization in a community health service provider].
AB  - As the second largest health service provider organization in Israel, we have
      been progressively computerized. The process was begun in 1988, focusing on
      improving administrative and financial processes. Today there is a single
      centralized database for 6,000 users. The system monitors member eligibility,
      accounting procedures and clinical processes, including diagnoses, laboratory
      tests, imaging procedures and drug-prescribing. The potential of the computer for
      physician support is now being realized through integration of clinical
      guidelines and reminder systems into the computerized clinical record. In
      addition, the centralized database is used for quality improvement, facilitating
      cost-effective drug-prescribing and efficient use of technology. The
      establishment of a computerized working environment for 2,000 physicians and
      4,000 other healthcare workers serving 1.3 million patients is a unique model for
      the development of community health services. Data regarding demographics,
      disease patterns, drug-prescribing, use of new technology and costs are now
      readily available to all, from senior management to the individual physician in
      independent practice. The computer revolution has also presented a new set of
      problems such patient-record confidentiality and the effect of the computer on
      the physician-patient encounter.

PMID- 12415969
TI  - [Knowledge, attitudes and training of family physicians with regard to addiction
      to illicit drugs].
AB  - Substance abuse is one of the most serious problems in Israel. Recent studies
      show the situation is getting worse. The deleterious outcomes of psychoactive
      substance abuse include crime, car accidents, physical and mental illness,
      violence and work injuries. 48 family physicians in the Negev completed a
      questionnaire which included training, diagnostic and treatment skills,
      attitudes, knowledge and need for training in this field. 38 family physicians
      (81%) had had no training, most (96%) indicated the importance of such training.
      34 (71%) said that their medical skills could not cope with the problems of
      addiction, and 29 (64.5%) claimed that the quality of care of addict patients is
      reduced because of lack of knowledge and diagnostic skills. These findings
      support the conclusion that efforts should be invested in training family
      physicians in the field of psychoactive drugs, licit and illicit.

PMID- 12415970
TI  - [Post-traumatic stress disorder with psychotic features].
AB  - Post-traumatic stress disorder (PTSD) is often accompanied by psychiatric
      comorbidity, usually depressive and anxiety disorders. Comorbidity with psychosis
      has seldom been described. We present 6 case-studies of Israeli military veterans
      with PTSD and psychosis (all men aged 28-43). All developed PTSD shortly after a
      period of months or even years, sometimes following trauma-related triggering.
      Psychotic symptoms such as delusions or auditory hallucinations usually had
      paranoid or depressive features related in content to the traumatic experience.
      The combined course and interaction between PTSD and psychotic disorder is
      discussed, as well as the diagnosis of PTSD with psychotic features.

PMID- 12415971
TI  - [Symptom severity among chronic schizophrenics in hospital and in the community].
AB  - We compared severity of symptoms of chronic schizophrenics in a psychiatric
      hospital with those treated in its outpatient clinics. The Positive and Negative
      Syndrome Scale and the Mini-Mental State examination were used to assess the
      schizophrenic symptoms and cognitive performance, respectively, of 25 chronic
      schizophrenic inpatients matched for gender, age and education with 25 chronic
      schizophrenic outpatients. The Global Assessment Scale and the Clinical Global
      Impression Scale were used to test global functioning. Assessment included
      psychiatric and medical history and treatment and demographic characteristics. In
      patients had significantly more positive, negative and general psychiatric
      symptoms. Their cognitive and general functioning were impaired. Most in-patients
      also had medical problems. Age of onset of schizophrenia among the in-patients
      was younger. Results show a marked difference in severity of symptoms and level
      of functioning between chronic schizophrenic in-patients and out-patients. These
      differences should be considered in the planning of discharge of chronic in
      patients from psychiatric hospitals into the community.

PMID- 12415972
TI  - [Elastofibroma, a rare cause of snapping scapula syndrome].
AB  - Scapular pain is a common complaint in daily orthopedic practice. A different
      type of scapular discomfort, the snapping scapula syndrome that occurs when
      smooth gliding motion of the scapula upon the chest wall is interfered with is
      much less common. We studied the syndrome of periscapular pain and discomfort,
      and present a rare etiology: elastofibroma dorsi, a unique, benign, soft tissue
      tumor with unique characteristics. Elastofibroma appears deep to the lower
      scapular pole, is often bilateral, and consists of a mixture of collagen, elastic
      fibers and fibroblasts. We present 6 cases, in 3 men and 3 women aged 51-65.

PMID- 12415973
TI  - [Cryptococcal meningitis following cryptococcal pneumonia in an immunocompetent].
AB  - Cryptococcal meningitis (CM) is common in the immunocompromised (especially due
      to AIDS), but also occurs in immunocompetent subjects. CM can complicate
      cryptococcal pneumonia (CP) not only in the immunocompromised but also in the
      immunocompetent. We describe a healthy 26-year-old man who developed a prolonged
      lung infection. Diagnosis of cryptococcal pneumonia was established from
      bronchoscopic washings. He recovered spontaneously, so no antifungal treatment
      was given. 4 months later he was admitted with cryptococcal meningitis and was
      treated successfully with amphotericin B. An extensive immunologic study revealed
      no abnormalities. Since CM can complicate cryptococcal pneumonia, it is
      recommended that patients with CP be followed, even if recovery is apparently
      complete.

PMID- 12415974
TI  - [On the politicization of scientific journals].

PMID- 12415975
TI  - [Improving the recognition, diagnosis and treatment of genital herpes simplex
      virus infection].

PMID- 12415976
TI  - [Prevention of inherited disorders: carrier screening, its benefits and potential
      harm].

PMID- 12415977
TI  - [Silicone breast implants: an update].

PMID- 12415978
TI  - [Brain damage in patients resuscitated from cardiac arrest].

PMID- 12415979
TI  - [Methods for preventing ovarian hyperstimulation syndrome].

PMID- 12415980
TI  - [Interleukin IL-13: a central mediator in allergic asthma].

PMID- 12415981
TI  - [Penile fracture].

PMID- 12415982
TI  - [Neonatal tuberculosis].

PMID- 12415984
TI  - [Fraud, dishonesty, and misrepresentation in medical publications and the fight
      against them].

PMID- 12415983
TI  - [Thymopoietin protein: from thymic hormone to proteins involved in nuclear
      architecture and cell cycle control].

PMID- 12415985
TI  - [Evaluation of clinical findings in occupational health examinations].
AB  - Findings in occupational health examinations of a regional service are analyzed.
      The service provides pre-employment, surveillance and work-capacity evaluations
      for about 150,000 workers from many types of work-sites and occupations. The
      average number of pre-employment examinations (during 1993-97) was 4,800/year,
      and there were relevant pathological findings in about 6.6%. Most findings
      involved the respiratory (11%) and cardiovascular systems (10%) or eyes (10%).
      The average annual number of surveillance system examinations was 10,750. There
      were relevant findings in about 16%, mainly of the respiratory system (17%) and
      noise-induced hearing damage (about 80%). Work-capacity examinations constituted
      about 35% of the work-load (9,250 examinees/year). In 53% a significant health
      problem affecting an individual's job performance was identified. Pathological
      findings were found in the musculoskeletal (21%), cardiovascular (7.5%),
      respiratory (3%), and neurological systems (2%). Occupational health examinations
      can identify areas in which prevention and intervention or cooperation with other
      medical specialties are indicated, as well as specific topics requiring further
      training of occupational physicians.

PMID- 12415986
TI  - [The non-operative management of low velocity anterior abdomen gunshot wounds].

PMID- 12415987
TI  - The potential dangers of DEHP-containing devices--are alternatives the answer?

PMID- 12415988
TI  - Exception to the CON rule. HealthSouth's exemption from certificate-of-need law
      draws Alabama Hospital Association into legal fray.
AB  - The Alabama Hospital Association, like many healthcare industry lobby groups, has
      always taken a cautious and impartial approach to disputes among its members. But
      this summer, the association (headed by Michael Horsley, left) joined two
      hospitals in their legal battle against HealthSouth Corp. and its plan to build a
      "digital" facility. A hearing later this month may determine whether it ever
      opens for business.

PMID- 12415989
TI  - Amid controversies, JCAHO is still riding high. Between parent and subsidiary,
      the agency continues to be financially strong with record profits in 2001.

PMID- 12415990
TI  - Seeds of discord. Some Alabama hospitals, feeling lobbying slight, threaten to
      leave AHA.

PMID- 12415991
TI  - A difference of mission. Saint Luke's parts ways amicably with Shawnee.

PMID- 12415992
TI  - Legal ammo. Court decision favoring hospital may boost defense against physician
      joint ventures.

PMID- 12415993
TI  - Straight shooting. Texas consumers at last get look at hospital report card.

PMID- 12415994
TI  - End of bankruptcy in sight. W.Va. hospital could convert to for-profit in sale.

PMID- 12415995
TI  - Clinical trials: a medical Catch-22. Researchers, institution boards must take
      appropriate steps to protect participants.

PMID- 12415996
TI  - Web survey. September results: 'healthcare issues in the news'.

PMID- 12415997
TI  - A house divided. It's been board members vs. politicians in a tug of war
      involving the governance of a South Carolina public hospital. And facility
      operations have suffered during the lengthy struggle.

PMID- 12415999
TI  - [Internal urethrotomy: procedure].
AB  - Internal urethrotomy (IU) can be considered the first surgical modality of
      treatment of the urethral stenosis (US). Most US are iatrogenic. Others are of
      inflammatory, traumatic or congenital. The rationale of IU is to incise the scar
      and to allow the urethra to open, hoping that it will maintain this increase in
      calibre as healing progresses. IU is helpful when the spongiofibrosis associated
      with the stricture is superficial. Usually a single incision at the 12 o'clock is
      made, but other incisions can be performed. A soft catheter is left in the
      urethra after an IU for some days. IU can be a curative modality, but often the
      results are disappointing. In literature a 20-40% of success is reported. It is
      generally believed that IU can be repeated at maximum 2 or 3 times. Some authors
      suggest intermittent catheterisation (IC) to improve the final outcome.

PMID- 12415998
TI  - [Pathology and physiopathology of urethral stenosis].
AB  - The research of new techniques for surgical repair of urethral stenosis, has
      developed interest and knowledge toward tissue handling and transfer in urology.
      Successful surgical repair of "long" stenosis is possible nowadays, using graft
      or flap tissue transfer. The knowledge of methral anatomy and of histopathology
      urethral anatomy, histopathology and physiopathology of the mechanism involved in
      process of urethral narrowing, is necessary for the diagnosis and the surgical
      indication of this pathology. To review physiopatological and anatomopathological
      aspects of urethral stenosis is the aim of the authors.

PMID- 12416000
TI  - [The use of temporary stents in the treatment of urethral stenosis].
AB  - The Authors report their past experience in the treatment of urethral strictures
      by means of temporary stent implants (Urocoil). The results at a long-term follow
      up were poor in strictures of the bulbous and penile urethra (2/19 at 36 months)
      and very good in strictures of bladder neck and prostatic urethra (10/10 at 45
      months). They conclude that this treatment has been at present abandoned due to
      high costs and poor results. It could however be effective in the treatment of
      postsurgical bladder neck strictures recurring after endoscopic treatment.

PMID- 12416001
TI  - [Permanent urethral stents in urethral stenosis].
AB  - The first-line treatment for bulbar urethral strictures is still dilation. The
      second-line treatment is usually optical urethrotomy. A real challenge for the
      urologist is a recurrent bulbar urethral stricture following 1 or more of these
      procedures. In patients with important spongiofibrosis, repeat dilation or
      urethrotomy is destined to fail. Urethroplasty is the ideal treatment option for
      recurrent bulbar urethral strictures. However, some patients with recurrent
      strictures are either not interested in or are not candidates for surgical
      urethroplasty. In this group of patients, the placement of an endourethral
      prosthesis allows a method for maintaining adequate urethral patency without the
      need for repeat dilation or urethrotomy. The use of endourethral stents provides
      another form of therapy in this relatively common and often troublesome disease.
      This article reviews indications for usage, placement technique, results, and
      complications associated with permanent stent placement.

PMID- 12416002
TI  - [Comparison of surgical techniques: resection and termino-terminal anastomosis].
AB  - There are different surgical options for the treatment of anterior stricture
      diseases such as anastomotic repair, substitution urethroplasty and two stage
      procedures. The choice of the adequate technique must be based on a correct
      urethral stricture selection (aetiology, length, previous treatments, local
      factors). The urethroplasty failures are generally secondary to incorrect
      selection or execution of the operations and sometimes to spongiofibrosis relapse
      or prolonged tessutal ischemia. End-to-end anastomosis is the treatment of choice
      for strictures, particularly post traumatic, of the bulbous urethra no longer
      than 2 cm. The dorsal roof-strip anastomosis is indicated for bulbar urethral
      strictures longer than 2 to 3 cm. It is a combined end-to-end and substitution
      urethroplasty technique.

PMID- 12416003
TI  - [Urethro-autoplasty: scrotal in-lay, mesh-graft, buccal on-lay].
AB  - The surgical therapy of the urethral strictures is still controversial as it
      interests the choice of an appropriate technique among many methods. In cases of
      complex urethral strictures, urethroplasties using genital or extragenital tissue
      for reconstruction are indicated. Scrotal in-lay was popular some years ago, but
      the complications rate was high. Nowdays, the two techniques with better outcome
      are the mesh graft urethroplasty and the buccal mucosa on-lay urethroplasty.

PMID- 12416005
TI  - [Diagnostic value of ultrasound-guided anastomotic biopsies in patients with high
      PSA (> or = 0,4 ng/ml) after radical prostatectomy].
AB  - OBJECTIVES: The authors report their experience on the use of a high number of
      biopsies for the diagnosis of a vesicourethral anastomosis tumor recurrence in
      patients who underwent radical prostatectomy with a PSA elevation. METHODS: Sixty
      five patients with PSA > or = 0.4 ng/ml after radical prostatectomy received 6 to
      8 transrectal ultrasound (TRUS) guided biopsies of the vesicourethral
      anastomosis. RESULTS: The biopsy scheme with 6 random anastomotic biopsies plus
      additional biopsies through TRUS detectable lesions was able to diagnose a local
      recurrence in more than 60% of the cases. In presence of a post-operative PSA <
      1.0 ng/ml and in absence of ultrasound detectable or palpable lesions a local
      neoplastic recurrence was detected in 58% of the cases. In presence of a palpable
      or ultrasound visible lesions, the detection rate increases to 80% of the cases.

PMID- 12416004
TI  - [Reconstructive urethroplasty using porcine acellular matrix: preliminary
      results].
AB  - OBJECTIVE: The use of "porcine acellular matrix", obtained from small intestine
      submucosa, could simplify the repair of long urethral strictures, whereas single
      stage techniques can be carried out only by means of grafts, as buccal mucosa; or
      flaps, as prepucial skin. To our knowledge we report the first use of porcine
      intestine submucosa in urethroplastic surgery. MATERIALS AND METHODS: From May
      2001 to December 2001, five urethral reconstructions were completed using
      "porcine acellular matrix". Four male patients had urethral strictures longer
      than 10 cm. After circumcision and penile degloving, we extended the surgical
      approach to the perineum-scrotal region by a midline longitudinal incision. The
      urethra was exposed, dissected from corpora cavernosa, then rotated of 180
      degrees and on this side longitudinally incised throughout all the stenotic
      length. Urethroplasty was accomplished with matrix tissue modelled according to
      the length of the stenosis and grafted by a 5-0 polyglycolic acid running suture.
      The enlarged urethra was then derotated, laying the graft dorsally, closed to
      corpora cavernosa, to prevent pouching. A further graft was accomplished in a
      female patient with a 3 cm long urethral stricture. All urethroplasties were
      stented for 14 days. No complication developed. RESULTS: After 1 month urethral
      patency was satisfactory compared with preoperatory images and the urinary flow
      was normal. After 2 months the urethra was endoscopically verified: it was easy
      to appreciate the homogeneous transformation of the graft into the native tissue.
      At 6-month follow-up radiological and urodynamic outcome is still satisfactory in
      all patients. CONCLUSIONS: According to our preliminary experience "porcine
      acellular matrix" is a promising approach for the repair of long urethral
      strictures. Its safety and effectiveness encourage us to treat more cases in male
      and female patients.

PMID- 12416006
TI  - [Prevention of venous thromboembolism in urologic neoplasms].
AB  - PURPOSE: We report our past experience on a sample of patients who underwent
      pelvic surgery to treat infiltrating bladder tumours. RESULTS: We observed the
      highest incidence of TVP (33.3%, 3 out of 9) in those patients with higher risk
      due to anaesthesia and type of surgery. One of our patients died of pulmonary
      embolism. DISCUSSION: Abdominal pelvic surgery in tumour-bearing patients can be
      risky due to high incidence of distal and proximal venous thrombosis often
      resulting in fatal pulmonary embolism (EP). The general risk factors should be
      evaluated. The diagnosis of venous thrombosis can be difficult to achieve only by
      clinical examination. Heparin administration as well as surgical techniques and
      physiotherapy are used as prophylactic measures to reduce the risk of venous
      thrombosis and to speed up recovery. Nowadays, there is an increasing risk of
      running into legal problems if appropriate measures to minimise the
      thromboembolism are not taken.

PMID- 12416007
TI  - Detrusor pressure uroflowmetry studies in women: effect of 4 Fr transurethral.
AB  - PURPOSE: Pressure flow technique on males is considered a standard diagnostic
      procedure to investigate the voiding process, while on female this is still under
      investigation. Many studies have been conducted in order to establish a female
      bladder outlet obstruction nomograms using a 7 Fr catheter, but recently a report
      showed that 7 Fr catheter may adversely affect the voiding process on women. We
      studied the effect of 4 Fr urethral catheter in women undergoing pressure flow
      evaluation in order to assess any detrimental effect in the voiding process.
      MATERIALS: We evaluated a database of 85 patients referred for lower urinary
      tract symptoms. First, all patients had free uroflowmetry and then underwent
      pressure flow studies utilizing two catheters: a 12 Fr for filling and a 4 Fr
      mono J for measuring detrusor pressure. After filling we removed the 12 Fr
      catheter and pressure flow was performed leaving the 4 Fr only in the urethra. As
      positive correlation of flow rate with voided volume is well established, we
      selected only 33 patients who had similar prevoided volumes varying by less than
      30% and free and intubated flow parameters were compared according to volume
      categories in order to strengthen the statistic analysis. RESULTS: In each group
      all the free and pressure flow parameters were not statistically different. Only
      in the group who voided within 250 and 500 ml we found the pressure flow voiding
      time to be almost longer than the free flow equivalent, but not statistically
      different (31.1 +/- 15 versus 56.7 +/- 49.3; p = 0.05). Furthermore we did not
      find any difference in free and intubated morphology of curves. CONCLUSIONS: A 4
      Fr transurethral catheter does not affect adversely the voiding process in women
      undergoing pressure flow studies for lower urinary tract symptoms. This finding
      has very important clinical implications for interpreting female voiding patterns
      and may be considered the best tool to define bladder outlet obstruction on
      women.

PMID- 12416008
TI  - [Suburethral sling for male urinary incontinence].
AB  - This article describe a new technique for treating post-prostatectomy urinary
      incontinence. We performed this procedure on 15 patients with a follow-up of 2 to
      9 months. All of the patients had radical retropubic prostatectomies and a
      urodynamically confirmed stress urinary incontinence for more than one year; 3 of
      the 15 (20%) had detrusor instability. We used the exaggerated lithotomy position
      and a perineal approach. Three 5 mm titanium bone screw with pre-loaded No 1
      polypropylene sutures (In fast Straight-In bone Screw Suture system) were placed
      on each side of the inner surface of the descending pubic ramus. To support the
      bulbar urethra was used a cadaveric fascia lata graft, reinforced with a piece of
      folded polypropylene mesh and tied to the pubic bone using the sutures attached
      to the bone anchors. Urethral resistance was increased to 45 cm H2O above
      baseline pressure. Thirteen patients (86.6%) are completely cured, i.g., do not
      require any pads. We have seen total failure in 1/15 patients (6.6%) and minimal
      improvement in 1/15 patients (6.6%). Urgency incontinence was reported in 3/15
      patients (20%). All responded to the use of anticholinergic therapy. Two of the
      three patients with post-operative urgency incontinence had preoperative detrusor
      instability documented on urodynamic evaluation. This minimally invasive male
      sling procedure is efficacious. Long-term follow-up will be necessary before a
      final assessment of this new technique is rendered.

PMID- 12416009
TI  - [Small cell carcinoma of the bladder. Report of 3 cases and review of the
      literature].
AB  - Primary small cell carcinoma of the urinary bladder is a highly aggressive
      disease and accounts for less than 0.5% of all primary bladder tumors. Quite
      often, clinical presentation is related to local and/or systemic involvement of
      the disease. Histogenesis is still unknown, but investigators consider the tumor
      originating from a multipotent undifferentiated stem cell of the bladder
      urothelium. Hematuria is the first and most frequent symptom that patients
      complain at the clinical presentation of the disease. The primary local tumor is
      treated by radical surgery or radiation therapy, while systemic involvement
      requires polychemotherapy according to the M-VAC protocol. Prognosis is worse and
      related to the pathological stage of the disease and to chemotherapy reply.
      Herein we report on 3 cases of primary small cell carcinoma of the urinary
      biadder. We also review and update the literature concerning this topic.

PMID- 12416010
TI  - Incidentally discovered adrenal myelolipoma. Report on 3 operated patients and
      update of the literature.
AB  - INTRODUCTION AND OBJECTIVES: Adrenal myelolipomas are rare benign non functioning
      tumors which are mostly detected incidentally by imaging (8-15%). The aim of this
      study was to find out the clinical outcome of 3 patients operated for
      incidentally discovered adrenal myelolipoma as well as to update the literature
      concerning this topic. PATIENTS AND METHODS: During a 24 year period (1976-2000)
      we operated on 28 of 39 (72%) patients for incidentally discovered adrenal mass
      and pathology assessed 3 myelolipomas (11%). All patients were males and average
      age was 54.3 years (range 46-66). Myelolipoma was associated with arterial
      hypertension in 2 patients and BPH in 1. Patients underwent unilateral
      adrenalectomy. Results Myelolipomas, all unilateral, were right-sided in 2 cases
      (67%) and left sided in 1. Average tumor diameter, as detected by CT scan,
      resulted 10.3 cm range (3-17). Endocrine investigation was negative. Average
      tumor size, as detected by pathology, resulted 9.3 cm (range 3-14) and mean
      weight 653 gr (range 210-980). Histopathology assessed primary adrenal
      myelolipoma in all cases. Mean follow-up is 110.6 months (range 102-128) and all
      patients are alive and disease free. CONCLUSIONS: Ultrasound (US), computed
      tomography (CT) and magnetic resonance imaging (MRI) are effective in diagnosing
      adrenal myelolipomas in about 90% of cases. Fine needle aspiration (FNA) cytology
      under CT or US control has an important role in investigating as well as
      diagnosing undefined masses suspected of adrenal or extraadrenal myelolipoma thus
      avoiding unnecessary surgery. The increasing number of incidentally discovered
      adrenal myelolipomas arise the question of appropriate treatment modalities which
      range from watchful waiting to surgical removal. Small asymptomatic tumors sized
      less than 4 cm can be monitored expectantly. Tumors when symptomatic or larger
      than 4 cm should be removed since the risk of spontaneous rupture with
      retroperitoneal hemorrhage and life threatening shock. Bilateral adrenalectomy
      for large and symptomatic tumors implies lifelong substitution with
      hydrocortisone. Actually, laparoscopic adrenalectomy is the new gold standard in
      treating myelolipomas since both showing more effective postoperative recovery
      than open surgery as well as reducing the number of patients who undergo long and
      close follow up.

PMID- 12416011
TI  - [Evaluation of FSH and Leydig cells function in patients with varicocele].
AB  - The endocrine alterations in patients affected with varicocele are heterogenous
      in relation to some clinical aspects: orchidometry, bilateral lesion, decreased
      spermatozoa count and disease history. The decreased function of Leydig cells in
      patients affected with varicocele is related to alterations of the serotonin
      metabolism and to the impairment of testosterone biosynthesis. An exaggerated
      increase of FSH and LH after GnRH stimulation can be observed. The response to
      GnRH stimulation can predict a positive outcome of surgical treatment of
      infertile patients with varicocele. Finally it was to be emphasized the role of
      an increased 17 OH-progesterone/testosterone ratio and of the loss of the inverse
      relationship between inhibition and FSH values.

PMID- 12416012
TI  - Infant feeding: what does the latest UK survey tell us?

PMID- 12416013
TI  - Childhood obesity: an approach to weight management.

PMID- 12416014
TI  - Health benefits of omega-3s for the whole family.
AB  - A research dietitian summarises the health benefits of omega-3 fatty acids in the
      diet as suggested by recent research. Reasons for the current shortfall in
      intakes are explained and readily available dietary sources of omega-3s given.
      Although the public is now better educated about saturated and unsaturated fats,
      health professionals need to give people more guidance on the sources and health
      benefits of omega-3 fatty acids in the diet.

PMID- 12416015
TI  - Coeliac disease and infertility: making the connection and achieving a successful
      pregnancy.
AB  - Undiagnosed coeliac disease is not uncommon in adults in the UK and can be a
      cause of unexplained infertility in women. Studies suggest that dietary treatment
      of women with coeliac disease may result in successful conception. The diet of a
      woman with coeliac disease during pregnancy is discussed and agencies offering
      support are listed.

PMID- 12416016
TI  - Adoption--1: Adopting a child today.
AB  - In the first of a three-part series, some of the early difficulties of an
      adoption placement are outlined, with some practical advice on supporting the
      adoptive parents.

PMID- 12416017
TI  - Identifying and managing bacterial vaginosis.
AB  - The diagnosis and management of bacterial vaginosis are discussed, including the
      role of the nurse and midwife in testing and treatment.

PMID- 12416018
TI  - Hormone replacement therapy: all a woman could desire?
AB  - A nurse practitioner discusses the benefits and possible disadvantages of hormone
      replacement therapy both for menopausal symptoms and for longer-term health. The
      author recommends health professionals to be aware of alternatives to hormone
      replacement therapy and to adopt a holistic approach to the menopausal woman.

PMID- 12416019
TI  - An approach to weight management in children and adolescents (2-18 years) in
      primary care.

PMID- 12416020
TI  - The obesity epidemic.

PMID- 12416021
TI  - The obesity epidemic.

PMID- 12416022
TI  - When to introduce solids.

PMID- 12416024
TI  - Correlation of nucleoside and nucleobase transporter gene expression with
      antimetabolite drug cytotoxicity.
AB  - Antimetabolite drugs that inhibit nucleic acid metabolism are widely used in
      cancer chemotherapy. Nucleoside and nucleobase transporters are important for the
      cellular uptake of nucleic acids and their corresponding anticancer analogue
      drugs. Thus, these transporters may play a role both in antimetabolite drug
      sensitivity, by mediating the uptake of nucleoside analogues, and in
      antimetabolite drug resistance, by mediating the uptake of endogenous nucleosides
      that may rescue cells from toxicity. Therefore, we examined the relation of the
      expression of nucleoside and nucleobase transporters to antimetabolite
      cytotoxicity. We measured the RNA levels of all eight known nucleoside and
      nucleobase transporters in 50 cell lines included in the National Cancer
      Institute's Anticancer Drug Screen panel. RNA levels of concentrative nucleoside
      transporters (CNTs), equilibrative nucleoside transporters (ENTs) and nucleobase
      transporters (NCBTs) were determined by quantitative RT-PCR using real-time
      fluorescence acquisition. This method was validated by measuring the expression
      of the MDR1 gene, and correlating our results with independently determined
      measurements of MDR1 RNA levels and protein function in these cell lines. We then
      correlated the pattern of RNA levels to the pattern of cytotoxicity of anticancer
      drugs in the NCI drug screen database using the COMPARE analysis. Several
      hypothesized relations between transporter gene expression and cytotoxicity,
      based upon known interactions between certain nucleoside analogues and
      transporter proteins, were not observed, suggesting that expression of individual
      transporters may not be a significant determinant of the cytotoxicity of these
      drugs. The most closely correlated drug cytotoxicity patterns to transporter gene
      expression patterns (where increased expression corresponds to increase
      sensitivity) included those between CNT1 and O6-methylguanine and between ENT2
      and hydroxyurea. We also observed that p53 status influenced correlations between
      ENT1 transporter gene RNA levels and sensitivity to the drugs tiazafurin, AZQ and
      3-deazauridine. One of three drugs identified by correlation of cytotoxicity
      patterns with ENT1 RNA levels, 3-deazauridine, inhibited uptake of the classic
      ENT1 substrate uridine, demonstrating a physical interaction between an
      identified drug and the transporter. These studies demonstrate that it is
      possible to correlate genetic information to functional databases to determine
      the influence of transport gene expression on drug sensitivity and to identify
      transporter-drug interactions.

PMID- 12416023
TI  - Inhibitory effect of vitamin D3 on 3'methyl-4-dimethyl-amino-azobenzene-induced
      rat hepatocarcinogenesis: a study on antioxidant defense enzymes.
AB  - The anticarcinogenic effect of vitamin D3 (VD3) on 3,-methyl-4-dimethyl-amino
      azobenzene (3,-Met-DAB)-induced hepatocarcinogenesis was investigated in male
      Sprague-Dawley rats. Anticancer efficacy of VD3 was estimated using different
      possible biomarkers, namely reduced glutathione (GSH) concentration, gamma
      glutamyl transpeptidase (GGT) activity, glutathione S-transferase (GST) activity,
      glutathione reductase (GRd) activity, glutathione peroxidase (GPx) activity in
      hyperplastic nodules (HNs) and non-nodular surrounding parenchyma (NNSP) liver
      areas. VD3 was found to control the carcinogen-induced alterations in GSH level,
      GST, GGT, GRd and GPx activity both in HNs and NNSP liver areas during long-term
      exposure. A decrease in the number of HNs was also evident in the present
      investigation. VD3 was proved to be an effective antitumor drug during the
      initiation/promotion phases of hepatic carcinogenesis but the effect was found to
      be less prominent during initiation and promotion phases.

PMID- 12416025
TI  - Hexadecylphosphocholine does not influence phospholipase D and sphingomyelinase
      activity in human leukemia cells.
AB  - Hexadecylphosphocholine (HePC) is the first representative of the
      alkylphosphocholines (APC), a new group of biologically active compounds. HePC
      has pronounced antiproliferative effects on neoplastic cells in vitro and in
      vivo. The molecular mechanism by which HePC exerts its biological effects is
      still under investigation. Recently there has been growing evidence that HePC
      probably interferes with cellular signalling via phospholipases. It has been
      shown to inhibit both forms of phospholipase C (PLC), the phosphatidylinositol-
      and the phosphatidylcholine-specific PLC, and phospholipase A2. Here we present
      data showing that HePC inhibits the activity of phospholipase D in vitro, whereas
      the action of this enzyme in leukemic cell lines is not affected. Furthermore
      HePC does not seem to disturbed the activity of sphingomyelinase, another enzyme
      of phospholipid metabolism which has been shown to play an important role in
      cellular signalling as well.

PMID- 12416026
TI  - In vivo antitumor activity of F 11782, a non-intercalating dual catalytic
      inhibitor of topoisomerases I and II, against a panel of human tumor xenografts.
AB  - The marked in vivo antitumor activity of F 11782 against murine experimental
      tumors (Kruczynski et al., Br J Cancer 83: 1516-24, 2000) has now been confirmed
      in a panel of human tumor xenografts. Using an intermittent schedule of six
      administrations over 2 weeks, F 11782 showed major activity in four of eight
      xenograft models. Excellent activity was noted versus the CAKI-1 (renal) model,
      with regressions at the two highest doses, and marked activity against DLD-1
      (colon) xenografts, also resulting in regressions at the MTD. Marked antitumor
      activity was also observed against DU 145 (prostate) and GLC4 (small-cell lung)
      tumors. At optimal doses, significant T/C values ranged from 3 to 29%, with
      significant growth delays of 1.5-5.6, without major body weight loss. This tumor
      growth inhibition induced by F 11782 was sustained with time for > or = 6 weeks
      post implant. In contrast, no real activity was recorded against NCI-H460 (non
      small-cell lung) tumors and only minor responses, with optimal T/C values of <
      42%, noted in the rapidly proliferating SF-295 (CNS) and LOX IMVI (melanoma)
      xenografts or the chemo-refractory LoVo (colon) model. Overall, this study
      showing a 50% response rate with definite antitumor activity across a broad
      spectrum, coupled with its unique mechanistic profile, has prompted the further
      development of F 11782.

PMID- 12416027
TI  - Discovery and development of anticancer agents from plants.
AB  - A novel in vitro assay for the discovery of anticancer agents was used to examine
      aqueous and organic extracts from 1847 plants collected mainly in the U.S.
      Southwest and West. The assay results were separated into 5 categories: inactive
      (62%), equally active (36%), equally active and potent (0.5%), solid tumor
      selective (1.4%), and human selective (0.8%). Extracts from the latter three
      categories were fractionated using the in vitro assay to biodirect each step.
      Psorothamnus emoryi extracts were solid tumor selective and yielded two active
      compounds upon fractionation: dalrubone and 5-methoxydalrubone. Calocedrus
      decurrens was equally active and potent and yielded deoxypodophyllotoxin as the
      active compound. Linanthus floribundus was human selective and yielded
      strophanthidin as the active compound. The potential of this assay to discover
      novel anticancer agents from the active extracts is discussed.

PMID- 12416028
TI  - Src protein kinase pp60c-src influences adhesion stabilization of HT-29 colon
      carcinoma cells to extracellular matrix components under dynamic conditions of
      laminar flow.
AB  - Tumor cell adhesion to extracellular matrix (ECM) and its stabilization are
      important determinants in metastasis formation, and they are mediated, in part,
      by integrins and regulated by a variety of protein kinases. Protein tyrosine
      kinase pp60c-src is found in adhesion-dependent focal adhesion plaques where it
      may regulate different integrin-mediated signaling cascades. Using human HT-29
      colon carcinoma cells stably transfected with pp60c-src--specific antisense
      oligonucleotides (HT-29AS15), we investigated the role of pp60c-src in integrin
      mediated adhesion and its stabilization to ECM components collagen I or IV under
      static and laminar fluid flow conditions. Under static adhesion conditions
      transfection of pp60c-src antisense oligonucleotides did not modify adhesive
      properties. Phosphorylation of focal adhesion kinase (FAK) and paxillin induced
      by static adhesion to collagen I or IV were similar in HT-29P and HT-29AS15
      cells. However, using hydrodynamic conditions in a laminar flow chamber we found
      a slight reduction in early adhesion events and an even greater difference in
      adhesion stabilization rates (ASRs). The transfected cells showed a significant
      reduction in their ability to withstand shear forces and stabilize adhesive
      bounds. These changes correlated with the cellular expression levels of pp60c
      src. Our results suggest that pp60c-src may be involved in stabilization of
      dynamic HT-29 cell adhesion to ECM components, and this kinase appears to be part
      of a mechanosensory protein complex during integrin-mediated cell adhesion.

PMID- 12416029
TI  - Cellular drug action profile paradigm applied to XK469.
AB  - The cellular paradigm presented here defines the cellular action profile of new
      anticancer agents that complements our discovery and development paradigm. The
      main elements of this profile include a concentration clonogenicity response
      relationship on proliferating and plateau phase cells, flow cytometry studies
      assessing progression delay and apoptosis, macromolecular synthesis inhibition,
      and DNA damage assessment by the comet assay; other specific assessments then
      derive from these findings such as topoisomerase assays. XK469 is a new
      anticancer agent derived from the herbicide Assure that is the inactive parent
      compound of a family of quinoxaline analogs found to have anticancer activity in
      vivo. We have applied the described cellular action profile paradigm to XK469 to
      define a novel action at the cellular level. XK469 is a G2M phase-specific,
      antiproliferative agent whose activity is related to the 7-position of the
      chlorine ion in the benzene ring and expressed through a unique cellular action
      profile resulting in the irreversible increase in cyclin B1 (possibly by specific
      inhibition of its ubiquitination) and leading, in the absence of apoptosis, to
      the final mitotic arrest of HCT-116 cells in prophase with subsequent loss of
      clonogenicity.

PMID- 12416030
TI  - Severe folate restriction results in depletion of and alteration in the
      composition of the intracellular folate pool, moderate sensitization to
      methotrexate and trimetrexate, upregulation of endogenous DHFR activity, and
      overexpression of metallothionein II and folate receptor alpha that, upon folate
      repletion, confer drug resistance to CHL cells.
AB  - DC-3F/FA3 cells (FA3) were derived from antifolate-sensitive CHL cells by
      selection for growth in folate-free media containing 15 pM [6S]-5CHOFH4. These
      cells undergo a 30-fold decrease in intracellular folates, overexpress folate
      receptor alpha (FR alpha) and metallothionein II, and display increased
      sensitivity to the dihydrofolate reductase (DHFR) targeted anti-folates
      methotrexate (MTX) and trimetrexate (TMTX), which can be attributed primarily to
      the folate pool status. Upon folate repletion by growth in 15 nM [6S]-5CHOFH4,
      they display a 5- and 10-fold increase in resistance to both drugs, respectively,
      even though folate pools are restored by only 43%. Enforced overexpression of FR
      alpha in transfectants cultured in nanomolar folate did not confer resistance to
      MTX but did support a modest 2-fold increase in resistance to TMTX. Enforced
      overexpression of MTII had a similar effect, but when both were overexpressed
      together no increase in resistance beyond that conferred by each one separately
      was noted, suggesting that both confer resistance to TMTX through a common
      downstream mechanism. Analysis of three independent low folate selected clones,
      FA3, FA7, and FA14, showed that each had a 5- to 6-fold increase in DHFR activity
      accompanied by a similar increase in DHFR protein level. However, no differences
      were detected in the DHFR gene copy number or in the steady-state amount of DHFR
      mRNA, suggesting that a posttranscriptional mechanism was responsible for the
      increase in DHFR expression.

PMID- 12416031
TI  - Murine pharmacokinetics and metabolism of oleandrin, a cytotoxic component of
      Nerium oleander.
AB  - Pharmacokinetic studies of [3H]oleandrin, a cardiac glycoside component of
      Anvirzel, were conducted in mice after either an i.v. dose (40 micrograms/kg) or
      a p.o. dose (80 micrograms/kg). Oleandrin was rapidly absorbed after oral dosing
      (Cmax at 20 min) although the elimination half-life was longer (2.3 +/- 0.5 h)
      than that after i.v. dosing (0.4 +/- 0.1 h). The AUC0-infinity values obtained
      after i.v. and p.o. dosing were 24.6 +/- 11.1 and 14.4 +/- 4.3 (ng.h/ml),
      respectively, resulting in an oral bioavailability of approximately 30%. After
      i.v. administration, oleandrin concentration in liver was approximately twice
      that measured in heart or kidney tissue. Oleandrigenin, the aglycone of
      oleandrin, was also found in these tissues. At 5 min, > 60% of the total
      radioactivity in liver was due to oleandrin while 28% of the given dose was
      present as oleandrigenin. Twenty-four hours following injection, 8% of total
      radioactivity was excreted in urine and contained both oleandrigenin (4.4% of the
      injected dose) and oleandrin (1.9%). Sixty-six percent of injected radioactivity
      was found in feces and consisted of oleandrin and oleandrigenin in equal amounts.
      Uptake of oleandrin in brain after i.p. injection of oleandrin (3 mg/kg) or
      oleander extract (700 mg/kg) was examined. Measured by LC/MS/MS, oleandrin
      content in brain was higher following injection of extract than it was with an
      equivalent dose of oleandrin. The data suggest that components within oleander
      extract may enhance transport of oleandrin across the blood brain barrier.

PMID- 12416032
TI  - Type-1 transforming growth factor-beta differentially modulates tumoricidal
      activity of murine peritoneal macrophages against metastatic variants of the B16
      murine melanoma.
AB  - Transforming growth factor-beta 1 (TGF-beta 1) renders mouse peritoneal
      macrophages tumoricidal against metastatic variants of the B16 mouse melanoma in
      vitro. Both direct cytotoxicity and indirect cytotoxicity were observed. A
      subthreshold concentration (10 U/ml) of recombinant murine interferon-gamma
      (rMuIFN-gamma) enhanced the direct tumoricidal activity of TGF-beta 1-activated
      macrophages from 29% to 88% but did not change their indirect tumoricidal
      profile. Data obtained from macrophages preincubated with either TGF-beta 1 or
      rMuIFN-gamma showed that TGF-b1 can initiate tumoricidal activity better than
      rMuIFN-gamma. These effects were plasma-membrane mediated because targeting
      macrophages with liposomal TGF-beta 1 was ineffective. The order of tumoricidal
      susceptibility of the B16 melanoma lines to activated macrophages was B16F1 >
      B16F10 > B16BL6, in inverse order of metastatic potential.

PMID- 12416034
TI  - Visualization of internal structures.

PMID- 12416033
TI  - Enhancement of the antitumor effect of cyclophosphamide with the hypoxia
      selective cytotoxin NLCQ-1 against murine tumors and human xenografts.
AB  - The antitumor effect of cyclophosphamide (CPM) was investigated against SCCVII
      murine tumors and PC-3 human xenografts in combination with the hypoxia-selective
      cytotoxin 4-[3-(2-nitro-1-imidazolyl)-propylamino]-7-chloroquinoline
      hydrochloride (NLCQ-1). The in vivo-in vitro and the tumor regrowth assays were
      used, respectively, as end points. In certain cases the hypoxia-selective
      cytotoxin tirapazamine (TPZ) was included for comparison purposes. In the
      SCCVII/C3H model, bone marrow toxicity studies were performed in parallel by
      using a modified CFU-GM assay. In the SCCVII/C3H model, when NLCQ-1 (10 mg/kg
      i.p.) was given 1 h before cyclophosphamide (CPM; 75-200 mg/kg i.p.), dose
      modification factors (DMFs) of 1.9 and 1.0 were achieved for the antitumor effect
      and bone marrow toxicity, respectively. The corresponding DMF values obtained
      with TPZ (23 mg/kg) given 2.5 h (optimal time) before CPM were 1.3 and 1.0,
      respectively. Thus, therapeutic indices (T.I.) of 1.9 and 1.3 were achieved with
      NLCQ-1 and TPZ, respectively. In the PC-3/athymic nude mouse model, NLCQ-1 (10
      mg/kg) given 90 min before CPM (36 mg/kg), qd x 4, increased tumor regrowth delay
      by 8.7 days compared to CPM alone, at 16-fold the original tumor size. The
      corresponding log cell kill was 0.86 and -0.03 for NLCQ-1 + CPM and CPM alone,
      respectively. In general, NLCQ-1 in combination with nontoxic but inactive CPM
      doses (36 or 54 mg/kg, qd x 4) elicited good antitumor activity without
      subsequent additive systemic toxicity, whereas NLCQ-1 had minimal effect in
      combination with the active but toxic (> 10% mean net weight loss) CPM dose of 80
      mg/kg. These results suggest a potential use of NLCQ-1 in the clinic as an
      adjuvant to chemotherapy with CPM.

PMID- 12416035
TI  - All in the family. Treating obesity in children and adolescents.

PMID- 12416036
TI  - Spironolactone for heart failure: a worthy addition to therapy.

PMID- 12416037
TI  - These barriers need breaking. An exclusive report on NP authority to prescribe
      controlled substances.

PMID- 12416038
TI  - Plant sterol margarines. Nutraceuticals for lowering cholesterol.

PMID- 12416039
TI  - Vulvar biopsy. Techniques for reducing patient discomfort.

PMID- 12416040
TI  - Home care for patients with AIDS. Professional and personal perspectives.

PMID- 12416041
TI  - Food biotechnology. Understanding the science, exploring the issues.

PMID- 12416043
TI  - Landing your first NP position. Your RN experience does count!

PMID- 12416042
TI  - Setting the stage. Pregnancy is the ideal time for preventing allergies and
      asthma.

PMID- 12416044
TI  - Anticoagulation with warfarin. A review of monitoring issues.

PMID- 12416045
TI  - Advocating for better policy. ACNP makes legislation and regulation its business.

PMID- 12416046
TI  - Facts support immunization.

PMID- 12416047
TI  - Be wary of recommending off-label use of meds.

PMID- 12416048
TI  - More on PCOS.

PMID- 12416049
TI  - Follow-up for a fearful patient.

PMID- 12416050
TI  - Tracking through data banks.

PMID- 12416051
TI  - Asian ginseng: potential therapeutic uses.

PMID- 12416052
TI  - Childhood vaccination update. A new weapon against pneumococcal bacteria.

PMID- 12416053
TI  - Complications of mild traumatic brain injury. Assessing and treating post
      concussion symptoms.

PMID- 12416054
TI  - Attention deficit-hyperactivity disorder. An overview of assessment and treatment
      issues.

PMID- 12416055
TI  - New radiopharmaceutical may settle ADHD treatment debate.

PMID- 12416056
TI  - An unlikely vice: Ritalin.

PMID- 12416057
TI  - Transitioning to table foods. The parent offers and the child eats ... sometimes.

PMID- 12416058
TI  - Otitis media: current treatment issues & trends.

PMID- 12416059
TI  - The mouth as a mirror of diabetes. Early detection to prevent periodontal
      disease.

PMID- 12416060
TI  - Patient information. Dental concerns for people with diabetes.

PMID- 12416061
TI  - You've got mail! E-mail in the 21st-century practice.

PMID- 12416062
TI  - Hand wounds. Assessment and treatment issues.

PMID- 12416063
TI  - Alike yet different somehow. The story of Brendan and Luke.

PMID- 12416064
TI  - Improving care for children and practitioners. NAPNAP's roots reach back to
      profession's early days.

PMID- 12416065
TI  - Connecting with gay patients.

PMID- 12416067
TI  - [Research in general practice].

PMID- 12416068
TI  - [The surgical crisis].

PMID- 12416069
TI  - [Frequent attenders in general practice. Who are they and how are they managed?].
AB  - INTRODUCTION: Frequent attenders (FAs) account for a large number of the
      consultations and a large part of the workload in general practice. We need
      knowledge about the way general practitioners (GPs) characterise this group of
      patients and about their proposals for clinical management. This study aims to
      describe the types of FAs seen in general practice and their proposed management.
      MATERIAL AND METHODS: Six randomly sampled CME groups in Aarhus County were
      offered a meeting about frequent attendance in general practice, and five groups
      with a total of 89 GPs accepted. FAs were defined as the top 10% patients
      attending during 12 months. One week before the meeting, each GP received an
      introduction to the meeting and the names of two FAs listed with the practice.
      Through exploratory focus group interviews, supplemented by a small group-based
      CME method, the GPs were asked to discuss FA characteristics and to make
      proposals for clinical management. A total of 59 (66.3%) participated in the five
      meetings. RESULTS: Eight FA types consistently emerged from the discussions, and
      the GPs suggested 12 possible ways of managing them. These aspects involved
      communicative, organisational (planning), and biopsychosocial skills. DISCUSSION:
      The variety of types shows that FAs are not solely the so-called difficult
      patients, but a diverse group demanding many different aspects of care. Hence,
      the GPs are in a key position demanding specific skills to manage these patients.

PMID- 12416070
TI  - [Outpatient treatment. What is the evidence?].
AB  - In relation to the development of quality standards for the national quality
      development study, DGMA, a search was made through the literature on outpatient
      care. The literature was scanty, but some evidence was found on the following:
      Continuity of care is a patient demand, and several studies show more effective
      and less expensive treatment when this is ensured. Two studies show impaired
      quality of treatment, but quality is not defined either precisely or uniformly.
      Waiting times dissatisfy patients and perhaps diminish the result of treatment
      and information. Failure to turn up for appointments affects up to 29 per cent of
      consultations. Non-attendances could be cut down if patient factors and
      continuity of care are taken into account. Some outpatient consultations could
      take place in the general practitioner's surgery, if hospital doctors knew more
      about their capabilities.

PMID- 12416071
TI  - [Ambulatory 24-hour blood pressure monitoring in a case of liquorice-induced
      hypertension].
AB  - We report on the use of ambulatory blood pressure monitoring in a young female
      with liquorice-induced hypertension. Blood pressure monitoring provides objective
      documentation of the cardiovascular effects of liquorice, which may be useful in
      the management of this disorder.

PMID- 12416072
TI  - [Can electronic media be used in patient information? Information about coronary
      arteriography on CD-ROM and Internet].

PMID- 12416073
TI  - [Continuing medical education of general practitioners. A prospective study from
      the Aarhus county].
AB  - INTRODUCTION: Danish general practitioners' (GPs') participation in continuing
      medical education (CME) has often been the subject of debate, but actually very
      little is known about the extent and the contents of the activities. MATERIAL AND
      METHODS: One hundred and sixty-one Danish GPs participated in this one-year
      prospective study by collecting data on their own CME activities. RESULTS: We
      received 9980 data registration sheets. Over a period of 8.4 months, an average
      Danish GP spent 67 hours on traditional CME, equivalent to about 96 hours per
      year, and 12 hours on small group-based CME per year, i.e. a total of 108 hours
      per year. In addition, he or she spent 90 hours per year reading books, journals,
      etc. Thus, the time spent on CME totalled more than 200 hours per year. Most of
      the CME courses were held outside surgery hours. DISCUSSION: We conclude that the
      GPs in Aarhus County participate in a large number of CME activities--even more
      than expected by their own organisation.

PMID- 12416074
TI  - [Long-memory of labor pain].
AB  - BACKGROUND: The aim of the study was to investigate the stability of labour pain
      recall 14-21 months after delivery, and to relate it to events during labour.
      MATERIAL AND METHODS: One hundred and fifteen primipara completed a visual
      analogue scale (VAS) on the second day after delivery, and a similar VAS 14-21
      months later. Women who were delivered before completing 37 gestational weeks,
      had a multiple pregnancy, needed epidural analgesia, or whose infant was
      transferred to the neonatal care unit were excluded. Data were analysed by three
      different methods to minimise bias. By method 1, the proportion of VAS 2 > VAS 1
      was calculated. By method 2, the accuracy of recall was defined from the equation
      -1 < or = VAS 2--VAS 1 < or = 1. By method 3, the VAS used was regarded as an
      unlimited scale, but with all observations shortened to the interval, 0 to 10 cm.
      Pain scores were related to obstetrical data: instrument delivery, fetal weight,
      duration of second stage of labour, use of pethidine and use of pudendal
      analgesia. RESULTS: Thirteen of 20 women (65%) who had received pethidine during
      labour reported a higher VAS 2 than VAS 1, compared to 27 of 95 (28%) women who
      had not received pethidine (p = 0.003). According to method 2, 35% of the
      pethidine-treated women overestimated labour pain on recall, compared to 13% in
      the non-pethidine-treated group (p < 0.05). According to method 3, women who were
      not treated with pethidine showed a decrease of 0.81 cm on the recalled VAS,
      compared to an increase of 1.13 cm in the pethidine-treated group (p < 0.01).
      None of the other investigated events during labour were related to pain recall.
      DISCUSSION: In general, labour pain recall fades over time or tends to be stable,
      but to a significantly higher number of women receiving pethidine, pain seems to
      intensify on recall. If further investigations show that this is an effect of
      pethidine itself, opioids should be used with caution during labour.

PMID- 12416075
TI  - [Neonatal dehydration (dehydration fever) in newborn infants].
AB  - INTRODUCTION: The aim was to identify characteristics in infants suffering from
      dehydration caused by breast-feeding malnutrition over a period of 21 months in
      South Denmark. MATERIAL AND METHODS: Infants admitted to a regional Paediatric
      Clinical Department in a rural area with a population of 254,000 and
      approximately 3000 live births per year. The infants were admitted with the
      diagnosis of dehydration fever, jaundice and dehydration, hypernatraemic
      dehydration or malnutrition. The cases were reviewed retrospectively and the
      outcome measures were maternal age and parity, the gestational age of the infant,
      birth weight, per cent loss from birth weight, complaints at presentation, age on
      admission, temperature on admission, and levels of blood glucose and serum
      sodium. RESULTS: Fifty-four newborn infants were identified. Thirty-five infants
      had a temperature between 37.6 and 39.7 degrees C on admission. Thirty-seven
      infants had lost between 8% and 23.3% of their birthweight. Twenty infants
      suffered from hypernatraemic dehydration, their serum-sodium levels were 147-159
      mmol/l. Four infants with hypernatraemic dehydration had lost less than 8% of the
      birth weight. Ten infants were large for gestational age (LGA). Compared to a
      control group, there was an overrepresentation of LGA children in the study group
      (p = 0.003). Thirty-one of 50 mothers were primigravida (p = 0.002). Thirty-one
      of 54 mothers were 30 years old or older (p = 0.05). There was a positive
      correlation between weight loss and high serum sodium levels (p = 0.01).
      DISCUSSION: We found that a rise in temperature can be a sign of neonatal
      dehydration and malnutrition in breast-fed infants. Hypernatraemic dehydration
      can occur even if the weight loss is less than 10% of the birth weight. Infants
      who are LGA can also develop neonatal dehydration.

PMID- 12416076
TI  - [The incidence of reversible dementia in 145 patients referred on suspicion of
      dementia].
AB  - INTRODUCTION: We performed a retrospective study of 145 consecutive patients
      referred on suspicion of dementia. We were particularly interested in the
      occurrence of reversible dementia. Dementia was defined with reference to the ICD
      10 criteria. MATERIAL AND METHODS: All patients underwent a clinical neurological
      examination, a battery of blood tests, and a CT scan of the brain. RESULTS:
      Dementia was found in 63% and in only 4% was it potentially reversible: Three
      patients had subnormal cobalamin and one patient had normal pressure
      hydrocephalus. However, treatment did not influence the state of dementia. Hence,
      patients with reversible dementia were not identified in this study. In the group
      without dementia one patient had a meningoma. Mental depression was the most
      common "second" diagnosis in both groups. DISCUSSION: The number of patients with
      potential dementia was surprisingly small. We conclude that most patients with
      reversible dementia are detected by their general practitioner and that the
      majority of patients suspected of dementia can be diagnosed by the general
      practitioner, especially if access to CT scans is further liberalised.

PMID- 12416077
TI  - [Tuberculous spondylitis with a psoas abscess in a young man without an immigrant
      background].
AB  - Tuberculosis is a common disease in Africa, Asia, and South America. In Denmark
      the incidence is 10/100,000 and highest in HIV positive patients, alcoholics, and
      some immigrant groups. We describe a young Dane, who was referred to the
      department of rheumatology for back pain. It turned out to be tuberculosis
      spondylitis with a major psoas abscess.

PMID- 12416079
TI  - [Testosterone treatment of elderly men. The so called andropause doesn't exist].

PMID- 12416078
TI  - [Gestational diabetes insipidus].
AB  - We report a case of transient diabetes insipidus in late pregnancy. This rare
      condition is characterised by excessive thirst and polyuria and is associated
      with pre-eclampsia. The aetiology is most likely due to increased vasopressinase
      activity. Suspected cases should be referred to an obstetric centre, since
      termination of pregnancy is recommended. The condition normally resolves within a
      few days of delivery.

PMID- 12416080
TI  - [Liberalized use of Letigen--how is the documentation?].

PMID- 12416081
TI  - [Letigen, insulin resistance and treatment of obesity--again].

PMID- 12416082
TI  - [COX-2 inhibitors--can we rely on the articles?].

PMID- 12416083
TI  - Preconception health care.

PMID- 12416084
TI  - Genetics issues in preconception health care.
AB  - Genetics is an important area of focus for the preconception visit (Table 4).
      Folic acid should be recommended for all women. The genetic and pregnancy history
      should be evaluated for clues to a genetic disorder. Preconception screening and
      counseling are available for many diseases that are indicated in the family
      history. Screening may be offered for sickle cell anemia, thalassemia, Tay Sachs
      disease, and cystic fibrosis in the appropriate population groups. Older couples
      should be counseled about their increased risks for having complications during
      pregnancy and for having children with genetic disorders.

PMID- 12416085
TI  - Preconception counseling about nutrition and exercise.
AB  - Being overweight and being underweight can both cause problems during pregnancy.
      Corrective intervention should be addressed during the preconception period.
      Preconception counseling is of particular importance for women on special diets
      or those who have conditions such as pica, anorexia nervosa, bulimia, and lactose
      intolerance. Supplements of folic acid and iron should be considered. Excesses of
      vitamin A, vitamin D, and caffeine should be avoided. Appropriate levels of
      exercise may be maintained during pregnancy and should be encouraged.

PMID- 12416086
TI  - Preconception counseling about teratogens.

PMID- 12416087
TI  - Preconception management of chronic diseases.
AB  - Preconception counseling and evaluation are particularly important for women with
      chronic diseases. Women with diabetes and phenylketonuria should have their
      diseases under excellent control before conception to prevent miscarriage or
      birth defects. Counseling of women with asthma, epilepsy, hypertension, and
      depression can clarify concerns about possible adverse effects on the fetus of
      the medications used to treat their conditions. Women with a history of venous
      thrombosis should be assessed for prophylactic treatment during pregnancy, and
      this is best done before conception. Women with autoimmune diseases, cardiac
      disease, and renal disease should be assessed for severity of disease and advised
      of the risks of pregnancy.

PMID- 12416088
TI  - Congenital infections and preconception counseling.
AB  - Given the risks of congenital infections, the frequent occurrence of unintended
      pregnancy, and the lack of prenatal care in the first trimester, physicians
      should seek opportunities to discuss immunizations and disease prevention with
      women of childbearing age. Discussions of the following topics would be
      beneficial: 1. Encourage women to seek medical care at the first missed period.
      2. Discuss safe sex and abstinence for prevention of sexually transmitted
      diseases. (See "Clinical Prevention Guidelines" in the CDC's 1998 Guidelines for
      Treatment of Sexually Transmitted Diseases.) 3. Encourage early medical care for
      vaginal discharge, pelvic pain, or possible exposure to sexually transmitted
      diseases. 4. Encourage good handwashing, especially before and after handling
      food or changing diapers. 5. Encourage the use of universal precautions when
      exposed to body fluids or blood. 6. Educate the patient on the importance of
      cooking food thoroughly and avoiding raw meat and unpasteurized dairy products.
      7. Ensure vaccination against hepatitis B, rubella, and varicella.

PMID- 12416216
TI  - [Assessment of the quality of life of cardiological patients: current approach].
AB  - The analysis of the literature data on quality of life (QL) in arterial
      hypertension (AH) demonstrates that ACE inhibitors and calcium antagonists
      improve QL while such data on diuretics effect are contradictable. The comparison
      of pharmacological and surgical treatment effects on QL in patients with coronary
      heart disease shows that functionally and emotionally CHD patients benefit more
      from coronary artery bypass surgery. In early chronic cardiac failure QL falls
      because of the necessity to take treatment, lower everyday activity, work
      limitations. Later, QL deterioration depends on severity of cardiac activity
      decompensation is independent of central hemodynamics, myocardial contractility
      and psychological status of the patient. Adequate use of QL assessment may raise
      efficacy of treatment of circulatory diseases.

PMID- 12416217
TI  - [Policy of antihypertensive therapy in arterial hypertension in the elderly. II].

PMID- 12416218
TI  - [Hepatology at the turn of centuries].
AB  - Current achievements in clinical hepatology according to literature, materials of
      the congresses and symposia, rich personal medical and research experience are
      reviewed.

PMID- 12416219
TI  - [Drug-induced hypertension and hypertensive crisis].
AB  - Hypertensive reactions and hypertensive crises are observed in the use of various
      drugs because of hypersympathicotonia, activation of the system renin-angiotensin
      aldosteron, delay of sodium and water in the organism, suppressed synthesis of
      prostaglandins, reaction to antihypertensive drugs withdrawal. How to cope with
      hypertensive crises, especially in outpatient setting, is described. Thus, when
      prescribing antihypertensive drugs, practitioners should take into consideration
      hypertensive reactions and crises.

PMID- 12416220
TI  - [Autonomic nervous system function and effects of beta-adrenoblockers on heart
      rhythm variability in patients with myocardial infarction].
AB  - Heart rhythm variability on myocardial infarction (MI) day 1, 3, 7 and 11 was
      assessed mathematically to study function of the autonomic nervous system in 101
      MI patients. The initial autonomic tonicity (IAT), autonomic reactivity (AR) and
      autonomic maintenance (AM) were studied. Depending on the site of the infarction
      in the myocardium, different type of autonomic homeostasis were identified.
      Moderate sympathicotonia, sympathicotonic type of AR and adequate AM irrespective
      of IM location were found most favourable in relation to the MI course and
      prognosis. The spectral analysis of the heart rhythm showed a significant shift
      of the frequency spectrum in the inferior MI to high frequencies and in anterior
      MI--to low frequencies. Autonomic dysfunction score is higher in the anterior MI.
      Psychoemotional state of the patients was determined by Spilberg-Khanin test
      evaluating reactive and personality anxieties. These characteristics were
      moderate and high in patients with MI and effort angina, respectively. The study
      of selective beta-adrenoblockers effect on heart rhythm variability proved that
      lokren (betaxolol) in a dose of 10 mg/day significantly and positively influences
      heart rhythm and objective status of the patients. Less effective is betacard
      (atenolol). Nebivolol is not indicated in acute MI. Significant correlations are
      found between the findings of IAT mathematical analysis, psychoemotional features
      of the patients and complications of MI. Parameters of an unfavourable course and
      outcome of MI are described.

PMID- 12416221
TI  - [Baker's cysts in patients with gonarthrosis in early stages according to
      arthrosonography and magnetic resonance tomography].
AB  - We studied potentialities of MR-tomography (MRT) and arthrosonography (ASG) for
      diagnosis of Baker's cysts in patients with early gonarthrosis (GA) regarding X
      ray stage and presence of reactive synovitis. A total of 50 GA patients were
      examined. 100 knee joints were examined by x-ray and ASG, 79 ones by MRT (ALOKA
      2200 ultrasound unit, 7.5 MHz sensor; 1.5 T Eclipse tomography, 1.5 T, Marconi,
      Picker). The ultrasound sensor was applied to the anterior and posterior surface
      of the knee joints in maximally extended joint in a dorsal position. MRT was made
      in a partially flexed fixed joint. It was found that the percentage of Baker's
      cyst (BC) diagnosis by MRT and ASG varies insignificantly (35.4 and 30.4%,
      respectively). Combined use of MRT and ASG detected the cysts more frequently in
      GA stage II by Kellgren (60.7% by MRT and 62.5% by ASG, p > 0.05). Combination of
      subclinical synovitis and the cysts was detected by MRT and sonography in 66.6
      and 60% of the joints. Both MRT and ASG revealed no correlations between the
      frequency of BC and clinical synovitis. Both methods more frequently detected
      popliteal cysts and BC in subclinical synovitis.

PMID- 12416222
TI  - [Acute chlamydial lesions of the nervous system: etiology, diagnosis, clinical
      aspects].
AB  - The examination of 180 patients with acute neuroinfection (105 males, 75 females
      at the age from 18 to 45 years) has detected C. trachomatis in 23.8%, C.
      Pneumoniae in 66.6%, C. psittaci in 9.5% patients. Acute and chlamydial lesions
      of the central nervous system were characterized by all forms of neuroinfection:
      serous and purulent meningitides, meningoencephalitides. Development of acute
      neuroinfection is accompanied by sluggish chlamydial infection of the viscera.

PMID- 12416223
TI  - [Correlations between clinical features, personality disorders and the
      antioxidant system in patients with peptic ulcer].
AB  - The examination of 68 patients with duodenal ulcer (DU) has found correlations
      between relations in married couples, the level of the subjective control,
      behavior stereotype, anxiety, neurotism, extra-introversion of the patients and
      antioxidant activity (AOA) of blood plasm (BP) in various clinical symptoms of
      the diseases. The relations between psychological factors in DU patients and BP
      AOA were seen in mild disease: regular terms of scarring, rare recurrences, weak
      mucosal inflammation, short disease duration, minimal psychological changes. A
      correlation analysis of interrelations between psychological factors and activity
      of the antioxidant system in patients with DU can be used for prognostication of
      the disease course.

PMID- 12416224
TI  - [Paratuberculous nephritis].
AB  - The paper shows tuberculous origin of bilateral diffuse nephritis in many
      patients. Etiology of nephritis can be proved using standard skin tests with
      microbal allergens, tuberculin in particular. Nephritis etiology can be proved by
      the presence of general reaction 1-2 days after introduction of the allergen.
      Local reaction alone indirectly evidence the nature of nephritis. In 72 patients
      with acute diffuse glomerulonephritis local reactions to Mantoux, Pirquet tests
      appeared positive in 69 of 72 patients. Focal and general reactions to these
      tests were documented in half (n = 36) patients. This group of paratuberculous
      nephritis consisted of seriously ill patients, all cases with common symptoms of
      nephritis (edemas, hypertension, hematuria) and all cases with changes in serous
      cavities. Tuberculosis foci in the chest were small or absent. In mild cases the
      recovery occurred after standard nonspecific treatment. Antituberculous
      chemotherapy was effective in severe and long-standing nephritis. In one case of
      lethal outcome paratuberculous nature of nephritis was proved morphologically.
      Streptococcal, staphylococcal allergy in skin tests was absent or mild, failed to
      produce general and focal reactions and therefore could not be considered as an
      etiological factor of acute nephritis in our patients.

PMID- 12416225
TI  - [Effectiveness of mexidol in acute pancreatitis].
AB  - Mexidol effectiveness was tried in acute pancreatitis (AP). It was found that in
      acute pancreatitis mexidol provides a reliable defence of membrane structures,
      decreased the rate of lipid peroxidation, enhanced the activity of the
      antioxidative system. This eventually results in reduced number of AP
      complications (by 9-13%) and mortality (by 7%). In AP mexidol should be injected
      intraductally.

PMID- 12416226
TI  - [Comparative clinico-pharmacological characteristics of nimodipine, nifedipine
      and foridon in the treatment of patients with ischemic stroke in late
      rehabilitative and residual periods].
AB  - A comparative study of pharmacodynamics and clinical efficacy of nimodipine,
      nifedipine and foridon in ischemic stroke (late recovery and residual period) was
      performed in 97 patients with ischemic stroke. It was found that nimodipine,
      nifedipine and foridon at late recovery or residual stages significantly improved
      higher psychic functions, promoted regression of neurologic disorders and
      optimized social rehabilitation. Nimodipine, primarily, decreased the intensity
      of neurological disorders, improved higher psychic functions and had a positive
      impact on cerebral hemodynamics. Nifedipine primarily improved central
      hemodynamics (increased stroke output and ejection fraction). Foridon is most
      effective selective pharmacodynamic impact on peripheral hemodynamics (stimulated
      arteriolar blood flow, diminished venous capacity and spasticity), i.e.
      normalized peripheral blood flow.

PMID- 12416227
TI  - [Results of pre- and postoperative treatment of complicated duodenal ulcers with
      proton pump inhibitors ].
AB  - Benefit of monotherapy of duodenal ulcers by lanzap in 36 patients was compared
      to that of combined therapy including panitidin in 26 patients. Lanzap brought
      about ulcer healing within 7-10 days in 55.6%, within 14-16 days ulcer scarring
      was observed in 35 patients (97.2%). Ulcer healing progressed depending on ulcer
      size. Combined treatment with ranitidine promoted ulcer scarring in 14-16 days in
      73% patients. Lanzap monotherapy in preoperative period promoted fast healing of
      ulcer defect anf provided optimal conditions for surgery.

PMID- 12416228
TI  - [Effects of tycveinol on the lipid transport system and hemostasis and
      fibrinolysis systems in patients with ischemic heart disease].
AB  - 33 patients with ischemic heart diseases, hyperlipidemia and blood
      hypercoagulation took tycveinol which consists of polyunsaturated fatty acids in
      a dose of 2.0 g twice a day for 2 months. A positive result manifested by a 14%
      drop in cholesterol, 29.7% in triglycerides, 21% in beta-lipoproteins. Alpha
      lipoproteins rose by 26%, atherogenic index reduced from 3.24 to 1.89.
      Hypercoagulatory tension relieved due to normalization of euglobulin lysis,
      higher activity of plasminogen tissue activator, slow blood clotting. Side
      effects on hepatic or renal function, mineral metabolism were not observed.

PMID- 12416229
TI  - [Antianginal and anti-ischemic effects of Mono Mac 50D preparation as an agent in
      combined treatment of patients with stable angina].

PMID- 12416230
TI  - [A case of familial restrictive cardiomyopathy].
AB  - According to estimates of WHO experts cases with diagnosed cardiomyopathy account
      for 40-60 per 100,000. Restrictive cardiopathy (RCP) is encountered in 5% of all
      the diagnosed cases of cardiomyopathy. Two patients (a mother and her daughter)
      with suspected of family RCP were examined using ECG, Holter ECG monitoring, echo
      CG, histological tests, x-ray, blood biochemical tests. Echo-CG was most
      informative for verification of RCP diagnosis. The daughter had edema, enlarged
      liver, arterial hypertension, cardiac arrhythmia. The mother had arrhythmia,
      dyslipidemia. Based on the above symptoms, the patients received combined drug
      therapy with positive results.

PMID- 12416231
TI  - [Idiopathic fibrosing alveolitis in therapeutic practice].
AB  - Three cases of idiopathic fibrosing alveolitis (IFA) are reported. An algorithm
      of differential diagnosis with pneumonia is provided. IFA suspects should be
      referred to specialized pulmonological centers where they should be examined with
      performance of lung biopsy, high-resolution computed tomography with subsequent
      pathogenetic therapy with glucocorticoids.

PMID- 12416232
TI  - [Concerning the discussion article by I. A. Morozov "Choice of the
      gastroenterologist"].

PMID- 12416233
TI  - Trichinellosis: old facts and new developments.
AB  - Trichinellosis is a helminth zoonosis, which is known since long, but which is
      emerging or re-emerging in several regions of the world. During the last years
      the number of cases of trichinellosis in pigs and man in several East-European
      countries has increased very much due to the breakdown of the veterinary services
      because of the difficult political and socio-economic situation. In several third
      world countries on the other hand trichinellosis has become more important due to
      the increasing number of small traditional pig farms, in which the hygienic
      conditions are suboptimal. Furthermore, outbreaks of human trichinellosis have
      been reported due to recently discovered new species such as T. pseudospiralis
      and T. papuae. Over the last 25 years horsemeat has been more important as a
      source of human trichinellosis within the European Union than pork or wild boar
      meat. In Belgium, however, no cases of human trichinellosis have been reported
      since 1979. A review is presented of the available data on animal trichinellosis
      in Belgium. The potential risk for the consumer is discussed. Finally, some
      suggestions are made for a new approach of trichinellosis control in Belgium and
      the European Union.

PMID- 12416234
TI  - [Motor proteins and pigmentation].
AB  - One essential part of the process of skin pigmentation comprises the production
      of melanosomes, the melanin-containing organelles, and correct transport towards
      their target cells, the keratinocytes. In this overview the molecular mechanisms
      of these processes are discussed in view of a number of pigmentation syndromes.

PMID- 12416235
TI  - Multiple myeloma, a model for fundamental and clinical research.
AB  - Multiple myeloma (MM) is a malignant B cell disorder characterized by the
      uncontrolled proliferation of monoclonal plasma cells (PC) in the bone marrow
      (BM) and the presence of monoclonal immunoglobulin in serum and/or urine. Despite
      recent advances in the understanding of the pathophysiology of MM, the exact
      etiology of MM still remains unknown. MM cells are characterized by a profound
      degree of genetic instability with several chromosomal abnormalities. The
      survival and proliferation of MM cells are largely dependent on a supportive
      microenvironment. The development and progression of MM can be regard as a
      multistep process of molecular alterations resulting in uncontrolled growth and
      therapy resistance. Although considerable progress has been made in the therapy
      of MM, it still remains an uncurable disease with conventional treatment. Novel
      therapeutic modalities targeting the MM cell and the microenvironment such as
      inhibitors of angiogenesis (thalidomide and derivatives, arsenic trioxide) and
      inhibitors of transcription factor NF-kappa B (proteasome inhibitors) are
      currently being evaluated in clinical trials and hopefully will result in
      prolonged disease-free and overall survival.

PMID- 12416236
TI  - Research on biological and mechanical heart valves: experimental studies in
      chronic animal models.
AB  - In the total pre-clinical evaluation of new heart valve substitutes, there is an
      absolute need for chronic experimental valve testing in different animal models.
      Also fundamental research towards mechanisms of calcification, tissue
      degeneration and valve thrombosis requires standardized and well-controlled
      animal models. Possible clinical use of a new experimental valve type and/or
      future developments and improvements in prosthetic heart valves, all depend on
      such research activities. Our recent studies concerning prosthetic heart valves
      resulted in following conclusions. 1. Photo-oxidation, a new tissue treatment,
      seems to have many possible advantages over currently existing valve fixation
      techniques (glutaraldehyde-fixation). The stentless porcine photo-fixed valve
      shows, in contrast to standard stentless valves, no aortic wall mineralization
      together with a good preservation of cuspal function. 2. For clinical right-sided
      valve implantations, the presence of a stent, together with the fixation pressure
      of the valve, can have its influence on the long-term behaviour of the valves in
      this low-pressure environment. Both stented valves, as valves fixed under
      pressure, seem to suffer more from fibrous tissue overgrowth 3. Mechanical stress
      is an important factor in the degeneration and calcification of biological valve
      tissue, mainly when an unfavourable stress pattern is present. Not all currently
      used animal models are equally reliable for valve testing and evaluation. 4.
      Implantation of aortic wall samples in the jugular vein of juvenile sheep is a
      simple, reliable and cost-effective model of aortic wall calcification.
      Calcification of glutaraldehyde-fixed aortic wall tissue is initiated at the
      level of cellular remnants, with little or no contribution from elastic fibers.
      Acellularization can avoid this cell-mediated calcification, but an additional
      treatment will be necessary to avoid the inflammation leading to elastolysis and
      consequent calcification of elastic fibers. 5. Mechanical valve implantation in
      pulmonary position delivers a reliable and reproducible test of mechanical valve
      thrombosis. The model allows us to compare the thrombogenic potential of
      different mechanical valve types, while it can also serve as a test for new
      therapeutic or diagnostic tools for mechanical valve thrombosis.

PMID- 12416237
TI  - Low-powder gloves = high safety.

PMID- 12416238
TI  - Building trust.

PMID- 12416239
TI  - Standards of good practice provide a roadmap.

PMID- 12416240
TI  - Going mobile.

PMID- 12416241
TI  - Plant operations for industrial hygienists.

PMID- 12416242
TI  - Identification and treatment of toxic molds.

PMID- 12416243
TI  - Top of the heap.

PMID- 12416244
TI  - Safety and the professional welder, Part 2.

PMID- 12416245
TI  - Job-site evaluations for emergency fixtures.

PMID- 12416246
TI  - Safety goggles at a glance.

PMID- 12416247
TI  - Prescription safety eyewear: today vs. yesterday.

PMID- 12416248
TI  - Training done right.

PMID- 12416249
TI  - Implementing an AED program across multiple states.

PMID- 12416250
TI  - Managing contract security.

PMID- 12416251
TI  - The five essentials of safety.

PMID- 12416252
TI  - The "dumb worker"--a new perspective.

PMID- 12416253
TI  - Exercise, cachexia, and cancer therapy: a molecular rationale.
AB  - Evidence from recent publications indicates that repeated exercise may enhance
      the quality of life of cancer patients. The lack of reported negative effects and
      the consistency of the observed benefits lead one to conclude that physical
      exercise may provide a low-risk therapy that can improve patients' capacity to
      perform activities of daily living and improve their quality of life. Repeated
      physical activity may attenuate the adverse effects of cancer therapy, prevent or
      reverse cachexia, and reduce risk for a second cancer through suppression of
      inflammatory responses or enhancement of insulin sensitivity, rates of protein
      synthesis, and anti-oxidant and phase II enzyme activities. These results most
      likely come about through the ability of physical exercise to attenuate a chronic
      inflammatory signaling process and to transiently activate the mitogen-activated
      protein kinase, c-Jun NH2-terminal kinase, c-Jun NH2-terminal kinase-mitogen
      activated protein kinase, and nuclear factor-kappa B pathways and through its
      ability to enhance insulin sensitivity. Expanded molecular-based research into
      these areas may provide new insights into the biological mechanisms associated
      with cancer rehabilitation and endogenous risk.

PMID- 12416254
TI  - Nutrient intake and nutritional indexes in adults with metastatic cancer on a
      phase I clinical trial of dietary methionine restriction.
AB  - Animal studies have shown that dietary methionine restriction selectively
      inhibits growth of a variety of human tumor xenografts but has relatively few
      deleterious effects on normal tissues. The objectives of the present study were
      to determine whether enteral methionine restriction is safe and tolerable in
      adults with metastatic cancer and whether it reduces plasma methionine levels.
      Eight patients with a variety of metastatic solid tumors were enrolled in a phase
      I clinical trial. A commercially available methionine-free medical food served as
      the primary dietary protein source for all patients. Patients were prescribed
      diets containing 0.6-0.8 g of protein, 25-35 kcal, and 2 mg of methionine per
      kilogram per day. Participants remained on the experimental diet for an average
      of 17.3 wk (range 8-39 wk). Plasma methionine levels fell from 21.6 +/- 7.3 to 9
      +/- 4 microM within 2 wk, representing a 58% decline. Serum albumin and
      prealbumin levels remained stable or increased. Mean energy intake increased
      during participation compared with baseline, and protein intake was maintained at
      target levels. The only side effect was weight loss of approximately 0.5% of body
      mass index (0.5 kg) per week. We conclude that enteral dietary methionine
      restriction is safe and tolerable in adults with metastatic solid tumors and
      results in significant reduction in plasma methionine levels.

PMID- 12416255
TI  - Dietary carotenoid intake and colorectal cancer risk.
AB  - Several studies have found inverse associations between fruit and vegetable
      consumption and colorectal cancer risk, suggesting the potential etiological
      importance of carotenoids (and other phytochemicals) contained in these foods.
      However, only one study (a case-control study) has examined the association
      between dietary carotenoids other than beta-carotene and colorectal cancer risk.
      In the study reported here, we examined the relationships between dietary intakes
      of beta-carotene, alpha-carotene, lycopene, lutein, and beta-cryptoxanthin and
      colorectal cancer risk in a large cohort study of Canadian women. A case-cohort
      analysis was undertaken within the cohort of 56,837 women who were enrolled in
      the Canadian National Breast Screening Study and who completed a self
      administered dietary questionnaire. During follow-up to the end of 1993, a total
      of 388 women were diagnosed with colorectal cancer. For comparative purposes, a
      subcohort of 5,681 women was randomly selected. After exclusions for various
      reasons, the analyses were based on 295 cases and 5,334 noncases. We did not find
      any clear association between intake of any of the studied carotenoids and
      colorectal cancer risk in the study population as a whole or in subgroups defined
      by smoking status, relative body weight (body mass index), intakes of total fat,
      energy, alcohol, and folic acid, or menopausal status. Our data do not support
      any association between dietary intakes of the studied carotenoids and colorectal
      cancer risk. However, given that this is the first prospective cohort study of
      carotenoids in relation to colorectal cancer, further studies are warranted.

PMID- 12416256
TI  - Low-energy reporters: evaluation of potential differential reporting in case
      control studies.
AB  - Errors in measuring dietary intake can threaten validity of data. Low-energy
      reporters (LER) are individuals who report lower levels of energy intake than
      deemed feasible given their basal metabolic rate and physical activity level
      (PAL). The purpose of this study was to determine whether LER differ by
      case/control status or by extent of disease of cases. Data from a large
      population-based case-control study of colon cancer were used to identify LER.
      Dietary data were collected using a diet history questionnaire. Age- and gender
      specific basal metabolic rate was estimated, and Goldberg cut points were used to
      estimate plausible energy intake and adjusted for PAL. On the basis of standard
      methods that do not take PAL into account, 16.7% of male cases, 19.8% of male
      controls, 20.9% of female cases, and 22.2% of female controls were considered
      LER. There were no case-control differences in the proportion of LER in men or
      women when PAL-adjusted cut points were used, although more individuals were
      considered LER. Likewise, there were no differences in LER by colon cancer
      disease stage. Excluding LER from the population and assessing associations
      between energy intake and colon cancer yielded results similar to those observed
      for the total population. In this population, LER were significantly more likely
      to be older, never to have smoked cigarettes, to be more physically active, and
      to be overweight or obese. LER reported fewer total food items than non-LER.
      There does not appear to be differential reporting of low energy intake by cases
      and controls or by disease stage among cases. However, LER appear to differ
      depending on exposure characteristics that may be importantly associated with
      cancer.

PMID- 12416257
TI  - Long-chain n-3-to-n-6 polyunsaturated fatty acid ratios in breast adipose tissue
      from women with and without breast cancer.
AB  - Animal studies suggest that dietary polyunsaturated fatty acids (PUFAs) of the n
      6 class, found in corn and safflower oils, may be precursors of intermediates
      involved in the development of mammary tumors, whereas long-chain (LC) n-3 PUFAs,
      found in fish oil, can inhibit these effects. This case-control study was
      designed to examine the relationship between the PUFA composition of breast
      adipose tissue and the risk of breast cancer. Using fatty acid levels in breast
      adipose tissue as a biomarker of past qualitative dietary intake of fatty acids,
      we examined the hypothesis that breast cancer risk is negatively associated with
      specific LC n-3 PUFAs (eicosapentaenoic acid and docosahexaenoic acid) and
      positively associated with n-6 PUFAs (linoleic acid and arachidonic acid). Breast
      adipose tissue was collected from 73 breast cancer patients and 74 controls with
      macromastia. The fatty acid levels were determined by gas-liquid chromatography.
      A logistic regression model was used to obtain odds ratio estimates while
      adjusting for age. The age-adjusted n-6 PUFA (linoleic acid and arachidonic acid)
      content was significantly higher in cases than in controls (P = 0.02). There was
      a trend in the age-adjusted data suggesting that, at a given level of n-6 PUFA,
      LC n-3 PUFAs (eicosapentaenoic acid and docosahexaenoic acid) may have a
      protective effect (P = 0.06). A similar inverse relationship was observed with LC
      n-3-to-n-6 ratio when the data were adjusted for age (P = 0.09). We conclude that
      total n-6 PUFAs may be contributing to the high risk of breast cancer in the
      United States and that LC n-3 PUFAs, derived from fish oils, may have a
      protective effect.

PMID- 12416258
TI  - Fecal levels of short-chain fatty acids and bile acids as determinants of colonic
      mucosal cell proliferation in humans.
AB  - We studied the correlation between fecal levels of short-chain fatty acids
      (SCFA), bile acids (BA), and colonic mucosal proliferation in humans on a free
      diet. Subjects [n = 43: 27 men and 16 women; 61 +/- 7 and 59 +/- 6 (SE) yr old,
      respectively] were outpatients who previously underwent resection of at least two
      sporadic colon polyps. Mucosal proliferation was determined by [3H]thymidine
      incorporation in vitro in three colorectal biopsies obtained without cathartics
      and was expressed as labeling index (LI). BA were analyzed in feces by mass
      spectrometry and SCFA by gas chromatography. We found that increasing levels of
      BA in feces did not correlate with higher LI. On the contrary, higher levels of
      SCFA were significantly associated with lower LI in the colonic mucosa (P for
      trend = 0.02). In conclusion, in humans on a free diet, intestinal proliferation
      seems to be regulated by the levels of SCFA in feces and not by BA. Because a
      lower intestinal proliferation is associated with a decreased colon cancer risk,
      treatments or diets that increase colonic levels of SCFA might be beneficial for
      colonic mucosa.

PMID- 12416259
TI  - Performance status of male and female advanced cancer patients is independently
      predicted by mid-upper arm circumference measurement.
AB  - In the advanced cancer patient, performance status has considerable prognostic
      power. Karnofsky performance status, together with variables reported to
      influence its score, was measured in advanced gastrointestinal cancer patients (n
      = 148). For male and female patients, age, body mass index, weight loss, triceps
      skinfold thickness, mid-upper arm circumference, albumin, C-reactive protein, and
      tumor type and stage were regressed against Karnofsky performance status. On
      multiple regression analysis, only mid-upper arm circumference and log10 C
      reactive protein in men (r2 = 0.462, P < 0.0001) and only mid-upper arm
      circumference and weight loss in women (r2 = 0.485, P < 0.01) were independent
      predictors of Karnofsky performance status. There was a significant partial
      correlation, with gender as a covariable, between log10 C-reactive protein and
      albumin (r = -0.530, P < 0.0001) and mid-upper arm circumference (r = -0.269, P =
      0.035) and weight loss (r = 0.286, P = 0.024). The results of the present study
      indicate that mid-upper arm circumference is a major factor that influences
      performance status in male and female patients with advanced gastrointestinal
      cancer.

PMID- 12416260
TI  - Different effects of short- and long-chained fructans on large intestinal
      physiology and carcinogen-induced aberrant crypt foci in rats.
AB  - Inulin-type fructans, which are nondigestible carbohydrates, have been shown to
      modulate the number of induced preneoplastic lesions in the colon as well as the
      colonic microflora in laboratory animals. The present study was designed to
      investigate the effect of a short- and long-chained inulin-type fructan on 1,2
      dimethylhydrazine dihydrochloride-induced aberrant crypt foci (ACF) in the rat
      colon. In addition, the present study investigated the influence of chain length,
      dietary level (5% or 15%), and duration of feeding (5 or 10 wk) on the following
      intestinal parameters supposed to be involved in the development of ACF:
      microflora, short-chain fatty acids, pH, and cell proliferation. A 3-wk
      pretreatment period with both fructans was included. Feeding the long-chained
      fructan (5% or 15%) significantly inhibited the numbers of small and total ACF
      after 5 and 10 wk. The short-chained fructan (15%) inhibited the number of small
      and total ACF after 5 and 10 wk but significantly increased the numbers of medium
      and large ACF after 10 wk. In conclusion, the effect on ACF outcome was
      influenced by the chain length of the fructans.

PMID- 12416261
TI  - Regulation of male sex hormone levels by soy isoflavones in rats.
AB  - Several studies have suggested that soybean intake is associated with a lower
      risk of prostate cancer. However, the mechanism of prostate cancer prevention by
      soybeans remains unclear. Because prostate cancer is reported to have an
      association with an increased level of dihydrotestosterone (DHT) and soybean
      isoflavones are known to inhibit 5 alpha-reductase, which is involved in the
      conversion of testosterone to DHT, the effects of soybean extract and isoflavones
      on the plasma levels of male sex hormones were investigated using male rats. In
      Experiment I, Sprague-Dawley rats were fed diets with and without soy flour; in
      Experiment II, rats were fed diets containing 2% soy methanol extract or 0.2%
      semipurified isoflavones or a control diet. The study showed a reduction of
      plasma DHT along with an increase in total plasma androgen in rats fed soy flour
      or semipurified isoflavones for 1 wk. These results suggest that soy isoflavone
      intake may reduce plasma DHT level.

PMID- 12416262
TI  - Simultaneous treatment with benzyl isothiocyanate, a strong bladder promoter,
      inhibits rat urinary bladder carcinogenesis by N-butyl-N-(4
      hydroxybutyl)nitrosamine.
AB  - Effects of benzyl isothiocyanate (BITC) on urinary bladder carcinogenesis were
      examined in rats simultaneously treated with N-butyl-N-(4
      hydroxybutyl)nitrosamine (BBN). Groups of 20 6-wk-old Fischer 344 male rats were
      given 10, 100, or 1,000 ppm BITC in the diet or a basal diet with 50 ppm BBN in
      the drinking water for 40 wk and then killed for autopsy. Additional groups
      consisting of 10 or 9 rats were similarly given BITC or the basal diet alone
      without BBN treatment. With BBN treatment, dysplasia, papilloma, and carcinoma
      incidences and multiplicities were dramatically decreased by simultaneous
      treatment with BITC in a clear dose-dependent manner. In contrast, epithelial
      hyperplasia was induced in rats treated with 100 and 1,000 ppm BITC without BBN.
      These results clearly indicate that although BITC may have weak carcinogenic
      potency, it is a potent chemopreventive agent against bladder tumor induction by
      BBN.

PMID- 12416263
TI  - Inhibition of 12-O-tetradecanoylphorbol-13-acetate-induced inflammatory skin
      edema and ornithine decarboxylase activity by theaflavin-3,3'-digallate in mouse.
AB  - Among black tea polyphenols, theaflavins were generally considered to be the most
      effective in cancer chemoprevention. In this study, we examined the inhibitory
      effects of black tea polyphenols, including theaflavin (TF-1), a mixture (TF-2)
      of theaflavin-3-gallate and theaflavin-3'-gallate, theaflavin-3,3'-digallate (TF
      3), and the green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) on 12-O
      tetradecanoylphorbol-13-acetate (TPA)-induced edema and ornithine decarboxylase
      (ODC) activity. Topical application of these polyphenols onto the mouse resulted
      in inhibition of TPA-induced ear edema and skin epidermal ODC activity. The
      inhibitory order was as follows: TF-3 > TF-2 approximately equal to EGCG > TF-1.
      Western and Northern blots indicated that TF-3 significantly reduced the protein
      and mRNA levels of ODC in TPA-treated mouse skin and NIH 3T3 cells, whereas EGCG
      showed less activity. EGCG and TF-3 were able to inhibit the ODC enzyme activity
      in vitro. Furthermore, TF-3 also significantly reduced the basal promoter
      activity of the ODC gene in NIH 3T3 cells that were transiently transfected with
      ODC reporter plasmid. These results suggested that TF-3 was a potential inhibitor
      of ODC activity and TPA-induced edema and might be effective in cancer
      chemoprevention.

PMID- 12416264
TI  - A comparative study of growth-inhibitory effects of isoflavones and their
      metabolites on human breast and prostate cancer cell lines.
AB  - The possible growth-inhibitory properties of the recently synthesized novel
      metabolite 1-(2,4-dihydrobenzoyl)-1-(4-hydroxyphenyl)ethylene (2-de-O-DMA) and
      six other metabolites of isoflavones were investigated and compared with those of
      the major isoflavones genistein, daidzein, and glycitein on human breast
      noncancer and breast and prostate cancer cell lines in vitro. The novel
      metabolite 2-de-O-DMA was found to be a more potent inhibitor than genistein on
      human breast cancer MCF-7, MDA-MB-468, and SK-BR-3 cells and breast noncancer MCF
      10A cells. In prostate cancer cell lines, LNCaP and DU145, 2-de-O-DMA elicited a
      six- to sevenfold more potent inhibition than genistein. Flow cytometric analysis
      showed that 2-de-O-DMA and genistein blocked cells at the G2/M phase of the cell
      cycle. Genistein and 2-de-O-DMA led to apoptosis of a variety of cancer cell
      lines. The rapid response of growth inhibition induced by 2-de-O-DMA compared
      with genistein strongly suggests that the observed antiproliferation effects
      elicited by this novel metabolite are mediated via a biological pathway different
      from that induced by genistein. 2-de-O-DMA, a novel metabolite of isoflavone,
      could have a potential role in chemopreventive and chemotherapeutic treatment of
      hormonal breast and prostate cancers.

PMID- 12416265
TI  - The cruciferous nitrile crambene has bioactivity similar to sulforaphane when
      administered to Fischer 344 rats but is far less potent in cell culture.
AB  - The anticarcinogenic properties of broccoli are believed to be due to
      modification of detoxification enzymes by a group of isothiocyanates, hydrolysis
      products of glucosinolates, particularly sulforaphane. We previously showed that
      the nitrile crambene (1-cyano-2-hydroxy-3-butene), present in most Brassica
      vegetables, induces hepatic quinone reductase activity when administered to rats.
      In this study, we compared the effects of seven daily oral doses of crambene (50
      mg/kg rat/day) and sulforaphane (50 mg/kg rat/day) on induction of hepatic
      quinone reductase activity in Fischer 344 rats. The two treatments produced
      similar effects, with crambene and sulforaphane producing 1.5- and 1.7-fold
      induction in hepatic quinone reductase activity, respectively. Additionally, we
      evaluated the effect of crambene on quinone reductase activity in Hepa 1c1c7
      cells, because this system had been shown to possess high sensitivity to
      sulforaphane and is commonly used for screening anticarcinogenic compounds.
      Crambene (5 mM) induced quinone reductase activity and caused cell cycle arrest
      in the G2/M phase in mouse Hepa 1c1c7 cells, rat H4IIEC3 cells, and human Hep G2
      cells (> 95% viability). Doses of crambene needed for induction of quinone
      reductase in cell culture were approximately 100-fold greater than effective
      doses of sulforaphane. These findings indicate that hepatoma cell lines may not
      accurately reflect relative potency of anticarcinogens in Fischer 344 rats.

PMID- 12416266
TI  - Z-ajoene induces apoptosis of HL-60 cells: involvement of Bcl-2 cleavage.
AB  - Garlic organosulfur components exhibit antitumor activity, but the molecular
      mechanisms underlying these effects have not been well characterized. We showed
      that Z-ajoene, a sulfur-rich compound purified from garlic, induced time- and
      dose-dependent apoptosis in HL-60 cells. This process implied the activation of
      caspase-3 and the cleavage of the antiapoptotic protein Bcl-2. The caspase
      inhibitor benzyloxycarbonyl-Val-Ala-Asp-[OMe]-fluoromethylketone inhibited Bcl-2
      cleavage and apoptosis induced by Z-ajoene. This effect was partially prevented
      by treatment of HL-60 cells with the antioxidant N-acetylcysteine. Hence, the
      transmission of apoptotic signal induced by Z-ajoene involved a reactive oxygen
      species-dependent pathway leading to caspase-dependent Bcl-2 cleavage.

PMID- 12416267
TI  - Genistein-induced apoptosis of p815 mastocytoma cells is mediated by Bax and
      augmented by a proteasome inhibitor, lactacystin.
AB  - Although genistein has been demonstrated to induce apoptosis of various cells,
      there is no report of its effect on mast cell proliferation. Here we show that
      genistein reduced the viability of mast cell tumor cell lines, p815 and RBL-2H,
      but not of a human mast cell line, HMC-1. Further investigation on its growth
      inhibitory mechanism was undertaken on p815 mastocytoma cells. Genistein induced
      G2/M arrest and subsequent apoptotic death. p815 cells undergoing apoptosis
      showed many apoptotic manifestations, such as reduction of mitochondrial membrane
      potential, release of cytochrome c to cytosol, translocation of apoptosis
      inducing factor to nucleus, activation of caspase-3, nuclear condensation, and
      generation of DNA fragmentation. Genistein treatment resulted in the increase of
      Bax expression and its translocation into mitochondria, whereas expression levels
      of Bcl-2 remained unchanged. Proteasome activity decreased at the early time
      points after genistein treatment, but thereafter it fluctuated at increased
      levels. A proteasome inhibitor, lactacystin, potentiated the induction of
      apoptosis. Taken together, genistein-induced apoptosis of p815 mastocytoma cells
      is at least in part mediated by proteasome, Bax, apoptosis-inducing factor, and
      caspase and augmented by cotreatment with a proteasome inhibitor, lactacystin.

PMID- 12416268
TI  - Understanding of endocarditis risk improves compliance with prophylaxis.
AB  - BACKGROUND: Congenital heart disease (CHD) is the most common predisposing cause
      for childhood infective endocarditis (IE), accounting for 80% of cases. Knowledge
      about the disease and its complications is a key factor in promoting adherence to
      prophylaxis recommendations. OBJECTIVE: To assess the level of understanding
      among caregivers of children with CHD of their disease, risks of IE and attitudes
      concerning oral health and antibiotic prophylaxis of IE. PATIENTS AND METHODS:
      Caregivers' knowledge was assessed during outpatient visits using a 15-item
      questionnaire developed for this study. Answers were related to patients' age,
      cardiac condition and risk of IE and respondents' age and education level.
      RESULTS: Of the 97 questionnaires completed, 83 were considered valid. The mean
      age of patients was 7.7 +/- 5.9 years (range 1 to 24 years). Eleven (13%)
      patients were at high risk for IE and 30 (36%) at moderate risk. Most respondents
      (80%) alleged that they knew the patient's cardiac condition but only 37%
      described it correctly. Twenty-nine respondents (35%) were aware of the risk of
      IE, while only 13 related that risk to dental procedures. Knowledge of IE risk
      was associated with respondents' education level (p = 0.03) but not with
      respondents' age or patients' actual risk of IE. Most respondents (76%) recalled
      having been advised on oral hygiene measures and declared that their child
      brushed their teeth at least once a day (92%). Forty-three children (52%) had
      already been to the dentist and 27 had done so in the previous six-month period.
      Almost all (42 out of 43) informed the dentist about the child's CHD, but only 20
      (48%) reported having received antibiotics before dental procedures. Antibiotic
      prophylaxis was associated with patients' age (p = 0.04) but not with
      respondents' education level or actual risk of IE. Being aware of IE risk was
      significantly associated with better oral hygiene (p = 0.001) and more frequent
      dental appointments (p = 0.03), independently of education level. CONCLUSIONS:
      The results of this survey support the need to reinforce information about risks
      of IE and prophylaxis recommendations among caregivers of children with CHD.

PMID- 12416269
TI  - Tissue Doppler imaging assessment of long axis left ventricular function in
      hypertrophic cardiomyopathy.
AB  - BACKGROUND: Hypertrophic cardiomyopathy is classically defined as a diastolic
      disease with normal systolic function. Long axis left ventricular function is an
      important and sensitive determinant of global ventricular function but its
      assessment is often difficult and complex. Tissue Doppler imaging of the mitral
      annulus allows the study of long axis left ventricular function. METHODS: 47
      patients with non-obstructive hypertrophic cardiomyopathy and 45 healthy
      volunteers, matched by age and sex, were studied with pulsed tissue Doppler
      imaging of the 4 sides of the mitral annulus (septal, lateral, inferior,
      anterior) in 4 and 2 chamber views. In each wave (systolic-s, rapid filling-e,
      atrial contraction-a) we analyzed velocities, time intervals and velocity-time
      integrals, as well as heterogeneity and asynchrony. Data were compared among the
      different sides in each group, between groups and with conventional Doppler data.
      RESULTS: In contrast to normal subjects, hypertrophic cardiomyopathy patients
      showed: 1--Systolic function: lower velocities, longer systolic time intervals
      (isovolumic relaxation time, time to peak s, ejection time), higher systolic
      asynchrony (time to peak s, ejection time, systolic time) and lower s/shortening
      fraction ratio. These changes occurred despite normal indices of global systolic
      function. 2--Diastolic function: lower velocities (much lower rapid filling
      velocity, lower atrial contraction velocity, lower septal e/a), higher e/a
      heterogeneity index, longer protodiastolic times (isovolumic relaxation time and
      time to peak e), higher diastolic asynchrony (time to peak e) and lower e wave
      integral. Hypertrophic cardiomyopathy patients also showed higher average number
      of annular sides with e/a < 1 per patient and higher percentage of e/a < 1,
      mainly on the septal side. CONCLUSIONS: This study shows that: 1--Tissue Doppler
      imaging allows the detailed analysis of long axis left ventricular function in
      hypertrophic cardiomyopathy patients. 2--Long axis systolic function is abnormal
      in this disease, even in the presence of normal indices of global systolic
      function. 3--Long axis diastolic function is deeply disturbed in hypertrophic
      cardiomyopathy, at ventricular and atrial levels. 4--Long axis dysfunction occurs
      in annular sides contiguous to hypertrophied and non-hypertrophied walls,
      highlighting the role of other factors in its pathophysiology.

PMID- 12416270
TI  - Perioperative mortality and long-term outcome of infective endocarditis.
AB  - INTRODUCTION AND OBJECTIVES: Infective endocarditis (IE) is a disease with a high
      morbidity and mortality during the active phase and a considerable risk of
      complications during follow-up. The aim of this study is to describe the clinical
      features of IE associated with perioperative mortality in patients undergoing
      surgery and the short- and long-term prognosis of this disease after surgical
      treatment. PATIENTS AND METHODS: The clinical files of 150 patients (pts)
      admitted to our institution between 1989 and 2001 and whose final diagnosis was
      IE (Duke criteria) were retrospectively reviewed. Thus all patients included
      underwent at least 1 transthoracic examination, and a transesophageal examination
      if indicated. The study population was 69 patients with IE, 62 of whom (90%)
      underwent prosthetic valve replacement and 7 (10%) underwent explanation of
      pacemaker electrocatheter. In the statistical analysis, quantitative variables
      are expressed as means +/- SD and qualitative variables as proportions
      (percentages). Differences in survival were determined using the Kaplan-Meier log
      rank method. Associations were considered statistically significant when the p
      value was < 0.05. RESULTS: The mean age was 56 +/- 15 years. Thirty-five cases
      (51%) had prosthetic valve endocarditis, 30 (39%) had native valve IE and 7 (10%)
      pacemaker electrocatheter IE. Fifty-two patients (75%) had positive blood
      cultures. The most frequent agents were S. epidermidis (14.5%), S. aureus
      (14.5%), Enterococci (13%) and S. viridans (10%). Total perioperative mortality
      was 17.4% (n = 12), and surgical mortality was 19.4%. Our study shows a
      statistical tendency for higher mortality in diabetic patients (50% vs. 14%, p =
      0.052) and in women (29% vs. 11%, p = 0.065). In multivariate analysis, the
      presence of heart failure was an independent predictor of perioperative mortality
      (OR = 11.4; 95% CI: 2.0-215.2; p = 0.024). Accumulated mortality in the first
      year was 28% and 5-year mortality was 48%. CONCLUSIONS: Prosthetic valve
      replacement in patients with IE is associated with high perioperative mortality
      (17.4%). Despite good early postoperative results, the mortality rate increases
      during the first year as well as the need for reoperation.

PMID- 12416271
TI  - Infective endocarditis--still a poor prognosis despite the increasing use of
      cardiac surgery.

PMID- 12416272
TI  - Myocardial effects of ETB receptor stimulation.
AB  - INTRODUCTION: Endothelin-1 (ET-1) is an endogenous peptide whose effects are
      mediated by two distinct types of receptors, ETA and ETB. Whereas the ETA
      receptors promote vasoconstriction and mitogenesis and increase inotropism, ETB
      receptors have vasodilatory and anti-mitogenic properties mediated by nitric
      oxide release. In this study we investigated the myocardial effects of selective
      ETB receptor stimulation. METHODS: The study was performed on right papillary
      muscles (n = 30) from New Zealand white rabbits (Krebs-Ringer; 1.8 mM CaCl2; 35
      degrees C). The effects of selective ETB receptor activation by Sarafotoxin S6c
      (0.2 microM; n = 6) and of non-selective ETA and ETB receptor activation by ET-1
      (1 nM; n = 9) were studied. The effects of ET-1 were also evaluated in the
      presence of a selective ETA receptor antagonist, BQ-123 (0.1 microM; n = 9) and
      of a selective ETB receptor antagonist BQ-788 (0.1 microM; n = 6). Only
      significant results (mean +/- SE; p < 0.05) are given, expressed as % baseline.
      RESULTS: Sarafotoxin S6c reduced active tension (AT) by 8.1 +/- 5.5% and peak
      rate of tension development (dT/dtmax) by 8.6 +/- 5.6%. Alone, ET-1 increased AT
      by 64.2 +/- 18.2% and dT/dtmax by 58.6 +/- 20.2%. These effects of ET-1 were
      exacerbated in the presence of BQ-788 (AT increased by 82.6 +/- 17.5% and
      dT/dtmax by 121.3 +/- 26.6%) and inverted in the presence of BQ-123 (AT decreased
      by 12.8 +/- 2.7% and dT/dtmax by 16.1 +/- 3.0%). CONCLUSIONS: This study
      demonstrates, for the first time, that selective stimulation of ETB receptors has
      a negative inotropic effect. Detailed characterization of the effects of
      stimulation of each type of ET-1 receptor is of particular relevance as selective
      and non-selective inhibitors of these receptors are currently being tested for
      treatment of heart failure.

PMID- 12416273
TI  - Anterograde balloon dilatation in neonatal critical aortic stenosis.
AB  - INTRODUCTION: Percutaneous valvotomy is an alternative therapy to surgery in
      newborns with critical aortic stenosis. However, the retrograde technique
      commonly used has significant morbidity and mortality. We decided to introduce
      anterograde percutaneous aortic valvotomy in newborns in a Pediatric Cardiology
      Unit and assess the immediate and follow-up results. MATERIAL AND METHODS:
      Between July and December 2000, three newborns with critical aortic stenosis
      underwent transcatheter anterograde valvotomy. All were in mechanical ventilation
      and dissociative anesthesia; vascular access was through puncture of the right
      femoral vein. An end-hole catheter was advanced, via the foramen ovale, to the
      left ventricle; a guide wire was placed in the ascending aorta; the end-hole
      catheter was then exchanged for a coronary balloon catheter and the aortic valve
      was predilated; afterwards, other low profile balloon catheters were advanced but
      the largest balloon never exceeded 95% of the aortic annulus diameter, previously
      measured by 2D echo and angiography. Data of the pre- and post-dilatation left
      ventricular pressures were registered; aortic valve function in the follow-up
      period was monitored by Doppler. RESULTS: Transaortic gradients decreased after
      the procedure in all three patients; no aortic regurgitation was detected. No
      morbidity or mortality was associated with the technique. In the follow-up
      period, all the patients remained in class I NYHA; the echocardiogram revealed a
      significant aortic gradient in one patient with a small aortic annulus and mild
      aortic regurgitation in another patient. CONCLUSIONS: Anterograde percutaneous
      valvotomy in newborns with critical stenosis is a useful technique and overcomes
      the problems associated with surgery and the retrograde technique: it should be
      more widely used.

PMID- 12416274
TI  - Drug class effects: definitions and practical applications.
AB  - The concept of drug class effect is profoundly rooted in clinical practice. The
      use of drugs seen as similar in their clinical effects--and therefore
      interchangeable--is very frequent: two examples of this are the use of beta
      blockers in arterial hypertension and angiotensin-converting enzyme (ACE)
      inhibitors in congestive heart failure. The definition of drug class effect is
      based on three concepts: a similar chemical structure (for example, the
      dihydropyridine ring of some calcium channel blockers), a similar mechanism of
      action (beta-blockers block adrenoreceptors), or similar pharmacological effects
      (antihypertensives, antianginals, etc.). In this article, we will describe the
      type of evidence that a cardiologist can use in order to select a specific drug
      (from within a class). It constitutes a clinical approach, different from the one
      that might be used by a third party payer (more interested in cost-effectiveness
      issues) or the pharmaceutical industry (more interested in promoting sales). As
      usual, the recommendations are based on the strength of scientific evidence.

PMID- 12416275
TI  - Post-traumatic false aneurysm of the descending thoracic aorta.

PMID- 12416276
TI  - [Smoking: a poor choice].

PMID- 12416277
TI  - Surgical management of obesity.
AB  - Although surgery should be considered the last resort to treat morbid obesity, it
      is also the only treatment that works for this condition. In the era of minimally
      invasive surgery, laparoscopic adjustable banding and laparoscopic gastric bypass
      appear to offer the next logical step in the field of bariatric surgery.
      Laparoscopic gastric banding in particular has wide appeal since it demands less
      time and relative skill compared to the laparoscopic gastric bypass; however,
      knowledge of subtle details and expertise is required to reproduce favorable
      outcomes of permanent weight reduction and minimal complications. Still, there
      was a high failure rate of the LASGB in a multi-centre U.S. trail reported
      despite very promising results from Europe and Australia. Which procedure is more
      favorable, LASGB or laparoscopic GBP, is still under discussion and requires
      further prospective and comparative studies [26].

PMID- 12416278
TI  - [Numbers and the living].

PMID- 12416279
TI  - Immunomodulatory effects of vasoactive catecholamines.
AB  - The immunological side effects of catecholamines have recently gained specific
      attention in the area of sepsis related research, since stimulation of adrenergic
      and dopaminergic receptors can lead to a modulation of the cytokine network.
      Catecholamines alter the production of these immune mediators in peripheral blood
      cells but also in various tissues such as liver, spleen, lung, heart, kidney and
      the skin. The sympathetic regulation of cytokines is highly dependent on which
      type of receptor is stimulated. Whereas ligation of the alpha-adrenoreceptor is
      associated with predominantly immunostimulating effects (i.e. the induction of
      TNF alpha and IL-1 beta), stimulation of the beta-adrenoreceptor usually has
      immunosuppressive consequences (i.e. inhibition of TNF alpha and IL-1 beta,
      induction of IL-10). In case both receptors are stimulated (i.e. by epinephrine)
      the beta-adrenoreceptor mediated effects usually dominate those induced by alpha
      adrenoreceptor stimulation. Moreover, the adrenergic immunostimulation can be
      differentially regulated depending on which type of cell or tissue is stimulated.
      This suggests locoregional effects. Dopaminergic immunomodulation is dominated by
      immunosuppressive effects, such as the induction of IL-6, the inhibition of TNF
      alpha, the attenuation of the chemoattractant effect of IL-8 and the inhibition
      of endothelial adhesion. Catecholamines also alter the number and function of
      neutrophils and lymphocytes. This again depends on which type of receptor is
      stimulated. Whereas beta-adrenergic stimulation leads to lymphocytosis, alpha
      adrenoreceptors mediate lymphocyte homing. Catecholamine induced neutrophilia
      involves alpha 1-adrenoreceptor ligation. With respect to neutrophil function,
      epinephrine increases the respiratory burst. Up to now, most of the available
      data on catecholamine-induced immunomodulation were obtained in experimental
      settings. The overwhelming, clear results indicate that this system might have
      important implications for the pathophysiology of immunological diseases such as
      septic shock, which are accompanied by increased levels of catecholamines.

PMID- 12416280
TI  - Smoking habits of office-based general practitioners and internists in Austria
      and their smoking cessation efforts.
AB  - Tobacco smoking is the major cause of lung disease. This study aimed to
      determine: 1) the prevalence of tobacco smoking among office-based physicians; 2)
      their readiness to inquire about their patients' smoking habits and, if need be,
      to motivate them to stop smoking; 3) whether non-smoking doctors advise their
      patients more frequently to stop smoking than their smoker colleagues do. A self
      designed questionnaire on a post card was sent to 7674 office-based general
      practitioners (GPs) and internists. 1395 (18.2%) questionnaires were returned.
      Independent telephone interviews with 91 doctors were also carried out to
      minimize the bias of self-presentation. Just under 11% of doctors were smokers.
      About 50% of all doctors who responded described themselves as ex-smokers. 38% of
      the smokers would accept outside help to stop smoking. About 50% of GPs and 90%
      of internists inquire about the smoking habits of their patients during history
      taking. Of these, 85% of GPs and 92% of internists recommend their patients to
      stop smoking. Doctors who themselves are smokers do so less than their non-smoker
      colleagues. For this reason, a further reduction in the smoking prevalence among
      doctors would be of special importance. Inquiry about smoking habits in the
      initial history taking should be stressed more to identify any smoker who can be
      subsequently encouraged to stop smoking.

PMID- 12416281
TI  - Mortality of patients with pulmonary embolism.
AB  - BACKGROUND: Pulmonary embolism (PE) is a potentially fatal disorder with highly
      varying mortality rates. To provide information that is more precise for
      prospective intervention studies, we analysed the data of our patients with PE,
      defining clinically relevant subgroups with respect to their individual mortality
      rates. METHODS: We studied 283 consecutive patients with confirmed PE diagnosis,
      with respect to demographic data, risk factors for thromboembolic disease and
      clinical signs. In addition, diagnostic and therapeutic interventions such as
      blood gas analysis (BGA), lactate and D-dimer determination, electrocardiography
      (ECG), echocardiography, spiral computer tomography (Spiral CT),
      ventilation/perfusion lung scintigraphy (V/Q-Scan), thrombolytic therapy,
      mechanical ventilation, and cardiopulmonary resuscitation (CPR), were accounted
      for. Study endpoint was mortality rates on day three. RESULTS: Overall, mortality
      rate was 15% (42 of 283). Mortality rates differed considerably; 95% of patients
      with cardiac arrest on arrival (21 of 22), 85% of patients with cardiac arrest-
      not in hospital (28 of 33), 80% of patients receiving mechanical ventilation (40
      of 50), 77% of patients needing cardiopulmonary resuscitation within the first 24
      hours (37 of 48), 37% of patients with syncope (18 of 49), 30% of patients
      receiving thrombolytic treatment (25 of 87), 26% of patients on whom lactate
      measurement was performed (36 of 139), 18% of patients on whom blood gas analysis
      was done (35 of 197), 17% of patients on whom echocardiography was performed (34
      of 195), 8% of patients with twelve complete lead ECG recordings (21 of 262) and
      D-Dimer determination (12 of 148), 2% of patients tested on Spiral CT (5 of 226)
      and 1% where a V/Q-Scan was performed (1 of 74). CONCLUSION: Patients with PE who
      received mechanical ventilation, cardiopulmonary resuscitation, and thrombolytic
      treatment had very high mortality rates of 80, 77 and 30% respectively. However,
      patients stable enough for diagnostic procedures as Spiral CTs and V/Q-Scans had
      mortality rates of 1 to 2%. These facts are to be considered when planning
      pulmonary embolism intervention trials in which reduction of mortality is a
      defined endpoint.

PMID- 12416282
TI  - Awareness of Austrian physicians of risk factors for the development of
      atherosclerosis.
AB  - OBJECTIVE: In industrialised countries, coronary heart- (CHD) and other
      atherosclerosis-associated diseases (AAD) are, with an increasing incidence,
      responsible for almost half of the deaths among their respective populations.
      There is unequivocal evidence that medicine should try to achieve a reduction in
      manifestations of atherosclerosis by efficient preventive strategies. A variety
      of guidelines have been published during the last decades; nevertheless there is
      a gap between established recommendations and its application in everyday
      practice by Austrian physicians. The aim of this survey was to investigate
      physicians' knowledge of and attitude towards risk factors, preventive strategies
      and therapy of CHD and other AAD. METHODS: The self-administered questionnaire
      was mailed to 1000 physicians. We obtained an answer from a total of 286
      physicians (general practitioners, GP) and specialists in internal medicine,
      IMS), who were asked about selected items concerning CHD and other AAD and an
      eventual modification in attitude towards diagnosis and treatment according to
      their own, personal risk profile. RESULTS: Risk factors for developing AAD such
      as elevated CH was identified in 77% (74% GP vs. 84% IMS), hypertension in 77%
      (76% GP vs. 81% IMS), elevated TG in 37% (40% GP vs. 26% IMS), excess alcohol
      consumption in 14% of all interrogated physicians (16% GP vs. 9% IMS)
      respectively. 77% (75% GP vs. 81% IMS) of the physicians considered the CH/HDL
      ratio to be important in primary prevention and 83% (81% GP vs. 87% IMS) in
      secondary prevention; Lipoprotein(a) was considered important in only 9% (8% GP
      vs. 14% IMS) and 24% (19% GP vs. 41% IMS), respectively. CONCLUSION: In summary,
      all mentioned risk factors were heavily underestimated by Austrian physicians,
      partly leading to insufficient evaluation and therapeutic interventions.
      Secondary prevention was managed quite satisfactorily by both GP and IMS
      according to the Austrian guidelines. The knowledge about primary prevention
      strategies was significantly worse in GP compared to IMS. There is still a great
      need for information and training-programs for Austrian physicians to make
      primary and secondary prevention strategies work more effectively.

PMID- 12416283
TI  - [Pregnancy and labor after adjustable gastric banding for therapy of morbid
      obesity].
AB  - Surgical placement of an adjustable gastric band has become a widely used method
      for treatment of morbid obesity. As a consequence, a higher number of pregnancies
      after weight loss is observed. Information is limited on pregnancy outcome after
      gastric banding, whereas metabolic and nutritional complications are reported
      after gastric bypass procedures. We report on two cases of pregnancy after
      laparoscopic gastric banding. Both patients had uncomplicated full-term
      pregnancies. In both cases, neither during nor after the pregnancy fluid removal
      from the gastric band was necessary. There seems to be a low probability for
      gestational and metabolic complications in pregnancy due to gastric banding.
      However, more specific information about pregnancies and fetal outcomes after
      gastric banding in a larger patient population would be desirable.

PMID- 12416284
TI  - Pneumocystis carinii in a patient with hypercalcemia and renal failure secondary
      to sarcoidosis.
AB  - A case of severe dyspnea, hypercalcemia and renal failure secondary to
      sarcoidosis is reported. The clinical diagnosis of sarcoidosis in a 48-year-old
      man was confirmed by histology and cytology. Transiently decreased numbers of
      CD4+ T cells (282/microliter) indicated impaired immunity in the absence of HIV
      infection during the acute phase of the disease. Surprisingly, numerous
      "trophozoites" of Pneumocystis carinii were detected by immunofluorescence
      staining and PCR in the bronchoalveolar fluid indicating infection or
      colonization of the lungs. Corticosteroid therapy was administered together with
      trimethoprim-sulfamethoxazole and rapidly reduced elevated serum calcium and
      creatinine concentrations. Since airborne person-to-person transmission of P.
      carinii to susceptible individuals might be possible, patients with sarcoidosis
      could be a previously unrecognized reservoir for P. carinii distribution in
      hospitals and in the community at large.

PMID- 12416285
TI  - [Bozzinian guide lights--the first endoscope: an international scientific
      historical instrument returns to Vienna].

PMID- 12416286
TI  - Pacifier use and sudden infant death syndrome: should health professionals
      recommend pacifier use based on present knowledge?
AB  - The aim of this paper is to review and compare results from different studies
      describing the possible preventive effect of pacifiers on the sudden infant death
      syndrome. A Medline and Pubmed search was performed in order to find relevant
      references. Four groups of researchers were found, and referring to the most
      recent publications of each working group, these papers were reviewed with regard
      to sample size, setting of the studies, odds ratios and confidence intervals. All
      four research groups found an association between pacifier use and a reduced risk
      of sudden infant death syndrome, but they all concluded that the association does
      not necessarily imply that the use of a pacifier is protective against the sudden
      infant death syndrome. Therefore, they provide no definite recommendation for
      pacifier use on the grounds of protection against the sudden infant death
      syndrome.

PMID- 12416288
TI  - Does professional counseling improve infant home monitoring? Evaluation of an
      intensive instruction program for families using home monitoring on their babies.
AB  - Home apnea/bradycardia monitoring was widely used in the 80s and 90s in the hope
      that Sudden Infant Death (SID) could be prevented. As no evidence could be found
      in favor of this hypothesis, HM today is restricted to symptomatic preterm
      infants, infants with cardiorespiratory problems and infants after an apparent
      life threatening event (ALTE). HM can impose substantial stress on families,
      especially mothers. We introduced an intensive counseling program (IC) for home
      monitoring and evaluated its effects, using a questionnaire. The control group
      consisted of families who were using a home monitor before the IC program was
      instituted, and were instructed according to the standard protocol given by the
      "Austrian SIDS-Consensus". The IC program consisted of standard monitor
      instruction as well as instruction in infant cardiopulmonary resuscitation, and
      was extended by providing intensive support at the beginning and throughout the
      monitoring period with special regard to the monitor weaning phase. RESULTS:
      Fifty-eight percent of the 90 questionnaires of the IC-families and 66% of the 70
      questionnaires of the control families were returned. Home monitoring was
      considered to be reassuring by more than 60% of the families. We found the
      following differences between the two groups: parents taking part in the IC
      program liked the instruction better, were less stressed by the monitor and
      reacted less aggressively to monitor alarms. They used the monitor predominantly
      during sleeping periods and for a shorter period of time (6 vs. 7 1/2 months). IC
      could not reduce SID related anxiety or change the feelings associated with the
      use of the home monitor. CONCLUSION: Intensive counseling leads to a better use
      of home monitoring and reduces parents' stress. Even if home monitoring is used
      less frequently today, families should still be instructed and counselled
      intensively.

PMID- 12416287
TI  - [Sudden infant death in Austria--status quo and recommendations of the SIDS
      Consensus Working Group for Improved Registration].
AB  - Sudden infant death (SID) is the most common cause of death among infants aged 2
      to 12 months in Austria. The complete autopsy required in order to diagnose SID,
      including the additional investigations, and the comprehensive autopsies needed
      for epidemiological studies are not common practice because of the different
      statutory regulations in the provinces and the absence of a uniform federal law
      in this regard. According to statistics, in the last four years only 83% (1997)
      to 70% (1999) of the reported SID cases in Austria were autopsied. Our survey in
      the forensic medicine and pathological institutes of Austria also revealed
      markedly different practices in regard of the manner in which autopsies are
      performed and parents are interviewed and followed up. For this reason, the SIDS
      Consensus Work Group of Austrian centers for the prevention of sudden infant
      death recommends the following: a) a comprehensive autopsy by a trained
      specialist to be established as a prerequisite for diagnosing "SIDS"; b)
      performing autopsies on a centralized basis in those forensic or pathological
      institutes that have agreed to adhere to protocol-based autopsy standards; c) the
      introduction of quality control in terms of a regional clinical-pathological
      conference; and d) standardizing the elements of the interview with parents of
      SID victims. Implementing these measures and entering the collected information
      into a data base in which the master data are encoded by the individual
      institutions, will help to evaluate the role of major epidemiological risk
      factors that information campaigns are focused upon, namely sleeping in prone
      position, the role of nicotine, etc. In addition, it will be necessary to
      formulate federal laws that standardize the divergent provincial regulations.

PMID- 12416289
TI  - [Objective assessment and therapeutic efficacy of an improved mandibular
      advancement device for snoring and sleep apnea syndromes with polysomnography].
AB  - In the treatment of snoring (SN) and sleep-related breathing disorders (SRBD),
      mandibular advancement devices (MAD) are of increasing importance. Their mode of
      action is based on the advancement of the mandible, thereby increasing various
      upper airway dimensions and thus airway patency and airflow during sleep. The aim
      of the present study was to investigate efficacy and tolerability of an
      individually fitted MAD on 11 patients (10 males, 1 female), mean age 57 years,
      using sleep laboratory methods in 3 subsequent nights (adaptation-, baseline-,
      treatment night). The MAD consists of 2 separate parts that attach to both dental
      arches. On occlusion the upper maxillary part with a protruding cone meets an
      inclined plane of the lower mandibulary part, thereby forcing the mandible to
      advance. 10 patients (6 with obstructive sleep apnea, 3 with obstructive hypopnea
      and 1 primary snorer) tolerated the MAD well; one patient (primary snorer)
      removed the MAD after 1 hour. Regarding the target variable, the snoring index
      (SI), confirmatory statistics demonstrated a significant improvement from 108 to
      53/h sleep, though normalisation could not be achieved. Descriptive data analysis
      showed significant improvement of the apnea-hypopnea index (AHI) from 15 to 5.5/h
      and of the oxygen desaturation index (O2-DI) from 21 to 13/h sleep. Arousal
      variables and periodic leg movement index (PLMI) improved as well. Objective
      sleep efficiency and subjective sleep- and awakening quality remained unchanged.
      Thus, besides the good therapeutic efficacy (the medians of improvement of the
      SI, AI, AHI, O2-DI and PLMI were 37, 48, 53, 51 and 29%, respectively), acute
      acceptance of the MAD was also satisfactory. Last but not least our present study
      showed once more the necessity of an adaptation night, as from the first to the
      second sleep laboratory night respiratory indices deteriorated significantly.

PMID- 12416290
TI  - Nymphea: the concrete and the symbolic. An introduction.

PMID- 12416291
TI  - Nymphea: from psychic breakdown to the emergence of subjectivity.
AB  - In the first part of the paper the author presents an account of the analysis of
      a woman who is psychically extremely disturbed. This clinical presentation
      focuses on the unfolding of the transference process, and on the
      countertransference difficulties encountered during the course of the treatment
      which lasted more than ten years. In the second part of the paper the author
      proposes a theoretical approach to the breakdown experienced by the patient, and
      puts forward the hypothesis that there was insufficient differentiation between
      her internal objects and the archetypes, and that this prevented the development
      of symbolization. The author proposes the idea of a collapse between internal and
      external objects, which destroys the space necessary for representation and
      symbolization that normally arise between the two poles of the object. The
      account of this transference process between the analyst and the patient is thus
      seen as the account of the (re)construction of true internal objects, and of the
      resumption of a symbolic process to make possible the development of
      subjectivity.

PMID- 12416292
TI  - Reactions to Francois Martin-Vallas's paper.

PMID- 12416293
TI  - Exploring racism.
AB  - Whilst the concept of 'race' has no basis in genetics or biology, the dynamics of
      racism pervade all aspects of modern life--including the consulting room. In this
      paper the relationship between a white therapist and a black patient is explored
      through an unbidden thought and a verbal slip that occurred in the course of the
      therapy. The amplification and examination of these unwanted 'slips' are used to
      shed light on the subtleties of the effects of difference in colour on the
      relationship. It is argued here that the interaction reflects and illuminates the
      asymmetrical relationship between 'black' and 'white' in modern-western society.
      This is then considered using the concepts of the cultural unconscious and social
      unconscious as ways of understanding the tenacity of racism in ourselves.

PMID- 12416294
TI  - Temenos regained: reflections on the absence of the analyst.
AB  - The importance of the temenos as a metaphor to conceptualize therapeutic
      containment is discussed. Jung drew the analogy between the consulting room and
      the temenos, at the centre of the Greek Temple as a sacred and inviolate place
      where the analysand might encounter the Self. Although Jung believed that whether
      called or not, the gods would appear, under certain conditions, patients may
      experience 'temenos lost', the loss of the holding function of the analytic
      space. Two cases are presented in which temenos issues played a central role. In
      one case, an unorthodox method was used to preserve the analytic container during
      the absence of the analyst and in the other, the impact of an extra-analytical
      encounter had a dramatic effect on the holding function of the temenos. A
      discussion is presented of the appropriate circumstances in which analysts may
      deviate from traditional analytic practice in order to preserve the temenos and
      transform a 'temenos lost' into a 'temenos regained'.

PMID- 12416295
TI  - Analytical psychology and its relation to psychoanalysis. A personal view.
AB  - Jungian analysis is a process based on analytical psychology; it shows local
      variations giving emphasis to different aspects of Jung's work within the various
      societies which make up the IAAP. I describe the orientation of the Society of
      Analytical Psychology (SAP). I have emphasized the different origins of
      psychoanalysis and analytical psychology and described how, because we encounter
      the same clinical phenomena, our differences centre on technique and
      interpretation in the context of our theoretical differences (see Astor 1998, p.
      697 & 2001). In the main the link to psychoanalysis has come from the connection
      forged by Fordham, who recognized that Jung and Klein shared a similar perception
      of the significance of unconscious phantasy. For Klein unconscious phantasy was
      the primary unconscious content, and this is different, as Spillius has recently
      pointed out, from Freud for whom, 'the prime mover, so to speak, is the
      unconscious wish.

PMID- 12416296
TI  - Aristotle's ontogenesis: a theory of individuation which integrates the classical
      and developmental perspectives.
AB  - The effects of the classical/developmental split in analytical psychology are
      described. No underlying issues explaining the nature of the split have been
      clearly enunciated. The schools can, however, be distinguished by their differing
      epistemologies. These are the hermeneutic and transcendental branches of
      phenomenology. The use of these epistemologies leads their proponents to either
      an immanent or transcendent concept of the divine, respectively. The theoretical
      break between Freud and Jung can, in part, be attributed to their espousal of
      determinism and teleology, respectively. This conflict has been continued in
      analytical psychology with the developmentalists most often advocating
      determinism, and the classicists usually championing teleology. The dissimilar
      causal theories lead to different concepts of the nature of individuation.
      Aristotle's fourfold theory of causality, of which determinism and teleology are
      two categories, can be seen to be an ontogenic theory rather than a
      classification of causal influences. Applying his theory to the process of
      individuation provides an ontogenesis that more accurately describes the process
      itself, and unifies the developmental and classical theories. Intimations of this
      formulation in Jung's work are described. More explicit conceptions of this idea
      in the work of two contemporary analytical psychologists and that of Wilfred Bion
      are also presented.

PMID- 12416297
TI  - The goal as process: music and the search for the Self.
AB  - This paper explores and compares the processes of music and analysis from the
      author's experience as a musician, piano teacher and analyst. It explains how the
      use of music improvisation in analysis (with simple percussion instruments) can
      powerfully enhance the dialogue between the unconscious and conscious psyche, as
      well as deepen the relationship between analyst and analysand. This is connected
      theoretically to Jung's active imagination and Winnicott's concept of play within
      the analytic encounter. Finally, the question is raised whether analytic
      trainings could do more to expose trainees to the possibility of using music
      within the analytic encounter. This touches on the more basic and controversial
      issue (which often separates analytical psychology and psychoanalysis) of whether
      expressive therapy should be used in analysis at all.

PMID- 12416298
TI  - Application of FLP/FRT site-specific DNA recombination system in plants.

PMID- 12416299
TI  - Protein quality control in bacterial cells: integrated networks of chaperones and
      ATP-dependent proteases.

PMID- 12416300
TI  - Regulation of the Ras-MAPK pathway at the level of Ras and Raf.

PMID- 12416301
TI  - Plant virus gene vectors: biotechnology applications in agriculture and medicine.

PMID- 12416303
TI  - Foreign DNA: integration and expression in transgenic plants.

PMID- 12416302
TI  - Integrins and the myocardium.

PMID- 12416304
TI  - Novel approaches to controlling transcription.

PMID- 12416305
TI  - The use of DNA polymorphisms in genetic mapping.
AB  - The introduction of molecular markers has revolutionized genetics. The range of
      polymorphisms that are available is increasing and the advent of large-scale cDNA
      and genomic sequencing is a source of an ever-increasing set of available
      markers. The ease with which any particular marker type can be applied to an
      experimental system depends, to some extent, on the amount of genomic information
      available for that system. However, comparative genomics is enabling a wider
      range of marker technology to be applied to relatively information-poor systems.
      The types of markers that are available include restriction fragment length
      polymorphisms, amplified fragment length polymorphisms, ransom amplified
      polymorphic DNAs, simple sequence repeats, single nucleotide polymorphisms and
      small insertions/deletions. The types of questions that can be addressed with
      these molecular markers include the generation of genetic and physical maps for
      the identification of interesting loci, the development of marker-based gene
      tags, map-based cloning of agronomically important genes, synteny mapping, marker
      assisted selection and quantitative trait analysis. The continued development of
      technology including new high throughput methods, for example those being applied
      to single nucleotide polymorphisms, will change the ease with which current
      questions can be answered as well as enable new analyses that are presently
      impossible to undertake.

PMID- 12416306
TI  - Import of nuclear encoded RNAs into yeast and human mitochondria: experimental
      approaches and possible biomedical applications.
AB  - Mitochondria import from the cytoplasm the vast majority of proteins and some
      RNAs. Although there exists extended knowledge concerning the mechanisms of
      protein import, the import of RNA is poorly understood. It was almost exclusively
      studied on the model of tRNA import, in several protozoans, plants and yeast.
      Mammalian mitochondria, which do not import tRNAs naturally, are hypothesized to
      import other small RNA molecules from the cytoplasm. We studied tRNA import in
      the yeast system, both in vitro and in vivo, and applied similar approaches to
      study 5S rRNA import into human mitochondria. Despite the obvious divergence of
      RNA import systems suggested for different species, we find that in yeast and
      human cells this pathway involves similar mechanisms exploiting cytosolic
      proteins to target the RNA to the organelle and requiring the integrity of pre
      protein import apparatus. The import pathway might be of interest from a
      biomedical point of view, to target into mitochondria RNAs that could suppress
      pathological mutations in mitochondrial DNA. Yeast represents a good model to
      elaborate such a gene therapy approach. We have described here the various
      approaches and protocols to study RNA import into mitochondria of yeast and human
      cells in vitro and in vivo.

PMID- 12416307
TI  - An introduction to 13C metabolic flux analysis.

PMID- 12416308
TI  - Gene silencing--principles and application.

PMID- 12416309
TI  - Essentially environmental. Pediatrician Carolyn McKay looks beyond the child to
      the child's world.

PMID- 12416310
TI  - Antimicrobial use in animal feed an ecological and public health problem.

PMID- 12416311
TI  - A new use for medical surplus.

PMID- 12416312
TI  - Minesota exposed.

PMID- 12416313
TI  - Idiopathic environmental intolerances.
AB  - Health concerns related to the quality of the environment in offices, schools,
      homes, and residences have increased dramatically over the past 2 decades. One
      health problem frequently confronting medical practitioners and often attributed
      to environmental quality problems is idiopathic environmental intolerances (IEI).
      Formerly known as multiple chemical sensitivities, IEI is an acquired disorder
      characterized by adverse reactions attributed to exposure to a variety of
      substances under ordinary conditions. Alleged precipitants include solvents,
      pesticides, detergents, dusts, and fragrances. Symptoms include fatigue, malaise,
      headache, concentration and memory difficulties, lightheadedness, cough,
      hoarseness, and rhinitis without objective physical signs or consistent
      laboratory abnormalities. The role of the environment in precipitating these
      complaints continues to be controversial, and no intervention or treatment has
      thus far been proven to be effective. While not progressive or life threatening,
      IEI is often functionally disabling and very distressing to affected individuals.
      The investigation of IEI should involve, at a minimum, a clinical evaluation of
      the affected person and in most cases an environmental evaluation as well. IEI
      should be managed without overutilization of diagnostic tests or prescription of
      unnecessary environmental, occupational, or dietary restrictions.

PMID- 12416314
TI  - Community and environmental health effects of concentrated animal feeding
      operations.
AB  - High-density concentrated animal feeding operations (CAFOs) have become an
      increasing source of concern with respect to their impact on health, the
      environment, and quality of life in the communities in which they are located. A
      growing body of literature has identified a number of potential adverse effects,
      including the development of antimicrobial resistance patterns, groundwater
      contamination, and occupational respiratory disease. The odor associated with
      CAFOs has had a detrimental effect on the quality of life of rural residents, and
      there may also be associated adverse health effects. Physicians in rural areas
      may be asked to assess patients with concerns related to neighboring CAFOs and
      may be drawn into a political battle regarding the authorization of the
      development of additional CAFOs. This article reviews current research on the
      community, environmental, and occupational health effects associated with high
      density animal production facilities. It also discusses recommendations for
      evaluating patients affected by CAFO odors and steps to decrease occupational and
      community exposure.

PMID- 12416315
TI  - Minnesota childhood blood lead guidelines.
AB  - Lead poisoning continues to pose a major environmental health threat to
      Minnesota's children. Currently, about 2,000 children a year in Minnesota are
      identified as having elevated blood lead (greater than 10 micrograms/dL). The
      Minnesota Department of Health has developed statewide guidelines for screening,
      case management, and clinical treatment of children who have been exposed to
      lead. The screening guidelines target children with the highest risk of exposure.
      The case management guidelines provide information to public health agencies on
      recommended steps for dealing with an elevated blood lead case. The clinical
      treatment guidelines assist physicians and other health care professionals with
      the medical aspects of a lead case. These guidelines are based on state data,
      were developed using diverse work groups, and have been endorsed by the medical
      community. They provide Minnesota-specific guidance on how to best identify and
      treat a child exposed to lead and to minimize exposure.

PMID- 12416316
TI  - Drinking water in Minnesota.

PMID- 12416317
TI  - Mujeres Latinas--Santas y Marquesas.
AB  - This presidential address is a conceptualization and application of
      psychohistorical and mestizo psychology frameworks to address gender and ethnic
      identity conflicts for contemporary Latinas. Connections are made between
      historical and cultural icons and Latina literature of the 21st century with
      protagonists who give voice to the struggles of acculturated and self-empowered
      women. Spanish terms are used to communicate and give emphasis to the Latino
      landscape. The article comes to conclusion with personal reflections about Maria
      Morales de Zaldivar, or Mama, the author's grandmother, who embodies the santa y
      marquesa life script.

PMID- 12416318
TI  - A conceptual model of cultural predictors of anxiety among Japanese American and
      part-Japanese American adolescents.
AB  - A model integrating Japanese ethnicity, cultural identity, and anxiety was
      developed and assessed in Japanese American and part-Japanese American high
      school seniors (N = 141). Using measures from the Hawaiian High Schools Health
      Survey, the model incorporated the State-Trait Anxiety Inventory, the Major Life
      Events Scale, and the Japanese Culture Scale (JCS). Japanese American adolescents
      scored higher on the JCS and reported fewer anxiety symptoms than part-Japanese
      American adolescents. Predictors for anxiety were being Japanese American versus
      part-Japanese American, income, and culturally intensified events. A significant
      interaction of behavior by self-identification was obtained. The model had good
      overall fit, suggesting that cultural identity formation may contribute to
      anxiety experienced particularly by adolescents of mixed heritage.

PMID- 12416319
TI  - The factor structure underlying three self-report multicultural counseling
      competence scales.
AB  - This study examined the extent to which 3 self-report multicultural scales were
      measuring the predominant 3-factor conceptualization of multicultural counseling
      competence as consisting of multicultural attitudes/beliefs, knowledge, and
      skills. Results of a confirmatory factor analysis revealed that the 3-factor
      model was not fully supported. An exploratory factor analysis identified a 2
      factor structure (i.e., self-perceived multicultural counseling skills and
      multicultural counseling attitudes/beliefs) underlying these instruments.
      Implications of the findings for clinical practice, training, and research are
      discussed.

PMID- 12416320
TI  - Effects of speech accents on interpersonal evaluations: implications for
      counseling practice and research.
AB  - This article reviews literature from the fields of psycholinguistics,
      communications, and social psychology that has examined the effects of speech
      accents (i.e., regional, national, and international variations in same-language
      use) on interpersonal attitudes, casual attributions, and subsequent behaviors.
      The authors link selected findings from this literature to the field of
      counseling to show that these findings can inform service delivery, particularly
      counseling conducted with ethnic minority and immigrant populations in the United
      States. Implications for practice and ideas for future research in this area are
      also discussed.

PMID- 12416321
TI  - Personal dimensions of identity and empirical research in APA journals.
AB  - This study reviewed 402 empirical research papers published during 1999 in 9
      American Psychological Association journals from the perspective of the Personal
      Dimensions of Identity (PDI) model. Descriptions of participants were reviewed to
      determine whether researchers reported information concerning Dimensions A, B,
      and C of the PDI model. PDI A and B Dimensions of age, gender, education, and
      geographic location were reported with the highest frequency: 88.56%, 89.30%,
      78.50%, and 73.88%, respectively, whereas race/ethnicity was reported with
      moderate frequency, 60.70%. The remaining PDI A Dimensions of language, physical
      disability, sexual orientation, and social class, and the remaining B Dimensions
      of citizenship status, employment status, income, marital status, military
      experience, occupation, and religion, were reported in relatively low percentages
      of studies.

PMID- 12416322
TI  - Effect of ethnic group membership on ethnic identity, race-related stress, and
      quality of life.
AB  - This study examined the effect of ethnic group membership on ethnic identity,
      race-related stress, and quality of life (QOL). The Multigroup Ethnic Identity
      Measure, the Index of Race Related Stress--Brief Version, and the World Health
      Organization Quality of Life--Brief Version were administered to 160 male and
      female participants from 3 ethnic groups (African American, Asian American, and
      Latino American). Results indicated that African American participants had
      significantly higher race-related stress, ethnic identity, and psychological QOL
      scores than did Asian and Latino American participants. A stepwise multiple
      regression analysis revealed that ethnic identity and cultural racism were
      significant predictors of QOL and accounted for 16% of the total variance for the
      entire sample.

PMID- 12416323
TI  - Ethnicity, gender, and academic self-concept: a preliminary examination of
      academic disidentification and implications for psychologists.
AB  - This study examined data from 358 African American students and 229 European
      American students to determine if the phenomenon of academic disidentification
      occurred. Analyses revealed that among African American male students, the
      relationship between academic self-concept and grade point average (GPA)
      significantly decreased, whereas the relationship between academic self-concept,
      self-esteem, and GPA significantly increased for European American female
      students. The relationship between academic self-concept and GPA remained
      significant for African American female and European American male students.
      Research and counseling implications are discussed.

PMID- 12416324
TI  - Comparison of Egyptian and Canadian children on a picture apperception test.
AB  - Individualism-collectivism theory predicted that Egyptian and Canadian children's
      performance would differ on relevant scales of the Roberts Apperception Test for
      Children (RATC). The RATC was administered to 34 Egyptian and 34 Canadian
      children ages 6-13 years. Canadian children scored higher on autonomy and lower
      on receiving support from others and parental limit setting. At older ages,
      Egyptian children manifested less rejection, desire for help from others, and
      aggression. There were no cultural differences in anxiety or depression and few
      differences on indicator and resolution scales related to understanding the task
      and resolving problems. The findings validated cross-cultural use of the RATC and
      demonstrated that the increasingly general theory of collectivism allowed
      meaningful predictions about personality and clinical traits.

PMID- 12416325
TI  - New metals for old: real and imaginary properties.

PMID- 12416326
TI  - New biointeracting materials.
AB  - This article reports on advances in haemocompatible and antimicrobial coatings. A
      polymer is described that has nonthrombogenic and antithrombogenic properties on
      the same polymer backbone, which prevents protein adsorption and inhibits
      thrombin at the same time. A separate polymer formulation has also been developed
      that is reportedly biocompatible, lubricious and antimicrobial.

PMID- 12416328
TI  - Stainless steel tubing basic design considerations.

PMID- 12416327
TI  - In-mould decorating.
AB  - Advances in plastics moulding technology and the use of in-mould decorating are
      giving medical device manufacturers an opportunity to expand the variety of their
      products and reduce the cost of the final product. Other industries have tested
      the waters and found them friendly. The medical device industry could be next.

PMID- 12416329
TI  - The technological edge.
AB  - An inflatable penile cuff has been developed as a noninvasive technique for
      measuring bladder outflow to help determine a patient's need for a prostatectomy.

PMID- 12416330
TI  - The new FDA combination products programme.
AB  - The United States (US) Food and Drug Administration (FDA) has established a
      Combination Products Programme and developed a new internal procedure to increase
      its effectiveness in regulating products consisting of combinations of drugs,
      devices and biological products. This article provides a brief overview of the
      FDA regulation of combination products and discusses the new Programme.

PMID- 12416331
TI  - Risk management: countdown to December 2003. (Part II).

PMID- 12416332
TI  - The Netherlands: at the hub of distribution.

PMID- 12416333
TI  - Automated assembly and testing in medical device production.

PMID- 12416334
TI  - Business opportunities abound in Israel.

PMID- 12416335
TI  - Laser marking provides traceability.

PMID- 12416336
TI  - Helping each other.

PMID- 12416337
TI  - Mentoring dialogue: critical questions and answers.

PMID- 12416338
TI  - Coach, challenge, lead: developing an indispensable management team.

PMID- 12416339
TI  - Getting the job you want in healthcare management: 10 steps to success.

PMID- 12416341
TI  - The scope and benefits of expert services. Providers can build on their vendors'
      expertise.

PMID- 12416340
TI  - Networking resources from ACHE.

PMID- 12416342
TI  - Reconciling conflicts of interest.

PMID- 12416343
TI  - IT recruitment and retention.

PMID- 12416344
TI  - Communicating strategically in a crisis. During a crisis, the organization's
      credibility rests on the CEO.

PMID- 12416345
TI  - Empty the cup, open the mind. How receptive to learning are you?

PMID- 12416346
TI  - Involving employees. Employees lend a helping hand to migrant farmworkers.

PMID- 12416347
TI  - Patient safety legislation.

PMID- 12416348
TI  - Careers in the uniformed services.

PMID- 12416349
TI  - Going the extra mile in patient care. An innovative program helps breast cancer
      patients navigate the healthcare system.

PMID- 12416350
TI  - [Smoking cessation].
AB  - We estimate that more than 80% of tobacco-smokers hope that they will stop
      smoking one day. The major obstacle is the psychologic and pharmacologic
      dependence generated by the cigarette. Different weaning methods have been tried,
      but their rate of success remains low. The nicotinic sustitution by transdermic
      track (patch) will give good results providing it is prescribed within the
      framework of a medical help to wean away from smoking tobacco.

PMID- 12416351
TI  - [Acute gravidic steatosis: review and management].
AB  - The acute gravidic steatosis is a specific hepatopaty of pregnancy that has a low
      frequency witch often very serious. On the light of a gravidic steatosis case
      histological proved progenitors analyse the clinical criteria of positive
      diagnosis. The coexistence of an hepatic anomaly that is of an hyperuricemia with
      a normotensive woman is too suggestive of the diagnosis. The maternal mortality
      exceeded 92% before 1970, now it has reached 10%. his amelioration is mainly due
      the obstetric attitude of evacuation and the progress of reanimation.

PMID- 12416352
TI  - [Relevant factors in mitral valve reconstructive surgery. Report of 150 cases].
AB  - 150 patients had mitral valve repair for mitral valve incompetence. There were 57
      males and 93 females with a mean age of 22 years, 39% were less than 15 years of
      age. 60% of the patients were in Class II NYHA and 40% in Class III and IV.
      According to Carpentier's classification, isolated type I was present in 18
      patients (12%), type II in 98 patients (64%) and type III in 34 cases (24%).
      Mitral repair included correction of valve prolapse, valvular enlargement with
      pericardial patch and annuloplasty with semi-rigid ring in 128 cases and PTFE
      patch along the posterior leaflet in 12 cases. The perioperative mortality rate
      was 2.6% (4 patients). All patients had early post-operative echocardiography.
      According to this, mitral regurgitation was absent or tiny in 135 patients (92%),
      grade II in 10 cases and grade III in 2 cases. It was moderate or important in
      twelve patients (8%). In the late post-operative period, three patients were lost
      to follow-up. All the others patients were reoperated upon for mitral dysfunction
      in a mean time of 37 months. The reason for reoperation was in the majority of
      the cases the recurrence of mitral regurgitation related to increase of valvular
      and sub valvular disease. The late mortality rate is 7% (10 patients). Out of 126
      reviewed survivors on the long run, 71 patients (56%) are asymptomatic in class
      I, 53 patients (42%) in class II and 2 patients in class III NYHA. Mitral
      valvuloplasty is the preferred procedure in mitral insufficiency surgical
      management. It is associated to a low early mortality and morbidity rate. Despite
      the need for reoperation in about 10% of the cases in the long follow-up, mitral
      repair offers a good quality of life without anticoagulant treatment.

PMID- 12416353
TI  - [Epidemiologic and prognostic aspects of nosocomial bacteremia in the intensive
      care unit].
AB  - The nosocomial bacteremia (NB) are frequent and associated to a high mortality
      and morbidity with extension of stay in the intensive care unit (ICU). The aim of
      this study is to evaluate epidemiological aspect and prognosis of NB. It is a
      retrospective study about 872 patients hospitalized in our unit during 2 years.
      The diagnosis of the NB is based on two positive hemocultures with 24 hours of
      interval in the patients who are hospitalized more than 48 hours. The incidence
      of the bacteremia represents 6.6% (n = 58). The portal of entry is noticed in 55%
      of the cases (n = 32). The most frequent origin is respiratory infection 24% (n =
      14), whereas bacteremia after catheter colonization represents 3.4% (n = 2). Gram
      Positive cocci were incriminated in more than 53% of the cases (n = 39).
      Staphylococcus aureus was the first causal germ (n = 28) whereas the Pseudomonas
      is the most frequent of the gram negative bacilli that represent 41% of the
      isolate germs (n = 31). The sensitibility of this germ to ceftazidim and imipenen
      was respectively 18% and 19%. The rate of the resistant Staphylococcus to
      meticilline was 38%. The whole mortality represented 28% (n = 16) that 7% (n =
      14) of the cases were directly in relationship with the septic shock. Among
      prognostic factors evaluated, only septic shock and multivisceral failures are
      correlated to mortality. NB mortality is not negligible in ICU. Staphylococcus
      and Pseudomonas are the most frequent germs. Limitation of invasive acts,
      rigorous antibiotherapy management and observance of hygienic measures will
      significantly reduce incidence of NB.

PMID- 12416354
TI  - [Treatment and outcome of Crohn's disease without initial complications. Results
      of a retrospective, multicenter Tunisian study].
AB  - The purpose of this study was to estimate and achieve the factors that have an
      influence on the evolution of the Chron's disease. This study was done in 124
      patients reaching the diagnosis of Chron's disease between 1988 and 1997. The
      evolution of this disease was achieved in 87 patients. The Chron's disease was
      inactive among 31 patients (35-6%)--with discontinous evolution in 42 patients
      (48.3%) and active chronic in 14 patients (16-1%). The active chronic form of
      Chron's disease was twice more frequent among the smokers and the patients with
      age above 40 years--but this difference has no statistical significance. The
      indication of surgical treatment was realised in 21 patients and it takes place
      as result of failure of medical treatment in 16 patients (76-2%)--an abcess in 2
      patents (9-5%) and iatrogenic perforation in 1 patient (4-8%). The age-sexe-smoke
      -the intensity of the initial attack and the nature of the treatment had no
      influence in the need of the surgical interfference. The Chron's disease showed
      the less severe evolution in this study--the age above 40 years and the
      consumption of smoke increased the frequency of active chronic form.

PMID- 12416355
TI  - [Epidemiologic, clinical and cytohematologic characteristics of adult acute
      lymphoblastic leukemia in Tunisia].
AB  - Through a national retrospective study, the authors report the clinical and
      hematological characteristics of 124 acute lymphoblastic leukemia of the adult
      diagnosed during 5 years (1993-1997). The national prevalence is of 0.28/100.000
      inhabitants/year. The sex-ratio is of 1.3. Sixty six per cent of patients were 16
      35 years of age, and only 10% of them were more than 60 years of age. A tumoral
      syndrome was present at 71% of the cases with peripheral adenopathies in 55%,
      splenomegaly in 40%, hepatomegaly in 19% and a mediastinal tumor in 18% of the
      cases. The bone pain were rarely signaled (10%) and neuro-meningeal affection was
      found in only 3% of cases. There was no testicular lesions. The white blood cells
      count was less than 30.000/mm3 in 60% whereas an important hyperleucocytosis
      superior than 100.103/mm3 was observed in 20% of the cases. Anemia and
      thrombopenia were noted in 94% and 90% of the cases respectively. Acute
      lymphoblastic leukemia typing by cytological study of Bone marrow according to
      the Fransh-American-Britain criteria (FAB) had found 43%, 48% and 4% for type 1,2
      and 3 respectively. In 5% of the cases the type of the acute lymphoblastic
      leukemia was not precised (diagnosis based on the Bone biopsy).

PMID- 12416356
TI  - [Cervical cancer screening by Pap smear: experience of the National Research
      Center in Reproductive Health. ONFP].
AB  - We have analysed the result of 17,173 pap smears screened in the national
      research center in reproductive health of Ariana from 1 may 1993 to 30 april
      1997. Among these pap smears, 613 colposcopy and 380 biopsy have been performed.
      The results show that: 1.9% of pap smears present cytological anomalies with
      0.79% of low Squamous Intraepithelial lesions and 0.66% high Squamous
      Intraepithelial lesions. The incidence of CIN III is 1.8% and 0.9% for invasive
      cancer. The age interval 35-44 years is at high risk of CIN III and invasive
      cancer of the cervix. evaluation of our diagnostic approach shows that: positive
      predictive value of pap smears with low SLI is 43.2% positive predictive value of
      pap smears with high SLI is 37.3%.

PMID- 12416357
TI  - [Study of Salmonella contamination of restaurant meat products collected over a
      period of one year].
AB  - The study has been carried out on 898 food samples of animal origin: bovin meat,
      ovin, porcin, rabbit, turkey and chicken in 1998 from auto-control food service
      of Chahed laboratory. II consisted in studying and identifying salmonella
      serovars and to determine the nature of the most contaminated meat products. The
      results of the study are as follows: 3.7% of meat product samples are
      contaminated by salmonella. On the 480 samples of bovin meat, 4.2% are
      contaminated by salmonella. 3.8% ovin meat is contaminated by salmonella, 1.7%
      turkey meat and 3.6% chicken meat. Rabbit meat are not contaminated by
      salmonella. As far as the products of a bovin origin are concerned the results
      are as follows: -2.7% of meat is contaminated by salmonella, 5.3% of mechanically
      separated meat and 7.7% of giblets are also contaminated. Therefore salmonella
      contaminates 4.3% of red meat and 2.6% of fowl. S. anatum, Corvallis,
      typhimurium, Braenderup, Zanzibar, Enteritidis, Livingstone are different
      detected serovars. S. anatum represents 40% of contamination whereas. S.
      typhimurium represents 12% Of contaminations.

PMID- 12416358
TI  - [Cimetidine therapy for multiple warts in children].
AB  - Various treatment modalities are used to treat warts and this indicates that none
      is uniformly effective. Cimetidine, an H2-receptor antagonist, has been tried to
      treat warts because of its immunomodulatory effects. Sixty children with multiple
      and recalcitrant warts were included in a placebo-controlled, double-blind study.
      Patients were randomly allocated to treatment groups equally. The groups received
      cimetidine, 25 to 30 mg/kg daily, or placebo for 2 months. At the end of the
      therapy, only 10 cimetidine-treated and 9 placebo-treated were examined. Cure
      rates obtained were 60% in the cimetidie-treated group and 33% in the placebo
      treated group. Among our data and the review of the literature, we believe that
      cimetidine is not appropriate as standard therapy for warts, but it may be an
      interested therapy for multiple and recalcitrant warts of children.

PMID- 12416359
TI  - [Role of auriculotherapy in smoking cessation. Personal experience].
AB  - Smoking is one of the main causes of poor health and early death. In line with
      the 1999 law which aims at reducing smoking, we have tested auriculotherapy as an
      aid for giving up smoking. We tried this treatment on 39 people who wanted to
      give up smoking. After two months of treatment, 15 people (38.5%) had given up
      completely and 24 people had reduced their smoking by more than half.
      Auriculotherapy is an useful aid for giving up smoking. It is easy and painless,
      has no secondary effects and it is economic.

PMID- 12416360
TI  - [Pancreatic sarcoidosis].
AB  - Pancreatic involvement in sarcoidosis is exceptional. We report a case of
      pancreatic sarcoidosis diagnosed during the etiologic work-up done for a
      pancreatic mass associated to a polyadenopathy. Under corticotherapy evolution is
      favorable with regression of the pancreatic lesions.

PMID- 12416361
TI  - [Peutz-Jeghers syndrome. Two case reports].
AB  - The Peutz jeghers syndrome is a familial affection with dominant autosomic
      transmission characterized by a hamartoma digestive polyposis and a cutaneous
      mucous lentiginosis with periorifice predominance. This affection represented 3
      into 10% for the familial polyps. The digestive polyps constitute the must
      important part of the pentz jeghers syndrome because they determined to only the
      clinic manifestation and the disease prognostic with there complications:
      intestinal invaginations, haemorrhage. In this work, we report two observations
      of patients presented a Peurtz Jeghers syndrome, and we determine, after
      literature review the epidemiologic, pathogenic, clinic, anatomy pathologic,
      prognosis and therapeutics of this effection.

PMID- 12416362
TI  - [Dubin-Johnson syndrome: molecular basis and pathogenesis].
AB  - The Dubin-Johnson syndrome (DJS) is an autosomal recessive liver disorder
      characterized by a chronic conjugated hyperbilirubinemia a dark greenish
      appearance of liver tissue, a double peaked sulfobromophthalein clearance curve,
      and a characteristic lysosomal accumulation of black pigment "melanine-like" in
      the hepatocytes. Laboratory datas indicated an increased urinary excretion of
      coproporphrin isomer I and leukotriene metabolites. In an effort to understand
      the morphological pattern and the pathogenesis of this disease we reviewed four
      cases of DJS.

PMID- 12416363
TI  - [Subcapsular liver hematoma, severe complication of pregnancy toxemia. A case
      report].
AB  - Subcapsular liver hematoma is a rare and severe complication of pregnancy. This
      event is already known to have a poor maternal and foetal prognosis. The authors
      report a case of spontaneous rupture of subcapsular hematoma of the liver in 40
      year old multiparous. Confirmation of diagnosis is obtained by abdominal
      echotomography or TOM. The surgical treatment of this hematoma joints the
      traumatic surgery of the liver. In every case foetal extraction by cesarean
      section constitutes the first therapeutic procedure.

PMID- 12416364
TI  - Radical revision of survey process may ease compliance burden.

PMID- 12416365
TI  - Changes make integration of services a priority.

PMID- 12416366
TI  - Long-term focus pays off with perfect score.

PMID- 12416367
TI  - Take time to prepare, include others in survey preparation.

PMID- 12416368
TI  - Develop a patient safety management system. Part 3.

PMID- 12416370
TI  - 2002 salary survey results. Improve your income with better data skills,
      leadership.

PMID- 12416371
TI  - 'Caducean ceiling' blocks docs from CEO posts.
AB  - Physician executives face numerous obstacles in their quest to become CEOs. Take
      a look at what's standing in the way.

PMID- 12416372
TI  - Breaking through the caducean ceiling.

PMID- 12416373
TI  - 8 keys to the chief executive suite.
AB  - What makes a great CEO? Take a look at some of the critical skills you need to
      develop if you expect to land the top spot.

PMID- 12416374
TI  - CEOs as saviors?

PMID- 12416375
TI  - The active physician executive of the future.

PMID- 12416376
TI  - Physician-led: good idea or not?
AB  - Whether physicians or not, leaders must possess certain skills and qualities to
      achieve success. Take a look at what's required to be an effective leader.

PMID- 12416377
TI  - Concierge medicine gaining ground. Competition forces medical center into
      'boutique' business.

PMID- 12416378
TI  - L.A. physician sees electronic medical record as key to better public health.

PMID- 12416379
TI  - Physician executives share insights on ways to influence people--Part II.

PMID- 12416380
TI  - U.S. health care in conflict--Part II. The challenges of balancing cost quality
      and access.
AB  - Faced with the technology explosion, the aging population and the growing
      uninsured, our health care system confronts an uncertain and troubling future. In
      this second part of a two-part series, look at some proposed solutions to the
      problems.

PMID- 12416381
TI  - Public speaking maxim No. 101. The corpse is more comfortable than the eulogizer
      at a funeral.
AB  - Making a presentation can be a grueling experience. But imagine making one
      without any preparation--as a job candidate, no less.

PMID- 12416383
TI  - Will you get promoted over an outside candidate?

PMID- 12416384
TI  - Selecting and hiring a practice administrator.
AB  - Finding the perfect person to run your practice isn't easy. Here are some steps
      you should take as you go about your search.

PMID- 12416386
TI  - How much is your practice worth?--Part II.

PMID- 12416385
TI  - Good 'traction' can help you achieve change.
AB  - Examine the abstract idea of traction. Explore how traction in your job can help
      you motivate meaningful change.

PMID- 12416387
TI  - Physician retirement plans: the impact of organizational structure.
AB  - A primary concern of many physicians is the accumulation of adequate funds while
      practicing to maintain their lifestyles after retirement. Take a look at how some
      business arrangements can affect retirement planning.

PMID- 12416388
TI  - Smallpox vaccine policy: the national debate.
AB  - As a result of the 2001 anthrax attacks, the U.S. government is trying to forge a
      plan to handle something much worse: an outbreak of smallpox due to terrorist
      activity. Here's a look at where the debate stands today.

PMID- 12416389
TI  - Ultrastructural studies of experimental scrapie and Creutzfeldt-Jakob disease in
      hamsters. I. Alterations of myelinated axons.
AB  - Classical and ultrastructural neuropathology of prion diseases are generally well
      described. Here we report that alterations of myelinated fibres in hamsters
      infected either with polioencephalopathic strains of scrapie or
      panencephalopathic strains of CJD (Echigo-1) are virtually identical and differ
      only quantitatively. In contrast, mice infected with the panencephalopathic
      Fujisaki strain of CJD exhibited much more elaborate changes of myelinated
      fibres.

PMID- 12416390
TI  - Ultrastructural studies of experimental scrapie and Creutzfeldt-Jakob disease in
      hamsters. II. Astrocytic and macrophage reaction towards axonal destruction.
AB  - We report here the microglial (macrophage) and astrocytic reaction in several
      models of transmissible spongiform encephalopathies (TSEs) or prion diseases.
      With the low power electron microscopy it was readily apparent that myelinated
      vacuoles were surrounded by cells and their processes. The latter belonged either
      to hyperplastic reactive astrocytes or to macrophages. Typically, reactive
      astrocytes exhibited cytoplasm filled with innumerable glial filaments and,
      occasionally, other organelles (like cilia) and abundant tortuous intercellular
      junctions of adhesive plaque junction type. Desmosome-like junctions connecting
      astrocytic elements were also seen. As described earlier, astrocytic processes
      were occasionally interdigitated with oligodendroglial cells and their processes.
      Two types of macrophages were readily described. The majority of them exhibited
      electron-dense cytoplasm and numerous "empty" vacuoles (digestive chambers)
      containing cellular debris. Occasional vacuoles were surrounded by a thin collar
      reminiscent of "lyre-like inclusions" of the second type of macrophages. Several
      mylinated fibres were clearly engulfed by the cytoplasm of a macrophage
      containing unusual annulate lamellae.

PMID- 12416391
TI  - How do neurons degenerate in prion diseases or transmissible spongiform
      encephalopathies (TSEs): neuronal autophagy revisited.
AB  - As in other neurodegenerative diseases such as Alzheimer's disease, neurons in
      prion diseases or transmissible spongiform encephalopathies (TSEs) die via
      programmed cell death of which the apoptotic process is relatively well
      characterized. A subcellular alteration linked to apoptosis is the formation of
      autophagic vacuoles, which we and others demonstrated in CJD- and scrapie
      affected rodent brains. Autophagy may co-exist with apoptosis or may precede it
      and the process may be induced by apoptotic stimuli. Here, we extend these
      observations using different model of scrapie and CJD. Both scrapie models (the
      263K and 22C-H) demonstrated autophagic vacuoles with the same frequency; hence,
      they will be described together. While the following changes had been observed
      simultaneously in different areas of the same sample, this description is
      organised as if it followed a sequence of events. First, a part of the neuronal
      cytoplasm was sequestrated by concentric arrays of membrane; that part of the
      cytoplasm closed by membranes appeared relatively normal but its density often
      appeared increased. Next, electron density of the central dramatically increased.
      Then, membranes proliferated within the cytoplasm in a labyrinth-like manner and
      an area sequestrated by these membranes enlarged and became more complex
      structure consisting of vacuoles, electron-dense area and areas of normally
      looking cytoplasm connected with convoluted membranes. Finally, a large area of
      the cytoplasm was transformed into a collection of autophagic vacuoles of
      different sizes. Virtually identical alterations, albeit with much lower
      frequency, were seen in terminally ill CJD-affected hamsters.

PMID- 12416392
TI  - Codon 219 in Creutzfeldt-Jakob disease in Poland.
AB  - Prion diseases are a group of etiologically heterogenous diseases. In addition to
      familial cases linked to mutations of PRNP open reading frame they include also
      cases of unknown etiology. One of the susceptibility factors to sporadic as well
      as iatrogenic prion diseases are PRNP polymorphisms. In the present study, we
      analyzed sequences of the PRNP gene codon 219 of 16 Polish CJD cases and we found
      heterozygous GAG to GAT changes on the sense strand and only wild type sequence
      on an antisense strand. The RFLP technique was used to verify this divergence and
      only wild type sequences were revealed.

PMID- 12416393
TI  - Molecular biology of prions.
AB  - The "protein only" hypothesis holds that the infectious agent causing
      transmissible spongiform encephalopathies is a conformational isomer of PrP, a
      host protein predominantly expressed in brain and is strongly supported by many
      lines of evidence. Prion diseases are so far unique among conformational diseases
      in that they are transmissible, not only experimentally but also by natural
      routes, mainly by ingestion. The pathway of prions to the brain has been
      elucidated in outline. A striking feature of prions is their extraordinary
      resistance to conventional sterilisation procedures, and their capacity to bind
      to surfaces of metal and plastic without losing infectivity. This property, first
      observed in a clinical setting, is now being investigated in experimental
      settings, both in animals and in cell culture.

PMID- 12416394
TI  - Variant Creutzfeldt-Jakob disease.
AB  - Variant Creutzfeldt-Jakob disease is caused by the transmission of bovine
      spongiform encephalopathy to humans. The clinical and investigative features of
      variant CJD are relatively distinct from sporadic CJD. The number of cases of
      vCJD are increasing with time in the UK, but the total future number of cases of
      vCJD is uncertain.

PMID- 12416395
TI  - Neuropathology of variant Creutzfeldt-Jakob disease.
AB  - The clinical, neuropathological genetic and biochemical features of variant
      Creutzfeldt-Jakob disease (vCJD) are compared to the 926 other cases of suspected
      CJD referred to the National CJD Surveillance Unit laboratory from 1990-2001.
      Histological studies of the central nervous system, lymphoid tissues and other
      organs were accompanied by immunocytochemistry for prion protein (PrP); Western
      blot analysis of PrPRES was performed on frozen brain tissue. The pathology of
      vCJD showed relatively uniform morphological and immunocytochemical
      characteristics, with PrP accumulation in lymphoid tissues, but not in other non
      neural tissues. PrPRES accumulation in vCJD showed a uniform glycotype pattern
      distinct from sporadic CJD. All cases of vCJD were methionine homozygotes at
      codon 129 of the PrP gene. In view of the spread of bovine spongiform
      encephalopathy in Europe and Japan, continuing surveillance is required for all
      forms of CJD, with histological and biochemical analysis of suspected cases to
      allow an accurate laboratory diagnosis.

PMID- 12416396
TI  - Bovine spongiform encephalopathy. Update.
AB  - Bovine spongiform encephalopathy (BSE) is a zoonosis being the origin of variant
      Creutzfeldt-Jakob disease and an important cattle disease in its own right.
      Countries have been slow to learn the importance of protecting, not only their
      cattle populations, but also their human populations. Since 2000, several
      additional European countries have reported BSE in native-born stock and this has
      led to a concern about the BSE status of countries that have imported cattle and
      cattle products from infected countries. Extensive feed and offal bans and
      application of newly-developed, 'Rapid' tests for prion protein in central
      nervous tissue of targeted, high-risk animals and slaughter cattle over 30 months
      old now provides the tools whereby the public are fully protected and BSE can be
      eradicated.

PMID- 12416397
TI  - Prion diseases: a dual view of the prion hypothesis as seen from a distance.
AB  - We review the historical background and principles of the prion theory in its
      current shape. We showed that most of data may be still interpreted dually
      according to the protein only hypothesis and according to the theory in which
      additional component is necessary to comprise the infectivity. The enormous
      impact of structural biological studies is also stressed.

PMID- 12416398
TI  - Lessons learned. Implementing a clinical information system can offer a rich
      education.

PMID- 12416399
TI  - 10 IT innovators. Key players use teamwork and creativity to make their visions
      into accomplishments.

PMID- 12416400
TI  - Claiming the future. Clearinghouses are working to reinvent themselves for
      tomorrow's market.

PMID- 12416401
TI  - Strength in numbers. Healthcare IT collaboratives are making connections that
      offer advantages to everyone.

PMID- 12416402
TI  - The goal of uptime. With the right framework, you can fashion a guaranteed system
      availability contract that works for you.

PMID- 12416403
TI  - HIPAA's proposal for claims attachments. Healthcare providers must comment to the
      Feds to balance some payers.

PMID- 12416404
TI  - Cashing in on technology's dividends. Embracing HIPAA can shift administrative
      dollars to patient care.

PMID- 12416405
TI  - Better ambulatory care with IT. A custom-made ambulatory information system at
      Harbor-UCLA Medical Center offers physicians several important capabilities.

PMID- 12416406
TI  - Securing the corporate network. With advanced open business connection solutions,
      you don't have to worry when your data leaves the nest.

PMID- 12416407
TI  - Don't mess with mother nature. Vertical solutions have evolved for a reason.

PMID- 12416408
TI  - Escapist medicine.

PMID- 12416409
TI  - The elephant in the room.

PMID- 12416410
TI  - Is discounting fees fraudulent?

PMID- 12416411
TI  - Great guide to error reduction.

PMID- 12416412
TI  - New ICD-9 codes take effect this month.

PMID- 12416413
TI  - Medicare payment increases expected, Rx drug benefit less certain.

PMID- 12416414
TI  - Why I love my EMR.

PMID- 12416415
TI  - 10 reasons to be a self-employed family physician and 10 ways to do it.

PMID- 12416416
TI  - Understanding the physician liability insurance crisis.

PMID- 12416417
TI  - Rethinking refills.

PMID- 12416418
TI  - Good medicine: E-prescribing.

PMID- 12416419
TI  - This is not your parents' security system. Defining user roles and creating audit
      trails in a HIPAA-compliant system are two critical steps to successful
      compliance.

PMID- 12416420
TI  - Intelligent solutions for radiology data management and storage.

PMID- 12416421
TI  - Technology's impact on reducing medication errors. At Danville Regional Medical
      Center, not a single medication is administered without the benefit of bar code
      verification technology.

PMID- 12416422
TI  - Setting a new standard. A standardized approach to ERP saves a Michigan-based
      hospital $4 million in the first year.

PMID- 12416423
TI  - Taking the next step. A Florida hospital transitions to a Web-enabled
      infrastructure based on distributed processing and improves business efficiency.

PMID- 12416424
TI  - A new "cop" on a new beat. The state of Ohio takes giant steps toward helping
      physicians receive full and timely payer reimbursements with "Prompt Payment
      Robocap".

PMID- 12416425
TI  - Wireless for all. A small community hospital successfully faces the challenge of
      implementing an enterprise-wide wireless infrastructure while installing a new
      HCIS.

PMID- 12416426
TI  - Calm during crisis. Pennsylvania hospital averts IT catastrophe by following its
      comprehensive disaster recovery plan--assisted by a little on-the-spot ingenuity.

PMID- 12416427
TI  - IT outsourcing secures confidentiality. Healthcare provider of long-term care
      services enables remote access and saves money doing it.

PMID- 12416428
TI  - What works. Dictate this. Speech recognition brings workflow improvements and
      cost savings to a Florida-based hospital.

PMID- 12416429
TI  - What works. Three's company. When a Texas radiology group outsourced to an IT
      consultancy and a data center, it was the prescription for IT success.

PMID- 12416430
TI  - PACS/radiology/imaging hotlist.

PMID- 12416431
TI  - The changing face of outsourcing.

PMID- 12416432
TI  - Point and bet. Internet gambling's explosive growth has made it the Web's killer
      app. Now critics are trying to pull the plug.

PMID- 12416433
TI  - The great salmon debate.

PMID- 12416434
TI  - The sachems of Satan. A new theory to explain the Salem witchcraft crisis.

PMID- 12416435
TI  - Close, but no cigar. The Vatican pushes back the U.S. plan on sex abuse.

PMID- 12416437
TI  - China's coal addiction.

PMID- 12416438
TI  - Just shocking!
AB  - Electrical shock injuries can be fatal. Rescues of electrical shock victims also
      can be fatal if not handled correctly. Using "best practices" at work (and at
      home) will reduce the risk of an event from ever occurring and prevent the
      injury. Do not attempt to touch someone in contact with an electrical source.
      Shut off the power first, then attempt the rescue. Immediately call for emergency
      assistance. Always look for life-threatening conditions first, then treat any
      wounds. Always look for two external wounds and cover with dry dressing. Continue
      to monitor the patient for breathing and heart rate. Transport the patient to a
      medical facility as soon as possible. Each of us has the ability to choose how we
      perform an assigned task. You do have control over your work environment.
      Exercise that control and choose wisely to stay alive!

PMID- 12416439
TI  - Choosing the safest protective lighting option.

PMID- 12416440
TI  - Who needs doctors?

PMID- 12416441
TI  - The secret sacrifice. To get help for their mentally ill children, some parents
      have to give them up.

PMID- 12416442
TI  - What makes us do it? In the age-old debate of nature vs. nurture, an M.I.T. prof
      says our genes don't get enough respect.

PMID- 12416443
TI  - Sleuth without a badge.

PMID- 12416444
TI  - Shakin' all over. Belly dancing has its roots in the ancient world, but its
      merits are being discovered by modern women.

PMID- 12416445
TI  - Sex and the serious cyclist. Can prolonged bicycling put enough pressure on a
      man's anatomy to cause impotence?

PMID- 12416446
TI  - Dynamics and evolution of HIV-1 during structured treatment interruptions.
AB  - Our understanding of the way in which HIV responds to highly active
      antiretroviral therapy (HAART) has benefited greatly from the use of mathematical
      models of viral dynamics and evolution. In this paper, I review the role that
      these models may play in the design and analysis of studies of structured
      treatment interruptions (STIs). STIs are being investigated in several different
      contexts: to reduce drug toxicities; to boost HIV-specific immune responses; and
      to allow reversion of drug resistance mutations in highly drug-experienced
      patients. I illustrate how models can help to compare the dynamics and evolution
      of HIV in these different scenarios, and to assess the risks and benefits of
      STIs.

PMID- 12416447
TI  - NNRTI plus PI combinations in the perspective of nucleoside-sparing or nucleoside
      failing antiretroviral regimens.
AB  - Although not yet recommended, regimens combining both a non-nucleoside reverse
      transcriptase inhibitor (NNRTI) and protease inhibitors (PI) can be used as first
      line therapy, or as second-line or salvage therapy in patients who need to change
      antiretroviral treatment because of nucleoside reverse transcriptase inhibitors
      (NRTI) intolerance or virological failure with resistance to NRTI. Such
      combinations should not be used in patients infected with HIV-1 group O and HIV
      2, due to the natural resistance to NNRTI of these subtypes. Dual NNRTI and PI
      combinations used as first-line therapy allow to spare NRTI, leaving a fully
      active class of drugs for later use, and delaying the risk of toxicity related to
      NRTI exposure, particularly mitochondrial toxicity. Several studies have shown
      that adding a NNRTI improves the efficacy of a second-line or salvage therapy
      based on a new combination of PI(s) and new or recycled NRTI(s). A possible
      explanation for the efficacy of NNRTI-containing regimens in NRTI-pretreated
      patients is that mutations conferring resistance to NRTI can increase the
      susceptibility of the viruses to the NNRTI. However, the decision to use a NNRTI
      in a salvage regimen needs to be weighed against the concern that subsequent
      failure will exhaust therapeutic options with any compound of this class, due the
      large degree of cross-resistance between the three available NNRTI. NNRTI and PIs
      are extensively metabolized in the liver through cytochrome P450, leading to
      pharmacokinetic interactions. The decrease in PIs plasma concentrations observed
      when they are combined with nevirapine or efavirenz is reduced when low doses of
      ritonavir, which strongly inhibits cytochrome P450, are associated with the
      combination of PI and NNRTI.

PMID- 12416448
TI  - Update on mitochondrial toxicity of antiretrovirals and its link to
      lipodystrophy.
AB  - The dramatic improvement seen in the latest years in the prognosis of HIV
      infection has been threatened by long-term toxicities of antiretroviral drugs.
      Nucleoside analogs remain the cornerstone of antiretroviral therapy, but these
      compounds seem to produce mitochondrial damage leading to a broad range of side
      effects, which depend of the organ/tissue affected. Among those toxicities are of
      particular concern lipoatrophy and hyperlactatemia syndromes. This review will
      focus on the pathogenesis of mitochondrion damage caused by nucleoside analogs
      and its clinical consequences, particularly in respect to body-shape changes.

PMID- 12416449
TI  - Genotypic drug resistance interpretation systems--the cutting edge of
      antiretroviral therapy.
AB  - The technical quality of genotypic and phenotypic drug resistance testing has
      considerably improved, and therefore the major challenge now lies in the
      interpretation of drug resistance. This is due to several facts: (i) in times of
      combination therapy, the effect of drug resistance-associated mutations cannot be
      considered independently, (ii) many additive and subtractive interactions between
      mutations exist, and resistant strains may exhibit varying degrees of cross
      resistance, (iii) the phenotype cannot adequately determine slight, but
      clinically relevant, differences for those drugs with a narrow range of
      resistance, and (iv) pharmacokinetic interactions may shift relevant levels of
      drug resistance. Genotypic drug resistance interpretation systems are designed to
      solve these problems. Rule-based systems incorporate current knowledge about
      correlations between genotype, phenotype and clinical response. Database-driven
      systems use the information provided by paired geno- and phenotypic data,
      applying database matching search or bioinformatic approaches. For detailed
      comparison, 11 interpretation systems were selected which present a comprehensive
      system for most of the available drugs, can easily be accessed via the Internet
      and are regularly updated. The systems were characterized for the source data,
      access, input, output, and availability of clinical studies. For further
      comparison, existing clinical databases should be merged into one large database
      to allow competition between the systems. This may also solve the burning problem
      of clinically relevant cut-offs. Head-to-head comparisons of interpretation
      systems require large prospective randomized trials in which only the
      interpretation system is different between groups, before a consensus can be
      achieved for the best antiretroviral therapy of the individual patient.

PMID- 12416450
TI  - Immune restoration after treatment of HIV-1 infection with highly active
      antiretroviral therapy (HAART).
AB  - The availability of combination antiretroviral therapy (HAART) has been
      associated with dramatic decreases in HIV-related morbidity and mortality. These
      clinical benefits are probably mediated by a decrease in HIV-1 replication and an
      increase in the number and function of peripheral blood CD4+ lymphocytes. Despite
      many years of maintaining plasma HIV-1 RNA levels below the limits of detection,
      many patients do not achieve normal CD4+ lymphocyte counts. A larger proportion
      of patients who delay HAART for longer have incomplete numerical CD4+ restoration
      compared to patients who start therapy earlier. Even in patients who normalize
      their CD4+ lymphocytes insert counts, immune function remains impaired among
      those who delay HAART for longer periods. Whether subclinical immune deficiency
      will be associated over longer periods of follow-up with adverse clinical
      outcomes such as an increased number of infections and malignancies remains to be
      determined. If prolonged subclinical immunodeficiency is associated with adverse
      outcomes, the use of immune-based therapies may benefits patients while helping
      us ascertain the residual deficits responsible for incomplete immune restoration.

PMID- 12416451
TI  - Impact of tuberculosis on HIV-1 replication, diversity, and disease progression.
AB  - HIV and Mycobacterium tuberculosis not only co-circulate throughout the
      developing world but each has contributed to prevalence and mortality caused by
      the other. Several reports have described how HIV-1 increases the incidence of
      new M. tuberculosis infections, exacerbates the severity of tuberculosis (TB),
      and re-activates latent M. tuberculosis. However, the converse relationship is
      more difficult to understand considering TB can emerge in asymptomatic
      individuals and as an opportunistic infection during AIDS. Development of TB in
      HIV infected individuals with higher CD4 cell counts (> 200/mm3) appears to
      increase the rate of disease progression and mortality. Higher viral loads,
      increased HIV-1 diversity, and changes in cytokine/chemokine levels in HIV
      infected individuals with TB appear to be related to a localized immune
      stimulation. Specifically, increased levels of TNF alpha and MCP-1, induced by
      TB, may activate HIV replication in lymphocytes, monocytes, and macrophages that
      are resident or have migrated to M. tuberculosis infected organs (e.g. pleura or
      lung). The HIV-1 found in blood following this TB-mediated burst in load and
      diversity appear to be phylogenetically-related to HIV-1 clones that have evolved
      independently in the lung or pleural compartments, now infected by M.
      tuberculosis.

PMID- 12416452
TI  - Patients must be responsible.

PMID- 12416453
TI  - Insurance. California, here we come.
AB  - In 1975, California modified its tort laws to cap jury awards in certain health
      care cases: The result: insurance premiums have been stable there, unlike those
      in the rest of the country. Is this a model for the rest of the nation to follow?

PMID- 12416454
TI  - Nurses. Plugged in.
AB  - Infrared technology allows hospitals to keep track of where their nurses are.
      Hundreds of hospitals use such systems--but some nurses say that they violate
      their privacy.

PMID- 12416455
TI  - Disease management. Coach's assist.

PMID- 12416457
TI  - Physician order entry. IMKI to success. Institute for Medical Knowledge
      Implementation.

PMID- 12416456
TI  - Minorities and health care. Equal access for all.
AB  - At this point the research is clear: even accounting for case-mix load and other
      variables, minorities still receive lower-quality care than whites do. Some
      hospitals are seeking to make sure that doesn't happen at their institutions.

PMID- 12416458
TI  - Workforce. Code blue.

PMID- 12416459
TI  - 1Q[3a]. When will hospitals feel the baby boomer effects?

PMID- 12416460
TI  - Middle managers matter.

PMID- 12416461
TI  - Forward motion. Interview by Mary Grayson.
AB  - David L. Bernd, CEO of Sentara Healthcare, Norfolk, Va., believes that with
      active, involved leaders health care can confront many of its most daunting
      challenges, and he sees opportunities in innovations now emerging. In this
      article, the new chair-elect of the American Hospital Association discusses the
      current state of health care and his hopes for its future.

PMID- 12416462
TI  - Planetree (25 years older).
AB  - "Patient-centered care" sounds like the slogan for an era in which consumers are
      taking more responsibility for their health care choices. In fact, it has been
      the foundation of the Planetree Model since 1978, when disenchantment with the
      hospital experience led to a philosophy that puts patients first. Twenty-five
      years later, Planetree-affiliated hospitals say the payoff is significant in
      terms of patient and staff satisfaction, and the bottom line.

PMID- 12416463
TI  - Keeping nurses. How one hospital and two systems cured their staffing ills.
AB  - The nurse shortage is threatening to reach crisis proportions for hospitals
      around the nation. But one hospital and two health care systems have virtually
      eliminated their nurse vacancy rates through strategies that respect and energize
      their nursing staffs.

PMID- 12416464
TI  - Contract management survey 2002.
AB  - Spending on clinical contracts continues to outpace spending on business
      services, but may be leveling off. The 12th annual Contract Management Survey
      shows that the performance of clinical vendors is now comparable to business
      service vendors in meeting savings targets. Both business and clinical vendors
      are receiving higher marks from hospital leaders, but execs quickly respond to
      low marks by bringing the service back in-house of changing vendors. This report
      examines trends in outsourcing, satisfaction levels, the decision-making process,
      contract features and performance, and spending.

PMID- 12416465
TI  - Staying power. Community health initiatives face financial pressure, but they are
      hanging on.

PMID- 12416466
TI  - Benefits and menaces related to the use of statins in patients after renal
      transplantation.
AB  - Hypercholesterolemia in patients after renal transplantation composes a
      significant risk factor of cardio-vascular disease, it may also worsen graft
      survival. Statins are the most potent drugs to lower blood cholesterol. They also
      posses numerous pleiotropic abilities. The paper presents benefits of the use of
      statins in patients after renal transplantation, as well as the dangers related
      to the side effects of these drugs. It underlines that adequate use of statins is
      worth considering in patients after renal transplantation, taking into account
      not only their ability to lower cholesterol but also their additional properties
      positively influencing graft survival.

PMID- 12416467
TI  - Atrial resynchronization in patients after heart transplantation.
AB  - Lower-Shumway technique (atrioatrial anastomosis) is the most frequently used
      technique for orthotopic heart transplantation and such a patient has two right
      atria and two sinus nodes. Sinus node dysfunction (SND) is a frequent finding in
      pts. after OHT; taking advantage of the frequency of innervated sinus node of
      recipient's atrial remnant as a natural biosensor for triggered pacing of donor
      atrium is an interesting option for these pts. THE AIMS OF OUR STUDY: 1. the
      analysis of possibility of utility of recipient atrial sinus node as natural
      biosensor for triggered donor atrium permanent pacing in transplanted patients
      with SND. 2. the evaluation of pacing and sensing conditions of the recipient's
      atrium in the some pts.. 3. long-term observation of effectiveness A2A2T(/D)
      pacing mode. METHODS: 10 out of 37 pts. received A2A2T (8 pts.) and A2A2T/D (2
      pts) pacing systems. In pts. with NSR of recipients atrium, we evaluated
      acceleration of its frequency during slight exercise and atropine. RESULTS: In
      recipient's atrium among 37 pts we recognized NSR only in 15/37 pts.; in the
      remaining 22 pts. we found: sinus bradycardia--in 3, atrial flutter--in 3, low
      voltage AF--in 12 and no electrical activity--in 4 pts. Positive response to
      isometric exercise and atropine was observed in 12/15 pts. and 8 of them received
      A2A2T or A2A2T/D pacing system. We found much better sensing and pacing
      conditions in donor (A wave 2.1 mV, p. threshold 0.8 V) than in recipient atrium
      (1.1 mV and 1.4 V respectively). We observed some problems with sensing of
      recipient atrium in 4 of 10 pts. and changes SST to AAI-R mode solved the problem
      without loss of atrial resynchronization. 9 out of 10 pts. preferred AAT to AAI-R
      pacing program. One dislodged lead required revision during postoperative period
      (1/44, 2%). There was no dislodgement related to endomyocardial biopsy. In one
      patient, atrial flutter in recipient atria was transmitted to atrium of
      transplanted heart by pacing system with 2:1 conduction; arrhythmia was
      interrupted with drugs and did not return. CONCLUSIONS: 1. Atrial
      resynchronization is possible only in about 1/4 patients with SND after OHT due
      to frequently noted electrophysiological changes in recipient atrium. 2. In
      transplanted heart patients sensing and pacing conditions are much more favorable
      in donor's than recipient's atrium. 3. Atrial resynchronization can be
      subjectively (positively) recognised by most of patient after OHT and it still
      remains a promising pacing mode for selected patients after OHT with SND.

PMID- 12416468
TI  - Atrial pacing of transplanted heart.
AB  - Orthotopic heart transplantation (OHT) is most effective method for treatment of
      irreversible heart failure. Patients after OHT considered for permanent pacing
      consist still present a challenge for the implanting physician due to distorted
      atrial geometry and specific electrophysiological conditions of atrium. The aim
      of our study was to analyse the effectiveness of permanent atrial pacing in these
      patients. PATIENTS AND METHODS: We implanted atrial lead in 37 SND pts., 2 months
      -7 years after OHT, (3 pts with coexisting AV block received ventricular lead).
      Only straight BP screw-in leads and manually formed stylets were used; we found
      satisfactory pacing/sensing conditions in 25 pts in RA appendage or
      anterior/lateral wall, in 10 pts--in CS ostium region and in 2--in proximal part
      of CS. RESULTS: All implantations were successful and no patient received VVI
      pacing system. One dislodged lead required revision (1/37, 3%) but this was not
      related to endomyocardial biopsy. In 2 pts, due to unacceptable low RA potential
      and/or high PTh values atrial lead was implanted to CS for sensing/pacing of left
      atrium. The average acute value of A wave were 2.4 mV and chronic 2.2 mV; values
      of pacing threshold were 0.9 V and 1.6 V respectively. Only in 13/37 pts native A
      waves were recorded but with amplitude < 0.6 mV. Wenckebach point was 120/min
      only in 2 pts., in borders 130-160 bpm in 15 pts. and exceeded 170 bpm. in
      remained 20 pts. Retrograde VA conduction was intact in 33/37 pts, but in 4 pts
      exceeded 260/min. During long term follow-up in no patient we observed AV
      conduction disturbances. In 6 pts. treadmill exercise (Bruce's protocol) was
      repeated three times during: sinus (spontaneous) rhythm, AAI pacing 70/min, AAI-R
      (DDD-R) pacing. AAI 70 bpm did not influence significantly attained workload,
      heart rate on peak exercise or duration of exercise. But atrial rate modulated
      pacing increased values of examined parameters significantly. CONCLUSIONS: 1.
      Atrial pacing (and atrial based pacing modes) are possible in majority of
      transplanted heart patients. 2. Frequency of atrial lead dislocation, appearance
      of atrial sensing problems and AV conduction disturbances (all in about 3%) are
      comparable to non-transplanted patients. 3. In most patients with SND after OHT
      AV conduction remains within normal limits; it indicates safety of rate
      responsive pacing modes in these patients. 4. Rate modulated atrial pacing
      improves exercise tolerance in heart transplanted patients with SND. 5. High
      ("supra-normal") values of Wenckebach's point observed in most of patients with
      transplanted (dennervated) heart may have clinical importance in cases of atrial
      arrhythmias in these patients.

PMID- 12416469
TI  - Effect of L-arginine on oxygen consumption and haemodynamic function of rat's
      heart exposed to cold cardioplegic ischaemia and reperfusion.
AB  - BACKGROUND: Ischaemia--reperfusion damage causes injury of all heart cells. Loss
      of endothelium function and biologically active substances secreted by it can be
      essential to development of the damage. Ischaemia and reperfusion decreases the
      release of nitric oxide, which influences postischaemic coronary flow and return
      of ventricular function. Administration of L-arginine to cardioplegic and
      reperfusion solution can improve protection of heart and cause the return of left
      ventricular function after hypothermic ischaemia through preservation of
      endothelial cell functions and increase of release of nitric oxide. OBJECTIVE:
      How addition of L-arginine to cardioplegic solution influences oxygen consumption
      by myocardium and its postischaemic haemodynamic function. METHODS: The research
      was conducted on isolated heart model of 56 rats, divided into seven equal
      groups. The hearts were prepared with modified Neely method and were perfused
      with the use of apparatus in accordance with modified Langendorf method. The
      research was carried out in the following order: initial perfusion of the non
      working and working heart, perfusion with cardioplegic solution, cold
      cardioplegic arrest and reperfusion of the non-working heart. RESULTS: During
      initial perfusion, oxygen consumption was comparable in all groups. During
      cardioplegic perfusion, oxygen consumption was reduced in every group. At the
      time of reperfusion of non-working heart model, consumption of oxygen was
      increased. During reperfusion of the working heart, the lowest oxygen consumption
      was noted in group P, the highest in group DI. The decrease in cardiac output
      during postischaemic period was noted in control group and groups where L
      arginine was added to reperfusion solution. CONCLUSION: Addition of L-arginine to
      cardioplegic solution significantly decreases oxygen consumption by myocardium. L
      arginine added to cardioplegic solution improves postischaemic haemodynamic
      function of heart.

PMID- 12416470
TI  - Pituitary function test and endocrine status in patient with cirrhosis of the
      liver before and after hepatic transplantation.
AB  - OBJECTIVE: Hormonal alterations caused by chronic liver disease are well
      described. In contrast, the reversibility of peripheral hormonal changes after
      orthotopic liver transplantation (OLT) has only partially been analyzed since the
      establishment of OLT as treatment of chronic hepatic failure. In addition it is
      not finally verified if chronic liver failure and especially hepatic
      encephalopathy also affect pituitary function. We therefore performed extensive
      endocrine studies including a global pituitary stimulation test before and after
      liver transplantation. METHODS: 22 patients with chronic alcoholic and non
      alcoholic liver failure were included in this prospective study. Basal hormone
      values (ACTH, cortisol, FSH, GH, IGF-I, LH, oestradiol, PRL, thyroid hormones and
      testosterone) were measured before and up to 5 years after OLT. Furthermore all
      patients underwent pituitary function tests with application of GRF, TRH, GnRH,
      and CRF before, 3 weeks and 3 months after OLT. RESULTS: Estradiol, LH and FSH
      increased significantly in postmenopausal and only slightly in premenopausal
      female patients after OLT. Total testosterone revealed no marked changes and was
      normal before and up to five years after OLT in male patients. After stimulation
      with GnRH the LH response in females and the FSH response in males was
      significantly higher three months after OLT than pretransplant. LH response in
      males and FSH response in females was only slightly higher after OLT. Peripheral
      IGF-I was low and growth hormone was elevated in all patients prior OLT. Growth
      hormone declined significantly three months afterwards. The response to GRF was
      highest prior OLT and decreased afterwards. Prolactin values were normal prior
      and post OLT. After stimulation with TRH prolactin values in male patients were
      significantly higher before OLT than afterwards. CONCLUSION: In the observed
      relatively small number of patients gross pituitary function in chronic liver
      failure remained intact, whereas slight alterations in several axis were found.
      These pituitary alterations are presumably only partially caused by feedback
      mechanisms. Both a normalisation of peripheral endocrine parameters and pituitary
      function were achieved by OLT despite significant alterations pretransplant.

PMID- 12416471
TI  - High intensity regimens with autologous hematopoietic stem cell transplantation
      as treatment of multiple myeloma.
AB  - The treatment of multiple myeloma still remains under investigation. Conventional
      chemotherapy with currently used agents (i.e., Melphalan) effects complete
      remission in no more than 5% of patients. High dose chemotherapy followed by
      hematopoietic stem cells transplantation results in complete remission rates
      between 25% and 75% and a 3-year probability of event-free survival between 40%
      and 60% but is not curative since most patients relapse after 1.5 to 3 years.
      Therefore, it becomes the treatment of choice for multiple myeloma. The drugs
      used in high dose therapy include: high dose melphalan (200 mg/m2) as single
      agent., melphalan (140 mg/m2) and total body irradiation (TBI), Busulfan and
      melphalan... etc. The use of the peripheral blood stem cell transplantation has
      allowed a reduction in the toxicity of high-dose regimens, but has not led to an
      increase in the overall response rate or survival. Hematopoietic stem cells from
      peripheral blood are preferred for transplantation because they restore
      hematopoiesis more rapidly than do bone marrow cells and the numbers of tumor
      cells are lower in peripheral blood than bone marrow cells. Peripheral blood stem
      cell transplantation was associated with significant reduction in the duration of
      aplasia and transfusion requirements. Several regimens have been proposed for
      stem cells mobilization including: High-dose cyclophosphamide and G or GM-CSF, G
      CSF alone, and cyclophosphamide and etoposide with G-CSF... ect.. Further
      attempts to improve the results of autotransplantation have included
      intensification with tandem transplantations (double transplants) and reduction
      of tumor cells in stem cell infusion. The aim of this review is to summarize the
      current knowledge about the treatment of multiple myeloma with high dose
      chemotherapy with autologous hematopoietic stem cell transplantation.

PMID- 12416472
TI  - First kidney transplantation from a non-heart-beating donor in the Czech
      Republic.
AB  - The long-lasting decline in the number of kidney donors with brain death in
      recent years is the reason for a quest for new sources of kidney donors in the
      Czech Republic. One possible source to increase the number of donor kidneys is
      the program of obtaining kidneys from non-heart-beating donors (NHBDs). Based on
      previous experience abroad, optimum hospital conditions, and, first of all, three
      years of experimental work, it was possible to realise an NHBD program for the
      first time in the Czech Republic, in the Transplant Centre of the Plzen Hospital
      in early 2002. The first two kidneys were obtained from a donor with a
      devastating gunshot brain injury (Maastricht criteria, Class III). After machine
      perfusion (RM3 renal perfusion system, Waters Medical) both kidneys were
      transplanted into two recipients with chronic renal insufficiency (chronic
      glomerulonephritis, nephrosclerosis). Both kidneys resumed their function
      immediately. For immunosuppression, basiliximab (Simulect, Novartis), rapamycin
      (Rapamune, Wyeth), and methylprednisolone (Urbason solubile forte, Hoechst) were
      used. To improve renal function, cyclosporine A (Sandimmune Neoral, Novartis) was
      started later in the course, simultaneously reducing the dose of rapamycin. The
      postoperative course was uneventful and both patients could be discharged on the
      twenty-first day of hospitalisation for further care at home.

PMID- 12416473
TI  - Prolongation of rat kidney graft survival after inoculation of allogeneic spleen
      cells: the effect of various routes of cell transfer.
AB  - OBJECTIVES: It has been clearly demonstrated that after donor-specific cell
      transfer the prolongation of allograft survival can be obtained, but the problem
      of how to inoculate cells remains unresolved. In this study, the effect of either
      portal venous (PV) or systemic intravenous (i.v.) inoculations of rat donor
      specific spleen cells on subsequent renal graft survival was evaluated. METHODS:
      LEW recipients received 10(6) of spleen cells from allogeneic Fischer or
      syngeneic donors 30 days before kidney transplantation by either PV or i.v.
      routes. Animals from the control group obtained buffered saline by the same
      routes. RESULTS: Fischer grafts in nonimmunized LEW recipients were rejected
      after 9.6 +/- 1.3 days. In contrast, the immunization of the recipients by the
      pretreatment with donor spleen cells prolonged renal allograft survival
      significantly (p < 0.002). However, no difference in the graft survival was
      observed between animals inoculated with cells either by PV or by i.v. routes. In
      each studied group, long-time graft survival (> 100 days) was achieved in one
      case. CONCLUSIONS: These observations suggest that the effect of the various
      routes of allogeneic cell inoculations on subsequent organ graft survival time
      depends on the interval between the cell transfer and organ transplantation.
      Intravenous route seems to be as effective as PV route when transplantation is
      performed several days after donor-specific cell transfusion.

PMID- 12416474
TI  - The State of Health Privacy Law. HIPAA vs. New York State Statutes.

PMID- 12416475
TI  - Not interested.

PMID- 12416476
TI  - Foundation unveils anti-smoking posters.

PMID- 12416477
TI  - Dental caries prevalence and treatment need among racial/ethnic minority
      schoolchildren.
AB  - A study was undertaken to estimate dental caries prevalence and treatment need
      among racial/ethnic minority schoolchildren in the Bronx. Oral examinations were
      conducted on 148 second graders, 193 fourth graders and 299 sixth graders in
      three different schools. A single examiner trained to use the DMFS index
      according to National Institute of Dental and Craniofacial Research (NIDCR)
      diagnostic criteria and procedures examined all the children between November
      1999 and July 2000. The study revealed that 39% of the children exhibited dental
      caries experience in their permanent dentition (mean DMFS = 1.45), treatment need
      (D/DMFS = 28%); 26.4% of children in their primary dentition (mean dfs = 1.01)
      and treatment need (d/dfs = 18%). Hispanic children (mean DMFS = 1.71) had higher
      dental caries experience compared to African-Americans (mean DMFS = 1.14). This
      was found to be statistically significant (p = 0.004). Treatment need in
      Hispanics was (30%, 17%) and in African-Americans (30%, 18%) in permanent and
      primary dentition respectively. Treatment need was highest among sixth grade
      African-Americans in their permanent dentition and in second grade Hispanics in
      the primary dentition. The study showed a difference in dental caries prevalence,
      but the treatment need percentages did not differ between Hispanics and African
      Americans in both dentition.

PMID- 12416478
TI  - Clinical education in dentistry. In light of form & content issues.
AB  - Dentistry exists to serve people in need of medical care, with special focus on
      oral and maxillofacial care. In order to perform at the most optimal level in
      today's society, dental practitioners must be attuned to and be able to respond
      to assessed changes in the dental needs of the general population it serves. In
      what other way can the profession of dentistry meet this need unless future
      practitioners are given the education and tools, in light of these changes, to do
      so? With the publication of the Institute of Medicine study on the future of
      dental education in 1995 and the Surgeon General's Report on Oral Health in 2000,
      the need for greater integration and collaboration of dental schools with
      medicine is becoming more apparent. Aside from just expanding the medical content
      of the curriculum, are there ways to enhance the integration of that medical
      knowledge into patient-focused comprehensive care in the clinic? Perhaps lessons
      relating to this question can be gleaned from both the history of dental
      education and from the medical model of student education.

PMID- 12416479
TI  - Utilization of learning styles in dental curriculum development.
AB  - This study addresses the disparity between methods of education and how dental
      students assimilate information. Dental students are adult learners who come into
      professional school with different styles of learning, acquired through many
      years of study. However, these learning styles are not factored into the way
      dental schools educate future dentists. A survey of all four years of predoctoral
      students at Columbia University School of Dental and Oral Surgery (SDOS) was
      conducted to obtain data on different learning styles of dental students and
      their preferred teaching methods. The data was analyzed to identify the
      predominant learning style, through which curriculum changes can be developed to
      provide an optimal learning experience for students.

PMID- 12416480
TI  - FDA OK's two drugs for irritable bowel syndrome. The arsenal of IBS drugs is
      growing, but diagnosis is tricky.

PMID- 12416481
TI  - West Nile virus: time for prevention, not panic. As the virus spreads, the risk
      of severe illness remains low.

PMID- 12416482
TI  - Who needs growth hormone therapy? Growth hormone helps some, but its use as an
      "anti-aging" agent is dubious.

PMID- 12416483
TI  - Good and bad news about vitamin E.

PMID- 12416485
TI  - Obesity surgery: is less invasive better?

PMID- 12416484
TI  - Weighing in on water.

PMID- 12416486
TI  - Botox helps stroke recovery.

PMID- 12416487
TI  - Potassium, diuretics, and stroke.

PMID- 12416488
TI  - Niacin seems OK for people with diabetes.

PMID- 12416489
TI  - Walking or vigorous exercise: what works?

PMID- 12416490
TI  - Alcohol's benefits, risks may be age-dependent.

PMID- 12416491
TI  - BP drug approved for heart failure.

PMID- 12416492
TI  - I've read that earwax buildup can impair hearing. How can I safely get rid of
      excess earwax?

PMID- 12416493
TI  - What is thrush, and how is it treated?

PMID- 12416494
TI  - Stirring up helpful bacteria.

PMID- 12416495
TI  - Conquering claustrophobia during your MRI.

PMID- 12416496
TI  - Easing through menopause without HRT.

PMID- 12416498
TI  - Is there a benefit to hormone replacement in men?

PMID- 12416497
TI  - Recognizing a headache that's truly dangerous.

PMID- 12416499
TI  - [Physicians and medical visitors...evolution of a relationship].

PMID- 12416501
TI  - [Health structures and hygiene in Lebanese prisons].
AB  - Since the end of the civil war in Lebanon (1991), the jailed population has more
      than doubled, while the real capacity of jails remained the same as in the 70s. A
      cross-sectional survey was conducted in 1999 in all 17 jails then operating in
      the country, to evaluate the impact of this newly developing situation regarding
      the structures of hygiene and health services available to prisoners. The stated
      objectives of this survey were: 1) To identify structural problems; 2) To
      appreciate those variables affecting the structures which could be modified; 3)
      To recommend improvement in health conditions in jails The survey included a
      visit to each jail to evaluate the health structures and services using a
      standardized check-list, and to interview the jail director. Results indicated
      that health conditions in jails were inadequate. Each prisoner had 1.3 m2 of
      personal space on average, in cells most often overcrowded. There were 1.3
      shower/100 prisoners on average, with soap and toilet paper rarely provided by
      the administration. On average, less than 2 general practitioners were found
      providing about 3 weekly visits per 100 prisoners. Possible interventions
      involving various social entities were discussed.

PMID- 12416500
TI  - [Augmentation cystoplasty and/or continent urinary diversion. Review of eleven
      cases].
AB  - Urinary incontinence secondary to neurogenic or malformafive bladders is a major
      problem influencing social insertion and has been totally transformed by bladder
      augmentation associated to continent urinary diversion as described by
      Mitroffanof. We present our experience in eleven cases and try to emphasize on
      three major points. Combining urinary continent diversion to bladder augmentation
      guarantees optimal urinary continence. Concomitant bladder neck closure is not
      necessary to obtain urinary continence; on the contrary, it eliminates a useful
      pop-off mechanism. Neocystoureterostomy is not requested for every refluxing
      ureter unless it could be realized on the original bladder.

PMID- 12416502
TI  - [Asthma in children: recent comments and management].

PMID- 12416503
TI  - [Parathyroid adenoma localized in the mediastinum. Case report and review of the
      literature].
AB  - In the primary hyperparathyroidism the vast majority of enlarged parathyroid
      glands may be excised by cervicotomy. Rarely the excision of ectopic mediastinal
      parathyroid adenoma, not accessible by cervical incision, necessitates another
      approach for parathyroidectomy. We report herein the case of primary
      hyperparathyroidism due to mediastinal adenoma treated by sternotomy with review
      of the literature for different modalities of treatment for mediastinal
      localization.

PMID- 12416504
TI  - The origin of a most contentious rock.

PMID- 12416505
TI  - The search for an amyloid solution.

PMID- 12416506
TI  - Retraction.

PMID- 12416507
TI  - Low and very low birth weight after use of assisted reproductive technology.

PMID- 12416508
TI  - Flu vaccine is safe for asthmatics, study finds.

PMID- 12416509
TI  - Stress management helps control glucose in type 2 diabetics.

PMID- 12416510
TI  - Nursing homes lack systematic approach to guideline implementation.

PMID- 12416511
TI  - Failed depression CQI project yields important lessons.

PMID- 12416512
TI  - Seventeenth Annual Meeting of the American Society of Hypertention, Neww York,
      NY, May 14-18, 2002.

PMID- 12416513
TI  - DHHS survey shows shortage of nurses.

PMID- 12416514
TI  - Census Bureau profiles foreign-born and first-generation U.S. residents.

PMID- 12416515
TI  - On the other side of the OR doors.

PMID- 12416516
TI  - [Effectiveness of various whitening techniques and their effects on the enamel
      surface].
AB  - The objective of this in vitro study was to compare three different bleaching
      techniques with respect to the bleaching times required to achieve six grades of
      whitening in human teeth, i.e. from shade A4 to A3 of the VITAPAN classical shade
      guide. Additionally, the enamel surfaces were analyzed by SEM after each
      bleaching procedure to detect potential surface changes. A total of 24 anterior
      teeth extracted for periodontal reasons (baseline shade A4) were randomized to
      three different bleaching treatments (n=8): Group A Illumine home (home-bleaching
      technique); group B Whitestrips (over-the-counter technique); and group C
      Opalescence Xtra (in-office technique). The bleaching cycles were carried out
      according to the manufacturers' instructions, with one bleaching cycle taking
      eight hours for product A, 30 minutes for product B, and 15 minutes for product
      C. The mean treatment time required to achieve a defined shade (A3) was 6.88
      cycles (=3300 minutes) in group A, 36.25 cycles (=1087 minutes) in group B, and
      4.25 cycles (63.75 minutes) in group C. None of the teeth studied showed
      detectable surface changes in the subsequent SEM (2000 X) analysis of the enamel
      surface. In this in vitro study all three techniques studied resulted in the
      desired tooth whitening within the recommended application time periods, and none
      of the three products tested created any detectable enamel surface changes.

PMID- 12416517
TI  - [The role of the pediatrician in prenatal care. Example of the fetal neurological
      consultation].

PMID- 12416518
TI  - Bibliography. Current world literature. Myositis and myopathies.

PMID- 12416519
TI  - Bibliography. Current world literature. Raynaud's phenomenon, scleroderma,
      overlap syndromes and other fibrosing syndromes.

PMID- 12416520
TI  - [Seborrheic dermatitis of infancy].

PMID- 12416521
TI  - User rights and the frail aged.
AB  - There is a growing acceptance of user rights models with regard to dependent
      populations such as nursing home residents, but classic theories of rights
      presuppose levels of human rationality and human agency often lacking in the case
      of highly dependent populations. While user rights models have strong advantages
      at a rhetorical level, the reduced capacity for dependent groups to assert their
      rights constitutes a significant limitation. Policies, practices and regulatory
      strategies developed on the assumption that very dependent groups can indeed
      assert such rights thus proceed on a premise which is fatally flawed.

PMID- 12416522
TI  - [2nd International Symposium on Sport Dentistry and Dental Trauma. Bern. 28-30
      June 2002].

PMID- 12416523
TI  - Util-izing animals.
AB  - Biomedical experimentation on animals is justified, researchers say, because of
      its enormous benefits to human beings. Sure, animals suffer and die, but that is
      morally insignificant since the benefits of research incalculably outweigh the
      evils. Although this utilitarian claim appears straightforward and relatively
      uncontroversial, it is neither straightforward nor uncontroversial. This defence
      of animal experimentation is likely to succeed only by rejecting three widely
      held moral presumptions. We identify these assumptions and explain their
      relevance to the justification of animal experimentation. We argue that, even if
      non-human animals have considerably less moral worth than humans, experimentation
      is justified only if the benefits are overwhelming. By building on and expanding
      on arguments offered in earlier papers, we show that researchers cannot
      substantiate their claims on behalf of animal research. We conclude that there is
      currently no acceptable utilitarian defence of animal experimentation. Moreover,
      it is unlikely that there could be one. Since most apologists of animal
      experimentation rely on utilitarian justifications of their practice, it appears
      that biomedical experimentation on animals is not morally justified.

PMID- 12416524
TI  - Women, ectogenesis and ethical theory.
AB  - The nature of two influential theories on the moral status of abortion logically
      commits them to welcoming the advent of ectogenesis (the gestation of human
      beings outside the womb) as a solution to the abortion conflict. However,
      qualitative research into women's response to ectogenesis reveals that both women
      in favour and women opposed to abortion rights reject the technology on
      surprisingly similar grounds. The abortion framework which led women to reject
      ectogenesis as an ethical resolution to unwanted pregnancy is contrasted with the
      moral framework which shapes formal ethical discussions of abortion. It is argued
      that the need for ethical relevance requires the views of ethicists to move
      closer to those of women.

PMID- 12416525
TI  - The ethics of social science research.
AB  - Ethical thinking about social science research is dominated by a biomedical model
      whose salient features are the assumption that only potential harms to subjects
      of research are relevant in the ethical evaluation of that research, and in the
      emphasis on securing informed consent in order to establish ethical proxy. A
      number of counter-examples are considered to the assumption, a number of defences
      against these counter-examples are examined, and an alternative model is proposed
      for the ethical evaluation of social science research: a model which can cope
      with the systemic harms (harms other than those to participants as participants)
      which have been identified. This model is based on John Rawls's idea of original
      position reasoning and treats social science research as an institutional feature
      of the basic structure of society.

PMID- 12416526
TI  - In vitro edible muscle protein production system (MPPS): stage 1, fish.
AB  - The working efficiency and state-of-mind of a Space vehicle crew on long-term
      missions is dependent on the suitability of living conditions including food. Our
      purpose was to establish the feasibility of an in vitro muscle protein production
      system (MPPS) for the fabrication of surrogate muscle protein constructs as food
      products for Space travelers. In the experimental treatments, we cultivated the
      adult dorsal abdominal skeletal muscle mass of Carassius (Gold fish). An ATCC
      fish fibroblast cell line was used for tissue engineering investigations. No
      antibiotics were used during any phase of the research. Our four treatments
      produced these results: a low contamination rate, self-healing, cell
      proliferation, a tissue engineered construct of non-homologous co-cultured cells
      with explants, an increase in tissue size in homologous co-cultures of explants
      with crude cell mixtures, maintenance of explants in media containing fetal
      bovine serum substitutes, and harvested explants which resembled fresh fish
      filets. We feel that not only have we pointed the way to an innovative, viable
      means of supplying safe, healthy, nutritious food to Space voyagers on long
      journeys, but our research also points the way to means of alleviating food
      supply and safety problems in both the public and private sectors worldwide.

PMID- 12416527
TI  - Sending the drug message home.

PMID- 12416528
TI  - Is killing no worse than letting die?
AB  - Those who wish to refute the view that it is worse to kill than to let die
      sometimes produce examples of cases in which an agent lets someone die but would
      be generally agreed to be no less reprehensible than if he had killed. It is
      argued that the examples produced typically possess a feature which makes their
      use in this context illegitimate, and that when modified to remove this feature,
      they provide support for the view which they were designed to undermine.

PMID- 12416529
TI  - Spinal surgery: extending the technical envelope.

PMID- 12416530
TI  - Minimally invasive spine surgery.

PMID- 12416531
TI  - Recovering for burnout.

PMID- 12416532
TI  - Retraction. Experience-dependent modulation of motor corticospinal excitability
      during action observation.

PMID- 12416533
TI  - Judgment of excellence in scholarship.

PMID- 12416534
TI  - Deciduous tooth crown size and asymmetry in strabismic children.
AB  - OBJECTIVES: To explore deciduous tooth crown dimensions in strabismic children
      and the relationship between the type of strabismus and tooth crown mesio-distal
      (M-D) and labio-lingual (L-L) size asymmetries. MATERIAL: Dental casts at mixed
      dentition of 2159 Collaborative Perinatal Study black and white children were
      measured, 123 of them strabismic at 1 year of age, age ranging from 6 to 12
      years. METHODS: Directional and fluctuating asymmetries in antimeric teeth were
      explored in various types of strabismus having unilateral, bilateral or
      alternating expression. ANOVA and T-square test were used for size comparisons
      and calculated asymmetries were explored by comparing the variances and Pearson
      correlations. RESULTS: Strabismus was associated with significant M-D size
      increase of deciduous maxillary canines in black boys and white girls, black
      girls had size reduction in their mandibular canine, but white boys were
      unaffected. Right side size dominance was found in the strabismic children in the
      lower second deciduous molar M-D dimensions and in the children with alternating
      strabismus in their upper deciduous canine M-D dimensions. Children with
      unilateral strabismus had random fluctuating dental asymmetry in their upper
      deciduous second molar L-L dimensions when compared with healthy normals. Higher
      left-right correlations were found in lower second deciduous molar dimensions in
      strabismic girls when compared with that in controls and in strabismic boys,
      suggesting better developmental canalization in female. CONCLUSIONS: Asymmetries
      in the head area, such as promoted here in strabismic children, may have
      associations with asymmetries in the dentition, focusing the embryonal origins
      and timing of developmental processes.

PMID- 12416535
TI  - Different morphotypes of functional dentition in the lower molar region of tabby
      (EDA) mice.
AB  - OBJECTIVES: To sort and classify the highly variable lower molar dentition in
      tabby (Ta) mice postnatally. The Ta syndome is homologous to the anhidrotic
      (hypohidrotic) ectodermal dysplasia (EDA) in human and includes severe
      developmental defects of teeth, hair and sweat glands. DESIGN: Analysis of tooth
      shape and cusp pattern and measurement of the mesio-distal crown length. SETTING
      AND SAMPLE POPULATION: Institute of Experimental Medicine, Academy of Sciences,
      Prague. Fixed heads of 107 tabby (Ta) homozygous and hemizygous mice and 90 wild
      type mice aged from post-natal day 11 to adulthood, collected during 1995-2001.
      OUTCOME MEASURE: Identification of distinct morphotypes of Ta dentition. Reduced
      tooth length in Ta teeth and specific differences in tooth length between
      distinct morphotypes. RESULTS: The variable dentitions in the lower molar region
      of Ta mice were classified in two basic morphotypes I and II. The morphotype I
      was further subdivided into particular morphotypes Ia, Ib and Ic. Proportion of
      the basic morphotypes I and II was different in the offspring of heterozygous
      (84% and 12%) compared with homozygous + hemizygous (45% and 52%) mothers. The
      proportions of particular morphotypes within a basic morphotype were similar in
      both offspring groups. CONCLUSION: The identification of the distinct morphotypes
      made possible to classify the structural variability of the mandibular functional
      dentition in Ta mice.

PMID- 12416536
TI  - Different morphotypes of the tabby (EDA) dentition in the mouse mandible result
      from a defect in the mesio-distal segmentation of dental epithelium.
AB  - OBJECTIVES: Prenatal identification of the different dentition morphotypes, which
      exist in the lower molar region of tabby (Ta) adult mice, and investigation of
      their origin. The mouse Ta syndrome and its counterpart anhidrotic (hypohidrotic)
      ectodermal dysplasia (EDA) in human are characterized by absence or hypoplasia of
      sweat glands, hair and teeth. DESIGN: Analysis of tooth morphogenesis using
      serial histological sections and 3D computer aided reconstructions of the dental
      epithelium in the cheek region of the mandible. SETTING AND SAMPLE POPULATION:
      Institute of Experimental Medicine, Academy of Sciences, Prague. Heads of 75 Ta
      homozygous and hemizygous mice and 40 wild type (WT) control mice aged from
      embryonic day (ED) 14.0-20.5 (newborns), harvested during 1995-2001. OUTCOME
      MEASURE: Prenatal identification of five distinct morphotypes of Ta dentition on
      the basis of differences in tooth number, size, shape, position and developmental
      stage and of the morphology of the enamel knot in the most mesial tooth
      primordium. RESULTS: The mesio-distal length of the dental epithelium was similar
      in the lower cheek region in Ta and WT mice. In Ta embryos, there was altered the
      mesio-distal segmentation of the dental epithelium giving rise to the individual
      tooth primordia. Prenatally, two basic morphotypes I and II and their particular
      subtypes (Ia, Ib, Ic, and IIa, IIb, respectively) of the developing dentition
      were identified from day 15.5. The incidence of the distinct morphotypes in the
      present sample did not differ from postnatal data. The proportion of the
      morphotype I and II was dependent on mother genotype. CONCLUSION: The different
      dentition morphotypes in Ta mice originate from a defect in the mesio-distal
      segmentation of the dental epithelium in mouse embryos. This defect presumably
      leads to variable positions of tooth boundaries that do not correspond to those
      of the WT molars. One tooth primordium of Ta mice might be derived from adjacent
      parts of two molar primordia in WT mice.

PMID- 12416537
TI  - Tgf-beta1, Tgf-beta2, Tgf-beta3 and Msx2 expression is elevated during
      frontonasal suture morphogenesis and during active postnatal facial growth.
AB  - OBJECTIVES: It is hypothesized that regulation of facial suture morphogenesis is
      similar to that of cranial sutures, with expression of similar regulatory
      molecules, governing suture formation and patency. The present study was designed
      to characterize the morphology of the frontonasal (FN) suture of the rat at
      different developmental stages and to investigate the presence and temporal
      spatial expression of transforming growth factor-beta 1 (Tgf-beta1), Tgf-beta2,
      Tgf-beta3 and Msx2 mRNA within these structures. SETTING AND SAMPLE POPULATION:
      The Department of Biomedical Sciences at Texas A&M University System Health
      Science Center, Baylor College of Dentistry, Dallas, TX USA. Histological
      sections and RNA isolated from FN suture tissues of Sprague-Dawley rats, aged
      embryonic day 16 through postnatal day 20. METHOD: Sections were examined after
      immunohistochemical staining. Gene expression was determined by densitometric
      analysis of RT-PCR products run on agarose gels. RESULTS: FN sutures develop
      slightly later than cranial sutures and show increased complexity over time when
      compared to cranial sutures. FN sutures were closely associated with the nasal
      capsular cartilage, with intervening layers of perichondrium and periosteum. The
      pattern of expression of Tgf-betas within the FN suture tissues was similar to
      that seen in the cranial sutures. However, mRNA and protein of the Tgf-betas were
      differentially expressed over time compared to cranial sutures. In FN sutures,
      Tgf-beta mRNA levels were elevated both during the period of suture morphogenesis
      and during active bone growth from the suture in the early postnatal period. Msx2
      mRNA expression was elevated in both the prenatal and postnatal periods, similar
      to Tgf-beta mRNA expression. CONCLUSION: Tgf-beta and Msx2 are present in facial
      sutures similar to cranial sutures, but are differentially expressed over time,
      perhaps reflecting different bone growth rates from these sutures.

PMID- 12416538
TI  - Upper removable appliance or Jones Jig for distalizing first molars? A randomized
      clinical trial.
AB  - AIM: To compare the effectiveness of two intra-oral methods of distalizing upper
      first permanent molars: an upper removable appliance (URA) and a Jones Jig.
      SAMPLE: Twelve patients were randomly allocated to URA treatment and 11 patients
      to a Jones Jig. METHODS: Upper study models were collected at the start of
      treatment and after 6 months of appliance wear. The amount of distal movement,
      tipping and rotation of the upper first permanent molars and mesial movement of
      the upper first permanent premolars was measured using a reflex metrograph.
      RESULTS: There were no statistically significant differences between the two
      treatment methods for any of the outcome measures (P < 0.05). Distal movement
      obtained by both appliances was approximately 1 mm. CONCLUSIONS: The amount of
      distal movement obtained with both appliances was small and no differences were
      shown in the amount of molar tooth movement. It is suggested that there is no
      advantage in using the Jones Jig as a non-compliance appliance.

PMID- 12416539
TI  - Atypical expression of cleidocranial dysplasia: clinical and molecular-genetic
      analysis.
AB  - Cleidocranial dysplasia (CCD) and the Rubinstein-Taybi syndrome (RTS) are two
      rare congenital syndromes that have many clinical signs in common. We present an
      18-year-old-patient with untypical CCD expression who was misdiagnosed with RTS
      at the age of 2 years. An extensive craniofacial examination was carried out with
      respect to morphological and dental aspects. The molecular-genetic analysis of
      two underlying genes (CBFA1 and CBP) for CCD and RTS was performed using SSCP,
      direct sequencing and FISH. While the clinical examination showed
      uncharacteristic CCD symptoms with some findings common for RTS, the molecular
      genetic analysis revealed a missense mutation in the CBFA1 gene, which is
      considered to be the etiological factor for CCD. Our findings with this patient
      presented clear evidence for the wide morphologic variety that can be related to
      a certain gene such as CBFA1. The diagnosis of rare diseases is currently based
      on the clinical phenomenology of small groups or single cases. The use of
      molecular-genetic biology extends the horizon of diagnostic and scientific
      possibilities. In this patient, it allowed us to compare the clinically diagnosis
      to molecular-genetic data. We conclude that molecular-genetic analysis may be a
      helpful tool in the differential diagnosis of many congenital diseases such as
      CCD and RTS.

PMID- 12416540
TI  - Conditional expression of the tumor suppressor p16 in a heterotopic glioblastoma
      model results in loss of pRB expression.
AB  - We have expressed the tumor suppressor p16 under the control of a tetracycline
      sensitive promoter in two human glioblastoma cell lines which do not contain
      endogenous p16. Ectopic p16 expression led to a stable but reversible G1 phase
      cell cycle arrest, reduced the growth of both cell lines in cell culture, and
      almost abolished their in vitro tumorigenicity. U-87MG-tTA-p16 glioblastoma cells
      consistently formed tumors after subcutaneous injection into the flanks of nude
      mice. p16 expression in these tumors was strictly dependent on the presence or
      absence of tetracycline in the drinking water. Ectopic p16 reduced the tumor take
      rate (in vivo tumorigenicity) of U-87MG-tTA-p16 cells from 18/20 (90%) to 5
      tumors/12 (42%) tumor cell injections. p16 positive and negative tumors differed
      with respect to their Ki67 labeling indices (34 +/- 4% vs. 52 +/- 6% , P < 0.001,
      student's t-test). These data are consistent with an in vitro and in vivo glioma
      suppressor role for p16. Interestingly, we observed a secondary reduction of pRB
      expression in tumors (and cell cultures) exposed to p16 for > or = 10 (6) days.
      pRB is p16's major downstream target. Hence, this finding might explain, why p16
      expression neither significantly affected the morphology nor led to a reduction
      of size or growth rate of the tumors. Loss of pRB following p16 expression might
      severely limit the potential benefit of p16 gene therapy for glioblastoma.

PMID- 12416541
TI  - Adenovirus-mediated gene transfer of B7.1 induces immunological anti-tumor
      effects in a murine brain tumor.
AB  - The purpose of the present study was to determine if adenovirus-mediated
      transfection of a syngeneic mouse brain tumor with the gene encoding B7.1
      enhances immunogenicity against tumor. Malignant astrocytoma cells were
      transfected with adenoviral vectors carrying the B7.1 gene (AdB7).
      Immunocytochemical analysis confirmed the expression of B7.1 in vitro and in
      vivo. To investigate the effects of B7.1 expression on tumorigenicity of the
      malignant astrocytoma, mice were implanted intracerebrally with B7.1-transfected
      glioma cells. There was no significant difference in proliferation between B7.1
      transfected cells and controls in vitro. Nevertheless, mice implanted with B7. 1
      transfected cells survived significantly longer than those in the control groups.
      Immunocytochemical analysis of the tumors showed that there was infiltration of a
      number of CD8+ T-cells and CD25+ activated T-cells in the brain implanted with
      B7.1-transfected glioma cells. The results showed the possibility that adenovirus
      mediated B7.1 gene transfection to a brain tumor induced activation of CD8+
      cytotoxic T-lymphocytes.

PMID- 12416542
TI  - Triple-dose contrast/magnetization transfer suppressed imaging of 'non-enhancing'
      brain gliomas.
AB  - PURPOSE: Triple-dose (TD) gadolinium contrast administration and magnetization
      transfer suppression (MTS) in brain magnetic resonance imaging (MRI) have proven
      to be useful for demonstrating additional enhancing lesions in some diseases. The
      purpose of this study was to determine if there is a subset of brain tumors that
      demonstrate contrast enhancement with TD and MTS that do not enhance with
      standard imaging and standard contrast dose. MATERIALS AND METHODS: Fifteen
      patients with either newly diagnosed primary brain tumor or brain tumor that had
      been followed for more than 2 years were enrolled. T1-weighted MTS images without
      IV contrast, with 0.1 mmol/kg without MTS (single-dose (SD) images), and with
      additional 0.2 mmol/kg gadolinium and MTS ('TD/MTS') were obtained. RESULTS: None
      of the patients had enhancement on SD images. Six patients had areas of
      enhancement on TD/MTS images ('exact' chi-squared p = 0.017). CONCLUSION: A
      statistically significant increased rate of contrast enhancement was found on
      TD/MTS images in patients whose tumors did not enhance at single dose without
      MTS. It is possible that small areas of enhancement seen only with TD/MTS might
      represent areas of higher-grade tumor.

PMID- 12416543
TI  - Meningeal chloroma (granulocytic sarcoma) in acute lymphoblastic leukemia
      mimicking a falx meningioma.
AB  - Isolated chloromas (granulocytic sarcomas) are rare tumors. Chloromas are masses
      composed of immature granulocytic cells. Granulocytic sarcoma occurs primarily in
      patients with acute myelogenous leukemia and may also arise in patients with
      other myeloproliferative disorders, but rarely in patients with acute
      lymphoblastic leukemia (ALL). When dural-based, granulocytic sarcoma may be
      indistinguishable from meningioma radiologically. We now describe one patient
      affected by ALL with isolated granulocytic sarcoma mimicking a falx meningioma as
      initial CNS relapses. These unusual clinical manifestation and radiological
      finding in ALL should be considered as recurrence of leukemia. Early detection
      and antileukemic treatment of granulocytic sarcoma are necessarily important for
      favorable prognosis.

PMID- 12416544
TI  - A phase I trial of continuously infused intratumoral bleomycin for the treatment
      of recurrent glioblastoma multiforme.
AB  - Intratumoral (IT) chemotherapy has theoretical advantages in the treatment of
      brain tumors. The blood-brain barrier is not a factor in drug delivery, and large
      concentrations of drug can be instilled in the tumor with little systemic
      toxicity. Bleomycin has activity against gliomas and is a cell cycle selective
      agent whose efficacy should be enhanced by continuous infusion. We performed a
      phase I trial to test the feasibility of IT chemotherapy using a refillable,
      sustained release device, and to determine the maximum tolerable dose of IT
      bleomycin. The study was an open-ended dose escalation study. A modified Ommaya
      reservoir (containing a semipermeable membrane) was implanted with the delivery
      tube in the center of the tumor. Groups of three patients with recurrent
      glioblastoma multiforme were entered at progressively higher dose levels of
      bleomycin. The study closed when all patients at a given starting dose level
      developed toxicity. Nine patients received doses ranging from 5 to 34 U/wk; the
      median total cumulative dose was 195 U. No dose limiting systemic toxicity was
      detected. Neurologic toxicity occurred only at doses above 16 U/wk. We conclude
      that continuously infused IT bleomycin is well tolerated; the MTD (and
      recommended dose for a phase II efficacy trial) of IT bleomycin is 16 U/wk.

PMID- 12416545
TI  - Supratentorial primitive neuroectodermal tumors in adults.
AB  - A retrospective clinical analysis was made of 12 patients with supratentorial
      primitive neuroectodermal tumor (PNET) who ranged in age from 20 to 62 years
      (median 24) and were managed at Seoul National University Hospital between
      January 1987 and December 1997. Six patients were male and six were female. Most
      presented with symptoms of increased intracranial pressure and mean duration of
      symptoms was four months (range: 1-12 months). The tumors were located in the
      posterior parieto-occipital area in six cases and the mean diameter of mass of
      these tumors was 5.3 cm. The characteristic magnetic resonance image finding was
      a large well-demarcated lobulating mass with intratumoral cyst, necrosis, and/or
      hemorrhage. Calcification was seen in five out of six patients who underwent
      computed tomography scan. All patients underwent craniotomy and three of them
      received subsequent operations due to local recurrence. Ten patients received
      postoperative whole neuraxis radiation therapy and five patients received
      additional chemotherapy. Mean survival after diagnosis was 86 months. The
      patients having intratumoral calcifications are all alive and two out of three
      showing a Ki-67 labelling index greater than 30% died at eight and 20 months
      after operation, respectively. In conclusion, supratentorial PNET must be
      included, even in adults, in the differential diagnoses if a tumor has
      characteristic radiological features. The adult supratentorial PNET seemed
      similar to that of children in the clinical features and the prognosis.
      Intratumoral calcifications and the Ki-67 labelling index might be prognostic
      factors, however, it should be considered that the sample size is too small and
      not all patients were evaluated.

PMID- 12416546
TI  - Local chemotherapy with cisplatin-depot for glioblastoma multiforme.
AB  - Glioblastoma multiforme (GBM) makes up as many as 30% of all primary brain
      tumors. Despite the employment of multimodal antitumor treatment, the overall
      survival is less than one year. Between 06/01/1998 and 06/01/2000 17 patients
      (Group A) with GBM (11 males, 6 females; median age 54.3 years) were administered
      local chemotherapy with cisplatin incorporated into biodegradable 6
      carboxylcellulose polymer (cisplatin-depot (CDDP-D)). After the subtotal removal
      of GBM, twenty 1.5 x 1.5 cm polymer plates with a total area of 45 cm2 (the
      density of cisplatin immobilization on 6-carboxylcellulose being 1 mg/cm2, a
      total cisplatin dose of 45 mg) were implanted into the tumor bed. Group B (21
      patients with GBM; 11 males, 10 females; median age 53.2 years) was control: the
      subtotal tumor ablation without CDDP-D implantation. Two to three weeks after the
      surgery all the patients of Groups A and B started a course of radiation therapy.
      A total dose of cranial irradiation was 20 Gy (1 fraction/day, 5 days/week; a
      daily dose of 2 Gy) followed by a boost tumor bed irradiation (1 fraction/day, 5
      days/week; a daily dose of 2 Gy) up to the conventional dose of 60 Gy. Survival
      data for the patients were processed using the Kaplan-Meier method and analyzed
      by logrank test. All the patients of Group A tolerated surgical ablation of the
      brain tumor without side effects (brain edema, seizures, etc.). No patient of
      Group A had a reduction in blood cell counts during six weeks that would indicate
      systemic exposure to cisplatin. Blood chemistry and urinalysis did not show
      evidence of renal injury. No side effects of radiotherapy were registered in
      Group B either, regarding both the psychoneurological status of the patients and
      the basic values of homeostasis. Karnofsky performance scale (KPS) score of Group
      A and Group B patients demonstrated no significant differences before and after
      the surgery. The median overall survivals for patients of Group A and Group B
      were 427.5 and 211.0 days respectively (p = 0.00001; overall logrank test).
      Conclusion. Local chemotherapy of GBM with CDDP-D followed by irradiation is well
      tolerated and effective.

PMID- 12416547
TI  - Trend of brain tumor incidence by histological subtypes in Japan: estimation from
      the Brain Tumor Registry of Japan, 1973-1993.
AB  - In order to estimate the risk of primary brain tumor (PBT), we attempted to
      estimate the national incidence rates of PBT by histological subtypes using the
      Brain Tumor Registry of Japan (BTR). The number of deaths due to PBT in a certain
      year is the sum of the deaths among patients diagnosed in different years.
      Registered cases in the BTR represent incident cases of PBT in the whole country
      multiplied by a cover rate. The cover rate is defined as the proportions of PBT
      cases that the Registry counts in relation to all the cases in the country in a
      given year. If the survival experience among the registered cases represents the
      survival experience of all cases, then the rate of registered deaths represents
      all deaths due to PBT in Japan. By this logic, we estimated the cover rates and
      incidence rates from 1973 to 1993 using the BTR and National Vital Statistics
      data. Our estimates showed three patterns of time trends: (1) a gradual linear
      increasing trend before the 1980s followed by a plateau (total PBT, gliomas,
      meningioma, and hemangioblastoma), (2) a trend with a step-up increase in the
      1980s followed by a plateau (germ cell tumor and pituitary tumor), and (3) a
      linear increasing trend throughout the observation period with no plateau
      (malignant lymphoma and neurinoma). Furthermore, obvious sex differences in time
      trends were observed in rates of meningioma, germ cell tumor, and pituitary
      tumor. The results of this study demonstrated several distinctive patterns in
      time trends, which give us insight into the possible etiologies of brain tumors.
      Further epidemiological study is needed to elucidate these findings.

PMID- 12416548
TI  - Local recurrence of metastatic brain tumor after stereotactic radiosurgery or
      surgery plus radiation.
AB  - In this study, we compared the recurrence of metastatic brain tumors after
      radiosurgery versus after surgery plus radiation, and analyzed the factors
      associated with the recurrence of brain metastases. Twenty-eight and 35 patients
      with metastatic brain tumors underwent radiosurgery (52 lesions) and surgery plus
      radiation (46 lesions), respectively, between 1995 and 2001. The median tumor
      volume was 1.55 ml (range: 0.02-10.4 ml) in radiosurgery patients and 17.9 ml
      (range: 0.26-195 ml) in surgery plus radiation patients. The median radiosurgical
      tumor central and margin doses were 28.9 and 23.8 Gy (range: 20-35 and 25-15 Gy),
      respectively. The median total dose was 46.7 Gy (range: 30-63 Gy) in the surgery
      plus radiation group. The recurrence time from surgery plus radiation group (25
      months) was significantly longer than that from the radiosurgery group (7.2
      months) (p = 0.0199). The factors affecting the recurrence of brain metastases
      after radiosurgery were size, central dose of radiation and histology (colon vs.
      others). No factors affected the recurrence of brain metastases after surgery
      plus radiation. To avoid early recurrences of metastatic brain tumors, surgery
      plus radiation is the preferable therapeutic modality. The size and histology of
      brain metastases, and the dose of radiation should be considered for the
      effective treatment of tumors by radiosurgery.

PMID- 12416549
TI  - Current options for the treatment of neoplastic meningitis.
AB  - Neoplastic meningitis, which is the diffuse involvement of the leptomeninges by
      infiltrating cancer cells, may be caused by many systemic tumors. The treatment
      options for neoplastic meningitis disease remain unsatisfactory. In this review
      article, we discuss the pathogenesis and cytology of neoplastic meningitis and
      the options for treatment, including intrathecal chemotherapy, systemic
      chemotherapy, and newer agents such as cytokines and monoclonal antibodies.

PMID- 12416550
TI  - Ultrastructural and MRI study of the substantia nigra evolving exofocal post
      ischemic neuronal death in the rat.
AB  - To clarify the morphological characteristics of exofocal post-ischemic neuronal
      death (EPND) in the substantia nigra (SN), we investigated the course of light-
      and electron-microscopic changes of the SN of rats subjected to occlusion of the
      left middle cerebral artery (MCA) for 1, 2, 4, 7 and 12 days. To assess cellular
      edema, sequential magnetic resonance (MR) mapping of the apparent diffusion
      coefficient (ADC) and the T2 value test was performed. Histological and electron
      microscopic examination on day 1 showed dotted chromatin clumps in the nuclei of
      some neurons and mild swelling of the perivascular endfeet of astrocytes in the
      ipsilateral SN. On day 2, a few cells of the ipsilateral SN pars reticulata (SNr)
      revealed key morphological signs of apoptosis--apoptotic body-like condensation
      and segregation of the chromatin and DNA fragmentation-like nuclear remnants. On
      day 4, 38% of neurons became swollen (pale neurons) with cytoplasmic
      microvacuoles, which appeared to originate from rough endoplasmic reticulum
      (rER), mitochondria and Golgi apparatus. Twenty percent of neurons showed massive
      proliferation of the cisternae of the rER, some of which were fragmented or had
      lost their normal parallel arrangement. In addition, MR mapping revealed a
      transient ADC decrease with a T2 increase (signifying a phase of cellular edema),
      which coordinated with the phase of ultrastructural cellular swelling. Further,
      the total number of neurons started to decrease gradually, the perivascular
      endfeet of astrocytes were markedly swollen, and the neuropil became loose on day
      4. On day 7, reactive astrocytes and dark neurons occurred most frequently. These
      results suggest that the EPND in the SN after occlusion of the MCA in adult rats
      is due to both apoptosis and necrosis, although necrosis seems to be the dominant
      mechanism of the EPND. However, the morphologic resemblances of EPND to delayed
      neuronal death suggest these processes have a common pathomechanism.

PMID- 12416551
TI  - Periventricular leukomalacia, inflammation and white matter lesions within the
      developing nervous system.
AB  - Periventricular leukomalacia (PVL) occurring in premature infants, represents a
      major precursor for neurological and intellectual impairment, and cerebral palsy
      in later life. The disorder is characterized by multifocal areas of necrosis
      found deep in the cortical white matter, which are often symmetrical and occur
      adjacent to the lateral ventricles. There is no known cure for PVL. Factors
      predisposing to PVL include birth trauma, asphyxia and respiratory failure,
      cardiopulmonary defects, premature birth/low birthweight, associated immature
      cerebrovascular development and lack of appropriate autoregulation of cerebral
      blood flow in response to hypoxic-ischemic insults. The intrinsic vulnerability
      of oligodendrocyte precursors is considered as central to the pathogenesis of
      PVL. These cells are susceptible to a variety of injurious stimuli including free
      radicals and excitotoxicity induced by hypoxic-ischemic injury (resulting from
      cerebral hypoperfusion), lack of trophic stimuli, as well as secondary associated
      events involving microglial and astrocytic activation and the release of pro
      inflammatory cytokines TNF-alpha and IL-6. It is yet unclear whether activated
      astrocytes and microglia act as principal participants in the development of PVL
      lesions, or whether they are representatives of an incidental pathological
      response directed towards repair of tissue injury in PVL. Nevertheless, the
      accumulated evidence points to a pathological contribution of microglia towards
      damage. The topography of lesions in PVL most likely reflects a combination of
      the relatively immature cerebrovasculature together with a failure in perfusion
      and/or hypoxia during the greatest period of vulnerability occurring around mid
      to-late gestation. Mechanisms underlying the pathogenesis of PVL have so far been
      related to prenatal ischemic injury to the brain initiated within the third
      trimester, which result in global cognitive and developmental delay and motor
      disturbances. Over the past few years, several epidemiological and experimental
      studies have implicated intrauterine infection and chorioamnionitis as causative
      in the pathogenesis of PVL. In particular, recent investigations have shown that
      inflammatory responses in the fetus and neonate can contribute towards neonatal
      brain injury and development-related disabilities including cerebral palsy. This
      review presents current concepts on the pathogenesis of PVL and emphasizes the
      increasing evidence for an inflammatory pathogenic component to this disorder,
      either resulting from hypoxic-ischemic injury or from infection. These findings
      provide the basis for clinical approaches targeted at protecting the premature
      brain from inflammatory damage, which may prove beneficial for treating PVL, if
      identified early in pathogenesis.

PMID- 12416552
TI  - Are pathological lesions in neurodegenerative disorders the cause or the effect
      of the degeneration?
AB  - Pathological lesions in the form of extracellular protein deposits, intracellular
      inclusions and changes in cell morphology occur in the brain in the majority of
      neurodegenerative disorders. Studies of the presence, distribution, and molecular
      determinants of these lesions are often used to define individual disorders and
      to establish the mechanisms of lesion pathogenesis. In most disorders, however,
      the relationship between the appearance of a lesion and the underlying disease
      process is unclear. Two hypotheses are proposed which could explain this
      relationship: (i) lesions are the direct cause of the observed neurodegeneration
      ('causal' hypothesis); and (ii) lesions are a reaction to neurodegeneration
      ('reaction' hypothesis). These hypotheses are considered in relation to studies
      of the morphology and molecular determinants of lesions, the effects of gene
      mutations, degeneration induced by head injury, the effects of experimentally
      induced brain lesions, transgenic studies and the degeneration of anatomical
      pathways. The balance of evidence suggests that in many disorders, the appearance
      of the pathological lesions is a reaction to degenerative processes rather than
      being their cause. Such a conclusion has implications both for the classification
      of neurodegenerative disorders and for studies of disease pathogenesis.

PMID- 12416553
TI  - Regional quantitative study of formation process of neurofibrillary tangles in
      the hippocampus of non-demented elderly brains: comparison with late-onset
      Alzheimer's disease brains.
AB  - We quantitatively investigated the formation process of neurofibrillary tangles
      (NFT) in the hippocampus of 32 brains from non-demented elderly persons using tau
      immunohistochemistry, compared with 13 brains from patients with late-onset
      Alzheimer's disease (AD). The 32 non-demented elderly brains were classified into
      16 brains in group I and 16 brains in group II mainly based on the distribution
      of tau-positive neurons in the hippocampus. Tau-positive neurons were found
      predominantly in the CA2 in group I, while they were found predominantly in the
      subiculum-pre-CA1 in group II. Most late-onset AD brains showed a distribution of
      tau-positive neurons similar to that in group II. In addition, the distribution
      pattern of tau-positive neurons in the hippocampus was closely related to
      degeneration of the perforant pathway with the accumulation of tau. These
      findings suggest that NFT occur first in the CA2 and extend to the subiculum-pre
      CA1 in group I, while they occur first in the subiculum-pre-CA1 and extend to the
      CA2 later in group II, and that the NFT occurring in the subiculum-pre-CA1 are
      mainly related to degeneration of the perforating route and in the CA2 are
      related to the degeneration of the non-perforating route.

PMID- 12416554
TI  - Alterations of NMDAR1 and NMDAR2a/B immunoreactivity in the hippocampus after
      perforant pathway lesion.
AB  - Immunohistochemical techniques were employed to examine the changes in
      immunolabeling of the N-methyl-D-aspartate (NMDA) receptor subunits NMDAR1 and
      NMDAR2A/B within the hippocampus 1, 3, 7, 14 and 30 days after a unilateral
      perforant pathway lesion was made in a rat brain. At 1 day post-lesion, we
      observed a decrease in NMDAR1 immunolabeling in the granule cells in the dentate
      gyrus as well as in the mossy cells in the polymorphic region ipsilateral to the
      lesion, while an increase in diffuse neuropil labeling was observed. At 3 days
      post-lesion, we observed a marked increase in NMDAR1 immunolabeling in the outer
      molecular-layer of the dentate gyrus as well as in the stratum moleculare in the
      CA fields ipsilateral to the lesion. Although this increase was less marked at 7
      and 14 days post-lesion, an increase in NMDAR1 immunolabeling was evident at 30
      days post-lesion. In contrast, although a transient increase in NMDAR2A/B
      immunolabeling was observed in the outer molecular layer at 3 days post-lesion,
      no other changes were detectable at any of the time points examined. Our study
      suggests that each subunit of the NMDA receptor displays a different response to
      deafferentation of the perforant pathway. We have previously observed that
      changes in the immunoreactivity of the receptor subunits of another class of
      glutamate receptor, a-amino-3-hydroxy-5-methyl-4-isoaxolepropionate (AMPA), occur
      at 30 days post-lesion but not after a relatively short survival time. NMDA
      receptor subunits demonstrate an earlier response to the loss of the perforant
      pathway fibers than do the AMPA receptor subunits.

PMID- 12416555
TI  - Degeneration of retinal neuronal processes and pigment epithelium in the early
      stage of the streptozotocin-diabetic rats.
AB  - Early pathological and electro-physiological changes of the retina in the
      streptozotocin (STZ)-diabetic rats were investigated through optical and electron
      microscopy in two strains and electro-retinography in one strain. In Sprague
      Dawley (SD) rats I month after the onset of diabetes, the thickness of the inner
      plexiform layer (IPL) and photoreceptor segment layer (PSL) was significantly
      reduced by 9.9% and 18.9%, respectively (P < 0.01, P < 0.05). In Brown-Norway
      (BN) rats STZ-diabetic for 1 month, the thickness of the IPL was also
      significantly reduced by 15.7% (P < 0.05). Cytochemical study using peanut
      agglutinin (PNA), a lectin binding selectively to the cone photoreceptor
      associated domains of the inter-photoreceptor matrix, revealed a marked reduction
      in intensity, number and length of the PNA-binding cone photoreceptors. Electron
      microscopy showed deepened hollows in the basal infoldings of the retinal pigment
      epithelium (RPE) of STZ-rats diabetic for 1 month and large concavities into the
      cytoplasm in STZ-rats diabetic for 6 months. Blood vessels in the retina and
      choroid were unremarkable. Single-flash electro-retinogram revealed a reduction
      in the amplitudes of alpha- and beta-waves of electro-retinogram (ERG) of 1 month
      STZ BN rats (P < 0.05). These findings indicate that the degeneration of
      rods/cones in the PSL and RPE are the most prominent pathological alteration
      sites in the early stage of diabetic rats.

PMID- 12416556
TI  - Chronic low-Ca/Mg high-Al diet induces neuronal loss.
AB  - To evaluate the causative role of environmental aluminum (Al) in the development
      of neurodegeneration in Kiiamyotrophic lateral sclerosis (ALS), we examined how
      chronic exposure to a low-Ca/Mg and high-Al diet induced neuronal loss and tau
      related neuronal degeneration in experimental animals. Optical microscopic
      examination showed tau-positive cells, atrophic neurons with darkly stained
      cytoplasms or swollen perikarya in the cerebrum, hippocampus and the brainstem of
      mice fed a low-Ca/Mg high-Al diet (Group 3). The neuronal loss was found in the
      frontal and parietal cortices of the mice and was not due to a classical
      apoptosis as detected by the terminal de ynucl otidyl transferase-mediated dUTP
      digoxigenin nick end-labeling (TUNEL) method. Neuronal degeneration and spheroid
      formation was also seen in the spinal cord of the Group 3 mice. The Morin
      fluorescence technique showed Al and Ca deposition in the cortical neurons and
      vessels in the basal ganglia of these mice. An electron microscopic examination
      showed intranuclear filamentous structures, intracytoplasmic vacuoles and/or
      darkly stained cytoplasm in the cortical neurons of Group 3 mice. These findings
      were seen in mice of the 11-month-experimental period and increased until the 25
      month-experimental period. The present findings suggested that chronic exposure
      to a low-Ca/Mg high Al condition induced an accumulation of hyperphosphorylated
      tau in the cortical neurons, swelling of the neuronal cytoplasm and loss in the
      cerebrum and spinal cord of mice. Environmental factors such as a low-Ca/Mg high
      Al exposure might be one of the risk factors for the development of neuronal
      degeneration of ALS in the Kii Peninsula.

PMID- 12416557
TI  - Degeneration of Pick bodies visualized by methenamine-silver staining and
      immunohistochemistry.
AB  - The degeneration process of Pick's bodies (PB) was investigated using methenamine
      silver (MS) staining and immunohistochemistry. Methenamine-silver staining
      sensitively detected extracellular PB as well as intracellular PB in the granular
      cell layer of the dentate gyrus. Extracellular PB appeared as granular masses
      with ill-defined boundaries in the neuropil. For MS electron microscopy, the
      extracellular PB were composed of randomly oriented fibrillary components
      measuring 9-12 nm in diameter with astroglial processes and degenerated
      organelles. Tau immunoreactivity of extracellular PB was reduced or abolished.
      These findings indicate that MS staining is a convenient method for detecting
      extracellular PB. In addition, it was shown that microglial involvement was
      associated with PB-bearing neurons at the late stage of the degeneration process
      and that extracellular PB remained in the neuropil with astroglial reaction.

PMID- 12416558
TI  - Thalamic retrograde degeneration in the congenitally hydrocephalic rat is
      attributable to apoptotic cell death.
AB  - Congenitally hydrocephalic HTX rats develop ventricular dilatation with extensive
      damage of the cerebral white matter. Recently, we have reported that neuronal
      cell death also occurs in the thalamus of HTX rats. To investigate the mechanism
      underlying this thalamic degeneration in these animals, we carried out a
      histopathological study of the brain at different phases of postnatal
      development. Eosinophilic neurons with condensed chromatin or fragmented nuclei
      were observed in the thalamus from postnatal day 17 onward. The incidence of cell
      death in the thalamus increased with the progression of hydrocephalus.
      Ultrastructurally, thalamic neurons occasionally had apoptotic features including
      nuclear chromatin condensation and marginalization. Immunohistochemically, single
      stranded DNA-positive neuronal nuclei were found in the thalamus. They were also
      positively stained with the TUNEL method. Marked loss of myelin and axons with
      many TUNEL-positive oligodendrocytes were found in the cerebral white matter.
      These findings suggest that the neuronal cell death observed in the thalamus in
      hydrocephalic HTX rats is retrograde degeneration due to extensive damage of
      axons in the cerebral white matter and that the thalamic retrograde degeneration
      is attributable to apoptotic cell death.

PMID- 12416559
TI  - Overexpression of mdm2 and p53 and association with progesterone receptor
      expression in benign meningiomas.
AB  - The progesterone receptor is frequently found expressed in meningiomas at robust
      levels. As several studies of breast and endometrial tumors have shown an inverse
      correlation between progesterone receptor expression and p53 overexpression, we
      sought to determine if a similar relationship existed in meningiomas. As p53 may
      also be inactivated by the overexpression of mdm2, we examined a cohort of 90
      benign meningiomas immunohistochemically for the presence of the progesterone
      receptor as well as overexpression of p53 and mdm2. The progesterone receptor was
      detected in 67% (61/90) of cases, while p53 and mdm2 overexpression were detected
      in 14% (13/90) and 46% (42/90) of cases, respectively. An absolute correlation
      was observed between the overexpression of nuclear mdm2 and overexpression of the
      progesterone receptor, with nuclear mdm2 overexpression being confined to
      progesterone receptor-positive tumors (P = 0.001). While p53 overexpression was
      not associated with progesterone receptor expression, a combination of mdm2
      overexpression and/or p53 overexpression was significantly associated with the
      presence of the progesterone receptor (P = 0.025). These results suggest the
      existence of a novel relationship between p53 (and its regulatory control) and
      the presence of the progesterone receptor and, as such, may have fundamental
      consequences in developing progesterone receptor-targeted therapies for
      meningiomas.

PMID- 12416560
TI  - Astroblastoma with unusual signet-ring-like cell components: a case report and
      literature review.
AB  - We report a case of astroblastoma with unusual signet-ring-like cell components.
      A 33-year-old-woman presented with occasional partial seizures of the face.
      Radiological studies revealed an enhanced frontal mass lesion. At surgery, a
      gray, soft, well-circumscribed mass was seen and shelled out. Histologically, the
      tumor showed a perivascular arrangement and papillary-like patterns with compact
      cellularity. The tumor cells radiating from the hyalinized vessels showed
      broader, shorter, less tapered processes. A part of each tumor cell displayed
      prominent islands of signet-ring-like cells. Glial fibrillary acidic protein
      reaction revealed strongly positive staining of tumor cells and signet-ring-like
      cells. Eight years after the operation the patient remains well with no tumor
      recurrence. It remains to be determined whether, in this astroblastoma, the
      unusual signet-ring-like cell components were related to benign biological
      characteristics or to the tumor's low-grade form with incidental signet-ring-like
      cell appearance.

PMID- 12416561
TI  - Autopsy case of aluminum encephalopathy.
AB  - We report the case of a 59-year-old female aluminum encephalopathy patient who
      had chronic renal failure and took 3.0 g hydroxy-aluminum gel per day for the
      control of serum phosphorus level during a 15-year period. Nine months before her
      death she developed disorientation, memory disturbance, emotional incontinence,
      general convulsions and consciousness disturbance. Neuropathologically, the brain
      showed nerve cell atrophy and mild loss with stromal spongiosis, proliferation of
      astrocytes and microglia in the cerebral cortex, basal ganglia and thalamus. Some
      nerve cells were stained immunohistochemically by phosphorylated neurofilament,
      but apparent neurofibrillary tangles were not observed. Aluminum was detected in
      the nerve cells of the cerebral cortex by X-ray microanalysis. Despite the long
      term intake of aluminum, there were no neuropathological findings of Alzheimer's
      disease. The findings in our case suggested that aluminum alone might not develop
      Alzheimer's disease.

PMID- 12416562
TI  - Cerebellar granular layer aplasia in congenital hydrocephalus.
AB  - An unusual case of cerebellar granular layer aplasia is reported. A 5-year-old
      boy was born with hydrocephalus and a peritoneal drainage shunt was placed after
      the delivery. Symptoms of cerebral paralysis, impaired mental function and
      cerebellar ataxia had developed gradually. Patient's karyotype was 46,XY.
      Laboratory tests for cytomegalovirus, Herpes simplex virus, Toxoplasma gondii,
      human immunodeficiency virus, rubella and hepatitis B virus were negative.
      Further laboratory investigation showed no signs of Tay-Sachs disease, Niemann
      Pick disease, Gaucher disease, phenylketonuria, galactosemia or glycogen storage
      disease. No congenital malformations were traced in other family members for
      three generations. Radiation exposure and infections during the pregnancy were
      refuted.

PMID- 12416563
TI  - An autopsy case of amebic meningoencephalitis. The first Japanese case caused by
      Balamuthia mandrillaris.
AB  - We report here the first case of amebic meningoencephalitis caused by Balamuthia
      mandrillaris in a 78-year-old Japanese woman with Sjogren's syndrome. Fourteen
      days before her death, she presented with high fever and lost consciousness and
      later developed neck stiffness and abducens palsy. Computed tomography scans of
      the brain demonstrated multiple low-density areas throughout the brain.
      Neuropathologically, hemorrhagic and necrotic lesions with many amebic
      trophozoites were scattered in the brain and spinal cord. Granulomatous lesions
      were only rarely found. The amebas were identified as Balamuthia mandrillaris
      based on immunofluorescence assay. Clinicopathologically, our case was thought to
      be an intermediate between primary amebic meningoencephalitis due to Negleria
      fowleri and granulomatous amebic encephalitis due to Acanthameba species.
      Essentially, the case was one of an elderly person with suspected
      immunodeficiency with fulminant necrotic meningoencephalitis and scanty
      granulomatous lesions of 14 days course.

PMID- 12416564
TI  - Effects of habitual cigarette smoking on higher cortical function in patients
      with unruptured cerebral aneurysms.
AB  - Postoperative changes in higher cortical function and cerebral blood flow (CBF)
      were investigated in patients with unruptured cerebral aneurysms to assess the
      effect of habitual smoking on the known transient changes after aneurysm surgery.
      Fifty-six adults with unruptured cerebral aneurysms, including 11 heavy smokers
      (smoking index > or = 600) and 45 non-smokers, were evaluated using three
      neuropsychological examinations, the Mini-Mental State Examination, the Maze
      test, and the Kana-hiroi test, and single photon emission computed tomography to
      measure CBF before and after surgery. Neuropsychological changes were assessed by
      reliable change indices to take into account the practice effects. The scores of
      at least one examination decreased in 15 of 56 patients 1 month after surgery. On
      the Maze test, five of 11 heavy smokers and five of 45 non-smokers deteriorated
      after surgery, showing a significant difference (p = 0.018). The CBF in heavy
      smokers often decreased after surgery, but there was no statistically significant
      difference in logistic regression. Three months after surgery, the
      neuropsychological scores of 13 of the 15 deteriorated patients recovered to the
      preoperative level. Higher cortical function in heavy smokers with unruptured
      cerebral aneurysms often decreases transiently after operation, compared to non
      smokers. Therefore, surgery planning for heavy smokers with unruptured cerebral
      aneurysms should consider this outcome.

PMID- 12416565
TI  - Bilateral ophthalmic segment "kissing" aneurysms presenting with subarachnoid
      hemorrhage--case report.
AB  - A 31-year-old woman presented with bilateral ophthalmic segment "kissing"
      aneurysms causing subarachnoid hemorrhage manifesting as sudden severe headache
      and nausea 3 days before admission. Cerebral angiography demonstrated bilateral
      internal carotid-superior hypophyseal artery aneurysms, both projecting medially
      from the medial surface of the internal carotid arteries and appearing to touch
      each other. Both aneurysms had to be clipped in the same operation, because of
      uncertainty over which aneurysm had bled. She underwent bilateral frontotemporal
      craniotomy on the day after admission. Intraoperatively, the two aneurysms were
      in contact with each other in the suprasellar cistern. Each aneurysm was clipped
      through the ipsilateral approach without any incident. The patient returned home
      a month after the operation and has since resumed her previous work.
      Identification of this rare entity of bilateral ophthalmic segment "kissing"
      aneurysms is important for surgical planning. Closely situated, bilateral
      ophthalmic segment aneurysms require a modified surgical strategy for proximal
      arterial control and the approach to each aneurysm.

PMID- 12416566
TI  - Direct approach to the ventrolateral medulla for cavernous malformation--case
      report.
AB  - A 49-year-old man presented with symptomatic cavernous malformation in the
      ventrolateral portion of the medulla oblongata manifesting as left-sided numbness
      and gait disturbance. Neurological examination disclosed sensory disturbance on
      the left, cerebellar ataxia, nystagmus, dysphagia, and right hypoglossal nerve
      paresis. Magnetic resonance imaging revealed a cavernous malformation with
      hemorrhage occupying the right paramedian field of the medulla oblongata. The
      patient underwent complete removal of the lesion through vertical incision of the
      bulging surface of the ventrolateral medulla, anatomically coinciding with the
      inferior olive. The neurological deficits improved without additional
      postoperative deficits. This unusual microsurgical approach through a
      ventrolateral medullary incision permits direct resection of a subpial intrinsic
      lesion, even on the ventral medulla.

PMID- 12416567
TI  - Patch angioplasty to repair the arteriotomy defect in the wall of the middle
      cerebral artery after failure of superficial temporal artery-middle cerebral
      artery anastomosis in moyamoya disease--case report.
AB  - A 65-year-old woman presented with moyamoya disease associated with a saccular
      aneurysm of the posterior cerebral artery. The surgical plan required superficial
      temporal artery (STA)-middle cerebral artery (MCA) anastomosis to be conducted
      before neck clipping of the aneurysm to provide collateral flow via the STA to
      prevent ischemia if temporary occlusion of the parent artery of the aneurysm was
      needed. However, the anastomotic procedure failed because the STA was occluded at
      the site of temporary clip application. End-to-end anastomosis of the STA was
      planned after excising the occluded site of the STA, but end-to-end anastomosis
      could not be performed because the donor artery was too short for anastomosis to
      the branch of the MCA. Therefore, patch grafting using a piece of wall of the STA
      was performed to repair the arteriotomy defect in the wall of the MCA, followed
      by neck clipping of the saccular aneurysm in the posterior circulation via the
      subtemporal approach. Vascular reconstruction can be recommended if arterial
      anastomosis between a superficial skin artery and a branch of the MCA is
      impossible due to an intraoperative accident or technical difficulty and
      reperfusion is necessary.

PMID- 12416568
TI  - Recurrent angiofibroma invading the skull base--case report.
AB  - A 16-year-old male presented with a massive nasopharyngeal angiofibroma arising
      in the nasopharynx, nasal cavity, pterygopalatine fossa, and infratemporal fossa,
      and eroding the pterygoid process of the sphenoid bone. Neuroimaging showed the
      tumor had infiltrated the parasellar region from the middle cranial fossa and
      reached the cavernous sinus. The tumor was almost completely removed
      macroscopically by a modified transbasal approach.

PMID- 12416569
TI  - Bilateral thalamic glioma--case report.
AB  - A 35-year-old woman presented with a bilateral thalamic glioma manifesting as
      dysesthesia over the left side of the body and mental deterioration. T1-weighted
      magnetic resonance imaging revealed enlarged bilateral thalami with homogeneous
      isointensity and no enhancement after gadolinium administration. Histological
      examination of a stereotactic biopsy specimen identified anaplastic astrocytoma.
      Radiotherapy and chemotherapy failed to arrest tumor growth. She subsequently
      died. Magnetic resonance imaging and clinical findings support the view that
      bilateral thalamic gliomas represent a distinct clinicopathologic entity among
      thalamic tumors.

PMID- 12416570
TI  - Osteomyelitis of the odontoid process associated with meningitis and
      retropharyngeal abscess--case report.
AB  - A 52-year-old man complaining of headache and nuchal pain was treated initially
      under a diagnosis of bacterial meningitis. The meningitis resisted antibiotic
      therapy, and one week later was complicated by a ruptured retropharyngeal
      abscess, which led to the correct diagnosis of osteomyelitis of the odontoid
      process of the axis. His neck was immobilized in a high neck collar and the
      retropharyngeal abscess was treated by repeated drainage and irrigation. A long
      course of antibiotic administration finally resolved the infection. Osteomyelitis
      of the odontoid process is rare and presents with peculiar signs and symptoms.
      Careful consideration of the differential diagnosis is needed for the early
      detection of this potentially serious condition.

PMID- 12416571
TI  - Endoscopic fenestration of posterior fossa arachnoid cyst for the treatment of
      presyrinx myelopathy--case report.
AB  - A 32-year-old man presented with an arachnoid cyst of the posterior fossa
      manifesting as cervical syringomyelic myelopathy. Magnetic resonance (MR) imaging
      demonstrated edematous enlargement and T2 prolongation of the cervical spinal
      cord, indicating a "presyrinx" state. MR imaging showed the inferior wall of the
      cyst, which disturbed cerebrospinal fluid (CSF) pulsatile movement between the
      intraspinal and intracranial subarachnoid spaces. The cyst wall was fenestrated
      with a neuroendoscope. The presyrinx state and the CSF movement improved.
      Posterior fossa arachnoid cyst, as well as Chiari malformation, can cause CSF
      flow disturbance at the craniocervical junction and syringomyelia. Endoscopic
      fenestration is less invasive than foramen magnum decompression and should be the
      procedure of choice.

PMID- 12416572
TI  - Development of magnetoencephalography-magnetic resonance imaging integration
      software--technical note.
AB  - A new software program can provide images of electrically equivalent current
      dipoles and sensor arrays superimposed on three-dimensional magnetic resonance
      images. The images will be helpful for identifying locations between arbitrary
      sensors and directly projected brain surfaces, or planning surgical approaches.

PMID- 12416573
TI  - Image fusion for skull base neuronavigation. Technical note.
AB  - An automatic image fusion module (BrainLab, Munich, Germany) is used for the
      fusion of the magnetic resonance (MR) imaging and computed tomography (CT) data
      sets. The procedure of image fusion takes 5 minutes prior to surgery. The image
      fusion of CT and MR imaging data visualizes the skull base and tumor margins
      clearly. Color display of the different data sets allows the tumor and the skull
      base to be distinguished easily. The fused CT data in bone window mode provides
      useful additional information on the osseous skull base.

PMID- 12416574
TI  - Measurement of heterogeneous distribution on Technegas SPECT images by three
      dimensional fractal analysis.
AB  - This review article describes a method for quantifying heterogeneous distribution
      on Technegas (99mTc-carbon particle radioaerosol) SPECT images by three
      dimensional fractal analysis (3D-FA). Technegas SPECT was performed to quantify
      the severity of pulmonary emphysema. We delineated the SPECT images by using five
      cut-offs (15, 20, 25, 30 and 35% of the maximal voxel radioactivity), and
      measured the total number of voxels in the areas surrounded by the contours
      obtained with each cut-off level. We calculated fractal dimensions from the
      relationship between the total number of voxels and the cut-off levels
      transformed into natural logarithms. The fractal dimension derived from 3D-FA is
      the relative and objective measurement, which can assess the heterogeneous
      distribution on Technegas SPECT images. The fractal dimension strongly correlate
      pulmonary function in patients with emphysema and well documented the overall and
      regional severity of emphysema.

PMID- 12416575
TI  - Preclinical studies on [11C]MPDX for mapping adenosine A1 receptors by positron
      emission tomography.
AB  - In previous in vivo studies with mice, rats and cats, we have demonstrated that
      [11C]MPDX ([1-methyl-11C]8-dicyclopropylmethyl-1-methyl-3-propylxanthine) is a
      potential radioligand for mapping adenosine A1 receptors of the brain by positron
      emission tomography (PET). In the present study, we performed a preclinical
      study. The radiation absorbed-dose by [11C]MPDX in humans estimated from the
      tissue distribution in mice was low enough for clinical use, and the acute
      toxicity and mutagenicity of MPDX were not found. The monkey brain was clearly
      visualized by PET with [11C]MPDX. We have concluded that [11C]MPDX is suitable
      for mapping adenosine A1 receptors in the human brain by PET.

PMID- 12416576
TI  - Japan's contribution to nuclear medical research.
AB  - We investigated the degree of Japan's contribution to the nuclear medical
      research in the last decade. Articles published in 1991-2000 in highly reputed
      nuclear medical journals were accessed through the MEDLINE database. The number
      of articles having affiliation with a Japanese institution was counted along with
      publication year. In addition, shares of top-ranking countries were determined
      along with their trends over time. Of the total number of articles (7,788),
      Japan's share of articles in selected nuclear medical journals was 11.4% (889
      articles) and ranked 2nd in the world after the USA (2,645 articles). The recent
      increase in the share was statistically significant for Japan (p = 0.02, test for
      trend). Japan's share in nuclear medical research output is much higher than that
      in other biomedical fields.

PMID- 12416577
TI  - Prognostic value of myocardial MIBG scintigraphy findings in patients with
      cardiomyopathy--importance of background correction for quantification of MIBG
      activity.
AB  - OBJECTIVE: To assess the prognostic value of I-123 metaiodobenzylguanidine (MIBG)
      scintigraphy findings, and establish the most appropriate method for calculating
      myocardial MIBG activity in patients with left ventricular dysfunction due to
      cardiomyopathy (CM). METHODS: Predictors of cardiac death related to progressive
      heart failure (HF) were examined in 150 patients with CM (80 patients with
      idiopathic CM and 70 patients with ischemic CM). All patients underwent MIBG
      scintigraphy at rest and other hemodynamic studies when their clinical status was
      stable. MIBG scintigrams were obtained 15 minutes and 4 hours after the injection
      of the isotope. The parameters for quantification of myocardial MIBG activity
      were heart/mediastinal activity ratio (H/M) and myocardial washout rate (WR). The
      WR was calculated with and without background (BG) correction. RESULTS: The WR
      showed better correlation with plasma norepinephrine and left ventricular
      ejection fraction after BG correction. During a mean follow-up period of 33 +/- 9
      (7 to 54) months, 12 patients died due to HF; 7 patients due to progressive HF
      and 5 patients due to sudden cardiac death. Cox regression analysis indicated,
      the H/M and the WR with and withoutBG correction, were significant predictors of
      cardiac death (Wald chi-squared value: H/M [ 15 min] = 9.7, H/M [4 hr] = 19.5, WR
      with BG correction = 29.9, WR without BG correction = 12.6). WR prognostic value
      was better after BG correction, and a high WR with BG correction was the only
      independent predictor of cardiac death (relative risk [RR] = 1.174, p < 0.0001).
      CONCLUSIONS: Accelerated WR is a powerful predictor of the patient's prognosis
      and BG correction is essential for calculating WR.

PMID- 12416578
TI  - The role of bone scintigraphy in determining the etiology of heel pain.
AB  - In this study we aimed to determine the role of bone scintigraphy as an objective
      diagnostic method in patients with heel pain. 67 heels of 50 of 182 patients with
      defined features who attended the orthopedics outpatient clinic with heel pain
      over a 3-year period, were treated with combined methods such as nonsteroidal
      anti-inflammatory drugs (NSAID) and contrast baths, stretching exercises and
      changing of footwear habits. A one year follow-up was established. The criteria
      identified by Wolgin et al. were used in assessing the results of the treatment.
      Subcalcaneal spur was demonstrated by radiography in 44 of the 67 heels. There
      were two different imaging patterns observed on three phase bone scintigraphy.
      Type I imaging pattern: Focal increased activity in the heel region or normal
      activity on dynamic and the blood pool phases and focal increased activity at the
      inferior calcaneal surface in the late static phase. Type II imaging pattern:
      Diffuse increased activity along the plantar fascia in the dynamic and the blood
      pool phase, and focal increased activity at the inferior calcaneal surface in the
      late static phase. There were 34 (50.7%) type I and 18 (26.8%) type II imaging
      patterns on the scans. Type I and type II imaging patterns were described as
      osseous and fascial respectively. At the final examination, the results for
      pattern type I were good in 16 patients (66.7%), fair in 6 patients (25%) and
      poor in 2 patients (8.3%), whereas in pattern type II results were good in 12
      patients (80%) and fair in 3 patients (20%). The recurrence frequency was 4.1%
      and 6.6%, respectively. Subcalcaneal spur was determined in 70.5% of the patients
      with osseous pathology and 55.5% of the patients with fascial pathology. Based on
      this result, it can be ascertained that calcaneal spurs develop during the
      pathological process causing heel pain. Other findings supporting this claim were
      the differences in symptom periods of the patients with type I and type II
      imaging patterns and scintigraphies were normaly in 10 of 44 heels indicating
      subcalcaneal spurs on radiographies. These findings suggested that metabolic
      changes contributing to subcalcaneal spur were complete. Three phase bone
      scintigraphy is an objective method which can be used to diagnose heel pain,
      especially when determining the etiological factors and prognosis.

PMID- 12416579
TI  - Chemo-radionuclide therapy for thyroid cancer: initial experimental study with
      cultured cells.
AB  - Radioiodine therapy has long been used for distant metastases of thyroid cancer.
      Although partially effective in most cases, it can render a complete cure only in
      a limited number of patients. One way to enhance its efficacy would be to combine
      it with antineoplastic agents. Here we describe an initial in vitro evaluation
      with 4 thyroid cancer cell lines. METHODS: Cells were sparsely seeded in
      microtiter plates and allowed to grow for 2 days; then they were exposed to
      sublethal concentrations of cisplatin (CDDP), doxorubicin (Dox), or 5
      fluorouracil (5-FU), followed by treatment with I-131 for 48 hr. Cell survival
      was measured with a commercial kit based on the colorimetry of succinate
      dehydrogenase activity. RESULTS: Chemotherapeutic drugs exerted similar
      concentration-dependent cytotoxic effects in all 4 cell lines. The doses
      necessary to reduce the surviving fraction to half of the control were about 3
      microg/ml for CDDP, 0.3 microg/ml for Dox, and 3 microg/ml for 5-FU (when used
      continuously for 48 hours). On the other hand, sensitivity to I-131 irradiation
      differed among the lines; same doses (7.4-14.8 MBq/ml) caused the greatest damage
      in FRO cells, a modest effect in NPA and WRO, and only minimal change in B-CPAP.
      The combined effect was most demonstrable in wells treated with Dox and
      radioiodine, whereas the addition of CDDP or 5-FU had marginal or insignificant
      merit, respectively. In FRO cells, half-lethal doses of the above mentioned CDDP,
      Dox, and 5-FU, when used together with 14.8 MBq/ml I-131, reduced cell survival
      to 54.5%, 29.4% and 33.4%, respectively, vs. 60.2% with radioiodine alone.
      CONCLUSION: In vitro, clinical concentrations of Dox can accelerate the killing
      of thyroid cancer cells by radioiodine. These favorable experimental results
      warrant future studies to evaluate whether this new bidisciplinary approach is
      clinically relevant and feasible.

PMID- 12416580
TI  - FDG-PET after radiotherapy is a good prognostic indicator of rectal cancer.
AB  - In the management of rectal cancer after the combined therapy of the radiation
      and surgical operation, the evaluation of the prognosis is important. Although
      fluoro- 18-deoxyglucose positron emission tomography (FDG-PET) is considered as a
      useful tool for evaluation of therapeutic effect of this cancer as well as the
      other cancers, however, there are few articles that clearly describe the
      appropriate procedure of the FDG-PET in order to obtain the best prognostic
      value. The purpose of the present study is to compare several variations of a
      semi-quantification method, the Standardized Uptake Values (SUV) and to determine
      the most appropriate parameter, for the prognostic prediction and to propose the
      quantitative guideline of the FDG-PET. Especially, the authors focused on the SUV
      after radiotherapy, which had not been considered as a key quantitative value, as
      it was rather taken as a mere indicator of the therapeutic (radiotherapeutic)
      effect, not a direct indicator of the prognosis for the cancer itself. METHODS:
      Forty patients with rectal cancer in the lower rectal region underwent two series
      of FDG-PET study before and after pre-operative radiotherapy. Their SUVs were
      calculated from FDG-PET data and compared with the results of the long-term
      follow-up of the patients as well as with histopathological outcomes. RESULTS:
      All 40 patients had high FDG uptake before radiotherapy. The mean value of SUV
      before radiotherapy (SUV1) was 7.6. After radiotherapy, the mean value of SUV
      (SUV2) decreased to 4.2. There was a significant difference in SUV2 between the
      groups with and without recurrence (p < 0.05), however, SUVI or SUV ratio
      (SUV2/SUV1) displayed no significant difference with the incidence of recurrence.
      CONCLUSION: SUV2 was considered to be a good prognostic indicator for long-term
      prognosis of rectal cancer patients. SUV1 nor SUV ratio SUV2/SUV1 did not have
      the equivalent prognostic usefulness. Subsets of patients with SUV2 greater than
      3.2 should be observed closely.

PMID- 12416581
TI  - Differential diagnosis in patients with ring-like thallium-201 uptake in brain
      SPECT.
AB  - This study was performed to investigate lesions with ring-like thallium-201
      (201Tl) uptake and to determine whether SPECT provides any information in
      differential diagnosis. METHODS: A total of 244 201Tl SPECT images were reviewed.
      In each study, early (15 min postinjection) and late (3 hr) brain SPECT images
      were obtained with 111 MBq of 201Tl. The early uptake ratio (ER; lesion to normal
      brain average count ratio) and the late uptake ratio (LR) and the L/E ratio
      (ratio of LR to ER) were calculated. RESULTS: Ring-like uptake was observed in
      pre-therapeutic 26 SPECT images, including ten glioblastoma multiformes (ER, 3.45
      +/- 0.64; LR, 2.74 +/- 0.54; L/E ratio 0.80 +/- 0.13), five meningiomas (6.48 +/-
      2.34; 4.41 +/- 1.41; 0.72 +/- 0.19), four metastatic lung cancers (3.47 +/- 1.23;
      2.40 +/- 0.98; 0.70 +/- 0.14), four brain abscesses (2.48 +/- 1.06; 1.59 +/-
      0.30; 0.78 +/- 0.15), one invasive lesion of squamous cell carcinoma from the
      ethmoid sinus (1.54; 1.52; 0.99), one medulloblastoma (3.53; 3.52; 1.00) and one
      hematoma (3.32; 2.36; 0.71). The ER of meningioma was significantly higher than
      those of glioblastoma multiforme (p < 0.0005), metastatic lung cancer (p < 0.005)
      and brain abscess (p < 0.0005). There were no significant differences among these
      three entities. The LR of meningioma was significantly higher than those of
      glioblastoma multiforme (p < 0.005), metastatic lung cancer (p < 0.005) and brain
      abscess (p < 0.0001). The LR of brain abscess was significantly lower than that
      of glioblastoma multiforme (p < 0.05). The L/E ratio could not differentiate
      these four entities. CONCLUSION: High ER and high LR in a lesion with ring-like
      uptake is likely an indicator of meningioma. The LR of brain abscess was
      significantly lower than that of glioblastoma multiforme, but 201T1 SPECT has
      still difficulty in differentiating abscess from brain tumor.

PMID- 12416582
TI  - Tophaceous gout.

PMID- 12416583
TI  - Quantification of regional pulmonary flow with 9mTc-MAA SPECT and cine phase
      contrast MR imaging.
AB  - The purpose of this study was to evaluate the relationship between left and right
      pulmonary arterial flow measured by cine phase contrast magnetic resonance
      imaging (cine PCMRI) and the distribution of perfusion on 99mTc-MAA SPECT and to
      determine whether the regional pulmonary flow quantification was feasible with
      the combined use of these techniques. Twenty patients with different pulmonary
      diseases were evaluated. Left and right lung counts on 99mTc-MAA SPECT images
      were separately summed and the left-to-total count ratio was calculated. The left
      to-total pulmonary flow ratio was calculated from the left and right main
      pulmonary flows measured with cine PCMRI. We evaluated the correlation and
      agreement between the ratio determined with 99mTc-MAA SPECT and cine PCMRI by
      linear regression analysis and Bland-Altman analysis. The left-to-total ratios
      obtained by 99mTc-MAA and cine PCMRI were 52.0 +/- 22.1% and 52.2 +/- 20.8%,
      respectively, and showed a strong correlation (r = 0.99, p < 0.001). The mean
      difference between the two methods in the ratio was 0.25 +/- 2.3% with a 95%
      confidence interval from -0.84 to 1.34. The results showed that the regional
      pulmonary flow was calculated with both the left and right pulmonary flow
      measured with cine PCMRI and the ratio of regional distribution on 99Tc-MAA SPECT
      images.

PMID- 12416584
TI  - Attenuation correction of myocardial SPECT images with X-ray CT: effects of
      registration errors between X-ray CT and SPECT.
AB  - PURPOSE: Attenuation correction with an X-ray CT image is a new method to correct
      attenuation on SPECT imaging, but the effect of the registration errors between
      CT and SPECT images is unclear. In this study, we investigated the effects of the
      registration errors on myocardial SPECT, analyzing data from a phantom and a
      human volunteer. METHODS: Registerion (fusion) of the X-ray CT and SPECT images
      was done with standard packaged software in three dimensional fashion, by using
      linked transaxial, coronal and sagittal images. In the phantom study, an X-ray CT
      image was shifted 1 to 3 pixels on the x, y and z axes, and rotated 6 degrees
      clockwise. Attenuation correction maps generated from each misaligned X-ray CT
      image were used to reconstruct misaligned SPECT images of the phantom filled with
      201Tl. In a human volunteer, X-ray CT was acquired in different conditions
      (during inspiration vs. expiration). CT values were transferred to an attenuation
      constant by using straight lines; an attenuation constant of 0/cm in the air (CT
      value = -1,000 HU) and that of 0.150/cm in water (CT value = 0 HU). For
      comparison, attenuation correction with transmission CT (TCT) data and an
      external gamma-ray source (99mTc) was also applied to reconstruct SPECT images.
      RESULTS: Simulated breast attenuation with a breast attachment, and inferior wall
      attenuation were properly corrected by means of the attenuation correction map
      generated from X-ray CT. As pixel shift increased, deviation of the SPECT images
      increased in misaligned images in the phantom study. In the human study, SPECT
      images were affected by the scan conditions of the X-ray CT. CONCLUSION:
      Attenuation correction of myocardial SPECT with an X-ray CT image is a simple and
      potentially beneficial method for clinical use, but accurate registration of the
      X-ray CT to SPECT image is essential for satisfactory attenuation correction.

PMID- 12416585
TI  - A review of intensity modulated radiation therapy: incorporating a report on the
      seventh education workshop of the ACPSEM--ACT/NSW branch. Australasian College of
      Physical Scientists and Engineers in Medicine.
AB  - Intensity modulated radiation therapy (IMRT) is an evolving treatment technique
      that has become a clinical treatment option in several radiotherapy centres
      around the world. In August 2001 the ACT/NSW branch of the ACPSEM held its
      seventh education workshop, the subject was IMRT. This review considers the
      current use of IMRT and reports on the proceedings of the workshop. The workshop
      provided some of the theory behind IMRT, discussion of the practical issues
      associated with IMRT, and also involved presentations from Australian centres
      that had clinically implemented IMRT. The main topics of discussion were patient
      selection, plan assessment, multi-disciplinary approach, quality assurance and
      delivery of IMRT. Key points that were emphasised were the need for a balanced
      multi-disciplinary approach to IMRT, in both the establishment and maintenance of
      an IMRT program; the importance of the accuracy of the final dose distribution as
      compared to the minor in-field fluctuations of individual beams; and that IMRT is
      an emerging treatment technique, undergoing continuing development and
      refinement.

PMID- 12416586
TI  - Review of Ge detectors for gamma spectroscopy.
AB  - A review is given of the use of germanium detectors for gamma spectroscopy. The
      advantages, principles of operation, and fabrication processes of semiconductor
      radiation detectors are described.

PMID- 12416587
TI  - A simplified approach for exit dose in vivo measurements in radiotherapy and its
      clinical application.
AB  - This is a study using LiF:Mg;Ti thermoluminescent dosimeter (TLD) rods in
      phantoms to investigate the effect of lack of backscatter on exit dose. Comparing
      the measured dose with anticipated dose calculated using tissue maximum ratio
      (TMR) or percentage depth dose (PDD) gives rise to a correction factor. This
      correction factor may be applied to in-vivo dosimetry results to derive true dose
      to a point within the patient. Measurements in a specially designed humanoid
      breast phantom as well as patients undergoing radiotherapy treatment were also
      been done. TLDs with reproducibility of within +/- 3% (1 SD) are irradiated in a
      series of measurements for 6 and 10 MV photon beams from a medical linear
      accelerator. The measured exit doses for the different phantom thickness for 6 MV
      beams are found to be lowered by 10.9 to 14.0% compared to the dose derived from
      theoretical estimation (normalized dose at dmax). The same measurements for 10 MV
      beams are lowered by 9.0 to 13.5%. The variations of measured exit dose for
      different field sizes are found to be within 2.5%. The exit doses with added
      backscatter material from 2 mm up to 15 cm, shows gradual increase and the
      saturated values agreed within 1.5% with the expected results for both beams. The
      measured exit doses in humanoid breast phantom as well as in the clinical trial
      on patients undergoing radiotherapy also agreed with the predicted results based
      on phantom measurements. The authors' viewpoint is that this technique provides
      sufficient information to design exit surface bolus to restore build down effect
      in cases where part of the exit surface is being considered as a target volume.
      It indicates that the technique could be translated for in vivo dose
      measurements, which may be a conspicuous step of quality assurance in clinical
      practice.

PMID- 12416588
TI  - Dosimetry of a low-kV intra-operative X-ray source using basic analytical beam
      models.
AB  - The low energy (30-50 kVp) beams from an intra-operative X-ray source are
      modelled using a basic analytical model considering just primary beam attenuation
      and absorption. Spatial dosimetry at such low energies is difficult due to the
      rapid changes in dose-rate from the radiation source. The purpose of the model
      was to determine the variation with distance in water of coefficients required
      for beam dosimetry and to validate beam measurements performed in water of high
      gradient dose distributions. The model predicts a change in mean mass-energy
      absorption coefficient of up to 3 % over the range of clinically-relevant
      distances in water. Distance-dose distributions (variation in dose with distance
      in water) for the X-ray source were calculated with the model and found to be in
      agreement with measurement (at clinically-relevant distances), to within a
      spatial distance comparable to the dimensions and positional accuracy of the
      ionization chamber used, and comparable to the expected dosimetric anisotropy of
      the radiation source. Measured and calculated distance-doses begin to diverge at
      relatively large distances from the radiation source, which is where dose-rates
      are so low that detector signal levels are comparable with noise.

PMID- 12416589
TI  - Neural networks in cardiac electrophysiological signal classification.
AB  - The aim of this work was to develop a method by which intra-cardiac electrograms
      could be classified. A new algorithm for training this particular network has
      been established and applied to the task of finding the onset times of intra
      cardiac electrograms. The algorithm is based on adding a choice function to the
      combination function of each neuron. The choice function enables the network to
      consider delays in each of its synapses. The gradient of error is then calculated
      with respect to the weights and delays. A synaptic delay-based artificial neural
      network was implemented using MATLAB and used to detect the onset times of the
      atrial, His and ventricular electrograms from the His catheter recordings.
      Results from a subset of a clinical, 12-channel electrophysiology study
      demonstrated the ability of the network to successfully identify peak potentials
      and onset times. Errors in detection of onset times were in the range of 1-2 ms.
      This method, which does not utilise traditional windowing and/or thresholding
      operations, can be effectively used to detect temporal patterns in a range of
      electrophysiological and biological signals.

PMID- 12416590
TI  - An application of linear output error modelling for studying lymphocyte migration
      in peripheral lymphoid tissues.
AB  - Lymphocyte recirculation between lymphatic and blood vessels and migration
      through tissues are essential mechanisms underlying immunological surveillance.
      However, the kinetics of lymphocyte migration through lymphoid tissues remains
      poorly understood. The present study of lymphocyte migration, based on a sheep
      model and entailing the long term cannulation of blood vessels and lymphatic
      vessels efferent from lymph nodes, represents the first attempt to apply control
      engineering based models to overcome some of the experimental impediments to
      understanding the complex phenomena involved in lymphocyte migration. An output
      error model order (1,2,nk) was systematically selected under given criteria from
      four classes of Linear Time-Invariant Single-Input Single-Output, (LTI-SISO)
      systems to represent the peripheral lymph node system. The unit impulse responses
      were simulated under noise free conditions and their features were extracted to
      describe the dynamics of the system. The findings from this study revealed novel
      information about several aspects of the dynamics of lymphocyte migration.

PMID- 12416591
TI  - An investigation into the source of low energy scattered radiation of
      significance in film dosimetry.
AB  - The nature of the background optical density on films exposed to orthovoltage x
      rays and electron beams has been studied for correction purposes. A higher than
      expected background value can be demonstrated by comparing the film scanned beam
      profile with water phantom ionisation scans of the same beam. A range of 3-5%
      increased background in the penumbral tail, with energy dependence, has been
      shown experimentally. Testing the assumption that this increased background is
      due to Cerenkov radiation produced in the film, Filmstrips were interleaved in a
      solid water equivalent phantom and exposed to 300kV orthovoltage x-ray beams and
      5MeV to 12MeV electron beams. The film stacks were made up of single or multiple
      bare filmstrips, multiple filmstrips interleaved with black paper, and multiple
      filmstrips interleaved with overhead transparency sheet. The experimental result
      demonstrated that visible light was not significantly responsible for an enhanced
      film optical density, but rather that this was due to scattered radiation, with a
      complex low energy spectrum, arising from the film silver halide emulsion or
      base. An improved background correction technique is developed which incorporates
      this unexpected background value as an added component in the correction applied
      to the measured optical density. The resulting profiles exhibit improved
      agreement between film and ionization chamber measurements in the penumbra and
      tail regions.

PMID- 12416592
TI  - A proposed hierarchical fuzzy inference system for the diagnosis of arthritic
      diseases.
AB  - Development of computer-based medical inference systems is always confronted with
      some difficulties. In this paper, difficulties of designing an inference system
      for the diagnosis of arthritic diseases are described, including variations of
      disease manifestations under various situations and conditions. Furthermore, the
      need for a huge knowledge base would result in low efficiency of the inference
      system. We proposed a hierarchical model of the fuzzy inference system as a
      possible solution. With such a model, the diagnostic process is divided into two
      levels. The first level of the diagnosis reduces the scope of diagnosis to be
      processed by the second level. This will reduce the amount of input and mapping
      for the whole diagnostic process. Fuzzy relational theory is the core of this
      system and it is used in both levels to improve the accuracy.

PMID- 12416593
TI  - Independent actions on fear circuits may lead to therapeutic synergy for anxiety
      when combining serotonergic and GABAergic agents.
AB  - ISSUE: Both serotonin and GABA powerfully regulate the neuroanatomical circuit
      that mediates fear in anxiety disorders. This suggests that use of
      pharmacotherapies acting on both systems may provide synergistic therapeutic
      actions.

PMID- 12416595
TI  - A longitudinal view of triggers and thresholds of suicidal behavior in
      depression.
AB  - BACKGROUND: Recurrent brief depressive disorder (RBD) and major depressive
      disorder (MDD) share the same diagnostic picture of full-blown depression and are
      both associated with increased suicide attempt rates. However, longitudinal
      diagnostic shifts from RBD to MDD or vice versa, called "combined depression"
      (CD), have demonstrated a substantially higher risk of suicide attempts in
      epidemiologic and clinical studies. Following the stress-diathesis model of
      suicidal behavior, we compared possible triggers and thresholds for suicidal
      behavior among patients with RBD, MDD, and CD. RBD and MDD diagnoses were based
      on DSM-IV criteria. Furthermore, the goal of this study was to determine if
      impulsivity as an underlying factor could explain high suicide attempt rates in
      CD. METHOD: A structured clinical interview evaluating comorbid Axis I and II
      disorders and RBD and a battery of instruments assessing suicidal behavior were
      administered to 101 patients with RBD (N = 27), MDD (N = 33), or CD (N = 41).
      RESULTS: Patients with CD showed significantly higher (p < .05) scores on
      measures of suicidal behavior in comparison with RBD and MDD patients. Together
      with comorbid substance abuse and marital status, CD was among the highest
      ranking risk factors for suicide attempts. Impulsivity was identified as a major
      underlying factor, predicting 80.7% of suicide attempts. CONCLUSION: CD seems to
      be an important clinical risk factor for the prediction of suicide attempts,
      similar to risk factors such as substance use disorders and borderline
      personality disorder. All of these factors share the same diathesis for increased
      impulsivity and suicidal ideation, which could explain comorbidity and suicidal
      behavior. The coexistence of a greater propensity for suicidal ideation and
      impulsivity in RBD might also explain why such patients are more prone to attempt
      suicide, even if they do not, in the case of RBD, meet the duration criteria for
      MDD.

PMID- 12416594
TI  - The effects of novel antipsychotics on glucose and lipid levels.
AB  - BACKGROUND: The novel antipsychotics are extensively used based on their
      favorable extrapyramidal side effect profiles. However, accumulating evidence
      suggests that these agents, particularly clozapine and olanzapine, have serious
      side effects of their own, including weight gain and elevated glucose and
      triglyceride levels. The goal of this study is to compare the effects of novel
      antipsychotics clozapine, olanzapine, risperidone, and quetiapine and typical
      antipsychotics haloperidol and fluphenazine on glucose and lipid levels. METHOD:
      The charts of 590 patients were retrospectively reviewed. Of those, 215 patients
      had adequate laboratory data for inclusion. Glucose and lipid level data from 2
      1/2 years before and after initiation of the target antipsychotic were included.
      Covariates, including patients' age, the duration of antipsychotic treatment,
      other medications that may affect glucose or lipid levels, and the initial
      laboratory values, were controlled for in the analyses. RESULTS: Glucose levels
      were increased from baseline for patients treated with clozapine, olanzapine, and
      haloperidol. There were statistically and clinically significant differences
      among the medications' effects on lipid profiles (p < .05). Those receiving
      clozapine and olanzapine demonstrated statistically significant increases in
      triglyceride levels compared with the other groups. Over one third of patients
      treated with any of the novel antipsychotics had clinically meaningful
      triglyceride elevations. CONCLUSION: It has been shown that novel antipsychotics
      are associated with weight gain. This risk factor along with others, such as
      elevated glucose and triglyceride levels, compounds the risk for coronary artery
      disease. Routine monitoring of glucose and lipid levels during treatment with
      novel antipsychotics should be advocated.

PMID- 12416596
TI  - Sexual function and behavior in social phobia.
AB  - BACKGROUND: Social phobia is a type of performance and interpersonal anxiety
      disorder and as such may be associated with sexual dysfunction and avoidance. The
      aim of the present study was to evaluate sexual function and behavior in patients
      with social phobia compared with mentally healthy subjects. METHOD: Eighty
      subjects participated in the study: 40 consecutive, drug-free outpatients with
      social phobia (DSM-IV) attending an anxiety disorders clinic between November
      1997 and April 1999 and 40 mentally normal controls. The Structured Clinical
      Interview for DSM-IV Axis I Disorders and the Liebowitz Social Anxiety Scale were
      used to quantitatively and qualitatively assess sexual function and behavior.
      RESULTS: Men with social phobia reported mainly moderate impairment in arousal,
      orgasm, sexual enjoyment, and subjective satisfaction domains. Women with social
      phobia reported severe impairment in desire, arousal, sexual activity, and
      subjective satisfaction. In addition, compared with controls, men with social
      phobia reported significantly more frequent paid sex (p < .05), and women with
      social phobia reported a significant paucity of sexual partners (p < .05).
      CONCLUSION: Patients with social phobia exhibit a wide range of sexual
      dysfunctions. Men have mainly performance problems, and women have a more
      pervasive disorder. Patients of both genders show difficulties in sexual
      interaction. It is important that clinicians be aware of this aspect of social
      phobia and initiate open discussions of sexual problems with patients.

PMID- 12416597
TI  - Clozapine-induced fevers and 1-year clozapine discontinuation rate.
AB  - BACKGROUND: Clozapine-induced fever is a known side effect that can occur during
      clozapine initiation. This study aims to characterize patients who experience
      clozapine-induced fever, the nature of the fevers, and rates of clozapine
      continuation at 1 year in patients who develop fever versus those who do not.
      METHOD: A retrospective chart review of 93 consecutive clozapine initiations
      (1991-1999) was conducted. Fever was defined as any 1 temperature at or above
      38.0 degrees C (100.4 degrees F). Demographic information, presence or absence of
      clozapine-induced fevers, and continuation of clozapine treatment at 1 year were
      extracted from the charts. These variables were analyzed for significance, and
      subsample analysis was conducted for those with more severe fevers (at or above
      38.5 degrees C [101.3 degrees F]). RESULTS: Of the 93 patients, 20.4% (N = 19)
      developed clozapine-induced fevers. At 1 year, there was no significant
      difference in clozapine discontinuation rate between those patients who
      experienced fever and those who did not. Patients who experienced higher fevers
      (> or = 38.5 degrees C [101.3 degrees F]) tended to be significantly older than
      those who did not (p < .027). The mean fever duration was 3.8 days (range, 1-9
      days), with a mean temperature of 39.1 degrees C (102.4 degrees F) (range, 38.0
      41.0 degrees C [100.4-105.8 degrees F]). At 1 year, the patients who experienced
      fever showed no increased risk of severe reactions such as agranulocytosis. All
      patients with fevers continued clozapine treatment with good 1-year continuation
      rate on treatment with this medication. CONCLUSION: Clozapine-induced fever is
      not an indication for discontinuing this effective medication. It is a benign,
      self-limited phenomenon not predictive of drug discontinuation at 1 year. Older
      age at time of treatment may be a risk factor for developing clozapine-induced
      fever.

PMID- 12416598
TI  - Risperidone, 2 mg/day vs. 4 mg/day, in first-episode, acutely psychotic patients:
      treatment efficacy and effects on fine motor functioning.
AB  - BACKGROUND: The aim of this study was to examine differences in the improvement
      of clinical psychopathology and in fine motor functions at 2 doses of risperidone
      in first-episode, acutely psychotic patients. METHOD: In a double-blind, fixed
      dose study, 49 acutely psychotic, neuroleptic-naive patients who were admitted
      for the first time and who met DSM-IV criteria for schizophrenia,
      schizophreniform disorder, or schizoaffective disorder were randomly assigned to
      2 or 4 mg/day of risperidone. Treatment efficacy was measured using the Brief
      Psychiatric Rating Scale, the Scale for the Assessment of Negative Symptoms, The
      Clinical Global Impressions scale, and the Social and Occupational Functioning
      Assessment Scale. Fine motor functions were assessed using a computerized device
      (the Vienna Test System) and were compared with those of a control group of 20
      healthy subjects who were matched for age, gender, and educational level.
      RESULTS: Treatment with doses of 2 and 4 mg of risperidone daily significantly
      reduced positive (p < .0001) and negative (p < .01) symptoms at 8 weeks. Although
      there were no significant differences in motor movements as measured using the
      Barnes Akathisia Scale and the Simpson-Angus Scale, computerized fine motor
      assessment showed significantly less motor dysfunction in the 2-mg/day group at 8
      weeks. No significant correlations to plasma concentration of active moiety were
      found for data on psychopathology and fine motor functions. CONCLUSION: The 2
      doses of risperidone did not differ in terms of clinical improvement, but the 2
      mg/day dose produced fewer fine motor dysfunctions. These results suggest that a
      dose as low as 2 mg/day of risperidone may be effective for patients with first
      episode psychosis.

PMID- 12416599
TI  - Prevalence of and risk factors for medication nonadherence in patients with
      schizophrenia: a comprehensive review of recent literature.
AB  - OBJECTIVE: Nonadherence to prescribed antipsychotic medications places patients
      with schizophrenia at a greatly increased risk of illness exacerbation and
      rehospitalization. Identification of risk factors for nonadherence is an initial
      step toward designing effective interventions. This article reviews recent
      literature on the prevalence of and risk factors for medication nonadherence in
      patients with schizophrenia. DATA SOURCES: We searched the MEDLINE/HealthSTAR and
      PsycINFO databases using combinations of the keywords risk factor(s), adherence,
      compliance, antipsychotic, neuroleptic, schizophrenia, and psychosis for articles
      published since 1980 that identified risk factors for medication nonadherence in
      schizophrenia patients. We included reports that (1) were published in English
      and (2) specifically examined risk factors for medication nonadherence. Thirty
      nine articles met our selection criteria. DATA SYNTHESIS: Among the 10 reports
      that met a strict set of study inclusion criteria, we found a mean rate of
      nonadherence of 41.2%; the 5 reports that met a stricter set of inclusion
      criteria had a mean nonadherence rate of 49.5%. In the 39 articles reviewed,
      factors most consistently associated with nonadherence included poor insight,
      negative attitude or subjective response toward medication, previous
      nonadherence, substance abuse, shorter illness duration, inadequate discharge
      planning or aftercare environment, and poorer therapeutic alliance. Findings
      regarding an association between adherence and medication type were inconclusive,
      although few studies explored this relationship. Other factors such as age,
      gender, ethnicity, marital status, education level, neurocognitive impairment,
      severity of psychotic symptoms, severity of medication side effects, higher
      antipsychotic dose, presence of mood symptoms, route of medication
      administration, and family involvement were not found to be consistent predictors
      of nonadherence. Limitations of the published literature are discussed.
      CONCLUSION: Efforts to improve medication adherence in patients with
      schizophrenia should target relevant risk factors.

PMID- 12416600
TI  - Serum bupropion levels in 2 breastfeeding mother-infant pairs.
AB  - BACKGROUND: These are the first reported data on bupropion and hydroxybupropion
      levels in infants whose treated mothers were breastfeeding. The information will
      assist physicians and parents in the risk-benefit decision-making process for
      bupropion treatment during breastfeeding. METHOD: Serum samples were obtained by
      venipuncture from 2 mother-infant pairs. The serum was assayed for levels of
      bupropion and its most active metabolite, hydroxybupropion. RESULTS: Neither
      infant had quantifiable serum levels of bupropion or its metabolite at steady
      state. Neither infant had medical problems during the time of maternal therapy.
      CONCLUSION: We recommend obtaining and publishing additional serum level findings
      for breastfeeding mother-infant pairs since data for bupropion are favorable but
      limited.

PMID- 12416601
TI  - Personality impairment in male pedophiles.
AB  - BACKGROUND: Despite the large body of literature on the psychological sequelae of
      childhood sexual abuse, the literature on the psychopathology of pedophiles is
      surprisingly underdeveloped. The present article explores the hypothesis that
      pedophiles evidence deficits in interpersonal functioning (lack of assertiveness
      and empathy, passive-aggressiveness) and in self-concept, which might contribute
      to the motivation for pedophilic acts, as well as elevated sociopathy,
      impulsivity, and propensity for cognitive distortions, which might underlie the
      inhibitory failure. METHOD: Twenty male heterosexual pedophiles (DSM-IV criteria)
      recruited from an outpatient clinic for sex offenders were compared with 24
      demographically similar, healthy male controls using 3 personality instruments:
      the Millon Clinical Multiaxial Inventory-II, the Dimensional Assessment of
      Personality Impairment-Questionnaire, and the Temperament and Character
      Inventory. RESULTS: The data suggested that pedophiles have impaired
      interpersonal functioning, specifically, reduced assertiveness and elevated
      passive-aggressiveness, as well as impaired self-concept. Regarding disinhibitory
      traits, pedophiles demonstrated elevated sociopathy and propensity for cognitive
      distortions. CONCLUSION: Our data are consistent with previous reports of
      pathologic personality traits in pedophiles and lend support to a hypothesis that
      such pathology is related to both motivation for and failure to inhibit
      pedophilic behavior. Such information could potentially have important treatment
      implications.

PMID- 12416602
TI  - Differential effects of risperidone, olanzapine, clozapine, and conventional
      antipsychotics on type 2 diabetes: findings from a large health plan database.
AB  - BACKGROUND: Case series suggest that some antipsychotics may induce or exacerbate
      type 2 diabetes. This study measured the association of antipsychotic treatments
      with diabetes at a population level. METHOD: Claims data for psychosis patients
      (ICD-CM-9 290.xx-299.xx) within health plans encompassing 2.5 million individuals
      were analyzed. Patients reporting preexisting type 2 diabetes up to 8 months
      prior to observation were excluded. The frequency of newly reported type 2
      diabetes in untreated patients and among patients treated with antipsychotics
      from 5 categories (risperidone, olanzapine, clozapine, and high-potency and low
      potency conventionals) was compared. Logistic regression models compared the odds
      of diabetes based on exposure to each of the antipsychotic categories. RESULTS:
      Based on 12 months of exposure, the odds of type 2 diabetes for risperidone
      treated patients (odds ratio = 0.88, 95% CI = 0.372 to 2.070) was not
      significantly different from that for untreated patients, whereas patients
      receiving other antipsychotics had a significantly greater risk of diabetes than
      untreated patients (p < .05): olanzapine, 3.10 (95% CI = 1.620 to 5.934);
      clozapine, 7.44 (95% CI = 0.603 to 34.751); high-potency conventionals, 2.13 (95%
      CI = 1.097 to 4.134); and low-potency conventionals, 3.46 (95% CI = 1.522 to
      7.785). Older age and greater use of non-antipsychotic psychotropic medications
      also contributed to risk of type 2 diabetes. Olanzapine also showed significantly
      higher (p < .01) odds of diabetes associated with increasing dose. CONCLUSION:
      Consistent with previously published literature, these data suggest that
      olanzapine, clozapine, and some conventional antipsychotics appear to increase
      the risk of acquiring or exacerbating type 2 diabetes and that the effect may
      vary by drug. In contrast to these agents, risperidone was not associated with an
      increased risk of type 2 diabetes.

PMID- 12416603
TI  - Olanzapine in refractory schizophrenia after failure of typical or atypical
      antipsychotic treatment: an open-label switch study.
AB  - BACKGROUND: When patients with schizophrenia fail to respond to an atypical
      antipsychotic, they are sometimes switched to another atypical compound. However,
      the benefits of such a switch have not been adequately studied. We present an
      open-label prospective 14-week trial with olanzapine in patients with
      schizophrenia and schizoaffective disorder whose treatment resistance to
      clozapine, olanzapine, risperidone, and haloperidol had been determined
      prospectively. METHOD: The subjects were 45 inpatients with DSM-IV schizophrenia
      or schizoaffective disorder who failed to respond to treatment during a 14-week
      double-blind trial comparing clozapine, olanzapine, risperidone, and haloperidol.
      The patients had been selected for participation in the double-blind trial on the
      basis of a history of suboptimal response to previous treatment. Inclusion
      criteria for the present study were (1) completion of at least 8 weeks of the 14
      week double-blind trial, (2) treatment resistance to 1 of the 4 compounds tested
      as evidenced by a decrease in total PANSS score of less than 20%, and (3) total
      PANSS score > or = 60. Subjects were cross-titrated from the previous double
      blind treatment to open-label olanzapine, 10 to 40 mg/day, and were treated for
      14 weeks without concomitant psychotropic medication. Patients were evaluated
      weekly with the Positive and Negative Syndrome Scale (PANSS), Clinical Global
      Impressions scale, and Extrapyramidal Symptom Rating Scale. RESULTS: Open-label
      olanzapine treatment yielded no significant change in PANSS total, positive
      subscale, or negative subscale scores. There was a significant improvement for
      the PANSS cognitive factor (mean +/- SD change = 0.92 +/- 2.27; F = 7.5, df =
      1,44; p <.009) and a marginally significant worsening for the excitement factor
      (mean change = -1.36 +/- 4.64; F = 4.0, df = 1,44; p < .053). Nine percent of
      patients (N = 4) were classified as responders using the Kane et al. criteria.
      The worsening in the PANSS excitement factor was significantly associated with
      the length of illness (t = -2.10, df = 44, p < .04). There was a nonsignificant
      decrease in extrapyramidal side effects and a significant increase in weight
      (mean increase = 3.5 +/- 6.2 kg [7.8 +/- 13.8 lb]; F = 5.29, df = 1,42; p
      <.0005). CONCLUSION: Our results indicate that in patients with treatment
      resistant schizophrenia, a switch to olanzapine after treatment failure with an
      atypical agent or haloperidol may not reduce psychopathology in general, but may
      improve symptoms related to cognitive function.

PMID- 12416604
TI  - Risk factors for falls during treatment of late-life depression.
AB  - BACKGROUND: Prior studies have found that antidepressant medications are
      associated with an increased risk of falling in elderly persons. However, little
      is known about the prevention of falls during treatment for depression in elderly
      persons. This study evaluated the time course and potential risk factors for
      falls in a treatment protocol for late-life depression to identify specific at
      risk periods and risk factors for falls in this population. METHOD: One hundred
      four subjects aged 69 years and over were treated in a protocolized manner using
      paroxetine and interpersonal psychotherapy. Those who did not respond received
      augmentation therapy with bupropion, nortriptyline, or lithium. Subjects were
      assessed at baseline and weekly during treatment; demographic and clinical
      characteristics of those who experienced a fall during treatment were compared
      with those who did not fall. Cox proportional hazards models were used to define
      risk factors for falls in univariate and multivariate models. RESULTS: During a
      mean of 21 weeks of treatment, 40 subjects (38%) fell. About half (53%) of the
      subjects fell during the first 6 weeks of treatment. In the multivariate model,
      memory impairment and orthostatic changes in blood pressure during treatment were
      risk factors for falling. Additionally, augmentation with bupropion appeared to
      be a risk factor for falls in univariate analysis, but this result is preliminary
      due to the small number of subjects who took bupropion. CONCLUSION: Increased
      monitoring for falls is warranted during the acute treatment of late-life
      depression. When treating such patients, clinicians should be especially watchful
      of those with memory impairments or those who develop orthostatic blood pressure
      changes; orthostatic blood pressure should be measured throughout acute
      treatment. Additionally, augmenting paroxetine with bupropion may also increase
      the risk of falls, and this medication combination should be used with caution in
      elderly patients.

PMID- 12416606
TI  - Severe hypertriglyceridemia associated with olanzapine.

PMID- 12416605
TI  - Is response to prophylactic lithium a familial trait?
AB  - BACKGROUND: Selecting a drug according to the treatment response in a relative
      has been widely accepted advice in the management of mood disorders. However,
      this recommendation has not been adequately substantiated in the literature. We
      tested the hypothesis that response to long-term lithium treatment is a familial
      trait. METHOD: We compared response to long-term lithium treatment in bipolar
      relatives of bipolar lithium responders and bipolar controls. Twenty-four
      relatives with bipolar disorder (as determined using the Schedule for Affective
      Disorders and Schizophrenia-Lifetime version [SADS-L] and Research Diagnostic
      Criteria [RDC]) were identified in families of 106 patients with lithium
      responsive bipolar disorder. A consecutive series of 40 lithium-treated patients
      in a bipolar clinic (meeting RDC and DSM-IV criteria for bipolar disorder) served
      as a comparison group. Lithium response was evaluated on a rating scale
      reflecting the quality and quantity of available data. RESULTS: The prevalence of
      unequivocal response among the relatives was 67%, as compared with the response
      rate of 35% in the comparison group (chi2 = 6.04, df = 1, p = .014). CONCLUSION:
      This highly significant difference in response between relatives and the control
      group supports the view that the response to lithium prophylaxis clusters in
      families.

PMID- 12416607
TI  - Nicotine-induced angiogenesis.

PMID- 12416608
TI  - Genetics Society of Canada Award of Excellence. David L. Baillie.

PMID- 12416609
TI  - Genetics Society of Canada Young Scientist Award. Stephen Scherer.

PMID- 12416610
TI  - AFLP markers linked to resistance against Striga gesnerioides race 1 in cowpea
      (Vigna unguiculata).
AB  - Amplified fragment length polymorphism (AFLP) analysis was used in combination
      with bulked segregant analysis (BSA) to identify molecular markers linked to two
      cowpea (Vigna unguiculata (L.) Walp.) genes conferring resistance to Striga
      gesnerioides race 1. After AFLP analysis of an F2 population derived from a cross
      between the resistant cultivar Gorom and the susceptible cultivar Tvx 3236, seven
      AFLP markers were identified that are linked to Rsg3, the gene conferring race I
      resistance in 'Gorom'. The distances between these markers and Rsg3 ranged from
      9.9 to 2.5 cM, with two markers, E-AGA/M-CTA460 and E-AGA/M-CAG300, flanking Rsg3
      at 2.5 and 2.6 cM, respectively. Analysis of a second F2 population derived from
      the cross between 'Tvx 3236' and the resistant cultivar IT81D-994 identified five
      AFLP markers linked to the race 1 resistance gene 994-Rsg present in 'IT81D-994'.
      The two markers showing the tightest linkage to the 994-Rsg locus were E-AAG/M
      AAC450 and E-AAG/M-AAC150 at 2.1 and 2.0 cM, respectively. Two of the markers
      linked to 994-Rsg, E-AGA/M-CAG300 and E-AGA/M-CAG450, were also linked to Rsg3.
      The identification of molecular markers in common between the two sources of race
      1 resistance suggests that either Striga resistance genes are clustered in these
      plants or that these loci are allelic. Mapping of the resistance loci within the
      cowpea genome revealed that three markers linked to Rsg3 and (or) 994-Rsg are
      located on linkage group 6.

PMID- 12416611
TI  - Comparative analysis of QTLs affecting plant height and flowering among closely
      related diploid and polyploid genomes.
AB  - Quantitative trait loci (QTLs) affecting plant height and flowering were studied
      in the two Saccharum species from which modern sugarcane cultivars are derived.
      Two segregating populations derived from interspecific crosses between Saccharum
      officinarum and Saccharum spontaneum were genotyped with 735 DNA markers. Among
      the 65 significant associations found between these two traits and DNA markers,
      35 of the loci were linked to sugarcane genetic maps and 30 were unlinked DNA
      markers. Twenty-one of the 35 mapped QTLs were clustered in eight genomic regions
      of six sugarcane homologous groups. Some of these could be divergent alleles at
      homologous loci, making the actual number of genes implicated in these traits
      much less than 35. Four QTL clusters controlling plant height in sugarcane
      corresponded closely to four of the six plant-height QTLs previously mapped in
      sorghum. One QTL controlling flowering in sugarcane corresponded to one of three
      flowering QTLs mapped in sorghum. The correspondence in locations of QTLs
      affecting plant height and flowering in sugarcane and sorghum reinforce the
      notion that the simple sorghum genome is a valuable "template" for molecular
      dissection of the much more complex sugarcane genome.

PMID- 12416612
TI  - Expression and genomic organization of the zebrafish chaperonin gene complex.
AB  - Chaperonin 10 and chaperonin 60 monomers exist within the multimeric
      mitochondrial chaperonin folding complex with a stoichiometry of 2:1. This
      complex is located in the mitochondrial matrix, where it aids in the folding and
      acquisition of the tertiary structure of proteins. We have previously isolated
      the cpn10 cDNA in zebrafish (Danio rerio), and demonstrated that it is
      ubiquitously expressed during embryonic development and transcriptionally
      upregulated after exposure to heat shock. In the present study, we have isolated
      a cDNA encoding chaperonin 60 (cpn60) from zebrafish, and have shown that it is
      similarly expressed uniformly and ubiquitously throughout early embryonic
      development of zebrafish. Upregulation of cpn60 expression was also observed
      after exposure of zebrafish embryos to a heat shock of 1 h at 37 degrees C
      compared with control embryos raised at 27 degrees C. The induction of the cpn60
      heat shock response was greatest after 1 h of heat shock, whereas significant
      decreases of cpn60 mRNA were observed within 2 h following a return to 27 degrees
      C. We subsequently isolated genomic DNA sequences for both of these genes, and
      show that they are also arranged in a head-to-head organization and share a
      common bidirectional promoter that contains a single heat shock element (HSE).
      Our database analysis shows that this head-to-head organization is also found in
      human (Homo sapiens), rat (Rattus norvegicus), pufferfish (Fugu rubripes), and
      Caenorhabditis elegans, but not in Drosophila or yeast (Saccharomyces
      cerevisiae). The data suggest that the genomic organization of the cpn gene
      complex has been conserved across the vertebrates.

PMID- 12416613
TI  - Chromosome landing near avirulence gene vH13 in the Hessian fly.
AB  - AFLP markers in linkage disequilibrium with vH13, an avirulence gene in the
      Hessian fly (Mayetiola destructor) that conditions avirulence to resistance gene
      H13 in wheat (Triticum spp.), were discovered by bulked segregant analysis. Five
      AFLPs were converted into codominant site-specific markers that genetically
      mapped within 13 cM of this gene. Flanking markers used as probes positioned vH13
      near the telomere of the short arm of Hessian fly chromosome X2. These results
      suggest that the X-linked avirulence genes vH6, vH9, and vH13 are present on
      Hessian fly chromosome X2 rather than on chromosome X1 as reported previously.
      Genetic complementation demonstrated that recessive alleles of vH13 were
      responsible for the H13-virulence observed in populations derived from four
      different states in the U.S.A.: Georgia, Maryland, Virginia, and Washington.
      Results support the hypothesis that a gene-for-gene interaction exists between
      wheat and Hessian fly.

PMID- 12416614
TI  - Development and characterization of polymorphic microsatellite markers in taro
      (Colocasia esculenta).
AB  - Microsatellite-containing sequences were isolated from enriched genomic libraries
      of taro (Colocasia esculenta (L.) Schott). The sequencing of 269 clones yielded
      77 inserts containing repeat motifs. The majority of these (81.7%) were
      dinucleotide or trinucleotide repeats. The GT/CA repeat motif was the most
      common, accounting for 42% of all repeat types. From a total of 43 primer pairs
      designed, 41 produced markers within the expected size range. Sixteen (39%) were
      polymorphic when screened against a restricted set of taro genotypes from
      Southeast Asia and Oceania, with an average of 3.2 alleles detected on each
      locus. These markers represent a useful resource for taro germplasm management,
      genome mapping, and marker-assisted selection.

PMID- 12416615
TI  - Genome size and developmental parameters in the homeothermic vertebrates.
AB  - Although unrelated to any intuitive notions of organismal complexity, haploid
      genome sizes (C values) are correlated with a variety of cellular and organismal
      parameters in different taxa. In some cases, these relationships are universal-
      notably, genome size correlates positively with cell size in each of the
      vertebrate classes. Other relationships are apparently relevant only in
      particular groups. For example, although genome size is inversely correlated with
      metabolic rate in both mammals and birds, no such relationship is found in
      amphibians. More recently, it has been suggested that developmental rate and (or)
      longevity are related to genome size in birds. In the present study, a large
      dataset was used to examine possible relationships between genome size and
      various developmental parameters in both birds and mammals. In neither group does
      development appear to be of relevance to genome size evolution (except perhaps
      indirectly in birds through the intermediation of body size and (or) within the
      rodents), a situation very different from that found in amphibians. These
      findings make it clear that genome size evolution cannot be understood without
      reference to the particular biology of the organisms under study.

PMID- 12416616
TI  - Towards the saturation of the pepper linkage map by alignment of three
      intraspecific maps including known-function genes.
AB  - Three populations composed of a total of 215 doubled haploid lines and 151 F2
      individuals were used to design an intraspecific consensus map of pepper
      (Capsicum annuum L.). The individual maps varied from 685 to 1668 cM with 16 to
      20 linkage groups (LGs). The alignment of the three individual maps permitted the
      arrangement of 12 consensus major linkage groups corresponding to the basic
      chromosome number of pepper and displaying a complex correspondence with the
      tomato map. The consensus map contained 100 known-function gene markers and 5
      loci of agronomic interest (the disease-resistance loci L, pvr2, and Pvr4; the C
      locus, which determines capsaicin content; and the up locus, controlling the
      erect habit of the fruits). The locations of three other disease-resistance loci
      (Tsw, Me3, and Bs3) and the y locus, which determines the yellow fruit colour,
      were also found on this consensus map thanks to linked markers. Here we report on
      the first functional detailed map in pepper. The use of candidate gene sequences
      as genetic markers allowed us to localize four clusters of disease-resistance
      gene analogues and to establish syntenic relationships with other species.

PMID- 12416617
TI  - Tandem repeats and length variation in the mitochondrial DNA control region of
      Epirrita autumnata (Lepidoptera: Geometridae).
AB  - The organization of the mitochondrial DNA (mtDNA) control region (CR) of the
      autumnal moth, Epirrita autumnata, is described. The E. autumnata CR presents a
      distinct type of lepidopteran CR with domains of non-repetitive and repetitive
      sequences. The CRs show considerable length variation owing to a variable number
      of short approximately 29-bp sequence blocks that are repeated between 6 and 14
      times in tandem. The organization of such a tandem array is unique among the
      insect CRs examined so far. Furthermore, the E. autumnata CR, which may reach
      1075 bp in length, is considerably longer than previously reported lepidopteran
      CRs, which reach 311-499 bp in length. Like other lepidopteran CRs, the E.
      autumnata CR contains two long homopolymer runs that may be involved in mtDNA
      replication and (or) transcription.

PMID- 12416618
TI  - Genetic diversity of root-knot nematodes from Brazil and development of SCAR
      markers specific for the coffee-damaging species.
AB  - RAPD markers were used to characterize the genetic diversity and relationships of
      root-knot nematodes (RKN) (Meloidogyne spp.) in Brazil. A high level of
      infraspecific polymorphism was detected in Meloidogyne arenaria, Meloidogyne
      exigua, and Meloidogyne hapla compared with the other species tested.
      Phylogenetic analyses showed that M. hapla and M. exigua are more closely related
      to one another than they are to the other species, and illustrated the early
      divergence of these meiotically reproducing species from the mitotic ones. To
      develop a PCR-based assay to specifically identify RKN associated with coffee,
      three RAPD markers were further transformed into sequence-characterized amplified
      region (SCAR) markers specific for M. exigua, Meloigogyne incognita and
      Meloidogyne paranaensis, respectively. After PCR using the SCAR primers, the
      initial polymorphism was retained as the presence or absence of amplification.
      Moreover, multiplex PCR using the three pairs of SCAR primers in a single
      reaction enabled the unambiguous identification of each species, even in
      mixtures. Therefore, it is concluded that the method developed here has potential
      for application in routine diagnostic procedures.

PMID- 12416619
TI  - Photographic polytene chromosome maps for Glossina morsitans submorsitans
      (Diptera: Glossinidae): cytogenetic analysis of a colony with sex-ratio
      distortion.
AB  - Photographic polytene chromosome maps from trichogen cells of pharate adult
      Glossina morsitans submorsitans were constructed. Using the standard system
      employed to map polytene chromosomes of Drosophila, the characteristic landmarks
      were described for the X chromosome and the two autosomes (L1 and L2). Sex-ratio
      distortion, which is expressed in male G. m. submorsitans, was found to be
      associated with an X chromosome (X8) that contains three inversions in each arm.
      Preliminary data indicate no differences in the fecundity of X(A)X(A) and
      X(A)X(B) females, but there are indications that G. m. submorsitans in colonies
      originating from Burkina Faso and Nigeria have genes on the autosomes and (or)
      the Y chromosome that suppress expression of sex-ratio distortion.

PMID- 12416620
TI  - A method for assaying the sensitivity of Drosophila replication checkpoint
      mutants to anti-cancer and DNA-damaging drugs.
AB  - In multi-cellular organisms, failure to properly regulate cell-cycle progression
      can result in inappropriate cell death or uncontrolled cell division leading to
      tumor formation. To guard against such events, conserved regulatory mechanisms
      called "checkpoints" block progression into mitosis in response to DNA damage and
      incomplete replication, as well as in response to other signals. Checkpoint
      mutants in organisms as diverse as yeast and humans are sensitive to various
      chemical agents that inhibit DNA replication or cause DNA damage. This phenomenon
      is the primary rationale for chemotherapy, which uses drugs that preferentially
      target tumor cells with compromised checkpoints. In this study, we demonstrate
      the use of Drosophila checkpoint mutants as a system for assaying the effects of
      various DNA-damaging and anti-cancer agents in a developing multicellular
      organism. Dwee1, grp and mei-41 are genes that encode kinases that function in
      the DNA replication checkpoint. We tested zygotic mutants of each gene for
      sensitivity to the DNA replication inhibitor hydroxyurea (HU), methyl
      methanosulfonate (MMS), ara-C, cisplatin, and the oxygen radical generating
      compound paraquat. The mutants show distinct differences in their sensitivity to
      each of the drugs tested, suggesting an underlying complexity in the responses of
      individual checkpoint genes to genotoxic stress.

PMID- 12416621
TI  - Highly informative nature of inter simple sequence repeat (ISSR) sequences
      amplified using tri- and tetra-nucleotide primers from DNA of cauliflower
      (Brassica oleracea var. botrytis L.).
AB  - Inter simple sequence repeat (ISSR) sequences as molecular markers can lead to
      the detection of polymorphism and also be a new approach to the study of SSR
      distribution and frequency. In this study, ISSR amplification with nonanchored
      primer was performed in closely related cauliflower lines. Fourty-four different
      amplified fragments were sequenced. Sequences of PCR products are delimited by
      the expected motifs and number of repeats, which validates the ISSR nonanchored
      primer amplification technique. DNA and amino acids homology search between
      internal sequences and databases (i) show that the majority of the internal
      regions of ISSR had homologies with known sequences, mainly with genes coding for
      proteins implicated in DNA interaction or gene expression, which reflected the
      significance of amplified ISSR sequences and (ii) display long and numerous
      homologies with the Arabidopsis thaliana genome. ISSR amplifications revealed a
      high conservation of these sequences between Arabidopsis thaliana and Brassica
      oleracea var. botrytis. Thirty-four of the 44 ISSRs had one or several perfect or
      imperfect internal microsatellites. Such distribution indicates the presence in
      genomes of highly concentrated regions of SSR, or "SSR hot spots." Among the four
      nonanchored primers used in this study, trinucleotide repeats, and especially
      (CAA)5, were the most powerful primers for ISSR amplifications regarding the
      number of amplified bands, level of polymorphism, and their nature.

PMID- 12416622
TI  - Genetic diversity among Canadienne, Brown Swiss, Holstein, and Jersey cattle of
      Canada based on 15 bovine microsatellite markers.
AB  - The genetic diversity among Canadienne, Brown Swiss, Holstein, and Jersey cattle
      was estimated from relationships determined by genotyping 20 distantly related
      animals in each breed for 15 microsatellites located on separate chromosomes. The
      Canadienne, Holstein, and Jersey cattle had an average of six alleles per loci
      compared with five alleles for Brown Swiss. Furthermore, a number of potentially
      breed-specific alleles were identified. The allele size variance among breeds was
      similar, but varied considerably among loci. All of the loci studied were equally
      heterozygous, as were Brown Swiss, Canadienne, and Holstein cattle (0.68-0.69)
      whereas Jersey cattle showed lower heterozygosity (0.59). The within-breed
      estimates of genetic distance were greater than zero and significant. The genetic
      distance between Canadienne and Holstein (0.156), Brown Swiss (0.243), and Jersey
      (0.235) was negligible, suggesting close relationship. Concurrently, Brown Swiss
      and Holstein (0.211) cattle also demonstrated close relationship. In contrast,
      the Jersey breed was genetically distant from the Brown Swiss and Holstein cattle
      (0.427 and 0.320, respectively). The characterization of Canadienne cattle, as
      part of the genetic resource conservation effort currently underway in Canada,
      underscores the difficulty in scientifically establishing unique breeds.
      Therefore, the need to consider all relevant morphological characteristics and
      production performance in combination with available cultural, historical,
      pedigree, and molecular information becomes relevant when identifying breeds for
      conservation.

PMID- 12416623
TI  - Molecular characterization and expression analysis of 1-aminocyclopropane-1
      carboxylate oxidase homologs from potato under abiotic and biotic stresses.
AB  - In this work, we report cloning of two full-length 1-aminocyclopropane-1
      carboxylate oxidase (ACO) cDNAs (ACO1 and ACO2) from potato (Solanum tuberosum)
      and their expression in potato tissues. The sequence data indicate that the two
      cDNAs share a high degree of homology with each other, and with known ACO genes
      from other plant species, including monocots and dicots. However, these potato
      genes lack homology at the 5' and 3' ends, despite similarities in their open
      reading frames and encoded amino acids. Phylogenetic analysis places them in two
      subfamilies of ACOs. The genes are tissue specific: expression is high in leaves
      and low in roots and tubers. In sprouts and tubers, ACO1 is induced by heat (40
      degrees C) and cold (0 degrees C) stresses, whereas ACO2 is induced only by cold
      (0 degrees C). ACO1 is markedly induced in leaves by wounding, soil-flooding, and
      exogenous application of 1-aminocyclopropane-1-carboxylic acid (ACC). In
      contrast, ACO2 induction is lower under these treatments. ACO1 and ACO2 are
      regulated very differently in potato leaves with respect to senescence. ACO2
      expression is unaffected by senescence, whereas that of ACO1 is closely related
      to the age and senescence in both attached and detached leaves. Exogenous ACC not
      only induces ACO1, but also accelerates leaf senescence. ACO1 transcripts are
      induced significantly in leaves, stems, and tubers in the Potato virus A (PVA)
      resistant potato cultivar Shepody when graft inoculated with PVA.

PMID- 12416624
TI  - Application of AFLP markers for QTL mapping in the rabbit.
AB  - Two rabbit (Oryctolagus cuniculus) inbred strains (AX/JU and IIIVO/JU) have been
      used for genetic analysis of quantitative traits related to dietary cholesterol
      susceptibility. Application of the AFLP (amplified fragment length polymorphism)
      technique with 15 primer combinations revealed 226 polymorphisms between the 2
      inbred strains. A total of 57 animals from a backcross progeny (IIIVO/JU x
      [IIIVO/JU x AX/JU]F1) were available for the genetic analysis. These backcross
      animals were fed a commercial pelleted diet fortified with 0.3% w/w cholesterol
      during a test period that lasted five weeks. A male genetic map could be
      constructed, consisting of 12 linkage groups and 103 AFLP markers. Linkage
      analysis between the cholesterol-related traits and marker loci revealed a
      significant LOD score for the relative weight of adrenal glands in males (LOD
      score = 3.83), whereas suggestive linkages were found for basal serum total
      cholesterol levels in females (LOD score = 2.69), for serum total cholesterol
      response (area under the curve) in males (LOD score = 2.21), and for hematocrit
      in males (LOD score = 3.24).

PMID- 12416625
TI  - Comparative analysis of different satellite DNAs in four Mytilus species.
AB  - We report the characterization of three satellite DNAs in four species of mussel:
      Mytilus edulis, Mytilus galloprovincialis, Mytilus trossulus, and Mytilus
      californianus. The monomers of the Apa I satellite DNAs were 173, 161, and 166 bp
      long. These satellite monomers were used to construct phylogenetic trees to infer
      relationships among these species. The topologies obtained clearly indicate that
      M. californianus is the most divergent species with respect to the other three.
      Furthermore, localization of satellite DNAs on metaphase chromosomes was
      performed using fluorescent in situ hybridization (FISH). Fluorescent signals
      revealed a different organization and distribution of these three satellite DNAs.

PMID- 12416626
TI  - DNA methylation analysis of a male reproductive organ specific gene (MROS1)
      during pollen development.
AB  - Pollen grains of angiosperm plants represent a good model system for studies of
      chromatin structure and remodelling factors, but very little is known about the
      DNA methylation status of particular genes in pollen. In this study, we present
      an analysis of the DNA methylation patterns of the MROS1 gene, which is expressed
      in the late phases of pollen development in Silene latifolia (syn. Meladrium
      album). The genomic sequencing technique revealed similar DNA methylation
      patterns in leaves, binucleate pollen, and trinucleate pollen. Extremely high DNA
      methylation levels occurred in the CG dinucleotides of the upstream region (99%),
      whereas only a low level of CG methylation was observed in the transcribed
      sequence (7%). Low levels of methylation were also observed in asymmetric
      sequences (in both regions; 2% methylated). The results obtained in the MROS1
      gene are discussed in consequence with the immunohistochemical data showing a
      hypermethylation of DNA in the vegetative nucleus.

PMID- 12416627
TI  - Resolving the aphid resistance locus Sd-1 on a BAC contig within a sub-telomeric
      region of Malus linkage group 7.
AB  - Aphids cause serious physical and economic damage to most major crops throughout
      the world, and there is a pressing requirement to isolate genes conferring aphid
      resistance. The Sd-1 locus in Malus spp. (apple) confers resistance against the
      rosy leaf-curling aphid (Dysaphis devecta Wlk.), and was recently positioned
      within a 1.3-cM region on linkage group 7, flanked by molecular markers. These
      markers were used as a basis for development of a BAC contig spanning the locus,
      together with adapter-mediated amplification of flanking sequences to obtain BAC
      insert-end sequences, and fingerprinting of BAC clones. Approximately 800 kb of
      the Sd-1 genomic region was covered by 19 overlapping BACs, with an average
      insert size of 75-150 kb. The physical-genetic distance ratio was estimated at
      460 kb/cM, although the distribution of recombination events was irregular with
      respect to estimated physical distance. Recombinant analysis and development of
      new markers allowed Sd-1 to be positioned within an interval of approximately 180
      kb located on either of two overlapping BACs. From one of these, an insert end
      sequence showed a significant degree of similarity to nucleotide binding site
      leucine rich repeat (NBS-LRR) resistance genes. Fluorescent in situ hybridization
      (FISH) of BAC clones within the contig enabled positioning and orientation of the
      locus within a euchromatic region, very close to the telomere of linkage group 7.

PMID- 12416628
TI  - Genus-specific localization of the TaiI family of tandem-repetitive sequences in
      either the centromeric or subtelomeric regions in Triticeae species (Poaceae) and
      its evolution in wheat.
AB  - The TaiI family sequences are classified as tandem repetitive DNA sequences
      present in the genome of tribe Triticeae, and are localized in the centromeric
      regions of common wheat, but in the subtelomeric heterochromatic regions of
      Leymus racemosus and related species. In this study, we investigated the
      chromosomal distribution of TaiI family sequences in other Triticeae species. The
      results demonstrated a centromeric localization in genera Triticum and Aegilops
      and subtelomeric localization in other genera, thus showing a genus-dependent
      localization of TaiI family sequences in one or the other region. The copy
      numbers of TaiI family sequences in species in the same genus varied greatly,
      whether in the centromeric or subtelomeric regions (depending on genus). We also
      examined the evolution of TaiI family sequences during polyploidization of
      hexaploid common wheat. A comparison of chromosomal locations of the major TaiI
      family signals in common wheat and in its ancestral species suggested that the
      centromeric TaiI family sequences in common wheat were inherited from its
      ancestors with little modification, whereas a mixed origin for the B genome of
      common wheat was indicated.

PMID- 12416629
TI  - Molecular analysis of the complete set of length mutations found in the plastomes
      of Triticum-Aegilops species.
AB  - Precise location and nature of each of 14 length mutations detected among
      chloroplast DNAs of Triticum-Aegilops species by RFLP analysis were determined at
      the nucleotide sequence level. Each mutation was compared with at least three non
      mutated wild-type plastomes as standards. These 14 length mutations were
      classified into 4 duplications and 10 deletions. One duplication occurred in the
      small single-copy region close to the border of the inverted repeat, and the
      remaining 13 length mutations took place in the large single-copy region. All
      length mutations occurred in the intergenic regions, suggesting that these length
      mutations do not affect plastid gene expression. Saltatory replication was the
      cause of all duplications, whereas intramolecular recombination mediated by short
      direct repeats played a substantial role in the deletions. Recurrent occurrences
      of certain deletion events were found in some AT-rich regions, which constituted
      hot spots for deletion. Out of four hypervariable regions detected among the
      grass plastomes, two (downstream of rbcL and a tRNA gene accumulated region) were
      still active after differentiation of Triticum and Aegilops complex.

PMID- 12416630
TI  - Analysis of 106 kb of contiguous DNA sequence from the D genome of wheat reveals
      high gene density and a complex arrangement of genes related to disease
      resistance.
AB  - Vast differences exist in genome sizes of higher plants; however, gene count
      remains relatively constant among species. Differences observed in DNA content
      can be attributed to retroelement amplification leading to genome expansion.
      Cytological and genetic studies have demonstrated that genes are clustered in
      islands rather than distributed at random in the genome. Analysis of gene islands
      within highly repetitive genomes of plants like wheat remains largely unstudied.
      The objective of our work was to sequence and characterize a contiguous DNA
      sequence from chromosome IDS of Aegilops tauschii. An RFLP probe that maps to the
      Lr21 region of IDS was used to isolate a single BAC. The BAC was sequenced and is
      106 kb in length. The contiguous DNA sequence contains a 46-kb retroelement-free
      gene island containing seven coding sequences. Within the gene island is a
      complex arrangement of resistance and defense response genes. Overall gene
      density in this BAC is 1 gene per 8.9 kb. This report demonstrates that wheat and
      its relatives do contain regions with gene densities similar to that of
      Arabidopsis.

PMID- 12416631
TI  - Localization of a new highly repeated DNA sequence of Lemur cafta (Lemuridae,
      Strepsirhini).
AB  - We have isolated and cloned an 800-bp highly repeated DNA (HRDNA) sequence from
      Lemur catta (LCA) and described its localization on LCA chromosomes. Lemur catta
      HRDNA sequences were localized by performing FISH experiments on standard and
      elongated metaphasic chromosomes using an LCA HRDNA probe (LCASAT). A complex
      hybridization pattern was detected. A strong pericentromeric hybridization signal
      was observed on most LCA chromosomes. Chromosomes 7 and 13 were lit in
      pericentromeric regions, as well as in the interspersed heterochromatin.
      Chromosomes 1, 3, 4, 17, 19, X, and microchromosomes (20, 25, 26, and 27) showed
      no signals in the pericentromeric region, but chromosomes 3 and 4 showed a
      positive hybridization in heterochromatic regions. The 800-bp L catta HRDNA was
      species specific. We performed FISH experiments with the LCASAT probe on Eulemur
      macaco macaco (EMA) and Eulemur fulvus fulvus (EFU) metaphases and no positive
      signal of hybridization was detected. These findings were also confirmed by
      Southern blot analysis and PCR.

PMID- 12416632
TI  - Direct capture and cloning of receptor kinase and peroxidase genes from genomic
      DNA.
AB  - A direct DNA capture and cloning procedure with magnetic bead separation was used
      to isolate receptor kinase like and peroxidase genes from oat (Avena sativa) and
      wheat (Triticum aestivum L.) genomic DNA, respectively. In this procedure, the
      digoxigenin-labeled probe DNA and target genomic DNA fragments were mixed,
      denatured, and hybridized. The double-helix complexes formed were captured with
      anti-digoxigenin immunoglobulin-coated magnetic beads and then cloned into either
      the lambdaBlueSTAR or pUC18 vector. The effectiveness of this procedure was
      demonstrated by using two specific DNA probes to capture receptor-like kinase
      genes and surrounding sequences from oat genomic DNA and a peroxidase gene from
      wheat genomic DNA.

PMID- 12416633
TI  - A set of microsatellite markers for fingerprinting and breeding applications in
      Pinus radiata.
AB  - Fifty microsatellite markers were developed and characterized in Pinus radiata,
      and from among these, a subset of 10 easily scored and highly polymorphic markers
      was selected for use in fingerprinting, quality control, and breeding
      applications. The markers were characterized based on reliable and reproducible
      amplification, observed and expected heterozygosities, number of alleles, a low
      frequency of null alleles, and a lack of close linkage with other selected
      markers. Allele numbers and frequencies were estimated using 24 first-generation
      breeding clones from Australia and New Zealand. Observed heterozygosities for the
      selected markers were all greater than 0.67, and there was an average of 10.5
      alleles/locus. The occurrence of null alleles was checked with megagametophytes
      from mother trees for loci that appeared to be homozygous. The 10 markers are not
      closely linked (r < 0.20 and LOD > 3) to each other. The selected microsatellites
      fall into three discrete size classes, and with appropriate selection of
      fluorescent dyes for 5' end labeling, can be multiplexed with up to 6
      markers/sample on an ABI PRISM 310 or similar instrument.

PMID- 12416634
TI  - Personality profiles of youngsters with velo-cardio-facial syndrome.
AB  - The personality profile of 48 youngsters (24 males and 24 females, mean age 8
      years, 5 months) with Velo-Cardio-Facial Syndrome (VCFS) was compared with a
      group of 240 non VCFS control youngsters (matched on age and gender), and, in
      addition, with groups of youngsters with Prader-Willi (PWS), Fragile X (FXS), and
      Williams Syndromes (WS). Personality characteristics of each youngster were rated
      by both parents, using the California Child Q-set (CCQ). The scores on eight
      personality dimensions were compared, i.e., Extraversion, Agreeableness,
      Conscientiousness, Emotional Stability, Openness, Motor Activity, Irritability,
      and Dependency. Moreover, Individual differences in personality of VCFS
      youngsters were related to IQ level, presence or absence of cardiac defects, and
      de novo versus familial origin of VCFS. The personality profile of VCFS
      youngsters was markedly different from all non-VCFS groups. Compared to the 240
      control children, they were equally extravert and agreeable, less conscientious
      and emotional stable and more Irritable and dependent. Some personality
      characteristics in youngsters with VCFS were related to IQ and Age, but not to
      cardiac defects or de novo versus familial genetic origin of the 22q11 deletion.

PMID- 12416635
TI  - An unusual human mosaic for skin pigmentation.
AB  - Patterned pigmentary disturbances are seen in a large variety of human genetic
      disorders. Cytogenetic studies have provided evidence that such skin lesions
      often reflect chromosomal mosaicism. In addition to the well-known pattern of
      Blaschko's lines a classification of several distinct types was proposed by
      Happle. This report add the case of a boy with an unusual mosaic-like
      distribution of skin pigmentation and a further chromosomal anomaly which has not
      been described in pigmentary mosaicism previously. The proband was born after an
      uneventful pregnancy and delivery. Developmental milestones were delayed. A
      generalised hirsutism was noted with a facial dysmorphia: coarse facies. short
      philtrum, synophris, and large low set years. Hyperpigmentation followed a
      checkerboard pattern: alternating squares of pigmentary anomalies with a sharp
      midline separation. Cytogenetic findings Included a normal karyotype (peripheral
      blood) and a mosaicism 12q;14q translocation (70% of fibroblasts). The present
      case stresses the importance of careful chromosomal analysis of different tissues
      in patients with pigmentary anomalies.

PMID- 12416636
TI  - Severe hypophosphatasia due to mutations in the tissue-nonspecific alkaline
      phosphatase (TNSALP) gene.
AB  - Hypophosphatasia is a rare autosomal recessive inborn error of metabolism
      characterized by a defective bone mineralisation and deficiency of serum and
      tissue liver/bone/kidney alkaline phosphatase activity. We report the
      characterisation of tissue-nonspecific alkaline phosphatase (TNSALP) gene
      mutation in a patient affected by infantile hypophosphatasia. This boy was the
      first child of non affected, non related parents. At 1 month of age he presented
      with palsy of the left upper limb with hypotonia. Length was - 2SD. The anterior
      fontanel was large. There was a markedly decreased ossification of all bones. All
      limbs were shortened. Ultrasonographic examination of the kidneys showed
      nephrocalcinosis. Level of alkaline phosphatases was decreased in the child as
      well as in the parents. Bone density was decreased. At 2 years of age development
      was delayed. Weight was - 3,5 SD and OFC - 3SD. The child had craniosynostosis.
      Molecular studies showed 2 missense mutations, both in exon 6 of the TNSALP gene.

PMID- 12416637
TI  - Wolf-Hirschhorn (4p-)syndrome in a near adult with major depression; successful
      treatment with citalopram.
AB  - The Wolf-Hirschhorn Syndrome (WHS) or 4p-deletion syndrome is characterized by
      mental retardation, growth retardation, microcephaly and typical facial features.
      In addition, a wide spectrum of somatic abnormalities can be associated that may
      cause comorbidity. The syndrome has been extensively described in children, but
      less information is available about adult patienis. In this case report a near
      adult female WHS patient is described who developed a major depression with
      atypical symptoms that was successfully treated with citalopram. Treatment for
      one year in the effective dose prevented recurrence of depressive symptomatology.

PMID- 12416638
TI  - Terminal tandem duplication of 16p: a case with "pure" partial trisomy (16)(pter-
      >p13).
AB  - A new-born infant was found to have multiple congenital anomalies Including
      bilateral cleft of lip and palate, club-hands and feet, and heart defects. High
      resolution chromosome analysis showed a de novo tandem duplication of the
      terminal part of the short arm of chromosome 16, resulting in a dup(16)(pter-
      >p13). Fluorescent in situ hybridization with a chromosome 16-specific paint
      confirmed that the extra material belonged to chromosome 16.

PMID- 12416639
TI  - Spondylothoracic dysostosis associated with diaphragmatic hernia and
      camptodactyly.
AB  - We present a case of a female newborn with a combination of congenital
      diaphragmatic hernia, skeletal defects, craniofacial dysmorphism, dextrocardia
      and persistent ductus arteriosus, and normal female karyotype. History of family
      and pregnancy-labour were non-contributory. The findings in the present patient
      are most compatible with the diagnosis of a spondylothoracic dysostosis with a
      set of uncommon anomalies.

PMID- 12416640
TI  - Association of ectrodactyly and distal phocomelia.
AB  - Ectrodactyly and phocomelia are well known limbs malformations. They can be a
      part of various syndromes, and are more often transmitted with dominant autosomal
      Inheritance with variable expression and Incomplete penetrance. Different loci
      have been Identified for ectrodactyly (SHFM1 at 7q21.3q22.1, SHFM2 at Xq26, SHFM3
      at 10q24q25, SHFM4 at 3q27), and two genes are known (DSS1 for SHFM1, p63 for
      SHFM4). We report the case of a 33 year-old female affected with the association
      of ectrodactyly and phocomelia. It could be a "new" association, or a mild or
      partial expression of the syndrome Including ectrodactyly, phocomelia, deafness
      and sinusal arythmia.

PMID- 12416641
TI  - Unilateral absent scaphoid in a patient with "Holt-Oram" syndrome.
AB  - The absence of the scaphold in a patient with Holt-Oram syndrome is reported.
      Only a few similar cases have been published.

PMID- 12416642
TI  - Classification for congenital anomalies of the hand: the IFSSH classification and
      the JSSH modification.
AB  - The purpose of a classification for clinical problems which, except for a few
      specialized centers, occur only sporadically is to provide a system where these
      cases can be stored. This should allow all involved investigators to speak the
      same language; so-doing syndromes can be delinated, frequencies of occurence
      established and results of--different--treatments compared. A classification
      system should be simple to use, reliable and uniformly accepted. It should allow
      space for adaptations and/or extensions. The IFSSH proposed a 7 categories
      classification based on the proposed classification of Swanson et al. in 1976.
      This classification, was based on, which was thought in the seventies,
      etiopathogenic pathways. These 7 groups are: I. Failure of formation; transverse
      (A), or longitudinal (B) II. Failure of differentiation III. Polydactyly IV.
      Overgrowth V. Undergrowth VI. Amniotic band syndrome VII. Generalized skeletal
      syndromes. The extended classification proposed by IFSSH was used to classify
      1013 hand differences in 925 hands of 650 patients. We found associated anomalies
      in 26.7%. The classification was straightforward in 86%, difficult in 6.6% and
      not possible in 7.8%. Group II was the most numerous group including 513
      anomalies. We propose to include in this group the Madelung deformity, the Kirner
      deformity and congenital trigger fingers and trigger thumbs. In group I the
      radial and ulnar deficiencies, limited to the hand without forearm deficlencies
      should be Included. Triphalangeal thumbs are a problem, we suggest it to be
      listed in group III and consider it as a duplication in length. It is not always
      possible to evaluate the (transverse) absence of the fingers or hand.
      Longitudinal deficiencies (group IIB), symbrachydactyly (group V), and amniotic
      bands (group IV) occasionally develop a phenotype similar to the genuine
      transverse deficiency (group IA). Recently, the Japanese Society for Surgery of
      the Hand (JSSH) (16) proposed an extension/modification of the IFSSH
      classification. Based on newer knowledge on teratology, symbrachydactyly in all
      stages were transfered to group I. Two new groups were introduced. A group
      "failure of finger ray induction" including typical cleft hand (IC), central
      polydactyly (III) and (bony) syndactyly (II)--was included. Also a group of
      "unclassifiable" cases was added. This Japanese proposed classification is a real
      improvement and most clinicians and surgeons tend to use it in the future.

PMID- 12416643
TI  - Antioxidant system in Down syndrome: a possible role in cataractogenesis.
AB  - Recent studies show a relationship between oxidants, antioxidants, and
      degenerative disease of aging like cataract formation. Focal lens cortical
      changes and cortical liquification have been reported in patients with Down
      syndrome (DS) over 14 years. There is evidence supporting the hypothesis that
      trisomy 21 patients have an increase in free radical reactions. These changes in
      antioxidant system may play a role in cataractogenesis in Down syndrome. We
      screened serum samples from 12 patients with DS and cataract: and 12 healthy age
      and sex-matched persons. We evaluated the antioxidant enzyme activities of
      superoxide dismutase (SOD), glutathione peroxidase (GSHPx), glutathione-S
      transferase (GST) and reduced glutathione (GSH) in erythrocytes. SOD and GSHPx
      levels of patients with DS were significantly higher than the control group. No
      significant changes were observed in GST and GSH levels between the DS and
      control groups. These findings suggest impairment in antioxidant system, which
      may be a possible mechanism for early cataract formation in DS.

PMID- 12416644
TI  - Filippi syndrome: a specific MCA/MR complex within the spectrum of so called
      "craniodigital syndromes". Report of an additional patient with a peculiar mpp
      and review of the literature.
AB  - Filippi syndrome is a specific Multiple Congenital Abnormalities/Mental
      Retardation (MCA/MR) complex which must not be confused with other so called
      "craniodigital syndromes", a heterogeneous group of pathological conditions
      simply lumped for the combination of different cranial and digital anomalies. We
      report on a new patient with the characteristic features of Filippi syndrome,
      comparing him with other reported cases and underlining the peculiar and specific
      shape of the nasal bridge. The metacarpophalangeal profile in our patient is also
      quite unusual and could be, if confirmed, a good marker of this syndrome.

PMID- 12416645
TI  - Costello syndrome in two siblings and minor manifestations in their mother.
      Further evidence for autosomal dominant inheritance?
AB  - We report on two siblings: the index patient, a 9 months old boy and his 2.5
      years old sister, both presenting the main clinical signs and symptoms of
      Costello syndrome (CS): severe mental and motor retardation, feeding
      difficulties, failure to thrive in the first months of life, coarse facial
      appearance, skin hyperlaxity and skeletal deformities. Their mother presented
      with mild to moderate mental retardation, short stature, facial fullness and wart
      like lesions on her face. The present observation confirms previous data on the
      apparent autosomal dominant pattern of inheritance in Costello syndrome with
      variable expression.

PMID- 12416646
TI  - Gaucher disease in a Turkish family.

PMID- 12416647
TI  - De novo mosaic 46,XX,del(3)(q21q25)/46,XX karyotype in a patient with BPES.

PMID- 12416648
TI  - Ovarian response to gonadotropin stimulation in repeated IVF cycles after
      unilateral salpingectomy.
AB  - PURPOSE: This study aimed to examine ovarian response to gonadotrpoin stimulation
      after repeated IVF treatment cycles in patients who underwent previous unilateral
      salpingectomy for tubal pregnancy. METHODS: The study group included 26 patients
      who underwent unilateral salpingectomy for tubal pregnancy 1-9 years prior to
      starting IVF treatment. A control group of 52 patients with anatomically intact
      pelvis was treated during the same time period by ICSI. The two groups were
      matched for age, number of gonadotropin ampules, and length of stimulation. End
      point measurements included number of follicles, oocytes, and cleaved embryos in
      consecutive treatment cycles of each group. RESULTS: There were 98 cycles in the
      study group and 154 cycles in the control group. The mean number of follicles,
      retrieved oocytes, and cleaved embryos were not different in the two groups, and
      no reductions in these parameters were noted up to 10 cycles of treatment. The
      mean number of follicles ipsilateral to the operated side was similar to the
      number of follicles of the contralateral ovary and was not different whether
      salpingectomy was by laparoscopy or laparotomy. CONCLUSIONS: Unilateral
      salpingectomy does not affect ipsilateral ovarian response to gonadotropin
      stimulation even after repeated IVF treatment cycles.

PMID- 12416649
TI  - Zygote versus embryo transfer: a prospective randomized multicenter trial.
AB  - PURPOSE: To determine the efficiency of transferring human zygotes as opposed to
      human day 2 or 3 embryos. METHODS: A prospective, randomized, Multicenter trial.
      Patients were randomized into zygote or embryo transfer. Patients were prepared
      for oocyte retrieval using standardized protocols. Oocyte retrieval was performed
      under general anesthesia. Oocytes and spermatozoa were treated using standard
      laboratory techniques. All protocols were coordinated by the coordinating center.
      RESULTS: A total of 386 patients were included in the trial. Pregnancy rates were
      36.5% after zygote transfer and 42% after embryo transfer. Implantation rates
      were equivalent (17%) in both groups. CONCLUSIONS: No general difference was
      observed for zygote or embryo transfer. The results suggest that zygote transfer
      is a valid alternative to embryo transfer.

PMID- 12416650
TI  - A comparison of oocyte donors' and gestational carriers/surrogates' attitudes
      towards third party reproduction.
AB  - PURPOSE: This study was designed to compare levels of satisfaction for ovum
      donors and gestational carriers/surrogates (GCS), investigate attitudes, and
      explore beliefs about the role genetics, gestation, and environment play in
      various characteristics. DESIGN: An east coast IVF center and two California
      based agencies recruited donor and GCS candidates. METHODS: Participants received
      mailed questionnaires that included sections on demographics, attitudes, and
      beliefs. RESULTS: Both groups were highly satisfied with their participation.
      Donors were not willing to be GCS, and GCS were not willing to be donors. GCS
      thought about and disclosed their participation, felt children should be told
      about GCS, and desired future contact with the child(ren) more than did donors (p
      < 0.002). Donors did not indicate a preference about disclosure. Contact with
      recipients did not correlate with satisfaction. CONCLUSION: Women who chose to
      donate eggs or to be GCS hold distinct and different beliefs about the role of
      gestation and genetics.

PMID- 12416651
TI  - A group-comparative, randomized, double-blind comparison of the efficacy and
      efficiency of two fixed daily dose regimens (100- and 200-IU) of recombinant
      follicle stimulating hormone (rFSH, Puregon) in Asian women undergoing ovarian
      stimulation for IVF/ICSI.
AB  - PURPOSE: To compare the efficacy, efficacy and safety of a fixed daily dose of
      recombinant FSH (Puregon) of a 100- and 200-IU regimen in Asian women undergoing
      ovarian stimulation for IVF/ICSI. METHODS: This was a prospective, randomized,
      double-blind, multicenter (n = 9) study. Prior to the start of rFSH, all women
      were pretreated with a gonadotropin releasing hormone agonist (GnRH-a) for
      pituitary downregulation. RESULTS: A total of 330 women were treated with rFSH:
      163 subjects with 100 IU and 167 subjects with 200 IU. In the 200 IU treatment
      group, significantly more oocytes were retrieved compared to the 100 IU group
      (9.6 vs. 5.0 oocytes, p < 0.001). The total dose rFSH needed to develop at least
      three follicles with a diameter of >17 mm was significantly lower in the 100 IU
      treatment group (1,194 vs. 2,034 IU, p < 0.001). Although more cycle
      cancellations were seen in the 100 IU group (24 vs. 13%), the ongoing pregnancy
      rate per started cycle was comparable between both groups (16.6% in the 100 IU
      group vs. 15.0% in the 200 IU group). CONCLUSIONS: The use of a 100 IU fixed dose
      is less effective in terms of the number of oocytes retrieved and the higher
      cancellation rate, but more efficient as indicated by a lower total recombinant
      FSH dose needed.

PMID- 12416652
TI  - Sperm MTT viability assay: a new method for evaluation of human sperm viability.
AB  - PURPOSE: MTT (3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide)
      assay is commonly used as a cell proliferation assay. The objective of this study
      was to evaluate the capability of MTT assay to discriminate between viable and
      nonviable sperms and compare it sefficiency with E&N (eosin and nigrosin) and
      HOST (hypo-osmotic swelling test). METHODS: MTT assay was modified to obtain
      optimal result for assessment of sperm viability. After standardization of
      method, MTT, E&N, and HOST were carried out simultaneously on 57 semen samples
      from patients referring to Isfahan Fertility and Infertility Center. The
      correlation coefficient between these tests and sperm motility was calculated
      using the SPSS statistical program. Specificity and sensitivity of each test was
      also obtained. RESULTS: The optimal conditions for sperm MTT viability assay were
      2 h after addition of sperm to MTT in HAM'S F10 + 25 mM HEPES + 10% HSA at 37
      degrees C and pH 7.4-7.45. Inter- and intra-assay coefficients of variations were
      9 and 7%, respectively. The sensitivity and specificity for sperm MTT viability
      assay, E&N, and HOST were 97,98, and 99%, and 100, 100, and 83% respectively.
      High significant correlations were obtained between sperm MTT viability assay,
      E&N, HOST and motility. CONCLUSIONS: Sperm MTT viability assay can be used as a
      diagnostic test for discrimination of viable sperms from sperm population.

PMID- 12416653
TI  - Screening of novel matrix metalloproteinases (MMPs) in human fetal membranes.
AB  - OBJECTIVE: Endogenous activation of matrix metalloproteinase (MMP) in human fetal
      membranes is hypothesized to contribute to membrane weakening leading to early
      rupture and is also involved in the initiation of labor. Our laboratory and
      several others have studied the source and action of some of these MMPs. The
      objective of this study is to document the expression pattern of most of the MMPs
      cloned and sequenced so far in amniochorion during preterm premature rupture of
      membranes (pPROM), at term not in labor and during term labor. MATERIALS AND
      METHODS: Placentas were collected from women with PROM, term not in labor after C
      sections and from women after term vaginal delivery. Membranes were separated
      from the placenta and a section away from the rupture site was selected.
      Amniochorion were separated from the placenta. RT-PCR was performed to study the
      expression pattern of MMP15 (MT2-MMP), MMP16 (MT3-MMP), MMP17 (MT4-MMP), MMP18,
      MMP20, MMP23, MMP24 (MT5-MMP), MMP25 (MT6-MMP), and MMP 26 using specific
      primers. RESULTS: A differential pattern of expression was noted for some of the
      novel MMPs screened in this study in human fetal membranes. mRNA for most of the
      MMPs were expressed by amniochorion. MMP16 [membrane type metalloproteinase 3],
      MMP20 [enamelysin], and MMP26 [matrilysin] were not expressed. CONCLUSION:
      Amniochorion expresses several of the MMP genes at the time of pPROM, term not in
      labor and during active labor. We have previously reported the expression pattern
      of other MMPs and their inhibitors and their potential role in PROM. These
      findings support our hypothesis that amniochorion has a fully functional MMP
      system.

PMID- 12416654
TI  - Enhanced cryosurvival of bovine blastocysts produced in vitro in serum-free
      medium.
AB  - PURPOSE: Culture systems affect the development of IVP embryos and consequently
      their cryosurvival potential. The viability of postthawed bovine IVP embryos
      developed from IVM/IVC medium in the presence or absence of serum was compared.
      METHODS: Cumulus-oocyte complexes were matured in IVM medium supplemented with or
      without serum. Some oocytes were evaluated for nuclear maturation status and
      others were inseminated with semen. Presumptive zygotes were cultured in IVC
      medium supplemented with or without serum for 9 days. Blastocysts were
      cryopreserved with 1.5 M ethylene glycol in PBS. RESULTS: No difference was
      observed in the nuclear maturation status and cleavage rates in both groups, but
      significantly (P < 0.05) higher in blastocyst rates in the serum-supplemented
      group. After freezing, survival of blastocysts was higher in the serum-free
      group. At 36 h culture after thawing, blastocysts developed without serum had
      significantly (P < 0.05) higher cell number than those cultured with serum.
      CONCLUSIONS: We conclude that serum-free culture system enhances the viability of
      frozen-thawed bovine embryos.

PMID- 12416655
TI  - Resumption of meiosis-I tissue to enucleated preovulatory oocytes: a preliminary
      report.
AB  - PURPOSE: Ovarian tissue banking may be the best strategy to preserve female
      fertility. But optimal method to obtain viable mature oocytes remains
      challenging. In order to bypass the long in vitro oocyte growth period, we
      developed this study to test whether reconstruction of thawed primordial oocytes
      with enucleated preovulatory germinal vesicle (GV) oocytes could induce dictyate
      nuclei to undergo chromosomal condensation and meiotic maturation. METHODS:
      Isolated primordial oocytes from thawed mouse ovarian tissue were reconstructed
      with enucleated GV oocytes. After electrofusion and in vitro maturation, the
      reconstituted oocytes were assessed for first polar body extrusion, cytoskeleton
      configuration, and chromosome abnormalities. RESULTS: Primordial oocytes from
      thawed ovarian tissue showed a high survival rate. Following transfer and
      electrofusion, they could be fused with enucleated GV oocytes (35.6%, 36/101) and
      extruded a first polar body (52.8%,19/36). These mature oocytes showed a normal
      spindle configuration and chromosome number. CONCLUSIONS: We successfully
      established a mouse cell model to prove that omitting the whole growth and
      maturation period by transfer of primordial oocytes to developmentally older
      enucleated oocytes would bypass the long growth period required to the
      preovulatory stage. Polar body extrusion could also ensue after in vitro growth.
      This study provided an alternative approach for future investigations in oocyte
      maturation.

PMID- 12416656
TI  - Possible direct cytoxicity effects of cyclophosphamide on cultured human
      follicles: an electron microscopy study.
AB  - PURPOSE: To evaluate the direct effect of cyclophosphamide on cultured human
      ovarian follicles. METHODS: Human ovarian cortical slices from premenopausal
      women were incubated with medium containing cyclophosphamide (0.0005-0.5 mg/mL)
      for 2-48 h and assessed by transmission electron microscopy. Noncultured
      specimens and samples cultured without cyclophosphamide were used as controls.
      RESULTS: There were significantly more damaged granulosa cell nuclei after
      incubation with 0.5 mg/mL cyclophosphamide for at least 4 h. There were also more
      changes in the basement membrane after incubation with cyclophosphamide at
      concentrations of 0.05 and 0.5 mg/mL. CONCLUSIONS: Although the cyclophosphamide
      dose that caused damage to the granulosa cell nuclei was above the
      pharmacological level, our results suggest that cyclophosphamide, and not only
      its active metabolite phospharamide mustard, might have a destructive effect on
      human follicles, as it remains in the circulation longer. This effect could be
      mediated by damage to the granulosa cells and perhaps the basement membrane.

PMID- 12416657
TI  - Long-term effect of fish oil diet on basal and stimulated plasma glucose and
      insulin levels in ob/ob mice.
AB  - In this study, the ob/ob mouse model was used to investigate epidemiological
      evidence linking fish intake to relative reduction in incidence of Type 2
      diabetes mellitus and glucose. We have investigated, in comparison to low and
      high fat diets, the effect of a fish oil diet on basal and stimulated plasma
      glucose and insulin levels in male and female ob/ob mice. Mice were fed for 12
      months with a saturated fat diet containing 25% lard, with a low fat diet
      containing 5% soybean oil, with a polyunsaturated fat diet containing 25%
      safflower seed oil (n-6) or with polyunsaturated fat diet containing 23% fish oil
      (n-3). Total body weight increased to approximately 100 g at the end of the
      experiment, with the highest increase in the order of lard > safflower oil > fish
      oil > soybean oil diet. Intercurrent deaths were found especially in the fish oil
      diet group. Compared to the other diet groups, plasma insulin levels of the fish
      oil diet group were significantly increased 3 months after the start of the diet
      and remained higher for another 3 months. Thereafter, the level declined to those
      of the other diet groups. Glucose-tolerance tests at 3, 6, 8 and 10 months showed
      a tendency of more efficient tissue glucose uptake in the fish oil group compared
      to the other groups, which was in accordance with a higher plasma insulin levels.
      At 12 months, microscopy revealed an increased severity of hepatic brown pigment
      accumulation and extramedullary haematopoiesis in the spleen of mice fed with
      fish oil. We conclude that fish oil diet in ob/ob mice reduced the body weight
      gain and increased the glucose-induced insulin secretion. Fish oil diet also
      increased intercurrent mortality. However, a consistent course of death could not
      be established using morphological parameters.

PMID- 12416658
TI  - Predicting Type 2 diabetes using an electronic nose-based artificial neural
      network analysis.
AB  - Diabetes is a major health problem in both industrial and developing countries,
      and its incidence is rising. Although detection of diabetes is improving, about
      half of the patients with Type 2 diabetes are undiagnosed and the delay from
      disease onset to diagnosis may exceed 10 yr. Thus, earlier detection of Type 2
      diabetes and treatment of hyperglycaemia and related metabolic abnormalities is
      of vital importance. The objectives of the present study were to examine urine
      samples from Type 2 diabetic patients and healthy volunteers using the electronic
      nose technology and to evaluate possible application of data classification
      methods such as self-learning artificial neural networks (ANN) and logistic
      regression (LR) in comparison with principal components analysis (PCA). Urine
      samples from Type 2 diabetic patients and healthy controls were processed
      randomly using a simple 8-sensors electronic nose and individual electronic nose
      patterns were qualitatively classified using the "Approximation and
      Classification of Medical Data" (ACMD) network based on 2 output neurons, binary
      LR analysis and PCA. Distinct classes were found for Type 2 diabetic subjects and
      controls using PCA, which had a 96.0% successful classification percentage mean
      while qualitative ANN analysis and LR analysis had successful classification
      percentages of 92.0% and 88.0%, respectively. Therefore, the ACMD network is
      suitable for classifying medical and clinical data.

PMID- 12416659
TI  - Silybin-beta-cyclodextrin in the treatment of patients with diabetes mellitus and
      alcoholic liver disease. Efficacy study of a new preparation of an anti-oxidant
      agent.
AB  - BACKGROUND AND AIMS: In patients with non-insulin dependent diabetes mellitus
      (T2DM) and associated chronic liver disease, plasma levels of glucose, insulin
      and triglycerides are high, lipid peroxidation is increased and natural
      antioxidant reserves are reduced. Thus, we hypothesised that the re-balancing of
      cell redox levels and amelioration of liver function could result in a better
      glucose and lipid metabolism. To study this, we assessed the effect of a new oral
      formulation of an antioxidant agent - silybin-beta-cyclodextrin (named IBI/S) -
      in patients with chronic alcoholic liver disease and concomitant T2DM. METHODS:
      Sixty outpatients were enrolled in a three-centre, double blind, randomised,
      IBI/S vs placebo study. Forty-two (21 in the group IBI/S - 135 mg/d silybin per
      os - and 21 in the placebo group) concluded the 6-month treatment period. The
      efficacy parameters included fasting and mean daily plasma glucose levels,
      glycosylated hemoglobin (HbA1c), basal, stimulated C-peptide and insulin levels,
      total-, HDL-cholesterol and triglycerides levels in addition to conventional
      liver function tests. Insulin sensitivity was estimated by HOMA-IR.
      Malondialdehyde (MDA) was also measured before and after treatment as an index of
      oxidative stress. RESULTS: Fasting blood glucose levels, which were similar at
      baseline in IBI/S group and in the placebo group (173.9 mg/dl and 177.1 mg/dl,
      respectively), decreased to 148.4 mg/dl (-14.7% vs baseline; p = 0.03) in the
      IBI/S group while they were virtually unchanged in the placebo group. The
      comparison between the groups at mo 6 (T6) also showed a significant reduction of
      glucose levels in the IBI/S group (p = 0.03). The same trend was observed in mean
      daily blood glucose levels, HbA1c and HOMA-IR, although differences were not
      significant. Basal and stimulated C-peptide values showed that only a few changes
      had occured in both groups. Such results indicate that insulin secretion was
      virtually unaffected, as confirmed also by the insulinemia data. Plasma
      triglycerides concentrations dropped from a baseline value of 186 mg/dl to 111
      mg/dl (T6) in the IBI/S group, with significant differences at all instances with
      respect to baseline values. By contrast, triglycerides increased from 159 mg/dl
      at entry to 185 mg/dl (T6) in the placebo group. The difference between the
      groups at T6 was highly significant (p < 0.01). Total and HDL cholesterol as well
      as liver function tests did not change significantly during the study in both
      groups. MDA decreased significantly only in the group receiving IBI/S. No
      clinically relevant side effects were observed in either group. CONCLUSIONS: Oral
      administration silybin-beta-cyclodextrin in patients with T2DM and compensated
      chronic alcoholic liver disease causes a significant decrease in both glucose and
      triglyceride plasma levels. These effects may be due to the recovery of energy
      substrates, consistent with a reduced lipid peroxidation and an improved insulin
      activity.

PMID- 12416660
TI  - Glycaemic control and microvascular complications in a large cohort of Italian
      Type 1 diabetic out-patients.
AB  - The purpose of this cross-sectional study was to evaluate the degree of metabolic
      control, the prevalence of microvascular complications (nephropathy, retinopathy,
      and peripheral neuropathy) and their association with risk factors for
      cardiovascular diseases in all adult Type 1 diabetic out-patients attending 2
      Diabetes Clinics of Northern Italy over 12 months. A total of 458 patients (mean
      age 37 +/- 12 yr, duration of diabetes 15.3 +/- 10.6 yr, BMI 23.2 +/- 3.1 kg/m2)
      were studied. Clinical characteristics and microvascular complications were
      evaluated. The proportion of patients with a good glycaemic control (HbA1c < 7%)
      was 14.7%. Nephropathy was observed in 24.4%, retinopathy in 41%, peripheral
      neuropathy in 23.7%. The prevalence of hypertension was 30.3%. Microvascular
      complications were associated with age, duration of diabetes, systolic blood
      pressure, creatinine, triglycerides and cholesterol plasma levels. Mean HbA1c was
      8.5 +/- 1.6. Patients with HbA1c levels < 7% presented a lower prevalence of
      complications and lower levels of cholesterol, triglycerides, systolic blood
      pressure than patients with HbA1c > 9%. Our study indicates that an acceptable
      metabolic control is achieved in a too low proportion of Type 1 diabetic
      patients, even under multiple insulin injections. The association of poor
      metabolic control and microalbuminuria identifies a group of patients at higher
      risk of diabetic complications.

PMID- 12416661
TI  - Variation in consumption of cow milk proteins and lower incidence of Type 1
      diabetes in Iceland vs the other 4 Nordic countries.
AB  - BACKGROUND: The incidence of Type 1 diabetes is lower in Iceland than in the
      other 4 Nordic Countries. Earlier studies have showed that the cow milk proteins
      A1 and B beta-casein, suggested to be diabetogenic, are in lower amount in
      Icelandic cow milk than in milk from the other 4 Nordic Countries, and the per
      capita consumption of these proteins correlates with the incidence of Type 1
      diabetes. OBJECTIVE: To investigate whether lower consumption of the cow milk
      protein bovine serum albumin (BSA) (suggested to be diabetogenic) or higher
      consumption of immunoglobulin (Ig) or lactoferrin (LF) (suggested to be
      protective) is related to the lower incidence of Type 1 diabetes in Iceland.
      METHODS: The per capita consumption of milk proteins was calculated from an
      international database on consumption of milk and milk products and from the
      analysis of cow's milk samples. The samples were randomly collected from the
      largest consumption areas in Iceland and in the other 4 Nordic Countries.
      RESULTS: The per capita consumption of BSA was higher in Iceland (0.79 +/- 0.02
      g/person per day) (mean +/- SEM) than in the other 4 Nordic Countries (0.43 +/-
      0.05 g/person per day) (p = 0.025). The per capita consumption of Ig was also
      higher in Iceland than in the other 4 Nordic Countries (p = 0.025), while the
      consumption of LF was similar. Consumption of these 3 individual milk proteins
      did not correlate with the incidence of Type 1 diabetes in the 5 countries
      studied. CONCLUSION: Consumption of BSA, Ig or LF does not seem to explain the
      lower incidence of Type 1 diabetes in Iceland, compared with the other 4 Nordic
      Countries, while A1 and B beta-casein may contribute to varying diabetogenicity
      of cow's milk and explain the difference in incidence of Type 1 diabetes.

PMID- 12416662
TI  - Two-year prospective evaluation of the factors affecting honeymoon frequency and
      duration in children with insulin dependent diabetes mellitus: the key-role of
      age at diagnosis.
AB  - The aim of this study was to investigate the influence of pre-treatment variables
      on subsequent insulin requirement (IR) and partial remission (PR) in children
      with insulin-dependent diabetes mellitus (T1DM). Sixty-seven children with newly
      diagnosed T1DM, admitted to our Clinic during a 3-year recruitment period, were
      longitudinally evaluated for 2 yr. Patients were characterized by sex, age,
      parental education, duration of symptomatic history at diagnosis, admission
      duration, ketoacidosis or absence of ketoacidosis and residual beta-cell
      activity. More than 80% of the children experienced a PR, which lasted more than
      12 months in 41.7% and at least 24 months in 16.4% of cases. The prevalence of PR
      at different ages after T1DM onset was significantly lower in children diagnosed
      while younger than 5 years than in those diagnosed after 5 years. The mean
      duration of the remission period was 11.7 +/- 8.9 months, irrespectively of sex,
      duration of the symptomatic period preceding T1DM diagnosis, parental education,
      blood pH and base excess, HbA1c concentration and admission duration. Beta-cell
      residual function evaluated after glucagons stimulation test (basal and 6 min C
      peptide) was statistically different in PR patients and in those who experienced
      no remission. Age at diagnosis was the only pre-treatment factor which, on
      stepwise regression analysis, affected both PR duration and IR at the end of
      follow-up. To conclude, honeymoon frequency and duration are strictly conditioned
      by both residual beta-cell function and IR at T1DM onset. Since IR is higher in
      younger subjects, early onset of T1DM can be considered the factor with the most
      detrimental influence on honeymoon incidence. Other pre-treatment variables have
      no significant impact on PR.

PMID- 12416663
TI  - Short-term effects of exercise on body water distribution of severely obese
      subjects as determined by bioelectrical impedance analysis.
AB  - We have previously shown that a short-term weight (Wt) reduction programme
      consisting of energy restriction, physical activity and psychological
      counselling, produces physiological changes of body water distribution (BWD) in
      obese subjects as detected by bioelectrical impedance analysis. The present study
      was aimed at testing the contribution of diet and physical activity to the
      observed changes in BWD. A number of 96 obese inpatients were consecutively
      enrolled in the study at our Obesity Clinic. During a 3-wk period, they underwent
      a body Wt reduction programme comprising the same dietary strategy and
      psychological counselling. The programme differed as far as physical activity is
      concerned, with 52 subjects randomized to a baseline exercise programme (BEP), 22
      to a cardiovascular exercise programme (CEP) and 22 to a cardiovascular and
      strength programme (CSP). Absolute and percent Wt reduction was significantly
      higher in CSP than BEP subjects (p < 0.05) and the same hold for the changes in
      impedance (Z) at frequencies of 5, 50 and 100 kHz (p < 0.05). The change in the
      Z5/Z100 ratio did not show however any between-group difference (p = NS). The
      average values of Z changes were 1.5 to 2 times higher in CEP and 5.0 to 5.5
      times higher in CSP than BEP subjects. We conclude that the type of exercise
      performed does influence the absolute changes of total body water and
      extracellular water but not BWD in severely obese subjects undergoing Wt loss.

PMID- 12416664
TI  - Serum complement C3c concentration in non-obese young insulin-resistant Mexicans.
AB  - The aim of this study was to compare the serum complement C3 concentration
      between non-obese young insulin-sensitive and insulin-resistant Mexicans. A cross
      sectional study was carried out in 28 healthy, non-obese [Body mass index (BMI) <
      26 kg/m2] young (age 19-25 yr), male volunteers to measure the serum C3
      concentration. In accordance with the constant for rate serum glucose
      disappearance (KITT) obtained from the insulin tolerance test, the subjects were
      divided into quartiles, considering as insulin-resistant individuals those in
      quartile 1, and insulin-sensitive subjects those in quartile 4. Serum C3c
      concentration was measured by a nephelometric method. Other biochemical
      characteristics were measured, like lipid profile and uric acid using enzymatic
      techniques. The serum C3 concentrations were similar (p = 0.949) between insulin
      resistant and insulin-sensitive groups respectively (1.4 +/- 0.2 vs 1.3 +/- 0.1
      g/l). There were no significant correlations between serum C3 concentrations and
      serum glucose, insulin levels, KITT and lipid profile. In conclusion, the serum
      complement C3c concentrations were similar between non-obese young insulin
      sensitive and insulin-resistant Mexicans.

PMID- 12416665
TI  - Glucagon is paradoxically secreted at high concentrations of glucose in rat
      pancreas perfused with diazoxide.
AB  - To study the role of B-cells in the regulation of glucagon secretion by glucose,
      the rat pancreas was perfused with 0.4 mmol/l diazoxide. Perfusate glucose was 5
      mmol/l of a basal concentration, and then was decreased to 1 mmol/l, or was
      increased to 15 mmol/l. Insulin secretion was suppressed by diazoxide below the
      detectable level at each glucose concentration. Glucagon secretion was increased
      two-fold during the glucopenic perfusion without diazoxide, but was not changed
      at a low glucose concentration in the presence of diazoxide. During the glucose
      excessive perfusion for 15 min, glucagon secretion was lowered from 0.69 +/- 0.17
      pmol at 5 mmol/l glucose to 0.36 +/- 0.10 pmol at 15 mmol/l glucose (p < 0.05)
      without diazoxide, whereas that was inversely increased from 0.55 +/- 0.14 at 5
      mmol/l glucose to 0.85 +/- 0.13 pmol at 15 mmol/l glucose (p < 0.05) in the
      presence of diazoxide. These results suggest that appropriate insulin secretion
      is necessary for the normal responses of glucagon secretion to hypoglycemia and
      hyperglycemia in the non-diabetic rat pancreas.

PMID- 12416666
TI  - Overview of present day medical education.

PMID- 12416667
TI  - A profile of renal/renovascular abnormalities in patients of hypertension.
AB  - After a thorough dinical examination and laboratory investigations,
      ultrasonography (USG) followed by minute sequence urography (MSU) and aortography
      and/or selective renal angiography were done in 108 patients, clinically
      suspected of having renal hypertension of which 32 patients (29.6%) were found to
      be positive for renal/renovascular disease. Out of 82 patients, who were only
      young hypertensives, a definite diagnosis of renal/renovascular disease could be
      made in only 15 cases (18.3%), whereas the pick up rate increased to 65.4% in the
      rest of the 26 patients who had some other clinical criteria besides hypertension
      and it further increased up to 92.3% (out of these 26 patients) who had 2 or more
      than 2 clinical criteria of selection of patients besides hypertension. USG was
      useful in diagnosing renal parenchymal disease/ suggesting renal abnormalities in
      30 cases and MSU was able to detect renal changes in 31 patients. Aortography
      and/or selective renal angiography could make a definite diagnosis of
      renovascular disease in 17 cases and renal agenesis in one case.

PMID- 12416668
TI  - Spigelion hernia: fascia lata repair is an alternative option in absence of
      prolene mesh.
AB  - Spigelian hernia is rare. Seven cases of Spigelian hernia are presented. These
      include two recurrent Spigelian hernias. Incisional hernias through Spigelian
      aponeurosis after Pfannensteil incision are not included. Clinical examination is
      the mainstay of diagnosis. The true incidence is possibly higher, as a low
      Spigelian hernia is not recognised and often diagnosed as a direct inguinal
      hernia. Ultrasound scanning is recommended, as it is non-invasive and easily
      available and can detect the hernial orifice in the Spigelian fascia at an early
      stage. Recurrence of Spigelian hernia took place in two cases through the site of
      prolene stitch of a previous repair. Hernioplasty with tension free fascia lata
      graft/prolene mesh was carried out in all cases. The cost of fascia lata graft is
      only a scar in the thigh. In a mean follow-up of 3.1 -year no patient has
      reported back with recurrence This is the ideal substitute for the patients in
      developing countries where synthetic meshes are still not freely available.

PMID- 12416670
TI  - Pulmonary tuberculosis and diabetes mellitus--a study.
AB  - One hundred diabetes mellitus patients attending the diabetic clinic and those
      admitted in the medical wards of the Regional Institute of Medical Sciences,
      Imphal, were selected randomly to study the prevalence of pulmonary tuberculosis
      with the age-and the sexwise distribution in diabetes mellitus patients. The
      diagnosis of diabetes mellitus was established from the dinical symptoms and the
      estimation of blood sugar levels whereas pulmonary tuberculosis was diagnosed
      from clinical, radiological and bacteriological examinations. The majority of the
      patients were above the age of 40 years, the mean age was 55.4 years (SD +/-
      13.5). The prevalence of pulmonary tuberculosis in diabeties was 27% by
      radiological diagnosis and 6% by sputum positivity. Out of the 27 patients with
      radiological findings 11 had minimal lesions, 7 had moderate lesions and 9
      patients were found to have far advanced lesions; cavitation was found in 3
      patients, fibrosis in 4, homogeneous opacities in 6, heterogeneous opacities in
      10, pleural effusion in 3 and consolidation and Fibrosis in only one patient.
      Mean duration of diabetes mellitus was 7.6 years (SD +/- 6.24). Duration of
      diabetes mellitus did not correlate well with the prevalence of pulmonary
      tuberculosis. No correlation could be found with the history of contact with
      tuberculosis.

PMID- 12416669
TI  - A study on the comparison between clinical and microbiological diagnoses of
      sexually transmitted diseases.
AB  - The efficacy of microbiological diagnosis in sexually transmitted diseases (STDs)
      has been evaluated in comparison with the clinical diagnosis. Amongst the
      clinical diagnoses of single STDs, syphilis, genital warts, gonorrhoea and herpes
      genitalis were the predominant ones. Syphilis was the most predominant infection
      in both the single and mixed STD infections in Chennai. Clinical diagnoses of
      trichomoniasis, genital chlamydiasis and genital herpes were more accurate and
      correlated well with laboratory investigations. On the other hand, clinical
      diagnoses of gonorrhoea, candidiasis and syphilis were less accurate. More over
      many of these cases, clinically diagnosed as single, infection, were also
      positive for other STDs in the laboratory investigations. Double infections were
      clinically diagnosed only in 7 cases as against 11 cases in microbiological tests
      and one triple infection diagnosed in microbiological tests was diagnosed only as
      single disease clinically. Therefore, the laboratory/microbiological
      investigations have been emphasised to have better accuracy of diagnosis of STDs.

PMID- 12416671
TI  - Fine needle aspiration cytology of thyroid gland and histopathological
      correlation--revisited.
AB  - Fine needle aspiration of the thyroid gland, followed by cytological studies and
      their correlation with histopathological diagnosis have been undertaken to assess
      the effectiveness of fine needle aspiration cytology in diagnosing disorders of
      this gland. The cases in which discrepancies had arisen between these two methods
      of diagnosis have also been reviewed. Out of the total 100 patients studied, 28
      were cases of simple colloid goitre, 17 of adenomatoid goitre, 10 of autoimmune
      thyroiditis ranging from lymphocytic thyroiditis to Hashimoto's thyroiditis, 28
      of follicular neoplasia, 10 of papillary carcinoma, one of medullary carcinoma, 2
      of anaplastic carcinoma and 4 of cystic lesions of the thyroid gland. Although,
      fine needle aspiration cytology of the thyroid gland was diagnostic in 75% of
      cases, it did not correlate with the histopathological diagnosis in the remaining
      25% of cases. Possible reasons behind these discrepancies have been discussed.

PMID- 12416672
TI  - Role of nutrition in the management of HIV infection/AIDS.
AB  - In patients with HIV infection/AIDS, in addition to the antiretrovival therapy
      nutritional support is needed to maintain optimum nutrition during the
      symptomatic period, to prevent further deterioration of nutritional status during
      acute episodes of infections and to improve nutritional status during the stable
      symptom free period. This can be achieved by (a) nutritional assessment, (b)
      nutritional screening, (c) nutritional intervention and by providing (d)
      psychosocial support for nutrition.

PMID- 12416673
TI  - Infertility: planning a prototype action plan in the existing health care system.
AB  - Infertility is considered as a social stigma in our country and has been
      incorporated in reproductive and child health programme. Research areas
      emphasised are (a) A database; (b) Management in primary, secondary and tertiary
      levels of health care services; (c) Training of doctors and health care workers;
      (d) Costing. Infertility is to be priortised as an important public health
      problem as it affects human being's mental, social, physical and reproductive
      health.

PMID- 12416674
TI  - Evaluation of sparfloxacin eye drop in the management of conjunctival and corneal
      infection.
AB  - Sparfloxacin 03% eye drop was evaluated in consecutive culture proven cases of
      conjunctivitis and corneal infection. Sparfloxacin 03% eye drop was found to
      provide 100% cure rate clInIcally as well as bacteriologically. This can be due
      to better ocular penetration and higher therapeutic index of sparfloxacin 03% eye
      drops. Sparfloxacin seems to be a better antibiotic for topical application for
      themanagement of external ocular Infections like conjunctivitis, keratitis and
      corneal ulcers.

PMID- 12416675
TI  - The complete nucleotide sequence of the PanAsia strain of foot-and-mouth disease
      virus isolated in Japan.
AB  - The complete nucleotide sequence of the foot-and-mouth disease virus (FMDV)
      O/JPN/2000 strain, the PanAsia strain, was determined by cycle sequencing and
      primer walking. The 5' end of the genome upstream from homopolymeric poly(C)
      tract (S-fragment) was 367 nucleotides in length, and the remainder of the genome
      (L-fragment), excepting the poly(A) tail, was 7808 nucleotides. The L-fragment
      contains a single open reading frame of 6996 nucleotides terminating at a UAA
      codon 96 bases from the 3' poly(A) sequence. Comparison of sequences shows that
      the length of the structural and non-structural protein coding regions are
      identical to those in the O1/Kaufbeuren strain, and no striking differences such
      as deletion or insertion were observed between them.

PMID- 12416676
TI  - A novel fish rhabdovirus from sweden is closely related to the Finnish
      rhabdovirus 903/87.
AB  - A novel rhabdovirus, preliminary designated as the Sea trout rhabdovirus 28/97
      (STRV 28/97), was isolated from sea trout (Salmo trutta trutta) in Sweden in
      1996. The fish showed central nervous symptoms, and at the autopsy petechial
      bleedings in the mesenteric fat were visible. STRV 28/97 was shown to be
      serologically related to the vesiculotype rhabdovirus 903/87 isolated from brown
      trout (Salmo trutta lacustris) in Finland [1,3]. The sequences for the
      nucleocapsid protein, phosphoprotein, matrix protein, glycoprotein and beginning
      of the polymerase protein of STRV 28/97 were determined. At the amino acid level
      the genes were over 97% similar to virus 903/87. The nucleocapsid proteins,
      glycoproteins and beginning of the polymerase protein of STRV 28/97 and virus
      903/87 were clustered with the vesiculoviruses and the phosphoproteins close to
      the vesiculoviruses in protein parsimony analysis. The matrix proteins formed a
      distinct clade in protein parsimony analysis.

PMID- 12416677
TI  - Detection of a double-stranded RNA virus from a strain of the violet root rot
      fungus Helicobasidium mompa Tanaka.
AB  - Three double-stranded (ds) RNA species (ca. 1.30, 1.27 and 1.23 x 106) were
      isolated by CF-11 cellulose chromatography from a strain of the violet root rot
      fungus Helicobasidium mompa recovered from apple roots. Purified virion
      preparations contained isometric particles about 25 nm in diameter, and also the
      same three species of dsRNA isolated from total extracts by CF-11 cellulose
      chromatography. The molecular mass of the coat protein was about 67 K when
      estimated by SDS-PAGE. The largest dsRNA (referred to as dsRNA1) contains a
      single, long open reading frame of 1794 nucleotides that encodes a putative
      polypeptide containing 598 amino acid residues with a molecular mass of 69.9 K.
      This polypeptide contains amino acid sequence motifs conserved in putative RNA
      dependent RNA polymerases of RNA viruses. Phylogenetic analysis revealed
      similarities to RNA-dependent RNA polymerases from Atkinsonella hypoxylon 2H
      virus, a member of the family Partitiviridae.

PMID- 12416678
TI  - In vivo transmission and dynamics of deleted genomes after experimental infection
      of woodchuck hepatitis B virus in adult animals.
AB  - The presence of Deleted Genomes has been shown in a number of viral models
      including Hepadnaviridae. The analysis of woodchuck hepatitis B virus (WHV)
      population after experimental infection of woodchuck 197 (W197) with WHV7-PI
      inoculum revealed the presence of two Deleted Genomes: DG600 lacking a 1330 bp
      region (Core/Polymerase/PreS1) and DG900 showing a deletion of 869 nts
      (Pol/PreS/S). These mutants were also present in WHV7-PI. The successive WHV
      experimental infections in adult animals were performed using W197-w7 inoculum
      containing DG600 and DG900. Infections were divided into three groups presenting
      different patterns of viral replication, different presence of markers,
      occurrence of variants and persistence of infection. The first group displayed 2
      3 weeks viremic phase and WHV-DNA titres of 10-30 ng/ml; the second a longer
      viremic phase (8-9 weeks) and higher WHV-DNA titres (up to 78 ng/ml). In
      contrast, the third group exhibited lifetime presence of WHV-DNA and WHVeAg in
      serum and viral replication in liver. The Deleted Genomes were transmitted in the
      newly infected animals with the same genomic organization. DG600 was persistently
      found only in chronically infected woodchuck, whereas a different pattern of
      presence was described for DG900. The characterization of these classes of
      deleted mutants in woodchuck-WHV model raises new questions on the link between
      DGs and persistent infections.

PMID- 12416679
TI  - Molecular characterization of a full genome Turkish hepatitis C virus 1b isolate
      (HCV-TR1): a predominant viral form in Turkey.
AB  - Based on direct sequencing information from 5'UTR and NS5B regions, we identified
      subtype lb as a predominant hepatitis C virus genome in Turkey, which affected
      more than 91% of 79 patients studied. Next, the full genome sequence of a Turkish
      lb isolate was obtained by the cloning of polypeptide-encoding region into 7
      overlapping fragments. Turkish 1b isolate, which was named HCV-TR1, comprises
      9361 nucleotides, including 306 nucleotides of 5'UTR, a single long open reading
      frame of 9033 nucleotides, and 22 nucleotides of 3'UTR. When compared to HCV lb
      polypeptide sequences available at GenBank, the predicted polypeptide displayed a
      total of 36 amino acid substitutions, of which 16 was specific for HCV-TR1
      isolate. Despite these changes, major structural and functional motifs of HCV
      proteins were maintained in HCV-TR1. In contrast, HCV-TR1 displayed amino acid
      substitutions in 6 out of 9 major cytotoxic T-cell epitopes. These data suggest
      that HCV-TR1 encodes functionally intact viral proteins, but it also encodes
      altered viral epitopes, which may affect host immune-response.

PMID- 12416680
TI  - Immunization with combined HSV-2 glycoproteins B2 : D2 gene DNAs: protection
      against lethal intravaginal challenges in mice.
AB  - The immunity of a combined DNA vaccine of HSV-2 glycoproteins B2 (gB2) and D2
      (gD2) genes in comparison to individual vaccines was studied with regard to
      protecting against the HSV infection. Two recombinant DNA vaccines of the pHS2
      gB2 or pHS2-gD2 were constructed and formulated. The neutralizing antibody titers
      appeared higher in the B2 : D2 gene cocktail-vaccinated mice than that of the
      individual B2 or D2 gene-vaccinated group alone, and the positive KOS control
      induced higher titer of the neutralizing antibody than combined or individual
      gene vaccines. The mock-immunized mice failed to induce enough. The ranks for the
      CTL activity and the protection rates against the lethal intravaginal challenge
      were shown as KOS > B2:D2 cocktail > D2 > B2 gene vaccines. The vaginal external
      diseases in the B2 : D2 or D-vaccinated mice were significantly reduced against
      the challenging dosages. The virus titers in the vaginal secretions of the
      vaccinated mice significantly reduced with time, and the B2 : D2 gene vaccine
      decreased more than each individual vaccine alone. It can be concluded that the
      cocktailed vaccines are more effective in the humoral and cellular immune
      responses in the mice, and in the protection of the mice against the intravaginal
      challenging dosages when compared with individual gene vaccines. All the DNA
      vaccines failed to block the latent infection in sensory nerves.

PMID- 12416681
TI  - Identification of mutations associated with attenuation of virulence of a field
      Sendai virus isolate by egg passage.
AB  - Abstract. We have reported that attenuation of the virulence of a field Sendai
      virus (SeV) isolated by egg passage is associated with an impediment of viral
      genome replication in mouse respiratory cells (Kiyotani et al., Arch Virol 146,
      893-908, 2001). To determine the molecular basis for the attenuation, we
      sequenced entire genomes of representative SeV clones isolated during egg
      passages and compared those with that of the parental SeV clone E0. E15c2, a 165
      fold attenuated clone in 50% mouse lethal dose (MLD50) isolated at the 15th egg
      passage, possessed only four mutations in the entire genome: U to A at position
      20 (U20A) and U24A in the leader promoter region and A9362G and A12174U in the L
      gene from the 5'-end of antigenome. The former mutation in the L gene was silent
      and the latter changed deduced amino acid Ser at position 1207 to Cys
      (Serl207Cys) in the L protein, a catalytic subunit of viral polymerase. E30c12, a
      further 6-fold attenuated clone isolated at the 30th egg passage, had an
      additional four mutations: A8074G (Glu461Gly) and A8077G (Asp462Gly) in the
      hemagglutinin-neuraminidase (HN) gene and A13598C (silent) and G13927A
      (Ser1791Asn) in the L gene. On the other hand, a virulent revertant clone,
      E30M15c15, which was obtained by 15 mouse passages of E30c12 and had 250-fold
      mouse virulence compared to E30c12, possessed eight mutaions: A24U in the leader,
      C1325U (silent) in the nucleocapsid gene, G8074A (Gly461Glu) in the HN gene,
      G10433U (Lys626Asn), C13598A (silent), A13927G (Asn1791Ser), C14626U (Thr2024Ile)
      and A15272C in the L gene. Among these, the mutations in the leader and the HN
      gene and two of the mutations in the L gene (C13598A and A13927G) were true
      reversions to E0. The significance of the mutations detected in the leader as
      well as in the L and HN genes was discussed in the context of attenuation of SeV
      pathogenicity by egg passage.

PMID- 12416682
TI  - Nucleotide sequence of glycoprotein genes B, C, D, G, H and I, the thymidine
      kinase and protein kinase genes and gene homologue UL24 of an Australian isolate
      of canine herpesvirus.
AB  - We report the complete nucleotide (nt) sequence of nine genes of an Australian
      isolate of canine herpesvirus (CHV). Four of them are located in the unique short
      (US) region: glycoprotein (g) genes gG, gD and gI, and the protein kinase gene.
      Five are in the unique long (UL) region: the thymidine kinase gene, gB, gC, gH,
      and gene homologue UL24. Partial sequence was determined for four genes, two in
      the UL region (UL21 and virion protein) and two in the US region (US2 and gE). A
      repeat sequence of 382 nt with unknown function was identified in the 615 nt
      intergenic region between gH and UL21. A total of 16.93 kb was sequenced and
      compared with sequences from CHV isolates from the USA, France, Japan and
      Australia. Only minor nt and/or amino acid (aa) differences were observed.

PMID- 12416683
TI  - Phylogenetic analysis reveals that a dwarfing disease on different cereal crops
      in China is due to rice black streaked dwarf virus (RBSDV).
AB  - A viral disease with dwarfing symptoms is associated with severe damage of
      different cereal crops including rice, maize, wheat and sorghum grown in China.
      It is believed that the pathogenic agent of the disease on rice and sorghum is
      rice black streaked dwarf virus (RBSDV), however, the cause of maize dwarf
      disease in China is still inconclusive. In this report, dsRNA was isolated from
      virus particles obtained from the diseased plants of rice, maize, wheat and
      sorghum from two Chinese provinces. Full-length cDNAs of genome segments 9 (S9)
      and 10 (S 10) were obtained through a RT-PCR approach. Sequence analysis showed
      that the S9 sequences of Chinese isolates and Japanese RBSDV isolate were very
      similar to each other (89.1-89.6% identity at the nucleotide level, 92.3-92.9%
      and 95.8-98.6% identity at the amino acid level for ORF1 and ORF2, respectively).
      In addition, the S10 sequences of Chinese isolates and Japanese RBSDV were very
      similar to each other (93.0-95.4% identical nucleotides and 96.2-97.0% identical
      amino acids, respectively). However, there were lower similarities for S9 and S10
      sequences between Chinese isolates and an Italian Maize Rough Dwarf Virus (MRDV)
      isolate. Phylogenetic analysis indicates that Chinese viral isolates found to
      infect rice, maize, wheat and sorghum and leading to similar cereal dwarfing
      manifestations could be grouped to the same virus species, RBSDV.

PMID- 12416684
TI  - Subcellular location of the helper component-proteinase of Cowpea aphid-borne
      mosaic virus.
AB  - The helper component-proteinase (HC-Pro) of Cowpea aphid-borne mosaic virus
      (CABMV) was expressed in Escherichia coli and used to obtain HC-Pro antiserum
      that was used as an analytical tool for HC-Pro studies. The antiserum was used in
      immunofluorescence assays to study the subcellular location of HC-Pro expressed
      with other viral proteins in cowpea protoplasts in a natural CABMV infection, or
      in protoplasts transfected with a transient expression construct expressing HC
      Pro separately from other viral proteins under the control of the 35S promoter.
      In both cases the protein showed a diffuse cytoplasmic location. Similar
      localisation patterns were shown in live protoplasts when the transient
      expression system was used to express HC-Pro as a fusion with the green
      fluorescent protein as a reporter. In an alternative expression system, the HC
      Pro coding region was subcloned in-frame between the movement protein and large
      coat protein genes of RNA2 of Cowpea mosaic virus (CPMV). Upon transfection of
      protoplasts with this construct, HC-Pro was expressed as part of the RNA2 encoded
      polyprotein from which it was fully processed. In this case, the protein
      localised in broad cytoplasmic patches reminiscent of the typical CPMV induced
      cytopathic structures in which CPMV replication occurs, suggesting an interaction
      of HC-Pro with CPMV proteins or host factors in these structures. Finally,
      recombinant CPMV expressing HC-Pro showed a strongly enhanced virulence on cowpea
      and Nicotiana benthamiana consistent with the role of HC-Pro as a pathogenicity
      determinant, a phenomenon now known to be linked to its role as a suppressor of
      host defense responses based on post-transcriptional gene silencing.

PMID- 12416685
TI  - How to make large self-organizing maps for nonvectorial data.
AB  - The self-organizing map (SOM) represents an open set of input samples by a
      topologically organized, finite set of models. In this paper, a new version of
      the SOM is used for the clustering, organization, and visualization of a large
      database of symbol sequences (viz. protein sequences). This method combines two
      principles: the batch computing version of the SOM, and computation of the
      generalized median of symbol strings.

PMID- 12416686
TI  - Analysis and visualization of gene expression data using self-organizing maps.
AB  - Cluster structure of gene expression data obtained from DNA microarrays is
      analyzed and visualized with the Self-Organizing Map (SOM) algorithm. The SOM
      forms a non-linear mapping of the data to a two-dimensional map grid that can be
      used as an exploratory data analysis tool for generating hypotheses on the
      relationships, and ultimately of the function of the genes. Similarity
      relationships within the data and cluster structures can be visualized and
      interpreted. The methods are demonstrated by computing a SOM of yeast genes. The
      relationships of known functional classes of genes are investigated by analyzing
      their distribution on the SOM, the cluster structure is visualized by the U
      matrix method, and the clusters are characterized in terms of the properties of
      the expression profiles of the genes. Finally, it is shown that the SOM
      visualizes the similarity of genes in a more trustworthy way than two alternative
      methods, multidimensional scaling and hierarchical clustering.

PMID- 12416687
TI  - Statistical tools to assess the reliability of self-organizing maps.
AB  - Results of neural network learning are always subject to some variability, due to
      the sensitivity to initial conditions, to convergence to local minima, and,
      sometimes more dramatically, to sampling variability. This paper presents a set
      of tools designed to assess the reliability of the results of self-organizing
      maps (SOM), i.e. to test on a statistical basis the confidence we can have on the
      result of a specific SOM. The tools concern the quantization error in a SOM, and
      the neighborhood relations (both at the level of a specific pair of observations
      and globally on the map). As a by-product, these measures also allow to assess
      the adequacy of the number of units chosen in a map. The tools may also be used
      to measure objectively how the SOM are less sensitive to non-linear optimization
      problems (local minima, convergence, etc.) than other neural network models.

PMID- 12416688
TI  - Recursive self-organizing maps.
AB  - This paper explores the combination of self-organizing map (SOM) and feedback, in
      order to represent sequences of inputs. In general, neural networks with time
      delayed feedback represent time implicitly, by combining current inputs and past
      activities. It has been difficult to apply this approach to SOM, because feedback
      generates instability during learning. We demonstrate a solution to this problem,
      based on a nonlinearity. The result is a generalization of SOM that learns to
      represent sequences recursively. We demonstrate that the resulting
      representations are adapted to the temporal statistics of the input series.

PMID- 12416689
TI  - Self-organizing maps with recursive neighborhood adaptation.
AB  - Self-organizing maps (SOMs) are widely used in several fields of application,
      from neurobiology to multivariate data analysis. In that context, this paper
      presents variants of the classic SOM algorithm. With respect to the traditional
      SOM, the modifications regard the core of the algorithm, (the learning rule), but
      do not alter the two main tasks it performs, i.e. vector quantization combined
      with topology preservation. After an intuitive justification based on geometrical
      considerations, three new rules are defined in addition to the original one. They
      develop interesting properties such as recursive neighborhood adaptation and non
      radial neighborhood adaptation. In order to assess the relative performances and
      speeds of convergence, the four rules are used to train several maps and the
      results are compared according to several error measures (quantization error and
      topology preservation criterions).

PMID- 12416690
TI  - Data visualisation and manifold mapping using the ViSOM.
AB  - The self-organising map (SOM) has been successfully employed as a nonparametric
      method for dimensionality reduction and data visualisation. However, for
      visualisation the SOM requires a colouring scheme to imprint the distances
      between neurons so that the clustering and boundaries can be seen. Even though
      the distributions of the data and structures of the clusters are not faithfully
      portrayed on the map. Recently an extended SOM, called the visualisation-induced
      SOM (ViSOM) has been proposed to directly preserve the distance information on
      the map, along with the topology. The ViSOM constrains the lateral contraction
      forces between neurons and hence regularises the interneuron distances so that
      distances between neurons in the data space are in proportion to those in the map
      space. This paper shows that it produces a smooth and graded mesh in the data
      space and captures the nonlinear manifold of the data. The relationships between
      the ViSOM and the principal curve/surface are analysed. The ViSOM represents a
      discrete principal curve or surface and is a natural algorithm for obtaining
      principal curves/surfaces. Guidelines for applying the ViSOM constraint and
      setting the resolution parameter are also provided, together with experimental
      results and comparisons with the SOM, Sammon mapping and principal curve methods.

PMID- 12416691
TI  - Gamma-observable neighbours for vector quantization.
AB  - We define the gamma-observable neighbourhood and use it in soft-competitive
      learning for vector quantization. Considering a datum v and a set of n units w(i)
      in a Euclidean space, let v(i) be a point of the segment [vw(i)] whose position
      depends on gamma a real number between 0 and 1, the gamma-observable neighbours
      (gamma-ON) of v are the units w(i) for which v(i) is in the Voronoi of w(i), i.e.
      w(i) is the closest unit to v(i). For gamma = 1, v(i) merges with w(i), all the
      units are gamma-ON of v, while for gamma = 0, v(i) merges with v, only the
      closest unit to v is its gamma-ON. The size of the neighbourhood decreases from n
      to 1 while gamma goes from 1 to 0. For gamma lower or equal to 0.5, the gamma-ON
      of v are also its natural neighbours, i.e. their Voronoi regions share a common
      boundary with that of v. We show that this neighbourhood used in Vector
      Quantization gives faster convergence in terms of number of epochs and similar
      distortion than the Neural-Gas on several benchmark databases, and we propose the
      fact that it does not have the dimension selection property could explain these
      results. We show it also presents a new self-organization property we call 'self
      distribution'.

PMID- 12416692
TI  - Kernel-based topographic map formation achieved with an information-theoretic
      approach.
AB  - A new information-theoretic learning algorithm is introduced for kernel-based
      topographic map formation. The kernels are allowed to overlap and move freely in
      the input space, and to have differing kernel ranges. We start with Linsker's
      infomax principle and observe that it cannot be readily extended to our case,
      exactly due to the presence of kernels. We then consider Bell and Sejnowski's
      generalization of Linsker's infomax principle, which suggests differential
      entropy maximization, and add a second component to be optimized, namely, mutual
      information minimization between the kernel outputs, in order to take into
      account the kernel overlap, and thus the topographic map's output redundancy. The
      result is joint entropy maximization of the kernel outputs, which we adopt as our
      learning criterion. We derive a learning algorithm and verify its performance
      both for a synthetic example, for which the optimal result can be derived
      analytically, and for a classic real-world example.

PMID- 12416693
TI  - A self-organising network that grows when required.
AB  - The ability to grow extra nodes is a potentially useful facility for a self
      organising neural network. A network that can add nodes into its map space can
      approximate the input space more accurately, and often more parsimoniously, than
      a network with predefined structure and size, such as the Self-Organising Map. In
      addition, a growing network can deal with dynamic input distributions. Most of
      the growing networks that have been proposed in the literature add new nodes to
      support the node that has accumulated the highest error during previous
      iterations or to support topological structures. This usually means that new
      nodes are added only when the number of iterations is an integer multiple of some
      pre-defined constant, A. This paper suggests a way in which the learning
      algorithm can add nodes whenever the network in its current state does not
      sufficiently match the input. In this way the network grows very quickly when new
      data is presented, but stops growing once the network has matched the data. This
      is particularly important when we consider dynamic data sets, where the
      distribution of inputs can change to a new regime after some time. We also
      demonstrate the preservation of neighbourhood relations in the data by the
      network. The new network is compared to an existing growing network, the Growing
      Neural Gas (GNG), on a artificial dataset, showing how the network deals with a
      change in input distribution after some time. Finally, the new network is applied
      to several novelty detection tasks and is compared with both the GNG and an
      unsupervised form of the Reduced Coulomb Energy network on a robotic inspection
      task and with a Support Vector Machine on two benchmark novelty detection tasks.

PMID- 12416694
TI  - Generalized relevance learning vector quantization.
AB  - We propose a new scheme for enlarging generalized learning vector quantization
      (GLVQ) with weighting factors for the input dimensions. The factors allow an
      appropriate scaling of the input dimensions according to their relevance. They
      are adapted automatically during training according to the specific
      classification task whereby training can be interpreted as stochastic gradient
      descent on an appropriate error function. This method leads to a more powerful
      classifier and to an adaptive metric with little extra cost compared to standard
      GLVQ. Moreover, the size of the weighting factors indicates the relevance of the
      input dimensions. This proposes a scheme for automatically pruning irrelevant
      input dimensions. The algorithm is verified on artificial data sets and the iris
      data from the UCI repository. Afterwards, the method is compared to several well
      known algorithms which determine the intrinsic data dimension on real world
      satellite image data.

PMID- 12416695
TI  - Principles and networks for self-organization in space-time.
AB  - In this paper, we develop a spatio-temporal memory that blends properties from
      long and short-term memory and is motivated by reaction diffusion mechanisms. The
      winning processing element of a self-organizing network creates traveling waves
      on the output space that gradually attenuate over time and space to diffuse
      temporal information and create localized spatio-temporal neighborhoods for
      clustering. The novelty of the model is in the creation of time varying Voronoi
      tessellations anticipating the learned input signal dynamics even when the
      cluster centers are fixed. We test the method in a robot navigation task and in
      vector quantization of speech. This method performs better than conventional
      static vector quantizers based on the same data set and similar training
      conditions.

PMID- 12416696
TI  - Image denoising using self-organizing map-based nonlinear independent component
      analysis.
AB  - This paper proposes the use of self-organizing maps (SOMs) to the blind source
      separation (BSS) problem for nonlinearly mixed signals corrupted with
      multiplicative noise. After an overview of some signal denoising approaches, we
      introduce the generic independent component analysis (ICA) framework, followed by
      a survey of existing neural solutions on ICA and nonlinear ICA (NLICA). We then
      detail a BSS method based on SOMs and intended for image denoising applications.
      Considering that the pixel intensities of raw images represent a useful signal
      corrupted with noise, we show that an NLICA-based approach can provide a
      satisfactory solution to the nonlinear BSS (NLBSS) problem. Furthermore, a
      comparison between the standard SOM and a modified version, more suitable for
      dealing with multiplicative noise, is made. Separation results obtained from test
      and real images demonstrate the feasibility of our approach.

PMID- 12416697
TI  - Integrating contextual information to enhance SOM-based text document clustering.
AB  - Exploration of text corpora using self-organizing maps has shown promising
      results in recent years. Topographic map approaches usually use the original
      vector space model known from Information Retrieval for text document
      representation. In this paper I present a two stage model using features based on
      sentence categories as alternative approach which includes contextual
      information. Algorithmic optimizations required by this computationally expensive
      model are shown and evaluated. Also a method for model independent comparison of
      document maps by evaluation of document distribution on maps is introduced and
      used to compare results obtained with both the new model and the vector space
      model.

PMID- 12416698
TI  - Applications of the self-organising map to reinforcement learning.
AB  - This article is concerned with the representation and generalisation of
      continuous action spaces in reinforcement learning (RL) problems. A model is
      proposed based on the self-organising map (SOM) of Kohonen [Self Organisation and
      Associative Memory, 1987] which allows either the one-to-one, many-to-one or one
      to-many structure of the desired state-action mapping to be captured. Although
      presented here for tasks involving immediate reward, the approach is easily
      extended to delayed reward. We conclude that the SOM is a useful tool for
      providing real-time, on-line generalisation in RL problems in which the latent
      dimensionalities of the state and action spaces are small. Scalability issues are
      also discussed.

PMID- 12416699
TI  - BYY harmony learning, structural RPCL, and topological self-organizing on mixture
      models.
AB  - The Bayesian Ying-Yang (BYY) harmony learning acts as a general statistical
      learning framework, featured by not only new regularization techniques for
      parameter learning but also a new mechanism that implements model selection
      either automatically during parameter learning or via a new class of model
      selection criteria used after parameter learning. In this paper, further advances
      on BYY harmony learning by considering modular inner representations are
      presented in three parts. One consists of results on unsupervisedmixture models,
      ranging from Gaussian mixture based Mean Square Error (MSE) clustering, elliptic
      clustering, subspace clustering to NonGaussian mixture based clustering not only
      with each cluster represented via either Bernoulli-Gaussian mixtures or
      independent real factor models, but also with independent component analysis
      implicitly made on each cluster. The second consists of results on supervised
      mixture-of-experts (ME) models, including Gaussian ME, Radial Basis Function
      nets, and Kernel regressions. The third consists of two strategies for extending
      the above structural mixtures into self-organized topological maps. All these
      advances are introduced with details on three issues, namely, (a) adaptive
      learning algorithms, especially elliptic, subspace, and structural rival
      penalized competitive learning algorithms, with model selection made
      automatically during learning; (b) model selection criteria for being used after
      parameter learning, and (c) how these learning algorithms and criteria are
      obtained from typical special cases of BYY harmony learning.

PMID- 12416700
TI  - Review of the Laboratory Virology and Serology Reporting Scheme.

PMID- 12416701
TI  - The Laboratory Virology and Serology Reporting Scheme, 1991 to 2000.
AB  - Between 1991 and 2000, the Laboratory Virology and Serology Surveillance Scheme
      (LabVISE) received 340,730 laboratory reports of viral and non-viral pathogen
      identifications. In this report, data on 136 viruses and 31 non-viral pathogens
      is analysed. The age and sex distribution and seasonal fluctuations in infections
      are described. The major clinical diseases associated with LabVISE pathogens are
      reviewed together with a survey of recent activity reported in Australia. The
      contribution of LabVISE over the 10-year period to surveillance of poliomyelitis
      in Australia, up to and beyond the eradication goal, is described. The
      contribution of LabVISE to influenza surveillance and control in Australia is
      also described. Prospects for the continued role of LabVISE in the surveillance
      and control of viral meningitis, viral gastroenteritis and viral respiratory
      diseases are reviewed.

PMID- 12416702
TI  - Enhancing foodborne disease surveillance across Australia in 2001: the OzFoodNet
      Working Group.
AB  - In 2000, the OzFoodNet network was established to enhance surveillance of
      foodborne diseases across Australia. OzFoodNet consists of 7 sites and covers 68
      per cent of Australia's population. During 2001, sites reported 15,815 cases of
      campylobacteriosis, 6,607 cases of salmonellosis, 326 cases of shigellosis, 71
      cases of yersiniosis, 61 cases of listeriosis, 47 cases of shiga-toxin producing
      E. coli and 5 cases of haemolytic uraemic syndrome. Sites reported 86 foodborne
      outbreaks affecting 1,768 people, of whom 4.0 per cent (70/1,768) were
      hospitalised and one person died. There was a wide range of foods implicated in
      these outbreaks and the most common agent was S. Typhimurium. Sites reported two
      international outbreaks; one of multi-drug resistant S. Typhimurium Definitive
      Type 104 due to helva imported from Turkey, and one of S. Stanley associated with
      dried peanuts from China. The National Centre for Epidemiology and Population
      Health conducted a national survey of gastroenteritis. Preliminary data from
      interviews of 2,417 people suggests that the incidence of foodborne illness is
      significantly higher than previously thought. OzFoodNet initiated case control
      studies into risk factors for Campylobacter, Salmonella, Listeria, and shiga
      toxin producing E. coli. OzFoodNet developed a foodborne disease outbreak
      register for Australia; established a network of laboratories to type
      Campylobacter; prepared a survey of pathology laboratories; reviewed Australian
      data on listeriosis; and assessed the usefulness of sentinel surveillance for
      gastroenteritis. This program of enhanced surveillance has demonstrated its
      capacity to nationally investigate and determine the causes of foodborne disease.

PMID- 12416703
TI  - Annual report of the Australian Meningococcal Surveillance Programme, 2001.
AB  - Since 1994, The National Neisseria Network has examined and analysed isolates of
      Neisseria meningitidis from cases of invasive meningococcal disease in Australia
      by means of a collaborative laboratory program. The phenotypes (serogroup,
      serotype and serosubtype) and antibiotic susceptibility of 338 isolates of N.
      meningitidis from invasive cases of meningococcal disease were determined in
      2001. Most disease was caused by serogroup B (206 isolates, 61%) or serogroup C
      (122 isolates, 36%) meningococci. However, there was considerable diversity in
      the phenotypes circulating in the different states and territories. Serogroup B
      strains predominated in all jurisdictions except Victoria and Tasmania and were
      isolated from sporadic cases of invasive disease. Serogroup B phenotypes were
      generally disparate with phenotype B:4:P1.4 being the most common and phenotype
      B:15:P1.7 was also widely distributed. Infections with a novel phenotype that was
      first noted in 1999, C:2a:P1.4(7), were again common in Victoria, especially in
      adolescents and adults, but were infrequently seen elsewhere in Australia. In
      Tasmania, a different phenotype, C:2a:P1.5,2 accounted for 11 of 16 isolates,
      again predominantly in infections of young adults. The number of isolates in
      Queensland increased to 78 from 43 in 2000 and was due to more strains of both
      serogroup B and serogroup C meningococci. About two-thirds of all isolates showed
      decreased susceptibility to the penicillin group of antibiotics (MIC 0.06 to 0.5
      mg/L). All isolates tested were susceptible to third generation cephalosporins.
      From 1999, reports have also included diagnoses made by non-culture based methods
      in these analyses. Data relating to 135 laboratory-confirmed but culture negative
      cases supplemented information on culture-confirmed cases in this report.

PMID- 12416704
TI  - Annual report of the Australian National Poliovirus Reference Laboratory and
      summary of acute flaccid paralysis surveillance, 2001.
AB  - The National Poliovirus Reference Laboratory at the Victorian Infectious Diseases
      Reference Laboratory (VIDRL) is responsible for poliovirus testing for Australia
      and the Pacific Island countries. It is also a regional reference laboratory for
      the Western Pacific Region of the World Health Organization. Surveillance for
      acute flaccid paralysis, a clinical manifestation of poliomyelitis, is
      coordinated at VIDRL in collaboration with the Australian Paediatric Surveillance
      Unit. There were 60 unique notifications of acute flaccid paralysis (AFP) in
      2001, of which 44 were classified by the polio expert committee as eligible non
      polio AFP cases, that is, from patients resident in Australia and aged less than
      15 years. Polioviruses were Isolated from one AFP patient and characterised as
      Sabin oral poliovirus vaccine-like for all 3 serotypes. In the same period, the
      National Poliovirus Reference Laboratory identified 40 Sabin-like viruses from 74
      referred isolates and specimens, and an additional five non-Sabin-like
      polioviruses as part of the laboratory containment of poliovirus. The Western
      Pacific Region, of which Australia is a member nation, was declared free of
      circulating wild poliovirus in October 2000. However, during 2001, viruses
      derived from the Sabin oral poliovirus vaccine caused 3 cases of poliomyelitis in
      the Philippines, also a member nation of the Western Pacific Region. The
      identification of circulating vaccine-derived poliovirus in the Philippines has
      emphasised the necessity of maintaining a high level of vaccination coverage
      within Australia and an effective surveillance system to detect cases of
      poliomyelitis.

PMID- 12416705
TI  - Sentinel Chicken Surveillance Programme in Australia, 1 July 2001 to 30 June
      2002.
AB  - Detection of flavivirus seroconversions in sentinel chicken flocks located
      throughout Australia is used to provide an early warning of increased levels of
      Murray Valley encephalitis (MVE) and Kunjin virus activity in the region. During
      the 2001/2002 season low levels of flavivirus activity were detected in northern
      Australia compared to previous years. MVE and Kunjin virus activity was detected
      in the Kimberley and Pilbara regions of Western Australia and the Northern
      Territory but not in north Queensland, New South Wales or Victoria. This is in
      contrast to the previous season when MVE activity was detected both in northern
      Australia and, for the first time in over 20 years, in New South Wales. Two cases
      of Murray Valley encephalitis were reported from the north of Western Australia
      during the 2001/2002 wet season.

PMID- 12416706
TI  - OzFoodNet: enhancing foodborne disease surveillance across Australia: quarterly
      report, January to March 2002.

PMID- 12416707
TI  - Diarrhoea associated with consumption of escolar (rudderfish).

PMID- 12416708
TI  - Outbreaks of diarrhoea associated with butterfish in Victoria.

PMID- 12416709
TI  - Illness associated with rudderfish/escolar in South Australia.

PMID- 12416710
TI  - An outbreak of gastrointestinal illness associated with the consumption of
      escolar fish.
AB  - An outbreak of gastrointestinal illness occurred amongst attendees of a
      conference lunch in the Hunter area, New South Wales, in October 2001. A
      distinctive symptom reported by many ill persons was the presence of oily
      diarrhoea. The Hunter Public Health Unit investigated the outbreak by conducting
      a telephone interview of the cohort of conference attendees using a standard
      questionnaire. Twenty persons out of 44 attendees (46%) became ill following the
      conference. The median incubation period was 2.5 hours (range 1-90 hours). The
      most common symptoms reported were; diarrhoea (80%)-38 per cent of these reported
      oily diarrhoea; abdominal cramps (50%); nausea (45%); headache (35%) and vomiting
      (25%). For analyses, a case was defined as a person who developed oily diarrhea,
      or diarrhoea within 48 hours, or had at least two other symptoms of
      gastroenteritis within 6 hours, of the conference lunch. Seventeen persons had
      symptoms that met the case definition. None of the foods or beverages consumed
      were significantly associated with illness, however, all cases had consumed fish
      and none of those who did not eat fish (4 persons) became ill. Moreover, only
      'fish' or 'potato chips' could explain a significant proportion of the illness.
      Analysis of the oil composition of the fish consumed was consistent with the
      known profile of the species marketed as 'escolar'. Among those who consumed fish
      the following potential risk factors did not have a significant association with
      the illness; Body Mass Index, age, health status and the amount of fish consumed.
      We concluded that consumption of fish within the marketing group escolar can
      cause severe abdominal cramping, nausea and vomiting, in addition to incontinent
      diarrhoea.

PMID- 12416711
TI  - Gastroenteritis outbreak in a sporting team linked to barbecued chicken.

PMID- 12416712
TI  - Outbreak of Cryptosporidium linked to drinking unpasteurised milk.

PMID- 12416713
TI  - Observational methods in epidemiologic assessment of vaccine effectiveness.
AB  - Observational methods are important in the measurement of vaccine effectiveness
      (VE) as experimental designs cannot be used for measurement of vaccines already
      on the vaccination schedule. Furthermore, efficacy measured in clinical trials
      under ideal conditions may differ to effectiveness in the field under non-ideal
      conditions and in different populations. In addition to post-licensure
      surveillance, observational VE studies are particularly important when disease
      incidence does not predictably decrease with increased vaccine coverage, when
      high proportions of vaccine failure among reported cases suggest a problem with
      the vaccine or when issues arise that were not predicted in pre-licensure
      evaluations. Commonly used study types for evaluating VE include cohort studies,
      household contact studies, case-control studies, the screening method and case
      cohort studies. There are many potential biases in all observational VE studies
      which should be considered in the study design and analysis stage. Of the five
      observational study types reviewed, cohort studies undertaken during an outbreak
      investigation offer the simplest means of VE estimation and is the preferred
      study design where the situation permits. Where this is not possible the
      screening method is the most economical and rapid method. It is essential that
      the effectiveness of all vaccination programs be evaluated. As new vaccines are
      introduced to the schedule, booster doses are added and the timing of doses
      changed, the role of observational methods in the evaluation of VE will become
      even more important. To date, few observational VE studies have been undertaken
      in Australia, suggesting the under-utilisation of these methods.

PMID- 12416714
TI  - Reduction in the hepatitis B related burden of disease--measuring the success of
      universal immunisation programs.
AB  - There is collective evidence from countries of both low and high endemicity that
      administration of hepatitis B vaccination at birth saves lives and reduces the
      burden of disease from acute and chronic infection. However, a discussion on the
      cost-effectiveness of vaccination for HBV is beyond the scope of this article. In
      Australia, longer term follow-up of HBV disease burden is required following the
      more recent introduction of routine and universal infant vaccination. Universal
      vaccination for HBV at birth can be seen as a 'safety-net' against infection at a
      very young age. However, it is estimated that the effect of universal infant
      vaccination will not be evident for at least another 15 years in Australia. The
      obstacles to vaccination with HBV, which have historically included fears that
      the vaccine may be linked to multiple sclerosis, should be put to rest, and
      concerns about the thiomersal content allayed by communicating the current
      availability of thiomersal-free vaccines to all providers and parents or care
      givers. Furthermore, ongoing adverse events surveillance should be in place to
      detect any rare adverse events which may be related to the vaccine. Currently,
      more than one half of the world's infants are still not being immunised for HBV,
      and the need for a global initiative for universal infant hepatitis B vaccination
      is apparent. This is especially true for countries with high prevalence, and the
      costing issues and logistics of such an initiative still remain to be addressed.
      In addition, there is a need to address the implementation of guidelines for
      screening and vaccination of families who have immigrated to Australia from
      countries with a high prevalence of hepatitis B.

PMID- 12416715
TI  - A review of national legionellosis surveillance in Australia, 1991 to 2000.
AB  - A study was undertaken to analyse legionellosis notifications for the period 1991
      to 2000 to establish the distribution of legionellosis in Australia with the aim
      of identifying risk factors amenable to public health intervention. Legionellosis
      notification rates ranged from 0.6 cases per 100,000 population in 1991 to 2.5
      cases per 100,000 population in 2000. Notifications were highest in autumn (March
      to May). Sixty-nine per cent of cases were males. At-risk population included
      those aged over 50 years. The upward trend in notification rates of legionellosis
      indicated that this disease remains a significant public health problem
      particularly among older people. Seasonal differences in notification rates
      require further investigation to develop appropriate prevention and control
      strategies. To have a better understanding of the epidemiology of legionellosis,
      further information is needed on smoking history, chronic illnesses, whether the
      notification is outbreak-related and the species of Legionella isolated.

PMID- 12416716
TI  - Communicable diseases surveillance. Highlights for 2nd quarter, 2002.

PMID- 12416717
TI  - Characterization of specific GTP binding sites in C2C12 mouse skeletal muscle
      cells.
AB  - Receptor sites, specific for guanosine 5'-triphosphate (GTP) were characterised
      in myoblasts and myotubes of C2C12 mouse skeletal muscle cells, using binding
      experiments and measurements of intracellular Ca2+ concentration ([Ca2+]i). We
      identified two GTP binding sites in myoblasts membranes: a high affinity site (Kd
      = 15.4 +/- 4.6 microM; Bmax = 1.7 +/- 0.5 nmol mg(-1) protein); and a low
      affinity site (Kd = 170 +/- 94.5 microM; Bmax = 14.2 +/- 3.9 nmol mg(-1)
      protein). In myotube membranes only a low affinity binding site for GTP (Kd = 169
      +/- 39 microM; Bmax = 12.3 +/- 1.4 nmol mg(-1) protein) was detected. In
      myoblasts GTP binding was not displaced by ATP or UTP, even at high
      concentrations (up to of 1 mM), but it was affected by treatments with suramin or
      Reactive Blue 2 (RB2), the non-selective purine receptor antagonists. In
      contrast, in myotubes GTP binding was partially displaced by high concentrations
      of ATP, but treatments with the non-selective purine receptor antagonists,
      suramin or RB2, and with UTP had no effect on GTP binding. The addition of GTP to
      myoblasts, and to myotubes, resulted in elevations of [Ca2+]i. The patterns of
      Ca2+ response however, were different in the two cell phenotypes. In myoblasts
      the addition of GTP induced two types of Ca2+ responses: (1) a fast increase in
      [Ca2+]i, followed by a sustained [Ca2+]i elevation, and (2) a slow raising and
      steady prolonged increase in [Ca2+]i. In myotubes, however only fast Ca2+
      responses were observed following the addition of 500 microM GTP. In the
      myoblasts and myotubes GTP-stimulated [Ca2+]i increases were abolished by
      treatments with suramin or RB2 at concentrations which had no effect on the ATP
      induced Ca2+ responses. We conclude, that C2C12 cells express two distinct
      binding sites for GTP before differentiation, but only one after, the low
      affinity binding site. These results suggest a possible role of the high affinity
      GTP binding site in early stage of development of skeletal muscle.

PMID- 12416718
TI  - RNA-protein interactions of the 3' untranslated regions of myosin heavy chain
      transcripts.
AB  - The RNA-protein interactions of the myosin heavy chain (MyHC) 3' untranslated
      regions (3'UTRs) were investigated using gel mobility shift assays. Marine
      skeletal myosin heavy chain mRNAs were amplified using reverse transcription
      coupled with the polymerase chain reaction (RT-PCR). Four cloned MyHC sequences
      were identified as slow type 1, fast 2a, fast 2b and fast 2x. The 3'UTRs of the
      four MyHC mRNAs were shown to interact with muscle protein in a tissue-specific
      manner as illustrated by gel retardation assays with protein extracts from
      various tissues. Competition assays indicate that this interaction is specific to
      the MyHC 3'UTR sequence. UV cross-linking suggests that several small proteins
      bind to the 3'UTR's. Peptide sequencing identified aldolase A and glyceraldehyde
      3-phosphate dehydrogenase (GAPDH) as MyHC 3'UTR RNA-binding proteins. The
      implications of these interactions and post-transcriptional regulation of the
      MyHC genes are discussed.

PMID- 12416719
TI  - The expression of alpha-dystrobrevin and dystrophin during skeletal muscle
      regeneration.
AB  - The expression of alpha-dystrobrevin and dystrophin in rat tibialis anterior
      muscles was chronologically evaluated during a cycle of regeneration after
      myonecrosis induced by the injection of cardiotoxin. In immunohistochemical
      studies, alpha-dystrobrevin and dystrophin were first stained weakly at the
      sarcolemma of some regenerating muscle fibers on day 5. On day 7, alpha
      dystrobrevin was still stained weakly, whereas dystrophin was stained
      conspicuously. After day 10, alpha-dystrobrevin and dystrophin were both stained
      conspicuously on almost all regenerating muscle fibers. In the Western blot
      analysis, alpha-dystrobrevin and dystrophin were first detected as visible bands
      on days 5 and 7, respectively. The bands of alpha-dystrobrevin and dystrophin
      both darkened sequentially up to day 10. The protein levels based on the
      densitometrical analysis of the bands on each day were converted to the
      percentage of the protein level on day 28, which was taken as 100%. The
      sequential line based on these data showed that alpha-dystrobrevin and dystrophin
      reached 50% of the protein level on day 28 by 6.6 and 5.3 days, respectively.
      These data provide evidence that alpha-dystrobrevin regenerates more slowly than
      dystrophin in skeletal muscle.

PMID- 12416720
TI  - The expression of neuronal nitric oxide synthase and dystrophin in rat
      regenerating muscles.
AB  - We investigated the expression of neuronal nitric oxide synthase (nNOS) and
      dystrophin in the regenerating skeletal muscles of rats after cardiotoxin-induced
      myonecrosis by immunohistochemical studies and western blot analysis. In normal
      muscles, nNOS was moderately immunostained on type 2B fibers, but was faintly
      immunostained on type 2A or type 1 fibers. In immunohistochemical studies of
      regenerating muscles, nNOS was first observed at the sarcolemma of type 2B fibers
      on day 10, when the type discrimination between types 2A and 2B was first
      detected by ATP reactions. Subsequently, the immunostaining of nNOS grew
      progressively stronger in type 2B fibers, with faint staining in type 2A and type
      I fibers until day 28. Meanwhile, the immunostaining of dystrophin grew stronger
      equally in all three fibers until day 21. In western blot analysis of
      regenerating muscles, nNOS regenerated more slowly than dystrophin. The present
      data suggest that the expression of nNOS is related to the muscle fiber type
      differentiation, and that the role of nNOS is related to the function of the type
      2B fibers of the muscle.

PMID- 12416721
TI  - Myosin heavy chain isoform expression and Ca2 +-stimulated ATPase activity in
      single fibres of toad rectus abdominis muscle.
AB  - Segments of single fibres from the rectus abdominis (RA) muscles of adult and
      juvenile cane toads (Bufo marinus) were examined for myosin heavy chain (mHC)
      isoform expression and Ca2+-stimulated MgATPase activity. mHC isoform analyses
      were carried out using the recently developed alanine-SDS-PAGE method, which
      separates one tonic (BmHCT) and three twitch (BmHC1, BmHC2, BmHC3) mHC isoforms
      in toad skeletal muscle. Ca2+-stimulated MgATPase activity was measured by
      spectrophotometric determination of Pi, under conditions in which the ATPase
      associated with the sarcoplasmic reticulum (SR ATPase) was suppressed by feedback
      inhibition. The mHC-based fibre types identified in this study include three pure
      twitch fibre types (t1, t2 and t3), expressing BmHC1, BmHC2 or BmHC3
      respectively, and seven hybrid fibre types co-expressing a combination of two or
      three twitch and tonic or twitch and twitch mHC isoforms. The fibre populations
      dissected from juvenile and adult toad muscles contained 49.4% (juvenile) and
      73.7% (adult) mHC hybrids. The average values for Ca2+-stimulated MgATPase in
      pure twitch fibres and in fibres expressing predominantly (> or = 95%) the tonic
      mHC isoform (Tp fibres) differed significantly (P < 0.05) from each other and
      decreased in the order t1 > t2 > t3 > Tp. We conclude that (i) in RA muscles of
      both juvenile and adult cane toads there is a large proportion of mHC hybrids,
      some of which co-express twitch and tonic mHC isoforms and (ii) ATPase activities
      associated with the four mHC isoforms expressed in toad skeletal muscles decrease
      in the order BmHC1 > BmHC2 > BmHC3 > BmHCT.

PMID- 12416722
TI  - Adrenaline diminishes K+ contractures and Ba2+-current in chicken slow skeletal
      muscle fibres.
AB  - The effects of adrenaline and the beta-adrenergic agonist isoprenaline on K+
      evoked tension (K+-contracture) and Ba2+ current were investigated in chicken
      slow (anterior latissimus dorsi (ald)) muscle using isometric-tension
      measurements and current recording. Addition of adrenaline (10(-7) - 10(-5) M) or
      isoprenaline (10(-6) - 10(-5) M) to the bath reduced the amplitude of the K+
      contractures. These effects were blocked by the beta-antagonist propranolol (5 x
      10(-6) M). External application of a cAMP analogue (8-bromo cyclic AMP; 1 x 10(
      4) M) also decreased the amplitude of the K+-contractures. To analyze the
      possible relationship between the induced tension reduction and effects on
      sarcolemmal Ca2+ channels, a slow action potential and a slow inward membrane
      current were studied in intact ald chicken muscle fibres. When the ald muscle was
      immersed in a Na+- and Cl--free solution containing Ba2+ and depolarizing pulses
      were delivered from a -80 mV holding potential, the muscle fibres exhibited a
      small, slow Ba2+-dependent potential (observed at about -26 mV, peak amplitude,
      around -10 mV). The response was blocked by the addition of Co2+ (5 mM) or Cd2+
      (2 mM). Using the three-microelectrode voltage-clamp technique, a slow inward
      membrane current underlying the Ba2+ potential could be discerned. The current
      had a mean threshold of -60 mV, reached maximum at about -5 mV and ranged from
      ca. 9 to 19 pA/cm2 (depending on the external Ba2+ concentration). It had a mean
      reversal potential of +45 mV. The Ba2+ inward current was diminished when
      adrenaline or isoprenaline was added to the bath (1 x 10(-5) M); however, this
      decrease did not occur when propranolol was present (5 x 10-6 M). These results
      suggest that the decreases in the tension of K+-contractures induced by
      adrenaline and isoprenaline may occur through beta-adrenergic effects on
      sarcolemmal Ca2+ channels in ald chicken slow muscle fibres.

PMID- 12416723
TI  - Tubular localization of silent calcium channels in crustacean skeletal muscle
      fibers.
AB  - Ca2+-induced Ca2+ release (CICR) in the superficial abdominal flexor muscle of
      the crustacean Atya lanipes appears to be mediated by a local control mechanism
      similar to that of vertebrate cardiac muscle, but with an unusually high gain.
      Thus, Ca2+ influx increases sufficiently the local concentration of Ca2+ in the
      immediate vicinity of the sarcoplasmic reticulum Ca2+ release channels to trigger
      the highly amplified release of Ca2+ required for contraction, but is too low to
      generate a macroscopic inward current (i.e., the Ca2+ channels are silent). To
      determine the localization of the silent Ca2+ Channels, the mechanical,
      electrophysiological and ultrastructural properties of the muscle were examined
      before and after formamide treatment, a procedure that produces the disruption of
      transverse tubules of striated muscle. We found that tubular disruption decreased
      tension generation by about 90%; reduced inward current (measured as Vmax, the
      maximum rate of rise of Sr2+ action potentials) by about 80%; and decreased
      membrane capacitance by about 77%. The results suggest that ca. 80% of the silent
      Ca2+ channels are located in the tubular system. Thus, these studies provide
      further evidence to support the local control mechanism of CICR in crustacean
      skeletal muscle.

PMID- 12416724
TI  - Colocalization of Ca2+-ATPase and GRP94 with p58 and the effects of thapsigargin
      on protein recycling suggest the participation of the pre-Golgi intermediate
      compartment in intracellular Ca2+ storage.
AB  - We have studied the localization of functional components of cellular Ca2+
      transport and storage and the effects of thapsigargin (TG), a specific inhibitor
      of the sarco-endoplasmic reticulum Ca2+-ATPase (SERCA), with respect to the p58
      containing pre-Golgi intermediate compartment (IC). The depletion of Ca2+ stores
      in normal rat kidney (NRK) cells by TG abolished the retention of the KDEL
      containing, Ca2+-binding, luminal ER chaperones GRP94/endoplasmin and GRP78/BiP,
      and resulted in the appearance of the proteins in the culture medium before
      inducing their synthesis. Immunolocalization of GRP94 in TG-treated cells showed
      that the protein was transported to the Golgi complex and, in parallel, the KDEL
      receptor was redistributed from the Golgi to p58-positive IC structures, but was
      not transported further to the ER. Similarly, p58 that normally cycles between
      the ER, IC, and cis-Golgi, was largely depleted from the cell periphery and
      arrested in large-sized IC elements and numerous vesicles or buds in the Golgi
      region, showing that TG selectively blocks its recycling from the IC back to the
      ER. Importantly, cell fractionation analyses and confocal fluorescence microscopy
      provided evidence that the IC elements in unperturbed cells contain SERCA and a
      considerable pool of GRP94. Thus, the observed effects of TG on protein retention
      and recycling can be explained by a change in the luminal Ca2+ concentration of
      the IC. Moreover, the compositional properties of the IC elements suggest that
      they participate in intracellular Ca2+ storage.

PMID- 12416725
TI  - Targeting of the GRIP domain to the trans-Golgi network is conserved from
      protists to animals.
AB  - The GRIP domain, found in a family of coiled-coil peripheral membrane Golgi
      proteins, is a specific targeting sequence for the trans-Golgi network of animal
      cells. In this study we show that a coiled-coil protein with a GRIP domain occurs
      in the primitive eukaryote, Trypanosoma brucei, and that reporter proteins
      containing this domain can be used as a marker for the poorly characterized trans
      Golgi/trans-Golgi network of trypanosomatid parasites. The T. brucei GRIP domain,
      when fused to the carboxyl terminus of the green fluorescent protein (GFP
      TbGRIP), was efficiently localized to the Golgi apparatus of transfected COS
      cells. Overexpression of GFP-TbGRIP in COS cells displaced the endogenous GRIP
      protein, GCC1p, from the Golgi apparatus indicating that the trypanosomatid and
      mammalian GRIP sequences interact with similar membrane determinants. GFP fusion
      proteins containing either the T. brucei GRIP domain or the human p230 GRIP
      (p230GRIP) domain were also expressed in the trypanosomatid parasite, Leishmania
      mexicana, and localized by fluorescence and immuno-electron microscopy to the
      trans face of the single Golgi apparatus and a short tubule that extended from
      the Golgi apparatus. Binding of GFP-p230GRIP to Golgi membranes in L. mexicana
      was abrogated by mutation of a critical tyrosine residue in the p230 GRIP domain.
      The levels of GFP-GRIP fusion proteins were dramatically reduced in stationary
      phase L. mexicana promastigotes, suggesting that specific Golgi trafficking steps
      may be down-regulated as the promastigotes cease dividing. This study provides a
      protein marker for the trans-Golgi network of trypanosomatid parasites and
      suggests that the GRIP domain binds to a membrane component that has been highly
      conserved in eukaryotic evolution.

PMID- 12416726
TI  - Carbachol-induced fluid movement through methazolamide-sensitive bicarbonate
      production in rat parotid intralobular ducts: quantitative analysis of
      fluorescence images using fluorescent dye sulforhodamine under a confocal laser
      scanning microscope.
AB  - Fluid secretion is observed at the openings of ducts in the exocrine gland. It
      remains unclear whether the ducts are involved in fluid secretion in the salivary
      glands. In the present study, we investigated the exclusion of fluorescent dye
      from the duct lumen by carbachol (CCh) in isolated parotid intralobular duct
      segments to clarify the ability of the ducts for the fluid secretion. When the
      membrane-impermeable fluorescent dye, sulforhodamine, was added to the superfused
      extracellular solution, quantitative fluorescence images of the duct lumen were
      obtained under the optical sectioning at the level of the duct lumen using a
      confocal laser scanning microscope. CCh decreased the fluorescent intensity in
      the duct lumen during the superfusion of the fluorescent dye, and CCh flushed out
      small viscous substances stained with the fluorescent dye from isolated duct
      lumen, suggesting that CCh might induce fluid secretion in the duct, leading to
      the clearance of the dye and small stained clumps from the duct lumen. CCh
      induced clearance of the fluorescent dye was divided into two phases by the
      sensitivity to external Ca2+ and methazolamide, an inhibitor for carbonic
      anhydrase. The initial phase was insensitive to these, and the subsequent late
      phase was sensitive to these. A major portion in the late phase was inhibited by
      removal of bicarbonate in the superfusion solution and DPC, but not low
      concentration of external Cl-, bumetanide or DIDS, suggesting that methazolamide
      sensitive production of HCO3-, but not the Cl- uptake mechanism, might contribute
      to the CCh-induced clearance of the dye from the duct lumen. These results
      represent the first measurements of fluid movement in isolated duct segments, and
      suggest that carbachol might evoke fluid secretion possibly through Ca2+
      activated, DPC-sensitive anion channels with HCO3- secretion in the rat parotid
      intralobular ducts.

PMID- 12416727
TI  - The ionic composition of the contractile vacuole fluid of Paramecium mirrors ion
      transport across the plasma membrane.
AB  - In vivo K+, Na+, Ca2+, Cl- and H+ activities in the cytosol and the contractile
      vacuole fluid, the overall cytosolic osmolarity, the fluid segregation rate per
      contractile vacuole and the membrane potential of the contractile vacuole complex
      of Paramecium multimicronucleatum were determined in cells adapted to 24 or 124
      mosm l(-1) solutions containing as the monovalent cation(s): 1) 2 mmol l(-1) K+;
      2) 2 mmol l(-1) Na+; 3) 1 mmol l(-1) K+ plus 1 mmol l(-1) Na+; or 4) 2 mmol l(-1)
      choline. In cells adapted to a given external osmolarity i) the fluid segregation
      rate was the same if adapted to either K+ or Na+, twice as high when adapted to
      solutions containing both K+ and Na+, and reduced by 50% or more in solutions
      containing only choline, ii) the fluid of the contractile vacuole was always
      hypertonic to the cytosol while the sum of the ionic activities measured in the
      fluid of the contractile vacuole was the same in cells adapted to either K+ or
      Na+, at least 25% higher in cells adapted to solutions containing both K+ and
      Na+, and was reduced by 55% or more in solutions containing only choline, iii)
      the cytosolic osmolarity was the same in cells adapted to K+ alone, to Na+ alone
      or to both K+ and Na+, whereas it was significantly lower in cells adapted to
      choline. At a given external osmolarity, a positive relationship between the
      osmotic gradient across the membrane of the contractile vacuole complex and the
      fluid segregation rate was observed. We conclude that both the plasma membrane
      and the membrane of the contractile vacuole complex play roles in fluid
      segregation. The presence of external Na+ moderated K+ uptake and caused the Ca2+
      activity in the contractile vacuole fluid to rise dramatically. Thus, Ca2+ can be
      eliminated through the contractile vacuole complex when Na+ is present
      externally. The membrane potential of the contractile vacuole complex remained
      essentially the same regardless of the external ionic conditions and the ionic
      composition of the fluid of the contractile vacuole. Notwithstanding the large
      number of V-ATPases in the membrane of the decorated spongiome, the fluid of the
      contractile vacuole was found to be only mildly acidic, pH 6.4.

PMID- 12416728
TI  - External GTP binding and induction of cell division in starved Tetrahymena
      thermophila.
AB  - The extracellular nucleotide, guanosine 5'-triphosphate (GTP) is known to be a
      chemorepellent for ciliated protozoa such as Paramecium and Tetrahymena. Here, we
      studied the surface localization of GTP binding sites and also its effects on the
      cell division of Tetrahymena thermophila. When a ribose-modified and fluorescent
      analog of GTP, 2'-(or -3')-O-trinitrophenyl (TNP)-GTP was added to the cells
      starved in non-nutrient buffer, a remarkable fluorescence was observed at the
      compound cilia of the oral area, while it was weak at other cilia and the somatic
      membrane. Following transfer of the cells to the starvation medium, the intensity
      of TNP-GTP fluorescence at the oral area gradually increased and was saturated at
      3-4 hours. Addition of GTP to the starved cell induced not only an avoiding
      reaction in swimming, but also induced a synchronous cell division that occurred
      2 hours later. An attempt to search for other stimuli, which induced cell
      division, revealed that mechanical stimulation by a short period of
      centrifugation was almost as effective as the addition of GTP. The supernatant
      after centrifugation had the ability to induce cell division, and such activity
      was abolished after the supernatant was treated with the phosphatase, apyrase,
      suggesting the release of GTP by the mechanical stimulation. These results
      indicate that the released GTP binds mainly to the oral area and this then
      induces the cell division of starved T. thermophila.

PMID- 12416729
TI  - HFE and non-HFE hemochromatosis.
AB  - Hereditary hemochromatosis (HH) is a disorder of iron metabolism in which
      enhanced absorption of dietary iron causes increased iron accumulation in the
      liver, heart, and pancreas. Most individuals with HH are homozygous for a point
      mutation in the HFE gene, leading to a C282Y substitution in the HFE protein. The
      function of HFE protein is unknown, but the available evidence suggests that it
      acts in association with beta2-microglobulin and transferrin receptor 1 to
      regulate iron uptake from plasma transferrin by the duodenum, the proposed
      mechanism by which body iron levels are sensed. The identification of HFE has
      established the foundation for a better understanding of the molecular and
      cellular biology of iron homeostasis and its altered regulation in HH.
      Additionally, the ability to accurately diagnose iron overload disorders has been
      strengthened, family screening has been improved, and evaluation of patients with
      other forms of liver disease complicated by moderate-to-severe iron overload is
      now possible. However, the role of HFE testing in generalized population
      screening for HH is still controversial. Recently, other forms of HH have been
      described that are not related to HFE but are due to mutations in genes coding
      iron transport proteins.

PMID- 12416730
TI  - Recent advance in molecular iron metabolism: translational disorders of ferritin.
AB  - Ferritin, composed of H-subunits and L-subunits, plays important roles in iron
      storage and in the control of intracellular iron distribution. Synthesis of both
      subunits is controlled by common cytoplasmic proteins, iron regulatory proteins
      (IRP-1 and IRP-2) that bind to the iron-responsive element (IRE) in the 5'
      untranslated region of ferritin messenger RNA (mRNA). When intracellular iron is
      scarce, IRPs display IRE binding to suppress translation of mRNA. When cellular
      iron is abundant, IRPs become inactivated (IRP-1) or degraded (IRP-2). In the
      last few years, IRE mutations that cause disorders due to dysregulation of
      ferritin subunit synthesis have been identified. Hereditary hyperferritinemia
      cataract syndrome is associated with point mutations or deletions in the IRE of L
      subunit mRNA and is characterized by constitutively increased synthesis of L
      subunits but is unrelated to iron overload. A single-point mutation in the IRE of
      H-subunit mRNA in members of a family affected with dominantly inherited iron
      overload has been reported. This review summarizes the current understanding of
      the translational disorders caused by IRE mutations in ferritin mRNA.

PMID- 12416731
TI  - Transferrin receptor in tissue and serum: updated clinical significance of
      soluble receptor.
AB  - The transferrin receptor is an essential component of cellular uptake of iron,
      and it binds to serum transferrin. Recently, 2 different types of transferrin
      receptors have been recognized: transferrin receptor (TfR or transferrin receptor
      1) and transferrin receptor 2. Most cells possess a ubiquitous system controlling
      the biosynthesis of TfR at the posttranscriptional level to avoid excess iron
      influx into the cells through TfR. During the process of recycling of transferrin
      receptors, some are shed and appear as soluble or serum transferrin receptors.
      Measurement of serum transferrin receptor is a new marker of iron metabolism that
      reflects body iron stores and total erythropoiesis. It has been shown that serum
      transferrin receptor to ferritin ratios have significant predictive value for
      differentiating iron deficiency anemia from non-iron deficiency anemia, such as
      anemia of chronic disorders, whereas serum ferritin is the only significant
      independent predictor of iron deficiency anemia.

PMID- 12416734
TI  - Expression and affinity of homing-related molecules on steady-state adult and
      neonate human PB CD34+ cells and their SRC activity.
AB  - Although the vast majority of hematopoietic progenitor cells (HPCs) reside within
      the bone marrow (BM), a small number of HPCs also continuously circulate in the
      peripheral blood (PB). The examination of the fate of blood-borne HPCs in
      parabiotic mice, which are surgically conjoined and share a common circulation,
      recently revealed that steady-state PB HPCs play a physiological role in, at
      least, the functional re-engraftment of unconditioned BM. To assess the
      possibility that human HPCs have a similar function, in this study we examined
      the expression level and affinity of the homing-related molecules, as well as the
      SCID mouse reconstituting cell (SRC) activity of human PB CD34+ cells, and
      compared adults with neonates. There was no remarkable difference between adults
      and neonates in the expression of E- and/or P-selectin ligands by PB CD34+ cells
      or in these cells' affinity to VCAM-1. In contrast, the expression level of CXCR4
      on PB CD34+ cells was much lower in adults than in neonates. Adult cells also
      showed a much lower SRC activity than neonates. These results suggest that human
      PB HPCs may contribute to steady-state hematopoiesis in the BM of neonates to
      some extent, but not so much in adults.

PMID- 12416733
TI  - Long-term feto-maternal microchimerism: nature's hidden clue for alternative
      donor hematopoietic cell transplantation?
AB  - During pregnancy, fetal hematopoietic cells carrying paternal human leukocyte
      antigens (HLA) migrate into maternal circulation, and, vice versa, maternal
      nucleated cells can be detected in fetal organs and umbilical cord blood,
      indicating the presence of bidirectional cell traffic between mother and fetus.
      By taking advantage of fluorescence in-situ hybridization or polymerase chain
      reaction-based techniques, researchers recently found that postpartum persistence
      of such reciprocal chimerism was common among healthy individuals and may
      sometimes cause tissue chimerism. Although the biological significance of long
      lasting feto-maternal microchimerism is unknown, a number of investigations have
      suggested its association with the development of "autoimmune" diseases such as
      systemic sclerosis. However, the very common presence of feto-maternal
      microchimerism among subjects without any autoimmune attack may allow us the more
      appealing hypothesis that it is an indicator for the acquired immunological
      hyporesponsiveness to noninherited maternal or fetal HLA antigens. An offspring's
      tolerance to noninherited maternal antigens has been clinically suggested by the
      retrospective analysis of renal transplantations or haploidentical hematopoietic
      stem cell transplantations, and whether postpartum mothers can tolerate
      paternally derived fetal antigens is an intriguing question. Although an exact
      linkage between microchimerism and transplantation tolerance is yet to be
      elucidated, long-term acceptance of a recipient's cell in the donor may have a
      favorable effect on preventing the development of severe graft-versus-host
      disease, and the donor cell microchimerism in the recipient might facilitate the
      graft acceptance. If this concept holds true, HLA-mismatched hematopoietic stem
      cell transplantation would be more feasible among haploidentical family members
      mutually linked with feto-maternal microchimerism. Further studies are warranted
      to investigate the potential role of feto-maternal microchimerism in human
      transplantation medicine.

PMID- 12416732
TI  - Iron toxicity and chelation therapy.
AB  - Iron is an essential mineral for normal cellular physiology, but an excess can
      result in cell injury. Iron in low-molecular-weight forms may play a catalytic
      role in the initiation of free radical reactions. The resulting oxyradicals have
      the potential to damage cellular lipids, nucleic acids, proteins, and
      carbohydrates; the result is wide-ranging impairment in cellular function and
      integrity. The rate of free radical production must overwhelm the cytoprotective
      defenses of cells before injury occurs. There is substantial evidence that iron
      overload in experimental animals can result in oxidative damage to lipids in
      vivo, once the concentration of iron exceeds a threshold level. In the liver,
      this lipid peroxidation is associated with impairment of membrane-dependent
      functions of mitochondria and lysosomes. Iron overload impairs hepatic
      mitochondrial respiration primarily through a decrease in cytochrome C oxidase
      activity, and hepatocellular calcium homeostasis may be compromised through
      damage to mitochondrial and microsomal calcium sequestration. DNA has also been
      reported to be a target of iron-induced damage, and this may have consequences in
      regard to malignant transformation. Mitochondrial respiratory enzymes and plasma
      membrane enzymes such as sodium-potassium-adenosine triphosphatase (Na(+) + K(+)
      ATPase) may be key targets of damage by non-transferrin-bound iron in cardiac
      myocytes. Levels of some antioxidants are decreased during iron overload, a
      finding suggestive of ongoing oxidative stress. Reduced cellular levels of ATP,
      lysosomal fragility, impaired cellular calcium homeostasis, and damage to DNA all
      may contribute to cellular injury in iron overload. Evidence is accumulating that
      free-radical production is increased in patients with iron overload. Iron-loaded
      patients have elevated plasma levels of thiobarbituric acid reactants and
      increased hepatic levels of aldehyde-protein adducts, indicating lipid
      peroxidation. Hepatic DNA of iron-loaded patients shows evidence of damage,
      including mutations of the tumor suppressor gene p53. Although phlebotomy therapy
      is effective in removing excess iron in hereditary hemochromatosis, chelation
      therapy is required in the treatment of many patients who have combined secondary
      and transfusional iron overload due to disorders in erythropoiesis. In patients
      with beta-thalassemia who undergo regular transfusions, deferoxamine treatment
      has been shown to be effective in preventing iron-induced tissue injury and in
      prolonging life expectancy. The use of the oral chelator deferiprone remains
      controversial, and work is continuing on the development of new orally effective
      iron chelators.

PMID- 12416735
TI  - Long-term follow-up of patients with aplastic anemia and refractory anemia
      responding to combination therapy with recombinant human granulocyte colony
      stimulating factor and erythropoietin.
AB  - In our previous study, approximately 60% of aplastic anemia (AA) and refractory
      anemia (RA) patients treated with recombinant human granulocyte colony
      stimulating factor (rhG-CSF) and recombinant human erythropoietin (rhEpo) showed
      a multilineage response. In this study, we analyzed the long-term follow-up of
      the multilineage responders (multi-R). In the follow-up analysis of 11 multi-R (6
      AA and 5 RA), 10 patients (5 AA and 5 RA) were evaluable. The range of time from
      the start of treatment to the final contact was 50 to 125 months. Analysis of
      survival times revealed a significant difference between multi-R and non-multi-R
      among AA patients given this treatment (P = .016). One AA and 1 RA patient among
      the multi-R developed acute leukemia. Of 7 living multi-R, 3 AA and 2 RA patients
      did not need transfusion at final contact. Four of them maintained the target
      hemoglobin concentration of more than 11 g/dL for quality-of-life benefit. The
      findings suggested that this result is an important advantage of this treatment.

PMID- 12416736
TI  - Two groups of Philadelphia chromosome-positive childhood acute lymphoblastic
      leukemia classified by pretreatment multidrug sensitivity or resistance in in
      vitro testing.
AB  - The development of effective chemotherapy is imperative for children with
      Philadelphia chromosome-positive (Ph) acute lymphoblastic leukemia (ALL) because
      of the poor prognosis of this condition. Initial cellular drug resistance is
      thought to be an important cause of induction failure and early relapse. We
      carried out in vitro tests using a methyl-thiazol-tetrazolium assay on bone
      marrow samples from 274 children with newly diagnosed ALL. Sixteen children
      (5.8%) had Ph-positive results of cytogenetic analysis. We examined in vitro drug
      resistance to 14 agents and found that leukemic cells in Ph ALL were
      significantly more resistant than were cells in non-Ph ALL to melphalan,
      bleomycin, etoposide, mitoxantrone, L-asparaginase, and vinblastine. With the
      prednisolone, L-asparaginase, and vincristine (PAV) combination of drugs, 10 of
      the 16 Ph patients with ALL (62.5%) showed relative resistance (RR) (sensitivity
      to only 1 or to none of the 3 drugs) at initiation of treatment. These 10
      patients experienced significantly poorer event-free survival (EFS) than did the
      6 patients with supersensitivity (SS) (defined as sensitivity to all 3 or to 2 of
      the 3 drugs, P = .019). Leukemic cells from RR patients were found to be
      multiresistant to 12 drugs with 2.0- to 58.4-fold RR compared with cells from SS
      patients. This PAV sensitivity delineates initially sensitive and resistant
      groups. Of these, the SS subgroup of Ph ALL patients may be curable with
      chemotherapy and stem cell transplantation. For EFS improvement in the RR group,
      it may be necessary to use a new chemotherapy approach from initiation.

PMID- 12416737
TI  - OX40 signaling renders adult T-cell leukemia cells resistant to Fas-induced
      apoptosis.
AB  - We reported previously that OX40, a member of the tumor necrosis factor receptor
      family, is expressed constitutively on fresh leukemia/lymphoma cells isolated
      from patients with adult T-cell leukemia (ATL). In this study, we tested whether
      OX40 signaling affects the Fas-mediated apoptosis of fresh ATL cells isolated
      from 7 patients (3 acute type, 3 chronic type, and 1 smoldering type). In all
      these patients, the coculture of ATL cells with MMCE/OX40 ligand gp34, a stable
      human gp34 transfectant of a mouse epithelial cell line, resulted in a decrease
      in the percentage of apoptotic cells after treatment with anti-Fas monoclonal
      antibody, compared to coculture with MMCE/mock controls. Similar findings were
      obtained in OX40(+)- human T-cell leukemia virus type I-transformed T-cell lines.
      To elucidate the molecular mechanism of this phenomenon, we used Kit225/OX40, a
      stable OX40 transfectant of an IL-2-dependent T-cell line, and its deletion
      mutant, Kit225/del-OX40, in which the intracytoplasmic domain of OX40 had been
      deleted. Coculture with MMCE/gp34 inhibited the apoptosis of Kit225/OX40, but
      Kit225/del-OX40 apoptosis was hardly affected. These results suggest that ATL
      cells may escape Fas-mediated destruction of the immune system through OX40
      signaling.

PMID- 12416739
TI  - Platelet dysfunction in myelodysplastic syndromes: a clinicopathological study.
AB  - Forty-eight patients with myelodysplastic syndromes and a platelet count greater
      than 80 x 10(9)/L were the subjects of a study of platelet function. A whole
      blood platelet lumi-aggregometer was used for simultaneous measurement of
      platelet aggregation by the impedance method and of adenosine triphosphate-dense
      granule release. The results were correlated with skin bleeding time and episodes
      of clinical bleeding or thrombosis. Thirty-five patients had at least 1 abnormal
      result indicating platelet hypoactivity; 7 patients had mixed platelet
      hypoactivity and hyperactivity; and 4 patients had platelet hyperactivity. Only 2
      patients had normal results. There was good correlation between platelet
      hypoactivity and prolonged skin bleeding time (P = .005); however, several
      patients with platelet hypoactivity had normal skin bleeding times. This finding
      suggested that whole-blood platelet aggregation studies may be more sensitive
      than bleeding time in identification of patients at risk of bleeding. Clinical
      hemorrhage was frequent (32 patients) in this cohort despite platelet counts
      greater than 100 x 10(9)/L. This finding indicated platelet hypofunction was
      clinically important. In contrast, only 2 of the 13 patients with thrombotic
      events had evidence of platelet hyperactivity, suggesting that other clinical
      factors are probably more important determinants of thrombosis. These
      observations confirm that platelet dysfunction is common in patients with
      myelodysplastic syndromes and suggest a useful role for routine whole-blood
      platelet aggregation studies to identify patients at risk of bleeding.

PMID- 12416738
TI  - The association of HLA antigen and GVHD in allogeneic hemopoietic stem cell
      transplantation with histocompatible sibling donor: a single-center experience in
      Korea.
AB  - We analyzed the association of HLA antigens with incidence of organ-specific
      graft-versus-host disease (GVHD) after allogeneic hemopoietic stem cell
      transplantation (allo-HSCT) from an HLA-matched sibling donor. We retrospectively
      reviewed the clinical records of allo-HSCT recipients and found 389 patients who
      had received matched-sibling HSCT. HLA types, GVHD grades, and the development of
      acute or chronic GVHD, factors that reflect a certain immunological impact
      associated with involved organs, were investigated. The overall incidence of
      acute and chronic GVHD was 24.8% (96 cases) and 21.2% (82 cases), respectively.
      The incidence of acute GVHD with grades II through IV was higher among patients
      who had HLA-B61 (P = .0153) and HLA-Cw3 (P = .0208). The donor sex (P = .0040)
      and the conditioning regimen (P = .0010) were also associated with severe acute
      GVHD. The extensive-type chronic GVHD incidence was higher in patients who had
      HLA-B54 (P = .0159). The donor sex (P = .0406) and the pretransplantation
      diagnosis (P = .0184) were other factors associated with the development of
      extensive-type chronic GVHD. Furthermore, HLA-B35 (P = .0226) and HLA-B54 (P =
      .0091) were associated with a higher incidence of severe acute skin GVHD and
      chronic skin and oral GVHD (in descending order of incidence rates). HLA-B7,27
      was associated with chronic liver GVHD (P = .0476) in addition to other
      parameters including patient (P = .0246) and donor sex (P = .0019). This study
      shows that these remarkable HLA antigens may be potent transplantation immune
      regulators, but there is a need for further evaluation using larger study
      samples.

PMID- 12416740
TI  - Treatment with cerivastatin in primary mixed hyperlipidemia induces changes in
      platelet aggregation and coagulation system components.
AB  - Platelet activation, impairment of fibrinolysis, activation of the coagulation
      pathway, and dyslipidemia are important factors in the pathogenesis and
      progression of ischemic heart disease, and patients generally need to use an
      antiplatelet agent. Lipid-lowering cerivastatin, a novel 3-hydroxy-3
      methylglutaryl coenzyme A reductase inhibitor, was administered to 20 patients
      with primary mixed hyperlipidemia for the assessment of the effect of
      cerivastatin on lipid levels, plasma fibrinogen concentration, factor VII, VIII,
      and X levels, plasminogen and antiplasmin concentrations, platelet count, and
      aggregation (adenosine diphosphate [ADP], collagen, and epinephrine induced).
      Assessments were made immediately after 2 months of a standard lipid-lowering
      diet, 4 weeks of placebo administration, and 4 weeks of cerivastatin treatment.
      Cerivastatin achieved significant reductions in triglyceride, total cholesterol,
      and low-density lipoprotein cholesterol levels. The significant improvement of
      the lipid profile was associated with platelet aggregation reduction in vitro
      stimulated by ADP, collagen, and epinephrine (P < .05, P = .05, P < .005,
      respectively). Significantly lower levels of factor VII and fibrinogen were
      observed (P = .001, P < .0001) immediately after cerivastatin treatment. No
      significant differences were detected in factor VIII level, plasminogen and
      antiplasmin concentrations, and platelet count after cerivastatin treatment. It
      was concluded that cerivastatin in mixed hyperlipidemia can exert beneficial
      changes on specific hemostatic variables and platelet aggregation in addition to
      its positive effects on plasma lipid values.

PMID- 12416741
TI  - Late response to cyclosporine in refractory thrombotic thrombocytopenic purpura.
AB  - Plasma exchange (PEX) with fresh frozen plasma, usually in association with
      steroid therapy, has been shown to be the first-line treatment of thrombotic
      thrombocytopenic purpura. It works by removing ultralarge von Willebrand factor
      (vWF) multimers and inhibitory antibody and by supplying normal protease. For
      patients with disease refractory to PEX, there is no standardized treatment.
      Limited and sporadic success with different therapies (vincristine sulfate,
      prostacyclin, intravenous immunoglobulins, splenectomy) has been described. We
      report the case of a woman who developed refractory disease after an initial
      response to PEX and despite a very high number of PEX procedures performed. Low
      activity (< 5%) of serum vWF-cleaving protease and a low level of protease
      inhibitor were documented. The patient had a slow but sustained response when
      oral cyclosporine was administered concomitantly with PEX, which was slowly
      tapered. The activity of serum vWF-cleaving protease normalized. At relapse,
      treatment with cyclosporine, added after the failure of steroids and PEX, led to
      a lasting response. It is possible that in some cases cyclosporine therapy must
      be of particularly long duration before being considered ineffective.

PMID- 12416742
TI  - Rapid proliferation of a different clone early after autologous peripheral blood
      stem cell transplantation for non-Hodgkin's lymphoma.

PMID- 12416743
TI  - Sequential quantification of Epstein-Barr virus DNA in a case of Epstein-Barr
      virus-associated hemophagocytic syndrome.

PMID- 12416744
TI  - Color Doppler and laser velocimetry studies in the assessment of portal
      hemodynamics and severity of chronic liver disease.

PMID- 12416745
TI  - Assessment of portal hemodynamics by ultrasound color Doppler and laser Doppler
      velocimetry in liver cirrhosis.
AB  - BACKGROUND: Color Doppler is a noninvasive method for assessing portal
      hemodynamics. Laser Doppler velocimetry is useful in assessment of
      microcirculatory abnormalities in portal hypertensive gastropathy (PHG). AIMS: To
      study portal hemodynamics by color Doppler and gastric mucosal blood flow (GMBF)
      by laser Doppler velocimetry in patients with cirrhosis. METHODS: Twenty-eight
      patients with cirrhosis of liver (24 men) and 10 healthy subjects (7 men) were
      studied. Portal venous blood flow (PVBF) and portal flow velocity (PFV) were
      assessed by color Doppler at the level where the hepatic artery crosses the
      portal vein, and GMBF was measured by laser Doppler velocimetry. RESULTS: PVBF
      (379.5 [102.9] mL/min), PFV (5.3 [1.1] cm/sec) and GMBF (3.5 [0.8] volts) were
      significantly lower in patients with cirrhosis than in controls. PVBF and PFV
      were significantly lower in patients in Child class B and C than those in class
      A. Patients with ascites had significantly lower PVBF, PFV and GMBF than those
      without; values were also lower in patients with PHG than in those without.
      History of bleeding had no relation with PVBF and PFV. GMBF showed good
      correlation with PVBF (r=0.58, p<0.001) and with PFV (r=0.48, p<0.01).
      CONCLUSIONS: In cirrhosis of liver, PVBF, PFV and GMBF are significantly lower,
      and the changes increase with increasing severity of liver disease.

PMID- 12416746
TI  - Effect of red chillies on small bowel and colonic transit and rectal sensitivity
      in men with irritable bowel syndrome.
AB  - BACKGROUND: Altered motility and threshold for pain have been incriminated in the
      pathogenesis of the irritable bowel syndrome (IBS). Capsaicin affects visceral
      sensory perception and chillies, which contain capsaicin, have been shown to
      accelerate gut transit. AIMS: To evaluate the effect of red chillies on small
      bowel transit (SBT) and colonic transit (CT) and rectal sensitivity in normal men
      and men with IBS. METHODS: Twenty-nine men with IBS diagnosed using Manning's
      criteria, and 21 healthy men, were studied before and after ingestion of 10 g red
      chilli powder (capsaicin equivalent 14 mg). SBT time was measured as the time
      taken for 99mTc-sulfur colloid to reach the cecum after leaving the stomach.
      Total and segmental CT times were assessed using radio-opaque markers. Rectal
      sensitivity and pain threshold to intrarectal balloon distension were measured.
      RESULTS: The median (range) bowel frequency in patients and healthy men was 2 (1
      6) and 1 (1-3) per day (p=0.03), respectively. After ingestion of chillies, it
      increased to 3 (1-8) per day and 2 (1-4) per day (p=0.01), respectively. There
      was no difference in transit times between patients and healthy men; chilli
      ingestion did not alter SBT time, total or segmental CT time. IBS patients had a
      lower threshold to balloon distension for both discomfort and pain in the basal
      state (p<0.01). Chillies increased this threshold in healthy men (p<0.01).
      CONCLUSIONS: Men with IBS do not have SBT or CT abnormalities, but have a lower
      rectal balloon sensitivity threshold. Chilli powder does not alter either SBT or
      CT in men with IBS or healthy men; however, it increases the rectal threshold for
      pain in the latter.

PMID- 12416747
TI  - Spectrum of viral hepatitis in thalassemic children receiving multiple blood
      transfusions.
AB  - AIM: To investigate the prevalence of infection with hepatitis viruses in
      children with thalassemia receiving multiple blood transfusions. METHODS: Sera
      from 50 children with thalassemia aged 5-15 years (30 boys), who had each
      received over 80 units of blood, were evaluated for the presence of markers for
      hepatitis A virus (HAV; IgG and IgM anti-HAV), hepatitis B virus (HBV; HBsAg, and
      IgG and IgM anti-HBc), hepatitis C virus (HCV; IgG and IgM anti-HCV, and HCV RNA)
      and hepatitis E virus (HEV; IgG and IgM anti-HEV). IgM anti-hepatitis D virus
      (HDV) was looked for only in HBsAg or IgM anti-HBc positive sera. RESULTS: No
      child had evidence of recent HAV or HDV infection. IgG anti-HAV was positive in
      12 children. One patient had acute HBV infection. Nine patients were HBsAg
      positive. HCV infection was present in 15 cases; six of them were HCV RNA
      positive, and three had superinfection with hepatitis B. Recent HEV infection was
      present in 5 cases. CONCLUSION: Thalassemic patients receiving multiple blood
      transfusions often acquire hepatitis B (20%) and C (30%) infections. Recent
      hepatitis E infection was documented in 10% in this one-point study.

PMID- 12416748
TI  - Prevalence of anti-HCV antibodies among family contacts of hepatitis C virus
      infected patients.
AB  - BACKGROUND: Non-parenteral transmission of hepatitis C virus (HCV) is
      controversial. There are no data on intrafamilial spread of HCV from India, where
      the family set-up differs from that in developed countries. METHODS: First-degree
      relatives of patients with HCV-related chronic liver disease underwent testing
      for anti-HCV antibody and levels of transaminases. History of exposure to
      blood/blood products, surgery or other known risk factors, and of alcohol intake
      was recorded. Total duration of residence with the patient, and duration of
      residence after establishment of diagnosis in the patient was also recorded.
      RESULTS: Of 272 first-degree relatives, 125 agreed to participate. Of these, 20
      (16%) tested positive for anti-HCV. This rate was significantly higher than the
      1.6% anti-HCV positivity rate in our volunteer blood donors. Twelve anti-HCV
      positive and 4 anti-HCV negative contacts had elevated transaminases. Alcohol
      consumption by contact, longer duration of residence with the index case after
      the diagnosis of liver disease, and presence of cirrhosis in the index case were
      associated with increased risk of HCV infection among contacts. CONCLUSIONS:
      Family contacts of patients with HCV-related chronic liver disease have an
      increased risk of HCV infection; this risk is particularly high if they consume
      alcohol, have a long duration of residence with the index case after diagnosis of
      liver disease, and if the index case has cirrhosis.

PMID- 12416749
TI  - Correlation of trauma scoring systems with abdominal septic complications in
      abdominal trauma.
AB  - INTRODUCTION: Anatomical trauma scoring systems can predict the occurrence of
      postoperative abdominal septic complications (ASC) after major abdominal trauma;
      however, this has not been validated in any Indian study. We attempted such an
      evaluation in patients attending a teaching hospital in central India. METHOD: A
      retrospective analysis of data from 169 patients who had undergone emergency
      laparotomy for penetrating or blunt abdominal injury between August 1996 and July
      2001 was done. Every patient was scored using three trauma severity indices and
      the occurrence of ASC was identified. RESULTS: Patients who developed ASC had
      higher trauma severity scores than those who did not. Thirty-eight patients had
      isolated small bowel injury; trauma scores underestimated the occurrence of ASC
      in these patients. CONCLUSIONS: Trauma severity indices may serve as useful tools
      to predict the occurrence of postoperative ASC in patients with abdominal trauma,
      except in those with isolated small bowel injury. There is thus a need to modify
      the weight of small bowel injury in these scoring systems.

PMID- 12416750
TI  - Pneumatic dilation versus intrasphincteric botulinum toxin injection in the
      treatment of achalasia cardia in India: an economic analysis.
AB  - BACKGROUND: Pneumatic dilation (PD) is an established therapeutic option for
      achalasia cardia. Recently, intrasphincteric botulinum toxin (BT) has been used
      to treat achalasia cardia in view of its simplicity and safety. However, it is
      likely to be a costly treatment as repeated injections are often needed due to
      its short-lasting effect. No economic analysis of PD and BT strategies has been
      done in India. METHODS: A decision tree was constructed using decision analysis
      software (DATA 4.0; TreeAge Software, Williamstown, MA, USA). Probability
      estimates for BT injection and PD (and, in case of failure, surgery) were
      obtained from published literature, preferably from India. Direct "out-of-pocket"
      costs (in Indian rupees; currently US$ 1 = 49 rupees approximately) for baseline
      analysis were obtained from our hospital and from some private hospitals.
      Sensitivity analysis was done using a wide range of probability and cost
      estimates. RESULTS: Intrasphincteric BT injection strategy was more costly at
      18,520 rupees per patient than PD strategy (4,568 rupees), yielding an
      incremental cost of 13,952 rupees per patient successfully treated. Sensitivity
      analysis supported the conclusions of the baseline analysis. CONCLUSION: Primary
      intrasphincteric BT injection strategy was costlier than primary PD strategy in
      the treatment of achalasia cardia in India, and therefore cannot be justified
      despite its efficacy, relative ease of administration and safety.

PMID- 12416751
TI  - Pseudoaneurysm of inferior epigastric artery following abdominal paracentesis.
AB  - We report a 31-year-old man with chronic renal failure and ascites who developed
      severe abdominal pain and a local non-pulsatile mass after therapeutic
      paracentesis. Doppler study confirmed a pseudoaneurysm of the right inferior
      epigastric artery. The patient recovered after the artery was ligated and the
      aneurysm excised.

PMID- 12416752
TI  - True giant intra-abdominal esophageal cyst.
AB  - Isolated intra-abdominal duplication cysts of foregut origin are extremely rare
      and are discovered incidentally. We report a 70-year-old lady with a giant, truly
      intra-abdominal esophageal duplication cyst. She was symptom-free one year after
      excision of the cyst.

PMID- 12416753
TI  - Sporadic intra-abdominal desmoid with acute abdomen.
AB  - We report a 72-year-old man with sporadic intra-abdominal desmoid tumor
      manifesting as acute abdomen. CT scan revealed an air-containing tumor 7 cm in
      diameter; three weeks later, the tumor had shrunk to 4 cm on antibiotics. At
      surgery, a tumor arising from the transverse colon mesentery and infiltrating the
      jejunum was resected. No recurrence occurred over a 1-year follow-up.

PMID- 12416754
TI  - Extraserosal pedunculated leiomyoma of stomach.
AB  - Leiomyoma of the stomach, a type of gastrointestinal stromal tumor, is uncommon.
      We report a 51-year-old woman with an extraserosal pedunculated leiomyoma of the
      stomach.

PMID- 12416755
TI  - Large Brunneroma presenting with bleeding.
AB  - Brunner's gland adenoma (Brunneroma) is a rare entity. We report a patient who
      presented with severe anemia due to bleed from a large Brunneroma arising from
      the duodenal bulb, and was managed successfully by surgical excision of the
      tumor.

PMID- 12416756
TI  - Rectal botryomycosis mimicking carcinoma.
AB  - Botryomycosis is a granulomatous disease that was first recognized in horses. The
      lesion is infective with fungus-like grains similar to the sulfur granules in
      actinomycosis. We report 54-year-old woman with a strong suspicion of rectal
      carcinoma that turned out to be rectal botryomycosis. She responded to
      erythromycin.

PMID- 12416757
TI  - Colonic pseudo-obstruction due to herpes zoster.
AB  - Visceral motor complications are uncommon manifestations of herpes zoster
      (varicella zoster). We report a 59-year-old man who developed acute colonic
      pseudo-obstruction, which followed the appearance of dermatomal herpes zoster.

PMID- 12416759
TI  - Severity of esophagitis in southern Indians.

PMID- 12416758
TI  - Acute intestinal obstruction due to solitary jejunal diverticulum.
AB  - We report a 26-year-old man who presented with acute intestinal obstruction.
      Laparotomy revealed a solitary jejunal diverticulum with a meso-diverticular
      band, through which a loop of bowel had herniated. He underwent wedge resection
      of the diverticulum and excision of the band.

PMID- 12416760
TI  - Treatment of typhoid ileal perforation by resection and temporary ileostomy.

PMID- 12416761
TI  - Mixed infection due to leptospira and dengue.

PMID- 12416762
TI  - Compressed air injury of the colon--delayed presentation.

PMID- 12416763
TI  - Colonic metastasis from squamous cell carcinoma of esophagus.

PMID- 12416764
TI  - Plasmodium vivax and hepatitis E co-infection--a rare cause of malarial jaundice.

PMID- 12416765
TI  - Root surface area of the mandibular cuspid and bicuspids.
AB  - BACKGROUND: The purpose of this study was to determine the total root surface
      area of extracted teeth by computerized image analysis and the amount of
      remaining attachment area assuming various amounts of bone loss due to
      periodontal disease. METHODS: One hundred fifty extracted mandibular teeth were
      evaluated, and measured from cusp tip to the cemento-enamel junction (CEJ), CEJ
      to root apex, and cusp tip to root apex. The fulcrum point of the tooth was also
      measured, along with the total root surface area of attachment and total surface
      area of attachment remaining following simulation of attachment loss in 2 mm
      increments. Measurements were made on 80 teeth on one proximal surface and either
      the buccal or lingual surface and multiplied by a factor of 2. Measurements on 70
      teeth were made on all 4 root surfaces to predict the accuracy of measuring only
      2 surfaces to determine root surface area. Images of the tooth surfaces were
      obtained by video camera and converted to computer image with measurement of the
      surface areas. RESULTS: The total root surface area for the mandibular cuspids
      and first and second bicuspids was 275.88 mm2, 251.45 mm2, and 271.81 mm2,
      respectively. The 2-sided and 4-sided measurements for the mandibular first
      bicuspid were 252.55 mm2 and 247.02 mm2, respectively (P>0.05). CONCLUSIONS: This
      study found the total root surface area to be greater than that in most previous
      studies. Increasing attachment loss is related to decreasing root surface area;
      however, this relationship is not directly proportional. No statistical
      difference was found between measuring 4 surfaces versus only 2 surfaces.

PMID- 12416766
TI  - Specific fibronectin fragments as markers of periodontal disease status.
AB  - BACKGROUND: The diagnosis of progressing periodontal disease typically relies on
      retrospective methods that detect changes in the amount of periodontal breakdown.
      Fibronectin (FN) fragments are found in vivo in association with periodontal
      disease, and specific FN fragments compromise periodontal ligament cell functions
      in vitro. The overall goal of this cross-sectional study was to determine whether
      specific FN fragments are present in gingival crevicular fluid (GCF) and can be
      used as markers for periodontal disease status. The eventual goal is to test
      these FN fragments in a longitudinal study as potential markers of disease
      activity. METHODS: GCF was collected from 94 subjects with untreated
      periodontitis from clinically healthy, mild/moderate periodontitis, and severe
      periodontitis sites. Sites were defined on the basis of clinical criteria,
      including gingival bleeding index, probing depth, and clinical attachment level.
      Western immunoblotting was used to detect FN fragments in GCF using antibodies to
      specific FN domains, including the collagen/gelatin-, central cell-, and carboxyl
      terminal heparin-binding domains, plus the CS-1 site on the alternatively spliced
      V region and the EIIIA region. FN fragments identified by immunoblotting and
      analyzed by NIH image software were scored based on pixel intensity and an
      ordinal grade scale. RESULTS: We identified several fragments highly associated
      with severe periodontitis sites, including 40-kDa, 120-kDa, and 68-kDa fragments.
      CONCLUSIONS: This study demonstrates that specific FN fragments are markers for
      periodontal disease status and supports the role of FN fragments as potential
      components in the pathogenesis of periodontal disease.

PMID- 12416767
TI  - Influence of the size of the microgap on crestal bone levels in non-submerged
      dental implants: a radiographic study in the canine mandible.
AB  - BACKGROUND: Accumulating evidence suggests that alveolar crestal bone resorption
      occurs as a result of the microgap that is present between the implant-abutment
      interface in dental implants. The objective of this longitudinal radiographic
      study was to determine whether the size of the interface or the microgap between
      the implant and abutment influences the amount of crestal bone loss in unloaded
      non-submerged implants. METHODS: Sixty titanium implants having sandblasted with
      large grit, acid-etched (SLA) endosseous surfaces were placed in edentulous
      mandibular areas of 5 American fox hounds. Implant groups A, B, and C had a
      microgap between the implant-abutment connection of <10 microm, 50 microm, or 100
      microm, respectively, as did groups D, E, and F, respectively. Abutments were
      either welded (1 -piece) in groups A, B, and C or non-welded (2-piece screwed) in
      D, E, and F. All abutment interfaces were placed 1 mm above the alveolar crest.
      Radiographic assessment was undertaken to evaluate peri-implant crestal bone
      levels at baseline and at 1, 2, and 3 months after implant placement whereupon
      all animals were sacrificed. RESULTS: The size of the microgap at the
      abutment/implant interface had no significant effect upon crestal bone loss. At 1
      month, most implants developed crestal bone loss compared with baseline levels.
      However, during this early healing period, the non-welded group (D, E, and F)
      showed significantly greater crestal bone loss from baseline to one month (P
      <0.04) and 2 months (P < 0.02) compared with the welded group (A, B, and C). No
      significant differences were observed between these 2 groups at 3 months (P >
      0.70). CONCLUSIONS: Crestal bone loss was an early manifestation of wound healing
      occurring after 1 month of implant placement. However, the size of the microgap
      at the implant-abutment interface had no significant effect upon crestal bone
      resorption. Thus, 2-piece non-welded implants showed significantly greater
      crestal bone loss compared with 1-piece welded implants after 1 and 2 months
      suggesting that the stability of the implant/abutment interface may have an
      important early role to play in determining crestal bone levels. At 3 months,
      this influence followed a similar trend but was not observed to be statistically
      significant. This finding implies that implant configurations incorporating
      interfaces will be associated with biological changes regardless of interface
      size and that mobility between components may have an early influence on wound
      healing around the implant.

PMID- 12416768
TI  - Clinical response to 2 different therapeutic regimens to treat peri-implant
      mucositis.
AB  - BACKGROUND: Maintenance of implants is imperative, since implants, like teeth,
      are susceptible to bacterial plaque accumulation and calculus formation, and thus
      at risk of developing peri-implant mucositis or peri-implantitis. METHODS: This
      study determined the clinical effects of chlorhexidine treatment on peri-implant
      mucositis at 1 and 3 months as determined by the modified plaque index, the
      modified sulcus bleeding index, clinical attachment level, and probing depth.
      Through DNA probes, the effect of chlorhexidine on the microbial flora of
      mucositic lesions was also evaluated. The population consisted of 16 adult male
      and female subjects (ages 34 to 76). After the baseline examination, the subjects
      received a dental prophylaxis and were randomly assigned to the test or control
      group. Subjects in the test group received antiseptic therapy (Treatment 1),
      which included mechanical cleansing and oral hygiene instructions supplemented by
      the local irrigation with chlorhexidine 0.12%, using a plastic syringe, and the
      topical application of a 0.12% chlorhexidine gel. The subjects in the control
      group received only mechanical cleansing and oral hygiene instructions (Treatment
      2). RESULTS: Both modalities of treatment were effective in reducing peri-implant
      mucositis and probing depths, and improving attachment levels. The trends
      suggested that mechanical cleansing alone may be sufficient to treat and reduce
      peri-implant mucositis at 1 and 3 months after treatment. The addition of
      chlorhexidine to mechanical debridement did not enhance the results as compared
      to mechanical debridement alone. CONCLUSIONS: Mechanical debridement as well as
      mechanical debridement supplemented with chlorhexidine can be beneficial to
      patients with peri-implant mucositis. Both treatments resulted in a reduction of
      plaque, inflammation, and probing depth, as well as a gain in clinical attachment
      level, and are effective in suppressing or eradicating the pathogenic bacteria
      often associated with peri-implant inflammation.

PMID- 12416769
TI  - The effect of recombinant human bone morphogenetic protein-4 on the osteoblastic
      differentiation of mouse calvarial cells affected by Porphyromonas gingivalis.
AB  - BACKGROUND: A number of studies have shown effective bone regeneration induced by
      bone morphogenetic proteins (BMPs), but it is not clear whether the presence of
      periodontopathic bacteria has any significant modulation effect on the bone
      regeneration ability of BMPs. The present study examined whether pretreatment of
      mouse calvarial cells with Porphyromonas gingivalis extracts can make a
      difference in their osteoblastic differentiation exerted by recombinant human
      bone morphogenetic protein-4 (rhBMP-4). METHODS: Primary mouse calvarial
      osteoblastic (MCO) cells were cultured until they reached confluence. At
      confluence, cells were untreated or pretreated with 1 microgram/ml of sonicated P
      gingivalis extracts (SPEs) for 2 days. After washing, the cells were further
      incubated in the presence of rhBMP-4 (0 to 100 ng/ml) for 3 days. At the end of
      the treatment, the cells were harvested and lysed for measurement of the alkaline
      phosphatase (ALP) activity. Total RNA was extracted, and reverse transcription
      polymerase chain reaction (RT-PCR) analysis for expression of ALP mRNA was
      conducted. The amount of prostaglandin E2 (PGE2) secreted into the culture
      supernatant was determined using an enzyme immunoassay. RESULTS: The stimulatory
      effect of rhBMP-4 on ALP activity was observed in both untreated MCO cells and in
      cells pretreated with 1 microgram/ml of SPEs in a dose-dependent manner. The ALP
      activities were significantly reduced in the cells pretreated with SPEs at all
      concentrations of rhBMP-4 used in the study when compared to untreated cells.
      Similar results were obtained in the RT-PCR analysis for ALP mRNA. Cells
      pretreated with SPEs released significantly larger amounts of PGE2 than untreated
      cells, but the treatment with 100 ng/ml of rhBMP-4 had no significant effect on
      the amount of PGE2 released. These results suggest that the stimulatory effect of
      rhBMP-4 on osteoblastic differentiation might be significantly reduced by P
      gingivalis, possibly through the endogenous PGE2 pathway, but rhBMP-4 still has a
      stimulatory effect on osteoblastic differentiation of mouse calvarial cells
      affected by P gingivalis. CONCLUSION: Our results suggest that supplemental BMPs
      would be beneficial for improved treatment of osseous defects, although their
      biologic effect might be significantly reduced by periodontopathic bacteria.

PMID- 12416770
TI  - The role of CD4+ cells in vivo on the induction of the immune response to
      Porphyromonas gingivalis in mice.
AB  - BACKGROUND: It has previously been suggested that CD4+ T cells play a pivotal
      role in regulating the immune response to periodontal pathogens. The aim of the
      present study therefore was to determine delayed type hypersensitivity (DTH),
      spleen cell proliferation, serum and splenic anti-Porphyromonas gingivalis
      antibody levels, and lesion sizes following challenge with viable P. gingivalis
      in CD4-depleted BALB/c mice immunized with P. gingivalis outer membrane proteins
      (OMP). METHODS: Four groups of BALB/c mice were used. Groups 1 and 2 were
      injected intraperitoneally (ip) with saline for 3 consecutive days and then
      weekly throughout the experiment. Groups 3 and 4 were injected ip with rat
      immunoglobulin and a monoclonal rat anti-mouse CD4 antibody, respectively. Two
      days later, group 1 mice were injected ip with saline only, while all the other
      groups were immunized ip with P gingivalis OMP weekly for 3 weeks. One week later
      following the last immunization of OMP, 3 separate experiments were conducted to
      determine: 1) the DTH response to P gingivalis OMP by measuring footpad swelling;
      2) the levels of antibodies to P gingivalis in serum samples and spleen cell
      cultures using an enzyme-linked immunosorbent assay, as well as spleen cell
      proliferation after stimulation with OMP; and 3) the lesion sizes after a
      subcutaneous challenge with viable P. gingivalis cells. RESULTS: In CD4+ T-cell
      depleted mice (group 4), the DTH response and antigen-stimulated cell
      proliferation were significantly suppressed when compared to groups 2 and 3.
      Similarly, the levels of serum and splenic IgM, IgG, and all IgG subclass
      antibodies to P. gingivalis OMP were depressed. Delayed healing of P gingivalis
      induced lesions was also observed in the CD4+ T-cell-depleted group. CONCLUSIONS:
      This study has shown that depletion of CD4+ T cells prior to immunization with P
      gingivalis OMP led to the suppression of both the humoral and cell-mediated
      immune response to this microorganism and that this was associated with delayed
      healing. These results suggest that the induction of the immune response to P.
      gingivalis is a CD4+ T-cell-dependent mechanism and that CD4+ T cells are
      important in the healing process.

PMID- 12416771
TI  - Effects of simvastatin gels on murine calvarial bone.
AB  - BACKGROUND: The cholesterol-lowering drug simvastatin has been shown to stimulate
      murine calvarial bone growth after multiple injections. The purpose of this study
      was to test if similar bone stimulation could be induced by 2 single-dose drug
      delivery systems appropriate to periodontal therapy. METHODS: ICR Swiss mice were
      treated with the following protocols: 1) injection of methylcellulose gel alone,
      subcutaneously over the calvarium (INJ-GEL; n = 8); 2) injection of gel with
      simvastatin (INJ-SIM; 2.2 mg, n = 16); 3) polylactide membrane (PLA) containing
      gel alone implanted over calvarium (MEM-GEL; n = 10); 4) implanted PLA membrane
      containing gel and simvastatin (MEM-SIM; n = 10); and 5) untreated mice (n = 12).
      Animals were sacrificed after 22 or 44 days, calvaria decalcified and stained
      with hematoxylin and eosin, and images digitized and measured for bone thickness
      and area. Data were compared using analysis of variance. RESULTS: INJ-SIM
      stimulated a 53% (P = 0.02) increase at the thickest point of calvarial bone,
      while MEM-SIM caused a highly significant (P < or = 0.0005) increase in bone
      thickness (159% to 172%) and bone area (144% to 180%) compared to gel controls.
      Simvastatin gels caused soft tissue inflammation, which appeared to be related to
      bone increases. If INJ-SIM animals showing leakage of gel and/or no inflammation
      were excluded from analysis, INJ-SIM resulted in more bone (58% to 83%) than gel
      controls. An insignificant amount of SIM-stimulated bone was lost over the long
      term (44 days). CONCLUSIONS: A single, high dose of simvastatin gel can stimulate
      murine cranial bone apposition, particularly when delivered under an occlusive
      membrane. Both approaches should be investigated further for possible development
      for periodontal therapy.

PMID- 12416772
TI  - The effect of duration and force of mechanical toothbrushing stimulation on
      proliferative activity of the junctional epithelium.
AB  - BACKGROUND: Gingival bleeding is frequently accompanied by an ulcerated
      epithelium, with repair depending on the proliferative activity of the epithelial
      cells. The present study examined the proliferative activity of the junctional
      epithelium (JE) under several different methods of toothbrushing stimulation.
      METHODS: Twelve dogs were used in this 3-week experiment. Prior to the
      experiment, all teeth underwent daily removal of plaque and calculus using a
      scaler. Teeth were then divided into quadrants: 9 teeth in 3 quadrants (test, 3
      per quadrant) were mechanically stimulated by toothbrushing for various time
      intervals (10, 20, or 40 seconds) and at various forces (100, 200, or 250 gf).
      The 3 teeth in the fourth quadrant served as controls. The proliferative activity
      of the basal cells of the junctional epithelium was evaluated for expression of
      proliferating cell nuclear antigen (PCNA). The numbers of PCNA-positive basal
      cells and total basal cells were counted, and the width of the junctional
      epithelium was measured. RESULTS: Toothbrushing force significantly affected the
      PCNA-positive basal cell ratio (P < 0.05). The 200 g toothbrushing force produced
      the highest PCNA-positive basal cell ratio, which was significantly higher than
      that using the 100 g force (P < 0.05). CONCLUSION: In junctional epithelium
      stimulated with a toothbrush, the PCNA-positive basal cell ratio is more
      sensitive to toothbrushing force than to duration.

PMID- 12416773
TI  - Bone regeneration of localized chronic alveolar defects utilizing cell binding
      peptide associated with anorganic bovine-derived bone mineral: a clinical and
      histological study.
AB  - BACKGROUND: Osteoinduction to treat osseous defects has been attempted by several
      means. Some clinical studies have demonstrated that a synthetic cell binding
      peptide (P-15) with anorganic bovine derived bone matrix (ABM) has the ability to
      enhance bone regeneration. These studies suggest that more histological data are
      necessary to better understand this process. We have developed a Class III
      chronic alveolar defect animal model to investigate space-maintaining
      regenerative materials. The objective of this study was to clinically and
      histologically evaluate the use of P-15/ABM with or without a bioabsorbable
      membrane (M) to regenerate localized chronic alveolar ridge defects in dogs.
      METHODS: Six adult, male mongrel dogs were used in this study. Bilateral, Class
      III, alveolar defects were surgically produced following extraction of the
      mandibular second premolar teeth and local reduction of the alveolar ridge. After
      an 8-week healing interval, mucoperiosteal flaps were elevated. P-15/ABM with or
      without bioabsorbable membranes were implanted into contralateral defects in 10
      sites. Two sites received no biomaterial (controls). Mucoperiosteal flaps were
      advanced over the P-15/ABM or P-15/ABM/M constructs and sutured. Pre- and
      postaugmentation clinical evaluation was done utilizing periodontal probes and
      calipers. The animals were sacrificed 12 weeks postaugmentation and block
      specimens processed for histologic evaluation. RESULTS: Clinical results showed
      no significant statistical augmentation on the control group (0.0 +/- 0.6 mm). In
      all experimental sites utilizing P-15/ABM or P-15/ABM/M, relevant ridge
      augmentation was observed (3.6 +/- 2.0 mm and 2.9 +/- 1.9 mm, respectively).
      Histologically, all experimental sites showed active bone formation with plump
      osteoblast and osteoid matrix deposition in the treated area. Bone ingrowth
      filled the area of the defects treated with P-15/ABM/M. Few P-15/ABM particles
      were seen in the cellular fibrous tissue surrounding the new formed bone
      trabeculae. CONCLUSIONS: P-15/ABM with or without membranes can produce a
      significant clinical ridge augmentation. Bone formation was histologically
      observed in all test areas. The association of a membrane with P-15/ABM seemed to
      enhance the process of bone formation.

PMID- 12416774
TI  - The effect of shared genetic and environmental factors on periodontal disease
      parameters in untreated adult siblings in Guatemala.
AB  - BACKGROUND: Increasing evidence supports the role of genetic factors in
      susceptibility to infectious diseases, including chronic periodontitis. The role
      of genetic factors in phenotypic expression can be estimated from the degree of
      resemblance between relatives, as compared with that of unrelated members of a
      population. Heritability is an estimate of the proportion of total phenotypic
      variation of a quantitative trait, which is attributable to genetic factors, and
      is based on the variance within versus between family members. The aim of this
      study was to determine whether there is a familial basis for periodontal disease
      status in an untreated population in Guatemala using heritability estimates as a
      measure of familial clustering of disease. METHODS: One-hundred and thirteen
      adult subjects (including both siblings and spouse pairs), age range 35 to 60
      years, participated in this study. Full-mouth periodontal examinations were
      performed and heritability estimates were calculated for mean plaque score, mean
      gingival index (GI), probing depth (PD), and clinical attachment level (CAL).
      Intraclass correlation coefficients (ICCs) were calculated using the same
      parameters for spouses to determine whether a common family environment in
      adulthood plays a role in disease expression. RESULTS: Only in the case of mean
      plaque score and mean recession score were heritability estimates significantly
      above zero at alpha = 0.05. For spouse pairs, mean GI score, mean PD, and
      percentage of sites of PD > or = 5 mm showed a statistically significant ICC.
      CONCLUSIONS: These results lead us to reject the hypothesis that there is
      substantial heritability for periodontal disease expression in this population.
      This may be due to an underlying lack of genetic variation within this sample or
      may indicate that, compared with the role of environmental factors, the genetic
      contribution to periodontal disease phenotypes is relatively minor.

PMID- 12416775
TI  - Investigation of the association between angiographically defined coronary artery
      disease and periodontal disease.
AB  - BACKGROUND: The association between periodontal disease and coronary artery
      disease (CAD) has been investigated in numerous studies with inconsistent
      results. Resolving these differences is complicated by the use of varying
      definitions of CAD. The aim of this study was to investigate the association
      between angiographically-defined CAD and periodontal disease. METHODS: Non
      smoking, non-diabetic patients, over 40 years of age, with no history of a
      myocardial infarction in the previous 6 months and who had undergone cardiac
      catheterization within the previous 12 months were enrolled in this study.
      Subjects were classified as having CAD (CAD+) if they had 50% stenosis in at
      least one major epicardial artery and classified as CAD negative (CAD-) if they
      had <50% stenosis in all identified arteries. Periodontal disease severity was
      measured through bleeding on probing, probing depth, clinical attachment level
      (CAL), gingival recession, number of missing teeth, and radiographic bone loss.
      RESULTS: One hundred (53 = CAD+; 47 = CAD-) patients were examined. CAD+ patients
      were more likely to be male (CAD+ 83.0% male; CAD- 40.4% male; P= 0.001), and
      were older (CAD+ 65.3 years; CAD- 60.8 years; P= 0.0138). Although all patients
      reported they were currently non-smokers and had not smoked for at least 5 years,
      the fraction who were former smokers was greater for CAD+ patients (66% versus
      24.4%; P = 0.0001) and mean pack/year history of smoking was higher for CAD+
      patients (15.8 versus 4.5; P = 0.0003). Mean CAL (3.13 mm versus 2.78 mm; P
      0.0227), number of sites with CAL > or = 6 mm (6.85 versus 3.32; P = 0.0242),
      radiographic bone loss (3.60 mm versus 3.18 mm; P = 0.0142) were greater for CAD+
      patients than for CAD- patients. However, after adjustment for age and previous
      smoking history, factors common to both diseases, the associations of CAD and
      periodontal disease were reduced and were not statistically significant (odds
      ratio [OR]: mean CAL OR = 1.06; number of sites with CAL > or = 6 mm OR = 1.03;
      mean radiographic bone loss OR = 1.31; P > or = 0.2055). CONCLUSIONS: After
      accounting for factors common to both periodontal disease and CAD, there was no
      significant association between periodontal disease and chronic CAD as assessed
      angiographically. Further investigations into the relationship between
      periodontal disease and CAD should clearly separate chronic CAD and acute
      coronary events.

PMID- 12416776
TI  - Relationship between periodontal disease in pregnant women and the nutritional
      condition of their newborns.
AB  - BACKGROUND: The purpose of this study was to determine whether maternal
      periodontal disease (PD) could be associated with the nutritional condition of
      newborns. METHODS: After controlling for traditional risk factors for premature
      childbirth and low birth weight, 69 mothers were selected: 13 were periodontally
      healthy and 56 had varying stages of PD. They and their newborns formed the study
      population. PD presence and severity were clinically determined using Russell's
      periodontal index. The nutritional evaluation of the newborns was determined by
      Lubchenco's modified growth patterns. RESULTS: A decrease in the average
      newborn's weight and gestational age was observed as the mother's level of PD
      increased. Correlation analysis demonstrated a highly significant clinical
      relationship between more severe PD and lower birth weight (r = -0.49; P < 0.01);
      a highly significant relationship was also clinically demonstrated between
      increasing PD severity and decreasing gestational age of the newborn babies (r = 
      0.59; P < 0.01). There were significant differences in the weight and gestational
      age of the newborns of mothers with PD. CONCLUSIONS: These data suggest that PD
      in pregnant women could be a clinically significant risk factor for preterm
      deliveries and low birth weight. There was considerable variability in the
      results, and these preliminary findings need to be confirmed in larger studies.

PMID- 12416777
TI  - Maximal bite force in patients with reduced periodontal tissue support with and
      without splinting.
AB  - BACKGROUND: Chewing and biting forces are supposed to be limited by sensory input
      from periodontal mechanoreceptors. This is why the threshold level of those
      receptors should be lower in teeth with reduced periodontal tissue support. The
      purposes of the present study were to evaluate the influence of reduced
      periodontal tissue support on maximal bite force in natural dentitions and to
      study the effect of splinting on maximal bite force. METHODS: In 10 patients with
      reduced periodontal tissue support (test), as well as in 10 periodontally healthy
      subjects (control), maximal bite force was measured. The remaining periodontal
      ligament area in the test group was calculated from x-rays. Bite force was
      assessed at 4 mm mouth opening in the premolar region without and following
      splinting of the posterior teeth and transduced using a strain-gauge (full-bridge
      circuit). Maximal bite force measured with and without splinting was compared
      between test and control subjects, and within each group. RESULTS: In test
      subjects, the mean periodontal ligament area was 48.5% (SD = 10.1) across first
      premolars and 50.0% (SD = 12.2) across posterior teeth (control: 100%). In test
      subjects, the mean maximal bite force without splinting was 357 N (SD = 70), and
      in control subjects, 378 N (SD = 66; P > 0.05). After splinting, the bite force
      in test subjects was 509 N (SD = 75), and in control subjects, 534 N (SD = 49; P
      > 0.05). Bite force before and after splinting was P < 0.05 within each group.
      CONCLUSIONS: Reduced periodontal tissue support does not seem to limit bite force
      with maximal strength in natural dentitions as measured by a device that opens
      the bite by 4 mm. Furthermore, maximal biting forces at 4 mm mouth opening are
      increased when molar teeth are included in a posterior splint.

PMID- 12416778
TI  - Rationale for use of antibiotics in periodontics.
AB  - The purpose of this review is to provide the clinician with some practical
      rationale for the selection and use of antibiotics in the treatment of
      destructive periodontal diseases. We have attempted to integrate approximately 20
      years of periodontal literature describing antibiotic therapy with personal
      experience and 21st century ideas. This article addresses antibiotic use during
      treatment of aggressive periodontitis with emphasis on juvenile disease and adult
      refractory diseases. The literature review revealed few large, controlled studies
      that compared efficacy of adjunctive antibiotic use to mechanical therapy alone.
      Even fewer studies evaluated the efficacy of one antibiotic relative to another.
      However, based on the evidence available, certain conclusions were drawn.
      Adjunctive use of an antibiotic along with mechanical debridement is recommended
      for the treatment of Actinobacillus actinomycetemcomitans-associated
      periodontitis as an acceptable therapeutic regimen. Due to the emergence of
      tetracycline-resistant A. actinomycetemcomitans, the combination of metronidazole
      and amoxicillin may be preferable. In aggressive refractory periodontitis,
      compelling evidence exists that the use of an appropriate adjunctive antibiotic
      frequently gives a more favorable clinical response than mechanical therapy
      alone. Unfortunately, the selection of antibiotic is not as clear and is probably
      case-dependent. Positive responses have been reported with amoxicillin/clavulanic
      acid, clindamycin, metronidazole, and the combination therapy metronidazole plus
      amoxicillin. The introduction of local delivery antibiotics specifically for the
      treatment of periodontitis offers a novel concept for the treatment of localized
      disease. The latter, in particular, may prove useful in the treatment of
      recurrent disease activity or where only a few individual sites are involved.

PMID- 12416779
TI  - Serendipitous diagnosis of protein S deficiency.
AB  - A 46-year-old male sought periodontal care for a swelling on his right mandibular
      gingiva. An excisional biopsy revealed a well-differentiated squamous cell
      carcinoma. Surgical treatment consisted of a right segmental mandibulectomy with
      ipsilateral right neck dissection and fibular free flap reconstruction. Two days
      after the surgical procedure, a weakened Doppler signal suggested vascular
      compromise of the graft. The patient was returned to the operating room where
      complete thrombosis of the internal jugular vein (recipient vessel) was observed.
      This event prompted a complete hematological evaluation that disclosed low serum
      levels of protein S. The patient was started on systemic heparin and local
      medicinal leeches. A week later, systemic warfarin sodium was added and
      successfully resolved the vascular compromise of the graft. Two years later, the
      patient is active and lives a full life with occasional adjustments of warfarin
      sodium. This case represents the first report on the treatment of gingival
      carcinoma that led to the serendipitous discovery of an unrelated and unusual
      systemic condition, protein S deficiency.

PMID- 12416780
TI  - Clinical application of spiral tomography in anterior implant placement: case
      report.
AB  - BACKGROUND: Placement of endosseous dental implants in edentulous areas of the
      anterior maxilla poses a unique challenge due to variations in the amount of
      residual alveolar bone. Implant position becomes crucial in cases demanding high
      esthetic results but possessing minimal ridge width or in cases requiring
      augmentation. Recent advances in spiral tomography have allowed for more precise
      planning and placement of endosseous implants in these challenging areas.
      METHODS: The purpose of this report is to describe a series of clinical cases in
      which spiral tomography was utilized in the planning and placement of endosseous
      dental implants. Two cases will be described utilizing initial spiral tomographic
      radiographs for implant planning and surgical guide fabrication, followed by post
      insertion tomography to evaluate the results of implant position and inclination.
      RESULTS: Preimplant spiral tomograms revealed that the initial prosthetic
      trajectory through the proposed incisal edge of each tooth replacement would
      result in a final osteotomy site that would compromise the overall thickness of
      the facial cortical plate. After adjusting for magnification and distortion
      factors, new prosthetic/surgical trajectories were fabricated into the surgical
      guide, and this information was utilized to prepare the final implant osteotomy
      site. This adjustment resulted in 2 mm of residual crestal facial bone
      postimplant insertion, which became wider at more apical measurements. These
      findings were verified in the postimplant serial tomograms. CONCLUSIONS: Spiral
      tomography was a valuable adjunct in the treatment planning phases of endosseous
      dental implant placement especially in cases with minimal crestal width, high
      esthetic demands, or where exact implant placement is critical for successful
      treatment outcomes.

PMID- 12416781
TI  - Strain relaxation of fibroblasts in the marginal periodontium is the common
      trigger for alveolar bone resorption: a novel hypothesis.
AB  - In summary, the present commentary proposes a hypothesis that alveolar bone
      remodeling and bone loss in periodontitis, periodontal surgery, and in
      orthodontic tooth movement is triggered by a common "strain relaxation" signaling
      pathway of gingival and periodontal fibroblasts. The abrupt splitting,
      degradation, or relaxation of collagen fibers in the marginal periodontium
      produces a "strain relaxation" signal in the local fibroblasts which reside on
      these fibers, activating an ECM-integrin-cytoskeleton pathway. A cascade of
      cellular reactions which lead to osteoclastic bone resorption starting on the
      inner aspect (periodontal) of the alveolar bone then persists. A novel
      therapeutic approach is suggested here by using locally delivered drugs
      intervening in the cell contractile apparatus.

PMID- 12416782
TI  - Re: Er: YAG laser scaling of diseased root surfaces. Frentzen M, Braun A, Aniol
      D. (2002;73;524-530).

PMID- 12416783
TI  - Re: Oral manifestations of acute myelomonocytic leukemia: a case report and
      review of the classification of leukemias. Wu J, Fantasia Je, Kaplan R.
      (2002;73:664-668).

PMID- 12416784
TI  - The American Academy of Periodontology statement regarding gingival curettage.

PMID- 12416785
TI  - Lasers in periodontics.
AB  - Publicity about the use of lasers in dentistry has generated considerable
      interest in both professional and lay audiences. The purpose of this report is to
      provide information for members of the dental profession about the current and
      potential application of laser technology to periodontal practice. This report
      was prepared by the Research, Science and Therapy Committee of the American
      Academy of Periodontology.

PMID- 12416786
TI  - Cardiorenal differences among NSAIDs and coxibs: real-world experience.

PMID- 12416788
TI  - Prevalence of cardiovascular disease risk factors among US adults with self
      reported osteoarthritis: data from the Third National Health and Nutrition
      Examination Survey.
AB  - OBJECTIVE: To estimate the prevalence of traditional risk factors for
      cardiovascular disease (CVD) among US adults with osteoarthritis (OA). METHODS:
      Using survey data from the Third National Health and Nutrition Examination
      Survey, we estimated the prevalence of selected CVD risk factors among a US OA
      and nonarthritic adult population. In additional analyses, we stratified the
      sample by gender and age (35-44, 45-64, and 65+ years) to further understand the
      CVD risk profile in an arthritic population and nonarthritic population. Relevant
      data on each survey participant's demographics, arthritis status, CVD risk
      factors, and sampling weights were obtained from the survey database. RESULTS: Of
      the 115.9 million US adults aged > or = 35 years, 24.3 million (21%) have OA.
      Hypertension is prevalent in approximately 40% of OA patients; 20% of the
      patients smoke and 11% have diabetes. Prevalence of high total cholesterol is
      estimated to be 32%, while prevalence of low high-density lipoprotein cholesterol
      is estimated at 13%. Approximately 37% of OA patients are estimated to have renal
      impairment, but less than 1% suffer from renal failure. CONCLUSION: National
      survey data suggest that, on average, US adults with OA have a high prevalence of
      cardiovascular risk factors. These findings highlight the need to consider
      patients' comorbidites when selecting the appropriate treatment options.

PMID- 12416789
TI  - Comparison of the baseline cardiovascular risk profile among hypertensive
      patients prescribed COX-2-specific inhibitors or nonspecific NSAIDs: data from
      real-life practice.
AB  - OBJECTIVE: To evaluate the baseline cardiovascular (CV) risk of hypertensive
      patients newly starting cyclooxygenase (COX)-2-specific inhibitors (celecoxib or
      rofecoxib) or nonspecific nonsteroidal anti-inflammatory drugs (NSAIDs). METHODS:
      Cross-sectional analysis was performed based on real-life practice data contained
      in the LifeLink Integrated Claims Solutions employer claims database. Patients
      who newly received treatment of celecoxib, rofecoxib, ibuprofen, naproxen, or
      diclofenac between January 1, 1999, and September 30, 2000, were identified from
      the database. Among them, only those who had a stable hypertensive condition for
      at least 3 consecutive months before the index prescription were included.
      Baseline characteristics were determined from claims data at the time of the
      index prescription. RESULTS: A total of 55 396 index prescriptions were
      identified, which consisted of 20,915 (37.8%) prescriptions for celecoxib, 12,952
      (23.4%) for rofecoxib, 10 789 (19.5%) for ibuprofen, 8,840 (16.0%) for naproxen,
      and 1,900 (3.4%) for diclofenac. Both univariate and multivariate analyses showed
      that the patients prescribed COX-2-specific inhibitors were older and more likely
      to be female than those given nonspecific NSAIDs. Patients prescribed COX-2
      specific inhibitors had a significantly higher baseline history of and/or current
      CV conditions, including ischemic heart disease, heart failure, other forms of
      heart disease, and cerebrovascular diseases or disorders, than patients
      prescribed nonspecific NSAIDs. The baseline proportion of patients with
      rheumatoid arthritis was also higher among COX-2-specific inhibitor users. In
      addition, COX-2-specific inhibitor users at baseline had higher prescription
      rates for medications that influence blood pressure, including estrogens, certain
      types of antidepressants, and corticosteroids. CONCLUSION: COX-2-specific
      inhibitors were prescribed preferentially to patients who, at the time of their
      index COX-2-specific inhibitor prescription, were at an increased baseline risk
      of CV events compared with patients prescribed nonspecific NSAIDs. Researchers
      aiming to compare the incidence of CV events between COX-2-specific inhibitors
      and nonspecific NSAIDs using observational study designs should take into account
      the underlying baseline CV risk of the populations being compared.

PMID- 12416790
TI  - Blood pressure destabilization and related healthcare utilization among
      hypertensive patients using nonspecific NSAIDs and COX-2-specific inhibitors.
AB  - OBJECTIVE: To determine the incremental cost of blood pressure (BP)
      destabilization among patients with stable hypertension who newly initiate
      therapy with celecoxib, rofecoxib, or 3 commonly used nonspecific nonsteroidal
      anti-inflammatory drugs (NSAIDs), ibuprofen, diclofenac, or naproxen, based on
      incidence rates of BP destabilization and costs of BP destabilization events
      obtained from a single observational data source. METHODS: Historical cohort
      observational analysis was performed based on real-life practice data that are
      contained in the LifeLink Integrated Claims Solutions employer claims databases.
      Patients with stable hypertension who had newly initiated therapy with rofecoxib,
      celecoxib, ibuprofen, diclofenac, or naproxen between January 1, 1999, and
      September 30, 2000, were identified from the database. The study consists of 3
      components. First, the incidence rate of BP destabilization, based on patients'
      time of exposure to studied drugs, was estimated. Then, the cost of a BP
      destabilization event was determined by matching all BP destabilization cases
      with non-BP destabilization cases and following them for 90 days. The differences
      in the total costs between cases and controls were considered an estimate of the
      costs associated with managing the BP destabilization event. Last, the drug
      specific incremental costs of BP destabilization of using each treatment were
      estimated in comparison with celecoxib. Incremental costs of BP destabilization
      were determined by multiplying the specific excess incidence rate of BP
      destabilization for each of the specific drugs, relative to celecoxib, by the
      cost of a BP destabilization event. RESULTS: The adjusted incidence rate of
      outpatient BP destabilization for celecoxib was 2.27 per 1000 patient-days vs
      2.66 for rofecoxib (P < .001) or 2.65 for nonspecific NSAIDs (P < .001). The
      incremental cost of BP destabilization per patient per day of drug utilization
      for the study drugs compared with celecoxib were $0.18 for rofecoxib and $0.17
      for nonspecific NSAIDs. The higher costs of BP destabilization relative to
      celecoxib were due to the higher incidence of outpatient BP destabilization
      associated with the other study drugs. The average incremental healthcare cost
      for an outpatient BP destabilization event within the first 90 days of the event
      was $459. The incidence of inpatient BP destabilization among rofecoxib users was
      significantly higher than among celecoxib users (risk rate = 4.17; 95% Cl, 1.86
      9.26; P< .001). Incremental cost was not estimated for inpatient BP
      destabilization because the sample size was too small to provide a stable result.
      CONCLUSION: The costs of managing BP destabilization were significantly lower for
      celecoxib compared with rofecoxib and nonspecific NSAIDs. The observed
      differences among these anti-inflammatory drugs in the costs of BP
      destabilization will have a significant impact on the total cost of therapy in
      patients with stable hypertension. In addition to the monetary cost of BP
      destabilization, the physical cost to the patient regarding development or
      exacerbation of this serious medical condition should be considered when choosing
      cyclooxygenase-2-specific inhibitor and nonspecific NSAID therapies.

PMID- 12416791
TI  - Cost of heart failure among hypertensive users of nonspecific NSAIDs and COX-2
      specific inhibitors.
AB  - OBJECTIVE: To determine the costs of heart failure in hypertensive patients
      receiving celecoxib, rofecoxib, and nonspecific nonsteroidal anti-inflammatory
      drugs (NSAIDs) in clinical practice. METHODS: Stable hypertensive patients
      without a history of heart failure and newly treated with celecoxib, rofecoxib,
      ibuprofen, naproxen, or diclofenac between January 1, 1999, and September 30,
      2000, were identified from the LifeLink Integrated Claims Solutions employer
      database. The incidence rate of inpatient and outpatient heart failure claims was
      determined based on patients' time of exposure to study drugs after adjusting for
      confounding factors. The heart failure costs of managing inpatient and outpatient
      events were estimated as the total healthcare costs for patients with heart
      failure claims minus the total healthcare costs among matched control groups
      without heart failure claims. Healthcare costs were computed for the 0 to 30 days
      and 31 to 90 days following the initial outpatient or inpatient claim. Finally,
      the excess incidence rate of patients with inpatient and outpatient heart failure
      claims, relative to celecoxib, were multiplied by the heart failure cost of an
      inpatient and outpatient event to determine the incremental costs of heart
      failure associated with each of the study drugs relative to celecoxib. RESULTS:
      Among 50 940 patients, 707 patients had outpatient heart failure claims and 229
      patients had inpatient heart failure claims. In this study, rofecoxib-treated
      patients were 26% more likely to have an outpatient claim (rate ratio [RR] =
      1.26; 95% confidence interval [CI], 1.06-1.48; P= .007) and 52% more likely to
      have an inpatient claim (RR = 1.52; 95% Cl, 1.15-2.02; P = .003) for heart
      failure than celecoxib-treated patients. The adjusted RR of heart failure claims
      was similar between celecoxib and NSAIDs. The average cost of outpatient heart
      failure was $1054 within 30 days and $221 for the period 31 to 90 days after the
      initial claim (total 90-day cost of $1275). The cost for a patient with inpatient
      heart failure was $5966 during the hospitalization. The 90-day
      posthospitalization heart failure cost was $245 (total 90-day cost of $6,211 for
      hospitalization and follow-up). The total heart failure-related incremental cost
      per patient per day of use was $0.15 for rofecoxib and $0.04 for nonspecific
      NSAIDs relative to celecoxib. CONCLUSION: The additional heart failure costs
      associated with the use of rofecoxib significantly add to its cost in patients
      with stable hypertension, relative to celecoxib and nonspecific NSAIDs. The
      higher heart failure costs of rofecoxib were attributable to the higher incidence
      of patients with inpatient and outpatient heart failure claims relative to
      celecoxib and nonspecific NSAID populations being compared.

PMID- 12416792
TI  - Differences between COX-2-specific inhibitors: clinical and economic
      implications.

PMID- 12416793
TI  - Impact of low concentration factor microfiltration on milk component recovery and
      Cheddar cheese yield.
AB  - The effect of microfiltration (MF) on the composition of Cheddar cheese, fat,
      crude protein (CP), calcium, total solids recovery, and Cheddar cheese yield
      efficiency (i.e., composition adjusted yield divided by theoretical yield) was
      determined. Raw skim milk was microfiltered twofold using a 0.1-microm ceramic
      membrane at 50 degrees C. Four vats of cheese were made in one day using milk at
      lx, 1.26x, 1.51x, and 1.82x concentration factor (CF). An appropriate amount of
      cream was added to achieve a constant casein (CN)-to-fat ratio across treatments.
      Cheese manufacture was repeated on four different days using a randomized
      complete block design. The composition of the cheese was affected by MF. Moisture
      content of the cheese decreased with increasing MF CF. Standardization of milk to
      a constant CN-to-fat ratio did not eliminate the effect of MF on cheese moisture
      content. Fat recovery in cheese was not changed by MF. Separation of cream prior
      to MF, followed by the recombination of skim or MF retentate with cream resulted
      in lower fat recovery in cheese for control and all treatments and higher fat
      loss in whey when compared to previous yield experiments, when control Cheddar
      cheese was made from unseparated milk. Crude protein, calcium, and total solids
      recovery in cheese increased with increasing MF CF, due to partial removal of
      these components prior to cheese making. Calcium and calcium as a percentage of
      protein increased in the cheese, suggesting an increase in calcium retention in
      the cheese with increasing CF. While the actual and composition adjusted cheese
      yields increased with increasing MF CF, as expected, there was no effect of MF CF
      on cheese yield efficiency.

PMID- 12416794
TI  - Impact of low concentration factor microfiltration on the composition and aging
      of Cheddar cheese.
AB  - The effect of microfiltration (MF) on proteolysis, hardness, and flavor of
      Cheddar cheese during 6 mo of aging was determined. Raw skim milk was
      microfiltered two-fold in two cheese making trials. In trial 1, four vats of
      cheese were made in 1 d using unconcentrated milk (1X), 1.26X, 1.51X, and 1.82X
      concentration factors (CF). Casein-(CN)-to-fat ratio was constant among
      treatments. Proteolysis during cheese aging decreased with increasing CF due to
      either limitation of substrate availability for chymosin due to low moisture in
      the nonfat substance (MNFS), inhibition of chymosin activity by high molecular
      weight milk serum proteins, such as alpha2-macroglobulin, retained in the cheese
      or low residual chymosin in the cheese. Hardness of fresh cheese increased, and
      cheese flavor intensity decreased with increasing CF. In trial 2, the 1X and 1.8X
      CF were compared directly. Changes made in the cheese making procedure for the
      1.8X CF (more chymosin and less cooking) increased the MNFS and made proteolysis
      during aging more comparable for the 1X and 1.8X cheeses. The significant
      difference in cheese hardness due to CF in trial 1 was eliminated in trial 2. In
      a triangle test, panelists could not differentiate between the 1X and 1.8X
      cheeses. Therefore, increasing chymosin and making the composition of the two
      cheeses more similar allowed production of aged Cheddar cheese from milk
      concentrated up to 1.8X by MF that was not perceived as different from aged
      Cheddar cheese produced without MF.

PMID- 12416795
TI  - Overexpression of peptidases in Lactococcus and evaluation of their release from
      leaky cells.
AB  - Walker and Klaenhammer (2001) developed a novel expression system in Lactococcus
      lactis that facilitated the release of beta-galactosidase (117 kDa monomer)
      without the need for secretion or export signals. The system is based on the
      controlled expression of integrated prophage holin and lysin cassettes via a
      lactococcal bacteriophage phi31 transcriptional activator (Tac31A) that resides
      on a high-copy plasmid. Approximately 85% of beta-galactosidase activity was
      detected in the supernatant of leaky lactococci without evidence of hindered
      growth, cell lysis, or membrane damage. The objective of this study was to
      determine if intracellular peptidases were externalized from leaky lactococci.
      Five L. lactis peptidases (PepA, PepC, PepN, PepO and PepXP) and two
      Lactobacillus helveticus peptidases (PepN and PepO) were cloned and overexpressed
      on two high-copy vectors. The lactococcal peptidases were also cloned into the
      high-copy vector that contained the Tac31A transcriptional activator to determine
      if they were externalized from the leaky prophage-containing L. lactis subsp.
      lactis strain NCK203. Two of the lactococcal peptidases (PepA and PepO) required
      an additional strong promoter (Lactobacillus paracasei P144) and optimized assay
      conditions to detect enzyme activity. Results showed different levels of
      enzymatic overexpression associated with the cellular fraction (2 to 250-fold
      increases in activity) and negligible amounts of activity present within the
      supernatant fraction (0 to 6% of total peptidase activity). The lactococcal phage
      based protein release mechanism did not facilitate the externalization of the
      lactococcal peptidases investigated in this study.

PMID- 12416796
TI  - Native vs. damaged milk fat globules: membrane properties affect the
      viscoelasticity of milk gels.
AB  - The storage modulus G' of rennet and acid milk gels filled with milk fat globules
      was measured as a function of the fat globule surface composition (native milk
      fat globule membrane, caseins and whey proteins, or a mixture of the three due to
      mechanical treatments) and surface area (i.e., the fat globule size). By
      different technological procedures, it was possible to obtain fat globules of
      constant surface composition but various sizes, and vice-versa, which had never
      been done. For both rennet and acid gels, a critical fraction of the fat globule
      surface covered by caseins and whey proteins was identified (approximately 40%),
      beyond which G' increased. Below this threshold, the gel viscoelasticity was
      unaffected by mechanical treatments. When the diameter of native milk fat
      globules decreased, the G' of rennet gels increased slightly, whereas that of
      acid gels decreased sharply. For both types of gels, G' increased when the
      diameter of partially disrupted fat globules decreased. For recombined globules
      completely covered with caseins and few whey proteins, G' increased with fat
      globule surface area for rennet gels whereas it decreased for acid gels. With the
      help of confocal microscopy and in the light of general structural differences
      between rennet and acid gels, a mechanism is proposed for the effect of fat
      globule damage and diameter on G', depending on the interactions the globules can
      undergo with the casein network.

PMID- 12416798
TI  - Influence of starter and nonstarter on the formation of biogenic amine in goat
      cheese during ripening.
AB  - Two commercial starters were investigated for their potential ability to
      decarboxylate amino acids during goat cheese ripening. Two batches of goat cheese
      were produced with identical pasteurized milk but different starter cultures. One
      of them contained Lactococcus lactis subsp. lactis and Lactococcus lactis subsp.
      cremoris and the other Lactococcus lactis subsp. lactis. The amine contents,
      microbial counts, proteolysis-related parameters, pH, total solids and salt
      content were studied in raw materials and cheeses. In raw materials, polyamines
      were the prevailing amines, whereas the main amines in cheeses were putrescine,
      tryptamine and, in particular, tyramine (94.59 mg/kg). Aerobic mesophilic
      microorganisms and Lactococcus counts increased throughout ripening, while
      Enterobacteriaceae were no longer detectable in cheese after 30 days of ripening.
      Amine concentration rose during cheese ripening in both batches. Moreover, the
      decarboxylase activity of microorganisms isolated from samples during cheese
      ripening was assayed and discussed.

PMID- 12416797
TI  - Amino acid catabolism and generation of volatiles by lactic acid bacteria.
AB  - Twelve isolates of lactic acid bacteria, belonging to the Lactobacillus,
      Lactococcus, Leuconostoc, and Enterococcus genera, were previously isolated from
      180-d-old Serra da Estrela cheese, a traditional Portuguese cheese manufactured
      from raw milk and coagulated with a plant rennet. These isolates were
      subsequently tested for their ability to catabolize free amino acids, when
      incubated independently with each amino acid in free form or with a mixture
      thereof. Attempts were made in both situations to correlate the rates of free
      amino acid uptake with the numbers of viable cells. When incubated individually,
      leucine, valine, glycine, aspartic acid, serine, threonine, lysine, glutamic
      acid, and alanine were degraded by all strains considered; arginine tended to
      build up, probably because of transamination of other amino acids. When incubated
      together, the degradation of free amino acids by each strain was dependent on pH
      (with an optimum pH around 6.0). The volatiles detected in ripened Serra da
      Estrela cheese originated mainly from leucine, phenylalanine, alanine, and
      valine, whereas in vitro they originated mainly from valine, phenylalanine,
      serine, leucine, alanine, and threonine. The wild strains tested offer a great
      potential for flavor generation, which might justify their inclusion in a
      tentative starter/nonstarter culture for that and similar cheeses.

PMID- 12416800
TI  - Production of pyroglutamic acid by thermophilic lactic acid bacteria in hard
      cooked mini-cheeses.
AB  - Pyroglutamic acid is present in high amounts (0.5g/ 100g) in many cheese
      varieties-and particularly in extensively ripened Italian cheeses such as Grana
      Padano and Parmigiano Reggiano. An in vivo model system for cooked mini-cheese
      production and ripening acceleration was set up to demonstrate the ability of
      thermophilic lactic acid bacteria, used as a starter, to produce pyroglutamic
      acid (pGlu). In mini-cheeses stored at 38 and 30 degrees C for up to 45 d, all
      starters tested produced different amounts of pGlu. In descending order of pGlu
      production, the bacteria analyzed were: Lactobacillus helveticus, Lactobacillus
      delbrueckii subsp. bulgaricus, Streptococcus thermophilus, and Lactobacillus
      delbrueckii subsp. lactis. Evidence for the presence of glutamine to pGlu cyclase
      activity in lactic acid bacteria was provided. Cell lysates obtained from
      cultures of L. helveticus, L. delbrueckii subsp. bulgaricus, L. delbrueckii
      subsp. lactis, and S. thermophilus showed the ability to cyclize glutamine to
      pGlu, resulting in processing yields from 1.4 to 30.3%, depending on the
      subspecies. Formation of pGlu from free glutamine appeared to be similar to that
      observed using a glutamine-glutamine dipeptide substrate. Under the experimental
      conditions applied, pGlu aminopeptidase activity was only detected in L.
      helveticus. Thus, pGlu formation in long-ripened cooked cheese may depend on the
      activity of thermophilic lactic acid bacteria.

PMID- 12416799
TI  - Effect of milk base and starter culture on acidification, texture, and probiotic
      cell counts in fermented milk processing.
AB  - In the present work, the compared effect of milk base and starter culture on
      acidification, texture, growth, and stability of probiotic bacteria in fermented
      milk processing, was studied. Two strains of probiotic bacteria were used,
      Lactobacillus acidophilus LA5 and L. rhamnosus LR35, with two starter cultures.
      One starter culture consisted only of Streptococcus thermophilus ST7 (single
      starter culture); the other was a yogurt mixed culture with S. thermophilus ST7
      and L. bulgaricus LB12 (mixed starter culture). For the milk base preparation,
      four commercial dairy ingredients were tested (two milk protein concentrates and
      two casein hydrolysates). The resulting fermented milks were compared to those
      obtained with control milk (without enrichment) and milk added with skim milk
      powder. The performance of the two probiotic strains were opposite. L.
      acidophilus LA5 grew well on milk but showed a poor stability during storage. L.
      rhamnosus LR35 grew weakly on milk but was remarkably stable during storage. With
      the strains tested in this study, the use of the single starter culture and the
      addition of casein hydrolysate gave the best probiotic cell counts. The
      fermentation time was of about 11 h, and the probiotic level after five weeks of
      storage was greater than 106 cfu/ml for L. acidophilus LA5 and 10(7) cfu/ml for
      L. rhamnosus LR35. However, an optimization of the level of casein hydrolysate
      added to milk base has to be done, in order to improve texture and flavor when
      using this dairy ingredient.

PMID- 12416801
TI  - Enhancement of lactase activity in milk by reactive sulfhydryl groups induced by
      heat treatment.
AB  - The effects of heat treatments of milk and whey prior to lactose hydrolysis with
      Kluyveromyces lactis beta-galactosidase were studied. It was observed that heat
      treatment of milk significantly increases lactase activity, with a maximum
      activity increase found when milk was heated at 55 degrees C. In whey from 55 up
      to 75 degrees C, beta-galactosidase activity decreased slightly. Nevertheless,
      heating whey at 85 degrees C for 30 min raised the rate of hydrolysis
      significantly. Electrophoretic patterns and UV spectra proved that the activity
      change correlated with milk protein denaturation, particularly that of beta
      lactoglobulin. Heating whey permeate did not increase the enzyme activity as
      heating whole whey; but heating whey prior to ultrafiltration also resulted in
      enzyme activation. Measurement of free sulfhydryl (SH) groups in both whey and
      heated whey permeate showed that the liberation of free SH is highly correlated
      to the change of the activity. Furthermore, this activation can be reversed by
      oxidizing the reactive sulfhydryl groups, proving that the observed effect may be
      related to the release of free SH to the medium, rather than to the denaturation
      of a thermolabile protein inhibitor.

PMID- 12416802
TI  - Effects of tail docking on milk quality and cow cleanliness.
AB  - The objective of this study was to determine the effect of tail docking on
      somatic cell count (SCC), intramammary infection (IMI), and udder and leg
      cleanliness in commercial dairy herds. Lactating dairy cows (n = 1250) from eight
      Wisconsin farms were blocked by farm and randomly allocated to tail docked (D) or
      control (C) groups. Milk samples, somatic cell counts, and hygiene scores were
      collected for 8 to 9 mo. The prevalence of IMI was determined for each of the
      five occasions when milk samples were obtained. Udder and leg cleanliness were
      assessed during milk sample collection. Docked and control animals were compared
      by logSCC, prevalence of IMI, and leg and udder cleanliness score. Variables were
      analyzed according to all treatment, period, and farm interactions. At the end of
      the study period 76 (12.2%) and 81 (13%) of cows were culled in the D and C
      groups, respectively. There were no significant differences in the initial data
      for parity, daily milk yield, logSCC, or DIM between treatment groups. Effects
      significant to farms were identified for all variables over all periods. Period
      was significant for all variables except for the prevalence of environmental
      pathogens, but no period x treatment interactions were detected. There was no
      significant difference between treatment groups for somatic cell count. The
      prevalence of contagious, environmental, or minor pathogens did not differ
      significantly between treatment groups. This study did not identify any
      differences in udder or leg hygiene or milk quality that could be attributed to
      tail docking.

PMID- 12416803
TI  - The effect of an intramammary teat seal on new intramammary infections.
AB  - As concern over the possible overuse of antibacterials increases, attention has
      focused on reduction of antibiotic usage and on nonantibiotic alternatives. A
      nonantibiotic intramammary teat sealant, Teat Seal (Cross Vetpharm Group Ltd.,
      Tallaght, Dublin, Ireland), has been available in Ireland, in combination with an
      intramammary tube of cloxacillin. Teat Seal has been reformulated for use in cows
      with low cell counts as an alternative to antibiotic dry cow therapy at the end
      of lactation. The product is now marketed as Orbeseal (Pfizer Animal Health). A
      comparison between this teat sealant and no treatment was made on new
      intramammary infections and clinical mastitis, on all cows within four herds, and
      on low cell count cows in three herds. No cases of clinical mastitis in the dry
      period were observed in cows treated with Teat Seal (n = 197), whereas a
      significant number (6 cows) were observed in the untreated cows (n = 204). In all
      herds, significantly more new infections at calving were found in the untreated
      group (62 cows in the untreated group compared with 21 cows in the Teat Seal
      group). In those quarters where infections were first detected at calving, the
      incidence of clinical mastitis was significantly greater in the untreated group.
      Quarters in both treatment groups that were infected at drying off with
      Corynebacterium spp. or coagulase-negative staphylococci were not protected
      against new infections and had an increased risk of new infection by
      Streptococcus uberis. The results will inform those restricting their use of
      antibiotic dry cow therapy in alternative management strategies and the
      additional risk of new intramammary infection.

PMID- 12416804
TI  - Effect of weaning system on milk composition and distribution of milk fat within
      the udder of East Friesian dairy ewes.
AB  - We investigated whether the inhibition of milk ejection during and/or between
      machine milkings is responsible for the low milk fat observed in commercial milk
      obtained from dairy ewes managed with a mixed system (MIX) of partial daily
      suckling (10 h) and once daily machine milking (after 14 h of udder filling).
      East Friesian crossbred dairy ewes were randomly allocated postpartum to the MIX
      system (n = 9) or to exclusive twice-daily machine milking (DY1, n = 8).
      Following wk 4, MIX ewes were permanently weaned from their lambs and milked
      twice daily. All ewes were injected with saline, oxytocin, or an oxytocin
      receptor antagonist prior to three morning milkings during wk 2,4, and 6 of
      lactation to study cisternal and alveolar milk distribution. Overall milk yield
      (cisternal + alveolar) for MIX ewes was 42% greater than for DY1 ewes during wk 2
      and 4, which demonstrates the beneficial effect of lamb suckling on milk
      production of dairy ewes. However, during normal machine milking, only the
      cisternal fraction was obtained from MIX ewes, confirming that milk ejection did
      not occur for as long as these ewes remained in partial daily contact with their
      lambs. Although the volume of milk stored within the cistern, and its
      concentration of milk protein was similar for the two weaning systems, milk of
      MIX ewes was significantly inferior in cisternal milk fat concentration and yield
      compared to DY1 ewes. This provides evidence that not only is there inhibition of
      milk ejection during machine milking of MIX ewes, there is additional inhibition
      of transfer of milk fat, but not milk protein, from the alveoli to the cistern
      during the evening when MIX ewes a reseparated from their lambs. Following
      weaning of MIX ewes, the majority of lactation traits studied were similar
      compared to DY1 ewes.

PMID- 12416805
TI  - Effects of selection for milk yield on growth hormone response to growth hormone
      releasing factor in growing Holstein calves.
AB  - Bull and heifer calves (n = 81) from genetic lines of Holstein cows that differed
      by more than 4000 kg milk/305-d lactation were used to determine effects of
      selection for milk yield on growth hormone (GH) response to a GH releasing factor
      (GRF) analog. Calves received GRF (4 microg/100 kg BW) on 10, 56, 140, 196, 252,
      and 364 +/- 3 d of age. Jugular blood samples (n = 15) were obtained from -30 to
      120 min relative to GRF administration. Area under the GH response curve (0 to 60
      min, AUC60) was quantified after subtracting mean prechallenge GH concentrations.
      Data were analyzed for effects of line, age, gender, and their interactions with
      PROC MIXED of SAS for repeated measures and incorporated the spatial power law
      for unequally spaced data with age as the repeated effect. Means were considered
      different when P < 0.05. Prechallenge GH concentrations did not differ between
      lines, were greater in bulls than heifers (4.6 vs. 3.7 ng/ml), and decreased with
      age. The AUC60 decreased with age but did not differ between lines. Heifers
      responded more to GRF than bulls (1550 vs. 1336 ng x min/ml). Peak GH
      concentration decreased with age and was less in bulls than heifers (54.7 vs.
      62.1 ng/ml) but did not differ between lines. Although plasma GH has been
      identified as an inheritable trait, we conclude the GH variables measured in this
      study were not useful in predicting genetic merit of calves from these
      substantially different lines of cows.

PMID- 12416806
TI  - Duodenal infusion of glucose decreases milk fat production in grass silage-fed
      dairy cows.
AB  - Four lactating dairy cows were arranged in a 4 x 4 Latin square design to study
      the effect of intestinal glucose supply on milk fat synthesis. Glucose (0, 443,
      963, and 2398 g/d) was continuously infused in the duodenum over 14-d periods.
      Grass silage-based diets were formulated to be isoenergetic and isonitrogenous
      and met 100 and 110% of energy and protein requirements according to INRA (1989).
      Mammary uptake of nutrients was estimated through assay of arteriovenous
      differences and blood flow measurements. Glucose infusions decreased arterial
      concentrations of acetate, beta-hydroxybutyrate, and nonesterified fatty acids
      linearly and total glycerides curvilinearly. Milk fat yield was slightly
      decreased (- 52 g/d) between 0 and 963 g/d of glucose and milk fatty acid
      composition was modified by a marked decrease in long-chain fatty acids and an
      increase in de novo synthesis. The decrease in long-chain fatty acids, related to
      the decreased mammary uptake of plasma total glycerides, was likely due to a
      decrease in lipoprotein lipase and esterification activities. In regards to the
      evolution of metabolite concentrations in milk, the enhanced de novo synthesis
      and chain elongation was probably allowed by a greater availability of NADPH
      synthesized through pentose phosphate pathway. The greatest dose of glucose
      clearly decreased milk fat yield (-234 g/d). A mammary cell mediated
      intracellular reaction likely caused a homothetic decrease in milk fatty acids.
      However, reduced synthesis was not due to a shortage of glycerol-3-phosphate
      because its milk concentration remained unchanged. In conclusion, changes in
      exogenous glucose supply, in cows fed a grass silage-based diet, decreased milk
      fat production and modified milk fatty acid composition.

PMID- 12416807
TI  - Individual differences in behavioral and physiological responsiveness of
      primiparous dairy cows to machine milking.
AB  - An experiment was performed in primiparous dairy cows (n = 23) to examine
      consistency of individual differences in reactivity to milking, and correlations
      between measures of behavior, physiology, and milk ejection. Responsiveness to
      milking was monitored during the first machine milking, on d 2 of lactation, and
      during milkings on d 4 and 130 of lactation. Measurements included kicking and
      stepping behavior, plasma cortisol and plasma oxytocin, heart rate, milk yield,
      milking time, milk flow rate, and residual milk obtained after administration of
      exogenous oxytocin. With repeated early lactation milkings, residual milk and the
      incidence of abnormal milk flow curves decreased. On d 130 of lactation all
      heifers exhibited normal milk ejection. Except for higher plasma cortisol
      concentrations on d 2, all measures were consistent over time between d 2 and 4
      of lactation as indicated by significant rank correlations. Individual
      differences in the behavioral response to udder preparation were consistent over
      time between early lactation milkings and d 130 of lactation. Residual milk, milk
      yield, maximum milk flow rate, plasma oxytocin and heart rate during udder
      preparation were similarly interrelated on d 2 and 4 of lactation. High heart
      rate responses on d 2 and 4 were associated with enhanced inhibition of milk
      ejection. In contrast, behavior recorded during the milking process was unrelated
      to ease of milk removal. Our results indicate that milking at the beginning of
      lactation may be stressful to some heifers, to the extent that milk ejection is
      inhibited, but less disturbing to others. The existence of consistent behavioral
      and physiological responses in the present study suggests that responsiveness of
      dairy heifers to milking is mediated by stable animal characteristics.

PMID- 12416808
TI  - Mechanisms involved in milk endogenous proteolysis induced by a
      lipopolysaccharide experimental mastitis.
AB  - Experimental mastitis has been induced by the lipopolysaccharide (LPS) of
      Escherichia coli on six dairy cows in order to study the mechanisms involved in
      milk endogenous proteolysis during the inflammatory process. Variations in
      somatic cell count (SCC), plasmin activity, and total casein (CN) content were
      measured, and proteose-peptone content and the percentage of pH 4.6 insoluble
      peptides including gamma-CN have been considered as indicators of endogenous
      proteolysis. Furthermore, polymorphonuclear neutrophils (PMN) maturity has been
      evaluated by optical microscopy, and proteolysis by PMN proteinases has been
      studied at neutral and acidic pH in order to establish a link between
      caseinolysis, proteinase class, and PMN maturation. Two peaks of proteose
      peptones content have been noticed for the six cows. First peak could be
      explained by both plasmin activity and SCC, while second peak was concomitant
      with a low plasmin activity but a SCC remaining high. The second peak of proteose
      peptones content confirmed the role of cellular proteases in milk caseinolysis.
      Casein breakdown by cellular proteases was confirmed by SDS-PAGE electrophoresis,
      and a link between neutral proteinases activity and immature PMN recruitment was
      shown. Acidic proteinases activity was effective with mature PMN and during the
      recovery phase.

PMID- 12416809
TI  - Efficacy of systemic ceftiofur as a therapy for severe clinical mastitis in dairy
      cattle.
AB  - The objectives of this study were to determine the efficacy of intramuscular
      administration of ceftiofur to reduce the incidence of case-related death and
      culling following severe clinical mastitis in lactating dairy cattle. A total of
      104 cows with severe clinical mastitis (systemic signs) were enrolled in the
      study and randomly assigned to one of two treatment groups. Immediately after
      detection of the case, one group was administered 2.2 mg/kg of ceftiofur
      intramuscularly, and the dose repeated at 24-h intervals for a total of five
      doses. The second group of cows did not receive systemic antibacterial therapy.
      Additionally, all cows in both treatment groups received intramammary pirlimycin
      (Pirsue) in the affected quarter every 24 h for a total of up to three doses.
      Also at the onset of the case, all cows on the trial were administered a
      supportive therapeutic regimen of fluids and anti-inflammatory agents that varied
      from farm to farm, but was standard within each herd at the discretion of the
      herd manager and veterinarian. Of all cases 14/104 (13.5%) resulted in a lost cow
      (died or culled). The proportion of cases that resulted in a lost cow and were
      treated with ceftiofur (4/51; 7.8%) did not statistically differ from cows that
      were not treated with ceftiofur (10/53; 18.9%). However, the proportion of cases
      that resulted in lost cows was higher for those cases that yielded a coliform
      organism on culture (14/56; 25.0%) than cases that did not yield coliforms (0/48;
      0.0%; P < 0.001). Thus, among coliform cases, cows that were not treated with
      ceftiofur were more likely to be culled or die (10/27, 37.0%; P < 0.05) than cows
      treated with ceftiofur (4/29, 13.8%). We conclude that intramuscular
      administration of ceftiofur did not affect the outcome of severe clinical
      mastitis when all etiologic agents are included in the analysis. However, for
      severe clinical mastitis cases caused by coliform organisms, ceftiofur therapy
      reduced the proportion of cases that resulted in cow death or culling. This
      benefit may be realized because of the amelioration of bacteremic-related
      pathogenesis.

PMID- 12416810
TI  - Robotic milking and its effect on fertility and cell counts.
AB  - The aim of this study was to analyze the effect of robotic milking (RM) on
      fertility and somatic cell counts (SCC) among dairy herds participating in the
      national Dutch milk recording system. It was hypothesized that RM, and a higher
      milking frequency in general, would have negative effects on fertility, due to
      expected and supposed deeper negative energy balance (NEB). Herds increasing
      milking frequency from two to three times daily consistently had increased
      production. Milk production during RM was intermediate between the amounts
      obtained by milking twice versus three times a day. Milking three times a day and
      the associated higher production had no significant effect on reproductive
      measures such as nonreturn rate at 56 d post insemination (NR56) or days to first
      service. Although RM did not affect NR56, use of the robot was associated with an
      increase in days to first service. An increase in milking frequency from two to
      three times daily did not affect SCC, but SCC were significantly increased after
      milking with the robot. Robotic milking has a significant positive effect on
      production and no negative effect on fertility as measured by NR56. The effect of
      RM in increasing days to first service appears due to reasons other than
      increased production and a more NEB. Increased SCC during RM is potentially of
      concern. From the data available, the relationship of RM to clinical mastitis
      could not be determined but this aspect needs further attention.

PMID- 12416811
TI  - Investigations of milk quality from teats with milk flow disorders.
AB  - The objective of this study was to investigate the quality of milk from teats
      with milk flow disorders. Somatic cell count, pathogens, and signs of mastitis
      (>100,000 cells/ml and pathogens detected) were determined in the milk from all
      teats of the udder before treatment of the affected teat, as well as 1 and 6 mo
      later. Teats with milk flow disorders were compared to all of the other teats
      from the same udder. Before treatment, the SCC from affected teats was 4.3
      million higher, the odds of detecting pathogens 6 times higher, and the odds of
      mastitis 11 times higher than in control teats (when adjusted for other
      significant explanatory variables). SCC and the risk of mastitis decreased after
      surgical treatment of the affected teats, whereas the chance of detecting
      pathogens was not affected. Six months after treatment, the SCC was 1.3 million
      higher, and the odds of mastitis 6.5 times higher than in control teats.
      Throughout the study period neither SCC, the odds of detecting pathogens, nor
      mastitis changed significantly in control teats. It may be concluded from this
      study that milk quality from teats with milk flow disorders is decreased before
      treatment and does not reach the milk quality from unaffected teats within 6 mo
      after treatment.

PMID- 12416812
TI  - Influence of dry period bacterial intramammary infection on clinical mastitis in
      dairy cows.
AB  - Milk samples were taken from 1920 quarters (480 cows, six herds) on four
      occasions to examine the relationship between quarter level intramammary
      infection (IMI) during the dry period and clinical mastitis in the next
      lactation. All quarters were sampled at drying off and within 1 wk of calving,
      and two quarters from each cow were sampled both 0 to 7 and 8 to 14 d before
      calving. Milk samples were collected from all cases of clinical mastitis during
      the following lactation. Logistic regression models were developed to investigate
      the associations between IMI present during the sampling period and clinical
      mastitis. The probability of a quarter succumbing to clinical mastitis increased
      when Streptococcus dysgalactiae, Streptococcus faecalis, Escherichia coli, or
      Enterobacter spp. were cultured at drying off and when Escherichia coli,
      coagulase-positive staphylococcus, Serratia spp., or Streptococcus faecalis were
      cultured in two out of three late dry and post-calving samples. Quarters from
      which Corynebacterium spp. were isolated at drying off were at an increased risk
      of clinical mastitis, whereas the presence of Corynebacterium spp. in the late
      dry and post-calving samples was associated with a reduction in the risk of
      clinical mastitis. The risk of mastitis for specific pathogens increased if the
      same species of bacteria that had caused mastitis was isolated at least twice in
      the late dry and post-calving samples. Kaplan-Meier survival plots indicated that
      clinical mastitis associated with dry period infections was more likely to occur
      earlier in lactation than clinical mastitis not associated with dry period
      infections. There was evidence of quarter susceptibility to IMI or the
      possibility that infection with one organism led to clinical mastitis with
      another.

PMID- 12416813
TI  - Short communication: relationship between body growth and mammary development in
      dairy heifers.
AB  - Our objective was to determine if prepubertal rate of body weight (BW) gain,
      independent of diet, was related to mammary development of dairy heifers. Data
      from two studies recently conducted at Michigan State University were used to
      identify factors, within a dietary treatment group, that would account for
      variation in first lactation milk production or amount of mammary parenchymal DNA
      at the time of puberty. Factors analyzed for variation in milk production during
      first lactation were: postpartum BW, prepubertal BW gain, gestational BW gain,
      postpartum BW gain, body condition score (BCS) at breeding, and BCS at calving.
      Factors analyzed for variation in mammary parenchymal DNA at puberty were: BW at
      slaughter, age at puberty, prepubertal BW gain and body protein and body fat
      content at slaughter. For both analyses, prepubertal BW gain did not account for
      any of the variation in mammary development. The only significant covariate for
      the milk production model (r2 = 0.44) was BCS at breeding. Similarly, the only
      significant covariate in the parenchymal DNA model (r2 = 0.22) was body fat
      content at slaughter. These results suggest that, within a dietary treatment,
      heifers that grow faster do not have impaired mammary development, and increased
      body fatness may be a better predictor of impaired mammary development than BW
      gain.

PMID- 12416814
TI  - Effects of Saccharomyces cerevisiae culture and Saccharomyces cerevisiae live
      cells on in vitro mixed ruminal microorganism fermentation.
AB  - The objective of this study was to examine the effects of a Saccharomyces
      cerevisiae live cell product and a S. cerevisiae culture product on the in vitro
      mixed ruminal microorganism fermentation of ground corn, soluble starch, alfalfa
      hay, and Coastal bermudagrass hay. In the presence of ground corn, neither
      concentration (0.35 or 0.73 g/L) of S. cerevisiae culture nor live cells had any
      effect on final pH, H2, CH4, propionate, or butyrate. The S. cerevisiae culture
      had no effect on acetate, but both concentrations of S. cerevisiae live cells
      decreased acetate and the acetate:propionate ratio. When soluble starch was the
      substrate, both concentrations of S. cerevisiae live cells and 0.73 g/L of S.
      cerevisiae culture decreased the acetate:propionate ratio. Although the treatment
      effects were not statistically significant, both concentrations of live cells and
      0.73 g/L of the culture decreased lactate concentrations compared with the
      control incubations. When alfalfa hay served as the substrate, neither the S.
      cerevisiae culture nor the live cells had an effect on propionate, butyrate, or
      the acetate:propionate ratio. Both concentrations of S. cerevisiae culture
      decreased the final pH and in vitro dry matter disappearance, and the 0.73 g/L
      treatment decreased the amount of acetate. However, both treatments of S.
      cerevisiae live cells increased final pH and decreased acetate and in vitro dry
      matter disappearance. Neither yeast treatment had much effect on the Coastal
      bermudagrass hay fermentations. In general, both S. cerevisiae supplements seemed
      to have similar effects on the mixed ruminal microorganism fermentation.

PMID- 12416815
TI  - Effects of dietary supplementation of rumen-protected conjugated linoleic acid in
      dairy cows during established lactation.
AB  - Short-term studies (< 5 d) involving abomasal infusion of a mixture of CLA
      isomers or pure trans-10, cis-12 CLA have demonstrated that supplements of
      conjugated linoleic acids (CLA) reduce milk fat synthesis during established
      lactation in dairy cows. Our objective was to assess longer term effects of
      supplementation during established lactation using a dietary supplement of rumen
      protected CLA. Thirty Holstein cows were blocked by parity and received a dietary
      fat supplement of either Ca-salts of palm oil fatty acids (control) or a mixture
      of Ca-salts of palm oil fatty acids plus Ca-salts of CLA (CLA treatment).
      Supplements provided about 90 g/d of fatty acids and were topdressed on the TMR.
      The CLA supplement provided 30.4 g/d of CLA in which the predominant isomers
      were: trans-8, cis-10 (9.2%), cis-9, trans-11 (25.1%), trans-10, cis-12 (28.9%),
      and cis-11, trans-13 (16.1%). All cows were pregnant; treatments were initiated
      on d 79 of pregnancy (approximately 200 d prepartum) and continued for 140 d
      until dry off. Twenty-three cows completed the study; those receiving CLA
      supplement had a lower milk fat test (2.90 versus 3.80%) and a 23% reduction in
      milk fat yield (927 versus 1201 g/d). Intake of DM, milk yield, and the yield and
      content of true protein and lactose in milk were unaffected by treatment. Milk
      fat analysis indicated that the CLA supplement reduced the secretion of fatty
      acids of all chain lengths. However, effects were proportionally greater on short
      and medium chain fatty acids, thereby causing a shift in the milk fatty acid
      composition to a greater content of longer-chain fatty acids. Changes in body
      weight gain, body condition score, and net energy balance were not significant
      and imply no differences in cows fed the CLA supplement in replenishment of body
      reserves in late lactation. Likewise, maintenance of pregnancy, gestation length,
      and calf birth weight were unaffected by treatment. Overall, feeding a dietary
      supplement of rumen-protected CLA to pregnant cows over the last 140 d of the
      lactation cycle resulted in a marked reduction in milk fat content and yield, and
      a shift in milk fatty acid composition, but other milk components, DMI,
      maintenance of pregnancy, and cow well-being were unaffected.

PMID- 12416816
TI  - Effect of supply of metabolizable protein on splanchnic fluxes of nutrients and
      hormones in lactating dairy cows.
AB  - The effect of the supply of metabolizable protein on splanchnic fluxes of
      nutrients and hormones was measured in six catheterized late-lactation Holstein
      cows in a crossover design. Two isonitrogenous diets (16.3% CP), but differing in
      rumen protein degradability and estimated metabolizable protein (MP) supply (1654
      g/ d, Lo-MP; 1930 g/d, Hi-MP) were fed, each over a 35-d experimental period. On
      d 34 or 35, net fluxes of nutrients and hormones across the portal-drained
      viscera, the liver, and total splanchnic tissues were determined. Portal
      absorption of total, essential, nonessential, and branched-chain amino acids (AA)
      increased with the Hi-MP diet. Approximately 76% of the additional metabolizable
      protein supply was recovered as extra AA-N absorption in the portal vein. Liver
      removal of AA was not different between diets, and this resulted in a greater net
      release across the splanchnic tissues for the Hi-MP diet. This extra AA supply
      provided substrates for the observed increased milk protein yield for the Hi-MP
      diet. Fractional efficiencies of conversion of absorbed individual essential AA
      into milk protein ranged from 0.42 to 0.68. The corresponding efficiencies for
      utilization of postsplanchnic AA supply were 0.42 to 1.80. Provision of
      methionine, phenylalanine, and histidine beyond the liver were similar to outputs
      in milk protein but the other essential AA were supplied to peripheral tissues in
      excess of milk output, indicative of oxidative mechanisms in nonhepatic tissues.
      Net fluxes of glucose, NH3-N, and urea were not affected by the diets. Neither
      arterial concentrations of insulin, somatotropin, or IGF-1, nor net transfers
      across the portal-drained viscera or liver of insulin, were affected by the
      diets. Although portal release of glucagon was not different between the diets, a
      smaller proportion was removed by the liver on the Hi-MP diet. Metabolism of AA
      across the splanchnic tissue bed is a major determinant of the quantity and the
      profile of AA delivered to peripheral tissues.

PMID- 12416817
TI  - Effect of supply of metabolizable protein on whole body and splanchnic leucine
      metabolism in lactating dairy cows.
AB  - The effect of the supply of metabolizable protein (MP) on protein metabolism
      across the splanchnic tissues was determined in six catheterized lactating
      Holstein cows. In a crossover design, two isonitrogenous (16.3% CP) diets
      balanced to provide a low (Lo-MP) or high (Hi-MP) supply of MP were fed over 35-d
      periods. After 24 d of feeding, N balance was determined over a 6-d period. On d
      33, [13C] sodium bicarbonate was infused into one jugular vein for 6 h, and
      hourly breath samples were collected. On d 34 or 35, L[1-(13)C] leucine was
      infused into one jugular vein, and between 2 to 6 h of infusion, breath and blood
      samples were taken hourly from the portal and hepatic veins and an artery.
      Isotopic enrichments of plasma leucine, 4-methyl-2-oxopentanoate, and expired CO2
      were determined for calculation of leucine kinetics. Net leucine absorption was
      greater, either on a direct basis (leucine transfer only) or corrected for portal
      drained viscera metabolism to 4-methyl-2-oxopentanoate and CO2 for the Hi-MP
      diet. There were no effects of diet on hepatic net flux of leucine across the
      liver, and, thus, more leucine was available to peripheral tissues with the Hi-MP
      diet. Combined with an increment in portal absorption of most of essential AA,
      this led to increased milk protein output, although it only represented 16% of
      the additional available leucine. Whole body leucine oxidation was also greater
      for the Hi-MP diet, as was leucine used for protein synthesis. Despite these
      changes, MP supply did not affect irreversible loss rate of leucine by portal
      drained viscera and the liver; these averaged 35 and 20% of whole body
      irreversible loss rate, respectively. These ratios confirm the high metabolic
      activity of splanchnic tissues in lactating dairy cows, which are even greater
      than previously reported in growing ruminants.

PMID- 12416818
TI  - Influence of phosphorus intake on excretion and blood plasma and saliva
      concentrations of phosphorus in dairy cows.
AB  - Phosphorus (P) balance, and blood plasma P and saliva P concentrations were
      measured in multiparous dairy cows through two lactations and two dry periods.
      The cows were fed three amounts of P at either 100, 80 or 67% of the Dutch P
      recommendation, actually resulting in dietary P concentrations of 3.2 to 3.9, 2.6
      to 2.9 and 2.2 to 2.6 g P/kg dry matter during lactation for the three
      treatments, respectively. On the basis of plasma P values as low as 0.9 mmol/l
      and saliva P values as low as 5.1 mmol/l during the second lactation period
      within the experiment, the 67% group was considered to be deficient in P. By
      decreasing milk production, and thus lowering P losses with milk, P retention in
      the 67% group remained near zero. The P supply with the 80% ration was considered
      to be just sufficient. At high milk yield and marginal dietary P concentrations,
      plasma P and saliva P concentrations were decreased. The higher P intake in high
      compared with low-producing cows resulted in a constant absolute fecal P
      excretion, due to the fact that the apparent P digestibility was raised with
      increasing milk yield. There was a direct relationship between milk P output and
      the percentage of apparent P digestibility for individual animals.

PMID- 12416819
TI  - Effects of pretrial milk yield on responses of feed intake, digestion, and
      production to dietary forage concentration.
AB  - The relationships between pretrial milk yield and effects of dietary forage-to
      concentrate ratio on dry matter intake (DMI), digestion, and milk yield were
      evaluated using 32 Holstein cows in a crossover design with two 16-d periods.
      Cows were 197 +/- 55 (mean +/- SD) days in milk at the beginning of the
      experiment. Milk yield averaged 33.9 kg/d and ranged from 16.5 to 55.0 kg/d for
      the 4 d before initiation of treatments. Treatments were diets with forage-to
      concentrate ratios of 67:33 and 44:56. Forages were alfalfa silage and corn
      silage, each at 50% of forage dry matter (DM). Neutral detergent fiber (NDF)
      concentrations of high-forage and low-forage diets were 30.7 and 24.3% of DM,
      respectively. Dry matter intake was 1.7 kg/d higher for cows fed the low-forage
      diet. Milk yield was 2.3 kg/d greater on low forage than on high forage, but 3.5%
      fat-corrected milk yield and yield of milk fat were not different between
      treatments. Individual DMI response to the low-forage diet relative to the high
      forage diet (low-high) was positively and linearly related to pretrial fat
      corrected milk yield, but fat-corrected milk yield response demonstrated a
      quadratic relationship with pretrial fat-corrected milk yield. Milk yield
      responded more positively to low forage among low- and high-producing cows than
      among moderate-producing cows. Energy partitioned to body reserves and to milk,
      and passage rate of indigestible NDF, also responded to dietary forage level in
      quadratic relationships with pretrial milk energy output. Individual responses of
      intake, production, and fiber digestion to a change in forage-to-concentrate
      ratio were dependent on production level.

PMID- 12416820
TI  - Lactation performance by dairy cows fed wet brewers grains or whole cottonseed to
      replace forage.
AB  - Holstein cows starting at wk 8 of lactation were used to evaluate lactation
      performance when wet brewers grains, whole linted cottonseed, or starch-coated
      whole linted cottonseed (Easiflo) were substituted for forage. The wet brewers
      grains were added to diets to decrease forage neutral detergent fiber from 21%
      incrementally down to 15% while simultaneously decreasing nonfiber carbohydrate
      concentration from 40.3% down to about 33.8%. The cottonseed treatments all had
      similar concentrations of forage neutral detergent fiber (15%) and nonfiber
      carbohydrates (33.1 and 36.0%). Dry matter intake and milk production were
      similar across treatments. Milk fat percentage was decreased for Easiflo versus
      whole linted cottonseeds, but no other responses were detected. The current
      National Research Council (NRC) energy model was evaluated using individual cow
      data that were averaged over the entire 16-wk treatment period. For treatment
      means, the output of energy averaged 99% of the net energy of lactation intake,
      indicating very good corroboration of the model to account for energy usage for a
      group of cows. However, the ability to predict energy usage for individual cows
      was less accurate based on the comparison of residuals of observed and predicted
      body weight change regressed against predicted body weight change, apparently
      because of compounding of random errors in this prediction, which was alleviated
      over a larger number of observations. These results also corroborate current NRC
      guidelines for minimum forage neutral detergent fiber concentrations for
      lactating cows past the calving transition period.

PMID- 12416821
TI  - Energy balance profiles for the first three lactations of dairy cows estimated
      using random regression.
AB  - Daily animal solutions were predicted using random regression analysis for feed
      intake, milk yield, live weight, and condition score recorded on 189 cows at the
      Langhill Dairy Cattle Research Centre. All cows had three successive lactations.
      Energy balance for days 1 to 305 of each of the three lactations was calculated
      both from daily measures of feed intake and milk output and from weekly measures
      of live weight and condition score. Cows returned to positive energy balance at
      days 72, 75, and 95 in lactations 1, 2, and 3, respectively, based on energy
      balance calculated from feed intake and milk output records (EB1), and at days
      77, 83, and 73 based on energy balance calculated from body energy state changes
      (EB2). Correlations between energy balance at the same time in successive
      lactations ranged from 0.01 to 0.66 depending on the method of calculation and
      the stage of lactation. Energy balance over three lactations was modelled using
      sinusoidal functions which were associated with individual cows and allowed to
      vary between cows. The parameters of these curves are potentially useful since
      they have a biological interpretation. The phase relates to the period from
      calving to return to positive energy balance, and the amplitude relates to the
      degree of body energy loss (and recovery). The sinusoidal functions fitted to the
      curve removed a significant proportion of the variation, but accounted for only
      45% and 40% of the variation in EB1 and EB2, respectively. The relationship
      between energy balance in the first three lactations is likely to be more complex
      than a simple linear function, but the profile of energy balance over the first
      three lactations may be a useful selection criteria in a multi-trait index.
      Energy balance profile over lactations one to three can be modelled with moderate
      accuracy using sinusoidal functions, and this warrants further research.

PMID- 12416822
TI  - Short communication: characterization of a new genetic variant in the caprine
      kappa-casein gene.
AB  - A new polymorphism has been identified in the goat kappa-casein gene by
      evaluating genomic DNA from the Montefalcone breed in Italy. The polymorphic site
      consists of a single nucleotide substitution A to G at position 242 of the exon 4
      and produces an amino acid substitution Asp/Gly. A polymerase chain reaction
      restriction fragment length polymorphism protocol for rapid genotyping of the
      variant has been developed, using the HaeIII enzyme. Animals from Italian,
      Spanish, and French breeds have been analyzed to investigate the occurrence of
      the allele in other populations. The allele appears to be exclusive to the
      Montefalcone breed.

PMID- 12416823
TI  - Detection of quantitative trait loci influencing dairy traits using a model for
      longitudinal data.
AB  - A longitudinal-linkage analysis approach was developed and applied to an outbred
      population. Nonlinear mixed-effects models were used to describe the lactation
      patterns and were extended to include marker information following single-marker
      and interval mapping models. Quantitative trait loci (QTL) affecting the shape
      and scale of lactation curves for production and health traits in dairy cattle
      were mapped in three U.S. Holstein families (Dairy Bull DNA Repository families
      one, four, and five) using the granddaughter design. Information on 81
      informative markers on six Bos taurus autosomes (BTA) was combined with milk
      yield, fat, and protein percentage and somatic cell score (SCS) test-day records.
      Six percent of the single-marker tests surpassed the experiment-wise significance
      threshold. Marker BL41 on BTA3 was associated with decrease in milk yield during
      mid-lactation in family one. The scale and shape of the protein percentage
      lactation curve in family four varied with BMC4203 (BTA6) allele that the son
      received from the grandsire. Some map locations were associated with variation in
      the lactation pattern of multiple traits. In family four, the marker HUJI177
      (BTA3) was associated with changes in the milk yield and protein percentage
      curves suggesting a QTL with pleiotropic effects or multiple QTL in the region.
      The interval mapping model uncovered a QTL on BTA7 associated with variation in
      milk-yield pattern in family four and a QTL on BTA21 affecting SCS in family
      five. The developed approach can be extended to random regressions, covariance
      functions, spline, gametic and variance component models. The results from the
      longitudinal-QTL approach will help to understand the genetic factors acting at
      different stages of lactation and will assist in positional candidate gene
      research. Identified positions can be incorporated into marker-assisted selection
      decisions to alter the persistency and peak production or the fluctuation of SCS
      during a lactation.

PMID- 12416824
TI  - Heritability and genetic correlations of test day milk yield and composition,
      individual laboratory cheese yield, and somatic cell count for dairy ewes.
AB  - Genetic parameters for milk yield, contents of fat, total protein, casein and
      serum protein, individual laboratory cheese yield, and somatic cell counts (SCC)
      were estimated from 7492 monthly test-day records of 1119 Churra ewes. Estimates
      were from multivariate REML using analytical gradients (AG-REML) procedures.
      Except for fat content, estimates for the other routinely recorded traits (milk
      yield, protein content, and SCC) agreed with those previously obtained in this
      and other dairy sheep populations. Protein content and composition had the
      highest heritabilities and repeatabilities. Heritabilities for protein and casein
      contents were very similar (0.23 and 0.21, respectively), and genetic correlation
      between the traits was close to unity (0.99). Accordingly, casein content is not
      advisable as an alternative to protein content as a selection criterion in dairy
      ewes; it does not have any compelling advantages and costs more to measure.
      Individual laboratory cheese yield (ILCY) obtained with Churra ewes had a low
      heritability (0.08), suggesting that potential for selection for this parameter
      would be possible but is not recommended. All correlations with ILCY were high
      and positive except for milk yield. A high SCC was accompanied by an increase in
      serum protein content and involved a loss in milk yield.

PMID- 12416825
TI  - An empirical method for prediction of cheese yield.
AB  - Theoretical cheese yield can be estimated from the milk fat and casein or protein
      content of milk using classical formulae, such as the VanSlyke formula. These
      equations are reliable predictors of theoretical or actual yield based on
      accurately measured milk fat and casein content. Many cheese makers desire to
      base payment for milk to dairy farmers on the yield of cheese. In small
      factories, however, accurate measurement of fat and casein content of milk by
      either chemical methods or infrared milk analysis is too time consuming and
      expensive. Therefore, an empirical test to predict cheese yield was developed
      which uses simple equipment (i.e., clinical centrifuge, analytical balance, and
      forced air oven) to carry out a miniature cheese making, followed by a
      gravimetric measurement of dry weight yield. A linear regression of calculated
      theoretical versus dry weight yields for milks of known fat and casein content
      was calculated. A regression equation of y = 1.275x + 1.528, where y is
      theoretical yield and x is measured dry solids yield (r2 = 0.981), for Cheddar
      cheese was developed using milks with a range of theoretical yield from 7 to
      11.8%. The standard deviation of the difference (SDD) between theoretical cheese
      yield and dry solids yield was 0.194 and the coefficient of variation (SDD/mean x
      100) was 1.95% upon cross validation. For cheeses without a well-established
      theoretical cheese yield equation, the measured dry weight yields could be
      directly correlated to the observed yields in the factory; this would more
      accurately reflect the expected yield performance. Payments for milk based on
      these measurements would more accurately reflect quality and composition of the
      milk and the actual average recovery of fat and casein achieved under practical
      cheese making conditions.

PMID- 12416826
TI  - Cliometric metatheory: II. Criteria scientists use in theory appraisal and why it
      is rational to do so.
AB  - Definitive tests of theories are often impossible in the life sciences because
      auxiliary assumptions are problematic. In the appraisal of competing theories,
      history of science shows that scientists use various theory characteristics such
      as aspects of parsimony, the number, qualitative diversity, novelty, and
      numerical precision of facts derived, number of misderived facts, and
      reducibility relations to other accepted theories. Statistical arguments are
      offered to show why, given minimal assumptions about the world and the mind, many
      of these attributes are expectable correlates of verisimilitude. A statistical
      composite of these attributes could provide an actuarial basis for theory
      appraisal (cliometric metatheory).

PMID- 12416827
TI  - Response to Mowrer and McCarver's paper on multicultural perspective and life
      satisfaction.
AB  - It is argued that the article by Mowrer and McCarver (2002) misrepresents
      Ramirez's work by making assumptions based on an incomplete definition of
      multicultural identity and by inferring that multicultural psychotherapy can
      serve as a cure-all for psychopathology. It is shown that the authors did not
      test Ramirez's model, but instead merely used his conceptual framework to develop
      and test their own measure of multicultural perspective.

PMID- 12416828
TI  - Liking of personal names, self-esteem, and the Big Five Inventory.
AB  - 76 university students responded to the Big Five Inventory, the Coopersmith Self
      esteem Inventory, and rated how much they liked their first and middle names.
      Self-esteem positively correlated with scores on Agreeableness,
      Conscientiousness, and Extraversion and negatively with Neuroticism. Liking of
      one's first name correlated positively with scores on Conscientiousness only.

PMID- 12416829
TI  - Methodological diversity of research published in selected psychological journals
      in 1999.
AB  - 454 papers appearing in 10 journals published by the American Psychological
      Association during 1999 were reviewed to consider the frequency of publication of
      qualitative research. Journals reviewed included Health Psychology, Journal of
      Abnormal Psychology, Journal of Consulting and Clinical Psychology, Journal of
      Counseling Psychology, Journal of Educational Psychology, Journal of Experimental
      Psychology: General, Journal of Family Psychology, Professional Psychology:
      Research and Practice, Psychological Assessment, and Psychology and Aging. Papers
      were classified as quantitative, qualitative, or mixed qualitative/quantitative
      studies. Quantitative papers were also dichotomously classified as either
      primarily descriptive or experimental. Qualitative studies were classified by
      type of qualitative methods specified by the authors. Most papers (97.6.%) were
      classified as quantitative. Only three journals reviewed published qualitative
      studies.

PMID- 12416830
TI  - A pattern of common acoustic modification by human mothers to gain attention of a
      child and by macaques of others in their group.
AB  - Criticisms of how Niwano and Sugai (2002) conducted their analysis of pitch
      change in human mothers' repeated utterances to their children suggest mothers
      resort to utterance with elevated pitch when infants are initially unresponsive.
      When this phenomenon is compared with an evaluation of similar data for free
      ranging macaques, a certain common pattern of human mothers and the macaques may
      be observed in seeking to gain the attention of another.

PMID- 12416831
TI  - Accurate and false recall in the Deese/Roediger and McDermott procedure: a
      methodological note on sex of participant.
AB  - Research suggests that individuals may differ in their susceptibility to false
      memory in the Deese/Roediger and McDermott procedure. Prior studies of
      differences have focused on the effects of age, personality, personal past
      history of abuse, and neurological status on false memory susceptibility. This
      study examined whether sex might also differentially influence false memory.
      After listening to a series of word lists designed to elicit false recall of
      nonstudied associates, 50 male and 50 female college students free recalled the
      lists. Analysis showed no sex difference in accurate recall, false recall, or
      unrelated intrusions. A robust false memory effect was observed, but sex did not
      differentiate performance.

PMID- 12416832
TI  - Parental rearing behaviors and worry of normal adolescents.
AB  - Associations between scores on scales of perceived parental rearing behaviors and
      worry were examined for 220 adolescents. Analysis showed that anxious rearing and
      overprotection of both mother and father were significantly related to worry.

PMID- 12416833
TI  - Unrealistic optimism and perceived control: role of personal competence.
AB  - This work analyzed the effects of unrealistic optimism in the interaction between
      the emotional valence of future events, the perception of control over these
      events, and the person with whom one compares oneself. It was hypothesized that,
      if the person of comparison is judged as very competent, a pessimistic bias
      should be produced. Likelihood of four different types of events (positive and
      controllable, positive and uncontrollable, negative and controllable, and
      negative and uncontrollable) were rated by 133 university students (22 men and
      111 women) for themselves, for an average student, for their best friend, and for
      a bright friend. A pessimistic bias was observed on the relative likelihood of
      the events when the comparison was made between oneself and a competent and
      bright friend, when events were perceived as controllable, especially positive
      ones. Not enough is known, however, to provide meaningful interpretation at
      present; that must await further data and theoretical development.

PMID- 12416834
TI  - Self-defeating personality and memories of parents' child-rearing behaviour.
AB  - A group of 132 nonclinical volunteers was given the Self-defeating Personality
      Scale and a short version of the Egna Minnen Betraffande Uppfostran (EMBU) scale
      to explore correlations of scores for adults' self-defeating traits with memories
      of parents' child-rearing behaviours. For men, the recall of two rejecting
      parents and, for women, the memory of a nonsupportive father were significantly
      correlated with scores of self-defeating traits. The latter scores correlated
      positively with memories of both overinvolved mother and father for men, while no
      significant correlation was found among women.

PMID- 12416835
TI  - Psychometric properties of the Behavior and Symptom Identification Scale
      administered in a crisis residential mental health treatment setting.
AB  - The psychometric properties of the Behavior and Symptom Identification Scale,
      administered in a crisis residential mental health treatment setting, were
      investigated. Analyses indicated that Cronbach alpha reliabilities were very good
      compared to published research from inpatient and outpatient settings. Univariate
      and multivariate covariance analyses provided evidence supporting validity in
      terms of sensitivity to change during treatment and concurrent validity. Evidence
      supported the contention that women were more honest and realistic in their self
      assessments but also that crisis residence treatment was efficacious for both
      sexes.

PMID- 12416836
TI  - Beneficial and adverse effects of pets.
AB  - The beneficial and adverse effects of pets on people with special mental and
      physical conditions merit inclusion in psychological evaluations and treatments.

PMID- 12416837
TI  - Optimistic bias and pessimistic realism in judgments of contingency with aversive
      or rewarding outcomes.
AB  - A depressive personality influences judgments of contingency. This is called
      "depressive realism." The present experiment examined whether optimistic traits,
      as measured by various scales, are correlated with judgments of contingency. The
      valences of the target stimuli were aversive or rewarding (noise avoidance or
      gaining points). Analysis indicated that the optimistic subjects (as measured by
      explanatory style for negative events) tend to overestimate noncontingent events;
      however, optimism measured by other scales did not show such an effect. The
      findings are discussed in terms of a self-defensive attributional bias.

PMID- 12416838
TI  - Factor analysis of Furnham's Money Attitude Scale.
AB  - This paper offers a critique of Yang and Lester's analysis of Furnham's Money
      Attitude Scale.

PMID- 12416839
TI  - Initial internal reliability and descriptive statistics for a brief assessment
      tool for the Life Skills Training drug-abuse prevention program.
AB  - Adolescent drug use in the United States remains the highest in the
      industrialized world. Fortunately there have been significant advances in
      developing effective prevention programs for adolescent drug use. An important
      issue in evaluating such programs is that the self-report surveys have adequate
      psychometric properties and assess constructs targeted by an intervention. A
      questionnaire focusing on knowledge and drug-related measures was developed to
      evaluate the research-based Life Skills Training drug prevention intervention.
      The questionnaire showed good internal reliability, detected change from pretest
      to posttest, and was brief and easy to complete by 45 middle-school students.

PMID- 12416840
TI  - Parental and sibling effects in adolescent outcomes.
AB  - This study examined the differential effects of parenting and sibling influences
      (and the interaction between the two) in predicting adolescents' problem
      behaviors. The reliability and validity of the Sibling Relationship Questionnaire
      was also assessed. Subjects were 99 intact families from the San Francisco Bay
      area, all of whom contained both parents and at least one target child between 10
      and 18 years of age still living in the home. Analysis indicated that sibling
      behavior was a significant predictor of deviant behavior, as measured by the
      Child Behavior Checklist, even when parenting effects were statistically
      controlled. Parenting effects had a separate effect on adolescents' positive
      behaviors. The analysis of the Sibling Relationship Questionnaire indicated
      adequate test-retest and internal consistency reliability, and construct
      validity. Findings are discussed in terms of the larger literature on
      socialization on the different ways that siblings and parents influence
      adolescent outcomes.

PMID- 12416841
TI  - Evaluating the AWARE Inventory as a measure of relationship factors among a
      sample of high school students.
AB  - The Awareness of Attitudes and Relationship Expectations (AWARE) Inventory was
      administered to 160 high school students in Wyoming. Factor analysis showed the
      inventory did not have the expected 11 dimensional factor structure. Most of the
      intended 10-item scales yielded unacceptably low estimates of internal
      consistency reliability. Through an iterative process, one internally consistent
      scale of 17 items (alpha = .80) was derived. Researchers should be careful to
      evaluate the AWARE Inventory with their own samples before proceeding under an
      assumption that its scales reliably assess the 11 dimensions expected.

PMID- 12416843
TI  - Bulimic symptomatology, body-image, and personality characteristics of university
      men.
AB  - This study examined the relationships, using regression analysis, among bulimic
      symptomatology, body-image characteristics, and personality factors in a
      nonclinical sample of 46 undergraduate university men. They completed the Bulimia
      Test-Revised (a measure of bulimic symptomatology), the Eysenck Personality
      Questionnaire-Revised (a measure of personality characteristics), and the
      Multidimensional Body-Self Relations Questionnaire (a multidimensional measure of
      body-image parameters). Statistically significant relationships were identified
      among Appearance Evaluation, Neuroticism, and Psychoticism, and the BULIT-R
      scores.

PMID- 12416842
TI  - Physically active students' intentions and self-efficacy towards healthy eating.
AB  - This study investigated intentions and self-efficacy of physically active
      university students towards healthy eating. The application of Planned Behavior
      theory has shown that attitudes, intention, perceived behavioral control, and
      subjective norms play an important role in shaping people's behavior. 96
      students, who participated in physical activities, voluntarily completed the
      Questionnaire for the Planned Behavior Model and the Health Behavior
      Questionnaire. The former examines attitudes, intentions, perceived behavioral
      control, and the lately added attitude strength, and role identity towards the
      behavior factors. The latter assesses one's efficacy expectations towards healthy
      eating. The regression showed strong associations between the examined variables,
      signifying that attitudes, perceived behavioral control, and role identity could
      account for one's intention towards healthy eating behaviors. On the other hand,
      one's self-efficacy for healthy eating could be explained from the attitudes,
      intention, perceived behavioral control, and attitude strength held. Overall,
      systematic participation in physical activities appeared to be accompanied with a
      relatively healthier diet, while self-efficacy had a significant association with
      maintaining the healthy eating behaviors. Possible interpretations, limitations,
      and implications for health professionals are discussed.

PMID- 12416844
TI  - Factorial validity and internal reliability of Honey and Mumford's Learning
      Styles Questionnaire.
AB  - Honey and Mumford's Learning Styles Questionnaire was derived from the same
      conceptual basis as Kolb's Learning Style Inventory and may provide a more
      reliable and valid measure of Kolb's learning style constructs. The Learning
      Styles Questionnaire has not been psychometrically evaluated as extensively as
      the Learning Style Inventory. Since there is no published information on how the
      Learning Styles Questionnaire scales were derived, an attempt was made to factor
      analyze the responses to the questionnaire. Confirmatory factor analysis of 284
      psychology undergraduates' responses identified a four-factor oblimin solution as
      the most satisfactory model investigated. Implications for interpretation and use
      within higher education are discussed.

PMID- 12416845
TI  - An exploratory study of different types of violence presented in early Christian
      and Islamic historical documents.
AB  - Source documents for Islam and Christianity were analyzed for violent themes. The
      two religions both condemned criminal violence, and neither supported random
      violence. Nonviolence was more common in the Christian sources while active
      violence was much more common in the Islamic documents. Although violence themes
      are a very small proportion of the content of the documents of either religion,
      those who seek to justify active violence against perceived enemies may find more
      support for their actions in early Islamic sources than in early Christian
      sources. Results are interpreted from a perspective of symbolic interaction.

PMID- 12416846
TI  - Subjective well-being and dental treatment in elderly African Americans.
AB  - This preliminary study examined the effect of dental treatment on psychological
      well-being in a sample of elderly African Americans (64 women, 43 men) seeking
      routine care at an urban medical/dental clinic. Scores on two scales, the Index
      of Self-esteem and the Generalized Contentment Scale, self-administered at
      initial and final dental appointments, yielded no significant differences between
      times of test. Dental treatment apparently was not associated in this sample with
      perceived psychological well-being.

PMID- 12416847
TI  - Selective exposure and dissonance after decisions.
AB  - Well-known literature reviews from the 1960s question whether cognitive
      dissonance underlies experimental participants' selective exposure of themselves
      to consonant messages and avoidance of dissonant ones. A meta-analytic review of
      16 studies published from 1956 to 1996 and involving 1,922 total participants
      shows that experimental tests consistently support the supposition that
      dissonance is associated with selective exposure (r = .22, p < .001). Statistical
      power exceeded .99. Advances in statistical methodology and increased attention
      to selecting appropriate tests of dissonance theory were essential to finally
      resolving this question.

PMID- 12416848
TI  - Effects of sex of judge and sex of victim on recommended punishment of a male
      murderer in a mock scenario.
AB  - Two samples of undergraduates (36 women, 7 men; 44 women, 45 men) read a mock
      transcript in which a murderer's victim was a man or a woman, after which they
      made prison sentence and death penalty judgments. Female judges gave longer
      sentences for the female victim than for the male victim, whereas male judges
      gave longer sentences for the male victim than for the female victim. This same
      sex bias suggests that extralegal factors can affect judgments about sentencing.

PMID- 12416849
TI  - Sex differences in communication with close friends: testing Tannen's claims.
AB  - In 1990 Tannen reported that men have fewer close friends than women, men discuss
      less intimate topics with their friends than women, and men and women respond
      differently to close friends' problems. 168 students completed a three-page
      survey designed to examine Tannen's claims. Consistent with Tannen's
      observations, men discussed less intimate topics (politics and school or work)
      with their five closest friends and reportedly were less likely to comfort or
      listen to their friends' problems than women were. Inconsistent with Tannen's
      statements, these women and men did not differ in the number of close friends
      they reported having or in the likelihood of offering advice when presented with
      a friend's problem. Present self-reports corroborate other researchers who
      questioned Tannen's findings and concluded that sex differences in interpersonal
      communication are small.

PMID- 12416850
TI  - Holocaust survivors in a primary care setting: fifty years later.
AB  - Past studies have not assessed the prevalence of emotional disturbances in
      Holocaust survivors seeking medical treatment in a family practice environment.
      The present study examined the prevalence of lifetime (the presence of
      symptomatology at any time) and current posttraumatic stress disorder (PTSD)
      symptoms, general anxiety, and depression in Holocaust survivors seeking medical
      treatment in a primary care setting. 20 of the 27 Holocaust survivors in our
      sample received a current diagnosis of PTSD and reported significant symptoms of
      depression and general anxiety. Although 74% of the survivors were currently
      diagnosed with PTSD, participants in this study had reported an overall decline
      in reexperiencing, hyperarousal, and overall PTSD symptoms but exhibited
      increased avoidance and numbing symptoms throughout the lifespan. These
      preliminary results suggest that removing avoidance as a defense mechanism during
      the course of psychotherapy may leave these survivors without an adequate way for
      coping with their trauma, subsequently increasing their vulnerability to
      psychopathology. Implications for psychological interventions are provided.

PMID- 12416851
TI  - Variations in a university subject pool as a function of earlier or later
      participation and self-report: a replication and extension.
AB  - The present study replicated and extended earlier research on temporal sampling
      effects in university subject pools. Data were obtained from 236 participants, 79
      men and 157 women, in a university subject pool during a 15-wk. semester. Without
      knowing the purpose of the study, participants self-selected to participate
      earlier (Weeks 4 and 5; n = 105) or later (Weeks 14 and 15; n = 131). Three
      hypotheses were investigated: (1) that the personality patterns of earlier and
      later participants on the NEO Personality Inventory-Revised and the Personality
      Research Form differ significantly, with earlier participants scoring higher on
      the latter scales reflecting social responsibility and higher on former
      Conscientiousness and Neuroticism scales; (2) that there are similar significant
      differences between participants in the earlier and later groups compared to the
      male and female college normative samples for the two tests: and (3) that earlier
      participants will have higher actual Scholastic Assessment Test scores and Grade
      Point Averages. Also investigated was whether participants' foreknowledge that
      their actual Scholastic Assessment Test scores and Grade Point Averages would be
      obtained would affect their accuracy of self-report. In contrast to prior
      research, neither the first nor second hypothesis was supported by the current
      study; there do not appear to be consistent differences on personality variables.
      However, the third hypothesis was supported. Earlier participants had higher
      actual high school Grade Point Average, college Grade Point Average, and
      Scholastic Assessment Test Verbal scores. Foreknowledge that actual Scholastic
      Assessment Test scores and Grade Point Averages would be obtained did not affect
      the accuracy of self-report. In addition, later participants significantly over
      reported their scores, and significantly more women than men and more first-year
      than senior-year subjects participated in the early group.

PMID- 12416852
TI  - The Gordon Diagnostic System and WISC-III Freedom from Distractibility Index:
      validity in identifying clinic-referred children with and without ADHD.
AB  - Gordon Diagnostic System and WISC-III scores for clinic-referred 6- to 16-yr.
      olds (184 with ADHD Combined Type and 46 without ADHD) were analyzed to evaluate
      the combination of scores and cutpoints that maximized diagnostic accuracy. Using
      an "ADHD cutpoint" of IQ minus the GDS Composite score > or = 13, 87.8% of the
      children were correctly identified as having or not having ADHD. IQ minus Freedom
      from Distractibility > 0 yielded 73.5% accuracy. When the two meaures were
      combined to create new criteria (IQ minus GDS Composite > or = 13 or IQ minus
      Freedom from Distractibility > or = 11), diagnostic accuracy increased to 90.9%
      and negative predictive power improved substantially. Diagnostic agreement
      between the Gordon Diagnostic System and Freedom from Distractibility was 70%,
      suggesting that the two tests measure both similar and unique traits.

PMID- 12416853
TI  - Symptoms of anxiety disorders and teacher-reported school functioning of normal
      children.
AB  - Correlations between scores on the Spence Children's Anxiety Scale, a
      questionnaire for measuring symptoms of anxiety disorders and a report of school
      functioning by teachers were computed for 317 primary school children and 13
      teachers in The Netherlands. Analysis showed a small but significant negative
      correlation between scores for total anxiety and school functioning (r = -.20, p
      < .001). The finding is consistent with the notion that high symptoms indicating
      anxiety disorders in children are accompanied by less optimal functioning in
      school.

PMID- 12416854
TI  - Factor structure of the Preschool Personality Questionnaire in Iran.
AB  - This study is of Triandis's pseudoetic variety, not a cross-cultural study per
      se. The Preschool Personality Questionnaire which was standardized in the SA and
      partially standardized in Colombia was administered to 600 preschool children in
      Iran. Data from the entire sample were analyzed by both principal components,
      maximum likelihood, and alpha factor analyses. 14 factors were derived. Odd and
      even records were likewise factored. Six of the first seven factors were found
      and matched from odd to even cases. At least five of the total sample factors
      were judged by inspection to match similar dimensions in the USA. Factor scores
      for children in the standardizing sample were created by postmultiplying the raw
      score matrix by the 14-factor "reduced" factor structure matrix. These raw factor
      scores were then converted to STEN scores. Utilizing the entire sample factor
      structure matrix, factor scores and sten scores were derived for each of the 4-,
      5-, and 6-yr.-old groups. By use of the norms based on this sample of Iranian
      children, further experiments can be carried out to investigate development of
      preschool children and other variables in Iran similar to those studied in the
      West.

PMID- 12416855
TI  - Note on the relationships among job satisfaction, organizational commitment, and
      organizational citizenship behavior.
AB  - Previous research which has established a relationship between organizational
      citizenship behavior and job satisfaction has involved primarily white collar
      workers. This study extends the prior research to a different sample--blue collar
      workers--and investigates the relations of organizational citizenship behavior to
      the various facets of job satisfaction as measured by the Job Descriptive Index.
      We also examine the relative effects of organizational commitment and job
      satisfaction on citizenship behaviors. Analysis of responses from a sample of 91
      machine operators employed by a clothing manufacturer in the southeastern United
      States indicates that citizenship behaviors of blue collar workers are related to
      satisfaction with coworkers, satisfaction with supervision, and satisfaction with
      pay, but not satisfaction with opportunities for advancement, satisfaction with
      the work itself, or organizational commitment.

PMID- 12416856
TI  - Relations of intrinsic spirituality with health status and symptom interference.
AB  - The purpose of this study was to examine the relationships between spiritual
      experience and current health status and between spiritual experience and
      subjective experience of symptom interference. Symptom interference is the extent
      to which symptoms of physical or psychological illness limited participants'
      activities of daily living. Participants were 49 volunteers who were enrolled in
      a spiritual fitness class at a variety of denominational Christian churches in
      Plano, Texas. The sample ranged in age from 22 to 65 years, and 84% were women.
      The Index of Core Spiritual Experiences and the Medical Symptoms Checklist were
      administered. Current health status and symptom interference were utilized from
      the self-report checklist. It was predicted that Index scores would be
      significantly different based on participants' health status and that Index
      scores would correlate significantly with participants' ratings of symptom
      interference. Analysis indicated that Index scores were significantly higher (p =
      .02) for participants with no current medical diagnosis than for those currently
      experiencing either a life-threatening or a chronic medical or psychological
      disorder. Also, the percentage-bend correlation between Index scores and scores
      for interference of symptoms in daily life was significant ((r)Pb = -.33, p =
      .02). These results suggest that the report of core spiritual experiences may be
      related to better current health status. These findings have implications for
      understanding the role of spirituality in the prevention of illness and in an
      individual's ability to cope with illness.

PMID- 12416857
TI  - Measurement of attitudes toward obese people among a Canadian sample of men and
      women.
AB  - A new scale for examining attitudes toward obese people had 44 items selected
      from previously published scales designed to indicate attitudes toward obese
      people. Reliability analysis yielded a Cronbach coefficient alpha of .92 for the
      total sample. A factor analysis yielded four factors. Employing the Body Mass
      Index as an indicator of obesity, the attitudes of 239 men and women were
      examined. Women were significantly more positive than men in their attitude
      toward obese people. When examining Body Mass Index as a factor, comparisons of
      obese and nonobese women indicated obese women were more positive on the Diet and
      Exercise factor of the scale. Suggestions for improvement and research are
      offered.

PMID- 12416858
TI  - Sex and racial differences in preference for a caring morality in a corporate
      environment that promotes diversity and equal opportunity.
AB  - This study investigated the caring moral perspective of managers in a corporation
      recognized as being a champion of promoting diversity and equal opportunity.
      Caring is described as a morality of responsibility and relationship, a
      sensitivity to the needs of persons. The study was based on the prediction that
      the attachment and caring shown elsewhere to be characteristic of the morality of
      females would be characteristic of all managers, regardless of sex or race in
      this kind of corporate environment. 121 male and female, African-American and
      Euro-American managers responded to a survey using three subscales of a Caring
      Morality Inventory: caring orientation, use of intuition and feeling to make a
      judgment, and concern with others in decision-making. Analysis showed female
      managers, regardless of race, scored significantly higher on the Caring Morality
      scale than the male managers, supporting other findings of sex differences in
      caring moral perspective and suggesting that working for a company actively
      promoting diversity and equal opportunity does not cancel out these differences.
      In addition, for this study it was assumed that, although African Americans, in
      general, may have been sensitized to lean more toward a caring morality, any
      racial differences in caring morality would be cancelled out by the fact that all
      of the managers work for the same prodiversity and, by assumption, more sensitive
      company. The Euro-American managers, regardless of sex, actually scored higher on
      the Caring Morality scale than did the African-American managers, with the
      difference being attributable solely to the greater tendency of the Euro-American
      managers to use intuition and feeling to make a judgment.

PMID- 12416859
TI  - Correlates of age-adjusted national homicide rates.
AB  - In 1980, the correlates of unadjusted and age-adjusted national homicide rates
      differed, so the age-structure of nations should be controlled for in cross
      national studies.

PMID- 12416860
TI  - Team Climate Inventory with a merged organization.
AB  - The present study examines the team climate for innovation in work teams within a
      newly merged organization. Four teams working at a regional head office of a
      Social Insurance organization answered the Team Climate Inventory. The results
      were compared to those of a study by Agrell and Gustafson of more stable teams.
      The comparison showed that participative safety and support for innovation were
      rated lower and that vision was rated higher in the newly merged teams. The 38
      item original inventory was used and based on the results, a 1999 proposed
      shortened version of 14 items by Kivimaki and Elovainio was compared with the
      original one. Analysis indicated that the short version can be a valid
      alternative to the original version but that further testing of the short version
      is needed.

PMID- 12416861
TI  - Developing a Short Affect Intensity Scale.
AB  - The purpose of this study was to construct a brief version of the 40-item Affect
      Intensity Measure. Since the assumed one-dimensionality of the scale has been
      criticized lately, special attention was paid to the factor structure of the full
      and the brief scales. The scales were tested in three different samples: 510
      Belgian citizens representative of the Belgian population, and 204 and 166
      students of the University of Antwerp. The Short Affect Intensity Scale has 20
      items. Mean scores on the original Affect Intensity Measure were 3.68, 3.67, and
      3.67 for the three samples, respectively, while for the Short Affect Intensity
      Scale the following respective mean scores were registered: 3.76, 3.78, and 3.75.
      Correlations between the original and brief scales were .94, .93, and .93 for the
      three samples, respectively. Three factors underlie the Short Affect Intensity
      Scale: Positive Intensity, Negative Affectivity, and Serenity. Furthermore, the
      scores for the Short Affect Intensity Scale suggest it is reliable and valid.

PMID- 12416862
TI  - Homosexual partnerships and homosexual longevity: a replication.
AB  - Replicating previous findings that homosexuals are underrepresented after middle
      age, the 1996 National Household Survey of Drug Abuse (N = 12,381) and 2000
      Kaiser Family Foundation 15-city survey (N = 405) reported that homosexual men
      and women are seldom aged 50+ yr. and that older homosexuals are more apt to have
      a homosexual partner. Deaths of 228 homosexuals as recorded in the Washington
      Blade 1999-2001 were examined. Although more apt to have a partner when older,
      the median age of death of 88 homosexually partnered men was 45 yr., while for
      118 unpartnered homosexual men it was 46 yr. This is consistent with the
      suggestion that homosexual partnering may be an additional hazard to men.

PMID- 12416863
TI  - Ego function assessment of nonclinical individuals.
AB  - Ego Function Assessment was adapted into a self-report inventory yielding 12
      operationalized function measures. 426 respondents from a stratified sample
      completed the inventory. In addition, 42 respondents completed the inventory
      twice within a 20-day period. A hierarchical algorithm was used to revise the 12
      scales to maximize internal consistencies. Their stabilities were assessed by
      analyzing the retest scores. Standardization, reliability, and stability data are
      presented for the original and revised scales. Results show adequate reliability,
      suggesting that the tool may be useful to measure ego functioning in nonclinical
      populations.

PMID- 12416864
TI  - The arterial supply to the eye of the bactrian camel (Camelus bactrianus).
AB  - The arterial supply to the eye of the bactrian camel (Camelus bactrianus) was
      studied by gross dissection. The supply came from the external ophthalmic,
      external ethmoidal and malar and maxillary tubercular arteries, ophthalmic rete
      mirabile, and the rostral epidural rete mirabile. The external ophthalmic artery
      gave rise to branches to supply the dorsal oblique muscle, lacrimal gland,
      superior and inferior eyelids, and the lateral angle of the eye, and to take part
      in the formation of the rostral epidural rete and the ophthalmic rete mirabile.
      The external ethmoidal artery detached off some branches to supply the ventral
      and medial dorsal rectus oblique muscles, the conjunctiva of the superior eyelid
      and the fat body of the orbit. The branches of the malar artery supplied the
      inferior, superior and third eyelids, ventral oblique muscle, and the medial
      angle of the eye. The ophthalmic rete mirabile gave off many branches to supply
      the rectus muscles of the eye, dorsal oblique and retractor oculi muscles,
      levator muscle of the superior eyelid, and the choroid.

PMID- 12416865
TI  - Comparative analysis of the outer membrane protein profiles of isolates of the
      Pasteurella multocida (B:2) associated with haemorrhagic septicaemia.
AB  - Outer membrane proteins (OMP) of P. multocida (serotype B:2) field isolates (n =
      6) and a vaccine strain (P-52) were extracted by a sarkosyl method and
      characterized using SDS-PAGE and immunoblotting. About 20 polypeptide bands were
      observed in the profile of the vaccine strain with MW ranging from 16 to 90 kDa
      and, based on band thickness and intensity of staining, three polypeptides of MW
      31, 33 and 37 kDa were considered to be the major OMPs. The profiles of the field
      isolates showed minor differences when compared with that of the vaccine strain.
      The OMP of 33 kDa was only expressed by the vaccine strain. Four field isolates
      expressed an OMP of 39 kDa, which did not appear in the profiles of the remaining
      two field isolates and the P-52 strain. Similarly, an OMP of 25 kDa was
      exclusively seen in the profile of a single isolate. By immunoblotting studies,
      using anti-P. multocida (P-52) whole-cell hyperimmune serum raised in rabbits as
      well as buffalo immune sera, it became evident that the polypeptide of 37 kDa was
      the most antigenic OMP in the profiles of all the isolates, including the P-52
      strain. Other polypeptides were either weakly antigenic or visible in the profile
      of only a few of the isolates. The study thus identified the major OMP of P.
      multocida (B:2) and suggested that this highly antigenic 37 kDa OMP has potential
      for further protective and immunodiagnostic studies.

PMID- 12416866
TI  - Apparent seroprevalence of Salmonella spp. in harp seals in the Greenland Sea as
      determined by enzyme-linked immunosorbent assay.
AB  - An indirect ELISA was developed as a possible tool for surveillance of the
      seroprevalence of Salmonella spp. in harp seals. This species is hunted for human
      consumption and thus transmission of disease to humans cannot be excluded. To
      cover a broad spectrum of serogroups, a mixture of the lipopolysaccharides (LPS)
      of S. typhimurium and S. choleraesuis was used as the antigen in this pilot
      study. Chicken anti-harp-seal immunoglobulin horseradish peroxidase conjugate
      served as the immunoconjugate. Sera from four captive harp seals, which were
      Salmonella culture-negative and had no clinical or historical evidence of
      salmonellosis, were used as negative controls. After immunization with an
      inactivated S. typhimurium vaccine, further sera from these seals were used as
      positive controls, as no serum from naturally infected animals was available.
      Serum samples from 93 harp seals caught in the Greenland sea in 1999 were
      examined, and anti-Salmonella antibodies were found in the samples from two
      individuals (seroprevalence 2.2%). Although Salmonella has been isolated from
      other pinniped species, this is the first documentation of Salmonella
      seropositive harp seals. This study contributes to the evaluation of the
      importance of salmonellosis in arctic marine mammals and thus to the prevention
      of potential outbreaks of this important zoonosis.

PMID- 12416867
TI  - Serum fructosamine concentrations in dogs with hypothyroidism.
AB  - Serum fructosamine concentrations were measured in 11 untreated hypothyroid dogs
      with normal serum glucose and serum protein concentrations. The fructosamine
      level ranged between 276 and 441 micromol/L (median 376 micromol/L; reference
      range 207-340 micromol/L). Nine of the 11 dogs had fructosamine levels above the
      reference range. The fructosamine levels decreased significantly during treatment
      with levothyroxine. It is suggested that serum fructosamine concentrations may be
      high in hypothyroid dogs because of decelerated protein turnover, independent of
      the blood glucose concentration.

PMID- 12416868
TI  - Detection of antibodies against peste des petits ruminants virus in sera of
      cattle, camels, sheep and goats in Sudan.
AB  - Detection of antibodies against peste des petits ruminants virus in sera of
      cattle, camels, sheep and goats in Sudan.

PMID- 12416869
TI  - Effects of three anthelmintic treatment regimes against Fasciola and nematodes on
      the performance of ewes and lambs on pasture in the highlands of Kenya.
AB  - The efficacy of strategic anthelmintic control of liver flukes (Fasciola) and
      gastrointestinal (GI) nematodes on the performance of ewes and lambs on pasture
      was assessed on a farm in the highlands of Kenya. In May 1999, 45 Corriedale
      ewes, aged between 2 and 3 years, were ear-tagged, weighed and allocated randomly
      to three equal treatment groups based on body weight. Faecal samples taken at
      this time revealed low levels of strongyle-type eggs per gram of faeces (EPG) and
      the presence of liver fluke eggs in only a few of the animals. All the animals
      were then set stocked for 12 months on separate paddocks in an area endemic for
      both Fasciola and GI nematodes. The ewes in group 1 were given a combined
      anthelmintic treatment against Fasciola and GI nematodes during the periods
      recommended for the control of Fasciola in the area (February, June and October).
      The ewes in group 2 were given the combined treatments 3 weeks after the onset of
      both the short and long rainy seasons (November and April, respectively). Those
      in group 3 were given separate treatments for Fasciola (February, June and
      October) and nematodes (3 weeks after the onset of the rainy seasons). The
      anthelmintic treatment against Fasciola consisted of triclabendazole at 10 mg per
      kg body weight, and that against nematodes was levamisole at 10 mg per kg body
      weight. The nematode EPG for the ewes in group 1 were higher than in groups 2 and
      3 during both rainy seasons. The nematode EPG did not differ significantly
      between groups 2 and 3. The prevalence of Fasciola eggs (number of ewes shedding
      eggs in a group) in the ewes in groups I and 3 remained very low throughout the
      study period compared to those in group 2. The highest birth weights and the
      weight gains of lambs were recorded for the group of ewes given separate
      anthelmintic treatments for Fasciola and nematodes (group 3). The results of this
      trial indicated that, in an area like Nyandarua District, where liver flukes and
      GI nematodes are important constraints to sheep production, the best practice is
      to give separate treatments for the two groups of parasites at the recommended
      times.

PMID- 12416870
TI  - Some pharmacokinetic parameters of pefloxacin in lactating goats.
AB  - The aim of this study was to elucidate some of the pharmacokinetic parameters of
      pefloxacin in lactating goats (n = 5) following intravenous (i.v.) or
      intramuscular (i.m.) injections of 10 mg/kg bw. Serially obtained serum, milk and
      urine samples were collected at precise time intervals, and the drug
      concentrations were assayed using a microbiological assay. A two-compartment open
      model best described the decrease of pefloxacin concentration in the serum after
      intravenous administration. The maximum serum concentration (C0(p)) was 8.4 +/-
      0.48 microg/ml; elimination half-life (t 1/2 beta) was 1.6 +/- 0.3 h; total body
      clearance (Cl(tot) was 3.6 +/- 0.3 L/kg/h; steady-state volume of distribution
      (V(dss)) was 5.14 +/- 0.21 L/kg; and the area under the curve (AUC) was 2.78 +/-
      0.22 microg.ml/h. Pefloxacin was absorbed rapidly after i.m. injection with an
      absorption half-life (t 1/2 ab) of 0.32 +/- 0.02 h. The peak serum concentration
      (Cmax) of 0.86 +/- 0.08 microg/ml was attained at 0.75 h (Tmax). The absolute
      bioavailability after i.m. administration was 70.63 +/- 1.13% and the serum
      protein-bound fraction ranged from 7.2% to 14.3%, with an average value of 9.8 +/
      1.6%. Penetration of pefloxacin from the blood into the milk was rapid and
      extensive, and the pefloxacin concentration in milk exceeded that in serum from 1
      h after administration. The drug was detected in milk and urine for 10 and 72 h,
      respectively; no samples were taken after 72 h.

PMID- 12416871
TI  - Pharmacokinetic disposition of subcutaneously administered enrofloxacin in goats.
AB  - The pharmacokinetic disposition of enrofloxacin was studied in goats after
      subcutaneous (s.c.) administration at a single dose of 7.5 mg/kg body weight.
      Blood samples were drawn from a jugular vein into heparinized tubes at
      predetermined time intervals after administration of the drug and the plasma was
      separated by centrifugation. The concentrations of enrofloxacin in the plasma
      were determined by a microbiological assay using Escherichia coli as the test
      organism. The plasma concentration-time data were analysed by non-compartmental
      methods. Enrofloxacin was rapidly absorbed, an appreciable concentration of the
      drug (0.30 +/- 0.13 microg/ml) being present in the plasma by 5 min after s.c.
      administration. The maximum plasma concentration of enrofloxacin and the time to
      reach that maximum were 2.91 +/- 0.39 microg/ml and 2.9 +/- 0.51 h. respectively.
      A detectable concentration of enrofloxacin persisted in the plasma for 12 h. The
      elimination half-life and mean residence time of enrofloxacin were 2.84 +/- 0.57
      and 5.74 +/- 0.28 h, respectively. It is suggested that enrofloxacin given
      subcutaneously may be useful in the treatment of susceptible bacterial infections
      in goats.

PMID- 12416872
TI  - The concentrations of LH, FSH, oestradiol-17beta and progesterone in the blood
      plasma of the female Bactrian camel (Camelus bactrianus) before and after
      intramuscular injection of seminal plasma.
AB  - The concentrations of LH, FSH, oestradiol-17beta and progesterone in the blood
      plasma of the female Bactrian camel (Camelus bactrianus) before and after
      intramuscular injection of seminal plasma.

PMID- 12416873
TI  - The use of PCR combined with restriction enzyme analysis to characterize fowl
      adenovirus field isolates from northern India.
AB  - Ten fowl adenoviruses (FAVs), isolated from suspected cases of inclusion body
      hepatitis (IBH) in quails and broilers, were characterized by a hexon-based
      polymerase chain reaction (PCR) combined with restriction enzyme analysis (REA)
      of the amplified DNA fragments. All the isolates could be detected using H1/H2
      and H3/H4 primer sets. Amplification of DNA with H1/H2 and H3/H4 primer sets
      resulted in fragments of approximately 1219 bp and 1319 bp, respectively. HaeII
      digestion of the H1/ H2 PCR products and HpaII digestion of the H3/H4 PCR
      products characterized all the isolates in FAV groups, known from genomic typing
      using the whole DNA. For some of the isolates, neutralization tests were used to
      confirm these results. The results revealed that, as well as FAV serotype 1,
      which is the sole member of DNA group A, FAVs of DNA group E are also associated
      with IBH in poultry in northern India. The FAV specific PCR combined with REA was
      found to be very useful in investigating the epidemiological situation in the
      field. It was even possible to define mixed infections with more than one FAV.

PMID- 12416874
TI  - Gas chromatographic methods for oil analysis.
AB  - In the past 50 years. gas chromatography (GC) has played a most important role in
      the analysis of oil. In this review, the early history is briefly reviewed; next
      developments in this highly relevant application area since about 1985 are
      highlighted. The main topic of interest are the introduction and decisive role of
      capillary GC, the use of selective detection techniques, the versatility of
      coupled-column techniques and, specifically, the additional power of
      comprehensive two-dimensional GC.

PMID- 12416875
TI  - Determination of phenols in landfill leachate-contaminated groundwaters by solid
      phase extraction.
AB  - A solid-phase extraction method for phenols in landfill leachates was developed
      and optimized in order to solve the expected and observed problems associated
      with an anaerobic matrix containing high concentrations of salts and organic
      matter. Isolute ENV+ cartridges exhibited the best retention of phenols of the
      four sorbents examined, and was the only cartridge which a 1 L leachate sample
      could pass through. With the other cartridges, clogging made this impossible. The
      final method, which included 27 different phenols, gave detection limits of <0.1
      microg/L (drinking water concentration limit for pesticides) for most phenols
      (25), and for 12 phenols <0.01 microg/L. Recovery rates (determined for four
      concentrations in the range 1-25 microg/L, two replicates of each) were in the
      range 79-104% (SD 1-12%), except for phenol (26+/-1.3%) and 2-methoxyphenol (62+/
      4.2%). Up to 12 different phenols could be identified in leachates from three
      Danish landfills, ranging in concentration from 0.01 to 29 microg/L, which is at
      the lower end of the concentration range usually found for phenols in landfill
      leachates (sub-microg/L to mg/L).

PMID- 12416876
TI  - Determination of atrazine and four organophosphorus pesticides in ground water
      using solid phase microextraction (SPME) followed by gas chromatography with
      selected-ion monitoring.
AB  - A rapid, sensitive, and convenient method is presented for the determination of
      atrazine and four organophosphorus pesticides (OPP) in small (10 ml) samples of
      ground water. Samples are initially fortified with ethion (internal standard),
      then extracted without organic solvent using a 65-microm thickness
      polydimethylsiloxane/divinylbenzene (PDMS-DVB) solid-phase microextraction (SPME)
      fiber. The analytes collected are thermally desorbed in a heated gas
      chromatographic inlet, separated using a fused-silica capillary column, and
      detected using a mass selective detector in its selected-ion monitoring (SIM)
      mode. Two independent statistical procedures were used to evaluate the detection
      limits, which typically range between 2 and 8 microg l(-1) for these analytes.
      Method performance was also evaluated using "performance evaluation" samples, in
      which clean authentic ground waters were fortified to known concentrations with
      at least two of the analytes of interest. Sample-to-sample analysis time is
      approximately 30 min, making the new method ideal for "quick turn"
      determinations.

PMID- 12416877
TI  - On-line liquid-chromatography-nuclear magnetic resonance spectroscopy-mass
      spectrometry coupling for the separation and characterization of
      secoisolariciresinol diglucoside isomers in flaxseed.
AB  - Two secoisolariciresinol diglucoside (SDG) diastereomers were extracted from
      flaxseed and liberated through alkaline hydrolysis. Anion-exchange and reversed
      phase chromatography were successfully employed to purify the hydrolyzed flaxseed
      extract. On-line LC-NMR-MS analyses revealed the structure of the isolated and
      purified SDG diastereomers, [2R,2'R]-2,3-bis[(4-hydroxy-3-methoxyphenyl)-methyl]
      1,4-butanediyl-bis-beta-glucopyranoside the predominant flaxseed lignan and
      [2R,2'S]-2,3-bis[(4-hydroxy-3-methoxyphenyl)methyl]-1,4-butanediyl-bis-beta
      glucopyranoside, a previously incompletely characterized minor flaxseed lignan.
      Circular dichroism (CD) analyses confirmed the presence of two distinguished
      optically active compounds present in the flaxseed extract.

PMID- 12416878
TI  - Concentration of chlorophenols in water with sodium dodecylsulfate-gamma-alumina
      admicelles for high-performance liquid chromatographic analysis.
AB  - Chlorophenols in water were sorbed onto sodium dodecylsulfate (SDS)-alumina
      (gamma-form) admicelles. The extent of sorption increased with increasing amount
      of SDS and decreasing solution pH. Conditions for good recovery were obtained
      when 100 mg SDS and 1.5 g alumina was used at pH 2. However, the yield decreased
      with a further increase in the SDS concentration due to the formation of normal
      SDS micelles. The extent of sorption also increased with increasing
      hydrophobicity of the chlorophenol, indicating that hydrophobic interactions
      predominate for the collection of analytes. When a cartridge column filled with
      admicelles was used, >90% of tetrachlorophenol and pentachlorophenol in 200 ml of
      water samples were rapidly recovered. The sorbed analytes were eluted with 1 ml
      acetonitrile. The accuracy and precision of the present method were demonstrated
      for the HPLC analysis with ultraviolet (290 nm) detection of microg l(-1) levels
      of tetrachlorophenol and pentachlorophenol in river water samples.

PMID- 12416879
TI  - Determination of the enantiomeric purity of nucleoside analogs related to d4T and
      acyclovir, new potential antiviral agents, using liquid chromatography on
      cellulose chiral stationary phases.
AB  - We reported a method of determination of enantiomeric purity of the new potential
      antiviral agents by direct analytical HPLC. Those agents are nucleoside analogs,
      having one chiral center. They are synthesized as a single enantiomer (R or S) by
      an asymmetric pathway. The chiral stationary phases chosen are silica-based
      cellulose tris-3,5-dimethylphenylcarbamate (Chiralcel OD-H), or tris
      methylbenzoate (Chiralcel OJ). Resolution was achieved using normal-phase
      chromatography with a mobile phase consisting of n-hexane-alcohol (ethanol or 2
      propanol) in various percentages. Furthermore the effects of structural features
      on retention, selectivity and resolution, as well as on the elution order were
      thoroughly studied. Differences in the lipophilicity of the compounds were also
      examined.

PMID- 12416880
TI  - High-performance liquid chromatographic separation and indirect fluorescence
      detection of thiols.
AB  - A fluorescent post-column reaction detection scheme has been devised for
      selective determination of thiols. The post-column reagent is 40 microM Cd2+ and
      100 microM 8-hydroxyquinoline-5-sulfonic acid (HQS) in non-complexing buffer at
      pH 10. HQS complexes Cd2+ to form a fluorescent product. Thiols in the HPLC
      effluent compete for complexation of the Cd2+, resulting in a decrease in the
      fluorescence response. Detection limits of 0.2 microM (0.04 ppm) are achieved for
      cysteine, homocysteine and glutathione in a 5 min separation. Recoveries from
      spiked synthetic urine samples are 87-120%.

PMID- 12416881
TI  - Determination of propamocarb in vegetables using polymer-based high-performance
      liquid chromatography coupled with electrospray mass spectrometry.
AB  - A method for the determination of propamocarb in vegetables with liquid
      chromatography-electrospray ionisation mass spectrometry (LC-ESI-MS) was
      developed. The performance of a polymer-based analytical LC column for the
      separation was investigated. Residues of propamocarb were extracted from the
      matrix with methanol. Subsequently, the extract was directly injected into the LC
      MS system, without any additional concentration or cleanup procedures. Separation
      of propamocarb from the matrix components was achieved on a polymethacrylate
      based analytical column. Propamocarb was concurrently detected with electrospray
      ionisation mass spectrometry in the selected ion monitoring mode and two-stage
      full scan MS application. Quantitation was done with matrix-matched calibration
      standards of propamocarb. Unambiguous confirmation was achieved by comparison of
      the full scan product ion mass spectrum of the chromatographic peak in the sample
      with the spectrum of a standard solution of propamocarb at the same retention
      time. The analytical performance of the method was validated for five relevant
      matrices, spiking propamocarb at fortification levels from 0.05 to 15.0 mg kg(
      1). This covers the range of maximum residue limits in agricultural commodities,
      stated in the Dutch national legislation. The mean recovery of propamocarb was
      better than 90% with a precision of less than 10% in both scanning applications.
      As could be concluded from the calibration curve and matrix background levels,
      observed in blank control samples, the estimated limit of detection was 25 microg
      kg(-1) for the two-stage full scan MS application. The method has been applied in
      a survey of 285 samples of lettuce, radish, leek, and cabbage for the presence of
      residues of propamocarb. In 50% of the samples analysed, a residue of propamocarb
      was detected.

PMID- 12416882
TI  - Effects of dehydration on the apolar surface energetics of inorganic paper
      fillers.
AB  - The surface energies of various inorganic fillers including kaolin clay, titanium
      dioxide, and talc were examined using inverse gas chromatography (IGC). In an
      earlier investigation that examined calcium carbonate fillers, dehydration by
      heating under a dry nitrogen purge had a substantial influence on the apolar
      (gammaS(LW)) and polar (gammaS(AB)) components of surface energy as measured
      using IGC. Using the same approach, the influence of such conditioning on several
      inorganic fillers used in papermaking were determined using preconditioning IGC
      from 100 to 300 degrees C, and sequential isothermal analysis at 100 degrees C.
      Results from IGC analysis of titanium dioxides (rutile and anatase) were similar
      to precipitated calcium carbonate (PCC) for temperatures up to 200 degrees C. PCC
      was significantly more energetic after preconditioning at 300 degrees C, which
      may indicate the onset of significant thermal decomposition that titanium
      dioxides will not exhibit. Kaolin clay samples had relatively high apolar surface
      energy similar to that of the chalk samples. Calcination gave lower gammaS(LW)
      values that could not be accounted for by changes in the microporous structure.
      More likely the differences resulted from contamination of highly energetic
      surface sites with adsorbates other than water. Talc samples exhibited relatively
      high apolar surface energies that increased with preconditioning temperature. The
      results provided insight into the significance of water on the final adhesion
      properties of fillers in the sheet structure or coating layer.

PMID- 12416883
TI  - Column switching-back flushing technique for the analysis of aromatic compounds
      in gasoline.
AB  - A simple method, based on the technique of capillary column switching-back
      flushing, has been developed for the detailed analysis of aromatic compounds in
      gasoline. The sample was first separated on a 30-m long OV-2330 polar precolumn
      and then backflushed onto a nonpolar analytical column. The early eluting
      components from the precolumn and the components of interest (aromatic compounds
      plus heavier compounds) eluting from the analytical column are all directed to
      the same flame ionization detection system through a T piece, which permits the
      quantitative analysis of aromatic hydrocarbons in gasoline by a normalization
      method using correcting factors. The switching time window of the method is +/-5
      s, resulting in easier operation and higher reliability. The reproducibility of
      the quantitative analysis was < or = 3% RSD for real gasoline samples.

PMID- 12416884
TI  - Gas chromatographic-mass spectrometric method for quantification of 3-chloro-4
      (dichloromethyl)-5-hydroxy-2[5H]-furanone in chlorinated water samples.
AB  - A method for the determination of 3-chloro-4-(dichloromethyl)-5-hydroxy-2[5H]
      furanone (MX), in drinking water by GC-MS with a limit of detection of 3.0
      microg/l and a limit of quantification of 7.0 microg/l is presented. Clean-up by
      SPE and extraction of water samples with dichloromethane were carried out before
      the preconcentration of MX, which was derivatized directly in the injector of the
      GC, and the MX trimethylsilyl derivative was identified and quantitatively
      determined by MS.

PMID- 12416885
TI  - Separation and quantitation of phycobiliproteins using phytic acid in capillary
      electrophoresis with laser-induced fluorescence detection.
AB  - The similar electrophoretic mobilities and sizes of several of the
      phycobiliproteins, which are derived from the photosynthetic apparatus of
      cyanobacteria and eukaryotic algae, render their separation and quantitation a
      challenging problem. However, we have developed a suitable capillary
      electrophoresis (CE) method that employs a phytic acid-boric acid buffer and
      laser-induced fluorescence (LIF) detection with a single 594 nm He-Ne laser. This
      method takes advantage of the remarkably high quantum yields of these naturally
      fluorescent proteins, which can be attributed to their linear tetrapyrrole
      chromophores covalently bound to cysteinyl residues. As such, limits of detection
      of 1.18 x 10(-14), 5.26 x 10(-15), and 2.38 x 10(-15) mol/l were obtained for R
      phycoerythrin, C-phycocyanin, and allophycocyanin proteins, respectively, with a
      linear dynamic range of eight orders of magnitude in each case. Unlike previously
      published CE-LIF methods, this work describes the separation of all three major
      classes of phycobiliproteins in under 5 min. Very good recoveries, ranging from
      93.2 to 105.5%, were obtained for a standard mixture of the phycobiliproteins,
      based on seven-point calibration curves for both peak height and peak area. It is
      believed that this development will prove useful for the determination of
      phycobiliprotein content in naturally occurring cyanobacteria populations, thus
      providing a useful tool for understanding biological and chemical oceanographic
      processes.

PMID- 12416886
TI  - Development and substantiation of a liquid chromatographic method for monitoring
      organic reactions involved in synthesis of 4-methoxyphenylacetic acid.
AB  - A simple and rapid reversed-phase high-performance liquid chromatographic method
      for monitoring the reactions involved in two different processes for the
      production of 4-methoxyphenylacetic acid (PMPA) was developed. Impurity profiles
      of PMPA were used for fingerprinting of the two different synthetic processes by
      HPLC. Impurities were separated and determined on a Hypersil C18 column with
      acetonitrile-0.1 M potassium dihydrogen orthophosphate-triethylamine
      (40:59.95:0.05, v/v) (pH 3.0) as the mobile phase and detection at 280 nm at
      ambient temperature. The method was substantiated with respect to accuracy,
      precision, linearity, robustness, limit of detection and quantification. The
      method was found to be suitable not only for monitoring the reactions but also
      for quality assurance of PMPA as it could detect impurities at the level of 4 x
      10(-9) g.

PMID- 12416887
TI  - Capillary zone electrophoresis in laboratory-made fluorinated ethylene propylene
      capillaries.
AB  - Capillaries made of fluorinated ethylene propylene (FEP) with an inner diameter
      of 50 microm have been employed in capillary zone electrophoresis with UV-Vis
      absorbance detection. The capillaries were made in the laboratory with a recently
      developed technique using fluoropolymer heat shrink/melt tubing and a tungsten
      wire as a template for the channel. An electroosmotic flow was obtained in the
      channels and it is shown that an FEP capillary is more effective for a cationic
      test solute than a fused-silica capillary. The compatibility of FEP capillaries
      with optical detection is evaluated briefly.

PMID- 12416888
TI  - Capillary electrophoresis of baclofen with argon-ion laser-induced fluorescence
      detection.
AB  - A capillary electrophoretic method with laser-induced fluorescence detection for
      baclofen (4-amino-3-p-chlorophenylbutyric acid) has been developed. 6
      Carboxyfluorescein succinimidyl ester was used for precolumn derivatization of
      the non-fluorescent drug. Optimal separation and detection were obtained with an
      electrophoretic buffer of 50 mM sodium borate (pH 9.5) and an air-cooled argon
      ion laser (excitation at 488 nm, emission at 520 nm). Linearity (r > or = 0.99)
      over three orders of magnitude was generally obtained and the lowest
      derivatizable concentration limit for baclofen in aqueous solution was 10 nM (2
      ng baclofen/ml). Coupled with a simple clean up procedure, the method can be
      applied to the analysis of baclofen in human plasma at micromolar level. Recovery
      of spiked baclofen in plasma was 95%. The relative standard deviation values on
      peak size (0.5 microM level) and migration time were 8.2 and 1.0% (n=7),
      respectively. The limit of detection of baclofen in plasma was 0.1 microM (21
      ng/ml).

PMID- 12416889
TI  - A perspective on the war on cancer.

PMID- 12416890
TI  - Care without chemotherapy: the role of the palliative care team.
AB  - So--what will be your answer to the medical student? What should you tell Barbara
      and her family? That's up to you. But whatever you chose, you can be confident
      that you will be able to provide for her comfort and help her maximize her
      quality of life. When you share your most honest estimate of her prognosis and
      help her reframe her hope, you can increase the chance that she will be able to
      define and accomplish her last goals, bring closure to her life, and do the work
      that will minimize the pain of her bereaved family. You are not alone in this
      work: you can enlist hospice and palliative care teams to help you. With their
      help, you can promise Barbara the same expert care with or without chemotherapy
      And then . . . it's up to her.

PMID- 12416891
TI  - The rapidly expanding role of rituximab in the treatment of aggressive B-cell
      lymphoma.

PMID- 12416892
TI  - Lymphocyte predominant Hodgkin's disease: more patience than patients.

PMID- 12416893
TI  - Changes in serum ganglioside and antibody levels in soft tissue sarcoma: are they
      the cause or the effect of tumor progression?

PMID- 12416894
TI  - Rituximab for aggressive non-Hodgkin's lymphomas relapsing after or refractory to
      autologous stem cell transplantation.
AB  - PURPOSE: The median survival for aggressive non-Hodgkin's lymphomas relapsing
      after or refractory to high-dose therapy and autologous stem cell transplantation
      therapy is 6.2 months. In these cases, there is limited salvageability with the
      use of conventional therapy. The purpose of this retrospective analysis was to
      evaluate single-agent rituximab as treatment for aggressive non-Hodgkin's
      lymphomas in these cases. PATIENTS AND METHODS: Between January 1997 and February
      2000, we treated 17 patients with aggressive non-Hodgkin's lymphomas whose
      disease was refractory to, or relapsed after, autologous stem cell
      transplantation. Treatment consisted of rituximab, 375 mg/m2 as a single agent
      for four weekly doses. Thirteen patients had diffuse large B-cell lymphoma, and
      four patients had mantle cell lymphoma. The median time from autologous stem cell
      transplantation to relapse was 10 months (range, 2-40 months). The median number
      of prior therapies, including autologous stem cell transplantation, was three
      (range, 2-6). RESULTS: The overall response rate to rituximab was 53%, and there
      were four complete responses and five partial responses. Seven of 13 patients
      with diffuse large B-cell lymphoma (three complete responses, four partial
      responses) responded, and two of four patients with mantle cell lymphoma (one
      complete responses, one partial responses) responded. The median progression-free
      survival for all responders was 13 months (range, 6-18 months). Four responders
      (two complete responses, two partial responses) were re-treated with a second
      course of rituximab for disease recurrence and responded to further antibody
      therapy. Rituximab was well tolerated with no serious adverse events. DISCUSSION:
      Rituximab is effective and well-tolerated palliative treatment for aggressive non
      Hodgkin's lymphomas that relapse after or is refractory to autologous stem cell
      transplantation.

PMID- 12416895
TI  - Radiotherapy alone for lymphocyte-predominant Hodgkin's disease.
AB  - PURPOSE: The purpose of the study was to analyze the results with radiotherapy
      alone in a select group of asymptomatic adults with nonbulky, early-stage
      lymphocyte-predominant Hodgkin's disease. PATIENTS AND METHODS: Between 1963 and
      1995, 36 patients with nonbulky stage IA (N = 27) or IIA (N = 9)
      supradiaphragmatic (N = 27) or subdiaphragmatic (N = 9) lymphocyte-predominant
      Hodgkin's disease were treated with radiotherapy alone. Eleven of the patients
      underwent laparotomy. Limited-field radiotherapy involving only one side of the
      diaphragm and extended-field radiotherapy encompassing both sides of the
      diaphragm were used in 28 and 8 cases, respectively. Median dose to involved
      areas was 40.0 Gy given daily in 20 2.0-Gy fractions. Salvage treatmentconsisted
      of MOPP (mechlorethamine, vincristine, prednisone, procarbazine), CVPP/ABDIC
      (cyclophosphamide, vinblastine, procarbazine and prednisone/doxorubicin,
      bleomycin, dacarbazine, lomustine, and prednisone), or ABVD (doxorubicin,
      bleomycin, vinblastine, dacarbazine) chemotherapy and/or involved-field
      radiotherapy. RESULTS: Median follow-up was 8.8 years (range, 3.0-34.4 years).
      None of the 15 patients with supradiaphragmatic disease who received limited
      field radiotherapy to regions that did not include the mediastinal or hilar nodes
      subsequently experienced relapse there. Only one of 20 patients who received
      supradiaphragmatic limited-field radiotherapy alone experienced relapse in the
      paraaortic nodes or spleen. The 5-year relapse-free and overall survival rates
      for the 20 patients with stage IA lymphocyte-predominant Hodgkin's disease
      treated with involved-field or regional radiotherapy were 95% and 100%,
      respectively. There were no cases of severe or life-threatening cardiac toxicity.
      No solid tumors have been observed in-field in patients treated with limited
      field radiotherapy, even though they have been followed up longer than those
      treated with extended-field radiotherapy (median follow-up, 11.6 vs 5.5 years);
      two solid tumors have developed in-field in patients who received extended-field
      radiotherapy. DISCUSSION: Involved-field or regional radiotherapy alone may be
      adequate in stage IA lymphocyte-predominant Hodgkin's disease patients. Longer
      follow-up will help to more clearly define the risks of cardiac toxicity and
      solid tumors that result from involved-field or regional radiotherapy, which
      appear to be low based on follow-up to date.

PMID- 12416896
TI  - Serum anti-ganglioside IgM antibodies in soft tissue sarcoma: clinical prognostic
      implications.
AB  - PURPOSE: Gangliosides are tumor-associated antigens with many biologic functions,
      including complex interactions with cytokines and other modulators of the immune
      system. Serum total ganglioside level may be an ideal surrogate marker to predict
      tumor burden and response to treatment. Antibodies produced against tumor
      gangliosides may help predict survival. The purpose of this study is to determine
      whether the serum total ganglioside levels might predict the tumor burden in
      patients with soft tissue sarcoma, and whether the augmented anti-ganglioside
      immunoglobulin M (IgM) response might reflect the clinical outcome of these
      patients. METHODS: Serum TG levels were measured in the cryopreserved sera by
      estimating lipid-associated sialic acids from 97 patients before surgical
      resection of soft tissue sarcoma and from 39 age- and gender-matched healthy
      volunteers. All sera were analyzed for IgM titers (expressed natural log) by
      enzyme-linked immunosorbent assay against eight gangliosides (GM1, GM2, GM3, GD3,
      GD2, GD1a, GD1b, and GT1b). Cox regression was used for univariate and
      multivariate analyses of the variables affecting progression-free and overall
      survival. RESULTS: Serum TG levels were higher in soft tissue sarcoma patients
      than in healthy individuals (21.8 + 7.7 vs 16.1 + 2.7 mg/dL; P = 0.001). Larger
      tumors, high histologic grade, and more advanced stage of disease correlated with
      higher serum total ganglioside levels (P < 0.05). Anti-ganglioside titers to GM3,
      GD2, and GT1b were significantly higher in patients with soft tissue sarcoma,
      whereas anti-GD1a and GD1b titers were significantly higher in healthy subjects.
      The titers of antibodies against GM1, GM2, and GD3 in patients with soft tissue
      sarcoma were comparable to those of the healthy individuals. When compared with
      healthy controls, patients with low-grade tumors had higher titers of anti-GT1b,
      anti-GM3, and anti-GD2 antibodies, and patients with high-grade tumors had higher
      titers of anti-GT1b and anti-GD2 antibodies. These data suggest that the
      predominant gangliosides expressed by sarcomas may include GT1b and GD2. In
      addition, low-grade tumors may express an immunogenic species of GM3. On both
      univariate and multivariate analyses, augmented anti-GD1a IgM titers, age > 50
      years, and retroperitoneal location were predictive of decreased overall
      survival, whereas augmented anti-GT1b titers were predictive of improved overall
      survival. CONCLUSIONS: Serum TG level may be a useful marker of tumor burden and
      response to treatment for soft tissue sarcoma. Anti-GD1a and anti-GT1b IgM titers
      predicted survival and may be of therapeutic and prognostic value in the
      management of soft tissue sarcoma.

PMID- 12416897
TI  - A phase II study of troglitazone, an activator of the PPARgamma receptor, in
      patients with chemotherapy-resistant metastatic colorectal cancer.
AB  - PURPOSE: Troglitazone, a potent activator of the peroxisome proliferator
      activated receptor-gamma, induces tumor differentiation in human liposarcomas and
      causes regression of tumors that are derived from human colon cancer cells in
      nude mice. We therefore assessed the efficacy of troglitazone in the treatment of
      metastatic colon cancer in humans. METHODS: Twenty-five patients with metastatic
      colorectal cancer were treated with oral troglitazone. Patients were followed up
      for evidence of toxicity, tumor response, and survival. RESULTS: The treatment
      was well tolerated: no grade 3/4 treatment-related toxicities were observed.
      However, no objective tumor responses were noted, and all 25 patients had
      progressive disease as their best response to therapy. The median progression
      free survival time was only 1.6 months, and the median survival time was 3.9
      months. DISCUSSION: Troglitazone is not an active agent for the treatment of
      metastatic colorectal cancer.

PMID- 12416898
TI  - Efficacy of Tc-99m depreotide scintigraphy in the evaluation of solitary
      pulmonary nodules.
AB  - PURPOSE: Tc-99m depreotide is a peptide analogue of a somatostatin receptor that
      preferentially binds to somatostatin receptors 2, 3, and 5. Many lung tumors may
      express these receptors to a greater extent than normal tissue. Tc 99m depreotide
      study is a noninvasive, receptor-specific imaging agent that is used to assess
      malignant versus benign single pulmonary nodules before biopsy. MATERIALS AND
      METHODS: Thirty-nine consecutive patients (15 men, 24 women), with mean age 56.6
      years (range 39-86) underwent 42 studies. The single-photon emission computed
      tomographic scan of the chest and whole-body imaging were performed 2 hours after
      intravenous injection of Tc 99m depreotide (average dose, 24 mCi). The region of
      interest was drawn around each lesion, and the tumor-to-background ratio was
      measured. Images were classified as true positive when the tumor uptake and
      histopathology were concordant. The results were classified as true negative when
      there was no uptake in the absence of malignancy. The results were classified as
      false positive when there was uptake in areas other than tumor and were false
      negative when no uptake in the tumor was identified. The computed tomographic and
      pathological correlations were performed. RESULTS: The comparison of technetium
      Tc 99m depreotide imaging with computed tomographic study revealed a sensitivity
      of 1.0 versus 0.9, a specificity 0.43 versus 0.19, accuracy 0.71 versus 0.55,
      positive predictive value 0.64 versus 0.53, and negative predictive value 1.0
      versus 0.67,. The tumor-to-background ratio ranged from 1.15 to 3.77. There was
      no relationship between the histology and the intensity of tumor uptake. The
      tumor uptake was high in sites of acute and active inflammation. CONCLUSION:
      Technetium Tc 99m depreotide imaging is a sensitive imaging modality with better
      specificity and negative predictive value than computed tomography. There is no
      relationship between tumor uptake and differentiation of the tumor. We recommend
      a technetium Tc 99m depreotide study forthe evaluation of solitary pulmonary
      nodules, especially when positron emission tomography is not available before
      biopsy.

PMID- 12416899
TI  - 5-HT3-receptor antagonists and the cytochrome P450 system: clinical implications.
AB  - Many patients with cancer receive multiple chemotherapy agents as well as other
      medications for coexisting medical conditions. Despite the introduction of 5-HT3
      receptor antagonists, the management of nausea and vomiting following cancer
      treatment and after cancer surgery remains complex, particularly when patients
      are receiving multiple prescription medications. As a drug class, the 5-HT3
      receptor antagonists have good antiemetic efficacy and an improved safety profile
      over conventional antiemetics. Nevertheless, pharmacologic differences exist
      between these agents, such as their interaction with the metabolic cytochrome
      P450 system. This review examines the major metabolic differences between the
      most frequently prescribed 5-HT3 receptor antagonists, dolasetron, granisetron,
      ondansetron, and tropisetron. The potential drug interactions that these
      differences may precipitate and key genetic interindividual variations in drug
      metabolism are also considered. To avoid or minimize potential drug interactions,
      the 5-HT3 receptor antagonist with the lowest risk of these interactions should
      be considered as first choice.

PMID- 12416900
TI  - Understanding the truth: arthroscopic surgery.

PMID- 12416901
TI  - Central third bone-patellar tendon-bone arthroscopic anterior cruciate ligament
      reconstruction: a 4-year follow-up.
AB  - This prospective study reports the 4-year follow-up results of 56 patients (44
      males and 12 females) who underwent arthroscopic reconstruction of the anterior
      cruciate ligament (ACL) using a central third bone-patellar tendon-bone free
      autologous graft and assesses the mid-term effectiveness of this technique. Mean
      patient age was 30.2 years (range: 17-44 years). Sports injuries were the primary
      cause of ACL deficiency in 93% of patients. All knees had an isolated ACL tear,
      and 31 had associated meniscal or chondral lesions. Patients in the acute phase
      did not undergo surgery for 3-4 weeks. In patients with subacute and chronic ACL
      ruptures, the mean interval between injury and surgery was 62 weeks (range: 8-104
      weeks). According to the International Knee Documentation Committee grading
      system, 53 (95%) knees were considered normal or nearly normal postoperatively.
      Improvement by at least 1 grade was noted in 12 knees, 30 knees had an
      improvement of at least 2 grades, 12 knees had a 3-grade improvement, and 1 had a
      grade that remained unchanged. One knee deteriorated from a grade C to a grade D,
      which was attributed to graft lysis 1 year postoperatively. For best results,
      subacute reconstruction between 3 and 5 weeks postinjury is recommended.

PMID- 12416902
TI  - Intraoperative measurements of male and female distal femurs during primary total
      knee arthroplasty.
AB  - The anteroposterior (AP) and medial-lateral (ML) dimensions of 200 consecutive
      osteoarthritic knees (100 males and 100 females) undergoing unilateral primary
      total knee arthroplasty were compared. For all patients, the mean AP dimension
      was 57.3 mm (range: 49-66 mm) and the dimension was 10.5% taller in height in men
      than women. The mean ML dimension was 71.6 mm (range: 56-85 mm), and the
      dimension was 13.7% wider in men than women. The mean AP/ML ratio was 0.8 for all
      patients, 0.82 (range: 0.73-0.93) for females and 0.79 (range: 0.70-0.89) for
      males (P<.001). The data suggest that for any given AP femoral dimension, women
      tend to have a narrower ML dimension than men, independent of AP height, and an
      AP/ML ratio of 0.80 most closely approximates a standard-sized distal femur
      across gender. This report documents important gender differences that may serve
      as a reference for femoral implant designers and knee surgeons.

PMID- 12416903
TI  - Standardized mortality ratios and fatal pulmonary embolism rates following total
      knee replacement: a cohort of 936 consecutive cases.
AB  - Mortality and fatal pulmonary embolism rates in 936 consecutive primary total
      knee replacements (TKR) were determined during a 3-month postoperative period.
      Postmortem examinations verified the cause of death in all but 3 patients, and
      follow-up was performed on all but 1 patient. All patients had elastic stockings
      as mechanical prophylaxis. No deaths occurred from pulmonary embolism confirmed
      by postmortem examinations. At worst, the fatal pulmonary embolism rate was 0.43%
      (4/936; confidence interval [CI]=0.14%-1.17%). The all-cause mortality rate was
      0.64% (6/936; CI=0.26%-1.46%). The patient mortality was compared with the
      population mortality of England and Wales using standardized mortality ratios.
      The standardized mortality ratios for both sexes combined was 0.74 (CI=0.29
      1.52). A lower mortality was observed in women (0.67) than in men (0.84) during
      the first 3 postoperative months compared to the general population. Fatal
      pulmonary embolism after TKR with the routine use of graded elastic stockings and
      early mobilization is rare. In this series, the death rate in patients undergoing
      TKR appears to be lower than that in the general population.

PMID- 12416904
TI  - Biologic resurfacing of the patella with quadriceps tendon flap: a rabbit study.
AB  - In this experimental study, 10 rabbits underwent arthrotomy with exposure of the
      patellar bone (group A), 10 rabbits underwent arthrotomy of the right knee
      without touching the patella (group B), and 10 rabbits comprised the control
      group (group C), which was included only for evaluation of functional scoring
      activities. A 2-mm thick flap of quadriceps tendon reflected downward to cover
      the patellar bone denuded of cartilage, which resulted in formation of hyaline
      cartilage in 87% of cases in group A and 89% in group B, incomplete
      differentiation of the mesenchymal tissue in 7% in group A and 9% in group B, and
      fibrous tissue or bone formation in 6% in group A and 2% in group B. In group A,
      22% of formed cartilage had a regular surface, 22% had superficial horizontal
      lamination, 44% had fissuring, and 12% showed severe disruption. In group B,
      these values were 56%, 33%, 11%, and 0%, respectively. In group A, normal
      cellularity was noted in 33% of cases, slight hypocellularity in 67%, and no
      moderate hypocellularity. In group B, these values were 56%, 33%, and 11%,
      respectively. This procedure should be considered in young patients with loss of
      articular cartilage for whom other procedures or patellectomy are unsuitable
      solutions.

PMID- 12416905
TI  - Knee arthroplasty for ochronotic arthropathy.

PMID- 12416906
TI  - Mobile bearing total knee arthroplasty.

PMID- 12416907
TI  - The Oxford meniscal unicompartmental knee.

PMID- 12416908
TI  - The role of rotating platform total knee replacements: design considerations,
      kinematics, and clinical results.

PMID- 12416909
TI  - Design concepts for a posterior stabilized mobile bearing knee prosthesis.

PMID- 12416910
TI  - Putting the brakes on prejudice: on the development and operation of cues for
      control.
AB  - A model concerning the establishment and operation of cues for control was
      developed and tested to understand how control can be exerted over (automatic)
      prejudiced responses. Cues for control are stimuli that are associated with
      prejudiced responses and the aversive consequences of those responses (e.g.,
      guilt). In Experiments 1 and 2, 3 events critical to the establishment of cues
      occurred: behavioral inhibition, the experience of guilt, and retrospective
      reflection. In Experiment 3, the presentation of already-established cues for
      control did, as expected, produce behavioral inhibition. In Experiment 4,
      participants were provided with an experience in which cues could be established.
      Later presentation of those cues in a different task resulted in behavioral
      inhibition and less racially biased responses.

PMID- 12416911
TI  - Spontaneous trait inferences are bound to actors' faces: evidence from a false
      recognition paradigm.
AB  - A false recognition paradigm showed that spontaneous trait inferences (STIs) are
      bound to the person performing a trait-implying behavior. In 6 experiments,
      participants memorized faces and behavioral sentences. When faces were paired
      with implied traits in a recognition test, participants falsely recognized these
      traits more often than unrelated traits paired with the same faces or the same
      traits paired with familiar faces. The effect was obtained for a large set of
      behaviors (120). each presented for 5 s, and for behaviors that participants did
      not subsequently recognize or recall. Antonyms of the implied traits were falsely
      recognized less often than unrelated traits, suggesting that STIs have extended
      implications. Explicit person-trait judgments predicted both false recognition
      and response times for implied traits.

PMID- 12416912
TI  - Seeing approach motivation in the avoidance behavior of others: implications for
      an understanding of pluralistic ignorance.
AB  - Four studies tested the hypothesis that observers tend to interpret others'
      actions as approach motivated even when they recognize that their own identical
      choices were motivated by avoidance. Study 1 found that voters in the 2000 U.S.
      Presidential election who chose a candidate primarily because of their aversion
      to the alternative thought that others who voted for the same candidate liked him
      more than they themselves did. In Studies 2, 3, and 4 participants who learned
      that others made the same choice as themselves between 2 unappealing flavors of
      soda orjelly beans estimated that the others would pay more than they would for
      their common choice. The relevance of these findings for an understanding of
      pluralistic ignorance is discussed.

PMID- 12416913
TI  - Perceived entitativity, stereotype formation, and the interchangeability of group
      members.
AB  - The authors investigated the effects of perceived entitativity of a group on the
      processing of behavioral information about individual group members and the
      extent to which such information was transferred to other group members. The
      results of 3 experiments using a savings-in-relearning paradigm showed that trait
      inferences about a group member, based on that member's behavior, were stronger
      for low entitative groups and for collections of individuals. However, the
      transference of traits from 1 group member to other members of the group was
      stronger for high entitative groups. These results provide strong evidence that
      the perception of high entitativity involves the abstraction of a stereotype of
      the group and the transfer of that stereotype across all group members.
      Implications for group impression formation and stereotyping are discussed.

PMID- 12416914
TI  - Group conversion versus group expansion as modes of change in majority and
      minority positions: all losses hurt but only some gains gratify.
AB  - This study examined reactions to minority and majority positions that were either
      stable or reversed through group conversion that transformed opponents
      (supporters) of the minority (majority) into supporters (opponents) or through
      group expansion that brought new supporters (opponents) for the minority
      (majority) into the group. Minorities who became majorities through group
      expansion, compared with those who changed through group conversion, perceived
      their supporters and the overall group as significantly more similar to the self,
      and had significantly higher expectations for future positive interactions within
      the group. Perception of similarity with the supporters mediated the effect of
      the experimental conditions on perception of the overall group-self similarity.
      Implications of changes through conversion and expansion for the functioning of
      social groups are discussed.

PMID- 12416915
TI  - Sex differences in jealousy: evolutionary mechanism or artifact of measurement?
AB  - Two studies are presented that challenge the evidentiary basis for the existence
      of evolved sex differences in jealousy. In opposition to the evolutionary view,
      Study I demonstrated that a sex difference in jealousy resulting from sexual
      versus emotional infidelity is observed only when judgments are recorded using a
      forced-choice response format. On all other measures, no sex differences were
      found; both men and women reported greater jealousy in response to sexual
      infidelity. A second study revealed that the sex difference on the forced-choice
      measure disappeared under conditions of cognitive constraint. These findings
      suggest that the sex difference used to support the evolutionary view of jealousy
      (e.g., D. M. Buss, R. Larsen, D. Westen, & J. Semmelroth, 1992; D. M. Buss et
      al., 1999) likely represents a measurement artifact resulting from a format
      induced effortful decision strategy and not an automatic, sex-specific response
      shaped by evolution.

PMID- 12416916
TI  - The influence of individual versus aggregate social comparison and the presence
      of others on self-evaluations.
AB  - In 5 studies, the authors investigated the effects of comparison with an
      individual versus comparison with the statistical average on self-evaluations of
      performance and ability. In Studies 1 and 2, participants took a test of lie
      detection ability and were provided with the average score and the score of an
      individual coactor. Both types of feedback significantly affected self
      evaluations of performance, but only comparison with the coactor significantly
      affected self-evaluations of ability. Studies 3 and 4 demonstrated that the
      presence of a coactor moderated the effect of aggregate social comparison on self
      evaluations of ability. The results provide preliminary support for the
      contention that minimizing the impact of comparison with the average is a self
      serving strategy that is facilitated by the presence of others.

PMID- 12416917
TI  - Disconnecting outcomes and evaluations: the role of negotiator focus.
AB  - Three experiments explored the role of negotiator focus in disconnecting
      negotiated outcomes and evaluations. Negotiators who focused on their target
      prices, the ideal outcome they could obtain, achieved objectively superior
      outcomes compared with negotiators who focused on their lower bound (e.g.,
      reservation price). Those negotiators who focused on their targets, however, were
      less satisfied with their objectively superior outcomes. In the final experiment,
      when negotiators were reminded of their lower bound after the negotiation, the
      satisfaction of those negotiators who had focused on their target prices was
      increased, with outcomes and evaluations becoming connected rather than
      disconnected. The possible negative effects of setting high goals and the
      temporal dimensions of the disconnection and reconnection between outcomes and
      evaluations are discussed.

PMID- 12416918
TI  - Subjective well-being is heritable and genetically correlated with dominance in
      chimpanzees (Pan troglodytes).
AB  - The hypothesis that subjective well-being (SWB) is heritable and genetically
      correlated with Dominance was tested using 128 zoo chimpanzees. Dominance was a
      chimpanzee-specific personality factor including items reflecting Extraversion
      and low Neuroticism. SWB was measured with a 4-item scale. The best behavior
      genetic model included additive genetic and nonshared environmental effects for
      SWB and Dominance, marginal matemal effects for SWB, a high genetic correlation,
      and a low nonshared environmental correlation. Results indicated that the shared
      variance between SWB and Dominance was a consequence of common genes and that the
      unique variance between SWB and Dominance was a consequence of the nonshared
      environment. These findings indicate that common genes may underlie the
      correlation between human personality factors and SWB.

PMID- 12416919
TI  - Resilience to loss and chronic grief: a prospective study from preloss to 18
      months postloss.
AB  - The vast majority of bereavement research is conducted after a loss has occurred.
      Thus, knowledge of the divergent trajectories of grieving or their antecedent
      predictors is lacking. This study gathered prospective data on 205 individuals
      several years prior to the death of their spouse and at 6- and 18-months
      postloss. Five core bereavement patterns were identified: common grief, chronic
      grief, chronic depression, improvement during bereavement, and resilience. Common
      grief was relatively infrequent, and the resilient pattern most frequent. The
      authors tested key hypotheses in the literature pertaining to chronic grief and
      resilience by identifying the preloss predictors of each pattern. Chronic grief
      was associated with preloss dependency and resilience with preloss acceptance of
      death and belief in a just world.

PMID- 12416920
TI  - A developmental perspective on personality in emerging adulthood: childhood
      antecedents and concurrent adaptation.
AB  - Personality and competence were examined in a community sample of 205 children
      ages 8-12 who were followed up 10 years later in emerging adulthood (ages 17-23).
      Adult Positive Emotionality (PEM), Negative Emotionality (NEM), and Constraint
      (CON) were presaged by childhood personality. PEM was associated with current
      success in social and romantic relationships. Low CON was associated with
      childhood and current antisocial conduct. NEM was broadly linked to childhood and
      current maladaptation, consistent with the possibility that failure in major
      developmental tasks increases NEM. Findings highlight the pervasive linkage of
      NEM to maladaptation and suggest that adult personality may develop from
      processes embedded in childhood adaptation as well as childhood personality.

PMID- 12416921
TI  - Maximizing versus satisficing: happiness is a matter of choice.
AB  - Can people feel worse off as the options they face increase? The present studies
      suggest that some people--maximizers--can. Study 1 reported a Maximization Scale,
      which measures individual differences in desire to maximize. Seven samples
      revealed negative correlations between maximization and happiness, optimism, self
      esteem, and life satisfaction, and positive correlations between maximization and
      depression, perfectionism, and regret. Study 2 found maximizers less satisfied
      than nonmaximizers (satisficers) with consumer decisions, and more likely to
      engage in social comparison. Study 3 found maximizers more adversely affected by
      upward social comparison. Study 4 found maximizers more sensitive to regret and
      less satisfied in an ultimatum bargaining game. The interaction between
      maximizing and choice is discussed in terms of regret, adaptation, and self
      blame.

PMID- 12416922
TI  - The motivating function of thinking about the future: expectations versus
      fantasies.
AB  - Two forms of thinking about the future are distinguished: expectations versus
      fantasies. Positive expectations (judging a desired future as likely) predicted
      high effort and successful performance, but the reverse was true for positive
      fantasies (experiencing one's thoughts and mental images about a desired future
      positively). Participants were graduates looking for a job (Study 1), students
      with a crush on a peer of the opposite sex (Study 2), undergraduates anticipating
      an exam (Study 3), and patients undergoing hip-replacement surgery (Study 4).
      Effort and performance were measured weeks or months (up to 2 years) after
      expectations and fantasies had been assessed. Implications for the self
      regulation of effort and performance are discussed.

PMID- 12416923
TI  - Intuition, affect, and personality: unconscious coherence judgments and self
      regulation of negative affect.
AB  - According to personality systems interaction theory, a negative mood was expected
      to reduce access to extended semantic networks and to reduce performance on
      intuitive judgments of coherence for participants who have an impaired ability to
      down-regulate negative affect (i.e., state-oriented participants). Consistent
      with expectations, state-oriented participants reporting higher levels of
      perseverating negative mood had a reduced discrimination between coherent and
      incoherent standard word triples (Study 1) and individually derived word triples
      describing persons (Study 2). Participants who are able to down-regulate negative
      affect (i.e., action-oriented participants) did not show this tendency. In
      addition, Study 2 revealed a dissociation between state orientation and
      Neuroticism that is discussed in terms of a functional difference between the two
      constructs.

PMID- 12416924
TI  - Construing action abstractly and blurring social distinctions: implications for
      perceiving homogeneity among, but also empathizing with and helping, others.
AB  - Most people's actions serve goals that, defined abstractly enough, are quite
      similar to one another. The authors thus proposed, and found, that construing
      action in abstract (vs. concrete) terms relates to perceiving greater similarity
      among persons both within and across different social groups (Studies 1-3). By
      fostering perspective taking, viewing action abstractly also related to
      empathizing with and expressing willingness to help nonstigmatized and
      stigmatized others (e.g., AIDS patients; Studies 3-5) and to donating money to
      help those in need (Study 6). These findings held when controlling for
      ideological, motivational, and broad personality variables. Abstract action
      construals, then, appear to blur social distinctions, fostering perspective
      taking and empathy on the one hand but also perceptions of group homogeneity on
      the other.

PMID- 12416925
TI  - Cultural variation in correspondence bias: the critical role of attitude
      diagnosticity of socially constrained behavior.
AB  - Upon observing another's socially constrained behavior, people often ascribe to
      the person an attitude that corresponds to the behavior (called the
      correspondence bias [CB]). The authors found that when a socially constrained
      behavior is still diagnostic of the actor's attitude, both Americans and Japanese
      show an equally strong CB. A major cultural difference occurred when the behavior
      was minimally diagnostic. Demonstrating their persistent bias toward
      dispositional attribution, Americans showed a strong CB. But Japanese did not
      show any CB (Study 1). Furthermore, a mediational analysis revealed that this
      cross-cultural difference was due in part to the nature of explicit inferences
      generated online during attitudinal judgment (Study 2). Implications for the
      cultural grounding of social perception are discussed.

PMID- 12416926
TI  - Estimation of macrophage IL-10 and NO secretion in the cytotoxicity against
      transplantable melanomas in relation to the progression of these tumours.
AB  - The relationship between the secretion of interleukin 10 (IL-10) and nitric oxide
      (NO) by hamster peritoneal macrophages and their cytotoxic effects on the cells
      of those two melanoma lines was studied. The nonuniform reaction of macrophages
      from hamsters bearing two transplantable melanoma lines has been observed. An
      increase in the cytotoxicity of macrophages from hamsters bearing the amelanotic
      melanoma line was accompanied by an inverse correlation between IL-10 and NO
      secretion. Such a relationship was not found in the case of macrophages from
      animals bearing the native-melanotic melanoma line. It is suggested that the
      phenotypical changes of melanomas connected with their progression modified the
      cytotoxic and secretory activity of the macrophages with regard to IL-10 and NO.

PMID- 12416927
TI  - Assessment of a gastric arterial network for oesophageal substitute by means of
      pulse oximetry.
AB  - Insufficient vascularisation of substitutes in the operative reconstruction of
      the oesophagus is one of the main causes of the occurrence of anastomotic leaks.
      In the present study, the blood oxygenation of gastric substitutes for the
      oesophagus was evaluated before and during the reconstruction. A pulse oximeter
      was used for the assessment (S&J Medico Teknik AIS, Albertslund, Denmark).
      Oxygenation in the examined places ranged from 79% to 98%. The values of blood
      oxygenation in places C1 (fundus of the stomach after the formation of the
      substitute) and C2 (fundus of the stomach after the formation and stretching of
      the substitute) were significantly lower than those in analogous places in the
      stomach before the transformation (C/C1 p < 0.02; C/C2 p < 0.03, Fisher test).
      There were no correlations between pulse oximetry values observed and the
      presence of anastomosis leak.

PMID- 12416929
TI  - Pecam-1 expression in patients with relapsing-remitting multiple sclerosis.
AB  - PECAM-1 is an adhesion molecule--a member of the immunoglobulin superfamily-
      involved in the transendothelial migration of leukocytes. PECAM-1 is expressed on
      lymphocytes, monocytes and granulocytes. It is also found on endothelial cells
      and platelets. We present data showing that the cell-bound form of PECAM-1
      expression on monocytes is increased in MS patients, compared to controls. We
      also show that PECAM-1 is significantly over-expressed on lymphocytes in patients
      with active MRI lesions, when compared to those without gadolinium-enhancing
      lesions. Our results suggest that the cell-bound form of PECAM-1 can be regarded
      as a marker of MS activity.

PMID- 12416928
TI  - Liver histological structure in adult European bison. Bison bonasus (Linnaeus,
      1758).
AB  - The histological structure of the liver in 12 European bison, 2-8 years old, was
      presented. The study of the hepatic lobule showed that in Bison bonasus there
      were no connective septa around the hepatic lobules. On the hepatic lobule
      territory, solitary bile ducts, respectively solitary arterioles, were sometimes
      observed. Every one of these vessels was isolated from the hepatic parenchyma by
      thick coats of collagen. In the adventitia of the hepatic sublobar vessels,
      capillaries of the vasa vasorum system were found. The thick capsule of Glisson
      presented an outer part lacking in blood vessels and an inner part vascularised
      with arterioles and capillaries originating from the subcapsular portal tracts.
      The ligament insertion in the liver parenchyma was described.

PMID- 12416930
TI  - Asymmetry of the ovale and spinous foramina in mediaeval and contemporary skulls
      in radiological examinations.
AB  - The aim of this work was to evaluate the morphology and asymmetry of the ovale
      and spinous foramina. Examinations were carried out on 102 mediaeval and 85
      contemporary male skulls. In both groups there predominated individuals who had
      died at mature (maturus) and adult (adultus) age. Radiological images in
      occipital projection were used in the study. Areas of the foramina ovale,
      distances between both openings and the distance from the midline running through
      the middle of the occipital foramen were calculated by means of PC software. The
      spinal foramen area could not be measured because of the too small surface
      accessible to the PC software used in our study. Correlation between the above
      measurements and cranial indexes (width-length and height-length) were
      calculated. Significant variety of the ovale and spinous foramina in size, shape,
      relation to each other and to the midline were analysed. Asymmetry of structure
      and location was observed in both examined groups of skulls. No cases of the lack
      of the ovale and spinous foramina were stated.

PMID- 12416931
TI  - Three-dimensional reconstruction of the lentiform nucleus from serial sections in
      man.
AB  - Three-dimensional (3-D) reconstruction of the lentiform nucleus was performed by
      using serial macroscopic anatomic sections, taken from a human cadaver. When the
      rendered form of this wire-frame reconstruction was examined, it was found that
      both the putamen and globus pallidus had upper and lower poles. The distances
      between the upper and lower poles were 2.23 cm in the putamen and 1.45 cm in the
      globus pallidus. The lower poles of the putamen and globus pallidus were about
      the same level but the upper pole of the putamen was 0.78 cm higher than in the
      globus pallidus. The vertical dimension of the lentiform nucleus was 22.9 mm.
      This is the first study reporting the three-dimensional reconstruction and the
      dimensions of the lentiform nucleus of the human brain. We believe that this
      study will be of help in future studies concerning the lentiform nucleus and its
      relations.

PMID- 12416932
TI  - Picture naming by children with hearing loss: I. Effect of semantically related
      auditory distractors.
AB  - Thirty children with hearing loss (HL) and 129 typically developing (TD) children
      representing comparable ages, vocabulary ability, or phonology skills named
      pictures while attempting to ignore semantically related or unrelated auditory
      distractors. The timing relation between the onsets of the distractors and
      pictures varied. A significant semantic interference effect, that is, slowed
      naming in the presence of the semantically related distractor, was observed in
      all groups, suggesting similar categorical knowledge in the HL and TD groups. The
      time course of semantic interference, however, was protracted in some children
      with HL, primarily those with unusually slow baseline naming speeds and early
      ages of identification/amplification of the loss. Thus, children with HL seem to
      develop normal lexical semantic representations. At the same time, the dynamics
      of semantic processing appear to be altered by the presence of early childhood
      HL.

PMID- 12416933
TI  - Picture naming by children with hearing loss: II. Effect of phonologically
      related auditory distractors.
AB  - Thirty children with hearing loss (HL) and 129 typically developing (TD) children
      representing comparable ages, vocabulary abilities, or phonology skills named
      pictures while attempting to ignore auditory distractors. The picture-distractor
      pairs were constructed to represent phonologically congruent or conflicting onset
      relations, for example, the picture "duck" with distractors of /[symbol: see
      text]/or /[symbol: see text]/, respectively. In children with good phoneme
      discrimination, congruent distractors speeded naming and conflicting distractors
      slowed naming, relative to a control condition. Effects were similar in HL and TD
      subgroups. In children with poorer phoneme discrimination, conflicting
      distractors did not influence naming in the HL subgroup, regardless of
      discrimination status, and consistently slowed naming only for discriminated
      contrasts in the TD subgroup. Phonologic representations appear suitably fine
      grained in HL children with good auditory perceptual abilities but may be less
      well specified, more holistic, and/or less auditory-linguistically based in HL
      children with poorer auditory perceptual abilities. Results are discussed in
      terms of the heterogeneous nature of phonologic processing in children with HL.

PMID- 12416934
TI  - Hearing loss, hearing handicap, and functional health status between African
      American and Caucasian American seniors.
AB  - This investigation examined the relations among hearing loss, handicap
      perception, and functional health status of 152 African American and Caucasian
      American seniors ranging in age from 60 to 89 years. Subjective measures were
      obtained from self-report scores on the Hearing Handicap Inventory for the
      Elderly (HHIE), the Medical Outcomes Study 36-Item Short Form Health Survey (SF
      36), and demographic profiles. Results indicated the following: (1) both subject
      groups exhibited nearly identical degrees of sensorineural hearing loss
      consistent with presbyacusis; (2) African American seniors reported significantly
      lower levels of completed education than did Caucasian American seniors; (3)
      differences between groups in self-report scores of hearing handicap (HHIE) were
      not statistically significant; (4) differences across groups in self-report
      scores of functional health status (SF-36) were not statistically significant;
      and (5) increasing levels of hearing loss produced significantly higher HHIE
      scores and significantly lower SF-36 scores in each group. These findings are
      discussed.

PMID- 12416935
TI  - Factors ensuring consistent audibility in pediatric hearing aid fitting.
AB  - Ensuring consistent audibility is an important objective when fitting hearing
      aids to children. This article reviews the factors that could affect the
      audibility of the speech signals to children. These factors range from a precise
      determination of the child's hearing loss to an accurate specification of gain in
      the chosen hearing aids. In addition, hearing aid technology and features such as
      multichannel processing, directional microphones, and feedback cancellation that
      could affect the achievement of consistent audibility are reviewed.

PMID- 12416936
TI  - Risks to students' lives: setting priorities.

PMID- 12416937
TI  - Guns and gun threats at college.
AB  - A random sample of more than 10,000 undergraduate students, selected from 119 4
      year colleges, answered a mailed questionnaire about gun possession and gun
      threats. Approximately 4.3% of the students reported that they had a working
      firearm at college, and 1.6% of them have been threatened with a gun while at
      school. Students are more likely to have a firearm at college and to be
      threatened with a gun while at college if they are male, live off campus, binge
      drink, engage in risky and aggressive behavior after drinking, and attend
      institutions in regions of the United States where household firearm prevalence
      is high. Having a firearm for protection is also strongly associated with being
      threatened with a gun while at college. Students who reported having firearms at
      college disproportionately reported that they engaged in behaviors that put
      themselves and others at risk for injury.

PMID- 12416938
TI  - Prevalence of allergy symptoms and associated medication use in a sample of
      college seniors.
AB  - The authors surveyed a random sample of college seniors at a university in Boston
      to determine the prevalence of allergy symptoms and the students' use of
      medications to relieve symptoms. Of the 400 individuals queries, 58.2% reported
      some symptoms during the previous year, and 63.0% of that group said their
      symptoms were moderate to severe. Just over 93.8% of the student respondents used
      medications to treat symptoms; 91.1% used over-the-counter (OTC) medications, and
      55.5% used prescription medications. More than one third had used OTC
      antihistamines before taking an examination during the previous year. Allergy
      like symptoms and associated medication use are common among college-aged
      students. The authors call for further research to determine whether these OTC
      and prescription medications affect academic performance.

PMID- 12416939
TI  - Physical activity among ethnically diverse college students.
AB  - The authors compared physical activity patterns among 874 Asian, 332 African,
      1,101 White, and 529 Hispanic American college students aged 18 to 25 years.
      According to self-report responses, 46.7% of the sample did not engage in
      vigorous physical activity and 16.7% were physically inactive. Among women,
      ethnic-specific rates of physical inactivity were Asian, 28.1%; African, 23.5%;
      White, 17.4%; and Hispanic, 20.3%. For men, rates of inactivity were Asian 11.7%;
      African, 7.7%; White, 12.0%; and Hispanic, 13.8. Weight-training activity,
      youthful physical activity, and TV viewing accounted for a significant portion of
      the variance in physical activity levels (13.1% for women and 14.8% for men). The
      results of this study support the need for physical activity interventions for
      college students, particularly minorities.

PMID- 12416940
TI  - A new approach to student alcohol abuse at Georgetown University.

PMID- 12416941
TI  - Harm reduction: a promising approach for college health.

PMID- 12416942
TI  - The meningococcal vaccine recommendation: what a tangled web we weave.

PMID- 12416943
TI  - Successful discontinuation of therapy for disseminated Mycobacterium avium
      complex infection after effective antiretroviral therapy.
AB  - BACKGROUND: Highly active antiretroviral therapy (HAART) is associated with
      improvement or resolution of several HIV-associated opportunistic infections.
      Although prophylaxis against disseminated Mycobacterium avium complex infection
      may be successfully discontinued after a favorable response to HAART, the 1999
      guidelines from the U.S. Public Health Service/Infectious Diseases Society of
      America recommend continuing therapy for disseminated M. avium complex infection,
      regardless of the response to HAART. OBJECTIVE: To examine the outcome among
      patients with disseminated M. avium complex infection whose antimycobacterial
      therapy was discontinued after a favorable response to HAART. DESIGN:
      Retrospective chart review between May 2000 and May 2001. SETTING: 13 Canadian
      HIV clinics. PATIENTS: 52 HIV-infected adults (43 men; mean age, 37.3 years) in
      whom successful antimycobacterial therapy for disseminated M. avium complex
      infection was discontinued after a favorable virologic response to HAART.
      MEASUREMENTS: Survival, survival free of disseminated M. avium complex infection,
      and CD4(+) cell count responses. RESULTS: At the time of diagnosis of
      disseminated M. avium complex infection, the median CD4(+) cell count was 0.016 x
      10(9) cells/L, and the median plasma HIV RNA level was 90 000 copies/mL (plasma
      HIV RNA levels were available for only 21 patients). The patients received a
      median of 32 months of antimycobacterial therapy that included ethambutol plus
      either clarithromycin or azithromycin. When antimycobacterial therapy was
      discontinued, the median CD4(+) cell count was 0.23 x 10(9) cells/L and the
      median plasma HIV RNA level was less than 50 copies/mL. A median of 20 months
      after discontinuation of antimycobacterial therapy, only 1 patient had developed
      recurrent M. avium complex disease (37 months after stopping antimycobacterial
      therapy). This patient had stopped HAART 2 months earlier because of uncontrolled
      HIV viremia. Twenty months after stopping antimycobacterial therapy, the other 51
      patients had a median CD4(+) cell count of 0.288 x 10(9) cells/L; 34 (67%) had
      undetectable plasma HIV RNA levels, and 8 (15%) had plasma HIV RNA levels of 50
      to 1000 copies/mL. CONCLUSIONS: Discontinuation of successful disseminated M.
      avium complex therapy after a successful response to HAART is safe and reduces
      patients' pill burdens, potential drug adverse effects, drug interactions, and
      costs of therapy.

PMID- 12416944
TI  - Next-day care for emergency department users with nonacute conditions. A
      randomized, controlled trial.
AB  - BACKGROUND: Because of overcrowding and cost-control efforts, emergency
      departments are under pressure to refer patients with nonacute conditions to
      other settings. However, no validated systematic methods exist for safely
      performing such referrals. OBJECTIVE: To determine the effects on health status
      and access to care of systematically referring patients with nonacute conditions
      to next-day primary care. DESIGN: Randomized, controlled trial. SETTING: An
      emergency department in a public hospital. PATIENTS: 156 adults who used the
      emergency department on weekdays from 7:00 a.m. to 3:00 p.m. and met criteria for
      deferred care. The criteria applied to three symptom complexes that account for
      33% of U.S. emergency department visits by adults. INTERVENTION: Next-day care at
      the study site's primary care center or usual same-day care. MEASUREMENTS: Self
      reported health status and use of health services during 1-week follow-up.
      RESULTS: Patients assigned to next-day care did not demonstrate clinically
      important disadvantages in health status or physician visits compared with usual
      care patients. In each group, more than 95% of patients were evaluated at least
      once by a physician, 4% sought health services after their initial evaluation,
      and no patients were hospitalized or died. At follow-up, both groups reported
      improved health status and fewer days in bed or with disability, although the
      deferred care group reported less improvement on all three measures. The 95% CIs
      were sufficiently narrow to exclude a clinically significant difference in self
      reported health status. However, the possibility of 1 additional day in bed or
      with disability in the deferred care group could not be excluded. CONCLUSIONS:
      Clinically detailed standardized screening criteria can safely identify patients
      at public hospital emergency departments for referral to next-day care. However,
      larger studies are needed to assess the possibility of adverse effects.

PMID- 12416945
TI  - Cardioselective beta-blockers in patients with reactive airway disease: a meta
      analysis.
AB  - OBJECTIVE: To assess the effect of cardioselective beta-blockers on respiratory
      function of patients with reactive airway disease. DATA SOURCES: Comprehensive
      searches of the EMBASE, MEDLINE, and CINAHL databases from 1966 to May 2001 and
      scanning of references of the identified articles and related reviews. STUDY
      SELECTION: Randomized, blinded, placebo-controlled trials that studied the
      effects of cardioselective beta-blockers on FEV1, symptoms, and the use of
      inhaled beta2-agonists in patients with reactive airway disease were selected.
      Interventions studied were the administration of a cardioselective beta-blocker
      and administration of beta2-agonist after the study drug. DATA EXTRACTION:
      Outcomes measured were the change in FEV1 from baseline, the number of patients
      with respiratory symptoms, and the use of inhaled beta2-agonists with active
      treatment compared with placebo. DATA SYNTHESIS: Nineteen studies on single-dose
      treatment and 10 studies on continued treatment were included. Administration of
      a single dose of a cardioselective beta-blocker was associated with a 7.46% (95%
      CI, 5.59% to 9.32%) decrease in FEV(1) and a 4.63% (CI, 2.47% to 6.78%) increase
      in FEV1 response to beta-agonist compared with placebo, with no increase in
      symptoms. Trials lasting from 3 days to 4 weeks produced no significant change in
      FEV1 (-0.42% [CI, -3.74% to 2.91%]), symptoms, or inhaler use compared with
      placebo but maintained an 8.74% (CI, 1.96% to 15.52%) increase in beta-agonist
      response. No significant treatment effect in terms of FEV1 was found in patients
      with concomitant chronic obstructive pulmonary disease, whether single doses
      (change in FEV1, -5.28% [CI, -10.03% to -0.54%]) or continued treatment (change
      in FEV1, 1.07% [CI, -3.3% to 5.44%]) was given. CONCLUSIONS: Cardioselective beta
      blockers do not produce clinically significant adverse respiratory effects in
      patients with mild to moderate reactive airway disease. The results were similar
      for patients with concomitant chronic airways obstruction. Given their
      demonstrated benefit in such conditions as heart failure, cardiac arrhythmias,
      and hypertension, cardioselective beta-blockers should not be withheld from
      patients with mild to moderate reactive airway disease.

PMID- 12416947
TI  - A novel incentive system for faculty in an academic medical center.
AB  - The need to contain health care costs has led some physicians to become salaried
      employees of health care organizations. However, the use of nonfinancial
      incentives for physicians in such an environment has not been broadly explored.
      The authors describe a novel incentive system that is designed to promote
      continuing high-quality care and to increase patient access to health care while
      enhancing clinical and academic productivity and physician satisfaction. Key
      components of this system include annual targets, flexibility in meeting these
      targets, and ability to convert clinical productivity generated in excess of what
      was necessary to meet the target to support scholarly activities. This system led
      to increased faculty productivity, improved patient access, enhanced scholarly
      activity, and overall enhanced career satisfaction.

PMID- 12416946
TI  - Concomitant leflunomide therapy in patients with active rheumatoid arthritis
      despite stable doses of methotrexate. A randomized, double-blind, placebo
      controlled trial.
AB  - BACKGROUND: Disease-modifying antirheumatic drugs may confer greater benefits
      when combined with the antimetabolite methotrexate. OBJECTIVE: To evaluate the
      efficacy and safety of leflunomide versus placebo when added to ongoing, stable
      dose methotrexate therapy in patients with persistently active rheumatoid
      arthritis. DESIGN: 24-week, multicenter, randomized, double-blind, placebo
      controlled trial. SETTING: 20 centers in the United States and Canada. PATIENTS:
      Patients with persistent rheumatoid arthritis, as defined by American College of
      Rheumatology (ACR) criteria, despite receiving methotrexate for at least 6
      months. INTERVENTION: Leflunomide or matching placebo added to existing
      methotrexate therapy. MEASUREMENTS: The primary efficacy variable was the rate of
      achievement of 20% improvement in ACR criteria (ACR20) at the end of the study.
      The Health Assessment Questionnaire Disability Index was assessed at each visit,
      and the Medical Outcomes Study 36-Item Short Form was completed as an end point
      analysis. RESULTS: In the leflunomide and placebo groups, 46.2% and 19.5% of
      patients, respectively, met ACR20 criteria at 24 weeks (P < 0.001). Clinical
      improvement was demonstrated by statistically significant mean changes in
      individual components of the ACR20 response criteria. Discontinuation rates were
      similar in both treatment groups (23.1% in the leflunomide group and 24.8% in the
      placebo group), as were the overall incidences of adverse events (89.2% vs.
      89.5%, respectively). Adverse events were predominantly mild or moderate.
      CONCLUSIONS: Combination therapy with leflunomide and methotrexate provides
      statistically significant clinical benefit in patients with active rheumatoid
      arthritis who are receiving methotrexate therapy. Leflunomide plus methotrexate
      is generally well tolerated and can be used safely with appropriate liver enzyme
      and hematologic monitoring.

PMID- 12416948
TI  - Diagnosis and treatment of acute tubular necrosis.
AB  - BACKGROUND: Acute tubular necrosis (ATN) is common in hospitalized patients,
      particularly in the intensive care unit. Over the past four decades, the
      mortality rate from ATN has remained at 50% to 80%. PURPOSE: To review recent
      studies of diagnosis and treatment strategies for ATN. DATA SOURCES: MEDLINE
      search for all clinical studies of therapies for ATN, supplemented by a review of
      the references of the identified articles. STUDY SELECTION: Prospective studies
      and major retrospective studies evaluating therapies for ATN. DATA EXTRACTION:
      Data on the study sample, interventions performed, results, side effects, and
      duration of follow-up. DATA SYNTHESIS: Early diagnosis of ATN by exclusion of
      prerenal and postrenal causes of acute renal failure, examination of urinary
      sediment, and analysis of urine measures (for example, fractional excretion of
      sodium in the absence of diuretics) can allow the early involvement of
      nephrologists and improve survival. Enteral rather than parenteral
      hyperalimentation in severely malnourished patients may improve survival. Sepsis
      causes 30% to 70% of deaths in patients with ATN; therefore, avoidance of
      intravenous lines, bladder catheters, and respirators is recommended. Because
      septic patients are vasodilated, large volumes of administered fluid accumulate
      in the lung interstitium of these patients. This condition necessitates
      ventilatory support, which when prolonged leads to acute respiratory distress
      syndrome, multiorgan failure, and increased mortality. More aggressive dialysis
      (for example, given daily) with biocompatible membranes may improve survival in
      some patients with acute renal failure. CONCLUSIONS: New information about the
      importance of early diagnosis and supportive care for patients with ATN has
      emerged. However, randomized trials of these interventions are needed to test
      their effect on the morbidity and mortality of ATN.

PMID- 12416949
TI  - Dysautonomias: clinical disorders of the autonomic nervous system.
AB  - The term dysautonomia refers to a change in autonomic nervous system function
      that adversely affects health. The changes range from transient, occasional
      episodes of neurally mediated hypotension to progressive neurodegenerative
      diseases; from disorders in which altered autonomic function plays a primary
      pathophysiologic role to disorders in which it worsens an independent pathologic
      state; and from mechanistically straightforward to mysterious and controversial
      entities. In chronic autonomic failure (pure autonomic failure, multiple system
      atrophy, or autonomic failure in Parkinson disease), orthostatic hypotension
      reflects sympathetic neurocirculatory failure from sympathetic denervation or
      deranged reflexive regulation of sympathetic outflows. Chronic orthostatic
      intolerance associated with postural tachycardia can arise from cardiac
      sympathetic activation after "patchy" autonomic impairment or blood volume
      depletion or, as highlighted in this discussion, from a primary abnormality that
      augments delivery of the sympathetic neurotransmitter norepinephrine to its
      receptors in the heart. Increased sympathetic nerve traffic to the heart and
      kidneys seems to occur as essential hypertension develops. Acute panic can evoke
      coronary spasm that is associated with sympathoneural and adrenomedullary
      excitation. In congestive heart failure, compensatory cardiac sympathetic
      activation may chronically worsen myocardial function, which rationalizes
      treatment with beta-adrenoceptor blockers. A high frequency of positive results
      on tilt-table testing has confirmed an association between the chronic fatigue
      syndrome and orthostatic intolerance; however, treatment with the salt-retaining
      steroid fludrocortisone, which is usually beneficial in primary chronic autonomic
      failure, does not seem to be beneficial in the chronic fatigue syndrome.
      Dysautonomias are an important subject in clinical neurocardiology.

PMID- 12416950
TI  - Deferred care for patients in the emergency department.

PMID- 12416951
TI  - Fresh Air and beta-blockade.

PMID- 12416953
TI  - Smell.

PMID- 12416955
TI  - Bryant.

PMID- 12416957
TI  - Subgroup results in the DASH-sodium trial.

PMID- 12416958
TI  - Public expectation for annual physical examinations.

PMID- 12416959
TI  - Public expectation for annual physical examinations.

PMID- 12416960
TI  - Public expectation for annual physical examinations.

PMID- 12416962
TI  - Diphtheria and tetanus immunity.

PMID- 12416964
TI  - Lyme disease controversy: use and misuse of language.

PMID- 12416965
TI  - Lyme disease controversy: use and misuse of language.

PMID- 12416967
TI  - Lyme disease controversy: use and misuse of language.

PMID- 12416968
TI  - Lyme disease controversy: use and misuse of language.

PMID- 12416969
TI  - Octreotide therapy for the Sjogren syndrome.

PMID- 12416971
TI  - Writing for our lives: physician narratives and medical practice.

PMID- 12416972
TI  - Summaries for patients. Safety of stopping treatment for Mycobacterium avium
      complex infection in patients with AIDS.

PMID- 12416973
TI  - Summaries for patients. Combination therapy for rheumatoid arthritis.

PMID- 12416974
TI  - Summaries for patients. Are beta-1-blockers safe for patients with lung disease?

PMID- 12416975
TI  - Summaries for patients. Deferring emergency room care.

PMID- 12416976
TI  - Inaccurate glucose determination by fingerstick in a patient with peripheral
      arterial disease.

PMID- 12416977
TI  - Impact of enzyme motion on activity.
AB  - Experimental and theoretical data imply that enzyme motion plays an important
      role in enzymatic reactions. Enzyme motion can influence both the activation free
      energy barrier and the degree of barrier recrossing. A hybrid theoretical
      approach has been developed for the investigation of the relation between enzyme
      motion and activity. This approach includes both electronic and nuclear quantum
      effects. It distinguishes between thermally averaged promoting motions that
      influence the activation free energy barrier and dynamical motions that influence
      the barrier recrossings. Applications to hydride transfer in liver alcohol
      dehydrogenase and dihydrofolate reductase resulted in the identification and
      characterization of important enzyme motions. These applications have also led to
      the proposal of a network of coupled promoting motions in enzymatic reactions.
      These concepts have important implications for protein engineering and drug
      design.

PMID- 12416978
TI  - Activation of angiogenic signaling pathways by two human tRNA synthetases.
AB  - Aminoacyl-tRNA synthetases establish the rules of the genetic code by joining
      amino acids to tRNAs that bear the anticodon triplets corresponding to the
      attached amino acids. The enzymes are thought to be among the earliest proteins
      to appear, in the transition from a putative RNA world to the theater of
      proteins. Over their long evolution, the enzymes have acquired additional
      functions that typically require specialized insertions or domain fusions.
      Recently, fragments of the closely related human tyrosyl- and tryptophanyl-tRNA
      synthetases were discovered to be active in angiogenesis signaling pathways. One
      synthetase fragment has proangiogenic activity, while the other is
      antiangiogenic. Activity was demonstrated in cell-based assays in vitro and in
      vivo in the chick embryo, and in the neonatal and adult mouse. The full-length,
      native enzymes are inactive in these same assays. Activation of angiogenesis
      activity requires fragment production from the native enzymes by protease
      cleavage or by translation of alternatively spliced pre-mRNA. Thus, these tRNA
      synthetases link translation to a major cell-signaling pathway in mammalian
      cells. The results with animals suggest that therapeutic applications are
      possible with these tRNA synthetases.

PMID- 12416980
TI  - Characterization of large peptide fragments derived from the N-terminal domain of
      the ribosomal protein L9: definition of the minimum folding motif and
      characterization of local electrostatic interactions.
AB  - A set of peptides derived from the N-terminal domain of the ribosomal protein L9
      (NTL9) have been characterized in an effort to define the minimum unit of this
      domain required to fold and to provide model peptides for the analysis of
      electrostatic interactions in the unfolded state. NTL9 is a 56-residue alpha-beta
      protein with a beta1-loop-beta2-alpha1-beta3-alpha2 topology. The beta-sheet
      together with the first helix comprise a simple example of a common
      supersecondary motif called the split beta-alpha-beta fold. Peptides
      corresponding to the beta1-loop-beta2 unit are unstructured even when constrained
      by an introduced disulfide. The pK(a)s of Asp-8 and Glu-17 in these peptides are
      slightly lower than the values found for shorter peptides but are considerably
      higher than the values in NTL9. A 34-residue peptide, which represents the beta1
      loop-beta2-alpha1 portion of NTL9, is also unstructured. In contrast, a 39
      residue peptide corresponding to the entire split beta-alpha-beta motif is folded
      and monomeric as judged by near- and far-UV CD, two-dimensional NMR, ANS binding
      experiments, pK(a) measurements, and analytical ultracentrifugation. The fold is
      very similar to the structure of this region in the intact protein. Thermal and
      urea unfolding experiments show that it is cooperatively folded with a DeltaG
      degrees of unfolding of 1.8-2.0 kcal/mol and a T(m) of 58 degrees C. This peptide
      represents the first demonstration of the independent folding of an isolated
      split beta-alpha-beta motif, and is one of only four naturally occurring
      sequences of fewer than 40 residues that has been shown to fold cooperatively in
      the absence of disulfides or ligand binding.

PMID- 12416979
TI  - Characterization of the surfactin synthetase C-terminal thioesterase domain as a
      cyclic depsipeptide synthase.
AB  - The C-terminal thioesterase domain of the nonribosomal peptide synthetase
      producing the lipopetide surfactin (Srf TE) retains autonomous ability to
      generate the cyclic peptidolactone skeleton of surfactin when provided with a
      soluble beta-hydroxy-butyryl-heptapeptidyl thioester substrate. Utilizing the
      recently solved crystal structure [Bruner, S. D., et al. (2002) Structure 10, 301
      310], the active-site nucleophile, Ser80, was changed to Cys, and the other
      members of the catalytic triad, Asp107 and His207, were changed to Ala, with the
      resulting mutants lacking detectable activity. Two cationic side chains in the
      active site, Lys111 and Arg120, were changed to Ala, causing an increased
      partitioning of the product to hydrolysis, as did a P26G mutant, mimicking the
      behavior of lipases. To evaluate recognition elements in substrates used by Srf
      TE, alterations to the fatty acyl group, the heptapeptide, and the thioester
      leaving group were made, and the resulting substrates were characterized for
      kinetic competency and flux of product to cyclization or hydrolysis. Alterations
      that could be accepted for cyclization were identified in all three parts of the
      substrate, although tolerance limits for changes varied. In addition, cocrystal
      structures of Srf TE with dipeptidyl boronate inhibitors were solved,
      illustrating the critical binding determinants of the substrate. On the basis of
      the structures and biochemical data, the cyclizing conformation of the surfactin
      peptide was modeled into the enzyme active site.

PMID- 12416981
TI  - Kinetic evidence for a substrate-induced fit in phosphonoacetaldehyde hydrolase
      catalysis.
AB  - Phosphonoacetaldehyde hydrolase (phosphonatase) from Bacillus cereus catalyzes
      hydrolytic P-C bond cleavage of phosphonoacetaldehyde (Pald) via a Schiff base
      intermediate formed with Lys53. A single turnover requires binding of Pald to the
      active site of the core domain, closure of the cap domain containing the Lys53
      over the core domain, and dissociation of the products following catalysis. The
      ligand binding and dissociation steps occur from the "open conformer" (domains
      are separated and the active site is solvent-exposed), while catalysis occurs
      from the "closed conformer" (domains are bound together and the active site is
      sequestered from solvent). To test the hypothesis that bound substrate stabilizes
      the closed conformer, thus facilitating catalysis, the rates of chemical
      modification of Lys53 in the presence and absence of inert substrate and/or
      product analogues were compared. Acetylation of Lys53 with 2,4
      dinitrophenylacetate (DNPA) resulted in the loss of enzyme activity. The pseudo
      first-order rate constant for inactivation varied with pH. The pH profile of
      inactivation is consistent with a pK(a) of 9.3 for Lys53. The inhibitors
      tungstate and vinyl sulfonate, which are known to bind to active site residues
      comprising the core domain, protected Lys53 from acetylation. These results are
      consistent with a dynamic equilibrium between the open and closed conformations
      of phosphonatase and the hypothesis that ligand binding stabilizes the closed
      conformation required for catalytic turnover.

PMID- 12416982
TI  - Differences in the efficiency of reductive activation of methionine synthase and
      exogenous electron acceptors between the common polymorphic variants of human
      methionine synthase reductase.
AB  - Methionine synthase reductase (MSR) catalyzes the conversion of the inactive form
      of human methionine synthase to the active state of the enzyme. This reaction is
      of paramount physiological importance since methionine synthase is an essential
      enzyme that plays a key role in the methionine and folate cycles. A common
      polymorphism in human MSR has been identified (66A --> G) that leads to
      replacement of isoleucine with methionine at residue 22 and has an allele
      frequency of 0.5. Another polymorphism is 524C --> T, which leads to the
      substitution of serine 175 with leucine, but its allele frequency is not known.
      The I22M polymorphism is a genetic determinant for mild hyperhomocysteinemia, a
      risk factor for cardiovascular disease. In this study, we have examined the
      kinetic properties of the M22/S175 and I22/S175 and the I22/L175 and I22/S175
      pairs of variants. EPR spectra of the semiquinone forms of variants I22/S175 and
      M22/S175 are indistinguishable and exhibit an isotropic signal at g = 2.00. In
      addition, the electronic absorption and reduction stoichiometries with NADPH are
      identical in these variants. Significantly, the variants activate methionine
      synthase with the same V(max); however, a 3-4-fold higher ratio of MSR to
      methionine synthase is required to elicit maximal activity with the M22/S175 and
      I22/L175 variant versus the I22/S175 enzyme. Differences are also observed
      between the variants in the efficacies of reduction of the artificial electron
      acceptors: ferricyanide, 2,6-dichloroindophenol, 3-acetylpyridine adenine
      dinucleotide phosphate, menadione, and the anticancer drug doxorubicin. These
      results reveal differences in the interactions between the natural and artificial
      electron acceptors and MSR variants in vitro, which are predicted to result in
      less efficient reductive repair of methionine synthase in vivo.

PMID- 12416983
TI  - Protein stabilization by urea and guanidine hydrochloride.
AB  - The urea, guanidine hydrochloride, salt, and temperature dependence of the rate
      of dissociation of CO from a nonequilibrium state of CO-bound native
      ferrocytochrome c has been studied at pH 7. The heme iron of ferrocytochrome c in
      the presence of denaturing concentrations of guanidine hydrochloride (GdnHCl) and
      urea prepared in 0.1 M phosphate, pH 7, binds CO. When the unfolded protein
      solution is diluted 101-fold into CO-free folding buffer, the protein chain
      refolds completely, leaving the CO molecule bonded to the heme iron.
      Subsequently, slow thermal dissociation of the CO molecule yields to the heme
      coordination of the native M80 ligand. Thus, the reaction monitors the rate of
      thermal conversion of the CO-liganded native ferrocytochrome c to the M80
      liganded native protein. The rate of this reaction, k(diss), shows a
      characteristic dependence on the presence of nondenaturing concentrations of the
      denaturants in the reaction medium. The rate decreases by approximately 1.9-3
      fold as the concentration of GdnHCl in the refolding medium increases from nearly
      0 to approximately 2.1 M. Similarly, the rate decreases by 1.8-fold as the urea
      concentration is raised from 0.l to approximately 5 M. At still higher
      concentrations of the denaturants the denaturing effect sets in, the protein is
      destabilized, and hence the CO dissociation rate increases sharply. The
      activation energy of the reaction, E(a), increases when the denaturant
      concentration in the reaction medium is raised: from 24.1 to 28.3 kcal mol(-1)
      for a 0.05-2.1 M rise in GdnHCl and from 25.2 to 26.9 kcal mol(-1) for a 0.1-26.9
      M increase in urea. Corresponding to these increases in denaturant concentrations
      are also increases in the activation entropy, S(diss)/R, where R is the gas
      constant of the reaction. The denaturant dependence of these kinetic and
      thermodynamic parameters of the CO dissociation reaction suggests that binding
      interactions with GdnHCl and urea can increase the structural and energetic
      stability of ferrocytochrome c up to the limit of the subdenaturing
      concentrations of the additives. NaCl and Na(2)SO(4), which stabilize proteins
      through their salting-in effect, also decrease the rate with a corresponding
      increase in activation entropy of CO dissociation from CO-bound native
      ferrocytochrome c, lending support to the view that low concentrations of GdnHCl
      and urea stabilize proteins. These results have direct relevance to the
      understanding and interpretation of the free energy-denaturant relationship and
      protein folding chevrons.

PMID- 12416984
TI  - Interaction of human DNA topoisomerase II alpha with DNA: quantification by
      surface plasmon resonance.
AB  - DNA topoisomerase II is an ATP-operated clamp that effects topological changes by
      capturing a double-stranded DNA segment and transporting it through another
      duplex. Surface plasmon resonance (SPR) was used to characterize interactions of
      human topoisomerase II alpha with different topological forms of DNA. Using a
      linear fragment of pUC18 DNA, the equilibrium binding constant of topoisomerase
      II alpha was determined to be 0.16 nM. The affinity was not affected by the
      absence of ATP or the presence of the bisdioxopiperazine catalytic inhibitor ICRF
      187. Besides, similar affinities were found for several bisdioxopiperazine
      resistant mutant enzymes. These results suggest that the mechanism of
      topoisomerase II alpha inhibition by ICRF-187 and its resistance does not
      directly involve the interaction of DNA with the enzyme. SPR was also adapted to
      measure levels of the closed clamp form of topoisomerase II present on DNA. As
      expected, a stable closed clamp form of the enzyme was detectable on circular DNA
      but not on linear DNA. Detection of the closed clamp required the presence of ATP
      and a bisdioxopiperazine, or a non-hydrolyzable analogue of ATP. In the presence
      of ATP and ICRF-187, several bisdioxopiperazine-resistant mutant enzymes failed
      to form detectable levels of stable closed clamp. Interestingly, a mutant of
      human topoisomerase II alpha with an altered active site tyrosine showed lower
      levels of closed clamp formation. In conclusion, SPR is able to (1) determine the
      kinetics of topoisomerase II with its DNA substrate and (2) quantify the enzyme's
      closed clamp formation under varying circumstances.

PMID- 12416985
TI  - Mutational analysis of baculovirus phosphatase identifies structural residues
      important for triphosphatase activity in vitro and in vivo.
AB  - Baculovirus phosphatase (BVP) and mammalian capping enzyme (Mce1) are members of
      the RNA triphosphatase branch of the cysteine phosphatase superfamily. Although
      RNA triphosphatases have a core alpha/beta fold similar to other cysteine
      phosphatases, there is little conservation of primary structure outside of the
      cysteine-containing P-loop motif, HCxxxxxR(S/T), that comprises the active site.
      However, there is extensive primary structure conservation between members of the
      RNA triphosphatase branch, whether from cellular or viral sources and whether
      they are bifunctional capping enzymes such as Mce1 or monofunctional RNA
      phosphatases such as BVP. To evaluate the functional significance of such
      sequence conservation, we performed a mutational analysis of 14 residues of BVP.
      We identified three side chains (Trp6, Lys25, and Arg153) as essential for
      triphosphatase activity in vitro, i.e., W6A, K25A, and R153A were <0.1% as active
      as wild-type BVP, and were unable to complement a yeast RNA triphosphatase null
      mutant in vivo. Six other BVP residues (Thr62, Tyr67, Tyr68, Lys82, Glu158, and
      Arg159) were deemed functionally important, i.e., Ala mutations reduced
      triphosphatase activity to <20% of wild-type. On the basis of the locations of
      the equivalent amino acids in the Mce1 crystal structure, we surmise that the
      essential/important BVP residues ensure proper conformation of the catalytic P
      loop (e.g., Arg153 and Tyr68) or other elements of the tertiary structure. Our
      results highlight a conserved Trp6-Lys25 pi-cation pair essential for BVP
      function.

PMID- 12416986
TI  - Isolation of a single activating allosteric interaction in phosphofructokinase
      from Escherichia coli.
AB  - Escherichia coli phosphofructokinase 1 (EcPFK) is a homotetramer with four active
      and four allosteric sites. Understanding of the structural basis of allosteric
      activation of EcPFK by MgADP is complicated by the multiplicity of binding sites.
      To isolate a single heterotropic allosteric interaction, hybrid tetramers were
      formed between wild-type and mutant EcPFK subunits in which the binding sites of
      the mutant subunits have decreased affinity for their respective ligands. The 1:3
      (wild-type:mutant) hybrid that contained only one native active site and one
      native allosteric site was isolated. The affinity for the substrate fructose-6
      phosphate (Fru-6-P) of a single wild-type active site is greatly decreased over
      that displayed by the wild-type tetramer due to the lack of homotropic
      activation. The free energy of activation by MgADP for this heterotropic
      interaction is -0.58 kcal/mol at 8.5 degrees C. This compares to -2.87 kcal/mol
      for a hybrid with no homotropic coupling but all four unique heterotropic
      interactions. Therefore, the isolated interaction contributes 20% of the total
      heterotropic coupling. By comparison, wild-type EcPFK exhibits a coupling free
      energy between Fru-6-P and MgADP of -1.56 kcal/mol under these conditions,
      indicating that the effects of MgADP are diminished by a homotropic activation
      equal to -1.3 kcal/mol. These data are not consistent with a concerted allosteric
      mechanism.

PMID- 12416987
TI  - A mutation in subunit I of cytochrome oxidase from Rhodobacter sphaeroides
      results in an increase in steady-state activity but completely eliminates proton
      pumping.
AB  - The heme-copper oxidases convert the free energy liberated in the reduction of
      O(2) to water into a transmembrane proton electrochemical potential (protonmotive
      force). One of the essential structural elements of the enzyme is the D-channel,
      which is thought to be the input pathway, both for protons which go to form H(2)O
      ("chemical protons") and for protons that get translocated across the lipid
      membrane ("pumped protons"). The D-channel contains a chain of water molecules
      extending about 25 A from an aspartic acid (D132 in the Rhodobacter sphaeroides
      oxidase) near the cytoplasmic ("inside") enzyme surface to a glutamic acid (E286)
      in the protein interior. Mutations in which either of these acidic residues is
      replaced by their corresponding amides (D132N or E286Q) result in severe
      inhibition of enzyme activity. In the current work, an asparagine located in the
      D-channel has been replaced by the corresponding acid (N139 to D; N98 in bovine
      enzyme) with dramatic consequences. The N139D mutation not only completely
      eliminates proton pumping but, at the same time, confers a substantial increase
      (150-300%) in the steady-state cytochrome oxidase activity. The N139D mutant of
      the R. sphaeroides oxidase was further characterized by examining the rates of
      individual steps in the catalytic cycle. Under anaerobic conditions, the rate of
      reduction of heme a(3) in the fully oxidized enzyme, prior to the reaction with
      O(2), is identical to that of the wild-type oxidase and is not accelerated.
      However, the rate of reaction of the fully reduced enzyme with O(2) is
      accelerated by the N139D mutation, as shown by a more rapid F --> O transition.
      Whereas the rates of formation and decay of the oxygenated intermediates are
      altered, the nature of the oxygenated intermediates is not perturbed by the N139D
      mutation.

PMID- 12416988
TI  - Structure of rhodopsin in monolayers at the air-water interface: a PM-IRRAS and X
      ray reflectivity study.
AB  - Monomolecular films of the membrane protein rhodopsin have been investigated in
      situ at the air-water interface by polarization modulation infrared reflection
      absorption spectroscopy (PM-IRRAS) and X-ray reflectivity in order to find
      conditions that retain the protein secondary structure. The spreading of
      rhodopsin at 0 or 5 mN m(-1) followed by a 30 min incubation time at 21 degrees C
      resulted in the unfolding of rhodopsin, as evidenced from the large increase of
      its molecular area, its small monolayer thickness, and the extensive formation of
      beta-sheets at the expense of the alpha-helices originally present in rhodopsin.
      In contrast, when spreading is performed at 5 or 10 mN m(-1) followed by an
      immediate compression at, respectively, 4 or 21 degrees C, the secondary
      structure of rhodopsin is retained, and the thickness of these films is in good
      agreement with the size of rhodopsin determined from its crystal structure. The
      amide I/amide II ratio also allowed to determine that the orientation of
      rhodopsin only slightly changes with surface pressure and it remains almost
      unchanged when the film is maintained at 20 mN m(-1) for 120 min at 4 degrees C.
      In addition, the PM-IRRAS spectra of rod outer segment disk membranes in
      monolayers suggest that rhodopsin also retained its secondary structure in these
      films.

PMID- 12416989
TI  - Stoichiometric production of hydrogen peroxide and parallel formation of ferric
      multimers through decay of the diferric-peroxo complex, the first detectable
      intermediate in ferritin mineralization.
AB  - The catalytic step that initiates formation of the ferric oxy-hydroxide mineral
      core in the central cavity of H-type ferritin involves rapid oxidation of ferrous
      ion by molecular oxygen (ferroxidase reaction) at a binuclear site (ferroxidase
      site) found in each of the 24 subunits. Previous investigators have shown that
      the first detectable reaction intermediate of the ferroxidase reaction is a
      diferric-peroxo intermediate, F(peroxo), formed within 25 ms, which then leads to
      the release of H(2)O(2) and formation of ferric mineral precursors. The
      stoichiometric relationship between F(peroxo), H(2)O(2), and ferric mineral
      precursors, crucial to defining the reaction pathway and mechanism, has now been
      determined. To this end, a horseradish peroxidase-catalyzed spectrophotometric
      method was used as an assay for H(2)O(2). By rapidly mixing apo M ferritin from
      frog, Fe(2+), and O(2) and allowing the reaction to proceed for 70 ms when
      F(peroxo) has reached its maximum accumulation, followed by spraying the reaction
      mixture into the H(2)O(2) assay solution, we were able to quantitatively
      determine the amount of H(2)O(2) produced during the decay of F(peroxo). The
      correlation between the amount of H(2)O(2) released with the amount of F(peroxo)
      accumulated at 70 ms determined by Mossbauer spectroscopy showed that F(peroxo)
      decays into H(2)O(2) with a stoichiometry of 1 F(peroxo):H(2)O(2). When the decay
      of F(peroxo) was monitored by rapid freeze-quench Mossbauer spectroscopy,
      multiple diferric mu-oxo/mu-hydroxo complexes and small polynuclear ferric
      clusters were found to form at rate constants identical to the decay rate of
      F(peroxo). This observed parallel formation of multiple products (H(2)O(2),
      diferric complexes, and small polynuclear clusters) from the decay of a single
      precursor (F(peroxo)) provides useful mechanistic insights into ferritin
      mineralization and demonstrates a flexible ferroxidase site.

PMID- 12416990
TI  - Regulation of elongation factor-2 kinase by pH.
AB  - Elongation factor-2 kinase (eEF-2K) is a Ca(2+)/calmodulin-dependent protein
      kinase that phosphorylates and inactivates eEF-2 and that can regulate the rate
      of protein synthesis at the elongation stage. Here we report that a slight
      decrease in pH, within the range observed in vivo, leads to a dramatic activation
      of eEF-2K. The activity of eEF-2K in mouse liver extracts, as well as the
      activity of purified recombinant human eEF-2K, is low at pH 7.2-7.4 and is
      increased by severalfold when the pH drops to 6.6-6.8. eEF-2K requires calmodulin
      for activity at neutral as well as acidic pH. Kinetic studies demonstrate that
      the pH does not affect the K(M) for ATP or eEF-2 and activation of eEF-2K at
      acidic pH is due to an increase in V(max). To analyze the potential role of eEF
      2K in regulating protein synthesis by pH, we constructed a mouse fibroblast cell
      line that expresses eEF-2K in a tetracycline-regulated manner. Overexpression of
      eEF-2K led to a decreased rate of protein synthesis at acidic pH, but not at
      neutral pH. Our results suggest that pH-dependent activation of eEF-2K may play a
      role in the global inhibition of protein synthesis during tissue acidosis, which
      accompanies such processes as hypoxia and ischemia.

PMID- 12416991
TI  - Kinetics of allopregnanolone formation catalyzed by human 3 alpha-hydroxysteroid
      dehydrogenase type III (AKR1C2).
AB  - Allopregnanolone is a neurosteroid which exhibits anxiolytic and anticonvulsant
      activities through potentiation of the GABA(A) receptor. The reduction of 5alpha
      dihydroprogesterone (5alpha-DHP), the last step in allopregnanolone biosynthesis,
      is catalyzed by 3alpha-hydroxysteroid dehydrogenases (3alpha-HSDs). While the
      mechanism of action of allopregnanolone and the physiological and pharmacological
      modulation of allopregnanolone concentrations in vivo have been extensively
      studied, there has been little characterization of the kinetics of human 3alpha
      HSD catalyzed allopregnanolone formation. We report here determination of the
      kinetic mechanism for 5alpha-DHP reduction catalyzed by human 3alpha-HSD type III
      by using steady-state kinetics studies and assessment of the ability of
      fluoxetine and various other small molecules to activate 3alpha-HSD type III
      catalyzed allopregnanolone formation. Enzyme-catalyzed 5alpha-DHP reduction
      yielded two products, allopregnanolone and 5alpha,20alpha-tetrahydroprogesterone,
      as measured by using a radiometric thin-layer chromatography assay, while 5beta
      DHP reduction yielded the neurosteroid pregnanolone as the only product. 5Beta
      DHP reduction proceeded with a catalytic efficiency 10 times higher than that of
      5alpha-DHP reduction. Two-substrate kinetic analysis and dead-end inhibition
      studies for 5alpha-DHP reduction and allopregnanolone oxidation indicated that
      3alpha-HSD type III utilized a ternary complex (sequential) kinetic mechanism,
      with nicotinamide adenine dinucleotide cofactor binding before steroid substrate
      and leaving after steroid product. Since previous reports suggested that
      fluoxetine and certain other small molecules increased allopregnanolone
      concentrations in vivo by activating 3alpha-HSD type III, we investigated whether
      these small molecules were able to activate human 3alpha-HSD type III. Our
      results showed that, at concentrations up to 50 microM, fluoxetine, paroxetine,
      sertraline, norfluoxetine, carbamazepine, clozapine, flurbiprofen, and
      sulfobromophthalein did not activate the enzyme. These results characterize the
      role of 3alpha-HSD type III in allopregnanolone formation and suggest that
      activation of this enzyme by fluoxetine is likely not the mechanism by which
      fluoxetine increases allopregnanolone concentrations.

PMID- 12416992
TI  - Myoglobin scavenges peroxynitrite without being significantly nitrated.
AB  - We have analyzed in detail hemoglobin (Hb) and myoglobin (Mb) after treatment of
      different forms of these proteins with variable amounts of peroxynitrite. HPLC
      analyses of the peroxynitrite-treated proteins subjected either to acid
      hydrolysis or Pronase digestion showed that only very low quantities of 3
      nitrotyrosine are formed when equivalent amounts of peroxynitrite are allowed to
      react with the oxy form of these proteins. Comparable amounts of nitrated amino
      acids are formed when metMb and metHb are treated with peroxynitrite under
      analogous conditions, but significantly larger yields are observed with apoMb and
      metMbCN. Interestingly, in addition we found that also the tryptophan residues of
      Mb and Hb are nitrated to a low but detectable extent. Taken together, our data
      suggest that the heme center of Mb may act as an efficient scavenger of
      peroxynitrite, protecting the globin from nitration. As peroxynitrite can
      irreversibly inhibit cytochrome c oxidase, oxyMb may utilize an additional
      important pathway to maintain mitochondrial respiration, that is, rapidly react
      with peroxynitrite and thus prevent nitration of other cellular components.

PMID- 12416994
TI  - Ellman's-reagent-mediated regeneration of trypanothione in situ: substrate
      economical microplate and time-dependent inhibition assays for trypanothione
      reductase.
AB  - Trypanothione reductase (TryR) is a key enzyme involved in the oxidative stress
      management of the Trypanosoma and Leishmania parasites, which helps to maintain
      an intracellular reducing environment by reduction of the small-molecular-mass
      disulphide trypanothione (T[S](2)) to its di-thiol derivative
      dihydrotrypanothione (T[SH](2)). TryR inhibition studies are currently impaired
      by the prohibitive costs of the native enzyme substrate T[S](2). Such costs are
      particularly notable in time-dependent and high-throughput inhibition assays. In
      the present study we report a protocol that greatly decreases the substrate
      quantities needed for such assays. This is achieved by coupling the assay with
      the chemical oxidant 5,5'-dithiobis-(2-nitrobenzoic acid) (DTNB), which can
      rapidly re-oxidize the T[SH](2) product back into the disulphide substrate
      T[S](2), thereby maintaining constant substrate concentrations and avoiding
      deviations from rate linearity due to substrate depletion. This has enabled the
      development of a continuous microplate assay for both classical and time
      dependent TryR inhibition in which linear reaction rates can be maintained for 60
      min or more using minimal substrate concentrations (<1 microM, compared with a
      substrate K (m) value of 30 microM) that would normally be completely consumed
      within seconds. In this manner, substrate requirements are decreased by orders of
      magnitude. The characterization of a novel time-dependent inhibitor, cis -3-oxo
      8,9b-bis-(N(1)-acrylamidospermidyl)-1,2,3,4,4a,9b-hexahydrobenzofuran (PK43), is
      also described using these procedures.

PMID- 12416993
TI  - Hepatocyte nuclear factor-4 alpha mediates the stimulatory effect of peroxisome
      proliferator-activated receptor gamma co-activator-1 alpha (PGC-1 alpha) on
      glucose-6-phosphatase catalytic subunit gene transcription in H4IIE cells.
AB  - It has recently been shown that adenoviral-mediated expression of peroxisome
      proliferator-activated receptor gamma co-activator-1 alpha (PGC-1 alpha) in
      hepatocytes stimulates glucose-6-phosphatase catalytic subunit (G6Pase) gene
      expression. A combination of fusion gene, gel retardation and chromatin
      immunoprecipitation assays revealed that, in H4IIE cells, PGC-1 alpha mediates
      this stimulation through an evolutionarily conserved region of the G6Pase
      promoter that binds hepatocyte nuclear factor-4 alpha.

PMID- 12416995
TI  - Ceramide 1-phosphate increases intracellular free calcium concentrations in
      thyroid FRTL-5 cells: evidence for an effect mediated by inositol 1,4,5
      trisphosphate and intracellular sphingosine 1-phosphate.
AB  - Sphingolipid (SP) derivatives have diverse effects on the regulation of
      intracellular free calcium concentrations ([Ca2+]i) in a multitude of non
      excitable cells. In the present investigation, the effect of C2-ceramide 1
      phosphate (C1P) on [Ca2+]i was investigated in thyroid FRTL-5 cells. C1P evoked a
      concentration-dependent increase in [Ca2+]i, both in a calcium-containing and a
      calcium-free buffer. A substantial part of the C1P-evoked increase in [Ca2+]i was
      due to calcium entry. The effect of C1P was attenuated by overnight pretreatment
      of the cells with pertussis toxin. Similar results were obtained with C8-ceramide
      1-phosphate, although the magnitude of the responses was smaller than with C1P.
      The phospholipase C inhibitor U73122 attenuated the effect of C1P. C1P invoked a
      small, but significant, increase in inositol 1,4,5-trisphosphate (IP3). However,
      the effect of C1P on [Ca2+]i was inhibited by neither Xestospongin C, 2
      aminoethoxydiphenylborate nor neomycin. C1P mobilized calcium from an IP3
      sensitive calcium store, as C1P did not increase [Ca2+]i in cells pretreated with
      thapsigargin. The effect of C1P on [Ca2+]i was potently attenuated by
      dihydrosphingosine and dimethylsphingosine, two inhibitors of sphingosine kinase,
      but not by the inactive SP-derivative N -acetyl sphingosine. Stimulating the
      cells with C1P evoked an increase in the production of intracellular sphingosine
      1-phosphate. C1P did not modulate DNA synthesis or the forskolin-evoked
      production of cAMP. The results indicate that C1P may be an important SP
      participating in cellular signalling.

PMID- 12416996
TI  - cDNA cloning, gene organization and expression analysis of human peptidylarginine
      deiminase type I.
AB  - Peptidylarginine deiminases (PADs) catalyse a post-translational modification of
      proteins through the conversion of arginine residues into citrullines. The
      existence of four isoforms of PAD (types I, II, III and IV) encoded by four
      different genes, which are distinct in their substrate specificities and tissue
      specific expression, was reported in rodents. In the present study, starting from
      epidermis polyadenylated RNA, we cloned by reverse transcriptase-PCR a full
      length cDNA encoding human PAD type I. The cDNA was 2711 bp in length and encoded
      a 663-amino-acid sequence. The predicted protein shares 75% identity with the rat
      PAD type I sequence, but displays only 50-57% identity with the three other known
      human isoforms. We have described the organization of the human PAD type I gene
      on chromosome 1p36. A recombinant PAD type I was produced in Escherichia coli and
      shown to be enzymically active. Human PAD type I mRNAs were detected by reverse
      transcriptase-PCR not only in the epidermis, but also in various organs,
      including prostate, testis, placenta, spleen and thymus. In human epidermis
      extracts analysed by Western blotting, PAD type I was detected as a 70 kDa
      polypeptide, in agreement with its predicted molecular mass. As shown by
      immunohistochemistry, the enzyme was expressed in all the living layers of human
      epidermis, with the labelling being increased in the granular layer. This is the
      first description of the human PAD type I gene and the first demonstration of its
      expression in epidermis.

PMID- 12416997
TI  - Human placental amino acid transporter genes: expression and function.
AB  - Recent findings on amino acid transporter genes are reviewed with particular
      focus on matching previously described transport systems to individual genes.
      Functional studies using cloned and expressed transporters are considered as the
      critical tool allowing identification of the functional properties of individual
      genes. Specifically, these experiments allow identification of the transported
      substrate amino acids and of the transport mechanism. We focus on the very recent
      discovery and properties of the heterodimeric family of amino acid transport
      proteins where two subunits encoded in different genes are required. For these
      transporters, co-expression of both subunits is mandatory for functional studies.
      The field of placental amino acid transport is further complicated by
      complexities arising from both gestational age-specific and species-specific gene
      expression. The function of the transporter also depends on its cellular
      localization in the trophoblast. In addition, for transporters that are coupled
      to ion gradients, both membrane potential and ion pumping will contribute to the
      rate of amino acid delivery to the fetus. Regulation of function is important not
      only for fetal nutrition but also for specific additional aspects of placental
      biology.

PMID- 12416998
TI  - Regulation of ovarian function: the role of anti-Mullerian hormone.
AB  - Anti-Mullerian hormone (AMH), also known as Mullerian inhibiting substance, is a
      member of the transforming growth factor beta superfamily of growth and
      differentiation factors. In contrast to other members of the family, which exert
      a broad range of functions in multiple tissues, the principal function of AMH is
      to induce regression of the Mullerian ducts during male sex differentiation.
      However, the patterns of expression of AMH and its type II receptor in the
      postnatal ovary indicate that AMH may play an important role in ovarian
      folliculogenesis. This review describes several in vivo and in vitro studies
      showing that AMH participates in two critical selection points of follicle
      development: it inhibits the recruitment of primordial follicles into the pool of
      growing follicles and also decreases the responsiveness of growing follicles to
      FSH.

PMID- 12416999
TI  - Sperm phospholipase Czeta from humans and cynomolgus monkeys triggers Ca2+
      oscillations, activation and development of mouse oocytes.
AB  - Fusion with a fertilizing spermatozoon induces the mammalian oocyte to undergo a
      remarkable series of oscillations in cytosolic Ca(2+), leading to oocyte
      activation and development of the embryo. The exact molecular mechanism for
      generating Ca(2+) oscillations has not been established. A sperm-specific zeta
      isoform of phospholipase C (PLCzeta) has been identified in mice. Mouse PLCzeta
      triggers Ca(2+) oscillations in mouse oocytes and exhibits properties synonymous
      with the 'sperm factor' that has been proposed to diffuse into the oocyte after
      gamete fusion. The present study isolated the PLCzeta homologue from human and
      cynomolgus monkey testes. Comparison with mouse and monkey PLCzeta protein
      sequences indicates a shorter X-Y linker region in human PLCzeta and predicts a
      distinctly different isoelectric point. Microinjection of complementary RNA for
      both human and cynomolgus monkey PLCzeta elicits Ca(2+) oscillations in mouse
      oocytes equivalent to those seen during fertilization in mice. Moreover, human
      PLCzeta elicits mouse egg activation and early embryonic development up to the
      blastocyst stage, and exhibits greater potency than PLCzeta from monkeys and
      mice. These results are consistent with the proposal that sperm PLCzeta is the
      molecular trigger for egg activation during fertilization and that the role and
      activity of PLCzeta is highly conserved across mammalian species.

PMID- 12417000
TI  - Modulation of nitric oxide concentration and lipid metabolism by 15-deoxy
      Delta12,14prostaglandin J2 in embryos from control and diabetic rats during early
      organogenesis.
AB  - The concentration of 15-deoxy Delta(12,14)PGJ(2) (15dPGJ(2)) and its effects on
      nitric oxide generation and neutral lipid in embryos from control and neonatal
      streptozotocin-induced (n-stz) diabetic rats during organogenesis were
      investigated. 15dPGJ(2) is produced in embryos during organogenesis, and its
      production is lower in embryos of n-stz diabetic rats than in embryos from
      control rats. Nitrate and nitrite concentrations were higher in embryos from n
      stz diabetic rats and were reduced in the presence of 15dPGJ(2) both in embryos
      from control and diabetic rats. Thus, decreased 15dPGJ(2) concentrations in
      embryos from n-stz diabetic rats may be related to the high nitric oxide
      concentrations found in those embryos. Exogenous 15dPGJ(2) decreased cholesterol
      and cholesteryl ester concentrations in embryos from control and n-stz diabetic
      rats, and reduced triacylglycerol concentrations in control embryos.
      Incorporation of [(14)C]acetate into lipids showed decreased de novo synthesis of
      cholesteryl ester and triacylglycerides in embryos from n-stz diabetic rats
      compared with controls. Exogenous 15dPGJ(2) reduced the incorporation of
      [(14)C]acetate into triacylglycerides, cholesterol and cholesteryl ester in
      embryos from both control and n-stz diabetic rats. 15dPGJ(2) is present in
      embryos during organogenesis, and reduces embryonic nitric oxide production and
      lipid synthesis. The lower 15dPGJ(2) concentration in embryos from n-stz diabetic
      rats may result in developmental alterations in this diabetic model.

PMID- 12417001
TI  - Marked extension of proliferation of rat Sertoli cells in culture using
      recombinant human FSH.
AB  - Previous studies indicate that proliferation of rat Sertoli cells in culture can
      only be maintained until the equivalent of days 10-12 after birth, irrespective
      of the age of the donor animal. This report describes methods for the isolation
      and culture of Sertoli cells from day 6 rat testes, which can proliferate in
      culture for 20-24 days (that is, until the equivalent of days 26-30 after birth).
      Cells were isolated by enzymatic digestion of seminiferous cords followed by
      selective depletion of contaminating peritubular cells by adhesion to a
      polystyrene surface. The purity of the Sertoli cells was assessed using a
      combination of markers to be > 99.5%. Proliferation was assayed using tritiated
      thymidine incorporation and further verified by bromodeoxyuridine histochemistry
      and flow cytometry. Sertoli cells proliferated at basal levels in Dulbecco's
      modified Eagle's medium (DMEM)-F12 media alone, and proliferation was stimulated
      further by addition of recombinant human FSH to the culture media. After 20-24
      days in culture, proliferation rapidly ceased, and cells assumed abnormal
      morphology and detached from the culture vessel; these events are consistent with
      the cells undergoing classic rodent cell senescence. The method described
      provides a useful tool for investigating the control of Sertoli cell division.
      Furthermore, these findings indicate that the timely differentiation of Sertoli
      cells is not dependent solely on an intrinsic timing mechanism, as has been
      suggested previously.

PMID- 12417002
TI  - Measured effect of collection and cooling conditions on the motility and the
      water transport parameters at subzero temperatures of equine spermatozoa.
AB  - The effects of extracellular ice and cryoprotective agents on the measured
      volumetric shrinkage response and the membrane permeability parameters of equine
      spermatozoa have been reported previously. The volumetric shrinkage data were
      obtained using a differential scanning calorimeter technique that was independent
      of cell shape. The aim of this study was to examine the effects of collection and
      cooling conditions on the motility and the water transport parameters at subzero
      temperatures of equine spermatozoa. Stallion semen samples were collected using
      either a commercial lubricating agent, which caused osmotic stress to the
      spermatozoa, or water-insoluble Vaseline( trade mark ) as the artificial vagina
      lubricant. In some experiments, spermatozoa were cooled at 1 degrees C min(-1)
      from 20 degrees C to 4 degrees C to induce cold shock. An Equitainer was used to
      achieve control cooling rates (< or = 0.3 degrees C min(-1)) at temperatures > 0
      degrees C. The water transport response of spermatozoa that were cold-shocked and
      osmotically shocked was significantly different from that of control spermatozoa
      (P < 0.01). Osmotic stress appeared to have an effect on the water transport
      response, although this effect was not significant. These results indicate that
      cold shock alters the behaviour of equine spermatozoa in cryopreservation
      protocols as a result of changes in the water transport properties of the plasma
      membrane. Although osmotic stress did not significantly affect water transport in
      equine spermatozoa, it did significantly decrease sperm motility in the extended
      semen samples (P < 0.01), which would, in turn, lower the quality of cold-stored
      or cryopreserved spermatozoa.

PMID- 12417003
TI  - Differential effects of activin A on basal and gonadotrophin-induced secretion of
      inhibin A and progesterone by granulosa cells from preovulatory (F1-F3) chicken
      follicles.
AB  - Previous work has shown that activin A is expressed selectively within the theca
      rather than the granulosa layer of preovulatory chicken follicles. In the present
      study, this finding was verified and the potential paracrine actions of activin A
      on basal and gonadotrophin-induced secretion of inhibin A, inhibin B and
      progesterone by granulosa cells from the three largest preovulatory follicles (F1
      F3) were investigated. Treatment with activin A (0, 0.25, 2.5 and 25 ng ml(-1))
      alone increased inhibin A secretion markedly in a follicle- and time-dependent
      manner, with the greatest response (up to 15-fold increase; P < 0.0001) in F1
      follicles after 3 days of treatment. In contrast, activin A alone had no effect
      on progesterone output at any time. Cells from F3 follicles were more responsive
      to FSH than were F1 cells in terms of both inhibin A (P < 0.02) and progesterone
      (P < 0.01) secretion. Furthermore, activin A greatly enhanced FSH-induced
      secretion of both inhibin A (up to tenfold; P < 0.0001) and progesterone (up to
      sixfold; P < 0.0001). In terms of LH-induced inhibin A and progesterone
      secretion, cells from F1, F2 and F3 follicles showed similar responses. Co
      treatment with activin A enhanced LH-induced secretion of inhibin A markedly (up
      to ninefold; P < 0.0001) but had only a marginal effect on LH-induced
      progesterone secretion (up to twofold; P < 0.001). The presence of activin
      receptor subtypes IA, IB, IIA and IIB in cultured granulosa cells from F1, F2 and
      F3 follicles was demonstrated using immunocytochemistry. These findings support
      the hypothesis that activin A secreted by the theca layers of avian preovulatory
      follicles exerts a local paracrine action on granulosa cells to modulate 'basal'
      inhibin A secretion and to upregulate gonadotrophin-induced secretion of both
      inhibin A and progesterone. However, the extent to which this local role of
      activin A contributes to the generation of the preovulatory LH-progesterone surge
      remains to be established.

PMID- 12417004
TI  - Immunohistochemical localization of active caspase-3 in the mouse ovary: growth
      and atresia of small follicles.
AB  - Caspase-3 belongs to a family of highly conserved cysteine proteases that mediate
      the course of apoptotic cell suicide. It is recognized that ovarian follicular
      atresia is associated with apoptosis, a process that has been characterized
      mainly in larger antral follicles. The aims of this study were to investigate the
      expression of caspase-3 in the mouse ovary, and determine whether active caspase
      3 is present within smaller follicles, which may constitute the resting pool. The
      inactive enzyme was expressed as a 32 kDa band on a western blot of tissue
      extracts, whereas the active form was localized immunohistochemically.
      Bromodeoxyuridine (BrdU) was administered to mice (n = 7) during a 12 h period
      and subsequently localized to identify potentially quiescent follicles.
      Measurements of BrdU-positive cells in the mouse ovary were extrapolated with
      data obtained by morphometric analyses of small follicles using the nucleator
      technique. BrdU was incorporated into the granulosa cells of follicles regardless
      of size and the number of cells they contained, but was absent in a large
      proportion (89%) of small, single layered follicles. Active caspase-3 was
      localized to both the oocyte and granulosa cells of follicles that were
      considered to be undergoing atresia, but was not localized to the granulosa cells
      of any small, single layered follicles. The results of this study indicate that,
      in small follicles, granulosa cell proliferation occurs independently of the size
      of follicles and the number of constituent cells, and that follicles of this type
      may be inherently less susceptible to the normal physiological factors that
      induce atresia.

PMID- 12417005
TI  - Amino acid turnover by elongating cattle blastocysts recovered on days 14-16
      after insemination.
AB  - Blastocyst elongation from day 14 to day 16 after insemination coincides with a
      major phase of embryo loss in cattle. Protein synthesis, reflected in protein
      content, increases markedly over this period but little is known about the amino
      acid requirement of elongating blastocysts at this time. Cattle blastocysts
      produced in vivo were recovered on days 14-16 after insemination and cultured
      individually for up to 8 h in synthetic oviduct fluid containing a physiological
      mixture of amino acids plus 1 mmol glutamine l(-1) and 0.1% (w/v) polyvinyl
      alcohol (SOFaaPVA). After 1, 4 and 8 h in culture, an aliquot of culture medium
      was removed and the rate of amino acid depletion or production was calculated per
      unit of protein and per hour of culture. Amino acids were depleted or produced at
      different rates. Arginine was depleted from the medium at a significant rate (P <
      0.05) during all culture periods. Alanine and glutamate were produced at a
      significant rate (P < 0.05) during all culture periods. The rate of alanine
      production was significantly greater (P < 0.05) in blastocysts recovered on day
      14 compared with days 15 or 16 after insemination. Alanine production and
      arginine depletion tended to be greater in smaller embryos recovered on day 14
      compared with larger and later stage embryos, indicating that earlier stage
      embryos may have higher metabolic activity than later stage embryos.
      Qualitatively, the pattern of amino acid consumption and production during
      elongation was similar to that shown from the zygote to early blastocyst stage.

PMID- 12417006
TI  - Activity of key enzymes involved in glucose and triglyceride catabolism during
      bovine oocyte maturation in vitro.
AB  - Little is known about the metabolic profile of cumulus-oocyte complexes (COCs)
      during maturation. The aim of this study was to determine the differential
      participation of enzymatic activity in cumulus cells and the oocyte during in
      vitro maturation of bovine oocytes, by measuring the activity of key enzymes
      involved in the regulation of glycolysis (phosphofructokinase), the pentose
      phosphate pathway (glucose-6-phosphate dehydrogenase) and lipolysis (lipase).
      COCs were matured in medium 199 plus 10% (v/v) steer serum for 22-24 h at 39
      degrees C in 5% CO(2):95% humidified air. Phosphofructokinase, glucose-6
      phosphate dehydrogenase and lipase activities were measured in immature and in
      vitro matured COCs, denuded oocytes and cumulus cells, respectively.
      Phosphofructokinase and glucose-6-phosphate dehydrogenase activities (enzymatic
      units) remained constant during in vitro maturation of COCs, but there was a
      significant decrease in lipase activity (units) (P < 0.05), as activity in
      cumulus cells decreased significantly (P < 0.05). For the three enzymes studied,
      enzyme activity (units) remained unchanged in the oocyte during in vitro
      maturation. Specific activity increased in the oocyte (P < 0.05) and decreased in
      cumulus cells as a result of maturation (P < 0.05). In cumulus cells,
      phosphofructokinase was the most abundant of the three enzymes followed by
      glucose-6-phosphate dehydrogenase and then lipase (P < 0.05), whereas in the
      denuded oocyte this order was reversed (P < 0.05). Thus, the metabolism of
      cumulus cells is adapted to control the flow of metabolites toward the oocyte,
      which maintains its enzymatic activity even when dissociated from cumulus cells
      during maturation. The high activity of phosphofructokinase in cumulus cells
      indicates that glucose is metabolized mainly via the glycolytic pathway in these
      cells. The greater relative activity of glucose-6-phosphate dehydrogenase
      recorded in the oocyte indicates that glucose uptake could be directed mainly
      toward the pentose phosphate pathway. The marked lipolytic activity concentrated
      in the oocyte indicates an active participation in lipid catabolism during
      maturation.

PMID- 12417007
TI  - Developmental competence and oxidative state of mouse zygotes heat-stressed
      maternally or in vitro.
AB  - Mammalian preimplantation embryos are sensitive to maternal and direct heat
      stress. However, the mechanisms by which heat stress affects early embryonic
      development in vivo or in vitro are unknown. This study examined whether heat
      stress-induced loss of developmental competence in mouse embryos was mediated by
      physiological changes in the maternal environment or by high temperatures alone.
      After fertilization, zygotes at the same stage were heat-stressed at 39.5 degrees
      C for 12 h either maternally (measured by maternal rectal temperature) or
      directly in culture. Zygotes in each group were cultured at 37.5 degrees C for a
      further 84 h to assess their developmental ability. Neither type of heat stress
      affected the first cleavage rate. However, the proportion of embryos that
      developed to morulae or blastocysts was significantly lower in the maternally
      heat-stressed group, but not in the directly heat-stressed group. Moreover,
      maternal heat stress significantly reduced intracellular glutathione
      concentrations and enhanced hydrogen peroxide concentrations in both zygotes and
      two-cell embryos that were recovered immediately after heat stress or 12 h later,
      respectively. In contrast, direct heat stress had little effect on concentrations
      of glutathione or hydrogen peroxide in cultured early embryos. These results
      demonstrate that maternal heat stress at the zygote stage reduces the
      developmental ability of mouse embryos via physiological changes in the maternal
      environment that lead to an increase in intracellular oxidative stress on the
      embryo.

PMID- 12417008
TI  - Hyperthyroidism and production of precocious involution in the mammary glands of
      lactating rats.
AB  - This study investigated the influence of chronic hyperthyroidism on mammary
      function in lactating rats and the effects on their pups. Thyroxine-treated (10
      microg per 100 g body weight per day; hyperthyroid (HT)) or vehicle-treated rats
      were mated 2 weeks after the start of treatment and killed with their litters on
      days 7, 14 and 21 of lactation. Serum concentrations of triiodothyronine (T(3))
      and tetraiodothyronine (T(4)) increased in thyroxine-treated rats. In HT mothers,
      serum prolactin decreased on day 7 and day 14 of lactation, whereas insulin-like
      growth factor I (IGF-I) and progesterone concentrations decreased, and
      corticosterone increased on day 7 of lactation. In HT pups, T(4) concentration
      increased on day 7 and day 14 of lactation, whereas T(3) increased only on day 14
      of lactation, and growth hormone increased on day 7 of lactation. Mammary
      prolactin binding sites did not vary, but there was an increase in the binding
      sites in the liver on day 14 of lactation in thyroxine-treated rats. In an acute
      suckling experiment, thyroxine-treated rats released less oxytocin, growth
      hormone and prolactin and excreted less milk than did control rats. Mammary
      casein, lactose and total lipid concentrations in thyroxine-treated rats were
      similar to those of control rats on day 14 of lactation. Histological studies of
      the mammary glands showed an increased proportion of alveoli showing reduced or
      no lumina and cells with condensed nuclei on day 14 and day 21 of lactation; the
      TdT-mediated dUTP nick-end labelling (TUNEL) test revealed an increase in
      apoptosis in alveolar cells on day 21 of lactation in thyroxine-treated rats.
      Expression of SGP-2, a gene expressed during mammary involution, increased in
      thyroxine-treated rats on day 14 and day 21 of lactation, whereas expression of
      insulin-like growth factor binding protein 5, a proapoptotic signal, was
      unchanged. Bcl-2, which promotes survival of mammary gland epithelial cells was
      unchanged, whereas expression of IGF-I, which also promotes survival of mammary
      gland epithelial cells, increased on day 21 of lactation in thyroxine-treated
      rats. These results indicate that thyroxine treatment produces some milk stasis
      as a result of impairments in suckling induced release of oxytocin that may
      initiate the first stage of mammary involution, increasing apoptosis in a gland
      that is otherwise actively producing and secreting milk.

PMID- 12417009
TI  - Expression of CD105 (endoglin) in arteriolar endothelial cells of human
      endometrium throughout the menstrual cycle.
AB  - The cellular mechanisms underlying normal and pathological endometrial bleeding
      are not well understood, although abnormalities in the structure of endometrial
      blood vessels may lead to menstrual disorders. Endothelial cells in different
      organs are heterogeneous and differ in structure, function, antigen composition,
      metabolic properties and responses to growth factors. Immunostaining was
      performed with anti-CD105, CD31, CD34 and von Willebrand factor (vWF), and lectin
      binding with Ulex europaeus agglutinin 1 (UEA 1), Bandeieraea simplicifolia
      agglutinin 1 (BS 1), Dolichos biflorus agglutinin (DBA) and Peanut agglutinin
      (PNA) to characterize endothelial cells in human endometrium throughout the
      menstrual cycle. Serial sections fixed with formalin were stained with primary
      antibodies and lectins after antigen retrieval. Positive staining for CD31, CD105
      and vWF was confined to the vascular endothelium. Endothelial expression of CD31
      was observed in all types of vessel, including single cells, and strong staining
      was found during the early proliferative and mid-secretory phases. Anti-vWF
      stained arterioles and veins, but there was little positive staining of
      capillaries. In contrast, staining for CD105 was confined to the arterioles.
      Although anti-CD34 strongly stained endothelial cells of small vessels and
      capillaries, staining was also observed on some non-endothelial stromal cells.
      Strong positive staining for UEA 1 was observed in endothelial cells of all types
      of vessel throughout the menstrual cycle. Binding of PNA, DBA and BS 1 was
      confined to the apical region of glandular epithelial cells. This study
      demonstrates that the differential binding of anti-CD31, CD34, CD105, vWF and UEA
      1 distinguishes between endometrial populations of endothelial cells.

PMID- 12417010
TI  - Effects of ions on the motility of fresh and demembranated paddlefish (Polyodon
      spathula) spermatozoa.
AB  - This study investigated the effects of different environmental conditions on the
      motility parameters of paddlefish (Polyodon spathula) spermatozoa. Paddlefish
      spermatozoa demonstrated the following characteristics: (i) all spermatozoa were
      motile 10 s after activation with a velocity of 130-160 microm s(-1); (ii) after
      2 min, velocity decreased to 80-130 microm s(-1); and (iii) motility was
      maintained for up to 9 min. Concentrations of 0.5-5.0 mmol KCl l(-1) prevented
      activation of spermatozoa. After transfer into a swimming medium (20 mmol Tris l(
      1), pH 8.2 and 1 mg BSA ml(-1)) containing 0.5 mmol KCl l(-1) (combined with 5
      mmol NaCl or MgCl(2) l(-1)), 80-100% of cells were motile with a velocity of
      about 120-150 microm s(-1). MgCl(2) significantly improved the velocity of
      spermatozoa at 10, 40, 50 and 60 s after activation and the stable velocity of
      spermatozoa was about 140 microm s(-1). Very low concentrations of CaCl(2) (0.125
      mmol l(-1)) combined with 0.5 mmol KCl l(-1) initiated motility in 20% of
      spermatozoa, whereas all spermatozoa were activated after 2 min with 0.25 mmol
      CaCl(2) l(-1) in similar medium for the full period of swimming with velocity of
      about 120 microm s(-1). This study demonstrated that potassium (5-15 mmol l(-1))
      inhibits demembranated spermatozoa. Thus, initiation of movement in paddlefish
      spermatozoa is under the reciprocal control of potassium and calcium ion
      concentrations.

PMID- 12417011
TI  - Folliculogenesis and ovarian expression of mRNA encoding aromatase in anoestrous
      sheep after 5 days of glucose or glucosamine infusion or supplementary lupin
      feeding.
AB  - Improved nutrition increases ovulation rate in sheep and there is evidence that
      intra-ovarian pathways mediate responses to nutrition. An experiment was
      conducted to examine the effect of dietary energy on folliculogenesis. Anoestrous
      Merino ewes were fed a diet of wheat straw alone (control, n = 5), or wheat straw
      supplemented with lupins (500 g day(-1), n = 5). Other ewes were fed wheat straw
      and infused with glucose (50 mmol h(-1), n = 5) or with glucosamine (3.5 mmol h(
      1), n = 5). Intravaginal progestagen sponges were inserted for 12 days, and
      nutritional treatments were started 5 days before sponge removal. At sponge
      removal, the ewes were injected with a regimen of GnRH pulses (500 ng every 4 h
      from 0 to 12 h; 250 ng every 2 h from 14 to 24 h; and 200 ng every 1 h from 25 to
      36 h) to simulate normal follicular development. Thirty-six hours after sponge
      removal, the animals were killed and the ovaries were collected and stored at -80
      degrees C. The ovaries were sectioned serially every 10 microm. Every 20th
      section was stained (to estimate number and diameter of follicles) and every 17
      19th section was probed by in situ hybridization for P(450) aromatase. Data were
      analysed using ANOVA and chi-squared tests. There was an effect of treatment (P <
      0.05) on the number of follicles 2-3, 3-4 and 6-7 mm in diameter. Aromatase
      positive follicles (1.6-7.9 mm) were detected in 31 follicles from 15 ewes across
      all four groups. In ten animals, the largest follicle was aromatase-positive. The
      diameters of aromatase-positive follicles were larger (P = 0.004) in lupin fed
      compared with glucose-infused ewes (4.9 +/- 0.5, 3.6 +/- 0.7, 5.3 +/- 0.5 and 4.2
      +/- 0.5 mm for control, glucose-infused, lupin-fed and glucosamine-infused
      groups, respectively). Treatment did not affect the plasma concentration of FSH
      when compared with controls, indicating that the energy supplements were
      modifying recruited (2-3 mm and 3-4 mm) and selected follicles (> 6 mm) directly.
      In conclusion, dietary energy can directly stimulate folliculogenesis in
      recruited and selected follicles, and this effect may be mediated by changes in
      systemic leptin concentrations and the hexosamine energy-sensing pathway in the
      follicle.

PMID- 12417012
TI  - Community based rehabilitation: a strategy for peace-building.
AB  - BACKGROUND: Certain features of peace-building distinguish it from peacekeeping,
      and make it an appropriate strategy in dealing with vertical conflict and low
      intensity conflict. However, some theorists suggest that attempts, through peace
      building, to impose liberal values upon non-democratic cultures are misguided and
      lack an ethical basis. DISCUSSION: We have been investigating the peace-building
      properties of community based approaches to disability in a number of countries.
      This paper describes the practice and impact of peace-building through Community
      Based Rehabilitation (CBR) strategies in the context of armed conflict. The
      ethical basis for peace-building through practical community initiatives is
      explored. A number of benefits and challenges to using CBR strategies for peace
      building purposes are identified. SUMMARY: During post-conflict reconstruction,
      disability is a powerful emotive lever that can be used to mobilize cooperation
      between factions. We suggest that civil society, in contrast to state-level
      intervention, has a valuable role in reducing the risks of conflict through
      community initiatives.

PMID- 12417013
TI  - Activation mechanisms of protein kinase C: maturation, catalytic activation, and
      targeting.
AB  - The biological function of protein kinase C (PKC) depends on its catalytic
      activity and spatial localization. Its catalytic competence and localization in
      the resting state are regulated by serine/threonine phosphorylations, i.e.,
      "maturation." Upon stimulation of various receptors, PKC is catalytically
      activated by several activators including diacylglycerol. In addition, PKC often
      translocates to particular subcellular compartments including the plasma membrane
      and Golgi complex, and such translation is here referred to as "targeting." In
      short, the physiological function of PKC is controlled by the three events:
      maturation, catalytic activation, and targeting. Catalytic activation and
      targeting contribute to temporal, spatial, and isotype-specific regulation of
      PKC. This review summarizes the evidence for the role of these three events in
      the isotype-specific activation of PKC, with particular emphasis on catalytic
      activation and targeting by lipid mediators.

PMID- 12417014
TI  - Protein kinase C alpha (PKC alpha): regulation and biological function.
AB  - Protein kinase C alpha (PKC alpha) is a serine/threonine kinase and a member of
      the conventional (classical) PKCs (cPKCs), which have four conserved (C1 to C4)
      regions. This ubiquitously expressed PKC isotype is activated in response to many
      different kinds of stimuli and translocates from cytosol to the specialized
      cellular compartments (nucleus, focal adhesion, caveolae, etc.) where it is
      presumed to work. Therefore, PKC alpha has been implicated in a variety of
      cellular functions including proliferation, apoptosis, differentiation, motility,
      and inflammation. However, the responses induced by activation or overexpression
      of PKC alpha vary depending on the types, and sometimes conditions, of cells. For
      example, in some types of cells, PKC alpha is implicated in cell growth. In
      contrast, it may play a role in cell cycle arrest and differentiation in other
      types of cells. Therefore, alterations of cell responses induced by PKC alpha are
      not an intrinsic property of this isoform. The responses are modulated by dynamic
      interactions with cell-type specific factors: substrates, modulators and
      anchoring proteins.

PMID- 12417015
TI  - Protein kinase C beta (PKC beta): normal functions and diseases.
AB  - PKC beta I and PKC beta II are DAG- and Ca(2+)-dependent conventional or
      classical isoforms of protein kinase C. Generated by alternative splicing from a
      single gene, they differ at their C-terminal 50 (beta I) or 52 (beta II)
      residues. They are expressed as major PKC isoforms in a variety of tissues, and
      thus the functions ascribed to "PKC" based on early studies using phorbol esters
      and PKC inhibitors could be attributed to them. As tools to probe into isoform
      specific functions have recently become available, our understanding of the
      normal functions of these isoforms has dramatically increased. This minireview
      will focus mainly on two areas of signal transduction where the roles of PKC beta
      I and PKC beta II are relatively well-characterized: immunoreceptor and insulin
      receptor systems. Their involvement in disorders due to pertubations in these
      signaling systems, i.e., immunodeficiencies and diabetes, is also reviewed.
      Finally, patterns of PKC action in these and other biologic systems are
      discussed.

PMID- 12417016
TI  - Protein kinase C gamma (PKC gamma): function of neuron specific isotype.
AB  - The gamma isotype of protein kinase C (PKC gamma) is a member of the classical
      PKC (cPKC) subfamily which is activated by Ca(2+) and diacylglycerol in the
      presence of phosphatidylserine. Physiologically, PKC gamma is activated by a
      mechanism coupled with receptor-mediated breakdown of inositol phospholipid as
      other cPKC isotypes such as PKC alpha and PKC beta. PKC gamma is expressed solely
      in the brain and spinal cord and its localization is restricted to neurons, while
      PKC alpha and PKC beta are expressed in many tissues in addition to the brain.
      Within the brain, PKC gamma is the most abundant in the cerebellum, hippocampus
      and cerebral cortex, where the existence of neuronal plasticity has been
      demonstrated. Pharmacological and electrophysiological studies have shown that
      several neuronal functions, including long term potentiation (LTP) and long term
      depression (LTD), specifically require PKC gamma. Generation of mice deficient in
      PKC gamma provided more information regarding the physiological functions of this
      isotype. PKC gamma deficient mice (i) have modified long term potentiation (LTP)
      in hippocampus, (ii) exhibit mild deficits in spatial and contextual learning
      (iii) exhibit impaired motor coordination due to persistent multiple innervations
      of climbing fibers on Purkinje cells, (iv) show attenuation of opioid receptor
      activation, and (v) show decreased effects of ethanol on type A of gamma
      aminobutyric acid (GABA) receptor. Furthermore, a point mutation in the PKC gamma
      gene may contribute to retinitis pigmentosa and Parkinsonian syndrome. This
      article reviews the specific functions of this neuron-specific isotype of PKC in
      neuronal signal transduction.

PMID- 12417017
TI  - Guide oligonucleotide-dependent DNA linkage that facilitates controllable
      polymerization of microgene blocks.
AB  - Faster and more efficient searches of a huge protein sequence space for the
      purpose of conducting experiments in protein evolution can be achieved through
      the development of a block shuffling-based evolution system. One of the key
      components of such a system is the accurate and efficient linkage of gene units.
      Here we introduce a new method that allows accurate and controllable linkage of
      microgene blocks. This method employs a thermostable DNA ligase that links two
      single-stranded microgene blocks when they hybridize a complementary guide
      oligonucleotide. At high temperature, the ligation of the microgene units is
      fully dependent on the guide oligonucleotide, which can exclude undesired polymer
      formation, including the incorporation of microgenes having illegitimate sizes
      and "head-to-head" and "tail-to-tail" ligation of blocks. We were also able to
      assemble three microgene units using two guide oligonucleotides. Using this
      method of controllable linkage should facilitate further development of a step-by
      step system for the polymerization of gene blocks, leading to a versatile block
      shuffling-based protein evolution system.

PMID- 12417018
TI  - Phosphorylation and regulation of beta-catenin by casein kinase I epsilon.
AB  - beta-Catenin transduces cytosolic signals to the nucleus in the Wnt pathway. The
      Wnt ligand stabilizes cytosolic beta-catenin protein, preventing its
      phosphorylation by inhibiting glycogen synthase kinase 3 (GSK3). Serine-33 and 
      37 of beta-catenin are GSK3 phosphorylation sites that serve as recognition sites
      for the beta-TRCP-ubiquitin ligase complex, which ultimately triggers beta
      catenin degradation. Mutations at those two sites, as well as in Ser-45,
      stabilize beta-catenin. Recently, casein kinase I epsilon (CKI epsilon) has been
      shown to be a positive regulator of the Wnt pathway. Its action mechanism,
      however, remains unknown. Here I show that Ser-45 is phosphorylated not by GSK3
      but by CKI epsilon. Axin, a scaffold protein that binds CKI epsilon and beta
      catenin, enhances this CKI epsilon-mediated phosphorylation. Overexpression of
      CKI epsilon in cells increases the amount of beta-catenin phosphorylated at Ser
      45. Ser-45 phosphorylated beta-catenin is a better substrate for GSK3, which
      suggests that CKI epsilon and GSK3 may co-operate in destabilizing beta-catenin.
      In spite of the fact that CKI epsilon was found as a positive regulator of the
      Wnt pathway, mutational analysis suggests that mutation of Ser-45 regulates beta
      catenin stability by inhibiting the ability of GSK3 to phosphorylate Ser-33 and 
      37, thereby disrupting the interaction between beta-catenin, beta-TRCP and Axin.
      I propose that phosphorylation of Ser-45 by CKI epsilon plays an important role
      in regulating beta-catenin stability.

PMID- 12417019
TI  - Identification of the ribosomal proteins present in the vicinity of globin mRNA
      in the 40S initiation complex.
AB  - The interaction of ribosomal proteins with mRNA in the 40S initiation complex was
      examined by chemical cross-linking. 40S initiation complexes were formed by
      incubating rat liver [(3)H]Met-tRNAi, rat liver 40S ribosomal subunits, rabbit
      globin mRNA, and partially purified initiation factors of rabbit reticulocytes in
      the presence of guanylyl(beta, gamma-methylene)-diphosphonate. The initiation
      complexes were then treated with 1,3-butadiene diepoxide to introduce crosslinks
      between the mRNA and proteins. The covalent mRNA-protein conjugates were isolated
      by chromatography on an oligo(dT) cellulose column in the presence of sodium
      dodecyl sulfate, followed by sucrose density gradient centrifugation. Proteins
      cross-linked to the mRNA were labeled with Na(125)I, extracted by extensive
      ribonuclease digestion, and analyzed by two-dimensional and diagonal
      polyacrylamide gel electrophoresis. Three ribosomal proteins, S6, S8, and
      S23/S24, together with small amounts of S3/S3a, S27, and S30, were identified as
      the protein components cross-linked to the globin mRNA protein complex, and were
      shown to attach directly to the mRNA. It is suggested that these proteins
      constitute the ribosomal binding site for mRNA in the 40S initiation complex.

PMID- 12417020
TI  - Role of a conserved J8/7 X P4 base-triple in the Tetrahymena ribozyme.
AB  - The Tetrahymena group I intron ribozyme folds into a complex three dimensional
      structure for performing the self-splicing reaction. Catalysis depends on its
      core structure comprising two helical domains, P4-P6 and P3-P7. The two domains
      are joined by three sets of conserved base-triple(s) and other tertiary
      interactions. We found that the disruption of J8/7 X P4, one such conserved base
      triple, causes the catalytic ability to deteriorate without altering the folding
      rate. This suggests that the base-triple stabilizes the active structure of the
      ribozyme but plays no significant role in RNA folding. By combining the present
      and previous results, it can be concluded that three sets of conserved base
      triples play distinct roles in the Tetrahymena ribozyme.

PMID- 12417021
TI  - Mapping of the sites responsible for factor I-cofactor activity for cleavage of
      C3b and C4b on human C4b-binding protein (C4bp) by deletion mutagenesis.
AB  - Human C4b-binding protein (C4bp) facilitates the factor I-mediated proteolytic
      cleavage of the active forms of complement effectors C3b and C4b into their
      inactive forms. C4bp comprises a disulfide-linked heptamer of alpha-chains with
      complement (C) regulatory activity and a beta-chain. Each alpha-chain contains 8
      short consensus repeat (SCR) domains. Using SCR-deletion mutants of recombinant
      multimeric C4bp, we identified the domains responsible for the C3b/C4b-binding
      and C3b/C4b-inactivating cofactor activity. The C4bp mutant with deletion of SCR2
      lost the C4b-binding ability, as judged on C3b/C4b-Sepharose binding assaying and
      ELISA. In contrast, the essential domains for C3b-binding extended more to the C
      terminus, exceeding SCR4. Using fluid phase cofactor assaying and deletion
      mutants of C4bp, SCR2 and 3 were found to be indispensable for C4b cleavage by
      factor I, and SCR1 contributed to full expression of the factor I-mediated C4b
      cleaving activity. On the other hand, SCR1, 2, 3, 4, and 5 participated in the
      factor I-cofactor activity for C3b cleavage, and SCR2, 3, and 4 were absolutely
      required for C3b inactivation. Thus, different sets of SCRs participate in C3b
      and C4b inactivation, and the domain repertoire supporting C3b cofactor activity
      is broader than that supporting C4b inactivation by C4bp and factor I.
      Furthermore, the domains participating in C3b/C4b binding are not always
      identical to those responsible for cofactor activity. The necessity of the wide
      range of SCRs in C3b inactivation compared to C4b inactivation by C4bp and factor
      I may reflect the physiological properties of C4bp, which is mainly directed to
      C4b rather than C3b.

PMID- 12417022
TI  - Trafficking of green fluorescent protein-tagged SNARE proteins in HSY cells.
AB  - SNARE proteins are widely accepted to be involved in the docking and fusion
      process of intracellular vesicle trafficking. VAMP-2, syntaxin-4, and SNAP-23 are
      plausible candidate SNARE proteins for non-neuronal exocytosis. Thus, we examined
      the localization, protein-protein interaction, and intracellular trafficking of
      these proteins by expressing them as green fluorescent protein (GFP)- and FLAG
      tagged fusion proteins in various cells, including HSY cells, a human parotid
      epithelial cell line. GFP-VAMP-2 was ex-pressed strongly in the Golgi area and
      weakly on the plasma membrane. Although GFP-SNAP-23 seemed to be expressed
      universally in the cytosol, the GFP signal was clearly seen on the plasma
      membrane, when soluble GFP-SNAP-23 was removed by treatment with saponin. GFP
      syntaxin-4 was undetectable on the plasma membrane but was strongly expressed on
      unidentified unusually large vesicles. GFP-syntaxin-4 without its transmembrane
      domain was still incompletely soluble and observed as aggregates. When syntaxin-4
      and munc18c were coexpressed, syntaxin-4 was translocated at least in part to the
      plasma membrane. The protein-protein interaction between syntaxin-4 and VAMP-2
      with their transmembrane domains was markedly inhibited on coexpression of
      munc18c. These results suggest that munc18c plays an important role in the
      trafficking of syntaxin-4 to its proper destination by preventing premature
      interactions with other proteins, including SNARE proteins.

PMID- 12417023
TI  - RNase 3 (ECP) is an extraordinarily stable protein among human pancreatic-type
      RNases.
AB  - There have been some attempts to develop immunotoxins utilizing human RNase as a
      cytotoxic domain of antitumor agents. We have recently shown that only human
      RNase 3 (eosinophil cationic protein, ECP) among five human pancreatic-type
      RNases excels in binding to the cell surface and has a growth inhibition effect
      on several cancer cell lines, even though the RNase activity of RNase 3 is
      completely inhibited by the ubiquitously expressed cytosolic RNase inhibitor.
      This phenomenon may be explained by that RNase 3 is very stable against
      proteolytic degradation because RNase 3 internalized through endocytosis could
      have a longer life time in the cytosol, resulting in the accumulation of enough
      of it to exceed the concentration of RNase inhibitor, which allows the
      degradation of cytosolic RNA molecules. Thus, we compared the stabilities of
      human pancreatic-type RNases (RNases 1-5) and bovine RNase A by means of
      guanidium chloride-induced denaturation experiments based on the assumption of a
      two-state transition for unfolding. It was demonstrated that RNase 3 is
      extraordinarily stabler than either RNase A or the other human RNases (by more
      than 25 kJ/mol). Thus, our data suggest that in addition to its specific affinity
      for certain cancer cell lines, the stability of RNase 3 contributes to its unique
      cytotoxic effect and that it is important to stabilize a human RNase moiety
      through protein engineering for the design of human RNase-based immunotoxins.

PMID- 12417024
TI  - Cellular catabolism of lipid poor apolipoprotein E via cell surface LDL receptor
      related protein.
AB  - Apolipoprotein E (apoE), an apoprotein involved in lipid transport in both the
      plasma and within the brain, mediates the binding of lipoproteins to members of
      the low density lipoprotein (LDL) receptor family including the LDL receptor and
      the LDL receptor-related protein (LRP). ApoE/LRP interactions may be particularly
      important in brain where both are expressed at high levels, and polymorphisms in
      the apoE and LRP genes have been linked to AD. To date, only apoE-enriched
      lipoproteins have been shown to be LRP ligands. To investigate further whether
      other, more lipid-poor forms of apoE interact with LRP, we tested whether lipid
      free apoE in the absence of lipoprotein particles interacts with its cell-surface
      receptors. No detectable lipid was found associated with bacterially expressed
      and purified apoE either prior to or following incubation with cells when
      analyzed by electrospray ionization mass spectrometry. We found that the
      degradation of lipid-poor (125)I-apoE was significantly higher in wild type as
      compared to LRP-deficient cells, and was inhibited by receptor-associated protein
      (RAP). In contrast, (125)I-apoE-enriched beta-VLDL was degraded by both LRP and
      the LDL receptor. When analyzed via a single cycle of endocytosis, (125)I-apoE
      was internalized prior to its subsequent intracellular degradation with kinetics
      typical of receptor-mediated endocytosis. Thus, we conclude that a very lipid
      poor form of apoE can be catabolized via cell surface LRP, suggesting that the
      conformation of apoE necessary for recognition by LRP can be imposed by
      situations other than an apoE-enriched lipoprotein.

PMID- 12417025
TI  - Cloning and biochemical characterization of astacin-like squid metalloprotease.
AB  - We have cloned four cDNAs encoding astacin-like squid metalloproteases (ALSMs)-I
      and -II from the Japanese common squid and ALSMs-I and -III from the spear squid.
      Analysis of the deduced amino acid sequences revealed that ALSMs possess a signal
      peptide and a pro-sequence followed by an astacin-like catalytic domain and an
      MAM (meprin, A5 protein, receptor protein-tyrosine phosphatase mu) domain.
      Phylogenetic analysis revealed that ALSM corresponds to a new cluster of
      astacins. To analyze the function of the MAM domain, wild-type ALSM and an MAM
      truncated mutant were expressed in a baculovirus expression system. The expressed
      protein encoding full-length ALSM hydrolyzed myosin heavy chain as effectively as
      native ALSM, whereas the MAM-truncated mutant possessed no protease activity,
      suggesting that the MAM domain contributes to substrate recognition. ALSM has
      been isolated from squid liver and mantle muscle. However, analysis with a
      specific antibody generated against ALSM indicated the presence of ALSM in a wide
      variety of tissues. ALSM was located in the extracellular matrix of mantle muscle
      cells. Thus, ALSM is a secreted protease, as are other members of the astacin
      family. The extracellular localization raises the possibility of substrates other
      than myosin. The physiological role of ALSM remains unknown, at this time.

PMID- 12417026
TI  - Structure of imidazole glycerol phosphate synthase from Thermus thermophilus HB8:
      open-closed conformational change and ammonia tunneling.
AB  - Imidazole glycerol phosphate synthase (IGPs) catalyzes the fifth step in the
      histidine biosynthetic pathway located at the branch point to de novo purine
      biosynthesis. IGPs is a multienzyme comprising glutaminase and synthase subunits.
      The glutaminase activity, which hydrolyzes glutamine to give ammonia, is coupled
      with substrate binding to the synthase subunit. The three-dimensional structure
      of the IGPs from Thermus thermophilus HB8 has been determined at 2.3 A
      resolution, and compared with the previously determined structures for the yeast
      and Thermotoga maritima enzymes. The structure of each subunit is similar to that
      of the corresponding domain in the yeast enzyme or subunit in the T. maritima
      enzyme. However, the overall structure is significantly different from the yeast
      and T. maritima enzymes, indicating that IGPs may change the relative orientation
      between the two subunits and close the glutaminase site upon glutamine binding.
      The putative ammonia tunnel, which carries nascent ammonia from glutaminase to
      the synthase site, has a closed gate comprising a cyclic salt bridge formed by
      four charged residues of the synthase subunit. The side chain of Lys100 in the
      cyclic salt bridge might change its side chain direction to form new interactions
      with the main chain carbonyl group of glutamine from the synthase subunit and the
      hydoxyl group of tyrosine from the glutaminase subunit, resulting in the opening
      of the gate for ammonia transfer.

PMID- 12417027
TI  - Biological activity of p-methylaminophenol, an essential structural component of
      N-(4-hydroxyphenyl)retinamide, fenretinide.
AB  - Fenretinide, N-(4-hydroxyphenyl)retinamide (4-HPR), is a synthetic amide of all
      trans-retinoic acid (RA), which inhibits cell growth, induces apoptosis, and is
      an antioxidant, and cancer chemopreventive and antiproliferative agent. These
      findings led us to investigate which structural component of 4-HPR contributes to
      these potent activities. Our approach was to examine 4-aminophenol (4-AP), p
      methylaminophenol (p-MAP), and p-acetaminophen (p-AAP). It was found that vitamin
      E, 4-AP and p-MAP scavenge alpha,alpha-diphenyl-beta-picrylhydrazyl (DPPH)
      radicals in a 1:2 ratio, in contrast to 4-HPR and p-AAP, for which 1:1 and 1:0.5
      ratios were observed relative to DPPH radicals. However, RA was inactive. Lipid
      peroxidation in rat liver microsomes was reduced by compounds (RA > p-MAP = 4-HPR
      > 4-AP) in a dose-dependent manner, while p-AAP was inactive. In addition, both p
      MAP and 4-HPR are potent inhibitors of cell growth and inducers of apoptosis in
      HL60 cells. p-MAP exhibits the same level of antiproliferative activity as 4-HPR
      against HL60R cells, which are a resistant clone against RA, and it inhibits the
      growth of various cancer cell lines (MCF-7, MCF-7/Adr(R), HepG2, and DU-145) to
      an extent greater than 4-AP and p-AAP, but is less potent than 4-HPR. Thus,
      although the antioxidant activity of p-MAP is more potent than that of 4-HPR, p
      MAP is less potent than 4-HPR in anticancer activity. These results suggest that
      both the anticancer and antioxidative activities shown by 4-HPR are due to the
      structure of p-MAP. The retinoyl residue or long alkyl chain substituent attached
      to an aminophenol may be significant for anticancer properties.

PMID- 12417028
TI  - Importance of a CDR H3 basal residue in V(H)/V(L) interaction of human
      antibodies.
AB  - Although the cooperativity of the V(H) and V(L) domains of an antibody in antigen
      binding has been extensively studied, the interaction between the V(H) and V(L)
      domains had not received sufficient attention. To systematically investigate the
      relationship between the amino acid sequence and V(H)/V(L) interaction strength,
      we here used a set of anti-bovine serum albumin antibodies having a single human
      framework for V(H) (V3-23/DP-47 and JH4b) and Vk (O12/O2/DPK9 and Jk1), but with
      different V(H)/V(L) interaction strengths. By phage display of a V(H) mini
      library and analysis of the interaction of amino acids with immobilized V(L)
      fragments, the residue at H95 (Kabat numbering) at the beginning of seven CDR H3
      residues was found to play a key role in determining the V(H)/V(L) interaction.
      On saturation mutagenesis of H95, Gly showed the strongest interaction, while
      Asp, Asn, and Glu showed lesser interaction in that order. The generality of the
      rule was confirmed by the test with urine-derived human L chain instead of a
      particular V(L). The results demonstrate that H95 plays a central role in
      deciding the V(H)/V(L) interaction of human Fvs that have most commonly found
      frameworks.

PMID- 12417029
TI  - Two enzyme-linked immunosorbent assay (ELISA) systems for N1,N8
      diacetylspermidine and N1,N12-diacetylspermine using monoclonal antibodies.
AB  - We obtained monoclonal antibodies against N(1),N(12)-diacetylspermine (DiAcSpm)
      and N(1),N(8)-diacetylspermidine (DiAcSpd), and developed two systems of
      competitive ELISA that utilize the antibodies and a common enzyme-labeled antigen
      to measure these di-acetylpolyamines. Cross-reactions with N(1)-acetylspermidine
      in the assay of DiAcSpm and with N8-acetylspermidine in the assay of DiAcSpd were
      as low as 0.26 and 0.6%, respectively, and were judged to be insignificant in
      clinical use for measuring urinary diacetylpolyamines. These assays were used to
      assess diurnal variations in diacetylpolyamine excretion in urine to show that
      the excretion of diacetylpolyamines after normalization for the concentration of
      creatinine is stable over a day with only minimal diurnal variation.

PMID- 12417030
TI  - Nucleotide-binding sites in V-type Na+-ATPase from Enterococcus hirae.
AB  - Enterococcus hirae V-ATPase, in contrast to most V-type ATPases, is resistant to
      N-ethylmaleimide (NEM). Alignment of the amino acid sequences of NtpA suggests
      that the NEM-sensitive Cys of V-type ATPases is replaced by Ala in E. hirae V
      ATPase. Consistent with this prediction, the V-ATPase became sensitive upon
      substitution of the Ala with Cys. The three-dimensional structure of the NtpB
      subunit of V-ATPase was modeled based on the structure of the corresponding
      subunit (alpha subunit) of bovine F(1)-ATPase by homology modeling. Overall, the
      3D structure of the subunit resembled that of alpha subunit of bovine F(1)
      ATPase. The NtpB subunit, which lacks the P-loop consensus sequence for
      nucleotide binding, was predicted to bind a nucleotide at the modeled nucleotide
      binding site. Experimental data supported the prediction that the E. hirae V
      ATPase had about six nucleotide-binding sites.

PMID- 12417031
TI  - Overexpression of the aryl hydrocarbon receptor (AhR) accelerates the cell
      proliferation of A549 cells.
AB  - The arylhydrocarbon receptor (AhR) is a ligand-activated transcription factor
      that mediates a spectrum of toxic and biological effects of 2,3,7,8
      tetrachlorodibenzo-p-dioxin (TCDD) and related compounds. Although the
      physiological ligand for the AhR has not yet been identified, several reports
      have suggested that the AhR may play important roles not only in the regulation
      of xenobiotic metabolism but also in the maintenance of homeostatic functions
      [Singh et al. (1996) Arch. Biochem. Biophys. 329, 47-55; Crawford et al. (1997)
      Mol. Pharmacol. 52, 921-927; Chang et al. (1998) Mol. Cell. Biol. 18, 525-535].
      Several lines of evidence suggest that one of the possible physiological roles of
      the AhR is regulation of cell proliferation. In this study, we first showed that
      treatment of A549 cells with the AhR agonist stimulates cell proliferation. The
      effect was antagonized by co-treatment with alpha-naphthoflavone. To obtain
      direct evidence that the AhR regulates cell proliferation, we isolated the clones
      that overexpress the AhR. These clones grow faster than control cells, and the
      rate of growth is proportional to the amount of the AhR. Cell cycle analysis
      revealed that the acceleration of cell growth by overexpression of the AhR is
      most probably due to shortening of the late M to S phases. Studies on the
      expression profiles of cell cycle regulators showed that the AhR or AhR ligand
      induces the expression of DP2, PCNA, and RFC38. DP2 is the transcription factor
      that forms the functional dimer with E2F and regulates the expression of several
      genes involved in DNA synthesis. Interestingly, both PCNA and RFC38 are target
      genes of E2F and the DP complex. Also, both of these factors are involved in
      regulating DNA polymerase delta activity. E2F activity was substantially
      increased in both the AhR-overexpressing cells and the AhR-agonist treated cells,
      suggesting that AhR-activated E2F/DP2 may induce the expression of PCNA and RFC38
      and subsequent DNA synthesis. Down-regulation of the expression of the Arnt by
      RNAi diminished the effects of the AhR on the cell proliferation of the A549
      cells. Consequently, we conclude that the AhR, presumably in collaboration with
      the Arnt, activates the DNA synthesis and the subsequent cell proliferation in
      A549 cells.

PMID- 12417032
TI  - Chaperone-like functions of high-mannose type and complex-type N-glycans and
      their molecular basis.
AB  - It has recently become apparent that high-mannose type N-glycans directly promote
      protein folding, whereas complex-type ones play a crucial role in the
      stabilization of protein functional conformations through hydrophobic
      interactions with the hydrophobic protein surfaces. Here an attempt was made to
      understand more deeply the molecular basis of these chaperone-like functions with
      the aid of information obtained from spacefill models of N-glycans. The promotion
      of protein folding by high-mannose N-glycans seemed to be based on their unique
      structure, which includes a hydrophobic region similar to the cyclodextrin
      cavity. The promotive features of high-mannose N-glycans newly observed under
      various conditions furnished strong support for the view that both intra- and
      extramolecular high-mannose N-glycans are directly involved in the promotion of
      protein folding in the endoplasmic reticulum. Further, it was revealed that the N
      acetyllactosamine units in complex-type N-glycans have an amphiphilic structure
      and greatly contribute to the formation of extensive hydrophobic surfaces and,
      consequently, to the N-glycan-protein hydrophobic interactions. The processing of
      high-mannose type N-glycans to complex-type ones seems to be an ingenious device
      to enable the N-glycans to perform these two chaperone-like functions.

PMID- 12417033
TI  - Proteomic analysis of stable protein methylation in lymphoblastoid cells.
AB  - We investigated the global distribution of methylaccepting proteins in
      lymphoblastoid cells by two-dimensional (2-D) gel electrophoresis. The 2-D
      electrophoreograms of normal and hypo-methylation (cells grown with a
      methyltransferase inhibitor adenosine dialdehyde) protein extracts did not
      exhibit significant differences. However, in vitro methylation of the
      hypomethylated extracts in the presence of the methyl-group donor S-adenosyl
      [methyl-3H]-methionine revealed close to a hundred signals. Less than one-fifth
      of the signals could be correlated with protein stains, indicating that most of
      the methylaccepting proteins are low abundant ones. We analyzed six of the spots
      that can be correlated with protein stains and suggested their identities. Among
      these putative protein methylacceptors, three are heterogeneous nuclear
      ribonucleoproteins (hnRNPA2/B1 and hnRNP K) that are reportedly methylated in
      their arginine- and glycine-rich RGG motifs.

PMID- 12417034
TI  - Three-dimensional structural model analysis of the binding site of an inhibitor,
      nervonic acid, of both DNA polymerase beta and HIV-1 reverse transcriptase.
AB  - Previously, we reported the three-dimensional molecular interactions of nervonic
      acid (NA) with mammalian DNA polymerase beta (pol beta) [Mizushina et al. (1998)
      J. Biol. Chem. 274, 25599-25607]. By three-dimensional structural model analysis
      and comparison with the spatial positioning of specific amino acids binding to NA
      on pol beta (Leu11, Lys35, His51, and Thr79), we obtained supplementary
      information that allowed us to build a structural model of human immunodeficiency
      virus type-1 reverse transcriptase (HIV-1 RT). In HIV-1 RT, Leu100, Lys65,
      His235, and Thr386 corresponded to these four amino acid residues. These results
      suggested that the NA binding domains of pol beta and HIV-1 RT are three
      dimensionally very similar. The effects of NA on HIV-1 RT are thought to be same
      as those on pol beta in binding to the rhombus of the four amino acid residues.
      NA dose-dependently inhibited the HIV-1 RT activity. For binding to pol beta, the
      kinetics were competitive when the rhombus was present on the DNA binding site.
      However, as the rhombus in HIV-1 RT was not present in the DNA binding site, the
      three-dimensional structure of the DNA binding site must be distorted, and
      subsequently the enzyme is inhibited non-competitively.

PMID- 12417035
TI  - Serum copper/zinc superoxide dismutase (Cu/Zn SOD) and gastric cancer risk: a
      case-control study.
AB  - We conducted a case-control study to evaluate the association between serum
      levels of copper/zinc superoxide dismutase (Cu/Zn SOD) and the risk of gastric
      cancer. Cases were 214 patients who had been diagnosed with gastric cancer and
      controls were 120 persons who underwent medical checkups. Serum levels of Cu/Zn
      SOD were determined by enzyme-linked immunosorbent assay (ELISA). Compared with
      the lowest quartile, the OR (odds ratio) was 4.54 (95% CI (confidence interval),
      1.62 - 12.66) for the third quartile and 15.75 (95% CI, 5.84 - 42.46) for the
      highest quartile. With both early and advanced cancers, as well as with the
      intestinal and diffuse types, a significant increase in risk was observed with
      increasing levels of serum Cu/Zn SOD. Our case-control study showed that serum
      levels of Cu/Zn SOD were significantly elevated in gastric cancer patients
      compared with apparently healthy controls, and higher Cu/Zn SOD levels may be
      associated with an increased risk of gastric cancer.

PMID- 12417036
TI  - Lack of a dose-response relationship for carcinogenicity in the rat liver with
      low doses of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline or N
      nitrosodiethylamine.
AB  - For a long period, it has been generally considered that carcinogens,
      particularly genotoxic ones, have no threshold in exerting their potential for
      cancer induction. However, the non-threshold theory can be challenged with regard
      to assessment of cancer risk to humans. Here we show that a food-derived,
      genotoxic hepatocarcinogen, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline, forms
      DNA adducts at low doses, but does not induce glutathione S-transferase placental
      form (GST-P)-positive foci (considered to be preneoplastic lesions) or 8-hydroxy
      2'-deoxyguanosine in rat liver. Moreover a N-nitroso compound, N
      nitrosodiethylamine, at low doses was also found not to induce GST-P-positive
      foci in rat liver. These results imply that there is a no-observed effect level
      for hepatocarcinogenesis by these genotoxic carcinogens.

PMID- 12417037
TI  - Synergistic promoting effects of Helicobacter pylori infection and high-salt diet
      on gastric carcinogenesis in Mongolian gerbils.
AB  - Helicobacter pylori (Hp) infection and high-salt diet administration are both
      considered to be important factors in gastric carcinogenesis in man. To
      investigate the interaction of these two factors on gastric carcinogenesis, an
      experimental study of the carcinogenesis model was performed. Mongolian gerbils
      were treated with 20 ppm of N-methyl-N-nitrosourea (MNU) in their drinking water
      for alternate weeks for a total of 5 weeks' exposure (groups 1, 2, 3 and 4) or
      were maintained as controls (groups 5, 6, 7 and 8). At week 11, the animals were
      inoculated with Hp (groups 1, 2, 5 and 6) or the vehicle alone (groups 3, 4, 7
      and 8), and after week 12, animals were fed a 10% high salt diet (groups 1, 3, 5
      and 7) or the control diet (groups 2, 4, 6 and 8). At week 50, the incidence of
      adenocarcinomas in group 1 (32.1%, 6 well-differentiated, 2 poorly-differentiated
      adenocarcinomas, and one signet-ring cell carcinoma) was significantly higher
      than in groups 3 (0%) (P < 0.005) and 4 (0%) (P < 0.01). The incidence of
      adenocarcinomas in group 2 (11.8%, one well-differentiated adenocarcinoma, and
      one signet-ring cell carcinoma) was also higher than in groups 3 and 4. A high
      salt diet enhanced the effects of Hp infection on gastric carcinogenesis, and
      these two factors acted synergistically to promote the development of stomach
      cancers. Moreover, Hp infection promoted gastric carcinomas more than the high
      salt diet.

PMID- 12417038
TI  - Enhanced expression of type IV collagen-binding protein (p29) in Fyn-transfected
      murine fibrosarcoma cells.
AB  - We investigated the mechanism of the enhancement of metastatic potential induced
      by transfection of the fyn gene, a member of the src family. We employed two
      murine fyn cDNA-transfected clones, ML-SN1 and ML-SN2, which were previously
      established from an ML-01 low-metastatic clone of Meth A sarcoma of BALB / c mice
      and were proven to have higher metastatic ability than ML-01 and the mock
      transfected clone ML-MT-neo (Takayama et al., 1993). Our present investigation
      revealed that the two transfectants showed higher metastatic ability and higher
      rates of adherence to type IV collagen than ML-MT-neo. However, no difference was
      found in in vitro or in vivo growth rates, attachment to laminin or endothelial
      cells or cell motility through a reconstituted basement membrane. Analysis of
      surface membrane proteins labeled with (125)I on SDS-PAGE showed that a 29 kD
      band specifically bound to type IV collagen-coupled beads was more intense in ML
      SN2 than in ML-MT-neo. Genistein, a protein tyrosine kinase inhibitor,
      dramatically reduced protein tyrosine kinase (PTK) activity of ML-SN2 in a dose
      dependent fashion, corresponding to the reduction of adhesiveness to type IV
      collagen. The expression of the type IV collagen-binding protein (p29) of ML-SN2
      was also reduced significantly by genistein treatment. These results suggested
      that the fyn product in Meth A cells augments the expression of a type IV
      collagen-binding protein through elevation of the PTK activity of the membrane
      fraction and thus facilitates the metastasis of Meth A.

PMID- 12417039
TI  - Cloning of the 5' upstream region of the rat p16 gene and its role in silencing.
AB  - Hypermethylation of the 5' upstream region (5' region) of the human p16(CDKN2A)
      (p16) gene is known to cause silencing, which is involved in a wide range of
      human cancers. For the rat p16 gene, its 5' region has not been cloned, and it is
      uncertain whether surrogate use of exon 1 alpha is adequate for analysis of p16
      silencing. In this study, we observed that methylation analysis of exon 1 alpha
      gave false positive results in three samples of normal rat mammary epithelia and
      in two of six primary mammary carcinomas. Therefore, we determined the nucleotide
      sequence of the 5' region of the rat p16 gene. To confirm that methylation status
      of the 5' region is correlated with p16 expression, the methylation status was
      analyzed by bisulfite sequencing and methylation-specific PCR in three samples of
      normal mammary glands, six samples of mammary carcinomas and four cell lines. The
      5' region was demethylated in all of the three normal and six carcinoma samples
      that fully expressed p16. On the other hand, the 5' region was highly methylated
      in the 3Y1 cell line, which lacked p16 expression, but without deletion. These
      results showed that the methylation status of the 5' region was more closely
      correlated with p16 expression than that of the exon 1 alpha and analysis of the
      methylation status is useful in examining p16 silencing in various rat tumors.

PMID- 12417040
TI  - Frequent epigenetic silencing of the p16 gene in non-small cell lung cancers of
      tobacco smokers.
AB  - Epidemiological studies have demonstrated a causal link between tobacco smoking
      and lung cancer. We investigated the association between inactivation of the p16
      gene and tobacco smoking in 51 non-small cell lung cancers (NSCLCs). Aberrations
      of the p16 gene were studied by PCR single-strand conformation polymorphism
      analysis, followed by direct sequencing, microsatellite analysis, methylation
      specific PCR, and immunohistochemistry. Mutations were detected in 3.9% (2/51) of
      the tumors; the tumors carrying mutations were from smokers. The incidences of
      loss of heterozygosity, homozygous deletion, and promoter methylation in 37
      smokers vs. 14 non-smokers were; 45.9% vs. 28.6%, 16.2% vs. 7.1%, and 35.1% vs.
      7.1%, respectively. Among these, only the association between promoter
      methylation and tobacco smoking was statistically significant (P < 0.05).
      Therefore, epigenetic aberration is considered to be a major causative event in
      p16 silencing by tobacco smoking. Loss of p16 protein expression was apparent in
      49% (25/51) of the tumors, and was associated with tobacco smoking (P < 0.05) and
      with histological type (P < 0.05). These findings suggest that tobacco smoking
      leads to inactivation of the p16 gene mainly through the epigenetic mechanism,
      ultimately increasing the risk of NSCLC, especially the squamous cell
      histological type.

PMID- 12417041
TI  - Differentially regulated genes as putative targets of amplifications at 20q in
      ovarian cancers.
AB  - Frequent amplification of DNA at 20q or part of 20q has been demonstrated by
      comparative genomic hybridization in ovarian cancer (OC), but the genetic
      target(s) of these amplification events remain unknown. We examined copy-number
      changes with respect to six candidate genes, E2F1 (20q11.2), TGIF2 (20q11.2),
      AIB1 (20q12), PTPN1 (20q13.1), ZNF217 (20q13.2), and BTAK (20q13), and then
      measured transcription levels of each candidate in 18 OC cell lines. Three
      distinct cores of amplification were identified: 20q11.2, harboring E2F1 and
      TGIF2 (region I; 1 of 18 cell lines, 5.6%); 20q13.1, harboring PTPN1 (region II;
      5 lines, 27.8%); and 20q13.2, harboring ZNF217 and BTAK (region III; 6 lines,
      33.3%). Among the six genes examined, expression levels of PTPN1 and ZNF217 were
      significantly correlated with absolute copy-number, and those of PTPN1 and TGIF2
      were significantly correlated with copy-number relative to the centromere of
      chromosome 20 (20cen). Among 19 primary OCs examined, moreover, we observed
      amplification of TGIF2, PTPN1 and ZNF217 in five (26.3%), ten (52.6%), and twelve
      (63.2%) tumors, respectively. Expression levels of PTPN1 and ZNF217 were
      significantly correlated with their copy-numbers in those primary OCs. Our
      results suggest that 20q amplifications in OCs can be extensive and complex,
      probably due to synergistic or non-synergistic amplification of separate regions
      of 20q, involving multiple, independently amplified targets.

PMID- 12417043
TI  - Expression of glycolipids bearing Lewis phenotypes in tissues and cultured cells
      of human gynecological cancers.
AB  - Transformation-associated expression of Le(b) (Lewis antigen-b) or Le(Y) in human
      colorectal carcinomas has been well described. To examine the expression of
      glycosphingolipids (GSLs) bearing Lewis-phenotypes in human gynecological
      carcinoma-derived cells, we determined the concentrations of all GSLs. Although
      neither Le(b) nor Le(Y) was present in HEC-108 cells established from the poorly
      differentiated type of endometrial adenocarcinoma, other cell lines from
      moderately or well-differentiated types expressed either Le(b) or Le(Y), or both,
      at concentrations of 0.01 to 0.03 microg per mg of dry cells, which comprised 0.3
      to 1.3% of the total GSLs. In the cervical and ovarian carcinoma-derived cell
      lines, Lewis phenotypes tended to be carried by nLc(4)Cer, which was accumulated
      in the cells without sialylation or fucosylation. These results indicated that
      expression of Le(b)- or Le(Y)-phenotypes was strongly dependent on the metabolic
      ability to supply the precursor GSLs. Both Le(b) and Le(Y) were successfully
      detected by monoclonal antibody MSN-1, which was a useful probe for the
      simultaneous detection of Le(b) and Le(Y). On application of MSN-1, either Le(b)
      or Le(Y) was detected in tissues from patients with well- and moderately
      differentiated types of endometrial adenocarcinoma at concentrations of 0.01 to
      0.04 microg per mg of dry tissues, but not in the tissues of poorly
      differentiated type. Normal endometria at the follicular and luteal phases also
      contained the antigens, but the concentrations and the frequency of antigen
      expression were lower than those in the well- and moderately differentiated types
      of endometrial adenocarcinoma.

PMID- 12417042
TI  - Clinical significance of glucose transporter 1 (GLUT1) expression in human breast
      carcinoma.
AB  - Glucose uptake and glycolytic metabolism are enhanced in cancer cells compared to
      normal cells and tissues. Increased expression of glucose transporter 1 (GLUT1)
      has been reported in human malignant cells. The aim of this study is to determine
      the expression of the facilitative glucose transporter protein GLUT1 in human
      breast carcinomas and a possible correlation between GLUT1 expression and
      clinical outcome including disease-free or overall survival. One hundred
      consecutive formalin-fixed, paraffin-embedded sections of invasive breast
      carcinomas were evaluated by means of immunohistochemical staining of GLUT1.
      Forty-seven (47%) of 100 breast carcinomas showed positive staining for GLUT1.
      Expression of GLUT1 correlated significantly with nuclear grade (P < 0.001),
      estrogen receptor status (P = 0.002), and progesterone receptor status (P =
      0.001). The mean disease-free survival periods of GLUT1-positive and -negative
      patients were 47 +/- 2.4 months and 54.3 +/- 1.3 months, respectively (P =
      0.017). The mean overall survival periods of GLUT1-positive and -negative
      patients were 48.7 +/- 2.2 and 56.1+/- 1.3 months, respectively (P = 0.043). In
      the multivariate analysis, disease-free survival correlated significantly with
      GLUT1, tumor size, and lymph node involvement (P = 0.043, P = 0.014, and P =
      0.045, respectively). In analysis of overall survival, however, lymph node
      involvement, tumor size, and nuclear grade were statistically significant (P =
      0.024, P = 0.023, and P = 0.003, respectively). Our data suggest that absence of
      GLUT1 expression significantly increases disease-free survival. These findings
      demonstrate that GLUT1 expression in breast carcinoma can be a marker of
      aggressive biological behavior and identifies a worse prognosis in breast
      carcinoma patients.

PMID- 12417044
TI  - The intraductal carcinoma component is a significant prognostic parameter in
      patients with invasive ductal carcinoma of the pancreas.
AB  - We have sometimes encountered invasive ductal carcinomas (IDCs) of the pancreas
      containing intraductal carcinoma components in the intra- and / or extra-tumor
      area. The purpose of this study was to investigate whether intraductal carcinoma
      components would be useful for predicting the outcome of IDC patients. Forty
      seven surgically treated IDCs were examined, and all histological tumor sections
      were stained with Elastica to accurately confirm intraductal carcinoma
      components. Well-known clinicopathological parameters that exhibited a
      significant correlation in the univariate analyses for predicting disease-free
      survival (DFS) and overall survival (OS) were entered into the Cox proportional
      hazard multivariate analysis. Since the lowest P-value predicting DFS or OS
      periods was observed in IDCs with more than 10% intraductal carcinoma components
      and those with 10% or less intraductal carcinoma components (P = 0.028 and P =
      0.019), we established the cutoff value of intraductal carcinoma components at
      10%. In the multivariate analyses for DFS and OS, the presence of more than 10%
      intraductal carcinoma components showed a marginally significant increase in the
      hazard rate (HR) of tumor recurrence (P = 0.067) and significantly increased the
      HR of mortality (P = 0.040). The present study demonstrated that IDCs with more
      than 10% intraductal carcinoma components were associated with a significantly
      better patient outcome than those with 10% or less intraductal carcinoma
      components.

PMID- 12417045
TI  - Pharmaceutical and biomedical differences between micellar doxorubicin (NK911)
      and liposomal doxorubicin (Doxil).
AB  - The stability and biological behavior of an in vitro system of doxorubicin (DXR)
      entrapped in NK911, polymer micelles, was examined and compared with those of DXR
      entrapped in Doxil, polyethylene-glycol-conjugated liposomes. The fluorescence of
      DXR inside micelles or liposomes in an aqueous solution is known to be strongly
      quenched by the outer shells of the micellar or liposomal formation. Thus, by
      measuring the fluorescence intensity of DXR released from NK911 or Doxil, we
      could determine the stability of the micellar or liposomal DXR formation.
      Furthermore, NK911 was found to be less stable than Doxil in saline solution. In
      drug distribution experiments using an in vitro solid tumor model, when spheroids
      formed from two human colonic cancer lines, HT-29 and WiDr, and a human stomach
      cancer line, MKN28, were exposed to NK911, DXR was distributed throughout the
      spheroids, including their center. On the other hand, when the spheroids were
      exposed to Doxil, DXR was distributed only to the surface of the spheroids. It
      has been suggested that Doxil can deliver DXR to a solid tumor more efficiently
      than NK911 via the EPR (enhanced permeability and retention) effect, because
      Doxil may be more stable in plasma than NK911. On the other hand, DXR packed in
      NK911 may be distributed by diffusion to cancer cells distant from the tumor
      vessel, because NK911 can leak out of the tumor vessel and may be able to release
      free DXR more easily than Doxil. It has been suggested that drug carrier systems
      such as liposomes and micelles should be selected appropriately bearing in mind
      the characteristics of the tumor vasculature and the tumor interstitium.

PMID- 12417046
TI  - Development of gene therapy using prostate-specific membrane antigen
      promoter/enhancer with Cre Recombinase/LoxP system for prostate cancer cells
      under androgen ablation condition.
AB  - To enhance the efficacy of suicide gene therapy for prostate cancer under
      androgen deprivation, we designed a promoter system that consists of the prostate
      specific membrane antigen (PSMA) promoter / enhancer (PEPM) and Cre-loxP DNA
      recombination system. We constructed two kinds of plasmids. One plasmid contains
      a Cre recombinase (Cre) under the control of PEPM and the other expresses CMV-lox
      luciferase / herpes simplex virus thymidine kinase (TK). In PSMA-positive LNCaP
      cells, the promoter activity of the PEPM-Cre plus CMV-lox-luciferase demonstrated
      800-fold greater activity compared with that of the PSMA promoter alone. However,
      no enhancement of the promoter activity was observed in the PSMA-negative cells.
      Furthermore, in contrast to prostate specific antigen promoter / enhancer (PP),
      the promoter activity of PEPM did not decrease when the LNCaP cells were cultured
      in charcoal-stripped fetal bovine serum (CFBS). In an in vitro gene therapy model
      with LNCaP cells, the cell growth inhibition in the presence of ganciclovir (GCV)
      was more evident in the cells transfected with the PEPM-Cre plus CMV-lox-TK than
      in the cells with the PP-TK, and the difference in efficacy between the two
      plasmids was more remarkable when the cells were maintained in CFBS medium. The
      therapeutic effect of PEPM-Cre plus CMV-lox-TK was also observed in xenografted
      LNCaP cells on nude mice when the plasmids were directly injected into tumors and
      GCV was administered intraperitoneally. These findings indicate that the
      combination of the PSMA promoter / enhancer and the Cre-loxP system can enhance
      the PSMA promoter activity even under androgen ablation conditions and can exert
      its anti-tumor effect both in vitro and in vivo.

PMID- 12417047
TI  - Phosphorylation of Fas-associated death domain contributes to enhancement of
      etoposide-induced apoptosis in prostate cancer cells.
AB  - Fas-associated death domain (FADD) plays an important role as an adapter molecule
      in Fas (CD95/APO-1)-mediated apoptosis and contributes to anticancer drug-induced
      cytotoxicity. We treated three human prostate cancer cell lines with etoposide, a
      toposiomerase II inhibitor with activity against various tumors including
      prostate cancer. We found that the overexpression of FADD sensitizes etoposide
      induced apoptosis through a rapid activation of c-Jun NH(2)-terminal kinase (JNK)
      and, subsequently, of caspase 3. In addition, phosphorylation of FADD at serine
      194 coincided with this sensitization. Treatment with the caspase 3 inhibitor, N
      acetyl-Asp-Glu-Val-Asp-aldehyde (DEVD-CHO), or overexpression of either mitogen
      activated protein kinase kinase (MKK) 7 or Bcl-xL canceled FADD-mediated
      sensitization to etoposide-induced apoptosis. Moreover, treatment with the
      caspase 8 inhibitor, benzyloxy-carbonyl-Val-Ala-Asp-fluoromethylketone (z-IETD
      fmk), or overexpression of viral FLICE/caspase-8-inhibitory protein (FLIP) from
      equine herpesvirus type 2 E8 also had an inhibitory effect, supporting a major
      involvement of a caspase 8-dependent mitochondrial pathway. Interestingly, FADD
      was phosphorylated, and etoposide-induced JNK/caspase activation and apoptosis
      were enhanced in the cells arrested at G2/M transition, but not in those
      overexpressing mutant FADD, in which 194 serine was replaced by alanine. Our
      results demonstrate that phosphorylated FADD-dependent activation of the
      JNK/caspase pathway plays a pivotal role in sensitization to etoposide-induced
      apoptosis in prostate cancer cells.

PMID- 12417049
TI  - Protein folding in the post-genomic era.
AB  - Protein folding is a topic of fundamental interest since it concerns the
      mechanisms by which the genetic message is translated into the three-dimensional
      and functional structure of proteins. In these post-genomic times, the knowledge
      of the fundamental principles are required in the exploitation of the information
      contained in the increasing number of sequenced genomes. Protein folding also has
      practical applications in the understanding of different pathologies and the
      development of novel therapeutics to prevent diseases associated with protein
      misfolding and aggregation. Significant advances have been made ranging from the
      Anfinsen postulate to the "new view" which describes the folding process in terms
      of an energy landscape. These new insights arise from both theoretical and
      experimental studies. The problem of folding in the cellular environment is
      briefly discussed. The modern view of misfolding and aggregation processes that
      are involved in several pathologies such as prion and Alzheimer diseases. Several
      approaches of structure prediction, which is a very active field of research, are
      described.

PMID- 12417048
TI  - Suppression of lung metastasis by aspirin but not indomethacin in an in vivo
      model of chemically induced hepatocellular carcinoma.
AB  - To examine the effect of non-steroidal anti-inflammatory drugs on metastasis
      formation, aspirin (ASP, 0.5% in diet) and indomethacin (IM, 0.005% in drinking
      water) were applied to an in vivo highly metastatic rat hepatocellular carcinoma
      (HCC) model in F344 male rats. Administration for 8 weeks after induction of
      highly metastatic HCC by sequential treatment with diethylnitrosamine and N
      nitrosomorpholine did not cause any significant change in survival rate or body
      weight. Multiplicity of HCC in the liver increased during ASP or IM treatment
      without any significant histological alteration. Although absent in the rats
      killed at the end of the period of carcinogen exposure, lung metastasis at the
      end of the experiment was found in 100%, 89% and 100% of rats in the control, ASP
      and IM groups, respectively. Degree of metastasis was classified into three
      groups according to the number of metastatic nodules, i.e., slight (1 - 5
      nodules), moderate (6 - 50) and severe (more than 51), which amounted to 0%, 43%
      and 57% in the control group. ASP significantly reduced the degree of metastasis,
      the incidences being 33%, 44%, and 11%, respectively, whereas IM was without
      significant influence. Both agents suppressed cell proliferation in HCCs, without
      any alteration of pan-cadherin expression. However, expression in HCC of mRNAs
      for intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, both
      of which are considered to play key roles in attachment of cancer cells to the
      endothelium, was significantly suppressed by ASP. Thus, the present study
      demonstrated that ASP, but not IM, has the potential to inhibit lung metastasis
      of rat HCC in vivo, possibly via reduced attachment of tumor cells to the
      vascular endothelium. Moreover, these data indicate this in vivo model for
      induction of rat highly metastatic HCC to be a useful tool for the assessment of
      the efficacy of therapeutic treatments to block metastasis formation.

PMID- 12417050
TI  - Biomedical applications of protein chips.
AB  - The development of microchips involving proteins has accelerated within the past
      few years. Although DNA chip technologies formed the precedent, many different
      strategies and technologies have been used because proteins are inherently a more
      complex type of molecule. This review covers the various biomedical applications
      of protein chips in diagnostics, drug screening and testing, disease monitoring,
      drug discovery (proteomics), and medical research. The proteomics and drug
      discovery section is further subdivided to cover drug discovery tools (on-chip
      separations, expression profiling, and antibody arrays), molecular interactions
      and signaling pathways, the identification of protein function, and the
      identification of novel therapeutic compounds. Although largely focused on
      protein chips, this review includes chips involving cells and tissues as a
      logical extension of the type of data that can be generated from these
      microchips.

PMID- 12417051
TI  - Targeting apoptosis in neurological disease using the herpes simplex virus.
AB  - Herpes Simplex Viruses type 1 (HSV-1) and 2 (HSV-2) cause central nervous system
      (CNS) disease ranging from benign aseptic meningitis to fatal encephalitis. In
      adults, CNS infection with HSV-2 is most often associated with aseptic meningitis
      while HSV-1 frequently produces severe, focal encephalitis associated with high
      mortality and morbidity. Recent studies suggested that the distinct neurological
      outcome of CNS infection with the two viruses may be due to their distinct
      modulation of apoptotic cell death: HSV-1 triggers neuronal apoptosis, while HSV
      2 is neuroprotective. Apoptosis also occurs in the etiology of neurodegenerative
      disorders such as Alzheimer's disease, Parkinson's disease and Down's syndrome,
      and determines the loss of specific neuronal populations and the decline in
      cognitive functions. Notwithstanding, the therapy of these disorders may rely on
      the use of replication-defective HSV-1 vectors to deliver anti-apoptotic
      transgenes to the CNS. However, the recent discovery of a neuroprotective
      activity innate to the HSV-2 genome (the ICP10 PK gene) suggests that: i) ICP10
      PK may constitute a novel therapeutic approach by targeting both the apoptotic
      cell death and the cognitive decline, and ii) HSV-2 may be more suitable than HSV
      1 as a vector for targeting neuronal disease.

PMID- 12417052
TI  - Angiogenesis and chemokines in rheumatoid arthritis and other systemic
      inflammatory rheumatic diseases.
AB  - Angiogenesis, the formation of new vessels, is important in the pathogenesis of
      rheumatoid arthritis (RA) and other inflammatory diseases. Chemotactic cytokines
      termed chemokines mediate the ingress of leukocytes, including neutrophils and
      monocytes into the inflamed synovium. In this review, authors discuss the role of
      the most important angiogenic factors and angiogenesis inhibitors, as well as
      relevant chemokines and chemokine receptors involved in chronic inflammatory
      rheumatic diseases. RA was chosen as a prototype to discuss these issues, as the
      majority of studies on the role of angiogenesis and chemokines in inflammatory
      diseases were carried out in arthritis. However, other systemic inflammatory
      (autoimmune) diseases including systemic lupus erythematosus (SLE), systemic
      sclerosis (SSc), Sjogren's syndrome (SS), mixed connective tissue disease (MCTD),
      polymyositis/dermatomyositis (PM/DM) and systemic vasculites are also discussed
      in this context. As a number of chemokines may also play a role in
      neovascularization, this issue is also described here. Apart from discussing the
      pathogenic role of angiogenesis and chemokines, authors also review the
      regulation of angiogenesis and chemokine production by other inflammatory
      mediators, as well as the important relevance of neovascularization and
      chemokines for antirheumatic intervention.

PMID- 12417053
TI  - Effects of oral supplement of L-glutamine on diverted colon wall.
AB  - Diverted colorectal segments can present trophic and inflammatory changes. These
      alterations are of special importance in the patients whose colostomy becomes
      permanent, as well as in the differential diagnosis with other inflammatory
      diseases. This study was accomplished to quantify these alterations and to
      determine if oral supplement of L-glutamine would avoid them. Twenty-six adult
      male Wistar rats were distributed in three groups: control, colostomized and
      colostomized+L-glutamine. The colostomized group received a loop colostomy. The
      colostomized+L-glutamine group received a colostomy similar to the previous group
      and oral supplement of L-glutamine. Partial volumes of all layers of the colonic
      wall were measured by image analysis stereology. The diversion caused a decrease
      of partial volumes of the mucosa and the epithelium as well, and also of the
      height of the intestinal crypts (p<0.05). There was an increase of partial
      volumes of the lamina propria, of the submucosa and of the muscularis mucosae vs
      controls (p<0.05). The partial volume of the muscularis propria didn't show
      significant alteration. The supplementation of L-glutamine was effective in
      preventing the atrophy of mucosa and epithelium (p<0.05), also avoiding the
      increase of partial volumes of the submucosa and lamina propria (p<0.05). This
      supplement didn't change significantly the muscular layers. In conclusion,
      colostomy causes the atrophy of the colon wall, mainly due to the atrophy of the
      epithelium. The supplementation of L-glutamine is able to avoid these changes.

PMID- 12417054
TI  - Angiotensinogen gene M235T variant and pre-eclampsia in Romanian pregnant women.
AB  - BACKGROUND: Association between the human angiotensinogen gene and essential
      hypertension has been confirmed in recent studies. Pre-eclampsia is a
      complication of pregnancy characterised by increased vascular resistance, high
      blood pressure, proteinuria and oedema, that appears in the second and third
      trimester of pregnancy. The aim of our study was the analysis of M235T mutation
      in the gene encoding angiotensinogen in Romanian women with different forms of
      hypertension during pregnancy. METHODS: Fourteen women with obstetric
      complications were tested for M235T angiotensinogen gene mutation. Indications
      for testing were: severe or mild pre-eclampsia and pre-eclampsia associated with
      chronic hypertension. We also tested for control 6 healthy women. The M235T
      angiotensinogen gene mutation was analysed by polymerase chain reaction followed
      by enzymatic digestion with Tth 111I restriction endonuclease enzyme and agarose
      gel electrophoresis of the products. RESULTS: Eleven (78.57%) of the 14 women
      with complications of pregnancy had M235T mutation: 9 (64.28%) were found to be
      heterozygous carriers of the M235T variant of the angiotensinogen gene and 2
      (14.28%) were found to be homozygous carriers. In the group of women with normal
      pregnancy, 3 (50%) of the 6 women had M235T mutation: 2 (33.33%) were found to be
      heterozygous carriers of the M235T variant of the angiotensinogen gene and 1
      (16.66%) was found to be homozygous carrier. CONCLUSIONS: Our study shows that
      the M235T variant in the gene encoding angiotensinogen could be a risk factor in
      mild and severe pre-eclampsia.

PMID- 12417055
TI  - Relationship between chromosomal changes complexity and disease aggressiveness in
      myeloid and lymphoid disorders.
AB  - In this paper are presented four cases, with unusual chromosomal abnormalities,
      identified at the first presentation, among over 100 patients with myeloid and
      lymphoid acute and chronic leukemias cytogenetically investigated. The complexity
      and nature of cytogenetic abnormalities was in direct relationship with the
      disease evolution. The first case, a 22 years old man with acute lymphoblastic
      leukemia type L3, exhibited many structural changes in bone marrow cells with
      diploid number of chromosomes: del(3)(q26); del (5)(p13); t(8;14) (q24;q32);
      del(9)(p11q11);inv(15)(p12qter). The second case, a 62 years old woman, diagnosed
      as poorly differentiated acute leukemia, refractory to treatment, showed
      hiperdiploidy (48-54 chromosomes) and 3-4 markers derived from chromosomes 5 and
      12. The third case, a young man of 27 years old, diagnosed as acute myeloid
      leukemia, apart of Philadelphia chromosome, presented trisomy 16, both in diploid
      and aneuploid cells. None of these three patients did respond to any medical
      therapy. Their rapid death was a powerful proof of the correlation between the
      complexity of genome changes and disease aggressiveness. In the fourth case, a
      constitutional translocation t(3;5)(q26.3;q21) identified in a 72 years old woman
      with essential thrombocythemia, appeared not to be involved in the etiology of
      the disease. In this case, the treatment with hydroxyurea was successful and the
      disease evolution was favourable. In conclusion, we appreciate that in the three
      cases of myeloid and lymphoid leukemias it was a direct relationship between the
      complexity of genomic changes and the aggressiveness of the disease.

PMID- 12417056
TI  - Oxidative stress in the pathogenesis of nonalcoholic fatty liver disease, in rats
      fed with a choline-deficient diet.
AB  - BACKGROUND/AIM: The pathogenesis of Nonalcoholic Fatty Liver Disease remains
      largely unknown, but oxidative stress seems to be involved. The aim of this study
      was to evaluate the role of oxidative stress in experimental hepatic steatosis
      induced by a choline-deficient diet. METHODS: Fatty liver disease was induced in
      Wistar rats by a choline-deficient diet. The animals were randomized into three
      groups: I (G1) and II (G2), n=6 each--fed with a choline-deficient diet for four
      and twelve weeks respectively; Group III (control-G3; n=6)--fed with a standard
      diet for twelve weeks. Samples of plasma and liver were submitted to biochemical,
      histological and oxidative stress analysis. Variables measured included serum
      levels of aminotransferases (AST, ALT), cholesterol and triglycerides. Oxidative
      stress was measured by lucigenin-enhanced luminescence and the concentration of
      hydroperoxides (CE-OOH-cholesteryl ester) in the liver tissue. RESULTS: We
      observed moderate macro- and microvesicular fatty change in periportal zones G1
      and G2 as compared to controls (G3). In G2, fatty change was more severe. The
      inflammatory infiltrate was scanty and no fibrosis was seen in any group. There
      was a significant increase of AST and triglycerides in G1 and G2 as compared to
      control group G3. The lucigenin-amplified luminescence (cpm/mg/min x 10(3)) was
      significantly increased in G1 (1393-/+790) and G2 (7191-/+500) as compared to
      controls (513-/+170), p<0.05. The concentrations of CE-OOH were higher in G1 (5.7
      /+0.9 nmol/mg protein) as compared to control (2.6-/+0.7 nmol/mg protein),
      p<0.05. CONCLUSION: 1) Oxidative stress was found to be increased in experimental
      liver steatosis; 2) The production of reactive oxygen species was accentuated
      when liver steatosis was more severe; 3) The alterations produced by oxidative
      stress could be an important step in the pathogenesis of nonalcoholic fatty liver
      disease.

PMID- 12417057
TI  - Evaluation of the cholesterol influence in type II collagen-induced arthritis in
      DBA/1J mice: an autoradiographic study.
AB  - In order to verify the cholesterol influence in RA severity in DBA/1J mice, we
      quantified the cholesterol present in the knee joints of normal (N) and with
      collagen II induced arthritis (CIA). Forty male DBA/1J mice, were divided in
      normal (n=20) and CIA group (n=20). Mice in CIA group were injected with 100
      microg of collagen II emulsified in Freund's complete adjuvant. Sixteen DBA/1J (8
      N and 8 CIA) received an injection of 2.96 x 10(6) Bq of (3)H-cholesterol and
      were anesthetized and sacrificed. Semi-fine sections were covered with LM-1
      emulsion, exposed for six weeks and developed. Collagen induced edema, erythema
      and dysfunction of knee joints in CIA group. Radioactive cholesterol was located
      more on the synovial membrane, where we found the greatest density of silver
      grains, significantly (P<0.0001) higher in group CIA vs. controls (61-/+2.3 X 18
      /+0.7). We conclude that the cholesterol deposits on the synovial membrane is
      related to CIA severity.

PMID- 12417058
TI  - Co-stimulatory and adhesion molecules of dendritic cells in rheumatoid arthritis.
AB  - Dendritic cells (DCs) in the rheumatoid arthritis (RA) joint mediate the
      immunopathological process and act as a potent antigen presenting cell. We
      compared the expression of co-stimulatory and adhesion molecules on DCs in RA
      patients versus controls with traumatic joint lesions and evaluated the
      correlation between the immunophenotypical presentation of DCs and the clinical
      status of the disease. Samples of peripheral venous blood, synovial fluid (SF)
      and synovial tissue (ST) were obtained from 10 patients with RA at the time of
      hip or knee replacement and from 9 control patients with knee arthroscopy for
      traumatic lesions. Clinical status was appreciated using the DAS28 score. Blood,
      SF and dissociated ST cell populations were separated by centrifugation and
      analyzed by flow cytometry. Cells phenotypes were identified using three-color
      flow cytometry analysis for the following receptors HLA-DR, CD80, CD83, CD86,
      CD11c, CD18, CD54, CD58, CD3, CD4, CD8, CD19, CD20, CD14, CD16, CD56. HLA-DR
      molecules, co-stimulatory receptors CD80, CD86, CD83 and adhesion molecules CD18,
      CD11c, CD54, CD58, were analyzed by two-color immunofluorescence microscopy on ST
      serial sections. In patients with active RA (DAS28>5.1) we found a highly
      differentiated subpopulation of DCs in the ST and SF that expressed an activated
      phenotype (HLA-DR, CD86+, CD80+, CD83+, CD11c+, CD54+, CD58+). No differences
      were found between circulating DCs from RA patients and control patients. Our
      data suggest an interrelationship between clinical outcome and the
      immunophenotypical presentation of DCs. Clinical active RA (DAS28>5.1) is
      associated with high incidence of activated DCs population in the ST and SF as
      demonstrated by expression of adhesion and co-stimulatory molecules.

PMID- 12417059
TI  - Three-dimensional visualization of bile canaliculi by confocal laser scanning
      microscopy.

PMID- 12417060
TI  - Tissue cultures from adult human postmortem subcortical brain areas.
AB  - Animal models used to study human aging and neurodegeneration do not display all
      symptoms of these processes as they are found in humans. Recently, we have shown
      that many cells in neocortical slices from adult human postmortem brain may
      survive for extensive periods in vitro. Such cultures may enable us to study age
      and disease related processes directly in human brain tissue. Here, we present
      observations on subcortical brain tissue.

PMID- 12417061
TI  - Selective protection by phosphatidic acid against staurosporine-induced neuronal
      apoptosis.
AB  - Phosphatidic acid, the main product of lipid breakdown through phospholipase D
      activation, has been implicated in important signal transduction pathways able to
      influence cell fate in many ways. The purpose of this work was to determine
      possible effects of phosphatidic acid on neuronal cell death pathways. Here we
      used cerebellar granular cell cultures and cell death was triggered with either
      staurosporine or H(2)O(2). Cell viability was quantified by spectrophotometry,
      using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT)
      test. Staurosporine (1-3 microM) or H(2)O(2) (50-800 microM) induced cell death
      in a dose-dependent manner. Using fluorescent staining (propidium iodide or
      annexin V-Cy3/6-carboxyfluorescein) we showed that cell death was mostly
      apoptotic in staurosporine treated cells and mostly non-apoptotic (necrotic) in
      H(2)O(2) treated cells. Phosphatidic acid was able to increase cell viability in
      staurosporine-, but not in H(2)O(2) - treated cells. We therefore conclude that
      phosphatidic acid has neuroprotective potential in neurons exposed to stimuli
      that trigger apoptosis.

PMID- 12417062
TI  - The role of fibroblast growth factor-2 in the vascularization of the chick embryo
      chorioallantoic membrane.
AB  - The CAM is an extraembryonic membrane which serves as a gas exchange surface and
      its respiratory function is provided by an extensive capillary network. The
      development of the vascular system of the CAM is a complex, highly regulated
      process that depends on genetic and epigenetic factors expressed by endothelial
      and non-endothelial cells. In spite of the evidence that several growth factors
      are angiogenic in the CAM assay, poorly investigated is their role in the
      development of the CAM's vascular system. This article reviews our studies
      concerning the role of exogenous and endogenous fibroblast growth factor-2 (FGF
      2) in the CAM vascularization. The findings in all these studies support the
      importance of FGF-2 as an autocrine paracrine stimulator of angiogenesis and its
      key role in the development of the vascular system in the avian embryo.

PMID- 12417063
TI  - [Variations of cellular membrane phospholipids with genesis and hepatic
      metastasis of large intestine cancer].
AB  - OBJECTIVE: To separate and detect membrane phospholipids and study the
      relationship of metabolism and signal transduction pathways of membrane
      phospholipids with genesis and hepatic metastasis of large intestinal carcinoma.
      METHODS: Forty-eight cases of colorectal cancer were detected with high
      performance liquid chromatography. Membrane phospholipids of phosphatidylinosital
      (PI), phosphatidylserine (PS), phosphatidylethanolamine (PE) and
      phosphatidylcholine (PC) in primary foci, paratumor intestinal mucosa and hepatic
      metastasis of large intestine cancer were separated and analyzed. RESULTS: In
      primary foci, paratumor intestinal mucosa, and hepatic metastasis of the 48
      cases, the contents (mg/g) of PI were: 0.92 +/- 0.12, 1.57 +/- 0.14, 1.54 +/-
      0.15 respectively, and PC 56.47 +/- 5.33, 108.57 +/- 6.37, 116.35 +/- 6.85. The
      contents of PI and PC were higher in primary foci and hepatic metastasis than in
      paratumor mucosa (F = 363.10, 870.10, P < 0.01). The contents of PE in the three
      tissues were 18.23 +/- 3.56, 42.02 +/- 4.33, 79.51 +/- 5.52, and in hepatic
      metastasis was the highest (F = 1 149.63, P < 0.01). PI and PC in primary foci of
      hepatic metastatic group and nonmetastasis group were not significantly different
      (t = 3.55, P > 0.05). But the PE content was higher in hepatic metastasis than in
      primary foci (t = 115.87, P < 0.01). CONCLUSIONS: Membrane phospholipids have
      obvious variations in genesis and hepatic metastasis of large intestine cancer.
      Rises of PI and PC were associated with genesis of large intestine carcinoma. The
      increase of PE content is closely related to invasion and hepatic metastasis of
      large intestine cancer.

PMID- 12417064
TI  - [Familial papillary thyroid carcinoma].
AB  - OBJECTIVE: To investigate the clinical features of familial papillary thyroid
      carcinoma (FPTC) and the criteria for its diagnosis and surgical treatment.
      METHODS: One hundred and forty-five patients with PTC were investigated randomly
      between January 1999 and November 2001, and 17 of them were from 7 families. Of
      the 17 patients, 14 were operated on at this hospital, and 3 were operated
      elsewhere. The specimens from the 17 patients were confirmed pathologically. They
      accounted for 9.3% (14/145) of all PTC patients. RESULTS: The patients were aged
      from 30 to 74 years (mean 45 years). The diameter of original focuses ranged from
      0.8 to 2.8 cm (mean diameter 1.7 cm). Of the 17 patients with PTC, 8 (47.5%) had
      bilateral carcinoma. In 3 families, 3 patients suffered from PTC (42.8%). In 4
      families, other members suffered from benign thyroid tumor or non-tumorous
      thyroid disease. Among the 17 patients, 10 had nodular goiters. Thyroidectomy,
      unilateral thyroidectomy plus isthmusectomy, and combined radical operation were
      performed in 8, 9, 14 patients, respectively. Early metastatic spread to local
      regional lymph nodes was noted in 14 patients (82.3% or 14/17). CONCLUSIONS: In
      this study, a FPTC rate of 10% was found. Almost 50% of FPTC patients had
      bilateral carcinoma. The frequency of metastatic spread to local-regional lymph
      nodes was high. Follow-up survey of family members should be performed in a long
      period of time.

PMID- 12417065
TI  - [Prognostic factor analysis of pneumonectomy for non-small cell lung cancer].
AB  - OBJECTIVES: To identify predictors of survival following pneumonectomy for non
      small cell lung cancer (NSCLC) and provide evidence for the revision of patient
      selection criteria. METHODS: 81 cases of pneumonectomy for NSCLC from January
      1990 to May 1996 at our hospital were reviewed retrospectively. There were 65 men
      (80.2%) and 16 women (19.8%), with a mean age 53.4 +/- 9.4 years (range 20 - 68
      years). Predominant histological types included squamous cell carcinoma (54.3%),
      adenocarcinoma (24.7%), and squamoadenocarcinoma (17.3%). After follow-up for
      more than 5 years, data were examined using the chi-square test, Kaplan-Meier
      method, and Cox-mantel test. The possible factors affecting survival were tested
      with univariate and multivariate analysis. RESULTS: The 5-year survival of N(0),
      N(1) and N(2) disease of NSCLC following pneumonectomy was (20.8 +/- 9.9)%, (15.4
      +/- 10.0)% and (4.0 +/- 2.8)%, respectively. There was no perioperative death.
      The operative complications morbidity was 22.2%. Factors adversely affecting
      survival with univariate analysis included age over 60 years for right
      pneumonectomy, cardiopulmonary complications, adenocarcinoma, peripheral
      location, tumor greatest dimension more than 10 cm, chest wall involvement and
      N(2) disease. Factors adversely affecting survival with multivariate analysis
      included cardiopulmonary complications, greatest tumor dimension more than 10 cm,
      chest wall involvement and N(2) disease. CONCLUSIONS: Pneumonectomy provides
      survival benefit with a high operative complications morbidity. Old age (>/= 60
      years) for right pneumonectomy, cardiopulmonary complications, adenocarcinoma,
      and N(2) disease may be negative prognostic factors of long-term survival.
      Patient selection should be based on cardiopulmonary evaluation and the stage of
      disease.

PMID- 12417067
TI  - [Surgical repair of transposition of great arteries with intact ventricular
      septum].
AB  - OBJECTIVE: To study the surgical management of transposition of the great
      arteries with intact ventricular septum (TGA/IVS). METHODS: Twelve patients with
      TGA/IVS were underwent repair during August 1999-December 2001. Senning procedure
      was used for age more than 2 months and switch operation for less than 1 month.
      RESULTS: Three patients with TGA/IVS underwent repair by Senning procedure. Nine
      patients received switch operation and one died of single coronary artery. All
      patients were followed up about 2 months to 2 years and the result was
      satisfactory. CONCLUSIONS: TGA/IVS must be diagnosed and repaired as early as
      possible. The best age for switch operation is less than 2 weeks or at best less
      than 1 month.

PMID- 12417066
TI  - [Changes of inflammatory factors in patients with coronary artery disease during
      perioperation].
AB  - OBJECTIVE: To investigate the proinflammatory cytocine factors in patients with
      coronary artery disease by different treatments during perioperation. METHODS:
      TNF-alpha, IL-6, c-reactive protein (CRP) were measured in 37 patients with
      coronary artery disease (CAD) and 10 patients with mitral valve replacement (MVR,
      control group) before operation and aortic clamping or before coronary artery
      bypass grafting (CABG) in the patients with cardiopulmonary bypass, or before
      transmyocardial laser reperfusion (TMLR), when aortic declamping and 3, 6, 24
      hours after operation. RESULTS: The level of proinflammatory factors increased
      more significantly after operation than before operation. TNF-alpha increased
      more significantly in the patients with CPB than in those without CPB after
      operation [(4.10 +/- 0.71) pg/ml vs. (1.34 +/- 0.29) pg/ml, P < 0.05)]. IL-6 was
      not the different among all groups after operation. CRP was higher in the CAD
      patients with CPB than in the control group after operation [(12.89 +/- 0.29)
      pg/ml vs. (12.00 +/- 0.31) pg/ml, P < 0.05]. CONCLUSION: Inflammatory response
      can be seen after operation in all CAD patients. In patients undergoing CABG
      without CPB or undergoing TMLR, the changes in flammatory response are milder
      than those in patients with CPB. Thus patients should undergo CABG without CPB if
      they are indicated.

PMID- 12417068
TI  - [Application of endoscopic ultrasonography in the diagnosis of mediastinal lymph
      node metastasis].
AB  - OBJECTIVES: To calculate the rate of detection for mediastinal lymph nodes and to
      set up a criteria for the diagnosis of metastatic mediastinal lymph nodes in lung
      neoplasm by means of endoscopic ultrasonography (EUS). METHODS: In 21 patients
      with lung cancer who underwent preoperative EUS on mediastinal lymph nodes, 103
      lymph nodes detected by EUS were resected and confirmed pathologically all. The
      difference between benign and malignant lymph nodes was analysed statistically.
      RESULTS: The rates of metastatic lymph nodes detected by EUS were significantly
      higher than these of non-metastatic lymph nodes (chi(2) = 11.752, P = 0.01) in
      levels 5, 7, 8, and 9 of mediastinal lymph node staging map (Union Internationale
      Contre le Cancer, 1997). The mean long and short axis of metastatic lymph nodes
      were significantly longer than those of non-metastatic lymph nodes (short axis: t
      = 4.541, P = 0.000; long axis: t = 3.278, P = 0.002). Metastatic lymph nodes
      showed some characteristic ultrasonographic features, including short axis >/=
      1.0 cm, long axis >/= 1.5 cm, and clear boundary. According to the equation
      P((1)) = 1/[1 + e(-(-2.963 + 2.041 X1 + 1.681 X2))], the lymph nodes were assumed
      to be malignant when P((1)) >/= 0.5. The accuracy, sensitivity, specificity of
      this methods were 72.8%, 72.7%, 72.9% respectively, and were superior to those of
      CT for the same nods in levels 5, 7, 8 and 9 (chi(2) = 6.812, P = 0.013).
      CONCLUSION: EUS is an effective method of diagnostic evaluation of mediastinal
      lymph nodes of lung cancer.

PMID- 12417069
TI  - [Hemocoagulase in abdominal operation and its effect on hemoagglutination].
AB  - OBJECTIVE: To evaluate the hemostatic role of hemocoagulase in abdominal
      operation and its effects on coagulation. METHODS: 180 patients receiving
      abdominal operation were studied prospectively by randomized, double-blind
      controlled and multicenter design. They were divided into Hemocoagulase group (60
      patients), lizhixue group (60), and manitol hexanitrate group (60). The groups
      were, observed in terms of the effects on hemostatic time, hemorrhagic volume,
      hemorrhagic volume per square unit, and body coagulation (BT, CT, PT, APTT and
      PLT) parameters. RESULTS: The groups received different drugs. The average
      hemostatic time in the hemocoagulase group was 121.6 s, hemorrhagic volume was
      9.6 g, and hemorrhagic volume per square unit was 0.2 g. The similar results were
      observed in the lizhixue group (P > 0.05), but they were significantly different
      (P < 0.05) from those of the manitol hexanitrate group (159.2 s, 12.49 g, 0.3 g).
      In the hemocoagulase and lizhixue groups hemorrhagic and hemoagglution time
      decreased 30 minutes and 1 day after operation. This finding was significantly
      differenct from that in the manitol hexanitrate group (P < 0.05). CONCLUSION:
      Hemocoagulase plays a good hemostatic role in the hemorrhagic capillary at
      abdominal incision.

PMID- 12417070
TI  - [Clinicopathologic features and diagnosis of metastatic carcinoma to the spleen].
AB  - OBJECTIVE: To study the clinicopathologic features and diagnosis of metastatic
      carcinoma to the spleen (MCS). METHODS: Four patients (1 man and 3 women, mean
      age 43.5 years) with MCS were analyzed clinicopathologically. RESULTS: The four
      MCS patients accounted for 1.3% of 308 patients having spleen biopsy from 1959 to
      1999. Their chief presentations were pain and mass in the left upper quadrant of
      the abdomen. The mass was located in the upper pole of the spleen (1 patient),
      the lower pole of the spleen (2), or the lower pole and hilum of the spleen (1).
      Macroscopically, all of the lesions were nodular. Histologic type of these MCSs
      included acinar cell carcinoma of the pancreas (2 patients), transverse colon
      adenocarcinoma (1), and hepatic cell carcinoma (1). Clinically, 1 patient was
      diagnosed as having MCS and 3 were misdiagnosed. According to Chinese literature,
      the clinicopathologic features of MCS were as follows: (1) 66.7% of the patients
      with MCS were aged 30 approximately 60 years, with a mean of 51.2 years. (2)
      76.3% of the patients presented with pain in the left upper quadrant of the
      abdomen and 63.2% with splenomegaly and splenic masses. (3) Macroscopically,
      nodular lesions accounted for 68.4%. (4) Microscopically, 84.2% of the lesions
      were adenocarcinomas and 70.3% originated from carcinomas of the colon, liver,
      ovary and pancreas. (5) B-mode ultrasonography and/or CT showed occupying lesions
      or masses in the spleen in 76.7%, and MCS in 11.8%. (6) Clinically, 73.7% of the
      patients were misdiagnosed. CONCLUSIONS: MCS is uncommon but its clinical
      misdiagnosis rate is high. Image examination is of value in clinical diagnosis.
      Cooperation of clinicians and pathologists may enhance the diagnostic level of
      MCS.

PMID- 12417071
TI  - [Congenital absence of the vagina in 126 patients].
AB  - OBJECTIVES: To investigate the clinical features and therapeutic results of
      multiple approaches for congenital absence of the vagina, and to find out the
      prevention of complications and reconstruction method. METHODS: We analysed
      retrospectively 126 patients with congenital absence of the vagina from 1979 to
      2002. RESULTS: Congenital absence of the vagina occurred in 31.25% urinary tract
      anomalies and 6.35% musculoskeletal anomalies. Of the 126 patients, 6 received 2
      or more than 2 operations, the remaining recovered after reconstruction of the
      vagina by using the inferior abdominal wall skin flap and pudendal-thigh skin
      flap. CONCLUSIONS: The techniques should be selected according to the conditions
      of the patient and features of multiple approaches. Damage to the rectum and
      urinary tract should be avoided in addition to postoperative retraction or
      prolapse of flaps and stenosis of the vaginal orifice.

PMID- 12417072
TI  - [Expression of core-binding factor a1 by human skin fibroblasts induced in
      vitro].
AB  - OBJECTIVE: To investigate the probabilities of core-biding factor a1 (Cbfa1)
      expression by human skin fibroblasts induced in vitro. METHODS: The fibroblasts
      were isolated, purified from human skin, and were grown in incubation in the
      media of TNF-alpha, BMP-2, and combined TNF-alpha and BMP-2 at certain
      concentrations, respectively. The changes in biological features of these
      fibroblasts correlated with osteogenesis were detected by immunohistochemistry
      and RT-PCR assay. RESULTS: TNF-alpha could switch phenotype of collagen in
      fibroblasts from Type I and III to Type I and induce fibroblasts to express Ras
      and BMP type I receptor (BMPR-IA). TNF-alpha in combination with BMP-2 could
      induce fibroblasts to express Cbfa1 and osteocalcin mRNA. CONCLUSION: Human skin
      fibroblast could be induced into pro-osteoblast expressing Cbfa1, an osteoblast
      specific transcription factor and a regulation of osteoblast differentiation, and
      combined use of TNF-alpha and BMP-2 was one of the regulating factors.

PMID- 12417073
TI  - [Preventive effect of anti-infective reconstituted bone xenograft on
      osteomyelitis in proximal tibia of the rabbit].
AB  - OBJECTIVE: To assess possible beneficial effect in prevention of osteomyelitis by
      anti-infective reconstituted bone xenograft (ARBX) in the rabbit. METHODS: A
      proximal tibia osteomyelitis rabbit model was used in which staphylococcus aureus
      was injected through a bony window, followed by immediate implantation of three
      ARBX pellets containing 30 mg of slowly-delivered gentamicin in group A, three
      pellets of RBX in conjunction with intramuscular gentamicin (30 mg) for 5 days in
      group B, three pellets of RBX without antibiotic in group C. Specimens were
      harvested 8 weeks postoperatively for gross observation, radiological,
      histological and bacteriological evaluation, comparing the three groups with
      regard to the beneficial effect of the above procedures in preventing
      osteomyelitis. RESULTS: (1) Bacteria counting, modified Norden scoring, and gross
      and microscopic evidence for osteomyelitis in group B were less than those in
      group C (P < 0.01). (2) In group A, bacteria culture and counting yielded 0
      values at 8 weeks, while radiologically modified Norden scoring for osteomyelitis
      gave by far the smallest values among all three groups (P < 0.01) with no
      evidence of osteomyelitis found in gross and histological examinations.
      CONCLUSIONS: (1) Conventional systemic administration of antibiotics are
      reasonably effective in prevention of infection, but the anti-infective effect
      usually is not strong enough to prevent osteomyelitis when used along with
      primary bone grafting. (2) Apart from its osteoconductive and osteoinductive
      effects, ARBX is capable of slowly delivering antibiotics, thus being highly anti
      infective when administered locally, so it could be used for primary grafting to
      repair a contaminated bone defect for effective prevention of osteomyelitis.

PMID- 12417074
TI  - [Effects of cartilage-derived growth factor on cultured rabbit chondrocytes].
AB  - OBJECTIVE: To investigate the effect of cartilage-derived growth factor (CDGF) on
      cultured rabbit chondrocytes, and the relation between CDGF, insulin-like growth
      factor-I (IGF-I), and proliferation and metabolism of chondrocytes. METHODS: CDGF
      was extracted from chicken xiphoid in our laboratory. Chondrocytes were isolated
      from 3-week-old New Zealand male rabbits, and cultured in Ham's F-12 medium
      containing 10% fetal calf serum. The chondrocyts of second generation were
      treated with CDGF and/or IGF-I of different concentrations. With chloramine T
      method and MTT method, we compared the content of hydroxyproline in Ham's F-12
      medium and observed proliferation and energy synthesis of chondrocytes. RESULTS:
      CDGF and IGF-I both stimulated the proliferation and synthesis of hydroxyproline
      of chondrocytes dose-dependently. The optimal concentration of CDGF was 16 ng/ml
      and 32 ng/ml respectively, and that of IGF-I was 30 ng/ml. There was obvious
      synergic effect between CDGF and IGF-I. CONCLUSION: CDGF can stimulate the
      proliferation and collagen synthesis of chondrocytes and has synergistic effect
      with IGF-I.

PMID- 12417075
TI  - [Enhancement of ionizing radiation on liposome-mediated gene delivery in human
      rectal cancer HR-8348 cells].
AB  - OBJECTIVES: To investigate the effect of ionizing radiation on liposome-mediated
      gene delivery and find out a way to improve gene transfection. METHODS: Prior to
      liposome transfection, HR-8348 cells were irradiated at doses of 0, 2, 4, 8 Gy
      selected according to the surviving fraction line of HR-8348 cells after
      different dosage of radiation. After 36 h of liposome transfection, green
      fluorocytes were counted. The transfection efficiency was figured out and
      compared with each other. RESULTS: The transfection efficiency of liposome
      mediated gene delivery was 21.32%, 62.17%, 68.00%, 77.78% at the dose of 0, 2, 4,
      8 Gy respectively and the clinical dose (2 Gy) was as high as 62.17%. Combined
      radiation and liposome-mediated gene delivery achieved the approximate
      transfection efficiency of virus vector. CONCLUSION: Ionizing radiation can
      improve the transfection efficiency of liposome-mediated gene delivery markedly
      and it is expected to treat human malignancy with liposome-mediated gene delivery
      combined with radiation.

PMID- 12417076
TI  - [Effect of angiogenesis inhibitor Rg3 on the growth and metastasis of gastric
      cancer in SCID mice].
AB  - OBJECTIVE: To study the effect of angiogenesis inhibitor Rg3 on the growth and
      metastasis of gastric cancer in SCID mice. METHODS: Metastatic model simulating
      human gastric cancer was established by orthotopic implantation of histologically
      intact human tumor tissue into the gastric wall of SCID mice. Rg3 was
      administered by gastric perfusion at doses of 0, 2.5, 5.0, 10.0 mg/kg every day
      for 6 weeks 1 week after tumor implantation. One week after last administration,
      the mice were killed and their tumor weight was measured and the presence of
      metastasis recorded. Intratumoral microvessel density was examined by
      immunohistochemical staining with anti-CD31 monoclonal antibody. RESULTS:
      Compared to the untreated controls, the growth of the orthotopically implanted
      tumor was significantly reduced in weight in mice treated with Rg3 with an
      inhibition rate of 52.3%, 63.3% and 71.6% at doses of 2.5, 5.0, 10.0 mg/kg,
      respectively. Tumor metastasis to the liver and peritoneum was also significantly
      inhibited in a dose-dependent manner. Decreased intratumoral microvessel density
      was noted in the treated mice. CONCLUSION: Angiogenesis inhibitor Rg3 has strong
      inhibitory effect on tumor growth and metastasis of human gastric cancer in SCID
      mice.

PMID- 12417077
TI  - [The role of alveolar macrophage activation in rats with lung injury associated
      with acute necrotizing pancreatitis].
AB  - OBJECTIVE: To discuss the role of alveolar macrophage activation in rats with
      acute necrotizing pancreatitis (ANP) associated with lung injury. METHODS: 30
      adult Sprague-Dawley rats were randomly divided into five groups (n = 6): normal
      control group, one-hour group, three-hour group, six-hour group and twelve-hour
      group after ANP induction. ANP was induced by intraductal administration of 3%
      sodium taurocholate, while the normal control received an infusion of
      physiological saline. Alveolar macrophages were harvested by bronchoalveolar
      lavage. The protein content of lavage fluids, the myeloperoxidase of lung tissue
      (MPO), and tumor necrosis factor alpha (TNFalpha) and nitric oxide (NO) secreted
      by alveolar macrophages were examined. The expression of TNFalpha mRNA and
      inducible nitric oxide synthase (iNOS) mRNA was measured with reverse
      transcription-polymerase chain reaction technique. Histology of the lung and
      pancreas was scored in a blinded fashion. RESULTS: Lung injury was gradually
      aggravated with disease progression. The level of myeloperoxidase of lung tissue
      and protein content of bronchoalveolar lavage fluids increased progressively and
      reached the peak at 12 hour [(10.78 +/- 0.58) U/g for MPO and (2 011.0 +/- 105.5)
      micro g/ml for protein respectively]. TNFalpha and NO secreted by alveolar
      macrophages were gradually elevated and peaked on the sixth hour, the maximums
      were (1 624.2 +/- 149.2) pg/ml and (88.8 +/- 6.5) micro mol/L respectively, but
      decreased on the twelfth hour. The expression of TNFalpha mRNA and iNOS mRNA was
      similar with the changes of TNFalpha and NO, upregulated after induction of acute
      necrotizing pancreatitis and reached their peaks on the sixth hour, then
      downregulated on the twelfth hour. All the parameters of ANP groups compared to
      control group were statistical significant (P < 0.05). The histology scores
      demonstrated an increasing damage of the lung. The expression of TNFalpha mRNA
      and iNOS mRNA is closely related to lung injury (r = 0.67 for TNFalpha mRNA and r
      = 0.64 for iNOS mRNA respectively, P < 0.01). CONCLUSION: The activation of
      alveolar macrophage may play an important role in lung injury associated with
      acute necrotizing pancreatitis.

PMID- 12417078
TI  - [Influence of spleen on cell cycle and expression of proliferating cell nuclear
      antigen of the liver during diethylnitrosamine-induced rat hepatocarcinogenesis].
AB  - OBJECTIVE: To investigate the role of the spleen on hepatocyte proliferative
      activity during experimental hepatocarcinogenesis in rats. METHODS: Cell-cycle
      and expression of proliferating cell nuclear antigen (PCNA) of hepatocytes were
      studied by immunohistochemical and flow cytometric technique in two groups:
      splenectomy (45 rats) and sham-operation with laparotomy (45 rats). RESULTS: (1)
      Hepatocirrhosis was formed in group A earlier than in group B. Marked
      degenerative changes of the liver parachyma showing vacuolization of hepatocytes
      were observed in hepatic lobules. (2) The proliferative level of hepatocytes
      increased with the progression of hepatocarcinogenesis, and topped at the 18 th
      week. (3) The proliferative level of the splenectomy group was lower than that of
      the sham-operation group in the mid-stage of carcinogenesis (t = 4.76, P < 0.05).
      After stopping feeding diethylnitrosamine (DENA), however, no difference was
      found in the hepatocyte proliferative activity between the two groups at the 18th
      week. CONCLUSIONS: There is a close relationship between hepatic proliferative
      activity and spleen, and the spleen may play an important role in facilitating
      hepatic proliferation.

PMID- 12417079
TI  - [Establishment and characterization of human extrahepatic growing hepatocellular
      carcinoma cell line EGHC-9901].
AB  - OBJECTIVE: To establish a new extrahepatic growing hepatocellular carcinoma cell
      line. METHODS: A specimen from extrahepatic growing hepatocellular carcinoma was
      cultured in vitro. Cancer cells were studied morphologically and subjected to
      karyotype analysis, DNA analysis, and tumor formation evaluation. RESULTS:
      Morphological observation and functional analysis showed that their features were
      similar to those of HCC. Chromosomes with a variation of 76 approximately 104
      were able to secret AFP in vitro and to form bile canaliculi with microvilli.
      CONCLUSION: EGHC-9901 cell line has characteristics of the extrahepatic growing
      hepatocellular carcinoma.

PMID- 12417080
TI  - [Bile excretion of hepatocytes cultured in vitro].
AB  - OBJECTIVE: To regain bile excretory function of hepatocytes cultured in vitro.
      METHODS: Sandwich configuration was used to culture hepatocytes and the structure
      of bile canaliculi as well as the function of bile excretion was observed by
      immunocytochemistry and the test of FDA metabolism with a single collagen
      configuration as a control. RESULTS: First, the formation of bile canaliculi was
      observed by immunocytochemistry. In sandwiched hepatocytes, the gradual
      development of bile canaliculi-like structures into an anastomotic network was
      observed. At 24 h after cell culture, the formation of bile canaliculi was
      observed. With time progressed, the bile canaliculi became more clear and the
      network was established at 120 h. In contrast, hepatocytes in single collagen
      configuration showed almost no network of bile canaliculi. Second, the ability
      for hepatocytes to internalize, metabolize and excrete compounds into bile was
      indicated by FDA metabolized in the hepatocytes. In sandwiched hepatocytes, the
      bile excretory function was shown at 96 h, but in single collagen system, no bile
      excretion was observed. CONCLUSION: Cultured hepatocytes are able to regain bile
      excretion in a given certain condition. Sandwich-cultured hepatocytes can
      reestablish bile canalicular structure and regain bile excretory function.

PMID- 12417081
TI  - [Inhibitory effects of murine angiostatin on implant carcinoma of nude mouse].
AB  - OBJECTIVE: To study the effects of murine angiostatin, which was transfected into
      the human hepatocellular cancer cell line SMMC-7721, on the implant carcinoma of
      nude mouse. METHODS: The human hepatocellular cancer cell line SMMC-7721, which
      could express murine angiostatin gene stably, was constructed. The animals were
      divided into three groups: SMMC-7721 cell was implanted into control group, SMMC
      7721/pcDNA3.1 (+) cell was implanted into vector group, and SMMC-7721/pcDNA3.1
      mAST cell was implanted into angiostatin group. The carcinoma volume, weight, and
      microvessel density (MVD) of each group were compared. RESULTS: The implant
      carcinoma volume in 35 days was (3 538.1 +/- 643.3) mm(3), (3 128.5 +/- 546.6)
      mm(3), and (755.8 +/- 198.2) mm(3) in the control group, vector group, and
      angiostatin group. The carcinoma weight of the control group, vector group, and
      angiostatin group was (6.0 +/- 0.7) g, (5.9 +/- 0.5) g, (2.1 +/- 0.5) g,
      respectively. The carcinoma MVD was 52.2 +/- 6.6, 49.4 +/- 7.0, and 25.5 +/- 4.1
      accordingly. The carcinoma volume, weight, and MVD of the angiostatin group were
      significantly smaller than those of the control group and vector group (P <
      0.01). The inhibitory rate of carcinoma reached 78.6%. CONCLUSIONS: Nude mouse
      experiments showed that the tumorigenic capacity of cells transfected had been
      reduced greatly, and that the carcinoma volume, weight and MVD were significantly
      lower than those of the control group. We conclude that angiostatin inhibits the
      growth of carcinoma by its inhibition of carcinoma angiogenesis.

PMID- 12417082
TI  - [Adenovirus-mediated transfer of the herpes simplex virus thymidine rinase gene
      used by several methods].
AB  - OBJECTIVE: To investigate the therapeutic effects of adenovirus-mediated transfer
      of the herpes simplex virus thymidine rinase gene (HSV-tk) used by several
      methods and the dose-effect relationship. METHODS: Diverse doses (1 x 10(9) PFU,
      1 x 10(10) PFU, 1 x 10(11) PFU) of adenovirus-mediated transfer of HSV-tk were
      given by intraparenchymatous, intravenous and intraperitoneal injection, and
      ganciclovir (GCV) (100 mg.kg(-1).d(-1)) was injected into the cavity of the
      peritoneum to treat human hepatocarcinoma. The change of tumors size was observed
      and the fragments of HSV-tk gene were tested. RESULTS: In nude mice after
      intraparenchymatous injection and high-dose (1 x 10(11) PFU) intravenous
      injection, the tumors were suppressed significantly (t = 13.1, 12.4, P < 0.01)
      and lots of fragments of HSV-tk gene were observed. In mice after intraperitoneal
      injection and low-dose (1 x 10(9) PFU, 1 x 10(10) PFU) intravenous injection, no
      suppressive effect was observed (t = 1.8, 1.0, 2.1, 1.1, 0.8, P > 0.05) with few
      or without fragments in the tumors. CONCLUSIONS: Adenovirus-mediated transfer of
      the HSV-tk by intraparenchymatous or intravenous injection is effective in
      treatment of hepatocarcinoma in nude mice, but intraperitoneal injection has no
      therapeutic effect.

PMID- 12417083
TI  - [Analyzing of prognosis of intestinal T-cell lymphoma].
AB  - OBJECTIVE: To investigate the roles of different clinicopathological features and
      expression of EBV genome in prognosis of intestinal T-cell lymphoma (ITCL).
      METHODS: Polymerase chain reaction for TCR-gamma gene rearrangement, in situ
      hybridization for EBER1/2 and immunohistochemical staining for CD4, CD8, CD45RO,
      CD56, TIA-1 were investigated and all patients followed-up. The LMP-1 expression
      was determined in forty-two ITCLs cases. The relationship between clinical data,
      different clinicopathological features, expression of EBV genome and prognosis
      were analyzed by SPSS10.0 program. RESULTS: (1) All 42 cases of ITCL had an
      extremely poor prognosis with a median survival of 3.0 months, of which the one
      year survival rate and two year survival rate being 30% and 22% respectively. (2)
      The patients without TCR-gamma gene rearrangements showed poorer prognosis than
      those with TCR-gamma gene rearrangements, and the patients who received operation
      and chemotherapy showed better prognosis than those who only received operation
      (P < 0.05). (3) No significant prognostic factor for ITCLs was determined.
      CONCLUSION: The special clinicopathological features of ITCL could be due to the
      cytotoxic function and the role of EBV infection in the pathogenesis of ITCL.

PMID- 12417084
TI  - [Clinicopathologic features of mantle cell lymphoma and the significance of
      cyclin D1 in diagnosis].
AB  - OBJECTIVE: To investigate the clinicopathologic features of mantle cell lymphoma
      (MCL) and the significance of immunostaining for cyclin D1 in diagnosis. METHODS:
      Clinicopathologic observation and immunohistochemical staining for CD20, CD45RO,
      cyclin D1, bcl-2, Ki-67, CD5 for 8 cases of mantle cell lymphoma were performed.
      RESULTS: The 8 cases of mantle cell lymphoma consisted of 6 males and 2 females,
      aged from 43 to 78 years (mean 57 years). Histopathologically, MCL demonstrated
      architectural destruction by a vaguely nodular monomorphic lymphoid proliferation
      with vaguely nodular, diffuse or mantle zone growth patterns. Analogous to
      centrocytes, the lymphoma cells with slightly to markedly irregular nuclear
      contours showed moderately dispersed chromatin and a low mitotic figure. Three
      cases were transformed into highly aggressive blastoid variants. The tumor cells
      were positive for CD20, CD5, bcl-2 and cyclinD1 in all 8 cases and negative for
      CD45RO. CONCLUSIONS: The clinicopathological features and special
      immunophenotypes were present in mantle cell lymphoma. This tumor can be
      differentiated from other small B-cell lymphomas on the basis of histopathologic
      features and positive cyclin D1 immunophenotype. The blastoid variant should also
      be differentiated from other variants.

PMID- 12417085
TI  - [A clinicopathologic study of CD30-positive sinusoidal large B-cell lymphoma].
AB  - OBJECTIVE: To explore the clinicopathologic features of CD30-positive sinusoidal
      large B-cell lymphoma (CD30 + SLBCL) and its relative correlation with Epstein
      Barr virus (EBV). METHODS: Two cases of CD30 + SLBCL, a 65-year-old men and a 85
      year-old women were morphologically and immunophenotypically analyzed. EBV status
      was also evaluated through not only the polymerase chain reaction (PCR)
      amplification to the EBV Bam HIW DNA sequence, but also an immunohistochemical
      detection of the latent membrane protein 1 (LMP1). RESULTS: The patients
      presented with similarly superficial lymphadenopathy. One of them died of the
      tumor within 10 months. Microscopically, both of the neoplasms were characterized
      by a cohesive sinus growth pattern and the monomorphic cytology of the tumor
      cells. Immunohistochemically, They were both positive for CD45, CD30, and CD20 or
      CD79alpha, whereas neither expressed EMA, ALK1, nor any histiocytic/T-lineage
      markers. No evidence of EBV-infection could be found either. CONCLUSIONS: CD30 +
      SLBCL is a morphologically and immunophenotypically distinctive variant of
      diffuse large B-cell lymphoma, which should be distinguished from T/null cell
      type anaplastic large cell lymphoma and some other nodal lesions with a
      predominantly sinusoidal infiltrative pattern. CD30 + SLBCL may not be
      correlation with EBV.

PMID- 12417086
TI  - [Detection of human herpes virus 8 in Kaposi sarcoma using polymerase chain
      reaction and single stranded probe in situ hybridization with a tyramide signal
      amplification system].
AB  - OBJECTIVE: To study the relationship between Kaposi's sarcoma (KS) and human
      herpes virus 8 (HHV8; Kaposi's sarcoma-associated herpes virus), and to develop
      an in situ hybridization (ISH) technique effective for clinical pathological
      diagnosis. METHODS: Polymerase chain reaction (PCR) technique was used to
      synthesize a digoxigenin-labeled single stranded DNA probe specific for HHV8 open
      reading frame 72 cyclin D homolog gene encoded mRNA as the probe accompanying
      with a tyramide signal amplification system (TSA) for ISH assay. Totally 20
      formalin-fixed and paraffin-embedded samples from 14 cases of KS from Danish
      patients were collected for HHV8 detection. In order to compare the result
      obtained, all of these cases were checked simultaneously using PCR technique.
      RESULTS: HHV8 was detected in 10 of 14 (71%) KS cases, of which 8 cases were
      positive for HHV8 by both ISH and PCR. In ISH, HHV8 hybridization signal was seen
      as a dot or patch located in the nuclei of both the neoplastic spindle cells and
      the endothelial cells. HHV8 was found in lesions in all the stages of KS
      including early patch, plaque and late nodular or tumor lesions, as well as in
      the primary and metastatic lesions. All the control cases showed a relevant
      positive or negative results. CONCLUSIONS: The results further confirmed that
      there is a strong association between Kaposi's sarcoma and HHV8. The ISH
      technique with single stranded probe and TSA would be helpful in clinical
      pathological diagnosis for HHV8 infected diseases, such as KS, primary effusion
      lymphoma and multicentric Castleman's disease.

PMID- 12417087
TI  - [The expressions of TGF-beta1 and Smad 2 mRNA on diseased glomeruli and their
      significance in the development of glomerulosclerosis].
AB  - OBJECTIVE: To explore the expressions of transforming growth factor-beta1 (TGF
      beta1) and its signaling transduction molecule Smad 2 and their significance in
      the development of glomerulosclerosis. METHODS: Using in situ hybridization and
      immunohistochemistry to detect Smad 2 mRNA expression and TGF-beta1, collagen IV,
      fibronectin expression in renal biopsies from 61 cases with a spectrum of
      glomerulonephritis including IgA nephropathy (40 cases), membranous
      glomerulonephritis (10 cases) and sclerosing glomerulonephritis (11 cases),
      compared with 11 cases of glomerular mild lesion with image analysis system.
      RESULTS: With the exception of Smad 2 mRNA expression in mild type IgA
      nephropathy, all other types of diseased glomeruli showed increased expression of
      both TGF-beta1 and Smad 2 mRNA when compared with the 11 cases of mild glomerular
      lesions. The expressions of glomerular TGF-beta1 and Smad 2 mRNA positively
      correlated with collagen IV and fibronectin deposition in the glomeruli.
      CONCLUSIONS: TGF-beta1 and Smad 2 may be involved in the excessive deposition of
      glomerular extracellular matrix and play an important role in the development of
      glomerulosclerosis.

PMID- 12417088
TI  - [A study of E-cadherin and beta-catenin expression and their correlation with
      prognosis of nonsmall cell lung carcinoma].
AB  - OBJECTIVE: To investigate the protein and mRNA expression of E-cadherin and beta
      catenin in nonsmall cell lung carcinoma (NSCLC) and to find their correlation
      with histological type, differentiation, metastasis and prognosis. METHODS: High
      sensitive S-P immunohistochemical method and in situ hibridization were used to
      detect the protein and mRNA expression of E-cadherin and beta-catenin. RESULTS:
      Immunohistochemistry revealed that among the 101 cases, the positive rates of E
      cadherin and beta-catenin were 68.3% and 81.2% respectively. The abnormal
      expression rates of these two proteins were 61.4% and 64.4% respectively. There
      was no significant relationship between E-cadherin and beta-catenin staining and
      histological type of the tumor (P > 0.05). However, there was a statistically
      significant difference between well and moderately differentiated cells and
      poorly differentiated cells (P < 0.05). In cases with lymphatic metastasis, the
      abnormal expression rates of E-cadherin and beta-catenin were significantly
      higher than those in nonmetastatic cases (P < 0.05). The mean survival time in
      cases with abnormal E-cadherin and beta-catenin expression were significantly
      shorter than that in cases with the expression grading (+ +) approximately (+ +
      +). In situ hybridization showed that in NSCLC, the positive rate of E-cadherin
      and beta-catenin mRNA was 38.9% and 47.2% respectively. Their concordant rates
      with (+ +) approximately (+ + +) protein expression were 78.6% and 82.4%,
      respectively. CONCLUSIONS: The concordant rate of E-cadherin and beta-catenin
      mRNA and protein expression was relatively high. They can be used as markers of
      prognosis of NSCLC in clinical practice.

PMID- 12417089
TI  - [Pathological study on the expression of cell adhesion molecules and metastasis
      suppressor gene in thyroid follicular carcinoma and papillary carcinoma].
AB  - OBJECTIVE: To investigate the relationship between expression of cell adhesion
      molecular CD44, epithelial cadherin (E-cad) and metastatic suppressor gene nm23
      H1 as well as the clinicopathologic features including cell differentiation,
      invasion and metastasis of thyroid follicular-derived carcinoma. METHODS: Forty
      two (42) thyroid follicular carcinomas (FTC) and 54 papillary carcinomas (PTC)
      were collected for studying the expression of CD44, E-cad and nm23-H1 using
      immunohistochemical staining. RESULTS: Neoplastic epithelium and infiltrating
      lymphocyte expressed CD44 in an intense plasma membrane pattern. CD44 expression
      rates in poorly differentiated FTC (80%) and PTC cases with metastasis (78%) were
      significantly higher than those of well-differentiated FTC cases (64%) and PTC
      without metastasis cases (59%) respectively. Thyroid carcinoma tissue was
      positive for E-cad and nm23-H1 in a cytoplasm pattern. Well-differentiated FTC
      presented a higher E-cad and nm23-H1 expression rate than poorly-differentiated
      FTC, but both had a lower expression rate than that of PTC (70% and 76%, P <
      0.01). The expression rate and intensity of E-cad and nm23-H1 were lower and less
      in metastatic PTC than those in primary PTC. Expression rate of CD44 (72%) in
      thyroid follicular-derived carcinoma was higher than those of E-cad (54%, P <
      0.01) and nm23-H1 (61%, P < 0.05). E-cad expression was adversely correlated with
      that of nm23-H1 (chi(2) = 15.75, P < 0.011, r = 0.522 2). There was a reverse
      relationship between expression of CD44 and E-cad or nm23 (P > 0.05).
      CONCLUSIONS: Cell differentiation degree in FTC and metastasis in PTC have
      positive correlation with the expression of E-cad and nm23, but have a reverse
      correlation with the expression of CD44. There was a relationship between
      expression of CD44, E-cad, nm23 and the characteristics of the degree of
      differentiation, metastatic potential and the prognosis of thyroid follicular
      derived carcinoma.

PMID- 12417090
TI  - [The promoter effects of sodium butyrate on the malignant transformation of the
      immortalized esophageal epithelium induced by human papillomavirus].
AB  - OBJECTIVE: Study on the promoter effects of sodium butyrate in high or low
      dosages on carcinogenesis process, based on the immortalization of human fetal
      esophageal epithelium induced by human papillomavirus (HPV) 18E(6)E(7) genes.
      METHODS: The immortalized esophageal epithelium SHEE was treated with high
      concentration of the sodium butyrate (80 mmol/L) and then with low concentration
      (5 mmol/L) for 8 weeks respectively. The cells were cultured continuously without
      sodium butyrate for 14 weeks. The morphology, proliferation and apoptosis of the
      cells were studied by phase contrast microscopy, immunohistochemistry and flow
      cytometry. The dead and the viable cells were assayed by fluorescent microscopy
      with Hoechst 33342 and Propidium iodide staining. Tumorigenesis of the cells was
      assessed by soft agar colony formation and by transplantation of cells into nude
      mice and SCID mice. RESULTS: When cells were exposed to high concentration of
      sodium butyrate, cell death was increased leaving few live cells. When cells were
      cultured in the medium with low concentration of sodium butyrate, the first
      proliferative stage appeared. Removal of the butyrate caused the cell to enter a
      crisis stage with a long doubling time resembling senescent cells. After the
      crisis stage, the cells progressed to the second proliferation stage with
      continuous replication and atypical hyperplasia. At the end of the second
      proliferative stage, carcinogenesis of the cells appeared with large colonies in
      soft-agar and tumor formation in transplanted SCID mice and nude mice.
      CONCLUSIONS: The malignant change of the immortalized epithelium by the effects
      of sodium butyrate is the consequence of a two-stage mortality mechanism: cells
      death by butyrate cytotoxicity and cell crisis by abrogation of sodium butyrate.
      These data reveal that in high dosage, sodium butyrate induces cell death and in
      low dosage, it induces cell proliferation, which emphasizes the importance of
      butyrate as a promotor of carcinogenesis.

PMID- 12417091
TI  - [Microdissection and PCR-SSCP detected mutation and expression of p53 and K-ras
      gene in carcinogenesis and development of induced rat lung carcinoma].
AB  - OBJECTIVE: To investigate the roles of p53 and K-ras gene in carcinogenesis and
      development of the lung carcinoma induced by 3-methylcholanthrene (MCA) and
      diethylinitrosamine (DEN) in Wistar rats, and to elucidate the relationships
      between the protein expression and gene mutation of p53 and K-ras. METHODS:
      Microdissection was used to obtain pure cell populations of each phase in the
      carcinogenesis and development of lung carcinoma induced by MCA and DEN. DNA of
      the microdissected cell populations was extracted and used to analyze the
      mutations of p53 exons 5 approximately 8 and K-ras exons 1 approximately 2 by PCR
      SSCP. The expressions of p53 and K-ras protein in each phase were detected by
      immunohistochemistry. RESULTS: No mutation and protein expression of p53 and K
      ras was found in the 30 cases with normal bronchial epithelium. Mutation of p53
      was detected in 3.1% of 18 hyperplasia and 14 squamous metaplasia cases, 28.6% of
      21 dysplasia, 30.0% of 12 carcinomas in situ, 51.2% of 43 infiltration
      carcinomas, 52.9% of 17 metastases. The positive immunostaining rate of p53
      protein was 0, 42.9%, 50.0%, 60.5% and 64.7% respectively. K-ras mutation rate
      was 0, 4.8%, 8.3%, 9.3%, 11.8% respectively, while the overexpression rate of K
      ras protein was 15.6%, 19.0%, 25.0%, 41.9%, 52.9% respectively. p53 protein
      expression was closely related with p53 mutation (P < 0.005, Pearson's R = 0.599
      6). There was no relationship between the protein expression and gene mutation of
      K-ras (P > 0.500). CONCLUSIONS: p53 gene mutation and K-ras overexpression were
      early events in the carcinogenesis and development of rat lung carcinoma induced
      by MCA and DEN, while K-ras mutation does not play any important role.

PMID- 12417092
TI  - [Effects of hypoxia and hyperoxia on the regulation of the expression and
      activity of matrix metalloproteinase-2 in hepatic stellate cell].
AB  - OBJECTIVE: To study the effects of hypoxia and hyperoxia on the expression and
      activity regulation of matrix metalloproteinase-2 (MMP-2) of the hepatic stellate
      cell (HSC). METHODS: The expression of MMP-2, tissue inhibitor of matrix
      metalloproteinase-2 (TIMP-2) and membrane type matrix metalloproteinase-1 (MT1
      MMP) in cultured rat HSC under hypoxic or hyperoxic conditions were detected with
      immunocytochemistry (LSAB method), the contents of MMP-2, TIMP-2 in culture
      supernatant with ELISA and the activity of MMP-2 in supernatant with zymography.
      RESULTS: (1) In the situation of hypoxia for 12 h, the expression of MMP-2
      increased (hypoxia group positive indexes: 5.7 +/- 2.0; control: 3.2 +/- 1.0; P <
      0.01), while TIMP-2 decreased (hypoxia group positive indexes: 2.5 +/- 0.7;
      control: 3.6 +/- 1.0; P < 0.05) in HSC, and the activity of MMP-2 in supernatant
      declined obviously (hypoxia group: 7.334 +/- 1.922; control: 17.277 +/- 7.424; P
      < 0.01). At the different time courses of hypoxia, the change of expression and
      activity of MMP-2 was most notable at 6 h. (2) In the situation of hyperoxia for
      12 h, the protein contents of MMP-2, TIMP-2 in supernatant were both higher than
      those of the control, especially the TIMP-2 (hyperoxia group A(450): 0.050 +/-
      0.014; control: 0.022 +/- 0.010; P < 0.01), and so was the activity of MMP-2
      (hyperoxia group total A: 5.252 +/- 0.771; control: 4.304 +/- 1.083; P < 0.05).
      The expression of MT1-MMP was also increased. CONCLUSIONS: The HSC is sensitive
      to the oxygen. Hypoxia accelerates the expression of MMP-2 and the effect is more
      marked at the early stage. Hyperoxia increases the activity of MMP-2.

PMID- 12417093
TI  - Predictive model for fetal lung maturity assessment incorporating Abbott FLM S/A
      II test results and obstetric estimates of gestational age.

PMID- 12417094
TI  - Neuropeptide Y and its receptors as potential therapeutic drug targets.
AB  - Neuropeptide Y (NPY) is a 36-amino-acid peptide that exhibits a large number of
      physiological activities in the central and peripheral nervous systems. NPY
      mediates its effects through the activation of six G-protein-coupled receptor
      subtypes named Y(1), Y(2), Y(3), Y(4), Y(5), and y(6). Evidence suggests that NPY
      is involved in the pathophysiology of several disorders, such as the control of
      food intake, metabolic disorders, anxiety, seizures, memory, circadian rhythm,
      drug addiction, pain, cardiovascular diseases, rhinitis, and endothelial cell
      dysfunctions. The synthesis of agonists and antagonists for these receptors could
      be useful to treat several of these diseases.

PMID- 12417095
TI  - Apoptosis: biochemical aspects and clinical implications.
AB  - Apoptosis and necrosis represent two distinct types of cell death. Apoptosis
      possesses unique morphologic and biochemical features which distinguish this
      mechanism of programmed cell death from necrosis. Extrinsic apoptotic cell death
      is receptor-linked and initiates apoptosis by activating caspase 8. Intrinsic
      apoptotic cell death is mediated by the release of cytochrome c from
      mitochondrial and initiates apoptosis by activating caspase 3. Cancer
      chemotherapy utilizes apoptosis to eliminate tumor cells. Agents which bind to
      the minor groove of DNA, like camptothecin and Hoechst 33342, inhibit
      topoisomerase I, RNA polymerase II, DNA polymerase and initiate intrinsic
      apoptotic cell death. Hoechst 33342-induced apoptosis is associated with
      disruption of TATA box binding protein/TATA box complexes, replication protein
      A/single-stranded DNA complexes, topoisomerase I/DNA cleavable complexes and with
      an increased intracellular concentration of E2F-1 transcription factor and nitric
      oxide concentration. Nitric oxide and transcription factor activation or
      respression also regulate the two apoptotic pathways. Some human diseases are
      associated with excess or deficient rates of apoptosis, and therapeutic
      strategies to regulate the rate of apoptosis include inhibition or activation of
      caspases, mRNA antisense to reduce anti-apoptotic factors like Bcl-2 and survivin
      and recombinant TRAIL to activate pro-apoptotic receptors, DR4 and DR5.

PMID- 12417096
TI  - Vegetarian lifestyle and monitoring of vitamin B-12 status.
AB  - Vegetarians are at risk to develop deficiencies of some essential nutrients,
      especially vitamin B-12 (cobalamin). Cobalamin occurs in substantial amounts only
      in foods derived from animals and is essential for one-carbon metabolism and cell
      division. Low nutritional intake of vitamin B-12 may lead to negative balance
      and, finally, to functional deficiency when tissue stores of vitamin B-12 are
      depleted. Early diagnosis of vitamin B-12 deficiency seems to be useful because
      irreversible neurological damages may be prevented by cobalamin substitution. The
      search for a specific and sensitive test to diagnose vitamin B-12 deficiency is
      ongoing. Serum vitamin B-12 measurement is a widely applied standard method.
      However, the test has poor predictive value. Optimal monitoring of cobalamin
      status in vegetarians should include the measurement of homocysteine (HCY),
      methylmalonic acid (MMA), and holotranscobalamin II. Vitamin B-12 deficiency can
      be divided into four stages. In stages I and II, indicated by a low plasma level
      of holotranscobalamin II, the plasma and cell stores become depleted. Stage III
      is characterized by increased levels of HCY and MMA in addition to lowered
      holotranscobalamin II. In stage IV, clinical signs become recognizable like
      macroovalocytosis, elevated MCV of erythrocytes or lowered haemoglobin. In our
      investigations, we have found stage III of vitamin B-12 deficiency in over 60% of
      vegetarians, thus underlining the importance of cobalamin monitoring in this
      dietary group.

PMID- 12417097
TI  - Prediction of respiratory distress syndrome using the Abbott FLM-II amniotic
      fluid assay.
AB  - BACKGROUND: Most laboratories using the Abbott FLM-II assay for assessing fetal
      lung maturity follow the manufacturer's recommendations for interpreting the
      surfactant to albumin ratio (S/A). Thus, values >55 mg/g are considered mature
      and values <40 mg/g, immature-leaving a wide range of indeterminate values.
      Little data is available to assist the clinician in interpreting values between
      40 and 55 mg/g. The goal of this study was to determine decision levels that
      would more clearly identify risk for RDS based on S/A results. METHODS:
      Respiratory distress syndrome was identified based on medical record review in 46
      infants (born at six hospitals), who had S/A measurements on amniotic fluid
      within 72 h of delivery. An additional 257 women, who had had the S/A test
      requested but had non-RDS infants, were also identified for this study. The
      probability of RDS was calculated based on S/A values and on gestational age.
      Odds ratios were computed for different S/A ratios and different gestational
      ages. RESULTS: Probability of RDS increased with decreasing S/A and decreasing
      gestational age. At gestational age >36 weeks, the probability of developing RDS
      ranged from 1% at S/A>44 mg/g to 39% at S/A</=20 mg/g. At gestational age <34,
      the probability of developing RDS ranged from 14% at S/A>44 mg/g to 92% at
      S/A</=20 mg/g. CONCLUSIONS: We report a risk-based approach for the clinical
      interpretation of the results of Abbott FLM-II assays based on a broad range of
      S/A values and gestational ages.

PMID- 12417098
TI  - Continuous monitoring of prostatic acid phosphatase using self-indicating
      substrates.
AB  - BACKGROUND: The continuous measurement of acid phosphatase (EC 3.1.3.2) activity
      in serum represents an analytical task not yet sufficiently accomplished.
      METHODS: Introducing two novel substrates-2-chloro-4-nitrophenyl phosphate (CNP
      P), which was preferred, and 4-nitronaphthyl-1-phosphate (NN-P)-an alternative
      assay to measure enzymatic activity was developed and compared with a
      modification of Hillmann's method (azo coupling of released naphth-1-ol with a
      diazonium compound). Apart from different substrate concentrations of 2-chloro-4
      nitrophenyl phosphate, 4 mmol/l, and naphthyl-1-phosphate (N-P), 8 mmol/l (with
      Fast Red TR, 5 mmol/l), respectively, following identical conditions were
      selected: Citrate, 50 mmol/l, pH 5.75; pentane-1,5-diol, 150 mmol/l; tartrate, 60
      mmol/l; 37 degrees C. RESULTS: Whereas intensity and stability of the azo dye
      unpredictably depend on the albumin concentration of the sample, the direct test
      with 2-chloro-4-nitrophenyl phosphate resisted sample interferences, showed no
      intrinsic hydrolysis by albumin, relied on stable reagents and proved superior in
      sensitivity, precision and ease of handling. In measuring prostatic phosphatase,
      the proposed procedure closely correlated with Hillmann's method. The preliminary
      0.95-reference intervals for adults were 1.2-3.9 kU/l and 5.8-14.8 U/l for total
      activity, respectively. CONCLUSIONS: The direct assay of the enzyme is suited as
      an economic, rapid and robust method for mechanized or manual use.

PMID- 12417099
TI  - Evaluation of the clinical performance of equimolar- and skewed-response total
      prostate-specific antigen assays versus complexed and free PSA assays and their
      ratios in discriminating between benign prostatic hyperplasia and prostate
      cancer.
AB  - BACKGROUND: Prostate-specific antigen (PSA) exists in human serum in two
      principal forms, free PSA (fPSA) and protein-complexed PSA, predominantly PSA-ACT
      (alpha(1)-antichymotrypsin). Equimolar response (EMR) total PSA (tPSA)
      immunoassays measure each of these forms equally while skewed-response (SKR)
      assays overestimate or underestimate the tPSA concentration. The advantages of
      EMR over SKR tPSA assays are controversial. METHODS: We used five nonhuman serum
      based samples each containing a different proportion of fSPA:PSA-ACT (0:100 to
      100:0, %:%) and patients' serum samples from men with histologically confirmed
      benign prostatic hyperplasia (BPH) (n=94) or PCA (n=30) and a wide range of fPSA
      concentrations to investigate the molar response status of six tPSA assays.
      Receiver-operator characteristic (ROC) curve analysis was used to compare the
      discriminatory power of these assays in distinguishing men with BPH from those
      with PCA. RESULTS: The Bayer Immuno-1 tPSA (BtPSA) assay demonstrated EMR
      characteristics and diagnostic accuracy similar to the Hybritech Tandem-E and
      Tandem-R tPSA assays. At 90% sensitivity, EMR tPSA assays had higher specificity
      than SKR tPSA assays. CONCLUSIONS: The BtPSA assay is an EMR tPSA assay and EMR
      assays provide improved diagnostic specificity over SKR tPSA assays.

PMID- 12417100
TI  - Is age-related macular degeneration associated with serum lipoprotein and
      lipoparticle levels?
AB  - OBJECTIVE: The etiology of age-related macular degeneration (ARMD) is poorly
      understood. Risk factors for cardiovascular disease have been thought to be
      associated with ARMD. Our purpose was to measure the concentration of atherogenic
      apolipoproteins (apo) and lipoparticles in serum from ARMD patients. METHODS: We
      analyzed lipids, lipoparticles and apolipoproteins concentrations in 84 unrelated
      patients with ARMD and compared the results with those of age- and sex-matched
      control subjects (n=62). Serum lipid concentrations were determined
      enzymatically; apolipoproteins levels by kinetic nephelometry and lipoparticles
      by electroimmunodiffusion. RESULTS: No difference in total cholesterol,
      triglycerides, phospholipids, high- and low-density lipoprotein-cholesterol (lHDL
      C and LDL-C) concentrations were observed between ARMD patients and controls. Apo
      E and LpE non-B concentrations were found to be higher in serum from patients
      than in serum from controls. In contrast, Apo C-III and LpC-III non-B
      concentrations were lower in serum from patients than in serum from controls.
      CONCLUSIONS: The main differences observed between ARMD patients and controls are
      in Apo E, Apo C-III, LpC-III non-B and LpE non-B concentrations. These
      lipoparticles belong to the HDL family, which is considered to consist of anti
      atherogenic lipoproteins. These results raise the possibility that cardiovascular
      risk factors are not associated with ARMD. Furthermore, we can hypothesize that
      ARMD development is linked to perturbations of HDL metabolism.

PMID- 12417101
TI  - Plasmatic homocysteine concentration and its relationship with complications
      associated to diabetes mellitus.
AB  - BACKGROUND AND METHODS: In the search for new factors of cardiovascular risk
      associated to diabetes mellitus (DM), special attention has been paid in recent
      years to hyperhomocysteinaemia. Therefore, we have established the concentration
      of homocysteine (Hcy) and other biochemical parameters in the plasma of a group
      of 57 type 1 and 32 type 2 diabetic patients and 54 control subjects and studied
      whether plasmatic homocysteinaemia was related to macroangiopathy, nephropathy,
      retinopathy and neuropathy. Because of significant differences for plasma Hcy
      values between men and women in the control group, we distinguished between both
      groups throughout the study. RESULTS: Patients with DM had higher Hcy than
      control subjects (11.7+/-5.4 vs. 10.1+/-2.4 micromol/l, p<0.05). Fasting
      hyperhomocysteinaemia was considered as the mean of the plasma Hcy for control
      subjects+2 SD (14.9 micromol/l in total group, 15.6 micromol/l in males and 13.9
      micromol/l in females). In the studied groups with complications, we found
      significant differences between normohomocysteinaemic type 1 diabetic patients
      and those considered hyperhomocysteinaemic by us. On the other hand, patients
      having type 1 DM and complications had higher plasmatic Hcy concentration than
      those with no complications. CONCLUSIONS: We have found a relationship between
      high Hcy levels and prevalence of macroangiopathy, retinopathy and nephropathy in
      the type 1 diabetic patients, which was not been observed in the type 2 diabetic
      patients of our study. As a result, we consider plasmatic Hcy a complication-risk
      indicator in type 1 DM, and we recommend its use together with already
      established biochemical parameters in the control of the evolution of the
      disease.

PMID- 12417102
TI  - Stable expression of human tartrate-resistant acid phosphatase isoforms by CHO
      cells.
AB  - OBJECTIVE: In human serum, type-5 tartrate-resistant acid phosphatase (TRACP)
      exists as two closely related isoforms: 5a and 5b. Serum isoform 5b is an
      osteoclast product that reflects bone resorption rate and is frequently increased
      in diseases of increased bone turnover. Isoform 5a protein is often increased in
      rheumatoid arthritis (RA) sera and may be a product of inflammatory macrophages.
      Our objective was to compare the biochemical characteristics of TRACP 5a and 5b.
      METHODS: We transfected the human ACP 5 gene into CHO cells and cloned a stable
      cell line (CHO/TRACP 8F5) that expresses high levels of TRACP activity both
      intracellularly and as a secreted product. Both enzyme preparations were purified
      on an anti-TRACP antibody column. Their biochemical properties were compared to
      the natural serum isoforms using colorimetric assays for activity and total
      protein. Their structural properties were compared to natural serum isoforms
      using denaturing and nondenaturing polyacrylamide gel electrophoresis. RESULTS:
      Both enzyme preparations were heterogeneous. The combined secreted recombinant
      TRACPs (rTRACP(ex)) had all the characteristics of natural serum TRACP 5a. There
      were seven uncleaved glycoproteins with a pH optimum of 5.2, relatively low
      specific activity (278 U/mg) and differentially sialylated. The combined
      intracellular TRACPs (rTRACP(in)) had all the characteristics of natural serum
      TRACP 5b. They consisted of two proteins, one of which was a processed
      heterodimer, with a pH optimum of 5.8, a relatively high specific activity (887
      U/mg) and lacked sialic acid. CONCLUSION: This cell line provides an avenue for
      the simultaneous study of the regulation, function and intracellular trafficking
      of separate TRACP isoforms and the identification of their physiologic substrates
      in a single uniform cell source.

PMID- 12417103
TI  - Optimisation of an enzymatic method for beta-galactosidase.
AB  - BACKGROUND: The enzyme beta-galactosidase present in the Kupffer cells of the
      liver has potential as a marker of liver dysfunction prior to transplantation.
      Spectrophotometric methods have insufficient sensitivity. METHODS: Fluorimetric
      methods have the required sensitivity and we have optimised such a method in a
      microtitre plate format to improve its utility. beta-galactosidase acts on the
      substrate 4-methylumbelliferyl-galactoside (MUG) to produce 4-methylumbelliferone
      (4-MU), detected fluorimetrically with excitation wavelength 355 nm and emission
      wavelength 460 nm. RESULTS: Reaction conditions in a citrate-phosphate buffer
      were optimised to give maximal enzyme activity: pH was optimal at 4.4 (range
      investigated 3.6-5.0) and substrate concentration at 3.33 mmol/l. A small
      specimen volume (10 microl) in 80 microl of substrate solution produced adequate
      fluorescent yield after an incubation period of 30 to 60 min at 37 degrees C.
      Reaction was terminated by addition of 200 microl of glycine-NaOH, pH 12.8. The
      assay is linear to 3,000 U/ml. The intra-assay coefficient of variation (CV%) at
      50, 502, and 2,012 U/ml was 4.7, 3.1, and 3.4, respectively (n=10). Inter-assay
      CV% at 51, 496, and 1,986 U/ml was 7.0, 4.0, and 3.9, respectively (n=10).
      CONCLUSIONS: The assay has greater practical utility and demonstrated significant
      differences in the perfusate beta-galactosidase between cold-stored and warm
      perfused livers in a porcine model of transplantation.

PMID- 12417104
TI  - Rapid spectrophotometric method for serum glutathione S-transferases activity.
AB  - BACKGROUND: Glutathione S-transferases (GST) are a family of polymorphic enzymes
      responsible for the metabolism of a broad range of xenobiotics including
      carcinogens and endogenous compounds. METHODS: The aim of this study was to
      develop a fully automated spectrophotometric method to determine serum GST
      activity. RESULTS: The method had a detection limit of 7 U/l. The within- and
      between-run repeatability reached 2% and 3%, respectively. The reproducibility
      tested over a 6-month period was 7%. Serum GST activity is stable for at least 1
      week at +37, +4 and -20 degrees C, 1 month at -20 degrees C and 6 months at -80
      and -196 degrees C. The GST activities were determined on 374 supposedly healthy
      subjects coming to the Center of Preventive Medicine for a health screening. The
      sample population comprised 178 males and 196 females 4-80 years of age. The mean
      value of the serum GST activity calculated for this healthy population was 28.2+/
      3.0 U/l without gender difference (range from 20.0 to 38.0 U/l). The global
      interindividual variability reached 11%. CONCLUSIONS: This report describes a
      spectrophotometric assay for monitoring the serum GST activities in human. This
      method will be useful in examining the relationships between serum GST activities
      and the GST polymorphisms, especially pi-GST.

PMID- 12417105
TI  - Measurement of erythrocyte lipids, lipid peroxidation, antioxidants and osmotic
      fragility in cervical cancer patients.
AB  - BACKGROUND: Our aim was to examine the structural integrity of red blood cells in
      cervical cancer patients by measuring the concentrations of thiobarbituric acid
      reactive substances (TBARS), antioxidant status, cholesterol/phospholipid (C/P)
      molar ratio, enzyme activity and osmotic fragility of erythrocytes. METHODS: This
      study has been conducted on 32 adult female cervical cancer patients and an equal
      number of age- and sex-matched normal subjects. Erythrocyte concentrations of
      lipids, TBARS, vitamin E, reduced glutathione and enzymic activities of catalase
      and Na(+)K(+)-ATPase were measured as well as plasma concentrations of sodium and
      potassium. The present study also examined the changes in erythrocyte osmotic
      fragility in cervical cancer patients and normal subjects. The red cell fluidity
      and permeability were determined by estimating the C/P ratio and Na(+)K(+)-ATPase
      activity, respectively. RESULTS: The release of thiobarbituric acid reactive
      substances was significantly higher in cervical cancer patients as compared to
      normal subjects. The increased lipid peroxidation with concomitant decrease in
      antioxidants was notable in cervical cancer patients. Red blood cells of cervical
      cancer patients were more fragile than those from normal subjects. Increase in
      red cell membrane C/P ratio and Na(+)K(+)-ATPase activity was noticed in cervical
      cancer patients as compared to normal subjects. CONCLUSIONS: Increased lipid
      peroxidation, insufficient antioxidant potential and changes in C/P molar ratio
      as well as activity of Na(+)K(+)-ATPase cause structural and functional
      abnormalities in the erythrocytes of cervical cancer patients.

PMID- 12417106
TI  - Measurement of glial fibrillary acidic protein in blood: an analytical method.
AB  - BACKGROUND: In the present study, a new assay for the measurement of glial
      fibrillary acidic protein (GFAP) in human blood is described. The aim of the
      study was to present the characteristics of a new GFAP assay for blood analysis.
      METHODS: The method, a newly developed enzyme-linked immunosorbent assay (ELISA),
      was validated using blood samples from healthy blood donors and from patients
      with severe traumatic brain injury (TBI). RESULTS: 22 out of 72 healthy blood
      donors had a detectable GFAP level. The reference values (percentiles) are as
      follows: P50=0.15 microg/l and P95=0.49 microg/l; range 0.15-0.76 microg/l.
      CONCLUSIONS: GFAP in blood might be a promising new marker for astrocyte
      involvement after acute brain damage.

PMID- 12417107
TI  - Coenzyme Q10 in plasma and erythrocytes: comparison of antioxidant levels in
      healthy probands after oral supplementation and in patients suffering from sickle
      cell anemia.
AB  - BACKGROUND: The membrane-associated antioxidant coenzyme Q10 (CoQ10) or
      ubiquinone-10 is frequently measured in serum or plasma. However, little is known
      about the total contents or redox status of CoQ10 in blood cells. METHODS: We
      have developed a method for determination of CoQ10 in erythrocytes. Total CoQ10
      in erythrocytes was compared to the amounts of ubiquinone-10 and ubihydroquinone
      10 in plasma using high-pressure liquid chromatography (HPLC) with
      electrochemical detection and internal standardisation (ubiquinone-9,
      ubihydroquinone-9). RESULTS: Investigations in 10 healthy probands showed that
      oral intake of CoQ10 (3 mg/kg/day) led to a short-term (after 5 h, 1.57+/-0.55
      pmol/microl plasma) and long-term (after 14 days, 4.00+/-1.88 pmol/microl plasma,
      p<0.05 vs. -1 h, 1.11+/-0.24 pmol/microl plasma) increase in plasma
      concentrations while decreasing the redox status of CoQ10 (after 14 days, 5.37+/
      1.31% in plasma, p<0.05 vs. -1 h, 6.74+/-0.86% in plasma). However, in these
      healthy probands, CoQ10 content in red blood cells remained unchanged despite
      excessive supplementation. In addition, plasma and erythrocyte concentrations of
      CoQ10 were measured in five patients suffering from sickle cell anemia, a genetic
      anemia characterised by an overall accelerated production of reactive oxygen
      species. While these patients showed normal or decreased plasma levels of CoQ10
      with a shifting of the redox state in favour of the oxidised part (10.8-27.2% in
      plasma), the erythrocyte concentrations of CoQ10 were dramatically elevated (280
      1,093 pmol/10(9) ERY vs. 22.20+/-6.17 pmol/10(9) ERY). CONCLUSIONS: We conclude
      that normal red blood cells may regulate their CoQ10 content independently from
      environmental supplementation, but dramatic changes may be expected under
      pathological conditions.

PMID- 12417108
TI  - Analysis of the C314T and A595G mutations in histamine N-methyltransferase gene
      in a Chinese population.
AB  - BACKGROUND: Histamine N-methyltransferase (HNMT) plays an important role in the
      metabolism of histamine, a biogenic amine that has many physiologic and
      pathological roles in human tissues. A missense mutation C314T (Thr105Ile) in the
      HNMT gene has been identified to represent a common functional polymorphism in
      Caucasians, whereas an A595G (Ile199Val) variant has been reported in one HNMT
      cDNA from a Japanese subject. METHODS: By using the polymerase chain reaction
      restriction fragment length polymorphism (PCR-RFLP) assay, the point mutations
      C314T and A595G within HNMT were both detected in 352 unrelated Chinese Han
      subjects. RESULTS: None of the 352 subjects contained the A595G mutation, whereas
      40 (11.6%) heterozygotes and 1 (0.3%) homozygote for the variant T314 allele were
      detected. The frequency of the variant T314 allele in this Chinese population was
      0.060 (95% CI: 0.042-0.078), not different from Japanese but significantly lower
      than American Caucasians. CONCLUSIONS: The C314T mutation represents a common
      functional genetic polymorphism in the Chinese Han population with a variant T314
      allele frequency similar to Japanese but lower than American Caucasians, whereas
      the A595G mutation does not appear to exist in this population.

PMID- 12417109
TI  - Effect of five flavonoid compounds isolated from leaves of Diospyros kaki on
      stimulus-induced superoxide generation and tyrosyl phosphorylation of proteins in
      human neutrophils.
AB  - BACKGROUND: The crude drug "kaki-yo" is a traditional medicine used in Japan as a
      hypotensive drug. METHODS: The effect of five flavonoid compounds isolated from
      the leaves of Diospyros kaki was investigated on the stimulus-induced superoxide
      generation and phosphorylation of tyrosine residues of protein in human
      neutrophils. The five compounds examined were kaempferol 3-O-beta-D
      galactopyranoside (TR), kaempferol 3-O-beta-D-glucopyranoside (AS), isorhamnetin
      3-O-beta-D-glucopyranoside (IS), quercetin 3-O-beta-D-galactopyranoside (HY),
      quercetin 3-O-beta-D-glucopyranosyl-(6-->1)-alpha-L-rhamnopyranoside (RU).
      RESULTS: When the cells were preincubated with these five compounds, the
      superoxide generation induced by N-formyl-methionyl-leucyl-phenylalanine (fMLP)
      was significantly suppressed in a concentration-dependent manner. The arachidonic
      acid (AA)-induced superoxide generation was suppressed by TR, AS, HY and RU. On
      the other hand, the superoxide generation was weakly enhanced by IS in low
      concentration (5-20 micromol/l), but was suppressed in high concentration (50
      micromol/l). The superoxide generation induced by phorbol 12-myristate 13-acetate
      (PMA) suppressed the TR, IS, HY and RU, but AS gave no effect. When the cells
      were incubated with fMLP in the presence of TR, IS and RU, fMLP-induced tyrosyl
      phosphorylation of 45-kDa proteins of the cells was dose-dependently suppressed
      in parallel to the suppression of fMLP-induced superoxide generation. These five
      flavonoids showed almost no hemolytic effect even at a concentration of 500
      micromol/l. CONCLUSION: Flavonoid compounds suppressed stimulus-induced
      superoxide generation and tyrosyl phosphorylation and may have pharmaceutical
      application.

PMID- 12417110
TI  - Detection of low-molecular-weight proteins in urine by dipsticks.
AB  - BACKGROUND: Testing of urines with dipsticks for proteinuria, glycosuria, etc.,
      is common practice. A deficiency with currently available dipsticks is their lack
      of chemical sensitivity and underestimation of low-molecular-weight proteins such
      as light chains. METHODS: We experimented with a number of dyes that gave an
      easily recognized color change on dipsticks for various low-molecular-weight
      proteins such as alpha-1-glycoprotein, alpha-1- and beta-2-microglobulin, and
      kappa and lambda light chains. We were successful in formulating a dye for
      impregnating dipsticks that gave a color change with low-molecular-weight
      proteins. RESULTS: Most dipsticks will measure proteins down to about 1 g/l. Our
      composite of two dyes (described here as the "TPR" dipsticks) gave reproducible
      results for protein concentrations of >/=300 mg/l, and detected low-molecular
      proteins. The TPR reagent is resistant to interferences from many compounds;
      also, the protein results are not altered in a given urine at a pH between 5 and
      8. CONCLUSIONS: We have developed a dipstick that detects low-molecular-weight
      proteins. The dipsticks are easy to use and are suitable for outpatient or point
      of-care testing. The precision of the dipsticks is satisfactory and is only
      marginally lower than quantitative spectrophotometric methods using pyrogallol
      red (PYR).

PMID- 12417111
TI  - Value of a single troponin T at the time of presentation as compared to serial CK
      MB determinations in patients with suspected myocardial ischemia.
AB  - BACKGROUND: Prior studies with cardiac markers have focused predominantly on
      subjects presenting to the emergency department with chest pain or unstable
      angina, and have relied on serial markers for the diagnosis of acute myocardial
      infarction. We evaluated the diagnostic utility of a single cardiac troponin T
      (cTnT) determination at the time of presentation as compared to serial creatine
      kinase (CK) MB determinations in a broad spectrum of patients with suspected
      myocardial ischemia. METHODS: A total of 267 consecutive patients presenting to
      the emergency department with suspected myocardial ischemia had a single, blinded
      cTnT determination drawn at the time of presentation to the emergency department
      in addition to routine serial electrocardiographic and CK-MB determinations.
      RESULTS: The specificity (93.7% vs. 87.1%; p<0.05) and positive predictive value
      (80.0% vs. 69.4%; p<0.05) of a single cTnT determination were superior to that of
      serial CK-MB determinations without compromising sensitivity. Forty-six percent
      of patients with confirmed myocardial infarction and an abnormal cTnT at
      presentation had a normal initial CK-MB determination. Conversely, 20% of
      patients without acute coronary syndromes had an abnormal CK-MB determination in
      the setting of a normal cTnT. The initial cTnT was abnormal in all patients with
      confirmed myocardial infarction and a symptom duration of at least 3.5 h.
      CONCLUSIONS: In a heterogeneous population of patients with suspected myocardial
      ischemia, the initial cTnT determination drawn at the time of presentation is a
      powerful diagnostic tool that, when used in context with symptom duration, allows
      for more rapid and accurate triage of patients than serial CK-MB determinations.

PMID- 12417112
TI  - Novel mutation and multiple mutations found in the human butyrylcholinesterase
      gene.
AB  - BACKGROUND: Mutations in human butyrylcholinesterase (BChE) are linked to low
      BChE activity and abnormal response to muscle relaxants. METHODS: Twenty Chinese
      patients with hepatic disease and low cholinesterase activity, and one Japanese
      patient and her mother were tested for BChE activity and BChE phenotype. The
      butyrylcholinesterase (BCHE gene) was amplified by polymerase chain reaction
      (PCR) and sequenced. Mutant BChE was expressed in 293 cells. RESULTS: A novel
      mutation was found in one Chinese patient at nucleotide 943, where A was changed
      to T (943 A-->T), causing substitution of threonine 315 by serine (T315S). The
      T315S mutant had half of the normal BChE activity. One Japanese patient with low
      BChE activity had three nucleotide substitutions, 355 C-->T, 988 T-->A, and 1615
      G-->A. The amino acid substitutions were Q119stop, L330I, and A539T,
      respectively. The single mutant L330I had low BChE activity, but the double
      mutant L330I/A539T had normal activity. CONCLUSIONS: The L330I and the novel
      T315S mutation caused a decreased BChE activity. The T315S mutation is one of the
      first BChE mutations reported in the Chinese population. Multiple mutations in
      BChE may interact with each other in an intramolecular manner.

PMID- 12417113
TI  - Acute hypermagnesemia: a rare complication of antacid administration after bone
      marrow transplantation.
AB  - INTRODUCTION: We reported a case of hypermagnesemia in whom hypotension,
      hypothermia, and coma developed after repetitive doses of a seemingly harmless
      antacid for epigastric pain following bone marrow transplantation. METHODS: For
      this case, serial electrolytes, blood urea nitrogen, creatinine, calcium, and
      magnesium were obtained. Issues addressed were the restoration of normal
      hydration by normal saline, together with forced diuresis to hasten the renal
      excretion of magnesium, and eventual changes in its levels. RESULTS: The highest
      measured magnesium concentration was 5.9 mmol/l. She recovered without dialysis.
      The patient's condition improved with intravenous doses of calcium gluconate,
      saline solution infusion, and cardiovascular support. CONCLUSION: Hypermagnesemia
      is rare in allogeneic stem cell recipients receiving cyclosporine therapy for
      prevention of acute graft-vs.-host disease (GVHD). A posttransplant status with
      possible GVHD, poor nutritional intake, impaired intestinal absorption,
      dehydration, and the use of aluminum magnesia oral suspension may have resulted
      in magnesium imbalance. This case report highlights several associated nonrenal
      risk factors for hypermagnesemia, which include gastrointestinal tract disease,
      dehydration, and concomitant medications, particularly, the antacids that contain
      magnesium.

PMID- 12417114
TI  - Bull exposure and an increased within-day milking to suckling interval reduced
      postpartum anoestrus in dual purpose cows.
AB  - It is hypothesized that the combined effects of suckling and milking in the dual
      purpose cows is one of the main suppressors of reproductive efficiency in this
      production system. The experiment described here examined whether managing the
      interval between milking and suckling could reduce the postpartum anoestrous
      period and whether the presence of a teaser bull could enhance the effects of
      these managements. The experiment involved 39 Bos taurus x Bos indicus cows which
      had an average weight of 523.0 +/- 12.8 kg (mean +/- S.E.M.) and body condition
      score of 5-7 (scale 1-9) at calving. The cows and calves grazed separate pastures
      and the cows were supplemented with 2 kg 17% CP concentrates and 1 kg molasses
      per cow per day. The experiment was conducted over the first 100 days postpartum.
      Cows were hand-milked once per day in the presence of the calf to stimulate milk
      release. The factors in the 2 x 2 design were the milking to suckling interval (0
      h, control suckling; CS versus 8 h prolonged-delay suckling; PDS) and no exposure
      versus exposure to a teaser bull (B). Cows were assigned at random within calving
      date to the four treatments: CS (n = 10), PDS (n = 10), CS-B (n = 9) and PDS-B (n
      = 10). Cows on treatments CS and CS-B had three-quarters of the udder milked and
      one-quarter was not milked. The entire udder was milked on those treatments where
      there was an interval between milking and suckling. The bull was introduced 7
      days after calving in treatments where the cows were exposed to a teaser bull.
      Body weights of cows and calves and cow milk yield were recorded. Weekly blood
      samples were collected for plasma progesterone assay. Data were analyzed by ANOVA
      in a 2 x 2 factorial design and by chi(2)-test. There were no statistically
      significant differences between treatments in cow body weight at calving and at
      100 days postpartum, nor in milk yield (overall mean 6.0 +/- 1.1 kg per day).
      Calf daily gain was 598 +/- 25 g for treatments CS and CS-B in which suckling
      immediately followed milking and 833 +/- 24 g for treatments PDS and PDS-B (P <
      0.001). The proportion of cows ovulating was CS 80.0%, PDS 100.0%, CS-B 88.8% and
      PDS-B 100.0%. The difference between CS and PDS or PDS-B was significant (P <
      0.05). CS-B did not differ significantly from the other three treatments. The
      calving to first ovulation interval was not improved when the interval between
      milking and suckling was increased from 0 h (56.5 +/- 5.0 days) to 8 h (64.8 +/-
      4.5 days). Exposure to a teaser bull, however, significantly (P < 0.001) reduced
      this interval from 77.0 +/- 2.7 days (no bull exposure) to 44.4 +/- 2.7 days
      (exposure to teaser bull). Exposure to a teaser bull significantly reduced the
      calving to first anoestrus interval. Delaying the start of suckling after milking
      did not improve the reproductive performance of the cows or alter the effect of
      bull exposure, however, delaying suckling after milking improved the performance
      of the calves without affecting milk yield.

PMID- 12417115
TI  - Plasma, milk and faecal progesterone concentrations during the oestrous cycle of
      lactating dairy cows with different milk yields.
AB  - The hypotheses tested in this study were that neither average progesterone (P4)
      concentrations in plasma and milk nor average progesterone metabolites
      concentrations in faeces would differ during an oestrous cycle in two groups of
      cows with differing daily milk yields. High producing (HP = 8) and low producing
      (LP = 8) dairy cows were selected randomly for the study. Their oestrous cycles
      were initially synchronised using P4 and prostaglandin F2alpha. Chromic oxide
      capsules were administered twice daily to measure total faecal output. Samples of
      blood, faeces and milk were taken daily throughout one oestrous cycle, plasma and
      milk P4, and faecal progesterone metabolites (FP4M) assayed. The average daily
      milk yields in the two groups were 30.8 and 21.9l per day, respectively (P <
      0.0001), although daily faecal output was similar in both the groups (HP, 7.7
      versus LP, 6.9 kg DM; P = 0.24). Mean plasma and milk P4 concentrations were
      similar in both the groups (plasma P4, 4.12 versus 4.05 ng/ml; P = 0.3; milk P4,
      8.2 versus 8.3; P = 0.9) during dioestrus. Average daily excretion of P4 to the
      milk was greater in HP than LP cows (252 versus 185 microg, P = 0.04). Neither
      concentration nor the daily yield of FP4Ms was affected by level of milk yield
      (concentration: 12.2 versus 11.5 microg/g; daily yield: 89.1 versus 82.9 mg per
      day; P > 0.05). These data showed that the concentrations of P4 in plasma and
      milk, and the concentrations and daily yields of FP4M were not affected by the
      level of daily milk yields which differed by about 41% of the LP average of
      21.9l.

PMID- 12417116
TI  - The effect of feeding and management practices on calving rate in dairy herds.
AB  - The objective of this study was to examine the effects of nutrition and
      management practices on reproductive performance in 31 Irish dairy herds
      participating in the Moorepark Dairy Management Information System (DairyMIS)
      during the period 1991-1998. Fifty variables relating to herd reproductive
      indices, calving events, stocking rate, disease, concentrate feeding, fertiliser
      usage, milk production and economic performance were studied using factor
      analysis. A factor analysis, followed by varimax rotation, identified 13 factors,
      which accounted for 83% of the total variance of the original variables. A
      regression model was used to predict calving rate from the orthogonal factor
      scores identified by factor analysis. Calving rate was defined as the proportion
      of services, for which an outcome was known, which resulted in a subsequent
      calving. Year, farm code and factor 3 (labelled herd size) together accounted for
      40% of the observed variation in calving rate. The factor scores for factor 3
      (herd size) were plotted against calving rate and because the plot was not
      linear, it was decided that dividing the factor scores into quartiles would
      produce a better fitting model. The factor scores for herd size were sorted and
      assigned to four equal categories (n = 47 per category), from lowest to highest.
      The ranges in herd size according to category were as follows: category 1 (34
      96), category 2 (47-103), category 3 (66-152) and category 4 (108-359). The
      calving rate (%), (+/-S.E.) was 67.0 +/- 2.5 for category 1, 61.8 +/- 1.8 for
      category 2, 56.9 +/- 1.5 for category 3 and 53.2 +/- 2.85 for category 4. Using
      pair-wise comparisons, calving rates differed significantly (P < 0.05) between
      all categories except between categories 3 and 4 (P > 0.05). Herd-level milk
      production was not associated with calving rate indicating that good management
      may overcome any adverse effects of high milk production on reproductive
      performance. Larger herds, in combination with other associated herd
      characteristics, are likely to have poorer calving rates than medium or small
      herds.

PMID- 12417117
TI  - Use of GnRH agonist implants for long-term suppression of fertility in
      extensively managed heifers and cows.
AB  - The ability of gonadotrophin releasing hormone (GnRH) agonist implants to
      suppress ovarian activity and prevent pregnancies, long-term, was examined in
      heifers and cows maintained under extensive management. At three cattle stations,
      heifers (2-year-old) and older cows (3- to 16-year-old) were assigned to a
      control group that received no treatment, or were treated with high-dose (12 mg,
      Station A) or low-dose (8 mg, Station B and Station C) GnRH agonist implants. The
      respective numbers of control and GnRH agonist-treated animals (heifers + cows)
      at each station were: Station A, 20 and 99; Station B, 19 and 89; Station C, 20
      and 76. Animals were maintained with 4% bulls and monitored for pregnancy at 2
      monthly intervals for approximately 12 months. Pregnancy rates for control
      heifers and control cows ranged from 60-90% and 80-100%, respectively, depending
      on the study site. The respective number of animals (heifers + cows) treated with
      GnRH agonist that conceived, and days to first conception, were: Station A, 9
      (9%) and 336 +/- 3 days; Station B, 8 (10%) and 244 +/- 13 days; Station C, 20
      (26%) and 231 +/- 3 days. Treatment with high-dose GnRH agonist prevented
      pregnancies for longer (approximately 300 days) than treatment with low-dose GnRH
      agonist (approximately 200 days). In the majority of heifers and cows treated
      with GnRH agonist, ovarian follicular growth was restricted to early antral
      follicles (2-4mm). The findings indicate that GnRH agonist implants have
      considerable potential as a practical technology to suppress ovarian activity and
      control reproduction in female cattle maintained in extensive rangelands
      environments. The technology also has broader applications in diverse cattle
      production systems.

PMID- 12417119
TI  - Factors affecting gestation length in the Thoroughbred mare.
AB  - In order to assist in the accurate prediction of the timing of parturition in the
      mare true gestation length, along with the potential effect of a number of
      factors, was investigated. Data from 433 Thoroughbred foal pregnancies were used.
      Sequential ultrasonic scanning allowed the true gestation length (fertilisation
      parturition) to be ascertained, as apposed to previous work, which used the
      mating-parturition interval. An average gestation length of 344.1 +/- 0.49 days
      was evident. Colt foal pregnancies were significantly (P < 0.001) longer (346.2
      +/- 0.72) than fillies (342.4 +/- 0.65). Month of birth had a significant effect
      on gestation length in all foals (P < 0.001). With foals born in January having
      the shortest gestation lengths and those born in April the longest. Mare age,
      year of birth, stallion age, stud farm and the interval between ovulation and
      mating had no significant effect. It is concluded that (i) the gestation length
      range (315-388 days), all resulting in viable foals is noteworthy and of clinical
      importance when considering the classification of dysmaturity in foals, (ii)
      mares carrying colt foals due to be born in the middle of the breeding season
      (April) are likely to have the longer gestation lengths.

PMID- 12417118
TI  - Season affects characteristics of the pre-ovulatory LH surge and embryo viability
      in superovulated ewes.
AB  - The aim of this study was to determine whether there are seasonal shifts in
      ovulatory response, and in the viability of ova recovered from superovulated
      ewes. Fifty mature ewes underwent a standard oestrous synchronisation (CIDR),
      superovulation (oFSH) and artificial insemination procedure during October (peak
      breeding season) and April (transition to anoestrus). In each month peripheral LH
      and progesterone concentrations were measured around the time of ovulation and
      embryos were recovered, graded and cryopreserved on day 6 after insemination.
      During the subsequent breeding season, grade 1 and 2 morulae and unexpanded
      blastocysts were thawed and transferred singly to synchronous recipients
      (October, n = 40; April, n = 40) or cultured in vitro for 18-20 h (October, n =
      107; April, n = 98). Following culture, viable embryos were stained to count cell
      nuclei or assayed to measure their capacity for glucose metabolism ([3H]glucose)
      and protein synthesis ([35S]methionine). Peak LH concentrations were higher in
      October than in April (38.2 +/- 3.26 ng ml(-1) versus 25.7 +/- 1.99 ng ml(-1),
      respectively; P < 0.01) and the pre-ovulatory LH surge was advanced by
      approximately 3 h (P < 0.05). Progesterone concentrations at CIDR withdrawal were
      lower in October than in April (3.1 +/- 0.16 ng ml(-1) versus 4.3 +/- 0.19 ng ml(
      1), respectively; P < 0.001) but were not different at embryo recovery. Season
      did not affect the numbers of corpora lutea per ewe or the numbers of ova
      recovered but the proportion of recovered ova that was unfertilised/degenerate
      was lower in October than in April (0.43 versus 0.58, respectively; P < 0.001).
      For embryos containing more than 16 cells, there was no effect of season on the
      median stage of development or morphological grade. The proportions of October
      and April embryos that established pregnancy following transfer to recipient ewes
      were 0.78 and 0.70 (not significantly different), and that were viable after in
      vitro culture were 0.66 and 0.37 (P < 0.05), respectively. Season did not affect
      the number of nuclei per viable embryo or the capacity for protein synthesis but
      the glucose uptake of October embryos was approximately double that of April
      embryos (3163+/-293.4 dpm versus 1550+/-358.9 dpm, respectively; P < 0.05).
      Results indicate that during the late compared to peak breeding season, there is
      an increased incidence of fertilisation failure as a possible consequence of
      seasonal shifts in LH secretion and (or) associated effects on follicular
      function. Frozen-thawed embryos produced at contrasting stages of the breeding
      season are equally viable in vivo but those produced during the late, as opposed
      to the peak breeding season have lower viability following in vitro culture.

PMID- 12417120
TI  - Lactose-egg yolk diluent supplemented with N-acetyl-D-glucosamine affect acrosome
      morphology and motility of frozen-thawed boar sperm.
AB  - These experiments were carried out to investigate the effect of N-acetyl-D
      glucosamine, and to obtain additional information about the effect of orvus es
      paste (OEP) and egg yolk concentration in the freezing of boar sperm in the maxi
      straw. The highest post-thaw acrosomes of normal apical ridge (NAR) and motility
      were obtained with 0.025 or 0.05% N-acetyl-D-glucosamine concentration in the
      first diluent. However, there were no effects of N-acetyl-D-glucosamine among the
      diluents with or without N-acetyl-D-glucosamine at the second dilution. The N
      acetyl-D-glucosamine in the first and second diluents was added at room
      temperatures (20-23 degrees C) and 5 degrees C, respectively. It is suggested
      that the temperature of N-acetyl-D-glucosamine addition is important for the
      effect of boar sperm protection during freezing and thawing. When the 0.05% N
      acetyl-D-glucosamine was supplemented in the first diluent, the optimum final OEP
      content was 0.5%. The optimum content of egg yolk in the diluent with 0.05% N
      acetyl-D-glucosamine concentration was 20% and egg yolk was one of the main
      cryoprotective agents. In conclusion, we found out that the diluent with 0.025 or
      0.05% soluble N-acetyl-D-glucosamine in the first diluent, 0.5% final orvus es
      paste concentration and 20% egg yolk concentration significantly enhanced NAR
      acrosomes and motility of boar sperm after freezing and thawing.

PMID- 12417121
TI  - Expression of membrane associated non-genomic progesterone receptor(s) in caprine
      spermatozoa.
AB  - Mammalian spermatozoa have been used recently to model the study of rapid, non
      genomic effects of progesterone on cell. Our study used progesterone-BSA
      fluorescein isothiocyanate conjugate to indicate the presence of a progesterone
      receptor on the surface of >90% of a goat sperm population. The sperm possessed
      the receptor at 0 h and capacitation had no modulating effect on the number of
      sperm responsive to P-BSA-FITC. Although a decrease in receptor bearing cells was
      observed during the course of capacitation, the effect may have been due to the
      induction of acrosome reaction (AR) by the conjugate. This decrease was blocked
      by the pre-treatment of the spermatozoa with EGTA. Binding of conjugate occurred
      at the apical portion of the acrosome and at the post-acrosomal region in all the
      sperm, possibly mediating sperm functions other than the acrosome reaction. The P
      BSA-FITC treated cells showed a single peak in a flow cytometer suggesting that
      the sperm population was homogeneous. Competition studies with free progesterone
      and GABA with P-BSA-FITC confirmed that the binding was specific and that
      progesterone mediated its action via a GABA(A)/Cl(-) channel complex akin to the
      one present in neuronal cells.

PMID- 12417122
TI  - Eukaryotic genomes contain a [2Fez.sbnd;2S] ferredoxin isoform with a conserved C
      terminal sequence motif.
AB  - Apicomplexan protists contain a single mitochondrial [2Fe-2S] ferredoxin sequence
      (mtFd) with a highly conserved C-terminal motif, VDGxxpxPH, that distinguishes it
      from other mtFd, which have heterogeneous C-termini. This isoform of mtFd, called
      'type II ferredoxin', is widespread in eukaryotes, some species having two
      isoforms and others possessing only one. Because of the known modulating role of
      the C-terminus of type I mtFd during association with itself and other
      interacting proteins, the presence of a conserved C-terminus in type II mtFd
      suggests it evolved either as a means for optimized homodimerization or to allow
      interaction with a highly conserved partner(s) that is yet to be defined.

PMID- 12417130
TI  - Botulinum and tetanus neurotoxins: structure, function and therapeutic utility.
AB  - The toxic products of the anaerobic bacteria Clostridium botulinum, Clostridium
      butyricum, Clostridium barati and Clostridium tetani are the causative agents of
      botulism and tetanus. The ability of botulinum neurotoxins to disrupt
      neurotransmission, often for prolonged periods, has been exploited for use in
      several medical applications and the toxins, as licensed pharmaceutical products,
      now represent the therapeutics of choice for the treatment for several
      neuromuscular conditions. Research into the structures and activities of
      botulinum and tetanus toxins has revealed features of these proteins that might
      be useful in the design of improved vaccines, effective inhibitors and novel
      biopharmaceuticals. Here, we discuss the relationships between structure,
      mechanism of action and therapeutic use.

PMID- 12417131
TI  - Analysis of membrane protein interactions using yeast-based technologies.
AB  - Proteins associated with membranes total approximately a third of all proteins in
      a typical eukaryotic cell. However, the analysis of interactions between membrane
      proteins is difficult because of the hydrophobic nature of these proteins, and
      conventional biochemical and genetic assays are often of limited use. We
      summarize here recent yeast-based interaction technologies that can be applied to
      membrane proteins.

PMID- 12417132
TI  - Mitochondria as we don't know them.
AB  - Biochemistry textbooks depict mitochondria as oxygen-dependent organelles, but
      many mitochondria can produce ATP without using any oxygen. In fact, several
      other types of mitochondria exist and they occur in highly diverse groups of
      eukaryotes - protists as well as metazoans - and possess an often overlooked
      diversity of pathways to deal with the electrons resulting from carbohydrate
      oxidation. These anaerobically functioning mitochondria produce ATP with the help
      of proton-pumping electron transport, but they do not need oxygen to do so.
      Recent advances in understanding of mitochondrial biochemistry provide many
      surprises and furthermore, give insights into the evolutionary history of ATP
      producing organelles.

PMID- 12417133
TI  - Telomerase: biochemical considerations for enzyme and substrate.
AB  - Telomerase extends chromosome ends by iterative reverse transcription of its RNA
      template. Following the addition of each telomeric repeat, the RNA template and
      the telomeric substrate reset their relative position in the active site provided
      by the telomerase reverse transcriptase (TERT). This step might require the
      formation of guanine-rich secondary structures in the nascent product. Results
      from numerous studies begin to delineate TERT sub-domains that orchestrate these
      events and support the model of cooperative action between distinct active sites
      within telomerase multimers. Natural telomere substrates are protein-DNA
      complexes that show an asymmetry between the two ends of a chromosome, possibly
      reflecting their differential mode of replication.

PMID- 12417134
TI  - Nuclear export of ribosomal subunits.
AB  - The partitioning of cells by a nuclear envelope ensures that precursors of
      ribosomes do not interact prematurely with other components of the translation
      machinery. Ribosomal subunits are assembled in nucleoli and exported to the
      cytoplasm in a CRM1/Ran-GTP-dependent fashion. Export of the large (60S) subunit
      requires a shuttling adaptor protein, NMD3, which binds to mature, correctly
      folded subunits. Immature or defective particles do not bind NMD3 and thus are
      excluded from the export pathway. This structural proofreading is extended into
      the cytoplasm, where it is believed that several energy-requiring steps release
      shuttling factors from the subunit, allowing it to function in translation.

PMID- 12417135
TI  - Affordable biocomputing for everyone: using the Internet, freeware and open
      source software.
AB  - How to build your own complete working biocomputing platform with nothing more
      than a desktop computer and an Internet connection.

PMID- 12417136
TI  - New electron microscopy database and deposition system.
AB  - To manage, organize and disseminate data on the structure of biological
      macromolecules solved by 3D electron microscopy, an electron microscopy database
      has been set up at the European Bioinformatics Institute.

PMID- 12417140
TI  - Revealing micro-RNAs in plants.
AB  - Recent work has resulted in the identification of >100 endogenous non-coding
      small RNA molecules in plants. These micro-RNAs (miRNAs) have the capacity to
      regulate a range of predicted target mRNAs, many of which are transcription
      factors involved in the control of meristem identity. Mutants defective in either
      CARPEL FACTORY or Hen1 fail to accumulate miRNAs and have severe developmental
      defects. Thus, miRNAs are implicated as potentially key regulatory molecules in
      plant development.

PMID- 12417141
TI  - A new class of lipid desaturase central to sphingolipid biosynthesis and
      signalling.
AB  - Sphingolipids and their phosphorylated metabolites play crucial roles in
      intracellular signalling in animals, and evidence is emerging for analogous
      situations in fungi and plants. Central to this signalling pathway is the
      phosphorylation of the sphingoid long chain base, sphingosine, which yields
      sphingosine-1-phosphate. Until recently, the enzyme responsible for the
      biosynthesis of sphingosine was unknown, but the Delta(4)-long chain base
      desaturase that carries out this reaction has now been identified. Orthologues
      are present in animals, plants and fungi, raising the possibility of using
      reverse genetics to determine the contribution of sphingosine-1-phosphate to
      signalling networks.

PMID- 12417142
TI  - Function of the alternative oxidase: is it still a scavenger?
AB  - The alternative oxidase is a respiratory chain protein found in all higher
      plants, fungi, non-fermentative yeasts and trypanosomes. Its primary structure
      suggests that it is a new member of the di-iron carboxylate protein family.
      Recent sequence analysis indicates an evolutionary relationship between primitive
      members of this protein family and the alternative oxidase, suggesting that its
      early function was to scavenge di-oxygen. However, modelling of plant growth
      kinetics suggests a different function.

PMID- 12417148
TI  - DICER-LIKE1: blind men and elephants in Arabidopsis development.
AB  - Genetic studies of embryo, ovule and flower development in Arabidopsis thaliana
      have led to the independent isolation of different mutant alleles of a single
      gene (SIN1/SUS1/CAF, now renamed DCL1) that encodes a complex RNA-processing
      enzyme. DCL1 shows similarity to the Dicer group of genes, which are required for
      RNA silencing in Drosophila and Caenorhabditis. These recent findings identify a
      novel but conserved mechanism of post-transcriptional gene regulation that is
      important for development in eukaryotes.

PMID- 12417149
TI  - Formins: intermediates in signal-transduction cascades that affect cytoskeletal
      reorganization.
AB  - The control of cell growth and polarity depends on a dynamic actin cytoskeleton
      that has the ability to reorganize in response to developmental and environmental
      stimuli. In animals and fungi, formins are just one of the four major classes of
      poly-L-proline-containing (PLP) proteins that form part of the signal
      transduction cascade that leads to rearrangement of the actin cytoskeleton.
      Analysis of the Arabidopsis genome sequence indicates that, unlike animals and
      fungi, formins are the only class of conserved profilin-binding PLP proteins in
      plants. Moreover, plant formins show significant structural differences compared
      with their animal and fungal counterparts, raising the possibility that plant
      formins are subject to novel mechanisms of control or perform unique roles in
      plants.

PMID- 12417150
TI  - Mutator transposons.
AB  - Mutator (Mu) element insertion has become the main way of mutating and cloning
      maize genes, but we are only beginning to understand how this transposon system
      is regulated. Mu elements are under tight developmental control and are subject
      to a form of epigenetic regulation that shares some features with the regulation
      of paramutable maize genes. Mu-like elements (MULEs) are widespread among
      angiosperms, and multiple diverged functional variants appear to have coexisted
      in genomes for long periods. In addition to its utility, the means by which this
      widespread and highly mutagenic system is held in check should help us to address
      fundamental issues concerning the stability of genomes.

PMID- 12417151
TI  - The plant E2F-Rb pathway and epigenetic control.
AB  - Plants and animals use the E2F-Rb pathway as a major mechanism of control in the
      decision to continue or stop cell division. The E2F-Rb pathway controls the G1-to
      S-phase transition by the timely activation of genes involved in DNA synthesis
      and cell-cycle control. Recent findings reveal that the E2F-Rb pathway
      communicates with chromatin-remodelling factors in the control of transcription
      and cell-cycle progression. This article highlights the fast-moving advances in
      the molecular and functional characterization of plant E2F proteins, and in our
      understanding of how the E2F-Rb pathway is activated and repressed.

PMID- 12417152
TI  - Evolution of signal transduction in intracellular symbiosis.
AB  - Plant roots form intracellular symbioses with fungi and bacteria resulting in
      arbuscular mycorrhiza and nitrogen-fixing root nodules, respectively. A novel
      receptor like-kinase has been discovered that is required for the transduction of
      both bacterial and fungal symbiotic signals. This kinase defines an ancient
      signalling pathway that probably evolved in the context of arbuscular mycorrhiza
      and has been recruited subsequently for endosymbiosis with bacteria. An ancestral
      symbiotic interaction of roots with intracellular bacteria might have emerged
      from such a recruitment, in the progenitor of the nodulating clade of plants.
      Analysis of symbiotic mutants of host plants and bacterial microsymbionts has
      revealed that present-day endosymbioses require the coordinated induction of more
      than one signalling pathway for development.

PMID- 12417155
TI  - Effect of thermal injury on relative anaplerosis and gluconeogenesis in the rat
      during infusion of [U-13C] propionate.
AB  - A new approach for the analysis of hepatic metabolism after burn injury is
      introduced. Relative anaplerotic, pyruvate recycling and gluconeogenic fluxes
      were measured by 13C NMR isotopomer analysis of blood glucose from rats with 40%
      body surface area injury, and from rats exposed to sham injury. A short chain
      fatty acid, [U-13C] propionate which is avidly extracted by the liver, was
      infused intravenously to deliver 13C into the citric acid cycle. There was no
      difference in the multiplets detected in the glucose carbon-2 (C-2) anomer from
      blood or liver after 45 or 60 min of infusion of propionate, indicating that
      steady-state isotopic conditions were achieved. Gluconeogenesis relative to
      citric acid cycle flux was not altered by burn injury; in both sham and burn
      groups the rate of glucose production was about equal to flux through citrate
      synthase. In the sham group of animals the rate of entry of carbon skeletons into
      the citric acid cycle was about four times citric acid cycle flux in animals
      after thermal injury. Similarly, flux through pyruvate kinase (again relative to
      citrate synthase) was significantly increased in burn injury.

PMID- 12417156
TI  - Deficient transforming growth factor beta and interleukin-10 responses contribute
      to the septic death of burned patients.
AB  - In order to understand the roles of pro-inflammatory and anti-inflammatory
      cytokines in burn injury and sepsis post-burn, serial changes in serum levels of
      transforming growth factor beta-1 (TGF-beta-1) were determined and compared to
      those of IL-6 and IL-10 in 15 burned patients. Among these 15 patients, 8
      recovered without sepsis. The other seven, who were septic, expired. Our results
      showed that an initial peak serum TGF-beta-1 response was detected within 1 day
      post-burn. Peak serum IL-6 and IL-10 responses were also detected within 4 days
      after the burn injury of these patients. Significant differences in peak serum IL
      6, IL-10 and TGF-beta-1 levels were not found between patients with total body
      surface area (TBSA) of greater or less than 50% and between patients who survived
      or expired from burn injury. Afterwards, levels of circulating IL-6 and IL-10
      remained low in the survivors. However, a second peak response in serum TGF-beta
      1 levels was observed in all burned patients analyzed. The second peak serum TGF
      beta-1 levels post-burn of the eight survivors and the seven non-survivors were
      from 28,542 to 76,554 pg/ml (a mean value of 51,256+/-14,264 pg/ml) and from 8616
      to 40,851 pg/ml (a mean value of 24,079+/-10,399 pg/ml), respectively. A
      significant difference (P<0.01) in mean values of the second peak TGF-beta-1
      responses between groups of survivors and non-survivors was detected. Levels of
      circulating IL-6 in the septic non-surviving patients showed a tendency to
      increase 1-2 weeks post-burn and reached high levels before the expiration of
      these patients. After an initial peak response, the serum IL-10 level remained
      low in one of the seven non-survivors, while it increased in the other six non
      survivors. However, marked increases in circulating IL-10 levels were observed
      only just before the death of these non-survivors. In conclusion, an initial
      increase in serum levels of IL-6, IL-10 and TGF-beta-1 was detected post-burn. A
      marked increase in serum levels of IL-6 before death suggests its role in the
      pathophysiology of sepsis in burned patients. In addition, a low secondary TGF
      beta-1 response and a lack and/or delay in the increase of circulating IL-10 in
      the non-survivors may all contribute to the pathophysiology of septic death in
      burned patients.

PMID- 12417157
TI  - Health status in Swedish burn patients. Assessment utilising three variants of
      the Burn Specific Health Scale.
AB  - Perceived health in a consecutive group of major burn patients treated at the
      Uppsala University Hospital Burn Unit from 1980 to 1995 is reported. The three
      published variants of the Burn Specific Health Scale (BSHS), i.e. BSHS
      Abbreviated (BSHS-A); BSHS-Revised (BSHS-R); BSHS-Brief (BSHS-B) were used in
      concert for this purpose in order to allow for a comparison of the instruments.
      Two hundred and forty-eight of 350 former patients (response rate 70.9%; mean
      total body surface area (TBSA) 23.1% (S.D.=16.2%)) responded to 94 items from
      previous versions of the BSHS at a mean of 9.3 (S.D.=4.8) years after injury. All
      three versions of the BSHS gave similar results with respect to global outcome on
      a group level. Correlations among the three different instruments were high, but
      were strongest between BSHS-B and BSHS-R (r=0.99). The largest impact on health
      was seen for Role Activities in BSHS-A, and Heat Sensitivity and Work in both
      BSHS-R and BSHS-B. There were significant relationships between sociodemographic
      variables (e.g. work, partnership and living) and self-reported outcome. Men
      reported better overall outcome than women did. The presence of a full thickness
      burn was associated with worse outcome with respect to several domains. The
      apparent variability in outcome pattern between different domains underscores the
      importance of utilising a broad instrument with adequate content validity.

PMID- 12417158
TI  - Post-traumatic stress disorder in burned patients.
AB  - The essential feature of post-traumatic stress disorder is the development of
      characteristic symptoms following exposure to a traumatic stressor involving
      direct personal experience of an event that involves threat of death oactual r
      serious injury, or other threat to one's physical integrity; or witnessing an
      event that involves death, injury, or a threat to physical integrity of another
      person; or learning about unexpected or violent death, serious harm, or threat of
      death or injury experienced by a family member or other close associate (DSM IV).
      The aim of this work is to assess the prevalence of post-traumatic stress
      disorder (PTSD) among the burned victims and its predicting factors. METHODS:
      Patients were recruited at the Burns Department in the Ibn Rushd University
      Hospital during the period between 1 October 1998 and 1 October 1999. All
      patients were psychiatrically interviewed and answered a questionnaire. The
      diagnosis of PTSD was done according to DSM IV criteria. Results were analyzed on
      Epi info software. RESULTS: Sixty patients gave their consent to participate in
      this study. The 23.3% met criteria for PTSD and 55% for major depressive
      disorder. In short, PTSD was related to age, explosion of gas containers for
      cooking purposes, depression and low social functioning. Otherwise, no
      relationship was found between PTSD and gender, length of hospitalization or
      severity of burn. CONCLUSION: Post-traumatic stress disorder remains a poorly
      known entity by clinicians and under-diagnosed in burned patients. Considering
      the frequency of this pathology, an anti-depressant treatment and a
      psychotherapeutic relationship are necessary to improve the health and the
      quality of life of these patients.

PMID- 12417159
TI  - Chemical assaults in Hong Kong: a 10-year review.
AB  - The aim of this study was to assess the patients admitted to Prince of Wales
      Hospital Burns Unit, Hong Kong between September 1991 and August 2001 following
      chemical assault. A total of 2319 burns were admitted during the study period of
      which 19 had been subjected to chemical assault. All victims sustained a burn
      injury to the head and neck area and 47% of victims' eyes were burnt. A total of
      84% required surgical intervention. Where a reason for the attack was admitted
      most were due to relationship difficulties. This study has defined the victims of
      chemical assault in Hong Kong. At a time when the overall number of assaults in
      Hong Kong is at its lowest level for 5 years it is of concern that there appears
      to have been a recent increase in the number of chemical assaults in Hong Kong.

PMID- 12417160
TI  - Gunpowder explosion burns in fireworks factory: causes of death and management.
AB  - The mortality rate of gunpowder explosion burns from fireworks factory accidents
      was high. The aim of this study was to evaluate the impact of different
      managements on outcome of these burns patients and to optimize treatment measures
      and decrease the morbidity and mortality. During the period from January 1987 to
      December 1999 in our center, 44 patients burned in gunpowder explosions died.
      Fifty sex-, age-, TBSA- and full-thickness-matched patients who survived were
      selected randomly as a comparison group. Data on time and causes of death, fluid
      resuscitation, and management of inhalation injury, associated injuries and wound
      were collected. Half of the deaths occurred during the first week after burn. The
      commonest cause of death was sepsis (27 patients), followed by MODS (11
      patients), then hypovolaemic shock (4 patients) and pulmonary infection (2
      patients). Thirty-six dead patients and 10 surviving patients had received
      insufficient fluid resuscitation and developed severe shock. Prophylactic
      tracheotomy was undertaken in 15 patients, of whom 6 died. Thirty-two patients
      had undergone emergency tracheotomies, of which 29 died. All associated injuries
      had been well-managed and no death was related to associated injuries or their
      complications directly. In the group of patients who died, 20 had undergone early
      excision (within 1 week of injury) and grafting. The number of patients in the
      survivor group who underwent early excision and grafting was 31. These results
      indicate that the sepsis and MODS are the two commonest causes of death for the
      patients who sustained burns by gunpowder explosions in fireworks factory. The
      optimal managements of this type of burn are as follows: (1) sufficient fluid
      resuscitation and invasive monitoring if necessary; (2) prophylactic tracheotomy
      and mechanical ventilation for the patients whose upper-airway edema is present
      or airway patency is threatened; (3) early excision and grafting of lager-deep
      wounds and covering with allograft with microautograft (1:10); (4) life
      threatening associated injuries must be treated immediately after admitting.

PMID- 12417161
TI  - Benefit-cost analysis of moist exposed burn ointment.
AB  - Burn injury is one of the most devastating injuries that may affect a patient.
      Even in economically deprived areas, burn care is largely driven by relatively
      plentiful resources equating quality of care with generous monitoring and
      clinical attention with little concern to management cost. Burn care costs have
      been the subject of very few investigations and are among the least studied by
      health services researchers. Nevertheless, it can be stated that local care of
      burn wounds accounts for a large proportion of the cost per day for treating
      patients. As economic times are changing and as market penetration of managed
      care contracts and stiff competition in the health care industry gains momentum,
      ways to reduce expenditures without adversely affecting the quality of care have
      become of primary importance. We report a randomized prospective comparative
      study analyzing the benefit-cost value of moist exposed burn ointment (MEBO)
      application, an exposed method for burn wound care without the need for a
      secondary covering dressing, as compared to conventional closed methods.

PMID- 12417162
TI  - Management of the burned trauma patient: balancing conflicting priorities.
AB  - PURPOSE: Approximately 5% of multiple trauma patients sustain concomitant burns.
      Complicated management issues arise in these patients as burn and trauma care
      often conflict. This study reviews 53 consecutive burned multiple trauma patients
      in order to examine common management conflicts and recommend appropriate
      compromises in caring for these difficult patients. PROCEDURE: A retrospective
      review of 53 consecutive burn patients with coincident trauma admitted to The
      Massachusetts General Hospital (MGH) from 1993-2001 was performed. FINDINGS: In
      the study period, 53 patients were admitted to the Massachusetts General Hospital
      with concomitant burns and trauma. Of this group, 42 (79%) were male. Average age
      was 31.5 +/- 15.0. Mechanisms included 11 motor vehicle collisions (MVC), 10
      explosions, 10 electrocutions with subsequent falls, nine house fires, four
      motorcycle collisions (MCC), three pedestrian versus car accidents, two falls
      into fires, two plane crashes, and one each of a lawnmower accident and a patient
      drawn into a machine. Average burn size was 25.4% +/- 22.4. The most common
      traumatic injury was fracture (52). Management of fractures in burn patients and
      resuscitation in head injured burn patient represented the most common conflicts
      in patient care. There were five deaths (9.4%) in this series. CONCLUSIONS: Burns
      are a rare but significant complication in the trauma patient. Outcomes are
      dependent on rapid trauma evaluation as well as effective resuscitation and wound
      management. Given the complexities of their problems, these patients necessitate
      a balanced multidisciplinary approach to maximize their potential for full
      recovery. Thoughtful compromise between trauma and burn priorities is frequently
      necessary.

PMID- 12417163
TI  - An amphoteric rinse used in the emergency treatment of a serious ocular burn.

PMID- 12417164
TI  - Use of the medial adipofascial flap of the leg for coverage of full-thickness
      burns exposing the tibial crest.
AB  - Bone exposure constitutes a frequent and difficult problem in burn patients.
      Where free flaps remain indicated in tibial osteomyelitis, a pedicled fascial or
      adipofascial flap provides an excellent alternative for coverage of simple tibial
      crest exposure. In fact, the adipofascial tissue of the anteromedial aspect of
      the leg can be mobilized over the whole length of the tibia. It is vascularized
      by the saphenous artery and the posterior tibial artery perforators. This pattern
      of blood supply allows a wide range of use for any size of burn defect in this
      area. Therefore, this local pedicled flap provides an excellent solution for
      coverage of the exposed tibia after severe burns.

PMID- 12417165
TI  - Facial reconstruction using the visor scalp flap.
AB  - In male burn victims, scar may cause grotesque disfigurement to the upper lip and
      lower face. There are many ways to address the problem, for simple skin grafting
      to complex flaps. Bipedicle scalp flaps are used sporadically for reconstruction
      of the upper lip. In this article, the use of bitemporal artery hair-bearing flap
      for reconstruction of the moustache and beard area in nine cases as a substitute
      for facial deformed skin is described. The results indicate that the scalp flap
      is one of the best-matched flaps for reconstruction of the mid and lower part of
      the male face. As a result of choosing the proper size of the flap, use of the
      tissue expander is omitted, the donor site may be closed primarily and early
      return of the patient to normal life is guaranteed. Although, the width of the
      flap is not sufficient enough to cover the whole lower face and the cheeks, it is
      enough to imitate a normal face and give a pleasant appearance.

PMID- 12417166
TI  - The use of tourniquets in the excision of unexsanguinated extremity burn wounds.
AB  - PURPOSE: Tangential excision of burns is complicated by blood loss. Tourniquet
      use decreases blood loss, but adequacy of excision has been questioned. An
      attempt was made to assess the value of not exsanguinating the limb prior to
      tourniquet inflation to improve visualization of bleeding points and subsequent
      engraftment. METHODS: Eleven excisions of bilateral extremity wounds were
      performed. One limb was excised without the benefit of a tourniquet, the other
      with tourniquet but without exsanguination. Tangential excision was performed,
      hemostasis achieved, and blood loss quantified. Engraftment of skin was assessed
      at first dressing change and at initial follow-up after discharge. RESULTS: Area
      of burn was the same, 4.8% with tourniquet, 5.1% without (P=0.38). Overall blood
      loss was less with tourniquet control, 100-259 cm(3) (P=0.002); as was blood loss
      per area, 0.19-0.58 cc/cm(2) (P=0.04). Graft take was similar, 98.2% early and
      98.1% later with tourniquet, with 98.2 and 96.8% take without (P>0.1).
      CONCLUSIONS: Tourniquet use in the unexsanquinated extremity reduced blood loss
      without affecting engraftment.

PMID- 12417167
TI  - Pre-fabricated lined axial flaps for reconstruction of extensive post-burn facial
      and forehead full-thickness composite defects.
AB  - From January 1996 to February 1998, three patients who suffered extensive post
      burn facial and forehead composite defects were treated successfully in our Burn
      Unit. The delto-pectoral flap and reverse radial forearm flap were pre-fabricated
      with lining of free split skin grafted onto the underside of the flap. The pre
      fabricated flaps were sutured in situ for 2 approximately 3 weeks. The pre
      fabricated lined axial flaps were then transferred for the reconstruction of
      facial and forehead composite defects. The flap had good blood supply and the
      wounds healed by first intention. The three cases presented all achieved
      satisfactory functional and aesthetic results. The results show that pre
      fabricated lined axial flaps for the reconstruction of extensive facial and
      forehead composite defects are safe, effective and relatively easy for clinical
      application.

PMID- 12417168
TI  - Before the paradigm shift: concepts and communication between doctors and nurses
      in a burns team.
AB  - The evolution of care delivered by a multidisciplinary burns team is a function
      of the effectiveness of the professional communication between team members. In
      this exercise, we have explored concepts and communication between nurses and
      doctors in a burns team. Loosely structured weekly meetings were held over a 4
      month period. The explicit objective was to determine and define the current
      model of burns care in a regional burn centre. The implicit objective, however,
      was to develop a mutual appreciation of actual and potential problems in
      communication. Consensus task identification was achieved at the end of each
      meeting with full compliance in completing the tasks before the next meeting.
      Although there was a unanimous commitment to the team concept, traditional,
      professional, paradigms persist. For nurses, the concept of holistic modelling
      predominated, whilst the disease centred paradigm remained the focus of medical
      modelling. Linguistic, cultural and professional barriers to effective
      communication were identified but did not readily conform to prior expectations.
      Experience in burns care can transcend these barriers more effectively than a
      common culture or profession. In conclusion, team work and team building is a
      complex process that can benefit from an ongoing process of re-evaluation. An
      obvious yet common error is to assume a level of mutual understanding that does
      not in fact exist. Stepping aside to re-explore fundamental principles on which
      team members base their personal and professional practice can help in
      elucidating and determining new paradigms of care, which can be evaluated and
      appropriately implemented. The consensus conclusion was that this approach was a
      very valuable investment in time in pursuing excellence in the field of burns
      care.

PMID- 12417169
TI  - Emergence of resistance of vancomycin-resistant Enterococcus faecium in a thermal
      injury patient treated with quinupristin-dalfopristin and cultured epithelial
      autografts for wound closure.
AB  - Vancomycin-resistant Enterococcus faecium and faecalis (VRE) remains a major
      complication among critically ill patients. A 26-year-old patient with 65% total
      body surface area burns (TBSA) was infected with several E. faecium strains
      during his admission that were resistant to vancomycin. Because chloramphenicol
      was the standard treatment at this time, this drug was initiated until, the
      organism was identified as E. faecium and reported as susceptible to quinupristin
      dalfopristin. Given these data, it was then decided to discontinue the
      chloramphenicol therapy. Quinupristin-dalfopristin therapy resulted in initial
      reduction of fever and white blood cell counts that continued over the next 5
      days. However, on day 7 of quinupristin-dalfopristin therapy, a return of fever
      and elevation of the white blood cell count was noted and a repeated E. faecium
      blood culture demonstrated sudden resistance to quinupristin-dalfopristin (Bauer
      Kirby zone size <14 mm). Chloramphenicol was restarted and the patient improved
      slowly over a period of 16 days. Our indigenous VRE had limited exposure to
      quinupristin-dalfopristin in the recent past; however, resistance emerged with
      the first commercial use of this agent in our burn treatment center. High-dose
      chloramphenicol treatment did not appear to impair engraftment of cultured
      epithelial autografts (CEA) in this patient.

PMID- 12417170
TI  - Myelopathy following high voltage electrical injury: a case report.

PMID- 12417171
TI  - Marjolin's ulcer on the nose.
AB  - Malignancies in scars are generally known as Marjolin's ulcer. The majority of
      these arise from burn injuries. Although Marjolin's ulcer consists of all kinds
      of skin cancer, squamous cell carcinoma is the main cancer type reported in the
      literature. The pathogenesis of this tumor is due to chronic irritation of the
      effected area and mostly involves the extremities and scalp area. This report
      presents an unusually located and rare type of Marjolin's ulcer: on the nose and
      baso-squamotic in type. A 54-year-old man, 33 years after burn, presented with an
      unhealed ulcer on his nose which had been present for 2 years. The case was
      managed by tumor excision and a naso-labial transposition flap. To our knowledge,
      this is the first report of Marjolin's ulcer developing on post-burned skin of
      the nose.

PMID- 12417172
TI  - In vitro effects of ascorbate and Trolox on the biocompatibility of dental
      restorative materials.
AB  - Previous in vitro studies on the cytotoxicity of eight dental restorative
      materials including composites, compomers, resin-modified glass ionomer cements
      and glass ionomer cements have demonstrated a depletion of intracellular
      glutathione in gingival fibroblasts incubated with eluates of these materials and
      a protective effect of N-acetylcysteine. In the present study, we investigate the
      effects of two other antioxidants: ascorbate and Trolox. It was found that Trolox
      reduced the cytotoxicity induced by resin-based biomaterial eluates. In contrast,
      ascorbate increased in a dose-dependent manner the toxic effect of all eluates
      except for Z100 MP and Tetric flow (composites). The effect of D-mannitol was
      studied for GC FUJI II and was found to neutralize the additional toxic effect of
      ascorbate. Ascorbate increased the depletion of intracellular glutathione of
      these dental material eluates (between 17% and 24%, depending on the material).
      Quantification of metal ions in the dental material eluates showed the presence
      of significant amounts of aluminum and iron in GC FUJI II > photac fil > GC FUJI
      II LC > F2000. The mechanism of this increased cytotoxicity could be explained by
      the Fenton reaction resulting from the pro-oxidant effect of ascorbate in the
      presence of iron (transition metal ions) and/or aluminum.

PMID- 12417173
TI  - A hydrogel prepared by in situ cross-linking of a thiol-containing poly(ethylene
      glycol)-based copolymer: a new biomaterial for protein drug delivery.
AB  - A new poly(ethylene glycol)-based copolymer containing multiple thiol (-SH)
      groups was cross-linked in situ to form a polymer hydrogel under mild conditions.
      No organic solvent, elevated temperature, or harsh pH is required in the
      formulation or patient administration processes, making it particularly useful
      for delivery of fragile therapeutics, such as proteins. The in vitro release of
      fluorescein-labeled bovine serum albumin and the in vivo release of the model
      proteins, erythropoietin, RANTES and three PEG-conjugated RANTES derivatives
      showed sustained release for 2-4 weeks and demonstrated prolonged biological
      activity of the released proteins in animals.

PMID- 12417174
TI  - In vitro corrosion behaviour and osteoblast response of thermally oxidised
      Ti6Al4V alloy.
AB  - In this work, the influence of thermal oxidation treatments of Ti6Al4V at 500
      degrees C and 700 degrees C for 1 h on the in vitro corrosion behaviour and
      osteoblast response is studied. The potential of these treatments, aimed to
      improve the wear surface performance as biomaterial, relies in the formation of
      an outer "ceramic" layer of rutile. The corrosion behaviour was evaluated in
      simulated human fluids by electrochemical impedance spectroscopy and anodic
      polarisation tests. The effect of these thermal oxidation treatments on
      osteoblastic behaviour was studied in primary cultures of human osteoblastic
      cells. Results show that thermal oxidation treatments do not decrease the high in
      vitro corrosion resistance of the Ti6Al4V alloy. Osteoblast adhesion studies
      indicate that thermal oxidation treatments do not impair the material
      biocompatibility. Moreover, the thermal oxidation at 700 degrees C enhances the
      in vitro osteoblastic cell attachment compared to the thermal oxidation at 500
      degrees C.

PMID- 12417175
TI  - Development of a bioluminescent ATP assay to quantify mammalian and bacterial
      cell number from a mixed population.
AB  - Modification of biomaterial surfaces is one approach aimed at improving cellular
      interactions and the subsequent integration of medical devices into the body.
      However, by optimising surfaces to enhance mammalian cell adhesion there is the
      potential risk that adhesion of bacteria will also be increased. Bacterial
      colonisation of biomaterials can be problematic as infection often results in
      morbidity and the consequent removal of the failing device from the body.
      Currently, quantifying cellular adhesion from a mixed population of bacterial and
      mammalian cells can only be determined by slow and laborious methods such as
      microscopy. ATP is a key molecule in the metabolism of both mammalian and
      bacterial cells and can be used to quantify cell numbers. In this study, we have
      modified a bioluminescence-based ATP assay to enable the differential measurement
      of both mammalian and bacterial cell ATP levels within the same culture. Mixed
      populations of Staphylococcus epidermidis and 3T3 fibroblasts were assessed both
      in suspension and adhered to a surface. ATP levels from cultures in suspension
      were selectively extracted and measured from both cell types, revealing a linear
      trend that would enable the differentiation of cell numbers from a mixed
      population. The application of the assay to adhered mixed cultures also allowed
      differences in ATP levels from both cell types to be distinguished. The data
      presented reveals that this assay would be useful for the rapid screening of
      cellular adhesion to modified surfaces although, its use in detecting subtle
      differences in ATP levels may be limited due to natural interactions between the
      two cell types.

PMID- 12417176
TI  - Liquid- and solid-state high-resolution NMR methods for the investigation of
      aging processes of silicone breast implants.
AB  - To investigate aging processes of silicone gel breast implants, which may include
      migration of free unreacted material from the gel and rubber to local (e.g.
      connective tissue capsule) or distant sites in the body, chemical alteration of
      the polymer and infiltration of body compounds, various approaches of
      multinuclear nuclear magnetic resonance (NMR) experiments (29Si, 13C, 1H) were
      evaluated. While 29Si, 13C, and 1H solid-state magic angle spinning (MAS) NMR
      techniques performed on virgin and explanted envelopes of silicone prostheses
      provided only limited information, high-resolution liquid-state NMR techniques of
      CDCl(3) extracts were highly sensitive analytical tools for the detection of
      aging related changes in the materials. Using 2D 1H, 1H correlation spectroscopy
      (COSY) and 29Si, 1H heteronuclear multiple bond coherence (HMBC) experiments with
      gradient selection, it was possible to detect lipids (mainly phospholipids) as
      well as silicone oligomer species in explanted envelopes and gels. Silicone
      oligomers were also found in connective tissue capsules, indicating that cyclic
      polysiloxanes can migrate from intact implants to adjacent and distant sites.
      Furthermore, lipids can permeate the implant and modify its chemical composition.

PMID- 12417177
TI  - Crystalline and dynamic mechanical behaviors of synthesized poly(sebacic
      anhydride-co-ethylene glycol).
AB  - A novel biomaterial: poly(sebacic anhydride-co-ethylene glycol) was synthesized
      by introducing poly(ethylene glycol) (PEG) into a polyanhydride system. This
      copolymer was synthesized using sebacic acid and PEG via melt-condensation
      polymerization. The crystalline behavior of these synthesized products was
      studied, and compared to that of polymer blends of poly(sebacic anhydride) (PSA)
      and PEG. The crystallinity of PSA chain segments can be significantly enhanced by
      increasing chain mobility via the introduction of PEG. The crystallinity of the
      PSA component in copolymers was substantially greater than that of blends.
      However, the crystalline growth of the PEG segments was totally hindered by the
      presence of PSA chain segments, such that no crystal for PEG component was found
      in these copolymers. Besides, a dynamic mechanical analysis of these materials
      was also performed to provide additional information concerning visco-elastic
      behavior for other biomedical applications, where it was found that the viscous
      behavior in copolymers was more significant than in neat PSA and PEG.

PMID- 12417178
TI  - Toxic characteristics of methoxy poly(ethylene glycol)/poly(epsilon-caprolactone)
      nanospheres; in vitro and in vivo studies in the normal mice.
AB  - Amphiphilic diblock polymeric nanospheres composed of methoxy poly(ethylene
      glycol) (MePEG) and poly(epsilon-caprolactone)(PCL) was prepared for application
      as a novel drug carrier. We could obtain the MePEG/PCL nanospheres that exhibited
      an average diameter of less than 200 nm with narrow size distribution and a
      relatively high drug-loading efficiency of about 41.98% and 20.8% for
      indomethacin and paclitaxel, respectively. To estimate the toxicity of
      nanospheres, we investigated cytotoxicity using the normal human fibroblast, the
      median lethal dose (LD(50)) and various organ toxicities using male ICR mice. The
      indomethacin-loaded nanosphere showed higher cell viability than indomethacin in
      the cytotoxicity test using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium
      bromide (MTT) assay. The LD(50) of MePEG/PCL nanospheres determined by Litchfield
      Wilcoxon method was 1.47 g/kg. After the mice were intraperitoneally injected
      with MePEG/PCL nanospheres as a half-dose level of LD(50) for 7 days, no
      significant histopathologic changes were observed in MePEG/PCL nanospheres
      treated mice compared with normal mice in the light and electron microscopic
      observations of various organs such as heart, lung, liver and kidney. It was
      suggested that MePEG/PCL nanospheres might be useful candidate as a novel
      injectable drug carrier for hydrophobic drugs such as indomethacin and
      paclitaxel.

PMID- 12417179
TI  - Proteins incorporated into biomimetically prepared calcium phosphate coatings
      modulate their mechanical strength and dissolution rate.
AB  - In a previous investigation, we demonstrated that when bovine serum albumin (BSA)
      is biomimetically co-precipitated with Ca(2+) and PO(4)(3-) ions upon titanium
      alloy implants, it becomes incorporated into the crystal lattice and is not
      merely deposited on its surface. Moreover, the protein elicited a change in
      crystal structure from an octacalcium phosphate type to a carbonated apatite one,
      which bears a closer resemblance to natural bone mineral. In the present study,
      we investigated the dissolution rate and mechanical strength of such BSA
      containing coatings as a function of protein concentration within the bathing
      medium (10 ng/ml to 1.0 mg/ml). BSA-containing coatings released Ca(2+) ions more
      slowly (5 ppm/min) than did non-BSA-containing ones (10 ppm/min), but this rate
      did not change as a function of protein concentration within the bathing medium.
      In contrast, the strength of coatings increased almost linearly as a function of
      protein concentration within the bathing medium, indicating that BSA incorporated
      into the crystal lattice enhances its mechanical strength in a concentration
      dependent manner.

PMID- 12417180
TI  - An ultrasonic pulse-echo technique for monitoring the setting of CaSO4-based bone
      cement.
AB  - We present a new ultrasonic technique for monitoring the entire setting process
      of injectable bone cement. The problem with existing standards is their
      subjectivity. Because of this the results are not comparable between different
      research groups. A strong advantage with the proposed technique is that it is non
      invasive and non-destructive, since no manipulation of the cement sample is
      needed once the measurement has started. Furthermore, the results are
      reproducible with small variations. The testing was performed on calcium sulfate
      cement using an ultrasonic pulse-echo approach. The results show that the
      acoustic properties of the cement are strongly correlated with the setting time,
      the density, and the adiabatic bulk modulus. The measured initial and final
      setting times agree well with the Gillmore needles standard. An important
      difference compared to the standards, is that the technique presented here allows
      the user to follow the entire setting process on-line.

PMID- 12417181
TI  - Gentamicin release from modified acrylic bone cements with lactose and
      hydroxypropylmethylcellulose.
AB  - Modified polymethylmethacrylate (PMMA) bone cements formulations were prepared by
      including different proportions of gentamicin and release modulators such as
      lactose or hydroxypropylmethylcellulose (HPMC). Surface aspect, gentamicin
      release and porosity of these modified formulations were studied by means of
      scanning electron microscopy (SEM), a specially designed system for the
      dissolution studies of the bone cements, and mercury intrusion porosimetry.
      Lactose modified cements presented an irregular surface with numerous hollows and
      voids due to the lactose dissolution. HPMC cements presented a characteristic
      laminated and flaky surface. The drug release of lactose formulations was up to
      four-fold greater (13%) than the commercial bone cement CMW1 Gentamicin one (3%).
      The amount of gentamicin eluted at the first withdrawn sample ranged from 30% to
      60% of total gentamicin released over the assay. Gentamicin release from lactose
      formulations increased as lactose percentage was increased which agree with the
      porosity results. Nevertheless, the use of release modulator HPMC increased
      porosity, but did not produce an increase in the gentamicin release. HPMC
      dissolution creates a surrounding sticky and viscous medium similar to a gel that
      makes the gentamicin release from the cement matrix difficult.

PMID- 12417182
TI  - An in vitro model of pericardial tissue healing.
AB  - INTRODUCTION: A previous study in our laboratory showed that a flap of fresh
      autologous pericardium bisecting the aorta of sheep retracted and became
      fibrotic. Histologic analyses suggested that activated cells within the
      pericardium contributed to the retraction of the implant. Here we report the
      development of an in vitro model to investigate the effects of serum on cellular
      proliferation and cell-mediated tissue contraction. METHODS: Sections of living
      and ethanol-treated sheep pericardium were incubated with 0.5%, 5%, 10%, 20%, and
      50% serum in medium for up to 8 days and evaluated for cellular proliferation and
      tissue contraction. These serum-stimulated events were further evaluated in the
      presence of Mitomycin C, Cytochalasin B and D, Aphidicolin, AraC, and
      Cycloheximide. RESULTS: Cellular proliferation and cell-mediated tissue
      contraction were induced by serum in a dose-dependent manner. Expression of PCNA
      was suppressed in the presence of Cytochalasin B, Cytochalasin D, Aphidicolin,
      and AraC. Tissue contraction was prevented by Cycloheximide. Mitomycin C
      inhibited both proliferation and tissue contraction. Ethanol-treated tissue,
      which was absent of living cells, did not respond to stimulation with serum.
      CONCLUSIONS: An in vitro model was developed to study the responses of cells
      within pericardial tissues to stimulation by serum. In this model, serum induced
      cellular proliferation and tissue contraction. Different chemical inhibitors
      independently modulated these serum-stimulated events. Pre-existing cells within
      pericardial tissues might respond to stimulus through differential pathways. This
      model may help to develop methods to make autologous pericardium a clinically
      useful biomaterial.

PMID- 12417183
TI  - TEM and STEM analysis on heat-treated and in vitro plasma-sprayed
      hydroxyapatite/Ti-6Al-4V composite coatings.
AB  - A cogent understanding of the microstructure, and indeed nano-structure, of
      hydroxyapatite (HA) and the interface between Ti-6Al-4V and HA is crucial to its
      appropriateness as a biomaterials. This paper reports the analysis of plasma
      sprayed HA/Ti-6Al-4V composites by transmission electron microscopy (TEM) and
      scanning transmission electron microscopy (STEM) to elucidate the intricate
      nature of the materials following plasma spray processing and in vitro
      evaluation. The novel Ti-6Al-4V/HA composite coating, with approximately 48 wt%
      HA, had demonstrated attractive tensile adhesion strength (approximately 28 MPa)
      and improved Young's modulus (approximately 55 GPa). Experimental results
      demonstrated that amorphous calcium phosphate and fine HA grains were formed
      during rapid splat solidification in the as-sprayed composite coatings. Small Ti
      6Al-4V grains were observed adjacent to the amorphous calcium phosphate. The
      coatings were further heat treated at 600 degrees C for 6 h, and significant
      crystallisation of the amorphous calcium phosphate phase took place. However,
      complete crystallisation was not achieved at this temperature, as the coatings
      invariably contained a small amount of amorphous calcium phosphate phase in some
      local regions. After immersion in simulated body fluid for 2 weeks and 10 weeks,
      TEM and STEM confirmed that the interfaces inside the coating maintained good
      microstructural integrity.

PMID- 12417184
TI  - Fluoride uptake by glass ionomer cements: a surface analysis approach.
AB  - Despite extensive research, the mechanism by which glass ionomer cements take up
      fluoride ions from solution remains unclear. To date, the majority of studies
      have concentrated on measuring the removal of ions from solution. In this study,
      we demonstrate the application of X-ray photoemission spectroscopy and secondary
      ion mass spectrometry to the surface analysis of the cements, after the
      introduction of fluoride either by doping or by immersion. Fluoride ion uptake
      from potassium fluoride solution is correlated with the formation of a surface
      layer which is rich in calcium as well as fluoride.

PMID- 12417185
TI  - The influence of protein adsorption and surface modifying macromolecules on the
      hydrolytic degradation of a poly(ether-urethane) by cholesterol esterase.
AB  - Previous investigations have demonstrated that the inflammatory cell derived
      enzyme, cholesterol esterase (CE) could degrade polyurethanes (PUs) by
      hydrolyzing ester and urethane bonds. Studies that have investigated the
      development of protective coatings for PUs have reported that the polymer
      degradation of polyester-urethanes (PESUs) can be reduced with the use of
      fluorine containing surface modifying macromolecules (SMMs). Since these latter
      studies were carried out in the presence of relatively pure enzyme, it has not
      been shown if SMMs would still provide an enhanced inhibitory effect if surfaces
      were pre-exposed to plasma proteins. This would be more representative of the in
      vivo scenario since protein adsorption would occur before the appearance of
      monocyte-derived macrophages which would be a primary source of esterase
      activities. The current investigation has focused on studying the influence of
      fibrinogen (Fg) as a simple model of protein adsorption in order to assess the
      effect of CE in combination with protein on polyether-urethane (PEU) surfaces.
      The materials were prepared with and without SMMs, and were pre-coated with Fg
      prior to carrying out biodegradation studies. The pre-adsorption of Fg onto the
      modified and non-modified surfaces provided a significant delay in the hydrolytic
      action of CE onto the PEU substrates. However, the effect was gone by 70 days and
      by the 126th day of incubation, both Fg coated and non-Fg coated groups had the
      same level of degradation. The difference between Fg coated and non-coated
      substrates was much smaller for materials containing SMMs. In addition, the pre
      adsorption of Fg did not alter the SMMs' ability to provide a more biostable
      surface over the 4 month incubation period.

PMID- 12417186
TI  - Cell adhesion and cytotoxicity studies over polyanionic collagen surfaces with
      variable negative charge and wettability.
AB  - This work describes the cytotoxicity, and the cell adhesion behavior of K562 cell
      line from human erythroleukemia transfected with the DNA for the alpha(2)beta(1)
      integrin over type-I collagen matrices with variable degree of carboxyl group and
      wettability. The results showed that type-I collagen materials with variable
      degree of carboxyl group prepared by selective hydrolysis of carboxyamide side
      chains of Asn and Gln residues present in the protein, independently from the
      extent of side chain hydrolysis, was characterized by preserved triple helix
      structure for materials with a carboxyl group content up to 87 +/- 17. Imbibition
      and wettability increased linearly with increasing carboxyl group content from 46
      +/- 12 to 87 +/- 17, and no signs of cytotoxicity were detected. Nevertheless, in
      comparison to native collagen, K562 cell adhesion to PACMs was significantly
      improved by factors ranging from 1.60 to 1.47x, with the reduction in cell
      adhesion observed with increasing carboxyl content attributed to a balance
      between the inhibition of increasing negative charge and the stimulation by
      increased wettability. On the other hand, the overall improvement of K562 cell
      adhesion to polyanionic collagen was attributed to the introduction of new
      distinct motifs described as the minimal active recognition sequence for
      alpha(2)beta(1) integrins binding with type-I collagen produced as a result of
      Asn-Gly Glu-Ala alpha2(I)294-297, and Gly Gln-Arg-Gly Val-Val carboxyamide side
      chains hydrolysis.

PMID- 12417187
TI  - The influence of inert packaging on the shelf ageing of gamma-irradiation
      sterilised ultra-high molecular weight polyethylene.
AB  - Ultra-high molecular weight polyethylene (UHMWPE) is used for wear applications
      in total hip prostheses and total knee prostheses. Sterilisation of these
      prostheses is commonly by gamma-irradiation. This process creates reactive free
      radicals in the UHMWPE, greatly increasing its susceptibility to oxidative
      degradation. This study has investigated the influence of air and vacuum
      packaging on the properties of gamma-irradiated UHMWPE (GUR1050) following 3
      years of shelf ageing. The findings indicate that vacuum packaging minimises
      oxidative degradation reactions that occur for UHMWPE during shelf ageing.
      However, gamma-irradiation of vacuum-packaged UHMWPE promotes a degree of cross
      linking. It is proposed that this may enhance the wear performance of UHMWPE.
      Accelerated ageing studies indicate that 3 years of shelf ageing would also seem
      to reduce the susceptibility of gamma-irradiated UHMWPE to oxidative degradation
      upon removal from its vacuum packaging.

PMID- 12417188
TI  - Protein adsorption onto two bioactive glass-ceramics.
AB  - Recent research suggests that the biocompatibility of an implant is to a large
      extent determined by selective adsorption of proteins from surrounding body
      fluids. Protein adsorption from human plasma onto two bioactive glass-ceramics
      (RKKP and AP40) which differ in La and Ta content, was studied by means of
      chromatography and two-dimensional polyacrylamide gel electrophoresis (2D-PAGE).
      The quantitative analysis showed that the glass-ceramics have good protein
      binding capacities indicating multilayer formation. A correlation between
      chemical composition and the amount of adsorbed proteins was observed. The
      presence of La and Ta decreased the protein adsorption, so AP40 bound
      significantly more protein per surface unit then did RKKP. Preferential
      adsorption of apolipoprotein J, fibrinogen and fibronectin was observed.

PMID- 12417189
TI  - Dentin bonding agents induce c-fos and c-jun protooncogenes expression in human
      gingival fibroblasts.
AB  - An important requirement for a dentin bonding agent is biologic compatibility;
      the bonding agent usually remains in close contact with living dental tissues
      over a long period of time. Information on the genotoxicity/mutagenicity and
      cacinogenicity potentials of dentin bonding agents is rare. It has been shown
      that c-fos and c-jun are induced rapidly by a variety of chemical and physical
      stimuli. Little is known about the induction of cellular signaling events and
      specific gene expression after cell exposure to dentin bonding agents. Therefore,
      we used primary human gingival fibroblasts to examine the effect of six dentin
      bonding agents on the expression of c-fos and c-jun protooncogenes to evaluate
      the genotoxicity/mutagenicity and cacinogenicity potential of the dentin bonding
      agents. The levels of mRNA were measured by the quantitative RT-PCR analysis. c
      fos and c-jun mRNA expression in dentin bonding agents-treated cells revealed a
      rapid accumulation of the transcript, a significant signal first was detectable
      after 1h of exposure. Persistent induction of c-jun and c-fos protooncogenes by
      dentine bonding agents may distribute systemically to cause some unexpected
      adverse effects on human beings. It would be necessary to identify the severely
      toxic compounds and replace these substances by better biocompatible components.
      Otherwise, leaching of those genotoxicity/mutagenicity and cacinogenicity
      components must be minimized or prevented.

PMID- 12417190
TI  - Behavior and properties of neat and filled gelatins.
AB  - The purpose of this study was to determine the mechanical properties and the
      atomistic structures of various gelatin hydrogels as a preliminary to using these
      in bioengineering applications. The hydrogels were investigated as neat materials
      and as particulate-reinforced composites both in the as-formed state and
      following cross-linking with formaldehyde and/or glutaraldehyde. The compressive
      modulus obtained using alumina particulates as the reinforcement was found to be
      enhanced significantly more than expected on the basis of considering a gel
      matrix to be similar to a thermoplastic one. From the electron paramagnetic
      resonance of a Cu(2+) probe ion implanted in these materials it was determined
      that the variation in the compressive moduli with Bloom indices results from a
      gradation in the relative weightings of two discrete coordination configurations.
      The cross-linking led to different coordinations following the formaldehyde vs.
      the glutaraldehyde treatments.

PMID- 12417191
TI  - Acrylonitrile-sodium methallylsulfonate copolymer. DSC approach to membrane
      porosity of foam and hollow fibers.
AB  - The porosity of membranes formed from acrylonitrile-sodium methallylsulfonate
      copolymer was characterized from the analysis of the depression of the melting
      point of absorbed water. Membranes were obtained either as a foam or as a hollow
      fiber; the foam consisted of interconnected macrocavities (mean diameter about
      equal to 1 mm) while the hollow fiber was a symmetric membrane used for blood
      ultrafiltration. Differential scanning calorimetry (DSC) of water revealed both
      the Gaussian distribution of pore sizes and correspondingly, their mean size: 5.2
      nm for the pores through the walls separating macrocavities in the foam and 5.6
      and 10.6 nm associated with two distributions representing nearly equal amounts
      of absorbed water, for the hollow fiber. In addition to DSC, the water magnetic
      relaxation showed that the isothermal dehydration of the foam was due to the
      deswelling of macrocavities while the increasing amount of absorbed water in
      pores reflects its strong interaction with the polymer.

PMID- 12417192
TI  - Indirect solid free form fabrication of local and global porous, biomimetic and
      composite 3D polymer-ceramic scaffolds.
AB  - Precise control over scaffold material, porosity, and internal pore architecture
      is essential for tissue engineering. By coupling solid free form (SFF)
      manufacturing with conventional sponge scaffold fabrication procedures, we have
      developed methods for casting scaffolds that contain designed and controlled
      locally porous and globally porous internal architectures. These methods are
      compatible with numerous bioresorbable and non-resorbable polymers, ceramics, and
      biologic materials. Phase separation, emulsion-solvent diffusion, and porogen
      leaching were used to create poly(L)lactide (PLA) scaffolds containing both
      computationally designed global pores (500, 600, or 800 microm wide channels) and
      solvent fashioned local pores (50-100 microm wide voids or 5-10 microm length
      plates). Globally porous PLA and polyglycolide/PLA discrete composites were made
      using melt processing. Biphasic scaffolds with mechanically interdigitated PLA
      and sintered hydroxyapatite regions were fabricated with 500 and 600 microm wide
      global pores. PLA scaffolds with complex internal architectures that mimicked
      human trabecular bone were produced. Our indirect fabrication using casting in
      SFF molds provided enhanced control over scaffold shape, material, porosity and
      pore architecture, including size, geometry, orientation, branching, and
      interconnectivity. These scaffolds that contain concurrent local and global
      pores, discrete material regions, and biomimetic internal architectures may prove
      valuable for multi-tissue and structural tissue interface engineering.

PMID- 12417193
TI  - Negative autoregulation speeds the response times of transcription networks.
AB  - Cells regulate gene expression using networks of transcription interactions; it
      is of interest to discover the principles that govern the dynamical behavior of
      such networks. An important characteristic of these systems is the rise-time: the
      delay from the initiation of production until half maximal product concentration
      is reached. Here we employ synthetic gene circuits in Escherichia coli to measure
      the rise-times of non-self-regulated and of negatively autoregulated
      transcription units. Non-self-regulated units have a rise-time of one cell-cycle.
      We demonstrate experimentally that negative autoregulation feedback (also termed
      autogenous control) reduces the rise-time to about one fifth of a cell-cycle.
      This agrees with an analytical solution of a mathematical model for negative
      autoregulation. This may help in understanding the function of negative
      autoregulation, which appears in over 40% of known transcription factors in
      E.coli.

PMID- 12417194
TI  - Replication factor C from the hyperthermophilic archaeon Pyrococcus abyssi does
      not need ATP hydrolysis for clamp-loading and contains a functionally conserved
      RFC PCNA-binding domain.
AB  - The molecular organization of the replication complex in archaea is similar to
      that in eukaryotes. Only two proteins homologous to subunits of eukaryotic
      replication factor C (RFC) have been detected in Pyrococcus abyssi (Pab). The
      genes encoding these two proteins are arranged in tandem. We cloned these two
      genes and co-expressed the corresponding recombinant proteins in Escherichia
      coli. Two inteins present in the gene encoding the small subunit (PabRFC-small)
      were removed during cloning. The recombinant protein complex was purified by
      anion-exchange and hydroxyapatite chromatography. Also, the PabRFC-small subunit
      could be purified, while the large subunit (PabRFC-large) alone was completely
      insoluble. The highly purified PabRFC complex possessed an ATPase activity, which
      was not enhanced by DNA. The Pab proliferating cell nuclear antigen (PCNA)
      activated the PabRFC complex in a DNA-dependent manner, but the PabRFC-small
      ATPase activity was neither DNA-dependent nor PCNA-dependent. The PabRFC complex
      was able to stimulate PabPCNA-dependent DNA synthesis by the Pabfamily D
      heterodimeric DNA polymerase. Finally, (i) the PabRFC-large fraction cross
      reacted with anti-human-RFC PCNA-binding domain antibody, corroborating the
      conservation of the protein sequence, (ii) the human PCNA stimulated the PabRFC
      complex ATPase activity in a DNA-dependent way and (iii) the PabRFC complex could
      load human PCNA onto primed single-stranded circular DNA, suggesting that the
      PCNA-binding domain of RFC has been functionally conserved during evolution. In
      addition, ATP hydrolysis was not required either for DNA polymerase stimulation
      or PCNA-loading in vitro.

PMID- 12417195
TI  - Digging deep for ancient relics: a survey of protein motifs in the intergenic
      sequences of four eukaryotic genomes.
AB  - We have examined conserved protein motifs in the non-coding, intergenic regions
      ("pseudomotif patterns") and surveyed their occurrence in the fly, worm, yeast
      and human genomes (chromosomes 21 and 22 only). To identify these patterns, we
      masked out annotated genes, pseudogenes and repeat regions from the raw genomic
      sequence and then compared the remaining sequence, in six-frame translation,
      against 1319 patterns from the PROSITE database. For each pseudomotif pattern,
      the absolute number of occurrences is not very informative unless compared
      against a statistical expectation; consequently, we calculated the expected
      occurrence of each pattern using a Poisson model and verified this with
      simulations. Using a p-value cut-off of 0.01, we found 67 pseudomotif patterns
      over-represented in fly intergenic regions, 34 in worm, 21 in human and six in
      yeast. These include the zinc finger, leucine zipper, nucleotide-binding motif
      and EGF domain. Many of the over-represented patterns were common to two or more
      organisms, but there were a few that were unique to specific ones. Furthermore,
      we found more over-represented patterns in the fly than in the worm, although the
      fly has fewer pseudogenes. This puzzling observation can be explained by a higher
      deletion rate in the fly genome. We also surveyed under-represented patterns,
      finding 23 in the fly, 12 in the worm, 18 in human and two in yeast. If
      intergenic sequences were truly random, we would expect an equal number of over
      and under-represented patterns. The fact that for each organism the number of
      over-represented patterns is greater than the number of under-represented ones
      implies that a fraction of the intergenic regions consist of ancient protein
      fragments that, due to accumulated disablements, have become unrecognizable by
      conventional techniques for gene and pseudogene identification. Moreover, we find
      that in aggregate the over-represented pseudomotif patterns occupy a substantial
      fraction of the intergenic regions. Further information is available at
      http://pseudogene.org

PMID- 12417196
TI  - Role of base flipping in specific recognition of damaged DNA by repair enzymes.
AB  - DNA repair enzymes induce base flipping in the process of damage recognition.
      Endonuclease V initiates the repair of cis, syn thymine dimers (TD) produced in
      DNA by UV radiation. The enzyme is known to flip the base opposite the damage
      into a non-specific binding pocket inside the protein. Uracil DNA glycosylase
      removes a uracil base from G.U mismatches in DNA by initially flipping it into a
      highly specific pocket in the enzyme. The contribution of base flipping to
      specific recognition has been studied by molecular dynamics simulations on the
      closed and open states of undamaged and damaged models of DNA. Analysis of the
      distributions of bending and opening angles indicates that enhanced base flipping
      originates in increased flexibility of the damaged DNA and the lowering of the
      energy difference between the closed and open states. The increased flexibility
      of the damaged DNA gives rise to a DNA more susceptible to distortions induced by
      the enzyme, which lowers the barrier for base flipping. The free energy profile
      of the base-flipping process was constructed using a potential of mean force
      representation. The barrier for TD-containing DNA is 2.5 kcal mol(-1) lower than
      that in the undamaged DNA, while the barrier for uracil flipping is 11.6 kcal
      mol(-1) lower than the barrier for flipping a cytosine base in the undamaged DNA.
      The final barriers for base flipping are approximately 10 kcal mol(-1), making
      the rate of base flipping similar to the rate of linear scanning of proteins on
      DNA. These results suggest that damage recognition based on lowering the barrier
      for base flipping can provide a general mechanism for other DNA-repair enzymes.

PMID- 12417197
TI  - A novel two-step mechanism for removal of a mitochondrial signal sequence
      involves the mAAA complex and the putative rhomboid protease Pcp1.
AB  - The yeast protein cytochrome c peroxidase (Ccp1) is nuclearly encoded and
      imported into the mitochondrial intermembrane space, where it is involved in
      degradation of reactive oxygen species. It is known, that Ccp1 is synthesised as
      a precursor with a N-terminal pre-sequence, that is proteolytically removed
      during transport of the protein. Here we present evidence for a new processing
      pathway, involving novel signal peptidase activities. The mAAA protease subunits
      Yta10 (Afg3) and Yta12 (Rca1) were identified both to be essential for the first
      processing step. In addition, the Pcp1 (Ygr101w) gene product was found to be
      required for the second processing step, yielding the mature Ccp1 protein. The
      newly identified Pcp1 protein belongs to the rhomboid-GlpG superfamily of
      putative intramembrane peptidases. Inactivation of the protease motifs in mAAA
      and Pcp1 blocks the respective steps of proteolysis. A model of coupled Ccp1
      transport and N-terminal processing by the mAAA complex and Pcp1 is discussed.
      Similar processing mechanisms may exist, because the mAAA subunits and the newly
      identified Pcp1 protein belong to ubiquitous protein families.

PMID- 12417199
TI  - Crystal structure of a thermostable lipase from Bacillus stearothermophilus P1.
AB  - We describe the first lipase structure from a thermophilic organism. It shares
      less than 20% amino acid sequence identity with other lipases for which there are
      crystal structures, and shows significant insertions compared with the typical
      alpha/beta hydrolase canonical fold. The structure contains a zinc-binding site
      which is unique among all lipases with known structures, and which may play a
      role in enhancing thermal stability. Zinc binding is mediated by two histidine
      and two aspartic acid residues. These residues are present in comparable
      positions in the sequences of certain lipases for which there is as yet no
      crystal structural information, such as those from Staphylococcal species and
      Arabidopsis thaliana. The structure of Bacillus stearothermophilus P1 lipase
      provides a template for other thermostable lipases, and offers insight into
      mechanisms used to enhance thermal stability which may be of commercial value in
      engineering lipases for industrial uses.

PMID- 12417198
TI  - Exploring the 3D molecular architecture of Escherichia coli type 1 pili.
AB  - An integrated approach combining information gained by Fourier transformation,
      linear Markham superposition (real space) and mass-per-length measurement by
      scanning transmission electron microscopy was used to analyze the helical
      structure of the rod-like type 1 pili expressed by uropathogenic Escherichia coli
      strain W3110. The 3D reconstruction calculated from the experimental data showed
      the pili to be 6.9nm wide, right-handed helical tubes with a 19.31(+/-0.34)nm
      long helical repeat comprising 27 FimA monomers associated head-to-tail in eight
      turns of the genetic one-start helix. Adjacent turns of the genetic helix are
      connected via three binding sites making the pilus rod rather stiff. In situ
      immuno-electron microscopy experiments showed the minor subunit (FimH) mediating
      pilus adhesion to bladder epithelial cells to be the distal protein of the pilus
      tip, which had a spring-like appearance at higher magnification. The subunits
      FimG and FimF connect FimH to the FimA rod, the sequential orientation being FimA
      FimF-FimG-FimH. The electron density map calculated at 18A resolution from an
      atomic model of the pilus rod (built using the pilin domain FimH together with
      the G1 strand of FimC as a template for FimA and applying the optimal helical
      parameters determined to the head-to-tail interaction model for pilus assembly)
      was practically identical with that of the actual 3D reconstruction.

PMID- 12417200
TI  - Phosphorylation driven motions in the COOH-terminal Src kinase, CSK, revealed
      through enhanced hydrogen-deuterium exchange and mass spectrometry (DXMS).
AB  - Previous kinetic studies demonstrated that nucleotide-derived conformational
      changes regulate function in the COOH-terminal Src kinase. We have employed
      enhanced methods of hydrogen-deuterium exchange-mass spectrometry (DXMS) to probe
      conformational changes on CSK in the absence and presence of nucleotides and
      thereby provide a structural framework for understanding phosphorylation-driven
      conformational changes. High quality peptic fragments covering approximately 63%
      of the entire CSK polypeptide were isolated using DXMS. Time-dependent deuterium
      incorporation into these probes was monitored to identify short peptide segments
      that exchange differentially with solvent. Regions expected to lie in loops
      exchange rapidly, whereas other regions expected to lie in stable secondary
      structure exchange slowly with solvent implying that CSK adopts a modular
      structure. The ATP analog, AMPPNP, protects probes in the active site and distal
      regions in the large and small lobes of the kinase domain, the SH2 domain, and
      the linker connecting the SH2 and kinase domains. The product ADP protects
      similar regions of the protein but the extent of protection varies markedly in
      several crucial areas. These areas correspond to the activation loop and helix G
      in the kinase domain and several inter-domain regions. These results imply that
      delivery of the gamma phosphate group of ATP induces unique local and long-range
      conformational changes in CSK that may influence regulatory motions in the
      catalytic pathway.

PMID- 12417201
TI  - A new zinc-protein coordination site in intracellular metal trafficking: solution
      structure of the Apo and Zn(II) forms of ZntA(46-118).
AB  - Zinc, a metal ion that functions in a wide variety of catalytic and structural
      sites in metalloproteins, is shown here to adopt a novel coordination environment
      in the Escherichia coli transport protein ZntA. The ZntA protein is a P-type
      ATPase that pumps zinc out of the cytoplasm and into the periplasm. It is
      physiologically selective for Zn(II) and functions with metalloregulatory
      proteins in the cell to keep the zinc quota within strict limits. Yet, the N
      terminal cytoplasmic domain contains a region that is highly homologous to the
      yeast Cu(I) metallochaperone Atx1. To investigate how the structure of this
      region may influence its function, this fragment, containing residues 46-118, has
      been cloned out of the gene and overexpressed. We report here the solution
      structure of this fragment as determined by NMR. Both the apo and Zn(II)-ZntA(46
      118) structures have been determined. It contains a previously unknown protein
      coordination site for zinc that includes two cysteine residues, Cys59 and Cys62,
      and a carboxylate residue, Asp58. The solvent accessibility of this site is also
      remarkably high, a feature that increasingly appears to be a characteristic of
      domains of heavy metal ion transport proteins. The participation of Asp58 in this
      ZntA metal ion binding site may play an important role in modulating the relative
      affinities and metal exchange rates for Zn(II)/Pb(II)/Cd(II) as compared with
      other P-type ATPases, which are selective for Cu(I) or Ag(I).

PMID- 12417202
TI  - Observation of slow dynamic exchange processes in Ras protein crystals by 31P
      solid state NMR spectroscopy.
AB  - The folding, structure and biological function of many proteins are inherently
      dynamic properties of the protein molecule. Often, the respective molecular
      processes are preserved upon protein crystallization, leading, in X-ray
      diffraction experiments, to a blurring of the electron density map and reducing
      the resolution of the derived structure. Nuclear magnetic resonance (NMR) is
      known to be an alternative method to study molecular structure and dynamics. We
      designed and built a probe for phosphorus solid state NMR that allows for the
      first time to study static properties as well as dynamic processes in single
      crystals of a protein by NMR spectroscopy. The sensitivity achieved is sufficient
      to detect the NMR signal from individual phosphorus sites in a 0.3mm(3) size
      single-crystal of GTPase Ras bound to the nucleotide GppNHp, that is, the signal
      from approximately 10(15) phosphorus nuclei. The NMR spectra obtained are
      discussed in terms of the conformational variability of the active center of the
      Ras-nucleotide complex. We conclude that, in the crystal, the protein complex
      exists in three different conformations. Magic angle spinning (MAS) NMR spectra
      of a powder sample of Ras-GppNHp show a splitting of one of the phosphate
      resonances and thus confirm this conclusion. The MAS spectra provide,
      furthermore, evidence of a slow, temperature-dependent dynamic exchange process
      in the Ras protein crystal.

PMID- 12417203
TI  - Quantifying the similarities within fold space.
AB  - We have used GRATH, a graph-based structure comparison algorithm, to map the
      similarities between the different folds observed in the CATH domain structure
      database. Statistical analysis of the distributions of the fold similarities has
      allowed us to assess the significance for any similarity. Therefore we have
      examined whether it is best to represent folds as discrete entities or whether,
      in fact, a more accurate model would be a continuum wherein folds overlap via
      common motifs. To do this we have introduced a new statistical measure of fold
      similarity, termed gregariousness. For a particular fold, gregariousness measures
      how many other folds have a significant structural overlap with that fold,
      typically comprising 40% or more of the larger structure. Gregarious folds often
      contain commonly occurring super-secondary structural motifs, such as beta
      meanders, greek keys, alpha-beta plait motifs or alpha-hairpins, which are
      matching similar motifs in other folds. Apart from one example, all the most
      gregarious folds matching 20% or more of the other folds in the database, are
      alpha-beta proteins. They also occur in highly populated architectural regions of
      fold space, adopting sandwich-like arrangements containing two or more layers of
      alpha-helices and beta-strands.Domains that exhibit a low gregariousness, are
      those that have very distinctive folds, with few common motifs or motifs that are
      packed in unusual arrangements. Most of the superhelices exhibit low
      gregariousness despite containing some commonly occurring super-secondary
      structural motifs. In these folds, these common motifs are combined in an unusual
      way and represent a small proportion of the fold (<10%). Our results suggest that
      fold space may be considered as continuous for some architectural arrangements
      (e.g. alpha-beta sandwiches), in that super-secondary motifs can be used to link
      neighbouring fold groups. However, in other regions of fold space much more
      discrete topologies are observed with little similarity between folds.

PMID- 12417204
TI  - Simulation of folding of a small alpha-helical protein in atomistic detail using
      worldwide-distributed computing.
AB  - By employing thousands of PCs and new worldwide-distributed computing techniques,
      we have simulated in atomistic detail the folding of a fast-folding 36-residue
      alpha-helical protein from the villin headpiece. The total simulated time exceeds
      300 micros, orders of magnitude more than previous simulations of a molecule of
      this size. Starting from an extended state, we obtained an ensemble of folded
      structures, which is on average 1.7A and 1.9A away from the native state in
      C(alpha) distance-based root-mean-square deviation (dRMS) and C(beta) dRMS sense,
      respectively. The folding mechanism of villin is most consistent with the
      hydrophobic collapse view of folding: the molecule collapses non-specifically
      very quickly ( approximately 20ns), which greatly reduces the size of the
      conformational space that needs to be explored in search of the native state. The
      conformational search in the collapsed state appears to be rate-limited by the
      formation of the aromatic core: in a significant fraction of our simulations, the
      C-terminal phenylalanine residue packs improperly with the rest of the
      hydrophobic core. We suggest that the breaking of this interaction may be the
      rate-determining step in the course of folding. On the basis of our simulations
      we estimate the folding rate of villin to be approximately 5micros. By analyzing
      the average features of the folded ensemble obtained by simulation, we see that
      the mean folded structure is more similar to the native fold than any individual
      folded structure. This finding highlights the need for simulating ensembles of
      molecules and averaging the results in an experiment-like fashion if meaningful
      comparison between simulation and experiment is to be attempted. Moreover, our
      results demonstrate that (1) the computational methodology exists to simulate the
      multi-microsecond regime using distributed computing and (2) that potential sets
      used to describe interatomic interactions may be sufficiently accurate to reach
      the folded state, at least for small proteins. We conclude with a comparison
      between our results and current protein-folding theory.

PMID- 12417205
TI  - Identifying unfolding intermediates of FN-III(10) by steered molecular dynamics.
AB  - Experimental studies have indicated that FN-III modules undergo reversible
      unfolding as a mechanism of elasticity. The unfolding of FN-III modules,
      including the cell-binding FN-III(10) module, has further been suggested to be
      functionally relevant by exposing buried cryptic sites or modulating cell
      binding. While steered molecular dynamics (SMD) simulations have provided one
      tool to investigate this process, computational requirements so far have limited
      detailed analysis to the early stages of unfolding. Here, we use an extended
      periodic box to probe the unfolding of FN-III(10) for extensions longer than 60A.
      Up to three plateaus, corresponding to three metastable intermediates, were
      observed in the extension-time profile from SMD stretching of FN-III(10). The
      first and second plateaus correspond to a twisted and an aligned state prior to
      unraveling FN-III(10) beta-strands. The third plateau, at an extension of
      approximately 100A, follows unraveling of FN-III(10) A and B-strands and precedes
      breaking of inter-strand hydrogen bonds between F and G-strands. The simulations
      revealed three forced unfolding pathways of FN-III(10), one of which is
      preferentially selected under physiological conditions. Implications for
      fibronectin fibrillogenesis are discussed.

PMID- 12417206
TI  - Proline-induced distortions of transmembrane helices.
AB  - Proline residues in the transmembrane (TM) alpha-helices of integral membrane
      proteins have long been suspected to play a key role for helix packing and signal
      transduction by inducing regions of helix distortion and/or dynamic flexibility
      (hinges). In this study we try to characterise the effect of proline on the
      geometric properties of TM alpha-helices. We have examined 199 transmembrane
      alpha-helices from polytopic membrane proteins of known structure. After
      examining the location of proline residues within the amino acid sequences of TM
      helices, we estimated the helix axes either side of a hinge and hence identified
      a hinge residue. This enabled us to calculate helix kink and swivel angles. The
      results of this analysis show that proline residues occur with a significant
      concentration in the centre of sequences of TM alpha-helices. In this location,
      they may induce formation of molecular hinges, located on average about four
      residues N-terminal to the proline residue. A superposition of proline-containing
      TM helices structures shows that the distortion induced is anisotropic and
      favours certain relative orientations (defined by helix kink and swivel angles)
      of the two helix segments.

PMID- 12417207
TI  - Pathogenicity of Aschersonia spp. against whiteflies Bemisia argentifolii and
      Trialeurodes vaporariorum.
AB  - Entomopathogenic fungi of the genus Aschersonia are specific for whitefly and
      scale insects. They can be used as biological control agents against silverleaf
      whitefly, Bemisia argentifolii and greenhouse whitefly, Trialeurodes
      vaporariorum. Forty-four isolates of Aschersonia spp. were tested for their
      ability to sporulate and germinate on semi-artificial media and to infect insect
      hosts. Seven isolates sporulated poorly (less than 1x10(7) conidia/dry weight)
      and 10 were not able to infect either of the whitefly species. Several isolates
      were able to produce capilliconidia. Infection level was not correlated with
      germination on water agar. After a selection based on spore production and
      infection, virulence of 31 isolates was evaluated on third instar nymphs of both
      whitefly species on poinsettia (Euphorbia pulcherrima). Whitefly infection levels
      varied between 2 and 70%, and infection percentages of B. argentifolii correlated
      with that of T. vaporariorum. However, mortality was higher for T. vaporariorum
      than for B. argentifolii, as a result of a higher 'mortality due to unknown
      causes.' Several isolates, among which unidentified species of Aschersonia
      originating from Thailand and Malaysia, A. aleyrodis from Colombia, and A.
      placenta from India showed high spore production on semi-artificial medium and
      high infection levels of both whitefly species.

PMID- 12417208
TI  - Comparison of parasitism by Cotesia glomerata with bacterial infection and
      wounding in Pieris brassicae: induction of new haemolymph polypeptides and
      changes in humoral immune response.
AB  - In Pieris brassicae, parasitism by Cotesia glomerata and bacterial infection are
      differentiated with respect to haemolymph protein arrays, and production or
      suppression of antibacterial agents. Bacteriolytic activity in haemolymph from
      parasitized larvae was slightly, but significantly, higher 24h post-treatment
      than that of untreated and wounded controls. Micrococcus lysodeikticus- or
      lipopolysaccharide-(LPS) injected insects exhibited an 11-fold greater response
      than those parasitized. At 24h post-treatment, antibacterial activity against
      Escherichia coli was observed in haemolymph from all but untreated larvae.
      Injection of Grace's medium, M. lysodeikticus or LPS, caused a greater than
      threefold response than parasitization or wounding. The protein banding patterns
      of parasitized hosts did not correspond to those of the other treatments. Two
      parasitoid-induced proteins (38 and 128 kDa) were examined. Both were found in
      parasitized insects, not in those wounded, injected with Grace's medium, M.
      lysodeikticus or LPS. Neither protein was bacteriolytic or bacteriostatic in
      inhibition zone assays.

PMID- 12417209
TI  - Attenuation of fungal infection in thermoregulating Locusta migratoria is
      accompanied by changes in hemolymph proteins.
AB  - Hemolymph proteins in the locust, Locusta migratoria migratorioides infected with
      the fungus Metarhizium anisopliae var acridum were analyzed with sodium dodecyl
      sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Under conditions that
      allowed locusts to thermoregulate, 2 proteins, ITB1 (ca. 18kDa) and ITB2 (ca.
      13kDa) were induced 48h post inoculation. In contrast, under non-thermoregulating
      conditions, only 1 band, INTB1 (ca. 18kDa) was induced with similar molecular
      mass to ITB1. ITB1 and ITB2 were N-terminally sequenced but showed little
      homology to known proteins. The induction of hemolymphal proteins in infected,
      thermoregulating locusts and implication in insect immune defence are discussed.

PMID- 12417210
TI  - Host cadavers protect entomopathogenic nematodes during freezing.
AB  - The entomopathogenic nematodes Heterorhabditis bacteriophora, Steinernema
      carpocapsae, Steinernema glaseri, and Steinernema feltiae were exposed to
      freezing while inside their hosts. Survival was assessed by observing live and
      dead nematodes inside cadavers and by counting the infective juveniles (IJs) that
      emerged after freezing. We (1) measured the effects of 24h of freezing at
      different times throughout the course of an infection, (2) determined the
      duration of freezing entomopathogenic nematodes could survive, (3) determined
      species differences in freezing survival. Highest stage-specific survival was IJs
      for S. carpocapsae, and adults for H. bacteriophora. When cadavers were frozen
      two or three days after infection, few IJs emerged from them. Freezing between
      five and seven days after infection had no negative effect on IJ production. No
      decrease in IJ production was measured for H. bacteriophora after freezing. H.
      bacteriophora also showed improved survival inside versus outside their host when
      exposed to freezing.

PMID- 12417211
TI  - Pathology and ultrastructure of Hz-2V infection in the agonadal female corn
      earworm, Helicoverpa zea.
AB  - The pathology and ultrastructure of the reproductive tract of Hz-2V-infected
      female corn earworm moths, Helicoverpa zea, were studied. The identity of
      malformed reproductive tissues found in virus-infected moths was determined by
      examining these tissues in moths that were infected with the virus at different
      life stages. Malformation of reproductive tissues in the progeny of virus
      infected female moths was first observed by 3 days post-pupation (dpp),
      indicating that virus replication had altered the differentiation of these
      tissues very early on in their development. The ultrastructure of the grossly
      malformed agonadal reproductive tissues from insects aged 3-10dpp revealed the
      absence of the cuticular lining found in the oviducts of normal moths, and the
      proliferation of epithelial cells in these infected oviduct tissues. In addition,
      large quantities of virus were found aggregated into a large mass in the lumen of
      the malformed cervix bursa of 10dpp agonadal female pharate adult moths. Prior to
      eclosion, the virus in the cervix bursa was observed separated into spherical
      masses, which are thought to exude through the ductus bursa and collect over the
      vulva, forming a viral "waxy plug" that is likely to play an important role in
      virus transmission.

PMID- 12417212
TI  - Yellow-head disease caused by a newly discovered Mattesia sp. in populations of
      the red imported fire ant, Solenopsis invicta.

PMID- 12417213
TI  - Development of the braconid wasp Cotesia congregata in a semi-permissive noctuid
      host, Trichoplusia ni.

PMID- 12417214
TI  - Incidence of infected Myzus persicae alatae trapped in flight imply place-to
      place dissemination of entomophthoralean fungi in aphid populations through
      migration.

PMID- 12417215
TI  - Isolation and characterization of a strong promoter from Bacillus sphaericus
      strain 2297.

PMID- 12417216
TI  - Discrepancy between cry gene-predicted and bioassay-determined insecticidal
      activities in Bacillus thuringiensis natural isolates.

PMID- 12417217
TI  - An emerging role for event-related potentials in the assessment of brain injury.

PMID- 12417218
TI  - The oscillatory activity in the Parkinsonian subthalamic nucleus investigated
      using the macro-electrodes for deep brain stimulation.
AB  - OBJECTIVES: To investigate the oscillatory activity in the Parkinsonian
      subthalamic nucleus using the macro-electrodes for deep brain stimulation.
      METHODS: During bilateral deep brain stimulating electrode implantation,
      spontaneous and evoked field potentials were recorded from the subthalamic
      nucleus (STN) in two patients with Parkinson's disease (PD) during spontaneous
      resting tremor, passive manipulation of the wrist, and following electrical
      stimulation of the contralateral STN. RESULTS: Frequency analysis of the STN
      field potentials recorded during spontaneous resting tremor showed significant
      coherence with electromyographic activity in the contralateral arm, suggesting a
      close involvement of the STN in the generation of resting tremor in PD. The STN
      responded to passive movement of the contralateral wrist, but not to ipsilateral
      movement. High frequency (100 Hz) electrical stimulation of the STN induced
      tremor (4 Hz) in both forearms, and also oscillation of the contralateral STN (4
      Hz). In contrast, low frequency (5 Hz) stimulation induced contralateral
      arrhythmic involuntary movement (3 Hz), but without altering the contralateral
      STN activity. CONCLUSIONS: We propose that the functional connection between the
      STN and arm muscles is mainly contralateral, but cross talk may occur between
      bilateral STN via a frequency-dependent pathway.

PMID- 12417219
TI  - Direct demonstration of long latency cortico-cortical inhibition in normal
      subjects and in a patient with vascular parkinsonism.
AB  - OBJECTIVE: The motor evoked potential to a single suprathreshold transcranial
      magnetic stimulus (TMS) is suppressed by a preceding stimulus given 100-200 ms
      before (long latency intracortical inhibition, LICI). The effect is enhanced in
      patients with Parkinson's disease. Although previous studies have agreed that the
      effect is cortical, there is disagreement over exactly which cortical mechanisms
      are involved. The aim of this study was to provide further evidence for cortical
      involvement in LICI. METHODS: Recordings of corticospinal volleys evoked by the
      TMS stimulation were made from electrodes inserted into the cervical epidural
      space of 4 conscious subjects. Three of the patients had received the electrodes
      for treatment of lumbo-sacral pain; the other patient had vascular parkinsonism,
      and had the electrode implanted to evaluate its effect on cerebral blood flow.
      The number and amplitude of the volleys were compared with and without a
      conditioning stimulus. RESULTS: In 3 pain patients, a conditioning stimulus
      suppressed the later components of the corticospinal volley (I2 and later waves)
      when the interval between stimuli was 100-150 ms; at 50 ms the responses were
      enhanced. Early components of the volley were not affected. Inhibition was much
      more pronounced and involved all descending volleys except the D wave in the
      patient with vascular parkinsonism. CONCLUSIONS: LICI, which is conventionally
      described in EMG recordings, is also evident in recordings of descending
      corticospinal volleys and appears enhanced in a patient with vascular
      parkinsonism.

PMID- 12417220
TI  - Effect of discharge desynchronization on the size of motor evoked potentials: an
      analysis.
AB  - OBJECTIVE: Motor evoked potentials (MEPs) after transcranial magnetic brain
      stimulation (TMS) are smaller than CMAPs after peripheral nerve stimulation,
      because desynchronization of the TMS-induced motor neurone discharges occurs
      (i.e. MEP desynchronization). This desynchronization effect can be eliminated by
      use of the triple stimulation technique (TST; Brain 121 (1998) 437). The
      objective of this paper is to study the effect of discharge desynchronization on
      MEPs by comparing the size of MEP and TST responses. METHODS: MEP and TST
      responses were obtained in 10 healthy subjects during isometric contractions of
      the abductor digiti minimi, during voluntary background contractions between 0%
      and 20% of maximal force, and using 3 different stimulus intensities. Additional
      data from other normals and from multiple sclerosis (MS) patients were obtained
      from previous studies. RESULTS: MEPs were smaller than TST responses in all
      subjects and under all stimulating conditions, confirming the marked influence of
      desynchronization on MEPs. There was a linear relation between the amplitudes of
      MEPs vs. TST responses, independent of the degree of voluntary contraction and
      stimulus intensity. The slope of the regression equation was 0.66 on average,
      indicating that desynchronization reduced the MEP amplitude on average by one
      third, with marked inter-individual variations. A similar average proportion was
      found in MS patients. CONCLUSIONS: The MEP size reduction induced by
      desynchronization is not influenced by the intensity of TMS and by the level of
      facilitatory voluntary background contractions. It is similar in healthy subjects
      and in MS patients, in whom increased desynchronization of central conduction was
      previously suggested to occur. Thus, the MEP size reduction observed may not
      parallel the actual amount of desynchronization.

PMID- 12417221
TI  - Different mechanisms contribute to motor cortex hyperexcitability in amyotrophic
      lateral sclerosis.
AB  - OBJECTIVES: Different physiological approaches demonstrated motor system
      hyperexcitability in amyotrophic lateral sclerosis (ALS), probably reflecting
      excitotoxic mechanisms. Transcranial magnetic stimulation (TMS) showed that both
      increased excitability of corticomotoneurons and reduced intracortical inhibition
      (ICI) contribute to motor cortex hyperexcitability, but the importance of these
      factors in inducing this cortical dysfunction is unknown. The aim of the study
      was to establish how different mechanisms interact to promote motor system
      hyperexcitability in ALS in relation to clinical features. METHODS: The resting
      motor threshold (RMT), the motor evoked potential (MEP) recruitment curve and the
      cortical silent period (CSP) to single-pulse TMS were evaluated in 35 patients
      with ALS. Early ICI and intracortical facilitation (ICF) and late ICI were
      evaluated by paired TMS. RESULTS: The main abnormal TMS findings were: (a) a
      steeper MEP recruitment curve associated with a lowering of the RMT; (b) reduced
      or even absent early and late ICI; (c) reduced CSP lengthening with increasing
      TMS intensity. ICF was not affected. RMT increased and the MEP recruitment curve
      became less steep with longer disease duration, but they did not correlate with
      the motor deficit, the type of motoneuron affection and the decrease of ICI.
      Impairment of early and late ICI were significantly correlated to each other, to
      disease severity and to clinical evidence of upper motor neuron involvement.
      CONCLUSIONS: Different and partially independent mechanisms contribute to motor
      cortex hyperexcitability in ALS. The increased gain in MEP recruitment with a
      lowering of the RMT appears to be a primary event reflecting an increase in the
      strength of corticospinal projections, probably related to changes in the ion
      channel permeability of the neuronal membrane. On the other hand, inhibitory
      functions linked to multiple neurotransmitter systems decline with disease
      progression. Both depletion of specific subpopulations of intracortical GABAergic
      neurons and mechanisms involved in motor cortex reorganization following
      progressive neuronal loss have been considered to account for the impaired
      inhibition. The clarification of the importance of these factors in the
      pathogenesis of ALS may have diagnostic and therapeutic implications.

PMID- 12417222
TI  - Hip angle induced modulation of H reflex amplitude, latency and duration in
      spinal cord injured humans.
AB  - OBJECTIVES: To investigate the modulation of the soleus H reflex in spinal cord
      injured (SCI) subjects resulting from imposed changes in hip angle and to
      establish whether changes in H reflex amplitude co-vary with changes in reflex
      latency and duration. METHODS: H reflexes were recorded using conventional
      methods in 7 SCI subjects in the supine position. The right leg was secured by a
      leg brace and positioned at various angles of hip flexion (30 degrees, 40 degrees
      ) and at 10 degrees of hip extension. RESULTS: We found that imposing 10 degrees
      of hip extension resulted in a significant facilitation in the size of the soleus
      H reflex in all of the SCI subjects tested (200% of control reflex; recorded at
      10 degrees of hip flexion). In contrast, positioning the hip at 30 degrees and at
      40 degrees of flexion resulted in a significant reduction of the H reflex in 6 of
      7 SCI subjects tested. In the remaining subject, an increase in the H reflex
      amplitude was observed. Modulation of H reflex amplitude coincided with shifts in
      both H reflex latency and duration. The reflex latency was prolonged when the
      reflex amplitude was reduced following hip flexion, while hip extension shortened
      the reflex latency. In contrast, the H reflex duration was prolonged with hip
      extended and shortened with hip flexed. CONCLUSIONS: When changes in static hip
      joint position are imposed in SCI subjects, changes in afferent feedback from hip
      proprioceptors are capable of promoting a switch between excitatory and
      inhibitory pathways. Associated changes in H reflex latency and duration are
      consistent with the hypothesis that oligosynaptic inputs contribute to the hip
      angle-induced H reflex modulation. Possible mechanisms for these effects are
      discussed.

PMID- 12417223
TI  - Interaction effects of galvanic vestibular stimulation and head position on the
      soleus H reflex in humans.
AB  - OBJECTIVES: The objective of this study is to measure the influence of galvanic
      vestibular stimulation and head-on-body alignment on the soleus H-reflex in prone
      human subjects. METHODS: We studied changes in the amplitude of the right soleus
      H-reflex to monopolar monaural galvanic stimulation in 10 healthy prone lying
      subjects. Trials were randomly administered according to head position (left or
      right) and stimulus polarity (anode or cathode). We also investigated the
      influence of the conditioning stimuli by examining the amplitude of the H-reflex
      based on head position without galvanic stimulation. A one-way and two-way
      repeated measures analysis of variance were used to compare the mean amplitudes
      of the test and conditioned H-reflexes. RESULTS: The greatest facilitation was
      observed when the head was turned to the left and coupled with cathodal
      stimulation. The largest inhibitory effect was found when the head was turned to
      the right and paired with anodal stimulation. However, when head left was paired
      with anodal stimulation or head right was coupled with cathodal stimulation, only
      minimal changes in amplitude were observed. CONCLUSIONS: The results demonstrate
      that there is an interaction between head position and galvanic stimulus polarity
      when measuring the excitability of the soleus motoneuron pool in prone lying
      subjects.

PMID- 12417224
TI  - Linking neurophysiological and neuropsychological measures for aphasia
      assessment.
AB  - OBJECTIVES: The objective of this study was to find the event-related brain
      potential (ERP) waveform features and parameters that maximize the correlation
      between the ERP components and behavioral performance on a neuropsychological
      test of language comprehension (PPVT-R) in order to develop an
      electrophysiological diagnostic technique that can be used in the assessment of
      aphasic patients. METHODS: ERPs were recorded during a computerized version of
      the Peabody Picture Vocabulary Test-Revised (PPVT-R, Form M). In the computerized
      version, a picture is presented followed by a congruent or incongruent spoken
      word. A derived measure was calculated from the ERP differentiation between
      congruent and incongruent words. The traditional PPVT-R (Form L) was also
      administered for comparison purposes. The participants included 10 left-sided
      stroke patients. RESULTS: The N400 was the primary component elicited to
      incongruent spoken words. Following optimization procedures, a statistical
      correlation (Pearson r=0.86) was found between the derived N400 measures and the
      neuropsychological test scores. Examination of the scatter plot confirmed that
      the relationship was linear. The derived N400 measure was defined primarily as
      the mean of the t-scores obtained from the incongruent and congruent waveform
      comparison, within the temporal interval that encompasses the N400. CONCLUSIONS:
      This novel quantification technique links ERPs with neuropsychological data at an
      unprecedented level. Given the high correlation, a regression line could
      reasonably be used to estimate a patient's language ability using only ERPs.
      However, before these findings can be accepted fully, these results need to be
      replicated in larger samples and across other paradigms.

PMID- 12417225
TI  - Skin potential response in letter recognition task as an alternative
      communication channel for individuals with severe motor disability.
AB  - OBJECTIVES: Skin potential responses (SPRs) to target and non-target stimuli in
      letter recognition tasks were studied to evaluate their potential as
      communication channels for individuals with severe motor disability. METHODS:
      SPRs were recorded from the palm or sole of 5 subjects with cerebral palsy and 6
      healthy subjects. Subjects discriminated target letters from non-target ones in a
      random sequence of single letters. In Task 1, subjects made a behavioral response
      upon presentation of the target. In Task 2, the target letters were presented as
      "go" or "nogo" signals. RESULTS: For target letters, irrespective of behavioral
      requirements ("go" or "nogo"), skin potential waves frequently occurred with
      latency consistent with the sympathetic skin response (SSR) latency, and were
      regarded as SPRs evoked by target stimuli. In Task 1, the occurrence rate of the
      SPR was 47% for target, and 4% for non-target stimuli. In Task 2, the SPR
      occurred in 34% of "go" target, 29% of "nogo" target, and 2% of non-target
      stimuli. CONCLUSIONS: SPRs with SSR latency are potentially useful in controlling
      signals of communication tools for individuals with severe motor disability.

PMID- 12417226
TI  - Brain responses to number sequences with and without active task requirement.
AB  - OBJECTIVE: To examine the effect of the active task involvement versus the
      passive knowledge of the structure of the stimulation on event-related potentials
      (ERPs) to violation in number sequences. This should contribute to future
      development of an ERP test for neurological patients. METHODS: ERPs were recorded
      in subjects who listened to 4-item sequences of numbers incrementing by one. Half
      of the sequences had an appropriate end item, whereas the other half ended
      inappropriately. The role of active versus passive condition was investigated in
      a between-subject design. RESULTS: Incorrectly ending sequences yielded a large
      P300 wave in all groups. Subjects who were explicitly informed about the nature
      of the stimulation but did not have a motor task displayed a slow negativity
      which followed P300 and slightly suppressed it. In addition, incorrect sequence
      endings elicited an early (70-200 ms) negativity at frontal sites. This effect
      was inverted on mastoids. CONCLUSIONS: Auditory perception of 3 consecutive
      numbers constituting a simple incrementing row leads to building a strong
      expectancy concerning the subsequent number, and unexpected events are detected
      already after the initial phoneme.

PMID- 12417227
TI  - Effects of task difficulty on evoked gamma activity and ERPs in a visual
      discrimination task.
AB  - OBJECTIVE: The present study examined oscillatory brain activity of the EEG gamma
      band and event-related potentials (ERPs) with relation to the difficulty of a
      visual discrimination task. METHODS: Three tasks with identical stimulus material
      were performed by 9 healthy subjects. The tasks comprised a passive control task,
      and an easy and a hard visual discrimination task, requiring discrimination of
      the color of circles. EEG was recorded from 26 electrodes. A wavelet transform
      based on Morlet wavelets was employed for the analysis of gamma activity.
      RESULTS: Evoked EEG gamma activity was enhanced by both discrimination tasks as
      compared to the passive control task. Within the two discrimination tasks, the
      latency of the evoked gamma peak was delayed for the harder task. Higher
      amplitudes of the ERP components N170 and P300 were found in both discrimination
      tasks as compared to the passive task. The N2b, which showed a maximum activation
      at about 260 ms, was increased in the hard discrimination task as compared to the
      easy discrimination task. CONCLUSIONS: Our results indicate that early evoked
      gamma activity and N2b are related to the difficulty of visual discrimination
      processes. A delayed gamma activity in the hard task indicated a longer duration
      of stimulus processing, whereas the amplitude of the N2b directly indicates the
      level of task difficulty.

PMID- 12417228
TI  - Target and non-target ERP disturbances in first episode vs. chronic
      schizophrenia.
AB  - OBJECTIVES: Event-related potential (ERP) abnormalities to target stimuli are
      reliably found in schizophrenia. However, as people with schizophrenia are
      thought to have difficulty discerning the relevance of incoming sensory stimuli
      it is also important to examine ERPs to non-targets. To differentiate between
      potential trait markers of the disease and deficits that might be associated with
      the consequence of illness chronicity, this study investigated ERPs to both
      target and non-target stimuli in groups of people with either first episode or
      chronic schizophrenia (CSz). METHODS: Using an auditory oddball paradigm, ERPs to
      target, non-target before target (Nt before) and non-target after target (Nt
      after) stimuli were analysed for 40 patients with CSz, 40 patients with first
      episode schizophrenia (FESz) and two groups of normal controls matched for age
      and sex with their patient counterparts. RESULTS: The FESz group showed the same
      pattern of amplitude disturbance as the CSz group to both targets (reduced N100,
      N200, P300 and increased P200) and non-targets (reduced N100) compared to
      controls. Both CSz and FESz groups also failed to show the changes to the P200
      N200 component between targets and non-target stimuli that was exhibited by
      controls (smaller earlier P200 to targets vs. increased delayed P200 to non
      targets) or the reduction in N100 amplitude of ERPs to the Nt after stimuli
      compared with ERPs to the Nt before stimuli. Previous literature has focussed on
      the sensitivity of P300 deficits in classifying persons into schizophrenia and
      non-schizophrenia groups. This study demonstrated improved accuracy in the
      classification of patients with schizophrenia from controls using discriminant
      analysis of target and non-target N100 and P200 components. CONCLUSIONS: The
      results suggest that ERP disturbances are evident at the time of first referral
      to mental health services and may be a potential trait (rather than secondary
      effect) of the illness. It is important to include both target and non-target
      stimuli processing, and their interrelationship in future research.

PMID- 12417229
TI  - Pattern ERG and VEP maturation in schoolchildren.
AB  - OBJECTIVE: The maturation of the visual system has been studied with pattern
      electroretinograms (PERG) and pattern visual evoked potentials (PVEP) mostly in
      children under the age of 6 years. To address the question of maturation of the
      visual system in childhood and adolescence we investigated age-dependent PERG and
      PVEP changes in children aged 7-18 years. METHODS: PERG were recorded with skin
      electrodes attached to the lower eyelid, and PVEP were recorded with 5
      electrodes. Visual stimuli, consisting of pattern-reversal 50' checks to full
      field and to half-field stimulation, were applied to obtain macular (N70, P100,
      N145) and paramacular waves (P80, N105, N135). RESULTS: We found an age-dependent
      decrease (linear regression P<0.05) of PERG P50 amplitude and full-field PVEP
      P100 latency to monocular right and left eye stimulation, indicating central
      retinal and postretinal changes. In addition, waveform changes were found in
      responses to half-field stimulation. The paramacular wave N105 was typically
      enhanced in younger schoolchildren and diminished with age. The age-dependent
      decrease (linear regression P<0.01) of paramacular N105 amplitude indicated the
      increasing predominance of the macular structures of the visual system.
      CONCLUSIONS: Our findings suggest that central retinal and postretinal
      electrophysiological maturation persists throughout childhood. Age-dependent PVEP
      changes seem to correlate with the morphological and metabolic findings that
      maturation of the visual cortex continues until puberty and even later.

PMID- 12417230
TI  - Effects of sustained, voluntary attention on amplitude and latency of steady
      state visual evoked potential: a costs and benefits analysis.
AB  - OBJECTIVE: Steady-state visual evoked potentials (VEPs) were recorded to study
      the mechanisms that underlie visual attention. METHODS: VEPs were recorded from 1
      cycle/degree sinusoidal grating contrast reversed at various temporal frequencies
      (6-10 Hz). This was displayed in one hemifield. A letter search display was
      flashed at a random rate in the other hemifield. The subject performed a
      demanding task on the recording stimulus (attended condition) or on the opposite
      side stimulus (unattended condition). Alternatively, he/she passively fixated on
      the fixation point (passive condition). RESULTS: Relative to the passive
      condition, attended stimuli elicited enhanced-amplitude and shortened-latency VEP
      (benefits). Costs (i.e. responses to passive vs. unattended stimuli) were more
      marked for latency. CONCLUSIONS: VEP latency may be the key of a priority-based
      attention mechanism acting at an early level.

PMID- 12417231
TI  - Early secondary somatosensory area (SII) SEPs. Data from intracerebral recordings
      in humans.
AB  - OBJECTIVE: To record somatosensory evoked potentials (SEPs) to median nerve
      stimulation by chronically implanted electrodes in the parieto-rolandic opercular
      area of 9 epileptic patients, in order to evaluate whether somatosensory evoked
      responses could be generated in the second somatosensory area (SII) earlier than
      40 ms after stimulus. METHODS: Nine patients (4 males, 5 females) with drug
      resistant partial epileptic seizures were investigated using stereotactically
      implanted electrodes in the parietal cortex, posterior to vertical anterior
      commissure plane and in the frontal opercular region rostral to vertical anterior
      commissure (VAC). RESULTS: The main finding of this study is the recording of an
      early somatosensory evoked potential, (N30op), by chronically implanted
      electrodes in the SII area of 8 epileptic patients. In 3 patients where SEPs were
      performed after ipsilateral median nerve (MN) stimulation, a N30op was recorded
      5.8+/-2 ms later than contralateral one. CONCLUSIONS: This is the first report of
      early SEPs recorded by electrodes implanted in SII area. The N30op potential,
      even if less consistent than later potentials, confirmed the important role of
      the SII area in the early processing of somatosensory inputs.

PMID- 12417232
TI  - The profile of the recovery cycle in human primary and secondary somatosensory
      cortex: a magnetoencephalography study.
AB  - OBJECTIVE: To estimate the lifetime of sensory memory in human primary (SI) and
      secondary (SII) somatosensory cortex with a view to furthering our understanding
      of the roles played by these cortices in the processing of tactile information.
      METHODS: Somatosensory evoked fields (SEFs) were recorded following trains of 5
      electrical pulses applied to the right median nerve at the wrist using a whole
      head 80 channel magnetoencephalography (MEG) system. Recordings were acquired for
      trains of pulses with differing interstimulus intervals (ISIs) occurring at 100,
      200, 300, 400 and 500 ms. The profile of SEF intensities for the different ISIs
      provided an estimate of the recovery cycle of evoked neuronal activity, and the
      time constant of the exponential curve fitted to the recovery cycle was
      calculated to obtain a putative measure of the lifetime of somatic sensory memory
      in SI and SII. RESULTS: The estimated time constants were 0.11+/-0.06 s (mean+/
      SD) in SI and 0.82+/-0.34 s in SII. The mean time constant in SII was
      significantly longer than that in SI (Student's paired t test: P=0.021; analysis
      of variance: F(1,3)=19.7, P=0.021). CONCLUSIONS: These data indicate that the
      lifetime of somatic sensory memory is of longer duration in higher order cortical
      areas than in primary sensory cortex in the somatosensory information processing
      system.

PMID- 12417233
TI  - The effects of stimulus rates on high frequency oscillations of median nerve
      somatosensory-evoked potentials--direct recording study from the human cerebral
      cortex.
AB  - OBJECTIVES: To study the effects of different stimulus rates on high-frequency
      oscillations (HFOs) of somatosensory-evoked potentials (SEPs), we recorded median
      nerve SEPs directly from the human cerebral cortex. METHODS: SEPs were recorded
      from subdural electrodes in 5 patients with intractable epilepsy, under the
      conditions of low (3.3Hz) and high (12.3Hz) stimulus rates. RESULTS: Increased
      stimulus rates to the median nerve from 3.3 to 12.3Hz showed a pronounced
      amplitude reduction of HFOs when compared with the primary N20-P20, area 3b, and
      P25, area 1, responses. CONCLUSIONS: HFOs were more sensitive to a high stimulus
      rate than the primary cortical responses, suggesting that the post-synaptic
      intracortical activities may greatly contribute to the HFO generation.

PMID- 12417234
TI  - Sleep organization pattern as a prognostic marker at the subacute stage of post
      traumatic coma.
AB  - OBJECTIVES: The aim of this study is to identify the predictive indexes for post
      traumatic coma prognosis, which is important to better direct acute and subacute
      treatments and rehabilitation efforts. The pattern of sleep organization is a
      potential prognostic marker, but its role has not been established yet in the
      context of modern critical care. In the present study, we used a new protocol to
      evaluate the prognostic value of the different levels of sleep-wake organization
      recorded at the subacute stage of post-traumatic coma. METHODS: Twenty-four head
      injured comatose patients were monitored with 24h polysomnographic recordings.
      The predictivity of the different levels of sleep-wake organization on
      polysomnography was compared with other possible prognostic indexes (i.e.
      neuroradiological findings, age and Glasgow Coma Scores (GCS)). Main outcome
      measures were survival and the degree of disability after recovery from coma.
      RESULTS: The presence of organized sleep patterns, but not GCS, was highly
      predictive of better outcome (odds ratio=10.78, P=0.01), even after correction
      for potentially confounding variables with multivariate analysis. CONCLUSIONS:
      Our study demonstrates that the sleep-wake organization pattern based on 24h
      polysomnographic recordings at the subacute stages of post-traumatic coma is a
      reliable prognostic marker, both for survival and for functional recovery.

PMID- 12417235
TI  - Sleep cyclic alternating pattern in normal school-age children.
AB  - OBJECTIVES: To evaluate cyclic alternating pattern (CAP) in sleep of school-age
      children in order to obtain a standardized database for CAP parameters in this
      age range. METHODS: CAP parameters were quantified in 10 normal healthy subjects
      (6 males and 4 females, mean age 8.3 years; range 6-10 years). All subjects
      underwent polysomnography recordings for two consecutive nights in a standard
      laboratory setting. Sleep data were stored on computer using a 16-channel
      polysomnography digital system. Sleep macrostructure was visually scored
      according to the criteria by Rechtschaffen and Kales (Brain Information
      Service/Brain Research Institute, University of California, Los Angeles, 1968);
      CAP was visually scored following the criteria by Terzano et al. (Sleep Med 2
      (2001) 537). RESULTS: CAP rate showed a progressive increase with the deepness of
      sleep, with high values during slow wave sleep (SWS). CAP time showed its longest
      duration during non-REM (NREM) sleep stage 2 (S2), followed by SWS and sleep
      stage 1 (S1). No differences across NREM sleep stages were found for CAP cycle
      and phase B mean duration; on the contrary, phase A showed longer duration during
      SWS than in S1 and S2. Phases A1 were the most numerous (84.45%) followed by A3
      (9.14%) and by A2 (6.44%). The distribution of phases A subtypes across NREM
      stages showed significant differences for the A1 subtypes that occurred more
      frequently during SWS than in S2 and S1 (and during S2 than in S1). Subtypes A3
      were more frequent during S1 than SWS while no differences were found for subtype
      A2. The analysis of A1 interval distribution showed a log-normal-like
      distribution with a peak around 25 s for the A1 phases and no clear peak for A2
      A3 phases. CONCLUSIONS: The analysis of CAP in school-age children is
      characterized by an increase of CAP rate during SWS and a high percentage of A1
      phases. The distribution of interval between consecutive A1 phases showed a peak
      around 25 s.

PMID- 12417236
TI  - Actigraphic assessment of sleep-wake rhythm during the first 6 months of life.
AB  - OBJECTIVES: To examine the validity of the "Gaehwiler" actigraph (Gaehwiler
      Electronics, model Z80-32k V(1)) for the assessment of sleep-wake (S/W) rhythm
      and sleep structure in infants during the first 6 months of life using an
      algorithm developed in our laboratory to differentiate sleep and wake states.
      METHODS: A continuous 72 h actigraphic recording was performed in 10 healthy
      infants at 1, 3 and 6 months of age. The actigraphic data were matched to direct
      observation of the infants' behavioural states. Using discriminant function
      analysis a scoring algorithm for automatic identification of S/W states from raw
      activity data was developed. The chi-square periodogram analysis was performed to
      estimate periodic components of S/W rhythm. RESULTS: The overall agreement rates
      between the actigraphic and observer scoring for S/W were between 87 and 95% for
      the infants after the third month of life, while for the 1-month-old infants they
      never exceeded 72%. The actigraphic discrimination between active and quiet sleep
      was the best in 3-month-old infants. The circadian influence on S/W rhythm was
      already present by the end of the first month of life. CONCLUSIONS: Using the
      "Gaehwiler" actigraph in our study, valid discrimination between sleep and wake
      states was obtained in infants during 3 and 6 months. The actigraph, however, did
      not provide valid active vs. quiet sleep state measures. The circadian rhythm of
      S/W was observed as early as during the first month of life.

PMID- 12417237
TI  - DC-EEG discloses prominent, very slow activity patterns during sleep in preterm
      infants.
AB  - OBJECTIVES: The objective of this study is to test the hypothesis that the
      immature human brain exhibits slow electrical activity that is not detected by
      conventional (i.e. high-pass filtered) electroencephalography (EEG). METHODS: Six
      healthy preterm infants (conceptional age 33-37 weeks) were recorded bedside with
      direct current (DC) EEG during sleep. Epochs with quiet sleep were selected to
      study the delta frequency bursts during discontinuous EEG patterns (trace
      discontinu or trace alternant), and we compared the waveforms obtained without
      filtering (i.e. genuine DC-EEG) to those seen after high pass filtering of the
      same traces. RESULTS: In all infants, DC-EEG demonstrated that the typical delta
      frequency bursts are consistently embedded in very large amplitude (200-700
      microV) and long lasting (1-5s) occipitally negative transients, which are not
      seen in conventional EEG. CONCLUSIONS AND SIGNIFICANCE: Our study demonstrates
      that (i) the most prominent spontaneous EEG activity of a sleeping preterm infant
      consists of very slow, large amplitude transients, and (ii) the most salient
      features of these transients are not seen in conventional EEG. Proper recording
      of this type of brain activity by DC-EEG provides a novel way for non-invasive
      assessment of neonatal brain function.

PMID- 12417238
TI  - An automatic method for the recognition and classification of the A-phases of the
      cyclic alternating pattern.
AB  - OBJECTIVES: The aim of this research has been to introduce an automatic method,
      simple from the mathematical and computational points of view, for the
      recognition and classification of the A-phases of the cyclic alternating pattern.
      METHODS: The automatic method was based on the computation of 5 descriptors,
      which were derived from the EEG signal and were able to provide a meaningful data
      reduction. Each of them corresponded to a different frequency band. RESULTS: The
      computation of these descriptors, followed by the introduction of two suitable
      thresholds and of simple criteria for logical discrimination, provided results
      which were in good agreement with those obtained with visual analysis. The method
      was versatile and could be applied to the study of other important microstructure
      phenomena by means of very small adaptations. CONCLUSIONS: The simplicity of the
      method leads to a better understanding and a more precise definition of the
      visual criteria for the recognition and classification of the microstructure
      phenomena.

PMID- 12417239
TI  - Reference values of motor unit potentials (MUPs) of the external anal sphincter
      muscle.
AB  - OBJECTIVE: To provide reference values for the isolated motor unit potentials
      (MUPs) in the external anal sphincter (EAS) muscle, as mean duration, mean
      amplitude, mean area, number of turns and number of phases, related to the age of
      the patient. These data are not available in worldwide literature in spite of the
      fact that the EAS muscle is being increasingly mentioned in relation to
      differential diagnosis. METHODS: Study of 235 subjects aged 0-80 years using an
      automated analysis program. RESULTS: The study performed shows a clear gradual
      progression of the mean duration with patient age. The variability of all other
      parameters tested is also analyzed. CONCLUSIONS: Our study shows that the
      classical values of MUPs isolated in the EAS muscle are directly related to age,
      and that this method is fully reliable to study its pathological conditions.

PMID- 12417240
TI  - Selective attention to spatial frequency: an ERP and source localization
      analysis.
AB  - OBJECTIVES: Physiological correlates of visual selective attention have been
      observed by recording ERPs to attended versus ignored target stimuli. Over many
      such studies, spatial attention has been observed to modulate early sensory
      components beginning 70 ms after stimulus onset, while effects of selection based
      on other stimulus features such as color and spatial frequency occur at longer
      latencies. Together, these findings argue for a primacy of location in early
      attentional selection. However, there have been some reports suggesting attention
      effects on short latency sensory-evoked potentials during selection of spatial
      frequency. The prime objective of the present study was to assess whether or not
      spatial frequency-dependent potentials are modulated by attention at a latency as
      early as 70-100 ms. METHODS: Checkerboard patterns were flashed to the subject,
      one being the target requiring a response. We investigated attentional effects
      using high-density scalp mapping and inverse dipole modeling. RESULTS: The
      earliest robust signs of selective attention to spatial frequencies consisted of
      an occipital selection negativity (OSN) and a frontal selection positivity (FSP).
      The OSN started at a latency of 140 ms, the FSP somewhat earlier at 120 ms. These
      attention effects were readily modeled by sources in cortical areas ventrally and
      laterally to the more primary areas generating the shorter-latency sensory
      components. CONCLUSIONS: This pattern of results has been found for non-spatial
      stimulus features in several studies, and is clearly different from the ERP
      correlates of spatial selection.

PMID- 12417241
TI  - Role of short latency evoked potentials in the diagnosis of brain death.
AB  - OBJECTIVE: The aim of this study is to confirm the effectiveness of auditory
      brain-stem responses (ABRs) and somatosensory evoked potentials (SEPs) in the
      diagnosis of brain death (BD). METHODS: ABRs and SEPs were recorded at the same
      session in 130 BD patients (age range 8-77 years, 81 male and 49 female). Twenty
      four cases were submitted to serial recordings from preterminal conditions
      through BD. RESULTS: ABRs were absent in 92 cases (70.8%), only waves I or I-II
      were present in 32 cases (24.6%), while in the remaining 6 patients (4.6%) waves
      V and/or III were still present, excluding the death of the brain-stem. In 4
      cases (3.1%) SEPs showed the absence of all components following the cervical N9,
      preventing the diagnosis of BD. Among 126 cases (96.9%) with preserved cervical
      N9-N13 SEPs confirmed the absence of brain-stem activity in 122 cases (93.7%), in
      whom no waves following P11 or P13 were recordable. SEPs excluded the diagnosis
      of BD in the remaining 4 cases (3.2%) showing preserved P14 and/or N18. In all
      pre terminal patients the far-field P14-N18 were present, and their disappearance
      was closely related to the onset of BD. CONCLUSIONS: The combined us of ABRs and
      SEPs was able to confirm BD in almost all patients, providing an objective
      confirmation of the diagnosis, and to exclude it in 7 cases, thus improving the
      reliability of diagnosis.

PMID- 12417242
TI  - Combined scalp-thalamic EEG recording in sleep and epilepsy.

PMID- 12417244
TI  - Combined scalp-thalamic EEG recording in sleep and epilepsy.

PMID- 12417245
TI  - HSP20, low-molecular-weight heat shock-related protein, acts extracellularly as a
      regulator of platelet functions: a novel defense mechanism.
AB  - We previously showed that a dissociated form of a low-molecular-weight heat shock
      related protein 20 (HSP20) but not an aggregated form of HSP20 suppresses
      platelet aggregation. In the present study, we investigated the behavior of HSP20
      in response to endothelial injury and the possible mechanism of HSP20 in platelet
      functions. The levels of HSP20 in vessel wall after endothelial injury were
      markedly reduced. This observation was supported by the results of Western
      blotting analysis and immunohistochemical analysis. Additionally, the plasma
      levels of HSP20 in cardiomyopathic hamsters were markedly elevated.
      Centrifugation on sucrose density gradients allowed detection mainly of the
      dissociated form of plasma HSP20 in these hamsters. Human platelets showed
      specific binding sites for HSP20. Moreover, HSP20 markedly reduced thrombin
      induced phosphoinositide hydrolysis by phospholipase C in human platelets. Taken
      together, our results strongly suggest that HSP20, which immediately responds to
      pathological events, acts extracellularly as a regulator of platelet functions.

PMID- 12417246
TI  - Pharmacokinetics and immunologic consequences of exposing macaques to purified
      homologous butyrylcholinesterase.
AB  - Exposure to organophosphorus compounds (OPs), in the form of nerve agents and
      pesticides poses an ever increasing military and civilian threat. In recent
      years, attention has focused on the use of exogenously administered
      cholinesterases as an effective prophylactic treatment for protection against
      OPs. Clearly, a critical prerequisite for any potential bioscavenger is a
      prolonged circulatory residence time, which is influenced by the size of protein,
      the microheterogeneity of carbohydrate structures, and the induction (if any) of
      anti-enzyme antibodies following repeated injections of the enzyme. Previously,
      it was demonstrated that multiple injections of equine butyrylcholinesterase
      (BChE) into rabbits, rats, or rhesus monkeys, resulted in a mean residence time
      spanning several days, and variable immune responses. The present study sought to
      assess the pharmacokinetics and immunological consequences of administration of
      purified macaque BChE into macaques of the same species at a dose similar to that
      required for preventing OP toxicity. An i.v. injection of 7,000 U of homologous
      enzyme in monkeys demonstrated much longer mean residence times in plasma (MRT =
      225 +/- 19 h) compared to those reported for heterologous Hu BChE (33.7 +/- 2.9
      h). A smaller second injection of 3,000 U given four weeks later, attained
      predicted peak plasma levels of enzyme activity, but surprisingly, the MRT in the
      four macaques showed wide variation and ranged from 54 to 357 h. No antibody
      response was detected in macaques following either injection of enzyme. These
      results bode well for the potential use of human BChE as a detoxifying drug in
      humans.

PMID- 12417247
TI  - Cyclic changes of plasma spermine concentrations in women.
AB  - Based on previous studies which suggest that blood polyamines fluctuate during
      the menstrual cycle, the present study was set to determine whether plasma
      concentrations of the polyamine spermine show menstrual cycle-associated changes
      and if so, how these changes relate to phasic variations in other female
      hormones. Blood samples were collected from a group of 9 healthy women of various
      ages at 5 defined periods during their menstrual cycle including 1 woman on oral
      contraceptives. Spermine concentrations were determined in plasma acid extracts
      by reversed-phase high performance liquid chromatography method. Plasma
      estradiol, LH and FSH were measured by microparticle enzyme immunoassay using an
      automatic analyzer. Spermine concentrations, 104.4 +/- 12.2 nmol/ml at 1-3 day of
      the cycle, were increased transiently with a peak (263.8 +/- 22.1 nmol/ml) at 8
      10 day and declined to 85.4 +/- 29.8 nmol/ml by 21-23 day of the cycle. The peak
      spermine concentrations coincided with the first increase in plasma estrogen
      levels. The individual variations in the temporal profile of spermine
      concentrations were of similar magnitude as individual differences in other
      female hormones. We conclude that: a) Plasma spermine concentrations undergo
      distinct cyclic alterations during the menstrual cycle with peak concentrations
      coinciding with the first estradiol increase, and b) Peak plasma spermine
      concentrations occur during the follicular phase, just prior to ovulation, during
      the period of rapid endometrial growth.

PMID- 12417248
TI  - Antidepressant-like effects of tramadol and other central analgesics with
      activity on monoamines reuptake, in helpless rats.
AB  - Affective states are regulated mainly by serotonin and noradrenaline. However the
      opioid system has been also related to antidepressant-induced mood improvement,
      and the mu-opioid receptor has been involved in affective responses to a
      sustained painful stimulus. Similarly, antidepressant drugs induce an
      antinociceptive effect via both the monoaminergic and opioid systems, probably
      involving sensorial and affective dimensions of pain. The aim of this study was
      to test three opiate analgesics, which also inhibit monoamine reuptake, in the
      learned helplessness model of depression in rats. Helpless rats receiving (+/
      )tramadol (10, 20 mg/Kg) or (-)methadone (2, 4 mg/Kg) showed a decreased number
      of failures to avoid or escape aversive stimulus (shock) in both the second and
      the third daily sessions, compared with controls. Rats receiving levorphanol
      (0.5, 1 mg/Kg) showed a decreased number of such failures in the third session.
      The number of crossings in the intertrial interval (ITI) was not significantly
      modified by (+/-)tramadol or (-)methadone. Levorphanol enhanced ITI crosses at 1
      mg/Kg. These results, together with other clinical and experimental data, suggest
      that analgesics with monoaminergic properties improve mood and that this effect
      may account for their analgesic effect in regulating the affective dimension of
      pain. From this, it seems probable that the analgesic effect of opiates could be
      induced by adding together the attenuation produced of both the sensorial and the
      affective dimensions of pain.

PMID- 12417249
TI  - Effects of chronic administration of a heme oxygenase substrate or inhibitor on
      progression of the estrous cycle, pregnancy and lactation of Sprague-Dawley rats.
AB  - The purpose of this study was to investigate whether a heme oxygenase substrate
      (hemin) or an inhibitor (chromium mesoporphyrin IX; CrMP) had any effect on the
      normal course of the estrous cycle, pregnancy, parturition or lactation in rats.
      The hypothesis was that these agents, acting on HO to increase or decrease
      endogenous production of carbon monoxide (CO) respectively, would disrupt these
      reproductive processes. The results showed that hemin administered s.c. at 30
      micromoles/kg for 10 or 11 days, did not markedly influence the estrous cycle;
      whereas CrMP blocked the estrous cycle in a dose dependant fashion. At 2 and 4
      micromoles/kg for 11 days CrMP significantly reduced the occurrence of estrus
      phase of the estrous cycle and the effect continued after the treatments were
      discontinued, while a dose of 1 micromole/kg produced no significant effects.
      CrMP, administered at 4 micromoles/kg during days 5-14 of pregnancy, led to
      massive fetal resorption with no live births from 14 successfully mated rats.
      Administration of hemin at 30 micromoles/kg for 10 days during lactation did not
      have any effect on milk production, whereas administration of CrMP at 4
      micromoles/kg significantly decreased lactational performance which was
      attributed to milk production and not to suckling intensity of the pups. From
      these observations we conclude that heme oxygenase, and presumably endogenous CO,
      play positive roles in female reproductive processes and lactation in the rat.

PMID- 12417250
TI  - Nociceptin/orphanin FQ and related peptides reduce the increase in plasma
      corticosterone elicited in mice by an intracerebroventricular injection.
AB  - Nociceptin/orphanin FQ (=N/OFQ), the endogenous ligand of ORL1 receptor (=NOP),
      has been reported to induce, in rodents, after intracerebroventricular (i.c.v.)
      administration, anti-stress and anxiolytic effects. We have observed that the
      handling of mice followed by an i.c.v. injection of saline, induced a marked
      increase in the plasma corticosterone level (+250%) measured 30 minutes later.
      When N/OFQ was injected intracerebroventricularly, using a 1 microg dose, the
      increase in plasma corticosterone was significantly lower than in saline injected
      mice. N/OFQ(1-13)NH(2), known as a NOP receptor agonist, at the same 1 microg
      dose, also induced a lesser increase in plasma corticosterone level than a saline
      i.c.v. injection. The pseudopeptide [Phe(1)-psi(CH(2)-NH)Gly(2)]N/OFQ(1-13)NH(2),
      defined either as an agonist or an antagonist of NOP receptor, at the 0.1 microg
      dose, behaved in a similar manner as N/OFQ, by decreasing the plasma
      corticosterone level. Finally, [Nphe(1)]N/OFQ(1-13)NH(2), although presumed to be
      a selective NOP receptor antagonist, also decreased the corticosterone level at
      the 0.1 microg dose. These observations suggest the implication of N/OFQ in the
      regulation of response to stress, through an action on the hypothalamo-pituitary
      adrenocortical axis. Moreover, they evidence a similar effect of N/OFQ and
      N/OFQ(1-13)NH(2), but also of two other related peptides displaying antagonist
      properties on NOP receptors. These data suggest that several subtypes of N/OFQ
      receptors could exist.

PMID- 12417251
TI  - Effects of fluoxetine on the activity of phagocytosis in stressed mice.
AB  - We studied the effects of 1, 2, 5, 10 and 20 mg/kg of fluoxetine on the activity
      of phagocytosis in mice subjected to a chronic auditory stressor. Both the in
      vitro and in vivo activity of phagocytosis, measured using the zymosan-particle
      uptake method and the carbon clearance test, respectively, were reduced after 2,
      4, 8 and 16 days of stress exposure. A partial recovery on the in vivo activity
      of phagocytosis was found on day 16th. Daily treatment with fluoxetine partially
      reversed the adverse effects of stress in a dose-dependent manner on both
      parameters but did not significantly affect the activity of phagocytosis in
      unstressed mice. Significant differences appeared when fluoxetine was
      administered at 2 mg/kg. Maximum effect was reached at 5 mg/kg.

PMID- 12417252
TI  - Levodopa modulating effects of inducible nitric oxide synthase and reactive
      oxygen species in glioma cells.
AB  - Neurological injury and Parkinson disease (PD) are often associated with the
      increase of nitric oxide (NO) and free radicals from resident glial cells in the
      brain. In vitro, exposure to L-3-4-dihydroxyphenylalanine (L-DOPA), one of the
      main therapeutic agents for the treatment of PD, can lead to neurotoxicity. In
      this study, lipopolysaccharide (LPS) and interferon-gamma (IFN-g) were used to
      stimulate C6 glioma cells in the presence of varying concentrations of L-DOPA (1
      microM-1 mM). The results indicated a slight augmentation of NO(2)(-) production
      at low concentrations of L-DOPA (<100 microM) and complete inhibition of NO(2)(-)
      at higher concentrations (500 microM, 1 mM), (p < 0.001). Western blot analysis
      corroborated that L-DOPA effects on iNOS was at the level of its protein
      expression. Total reactive oxygen species (ROS) were detected using 2', 7'
      dichlorofluorescein diacetate fluorescence dye (2', 7'-DCFC) and there was an
      increase of intensity with the increasing concentrations of L-DOPA. Furthermore,
      large amounts of superoxide (O(2)(-)) and hydrogen peroxide (H(2)O(2)) were
      generated from the autoxidation of L-DOPA. C6 cells contain high levels of
      catalase, with inadequate levels of superoxide dismutase (SOD); therefore, there
      was an accumulation of O(2)(-), tantamount to elevation in 2'7'-DCFC intensity.
      Simultaneous accumulation of O(2)(-) and NO(2)(-) would propel formation of
      peroxynitrite (ONOO-). SOD completely attenuated the autoxidation of L-DOPA and
      significantly reversed the inhibitory effects on iNOS at high concentrations. The
      data obtained confirmed that the observed effects on iNOS were not due to the
      activation of the D(1) or beta1 adrenergic receptors by L-DOPA. It was concluded
      from this study that L-DOPA contributed to the modulation of iNOS and to the
      increase of O(2)(-) production in the stimulated glioma cells in vitro.

PMID- 12417253
TI  - Effects of sphondin, isolated from Heracleum laciniatum, on IL-1beta-induced
      cyclooxygenase-2 expression in human pulmonary epithelial cells.
AB  - Recently, under large-scale screening experiments, we found that sphondin, a
      furanocoumarin derivative isolated from Heracleum laciniatum, possessed an
      inhibitory effect on IL-1beta-induced increase in the level of COX-2 protein and
      PGE(2) release in A549 cells. Accordingly, we examined in the present study the
      action mechanism of sphondin on the inhibition of IL-1beta-induced COX-2 protein
      expression and PGE(2) release in a human pulmonary epithelial cell line (A549).
      Pretreatment of cells with sphondin (10-50 microM) concentration-dependently
      attenuated IL-1beta-induced COX-2 protein expression and PGE(2) release. The IL
      1beta-induced increase in COX-2 mRNA expression was also attenuated by sphondin
      (50 microM). The selective COX-2 inhibitor, NS-398 (0.01-1 microM), inhibited the
      activity of the COX-2 enzyme in a concentration-dependent manner, while sphondin
      (10-50 microM) had no effect. Sphondin (50 microM) did not affect the IL-1beta
      induced activations of p44/42 MAPK, p38 MAPK, and JNK. Treatment of cells with
      sphondin (50 microM) or the NF-kappaB inhibitor, PDTC (50 microM) partially
      inhibited IL-1beta-induced degradation of IkappaB-alpha in the cytosol and
      translocation of p65 NF-kappaB from the cytosol to the nucleus. Furthermore, IL
      1beta-induced NF-kappaB-specific DNA-protein complex formation in the nucleus was
      partially inhibited by sphondin (50 microM) or PDTC (50 microM). Taken together,
      we demonstrate that sphondin inhibits IL-1beta-induced PGE(2) release in A549
      cells; this inhibition is mediated by suppressing of COX-2 expression, rather
      than by inhibiting COX-2 enzyme activity. The inhibitory mechanism of sphondin on
      IL-1beta-induced COX-2 expression may be, at least in part, through suppression
      of NF-kappaB activity. We conclude that sphondin may have the therapeutic
      potential as an anti-inflammatory drug on airway inflammation.

PMID- 12417255
TI  - Endoplasmic reticulum (ER) stress: hepatitis C virus induces an ER-nucleus signal
      transduction pathway and activates NF-kappaB and STAT-3.
AB  - Human hepatitis C virus (HCV) is the leading cause of chronic hepatitis, which
      often results in liver cirrhosis and hepatocellular carcinoma. The HCV RNA genome
      codes for at least ten proteins. The HCV non-structural protein 5A (NS5A) has
      generated considerable interest due to its effect on interferon sensitivity via
      binding and inactivating the cellular protein kinase, PKR. It has been shown that
      NS5A engages in the endoplasmic reticulum (ER)-nucleus signal transduction
      pathway. The expression of NS5A in the ER induces an ER stress ultimately leading
      to the activation of STAT-3 and NF-kappaB. This pathway is sensitive to
      inhibitors of Ca(2+) uptake in the mitochondria (ruthenium red), Ca(2+) chelators
      (TMB-8, EGTA-AM), and antioxidants (PDTC, NAC, Mn-SOD). The inhibitory effect of
      protein tyrosine kinase (PTK) inhibitors indicates the involvement of PTK in NF
      kappaB activation by NS5A. This implicates an alternate pathway of NF-kappaB
      activation by NS5A. The actions of NS5A have also been studied in the context of
      an HCV subgenomic replicon inducing a similar intracellular event. Thus,
      activation of NF-kappaB leads to the induction of cellular genes, which are
      largely antiapoptotic in function. These studies suggest a potential function of
      NS5A in inducing chronic liver disease and hepatocellular carcinoma associated
      with HCV infection.

PMID- 12417254
TI  - Phospholipase C axis is the preferential pathway leading to PKC activation
      following PTH or PTHrP stimulation in human term placenta.
AB  - Parathyroid-related peptide (PTHrP) is abundant in human syncytiotrophoblast
      where it was suggested to play an important role in maternal-fetal calcium
      homeostasis. On the other hand, parathyroid hormone (PTH), another hypercalcemic
      factor, would be implicated in the maintenance of the mother's calcium balance.
      In many cells, these hormones are associated to G-coupled receptors and activate
      protein kinase (PKC). Thus, the first aim of this study was to determine the
      cellular pathway (phospholipase; PLC and phosphatidyl-inositol-3 kinase; PI3K)
      leading to the activation of PKC following a PTH or PTHrP stimulation in brush
      border (BBM) and basal plasma membranes (BPM) of human term placenta. Both
      peptides were shown to be potent modulators of the PKC activity in these
      membranes with optimal concentrations of 10(-8)M and 10(-9)M for hPTH and hPTHrP,
      respectively. Furthermore, the use of bisindolylmaleimide (BIM), a non-selective
      PKC inhibitor, serves to demonstrate the specificity of the PKC-dependent MARCKS
      psd phosphorylation. While LY-294002, a PI3K inhibitor failed to counteract the
      hPTH- and hPTHrP-induced PKC stimulation in BBM and BPM, U-73122, a PLC
      inhibitor, totally abolished the PKC stimulation by hPTH and hPTHrP. Taken
      together, these data suggest that the activation of PKC by hPTH or hPTHrP, in BBM
      and BPM, is preferentially associated to the PLC pathway rather than the PI3K's.

PMID- 12417256
TI  - Role of noradrenaline on the expression of the Na+/K+-ATPase alpha2 isoform and
      the contractility of cultured rat vas deferens.
AB  - Rat vasa deferentia were cultured for 3 days in Dulbecco's modified Eagle's
      medium in the absence or presence of 1 microM noradrenaline (NA) to investigate
      if the lack of NA release is the key factor to explain the selective reduction of
      the Na(+)/K(+)-ATPase alpha(2) isoform previously observed after in vivo
      denervation of this organ (Quintas et al., Biochem Pharmacol 2000;60:741-7). The
      lack of effects of the indirect sympathomimetic tyramine and the neuronal amine
      uptake blocker cocaine on NA curves indicated that cultured organs were
      denervated completely. Organ culture induced supersensitivity, expressed as a 6.3
      fold increase of pD(2) and a 42% elevation of maximal contraction for NA but not
      for Ba(2+). Western blotting indicated that the level of the alpha(1) isoform of
      Na(+)/K(+)-ATPase was unchanged after organ culture, but the alpha(2) isoform was
      down-regulated drastically to levels that were barely detectable. The addition of
      NA to the culture medium did not prevent the reduction of alpha(2) expression
      although it did impede NA supersensitivity (in fact a 4-fold decrease of pD(2)
      and a 32% reduction of maximal response were observed after incubation in the
      presence of NA). A striking reduction of L-type Ca(2+) channel expression also
      was observed, indicated by an 85% decrease of [3H]isradipine binding sites. These
      data suggest that NA is a trophic factor relevant to the control of muscle
      contraction, mediated by alpha(1)-adrenoceptors, but not to the expression of
      either Na(+)/K(+)-ATPase or the L-type Ca(2+) channel.

PMID- 12417257
TI  - 5-Fluorouracil inhibits nitric oxide production through the inactivation of
      IkappaB kinase in stomach cancer cells.
AB  - The antimetabolite 5-fluorouracil (5-FU) is one of the more prominent clinical
      antitumor agents available for the treatment of stomach and colorectal cancers.
      In the present study, we characterized the effects of 5-FU on nitric oxide (NO)
      production by cells from the stomach cancer cell line NCI-N87. A cytokine mixture
      [interleukin (IL)-1beta/interferon (IFN)-gamma] increased the production of NO by
      stomach cancer cells in a concentration- and time-dependent manner. Pretreatment
      with 5-FU inhibited the production of NO that was stimulated by the cytokine
      mixture and reduced the expression of iNOS. The cytokine mixture activated
      nuclear factor kappaB (NF-kappaB) in a concentration- and time-dependent manner,
      which was blocked by 5-FU pretreatment. The pretreatment with 5-FU stabilized
      IkappaBalpha and inactivated IkappaB kinase. Collectively, these data suggest
      that the efficacy of 5-FU may include the inactivation of IkappaB kinase and the
      inhibition of NO production.

PMID- 12417258
TI  - Molecular cloning and characterization of mouse CYP2J6, an unstable cytochrome
      P450 isoform.
AB  - A cDNA encoding a new cytochrome P450 was cloned from a mouse liver library.
      Sequence analysis revealed that this 2046-bp cDNA encodes a 501-amino acid
      polypeptide that is 72-94% identical to other CYP2J subfamily P450s and is
      designated CYP2J6. Northern analysis demonstrated that CYP2J6 transcripts are
      abundant in the small intestine and present at lower levels in other mouse
      tissues. In situ hybridization revealed that CYP2J6 mRNAs are present in luminal
      epithelial cells of the gastrointestinal mucosa. The CYP2J6 cDNA was expressed in
      Sf9 cells using baculovirus. The heterologously expressed CYP2J6 protein
      displayed a typical P450 CO-difference spectrum; however, the protein was
      unstable as evidenced by the loss of the Soret maxima at 450nm and the appearance
      of a 420nm peak when CYP2J6-expressing cells were disrupted by mechanical
      homogenization, sonication, or freeze-thaw. Immunoblotting of mouse microsomes
      with the anti-human CYP2J2 IgG, which cross-reacts with rodent CYP2Js,
      demonstrated the presence of multiple distinct murine CYP2J immunoreactive
      proteins in various tissues. Immunoblotting with an antibody to a CYP2J6-specific
      peptide detected a prominent 55-57kDa protein in Sf9 cell extracts expressing
      recombinant CYP2J6 but did not detect a protein of similar molecular mass in
      mouse small intestinal microsomes. Mixing experiments demonstrated that
      recombinant CYP2J6 is degraded rapidly in the presence of small intestinal
      microsomes consistent with proteolysis at highly sensitive sites. Sf9 cells,
      which express both CYP2J6 and NADPH-P450 oxidoreductase, metabolized
      benzphetamine but not arachidonic acid. We conclude that CYP2J6 is an unstable
      P450 that is active in the metabolism of benzphetamine, but not arachidonic acid.

PMID- 12417259
TI  - Enhanced activity of human N-myristoyltransferase by dimethyl sulfoxide and
      related solvents in the presence of serine/threonine-containing peptide
      substrates.
AB  - Human N-myristoyltransferase (hNMT) activity was found to be stimulated several
      fold by DMSO and its analogues in the presence of serine-containing peptide
      substrates. DMSO caused a concentration-dependent 10-fold stimulation of hNMT
      activity in the presence of a pp60(src)-derived peptide substrate (Gly-Ser-Ser
      Lys-Ser-Lys-Pro-Lys-Arg). However, the stimulation of hNMT activity was not
      observed by DMSO when a cyclic AMP (cAMP)-dependent protein kinase-derived Ser
      free peptide substrate (Gly-Asn-Ala-Ala-Ala-Ala-Lys-Lys-Arg-Arg) was used. These
      findings suggested that the effect of DMSO is on the substrate rather than on the
      enzyme. When a MARCKS (myristoylated alanine-rich C-kinase substrate)-derived
      peptide substrate (Gly-Ala-Gln-Phe-Ser-Lys-Thr-Ala-Arg-Arg) and the M2 gene
      segment of the reovirus type 3 peptide substrate (Gly-Asn-Ala-Ser-Ser-Ile-Lys-Lys
      Lys) were used, hNMT activity was increased by approximately 8.5- and 7-fold,
      respectively. Dimethyl sulfone (20%) increased hNMT activity between 2.5- and 3.5
      fold in the presence of pp60(src), MARCKS, and M2 gene segment peptides. Dimethyl
      formamide (20%) increased the hNMT activity by 8.5-, 8.5-, 5.5- and 3.5-fold when
      pp60(src), MARCKS, M2, and cAMP-dependent protein kinase-derived peptide
      substrates were used, respectively. Acetone (20%) also increased the hNMT
      activity by 20-fold in the presence of the pp60(src) peptide substrate. Dimethyl
      ammonium chloride (20%) caused about 6.5- and 2.5-fold increases in the hNMT
      activity in the presence of the pp60(src) and cAMP-dependent protein kinase
      derived peptide substrates, respectively. Infrared spectroscopy showed a
      decreased intensity in the band at 3500-3600cm(-1) when the infrared spectrum of
      the pp60(src)-derived peptide was determined in the presence of DMSO. These
      results suggest the involvement of hydrogen bonding between the heteroatoms of
      the organic molecules and the hydrogen atoms of the free hydroxyl groups of the
      serine/threonine-containing peptide substrates. Such interactions appear to
      enhance the activity of hNMT towards its serine-containing substrates.

PMID- 12417260
TI  - UVB light suppresses nitric oxide production by murine keratinocytes and
      macrophages.
AB  - Nitric oxide is an important mediator of excessive cell growth and inflammation
      associated with many epidermal proliferative disorders. It is a highly reactive
      oxidant generated in keratinocytes and macrophages via the inducible form of the
      enzyme nitric oxide synthase (NOS2). In the present studies, we examined the
      effects of ultraviolet light (UVB, 2.5-25mJ/cm(2)) on interferon-gamma (IFN
      gamma)-induced expression of NOS2 in these cells. Transient transfection assays
      using wild-type and mutant NOS2 promoter/luciferase reporter constructs showed
      that DNA binding of the transcription factors Stat1 and NF-kappaB was essential
      for optimal expression of the NOS2 gene. Whereas NF-kappaB was constitutively
      expressed in both cell types, Stat1 phosphorylation and nuclear binding activity
      were dependent upon IFN-gamma. UVB light, which is used therapeutically to treat
      inflammatory dermatosis, was found to suppress IFN-gamma-induced expression of
      NOS2 mRNA and protein, and nitric oxide production in both keratinocytes and
      macrophages. In macrophages, this was associated with complete inhibition of NF
      kappaB nuclear binding activity and partial (approximately 20-25%) reduction of
      Stat1 activity. In keratinocytes, both responses were partially reduced at the
      highest doses of UVB light (15-25mJ/cm(2)). Whereas in macrophages UVB light
      suppressed NOS2 wild-type promoter-luciferase reporter activity, this activity
      was stimulated in keratinocytes. These data suggest that UVB light functions to
      suppress NOS2 gene expression in macrophages by inhibiting the activity of key
      regulatory transcription factors. In contrast, in keratinocytes, inhibition
      occurs downstream of NOS2 promoter activity.

PMID- 12417261
TI  - Differential effect of simvastatin on activation of Rac(1) vs. activation of the
      heat shock protein 27-mediated pathway upon oxidative stress, in human smooth
      muscle cells.
AB  - In the present study, we have analyzed the response of human smooth muscle cell
      (SMC)s to oxidative stress, in terms of recruitment of key elements of the stress
      activated protein kinase (SAPK) pathway, such as Rac(1), p38, and the small heat
      shock protein (HSP)27. The level of expression of three small HSPs, alphaB
      crystallin, HSP20, HSP27, as well as the phosphorylation levels of HSP27 and p38,
      were higher in cultured, asynchronously growing SMCs originating from left
      interior mammary artery (LIMA) than those originating from aorta, saphenous vein,
      and umbilical vein, validating the choice of SMCs from LIMA as a model system in
      our study. In synchronized, quiescent SMCs from LIMA, oxidative stress (H(2)O(2)
      stimulation)-induced membrane translocation of Rac(1), p38 phosphorylation,
      membrane translocation, and phosphorylation of HSP27. In these cells, simvastatin
      (S), an HMG-CoA reductase inhibitor, blocked, in a mevalonate-dependent way,
      oxidative stress-induced membrane translocation of Rac(1). However, S
      pretreatment prior to oxidative stress increased the levels of p38
      phosphorylation, HSP27 membrane translocation/phosphorylation, actin
      polymerization, and apoptosis in these cells, in a mevalonate-dependent way.
      These results establish that S pretreatment has a stimulatory effect on the
      stress-activated p38/HSP27 pathway, despite its blocking effect on Rac(1)
      activation.

PMID- 12417262
TI  - Analytical and pharmacokinetic studies with 5-chloro-2'-deoxycytidine.
AB  - 5-Chloro-2'-deoxycytidine (NSC 371331, CDC) is in development as a possible
      radiosensitizing agent for cancer treatment. Previous studies have been done to
      demonstrate the in vivo efficacy of CDC with various modulators of its
      metabolism. This paper describes our preclinical studies to determine the
      pharmacokinetic properties of CDC and the disposition of the drug, both alone and
      in the presence of the metabolic modulator tetrahydrouridine (THU), a cytidine
      deaminase inhibitor. Detection of the drug in biological fluids was performed by
      HPLC analysis using a C-18 column, gradient elution with solvents composed of
      aqueous trifluoroacetic acid and acetonitrile, and ultraviolet absorbance at 290
      nm. Samples were processed by treatment with ammonium sulfate prior to injection
      into the HPLC system. CDC was stable in aqueous solution and in mouse plasma.
      High doses of CDC (100mg/kg) were given i.v. or i.p. to mice for the
      determination of CDC plasma half-life (10 min). CDC was not detectable in plasma
      after oral administration. It was converted rapidly to 5-chloro-2'-deoxyuridine
      (CDU) by cytidine deaminase, and CDU was readily discernable in plasma and urine
      samples collected after i.v. and i.p. administration of CDC. When CDC in doses
      ranging from 5 to 100mg/kg was given with 100mg/kg of THU, increased plasma
      levels of CDC were seen. CDC was eliminated through the kidneys, as well as by
      enzymatic deamination, and did not bind to plasma proteins. The initial steps of
      the CDC metabolic pathway were determined in vitro with isolated enzymes.
      Cytidine deaminase from mouse kidney converted CDC into CDU; thymidine
      phosphorylase converted CDU into 5-chlorouracil (5-CU). The conclusions of these
      studies are: (a) CDC is a drug with a short half-life and (b) it is excreted
      through the kidney, mainly in metabolite form. Administration of THU
      substantially increased the concentrations of CDC in mouse plasma, supporting
      proposals that the combination of THU with CDC should be evaluated in clinical
      trials.

PMID- 12417263
TI  - Cytotoxicity of dopamine-derived tetrahydroisoquinolines on melanoma cells.
AB  - Tetrahydroisoquinolines (TIQs) are endogenous alkaloid compounds detected in
      urine, central nervous system and some peripheral tissues in Mammalia. No data
      are at present available on TIQ levels in skin, although in vitro biochemical
      evidences indicate that they may undergo auto-oxidation with production of
      reactive oxygen species or may be enzymatically converted into melanin pigments.
      The effect of two catechol-bearing TIQs, salsolinol (SAL) and
      tetrahydropapaveroline (THP), on the viability of melanotic or amelanotic
      melanoma cell lines was investigated. Both SAL and THP were well tolerated up to
      roughly 30 microM and became overtly toxic at higher concentrations, with SAL
      being better tolerated than THP. Intracellular activity of some antioxidant
      enzymes, tyrosinase and alpha-ketoglutarate dehydrogenase was also evaluated to
      assess the cell response to oxidative and metabolic challenge of TIQs treatment.
      Catalase and superoxide dismutase pre-treatment only partially prevented TIQs
      toxicity while a complete protection was obtained with N-acetylcysteine and GSH.
      TIQs were able to provoke upregulation of the scavenging enzymes catalase and DT
      diaphorase and to determine a decrease of the alpha-ketoglutarate dehydrogenase
      activity. SAL and THP enhanced tyrosinase activity and melanin production,
      suggesting that they were indeed tyrosinase substrates leading to melanin
      formation. The results support the evidence that TIQs were toxic toward melanoma
      cells, leading to their death by necrosis. TIQs toxicity was likely due to
      increased oxidative stress by generation of reactive oxygen species and oxidative
      metabolites. Our study represents an intent to furnish an additional contribution
      for the comprehension of catechol cytotoxicity.

PMID- 12417264
TI  - PXR-dependent induction of human CYP3A4 gene expression by organochlorine
      pesticides.
AB  - OCP are xenobiotics which display various toxic effects on animal and human
      health. One of their effects is to bind and activate estrogen receptor alpha
      (ERalpha). We have previously studied the down-regulation of induced CYP1A1
      (cytochrome P450) expression by this class of molecules in mammary carcinoma
      cells and shown the importance of ERalpha in this process. However, an
      alternative mechanism was suggested by those experiments in hepatoma cells. In
      this study, we have performed Northern blot and transient transfection assays in
      various cell lines and shown that OCP activate human pregnane X receptor (PXR)
      and subsequent CYP3A4 mRNA expression. This effect is mediated by the distal
      xenobiotic responsive element modulator of the promoter. The induction of CYP3A4
      by OCP was dose-dependent within the 1-10 microM range. The data suggest that
      chronic exposure to OCP could alter a major metabolite pathway in human liver and
      putatively modify the pharmacokinetics of drugs and pollutants.

PMID- 12417265
TI  - Antioxidants inhibit endothelin-1 (1-31)-induced proliferation of vascular smooth
      muscle cells via the inhibition of mitogen-activated protein (MAP) kinase and
      activator protein-1 (AP-1).
AB  - We previously found that human chymase cleaves big endothelins (ETs) at the
      Tyr(31)-Gly(32) bond and produces 31-amino acid ETs (1-31), without any further
      degradation products. In the present study, we investigated the effects of
      various antioxidants on the ET-1 (1-31)-induced change in intracellular signaling
      and proliferation of cultured rat aortic smooth muscle cells (RASMC). ET-1 (1-31)
      stimulated rapid and significant activation of the mitogen-activated protein
      (MAP) kinase family, i.e. extracellular signal-regulated kinase 1/2 (ERK1/2), c
      Jun NH(2)-terminal kinase (JNK), and p38 MAPK, in RASMC to an extent similar to
      that of ET-1. All of the antioxidants examined, i.e. N-acetyl-L-cysteine (NAC),
      diphenyleneiodonium chloride (DPI), and L-(+)-ascorbic acid (ascorbic acid),
      inhibited both ET-1 (1-31)- and ET-1-induced JNK and p38 MAPK activation but not
      ERK1/2 activation. Electron paramagnetic resonance (EPR) spectroscopy
      measurements revealed that NAC, DPI, and ascorbic acid inhibited xanthine oxidase
      induced superoxide (O(2)(.-)) generation in a cell-free system. ET-1 (1-31) in
      addition to ET-1 increased the generation of cellular reactive oxygen species
      (ROS) in RASMC. ET-1 (1-31)- and ET-1-induced cellular ROS generation was
      inhibited similarly by NAC, DPI, and ascorbic acid in RASMC. Gel-mobility shift
      analysis showed that ET-1 (1-31) and ET-1 caused an increase in activator protein
      1 (AP-1)-DNA binding activity in RASMC that was inhibited by the above three
      antioxidants. ET-1 (1-31) increased [3H]thymidine incorporation into cells to an
      extent similar to that of ET-1. This ET-1 (1-31)-induced increase in
      [3H]thymidine incorporation was also inhibited by NAC and DPI, but not by
      ascorbic acid. These results suggest that antioxidants inhibit ET-1 (1-31)
      induced RASMC proliferation by inhibiting ROS generation within the cells. The
      underlying mechanisms of the inhibition of cellular proliferation by antioxidants
      may be explained, in part, by the inhibition of JNK activation and the resultant
      inhibition of AP-1-DNA binding.

PMID- 12417266
TI  - Cellular energetics and glutathione status in NRK-52E cells: toxicological
      implications.
AB  - Cellular energetics and redox status were evaluated in NRK-52E cells, a stable
      cell line derived from rat proximal tubules. To assess toxicological implications
      of these properties, susceptibility to apoptosis induced by S-(1,2-dichlorovinyl)
      L-cysteine (DCVC), a well-known mitochondrial and renal cytotoxicant, was
      studied. Cells exhibited high activities of several glutathione (GSH)-dependent
      enzymes, including gamma-glutamylcysteine synthetase, GSH peroxidase, glutathione
      disulfide reductase, and GSH S-transferase, but very low activities of gamma
      glutamyltransferase and alkaline phosphatase, consistent with a low content of
      brush-border microvilli. Uptake and total cellular accumulation of [14C]alpha
      methylglucose was significantly higher when cells were exposed at the basolateral
      as compared to the brush-border membrane. Similarly, uptake of GSH was nearly 2
      fold higher across the basolateral than the brush-border membrane. High
      activities of (Na(+)+K(+))-ATPase and malic dehydrogenase, but low activities of
      other mitochondrial enzymes, respiration, and transport of GSH and dicarboxylates
      into mitochondria were observed. Examination of mitochondrial density by confocal
      microscopy, using a fluorescent marker (MitoTracker Orange), indicated that NRK
      52E cells contain a much lower content of mitochondria than rat renal proximal
      tubules in vivo. Incubation of cells with DCVC caused time- and concentration
      dependent ATP depletion that was largely dependent on transport and
      bioactivation, as observed in the rat, on induction of apoptosis, and on
      morphological damage. Comparison with primary cultures of rat and human proximal
      tubular cells suggests that the NRK-52E cells are modestly less sensitive to
      DCVC. In most respects, however, NRK-52E cells exhibited functions similar to
      those of the rat renal proximal tubule in vivo.

PMID- 12417268
TI  - Targeting the atherosclerotic process in clinical practice. A new look at
      established agents.

PMID- 12417269
TI  - Mechanisms of plaque stabilization for the dihydropyridine calcium channel
      blocker amlodipine: review of the evidence.
AB  - Coronary artery disease (CAD) is the consequence of atherosclerosis, a vascular
      disorder that is the leading cause of death and disability throughout much of the
      developed world. Certain cellular changes in the vulnerable atherosclerotic
      plaque are characterized by a loss of normal calcium regulation. This observation
      has led to interest in a potential antiatherogenic role for calcium channel
      blockers (CCBs), independent of their effects on vasodilation. The Prospective
      Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT)
      demonstrated that treatment with amlodipine, a third-generation CCB, in patients
      with documented CAD produced marked reductions in cardiovascular events as
      compared with placebo, without a reduction in coronary luminal loss. Amlodipine
      therapy was also associated with significant slowing in carotid atherosclerosis,
      an important surrogate marker for CAD, independent of blood pressure changes. The
      findings from PREVENT were remarkably consistent with another study known as the
      Coronary Angioplasty Amlodipine Restenosis Study (CAPARES). A reduction in the
      progression of carotid atherosclerosis has also been recently reported for
      lacidipine, another third-generation dihydropyridine CCB. These clinical findings
      have led to a renewed interest in potential plaque stabilization properties of
      certain CCBs, as will be systematically reviewed in this article. It is also
      probable that vascular protective agents, such as amlodipine may work in a
      synergistic fashion with other established treatments, including HMG-CoA
      reductase inhibitors, to effectively improve outcomes in patients who are at risk
      for or have established CAD.

PMID- 12417270
TI  - The genetic effect of the apoprotein AV gene on the serum triglyceride level in
      Japanese.
AB  - The newly identified apoprotein AV (apoAV) gene was suggested to have a
      significant effect on triglyceride (TG) metabolism in Caucasians. We studied the
      genetic effect of this gene on serum TG in a Japanese population. Participants
      (481 male and 412 female) were recruited at a health examination. A T/C single
      nucleotide polymorphism called SNP3 in the 5'-region of the apoAV gene was
      genotyped as described previously. The frequency of the C allele was much greater
      in Japanese than in Caucasians (0.34 vs. 0.08). The serum TG level in subjects
      with the TT genotype was significantly lower than the level in those with TC/CC
      (1.10, 1.25 and 1.21 mmol/l for TT, TC and CC, respectively, P=0.0003 by ANOVA),
      while there were no significant differences either in the serum total cholesterol
      or the low- and high-density lipoprotein cholesterol levels among the three
      genotypes. Multiple regression analysis indicated that SNP3 had a significant
      independent effect on the serum TG level in Japanese (P<0.0001). This result
      indicates that polymorphism in the apoAV gene influence serum TG in populations
      of different ethnicities.

PMID- 12417271
TI  - In vivo metabolism of apolipoprotein E within the HDL subpopulations LpE, LpE:A
      I, LpE:A-II and LpE:A-I:A-II.
AB  - High-density lipoproteins can be separated into distinct particles based on their
      apolipoprotein content. In the present study, the in vivo metabolism of apoE
      within the apoE-containing HDL particles LpE, LpE:A-I, LpE:A-II and LpE:A-I:A-II
      was assessed in control subjects and in patients with abetalipoproteinemia (ABL),
      in whom HDL are the sole plasma lipoproteins. The metabolism of apoE within these
      HDL subspecies was investigated in three separate studies which differed by donor
      or recipient status: (1) particles purified from normolipidemic plasma and
      reassociated with 125I or 131I-labeled apoE injected into normolipidemic subjects
      (study 1); (2) particles purified from ABL plasma injected into normolipidemic
      subjects (study 2); and (3) particles purified from ABL plasma injected into ABL
      subjects (study 3). The plasma residence times (RT, hours) in study 1 were 14.3+/
      2.9, 11.3+/-3.4, and 9.1+/-1.2 for apoE within LpE:A-I:A-II, LpE:A-II and LpE:A
      I, respectively, while those in study 2 were 10.1+/-2.2, 9.7+/-2.4, 7.9+/-1.0 and
      7.3+/-0.8 for apoE within LpE:A-I:A-II, LpE:A-II, LpE:A-I and LpE, respectively.
      In study 3, RTs for apoE within LpE:A-I:A-II and LpE were 8.7+/-0.9 and 6.8+/
      0.9, respectively. In comparison, RT for apoA-I on LpA-I:A-II has been reported
      to be 124.1+/-5.5 h and that for apoA-I on LpA-I 105.8+/-6.2 h. Thus, apoE within
      the different apoE-containing HDL particles was metabolized rapidly and at a
      similar rate in control and ABL subjects. The plasma RT of apoE was longest when
      injected on LpE:A-I:A-II particles and shortest when injected on LpE. In summary,
      our data show that: (1) the plasma RT of apoE within HDL is approximately ten
      times shorter than that of apoA-I within HDL, and (2) apoE within HDL is
      metabolized at a slower rate when apoproteins A-I and A-II are present (LpE:A-I:A
      II RT>LpE:A-II>LpE:A-I>LpE). These differences were related to the lipid and
      apolipoprotein composition of the HDL subspecies, and, in control subjects, to
      the transfer of apoE from HDL subspecies to apoB-containing lipoproteins as well.

PMID- 12417272
TI  - Decreased biglycan expression and differential decorin localization in human
      abdominal aortic aneurysms.
AB  - The hallmark feature of abdominal aortic aneurysm (AAA) is the progressive
      degeneration of aortic wall. Matrix proteoglycans (PGs) play important roles in
      the development of vascular diseases and the function of the tissue. In this
      study, we examined the concentration, expression and localization of the small
      extracellular matrix PG biglycan and decorin. The concentration of small PGs
      present in normal and aneurysmal aortas was determined by biochemical methods
      following extraction of the tissues with guanidine hydrochloride and treatment
      with collagenase/elastase, isolation by ion-exchange and gel chromatographies and
      identification by Western blotting. The levels of mRNA encoding for biglycan and
      decorin were evaluated in corresponding tissue samples by reverse transcriptase
      polymerase chain reaction (RT-PCR). Distribution of extracellular matrix
      macromolecules was examined using Movat's pentachrome staining and localization
      of biglycan and decorin by immunohistochemistry. Both normal and aneurysmal
      aortas contained almost equal amounts of decorin (1.13+/-0.08 and 1.22+/-0.10 mg
      uronic acid per g of dry defatted (dd) tissue, respectively). Furthermore, the
      expression of decorin was almost constant in both tissues. In normal specimens
      decorin accounts for 22% of total PGs, whereas in AAA ones for 60%, due to the
      significant loss of other matrix PGs. In contrast, the concentration of biglycan
      was markedly decreased in aneurysmal aortas (57%, 0.478+/-0.04 mg uronic acid per
      g of dd tissue) in comparison to normal ones (1.12+/-0.10 mg uronic acid per g of
      dd tissue). Biglycan accounts for 22% of total PGs in normal aortas and 25% of
      total in aneurysmal tissue. A similar decrease (60%) in the amounts of mRNA
      encoding for biglycan was observed in the AAA. Immunohistochemical study showed
      that all aortic layers of AAA were characterized by a significant loss of
      elastin, biglycan and other PGs/GAGs and replacement of these molecules with
      collagen fibrils and decorin. The obtained data suggest that the altered matrix
      architecture of aorta, i.e. the differential expression of biglycan and
      localization of decorin may well be crucial parameters accounting for the
      functional degeneration of the tissue and the development of aneurysmal
      dilatation.

PMID- 12417273
TI  - The magnitude of the immune response to heat shock protein-65 following BCG
      immunisation is associated with the extent of experimental atherosclerosis.
AB  - Several studies have reported associations between coronary heart disease (CHD)
      and infection. Recent studies have implicated immune responses to heat shock
      protein(s) (HSP) as a contributary factor. Using an immunisation model, we have
      assessed the relationship between the immune responses to HSP and subsequent
      atherosclerosis. Rabbits were immunised with bacillus Calmette-Guerin (BCG)
      vaccine (n=10) or saline (n=10) and subsequently fed a 0.25-1.0% cholesterol diet
      for 10 weeks. Plasma levels of IgG specific for mycobacterial antigen A60 and
      human HSP-60, but not for human HSP-70, rose following BCG immunisation, reaching
      a peak after 8 weeks. The percentage aortic area covered by atherosclerotic
      plaque was greater in animals immunised with BCG (30.5+/-3.8) compared to saline
      treated animals (16.4+/-2.6) (P<0.05). Furthermore, the individual titres of anti
      HSP-60 in the BCG-immunised animal antibodies at week 8 (prior to starting the
      cholesterol diet) correlated with the percentage aortic area covered by plaque
      after 18 weeks (R2=0.72; P<0.05). No correlation was found between anti-A60
      antibody titres and plaque area. Antiserum from BCG-immunised, but not control,
      animals stained heat-shocked endothelial cells. These data suggest that immune
      responses to HSP may be implicated in the relationship between specific
      infections and CHD.

PMID- 12417274
TI  - Lack of inhibitory effect of HDL on TNFalpha-induced adhesion molecule expression
      in human aortic endothelial cells.
AB  - Monocyte adhesion to and transmigration across the endothelium are initiating
      steps in atherogenesis. Cytokine-induced adhesion molecule expression in human
      umbilical vein endothelial cells (HUVEC) has been reported to be inhibited by
      either native HDL or reconstituted discoidal HDL (rHDL). In the present study we
      investigated these putative anti-atherosclerotic effects of HDL and rHDL in a
      more physiologically relevant cell type, i.e. human aortic endothelial cells
      (HAEC). HDL isolated by ultracentrifugation from eleven healthy subjects or rHDL
      made with apoA-I and either 1-palmitoyl-2-oleyl-sn-glycero-3-phosphocholine, 1
      palmitoyl-2-linoleoyl-sn-glycero-3-phosphocholine (PLPC), or 1,2-dimyristoyl-sn
      glycero-3-phosphocholine was incubated for 16 h with HAEC prior to stimulation
      with tumor necrosis factor-alpha (TNFalpha, 100 U/ml). Expression of E-selectin,
      vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1
      (ICAM-1) was measured by cell ELISA and Northern blot analysis. HDL (0.25, 0.5,
      1.0 and 2.0 mgprotein/ml) failed to significantly inhibit TNFalpha-induced mRNA
      and protein expression of all three adhesion molecules. Furthermore, of the three
      rHDL preparations (16 micromol/l apoA-I) only that containing the polyunsaturated
      PLPC significantly reduced TNFalpha-induced VCAM-1 expression (by 29.9+/-9.1%).
      These data contrast with previously reported results using plasma HDL and HUVEC,
      and show that human HDL and rHDL, except for PLPC-rHDL, are ineffective
      inhibitors of TNFalpha-induced adhesion molecule expression in HAEC. The ability
      of polyunsaturated phospholipids in HDL to affect endothelial activation remains
      to be further investigated.

PMID- 12417275
TI  - Determination of the cholesterol-collagen ratio of arterial atherosclerotic
      plaques using near infrared spectroscopy as a possible measure of plaque
      stability.
AB  - Particular danger associated with an arteriosclerotic plaque consists in the
      possible rupture of its cap, dependent on the thickness of the cap covering the
      lipid core, its composition and different inflammatory changes. The purpose of
      this study was to compare the total cholesterol and collagen contents of arterial
      walls, both measured by near infrared spectroscopy (NIRS), and to test whether
      the ratios of cholesterol to collagen correlate with histochemical parameters
      possibly being indicators for plaque stability. NIR spectra of 118 sections from
      36 human aortas were measured at 1000-2500 nm. Evaluation was performed by the
      partial least squares method (PLS), the chemical reference analysis by HPLC.
      Acceptable results were achieved for calibrations. With these calibrations 38
      further aortic sections taken at autopsy were NIR-spectroscopically analysed and
      ordered in relation to histological findings of fatty deposits, cap thickness
      over the lipid core, and the ratio of fatty deposits to cap thickness.
      Correlations were found to exist between the spectroscopically determined total
      cholesterol concentrations and the histologically estimated fatty deposits
      (r=0.887), between the spectroscopically determined collagen concentrations and
      the cap thickness over the lipid core (r=0.441), and between the ratios total
      cholesterol to collagen and the ratios fatty deposits to cap thickness (r=0.575).

PMID- 12417276
TI  - The adipocyte lipid binding protein (ALBP/aP2) gene facilitates foam cell
      formation in human THP-1 macrophages.
AB  - The critical initiating event in atherogenesis involves the invasion of monocytes
      through the endothelial wall of arteries, and their transformation from
      macrophages into foam cells. Human THP-1 monocytic cells can be induced to
      differentiate into macrophages by phorbol myristate acetate (PMA) treatment, and
      can then be converted into foam cells by exposure to oxidized low-density
      lipoprotein (oxLDL). To define genes that are specifically expressed during the
      transformation of macrophages into foam cells, we have performed a subtractive
      library screening utilizing mRNA isolated from THP-1 macrophages and foam cells.
      From this analysis, we have identified adipocyte lipid binding protein (ALBP/aP2)
      as a gene that is highly upregulated in foam cells in response to oxLDL.
      Furthermore, overexpression the ALBP gene using an adenovirus construct enhanced
      the accumulation of cholesterol ester in macrophage foam cells, probably due to
      an increase in transcription since oxLDL enhanced ALBP promoter activity in
      experiments using a promoter-luciferase reporter gene construct. The induction of
      ALBP by oxLDL probably involved activation of peroxisome proliferator-activated
      receptor gamma (PPARgamma) transcription factors, since four different endogenous
      PPARgamma ligands, including 9-hydroxyoctadecadienoic acid (9-HODE) and 13
      hydroxyoctadecadienoic acid (13-HODE), two oxidized lipid components of oxLDL, as
      well as 15-deoxy-delta12,14 prostaglandin J2 (15d-PGJ2) and retinoic acid (RA),
      all induced ALBP expression in macrophage/foam cells. Finally, ALBP was found to
      be highly expressed in vivo in macrophage/foam cells of human atherosclerotic
      plaques. These observations suggest that oxLDL-mediated increase in ALBP gene
      expression accelerate cholesterol ester accumulation, and that this is an
      important component of the genetic program regulating conversion of macrophages
      to foam cells. The observation that ALBP is readily detected in foam cells in
      active atherosclerotic lesions implicates a role for ALBP in human vascular
      disease. The induction of ALPB expression by oxLDL likely involves activation of
      PPARgamma by components of oxLDL (9-HODE and 13-HODE) that also function as
      PPARgamma ligands. Our results add to the concern that the clinical use of
      insulin-sensitizing PPARgamma agonists (i.e. thiazolidinediones) to treat Type 2
      Diabetes could exacerbate atherosclerosis, and highlight the need for clinical
      trials that address this issue.

PMID- 12417277
TI  - Soluble intercellular adhesion molecule-1 is related to endothelial vasodilatory
      function in healthy individuals.
AB  - OBJECTIVE: To investigate the associations between markers of systemic and
      vascular inflammation, and indicators of vascular morphology and function.
      METHODS: In 59 apparently healthy individuals, we measured serum levels of highly
      sensitive C-reactive protein (hsCRP), intercellular adhesion molecule-1 (ICAM-1),
      vascular cell adhesion molecule-1 (VCAM-1) and E-selectin. Endothelium-dependent
      (EDV) and -independent (EIDV) vasodilatation was evaluated in the forearm by
      venous occlusion plethysmography and local infusions of methacholine and sodium
      nitroprussid. Endothelial function index (EFI) was expressed as the EDV/EIDV
      ratio. The intima-media thickness (IMT) of the common carotid artery was
      investigated with ultrasound (far wall). RESULTS: EFI was inversely related only
      to ICAM-1 (r=-0.31, P<0.02) by univariate analysis. This association remained
      significant after adjustment for age, sex, blood pressure, smoking and serum
      cholesterol. EFI did not relate to hsCRP, VCAM-1 or E-selectin. Neither hsCRP,
      nor the adhesion molecules were significantly related to carotid artery IMT.
      CONCLUSION: ICAM-1 was related to endothelial vasodilatory function, but not to
      IMT, suggesting that endothelial inflammatory activation is related to an
      impaired vascular relaxation in apparently healthy individuals.

PMID- 12417278
TI  - Vitamin C prevents endothelial dysfunction induced by acute exercise in patients
      with intermittent claudication.
AB  - In patients with intermittent claudication, exercise is associated with a marked
      increase in oxidative stress, likely responsible for systemic endothelial
      perturbation. In 31 claudicant patients, we assessed the effect of vitamin C
      administration on the acute changes induced by maximal and submaximal exercise in
      endothelium-dependent, flow-mediated dilation (FMD), and in plasma levels of
      thiobarbituric acid-reactive substances (TBARS) and soluble intercellular
      adhesion molecule-1 (sICAM-1). In 16 claudicants, maximal exercise reduced FMD
      (from 8.5+/-0.9 to 3.7+/-0.8%, P<0.01), and increased plasma levels of TBARS
      (from 1.93+/-0.06 to 2.22+/-0.1 nmol/ml, P<0.02) and of sICAM-1 (from 282+/-17 to
      323+/-19 ng/ml, P<0.01). In eight of these patients, randomized to vitamin C,
      exercise-induced changes in FMD and biochemistry were abolished. This beneficial
      effect was not observed in the eight patients randomized to saline. In 15
      patients, who walked until the onset of claudication pain (submaximal exercise),
      and in ten control subjects, who performed maximal exercise, no changes were
      observed with exercise. Thus, in claudicants, vitamin C prevents the acute,
      systemic impairment in endothelial function induced by maximal exercise. This
      finding provides a rationale for trials investigating antioxidant therapy and
      cardiovascular risk in patients with intermittent claudication.

PMID- 12417279
TI  - Metabolic syndrome: major impact on coronary risk in a population with low
      cholesterol levels--a prospective and cross-sectional evaluation.
AB  - The prevalence and the excess coronary heart disease (CHD) risk of the metabolic
      syndrome (MS) and its components were investigated in the Turkish Adult Risk
      Factor Study in both a prospective and a cross-sectional manner. In a population
      sample, representative of Turkish adults who have low levels of high- and low
      density lipoprotein-cholesterol (HDL-C and LDL-C), MS was identified in
      conformity with the definition used in the recent NCEP guidelines. Prospective
      analysis was based on 2398 men and women (mean age at baseline 49.1+/-13 years)
      who had a baseline examination in 1997/98 and were followed-up for a mean of 3
      years. CHD was diagnosed based on clinical findings and Minnesota coding of
      resting electrocardiograms. Fatal and nonfatal CHD developed in 126 subjects. 27%
      of men and 38.6% of women were found to have MS at baseline examination. When
      adjusted for age, MS was an independent predictor of subsequent overall fatal and
      nonfatal CHD in both genders, displaying an RR of 1.71. At the final cross
      sectional evaluation, coronary risk associated with MS in men was primarily
      accounted for by standard MS components (largely inherent in glucose intolerance,
      hypertension and in a surrogate of small, dense LDL particles), in addition to a
      minor independent contribution by C-reactive protein (CRP). In women with MS, a
      substantial residual coronary risk remained after controlling for five
      components, which was partly accounted for by levels of LDL-C and CRP. It was
      estimated that MS was the culprit in just over half the cases of CHD in Turkey.
      CONCLUSION: MS was the major determinant of CHD risk in a population having
      generally low levels of HDL-C and LDL-C in middle-aged and elderly adults,
      extending to three out of every eight adults, and imposing an overall excess CHD
      risk of approximately 70%. In contrast to men, a substantial residual coronary
      risk is retained in Turkish women after controlling for five MS components.

PMID- 12417280
TI  - Family-based investigation of the C677T polymorphism of the
      methylenetetrahydrofolate reductase gene in ischaemic heart disease.
AB  - BACKGROUND: Elevated homocysteine is associated with ischaemic heart disease
      (IHD). The C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR)
      gene results in reduced MTHFR enzyme activity and reduced methylation of
      homocysteine to methionine resulting in mild hyperhomocysteinaemia. Case-control
      association studies of the role of the C677T MTHFR polymorphism in IHD have
      produced conflicting results. We therefore used newly described family-based
      association tests to investigate the role of this polymorphism in IHD, in a well
      defined population. METHODS: A total of 352 individuals from 129 families
      (discordant sibships and parent-child trios) were recruited. Linkage
      disequilibrium between the polymorphism and IHD was tested for using the combined
      transmission disequilibrium test (TDT)/sib-TDT and pedigree disequilibrium test
      (PDT). Homocysteine levels were measured. RESULTS: Both the TDT/sib-TDT and PDT
      analyses found a significantly reduced transmission of the T allele to affected
      individuals (P=0.016 and P=0.021). There was no significant difference in
      homocysteine levels between affected and unaffected siblings. TT homozygotes had
      mean homocysteine levels significantly higher than those of TC heterozygotes
      (P<0.001) and CC homozygotes (P<0.001). CONCLUSIONS: These data suggest that in
      contrast to the conventional hypothesis the T allele may be protective against
      IHD, independent of homocysteine levels.

PMID- 12417281
TI  - The effect of 17beta-estradiol on endothelial and inflammatory markers in
      postmenopausal women: a randomized, controlled trial.
AB  - BACKGROUND: Intervention trials in postmenopausal women with coronary artery
      disease have failed to demonstrate beneficial effects of hormone replacement
      therapy (HRT) on the course of disease, potentially due to pro-inflammatory
      effects of conjugated equine estrogens. We characterized the effects of 48 weeks
      treatment with two estradiol-based HRT regimens on nonspecific (high sensitivity
      C-reactive protein [hs-CRP], blood sedimentation rate [BSR], fibrinogen) and
      specific endothelial markers (cell adhesion molecules: ICAM-1, VCAM-1, E
      selectin). METHOD AND RESULTS: Postmenopausal women randomly received either 1 mg
      17beta-estradiol daily plus 25 microg gestodene for the last 12 days of each 28
      day cycle (=standard dose progestin; n=65), or gestodene added each third cycle
      only (=low dose progestin; n=65), or no HRT (n=73). Both HRT regimens reduced
      levels of ICAM-1 (-9%), VCAM-1 (-9%), E-selectin (-11%), fibrinogen (-12%), BSR (
      5%). No effect was observed on hs-CRP levels in any group. In smokers, E-selectin
      remained unchanged whereas ICAM-1 and VCAM-1 were lowered. Subjects on
      antihypertensive or lipid lowering medication showed effects comparable to the
      whole cohort. Effects of low and standard dose progestin were not different.
      CONCLUSION: We conclude that a combination therapy with 1 mg 17beta-estradiol
      favourably affects the vascular inflammation processes as indicated by a neutral
      effect on hs-CRP and reduction of cell adhesion molecules.

PMID- 12417282
TI  - A low high density lipoprotein (HDL) level is associated with carotid artery
      intima-media thickness in asymptomatic members of low HDL families.
AB  - Low serum high-density lipoprotein cholesterol (HDL-C) is a strong predictor of
      coronary heart disease (CHD). The aim of the present study was to evaluate the
      metabolic parameters predicting the atherosclerotic changes in asymptomatic
      members of low HDL-C families. We performed carotid B-mode ultrasonography with
      intima-media thickness (IMT) measurement for 89 asymptomatic members of Finnish
      low HDL-C families. The family members were categorized as affected or unaffected
      according to the 10th age-gender specific HDL-C percentile. In the affected
      group, the most marked decrease of HDL subclasses was observed for HDL2-C when
      compared with the unaffected (109% difference). In the partial correlation
      analyses, age and gender showed significant correlations with the mean IMT (for
      age, r=0.880, P<0.001, and for gender, r=-0.361, P=0.018). Importantly, HDL-C and
      HDL2-C were significantly inversely related to the mean carotid IMT, also after
      correction for age (for HDL-C, r=-0.186, P=0.043, for HDL2-C, r=-0.208, P=0.029,
      when adjusted for age). The correlation for HDL-C was significant also when
      adjusted for gender. In conclusion, low HDL-C is associated with increased
      carotid artery IMT in asymptomatic members of low HDL-C families.

PMID- 12417283
TI  - Apolipoproteins and carotid artery atherosclerosis in an elderly multiethnic
      population: the Northern Manhattan stroke study.
AB  - The association of apolipoproteins A-I and B (apo A-I and apo B) with
      cardiovascular disease has been studied in younger populations, but there is
      sparse information in the elderly. We determined whether apo A-I and apo B were
      associated with carotid artery atherosclerosis (CAA) in 507 stroke-free elderly
      community residents (mean age 70.1+/-11.7 years, 60% women, 41% Hispanics, 30%
      African American, 28% Caucasian). CAA severity was normal (no plaque or carotid
      stenosis) in 39%, mild (maximum plaque thickness < or =1.8 mm or carotid stenosis
      <40%) in 25%, and moderate/severe (maximum plaque thickness >1.8 mm or carotid
      stenosis > or =40%) in 36%. CAA severity increased with age in all race/ethnic
      groups (P<0.01). CAA was similar among African Americans and Caucasians, but less
      in Hispanics (age adjusted OR: 0.5, CI: 0.4-0.8). apo A-I <1.2 g/l (OR: 2.0, CI:
      1.0-3.3) and apo B > or =1.4 g/l (OR: 2.0, CI: 1.1-3.6) were associated with
      moderate-severe CAA. An apo B/apo A-I ratio > or =1 was associated with moderate
      severe CAA (OR: 2.4, CI: 1.3-4.4), and the association varied by race (Hispanics
      OR: 4.3, CI: 1.8-10; non-Hispanics, OR: 1.4, CI: 0.6-3.2). Total cholesterol,
      triglycerides and low density lipoprotein cholesterol were not associated with
      moderate-severe CAA, while high density lipoprotein cholesterol was protective
      (OR: 0.4, CI: 0.2-0.8). Thus, in an elderly population, apo A-I and B were
      determinants of moderate-severe CAA, and the degree of association varied by
      race/ethnicity

PMID- 12417284
TI  - Determinants of platelet aggregation in 50-70-year-old men from three Japanese
      communities.
AB  - To investigate the association of lifestyle and constitutional variables with
      platelet aggregation, we examined the platelet aggregation, serum fatty acid
      composition, alcohol intake, smoking, and dietary intake of seafood and soybean
      estimated by a 1-week dietary record in 448 males aged 50-70 in three rural
      Japanese communities: Ikawa, Akita prefecture (northeast coast), Noichi, Kochi
      prefecture (southwest coast), and Kyowa, Ibaraki prefecture (central inland).
      Platelet aggregatory threshold index (PATI) was used to determine the minimum
      concentration of adenosine 5'-diphosphate (ADP) that caused a non-reversible
      aggregation of platelets. Intake of seafood and n3-polyunsaturated fatty acid and
      ingestion of ethanol were higher in the northeast coastal community than in the
      other two communities. Mean platelet and white blood cell counts were lower in
      northeast coastal community than in the other two communities. The geometric mean
      PATI was higher (i.e. platelet aggregation was lower) in the northeast coastal
      community than the other two communities. Within the entire sample, platelet
      aggregation correlated inversely with serum level of n3-polyunsaturated fatty
      acids and gamma-glutamyl transpeptidase, an index of alcohol consumption, and
      positively with platelet and white blood cell counts. Platelet aggregation tended
      to correlate positively with serum arachidonic acid. There was no correlation
      between smoking and platelet aggregation. Our results suggest that seafood intake
      and moderate alcohol consumption reduce platelet aggregation.

PMID- 12417285
TI  - Molecular genetic analysis of familial hypercholesterolemia: spectrum and
      regional difference of LDL receptor gene mutations in Japanese population.
AB  - To determine the molecular basis of familial hypercholesterolemia (FH) in Japan,
      200 unrelated patients with clinically diagnosed heterozygous FH were screened
      for mutations in coding and promoter region of the low density lipoprotein (LDL)
      receptor gene using denaturing gradient-gel electrophoresis (DGGE), DNA
      sequencing and Southern blotting analysis. About 37 different mutations in the
      LDL receptor gene were identified in 125 (62.5%) of the patients, 22 of these
      mutations have not been described before. The most common mutations were K790X
      (19.5%), P664L (6.0%), FH-Tonami-1 (6.0%), IVS15-3C>A (5.5%) and FH-Tonami-2
      (4.5%), whereas the other mutations were rare. No apolipoprotein B (apoB)
      mutations responsible for familial ligand-defective apoB-100 (FDB) were
      identified. Polymorphisms of apolipoprotein E (apoE) and scavenger receptor class
      B type I (SR-BI) were observed to have minor effects on the lipid and lipoprotein
      profile. In 75 (32.5%) of the FH patients, LDL receptor gene mutations could not
      be identified. These patients had significantly lower total cholesterol (7.71+/
      1.64 vs. 8.68+/-1.47 mmol/l, P<0.001) and LDL-cholesterol (6.02+/-1.51 vs. 6.87+/
      1.47 mmol/l, P<0.001) in plasma, also a lower incidence of coronary heart disease
      (CHD) (22 vs. 29%, P=0.05) compared with patients with a LDL receptor gene
      mutation, suggesting that besides LDL receptor, defect of other genes involved in
      LDL metabolism may be a cause of FH with a milder phenotypic expression in
      Japanese population.

PMID- 12417286
TI  - The erythrocyte adhesiveness/aggregation test (EAAT). A new biomarker to reveal
      the presence of low grade subclinical smoldering inflammation in individuals with
      atherosclerotic risk factors.
AB  - BACKGROUND: Multiple acute phase proteins and atherosclerotic risk factors
      increase the aggregability of erythrocytes. METHODS AND RESULTS: We used a simple
      slide test and image analysis to determine the degree of erythrocyte
      adhesiveness/aggregation in the peripheral blood of 222 women and 221 men with
      no, one, two or more atherosclerotic risk factors. The degree of erythrocyte
      adhesiveness/aggregation correlated significantly with the concentration of
      commonly used variables of the acute phase response. We also showed that
      individuals with low erythrocyte adhesiveness/aggregation tend to be younger and
      to have fewer risk factors for atherosclerosis, including diabetes mellitus,
      hypertension, hyperlipidemia and smoking. CONCLUSIONS: The association between
      increased erythrocyte adhesiveness/aggregation, higher concentrations of acute
      phase proteins, and increased atherosclerotic risk factors points to a possible
      clinical applicability of the erythrocyte adhesiveness/aggregation test (EAAT) to
      reveal the presence of both low-grade subclinical smoldering inflammation and
      morbid biology in individuals with risk factors for atherosclerosis.

PMID- 12417287
TI  - Atherosclerosis and cognitive impairment are linked in the elderly. The Leiden 85
      plus Study.
AB  - Post-mortem analyses suggest that atherosclerosis more often contributes to late
      onset dementia than hitherto expected. We set out to further unravel the relation
      between atherosclerosis and cognitive impairment. We therefore tested the
      hypothesis that the number of cardiovascular pathologies is positively associated
      with cognitive impairment in elderly subjects, and that the smaller number of
      cardiovascular pathologies in women explains the better cognitive function of
      elderly women. Within the Leiden 85-plus Study, we assessed the atherosclerotic
      burden by counting the number of cardiovascular pathologies in the medical
      histories of a population-based sample of 599 subjects aged 85 years (response
      87%). Significantly more men than women had a history of cardiovascular
      pathologies (67% compared to 59%, P<0.001). In addition, cognitive function was
      assessed. All subjects completed the Mini-Mental State Examination (MMSE).
      Cognitive speed and memory were determined with specific neuro-psychological
      tests in those with a MMSE-score above 18 points. There was a highly significant
      dose-response relationship between the number of cardiovascular pathologies and
      cognitive impairment for both men and women. The median MMSE-score was 26 points
      in subjects without cardiovascular disease and decreased to 25 points for
      subjects who had two or more cardiovascular pathologies (P for trend =0.003).
      Similar associations were found for cognitive speed but not for memory. Our data
      confirm that in old age atherosclerosis significantly contributes to cognitive
      impairment. Since treatments for atherosclerosis appear to be particularly
      effective in elderly people, we consider our finding of utmost clinical
      importance in possibly preventing cognitive impairment and late-onset dementia.

PMID- 12417288
TI  - Differential hs-CRP reduction in patients with familial hypercholesterolemia
      treated with aggressive or conventional statin therapy.
AB  - BACKGROUND: High sensitivity C-reactive protein (hs-CRP) has emerged as the best
      studied and most promising marker of inflammation in atherosclerotic vascular
      disease. MATERIALS AND METHODS: The ASAP (effects of Atorvastatin vs. Simvastatin
      on Atherosclerosis Progression) study was a 2-year randomised, double-blind trial
      with 325 familial hypercholesterolemia patients, treated with torvastatin 80 mg
      or imvastatin 40 mg. Intima media thickness (IMT) of carotid artery segments and
      hs-CRP levels were determined at baseline, 1 and 2 years. RESULTS: Baseline
      median hs-CRP values were 2.1 mg/l (interquartile range (IQR) 0.9-5.2) and 2.0
      mg/l (IQR 0.8-3.0) and after 2 years these levels decreased to 1.1 mg/l (IQR 0.6
      2.4) and 1.5 mg/l (IQR 0.6-3.0) in the atorvastatin 80 mg and simvastatin 40 mg
      group, respectively. These changes were significant within as well as between the
      two groups. No correlations were observed between change in hs-CRP after 2 years
      and change in lipids. A significant correlation was found in univariate analysis
      between the decrease of hs-CRP and the reduction of IMT. CONCLUSIONS: Our results
      show that atorvastatin 80 mg reduces hs-CRP levels to a greater extent than
      simvastatin 40 mg. Furthermore, we show that the extent of hs-CRP reduction is
      associated with the progression rate of the atherosclerotic process as measured
      by IMT.

PMID- 12417289
TI  - The role of whole blood viscosity in premature coronary artery disease in women.
AB  - BACKGROUND: Impaired hemorheology has been demonstrated in atherosclerotic
      disease and has shown a relationship with classical risk factors. Blood viscosity
      (eta), being the ratio of shear stress over shear rate, is an important parameter
      of hemorheology. In women with premature coronary artery disease (CAD), the
      underlying risk factors are a matter of debate and the role of whole blood
      viscosity in its pathogenesis has not been documented. AIM: To investigate the
      association of whole blood viscosity with premature CAD in women, with complaints
      suggestive of angina pectoris. METHODS: Eighty-eight women (mean age 53 years)
      were divided into two groups, those with a high likelihood of CAD (LIKELI+) and
      those with a low likelihood of CAD (LIKELI-), based on medical history and
      technical investigations. Assessment of risk factors comprised smoking, diabetes
      mellitus, arterial hypertension, left ventricular hypertrophy (LVH), systolic and
      diastolic blood pressures, total low-density lipoprotein (LDL)- and high-density
      lipoprotein (HDL)-cholesterol, triglycerides, body mass index, menopause, hormone
      replacement therapy, uric acid and creatinine, and predicted 10-year
      cardiovascular risk according to the Framingham study was calculated. Whole blood
      viscosity was determined at 37 degrees C using a rotational cone-and-plate
      viscosimeter. RESULTS: Baseline characteristics did not differ significantly
      between the groups except for antiplatelet therapy (P=0.001), prevalence of
      diabetes mellitus (P=0.002), predicted 10-year cardiovascular risk (P=0.007),
      essential hypertension (P=0.02), LVH (P=0.03) and smoking habits (P=0.04).
      LIKELI+ women had a significantly higher whole blood viscosity at all shear rates
      compared with LIKELI- women (P<0.05). All blood viscosities measured from 25 to
      125 s(-1) were highly significantly (P<0.0001) correlated with eta(250s(-1)).
      Univariate correlates with eta(250s(-1)) comprised triglycerides (P=0.006) and
      haematocrit (P=0.026). Binary logistic multivariate regression analysis for high
      likelihood of CAD revealed that only presence of arterial hypertension (P<0.0001)
      was predictive. Multiple regression analysis demonstrated that haematocrit
      (P=0.001) and likelihood of CAD (P=0.01) were the only significant determinants
      of eta(250s(-1)). CONCLUSION: In this study, blood viscosity did not appear as an
      independent risk factor for the prediction of premature CAD in women. Viscosity
      may act as a marker of CAD or of classical risk factors.

PMID- 12417290
TI  - Lack of association between plasma homocysteine and angiographic coronary artery
      disease in the era of fortification of cereal grain flour with folic acid.
AB  - Homocysteine is associated with coronary disease (CAD). However, the strength of
      the association after accounting for traditional and emerging risk factors is
      unclear, particularly since flour fortification with folate was mandated in the
      USA. We analyzed the association between traditional and emerging risk factors
      and CAD in 504 patients undergoing clinically-indicated angiography between July
      1998 and January 1999. Significant CAD (> or =50% stenosis in > or =1 artery) was
      present in 271 patients (54%). Mean homocysteine (micromol/l) was 9.36+/-3.07;
      hyperhomocysteinemia (>13 micromol/l) was present in 7.9% of patients. Mean
      homocysteine was 9.29+/-3.02 in patients with no disease (no stenoses or stenoses
      <10%), 9.09+/-2.47 in patients with mild disease (stenoses 10-50%), 9.12+/-2.39
      in patients with one vessel disease (VD) (>50% stenosis in one coronary artery),
      9.28+/-3.19 in patients with two VD, and 10.1+/-3.89 in patients with three VD
      (P=0.0793). Multivariate analysis that included age, gender, smoking, LDL, HDL,
      Lp(a), apo A1, and apo B revealed no independent association between quartile of
      homocysteine and odds ratio (OR) for CAD. In summary, we found no association
      between homocysteine and CAD on angiography. The homocysteine-lowering effect of
      folate-fortified flour, or the inclusion of many traditional and emerging risk
      factors in multivariate analysis, are potential explanations.

PMID- 12417291
TI  - Acronyms must be defined.

PMID- 12417292
TI  - Simultaneous determination of apolipoprotein AIV T347S and Q360H genotypes using
      a heteroduplex generator.

PMID- 12417293
TI  - Changes in von Willebrand factor and soluble ICAM, but not soluble VCAM, soluble
      E selectin or soluble thrombomodulin, reflect the natural history of the
      progression of atherosclerosis.

PMID- 12417294
TI  - Lipoprotein(a): a longitudinal versus a cross-sectional study in normal pregnancy
      and its levels in preeclampsia.

PMID- 12417295
TI  - A GPVI polymorphism is a risk factor for myocardial infarction in Japanese.

PMID- 12417296
TI  - PSF and p54(nrb)/NonO--multi-functional nuclear proteins.
AB  - Proteins are often referred to in accordance with the activity with which they
      were first associated or the organelle in which they were initially identified.
      However, a variety of nuclear factors act in multiple molecular reactions
      occurring simultaneously within the nucleus. This review describes the functions
      of the nuclear factors PSF (polypyrimidine tract-binding protein-associated
      splicing factor) and p54(nrb)/NonO. PSF was initially termed a splicing factor
      due to its association with the second step of pre-mRNA splicing while
      p54(nrb)/NonO was thought to participate in transcriptional regulation. Recent
      evidence shows that the simplistic categorization of PSF and its homolog
      p54(nrb)/NonO to any single nuclear activity is not possible and in fact these
      proteins exhibit multi-functional characteristics in a variety of nuclear
      processes.

PMID- 12417297
TI  - Characterization of a novel human UDP-GalNAc transferase, pp-GalNAc-T10.
AB  - A novel member of the human UDP-N-acetyl-D-galactosamine:polypeptide N
      acetylgalactosaminyltransferase (pp-GalNAc-T) gene family was cloned as a homolog
      of human pp-GalNAc-T7, and designated pp-GalNAc-T10. pp-GalNAc-T10 transcript was
      found in the small intestine, stomach, pancreas, ovary, thyroid gland and spleen.
      In a polypeptide GalNAc-transfer assay, recombinant pp-GalNAc-T10 transferred
      GalNAc onto a panel of mucin-derived peptide substrates. Furthermore, pp-GalNAc
      T10 demonstrated strong transferase activity with glycopeptide substrates.

PMID- 12417298
TI  - Systemic tissue inhibitor of metalloproteinase-1 gene delivery reduces neointimal
      hyperplasia in balloon-injured rat carotid artery.
AB  - Metalloproteinases (MMP)-2 and MMP-9 play a role in smooth muscle cell (SMC)
      migration from the media to the intima following arterial injury. Intravenous
      administration of adenovirus encoding tissue inhibitor of metalloproteinase-1
      (TIMP-1) into balloon-injured rat arteries (3 x 10(11) viral particles/rat; n=7)
      resulted in a transient expression of TIMP-1 and a significant inhibition of
      neointima thickening within 16 days ( approximately 40% vs. control; P=0.012).
      Three days after injury, the number of intimal SMCs was decreased by
      approximately 98% in TIMP-1-treated rats. However, no alteration was seen in
      intimal SMC proliferation after 13 days of injury. Therefore, our results show
      that systemic gene transfer of TIMP-1 is a promising approach in early restenosis
      treatment.

PMID- 12417299
TI  - Response heterogeneity of human macrophages to ATP is associated with P2X7
      receptor expression but not to polymorphisms in the P2RX7 promoter.
AB  - A region 2 kb upstream of exon 1 of the P2X7 gene was sequenced using DNA from
      nine healthy individuals who exhibited three different ATP response phenotypes
      (i.e. high, low and interferon gamma-inducible). Five single nucleotide
      polymorphisms were identified within the nine donor promoter sequences but none
      were associated with a specific ATP response phenotype. A P2X7 loss of function
      polymorphism (1513 in exon 13) was also screened for within donor DNA but no
      response associations were identified. ATP response phenotype was positively
      associated with P2X(7) receptor expression, as assessed by flow cytometry, but
      not with any identified receptor or promoter gene polymorphisms.

PMID- 12417300
TI  - Identification and functional analysis of novel phosphorylation sites in Cx43 in
      rat primary granulosa cells.
AB  - The gap junctional intercellular communication mediated by Cx43 plays
      indispensable roles in both germ line development and postnatal folliculogenesis.
      In this study, we focused on the effect of follicle-stimulating hormone (FSH) on
      the Cx43 protein in rat primary granulosa cells and found that FSH stimulation
      elevated the phosphorylation in addition to the protein level of Cx43. Serine
      residues in the carboxyl-terminal region were exclusively phosphorylated in this
      system and we identified Ser365, Ser368, Ser369 and Ser373 as major
      phosphorylation sites by FSH stimulation. A Cx43 variant containing mutations at
      all these serine residues was found to severely reduce dye transfer activity when
      assayed in HeLa cells. The present study revealed a novel regulatory mechanism of
      Cx43-mediated gap junctional intercellular communication through phosphorylation
      in the carboxyl-terminus.

PMID- 12417301
TI  - Amyloid formation of native folded protein induced by peptide-based graft
      copolymer.
AB  - We report here that a native folded holo-myoglobin, when incubated with a
      synthetic amyloidogenic peptide in aqueous solutions, forms fibrils. These
      fibrils took a cross-beta form (inter-strand spacing: 4.65 A and inter-sheet
      spacing: 10.65 A) and bound the amyloidophilic dye Congo red as did the authentic
      amyloid fibrils. In contrast such fibril formation of myoglobin did not occur in
      the absence of the peptide. These results suggest the possibility that inter
      molecular interaction of native protein with the amyloidogenic peptide trigger
      the amyloid formation even for the non-pathogenic native protein like myoglobin,
      which itself exists as a globular form, under certain conditions.

PMID- 12417302
TI  - Mechanisms for 2-methoxyestradiol-induced apoptosis of prostate cancer cells.
AB  - Prostate and breast carcinomas are sex hormone-related carcinomas, which are
      known to be associated with an over-expression of the proto-oncogene Bcl-2. Here,
      we report that 2-methoxyestradiol (2-ME), an endogenous metabolite of estrogen
      that does not bind to nuclear estrogen receptors, effectively induces apoptosis
      in Bcl-2-expressing human prostate and breast carcinoma cells in vitro and in a
      rat prostate tumor model in vivo. In several cell lines derived from prostate,
      breast, liver and colorectal carcinomas, 2-ME treatment led to an activation of c
      Jun N-terminal kinase (JNK) and phosphorylation of Bcl-2, which preceded the
      induction of apoptosis. In summary, our data suggest that 2-ME induces apoptosis
      in epithelial carcinomas by causing phosphorylation of JNK, which appears to be
      correlated with phosphorylation of Bcl-2.

PMID- 12417303
TI  - Structural and functional analysis of aldolase B mutants related to hereditary
      fructose intolerance.
AB  - Hereditary fructose intolerance (HFI) is a recessively inherited disorder of
      carbohydrate metabolism caused by impaired function of human liver aldolase (B
      isoform). 25 enzyme-impairing mutations have been identified in the aldolase B
      gene. We have studied the HFI-related mutant recombinant proteins W147R, A149P,
      A174D, L256P, N334K and delta6ex6 in relation to aldolase B function and
      structure using kinetic assays and molecular graphics analysis. We found that
      these mutations affect aldolase B function by decreasing substrate affinity,
      maximal velocity and/or enzyme stability. Finally, the functional and structural
      analyses of the non-natural mutant Q354E provide insight into the catalytic role
      of Arg(303), whose natural mutants are associated to HFI.

PMID- 12417304
TI  - Altered shoot/root Na+ distribution and bifurcating salt sensitivity in
      Arabidopsis by genetic disruption of the Na+ transporter AtHKT1.
AB  - Sodium (Na+) is toxic to most plants, but the molecular mechanisms of plant Na+
      uptake and distribution remain largely unknown. Here we analyze Arabidopsis lines
      disrupted in the Na+ transporter AtHKT1. AtHKT1 is expressed in the root stele
      and leaf vasculature. athkt1 null plants exhibit lower root Na+ levels and are
      more salt resistant than wild-type in short-term root growth assays. In shoot
      tissues, however, athkt1 disruption produces higher Na+ levels, and athkt1 and
      athkt1/sos3 shoots are Na+-hypersensitive in long-term growth assays. Thus wild
      type AtHKT1 controls root/shoot Na+ distribution and counteracts salt stress in
      leaves by reducing leaf Na+ accumulation.

PMID- 12417305
TI  - Alteration in the ubiquitin structure and function in the human lens: a possible
      mechanism of senile cataractogenesis.
AB  - High-performance liquid chromatography purification followed by mass spectrometry
      analyses highlighted that human senile cataractous lens includes a 8182 Da
      species which is absent in the normal lens, whereas a 8566/8583 Da species is
      present in both lenses. Western blot analysis identified both species as
      ubiquitin. The species at lower molecular weight is a shorter form due to the
      cleavage of the C-terminal residues 73-76. As it is the last amino acid of
      ubiquitin which is involved in the protein degradation mechanism, we suggest that
      this structure modification compromises the function of ubiquitin and
      consequently the physiologically occurring degradation of the lens proteins.

PMID- 12417306
TI  - Apoptosis-specific protein (ASP 45 kDa) is distinct from human Apg5, the
      homologue of the yeast autophagic gene apg5.
AB  - We have examined whether the apoptosis-specific protein p45ASP and human Apg5 are
      identical proteins. Like p45ASP, myc-hApg5 cross-reacted with a c-Jun antibody
      and approximately 50% of myc-hApg5 was bound to a Triton X-100-insoluble fraction
      in HeLa cells. However, soluble myc-hApg5 was degraded during apoptosis induced
      by staurosporine or TNFalpha/cycloheximide whilst expression of soluble p45ASP
      was stabilised. Furthermore, myc-hApg5 degradation was blocked by the caspase
      inhibitor Boc-Asp(OMe)FMK whilst p45ASP expression was eliminated. Moreover, myc
      hApg5 ( approximately 32 kDa) never assumed the size of p45ASP (45 kDa). It is
      therefore likely that p45ASP and human Apg5 are distinct proteins although they
      do share some common characteristics.

PMID- 12417307
TI  - GluR2 ligand-binding core complexes: importance of the isoxazolol moiety and 5
      substituent for the binding mode of AMPA-type agonists.
AB  - X-ray structures of the GluR2 ligand-binding core in complex with (S)-Des-Me-AMPA
      and in the presence and absence of zinc ions have been determined. (S)-Des-Me
      AMPA, which is devoid of a substituent in the 5-position of the isoxazolol ring,
      only has limited interactions with the partly hydrophobic pocket of the ligand
      binding site, and adopts an AMPA-like binding mode. The structures, in comparison
      with other agonist complex structures, disclose the relative importance of the
      isoxazolol ring and of the substituent in the 5-position for the mode of binding.
      A relationship appears to exist between the extent of interaction of the ligand
      with the hydrophobic pocket and the affinity of the ligand.

PMID- 12417308
TI  - A heat-activated MAP kinase in tomato: a possible regulator of the heat stress
      response.
AB  - Adaptation to elevated temperatures is of major importance for the survival of
      plants. The role of kinases in heat stress response was studied in tomato by in
      gel and in solution kinase assays using myelin basic protein as substrate. The
      application of heat stress in a naturally occurring temperature range resulted in
      a fast and transient activation of a 50 kDa mitogen-activated protein (MAP)
      kinase both in a photoautotrophic cell suspension culture and in leaves of mature
      plants. The heat activation of the MAP kinase was shown to be calcium-dependent.
      The specific phosphorylation of tomato heat stress transcription factor HsfA3 by
      a partially purified preparation of the heat-activated MAP kinase supports a
      physiological role of the identified kinase activity in transducing the heat
      stress signal.

PMID- 12417309
TI  - Evidence of a trimolecular complex involving LPS, LPS binding protein and soluble
      CD14 as an effector of LPS response.
AB  - The kinetics of the interaction of lipopolysaccharide (LPS), lipopolysaccharide
      binding protein (LBP) and CD14 was studied using surface plasmon resonance. The
      association and dissociation rate constants for the binding of LPS and rsCD14
      were 2.9 x 10(4) M(-1) s(-1) and 0.07 s(-1) respectively, yielding a binding
      constant of 4.2 x 10(5) M(-1). Significantly, the presence of LBP increased not
      only the association rate but also the association constant for the interaction
      between LPS and CD14 by three orders of magnitude. Our experimental results
      suggest that LBP interacts with LPS and CD14 to form a stable trimolecular
      complex that has significant functional implications as it allows monocytes to
      detect the presence of LPS at a concentration as low as 10 pg/ml or 2 pM, and to
      respond by secreting interleukin-6. Thus, LBP is not merely transferring LPS to
      CD14 but it forms an integral part of the LPS-rLBP-rsCD14 complex.

PMID- 12417310
TI  - Protein kinase inhibitors block the stimulation of the AMP-activated protein
      kinase by 5-amino-4-imidazolecarboxamide riboside.
AB  - The AMP-activated protein kinase (AMPK) is the central component of a protein
      kinase cascade that plays a major role in energy sensing. AMPK is activated
      pharmacologically by 5-amino-4-imidazolecarboxamide (AICA) riboside monophosphate
      (ZMP), which mimics the effects of AMP on the AMPK cascade. Here we show that
      uptake of AICA riboside into cells, mediated by the adenosine transport system,
      is blocked by a number of protein kinase inhibitors. Under these conditions, ZMP
      does not accumulate to sufficient levels to stimulate AMPK. Our results
      demonstrate that careful interpretation is required when using AICA riboside in
      conjunction with protein kinase inhibitors to investigate the physiological role
      of AMPK.

PMID- 12417311
TI  - NRSF/REST confers transcriptional repression of the GPR10 gene via a putative
      NRSE/RE-1 located in the 5' promoter region.
AB  - The G protein-coupled receptor GPR10 is highly localized to areas of the brain.
      In an effort to reveal transcriptional determinants of this tissue specificity,
      we recognized a putative NRSE (neuron-restrictive silencer element) located in
      the 5' promoter region of the gene. The cognate NRSE binding protein NRSF (neuron
      restrictive silencer factor) restricts gene expression to mature neurons and
      endocrine cells by repressing their transcription in non-neuronal/-endocrine
      cells. In cell lines where NRSF-mediated gene repression has been functionally
      established, the activity of the GPR10 promoter was repressed in a manner
      consistent with NRSE-dependent regulation. A specific point mutation to confer
      non-functionality of the NRSE revealed a 10-fold de-repression of reporter gene
      expression. In contrast, in the GPR10-expressing cell line GH3, mRNA transcripts
      of NRSF were undetectable and suppression of promoter activity was not observed.
      However, transfection of a rat NRSF expression vector resulted in significant
      repression of transcription, which was reversed by mutation of the NRSE. In
      conclusion, we demonstrate that the GPR10 gene is specifically regulated by NRSF,
      and suggest this to be a contributory factor in the tissue-specific distribution
      of GPR10 in vivo.

PMID- 12417312
TI  - Increase in cellular glutamate levels stimulates exocytosis in pancreatic beta
      cells.
AB  - Glutamate has been implicated as an intracellular messenger in the regulation of
      insulin secretion in response to glucose. Here we demonstrate by measurements of
      cell capacitance in rat pancreatic beta-cells that glutamate (1 mM) enhanced Ca2+
      dependent exocytosis. Glutamate (1 mM) also stimulated insulin secretion from
      permeabilized rat beta-cells. The effect was dose-dependent (half-maximum at 5.1
      mM) and maximal at 10 mM glutamate. Glutamate-induced exocytosis was stronger in
      rat beta-cells and clonal INS-1E cells compared to beta-cells isolated from mice
      and in parental INS-1 cells, which correlated with the expressed levels of
      glutamate dehydrogenase. Glutamate-induced exocytosis was inhibited by the
      protonophores FCCP and SF6847, by the vacuolar-type H+-ATPase inhibitor
      bafilomycin A(1) and by the glutamate transport inhibitor Evans Blue. Our data
      provide evidence that exocytosis in beta-cells can be modulated by physiological
      increases in cellular glutamate levels. The results suggest that stimulation of
      exocytosis is associated with accumulation of glutamate in the secretory
      granules, a process that is dependent on the transgranular proton gradient.

PMID- 12417313
TI  - Cleavage of a DNA-RNA-DNA/DNA chimeric substrate containing a single
      ribonucleotide at the DNA-RNA junction with prokaryotic RNases HII.
AB  - We have analyzed the cleavage specificities of various prokaryotic Type 2
      ribonucleases H (RNases H) on chimeric DNA-RNA-DNA/DNA substrates containing one
      to four ribonucleotides. RNases HII from Bacillus subtilis and Thermococcus
      kodakaraensis cleaved all of these substrates to produce a DNA segment with a 5'
      monoribonucleotide. Consequently, these enzymes cleaved even the chimeric
      substrate containing a single ribonucleotide at the DNA-RNA junction (5'-side of
      the single ribonucleotide). In contrast, Escherichia coli RNase HI and B.
      subtilis RNase HIII did not cleave the chimeric substrate containing a single
      ribonucleotide. These results suggest that bacterial and archaeal RNases HII are
      involved in excision of a single ribonucleotide misincorporated into DNA.

PMID- 12417314
TI  - If space is provided, bulky modification on the rim of azurin's beta-barrel
      results in folded protein.
AB  - Pseudomonas aeruginosa azurin is a blue-copper protein with a beta-barrel fold.
      Here we report that, at conditions where thermal unfolding of apo-azurin is
      reversible, the reaction occurs in a single step with a transition midpoint
      (T(m)) of 69 degrees C (pH 7). The active-site mutation His117Gly creates a
      cavity in the beta-barrel near the surface but does not perturb the overall fold
      (T(m) of 64 degrees C, pH 7). Oxidation of the active-site cysteine (Cysteine
      112) in wild-type azurin, which occurs readily at higher temperatures, results in
      a modified protein that cannot adopt a native-like structure. In sharp contrast,
      Cysteine-112 oxidation in His117Gly azurin yields a modified apo-azurin that
      appears folded and displays cooperative, reversible unfolding (T(m) approximately
      55 degrees C, pH 7). We conclude that azurin's beta-barrel is a rigid structural
      element that constrains the structure of its surface; a bulky modification can
      only be accommodated if complementary space is provided.

PMID- 12417315
TI  - Abundance of the RSC nucleosome-remodeling complex is important for the cells to
      tolerate DNA damage in Saccharomyces cerevisiae.
AB  - The essential Nps1p/Sth1p is a catalytic subunit of the nucleosome-remodeling
      complex, RSC, of Saccharomyces cerevisiae that can alter nucleosome structure by
      using the energy of ATP hydrolysis. Besides the ATPase domain, Nps1p harbors the
      bromodomain, of which the function(s) have not yet been defined. We have isolated
      a temperature-sensitive mutant allele of NPS1, nps1-13, which has amino acid
      substitutions within the bromodomain. This mutation perturbed the interaction
      between the RSC components and enhanced the sensitivity of the cells to several
      DNA-damaging treatments at the permissive temperature. Reduced expression of NPS1
      also caused DNA damage sensitivity. These results suggest the importance of the
      Nps1p bromodomain in RSC integrity and a model in which high amounts of RSC would
      be required for the cells to overcome DNA damage.

PMID- 12417316
TI  - Zonal distribution of glycogen synthesis in isolated rat hepatocytes.
AB  - Incubation of hepatocytes isolated from fasted rats with [14C]glucose for short
      periods of time showed that the initial stages of glycogen synthesis occur near
      the plasma membrane. Incubation with [14C]glucose followed by cold glucose
      demonstrated that glycogen synthesis is always active at the hepatocyte periphery
      and that previously synthesised glycogen moves towards the centre of the cell,
      while its place is filled by newly synthesised molecules. However, the reverse
      experiment, incubation with cold glucose before addition of [14C]glucose, showed
      that, as glycogen synthesis progresses, it also becomes gradually active in more
      internal sites of the hepatocyte. These results indicate a spatial order in the
      synthesis of hepatic glycogen.

PMID- 12417317
TI  - Calcium-binding analysis and molecular modeling reveal echis coagulation factor
      IX/factor X-binding protein has the Ca-binding properties and Ca ion-independent
      folding of other C-type lectin-like proteins.
AB  - Many biologically active heterodimeric proteins of snake venom consist of two C
      type lectin-like subunits. One of these proteins, habu IX/X-bp, is a Gla domain
      binding protein whose subunits both bind to a Ca2+ ion, with a total of two Ca2+
      binding sites. The molecular modeling and Ca2+-binding analysis of echis IX/X-bp
      revealed that it lacks one of two Ca2+-binding sites, though the folding of this
      subunit is conserved. It is concluded that heterodimeric C-type lectin-like
      proteins function independent of Ca2+ and have essentially a similar folding to
      habu IX/X-bp.

PMID- 12417318
TI  - Gating of the expressed Cav3.1 calcium channel.
AB  - Intramembrane charge movement originating from Cav3.1 (T-type) channel expressed
      in HEK 293 cells was investigated. Ion current was blocked by 1 mM La3+. Charge
      movement was detectable for depolarizations above approximately -70 mV and
      saturated above +60 mV. The voltage dependence of charge movement followed a
      single Boltzmann function with half-maximal activation voltage +12.9 mV and +12.3
      mV and with slopes of 22.4 mV and 18.1 mV for the ON- and OFF-charge movement,
      respectively. Inactivation of I(Ca) by prolonged depolarization pulse did not
      immobilize intramembrane charge movement in the Cav3.1 channel.

PMID- 12417320
TI  - Spectral imaging and linear un-mixing enables improved FRET efficiency with a
      novel GFP2-YFP FRET pair.
AB  - Spectral variants of the green fluorescent protein (GFP) have been extensively
      used as reporters to image molecular interactions in living cells by fluorescence
      resonance energy transfer (FRET). However, those GFP variants which are the most
      efficient donor acceptor pairs for FRET measurements show a high degree of
      spectral overlap which has hampered in the past their use in FRET applications.
      Here we use spectral imaging and subsequent un-mixing to quantitatively separate
      highly overlapping donor and acceptor emissions in FRET measurements. We
      demonstrate the method in fixed and living cells using a novel GFP based FRET
      pair (GFP2-YFP (yellow)), which has an increased FRET efficiency compared to the
      most commonly used FRET pair consisting of cyan fluorescent protein and YFP.
      Moreover, GFP2 has its excitation maximum at 396 nm at which the YFP acceptor is
      excited only below the detection level and thus this FRET pair is ideal for
      applications involving sensitized emission.

PMID- 12417319
TI  - Regulation of the frontocortical sodium pump by Na+ in Alzheimer's disease:
      difference from the age-matched control but similarity to the rat model.
AB  - The Na+ and K+ dependence of the frontocortical Na,K-ATPase in Alzheimer's
      disease (AD) was compared with that in human control (Co) and rat AD model. In
      AD, the relationship between the Na/K ratio and the Na,K-ATPase activity showed
      noticeable left-shift with three-fold increase in the enzyme affinity for Na+
      (K(0.5)=10 and 30 mM in AD and Co, respectively). The Na+ dependence of the
      enzyme in AD showed two different Hill coefficients (n(H)), 1.1 and 0.3, whereas
      the Co value of n(H) was higher (1.4). The rat AD model generated by ibotenic
      acid revealed a Na+ dependence similar to AD. The K+ dependence of the Na,K
      ATPase showed no significant difference in AD and Co. Compared with Co, AD
      produced a shift in the break of the Na,K-ATPase Arrhenius plot, suggesting
      remarkable alterations in the enzyme lipid environment. Our findings support the
      hypothesis that dysfunction of the Na,K-ATPase in AD is provoked by altered Na+
      dependence of the enzyme. An impairment of the pump functionality might serve as
      an early mechanism of AD that should be interrupted by selective pharmacological
      agents.

PMID- 12417321
TI  - Identification of human Kir2.2 (KCNJ12) gene encoding functional inward rectifier
      potassium channel in both mammalian cells and Xenopus oocytes.
AB  - Arginine residue at position 285 (R285) in the intracellular C-terminal domain of
      inward rectifier potassium channel Kir2.2 is conserved in many species, but
      missing in previously reported human Kir2.2 sequences. We here identified the
      human Kir2.2 gene in normal individuals, which contained R285 in the deduced
      amino-acid sequence (hKir2.2/R285). All 30 individuals we examined were
      homozygous for Kir2.2/R285 gene. The hKir2.2/R285 was electrophysiologically
      functional in both mammalian cells and Xenopus oocytes. However, the hKir2.2
      missing R285 was functional only in Xenopus oocytes, but not in mammalian cells.
      Thus, R285 in Kir2.2 is important for its functional expression in mammalian
      cells.

PMID- 12417322
TI  - Identification of the amino terminal subunit of the glycoprotein of Borna disease
      virus.
AB  - The only surface membrane glycoprotein of Borna disease virus (BDV) is
      synthesized as a polypeptide with a molecular mass of 57 kDa and N-glycosylated
      to a precursor glycoprotein (GP) of about 94 kDa. It is processed by the cellular
      protease furin into the C-terminal membrane-anchored subunit GP-C, also known as
      gp43, and a presumptive N-terminal subunit GP-N, that is highly glycosylated and
      has a molecular mass of about 51 kDa. However, up to now the latter remained
      undetected in BDV-infected material. We describe a novel approach to identify
      glycan masked linear antigenic epitopes. In the present study, GP-N was
      identified in BDV-infected cells by a combination of lectin precipitation,
      enzymatic deglycosylation on blot and immunochemistry using an N-terminal
      specific antiserum. The GP-N has an apparent molecular mass of 45-50 kDa in its
      glycosylated form and 27 kDa in its deglycosylated form. N-glycan analysis
      revealed that the precursor GP contains only mannose-rich N-glycans, whereas GP-N
      and GP-C contain mannose-rich and complex-type N-glycans.

PMID- 12417323
TI  - A split-ubiquitin-based assay detects the influence of mutations on the
      conformational stability of the p53 DNA binding domain in vivo.
AB  - Many mutations in the human tumor suppressor p53 affect the function of the
      protein by destabilizing the structure of its DNA binding domain. To monitor the
      effects of those mutations in vivo the stability of the DNA binding domain of p53
      and some of its mutants was investigated with the split-ubiquitin (split-Ub)
      method. The split-Ub-derived in vivo data on the relative stability of the
      mutants roughly correlate with the quantitative data from in vitro denaturation
      experiments as reported in the literature. A variation of this assay allows
      visualizing the difference in stability between the wild-type p53 core and the
      mutant p53(V143A) by a simple growth assay.

PMID- 12417324
TI  - Maturation of the activities of recombinant mite allergens Der p 1 and Der f 1,
      and its implication in the blockade of proteolytic activity.
AB  - Recombinant pro-Der p 1 expressed in yeast Pichia pastoris was convertible into
      the prosequence-removed mature Der p 1 with full activities of cysteine protease
      and IgE-binding with or without N-glycosylation of the mature sequence as well as
      pro-Der f 1. The active recombinant variants will be the basis for various future
      studies. The major N-terminus of pro-Der p 1 with low proteolytic activity was
      the putative signal-cleavage site, while that of pro-Der f 1 contained not only
      the equivalent site but also 21 residues downstream, and pro-Der f 1 retained
      significant activity. Contribution of the N-terminal region of the Der p 1
      prosequence including an N-glycosylation motif on effective inhibition of
      proteolytic activity of pro-Der p 1 was suggested.

PMID- 12417325
TI  - Acidianus ambivalens type-II NADH dehydrogenase: genetic characterisation and
      identification of the flavin moiety as FMN.
AB  - The thermoacidophilic archaeon Acidianus ambivalens contains a monomeric 47 kDa
      type-II NADH dehydrogenase (NDH), which contains a covalently bound flavin. In
      this work, by a combination of several methods, namely (31)P-nuclear magnetic
      resonance and fluorescence spectroscopies, it is proven that this enzyme contains
      covalent FMN, a novelty among this family of enzymes, which were so far thought
      to mainly have the flavin dinucleotide form. Discrimination between several
      possible covalent flavin linkages was achieved by spectral and fluorescence
      experiments, which identified an 8alpha-N(1)-histidylflavin-type of linkage.
      Analysis of the gene-deduced amino acid sequence of type-II NDH showed no
      transmembranar helices and allowed the definition of putative dinucleotide and
      quinone binding motifs. Further, it is suggested that membrane anchoring can be
      achieved via amphipatic helices.

PMID- 12417326
TI  - Selective cyclooxygenase-2 inhibitors show a differential ability to inhibit
      proliferation and induce apoptosis of colon adenocarcinoma cells.
AB  - Although the influence of selective cyclooxygenase (COX)-2 inhibitors on the
      proliferation of colon adenocarcinoma cells have been the subject of much
      investigation, relatively little research has compared the effects of different
      COX-2 inhibitors. Celecoxib strongly suppressed the proliferation of COX-2
      expressing HT-29 cells at 10-40 microM. NS-398 and nimesulide also inhibited cell
      proliferation, whereas rofecoxib, meloxicam, and etodolac did not. Only celecoxib
      induced apoptosis of HT-29 cells, as detected on the basis of DNA fragmentation,
      TUNEL positivity, and caspase-3/7 activation. DNA fragmentation was also increasd
      in COX-2 non-expressing cell lines (SW-480 and HCT-116) by exposure to celecoxib
      for 6-24 h. All six COX-2 inhibitors suppressed the production of prostaglandin
      E(2) by HT-29 cells, suggesting that the pro-apoptotic effect of celecoxib was
      unrelated to inhibition of COX-2. Inactivation of Akt might explain the
      differential pro-apoptotic effect of these selective COX-2 inhibitors on colon
      adenocarcinoma cells.

PMID- 12417327
TI  - Regulation of the phosphorylation of elongation factor 2 by MEK-dependent
      signalling in adult rat cardiomyocytes.
AB  - The Gq-coupled agonists phenylephrine and endothelin-1 each activate protein
      synthesis in cardiomyocytes as part of the programme that leads to cardiac
      hypertrophy. Here we show that they each induce the dephosphorylation of
      elongation factor (eEF) 2, a protein that in its dephosphorylated state mediates
      the translocation step of elongation. The ability of both agonists to induce
      dephosphorylation of eEF2 requires signalling via the mTOR and MEK/Erk signalling
      pathways, but is independent of phosphoinositide 3-kinase. Expression of an
      activated form of MEK leads to dephosphorylation of eEF2, in an mTOR independent
      manner, indicating that signalling via MEK/Erk suffices to cause
      dephosphorylation of eEF2.

PMID- 12417328
TI  - Absence of a conserved proline and presence of a conserved tyrosine in the CB2
      cannabinoid receptor are crucial for its function.
AB  - A majority (84%) of G protein-coupled receptors have a proline (P5.50) in the
      middle of the fifth transmembrane domain. However, one of the unique structural
      features of cannabinoid receptors is the replacement of the conserved P5.50 by a
      leucine (L5.50). It has been shown that a conserved tyrosine (Y5.58), located at
      the cytoplasmic side of P5.50, is crucial for the signal transduction of several
      G protein-coupled receptors. We proposed that the replacement of P5.50 by L5.50
      and the presence of the conserved Y5.58 in this context are important for the
      function of CB2. Mutating L5.50 to a proline abolished ligand binding, whereas
      mutating Y5.58 to an alanine resulted in a rightward shift of the competition
      binding curves. Both of these mutations led to a complete loss of the ability of
      cannabinoid agonists to inhibit forskolin-stimulated cAMP accumulation.

PMID- 12417329
TI  - Anti-HIV-1 property of trichosanthin correlates with its ribosome inactivating
      activity.
AB  - Trichosanthin (TCS) is a type I ribosome inactivating (RI) protein possessing
      anti-tumor and antiviral activity, including human immunodeficiency virus (HIV).
      The mechanism of these actions is not entirely clear, but is generally attributed
      to its RI property. In order to study the relationship between the anti-HIV-1
      activity of TCS and its RI activity, three TCS mutants with different RI
      activities were constructed by using site-directed mutagenesis. The anti-HIV-1
      activities of the three mutants were tested in vitro. Results showed that two TCS
      mutants, namely TCS(M(120-123)), TCS(E160A/E189A), with the greatest decrease in
      RI activity, lost almost all of the anti-HIV activity and cytopathic effect.
      Another mutant TCS(R122G), which exhibited a 160-fold decrease in RI activity,
      retained some anti-HIV activity. The results from this study suggested that RI
      activity of TCS may have significant contribution to its anti-HIV-1 property.

PMID- 12417330
TI  - Hetero-oligomerization of adenosine A1 receptors with P2Y1 receptors in rat
      brains.
AB  - Adenosine and ATP modulate cellular and tissue functions via specific P1 and P2
      receptors, respectively. Although, in general, adenosine inhibits excitability
      and ATP functions as an excitatory transmitter in the central nervous system,
      little is known about the direct interaction between P1 and P2 receptors. We
      recently demonstrated that the G(i/o)-coupled adenosine A1 receptor (A1R) and
      G(q/11)-coupled P2Y1 receptor (P2Y1R) form a heteromeric complex with a unique
      pharmacology in cotransfected HEK293T cells using the coimmunoprecipitation of
      differentially epitope-tagged forms of the receptor [Yoshioka et al. (2001) Proc.
      Natl. Acad. Sci. USA 98, 7617-7622], although it remained to be determined
      whether this hetero-oligomerization occurs in vivo. In the present study, we
      first demonstrated a high degree of colocalization of A1R and P2Y1R by double
      immunofluorescence experiments with confocal laser microscopy in rat cortex,
      hippocampus and cerebellum in addition to primary cultures of cortical neurons.
      Then, a direct association of A1R with P2Y1R was shown in coimmunoprecipitation
      studies using membrane extracts from these regions of rat brain. Together, these
      results suggest the widespread colocalization of A1R and P2Y1R in rat brain, and
      both receptors can exist in the same neuron, and therefore associate as hetero
      oligomeric complexes in the rat brain.

PMID- 12417331
TI  - Transcription initiation sites and promoter structure of the human TRAIL-R3 gene.
AB  - TRAIL-R3 is a decoy receptor for TRAIL (tumor necrosis factor-related apoptosis
      inducing ligand), a member of the tumor necrosis factor ligand family. In several
      cell types decoy receptors inhibit TRAIL-induced apoptosis by binding TRAIL and
      preventing its binding to TRAIL pro-apoptotic receptors. Here we report the
      cloning of the promoter region of human TRAIL-R3 and the mapping of the
      transcriptional start sites. This gene contains a consensus TATA box and the
      minimal promoter lies within the first 33 nucleotides upstream of the
      transcription start site. Transient transfection assays of luciferase reporter
      plasmids demonstrate that human TRAIL-R3 promoter can be induced in doxorubicin
      treated MCF-7 cells in a p53-independent manner.

PMID- 12417332
TI  - Generation of a novel proteolysis resistant vascular endothelial growth factor165
      variant by a site-directed mutation at the plasmin sensitive cleavage site.
AB  - Vascular endothelial growth factor (VEGF) is a potent angiogenic mediator in
      tissue repair. In non-healing human wounds plasmin cleaves and inactivates
      VEGF165. In the present study, we generated recombinant VEGF165 mutants resistant
      to plasmin proteolysis. Substitution of Arg110 with Ala110 or Gln110, and Ala111
      with Pro111 yielded plasmin-resistant and biologically active VEGF165 mutants. In
      addition, substitution of Ala111 with Pro111 resulted in a substantial degree of
      stabilization when incubated in wound fluid obtained from non-healing wounds.
      These results suggest that the plasmin cleavage site Arg110/Ala111 and the
      carboxyl-terminal domain play an important role in the mitogenic activity of
      VEGF165.

PMID- 12417333
TI  - NMR structure of the unliganded Bombyx mori pheromone-binding protein at
      physiological pH.
AB  - The nuclear magnetic resonance structure of the unliganded pheromone-binding
      protein (PBP) from Bombyx mori at pH above 6.5, BmPBP(B), consists of seven
      helices with residues 3-8, 16-22, 29-32, 46-59, 70-79, 84-100, and 107-124, and
      contains the three disulfide bridges 19-54, 50-108, and 97-117. This polypeptide
      fold encloses a large hydrophobic cavity, with a sufficient volume to accommodate
      the natural ligand bombykol. The polypeptide folds in free BmPBP(B) and in
      crystals of a BmPBP-bombykol complex are nearly identical, indicating that the B
      form of BmPBP in solution represents the active conformation for ligand binding.

PMID- 12417334
TI  - Identification of the nuclear localization signal of p21(cip1) and consequences
      of its mutation on cell proliferation.
AB  - Overexpression of p21(cip1) induces cell cycle arrest. Although this ability has
      been correlated with its nuclear localization, the evidence is not conclusive.
      The mutants that were used to inhibit its nuclear translocation could no longer
      bind to several proteins known to interact with the last 25 amino acids of
      p21(cip1). Here we used point mutation analysis and fusion of the proteins to
      DsRed to identify which amino acids are essential for the nuclear localization of
      p21(cip1). We conclude that amino acids RKR(140-142) are essential for nuclear
      translocation of p21(cip1). While wild-type DsRed-p21 induces cell cycle arrest
      in 95% of transfected cells, overexpression of cytoplasmatic p21AAA(140-142)
      arrested only 20% of transfected cells. We conclude that cytoplasmatic p21, with
      no deletion in the C-terminal region, had a much lower capacity to arrest the
      cell cycle.

PMID- 12417335
TI  - The stimulation of heart glycolysis by increased workload does not require AMP
      activated protein kinase but a wortmannin-sensitive mechanism.
AB  - Increasing heart workload stimulates glycolysis by enhancing glucose transport
      and fructose-2,6-bisphosphate (Fru-2,6-P(2)), the latter resulting from 6
      phosphofructo-2-kinase (PFK-2) activation. Here, we investigated whether
      adenosine monophosphate (AMP)-activated protein kinase (AMPK) mediates PFK-2
      activation in hearts submitted to increased workload. When heart work was
      increased, PFK-2 activity, Fru-2,6-P(2) content and glycolysis increased, whereas
      the AMP:adenosine triphosphate (ATP) and phosphocreatine/creatine (PCr:Cr)
      ratios, and AMPK activity remained unchanged. Wortmannin, the well-known
      phosphatidylinositol-3-kinase inhibitor, blocked the activation of protein kinase
      B and the increase in glycolysis and Fru-2,6-P(2) content induced by increased
      work. Therefore, the control of heart glycolysis by contraction differs from that
      in skeletal muscle where AMPK is involved.

PMID- 12417336
TI  - Irreversible inactivation of magnesium-dependent neutral sphingomyelinase 1
      (NSM1) by peroxynitrite, a nitric oxide-derived oxidant.
AB  - Previous results have indicated that the generation of ceramide by hydrolysis of
      sphingomyelin by magnesium-dependent neutral sphingomyelinase 1 (NSM1) is
      reversibly inhibited by hydrogen peroxide (H2O2) and oxidized glutathione (GSSG).
      This redox-dependent reversible regulation of NSM1 activity has been shown to
      involve the reversible formation and breakage of disulfide bonds. In this paper,
      we show that peroxynitrite, a nitric oxide-derived oxidant generated by SIN1,
      inactivates dose-dependently the NSM1 activity in an irreversible manner. In
      addition, we show that, in contrast to the reversible inhibition of NSM1 by H2O2
      or GSSG which involves the formation of disulfide bonds, irreversible
      inactivation of this enzyme by peroxynitrite generated from SIN1 is likely due to
      definitive oxidative thiol modification. These results suggest that depending on
      the nature of the oxidative stress, the enzymatic activity of NSM1 could be
      reversibly or irreversibly inactivated.

PMID- 12417337
TI  - Pyrococcus furiosus ferredoxin is a functional dimer.
AB  - Pyrococcus furiosus ferredoxin is subject to a monomer/dimer equilibrium as a
      function of ionic strength. At physiological ionic strength, approximately 0.35 M
      NaCl, the protein is very predominantly homodimer. The monomeric form exhibits
      impaired electron transfer on glassy carbon; it also has a decreased S=3/2 over
      S=1/2 ratio as shown by electron paramagnetic resonance spectroscopy. Even
      following sterilization at 121 degrees C the dimer is stable in denaturing gel
      electrophoresis.

PMID- 12417338
TI  - HspBP1, a homologue of the yeast Fes1 and Sls1 proteins, is an Hsc70 nucleotide
      exchange factor.
AB  - The yeast FES1 and SLS1 genes encode conserved nucleotide exchange factors that
      act on the cytoplasmic and endoplasmic reticulum luminal Hsp70s, Ssa1p and BiP,
      respectively. We report here that mammalian HspBP1 is homologous to Fes1p and
      that HspBP1 promotes nucleotide dissociation from both Ssa1p and mammalian Hsc70.
      In contrast, Fes1p inefficiently strips nucleotide from mammalian Hsc70, and
      unlike HspBP1 does not inhibit chaperone-mediated protein refolding in vitro.
      Together, our data indicate that HspBP1 is a member of this new class of
      nucleotide exchange factors that exhibit varying degrees of compartment and
      species specificity.

PMID- 12417339
TI  - N-Myristoylethanolamine-cholesterol (1:1) complex: first evidence from
      differential scanning calorimetry, fast-atom-bombardment mass spectrometry and
      computational modelling.
AB  - The interaction of N-myristoylethanolamine (NMEA) with cholesterol is
      investigated by differential scanning calorimetry (DSC), fast-atom-bombardment
      mass spectrometry (FAB-MS) and computational modelling. Addition of cholesterol
      to NMEA leads to a new phase transition at 55 degrees C besides the chain-melting
      transition of NMEA at 72.5 degrees C. The enthalpy of the new transition
      increases with cholesterol content up to 50 mol%, but decreases thereafter,
      vanishing at 80 mol%. The enthalpy of the chain-melting transition of NMEA
      decreases with an increase in cholesterol; the transition disappears at 50 mol%.
      FAB-MS spectra of mixtures of NMEA and cholesterol provide clear signatures of
      the formation of ([NMEA+cholesterol]+) ([NMEA+cholesterol+Na]+). These results
      are consistent with the formation of a 1:1 complex between NMEA and cholesterol.
      Molecular modelling studies support this experimental finding and provide a
      plausible structural model for the complex, which highlights multiple H-bond
      interactions between the hydroxy group of cholesterol and the hydroxy and
      carbonyl groups of NMEA besides appreciable dispersion interaction between the
      hydrocarbon domains of the two molecules.

PMID- 12417340
TI  - IRF-8/ICSBP and IRF-1 cooperatively stimulate mouse IL-12 promoter activity in
      macrophages.
AB  - IRF-8/ICSBP and IRF-1 are IRF family members whose expression is induced in
      response to IFN-gamma in macrophages. IL-12 is a cytokine produced in macrophages
      that plays a critical role in host defense. IFN-gamma and bacterial
      lipopolysaccharide (LPS) induce IL-12p40 transcription, which is necessary for
      the production of IL-12. We have previously shown that IL-12p40 expression is
      impaired in ICSBP-deficient mice and that transfection of ICSBP together with IRF
      1 can activate IL-12p40 expression in mouse macrophage cells. To further study
      the role of ICSBP and IRF-1, we investigated murine IL-12p40 promoter activity in
      the macrophage cell line RAW 264.7. We show here that co-transfection of ICSBP
      and IRF-1 synergistically stimulates IL-12 promoter activity to a level
      comparable to that induced by IFN-gamma/LPS. Mutation of the Ets or NFkappaB site
      previously shown to be important for IL-12p40 transcription did not abolish the
      activation by ICSBP and IRF-1. However, mutation of the ISRE-like site found
      downstream from the NFkappaB and C/EBP sites abrogated the activation by ICSBP
      and IRF-1. Together, these results indicate that ICSBP and IRF-1 cooperatively
      stimulate murine IL-12 transcription through a novel regulatory element in the
      murine promoter.

PMID- 12417341
TI  - Differentially expressed genes in sporadic amyotrophic lateral sclerosis spinal
      cords--screening by molecular indexing and subsequent cDNA microarray analysis.
AB  - To analyze the genes related to the pathophysiology of sporadic amyotrophic
      lateral sclerosis (SALS) we performed gene profiling of SALS spinal cords using
      molecular indexing combined with cDNA microarray. Eighty-four fragments were
      cloned in the first screening procedure with molecular indexing. Subsequent
      quantitative microarray screening revealed 11 genes which were differentially
      expressed in SALS. Real-time RT-PCR verified that the expression level of the
      following six genes was altered in SALS: dorfin, metallothionein-3, 30 kDa TATA
      binding protein-associated factor, neugrin, ubiquitin-like protein 5 and
      macrophage-inhibiting factor-related protein-8. These results indicated that
      genes associated with the ubiquitin-proteasome system, oxidative toxicity,
      transcription, neuronal differentiation and inflammation might be involved in the
      pathogenesis of SALS.

PMID- 12417342
TI  - Expression and regulation of peroxiredoxin 5 in human osteoarthritis.
AB  - Reactive oxygen species (ROS) are implicated in the pathogenesis of
      osteoarthritis (OA). However, little is known about the antioxidant defence
      system in articular cartilage. We investigated the expression and regulation of
      peroxiredoxin 5 (PRDX5), a newly discovered thioredoxin peroxidase, in human
      normal and osteoarthritic cartilage. Our results show that human cartilage
      constitutively expresses PRDX5. Moreover, the expression is up-regulated in OA.
      Inflammatory cytokines tumour necrosis factor alpha and interleukin 1 beta
      contribute to this up-regulation by increasing intracellular ROS production. The
      present study suggests that PRDX5 may play a protective role against oxidative
      stress in human cartilage.

PMID- 12417343
TI  - Role of the carboxyl terminus on the catalytic activity of protein kinase
      CK2alpha subunit.
AB  - Protein kinase CK2 (also known as casein kinase 2) has catalytic (alpha, alpha')
      and regulatory (beta) subunits. The role of carboxyl amino acids in positions
      from 324 to 328 was studied for Xenopus laevis CK2alpha. Deletions and mutations
      of these residues were produced in recombinant CK2alpha, which was assayed for
      kinase activity. Activity dropped 7000-fold upon deletion of amino acids 324-328.
      The key residues are isoleucine 327 and phenylalanine 324. A three dimensional
      model of CK2alpha indicates that these hydrophobic residues of helix alphaN may
      interact with hydrophobic residues in helix alphaE which is linked to the
      catalytic center.

PMID- 12417344
TI  - Angiotensin-I-converting enzyme inhibitory peptides from tryptic hydrolysate of
      bovine alphaS2-casein.
AB  - Angiotensin-I-converting enzyme (ACE) inhibitory activity of a tryptic digest of
      bovine alpha(S2)-casein (alpha(S2)-CN) was extensively investigated. Forty-three
      peptide peaks were isolated and tested. Seven casokinins (i.e. CN-derived ACE
      inhibitory peptides) were identified and their IC50 values were determined. Four
      peptides exhibited an IC50 value lower than 20 microM. Peptides alpha(S2)-CN
      (f174-181) and alpha(S2)-CN (f174-179) had IC50 values of 4 microM. Surprisingly,
      deletion of the C-terminal dipeptide of two of these casokinins did not
      significantly alter their inhibitory activity.

PMID- 12417345
TI  - Biochemical characterization of Thermotoga maritima endoglucanase Cel74 with and
      without a carbohydrate binding module (CBM).
AB  - The genome of the hyperthermophilic bacterium Thermotoga maritima (Tm) encodes at
      least eight glycoside hydrolases with putative signal peptides; the biochemical
      characteristics of seven of these have been reported previously. The eighth, Tm
      Cel74, is encoded by an open reading frame of 2124 bp corresponding to a
      polypeptide of 79 kDa with a signal peptide at the amino-terminus. The gene
      (lacking the signal peptide) encoding Tm Cel74 was expressed as a 77 kDa
      monomeric polypeptide in Escherichia coli and found to be optimally active at pH
      6, 90 degrees C, with a melting temperature of approximately 105 degrees C. The
      cel74 gene was previously found to be induced during T. maritima growth on a
      variety of polysaccharides, including barley glucan, carboxymethyl cellulose
      (CMC), glucomannan, galactomannan and starch. However, while Tm Cel74 was most
      active towards barley glucan and to a lesser extent CMC, glucomannan and tamarind
      (xyloglucan), no activity was detected on other glycans, including galactomannan,
      laminarin and starch. Also, Tm Cel74 did not contain a carbohydrate binding
      module (CBM), versions of which have been identified in the amino acid sequences
      of other family 74 enzymes. As such, a CBM associated with a chitinase in another
      hyperthermophile, Pyrococcus furiosus, was used to create a fusion protein that
      was active on crystalline cellulose; Tm Cel74 lacked activity on this substrate.
      Based on the cleavage pattern determined for Tm Cel74 on glucan-based substrates,
      this enzyme likely initiates recruitment of carbohydrate carbon and energy
      sources by creating oligosaccharides that are transported into the cell for
      further processing.

PMID- 12417348
TI  - The complex nosological concept of vascular dementia.
AB  - The existence of vascular dementia (VaD) was first identified by Marie, who
      described the etat lacunaire, and by Binswanger, who identified white matter
      lesions in demented individuals. The role of cortical lesions, while clear to
      clinicians, was highlighted only later by the pathological studies of Tomlinson
      and the clinical demonstrations of Hachinski et al., who have defined multi
      infarct dementia. Lately, the emphasis shifted to pathogenic mechanisms with the
      identification of a multitude of processes, such as lipohyalinosis, cardiac
      dysfunction and genetic causes, to name only a few. Epidemiologic studies have
      demonstrated the high frequency of VaD, as well as the fact that vascular factors
      can contribute to Alzheimer's disease (AD). All these considerations converge to
      the realization that VaD is an extremely important clinical entity and that its
      prevention and treatment are within reach. In fact, there is more data on how to
      prevent strokes (and presumably VaD) than on how to prevent AD. Moreover, many
      factors which were identified as contributing to cerebrovascular disease in
      general and VaD in particular are frequently suspected as predisposing to AD as
      well. These unexpected findings highlight the importance of mixed vascular
      degenerative dementia as a disorder which has to be properly defined and has
      important implications on prevention and treatment.

PMID- 12417349
TI  - Vascular dementia may be the most common form of dementia in the elderly.
AB  - Cerebrovascular lesions, mainly lacunes and white matter ischemia, are common in
      elderly patients with dementia. Vascular dementia (VaD) is the second most common
      cause of dementia, after Alzheimer's disease (AD). However, lacunar strokes have
      become an important factor in the clinical expression of AD. Also, population
      based studies indicate that vascular risk factors increase the risk of developing
      AD. It is postulated here that the two main causes of VaD-stroke and ischemic
      heart disease (IHD)-may be responsible for the majority of cases of dementia in
      the elderly. STROKE RELATED VaD: Cerebrovascular disease (CVD) is the second
      leading cause of death worldwide. About 1/3 of stroke survivors [range: 25-41%]
      65 years old and above develop VaD within 3 months following the ictus. In the
      USA alone, 125,000 new cases/year of VaD occur after ischemic stroke (about 1/3
      of the 360,000 incident cases of AD). Therefore, more than 1 million elderly
      people are currently affected by poststroke VaD in the USA. Since current
      criteria identify "pure" cases of AD and VaD, it is likely that "AD plus CVD"
      ("mixed" dementia) could be responsible for a large number of cases currently
      diagnosed as probable AD. CARDIOGENIC VAD: By 2020, IHD leading to congestive
      heart failure (CHF) will become the leading cause of disability worldwide.
      Vascular cognitive impairment occurs in 26% of patients discharged from hospitals
      after treatment for CHF. Cognitive dysfunction correlates with left ventricular
      dysfunction and systolic blood pressure below 130 mm Hg. CHF is a leading cause
      of hospital admissions in Western nations (4.5 million cases in the USA alone)
      and is a growing problem in developing countries. Furthermore, over 800,000
      patients/year undergo coronary artery bypass graft (CABG) surgery worldwide,
      including 300,000 patients in the USA. Measurable cognitive dysfunction occurs
      post-CABG in 80-90% of patients at hospital discharge. Long-term (5 years)
      incidence of cognitive defects is 42%. Finally, an international study found
      short-term postoperative cognitive dysfunction in 26% of patients (>60 years)
      after abdominal or orthopedic surgery; most of them may be instances of VaD. In
      conclusion, VaD may be the most underdiagnosed and undertreated form of dementia
      in the elderly.

PMID- 12417350
TI  - The concept of vascular cognitive impairment.
AB  - Vascular dementia (VaD) is increasingly recognised to reflect an outmoded concept
      in that it identifies cases too late for preventive therapy to have an
      opportunity to prevent the development of dementia and uses a cognitive paradigm
      inappropriately based on Alzheimer's disease. A replacement is urgently required
      and a new concept, that of vascular cognitive impairment (VCI), has been proposed
      to meet this need. It is imperative that criteria for VCI are developed on the
      basis of knowledge and data rather than supposition and assumption, as was the
      case for VaD. This review details the state of knowledge that we have now reached
      concerning the fundamental points of severity and cognitive paradigm and also
      covers a number of other imaging-related essential points embracing atrophy,
      leukoaraiosis, infarct volume and infarct location. Finally, the increasingly
      important concept of mixed dementia (co-existent Alzheimer's disease and VCI) is
      discussed.

PMID- 12417351
TI  - Neuropsychological differentiation of small vessel disease, Alzheimer's disease
      and mixed dementia.
AB  - This study examined the neuropsychological profile of probable Alzheimer's
      disease (AD, n=72), vascular dementia due to diffuse subcortical small vessel
      disease (SVD, n=18) and mixed dementia (AD+SVD, n=18). Five simple tests were
      analysed, i.e. verbal recall and recognition memory, object naming, word fluency
      and clock reading. Pairwise discriminant analyses classified 79-83% of the cases
      correctly. Mixed dementia (MD) patients showed lower word fluency; otherwise,
      their profile was indistinguishable from AD. Recognition memory and clock reading
      were identified as predictors of SVD vs. AD diagnosis. The potential of single
      variables to distinguish the groups was tested by receiver operator
      characteristic curve analysis. A clock reading cut-off score close to maximum
      separated SVD from AD and MD. Recognition memory separated SVD from AD. These
      results show that neuropsychological tests can distinguish SVD and MD from AD
      with high sensitivity (88-94%). Due to the overlapping of scores and a higher
      prevalence of AD, specificity was moderate (65-76%) and positive predictive
      values were low, whereas sensitivity and negative predictive indices were high.

PMID- 12417352
TI  - Vascular cognitive impairment and vascular dementia.
AB  - The criteria for vascular dementia (VaD) depend on first diagnosing dementia
      using Alzheimer-type criteria, upon which are superimposed vascular events,
      usually following a stroke model. This if often inappropriate, however, as memory
      loss is not always prominent in VaD. Alzheimer-type criteria will not detect
      these patients, and much brain injury can occur without resulting in classical
      features of stroke. VaD is often only diagnosed when dementia is clinically
      manifest, already too late to influence the early progression of the disease.
      Moreover, the predominating consensus-based criteria have demonstrably poor
      reliability. These shortcomings in the diagnosis of VaD have led to the
      development of the concept of vascular cognitive impairment (VCI), a broader term
      that is intended to detect cognitive loss before the dementia advances beyond
      effective treatment. Criteria for VCI are in the early stages of development. A
      lack of data on the beginnings of cognitive loss has inhibited their
      formalization, but it appears that the level of cognition should be set at a
      sensitive rather than a specific level. Similarly, for routine purposes,
      neuroimaging evidence of any cerebrovascular disease may be sufficient to
      document VCI and specific localization is not required. The current clinical
      criteria for VaD are probably not applicable for the diagnosis of VCI since the
      presence of focal signs is inappropriate, and stepwise progression is more
      supportive than diagnostic of VCI. The purpose of defining the new concept of VCI
      is to identify preventable risk factors. Importantly, not only physical health
      but also mental health should be monitored and treated.

PMID- 12417353
TI  - Similarities between Alzheimer's disease and vascular dementia.
AB  - Alzheimer's disease (AD) and vascular dementia (VaD) are the two most common
      forms of dementia. In Europe, 800,000 people have a diagnosis of VaD out of 3.7
      million people with clinical dementia. These two dementia types share many common
      pathological, symptomatic and neurochemical features, and cholinergic treatments
      that have demonstrated robust, broad-ranging and long-term efficacy in AD are now
      being assessed for the treatment of dementia related to cerebrovascular disease
      (CVD). There has been recent recognition that dementia in the elderly is a
      continuum of pathologies, with pure AD and VaD representing the two extremes, and
      'mixed' dementia (AD with CVD) in between and perhaps comprising the majority of
      cases. 'Mixed' dementia is rarely diagnosed in the clinic, however, as the
      majority of diagnostic procedures are biased toward a diagnosis of AD. Here, the
      risk factors, pathophysiological mechanisms and clinical symptoms of AD and VaD
      are described, identifying their overlap as well as some of the differences in
      both cognitive and noncognitive symptoms. Important findings indicating the high
      prevalence of 'mixed' dementia in the clinical dementia population are also
      discussed. In particular, evidence of a causal connection between stroke or CVD
      and AD is addressed. Regarding effective therapeutic management of dementia
      patients, further concerted epidemiological study of these related dementia types
      should aid in clinical decisions on the applicability of cholinergic treatments.

PMID- 12417355
TI  - Relevant clinical outcomes in probable vascular dementia and Alzheimer's disease
      with cerebrovascular disease.
AB  - Two important prerequisites for assessing therapeutic benefits in patients with
      vascular dementia (VaD), or Alzheimer's disease (AD) with cerebrovascular disease
      (CVD), are the inclusion of appropriate patients and the use of relevant outcome
      measures. There is substantial overlap in the clinical symptomatology, risk
      factors, imaging changes, pathophysiology and neurochemical mechanisms between
      VaD, AD and AD with CVD. While validated and acceptable clinical criteria
      suitable for clinical trials have been developed for VaD, there is still debate
      as to how mixed cases (i.e. AD with CVD) are best conceptualized. As with AD,
      there is consensus that outcome measures in studies of patients with VaD, or AD
      with CVD, should include assessments of cognitive and global function, of ability
      to perform activities of daily living (ADL) and of behavioral symptoms. Other
      measures, e.g., caregiver burden, would be desirable. Care must be taken in
      extrapolating AD-specific evaluations to VaD, however, because different specific
      domains are affected and the disease course is different. In clinical trials,
      cognitive performance and global function decline steadily in patients with
      untreated AD compared with smaller changes in patients with untreated VaD, while
      behavior and ADL deteriorate over 6 months in patients with either untreated AD
      or untreated VaD. Such differences in untreated outcome need to be considered
      when interpreting trial results using outcome measures that were largely designed
      for studies of patients with AD.

PMID- 12417354
TI  - The costs of vascular dementia: a comparison with Alzheimer's disease.
AB  - OBJECTIVES: To estimate the costs of Medicare patients with vascular dementia
      (VaD). To compare the costs of VaD to Alzheimer's disease (AD) and controls
      without dementia. METHODS: The study samples were drawn from community-dwelling
      patients in a large Medicare managed care organization (MCO) operating in the
      Northeast region of the USA. Costs for three study groups were contrasted in the
      study: 240 cases with vascular dementia (VaD), 1,366 cases with Alzheimer's
      disease (AD), and 19,300 controls without dementia. Costs were estimated from
      medical and pharmacy claims data. Estimated cost differences are controlled for
      age, gender, and comorbid conditions using regression analysis. RESULTS: VaD
      patients accounted for 6% of all dementia patients identified in the health plan.
      VaD patients had substantially higher prevalence rates for 10 cardiovascular
      conditions compared with AD patients and controls. Annual costs for VaD patients
      were US$6,797 greater than AD patients. Compared with controls, costs were
      US$10,545 higher for VaD patients and US$3,748 higher for AD patients. Higher
      costs for VaD and AD patients relative to controls were largely attributable to
      higher inpatient costs. CONCLUSIONS: Annual medical costs for VaD patients were
      substantially higher than costs for patients with AD and control patients without
      dementia. The high cost of VaD patients suggests a need to improve medical
      management and treatment of these patients to optimize patient outcomes and
      medical costs.

PMID- 12417356
TI  - Progression of cognitive impairment after stroke: one year results from a
      longitudinal study of Singaporean stroke patients.
AB  - BACKGROUND AND PURPOSE: Vascular dementia accounts for 40-50% of dementia cases
      in Singapore. The aim of this study is to examine the prevalence and natural
      history of cognitive impairment in a cohort of Singaporean post-stroke patients.
      METHODS: The Vascular Dementia Battery (VDB) was offered to 252 patients with a
      transient ischaemic attack (TIA) or non-disabling ischaemic stroke at baseline
      (within 6 months post index stroke) and annually thereafter. The VDB assesses six
      cognitive domains: attention, language, verbal memory (recall and recognition),
      visual memory (recall and recognition), visuoconstruction and visuomotor speed.
      Dementia was diagnosed using the DSM-IV criteria. Patients who did not meet the
      DSM-IV criteria but were impaired in one or more cognitive domains were
      classified as 'cognitively impaired but not demented'. Those who were unimpaired
      in all cognitive domains were classified as 'cognitively intact'. RESULTS: At
      baseline, 56% of patients were 'cognitively intact', 40% were 'cognitively
      impaired but not demented' and 4% were 'demented'. At 1-year follow-up, 33%
      patients had a changed classification from baseline. While 31% of those who were
      'cognitively impaired but not demented' at baseline improved to 'cognitively
      intact', 10% of the 'cognitively intact' group deteriorated to 'cognitively
      impaired but not demented' and 11% deteriorated from 'cognitively impaired but
      not demented' to 'demented'. Cognitive performance at baseline predicted for
      deterioration. CONCLUSIONS: This study suggests that the long-term cognitive
      performance in stroke patients change over time. Further studies are required to
      identify risk factors and effective treatment for cognitive deterioration after
      stroke.

PMID- 12417357
TI  - Natural history of dementia associated with lacunar infarctions.
AB  - BACKGROUND: Lacunar stroke (VaD-L) is the most common stroke subtype associated
      with vascular dementia (VaD). OBJECTIVE: To evaluate the rate of cognitive and
      behavioral changes in patients with probable VaD-L. METHODS: We measured rates of
      change on the Mini-Mental State Examination (MMSE), Digit Span, Logical Memory,
      Controlled Oral Word Association Test, CERAD battery and the Neuropsychiatric
      Inventory (NPI) of 77 [age at entry 65.9+/-8.1 (mean+/-standard deviation) years]
      patients with probable VaD, periventricular white matter and basal ganglia
      lacunae, longitudinally studied for 25.7+/-11 months. RESULTS: Mean number of
      follow-up visits was 2.6. Overall annual vascular event rate was 0.25. VaD-L in
      mildly and moderately impaired patients is characterized by progressive cognitive
      and behavioral decline. The rate of cognitive and behavioral progression depends
      on the occurrence of vascular episodes (VE) during the course of the illness [(
      1.1) MMSE and (+4.0) NPI points annually without VE vs. (-2.0) and (+10.3) points
      following VE]. The rates of progression are a function of the severity of the
      cognitive and behavioral impairment. Impaired cognition is associated with
      impaired behavior. A subgroup of VaD-L patients runs a progressively
      deteriorating course despite the absence of clinically apparent new vascular
      episodes. CONCLUSION: VaD-L is characterized by cognitive and behavioral decline
      in 83% of the patients. The rate of decline is determined mainly by the severity
      of the cognitive and behavioral impairment at baseline and by the occurrence of
      new vascular episodes.

PMID- 12417358
TI  - Patient populations in clinical trials of the efficacy and tolerability of
      donepezil in patients with vascular dementia.
AB  - There is increasing evidence to suggest that patients with vascular dementia
      (VaD) exhibit a cholinergic deficit. These patients may therefore benefit from
      treatment with cholinesterase (ChE) inhibitors such as donepezil. However, there
      are difficulties in accurately defining patients with VaD. Clinical trials to
      assess the efficacy and tolerability of donepezil in patients with VaD have been
      completed. National Institute of Neurological Disorders and Stroke and the
      Association Internationale pour la Recherche et l'Enseignement en Neurosciences
      (NINDS-AIREN) criteria were used to establish inclusion and exclusion criteria:
      evidence of dementia (impaired memory and two other cognitive domains), and
      evidence of cerebrovascular disease (CVD) from neuroimaging and physical
      examination and a possible or probable relationship between dementia and CVD were
      required for enrollment. Patients with a diagnosis of Alzheimer's disease (AD) or
      dementia caused by other conditions not associated with the cardiovascular system
      (e.g., MS, chronic infections, hypothyroidism) were excluded. These criteria
      ensured that only patients with probable or possible VaD were enrolled. Enrolled
      patients had a mean Hachinski score of 9.7, with memory impairment the most
      prominent feature of their dementia. Sixty percent of patients had a history of
      at least one stroke and 18% of patients had a history of transient ischemic
      attack (TIA) pre-dementia. Cortical and subcortical infarcts were among the
      lesions observed on computer-assisted tomography and magnetic resonance imaging
      scans with significant white matter lesions also present in some patients.
      Placebo-treated patients demonstrated stable cognitive and global function over
      the 24 weeks of the study. These observations suggest that the patients enrolled
      in these trials have a broad range of CVD, and are different from those enrolled
      in AD trials.

PMID- 12417359
TI  - Stroke vs. chronic progressive cerebrovascular disease: a magnetic resonance
      imaging study of symptomatic outpatients.
AB  - Stroke is the main manifestation of cerebrovascular disease (CVD). Few studies
      report the insidious and progressive development of CVD. The aim of this study
      was the characterization of a CVD form without stroke in association with
      vascular subtypes and risk factors (VRF). From 105 CVD patients, 65 had stroke
      (62%), 13 of them had more than one stroke (20%), and 40 patients had a chronic
      progressive form (CPF) (38%). Mean evolution times up to maximum neurological
      deficiency were 1.57+/-0.94 and 344.25+/-210.96 days, respectively. Group results
      significantly associated with VRFs: hypertension (p=0.0046), hyperlipemia
      (p=0.0046) and atrial fibrillation (p=0.0173); with clinical manifestations:
      aphasia (p=0.0018), pyramidal syndrome (p=0.0000001) and small vessel disease
      (SVD) (p=0.0000001); and with MRI: bilateral infarctions (p=0.00009) and
      incomplete white matter lesions (IWMLs) (p=0.0061). Within the CPF group,
      dysarthria and complete infarctions were associated (p=0.00036). Most
      neurological disorders associated with CVD are related to CPF. The significant
      correlations of SVD, bilateral infarcts, IWMLs, dysarthria, several VRFs and the
      strong difference in evolution time up to maximum neurological deficiency values
      characterize CPF as a separate entity within CVD.

PMID- 12417360
TI  - Vascular dementia among elderly Arabs in Wadi Ara.
AB  - Dementia of the Alzheimer type (DAT) and vascular dementia (VaD) are the two
      major subtypes of dementia. In our epidemiological study of DAT in an Arab
      community in Wadi Ara, Israel, we found a high prevalence of late onset DAT.
      Illiteracy, smoking, diabetes mellitus (DM) and hypertension are very frequent in
      Wadi Ara. These factors led us to study the prevalence of VaD and various risk
      factors in this population. All people aged 60 years or older (n=823) in a
      defined region were examined for identification of DAT and VaD (DSM-IV criteria),
      using clinical examinations and a semi-structured questionnaire for detecting
      cognitive dysfunction. We identified 49 demented patients (29 males) fulfilling
      criteria of VaD with a prevalence rate of 49/823 (5.9%), compared to 168/823
      (20.5%) for DAT. All had suffered from strokes. Male gender and hypertension were
      more common among VaD cases. Illiteracy was significantly more common among VaD
      patients than among healthy subjects (79.6% vs. 40.2%, P=0.001) but less common
      than among DAT patients (94.6%, P=0.001). Thus, our results show that VaD
      constitutes about 22% of the total dementia population in Wadi Ara. We confirm
      the association between VaD, illiteracy and hypertension. Smoking and gender do
      not represent risk factors for VaD in this population. While suggestive, DM is
      not a statistically significant risk factor for VaD.

PMID- 12417361
TI  - Cerebral autosomal dominant arteriopathy with subcortical infarcts and
      leukoencephalopathy: phenotypic and mutational spectrum.
AB  - Mutations in NOTCH3 are the cause of cerebral autosomal dominant arteriopathy
      with subcortical infarcts and leukoencephalopathy (CADASIL) an inherited small
      vessel disease leading to subcortical strokes and dementia. Since the vascular
      pathology is clearly defined, CADASIL may provide important insights into the
      mechanisms underlying lacunar infarcts, ischemic white matter changes, and
      vascular dementia. Evidence from different sources suggests a central role for
      vascular smooth muscle cells (VSMC) in the pathophysiology of the disease. This
      article gives a brief overview on the phenotypic spectrum of the disease and
      discusses some of the relevant disease mechanisms that lead from Notch3 mutations
      to ischemic infarcts.

PMID- 12417362
TI  - Prevalence and clinical features of dementia associated with the antiphospholipid
      syndrome and circulating anticoagulants.
AB  - The increasing prevalence with age of antiphospholipid antibodies (aPL), of
      dementia and of stroke complicates the study of a causal relationship between
      antiphospholipid syndrome (APS) and dementia. Prolonged aPTT due to circulating
      anticoagulants (CAC) may serve as a more specific laboratory marker of APS. In a
      hospital-based study, we examined all patients with CAC and included 23 who
      fulfilled standard criteria for primary APS. These patients were assessed for
      dementia, vascular brain disease, autoimmune disease activity and dementia risk
      factors. Among CAC-positive APS patients, 13 of the 23 (56%) were demented and
      these were significantly older (mean age+/-S.E., 68+/-3 years) than the
      nondemented APS group (n=10, 51+/-4 years; p<0.01, Student's t-test). The
      demented patients had significantly more pathology on computerized brain
      tomography (CT) and electroencephalography (EEG) studies but six of them had no
      clinical or CT evidence of vascular brain disease. Erythrocyte sedimentation rate
      was significantly lower in the dementia group, in which there was also a
      significant negative correlation between levels of aPL and age. CAC-positive APS
      patients seem to be at risk for developing dementia with age, suggesting a
      pathogenic role for prolonged exposure to elevated aPL.

PMID- 12417363
TI  - Single stroke dementia: insights from 12 cases in Singapore.
AB  - BACKGROUND: Vascular dementia (VaD) is occasionally caused by a single,
      strategically located stroke. In this report, we describe the clinical and
      anatomical features of 12 cases of strategic single infarct dementia (SSID) from
      Singapore. METHODS: Each patient completed a standardized diagnostic evaluation
      including history, neurological and neuropsychological examination, laboratory
      testing, and brain imaging. Dementia was diagnosed using the Diagnostic and
      Statistical Manual, 3rd edition, revised (DSM-III-R) criteria, and VaD was
      diagnosed using the National Institute of Neurologic Disorders and Stroke and the
      Association Internationale pour la Recherche et l'Enseignement en Neurosciences
      (NINDS-AIREN) criteria. VaD patients whose brain imaging study revealed a single
      cerebrovascular event were diagnosed with SSID. RESULTS: We identified 12 cases
      of SSID among 125 VaD patients (9.6%). Stroke mechanism was lacunar infarction in
      five cases, embolism in four cases, large vessel thrombosis in two cases, and
      parenchymal hemorrhage in one case. The most commonly impaired cognitive domains
      on neuropsychological testing were visual memory, visuoconstruction, and
      language. In 11 of the 12 SSID cases, the stroke was located in the left
      hemisphere. The thalamus, either alone or as the proximal portion of a posterior
      cerebral artery infarction, was involved in 8 of the 12 cases. Stroke locations
      in the nonthalamic SSID cases included left angular gyrus, subcortical left
      frontal lobe including minor forceps, left basal forebrain and medial frontal
      lobe plus anterior corpus callosum (proximal anterior cerebral artery
      infarction), and anterior corpus callosum alone. CONCLUSIONS: Various stroke
      mechanisms may produce SSID. In our SSID cases, vascular damage almost always
      involved the left hemisphere and frequently involved the thalamus and major
      interhemispheric or intrahemispheric white matter pathways.

PMID- 12417364
TI  - Strategic infarcts of the thalamus in vascular dementia.
AB  - Strategic infarcts or focal hemorrhages involving the paramedian nuclei of the
      thalamus may alter consciousness and produce complex neuropsychological symptoms
      such as impairment of memory, attention and motivation. Lesions disrupting the
      thalamo-prefrontal circuits lead to severe subcortical dementia. We analysed here
      the clinical, neuropsychological and neuroimaging data of 19 patients with
      cerebrovascular lesions in the thalamus. In six patients with bilateral
      paramedian infarcts, and in two with anterior thalamic infarcts, vascular
      dementia and severe personality changes developed. SPECT findings did not
      correlate with the neuropsychological symptoms. Transcortical sensory and motor
      aphasia was observed in four patients with thalamic hemorrhages and infarcts. In
      these patients SPECT detected hypoperfusion in adjacent cortical areas. Clinical
      symptoms and outcome of four patients are reported in detail. The clinico
      morphological correlations of the thalamo-cortical circuits are reviewed and the
      possible causes of multiple cognitive and behavioural consequences of vascular
      thalamic lesions are discussed.

PMID- 12417365
TI  - Subcortical features and cognitive performance in Hungarian cerebrovascular
      outpatients.
AB  - Cerebrovascular diseases are common in Central and East Europe, and the resulting
      cognitive impairment is probably also frequent. Although this problem attracted a
      lot of attention in the last decade, systematic examination of cognitive
      functions is not routinely performed in cerebrovascular patients. In our study
      involving cerebrovascular outpatients, we used the MMSE and the Barthel Index
      combined with a checklist for the evaluation of subcortical features. From a
      total of 176 cases, 32% had at least one subcortical sign. Except for gait
      disturbance and unprovoked falls, patients with subcortical dysfunction had lower
      performances on MMSE and lower Barthel scores. Their mean age did not differ
      significantly from the age of patients without subcortical signs, except for the
      subgroups with urinary and gait disturbances. Cognitive deficit could be detected
      in 27 patients, nine of them fulfilled the criteria for dementia. Subcortical
      signs and cognitive impairment can also be present in apparently well-being
      cerebrovascular patients. The routine evaluation of these deficiencies must be an
      integral part of the management of cerebrovascular patients and in planning their
      complex rehabilitation. Short, widely usable and easily executable tests are
      recommended.

PMID- 12417366
TI  - The role of carotid stenosis in vascular cognitive impairment.
AB  - As the contribution of carotid stenosis to cognitive impairment still remains
      unclear, neuropsychological function and soft neurological signs were examined in
      patients aged 65 and over. Twenty-five patients with symptomatic carotid stenosis
      (CS) of 75% or more were compared with 25 patients with first anterior
      circulation stroke, 25 with peripheral vascular disease and 25 healthy controls.
      All patients were assessed using CAMCOG (Cambridge Cognitive Examination), tests
      examining frontal lobe function (Behavioural Dyscontrol Scale [BDYS], Trail
      Making Tests A and B, Controlled Word Association Test) and a scale for primitive
      reflexes (Frontal Release Signs Scale). Patients with symptomatic CS showed
      greater global impairment on CAMCOG and more severe impairment in frontal lobe
      function than controls. Those patients scoring less than 15 on the BDYS were more
      likely to have experienced transient ischemic attacks (TIA) for 5 or more years.
      Frontal lobe dysfunction, suicidal thinking and age were all independent
      predictors of global cognitive impairment. Mean number of frontal release signs
      was higher in patients with CS than in controls, with a higher proportion of
      patients showing all release signs except glabellar, paratonia and snout
      reflexes. The study is limited by small numbers and the absence of brain imaging,
      but provides some evidence for an association between severe carotid stenosis and
      neuropsychological impairment. The presence of clinically 'silent'
      cerebrovascular disease affecting frontal lobe function may be missed in routine
      clinical practice.

PMID- 12417367
TI  - The validity and reliability of a Computerized Dementia Screening Test developed
      in Korea.
AB  - OBJECTIVE: This study was done to verify the validity and the reliability of the
      newly developed Computerized Dementia Screening Test (CDST) to be easily used in
      the primary care setting of Korea. DESIGN: Comparison of the results of CDST
      between 103 healthy control subjects and 41 patients who were diagnosed as having
      mild cognitive impairment or early dementia, having a clinical dementia rate of
      0.5-1 from one health examination center and two neurology clinics in university
      hospitals. MEASUREMENTS: In order to estimate the criterion-related validity,
      logistic regression analysis for dementia was done using the four individual test
      results of CDST, age and educational level. The correlation between Korean Mini
      Mental State Examination (K-MMSE) and the predicted probability of mild cognitive
      impairment and early dementia from the logistic regression was measured to verify
      its validity. The reliability of CDST was measured by test-retest reliability.
      RESULTS: The sensitivity and specificity of CDST were 75.6% and 94.2%,
      respectively, if the cut-off point was set to be 0.5 in the logistic regression
      model. The Pearson's Correlation Coefficient between K-MMSE and the predicted
      probability of mild cognitive impairment and early dementia from the logistic
      regression analysis was 0.59 (P<0.001). The overall test-retest reliability using
      the predicted probability of dementia from the logistic regression analysis of
      CDST was 0.89 (P=0.01). CONCLUSION: The validity and reliability of CDST is
      adequate for use as a screening tool to identify mild cognitive impairment and
      early dementia in Korean primary care.

PMID- 12417368
TI  - Vascular cognitive disorders: memory, mental speed and cognitive flexibility
      after stroke.
AB  - This study investigated the occurrence of cognitive disorders 1 and 6 months
      after stroke in a cohort of patients with a first-ever stroke. In addition, it
      was investigated whether age, sex and level of education are risk factors for
      vascular cognitive disorders. Memory, simple speed, cognitive flexibility and
      overall cognitive functioning were examined in 139 patients at 1 and 6 months
      post-stroke. Inclusion criteria on admission were first cerebral stroke,
      age>/=40, no other neurological or psychiatric disorders and ability to
      communicate. Mean age was 69.3 years (S.D.=12.3). Patients were compared with a
      healthy control group matched for age, sex and level of education. A large group
      of patients who, at 1 month after stroke, scored below the cutoff on cognitive
      domains, scored above the cutoff on most of these cognitive domains at 6 months.
      For overall cognitive functioning, 16 out of 39, for memory, 13 out of 26 and for
      cognitive flexibility, 15 out of 49 patients, who at 1 month scored below the
      cutoff, scored above the cutoff at 6 months. Simple speed did not change; 12
      patients scored above the cutoff and 7 patients scored below the cutoff at 6
      months after stroke. Speaking in terms of improvement or deterioration, most
      people remained stable on the four cognitive domains (ranging from 37.6% to
      83.5%), and a substantial group improved (ranging from 12.9% to 52.1%). Older and
      female patients had more cognitive disturbances. Overall, the conclusion is that
      the prognosis of cognitive functioning after stroke is general favourable,
      especially in younger patients.

PMID- 12417369
TI  - Vitamin intervention for stroke prevention.
AB  - Vitamin Intervention for Stroke Prevention (VISP) is designed to determine
      whether the utilization of folic acid, vitamins B(6) and B(12), in addition to
      other risk factor reducing measures, have a demonstrable effect on prevention of
      recurrent stroke. The entry criteria are a first-ever nondisabling stroke, the
      patient signs informed consent with willingness to participate and randomization
      to a high- or low-dose vitamin intervention regimen. Case acquisition of 3,688
      individuals has been completed, half in the high-dose and the other half in the
      low-dose intervention arm. Follow-up is in progress and the end results are
      expected within the year. The Vitamins to Prevent Stroke (VITATOPS) is a parallel
      study based in Australia with similar goals, and, hopefully, the data from the
      two will be comparable and supportive.

PMID- 12417370
TI  - Treatment options: the latest evidence with galantamine (Reminyl).
AB  - Vascular dementia (VaD) has a great deal of overlap (in terms of features and
      symptoms) with Alzheimer's disease (AD). Mixed dementia, or AD with concomitant
      cerebrovascular disease (AD with CVD), is increasingly being recognized as a
      distinct clinical condition that occurs with substantial frequency. The robust
      evidence for the effectiveness of cholinergic treatments such as galantamine
      (Reminyl) in AD suggests its potential use in the treatment of dementias related
      to CVD, and preclinical evidence supports this rationale. Galantamine, which has
      a unique dual cholinergic mode of action, may be of particular benefit in VaD and
      AD with CVD. For example, behavioral symptoms, which can be more severe in VaD
      than in AD and are important determinants of the impact of dementia, may be
      especially benefited by galantamine. This results from its potential to modulate
      systems involving other neurotransmitters such as 5-HT (serotonin) and dopamine,
      which affect mood and emotional balance. The results of a recent landmark
      clinical trial with galantamine in patients with VaD, or AD with CVD, indicate
      that galantamine produces benefits across a broad range of symptoms of dementia
      in both patient populations. Significant cognitive improvements over 6 months,
      long-term maintenance of cognition for at least 12 months, and global benefits,
      as well as efficacy in both behavioral and functional symptoms, indicate efficacy
      with galantamine that is so far unsurpassed by any other drug treatment for
      dementia. Galantamine therefore has potential to benefit a wide range of patients
      with dementia in the clinic.

PMID- 12417371
TI  - The rationale behind cholinergic drug treatment for dementia related to
      cerebrovascular disease.
AB  - Common to all subtypes of dementia, including Alzheimer's disease (AD), and those
      associated cerebrovascular disease (CVD), Lewy body pathology and Parkinson's
      disease, is degeneration of cholinergic neurotransmission. The cholinergic
      hypothesis of AD is based on evidence of reduced cholinergic markers and
      decreased numbers of cholinergic neurons and nicotinic acetylcholine receptors
      (nAChR) in the hippocampus and cortex of the brain-both areas associated with
      memory, learning and executive function impairments characteristic of cognitive
      decline in AD. There is growing evidence for the involvement of the cholinergic
      system in vascular dementia (VaD). Attention has, therefore, recently turned to
      the use of cholinergic treatments such as galantamine (Reminyl), which has
      demonstrated broad-spectrum and long-term efficacy in AD, for the treatment of
      patients with VaD or AD with CVD. Galantamine is both a moderate, reversible,
      competitive acetylcholinesterase inhibitor, and an allosteric modulator of nAChR.
      Recent evidence suggests that the unmatched efficacy of galantamine in cognitive
      as well as behavioral and functional symptoms in patients with AD, as well as
      those with VaD or AD with CVD, may at least partly result from its unique dual
      cholinergic mode of action. Here, the rationale for using galantamine to treat
      dementia related to CVD is discussed. In particular, some interesting findings
      are covered which indicate the potential of galantamine to modulate other
      neurotransmitter systems (e.g. serotonergic, dopaminergic), which may be of
      specific relevance in the behavioral symptoms of dementia related to CVD.

PMID- 12417372
TI  - Treatment with donepezil in Alzheimer patients with and without cerebrovascular
      disease.
AB  - Donepezil, a selective acetylcholinesterase inhibitor, is approved for the
      symptomatic treatment of mild to moderate Alzheimer's disease (AD). In a post
      marketing surveillance (PMS) study in Germany, patients under routine treatment
      conditions were observed while treatment was switched from other antidementia
      drugs (i.e., nootropics) to donepezil. A total of 913 patients were enrolled
      (60.1% female, mean+/-S.D. age 73.4+/-8.6 years, mean Mini-Mental Status
      Examination [MMSE] 18.0+/-5.3), and were treated with donepezil (5 or 10 mg/day
      according to recommended dosing). 709/913 (77.1%) of patients had been pretreated
      with other antidementive drugs (piracetam, memantine, ginkgo, and others). In
      29.6% of patients, investigators documented concomitant cerebrovascular disease
      (CVD+) according to their clinical judgment. Observation period was 3 months for
      the individual patient. Efficacy parameters were changes in MMSE, global clinical
      (investigators) judgment of efficacy, and a clinical judgment about the patients'
      quality of life (QoL). Adverse events were also analyzed. The objective of the
      present investigation was to compare-in a "real-life" setting-the differential
      efficacy and tolerability of donepezil in AD patients with and without
      concomitant cerebrovascular disease. After 3 months, patients had improved by a
      mean MMSE change from baseline of 2.2 points (CVD+: 2.4 pts, CVD-: 2.1 pts). QoL
      was judged "improved" in 70.0% of patients (CVD+: 72.5%, CVD-: 69.6%). Adverse
      events were reported in 85/913 (9.3%) of patients (CVD+: 11.2%, CVD-: 7.9%).
      Reported adverse events were substantially less than reported previously in
      controlled clinical trials. This suggests that donepezil therapy is effective and
      well tolerated in AD patients, both with and without concomitant cerebrovascular
      disease.

PMID- 12417373
TI  - Rivastigmine in subcortical vascular dementia: an open 22-month study.
AB  - Further to recent data indicating that patients with vascular dementia (VaD) show
      a cholinergic deficit, we aimed to determine whether rivastigmine, a dual
      inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), has
      any effects on the symptoms of VaD. Patients aged 65-80, with a diagnosis of
      dementia and probable VaD, received rivastigmine 3-6 mg/day (n=8) or
      cardioaspirin (n=8) in an open study for 22 months. At 22 months, patients
      treated with rivastigmine showed significant improvements in executive function
      and behavioural symptoms (both p<0.05 vs. both baseline and control group), which
      were reflected in reduced caregiver stress (p<0.05 vs. baseline and controls).
      Baseline scores of global response, cognition, word fluency and activities of
      daily living were maintained in patients receiving rivastigmine, and there was no
      increase in benzodiazepine or neuroleptic intake. In contrast, the control group
      showed no improvements in any domain, and significant deterioration in global
      response and executive function (both p<0.05 vs. baseline and rivastigmine
      group). Side effects in both groups were tolerable and there were no study
      withdrawals. Long-term rivastigmine treatment appeared to be safe and effective
      in this patient population. In particular, improvements in domains particularly
      relevant to this condition were observed. These benefits may reflect the drug's
      dual inhibitory effects on the cholinergic system, and its particular activity in
      frontal areas of the brain. A large, double-blind study of rivastigmine in
      patients with VaD would be worthwhile.

PMID- 12417374
TI  - Protective effect of anti-hypertensive treatment on cognitive function in
      essential hypertension: analysis of published clinical data.
AB  - Hypertension is a risk factor for stroke and may also contribute to the
      development of vascular cognitive impairment (VCI) and vascular dementia (VaD).
      Cognitive complications of hypertension and the influence of anti-hypertensive
      treatment were underestimated until recently. In this paper, trials investigating
      the effect of anti-hypertensive treatment on cognitive function were evaluated.
      Analysis of these studies revealed that until approximately 1990-1995
      investigations have assessed primarily if anti-hypertensive treatment impaired
      cognitive function. Only more recent studies have investigated positive effects
      on cognition of anti-hypertensive medication. Drugs more extensively evaluated
      were diuretics, beta-blockers, angiotensin-converting enzyme (ACE) inhibitors,
      sartanes and Ca(2+) channel blockers. Available studies have confirmed that
      elevated diastolic blood pressure or pulse pressure and isolated systolic
      hypertension play an important role in the development of cognitive impairment.
      Randomized placebo-controlled trials have provided evidence that reduction of
      hypertension safely and effectively decreases morbidity and mortality rates and
      cognitive complications of hypertension. Ca(2+) channel blockers and ACE
      inhibitors have been shown to be effective and probably better than diuretics and
      beta-blockers on cognitive domains of hypertension. More extensive investigations
      could contribute to establishing optimal choice and drug dosage for the treatment
      of cognitive complications of hypertension.

PMID- 12417375
TI  - The pathology of ischemic-vascular dementia: an update.
AB  - In Western memory clinic-based series, ischemic-vascular dementia (IVD) is seen
      in 8-10% of cognitively impaired elderly subjects. Its prevalence in autopsy
      series ranges from 0.03% to 58% with reasonable values of 4-10%, while in Japan,
      IVD is seen in 22-35% and mixed-type dementia (MTD) (Alzheimer disease/AD+IVD) in
      6-11%. In a large Viennese autopsy series, "pure" IVD was observed in 9.4% of
      demented elderly and in 2.9% of those clinically diagnosed as possible/probable
      AD MTD was observed in 3.1% and 1.3% respectively. The major morphological types
      of IVD are multi-infarct encephalopathy (MIE), small vessel infarct type
      strategic infarct dementia (SID), subcortical arteriosclerotic
      leukoencephalopathy (Binswanger), multilacunar state, mixed cortico-subcortical
      type, granular cortical atrophy, and post-ischemic encephalopathy. In contrast to
      previous suggestions that IVD is mainly the result of large hemispheral infarcts
      or losses of over 100 ml of brain tissue, recent data indicate that cognitive
      decline is commonly associated with widespread small ischemic or vascular lesions
      (microinfarcts, lacunes) throughout the brain with predominant involvement of the
      basal ganglia, white matter, and hippocampus. The lesion pattern of "pure" IVD,
      which is related to arteriolosclerosis and hypertensive microangiopathy, differs
      from that in mixed-type dementia, more often showing large infarcts. Although
      recent studies suggest that concomitant small cerebral infarcts do not
      significantly influence the overall rate of cognitive decline in AD patients or
      may be important for mental decline in early AD, both mild AD pathology and
      microvascular cerebral lesions appear to be common and may interact in
      "unmasking" or promoting dementia.

PMID- 12417376
TI  - Venous collagenosis and arteriolar tortuosity in leukoaraiosis.
AB  - Leukoaraiosis (LA), an age-related white matter degeneration, is thought to be
      caused by chronic ischemia. To understand the pathogenesis of LA, we studied the
      pathology, particularly of the blood vessels, in 186 brains [84 of them with
      magnetic resonance imaging (MRI)] over the past 10 years. With normal aging,
      there is gradual thickening of the walls of periventricular veins and venules
      with collagen subtypes I and III. This venous collagenosis (VC) was increased in
      brains with LA. Occasionally, LA lesions are not periventricular, but nearer the
      cortex. In such cases, the most severe VC occurs in the LA lesion rather than
      near the ventricle. Therefore, LA and VC are not independent degenerative
      processes coincidentally found near the ventricles, and although damage to the
      ependyma could be a cause of VC, it cannot be the only cause. Whether VC precedes
      LA is unknown, but our experience suggests that severe VC is usually accompanied
      by LA. Arteriolar tortuosity, another age-related vascular pathology, is common
      in LA. Our thick celloidin sections show three-dimensional views of tortuous
      arterioles. The tortuosity is much more severe in the white matter and there is
      considerable loss of parenchyma around them. Staining for collagen IV in the
      basal lamina reveals tortuous vessels in an "empty bag" that represents the
      limits of the surrounding parenchyma. These enlarged perivascular spaces
      correspond to etat crible. The demyelination in LA lesions is accompanied by loss
      of cells, mostly oligodendrocytes. In studies of apoptosis in LA, we found
      increased apoptosis within the lesion compared to the surrounding white matter.
      In conclusion, our studies support the concept that LA results from chronic
      ischemia due to age-related vascular pathology.

PMID- 12417377
TI  - A three-dimensional study of brain string vessels using celloidin sections
      stained with anti-collagen antibodies.
AB  - The purpose of this study was to explain the morphology and significance of
      string vessels in human brains. Brain slices (1.5 cm thick) were embedded in
      celloidin, sections cut at 100 microm and stained with antibody to collagen IV. A
      second component of the study was a 3-D rotational study for which we used
      sections stained with propidium iodide for cell nuclei and anti-collagen stain
      for blood vessel basement membranes. The materials consisted of brain from two
      infants at 28 and 35 weeks gestation, two term infants at 20 days and 3 months,
      one 5 years old, and 3 adults aged 25, 57, and 84 years. String vessels were
      counted in at least six fields of deep white matter using a 10x objective and the
      counts averaged and expressed as string vessels per cubic mm. The 3-D rotational
      study using confocal microscopy was designed to find nuclei in string vessels.
      The least number of string vessels were present in the premature infant. All
      others had comparably similar numbers of string vessels except the two term-born
      infants in whom there was a 3-5-fold increase. However, the two brains had other
      pathologic lesions, which could affect the counts. In normal brains, string
      vessels appear as a singe line of stain and usually connect two arterioles or
      capillaries. They can form loops and occasionally a string vessel may continue
      into a normal capillary. String vessels have rare nuclei. Our study indicates
      that string vessels are present in utero, increase in number and are present
      throughout life. Their exact nature remains unexplained. They apparently do not
      represent age-related acquired atrophy of capillaries because they are present at
      all ages and do not progressively increase with normal aging. This technique
      appears suitable for the study of large number of string vessels.

PMID- 12417378
TI  - Apoptosis in leukoaraiosis lesions.
AB  - Leukoaraiosis (LA), an age-related degenerative condition, appears as an area of
      hyperintense signal in the deep white matter on MRI. It may be caused by chronic
      ischemia. LA lesions are characterized by demyelination, loss of glial cells,
      spongy appearance, and occlusion of veins and venules by collagenous thickening
      of the vessel walls. Since necrosis is not obvious in LA lesions, we investigated
      the occurrence of apoptosis. We obtained 1.5-cm-thick coronal brain slices at
      autopsy from two patients with LA. MRI was performed on the brain slices. Blocks
      were fixed in formalin, embedded in paraffin, and sectioned. Sections were
      stained by several methods including the TUNEL method for DNA fragmentation. Some
      TUNEL-positive cells showed nuclear morphology indicative of apoptosis. In case
      1, TUNEL-positive cells were more numerous in an LA lesion than in nearby
      unaffected white matter (P=0.008). In case 2, LA lesions were examined in six
      areas; left and right frontal, middle, and occipital slices. TUNEL-positive cells
      were more numerous in the LA lesions than in nearby white matter (P=0.002). We
      also found TUNEL-positive cells in the cortex and in the walls of blood vessels.
      In case 1, more severe venous collagenosis was found in the LA lesion, which was
      near the cortex, than in the periventricular area, where venous collagenosis and
      LA are more commonly found. The presence of numerous scattered cells in the LA
      lesions showing DNA fragmentation suggests that those cells are damaged and
      dying, at least some by apoptosis. The apoptosis in the white matter adjacent to
      the LA lesions suggests progressive cell loss and expansion of the LA lesions.

PMID- 12417379
TI  - APOE genotype in cerebrovascular disease and vascular dementia.
AB  - BACKGROUND: The fact that the allele epsilon 4 of the Apolipoprotein E (APOE)
      gene could act like a risk factor not only in late-onset familial and sporadic
      Alzheimer's disease (AD) but also in cerebrovascular disease (CVD) and vascular
      dementia (VaD) is still controversial. METHODS: In order to study if epsilon 4
      allele is overrepresented not only in AD but also in CVD and VaD, APOE genotyping
      was undertaken in a series of 247 patients: 26 cases with VaD, 41 cases with CVD
      but without cognitive impairment (CVD-C), 83 cases with AD and 97 aged-matched
      "healthy controls" (HC). RESULTS: Percentages of subjects bearing one or two
      copies of the epsilon 4 allele was much higher in AD patients (54%) than in
      either CVD-C (29%) (p<0.05), VaD (15%) (p<0.001) or HC (13%) (p<0.001).
      CONCLUSIONS: These results strengthen the hypothesis that involves the APOE
      epsilon 4 allele as a predisposing factor for AD, but not for CVD or VaD.

PMID- 12417380
TI  - Apolipoprotein E epsilon 4 allele frequency in demented and cognitively impaired
      patients with and without cerebrovascular disease.
AB  - Controversy exists regarding the apolipoprotein E (ApoE) epsilon 4 allele
      association with vascular dementia (VaD). The results range from increased
      epsilon 4 frequency, similar to that found for Alzheimer's disease (AD), to no
      association at all. Our objective was to clarify the relationship between ApoE
      epsilon 4 allele and cerebrovascular disease (CVD) in demented and cognitively
      impaired patients. We examined the ApoE phenotypes in a sample of 452 subjects:
      219 with AD, 45 with VaD, 62 with mixed dementia (MD), 45 with mild cognitive
      impairment (MCI) without CVD, 27 in which vascular disease was the most probable
      cause of cognitive decline (vascular mild cognitive impairment, VMCI) and 54
      normal controls (NC). The study of the epsilon 4 allele frequency showed
      significant differences between: AD group and the VaD, VMCI and NC groups; MCI
      group compared with VMCI and NC groups; and MD group versus the VaD and NC groups
      (p<0.05-0.0001). The frequency of the epsilon 4 allele in the VaD and VMCI groups
      did not differ significantly from NC. In contrast to other studies, we did not
      detect a relationship between ApoE epsilon 4 allele and clinically diagnosed VaD.
      Our results also show that the epsilon 4 allele is not associated with cognitive
      impairment of vascular origin. In addition, we have confirmed that the ApoE
      epsilon 4 allele occurs frequently in late-onset AD and we have found similar
      association in cognitively impaired individuals without clinical CVD. These
      findings should contribute to the assessment of dementia risk profile in the
      elderly.

PMID- 12417381
TI  - Effect of APOE genotype on microvascular basement membrane in Alzheimer's
      disease.
AB  - APOE4 homozygosity has been associated with an increased risk of sporadic
      Alzheimer's disease through a mechanism, which has yet to be defined. Recent
      evidence has suggested that microvascular basement membrane injury may be a
      critical factor in the pathogenesis of AD-related dementia. In previous studies,
      we have shown that the synaptic organizing protein agrin can be found in neurons,
      and is a major component of the brain microvascular basement membrane. Here, we
      compare the basement membrane surface area of cortical microvasculature in AD
      brains by staining with an anti-agrin antibody. Quantitative morphometric
      analysis was used to determine the mean basement area (micro(2)) of prefrontal
      cortical microvessels. An average of 10 capillaries was measured in each of 35
      cases of AD genotyped for APOE status. APOE4,4 homozygotes had smaller capillary
      basement membrane areas (17.4 micro(2))+/-6.2) than APOE3,3 homozygotes (26.9
      micro(2)+/-6.5), p<0.001. The capillary basement membrane areas (CBMA) of
      heterozygotes APOE3,4 did not differ significantly from APOE3,3 or APOE4,4. Braak
      stage did not contribute significantly to CBMA. However, a preliminary analysis
      suggests an interaction between APOE4,4 and Braak V-VI producing smaller CBMA, a
      finding which needs to be confirmed with a larger sample. These data support the
      hypothesis that APOE4,4 is associated with thinning of the microvascular basement
      membrane in Alzheimer's disease.

PMID- 12417382
TI  - Microvascular damage and platelet abnormalities in early Alzheimer's disease.
AB  - Accumulating evidence from epidemiological and clinical studies suggests that
      vascular risk factors may be involved in Alzheimer disease (AD). Although the
      precise contribution of vascular disturbances to the pathogenesis of AD is still
      unclear, various biochemical and neuropathological data strengthen the view that
      cerebrovascular deficiencies such as reduced blood supply to the brain and
      disrupted microvascular integrity in brain parenchyma play a direct or
      intermediate role in the chain of events ending with a dementia syndrome. The
      present review focuses on platelet abnormalities and hemostatic alterations in
      AD. In particular, data from our group, along with current literature, are
      discussed with regard to the evidence of platelets amyloid precursor protein
      (APP) processing disturbances in early AD as well as to the recent observations
      of increased serum levels of thrombomodulin and sE-selectin, which are sensitive
      markers of endothelial dysfunction. These findings strongly indicate that
      platelet dysfunction and microvasculature deficiencies occur rather early during
      the course of AD, thus suggesting a further link between AD-related processes and
      vascular disorders.

PMID- 12417383
TI  - Plasma antioxidant activity and vascular dementia.
AB  - Little is known about the role of antioxidant activity in the pathogenesis of
      stroke-associated neuronal damage and impairment following a stroke. Increased
      free radical formation together with reduced antioxidant defense may increase
      neuronal injury. A low concentration of antioxidants such as alpha-tocopherol may
      influence the development of post-stroke dementia. The aim of this study was to
      evaluate the level of alpha-tocopherol and susceptibility of LDL to oxidation in
      a group of patients with dementia in comparison to controls. In a group of 68
      patients with dementia, according to DSM-IV criteria, 42 with vascular dementia
      (VaD), 26 with Alzheimer type of dementia (AD) and 46 age-matched persons, with
      no signs of cognitive disorders (control group), we measured lipids, alpha
      tocopherol and the kinetics of LDL oxidation. The levels of triglycerides (TG)
      and low-density lipoprotein (LDL) were significantly lower in patients with VaD
      in comparison to AD patients, but the atherogenic index was similar in both
      groups. alpha-Tocopherol was significantly lower in patients with VaD in
      comparison to patients with AD and controls: 9.9, 12.6 and 12.6 ng/ml,
      respectively, p<0.0001. Susceptibility of LDL to oxidation, measured by duration
      of lag phase did not reveal statistically significant differences between the
      groups. In patients with VaD, low levels of plasma alpha-tocopherol were
      observed, which indicate a reduced antioxidant defense in these subjects.

PMID- 12417384
TI  - Analysis of cerebral blood flow of subcortical vascular dementia with single
      photon emission computed tomography: adaptation of statistical parametric
      mapping.
AB  - BACKGROUND AND OBJECTIVES: Subcortical vascular dementia (VaD) is a relatively
      homogeneous subtype of VaD, but the mechanisms of cognitive dysfunction of
      subcortical VaD are not fully understood. This study investigates the changes of
      cerebral blood flow (CBF) in patients with subcortical VaD and the contribution
      of the white matter hyperintensity (WMHI) and clinical severity to CBF changes.
      METHODS: 99mTc-ethyl cysteinate dimer single photon emission computed tomography
      (SPECT) was performed to measure the regional CBF and statistical parametric
      mapping SPM99 software was applied to automated and objective analysis of the
      SPECT image data. Twenty-three patients (12 male, 11 female) with mild to
      moderate dementia who met both the criteria of the DSM-IV and probable and
      possible NINDS-AIREN for VaD and had subcortical white matter changes and lacunar
      infarctions in brain MRI were evaluated against 17 normal control subjects (7
      male, 10 female). The severity of the WMHI was measured by the semi-quantitative
      scale method proposed by Mantyla. The Clinical Dementia Rating scale measured the
      severity of dementia. RESULTS: SPM analysis of the SPECT image reveals
      significantly reduced regional CBF in the right thalamus, left caudate nucleus,
      cingulate, bilateral superior temporal, and left ventral subcallosal gyri in
      subcortical VaD patients compared to the normal controls (corrected P<0.001). Of
      four WMHIs, only the deep WMHI was associated with the small CBF reduction in the
      left superior temporal gyrus (uncorrected P<0.01). The reduction of the CBF
      according to the severity of dementia was noted in the anterior and posterior
      association areas (uncorrected P<0.01). CONCLUSIONS: Our study suggests that
      cognitive dysfunction of subcortical VaD may be related to the reduction of the
      CBF in the brain areas mentioned, which are probably not associated with the
      severity of periventricular WMHI and dementia.

PMID- 12417385
TI  - Cerebrospinal fluid tissue transglutaminase in vascular dementia.
AB  - The enzyme tissue transglutaminase (tTG), an indicator of acute cell death, is
      found in brains of Alzheimer's and Huntington's disease patients. tTG, as a
      specific marker for apoptosis, may therefore be a powerful biochemical marker of
      the acute degenerating process in vivo and may be useful in discrimination
      between vascular dementia (VaD) and Alzheimer's disease (AD). It may serve as
      completion of CSF analysis in diagnosis of dementing disorders and be a simple
      way of assessing the efficacy of possible new anti-apoptotic drugs.

PMID- 12417386
TI  - Cerebral microemboli and cognitive impairment.
AB  - Transcranial Doppler Ultrasound (TCD) may be used to detect cerebral microemboli
      in patient groups with an increased stroke risk and during invasive
      cardiovascular examinations and operations. Although these microemboli do not
      cause immediate symptoms, there is growing evidence which suggests that they may
      cause cognitive impairment if they enter the cerebral circulation in significant
      numbers. This has been studied in detail in patients who have had coronary artery
      bypass surgery. In these patients, an association has been found between the
      number of intraoperative cerebral microemboli detected by transcranial Doppler
      and postoperative neuropsychological outcome. It is also possible that cerebral
      microemboli may be the cause of cognitive impairment in patients with
      cerebrovascular disease. Cerebral microemboli are often found in patients with
      atherosclerosis, especially of the carotid arteries and aortic arch, and in
      patients with heart disease. There is also an increased risk for silent strokes
      and cognitive impairment in these patients. Prospective clinical studies are
      therefore required to determine if continuous cerebral microembolization to the
      brain will lead to progressive cognitive impairment.

PMID- 12417387
TI  - SPECT as a diagnostic test in the investigation of dementia.
AB  - Single photon emission tomography (SPECT) permits the assessment of the decrease
      of regional cerebral blood flow (rCBF). The aim of this study was to assess the
      relationship between the different types of dementia (Alzheimer's disease (AD),
      vascular dementia (VaD) and frontotemporal dementia (FTD)) and the rCBF in the
      SPECT examination. In patients with AD, the SPECT examination showed
      hypoperfusion in temporoparietal regions, contrary to patients with
      frontotemporal dementia, where hypoperfusion was limited to the frontal area, and
      compared to patients with VaD, where "patchy" rCBF changes were observed in
      different regions. In mild cases of AD, perfusion deficits were observed in the
      frontal regions equal to those in VaD. The study shows that the SPECT examination
      may be useful in distinguishing between AD, VaD, and FTD; however, for proper
      diagnosis in the early stages of AD, additional factors must be taken into
      consideration.

PMID- 12417388
TI  - Age-related white matter changes and cognitive impairment.
AB  - Age-related white matter changes (WMC) are a frequent finding in CT/MRI of older
      subjects. The role of WMC in cognitive impairment has been studied in community
      dwelling and healthy old people, subjects with vascular risk factors, stroke
      patients, depressed and demented subjects. Although there are several negative
      studies, the majority of the evidence points towards an association between WMC
      and cognitive impairment. Speed of mental processes, attention, concentration,
      executive functions and visual spatial skills are the cognitive domains more
      commonly affected. The methodological problems of the negative studies are
      discussed, a number of unsolved issues are raised stressing the need for
      longitudinal studies of WMC with a adequate inception cohort.

PMID- 12417389
TI  - MRI subcortical hyperintensities in old and very old depressed outpatients: the
      important role of age in late-life depression.
AB  - OBJECTIVE: There is increasing evidence that cerebrovascular factors play a key
      role in the etiology of late-life depression. This study examined the severity of
      subcortical hyperintensities (SH) and the relationship between SH and depression
      characteristics in two samples of elderly depressed outpatients differing in age.
      METHODS: The samples consisted of 59 subjects age 60 and over, (69+/-5.6 years),
      who participated in a trial of sertraline, and 111 subjects age 75 and over,
      (79+/-4.1 years), who participated in a trial of citalopram. RESULTS: The
      citalopram group was significantly older than the sertraline group and had more
      severe SH (72% vs. 42% high ratings). The High SH group was significantly older
      than the Low SH group in the sertraline study but there was no difference in age
      in the SH groups in the citalopram sample. There was no relationship between SH
      severity and baseline depression or age of onset. However, age strongly
      correlated with later age of onset. There was no relationship between SH severity
      and cardiovascular risk factors or treatment response in the sertraline sample.
      CONCLUSION: Age is a major factor for the development of SH and late-life
      depression. There may not be an association between SH and depression severity,
      cardiovascular risk factors, or treatment response in geriatric depressed
      outpatients. The etiologic factors and clinical course of late-life depression
      requires further study.

PMID- 12417390
TI  - High b value q-space-analyzed diffusion MRI in vascular dementia: a preliminary
      study.
AB  - High b value diffusion weighted magnetic resonance imaging (high-b DWI) was used
      to characterize white matter changes in the brain of patients with vascular
      dementia (VaD). Hyperintense white matter areas detected by T2-weighted magnetic
      resonance imaging (MRI) represent lesions, also termed leukoaraiosis that are
      very common in VaD as well as in other types of dementia. Therefore, the role of
      white matter changes in the cognitive and memory decline that occurs in VaD
      patients is still under debate. High-b DWI, analyzed using the q-space approach,
      is a more sensitive MRI method for detection of white matter changes. High-b DWI
      revealed massive white matter loss in VaD patients that surpassed the boundaries
      of T2 hyperintensities. This technique, therefore, might serve as a better
      indication for the extensive nerve fiber loss in the white matter that is caused
      by vascular disease.

PMID- 12417391
TI  - Development of a CT-based weighted rating scale for subcortical cerebrovascular
      disease sensitive to mild clinical symptoms.
AB  - OBJECTIVE: To devise and validate a CT-based visual rating scale sensitive to
      subcortical cerebrovascular disease (sCVD) in patients with cognitive impairment.
      METHODS: Three types of vascular lesions were rated separately in 16 brain
      regions. A unique vascular score was computed weighing the regression
      coefficients of the three scores in linear models. Thereafter, subcortical
      vascular classes (SVC) of increasing severity (0-3) were created. Known-group and
      convergent validity of the SVC was tested in 122 cognitively impaired patients
      with MMSE of 18 and higher. These patients were grouped according to clinical
      diagnosis in degenerative, mixed, and vascular. RESULTS: Intraclass correlation
      coefficients were between 0.86 and 0.94. The subcortical vascular score was 8.0+/
      9.4 in the degenerative, 33.0+/-17.2 in the mixed, and 36.8+/-14.8 in the
      vascular patients (p=0.0001). In particular, none of the degenerative patients
      had SVC=3, and only 14% had SVC=2. On the contrary, none of the mixed and
      vascular patients had SVC=0, while about 50% had SVC=3 in both groups. The
      prevalence of hypertension was increasing with increasing SVC (p for trend=0.02).
      The performance on tasks evaluating balance, gait, and bradykinesia decreased
      with increasing SVC severity (p for trend=0.006, 0.01, 0.001, respectively).
      CONCLUSION: The scale is a valid tool to estimate the vascular component in
      patients with cognitive impairment.

PMID- 12417392
TI  - Functional neuroimaging in Alzheimer's type dementia.
AB  - This article aims to review the role of the functional neuroimaging modality of
      positron emission tomography (PET) in the early diagnosis of Alzheimer's disease
      (AD). Clinical diagnosis in the early disease stages is difficult and treatments
      are emerging which rather than reversing structural damage are likely to slow or
      halt the disease process. While currently no routine diagnostic test confirms AD
      presence, imaging techniques are an important expanding field in biological
      neuropsychiatry. The challenge for neuroimaging methods is to achieve high
      specificity and sensitivity in early disease stages. Glucose metabolic PET
      imaging with fluorodeoxyglucose (FDG) has the potential to detect very early
      neocortical dysfunction before even abnormal neuropsychological testing is
      obtainable. The implications are for the identification of minimally symptomatic
      patients that could benefit most from treatment strategies, as well as the
      monitoring of treatment response and possible therapeutic deceleration of the
      disease. FDG PET correlates with AD neuropathology and is able to indicate
      disease progression or severity, meeting both functional neuroimaging
      prerequisites in diagnosing AD. A combination of functional neuroimaging with
      different techniques should be able to provide highest diagnostic specificity in
      diagnosing dementia. This may even lead to a new classification of dementias
      according to differences in the causative aetiology.

PMID- 12417393
TI  - The natural course of MRI white matter hyperintensities.
AB  - The rate and extent of progression of white matter hyperintensities (WMH) over
      time in elderly subjects is yet unclear. These abnormalities may represent an
      early form of subcortical vascular dementia. As to whether such changes could be
      used, as a surrogate marker for this subtype of vascular dementia remains to be
      determined. So far there exists only a very limited number of studies determining
      the rate, clinical predictors and cognitive consequences of WMH evolution. There
      is evidence that these changes do progress over time, however the results of the
      different studies cannot be compared due to methodological differences. The
      Austrian Stroke Prevention Study reported that 17.9% of normal individuals show
      progression over time. The only published quantitative data demonstrated an
      absolute increase of 1.1 cm(3) over an observational period of 4 years in healthy
      subjects. Diastolic blood pressure, early confluent or confluent WMH at baseline
      and genetic variants in the angiotensinogen gene are so far the only known
      predictors of WMH progression. The Austrian Stroke Prevention Study did not find
      an association between the evolution of WMH and cognitive functioning but the
      statistical power of this analysis was small and the relationship needs to be
      further explored.

PMID- 12417394
TI  - Clinical and non-clinical investigations using positron emission tomography, near
      infrared spectroscopy and transcranial Doppler methods on the neuroprotective
      drug vinpocetine: a summary of evidences.
AB  - Vinpocetine (Cavinton, Gedeon Richter, Budapest) is widely used as a
      neuroprotective drug in the prevention and treatment of cerebrovascular diseases.
      Vinpocetine is a potent inhibitor of the voltage-dependent Na(+) channels and a
      selective inhibitor of the Ca(2+)/caldmoduline-dependent phosphodiesterase 1. The
      clinical efficacy has been supported by several previous studies. Positron
      emission tomography (PET) is a powerful method to evaluate the fate, the site of
      action, the pharmacological and physiological effects of a drug in the brain and
      other organs. We have demonstrated in monkey that the [11C]-labelled vinpocetine
      rapidly enters the brain after intravenous (i.v.) injection, the maximal uptake
      being approximately 5% of the total injected radioactivity. The distribution
      pattern of vinpocetine in the brain was heterogenous, with the highest uptake in
      the thalamus, basal ganglia and visual cortex. These findings were confirmed in
      healthy humans, where the i.v. administered [11C]-labelled vinpocetine had a
      similar distribution pattern. The highest uptake in the brain was 3.71% of the
      total administered radioactivity. Quite recently, we have shown that [11C]
      labelled vinpocetine administered orally to healthy human volunteers also rapidly
      appears in the brain and shows a similar distribution pattern, the highest uptake
      being 0.71% of the total administered radioactivity. In two separate sets of
      clinical studies where chronic ischaemic post-stroke patients were either treated
      with a single infusion (Study 1) or with daily vinpocetine infusion for 2 weeks
      (Study 2), we have shown that vinpocetine increases the regional cerebral glucose
      uptake and to a certain extent glucose metabolism in the so-called peri-stroke
      region as well as in the relatively intact brain tissue. The 2-week-long
      treatment also increased the regional cerebral blood flow (CBF) especially in the
      thalamus, basal ganglia and visual cortex of the nonsymptomatic hemisphere. We
      have demonstrated the cerebral perfusion-enhancing and parenchymal oxygen
      extraction-increasing effects of vinpocetine in subacute ischaemic stroke
      patients by near infrared spectroscopy (NIRS) and transcranial Doppler (TCD)
      methods.

PMID- 12417396
TI  - Transient focal ischemia induces motor deficit but does not impair the cognitive
      function in middle cerebral artery occlusion model of stroke in rats.
AB  - The effect on cognition was evaluated in the transient ischemia model of stroke
      in rats. Male Wistar rats were subjected to 2 h of transient ischemia by
      occluding the middle cerebral artery using the 4-0 intraluminal nylon thread.
      Neurological tests performed after 24 h, 7 and 15 days of middle cerebral artery
      (MCA) occlusion showed motor impairment as evidenced by decrease in the rota rod
      performance test. This was also confirmed histologically. However, when the
      learning and memory tests were performed, no change was observed in the learning
      and behavior as evidenced by insignificant difference in the retention latency in
      the passive avoidance test (334+/-31 s) and the transfer latency in the elevated
      plus maze (11+/-4.5 s) as compared to the sham-operated rats 369+/-34 and 8+/-1.7
      s, respectively. The results of the present study demonstrates that transient
      occlusion of middle cerebral artery does not impair the learning and memory
      behavior of the rats.

PMID- 12417395
TI  - Cognitive impairment and chronic cerebral hypoperfusion: what can be learned from
      experimental models.
AB  - The relation between chronic cerebral hypoperfusion and cognitive functions has
      not been completely clarified. The resolution of cerebral hypoperfusion states,
      such as those induced by arteriovenous malformations or carotid
      stenosis/occlusion, has been reported to improve mental decline in humans.
      Subcortical vascular dementia is another human condition supposed to be linked
      with chronic cerebral hypoxia/ischemia. The extent of this cause/effect relation
      is, however, difficult to be assessed in humans, where different factors, such as
      ageing or subtle degenerative processes, can coexist and interact influencing
      cognitive performances. Experimental studies can help to elucidate this relation
      because they can use models of pure chronic/moderate cerebral hypoperfusion. An
      experimental model of chronic ischemia is the bilateral common carotid artery
      occlusion in the rat. In this paper, we present a review of experimental studies
      that evaluated cognitive functions in the rat with bilateral common carotid
      artery occlusion. We then present an experimental model of bilateral common
      carotid artery occlusion in the rat modified with respect to previous papers
      regarding both the surgical procedure and the neurocognitive evaluation that is
      focused on cognitive domains depending on subcortical-frontal circuits. We
      propose this model to investigate subcortical vascular dementia.

PMID- 12417397
TI  - Protective effect of systemic treatment with cyclosporine A after global ischemia
      in rats.
AB  - Systemic administration of cyclosporine A (CsA) in single daily doses provides a
      powerful protection to the ischemic rat brain only to sites where the blood-brain
      barrier (BBB) is disrupted. This study was aimed at evaluating the effectiveness
      of prolonged treatment and multiple daily doses of systemic CsA following
      transient global ischemia in rats without BBB breakdown. Multiple daily doses
      selectively enhanced cell survival at 7-day recovery in regions displaying
      delayed neuronal death (DND). The effect was dose dependent, enhanced by
      prolonging the treatment or further fractionating daily doses, and not
      accompanied by drug-induced hypothermia. These results suggest that CsA
      susceptible immune mediators of DND may be active during the first days following
      transient global ischemia. Conversely, postischemic hyperthermia may enhance
      and/or perpetuate similar mechanisms and trigger Alzheimer-like
      neurodegeneration, as recently reported.

PMID- 12417398
TI  - Glial expression of the beta-amyloid peptide in cardiac arrest.
AB  - We have investigated in the rat, immunocytochemically, the expression of beta
      amyloid peptide in glial cells following ischemia-reperfusion brain injury. The
      postischemic brain injuries were studied at survival times from 2 days to 12
      months. The reactive astrocytes with indirect staining for beta-amyloid peptide
      were observed in brain till 7 days postischemia. beta-Amyloid positive astrocytes
      disappeared transiently on the 14 days and then reappeared in the 6 months and
      again disappeared at 9 months after brain injury. Transient ischemia temporarily
      induced beta-amyloid peptide expression in reactive astrocytes, but this
      expression peaked at 7 days and 6 months. A glial appearance of beta-amyloid
      peptide direct staining occurred at a time when extensive neuronal loss was
      evident.

PMID- 12417399
TI  - BBA special issue on developmental glycobiology dedicated to Roland Walter
      Schauer and Johannes Frederik Gerardus Vliegenthart.

PMID- 12417400
TI  - Johannes Frederik Gerardus Vliegenthart.

PMID- 12417401
TI  - Thanks to Mr. Sialic Acid.

PMID- 12417402
TI  - Heparan sulfate and development: differential roles of the N-acetylglucosamine N
      deacetylase/N-sulfotransferase isozymes.
AB  - Heparan sulfates (HSs) are N- and O-sulfated polysaccharide components of
      proteoglycans, which are important constituents of the cell surface as well as
      the extracellular matrix. Heparin, with extensive clinical application as an
      anticoagulant, is a highly sulfated form of HS present within the granules of
      connective tissue type mast cells. The diverse functions of HS, which include the
      modulation of growth factor/cytokine activity, interaction with matrix proteins
      and binding of enzymes to cell surfaces, depend greatly on the presence of
      specific, high affinity regions on the chains. N-acetylglucosamine N
      deacetylase/N-sulfotransferases, NDSTs, are an important group of enzymes in HS
      biosynthesis, initiating the sulfation of the polysaccharide chains and thus
      determining the generation of the high affinity sites. Here, we review the role
      of the four vertebrate NDSTs in HS biosynthesis as well as their regulated
      expression. The main emphasis is the phenotypes of mice lacking one or more of
      the NDSTs.

PMID- 12417403
TI  - Mutation of Large, which encodes a putative glycosyltransferase, in an animal
      model of muscular dystrophy.
AB  - The myodystrophy (myd) mutation arose spontaneously and has an autosomal
      recessive mode of inheritance. Homozygous mutant mice display a severe,
      progressive muscular dystrophy. Using a positional cloning approach, we
      identified the causative mutation in myd as a deletion within the Large gene,
      which encodes a putative glycosyltransferase with two predicted catalytic
      domains. By immunoblotting, the alpha-subunit of dystroglycan, a key muscle
      membrane protein, is abnormal in myd mice. This aberrant protein might represent
      altered glycosylation of the protein and contribute to the muscular dystrophy
      phenotype. Our results are discussed in the light of recent reports describing
      mutations in other glycosyltransferase genes in several forms of human muscular
      dystrophy.

PMID- 12417405
TI  - Early developmental expression of the gene encoding glucosylceramide synthase,
      the enzyme controlling the first committed step of glycosphingolipid synthesis.
AB  - Glycosphingolipids (GSLs) are ubiquitous plasma membrane components composed of a
      ceramide lipid anchor attached to one of a diverse complement of oligosaccharide
      structures. Fundamentally important activities have been attributed to GSLs
      including formation of plasma membrane structures involved in membrane
      trafficking, signal transduction and cell-cell interactions. Glucosylceramide
      synthase converts ceramide to glucosylceramide, a core structure of the vast
      majority of GSLs. Disruption of the gene encoding glucosylceramide synthase
      (Ugcg) caused embryonic lethality in mice during gastrulation. To further
      investigate the role of GSL synthesis during embryogenesis, we produced mice with
      a Lacz reporter gene inserted into the glucosylceramide synthase locus. These
      mice allowed the visualization of glucosylceramide synthase expression during
      early embryonic development.

PMID- 12417404
TI  - Golgi alpha-mannosidase II deficiency in vertebrate systems: implications for
      asparagine-linked oligosaccharide processing in mammals.
AB  - The maturation of N-glycans to complex type structures on cellular and secreted
      proteins is essential for the roles that these structures play in cell adhesion
      and recognition events in metazoan organisms. Critical steps in the biosynthetic
      pathway leading from high mannose to complex structures include the trimming of
      mannose residues by processing mannosidases in the endoplasmic reticulum (ER) and
      Golgi complex. These exo-mannosidases comprise two separate families of enzymes
      that are distinguished by enzymatic characteristics and sequence similarity.
      Members of the Class 2 mannosidase family (glycosylhydrolase family 38) include
      enzymes involved in trimming reactions in N-glycan maturation in the Golgi
      complex (Golgi mannosidase II) as well as catabolic enzymes in lysosomes and
      cytosol. Studies on the biological roles of complex type N-glycans have employed
      a variety of strategies including the treatment of cells with glycosidase
      inhibitors, characterization of human patients with enzymatic defects in
      processing enzymes, and generation of mouse models for the enzyme deficiency by
      selective gene disruption approaches. Corresponding studies on Golgi mannosidase
      II have employed swainsonine, an alkaloid natural plant product that causes
      "locoism", a phenocopy of the lysosomal storage disease, alpha-mannosidosis, as a
      result of the additional targeting of the broad-specificity lysosomal mannosidase
      by this compound. The human deficiency in Golgi mannosidase II is characterized
      by congenital dyserythropoietic anemia with splenomegaly and various additional
      abnormalities and complications. Mouse models for Golgi mannosidase II deficiency
      recapitulate many of the pathological features of the human disease and confirm
      that the unexpectedly mild effects of the enzyme deficiency result from a tissue
      specific and glycoprotein substrate-specific alternate pathway for synthesis of
      complex N-glycans. In addition, the mutant mice develop symptoms of a systemic
      autoimmune disorder as a consequence of the altered glycosylation. This review
      will discuss the biochemical features of Golgi mannosidase II and the
      consequences of its deficiency in mammalian systems as a model for the effects of
      alterations in vertebrate N-glycan maturation during development.

PMID- 12417406
TI  - The role of glypicans in mammalian development.
AB  - Glypicans are a family of heparan sulfate proteoglycans that are bound to the
      cell surface by a glycosyl-phosphatidylinositol anchor. Six members of this
      family have been identified in mammals. In general, glypicans are highly
      expressed during development, and their expression pattern suggests that they are
      involved in morphogenesis. One member of this family, glypican-3, is mutated in
      the Simpson-Golabi-Behmel syndrome. This syndrome is characterized by overgrowth
      and various developmental abnormalities that indicate that glypican-3 inhibits
      proliferation and cell survival in the embryo. It has consequently been proposed
      that glypicans can regulate the activity of several growth factors that play a
      critical role in morphogenesis.

PMID- 12417407
TI  - The Caenorhabditis elegans sqv genes and functions of proteoglycans in
      development.
AB  - In the nematode Caenorhabditis elegans, the vulva is a simple tubular structure
      linking the gonads with the external cuticle. In this review we summarize
      knowledge of inter- and intracellular signaling during vulval development and of
      the genes required for vulval invagination. Mutants of one set of these genes,
      the sqv genes, have a normal number of vulval precursor cells (VPCs) with an
      unperturbed cell lineage but the invagination space, normally a tube, is either
      collapsed or absent. We review evidence that the sqv genes are involved in
      glycosaminoglycan synthesis and speculate on ways in which defective
      glycosaminoglycan formation might lead to collapse of the vulval structure.

PMID- 12417408
TI  - Targeted mutations in beta1,4-galactosyltransferase I reveal its multiple
      cellular functions.
AB  - Beta1,4-galactosyltransferase I (GalT I) is one of the most extensively studied
      glycosyltransferases. It is localized in the trans-Golgi compartment of most
      eukaryotic cells, where it participates in the elongation of oligosaccharide
      chains on glycoproteins and glycolipids. GalT I has also been reported in non
      Golgi locations, most notably the cell surface, where it has been suggested to
      function non-biosynthetically as a receptor for extracellular glycoside
      substrates. Cloning of the GalT I cDNAs revealed that the gene encodes two
      similar proteins that differ only in the length of their cytoplasmic domains.
      Whether these different GalT I proteins, or isoforms, have similar or different
      biological roles is a matter of active investigation. The functions of the GalT I
      proteins have been addressed by targeted mutations that eliminate either both
      GalT I isoforms or just the long GalT I isoform. Eliminating both GalT I proteins
      abolishes most, but not all, GalT activity, an observation that led to the
      realization that other GalT family members must exist. The loss of both GalT I
      isoforms leads to neonatal lethality due to a wide range of phenotypic
      abnormalities that are most likely the result of decreased galactosylation. When
      the long isoform of GalT I is eliminated, galactosylation proceeds grossly normal
      via the short GalT I isoform, but specific defects in cell interactions occur
      that are thought to depend upon a non-biosynthetic function of the long GalT I
      isoform.

PMID- 12417409
TI  - UDP-N-acetylglucosamine:alpha-3-D-mannoside beta-1,2-N
      acetylglucosaminyltransferase I and UDP-N-acetylglucosamine:alpha-6-D-mannoside
      beta-1,2-N-acetylglucosaminyltransferase II in Caenorhabditis elegans.
AB  - UDP-N-acetylglucosamine:alpha-3-D-mannoside beta-1,2-N
      acetylglucosaminyltransferase I (GnT I) and UDP-N-acetylglucosamine:alpha-6-D
      mannoside beta-1,2-N-acetylglucosaminyltransferase II (GnT II) are key enzymes in
      the synthesis of Asn-linked hybrid and complex glycans. We have cloned cDNAs from
      Caenorhabditis elegans for three genes homologous to mammalian GnT I (designated
      gly-12, gly-13 and gly-14) and one gene homologous to mammalian GnT II. All four
      cDNAs encode proteins which have the domain structure typical of previously
      cloned Golgi-type glycosyltransferases and show enzymatic activity (GnT I and GnT
      II, respectively) on expression in transgenic worms. We have isolated worm
      mutants lacking the three GnT I genes by the method of ultraviolet irradiation in
      the presence of trimethylpsoralen (TMP); null mutants for GnT II have not yet
      been obtained. The gly-12 and gly-14 mutants as well as the gly-14;gly-12 double
      mutant displayed wild-type phenotypes indicating that neither gly-12 nor gly-14
      is necessary for worm development under standard laboratory conditions. This
      finding and other data indicate that the GLY-13 protein is the major functional
      GnT I in C. elegans. The mutation lacking the gly-13 gene is partially lethal and
      the few survivors display severe morphological and behavioral defects. We have
      shown that the observed phenotype co-segregates with the gly-13 deletion in
      genetic mapping experiments although a second mutation near the gly-13 gene
      cannot as yet be ruled out. Our data indicate that complex and hybrid N-glycans
      may play critical roles in the morphogenesis of C. elegans, as they have been
      shown to do in mice and men.

PMID- 12417410
TI  - Heparan sulfate proteoglycan modulation of developmental signaling in Drosophila.
AB  - Heparan sulphate proteoglycans (HSPG's) are cell surface proteins to which long,
      unbranched chains of modified sugars called heparan sulphate glycosaminoglycans
      have been covalently attached. Cell culture studies have demonstrated that HSPG's
      are required for optimal signal transduction by many secreted cell signaling
      molecules. Now, genetic studies in both Drosophila and vertebrates have
      illustrated that HSPG's play important roles in signal transduction in vivo and
      have also begun to reveal new roles for HSPG's in signaling events. In
      particular, HSPG's have been shown to be important in ligand sequestration of
      wingless, for the transport of the Hedgehog ligand, and for modulation of the Dpp
      morphogenetic gradient.

PMID- 12417411
TI  - The role of the GlcNAc(beta)1,2Man(alpha)- moiety in mammalian development. Null
      mutations of the genes encoding UDP-N-acetylglucosamine:alpha-3-D-mannoside beta
      1,2-N-acetylglucosaminyltransferase I and UDP-N-acetylglucosamine:alpha-D
      mannoside beta-1,2-N-acetylglucosaminyltransferase I.2 cause embryonic lethality
      and congenital muscular dystrophy in mice and men, respectively.
AB  - The GlcNAc(beta)1,2Man(alpha)- moiety can be synthesized by at least two
      mammalian glycosyltransferases, UDP-GlcNAc:alpha-3-D-mannoside beta1,2-N
      acetylglucosaminyltransferase I (GnT I, EC 2.4.1.101) and UDP-GlcNAc:alpha-D
      mannoside beta1,2-N-acetylglucosaminyltransferase I.2 (GnT I.2). GnT I adds a
      GlcNAc residue in beta1,2 glycosidic linkage to the Man(alpha)1,3 arm of the N
      glycan core to initiate the biosynthesis of hybrid and complex N-glycans. GnT I.2
      can add GlcNAc in beta1,2 linkage to any alpha-linked terminal Man residue but
      has a strong preference for the Man(alpha)1-O-Thr- moiety which occurs in alpha
      dystroglycan and other O-mannosylated glycoproteins. Mouse embryos lacking a
      functional GnT I gene (MgatI) were unable to synthesize complex N-glycans and
      none survived past 10.5 days after fertilization. The embryos showed
      multisystemic defects in various morphogenic processes such as neural tube
      formation, vascularization and the determination of left-right body plan
      asymmetry. Six human patients with muscle-eye-brain disease (MEB) were recently
      shown to have point mutations in the gene encoding GnT I.2 (MGATI.2). MEB is an
      autosomal recessive disease characterized by congenital muscular dystrophy,
      ocular abnormalities, brain malformations and other multisystemic defects. Both
      the MGATI.2 gene and MEB disease have been mapped to chromosome 1p32-p34. At
      least one of the biochemical sites affected by the MGATI.2 mutations is probably
      the interaction between laminin in the extracellular matrix and the peripheral
      membrane glycoprotein alpha-dystroglycan since this interaction is believed to
      require the presence of the
      sialyl(alpha)2,3Gal(beta)1,4GlcNAc(beta)1,2Man(alpha)1-O-Ser/Thr moiety on alpha
      dystroglycan. It can be concluded that the GlcNAc(beta)1,2Man(alpha)- moiety is
      important for mammalian development due to an essential role in two distinct
      biochemical pathways.

PMID- 12417412
TI  - Mice with a homozygous deletion of the Mgat2 gene encoding UDP-N
      acetylglucosamine:alpha-6-D-mannoside beta1,2-N-acetylglucosaminyltransferase II:
      a model for congenital disorder of glycosylation type IIa.
AB  - Mice homozygous for a deletion of the Mgat2 gene encoding UDP-N
      acetylglucosamine:alpha-6-D-mannoside beta1,2-N-acetylglucosaminyltransferase II
      (GlcNAcT-II, EC 2.4.1.143) have been reported. GlcNAcT-II is essential for the
      synthesis of complex N-glycans. The Mgat2-null mice were studied in a comparison
      with the symptoms of congenital disorder of glycosylation type IIa (CDG-IIa) in
      humans. Mutant mouse tissues were shown to be deficient in GlcNAcT-II enzyme
      activity and complex N-glycan synthesis, resulting in severe gastrointestinal,
      hematologic and osteogenic abnormalities. All mutant mice died in early post
      natal development. However, crossing the Mgat2 mutation into a distinct genetic
      background resulted in a low frequency of survivors exhibiting additional and
      novel disease signs of CDG-IIa. Analysis of N-glycan structures in the kidneys of
      Mgat2-null mice showed a novel bisected hybrid N-glycan structure in which the
      bisecting GlcNAc residue was substituted with a beta1,4-linked galactose or the
      Lewis(x) structure. These studies suggest that some of the functions of complex N
      glycan branches are conserved in mammals and that human disease due to aberrant
      protein N-glycosylation may be modeled in the mouse, with the expectation in this
      case of gaining insights into CDG-IIa disease pathogenesis. Further analyses of
      the Mgat2-deficient phenotype in the mouse have been accomplished involving cells
      in which the Mgat2 gene is dispensable, as well as other cell lineages in which a
      severe defect is present. Pre-natal defects appear in a significant number of
      embryos, and likely reflect a limited window of time in which a future
      therapeutic approach might effectively operate.

PMID- 12417413
TI  - Heparan sulfate fine structure and specificity of proteoglycan functions.
AB  - Heparan sulfate chains have markedly heterogeneous structures in which distinct
      patterns of sulfation determine the binding specificity for ligand proteins.
      These "fine structures" of heparan sulfate are mainly produced by the regulated
      introduction of sulfate groups at the N-, 2-O-, 6-O-, and 3-O-positions of the
      sugar chain. Recent biochemical, histochemical, and genetic studies have
      demonstrated that different fine structures mediate distinct molecular
      recognition events to regulate a variety of cellular functions. In this review,
      we focus on the molecular basis of growth factor control by the sulfation status
      of heparan sulfate.

PMID- 12417414
TI  - Role of heparan sulfate-2-O-sulfotransferase in the mouse.
AB  - Heparan sulfate (HS) is a long unbranched polysaccharide found covalently
      attached to various proteins at the cell surface and in the extracellular matrix.
      It plays a central role in embryonic development and cellular function by
      modulating the activities of an extensive range of growth factors and morphogens.
      HS 2-O-sulfotransferase (Hs2st) occupies a critical position in the succession of
      enzymes responsible for the biosynthesis of HS, catalysing the transfer of
      sulfate to the C2-position of selected hexuronic acid residues within the nascent
      HS chain. Previous studies have concluded that 2-O-sulfation of HS is essential
      for it to cooperate in many growth factor/receptor interactions. Surprisingly
      therefore, embryos lacking functional Hs2st survive until birth, but die
      perinatally, suffering complete failure to form kidneys. However, this rather
      late lethality belies a more intricate involvement of 2-O-sulfated HS during
      development. The purpose of this review is to summarise the requirements for 2-O
      sulfated HS during mouse development, at the morphological and molecular level.
      The implications that altered HS structure may have on growth factor/receptor
      signalling in vivo will be discussed.

PMID- 12417415
TI  - Modulation of receptor signaling by glycosylation: fringe is an O-fucose-beta1,3
      N-acetylglucosaminyltransferase.
AB  - The Notch family of signaling receptors plays key roles in determining cell fate
      and growth control. Recently, a number of laboratories have shown that O-fucose
      glycans on the epidermal growth factor (EGF)-like repeats of the Notch
      extracellular domain modulate Notch signaling. Fringe, a known modifier of Notch
      function, is an O-fucose specific beta1,3-N-acetylglucosaminyltransferase. The
      transfer of GlcNAc to O-fucose on Notch by fringe results in the potentiation of
      signaling by the Delta class of Notch ligands, but causes inhibition of signaling
      by the Serrate/Jagged class of Notch ligands. Interestingly, addition of a
      beta1,4 galactose by beta4GalT-1 to the GlcNAc added by fringe is required for
      Jagged1-induced Notch signaling to be inhibited in a co-culture assay. Thus, both
      fringe and beta4GalT-1 are modulators of Notch function. Several models have been
      proposed to explain how alterations in O-fucose glycans result in changes in
      Notch signaling, and these models are discussed.

PMID- 12417416
TI  - Intracellular glycosylation and development.
AB  - O-linked N-acetylglucosamine (O-GlcNAc) is a highly dynamic post-translational
      modification of cytoplasmic and nuclear proteins. Although the function of this
      abundant modification is yet to be definitively elucidated, all O-GlcNAc proteins
      are phosphoproteins. Further, the serine and threonine residues substituted with
      O-GlcNAc are often sites of, or close to sites of, protein phosphorylation. This
      implies that there may be a dynamic interplay between these two post
      translational modifications to regulate protein function. In this review, the
      functions of some of the proteins that are modified by O-GlcNAc will be
      considered in the context of the potential role of the O-GlcNAc modification.
      Furthermore, predictions will be made as to how cellular function and
      developmental regulation might be affected by changes in O-GlcNAc levels.

PMID- 12417417
TI  - Hereditary multiple exostoses and heparan sulfate polymerization.
AB  - Hereditary multiple exostoses (HME, OMIM 133700, 133701) results from mutations
      in EXT1 and EXT2, genes encoding the copolymerase responsible for heparan sulfate
      (HS) biosynthesis. Members of this multigene family share the ability to transfer
      N-acetylglucosamine to a variety of oligosaccharide acceptors. EXT1 and EXT2
      encode the copolymerase, whereas the roles of the other EXT family members
      (EXTL1, L2, and L3) are less clearly defined. Here, we provide an overview of
      HME, the EXT family of proteins, and possible models for the relationship of
      altered HS biosynthesis to the ectopic bone growth characteristic of the disease.

PMID- 12417418
TI  - Beta1,4-N-acetylgalactosaminyltransferase--GM2/GD2 synthase: a key enzyme to
      control the synthesis of brain-enriched complex gangliosides.
AB  - Beta1,4-N-acetylgalactosaminyltransferase (GM2/GD2 synthase) is a key enzyme
      which catalyzes the conversion of GM3, GD3 and lactosylceramide (LacCer) to GM2,
      GD2 and asialo-GM2 (GA2), respectively. This step is critical for the synthesis
      of all complex gangliosides enriched in the nervous system of vertebrates.
      Following the cloning of cDNAs encoding GM2/GD2 synthase by an expression cloning
      approach, substantial evidence for the roles of complex gangliosides have been
      obtained. Above all, knock-out mice lacking all complex gangliosides revealed
      important roles of complex gangliosides in vivo, i.e., in the maintenance and
      repair of nervous tissues, in the intact differentiation of spermatocytes via the
      transport of testosterone, and in the regulation of interleukin-2 receptor
      complex. Molecular mechanisms for these functions of complex gangliosides in vivo
      remain to be clarified.

PMID- 12417419
TI  - Biological consequences of overexpressing or eliminating N
      acetylglucosaminyltransferase-TIII in the mouse.
AB  - N-acetylglucosaminyltransferase III (GlcNAc-TIII), a product of the human MGAT3
      gene, was discovered as a glycosyltransferase activity in hen oviduct. GlcNAc
      TIII transfers GlcNAc in beta4-linkage to the core Man of complex or hybrid N
      glycans, and thereby alters not only the composition, but also the conformation
      of the N-glycan. The dramatic consequences of the addition of this bisecting
      GlcNAc residue are reflected in the altered binding of lectins that recognize Gal
      residues on N-glycans. Changes in GlcNAc-TIII expression correlate with hepatoma
      and leukemia in rodents and humans, and the bisecting GlcNAc on Asn 297 of human
      IgG antibodies enhances their effector functions. Overexpression of a cDNA
      encoding GlcNAc-TIII alters growth control and cell-cell interactions in cultured
      cells, and in transgenic mice. While mice lacking GlcNAc-TIII are viable and
      fertile, they exhibit retarded progression of diethylnitrosamine (DEN)-induced
      liver tumors. Further biological functions of GlcNAc-TIII are expected to be
      uncovered as mice with a null mutation in the Mgat3 gene are challenged.

PMID- 12417420
TI  - Glycobiology of the synapse: the role of glycans in the formation, maturation,
      and modulation of synapses.
AB  - Synapses, which are the fundamental functional unit of the nervous system, are
      considered to be highly specialized cell adhesion structures. Studies since the
      1960s demonstrated that various carbohydrates and glycoproteins are expressed in
      synapses in the central and peripheral nervous system. Although the functional
      roles of these synaptic carbohydrates and glycoproteins remain to be determined,
      rapidly accumulating data suggest that they may play critical roles in the
      formation, maturation, and functional modulation of synapses.

PMID- 12417421
TI  - Galactosyltransferase I is a gene responsible for progeroid variant of Ehlers
      Danlos syndrome: molecular cloning and identification of mutations.
AB  - A human cDNA encoding a novel galactosyltransferase was identified based on BLAST
      analysis of expressed sequence tags, and the cDNA clones were isolated, showing a
      type II membrane protein with 327 amino acids and 38% homology to the
      Caenorhabditis elegans sqv-3 gene involved in vulval invagination and oocyte
      development. This cDNA exhibited marked galactosyltransferase activity specific
      for p-nitrophenyl-beta-D-xylopyranoside, and also restored glycosaminoglycan
      (GAG) synthesis to galactosyltransferase I-deficient CHO mutant pgsB-761 cells.
      The enzyme product contained beta-1,4-linked galactosyl residues, indicating that
      the enzyme is galactosyltransferase I (UDP-D-galactose: D-xylose beta-1,4-D
      galactosyltransferase; EC 2.4.1.133) involved in the synthesis of the GAG-protein
      linkage region of proteoglycans. Mutations of this gene were investigated in a
      case of Ehlers-Danlos syndrome (progeroid variant), since reduced activity of
      galactosyltransferase I had been reported in this disease by others. As expected,
      the patient gene contained two different mutations (A186D, L206P). The mutations
      showed, respectively, 10-50% and 0% of the enzyme activity compared with wild
      type, suggesting that galactosytransferase I (XGal-T1) is at least one of the
      genes responsible for Ehlers-Danlos syndrome (progeroid variant).

PMID- 12417422
TI  - In vivo role of alpha-mannosidase IIx: ineffective spermatogenesis resulting from
      targeted disruption of the Man2a2 in the mouse.
AB  - Alpha-mannosidase IIx (MX) is an enzyme closely related to the Golgi N-glycan
      processing enzyme alpha-mannosidase II (MII). The enzymatic activity of MX in
      vitro is minimal. Therefore, the in vivo role of MX in N-glycan processing is as
      yet unclear. The targeted disruption of the gene encoding MX in the mouse
      resulted in an obvious phenotype, i.e., MX-deficient males were found to be
      infertile. Testes from homozygous mutant male mice are smaller than those from
      wild-type or heterozygous littermates. Histology of the MX null mouse testis
      showed significant reduction of spermatogenic cells in the seminiferous tubules.
      Electron microscopy showed that prominent intercellular spaces surround MX
      deficient spermatogenic cells, suggesting a failure of germ cell adhesion to
      Sertoli cells. Quantitative structural analyses of N-glycans from wild-type and
      MX-deficient mouse testis showed that wild-type testes contain GlcNAc-terminated
      complex type N-glycans, while they are significantly reduced in MX-deficient
      mutant testis. An in vitro assay for adhesion of spermatogenic cells to Sertoli
      cells was carried out. By testing the effect of each purified N-glycan
      oligosaccharide, it was demonstrated that a GlcNAc-terminated tri-antennary,
      fucosylated N-glycan has an activity on the adhesion between germ cells and
      Sertoli cells. Thus, the targeted disruption of the gene encoding MX uncovered a
      novel carbohydrate recognition system in a biologically important process,
      spermatogenesis.

PMID- 12417423
TI  - Human disorders in N-glycosylation and animal models.
AB  - Genes that cause human disorders in N-linked oligosaccharide biosynthesis have
      appeared much faster than animal model systems to study them. In most models, a
      single gene is altered or deleted while other genes and the environment are held
      constant. Since humans have variable genetic backgrounds and environments, model
      systems may only partially mimic the actual disorders. Mutations in seven of the
      30-40 genes needed for the synthesis and transfer of oligosaccharides from the
      lipid donor to the nascent protein acceptors in the endoplasmic reticulum cause
      Type I Congenital Disorders of Glycosylation (CDG). Since all of these gene
      products ultimately contribute to the same final step, one might suspect that all
      the diseases would be very similar. However, even patients with mutations in the
      same gene show considerable phenotypic variability. Modifier, or susceptibility
      genes in the background likely explain some variations of the "primary" gene
      chosen for study. Add to this the stress of infections, dietary insufficiencies,
      and the demands of growth itself. These issues are particularly important during
      development when the temporal and spatial specific interplay of cell adhesions
      and signals has only a single opportunity. Multiple hypomorphic alleles of genes
      in the same pathway may have synergistic effects. Investigators designing model
      systems to study human glycosylation disorders may want to construct strains with
      several heterozygous hypomorphic alleles in rate-limiting steps in the
      glycosylation pathway.

PMID- 12417424
TI  - Roles of mucin-type O-glycans in cell adhesion.
AB  - Mucin-type O-glycans containing Core2 branches have distinctly different
      functions from those O-glycans that contain Core1 structures. Core2 branched O
      glycans can have terminal structures that function as ligands for carbohydrate
      binding proteins. However, sialylated Core2 branched O-glycans without additional
      modifications exhibit anti-adhesive properties. These results demonstrate that
      certain mucin-type O-glycans can either facilitate or attenuate cell adhesion
      depending on the core structures and the structures of the non-reducing termini.

PMID- 12417425
TI  - Galactolipids are molecular determinants of myelin development and axo-glial
      organization.
AB  - Myelination is a developmentally regulated process whereby myelinating glial
      cells elaborate large quantities of a specialized plasma membrane that ensheaths
      axons. The myelin sheath contains an unusual lipid composition in that the
      glycolipid galactosylceramide (GalC) and its sulfated form sulfatide constitute a
      large proportion of the total lipid mass. These glycolipids have been implicated
      in a range of developmental processes such as cell differentiation and
      myelination initiation, but analyses of mice lacking UDP-galactose:ceramide
      galactosyltransferase (CGT), the enzyme required for myelin galactolipid
      synthesis, have more recently demonstrated that the galactolipids more subtly
      regulate myelin formation. The CGT mutants display a delay in myelin maturation
      and axo-glial interactions develop abnormally. By interbreeding the CGT mutants
      with mice that lack myelin-associated glycoprotein, it has been shown that these
      specialized myelin lipids and proteins act in concert to promote axo-glial
      adhesion during myelinogenesis. The analysis of the CGT mutants is helping to
      clarify the roles myelin galactolipids play in regulating the development, and
      ultimately the function of the myelin sheath.

PMID- 12417426
TI  - UDP-N-acetylglucosamine:alpha-6-D-mannoside beta1,6 N
      acetylglucosaminyltransferase V (Mgat5) deficient mice.
AB  - Targeted gene mutations in mice that cause deficiencies in protein glycosylation
      have revealed functions for specific glycans structures in embryogenesis, immune
      cell regulation, fertility and cancer progression. UDP-N-acetylglucosamine:alpha
      6-D-mannoside beta1,6 N-acetylglucosaminyltransferase V (GlcNAc-TV or Mgat5)
      produces N-glycan intermediates that are elongated with poly N-acetyllactosamine
      to create ligands for the galectin family of mammalian lectins. We generated
      Mgat5-deficient mice by gene targeting methods in embryonic stem cells, and
      observed a complex phenotype in adult mice including susceptibility to autoimmune
      disease, reduced cancer progression and a behavioral defect. We found that Mgat5
      modified N-glycans on the T cell receptor (TCR) complex bind to galectin-3,
      sequestering TCR within a multivalent galectin-glycoprotein lattice that impedes
      antigen-dependent receptor clustering and signal transduction. Integrin receptor
      clustering and cell motility are also sensitive to changes in Mgat5-dependent N
      glycosylation. These studies demonstrate that low affinity but high avidity
      interactions between N-glycans and galectins can regulate the distribution of
      cell surface receptors and their responsiveness to agonists.

PMID- 12417427
TI  - Glycosylation processing inhibition by castanospermine prevents experimental
      autoimmune encephalomyelitis by interference with IL-2 receptor signal
      transduction.
AB  - In this study, we explored the therapeutic targets of the glycosylation
      processing inhibitor, castanospermine (CAST), in murine passive transfer
      experimental autoimmune encephalomyelitis (EAE), a model disease of multiple
      sclerosis. By using lymphocytic-endothelial adhesion and transmigration assays,
      FACScan and Western blotting, we defined the effects of CAST on expression,
      function and signal transduction of glycoproteins crucial in the pathophysiology
      of this disease. CAST prevented clinical signs of EAE and completely inhibited
      inflammatory CNS infiltrates associated with this disease. Here, we showed that
      CAST blocks antigen-induced lymphocytic activation and clonal expansion in a dose
      dependent manner. Importantly, we observed that CAST strongly impairs IL-2
      induced signal transduction of the IL-2 receptor. In contrast, neither expression
      nor binding ability of the IL-2 receptor was affected by this drug. In addition,
      we were able to exclude major effects of CAST on expression and function of
      different glycoproteins important in antigen presentation as well as lymphocytic
      endothelial adhesion and transmigration. In conclusion, CAST strongly interferes
      in the signal transduction of the IL-2 receptor. This could explain both
      inhibitory effects of CAST in clonal T cell expansion and development of transfer
      EAE. This relatively selective pharmacological effect of CAST highlights its
      potential as a novel immunomodulatory approach in multiple sclerosis.

PMID- 12417428
TI  - Contralateral non-operated nerve to transected rat sciatic nerve shows increased
      expression of IL-1beta, TGF-beta1, TNF-alpha, and IL-10.
AB  - Recent reports indicate that after a peripheral nerve injury, the uninjured
      contralateral nerve is also affected. Because cytokines play an important role in
      the peripheral nerve injury, we studied the expression of five different mRNAs
      (interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha),
      interleukin-10 (IL-10), transforming growth factor-beta1 (TGF-beta1) and
      interleukin-4 (IL-4)) in the contralateral, non-operated, left sciatic nerve when
      the right rat sciatic nerve was transected. This study extended up to 42 days
      after the transection. No IL-4 expression was noted. During the first 3 days,
      high expression of the other studied cytokines was noted in the endoneurium. At
      day 7, the expression diminished to the control levels. After this, a cyclic
      expression pattern appeared, which was most pronounced in the endoneurium at 35
      days. We also show that the expression pattern in the endoneurium is different
      from that in the surrounding epi- and perineurium. Also, our present study shows
      clearly that contralateral nerves are poor controls after injury.

PMID- 12417429
TI  - Inhibition of LPS-induced p42/44 MAP kinase activation and iNOS/NO synthesis by
      parthenolide in rat primary microglial cells.
AB  - Nitric oxide (NO) has been implicated in the etiopathology of central nervous
      system (CNS) diseases such as multiple sclerosis (MS). Inhibition of NO synthesis
      has been proposed to be a possible mechanism of action of relevance in the
      treatment of multiple sclerosis and migraine. Here, we investigated the effect of
      parthenolide on inducible NO synthase (iNOS) synthesis and NO release using
      primary rat microglia. We found parthenolide to be an inhibitor of iNOS/NO
      synthesis. Investigating the molecular mechanisms by which parthenolide prevents
      iNOS/NO synthesis, we found that parthenolide inhibits the activation of p42/44
      mitogen-activated protein kinase (MAPK), but not IkBalpha (IkappaBalpha)
      degradation or nuclear factor-kappaB (NF-kappaB) p65 activation. The data suggest
      that parthenolide might have a potential in the treatment of CNS diseases where
      NO is part of the pathophysiology.

PMID- 12417430
TI  - NPY modulates epinephrine-induced leukocytosis via Y-1 and Y-5 receptor
      activation in vivo: sympathetic co-transmission during leukocyte mobilization.
AB  - Sympathetic nervous system (SNS) activation mobilizes blood leukocytes. Under
      these circumstances, both epinephrine (EPI) and neuropeptide Y (NPY) are
      released. Therefore, we investigated a possible interaction between these
      transmitters during leukocyte mobilization, using intravenous catheterization of
      male adult Lewis rats. Intravenous application of NPY followed by EPI, dose
      dependently facilitated, intensified and inhibited EPI-induced leukocytosis with
      subset-specificity for NK-cells, monocytes, and B-lymphocytes. Pharmacological
      assessment of NPY receptors involved revealed a Y-1R-mediated inhibition and a Y
      5R-mediated facilitation. RT-PCR on peripheral blood mononuclear cells (PBMC)
      detected Y-1R mRNA only, suggesting direct Y-1R-mediated effects on leukocytes
      and indirect effects via the Y-5R. Thus, via a specific Y-1R/Y-5R interplay, NPY
      acts as a neuroimmune co-transmitter in vivo.

PMID- 12417431
TI  - Dopamine receptor expression on human T- and B-lymphocytes, monocytes,
      neutrophils, eosinophils and NK cells: a flow cytometric study.
AB  - This study documents expression of dopamine (DA) receptors on leukocyte
      subpopulations using flow cytometric techniques to identify dopamine receptors
      with subtype-specific antibodies. Of the D1-like receptor family (D(1) and D(5)),
      only D(5) was detected, and of the D2-like receptor family (D(2), D(3) and D(4)),
      all dopamine receptors were detected. T-lymphocytes and monocytes had low
      expression of dopamine receptors, whereas neutrophils and eosinophils had
      moderate expression. B cells and NK cells had higher and more consistent
      expression. Dopamine receptors D(3) and D(5) were found in most individuals
      whereas D(2) and D(4) had more variable expression. D(1) was never found.

PMID- 12417432
TI  - Resistance to ocular herpes simplex virus type 1 infection in IL-12 transgenic
      mice.
AB  - Interleukin-12 (IL-12) is a potent inflammatory cytokine that influences the
      innate and adaptive immune response to microbial pathogens including viruses. It
      was reasoned that constitutive IL-12 production in mice would enhance resistance
      to herpes simplex virus type 1 (HSV-1) infection. To test this hypothesis,
      transgenic mice expressing the p35 and p40 genes of IL-12 under a glial
      fibrillary acidic protein (GFAP) promoter were ocularly infected with HSV-1.
      These mice displayed increased survival and reduced viral titers in the eye,
      trigeminal ganglion (TG), and brain stem in comparison to wild type controls.
      Consistent with these results, HSV-1 immediate early and early gene expression
      were reduced to 50-130-fold in the trigeminal ganglion of infected transgenic
      mice compared to infected, non-transgenic counterparts as determined by real time
      PCR. Associated with viral resistance, IL-12 and IFN-gamma mRNA levels and IL-12
      protein were elevated in the eyes of the transgenic versus non-transgenic mice
      during the acute infection. Collectively, the data show the inherent resistance
      of mice constitutively expressing IL-12 to ocular HSV-1 infection-an outcome that
      is independent of the adaptive immune system at the time of infection.

PMID- 12417433
TI  - Reduced Th1 and enhanced Th2 immunity after immunization with Alzheimer's beta
      amyloid(1-42).
AB  - It has been demonstrated that immunization of transgenic mouse models of
      Alzheimer's disease (AD) with amyloid-beta(1-42) peptide (Abeta(1-42)) results in
      prevention of Abeta plaque formation and amelioration of established plaques in
      the brain. As the response of the T lymphocyte helper (Th) arm of the immune
      response had not yet been investigated after Abeta immunization, we i.p.
      immunized C57BL/6 mice with Abeta(1-42), Abeta(1-40), or phosphate-buffered
      saline (PBS), and examined markers of Th1 and Th2 immune responses in spleen and
      in splenocytes from these mice. Spleens from Abeta(1-42)-immunized mice
      demonstrated decreased interleukin-12 receptor beta chain expression compared to
      mice immunized with Abeta(1-40) or PBS. Consistently, following stimulation with
      concanavalin A or anti-CD3 antibody, primary splenocytes from Abeta(1-42)
      immunized mice demonstrated elevated secretion of interleukin-4 and interleukin
      10, and decreased levels of interferon-gamma. To validate this Th1-->Th2 shift in
      a transgenic mouse model of AD, we immunized Tg APP(sw) mice (line 2576) with
      Abeta(1-42) and found decreased Th1 (interleukin-2 and interferon-gamma) and
      elevated Th2 (interleukin-4 and interleukin-10) cytokines in their stimulated
      primary splenocytes. Interferon-gamma was markedly reduced and interleukin-10 was
      increased in blood plasma from these mice, effects that were associated with
      dramatically mitigated Abeta deposition after Abeta(1-42) immunization. Taken
      together, these results show enhanced Th2 and down-regulated Th1 immunity
      following immune challenge with Abeta(1-42).

PMID- 12417434
TI  - Astrocyte-induced T cell elimination is CD95 ligand dependent.
AB  - The brain has an intrinsic capacity to remove infiltrating T cells by inducing
      apoptosis. However, the pathways and cellular components driving this process are
      still under debate. Astrocytes seem to play an important role because they
      colocalize with apoptotic lymphocytes in vivo and induce apoptosis of transformed
      T cells in vitro. Since we previously demonstrated the expression of the death
      ligand CD95L (APO-1L/FasL) on astrocytes in the brain, we wanted to know whether
      nontransformed astrocytes induce cell death in nontransformed T cells, reflecting
      the in vivo situation and, if so, whether CD95/CD95 ligand interaction is
      important. T cell apoptosis measured by Annexin V binding and DNA fragmentation
      was significantly lower using CD95 ligand-deficient (gld) astrocytes compared to
      nondeficient controls. Moreover, neutralizing anti-CD95 ligand antibody reduced
      astrocyte-induced T cell apoptosis. Thus, adult astrocytes are capable of
      inducing the apoptotic death of T cells by involving the CD95/CD95 ligand pathway
      without undergoing cell death in vitro. Since astrocytic end-feet contribute to
      the formation of the blood-brain barrier, this depletion mechanism may play an
      important role as the first line of defense in the brain.

PMID- 12417435
TI  - Social stress alters splenocyte phenotype and function.
AB  - Social stress of group-housed male mice induced a state of functional
      glucocorticoid (GC) resistance in splenocytes. The following studies examined the
      effects of paired-fighting (PF) stress on immune cell distribution and function
      in spleens of male mice. Following six daily PF stress sessions, splenic
      monocytes and neutrophils increased and lymphocytes decreased. PF also altered
      the distribution of CD62L and CD11b positive monocytes. Additionally, PF
      augmented proliferation and lowered the sensitivity of LPS-stimulated splenocytes
      to the antiproliferative effects of corticosterone, suggesting that PF induced a
      state of GC resistance in splenocytes. Together, these findings indicate that
      social stress altered phenotype and function of splenic immune cells. These
      findings may have implications for the healing of bite wounds that are often
      associated with social stress in rodents.

PMID- 12417436
TI  - Mechanism of CAR syndrome: anti-recoverin antibodies are the inducers of retinal
      cell apoptotic death via the caspase 9- and caspase 3-dependent pathway.
AB  - Anti-recoverin autoantibodies have been associated with cancer-associated
      retinopathy (CAR), a paraneoplastic blinding disease. Those antibodies have been
      shown to induce apoptotic death of photoreceptor cells. The objective was to
      ascertain the mechanisms of retinal death induced by anti-recoverin antibody in
      vitro by examining the apoptotic pathway involved in retinal cell death.
      Internalization of anti-recoverin antibody or its Fab fragments by retinal cells
      mediated by endocytosis lead to cytotoxicity. Antibody cellular translocation
      induced the increase of bcl-x(s) and bax and the decrease in the bcl-x(L)
      protein. We detected the release of cytochrome c and down-regulation of the apaf
      1 protein. This correlated with the sequential activation of caspase 9 and
      caspase 3, as well as the degradation of the caspase substrate PARP and the
      fragmentation of DNA. Our data show that anti-recoverin antibodies are inducers
      of apoptosis through the mitochondrial pathway involving caspases 9 and 3. We
      propose that a similar mechanism may be in place in patients with CAR syndrome
      where high levels of circulating antibodies have been associated with retinal
      degeneration.

PMID- 12417437
TI  - Semliki Forest virus infection is enhanced in Th1-prone SJL mice but not in Th2
      prone BALB/c mice during Linomide-induced immunomodulation.
AB  - Linomide (quinoline-3-carboxamide) is an immunomodulator with diverse effects on
      the immune system. Its beneficial effects on experimental autoimmune disease
      models have been linked to downregulation of Th1 cytokines and altered macrophage
      functions. We studied this effect of downregulation of Th1-type of immune
      response on Semliki Forest A7 virus infection in experimental autoimmune
      encephalomyelitis (EAE) susceptible Th1-prone SJL mice and in EAE-resistant Th2
      prone BALB/c mice. We aimed at addressing the target-cell population of Linomide
      responsible for this Th1 downregulation. Treatment with Linomide led to increased
      virus infection in brain and this effect coincided with decreased production of
      IL-12 and IFN-gamma from stimulated spleen cells in SJL mice. In contrast, IL-12
      and IFN-gamma expression were increased in Linomide-treated BALB/c mice.
      Treatment of infected SJL mice resulted in decreased percentage of CD11b+ and
      CD11c+ cells. Thus, the target cell population of Linomide may be antigen
      presenting cells (APC) which are considered as candidates for regulatory cells of
      Th1/Th2 balance.

PMID- 12417439
TI  - Immune response gene expression increases in the aging murine hippocampus.
AB  - Using GeneChips, basal and lipopolysaccharide (LPS)-induced gene expression was
      examined in the hippocampus of 3-, 12-, 18- and 24-month-old male C57BL/6 mice to
      identify genes whose altered expression could influence hippocampal function in
      advanced age. Gene elements that changed with age were selected with a t
      statistic and specific expression patterns were confirmed with real-time
      quantitative PCR. Basal expression of 128 gene elements clearly changed with age
      in the hippocampus. Fourteen gene elements showed increased expression with age
      and these increases were validated after LPS stimulation. Major
      histocompatibility complex (MHC) TL region and thymic shared antigen (TSA-1) gene
      expression increased, suggesting T cell activation in the hippocampus with age.
      Cytokine (interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha) and
      chemokine (macrophage chemotactic protein-1) expression increased sharply in 24
      month-old mice. These findings are in contrast to a decrease in the peripheral
      immune response, documented by decreased T cell proliferation and decreased
      ratios of naive to memory T cells. Age-related increases in inflammatory
      potential in the brain may contribute to neurodegenerative diseases of the aged.

PMID- 12417438
TI  - Vascular endothelial growth factor induces chemotaxis and proliferation of
      microglial cells.
AB  - Vascular endothelial growth factor (VEGF) is an angiogenic peptide that is
      produced in the brain after ischemia, injury or in malignant gliomas. Since these
      pathological conditions are associated with the infiltration of microglial cells,
      we investigated the expression of VEGF receptors (VEGFR) and possible effects of
      VEGF on cultivated microglial cells. As shown by reverse transcription-polymerase
      chain reaction and immunocytochemistry, rat microglial cells as well as the
      murine cell line BV-2 express the VEGFR-1, but not VEGFR-2. Murine VEGF induced
      3H-thymidine incorporation into DNA of murine and rat microglial cells as well as
      chemotaxis in Boyden chamber assays. However, VEGF did not alter the
      phosphorylation of mitogen-activated protein kinases and only slightly that of
      the kinase Akt. These results show that microglial cells are targets for VEGF
      which induces migration and proliferation of these immunocompetent cells in the
      brain.

PMID- 12417440
TI  - Induction of antibodies against murine full-length prion protein in wild-type
      mice.
AB  - The causative and infectious agent of the transmissible spongiform
      encephalopathies, e.g. bovine spongiform encephalopathy in cattle or variant
      Creutzfeldt-Jakob disease in humans, is a pathogenic form of the scrapie prion
      protein (PrP(Sc)) generated by a conformational rearrangement in the normal
      cellular prion protein (PrP(C)). Anti-PrP antibodies have been shown to exert a
      protective effect against infection with PrP(Sc). However, the generation of anti
      PrP antibodies has proven quite difficult in wild-type animals, PrP being a
      notoriously poor immunogen. We developed a vaccine against PrP by mixing
      recombinant murine PrP 23-231 with DnaK, an Hsp70 homolog in Escherichia coli,
      and cross-linking the two proteins by means of glutaraldehyde. After three
      injections of the vaccine into BALB/c mice at 6, 8 and 9 weeks of age, a low
      titer immune response was detected with ELISA in all animals. The specificity of
      the antibodies for PrP was confirmed with Western blotting. The straightforward
      procedure might render active immunization against prion infection feasible.

PMID- 12417441
TI  - Induction of autoimmune encephalomyelitis and uveitis in B6 and (B6 x SJL) mice
      by peptides derived from myelin/oligodendrocyte glycoprotein.
AB  - Previous studies have shown that immunization of the Lewis rat with myelin basic
      protein (MBP), an encephalitogenic antigen derived from the myelin sheath of the
      CNS, induced both experimental autoimmune encephalomyelitis (EAE) and anterior
      uveitis (AU). In the current study, we show that a major peptide derived from
      another encephalitogenic myelin protein-the myelin/oligodendrocyte glycoprotein
      (MOG35-55)-induced both encephalomyelitis and uveitis in (B6 x SJL) F1 and wt-B6
      mice. Pathological studies documented that an anterior uveitis was induced by
      MOG35-55. A similar disease pattern was induced by either active immunization
      with peptideMOG35-55 (pMOG35-55) or adoptive transfer of MOG35-55-specific T
      cells. The induced uveitis persisted for >60 days without remission. Our studies
      demonstrate for the first time that MOG is uveitogenic in mice that express the H
      2(b) genetic background. This new experimental model should provide a useful tool
      for the study of the pathogenesis of chronic AU and determination of the
      pathogenic mechanisms by which a large portion of MS patients develops uveitis.

PMID- 12417442
TI  - Inorganic lead enhances cytokine-induced elevation of matrix metalloproteinase
      MMP-9 expression in glial cells.
AB  - Inorganic lead (Pb) is a ubiquitous environmental contaminant that produces a
      variety of deleterious effects in the central nervous system (CNS). Matrix
      metalloproteinases (MMPs), specifically MMP-9, induced by inflammatory cytokines,
      are increasingly being implicated in CNS pathology. The present study
      demonstrates that low concentrations of either pro-inflammatory cytokines (TNF
      alpha and IL-1beta) or Pb did not influence the MMP-9 expression in a glial cell
      line (C6) when added separately. However, combined administration of Pb and
      cytokines induced a marked synergized elevation of MMP-9 expression in spite of a
      reduction in the number of glial cells. These results demonstrate a possible new
      mechanism by which Pb may induce neuropathological processes.

PMID- 12417443
TI  - Compromised peripheral immunity of mice injected intrastriatally with six
      hydroxydopamine.
AB  - Intracisternal or intracerebroventricular administration of six-hydroxydopamine
      (6-OHDA), which results in decreased norepinephrine (NE) and dopamine (DA) levels
      throughout the brain, causes impaired peripheral immunity. However, in vivo
      immunocompetence following selective striatal depletion of DA by 6-OHDA has not
      been investigated. Thus, we sought to determine whether striatal DA depletion
      compromises host resistance to Listeria monocytogenes (LM) and impairs the immune
      response to keyhole limpet hemocyanin (KLH). Mice treated with 6-OHDA (90%
      decrease in striatal DA) had (i) increased LM colonization in liver and spleen,
      (ii) lower primary IgM and IgG(1) antibody titers, as well as secondary IgM
      titers, and (iii) compromised DTH response compared to controls. Co
      administration of a DA uptake inhibitor partially (40%) spared striatal DA
      depletion and completely prevented the increase in LM burden, but was ineffective
      in preventing any of the 6-OHDA-induced suppressions of the immune responses to
      KLH. Thus, striatal DA is suggested to play a response-specific role in
      peripheral immunological functions.

PMID- 12417444
TI  - Iron overload exacerbates experimental meningoencephalitis by Cryptococcus
      neoformans.
AB  - This study was aimed at investigating the effects of iron overload on the onset
      and outcome of cerebral cryptococcosis. To this purpose, iron dextran
      administered mice were intracerebrally challenged with virulent melanogenic and
      avirulent non-melanogenic strains of Cryptococcus neoformans. The results shown
      here provide the first evidence that iron overload exacerbates the outcome of
      cryptococcal meningoencephalitis, irrespective of the fungal strain employed;
      pathogen colonization of the brain is facilitated, local cytokine response is
      delayed and/or prevented.

PMID- 12417445
TI  - Immunochemical and immunocytochemical characterization of cholinergic markers in
      human peripheral blood lymphocytes.
AB  - Cholinergic markers and the expression of M(2)-M(5) muscarinic cholinergic
      receptor subtypes were investigated in human peripheral blood lymphocytes by
      Western blot analysis and immunocytochemistry. The totality of peripheral blood
      lymphocytes express acetylcholine (ACh) immunoreactivity, choline
      acetyltransferase (ChAT), acetylcholinesterase (AChE), vesicular ACh transporter
      (VAChT) and M(2)-M(5) muscarinic cholinergic receptor protein immunoreactivity.
      Western blot analysis performed independently on T and B lymphocytes using anti
      ChAT and anti-AChE antibodies revealed labelling of single bands of approximately
      68-70 and 70 kDa, respectively, whereas VAChT was bound to two bands of
      approximately 80 and 45 kDa. The pattern of immunoblotting was similar in
      membranes of lymphocytes and striatum, used as a reference brain tissue. Western
      blot analysis using anti M(2)-M(5) receptor antibodies revealed labelling of
      single bands of approximately 55, 85-90, 50 and 81 kDa, respectively. Confocal
      laser immunofluorescence showed the localization of ACh and VAChT
      immunoreactivity in punctiform areas likely corresponding to cytoplasmic
      vesicles. ChAT and AChE were diffused to the cytoplasm and plasma membrane.
      Muscarinic receptor immunoreactivity was located in lymphocyte plasma membrane.
      Although the role of lymphocyte cholinergic system is still unclear, the
      demonstration of cholinergic markers in T and B human blood lymphocytes supports
      the view that a cholinergic systems may contribute to the regulation of immune
      function. The characterization of these cholinergic markers may also contribute
      to define if their evaluation can be used for assessing the status of brain
      cholinergic system.

PMID- 12417446
TI  - Expression of the EGF-TM7 receptor CD97 and its ligand CD55 (DAF) in multiple
      sclerosis.
AB  - CD97 is a recently identified seven-span transmembrane (7-TM) protein that is
      expressed by leukocytes early after activation. CD97 binds to its cellular ligand
      CD55 (decay accelerating factor), which protects several cell types from
      complement-mediated damage. The functional consequences of CD97-CD55 binding are
      largely unknown, but previous data imply that CD97-CD55 interactions play a role
      in cellular activation, migration, and adhesion under inflammatory conditions.
      Here we examined the expression of CD97 and CD55 by immunohistochemistry in
      multiple sclerosis (MS). On the basis of established criteria for inflammation
      and demyelination, different lesion stages were distinguished in MS post-mortem
      brain tissue. In normal white matter, CD97 expression was not found, but CD55 was
      expressed with weak staining intensity on endothelial cells. In pre-active
      lesions, defined by abnormalities of the white matter, many infiltrating T cells,
      macrophages (MPhi) and microglia expressed CD97. CD55 was highly expressed by
      endothelial cells. In active lesions with myelin degradation, MPhi and microglia
      expressed both CD55 and CD97. Furthermore, a sandwich ELISA showed significantly
      (p<0.05) elevated levels of soluble CD97 in serum but not in cerebrospinal fluid
      of MS patients (37%) compared to healthy controls (8%).Collectively, these data
      suggest that CD97-CD55 interactions are involved in the inflammatory processes in
      MS. CD55, which is expressed in lesions by vessels to protect against complement
      mediated damage, might bind to CD97 on infiltrating leukocytes. This interaction
      may facilitate cell activation and migration through the blood-brain barrier. In
      addition, CD97-CD55 interactions in the parenchyma of the brain may contribute to
      the inflammation.

PMID- 12417447
TI  - CD45 isoform alteration in CD4+ T cells as a potential diagnostic marker of
      Alzheimer's disease.
AB  - Aging represents the greatest risk for development of Alzheimer's disease (AD),
      and changes in peripheral immune cell phenotypes have been found to be associated
      with aging. Using flow cytometry, we measured the relative expression levels of
      CD45 isoforms, a marker of nai;ve versus memory CD4+ T cell status, on isolated
      CD4+ T lymphocytes from patients with a clinical diagnosis of probable
      Alzheimer's disease, normal elderly, cognitively abnormal elderly, and patients
      with clinically diagnosed other forms of dementia. Data show significantly lower
      levels of CD45RA, and an increase in the CD45RO/CD45RA ratio, on CD4+ T cells in
      patients diagnosed with probable Alzheimer's disease (n=46) and in cognitively
      abnormal individuals (n=37) compared to age-matched normal participants (n=90).
      Patients diagnosed with other forms of dementia (n=19) did not significantly
      differ from normal individuals. Both CD45RA and the CD45RO/CD45RA ratio had
      higher positive and negative predictive values and were more sensitive biomarkers
      of probable AD than the apolipoprotein E epsilon 4 allele, and had greater
      predictive ability for probable AD by regression analyses. Additionally, a
      testing strategy employing apolipoprotein E genotyping and CD45RA or the
      CD45RO/CD45RA ratio revealed increased sensitivity, positive and negative
      predictive values, and predictive ability over the apolipoprotein E epsilon 4
      allele. These data show altered peripheral immunity in AD patients, and raise the
      possibility that a testing strategy using CD45 isoform alteration on CD4+ T cells
      and apolipoprotein E genotype may be clinically valuable for diagnosing probable
      AD.

PMID- 12417449
TI  - Brain-derived neurotrophic factor in patients with multiple sclerosis.
AB  - The aim of the present research was to verify the production of BDNF by
      peripheral blood mononuclear cells (PBMCs), unstimulated and stimulated with
      phytohemagglutinin (PHA), anti-OKT3 Ab and myelin basic protein (MBP), in 35
      patients affected by multiple sclerosis (MS), 20 with relapsing-remitting (R-R)
      MS and 15 with secondary progressive (SP) MS. Seven R-R MS patients were assessed
      during the attack, in the subsequent recovery phase and also 3 months after
      relapse. The production of BDNF by PBMCs was also evaluated in 20 age- and sex
      matched control subjects. Levels of BDNF were also determined in CSF of both
      patient groups and 20 control subjects. RESULTS: Levels of BDNF (pg/ml) in the
      supernatants of unstimulated and PHA-, anti-OKT3 Ab- and MBP-stimulated PBMCs in
      patients with R-R MS were significantly higher during relapse and in the recovery
      phase compared with values detected in the stable phase of the disease.
      Significantly lower BDNF values were found in unstimulated and stimulated PBMC
      supernatants of patients with SP MS compared to control subjects. This reduction
      was greater in patients with a 1-point increase in the EDSS score in the last 6
      months compared with that in patients without a progression of the disability
      score. Reduction in the levels of BDNF was also confirmed in the CSF of SP MS
      patients compared with R-R MS patients assessed during a stable phase of the
      disease and control subjects. DISCUSSION: On the basis of recent experimental
      findings, a neuroprotective effect of BDNF produced by inflammatory cells can be
      hypothesized during relapses in MS. This can favor remyelination. The reduced
      production of BDNF by PBMCs of patients with SP MS can contribute to the
      progression of demyelinating disease and axonal loss in this form.

PMID- 12417448
TI  - The effects of spaceflight on adrenergic receptors and agonists and cell adhesion
      molecule expression.
AB  - Twenty-two astronauts who flew aboard 10 different US Space Shuttle flights were
      studied 10 days before launch, on landing day, and 2-4 days post-landing. After
      landing, plasma levels of norepinephrine (p<0.01) were elevated. Lymphocyte
      beta(2)-adrenergic receptors were desensitized 2-4 days post-landing (p<0.02).
      The density of CD62L on lymphocytes was unchanged but the densities of CD11a
      (p<0.01) and CD54 (p<0.001) were down-regulated. CD11a density was also down
      regulated on monocytes (p<0.01). Neutrophils showed an up-regulation of CD11a
      (p<0.01) and a down-regulation of CD54 (p<0.01). CD11a density on neutrophils
      remained up-regulated (p<0.01) and CD54 density remained down-regulated (p<0.01)
      at 2-4 days post-landing. Circulating levels of soluble ICAM-1 (CD54) and soluble
      E-selectin (CD62E) were decreased after landing (p's<0.05). The data suggest that
      spaceflight leads to an environment that would support reduced leukocyte
      endothelial adhesion. Sympathetic activation may contribute to this phenomenon.

PMID- 12417450
TI  - Oral terbutaline differentially affects cytokine (IL-10, IL-12, TNF, IFNg)
      release in multiple sclerosis patients and controls.
AB  - Administration of beta-receptor agonists alleviate experimental multiple
      sclerosis (MS) in animal models. In this study, we investigated the effects of
      terbutaline (5 mg) on IL-10, IL-12, IFN-gamma and TNF-alpha production in whole
      blood stimulation cultures. IL-10 and IL-12 production were significantly
      enhanced in controls but not in MS patients (p=0.03 and p=0.001). Effects were
      not associated with an ongoing immunomodulatory therapy. We conclude that
      administration of terbutaline induces anti-inflammatory (IL-10) as well as IL-12
      protein production in healthy controls but not in MS patients. Our findings might
      reflect a disturbed autonomic control of the immune system in MS.

PMID- 12417451
TI  - Expectation-based attentional modulation of visual extinction in spatial neglect.
AB  - Visual extinction, the failure of patients with unilateral focal brain damage to
      report the contralesional of two simultaneously presented stimuli, may be
      modulated by characteristics of the display such as similarity, collinearity, or
      connectedness. Since these factors affect the perceptual configuration of
      stimuli, the modulation of extinction is believed to reflect low-level perceptual
      grouping. In the present study, patient AG did not show any modulation of
      contralesional detection when the ipsilesional and contralesional stimulus
      grouped by colour, by form, or both (Experiment 1). In contrast, identification
      of the contralesional stimulus was facilitated when the stimuli grouped
      (Experiment 2), suggesting a modulation of extinction by specific task demands.
      Experiment 3 used a cueing procedure to demonstrate modulation of extinction by
      expectation biases. Prior to stimulus presentation, AG was cued to attend to a
      particular feature (e.g. colour). After stimulus exposure he was prompted to
      identify the expected feature on valid trials and the unexpected feature on
      invalid trials. AG showed a significant validity effect for contralesional
      stimuli i.e. he identified the expected feature (e.g. colour) significantly
      better than the unexpected feature (e.g. form). These results suggest that
      competition for selection between visual stimuli may not only be influenced by
      perceptual characteristics of the display, but also by high-level factors such as
      the response criterion or expectation biases.

PMID- 12417452
TI  - Spatial and temporal influences on extinction.
AB  - This study investigated the spatial and temporal characteristics of the
      attentional deficit in patients exhibiting extinction to determine the extent to
      which these characteristics can be explained by a theory of an underlying
      gradient resulting from the differential contribution of interacting cell
      populations. The paradigm required the identification of two letters whose
      spatial location was varied both within and across hemifields. Additionally, the
      interval between the appearances of the two stimuli was manipulated by changing
      the stimulus onset asynchrony (SOA). A final variable, that of expectancy, was
      introduced by making the stimulus location more or less predictable and examining
      the effect of this top-down contingency on performance. The findings were
      consistent across two patients and indicated the joint contribution of both
      spatial and temporal factors: the contralesional stimulus was maximally
      extinguished when it was preceded by the ipsilesional stimulus by 300-900 ms, but
      this extinction was reduced when the stimuli appeared further ipsilesionally.
      Interestingly, there was increased extinction of the contralesional stimulus when
      location was predictable. These findings support the hypothesis that the
      attentional deficit in extinction patients arises from a contralesional-to
      ipsilesional gradient of cell populations that interact in a mutually inhibitory
      manner.

PMID- 12417453
TI  - Working memory and apolipoprotein E: what's the connection?
AB  - Two robust findings in the Alzheimer's literature are that patients with
      Alzheimer's disease (AD) show executive function and primacy deficits. The
      present study examined whether we would find similar deficits when comparing two
      groups of middle-aged individuals who differed with respect to genetic risk for
      AD, based on their apolipoprotein E (APOE) genotype. All individuals were
      screened as normal on a battery of standardized cognitive measures. They were
      tested on the "Operation span task", which engages the central executive
      component of working memory [J. Exp. Psychol.: Gen. 128 (1999) 309, J. Exp.
      Psychol.: Gen. 126 (1997) 211, J. Mem. Language 39 (1998) 418] by dividing
      attention between processing math operations and remembering words. Individuals
      were grouped according to APOE genotype ( epsilon 4 carrier versus epsilon 4 non
      carrier), matched on age and education, and their Total span and Primacy scores
      were compared. Despite having no overt symptoms of dementia or deficits on a
      series of standardized psychometric tests, the epsilon 4 carriers showed divided
      attention and primacy deficits on the Operation span task, when compared to the
      epsilon 4 non-carriers. As a point of comparison, Primacy scores were extracted
      from the first trial of the "Buschke selective reminding task" [J. Verbal Learn.
      Verbal Behav. 12 (1973) 543] for these same individuals, and no group differences
      were found. The Buschke task is a list-learning task that does not require
      divided attention. These findings suggested that the epsilon 4 carriers were less
      able to divide their attention, when compared to the epsilon 4 non-carriers. The
      findings provide the first direct evidence for a relationship between APOE
      genotype and cognitive performance on measures of divided attention and primacy
      with non-demented individuals who showed no cognitive impairments on standardized
      measures.

PMID- 12417454
TI  - SRT lengthening: role of an alertness deficit in frontal damaged patients.
AB  - Numerous studies have documented the lengthening of reaction time (RT) following
      brain damage. However, the origin of response retardation and its anatomical
      basis still remain unknown. This study assessed simple RT (SRT) and choice RT
      (CRT) in patients with frontal or posterior damage. It showed (i) that RTs were
      longer in frontal damaged patients; (ii) with a constant response retardation
      across SRT and CRT tests; (iii) that minimum and percentile 25th SRTs of the
      frontal group were within normal ranges, indicating that they were able to
      produce fast responses; (iv) that percentiles 50 and 75th SRTs of the frontal
      group were longer, indicating that they produced a lower proportion of fast
      responses; (v) an interpretation supported by the decrement of the peak of SRT
      distribution. Such a pattern is highly suggestive of a disorder of an attentional
      process required to trigger the same response as fast as possible throughout the
      test. According to Posner's model of attention, this function is devoted to the
      alerting network and the present study supports the key role of the frontal lobes
      for alertness.

PMID- 12417455
TI  - Hits to the left, flops to the right: different emotions during listening to
      music are reflected in cortical lateralisation patterns.
AB  - In order to investigate the neurobiological mechanisms accompanying emotional
      valence judgements during listening to complex auditory stimuli, cortical direct
      current (dc)-electroencephalography (EEG) activation patterns were recorded from
      16 right-handed students. Students listened to 160 short sequences taken from the
      repertoires of jazz, rock-pop, classical music and environmental sounds (each
      n=40). Emotional valence of the perceived stimuli were rated on a 5-step scale
      after each sequence. Brain activation patterns during listening revealed
      widespread bilateral fronto-temporal activation, but a highly significant
      lateralisation effect: positive emotional attributions were accompanied by an
      increase in left temporal activation, negative by a more bilateral pattern with
      preponderance of the right fronto-temporal cortex. Female participants
      demonstrated greater valence-related differences than males. No differences
      related to the four stimulus categories could be detected, suggesting that the
      actual auditory brain activation patterns were more determined by their affective
      emotional valence than by differences in acoustical "fine" structure. The results
      are consistent with a model of hemispheric specialisation concerning perceived
      positive or negative emotions proposed by Heilman [Journal of Neuropsychiatry and
      Clinical Neuroscience 9 (1997) 439].

PMID- 12417456
TI  - Motivation, reward, and Parkinson's disease: influence of dopatherapy.
AB  - "Orbitofrontal" and "cingulate" striatofrontal loops and the mesolimbic
      dopaminergic system that modulates their function have been implicated in
      motivation and sensitivity to reinforcement in animals. Parkinson's disease (PD)
      provides a model to assess their implications in humans. The aims of the study
      were to investigate motivation and sensitivity to reinforcement in non-demented
      and -depressed PD patients and to evaluate the influence of dopaminergic therapy
      by comparing patients in "on" (with L-Dopa) and "off" (without L-Dopa) states.
      Twenty-three PD patients were compared, in both the "on" and "off" states, to 28
      controls, using: (1) an Apathy Scale; (2) Stimulus-Reward Learning, Reversal, and
      Extinction tasks; and (3) a Gambling task. PD patients were found: (1) mildly
      apathetic; (2) impaired on Stimulus-Reward Learning and Reversal, but not on
      Extinction; and (3) able to progress in the Gambling task during the first, but
      not the second assessment. There was no significant correlation between these
      various deficits. L-Dopa treatment clearly improved motivation, but had more
      limited and contrasting effects on other variables, decreasing the number of
      omission errors in Reversal, but increasing the number of perseveration errors in
      Extinction. These results suggest: (1) an implication of striatofrontal loops in
      human motivation and explicit and implicit sensitivity to reinforcement; (2) a
      positive influence of L-Dopa treatment on the subjective evaluation of
      motivation, but contrasting effects on reward sensitivity.

PMID- 12417457
TI  - Category-specific impairment in patients with Alzheimer's disease as a function
      of disease severity: a cross-sectional investigation.
AB  - Several questions about category specificity associated with lexical-semantic
      deficits in Alzheimer's disease (AD) patients are still being debated. In this
      study, we enrolled 53 AD patients and 30 normal control subjects to investigate
      the following issues: Is category specificity consistently associated with AD? Do
      AD patients show both possible patterns of category specific impairment, i.e.
      selective impairment for either living things or artifacts? Is the direction of
      the category specific effect predictable as a function of disease severity? Is a
      selective impairment for living things secondary to a disproportionate loss of
      perceptual knowledge? We found an overall advantage for artifacts even when
      controlling for several confounding factors. We did not find any relation between
      direction of category specificity and severity of the disease or between category
      specificity and loss of knowledge about perceptual or functional attributes.

PMID- 12417459
TI  - ERP 'old/new' effects: memory strength and decisional factor(s).
AB  - Event-related potentials (ERPs) were recorded while subjects made old/new
      recognition judgments on new unstudied words and old words which had been
      presented at study either once ('weak') or three times ('strong'). The
      probability of an 'old' response was significantly higher for strong than weak
      words and significantly higher for weak than new words. Comparisons were made
      initially between ERPs to new, weak and strong words, and subsequently between
      ERPs associated with six strength-by-response conditions. The N400 component was
      found to be modulated by memory trace strength in a graded manner. Its amplitude
      was most negative in new word ERPs and most positive in strong word ERPs. This
      'N400 strength effect' was largest at the left parietal electrode (in ear
      referenced ERPs). The amplitude of the late positive complex (LPC) effect was
      sensitive to decision accuracy (and perhaps confidence). Its amplitude was larger
      in ERPs evoked by words attracting correct versus incorrect recognition
      decisions. The LPC effect had a left>right, centro-parietal scalp topography (in
      ear-referenced ERPs). Hence, whereas, the majority of previous ERP studies of
      episodic recognition have interpreted results from the perspective of dual
      process models, we provide alternative interpretations of N400 and LPC old/new
      effects in terms of memory strength and decisional factor(s).

PMID- 12417458
TI  - Repetitive transcranial magnetic stimulation of human area MT/V5 disrupts
      perception and storage of the motion aftereffect.
AB  - Following adaptation to a moving stimulus, the introduction of a stationary
      pattern creates the illusion of motion. This phenomenon, known as the motion
      aftereffect (MAE), can be delayed by placing a blank storage interval between the
      adapting and test stimuli. Human motion selective area MT/V5 has been proposed as
      the likely neural origin of MAEs. To examine the role of MT/V5 in perceiving and
      storing MAEs, we applied repetitive transcranial magnetic stimulation (rTMS) to
      this area during a 10s storage interval and while subjects perceived illusory
      motion. Our results show that rTMS disrupts perception of the MAE when it is
      delivered in the early parts of the storage period and when it is applied during
      the perceptual MAE itself. Stimulation of control regions corresponding to V1 or
      Cz did not affect the MAE. In addition, magnetic stimulation of dorsolateral
      prefrontal and posterior parietal cortices did not disrupt MAE perception. These
      data provide experimental support for the notion that MT/V5 subserves perception
      and storage of the motion aftereffect.

PMID- 12417460
TI  - Face context interferes with local part processing in a prosopagnosic patient.
AB  - We investigated the role of local and global information on perceptual encoding
      of faces in patient HJA, who shows prosopagnosia and visual agnosia following
      occipito-temporal damage. HJA and an age-matched control were tested in a
      simultaneous matching task which focused on detection of local changes in faces:
      the inversion of central parts (eyes and mouth) relative to their context (as in
      the Thatcher illusion). Same-different judgements were made to normal, "that
      cherised" and mixed type face pairs. Whole faces (Experiment 1), or face parts
      (Experiment 2), were presented in upright and inverted orientations. Compared to
      the control, HJA was severely impaired at matching whole faces, but he improved
      dramatically when face parts were presented in isolation. This suggests an
      inhibitory influence of face context on HJAs processing of local parts and a
      relatively intact ability to process part-based information from a face (when
      context cannot interfere). Face inversion did not affect HJAs performance. A
      control experiment (Experiment 3) with non-face stimuli (houses) suggested that
      the inhibitory influence of context on HJAs performance was restricted to faces.
      These results indicate that contextual information in a face can have an adverse
      influence on the processing of local part-based information in prosopagnosia.

PMID- 12417461
TI  - Recognition memory for faces in schizophrenia patients and their first-degree
      relatives.
AB  - It has consistently been shown that schizophrenia patients are impaired in
      recognition memory for faces. However, studies have not examined the specificity
      of this deficit relative to other cognitive functions nor the relationship
      between this deficit and particular schizophrenia symptoms. In addition, no
      studies have examined recognition memory for faces in unaffected biological
      relatives of schizophrenia patients who likely share some of the genetic
      diathesis for this disorder without presenting the potential confounds of
      mentally ill study samples. The Faces subtests from the Wechsler Memory Scale
      Third Edition were used to evaluate recognition memory for faces in 39
      schizophrenia patients, 33 of their first-degree relatives and 56 normal
      controls. Both schizophrenia patients and their relatives were impaired, relative
      to control participants, in recognition memory for faces after partialing out
      group differences in spatial attention or verbal memory. Further, recognition
      memory for faces was associated with positive symptoms in the schizophrenia group
      and schizotypal personality traits in the relative group. These findings may have
      important implications for reducing etiological heterogeneity among schizophrenia
      populations, identifying disorder susceptibility among their relatives and
      furthering understanding of disorder etiology.

PMID- 12417462
TI  - Multiple mechanisms of selective attention: differential modulation of stimulus
      processing by attention to space or time.
AB  - Two studies compared the modulatory effects of orienting attention to spatial
      locations versus temporal intervals using event-related potentials (ERPs). In
      both experiments subjects performed attentional orienting tasks, which used
      identical stimuli in both spatial and temporal orienting conditions. The first
      experiment (N=16) used bilateral peripheral targets (7.5 degrees eccentricity) at
      two different time intervals (600, 1200 ms after cue onset). During spatial
      orienting a symbolic central cue predicted (75% probability) the spatial location
      (left, right) of the relevant target. No information was given about the probable
      target interval (short, long). In temporal orienting the cue predicted the target
      interval but not its location. Valid cueing produced significantly shorter
      reaction times in both the spatial and temporal orienting conditions. ERPs to
      identical, non-target stimulus arrays were analysed, to isolate endogenous
      attentional mechanisms. Spatial and temporal attention had distinct modulatory
      effects upon stimulus processing. Focused spatial attention affected the
      amplitude of early visual components. Modulation by temporal attention started
      later, and mainly affected potentials linked to decisions and responses. The
      second experiment (N=12) used unilateral target stimuli, and equated the
      probability of stimulus occurrence at short and long time intervals and at left
      or right of fixation. The results confirmed the distinct pattern of modulation of
      stimulus processing by spatial and temporal orienting. The optimisation of
      behaviour by attention can thus be achieved as a consequence of distinct
      modulatory processes, illustrating the flexibility of attentional functions in
      the human brain.

PMID- 12417463
TI  - Number representation deficit: a bilingual case of failure to access written
      verbal numeral representations.
AB  - This study reports the case of a Greek-German bilingual patient (S.V.) with
      specific deficit in Arabic number production from written German number words.
      S.V. was able to successfully complete the reverse task, i.e. to convert Arabic
      numerals into written or oral German number words. She also showed preserved
      ability to produce both German and Greek numbers and to accurately make oral
      magnitude judgments in both languages. However, when transcoding two-digit
      numbers from German written numerals to Arabic numbers she consistently reversed
      the digits. A series of in-house tasks were used to test her general abilities of
      number processing, i.e. number synesthesia and calculation. Moreover, a number
      magnitude comparison task was developed specifically for pairs of numbers with
      reverse digits and we found that out of pairs of numbers with reverse digits with
      magnitude less than 100, there exist 19 pair combinations for which distance and
      relative distance are not concordant. The results suggest that S.V.'s performance
      was significantly worse as the absolute distance between the numbers in the
      number pairs increased. These investigations are discussed in analogy with a
      grammatical rule problem related to absolute and relative distance effects.

PMID- 12417464
TI  - ERPs and behavioural indices of long-term preattentive and attentive deficits
      after closed head injury.
AB  - Attentional deficits are often reported even years after sustaining a closed head
      injury (CHI). Disturbance of cognitive attentional functions following CHI has
      been documented in both behavioural and event-related brain potential (ERP)
      studies. Recently, the possibility that the sequelae of CHI extend to
      preattentive processes of attention has been pointed out. We used a paradigm that
      makes it possible to assess simultaneously the processing of relevant information
      and involuntary mechanisms of attention to gain further insight in this matter.
      Eleven patients with CHI greater than 1 year post-trauma and 14 age-matched
      control subjects were engaged in the performance of a continuous visual reaction
      time (RT) discrimination task while ignoring streams of auditory task-irrelevant
      stimuli. The main characteristic in the paradigm was that all visual stimuli were
      shortly preceded by an auditory stimulus, which could be a repeated (90%) or a
      different (deviant) tone. We measured performance on the discrimination task, and
      ERP indices of preattentive (mismatch negativity MMN) and attentive information
      processing (P1, N165, P3b). In relation to control subjects, CHI patients showed
      an attenuation of the MMN evoked by the deviant-tone. In response to the visual
      stimuli, CHI patients showed a delay of P1, and a reduction of the N165 and P3b
      components. Moreover, they had slower RT and missed more responses in a visual
      discrimination task. These results indicate both preattentive and attentive
      deficits, which is consistent with the typical diffuse axonal injury (DAI)
      resulting after CHI.

PMID- 12417465
TI  - The effect of retrieval instructions on false recognition: exploring the nature
      of the gist memory impairment in amnesia.
AB  - In previous studies, we found that amnesic patients show reduced levels of false
      recognition in a converging semantic associates paradigm. This finding was
      interpreted as reflecting an impairment in amnesia in the ability to form, retain
      and/or retrieve a well-organized representation of the semantic 'gist' of studied
      items. To further explore the nature of amnesics' impairment in gist memory, the
      current study compared performance in two retrieval conditions. In a standard
      retrieval condition, participants were asked to endorse on a recognition test
      only items that had appeared on the study list. In a meaning retrieval condition,
      participants were asked to endorse any item that shared the meaning of studied
      items. Meaning retrieval instructions failed to eliminate the reduction in false
      recognition in amnesia. These results suggest that amnesics' impairment in gist
      memory is not attributable to a failure to access well-formed gist
      representations when given item-specific retrieval cues. Rather, it suggests that
      amnesic patients are impaired in their ability to encode, store, or maintain
      strong gist information.

PMID- 12417466
TI  - Effects of divided attention on episodic memory in chronic traumatic brain
      injury: a function of severity and strategy.
AB  - Eleven patients with mild traumatic brain injury (MTBI) and 13 patients with
      moderate-to-severe TBI (STBI) were compared to 10 matched controls on episodic
      memory for pictorial scene-object associations (e.g. kitchen-bread) and a range
      of standardized neuropsychological tests of memory and frontal-lobe functions. We
      tested the hypothesis that deficits in episodic memory result from impaired
      attentional resources and/or strategic control by manipulating attentional load
      at encoding (focused versus divided attention) and environmental support at
      retrieval (free recall and recalled cued by scene versus recognition of object
      and scene). Patients with TBI were disproportionately affected by the divided
      attention manipulation, but this effect was modulated by injury severity and
      encoding strategy. Overall, MTBI patients were impaired only when items were
      encoded under divided attention, indicating memory deficits that were secondary
      to deficits in the executive control. STBI patients could be differentiated into
      two distinct functional subgroups based on whether they favored a strategy of
      attending to the encoding or digit-monitoring task. The subgroup favoring the
      digit-monitoring task demonstrated deficits in the focused attention condition,
      and disproportionate memory deficits in the divided attention condition. In
      contrast, the subgroup favoring the encoding task demonstrated intact performance
      across all memory measures, regardless of attentional load, and despite
      remarkable similarity to the other STBI subgroup on demographic,
      neuropsychological, and acute injury severity measures. We discuss these outcome
      differences in terms of the relationship between strategy and executive control
      and highlight the need for more sensitive anatomical and behavioral measurement
      at both acute and chronic stages of injury.

PMID- 12417467
TI  - Alzheimer's disease and feeling-of-knowing in episodic memory.
AB  - Episodic memory feeling-of-knowing (FOK) was examined in 16 patients with
      Alzheimer's disease (AD), 16 elderly participants, and 16 younger adults.
      Participants were given cued recall and recognition tests of 20 critical cue
      target words. Subsequently, they judged their FOK for non-recalled words in terms
      of how likely they thought they would be to recognize the keywords on a
      subsequent recognition test. The results indicated dementia-related deficits on
      both the recall and recognition tests. Compared to older adults, AD patients
      exhibited impaired FOK accuracy. This pattern of outcome indicates that early AD
      is associated with a deficit in episodic memory and a deficit in memory
      monitoring for newly learned information. Furthermore, our observation revealed
      that in AD, episodic memory may be a more important factor than executive
      function in explaining the FOK inaccuracy.

PMID- 12417469
TI  - Inter-hemispheric interaction facilitates face processing.
AB  - Many recent studies have revealed that interaction between the left and right
      cerebral hemispheres can aid in task performance, but these studies have tended
      to examine perception of simple stimuli such as letters, digits or simple shapes,
      which may have limited naturalistic validity. The present study extends these
      prior findings to a more naturalistic face perception task. Matching tasks
      required subjects to indicate when a target face matched one of two probe faces.
      Matches could be either across-field, requiring inter-hemispheric interaction, or
      within-field, not requiring inter-hemispheric interaction. Subjects indicated
      when faces matched in emotional expression (Experiment 1; n=32) or in character
      identity (Experiment 2; n=32). In both experiments, across-field performance was
      significantly better than within-field performance, supporting the primary
      hypothesis. Further, this advantage was greater for the more difficult character
      identity task. Results offer qualified support for the hypothesis that inter
      hemispheric interaction is especially advantageous as task demands increase.

PMID- 12417468
TI  - Women and men exhibit different cortical activation patterns during mental
      rotation tasks.
AB  - The strongest sex differences on any cognitive task, favoring men, are found for
      tasks that require the mental rotation of three-dimensional objects. A number of
      studies have explored functional brain activation during mental rotation tasks,
      and sex differences have been noted in some. However, in these studies there was
      a substantial confounding factor because male and female subjects differed in
      overall performance levels. In contrast, our functional brain activation study
      examined cortical activation patterns for males and females who did not differ in
      overall level of performance on three mental rotation tasks. This allowed us to
      eliminate any confounding influences of overall performance levels. Women
      exhibited significant bilateral activations in the intraparietal sulcus (IPS) and
      the superior and inferior parietal lobule, as well as in the inferior temporal
      gyrus (ITG) and the premotor areas. Men showed significant activation in the
      right parieto-occitpital sulcus (POS), the left intraparietal sulcus and the left
      superior parietal lobule (SPL). Both men and women showed activation of the
      premotor areas but men also showed an additional significant activation of the
      left motor cortex. No significant activation was found in the inferior temporal
      gyrus. Our results suggest that there are genuine between-sex differences in
      cerebral activation patterns during mental rotation activities even when
      performances are similar. Such differences suggest that the sexes use different
      strategies in solving mental rotation tasks.

PMID- 12417470
TI  - Evidence for asymmetric frontal-lobe involvement in episodic memory from
      functional magnetic resonance imaging and patients with unilateral frontal-lobe
      excisions.
AB  - Recently, there has been considerable debate regarding the involvement of the
      left and right prefrontal cortices in the encoding and retrieval of episodic
      memory. In a previous PET study, we found that the use of easily verbalisable
      material may lead to activation predominantly in the left lateral frontal cortex
      whilst the use of non-easily verbalisable material may lead to activation
      predominantly in the right lateral frontal cortex, in both cases irrespective of
      encoding and retrieval processes. In order to replicate and extend these
      findings, the same task was modified for use with fMRI. Six healthy volunteers
      were scanned while encoding and then recalling stimuli that either emphasised
      visual or verbal processes. It was found that, in comparison to a baseline
      condition, the encoding of visual stimuli led to a bilateral activation of the
      prefrontal cortex whilst the encoding of verbal stimuli led to a preferential
      activation of the left prefrontal cortex. An effect of stimulus type was less
      evident during retrieval, with both visual and verbal stimuli leading to
      bilateral prefrontal cortex activation. Overall, encoding and retrieval activated
      similar regions of the prefrontal cortex suggesting that these areas mediate
      processes that are fundamental to both aspects of memory. To extend these
      findings further, the tasks used in the fMRI study were used to assess a group of
      patients with unilateral frontal lesions and a group of healthy control
      volunteers. The patients were significantly impaired compared to the healthy
      volunteers, although no significant differences were found in performance between
      the right- and left-sided lesioned patients. This result suggests that the memory
      related asymmetries observed during functional neuroimaging studies may not be
      critical for task performance.

PMID- 12417471
TI  - The electrophysiology of tactile extinction: ERP correlates of unconscious
      somatosensory processing.
AB  - We examined the electrophysiological correlates of left-sided tactile extinction
      in a patient with right-hemisphere damage. Computer-controlled punctate touch was
      presented to the left, right or both index fingers in an unpredictable sequence.
      The patient reported his conscious tactile percept ("left", "right" or "both").
      He showed extinction on 75% of bilateral trials, reporting only right stimulation
      for these. Somatosensory evoked potentials for unilateral stimulation showed
      early components over contralateral somatosensory areas (P60 and N110) for either
      hand. In contrast to the results observed for age-matched controls, the patient's
      P60 was smaller in amplitude for left-hand touch over the right hemisphere than
      for right-hand touch over the intact hemisphere. Bilateral trials with extinction
      revealed residual P60 and N110 components over the right hemisphere in response
      to the extinguished left touch. These results demonstrate residual unconscious
      somatosensory processing of extinguished touch. They also suggest that tactile
      extinction can be caused by attenuation rather than elimination of somatosensory
      responses in the damaged hemisphere, with an underlying deficit even on
      unilateral trials.

PMID- 12417472
TI  - Watching where you look: modulation of visual processing of foveal stimuli by
      spatial attention.
AB  - Two experiments investigated the effect of sustained selective spatial attention
      upon the perceptual analysis of stimuli within the center of gaze. Spatial
      attention has typically been studied in relation to peripheral stimuli, and its
      relevance to the processing of central stimuli has remained relatively ignored.
      Here, behavioral measures in normal human volunteer participants showed that
      focused spatial attention can also influence responses to central stimuli, over
      and beyond the advantage conferred by their foveation. Event-related potentials
      (ERPs) showed that the action of attention upon foveal stimuli included the
      modulation of perceptual processing in extrastriate visual areas. Surprisingly,
      the visual modulation revealed an intriguing and consistent pattern of
      hemispheric asymmetry, in both experiments. These findings show that in addition
      to the established right hemisphere dominance of the brain areas that direct
      attention, the consequences of directed attention may also be asymmetrical.

PMID- 12417473
TI  - Language acquisition in special populations: a comparison between Down and
      Williams syndromes.
AB  - To investigate the relationship between language acquisition and cognition, we
      evaluated linguistic abilities in 12 Italian-speaking children with Williams
      syndrome (WS) and 12 with Down syndrome (DS) of comparable global cognitive
      level. Another control group included 12 typically developing (TD) children,
      matched for mental age. Linguistic measures included a parent questionnaire to
      assess vocabulary, a verbal comprehension test, a sentence repetition test and
      MLU calculated on spontaneous production. No dissociation was evident between
      lexical and cognitive abilities, but specific morphosyntactic difficulties
      emerged both in comprehension and production in children with DS. Individuals
      with WS, albeit less compromised than DS, also had difficulty in the phrase
      repetition task and, particularly, using content words. Our results demonstrate
      that the linguistic abilities of infants with WS are not above their cognitive
      level and that language development in these special populations is not only
      delayed, but follows a different developmental trajectory.

PMID- 12417474
TI  - A lesion of the posterior parietal cortex disrupts on-line adjustments during
      aiming movements.
AB  - It is long known that the posterior parietal cortex (PPC) is critically involved
      in goal-directed movements. Nevertheless, there are still some controversies
      about its specific functions. Although most published studies have emphasised the
      role of PPC in sensorimotor planning processes, it has been recently suggested
      that PPC can also participate to on-line movement control. We studied kinematics
      of hand movements in a patient with a bilateral PPC lesion who exhibited no
      deficit in planning of her grasping movements in central vision. She was
      instructed to reach and grasp a cylinder presented at different locations and her
      motor performance was compared to that of four healthy control subjects. To
      address on-line control specifically, the cylinder was quickly and unexpectedly
      jumped, on a few trials, at movement onset, to a new location some 10 degrees (of
      apparent visual angle) from the original location. The patient could easily grasp
      stationary objects seen in foveal vision, exhibiting the same kinematic pattern
      as controls. Therefore, she could plan movements accurately. In response to the
      object jump, unlike the controls, the patient was unable to amend her ongoing
      movement. In this situation, she completed two distinct movements, a first one
      toward the initial object location and a second one toward the final object
      location. These results support the hypothesis that beyond a role in movement
      planning, PPC plays a major role in the on-line control of reach-to-grasp
      movements.

PMID- 12417475
TI  - The health impacts of exposure to indoor air pollution from solid fuels in
      developing countries: knowledge, gaps, and data needs.
AB  - Globally, almost 3 billion people rely on biomass (wood, charcoal, crop residues,
      and dung) and coal as their primary source of domestic energy. Exposure to indoor
      air pollution (IAP) from the combustion of solid fuels is an important cause of
      morbidity and mortality in developing countries. In this paper, we review the
      current knowledge on the relationship between IAP exposure and disease and on
      interventions for reducing exposure and disease. We take an environmental health
      perspective and consider the details of both exposure and health effects that are
      needed for successful intervention strategies. We also identify knowledge gaps
      and detailed research questions that are essential in successful design and
      dissemination of preventive measures and policies. In addition to specific
      research recommendations, we conclude that given the interaction of housing,
      household energy, and day-to-day household activities in determining exposure to
      indoor smoke, research and development of effective interventions can benefit
      tremendously from integration of methods and analysis tools from a range of
      disciplines in the physical, social, and health sciences.

PMID- 12417476
TI  - Daily average exposures to respirable particulate matter from combustion of
      biomass fuels in rural households of southern India.
AB  - Indoor air pollution resulting from combustion of biomass fuels in rural
      households of developing countries is now recognized as a major contributor to
      the global burden of disease. Accurate estimation of health risks has been
      hampered by a paucity of quantitative exposure information. In this study we
      quantified exposures to respirable particulate matter from biomass-fuel
      combustion in 436 rural homes selected through stratified random sampling from
      four districts of Tamil Nadu, India. The study households are a subset of a
      larger sample of 5,028 households from the same districts in which socioeconomic
      and health information has been collected. Results of measurements for personal
      exposures to respirable particulate matter during cooking were reported earlier.
      This has been extended to calculation of 24-hr exposures with the aid of
      additional measurements during noncooking times and the collection of time
      activity records. Concentrations of respirable particulate matter ranged from 500
      to 2,000 micro g/m(3) during cooking in biomass-using households, and average 24
      hr exposures ranged from 90 +/- 21 micro g/m(3) for those not involved in cooking
      to 231 +/- 109 micro g/m(3) for those who cooked. The 24-hr exposures were around
      82 +/- 39 micro g/m(3) for those in households using clean fuels (with similar
      exposures across household subgroups). Fuel type, type and location of the
      kitchen, and the time spent near the kitchen while cooking were the most
      important determinants of exposure across these households among other parameters
      examined, including stove type, cooking duration, and smoke from neighborhood
      cooking. These estimates could be used to build a regional exposure database and
      facilitate health risk assessments.

PMID- 12417477
TI  - Cytogenetic monitoring in a population occupationally exposed to pesticides in
      Ecuador.
AB  - We analyzed the incidence of structural and numerical chromosomal aberrations
      (CAs) in workers of a plantation of flowers located in Quito, Ecuador, in South
      America. This study included 41 individuals occupationally exposed to 27
      pesticides, some of which are restricted in many countries and are classified as
      extremely toxic by the World Health Organization; among these are aldicarb and
      fenamiphos. The same number of individuals of the same age, sex, and geographic
      area were selected as controls. Workers exposed to these pesticides showed an
      increased frequency of CA compared with control group (20.59% vs. 2.73%; p <
      0.001). We conclude that screening for CA is an adequate biomarker for evaluating
      and detecting genotoxicity resulting from exposure to pesticides. Levels of
      erythrocyte acetylcholinesterase were also determined as a complementary
      metabolic study. Levels below the optimal (> 28 U/mL blood) were found in 88% of
      exposed individuals; this clearly shows the effect of organophosphate pesticides.
      When comparing the levels of acetylcholinesterase and structural CA frequencies,
      there was a negative linear correlation (r = 0.416; p < 0.01). We conclude that
      by using both analyses it may be possible to estimate damage produced by exposure
      to organophosphate pesticides.

PMID- 12417478
TI  - Developmental toxicity of a commercial herbicide mixture in mice: I. Effects on
      embryo implantation and litter size.
AB  - We investigated the developmental toxicity in mice of a common commercial
      formulation of herbicide containing a mixture of 2,4-dichlorophenoxyacetic acid
      (2,4-D), mecoprop, dicamba, and inactive ingredients. Pregnant mice were exposed
      to one of four different doses of the herbicide mixture diluted in their drinking
      water, either during preimplantation and organogenesis or only during
      organogenesis. Litter size, birth weight, and crown-rump length were determined
      at birth, and pups were allowed to lactate and grow without additional herbicide
      exposure so that they could be subjected to additional immune, endocrine, and
      behavioral studies, the results of which will be reported in a separate article.
      At weaning, dams were sacrificed, and the number of implantation sites was
      determined. The data, although apparently influenced by season, showed an
      inverted or U-shaped dose-response pattern for reduced litter size, with the low
      end of the dose range producing the greatest decrease in the number of live pups
      born. The decrease in litter size was associated with a decrease in the number of
      implantation sites, but only at very low and low environmentally relevant doses.
      Fetotoxicity, as evidenced by a decrease in weight and crown-rump length of the
      newborn pups or embryo resorption, was not significantly different in the
      herbicide-treated litters.

PMID- 12417479
TI  - Analysis of the biological and chemical reactivity of zeolite-based
      aluminosilicate fibers and particulates.
AB  - Environmental and/or occupational exposure to minerals, metals, and fibers can
      cause lung diseases that may develop years after exposure to the agents. The
      presence of toxic fibers such as asbestos in the environment plus the continuing
      development of new mineral or vitreous fibers requires a better understanding of
      the specific physical and chemical features of fibers/particles responsible for
      bioactivity. Toward that goal, we have tested aluminosilicate zeolites to
      establish biological and chemical structure-function correlations. Zeolites have
      known crystal structure, are subject to experimental manipulation, and can be
      synthesized and controlled to produce particles of selected size and shape.
      Naturally occurring zeolites include forms whose biological activity is reported
      to range from highly pathogenic (erionite) to essentially benign (mordenite).
      Thus, we used naturally occurring erionite and mordenite as well as an
      extensively studied synthetic zeolite based on faujasite (zeolite Y). Bioactivity
      was evaluated using lung macrophages of rat origin (cell line NR8383). Our
      objective was to quantitatively determine the biological response upon
      interaction of the test particulates/fibers with lung macrophages and to evaluate
      the efficacy of surface iron on the zeolites to promote the Fenton reaction. The
      biological assessment included measurement of the reactive oxygen species by flow
      cytometry and chemiluminescence techniques upon phagocytosis of the minerals. The
      chemical assessment included measuring the hydroxyl radicals generated from
      hydrogen peroxide by iron bound to the zeolite particles and fibers (Fenton
      reaction). Chromatography as well as absorption spectroscopy were used to
      quantitate the hydroxyl radicals. We found that upon exposure to the same mass of
      a specific type of particulate, the oxidative burst increased with decreasing
      particle size, but remained relatively independent of zeolite composition. On the
      other hand, the Fenton reaction depended on the type of zeolite, suggesting that
      the surface structure of the zeolite plays an important role.

PMID- 12417480
TI  - Developmental neurotoxicity of chlorpyrifos: what is the vulnerable period?
AB  - Previously, we found that exposure of neonatal rats to chlorpyrifos (CPF)
      produced brain cell damage and loss, with resultant abnormalities of synaptic
      development. We used the same biomarkers to examine prenatal CPF treatment so as
      to define the critical period of vulnerability. One group of pregnant rats
      received CPF (subcutaneous injections in dimethyl sulfoxide vehicle) on
      gestational days (GD) 17-20, a peak period of neurogenesis; a second group was
      treated on GD9-12, the period of neural tube formation. In the GD17-20 group, the
      threshold for a reduction in maternal weight gain was 5 mg/kg/day; at or below
      that dose, there was no evidence (GD21) of general fetotoxicity as assessed by
      the number of fetuses or fetal body and tissue weights. Above the threshold,
      there was brain sparing (reduced body weight with an increase in brain/body
      weight ratio) and a targeting of the liver (reduced liver/body weight). Indices
      of cell packing density (DNA per gram of tissue) and cell number (DNA content)
      similarly showed effects only on the liver; however, there were significant
      changes in the protein/DNA ratio, an index of cell size, in fetal brain regions
      at doses as low as 1 mg/kg, below the threshold for inhibition of fetal brain
      cholinesterase (2 mg/kg). Indices of cholinergic synaptic development showed
      significant CPF-induced defects but only at doses above the threshold for
      cholinesterase inhibition. With earlier CPF treatment (GD9-12), there was no
      evidence of general fetotoxicity or alterations of brain cell development at
      doses up to the threshold for maternal toxicity (5 mg/kg), assessed on GD17 and
      GD21; however, augmentation of cholinergic synaptic markers was detected at doses
      as low as 1 mg/kg. Compared with previous work on postnatal CPF exposure, the
      effects seen here required doses closer to the threshold for fetal weight loss;
      this implies a lower vulnerability in the fetal compared with the neonatal brain.
      Although delayed neurotoxic effects of prenatal CPF may emerge subsequently in
      development, our results are consistent with the preferential targeting of late
      developmental events such as gliogenesis, axonogenesis, and synaptogenesis.

PMID- 12417481
TI  - Alteration of pulmonary immunity to Listeria monocytogenes by diesel exhaust
      particles (DEPs). I. Effects of DEPs on early pulmonary responses.
AB  - It has been hypothesized that diesel exhaust particles (DEPs) aggravate pulmonary
      bacterial infection by both innate and cell-mediated immune mechanisms. To test
      this hypothesis, we investigated the effects of DEP exposure on the functions of
      alveolar macrophages (AMs) and lymphocytes from lung-draining lymph nodes using a
      rat Listeria monocytogenes infection model. In the present study, we focused on
      the effects of DEP exposure on AM functions, including phagocytic activity and
      secretion of proinflammatory cytokines. The Listeria infection model was
      characterized by an increase in neutrophil count, albumin content, and acellular
      lactate dehydrogenase activity in the bronchoalveolar lavage (BAL) fluid at 3 and
      7 days postinfection. Short-term DEP inhalation (50 and 100 mg/m(3), 4 hr)
      resulted in a dose-dependent suppression of lung clearance of Listeria, with the
      highest bacteria count occurring at day 3. This aggravated bacterial infection
      was consistent with the inhibitory effect of DEPs on macrophage functions. DEPs
      suppressed phagocytosis and Listeria-induced basal secretion of interleukin-1ss
      (IL-1ss) and IL-12 by AMs in a dose-dependent manner. The amount of IL-1ss and IL
      12 in the BAL fluid was also reduced by DEP exposure. In addition, DEPs decreased
      Listeria-induced lipopolysaccharide-stimulated secretion of tumor necrosis factor
      alpha (TNF-alpha), IL-1ss, and IL-12 from AMs. These results suggest that DEPs
      retard bacterial clearance by inhibiting AM phagocytosis and weaken the innate
      immunity by inhibiting AM secretion of IL-1ss and TNF-alpha. DEPs may also
      suppress cell-mediated immunity by inhibiting AM secretion of IL-12, a key
      cytokine for the initiation of T helper type 1 cell development in Listeria
      infection.

PMID- 12417482
TI  - Polychlorinated biphenyls alter extraneuronal but not tissue dopamine
      concentrations in adult rat striatum: an in vivo microdialysis study.
AB  - Polychlorinated biphenyls (PCBs) reduce tissue dopamine (DA) concentrations and
      increase media DA concentrations in both in vitro preparations of bovine adrenal
      chromaffin cells and adult rat striatal tissue. To determine whether these
      changes also occur in the intact animal, we used in vivo microdialysis to
      determine changes in concentrations of DA in striatal dialysates from freely
      moving adult male rats after exposure to 25 mg/kg/day Aroclor 1254 for varying
      periods of time. We also determined DA concentrations in striatal tissue obtained
      postmortem from similarly treated animals. The effects of PCBs on dialysate DA
      concentrations depended on the length of exposure; DA concentrations were
      significantly elevated after 3 days of exposure and were significantly reduced
      after exposure for periods of 1 week or longer. On the other hand, striatal
      tissue concentrations of DA, determined postmortem in rats exposed to PCBs for
      the same periods of time, were not significantly altered. We suggest that these
      time-dependent alterations in dialysate DA concentrations a) reflect PCB-induced
      alterations of both plasma membrane and vesicular DA transporter function; b)
      provide a more sensitive index of altered central DA function after exposure to
      PCBs than does measurement of postmortem tissue DA concentrations; and c) play an
      important role in mediating some PCB-mediated changes in behavior.

PMID- 12417484
TI  - Effect of ozonation on the removal of cyanobacterial toxins during drinking water
      treatment.
AB  - Water treatment plants faced with toxic cyanobacteria have to be able to remove
      cyanotoxins from raw water. In this study we investigated the efficacy of
      ozonation coupled with various filtration steps under different cyanobacterial
      bloom conditions. Cyanobacteria were ozonated in a laboratory-scale batch reactor
      modeled on a system used by a modern waterworks, with subsequent activated carbon
      and sand filtration steps. The presence of cyanobacterial toxins (microcystins)
      was determined using the protein phosphatase inhibition assay. We found that
      ozone concentrations of at least 1.5 mg/L were required to provide enough
      oxidation potential to destroy the toxin present in 5 X 10(5 )Microcystis
      aeruginosa cells/mL [total organic carbon (TOC), 1.56 mg/L]. High raw water TOC
      was shown to reduce the efficiency of free toxin oxidation and destruction. In
      addition, ozonation of raw waters containing high cyanobacteria cell densities
      will result in cell lysis and liberation of intracellular toxins. Thus, we
      emphasize that only regular and simultaneous monitoring of TOC/dissolved organic
      carbon and cyanobacterial cell densities, in conjunction with online residual
      O(3) concentration determination and efficient filtration steps, can ensure the
      provision of safe drinking water from surface waters contaminated with toxic
      cyanobacterial blooms.

PMID- 12417483
TI  - Mycobacterium terrae isolated from indoor air of a moisture-damaged building
      induces sustained biphasic inflammatory response in mouse lungs.
AB  - Occupants in moisture-damaged buildings suffer frequently from respiratory
      symptoms. This may be partly due to the presence of abnormal microbial growth or
      the altered microbial flora in the damaged buildings. However, the specific
      effects of the microbes on respiratory health and the way they provoke clinical
      manifestations are poorly understood. In the present study, we exposed mice via
      intratracheal instillation to a single dose of Mycobacterium terrae isolated from
      the indoor air of a moisture-damaged building (1 X 10(7), 5 X 10(7), or 1 X 10(8)
      microbes). Inflammation and toxicity in lungs were evaluated 2 hr later. The time
      course of the effects was assessed with the dose of 1 X 10(8) bacterial cells for
      up to 28 days. M. terrae caused a sustained biphasic inflammation in mouse lungs.
      The characteristic features for the first phase, which lasted from 6 hr to 3
      days, were elevated proinflammatory cytokine [i.e., tumor necrosis factor alpha
      (TNF-alpha) and interleukin-6 (IL-6)] levels in the bronchoalveolar lavage fluid
      (BALF). TNF-alpha was produced in the lungs more intensively than was IL-6.
      Neutrophils were the most abundant cells in the airways during the first phase,
      although their numbers in BALF remained elevated up to 21 days. The
      characteristics of the second phase, which lasted from 7 to 28 days, were
      elevated TNF-alpha levels in BALF, expression of inducible nitric oxide synthase
      in BAL cells, and recruitment of mononuclear cells such as lymphocytes and
      macrophages into the airways. Moreover, total protein, albumin, and lactate
      dehydrogenase concentrations were elevated in both phases in BALF. The bacteria
      were detected in lungs up to 28 days. In summary, these observations indicate
      that M. terrae is capable of provoking a sustained, biphasic inflammation in
      mouse lungs and can cause a moderate degree of cytotoxicity. Thus, M. terrae can
      be considered a species with potential to adversely affect the health of the
      occupants of moisture-damaged buildings.

PMID- 12417485
TI  - Indicator-based assessment of environmental hazards and health effects in the
      industrial cities of upper Silesia, Poland.
AB  - Using an indicator-based approach, we assessed environmental hazards and related
      health effects in populations of industrial cities with more than 100,000
      inhabitants in Upper Silesia, Poland, and analyzed the relationship between
      environment and health. We adopted the method developed by Dutkiewicz et al. for
      assessing large geographic areas. Based on routinely collected environmental and
      health data, two groups of indicators, environmental indicators (EIs) and health
      status indicators (HSIs), related to environmental contamination were selected.
      The EI and HSI values were normalized and aggregated into synthetic measures
      using Strahl's taxonometric method. The synthetic measures indicated the
      intensity of environmental hazards and health outcomes. We used a three-level
      index scale to compare and rank the cities under the study and, consequently, to
      facilitate decision making. Findings of the assessment identified cities where
      actions aimed at reducing environmental hazards and improving population health
      status should be established as priorities. These cities included Chorzow,
      Katowice, Sosnowiec, Bytom, and Zabrze. We found a high correlation between the
      synthetic measures of environmental indicators and the synthetic measure of
      health status indicators (r = 0.77), as well as a high level of consistency
      between environmental hazard indices and environmental-related health status
      indices (73%). This may indicate the existence of a causal relationship between
      the environmental contamination within industrial cities and the health status of
      their inhabitants.

PMID- 12417486
TI  - Exposures to the Kuwait oil fires and their association with asthma and
      bronchitis among gulf war veterans.
AB  - Military personnel deployed to the Persian Gulf War have reported a variety of
      symptoms attributed to their exposures. We examined relationships between
      symptoms of respiratory illness present 5 years after the war and both self
      reported and modeled exposures to oil-fire smoke that occurred during deployment.
      Exposure and symptom information was obtained by structured telephone interview
      in a population-based sample of 1,560 veterans who served in the Gulf War.
      Modeled exposures were exhaustively developed using a geographic information
      system to integrate spatial and temporal records of smoke concentrations with
      troop movements ascertained from global positioning systems records. For the oil
      fire period, there were 600,000 modeled data points with solar absorbance used to
      represent smoke concentrations to a 15-km resolution. Outcomes included
      respiratory symptoms (asthma, bronchitis) and control outcomes (major depression,
      injury). Approximately 94% of the study cohort were still in the gulf theater
      during the time of the oil-well fires, and 21% remained there more than 100 days
      during the fires. There was modest correlation between self-reported and modeled
      exposures (r = 0.48, p < 0.05). Odds ratios for asthma, bronchitis, and major
      depression increased with increasing self-reported exposure. In contrast, there
      was no association between the modeled exposure and any of the outcomes. These
      findings do not support speculation that exposures to oil-fire smoke caused
      respiratory symptoms among veterans.

PMID- 12417487
TI  - The concentrations of arsenic and other toxic elements in Bangladesh's drinking
      water.
AB  - For drinking water, the people of Bangladesh used to rely on surface water, which
      was often contaminated with bacteria causing diarrhea, cholera, typhoid, and
      other life-threatening diseases. To reduce the incidences of these diseases,
      millions of tubewells were installed in Bangladesh since independence in 1971.
      This recent transition from surface water to groundwater has significantly
      reduced deaths from waterborne pathogens; however, new evidence suggests disease
      and death from arsenic (As) and other toxic elements in groundwater are affecting
      large areas of Bangladesh. In this evaluation, the areal and vertical
      distribution of As and 29 other inorganic chemicals in groundwater were
      determined throughout Bangladesh. This study of 30 analytes per sample and 112
      samples suggests that the most significant health risk from drinking Bangladesh's
      tubewell water is chronic As poisoning. The As concentration ranged from < 0.0007
      to 0.64 mg/L, with 48% of samples above the 0.01 mg/L World Health Organization
      drinking water guideline. Furthermore, this study reveals unsafe levels of
      manganese (Mn), lead (Pb), nickel (Ni), and chromium (Cr). Our survey also
      suggests that groundwater with unsafe levels of As, Mn, Pb, Ni, and Cr may extend
      beyond Bangladesh's border into the four adjacent and densely populated states in
      India. In addition to the health risks from individual toxins, possible
      multimetal synergistic and inhibitory effects are discussed. Antimony was
      detected in 98% of the samples from this study and magnifies the toxic effects of
      As. In contrast, Se and Zn were below our detection limits in large parts of
      Bangladesh and prevent the toxic effects of As.

PMID- 12417489
TI  - International expert workshop on the analysis of the economic and public health
      impacts of air pollution: workshop summary.
AB  - Forty-nine experts from 18 industrial and developing countries met on 6 September
      2001 in Garmisch-Partenkirchen, Germany, to discuss the economic and public
      health impacts of air pollution, particularly with respect to assessing the
      public health benefits from technologies and policies that reduce greenhouse gas
      (GHG) emissions. Such measures would provide immediate public health benefits,
      such as reduced premature mortality and chronic morbidity, through improved local
      air quality. These mitigation strategies also allow long-term goals--for example,
      reducing the buildup of GHG emissions--to be achieved alongside short-term aims,
      such as immediate improvements in air quality, and therefore benefits to public
      health. The workshop aimed to foster research partnerships by improving
      collaboration and communication among various agencies and researchers; providing
      a forum for presentations by sponsoring agencies and researchers regarding
      research efforts and agency activities; identifying key issues, knowledge gaps,
      methodological shortcomings, and research needs; and recommending activities and
      initiatives for research, collaboration, and communication. This workshop summary
      briefly describes presentations made by workshop participants and the conclusions
      of three separate working groups: economics, benefits transfer, and policy;
      indoor air quality issues and susceptible populations; and development and
      transfer of dose-response relationships and exposure models in developing
      countries. Several common themes emerged from the working group sessions and
      subsequent discussion. Key recommendations include the need for improved
      communication and extended collaboration, guidance and support for researchers,
      advances in methods, and resource support for data collection, assessment, and
      research.

PMID- 12417488
TI  - The origin, fate, and health effects of combustion by-products: a research
      framework.
AB  - Incomplete combustion processes can emit organic pollutants, metals, and fine
      particles. Combustion by-products represent global human and environmental health
      challenges that are relevant not only in heavily industrialized nations, but also
      in developing nations where up to 90% of rural households rely on unprocessed
      biomass fuels for cooking, warmth, and light. These issues were addressed at the
      Seventh International Congress on Combustion By-Products, which convened 4-6 June
      2001 in Research Triangle Park, North Carolina. This congress included a diverse
      group of multidisciplinary researchers and practitioners who discussed recent
      developments and future goals in the control of combustion by-products and their
      effects of exposure on human and ecologic health. Participants recommended that
      interdisciplinary, coordinated research efforts should be focused to capitalize
      on the important potential synergisms between efforts to reduce the adverse human
      health effects linked to exposures to combustion by-products and broader efforts
      to reduce greenhouse gas emissions and save energy through efficiency. In this
      article we summarize the principal findings and recommendations for research
      focus and direction.

PMID- 12417490
TI  - Enviromental health and the coastal zone.

PMID- 12417491
TI  - The lack of environmental justice in Central and Eastern Europe.

PMID- 12417492
TI  - Diving deeper into the Pfiesteria mystery.

PMID- 12417493
TI  - Buildings awareness of the built environment.

PMID- 12417494
TI  - Coastal cities: living on the edge.

PMID- 12417495
TI  - The down-to-earth summit -- lessening our ecological footprint.

PMID- 12417496
TI  - Pooling data on coastal zones.

PMID- 12417497
TI  - Mite and pet allergen levels in homes of children born to allergic and
      nonallergic parents: the PIAMA study.
AB  - The Prevention and Incidence of Asthma and Mite Allergy (PIAMA) study is a birth
      cohort study that investigates the influence of allergen exposure on the
      development of allergy and asthma in the first several years of life. The
      objectives of this study were to investigate the relationship between a family
      history of allergy and/or asthma and exposure of newborn children to mite and pet
      allergen and to study the influence of different home and occupant
      characteristics on mite allergen exposure. Dust was sampled from the child's
      mattress and the parental mattress at 3 months after birth of the index child and
      analyzed for mite and pet allergens. Subjects were divided in groups according to
      history of asthma and allergy in their parents, and allergen exposure was studied
      in the different groups. Cat allergen exposure was significantly lower on
      parental mattresses in families with allergic mothers, but dog allergen exposure
      was not different. Mite allergen exposure was lower on parental mattresses in
      families with allergic mothers. Use of mite allergen-impermeable mattress covers
      reduced mite allergen exposure. Some other characteristics such as age of home
      and mattress were also found to influence mite allergen exposure. Parental
      mattresses in homes of allergic mothers had lower cat and mite (but not dog)
      allergen loadings than mattresses in homes of nonallergic parents. Paternal (as
      opposed to maternal) allergy seemed to have little influence.

PMID- 12417498
TI  - Sex ratios of children of Russian pesticide producers exposed to dioxin.
AB  - We investigated the sex ratio of children of pesticide workers who produced the
      biocide trichlorophenol and the herbicide 2,4,5-trichlorophenoxy acetic acid from
      1961 to 1988 in the city of Ufa, Bashkortostan, Russia. We measured exposure of
      the two related cohorts to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and other
      dioxins by analyzing 84 blood samples, which produced median TCDD toxic
      equivalents blood lipid values of 240 ng/kg, which are more than 30 times higher
      than background or normal exposure from the region. The sex ratio (fraction male)
      of the combined cohort of 227 children from 150 male and 48 female workers was
      0.40, significantly lower (z-test for proportions = 3.21; p < 0.001) than those
      for the city of Ufa (0.512) and elsewhere worldwide. When we analyzed the sex
      ratio of the children according to maternal or paternal exposure, we observed a
      decrease in the number of boys (ratio 0.38) for fathers and a normal number
      (ratio 0.51) for the mothers. Human exposure of these pesticide producers to high
      levels of dioxins is associated with the birth of more girls, but only for
      paternal exposures.

PMID- 12417499
TI  - Parent bisphenol A accumulation in the human maternal-fetal-placental unit.
AB  - Bisphenol A (BPA), an endocrine disruptor, is employed in the manufacture of a
      wide range of consumer products. The suggestion that BPA, at amounts to which we
      are exposed, alters the reproductive organs of developing rodents has caused
      concern. At present, no information exists concerning the exposure of human
      pregnant women and their fetuses to BPA. We therefore investigated blood samples
      from mothers (n = 37) between weeks 32 and 41 of gestation. Afer the births, we
      also analyzed placental tissue and umbilical cord blood from the same subjects.
      We developed a novel chemical derivatization-gas chromatography/mass spectrometry
      method to analyze parent BPA at concentrations < 1 micro g/mL in plasma and
      tissues. Concentrations of BPA ranged from 0.3 to 18.9 ng/mL (median = 3.1 ng/mL)
      in maternal plasma, from 0.2 to 9.2 ng/mL (median = 2.3 ng/mL) in fetal plasma,
      and from 1.0 to 104.9 ng/g (median = 12.7 ng/g) in placental tissue. BPA blood
      concentrations were higher in male than in female fetuses. Here we demonstrate
      parent BPA in pregnant women and their fetuses. Exposure levels of parent BPA
      were found within a range typical of those used in recent animal studies and were
      shown to be toxic to reproductive organs of male and female offspring. We suggest
      that the range of BPA concentrations we measured may be related to sex
      differences in metabolization of parent BPA or variable maternal use of consumer
      products leaching BPA.

PMID- 12417500
TI  - Vulvar lymphatic mapping: coming of age?

PMID- 12417501
TI  - Raising the bar for pancreaticoduodenectomy.

PMID- 12417502
TI  - Quality of surgery determinant for the outcome of patient with gastric cancer.

PMID- 12417503
TI  - The GIST of targeted cancer therapy: a tumor (gastrointestinal stromal tumor), a
      mutated gene (c-kit), and a molecular inhibitor (STI571).
AB  - Although gastrointestinal stromal tumor (GIST) is the most frequent mesenchymal
      neoplasm of the gastrointestinal tract, until recently it has been an obscure
      disease. Now, there is widespread scientific and clinical interest in GIST
      because its principal pathogenetic defect has been identified and a specific
      molecular inhibitor of GIST has been developed. Most GISTs contain a gain-of
      function mutation in the c-kit proto-oncogene. Mutation results in constitutive
      activation of the Kit receptor tyrosine kinase, which induces cellular
      proliferation. STI571 is an oral agent that selectively inhibits Kit. It is a
      landmark development in cancer treatment and marks a new era of targeted
      molecular therapy. Its efficacy proves that a specific inhibitor can counteract
      the effects of a genetic defect responsible for neoplasia. Although STI571 was
      first applied to GIST only 2 years ago, it has already revolutionized the
      treatment of patients with metastatic disease and is also currently being tested
      as an adjuvant therapy after the resection of primary GIST.

PMID- 12417504
TI  - Sentinel node biopsy in vulvar and vaginal melanoma: presentation of six cases
      and a literature review.
AB  - BACKGROUND: Urogenital melanoma is a rare neoplasm with poor prognosis. Its
      management in the past involved radical vulvectomy and complete bilateral
      inguinofemoral lymphadenectomy. Sentinel lymph node biopsy is an accurate low
      morbidity procedure when used in the context of cutaneous melanoma. However,
      prophylactic lymphadenectomy has not been shown to improve survival of melanoma
      patients. We wanted to determine the feasibility of sentinel lymph node biopsy in
      patients with female urogenital melanoma as a staging procedure. METHODS: Six
      patients with vulvar or vaginal melanomas underwent preoperative lymphatic
      mapping with (99m)Tc-labeled sulfur colloid followed by sentinel lymphadenectomy.
      In addition, we reviewed the literature on the application of sentinel lymph node
      biopsy in urogenital tract melanomas. RESULTS: One or more sentinel nodes were
      identified in all six patients by lymphoscintigraphy. All patients underwent
      sentinel lymphadenectomy, except for one patient with a deep vaginal melanoma
      that drained to pelvic nodes. The five successful cases had unilateral drainage
      patterns. None of the sentinel lymph nodes excised had tumor invasion. Combined
      with five other patients from the published literature, the success rate of
      localizing sentinel lymph nodes in the patients with urogenital melanoma
      approaches 100%. CONCLUSIONS: This experience, plus reports of a small number of
      patients from three similar studies, supports the impression that sentinel lymph
      node biopsy is feasible for vulvar and vaginal melanoma.

PMID- 12417505
TI  - National estimates of mortality rates for radical pancreaticoduodenectomy in
      25,000 patients.
AB  - BACKGROUND: Recent publications suggest an inverse relationship between mortality
      rates in the Whipple procedure for periampullary cancer and hospital
      volume/teaching status. METHODS: The Nationwide Inpatient Sample database from
      1988 to 1995, containing 24926 patients undergoing pancreatectomy for
      periampullary cancer, was used. RESULTS: The mean number of procedures per
      hospital per year was 1.5, and the overall mortality was 14%. The volume of
      procedures per year increased from the rural to the urban nonteaching hospitals
      to the urban teaching hospitals (.6, 1.1, and 2.7, respectively), with a steady
      decrease in mortality among the three hospital types (18%, 15%, and 11%). A
      multiple logistic regression model with mortality odds ratios (ORs) showed that
      male sex (OR, 1.3), increasing age (OR, 1.6 to 6.7 in decades from 50 to > or=80
      vs. <50 years), emergency admission (OR, 1.5), and hospital volume (less than one
      vs. one or more cases per year; OR, 1.5) were significantly predictive for
      increased in-hospital mortality. CONCLUSIONS: In-hospital mortality in the low
      volume hospital setting is prohibitive, and review of each institution's
      mortality rates must occur before these procedures are performed in those
      institutions. In addition, patients over the age of 60 years, male patients, and
      those with an urgent admission are at a significant risk of in-hospital death,
      and consideration should be given toward transfer to an experienced institution.

PMID- 12417506
TI  - Predictive factors associated with long-term survival in patients with
      neuroendocrine tumors of the pancreas.
AB  - BACKGROUND: Neuroendocrine tumors of the pancreas are rare tumors. We identified
      predictive factors that are associated with long-term survival (> or=5 years).
      METHODS: Fifty patients with a diagnosis of neuroendocrine tumors of the pancreas
      were retrospectively evaluated. The following factors were evaluated for disease
      specific mortality: age, sex, primary tumor location, functional status, type of
      primary tumor treatment, presence or absence of liver metastases, timing of liver
      metastases occurrence, and type of liver metastases treatment. Aggressive
      treatment of the liver metastases included surgery, chemoembolization, or
      intrahepatic arterial infusion chemotherapy. RESULTS: Twenty-three patients (47%)
      had tumor located in the head of the pancreas, and 29 patients (58%) had
      nonfunctioning tumor. Thirty-nine patients (78%) had liver metastases. The median
      follow-up for the entire group was 35 months (range,.76-206 months). The median
      survival for the entire group was 40 months, and the overall 1-, 2-, and 5-year
      survival rates were 84%, 69%, and 36%, respectively. Factors that had a
      significant favorable effect on survival included curative resection of the
      primary tumor, metachronous liver metastases, absence of liver metastases, and
      aggressive treatment of the liver metastases. CONCLUSIONS: Definitive surgical
      resection of the primary tumor, absence of liver metastases, metachronous liver
      metastases, and aggressive treatment of the liver metastases were predictors of
      long-term survival in patients with neuroendocrine tumors of the pancreas.

PMID- 12417507
TI  - Resection of peritoneal implantation from hepatocellular carcinoma.
AB  - BACKGROUND: Peritoneal implantation is a rare presentation of hepatocellular
      carcinoma (HCC). This article presents the clinical features and surgical
      outcomes of 16 patients with HCC in whom isolated peritoneal implantation from
      HCC was found and who underwent surgical resection. METHODS: From 1988 to 2000,
      16 patients with HCC after hepatic resection who underwent resection of
      peritoneal implantation of HCC were retrospectively reviewed. RESULTS: Four
      hundred sixty-five of 749 patients (62.1%) had recurrence of HCC after hepatic
      resection. Sixteen (3.4%) developed isolated peritoneal implantation and
      underwent resection. During the detection of the peritoneal implantation, the
      alfa fetoprotein level was increased in 13 of these 16 patients. Five of 15
      patients had a peritoneal mass discovered by ultrasonography, and 14 of 15
      patients had a mass discovered by computed tomography. The follow-up period
      ranged from 2.1 to 81.6 months (median, 16 months). The median disease-free and
      overall survivals of the 16 patients were 7.89 and 15.98 months, respectively.
      CONCLUSIONS: Peritoneal implantation occurs infrequently in posthepatectomy
      patients. Increased alfa fetoprotein values after hepatic resection should
      suggest recurrence of HCC. Computed tomography is superior to ultrasonography in
      detection of peritoneal implantation from HCC. Surgical resection of peritoneal
      implantation from HCC might prolong survival in selected patients.

PMID- 12417508
TI  - Periampullary pancreatic somatostatinoma.
AB  - BACKGROUND: Somatostatinomas involving the gastrointestinal tract are extremely
      rare neoplasms that typically present with indolent, nonspecific symptoms in the
      absence of systemic neuroendocrine manifestations that characterize the
      somatostatinoma syndrome. Because of a relatively large size at the time of
      presentation (average diameter of 5 cm) and common location within the head of
      the pancreas, the Whipple procedure (pancreaticoduodenectomy) serves as the
      predominant modality for curative and palliative surgical approaches. METHODS:
      Two cases of somatostatinoma involving the minor duodenal papilla with
      concomitant pancreatic divisum were reviewed, with a general overview of this
      unique islet cell tumor. RESULTS: Unlike typical somatostatinomas, these two
      tumors were subcentimeter in size but were associated with synchronous regional
      metastasis. CONCLUSIONS: Somatostatinomas are often associated with regional
      and/or portal metastases at the time of diagnosis, and only 60% to 70% of
      surgical cases result in complete tumor resection. Predictors of an unfavorable
      prognosis include size >3 cm, poor cytological differentiation, regional and/or
      portal metastasis, and incomplete surgical resection. Even in the presence of
      synchronous metastases, the 5-year overall survival for patients with
      somatostatinoma is approximately 40%. Currently, there are no clinical trials
      demonstrating significant improvement in survival with the use of adjuvant
      therapy.

PMID- 12417509
TI  - The management of variant arterial anatomy during hepatic arterial infusion pump
      placement.
AB  - BACKGROUND: The success of hepatic arterial infusion pump (HAIP) placement in
      patients with variant arterial anatomy has not been well described. METHODS:
      Patients who underwent HAIP placement over a 5-year time period were evaluated.
      Arterial- and catheter-related pump complication rates and pump survival were
      compared between patients with normal and variant arterial anatomy. RESULTS:
      Pumps were placed in 265 patients. Variant anatomy was present in 98 (37%)
      patients. The presence of variant versus normal anatomy did not increase pump
      complication rates (8% vs. 4%; P =.18) or decrease pump survival (P =.12). In all
      patients with an isolated variant right or left hepatic artery (n = 56), ligation
      of the variant vessel and cannulation of the gastroduodenal artery (GDA) resulted
      in complete hepatic perfusion and no pump complications. Cannulation of vessels
      other than the GDA (n = 22) was associated with increased pump complication rates
      (27% vs. 4%; P =.0001) and decreased pump survival (P =.002). CONCLUSIONS: In
      this study, HAIP placement in patients with variant anatomy was not associated
      with increased pump complication rates or decreased pump survival. An optimal
      strategy for managing variant anatomy is to ligate isolated variant vessels and
      cannulate the GDA.

PMID- 12417510
TI  - Comparison of hepatic resection and hepatic transplantation in the treatment of
      hepatocellular carcinoma among cirrhotic patients.
AB  - BACKGROUND: The benefits of hepatic transplantation (HT) compared with hepatic
      resection (HR) in treating hepatocellular carcinoma (HCC) in patients with
      cirrhosis are controversial. The aim of this study was to compare the results of
      these therapeutic options. METHODS: The charts of all patients with cirrhosis who
      underwent HR or HT for HCC between 1997 and 2000 were analyzed. RESULTS: The
      cohort included 44 patients who underwent HR compared with 65 with HT. All
      patients in the HR group had Child's A disease, in contrast to the HT group,
      which included 23% Child's A and 77% Child's B and C patients. Whereas all HT
      patients spent at least three nights in the intensive care unit, 41% of the HR
      group never required critical care. Perioperative mortality was 7% in both
      groups. Pathologic analysis revealed T1/T2 disease in 43% of the HR group
      compared with 75% of the HT group. After 36 months of follow-up, there was no
      significant difference in overall survival (57% vs. 66%) or disease-free survival
      (36% vs. 66%) between the two groups. CONCLUSIONS: With overall survival and
      disease-free survival as the main outcomes, the results of HR versus HT are
      comparable in Child's A patients with HCC. In this patient subset, HR not only is
      an effective form of therapy, but is also associated with quicker recovery.

PMID- 12417511
TI  - Correlation of MUC5AC immunoreactivity with histopathological subtypes and
      prognosis of gastric carcinoma.
AB  - BACKGROUND: MUC5AC represents a mucin peptide core expressed in normal gastric
      epithelia. Its presence in gastric carcinomas was previously described as a
      characteristic of gastric differentiation. METHODS: MUC5AC reactivity was
      investigated by immunohistochemistry and correlated with clinicopathological
      variables in a large series (n = 200) of gastric carcinomas. RESULTS: A
      statistically significant association between MUC5AC positivity and parameters of
      cancer progression (pTNM staging and grading) could not be observed. However,
      MUC5AC exhibited correlations with certain subtypes of histopathological
      differentiation. A significant reduction of MUC5AC expression was evident in
      mucinous and undifferentiated carcinomas according to the World Health
      Organization classification, as well as in type III cancers according to the
      Goseki classification system. Furthermore, reduced MUC5AC reactivity (confined to
      up to 35% of the tumor area) was significantly correlated with an unfavorable
      prognosis of all patients in univariate and multivariate analysis. The same
      association could be observed in the subgroup of pTNM stage I patients (n = 60).
      CONCLUSIONS: A significant reduction of gastric differentiation as reflected by
      MUC5AC immunoreactivity represents a marker of worse survival probability in
      gastric cancer. Finally, reduced MUC5AC positivity defines a high-risk subgroup
      of pTNM stage I patients.

PMID- 12417512
TI  - Survival benefit of extended D2 lymphadenectomy in gastric cancer with
      involvement of second level lymph nodes: a longitudinal multicenter study.
AB  - BACKGROUND: The survival benefit of extended lymphadenectomy in the surgical
      treatment of gastric cancer is still being debated. The aim of this longitudinal
      multicenter study was to evaluate long-term survival in a group of patients with
      involvement of second level lymph nodes, which would not have been removed in the
      case of a limited lymphadenectomy. Results were compared with those in patients
      with involvement of first level lymph nodes. METHODS: Between 1991 and 1997, 451
      patients with primary gastric cancer underwent curative resection with extended
      lymphadenectomy at three surgical departments in Italy according to the rules of
      the Japanese Research Society for Gastric Cancer. RESULTS: In 451 cases treated
      by extended lymphadenectomy, morbidity and mortality rates were 17.1% and 2%,
      respectively. In 126 patients (27.9%) (group A), metastases were found in lymph
      node stations 7 to 12; 109 patients (24.2%) had metastases confined to the first
      level (group B). Lymph node stations 7 and 8 showed the highest incidence of
      metastases in the second level (17.1% and 12.4%, respectively). A significant
      difference in 5-year survival was observed between group A and group B (32% vs.
      54%; P =.0005). This difference disappeared when cases were stratified according
      to the number of positive lymph nodes. By multivariate analysis, only the number
      of positive lymph nodes (relative risk, 1.8; P <.0001) and the depth of invasion
      (relative risk, 2.1; P <.0001), but not the level of involved nodes, showed to be
      independent predictors of poor prognosis. CONCLUSIONS: Japanese-type extended
      lymphadenectomy yields low morbidity and mortality rates if performed in
      specialized centers. This procedure could provide a good probability of long-term
      survival, even for patients with involvement of regional lymph nodes.

PMID- 12417513
TI  - Germline SMAD4 or BMPR1A mutations and phenotype of juvenile polyposis.
AB  - BACKGROUND: Juvenile polyposis (JP) is an inherited condition predisposing to
      upper gastrointestinal (UGI) polyps and colorectal cancer. Two genes are known to
      predispose to JP, SMAD4 and bone morphogenetic protein receptor type 1A (BMPR1A).
      The object of this study was to determine the differences in phenotype of
      patients with SMAD4 or BMPR1A mutations (MUT+) compared with those without (MUT
      ). METHODS: DNA was extracted from 54 JP probands and used for polymerase chain
      reaction of all exons of SMAD4 and BMPR1A. Products were then sequenced and
      analyzed for mutations. Medical record data were used to create a JP database,
      and statistical analysis was performed using Fisher's exact and unpaired t-tests.
      RESULTS: Nine of 54 patients had germline SMAD4 mutations, 13 had BMPR1A
      mutations, and 32 had neither. There were no significant differences between
      SMAD4+ and BMPR1A+ cases in terms of clinical factors examined, except for a
      family history of UGI involvement (P <.01). There was a higher prevalence of
      familial cases in MUT+ patients (P =.09), >10 lower gastrointestinal polyps (P
      =.06), and frequency of family history of gastrointestinal cancer compared with
      MUT- patients (P =.01). CONCLUSIONS: Patients with germline SMAD4 or BMPR1A
      mutations have a more prominent JP phenotype than those without, and SMAD4
      mutations predispose to UGI polyposis.

PMID- 12417514
TI  - Palliative thyroidectomy for malignant lymphoma of the thyroid.
AB  - BACKGROUND: Current treatment of malignant lymphoma of the thyroid consists of
      chemotherapy and external beam radiation. The diagnosis can routinely be made by
      fine-needle aspiration, obviating the need for surgery. However, a significant
      number of patients present with symptoms of obstruction, necessitating
      thyroidectomy for palliation. METHODS: To determine the outcomes of patients with
      malignant thyroid lymphoma after palliative thyroidectomy, we reviewed our
      experience. Between 1980 and 2001, 27 patients with thyroid lymphoma and symptoms
      or signs of airway and/or esophageal obstruction were evaluated at 1 of 3
      academic institutions. RESULTS: The mean age of the patients was 66 +/- 3 years,
      and the majority was female. Patients presented with symptoms of dyspnea/stridor
      (30%), dysphagia/pain (30%), or impending airway obstruction (40%). All underwent
      palliative surgery. In addition to surgery, 10 patients had combined chemo- and
      radiotherapy, 10 had radiotherapy alone, and 4 had only chemotherapy. Symptom
      free survival after palliative surgery was determined by Kaplan-Meier analysis.
      The mean actuarial symptom-free survival of patients with symptomatic, malignant
      thyroid lymphoma was 10 years (95% confidence interval, 7.67 to 12.33 years).
      CONCLUSIONS: Patients with malignant lymphoma of the thyroid can present with
      obstructive symptoms requiring palliative intervention. In this group of
      patients, thyroidectomy can be associated with good long-term palliation and low
      morbidity.

PMID- 12417515
TI  - Breast-conservation therapy in early-stage breast cancer patients with a positive
      family history.
AB  - BACKGROUND: Our goal was to evaluate the role of breast-conservation therapy in
      early-stage breast cancer patients with a family history (FH) of breast cancer.
      METHODS: Between 1970 and 1994, 1324 female patients with breast cancer were
      treated with breast-conservation therapy at our institution. From these, we
      identified 985 patients with stage 0-II breast cancer and who had available
      information on FH status. FH was considered positive in any patient who had a
      relative who had been previously diagnosed with breast cancer. Disease-specific
      survival was calculated from the date of initial diagnosis using the Kaplan-Meier
      method. RESULTS: The stage distribution for the 985 patients was as follows: 0 in
      65 (7%), I in 500 (51%), and II in 420 (43%). The median age was 50 years (range,
      21-88), with a median follow-up time of 8.8 years (range,.25-29). The median
      tumor size was 1.5 cm. FH was positive in 31%. There were no significant
      differences in locoregional recurrence, distant recurrence, disease-specific
      survival, or incidence of contralateral breast cancer in patients with a positive
      FH versus patients with a negative FH. CONCLUSIONS: Breast-conservation therapy
      is not contraindicated in early-stage breast cancer patients with a positive FH.

PMID- 12417516
TI  - Routine operative breast endoscopy for bloody nipple discharge.
AB  - BACKGROUND: Submillimeter endoscopes are now available and have been described to
      assist surgeons in the evaluation and management of symptomatic nipple discharge.
      METHODS: To evaluate its potential use, a microendoscope (0.9 mm Acueity) was
      used on all patients in a single surgeon's practice who were undergoing nipple
      exploration for spontaneous hemoccult positive nipple discharge. This procedure
      was performed at the surgical resection of the symptomatic retro-areolar duct,
      and 27 patients underwent the endoscopy during the period from January 2000 to
      August 2001. RESULTS: In 96% (26 of 27) of the patients, the endoscope was
      successfully introduced into the lactiferous sinus, and the proximal breast ducts
      were successfully visualized. A lesion accounting for the bleeding was seen in
      all 26 patients, with 70% (n = 19) having multiple intraluminal defects. Cancers
      were identified in two cases (7.4%), and in both cases, there was a more proximal
      papilloma in the same ductal system. Similarly, in 33% of the benign cases, both
      papillomas and usual or atypical ductal hyperplasia were present. Lesions were
      identified that extended up to 7.5 cm deep to the nipple. The deepest lesion was
      one of the endoscopically identified cancers in a patient with normal mammogram
      and breast ultrasound. Surgical resection could be directed by simple
      transillumination of the skin during endoscopy. CONCLUSIONS: This series
      demonstrates the clinical feasibility of routine operative breast endoscopy in
      the management of bloody nipple discharge. The high incidence of multiple lesion
      identification suggests that the classic blind resection of a limited distance of
      duct in the retroareolar space may significantly underestimate the true extent of
      proliferative disease accounting for pathologic nipple discharge.

PMID- 12417517
TI  - Stage migration after biopsy of internal mammary chain lymph nodes in breast
      cancer patients.
AB  - BACKGROUND: Involvement of the internal mammary chain lymph nodes (IMNs) is
      associated with worsened prognosis in breast cancer. Use of lymphoscintigraphy to
      visualize sentinel nodes reveals that IMNs often receive lymph from the area
      containing the tumor. METHODS: We biopsied IMNs in 182 patients because there was
      radiouptake to the IMNs or because the tumor was located in the medial portion of
      the breast. After tumor removal, pectoralis major fibers were divided to expose
      intercostal muscle. A portion of intercostal muscle adjacent to the sternum was
      removed. Lymph nodes and surrounding fatty tissue in the intercostal space were
      freed, removed, and analyzed histologically. The pleural cavity was breached in
      four cases (2.2%), with spontaneous resolution. RESULTS: IMNs were found in 160
      (88%) of 182 patients; 146 (94.4%) were negative and 14 (8.8%) were positive. The
      latter received internal mammary chain radiotherapy. The axilla was negative in 4
      of 14 cases and positive in 10. CONCLUSIONS: IMNs can be quickly and easily
      removed via the breast incision with insignificant risk and no increase in
      postoperative hospitalization. The patients with a positive IMN migrated from N0
      (4 cases) or N1 (10 cases) to N3, prompting modification of both local
      (radiotherapy to internal mammary chain) and systemic treatment; without IMN
      sampling, they would have been understaged.

PMID- 12417518
TI  - The definition of the sentinel lymph node in melanoma based on radioactive
      counts.
AB  - BACKGROUND: There is no consensus on the definition of a hot, nonblue sentinel
      lymph node (SLN), despite the widespread use of radiocolloid in SLN mapping.
      METHODS: A retrospective review of 592 patients with malignant melanoma who
      underwent SLN mapping was performed. Ex vivo SLN counts and nodal bed counts were
      obtained by using a gamma probe. The size of each metastatic deposit in an SLN
      was defined as macrometastases (>2 mm), micrometastases (< or =2 mm), a cluster
      of cells, or isolated melanoma cells. RESULTS: A total of 1175 SLNs (SLN(-), n =
      1041; SLN(+), n = 134) were evaluated. The mean SLN count/bed counts were SLN(-),
      322 +/- 980 and SLN(+), 450 +/- 910 (not significant [NS]) (>2 mm, 270 +/- 792
      [NS]; < or =2 mm, 446 +/- 693 [NS]; isolated melanoma cells/cluster of cells, 677
      +/- 1189 [P =.036]). Overall, 16 (1.4%) of the SLNs collected had an overall
      ratio of < or =2. This included two positive SLNs (1.5%), both of which contained
      macrometastatic disease. Forty-seven positive nodal basins had at least one
      negative SLN. The hottest SLNs in these basins were negative for metastatic
      disease in nine cases (19.1%). In one basin (2.1%), the positive SLN count was
      <10% of the hottest lymph node count. CONCLUSIONS: Removal of lymph nodes until
      the bed count is 10% of the hottest lymph node will remove 98% of positive SLNs.
      Lymph node tumor burden influences radioactive counts.

PMID- 12417520
TI  - Frequency of nonsentinel lymph node metastasis in melanoma.

PMID- 12417521
TI  - Identification of the coding sequences responsible for Tsc2-mediated tumor
      suppression using a transgenic rat system.
AB  - Hereditary renal carcinomas in the Eker rat are caused by germline
      retrotransposon insertion in the tuberous sclerosis-2 (Tsc2) gene. We established
      previously a transgenic Eker rat model into which was introduced a wild-type Tsc2
      gene. The embryonic lethality of mutant homozygotes and renal carcinogenesis of
      heterozygotes were completely suppressed by this transgene (Tg). The function of
      the Tsc2 product (tuberin) is not fully understood, although several findings
      have been obtained mainly in vitro. Therefore, to elucidate the functional
      domains of Tsc2 in vivo, we generated transgenic Eker rats carrying deletion
      mutants of the Tsc2 gene. A Tg coding for the C-terminal region (amino acids 1425
      1755) suppressed renal carcinogenesis in the Eker rat and interestingly the
      degree of this suppression correlated with the level of expression of the Tg.
      Notably, the product of this Tg lacks the ability to bind to the Tsc1 product
      (hamartin). Surprisingly, while a Tg lacking the C-terminus of tuberin (amino
      acids 1-1755) completely suppressed renal carcinogenesis, it partially rescued
      homozygous mutants from embryonic lethality. In conclusion, we have determined
      the minimal region of tuberin necessary for tumor suppression but the suppressive
      effect was quantitative. Tuberin could function as a tumor suppressor without
      binding to hamartin. The requirement of the functional domain(s) of tuberin might
      differ for prevention of embryonic lethality and for suppression of renal
      carcinogenesis.

PMID- 12417522
TI  - Trapping of messenger RNA by Fragile X Mental Retardation protein into
      cytoplasmic granules induces translation repression.
AB  - Absence of Fragile X Mental Retardation Protein (FMRP), an RNA-binding protein,
      is responsible for the Fragile X syndrome, the most common form of inherited
      mental retardation. FMRP is a cytoplasmic protein associated with mRNP complexes
      containing poly(A)+mRNA. As a step towards understanding FMRP function(s), we
      have established the immortal STEK Fmr1 KO cell line and showed by transfection
      assays with FMR1-expressing vectors that newly synthesized FMRP accumulates into
      cytoplasmic granules. These structures contain mRNAs and several other RNA
      binding proteins. The formation of these cytoplasmic granules is dependent on
      determinants located in the RGG domain. We also provide evidence that FMRP acts
      as a translation repressor following co-transfection with reporter genes. The
      FMRP-containing mRNPs are dynamic structures that oscillate between polyribosomes
      and cytoplasmic granules reminiscent of the Stress Granules that contain
      repressed mRNAs. We speculate that, in neurons, FMRP plays a role as a mRNA
      repressor in incompetent mRNP granules that have to be translocated from the cell
      body to distal locations such as dendritic spines and synaptosomes.

PMID- 12417523
TI  - Molecular mechanisms of autosomal recessive hypercholesterolemia.
AB  - Mutations in the phosphotyrosine-binding domain protein ARH cause autosomal
      recessive hypercholesterolemia (ARH), an inherited form of hypercholesterolemia
      due to a tissue-specific defect in the removal of low density lipoproteins (LDL)
      from the circulation. LDL uptake by the LDL receptor (LDLR) is markedly reduced
      in the liver but is normal or only moderately impaired in cultured fibroblasts of
      ARH patients. To define the molecular mechanism underlying ARH we examined ARH
      mRNA and protein in fibroblasts and lymphocytes from six probands with different
      ARH mutations. None of the probands had detectable full-length ARH protein in
      fibroblasts or lymphoblasts. Five probands were homozygous for mutations that
      introduced premature termination codons. No relationship was apparent between the
      site of the mutation in ARH and the amount of mRNA. The only mutation identified
      in the remaining proband was a SINE VNTR Alu (SVA) retroposon insertion in intron
      1, which was associated with no detectable ARH mRNA. (125)I-LDL degradation was
      normal in ARH fibroblasts, as previously reported. In contrast, LDLR function was
      markedly reduced in ARH lymphoblasts, despite a 2-fold increase in LDL cell
      surface binding in these cells. These data indicate that all ARH mutations
      characterized to date preclude the synthesis of full-length ARH and that ARH is
      required for normal LDLR function in lymphocytes and hepatocytes, but not in
      fibroblasts. Residual LDLR function in cells that do not require ARH may explain
      why ARH patients have lower plasma LDL levels than do patients with homozygous
      familial hypercholesterolemia who have no functional LDLRs.

PMID- 12417524
TI  - Two independent apolipoprotein A5 haplotypes influence human plasma triglyceride
      levels.
AB  - The recently identified apolipoprotein A5 gene (APOA5) has been shown to play an
      important role in determining plasma triglyceride concentrations in humans and
      mice. We previously identified an APOA5 haplotype (designated APOA5*2) that is
      present in approximately 16% of Caucasians and is associated with increased
      plasma triglyceride concentrations. In this report we describe another APOA5
      haplotype (APOA5*3) containing the rare allele of the single nucleotide
      polymorphism c.56C>G that changes serine to tryptophan at codon 19 and is
      independently associated with high plasma triglyceride levels in three different
      populations. In a sample of 264 Caucasian men and women with plasma triglyceride
      concentrations above the 90th percentile or below the 10th percentile, the
      APOA5*3 haplotype was more than three-fold more common in the group with high
      plasma triglyceride levels. In a second independently ascertained sample of
      Caucasian men and women (n=419) who were studied while consuming their self
      selected diets as well as after high-carbohydrate diets and high-fat diets, the
      APOA5*3 haplotype was associated with increased plasma triglyceride levels on all
      three dietary regimens. In a third population comprising 2660 randomly selected
      individuals, the APOA5*3 haplotype was found in 12% of Caucasians, 14% of African
      Americans and 28% of Hispanics and was associated with increased plasma
      triglyceride levels in both men and women in each ethnic group. These findings
      establish that the APOA5 locus contributes significantly to inter-individual
      variation in plasma triglyceride levels in humans. Together, the APOA5*2 and
      APOA5*3 haplotypes are found in 25-50% of African-Americans, Hispanics and
      Caucasians and support the contribution of common human variation to quantitative
      phenotypes in the general population.

PMID- 12417525
TI  - Relative contribution of variation within the APOC3/A4/A5 gene cluster in
      determining plasma triglycerides.
AB  - Since triglycerides (TG) are a major independent risk factor for coronary heart
      disease, understanding their genetic and environmental determinants is of major
      importance. Mouse models indicate an inverse relationship between levels of the
      newly identified apolipoprotein AV (APOAV) and TG concentrations. We have
      examined the relative influence of human APOA5 variants on plasma lipids,
      compared to the impact of variation in APOC3 and APOA4 which lie in the same
      cluster. Single nucleotide polymorphisms (SNPs) in APOA5 (S19W, -1131T>C) and
      APOA4 (T347S, Q360H) and an APOA4/A5 intergenic T>C SNP were examined in a large
      study of healthy middle-aged men (n=2808). APOA5 19WW and -1131CC men had 52% and
      40% higher TG (P<0.003) compared to common allele homozygotes, respectively,
      effects which were independent and additive. APOA4 347SS men had 23% lower TG
      compared to TT men (P<0.002). Haplotype analysis was carried out to identify TG
      raising alleles and included, in addition, four previously genotyped APOC3 SNPs (
      2845T>G, -482C>T, 1100C>T, and 3238C>G). The major TG-raising alleles were
      defined by APOA5 W19 and APOC3 -482T. This suggests that the TG-lowering effect
      of APOA4 S347 might merely reflect the strong negative linkage disequilibrium
      with the common alleles of these variants. Thus variation in APOA5 is associated
      with differences in TGs in healthy men, independent of those previously reported
      for APOC3, while association between APOA4 and TG reflects linkage disequilibrium
      with these sites. The molecular mechanisms for these effects remain to be
      determined.

PMID- 12417526
TI  - A novel gene, Pog, is necessary for primordial germ cell proliferation in the
      mouse and underlies the germ cell deficient mutation, gcd.
AB  - Primordial germ cells (PGCs) are the precursor of the germ cells in adult gonads.
      They arise extra-gonadally and migrate through somatic tissues to the presumptive
      genital ridges, where they proliferate and differentiate into oogonia or
      spermatogonia cells. Abnormalities in this developmental process can cause
      embryonic depletion of germ cells leading to infertility in the adult. We report
      here that the mouse gcd (germ cell deficient) mutant phenotype, characterized by
      reduced numbers of PGCs and adult sterility, is due to reduced PGC proliferation
      rather than aberrant migration and is caused by the partial deletion of a single
      novel gene, Pog (proliferation of germ cells). Pog is critical for normal PGC
      proliferation, starting between 9.5 and 10.25 dpc when germ cells begin to
      migrate to the developing genital ridge. Deletion of Pog is also accompanied by
      reduced embryonic body weight and, on some genetic backgrounds, embryonic
      lethality. Thus, in addition to being necessary for PGC proliferation, Pog may
      have a wider significance in early embryonic development.

PMID- 12417527
TI  - A cellular model for Friedreich Ataxia reveals small-molecule glutathione
      peroxidase mimetics as novel treatment strategy.
AB  - Friedreich Ataxia (FRDA), the most prevalent of the inherited ataxias, is a multi
      systemic disease with loss of sensory neurons and life-threatening hypertrophic
      cardiomyopathy as its most severe manifestations. Reduced levels of the
      mitochondrial protein frataxin lead to cell-damaging oxidative stress and
      consequently FRDA is considered as a model for more common neurodegenerative
      disorders in which reactive radicals and oxidative stress are involved. We have
      developed a cellular assay system that discriminates between fibroblasts from
      FRDA patients and unaffected donors on the basis of their sensitivity to
      pharmacological inhibition of de novo synthesis of glutathione. With this assay
      we observed that supplementation with selenium effectively improved the viability
      of FRDA fibroblasts, indicating that basal selenium concentrations are not
      sufficient to allow an adequate increase in the activity of certain
      detoxification enzymes (such as GPX). Furthermore, we characterized potential
      drug candidates and found that idebenone, a mitochondrially localized antioxidant
      that ameliorates cardiomyopathy in FRDA patients, as well as other lipophilic
      antioxidants protected FRDA cells from cell death. Our results also demonstrate
      for the first time that small-molecule GPX mimetics have potential as a novel
      treatment strategy for Friedreich Ataxia and presumably also for other
      neurodegenerative diseases with mitochondrial impairment.

PMID- 12417528
TI  - Localization in the human retina of the X-linked retinitis pigmentosa protein
      RP2, its homologue cofactor C and the RP2 interacting protein Arl3.
AB  - Mutations in the retinitis pigmentosa 2 (RP2) gene cause a severe form of X
      linked retinal degeneration. RP2 is a ubiquitous 350 amino acid plasma membrane
      associated protein, which shares homology with the tubulin-specific chaperone
      cofactor C. RP2 protein, like cofactor C, stimulates the GTPase activity of
      tubulin in combination with cofactor D. RP2 has also been shown to interact with
      ADP ribosylation factor-like 3 (Arl3) in a nucleotide and myristoylation
      dependant manner. In this study we have examined the relationship between RP2,
      cofactor C and Arl3 in patient-derived cell lines and in the retina. Examination
      of lymphoblastoid cells from patients with an Arg120stop nonsense mutation in RP2
      revealed that the expression levels of cofactor C and Arl3 were not affected by
      the absence of RP2. In human retina, RP2 was localized to the plasma membrane of
      cells throughout the retina. RP2 was present at the plasma membrane in both rod
      and cone photoreceptors, extending from the outer segment through the inner
      segment to the synaptic terminals. There was no enrichment of RP2 staining in any
      photoreceptor organelle. In contrast, cofactor C and Arl3 localized predominantly
      to the photoreceptor connecting cilium in rod and cone photoreceptors. Cofactor C
      was cytoplasmic in distribution, whereas Arl3 localized to other microtubule
      structures within all cells. Arl3 behaved as a microtubule-associated protein: it
      co-localized with microtubules in HeLa cells and this was enhanced following
      microtubule stabilization with taxol. Furthermore, Arl3 co-purified with
      microtubules from bovine brain. Following microtubule depolymerization with
      nocodazole, Arl3 relocalized to the nuclear membrane. These data suggest that RP2
      functions in concert with Arl3 to link the cell membrane with the cytoskeleton in
      photoreceptors as part of the cell signaling or vesicular transport machinery.

PMID- 12417531
TI  - Intracellular retention of mutant retinoschisin is the pathological mechanism
      underlying X-linked retinoschisis.
AB  - X-linked retinoschisis results in visual loss in early life with splitting within
      the inner retinal layers. Many missense and protein truncating mutations of the
      causative gene RS1 (encoding retinoschisin) have been identified but disease
      severity is not mutation-dependent. Retinoschisin is a soluble secretory protein
      predicted to have a globular conformation. Missense mutations would be expected
      to interfere with protein folding leading to an abnormal conformation and
      intracellular retention and elimination. To test this hypothesis we have
      expressed seven pathological RS1 mutations (L12H, C59S, G70S, R102W, G109R, R141G
      and R213W) in COS-7 cells and investigated their intracellular processing and
      transport. Using immunoblotting and confocal fluorescent immunocytochemistry we
      show normal secretion of WT RS1, but either reduced (C59S and R141G) or absent
      (L12H, G70S, R102W, G109R and R213W) secretion of mutant RS1 and intracellular
      retention. In addition, we show that L12H RS1 is degraded by proteasomes and in
      vitro transcription/translation revealed the defects in both cleavage of its
      signal peptide and translocation into the endoplasmic reticulum. Our results
      indicate the pathological basis of RS1 is intracellular retention of the majority
      of mutant proteins, which may explain why disease severity is not mutation
      specific. Furthermore, we have shown that in vitro expression of RS1 may be a
      useful functional assay to investigate the pathogenicity of sequence changes
      within the RS1 gene.

PMID- 12417529
TI  - Sox10 haploinsufficiency affects maintenance of progenitor cells in a mouse model
      of Hirschsprung disease.
AB  - Hirschsprung disease, or congenital megacolon, is characterized by aganglionosis
      of the terminal bowel, which leads to intestinal obstruction and chronic
      constipation. Several genes involved in the disease have been identified. In
      particular, haploinsufficiency of SOX10, which encodes a transcription factor,
      results in megacolon, often in combination with other disorders. Although
      Hirschsprung disease has been recognized as a neurocristopathy, the cellular
      mechanisms that lead to aganglionosis in affected individuals are unclear.
      Failure of mutant enteric progenitor cells to migrate into the gut, to survive,
      or to differentiate into appropriate cell types at the appropriate time and in
      correct numbers might contribute to the disease phenotype. In the present study,
      we use mice with a targeted deletion of Sox10 to study the etiology of
      Hirschsprung disease. We demonstrate that neural crest-derived enteric
      progenitors that are heterozygous for the Sox10 mutation colonize the proximal
      intestine and are unaffected in their survival capacity. However, unlike their
      wild-type counterparts, mutant enteric neural crest-derived cells are unable to
      maintain their progenitor state and acquire preneuronal traits, which results in
      a reduction of the progenitor pool size. Thus, the cells that normally colonize
      the hindgut are depleted in the Sox10 mutant, causing the distal bowel to become
      aganglionic.

PMID- 12417530
TI  - Mutations in congenital myasthenic syndromes reveal an epsilon subunit C-terminal
      cysteine, C470, crucial for maturation and surface expression of adult AChR.
AB  - Many congenital myasthenic syndromes (CMS) are associated with mutations in the
      genes encoding the acetylcholine receptor (AChR), an oligomeric protein with the
      structure alpha(2)betadelta epsilon. AChR deficiency is frequently due to
      homozygous or heteroallelic mutations in the AChR epsilon subunit, most of which
      cause truncation of the polypeptide chain and loss of surface expression of AChR.
      Here we identified mutations epsilon 1369delG and epsilon Y458X, located in the
      18 amino acid epsilon subunit C-terminus that lies extracellular to the M4
      transmembrane domain. We then incorporated green fluorescent protein (GFP) into
      the intracellular loop between M3 and M4 of mutant or wild-type epsilon subunits
      and expressed the AChRs in RD or HEK 293 cells. AChR containing wild-type GFP
      tagged epsilon subunits were incorporated into the surface membrane, whereas the
      GFP-tagged AChR mutant epsilon subunits co-localized with an endoplasmic
      reticulum (ER) marker and were not expressed on the cell surface. In addition,
      mutant AChRs did not reach the cell surface, as measured by labelling of intact
      cells with (125)I-alpha-bungarotoxin and precipitation with an epsilon-subunit
      specific antiserum. Mutagenesis studies showed that cysteine 470, located four
      amino acids from the C-terminus, is essential for alpha/epsilon assembly and
      surface expression of adult AChR. Replacement of cysteine 470 by serine does not
      restore alpha/epsilon assembly or surface expression. Our results provide the
      first use of GFP-tagged AChR as a tool for investigation of CMS and demonstrate a
      previously undetermined role for a disulphide-bonded cystine in the epsilon
      subunit C-terminus, which plays a crucial role in expression of the adult AChR.

PMID- 12417532
TI  - Rescue of neurodegeneration in Niemann-Pick C mice by a prion-promoter-driven
      Npc1 cDNA transgene.
AB  - Niemann-Pick disease type C (NPC) is a neurodegenerative disorder with major
      visceral complications, including liver disease that can be fatal before onset of
      neurodegeneration. We have sought to determine the extent to which visceral
      disease contributes to neurodegeneration by making transgenic mice in which the
      wild-type NPC1 protein is expressed primarily in the CNS using the prion
      promoter. When the transgene was introduced into the npc1(-/-) animals
      neurodegeneration was prevented, a 'normal' lifespan occurred and the sterility
      of npc1(-/-) mice was corrected. The rescue did not provide complete neurological
      correction in the CNS as GM2 and GM3 gangliosides were observed to accumulate in
      some neurons and glia of transgenic animals. Two of three transgenic lines
      demonstrated some low-level ectopic expression resulting in correction of
      visceral phenotypes in liver and spleen. Interestingly, the third transgenic line
      continued to have moderate histocytosis in liver and spleen, yet had no
      detectable neurodegeneration. Thus, it is primarily the lack of NPC1 in the CNS
      and not the secondary effects of the visceral involvement that causes the
      neurological decline in NPC disease. In addition, the expression levels of NPC1
      found in the CNS of transgenic animals were much greater than in normal
      littermates, demonstrating that overexpression of NPC1 is not harmful and
      allowing possibilities for genetic therapy interventions that utilize
      overexpression.

PMID- 12417534
TI  - Chlamydia pneumoniae-atherosclerosis link: a sound concept in search for clinical
      relevance.

PMID- 12417535
TI  - Sympathetic nervous system in heart failure.

PMID- 12417536
TI  - Cardiology patient pages. Hypertrophic cardiomyopathy.

PMID- 12417537
TI  - Calcium antagonist lacidipine slows down progression of asymptomatic carotid
      atherosclerosis: principal results of the European Lacidipine Study on
      Atherosclerosis (ELSA), a randomized, double-blind, long-term trial.
AB  - BACKGROUND: Most cardiovascular events associated with hypertension are
      complications of atherosclerosis. Some antihypertensive agents influence
      experimental models of atherosclerosis through mechanisms independent of blood
      pressure lowering. METHODS AND RESULTS: The European Lacidipine Study on
      Atherosclerosis (ELSA) was a randomized, double-blind trial in 2334 patients with
      hypertension that compared the effects of a 4-year treatment based on either
      lacidipine or atenolol on an index of carotid atherosclerosis, the mean of the
      maximum intima-media thicknesses (IMT) in far walls of common carotids and
      bifurcations (CBM(max)). This index has been shown by epidemiological studies to
      be predictive of cardiovascular events. A significant (P<0.0001) effect of
      lacidipine was found compared with atenolol, with a treatment difference in 4
      year CBM(max) progression of -0.0227 mm (intention-to-treat population) and 
      0.0281 mm (completers). The yearly IMT progression rate was 0.0145 mm/y in
      atenolol-treated and 0.0087 mm/y in lacidipine-treated patients (completers, 40%
      reduction; P=0.0073). Patients with plaque progression were significantly less
      common, and patients with plaque regression were significantly more common in the
      lacidipine group. Clinic blood pressure reductions were identical with both
      treatments, but 24-hour ambulatory systolic/diastolic blood pressure changes were
      greater with atenolol (-10/-9 mm Hg) than with lacidipine (-7/-5 mm Hg). No
      significant difference between treatments was found in any cardiovascular events,
      although the relative risk for stroke, major cardiovascular events, and mortality
      showed a trend favoring lacidipine. CONCLUSION: The greater efficacy of
      lacidipine on carotid IMT progression and number of plaques per patient, despite
      a smaller ambulatory blood pressure reduction, indicates an antiatherosclerotic
      action of lacidipine independent of its antihypertensive action.

PMID- 12417538
TI  - Reduced progression of early carotid atherosclerosis after antibiotic treatment
      and Chlamydia pneumoniae seropositivity.
AB  - BACKGROUND: Chlamydia pneumoniae (Cp) infection has been associated with
      atherosclerosis, and a beneficial effect of antibiotic therapy on future
      cardiovascular events was described. METHODS AND RESULTS: We evaluated the effect
      of roxithromycin therapy (150 mg twice daily for 30 days) on the progression of
      the intima-to-media thickness (IMT) of the common carotid artery using duplex
      ultrasonography in a prospective and randomized trial with a follow-up of 2 years
      in 272 consecutive patients with ischemic stroke aged over 55 years in whom the
      first IMT measurement and Cp testing (IgG and IgA) were performed at least 3
      years before the roxithromycin treatment. Cp IgG antibodies (> or =1:64) were
      initially found in 123 (45%) patients and IgA antibodies (> or =1:16) in 112
      (41%) patients. During the 3 years before antibiotic therapy, Cp-positive
      patients showed an enhanced IMT progression, even after adjustment for other
      cardiovascular risk factors (0.12 [95% CI, 0.11 to 0.14] versus 0.07 [0.05 to
      0.09] mm/year; P<0.005). The 62 Cp-positive patients given roxithromycin showed a
      significantly decreased IMT progression after 2 years compared with the Cp
      positive patients without therapy (0.07 [0.045 to 0.095] versus 0.11 [0.088 to
      0.132] mm/year; P<0.01). No significant difference in the occurrence of future
      cardiovascular events was found between both groups during follow-up. No change
      of IMT was observed in Cp-negative patients given roxithromycin (n=74) compared
      with those without therapy (0.06 [0.03 to 0.09] versus 0.07 [0.05 to 0.09]
      mm/year). CONCLUSIONS: Our findings suggest a positive impact of antibiotic
      therapy on early atherosclerosis progression in Cp-seropositive patients with
      cerebrovascular disease.

PMID- 12417539
TI  - Beta2 integrin-dependent neutrophil adhesion induced by minimally modified low
      density lipoproteins is mainly mediated by F2-isoprostanes.
AB  - BACKGROUND: Oxidation of LDL produces a series of biologically active, oxidized
      lipids. Among them, isoprostanes, and in particular iPF(2alpha)-III, seem to be
      crucial in mediating some of the key cellular events seen in myocardial ischemia
      reperfusion injury. METHODS AND RESULTS: Minimally modified LDL (MM-LDL) triggers
      a dose-dependent, very rapid neutrophil adhesion to human fibrinogen. Rapid
      adhesion triggering correlates with degree of LDL oxidation and accumulation of
      isoprostanes. Isoprostanes accumulated in MM-LDL are major determinants of the
      proadhesive effect of oxidized LDL, as shown by experiments of receptor
      functional deletion. Moreover, evidence is provided of expression on human
      neutrophils of a biological active isoprostane receptor distinct from the
      classical thromboxane A2 receptor. CONCLUSIONS: These data suggest that
      isoprostanes are major contributors to the proadhesive effect induced by MM-LDL
      on neutrophils and provide additional evidence for the involvement of
      isoprostanes in the pathogenesis of myocardial ischemia/reperfusion injury.

PMID- 12417540
TI  - Elevated numbers of tissue-factor exposing microparticles correlate with
      components of the metabolic syndrome in uncomplicated type 2 diabetes mellitus.
AB  - BACKGROUND: Type 2 diabetes is associated with accelerated atherosclerosis.
      Because cell-derived microparticles support coagulation and inflammation, they
      may be involved in atherogenesis. We characterized circulating microparticles
      both in patients with uncomplicated, well-regulated type 2 diabetes and in
      healthy subjects, as well as their relationship with coagulation and metabolic
      control. METHODS AND RESULTS: Microparticles were isolated from plasma, stained
      with annexin V, cell-specific monoclonal antibodies (MoAbs) and a MoAb directed
      against tissue factor (TF), and analyzed by flow cytometry. Microparticle numbers
      and origin were comparable in the two groups, but the median number of TF
      positive microparticles was twice as high in patients than in controls (P=0.018).
      Patients had higher percentages of TF-positive microparticles from T-helper cells
      (P=0.045), granulocytes (P=0.004), and platelets (P=0.002). Subpopulations of TF
      positive microparticles from platelets and T-helper cells exposed granulocytic
      markers. Correlations were found between the numbers of various TF-positive
      microparticle subpopulations and body mass index, fasting plasma glucose and
      insulin, or tumor necrosis factor-alpha and serum HDL cholesterol. Microparticles
      from patients generated less thrombin in vitro (P=0.007). Microparticle numbers
      did not correlate with in vivo coagulation markers prothrombin fragment F(1+2)
      and thrombin-antithrombin complexes. CONCLUSIONS: TF, possibly of granulocytic
      origin, is exposed on microparticle subpopulations in asymptomatic patients with
      well-regulated type 2 diabetes. TF-positive microparticles are associated with
      components of the metabolic syndrome but not with coagulation. Thus, TF on
      microparticles may be involved in processes other than coagulation, including
      transcellular signaling or angiogenesis.

PMID- 12417541
TI  - Potential role of autoantibodies belonging to the immunoglobulin G-3 subclass in
      cardiac dysfunction among patients with dilated cardiomyopathy.
AB  - BACKGROUND: Immunoadsorption capable of removing circulating autoantibodies
      represents an additional therapeutic approach in dilated cardiomyopathy (DCM).
      The role played by autoantibodies belonging to the immunoglobulin (Ig) subclass G
      3 in cardiac dysfunction remains to be elucidated. METHODS AND RESULTS: Patients
      with DCM (left ventricular ejection fraction <30%) participated in this case
      control study. Nine patients underwent immunoadsorption with protein A (low
      affinity to IgG-3), and 9 patients were treated with anti-IgG, which removes all
      IgG subclasses. Immunoadsorption was performed in 4 courses at 1-month intervals
      until month 3. In the 2 groups, immunoadsorption induced comparable reduction of
      total IgG (>80%). IgG-3 was effectively eliminated only by anti-IgG adsorption
      (eg, during the first immunoadsorption course; protein A, -37+/-4%; anti-IgG, 
      89+/-3%; P<0.001 versus protein A). The beta1-receptor autoantibody was
      effectively reduced only by anti-IgG (P<0.01 versus protein A). Hemodynamics did
      not change in the protein A group. In the anti-IgG group during the first
      immunoadsorption course, cardiac index increased from 2.3+/-0.1 to 3.0+/-0.1 L x
      min(-1) x m(-2) (P<0.01 versus protein A). After 3 months, before the last
      immunoadsorption course, cardiac index was 2.2+/-0.1 L x min(-1) x m(-2) in the
      protein A group and 3.0+/-0.2 L x min(-1) x m(-2) in the anti-IgG group (P<0.01
      versus protein A). Left ventricular ejection fraction increased only in the anti
      IgG group (P<0.05 versus protein A). CONCLUSIONS: Autoantibodies belonging to IgG
      3 may play an important role in cardiac dysfunction of DCM. The removal of
      antibodies of the IgG-3 subclass may represent an essential mechanism of
      immunoadsorption in DCM.

PMID- 12417542
TI  - Effects of valsartan on circulating brain natriuretic peptide and norepinephrine
      in symptomatic chronic heart failure: the Valsartan Heart Failure Trial (Val
      HeFT).
AB  - BACKGROUND: Brain natriuretic peptide (BNP) and norepinephrine (NE) are strongly
      related to severity of and are independent predictors of outcome in heart
      failure. The long-term effects of angiotensin receptor blockers on BNP and NE in
      heart failure patients are not known. METHODS AND RESULTS: Both BNP and NE were
      measured in 4284 patients randomized to valsartan or placebo in the Valsartan
      Heart Failure Trial (Val-HeFT) at baseline and 4, 12, and 24 months after
      randomization. The effects of valsartan were tested by ANCOVA, controlling for
      baseline values and concomitant ACE inhibitors and/or beta-blockers. BNP and NE
      concentrations were similar at baseline in the 2 groups and were decreased by
      valsartan starting at 4 months and up to 24 months. BNP increased over time in
      the placebo group. At the end point, least-squares mean (+/-SEM) BNP increased
      from baseline by 23+/-5 pg/mL in the placebo group (n=1979) but decreased by 21+/
      5 pg/mL (n=1940) in the valsartan group (P<0.0001). NE increased by 41+/-6 pg/mL
      (n=1979) and 12+/-6 pg/mL (n=1941) for placebo and valsartan, respectively
      (P=0.0003). Concomitant therapy with both ACE inhibitors and beta-blockers
      significantly reduced the effect of valsartan on BNP but not on NE (P for
      interaction=0.0223 and 0.2289, respectively). CONCLUSIONS: In Val-HeFT, the
      largest neurohormone study in patients with symptomatic chronic heart failure,
      BNP and NE rose over time in the placebo group. Valsartan caused sustained
      reduction in BNP and attenuated the increase in NE over the course of the study.
      These neurohormone effects of valsartan are consistent with the clinical benefits
      reported in Val-HeFT.

PMID- 12417543
TI  - Paradoxical effect of sibutramine on autonomic cardiovascular regulation.
AB  - BACKGROUND: Sibutramine, a serotonin and norepinephrine transporter blocker, is
      widely used as an adjunctive obesity treatment. Norepinephrine reuptake
      inhibition with sibutramine conceivably could exacerbate arterial hypertension
      and promote cardiovascular disease. METHODS AND RESULTS: In 11 healthy subjects
      (7 men, age 27+/-2 years, body mass index 23.1+/-0.7 kg/m2), we compared the
      effect of sibutramine or matching placebo (ingested 26, 14, and 2 hours before
      testing) on cardiovascular responses to autonomic reflex tests and to a graded
      head-up tilt test. In addition, we tested sibutramine in combination with
      metoprolol. Testing was conducted in a double-blind and crossover fashion. Supine
      systolic blood pressure was 113+/-3 mm Hg with placebo, 121+/-3 mm Hg with
      sibutramine (P<0.001 versus placebo), and 111+/-2 mm Hg with the combination of
      sibutramine and metoprolol. Similarly, sibutramine increased upright blood
      pressure. Sibutramine substantially increased upright heart rate. This effect was
      abolished with metoprolol. The blood pressure response to cold pressor and
      handgrip testing was attenuated with sibutramine compared with placebo.
      Furthermore, sibutramine decreased low-frequency oscillations of blood pressure
      and plasma norepinephrine concentrations in the supine position. CONCLUSIONS: The
      cardiovascular effect of the antiobesity drug sibutramine results from a complex
      interaction of peripheral and central nervous system effects. The inhibitory
      clonidine-like action of sibutramine on the central nervous system attenuates the
      peripheral stimulatory effect. Our findings strongly suggest that current
      concepts regarding the action of sibutramine on the sympathetic nervous system
      should be reconsidered.

PMID- 12417544
TI  - Relation of ejection fraction and inducible ventricular tachycardia to mode of
      death in patients with coronary artery disease: an analysis of patients enrolled
      in the multicenter unsustained tachycardia trial.
AB  - BACKGROUND: Fifty percent of deaths in patients with coronary disease occur
      suddenly. Although many factors correlate with increased mortality, there is
      little information regarding the influence of these factors on mode of death. As
      such, optimum methods to determine patients most likely to benefit from
      implantable defibrillator therapy are unclear. METHODS AND RESULTS: We analyzed
      the relation of ejection fraction and inducible ventricular tachyarrhythmias to
      mode of death in all 1791 patients enrolled in the Multicenter Unsustained
      Tachycardia Trial who did not receive antiarrhythmic therapy. Total mortality and
      arrhythmic deaths/cardiac arrests occurred more frequently in patients with
      ejection fraction <30% than in those with ejection fraction of 30% to 40%. The
      percentage of deaths classified as arrhythmic was similar in patients with
      ejection fraction <30% or > or =30%. The relative contribution of arrhythmic
      events to total mortality was significantly higher in patients with inducible
      tachyarrhythmia (58% of deaths in inducible patients versus 46% in noninducible
      patients, P=0.004). The higher percentage of events that were arrhythmic among
      patients with inducible tachyarrhythmia appeared more distinct among patients
      with an ejection fraction > or =30% (61% of events were arrhythmic among
      inducible patients with ejection fraction > or =30% and only 42% among
      noninducible patients, P=0.002). CONCLUSIONS: Both low ejection fraction and
      inducible tachyarrhythmias identify patients with coronary disease at increased
      mortality risk. Ejection fraction does not discriminate between modes of death,
      whereas inducible tachyarrhythmia identifies patients for whom death, if it
      occurs, is significantly more likely to be arrhythmic, especially if ejection
      fraction is > or =30%.

PMID- 12417545
TI  - Ambulatory electrocardiographic evidence of transmural dispersion of
      repolarization in patients with long-QT syndrome type 1 and 2.
AB  - BACKGROUND: Transmural dispersion of repolarization (TDR) may be related to the
      genesis of torsade de pointes (TdP) in patients with the long-QT (LQT) syndrome.
      Experimentally, LQT2 models show increased TDR compared with LQT1, and beta
      adrenergic stimulation increases TDR in both models. Clinically, LQT1 patients
      experience symptoms at elevated heart rates, but LQT2 patients do so at lower
      rates. The interval from T-wave peak to T-wave end (TPE interval) is the clinical
      counterpart of TDR. We explored the relationship of TPE interval to heart rate
      and to the presence of symptoms in patients with LQT1 and LQT2. METHODS AND
      RESULTS: We reviewed Holter recordings from 90 genotyped subjects, 31 with LQT1,
      28 with LQT2, and 31 from unaffected family members, to record TPE intervals by
      use of an automated computerized program. The median TPE interval was greater in
      LQT2 (112+/-5 ms) than LQT1 (91+/-2 ms) or unaffected (86+/-3 ms) patients
      (P<0.001 for all group comparisons), and the maximal TPE values differed as well.
      LQT1 patients showed abrupt increases in TPE values at RR intervals from 600 to
      900 ms, but LQT2 patients did so at RR intervals from 600 to 1400 ms (longest RR
      studied). Asymptomatic and symptomatic patients showed similar TDRs. CONCLUSIONS:
      TDR is greater in LQT2 than in LQT1 patients. LQT1 patients showed a capacity to
      increase TDR at elevated heart rates, but LQT2 patients did so at a much wider
      rate range. The magnitude of TDR is not related to a history of TdP.

PMID- 12417546
TI  - Distinctive electrophysiological properties of pulmonary veins in patients with
      atrial fibrillation.
AB  - BACKGROUND: Atrial fibrillation (AF) is frequently initiated from pulmonary veins
      (PVs), but little is known of the electrophysiological properties of PVs. METHODS
      AND RESULTS: Two groups were studied: 28 patients (49+/-13 years old) with
      paroxysmal AF and 20 control patients (49+/-14 years old) without AF. Effective
      and functional refractory period and conduction time from PV to left atrium (LA)
      were compared in the 2 groups by use of programmed stimulation with a single
      extrastimulus in the PVs and LA. In the AF group, the venous effective refractory
      periods (ERPs) were shorter than that of the LA: 185+/-71 versus 253+/-21 ms,
      P<0.001, whereas in the control group, they were longer (282+/-45 versus 253+/-41
      ms, P=0.009). The venous ERPs and functional refractory periods in patients with
      AF were also shorter than that observed in control subjects (185+/-71 versus
      282+/-45 ms and 210+/-77 versus 315+/-43 ms, respectively, P<0.001), whereas LA
      ERPs were not significantly different. Decremental conduction in PVs was more
      frequent (93% versus 56%, P=0.01) and had a greater increment (102+/-65 versus
      42+/-40 ms, P<0.001) in patients with AF. Finally, AF was more frequently induced
      when pacing was performed in PVs (22 of 90) versus LA (1 of 81) in patients with
      AF (P<0.001). CONCLUSIONS: The PVs of patients with AF exhibited distinctive
      electrophysiological properties, which were strikingly different from those of
      patients devoid of AF, potentially explaining their arrhythmogenicity.

PMID- 12417547
TI  - Maturation-dependent acquired coronary structural alterations and atherogenesis
      in the Dahl sodium-sensitive hypertensive rat.
AB  - BACKGROUND: The Dahl sodium-sensitive hypertensive rat exhibits atherogenic
      lesions after the initiation of a high-sodium/high-fat diet. This study was
      designed to gauge the effect of a preadolescent high-fat diet on the
      postadolescent rate of atherogenesis after supplementation of the diet with
      sodium. METHODS AND RESULTS: Fifty-three Dahl S male rats were assigned to 2
      dietary groups for the postweaning to early adolescence period (3 to 12 weeks):
      29 to a standard diet (low-fat/low-sodium) and 24 to a high-fat/low-sodium diet.
      At age 9 weeks (just after puberty), animals from the high-fat group exhibited a
      relatively diminished density of coronary elastic fibers. There was no evidence
      of either lipid or monocytic infiltration of the subendothelial space. At age 12
      weeks, most or all of the remaining animals in both groups were switched to a
      high-sodium/high-fat diet and were sampled through the following 8 weeks for the
      appearance of arterial lipid. After the switch, the high-fat-conditioned animals
      developed more extensive atherosclerotic pathological lesions more rapidly than
      their prepubertal standard-diet counterparts. The importance of the animal's
      stage of maturation in this effect was underscored by the observation that
      delaying onset of the high-fat diet to early adolescence resulted in no ultimate
      difference from the pubertal controls in elastic fiber density. CONCLUSIONS: The
      maturation-dependent high-fat conditioning of these postweanling rats correlated
      with an accelerated rate of atherogenesis on the initiation of the high
      sodium/high-fat diet, possibly as a direct result of an alteration in arterial
      elasticity.

PMID- 12417548
TI  - Feedback inhibition of catecholamine release by two different alpha2-adrenoceptor
      subtypes prevents progression of heart failure.
AB  - BACKGROUND: Elevated plasma norepinephrine levels are associated with increased
      mortality in patients and in animal models with chronic heart failure. To test
      which alpha2-adrenoceptor subtypes operate as presynaptic inhibitory receptors to
      control norepinephrine release in heart failure, we investigated the response of
      gene-targeted mice lacking alpha2-adrenoceptor subtypes (alpha2-KO) to chronic
      left ventricular pressure overload. In addition, we determined the functional
      consequences of genetic variants of alpha2-adrenoceptors in human patients with
      chronic heart failure. METHODS AND RESULTS: Cardiac pressure overload was induced
      by transverse aortic constriction. Three months after aortic banding, survival
      was dramatically reduced in alpha2A-KO (52%) and alpha2C-KO (47%) mice compared
      with wild-type and alpha2B-deficient (86%) animals. Excess mortality in alpha2A-
      and alpha2C-KO strains was attributable to heart failure with enhanced left
      ventricular hypertrophy and fibrosis and elevated circulating catecholamines. The
      clinical importance of this finding is emphasized by the fact that heart failure
      patients with a dysfunctional variant of the alpha2C-adrenoceptor had a worse
      clinical status and decreased cardiac function as determined by invasive
      catheterization and by echocardiography. CONCLUSIONS: Our results indicate an
      essential function of alpha2A- and alpha2C-adrenoceptors in the prevention of
      heart failure progression in mice and human patients. Identification of heart
      failure patients with genetic alpha2-adrenoceptor variants as well as new alpha2
      receptor subtype-selective drugs may represent novel therapeutic strategies in
      chronic heart failure and other diseases with enhanced sympathetic activation.

PMID- 12417549
TI  - Perivascular superoxide anion contributes to impairment of endothelium-dependent
      relaxation: role of gp91(phox).
AB  - BACKGROUND: Like endothelial and smooth muscle cells, vascular adventitial
      fibroblasts contain a substantial NAD(P)H oxidase superoxide anion (O2-)
      generating system activated by angiotensin II (Ang II). Based on the ability of
      nitric oxide (NO*) to diffuse rapidly through tissue and the fast reaction rate
      of NO* and O2-, we postulated that the interaction between NO. and adventitial
      NAD(P)H oxidase-derived O2- contributes to impairment of endothelium-dependent
      relaxation (EDR). METHODS AND RESULTS: C57Bl/6 mouse abdominal aortas were
      simultaneously perfused intraluminally and suffused adventitially with
      physiological buffer at 37 degrees C. After constricting the vessels with
      phenylephrine, an acetylcholine dose-response curve was obtained while monitoring
      changes in diameter by videomicroscopy. Endogenous O2- was increased by treating
      the adventitial side of the aortas with Ang II (10 pmol/L), leading to impairment
      of EDR. EDR impairment was reversed by adventitial suffusion of superoxide
      dismutase (SOD) of aortas from wild-type mice. Ang II-treated aortas from
      gp91(phox-/-) mice, which lack significant adventitial O2-, exhibited greater EDR
      and were not affected by SOD. Adventitially suffused SOD failed to penetrate the
      media, indicating that the effects of SOD were localized to the adventitia.
      Adventitial application of the O2--generating system xanthine/xanthine oxidase or
      the potent NO scavenger oxyhemoglobin impaired EDR. CONCLUSIONS: O2- derived from
      adventitial gp91(phox)-based NAD(P)H oxidase contributes to impairment of the
      action of endothelium-derived NO.

PMID- 12417550
TI  - Inactivation of the lysyl oxidase gene Lox leads to aortic aneurysms,
      cardiovascular dysfunction, and perinatal death in mice.
AB  - BACKGROUND: The lysyl oxidases are extracellular copper enzymes that initiate the
      crosslinking of collagens and elastin, 5 human isoenzymes having been
      characterized so far. The crosslinks formed provide the tensile strength and
      elastic properties for various extracellular matrices, including vascular walls.
      We studied the role of the first described isoenzyme Lox by inactivating its gene
      in mice. METHODS AND RESULTS: Murine Lox gene was disrupted by routine methods.
      Lox(-/-) mice died at the end of gestation or as neonates, necropsy of the live
      born pups revealing large aortic aneurysms. In light microscopy, hazy and
      unruffled elastic lamellae in the Lox(-/-) aortas were observed, and electron
      microscopy of the aortic walls of the Lox(-/-) fetuses showed highly fragmented
      elastic fibers and discontinuity in the smooth muscle cell layers in Lox(-/-)
      fetuses. The wall of the aorta in the Lox(-/-) fetuses was significantly thicker,
      and the diameter of the aortic lumen was significantly smaller than that in the
      Lox(+/+) aortas. In Lox(-/-) fetuses, Doppler ultrasonography revealed increased
      impedance in the umbilical artery, descending aorta, and intracranial artery
      blood velocity waveforms, decreased mean velocities across cardiac inflow and
      outflow regions, and increased pulsatility in ductus venosus blood velocity
      waveforms. CONCLUSIONS: Lox has an essential role in the development and function
      of the cardiovascular system. Inactivation of the Lox gene causes structural
      alterations in the arterial walls, leading to abnormalities in the cardiovascular
      functions. Alterations in LOX activity may also play a critical role in certain
      human cardiovascular diseases.

PMID- 12417551
TI  - Nitrate tolerance: a unifying hypothesis.

PMID- 12417552
TI  - Proposed diagnostic criteria for the Brugada syndrome: consensus report.

PMID- 12417553
TI  - Images in cardiovascular medicine. Cardiac hemangioma.

PMID- 12417554
TI  - Proceedings of the Jones Criteria workshop.

PMID- 12417555
TI  - Images in cardiovascular medicine. Fistulous communication between coronary sinus
      and left atrium.

PMID- 12417556
TI  - Treating Chlamydia pneumoniae in patients with early atherosclerosis.

PMID- 12417557
TI  - The cellular response to aggregated proteins associated with human disease.

PMID- 12417558
TI  - Protein aggregation in disease: a role for folding intermediates forming specific
      multimeric interactions.

PMID- 12417559
TI  - Sgk: an old enzyme revisited.

PMID- 12417560
TI  - Dual innervation of white adipose tissue: some evidence for parasympathetic
      nervous system involvement.

PMID- 12417561
TI  - Modeling the benefits of pamidronate in children with osteogenesis imperfecta.

PMID- 12417562
TI  - Selective parasympathetic innervation of subcutaneous and intra-abdominal fat-
      functional implications.
AB  - The wealth of clinical epidemiological data on the association between intra
      abdominal fat accumulation and morbidity sharply contrasts with the paucity of
      knowledge about the determinants of fat distribution, which cannot be explained
      merely in terms of humoral factors. If it comes to neuronal control, until now,
      adipose tissue was reported to be innervated by the sympathetic nervous system
      only, known for its catabolic effect. We hypothesized the presence of a
      parasympathetic input stimulating anabolic processes in adipose tissue. Intra
      abdominal fat pads in rats were first sympathetically denervated and then
      injected with the retrograde transneuronal tracer pseudorabies virus (PRV). The
      resulting labeling of PRV in the vagal motor nuclei of the brain stem reveals
      that adipose tissue receives vagal input. Next, we assessed the physiological
      impact of these findings by combining a fat pad-specific vagotomy with a
      hyperinsulinemic euglycemic clamp and RT-PCR analysis. Insulin-mediated glucose
      and FFA uptake were reduced by 33% and 36%, respectively, whereas the activity of
      the catabolic enzyme hormone-sensitive lipase increased by 51%. Moreover,
      expression of resistin and leptin mRNA decreased, whereas adiponectin mRNA did
      not change. All these data indicate an anabolic role for the vagal input to
      adipose tissue. Finally, we demonstrate somatotopy within the central part of the
      autonomic nervous system, as intra-abdominal and subcutaneous fat pads appeared
      to be innervated by separate sympathetic and parasympathetic motor neurons. In
      conclusion, parasympathetic input to adipose tissue clearly modulates its insulin
      sensitivity and glucose and FFA metabolism in an anabolic way. The implications
      of these findings for the (patho)physiology of fat distribution are discussed.

PMID- 12417563
TI  - Insights into the molecular mechanisms of bradycardia-triggered arrhythmias in
      long QT-3 syndrome.
AB  - Congenital long QT syndrome is a rare disease in which the electrocardiogram QT
      interval is prolonged due to dysfunctional ventricular repolarization. Variant 3
      (LQT-3) is associated with mutations in SCN5A, the gene coding for the heart
      Na(+) channel alpha subunit. Arrhythmias in LQT-3 mutation carriers are more
      likely to occur at rest, when heart rate is slow. Several LQT-3 Na(+) channel
      mutations exert their deleterious effects by promoting a mode of Na(+) channel
      gating wherein a fraction of channels fails to inactivate. This gating mode,
      termed "bursting, " results in sustained macroscopic inward Na(+) channel current
      (I(sus)), which can delay repolarization and prolong the QT interval. However,
      the mechanism of heart-rate dependence of I(sus) has been unresolved at the
      single-channel level. We investigate an LQT-3 mutant (Y1795C) using experimental
      and theoretical frameworks to elucidate the molecular mechanism of I(sus) rate
      dependence. Our results indicate that mutation-induced changes in the length of
      time mutant channels spend bursting, rather than how readily they burst,
      determines I(sus) inverse heart-rate dependence. Our results indicate that
      mutation-induced changes in the length of time mutant channels spend bursting,
      rather than how readily they burst, determines I(sus) inverse heart-rate
      dependence. These results link mutation-induced changes in Na+ channel gating
      mode transitions to heart rate-dependent changes in cellular electrical activity
      underlying a key LQT-3 clinical phenotype.

PMID- 12417564
TI  - Impaired renal Na(+) retention in the sgk1-knockout mouse.
AB  - The serum- and glucocorticoid-regulated kinase (sgk1) is induced by
      mineralocorticoids and, in turn, upregulates heterologously expressed renal
      epithelial Na(+) channel (ENaC) activity in Xenopus oocytes. Accordingly, Sgk1 is
      considered to mediate the mineralocorticoid stimulation of renal ENaC activity
      and antinatriuresis. Here we show that at standard NaCl intake, renal water and
      electrolyte excretion is indistinguishable in sgk1-knockout (sgk1(-/-)) mice and
      wild-type (sgk1(+/+)) mice. In contrast, dietary NaCl restriction reveals an
      impaired ability of sgk1(-/-) mice to adequately decrease Na(+) excretion despite
      increases in plasma aldosterone levels and proximal-tubular Na(+) and fluid
      reabsorption, as well as decreases in blood pressure and glomerular filtration
      rate.

PMID- 12417565
TI  - Markedly enhanced susceptibility to experimental autoimmune myasthenia gravis in
      the absence of decay-accelerating factor protection.
AB  - Myasthenia gravis (MG) is an autoimmune neuromuscular transmission disorder
      characterized by loss of acetylcholine receptors (AChR's) due primarily to the
      production of anti-AChR autoantibodies. In this study we investigated whether the
      presence of decay-accelerating factor (DAF or CD55), an intrinsic complement
      regulator, protects against the development of disease. Experimental autoimmune
      MG was induced in Daf1(-/-) mice (devoid of neuromuscular DAF protein) and their
      Daf1(+/+) littermates by injection of rat anti-AChR mAb McAb-3. After twenty-four
      hours, grip strength assessment revealed that Daf1(-/-) mice exhibited hold times
      of less than 30 seconds, compared with more than 8 minutes for the Daf1(+/+)
      controls. The weakness was reversed by edrophonium, consistent with a myasthenic
      disorder. Immunohistochemistry revealed greatly augmented C3b deposition
      localized at postsynaptic junctions, and radioimmunoassays showed more profound
      reductions in AChR levels. Electron microscopy demonstrated markedly greater
      junctional damage in the Daf1(-/-) mice compared with the Daf1(+/+) littermates.
      Control studies showed equivalent levels of other cell surface regulators, i.e.,
      Crry and CD59. The results demonstrate that mice that lack DAF are markedly more
      susceptible to anti-AChR-induced MG, which simulates the primary mechanism in the
      human disease, and strongly suggest that in disease flares complement inhibitors
      might have therapeutic value.

PMID- 12417566
TI  - In vivo regulation of plasminogen function by plasma carboxypeptidase B.
AB  - The major functions of plasminogen (Plg) in fibrinolysis and cell migration
      depend on its binding to carboxy-terminal lysyl residues. The ability of plasma
      carboxypeptidase B (pCPB) to remove these residues suggests that it may act as a
      suppressor of these Plg functions. To evaluate this role of pCPB in vivo,
      homozygote pCPB-deficient mice were generated by homologous recombination, and
      the resulting pCPB(-/-) mice, which were viable and healthy, were mated to Plg(-/
      ) mice. Plg(+/-) mice show intermediate levels of fibrinolysis and cell migration
      compared with Plg wild-type and deficient mice, reflecting the intermediate
      levels of the Plg antigen in their plasma. Differences in Plg-dependent functions
      between pCPB(+/+), pCPB(+/-), and pCPB(-/-) mice were then analyzed in a Plg(+/-)
      background. In a pulmonary clot lysis model, fibrinolysis was significantly
      increased in mice with partial (pCPB(+/-)) or total absence (pCPB(-/-)) of pCPB
      compared with their wild-type counterparts (pCPB(+/+)). In a thioglycollate model
      of peritoneal inflammation, leukocyte migration at 72 hours increased
      significantly in Plg(+/-)/pCPB(+/-) and Plg(+/-)/pCPB(-/-) compared with their
      wild-type counterparts. These studies demonstrate a definitive role of pCPB as a
      modulator of the pivotal functions of Plg in fibrinolysis and cell migration in
      vivo.

PMID- 12417567
TI  - Allergen-specific CD8(+) T cells and atopic disease.
AB  - Considerable evidence suggests that IL-10 may have a role in the manifestation of
      atopic disease. We sought to test the hypothesis that at the single cell level,
      allergen-specific T cells have diminished IL-10 production capacity in severely
      affected atopics compared with asymptomatic atopics. We defined three A*0201
      restricted Der p 1 CD8(+) T cell epitopes. Using human leukocyte antigen-A*0201
      peptide (HLA-A*0201-peptide) tetrameric complexes and enzyme-linked immunospot
      assays to analyze peripheral blood mononuclear cells from A*0201-positive
      severely symptomatic atopics, asymptomatic atopics, and nonatopic controls, we
      observed a significant association between the frequency of the Der p 1-specific
      CD8(+) T cells and disease activity. The specific T cells expressed an antigen
      experienced cell surface phenotype, and 45.7% were positive for cutaneous
      lymphocyte-associated antigen. The specific T cells were able to produce IFN
      gamma efficiently, but their IL-10 production was significantly reduced in
      severely affected atopics. In contrast, viral-specific CD8(+) T cells were able
      to produce equivalent amounts of IL-10 in the severely affected atopics compared
      with asymptomatic atopics and nonatopics. Through defining the first human atopic
      allergen HLA class I epitopes, we have provided a possible cellular mechanism to
      link the previous association of low IL-10 levels and severe atopic disease.
      These data are consistent with a role for CD8(+) T cells in atopic disease
      pathogenesis and may provide a basis for future T cell immunotherapy strategies.

PMID- 12417568
TI  - The effects of intravenous pamidronate on the bone tissue of children and
      adolescents with osteogenesis imperfecta.
AB  - Cyclical pamidronate infusions increase bone mass in children suffering from
      osteogenesis imperfecta. The histological basis for these effects remains
      unknown. Therefore, we compared parameters of iliac bone histomorphometry from 45
      patients before and after 2.4 +/- 0.6 years of pamidronate treatment (age at the
      time of the first biopsy, 1.4-17.5 years; 23 girls). Although biopsy size did not
      change significantly (P = 0.30), cortical width increased by 88%. Cancellous bone
      volume increased by 46%. This was due to a higher trabecular number, whereas
      trabecular thickness remained stable. Bone surface-based indicators of cancellous
      bone remodeling decreased by 26-75%. There was no evidence for a mineralization
      defect in any of the patients. These results suggest that, in the growing
      skeleton, pamidronate has a twofold effect. In remodeling, bone resorption and
      formation are coupled and consequently both processes are inhibited. However,
      osteoclasts and osteoblasts are active on different surfaces (and are thus
      uncoupled) during modeling of cortical bone. Therefore resorption is selectively
      targeted, and continuing bone formation can increase cortical width.

PMID- 12417569
TI  - Hereditary sensory neuropathy type 1 mutations confer dominant negative effects
      on serine palmitoyltransferase, critical for sphingolipid synthesis.
AB  - Hereditary sensory neuropathy type 1 (HSN1) is a dominantly inherited
      degenerative disorder of the peripheral nerves. HSN1 is clinically and
      genetically heterogeneous. One form arises from mutations in the gene SPTLC1
      encoding long-chain base 1 (LCB1), one of two subunits of serine
      palmitoyltransferase (SPT), the enzyme catalyzing the initial step of
      sphingolipid synthesis. We have examined the effects of the mutations C133Y and
      C133W, which we have identified in two HSN1 families, on the function of SPT.
      Although in HSN1 lymphoblasts, the C133Y and C133W mutations do not alter the
      steady-state levels of LCB1 and LCB2 subunits, they result in reduced SPT
      activity and sphingolipid synthesis. Moreover, in a mutant Chinese hamster ovary
      (CHO) cell strain with defective SPT activity due to a lack of the LCB1 subunit,
      these mutations impair the ability of the LCB1 subunit to complement the SPT
      deficiency. Furthermore, the overproduction of either the LCB1C133Y or LCB1C133W
      subunit inhibits SPT activity in CHO cells despite the presence of wild-type
      LCB1. In addition, we demonstrate that in CHO cells the mutant LCB1 proteins,
      similar to the normal LCB1, can interact with the wild-type LCB2 subunit. These
      results indicate that the HSN1-associated mutations in LCB1 confer dominant
      negative effects on the SPT enzyme.

PMID- 12417570
TI  - Transport of paclitaxel (Taxol) across the blood-brain barrier in vitro and in
      vivo.
AB  - Paclitaxel concentrations in the brain are very low after intravenous injection.
      Since paclitaxel is excluded from some tumors by p-glycoprotein (p-gp), the same
      mechanism may prevent entry into the brain. In vitro, paclitaxel transport was
      examined in capillaries from rat brains by confocal microscopy using BODIPY Fl
      paclitaxel. Western blots and immunostaining demonstrated apical expression of p
      gp in isolated endothelial cells, vessels, and tissue. Secretion of BODIPY Fl
      paclitaxel into capillary lumens was specific and energy-dependent. Steady state
      luminal fluorescence significantly exceeded cellular fluorescence and was reduced
      by NaCN, paclitaxel, and SDZ PSC-833 (valspodar), a p-gp blocker. Leukotriene
      C(4) (LTC(4)), an Mrp2-substrate, had no effect. Luminal accumulation of NBDL
      cyclosporin, a p-gp substrate, was inhibited by paclitaxel. In vivo, paclitaxel
      levels in the brain, liver, kidney, and plasma of nude mice were determined after
      intravenous injection. Co-administration of valspodar led to increased paclitaxel
      levels in brains compared to monotherapy. Therapeutic relevance was proven for
      nude mice with implanted intracerebral human U-118 MG glioblastoma. Whereas
      paclitaxel did not affect tumor volume, co-administration of paclitaxel
      (intravenous) and PSC833 (peroral) reduced tumor volume by 90%. Thus, p-gp is an
      important obstacle preventing paclitaxel entry into the brain, and inhibition of
      this transporter allows the drug to reach sensitive tumors within the CNS.

PMID- 12417571
TI  - Impaired glucose phosphorylation and transport in skeletal muscle cause insulin
      resistance in HIV-1-infected patients with lipodystrophy.
AB  - Insulin resistance is a frequently observed side effect of highly active
      antiretroviral therapy (HAART). Currently, very little is known about the
      mechanisms or specific tissues involved. We aimed to identify possible defects in
      skeletal muscle glucose uptake and metabolism in HIV patients receiving HAART.
      Whole-body glucose disposal and oxidation were determined by combination of the
      euglycemic-hyperinsulinemic clamp technique and indirect calorimetry. Muscle
      glucose uptake of the thighs was measured simultaneously by dynamic
      2[(18)F]fluoro-2-deoxy-D-glucose positron emission tomography. Patients receiving
      HAART had signs of lipodystrophy as confirmed by dual energy x-ray
      absorptiometry. Whole-body glucose disposal was significantly reduced in these
      patients compared with untreated patients. Analysis of kinetic constants using a
      three-compartment model indicated reduced skeletal glucose uptake caused by
      significantly impaired glucose transport and phosphorylation. Skeletal muscle
      glucose uptake was reduced by 66% in treated patients and explained 46% and 43%
      of whole-body glucose disposal in patients on HAART and therapy-naive patients,
      respectively. Insulin-stimulated whole-body oxidative and nonoxidative glucose
      disposal was significantly lower in the treated group, as was suppressive insulin
      action on lipolysis. To our knowledge, this is the first report providing in vivo
      evidence that, in lipodystrophic HIV patients, impaired glucose transport and
      phosphorylation cause reduced insulin-mediated glucose uptake.

PMID- 12417572
TI  - A novel dispersin protein in enteroaggregative Escherichia coli.
AB  - Enteroaggregative Escherichia coli (EAEC) is a diarrheal pathogen defined by its
      characteristic aggregative adherence (AA) to HEp-2 cells in culture. We have
      previously shown that EAEC strains secrete a 10-kDa protein that is immunogenic
      in a human EAEC challenge model. We report here that this protein is encoded by a
      gene (called aap) lying immediately upstream of that encoding the AggR
      transcriptional activator, and that aap is under AggR control. The product of aap
      has a typical signal sequence and is secreted to the extracellular milieu, where
      it remains noncovalently attached to the surface of the bacterium. EAEC aap
      mutants aggregate more intensely than the wild-type parent in a number of assays,
      forming larger aggregates and fewer individual bacteria. Infection of colonic
      biopsies with wild-type EAEC strain 042 and its aap mutant revealed more dramatic
      autoagglutination of the mutant compared with the wild-type parent. Our data
      suggest that the aap gene product participates in formation of a surface coat
      that acts to disperse the bacteria, thus partially counteracting aggregation
      mediated by aggregative adherence fimbriae. We have therefore named the aap gene
      product "dispersin," and we propose that it may be representative of a functional
      class of colonization factors. Since dispersin is expressed in vivo, is highly
      immunogenic, and is present in most EAEC strains, it holds considerable promise
      as an EAEC immunogen.

PMID- 12417573
TI  - The functional CD8 T cell response to HIV becomes type-specific in progressive
      disease.
AB  - High levels of HIV-specific CD8 T cells are demonstrable throughout HIV disease
      using laboratory assays that measure responses to consensus epitopes. In acute
      infection, the dynamics of the antiviral CD8 T cell response correlate well with
      the decline in viremia. However in chronic infection, although responses are
      detected against a broader spectrum of epitopes, virus-specific CD8 T cells are
      apparently unable to control viral replication. To investigate whether CD8 T
      cells responding to consensus epitopes may have lost their in vivo relevance in
      the chronic phase because of viral evolution driven by immune pressure, we
      compared the CD8 T cell response to CD4 T cell targets infected with either lab
      adapted HIV(IIIB) or the patient's own virus. The magnitude of the IFN-gamma
      response declined with disease progression, especially to autologous virus. T
      cell receptor (TCR) clonotypes of HIV(IIIB) and autologous virus-responding cells
      were determined by sequencing TCR beta chain variable (TCRBV) genes. In two of
      three asymptomatic donors, the dominant clonotypes overlapped, whereas in five
      symptomatic patients, the TCR clonotypes responding to HIV(IIIB) virus were
      completely different from those responding to autologous virus. Moreover, in
      cytolytic assays, T cell lines derived from IFN-gamma(+) cells responding to lab
      adapted or autologous virus cross-recognized target cells infected with either
      virus in asymptomatic subjects with shared TCR clonotypes but not in progressors
      with differing clonotypes. Therefore, in advanced-stage patients, viral-specific
      CD8 T cells recognizing consensus epitopes persist from an earlier response but
      no longer effectively recognize autologous virus.

PMID- 12417574
TI  - P311 induces a TGF-beta1-independent, nonfibrogenic myofibroblast phenotype.
AB  - P311, also called PTZ17, was identified by suppressive subtraction hybridization
      as potentially involved in smooth muscle (SM) myogenesis. P311 is an 8-kDa
      protein with several PEST-like motifs found in neurons and muscle. P311
      transfection into two fibroblast cell lines, NIH 3T3 and C3H10 T1/2, induced
      phenotypic changes consistent with myofibroblast transformation, including
      upregulation of SM alpha-actin and SM22, induction of FGF-2, VEGF, PDGF, and PDGF
      receptors, upregulation of integrins alpha3 and alpha5, and increased
      proliferation rate. The P311-mediated changes differed, however, from the well
      characterized myofibroblast in that P311 inhibited TGF-beta1, TGF-beta receptor
      2, and TGF-beta1-activating MMP-2 and MMP-9, with the resultant decrease in
      collagen 1 and 3 expression. The effect of P311 on collagen was overcome by
      exogenous TGF-beta1, indicating that the cells were responsive to TGF-beta1
      paracrine stimulus. In support of a role for P311 in vivo, immunohistochemical
      examination of human wounds showed P311 only in myofibroblasts and their
      activated precursors. To our knowledge, these studies are the first to implicate
      P311 in myofibroblast transformation, to demonstrate that transformation may
      occur independently of TGF-beta1, and to suggest that P311 may prevent fibrosis.

PMID- 12417575
TI  - Manipulation of lymphoid microenvironments in nonhuman primates by an inhibitor
      of the lymphotoxin pathway.
AB  - Reticular networks in lymphoid organs play critical roles in the organization of
      local microenvironments. A number of these elements are maintained by continual
      signaling through the lymphotoxin system. Evaluation of the lymphotoxin (LT)
      pathway in primates using a fusion protein decoy provides a unique opportunity to
      assess modulation of splenic microenvironments in a species with considerably
      greater background immunological activity compared with rodents. Within the
      germinal center microenvironment, treatment resulted in a collapse of follicular
      dendritic cell (FDC) networks and in the disappearance of a ringlike network of
      immune complex-carrying cells, although some other attributes of the germinal
      center appeared to be unaltered. Treatment also resulted in changes in the
      splenic marginal zone, a microenvironment where the architecture is notably
      different from that of the rodent. Cessation of treatment and recovery allowed us
      to monitor reemergence of these cell types and revealed that FDCs rely on LT
      dependent signals to recompact into appropriately positioned tight networks.
      Despite the loss of FDC networks, the primary Ab response to keyhole limpet
      hemocyanin was unaltered over a 20-day period. Manipulation of these
      microenvironments may represent a novel approach to modulating immune function in
      human disease.

PMID- 12417576
TI  - Visualization of the intracellular behavior of HIV in living cells.
AB  - To track the behavior of human immunodeficiency virus (HIV)-1 in the cytoplasm of
      infected cells, we have tagged virions by incorporation of HIV Vpr fused to the
      GFP. Observation of the GFP-labeled particles in living cells revealed that they
      moved in curvilinear paths in the cytoplasm and accumulated in the perinuclear
      region, often near the microtubule-organizing center. Further studies show that
      HIV uses cytoplasmic dynein and the microtubule network to migrate toward the
      nucleus. By combining GFP fused to the NH2 terminus of HIV-1 Vpr tagging with
      other labeling techniques, it was possible to determine the state of progression
      of individual particles through the viral life cycle. Correlation of
      immunofluorescent and electron micrographs allowed high resolution imaging of
      microtubule-associated structures that are proposed to be reverse transcription
      complexes. Based on these observations, we propose that HIV uses dynein and the
      microtubule network to facilitate the delivery of the viral genome to the nucleus
      of the cell during early postentry steps of the HIV life cycle.

PMID- 12417577
TI  - Accumulation of endoplasmic membranes and novel membrane-bound ribosome-signal
      recognition particle receptor complexes in Escherichia coli.
AB  - In Escherichia coli, ribosomes must interact with translocons on the membrane for
      the proper integration of newly synthesized membrane proteins, cotranslationally.
      Previous in vivo studies indicated that unlike the E. coli signal recognition
      particle (SRP), the SRP receptor FtsY is required for membrane targeting of
      ribosomes. Accordingly, a putative SRP-independent, FtsY-mediated ribosomal
      targeting pathway has been suggested (Herskovits, A.A., E.S. Bochkareva, and E.
      Bibi. 2000. Mol. Microbiol. 38:927-939). However, the nature of the early contact
      of ribosomes with the membrane, and the involvement of FtsY in this interaction
      are unknown. Here we show that in cells depleted of the SRP protein, Ffh or the
      translocon component SecE, the ribosomal targeting pathway is blocked downstream
      and unprecedented, membrane-bound FtsY-ribosomal complexes are captured.
      Concurrently, under these conditions, novel, ribosome-loaded intracellular
      membrane structures are formed. We propose that in the absence of a functional
      SRP or translocon, ribosomes remain jammed at their primary membrane docking
      site, whereas FtsY-dependent ribosomal targeting to the membrane continues. The
      accumulation of FtsY-ribosome complexes induces the formation of intracellular
      membranes needed for their quantitative accommodation. Our results with E. coli,
      in conjunction with recent observations made with the yeast Saccharomyces
      cerevisiae, raise the possibility that the SRP receptor-mediated formation of
      intracellular membrane networks is governed by evolutionarily conserved
      principles.

PMID- 12417578
TI  - Gag proteins of the two Drosophila telomeric retrotransposons are targeted to
      chromosome ends.
AB  - Drosophila telomeres are formed by two non-LTR retrotransposons, HeT-A and TART,
      which transpose only to chromosome ends. Successive transpositions of these
      telomeric elements yield arrays that are functionally equivalent to the arrays
      generated by telomerase in other organisms. In contrast, other Drosophila non-LTR
      retrotransposons transpose widely through gene-rich regions, but not to ends. The
      two telomeric elements encode very similar Gag proteins, suggesting that Gag may
      be involved in their unique targeting to chromosome ends. To test the intrinsic
      potential of these Gag proteins for targeting, we tagged the coding sequences
      with sequence of GFP and expressed the constructs in transiently transfected
      Drosophila-cultured cells. Gag proteins from both elements are efficiently
      transported into the nucleus where the protein from one element, HeT-A, forms
      structures associated with chromosome ends in interphase nuclei. Gag from the
      second element, TART, moves into telomere-associated structures only when
      coexpressed with HeT-A Gag. The results suggest that these Gag proteins are
      capable of delivering the retrotransposons to telomeres, although TART requires
      assistance from HeT-A. They also imply a symbiotic relationship between the two
      elements, with HeT-A Gag directing the telomere-specific targeting of the
      elements, whereas TART provides reverse transcriptase for transposition.

PMID- 12417580
TI  - Mechanical tension can specify axonal fate in hippocampal neurons.
AB  - Here we asked whether applied mechanical tension would stimulate undifferentiated
      minor processes of cultured hippocampal neurons to become axons and whether
      tension could induce a second axon in an already polarized neuron. Experimental
      tension applied to minor processes produced extensions that demonstrated axonal
      character, regardless of the presence of an existing axon. Towed neurites showed
      a high rate of spontaneous growth cone advance and could continue to grow out for
      1-3 d after towing. The developmental course of experimental neurites was found
      to be similar to that of unmanipulated spontaneous axons. Furthermore, the
      experimentally elongated neurites showed compartmentation of the axonal markers
      dephospho-tau and L-1 in towed outgrowth after 24 h. Extension of a second axon
      from an already polarized neuron does not lead to the loss of the spontaneous
      axon either immediately or after longer term growth. In addition, we were able to
      initiate neurites de novo that subsequently acquired axonal character even though
      spontaneous growth cone advance began while the towed neurite was still no longer
      than its sibling processes. This suggests that tension rather than the
      achievement of a critical neurite length determined axonal specification.

PMID- 12417581
TI  - Functional cooperation of epithelial heteromeric amino acid transporters
      expressed in madin-darby canine kidney cells.
AB  - The heteromeric amino acid transporters b(0,+)AT-rBAT (apical), y(+)LAT1-4F2hc,
      and possibly LAT2-4F2hc (basolateral) participate to the (re)absorption of
      cationic and neutral amino acids in the small intestine and kidney proximal
      tubule. We show now by immunofluorescence that their expression levels follow the
      same axial gradient along the kidney proximal tubule (S1>S2S3). We reconstituted
      their co-expression in MDCK cell epithelia and verified their polarized
      localization by immunofluorescence. Expression of b(0,+)AT-rBAT alone led to a
      net reabsorption of l-Arg (given together with l-Leu). Coexpression of
      basolateral y(+)LAT1-4F2hc increased l-Arg reabsorption and reversed l-Leu
      transport from (re)absorption to secretion. Similarly, l-cystine was (re)absorbed
      when b(0,+)AT-rBAT was expressed alone. This net transport was further increased
      by the coexpression of 4F2hc, due to the mobilization of LAT2 (exogenous and/or
      endogenous) to the basolateral membrane. In summary, apical b(0,+)AT-rBAT
      cooperates with y(+)LAT1-4F2hc or LAT2-4F2hc for the transepithelial reabsorption
      of cationic amino acids and cystine, respectively. The fact that the reabsorption
      of l-Arg led to the secretion of l-Leu demonstrates that the implicated
      heteromeric amino acid transporters function in epithelia as exchangers coupled
      in series and supports the notion that the parallel activity of unidirectional
      neutral amino acid transporters is required to drive net amino acid reabsorption.

PMID- 12417579
TI  - cGMP-mediated signaling via cGKIalpha is required for the guidance and
      connectivity of sensory axons.
AB  - Previous in vitro studies using cGMP or cAMP revealed a cross-talk between
      signaling mechanisms activated by axonal guidance receptors. However, the
      molecular elements modulated by cyclic nucleotides in growth cones are not well
      understood. cGMP is a second messenger with several distinct targets including
      cGMP-dependent protein kinase I (cGKI). Our studies indicated that the alpha
      isoform of cGKI is predominantly expressed by sensory axons during developmental
      stages, whereas most spinal cord neurons are negative for cGKI. Analysis of the
      trajectories of axons within the spinal cord showed a longitudinal guidance
      defect of sensory axons within the developing dorsal root entry zone in the
      absence of cGKI. Consequently, in cGKI-deficient mice, fewer axons grow within
      the dorsal funiculus of the spinal cord, and lamina-specific innervation,
      especially by nociceptive sensory neurons, is strongly reduced as deduced from
      anti-trkA staining. These axon guidance defects in cGKI-deficient mice lead to a
      substantial impairment in nociceptive flexion reflexes, shown using
      electrophysiology. In vitro studies revealed that activation of cGKI in embryonic
      dorsal root ganglia counteracts semaphorin 3A-induced growth cone collapse. Our
      studies therefore reveal that cGMP signaling is important for axonal growth in
      vivo and in vitro.

PMID- 12417582
TI  - A hypodermally expressed prolyl 4-hydroxylase from the filarial nematode Brugia
      malayi is soluble and active in the absence of protein disulfide isomerase.
AB  - The collagen prolyl 4-hydroxylase (P4H) class of enzymes catalyze the
      hydroxylation of prolines in the X-Pro-Gly repeats of collagen chains. This
      modification is central to the synthesis of all collagens. Most P4Hs are
      alpha(2)beta(2) tetramers with the catalytic activity residing in the alpha
      subunits. The beta subunits are identical to the enzyme protein disulfide
      isomerase. The nematode cuticle is a collagenous extracellular matrix required
      for maintenance of the worm body shape. Examination of the model nematode
      Caenorhabditis elegans has demonstrated that its unique P4Hs are essential for
      viability and body morphology. The filarial parasite Brugia malayi is a causative
      agent of lymphatic filariasis in humans. We report here on the cloning and
      characterization of a B. malayi P4H with unusual properties. The recombinant B.
      malayi alpha subunit, PHY-1, is a soluble and active P4H by itself, and it does
      not become associated with protein disulfide isomerase. The active enzyme form is
      a homotetramer with catalytic and inhibition properties similar to those of the
      C. elegans P4Hs. High levels of B. malayi phy-1 transcript expression were
      observed in all developmental stages examined, and its expression was localized
      to the cuticle-synthesizing hypodermal tissue in the heterologous host C.
      elegans. Although active by itself, the B. malayi PHY-1 was not able to replace
      enzyme function in a C. elegans P4H mutant.

PMID- 12417583
TI  - Purification, cloning, expression, and properties of mycobacterial trehalose
      phosphate phosphatase.
AB  - The trehalose-phosphate phosphatase (TPP) was purified from the cytosol of
      Mycobacterium smegmatis to near homogeneity using a variety of conventional steps
      to achieve a purification of about 1600-fold with a yield of active enzyme of
      about 1%. Based on gel filtration, the active enzyme had a molecular weight of
      about 27,000, and the most purified fraction also gave a major band on SDS-PAGE
      corresponding to a molecular weight of about 27,000. A number of peptides from
      the 27-kDa protein were sequenced and these sequences showed considerable
      homology to the trehalose-P phosphatase (otsB) of Escherichia coli. Based on
      these peptides, the M. smegmatis gene for TPP was cloned and expressed in E.
      coli. The recombinant protein was synthesized with a (His)(6) tag at the amino
      terminus. Most of the TPP activity in the crude E. coli sonicate was initially
      found in the membrane fraction, but it became solubilized in the presence of 0.2%
      Sarkosyl. The solubilized protein was purified to apparent homogeneity on a metal
      ion column and this fraction had high phosphatase activity that was completely
      specific for trehalose-P. The purified enzyme, either isolated from M. smegmatis,
      or expressed in E. coli, rapidly dephosphorylated trehalose-6-P, but had
      essentially no activity on any other sugar phosphates, or on p-nitrophenyl
      phosphate. The K(m) for trehalose-6-P was about 1.6 mm, and the pH optimum was
      about 7.5. The native enzyme showed an almost absolute requirement for Mg(2+) and
      was not very active with Mn(2+), whereas both of these cations were equally
      effective with the recombinant TPP. The enzyme activity was inhibited by the
      antibiotics, diumycin and moenomycin, but not by a number of other antibiotics or
      trehalose analogs. TPP activity was strongly inhibited by the detergents,
      Sarkosyl and deoxycholate, even at 0.025%, but it was not inhibited by Nonidet P
      40, Triton X-100, or octyl glucoside, even at concentrations up to 0.3%. The
      purified enzyme was stable to heating at 60 degrees C for up to 6 min, but was
      slowly inactivated at 70 degrees C. Circular dichroism studies on recombinant TPP
      indicate that the secondary structure of this protein has considerable beta
      pleated sheet and is very compact. TPP may play a key role in the biosynthesis of
      trehalose compounds, such as trehalose mycolates, and therefore may represent an
      excellent target site for chemotherapy against tuberculosis and other
      mycobacterial diseases.

PMID- 12417584
TI  - Mechanism and substrate specificity of the flavin reductase ActVB from
      Streptomyces coelicolor.
AB  - ActVB is the NADH:flavin oxidoreductase participating in the last step of
      actinorhodin synthesis in Streptomyces coelicolor. It is the prototype of a whole
      class of flavin reductases with both sequence and functional similarities. The
      mechanism of reduction of free flavins by ActVB has been studied. Although ActVB
      was isolated with FMN bound, we have demonstrated that it is not a flavoprotein.
      Instead, ActVB contains only one flavin binding site, suitable for the flavin
      reductase activity and with a high affinity for FMN. In addition, ActVB proceeds
      by an ordered sequential mechanism, where NADH is the first substrate. Whereas
      ActVB is highly specific for NADH, it is able to catalyze the reduction of a
      great variety of natural and synthetic flavins, but with K(m) values ranging from
      1 microm (FMN) to 69 microm (lumiflavin). We show that both the ribitol-phosphate
      chain and the isoalloxazine ring contribute to the protein-flavin interaction.
      Such properties are unique and set the ActVB family apart from the well
      characterized Fre flavin reductase family.

PMID- 12417585
TI  - Structure-function relationship between the human chemokine receptor CXCR3 and
      its ligands.
AB  - I-TAC, IP10, and Mig are interferon-gamma inducible CXC chemokines that share the
      same G-protein-coupled receptor CXCR3, which is preferentially expressed on Th1
      lymphocytes. We have explored the structure-function relationship of the CXCR3
      ligands, in particular of I-TAC, which has highest affinity for CXCR3 and is the
      most potent agonist. A potent antagonist for CXCR3 was obtained by NH(2)-terminal
      truncation of I-TAC. I-TAC (4-73), which lacks the first three residues, has no
      agonistic activity but competes for the binding of I-TAC to CXCR3-bearing cells
      and inhibits migration and Ca(2+) changes in such cells in response to
      stimulation with I-TAC, IP10, and Mig. It does also not induce internalization of
      CXCR3, which is in support of the lack of agonistic effects. Hybrid chemokines
      between I-TAC and IP10 were used to identify regions responsible for the higher
      activity of I-TAC. I-TAC-like IP10 analogs are obtained by substituting the NH(2)
      terminus (residues 1-8) or N-loop region (residues 12-17) of IP10 with those of I
      TAC, suggesting that the differences in function of the CXCR3 ligands can be
      assigned to distinct regions and that these regions are interchangeable.
      Structure-activity studies with Mig showed that the extended basic COOH-terminal
      region, which is not present in I-TAC and IP10, is important for binding and
      activity.

PMID- 12417586
TI  - Functional dissection of the eukaryotic-specific tRNA-interacting factor of lysyl
      tRNA synthetase.
AB  - In the cytoplasm of higher eukaryotic cells, aminoacyl-tRNA synthetases (aaRSs)
      have polypeptide chain extensions appended to conventional prokaryotic-like
      synthetase domains. The supplementary domains, referred to as tRNA-interacting
      factors (tIFs), provide the core synthetases with potent tRNA-binding capacities,
      a functional requirement related to the low concentration of free tRNA prevailing
      in the cytoplasm of eukaryotic cells. Lysyl-tRNA synthetase is a component of the
      multi-tRNA synthetase complex. It exhibits a lysine-rich N-terminal polypeptide
      extension that increases its catalytic efficiency. The functional
      characterization of this new type of tRNA-interacting factor has been conducted.
      Here we describe the systematic substitution of the 13 lysine or arginine
      residues located within the general RNA-binding domain of hamster LysRS made of
      70 residues. Our data show that three lysine and one arginine residues are major
      building blocks of the tRNA-binding site. Their mutation into alanine led to a
      reduced affinity for tRNA(3)(Lys) or minimalized tRNA mimicking the acceptor
      TPsiC stem-loop of tRNA(3)(Lys) and a decrease in catalytic efficiency similar to
      that observed after a complete deletion of the N-terminal domain. Moreover,
      covalent continuity between the tRNA-binding and core domain is a prerequisite
      for providing LysRS with a tRNA binding capacity. Thus, our results suggest that
      the ability of LysRS to promote tRNA(Lys) networking during translation or to
      convey tRNA(3)(Lys) into the human immunodeficiency virus type 1 viral particles
      rests on the addition in evolution of this tRNA-interacting factor.

PMID- 12417587
TI  - Translocation of analogues of the antimicrobial peptides magainin and buforin
      across human cell membranes.
AB  - Cationic antimicrobial peptides play important roles in innate immunity. Compared
      with extensive studies on peptide-bacteria interactions, little is known about
      peptide-human cell interactions. Using human cervical carcinoma HeLa and
      fibroblastic TM12 cells, we investigated the cellular uptake of fluorescent
      analogues of the two representative antimicrobial peptides magainin 2 and buforin
      2 in comparison with the representative Arg-rich cell-penetrating Tat-(47-57)
      peptide (YGRKKRRQRRR). The dose, time, temperature, and energy dependence of
      translocation suggested that the three peptides cross cell membranes through
      different mechanisms. The magainin peptide was internalized within a time scale
      of tens of minutes. The cooperative concentration dependence of uptake suggested
      that the peptide forms a pore as an intermediate similar to the observations in
      model membranes. Furthermore, the translocation was coupled with cytotoxicity,
      which was larger for tumor HeLa cells. In contrast, the buforin peptide
      translocated within 10 min by a temperature-independent, less concentration
      dependent passive mechanism without showing any significant cytotoxicity at the
      highest concentration investigated (100 microm). The uptake of the Tat peptide
      was proportional to the peptide concentration, and the concentration dependence
      was lost upon ATP depletion. The peptide exhibited a moderate cytotoxicity at
      higher concentrations. The time course did not show saturation even after 120
      min. The buforin peptide, covalently attached to the 28-kDa green fluorescent
      protein, also entered cells, suggesting a potency of the peptide as a vector for
      macromolecular delivery into cells. However, the mechanism appeared to be
      different from that of the parent peptide.

PMID- 12417588
TI  - c-Jun N-terminal kinase (JNK) mediates feedback inhibition of the insulin
      signaling cascade.
AB  - Activation of the c-Jun N-terminal kinase (JNK) by proinflammatory cytokines
      inhibits insulin signaling, at least in part, by stimulating phosphorylation of
      rat/mouse insulin receptor substrate 1 (Irs1) at Ser(307) (Ser(312) in human
      IRS1). Here we show that JNK mediated feedback inhibition of the insulin signal
      in mouse embryo fibroblasts, 3T3-L1 adipocytes, and 32D(IR) cells. Insulin
      stimulation of JNK activity required phosphatidylinositol 3-kinase and Grb2
      signaling. Moreover, activation of JNK by insulin was inhibited by a cell
      permeable peptide that disrupted the interaction of JNK with cellular proteins.
      However, the direct binding of JNK to Irs1 was not required for its activation by
      insulin, whereas direct binding was required for Ser(307) phosphorylation of
      Irs1. Insulin-stimulated Ser(307) phosphorylation was reduced 80% in cells
      lacking JNK1 and JNK2 or in cells expressing a mutant Irs1 protein lacking the
      JNK binding site. Reduced Ser(307) phosphorylation was directly related to
      increased insulin-stimulated tyrosine phosphorylation, Akt phosphorylation, and
      glucose uptake. These results support the hypothesis that JNK is a negative
      feedback regulator of insulin action by phosphorylating Ser(307) in Irs1.

PMID- 12417589
TI  - Proteolytic processing of the hepatitis B virus e antigen precursor. Cleavage at
      two furin consensus sequences.
AB  - The Hepatitis B virus P22 protein is a nonstructural protein that is the
      precursor of the 17-kDa secreted e antigen (HBeAg). The mature HBeAg is obtained
      after the removal of the C-terminal region of P22, a process which involves a
      proprotein convertase. Our studies show first that the protease could cleave P22
      at the C-terminal side of Arg(167) or Arg(154) and second, that the maturation
      process can be either done in one step or in two steps with the generation of a
      processing intermediate (P20). Our data also demonstrate that the removal of the
      P22 C terminus, which occurs mainly in the trans-Golgi network, can also be
      achieved after exocytosis. Keeping in mind this characteristic and the amino acid
      sequence of the cleavage sites, we concluded that furin is involved in the
      maturation of the HBeAg. In addition, we show that in our experimental system,
      the HBeAg is a 164-amino acid protein and not a 159-amino acid protein as
      previously reported.

PMID- 12417590
TI  - Interleukin-23 promotes a distinct CD4 T cell activation state characterized by
      the production of interleukin-17.
AB  - Interleukin (IL)-17 is a pro-inflammatory cytokine that is produced by activated
      T cells. Despite increasing evidence that high levels of IL-17 are associated
      with several chronic inflammatory diseases including rheumatoid arthritis,
      psoriasis, and multiple sclerosis, the regulation of its expression is not well
      characterized. We observe that IL-17 production is increased in response to the
      recently described cytokine IL-23. We present evidence that murine IL-23, which
      is produced by activated dendritic cells, acts on memory T cells, resulting in
      elevated IL-17 secretion. IL-23 also induced expression of the related cytokine
      IL-17F. IL-23 is a heterodimeric cytokine and shares a subunit, p40, with IL-12.
      In contrast to IL-23, IL-12 had only marginal effects on IL-17 production. These
      data suggest that during a secondary immune response, IL-23 can promote an
      activation state with features distinct from the well characterized Th1 and Th2
      profiles.

PMID- 12417591
TI  - Human umbilical vein endothelium-derived cells retain potential to differentiate
      into smooth muscle-like cells.
AB  - Mouse embryonic stem-derived cells were recently shown to differentiate into
      endothelial and smooth muscle cells. In the present study, we investigated
      whether human umbilical vein endothelium-derived cells retain the potential to
      differentiate into smooth muscle cells. Examination of biochemical markers,
      including basic calponin, SM22alpha, prostaglandin E synthase, von Willebrand
      factor, and PECAM-1, as well as cell contractility, showed that whereas
      endothelium-derived cells cultured with fibroblast growth factor can be
      characterized as endothelial cells, when deprived of fibroblast growth factor, a
      significant fraction differentiates into smooth muscle-like cells. Reapplication
      of fibroblast growth factor reversed this differentiation. Activin A was up
      regulated in fibroblast growth factor-deprived, endothelium-derived cells;
      moreover, the inhibitory effects of exogenous follistatin and overexpressed Smad7
      on smooth muscle-like differentiation confirmed that the differentiation was
      driven by activin A signaling. These findings indicate that when deprived of
      fibroblast growth factor, human umbilical vein endothelium-derived cells are
      capable of differentiating into smooth muscle-like cells through activin A
      induced, Smad-dependent signaling, and that maintenance of the endothelial cell
      phenotype and differentiation into smooth muscle-like cells are reciprocally
      controlled by fibroblast growth factor-1 and activin A.

PMID- 12417592
TI  - Phosphorylation of spinophilin modulates its interaction with actin filaments.
AB  - Spinophilin is a protein phosphatase 1 (PP1)- and actin-binding protein that
      modulates excitatory synaptic transmission and dendritic spine morphology. We
      report that spinophilin is phosphorylated in vitro by protein kinase A (PKA).
      Phosphorylation of spinophilin was stimulated by treatment of neostriatal neurons
      with a dopamine D1 receptor agonist or with forskolin, consistent with
      spinophilin being a substrate for PKA in intact cells. Using tryptic
      phosphopeptide mapping, site-directed mutagenesis, and microsequencing analysis,
      we identified two major sites of phosphorylation, Ser-94 and Ser-177, that are
      located within the actin-binding domain of spinophilin. Phosphorylation of
      spinophilin by PKA modulated the association between spinophilin and the actin
      cytoskeleton. Following subcellular fractionation, unphosphorylated spinophilin
      was enriched in the postsynaptic density, whereas a pool of phosphorylated
      spinophilin was found in the cytosol. F-actin co-sedimentation and overlay
      analysis revealed that phosphorylation of spinophilin reduced the stoichiometry
      of the spinophilin-actin interaction. In contrast, the ability of spinophilin to
      bind to PP1 remained unchanged. Taken together, our studies suggest that
      phosphorylation of spinophilin by PKA modulates the anchoring of the spinophilin
      PP1 complex within dendritic spines, thereby likely contributing to the efficacy
      and plasticity of synaptic transmission.

PMID- 12417593
TI  - Activation of RAF-1 through Ras and protein kinase Calpha mediates 1alpha,25(OH)2
      vitamin D3 regulation of the mitogen-activated protein kinase pathway in muscle
      cells.
AB  - We have previously shown that stimulation of proliferation of avian embryonic
      muscle cells (myoblasts) by 1alpha,25(OH)(2)-vitamin D(3) (1alpha,25(OH)(2)D(3))
      is mediated by activation of the mitogen-activated protein kinase (MAPK; ERK1/2).
      To understand how 1alpha,25(OH)(2)D(3) up-regulates the MAPK cascade, we have
      investigated whether the hormone acts upstream through stimulation of Raf-1 and
      the signaling mechanism by which this effect might take place. Treatment of chick
      myoblasts with 1alpha,25(OH)(2)D(3) (1 nm) caused a fast increase of Raf-1 serine
      phosphorylation (1- and 3-fold over basal at 1 and 2 min, respectively),
      indicating activation of Raf-1 by the hormone. These effects were abolished by
      preincubation of cells with a specific Ras inhibitor peptide that involves Ras in
      1alpha,25(OH)(2)D(3) stimulation of Raf-1. 1alpha,25(OH)(2)D(3) rapidly induced
      tyrosine de-phosphorylation of Ras-GTPase-activating protein, suggesting that
      inhibition of Ras-GTP hydrolysis is part of the mechanism by which
      1alpha,25(OH)(2)D(3) activates Ras in myoblasts. The protein kinase C (PKC)
      inhibitors calphostin C, bisindolylmaleimide I, and Ro 318220 blocked
      1alpha,25(OH)(2)D(3)-induced Raf-1 serine phosphorylation, revealing that hormone
      stimulation of Raf-1 also involves PKC. In addition, transfection of muscle cells
      with an antisense oligodeoxynucleotide against PKCalpha mRNA suppressed serine
      phosphorylation by 1alpha,25(OH)(2)D(3). The increase in MAPK activity and
      tyrosine phosphorylation caused by 1alpha,25(OH)(2)D(3) could be abolished by Ras
      inhibitor peptide, compound PD 98059, which prevents the activation of MEK by Raf
      1, or incubation of cell lysates before 1alpha,25(OH)(2)D(3) exposure with an
      anti-Raf-1 antibody. In conclusion, these results demonstrate for the first time
      in a 1alpha,25(OH)(2)D(3) target cell that activation of Raf-1 via Ras and
      PKCalpha-dependent serine phosphorylation plays a central role in hormone
      stimulation of the MAPK-signaling pathway leading to muscle cell proliferation.

PMID- 12417594
TI  - The LIM protein Ajuba is recruited to cadherin-dependent cell junctions through
      an association with alpha-catenin.
AB  - Cell-cell adhesive events affect cell growth and fate decisions and provide
      spatial clues for cell polarity within tissues. The complete molecular
      determinants required for adhesive junction formation and their function are not
      completely understood. LIM domain-containing proteins have been shown to be
      present at cell-cell contact sites and are known to shuttle into the nucleus
      where they can affect cell fate and growth; however, their precise localization
      at cell-cell contacts, how they localize to these sites, and what their functions
      are at these sites is unknown. Here we show that, in primary keratinocytes, the
      LIM domain protein Ajuba is recruited to cadherin-dependent cell-cell adhesive
      complexes in a regulated manner. At cadherin adhesive complexes Ajuba interacts
      with alpha-catenin, and alpha-catenin is required for efficient recruitment of
      Ajuba to cell junctions. Ajuba also interacts directly with F-actin.
      Keratinocytes from Ajuba null mice exhibit abnormal cell-cell junction formation
      and/or stability and function. These data reveal Ajuba as a new component at
      cadherin-mediated cell-cell junctions and suggest that Ajuba may contribute to
      the bridging of the cadherin adhesive complexes to the actin cytoskeleton and as
      such contribute to the formation or strengthening of cadherin-mediated cell-cell
      adhesion.

PMID- 12417595
TI  - Identification of allosteric peptide agonists of CXCR4.
AB  - The chemokine receptor CXCR4 is a co-receptor for T-tropic strains of HIV-1. A
      number of small molecule antagonists of CXCR4 are in development but all are
      likely to lead to adverse effects due to the physiological function of CXCR4. To
      prevent these complications, allosteric agonists may be therapeutically useful as
      adjuvant therapy in combination with small molecule antagonists. A synthetic cDNA
      library coding for 160,000 different SDF-based peptides was screened for CXCR4
      agonist activity in a yeast strain expressing a functional receptor. Peptides
      that activated CXCR4 in an autocrine manner induced colony formation. Two
      peptides, designated RSVM and ASLW, were identified as novel agonists that are
      insensitive to the CXCR4 antagonist AMD3100. In chemotaxis assays using the acute
      lymphoblastic leukemia cell line CCRF-CEM, RSVM behaves as a partial agonist and
      ASLW as a superagonist. The superagonist activity of ASLW may be related to its
      inability to induce receptor internalization. In CCRF-CEM cells, the two peptides
      are also not inhibited by another CXCR4 antagonist, T140, or the neutralizing
      monoclonal antibodies 12G5 and 44717.111. These results suggest that alternative
      agonist-binding sites are present on CXCR4 that could be screened to develop
      molecules for therapeutic use.

PMID- 12417596
TI  - Two novel metabolic pathways of 22-oxacalcitriol (OCT). C-25 dehydration and C-3
      epimerization and biological activities of novel OCT metabolites.
AB  - 22-Oxacalcitriol (OCT) is an analog of calcitriol, characterized by potent
      differentiation-inducing activity and low calcemic liability. The metabolism of
      OCT has been studied and its polar metabolites, such as 24/26-hydroxylated-OCT
      and hexanor-1 alpha,20-dihydroxyvitamin D(3) (1 alpha,20(OH)(2)D(3)), have been
      identified. In contrast, little is known about the less polar metabolites of OCT,
      which have been found in relatively large amounts. In this study, the in vitro
      metabolism of OCT was studied in UMR 106, Caco-2, and LLC-PK(1) cells to identify
      the less polar metabolites and to assess their biological activity. OCT was
      initially metabolized to three less polar metabolites, 3-epi-OCT and two
      dehydrates, 25-dehydroxy- 25-ene-22-oxa-1 alpha(OH)D(3) (25-ene-22-oxa-1
      alpha(OH)D(3)) and 25-dehydroxy-24-ene-22-oxa-1 alpha(OH)D(3) (24-ene-22-oxa-1
      alpha(OH)D(3)). We also observed further metabolites, the two C-3 epimers of the
      C-25 dehydrates, 25-ene-3-epi-22-oxa-1 alpha(OH)D(3) and 24-ene-3-epi-22-oxa-1
      alpha(OH)D(3). The structures of these metabolites were successfully assigned by
      (1)H NMR and LC-MS analyses. The three cell lines differ in their ability to
      metabolize OCT through the C-3 epimerization or the C-25 dehydration pathway. The
      biological activity of the OCT metabolites assessed by a luciferase reporter gene
      transcriptional activation system, binding assays for the vitamin D receptor
      (VDR) and vitamin D-binding protein (DBP), and assays for regulatory activities
      of cell differentiation and proliferation was found to be lower than that of OCT.
      Thus, both the C-3 epimerization and C-25 dehydration may work to reduce the
      biological activity of OCT.

PMID- 12417597
TI  - Low incidence of p53 mutations in well-differentiated tongue squamous cell
      carcinoma in Japan.
AB  - BACKGROUND: Despite an increasing number of patients suffering from squamous cell
      carcinomas of the tongue, little is known about the molecular mechanisms involved
      in the origin and development of these neoplasms. METHODS: We screened
      microdissected tongue squamous cell carcinoma (TSC) specimens from 28
      consecutive, previously untreated, Japanese patients for mutations in the p53
      tumor-suppressor gene single-strand conformation polymorphism analysis (exons 5,
      6, 7, 8) and direct genomic sequencing. RESULTS: Among them, 24 tumor specimens
      were well differentiated, three moderately and one poorly differentiated,
      according to the WHO classification. Mutations in the p53 tumor-suppressor gene
      were detected in only two out of the 28 (7%) tumor specimens. One was well
      differentiated and the other was poorly differentiated. CONCLUSIONS: Our results
      suggest that p53 gene mutations are less frequent in well differentiated TSC.
      These results indicate that mutations in the p53 gene may not be strongly
      involved in the development of well differentiated TSC.

PMID- 12417598
TI  - p53 and c-erbB-2 but not bcl-2 are predictive of metastasis-free survival in
      breast cancer patients receiving post-mastectomy adjuvant radiotherapy in Taiwan.
AB  - BACKGROUND: Patients with breast cancer often receive radiotherapy after
      mastectomy if they are at a high risk of local recurrence, but the prognosis
      varies among patients. We conducted a study to evaluate p53, bcl-2 and c-erbB-2
      as predictors of prognosis in breast cancer patients receiving post-mastectomy
      radiotherapy, which has not been well defined in the Taiwanese population.
      METHODS: We recruited 74 consecutive patients with primary operable breast cancer
      who were treated with mastectomy followed by locoregional radiotherapy and
      studied the presence of p53, bcl-2 and c-erbB-2 expressions in tumor tissues by
      immunohistochemical staining. Associations between the protein expressions and
      clinical outcomes, including local recurrence-free survival (LRFS), metastasis
      free survival (MFS) and overall survival (OS), were evaluated. RESULTS: The
      median follow-up time was 55 months. Expressions of p53, bcl-2 and c-erbB-2 were
      observed in 14 (19%), 28 (38%) and 39 (53%) patients, respectively. Both p53 and
      c-erbB-2 were significant predictors of MFS. The 5-year MFS for p53-negative and
      p53-positive tumors were 61.2 and 35.7% (P = 0.01) and 5-year MFS for c-erbB-2
      negative and c-erbB-2-positive tumors were 71.3 and 42.4% (P = 0.01). Whereas
      expression of bcl-2 protein is associated with favorable clinicopathological
      features, it was not related to LRFS, MFS or OS. Multivariate analyses confirmed
      c-erbB-2 and p53 expressions as predictors of MFS independent of tumor size,
      histological grading and lymph node involvement. CONCLUSION: Expressions of p53
      and c-erbB-2 are independent predictors of MFS in this Taiwanese population.
      Further research should be conducted on their application in the treatment and
      follow-up of patients.

PMID- 12417599
TI  - Evaluation of esophageal cancer by positron emission tomography.
AB  - BACKGROUND: A retrospective study was performed to determine the indications for
      positron emission tomography (PET) using [(18)F]fluorodeoxyglucose (FDG) in
      patients with esophageal cancer, including those with early cancer, and to
      investigate whether the tumor-to-normal ratio (T/N ratio) could be used as a
      substitute for the standardized uptake value (SUV). METHODS: Thirty-six patients
      were included in the study. Thirty-one patients who had 36 biopsy-proven lesions
      (35 squamous cell carcinomas and one small cell carcinoma) underwent PET study
      prior to treatment. PET images were evaluated visually and the relationship
      between the depth of invasion and the PET findings were examined in 22 lesions of
      19 patients from whom specimens were obtained from the primary tumor by surgery
      or endoscopic mucosal resection. PET results were also compared with computed
      tomography (CT) and endoscopic ultrasonography (EUS) for detection of regional
      lymph node metastases in 18 patients who underwent extended lymph node
      dissection. Five patients underwent PET studies for the detection of recurrence
      and the PET findings were compared with their CT findings. The T/N ratio and the
      SUV were calculated for 20 primary tumors. RESULTS: Among the 15 tumors that were
      pT1b or greater, all 15 were positive on PET and all seven of the lesions
      confined to the mucosa (Tis or T1a) were negative. The sensitivity, specificity
      and accuracy of detecting nodal involvement were, respectively, 37.5, 96.1 and
      88.3% by CT, 30.8, 88.5 and 81.0% by EUS and 41.7, 100 and 92.2% by PET. More
      sites of recurrence were detected by PET than by CT. There was no statistically
      significant correlation between the SUV and the T/N ratio. CONCLUSIONS: PET
      imaging can detect primary esophageal cancer with a depth of invasion of T1b or
      greater, but Tis and T1a tumors are undetectable. PET seems to be more accurate
      than CT or EUS for diagnosing lymph node metastasis. The T/N ratio cannot be used
      as a substitute for the SUV.

PMID- 12417600
TI  - Helpful parameter for malignant potential of gastrointestinal stromal tumors
      (GIST).
AB  - BACKGROUND: Although a series of histopathological criteria have been suggested,
      the prediction of the malignant potential of gastrointestinal stromal tumors
      (GIST) is still difficult. The older literature called all gastrointestinal
      stromal tumors smooth muscle tumors or mixed GIST with true smooth muscle tumors.
      Reports on GIST including homogeneous cases were rare. METHODS: We examined 73
      cases of GIST, which were immunohistochemically positive for c-kit and/or CD34,
      and mainly focused on the correlation between mitotic count and the other
      clinicopathological features to establish any helpful and reproducible parameters
      to indicate the malignant potential and to be used practically and objectively in
      the routine histopathological diagnosis of GIST. RESULTS: The results showed that
      there was a statistically significant difference in mitotic count between benign
      and malignant groups. Other proposed parameters, such as high cellularity, tumor
      size > or =5 cm, stomach and intestinal location, hemorrhage, necrosis, p53
      expression and Ki-67 labeling index >10%, were frequently observed in tumors with
      mitotic figure. Three patients with one mitotic figure in 50HPF died from
      metastasis or recurrence of the tumors. CONCLUSIONS: Ki-67 index and cellularity
      should be used as predictors for the malignant potential of GIST. When other
      morphological features appear benign, mitotic count might also be a helpful
      practical factor in the prediction of the malignant potential of GIST.

PMID- 12417601
TI  - Oral uracil/ftorafur (UFT) plus leucovorin as first-line chemotherapy and salvage
      therapy with weekly high-dose 5-fluorouracil/leucovorin for the treatment of
      metastatic colorectal cancer.
AB  - BACKGROUND: The purpose of this study was to determine the efficacy and toxicity
      of uracil/ftorafur (UFT) plus oral leucovorin (LV) as first-line chemotherapy for
      patients with metastatic colorectal cancer and salvage chemotherapy with weekly
      high-dose 5-fluorouracil (5-FU)/LV 24 h infusion. METHODS: Adult patients with no
      prior chemotherapy for metastatic diseases were enrolled to receive oral UFT 300
      mg/m(2)/d plus LV 90 mg/d for 28 days. Treatment was given continuously for 28
      days followed by a 7 day rest period from all treatment. For UFT failed patients,
      weekly 24 h infusion of 5-FU 2600 mg/m(2) plus LV 100 mg/m(2) was used as salvage
      therapy. RESULTS: Fifty-one patients with metastatic colorectal cancer were
      enrolled in the study. The objective response rate was 29.5% [95% confidence
      interval (CI), 16.8-45.2%] among the 44 evaluable patients and 25.5% in the
      intent-to-treat population. The median survival for all 51 patients was 16.6
      months. The median time to progression was 5.9 months. Diarrhea was the major
      adverse effect of UFT/LV that made patients reduce dosage. Grade 3 or 4 diarrhea
      developed in 13.7% of patients. Twenty-six patients were treated with weekly 24 h
      infusional 5-FU/LV as salvage therapy and only two patients responded.
      CONCLUSION: Our results suggest that this 28 day schedule of UFT/LV regimen may
      offer a well-tolerated, full oral treatment option with efficacy that appears
      comparable to that of intravenous 5-FU/LV regimens. Parenteral 5-FU/LV as salvage
      therapy for UFT refractory patients is not recommended.

PMID- 12417602
TI  - Mutation and expression of the beta-catenin-interacting protein ICAT in human
      colorectal tumors.
AB  - BACKGROUND: Aberrant activation of Wnt signaling caused by mutations in the tumor
      suppressor adenomatous polyposis coli or beta-catenin is a critical event in the
      development of human colorectal tumors. We have recently identified the ICAT
      gene, which encodes a small protein that interacts with beta-catenin and
      represses Wnt signaling. METHODS: We examined the prevalence of mutations in the
      entire ICAT coding sequence and intronic splice donor and acceptor regions of
      ICAT by PCR-SSCP and also the expression of the ICAT gene by RT-PCR. RESULTS: The
      ICAT gene was mapped to chromosome 1p36.1-p36.2, which is implicated in the
      pathogenesis of various types of cancers. However, no mutations in ICAT were
      detected among 128 colorectal tumors. Instead, ICAT was found to be overexpressed
      in almost half of colorectal carcinomas. Cases exhibiting ICAT overexpression
      showed a significantly higher incidence of well-differentiated adenocarcinoma and
      positive lymphatic permeation. CONCLUSION: Our results suggest that ICAT is not
      the putative tumor suppressor on 1p36.1-p36.2, although aberrant overexpression
      of ICAT may play a role in the pathogenesis of colorectal carcinomas.

PMID- 12417603
TI  - Randomized controlled trial to evaluate splenectomy in total gastrectomy for
      proximal gastric carcinoma: Japan clinical oncology group study JCOG 0110-MF.
AB  - A randomized controlled trial has started in Japan to evaluate the role of
      splenectomy in the surgical management of gastric cancer. Patients with T2 or
      deeper carcinoma in the proximal third of the stomach are intra-operatively
      randomized to either splenectomy or spleen preservation. Tumors invading the
      greater curvature of the stomach or those with apparent nodal involvement in the
      splenic hilum are excluded. Surgeons in 29 specialized institutions will recruit
      500 patients. Endpoints are overall survival, operative morbidity, operative time
      and blood loss.

PMID- 12417604
TI  - Acute myeloid leukemia complicated with staghorn calculus.
AB  - An 11-year-old girl who presented with hyperleukocytosis accompanied by
      significant increases in serum uric acid and lactate dehydrogenase levels was
      discovered to be suffering from acute myeloid leukemia (AML). Subsequently a
      staghorn calculus was identified 22 months after the start of chemotherapy. The
      diagnosis of staghorn calculi was suggested by plain abdominal X-ray and
      ultrasonography. This paper describes the course of an adolescent patient with
      AML and focuses specifically upon her urological complications. To the best of
      our knowledge, this is the first reported pediatric case of AML complicated with
      staghorn calculi, which developed following repeated episodes of septicemia.

PMID- 12417605
TI  - A novel six-nucleotide insertion in exon 4 of the MEN1 gene, 878insCTGCAG, in
      three patients with familial insulinoma and primary hyperparathyroidism.
AB  - Three Japanese patients (a man and his two sons) in a family with clinical
      diagnosis of familial multiple endocrine neoplasia type 1 (MEN1) suffered from
      insulinoma(s), primary hyperparathyroidism and pituitary microadenoma. Genomic
      DNA of the patients was analyzed by sequencing for the MEN1 gene and an insertion
      of six nucleotides, CTGCAG, in exon 4, resulting in insertion of two amino acids,
      Leu-Gln, after the 256th amino acid of the menin (256insLQ), was identified.
      CTGCAG is a palindromic sequence and repeated twice in the wild-type allele
      (nucleotides 879-890). It is speculated that mutations involving only exon 4 of
      the MEN1 gene might induce development of insulinoma(s).

PMID- 12417606
TI  - Report of the fifteenth international symposium of the foundation for promotion
      of cancer research: new horizons in the diagnosis and treatment of hematological
      malignancies based on molecular genetic features.
AB  - The Fifteenth International Symposium of the Foundation for Promotion of Cancer
      Research entitled 'New Horizons in the Diagnosis and Treatment of Hematological
      Malignancies Based on Molecular Genetic Features' was held in Tokyo on January 15
      17, 2002. Twenty-nine invited speakers, including 12 from abroad and 17 from
      Japan, presented the updated results of their research. After an overview of the
      classification of hematological malignancies, new findings on some disease
      entities based on novel immunophenotypic and molecular genetic features were
      presented. The results of gene expression profiling and BCL6 and C-MYC gene
      rearrangement in diffuse large B-cell lymphoma were presented and oncogenic
      mechanism of acute myeloid leukemia was discussed. In the treatment of non
      Hodgkin's lymphoma and acute leukemia, the present consensus and future
      directions were discussed based on the results of multicenter trials in the USA
      and Japan. As a molecular targeting therapy, the remarkable effect of a BCR-ABL
      tyrosine kinase inhibitor, STI571, in chronic myeloid leukemia and
      gastrointestinal stromal tumor was presented. Thereafter, promising results of
      active immunotherapy, chimeric anti-CD20 monoclonal antibody, anti-CD20
      radioimmunoconjugate and anti-CD22 immunotoxin for B-cell lymphoma were
      presented. Finally, recent advances in allogeneic hematopoietic stem cell
      transplantation were discussed, focusing on reduced-intensity preparative
      regimens. The recent advances in basic and clinical research on hematological
      malignancies would lead to further improvement in the prognosis and quality of
      life of patients suffering from leukemia or lymphoma.

PMID- 12417607
TI  - A novel quality control slide for quantitative immunohistochemistry testing.
AB  - We introduce a novel quality control technology that may improve intra- and
      interlaboratory immunohistochemistry (IHC) standardization. The technology
      involves the creation of standardized antibody targets that are attached to the
      same slides as the patient sample. After IHC staining, the targets turn the same
      color as the stained cells or tissue elements. Unlike current clinical practice,
      our proposed targets are neither cells nor tissue sections. To create
      reproducible standards that are available in unlimited supply, we use short
      constrained peptides as antibody targets. These peptides are attached directly to
      the glass slide. We show that these peptides simulate the portion of the native
      antigen to which the antibody binds. They are useful in detecting subtle changes
      in IHC staining efficacy. Moreover, the peptides do not degrade after
      deparaffinization or antigen retrieval treatments. This technology may be
      valuable in creating nationally standardized controls to quantify IHC analytical
      variability.

PMID- 12417608
TI  - NTPDase1 and NTPDase2 immunolocalization in mouse cochlea: implications for
      regulation of p2 receptor signaling.
AB  - Cellular, molecular, and physiological studies have demonstrated an important
      signaling role for ATP and related nucleotides acting via P2 receptors in the
      cochlea of the inner ear. Signal modulation is facilitated by ectonucleotidases,
      a heterologous family of surface-located enzymes involved in extracellular
      nucleotide hydrolysis. Our previous studies have implicated CD39/NTPDase1 and
      CD39L1/NTPDase2, members of the ectonucleoside triphosphate diphosphohydrolase (E
      NTPDase) family, as major ATP-hydrolyzing enzymes in the tissues lining the
      cochlear endolymphatic and perilymphatic compartments. NTPDase1 hydrolyzes both
      nucleoside triphosphates and diphosphates. In contrast, NTPDase2 is a
      preferential nucleoside triphosphatase. This study characterizes expression of
      these E-NTPDases in the mouse cochlea by immunohistochemistry. NTPDase1 can be
      immunolocalized to the cochlear vasculature and neural tissues (primary auditory
      neurons in the spiral ganglion). In contrast, NTPDase2 immunolabeling was
      principally localized to synaptic regions of the sensory inner and outer hair
      cells, stereocilia and cuticular plates of the outer hair cells, supporting cells
      of the organ of Corti (Deiters' cells and inner border cells), efferent nerve
      fibers located in the intraganglionic spiral bundle, and in the outer sulcus and
      root region of the spiral ligament. This differential expression of NTPDase1 and
      2 in the cochlea suggests spatial regulation of P2 receptor signaling,
      potentially involving different nucleotide species and hydrolysis kinetics.

PMID- 12417609
TI  - Distribution of the human intracellular serpin protease inhibitor 8 in human
      tissues.
AB  - Ovalbumin-like serine protease inhibitors are mainly localized intracellularly
      and their in vivo functions are largely unknown. To elucidate their physiological
      role(s), we studied the expression of one of these inhibitors, protease inhibitor
      8 (PI-8), in normal human tissues by immunohistochemistry using a PI-8-specific
      monoclonal antibody. PI-8 was strongly expressed in the nuclei of squamous
      epithelium of mouth, pharynx, esophagus, and epidermis, and by the epithelial
      layer of skin appendages, particularly by more differentiated epithelial cells.
      PI-8 was also expressed by monocytes and by neuroendocrine cells in the pituitary
      gland, pancreas, and digestive tract. Monocytes showed nuclear and cytoplasmic
      localization of PI-8, whereas neuroendocrine cells showed only cytoplasmic
      staining. In vitro nuclear localization of PI-8 was confirmed by confocal
      analysis using serpin-transfected HeLa cells. Furthermore, mutation of the P(1)
      residue did not affect the subcellular distribution pattern of PI-8, indicating
      that its nuclear localization is independent of the interaction with its target
      protease. We conclude that PI-8 has a unique distribution pattern in human
      tissues compared to the distribution patterns of other intracellular serpins.
      Additional studies must be performed to elucidate its physiological role.

PMID- 12417610
TI  - Localization of transcriptional co-activator CBP in the ameloblasts and the other
      enamel organ-derived cells of the rat incisor.
AB  - CREB-binding protein (CBP) was examined in ameloblasts and in other enamel organ
      derived cells of the rat incisor, using Western blotting analysis and
      immunocytochemistry by specific antibodies. Western blotting of labial tissues,
      including ameloblasts of the incisors, detected a single band with a molecular
      weight equivalent to the reported value of CBP. In immunocytochemistry, CBP was
      localized in ameloblast nuclei in the maturation zone but not in the secretion
      and transition zones. The nuclei of the other enamel organ-derived cells were
      also positive. Because this protein is suggested to take part in c-Jun-mediated
      transcription, the present study and the results of a previous report showing c
      Jun localization in the nuclei of enamel organ-derived cells suggest that the
      enamel organ-derived cells, including maturation ameloblasts, undergo active
      transcriptional regulation.

PMID- 12417611
TI  - Expression of hepatocyte growth factor mRNA in rat liver cirrhosis induced by N
      nitrosodimethylamine as evidenced by in situ RT-PCR.
AB  - Hepatocyte growth factor (HGF) is a potent inducer of hepatocyte proliferation
      and is expressed during liver failure. In this study we used the in situ reverse
      transcriptase-polymerase chain reaction (RT-PCR) method to detect HGF mRNA
      expression in normal rat livers and cirrhotic rat livers induced by treatment
      with N-nitrosodimethylamine (DMN). In normal control livers, in situ RT-PCR
      detected HGF mRNA expression in Ito cells and Kupffer cells, both of which showed
      rounded morphologies. However, in the cirrhotic livers induced by DMN, HGF mRNA
      positive cells were spindle-shaped and surrounded the hepatocytes located around
      the sinusoids. These cells appeared to be sinusoidal endothelial cells as well as
      Ito and Kupffer cells. Because it has been suggested that HGF expression is
      related to transforming growth factor-beta (TGF-beta) levels that may play an
      essential role in disease progression in cirrhotic livers, TGF-beta mRNA
      expression in normal and cirrhotic livers was also compared using in situ RT-PCR.
      Our results confirmed that expression of TGF-beta mRNA co-localized with HGF mRNA
      expression in the cirrhotic liver.

PMID- 12417612
TI  - A quantitative method to determine the orientation of collagen fibers in the
      dermis.
AB  - We have developed a quantitative microscopic method to determine changes in the
      orientation of collagen fibers in the dermis resulting from mechanical stress.
      The method is based on the use of picrosirius red-stained cryostat sections of
      piglet skin in which collagen fibers reflect light strongly when epipolarization
      microscopy is used. Digital images of sections were converted into binary images
      that were analyzed quantitatively on the basis of the length of the collagen
      fibers in the plane of the section as a measure for the orientation of the
      fibers. The length of the fibers was expressed in pixels and the mean length of
      the 10 longest fibers in the image was taken as the parameter for the orientation
      of the fibers. To test the procedure in an experimental setting, we used skin
      after 0 and 30 min of skin stretching. The orientation of the fibers in sections
      of control skin differed significantly from the orientation of fibers in sections
      of skin that was stretched mechanically for 30 min [76 +/- 15 (n=5) vs 132 +/- 36
      (n=5)]. The method described here is a relatively simple way to determine
      (changes in) the orientation of individual collagen fibers in connective tissue
      and can also be applied for analysis of the orientation of any other structural
      element in tissues so long as a representative binary image can be created.

PMID- 12417613
TI  - Immunohistochemical recognition of human follicular dendritic cells (FDCs) in
      routinely processed paraffin sections.
AB  - A number of monoclonal antibodies (MAbs) that recognize human follicular
      dendritic cells (FDCs) have been identified. Although some of them have already
      been applied individually in routine immunolabeling using formalin-fixed paraffin
      sections for diagnostic and experimental purposes, many antibodies are still
      employed only for immunolabeling using cryostat sections or particularly
      processed sections because they have been thought unsuitable for routine
      sections. A comprehensive examination re-evaluating their suitability in paraffin
      sections has not been reported. Accordingly, there is limited ability to examine
      the immunopathological contribution or diagnostic value of FDCs using routinely
      processed specimens or archived materials. In this study a broad panel of
      antibodies was systematically applied to the immunolabeling of paraffin sections
      of reactive tonsils or lymph nodes, in combination with advanced antigen
      retrieval (AR) techniques. Several antibodies, including Ki-M4p, X-11, 12B1,
      CNA.42, 1F8/BU32 (anti-CD21), BU38/1B12 (anti-CD23), Ber-MAC-DRC/To5 (anti-CD35),
      1.4C3 (anti-CD106), NGFR5 (anti-nerve growth factor receptor p75), IIH6 (anti
      CD55), 55K-2 (anti-fascin), and anti-S100 protein alpha-chain, were found to
      label FDCs in routine sections when combined with suitable AR techniques. Our
      results are easily adaptable for routine practice and provided useful suggestions
      concerning the immunopathological behavior and diversity of the particular cells.

PMID- 12417614
TI  - Chromogranin A in the human gastrointestinal tract: an immunocytochemical study
      with region-specific antibodies.
AB  - We studied the immunoreactivity of 12 different region-specific antibodies to the
      chromogranin A (CgA) molecule in the various neuroendocrine cell types of the
      human gastrointestinal (GI) tract by using double immunofluorescence techniques.
      These staining results were compared with others obtained with a commercial
      monoclonal CgA antibody (LK2H10). G (gastrin)-cells showed immunoreactivity to
      virtually all region-specific antibodies, but with varying frequency. Most
      intestinal EC (enterochromaffin)- and L (enteroglucagon)-cells were
      immunoreactive to the antibodies to the N-terminal and mid-portion of the CgA
      molecule, whereas the EC-cells in the stomach reacted with fewer region-specific
      antibodies. D (somatostatin)-cells reacted to the CgA 411-424 antibody and only
      occasionally showed immunoreactivity to the other CgA antibodies. A larger
      cytoplasmic area was stained with the antibodies to CgA 17-38 and 176-195 than
      with the other antibodies tested. These differences in staining pattern may
      reflect different cleavage of the CgA molecule in different cell types and at
      different regions of the GI tract.

PMID- 12417615
TI  - Changes in gap junction distribution and connexin expression pattern during human
      fetal skin development.
AB  - Gap junctions are intercellular channels composed of connexin subunits that
      mediate cell-cell communication. The functions of gap junctions are believed to
      be associated with cell proliferation and differentiation and to be important in
      maintaining tissue homeostasis. We therefore investigated the expression of
      connexins (Cx)26 and 43, the two major connexins in human epidermis, and examined
      the formation of gap junctions during human fetal epidermal development. By
      immunofluorescence, Cx26 expression was observed between 49 and 96 days'
      estimated gestational age (EGA) but was not present from 108 days' EGA onwards.
      Conversely, Cx43 expression was observed from 88 days' EGA onwards. Using
      electron microscopy, the typical structure of gap junctions was observed from 120
      days' EGA. The number of gap junctions increased over time and they were more
      common in the upper layers, within the periderm and intermediate keratinocyte
      layers rather than the basal layer. Immunoelectron microscopy revealed Cx43
      labeling on the gap junction structures after 105 days' EGA. Formation of gap
      junctions increased as skin developed, suggesting that gap junctions may play an
      important role in fetal skin development. Furthermore, the changing patterns of
      connexin expression suggest that Cx26 is important for early fetal epidermal
      development.

PMID- 12417616
TI  - The cellular localization of increased atrial natriuretic peptide mRNA and
      immunoreactivity in diabetic rat kidneys.
AB  - Increased intrarenal atrial natriuretic peptide (ANP) mRNA expression has been
      reported in several disorders. To further investigate the action of renal ANP, we
      need to elucidate the exact site of its alteration in diseased kidneys. ANP mRNA
      and ANP were detected by in situ hybridization and immunohistochemistry in the
      kidneys from five normal and five diabetic rats. Renal ANP mRNA in eight normal
      and nine diabetic rats was measured by RT-PCR with Southern blot hybridization.
      In normal and diabetic rats, the distribution of ANP mRNA and ANP-like peptide
      was mainly located in proximal, distal, and collecting tubules. However, diabetic
      rats had significant enhancement of ANP mRNA and ANP-immunoreactive staining in
      the proximal straight tubules, medullary thick ascending limbs, and medullary
      collecting ducts. ANP mRNA in the outer and inner medulla of nine diabetic rats
      increased 5.5-fold and 3.5-fold, but only 1.8-fold in the renal cortex. This
      preliminary study showed that ANP mRNA and ANP immunoreactivity in proximal
      straight tubules, medullary thick ascending limb, and medullary collecting ducts
      apparently increased in diabetic kidneys. These findings imply that ANP synthesis
      in these nephrons may involve in adaptations of renal function in diabetes.

PMID- 12417617
TI  - Immunohistochemical localization of carboxypeptidases D, E, and Z in pituitary
      adenomas and normal human pituitary.
AB  - Carboxypeptidases may play important role(s) in prohormone processing in normal
      and neoplastic adenohypophyseal cells of the pituitary. We have recently
      demonstrated carboxypeptidase E (CPE) and carboxypeptidase Z (CPZ) in the
      majority of adenohypophyseal cells with carboxypeptidase D (CPD) immunoreactivity
      largely confined to adrenocorticotrophs. This study evaluated the expression
      patterns of CPE, CPD, and CPZ immunoreactivity in 48 pituitary adenomas. Our
      immunohistochemistry demonstrated extensive intracytoplasmic immunoreactivity for
      CPE, CPD, and CPZ in adrenocorticotrophic hormone (ACTH)-producing
      adrenocorticotroph cells, prolactin-producing lactotroph cells, and growth
      hormone (GH)-producing somatotroph cell adenomas, all of which require
      carboxypeptide processing of prohormones to produce active endocrine hormones. In
      contrast to the restricted expression in the normal adenohypophysis, CPD appeared
      to be widespread in the majority of adenomas, suggesting that CPD levels are
      increased in adenomas. In luteinizing hormone/follicle-stimulating hormone
      (LH/FSH)-producing gonadotroph adenomas, which do not require carboxypeptidases
      to produce gonadotropins, only CPZ immunostaining was demonstrated. In null-cell
      adenomas, CPE immunoreactivity was detected in the majority of tumors, but CPD
      and CPZ were identified only in a minority of cases. CPE in these cells may
      process other peptides critical for pituitary cell function, such as chromogranin
      A or B. These findings suggest that CPs participate in the functioning of
      pituitary adenomas.

PMID- 12417618
TI  - Effects of estradiol on prostate epithelial cells in the castrated rat.
AB  - There is evidence that estrogens can modulate the activity of prostate epithelial
      cells. To determine whether estradiol can have a direct influence on rat
      prostate, this study examined the effects of estradiol-17beta (E(2)) administered
      alone or in combination with dihydrotestosterone (DHT) to castrated rats for 3
      weeks on prostate binding protein (PBP) C1 mRNA expression and androgen receptor
      (AR) localization. PBP C1 mRNA levels were measured by semi-quantitative in situ
      hybridization using a (35)S-labeled cDNA probe. In intact animals, strong
      hybridization signal could be observed in prostate sections after 12 hr of
      exposure to Kodak X-Omat films. In castrated rats, no PBP C1 mRNA could be
      detected even with longer exposure times, an effect that was prevented by
      administration of DHT. E(2) administered alone induced a detectable hybridization
      signal, and the concomitant administration of E(2) and DHT induced an increase in
      PBP C1 mRNA that significantly exceeded that obtained in animals that received
      only DHT. In prostate epithelial cells of intact animals, AR immunostaining was
      restricted to the nucleus. In castrated animals the alveoli were decreased in
      size and the epithelial cells were atrophied. AR staining was weak and was
      detected in both cytoplasm and nucleus. DHT administration completely obviated
      the effect of castration on epithelial cell histology and on AR immunostaining
      distribution and intensity. Interestingly, E(2) administration alone induced
      moderate hypertrophy of epithelial cells compared to the histological appearance
      of cells in untreated castrated rats. Moreover, in E(2)-treated animals the
      nuclear staining was much stronger than that detected in untreated castrated
      rats, whereas the cytoplasmic staining was not modified by the treatment. In
      animals that received both DHT and E(2), the staining was similar to that seen in
      DHT-treated rats. These results suggest that E(2) can influence the activity of
      rat prostate epithelial cells by mechanisms that remain to be fully clarified.

PMID- 12417619
TI  - Specific responses in rat small intestinal epithelial mRNA expression and protein
      levels during chemotherapeutic damage and regeneration.
AB  - The rapidly dividing small intestinal epithelium is very sensitive to the
      cytostatic drug methotrexate. We investigated the regulation of epithelial gene
      expression in rat jejunum during methotrexate-induced damage and regeneration.
      Ten differentiation markers were localized on tissue sections and quantified at
      mRNA and protein levels relative to control levels. We analyzed correlations in
      temporal expression patterns between markers. mRNA expression of enterocyte and
      goblet cell markers decreased significantly during damage for a specific period.
      Of these, sucrase-isomaltase (-62%) and CPS (-82%) were correlated. Correlations
      were also found between lactase (-76%) and SGLT1 (-77%) and between I-FABP (-52%)
      and L-FABP (-45%). Decreases in GLUT5 (-53%), MUC2 (-43%), and TFF3 (-54%) mRNAs
      occurred independently of any of the other markers. In contrast, lysozyme mRNA
      present in Paneth cells increased (+76%). At the protein level, qualitative and
      quantitative changes were in agreement with mRNA expression, except for Muc2
      (+115%) and TFF3 (+81%), which increased significantly during damage, following
      independent patterns. During regeneration, expression of each marker returned to
      control levels. The enhanced expression of cytoprotective molecules (Muc2, TFF3,
      lysozyme) during damage represents maintenance of goblet cell and Paneth cell
      functions, most likely to protect the epithelium. Decreased expression of
      enterocyte-specific markers represents decreased enterocyte function, of which
      fatty acid transporters were least affected.

PMID- 12417620
TI  - In vitro matrix assembly induced by critical assembly concentration (CAC).
AB  - L-2 cells are an immortalized cell line derived from yolk sac parietal endoderm
      cells, which are responsible for the production of Reichert's membrane, a thick
      basement membrane produced during rat gestation. Although the L-2 cells secrete
      all the major components of the basal lamina, they do not assemble a robust
      matrix in cell culture. We hypothesized that the reason L-2 cells fail to
      assemble a matrix in cell culture is because the concentrations of matrix
      components necessary for this matrix assembly do not reach a critical association
      concentration (CAC) under standard cell culture conditions. To limit the
      diffusion of secreted molecules while maintaining a nutrient-rich environment for
      the cells to thrive, we developed a technique that uses a dialysis membrane to
      limit protein diffusion in a 2-well plate format. This technique permits L-2
      cells to assemble a robust matrix in as little as 24 hr that continues to be
      formed for at least 72 hr. This technique may address some of the physical
      limitations imposed by cell culture and could be readily applied to other cell
      types and medium conditions.

PMID- 12417621
TI  - Expression of myosin heavy chain isoforms along intrafusal fibers of rat soleus
      muscle spindles after 14 days of hindlimb unloading.
AB  - Morphological, contractile, histochemical, and electrophoretical characteristics
      of slow postural muscles are altered after hindlimb unloading (HU). However, very
      few data on intrafusal fibers (IFs) are available. Our aim was to determine the
      effects of 14 days of hindlimb unloading on the morphological and
      immunohistochemical characteristics of IF in rat soleus muscle. Thirty-three
      control and 32 unloaded spindles were analyzed. The number and distribution of
      muscle spindles did not appear to be affected after unloading. There was no
      significant difference in number, cross-sectional area, and histochemical
      properties of IF between the two groups. However, after unloading, a significant
      decrease in slow type 1 MHC isoform and a slight increase in slow-tonic MHC
      expression were observed in the B and C regions of the bag1 fibers. The alpha
      cardiac MHC expression was significantly decreased along the entire length of the
      bag2 fibers and in the B and C regions of the bag1 fibers. In 12 muscle spindles,
      the chain fibers expressed the slow type 1 and alpha-cardiac MHC isoforms over a
      short distance of the A region, although these isoforms are not normally
      expressed. The most striking finding of the study was the relative resistance of
      muscle spindles to perturbation induced by HU.

PMID- 12417622
TI  - Angioarchitecture of primary oral malignant melanomas.
AB  - Angiogenesis is an essential process in the progression of malignant tumors.
      However, little is known of the angioarchitecture in primary oral malignant
      melanoma. We sought to determine this by the use of periodic acid-Schiff (PAS)
      stain, endothelial markers (CD34, CD105) and laminin, and by transmission
      electron microscopy in two cases. The results demonstrated that endothelium-lined
      vessels dominated the tumor microvasculature and these stained positively for
      PAS, laminin, and endothelial markers. Mosaic and tumor-lined vessels were
      infrequently encountered. Most PAS-positive patterned networks and loops
      ultrastructurally represented intratumor microhemorrhages that probably arose
      secondary to tumor vessel leakiness. Vascular channels of the vasculogenic
      mimicry type were rare. They stained for laminin but not for endothelial markers.

PMID- 12417623
TI  - Mitochondrial apoptosis and the peripheral benzodiazepine receptor: a novel
      target for viral and pharmacological manipulation.

PMID- 12417624
TI  - The myxoma poxvirus protein, M11L, prevents apoptosis by direct interaction with
      the mitochondrial permeability transition pore.
AB  - M11L, an antiapoptotic protein essential for the virulence of the myxoma
      poxvirus, is targeted to mitochondria and prevents the loss of mitochondrial
      membrane potential that accompanies cell death. In this study we show, using a
      cross-linking approach, that M11L physically associates with the mitochondrial
      peripheral benzodiazepine receptor (PBR) component of the permeability transition
      (PT) pore. Close association of M11L and the PBR is also indicated by
      fluorescence resonance energy transfer (FRET) analysis. Stable expression of M11L
      prevents the release of mitochondrial cytochrome c induced by staurosporine or
      protoporphyrin IX (PPIX), a ligand of the PBR. Transiently expressed M11L also
      prevents mitochondrial membrane potential loss induced by PPIX, or induced by
      staurosporine in combination with PK11195, another ligand of the PBR. Myxoma
      virus infection and the associated expression of early proteins, including M11L,
      protects cells from staurosporine- and Fas-mediated mitochondrial membrane
      potential loss and this effect is augmented by the presence of PBR. We conclude
      that M11L regulates the mitochondrial permeability transition pore complex, most
      likely by direct modulation of the PBR.

PMID- 12417625
TI  - Changes in the proliferative activity of human hematopoietic stem cells in
      NOD/SCID mice and enhancement of their transplantability after in vivo treatment
      with cell cycle inhibitors.
AB  - Human hematopoietic tissue contains rare stem cells with multilineage
      reconstituting ability demonstrable in receptive xenogeneic hosts. We now show
      that within 3 wk nonobese diabetic severe combined immunodeficiency (NOD/SCID)
      mice transplanted with human fetal liver cells regenerate near maximum levels of
      daughter human hematopoietic stem cells (HSCs) able to repopulate secondary
      NOD/SCID mice. At this time, most of the human HSCs (and other primitive
      progenitors) are actively proliferating as shown by their sensitivity to
      treatments that kill cycling cells selectively (e.g., exposure to high specific
      activity [(3)H]thymidine in vitro or 5-fluorouracil in vivo). Interestingly, the
      proliferating human HSCs were rapidly forced into quiescence by in vivo
      administration of stromal-derived factor-1 (SDF-1) and this was accompanied by a
      marked increase in the numbers of human HSCs detectable. A similar result was
      obtained when transforming growth factor-beta was injected, consistent with a
      reversible change in HSCs engrafting potential linked to changes in their cell
      cycle status. By 12 wk after transplant, most of the human HSCs had already
      entered G(o) and treatment with SDF-1 had no effect on their engrafting activity.
      These findings point to the existence of novel mechanisms by which inhibitors of
      HSC cycling can regulate the engrafting ability of human HSCs executing self
      renewal divisions in vivo.

PMID- 12417626
TI  - Reduced self-reactivity of an autoreactive T cell after activation with cross
      reactive non-self-ligand.
AB  - Autoreactive CD4(+) T lymphocytes are critical to the induction of autoimmune
      disease, but because of the degenerate nature of T cell receptor (TCR) activation
      such receptors also respond to other ligands. Interaction of autoreactive T cells
      with other non-self-ligands has been shown to activate and expand self-reactive
      cells and induce autoimmunity. To understand the effect on the autoreactivity of
      naive cross-reactive T cells of activation with a potent nonself ligand, we have
      generated a TCR transgenic mouse which expresses a TCR with a broad cross
      reactivity to a number of ligands including self-antigen. The activation of naive
      transgenic recombination activating gene (Rag)2(-)(/)(-) T cells with a potent
      non-self-ligand did not result in a enhancement of reactivity to self, but made
      these T cells nonresponsive to the self-ligand and anti-CD3, although they
      retained a degree of responsiveness to the non-self-ligand. These desensitized
      cells had many characteristics of anergic T cells. Interleukin (IL)-2 production
      was selectively reduced compared with interferon (IFN)-gamma. p21(ras) activity
      was reduced and p38 mitogen-activated protein kinase (MAPK) was relatively
      spared, consistent with known biochemical characteristics of anergy.
      Surprisingly, calcium fluxes were also affected and the anergic phenotype could
      not be reversed by exogenous IL-2. Therefore, activation with a hyperstimulating
      non-self-ligand changes functional specificity of an autoreactive T cell without
      altering the TCR. This mechanism may preserve the useful reactivity of peripheral
      T cells to foreign antigen while eliminating responses to self.

PMID- 12417627
TI  - Quantitative and qualitative changes in V-J alpha rearrangements during mouse
      thymocytes differentiation: implication for a limited T cell receptor alpha chain
      repertoire.
AB  - Knowledge of the complete nucleotide sequence of the mouse TCRAD locus allows an
      accurate determination V-J rearrangement status. Using multiplex genomic PCR
      assays and real time PCR analysis, we report a comprehensive and systematic
      analysis of the V-J recombination of TCR alpha chain in normal mouse thymocytes
      during development. These respective qualitative and quantitative approaches give
      rise to four major points describing the control of gene rearrangements. (a) The
      V-J recombination pattern is not random during ontogeny and generates a limited
      TCR alpha repertoire; (b) V-J rearrangement control is intrinsic to the thymus;
      (c) each V gene rearranges to a set of contiguous J segments with a gaussian-like
      frequency; (d) there are more rearrangements involving V genes at the 3' side
      than 5' end of V region. Taken together, this reflects a preferential association
      of V and J gene segments according to their respective positions in the locus,
      indicating that accessibility of both V and J regions is coordinately regulated,
      but in different ways. These results provide a new insight into TCR alpha
      repertoire size and suggest a scenario for V usage during differentiation.

PMID- 12417628
TI  - Failure to censor forbidden clones of CD4 T cells in autoimmune diabetes.
AB  - Type 1 diabetes and other organ-specific autoimmune diseases often cluster
      together in human families and in congenic strains of NOD (nonobese diabetic)
      mice, but the inherited immunoregulatory defects responsible for these diseases
      are unknown. Here we track the fate of high avidity CD4 T cells recognizing a
      self-antigen expressed in pancreatic islet beta cells using a transgenic mouse
      model. T cells of identical specificity, recognizing a dominant peptide from the
      same islet antigen and major histocompatibility complex (MHC)-presenting
      molecule, were followed on autoimmune susceptible and resistant genetic
      backgrounds. We show that non-MHC genes from the NOD strain cause a failure to
      delete these high avidity autoreactive T cells during their development in the
      thymus, with subsequent spontaneous breakdown of CD4 cell tolerance to the islet
      antigen, formation of intra-islet germinal centers, and high titre immunoglobulin
      G1 autoantibody production. In mixed bone marrow chimeric animals, defective
      thymic deletion was intrinsic to T cells carrying diabetes susceptibility genes.
      These results demonstrate a primary failure to censor forbidden clones of self
      reactive T cells in inherited susceptibility to organ-specific autoimmune
      disease, and highlight the importance of thymic mechanisms of tolerance in organ
      specific tolerance.

PMID- 12417629
TI  - B lymphocyte memory: role of stromal cell complement and FcgammaRIIB receptors.
AB  - To dissect the influence of CD21/CD35 and FcgammaRIIB in antigen retention and
      humoral memory, we used an adoptive transfer model in which antigen-primed B and
      T lymphocytes were given to sublethally irradiated wild-type mice or mice
      deficient in CD21/CD35 (Cr2(-/-)) or FcgammaRIIB receptors (FcgammaRIIB(-/-)).
      Cr2(-/-) chimeras showed impaired memory as characterized by a decrease in
      antibody titer, reduced frequency of antibody secreting cells, an absence of
      affinity maturation, and significantly reduced recall response. The impaired
      memory in Cr2(-/-) chimeras corresponded with the reduced frequency of antigen
      specific memory B cells. Interestingly, FcgammaRIIB(-/-) chimeras showed a
      differential phenotype with impaired splenic but normal bone marrow responses.
      These data suggest that CD21/CD35 on stroma, including follicular dendritic
      cells, is critical to the maintenance of long-term B lymphocyte memory.

PMID- 12417630
TI  - PECAM-1 (CD31) homophilic interaction up-regulates alpha6beta1 on transmigrated
      neutrophils in vivo and plays a functional role in the ability of alpha6
      integrins to mediate leukocyte migration through the perivascular basement
      membrane.
AB  - Platelet-endothelial cell adhesion molecule (PECAM)-1 has been implicated in
      leukocyte migration through the perivascular basement membrane (PBM) though the
      mechanisms involved are unclear. The present results demonstrate that the ability
      of alpha(6) integrins to mediate neutrophil migration through the PBM is PECAM-1
      dependent, a response associated with PECAM-1-mediated increased expression of
      alpha(6)beta(1) on transmigrating neutrophils in vivo. An anti-alpha(6) integrins
      mAb (GoH3) inhibited (78%, P < 0.001) neutrophil migration through interleukin
      (IL)-1beta-stimulated cremasteric venules, primarily at the level of the PBM, as
      analyzed by intravital and electron microscopy. In PECAM-1-deficient mice (KO), a
      reduced level of neutrophil transmigration elicited by IL-1beta (4-h reaction)
      was observed in both the cremaster muscle (55% inhibition, P < 0.05) and in the
      peritoneum (57% inhibition, P < 0.01) but GoH3 had no additional inhibitory
      effect on these responses. FACS((R)) analysis of neutrophils demonstrated
      increased expression of alpha(6)beta(1) on transmigrated peritoneal neutrophils,
      as compared with blood neutrophils, in wild-type but not KO mice even though
      neutrophils from both strains of mice exhibited comparable levels of
      intracellular expression of alpha(6) as observed by immunofluorescent staining
      and confocal microscopy. Furthermore, mice deficient in either leukocyte or
      endothelial cell PECAM-1, as developed by bone marrow transplantation,
      demonstrated a similar level of reduced neutrophil transmigration and expression
      of alpha(6)beta(1) on transmigrated neutrophils as that detected in KO mice. The
      results demonstrate a role for PECAM-1 homophilic interaction in neutrophil
      transmigration and increased expression of alpha(6)beta(1) on the cell surface of
      transmigrated neutrophils in vivo, a response that could contribute to the
      mechanism of PECAM-1-mediated neutrophil migration through the PBM.

PMID- 12417631
TI  - Human autoimmune sera as molecular probes for the identification of an
      autoantigen kinase signaling pathway.
AB  - Using human autoimmune sera as molecular probes, we previously described the
      association of phosphorylated serine/arginine splicing factors (SR splicing
      factors) with the U1-small nuclear ribonucleoprotein (U1-snRNP) and U3-small
      nucleolar RNP (snoRNP) in apoptotic cells. SR proteins are highly conserved
      autoantigens whose activity is tightly regulated by reversible phosphorylation of
      serine residues by at least eight different SR protein kinase kinases (SRPKs),
      including SRPK1, SRPK2, and the scleroderma autoantigen topoisomerase I. In this
      report, we demonstrate that only one of the known SRPKs, SRPK1, is associated
      with the U1-snRNP autoantigen complex in healthy and apoptotic cells. SRPK1 is
      activated early during apoptosis, followed by caspase-mediated proteolytic
      inactivation at later time points. SRPKs are cleaved in vivo after multiple
      apoptotic stimuli, and cleavage can be inhibited by overexpression of bcl-2 and
      bcl-x(L), and by exposure to soluble peptide caspase inhibitors. Incubation of
      recombinant caspases with in vitro-translated SRPKs demonstrates that SRPK1 and
      SRPK2 are in vitro substrates for caspases-8 and -9, respectively. In contrast,
      topoisomerase I is cleaved by downstream caspases (-3 and -6). Since each of
      these SRPKs sits at a distinct checkpoint in the caspase cascade, SRPKs may serve
      an important role in signaling pathways governing apoptosis, alternative mRNA
      splicing, SR protein trafficking, RNA stability, and possibly the generation of
      autoantibodies directed against splicing factors.

PMID- 12417632
TI  - AML1-ETO inhibits maturation of multiple lymphohematopoietic lineages and induces
      myeloblast transformation in synergy with ICSBP deficiency.
AB  - The translocation (8;21), generating the AML1-ETO fusion protein, is one of the
      most frequent chromosomal abnormalities associated with acute myelogenous
      leukemia (AML). To elucidate its role in oncogenesis, bone marrow (BM) cells were
      infected with a retroviral vector carrying AML1-ETO and transplanted into mice.
      In contrast to previous transgenic mouse models, we show that AML1-ETO directly
      stimulates granulopoiesis, suppresses erythropoiesis, and impairs the maturation
      of myeloid, B, and T lymphoid cells in vivo. To determine the significance of
      earlier findings that expression of the tumor suppressor ICSBP is often
      downregulated in AML myeloblasts, AML1-ETO was introduced into BM cells derived
      from mice lacking the interferon regulatory factor ICSBP. Our findings
      demonstrate that AML1-ETO synergizes with an ICSBP deficiency to induce
      myeloblastic transformation in the BM, reminiscent of AML.

PMID- 12417633
TI  - A key role for old yellow enzyme in the metabolism of drugs by Trypanosoma cruzi.
AB  - Trypanosoma cruzi is the etiological agent of Chagas' disease. So far, first
      choice anti-chagasic drugs in use have been shown to have undesirable side
      effects in addition to the emergence of parasite resistance and the lack of
      prospect for vaccine against T. cruzi infection. Thus, the isolation and
      characterization of molecules essential in parasite metabolism of the anti
      chagasic drugs are fundamental for the development of new strategies for rational
      drug design and/or the improvement of the current chemotherapy. While searching
      for a prostaglandin (PG) F(2alpha) synthase homologue, we have identified a novel
      "old yellow enzyme" from T. cruzi (TcOYE), cloned its cDNA, and overexpressed the
      recombinant enzyme. Here, we show that TcOYE reduced 9,11-endoperoxide PGH(2) to
      PGF(2alpha) as well as a variety of trypanocidal drugs. By electron spin
      resonance experiments, we found that TcOYE specifically catalyzed one-electron
      reduction of menadione and beta-lapachone to semiquinone-free radicals with
      concomitant generation of superoxide radical anions, while catalyzing solely the
      two-electron reduction of nifurtimox and 4-nitroquinoline-N-oxide drugs without
      free radical production. Interestingly, immunoprecipitation experiments revealed
      that anti-TcOYE polyclonal antibody abolished major reductase activities of the
      lysates toward these drugs, identifying TcOYE as a key drug-metabolizing enzyme
      by which quinone drugs have their mechanism of action.

PMID- 12417634
TI  - Parasite-induced lipoxin A4 is an endogenous regulator of IL-12 production and
      immunopathology in Toxoplasma gondii infection.
AB  - The production of interleukin (IL)-12 is critical for the development of
      interferon (IFN)-gamma-dependent resistance to Toxoplasma gondii. Nevertheless,
      when this response is dysregulated, such as occurs in the absence of IL-10, the
      uncontrolled inflammation that results can have lethal consequences for the host.
      Recently, we demonstrated that lipoxin (LX)A(4), an eicosanoid mediator that
      depends on 5-lipoxygenase (LO) for its biosynthesis, exerts a regulatory role on
      dendritic cell IL-12 production triggered artificially by a T. gondii extract. We
      now formally establish the physiological relevance of this pathway in the
      systemic control of IL-12 production induced by live T. gondii infection and
      demonstrate its function to be distinct from that of IL-10. Thus, T. gondii
      exposed wild-type, but not 5-LO-deficient animals, produced high levels of serum
      LXA(4) beginning at the onset of chronic infection. Moreover, 5-LO(-/-), in
      contrast to wild-type mice, succumbed during the same period displaying a marked
      encephalitis. The increased mortality of the 5-LO(-/-) animals was also
      associated with significant elevations of IL-12 and IFN-gamma and was completely
      prevented by the administration of a stable LXA(4) analogue. Together, these
      findings demonstrate a new pathway involving the induction of host LXs for the in
      vivo regulation of proinflammatory responses during microbial infection.

PMID- 12417635
TI  - Invariant chain controls the activity of extracellular cathepsin L.
AB  - Secretion of proteases is critical for degradation of the extracellular matrix
      during an inflammatory response. Cathepsin (Cat) S and L are the major
      elastinolytic cysteine proteases in mouse macrophages. A 65 amino acid segment of
      the p41 splice variant (p41(65aa)) of major histocompatibility complex class II
      associated invariant chain (Ii) binds to the active site of CatL and permits the
      maintenance of a pool of mature enzyme in endosomal compartments of macro-phages
      and dendritic cells (DCs). Here we show that interaction of p41(65aa) with mature
      CatL allows extracellular accumulation of the active enzyme. We detected mature
      CatL as a complex with p41(65aa) in culture supernatants from antigen-presenting
      cells (APCs). Extracellular accumulation of mature CatL is up-regulated by
      inflammatory stimuli as observed in interferon (IFN)-gamma-treated macrophages
      and lipopolysaccharide (LPS)-activated DCs. Despite the neutral pH of the
      extracellular milieu, released CatL associated with p41(65aa) is catalytically
      active as demonstrated by active site labeling and elastin degradation assays. We
      propose that p41(65aa) stabilizes CatL in the extracellular environment and
      induces a local increase in the concentration of matrix-degrading enzymes during
      inflammation. Through its interaction with CatL, Ii may therefore control the
      migratory response of APCs and/or the recruitment of effectors of the
      inflammatory response.

PMID- 12417636
TI  - Drosophila HB9 is expressed in a subset of motoneurons and interneurons, where it
      regulates gene expression and axon pathfinding.
AB  - Motoneurons are an essential component of all metazoan nervous systems, but it is
      unknown whether there is an evolutionarily conserved mechanism for generating
      motoneurons during neurogenesis. In the vertebrate CNS, HB9/MNR2 transcription
      factors are specifically expressed in all somatic motoneurons and are necessary
      to distinguish motoneurons from interneurons, in part by repressing interneuron
      specific gene expression. Here, we identify and characterize the single
      Drosophila ortholog of the HB9/MNR2 gene family. Drosophila HB9 is detected in a
      subset of motoneurons with ventral muscle targets and in a small group of
      interneurons, including the well characterized serotonergic interneurons. RNA
      interference knockdown of HB9 levels leads to defects in motoneuron ventral
      muscle target recognition, ectopic expression of a marker for dorsally projecting
      motoneurons (Even-skipped), and defects in serotonergic interneuronal
      projections. Conversely, ectopic HB9 expression causes an expansion of ventral
      motoneuron projections and repression of Even-skipped. Thus, Drosophila HB9 is
      required in a subset of motoneurons and interneurons for establishing proper axon
      projections but does not have a general role in distinguishing motoneuron and
      interneuron cell types.

PMID- 12417637
TI  - D-amphetamine fails to increase extracellular dopamine levels in mice lacking
      alpha 1b-adrenergic receptors: relationship between functional and nonfunctional
      dopamine release.
AB  - It was found recently that locomotor and rewarding effects of psychostimulants
      and opiates were dramatically decreased or suppressed in mice lacking alpha1b
      adrenergic receptors [alpha1b-adrenergic receptor knock-outs (alpha1bAR-KOs)]
      (Drouin et al., 2002). Here we show that blunted locomotor responses induced by 3
      and 6 mg/kg d-amphetamine in alpha1bAR-KO mice [-84 and -74%, respectively, when
      compared with wild-type (WT) mice] are correlated with an absence of d
      amphetamine-induced increase in extracellular dopamine (DA) levels in the nucleus
      accumbens of alpha1bAR-KO mice. Moreover, basal extracellular DA levels in the
      nucleus accumbens are lower in alpha1bAR-KO than in WT littermates (-28%; p <
      0.001). In rats however, prazosin, an alpha1-adrenergic antagonist, decreases d
      amphetamine-induced locomotor hyperactivity without affecting extracellular DA
      levels in the nucleus accumbens, a finding related to the presence of an
      important nonfunctional release of DA (Darracq et al., 1998). We show here that
      local d-amphetamine releases nonfunctional DA with the same affinity but a more
      than threefold lower amplitude in C57BL6/J mice than in Sprague Dawley rats.
      Altogether, this suggests that a trans-synaptic mechanism amplifies functional DA
      into nonfunctional DA release. Our data confirm the presence of a powerful
      coupling between noradrenergic and dopaminergic neurons through the stimulation
      of alpha1b-adrenergic receptors and indicate that nonfunctional DA release is
      critical in the interpretation of changes in extracellular DA levels. These
      results suggest that alpha1b-adrenergic receptors may be important therapeutic
      pharmacological targets not only in addiction but also in psychosis because most
      neuroleptics possess anti-alpha1-adrenergic properties.

PMID- 12417638
TI  - Periadolescent mice show enhanced DeltaFosB upregulation in response to cocaine
      and amphetamine.
AB  - Children and adolescents are increasingly exposed to psychostimulants, either
      illicitly or for the treatment of common neuropsychiatric conditions, such as
      attention deficit disorder with and without hyperactivity. Despite the widespread
      use of psychomotor stimulants in younger age groups, little is known regarding
      the chronic molecular neuroadaptive responses to these agents in the immature
      brain. Here we demonstrate that, after chronic administration of the
      psychostimulants cocaine and amphetamine, the transcription factor DeltaFosB is
      upregulated in the nucleus accumbens of periadolescent mice but not in post
      weanling or adult mice. Induction of DeltaFosB also occurs exclusively in the
      caudate putamen of periadolescent mice after amphetamine administration. These
      results demonstrate the unique plasticity in the adolescent brain of a critical
      molecule that regulates psychostimulant action and suggest that these
      neuroadaptive changes may be involved in the mediation of enhanced addictive
      tendencies in the adolescent relative to the adult.

PMID- 12417639
TI  - Past-A, a novel proton-associated sugar transporter, regulates glucose
      homeostasis in the brain.
AB  - The ventral medullary surface (VMS) of the medulla oblongata is known to be the
      site of the central chemosensitive neurons in mammals. These neurons sense excess
      H+/CO2 dissolved in the CSF and induce hyperventilation. To elucidate the
      mechanism of neuronal cell adaptation to changes of H+/CO2, we screened for
      hypercapnia-induced genes in the VMS. Here, we report cloning and
      characterization of a novel gene called proton-associated sugar transporter-A
      (Past-A), which is induced in the brain after hypercapnia and mediates glucose
      uptake along the pH gradient. Past-A comprises 751 amino acid residues containing
      12 membrane-spanning helices, several conserved sugar transport motifs, three
      proline-rich regions, and leucine repeats. Past-A transcript was expressed
      predominantly in the brain. Moreover, the Past-A-immunoreactive neural cells were
      found in the VMS of the medulla oblongata, and the number of immunoreactive cells
      was increased by hypercapnic stimulation. Transient transfection of Past-A in COS
      7 cells leads to the expression of a membrane-associated 82 kDa protein that
      possesses a glucose transport activity. The acidification of extracellular medium
      facilitated glucose uptake, whereas the addition of carbonyl cyanide m
      chlorophenylhydrazone, a protonophore, inhibited glucose import. Together, our
      results indicate that Past-A is a brain-specific glucose transporter that may
      represent an adaptation mechanism regulating sugar homeostasis in neuronal cells
      after hypercapnia.

PMID- 12417640
TI  - Correlations between visual recognition memory and neocortical and hippocampal
      glucose metabolism after bilateral rhinal cortex lesions in the baboon:
      implications for Alzheimer's disease.
AB  - In Alzheimer's disease (AD), the rhinal cortex is the area earliest and most
      affected by neurofibrillary tangles, and the degree of temporoparietal glucose
      hypometabolism and rhinal cortex atrophy are both correlated with dementia
      severity. In monkeys, damage to the rhinal cortex leads to severe impairment in
      declarative memory, which is also affected preferentially in early AD. To
      investigate the contribution of rhinal alterations to the interrelationships
      between cerebral hypometabolism and declarative memory impairment observed in AD,
      we studied the effects of excitotoxic bilateral rhinal lesions in baboons on
      cerebral glucose consumption (CMRglc) as measured by positron emission tomography
      and performance on a visual recognition memory task as assessed in parallel by a
      delayed nonmatching-to-sample task. We reported previously that these rhinal
      lesions induce both a long-lasting hypometabolism in several remote brain regions
      (Meguro et al., 1999) and impaired memory performance (Chavoix et al., 2002). The
      present analysis indicates that across lesioned and sham baboons, memory scores
      were significantly positively correlated (p < 0.05; Spearman) with concomitant
      CMRglc values of several brain areas, such as neocortical associative and
      posterior hippocampal regions. These findings, reminiscent of those reported in
      AD, suggest that the neurodegenerative process that affects the rhinal cortex in
      early AD plays a crucial role in the pattern of brain hypometabolism and
      consequently in the declarative memory impairments characteristic of this
      disease.

PMID- 12417641
TI  - Lesion-induced thalamocortical axonal plasticity in the S1 cortex is independent
      of NMDA receptor function in excitatory cortical neurons.
AB  - Neural activity plays an important role in refinement and plasticity of synaptic
      connections in developing vertebrate sensory systems. The rodent whisker-barrel
      pathway is an excellent model system to investigate the role of activity in
      formation of patterned neural connections and their plasticity. When whiskers on
      the snout or the sensory nerves innervating them are damaged during a critical
      period in development, whisker-specific patterns are altered along the trigeminal
      pathway, including the primary somatosensory (S1) cortex. In this context, NMDA
      receptor (NMDAR)-mediated activity has been implicated in patterning and
      plasticity of somatosensory maps. Using CxNR1KO mice, in which NMDAR1 (NR1), the
      essential NMDAR subunit gene, is disrupted only in excitatory cortical neurons,
      we showed that NMDAR-mediated activity is essential for whisker-specific
      patterning of barrel cells in layer IV of the S1 cortex. In CxNR1KO mice,
      thalamocortical axons (TCAs) representing the large whiskers segregate into
      rudimentary patches, but barrels as cellular modules do not develop. In this
      study, we examined lesion-induced TCA plasticity in CxNR1KO mice. TCA patterns
      underwent normal structural plasticity when their peripheral inputs were altered
      after whisker lesions during the critical period. The extent of the lesion
      induced morphological plasticity and the duration of the critical period were
      quantitatively indistinguishable between CxNR1KO and control mice. We conclude
      that TCA plasticity in the neocortex is independent of postsynaptic NMDAR
      activity in excitatory cortical neurons, and that non-NMDAR-mediated cortical
      activity and/or subcortical mechanisms must be operational in this process.

PMID- 12417642
TI  - Expression and functional characterization of GABA transporters in crayfish
      neurosecretory cells.
AB  - The effect of GABA on membrane potential and ionic currents of X-organ neurons
      isolated from the crayfish eyestalk was investigated. Under voltage-clamp
      conditions, GABA elicited an inward Na+ current followed by a sustained outward
      chloride current. Sodium current was partially blocked in a dose-dependent manner
      by antagonists of GABA plasma membrane transporters such as beta-alanine,
      nipecotic acid, 1-[2([(diphenylmethylene)imino]oxy)ethyl]-1,2,5,6-tetrahydro-3
      pyridinecarboxylic acid hydrochloride (NO 711), and SKF89976-A at concentrations
      between 1 and 100 microm. This current was totally blocked by the combined
      application of NO 711 (5 microm) and beta-alanine (50 microm). We obtained an
      EC(50) of 5 microm and a Hill coefficient of 0.97 for the GABA transport mediated
      response. These results together with studies of immunolocalization using
      antibodies against neuronal vertebrate GABA transporters (GATs) indicate the
      presence of GAT-1- and GAT-3-like proteins in X-organ neurons. To isolate the
      sustained outward Cl- current, extracellular free sodium solution was used to
      minimize the contribution of GAT activity. We concluded that this current was
      caused by the activation of GABA(A)-like receptors with an EC50 of 10 microm and
      a Hill number of 1.7. To assign a functional role to the GATs in the X-organ
      sinus gland system, we determine the GABA concentration (0.46-0.15 microm) in
      hemolymph samples using HPLC. In summary, our results suggest that a sodium
      dependent electrogenic GABA uptake mechanism has a direct influence on the
      excitability of the X-organ neurons, maintaining an excitatory tone that is
      dependent on the circulating GABA level.

PMID- 12417643
TI  - Dopamine D4 receptors modulate GABAergic signaling in pyramidal neurons of
      prefrontal cortex.
AB  - Dopaminergic neurotransmission in the prefrontal cortex (PFC) plays an important
      role in regulating cognitive processes and emotional status. The dopamine D4
      receptor, which is highly enriched in the PFC, is one of the principal targets of
      antipsychotic drugs. To understand the cellular mechanisms and functional
      implications of D4 receptors, we examined the impact of D4 receptors in PFC
      pyramidal neurons on GABAergic inhibition, a key element in the regulation of
      "working memory." Application of the D4 agonist N-(methyl)-4-(2
      cyanophenyl)piperazinyl-3-methylbenzamide maleate caused a reversible decrease in
      postsynaptic GABA(A) receptor currents; this effect was blocked by the D4
      antagonist 3-[(4-[4-chlorophenyl]piperazine-1-yl)methyl]-[1H]-pyrrolo[2,3
      b]pyridine but not by the D2 antagonist sulpiride, suggesting mediation by D4
      receptors. Application of PD168077 also reduced the GABA(A) receptor-mediated
      miniature IPSC amplitude in PFC pyramidal neurons recorded from slices. The D4
      modulation of GABA(A) receptor currents was blocked by protein kinase A (PKA)
      activation and occluded by PKA inhibition. Inhibiting the catalytic activity of
      protein phosphatase 1 (PP1) also eliminated the effect of PD168077 on GABA(A)
      currents. Furthermore, disrupting the association of the PKA/PP1 complex with its
      scaffold protein Yotiao significantly attenuated the D4 modulation of GABA(A)
      currents, suggesting that Yotiao-mediated targeting of PKA/PP1 to the vicinity of
      GABA(A) receptors is required for the dopaminergic signaling. Together, our
      results show that activation of D4 receptors in PFC pyramidal neurons inhibits
      GABA(A) channel functions by regulating the PKA/PP1 signaling complex, which
      could underlie the D4 modulation of PFC neuronal activity and the actions of
      antipsychotic drugs.

PMID- 12417644
TI  - Gene-targeted deletion of neurofibromin enhances the expression of a transient
      outward K+ current in Schwann cells: a protein kinase A-mediated mechanism.
AB  - Mutations in the neurofibromatosis type 1 gene predispose patients to develop
      benign peripheral nerve tumors (neurofibromas) containing Schwann cells (SCs).
      SCs from neurofibromatosis type-1 gene (Nf1) null mutant mice showed increased
      levels of Ras-GTP and cAMP. The proliferation and differentiation of SCs are
      regulated by Ras-GTP and cAMP-mediated signaling, which have been linked to
      expression of K+ channels. We investigated the differential expression of K+
      currents in Nf1 null mutant SCs (Nf1-/-) and their wild-type (Nf1+/+)
      counterparts and determined the mechanisms underlying the differences. The
      current densities of the sustained component of K+ currents were similar in the
      two genotypes. However, Nf1-/- SCs showed a significant increase (approximately
      1.5-fold) in a 4-aminopyridine-sensitive transient outward K+ current (I(A)).
      Nonstationary fluctuation analysis revealed a significant increase in the number
      of functional channels in the null mutant cells. When the involvement of the Ras
      pathway in the modulation of the K+ current was examined using adenoviral
      mediated gene transfer of a dominant-negative H-Ras N17 or the known H-Ras
      inhibitor (L-739,749), an additional increase in I(A) was observed. In contrast,
      protein kinase A (PKA) inhibitors, H89 and [PKI(2-22)amide] attenuated the
      enhancement of the current in the Nf1-/- cells, suggesting that the increase in
      I(A) was mediated via activation of protein kinase A. The unitary conductance of
      the channel underlying I(A) was unaltered by inhibitors of PKA. Activation of
      I(A) is thus negatively regulated by Ras-GTP and positively regulated by PKA.

PMID- 12417645
TI  - Barbiturates induce mitochondrial depolarization and potentiate excitotoxic
      neuronal death.
AB  - Barbiturates are widely used as anesthetics, anticonvulsants, and neuroprotective
      agents. However, barbiturates may also inhibit mitochondrial respiration, and
      mitochondrial inhibitors are known to potentiate NMDA receptor-mediated
      neurotoxicity. Here we used rat cortical cultures to examine the effect of
      barbiturates on neuronal mitochondria and responses to NMDA receptor stimulation.
      The barbiturates tested, secobarbital, amobarbital, and thiamylal, each
      potentiated NMDA-induced neuron death at barbiturate concentrations relevant to
      clinical and experimental use (100-300 microm). By using rhodamine-123 under
      quenching conditions, barbiturates in this concentration range were shown to
      depolarize neuronal mitochondria and greatly amplify NMDA-induced mitochondrial
      depolarization. Barbiturate-induced mitochondrial depolarization was increased by
      the ATP synthase inhibitor oligomycin, indicating that barbiturates act by
      inhibiting electron transport sufficiently to cause ATP synthase reversal.
      Barbiturates similarly amplified the effects of NMDA on cytoplasmic free calcium
      concentrations. The cell-impermeant barbiturate N-glucoside amobarbital did not
      influence mitochondrial potential or potentiate NMDA neurotoxicity or calcium
      responses. However, all of the barbiturates attenuated NMDA-induced calcium
      elevations and cell death when present at millimolar concentrations. Whole-cell
      patch-clamp studies showed that these effects may be attributable to actions at
      the cell membrane, resulting in a block of NMDA-induced current flux at
      millimolar barbiturate concentrations. Together, these findings reconcile
      previous reports of opposing effects on barbiturates on NMDA neurotoxicity and
      show that barbiturate effects on neuronal mitochondria can be functionally
      significant. Effects of barbiturates on neuronal mitochondria should be
      considered in experimental and clinical application of these drugs.

PMID- 12417646
TI  - Changes in spinal delta and kappa opioid systems in mice deficient in the A2A
      receptor gene.
AB  - A large body of evidence indicates important interactions between the adenosine
      and opioid systems in regulating pain at both the spinal and supraspinal level.
      Mice lacking the A(2A) receptor gene have been developed successfully, and these
      animals were shown to be hypoalgesic. To investigate whether there are any
      compensatory alterations in opioid systems in mutant animals, we have performed
      quantitative autoradiographic mapping of mu, delta, kappa, and opioid receptor
      like (ORL1) opioid receptors in the brains and spinal cords of wild-type and
      homozygous A(2A) receptor knock-out mice. In addition, mu-, delta-, and kappa
      mediated antinociception using the tail immersion test was tested in wild-type
      and homozygous A(2A) receptor knock-out mice. A significant reduction in
      [3H]deltorphin-I binding to delta receptors and a significant increase in [3H]CI
      977 binding to kappa receptors was detected in the spinal cords but not in the
      brains of the knock-out mice. Mu and ORL1 receptor expression were not altered
      significantly. Moreover, a significant reduction in delta-mediated
      antinociception and a significant increase in kappa-mediated antinociception were
      detected in mutant mice, whereas mu-mediated antinociception was unaffected.
      Comparison of basal nociceptive latencies showed a significant hypoalgesia in
      knock-out mice when tested at 55 degrees C but not at 52 degrees C. The results
      suggest a functional interaction between the spinal delta and kappa opioid and
      the peripheral adenosine system in the control of pain pathways.

PMID- 12417647
TI  - Ciliary neurotrophic factor (CNTF) enhances myelin formation: a novel role for
      CNTF and CNTF-related molecules.
AB  - In multiple sclerosis, myelin repair is generally insufficient despite the
      relative survival of oligodendrocytes within the plaques and the recruitment of
      oligodendrocyte precursors. Promoting remyelination appears to be a crucial
      therapeutic challenge. Using a newly developed enzymatic index of myelination, we
      screened different neurotrophic factors for their ability to enhance myelination.
      Neurotrophins [NGF, neurotrophin-3 (NT-3), NT-4/5, BDNF], glial cell line-derived
      neurotrophic factor (GDNF)-related factors (GDNF, neurturin), and growth factors
      such as PDGF-AA, FGF-2, and insulin did not increase myelinogenesis. In contrast,
      among factors belonging to the CNTF family, CNTF, leukemia inhibitory factor,
      cardiotrophin-1, and oncostatin M induced a strong promyelinating effect. We
      provide evidence that CNTF acts on oligodendrocytes by favoring their final
      maturation, and that this effect is mediated through the 130 kDa glycoprotein
      receptor common to the CNTF family and transduced through the Janus kinase
      pathway. Our results demonstrate a novel role for neurotrophic factors of the
      CNTF family and raise the possibility that these factors might be of therapeutic
      interest to promote remyelination in multiple sclerosis.

PMID- 12417648
TI  - Microglia-Muller glia cell interactions control neurotrophic factor production
      during light-induced retinal degeneration.
AB  - Activation of microglia commonly occurs in response to a wide variety of
      pathological stimuli including trauma, axotomy, ischemia, and degeneration in the
      CNS. In the retina, prolonged or high-intensity exposure to visible light leads
      to photoreceptor cell apoptosis. In such a light-reared retina, we found that
      activated microglia invade the degenerating photoreceptor layer and alter
      expression of neurotrophic factors such as nerve growth factor (NGF), ciliary
      neurotrophic factor (CNTF), and glial cell line-derived neurotrophic factor
      (GDNF). Because these neurotrophic factors modulate secondary trophic factor
      expression in Muller glial cells, microglia-Muller glia cell interaction may
      contribute to protection of photoreceptors or increase photoreceptor apoptosis.
      In the present study, we demonstrate the possibility that such functional glia
      glia interactions constitute the key mechanism by which microglia-derived NGF,
      brain-derived neurotrophic factor (BDNF), and CNTF indirectly influence
      photoreceptor survival, although the receptors for these neurotrophic factors are
      absent from photoreceptors, by modulating basic fibroblast growth factor (bFGF)
      and GDNF production and release from Muller glia. These observations suggest that
      microglia regulate the microglia-Muller glia-photoreceptor network that serves as
      a trophic factor-controlling system during retinal degeneration.

PMID- 12417649
TI  - Kainate receptor-dependent short-term plasticity of presynaptic Ca2+ influx at
      the hippocampal mossy fiber synapses.
AB  - Transmitter release at the hippocampal mossy fiber (MF)-CA3 synapse exhibits
      robust use-dependent short-term plasticity with an extremely wide dynamic range.
      Recent studies revealed that presynaptic kainate receptors (KARs), which
      specifically localized on the MF axons, mediate unusually large facilitation at
      this particular synapse in concert with the action of residual Ca2+. However, it
      is currently unclear how activation of kainate autoreceptors enhances transmitter
      release in an activity-dependent manner. Using fluorescence recordings of
      presynaptic Ca2+ and voltage in hippocampal slices, here we demonstrate that
      paired-pulse stimulation (with 20-200 msec intervals) resulted in facilitation of
      Ca2+ influx into the MF terminals, as opposed to other synapses, such as the
      Schaffer collateral-CA1 synapse. These observations deviate from typical residual
      Ca2+ hypothesis of facilitation, assuming an equal amount of Ca2+ influx per
      action potential. Pharmacological experiments reveal that the facilitation of
      presynaptic Ca2+ influx is mediated by activation of KARs. We also found that
      action potentials of MF axons are followed by prominent afterdepolarization,
      which is partly mediated by activation of KARs. Notably, the time course of the
      afterdepolarization approximates to that of the paired-pulse facilitation of Ca2+
      influx, suggesting that these two processes are closely related to each other.
      These results suggest that the novel mechanism amplifying presynaptic Ca2+ influx
      may underlie the robust short-term synaptic plasticity at the MF-CA3 synapse in
      the hippocampus, and this process is mediated by KARs whose activation evokes
      prominent afterdepolarization of MF axons and thereby enhances action potential
      driven Ca2+ influx into the presynaptic terminals.

PMID- 12417650
TI  - Pituitary adenylate cyclase-activating polypeptide and sonic hedgehog interact to
      control cerebellar granule precursor cell proliferation.
AB  - Although positive and negative signals control neurogenesis in the embryo,
      factors regulating postnatal proliferation are less well characterized. In the
      vertebrate cerebellum, Sonic Hedgehog (Shh) is an efficacious mitogen for
      cerebellar granule neuron precursors (GNPs), and mutations activating the Shh
      pathway are linked to medulloblastoma, a tumor derived from GNPs. Although the
      mitogenic effects of Shh can be blocked by increasing cAMP or protein kinase A
      activity, the physiological factors antagonizing this stimulation are undefined.
      In the embryo, pituitary adenylate cyclase-activating polypeptide (PACAP)
      receptor 1 (PAC1) signaling regulates neural precursor proliferation. We now show
      that in the developing cerebellum, PAC1 mRNA colocalizes with gene transcripts
      for Shh receptor Patched 1 and target gene Gli1 in the external germinal layer.
      We consequently investigated the interactions of PACAP and Shh in proliferation
      of purified GNPs in culture. Shh exhibited mitogenic activity in both rat and
      mouse cultures, stimulating DNA synthesis approximately 10-fold after 48 hr of
      exposure. PACAP markedly inhibited Shh-induced thymidine incorporation by 50 and
      85% in rat and mouse GNPs, respectively, but did not significantly affect the
      stimulation induced by other mitogens. This selective effect was reproduced by
      the specific PAC1 agonist maxadilan, as well as by the adenylate cyclase
      activator forskolin, suggesting that PAC1 provides a potent inhibitory signal for
      Shh-induced proliferation in developing cerebellum. In contrast, in the absence
      of Shh, PACAP and maxadilan modestly stimulated DNA synthesis, an effect
      reproduced by activating protein kinase C. These observations suggest that G
      protein-coupled receptors, such as PAC1, serve as sensors of environmental cues,
      coordinating diverse neurogenetic signals.

PMID- 12417651
TI  - The extraretinal eyelet of Drosophila: development, ultrastructure, and putative
      circadian function.
AB  - Circadian rhythms can be entrained by light to follow the daily solar cycle. In
      Drosophila melanogaster a pair of extraretinal eyelets expressing
      immunoreactivity to Rhodopsin 6 each contains four photoreceptors located beneath
      the posterior margin of the compound eye. Their axons project to the region of
      the pacemaker center in the brain with a trajectory resembling that of Bolwig's
      organ, the visual organ of the larva. A lacZ reporter line driven by an upstream
      fragment of the developmental gap gene Kruppel is a specific enhancer element for
      Bolwig's organ. Expression of immunoreactivity to the product of lacZ in Bolwig's
      organ persists through pupal metamorphosis and survives in the adult eyelet. We
      thus demonstrate that eyelet derives from the 12 photoreceptors of Bolwig's
      organ, which entrain circadian rhythmicity in the larva. Double labeling with
      anti-pigment-dispersing hormone shows that the terminals of Bolwig's nerve
      differentiate during metamorphosis in close temporal and spatial relationship to
      the ventral lateral neurons (LN(v)), which are essential to express circadian
      rhythmicity in the adult. Bolwig's organ also expresses immunoreactivity to
      Rhodopsin 6, which thus continues in eyelet. We compared action spectra of
      entrainment in different fly strains: in flies lacking compound eyes but
      retaining eyelet (so(1)), lacking both compound eyes and eyelet (so(1);gl(60j)),
      and retaining eyelet but lacking compound eyes as well as cryptochrome
      (so(1);cry(b)). Responses to phase shifts suggest that, in the absence of
      compound eyes, eyelet together with cryptochrome mainly mediates phase delays.
      Thus a functional role in circadian entrainment first found in Bolwig's organ in
      the larva is retained in eyelet, the adult remnant of Bolwig's organ, even in the
      face of metamorphic restructuring.

PMID- 12417652
TI  - Purification of polyglutamine aggregates and identification of elongation factor
      1alpha and heat shock protein 84 as aggregate-interacting proteins.
AB  - Aggregates of green fluorescent protein (GFP)-fused truncated N-terminal
      huntingtin containing abnormally long polyglutamine tracts (150 repeats of
      glutamine residue) were purified from an ecdysone-inducible mutant neuro2A cell
      line (HD150Q-28) by using a fluorescence-activated cell sorter. To analyze the
      aggregate-interacting proteins, we subjected the purified aggregates to SDS-PAGE;
      prominent protein bands in the gel were digested with Achromobactor lysyl
      endopeptidase, followed by a HPLC-mass spectrometry (MS) analysis. The resulting
      data of tandem MS analysis revealed that, in addition to ubiquitin and widely
      reported chaperone proteins such as heat shock cognate 70 (HSC70), human DNA J-1
      (HDJ-1), and HDJ-2, the translational elongation factor-1alpha (EF-1alpha) and
      heat shock protein 84 (HSP84) also were recognized as aggregate-interacting
      proteins. Sequestration of these proteins to aggregates was confirmed further by
      several immunochemical methods. We confirmed that, in addition to the other known
      proteins, EF-1alpha and HSP84 also colocalized with the intracellular aggregates.
      An assay of the transient expression of EF-1alpha and HSP84 in HD150Q-28 cells
      revealed that both proteins improved cell viability. Moreover, the rate of
      aggregate formation decreased in both transfectants. Our study suggests that both
      EF-1alpha and HSP84 are involved in the neurodegenerative process of
      polyglutamine diseases.

PMID- 12417653
TI  - Protein kinase C-dependent phosphorylation of synaptosome-associated protein of
      25 kDa at Ser187 potentiates vesicle recruitment.
AB  - Activation of protein kinase C (PKC) constitutes a key event in the upregulation
      of secretory strength in neurons and neurosecretory cells during extensive
      stimulation, presumably by speeding up vesicle supply. However, the molecular
      targets and their mode of action remain elusive. We studied the only PKC
      dependent phosphorylation site in the neuronal soluble N-ethylmaleimide-sensitive
      factor attachment protein receptor (SNARE) complex, Ser(187), in synaptosome
      associated protein of 25 kDa (SNAP-25). This phosphorylation site is located
      within the negatively charged C-terminal end of SNAP-25, which has been shown to
      be of critical importance in calcium-triggered exocytosis. We combined mutational
      studies that used overexpression in chromaffin cells with capacitance
      measurements and flash photolysis of caged calcium, allowing for high time
      resolution during both the stimulation and measurement of exocytosis.
      Overexpression of mutants simulating the phosphorylated form of Ser(187)
      accelerated vesicle recruitment after the emptying of the releasable vesicle
      pools. Overexpression of mutants simulating the nonphosphorylated form, or block
      of PKC, impaired the refilling of the vesicle pools to similar extents.
      Biochemical studies verified the phosphorylation of a subpopulation of SNAP-25
      after elevation of intracellular calcium concentrations. Some of the mutations
      led to a moderately decreased fast exocytotic burst component, which did not seem
      to be associated with the phosphorylation state of SNAP-25. Thus the C terminus
      of SNAP-25 plays a role for both fast exocytosis triggering and vesicle
      recruitment, and the latter process is regulated by PKC-dependent
      phosphorylation.

PMID- 12417654
TI  - Insulin-like growth factor-I blocks Bcl-2 interacting mediator of cell death
      (Bim) induction and intrinsic death signaling in cerebellar granule neurons.
AB  - Cerebellar granule neurons depend on insulin-like growth factor-I (IGF-I) for
      their survival. However, the mechanism underlying the neuroprotective effects of
      IGF-I is presently unclear. Here we show that IGF-I protects granule neurons by
      suppressing key elements of the intrinsic (mitochondrial) death pathway. IGF-I
      blocked activation of the executioner caspase-3 and the intrinsic initiator
      caspase-9 in primary cerebellar granule neurons deprived of serum and
      depolarizing potassium. IGF-I inhibited cytochrome c release from mitochondria
      and prevented its redistribution to neuronal processes. The effects of IGF-I on
      cytochrome c release were not mediated by blockade of the mitochondrial
      permeability transition pore, because IGF-I failed to inhibit mitochondrial
      swelling or depolarization. In contrast, IGF-I blocked induction of the BH3-only
      Bcl-2 family member, Bim (Bcl-2 interacting mediator of cell death), a mediator
      of Bax-dependent cytochrome c release. The suppression of Bim expression by IGF-I
      did not involve inhibition of the c-Jun transcription factor. Instead, IGF-I
      prevented activation of the forkhead family member, FKHRL1, another
      transcriptional regulator of Bim. Finally, adenoviral-mediated expression of
      dominant-negative AKT activated FKHRL1 and induced expression of Bim. These data
      suggest that IGF-I signaling via AKT promotes survival of cerebellar granule
      neurons by blocking the FKHRL1-dependent transcription of Bim, a principal
      effector of the intrinsic death-signaling cascade.

PMID- 12417655
TI  - Increased extracellular amyloid deposition and neurodegeneration in human amyloid
      precursor protein transgenic mice deficient in receptor-associated protein.
AB  - The low-density lipoprotein receptor-related protein (LRP) is an abundant
      neuronal cell surface receptor that regulates amyloid beta-protein (Abeta)
      trafficking into the cell. Specifically, LRP binds secreted Abeta complexes and
      mediates its degradation. Previously, we have shown in vitro that the uptake of
      Abeta mediated by LRP is protective and that blocking this receptor significantly
      enhances neurotoxicity. To further characterize the effects of LRP and other
      lipoprotein receptors on Abeta deposition, an in vivo model of decreased LRP
      expression, receptor-associated protein (RAP)-deficient (RAP-/-) mice was crossed
      with human amyloid protein precursor transgenic (hAPP tg) mice, and plaque
      formation and neurodegeneration were analyzed. We found that, although the age of
      onset for plaque formation was the same in hAPP tg and hAPP tg/RAP-/- mice, the
      amount of amyloid deposited doubled in the hAPP tg/RAP-/- background. Moreover,
      these mice displayed increased neuronal damage and astrogliosis. Together, these
      results further support the contention that LRP and other lipoprotein receptors
      might be neuroprotective against Abeta toxicity and that this receptor might play
      an integral role in Abeta clearance.

PMID- 12417656
TI  - Genome-wide expression analysis in Drosophila reveals genes controlling circadian
      behavior.
AB  - In Drosophila, a number of key processes such as emergence from the pupal case,
      locomotor activity, feeding, olfaction, and aspects of mating behavior are under
      circadian regulation. Although we have a basic understanding of how the molecular
      oscillations take place, a clear link between gene regulation and downstream
      biological processes is still missing. To identify clock-controlled output genes,
      we have used an oligonucleotide-based high-density array that interrogates gene
      expression changes on a whole genome level. We found genes regulating various
      physiological processes to be under circadian transcriptional regulation, ranging
      from protein stability and degradation, signal transduction, heme metabolism,
      detoxification, and immunity. By comparing rhythmically expressed genes in the
      fly head and body, we found that the clock has adapted its output functions to
      the needs of each particular tissue, implying that tissue-specific regulation is
      superimposed on clock control of gene expression. Finally, taking full advantage
      of the fly as a model system, we have identified and characterized a cycling
      potassium channel protein as a key step in linking the transcriptional feedback
      loop to rhythmic locomotor behavior.

PMID- 12417657
TI  - Dopamine activates noradrenergic receptors in the preoptic area.
AB  - Dopamine (DA) facilitates male sexual behavior and modulates aromatase activity
      in the quail preoptic area (POA). Aromatase neurons in the POA receive
      dopaminergic inputs, but the anatomical substrate that mediates the behavioral
      and endocrine effects of DA is poorly understood. Intracellular recordings showed
      that 100 microm DA hyperpolarizes most neurons in the medial preoptic nucleus
      (80%) by a direct effect, but depolarizes a few others (10%). DA-induced
      hyperpolarizations were not blocked by D1 or D2 antagonists (SCH-23390 and
      sulpiride). Extracellular recordings confirmed that DA inhibits the firing of
      most cells (52%) but excites a few others (24%). These effects also were not
      affected by DA antagonists (SCH-23390 and sulpiride) but were blocked by alpha2
      (yohimbine) and alpha1-(prazosin) noradrenergic receptor antagonists,
      respectively. Two dopamine-beta-hydroxylase (DBH) inhibitors (cysteine and
      fusaric acid) did not block the DA-induced effects, indicating that DA is not
      converted into norepinephrine (NE) to produce its effects. The pK(B) of yohimbine
      for the receptor involved in the DA- and NE-induced inhibitions was similar,
      indicating that the two monoamines interact with the same receptor. Together,
      these results demonstrate that the effects of DA in the POA are mediated mostly
      by the activation of alpha2 (inhibition) and alpha1 (excitation) adrenoreceptors.
      This may explain why DA affects the expression of male sexual behavior through
      its action in the POA, which contains high densities of alpha2-noradrenergic but
      limited amounts of DA receptors. This study thus clearly demonstrates the
      existence of a cross talk within CNS catecholaminergic systems between a
      neurotransmitter and heterologous receptors.

PMID- 12417658
TI  - Alternative splicing of a beta4 subunit proline-rich motif regulates voltage
      dependent gating and toxin block of Cav2.1 Ca2+ channels.
AB  - Ca2+ channel beta subunits modify alpha1 subunit gating properties through direct
      interactions with intracellular linker domains. In a previous report (Helton and
      Horne, 2002), we showed that alternative splicing of the beta4 subunit had alpha1
      subunit subtype-specific effects on Ca2+ channel activation and fast
      inactivation. We extend these findings in the present report to include effects
      on slow inactivation and block by the peptide toxin omega-conotoxin (CTx)-MVIIC.
      N-terminal deletion and site-directed mutagenesis experiments revealed that the
      effects of alternative splicing on toxin block and all aspects of gating could be
      attributed to a proline-rich motif found within N-terminal beta4b amino acids 10
      20. Interestingly, this motif is conserved within the third postsynaptic density
      95 (PSD-95)/Discs large/zona occludens-1 domain of the distantly related membrane
      associated guanylate kinase homolog, PSD-95. Sequence identity of approximately
      30% made possible the building of beta4a and beta4b three-dimensional structural
      models using PSD-95 as the target sequence. The models (1) reveal that
      alternative splicing of the beta4 N terminus results in dramatic differences in
      surface charge distribution and (2) localize the proline-rich motif of beta4b to
      an extended arm structure that flanks what would be the equivalent of a highly
      modified PSD-95 carboxylate binding loop. Northern blot analysis revealed a
      markedly different pattern of distribution for beta4a versus beta4b in the human
      CNS. Whereas beta4a is distributed throughout evolutionarily older regions of the
      CNS, beta4b is concentrated heavily in the forebrain. These results raise
      interesting questions about the functional role that alternative splicing of the
      beta4 subunit has played in the evolution of complex neural networks.

PMID- 12417659
TI  - Abundant tau filaments and nonapoptotic neurodegeneration in transgenic mice
      expressing human P301S tau protein.
AB  - The identification of mutations in the Tau gene in frontotemporal dementia and
      parkinsonism linked to chromosome 17 (FTDP-17) has made it possible to express
      human tau protein with pathogenic mutations in transgenic animals. Here we report
      on the production and characterization of a line of mice transgenic for the 383
      aa isoform of human tau with the P301S mutation. At 5-6 months of age, homozygous
      animals from this line developed a neurological phenotype dominated by a severe
      paraparesis. According to light microscopy, many nerve cells in brain and spinal
      cord were strongly immunoreactive for hyperphosphorylated tau. According to
      electron microscopy, abundant filaments made of hyperphosphorylated tau protein
      were present. The majority of filaments resembled the half-twisted ribbons
      described previously in cases of FTDP-17, with a minority of filaments resembling
      the paired helical filaments of Alzheimer's disease. Sarkosyl-insoluble tau from
      brains and spinal cords of transgenic mice ran as a hyperphosphorylated 64 kDa
      band, the same apparent molecular mass as that of the 383 aa tau isoform in the
      human tauopathies. Perchloric acid-soluble tau was also phosphorylated at many
      sites, with the notable exception of serine 214. In the spinal cord,
      neurodegeneration was present, as indicated by a 49% reduction in the number of
      motor neurons. No evidence for apoptosis was obtained, despite the extensive
      colocalization of hyperphosphorylated tau protein with activated MAP kinase
      family members. The latter may be involved in the hyperphosphorylation of tau.

PMID- 12417661
TI  - Growth cone turning induced by direct local modification of microtubule dynamics.
AB  - Pathfinding by nerve growth cones depends on attractive and repulsive turning in
      response to a variety of guidance cues. Here we present direct evidence to
      demonstrate an essential and instructive role for microtubules (MTs) in growth
      cone steering. First, both growth cone attraction and repulsion induced by
      diffusible cues in culture can be completely blocked by low concentrations of
      drugs that specifically inhibit dynamic microtubule ends in the growth cone.
      Second, direct focal photoactivated release of the microtubule-stabilizing drug
      taxol on one side of the growth cone consistently induces attraction (turning
      toward the site of application). Using the focal pipette application method, we
      also show that local MT stabilization by taxol induces growth cone attraction,
      whereas local MT destabilization by the microtubule-disrupting drug nocodazole
      induces repulsion (turning away). Finally, the microtubule-initiated attractive
      turning requires the participation of the actin cytoskeleton: local microtubule
      stabilization induces preferential protrusion of lamellipodia before the
      attractive turning, and the attraction can be abolished by inhibition of either
      actin polymerization or the Rho family GTPases. Together, these results
      demonstrate a novel steering mechanism for growth cones in which local and
      selective modification of dynamic microtubules can initiate and instruct
      directional steering. With the subsequent concerted activity of the actin
      cytoskeleton, this microtubule-initiated mechanism provides the growth cone with
      the additional means to efficiently navigate through its environment.

PMID- 12417660
TI  - Miswiring of limbic thalamocortical projections in the absence of ephrin-A5.
AB  - Axon guidance cues of the ephrin ligand family have been hypothesized to regulate
      the formation of thalamocortical connections, but in vivo evidence for such a
      role has not been examined directly. To test whether ephrin-mediated repulsive
      cues participate in sorting the projections originating from distinct thalamic
      nuclei, we analyzed the organization of somatosensory and anterior cingulate
      afferents postnatally in mice lacking ephrin-A5 gene expression. Projections from
      ventrobasal and laterodorsal nuclei to their respective sensory and limbic
      cortical areas developed normally. However, a portion of limbic thalamic neurons
      from the laterodorsal nucleus also formed additional projections to somatosensory
      cortical territories, thus maintaining inappropriate dual projections to multiple
      cortical regions. These results suggest that ephrin-A5 is not required for the
      formation of normal cortical projections from the appropriate thalamic nuclei,
      but rather acts as a guidance cue that restricts limbic thalamic axons from
      inappropriate neocortical regions.

PMID- 12417662
TI  - Fibroblast growth factor signaling regulates pillar cell development in the organ
      of corti.
AB  - One of the most striking aspects of the cellular pattern within the sensory
      epithelium of the mammalian cochlea is the presence of two rows of pillar cells
      in the region between the single row of inner hair cells and the first row of
      outer hair cells. The factors that regulate pillar cell development have not been
      determined; however, previous results suggested a key role for fibroblast growth
      factor receptor 3 (FGFR3). To examine the specific effects of FGFR3 on pillar
      cell development, we inhibited receptor activation in embryonic cochlear explant
      cultures. Results indicated that differentiation of pillar cells is dependent on
      continuous activation of FGFR3. Moreover, transient inhibition of FGFR3 did not
      inhibit the pillar cell fate permanently, because reactivation of FGFR3 resulted
      in the resumption of pillar cell differentiation. The effects of increased FGFR3
      activation were determined by exposing cochlear explants to FGF2, a strong ligand
      for several FGF receptors. Treatment with FGF2 led to a significant increase in
      the number of pillar cells and to a small increase in the number of inner hair
      cells. These effects were not dependent on cellular proliferation, suggesting
      that additional pillar cells and inner hair cells were a result of increased
      recruitment into the prosensory domain. These results indicate that FGF signaling
      plays a critical role in the commitment and differentiation of pillar cells.
      Moreover, the position of the pillar cells appears to be determined by the
      activation of FGFR3 in a subset of the progenitor cells that initially express
      this receptor.

PMID- 12417663
TI  - Identification of the neuroprotective molecular region of pigment epithelium
      derived factor and its binding sites on motor neurons.
AB  - Pigment epithelium-derived factor (PEDF), a member of the serine protease
      inhibitor (serpin) family, is a survival factor for various types of neurons. We
      studied the mechanisms by which human PEDF protects motor neurons from
      degeneration, with the goal of eventually conducting human clinical trials. We
      first searched for a molecular region of human PEDF essential to motor neuron
      protection. Using a spinal cord culture model of chronic glutamate toxicity, we
      show herein that a synthetic 44 mer peptide from an N-terminal region of the
      human PEDF molecule that lacks the homologous serpin-reactive region contains its
      full neuroprotective activity. We also investigated the presence and distribution
      of PEDF receptors in the spinal cord. Using a fluoresceinated PEDF probe, we show
      that spinal motor neurons contain specific binding sites for PEDF. Kinetics
      analyses using a radiolabeled PEDF probe demonstrate that purified rat motor
      neurons contain a single class of saturable and specific binding sites. This
      study indicates that a small peptide fragment of the human PEDF molecule could be
      engineered to contain all of its motor neuron protective activity, and that the
      neuroprotective action is likely to be mediated directly on motor neurons via a
      single class of PEDF receptors. The data support the pharmacotherapeutic
      potential of PEDF as a neuroprotectant in human motor neuron degeneration.

PMID- 12417664
TI  - Insulin and fibroblast growth factor 2 activate a neurogenic program in Muller
      glia of the chicken retina.
AB  - We have reported previously that neurotoxic damage to the chicken retina causes
      Muller glia to dedifferentiate, proliferate, express transcription factors common
      to retinal progenitors, and generate new neurons and glia, whereas the majority
      of newly produced cells remain undifferentiated (Fischer and Reh, 2001). Because
      damaged retinal cells have been shown to produce increased levels of insulin
      related factors and FGFs, in the current study we tested whether intraocular
      injections of growth factors stimulate Muller glia to proliferate and produce new
      neurons. We injected growth factors and bromodeoxyuridine into the vitreous
      chamber of the eyes of chickens and assayed for changes in glial phenotype and
      proliferation within the retina. Although insulin or FGF2 alone had no effect,
      the combination of insulin and FGF2 caused Muller glia to coexpress transcription
      factors common to retinal progenitors (Pax6 and Chx10) and initiated a wave of
      proliferation in Muller cells that began at the retinal margin and spread into
      peripheral regions of the retina. Most of the newly formed cells remain
      undifferentiated, expressing Pax6 and Chx10, whereas some differentiate into
      Muller glia, and a few differentiate into neurons that express the neuronal
      markers Hu or calretinin. There was no evidence of retinal damage in eyes treated
      with insulin and FGF2. We conclude that the combination of insulin and FGF2
      stimulated Muller glia to dedifferentiate, proliferate, and generate new neurons.
      These findings imply that exogenous growth factors might be used to stimulate
      endogenous glial cells to regenerate neurons in the CNS.

PMID- 12417665
TI  - Differential regulation of active zone density during long-term strengthening of
      Drosophila neuromuscular junctions.
AB  - In this study we established a transgenic Ca2+ imaging technique in Drosophila
      that enabled us to target the Ca2+ sensor protein yellow Cameleon-2 specifically
      to larval neurons. This noninvasive method allowed us to measure evoked Ca2+
      signals in presynaptic terminals of larval neuromuscular junctions (NMJs). We
      combined transgenic Ca2+ imaging with electrophysiological recordings and
      morphological examinations of larval NMJs to analyze the mechanisms underlying
      persistently enhanced evoked vesicle release in two independent mutants. We show
      that persistent strengthening of junctional vesicle release relies on the
      recruitment of additional active zones, the spacing of which correlated with the
      evoked presynaptic Ca2+ dynamics of individual presynaptic terminals. Knock-out
      mutants of the postsynaptic glutamate receptor (GluR) subunit DGluR-IIA, which
      showed a reduced quantal size, developed NMJs with a smaller number of
      presynaptic boutons but a strong compensatory increase in the density of active
      zones. This resulted in an increased evoked vesicle release on single action
      potentials and larger evoked Ca2+ signals within individual boutons; however, the
      transmission of higher frequency stimuli was strongly depressed. A second mutant
      (pabp(P970)/+), which showed enhanced evoked vesicle release triggered by
      elevated subsynaptic protein synthesis, developed NMJs with an increased number
      of presynaptic boutons and active zones; however, the density of active zones was
      maintained at a value typical for wild-type animals. This resulted in wild-type
      evoked Ca2+ signals but persistently strengthened junctional signal transmission.
      These data suggest that the consolidation of strengthened signal transmission
      relies not only on the recruitment of active zones but also on their equal
      distribution in newly grown boutons.

PMID- 12417666
TI  - Damage-induced neuronal endopeptidase (DINE/ECEL) expression is regulated by
      leukemia inhibitory factor and deprivation of nerve growth factor in rat sensory
      ganglia after nerve injury.
AB  - Damage-induced neuronal endopeptidase (DINE) is a novel metallopeptidase and is
      expressed in response to various neuronal injuries. The expression regulation of
      DINE mRNA in the dorsal root ganglia (DRGs) after sciatic nerve injury is
      examined. A substantial increase of DINE mRNA expression was observed in
      relatively small-sized DRG neurons after nerve injury. The expression was
      observed in isolectin B4-negative and partly TrkA-positive neurons, and the
      expression profile was fairly similar to that of the neuropeptide galanin. More
      than 80% of DINE mRNA-positive neurons simultaneously demonstrated galanin
      immunoreactivity after nerve injury. In cultured DRG, DINE mRNA expression was
      enhanced by leukemia inhibitory factor (LIF) but not by other growth factors and
      cytokines. LIF treatment to rat sciatic nerve induced DINE mRNA expression in DRG
      without nerve injury, and, conversely, the intranerve injection of anti-gp130
      antibody after sciatic nerve injury significantly inhibited the upregulation of
      DINE mRNA in DRG. Furthermore, nerve growth factor (NGF) deprivation, which can
      induce galanin expression, also enhanced DINE mRNA expression in vitro and in
      vivo. Both LIF application and NGF deprivation additively enhanced DINE
      expression in vitro. These results suggest that DINE gene expression is regulated
      separately by both LIF and NGF deprivation, and this regulation pattern is
      similar to that of galanin gene expression. Because both DINE and galanin have a
      neuroprotective function, their simultaneous induction may provide more
      successful protection for injured sensory neurons.

PMID- 12417667
TI  - Decoupling eye-specific segregation from lamination in the lateral geniculate
      nucleus.
AB  - To determine whether there is a critical period for development of eye-specific
      layers in the lateral geniculate nucleus (LGN), we prevented the normal
      segregation of retinogeniculate afferents and then allowed an extended period of
      time for recovery. After recovery, both anatomy and physiology revealed strictly
      nonoverlapping territories of input from the two eyes. However, the normal
      stereotyped pattern of eye-specific afferent and cellular layers never developed.
      Instead, the eye-specific territories of afferent input emerged as variable and
      disorganized patches with no corresponding interlaminar spaces in the LGN. These
      findings reveal a critical period for coordinating the development of three
      processes in the LGN: the segregation of afferents from the two eyes, the spatial
      organization of those afferents into layers, and the alignment of postsynaptic
      cytoarchitecture with the afferent inputs. We also assessed the physiological
      consequences of preventing normal lamination and found normal single-cell
      responses and topographic representation of visual space in the LGN. Clusters of
      ON-center and OFF-center LGN cells were segregated from one another as in normal
      animals. However, the organization of ON and OFF sublaminas in the treated
      animals was disrupted.

PMID- 12417668
TI  - Neuronal activity regulates correlated network properties of spontaneous calcium
      transients in astrocytes in situ.
AB  - Spontaneous neuronal activity is essential to neural development. Until recently,
      neurons were believed to be the only excitable cells to display spontaneous
      activity. However, cultured astrocytes and, more recently, astrocytes in situ are
      now known to exhibit spontaneous Ca2+ transients. Here we used Ca2+ imaging of
      astrocytes from transgenic mice for the simultaneous monitoring of [Ca2+]i
      changes in large numbers of astrocytes. We found that spontaneous activity is a
      common property of most brain astrocytes that is lost in response to a lesion.
      These spontaneous [Ca2+]i oscillations require extracellular and intracellular
      Ca2+. Moreover, network analysis revealed that most astrocytes formed correlated
      networks of dozens of these cells, which were synchronous with both astrocytes
      and neurons. We found that decreasing spontaneous [Ca2+]i transients in neurons
      by TTX does not alter the number of active astrocytes, although it impairs their
      synchronous network activity. Conversely, bicuculline-induced epileptic patterns
      of [Ca2+]i transients in neurons cause an increase in the number of active
      astrocytes and in their network synchrony. Furthermore, activation of non-NMDA
      and NMDA ionotropic glutamate receptors is required to correlate astrocytic
      networks. These results show that spontaneous activity in astrocytes and neurons
      is patterned into correlated neuronal/astrocytic networks in which neuronal
      activity regulates the network properties of astrocytes. This network activity
      may be essential for neural development and synaptic plasticity.

PMID- 12417669
TI  - Developmental regulation of neurotransmitter phenotype through
      tetrahydrobiopterin.
AB  - During development, sympathetic neurons innervating rodent sweat glands undergo a
      target-induced change in neurotransmitter phenotype from noradrenergic to
      cholinergic. Although the sweat gland innervation in the adult mouse is
      cholinergic and catecholamines are absent, these neurons continue to express
      tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine synthesis.
      The developmental suppression of noradrenergic function in these mouse
      sympathetic neurons is not well understood. We investigated whether the
      downregulation of the enzyme aromatic l-amino acid decarboxylase (AADC) or the TH
      cofactor tetrahydrobiopterin (BH4) could account for the loss of catecholamines
      in these neurons. AADC levels did not decrease during development, and adult
      cholinergic sympathetic neurons were strongly immunoreactive for AADC. In
      contrast, BH4 levels dropped significantly in murine sweat gland-containing
      footpads during the time period when the gland innervation was switching from
      making norepinephrine to acetylcholine. Immunoreactivity for the rate-limiting
      BH4 synthetic enzyme GTP cyclohydrolase (GCH) became undetectable in the sweat
      gland neurons during this phenotypic conversion, suggesting that sweat glands
      reduce BH4 levels by suppressing GCH expression during development. Furthermore,
      extracts from sweat gland-containing footpads suppressed BH4 in cultured mouse
      sympathetic neurons, and addition of the BH4 precursor sepiapterin rescued
      catecholamine production in neurons treated with footpad extracts. Together,
      these results suggest that the mouse sweat gland-derived cholinergic
      differentiation factor functionally suppresses the noradrenergic phenotype during
      development by inhibiting production of the TH cofactor, BH4. These data also
      indicate that GCH expression, which is often coordinately regulated with TH
      expression, can be controlled independently of TH during development.

PMID- 12417670
TI  - Hypocretins (orexins) regulate serotonin neurons in the dorsal raphe nucleus by
      excitatory direct and inhibitory indirect actions.
AB  - The hypocretins (hcrt1 and hcrt2) are expressed by a discrete population of
      hypothalamic neurons projecting to many regions of the CNS, including the dorsal
      raphe nucleus (DRN), where serotonin (5-HT) neurons are concentrated. In this
      study, we investigated responses to hcrts in 216 physiologically identified 5-HT
      and non-5-HT neurons of the DRN using intracellular and whole-cell recording in
      rat brain slices. Hcrt1 and hcrt2 induced similar amplitude and dose-dependent
      inward currents in most 5-HT neurons tested (EC50, approximately 250 nm). This
      inward current was not blocked by the fast Na+ channel blocker TTX or in a Ca2+
      free solution, indicating a direct postsynaptic action. The hcrt-induced inward
      current reversed near -18 mV and was primarily dependent on external Na+ but not
      on external or internal Ca2+, features typical of Na+/K+ nonselective cation
      channels. At higher concentrations, hcrts also increased spontaneous postsynaptic
      currents in 5-HT neurons (EC50, approximately 450-600 nm), which were TTX
      sensitive and mostly blocked by the GABA(A) antagonist bicuculline, indicating
      increased impulse flow in local GABA interneurons. Accordingly, hcrts were found
      to increase the basal firing of presumptive GABA interneurons. Immunolabeling
      showed that hcrt fibers projected to both 5-HT and GABA neurons in the DRN. We
      conclude that hcrts act directly to excite 5-HT neurons primarily via a TTX
      insensitive, Na+/K+ nonselective cation current, and indirectly to activate local
      inhibitory GABA inputs to 5-HT cells. The greater potency of hcrts in direct
      excitation compared with indirect inhibition suggests a negative feedback
      function for the latter at higher levels of hcrt activity.

PMID- 12417671
TI  - Restoration of movement using functional electrical stimulation and Bayes'
      theorem.
AB  - Various computational approaches have been applied to predict aspects of animal
      behavior from the recorded activity of populations of neurons. Here we invert
      this process to predict the requisite neuromuscular activity associated with
      specified motor behaviors. A probabilistic method based on Bayes' theorem was
      used to predict the patterns of muscular activity needed to produce various types
      of desired finger movements. The profiles of predicted activity were then used to
      drive frequency-modulated muscle stimulators to evoke multijoint finger
      movements. Comparison of movements generated by electrical stimulation with
      desired movements yielded root mean squared errors between approximately 18 and
      26%. This reasonable correspondence between desired and evoked movements suggests
      that this approach might serve as a useful strategy to control neuroprosthetic
      systems that aim to restore movement to paralyzed individuals.

PMID- 12417672
TI  - Response of neurons in the lateral intraparietal area during a combined visual
      discrimination reaction time task.
AB  - Decisions about the visual world can take time to form, especially when
      information is unreliable. We studied the neural correlate of gradual decision
      formation by recording activity from the lateral intraparietal cortex (area LIP)
      of rhesus monkeys during a combined motion-discrimination reaction-time task.
      Monkeys reported the direction of random-dot motion by making an eye movement to
      one of two peripheral choice targets, one of which was within the response field
      of the neuron. We varied the difficulty of the task and measured both the
      accuracy of direction discrimination and the time required to reach a decision.
      Both the accuracy and speed of decisions increased as a function of motion
      strength. During the period of decision formation, the epoch between onset of
      visual motion and the initiation of the eye movement response, LIP neurons
      underwent ramp-like changes in their discharge rate that predicted the monkey's
      decision. A steeper rise in spike rate was associated with stronger stimulus
      motion and shorter reaction times. The observations suggest that neurons in LIP
      integrate time-varying signals that originate in the extrastriate visual cortex,
      accumulating evidence for or against a specific behavioral response. A threshold
      level of LIP activity appears to mark the completion of the decision process and
      to govern the tradeoff between accuracy and speed of perception.

PMID- 12417673
TI  - Functional dissection of neuroanatomical loci regulating ethanol sensitivity in
      Drosophila.
AB  - Ethanol has complex but similar effects on behavior in mammals and the fruit fly
      Drosophila melanogaster. In addition, genetic and pharmacological approaches have
      implicated the cAMP pathway in the regulation of ethanol-induced behaviors in
      both flies and rodents. Here we examine the neuroanatomical loci that modulate
      ethanol sensitivity in Drosophila by targeting the expression of an inhibitor of
      cAMP-dependent protein kinase (PKA) to specific regions in the fly's brain.
      Expression of the inhibitor in most brain regions or in muscle has no effect on
      behavior. In contrast, inhibition of PKA in a relatively small number of cells,
      possibly neurosecretory cells, in the fly's brain is sufficient to decrease
      sensitivity to the incoordinating effects of ethanol. Additional brain areas are,
      however, also involved. The mushroom bodies, brain structures where cAMP
      signaling is required for olfactory classical conditioning, are dispensable for
      the regulation of ethanol sensitivity. Finally, different behavioral effects of
      ethanol, motor incoordination and sedation, appear to be regulated by PKA
      function in distinct brain regions. We conclude that the regulation of ethanol
      induced behaviors by PKA involves complex interactions among groups of cells that
      mediate either increased or reduced sensitivity to the acute intoxicating effects
      of ethanol.

PMID- 12417674
TI  - Electrophysiological responses in the human amygdala discriminate emotion
      categories of complex visual stimuli.
AB  - The human amygdala has been shown to participate in processing emotionally
      salient stimuli related to threat, danger, and aversion, data that have come
      primarily from functional imaging and lesion studies. Recording intracranial
      field potentials from five amygdalas in four patients with chronically implanted
      depth electrodes, we analyzed responses in the gamma frequency range, a region of
      the power spectrum thought to reflect especially the contribution of neuronal
      activity to cognitive processes. Significant changes in the power amplitude of
      responses were obtained selectively to visual images judged to look aversive but
      not to those judged to look pleasant or neutral. Several possible confounds were
      addressed: all four patients had been carefully selected so that the amygdalas
      from which recordings were obtained were distal to epileptogenic foci, making it
      likely that we recorded from healthy tissue, and the observed responses could not
      be attributed to luminance or color differences between the stimuli. A further
      analysis of differences in power between the high and low gamma bands revealed an
      additional structure that discriminated those stimuli related to bodily injury
      from those related to disgust. Despite the increased power amplitude in the gamma
      range, there was no stimulus-locked phase coherence. The observed responses in
      the gamma frequency range may reflect the role of the amygdala in binding
      perceptual representations of the stimuli with memory, emotional response, and
      modulation of ongoing cognition, on the basis of the emotional significance of
      the stimuli.

PMID- 12417675
TI  - Olfactory fingerprints for major histocompatibility complex-determined body odors
      II: relationship among odor maps, genetics, odor composition, and behavior.
AB  - The olfactory system detects small differences in the composition of natural
      odorants, made up of hundreds of molecules. Odorous quality is hypothetically
      represented by a combinatorial code: activation of distinct but overlapping
      subsets of olfactory receptors resulting in activation of a distinct subset of
      glomeruli in the main olfactory bulb (MOB). Here we show that modification of a
      single gene (the K gene of the major histocompatibility locus), which results in
      a subtle change in the odiferous quality of urine, causes a small but significant
      change in the composition of urine volatiles and consequently the evoked
      glomerular activation pattern in the MOB. The magnitude of disparity between
      urine-evoked glomerular activation patterns is predictive of the extent of (1)
      the genetic difference among the urine donors, (2) the difference in the chemical
      composition of urine, and (3) the odor detector's ability to discriminate. These
      data on natural odors are consistent with the combinatorial code hypothesis and
      identify subsets of glomeruli that are apt to play a significant role in
      mediating individual recognition.

PMID- 12417676
TI  - Primary afferent terminals in spinal cord express presynaptic AMPA receptors.
AB  - Larger dorsal root ganglion neurons are stained by an antibody for the C terminus
      of glutamate receptor subunit 2 (GluR2) and GluR3 (GluR2/3) rather than by an
      antibody for GluR4. In dorsal roots, anti-GluR2/3 stains predominantly myelinated
      fibers; anti-GluR4 or anti-GluR2/4 stains predominantly unmyelinated fibers. In
      the dorsal horn, puncta immunopositive for synaptophysin and GluR2/3 are
      predominantly in laminas III and IV, whereas puncta immunopositive for
      synaptophysin and GluR4 or GluR2/4 are predominantly in laminas I and II. Puncta
      immunopositive for GluR2/3 costain with the B subunit of cholera toxin, whereas
      puncta immunopositive for GluR2/4 costain with isolectin B4 after injections of
      these tracers in the sciatic nerve. No puncta costain with calcitonin gene
      related peptide and AMPA receptor subunits. Electron microscopy indicates that
      AMPA receptor-immunopositive terminals are more numerous than suggested by
      confocal microscopy. Of all synapses in which immunostaining is presynaptic,
      postsynaptic, or both, the percentage of presynaptic immunostain is approximately
      70% with anti-GluR4 or anti-GluR2/4 (in laminas I-III), 25-30% with anti-GluR2/3
      (in laminas III and IV), and 5% with anti-GluR2 (in laminas I-III). Because of
      fixation constraints, the types of immunostained terminals could be identified
      only on the basis of morphological characteristics. Many terminals immunostained
      for GluR2/3, GluR4, or GluR2/4 have morphological features of endings of primary
      afferents. Terminals with morphological characteristics of presumed GABAergic
      terminals are also immunostained with anti-GluR2/4 and anti-GluR4 in laminas I
      and II and with anti-GluR2/3 in laminas III and IV. The conspicuous and selective
      expression of presynaptic AMPA receptor subunits may contribute to the
      characteristic physiological profile of different classes of primary afferents
      and suggests an important mechanism for the modulation of transmitter release by
      terminals of both myelinated and unmyelinated primary afferents.

PMID- 12417677
TI  - Middle temporal visual area microstimulation influences veridical judgments of
      motion direction.
AB  - Microstimulation of direction columns in the middle temporal visual area (MT, or
      V5) provides a powerful tool for probing the relationship between cortical
      physiology and visual motion perception. In the current study we obtained
      "veridical" reports of perceived motion from rhesus monkeys by permitting a
      continuous range of possible responses that mapped isomorphically onto a
      continuous range of possible motion directions. In contrast to previous studies,
      therefore, the animals were freed from experimenter-imposed "categories" that
      typify forced choice tasks. We report three new findings: (1) MT neurons with
      widely disparate preferred directions can cooperate to shape direction estimates,
      inconsistent with a pure "winner-take-all" read-out algorithm and consistent with
      a distributed coding scheme like vector averaging, whereas neurons with nearly
      opposite preferred directions seem to compete in a manner consistent with the
      winner-take-all hypothesis, (2) microstimulation can influence direction
      estimates even when paired with the most powerful motion stimuli available, and
      (3) microstimulation effects can be elicited when a manual response (instead of
      our standard oculomotor response) is used to communicate the perceptual report.

PMID- 12417678
TI  - Neural correlates of successful encoding identified using functional magnetic
      resonance imaging.
AB  - Neural activity that occurs during the creation of a new memory trace can be
      observed using functional magnetic resonance imaging (fMRI). Event-related
      designs have been used to demonstrate that activity in prefrontal and medial
      temporal lobe areas is associated with successful memory storage. Here we
      contrasted activity associated with encoding success and encoding effort.
      Participants viewed a series of 150 words but attempted to remember only half of
      them. Encoding effort was manipulated using a cue in the form of a letter (R or
      F) presented after each word to instruct participants either to remember or to
      forget that word. Increased activity in left inferior prefrontal cortex was
      observed when words were followed by the cue to remember. In contrast, increased
      left medial temporal lobe activity was observed for words that were successfully
      recalled later. These results show that fMRI correlates of the intention to
      encode a word are different from fMRI correlates of whether that encoding is
      successful. Prefrontal activation was strongly associated with intentional verbal
      encoding, whereas left medial temporal activation was crucial for the encoding
      that actually led to successful memory on the subsequent test.

PMID- 12417679
TI  - Neural correlates of recency judgment.
AB  - The prefrontal cortex plays a critical role in recollecting the temporal context
      of past events. The present study used event-related functional magnetic
      resonance imaging (fMRI) and explored the neural correlates of temporal-order
      retrieval during a recency judgment paradigm. In this paradigm, after study of a
      list of words presented sequentially, subjects were presented with two of the
      studied words simultaneously and were asked which of the two words was studied
      more recently. Two types of such retrieval trials with varied (high and low)
      levels of demand for temporal-order retrieval were intermixed and compared using
      event-related fMRI. The intraparadigm comparison of high versus low demand trials
      revealed brain regions with activation that was modulated on the basis of demand
      for temporal-order retrieval. Multiple lateral prefrontal regions including the
      middle and inferior lateral prefrontal cortex were prominently activated.
      Activation was also observed in the anterior prefrontal cortex and the medial
      temporal cortex, regions well documented to be related to memory retrieval in
      general. The modulation of brain activity in these regions suggests a detailed
      pathway that is engaged during recency judgment.

PMID- 12417680
TI  - Neural coding of the location and direction of a moving object by a spatially
      distributed population of mechanoreceptors.
AB  - A neural code for the location and direction of an object moving over the
      fingerpad was constructed from the responses of a population of rapidly adapting
      type I (RAs) and slowly adapting type I (SAs) mechanoreceptive nerve fibers. The
      object was either a sphere with a radius of 5 mm or a toroid with radii of 5 mm
      on the major axis and either 1 or 3 mm on the minor axis. The object was stroked
      under constant velocity and contact force along eight different linear
      trajectories. The spatial locations of the centers of activity of the population
      responses (PLs) were determined from nonsimultaneously recorded responses of 99
      RAs and 97 SAs with receptive fields spatially distributed over the fingerpad of
      the anesthetized monkey. The PL at each moment during each stroke was used as a
      neural code of object location. The angle between the direction of the trajectory
      of the PL and mediolateral axis was used to represent the direction of motion of
      the object. The location of contact between the object and skin was better
      represented in SA than in RA PLs, regardless of stroke direction or object
      curvature. The PL representation of stroke direction was linearly related to the
      actual direction of the object for both RAs and SAs but was less variable for SAs
      than for RAs. Both the SA and RA populations coded spatial position and direction
      of motion at acuities similar to those obtained in psychophysical studies in
      humans.

PMID- 12417681
TI  - Evidence that androgen acts through NMDA receptors to affect motoneurons in the
      rat spinal nucleus of the bulbocavernosus.
AB  - In adult male rats, spinal nucleus of the bulbocavernosus (SNB) motoneurons
      shrink after castration and are restored in size after androgen treatment. Sixty
      day-old Sprague Dawley males were castrated and implanted with SILASTIC capsules
      containing testosterone (T) or nothing, and osmotic minipumps continuously
      infusing MK-801, a noncompetitive NMDA receptor antagonist, or saline. Twenty
      five days later, bulbocavernosus muscles were injected with the retrograde tracer
      cholera toxin-horseradish peroxidase conjugate (CT-HRP) to label SNB cells. As
      seen previously, among saline-treated rats, SNB somata of T-treated castrates
      were significantly larger than those of castrates receiving blank capsules (p <
      0.0001). MK-801 treatment blocked this effect of T on the SNB. MK-801 had no
      effect on non-androgen-responsive spinal motoneurons in the neighboring
      retrodorsolateral nucleus (RDLN), nor did the drug affect SNB soma size in the
      absence of androgen treatment. Motoneuronal soma size in Nissl stain revealed the
      same pattern of results seen with CT-HRP fills. In situ hybridization indicated
      that SNB motoneurons express mRNA for the NMDA receptor subunits R1, R2a, and
      R2b. Castration reduced the expression of R1 mRNA in SNB motoneurons, an effect
      that was blocked by androgen replacement in castrates. R2A and R2B mRNA
      expression in SNB cells was not affected by androgen manipulations. Likewise,
      androgen manipulations had no effect on the expression of any NMDA receptor
      subtypes in RDLN motoneurons. These results suggest that androgen affects the
      size of SNB motoneurons by influencing their expression of the NMDA receptor, and
      therefore the response of the motoneurons to endogenous glutamate.

PMID- 12417682
TI  - Nonspatial and subdivision-specific working memory deficits after selective
      lesions of the avian prefrontal cortex.
AB  - Association areas in the avian forebrain are shown to subserve higher cognitive
      functions, including working memory. One of these areas, the neostriatum
      caudolaterale (NCL) of pigeons, has been functionally compared with the mammalian
      prefrontal cortex (PFC) because of its prominent role in spatial delay and
      reversal tasks and its innervation by the dopaminergic system that modulates
      these functions. However, whereas the PFC maintains in working memory information
      of different domains, the essential role of the NCL in working memory has been
      demonstrated only for spatial tasks. To investigate whether the avian NCL is also
      crucial for nonspatial working memory functions, pigeons were tested in an object
      related (color) delayed matching-to-sample (DMTS) task. Bilateral lesions were
      placed in the entire, dorsal, or ventral NCL to test for possible functional
      subdivisions that were proposed to exist on the basis of neurochemical and
      behavioral data. Pigeons with total, dorsal, and ventral NCL lesions showed
      significant deficits in their DMTS performance, whereas controls were not
      impaired. Thus, the avian NCL is critically involved in nonspatial working memory
      processes. Recovery from performance deficits was observed in animals with
      ventral or total NCL lesions, whereas animals with dorsal NCL lesions showed no
      improvement. Ventral NCL may mediate perseverative behavior, whereas dorsal NCL
      might be involved in active working memory. Differences in the connections of
      these subdivisions with striatal areas and other association areas in the
      frontomedial forebrain underline functional differences. The data indicate a
      possible segregation of functions in the avian NCL.

PMID- 12417683
TI  - Nitric oxide is necessary for multiple memory processes after learning that a
      food is inedible in aplysia.
AB  - Nitric oxide (NO) signaling was inhibited via N(omega)-nitro-L-arginine methyl
      ester (L-NAME) during and after training Aplysia that a food is inedible.
      Treating animals with L-NAME 10 min before the start of training blocked the
      formation of three separable memory processes: (1) short-term, (2) intermediate
      term, and (3) long-term memory. The treatment also attenuated, but did not block,
      a fourth memory process, very short-term memory. L-NAME had little or no effect
      on feeding behavior per se or on most aspects of the animals' behavior while they
      were being trained, indicating that the substance did not cause a pervasive
      modulation or poisoning of many aspects of feeding and other behaviors.
      Application of L-NAME within 1 min after the training had no effect on short- or
      long-term memory, indicating that NO signaling was not needed during memory
      consolidation. Treating animals with the NO scavenger 2-phenyl-4,4,5,5
      tetramethyl-imidazdine-1-oxy-3-oxide before training also blocked long-term
      memory. Memory was not blocked by D-NAME, or by the simultaneous treatment with L
      NAME and the NO donor S-nitroso-N-acetyl-penicillamine, confirming that the
      effect of L-NAME is attributable to its effect as a competitive inhibitor of L
      arginine for NO synthase in the production of NO rather than to possible effects
      at other sites. These data indicate that NO signaling during training plays a
      critical role in the formation of multiple memory processes.

PMID- 12417684
TI  - Dopamine D3 receptor antagonism inhibits cocaine-seeking and cocaine-enhanced
      brain reward in rats.
AB  - dopamine D3 receptor is preferentially localized to the mesocorticolimbic
      dopaminergic system and has been hypothesized to play a role in cocaine
      addiction. To study the involvement of the D3 receptor in brain mechanisms and
      behaviors commonly assumed to be involved in the addicting properties of cocaine,
      the potent and selective D3 receptor antagonist trans-N-[4-[2-(6-cyano-1,2,3,4
      tetrahydroisoquinolin-2-yl)ethyl] cyclohexyl]-4-quinolininecarboxamide (SB-277011
      A) was administered to laboratory rats, and the following measures were assessed:
      (1) cocaine-enhanced electrical brain-stimulation reward, (2) cocaine-induced
      conditioned place preference, and (3) cocaine-triggered reinstatement of cocaine
      seeking behavior. Systemic injections of SB-277011-A were found to (1) block
      enhancement of electrical brain stimulation reward by cocaine, (2) dose
      dependently attenuate cocaine-induced conditioned place preference, and (3) dose
      dependently attenuate cocaine-triggered reinstatement of cocaine seeking
      behavior. Thus, D3 receptor blockade attenuates both the rewarding effects of
      cocaine and cocaine-induced drug-seeking behavior. These data suggest an
      important role for D3 receptors in mediating the addictive properties of cocaine
      and suggest that blockade of dopamine D3 receptors may constitute a new and
      useful target for prospective pharmacotherapies for cocaine addiction.

PMID- 12417685
TI  - Differential effects of direct and indirect dopamine agonists on prepulse
      inhibition: a study in D1 and D2 receptor knock-out mice.
AB  - Stimulation of the dopamine (DA) system disrupts prepulse inhibition (PPI) of the
      acoustic startle response. On the basis of rat studies, it appeared that DA D2
      receptors (D2Rs) rather than D1 receptors (D1Rs) regulate PPI, albeit possibly in
      synergism with D1Rs. To characterize the DA receptor modulation of PPI in another
      species, we tested DA D1R and D2R mutant mice with direct and indirect DA
      agonists and with the glutamate receptor antagonist, dizocilpine (MK-801).
      Neither the mixed D1/D2 agonist apomorphine (5 mg/kg) nor the more selective D1
      like agonist SKF82958 (0.3 mg/kg) altered PPI in D1R knock-out mice, although
      both compounds disrupted PPI in D2R mutant and wild-type mice, suggesting that
      the D1R alone might modulate PPI in mice. However, amphetamine (10 mg/kg)
      significantly lowered PPI in each genotype of D1R mice, suggesting that the D1R
      is not necessary for the PPI-disruptive effect of the indirect agonist in mice.
      As reported previously, amphetamine (10 mg/kg) failed to disrupt PPI in D2R knock
      out mice, supporting a unique role of the D2R in the modulation of PPI.
      Dizocilpine (0.3 mg/kg) induced similar PPI deficits in D1R and D2R mutant mice,
      confirming that the influences of the NMDA receptor on PPI are independent of
      D1Rs and D2Rs in rodents. Thus, both D1Rs and D2Rs modulate aspects of PPI in
      mice in a manner that differs from dopaminergic modulation in rats. These
      findings emphasize that further cross-species comparisons of the pharmacology of
      PPI are essential to understand the relevance of rodent PPI studies to the
      deficits in PPI observed in patients with schizophrenia.

PMID- 12417686
TI  - A peripheral mechanism for CB1 cannabinoid receptor-dependent modulation of
      feeding.
AB  - Recent studies suggest that the endocannabinoid system modulates feeding. Despite
      the existence of central mechanisms for the regulation of food intake by
      endocannabinoids, evidence indicates that peripheral mechanisms may also exist.
      To test this hypothesis, we investigated (1) the effects of feeding on intestinal
      anandamide accumulation; (2) the effects of central (intracerebroventricular) and
      peripheral (intraperitoneal) administration of the endocannabinoid agonist
      anandamide, the synthetic cannabinoid agonist R-(+)-(2,3-dihydro-5-methyl-3-[(4
      morpholinyl)methyl]pyrol[1,2,3-de]-1,4-benzoxazin-6-yl)(1-naphthalenyl) methanone
      monomethanesulfonate (WIN55,212-2), and the CB1-selective antagonist N-piperidino
      5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide
      (SR141716A) on food intake in rats; and (3) the effects of sensory
      deafferentation on the modulation of feeding by cannabinoids. Food deprivation
      produced a sevenfold increase in anandamide content in the small intestine but
      not in the brain or stomach. Refeeding normalized intestinal anandamide levels.
      Peripheral but not central administration of anandamide or WIN55,212-2 promoted
      hyperphagia in partially satiated rats. Similarly, peripheral but not central
      administration of SR141716A reduced food intake. Capsaicin deafferentation
      abolished the peripheral effects of both cannabinoid agonists and antagonists,
      suggesting that these agents modulate food intake by acting on CB1 receptors
      located on capsaicin-sensitive sensory terminals. Oleoylethanolamide, a
      noncannabinoid fatty ethanolamide that acts peripherally, prevented hyperphagia
      induced by the endogenous cannabinoid anandamide. Pretreatment with SR141716A
      enhanced the inhibition of feeding induced by intraperitoneal administration of
      oleoylethanolamide. The results reveal an unexpected role for peripheral CB1
      receptors in the regulation of feeding.

PMID- 12417687
TI  - Perception of brightness and brightness illusions in the macaque monkey.
AB  - Recent physiological studies show that neural responses correlated with the
      perception of brightness are found in cortical area V1 but not earlier in the
      visual pathway (Kayama et al., 1979; Reid and Shapley, 1989; Squatrito et al.,
      1990; Komatsu et al., 1996; Rossi et al., 1996; MacEvoy et al., 1998; Rossi and
      Paradiso, 1999; Hung et al., 2001; Kinoshita and Komatsu, 2001; MacEvoy and
      Paradiso, 2001). However, these studies are based on comparisons of neural
      responses in animals with brightness perception in humans. Very little is known
      about the perception of brightness in animals typically used in physiological
      experiments. In this study, we quantify brightness discrimination, brightness
      induction, and White's effect in macaque monkeys. The results show that,
      qualitatively and quantitatively, the perception of brightness in macaques and
      humans is quite similar. This similarity may be an indication of common
      underlying neural computations in the two species.

PMID- 12417688
TI  - Induction and experience-dependent consolidation of stable long-term potentiation
      lasting months in the hippocampus.
AB  - Long-term potentiation (LTP) is widely regarded as a memory mechanism, but it is
      not known whether it can last long enough to underlie very long-term memory. We
      report that high-frequency stimulation (HFS) paradigms applied to the rat dentate
      gyrus can elicit stable LTP lasting months and up to at least 1 year. The
      induction of stable LTP was sensitive to stimulation variables on the day of HFS
      and was associated with phosphorylation of cAMP response element-binding protein.
      The maintenance of stable LTP was also experience-dependent, because it was
      reversed when animals were exposed repeatedly to an enriched environment
      beginning 14 d post-HFS. However, stable LTP eventually consolidated over time
      and became resistant to reversal, because exposure to enriched environments 90 d
      post-HFS failed to influence stable LTP maintenance. Thus, LTP can be shown to
      meet one of the principal criteria for a very long-term memory storage mechanism.
      However, under naturalistic environmental conditions, LTP may normally be
      retained in the hippocampus for only short periods of time.

PMID- 12417689
TI  - Evidence that 5-HT2A receptors in the hypothalamic paraventricular nucleus
      mediate neuroendocrine responses to (-)DOI.
AB  - The present study determined whether the serotonin2A (5-HT2A) receptors in the
      hypothalamic paraventricular nucleus mediate the neuroendocrine responses to a
      peripheral injection of the 5-HT2A/2C receptor agonist (-)DOI [(-)1-(2,5
      dimethoxy-4-iodophenyl)-2-aminopropane]. The 5-HT2A receptor antagonist
      MDL100,907 ((+/-)-alpha(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4
      piperidinemethanol), the 5-HT2C receptor antagonist SB-242084 (6-chloro-5-methyl
      1-[[2-[(2-methyl-3-pyridyl)oxy]-5-pyridyl]carbamoyl]-indoline), or vehicle were
      microinjected bilaterally through a chronically implanted double-barreled cannula
      into the hypothalamic paraventricular nucleus 15 min before a peripheral
      injection of (-)DOI in conscious rats. (-)DOI significantly elevated plasma
      levels of oxytocin, prolactin, ACTH, corticosterone, and renin. Neither the 5
      HT2A receptor antagonist nor the 5-HT2C receptor antagonist, injected alone,
      altered the basal levels of these hormones. MDL100,907 (0.748, 7.48, and 18.7
      nmol) dose dependently inhibited the (-)DOI-induced increase in all of the
      hormones except corticosterone. In contrast, SB-242084 (10 nmol) did not inhibit
      (-)DOI-increased hormone levels. To confirm the presence of 5-HT2A receptors in
      the hypothalamic paraventricular nucleus, 5-HT2A receptors were mapped using
      immunohistochemistry. Densely labeled magnocellular neurons were observed
      throughout the anterior and posterior magnocellular subdivisions of the
      hypothalamic paraventricular nucleus. Moderately to densely labeled cells were
      also observed in parvicellular regions. Thus, it is likely that 5-HT2A receptors
      are present on neuroendocrine cells in the hypothalamic paraventricular nucleus.
      These data provide the first direct evidence that neuroendocrine responses to a
      peripheral injection of (-)DOI are predominantly mediated by activation of 5-HT2A
      receptors in the hypothalamic paraventricular nucleus.

PMID- 12417690
TI  - Effects of furosemide applied chronically to the round window: a model of
      metabolic presbyacusis.
AB  - Hearing thresholds in elderly humans without a history of noise exposure commonly
      show a profile of a flat loss at low frequencies coupled with a loss that
      increases with frequency above approximately 2 kHz. This profile and the
      relatively robust distortion product otoacoustic emissions that are found in
      elderly subjects challenge the common belief that age-related hearing loss
      (presbyacusis) is based primarily on sensory-cell disorders. Here, we examine a
      model of presbyacusis wherein the endocochlear potential (EP) is reduced by means
      of furosemide applied chronically to one cochlea of a young gerbil. The model
      results in an EP that is reduced from 90 to approximately 60 mV, a value often
      seen in quiet-aged gerbils, with no concomitant loss of hair cells. Resulting
      measures of cochlear and neural function are quantitatively similar to those seen
      in aging gerbils and humans, e.g., a flat threshold loss at low frequencies with
      a high-frequency roll-off of approximately -8.4 dB/octave. The effect of the EP
      on neural thresholds can be parsimoniously explained by the known gain
      characteristics of the cochlear amplifier as a function of cochlear location: in
      the apex, amplification is limited to approximately 20 dB, whereas in the base,
      the gain can be as high as 60 dB. At high frequencies, amplification is directly
      proportional to the EP on an approximately 1 dB/mV basis. This model suggests
      that the primary factor in true age-related hearing loss is an energy-starved
      cochlear amplifier that results in a specific audiogram profile.

PMID- 12417691
TI  - Abscisic acid biosynthesis gene underscores the complexity of sugar, stress, and
      hormone interactions.

PMID- 12417692
TI  - Genomics and forest biology: Populus emerges as the perennial favorite.

PMID- 12417694
TI  - The Chlamydomonas reinhardtii plastid chromosome: islands of genes in a sea of
      repeats.
AB  - Chlamydomonas reinhardtii is a unicellular eukaryotic alga possessing a single
      chloroplast that is widely used as a model system for the study of photosynthetic
      processes. This report analyzes the surprising structural and evolutionary
      features of the completely sequenced 203,395-bp plastid chromosome. The genome is
      divided by 21.2-kb inverted repeats into two single-copy regions of approximately
      80 kb and contains only 99 genes, including a full complement of tRNAs and
      atypical genes encoding the RNA polymerase. A remarkable feature is that >20% of
      the genome is repetitive DNA: the majority of intergenic regions consist of
      numerous classes of short dispersed repeats (SDRs), which may have structural or
      evolutionary significance. Among other sequenced chlorophyte plastid genomes,
      only that of the green alga Chlorella vulgaris appears to share this feature. The
      program MultiPipMaker was used to compare the genic complement of Chlamydomonas
      with those of other chloroplast genomes and to scan the genomes for sequence
      similarities and repetitive DNAs. Among the results was evidence that the SDRs
      were not derived from extant coding sequences, although some SDRs may have arisen
      from other genomic fragments. Phylogenetic reconstruction of changes in plastid
      genome content revealed that an accelerated rate of gene loss also characterized
      the Chlamydomonas/Chlorella lineage, a phenomenon that might be independent of
      the proliferation of SDRs. Together, our results reveal a dynamic and unusual
      plastid genome whose existence in a model organism will allow its features to be
      tested functionally.

PMID- 12417695
TI  - The Chlamydomonas reinhardtii organellar genomes respond transcriptionally and
      post-transcriptionally to abiotic stimuli.
AB  - The Chlamydomonas reinhardtii plastid and mitochondrial transcriptomes were
      surveyed for changes in RNA profiles resulting from growth in 12 culture
      conditions representing 8 abiotic stimuli. Organellar RNA abundance exhibited
      marked changes during nutrient stress and exposure to UV light, as revealed by
      both RNA gel blot and DNA microarray analyses. Of particular note were large
      increases in tufA and clpP transcript abundance during nutrient limitation.
      Phosphate and sulfur limitation resulted in the most global, yet opposite,
      effects on organellar RNA abundance, changes that were dissected further using
      run-on transcription assays. Removal of sulfate from the culture medium, which is
      known to reduce photosynthesis, resulted in 2-fold to 10-fold decreases in
      transcription rates, which were reflected in lower RNA abundance. The decrease in
      transcriptional activity was completely reversible and recovered to twice the
      control level after sulfate replenishment. Conversely, phosphate limitation
      resulted in a twofold to threefold increase in RNA abundance that was found to be
      a post-transcriptional effect, because it could be accounted for by increased RNA
      stability. This finding is consistent with the known metabolic slowdown under
      phosphate stress. Additionally, inhibitor studies suggested that unlike those in
      higher plants, Chlamydomonas chloroplasts lack a nucleus-encoded plastid RNA
      polymerase. The apparently single type of polymerase could contribute to the
      rapid and genome-wide transcriptional responses observed within the chloroplast.

PMID- 12417696
TI  - VH1, a provascular cell-specific receptor kinase that influences leaf cell
      patterns in Arabidopsis.
AB  - The formation of the venation pattern in leaves is ideal for examining signaling
      pathways that recognize and respond to spatial and temporal information, because
      the pattern is two-dimensional and heritable and the resulting veins influence
      the three-dimensional spatial organization of the surrounding differentiating
      leaf cell types. We identified a provascular/procambial cell-specific gene that
      encodes a Leu-rich repeat receptor kinase, which we named VASCULAR HIGHWAY1
      (VH1). A change in the expression domain and level of VH1 marks the transition
      from an uncommitted provascular state to a committed procambial state in early
      vascular development. The coding sequence, expression pattern, and transgenic
      phenotypes together suggest that VH1 transduces extracellular spatial and
      temporal signals into downstream cell differentiation responses in
      provascular/procambial cells.

PMID- 12417697
TI  - A unique short-chain dehydrogenase/reductase in Arabidopsis glucose signaling and
      abscisic acid biosynthesis and functions.
AB  - Glc has hormone-like functions and controls many vital processes through mostly
      unknown mechanisms in plants. We report here on the molecular cloning of GLUCOSE
      INSENSITIVE1 (GIN1) and ABSCISIC ACID DEFICIENT2 (ABA2) which encodes a unique
      Arabidopsis short-chain dehydrogenase/reductase (SDR1) that functions as a
      molecular link between nutrient signaling and plant hormone biosynthesis. SDR1 is
      related to SDR superfamily members involved in retinoid and steroid hormone
      biosynthesis in mammals and sex determination in maize. Glc antagonizes ethylene
      signaling by activating ABA2/GIN1 and other abscisic acid (ABA) biosynthesis and
      signaling genes, which requires Glc and ABA synergistically. Analyses of
      aba2/gin1 null mutants define dual functions of endogenous ABA in inhibiting the
      postgermination developmental switch modulated by distinct Glc and osmotic
      signals and in promoting organ and body size and fertility in the absence of
      severe stress. SDR1 is sufficient for the multistep conversion of plastid- and
      carotenoid-derived xanthoxin to abscisic aldehyde in the cytosol. The
      surprisingly restricted spatial and temporal expression of SDR1 suggests the
      dynamic mobilization of ABA precursors and/or ABA.

PMID- 12417699
TI  - YABBY polarity genes mediate the repression of KNOX homeobox genes in
      Arabidopsis.
AB  - The YABBY (YAB) genes specify abaxial cell fate in lateral organs in Arabidopsis.
      Loss-of-function mutants in two early-expressing YAB genes, FILAMENTOUS FLOWER
      (FIL) and YAB3, do not exhibit vegetative phenotypes as a result of redundancy.
      Mutations in these genes result in the derepression of the KNOX homeobox genes
      SHOOTMERISTEMLESS (STM), BREVIPEDICELLUS, and KNAT2 in the leaves and in the
      partial rescue of stm mutants. Here, we show that fil yab3 double mutants exhibit
      ectopic meristem formation on the adaxial surfaces of cotyledons and leaf blades.
      We propose that in addition to abaxial specification, lateral organ development
      requires YAB function to downregulate KNOTTED homeobox genes so that meristem
      initiation and growth are restricted to the apex.

PMID- 12417698
TI  - Plant Rac-like GTPases are activated by auxin and mediate auxin-responsive gene
      expression.
AB  - The auxin indole-3-acetic acid is a key plant hormone essential for a broad range
      of growth and developmental processes. Here, we show that auxin activates Rac
      like GTPases (referred to as Rac/Rop GTPases), and they in turn stimulate auxin
      responsive gene expression. In particular, we show that overexpressing a wild
      type tobacco Rac/Rop GTPase, NtRac1, and its constitutively active mutant form
      activates auxin-responsive gene expression. On the other hand, overexpressing
      dominant-negative NtRac1 and Rac-negative regulators, or reducing the endogenous
      NtRac1 level, suppresses auxin-induced gene expression. Furthermore,
      overexpression of NtRac1 activity or suppression of its expression in transgenic
      seedlings induces phenotypes that are similar to auxin-related defects. Together,
      our results show that a subset of plant Rac/Rop GTPases functions in mediating
      the auxin signal to downstream responsive genes.

PMID- 12417700
TI  - Global and hormone-induced gene expression changes during shoot development in
      Arabidopsis.
AB  - A global analysis of gene expression events during shoot development in
      Arabidopsis was conducted using oligonucleotide array analysis. Shoots can be
      induced in tissue culture by preincubating root explants on an auxin-rich callus
      induction medium (CIM) and by transferring explants to a cytokinin-rich shoot
      induction medium (SIM), during which time explants become committed to shoot
      formation and ultimately form shoots. Oligonucleotide array data obtained during
      shoot development from approximately 8000 Arabidopsis genes were subjected to
      principal component analysis, which demonstrated that the major components of
      variation in gene expression during shoot development can be represented by
      groups of genes, each group of which is upregulated at only one developmental
      stage. Two percent to three percent of the approximately 8000 Arabidopsis genes
      monitored in this study were upregulated by fourfold or more at any one stage
      during shoot development. When upregulated and downregulated genes were
      categorized by function, it was observed that numerous hormone response genes
      were upregulated during preincubation on CIM. Groups of genes involved in
      signaling and/or transcription were induced at or before the time of shoot
      commitment, and genes that encode components of the photosynthetic apparatus were
      upregulated later in development before shoot emergence. Primary hormone response
      genes, such as Aux/IAA genes, were upregulated during preincubation on auxin-rich
      CIM, and cytokinin-responsive response regulator genes were upregulated during
      incubation on cytokinin-rich SIM. The expression of ARABIDOPSIS RESPONSE
      REGULATOR5, a type-A response regulator gene, was upregulated at the time of
      shoot commitment, and its expression was localized to sites of presumptive shoot
      formation. Two "hybrid" His kinases involved in cytokinin responses, CRE1, which
      encodes a cytokinin receptor, and CKI1, a gene that is capable of conferring
      cytokinin-independent shoot development, were upregulated during incubation on
      SIM.

PMID- 12417701
TI  - Plasma membrane-associated ROP10 small GTPase is a specific negative regulator of
      abscisic acid responses in Arabidopsis.
AB  - Abscisic acid (ABA) is an important plant hormone that modulates seed germination
      and plant growth and stress responses, but its signaling remains poorly
      understood. We investigated the role of ROP10, a member of the Arabidopsis Rop
      subfamily of Rho GTPases, in ABA signaling. A null rop10 mutant exhibits enhanced
      responses to ABA in seed germination, root elongation, and stomatal closure
      assays and in the induction of expression of the transcription factor MYB2, but
      it shows wild-type levels of ABA and normal responses to other hormones.
      Consistently, transgenic expression of a constitutively active form of ROP10
      reduces ABA inhibition of seed germination, whereas dominant-negative mutants of
      ROP10 enhance ABA response and partially suppress abi2. Furthermore, ABA
      specifically downregulates ROP10 transcription in root tips. ROP10 is localized
      to the plasma membrane (PM), and PM localization is crucial for its function.
      These results suggest that ROP10 is a PM-localized signaling molecule that is
      involved specifically in the negative regulation of ABA signaling.

PMID- 12417702
TI  - AtOPT3, a member of the oligopeptide transporter family, is essential for embryo
      development in Arabidopsis.
AB  - A T-DNA-tagged population of Arabidopsis was screened for mutations in AtOPT3,
      which encodes a member of the oligopeptide (OPT) family of peptide transporters,
      and a recessive mutant allele, opt3, was identified. Phenotypic analysis of opt3
      showed that most homozygous embryos were arrested at or before the octant stage
      of embryo development and that none showed the usual periclinal division leading
      to the formation of the protoderm. This defective phenotype could be reversed by
      complementation with the full-length, wild-type AtOPT3 gene. A beta-glucuronidase
      (GUS) fusion to DNA sequences upstream of the putative AtOPT3 ATG start codon was
      constructed, and the expression pattern was assayed in transgenic plants. AtOPT3
      was expressed in the vascular tissues of seedlings and mature plants as well as
      in pollen. Consistent with the function of AtOPT3 in embryogenesis, AtOPT3::GUS
      expression also was detected in developing embryos and in the maternal tissues of
      seeds. These data suggest a critical role for peptide transport in early embryo
      development.

PMID- 12417703
TI  - Early gene expression associated with the commitment and differentiation of a
      plant tracheary element is revealed by cDNA-amplified fragment length
      polymorphism analysis.
AB  - Isolated mesophyll cells from Zinnia elegans are induced by auxin and cytokinin
      to form tracheary elements (TEs) in vitro with high synchrony. To reveal the
      changing patterns of gene expression during the 48 h of transdifferentiation from
      mesophyll to TE cell fate, we used a cDNA-amplified fragment length polymorphism
      approach to generate expression profiles of >30,000 cDNA fragments.
      Transcriptional changes of 652 cDNA fragments were observed, of which 304 have no
      previously described function or sequence identity. Sixty-eight genes were
      upregulated within 30 min of induction and represent key candidates for the
      processes that underlie the early stages of commitment and differentiation to a
      TE cell fate.

PMID- 12417704
TI  - Centromeric retroelements and satellites interact with maize kinetochore protein
      CENH3.
AB  - Maize centromeres are composed of CentC tandem repeat arrays, centromeric
      retrotransposons (CRs), and a variety of other repeats. One particularly well
      conserved CR element, CRM, occurs primarily as complete and uninterrupted
      elements and is interspersed thoroughly with CentC at the light microscopic
      level. To determine if these major centromeric DNAs are part of the functional
      centromere/kinetochore complex, we generated antiserum to maize centromeric
      histone H3 (CENH3). CENH3, a highly conserved protein that replaces histone H3 in
      centromeres, is thought to recruit many of the proteins required for chromosome
      movement. CENH3 is present throughout the cell cycle and colocalizes with the
      kinetochore protein CENPC in meiotic cells. Chromatin immunoprecipitation
      demonstrates that CentC and CRM interact specifically with CENH3, whereas knob
      repeats and Tekay retroelements do not. Approximately 38 and 33% of CentC and CRM
      are precipitated in the chromatin immunoprecipitation assay, consistent with data
      showing that much, but not all, of CENH3 colocalizes with CentC.

PMID- 12417705
TI  - Molecular mechanisms of proline-mediated tolerance to toxic heavy metals in
      transgenic microalgae.
AB  - Pro has been shown to play an important role in ameliorating environmental stress
      in plants and microorganisms, including heavy metal stress. Here, we describe the
      effects of the expression of a mothbean delta(1)-pyrroline-5-carboxylate
      synthetase (P5CS) gene in the green microalga Chlamydomonas reinhardtii. We show
      that transgenic algae expressing the mothbean P5CS gene have 80% higher free-Pro
      levels than wild-type cells, grow more rapidly in toxic Cd concentrations (100
      microM), and bind fourfold more Cd than wild-type cells. In addition, Cd-K edge
      extended x-ray absorption fine structure studies indicated that Cd does not bind
      to free Pro in transgenic algae with increased Pro levels but is coordinated
      tetrahedrally by sulfur of phytochelatin. In contrast to P5CS-expressing cells,
      Cd is coordinated tetrahedrally by two oxygen and two sulfur atoms in wild-type
      cells. Measurements of reduced/oxidized GSH ratios and analyses of levels of
      malondialdehyde, a product of the free radical damage of lipids, indicate that
      free Pro levels are correlated with the GSH redox state and malondialdehyde
      levels in heavy metal-treated algae. These results suggest that the free Pro
      likely acts as an antioxidant in Cd-stressed cells. The resulting increased GSH
      levels facilitate increased phytochelatin synthesis and sequestration of Cd,
      because GSH-heavy metal adducts are the substrates for phytochelatin synthase.

PMID- 12417706
TI  - Disruption of a guard cell-expressed protein phosphatase 2A regulatory subunit,
      RCN1, confers abscisic acid insensitivity in Arabidopsis.
AB  - Pharmacological studies have led to a model in which the phytohormone abscisic
      acid (ABA) may be positively transduced via protein phosphatases of the type 1
      (PP1) or type 2A (PP2A) families. However, pharmacological evidence also exists
      that PP1s or PP2As may function as negative regulators of ABA signaling.
      Furthermore, recessive disruption mutants in protein phosphatases that function
      in ABA signal transduction have not yet been identified. A guard cell-expressed
      PP2A gene, RCN1, which had been characterized previously as a molecular component
      affecting auxin transport and gravity response, was isolated. A T-DNA disruption
      mutation in RCN1 confers recessive ABA insensitivity to Arabidopsis. The rcn1
      mutation impairs ABA-induced stomatal closing and ABA activation of slow anion
      channels. Calcium imaging analyses show a reduced sensitivity of ABA-induced
      cytosolic calcium increases in rcn1, whereas mechanisms downstream of cytosolic
      calcium increases show wild-type responses, suggesting that RCN1 functions in ABA
      signal transduction upstream of cytosolic Ca(2+) increases. Furthermore, rcn1
      shows ABA insensitivity in ABA inhibition of seed germination and ABA-induced
      gene expression. The PP1 and PP2A inhibitor okadaic acid phenocopies the rcn1
      phenotype in wild-type plants both in ABA-induced cytosolic calcium increases and
      in seed germination, and the wild-type RCN1 genomic DNA complements rcn1
      phenotypes. These data show that RCN1 functions as a general positive transducer
      of early ABA signaling.

PMID- 12417707
TI  - Redundant proteolytic mechanisms process seed storage proteins in the absence of
      seed-type members of the vacuolar processing enzyme family of cysteine proteases.
AB  - Seed-type vacuolar processing enzyme (VPE) activity is predicted to be essential
      for post-translational proteolysis of seed storage proteins in the protein
      storage vacuole of developing seeds. To test this hypothesis, we examined the
      protein profiles of developing and germinating seeds from Arabidopsis plants
      containing transposon-insertional knockout mutations in the genes that encode the
      two seed-type VPEs in Arabidopsis, betaVPE, which was identified previously, and
      deltaVPE, which is described here. The effects of these mutations were studied
      individually in single mutants and together in a double mutant. Surprisingly, we
      found that most of the seed protein still was processed proteolytically in seed
      type VPE mutants. The minor differences observed in polypeptide accumulation
      between wild-type and betaVPE mutant seeds were characterized using a two
      dimensional gel/mass spectrometric analysis approach. The results showed
      increased amounts of propolypeptide forms of legumin-type globulins accumulating
      in mutant seeds. However, the majority of protein (>80%) still was processed to
      mature alpha- and beta-chains, as observed in wild-type seeds. Furthermore, we
      identified several legumin-type globulin polypeptides, not corresponding to pro
      or mature forms, that increased in accumulation in betaVPE mutant seeds compared
      with wild-type seeds. Together, these results indicate the existence of both
      redundant and alternative processing activities in seeds. The latter was
      substantiated by N-terminal sequencing of a napin-type albumin protein,
      indicating cleavage consistent with previous in vitro studies using purified
      aspartic protease. Analysis of genome-wide transcript profiling data sets
      identified six protease genes (including an aspartic protease gene and betaVPE)
      that shared spatial and temporal expression patterns with seed storage proteins.
      From these results, we conclude that seed-type VPEs constitute merely one pathway
      for processing seed storage protein and that other proteolytic enzymes also can
      process storage proteins into chains capable of stable accumulation in mature
      seeds.

PMID- 12417708
TI  - Inducible DNA demethylation mediated by the maize Suppressor-mutator transposon
      encoded TnpA protein.
AB  - Heritable epigenetic inactivation of the maize Suppressor-mutator (Spm)
      transposon is associated with promoter methylation, and its reversal is mediated
      by the transposon-encoded TnpA protein. We have developed an assay that permits
      demethylation of the Spm sequence to be controlled by inducing the expression of
      TnpA in plant cells. Using this assay, we show that demethylation is a rapid,
      active process. TnpA is a weak transcriptional activator, and deletions that
      abolish its transcriptional activity also eliminate its demethylation activity.
      We show that cell cycle and DNA synthesis inhibitors interfere with TnpA-mediated
      Spm demethylation. We further show that TnpA has a much lower affinity for fully
      methylated than for hemimethylated or unmethylated DNA fragments derived from Spm
      termini. Based on these observations, we suggest that TnpA binds to the
      postreplicative, hemimethylated Spm sequence and promotes demethylation either by
      creating an appropriate demethylation substrate or by itself participating in or
      recruiting a demethylase.

PMID- 12417709
TI  - A two-component Mn2+-sensing system negatively regulates expression of the mntCAB
      operon in Synechocystis.
AB  - Mn is an essential component of the oxygen-evolving machinery of photosynthesis
      and is an essential cofactor of several important enzymes, such as Mn-superoxide
      dismutase and Mn-catalase. The availability of Mn in the environment varies, and
      little is known about the mechanisms for maintaining cytoplasmic Mn(2+) ion
      homeostasis. Using a DNA microarray, we screened knockout libraries of His
      kinases and response regulators of Synechocystis sp PCC 6803 to identify possible
      participants in this process. We identified a His kinase, ManS, which might sense
      the extracellular concentration of Mn(2+) ions, and a response regulator, ManR,
      which might regulate the expression of the mntCAB operon for the ABC-type
      transporter of Mn(2+) ions. Furthermore, analysis with the DNA microarray and by
      reverse transcription PCR suggested that ManS produces a signal that activates
      ManR, which represses the expression of the mntCAB operon. At low concentrations
      of Mn(2+) ions, ManS does not generate a signal, with resulting inactivation of
      ManR and subsequent expression of the mntCAB operon.

PMID- 12417710
TI  - Regulation of the pollen-specific actin-depolymerizing factor LlADF1.
AB  - Pollen tube growth is dependent on a dynamic actin cytoskeleton, suggesting that
      actin-regulating proteins are involved. We have examined the regulation of the
      lily pollen-specific actin-depolymerizing factor (ADF) LlADF1. Its actin binding
      and depolymerizing activity is pH sensitive, inhibited by certain
      phosphoinositides, but not controlled by phosphorylation. Compared with its F
      actin binding properties, its low activity in depolymerization assays has been
      used to explain why pollen ADF decorates F-actin in pollen grains. This low
      activity is incompatible with a role in increasing actin dynamics necessary to
      promote pollen tube growth. We have identified a plant homolog of actin
      interacting protein, AIP1, which enhances the depolymerization of F-actin in the
      presence of LlADF1 by approximately 60%. Both pollen ADF and pollen AIP1 bind F
      actin in pollen grains but are mainly cytoplasmic in pollen tubes. Our results
      suggest that together these proteins remodel actin filaments as pollen grains
      enter and exit dormancy.

PMID- 12417711
TI  - The tomato R gene products I-2 and MI-1 are functional ATP binding proteins with
      ATPase activity.
AB  - Most plant disease resistance (R) genes known today encode proteins with a
      central nucleotide binding site (NBS) and a C-terminal Leu-rich repeat (LRR)
      domain. The NBS contains three ATP/GTP binding motifs known as the kinase-1a or P
      loop, kinase-2, and kinase-3a motifs. In this article, we show that the NBS of R
      proteins forms a functional nucleotide binding pocket. The N-terminal halves of
      two tomato R proteins, I-2 conferring resistance to Fusarium oxysporum and Mi-1
      conferring resistance to root-knot nematodes and potato aphids, were produced as
      glutathione S-transferase fusions in Escherichia coli. In a filter binding assay,
      purified I-2 was found to bind ATP rather than other nucleoside triphosphates.
      ATP binding appeared to be fully dependent on the presence of a divalent cation.
      A mutant I-2 protein containing a mutation in the P-loop showed a strongly
      reduced ATP binding capacity. Thin layer chromatography revealed that both I-2
      and Mi-1 exerted ATPase activity. Based on the strong conservation of NBS domains
      in R proteins of the NBS-LRR class, we propose that they all are capable of
      binding and hydrolyzing ATP.

PMID- 12417712
TI  - Positioning of nuclei in Arabidopsis root hairs: an actin-regulated process of
      tip growth.
AB  - In growing Arabidopsis root hairs, the nucleus locates at a fixed distance from
      the apex, migrates to a random position during growth arrest, and moves from
      branch to branch in a mutant with branched hairs. Consistently, an artificial
      increase of the distance between the nucleus and the apex, achieved by entrapment
      of the nucleus in a laser beam, stops cell growth. Drug studies show that
      microtubules are not involved in the positioning of the nucleus but that
      subapical fine F-actin between the nucleus and the hair apex is required to
      maintain the nuclear position with respect to the growing apex. Injection of an
      antibody against plant villin, an actin filament-bundling protein, leads to actin
      filament unbundling and movement of the nucleus closer to the apex. Thus, the
      bundled actin at the tip side of the nucleus prevents the nucleus from
      approaching the apex. In addition, we show that the basipetal movement of the
      nucleus at root hair growth arrest requires protein synthesis and a functional
      actin cytoskeleton in the root hair tube.

PMID- 12417713
TI  - Proteomic characterization of the small subunit of Chlamydomonas reinhardtii
      chloroplast ribosome: identification of a novel S1 domain-containing protein and
      unusually large orthologs of bacterial S2, S3, and S5.
AB  - To understand how chloroplast mRNAs are translated into functional proteins, a
      detailed understanding of all of the components of chloroplast translation is
      needed. To this end, we performed a proteomic analysis of the plastid ribosomal
      proteins in the small subunit of the chloroplast ribosome from the green alga
      Chlamydomonas reinhardtii. Twenty proteins were identified, including orthologs
      of Escherichia coli S1, S2, S3, S4, S5, S6, S7, S9, S10, S12, S13, S14, S15, S16,
      S17, S18, S19, S20, and S21 and a homolog of spinach plastid-specific ribosomal
      protein-3 (PSRP-3). In addition, a novel S1 domain-containing protein, PSRP-7,
      was identified. Among the identified proteins, S2 (57 kD), S3 (76 kD), and S5 (84
      kD) are prominently larger than their E. coli or spinach counterparts, containing
      N-terminal extensions (S2 and S5) or insertion sequence (S3). Structural
      predictions based on the crystal structure of the bacterial 30S subunit suggest
      that the additional domains of S2, S3, and S5 are located adjacent to each other
      on the solvent side near the binding site of the S1 protein. These additional
      domains may interact with the S1 protein and PSRP-7 to function in aspects of
      mRNA recognition and translation initiation that are unique to the Chlamydomonas
      chloroplast.

PMID- 12417714
TI  - Transduction of growth or mitogenic signals into translational activation of TOP
      mRNAs is fully reliant on the phosphatidylinositol 3-kinase-mediated pathway but
      requires neither S6K1 nor rpS6 phosphorylation.
AB  - Translation of terminal oligopyrimidine tract (TOP) mRNAs, which encode multiple
      components of the protein synthesis machinery, is known to be controlled by
      mitogenic stimuli. We now show that the ability of cells to progress through the
      cell cycle is not a prerequisite for this mode of regulation. TOP mRNAs can be
      translationally activated when PC12 or embryonic stem (ES) cells are induced to
      grow (increase their size) by nerve growth factor and retinoic acid,
      respectively, while remaining mitotically arrested. However, both growth and
      mitogenic signals converge via the phosphatidylinositol 3-kinase (PI3-kinase)
      mediated pathway and are transduced to efficiently translate TOP mRNAs.
      Translational activation of TOP mRNAs can be abolished by LY294002, a PI3-kinase
      inhibitor, or by overexpression of PTEN as well as by dominant-negative mutants
      of PI3-kinase or its effectors, PDK1 and protein kinase Balpha (PKBalpha).
      Likewise, overexpression of constitutively active PI3-kinase or PKBalpha can
      relieve the translational repression of TOP mRNAs in quiescent cells. Both
      mitogenic and growth signals lead to phosphorylation of ribosomal protein S6
      (rpS6), which precedes the translational activation of TOP mRNAs. Nevertheless,
      neither rpS6 phosphorylation nor its kinase, S6K1, is essential for the
      translational response of these mRNAs. Thus, TOP mRNAs can be translationally
      activated by growth or mitogenic stimuli of ES cells, whose rpS6 is
      constitutively unphosphorylated due to the disruption of both alleles of S6K1.
      Similarly, complete inhibition of mammalian target of rapamycin (mTOR) and its
      effector S6K by rapamycin in various cell lines has only a mild repressive effect
      on the translation of TOP mRNAs. It therefore appears that translation of TOP
      mRNAs is primarily regulated by growth and mitogenic cues through the PI3-kinase
      pathway, with a minor role, if any, for the mTOR pathway.

PMID- 12417715
TI  - Identification of a human decapping complex associated with hUpf proteins in
      nonsense-mediated decay.
AB  - Decapping is a key step in general and regulated mRNA decay. In Saccharomyces
      cerevisiae it constitutes a rate-limiting step in the nonsense-mediated decay
      pathway that rids cells of mRNAs containing premature termination codons. Here
      two human decapping enzymes are identified, hDcp1a and hDcp2, as well as a
      homolog of hDcp1a, termed hDcp1b. Transiently expressed hDcp1a and hDcp2 proteins
      localize primarily to the cytoplasm and form a complex in human cell extracts.
      hDcp1a and hDcp2 copurify with decapping activity, an activity sensitive to
      mutation of critical hDcp residues. Importantly, coimmunoprecipitation assays
      demonstrate that hDcp1a and hDcp2 interact with the nonsense-mediated decay
      factor hUpf1, both in the presence and in the absence of the other hUpf proteins,
      hUpf2, hUpf3a, and hUpf3b. These data suggest that a human decapping complex may
      be recruited to mRNAs containing premature termination codons by the hUpf
      proteins.

PMID- 12417716
TI  - Mot1 associates with transcriptionally active promoters and inhibits association
      of NC2 in Saccharomyces cerevisiae.
AB  - Mot1 stably associates with the TATA-binding protein (TBP), and it can dissociate
      TBP from DNA in an ATP-dependent manner. Mot1 acts as a negative regulator of TBP
      function in vitro, but genome-wide transcriptional profiling suggests that Mot1
      positively affects about 10% of yeast genes and negatively affects about 5%.
      Unexpectedly, Mot1 associates with active RNA polymerase (Pol) II and III
      promoters, and it is rapidly recruited in response to activator proteins. At Pol
      II promoters, Mot1 association requires TBP and is strongly correlated with the
      level of TBP occupancy. However, the Mot1/TBP occupancy ratio at both Mot1
      stimulated and Mot1-inhibited promoters is high relative to that at typical
      promoters, strongly suggesting that Mot1 directly affects transcriptional
      activity in a positive or negative manner, depending on the gene. The effect of
      Mot1 at the HIS3 promoter region depends on the functional quality and DNA
      sequence of the TATA element. Unlike TBP, Mot1 association is largely independent
      of the Srb4 component of Pol II holoenzyme, and it also can occur downstream of
      the promoter region. Mot1 removes TBP, but not TBP complexes or preinitiation
      complexes, from inappropriate genomic locations. Mot1 inhibits the association of
      NC2 with promoters, suggesting that the TBP-Mot1 and TBP-NC2 complexes compete
      for promoter occupancy in vivo. We speculate that Mot1 does not form
      transcriptionally active TBP complexes but rather regulates transcription in vivo
      by modulating the activity of free TBP and/or by affecting promoter DNA
      structure.

PMID- 12417717
TI  - Biallelic mutations in p16(INK4a) confer resistance to Ras- and Ets-induced
      senescence in human diploid fibroblasts.
AB  - The INK4a/ARF tumor suppressor locus is implicated in the senescence-like growth
      arrest provoked by oncogenic Ras in primary cells. INK4a and ARF are distinct
      proteins encoded by transcripts in which a shared exon is decoded in alternative
      reading frames. Here we analyze dermal fibroblasts (designated Q34) from an
      individual carrying independent missense mutations in each copy of the common
      exon. Both mutations alter the amino acid sequence of INK4a and functionally
      impair the protein, although they do so to different degrees. Only one of the
      mutations affects the sequence of ARF, causing an apparently innocuous change
      near its carboxy terminus. Unlike normal human fibroblasts, Q34 cells are not
      permanently arrested by Ras or its downstream effectors Ets1 and Ets2. Moreover,
      ectopic Ras enables the cells to grow as anchorage-independent colonies, and in
      relatively young Q34 cells anchorage independence can be achieved without
      addition of telomerase or perturbation of the p53 pathway. Whereas ARF plays the
      principal role in Ras-induced arrest of mouse fibroblasts, our data imply that
      INK4a assumes this role in human fibroblasts.

PMID- 12417719
TI  - Normal p53 function in primary cells deficient for Siah genes.
AB  - Overexpression studies have suggested that Siah1 proteins may act as effectors of
      p53-mediated cellular responses and as regulators of mitotic progression. We have
      tested these hypotheses using Siah gene knockout mice. Siah1a and Siah1b were not
      induced by activation of endogenous p53 in tissues, primary murine embryonic
      fibroblasts (MEFs) or thymocytes. Furthermore, primary MEFs lacking Siah1a,
      Siah1b, Siah2, or both Siah2 and Siah1a displayed normal cell cycle progression,
      proliferation, p53-mediated senescence, and G(1) phase cell cycle arrest. Primary
      thymocytes deficient for Siah1a, Siah2, or both Siah2 and Siah1a, E1A-transformed
      MEFs lacking Siah1a, Siah1b, or Siah2, and Siah1b-null ES cells all underwent
      normal p53-mediated apoptosis. Finally, inhibition of Siah1b expression in Siah2
      Siah1a double-mutant cells failed to inhibit cell division, p53-mediated
      induction of p21 expression, or cell cycle arrest. Our loss-of-function
      experiments do not support a general role for Siah genes in p53-mediated
      responses or mitosis.

PMID- 12417718
TI  - Phosphorylation of Tyr342 in the linker region of Syk is critical for Fc epsilon
      RI signaling in mast cells.
AB  - The linker region of Syk and ZAP70 tyrosine kinases plays an important role in
      regulating their function. There are three conserved tyrosines in this linker
      region; Tyr317 of Syk and its equivalent residue in ZAP70 were previously shown
      to negatively regulate the function of Syk and ZAP70. Here we studied the roles
      of the other two tyrosines, Tyr342 and Tyr346 of Syk, in Fc epsilon RI-mediated
      signaling. Antigen stimulation resulted in Tyr342 phosphorylation in mast cells.
      Syk with Y342F mutation failed to reconstitute Fc epsilon RI-initiated histamine
      release. In the Syk Y342F-expressing cells there was dramatically impaired
      receptor-induced phosphorylation of multiple signaling molecules, including LAT,
      SLP-76, phospholipase C-gamma2, but not Vav. Compared to wild-type Syk, Y342F Syk
      had decreased binding to phosphorylated immunoreceptor tyrosine-based activation
      motifs and reduced kinase activity. Surprisingly, mutation of Tyr346 had much
      less effect on Fc epsilon RI-dependent mast cell degranulation. An anti-Syk
      phospho-346 tyrosine antibody indicated that antigen stimulation induced only a
      very minor increase in the phosphorylation of this tyrosine. Therefore, Tyr342,
      but not Tyr346, is critical for regulating Syk in mast cells and the function of
      these tyrosines in immune receptor signaling appears to be different from what
      has been previously reported for the equivalent residues of ZAP70.

PMID- 12417720
TI  - HTL1 encodes a novel factor that interacts with the RSC chromatin remodeling
      complex in Saccharomyces cerevisiae.
AB  - RSC is an essential chromatin remodeling complex in Saccharomyces cerevisiae that
      performs central roles in transcriptional regulation and cell cycle progression.
      Here we identify Htl1 as a novel factor that associates with the RSC complex both
      physically and functionally. We isolated HTL1 through a genetic screen for
      mutants that displayed additive growth defects with a conditional mutation in the
      protein kinase C gene (PKC1), which has been suggested through genetic
      connections to interact functionally with RSC. Several lines of evidence connect
      HTL1 to RSC function. First, an htl1Delta mutant displayed temperature-sensitive
      growth and a G(2)/M cell cycle arrest at restrictive temperatures, a phenotype
      similar to that of strains with conditional mutations in essential RSC
      components. Second, we isolated RSC3, which encodes a component of the RSC
      complex, as a dosage suppressor of the htl1Delta growth arrest. Third, an
      htl1Delta mutant displayed additive growth defects with conditional rsc3 alleles.
      Fourth, overexpression of HTL1 suppressed the growth defect of a strain with a
      conditional mutation in another RSC component, RSC8. Finally, we demonstrate that
      Htl1 is a nuclear protein that can associate in vivo with a fraction of the RSC
      complex. We propose that an RSC-Htl1 complex acts coordinately with protein
      kinase C to regulate the G(2)/M transition.

PMID- 12417721
TI  - The p65/RelA subunit of NF-kappaB suppresses the sustained, antiapoptotic
      activity of Jun kinase induced by tumor necrosis factor.
AB  - Tumor necrosis factor (TNF) signaling through the TNF receptors involves the
      recruitment of key signaling factors, leading to the activation of both the
      transcription factor NF-kappaB and the stress-activated Jun kinase (JNK). In most
      cells, TNF signaling leads to a rapid and transient increase in JNK activity.
      However, we show that TNF treatment leads to the sustained activation of JNK in
      cells that are null for the p65/RelA subunit of NF-kappaB as well as in cells
      expressing the super-repressor form of IkappaB. In addition, the data indicate
      that the ability of p65/RelA to regulate gene expression is required to suppress
      the persistent activation of JNK. Interestingly, this suppression occurs upstream
      of JNK, within the signal transduction cascade leading to JNK activation, without
      affecting the stress-activated kinase p38. Since NF-kappaB has previously been
      shown to be involved in the suppression of TNF-induced apoptosis, we were
      interested in determining the role of deregulated JNK activity, induced by the
      loss of NF-kappaB, in controlling the cell death response. Through the use of
      different approaches for inhibition of JNK, we show that the suppression of JNK
      activity in cells that lack active NF-kappaB enhances the apoptotic response to
      TNF. These data suggest that the activity of JNK in cells blocked for NF-kappaB
      function provides an antiapoptotic signal and explains, at least partly, why a
      significant number of NF-kappaB null cells remain viable following TNF treatment.

PMID- 12417722
TI  - Rapamycin potentiates transforming growth factor beta-induced growth arrest in
      nontransformed, oncogene-transformed, and human cancer cells.
AB  - Transforming growth factor beta (TGF-beta) induces cell cycle arrest of most
      nontransformed epithelial cell lines. In contrast, many human carcinomas are
      refractory to the growth-inhibitory effect of TGF-beta. TGF-beta overexpression
      inhibits tumorigenesis, and abolition of TGF-beta signaling accelerates
      tumorigenesis, suggesting that TGF-beta acts as a tumor suppressor in mouse
      models of cancer. A screen to identify agents that potentiate TGF-beta-induced
      growth arrest demonstrated that the potential anticancer agent rapamycin
      cooperated with TGF-beta to induce growth arrest in multiple cell lines.
      Rapamycin also augmented the ability of TGF-beta to inhibit the proliferation of
      E2F1-, c-Myc-, and (V12)H-Ras-transformed cells, even though these cells were
      insensitive to TGF-beta-mediated growth arrest in the absence of rapamycin.
      Rapamycin potentiation of TGF-beta-induced growth arrest could not be explained
      by increases in TGF-beta receptor levels or rapamycin-induced dissociation of
      FKBP12 from the TGF-beta type I receptor. Significantly, TGF-beta and rapamycin
      cooperated to induce growth inhibition of human carcinoma cells that are
      resistant to TGF-beta-induced growth arrest, and arrest correlated with a
      suppression of Cdk2 kinase activity. Inhibition of Cdk2 activity was associated
      with increased binding of p21 and p27 to Cdk2 and decreased phosphorylation of
      Cdk2 on Thr(160). Increased p21 and p27 binding to Cdk2 was accompanied by
      decreased p130, p107, and E2F4 binding to Cdk2. Together, these results indicate
      that rapamycin and TGF-beta cooperate to inhibit the proliferation of
      nontransformed cells and cancer cells by acting in concert to inhibit Cdk2
      activity.

PMID- 12417723
TI  - Disseminated candidiasis and hepatic malarial infection in mannose-binding-lectin
      A-deficient mice.
AB  - To examine the physiological functions of mannose-binding lectin A (MBL-A), we
      generated mice that were deficient in MBL-A and examined their susceptibilities
      to the microbial pathogens Candida albicans and Plasmodium yoelii, an accepted
      experimental malaria model in mouse. We found no differences in the survival
      rates and fungal burdens of wild-type and MBL-A(-/-) mice with disseminated C.
      albicans infection. The two mouse strains were also similar in their abilities to
      resist hepatic accumulation of P. yoelii parasites. We conclude that MBL-A
      deficiency does not alter resistance to disseminated candidiasis or initial
      hepatic invasion by P. yoelii.

PMID- 12417724
TI  - Mitochondrial glycerol-3-phosphate acyltransferase-deficient mice have reduced
      weight and liver triacylglycerol content and altered glycerolipid fatty acid
      composition.
AB  - Microsomal and mitochondrial isoforms of glycerol-3-phosphate acyltransferase
      (GPAT; E.C. 2.3.1.15) catalyze the committed step in glycerolipid synthesis. The
      mitochondrial isoform, mtGPAT, was believed to control the positioning of
      saturated fatty acids at the sn-1 position of phospholipids, and nutritional,
      hormonal, and overexpression studies suggested that mtGPAT activity is important
      for the synthesis of triacylglycerol. To determine whether these purported
      functions were true, we constructed mice deficient in mtGPAT. mtGPAT(-/-) mice
      weighed less than controls and had reduced gonadal fat pad weights and lower
      hepatic triacylglycerol content, plasma triacylglycerol, and very low density
      lipoprotein triacylglycerol secretion. As predicted, in mtGPAT(-/-) liver, the
      palmitate content was lower in triacylglycerol, phosphatidylcholine, and
      phosphatidylethanolamine. Positional analysis revealed that mtGPAT(-/-) liver
      phosphatidylethanolamine and phosphatidylcholine had about 21% less palmitate in
      the sn-1 position and 36 and 40%, respectively, more arachidonate in the sn-2
      position. These data confirm the important role of mtGPAT in the synthesis of
      triacylglycerol, in the fatty acid content of triacylglycerol and cholesterol
      esters, and in the positioning of specific fatty acids, particularly palmitate
      and arachidonate, in phospholipids. The increase in arachidonate may be
      functionally significant in terms of eicosanoid production.

PMID- 12417725
TI  - NuA4 subunit Yng2 function in intra-S-phase DNA damage response.
AB  - While regulated transcription requires acetylation of histone N-terminal tails to
      promote an open chromatin conformation, a similar role for histone acetylation in
      DNA replication and/or repair remains to be established. Cells lacking the NuA4
      subunit Yng2 are viable but critically deficient for genome-wide nucleosomal
      histone H4 acetylation. We found that yng2 mutants are specifically sensitized to
      DNA damage in S phase induced by cdc8 or cdc9 mutations, hydroxyurea,
      camptothecin, or methylmethane sulfonate (MMS). In yng2, MMS treatment causes a
      persistent Mec1-dependent intra-S-phase checkpoint delay characterized by slow
      DNA repair. Restoring H4 acetylation with the histone deacetylase inhibitor
      trichostatin A promotes checkpoint recovery. In turn, mutants lacking the histone
      H3-specific acetyltransferase GCN5 are similarly sensitive to intra-S-phase DNA
      damage. The inviability of gcn5 yng2 double mutants suggests overlapping roles
      for H3 and H4 acetylation in DNA replication and repair. Paradoxically, haploid
      yng2 mutants do not tolerate mutations in genes important for nonhomologous end
      joining repair yet remain proficient for homologous recombination. Our results
      implicate nucleosomal histone acetylation in maintaining genomic integrity during
      chromosomal replication.

PMID- 12417726
TI  - PEX11alpha is required for peroxisome proliferation in response to 4
      phenylbutyrate but is dispensable for peroxisome proliferator-activated receptor
      alpha-mediated peroxisome proliferation.
AB  - The PEX11 peroxisomal membrane proteins promote peroxisome division in multiple
      eukaryotes. As part of our effort to understand the molecular and physiological
      functions of PEX11 proteins, we disrupted the mouse PEX11alpha gene.
      Overexpression of PEX11alpha is sufficient to promote peroxisome division, and a
      class of chemicals known as peroxisome proliferating agents (PPAs) induce the
      expression of PEX11alpha and promote peroxisome division. These observations led
      to the hypothesis that PPAs induce peroxisome abundance by enhancing PEX11alpha
      expression. The phenotypes of PEX11alpha(-/-) mice indicate that this hypothesis
      remains valid for a novel class of PPAs that act independently of peroxisome
      proliferator-activated receptor alpha (PPARalpha) but is not valid for the
      classical PPAs that act as activators of PPARalpha. Furthermore, we find that
      PEX11alpha(-/-) mice have normal peroxisome abundance and that cells lacking both
      PEX11alpha and PEX11beta, a second mammalian PEX11 gene, have no greater defect
      in peroxisome abundance than do cells lacking only PEX11beta. Finally, we report
      the identification of a third mammalian PEX11 gene, PEX11gamma, and show that it
      too encodes a peroxisomal protein.

PMID- 12417727
TI  - Stable mRNP formation and export require cotranscriptional recruitment of the
      mRNA export factors Yra1p and Sub2p by Hpr1p.
AB  - Yra1p/REF participates in mRNA export by recruiting the export receptor Mex67p to
      messenger ribonucleoprotein (mRNP) complexes. Yra1p also binds Sub2p, a DEAD box
      ATPase/RNA helicase implicated in splicing and required for mRNA export. We
      identified genetic and physical interactions between Yra1p, Sub2p, and Hpr1p, a
      protein involved in transcription elongation whose deletion leads to poly(A)(+)
      RNA accumulation in the nucleus. By chromatin immunoprecipitation (ChIP)
      experiments, we show that Hpr1p, Sub2p, and Yra1p become associated with active
      genes during transcription elongation and that Hpr1p is required for the
      efficient recruitment of Sub2p and Yra1p. The data indicate that transcription
      and export are functionally linked and that mRNA export defects may be due in
      part to inefficient loading of essential mRNA export factors on the growing mRNP.
      We also identified functional interactions between Yra1p and the exosome
      components Rrp45p and Rrp6p. We show that yra1, sub2, and Deltahpr1 mutants all
      present defects in mRNA accumulation and that deletion of RRP6 in yra1 mutants
      restores normal mRNA levels. The data support the hypothesis that an exosome
      dependent surveillance mechanism targets improperly assembled mRNPs for
      degradation.

PMID- 12417728
TI  - Interactions between mRNA export commitment, 3'-end quality control, and nuclear
      degradation.
AB  - Several aspects of eukaryotic mRNA processing are linked to transcription. In
      Saccharomyces cerevisiae, overexpression of the mRNA export factor Sub2p
      suppresses the growth defect of hpr1 null cells, yet the protein Hpr1p and the
      associated THO protein complex are implicated in transcriptional elongation.
      Indeed, we find that a pool of heat shock HSP104 transcripts are 3'-end truncated
      in THO complex mutant as well as sub2 mutant backgrounds. Surprisingly, however,
      this defect can be suppressed by deletion of the 3'-5' exonuclease Rrp6p. This
      indicates that incomplete RNAs result from nuclear degradation rather than from a
      failure to efficiently elongate transcription. RNAs that are not degraded are
      retained at the transcription site in a Rrp6p-dependent manner. Interestingly,
      the addition of a RRP6 deletion to sub2 or to THO complex mutants shows a strong
      synthetic growth phenotype, suggesting that the failure to retain and/or degrade
      defective mRNAs is deleterious. mRNAs produced in the 3'-end processing mutants
      rna14-3 and rna15-2, as well as an RNA harboring a 3' end generated by a self
      cleaving hammerhead ribozyme, are also retained in Rrp6p-dependent transcription
      site foci. Taken together, our results show that several classes of defective
      RNPs are subject to a quality control step that impedes release from
      transcription site foci and suggest that suboptimal messenger ribonucleoprotein
      assembly leads to RNA degradation by Rrp6p.

PMID- 12417729
TI  - Linking sister chromatid cohesion and apoptosis: role of Rad21.
AB  - Rad21 is one of the major cohesin subunits that holds sister chromatids together
      until anaphase, when proteolytic cleavage by separase, a caspase-like enzyme,
      allows chromosomal separation. We show that cleavage of human Rad21 (hRad21) also
      occurs during apoptosis induced by diverse stimuli. Induction of apoptosis in
      multiple human cell lines results in the early (4 h after insult) generation of
      64- and 60-kDa carboxy-terminal hRad21 cleavage products. We biochemically mapped
      an apoptotic cleavage site at residue Asp-279 (D(279)) of hRad21. This apoptotic
      cleavage site is distinct from previously described mitotic cleavage sites.
      hRad21 is a nuclear protein; however, the cleaved 64-kDa carboxy-terminal product
      is translocated to the cytoplasm early in apoptosis before chromatin condensation
      and nuclear fragmentation. Overexpression of the 64-kDa cleavage product results
      in apoptosis in Molt4, MCF-7, and 293T cells, as determined by TUNEL (terminal
      deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling) and Annexin V
      staining, assaying of caspase-3 activity, and examination of nuclear morphology.
      Given the role of hRad21 in chromosome cohesion, the cleaved C-terminal product
      and its translocation to the cytoplasm may act as a nuclear signal for apoptosis.
      In summary, we show that cleavage of a cohesion protein and translocation of the
      C-terminal cleavage product to the cytoplasm are early events in the apoptotic
      pathway and cause amplification of the cell death signal in a positive-feedback
      manner.

PMID- 12417730
TI  - Multimerization via its myosin domain facilitates nuclear localization and
      inhibition of core binding factor (CBF) activities by the CBFbeta-smooth muscle
      myosin heavy chain myeloid leukemia oncoprotein.
AB  - In CBFbeta-SMMHC, core binding factor beta (CBFbeta) is fused to the alpha
      helical rod domain of smooth muscle myosin heavy chain (SMMHC). We generated
      Ba/F3 hematopoietic cells expressing a CBFbeta-SMMHC variant lacking 28 amino
      acids homologous to the assembly competence domain (ACD) required for
      multimerization of skeletal muscle myosin. CBFbeta-SMMHC(DeltaACD) multimerized
      less effectively than either wild-type protein or a variant lacking a different
      28-residue segment. In contrast to the control proteins, the DeltaACD mutant did
      not inhibit CBF DNA binding, AML1-mediated reporter activation, or G(1) to S cell
      cycle progression, the last being dependent upon activation of CBF-regulated
      genes. We also linked the CBFbeta domain to 149 or 83 C-terminal CBFbeta-SMMHC
      residues, retaining 86 or 20 amino acids N-terminal to the ACD. CBFbeta
      SMMHC(149C) multimerized and slowed Ba/F3 proliferation, whereas CBFbeta
      SMMHC(83C) did not. The majority of CBFbeta-SMMHC and CBFbeta-SMMHC(149C) was
      detected in the nucleus, whereas the DeltaACD and 83C variants were predominantly
      cytoplasmic, indicating that multimerization facilitates nuclear retention of
      CBFbeta-SMMHC. When linked to the simian virus 40 nuclear localization signal
      (NLS), a significant fraction of CBFbeta-SMMHC(DeltaACD) entered the nucleus but
      only mildly inhibited CBF activities. As NLS-CBFbeta-SMMHC(83C) remained
      cytoplasmic, we directed the ACD to CBF target genes by linking it to the AML1
      DNA binding domain or to full-length AML1. These AML1-ACD fusion proteins did not
      affect Ba/F3 proliferation, in contrast to AML1-ETO, which markedly slowed G(1)
      to S progression dependent upon the integrity of its DNA-binding domain. Thus,
      the ACD facilitates inhibition of CBF by mediating multimerization of CBFbeta
      SMMHC in the nucleus. Therapeutics targeting the ACD may be effective in acute
      myeloid leukemia cases associated with CBFbeta-SMMHC expression.

PMID- 12417731
TI  - Esc1, a nuclear periphery protein required for Sir4-based plasmid anchoring and
      partitioning.
AB  - A targeted silencing screen was performed to identify yeast proteins that, when
      tethered to a telomere, suppress a telomeric silencing defect caused by
      truncation of Rap1. A previously uncharacterized protein, Esc1 (establishes
      silent chromatin), was recovered, in addition to well-characterized proteins
      Rap1, Sir1, and Rad7. Telomeric silencing was slightly decreased in Deltaesc1
      mutants, but silencing of the HM loci was unaffected. On the other hand, targeted
      silencing by various tethered proteins was greatly weakened in Deltaesc1 mutants.
      Two-hybrid analysis revealed that Esc1 and Sir4 interact via a 34-amino-acid
      portion of Esc1 (residues 1440 to 1473) and a carboxyl-terminal domain of Sir4
      known as PAD4 (residues 950 to 1262). When tethered to DNA, this Sir4 domain
      confers efficient partitioning to otherwise unstable plasmids and blocks the
      ability of bound DNA segments to rotate freely in vivo. Here, both phenomena were
      shown to require ESC1. Sir protein-mediated partitioning of a telomere-based
      plasmid also required ESC1. Fluorescence microscopy of cells expressing green
      fluorescent protein (GFP)-Esc1 showed that the protein localized to the nuclear
      periphery, a region of the nucleus known to be functionally important for
      silencing. GFP-Esc1 localization, however, was not entirely coincident with
      telomeres, the nucleolus, or nuclear pore complexes. Our data suggest that Esc1
      is a component of a redundant pathway that functions to localize silencing
      complexes to the nuclear periphery.

PMID- 12417732
TI  - Inhibitors of histone deacetylase and DNA methyltransferase synergistically
      activate the methylated metallothionein I promoter by activating the
      transcription factor MTF-1 and forming an open chromatin structure.
AB  - Inhibitors of DNA methyltransferase (Dnmt) and histone deacetylases (HDAC)
      synergistically activate the methylated metallothionein I gene (MT-I) promoter in
      mouse lymphosarcoma cells. The cooperative effect of these two classes of
      inhibitors on MT-I promoter activity was robust following demethylation of only a
      few CpG dinucleotides by brief exposure to 5-azacytidine (5-AzaC) but persisted
      even after prolonged treatment with the nucleoside analog. HDAC inhibitors
      (trichostatin A [TSA] and depsipeptide) either alone or in combination with 5
      AzaC did not facilitate demethylation of the MT-I promoter. Treatment of cells
      with HDAC inhibitors increased accumulation of multiply acetylated forms of H3
      and H4 histones that remained unaffected after treatment with 5-AzaC. Chromatin
      immunoprecipitation (ChIP) assay showed increased association of acetylated
      histone H4 and lysine 9 (K9)-acetyl H3 with the MT-I promoter after treatment
      with TSA, which was not affected following treatment with 5-AzaC. In contrast,
      the association of K9-methyl histone H3 with the MT-I promoter decreased
      significantly after treatment with 5-AzaC and TSA. ChIP assay with antibodies
      specific for methyl-CpG binding proteins (MBDs) demonstrated that only methyl-CpG
      binding protein 2 (MeCP2) was associated with the MT-I promoter, which was
      significantly enhanced after TSA treatment. Association of histone deacetylase 1
      (HDAC1) with the promoter decreased after treatment with TSA or 5-AzaC and was
      abolished after treatment with both inhibitors. Among the DNA methyltransferases,
      both Dnmt1 and Dnmt3a were associated with the MT-I promoter in the lymphosarcoma
      cells, and association of Dnmt1 decreased with time after treatment with 5-AzaC.
      Treatment of these cells with HDAC inhibitors also increased expression of the
      MTF-1 (metal transcription factor-1) gene as well as its DNA binding activity. In
      vivo genomic footprinting studies demonstrated increased occupancy of MTF-1 to
      metal response elements of the MT-I promoter after treatment with both
      inhibitors. Analysis of the promoter by mapping with restriction enzymes in vivo
      showed that the MT-I promoter attained a more open chromatin structure after
      combined treatment with 5-AzaC and TSA as opposed to treatment with either agent
      alone. These results implicate involvement of multifarious factors including
      modified histones, MBDs, and Dnmts in silencing the methylated MT-I promoter in
      lymphosarcoma cells. The synergistic activation of this promoter by these two
      types of inhibitors is due to demethylation of the promoter and altered
      association of different factors that leads to reorganization of the chromatin
      and the resultant increase in accessibility of the promoter to the activated
      transcription factor MTF-1.

PMID- 12417733
TI  - BOB.1/OBF.1 deficiency affects marginal-zone B-cell compartment.
AB  - Marginal-zone (MZ) B cells represent a first line of defense against particulate
      blood-borne antigens. Together with the B1 cells, they are responsible for the
      early response against type II T-independent antigens. The molecular pathways
      controlling the development of MZ B cells are only poorly understood. We found
      that these cells are virtually absent in mice deficient in the BOB.1/OBF.1
      coactivator. Loss of these B cells was demonstrated by the lack of cells showing
      the appropriate cell surface phenotype but also by histological analyses and tri
      nitro-phenol-Ficoll capturing. The lack of these cells is a B-cell-intrinsic
      defect, as shown by bone marrow complementation experiments. We also show that
      the expression of BOB.1/OBF.1 in peripheral B cells is required for the
      development of MZ B lymphocytes. Our analysis of BOB.1/OBF.1-deficient splenic B
      cells reveals alterations in cell motility, tumor necrosis factor receptor
      expression, and B-cell receptor (BCR) signaling. These changes could contribute
      to the loss of MZ B lymphocytes by altering the maturation of the cells.
      Interestingly, development of and BCR signaling in B1 B cells are completely
      normal in BOB.1/OBF.1 mutant mice.

PMID- 12417734
TI  - Transport of fragile X mental retardation protein via granules in neurites of
      PC12 cells.
AB  - Lack of fragile X mental retardation protein (FMRP) causes fragile X syndrome, a
      common form of inherited mental retardation. FMRP is an RNA binding protein
      thought to be involved in translation efficiency and/or trafficking of certain
      mRNAs. Recently, a subset of mRNAs to which FMRP binds with high affinity has
      been identified. These FMRP-associated mRNAs contain an intramolecular G-quartet
      structure. In neurons, dendritic mRNAs are involved in local synthesis of
      proteins in response to synaptic activity, and this represents a mechanism for
      synaptic plasticity. To determine the role of FMRP in dendritic mRNA transport,
      we have generated a stably FMR1-enhanced green fluorescent protein (EGFP)
      transfected PC12 cell line with an inducible expression system (Tet-On) for
      regulated expression of the FMRP-GFP fusion protein. After doxycycline induction,
      FMRP-GFP was localized in granules in the neurites of PC12 cells. By using time
      lapse microscopy, the trafficking of FMRP-GFP granules into the neurites of
      living PC12 cells was demonstrated. Motile FMRP-GFP granules displayed two types
      of movements: oscillatory (bidirectional) and unidirectional anterograde. The
      average velocity of the granules was 0.19 micro m/s with a maximum speed of 0.71
      micro m/s. In addition, we showed that the movement of FMRP-GFP labeled granules
      into the neurites was microtubule dependent. Colocalization studies further
      showed that the FMRP-GFP labeled granules also contained RNA, ribosomal subunits,
      kinesin heavy chain, and FXR1P molecules. This report is the first example of
      trafficking of RNA-containing granules with FMRP as a core constituent in living
      PC12 cells.

PMID- 12417735
TI  - Conserved stem II of the box C/D motif is essential for nucleolar localization
      and is required, along with the 15.5K protein, for the hierarchical assembly of
      the box C/D snoRNP.
AB  - The 5' stem-loop of the U4 snRNA and the box C/D motif of the box C/D snoRNAs can
      both be folded into a similar stem-internal loop-stem structure that binds the
      15.5K protein. The homologous proteins NOP56 and NOP58 and 61K (hPrp31) associate
      with the box C/D snoRNPs and the U4/U6 snRNP, respectively. This raises the
      intriguing question of how the two homologous RNP complexes specifically assemble
      onto similar RNAs. Here we investigate the requirements for the specific binding
      of the individual snoRNP proteins to the U14 box C/D snoRNPs in vitro. This
      revealed that the binding of 15.5K to the box C/D motif is essential for the
      association of the remaining snoRNP-associated proteins, namely, NOP56, NOP58,
      fibrillarin, and the nucleoplasmic proteins TIP48 and TIP49. Stem II of the box
      C/D motif, in contrast to the U4 5' stem-loop, is highly conserved, and we show
      that this sequence is responsible for the binding of NOP56, NOP58, fibrillarin,
      TIP48, and TIP49, but not of 15.5K, to the snoRNA. Indeed, the sequence of stem
      II was essential for nucleolar localization of U14 snoRNA microinjected into HeLa
      cells. Thus, the conserved sequence of stem II determines the specific assembly
      of the box C/D snoRNP.

PMID- 12417736
TI  - Histone H3 and the histone acetyltransferase Hat1p contribute to DNA double
      strand break repair.
AB  - The modification of newly synthesized histones H3 and H4 by type B histone
      acetyltransferases has been proposed to play a role in the process of chromatin
      assembly. The type B histone acetyltransferase Hat1p and specific lysine residues
      in the histone H3 NH(2)-terminal tail (primarily lysine 14) are redundantly
      required for telomeric silencing. As many gene products, including other factors
      involved in chromatin assembly, have been found to participate in both telomeric
      silencing and DNA damage repair, we tested whether mutations in HAT1 and the
      histone H3 tail were also sensitive to DNA-damaging agents. Indeed, mutations
      both in specific lysine residues in the histone H3 tail and in HAT1 resulted in
      sensitivity to methyl methanesulfonate. The DNA damage sensitivity of the histone
      H3 and HAT1 mutants was specific for DNA double-strand breaks, as these mutants
      were sensitive to the induction of an exogenous restriction endonuclease, EcoRI,
      but not to UV irradiation. While histone H3 mutations had minor effects on
      nonhomologous end joining, the primary defect in the histone H3 and HAT1 mutants
      was in the recombinational repair of DNA double-strand breaks. Epistasis analysis
      indicates that the histone H3 and HAT1 mutants may influence DNA double-strand
      break repair through Asf1p-dependent chromatin assembly.

PMID- 12417737
TI  - Two ubiquitin-conjugating enzymes, Rhp6 and UbcX, regulate heterochromatin
      silencing in Schizosaccharomyces pombe.
AB  - Methylation of histone H3 has been linked to the assembly of higher-order
      chromatin structures. Very recently, several examples, including the
      Schizosaccharomyces pombe mating-type region, chicken beta-globin locus, and
      inactive X-chromosome, revealed that H3-Lys9-methyl (Me) is associated with
      silent chromatin while H3-Lys4-Me is prominent in active chromatin. Surprisingly,
      it was shown that homologs of Drosophila Su(var)3-9 specifically methylate the
      Lys9 residue of histone H3. Here, to identify putative enzymes responsible for
      destabilization of heterochromatin, we screened genes whose overexpressions
      disrupt silencing at the silent mat3 locus in fission yeast. Interestingly, we
      identified two genes, rhp6(+) and ubcX(+) (ubiquitin-conjugating enzyme
      participating in silencing), both of which encode ubiquitin-conjugating enzymes.
      Their overexpression disrupted silencing at centromeres and telomeres as well as
      at mat3. Additionally, the overexpression interfered with centromeric function,
      as confirmed by elevated minichromosome loss and antimicrotubule drug
      sensitivity. On the contrary, deletion of rhp6(+) or ubcX(+) enhanced silencing
      at all heterochromatic regions tested, indicating that they are negative
      regulators of silencing. More importantly, chromatin immunoprecipitation showed
      that their overexpression alleviated the level of H3-Lys9-Me while enhancing the
      level of H3-Lys4-Me at the silent regions. On the contrary, their deletions
      enhanced the level of H3-Lys9-Me while alleviating that of H3-Lys4-Me. Taken
      together, the data suggest that two ubiquitin-conjugating enzymes, Rhp6 and UbcX,
      affect methylation of histone H3 at silent chromatin, which then reconfigures
      silencing.

PMID- 12417738
TI  - In vivo interference with Skp1 function leads to genetic instability and
      neoplastic transformation.
AB  - Skp1 is involved in a variety of crucial cellular functions, among which the best
      understood is the formation together with Cul1 of Skp1-cullin-F-box protein
      ubiquitin ligases. To investigate the role of Skp1, we generated transgenic (Tg)
      mice expressing a Cul1 deletion mutant (Cul1-N252) able to sequestrate and
      inactivate Skp1. In vivo interference with Skp1 function through expression of
      the Cul1-N252 mutant into the T-cell lineage results in lymphoid organ hypoplasia
      and reduced proliferation. Nonetheless, after a period of latency, Cul1-N252 Tg
      mice succumb to T-cell lymphomas with high penetrance (>80%). Both T-cell
      depletion and the neoplastic phenotype of Cul1-N252 Tg mice are largely rescued
      in Cul1-N252, Skp1 double-Tg mice, indicating that the effects of Cul1-N252 are
      due to a sequestration of the endogenous Skp1. Analysis of Cul1-N252 lymphomas
      demonstrates striking karyotype heterogeneity associated with c-myc amplification
      and c-Myc overexpression. We show that the in vitro expression of the Cul1-N252
      mutant causes a pleiotrophic phenotype, which includes the formation of
      multinucleated cells, centrosome and mitotic spindle abnormalities, and impaired
      chromosome segregation. Our findings support a crucial role for Skp1 in proper
      chromosomal segregation, which is required for the maintenance of euploidy and
      suppression of transformation.

PMID- 12417739
TI  - Short constrained peptides that inhibit HIV-1 entry.
AB  - Peptides corresponding to the C-terminal heptad repeat of HIV-1 gp41 (C-peptides)
      are potent inhibitors of HIV-1 entry into cells. Their mechanism of inhibition
      involves binding in a helical conformation to the central coiled coil of HIV-1
      gp41 in a dominant-negative manner. Short C-peptides, however, have low binding
      affinity for gp41 and poor inhibitory activity, which creates an obstacle to the
      development of small drug-like C-peptides. To improve the inhibitory potency of
      short C-peptides that target the hydrophobic pocket region of gp41, we use two
      strategies to stabilize the C-peptide helix: chemical crosslinking and
      substitution with unnatural helix-favoring amino acids. In this study, the short
      linear peptide shows no significant inhibitory activity, but a constrained
      peptide (C14linkmid) inhibits cell-cell fusion at micromolar potency. Structural
      studies confirm that the constrained peptides bind to the gp41 hydrophobic
      pocket. Calorimetry reveals that, of the peptides analyzed, the most potent are
      those that best balance the changes in binding enthalpy and entropy, and
      surprisingly not those with the highest helical propensity as measured by
      circular dichroism spectroscopy. Our study reveals the thermodynamic basis of
      inhibition of an HIV C-peptide, demonstrates the utility of constraining methods
      for a short antiviral peptide inhibitor, and has implications for the future
      design of constrained peptides.

PMID- 12417740
TI  - Transcriptional activating regions target a cyclin-dependent kinase.
AB  - Several yeast activators are phosphorylated by SRB10, a cyclin-dependent kinase
      associated with the transcriptional machinery. Sites of phosphorylation are found
      outside the activating region in each case, and the modification has different
      physiological consequences in different cases. We show here that certain acidic
      transcriptional activating regions contact SRB10 as assayed both in vivo and in
      vitro. The interaction evidently positions each activator, as it activates
      transcription, so that it gets phosphorylated by SRB10, and thus a common
      mechanism targets disparate substrates to the kinase.

PMID- 12417741
TI  - Mbd4 inactivation increases Cright-arrowT transition mutations and promotes
      gastrointestinal tumor formation.
AB  - Mbd4 (methyl-CpG binding domain 4) is a novel mammalian repair enzyme that has
      been implicated biochemically in the repair of mismatched G-T residues at
      methylated CpG sites. In addition, the human protein has been shown to interact
      with the DNA mismatch repair protein MLH1. To clarify the role of Mbd4 in DNA
      repair in vivo and to examine the impact of Mbd4 inactivation on gastrointestinal
      (GI) tumorigenesis, we introduced a null mutation into the murine Mbd4 gene by
      gene targeting. Heterozygous and homozygous Mbd4 mutant mice develop normally and
      do not show increased cancer susceptibility or reduced survival. Although Mbd4
      inactivation did not increase microsatellite instability (MSI) in the mouse
      genome, it did result in a 2- to 3-fold increase in C-->T transition mutations at
      CpG sequences in splenocytes and epithelial cells of the small intestinal mucosa.
      The combination of Mbd4 deficiency with a germ line mutation in the adenomatous
      polyposis coli (Apc) gene increased the tumor number in the GI tract and
      accelerated tumor progression. The change in the GI cancer phenotype was
      associated with an increase in somatic C-->T mutations at CpG sites within the
      coding region of the wild-type Apc allele. These studies indicate that, although
      inactivation of Mbd4 does not by itself cause cancer predisposition in mice, it
      can alter the mutation spectrum in cancer cells and modify the cancer
      predisposition phenotype.

PMID- 12417742
TI  - Resistance to the macrolide antibiotic tylosin is conferred by single
      methylations at 23S rRNA nucleotides G748 and A2058 acting in synergy.
AB  - The macrolide antibiotic tylosin has been used extensively in veterinary medicine
      and exerts potent antimicrobial activity against Gram-positive bacteria. Tylosin
      synthesizing strains of the Gram-positive bacterium Streptomyces fradiae protect
      themselves from their own product by differential expression of four resistance
      determinants, tlrA, tlrB, tlrC, and tlrD. The tlrB and tlrD genes encode
      methyltransferases that add single methyl groups at 23S rRNA nucleotides G748 and
      A2058, respectively. Here we show that methylation by neither TlrB nor TlrD is
      sufficient on its own to give tylosin resistance, and resistance is conferred by
      the G748 and A2058 methylations acting together in synergy. This synergistic
      mechanism of resistance is specific for the macrolides tylosin and mycinamycin
      that possess sugars extending from the 5- and 14-positions of the macrolactone
      ring and is not observed for macrolides, such as carbomycin, spiramycin, and
      erythromycin, that have different constellations of sugars. The manner in which
      the G748 and A2058 methylations coincide with the glycosylation patterns of
      tylosin and mycinamycin reflects unambiguously how these macrolides fit into
      their binding site within the bacterial 50S ribosomal subunit.

PMID- 12417743
TI  - Varitint-waddler: a double whammy for hearing.

PMID- 12417744
TI  - Engineered herpes simplex virus 1 is dependent on IL13Ralpha 2 receptor for cell
      entry and independent of glycoprotein D receptor interaction.
AB  - In the first stage of engineering a herpes simplex virus (HSV)-1 that
      specifically targets human malignant glioma cells, we constructed a recombinant
      virus designated R5111 in which we have ablated the binding sites for sulfated
      proteoglycans in glycoproteins B and C, replaced the amino-terminal 148 aa in
      glycoprotein C by IL-13 flanked at its amino terminus with a signal peptide, and
      inserted a second copy of IL-13 after the amino acid 24 of glycoprotein D. In the
      process, the binding site for HveA, a viral entry receptor, was disrupted. We
      have also transformed a cell line (J1.1) lacking HSV-1 receptors to express
      IL13Ralpha2 receptor (J13R cells). We report the following: the R5111 recombinant
      virus replicates as well as wild-type virus in a variety of cell lines including
      cell lines derived from brain tumors. R5111 failed to replicate in the parent
      J1.1 cell line but multiplied to titers similar to those obtained in other cell
      lines in the J13R cell line. On the basis of the evidence that R5111 can use the
      IL13Ralpha2 receptor for entry, we conclude that HSV-1 can use receptors other
      than HveA or nectins, provided it can bind to them. The domains of gD that
      interact with HveA and nectin receptors are independent of each other. Lastly,
      the fusogenic activities of the glycoproteins in the viral envelope are not
      dependent on a set of unique interactions between glycoprotein D and its
      receptor. The construction of R5111 opens the way for construction of viruses
      totally dependent on selected receptors for entry or imaging of targeted cells.

PMID- 12417745
TI  - The inflationary effects of environmental fluctuations in source-sink systems.
AB  - Ecological communities are open to the immigration of individuals and are
      variable through time. In open habitats immigration may permit populations of a
      species to persist locally even though local biotic and abiotic processes tend to
      exclude such "sink" populations. A general model for a sink population reveals
      that autocorrelated environmental variation can dramatically inflate local
      abundance and that such populations display a characteristic "outbreak" pattern.
      An experimental protist microcosm exhibits these predicted effects. Because the
      many ecological and environmental processes that set the rate of exclusion are
      typically autocorrelated, these theoretical and empirical results have broad
      implications for our understanding of community structure and highlight a
      previously unsuspected potential effect of anthropogenic climate change.

PMID- 12417746
TI  - Increased mitochondrial mass in mitochondrial myopathy mice.
AB  - We have generated an animal model for mitochondrial myopathy by disrupting the
      gene for mitochondrial transcription factor A (Tfam) in skeletal muscle of the
      mouse. The knockout animals developed a myopathy with ragged-red muscle fibers,
      accumulation of abnormally appearing mitochondria, and progressively
      deteriorating respiratory chain function in skeletal muscle. Enzyme
      histochemistry, electron micrographs, and citrate synthase activity revealed a
      substantial increase in mitochondrial mass in skeletal muscle of the myopathy
      mice. Biochemical assays demonstrated that the increased mitochondrial mass
      partly compensated for the reduced function of the respiratory chain by
      maintaining overall ATP production in skeletal muscle. The increased
      mitochondrial mass thus was induced by the respiratory chain deficiency and may
      be beneficial by improving the energy homeostasis in the affected tissue.
      Surprisingly, in vitro experiments to assess muscle function demonstrated that
      fatigue development did not occur more rapidly in myopathy mice, suggesting that
      overall ATP production is sufficient. However, there were lower absolute muscle
      forces in the myopathy mice, especially at low stimulation frequencies. This
      reduction in muscle force is likely caused by deficient formation of force
      generating actin-myosin cross bridges and/or disregulation of Ca(2+) homeostasis.
      Thus, both biochemical measurements of ATP-production rate and in vitro
      physiological studies suggest that reduced mitochondrial ATP production might not
      be as critical for the pathophysiology of mitochondrial myopathy as thought
      previously.

PMID- 12417747
TI  - Posttranslational modifications in the CP43 subunit of photosystem II.
AB  - Photosystem II (PSII) catalyzes the light-driven oxidation of water and the
      reduction of plastoquinone; the oxidation of water occurs at a cluster of four
      manganese. The PSII CP43 subunit functions in light harvesting, and mutations in
      the fifth luminal loop (E) of CP43 have established its importance in PSII
      structure and/or assembly [Kuhn, M. G. & Vermaas, V. F. J. (1993) Plant Mol.
      Biol. 23, 123-133]. The sequence A(350)PWLEPLR(357) in luminal loop E is
      conserved in CP43 genes from 50 organisms. To map important posttranslational
      modifications in this sequence, tandem mass spectrometry (MS/MS) was used. These
      data show that the indole side chain of Trp-352 is posttranslationally modified
      to give mass shifts of +4, +16, and +18 daltons. The masses of the modifications
      suggest that the tryptophan is modified to kynurenine (+4), a keto-/amino
      /hydroxy- (+16) derivative, and a dihydro-hydroxy- (+18) derivative of the indole
      side chain. Peptide synthesis and MS/MS confirmed the kynurenine assignment. The
      +16 and +18 tryptophan modifications may be intermediates formed during the
      oxidative cleavage of the indole ring to give kynurenine. The site-directed
      mutations, W352C, W352L, and W352A, exhibit an increased rate of photoinhibition
      relative to wild type. We hypothesize that Trp-352 oxidative modifications are a
      byproduct of PSII water-splitting or electron transfer reactions and that these
      modifications target PSII for turnover. As a step toward understanding the
      tertiary structure of this CP43 peptide, structural modeling was performed by
      using molecular dynamics.

PMID- 12417748
TI  - Amino acids regulate the intracellular trafficking of the general amino acid
      permease of Saccharomycescerevisiae.
AB  - The delivery to the plasma membrane of the general amino acid permease, Gap1p, of
      Saccharomyces cerevisiae is regulated by the quality of the nitrogen source in
      the growth medium. In an effort to define how different nitrogen sources control
      Gap1p sorting, we find that mutations in GDH1 and GLN1 that decrease the flux
      through the glutamate and glutamine synthesis pathways result in increased Gap1p
      sorting to the plasma membrane. Conversely, deletion of MKS1, which increases
      glutamate and glutamine synthesis, decreases Gap1p sorting to the plasma
      membrane. Glutamate and glutamine are not unusual in their ability to regulate
      Gap1p sorting, because the addition of all natural amino acids and many amino
      acid analogs to the growth medium results in increased Gap1p sorting to the
      vacuole. Importantly, amino acids have the capacity to signal Gap1p sorting to
      the vacuole regardless of whether they can be used as a source of nitrogen.
      Finally, we show that rapamycin does not affect Gap1p sorting, indicating that
      Gap1p sorting is not directly influenced by the TOR pathway. Together, these data
      show that amino acids are a signal for sorting Gap1p to the vacuole and imply
      that the nitrogen-regulated Gap1p sorting machinery responds to amino acid-like
      compounds rather than to the overall nutritional status associated with growth on
      a particular nitrogen source.

PMID- 12417750
TI  - Retroviral delivery of small interfering RNA into primary cells.
AB  - RNA interference is an evolutionarily conserved process in which recognition of
      double-stranded RNA ultimately leads to posttranscriptional suppression of gene
      expression. This suppression is mediated by short (21- to 22-nt) small
      interfering RNAs (siRNAs), which induce degradation of mRNA based on
      complementary base pairing. The silencing of gene expression by siRNAs is
      emerging rapidly as a powerful method for genetic analysis. Recently, several
      groups have reported systems designed to express siRNAs in mammalian cells
      through transfection of either oligonucleotides or plasmids encoding siRNAs.
      Because these systems rely on transfection for delivery, the cell types available
      for study are restricted generally to transformed cell lines. Here, we describe a
      retroviral system for delivery of siRNA into cells. The use of retroviral vectors
      can greatly expand the types of cells available for RNA interference analysis.
      Furthermore, we demonstrate that this retroviral system allows for stable
      inactivation of genes in primary cells.

PMID- 12417749
TI  - East Asian genotypes of Helicobacter pylori strains in Amerindians provide
      evidence for its ancient human carriage.
AB  - Phylogenies of indigenous microbes have been used as surrogates for the origins
      of the hosts that carry them. Conversely, polymorphisms may be used to date the
      spread of a microbial species when information about their host populations is
      available. Therefore, we examined polymorphisms in Helicobacter pylori, which
      persistently colonize the human stomach, to test the hypothesis that they have
      been ancient inhabitants of humans. Three H. pylori loci that previously have
      been shown to have phylogeographic affinity have been analyzed for two
      populations with different ethnic origins from Venezuela. In a group of
      Amerindian subjects from Amazonia, East Asian H. pylori genotypes were present
      for each of the loci examined but were absent in a mestizo population from
      Caracas. These findings provide evidence that H. pylori has been present in
      humans at least since ancestors of Amerindians migrated from Asia more than
      11,000 years ago.

PMID- 12417751
TI  - Shedding light on an underground problem.

PMID- 12417752
TI  - Uncoupling direct and indirect components of female choice in the wild.
AB  - One of the most controversial debates in evolutionary biology concerns the
      fitness consequences of female choice in nature. Discriminating females may
      benefit from high-quality territories and/or sires with high-quality genes. Here
      we experimentally dissociate female preferences for high-quality territories and
      male body size in a wild population of side-blotched lizards, Uta stansburiana.
      Females preferred experimentally improved territories but still chose high
      quality sires for their progeny. High-quality territories were associated with
      earlier egg-laying dates and larger eggs. These maternal effects, evidently
      stimulated by high-quality territories, have been shown to enhance competitive
      ability and therefore the likelihood that philopatric offspring will capitalize
      on the direct benefits of superior territories, previously shown to promote
      progeny growth rate and survival (most offspring do not disperse from their natal
      area). Paternity analysis within clutches co-sired by two males revealed that
      female preferences for large males were also adaptive in terms of indirect
      benefits. Females used sperm from large sires to produce sons and sperm from
      small sires to produce daughters. Differential allocation of resources and
      progeny sex was adaptive and demonstrates a high degree of female control in the
      mating system.

PMID- 12417753
TI  - Suppression of bone resorption by madindoline A, a novel nonpeptide antagonist to
      gp130.
AB  - IL-6 is a multifunctional cytokine involved in regulation of differentiation,
      antibody production, and growth of certain types of tumor cells. Its excessive
      production plays a major role in pathogenesis of multiple myeloma and
      postmenopausal osteoporosis. In the course of a screening program aimed at IL-6
      inhibitor from microbial products, we found madindoline A (MDL-A) and madindoline
      B, which have a fuloindoline structure with diketocyclopentene bound to the
      methyl group. MDL-A has no cytotoxic activities. It inhibited only activities of
      both IL-6 and IL-11 without affecting the IL-6-specific signal transduction
      cascade, JAK2/STAT3. In a dose-dependent manner [(3)H]MDL-A binds to gp130, which
      is a signal transducing 130-kDa glycoprotein, but formation of the trimeric
      complex IL-6/IL-6 receptor/gp130 was not inhibited, suggesting that MDL-A
      suppresses dimerization of trimeric complexes. Not only did MDL-A markedly
      inhibit IL-6- and IL-11-induced osteoclastogenesis in vitro, but it also
      inhibited IL-6-stimulated serum amyloid A production and bone resorption in an
      experimental model of postmenopausal osteoporosis in vivo by a different
      mechanism from that of 17beta-estradiol. Here we show that MDL-A has a highly
      selective inhibitory effect on IL-6 and IL-11 activities by inhibiting a gp130
      activity while suppressing bone loss in ovariectomized mice. MDL-A is anticipated
      as a lead compound for treatment of hormone-dependent postmenopausal
      osteoporosis, which has no serious side effects, and as a new mechanism of
      action, gp130 blocking.

PMID- 12417754
TI  - Shape perception reduces activity in human primary visual cortex.
AB  - Visual perception involves the grouping of individual elements into coherent
      patterns that reduce the descriptive complexity of a visual scene. The
      physiological basis of this perceptual simplification remains poorly understood.
      We used functional MRI to measure activity in a higher object processing area,
      the lateral occipital complex, and in primary visual cortex in response to visual
      elements that were either grouped into objects or randomly arranged. We observed
      significant activity increases in the lateral occipital complex and concurrent
      reductions of activity in primary visual cortex when elements formed coherent
      shapes, suggesting that activity in early visual areas is reduced as a result of
      grouping processes performed in higher areas. These findings are consistent with
      predictive coding models of vision that postulate that inferences of high-level
      areas are subtracted from incoming sensory information in lower areas through
      cortical feedback.

PMID- 12417755
TI  - Heme deficiency may be a factor in the mitochondrial and neuronal decay of aging.
AB  - Heme, a major functional form of iron in the cell, is synthesized in the
      mitochondria by ferrochelatase inserting ferrous iron into protoporphyrin IX.
      Heme deficiency was induced with N-methylprotoporphyrin IX, a selective inhibitor
      of ferrochelatase, in two human brain cell lines, SHSY5Y (neuroblastoma) and U373
      (astrocytoma), as well as in rat primary hippocampal neurons. Heme deficiency in
      brain cells decreases mitochondrial complex IV, activates nitric oxide synthase,
      alters amyloid precursor protein, and corrupts iron and zinc homeostasis. The
      metabolic consequences resulting from heme deficiency seem similar to
      dysfunctional neurons in patients with Alzheimer's disease. Heme-deficient SHSY5Y
      or U373 cells die when induced to differentiate or to proliferate, respectively.
      The role of heme in these observations could result from its interaction with
      heme regulatory motifs in specific proteins or secondary to the compromised
      mitochondria. Common causes of heme deficiency include aging, deficiency of iron
      and vitamin B6, and exposure to toxic metals such as aluminum. Iron and B6
      deficiencies are especially important because they are widespread, but they are
      also preventable with supplementation. Thus, heme deficiency or dysregulation may
      be an important and preventable component of the neurodegenerative process.

PMID- 12417756
TI  - The catalytic domain of RNase E shows inherent 3' to 5' directionality in
      cleavage site selection.
AB  - RNase E, a multifunctional endoribonuclease of Escherichia coli, attacks
      substrates at highly specific sites. By using synthetic oligoribonucleotides
      containing repeats of identical target sequences protected from cleavage by 2'-O
      methylated nucleotide substitutions at specific positions, we investigated how
      RNase E identifies its cleavage sites. We found that the RNase E catalytic domain
      (i.e., N-Rne) binds selectively to 5'-monophosphate RNA termini but has an
      inherent mode of cleavage in the 3' to 5' direction. Target sequences made
      uncleavable by the introduction of 2'-O-methyl-modified nucleotides bind to RNase
      E and impede cleavages at normally susceptible sites located 5' to, but not 3'
      to, the protected target. Our results indicate that RNase E can identify cleavage
      sites by a 3' to 5' "scanning" mechanism and imply that anchoring of the enzyme
      to the 5'-monophosphorylated end of these substrates orients the enzyme for
      directional cleavages that occur in a processive or quasiprocessive mode. In
      contrast, we find that RNase G, which has extensive structural homology with and
      size similarity to N-Rne, and can functionally complement RNase E gene deletions
      when overexpressed, has a nondirectional and distributive mode of action.

PMID- 12417757
TI  - Expression profiling of CD34+ hematopoietic stem/ progenitor cells reveals
      distinct subtypes of therapy-related acute myeloid leukemia.
AB  - One of the most serious consequences of cytotoxic cancer therapy is the
      development of therapy-related acute myeloid leukemia (t-AML), a neoplastic
      disorder arising from a multipotential hematopoietic stem cell. To gain insights
      into the molecular basis of this disease, we performed gene expression profiling
      of CD34(+) hematopoietic progenitor cells from t-AML patients. Our analysis
      revealed that there are distinct subtypes of t-AML that have a characteristic
      gene expression pattern. Common to each of the subgroups are gene expression
      patterns typical of arrested differentiation in early progenitor cells. Leukemias
      with a -5/del(5q) have a higher expression of genes involved in cell cycle
      control (CCNA2, CCNE2, CDC2), checkpoints (BUB1), or growth (MYC), and loss of
      expression of the gene encoding IFN consensus sequence-binding protein (ICSBP). A
      second subgroup of t-AML is characterized by down-regulation of transcription
      factors involved in early hematopoiesis (TAL1, GATA1, and EKLF) and
      overexpression of proteins involved in signaling pathways in myeloid cells (FLT3)
      and cell survival (BCL2). Establishing the molecular pathways involved in t-AML
      may facilitate the identification of selectively expressed genes that can be
      exploited for the development of urgently needed targeted therapies.

PMID- 12417758
TI  - Finding important sites in protein sequences.
AB  - By using sequence information from an aligned protein family, a procedure is
      exhibited for finding sites that may be functionally or structurally critical to
      the protein. Features based on sequence conservation within subfamilies in the
      alignment and associations between sites are used to select the sites. The sites
      are subject to statistical evaluation correcting for phylogenetic bias in the
      collection of sequences. This method is applied to two families: the
      phycobiliproteins, light-harvesting proteins in cyanobacteria, red algae, and
      cryptomonads, and the globins that function in oxygen storage and transport. The
      sites identified by the procedure are located in key structural positions and
      merit further experimental study.

PMID- 12417759
TI  - Conformational energetics of stable and metastable states formed by DNA triplet
      repeat oligonucleotides: implications for triplet expansion diseases.
AB  - We have embedded the hexameric triplet repeats (CAG)(6) and (CTG)(6) between two
      (GC)(3) domains to produce two 30-mer hairpins with the sequences
      d[(GC)(3)(CAG)(6)(GC)(3)] and d[(GC)(3)(CTG)(6)(GC)(3)]. This construct reduces
      the conformational space available to these repetitive DNA sequences. We find
      that the (CAG)(6) and (CTG)(6) repeats form stable, ordered, single-stranded
      structures. These structures are stabilized at 62 degrees C by an average
      enthalpy per base of 1.38 kcal.mol(-1) for the CAG triplet and 2.87 kcal.mol(-1)
      for the CTG triplet, while being entropically destabilized by 3.50 cal.K(-1).mol(
      1) for the CAG triplet and 7.6 cal.K(-1).mol(-1) for the CTG triplet. Remarkably,
      these values correspond, respectively, to 1/3 (for CAG) and 2/3 (for CTG) of the
      enthalpy and entropy per base values associated with Watson-Crick base pairs. We
      show that the presence of the loop structure kinetically inhibits duplex
      formation from the two complementary 30-mer hairpins, even though the duplex is
      the thermodynamically more stable state. Duplex formation, however, does occur at
      elevated temperatures. We propose that this thermally induced formation of a more
      stable duplex results from thermal disruption of the single-stranded order,
      thereby allowing the complementary domains to associate (perhaps via "kissing
      hairpins"). Our melting profiles show that, once duplex formation has occurred,
      the hairpin intermediate state cannot be reformed, consistent with our
      interpretation of kinetically trapped hairpin structures. The duplex formed by
      the two complementary oligonucleotides does not have any unusual optical or
      thermodynamic properties. By contrast, the very stable structures formed by the
      individual single-stranded triplet repeat sequences are thermally and
      thermodynamically unusual. We discuss this stable, triplet repeat, single
      stranded structure and its interconversion with duplex in terms of triplet
      expansion diseases.

PMID- 12417761
TI  - Explaining the Pleistocene megafaunal extinctions: models, chronologies, and
      assumptions.
AB  - Understanding of the Pleistocene megafaunal extinctions has been advanced
      recently by the application of simulation models and new developments in
      geochronological dating. Together these have been used to posit a rapid demise of
      megafauna due to over-hunting by invading humans. However, we demonstrate that
      the results of these extinction models are highly sensitive to implicit
      assumptions concerning the degree of prey naivety to human hunters. In addition,
      we show that in Greater Australia, where the extinctions occurred well before the
      end of the last Ice Age (unlike the North American situation), estimates of the
      duration of coexistence between humans and megafauna remain imprecise. Contrary
      to recent claims, the existing data do not prove the "blitzkrieg" model of
      overkill.

PMID- 12417760
TI  - Antiepileptic drugs and apoptotic neurodegeneration in the developing brain.
AB  - Epilepsy is the most common neurological disorder of young humans. Each year
      150,000 children in the United States experience their first seizure.
      Antiepileptic drugs (AEDs), used to treat seizures in children, infants, and
      pregnant women, cause cognitive impairment, microcephaly, and birth defects. The
      cause of unwanted effects of therapy with AEDs is unknown. Here we reveal that
      phenytoin, phenobarbital, diazepam, clonazepam, vigabatrin, and valproate cause
      apoptotic neurodegeneration in the developing rat brain at plasma concentrations
      relevant for seizure control in humans. Neuronal death is associated with reduced
      expression of neurotrophins and decreased concentrations of survival-promoting
      proteins in the brain. beta-Estradiol, which stimulates pathways that are
      activated by neurotrophins, ameliorates AED-induced apoptotic neurodegeneration.
      Our findings present one possible mechanism to explain cognitive impairment and
      reduced brain mass associated with prenatal or postnatal exposure of humans to
      antiepileptic therapy.

PMID- 12417762
TI  - Coordination of the two heads of myosin during muscle contraction.
AB  - We have used luminescence resonance energy transfer between regulatory light
      chains (RLC) to detect structural changes within the dimeric myosin molecule in
      contracting muscle fibers. Fully functional scallop muscle fibers were prepared
      such that each myosin molecule contained a terbium-labeled (luminescent donor)
      RLC on one head and a rhodamine-labeled (acceptor) RLC on the other. Time
      resolved luminescence energy transfer between the two heads increased upon the
      transition from relaxation (ATP) to contraction (ATP plus Ca) and increased
      further in rigor (no ATP). Combined with experiments on mutant RLCs labeled
      specifically at other sites, these results support a model in which the force
      generating weak-to-strong transition causes one myosin LC domain to tilt through
      a 30 degrees angle toward the other, thus acting as a coordinated lever arm.

PMID- 12417763
TI  - S-layer-streptavidin fusion proteins as template for nanopatterned molecular
      arrays.
AB  - Biomolecular self-assembly can be used as a powerful tool for nanoscale
      engineering. In this paper, we describe the development of building blocks for
      nanobiotechnology, which are based on the fusion of streptavidin to a crystalline
      bacterial cell surface layer (S-layer) protein with the inherent ability to self
      assemble into a monomolecular protein lattice. The fusion proteins and
      streptavidin were produced independently in Escherichia coli, isolated, and mixed
      to refold and purify heterotetramers of 1:3 stoichiometry. Self-assembled
      chimeric S-layers could be formed in suspension, on liposomes, on silicon wafers,
      and on accessory cell wall polymer containing cell wall fragments. The two
      dimensional protein crystals displayed streptavidin in defined repetitive
      spacing, and they were capable of binding d-biotin and biotinylated proteins.
      Therefore, the chimeric S-layer can be used as a self-assembling nanopatterned
      molecular affinity matrix to arrange biotinylated compounds on a surface. In
      addition, it has application potential as a functional coat of liposomes.

PMID- 12417764
TI  - Cytoskeletal-assisted dynamics of the mitochondrial reticulum in living cells.
AB  - Subcellular organelle dynamics are strongly influenced by interactions with
      cytoskeletal filaments and their associated motor proteins, and lead to complex
      multiexponential relaxations that occur over a wide range of spatial and temporal
      scales. Here we report spatio-temporal measurements of the fluctuations of the
      mitochondrial reticulum in osteosarcoma cells by using Fourier imaging
      correlation spectroscopy, over time and distance scales of 10(-2) to 10(3) s and
      0.5-2.5 microm. We show that the method allows a more complete description of
      mitochondrial dynamics, through the time- and length-scale-dependent collective
      diffusion coefficient D(k,tau), than available by other means. Addition of either
      nocodazole to disrupt microtubules or cytochalasin D to disassemble
      microfilaments simplifies the intermediate scattering function. When both drugs
      are used, the reticulum morphology of mitochondria is retained even though the
      cytoskeletal elements have been de-polymerized. The dynamics of the organelle are
      then primarily diffusive and can be modeled as a collection of friction points
      interconnected by elastic springs. This study quantitatively characterizes
      organelle dynamics in terms of collective cytoskeletal interactions in living
      cells.

PMID- 12417765
TI  - Motion perception of saccade-induced retinal translation.
AB  - Active visual perception relies on the ability to interpret correctly retinal
      motion signals induced either by moving objects viewed with static eyes or by
      stationary objects viewed with moving eyes. A motionless environment is not
      normally perceived as moving during saccadic eye movements. It is commonly
      believed that this phenomenon involves central oculomotor signals that inhibit
      intrasaccadic visual motion processing. The keystone of this extraretinal theory
      relies on experimental reports showing that physically stationary scenes
      displayed only during saccades, thus producing high retinal velocities, are never
      perceived as moving but appear as static blurred images. We, however, provide
      evidence that stimuli optimized for high-speed motion detection elicit clear
      motion perception against saccade direction, thus making the search for
      extraretinal suppression superfluous. The data indicate that visual motion is the
      main cue used by observers to perform the task independently of other perceptual
      factors covarying with intrasaccadic stimulation. By using stimuli of different
      durations, we show that the probability of perceiving the stimulus as static,
      rather than moving, increases when the intrasaccadic stimulation is preceded or
      followed by a significant extrasaccadic stimulation. We suggest that
      intrasaccadic motion perception is accomplished by motion-selective magnocellular
      neurons through temporal integration of rapidly increasing retinal velocities.
      The functional mechanism that usually prevents this intrasaccadic activity from
      being perceived seems to rely on temporal masking effects induced by the static
      retinal images present before and/or after the saccade.

PMID- 12417766
TI  - Distinct neural systems subserve person and object knowledge.
AB  - Studies using functional neuroimaging and patient populations have demonstrated
      that distinct brain regions subserve semantic knowledge for different classes of
      inanimate objects (e.g., tools, musical instruments, and houses). What this work
      has yet to consider, however, is how conceptual knowledge about people may be
      organized in the brain. In particular, is there a distinct functional
      neuroanatomy associated with person knowledge? By using event-related functional
      magnetic resonance imaging (fMRI), we measured neural activity while participants
      made semantic judgments about people or objects. A unique pattern of brain
      activity was associated with person judgments and included brain regions
      previously implicated in other aspects of social-cognitive functioning: medial
      prefrontal cortex, superior temporal cortex, intraparietal sulcus, and fusiform
      gyrus. These regions were generally marked by relatively little change from
      baseline brain activity for person judgments along with significant deactivations
      for object judgments. Together, these findings support the notion that person
      knowledge may be functionally dissociable from other classes of semantic
      knowledge within the brain.

PMID- 12417768
TI  - Role of transtympanic endoscopy of the middle ear in the diagnosis of
      perilymphatic fistula in patients with sensorineural hearing loss or vertigo.
AB  - BACKGROUND: The diagnosis of perilymphatic fistula (PLF) is often difficult, and
      therefore the condition can be overlooked. Tympanoscopy presents an alternative
      procedure for visualising the middle ear anatomy, and it may help to diagnose
      PLF. AIM: The aim of this study was to evaluate the use of middle ear endoscopy
      in establishing the diagnosis of PLF and in defining its incidence in patients
      with sensorineural hearing loss and/or vertigo and tinnitus. SUBJECTS AND
      METHODS: Two hundred and sixty-five patients (22-80 years of age, mean 48 years)
      were prospectively and consecutively referred for middle ear examination with
      tympanoscopy. Tympanoscopy was performed using endoscopes with visual angles of 5
      and 25 degrees and an outer diameter of 1.7 mm. The round window niche (with its
      secondary membrane), the oval window with a stapes superstructure, a part of the
      facial recess and the area in the fissula ante fenestram were examined and video
      recorded. RESULTS: For 1 patient, tympanoscopy revealed fistula in the round
      window membrane that was covered with a fibrinous layer. In 4 cases abnormal
      mucosal shining appeared in the round window, but no PLF was present. In 7 cases
      the tympanic cavity could not be visualised because of the adhesive tympanic
      membrane, abnormal anatomy or the prominent exostoses of the external ear canal.
      In 6 cases a postendoscopic middle ear infection was found. No permanent tympanic
      membrane perforation occurred in any of the patients in this study. CONCLUSIONS:
      Tympanoscopy is a rapid examination tool with which to verify certain areas of
      the middle ear anatomy, but it is of limited value for ruling out the presence of
      PLF.

PMID- 12417767
TI  - PsbS-dependent enhancement of feedback de-excitation protects photosystem II from
      photoinhibition.
AB  - Feedback de-excitation (qE) regulates light harvesting in plants to prevent
      inhibition of photosynthesis when light absorption exceeds photosynthetic
      capacity. Although the mechanism of qE is not completely understood, it is known
      to require a low thylakoid lumen pH, de-epoxidized xanthophylls, and the
      photosystem II protein PsbS. During a short-term 4-h exposure to excess light,
      three PsbS- and qE-deficient Arabidopsis thaliana mutants that differed in
      xanthophyll composition were more photoinhibited than the wild type. The extent
      of photoinhibition was the same in all of the mutants, suggesting that qE
      capacity rather than xanthophyll composition is critical for photoprotection in
      short-term high light, in contrast to longer-term high light conditions (days)
      when additional antioxidant roles of specific xanthophylls are evident. Plants
      with a 2-fold increase in qE capacity were generated by overexpression of PsbS,
      demonstrating that the level of PsbS limits the qE capacity in wild-type
      Arabidopsis. These results are consistent with the idea that variations in PsbS
      expression are responsible for species-specific and environmentally induced
      differences in qE capacity observed in nature. Furthermore, plants with higher qE
      capacity were more resistant to photoinhibition than the wild type. Increased qE
      was associated with decreased photosystem II excitation pressure and changes in
      the fractional areas of chlorophyll a fluorescence lifetime distributions, but
      not the lifetime centers, suggesting that qE protects from photoinhibition by
      preventing overreduction of photosystem II electron acceptors. Engineering of qE
      capacity by PsbS overexpression could potentially yield crop plants that are more
      resistant to environmental stress.

PMID- 12417769
TI  - Functional results in stapedotomy with and without CO(2) laser.
AB  - The authors have studied the use of the CO(2) laser in performing primary
      stapedotomy in 451 patients affected by otosclerosis, operated between 1996 and
      2000. Footplate perforation was practised with a traditional method, by means of
      a microdrill, in 169 subjects. A CO(2) laser was instead used in other 282 cases;
      the authors effected the platinotomy with a single spot, repeated if necessary,
      with the diameter adjusted to the caliber of the prosthesis. This procedure
      allowed a smooth-edged perforation to be obtained. In the 282 laser-operated
      patients, there was a significantly higher proportion having closure of the
      cochlear reserve within 10 dB than that found in the cases where the microdrill
      was used. Moreover, no postoperative anacusia or severe vertigo were recorded;
      this confirms the safety of the CO(2) laser as regards the inner ear. The
      functional results, therefore, document the validity of the exposed technique.

PMID- 12417770
TI  - Long-term results of a new stapedotomy prosthesis.
AB  - The long-term results of a new, home-made stapedotomy prosthesis are presented.
      The innovations of this prosthesis concern both portions, design for attachment
      to the incus and shaft. Our series include a total number of 42 individuals with
      stapes fixation, operated using the new prosthesis, with a medical follow-up
      period between eighteen months and five years. Our innovations offer a proper and
      safe insertion of the prosthesis into the oval window associated with excellent
      manipulation and handling. These advantages could be of major importance for
      younger surgeons and trainees. Postoperative hearing results are similar to those
      achieved with other commercially available pistons.

PMID- 12417771
TI  - Cochlear dysfunction in patients with mitochondrial myopathy.
AB  - The present study investigates cochlear function in a group of 11 patients
      suffering from mitochondrial myopathy with normal or near normal audiometric pure
      tone thresholds, in most of whom diagnosis was histologically confirmed. A
      complete ENT, neurologic and audiological work-up, including transiently evoked
      otoacoustic emissions, was performed in all patients in order to estimate
      cochlear function. Compared to control subjects, most patients had absent
      otoacoustic emissions (OAE) in spite of normal hearing, indicating cochlear
      dysfunction. These findings suggest that subclinical involvement of the cochlea
      is quite common in patients with mitochondrial myopathy. Damage of the cochlea
      can be explained on the grounds of its increased metabolic rate, resulting in
      failure of the stria vascularis and the outer hair cells. Otoacoustic emissions
      might provide a useful tool in the clinical work-up and follow-up of these
      patients.

PMID- 12417772
TI  - Prelingual nonsyndromic hearing loss in Greece. Molecular and clinical findings.
AB  - Mutations in the gene encoding the gap-junction protein connexin 26 (GJB2) on
      chromosome 13q11 have been shown as a major contributor to prelingual,
      sensorineural, nonsyndromic deafness. One specific mutation, 35delG, has
      accounted for the majority of the mutations detected in the GJB2 gene in
      Caucasian populations and is one of the most frequent disease mutations
      identified so far with highest carrier frequency of 3,5% in the Greek population.
      In a collaboration with the major referral centers for childhood deafness in
      Greece, patients were examined by an extensive questionnaire to exclude syndromic
      forms and environmental causes of deafness and by allele-specific PCR for the
      detection of the 35delG mutation. The 35delG mutation was found in 32.1% of the
      alleles in 173 unrelated cases of prelingual deafness: 50 homozygotes and 11
      heterozygotes. Individuals heterozygous for the 35delG mutation were further
      analyzed by direct genomic sequencing of the coding region of the GJB2 gene,
      which revealed R184P and 486insT mutations in single alleles. We conclude that
      the 35delG GJB2 mutation is responsible for one third of prelingual,
      sensorineural deafness in Greece, which is higher than the usually quoted 20% for
      Caucasian populations.

PMID- 12417773
TI  - Expression of gap junction proteins (connexin 26, 30, 32, 43) in normal mucosa,
      hyperkeratosis and carcinoma of the human larynx.
AB  - INTRODUCTION: Gap junction proteins (connexins = Cx) form transmembrane channels
      and mediate the transfer of small molecules and ions between the cytoplasm of
      adjacent cells. Most tissues express several Cx isoforms. The precise combination
      might play an important role in the maintenance of cell differentiation. Human
      carcinogenesis is accompanied by aberrant expression and function of Cx. While
      the larynx is a target organ for many tumor promoters, no data on Cx expression
      in laryngeal mucosa are available. The goal of the study was to observe the
      expression of different Cx (Cx26, -30, -32 and -43) in the normal mucosa,
      hyperkeratoses and carcinomas of the human larynx. METHOD: The immunofluorescence
      method was performed in normal (n = 7) and dysplastic (n = 6) laryngeal mucosa
      and in squamous cell carcinoma (n = 7) using affinity-purified polyclonal rabbit
      antibodies against the 4 Cx isoforms and FITC-conjugated secondary antibodies.
      RESULTS: The immunofluorescence staining of the normal human vocal fold's
      epithelium showed the expression of Cx26 and Cx30 in the parabasal and
      intermediate layers, whereas Cx43 was localized in the basal, parabasal and lower
      intermediate layers. Cx epitopes could not be found in the upper layers. The
      precanceroses showed a similar expression of the Cx compared to normal laryngeal
      epithelium. Due to the higher degree of staining observed in dysplastic
      specimens, a hyperexpression of Cx26, -30 and -43 could be assumed. The squamous
      cell carcinomas were characterized by inhomogeneous staining for Cx26, -30 and 
      43. Regions of intensive expression alternated with regions of no expression.
      Cx32 could not be observed by immunofluorescence staining in laryngeal tissue.
      CONCLUSION: In immunohistochemical terms, there was no alteration of the
      expression of Cx isoforms during carcinogenesis in the laryngeal epithelium.
      These results do not exclude a loss of functional intercellular gap junction
      communication by posttranslational modifications of Cx isoforms or disturbed Cx
      integration into the gap junction channel. Further studies should investigate
      potential defective gap junctional intercellular communication in cancer cells
      based on molecular studies.

PMID- 12417774
TI  - Neuronal nitric oxide synthase-immunoreactivity. A neuromodulating system
      independent of peripheral nasal gland denervation in guinea pig nasal mucosal
      tissue after treatment with botulinum toxin type A.
AB  - The influence of botulinum toxin type A (BTA) on cellular mechanisms has not been
      studied in much detail. Since nitric oxide (NO) is of increasing interest as a
      neuromodulator in the innervation of the nose, its localization was examined in
      the nasal mucosa of guinea pigs treated with BTA or saline. Neuronal nitric oxide
      synthase-immunoreactivity (nNOS-IR) was found around vessels and nasal glands.
      Immunoreactivity was seen in the respiratory epithelium, in the periost and the
      osteocytes of the turbinate bone. A distinct interindividual difference in the
      strength of nNOS-IR was obvious among the animals, but there was no difference in
      the strength of immunoreactivity between the animals treated with BTA or saline.
      NO might therefore contribute to the regulation of vascular tone, glandular
      function, respiratory epithelial cell function and bone metabolism. BTA does not
      seem to influence the processes regulated and modulated by NO. This may represent
      a benefit for the application of BTA.

PMID- 12417775
TI  - Clinicocytological correlation in establishing the aetiology of chronic rhinitis.
AB  - Two hundred patients clinically diagnosed as having chronic rhinitis were
      provisionally grouped into allergic and non-allergic types of rhinitis on the
      basis of history, clinical examination, X-ray of the paranasal sinuses using the
      occipitomental view and other relevant investigations like differential and total
      leucocyte count. Whereas 158 cases were categorized into allergic rhinitis, 13
      were diagnosed as suffering from vasomotor rhinitis, 25 from infective rhinitis
      and 4 patients from atrophic rhinitis. A nasal cytogram performed in all these
      cases showed allergic rhinitis in 107 cases, vasomotor rhinitis in 30 cases,
      infective on top of allergic rhinitis in 32 cases, common cold over allergic
      rhinitis in 3 cases, infective rhinitis in 20 cases, a non-infective non-allergic
      type in 4 cases and atrophic rhinitis in 4 cases. There was a good
      clinicocytological correlation; however, 30 patients clinically suspected to be
      having allergic rhinitis had an infective episode alone or on top of allergic
      rhinitis. Nasal cytology was thus found useful in modifying the treatment. It is
      a simple, easy and reliable investigation that can be done routinely in the out
      patient department.

PMID- 12417776
TI  - Postoperative pain in tonsillectomy: comparison of ultrasonic tonsillectomy
      versus blunt dissection tonsillectomy.
AB  - Intraoperative blood loss, postoperative pain, and postoperative appetite were
      compared between 15 adult patients who underwent tonsillectomy using an
      ultrasonically activated scalpel (UT) and 15 adult patients who underwent blunt
      dissection tonsillectomy with cold steel instruments (BT). The average
      intraoperative blood loss of the UT group was 4.6 +/- 1.9 ml (mean +/- standard
      deviation), while that of BT group was 41.9 +/- 12.9 ml. This difference was
      highly statistically significant (p < 0.0001). In contrast, there were no
      significant differences in the VAS pain and appetite scores between patients who
      underwent UT and those who underwent BT on any day in the 6-day postoperative
      period. Our current results show that UT is a safe technique, and we believe that
      it should be considered a useful alternative for tonsil surgery.

PMID- 12417777
TI  - Severe hearing loss in Pallister-Killian syndrome.
AB  - Pallister-Killian syndrome is a rare disorder characterised by a specific
      combination of anatomic anomalies, mental retardation and lack of speech
      acquisition due to tetrasomy 12p. Hearing loss does not seem to be characteristic
      for this syndrome, although it was reported in several cases. We present the case
      of a girl first seen in our department at the age of 6 months. A severe sensory
      hearing loss was confirmed by subjective and objective audiometry. The child was
      successfully equipped with hearing aids. In the literature almost all children
      with Pallister-Killian syndrome are described as not developing verbal speech.
      Surprisingly their hearing abilities were not examined systematically. We advise
      audiological testing of children with Pallister-Killian syndrome.

PMID- 12417778
TI  - Recovery of vestibular-evoked myogenic potential: relationship to other neural
      disorders in two patients with acute sensorineural hearing loss.
AB  - We report the recovery of the inferior vestibular neural system disorder by
      monitoring the vestibular-evoked myogenic potential (VEMP) in two patients
      suffering from acute sensorineural hearing loss with vertigo. Patients presented
      absent VEMP, canal paresis, and severe hearing disorder. After 10 months, the
      function of the inferior vestibular neural system was recovered in both cases
      while that of the superior vestibular neural system was recovered in one case and
      partially recovered in the other. In addition, the hearing sensitivity was only
      partially recovered in both cases. The recovery of the inferior vestibular neural
      system was confirmed by our current results. These results suggested that time
      course of recoveries of the superior and inferior vestibular neural systems, and
      of the cochlear neural system, were somewhat different in the two cases.

PMID- 12417779
TI  - Inner ear dysplasia in sporadic lacrimo-auriculo-dento-digital syndrome. A case
      report and review of the literature.
AB  - The lacrimo-auriculo-dento-digital (LADD) syndrome is a rare inherited disorder
      affecting the lacrimal, auricular, salivary, and osseous system. Only very
      limited data on LADD associated petrous bone lesions are available up to now. We
      describe a young girl suffering from the LADD syndrome with sensorineural hearing
      loss and inner ear dysplasia. This case suggests, that inner ear dysplasia might
      be a more common feature of the LADD syndrome than has been assumed so far.

PMID- 12417780
TI  - Immediate facial nerve palsy following stapedectomy.
AB  - Iatrogenic facial nerve palsy following stapedectomy is a rare but devastating
      complication. The authors describe a case of a 20-year-old man who presented for
      legal advice concerning an immediate facial nerve palsy following a left
      stapedectomy. The incidence, management and prognosis of such injuries are
      discussed.

PMID- 12417781
TI  - Ultrastructural morphology of a middle ear ceruminoma.
AB  - The ultrastructural morphology of a ceruminous gland adenoma in the middle ear
      was examined electron microscopically. The epithelial tumor cells displayed
      apocrine caps, microvilli, cell junctions, secretory granules, vacuoles, lipid
      droplets and siderosomes, which are the characteristic ultrastructural features
      of apocrine glands. Concentric membranous bodies of the endoplasmic reticulum,
      phagocytic activity of the tumor cells, intracytoplasmic lumina, ciliated cells
      and also spiny collagen in the tumor stroma could be seen. The myoepithelial
      cells are an important tumor marker in the differential diagnosis between
      ceruminomas and adenomas of the middle ear. The ectopic origin in the modified
      apocrine ceruminous glands, the specific localization, the clinical features and
      the extremely rare occurrence of the ceruminoma makes this tumor a unique
      neoplastic entity.

PMID- 12417782
TI  - A rare case of metastases to the maxillary sinus from sigmoid colon
      adenocarcinoma.
AB  - Metastases of malignant tumors to the nasal cavity and paranasal sinuses are
      rare. A review of the world's literature reports only four cases of antral
      metastases from carcinoma of gastrointestinal tract. We present a case of a
      stenosing adenocarcinoma of the sigmoid colon with metastases within the
      maxillary sinus. The ENT physical examination revealed a mass involving the right
      alveolar ridge, the right hard palate. CT scan of the head and the neck showed a
      large and irregular mass involving the right maxillary sinus, the infratemporal
      fossa and the pterygoid muscles with resorption of the bone of the posterior
      portion of the right alveolar ridge and of the posterior wall of the right
      maxillary sinus. The neoplastic tissue showed marked positivity for CEA and
      expressed cytokeratin 20, confirming the diagnosis of metastases to the maxillary
      sinus from colorectal adenocarcinoma. When a differential diagnosis between a
      second primary tumor of the maxillary sinus and a metastasis has to be carried
      out, the gastrointestinal tract should be taken into account and detailed
      immunohistochemical should be performed.

PMID- 12417783
TI  - Manometric abnormality in dysphagic patients after medullary cerebrovascular
      accidents.
AB  - We investigated the pharyngeal swallowing function using videomanofluorometry
      (VMF) in patients after medullary cerebrovascular accidents. Upper esophageal
      sphincter pressure, which should drop when a bolus arrives at the hypopharynx,
      increased at the same time as the elevation of oropharyngeal and hypopharyngeal
      pressures. A reduction of oropharyngeal and hypopharyngeal swallowing pressures
      was also observed. Our results suggest that a misprogrammed excitatory output
      from the central pattern generators of the brain stem would cause an abnormal
      pressure-traveling pattern of pharyngeal swallowing. VMF was useful to assess the
      pharyngeal swallowing function and to determine the indications for
      cricopharyngeal myotomy for patients after medullary cerebrovascular accidents.

PMID- 12417784
TI  - Plasmacytoma of the cricoid cartilage with airway mass effect.
AB  - Although multiple myeloma is a common plasma cell dyscrasia, the deposition and
      organization of these malignant cells in the cricoid cartilage is rare. We report
      a case of plasmacytoma of the cricoid cartilage and secondary airway obstruction.
      This important report emphasizes the potential difficulty in diagnosing this
      condition, consequences of advanced disease, and the importance of combining
      laryngofissure biopsy and detailed imaging modalities to confirm the diagnosis
      and guide treatment.

PMID- 12417785
TI  - Prediction of response to hormonal treatment in metastatic breast cancer.
AB  - Prediction of outcome and individualization of therapeutic strategies are
      challenging problems in oncology. Predictive parameters for response to hormonal
      treatment include the expression of hormone receptor, the extent and location of
      metastatic spread, disease-free interval, patient age, response to prior hormonal
      therapy, grading, and more recently, some molecular markers like the expression
      of HER-2/neu. The use of conventional statistics for prediction of response to
      hormonal treatment is limited by non-linearities and complex interactions between
      predictive factors. Modern computational mathematical models like artificial
      neural networks, entropy-based inductive algorithms or chi(2) interaction
      detection algorithms can describe these interactions and generate classification
      models and decision structures. They can be used to predict the clinical outcome
      for individual patients. In contrast to conventional methods, the level of
      confidence for the predictions can reach 90% and more. This might be an important
      step towards further individualization of therapeutic strategies.

PMID- 12417786
TI  - The role of the IGF system in cancer: from basic to clinical studies and clinical
      applications.
AB  - Insulin-like growth factors (IGFs) are important mediators of growth,
      development, and survival, are synthesized by almost any tissue in the body, and
      their action is modulated by a complex network of molecules, including binding
      proteins, proteases and receptors, which all comprise the IGF system. Evidence
      from in vitro and animal studies suggests that overexpression of IGFs by cancer
      cells and/or the nearby stroma as well as the type IGF-I receptor by the cancer
      cells may play a significant role in establishing a transformed phenotype in an
      increasing number of malignancies. More specifically, IGFs may promote cell cycle
      progression and inhibition of apoptosis either by directly associating with other
      growth factors or indirectly by interacting with other molecular systems which
      have an established role in carcinogenesis and cancer promotion, such as the
      steroid hormones and integrins. In addition, a growing number of epidemiologic
      studies suggest that increased serum levels of IGFs and/or altered levels of
      their binding proteins are associated with increased risk for developing several
      malignancies. These data indicate that IGF dysregulation should now be considered
      as an important independent factor for cancer risk, and a potential target for
      novel antineoplastic therapies and/or preventative strategies in high-risk
      groups.

PMID- 12417787
TI  - Docetaxel in combination with dacarbazine in patients with advanced melanoma.
AB  - OBJECTIVES: The number of agents that are active in patients with metastatic
      melanoma is limited and cure is not a realistic objective for treatment at this
      stage. The aim of the study was to evaluate the efficacy and safety of new
      combination regimen cosisting of docetaxel and dacarbazine (DTIC), as first-line
      chemotherapy, in patients with advanced melanoma. PATIENTS AND METHODS: Patients
      with advanced melanoma (including cerebral metastases) were eligible. Docetaxel
      80 mg/m(2), i.v. over 1 h infusion on day 1, and DTIC 400 mg/m(2), i.v. over 45
      min on days 1 and 2, were given every 21 days, for six cycles. All patients were
      premedicated, prior to each course, with methylprednisolone per os. RESULTS:
      Forty-one patients entered the study. Thirty-nine were assessable for response
      and 40 for toxicity. Objective responses were seen in 10 patients (24% of the
      eligible; 95% CI = 12.4-40.3%, 26% of the assessable and 28% of patients with
      cerebral metastases were excluded). Three of them achieved a complete response
      (7%; 95% CI = 1.5-19.9) and 7 a partial response (17%; 95% CI = 7.1-32.0), while
      8 patients demonstrated stabilization of their disease (20%; 95% CI = 8.8-34.9).
      After a median follow-up of 20 months, the median time to progression was 7
      months (range 0.5-22) and the median survival was 10 months (1-24+). The main
      toxicity (G3-4) was neutropenia which occurred in 8/40 (20%) patients. Additional
      patients had reversible G3-4 toxicities including alopecia, nausea and vomiting
      and fatigue; 3 of them presented mild to moderate hypersensitivity reactions to
      docetaxel. No toxic death was noted. CONCLUSIONS: The combination of docetaxel
      and DTIC is active and well tolerated in patients with advanced melanoma. While
      this combination is at least as effective as various combination regimens, it
      does not differ from that reported for single-agent DTIC.

PMID- 12417788
TI  - Multidisciplinary approach in advanced cancer of the oral cavity: outcome with
      neoadjuvant chemotherapy according to intention-to-treat local therapy. A phase
      II study.
AB  - OBJECTIVES: To determine outcomes in local-regional control and overall survival
      in patients with squamous locally advanced cancer of the oral cavity, based on
      intention-to-treat with neoadjuvant chemotherapy followed by surgery or radiation
      therapy. METHODS: Two hundred and four out of 1,089 patients analyzed met the
      defined criteria. All had squamous cell carcinomas of the oral cavity in stage
      III or in nonmetastatic stage IV and were selected for surgery or radiation
      therapy (if located in the tonsils or in the base of the tongue). Chemotherapy
      was based on cisplatin 120 mg/m(2) i.v. day 1 plus bleomycin 20 mg/m(2) days 1-5
      in continuous i.v. perfusion or plus 5-fluorouracil 1,000 mg/m(2) days 1-5 in
      continuous i.v. perfusion. A total of 418 cycles were given to 204 patients (mean
      2.049 per patient). Definitive surgery (n = 73; plus adjuvant radiation therapy)
      or definitive radiation therapy (n = 131) was performed. RESULTS: One hundred
      thirty-five out of 204 (66%) patients were chemotherapy responders, 16% complete
      and 50% partial. One hundred ninety-four patients (95%) completed 2 courses of
      chemotherapy. After neoadjuvant chemotherapy, 34 out of 46 patients considered
      inoperable initially (74%) obtained a disease-free status with surgery. Eighty
      three percent of surgical patients obtained a disease-free status (initial tumor
      control) versus 72% of radiation therapy patients. Disease-free survival rates at
      5 years were 26 and 22%, respectively. A better prognosis was observed in stage
      III over IV (p = 0.02); primary tumor in the retromolar trigone, palate or buccal
      mucosa over tongue, tonsil or floor of the mouth (p = 0.0085); negative cervical
      nodes over positive (p = 0.0186); responders to chemotherapy over nonresponders
      (p = 0.0003); and adjuvant postsurgical radiation therapy (p = 0.0013). Causes of
      death were relapses in local area (86%), regional nodes (10.5%) or distant
      metastases (3.5%). Eleven patients (5%) died of a second primary. The main toxic
      effects were vomiting in 9% of patients and hemolytic-uremic syndrome in 3% of
      the patients treated with bleomycin. CONCLUSIONS: In locally advanced squamous
      cell carcinoma of the oral cavity, neoadjuvant chemotherapy induces a high
      response rate that may facilitate definitive surgery or radiotherapy. In this
      study, patients have an acceptable long-term survival.

PMID- 12417789
TI  - Human pharmacokinetic study of heated intraperitoneal oxaliplatin in increasingly
      hypotonic solutions after complete resection of peritoneal carcinomatosis.
AB  - PURPOSE: We studied the pharmacokinetics of heated intraoperative intraperitoneal
      (i.p.) oxaliplatin (LOHP) solution and its safety profile in increasingly
      hypotonic solutions. This is the first clinical study of i.p. chemohyperthermia
      with hypotonic solutions. METHODS: Patients with peritoneal carcinomatosis (PC)
      underwent complete cytoreductive surgery followed by intraoperative i.p.
      chemohyperthermia (IPCH) with successive dextrose solutions of 300, 200, 150 and
      100 mosm/l. LOHP (460 mg/m(2)) was administered in 2 liters of solution/m(2) at
      an i.p. temperature of 42-44 degrees C for 30 min. IPCH was performed using an
      open procedure (skin pulled upwards) with a continuous closed circuit. Patients
      received intravenous leucovorin (20 mg/m(2)) and 5-fluorouracil (400 mg/m(2))
      just before IPCH to maximize the effect of LOHP. i.p. plasma and tissue samples
      were analyzed by means of atomic absorption spectrophotometry. Sixteen
      consecutive patients with PC of either gastrointestinal or peritoneal origin were
      treated. The safety of the procedure was studied. RESULTS: Pharmacokinetics: The
      mean duration of the entire procedure was 7.7 +/- 2.6 h. Half the LOHP dose was
      absorbed within 30 min at all dose levels. Absorption was not higher with
      hypotonic solutions than with isotonic solutions. The area under the curve of
      LOHP in plasma did not increase with decreasing osmolarity of the i.p. solutions.
      Intratumoral LOHP penetration was high; it was similar to that at the peritoneal
      surface, and about 18 times higher than that in nonbathed tissues. LOHP
      penetration was not significantly increased by using hypotonic solutions. SAFETY:
      There was a very high incidence of unexplained postoperative peritoneal bleeding
      (50%) and unusually severe thrombocytopenia in the 150 and 100 mosm/l groups.
      CONCLUSION: Contrary to experimental studies, this clinical study showed no
      increase in tumoral or systemic penetration of LOHP with i.p. hypotonic solutions
      (200, 150 or 100 mosm/l) during IPCH. A high incidence of i.p. hemorrhage and
      thrombocytopenia was observed.

PMID- 12417790
TI  - Combined evaluation of expressions of p53 and p21 proteins as prognostic factors
      for patients with gastric carcinoma.
AB  - BACKGROUND: The tumor suppressor gene p53 is a nuclear protein which plays a key
      role in tumor progression by regulating DNA repair, cell division and apoptosis.
      One major function of wild-type p53 is to control the onset of DNA replication at
      the G1-S boundary by inducing p21 protein, which promotes cell cycle arrest by
      inhibiting the phosphorylation of the cyclin-dependent kinases' complexes and
      blocking cell cycle progression to the S-phase. METHODS: 195 human gastric cancer
      specimens were prepared for immunohistochemical staining, using antibodies
      against p53 and p21. Clinicopathological factors and the clinical prognosis were
      examined for each indicator. RESULTS: Of those 195, positive rates of p53 and p21
      were 37.9% (74/195) and 42.6% (83/195), respectively. p53-negative patients had a
      better 5-year survival rate compared with positive ones (p < 0.05), and p21
      positive cases had better 5-year survival rate compared with negative ones (p <
      0.05). Four separate groups were prepared, based on expressions of p53 and p21,
      and the prognoses were compared. The incidence of the p53(-)/p21(+) group was
      27.2% (53/195 cases) and that of the p53(-)/p21(-), p53(+)/p21(-) and
      p53(+)/p21(+) groups was totally 72.8% (142/195 cases). The 5-year survival time
      of the former group was 67.5% and was significantly longer than the combined 5
      year survival time of the latter groups of 45.9% (p < 0.05). CONCLUSIONS: The
      incidence in cases where functions of either or both of p53 and p21 proteins were
      diminished exceeded 70% of all the cases. The survival time for the p53(-)/p21(+)
      group with proper functions of both proteins and the signal pathway was
      significantly longer. The combined evaluation of expressions of p53 and p21
      proteins in gastric cancer tissues aids in predicting the clinical prognosis for
      surgically treated gastric cancer patients.

PMID- 12417791
TI  - Pathological features of betel quid-related oral epithelial lesions in taiwan
      with special emphasis on the tumor progression and human papillomavirus
      association.
AB  - Betel quid (BQ) chewing has been a well-documented cause of oral epithelial
      lesions (OEL). Evolution from early hyperplastic lesions to the late or
      carcinomatous stage has been recognized. The pathobiological and molecular
      mechanism, however, remains to be elucidated. In this study, a total of 232
      samples obtained from 153 cases of BQ-related OEL were retrospectively evaluated
      for the expression of p53 and bcl-2 in comparison with 26 cases of BQ-unrelated
      lesions (n = 29). The possible role of human papillomavirus (HPV) was also
      investigated. These BQ-related OELs included verrucous hyperplasia (VIH, n = 57,
      24.6%), epithelial dysplasia (n = 23, 9.9%), verrucous carcinoma (VC, n = 5,
      2.1%) and squamous cell carcinoma (SCC, n = 106, 45.7%). Fifty-four cases (35.3%)
      had multiple lesions. In comparison with the BQ-unrelated OELs, the
      characteristics of BQ-related OELs were a younger age, male predilection and
      multicentricity. In contrast to the tongue in BQ-unrelated OELs, the most common
      site for all types of BQ-related lesions was the buccal mucosa.
      Immunohistochemical studies of BQ-related lesions showed p53 staining in 30% of
      dysplasia and 38% of SCC, but a consistent absence in VH and VC. The cases with
      p53-positive SCC had a higher recurrence rate than p53-negative ones. Bcl-2
      expression was negligible for all types of lesions. HPV-6/11 was detectable in
      10% of dysplasia and 13% of SCC, but in neither VH nor VC. HPV-16/18, however,
      was consistently negative for all types of lesions. Our data suggest that p53,
      but not bcl-2, may play a role in tumor progression of BQ-related OELs, and that
      VH and VC are distinct and closely related histological lesions. The consistent
      absence of the malignant-type HPV in all BQ-related lesions suggests that HPV
      plays an insignificant role in the tumorigenesis of BQ-related oral cancers,
      although a cooperative role may exist between the benign-type HPV and BQ chewing.

PMID- 12417792
TI  - Postoperative hyperprolactinemia could predict longer disease-free and overall
      survival in node-negative breast cancer patients.
AB  - OBJECTIVES: Breast manipulation determines a physiological increase in prolactin
      (PRL) blood levels, but the clinical and biological impact of surgery-induced
      changes in PRL secretion still has to be clarified. The postoperative
      hyperprolactinemia has been related to aggressiveness of the tumor, early disease
      relapse or metastases, and poor overall survival in node-negative breast cancer
      patients. Surgery-induced hyperprolactinemia may be associated with a longer
      disease-free survival in both patients with or without node involvement. METHODS:
      One hundred twenty-seven consecutive node-negative breast cancer patients, who
      were hospitalized from June 1985 to September 1990, were included in this study.
      The median follow-up was 12 years. To evaluate PRL secretion, venous blood
      samples were obtained at day 7th after surgery. In order to exclude the influence
      of stress and gonadal status, GH and estradiol serum levels were measured in the
      same blood samples. All endocrine examination were made during the morning,
      starting at 8.00 a.m. after overnight fasting. Hormonal serum levels were
      determined by the double antibody radioimmunoassay method. RESULTS:
      Hyperprolactinemia was significantly more frequent in women younger than 50 years
      compared with the older ones, while the premenopausal status and T1 stage showed
      only a borderline significant association with hyperprolactinemia. Patients with
      normal postsurgical prolactinemia had 5- and 10-year disease-free survival rates
      of 64 and 56%, respectively, and 5- and 10-year overall survival rates of 84 and
      70%, respectively. Patients with postsurgical hyperprolactinemia had 5- and 10
      year disease-free survival rates of 89 and 81%, respectively, and 5- and 10-year
      overall survival rates of 94 and 81%, respectively. The difference in overall
      survival between the hyperprolactinemic and the normoprolactinemic groups,
      assessed by the log-rank test, was statistically significant (p = 0.02), and the
      difference in disease-free survival was highly significant (p = 0.0008).
      CONCLUSIONS: Our study shows that postsurgical hyperprolactinemia is associated
      with a significantly lower recurrence rate and longer disease-free and overall
      survival in operable node-negative breast cancer patients. Our data suggest that
      postoperative hyperprolactinemia could be crucial in the development of
      recurrence in operable breast cancer. Looking at results, the recurrence rate of
      node-negative patients who did not show postoperative hyperprolactinemia would
      be, in theory, similar to that of patients with node-positive disease, suggesting
      that normal postoperative PRL levels could identify a group of node-negative
      patients at high risk for recurrence.

PMID- 12417793
TI  - Clinicopathological significance of human macrophage metalloelastase expression
      in esophageal squamous cell carcinoma.
AB  - OBJECTIVE: Human macrophage metalloelastase is referred to as matrix
      metalloproteinase (MMP-12), its function in tumors is contradictory. The current
      study was undertaken to investigate the role of MMP-12 in esophageal squamous
      cell carcinoma (SCC). PATIENTS AND METHODS: We analyzed the levels of MMP-12 mRNA
      expression in 67 patients with primary esophageal SCC by Northern blot analysis
      and the tissues were subjected to in situ hybridization analysis for MMP-12.
      Immunohistochemical staining was performed to detect the macrophages infiltrated
      in esophageal SCCs. RESULTS: MMP-12 mRNA was detected in 27 of 67 esophageal SCC
      samples by Northern blot analysis. In situ hybridization and immunohistochemical
      staining revealed that MMP-12 mRNA signals are located mainly in tumor cells. The
      frequency of lymph node metastasis was significantly higher in the MMP-12
      positive (MMP-12(+)) subgroup than MMP-12-negative (MMP-12(-)) subgroup (p <
      0.05); furthermore, invasion was significantly deeper in the MMP- 12(+) subgroup
      than in the MMP-12(-) subgroup (p < 0.01). MMP-12 mRNA was inversely correlated
      with prognosis (p < 0.05). However, Cox multivariate analysis revealed that
      upregulation of MMP-12 was not related to prognosis. CONCLUSIONS: MMP-12 gene
      expression was associated with the progression of esophageal SCC; however, it was
      not an independent prognostic factor.

PMID- 12417794
TI  - Investigations for fine mapping of amplifications in chromosome 3q26.3-28
      frequently occurring in squamous cell carcinomas of the head and neck.
AB  - OBJECTIVE: Overrepresentations of chromosomal material on the long arm of
      chromosome 3 frequently occur in squamous cell carcinoma of the head and neck.
      This experimental study was conducted for further fine mapping of these
      overrepresentations by interphase fluorescence in situ hybridization (FISH) of
      tumor cells in cell lines. METHODS: Seven cell lines derived from squamous cell
      carcinomas of the head and neck were investigated by comparative genomic
      hybridization to analyze unbalanced chromosomal aberrations. Overrepresentations
      of chromosomal material on the telomeric part of the long arm of chromosome 3
      were further analyzed by interphase FISH using YAC contig clones. RESULTS:
      Chromosomal aberrations which frequently occurred were overrepresentations on 5p
      (n = 4), 7p (n = 5), 11q13 (n = 3), 15q (n = 5), 17q (n = 3), 19q (n = 2), 20q (n
      = 2) and 22q (n = 3). Reoccurring losses of chromosomal material were found in 3p
      (n = 3), 7q (n = 2), 18q (n = 3) and 19p (n = 2). Gains of chromosomal material
      on chromosome 3q were found in 4 out of 7 cell lines, with a high copy number of
      amplifications occurring in the chromosomal region of 3q26.3-28. Further
      experiments revealed a physical mapping of this amplification to a narrow band of
      13.8 Mbp on chromosome 3q, whose amplification borders were represented by the
      YAC clones 754_f_3 centomeric and 955_b_2 telomeric. CONCLUSIONS: By FISH, the
      amplification of chromosomal material on 3q could be fine mapped on a narrow band
      on 3q26.3-27. This aberration can be considered as a breakpoint in tumorigenesis.
      Putative candidate oncogenes and tumor suppressor genes located in this region
      might be a target for mutations leading to tumor progression.

PMID- 12417795
TI  - Heterogeneity of O(6)-alkylguanine-DNA alkyltransferase activity in colorectal
      cancer: implications for treatment.
AB  - OBJECTIVES: MGMT (O(6)-alkylguanine-DNA alkyltransferase) reverses the
      carcinogenic, mutagenic and cytotoxic effects of alkylating agents. Measurement
      of MGMT activity in tumours might thus be of use in selecting those patients with
      colorectal cancer who may be sensitive to adjuvant alkylating agent therapy. The
      aim of this study was to assess whether measurement of MGMT activity in a single
      tumour biopsy is representative of the whole tumour. METHODS: Multiple
      symmetrically spaced biopsies were taken from colorectal cancers obtained from 9
      patients. MGMT activity was then measured in cell-free extracts by quantifying
      the transfer of [(3)H]methyl group from calf thymus DNA methylated in vitro with
      N-nitroso-N-[(3)H]-methylurea to the MGMT protein. RESULTS: MGMT activity was
      detected in all tumour samples with the activity ranging between 3.6 and 36.2
      fmol/microg DNA and 202-1,986 fmol/mg protein. Heterogeneity in MGMT activity
      (ratio of maximum/minimum MGMT levels per tumour) varied between 1.3 and 5.4.
      CONCLUSIONS: Measurement of MGMT activity in a single biopsy is not necessarily
      indicative of the level throughout the tumour. The response of colorectal cancers
      to alkylating agent treatment is likely to be non-uniform both within the tumour
      and between patients.

PMID- 12417797
TI  - Correlation of instrumental voice evaluation with perceptual voice analysis using
      a modified visual analog scale.
AB  - Various rating scales have been used for perceptual voice analysis including
      ordinal (ORD) scales and visual analog (VA) scales. The purpose of this study was
      to determine the most suitable scale for studies using perceptual voice analysis
      as a gold standard for validation of objective analysis protocols. The study was
      carried out on 74 female voice samples from 68 dysphonic patients and 6 controls.
      A panel of 4 raters with experience in perceptual analysis was asked to score
      voices according to the G component (overall quality) of the GRBAS system. Two
      rating scales were used. The first was a conventional 4-point ORD scale. The
      second was a modified VA (mVA) scale obtained by transforming the VA scale into
      an ORD scale using a weighted conversion scheme. Objective voice evaluation was
      performed using the EVA workstation. Objective measurements included acoustic,
      aerodynamic, and physiologic parameters as well as parameters based on nonlinear
      mathematics (e.g., Lyapunov coefficient). Instrumental measurements were compared
      with results of perceptual analysis using either the conventional ORD scale or
      mVA scale. Results demonstrate that correlation between perceptual and objective
      voice judgments is better using a mVA scale than a conventional ORD scale
      (concordance, 88 vs. 64%). Data also indicate that the mVA scale described herein
      improves the correlation between objective and perceptual voice analysis.

PMID- 12417796
TI  - Transfection of p27(Kip1) threonine residue 187 mutant type gene, which is not
      influenced by ubiquitin-mediated degradation, induces cell cycle arrest in oral
      squamous cell carcinoma cells.
AB  - OBJECTIVE: It is well known that reduction of the cyclin-dependent kinase
      inhibitor p27(Kip1) protein correlates with the malignant behavior of various
      cancers including oral squamous cell carcinoma (OSCC). The loss of p27(Kip1)
      protein is suggested to be due to the enhancement of its posttranslational
      degradation. In the present study, to evaluate the effects of p27(Kip1)
      transfection on the cell cycle, we transfected OSCC cell lines with a high
      activity of p27(Kip1) degradation with p27(Kip1) threonine 187-to-alanine (T187A)
      mutant gene, which is not influenced by ubiquitin-mediated degradation, as well
      as with wild type gene. METHODS: We transfected p27(Kip1) T187A mutant and wild
      type gene into OSCC cell lines (HSC2 and HSC3) by using an ecdysone-inducible
      gene expression system. RESULTS: After treatment with ponasterone A, we could
      find an induction of both p27(Kip1) wild type and T187A mutant protein. Both wild
      type and T187A mutant protein induced by 5 microM ponasterone A inhibited cell
      growth and increased cell number at the G1 phase. After treatment with 1 microM
      ponasterone A, ectopic p27(Kip1) protein was degraded in wild type clones, but
      not in T187A mutant clones. Moreover, transfection of the T187A mutant gene was
      more effective in inhibiting cell growth even by induction of a small amount of
      protein. CONCLUSION: We suggest that the transfection of the p27(Kip1) T187A
      mutant gene can be a modality of cancer gene therapy for OSCC.

PMID- 12417798
TI  - Changes in teachers' speech during a working day with and without electric sound
      amplification.
AB  - An increase in fundamental frequency (F(0)) and in sound pressure level (SPL) has
      been reported both after vocal loading tests and after a teacher's working day.
      This increase has been found to be greater among teachers with fewer voice
      complaints. The present study investigated speech changes during a teacher's
      working day (a) in ordinary conditions and (b) when using electric sound
      amplification while teaching. Five Icelandic teachers (mean age 51 years)
      volunteered as subjects. Classroom speech was recorded with a portable DAT
      recorder and a head-mounted microphone first in ordinary conditions, and the next
      week while using electrical sound amplification. Recordings were made during the
      first and the last lesson of the hardest working day of the week. F(0) and SPL
      were analyzed. The subjects' comments were gathered by questionnaire. An increase
      in F(0) and SPL was found during the working day in both teaching conditions but
      the change was larger and for F(0) statistically significant when amplification
      was used. All 5 teachers reported less tiredness of the vocal mechanism when
      using amplification. The results support the suggestion that a vocal loading
      related increase in F(0) and SPL is not merely a sign of vocal fatigue but may
      even reflect an adequate adaptation to loading. Situational factors cannot be
      ignored, however.

PMID- 12417799
TI  - Blinded speech evaluation following pharyngeal flap surgery by speech
      pathologists and lay people in children with cleft palate.
AB  - METHODS: In order to assess intermediate-term speech outcome after pharyngeal
      flap surgery for velopharyngeal dysfunction in children with cleft palate between
      1980 and 1998, their pre- and postoperative speech performance was analyzed in a
      blinded fashion by speech pathologists and adult lay people. Speech was evaluated
      on the basis of tape recordings with regard to resonance, intelligibility,
      articulation, voice and secondary speech disorders. RESULTS: Twenty-three
      patients could be evaluated. Both lay assessors and speech pathologists noted a
      significant improvement in speech performance after pharyngeal flap surgery. The
      percentage of children who improved was 83% (19/23, 95% confidence interval: 0.68
      0.98, p = 0.002) when rated by lay people, and 87% (20/23, CI 0.73-1.01, p <
      0.0001) when rated by professionals. Rated on a 5-point scale, the mean
      improvement per speech characteristic was 0.52 +/- 0.32 scale points when judged
      by lay people, and 0.75 +/- 0.8 points when judged by experts. Experts considered
      none of the children to have normal speech after surgery. Agreement with regard
      to outcome between lay people and speech pathologists occurred in 87% of the
      patients. CONCLUSION: The cranially based pharyngeal flap can improve speech
      performance in cleft palate children with chronic velopharyngeal insufficiency.
      However, it cannot be expected that this type of surgery will result in normal
      speech.

PMID- 12417800
TI  - Speech loudness and quality 12 months after intensive voice treatment (LSVT) for
      Parkinson's disease: a comparison with an alternative speech treatment.
AB  - Thirty-five individuals with idiopathic Parkinson's disease were enrolled in
      speech treatment. Twenty-two were enrolled in a high-effort phonatory-respiratory
      treatment program (Lee Silverman Voice Treatment, LSVT) and 13 were enrolled in a
      high-effort respiratory treatment program (RET). Perceptual judgments of speech
      loudness and quality were made independently by 6 listeners on recordings of the
      'Rainbow Passage'. These recordings had been obtained just before treatment (pre)
      and at 12 months' follow-up (FU12). The speech samples in the LSVT group, but not
      in the RET group, were significantly more likely to be perceived 'louder' and
      'better quality' at FU12 than at pre (p < 0.0001). These findings, along with
      others, suggest that the long-term effects of the LSVT are perceptible,
      clinically significant and treatment-specific.

PMID- 12417801
TI  - Acoustic and aerodynamic measurements of voice production after near-total
      laryngectomy with epiglottoplasty.
AB  - Objective voice analysis based on simultaneous aerodynamic and acoustic
      measurements is not common and there have been no reports dealing specifically
      with aerodynamic features of laryngeal performance after partial laryngectomy.
      The present study describes objective voice analysis after near-total
      laryngectomy using the Tucker technique (NTLT). We performed and compared
      acoustic and aerodynamic measurements in patients who underwent NTLT (n = 21) and
      normal controls (n = 10). Acoustic indexes of instability of frequency and
      intensity (jitter and shimmer) were always higher in patients. Oral airflow and
      estimated subglottic pressure (ESPG) were significantly greater in patients than
      in controls (400 vs. 169 cm(3)/s and 23 vs. 6.2 hPa, respectively). Poor closure
      of the glottis after surgery leads to a significant increase in glottal leakage
      in comparison with controls. Higher ESGP values observed in patients are probably
      related to two factors. The first involves compensation for glottal leakage in
      order to achieve sufficient air pressure to initiate vibration of the mucosa. The
      second factor is the poor vibratory quality of the residual mucosa, which may
      require higher pressure levels than the more compliant normal cord to initiate
      vibration. Our findings confirm the adverse effects of NTLT on the aerodynamic
      efficiency of the larynx due to glottal leakage and poor compliance of
      postoperative mucosa. Aerodynamic measurements could provide the basis for
      standardized objective evaluation of postoperative voice quality.

PMID- 12417802
TI  - Magnitude and variability of oral pressure in tracheoesophageal speech.
AB  - The purpose of this study was to compare mean oral pressure (P(o)) and P(o)
      variability: (1) between tracheoesophageal (TE) and laryngeal speakers, and (2)
      between TE speakers' voiced and voiceless phonemes. Sixteen TE and 10 laryngeal
      speakers produced stops and fricatives in a phrase while P(o) was recorded. The
      TE group produced greater mean P(o) and P(o) variability than the control group.
      TE speakers did maintain a P(o) difference between cognate members with greater
      pressure on voiceless consonants. A number of possible explanations for the
      findings are reviewed, although clearer delineation of the issue will require
      further study.

PMID- 12417803
TI  - [Evaluation of inpatient naturopathic treatment--the Blankenstein model. Part II:
      Effective strength and health status of patients over the course of time].
AB  - BACKGROUND: In order to check the possibilities and limits of naturopathic
      treatment within the field of inpatient care, in January 1997 a model department
      of naturopathy was established at the Hospital Blankenstein, Hattingen. For a
      period of 3 years (starting on July 1,1999) it has been scientifically
      accompanied by the Chair of Medical Theory and Complementary Medicine at the
      University of Witten/ Herdecke. AIM: The scientific evaluation focuses on the
      following question: How does a 3-week inpatient treatment with naturopathic
      methods effect different outcome parameters regarding a pre-post comparison and a
      half-year follow-up? METHODS: A prospective observation study with 4 defined
      times of measurement (hospitalization, discharge, 3 and 6 months after the end of
      the inhospital stay) and an analysis of the subgroups of patients with rheumatic
      diseases. The data of 1026 patients of the department of naturopathy were
      considered, who have been treated because of rheumatic diseases, metabolic
      diseases, chronic-bronchial diseases and allergic discomforts from July 1, 1999
      to December 13, 2000. The mean value of age was 57.3 years, the median 58.5
      years. 69.4% of the patients were capable of gainful employment (17-65 years).
      The patients were treated with classical naturopathic methods (hydrotherapy,
      phytotherapy), individually adapted to the patient's situation. Outcome
      parameters were quality of life (measured with the HLQ and the SF-36), mood
      (measured with the Bf-S), physical complaints (measured with the GBB24) and pain
      perception (measured with the SES) of the patient. RESULTS: All subscales as well
      as the total scores of the psychometric test instruments showed highly
      significant changes (t test, p < 0.01) between the time 'hospitalization' and
      'discharge'. Within the follow-up these values were stabilized on a level
      significantly higher than the initial level. Patients with rheumatic diseases
      showed a profile different from that of patients with similar diseases.
      CONCLUSION: The results show a stabilization of the patients within the follow
      up, which proves the long-lasting effect of naturopathic treatment. This is of
      special importance for the section of naturopathy, where the temporal dimension
      of treatment plays an important role and it is often asserted that therapeutical
      effects can above all be recognized in the long term.

PMID- 12417804
TI  - [Efficacy of tea blends in the treatment of dyspeptic disorders--an application
      observation].
AB  - BACKGROUND: Medicinal teas present one of the oldest galenic preparations of
      herbal remedies. Their use is primarily determined by tradition and empirics. One
      of their traditional domains are gastrointestinal disorders, which belong to the
      most frequent wellness disorders. While the effectiveness and compatibility of
      essential oils, modern drug extracts, and alcoholic extracts from bitters and
      etheric-oil drugs in the treatment of dyspeptic disorders have been documented in
      placebo-controlled clinical trials, little attention has so far been given to
      aqueous extracts from bitters and etheric-oil drugs, which are equivalent to the
      standard method of preparing herbal teas. PURPOSE: The presented application
      observation in clinical practice tried to give evidence for effectiveness and
      tolerability of medicinal teas in the treatment of dyspeptic disorders and to
      quantify their extent. MATERIAL AND METHODS: We collected information about
      effectiveness, compatibility, and side effects of herbal teas from 89 patients (w
      = 56; m = 33) suffering from dyspeptic disorders. The data were reported with a
      questionnaire that was sent to physicians and pharmacists experienced in
      phytotherapy. RESULTS: It could be shown that complaints in patients with primary
      dyspeptic symptoms (n = 79) decreased by an average of 74%. Final overall
      assessment revealed that the physicians as well as the patients estimated an
      effectiveness of 2.9 points as good (3 = good). Compatibility was considered as
      good to very good (4 = very good), with an average rating of 3.3 points. Two
      patients stopped therapy because of an extreme aversion to the bitter taste of
      the teas. No other serious side effects were reported. CONCLUSION: The herbal
      teas can be considered effective, very well tolerable and to a large extent free
      from serious side effects. However, due to the limited observation time, no final
      conclusion could be given concerning long-term compatibility.

PMID- 12417805
TI  - Phantasy therapy in psychiatry: rediscovering reality in phantasy. A special
      treatment for in- and outpatients in general psychiatry.
AB  - Phantasy Therapy is an interdisciplinary depth-psychologically oriented group
      therapy form with focus on the treatment of psychoses in acute and remission
      phases. A different theme is presented to the patients every week on two
      consecutive days (90 min per session), coherently, via various sensory channels.
      On the first day, the theme is concretely and operationally introduced by means
      of an object, transformed into movement in the broadest sense of the word, and
      experienced directly with the body. The first session ends with a story, usually
      a fairy tale or parable, so that the body experiences can be further realized
      symbolically at the cognitive-emotional level. The second session treats the same
      theme via repetition of the chosen story with the deeper transformation of
      symbols into color and form. The first day is jointly led by a psychotherapist
      and a movement/ dance therapist, the second day by a psychotherapist and an art
      therapist. Our approach understands therapy as a somatesthetic experience- and
      synthetic expression-oriented encounter with the patient via the therapist's
      empathic imaginative identification with the patient by means of a progressively
      orchestrated, positivizing, cognitive-emotional, theme-centered rapport. In this
      connection six therapeutic elements are of importance: theme, object, movement,
      fairy tale, artwork, symbol. Phantasy Therapy offers the patient creative freedom
      in a humorous and playful way within a certain therapeutic security (Amae
      principle) and contradicts several classical prejudices concerning the treatment
      of psychotic patients.

PMID- 12417806
TI  - [The effects of Cardiodoron on cardio-respiratory coordination--a literature
      review].
AB  - BACKGROUND: In healthy subjects self-regulation of the organism establishes the
      order of rhythmical functions. This self-regulation is altered in patients
      suffering from idiopathic orthostatic syndrome resulting from disturbances of
      functional aspects only. Thus the cardio-respiratory coordination, which may
      serve as the representative of the order of rhythmical functions, is modified.
      OBJECTIVE: In the case of idiopathic orthostatic syndrome the anthroposophic
      medicine offers the medicament Cardiodoron(r). Does it stimulate self-regulation
      in order to normalise the cardio-respiratory coordination? MATERIAL AND METHODS:
      This claim is analysed by a systematic review of the literature. Only those
      publications were considered where the cardio-respiratory coordination was
      analysed in studies with patients or healthy subjects. RESULTS: The methods of
      the studies with patients and healthy subjects vary strongly. Nevertheless, a
      normalisation of the cardio-respiratory coordination could be found in studies
      with patients suffering from idiopathic orthostatic syndrome as well as in
      studies with healthy subjects. CONCLUSION: The studies show that the use of the
      medicament results in a normalisation of the cardiorespiratory coordination. By
      stimulating the self-regulation the medicament leads to an improvement of the
      order of rhythmical functions in the human organism.

PMID- 12417807
TI  - Atherosclerosis or atheroscleritis: what's in a name?

PMID- 12417808
TI  - B-type natriuretic peptide is related to left ventricular mass in hypertensive
      patients but not in athletes.
AB  - A positive correlation has been previously documented between B-type natriuretic
      peptide (BNP) levels and left ventricular mass index (LVMI) in hypertensive
      patients. We evaluated 8 cycling athletes, 8 healthy age-matched controls; 17
      hypertensive patients and 7 age-matched controls. LVMI was significantly higher
      in athletes and hypertensive patients than in their controls. Plasma levels of
      BNP in hypertensive patients were significantly higher than in athletes and their
      age-matched controls. No significant difference was found between athletes and
      their controls. Cycling athletes had significantly larger LVMI than hypertensive
      patients and controls, without elevated BNP levels. These results suggest that
      BNP levels are elevated in patients with increased LVM due to hypertension but
      not in physiologically increased LVM. Whether elevated BNP levels in athletes is
      a sign of structural heart disease merits further investigation.

PMID- 12417809
TI  - Human paraoxonase 1 gene polymorphisms and the risk of coronary heart disease: a
      community-based study.
AB  - Published data on the association between paraoxonase1 (PON1) polymorphisms and
      coronary heart disease (CHD) have yielded controversial results. The objective of
      this study was to determine the possible relationship between the two human PON1
      amino acid variants, the Leu55Met and the Gln192Arg polymorphism, and the risk of
      CHD in a community-dwelling cohort of European ancestry. PON1 genotypes of 152
      women and 151 men out of 1,998 randomly selected individuals aged 44-75 years
      were determined by polymerase chain reaction-based restriction enzyme digestion.
      Study participants underwent cardiological examination including a structured
      clinical interview, resting ECG, exercise testing and echocardiography. The
      diagnosis of CHD was based on history and/or appropriate findings during cardiac
      examination. Evidence for CHD was found in 43 (14.2%) study participants. The
      Leu/Leu (LL), Leu/Met (LM) and Met/Met (MM) genotypes at position 55 were noted
      in 131 (43.2%), 128 (42.2%) and 44 (14.5%) subjects; the Gln/Gln (QQ), Gln/Arg
      (QR) and Arg/Arg (RR) genotypes at codon 192 occurred in 167 (55.1%), 118 (38.9%)
      and 18 (5.9%) individuals, respectively. Homozygosity for the 55L-allele was
      significantly associated with CHD (p = 0.02), while the Gln192Arg polymorphism
      had no effect (p = 0.16). Logistic regression analysis demonstrated age (odds
      ratio 1.06/year), smoking (odds ratio 2.86), HDL cholesterol (odds ratio
      0.94/mg/dl) and the paraoxonase LL genotype (odds ratio 2.25) to be significant
      predictors of CHD. These data suggest that the paraoxonase LL genotype at
      position 55 may present a risk factor for CHD.

PMID- 12417810
TI  - Association of mannan-binding lectin deficiency with venous bypass graft
      occlusions in patients with coronary heart disease.
AB  - We investigated the effect of mannan-binding lectin (MBL) deficiency on the
      susceptibility to bypass graft occlusion in 62 patients with coronary heart
      disease. MBL deficiency appeared to be associated with occlusion (p = 0.0099). A
      high level of anti-cardiolipin IgG as well as the number of venous bypass grafts
      were also involved (p = 0.0018 and p = 0.0104, respectively). Since early
      occlusion (<5 years after surgery) of a venous bypass graft is considered to be
      caused by thrombosis or fibro-intimal hyperplasia superimposed by thrombosis, our
      finding also implies an association of MBL deficiency with thrombotic events. It
      remains unclear whether the previously confirmed effect of MBL deficiency in
      coronary disease is mediated through this possible thrombotic mechanism, or
      whether plaque formation is also involved in the process. Further studies are
      clearly warranted.

PMID- 12417811
TI  - Anaerobic threshold and maximal oxygen uptake in patients with coronary artery
      disease and stable angina before and after percutaneous transluminal coronary
      angioplasty.
AB  - In this study, we investigated the effect of percutaneous transluminal coronary
      angioplasty (PTCA) on functional exercise capacity, oxygen uptake at anaerobic
      threshold (VO(2 AT)) and maximal oxygen uptake (VO(2 max)) in patients with
      coronary artery disease (CAD). Twenty-five patients with CAD and stable angina
      pectoris underwent spiroergometry before and after PTCA. All patients had reduced
      functional capacity with Weber class B in 5, class C in 16 and class D in 4
      patients with mean VO(2 AT) of 9.4 +/- 1.5 ml.kg(-1).min(-1) and mean VO(2 max)
      of 13.3 +/- 3.3 ml. kg(-1).min(-1). After PTCA, VO(2 max) (15.8 +/- 3.1 ml.kg(
      1). min(-1)) increased significantly (p < 0.001) compared to before PTCA.
      Subgroup analysis revealed that patients with low functional capacity before PTCA
      (VO(2 max) <15 ml x kg(-1) x min(-1)) had the most benefit from PTCA with an
      increase in VO(2 AT) from 8.7 +/- 1.0 to 9.6 +/- 1.4 ml x kg(-1) x min(-1) (p <
      0.05) and of VO(2 max) from 11.3 +/- 2.2 to 14.8 +/- 3.5 ml x kg(-1) x min(-1) (p
      < 0.001) whereas in patients with VO(2 max) >15 ml x kg(-1) x min(-1), VO(2 AT)
      (p = 0.9) and VO(2 max) (p = 0.2) did not improve significantly. In conclusion,
      there is reduced functional capacity and VO(2 max) which improved after PTCA in
      CAD patients. In patients with low VO(2 max) before PTCA, functional capacity,
      VO(2 AT) and VO(2 max) significantly improved after PTCA, suggesting reversible
      myocardial impairment induced by intermittent myocardial ischemia. Patients with
      higher VO(2 max) had no significant benefit from PTCA with respect to functional
      capacity, VO(2 max) and VO(2 AT).

PMID- 12417812
TI  - Clinical features and outcome of coronary artery aneurysm in patients with acute
      myocardial infarction undergoing a primary percutaneous coronary intervention.
AB  - BACKGROUND: While coronary artery aneurysm is an uncommon anatomic disorder and
      has various forms, its clinical features and outcome and its impact on thrombus
      formation and the no-reflow phenomenon in the clinical setting of acute
      myocardial infarction (AMI) undergoing primary percutaneous coronary intervention
      (p-PCI) have not been discussed. The purpose of this study was to evaluate
      whether this anatomic disorder predisposes to a high burden of thrombus
      formation, and subsequently leads to the no-reflow phenomenon and untoward
      clinical outcome in patients with AMI undergoing p-PCI. METHODS AND RESULTS: In
      our hospital, emergency p-PCI was performed in 924 consecutive patients with AMI
      between May 1993 and July 2001. Of these 924 patients, 24 patients (2.6%) who had
      an infarct-related artery (IRA) with aneurysmal dilatation were retrospectively
      registered and constituted the patient population of this study. Angiographic
      findings demonstrated that the ectasia type (defined as diffuse dilatation of 50%
      or more of the length of the IRA) was found most frequently (70%), followed by
      the fusiform type (20%; defined as a spindle-shaped dilatation in the IRA) and
      the saccular type (10%; defined as a localized spherical-shaped dilatation in the
      IRA). The right coronary artery was the most frequently involved vessel (54.2%),
      followed by the left anterior descending (25.0%) and the left circumflex arteries
      (20.8%). Coronary angiography revealed that all of these aneurysmal IRA filled
      with heavy thrombus (indicated as high-burden thrombus formation). The no-reflow
      phenomenon (defined as <or=TIMI-2 flow) and distal embolization after p-PCI were
      found in 62.5 and 70.8% of the IRA, respectively. The incidence of cardiogenic
      shock and the 30-day mortality rate were 25 and 8.3%, respectively. The survival
      rate was 90.9% (20/22) during a mean follow-up of 19 +/- 30 months. CONCLUSIONS:
      While aneurysmal dilatation of an IRA is an uncommon angiographic finding in the
      clinical setting of AMI, it is frequently associated with high-burden thrombus
      formation and has a significantly lower incidence of successful reperfusion.
      However, the long-term survival of these patients is excellent.

PMID- 12417813
TI  - Outcome of myocardial infarction in patients treated with aspirin is enhanced by
      pre-hospital administration.
AB  - OBJECTIVE: Reducing time to reperfusion therapy is one of the goals in the
      management of acute myocardial infarction (AMI). We assessed the association
      between timing of aspirin administration and outcome of patients with AMI.
      PATIENTS: We studied 922 consecutive AMI patients with ST-segment elevation in
      Killip class I-III on admission. Patients were divided into two groups based upon
      the timing of emergency aspirin administration: before (early aspirin users) or
      after (late aspirin users) hospital admission. RESULTS: Early aspirin users (n =
      338; 37%) were younger, less likely to be women, and more likely to smoke (p <
      0.006) than late users (n = 584; 63%). Other baseline and clinical
      characteristics were similar. Early aspirin users were more likely to be treated
      with thrombolysis or primary percutaneous transluminal coronary angioplasty.
      Compared with late users, early aspirin users had significantly lower in-hospital
      complications and lower mortality rates at 7 (2.4 vs. 7.3%, p = 0.002) and 30
      days (4.9 vs. 11.1%, p = 0.001). By multivariate adjustment, pre-hospital aspirin
      was an independent determinant of survival at 7 (odds ratio 0.43; 95% confidence
      interval 0.18-0.92) and at 30 days (odds ratio, 0.60; 95% confidence interval
      0.32-1.08). Survival benefit associated with aspirin persisted for subgroups
      treated or not with reperfusion therapy. CONCLUSIONS: Outcome of AMI patients
      treated with aspirin is improved by pre-hospital administration. Our findings
      suggest that emergency pre-hospital aspirin might facilitate early reperfusion.

PMID- 12417814
TI  - Restrictive left ventricular filling pattern with preserved systolic function
      assessed by Doppler echocardiography: clinical, echocardiographic and prognostic
      implications.
AB  - From an echocardiographic laboratory database, echocardiographic characteristics
      of clinical and cardiovascular mortality were compared in patients with
      restrictive pattern of left ventricular filling (RPLVF) and left ventricular
      ejection fraction (LVEF) >50% (n = 36), with patients with RPLVF and LVEF <50% (n
      = 120) and echocardiographic controls (n = 160). Preserved LVEF was found in 21%
      of the patients with RPLVF. Mortality in patients with RPLVF was worst compared
      with echocardiographic controls regardless of their underlying LVEF after 2.7 +/-
      1 years of follow-up. Patients with RPLVF had distinctive predictors of
      cardiovascular death, with clinical and echocardiographic characteristics
      according to their LVEF.

PMID- 12417815
TI  - Morphologic characteristics of aortic valve sclerosis by transesophageal
      echocardiography: importance for the prediction of coronary artery disease.
AB  - Aortic valve sclerosis (AVS) is associated with myocardial infarction and
      mortality. Since it is not cost effective to test all patients with AVS for
      coronary artery disease (CAD), the identification of high-risk patients is
      important. We developed a morphologic classification system for AVS by
      transesophageal echocardiography and correlated the subtypes of AVS with the
      presence of cardiovascular disease. AVS in general was not associated with CAD.
      However, among patients with mixed nodular and diffuse AVS, the prevalence of CAD
      and previous coronary artery bypass graft surgery were higher than among those
      without this mixed type (p = 0.02 and 0.008, respectively). We concluded that the
      finding of mixed nodular and diffuse AVS identifies patients at increased risk
      for CAD. Thus, the echocardiographic assessment of AVS morphology is of clinical
      relevance.

PMID- 12417816
TI  - Aortic and mitral valve thickening with concentric left ventricular hypertrophy
      in an elite bodybuilder: a biochemical and/or physiological adaptation?

PMID- 12417817
TI  - Histological appearance of left ventricular hypertrabeculation/noncompaction.

PMID- 12417818
TI  - Prevalence of mitral valve prolapse and thick mitral valve in a non-selected
      outpatient population.

PMID- 12417819
TI  - The minicolumn and evolution of the brain.
AB  - The minicolumn is generally considered an elementary unit of the neocortex in all
      mammalian brains. This essential building block has been affected by changes in
      the circuitry of the cortex during evolution. Researchers believe that
      enlargement of the cortical surface occurs through the addition of minicolumns
      rather than of single neurons. Therefore, minicolumns integrate cortical
      encephalization with organization. Despite these insights, few studies have
      analyzed the morphometry of the minicolumn to detect subtle but important
      differences among the brains of diverse mammals. The notion that minicolumns are
      essentially unchanged across species is challenged by strong evidence to the
      contrary. Because they are subject to species-specific variation, they can be
      used as a way to study evolutionary changes. Unfortunately, comparative studies
      are marred by a lack of standardized techniques, tissue preparation, cortical
      regions, or anatomical feature studied. However, recent advances in methodology
      enable standardized, quantified comparisons of minicolumn morphology.

PMID- 12417820
TI  - Reduction of brain volume correlates with behavioral changes in queen ants.
AB  - The behavior of reproductive female ants distinctly changes during the transition
      from virgin to mature, egg-laying queen. A winged female ant flies only once
      during her lifetime when she engages in the nuptial flight. Once she is mated she
      sheds her wings, excavates a nest and starts laying eggs, the basis for her
      future colony. We show for two species of harvester ants that this transition is
      accompanied by changes in the performance of behavioral tests: flying virgins are
      positively phototactic and prefer open areas, whereas young queens prefer the
      dark, avoid open areas and, given the opportunity, dig into the soil. These
      behavioral changes coincide with morphological changes in the brain. The brains
      of mature queens are significantly smaller than those of virgin females at the
      time of their mating flight. A disproportionately large shrinkage occurs in the
      medulla and other parts of the visual system during the early adult life of the
      queen. The brain reduction appears to be adaptive as mature queens show reduced
      behavioral repertoires and live in the dark. In contrast to virgin females, they
      do not rely on vision and might increase their fitness by reducing metabolically
      costly neural tissue.

PMID- 12417821
TI  - A comparative analysis of brain size in relation to foraging ecology and
      phylogeny in the Chiroptera.
AB  - Variations in total brain mass and in the mass of three brain regions (main
      olfactory bulb, hippocampus, auditory nuclei) were examined using a data set for
      63 species of bats (Chiroptera). Using both conventional and phylogenetically
      based analysis of covariance (log body mass as covariate), we tested several
      hypotheses that relate total brain mass or the size of the components to
      variation in foraging ecology, categorized as phytophagous, gleaner, and aerial
      insectivore. In some analyses, the category phytophagous was split into
      phytophagous pteropodid and phytophagous phyllostomid to examine differences
      between two distinct clades of bats. Because the Megachiroptera orient primarily
      by vision and olfaction, whereas all other bats rely on laryngeal echolocation to
      locate their prey, we hypothesized that the former would differ in size of the
      main olfactory bulb, as compared with all other bats. This hypothesis was
      supported by our analyses. Our more general prediction was that insectivorous
      bats, which rely heavily on echolocation for the pursuit and capture of their
      prey, would have larger auditory nuclei than do phytophagous species. This, too,
      was supported. We also compared phytophagous (fruit or nectar consuming) bats in
      two families, the Pteropodidae and the Phyllostomidae. We hypothesized that the
      phyllostomids, which use echolocation while foraging, would have larger auditory
      nuclei. Although statistical power is low in phylogenetically informed
      comparisons of the two clades, we did find weak evidence in support of this
      hypothesis. We conclude that bat brains show evidence of adaptation to foraging
      ecology.

PMID- 12417822
TI  - The effects of spatially separated call components on phonotaxis in tungara
      frogs: evidence for auditory grouping.
AB  - Numerous animals across disparate taxa must identify and locate complex acoustic
      signals imbedded in multiple overlapping signals and ambient noise. A requirement
      of this task is the ability to group sounds into auditory streams in which sounds
      are perceived as emanating from the same source. Although numerous studies over
      the past 50 years have examined aspects of auditory grouping in humans,
      surprisingly few assays have demonstrated auditory stream formation or the
      assignment of multicomponent signals to a single source in non-human animals. In
      our study, we present evidence for auditory grouping in female tungara frogs. In
      contrast to humans, in which auditory grouping may be facilitated by the cues
      produced when sounds arrive from the same location, we show that spatial cues
      play a limited role in grouping, as females group discrete components of the
      species' complex call over wide angular separations. Furthermore, we show that
      once grouped the separate call components are weighted differently in recognizing
      and locating the call, so called 'what' and 'where' decisions, respectively.

PMID- 12417823
TI  - Lower is better: The Heart Protection Study.

PMID- 12417824
TI  - A controlled pilot study of stress management training of elderly patients with
      congestive heart failure.
AB  - The purpose of this study was to evaluate the effect of stress management
      training on quality of life, functional capacity, and heart rate variability in
      elderly patients with New York Heart Association class I-III congestive heart
      failure (CHF). While substantial research exists on stress management training
      for patients with coronary heart disease, there are few data on the value of
      psychosocial training on patients with CHF. Thirty-three multiethnic patients
      (mean age, 66+/-9 years) were assigned through incomplete randomization to one of
      two treatment groups or a wait-listed control group. The 14 participants who
      completed the treatment attended eight training sessions during a 10-week period.
      The training consisted of 75-minute sessions adapted from the Freeze-Frame stress
      management program developed by the Institute of HeartMath. Subjects were
      assessed at baseline and again at the completion of the training. Depression,
      stress management, optimism, anxiety, emotional distress, and functional capacity
      were evaluated, as well as heart rate variability. Significant improvements
      (p<0.05) were noted in perceived stress, emotional distress, 6-minute walk, and
      depression, and positive trends were noted in each of the other psychosocial
      measures. The 24-hour heart rate variability showed no significant changes in
      autonomic tone. The authors noted that CHF patients were willing study
      participants and their emotional coping and functional capacity were enhanced.
      This program offers a simple and cost-effective way to augment medical management
      of CHF. Given the incompleteness of CHF medical management and the exploding
      interest in complementary medical intervention, it seems imperative that further
      work in psychosocial treatment be undertaken.

PMID- 12417825
TI  - Cardiovascular medications taken by patients aged >or=70 years hospitalized for
      acute coronary syndromes before hospitalization and at hospital discharge.
AB  - A prospective study was performed in 177 patients, mean age 78+/-6 years,
      hospitalized with acute coronary syndromes. Obstructive coronary artery disease
      was documented by coronary angiography in 154 of 177 patients (87%). Coronary
      revascularization was performed in 96 of 177 patients (54%). Five of 177 patients
      (3%) died during hospitalization. Compared to use before hospitalization, at
      hospital discharge the use of aspirin increased from 43% to 84% (p<0.001), the
      use of clopidogrel increased from 21% to 54% (p<0.001), the use of beta blockers
      increased from 38% to 76% (p<0.001), the use of angiotensin-converting enzyme
      inhibitors or angiotensin receptor blockers increased from 42% to 70% (p<0.001),
      the use of long-acting nitrates increased from 15% to 31% (p<0.001), and the use
      of calcium channel blockers decreased from 28% to 23% (p=NS). Dyslipidemia was
      present in 62% of the 177 patients. The use of statins increased from 34% before
      hospitalization to 63% at hospital discharge (p<0.001).

PMID- 12417826
TI  - Prevention of sudden death in patients with coronary artery disease: do lipid
      lowering drugs play a role?
AB  - Ventricular arrhythmias are the most common cause of sudden cardiac death in
      patients with coronary artery disease. Since treatment of hypercholesterolemia in
      patients with coronary artery disease reduces the risk of major coronary events
      by about 30%, one could speculate that this treatment could also result in a
      reduction of arrhythmic episodes in high-risk patients. In this review, the
      importance of myocardial ischemia as a trigger for ventricular arrhythmias, as
      well as the available data that suggest a possible effect of anti-ischemic
      treatments, including lipid-lowering drugs, on these arrhythmias are presented.
      Also, possible mechanisms and future research to test the hypothesis that lipid
      lowering drugs can reduce life-threatening ventricular arrhythmias are discussed.

PMID- 12417827
TI  - Molecular mechanisms of diabetic cardiovascular disease.
AB  - Cardiovascular disease is a major cause of morbidity and mortality in persons
      with diabetes mellitus. This population represents an important target for
      preventive therapies aimed at reducing atherosclerosis. Recent molecular research
      has uncovered many of the cellular mechanisms that lead to atherosclerosis in the
      diabetic patient. This review, part 1 of a 2-part series, is geared toward
      clinicians and discusses these mechanisms as they pertain to prevention of
      cardiovascular disease in patients with diabetes.

PMID- 12417828
TI  - Reducing the global burden of cardiovascular disease: the role of risk factors.
AB  - During the last century, cardiovascular disease (CVD) has burgeoned from a
      relatively minor disease worldwide to a leading cause of morbidity and mortality.
      By 2020 it is projected that CVD will surpass infectious disease as the worlds
      leading cause of death and disability. Some of this increase in the relative
      importance of CVD is due to improved public health measures and medical care
      leading to longer life spans and reduced mortality from other causes. However, a
      substantial portion of the increasing global impact of CVD is attributable to
      economic, social, and cultural changes that have led to increases in risk factors
      for CVD. These changes are most pronounced in the countries comprising the
      developing world. Because the majority of the worlds population lives in the
      developing world, the increasing rate of CVD in these countries is the driving
      force behind the continuing dramatic worldwide increase in CVD. In order to blunt
      the impact of the global explosion in CVD, it will be crucial to attempt to
      understand and reduce the global increase in CVD risk factors. In this review,
      the authors describe the changes responsible for the global epidemic of CVD, with
      particular attention to the contributions of established risk factors and their
      impact on the growth of CVD among the worlds various economic sectors. The
      authors outline the major challenges facing countries in different economic
      sectors, and discuss ways to address these challenges with the goal of reducing
      the global burden of CVD.

PMID- 12417830
TI  - Did you know? Improving preventive cardiology: The 33rd Bethesda Conference.

PMID- 12417829
TI  - Statins and C-reactive protein: considering a novel marker of cardiovascular
      risk.
AB  - Landmark intervention trials have validated the importance of lipid control in
      reducing the incidence of coronary ischemic events, over a range of baseline
      lipid levels. With the release of the third iteration of the National Cholesterol
      Education Programs Adult Treatment Panel guidelines, there is renewed debate
      about the appropriate use of pharmacologic therapies in individual patients,
      especially in primary prevention. Markers of low-grade inflammation may capture
      the inflammatory aspect of atherosclerosis and may prove to be useful clinical
      predictors of excess coronary risk. C-reactive protein, an acute-phase reactant
      protein, appears to be one such promising measurement and may have important
      implications for the optimal targeting of statin therapy.

PMID- 12417831
TI  - Adherence to angiotensin-converting enzyme inhibitor therapy for heart failure.
AB  - This study examined adherence to angiotensin-converting enzyme inhibitor therapy
      among 171 heart failure clinic patients. Adherence was monitored over a 3-month
      period with an electronic event monitor housed in a medication bottle cap, which
      recorded the date and time the cap was opened and closed. The average percentage
      of days that the prescribed number of doses (regimen adherence) was taken over
      the observation period was 84%. Seventy-one percent of patients showed 85%-100%
      adherence with their daily regimen; 19% exhibited less than 70% adherence. The
      overall high rates of adherence to angiotensin-converting enzyme inhibitor
      therapy observed among heart failure clinic patients is consistent with research
      that shows improved outcomes for patients managed in heart failure clinics.
      Electronic medication monitoring can be useful in identifying a substantial
      fraction of patients who are poorly adherent so that interventions to improve
      adherence can be targeted toward them. Additional research is needed to develop
      and test adherence-enhancing interventions.

PMID- 12417832
TI  - Small LDL and its clinical importance as a new CAD risk factor: a female case
      study.
AB  - The underlying metabolic cause of coronary heart disease in many patients is not
      high blood cholesterol. In fact, the Framingham study has reported that 80% of
      individuals who go on to have coronary artery disease have the same total blood
      cholesterol values as those who do not go on to have a cardiovascular event. The
      most common metabolic contributor to coronary artery disease is the atherogenic
      lipoprotein profile, characterized by an abundance of highly atherogenic small,
      dense low-density lipoprotein particles and a deficiency of the high-density
      lipoprotein (HDL) subtype most associated with coronary artery disease protection
      (HDL(2b)). This trait is present in 50% of men with coronary artery disease and
      is not reflected by total or low-density lipoprotein cholesterol values. While
      fasting triglycerides tend to he higher, and HDL cholesterol lower in patients
      with the atherogenic lipoprotein profile, the majority have triglyceride and HDL
      cholesterol values generally accepted to be in the "normal" range. An abundance
      of basic science and clinical trial evidence convincingly indicates that the
      presence of an atherogenic lipoprotein profile signifies a three-fold increased
      risk for a cardiovascular event and rapid arteriographic progression, but it also
      identifies a group of patients who respond particularly well to specific
      therapeutic interventions. Often the most effective interventions are the least
      expensive.

PMID- 12417833
TI  - Role of inflammation in cardiovascular disease: how to use C-reactive protein in
      clinical practice.
AB  - Acute coronary syndromes, stroke, and sudden death are common complications of a
      disrupted atherosclerotic plaque. Unstable plaque is a result of multiple factors
      but is commonly characterized by an infiltrate of inflammatory cells. Medical
      research strongly supports a role for inflammation in the pathogenesis,
      progression, and disruption of atherosclerotic plaque. Medical science also has
      improved our understanding of the complex interactions between our environment
      and our immune, coagulation, and cardiovascular systems. Clinical studies have
      demonstrated systemic markers of inflammation to be strong predictors of clinical
      events, and specific treatments of atherosclerosis and its risk factors have been
      associated with reductions in inflammatory markers. The authors review the
      current understanding of the role of inflammation in the pathogenesis of
      atherosclerosis, the common inflammatory markers, and potential anti-inflammatory
      therapy. Among several potential circulating markers of vascular inflammation,
      high sensitivity C-reactive protein is best validated and standardized as a
      marker for cardiovascular risk assessment. Nevertheless, there remain many
      uncertainties in utilizing C-reactive protein in clinical practice. Here, the
      authors describe the central role of C-reactive protein in atherosclerosis,
      review the studies demonstrating predictive value of C-reactive protein, describe
      the factors requiring consideration when utilizing C-reactive protein, discuss
      clinical scenarios in which measurement of C-reactive protein may be helpful, and
      suggest ways to interpret and treat elevated C-reactive protein levels. Finally,
      the authors summarize future expectations for assessing and modulating the
      vascular inflammation to inhibit initiation and progression of the
      atherosclerotic process.

PMID- 12417834
TI  - Controlling hypertension to reduce the risk of stroke.
AB  - Long-term hypertension has been implicated as one of the greatest risk factors
      for the cause of stroke, but yet it is a very controllable one. The risks of
      stroke increase with age and, as the population of the United States grows older,
      the number of people who will experience a stroke will greatly increase. In the
      past, various antihypertensive therapies have proved to lower blood pressure with
      a resulting decrease in stroke. Stroke can be devastating in terms of quality of
      life and cost of care; therefore, prevention of stroke should become a priority
      for all health care professionals. As newer antihypertensive classes of drugs are
      being studied in high-risk cardiovascular populations, health care professionals
      need to educate themselves and their patients regarding new treatment options,
      where these options belong within treatment guidelines for hypertension, and
      their relevance in preventing the incidence of stroke. This review briefly
      summarizes the significance of controlling hypertension to reduce the risk of
      stroke by reviewing some of the clinical trials that support pharmacologic
      intervention.

PMID- 12417835
TI  - Meeting the challenge of acute pain management in coronary heart disease.

PMID- 12417836
TI  - Predicting coronary risk by measuring inflammation.

PMID- 12417837
TI  - Can a concave T wave in V(1) through V(3) be a predictor of deadly arrhythmia?

PMID- 12417838
TI  - Atrial fibrillation: many therapeutic options, but great uncertainty about
      optimal treatment.

PMID- 12417839
TI  - Atrial fibrillation in the elderly--a near epidemic.

PMID- 12417840
TI  - Ventricular rate control in the elderly: is digoxin enough?
AB  - The ventricular response in untreated patients with atrial fibrillation often
      exceeds 120 beats/min at rest. Digoxin can slow this rate, but its efficacy
      during exertion may be limited. Alternatives, or additions, to digoxin therapy
      include the beta blockers and diltiazem or verapamil. This review discusses the
      role of digoxin in relation to these other drugs, with particular reference to
      the elderly population.

PMID- 12417841
TI  - Atrial fibrillation in the elderly: anticoagulation strategies and indications in
      the very elderly.
AB  - With increasing life expectancy and the older mean age of the general population,
      the prevalence of atrial fibrillation is likely to increase, making this
      arrhythmia an even more important public health problem, especially in the
      elderly. While atrial fibrillation is increasingly common in the elderly,
      paradoxically, the data on intervention trials in atrial fibrillation among the
      elderly are limited. When considering anticoagulation in the elderly patient with
      atrial fibrillation, the following five questions should be addressed. 1) Is
      there a definite indication (for example, atrial fibrillation plus risk
      factor[s])? 2) Is there a high risk of bleeding or strong contraindication
      against anticoagulation? 3) Will concurrent medication or disease states
      significantly increase bleeding risk or interfere with anticoagulation control?
      4) Is drug compliance and attendance at anticoagulant clinic for monitoring
      likely to be a problem? 5) Will there be regular review of the patient,
      especially with regard to risks and benefits of anticoagulation? Careful and
      continuing evaluation of the elderly patient with atrial fibrillation is
      necessary to ensure that the risks of bleeding do not outweigh the benefits from
      anticoagulation.

PMID- 12417842
TI  - Indications and nonindications for ablation of atrioventricular conduction in the
      elderly: is it sensible to destroy normal tissue?
AB  - Atrial fibrillation is common in later life. The goals of therapy are
      maintenance/restoration of sinus rhythm and control of ventricular rate when
      atrial fibrillation occurs. The only nonpharmacologic therapy of proven benefit
      is atrioventricular junction ablation and pacing, but this approach is
      irreversible and requires clear guidelines for patient selection. In paroxysmal
      atrial fibrillation, ablation and pacing carries a high risk of progression to
      permanent atrial fibrillation within 6 months but is indicated only when at least
      two appropriate drug strategies have failed. In persistent atrial fibrillation,
      ablation and pacing will inevitably result in permanent atrial fibrillation; this
      may influence the decision for pacemaker type and the timing of the procedure. In
      permanent atrial fibrillation, there is clear evidence for benefit, especially in
      those with reduced left ventricular function. In conclusion, ablation and pacing
      offers symptomatic and functional benefit to patients with drug-refractory atrial
      fibrillation. Timing of the intervention relates to response to other
      pharmacologic therapy.

PMID- 12417843
TI  - Special problems with antiarrhythmic drugs in the elderly: safety, tolerability,
      and efficacy.
AB  - With advancing age, atrial fibrillation is increasingly likely to indicate
      underlying cardiovascular disease and risk. An understanding of this is
      particularly important in the elderly patient, where likely triggers to atrial
      fibrillation and the influence of other pathologies on the safety and efficacy of
      proposed treatments will all contribute to optimal care of these patients. It is
      not yet clear whether rate control or cardioversion to sinus rhythm is the best
      strategy for the generality of patients with atrial fibrillation, and still less
      so for individuals. Age and comorbidity add complexities to this decision, which
      should inform the choice of drugs to be used. Further uncertainties arise from a
      literature that has often excluded elderly patients and derived its conclusions
      about mode of drug action from studies undertaken during sinus rhythm rather than
      atrial fibrillation. Despite these difficulties the careful evaluation of elderly
      patients with atrial fibrillation and their involvement in relevant choices
      should ensure optimum treatment for the individual.

PMID- 12417844
TI  - Optimal investigation of the elderly and very elderly patient with atrial
      fibrillation--what must be done?
AB  - The investigation of atrial fibrillation should be tailored to match the needs of
      the patient. Those needs may differ between younger and older patients. While
      many different investigations might be used, the emphasis in this review will be
      on what must be done. It should be remembered that rigid protocols cannot be
      presented, however, because many of these important issues have not been
      subjected to critical scrutiny in elderly cohorts.

PMID- 12417845
TI  - Atrial pacing for the prevention and termination of atrial fibrillation.
AB  - Atrial fibrillation (AF) affects about 2% of the general population and 8%-11% of
      those older than 65 years. The demand for effective therapeutic strategies for AF
      is anticipated to increase substantially as the proportion of the elderly
      population increases. Atrioventricular nodal ablation accompanied by permanent
      pacemaker implantation is an established option in elderly patients with
      intractable arrhythmia and poor ventricular rate control. However, it renders
      most patients pacemaker dependent and does not eliminate symptoms associated with
      loss of atrial transport or reduce the risk of stroke. The considerable
      limitations of rhythm or rate control strategies prompted interest in
      preventative atrial pacing, which may reduce the incidence of AF by either
      eliminating the triggers and/or by modifying the substrate of AF. Atrial or dual
      chamber pacing has been proven to prevent or delay progression to permanent AF in
      elderly patients with sinus node dysfunction as compared with ventricular pacing.
      Patients with advanced atrial conduction delay may benefit from atrial
      resynchronization pacing. There may be additional benefits associated with the
      use of particular sites of pacing, specific pacing algorithms designed to target
      potential triggers of AF, and pace-termination of atrial tachycardia. Preventive
      and antitachycardia pacing algorithms incorporated in implantable cardioverter
      defibrillators and pacemakers are currently under investigation and may offer a
      valuable alternative to antiarrhythmic drug therapy in elderly patients with left
      ventricular dysfunction at high risk of proarrhythmia or worsening heart failure.
      The evolution of hybrid therapy, in which two or more different strategies are
      employed in the same patient, may be the most effective approach to management of
      AF.

PMID- 12417846
TI  - Is the presence of interatrial septal hypertrophy a marker for atrial
      fibrillation in the elderly?
AB  - Interatrial septal thickness (IST) appears to increase with heart weight, body
      surface area, and the presence of vacuolated fat cells within the atrial septum.
      The increased thickness of the atrial septum is an infrequently observed but
      readily recognized entity by echocardiography. Several reports have suggested
      that some cardiac arrhythmias, particularly those of atrial origin, may be a
      consequence of this fatty deposition. However, to date, no study has correlated
      the presence of atrial fibrillation with IST in the elderly. This is of
      particular importance as this rhythm is so prevalent in this population.
      Accordingly, a retrospective analysis was conducted in a group of 40 patients,
      age 65 and older, to measure IST using transthoracic echocardiography.
      Furthermore, measurements of right and left atrial size, body surface area, left
      ventricular wall thickness, and left ventricular ejection fraction were recorded.
      Group I consisted of 20 patients with known atrial fibrillation (eight males and
      12 females; mean age 78+/-8 years) and group II consisted of 20 patients in
      normal sinus rhythm (three males and 17 females; mean age 74+/-6 years). There
      was no difference between the two groups in terms of body surface area (1.83 vs.
      1.79 m2; p<0.78); left ventricular wall thickness (1.16 vs. 1.12 cm; p<0.58); and
      left ventricular ejection fraction (48% vs. 55%; p<0.17). Group I had somewhat
      larger right atrial (4.2 vs. 3.4 cm; p<0.001) and left atrial (4.7 vs. 4.1 cm;
      p<0.02) dimensions than group II. Furthermore, IST was found to be the most
      significant variable that differentiated patients with atrial fibrillation from
      patients with normal sinus rhythm (1.39 vs. 0.85 cm; p<0.0001). Even after
      adjusting for all the covariables, IST remained statistically significant
      (p<0.0001). The findings of this pilot study show a strong correlation between
      IST and atrial fibrillation. Although the stimulus for the increased thickness of
      the atrial septum remains elusive, IST may identify a structural cause for atrial
      fibrillation in elderly patients that is easily identified by transthoracic
      echocardiography.

PMID- 12417847
TI  - Atrial pacing stress echocardiography: an alternative diagnostic test for chest
      pain in the elderly.
AB  - The authors utilized rapid right atrial pacing and handgrip exercise to provoke
      myocardial ischemia in 20 participants (age >65 years) who, for reasons of
      disability, were not candidates for exercise and pharmacologic stress testing.
      Echocardiographic left ventricular ejection fraction and left ventricular wall
      motions were obtained during pacing at baseline and at maximal pacing rates and
      were compared with coronary angiography. Using the failure of left ventricular
      ejection fraction to increase with pacing as an indicator of myocardial ischemia,
      the test yielded a sensitivity of 75%, specificity of 100%, positive predictive
      value of 100%, and negative predictive value of 71%. When a pacing-induced
      decrease of wall-motion index was taken as an ischemia indicator, the sensitivity
      was 63%, specificity 100%, positive predictive value 100%, and negative
      predictive value 80%. Rapid atrial pacing echocardiography is a safe test. It may
      be considered in a select group of elderly patients as an alternative to exercise
      or pharmacologic tests before resorting to coronary angiography.

PMID- 12417848
TI  - Contrast echocardiographic demonstration of right to left shunting in an elderly
      patient with atrial septal aneurysm, atrial septal defect, and severe pulmonary
      hypertension.

PMID- 12417849
TI  - Osborne (J) waves in hypothermia.

PMID- 12417850
TI  - Ethical issue: giving bad news in a beautiful way.

PMID- 12417851
TI  - [A series on factual medicine (evidence-based medicine): for what objectives?].

PMID- 12417852
TI  - ["Sibilant" exacerbation of chronic obstructive pulmonary disease: a
      manifestation of pulmonary embolus?].

PMID- 12417853
TI  - [Cystic fibrosis: transition from child to adult. The stakes and the challenges].

PMID- 12417854
TI  - [Theoretical and pragmatic reflections on the difficulties of smoking cessation].

PMID- 12417855
TI  - [Classification of broncho-pulmonary cancer, WHO 1999: what's new?].

PMID- 12417856
TI  - [Genetic susceptibility to infections].

PMID- 12417857
TI  - [Pulmonary embolism and sibilant types of chronic obstructive pulmonary disease
      decompensations].
AB  - Pulmonary Embolism (PE) poses an important diagnostic problem in patients with
      chronic obstructive pulmonary disease (COPD). Indeed PE may aggravate the already
      precarious respiratory state of these fragile patients. Moreover, these two
      conditions share common symptoms: dyspnoea, wheezing, pleural pain, haemoptysis,
      palpitations and signs of right cardiac insufficiency. In two studies, one
      retrospective and the other prospective, we investigated the incidence of PE in
      patients with non-infective exacerbations of their COPD. The retrospective study
      was carried out over two years and involved 50 COPD patients with non-infective
      respiratory exacerbations. In this population, 10 patients out of 50 (20%) had a
      documented PE. No predictive factor was identified. The prospective study was
      conducted over one year and COPD patients admitted to hospital with exacerbations
      were included in the study if they had a positive D-dimer blood test and no
      evidence of acute respiratory infection. 31 patients were studied with Doppler
      ultra-sound examination of the legs and a lung perfusion scan. The presence or
      absence of PE was determined and the two groups were compared. 9 patients out of
      31 (29%) had a documented PE. Six of these nine patients had a deep venous
      thrombosis (DVT). Two predictive factors of PE were identified: existence of a
      DVT and a significant fall in PaO(2) from baseline state (DeltaPaO(2) > 22 mmHg).
      We conclude that PE is a frequent (20 to 30%) of non-infective respiratory
      decompensation in COPD patients. Faced with an unexplained respiratory
      exacerbation in these patients, a lung perfusion scan should be routinely
      undertaken to rule out a PE when the D-dimers are positive.

PMID- 12417858
TI  - [Outcome of adult patients with cystic fibrosis admitted to intensive care with
      respiratory failure: the role of non-invasive ventilation].
AB  - Recourse to mechanical ventilation may prove necessary in adult patients with
      cystic fibrosis who have reached the stage of severe respiratory insufficiency.
      We report the experience of an intensive care service using non-invasive
      ventilation (NIV) as the first step in the management of acute respiratory
      failure in these patients. The records of 16 patients with cystic fibrosis
      presenting with acute respiratory failure and treated with NIV were analysed
      retrospectively. The characteristics of the group were: mean age 26.9 +/- 9.5
      years; mean FEV1 21.5 +/- 10.4% predicted; mean body mass index 16.8 +/- 2.1;
      mean Pa CO(2) on admission 66 +/- 15 mm Hg. The mean duration of NIV in the ICU
      was 10 +/- 7 days. Eight patients (50%) died after having been intubated on
      account of failure of NIV. The eight survivors were discharged home with long
      term NIV (mean duration 235 +/- 158 days). Six of them have received a lung
      transplant. The mode of onset of respiratory failure was an important prognostic
      factor: a rapid onset (<7 days) was invariably associated with death, on the
      other hand a gradual deterioration (> 7 days) was noted in the eight patients
      able to leave the ICU. In conclusion NIV may be regarded as the treatment of
      choice in patients with cystic fibrosis admitted to ICU with respiratory failure.
      In the case of persistent hypercapnia after the acute episode long-term NIV may
      keep them stable while awaiting lung transplantation.

PMID- 12417860
TI  - [Smoking in Casablanca hospitals: knowledge, attitudes and practices].
AB  - This cross sectional study took place with a self administered questionnaire
      between June and September 1999 and involved 1,388 subjects of whom 62.4% were
      men and 37.6% women. The total prevalence of smoking was 14.9%, ranging from
      12.5% in paramedical staff to 15.5% in manual workers, 16.2% in doctors, 17.1% in
      laboratory staff, and 22.2% in administrators. The prevalence was 35.9% among men
      as against 2.2% among women. The study of smokers showed that 51.5% had started
      before the age of 21. The most common motive for starting smoking was "pleasure".
      Among the 45.5% who smoked at the workplace 60.5% felt concerned about it.
      Evaluation of the degree of nicotine dependence using the Fagerstrom score found
      high dependence in 21.3% of subjects. Only 24.5% of doctors warned patients
      against smoking in the absence of smoking related diseases or symptoms. In more
      than 75% of cases doctors advised against smoking in the workplace and in the
      home. 66.8% of staff were aware of the anti-smoking law but the legislative
      measures were poorly understood. Only 9% of those interviewed had taken part in
      an anti-smoking campaign. In conclusion, the prevalence of smoking in the
      hospitals of Casablanca has definitely diminished in the past 10 years but it
      remains relatively high in men. Hospital staff should be more involved in the
      fight against smoking.

PMID- 12417859
TI  - [Factors associated with smoking in sixth grade (11-13 years old)].
AB  - Because smoking begins most often in adolescence it is important to define
      clearly, with a view to prevention, the motivation of an adolescent to smoke. The
      role of the social group is well known. The aim of this study was to evaluate the
      potentially preventative role of knowledge in the field of respiration and the
      effects of cigarette smoke on one hand and of involvement in activities involving
      breathing on the other. The group studied was made up of 1,802 pupils at state
      schools, randomly selected, in the city of Marseilles. These pupils filled in an
      anonymous questionnaire in the classroom. The overall percentage of non
      responders was very small. Overall 10.5% if the children declared that they had
      already smoked, more often boys (13.1%) than girls (8.1%). In contrast to smoking
      by the father, smoking by the mother and siblings significantly influenced
      smoking in the child. The child was not influenced by smoking by a sibling of the
      same sex. The proportion of children having already smoked increased
      progressively in proportion to the number of smokers in the household. Using a
      logistical regression analysis the following were predictive of smoking: being a
      boy, having a best friend who smoked, and the number of smokers in the family. On
      the other hand a history of allergy, an understanding of the effects of the
      environment on the respiratory system, knowledge of the effects of cigarettes,
      and finally involvement in sport, playing a wind instrument or singing in a choir
      were not associated with a lower incidence of smoking. These results call into
      question the effectiveness of the standard preventative methods and of anti
      smoking programmes that are based on such strategies.

PMID- 12417861
TI  - [Peripheral muscle dysfunction in chronic obstructive pulmonary disease].
AB  - Patients with chronic obstructive pulmonary disease (COPD) often develop systemic
      complications of their disease. Peripheral muscle dysfunction is one such
      complication and is characterised by atrophy, weakness, and low oxidative
      capacity. These muscle changes influence exercise tolerance and quality of life
      independent of the impairment in lung function. In the following article, the
      evidence for peripheral muscle dysfunction in patients with COPD and the possible
      clinical implications of this problem will be discussed. Lastly, the available
      therapeutic options to improve peripheral muscle function in COPD will be
      reviewed.

PMID- 12417862
TI  - [Classification of broncho-pulmonary cancers (WHO 1999)].
AB  - Tumour classification systems provide the foundation for tumour diagnosis and
      patient therapy and a critical basis for epidemiological and clinical studies.
      This updated classification was developed with the aim to adhere to the
      principles of reproducibility, clinical significance, and simplicity in order to
      minimize the number of unclassifiable lesions. Major changes in the revised
      classification as compared to the previous one (WHO 1981) include the addition of
      two pre-invasive lesions to squamous dysplasia and carcinoma in situ: atypical
      adenomatous hyperplasia (AAH) and diffuse idiopathic pulmonary neuroendocrine
      cell hyperplasia. Another change is the subclassification of adenocarcinoma: the
      definition of bronchioloalveolar carcinoma has been restricted to non-invasive
      tumours. There has been substantial evolution of concepts in neuroendocrine lung
      tumour classification. Large cell neuroendocrine carcinoma (LCNEC) is now
      recognized as a histologically high-grade non-small cell carcinoma showing
      histopathological features of neuroendocrine differentiation as well as
      immunohistochemical neuroendocrine markers. The large cell carcinoma class has
      been enriched with several variants, including the large cell neuroendocrine
      carcinoma and the basaloid carcinoma, both of which have a poor prognosis.
      Finally, a new class has been defined called carcinoma with pleomorphic,
      sarcomatoid, or sarcomatous elements, which gathers a number of proliferations
      characterized by a spectrum of epithelial to mesenchymal differentiation.
      Immunohistochemistry and electron microscopy are invaluable techniques for
      diagnosis and subclassification, but our intention was to render the
      classification simple and practical to every surgical laboratory so that most
      lung tumours can be classified by light microscopic criteria.

PMID- 12417863
TI  - [Effect of diesel particles on allergic inflammatory response: cellular targets
      and molecular mechanisms].
AB  - The prevalence of allergic diseases has increased in industrialized western
      countries, and several hypotheses have been proposed to explain this rise.
      Besides the classical "hygiene theory" associated with improvements in living
      standards, a role for atmospheric pollution has been suggested, but this has as
      yet not been proven by epidemiological studies. By contrast, the impact of
      pollutants on the allergic inflammatory response is well documented. In this
      context, the effects of diesel exhaust particles and their organic extracts are
      the best known. In both human and animal studies, it has been demonstrated that
      diesel exhaust particles can cause an augmentation of respiratory symptoms, which
      are associated with the development of mucosal inflammation, an increase in
      airways resistance, and the development of non-specific bronchial hyper
      reactivity. The mechanisms of these airway modifications are better understood.
      Diesel exhaust particles interfere with several inflammatory cell-types, involved
      in the regulation of the immune response. Diesel particles act in synergy with
      antigens to selectively amplify the production of specific IgE, TH2 cytokines,
      chemokines, and to increase the expression of adhesion molecules. Diesel
      particles modify antigen presentation by the macrophage, and facilitate its
      interaction with T cell. Finally, diesel exhaust particles enhance mast cell and
      basophil histamine release, and might influence fibrotic bronchial remodeling. In
      essence, these data argue for an important role of such small respirable
      particles in the pathophysiology and, probably also, the epidemiological
      modification of allergic disease.

PMID- 12417864
TI  - [Clinical and radiological aspects of ageing of the respiratory tract].
AB  - The effects of ageing on the macroscopic appearance of the lung were recognized
      by Laennec, Andral suggesting that dyspnoea might be its clinical manifestation.
      At about the same time physiologists demonstrated the negative effects of ageing
      on the vital capacity, whereas anatomists defined its impact on the lung and
      thoracic cage structure. The prevalence of dyspnoea increases with ageing but co
      morbid disease should always be sought. The prevalence of cough is strongly
      associated with active and passive smoking. With regard to physical signs, barrel
      chest and crepitations heard over the dependent lung zones do not necessarily
      have pathological significance. The usefulness of measuring the forced expiratory
      time remains to be established in the elderly. There is no characteristic
      radiological feature of a senile lung. If an X-ray abnormality is discovered
      during a routine examination, it should be regarded as pathological, but in most
      cases its detection will not alter management of the patient.

PMID- 12417865
TI  - [Acute dyspnoea in elderly patients].
AB  - There is a natural physiological decline in pulmonary function and the
      cardiovascular system with age. In emergency medicine, acute dyspnoea is a common
      problem among elderly patients. Some causes, such as pulmonary embolism and
      diastolic heart failure, are probably under-diagnosed. A good clinical history
      and examination are as important as arterial blood gas analysis, chest
      radiography and electrocardiography. Few studies have examined acute dyspnoea in
      elderly patients, except in the setting of pneumonia. Establishing the underlying
      diagnosis is often difficult because of atypical presentation and the interaction
      between cardiac and pulmonary underlying functions. This topic describes several
      respiratory and cardiac diseases presenting as acute dyspnoea, especially
      "cardiac asthma" and pulmonary embolism. The clinical usefulness of new
      investigations such as cardiac and lung echography, pulmonary function tests,
      serum Brain Natriuretic Peptide and thoracic CT scan are discussed. Further
      studies looking at acute dyspnoea in elderly patients are needed.

PMID- 12417866
TI  - [Randomised controlled trials: a reading guide].
AB  - This paper, first of a series devoted to evidence-based medicine, describes how
      to critically read an article on a randomised controlled intervention trial. This
      guide is applied to the common clinical question, whether or not to prescribe
      systemic glucocorticoids for patients with exacerbation of chronic obstructive
      pulmonary disease, through the analysis of two recently published series. It
      comprises a three-step evaluation: the assessment of the study methods to ensure
      that the results are valid, the analysis of the results of the larger of the two
      studies, and the evaluation of whether the results can be applied to a patient
      whose clinical case illustrates this article. Finally, a few limitations of
      randomised controlled trials are discussed.

PMID- 12417867
TI  - [Bilateral pleural thickening pseudo-tumour due to tuberculosis].
AB  - The authors report the case of a 20 year old Senegalese woman in whom pulmonary
      and bone tuberculosis presented as bilateral, lobulated pleural thickening
      without effusion, associated with a vertebral abscess at D 9-10. The diagnosis
      was obtained by histological examination of a CT guided pleural biopsy. After 12
      months treatment there was complete resolution of the pleural disease.
      Tuberculous pleural disease is rarely bilateral and such presentation as a pseudo
      tumour is very rare in Europe. Anatomically the pleural disease would seem to
      have been secondary to the vertebral disease as the result of direct spread.

PMID- 12417868
TI  - [Pulmonary tuberculosis presenting as tubercular lupus].
AB  - Pulmonary tuberculosis can be associated with skin manifestations. We report a
      case in which cutaneous tuberculous lesions were associated with asymptomatic
      pulmonary tuberculosis. A 15-year old woman had four cutaneous tumoral lesions on
      her face back, a few of which had evolved over a period of several years. They
      were asymptomatic nodular lesions, with rounded bumps, with, in places, cheloidal
      features. The biopsy specimen revealed non-caseating epithelioid granulomas with
      giant cells and the culture grew Mycobacterium tuberculosis. Cavitating pulmonary
      tuberculosis was then revealed by CT scan and acid-fast bacilli were isolated in
      her sputum. The skin lesions disappeared with anti-tuberculosis therapy.
      Cutaneous manifestations of tuberculosis are rare, polymorphous, and can be
      associated with an underlying visceral infection. Lupus vulgaris is the most
      common cutaneous manifestation of tuberculosis in industrialised countries, but
      nevertheless it remains rare and it is a very unusual presenting feature of
      underlying pulmonary tuberculosis.

PMID- 12417869
TI  - [Air-filled cysts of tracheal origin: nosological problems and actual frequency].
AB  - Air-filled paratracheal bronchogenic cysts are extremely rare. They are lined by
      respiratory epithelium. We have operated on 2 patients whose cysts were diagnosed
      by CT scan: one presenting with bloody sputum and the other with dysphagia. Both
      patients had a history of neck surgery. Because such cases are rare in the
      literature, their exact origin, whether tracheocele, diverticulum or other form
      of air-filled cyst, remains a matter of debate. However, their frequency is
      probably underestimated because most cause few symptoms and are well tolerated.
      In a recent radiologic study their prevalence was found to be 2% in patients
      undergoing CT scan.

PMID- 12417870
TI  - [Unusual etiologies of multiple pulmonary opacities].

PMID- 12417871
TI  - [Skin testing with respiratory allergens: which techniques, which extracts, which
      battery?].

PMID- 12417872
TI  - [Blind pleural biopsy].

PMID- 12417873
TI  - [Acute bronchial constriction in a non-asthmatic patient provoked by Airbag(R)
      activation].

PMID- 12417875
TI  - Allergic bronchopulmonary aspergillosis.
AB  - Allergic bronchopulmonary aspergillosis (ABPA) complicates asthma and cystic
      fibrosis. The survival factors in Aspergillus fumigatus that support saprophytic
      growth in bronchial mucus are not understood. Prednisone remains the most
      definitive treatment but need not be administered indefinitely. MHC II 
      restricted CD4(+) T( H)2 clones have been derived from patients with ABPA. The
      total serum IgE concentration is elevated sharply but is "nonspecific. " IgE
      serum isotypic antibodies to A fumigatus are useful in diagnosis; this is in
      contrast to the situation for patients with asthma without ABPA. High-resolution
      computed tomography of the chest demonstrates multiple areas of bronchiectasis in
      most patients with ABPA and is a useful radiologic tool. Some asthma control
      patients might have a few bronchiectatic airways, but not to the extent seen in
      or of the same character as those in ABPA. This review discusses clinical,
      radiologic, investigational, pathogenetic, and treatment issues of ABPA.

PMID- 12417876
TI  - The role of suppressor T cells in regulation of immune responses.
AB  - Suppressor T cells play important roles in the regulation of immune responses and
      the mediation of dominant immunologic tolerance. Studies of suppressor T-cell
      function have been hampered until their recent identification as a minor fraction
      (approximately 10%) of CD4 ( +) T cells that coexpress CD25. CD4(+)CD25(+ ) T
      cells have been shown to play a critical role in the prevention of organ-
      specific autoimmunity and allograft rejection. Because tumor antigens are self-
      antigens, it is not surprising that CD4(+)CD25(+) T cells also inhibit the
      induction of tumor immunity. The spectrum of activity of CD4(+ ) CD25(+) cells
      extends to non-self-antigens, including infectious agents. Indeed, T cell
      mediated suppression might be responsible for the low level of chronic infection
      seen with many pathogens. Interestingly, however, this persistent level of
      infection might be beneficial to the host and needed for maintenance of
      immunologic memory. Although CD4(+ ) CD25(+) T cells are capable of inhibiting
      T(H)2 responses, their role in the suppression of allergic responses has not been
      firmly established. Depending on the desired immune response, enhancement or
      restraint of suppressor T-cell function might be required. Therefore immunologic
      or pharmacologic manipulation of regulatory T-cell populations represents an
      important future approach to immunotherapy of a wide range of immune responses.

PMID- 12417877
TI  - Asthma guidelines: a changing paradigm to improve asthma care.

PMID- 12417878
TI  - Immunostimulatory sequence oligodeoxynucleotide-based vaccination and
      immunomodulation: two unique but complementary strategies for the treatment of
      allergic diseases.
AB  - Despite a number of effective pharmaceutical options for the prevention and
      treatment of the pathophysiologic responses that occur in sensitized patients on
      allergen exposure, the termination of allergic hypersensitivities remains an
      elusive therapeutic goal. Traditional immunotherapy with allergen extracts is the
      only currently used intervention that has been shown to induce allergen
      tolerance, but it has a limited scope of efficacy. However, recent studies
      suggest that immunostimulatory sequence oligodeoxynucleotide (ISS-ODN) -based
      interventions might offer an alternative and potentially more effective means for
      extinguishing T (H)2-biased hypersensitivities. Three basic ISS-ODN -based
      immunotherapeutic strategies have been studied to date. Immunization with
      allergen mixed with ISS- ODN, immunization with allergen -ISS- ODN conjugates,
      and immunomodulation with ISS- ODN alone all have proved efficacy in the
      attenuation of the allergic phenotype in mice. Preliminary results with allergen 
      ISS- ODN conjugate vaccines in allergic patients have also been encouraging. This
      article will provide our perspective on the application of ISS-ODN -based
      vaccination and immunomodulation to the treatment of atopic diseases and the
      immunologic basis for their antiallergic activities.

PMID- 12417879
TI  - A methacholine challenge dose-response study for development of a pharmacodynamic
      bioequivalence methodology for albuterol metered- dose inhalers.
AB  - BACKGROUND: With the expiration of the patent on albuterol metered-dose inhalers
      (MDIs) in 1989, methods to assess in vivo bioequivalence of generic formulations
      required investigation. OBJECTIVE: In an effort to develop a sensitive method to
      document bioequivalence, bronchoprovocation with methacholine chloride was used
      to assess the dose-response relationship of albuterol as delivered by MDI.
      Sensitivity was assessed in terms of magnitudes of ED(50), the estimated
      albuterol dose required to achieve 50 % of the fitted maximal value of the
      pharmacodynamic effect above baseline, and change in response as a function of
      dose, with emphasis on 1 and 2 actuations. METHODS: On separate study days, 15
      nonsmokers with mild asthma received randomized nominal albuterol doses of 0 to
      576 microg by using specially manufactured MDI canisters. FEV(1) was measured 15
      minutes after MDI dosing. Serially increasing doses of methacholine were
      administered, and FEV(1) was measured after each methacholine dose until a 20 %
      decrease in FEV(1) (PD(20)) was achieved. RESULTS: Mean PD(20) values after use
      of each of the albuterol-containing MDIs were significantly greater than either
      mean screening or mean placebo PD(20) values (P <.05). Mean responses and most
      individual subject responses to 1 and 2 actuations (90 and 180 microg) of
      albuterol MDI were within the sensitive region of the dose- response curve. The
      mean estimated ED(50) value on the basis of nonlinear mixed effect modeling was
      119.2 microg (range, 33.3-337.1 microg), with an intersubject percentage
      coefficient of variation of 69.0 %. CONCLUSIONS: The methacholine
      bronchoprovocation model is safe and useful in the study of albuterol MDI dose
      response in asthmatic subjects. Bronchoprovocation studies may be used for
      determination of bioequivalence of multisource albuterol MDI products.

PMID- 12417880
TI  - Estimation of the dose of fluticasone propionate inhaled by infants after
      bronchiolitis: Effect on urinary cortisol excretion.
AB  - BACKGROUND: Information on the dose of steroid infants inhale from spacer devices
      and its potential effect on adrenal suppression is limited. OBJECTIVE: We sought
      to determine the total dose of fluticasone propionate (FP) inhaled from a spacer
      device (Babyhaler) with face mask attachment by infants recovering from acute
      bronchiolitis and the effect of inhaled FP on the infants' overnight urinary
      cortisol/creatinine ratios (UCCRs). METHODS: Infants studied were recovering from
      acute bronchiolitis. In study 1, 22 infants inhaled 150 microg of FP through the
      Babyhaler. The likely inhaled dose was estimated by trapping it on a filter held
      within the face mask. In study 2, 40 infants had UCCRs measured before and during
      3 months of treatment with either FP (150 microg twice daily, n = 20) or placebo
      (n = 20). RESULTS: In study 1 the mean +/- SD dose of captured FP was 12.8 +/-
      6.9 microg (ie, 2.1 +/- 1.2 microg/kg). In study 2 the pretreatment UCCR medians
      (interquartile ranges) were as follows: FP, 22.8 (23.0) nmol/mmol; placebo, 24.0
      (28.3) nmol/mmol. Within-group UCCR changes (median and interquartile range
      DeltaUCCR) were significantly different in the FP group (-8.9 and -20.6 nmol/mmol
      at 6 weeks and -12.6 and -25.9 nmol/mmol at 12 weeks, respectively; P =.0008) but
      not in the placebo group ( -5.8 and -10.7 nmol/mmol at 6 weeks and +0.3 and -17.9
      nmol/mmol at 12 weeks, respectively; P =.45). Intergroup changes were
      insignificant in the follow-up period (6 weeks, P =.52; 12 weeks, P =.19).
      CONCLUSION: After bronchiolitis, infants are likely to inhale approximately 8 %
      of the nominal steroid dose from the Babyhaler. UCCRs can be used to monitor the
      bioavailability of inhaled steroids in young infants.

PMID- 12417881
TI  - The effect of anti-IgE treatment on in vitro leukotriene release in children with
      seasonal allergic rhinitis.
AB  - BACKGROUND: Binding of allergens with IgE to the IgE receptors on mast cells and
      basophils results in the release of inflammatory mediators as sulfidoleukotrienes
      (SLTs), triggering allergic cascades that result in allergic symptoms, such as
      asthma and rhinitis. OBJECTIVE: We sought to investigate whether anti-IgE (Oma
      lizumab), a humanized monoclonal anti-IgE antibody, in addition to specific
      immunotherapy (SIT) affects the leukotriene pathway. METHODS: Ninety-two children
      (age range, 6-17 years) with sensitization to birch and grass pollens and with
      seasonal allergic rhinitis were included in a phase III, placebo- controlled,
      multicenter clinical study. All subjects were randomized to one of 4 treatment
      groups. Two groups subcutaneously received birch SIT and 2 groups received grass
      SIT for at least 14 weeks before the start of the birch pollen season. After 12
      weeks of SIT titration, placebo or anti-IgE was added for 24 weeks. The primary
      clinical efficacy variable was symptom load (ie, the sum of daily symptom
      severity score and rescue medication score during pollen season). Blood samples
      taken at baseline and at the end of study treatment after the grass pollen season
      were used for separation of leukocytes in this substudy. After in vitro
      stimulation of the blood cells with grass and birch pollen allergens, SLT release
      (LTC4, LTD4, and LTE4) was quantified by using the ELISA technique. RESULTS:
      Before the study treatment, SLT release to birch and grass pollen exposure did
      not differ significantly among the 4 groups. Under treatment with anti-IgE + SIT
      grass (n = 23), a lower symptom load occurred during the pollen season compared
      to placebo + SIT-grass (n = 24, P =.012). The same applied to both groups
      receiving birch SIT (n = 23 and n = 22, respectively; P =.03). At the end of
      treatment, the combination of anti-IgE plus grass SIT, as well as anti-IgE plus
      birch SIT, resulted in significantly lower SLT release after stimulation with the
      corresponding allergen (416 ng/L [5th-95th percentile, 1-1168] and 207 ng/L [1
      860 ng/L], respectively) compared with placebo plus SIT (2490 ng/L [384-6587
      ng/L], P =.001; 2489 ng/L [1-5670 ng/L], P =.001). In addition, treatment with
      anti-IgE was also followed by significantly lower SLT releases to the allergens
      unrelated to SIT (grass SIT: 300 ng/L [1-2432 ng/L] in response to birch
      allergen; birch SIT: 1478 ng/L [1-4593 ng/L] in response to grass pollen) in
      comparison with placebo (grass SIT: 1850 ng/L [1-5499 ng/L], P =.001; birch SIT:
      2792 ng/L [154-5839 ng/L], P =.04]. CONCLUSION: Anti-IgE therapy reduces
      leukotriene release of peripheral leukocytes stimulated with allergen in children
      with allergic rhinitis undergoing allergen immunotherapy independent of the type
      of SIT allergen used.

PMID- 12417882
TI  - A longitudinal analysis of wheezing in young children: the independent effects of
      early life exposure to house dust endotoxin, allergens, and pets.
AB  - BACKGROUND: It has been postulated that exposure to bacterial endotoxins and
      animals early in life might confer protection against the development of asthma
      and allergies. OBJECTIVE: We investigated the longitudinal effects of exposure to
      house dust endotoxin (HDE), allergen levels, and the presence of a dog in the
      home on wheezing in young children over a 4-year period. METHODS: Two hundred
      twenty-six children younger than 5 years were followed for 4 years. Endotoxin and
      allergen levels were measured from house dust collected at baseline. Longitudinal
      associations were investigated by using a proportional hazards technique that
      allowed for multiple outcomes per subject. RESULTS: Exposure to high
      concentrations of HDE of greater than the median level was associated with an
      increased risk for wheezing over the period of observation (multivariate relative
      risk, 1.52; 95 % CI, 1.07-2.14), but this risk rapidly decreased over time (P for
      trend =.005). Exposure to cockroach allergen was associated with increased risk
      for wheezing, whereas exposure to cat allergen and the presence of a dog in the
      home were both associated with decreased risk for wheezing. The risks associated
      with cockroach allergen, cat allergen, and dog did not change over the period of
      observation. CONCLUSION: The negative associations between exposures to dogs and
      cat allergen and wheeze appear to be independent of the effects of endotoxin and
      suggest that separate mechanisms might mediate the effects of HDE exposure and
      pet exposure on the developing immune system.

PMID- 12417883
TI  - Fine mapping of an IgE-controlling gene on chromosome 2q: Analysis of CTLA4 and
      CD28.
AB  - BACKGROUND: Several genomic regions have been identified that might contain genes
      contributing to the development of asthma and atopy. These include chromosome
      2q33, where we have observed evidence for linkage for variation in total serum
      IgE levels in a Dutch asthma population. Two candidate genes, CTLA4 and CD28,
      important homeostatic regulators of T-cell activation and subsequent IgE
      production, map within this candidate region. OBJECTIVE: We sought to fine-map
      the chromosome 2q33 region and evaluate CTLA4 and CD28 as candidate genes for the
      regulation of total serum IgE levels and related phenotypes. METHODS: The coding
      regions of CTLA4 and CD28 were resequenced in 96 individuals; 4 novel SNPs in
      CTLA4 and 10 in CD28 were identified. Polymorphisms in both genes were analyzed
      in 200 asthmatic probands and their spouses (n = 201). RESULTS: Subsequent fine-
      mapping in this region has resulted in an increased log of the odds (lod) score
      (1.96 to 3.16) for total serum IgE levels. For CTLA4, the +49 A/G single
      nucleotide polymorphism (SNP) in exon 1 and the 3 ' untranslated region
      microsatellite were significantly associated with total serum IgE levels (P
      =.0005 and.006, respectively). For the combined +49 A/G and 3 'untranslated
      region genotypes, individuals homozygous for the risk allele for both
      polymorphisms (AA and 86/86) had the highest total serum IgE values (87.1 IU/mL),
      whereas those individuals with the GG and XX/XX genotypes (anything but the 86-bp
      allele) had the lowest IgE values (29.3 IU/mL). Significant association was also
      observed for the CTLA4 -1147 C/T SNP with bronchial hyperresponsiveness (BHR) and
      asthma (P =.008 and.012, respectively), but not for allergy-related phenotypes.
      Promoter luciferase assays examining the -1147 polymorphism suggested that the T
      allele, which was associated with increased BHR susceptibility, was expressed at
      half the level of the C allele. Individuals with the risk genotypes for both BHR
      (-1147 CT or TT) and elevated IgE levels (+49 AA) were 4.5 times more likely to
      have asthma than individuals with both nonrisk genotypes (P =.0009). No
      significant associations were observed for SNPs in CD28. CONCLUSION: These data
      suggest that the costimulatory pathway, specifically CTLA4, is important in the
      development of atopy and asthma.

PMID- 12417884
TI  - Effects of inflammatory cytokines on the permeability of human lung microvascular
      endothelial cell monolayers and differential eosinophil transmigration.
AB  - BACKGROUND: Rhinovirus (RV) infections can result in asthma exacerbations in both
      adults and children. Respiratory epithelium, the primary site of RV replication,
      responds to the viral infection by generating a variety of cytokines and
      chemokines capable of promoting airway inflammation and hence might increase
      asthma severity. Some of these mediators might also affect the permeability of
      underlying vascular endothelium. OBJECTIVE: We hypothesized that RV infections
      can promote airway inflammation and thus asthma by enhancing local vascular
      permeability. METHODS: Confluent human lung microvascular endothelial cell (HMVEC
      L) monolayers were used as an in vitro model of vascular endothelium to determine
      whether cytokines associated with RV-induced infections are capable of modulating
      endothelial cell permeability as measured by means of transendothelial electrical
      resistance. Recombinant cytokines and chemokines were added to confluent HMVEC-L
      monolayers cultured on Transwell filters, and permeability was measured as
      decreased electrical resistance over time. Eosinophil transendothelial migration
      was assessed under the same experimental conditions. RESULTS: TNF- alpha, IL-1
      beta, and IFN- gamma significantly increased HMVEC-L permeability. In contrast,
      GM-CSF, G-CSF, IL-8, IL-6, and RANTES had no effect. Although incubation of HMVEC
      L monolayers with either TNF-alpha or IL-1beta promoted eosinophil migration, IFN
      gamma had no effect, indicating that enhanced permeability alone was not
      sufficient for eosinophil infiltration. CONCLUSION: Select cytokines, generated
      in response to RV infection, can increase vascular permeability and might provide
      a mechanism by which RV infection can lead to edema, cellular infiltration, and
      inflammation and thus compromised airflow.

PMID- 12417885
TI  - High-level expression of immunoreactive recombinant cat allergen (Fel d 1):
      Targeting to antigen-presenting cells.
AB  - BACKGROUND: Cat allergen Fel d 1 is a heterodimer encoded by 2 separate genes
      that has been difficult to produce as a fully immunoreactive molecule. OBJECTIVE:
      We sought to engineer recombinant (r) Fel d 1 with IgE and IgG antibody binding
      comparable with that of the natural allergen that could be targeted to antigen
      presenting cells. METHODS: The rFel d 1 chains were coexpressed in baculovirus,
      either linked to the anti-CD64 antibody H22 (rFel d 1 H22(+)) or alone (rFel d 1
      H22 (-)). Binding of expressed allergens to mouse and human antibodies was
      compared with that of natural (n) Fel d 1 by means of enzyme immunoassay and
      antigen-binding and inhibition RIAs. Binding of rFel d 1 H22 (+) to the CD64
      receptor on leukocyte subpopulations and on the THP -1 cell line was analyzed by
      means of flow cytometry. RESULTS: The baculovirus-expressed allergens migrated
      with molecular weights of 49 kd (rFel d 1 H22(+)) and 22 kd (rFel d 1 H22 (-)).
      The rFel d 1 inhibited IgG antibody binding to nFel d 1 by greater than 95% and
      showed identical dose-dependent inhibition curves. There was an excellent
      quantitative correlation between IgE and IgG antibody binding to rFel d 1 and
      nFel d 1 in sera from patients with cat allergy (IgE: n = 258, r = > 0.72,P
      <.001). The rFel d 1 H22(+) bound to monocytes but not to lymphocytes or
      neutrophils, and binding of rFel d 1 H22(+) to THP-1 cells was inhibited by a
      soluble CD64 fusion protein. CONCLUSIONS: Recombinant Fel d 1 chains have been
      successfully coexpressed as mature proteins with comparable immunoreactivities to
      nFel d 1. The rFel d 1 can be targeted to antigen-presenting cells through CD64.
      These constructs will facilitate structural studies of Fel d 1 and the
      development of improved allergy diagnostics and therapeutics.

PMID- 12417886
TI  - Involvement of the mannose receptor in the uptake of Der p 1, a major mite
      allergen, by human dendritic cells.
AB  - BACKGROUND: Immature dendritic cells (DCs) take up antigens in peripheral tissues
      and, after antigen processing, mature to efficiently stimulate T cells in
      secondary lymph nodes. In allergic airway diseases DCs have been shown to be
      involved in the induction and maintenance of a T(H)2-type profile. OBJECTIVE: The
      present study was undertaken to determine pathways of Der p 1 (a house dust mite
      allergen) uptake by human DCs and to compare Der p 1 uptake between DCs from
      patients with house dust mite allergy and DCs from healthy donors. METHODS:
      Monocyte-derived DCs (MD-DCs) were obtained from patients with house dust mite
      allergy (n = 13) and healthy donors (n = 11). Der p 1 was labeled with rhodamine.
      Der p 1 uptake by MD-DCs was analyzed by means of flow cytometry and confocal
      microscopy. RESULTS: Rhodamine- labeled Der p 1 was demonstrated to be taken up
      by MD-DCs in a dose-, time-, and temperature- dependent manner. The involvement
      of the mannose receptor (MR) in the Der p 1 uptake was demonstrated by using (1)
      inhibitors of the MR- mediated endocytosis (mannan and blocking anti-MR mAb),
      which inhibited the Der p 1 uptake from 40 % to 50 %, and (2) confocal microscopy
      showing the colocalization of rhodamine-labeled Der p 1 with FITC-dextran.
      Interestingly, compared with DCs from healthy donors, DCs from allergic patients
      expressed more MR and were more efficient in Der p 1 uptake. CONCLUSION: These
      results suggest that the MR could play a key role in the Der p 1 allergen uptake
      by DCs and in the pathogenesis of allergic diseases in dust mite -sensitive
      patients.

PMID- 12417887
TI  - T-cell proliferation induced by local application of LPS in the nasal mucosa of
      nonatopic children.
AB  - BACKGROUND: Recently, there has been a great deal of interest in the role of
      bacterial products in altering the allergic immune response in early life.
      OBJECTIVE: We sought to develop a model of bacterial inflammation in human
      subjects to characterize the ex vivo response to LPS in the nasal mucosa of young
      nonatopic children. METHODS: Using the explant technique, we cultured nasal
      mucosa in the presence or absence of increasing concentrations of LPS (0.001-1
      microg LPS/mL) for 24 hours. Immunocytochemistry and in situ hybridization were
      used to phenotype the cells and cytokines in the explant, and immunofluorescence
      was used to study proliferation of T cells in explants cultured with LPS and 5
      bromo-2'-deoxyuridine (BrdU). RESULTS: CD68, CD3, tryptase, elastase, IFN- gamma
      IL-12, and IL-10 immunoreactivity was detected in unstimulated tissue. LPS
      stimulation caused a dose-dependent increase in the number of CD3(+) (n = 7, P
      <.05), CD68(+) (n = 7, P <.01), elastase-positive (n = 7, P <.01), tryptase
      positive (n = 7, P <.05), IL-2 -positive (n = 6, P <.05), IL-12 -positive (n = 6,
      P <.05), and IFN- gamma-positive (n = 6, P <.05) cells compared with media alone.
      LPS had no effect on major basic protein, IL-4, IL-5, or IL-13 immunoreactivity.
      LPS (0.1 microg/mL) caused an increase in the number of BrdU-positive cells as
      early as 2 hours after incubation (n = 8, P <.001). The maximal BrdU
      immunoreactivity was seen 24 hours after incubation with LPS, at which time
      approximately 70% of BrdU- positive cells were CD3(+) T cells. CONCLUSIONS: Our
      results suggest that LPS is capable of inducing local inflammation, T(H)1
      cytokine immunoreactivity, and proliferation of CD3(+) activated T cells in the
      absence of de novo cell recruitment. This model holds promise for future studies
      investigating the importance of bacterial products in regulating local immune
      function in young atopic children.

PMID- 12417888
TI  - Clinical pharmacology of H1-antihistamines in the skin.
AB  - BACKGROUND: The extent of the distribution of H(1)- antihistamines into the skin
      and H(1)-antihistamine activity in the skin are clinically relevant in the
      treatment of allergic skin disorders. METHODS: In a prospective, randomized,
      double-blind, parallel-group, multiple-dose study, we gave fexofenadine 180 mg,
      loratadine 10 mg, or chlorpheniramine 8 mg to 21 men (7 in each group). Before
      dosing and at 1, 3, 6, 9, and 24 hours after the first antihistamine dose as well
      as at 168, 192, and 216 hours after the first dose (ie, 12, 36, and 60 hours
      after the seventh and last consecutive daily H(1)-antihistamine dose), we
      measured fexofenadine, loratadine, or chlorpheniramine concentrations in plasma
      and in skin tissue samples obtained through use of punch biopsies, along with
      suppression of histamine-induced skin wheals and flares. Loratadine metabolites,
      including desloratadine and its metabolites, were not measured, and
      chlorpheniramine metabolites were not measured. RESULTS: All 21 participants
      completed the study. Skin/plasma fexofenadine ratios ranged from 1.2 +/- 0.5 at 1
      hour to 110 +/- 74 at 24 hours, and skin fexofenadine concentrations exceeded
      loratadine and chlorpheniramine skin concentrations at each test time. This was
      reflected in significant wheal and flare suppression by fexofenadine in
      comparison with loratadine at 3 hours and in comparison with chlorpheniramine at
      6 and 9 hours (wheal) and from 3 to 24 hours and at 192 hours (flare). Compared
      with fexofenadine, loratadine significantly suppressed the wheal at 192 hours,
      and compared with chlorpheniramine, it significantly suppressed the wheal at 9
      hours and the flare at 24 and 192 hours. At no time did chlorpheniramine suppress
      the wheal or flare significantly more than fexofenadine or loratadine.
      CONCLUSIONS: In skin disorders for which H(1)-antihistamines are recommended,
      these results support the use of fexofenadine or loratadine, and they indicate
      the need for reexamination of the use of chlorpheniramine.

PMID- 12417889
TI  - Rising prevalence of allergy to peanut in children: Data from 2 sequential
      cohorts.
AB  - BACKGROUND: Allergy to peanut is common. However, it is not known whether the
      prevalence of sensitization and clinical allergy to peanut is increasing.
      OBJECTIVE: We sought to determine any change in the prevalence of peanut
      sensitization and reactivity in early childhood in 2 sequential cohorts in the
      same geographic area 6 years apart. METHODS: Of 2878 children born between
      September 1, 1994, and August 31, 1996, living on the Isle of Wight, 1273
      completed questionnaires, and 1246 had skin prick tests at the age of 3 to 4
      years. Those with positive skin prick test responses to peanut were subjected to
      oral peanut challenges, unless there was a history of immediate systemic
      reaction. These data were compared with information on sensitization and clinical
      allergy to peanut available from a previous cohort born in 1989 in the same
      geographic area. RESULTS: There was a 2-fold increase in reported peanut allergy
      (0.5 % [6/1218] to 1.0 % [13/1273]), but the difference was nonsignificant (P
      =.2). Peanut sensitization increased 3-fold, with 41 (3.3 %) of 1246 children
      sensitized in 1994 to 1996 compared with 11 (1.1 %) of 981 sensitized 6 years ago
      (P =.001). Of 41 sensitized children in the current study, 10 reported a
      convincing clinical reaction to peanut, and 8 had positive oral challenge
      results, giving an overall estimate of peanut allergy of 1.5% (18/1246).
      CONCLUSIONS: Sensitization to peanut had increased between 1989 and 1994 to 1996.
      There was a strong but statistically nonsignificant trend for increase in
      reported peanut allergy.

PMID- 12417890
TI  - Characterization of asparagus allergens: a relevant role of lipid transfer
      proteins.
AB  - BACKGROUND: No asparagus allergen has been characterized to date. Lipid transfer
      proteins (LTPs) have an ubiquitous distribution in plant foods and have been
      identified as relevant allergens in some fruits, seeds, and pollens. OBJECTIVE:
      We sought to identify asparagus allergens and to evaluate the potential
      involvement of the panallergen LTP family in asparagus allergy. METHODS: Eighteen
      patients with asthma, anaphylaxis, and/or contact urticaria after asparagus
      ingestion or exposure and positive skin prick test (SPT) responses and serum
      specific IgE levels to asparagus were selected. Two LTPs were isolated from crude
      asparagus extract by using chromatographic methods and characterized by means of
      N-terminal amino acid sequencing. Both isolated proteins were tested by means of
      immunodetection, CAP inhibition assays, and SPTs. Additional asparagus allergens
      were located by using immunodetection with a pool of sera from patients allergic
      to asparagus and with rabbit polyclonal antibodies to sunflower pollen profilin
      and anti-complex asparagine-linked glycans antibodies. RESULTS: The purified LTPs
      showed an N-terminal amino acid sequence similar to that of Pru p 3 and a strong
      reaction to anti-Pru p 3 antibodies. Each isolated protein reached inhibition
      values of up to 60% in CAP inhibition assays against asparagus extracts and
      elicited positive SPT responses in 9 of 18 patients with asparagus allergy.
      Immunodetection assays allowed us to identify profilin and cross-reacting
      carbohydrate determinants as asparagus IgE-binding components. CONCLUSION:
      Asparagus LTPs are relevant allergens. In addition, profilin and glycoproteins
      harboring complex asparagine-linked glycans can also be involved in asparagus
      allergy.

PMID- 12417891
TI  - Severe oral allergy syndrome and anaphylactic reactions caused by a Bet v 1-
      related PR-10 protein in soybean, SAM22.
AB  - BACKGROUND: Anaphylactic reactions to soy products have been attributed to stable
      class 1 food allergens. OBJECTIVE: IgE- mediated reactions to a soy-containing
      dietary food product in patients allergic to birch pollen were investigated.
      METHODS: Detailed case histories were taken from 20 patients. Their sera were
      analyzed for IgE (UniCAP) specific for birch, grass, mugwort, the recombinant
      birch allergens rBet v 1 and rBet v2, and soy protein. Extracts from birch
      pollen, soy isolate, rBet v 1, and the recombinant PR-10 soy protein rSAM22 were
      coupled to paper disks or nitrocellulose for IgE measurements (enzyme
      allergosorbent test) or Western blot analysis. Enzyme allergosorbent testing,
      Western blot inhibition, and histamine release studies were performed with the
      same allergens. RESULTS: Most patients (17/20) experienced facial, oropharyngeal,
      and/or systemic allergic symptoms within 20 minutes after ingesting the soy
      product for the first time. Birch pollen allergy (16/20) was common, along with
      oral allergy syndrome to apple (12/20) or hazelnut (11/20). IgE levels to birch
      and Bet v 1 but not to other inhalants were high in 18 of 20 patients.
      Significant IgE binding to rSAM22 occurred in 17 of 20 patients. Blot experiments
      with the soy isolate revealed IgE-binding bands at 17 kd (15/20), 22 kd (1/20),
      and 35 to 38 kd (2/20); the former was inhibited by preincubation of the sera
      with rBet v 1 or rSAM22. Birch extract and soy isolate, rBet v 1, and rSAM22
      induced dose-dependent histamine release in the nanomolar range. CONCLUSION:
      Immediate-type allergic symptoms in patients with birch pollen allergy after
      ingestion of soy protein-containing food items can result from cross-reactivity
      of Bet v 1 -specific IgE to homologous pathogenesis-related proteins,
      particularly the PR-10 protein SAM22.

PMID- 12417892
TI  - Isolation and biochemical characterization of a thaumatin-like kiwi allergen.
AB  - BACKGROUND: Kiwi fruit allergy, as well as its association with hypersensitivity
      to other foods and to pollen, has been extensively reported in the last few
      years. Several IgE-binding components have been detected in kiwi extract, but
      only one 30- kd allergen has been isolated; it was identified as actinidin (Act c
      1). Recently, we have reported a 24-kd kiwi protein to be a potential major
      allergen in a group of patients with oral allergy syndrome (OAS). OBJECTIVE: The
      aim of this study was to purify and characterize the 24-kd kiwi allergen
      biochemically. METHODS: Seven polysensitized patients with OAS to kiwi were used
      in this study. The kiwi allergen was isolated by using a combination of gel
      permeation, ion exchange, and immobilized metal ion affinity chromatography. Its
      biochemical characterization included determination of its isoelectric point,
      molecular weight, N-terminal sequencing, concanavalin A -binding ability,
      digestibility in simulated gastric fluid, and antifungal activity. Western
      blotting, 2-dimensional PAGE immunoblotting, and skin prick tests were performed
      to characterize the isolated protein immunochemically. RESULTS: All 7 patients
      recognized the isolated 24-kd kiwi protein as an allergen. The isolated protein
      consisted of 2 isoforms with isoelectric points of 9.4 and 9.5 migrated as one
      protein band of 20 kd after SDS-PAGE under nonreducing conditions or at 24 kd
      under reducing conditions. The partial N-terminal sequence revealed that it is a
      thaumatin-like protein (TLP) with concanavalin A -binding ability. The protein
      showed antifungal activity toward Saccharomyces carlsbergensis, and Candida
      albicans. The protein was degraded by the simulated gastric fluid within 1
      minute. Both isoforms bound IgE from a pool of sera in a 2-dimensional PAGE
      immunoblot. The TLP elicited positive skin prick test responses in 4 (80 %) of 5
      patients with OAS. CONCLUSION: This study reported isolation and full
      characterization of a new kiwi allergen, TLP (isoelectric points of 9.4 and 9.5
      and molecular weight of 24 kd), which belongs to the family of pathogenesis
      related proteins. The isolated protein expressed antifungal activity toward S
      carlsbergensis and C albicans.

PMID- 12417893
TI  - Endotoxin from synthetic and feather pillows.

PMID- 12417894
TI  - Infantile natural immunization to herpes group viruses is unrelated to the
      development of asthma and atopic phenotypes in childhood.

PMID- 12417895
TI  - Rapid desensitization and rush immunotherapy to trastuzumab (Herceptin).

PMID- 12417896
TI  - Identification of specific IgE to mesquite wood smoke in individuals with
      mesquite pollen allergy.

PMID- 12417897
TI  - Mosquito saliva-specific IgE and IgG antibodies in 1059 blood donors.

PMID- 12417898
TI  - Publication bias with cetirizine in atopic dermatitis: safe but ineffective?

PMID- 12417900
TI  - The scientific basis of reproductive medicine.

PMID- 12417901
TI  - Dilatation and curettage: praxeology.
AB  - OBJECTIVES: To determine variations in the rate of inpatient and outpatient
      dilatation and curettage (D&C), for the treatment of early pregnancy loss, and
      for the diagnosis of abnormal uterine bleeding, in 17 health regions across a
      Canadian province. DESIGN: Frequency of D&C was examined in a cohort of 1.36
      million women in Alberta. All inpatient and outpatient episodes in which
      dilatation and curettage was used for management of early pregnancy loss and for
      diagnosis or treatment of abnormal uterine bleeding were included. Variations in
      frequency among the 17 health regions were examined. RESULTS: Rates of D&Cs
      performed following miscarriage or pregnancy showed a 4-fold variation among the
      17 regions, between women aged 20 to 34 years and 35 to 49 years. Consistency
      within the regions, when comparing both groups of women, was significant (r2 =
      0.5542, p = 0.00006). The rates for D&C for abnormal uterine bleeding showed up
      to 5-fold variation among the 17 regions between women aged 20 to 34 years, 35 to
      49 years, and 50 years or more. The Pearson correlation coefficient for
      association of rates for procedure codes 69.02 and 69.09 across the regions was
      0.62 (p < 0.01). Percentages of procedures performed as inpatients ranged between
      33.3% and 83.3% for procedure code 69.02, and between 5% and 17% for procedure
      code 69.09. The Pearson correlation coefficient for inpatient surgery frequency
      was 0.5913 (p < 0.02) across the regions. Substantial variations in the frequency
      of D&C were observed among health regions, and between urban and rural dwellers.
      CONCLUSIONS: Substantial variations in D&C utilization were found in Alberta,
      rendering the need for a more detailed analysis. The extent of variation among
      regions is difficult to explain on grounds other than physician preference. High
      variation in rates of procedure codes 69.02 and 69.09 performed on an outpatient
      basis suggests that lower rates of inpatients could be achieved in many regions
      for both procedures. The higher estimated cost of D&C procedures compared to
      office biopsies in Alberta is a good incentive to re-examine the role of and need
      for performing D&Cs.

PMID- 12417902
TI  - Mechanisms of term and preterm birth.
AB  - Labour at term and preterm results from activation and then stimulation of the
      myometrium. Activation can occur through mechanical stretch of the uterus, and by
      endocrine pathways resulting from increased activity of the fetal hypothalamic
      pituitary-adrenal axis. In women and in experimental animals, cortisol likely
      contributes to increased prostaglandin production in fetal tissues through up
      regulation of the type 2 prostaglandin H2, synthase-2 (PGHS-2) and down
      regulation of 15-OH prostaglandin dehydrogenase. Cortisol increases expression of
      prostaglandin dehydrogenase in the chorion by reversing the stimulatory effect of
      progesterone, and may represent "progesterone withdrawal" in the primate. By
      competing with progesterone inhibition, cortisol also increases expression of
      placental corticotropin-releasing hormone. Other agents, such as pro-inflammatory
      cytokines, similarly up-regulate PGHS-2 and decrease expression of prostaglandin
      dehydrogenase. Oxytocin, produced locally within the intrauterine tissues, is
      also thought to be involved in parturition, and there is a marked increase in
      oxytocin receptor expression at term. There are thus several mechanisms by which
      labour at term or preterm may be initiated. These different mechanisms need to be
      considered in the development of strategies for the detection and management of
      women in preterm labour. Ongoing studies are investigating the use of oxytocin
      receptor antagonists, PGHS-2 inhibitors, and nitric oxide to prevent or regulate
      preterm labour. The presence of fibronectin in vaginal secretions, and elevated
      maternal serum levels of corticotropin-releasing hormone, estrogens, and
      cytokines have been examined as possible markers of preterm labour. However, at
      the present time, we do not have the ability to accurately predict or diagnose
      preterm labour, nor do we have specific or efficient methods to inhibit labour
      once it has started.

PMID- 12417903
TI  - It ain't necessarily so: most women do not strongly prefer female obstetrician
      gynaecologists.
AB  - OBJECTIVE: To examine whether Canadian women seeking care from obstetrician
      gynaecologists prefer to see female or male physicians or have no strong
      preference in this regard. METHODS: A self-administered questionnaire assessing
      women's "strong preference" for female or male obstetrician-gynaecologists, or
      their lack of a strong preference in this area, was completed by 409 women (93.8%
      response rate) attending two hospital-based obstetrics and gynaecology outpatient
      clinics in London, Ontario. RESULTS: Overall, 75% of women stated that they had
      no strong preference concerning the gender of their obstetrician-gynaecologist;
      21% strongly preferred a female obstetrician-gynaecologist; and 4% strongly
      preferred a male obstetrician-gynaecologist. Women who were single, pregnant, or
      had a history of abortion, sexual coercion, relationship violence, sexual
      dysfunction, or sexually transmitted disease were no more likely to prefer to see
      a female obstetrician-gynaecologist than were women without these
      characteristics. CONCLUSION: A clear majority of women expressed no strong
      preference for the gender of their obstetrician-gynaecologist, and preference for
      a female obstetrician-gynaecologist was not associated with a history of
      sensitive gender-related medical concerns. Nationally representative research is
      needed to clarify women's preferences in this domain across the regions of Canada
      and to determine the strength and correlates of any such preferences. Patient
      care and human rights implications of women's preference for the gender of their
      obstetrician-gynaecologist will need to be carefully considered as well.

PMID- 12417904
TI  - Factors affecting Yukon teen pregnancy decline in the mid and late 1990s.
AB  - Teen pregnancy has declined throughout North America in the 1990s. In Yukon
      Territory, Canada, teen pregnancy in the late 1990s was almost 40% lower than in
      the early 1990s. This rate of decline is significantly greater than most recently
      reported national rates of teen pregnancy decline in Canada and United States.
      Identifying possible causes of the Yukon decline may help policy makers and
      program managers plan and implement teen pregnancy prevention strategies. Data on
      Yukon teen pregnancy prevention initiatives were collected through numerous
      discussions and interviews with Yukon service providers, teens, and the general
      public between 1994 and 2001. Analysis of data demonstrates that multiple new
      initiatives spanning many sectors were implemented in the mid and late 1990s that
      could have contributed to the decline in Yukon teen pregnancy. A multi
      dimensional approach to teen pregnancy prevention that included researching and
      evaluating family planning programs and policies before, during, and after
      implementation, increasing access to longer-acting hormonal contraceptives,
      providing continuing family planning medical education to health care providers
      and other youth service providers, subsidization of contraceptives, delivery of
      innovative family planning mass media campaigns, and delivery of ongoing sexual
      health education programs may have significantly contributed to the decline in
      Yukon teen pregnancy. Collaboration among service providers across many service
      sectors (clinical, public health, education, First Nations, government
      communication and policy, grassroots) facilitated coordination of the multi
      dimensional approach.

PMID- 12417905
TI  - Screening for gestational diabetes mellitus.
AB  - OBJECTIVE: The purpose of this document is to briefly review the existing data
      regarding the effect of a diagnosis of gestational diabetes mellitus (GDM), the
      different screening and diagnostic practices for GDM, and, finally, outline the
      recommended options for GDM screening in Canada. OPTIONS: Consideration has been
      given to the existing screening practices for GDM including universal screening,
      risk factor-based screening, and the option of not screening for GDM. OUTCOMES:
      The short- and long-term maternal-fetal outcomes in GDM were reviewed with
      emphasis given to examination of the data regarding the effect of diagnosis and
      treatment of GDM on these outcomes. EVIDENCE: A comprehensive search of the
      literature from 1990 through April 2002 using MEDLINE and the Cochrane Database
      and a review of randomized controlled trials (RCTs) was undertaken. Additional
      studies and clinical guidelines published outside this time frame but with
      specific clinical relevance were also reviewed. The level of evidence of the
      recommendations in this document has been determined using the criteria described
      by the Canadian Task Force on the Periodic Health Examination. RECOMMENDATIONS:
      I. A single approach of testing for GDM cannot be recommended at the present as
      there is not enough evidence-based data proving the beneficial effect of a large
      screening program. Until a large prospective RCT shows a clear clinical benefit
      for screening and consequently treating GDM, recommendations will by necessity be
      based on consensus or expert opinion. Each of the following approaches is
      acceptable. a. Routine screening of women at 24-28 weeks of gestation may be
      recommended with the 50 g glucose challenge test (GCT), using a threshold of 7.8
      mmol/L (140 mg/dL), except in those women who fulfill the criteria for low risk,
      which includes the following: * maternal age < 25 * Caucasian or member of other
      ethnic group with low prevalence of diabetes * pregnant body mass index (BMI) </=
      27 * no previous history of GDM or glucose intolerance * no family history of
      diabetes in first-degree relative * no history of GDM-associated adverse
      pregnancy outcomes. The diagnostic test can be the 100 g oral glucose tolerance
      test (OGTT), as recommended by ACOG, or the 75 g OGTT, according to the American
      Diabetes Association (ADA) criteria. Use of the World Health Organization (WHO)
      criteria will approximately double the number of women diagnosed with GDM without
      an apparent clinical benefit. (III-C) b. A small but significant number of
      Canadian obstetricians and centres have a policy of non-screening for GDM. Until
      evidence is available from large RCTs that show a clear benefit from screening
      for glucose intolerance in pregnancy, the option of not screening for GDM is
      considered acceptable. Conversely, there are no compelling data to stop screening
      when it is practiced. (III-C) c. The clinician should consider the recommendation
      of the Fourth International Workshop-Conference that women considered at high
      risk for GDM should undergo a diagnostic test as early in pregnancy as possible
      and that testing should be repeated at 24-28 weeks if initial results are
      negative. (III-C) d. If GDM is diagnosed, glucose tolerance should be re-assessed
      with a 75 g OGTT 6-12 weeks postpartum in order to identify women with persistent
      glucose intolerance. (III-C)2. A large RCT is needed to quantify the advantages
      and dis-advantages of routine screening for GDM. Furthermore, the need for
      universally accepted, outcome-based diagnostic criteria for GDM is emphasized.
      (III-C) VALIDATION: This guideline was reviewed by the SOGC Maternal-Fetal
      Medicine Committee. SPONSOR: The Society of Obstetricians and Gynaecologists of
      Canada.

PMID- 12417906
TI  - [Detection of genetic materials in mammalian somatic cell cloning].
AB  - Following the production of cloned sheep, mice, goats, pigs, cats, rabbits and
      argali from somatic cells, the cellular and molecular biological tests of cloned
      animals and early embryos turn to be more important. In this review, chromosome
      analysis, nuclear DNA analysis, mitochondrial DNA analysis and telomeric DNA
      analysis that are applied in the detection of cloned mammal and early embryos are
      described.

PMID- 12417907
TI  - Structural analysis of a gene cluster encoding DFR-like proteins from rice
      chromosome 4.
AB  - Sequencing analysis of the 323 kb contig of rice chromosome 4 identified a gene
      cluster encoding 7 dihydroflavonol-4-reductase (DFR)-like proteins within a 56 kb
      region. The 7 DFR-like genes were found to be arranged in a tandem array, and all
      of them comprised 6 exons and 5 introns. Analysis of the predicted amino acid
      sequences demonstrated that these 7 proteins shared strong similarities with DFR
      and other enzymes of the phenylpropanoid biosynthesis pathway. RT-PCR revealed
      the expression pattern of the 7 genes was different in various rice tissues. The
      structural and functional features of these 7 DFR-like genes and their
      evolutionary implications are discussed.

PMID- 12417908
TI  - Purification and characterization of a novel chitinase from Bacillus brevis.
AB  - An extracellular chitinase secreted by Bacillus brevis was purified to
      homogeneity by a combination of ammonium sulfate precipitation, Phenyl-Sepharose
      hydrophobic-interaction chromatography and DEAE anion-exchange chromatography. On
      SDS-polyacrylamide gel electrophoresis analysis, the purified enzyme showed a
      mass of 85 kD even in the presence of beta mercaptoethanol, but shifted to 48 kD
      when heated in boiling water or treated with 8 mol/L urea at 50 degrees for 10
      min. The depolymerization of subunits was accompanied with the loss of chitinase
      activity, and removing denaturing factors by dialysis could restore the dimer
      structure and enzymatic activity. The enzyme had an isoelectric point of 5.5 and
      an optimal temperature of 60 degrees, and was most active at pH 8.0. The
      enzymatic activity was stable at pH 6-10, and inhibited by Ag(+). Ten N-terminal
      amino acids were determined to be AVSNSKIIGY, demonstrating that the purified
      enzyme was a novel one. The hydrolysis pattern of the purified enzyme indicated
      that the chitinase was an endochitinase. The extraordinary thermo-stability and
      high resistance to proteolysis provide the enzyme with a good prospect to be used
      as a new tool for biocontrol.

PMID- 12417909
TI  - Increasing bioactivity of Flt3 ligand by fusing two identical soluble domains.
AB  - Flt3 ligand (FL) is a hematopoietic growth factor, initiating its in tracellular
      signaling cascade by binding to counterpart receptor and driving receptor
      dimerization. The native form of soluble FL in vivo is mainly monomeric. In this
      study, we constructed a rFL-FL fusion protein cDNA by linking two copies of cDNA
      encoding the soluble domain of FL in tandem and expressed it in Pichia pastoris.
      On SDS-polyacrylamide gel electrophoresis, the rFL-FL fusion protein showed a
      molecular weight of 43 kD, agreeing well with the predicted value. The 43 kD
      protein was further confirmed by Western blot using polyclonal rabbit anti-human
      FL antibody. The rFL-FL fusion protein exhibited about 10-fold increment in its
      activity on colony formation of bone marrow progenitor cells. RFL-FL fusion
      protein also exerted more potent effect than monomeric FL on extending the
      survival of starving Raji cells.

PMID- 12417910
TI  - Transient expression of strictosidine synthase in tobacco leaves by vacuum
      infiltration.
AB  - Strictosidine synthase (STR) is the key enzyme involved in early steps of
      biosynthesis of monoterpenoid indole alkaloids. STR catalyzes the condensation of
      tryptamine with secologanin into strictosidine. The gene encoding STR targeted to
      different subcellular compartments was transiently expressed in the tobacco
      leaves. In vitro STR enzymatic activity was measured by the depletion of
      tryptamine indicated by fluorescence. The results showed that the recombinant STR
      was effectively expressed as soluble protein in three subcellular compartments
      chloroplast, vacuole and endoplasmic reticulum in the leaves of tobacco by
      Western blot analysis and STR enzymatic assay.

PMID- 12417911
TI  - Apoptosis of Spodoptera litura cells induced by AcMNPV ie-1 gene.
AB  - Apoptosis was induced in Spodoptera litura Sl-zsu-1 cells transfected with
      plasmid pAcie-1 DNA containing ie-1 gene of Autographa californica multicapsid
      nucleopolyhedrovirus (AcMNPV). Apoptotic bodies appeared 24 h post transfection
      and cell mortality peaked after 48 h. Electrophoresis of total DNA extract of Sl
      zsu-1 cells showed a DNA ladder, indicating that transfection of ie-1 gene alone
      can trigger apoptosis directly or indirectly. It was shown by cytochalasin D (CD)
      and ammonium chloride inhibition assays that the entry of virions into cytoplasm
      was required for induction of apoptosis. Reverse transcriptase PCR (RT-PCR) was
      used to demonstrate that ie-1 gene had transcribed in Sl-zsu-1 cells immediately
      after infection. Inhibition of DNA replication could not block the cell death
      process, suggesting that this apoptosis was independent on viral late replication
      events. Apoptosis did not occur when Sl-zsu-1 cells were infected with an AcMNPV
      mutant tsB821 at its nonpermissive temperature. Therefore, we concluded that the
      ie-1 gene is at least one of the factors inducing apoptosis in Sl-zsu-1 cells
      infected with AcMNPV.

PMID- 12417912
TI  - [Isolation and characterization of functional replication origin from
      Streptomyces avermitilis].
AB  - Most eubacteria contain highly conservative gene clusters in the adjacent regions
      of oriC. According to this principle, a 1.4 kb DNA fragment containing parts of
      dnaA and dnaN genes of Streptomyces avermitilis was cloned by degenerate PCR.
      Sequence analysis of this fragment indicated that it encoded two partial genes in
      the order dnaA (the putative initiator protein) and dnaN (the beta subunit of DNA
      polymerase III). The intergenic non-coding region between dnaA and dnaN was found
      to contain 19 putative DnaA boxes, i.e. 9 nt long DnaA protein recognition
      sequences. It was confirmed that the location, orientation and spacing of DnaA
      boxes in this intergenic region are conserved among Streptomyces. The consensus
      sequence of DnaA box identified is (T/C)(T/C)(G/A/C)TCCACA (preferred bases in
      italic). When this fragment was cloned into Escherichia coli plasmid pQC156,
      which is otherwise non-replicative in Streptomyces, it exhibited autonomous
      replication activity in Streptomyces lividans, a closely related Streptomyces
      strain. Different parts of the oriC contribute unequally to the stability and
      transformation efficiency. The 3' region of oriC may contain features that
      support stable autonomous replication. The implications of these results for the
      understanding of the S. avermitilis oriC replication initiation process and its
      future application are discussed.

PMID- 12417913
TI  - [Antigen presentation efficiency of recombinant Vaccinia virus expressing
      minigene product OVA(257-264) in eukaryotic cells].
AB  - rVV (recombinant vaccinia virus) expressing minigene products and rVV expressing
      full length OVA protein were used to infect several eukaryotic cells. Monoclonal
      antibody 25.D-1.16 (anti-OVA(257-264)/K(b)) was used to detect the conformation
      of H-2K(b)-OVA complex on the surface of these cells. The tetramer technique was
      used to determine their ability to induce antigen specific T cells. The results
      showed that the tetramer had been generated successfully. Moreover, L929-K(b)
      cells infected by rVV-OVA can be used as APC to induce CTL response. Specific CTL
      response was demonstrated by H-2K(b-OVA tetramer staining and cytotoxicity assay.
      Extracelluar IFN-gamma was also quantitatively analyzed. The results from H-2Kb)
      OVA tetramer staining were consistent with cytotoxicity assay. It can be
      concluded that rVV expressing minigene product is a more efficient source of
      peptides for class I molecules, and can be more immunogenic than rVV expressing
      full length protein.

PMID- 12417914
TI  - [High expression of a heat-stable phytase in Pichia pastoris].
AB  - It is difficult to obtain naturally occurring phytase having the required
      thermostability for application in animal feeding. The 1.3 kb thermal stable
      phytase gene (fphy) of Aspergillus fumigatus was synthesized by using a
      successive PCR method for the optimal expression in Pichia pastoris. Though the
      nucleotides of synthetic fphy share only 74% homology with the natural gene, the
      amino acid sequences coded by both genes were identical. After being cloned into
      the yeast expression vector (pPIC9) and inserted into the chromosome of Pichia
      pastoris by homologous recombination, phytase was expressed in the yeast and
      secreted from the cell. The strains for phytase over-expression were selected out
      by SDS-PAGE and enzyme analysis. After fermentation in 5 L fermention tank and
      induced by 0.5% methanol for 60 h, about 5.6 g purified phytase was obtained per
      liter culture fluid. The activity of phytase was 130 000 u per microlitre fluid.
      The thermostable phytase remained 40% active after exposure at 90 degrees for 80
      min.

PMID- 12417915
TI  - [Clonging, expression and activity determination of the recombinant human soluble
      B lymphocyte stimulator and its two mutants].
AB  - B lymphocyte stimulator (BLyS) is a member of the tumor necrosis factor (TNF)
      ligand superfamily that functionally involved in B cell proliferation. Here, the
      full length cDNA of human soluble BlyS (hsBLyS) was amplified by reverse
      transcription-PCR from total RNA of human peripheral blood lymphocytes and
      sequenced. The cloned cDNA fragments was inserted into pBV220, a thermo-sensitive
      expression plasmid, forming recombinant plasmid pBV220/hsBLyS. The two mutants of
      hsBLyS: hsBY-A (Cys(146) right curved arrow Ala(146), TGC right curved arrow GCT)
      and hsBY-V (Cys(146) right curved arrow Val(146), TGC right curved arrow GTT),
      were amplified by overlap PCR from pBV220/hsBLyS and inserted into the pBV220 to
      form pBV220/hsBY-A and pBV220/hsBY-V expression plasmids as the method above. The
      three expression plasmids were transformed into E.coli DH5alpha and it was found
      that the recombinant proteins were highly expressed as inclusion bodies. Pure
      recombinant proteins were obtained by Sephacryl-200 gel filtration and
      renaturation. The experimental results demonstrated that the sequences of the PCR
      products were identical with the published hsBLyS cDNA sequence or expected
      mutant sequence and the purity of the recombinant proteins obtained was
      relatively high. The activity of the purified recombinant proteins was very
      significant in the B cell survival and proliferation assay, and statistical tests
      indicated that the mutant rhsBY-V promoted proliferation of B lymphocyte cell
      remarkably better than the wild type.

PMID- 12417916
TI  - Cloning and expression of the AtGRP9 gene related to salt stress tolerance in
      Arabidopsis thaliana.
AB  - The fission yeast Schizosaccharomyces pombe is a single cell eukaryotic organism.
      Taking advantage of the genetic simplicity of S.pombe and of the functional
      conservation of some salt tolerance-related proteins, this organism was used as a
      simple system to identify Arabidopsis thaliana salt-tolerance proteins by
      screening for cDNA clones that confer salt resistance when overexpressed. By this
      "cross-phylogenetic" screen, an A.thaliana gene was isolated encoding a glycine
      rich protein, which was named AtGRP9. Overexpression of AtGRP9 in yeast cells led
      to significant increase in salt tolerance of the yeast strain. Northern blotting
      analysis revealed that AtGRP9 was expressed specifically in the roots of
      A.thaliana and was induced by NaCl. The growth of some transgenic plants was
      easily controlled by using the medium with different NaCl concentrations. Taken
      together, these results show that AtGRP9 may be involved in the salt stress
      response in A.thaliana.

PMID- 12417917
TI  - [IRE_FINDER-computational search of iron response element in human and mouse
      UTRs].
AB  - The iron response element (IRE) is a highly conserved RNA stem loop structure. It
      is the binding site of iron regulatory protein (IRP). IRP binding to IRE is
      regulated by cellular iron. When cells are derived of iron, IRP binds IRE. If IRE
      is located at 5'UTR, IRP binding will inhibit translation initiation, else if IRE
      is at 3'UTR, IRP binding will stabilize mRNA and prevent it from degradation. So
      far all known IREs have C at the 1 position and G at the 5 position of the loop
      (C1G5 type). In vitro studies suggest that the U1A5 type IRE, which has U and A
      at the 1 and 5 loop position respectively, binds well to IRP. However, U1A5
      type's in vivo existence is still elusive. IRE-IRP binding is involved in the
      regulation of iron metabolism, oxidative stress and possibly aging. Here we use
      an improved computation method performing a comprehensive search of IRE in human
      and mouse genes. We try to catalog potential human and mouse IRE containing
      genes, at the same time identify potential U1A5 IREs.

PMID- 12417918
TI  - [Effects of mechanical strain on the proliferation of pulmonary epithelial cells
      and reorganization of integrins].
AB  - Using a cyclic strain unit, the proliferation and reorganization of alpha(5),
      beta(1 ) integrins in human pulmonary epithelial A549 cells that underwent
      mechanical strain were studied. Flow cytometry revealed that cellular
      proliferative index reduced significantly after cells were subjected to 15%
      elongation at frequency 20 cycles/min or 40 cycles/min for 48 h. Confocal
      microscopy revealed that alpha(5), beta(1 ) integrins in human pulmonary
      epithelial A549 cells transferred from the apic al layer to the basal layer and
      created adhesion plaques after 24 h exposure to 15% elongation at frequency 40
      cycles/min. It is concluded that alpha(5), beta(1 ) integrins in pulmonary
      epithelial cells play an important role in transducing mechanical stress into
      intracellular signals.

PMID- 12417919
TI  - [Expression, purification of the recombinant protein fragment of the monkey
      epididymis expressed gene ESc-615 and preparation of polyclonal antisera to it].
AB  - ESc-615 is a gene which was specifically expressed in epididymis, newly
      discovered in our laboratory. To elucidate the function of ESc-6 15 in sperm
      maturation and fertilization at the protein level, its C-terminal 310 amino ac id
      residues fragment was expressed in E.coli and used to immunize rabbits to obtain
      polyclonal antiserum with titer of 100 000. The antisera could detect th e
      antigen as low as 3 ng. A 63 kD protein in rat epididymis protein extracts could
      be detected in Western blot by using this particular antiserum, in accordance
      with the size of Esc-615 homologue polypeptide deduced from its cDNA.
      Immunostaining results showed that Esc-615 was a secreted protein and could bind
      sperm s, which was similar with other carboxylesterases in male reproductive
      system; t he positive staining was eliminated after antigen absorption. All these
      results showed that this antiserum was not only effective but also highly
      specific, providing a useful tool in further functional studies of Esc-615.

PMID- 12417920
TI  - [Construction and growth properties of recombinant pseudorabies virus expressing
      modified enhanced green fluorescent protein].
AB  - The 1.0 kb DNA fragment containing the modified enhanced green fluorescent
      protein CDNA M1 (EGFP S147/P) and SV40 poly(A) signal sequence w as amplified and
      cloned in frame behind the first eight codons of the nonessential glycoprotein G
      (gG) of pseudorabies virus (PRV) to yield a transfer plasmid. The transfer
      plasmid was linearized and cotransfected with the genomic DNA of P RV Ea mutant
      gG(-)/LacZ(+). The resulting recombinant virus expressing M1, designated as gG(
      )/LacZ(+), was isolated and confirmed by plaque purification, PCR, Southern blot
      and Western blot. PK-15 cells were infected with the purified recombinant virus
      at 0.1 pfu/cell and fluorescence emission was monitored at different times post
      infection (p.i.) using fluorescence microscopy. Fluorescence emission could be
      detected as early as 6 h p.i. when there was no apparent cytopathic effects (CPE)
      yet. Fluorescence intensity increased drastically later. Maximum intensity was
      achieved at 24-36 h p.i. and fluorescence was stable. With the progress of the
      CPE, fluorescence vanished. The growth properties of gG(-)/M1(+) in tissue
      cultures were further examined and the titer of gG(-)/M1(+) was similar to that
      of PRV Ea wild strain and the parental strain gG(-)/LacZ(+). The above results
      indicated that the recombinant virus expressing the modified EGFP can be used as
      an in vivo marker to monitor replication and spread, as well as t o study the
      molecular pathogenesis of PRV.

PMID- 12417921
TI  - [The possible mechanisms underlying low expression of human beta-globin gene
      cloned in a retroviral vector].
AB  - Murine erythroleukemia (MEL) cell line was used as a model to evaluate the
      potential value of retroviral construct containing human beta-globin express io n
      cassette in gene therapy of beta-thalassemia and to explore possible mechanisms
      underlying low expression of retrovirally cloned human beta-globin gene. A
      recombinant retroviral vector was constructed, which harbored 2.0 kb beta-globin
      gene w it h a 374 bp deletion in intervening sequence II coupled with a mini
      locus control region (miniLCR) composed of DNaseI hypersensitive sites (HS) 2 and
      3 from human beta-LCR. The recombinant retroviruses were generated from an
      established psi-2 producer cell line, and by transient transfection of
      amphotropic packaging cell l ine psi-A, respectively. The integrity of provirus
      in transduced MEL cells was determined using Southern blot, and the expression of
      transferred human beta-globin gene was detected using RNase protection assay. The
      structure of provirus was further analyzed by sequence analysis of PCR products
      from genomic DNA of MEL individual clone as template. The results demonstrated
      that the average expression of human beta-globin gene was (52.4-/+11.2)% (n=12)
      and (73.8-/+14.3)% (n=12, without copy-number determination), compared with that
      of endogenous murine alpha-globin ge ne, in MEL cells transduced with the
      recombinant retrovirus from transient transfection of psi-A and MEL cells
      transfected with the construct, respectively. In M EL cells transduced with virus
      from psi-2 producer cell line, however, the average expression was less than 3%.
      A point mutation was detected in HS2 of provirus i n MEL cell clone with low
      expression of human beta-globin gene. The possible mechanisms involved in low
      expression, including position effect, DNA methylation a nd RNA interference are
      discussed in addition to the point mutation.

PMID- 12417922
TI  - Enhancement of proliferation of HeLa cells by the alpha-fetoprotein.
AB  - A lot of investigations showed that alpha-fetoprotein(AFP) could regulate the
      proliferation of tumors or neoplastic cells. In order to study the enhancement of
      this function, AFP was extracted from human cord blood serum and was allowed to
      act on HeLa cell in vitro. The cellular proliferation was investigated by using
      the MTT assay and the [(3)H]-incorporation, and the cell cycle was analysed with
      flow cytometry. Radioactive immunosorbent assay was utilized to detect cAMP
      accumulation, protein kinase A activity and confocal microscopy was used f or
      scanning intracellular calcium. The expression of mutant p53 and p21(ras) protein
      were analyzed by Western blotting. Our results showed that AFP (>10 mg/L ) had
      strong effect of enhancement on the proliferation of HeLa cells; AFP (20 mg /L)
      could significantly increase the concentration of cAMP (300%), Ca(2+) (154.9%)
      and protein kinase A activity (100%). It was also shown that the expression of
      mutant p53 and p21(ras) protein of HeLa cells were enhanced after t he treatment
      with AFP (20 mg/L) for 24 hours. Compared with control, the expression of mutant
      p53 protein was increased by 81.1% (24 h), p21(ras) protein was increased by
      96.2% (24 h) respectively; but the monoclonal antibody to AFP blocked these
      functions of AFP. In conclusion, AFP enhanced the proliferation of HeLa cells;
      AFP may regulate the growth of the cells by influencing the transmembrane signal
      pathway and enhancing the expression of the oncogenes.

PMID- 12417923
TI  - [Regulation by ovarian hormones of alpha 1,3-fucosyltransferase gene (FUT9)
      expression in human endometrium].
AB  - Recently it was found that alpha1,3-fucosyltransferase (FUT9) was an essential
      enzyme involved in the synthesis of Le(X) oligosaccharide. In this article, the
      expression of FUT9 gene at different hormonal levels and the regulating mechanism
      of Le(X) synthesis in human endometrium were investigated by using RT-PCR Immuno
      histochemistry staining and Western blotting. FUT9 mRNA was detected with human
      endometrium, and the levels of mRNA in secretory endometrium and in proliferative
      endometrium from patients who had taken mifepristone before operation, were
      higher than tha t of proliferative endometrium (P<0.01). Le(X) antigen was mainly
      located on the surface of epithelium. The floating level of Le(X) antigen
      expression was similar to that of FUT9 gene. There were three (33 kD, 35 kD and
      85 kD) LeX carrying proteins expressed in human endometrium, mifepristone
      treatment made 35 kD b and disappear. The results indicate that FUT9 gene is
      obviously expressed in human endometrium and can be upregulated by progesterone,
      and ovary hormones regulate the expression of Le(X) at the level of
      transcription.

PMID- 12417925
TI  - [The pH-dependent catalytic reaction of penicillin G acylase and its mutants].
AB  - The pH-dependence in the catalytic reaction of recombinant penicillin G acylase
      and its mutants from B.megaterium has been studied by using kinetic methods.
      pK(1) and pK(2)of the residues of the wild type penicillin G a cylase, involved
      in the catalyzed reaction, were 5.50-5.87 and 10.73, respectively, from the
      curves of logV(m) and log(V(m)/K(m)) versus pH. Results showed tha t the pK(1)
      and pK(2) values of these residues of the mutants were similar to that of the
      wild type. pK(1) of 5.64-5.86 for mutant A and 5.69-6.96 for mutant B were
      obtained, while pK(2) was 10.61 and 10.48 for mutant A and B, respectively. At
      the same time, pK values at different temperatures were investigated. The
      ionization enthalpies(deltaH) were 44.38-59.03 kJ/mol and 147.37 kJ/mol,
      respectively, from th e curve of pK versus temperature. It was presumed according
      to the results mentioned above that the ionizing residues, involved in the
      reaction, wer e histidine and lysine that are localized around the active site.

PMID- 12417924
TI  - Relationship between a novel polymorphism of hepatic lipase gene and coronary
      artery disease.
AB  - Hepatic lipase (HL) is a lipolytic enzyme involved in the catabolism of plasma
      lipoproteins, and is an important determinant of high density lipoproteins(HDL)
      concentration and low density lipoproteins(LDL) subclass distribution.
      Accordingly, HL activity may influence body's susceptibility to coronary artery
      disease (CAD). Association on the single nucleotide polymorphisms (SNPs) in the
      HL gene to post-heparin plasma HL activity and the plasma HDL-cholesterol
      concentration have been investigated thoroughly, but to date, little is known
      about th is in Chinese. In present study, the SNPs of the HL gene were analyzed.
      The promoter region and all the 9 exons with their flanking sequences of the HL
      gene were amplified from the Chinese patients with CAD and normal controls by PCR
      technique, and the PCR products were detected by denaturing high performance
      liquid chromatography (DHPLC) and sequenced with a dideoxy terminal termination
      method. As the result, a novel SNP-2T right curved arrow C in the promoter of HL
      gene was found. Compared with the control group, more CAD patients carried the 
      2C allele(TC+CC) (57.9% versus 42.7%, chi(2) =4.181, df=2, =0.041). The
      prevalence of the -2C allele was significantly higher in the CAD patients than in
      control subjects (chi(2)=3.988, df=1, P=0.046) and the odds ratio(OR) of -2C
      allele associated with the risk of CAD is 1.58 [95% confidence interval(CI): 1.01
      2.47]. The -2C allele homozygous carriers in the CAD patients had a significantly
      higher HDL-cholesterol level than the noncarriers [(1.13-/+0.24) mmol/L versus
      (0.91-/+0.14) mmol/L, P<0.05]. These suggest that a T right curved arrow C
      substitution at -2 of the HL promoter may be associated with th e variation of
      HDL-cholesterol concentration and therefore affect the risk of CAD in Chinese.

PMID- 12417926
TI  - [Effects of pituitary adenylate cyclase activating polypeptide (PACAP) on
      intracellular cAMP and Ca(2+) levels in common carp (Cyprinus carpio) pituitary
      cells in vitro].
AB  - In order to study signal transduction in PACAP-stimulated GH release, effects of
      ovine PACAPs (oPACAPs) on cAMP synthesis and intracellular free
      Ca(2+)([Ca(2+)](i)) levels in primarily cultured common carp (Cyprinus carpio)
      pituitary cells were investigated using radioimmunoassay (RIA) for cAMP and
      [Ca(2+)](i) Indo-1/AM loading techniques. The main results obtained could be
      briefly summarized as follows: parallel with their GH-releasing effects, oPACAP
      38 (0.01 nmol/L to 1 micromol/L) and oPACAP-27 (0.01 nmol/L to 1 micromol/L) were
      also effective in increasing cAMP release, cellular cAMP content, and total cAMP
      production in a dose-dependent manner in common carp pituitary cells. In addition
      to their cAMP synthesis, 0.5 micromol/L oPACAP-38 and 0.5 micromol/L oPACAP-27
      were also effective in elevating [Ca(2+)](i) levels in common carp pituitary
      cells preloaded with the Ca(2+)-sensitive dye Indo-1; the stimulatory actions
      were dependent on the presence of extracellular Ca(2+) ([Ca(2+)](e)), as removal
      of [Ca(2+)](e) by adding th e Ca(2+) chelator 4 mmol/L E GTA blocked the rise of
      [Ca(2+)](i) induced by oPACAP-38 and oPACAP-27, respectively. Besides, the rise
      in [Ca(2+)](i) induced by 0.5 micromol/L oPACAP-38 was b locked by treatment with
      10 micromol/L nifedipine, an inhibitor of "L-type" voltage-sensitive Ca(2+)
      channels (VSCC); but 0.5 micromol/L oPACAP-38 was not effective in elevating
      [Ca(2+)](i) levels after the cells treated with Ca(2+)-sensitive dye Indo-1 were
      challenged with 10 micromol/L nifedipine. These results, taken as a whole,
      strongly suggest the involvement of the cAMP- and Ca(2+)-dependent pathways in
      PACAP-stimulated GH release in common carp.

PMID- 12417927
TI  - [Molecular cloning of SRG2, a mouse testis spermatocyte apoptosis-related gene].
AB  - A novel mouse gene full-length cDNA sequence-SRG2 were identified (GenBank
      accession number AF395083), which was significantly changed in cryptorchidism,
      from a mouse testis cDNA library using a cDNA fragment (GenBank accession number
      BE644542) as an electronic probe. SRG2 was 1058 bp in length. The putative
      protein encoded by this gene was 295 amino acids with a theoretical molecular
      weight of 33 579 and isoelectric point of 9.64. The sequence shared no
      significant homology with any known protein in databases except TSARG2, with
      which its homology was 78%. RT-PCR showed that SRG2 was expressed significantly
      in testis.

PMID- 12417928
TI  - [Expression of histone-based fusion protein HNHG in E.coli].
AB  - Histone H1 contributes to condense nucleosome into super-structure during the
      transformation of chromatin into chromosome. It is shown in this rep or t that
      the fusion protein HNHG with the core of C-terminus of histone H1(0) expressed in
      BL21 (DE3) could also condense the plasmid DNA, just as histones did in nucleus.
      Under electron microscope, plasmid DNA condensed and supercoiled after t he
      addition of HNHG, in contrast to plasmid DNA control. This specific ability of
      the fusion protein HNHG of binding and condensing plasmids could be utilized to
      construct novel exogenous gene delivery systems. HNHG would be a promising
      candidate for gene delivery.

PMID- 12417929
TI  - Diversity of neuromuscular pathology in lethal multiple pterygium syndrome.
AB  - Lethal multiple pterygium syndrome (LMPS) is an uncommon fetal-onset disorder of
      unknown etiology. The pathogenesis of LMPS has been suggested to be early-onset
      fetal akinesia, fragile collagen, or generalized edema. Information on the
      neuromuscular pathology of LMPS in the literature is generally scanty. We present
      the findings from a review of 14 fetuses with features of LMPS from the archives
      of the Hammersmith Hospital Perinatal Pathology Department. Autopsy reports,
      photographs, fetograms, and histological sections were examined, and additional
      special stains and immunostaining were performed on muscle sections. In five
      cases, there was evidence of autosomal recessive inheritance. One case was later
      shown to be due to glycogen storage disease type IV. The skeletal muscle bulk was
      reduced in all fetuses and the remaining muscle showed a range of histological
      appearances including vacuolar degeneration, dystrophy, a generalized or patchy
      myotubular appearance, and generalized hypotrophy. In one, the histological
      appearance was essentially normal. Two cases had abnormalities in the brain.
      Large motor neurons were present in the anterior spinal horns of all fetuses in
      whom the spinal cord could be examined. There was no evidence of cartilaginous
      joint fusion. We conclude that LMPS is the phenotype resulting from fetal
      akinesia commencing in the first or early second trimester. In the majority of
      cases, the precise underlying cause will not be identified, however, occasionally
      a metabolic or neurodevelopmental disorder or a specific primary myopathy may be
      demonstrated, providing adequate autopsy investigations are undertaken.

PMID- 12417930
TI  - Video-assisted thoracoscopic sympathectomy for palmar hyperhidrosis: results in
      102 cases.
AB  - The purpose of this retrospective study was to evaluate the immediate and long
      term outcome of video-assisted thoracoscopic sympathectomy for idiopathic palmar
      hyperhidrosis. Between January 1996 and December 2000, a total of 67 patients
      underwent 102 sympathectomy procedures with excision of the sympathetic chain
      between the second and fourth sympathetic ganglion. The mean duration of
      hospitalization was 1.7 +/- 0.6 days. Five patients were lost to follow-up. Mean
      duration of follow-up for the 96 sympathectomy procedures in the remaining 62
      patients was 38 +/- 6.3 months. Patient outcome showed that video-assisted
      thoracoscopic sympathectomy is the treatment of choice for idiopathic palmar
      hyperhidrosis. Long-term patient satisfaction is excellent.

PMID- 12417931
TI  - Mobile thrombus of the thoracic aorta: diagnosis and treatment in 9 cases.
AB  - Detection of mobile thrombus of the thoracic aorta has become increasingly common
      thanks to routine exploration using transesophageal echography (TEE) after any
      embolic event. Although the indication for treatment remains controversial, there
      is a growing interest in understanding this potential source of arterial emboli
      and in defining proper diagnostic and therapeutic approaches. The purpose of this
      study was to evaluate the utility of different diagnostic and therapeutic
      modalities used in our department over the last 6 years. Between 1995 and 2000,
      mobile thrombus of the thoracic aorta was diagnosed in 9 patients (5 men, 4
      women) with a mean age of 49.2 years (range, 28 to 68 years). In all patients,
      aortic thrombus was suspected after a peripheral (n = 4) or cerebral (n = 5)
      vascular event. Treatment using intravenous heparin was attempted in all patients
      and allowed complete dissolution of thrombus in four. In the remaining five
      patients, repeat TEE demonstrated persistent thrombus and operative treatment was
      undertaken. In three patients with thrombosis in the aortic arch, thrombectomy
      was performed with cardiopulmonary bypass, and deep hypothermic circulatory
      arrest. In two patients presenting thrombosis in the descending thoracic aorta,
      thrombectomy was performed with an atriofemoral shunt. Thrombectomy was
      associated with repair of a wall defect in two patients and resection of
      atheromatous plaque in one patient. Postoperative recovery was uneventful but
      recurrence was noted in one patient because anticoagulation therapy was stopped
      too soon. On the basis of our experience and previous reports, we have defined
      the following therapeutic strategy. All patients are first treated with heparin.
      In case of failure, thrombectomy may be undertaken in young patients. Because of
      the highly invasive nature of the procedure, careful work-up including TEE should
      be performed to rule out any other cause of embolism and to determine that the
      lesion presents a high potential for embolism. Follow-up must include long-term
      coumadin therapy and routine surveillance using TEE or magnetic resonance
      imaging, since long-term outcome is unclear.

PMID- 12417932
TI  - Reversible protein phosphorylation regulates the dynamic organization of the
      pollen tube cytoskeleton: effects of calyculin A and okadaic acid.
AB  - We investigated the cytoskeleton of Lilium longiflorum pollen tubes and examined
      the effects of the type 2A protein phosphatase (PP2A) inhibitors calyculin A and
      okadaic acid. An improved method for actin visualization, the simultaneous
      fixation and staining with rhodamine-labelled phalloidin during microscopical
      observation, revealed abundant actin filaments of no preferential orientation in
      the apical clear zone. Microtubules, visualized by indirect immunofluorescence,
      were mostly absent from the apices of straight-growing pollen tubes but present
      in those with irregular shape. Double labelling showed that both actin bundles
      and microtubules had a similar longitudinal or slightly helical orientation in
      the pollen tube shaft. In the presence of 30 nM calyculin A or okadaic acid,
      pollen tubes grew very slowly, branched frequently, and contained isolated,
      randomly oriented, curved actin bundles and microtubules. Treating pollen tubes
      with calyculin A or okadaic acid after germination arrested growth immediately,
      reversibly altered the alignment of actin bundles from axial to transverse, and
      disassembled microtubules. The changes in actin organization caused by the PP2A
      inhibitors were similar to those observed upon overexpression of AtRop1 (Y. Fu,
      G. Wu, Z. Yang, Journal of Cell Biology 152: 1019-1032, 2001), suggesting that
      hyperphosphorylation interferes with the signalling pathway of small GTPases. The
      effects of the PP2A inhibitors could be ameliorated with nanomolar concentrations
      of latrunculin B.

PMID- 12417933
TI  - O-4-Linked coniferyl and sinapyl aldehydes in lignifying cell walls are the main
      targets of the Wiesner (phloroglucinol-HCl) reaction.
AB  - The nature and specificity of the Wiesner test (phloroglucinol-HCl reagent) for
      the aromatic aldehyde fraction contained in lignins is studied. Phloroglucinol
      reacted in ethanol-hydrochloric acid with coniferyl aldehyde, sinapyl aldehyde,
      vanillin, and syringaldehyde to yield either pink pigments (in the case of
      hydroxycinnamyl aldehydes) or red-brown pigments (in the case of
      hydroxybenzaldehydes). However, coniferyl alcohol, sinapyl alcohol, and highly
      condensed dehydrogenation polymers derived from these cinnamyl alcohols and
      aldehydes did not react with phloroglucinol in ethanol-hydrochloric acid. The
      differences in the reactivity of phloroglucinol with hydroxycinnamyl aldehydes
      and their dehydrogenation polymers may be explained by the fact that, in the
      latter, the unsubstituted (alpha,beta-unsaturated) cinnamaldehyde functional
      group, which is responsible for the dye reaction, is lost due to lateral chain
      cross-linking reactions involving the beta carbon. Fourier transform infrared
      spectroscopy and thioacidolysis analyses of phloroglucinol-positive lignifying
      plant cell walls belonging to the plant species Zinnia elegans L., Capsicum
      annuumvar. annuum, Populus albaL., and Pinus halepensisL. demonstrated the
      presence of 4- O-linked hydroxycinnamyl aldehyde end groups and 4- O-linked 4
      hydroxy-3-methoxy-benzaldehyde (vanillin) end groups in lignins. However, given
      the relatively low abundance of 4- O-linked vanillin in lignifying cell walls and
      the low extinction coefficient of its red-brown phloroglucinol adduct, it is
      unlikely that vanillin contributes to a great extent to the phloroglucinol
      positive stain reaction. These results suggest that the phloroglucinol-HCl pink
      stain of lignifying xylem cell walls actually reveals the 4- O-linked
      hydroxycinnamyl aldehyde structures contained in lignins. Histochemical studies
      showed that these aldehyde structures are assembled, as in the case of coniferyl
      aldehyde, during the early stages of xylem cell wall lignification.

PMID- 12417934
TI  - Localization of p210-related proteins in green flagellates and analysis of
      flagellar assembly in the green alga Dunaliella bioculatawith monoclonal anti
      p210.
AB  - Recently, p210 was identified as a component of the flagellar basal apparatus in
      the green flagellate Spermatozopsis similis. In a search for potential homologues
      to p210, isolated cytoskeletons of several green flagellates were probed with a
      monoclonal antibody, BAS4.13, against p210. In Western blots, cross-reacting
      bands in the molecular-mass range of 210 kDa were detected only in the
      quadriflagellate Spermatozopsis exsultans. As described earlier for S. similis,
      the flagellar transition region was decorated in Chlamydomonas reinhardtii and
      several other green flagellates, whereas in the marine alga Dunaliella bioculata
      the antigen was present in the proximal part of the axoneme. Double
      immunofluorescence of D. bioculata with an antitubulin antibody further revealed
      dotlike signals at sites where the probasal bodies are located. Since most of the
      antigen in D. bioculata was located in the axoneme, deflagellation offered a
      possibility to study the kinetics of its incorporation during flagellar
      regeneration. The antigen was only detected after a flagellum reached a length of
      3-4 microm and its integration into the growing flagellar proceeded from proximal
      to distal. A similar delay in the incorporation of the antigen was also observed
      during flagellar assembly on new basal bodies during cell division. Thus, the
      antigen of BAS4.13 was incorporated late and from proximal to distal into the
      growing flagellum. We conclude that the pace and site by which individual
      proteins are integrated into the flagellum differ greatly.

PMID- 12417935
TI  - Ultrastructure of vascular cambial cell cytokinesis in pine seedlings preserved
      by cryofixation and substitution.
AB  - Trees depend on the secondary vascular cambium to produce cells for new xylem and
      phloem. The fusiform cells of this lateral meristem are long and narrow,
      presenting special challenges for arranging the mitotic spindle and phragmoplast.
      Fusiform cambial cells of Pinus ponderosa and Pinus contorta were studied by
      cryofixation and cryosubstitution which preserved ultrastructure and phases of
      cytokinesis with a resolution not previously attained. Membranous structures
      including the plasma membrane, tonoplast, and those of other organelles were
      smooth and unbroken, indicating that they were preserved while the protoplasm was
      in a fully turgid state. Mitotic spindles separated daughter chromosomes
      diagonally across the radial width of the cells. The cell plate was initiated at
      an angle to the cell axis between the anaphase chromosomes by a microtubule array
      which organized vesicles at the phragmoplast midline. Within the phragmoplast,
      vesicles initially joined across thin tubular projections and then amalgamated
      into a tubulo-vesicular network. Axial expansion of the cell plate generated two
      opposing phragmoplasts connected by a thin, extended bridge of cell plate and
      cytoplasm that was oriented along the cell axis. In the cytoplasmic bridge
      trailing each phragmoplast, the callose-rich tubular network gradually
      consolidated into a fenestrated plate and then a complete cell wall. Where new
      membrane merged with old, the parent plasmalemma appeared to be loosened from the
      cell wall and the membranes joined via a short tubulo-vesicular network. These
      results have not been previously reported in cambial tissue, but the same phases
      of cytokinesis have been observed in cryofixed root tips and suspension-cultured
      cells of tobacco.

PMID- 12417936
TI  - The Commelina yellow mottle virus promoter drives companion-cell-specific gene
      expression in multiple organs of transgenic tobacco.
AB  - Previous work has demonstrated that some endogenous plant gene promoters are
      active in selective companion cells of the phloem, depending on organ types and
      developmental stages. Here we report that the Commelina yellow mottle virus
      (CoYMV) promoter is active in the companion cells of leaves, stems and roots of
      transgenic Nicotiana tabacum cv. Xanthi NN, using beta-glucuronidase (GUS) as a
      reporter. Thus, the CoYMV promoter has a broad organ specificity. This promoter
      can be useful in molecular studies on the functions of companion cells in many
      aspects of phloem biology, such as regulation of long-distance transport,
      macromolecular traffic, plant development and interaction with pathogens. It may
      also be useful in engineering crops that produce specific gene products in the
      companion cells to block long-distance movement of pathogens.

PMID- 12417937
TI  - A novel mechanism of silicon uptake.
AB  - Crystal-like structures in vacuoles, precipitates in the cytoplasm and on the
      tonoplast membrane have been found to store remarkable amounts of Si in a number
      of higher plants. In most of the cases the final storage product is a SiO(2) gel.
      Accumulation inside the cells presumes a membrane and cytoplasm passage, driven
      by unknown transporters. Beside this uptake into the cytoplasm, Si-accumulating
      species possess a mechanism that does not involve a membrane and cytoplasm
      passage. Unusual small invaginations comprising the two membranes, plasmalemma
      and tonoplast, which enclose a small border of cytoplasm, were observed. The same
      cells contained vacuolar vesicles surrounded by two membranes, obviously derived
      from the invaginations. By energy-dispersive X-ray analysis and electron
      spectroscopic imaging, Si was shown in the invaginations and vacuolar vesicles.
      This novel endocytotic process allows the uptake of condensed, higher-molecular
      weight Si compounds. In Zn hyperaccumulators, frequently SiO(2) precipitates were
      found in different cell compartments. Such plants showed the same invaginations
      and vacuolar vesicles, but Zn, colocalized with Si, was detected in these
      structures. Electron energy loss spectra confirmed the assumption that Zn
      silicate is present in the vesicles. In the vacuoles the unstable Zn-silicate is
      degraded, forming SiO(2) precipitates, while the released Zn is bound to an
      unknown partner.

PMID- 12417938
TI  - Differential localisation of GFP fusions to cytoskeleton-binding proteins in
      animal, plant, and yeast cells. Green-fluorescent protein.
AB  - The structure and functioning of the cytoskeleton is controlled and regulated by
      cytoskeleton-associated proteins. Fused to the green-fluorescent protein (GFP),
      these proteins can be used as tools to monitor changes in the organisation of the
      cytoskeleton in living cells and tissues in different organisms. Since the
      localisation of a specific cytoskeleton protein may indicate a particular
      function for the associated cytoskeletal element, studies of cytoskeleton-binding
      proteins fused to GFP may provide insight into the organisation and functioning
      of the cytoskeleton. In this article, we focused on two animal proteins, human T
      plastin and bovine tau, and studied the distribution of their respective GFP
      fusions in animal COS cells, plant epidermal cells (Allium cepa), and yeast cells
      (Saccharomyces cerevisiae). Plastin-GFP localised preferentially to membrane
      ruffles, lamellipodia and focal adhesion points in COS cells, to the actin
      filament cytoskeleton within cytoplasmic strands in onion epidermal cells, and to
      cortical actin patches in yeast cells. Thus, in these 3 very different types of
      cells plastin-GFP associated with mobile structures in which there are high rates
      of actin turnover. Chemical fixation was found to drastically alter the
      distribution of plastin-GFP. Tau-GFP bound to microtubules in COS cells and onion
      epidermal cells but failed to bind to yeast microtubules. Thus, animal and plant
      microtubules appear to have a common tau binding site which is absent in yeast.
      We conclude that the study of the distribution patterns of microtubule- and actin
      filament-binding proteins fused to GFP in heterologous systems should be a
      valuable tool in furthering our knowledge about cytoskeleton function in
      eukaryotic cells.

PMID- 12417939
TI  - Plasmalemmal voltage-activated K(+) currents in protoplasts from tobacco BY-2
      cells: possible regulation by actin microfilaments?
AB  - Plasmalemmal ionic currents from enzymatically isolated protoplasts of suspension
      cultured tobacco 'Bright Yellow-2' cells were investigated by whole-cell patch
      clamp techniques. In all protoplasts, delayed rectifier outward K(+) currents
      having sigmoidal activation kinetics, no inactivation, and very slow deactivation
      kinetics were activated by step depolarization. Tail current reversal potentials
      were close to equilibrium potential E(K) when external [K(+)] was either 6 or 60
      mM. Several channel blockers, including external Ba(2+), niflumic acid, and 5
      nitro-2-(3-phenylpropylamino)-benzoic acid, inhibited this outward K(+) current.
      Among the monovalent cations tested (NH(4)(+), Rb(+), Li(+), Na(+)), only Rb(+)
      had appreciable permeation (P(Rb)/P(K) (=) 0.7). In addition, in 60 mM K(+)
      solutions, a hyperpolarization-activated, time-dependent, inwardly rectifying
      K(+) current was observed in most protoplasts. This inward current activated very
      slowly, did not inactivate, and deactivated quickly upon repolarization. The tail
      current reversal potential was very close to E(K), and other monovalent cations
      (NH(4)(+), Rb(+), Li(+), Na(+)) were not permeant. The inward current was blocked
      by external Ba(2+) and niflumic acid. External Cs(+) reversibly blocked the
      inward current without affecting the outward current. The amplitude of the inward
      rectifier K(+) current was generally small compared to the amplitude of the
      outward K(+) current in the same cell, although this was highly variable. Similar
      amplitudes for both currents occurred in only 4% of the protoplasts in control
      conditions. Microfilament-depolymerizing drugs shifted this proportion to about
      12%, suggesting that microfilaments participate in the regulation of K(+)
      currents in tobacco 'Bright Yellow-2' cells.

PMID- 12417940
TI  - Structure, morphology, and composition of silicon biocomposites in the palm tree
      Syagrus coronata (Mart.) Becc.
AB  - Syagrus coronata is an economically important palm tree grown as an ornament, for
      the oil extracted from its seeds, and the wax from its leaves which has several
      applications in industry. Silicon biocomposites were analyzed in leaves of S.
      coronata. Silica bodies were found as extracellular silica masses between the
      hypodermal-layer cell walls and in granules present in the vacuoles of palisade
      cells. Scanning electron microscopy of the hypodermal layer of cells showed a
      collection of spherical bodies embedded in enveloping cavities that outlined the
      general structure of the bodies. Globular subunits with sharp edges formed the
      spherical bodies that ranged from 6 to 10 microm in diameter (average, 7.8
      microm). X-ray microanalysis detected only silicon and oxygen homogeneously
      distributed throughout the bodies. Vacuoles of palisade cells contained a large
      number of granules ranging from 20 nm to 1.2 microm in size (average, 300 nm).
      Transmission electron microscopy associated with electron spectroscopic imaging
      and electron energy loss spectroscopy were used to determine the elemental
      composition of the granules. Vacuolar granules were amorphous and composed of
      silicon and oxygen, suggesting they consist of amorphous silica biominerals. No
      nitrogen, indicative of organic matter, was detected in the granules.

PMID- 12417941
TI  - High accumulation of legumin and Lea-like mRNAs during maturation is associated
      with increased conversion frequency of somatic embryos from pedunculate oak
      (Quercus robur L.).
AB  - The expression patterns of the storage protein legumin gene and Em- and dehydrin
      like homologues were investigated in somatic embryos from Quercus robur L. The
      effect of different maturation treatments (1% agar, 6% sorbitol, or 5%
      polyethylene glycol) and partial desiccation on transcript accumulations as well
      as conversion capacity of somatic embryos was also investigated. Differential
      expression of putative Em- and two dehydrin-like homologues (designated as Dhn1a
      and Dhn1b) was detected in somatic oak embryos with heterologous probes. Low
      expression levels of legumin, Em- and dehydrin-like mRNAs were detected in
      somatic embryos prior to maturation treatment. A high accumulation of these
      transcripts was found in embryos that had been cultured on media supplemented
      with 6% sorbitol or 1% agar. These embryos also showed a high conversion
      frequency into plantlets. In contrast, no improvement in plant conversion as well
      as a low accumulation of legumin, Em-like and Dhn1b-like transcripts was observed
      in embryos that were matured on polyethylene glycol medium. Partial-desiccation
      treatment significantly enhanced the plant conversion. Nevertheless, a decline in
      expression of legumin, Em-like and Dhn1a-like homologues was detected upon
      dehydration. In contrast, Dhn1b and oak homologues to peach dehydrin were also
      strongly expressed in desiccated embryos. In addition, the treatment of embryos
      with abscisic acid promoted the accumulation of all investigated transcripts.
      These results suggest that the regulation of the legumin storage protein gene and
      Lea-like homologues in somatic oak embryos is under developmental control and
      that their regulation can be influenced by manipulating the culture conditions.

PMID- 12417942
TI  - Preprophase band loses its function as a cytokinetic apparatus in mitosis of neck
      canal mother cell.
AB  - Preprophase bands in the neck canal mother cell and the central cell of the
      archegonium of the fern Dryopteris crassirhizoma are observed with
      immunofluorescence microscopy. No phragmoplast is found during mitosis of the
      neck canal mother cell; however, the phragmoplast develops very well in the
      central cell. The neck canal mother cell undergoes karyokinesis but not
      cytokinesis and finally produces only one binucleate neck canal cell. However,
      the central cell undergoes cytokinesis and produces an egg cell and a ventral
      canal cell. These observations suggest that the preprophase band in the neck
      canal mother cell loses its function as a cytokinetic apparatus and becomes an
      evolutionary vestige in the development of the archegonium.

PMID- 12417943
TI  - The role of feline aminopeptidase N as a receptor for infectious bronchitis
      virus. Brief review.
AB  - Feline aminopeptidase N (fAPN) has been shown to serve as a receptor for feline,
      canine, porcine and human coronaviruses. Our objective was to determine if fAPN
      can serve as a receptor for infectious bronchitis virus (IBV). Feline kidney
      cells that express fAPN and hamster kidney fibroblasts that do not express fAPN
      were inoculated with IBV and monitored for replication by indirect fluorescent
      assay and confocal microscopy and in chicken embryonated eggs. The results showed
      that the feline cells were permissive to IBV but the hamster cells were not. The
      hamster cells became permissive to IBV after transfection with a fAPN cDNA
      suggesting that the feline APN molecule plays a role in IBV entry.

PMID- 12417944
TI  - Characterization of B virus glycoprotein antibodies induced by DNA immunization.
AB  - Genes encoding glycoproteins gB, gC, gD, gE, and gG of herpes B virus (species
      Cercopithecine herpesvirus 1) were cloned into mammalian expression vector
      pcDNA3.1/V5-His. Abilities of the plasmid constructs to express recombinant
      glycoproteins were confirmed by Western blot analysis of transfected CHO-K1 and
      COS-7 cells. Antibody production was induced in rabbits by intramuscular
      injections with the expression constructs at four-weekly intervals. Antibodies to
      gB were detected after the second DNA inoculation, while it took an additional
      plasmid injection to induce responses to gC, gD and gE. The gG plasmid failed to
      stimulate antibody production. Antisera ELISA titers varied greatly depending on
      the gene, with gB inducing highest (21,000) and gE inducing lowest (60) antibody
      titer. The induced antibodies were predominantly conformation-dependent. The gB,
      gC, and gD antisera contained HSV cross-neutralizing antibodies, but only gB
      antisera contained B virus neutralizing antibodies. The gB antisera cross-reacted
      with HSV antigens in Western blot, ELISA, dot-blot, plaque immunostaining and
      immunoprecipitation assays, whereas gD and gC antisera were mostly B virus
      specific. Thus, polyclonal antibodies to B virus glycoproteins can be generated
      by DNA immunization and used as diagnostic and research reagents.

PMID- 12417946
TI  - Viral DNA sequences of genes encoding the ATPase and the major capsid protein of
      tropical iridovirus isolates which are pathogenic to fishes in Japan, South China
      Sea and Southeast Asian countries.
AB  - Tropical iridovirus infection causes severe epizootic resulting in mass
      mortalities and large economic losses in freshwater ornamental fishes cultured in
      Southeast Asian countries, in wild fish seedlings captured in South China Sea,
      and in marine fishes farmed in Japan, Singapore, and Thailand. All of tropical
      iridovirus-infected fishes histopathologically showed the systemic formation of
      inclusion body-bearing cells and necrosis of virus-infected splenocytes and
      hematopoietic cells. We designed primer sets for the ATPase gene and the major
      capsid protein (MCP) gene and sequenced the PCR products derived from 5
      iridovirus isolates from sea bass in South China Sea, red sea bream in Japan,
      brown-spotted grouper with a grouper sleepy disease in Thailand, dwarf gourami
      from Malaysia and African lampeye from Sumatra Island, Indonesia. The ATPase gene
      and the MCP gene of these 5 viral isolates were highly homologous (> 95.8%, >
      94.9% identity, respectively) and the deduced amino acid sequences of the ATPase
      and the MCP were also highly identical (> 98.1%, > 97.2% identity, respectively).
      Based on the high homology, these 5 isolates of tropical iridovirus from various
      fishes in geographically different regions were determined to have a single
      origin and to be native to Southeast Asian regions. However, these sequences were
      far different from those of members of the genera Ranavirus, Lymphocystivirus and
      Iridovirus in the Family Iridoviridae. We propose a new genus "Tropivirus" for
      tropical iridovirus in the Family Iridoviridae.

PMID- 12417945
TI  - Phylogenetic relationships of dengue-1 viruses from Argentina and Paraguay.
AB  - We sequenced the Capsid-pre Membrane (C/prM) and the Envelope-Nonstructural
      protein 1 (E/NS1) regions of 24 recent isolates of dengue-1 (DEN-1) from South
      America. This included 12 Argentinean and 11 Paraguayan DEN-1 strains isolated in
      2000 plus a Paraguayan strain isolated in 1988. These sequences were compared
      with published sequences of DEN-1 isolated worldwide to determine the origin of
      these isolates. Pairwise comparisons of strains from Paraguay and Argentina
      revealed a nucleotide divergence of 0-5% in the E/NS1 region and 0-3% in the
      C/prM region. Our results showed that these viruses belong to the same genotype,
      but can be separated into two clades. Interestingly, both clades circulated
      simultaneously in the same geographic area during the 2000 outbreaks. Amino acid
      differences were found between both clades in the C/prM region at position 100
      (Lys vs. Arg) and in the E/NS1 region at positions 722 (Ala vs. Thr). Although
      the geographic movement of DEN-1 virus can not be unequivocally traced from the
      genetic relationship determined here, our results suggest that the recent
      epidemics in Argentina and Paraguay were due to the re-emergence of a previously
      circulating strain, or to the virus circulating unnoticed, rather than to the
      introduction of a new genotype.

PMID- 12417947
TI  - Phylogenetic comparison of the genus Lyssavirus using distal coding sequences of
      the glycoprotein and nucleoprotein genes.
AB  - The phylogenetic relationships between all seven genotypes within the genus
      Lyssavirus were compared at the nucleotide level utilising two distal regions of
      the viral genome. The resulting analysis of each region produced similar,
      although not identical, phylogenetic results, suggesting that the evolutionary
      pressures on individual proteins within the genome vary. These differences are in
      part due to the increased variability observed within the glycoprotein sequence
      over the nucleoprotein sequence. Pair-wise comparison using the glycoprotein
      partial sequence between different isolates demonstrate that within genotypes,
      viruses show between 80 and 100% sequence identity, whilst between genotypes,
      viruses show between 50 and 75% identity. This provides a consistent guide to
      assigning new viruses to existing genotypes. Alignment of the amino acid sequence
      for the truncated glycoprotein sequence to the Pasteur Virus vaccine strain show
      significant residue variation between positions 139 and 170. However, residue
      variation tends to vary with genotype implying that these changes have not
      evolved due to immunological pressure from the host but have occurred following
      the separation of viruses into discrete groups. Comparison of the phylogenetic
      analysis for this partial region of the glycoprotein suggest that it gives
      comparable results to studies that have used larger regions of the Lyssavirus
      genome.

PMID- 12417948
TI  - Recombinant adenovirus encoding the HA gene from swine H3N2 influenza virus
      partially protects mice from challenge with heterologous virus: A/HK/1/68 (H3N2).
AB  - Immunization with recombinant adenoviral vaccine that induces potent immunity has
      been applied to many infectious diseases. We report here developing a recombinant
      adenoviral vaccine encoding the HA gene from swine H3N2 influenza virus (SIV).
      Two replication-defective recombinant adenoviruses were generated: (1) rAd-HA:
      recombinant adenovirus encoding the HA gene from swine H3N2 influenza virus, and
      (2) rAd-vector: a control recombinant adenovirus containing adenovirus and
      transfer plasmids without a foreign HA gene. Mice given rAd-HA developed high
      titers of neutralizing and hemagglutination inhibition antibodies to SIV in
      comparison to mice inoculated with rAd-vector or PBS as early as 2 weeks after
      immunization, and these antibodies were substantially increased in the mice given
      rAd-HA within the next 3 weeks following the first dose. However, these
      antibodies were not able to neutralize the virus, A/HK/68 (H3N2), used for
      challenge. Nonetheless mice immunized with one or two doses of rAd-HA were
      protected from lethal challenge with heterologous virus, A/HK/1/68 (H3N2). A
      statistically significant ( P < 0.03) difference between survival rates of rAd-HA
      mice vs. rAd-vector or PBS mice was observed.

PMID- 12417949
TI  - The route of tomato spotted wilt virus inside the thrips body in relation to
      transmission efficiency.
AB  - The route of tomato spotted wilt virus (TSWV) in the body of its vectors,
      Frankliniella occidentalis and Thrips tabaci (Thysanoptera: Thripidae) was
      studied during their development. First instar larvae were allowed, immediately
      upon hatching, to acquire virus from mechanically infected Datura stramonium
      plants for 24 h. The rate of transmission by adults was determined in inoculation
      access feeding test on Emilia sonchifolia leaf disks. Thrips tissues were
      analysed for infection at 24 h intervals after the acquisition-access feeding
      period, and assayed by the whole-mount immuno-fluorescent staining technique. The
      virus was initially detected in the proximal midgut region in larvae of both
      species, and then in the second and third midgut regions, foregut, and salivary
      glands. Occasionally the first infections of the salivary glands were already
      detected in one-day-old second stage larvae. The intensity of the infection in
      the various organs of the thrips of each species was positively related to the
      transmission efficiency. In both thrips populations good agreement was found
      between the percentage of second instar larvae and adults with at least one
      infected salivary gland lobe and the percentage of transmitting adults. These
      results support the contention that the virus must reach the salivary glands
      before thrips pupation in order to be transmitted by old second instar larvae and
      adults.

PMID- 12417950
TI  - The effects of gamma interferon on replication of foot-and-mouth disease virus in
      persistently infected bovine cells.
AB  - Foot-and-mouth disease virus (FMDV) causes a highly contagious viral disease of
      cloven-hoofed animals, which has a considerable socio-economic impact on the
      countries affected. In addition, persistent infection can occur following
      clinical or sub-clinical disease in either vaccinated or non-vaccinated cattle.
      The mechanism(s) by which FMDV persistence is established and maintained is not
      fully understood. To better understand the basic mechanisms controlling the virus
      infection in cattle, the effects of interferon gamma (IFN-gamma) on the
      replication of FMDV was evaluated in vitro in persistently infected-epithelial
      cells isolated from FMDV infected cattle. Initially primary bovine thyroid (BTY)
      cells were treated with varying doses of bovine recombinant IFN-gamma. The
      cytokine activity was measured by detection of viral antigen in cell supernatants
      and viral RNA expression compared with cells without INF-gamma treatment.
      Pretreatment with IFN-gamma profoundly affected FMDV growth in BTY cells. The
      replication of FMDV was affected in the presence of more than 2.5 u/ml of IFN
      gamma and the effect was both dose-dependent and related to the time of exposure.
      Analysis of the mechanism of inhibition suggests that IFN-gamma did not inhibit
      the viral replication through induction of nitric oxide. More interesting is the
      finding that continuous treatment with IFN-gamma severely restricts FMDV
      replication or even cures persistently infected bovine epithelial cells,
      indicating that a cytokine-mediated pathway may be involved in the in vivo
      clearance of persistent FMDV.

PMID- 12417951
TI  - Cloning, sequencing, and promoter identification of Blueberry red ringspot virus,
      a member of the family Caulimoviridae with similarities to the "Soybean chlorotic
      mottle-like" genus.
AB  - The double-stranded DNA genome of Blueberry red ringspot virus (BRRV), a member
      of the family Caulimoviridae, was cloned and sequenced. The genome organization
      and relationships of the 8303 nt sequence revealed BRRV to be a tentative member
      of the genus that has been provisionally named "Soybean chlorotic mottle-like
      viruses", rather than a member of the genus Caulimovirus, in which it had been
      placed previously. Insertion of the putative 35S promoter homolog of BRRV into
      promoterless constructs carrying the UidA (beta-glucuronidase) gene resulted in
      high-level transient expression from cranberry and stable expression from
      transgenic tobacco. Sequences of 5'-RACE clones derived from transcripts from
      transgenic tobacco were consistent with the map position of the promoter.

PMID- 12417952
TI  - Molecular characterization of serotype G2 and G3 human rotavirus strains that
      have an apparently identical electropherotype of the short RNA pattern.
AB  - The literature is conflicting whether or not rotavirus strains with different G
      serotype have an identical electropherotype. This is a contentious but an
      important issue because large parts of molecular epidemiological studies of
      rotaviruses have been based on the conception that a single strain of rotavirus
      can be defined by a single electropherotype. Here, we examined in detail by
      reverse-transcription PCR genotyping, electropherotyping, sequencing, and
      genogrouping using RNA--RNA hybridization three human rotavirus strains isolated
      in India that had apparently identical electropherotypes although one strain was
      typed as P[4], G3 while the other two typed as P[4], G2. These three strains
      showed an identical electropherotype on 7.5% and 12.5% polyacrylamide gels, but
      co-electrophoresis on a 10% gel demonstrated that segment 8 of the P[4], G3
      strain migrated more slowly than the cognate segment of the P[4], G2 strains.
      Genogrouping assay and nucleotide sequencing provided evidence for the hypothesis
      that the P[4], G3 stain was an intergenogroup reassortant in which a P[4], G2
      strain of the DS-1 genogroup had acquired the VP7 gene from an yet-unidentified
      concurrently circulating G3 strain. While electropherotyping remains a valuable
      asset for molecular epidemiology of rotaviruses, this study underscores the
      importance of co-electrophoresis under different electrophoretic conditions when
      pinpointing subtle differences.

PMID- 12417953
TI  - Genetic and antigenic typing of rabies virus in Chile. Brief report.
AB  - Forty-one isolates of rabies virus from insectivorous bats and one from a
      domestic cat in Chile, were characterized using eight anti-nucleoprotein
      monoclonal antibodies (N-Mabs) and by nucleotide sequence analysis. Thirty-two
      isolates were identified as antigenic variant 4 associated with Tadarida
      brasiliensis bats, twenty-eight were genetically associated with variant Tadarida
      brasiliensis and four with Lasiurus sp. bats. One isolate was identified as
      antigenic variant 3 associated with Desmodus rotundus bats, and by genetic
      analysis was identified as variant Myotis sp. bat. Eight isolates were unrelated
      to any antigenic variant, and they were identified as a genetic variant
      associated with Histiotus sp. bats. These antigenic and genetic characterizations
      may establish epidemiological links between rabies cases and increase the
      understanding of rabies epidemiology in this country.

PMID- 12417954
TI  - Nucleotide sequence and taxonomy of Cycas necrotic stunt virus. Brief report.
AB  - Cycas necrotic stunt virus (CNSV) is the only well-characterized virus from
      gymnosperm. cDNA segments corresponding to the bipartite genome RNAs (RNA1, RNA2)
      were synthesized and sequenced. Each RNA encoded a single polyprotein, flanked by
      the 5' and 3' non-coding regions (NCR) and followed by a poly (A) tail. The
      putative polyproteins encoded by RNA1 and RNA2 had sets of motifs, which were
      characteristic of viruses in the genus Nepovirus. The polyproteins showed higher
      sequence identities to Artichoke Italian latent virus, Grapevine chrome mosaic
      virus and Tomato black ring virus, all of which belong to subgroup b of the genus
      Nepovirus, than to other nepoviruses. Phylogenetic analysis of RNA dependent RNA
      polymerase and coat protein also showed closer relationships with these viruses
      than other viruses. The data obtained supported the taxonomical status of CNSV as
      a definitive member of the genus Nepovirus, subgroup b.

PMID- 12417955
TI  - Nucleotide sequence, genome organisation and phylogenetic analysis of Indian
      citrus ringspot virus. Brief report.
AB  - The sequence of the single-stranded RNA genome of Indian citrus ringspot virus
      (ICRSV) consists of 7560 nucleotides. It contains six open reading frames (ORFs)
      which encode putative proteins of 187.3, 25, 12, 6.4, 34 and 23 kDa respectively.
      ORF1 encodes a polypeptide that contains all the elements of a replicase; ORFs 2,
      3 and 4 compose a triple-gene block; ORF5 encodes the capsid protein; the
      function of ORF6 is unknown. Phylogenetic analysis of the complete genome and
      each ORF separately, and database searches indicate that ICRSV, though showing
      some similarities to potexviruses, is significantly different, as in the presence
      of ORF6, the genome and CP sizes, and particle morphology. These differences
      favour its inclusion in a new virus genus.

PMID- 12417956
TI  - Full length nucleotide sequence of foot-and-mouth disease virus strain O1
      Campos/Bra/58. Brief report.
AB  - The complete nucleotide sequence of foot-and-mouth disease virus (FMDV) South
      American strain O(1) Campos/Bra/58 was determined. The 8,168 Kb sequence and the
      deduced amino acid sequence were compared to published FMDV sequences. They
      showed the highest sequence homology with the O(1) Kaufbeuren/FRG/66 strain, but
      closer evolutionary relatedness to the Argentinean strains.

PMID- 12417957
TI  - Complete nucleotide sequence of the genomic RNA of a French isolate of Pepino
      mosaic virus (PepMV). Brief report.
AB  - The complete nucleotide sequence of the genomic RNA of a French isolate of Pepino
      mosaic virus (PepMV) was determined. With a length of 6,425 nucleotides excluding
      the poly(A) tail at the 3' terminus, the PepMV genome contains five major open
      reading frames encoding a 164 kDa replicase, triple gene block proteins of 26
      kDa, 14 kDa and 9 kDa, and a 25 kDa coat protein. This genome organization, as
      well as characteristic consensus motifs and high degrees of similarity of PepMV
      proteins with those of other potexviruses confirmed that PepMV belongs to the
      Potexvirus genus. Phylogenetic analyses carried out on replicase, triple gene
      block protein 1 and coat protein amino acid sequences revealed that PepMV is
      closely related to species Narcissus mosaic virus (NMV), Scallion virus X (SVX),
      Cymbidium mosaic virus (CymMV), and Potato aucuba mosaic virus (PAMV).

PMID- 12417958
TI  - Analysis of genetic heterogeneity of hepatitis C viruses in Central America
      reveals a novel genetic lineage. Brief report.
AB  - Hepatitis C virus (HCV) has high genomic variability and at least six different
      types have been reported. The genotypes distribution is currently unknown among
      HCV strains circulating in Central America. In order to study the degree of
      genetic variability of strains isolated in Costa Rica, sequence data obtained
      from the 5' non coding region from 7 patients from Costa Rica were compared with
      published sequences from 57 strains of all types. The phylogenetic analysis
      revealed the existence of type 1 strains of a novel genetic lineage, recently
      described for some South American countries, and indicates an increasing
      diversification of HCV.

PMID- 12417959
TI  - Only italicised species names of viruses have a taxonomic meaning.

PMID- 12417960
TI  - The current naming of plant viruses: a critical appraisal.
AB  - The revised International Code of Virus Classification and Nomenclature [7]
      followed by the Seventh Report of the International Committee on Taxonomy of
      Viruses (ICTV) [9] have generated a lot of criticism [2,4-6]. The main causes of
      criticism are (i) use of monomials instead of non-latinized binomials, as has
      been practice for some time in the past, e.g., tobacco mosaic tobamovirus,
      tobacco ringspot nepovirus etc. (ii) in toto italicization of official virus
      names. Following the expression of different views among virologists on this
      issue, it is being debated and an opportunity has been provided for
      reconsideration of the revised ICTV code [1,8,10]. This note attempts to analyse
      the existing criticisms being raised and justifies the continuation of the
      present ICTV code.

PMID- 12417962
TI  - Portal biliopathy.
AB  - Herein we describe a case of obstructive jaundice and cholangitis originating
      from choledochal lithiasis secondary to a stricture of the common bile duct in a
      patient with cavernous transformation of the portal vein. In fact, portal
      cavernous transformation gives rise to many dilated pericholedochal and
      periportal collaterals that bypass the portal vein obstruction. Extrinsic
      compression of the common duct by dilated venous collaterals together with
      pericholedochal fibrosis from the inflammatory process causing portal thrombosis
      may lead to biliary stricture and dilatation of the proximal biliary tree. This
      condition sometimes causes the formation of secondary biliary stones and
      cholangitis. Treatment in our case could not be accomplished by a biliodigestive
      anastomosis because the patient suffered from a short bowel syndrome subsequent
      to extensive ileal resection for splanchnic venous thrombosis. We repeatedly
      attempted stone removal during endoscopic retrograde cholangiopancreatography
      (ERCP) but finally resorted to a percutaneous transhepatic approach, which
      permitted removal of the stones and treatment of the stricture by pneumatic
      dilatation. The patient remains well 3 years after the procedure and has shown no
      signs of jaundice or cholangitis.

PMID- 12417963
TI  - The effects of methylphenidate on prepulse inhibition during attended and ignored
      prestimuli among boys with attention-deficit hyperactivity disorder.
AB  - RATIONALE AND OBJECTIVES: The present study investigated attentional modification
      of prepulse inhibition of startle among boys with and without attention-deficit
      hyperactivity disorder (ADHD). Two hypotheses were tested: (1) whether ADHD is
      associated with diminished prepulse inhibition during attended prestimuli, but
      not ignored prestimuli, and (2) whether methylphenidate selectively increases
      prepulse inhibition to attended prestimuli among boys with ADHD. METHODS:
      Participants were 17 boys with ADHD and 14 controls. Participants completed a
      tone discrimination task in each of two sessions separated by 1 week. ADHD boys
      were administered methylphenidate (0.3 mg/kg) in one session and placebo in the
      other session in a randomized, double-blind fashion. During each series of 72
      tones (75 dB; half 1200-Hz, half 400-Hz), participants were paid to attend to one
      pitch and ignore the other. Bilateral eyeblink electromyogram startle responses
      were recorded in response to acoustic probes (50-ms, 102-dB white noise)
      presented following the onset of two-thirds of tones, and during one-third of
      intertrial intervals. RESULTS: Relative to controls, boys with ADHD exhibited
      diminished prepulse inhibition 120 ms after onset of attended but not ignored
      prestimuli following placebo administration. Methylphenidate selectively
      increased prepulse inhibition to attended prestimuli at 120 ms among boys with
      ADHD to a level comparable to that of controls, who did not receive
      methylphenidate. CONCLUSIONS: These data are consistent with the hypothesis that
      ADHD involves diminished selective attention and suggest that methylphenidate
      ameliorates the symptoms of ADHD, at least in part, by altering an early
      attentional mechanism.

PMID- 12417964
TI  - Effects of cigarette nicotine content and smoking pace on subsequent craving and
      smoking.
AB  - RATIONALE: The relative contribution of sensory and pharmacological variables in
      regulating craving and smoking remains unclear. Rapid smoking procedures and
      denicotinized cigarettes can be used to further disentangle these factors, and to
      explore the relationship between craving and smoking. OBJECTIVE: The present
      study examined the role of nicotine and sensory cues in mediating craving and
      smoking, and the relationship between craving and smoking. METHODS: Participants
      ( n=15) engaged in one session each of rapid smoking (up to nine cigarettes with
      puffs taken every 6 s) and normal paced smoking with nicotinized and
      denicotinized cigarettes (total of four sessions). During the next 3 h, craving
      and withdrawal assessments and smoking opportunities were scheduled every 15 min.
      Plasma nicotine levels were measured at baseline, immediately and 15 min after
      the smoking interventions, and subsequently at the time when the participant
      first chose to smoke. RESULTS: Craving ratings were equally suppressed
      immediately after all conditions. After self-paced conditions, both types of
      cigarettes produced equivalent effects on latency to smoke. Latency to smoke was
      significantly longer after rapid smoking of nicotinized cigarettes compared to
      all other conditions. Finally, changes in craving were associated with choices to
      smoke. CONCLUSIONS: The sensory cues associated with smoking suppressed craving
      ratings regardless of the smoking pace or nicotine content. Only at high doses
      did nicotine levels play an additional role in acutely suppressing smoking
      behavior. Small elevations in craving ratings were associated with choices to
      smoke.

PMID- 12417965
TI  - Effects of acute psychological stress on adhesion molecules, interleukins and sex
      hormones: implications for coronary heart disease.
AB  - RATIONALE: Subjects with high levels of daily stress suffer from an increased
      risk of coronary heart disease. Increased concentrations of the intercellular
      adhesion molecule-1 (ICAM-1) contribute to atherosclerosis. Cell adhesion
      molecules may be activated by psychological stress exposure, depending on their
      interaction with the interleukin network, sex hormones and cortisol secretion.
      OBJECTIVES: To assess effects of acute psychological stress on the interaction
      between cell adhesion molecules, interleukins, sex hormones and cortisol in
      healthy male subjects. METHODS: Cell adhesion molecules, interleukin-1 beta (IL
      1beta), IL-2, IL-6, sex hormones and cortisol levels of 18 healthy male
      physicians were measured before and after an academic oral presentation and on a
      control day. RESULTS: The oral presentation was perceived as a stressful event
      and was accompanied by a significant increase in cortisol secretion in all
      volunteers. Soluble ICAM-1 and IL-1beta also increased in all subjects after
      psychological stress exposure. The stress-associated increase in IL-2
      concentrations approached statistical significance and correlated negatively with
      luteinizing hormone plasma levels. Estradiol concentrations correlated positively
      with IL-6 levels. CONCLUSIONS: Subjective ratings and the increase in cortisol
      plasma concentrations support the validity of the chosen stress model. Acute
      stress exposure was followed by an increase in IL-1beta, IL-2 and soluble ICAM-1
      plasma concentrations, which can contribute to coronary heart disease and
      immunological disorders.

PMID- 12417966
TI  - Cognitive enhancing effects of modafinil in healthy volunteers.
AB  - RATIONALE: Modafinil, a novel wake-promoting agent, has been shown to have a
      similar clinical profile to that of conventional stimulants such as
      methylphenidate. We were therefore interested in assessing whether modafinil,
      with its unique pharmacological mode of action, might offer similar potential as
      a cognitive enhancer, without the side effects commonly experienced with
      amphetamine-like drugs. OBJECTIVES: The main aim of this study was to evaluate
      the cognitive enhancing potential of this novel agent using a comprehensive
      battery of neuropsychological tests. METHODS: Sixty healthy young adult male
      volunteers received either a single oral dose of placebo, or 100 mg or 200 mg
      modafinil prior to performing a variety of tasks designed to test memory and
      attention. A randomised double-blind, between-subjects design was used. RESULTS:
      Modafinil significantly enhanced performance on tests of digit span, visual
      pattern recognition memory, spatial planning and stop-signal reaction time. These
      performance improvements were complemented by a slowing in latency on three
      tests: delayed matching to sample, a decision-making task and the spatial
      planning task. Subjects reported feeling more alert, attentive and energetic on
      drug. The effects were not clearly dose dependent, except for those seen with the
      stop-signal paradigm. In contrast to previous findings with methylphenidate,
      there were no significant effects of drug on spatial memory span, spatial working
      memory, rapid visual information processing or attentional set-shifting.
      Additionally, no effects on paired associates learning were identified.
      CONCLUSIONS: These data indicate that modafinil selectively improves
      neuropsychological task performance. This improvement may be attributable to an
      enhanced ability to inhibit pre-potent responses. This effect appears to reduce
      impulsive responding, suggesting that modafinil may be of benefit in the
      treatment of attention deficit hyperactivity disorder.

PMID- 12417967
TI  - The relationship between dopamine D2 receptor occupancy and the vacuous chewing
      movement syndrome in rats.
AB  - RATIONALE: A dose-response relationship between dopamine D(2) occupancy and acute
      extrapyramidal symptoms (EPS) has been well established. However, the link with
      the induction of tardive dyskinesia (TD) is less clear. OBJECTIVES: To ascertain
      the nature and extent of D(2) receptor occupancy effects on haloperidol-induced
      vacuous chewing movements (VCMs) in a rat model of TD. METHODS: Groups of eight
      rats received haloperidol decanoate injections corresponding to daily doses of 0,
      0.08, 0.17, 0.33, or 1 mg/kg for 10-12 weeks. VCMs were measured on a weekly
      basis and D(2) occupancy levels were measured in vivo using [(3)H]-raclopride at
      the end of the experiment. RESULTS: Final VCM scores were significantly different
      between haloperidol doses ( P=0.001). Moderate but significant correlations were
      found between dose and average VCM scores (r=0.69, P<0.001) and between D(2)
      occupancy and average VCM scores (r=0.65, P<0.001). The rats that developed the
      VCM syndrome (>/=8 VCMs) had higher occupancies than rats that did not. Of the
      rats with an occupancy above 70%, 63% developed VCMs, compared with 37% of the
      rats with D(2) occupancy below that. CONCLUSIONS: These results indicate that
      chronic haloperidol induces VCMs in a dose-dependent manner, with doses leading
      to high D(2) occupancy increasing the likelihood of emergence of the VCM
      syndrome. While a certain level of D(2) occupancy may be necessary for inducing
      VCMs, it is not sufficient in and of itself to induce the VCM syndrome.

PMID- 12417969
TI  - Hereditary aspects of gastric cancer.
AB  - Although the etiology of gastric cancer and the mechanisms involved in its
      carcinogenesis are still poorly understood, dietary habits and life style as well
      as bacterial infections have been suggested to be important in the tumorigenic
      process. However, there is also an increasing evidence that a genetic
      predisposition in at least a subset of patients, plays an important role.
      Germline mutations in the E-cadherin gene have been described to be the molecular
      genetic cause of an hereditary diffuse type gastric cancer syndrome. In addition,
      gastric cancer is observed more frequently in association with some hereditary
      tumor syndromes which are mainly characterized by tumors in other organs. This
      article will summarize recent findings about the hereditary diffuse type gastric
      cancer syndrome and about gastric cancer in association with hereditary tumor
      syndromes with a known molecular genetic basis.

PMID- 12417970
TI  - [The hyperplasia-adenoma sequence: a case supporting this hypothesis].
AB  - We described the morphological, histochemical and immunohistochemical findings of
      a polyp detected in the left colon (splenic flexure) in which the diagnosis was
      atypical hyperplastic polyp. The description is focused on the capability of a
      hyperplastic polyp to evolve into adenomatous tissue through different
      modalities.

PMID- 12417971
TI  - [Fibromatosis of the breast: a clinical, radiological and pathological study of 6
      cases].
AB  - We describe the clinical, radiological and pathological features of a series of
      six cases of primary fibromatosis of the breast. Most patients (5 of 6) were
      women of 22-58 years of age; one case occurred in a 47-year-old man. The
      fibromatosis of the breast in all cases presented as a monolateral solid nodule,
      clinically suspicious for malignancy and in three cases was also associated with
      cutaneous and/or nipple retraction. None of the patients was affected by any
      genetic disorder characterized by fibromatoses involving multiple sites,
      including breast. Both echographic and mammographic examinations revealed solid
      masses with irregular margins but without calcifications, mimicking scirrhous
      carcinoma. All cases were surgically treated by lumpectomy (4 of 6) or
      quadrantectomy (2 of 6), and after a follow-up period ranging from 5 months to 13
      years all patients are well and disease-free. Histological examination revealed
      finger-like infiltrating margins entrapping adjacent breast parenchyma and
      adipose tissue in all cases. The hallmark of the lesion was the presence of bland
      looking spindle cells, with a low mitotic index, organized in long sweeping and
      intersecting fascicles. Three different morphological phases (i.e. proliferative,
      involutional and residual), identical to those observed in Dupuytren's
      superficial fibromatosis, variably coexisted in each case. At
      immunohistochemistry the cells which comprised the lesion exhibited a diffuse
      expression of vimentin and a heterogeneous immunoreactivity to a-smooth muscle
      actin, thus confirming their fibro-myofibroblastic nature. No expression of
      estrogen, progesterone or androgen receptors or of pS2 correlated-estrogen
      protein was observed. We discuss both the pathogenesis of the mammary
      fibromatosis, pointing to the fibroblastic cells of the mammary stroma as the
      putative precursors, and the differential diagnosis versus the bland-looking,
      monomorphic spindle cell tumor-like or tumorous lesions of the breast.

PMID- 12417972
TI  - [Small-cell mesothelioma of the pleura: description of a case].
AB  - A case of mesothelioma with a small cell component in a 53-year-old, non-smoker
      woman. The patient had a history of asbestos exposure, and presented with
      thoracic pain. A total body computed tomogram showed a left pleural effusion and
      a 7.5-cm pleural mass. Thoracoscopy revealed a diffuse nodular thickening of the
      left parietal pleura, and a biopsy was performed. The patient died of the disease
      4 months after diagnosis. Microscopically, the pleural neoplasm was composed of
      three different components: 40% of the tumor showed the classic histology of a
      malignant epithelial mesothelioma, 40% was composed of small- to medium-sized
      cells with open nuclear chromatin, evident nucleoli and high mitotic activity,
      and 20% of the neoplasm was indistinguishable from a small cell carcinoma.
      Immunohistochemically, the first component was diffusely and strongly positive
      for cytokeratin AE1/AE3, cytokeratin CAM 5.2 and EMA, focally positive for BER
      EP4, and negative for CD15, B 72.3, CEA, LCA, chromogranin, synaptophysin, TTF-1
      and CD99. The cells of the second component were positive only for cytokeratin
      AE1/AE3 and cytokeratin CAM 5.2, and the elements of the third component were
      negative for all the antibodies tested. Pleural mesothelioma with a small cell
      component is rare. The most useful parameters to distinguish it from other small
      cell malignancies that may involve the pleura, particularly small cell carcinoma
      of pulmonary origin, are discussed.

PMID- 12417973
TI  - [Benign metastasizing pulmonary leiomyoma: description of a case and review of
      the literature].
AB  - We report the case of a 48-year-old woman with multiple benign metastasizing
      leiomyomas in both lungs and a single retroperitoneal leiomyoma. The patient
      underwent surgical resection of the lesions 15 years after total hysterectomy for
      uterine myomas. Immunohistochemical studies performed on the retroperitoneal and
      pulmonary neoplasms showed them to be of mesenchymal derivation with smooth
      muscle differentiation; the samples were negative for HMB-45. Some histogenetic
      hypotheses for the multiple leiomyomas are presented.

PMID- 12417974
TI  - Hair cell death in the avian basilar papilla: characterization of the in vitro
      model and caspase activation.
AB  - Caspases are a family of proteases that have been implicated as key mediators of
      cell death. Although nonspecific inhibition of caspase activation has been
      reported to prevent mammalian sensory hair cell death, the exact roles of
      individual caspases during hair cell death are unclear. In other systems, the
      activation of initiator caspases, such as caspase-8 and caspase-9, can lead to
      the activation of the effector caspase-3. We have begun to systematically
      characterize hair cell death in an in vitro system by examining the activation of
      these specific caspases in degenerating hair cells after acutely damaging the
      whole avian basilar papilla with gentamicin. Basilar papillae (BP) displayed a
      dose-dependent hair cell loss after a 24-h treatment with gentamicin at
      concentrations of 0.1, 0.5, and 2.0 mM. When treated with 0.5 mM gentamicin for
      6, 12, or 24 h, hair cells first began to degenerate in the basal third of the BP
      and damage progressed apically. Supplementation of z-VAD-fmk, a general caspase
      inhibitor, provided short-term protection against gentamicin-induced hair cell
      death. Treatment with gentamicin for 6 or 12 h promoted the expression of active
      caspase-3 and active caspase-9 in many hair cells along the BP as shown by
      immunohistochemistry. At these time-points, specific fluorescent-labeled peptide
      substrates detected more active caspase-3, caspase-8, and caspase-9 in gentamicin
      treated hair cells relative to controls. Our data indicate that auditory hair
      cells degenerate as a result of gentamicin exposure in a caspase-dependent
      manner. Specifically, the upstream caspases, caspase-8 and caspase-9, and the
      downstream caspase-3 are activated in aminoglycoside-damaged hair cells.

PMID- 12417975
TI  - Scavengers protection of cells against ALA-based photodynamic therapy-induced
      damage.
AB  - The exogenously stimulated formation of intracellularly generated protoporphyrin
      IX, a precursor of haem, is becoming one of the fastest developing areas in the
      field of photodynamic therapy (PDT). We tested the action of several free radical
      scavengers, amino acids, antioxidants and sulphur-containing compounds as
      protectors from photodamage induced by 5-aminolaevulinic acid (ALA)-mediated PDT,
      employing the LM2 cell line, derived from a mammary murine adenocarcinoma. We
      exposed the cells to different concentrations of the compounds, 24 h before PDT,
      during PDT, and 19 h after treatment. We defined the protection grade (PG) as the
      ratio between cell survival after ALA-PDT treatment in the presence of the
      protector and cell survival of ALA-PDT treatment alone. We found that l 
      tryptophan (PG=9.2 at 2 m m ), reduced glutathione (GSH) (PG=5.8 at 0.8 m m ), N
      acetyl- l -cysteine (PG=4.86 at 30 m m ), melatonin (PG=4.5 at 8 m m ) and l 
      methionine (PG=4.0 at 0.8 m m ) are the best protectors from PDT damage, followed
      by l -cysteine (PG=2.8 at 0.8 m m ), mannitol (PG=2.6 at 20 m m ) and glycine
      (PG=2.4 at 40 m m ) whereas oxidised glutathione and S-adenosyl- l -methionine do
      not exert any protection. We did not found any photoactive action of the
      protectors in absence of ALA. These results can be considered to modulate the
      photodamage induced by ALA-PDT.

PMID- 12417976
TI  - Non-invasive pulsed ultrasound quantification of the resolution of basal cell
      carcinomas after photodynamic therapy.
AB  - The probability of local control of basal cell carcinomas (BCC) treated by
      photodynamic therapy (PDT) depends strongly on lesion thickness, thicker lesions
      often requiring two treatments. We examine the utility of 20 MHz pulsed
      ultrasound (US) for the non-invasive measurement of thickness and rate of
      regression after PDT treatment. PDT was by topically applied 20% aminolaevulinic
      acid, followed at 6 h by a standard 100 J/cm(2) of 630 nm light. Patients ( n=60)
      were selected as being difficult to treat with existing modalities for reasons of
      likely poor quality of healing or of cosmesis in this very largely elderly
      population. Ultrasound 'A' scans were made immediately before treatment, and at
      first and subsequent follow-ups. Parameters measured non-invasively for BCC,
      adjacent normal skin, and for fibroses after previous conventional therapies,
      were (a) thickness of skin or lesion, (b) linear density of ultrasound echoes and
      (c) linear density of high-amplitude echoes. Prior to treatment, median skin
      thickness (to the dermal/subcutaneous boundary) was 2.6 mm (range 1.2-5.7),
      fibroses 2.5 mm (1.4-5.6) and BCC 1.5 mm (0.5-4.4). Median linear density of
      echoes for normal skin, fibroses and BCC plus underlying tissue were 5.6, 5.5 and
      4.5, respectively, the BCC values being significantly lower ( p=0.002). The
      corresponding medians for high-amplitude echoes were 1.9, 1.9 and 1.1 (skin or
      fibrosis versus BCC, p=0.001). Patients whose BCCs appeared clinically to be
      controlled at up to 220 days after a single treatment, all had values of
      ultrasound parameters corresponding to skin/fibrosis and were significantly
      different from measurements on the same site prior to treatment. Patients whose
      tumours appeared to be reverting to the original BCC ultrasound pattern were
      subsequently found to be recurring as judged clinically. Non-invasive pulsed
      ultrasound indicates that rates of resolution vary widely between BCC of similar
      initial thickness and that the probability of clearance of BCC by PDT is
      determined largely by the deepest, sometimes small, regions within a lesion, with
      the overall area being relatively unimportant.

PMID- 12417977
TI  - Comparison of normal piglet bladder damage after PDT with oral or intravesical
      administration of ALA.
AB  - 5-Aminolaevulinic-acid (ALA) can be used as an alternative drug in photodynamic
      therapy of the bladder, since the selective formation of protoporphyrin IX (PpIX)
      in the tumour and the virtual absence of induced skin photosensitivity are
      theoretically advantageous for clinical use. A preclinical study was performed,
      using an in vivo normal piglet bladder model, in order to determine the maximum
      drug and light doses for reversible tissue damage. Various ALA doses were
      administered either orally or instilled in the bladder and different radiant
      exposures were applied. Bladder biopsies were taken at regular intervals and
      tissue damage was investigated histologically. After oral ALA-administration the
      PpIX concentration was determined in plasma, erythrocytes and various tissues. In
      the case of oral administration, reversible bladder damage was observed using 60
      75 mg/kg ALA combined with a radiant exposure of 100 J/cm(2) (direct radiant
      exposure plus scattered 632 nm light) 5-7 h later. For an oral ALA dose of up to
      150 mg/kg, the maximum PpIX concentration is reached at approximately 5 h
      following administration and in neither skin nor bladder tissue is PpIX present
      at 10-11 h after administration. This ALA dose combined with a radiant exposure
      of 200 J/cm(2) produces irreversible bladder damage (extensive necrosis and
      ulceration). In the case of intravesical instillation for 4-4.75 h, an ALA dose
      of 2.5 g in 50 ml phosphate buffered saline and a radiant exposure of 100 J/cm(2)
      are still too high to obtain reversible tissue damage; at this dose one of the 13
      pigs developed a shrunken bladder with a fibrotic, thickened bladder wall. These
      drug and light combinations reported above should be regarded as upper limits in
      pigs and can serve as an indication for the toxicity of the treatment in a
      clinical setting.

PMID- 12417978
TI  - The ablation threshold of Er:YAG and Er:YSGG laser radiation in dental enamel.
AB  - The scientific investigation of fundamental problems plays a decisive role in
      understanding the mode of action and the consequences of the use of lasers on
      biological material. One of these fundamental aspects is the investigation of the
      ablation threshold of various laser wavelengths in dental enamel. Knowledge of
      the relationships and influencing factors in the laser ablation of hard tooth
      tissue constitutes the basis for use in patients and the introduction of new
      indications. The present paper examines the ablation threshold of an Er:YAG laser
      (lambda=2.94 micro m) and an Er:YSGG laser (lambda=2.79 micro m) in human dental
      enamel. To this end, 130 enamel samples were taken from wisdom teeth and treated
      with increasing energy densities of 2-40 J/cm(2). The sample material was mounted
      and irradiated on an automated linear micropositioner. Treatment was performed
      with a pulse duration of tau(P(FWHM)) approximately 150 micro s and a pulse
      repetition rate of 5 Hz for both wavelengths. The repetition rate of the laser
      and the feed rate of the micropositioner resulted in overlapping of the single
      pulses. The surface changes were assessed by means of reflected light and
      scanning electron microscopy. On the basis of the results, it was possible to
      identify an energy density range as the ablation threshold for both the Er:YAG
      and the Er:YSGG laser. With the Er:YAG laser, the transition was found in an
      energy density range of 9-11 J/cm(2). The range for the Er:YSGG laser was
      slightly higher at 10-14 J/cm(2).

PMID- 12417979
TI  - Influence of the pulse duration of an Er:YAG laser system on the ablation
      threshold of dental enamel.
AB  - The present study examines the dependence of the ablation threshold on the
      duration of the applied laser pulses in the dental enamel of human wisdom teeth.
      To this end, 600 treatments with the Er:YAG laser (lambda=2940 nm) were carried
      out on a total of 50 extracted teeth. The laser light was coupled into a fluoride
      glass light guide for this purpose, in order to ensure almost gaussian
      distribution of the light in a radially symmetrical beam. The beam diameter on
      the specimen was 610 micro m. The radiant exposure on the tooth surface was
      varied between 2 and 20 J/cm(2), while the duration of the pulses applied was
      changed in four steps from 100 micro s to 700 micro s. The irradiated tooth
      surfaces were examined for visible signs of ablation under a reflected-light
      microscope. The experiments revealed that, when pulses of shorter duration are
      used, the limit at which ablation sets in is reduced by up to approx. 3 J/cm(2).
      This expands the ablation threshold range of Er:YAG laser radiation to between 6
      and 10 J/cm(2). In this context, both the pulse duration and the radiant exposure
      have a statistically significant influence on the ablation threshold (logistic
      regression, p<0.0001). Although the ablation threshold of the dental enamel can
      be changed by varying the pulse duration of the Er:YAG laser, no clinical
      consequences can be expected, as the shift is only slight.

PMID- 12417980
TI  - Bone tissue ablation with sub-microS pulses of a Q-switch CO(2) laser:
      histological examination of thermal side effects.
AB  - . The goal of this study is an in vitro evaluation of thermal side-effects by the
      application of short sub- micro s CO(2) laser pulses in combination with an air
      water spray on different types of bone tissue. A mechanically Q-switched CO(2)
      laser delivered 300 ns pulses at 9.6 micro m wavelength, which were focused down
      to a spot size of 440 micro m on the tissue (a corresponding energy density of 9
      J/cm(2)). Bone samples (blocks from pig femur, rib, or cartilage) were moved
      through the beam repeatedly until 1-5 mm deep cuts were produced. An air driven
      water spray was applied to prevent the tissue dehydration. Subsequent visual and
      histological examinations revealed no carbonisation, melting traces or fissuring
      of the tissue. An extremely narrow, 2-6 micro m thick thermally altered layer was
      observed at the cut border in compacta and cartilage. No accumulation of the
      thermal damage occurred with increasing cut depth. Laser incisions in trabecular
      tissue were accompanied with a 100-200 micro m thick zone of thermal necrosis in
      bone marrow. The difference from compacta and cartilage can be explained
      considering the particular character of the spreading of the ablation products in
      the trabecular meshwork. Minor thermal side effects make the Q-switched and
      probably other short pulsed CO(2) laser systems interesting for hard tissue
      surgery.

PMID- 12417981
TI  - Critical parameters in the cytotoxicity of photodynamic therapy using a pulsed
      laser.
AB  - Photodynamic therapy (PDT) using a pulsed laser is becoming popular, but its
      cytotoxic effect is still not clear. We therefore studied the cytotoxicity of PDT
      using a pulsed laser by changing its irradiation parameters and compared the
      degrees of cytotoxicity with those of PDT using continuous-wave (CW) light
      sources. Mice renal cell carcinoma cells were incubated with PAD-S31, a water
      soluble photosensitiser of which the excitation peak is 670 nm, and were then
      irradiated with either a tungsten lamp, a CW diode laser, or a nanosecond pulsed
      Nd:YAG laser-based optical parametric oscillator system. When the PAD-S31
      concentration and total light dose were constant (12 micro g/ml and 40 J/cm(2),
      respectively), the CW laser caused fluence rate-dependent decrease in cellular
      proliferation until the fluence rate reached 90 mW/cm(2), at which point
      inhibition of cellular proliferation was more than 80%. The cytotoxicity then
      became almost saturated at fluence rates of>90 mW/cm(2). On the other hand,
      inhibition of cellular proliferation in samples irradiated with the pulsed laser
      reached 80% even at the fluence rate of 15 mW/cm(2), and, interestingly, the
      cytotoxicity paradoxically decreased with increase in the fluence rate. Moreover,
      the cytotoxicity in the PDT using the pulsed laser depended on the repetition
      rate. The inhibition of cellular proliferation by PDT using 30-Hz irradiation was
      greater than that by PDT using 5-Hz irradiation when the same fluence rates were
      used. These results suggest that the efficacy of PDT using a pulsed laser depends
      considerably on fluence rate and repetition rate.

PMID- 12417982
TI  - Selective photothermal interaction using an 805-nm diode laser and indocyanine
      green in gel phantom and chicken breast tissue.
AB  - Laser immunotherapy, a novel therapy for breast cancer, utilises selective
      photothermal interaction to raise the temperature of tumour tissue above the cell
      damage threshold. Photothermal interaction is achieved with intratumoral
      injection of a laser-absorbing dye followed by non-invasive laser irradiation.
      When tumour heating is used in combination with immunoadjuvant to stimulate an
      immune response, antitumour immunity can be achieved. In this study, the
      selective photothermal effect was investigated using gel phantom and chicken
      breast tissue. An 805-nm diode laser and indocyanine green (ICG) were used. An
      ICG-containing gelatin phantom was constructed to simulate targeted tumour
      tissue. The target gel was buried inside chicken breast tissue and the tissue-gel
      construct was irradiated by the laser. Temperatures at different locations in the
      construct were measured during the laser irradiation. For comparison, the thermal
      effect of an Nd:YAG laser on the tissue-gel construct was also investigated.
      Selective heating of target gel containing 0.27% ICG and buried 1 cm below the
      chicken tissue surface was achieved with the 805-nm diode laser using a power of
      0.85 W and beam radius of 1 cm. The target gel experienced a temperature increase
      of more then 6 degrees C whereas the surrounding chicken breast tissue
      experienced only a minor temperature increase. The feasibility of this
      experimental set-up has been shown. It will be used in the future to optimise
      treatment parameters such as laser power, laser beam radius, and dye
      concentration.

PMID- 12417983
TI  - Photodynamic therapy with photofrin reduces invasiveness of malignant human
      glioma cells.
AB  - In this study we investigated the influence of Photofrin-based photodynamic
      therapy (PDT) on the migration of two human glioma cell lines in vitro. U87 and
      U25ln tumour cells were treated with Photofrin at various doses and subjected to
      a fixed optical (632 nm) dose of 100 mJ/cm(2). Photofrin cytotoxicity was
      determined using MTT and colony forming assays. Using a matrigel artificial
      basement membrane migration assay, we demonstrated that low doses of subcytotoxic
      PDT treatment, such as PDT with 2.5 micro g/ml Photofrin on U87 cells and 1 micro
      g/ml on U25ln cells, significantly ( p<0.001) inhibited in vitro migration of
      both cell lines. Furthermore, in a qualitative spheroid confrontation assay,
      subcytotoxic PDT of co-cultures between tumour spheroids and brain aggregates
      resulted in an absence of progressive tumour invasion and destruction of the
      brain aggregate. In conclusion, our data indicate that low-dose subcytotoxic PDT
      with Photofrin significantly inhibits invasiveness of U87 and U25ln cells.

PMID- 12417984
TI  - Cerebral vascular effects of non-invasive laserneedles measured by transorbital
      and transtemporal Doppler sonography.
AB  - Laserneedles represent a new non-invasive optical stimulation method which is
      described for the first time in this paper. We investigated 27 healthy volunteers
      (mean age+/-SD: 25.15+/-4.12 years; range: 21-38 years; 14 female, 13 male) in a
      randomised cross-over trial to study differences between laserneedle acupuncture
      and manual needle acupuncture in specific cerebral parameters. Mean blood flow
      velocity ( v(m)) showed specific and significant increases in the ophthalmic
      artery during laserneedle stimulation ( p=0.01) and during manual needle
      stimulation ( p<0.001) at vision-related acupoints. At the same time
      insignificant alterations in v(m) were found in the middle cerebral artery for
      both acupuncture methods. The eight laserneedles used in this study were arranged
      at the end of the optical fibres. Each fibre was connected to a semiconductor
      laser diode emitting at 685 nm with a primary output power of about 55 mW.
      Optical stimulation using properly adjusted laserneedles has the advantage that
      the stimulation can hardly be felt by the patient and the operator may also be
      unaware of whether the laserneedle system is active, and therefore true double
      blind studies in acupuncture research can be performed.

PMID- 12417986
TI  - Laser Florence 2002. Abstracts. October 28-31, 2002, Florence, Italy.

PMID- 12417988
TI  - Homogeneous preparation encoding (HoPE) in multislice imaging.
AB  - Fast magnetization preparation techniques acquire a series of echoes after a
      single magnetization preparation. If these echoes are acquired from different
      slices using a multislice technique the change in the preparation state of the
      echoes due to relaxation effects leads to different contrast modification for
      each slice. Encoding different preparation states along the phase-encoding
      direction of each slice instead of acquiring each slice in a different
      preparation state is introduced as a general concept to obtain images of
      identical contrast and point-spread function. This can be realized either by
      cycling the slice excitation order several times over the total number of
      repetitions or by moving the point of time at which the preparation is applied
      within each repetition. One possible application of this method is chemical shift
      selective fat saturation imaging. A homogeneous fat suppression across a
      multislice volume could be achieved using a FLASH sequence at a repetition time
      of TR = 145 ms, including a single fat saturation preparation. Conventional fat
      saturated spin-echo imaging at any TR can be accelerated significantly by
      reducing the number of applied preparations per repetition. A further application
      of the homogeneous preparation encoding (HoPE) method is described that encodes
      the spatial self-saturation of the multislice excitation order homogeneously in
      all slices. Only a reduced number of slices of the total volume are excited in
      each repetition and the slice excitation order is continuously moved along the
      imaging volume. This method is applied for time of flight (TOF) imaging. Using a
      TONE-like series of flip angles for the slice excitations of each repetition
      homogeneous TOF images can be obtained on the basis of a multislice acquisition.

PMID- 12417987
TI  - A missense mutation (R565W) in cirhin (FLJ14728) in North American Indian
      childhood cirrhosis.
AB  - North American Indian childhood cirrhosis (CIRH1A, or NAIC), a severe autosomal
      recessive intrahepatic cholestasis described in Ojibway-Cree children from
      northwestern Quebec, is one of several familial cholestases with unknown
      molecular etiology. It typically presents with transient neonatal jaundice, in a
      child who is otherwise healthy, and progresses to biliary cirrhosis and portal
      hypertension. Clinical and physiological investigations have not revealed the
      underlying cause of the disease. Currently, liver transplantation is the only
      effective therapy for patients with advanced disease. We previously identified
      the NAIC locus by homozygosity mapping to chromosome 16q22. Here we report that
      an exon 15 mutation in gene FLJ14728 (alias Cirhin) causes NAIC: c.1741C-->T in
      GenBank cDNA sequence NM_032830, found in all NAIC chromosomes, changes the
      conserved arginine 565 codon to a tryptophan, altering the predicted secondary
      structure of the protein. Cirhin is preferentially expressed in embryonic liver,
      is predicted to localize to mitochondria, and contains WD repeats, which are
      structural motifs frequently associated with molecular scaffolds.

PMID- 12417989
TI  - Variable-density adaptive imaging for high-resolution coronary artery MRI.
AB  - Variable-density (VD) spiral k-space acquisitions are used to acquire high
      resolution (0.78 mm), motion-compensated images of the coronary arteries. Unlike
      conventional methods, information for motion compensation is obtained directly
      from the coronary anatomy itself. Specifically, periods of minimal coronary
      distortion are identified by applying the correlation coefficient template
      matching algorithm to real-time images generated from the inner, high-density
      portions of the VD spirals. Combining the data associated with these images
      together, high-resolution, motion-compensated coronary images are generated.
      Because coronary motion is visualized directly, the need for cardiac-triggering,
      breath-holding, and navigator echoes is eliminated. The motion compensation
      capability of the technique is determined by the inner-spiral spatial and
      temporal resolution. Results indicate that the best performance is achieved using
      inner-spiral images with high spatial resolution (1.6-2.9 mm), even though
      temporal resolution (four to six independent frames per second) suffers as a
      result. Image quality within the template region in healthy volunteers was found
      to be comparable to that achieved with cardiac-triggered breath-hold scans,
      although extended acquisition times of around 5 min were needed to overcome
      reduced SNR efficiency.

PMID- 12417990
TI  - Evidence that both fast and slow water ADC components arise from intracellular
      space.
AB  - Evaluation of water diffusion in the brain has revealed both fast- and slow
      diffusing water populations. It has been suggested that these populations
      represent extra- and intracellular water, respectively. We have identified and
      characterized both populations in the intracellular space of the Xenopus oocyte.
      We have also determined their T(1) and T(2) relaxation properties. The fast and
      slow intracellular populations have diffusion coefficients of 1.06 +/- 0.05
      microm(2)/ms and 0.16 +/- 0.02 microm(2)/ms, respectively, with the fast fraction
      representing 89% +/- 1% of the total water signal. These values are quite similar
      to those for total water in brain and are observed in the absence of signal from
      the perfusate (extracellular) water population. Volumetric swelling (16% +/- 4%)
      of the oocyte in hypoosmotic media increased the diffusion coefficients of both
      intracellular populations (fast = 1.27 +/- 0.03 microm(2)/ms, slow = 0.22 +/-
      0.02 microm(2)/ms), but did not change their relative signal fractions. This
      phenomenon runs counter to the effects observed in brain injury, following which
      the apparent diffusion coefficient (ADC) decreases 30-50%. The results presented
      herein suggest that this ADC decrease in brain occurs despite cell swelling,
      which by itself would be expected to induce an increase in intracellular
      diffusion coefficients.

PMID- 12417991
TI  - Real-time autoshimming for echo planar timecourse imaging.
AB  - Head motion within an applied magnetic field alters the effective shim within the
      brain, causing geometric distortions in echo planar imaging (EPI). Even if
      subtle, change in shim can lead to artifactual signal changes in timecourse EPI
      acquisitions, which are typically performed for functional MRI (fMRI) or
      diffusion tensor imaging. Magnetic field maps acquired before and after head
      motions of clinically realistic magnitude indicate that motion-induced changes in
      magnetic field may cause translations exceeding 3 mm in the phase-encoding
      direction of the EPI images. The field maps also demonstrate a trend toward
      linear variations in shim changes as a function of position within the head,
      suggesting that a real-time, first-order correction may compensate for motion
      induced changes in magnetic field. This article presents a navigator pulse
      sequence and processing method, termed a "shim NAV," for real-time detection of
      linear shim changes, and a shim-compensated EPI pulse sequence for dynamic
      correction of linear shim changes. In vivo and phantom experiments demonstrate
      the detection accuracy of shim NAVs in the presence of applied gradient shims.
      Phantom experiments demonstrate reduction of geometric distortion and image
      artifact using shim-compensated EPI in the presence of applied gradient shims. In
      vivo experiments with intentional interimage subject motion demonstrate improved
      alignment of timecourse EPI images when using the shim NAV-detected values to
      update the shim-compensated EPI acquisition in real time.

PMID- 12417992
TI  - Inductively coupled stent antennas in MRI.
AB  - The development of intimal hyperplasia following stent deployment can lead to
      narrowing or even occlusion of the stent lumen. The underlying mechanisms leading
      to neointimal proliferation within stents remain largely unknown. Long-term
      evaluation of stent patency requires a noninvasive means for assessing the stent
      lumen. MR angiography (MRA) has shown potential to provide noninvasive assessment
      of the vascular system. However, a detailed assessment of the stent lumen with
      MRI is often hampered by material-dependent susceptibility artifacts, as well as
      by radiofrequency (RF) eddy currents generated inside the electrically conducting
      stent mesh. In this study, stent prototypes were designed to act as active
      resonant structures at the Larmor frequency of the MR system. Employing the
      principle of inductive coupling, the B(1) fields of the stents were coupled to
      that of an outside surface coil. The stents thus acted as local RF signal
      amplifiers. Various stent designs were investigated regarding their coupling to
      an external coil, signal homogeneity, and suitability for mechanical expansion
      for implantation purposes. The dependency of flip angle amplification on the
      quality factor Q of the stents was systematically investigated. Phantom
      experiments revealed signal amplification in all stent prototypes. Signal
      enhancement inside and close to the surface of the stents enabled their
      localization with high contrast in MR images. In vivo imaging experiments in the
      iliac, renal, and splenic arteries of two pigs confirmed the in vitro findings.
      Wireless active visualization of stents allows for detailed analysis of the stent
      lumen with high contrast and spatial resolution. The proposed method could thus
      provide a powerful diagnostic means for the noninvasive long-term follow-up of
      stent patency, thereby enhancing our understanding of the mechanisms of
      restenosis.

PMID- 12417994
TI  - Optimization of signal behavior in the transition to driven equilibrium in steady
      state free precession sequences.
AB  - A new technique to avoid the initial signal fluctuations in steady-state free
      precession (SSFP)-sequences, such as trueFISP, FIESTA, and refocused FFE, is
      presented. The "transition into driven equilibrium" (TIDE) sequence uses modified
      flip angles over the initialization phase of a SSFP experiment, which not only
      avoids image artifacts but also improves the signal-to-noise ratio (SNR) and
      contrast behavior compared to conventional approaches. TIDE is demonstrated to be
      robust against variations of T(1) and T(2), and leads to a monotonous signal
      evolution for off-resonance spins. The basic principles can also be applied
      repetitively to optimize continuous 3D acquisitions.

PMID- 12417993
TI  - Myocardial viability imaging using Gd-DTPA: physiological modeling of infarcted
      myocardium, and impact on injection strategy and imaging time.
AB  - Results of simulations are shown which illustrate how the concentration-time
      curves of an extravascular extracellular (EVEC) contrast agent, such as Gd-DTPA,
      vary in myocardial tissue. The simulations show that the variable permeability of
      dead myocytes within a recent myocardial infarction will significantly alter
      delayed enhancement patterns following a bolus injection, invariably reducing the
      sensitivity of this technique for the detection of permanently damaged tissue. It
      is further predicted that if the bolus injection is followed by a suitably
      selected constant infusion, the infarct size and infarct volume of distribution
      may be more accurately determined, even though the degree of enhancement of an
      infarcted region (with normal flow) above normal tissue is slightly higher for
      the bolus technique within the first 30 min following the injection. The degree
      of enhancement of an infarcted region (with normal flow) above normal tissue was
      comparable between the two techniques at the point in the constant infusion at
      which the volume of contrast injected was the same as in the bolus case, i.e., at
      approximately 30 min after the bolus injection. The constant infusion approach
      became superior thereafter as overall tissue concentrations became greater in
      both normal and infarcted tissue, and these concentrations remained more stable
      with the constant infusion approach. Preliminary experimental results in a canine
      model of infarction/reperfusion illustrated a delayed wash-in of contrast agent
      in infarcted tissue, which may be explained by a physiological model in which
      dead myocytes in infarcted myocardium have non-infinite permeability.

PMID- 12417995
TI  - Functional hepatocyte cation compartmentation demonstrated with 133Cs NMR.
AB  - This study utilized the large intrinsic chemical shift range of (133)Cs, a
      potassium congener, in an NMR study of intracellular cation distribution. It
      demonstrates two distinct intracellular environments in isolated perfused
      hepatocytes from cesium-fed rats, evident as compartments with different (133)Cs
      chemical shifts and containing different proportions of total detected cesium.
      The chemical shifts of the two intracellular compartments were 2.44 +/- 0.07 and
      1.21 +/- 0.18 ppm, relative to the cesium signal from the perfusate. The
      observation of two distinct intracellular cesium signals suggests slow exchange
      on an NMR chemical shift time-scale (k exchange > 0.02 s). The area of the high
      frequency component represented 62 +/- 10% (N = 12) of the total intracellular
      cesium signal. Manipulation of the intracellular environment using anoxia with
      aglycemia or digitonin produced changes in the distribution between the two
      intracellular compartments, showing their dynamic nature. Changes measured in
      association with metabolic manipulation suggest cytoplasm and mitochondria as the
      origin of the high and low-frequency intracellular peaks, respectively.

PMID- 12417996
TI  - Real-time changes in 1H and 31P NMR spectra of malignant human mammary epithelial
      cells during treatment with the anti-inflammatory agent indomethacin.
AB  - Choline metabolites in malignant human mammary epithelial cells (HMECs) are
      significantly altered compared to normal HMECs. (1)H NMR studies of cell extracts
      have shown that treatment of malignant HMECs with a nonsteroidal anti
      inflammatory agent, indomethacin, results in a distribution of choline compounds
      more typical of nonmalignant HMECs. To follow the time course of these changes,
      in this study real-time monitoring of choline compounds of malignant MDA-MB-231
      cells was performed during treatment with indomethacin. The contribution of
      changes in intra- and extracellular pH to changes in choline compounds was also
      examined. Changes in water-soluble choline phospholipid metabolites, such as
      phosphocholine (PC), glycerophosphocholine (GPC), and total choline, as well as
      intracellular pH, were monitored by (31)P and diffusion-weighted (1)H NMR
      spectroscopy of living cells using an NMR-compatible perfusion system. An
      accumulation of GPC and a decrease of PC, resulting in an increased [GPC]/[PC]
      ratio, were detected within 2 hr of treatment with 200 microM indomethacin. Since
      a decreased [GPC]/[PC] ratio is associated with increased malignancy, these data
      demonstrate that nonspecific cyclooxygenase inhibition by indomethacin alters the
      choline metabolite profile of malignant cells towards a less malignant phenotype.
      These changes were not related to alterations of intra- or extracellular pH.

PMID- 12417997
TI  - Separating changes in the intra- and extracellular water apparent diffusion
      coefficient following focal cerebral ischemia in the rat brain.
AB  - Selective intracellular (IC) and extracellular (EC) brain water apparent
      diffusion coefficient (ADC) values were measured in normal and ischemic rat
      brain. Selective T(1)-relaxation enhancement of the EC water, using
      intracerebroventricular (ICV) infusion of an NMR contrast reagent (CR), was used
      to separate the IC and EC signal contributions. In the CR-infused, normal brain
      (n = 4), T(1) = 235 +/- 10 ms and T(2) = 46 +/- 2 ms for IC water (85%) and T(1)
      = 48 +/- 8 ms and T(2) = 6 +/- 2 ms for EC water (15%). Volume-localized ADC(z)
      (z-gradient axis) values were 0.90 +/- 0.02 (EC+IC), 0.81 +/- 0.05 (IC), 0.51 +/-
      0.02 (EC+IC), and 0.53 +/- 0.07 (IC), for normal, CR-infused, ischemic, and
      ischemic/CR-infused groups, respectively (ADC values are x10(-3) mm(2)/s; n = 5
      for each group). Imaging ADC(z) values were 0.81 +/- 0.03 (EC+IC), 0.75 +/- 0.05
      (IC), 0.51 +/- 0.04 (EC+IC), and 0.52 +/- 0.05 (IC), respectively, for the same
      groups. Imaging ADC(av) (average diffusivity) values for the same groups were
      0.70 +/- 0.05 (EC+IC), 0.69 +/- 0.06 (IC), 0.45 +/- 0.06 (EC+IC), and 0.44 +/-
      0.06 (IC), respectively. These results suggest that the IC water ADC determines
      the overall water ADC value in normal and ischemic rat brain.

PMID- 12417998
TI  - GABAergic mechanisms of heroin-induced brain activation assessed with functional
      MRI.
AB  - Heroin has been hypothesized to activate opiate receptors and inhibit gamma
      aminobutyric acid (GABA) release from inhibitory GABAergic interneurons which, in
      turn, activates dopamine projection cells. Since the distal sites and
      consequences of this disinhibition are not well understood on a systems level,
      heroin-induced brain activity was measured using functional MRI (fMRI) in rats. A
      significant blood oxygen level-dependent (BOLD) signal increase was seen in
      cortical regions, including prefrontal cortex, cingulate, and olfactory cortex
      following acute heroin administration. In contrast, a significant signal decrease
      was seen in several subcortical areas, including the caudate and putamen, nucleus
      accumbens, thalamus, and hypothalamus. Pretreatment of gamma-vinyl GABA (GVG), an
      irreversible GABA transaminase inhibitor, significantly attenuated the heroin
      induced BOLD signal changes. Pretreatment of naloxone, an opiate mu receptor
      antagonist, eliminated the heroin-induced BOLD signal changes and posttreatment
      of naloxone reversed the heroin-induced BOLD signal changes. It is suggested that
      the heroin-induced negative and positive BOLD changes are due to direct
      inhibitory and indirect disinhibitory mechanisms of GABAergic activities.
      Administration of GVG altered these mechanisms and further suggested that
      involvement of the opiate's pharmacological actions can, at least in part, be
      mediated by inhibiting brain GABA release.

PMID- 12417999
TI  - MR angiography with a new rapid-clearance blood pool agent: Initial experience in
      rabbits.
AB  - The purpose of this study was to assess a new Gd-based macromolecular
      intravascular contrast agent (P792, Vistarem(R); Laboratoire Guerbet, Aulnay sous
      Bois, France) for MR angiography (MRA). P792 is a macrocyclic gadolinium compound
      based on a gadoterate meglumine structure substituted by hydrophilic arms. In
      vitro imaging of phantoms containing varying concentrations of P792 and
      gadoterate meglumine (Gd-DOTA) was performed. In rabbits (N = 5), arterial
      concentrations for P792 and Gd-DOTA were determined, and in vivo 3D MRA was
      performed. For gadolinium concentrations ranging from 200 to 3000 micromol/l, in
      vitro imaging showed higher SNR values for P792 compared to Gd-DOTA.
      Determination of arterial Gd concentration showed comparable bolus phase curves
      for P792 and Gd-DOTA. With P792, higher concentrations were obtained due to a
      restricted diffusion into the interstitial space. P792 allowed acquisition of
      high-quality MR angiograms. Image quality was rated as superior for P792 in the
      post-bolus phase images. In conclusion, P792 appears to be well suited for high
      quality first-pass and equilibrium-phase MRA. The intravascular properties lead
      to an excellent signal in the vasculature, with limited background enhancement.
      Since the agent is rapidly renally excreted, it should be well suited for
      perfusion and permeability imaging.

PMID- 12418000
TI  - In vivo 3D MRI staining of mouse brain after subcutaneous application of MnCl2.
AB  - Follow-up T(1)-weighted 3D gradient-echo MRI (2.35 T) of murine brain in vivo (N
      = 5) at 120 microm isotropic resolution revealed spatially distinct signal
      increases 6-48 hr after subcutaneous application of MnCl(2) (20 mg/kg). The
      effects result from a shortening of the water proton T(1) relaxation time due to
      the presence of unchelated paramagnetic Mn(2+) ions, which access the brain by
      systemic circulation and crossing of the blood-brain barrier (BBB). A pronounced
      Mn(2+)-induced signal enhancement was first seen in structures without a BBB,
      such as the choroid plexus, pituitary gland, and pineal gland. Within 24 hr after
      administration, Mn(2+) contrast highlighted the olfactory bulb, inferior
      colliculi, cerebellum, and the CA3 subfield of the hippocampus. The affinity of
      Mn(2+) to various brain systems suggests the neuronal uptake of Mn(2+) ions from
      the extracellular space and subsequent axonal transport. Thus, at least part of
      the Mn(2+) contrast reflects a functional brain response of behaving animals, for
      example, in the olfactory system. In vivo MRI staining of the brain by systemic
      administration of MnCl(2) may contribute to phenotyping mutant mice with
      morphologic and functional alterations of the central nervous system.

PMID- 12418001
TI  - Sensitivity-encoded single-shot spiral imaging for reduced susceptibility
      artifacts in BOLD fMRI.
AB  - Sensitivity encoding (SENSE) with iterative image reconstruction was used to
      shorten the readout duration in single-shot spiral imaging by a factor of 2. This
      enabled susceptibility-related blurring and signal loss artifacts to be reduced
      and spatial resolution to be improved. As a beneficial side effect, the gradient
      duty cycle was also reduced. The spiral SENSE technique was applied to functional
      MRI (fMRI) with blood oxygen level-dependent (BOLD) contrast and compared to a
      conventional spiral acquisition. Stimulation experiments were performed in seven
      volunteers using motor, visual, and taste paradigms. The signal-to-noise ratio
      (SNR) and signal-to-fluctuation-noise ratio (SFNR) of the SENSE acquisitions were
      reduced by 20% and 13%, respectively, with respect to the longer readout. The
      overall activation detected was comparable to that of the conventional spiral
      acquisition, even though difficulties in reproducing the stimulation response
      hampered the evaluation. In some cases, the application of SENSE enabled recovery
      of activation in regions affected by signal loss due to field inhomogeneity.

PMID- 12418002
TI  - Multiple gradient echo sequence optimized for rapid, single-scan mapping of
      R(2)(*) at high B0.
AB  - A multiple-gradient-echo sequence is proposed for accurately mapping R(2)(*) in
      the presence of in-slice macroscopic susceptibility gradients. In-slice signal
      loss caused by background macroscopic susceptibility gradients is mitigated by
      combining three successive gradient-echo images whose slice refocus gradients are
      successively incremented. The optimum incrementation of slice-refocusing
      gradients was determined by numerical simulation. By repeating further cycles of
      three images in the same sequence, artifact-compensated data spanning a range of
      echo times (TEs) was acquired leading to single-scan, R(2) (*) maps that are
      quantitatively reflective of microscopic field inhomogeneities. The performance
      of the sequence was demonstrated at 3.0T, first with a doped aqueous phantom, and
      then on the head of a normal volunteer. That performance is compared
      quantitatively with previously published work.

PMID- 12418003
TI  - Real-time quantification of T(2)(*) changes using multiecho planar imaging and
      numerical methods.
AB  - Conventional approaches to quantify whole brain T(2)(*) maps use nonlinear
      regression with intensive computational requirements that therefore likely limit
      quantitative T(2)(*) mapping for real-time applications. To overcome these
      limitations an alternative method, NumART(2)(*) (NUMerical Algorithm for Real
      time T(2)(*) mapping) that directly calculates T(2)(*) by a linear combination of
      images obtained at three or more different echo times was developed.
      NumART(2)(*), linear least-squares, and nonlinear regression techniques were
      applied to multiecho planar images of the human brain and to simulated data.
      Although NumART(2)(*) may overestimate T(2)(*), it yields comparable values to
      regression techniques in cortical and subcortical areas, with only moderate
      deviations for echo spacings between 18 and 40 ms. NumART(2)(*), like linear
      regression, requires 2% of the computational time needed for nonlinear regression
      and compares favorably with linear regression due to its higher precision. The
      use of NumART(2)(*) for continuous on-line T(2)(*) mapping in real time fMRI
      studies is shown.

PMID- 12418004
TI  - Method to correct for the effects of limited spatial resolution in phase-contrast
      flow MRI measurements.
AB  - Phase-contrast (PC) magnetic resonance imaging (MRI) flow measurements suffer
      from the effect of the point spread function (PSF) due to the limited sampling of
      k-space. The PSF, which in this case is a sinc function, deforms the flow profile
      and forms a ringing pattern around the vessel. In this work, an empirical method
      is presented that corrects for errors due to the deformation of the flow profile.
      The ringing pattern is used to obtain a well-defined vessel segmentation, which
      after correction provides more accurate vessel radius and volume flow rate (VFR).
      The correction method was developed from phantom measurements at constant flow
      and applied on phantom measurements at moderately pulsatile flow. After
      correction, the error of the estimated tube radius and the VFR was less than 10%
      and 5%, respectively. Corresponding errors without correction overestimated the
      radius by 60% and the VFR by 35%. Preliminary results indicate that the method is
      also valid in vivo. The variation in the estimated radius and VFR for different
      spatial resolution decreased when the method was applied. The presented method
      gives a more accurate estimation of the radius and VFR in vessels of the size of
      a few pixels without prior knowledge about the true vessel radius.

PMID- 12418005
TI  - Fast phase-contrast velocity measurement in the steady state.
AB  - A new method of encoding flow velocity as image phase in a refocused steady-state
      free precession (SSFP) sequence, called steady-state phase contrast (SSPC), can
      be used to generate velocity images rapidly while retaining high signal.
      Magnitude images with refocused-SSFP contrast are simultaneously acquired. This
      technique is compared with the standard method of RF-spoiled phase contrast (PC),
      and is found to have more than double the phase-signal to phase-noise ratio (PNR)
      when compared with standard PC at reasonable repetition intervals (TRs). As TR
      decreases, this advantage increases exponentially, facilitating rapid scans with
      high PNR efficiency. Rapid switching between the two necessary steady states can
      be accomplished by the insertion of a single TR interval with no flow-encoding
      gradient. The technique is implemented in a 2DFT sequence and validated in a
      phantom study. Preliminary results indicate that further TR reduction may be
      necessary for high-quality cardiac images; however, images in more stationary
      structures, such as the descending aorta and carotid bifurcation, exhibit good
      signal-to-noise ratio (SNR) and PNR. Comparisons with standard-PC images verify
      the PNR advantage predicted by theory.

PMID- 12418006
TI  - T1-insensitive flow suppression using quadruple inversion-recovery.
AB  - A new flow suppression method has been proposed for the acquisition of blood
      suppressed (black-blood) images in combination with administration of a positive
      contrast agent. The technique employs the quadruple inversion-recovery (QIR)
      preparative pulse sequence, which consists of two double-inversion modules
      followed by two delays. Within each double inversion, a nonselective RF pulse is
      immediately followed by a slice-selective one. The time intervals of the sequence
      can be calculated using an algorithm based on minimization of the variation of a
      signal equation over an entire range of T(1) occurring in blood before and after
      contrast administration. QIR is highly insensitive to variations of T(1),
      providing efficient suppression of a flow signal with T(1) in a range of 200-1200
      ms. The technique utilizes identical scan parameters for pre- and postcontrast
      acquisition, and thus allows reliable quantitative interpretation of contrast
      enhancement (CE). The clinical application of QIR was demonstrated in high
      resolution, contrast-enhanced, black-blood imaging of atherosclerotic plzzaque.

PMID- 12418007
TI  - Optimization of static field homogeneity in human brain using diamagnetic passive
      shims.
AB  - These preliminary studies demonstrate that static field inhomogeneity in the
      human inferior frontal cortex (IFC) is significantly diminished through placement
      of a small amount of strongly diamagnetic material in the roof of the mouth. As a
      result, susceptibility-related image artifacts in this region, as observed in
      blood oxygen level dependent (BOLD) functional MRI (fMRI), are considerably
      decreased without compromising the spatial or temporal resolution of the study.
      Simulations of the static field utilizing perturbation theory are shown, which
      support the experimental results. The limitations and possible future
      developments of the technique are described. The application of diamagnetic
      passive shimming on other regions of the brain is also discussed. Routine use of
      the proposed method within fMRI studies is practicable through subject-specific
      optimization of the technique utilizing the simulation algorithm.

PMID- 12418008
TI  - Observation and identification of metabolites emerging during postmortem
      decomposition of brain tissue by means of in situ 1H-magnetic resonance
      spectroscopy.
AB  - Postmortem decomposition of brain tissue was investigated by (1)H-magnetic
      resonance spectroscopy (MRS) in a sheep head model and selected human cases.
      Aiming at the eventual estimation of postmortem intervals in forensic medicine,
      this study focuses on the characterization and identification of newly observed
      metabolites. In situ single-voxel (1)H-MRS at 1.5 T was complemented by
      multidimensional homo- and heteronuclear high-resolution NMR spectroscopy of an
      extract of sheep brain tissue. The inclusion of spectra of model solutions in the
      program LC Model confirmed the assignments in situ. The first postmortem phase
      was characterized mainly by changes in the concentrations of metabolites usually
      observed in vivo and by the appearance of previously reported decay products.
      About 3 days postmortem, new metabolites, including free trimethylammonium,
      propionate, butyrate, and iso-butyrate, started to appear in situ. Since the
      observed metabolites and the time course is comparable in sheep and human brain
      tissue, the model system seems to be appropriate.

PMID- 12418009
TI  - Single-breathhold 3D-trueFISP cine cardiac imaging.
AB  - Cardiac MRI function measurements are typically based on multiple breathhold 2D
      sequences to acquire images of the entire heart. In the present study, the
      feasibility of a cine 3D TrueFISP technique in which several complete volumetric
      measurements may be obtained during a single breathhold is demonstrated. In
      contrast to 3D FLASH, the TrueFISP sequence offers an excellent contrast between
      the myocardium and the intraventricular cavity without the use of contrast agent.
      An ECG-gated 3D cine TrueFISP sequence was implemented with a repetition time of
      2.4-2.8 ms, which allows imaging of the complete heart within a single breathhold
      throughout 20-46 heartbeats with a 3D frame rate of 8-13 volumes per cardiac
      cycle and a spatial resolution of about 1.5 x 3.5 x 3.5 mm(3). Breathhold
      volumetric cine imaging with the 3D TrueFISP technique holds promise for rapid
      and accurate evaluation of the cardiac regional wall motion and the calculation
      of cardiac volume and ejection fraction.

PMID- 12418010
TI  - The long-term behavior of poly-L-lactide screws in a minipig fracture model:
      preliminary report.
AB  - The long-term degradation tissue response to poly-L-lactide (PLLA) screw was
      investigated for a minipig tibia fracture. As a bone-fracture model, three PLLA
      screws per animal were used to fix a tibia that had been subjected to a crank
      shaped osteotomy. A total of 12 nine-month-old male minipigs were used. In time
      period from 1 month to 3 years, clinical, radiographic, and pathological studies
      were conducted. On macroscopic examination, no clear granuloma or fistula
      formation was noted for 3 years. On microscopic examination, no osteoclasts or
      giant cells were detected around the screws during the 3 years postoperatively. A
      substantial degradation of PLLA screw was observed between 2 and 3 years. At 3
      years only slight residual breakdown products were found in macrophages. On
      electric microscopic examination, numerous degraded polymers were seen in a small
      number of macrophages around the screws. In this model, fixation of tibia
      fractures using PLLA screws was not associated with any side effects, and was
      safe and useful for up to 3 years.

PMID- 12418011
TI  - S/e-PTFE episcleral buckling implants: an experimental and histopathologic study.
AB  - To investigate tissue changes induced by the implantation of a silicone band
      coated with expanded polytetrafluoroethylene (S/e-PTFE) used as scleral buckling,
      an experimental and histopathological study was performed in rabbits. The right
      eyes of eight rabbits were implanted for 28-85 days with S/e-PTFE. No
      complications were encountered in any of the eyes, so histopathological
      examinations could be performed. Encapsulations combined with numerous giant
      cells were found to be surrounding the implants in seven eyes, and deposits from
      the mineral salts of calcium were found in three eyes, forming granulomas
      possibly caused by irregularities of the implant surface. The porous structure
      allowed a peripheral colonization by fibrovascular tissue. Taking into account
      the histological results, the use of this material does not appear suitable.
      However, this inflammation was limited and did not merge on surrounding tissues.

PMID- 12418012
TI  - Heparin release from slippery-when-wet guide wires for intravascular use.
AB  - Thin metallic wires with an adherent hydrophilic/ lubricious polymeric coating
      were manufactured in a new extrusion-like procedure. This procedure is part of a
      novel and efficient way of assembling lubricious guide wires for intravascular
      interventions, such as percutaneous transluminal angioplasty. It is reported that
      heparin can readily be incorporated in the hydrophilic coating. A set of heparin
      containing guidewire models was made and studied in detail. This showed that (i).
      immersion of the guide-wire models in an aqueous environment leads to release of
      heparin from their surface; (ii). the presence of heparin in the coating does not
      impede the lubricity of the coils; (iii). addition of stearic acid in the
      coating, next to heparin, does not influence the lubricity of the guide-wire
      models. Two different charges of heparin (designated heparin-low and heparin
      high) were incorporated in the coating. It is discussed that release of heparin
      from the surface of medical devices (e.g. guide wires and catheters) is much more
      effective than systemic heparinization, basically because dissolved heparin
      molecules have a much larger probability of simply passing a medical device's
      surface (axial convection) rather than contacting it (radial diffusion).

PMID- 12418013
TI  - Long-term stability of a coronary stent coating post-implantation.
AB  - A coronary stent possessing a phosphorylcholine-based polymer coating was removed
      from a human patient 6 months after implantation and analyzed for the presence of
      the coating. An atomic force microscopy (AFM) technique has been employed to
      scrape away several 10- micro m(2) areas on the struts of the explanted stent.
      Scanning-electron microscopy (SEM) and tapping-mode AFM confirmed a surface
      coating had been removed in each case. Cross-sectional analysis and force-of
      removal measurements showed that both coating depth and hardness were
      characteristic of that for the phosphorylcholine- (PC-) based coating prior to
      implantation. AFM amplitude-phase and distance curves from the explanted stent
      were comparable to those obtained when an unused stent was analyzed. Furthermore,
      laser ablation high-resolution inductively coupled-plasma mass spectometery (LA
      HR-ICP-MS) was used to detect the low level of silicon present in the PC coating
      after explantation. The results from these techniques confirm that the stent
      coating is the original PC polymer and is not of biological origin, and support
      the long-term stability of the coating in vivo.

PMID- 12418014
TI  - Osseointegration on metallic implant surfaces: effects of microgeometry and
      growth factor treatment.
AB  - Orthopedic implants often loosen due to the invasion of fibrous tissue. The aim
      of this study was to devise a novel implant surface that would speed healing
      adjacent to the surface, and create a stable interface for bone integration, by
      using a chemoattractant for bone precursor cells, and by controlling tissue
      migration at implant surfaces via specific surface microgeometry design.
      Experimental surfaces were tested in a canine implantable chamber that simulates
      the intramedullary bone response around total joint implants. Titanium and alloy
      surfaces were prepared with specific microgeometries, designed to optimize tissue
      attachment and control fibrous encapsulation. TGF beta, a mitogen and
      chemoattractant (Hunziker EB, Rosenberg LC. J Bone Joint Surg Am 1996;78:721-733)
      for osteoprogenitor cells, was used to recruit progenitor cells to the implant
      surface and to enhance their proliferation. Calcium sulfate hemihydrate (CS) was
      the delivery vehicle for TGF beta; CS resorbs rapidly and appears to be
      osteoconductive. Animals were sacrificed at 6 and 12 weeks postoperatively.
      Results indicated that TGFbeta can be reliably released in an active form from a
      calcium sulfate carrier in vivo. The growth factor had a significant effect on
      bone ingrowth into implant channels at an early time period, although this effect
      was not seen with higher doses at later periods. Adjustment of dosage should
      render TGF beta more potent at later time periods. Calcium sulfate treatment
      without TGF beta resulted in a significant increase in bone ingrowth throughout
      the 12-week time period studied. Bone response to the microgrooved surfaces was
      dramatic, causing greater ingrowth in 9 of the 12 experimental conditions.
      Microgrooves also enhanced the mechanical strength of CS-coated specimens. The
      grooved surface was able to control the direction of ingrowth. This surface
      treatment may result in a clinically valuable implant design to induce rapid
      ingrowth and a strong bone-implant interface, contributing to implant longevity.

PMID- 12418015
TI  - Hydroxyapatite-based composite for dental implants: an in vivo removal torque
      experiment.
AB  - Screw-shaped dental implants were fabricated from commercially pure Ti (c.p. Ti)
      and HA-based composites. The HA-based composites were fabricated by mixing HA
      with Al(2)O(3)-coated ZrO(2) powders. The mechanical properties of these
      composites were enhanced by a factor of 3. These were implanted into the rabbit
      tibiae and the removal torque to loosen the implants in vivo was measured in
      order to investigate the osteointegration. After a healing period of 6 weeks, the
      implants were retrieved with a torque gauge instrument. The HA-based composite
      implants showed an almost 2-times-higher removal torque when compared to the Ti
      implants (ANOVA, p < 0.05), indicating excellent biocompatibility to bone. Thus,
      HA-based composites had not only better mechanical properties but also similar
      bioactivity as HA itself. It is believed that a HA-based composite is suitable
      for artificial dental implants.

PMID- 12418016
TI  - Mechanical properties of coagulated albumin and failure mechanisms of liver
      repaired with the use of an argon-beam coagulator with albumin.
AB  - Hemostasis in the traumatized liver has been achieved by thermally denaturing
      topically applied albumin. In this article, the mechanical properties of liver
      and denatured albumin (solder) were measured, and the failure methods of liver
      repaired with albumin were identified. The ultimate tensile strength and Young's
      modulus were measured for healthy liver (N = 20) and thermally damaged liver (N =
      20). The ultimate tensile strength and Young's modulus were measured for three
      concentrations of coagulated albumin (25, 38, and 53%) in a single layer and for
      two layers of denatured 38% albumin. Failure under tension of argon-beam
      coagulator soldered liver on the parenchymal surface (N = 30) with 38% albumin in
      two layers had a 70% occurrence for tearing at a mean stress of 39 kPa and a 23%
      occurrence for shearing at a mean stress of 7 kPa. Liver repaired on the interior
      surface (N = 11) failed in tension by tearing (64%) at a mean stress of 34 kPa
      and by shearing (36%) at a mean stress of 6 kPa. Argon-beam coagulator soldering
      with 38% albumin took 6 s/cm(2) for two layers of solder and gave the best
      balance of usability, strength, and matching of mechanical properties with those
      of the liver.

PMID- 12418017
TI  - Knoop hardness depth profiles and compressive strength of selected dental
      composites polymerized with halogen and LED light curing technologies.
AB  - After the first light-emitting diode (LED) light curing units (LCUs) became
      available commercially, a comparison of mechanical properties between materials
      polymerized with conventional halogen lamps and this new technology was required.
      This study, therefore, investigated the curing performance of two conventional
      commercial halogen LCUs (Translux CL, Spectrum800), a custom-made LED LCU
      prototype, and one of the first commercially available LED LCUs (LUXoMAX). The
      Spectrum800 was adjusted to a similar irradiance to the custom-made LED LCU
      prototype. Both technologies were compared by measuring compressive strength and
      Knoop hardness depth profiles for selected dental composites polymerized for 20
      or 40 s. Four dental composites (Z100, Spectrum TPH, Solitaire2, and Definite)
      were used. Two of these composites (Solitaire2 and Definite) contain co
      initiators in addition to the standard photoinitiator camphorquinone. In general,
      the material hardness obtained with the LUXoMAX was statistically significantly
      (p < 0.05) lower at the depths of 0.1, 1.0, 1.9, and 3.1 mm, for all composites
      and curing times, than for the other three LCUs. The LED LCU prototype achieved,
      with one exception, up to a depth of 1.9 mm a material hardness for the
      composites Z100, Spectrum TPH and Solitaire2 that was not statistically
      significant different (p < 0.05) from the hardness obtained with the halogen
      LCUs. At a greater depth (3.1 mm), however, the LED LCU prototype showed
      statistically significantly lower hardness values than the halogen units. The
      compressive strength test showed at a 95% confidence level that similar
      compressive strengths were achieved with the LCUs LUXoMAX and Spectrum800, and
      the Translux and LED LCU prototype.

PMID- 12418018
TI  - Biaxial flex-fatigue and viral penetration of natural rubber latex gloves before
      and after artificial aging.
AB  - Barrier integrity of unaged and oven-aged (at 70 degrees C) natural rubber latex
      examination gloves was assessed with a biaxial flex-fatigue method where failure
      was detected electronically, and by live viral penetration testing performed
      according to a modified version of ASTM F1671-97a. When no change in barrier
      properties was detected during flex testing, no virus passage was found after
      viral challenge. Conversely, when a change in the barrier properties was
      indicated by the electrical signal, virus passage was found in 74% of the
      specimens. Flex-fatigue results indicated that unaged test specimens from
      powdered (PD) and powder-free (PF) nonchlorinated gloves had significantly longer
      fatigue lives than powder-free chlorinated (CL) gloves from the same
      manufacturer. Biaxial flexing of oven-aged glove specimens showed a marginal
      increase in fatigue life for the PF gloves, but no increase for the PD gloves.
      The fatigue life of the CL gloves was observed to increase significantly after
      oven aging. However, this appears to be due to a design feature of the test
      apparatus, wherein peak volume displacement of the worked specimen is held
      constant. An aging-induced change in the viscoelastic properties of the CL gloves
      permanent deformation of the specimens early in the fatigue test-relieves the
      stress magnitude applied as the test progresses. Thus, permanent deformation acts
      as a confounding factor in measuring durability of latex gloves by fixed
      displacement flex-fatigue.

PMID- 12418019
TI  - Effect of TEGDMA on the intracellular glutathione concentration of human gingival
      fibroblasts.
AB  - Previous studies revealed that primarily small and relatively hydrophilic
      comonomers, such as TEGDMA, leach out of resin-based restorative materials into
      aqueous media. Subsequently, these compounds may cause detrimental reactions with
      intracellular metabolic systems. The present experiments attempted to elucidate
      the interactions of TEGDMA with the important intracellular reducing agent
      glutathione (GSH). The influence of various concentrations of TEGDMA (0.5-7.5 mM)
      on viability and intracellular GSH concentration of primary human gingival
      fibroblasts was determined by means of a fluorescence assay (monobromobimane)
      performed in microtiter plates. Cells were treated with TEDGMA between 2 and 24
      h. The incubation of fibroblasts with TEGDMA even at subtoxic concentrations
      quickly decreased the intracellular glutathione level to 30-50% of controls
      within the first 2-6 hours. However, no simultaneous adverse effect on cell
      viability was found. Longer incubation periods up to 24 h caused a regulatory
      reincrease at TEGDMA concentrations <or= 2.5 mM, whereas higher concentrations
      resulted in a continuous depletion of glutathione concentration concomitant with
      a significant decrease of cell viability. Because glutathione plays an important
      role in protection and detoxification processes as well in the regulation of cell
      death, the early and extensive depletion of the intracellular glutathione pool
      due to TEGDMA may significantly contribute to the cytotoxic potency of this
      compound.

PMID- 12418020
TI  - In vitro and in vivo degradation of bioabsorbable PLLA spinal fusion cages.
AB  - The in vitro and in vivo degradation of poly-L-lactic acid cages used as an
      adjunct to spinal arthrodesis was investigated. In the in vitro experiments cages
      were subjected to aging up to 73 weeks in phosphate-buffered solution (pH 7.4) at
      37 degrees C. Inherent viscosity, crystallinity, and mechanical strength were
      determined at different time points. In the in vivo study, the poly-L-lactic acid
      cages were packed with bone graft and implanted in the L3-L4 spinal motion
      segment of 18 Dutch milk goats. At 12, 26, and 52 weeks, the motion segments were
      isolated and poly-L-lactic acid samples retrieved. On evaluation, the in vivo
      implanted cages showed an advanced decline in inherent viscosity compared to the
      cages subjected to in vitro degradation experiments. At 6 months of implantation,
      the geometrical shape and original height of 10 mm was maintained during 6 months
      of follow up. This finding fits well with the observation that mechanical
      strength was maintained for a period of 6 months in vitro. At 12 months, the poly
      L-lactic acid cage had been disintegrated into multiple fragments with signs of
      absorption. Despite the high-load-bearing conditions, the poly-L-lactic acid cage
      allowed interbody fusion to occur without collapse of the cage.

PMID- 12418021
TI  - Machinability of cast commercial titanium alloys.
AB  - This study investigated the machinability of cast orthopedic titanium (metastable
      beta) alloys for possible application to dentistry and compared the results with
      those of cast CP Ti, Ti-6Al-4V, and Ti-6Al-7Nb, which are currently used in
      dentistry. Machinability was determined as the amount of metal removed with the
      use of an electric handpiece and a SiC abrasive wheel turning at four different
      rotational wheel speeds. The ratios of the amount of metal removed and the wheel
      volume loss (machining ratio) were also evaluated. Based on these two criteria,
      the two alpha + beta alloys tested generally exhibited better results for most of
      the wheel speeds compared to all the other metals tested. The machinability of
      the three beta alloys employed was similar or worse, depending on the speed of
      the wheel, compared to CP Ti.

PMID- 12418022
TI  - Do multifilament alloplastic meshes increase the infection rate? Analysis of the
      polymeric surface, the bacteria adherence, and the in vivo consequences in a rat
      model.
AB  - Within the last decade hernia surgery has changed from suture repair to mesh
      repair. Biomaterials, and multifilaments in particular, are thought to increase
      the risk of infection. Therefore, the aim of this study was to study the
      influence of the presence of either a monofilament or a multifilament mesh
      material on the bacterial infection risk. The filament surface of a monofilament
      and a multifilament mesh were calculated on the basis of a theoretical model. The
      adherence of Staphylococcus aureus was measured in vitro by fluorescence
      analysis. Additionally, the two mesh materials (8-mm platelets) were implanted
      subcutaneously in Sprague-Dawley rats with daily surveillance for clinical signs
      of infection. After 7 days the meshes were explanted for histological and
      microbiological analysis. Calculations of the mesh surface area revealed a higher
      level for the multifilament mesh. The extent of adherent bacteria corresponded to
      the estimated filament surface in vitro. In vivo, the implantation of meshes in
      the presence of 5 x 10(6) S. aureus did not show an increased infection rate in
      rats with either monofilament or multifilament material, compared to the control
      groups (mesh implantation without S. aureus contamination). However, after 7 days
      bacteria were still detectable in the majority of the implantation sites, and a
      clinically inapparent intensification of local inflammation and fibrosis was
      induced. The increased surface area of a multifilament meshes promotes the
      persistence of bacteria in the implant bed, though this alone is not sufficient
      to create a clinically apparent infection. This might explain the development of
      mesh-related infections after a delay of several months or even years. In vivo,
      the adherence of bacteria to the implant material depends on the surface area,
      which favors the use of monofilament materials.

PMID- 12418023
TI  - Tissue reaction and biodegradation of implanted cross-linked high amylose starch
      in rats.
AB  - The biocompatibility and degradation characteristics of cross-linked high amylose
      starch (Contramid were investigated in rats over 4 months. Contramid pellets (3
      mm diameter and thickness) obtained by direct compression, were implanted
      subcutaneously and intramuscularly. On sequential time points, macroscopic
      observations of implantation sites were performed and tissue samples were
      removed, fixed, and histologically evaluated. No macroscopic inflammatory
      reaction was observed with Contramid.. Upon histologic examination, inflammatory
      reaction produced by Contramid was moderate and restricted to implantation sites.
      The sequence of inflammatory events with Contramid was similar regardless of
      implantation site. Degradation of Contramid pellets was characterized by
      fragmentation with formation of fibrovascular septa and phagocytosis by
      macrophages. Finally Contramid was mostly absorbed by the end of the 4-month
      period and substituted by adipocytes. It has been demonstrated that Contramid is
      a biocompatible and absorbable material.

PMID- 12418024
TI  - Lifetime prediction of CAD/CAM dental ceramics.
AB  - The dynamic fatigue method was used to obtain subcritical crack growth parameters
      n and A for a commercial feldspathic dental porcelain and for a lanthanum-glass
      infiltrated alumina glass ceramic. Five stress rates d sigma/dt ranging from 50
      to 0.01 MPa s(-1) were applied. The inert strength values were calculated with
      the use of Weibull statistics and maximum-likelihood approaches for the Weibull
      parameter m. Strength-probability-time (SPT) diagrams were derived for both
      materials. The alumina glass composite showed a high fracture strength sigma(0)
      (442 MPa) at a failure probability of P(F) = 63.2% and a high resistance against
      subcritical crack growth (n = 36.5). The development of strength under fatigue
      conditions was calculated for exemplary 1 year. The strength of the alumina glass
      material dropped to 228 MPa within this period. This fact is due to a low content
      of infiltrated lanthanum glass phase in the composite material (25 wt%). In
      contrast, for the high-silica-glass-containing porcelain a distinct decrease of
      strength sigma(0) from initial 133 to 47 MPa after 1 year was predicted. This,
      mainly because of a low crack growth resistance (n = 16.8) of the feldspathic
      porcelain. Much lower strength values were calculated, assuming a failure
      probability of P(F) = 5%. The decrease is mainly caused by the sensitivity of
      high-glass-containing ceramics against water corrosion.

PMID- 12418025
TI  - The anticorrosion ability of titanium nitride (TiN) plating on an orthodontic
      metal bracket and its biocompatibility.
AB  - Typically, an orthodontic metal bracket is made from stainless steel. It has been
      shown that such metal may corrode in an acid- and chloride-rich environment. The
      purpose of the current study was to investigate a titanium nitride (TiN) ion
      plated stainless steel orthodontic bracket's anticorrosion properties and compare
      its biocompatibility with that of non-TiN-plated brackets. The stainless-steel
      brackets studied here were tested in acidic artificial saliva. The plated metal
      bracket was produced by the titanium nitride (TiN) ion-plating method. The TiN
      plating on the bracket surface was demonstrated to be successful by EDX analysis.
      The quantity of metallic-ion release under test immersion solutions was analyzed
      by atomic absorption spectrophotometry. Both TiN- and non-TiN-plated brackets may
      release detectable ions into the test solution, including nickel, chromium,
      manganese, copper, and iron (ferric). The anticorrosion ability of the plated
      bracket was analyzed by means of inductively coupled plasma atomic emission
      spectroscopy. The results revealed that the TiN-plated metal bracket did not
      increase the anticorrosion ability of the standard bracket. The biocompatibility
      of the TiN plating versus the standard bracket material resulting from bracket
      immersion in the test solution revealed no toxicity on U2OS cells using a
      methylthiazole tetrazolium (MTT) colorimetric assay. Clearly, the search for an
      improved technique for enhancing the anticorrosion ability of the normal metal
      orthodontic bracket should be continued.

PMID- 12418026
TI  - Predictive modeling of the mechanical properties of particulate hydroxyapatite
      reinforced polymer composites.
AB  - The influence of particle geometry and volume fraction on the mechanical
      properties of a hydroxyapatite (HAp) particulate reinforced polymer (poly-L
      lactide and collagen) matrix composite was investigated through finite-element
      (FE) analysis. For cube-shaped (near sharp and curved corners and edges) embedded
      particles, it was found that the maximum stress concentration factor (SCF) in the
      matrix decreases with an increase of the HAp particle volume fraction (PVF). The
      maximum stress concentration in the matrix material containing a spherical
      inclusion has low sensitivity to the PVF. The compressive Young's modulus was
      found to be slightly dependent on particle shape, but very sensitive to PVF.
      Calculated stiffness values from FE analysis were compared to the experimental
      results available in the literature and with predictions from the Halpin-Tsai
      model.

PMID- 12418027
TI  - Effect of antibiotics on the properties of poly(methylmethacrylate)-based bone
      cement.
AB  - The goal of this study was to examine the relationship between gentamicin
      concentration in Palacos R bone cement (in the mass fraction range of 0-9.4%) and
      various properties of the cement. The results from the thermal, density, and
      static compression tests show that gentamicin favors the cement polymerization in
      its final steps, and forms a diphasic structure with the cement
      [poly(methylmethacrylate)] matrix. The static compression properties in the dry
      state are only slightly modified by the presence of the antibiotic. Concerning
      aging in water at 37 degrees C, two types of behavior can be distinguished: below
      a critical concentration, approximately 3-4%, the extraction of gentamicin by
      water is slow and there is only a slight change of static compression properties.
      In contrast, above this critical concentration, the gentamicin extraction is fast
      and almost complete after 48 weeks, and there is a considerable loss of static
      compression properties.

PMID- 12418028
TI  - In vivo release of vancomycin from biodegradable beads.
AB  - The current delivery system of antibiotics for the treatment of osteomyelitis
      uses polymethylmethacrylate (PMMA) beads as a local drug-release agent. The
      nonbiodegradable nature of the PMMA, however, necessitates a second operation to
      remove the beads. This article explores the alternative of using biodegradable
      polymers as antibiotic beads for a long-term drug release in vivo. To manufacture
      an antibiotic bead, lactide-glycolide copolymers were mixed with vancomycin. The
      mixture was compressed and sintered at 55 degrees C to form beads 8 mm in
      diameter. An in vivo animal model was proposed to characterize the elution rate
      of antibiotic over a 55-day period. Biodegradable beads released high
      concentrations of antibiotic (well above the breakpoint sensitivity
      concentration) in vivo for the period of time needed to treat bone infection;
      that is, 4-6 weeks. A bacterial inhibition test was also carried out to determine
      the relative activity of the released antibiotics. The diameter of the sample
      inhibition zone ranged from 8 to 18 mm, which is equivalent to 9.1 to 100% of
      relative activity. In addition, the antibiotic concentration of systemic blood
      was found to be very low. Antibiotic-impregnated biodegradable beads may have a
      potential role in the prevention and management of surgical infections.

PMID- 12418029
TI  - An evaluation of the cytotoxic effects of orthodontic bonding adhesives upon a
      primary human oral gingival fibroblast culture and a permanent, human oral cancer
      cell line.
AB  - The purpose of this investigation was to determine the cytotoxic effects of three
      different kinds of orthodontic adhesive on a human primary gingival fibroblast
      culture (GF) and a human oral cancer-cell line (OC2). The adhesives comprised a
      self-cure bonding resin, a light-cure bonding resin, and a hybrid glass ionomer.
      Any differences between the cytotoxic potencies of eluates of the orthodontic
      materials on GF and OC2 cells were quantified colorimetrically (MTT test). The
      results are as follows: For the hybrid glass ionomer, the survival rate of GF
      cells exposed to the liquid component revealed a significant dose-dependent
      decrease (p < 0.05). The liquid component and the mixed hybrid glass-ionomer
      material reflected a significant dose-dependent decrease (p < 0.05) in exposed
      OC2 cell survival. Associated with an increase in the cell exposure concentration
      of Resin A, Resin B, Paste A, Paste B, Resin A + B, Paste A + B and the set
      material of the self-cure resin adhesive, was a significant decrease in survival
      rate for cultured GF and OC2 cells (p < 0.05). Associated with an increase in the
      concentration of the primer, paste, and mixed material of the light-cure resin
      adhesive to which test cells were exposed, the survival rate reflected a decrease
      for GF cells (p < 0.05). The survival rate of cells exposed to light-cure resin
      paste reflected no difference for OC2 cells. It is concluded that the liquid of
      the hybrid glass-ionomer cement, Resin A and Resin B and Resin A + B of the self
      cure resin and the primer of the light-cure resin are toxic agents to the GF and
      OC2 cell lines. Primary human gingival fibroblasts were found to be more
      sensitive than the tested human oral carcinoma cell line from most of the
      substances.

PMID- 12418030
TI  - Immobilization of an oxalate-degrading enzyme on silicone elastomer.
AB  - Urinary biomaterials are compromised by device-related urinary tract infections,
      bacterial biofilm formation, and biomineral encrustation. In the absence of
      urinary infection, calcium oxalate is the prevalent encrustation mineral formed.
      Considering this, a novel approach was taken in the study reported here, in that
      an oxalate-degrading enzyme, oxalate oxidase (OXO), was immobilized on the
      surface of silicone elastomer (PDMS), a common urological biomaterial. It was
      hypothesized that the enzymatic action of OXO could lower urinary oxalate levels
      near the device surface, thereby preventing calcium oxalate crystal formation.
      The PDMS surface was functionalized with the use of radio-frequency plasma
      discharge (RFPD) in the presence of water vapor, then coated with 3
      aminopropyltriethoxysilane (AMEO). The resulting aminated surface was covalently
      coupled with OXO via glutaraldehyde bioconjugation. The ability of the OXO-coated
      PDMS to prevent calcium oxalate encrustation was evaluated with the use of a
      modified Robbins device (MRD) encrustation model. RFPD performed on PDMS resulted
      in an increase in the hydrophilicity of treated surfaces, as measured by contact
      angle. X-ray photoelectron spectroscopy studies showed increases in elemental
      oxygen, after water-vapor plasma, and in nitrogen after AMEO derivatization. The
      immobilized enzyme was shown to retain 47.5% of its specific enzymatic activity
      as compared to free enzyme. In vitro experiments for 6 days, with the use of a
      MRD, showed 53% less encrustation deposits on discs coated with OXO than control
      discs. The results from the current study suggest that PDMS-immobilized oxalate
      degrading enzymes are active against calcium oxalate encrustation.

PMID- 12418031
TI  - Light scattering and in vitro biocompatibility studies of poly (vinyl
      pyrrolidone) derivatives with amino-acid-dependent groups.
AB  - Two poly (vinyl pyrrolidone) (PVP) families with amino-acid residues (glycine,
      beta-alanine, gamma-aminobutiric acid and epsilon-aminocaproic acid) on the base
      of the co-polymer N-vinyl pyrrolidone and allyl-glycidyl ether (VP-AGE) and on
      the base of epoxidized PVP (EPVP) were synthesized. Static and dynamic light
      scattering measurements of these PVP derivatives in water showed that their
      structure/ behavior were similar to that of PVP. The bioreactivity was also
      similar to that of PVP. Further investigation of the immunoreactive properties of
      the derivatives in in vitro proliferation assays with fresh normal human
      peripheral blood lymphocytes and monocytes led to the determination of a
      costimulatory profile for each derivative in terms of polyclonal stimulation,
      specific antigen presentation, and immunoglobulin secretion. This profile allows
      the selection of an appropriate derivative as a carrier that would suit the
      immunoreactivity needs of the immobilized ligand.

PMID- 12418033
TI  - Wear of conventional and cross-linked ultra-high-molecular-weight polyethylene
      acetabular cups against polished and roughened CoCr femoral heads in a biaxial
      hip simulator.
AB  - The wear of acetabular cups made from conventional gamma-sterilized, and electron
      beam cross-linked ultra-high-molecular-weight polyethylene was studied with a
      biaxial hip wear simulator. The femoral heads were either polished or roughened
      so that they represented the type of roughening and the value of surface
      roughness (R(a) = 0.14-0.18 micro m) observed in the roughest explanted femoral
      heads. The lubricant was diluted calf serum, and the test length 3 million
      cycles. The mean wear rate and standard deviation of conventional polyethylene
      cups against polished and against roughened heads was 11.6 +/- 0.07 and 64.4 +/-
      10.1 mg per 1 million cycles, respectively. The latter value closely corresponds
      to that measured from explanted Charnley prostheses. Against polished heads,
      cross-linked polyethylene cups showed net weight gain, whereas against roughened
      heads, their mean wear rate was 2.4 +/- 0.3 mg per 1 million cycles. The mean
      equivalent circle diameters of polyethylene wear particles produced in the above
      four categories were: conventional/roughened 0.32 micro m, cross-linked/roughened
      0.29 micro m, conventional/polished 0.28 micro m, cross-linked/polished 0.23
      micro m. The size ranges and shapes were close to those seen in particles
      isolated from tissue samples. In conclusion, the tests indicated that electron
      beam irradiation effectively reduces the harmful polyethylene wear particle
      production in total hip arthroplasty.

PMID- 12418032
TI  - Immobilization of natural macromolecules on poly-L-lactic acid membrane surface
      in order to improve its cytocompatibility.
AB  - With the use of a grafting-coating method, three kinds of natural macromolecules,
      that is, gelatin, collagen, or chitosan, were immobilized on poly-L-lactic acid
      (PLLA) membrane surfaces with the goal of improving of cellular interactions.
      Attenuated total reflectance infrared spectroscopy (ATR-IR), x-ray photoelectron
      spectroscopy (XPS) and surface morphology analysis using scanning electronic
      microscopy (SEM) confirmed that the natural macromolecule layers adhered tightly
      to the hydrophobic PLLA membrane surfaces. Chondrocyte culture showed that the
      modified PLLA membranes had higher cell attachment, higher cell proliferation
      rate, and higher cell activity than the control PLLA membrane. Moreover, the
      chondrocytes were more spread out on the modified PLLA membranes than on the
      control PLLA membranes.

PMID- 12418034
TI  - Optimizing the tensile properties of polyvinyl alcohol hydrogel for the
      construction of a bioprosthetic heart valve stent.
AB  - Although bioprosthetic heart valves offer the benefits of a natural opening and
      closing, better hemodynamics, and avoidance of life-long anticoagulant therapy,
      they nevertheless tend to fail in 10-15 years from tears and calcification.
      Several authors, including the present ones, have identified the rigid stent as a
      factor contributing to these failures. The ultimate solution is an artificial
      heart valve that has mechanical properties that allow it to move in conformity
      with the aortic root during the cardiac cycle, has superior hemodynamics, is
      nonthrombogenic, will last more than 20 years, and mitigates the need for
      anticoagulants. We have identified a polymer, polyvinyl alcohol (PVA) hydrogel,
      that has mechanical properties similar to soft tissue. The purpose of this
      research is to match the tensile properties of PVA to the porcine aortic root and
      to fabricate a stent prototype for a bioprosthetic heart valve with the use of
      the PVA hydrogel. Specimens of 15% w/w PVA were prepared by processing through 1
      6 cycles of freezing (-20 degrees C) at 0.2 degrees C/min freeze rate and thawing
      (+20 degrees C) at different thawing rates (0.2 degrees C/min and 1 degrees
      C/min), for different holding times (1 and 6 h) at -20 degrees C. Subsequently
      tensile tests and stress-relaxation tests were conducted on the specimens. The
      different holding times at -20 degrees C demonstrated no difference in the
      result. The slower thawing rate improved the tensile properties but did not
      produce significant changes on the stress-relaxation properties. The nonlinear
      stress-strain curve for the PVA after the fourth freeze-thaw cycle matched the
      porcine aortic root within the physiological pressure range. The stress
      relaxation curve for PVA also approximated the shape of the aortic root. The
      complex geometry of an artificial heart valve stent was successfully injection
      molded. These results, in combination with other preliminary findings for
      biocompatibility and fatigue behavior, suggest that PVA hydrogel is a promising
      biomaterial for implants, catheters, and artificial skin.

PMID- 12418035
TI  - Oral contraceptives and the risk of breast cancer.

PMID- 12418036
TI  - Oral contraceptives and the risk of breast cancer.

PMID- 12418037
TI  - Major birth defects after assisted reproduction.

PMID- 12418038
TI  - Major birth defects after assisted reproduction.

PMID- 12418039
TI  - Male circumcision, penile human papillomavirus infection, and cervical cancer.

PMID- 12418040
TI  - Changes in the transmission of tuberculosis in New York.

PMID- 12418041
TI  - Changes in the transmission of tuberculosis in New York.

PMID- 12418042
TI  - Changes in the transmission of tuberculosis in New York.

PMID- 12418043
TI  - AIDS orphans.

PMID- 12418044
TI  - AIDS orphans.

PMID- 12418045
TI  - Cancers attributable to fallout from nuclear testing.

PMID- 12418046
TI  - Journal access for developing countries.

PMID- 12418048
TI  - WHO, UNICEF, UNAIDS, World Bank, UNESCO, and UNFPA report on response to
      infectious diseases.

PMID- 12418047
TI  - Oral health report card.

PMID- 12418049
TI  - The genetic pathogenesis of colorectal cancer.
AB  - Research over the past decade has established that the progression from normal
      colonic epithelium to colon cancer is in every case a step-wise process in which
      specific pathologic and molecular markers can be identified for study and
      clinical therapy. Genetic and epigenetic instability appears fundamentally
      important to this process. We have now determined that this neoplastic
      progression occurs along a limited set of pathways, in which specific tumor
      suppressors are inactivated or oncogenes activated in a defined order. Although
      incomplete, our new understanding of the process of carcinogenesis in the colon
      has already significantly impacted patient care and will continue to do so for
      the foreseeable future. Increasingly rapid research developments and technologic
      advances will transform the way we prevent, diagnose, and treat this common and
      deadly form of cancer.

PMID- 12418050
TI  - Primary prevention: phytoprevention and chemoprevention of colorectal cancer.
AB  - Considering the various stages of carcinogenesis and the numerous tumor types and
      available chemoprevention agents, knowledge of the etiology and the type of
      cancer to be treated, or possibly prevented, and understanding of the mechanisms
      by which agents exert their chemoprevention benefits may provide for improved
      strategy in designing therapeutic regimens. Because cancer usually develops over
      a 10- to 20-year period, it may be necessary for some agents to be provided
      before or early in the initiation steps of carcinogenesis to have beneficial
      effects. On the other hand, some agents may be more suitable for CRC prevention
      if provided at a later stage of carcinogenesis. Gene array, genomics, and
      proteomics are useful tools in advancing our understanding of the molecular
      events involved in carcinogenesis and in identifying markers of risk and
      surrogate end-points for colorectal cancer progression. These techniques may also
      serve for screening, identifying, and providing treatment targets for high-risk
      patients populations. Treatment could be developed depending on a patient's
      individual needs and genomic tumor profile. Clinical markers and surrogate end
      points should be considered, together with molecular measurements, to more
      accurately assess risk. NSAIDs and COXIBs are clinically recognized as
      chemoprevention agents, and clinical trials evaluating their efficacy are
      ongoing. Treatment protocols, including dose and timing, remain to be determined,
      however. DFMO may best be used in combination with other chemoprevention agents.
      Dietary fiber and calcium supplements, as part of an overall low-fat diet, may
      decrease CRC risk. Long-term compliance with this regimen may be necessary to
      effect a beneficial outcome. Folate holds promise but needs further
      investigation, especially because its beneficial effects may depend on cancer
      type. Phytochemicals have been identified as strong candidates for use as agents
      to prevent colorectal cancer in cell culture and in rodent models of
      carcinogenesis. Their potential as chemoprevention agents must be demonstrated in
      clinical trials. In vitro and animal studies indicated that combination therapy
      may be a promising strategy over the monotherapy approach; clinical trials
      addressing the safety and efficacy of some combinations (DFMO/sulindac,
      fiber/calcium) are underway. The gastrointestinal tract and other organs are
      constantly exposed to a mixture of potentially toxic compounds and molecules
      considered favorable to health. Homeostasis between stress-mediated by toxic
      compounds and defensive mechanisms, is key for the maintenance of health and the
      prevention of disease. Whereas aggressive pharmacologic treatment may be
      necessary for patients at high risk for cancer, dietary supplements may be useful
      for populations at normal risk. The message for cancer prevention in the general
      population may well remain: keep a balanced healthy diet, eating a variety from
      all food groups, as part of a healthy lifestyle that includes moderate exercise.

PMID- 12418052
TI  - Colonoscopy and polypectomy.
AB  - Colonoscopy and polypectomy, when performed by adequately trained physicians, is
      a safe and effective procedure that can decrease deaths resulting from colorectal
      cancer.

PMID- 12418051
TI  - Secondary prevention: screening and surveillance of persons at average and high
      risk for colorectal cancer.
AB  - Secondary prevention of colorectal cancer with FOBT and endoscopy with
      polypectomy decreases cancer deaths. Other available modalities include genetic
      tests and imaging studies, but outcomes data are not yet available. Issues remain
      concerning the most appropriate test, the optimal intervals, and cost-efficacy.
      Patients may be stratified by personal and family risk, and specific strategies
      may be used. Newer developments in genetic tests and imaging, including virtual
      colonoscopy, hold promise for the future. The most important issue at present is
      to have people screened or surveilled by any of the recommended modalities.

PMID- 12418053
TI  - Radiologic imaging modalities in the diagnosis and management of colorectal
      cancer.
AB  - Colorectal carcinoma poses a serious public health threat. Detection in its early
      stages in the best predictor for long-term survival, which is the impetus for
      population-based screening programs. We believe that full-colon imaging by either
      DCBE or colonoscopy is necessary for colon cancer screening because flexible
      sigmoidoscopy, even if perfect, only detects 50% to 60% of colon cancers, a rate
      far worse than even the worst rate reported for single-contrast barium enema.
      Screening for colon cancer with flexible sigmoidoscopy is equivalent to
      performing a "left" mammogram for the detection of breast cancer. The role of CT
      colonography is still to be determined. When confronted with a symptomatic
      patient, barium enema is applied in conjunction with CT to detect primary
      colorectal carcinoma, to differentiate it from other benign and malignant
      processes involving the colon, and to assess for disease extent before surgery in
      selected high-risk patient populations. Pelvic MRI may be useful in the
      preoperative assessment of patients with rectal carcinoma as a means for
      assisting surgical planning. CT, MRI, and barium enema are used in postoperative
      follow-up for detecting local recurrence and distant spread. In response to known
      difficulty in discriminating between normal postoperative changes and tumor
      recurrence and in determining the nature of certain liver lesions, FDG-PET has
      been approved for the detection and localization of recurrent colorectal cancer
      in patients with rising CEA levels and indeterminate findings on standard imaging
      studies. Given its current promise of offering high sensitivity, specificity, and
      accuracy, the indications for PET may well expand in the future, but its final
      role in still to be determined.

PMID- 12418055
TI  - Surgical treatment of colon and rectal cancer.
AB  - There are many indications for surgical intervention in the current treatment of
      cancer of the colon and rectum. The hallmark of surgical therapy remains en bloc
      resection of the primary tumor, accompanied by removal of the mesenteric lymph
      nodes. Surgical resection is also the principal and most successful treatment for
      local recurrences and isolated metastases. Although the application of minimally
      invasive techniques is growing in all aspects of surgery and is accepted in the
      treatment of benign lesions of the colon, laparoscopic resection for colorectal
      cancer cannot be recommended apart from randomized, controlled trials. Similarly,
      the role of sentinel lymph node biopsy in the surgical treatment of colorectal
      cancer remains to be defined. Various surgical modalities have been developed for
      the treatment of unresectable colorectal cancer metastatic to the liver. Further
      studies should help to elucidate the exact role of these therapies in the
      treatment of this common clinical problem. In summary, surgical treatment plays
      an important role in multiple aspects of the care of the patient with colorectal
      cancer.

PMID- 12418054
TI  - Endoscopic ultrasound and endoscopic mucosal resection for rectal cancers and
      villous adenomas.
AB  - EUS is the most accurate tool for local staging of rectal carcinoma. In addition
      to providing accurate T- and N-stages, EUS allows assessment of the internal and
      external anal sphincters. Accurate endosonographic staging directs the optimal
      method of management of rectal carcinoma, type of resection, and candidacy for
      neoadjuvant therapy. EMR may be applied to large rectal adenomas as an
      alternative to surgical resection in selected patients. EUS is important in
      discriminating lesions suitable for EMR.

PMID- 12418056
TI  - Surgical treatment of rectal cancer.
AB  - Rectal cancer should no longer be thought of as only a surgically treated
      disease. Centers that treat large numbers of rectal cancer patients should
      provide state of the art radiotherapy and chemotherapy as well as offer anatomic
      tumor-specific operations for advanced-stage cancers and local treatment options
      for favorable, early lesions.

PMID- 12418057
TI  - Regional therapy of hepatic metastases.
AB  - In conclusion, there are a variety of treatment approaches used by surgeons,
      interventional radiologists, and medical oncologists to treat metastatic cancer
      distributed throughout the liver. One conclusion is that the number of different
      techniques suggests that no single treatment has been uniformly successful to
      date. A second conclusion is that the number of techniques applied argues for the
      importance of this as a clinical problem in oncology today. The number of
      patients with metastatic disease to the liver and the potential for long-term
      survival if that disease can be controlled will lead to further combinations and
      refinements of these techniques in future clinical trials.

PMID- 12418058
TI  - Chemotherapy for colorectal cancer.
AB  - With effective chemotherapy as adjuvant treatment, the survival benefit is
      clearly achieved for certain (stage III) colorectal cancer patients, though there
      still exist many unsettled issues including the controversies in the treatment of
      stage II disease. Advances in the development of a new generation of cytotoxic
      agents in the past several years have allowed us to move forward from the
      "fluorouracil-only era" in the treatment of advanced/metastatic colorectal
      cancer. It is still not very clear how best to minimize toxicity without
      compromising efficacy of the combination therapy with newer agents, or how to
      maximize the benefit of chemotherapy (concurrent versus sequential). There are
      many current ongoing clinical trials designed to address these issues. With
      better understanding of the signal transduction and molecular biology
      characteristics of colorectal cancer, and the development of biologic and
      molecular target agents, the outcomes of patients with colorectal cancer will be
      improved further. Future clinical trials should be focused on optimizing and
      individualizing therapy for patients based on their molecular profiles to achieve
      maximal clinical benefit.

PMID- 12418059
TI  - Chemoradiotherapy in the treatment of rectal cancer.
AB  - The integration of radiotherapy to the adjuvant treatment of rectal cancer was
      prompted by the predominance of locoregional failures after curative surgery.
      This characteristic in the pattern of failure is one of the main reasons adjuvant
      radiotherapy plays a greater role in rectal cancer than in colon cancer. It has
      been demonstrated that local failure rates after surgery alone for rectal cancer
      are strongly dependent on the degree of bowel wall invasion, lymph node
      involvement, and margins of resection. These same locoregional factors are also
      predictive of distant metastasis and survival. In addition, local failure is
      associated with devastating symptoms that severely affect the quality of life of
      patients. For these reasons, locoregional control remains a major issue in the
      treatment of rectal cancer. This article summarizes the evidence that has
      established chemoradiotherapy as part of the standard of care for rectal cancer
      and the techniques used for its delivery.

PMID- 12418060
TI  - Endoscopic palliation of colorectal cancer.
AB  - Multiple endoscopic options exist for physicians seeking to provide palliative
      therapy for patients with colorectal cancer. Endoscopic decompression tubes can
      allow urgent stabilization for patients with malignant obstruction requiring some
      form of surgical palliation. Patients who are not candidates for palliative
      surgery can experience good symptomatic relief from malignant large bowel
      obstruction via laser therapy or placement of a colonic stent. Laser therapy can
      be used in conjunction with SEMS to recanalize and decompress large bowel in
      certain situations. The use of colonic stents is rapidly becoming more
      commonplace as acceptance of the technique becomes more widespread. Patients with
      unresectable disease may be able to avoid surgery altogether and achieve
      successful and lasting palliation of large bowel obstruction. Overall, they
      provide effective and durable palliation in patients with malignant obstruction,
      have an excellent risk/benefit profile, and are within the technical means of
      both gastroenterologists and interventional radiologists.

PMID- 12418061
TI  - Impact of endometriosis on implantation. Data from the Wilford Hall Medical
      Center IVF-ET Program.
AB  - OBJECTIVE: To investigate the effect of endometriosis on implantation. STUDY
      DESIGN: In a retrospective cohort study, 149 consecutive in vitro fertilization
      retrieved cycles were analyzed. Patients with endometriosis (n = 27, 31 cycles)
      were compared with a control group with tubal infertility (n = 104, 118 cycles).
      The main outcome measure was implantation rate (gestational sac per transferred
      embryo). RESULTS: The patients in the tubal infertility group were slightly
      younger and tended to have a better response to stimulation and increased number
      of oocytes retrieved than did the patients in the endometriosis group; however,
      there were no differences in fertilization rates, number of embryos transferred
      or clinical pregnancy rates per cycle between the endometriosis group and tubal
      infertility group. The overall clinical pregnancy rate per cycle was similar for
      women in the endometriosis and tubal infertility groups (54.8% and 55.1%,
      respectively). The implantation rate was not different in the endometriosis
      versus tubal infertility group (28% [28/100] and 29.8%, [108/363], respectively;
      P = .75, relative risk = .94, 95% confidence interval .66, 1.34). CONCLUSION: For
      women undergoing in vitro fertilization-embryo transfer with endometriosis, the
      implantation rate is not markedly different from that for women undergoing in
      vitro fertilization-embryo transfer with tubal infertility.

PMID- 12418062
TI  - Role of apoptosis, bcl-2 and bax protein expression in premature rupture of fetal
      membranes.
AB  - OBJECTIVE: To examine the degree of apoptosis in human fetal membranes associated
      with premature rupture of membranes (PROM) as compared with normal pregnancies
      and to evaluate the expression of proapoptotic bax and antiapoptotic bcl-2 gene
      products. STUDY DESIGN: Fetal membranes from 50 pregnancies were included in the
      study. Thirty of 50 pregnancies had PROM. Twenty pregnancies with intact
      membranes served as controls. Chorioamniotic membrane biopsies were taken from
      the rupture site of the membrane and periphery of the rupture side. In the
      control group, membrane biopsies were taken from the artificial rupture site,
      cervical pole of the membranes and membranes close to the edge of the placenta.
      In recognizing apoptotic figures, routinely processed samples were stained with
      hematoxylin and eosin for light microscopic evaluation. Quantification of the
      apoptotic cells was performed with high-power fields and expressed as the number
      per 100 cells. The membranes of both groups were then stained with bcl-2 and bax
      antibodies by using the standard steptavidin-biotin-immunoperoxidase method.
      Staining with both antibodies were compared between two groups. RESULTS:
      Apoptotic cells were detected in the amniotic epithelium, in chorionic cells and
      fibroblastic layer of the fetal membranes. Apoptotic cells were found mostly in
      the chorionic cells. There was a statistically significant difference between the
      apoptotic index in PROM and the control group in both rupture and peripheral
      sites (P < .05), although within each group peripheral and rupture sites showed
      no difference in terms of apoptotic cell counts. Both bax and bcl-2 expression
      was observed in 40% of control cases and in 57% and 50% of cases with PROM,
      respectively, mostly in the chorionic trophoblastic cells. The PROM and control
      groups showed no statistically significant difference in terms of bcl-2 and bax
      protein expression. CONCLUSION: Apoptosis may play a role in the pathogenesis of
      PROM, but the changes in apoptosis do not seem to be mediated by bcl-2 and bax
      genes in the amniotic membrane. Other regulatory mechanisms must be investigated.

PMID- 12418064
TI  - Improvement in sperm quality and function with French maritime pine tree bark
      extract.
AB  - OBJECTIVE: To determine the effects of Pycnogenol (French maritime pine tree bark
      extract) on sperm parameters and function in subfertile men. STUDY DESIGN:
      Prospective, nonrandomized, clinical study in a private infertility practice.
      Nineteen subfertile men were given 200 mg Pycnogenol daily orally for 90 days.
      Semen samples were analyzed before and after treatment for sperm count, motility
      score and strict morphology before and after capacitation, and mannose receptor
      binding. RESULTS: The mean sperm morphology following Ham's F-10 capacitation
      increased by 38% following Pycnogenol treatment, and the mannose receptor binding
      assay scores improved by 19%. CONCLUSION: Pycnogenol therapy resulted in improved
      capacitated sperm morphology and mannose receptor binding. The increase in
      morphologically and functionally normal sperm may allow couples diagnosed with
      teratozoospermia to forgo in vitro fertilization and either experience improved
      natural fertility or undergo less invasive and less expensive fertility-promoting
      procedures, such as intrauterine insemination.

PMID- 12418063
TI  - Polycystic ovary syndrome treated with laparoscopic ovarian drilling with a
      harmonic scalpel. A prospective, randomized study.
AB  - OBJECTIVE: To evaluate the endocrinologic profile and reproductive outcome after
      laparoscopic drilling using a harmonic scalpel for polycystic ovarian syndrome
      (PCOS) in clomiphene-resistant infertile women. STUDY DESIGN: We performed a
      prospective, randomized study of 34 infertile women with PCOS. Group A (17 women)
      underwent laparoscopic ovarian drilling using a harmonic scalpel laser. Group B
      (control group, 17 women) underwent laparoscopic ovarian drilling using a
      neodymium-yttrium-aluminum-garnet laser. Change in the hormonal profile after
      surgery, ovulation rate and pregnancy rate were compared between groups A and B.
      RESULTS: LH and testosterone serum levels and the LH-FSH ratio showed a
      statistically significant reduction after surgery, and the spontaneous ovulation
      rate was 94% in both groups. The cumulative pregnancy rates within two years of
      follow-up were 77% in group A and 60% in group B. CONCLUSION: Laparoscopic
      ovarian drilling using a harmonic scalpel is an effective treatment for PCOS in
      clomiphene-resistant, anovulatory women: it results in ovulation and conception
      without major complications.

PMID- 12418065
TI  - Comparing bimanual pelvic examination to ultrasound measurement for assessment of
      gestational age in the first trimester of pregnancy.
AB  - OBJECTIVE: To compare the accuracy of bimanual pelvic examination to ultrasound
      in the assessment of gestational age and to evaluate resident and faculty
      accuracy, and residents' learning to perform pelvic examination. STUDY DESIGN:
      Prospective, blinded, descriptive, correlational study of clinical bimanual
      examination versus ultrasound dating pregnancy prior to first-trimester abortion.
      Women scheduled to undergo abortion received transvaginal ultrasound assessment
      of gestational age. A resident and faculty physician, blinded to the ultrasound
      results, each performed a pelvic examination immediately prior to the procedure.
      The pelvic examination assessments were compared to the ultrasound calculations
      of gestational age. The absolute value of the difference between the bimanual
      examination and ultrasound dating were compared using the paired t test. Linear
      regression was used to evaluate the learning of residents. RESULTS: The pelvic
      examination agreed with the ultrasound (+/- 2 weeks) in 92% of cases for faculty
      and 75% for residents. Accuracy of the resident examinations did not change over
      their two-month rotations. CONCLUSION: If pelvic examination alone is used to
      assess gestational age in the setting of first-trimester abortion, 8% of patients
      may experience unnecessary interventions, possibly leading to a greater risk of
      complications.

PMID- 12418066
TI  - Victimization in patients with vulvar dysesthesia/vestibulodynia. Is there an
      increased prevalence?
AB  - OBJECTIVE: To examine the prevalence of physical or sexual violence victimization
      among women referred to a specialty clinic for management of vulvar
      dysesthesia/vestibulodynia as compared to a healthy gynecology clinic population.
      STUDY DESIGN: The subjects in this case-control study were women who had
      completed routine questionnaires prior to presentation to the University of
      Michigan Center for Vulvar Diseases. Study subjects were all given a diagnosis of
      vulvar dysesthesia/vestibulodynia. Women without complaints of vulvar pain
      presenting to a gynecology clinic were enrolled as controls. Information was
      obtained from the control subjects using a questionnaire similar to the history
      forms completed by the study group. RESULTS: Comparisons were made between 242
      patients with vulvar dysesthesia/vestibulodynia presenting to a specialty clinic
      and 113 controls. Cases were more likely to be Caucasian, to be married and to
      have a higher household income than controls but reported less drug or alcohol
      abuse and a lower frequency of sexual intercourse. After controlling for possible
      confounders, no relationship between sexual assault and the presence of vulvar
      dysesthesia/vestibulitis was found. CONCLUSION: The prevalence of victimization
      was not higher in patients with vulvar dysesthesia/vestibulodynia as compared to
      the control population after controlling for potential confounding variables.

PMID- 12418067
TI  - Age-related changes in ovarian volume, antral follicle counts and basal FSH in
      women with normal reproductive health.
AB  - OBJECTIVE: To investigate the relation between ultrasound-based ovarian volume
      and antral follicle counts and hormonal parameters of ovarian reserve in a group
      of women with normal reproductive health. STUDY DESIGN: Prospective study. One
      hundred eight women with at least one previous pregnancy reaching term were
      divided into three age groups (group 1 = 35-39 years, group 2 = 40-44 years, and
      group 3 = 45-50 years). Basal hormone measurements and transvaginal
      ultrasonography estimation of ovarian volume and follicle counts were performed
      in the early follicular phase (day 3) of the menstrual cycle. RESULTS: There were
      significant differences in FSH (P < .0001) and E2 (P < .002) levels when group I
      was compared to groups II and III. There was a significant decrease in mean
      follicle counts (MFC) between groups I and III (P < .05). The decrease in mean
      ovarian volume (MOV) with age was not statistically significant. Age strongly
      correlated with MFC (r = -.38, P < .001) and weakly with MOV (r = -.29, P < .05).
      However, basal FSH correlated positively with age (r = .50, P < .001) and
      negatively with MOV (r = -.590, P < .001) and MFC (r = -.658, P < .001). Basal E2
      correlated with MOV (r = .50, P < .001) and MFC (r = .50, P < .001). There was
      also a strong positive correlation between MFC and MOV (r = .777, P < .001).
      CONCLUSION: There was a decrease in MOV and MFC with aging coincident with
      increasing basal FSH levels after age 35 in women with normal reproductive
      health.

PMID- 12418068
TI  - Respiratory morbidity in well-dated twins approaching term. What are the risks of
      elective delivery?
AB  - OBJECTIVE: To evaluate morbidity, particularly respiratory, in well-dated, near
      term twins delivered electively and to compare them to those delivered either
      spontaneously or for obstetric indications. STUDY DESIGN: Charts from twin
      deliveries were reviewed for inclusion in this study. Inclusion criteria were
      well-dated twins (American College of Obstetricians and Gynecologists criteria
      for dating) and absence of (1) corticosteroids, (2) intravenous tocolysis, (3)
      lung maturity studies, (4) fetal malformations, (5) diabetes, and (6) medical
      indications for delivery in the elective delivery group. Those meeting the
      criteria were divided into elective and nonelective (both spontaneous and
      indicated) delivery groups. Outcome variables included incidence of transient
      tachypnea and respiratory distress syndrome in each group. RESULTS: During the
      study period, 168 sets of twins met the admission criteria. Controlling for
      gestational age, no difference was noted in the incidence of respiratory distress
      syndrome, transient tachypnea and admission to the special care nursery. Infants
      born during the 36th week of gestation were more likely to be admitted to the
      special care nursery (37.8% vs. 10.6%, P < .05) and had a greater incidence of
      respiratory complications (23.2% vs. 6.7%, P < .01) than those born after 37
      weeks. No difference was identified between the 37th and 38th weeks. CONCLUSION:
      In this large series of well-dated twin pregnancies, there was no evidence of
      increased respiratory morbidity or special care nursery admissions with elective
      delivery at or beyond 37 weeks. Twins delivered during the 36th week of gestation
      had increased respiratory morbidity and special care nursery admissions.

PMID- 12418069
TI  - Postpartum X-ray pelvimetry. Its use in calculating the fetal-pelvic index and
      predicting fetal-pelvic disproportion.
AB  - OBJECTIVE: To determine whether postpartum x-ray pelvimetry can be used to
      calculate the fetal-pelvic index (FPI) in future pregnancies. STUDY DESIGN: In
      stage I of the study, 10 gravid women, after 36 completed weeks' gestation,
      underwent x-ray pelvimetry before delivery. Pelvimetry was repeated within two
      days after delivery. Comparisons between antepartum and postpartum measurements
      were made using paired t tests and correlation coefficients. In stage II, 25
      gravid women, after 36 completed weeks' gestation, underwent fetal ultrasound for
      biometry. X-ray pelvimetry was performed within two days after delivery. FPI was
      calculated for each pregnancy using antepartum fetal ultrasound and postpartum
      pelvimetry measurements. FPI calculations were correlated with the incidence of
      fetal-pelvic disproportion (FPD), as indicated by the requirement for cesarean
      section for arrest of active labor. Sensitivity, specificity and predictive value
      of FPI were assessed. RESULTS: In stage I, mean anteroposterior and transverse
      diameters of the pelvic inlet, midpelvis and pelvic outlet did not differ
      significantly. In stage II, the sensitivity of FPI for detecting FPD was 100%,
      specificity 95%, positive predictive value 80%, and negative predictive value
      100%. CONCLUSION: Postpartum pelvimetry has the same association with FPD as
      antepartum pelvimetry. The strategy of using postpartum pelvimetry and antepartum
      fetal biometry to calculate FPI successfully identified 100% of the patients who
      ultimately required cesarean section for FPD, with a false positive rate of 5%.
      Pelvimetry performed postpartum in an index pregnancy may be used in future
      pregnancies, in combination with antepartum fetal ultrasound, to calculate FPI
      and predict the likelihood of FPD.

PMID- 12418070
TI  - Laparoscopic myomectomy technique. Use of colpotomy and the harmonic scalpel.
AB  - OBJECTIVE: To describe the use of colpotomy and the harmonic scalpel in
      laparoscopic myomectomy and to compare estimated blood loss when using unipolar
      cautery versus the harmonic scalpel and surgical time for colpotomy versus
      morcellation. STUDY DESIGN: A retrospective, cohort study was performed on 168
      patients who were diagnosed with and treated for uterine leiomyomata between
      January 1992 and January 2000. Patients presented with infertility,
      menometrorrhagia, dysmenorrhea, masses on ultrasound or a combination of these
      symptoms. Two patients required hysterectomy, and 1 required conversion to
      laparotomy due to bleeding, leaving 165 patients who underwent laparoscopic
      myomectomy, 143(87%) by colpotomy and 22 (13%) by morcellation. Unipolar cautery
      was used for uterine incision in 112 of the 165 myomectomies (68%) and the
      harmonic scalpel in 53 (32%). Surgery was performed at one of two community
      hospitals in the Seattle area or a general hospital in Taiwan. RESULTS: Mean
      estimated blood loss using the harmonic scalpel (243 mL, range 150-350) was
      significantly less (P < .01) than that using unipolar cautery (378 mL, range 203
      800) for uterine incision. Mean surgical time for colpotomy (144 minutes, range
      110-260) was less (P < .05) than that for morcellation (168 minutes, range 140
      244) despite having removed a larger median number of myomata per patient of
      comparable or larger size (seven by colpotomy versus four by morcellation).
      CONCLUSION: These data suggest that the harmonic scalpel is effective for uterine
      incision during myomectomy and may result in less bleeding than unipolar cautery
      while offering some advantages in safety. Multiple leiomyomata can generally be
      extracted more quickly via posterior colpotomy than by morcellation. This
      difference is smaller and therefore less important in patients with only a few
      small to medium-sized (< 10 cm) fibroids. For these patients, the minimal
      invasiveness of morcellation may offer a more significant benefit.

PMID- 12418071
TI  - Characteristics and initial diagnoses in women presenting to a referral center
      for vulvovaginal disorders in 1996-2000.
AB  - OBJECTIVE: To describe the demographics, presenting symptoms, physical
      examination and laboratory findings, and initial diagnoses in a cohort of women
      referred for evaluation of vulvovaginal problems. STUDY DESIGN: Descriptive
      review of medical records of new patients referred for evaluation of vulvar
      problems between January 1, 1996, and December 31, 1999. Electronic medical
      records and other documents were manually abstracted. RESULTS: Three hundred
      twenty-two women met the study criteria. The majority were Caucasian (93.8%) and
      married (63.9%). The mean age was 41 years, with a range of 13-88. The majority
      reported at least one vaginal delivery (72.9%) or cesarean section (10.6%). The
      most common symptoms were vulvar pain (86.3%), dyspareunia (70.8%), itching
      (36.0%) and skin changes (18.0%). Most patients received a diagnosis in more than
      one evaluation category. Prevalent diagnoses included Bartholin fossa pain
      (12.1%), vulvar vestibulitis (19.9%), restriction and fissuring of the posterior
      labial commissure (20.1%), dysesthetic vulvodynia (32.3%), pelvic floor
      dysfunction (39.8%) and dermatologic conditions (47.5%). CONCLUSION: Women
      presenting for evaluation of vulvar disorders represent a heterogeneous
      population. Among women with vulvar pain, abnormalities of the skin and pelvic
      floor are common and should be ruled out prior to making a diagnosis of vulvar
      vestibulitis or dysesthetic vulvodynia.

PMID- 12418072
TI  - Embolization for advanced abdominal pregnancy with a retained placenta. A case
      report.
AB  - BACKGROUND: Abdominal pregnancy is not encountered commonly, and management of
      the placenta is controversial. CASE: A 33-year-old woman presented with an
      abdominal pregnancy at 33 weeks' gestation with fetal death. The placental
      vasculature was embolized preoperatively. Following operative delivery. of the
      fetus, the placenta was left in situ in efforts to preserve fertility given its
      implantation on the reproductive organs. The patient suffered prolonged
      postoperative ileus but otherwise did well. Placental function ceased after two
      months. CONCLUSION: Placental vasculature embolization is a management option for
      a retained placenta associated with abdominal pregnancy.

PMID- 12418073
TI  - Cerebellar hemangioblastoma in pregnancy. A case report.
AB  - BACKGROUND: The incidence of symptomatic hemangioblastoma of the posterior fossa
      during pregnancy is extremely low. Previous reports have noted that pregnancy
      seems to aggravate the clinical course of intracranial tumors, but little is
      known about the possible reasons. Various theories have been proposed to explain
      the rapid neurologic deterioration of hemangioblastoma patients during pregnancy;
      however, the pathophysiologic behavior and histogenesis of this vascular tumor
      are still not well understood. CASE: A case of cerebellar hemangioblastoma was
      diagnosed during pregnancy. Urgent surgery was required due to rapid development
      of obstructive hydrocephalus and brainstem compression. CONCLUSION: Obstetricians
      and neurosurgeons should be aware of the rare clinic entity of hemangioblastoma
      during pregnancy. Surgery might be indicated as soon as the tumor becomes
      symptomatic.

PMID- 12418074
TI  - Interval delivery and aggressive tocolysis in high-order multiple gestation. A
      report of three cases.
AB  - BACKGROUND: High-order multiple pregnancy (four and above) should be avoided if
      at all possible. The major fetal risk of high-order multiple gestation is that of
      extreme prematurity. Interval delivery has been used with twin and triplet
      pregnancies. CASES: An octuplet, sextuplet and quadruplet pregnancies were
      managed with interval delivery. The interval from delivery of the first infant to
      the remainder of pregnancy was 12 days for the octuplet pregnancy, 24 for the
      sextuplet pregnancy and 12 for the quadruplet pregnancy. CONCLUSION: In high
      order multiple pregnancy, delayed interval delivery is strongly recommended,
      provided that there are no signs of chorioamnionitis, fetal distress or maternal
      compromise.

PMID- 12418075
TI  - Management of gigantomastia complicating pregnancy. A case report.
AB  - BACKGROUND: Gigantomastia during pregnancy is exceedingly rare, with an incidence
      of 1/28,000-100,000 pregnancies. Treatment during pregnancy is a dilemma, and
      postpartum reduction mammoplasty remains the mainstay of treatment. CASE: Massive
      bilateral breast enlargement occurred at 19 weeks of gestation in a 24-year-old
      woman, gravida 2, and led to ulceration and sloughing. Conservative management
      with bromocriptine resulted in healing of the ulcers and resolution of symptoms.
      After six months of bromocriptine therapy postpartum, marked involution of the
      breasts occurred without recurrence. CONCLUSION: Prolonged bromocriptine therapy
      should be given after delivery to a pregnant woman with gigantomastia during
      pregnancy before planning surgical reduction mammoplasty.

PMID- 12418076
TI  - Recurrence of microangiopathic hemolytic anemia after apparent recovery from the
      HELLP syndrome. A case report.
AB  - BACKGROUND: The syndrome of hemolytic anemia, elevated liver enzymes and low
      platelets (HELLP) can accompany preeclampsia and eclampsia. Delivery of the
      infant usually results in improvement in the mother's condition, with the
      recovery time dependent on the severity of the disease. We report a case of
      eclampsia with the HELLP syndrome in which microangiopathic hemolytic anemia
      (MAHA) and thrombocytopenia recurred after apparent recovery. CASE: A 28-year-old
      woman, gravida 4, para 0, therapeutic abortion 3, presented with signs and
      symptoms of severe preeclampsia and became eclamptic. The patient's condition
      improved as expected following cesarean delivery. However, the hemolytic anemia
      recurred and was successfully treated with a course of fresh frozen plasma (FFP).
      CONCLUSION: Hemolytic anemia in women with eclampsia and the HELLP syndrome
      occurs secondary to microvascular endothelial damage. In this case resolution of
      the HELLP syndrome and eclampsia occurred, as expected, in two to three days;
      however, MAHA and low platelets recurred on day 4. Treatment of MAHA with FFP was
      successful.

PMID- 12418077
TI  - Laparoscopic uterine suspension.

PMID- 12418078
TI  - Medical termination of early rudimentary horn pregnancy.

PMID- 12418079
TI  - Radial glias and radial fibers: what is the function of radial fibers?
AB  - Radial glias have been thought to serve as a scaffold to support and direct
      neurons in their radial migration during the development of the cerebral cortex.
      However, a recent series of studies on neocortical development showed that these
      cells behave as multifunctional cells. These studies have provided strong support
      for the idea that radial glias function as multipotential progenitor cells that
      give rise to various cell types, including neurons. Proliferation of the radial
      glia was thought to result in inheritance of the radial fiber by a postmitotic
      neuron, and it was considered that one role of the radial fiber was to act as a
      cable to lift the postmitotic neuron. In this review, we propose another function
      of the radial fiber in the developing neocortex. This novel function is proposed
      based on the fact that the characteristics of the radial glias are identical to
      those of neuroepithelial cells. Before neuron production, the neuroepithelial
      cells proliferate and increase in number, retaining and reproducing radial fibers
      attached to the surface of the basement membrane (the pia mater). During neuron
      production, the radial glias also reproduce radial fibers at the time of each
      cell division. We believe that the radial fiber functions to receive signals for
      morphogenesis, proliferation and differentiation from the pia mater and acts as a
      cable to conduct information transduced from such signals to the cell soma.

PMID- 12418080
TI  - Central and peripheral nerve regeneration by transplantation of Schwann cells and
      transdifferentiated bone marrow stromal cells.
AB  - In contrast to the peripheral nervous system (PNS), little structural and
      functional regeneration of the central nervous system (CNS) occurs spontaneously
      following injury in adult mammals. The inability of the CNS to regenerate is
      mainly attributed to its own inhibitorial environment such as glial scar
      formation and the myelin sheath of oligodendrocytes. Therefore, one of the
      strategies to promote axonal regeneration of the CNS is to experimentally modify
      the environment to be similar to that of the PNS. Schwann cells are the
      myelinating glial cells in the PNS, and are known to play a key role in Wallerian
      degeneration and subsequent regeneration. Central nervous system regeneration can
      be elicited by Schwann cell transplantation, which provides a suitable
      environment for regeneration. The underlying cellular mechanism of regeneration
      is based upon the cooperative interactions between axons and Schwann cells
      involving the production of neurotrophic factors and other related molecules.
      Furthermore, tight and gap junctional contact between the axon and Schwann cell
      also mediates the molecular interaction and linking. In this review, the role of
      the Schwann cell during the regeneration of the sciatic (representing the PNS)
      and optic (representing the CNS) nerves is explained. In addition, the
      possibility of optic nerve reconstruction by an artificial graft of Schwann cells
      is also described. Finally, the application of cells not of neuronal lineage,
      such as bone marrow stromal cells (MSCs), in nerve regeneration is proposed.
      Marrow stromal cells are known as multipotential stem cells that, under specific
      conditions, differentiate into several kinds of cells. The strategy to
      transdifferentiate MSCs into the cells with a Schwann cell phenotype and the
      induction of sciatic and optic nerve regeneration are described.

PMID- 12418081
TI  - Recent progress in studies on Merkel cell biology.
AB  - Merkel cells ubiquitously distribute in the skin of vertebrates, from cyclostomes
      to mammals. It is well known that mammalian Merkel cells coupled with axon
      terminals of type I sensory nerve fibers form slowly adapting mechanoreceptors,
      Merkel endings, within the epidermis. However, there are still many unresolved
      problems in the biology of Merkel cells. We reviewed recently acquired knowledge
      about the histochemical nature of Merkel cell granules, the morphological
      heterogeneity of Merkel cells and the roles of neurotrophins and their receptors
      for the development and survival of the cells. We discuss the functional
      significance of Merkel cell granules and the heterogeneity of Merkel cell
      populations.

PMID- 12418082
TI  - Comparative investigations of human and rat dermatoglyphics: palmar, plantar and
      digital pads and flexion creases.
AB  - The morphological features of the palmar, plantar and digital areas of the rat
      were studied and compared to the corresponding human traits. The location and the
      timing of appearance of the volar pads and flexion creases of human and rat
      fetuses were investigated to determine the feasibility of using rats as an
      experimental model for studying the factors influencing early development of the
      dermatoglyphics in humans. Comparisons between analogous developmental stages of
      human and rat fetuses demonstrate striking similarities in overall fetal
      development. However, marked differences between human and rat fetuses were found
      in the timing of developmental milestones and in some morphological features.
      Provided that these differences are taken into consideration, rats can serve as a
      useful experimental model in studies of the utility of the epidermal ridge
      configurations and flexion creases in medical disorders.

PMID- 12418083
TI  - Cell death of primary afferent nerve cells in neonatal mice treated with
      capsaicin.
AB  - Capsaicin (50 mg kg-1) or vehicle (control) was injected into 2-day-old mice, and
      apoptotic cell death of the lumbar dorsal root ganglion (DRG) cells was examined
      using in situ terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin
      nick end labeling (TUNEL) method at 5, 24, 48 and 72 h after treatment. Apoptotic
      cells were counted per section under a fluorescent microscope. The mean number of
      apoptotic cells showed a significant increase in the capsaicin-treated DRG at 24
      h, but the number was at most 1-2 per section. Thus, many previous findings of an
      approximate 70-80% loss of the small primary afferent neurons induced by
      capsaicin could not be explained by apoptosis alone. Moreover, according to the
      morphological changes, it appeared that capsaicin preferentially induced necrosis
      rather than apoptosis, at least in mice.

PMID- 12418084
TI  - Differences in the density of sympathetic nerve fibers in the arteriolar walls of
      the rat extensor digitorum longus muscle.
AB  - In this study, we electron-microscopically investigated a number of sympathetic
      axons in the arteriolar walls of the extensor digitorum longus muscles of the rat
      rear leg. Arterioles in the muscle were divided into two groups: (i) one group
      consisted of arterioles with accompanying muscle spindles, and (ii) the other
      consisted of arterioles without accompanying muscle spindles. The number of
      sympathetic axons present in the arteriolar walls and the ratios to the total
      number of sympathetic and non-sympathetic axons were compared between the groups.
      For electron-microscopic identification of sympathetic axons, 5-hydroxydopamine,
      a pseudotransmitter agent, was used. The number and ratio of sympathetic axons
      were significantly higher in arterioles with accompanying muscle spindles than
      arterioles possibly unrelated to muscle spindles. Additionally, amine- and
      immunohistochemistry were used to confirm the above observation.

PMID- 12418085
TI  - Erythropoietin and erythropoietin-receptor producing cells demonstrated by in
      situ hybridization in mouse visceral yolk sacs.
AB  - We have previously demonstrated that mRNAs for erythropoietin and the
      erythropoietin receptor temporarily express on the visceral yolk sacs on days 9
      11 of gestation in mice. In order to investigate the sites of expression, we
      performed in situ hybridization on visceral yolk sacs. Visceral yolk sacs from 10
      day-old mice embryos were frozen in liquid nitrogen, and processed for
      cryosections. Sections were hybridized with a 35S-labeled RNA probe complementary
      to mRNA coding for erythropoietin or erythropoietin receptor. Erythropoietin mRNA
      was detectable in 57.6% of the endodermal epithelial cells, while erythropoietin
      receptor mRNA was discerned in 90.8% of the endodermal cells and mesodermal
      cells, including hemocyteblasts. Moreover, erythropoietin protein was detectable
      in 52.8% of the endodermal epithelial cells, and on the surface of hemocyteblasts
      and mesothelial cells. Erythropoietin-receptor protein was discernible in 87.2%
      of the endodermal cells and in the corresponding mesodermal cells to those where
      erythropoietin protein was expressed by immunohistochemical examinations. The
      results indicate that erythropoietin-synthesizing cells are located in half of
      the endodermal epithelial cells, while the majority of cells in the visceral yolk
      sac are erythropoietin-receptor-producing cells, indicating that almost all cell
      population in the visceral yolk sac is erythropoietin-responding cells via both
      autocrine and paracrine routes.

PMID- 12418086
TI  - Configurations of the segmental and subsegmental bronchi and arteries in the
      right upper lobe of the human lung with special reference to their concomitant
      relations and double subsegmental arterial supply.
AB  - The basic, concomitant topographical relation between the segmental bronchus and
      artery shows derived figures in the dorsolateral part of the cranial portion of
      the mammalian lung, especially in humans. However, the pulmonary arterial supply
      has not been investigated well in the subsegmental level, even in humans. One or
      two subsegments of S2 received a double arterial supply from both the superior
      and inferior pulmonary trunks in 39.8% of the right upper lobes of 194 human lung
      dissections, whereas 20.6% did so in S3, although the latter cases were limited
      to one of the two subsegments. Moreover, we found several arterial patterns that
      were significantly frequently observed in a specific group of the bronchial tree
      in S2 and/or S3. Invasion of an additional artery of inferior trunk origin seemed
      to happen at the same time in both segments even without complementary
      territorial relations with the essential segmental artery of the superior trunk
      origin. S2 and S3 in the human right lung seemed to be the best fields for
      reconsideration of the basic rules in the lung segment system in mammals as a
      result of their having the largest sets of variations. We speculate that the
      discrepancy between the bronchial and arterial ramification patterns, which was
      frequently found in S2 and S3, is a result of a hypothetical secondary increase
      of the comparative volume of this area in evolution and/or development of the
      lung.

PMID- 12418087
TI  - Cytochemical investigation of gastric gland component cells with high-pressure
      freezing followed by freeze-substitution and hydrophilic resin embedding.
AB  - Gastric gland component cells were electron-microscopically and
      immunoelectronmicroscopically examined with high-pressure freezing followed by
      freeze substitution and a low-temperature embedding resin method and compared to
      that of the conventional chemical-fixation method. The rat gastric gland was high
      pressure frozen, freeze-substituted with acetone-containing osmium or acrolein,
      and embedded in Epon 812 or Lowicryl K4M, respectively. Using the high-pressure
      freezing method, the vitreous freezing range reached the depth of 150 microns
      from the surface. The ultrathin sections from both procedures embedding in Epon
      812 and Lowicryl K4M were doubly stained with uranyl acetate and lead acetate,
      and histochemically or immunohistochemically stained, respectively. In comparison
      to the conventional chemical fixation method, excellent results were obtained
      with respect to ultrastructural preservation. The stainings performed in this
      experiment included periodic acid-thiocarbohydrazide-silver proteinate staining,
      cationic colloidal cold at pH 2.5 staining, Helix pomatia lectin-staining, anti
      alpha or -beta subunit antibodies of H+K(+)-ATPase immunostaining and pepsinogen
      immunostaining. The staining intensity of those was stronger than that of the
      conventional immersion-chemical fixation method. In addition to these results,
      the labels also showed good specific localization. In this paper, we provide a
      description of the high-pressure freezing followed by freeze substitution and low
      temperature embedding resin method compared to the conventional chemical-fixation
      method. Our results suggest that this method is a suitable tool for
      ultrastructural and histochemical/immunohistochemical studies at high resolution.

PMID- 12418088
TI  - Aquaporins: a water channel family.
AB  - Water channel proteins, aquaporins, are integral membrane proteins serving in the
      permeation of water and some other small molecules. Eleven isoforms of aquaporins
      have been identified from various tissues to date. They are expressed in tissue-
      and cell-specific manners, and are closely related to the specific functions of
      tissues and cells. Aquaporins are usually localized to the plasma membrane. Some
      isoforms are present in cytoplasmic compartments, and their translocation to the
      plasma membrane is crucial in the regulation of water transfer. This review
      focuses on the localization of aquaporins in mammalian tissues and discusses the
      physiological importance of water channels.

PMID- 12418089
TI  - Cytodifferentiation of Bergmann glia and its relationship with Purkinje cells.
AB  - The Bergmann glia is composed of unipolar protoplasmic astrocytes in the
      cerebellar cortex. Bergmann glial cells locate their cell bodies around Purkinje
      cells, and extend radial or Bergmann fibers enwrapping synapses on Purkinje cell
      dendrites. During development, Bergmann fibers display a tight association with
      migrating granule cells, from which the concept of glia-guided neuronal migration
      has been proposed. Thus, it is widely known that the Bergmann glia is associated
      with granule cells in the developing cerebellum and with Purkinje cells in the
      adult cerebellum. As the information on how Bergmann glial cells are related
      structurally and functionally with differentiating Purkinje cells is quite
      fragmental, this issue has been investigated using cytochemical techniques for
      Bergmann glial cells. This review classifies the cytodifferentiation of Bergmann
      glial cells into four stages, that is, radial glia, migration, transformation and
      protoplasmic astrocytes, and then summarizes their structural relationship with
      Purkinje cells at each stage. The results conclude that the cytodifferentiation
      of Bergmann glial cells proceeds in correlation with the migration,
      dendritogenesis, synaptogenesis and maturation of Purkinje cells. Furthermore,
      morphological and molecular plasticity of this neuroglia appears to be regulated
      depending on the cytodifferentiation of nearby Purkinje cells. The functional
      relevance of this intimate neuron-glial relationship is also discussed with
      reference to recent studies in cell biology, cell ablation and gene knockout.

PMID- 12418090
TI  - Temporal changes in testis weight during the past 50 years in Japan.
AB  - The ever-increasing presence of environmental toxicants and their disruptive
      effect on the reproductive systems of wildlife raises the question of possible
      damage to the human reproductive system. Using medicolegal data from over 20,000
      Japanese men subjected to necropsy from 1948 to 1998, we investigated temporal
      changes in testis weight to find possible evidence of male reproductive
      disorders. We also carried out a histological examination of 747 testes collected
      from 1978 to 1998. Our detailed analyses of the development of testis weight over
      the past 50 years have revealed four clear phenomena: (i) the age at which testis
      weight reaches its maximum has decreased; (ii) peak weight showed a general
      increase until it started to decline in boys born after 1960; (iii) the decline
      rate at which testis weight decreases after its peak has greatly accelerated; and
      (iv) the onset of increasing testis weight of boys has occurred at a
      progressively younger age. Our quantitative analyses of testis weight indicate
      the possibility of a subtle reproductive disorder in Japanese men, especially in
      those born after 1960. Together with the accelerated development and decline in
      testis weight during the past 50 years, the decline in peak weight might be
      indicative of a subtle interference of environmental toxicants with male
      reproductive organogenesis.

PMID- 12418091
TI  - Endocytosis by absorptive cells in the middle segment of the suckling rat small
      intestine.
AB  - In neonatal suckling rats, the absorptive cells of the duodenum, jejunum and
      ileum endocytose maternal milk macromolecules, including antibodies from the
      lumen. To determine whether the absorptive cells from the middle segment of small
      intestine have an apical endocytic membrane system that is the same as that of
      the duodenum, jejunum or ileum, we applied horseradish peroxidase by intraluminal
      injection, and examined the absorptive cells using light and transmission
      electron microscopy. In the middle segment of the small intestine, the absorptive
      cells had an apical endocytic membrane system including apical coated pits,
      apical invaginations, coated vesicles, vesicles, tubules, early endosomes, late
      endosomes and a large homogeneous electron-dense lysosome at the supranuclear
      region. This would suggest that the endocytic membrane system in the absorptive
      cells from the middle segment of the small intestine is specialized for quick and
      active intracellular digestion. The apical endocytic membrane system of the
      absorptive cells varied according to the segment of the small intestine, and the
      absorptive cells made their transition gradually from jejunal type to middle
      type, and then from middle type to ileal type at the suckling stage. The jejunal
      and ileal type of absorptive cells increased with growth, in contrast to the
      middle type.

PMID- 12418092
TI  - Persistent left hepatic venous connection with the right atrium and the ductus
      venosus.
AB  - An anomalous left hepatic vein opening independently of the coronary sinus into
      the right atrium was found in the cadaver of an 88-year-old Japanese man. This
      vein originated from the left lobe of the liver, perforated the diaphragm at the
      left side of the vena caval foramen and opened into the right atrium. The left
      hepatic vein anastomosed mutually with the middle hepatic vein at the level of
      venule. The ligamentum venosum originated from the left branch of the portal vein
      and was connected directly to the left hepatic vein. The development of the
      central systemic venous system and a possible explanation for the morphogenesis
      of this anomaly were reviewed. As a result, the occurrence of this anomalous vein
      was explained as being due to the persistence of the left vitelline connection
      with the left sinus horn and the ductus venosus.

PMID- 12418093
TI  - Bilateral persistent sciatic arteries in a Japanese man.
AB  - During student dissecting practice, a rare developmental anomaly showing
      persistent sciatic artery (PSA) was found in the bilateral lower limbs of a 74
      year-old Japanese male cadaver. The PSA was a continuation of the internal iliac
      artery on both sides, did not anastomose with the perforating arteries and ended
      by anastomosing with the popliteal artery on both sides. The course and
      distribution of the PSA were relatively consistent with previous reports. In the
      present case, however, the PSA and inferior gluteal arteries existed
      simultaneously on both sides, despite the general assumption that the inferior
      gluteal artery is a remnant of sciatic artery regression.

PMID- 12418095
TI  - Sural-tibial nerve communications in humans.
AB  - We investigated the occurrence of a communication between the sural and tibial
      nerves in 49 legs of 28 Japanese cadavers. In front of the calcanean tendon, we
      found the communication in 7 legs (14.3%) or in 5 cadavers (18.9%). The sural
      nerve gave rise to a number of medial and lateral branches, including the lateral
      calcanean branch at the lateral side of the ankle. The communicating branch with
      the tibial nerve arose from the first medial branch and pierced the deep fascia
      of the leg. In 4 cases, the U-shaped communication was formed between the sural
      and tibial nerves, and in 3 cases, the Y-shaped communication.
      Electrophysiological evidence of an anomalous motor function of the sural nerve
      has been reported recently. We consider that the U-shaped communication between
      the sural and tibial nerves gives a morphological basis to the motor function of
      the sural nerve.

PMID- 12418094
TI  - Morphological study of a horseshoe kidney with special reference to the vascular
      system.
AB  - This is a morphological study on an autopsy case of horseshoe kidney found in a
      79-year-old-female cadaver. This kidney consisted of two distinct renal masses
      that were connected at their lower poles by a parenchymal isthmus that was
      located in the front of the abdominal aorta at the level of the fourth lumbar
      vertebra. The kidney was supplied by four arteries arising from the abdominal
      aorta. The distribution of intrarenal arteries showed that the nature of
      segmental arteries in the present case was basically the same as in the normal
      kidney, except that the isthmus had its own blood supply from the artery directly
      arising from the aorta approximately 28 mm below the origin of the inferior
      mesenteric artery. Venous drainage from the kidney, including the isthmus, was
      taken by three veins that opened independently into the inferior vena cava. No
      congenital malformations were found in other organs. We discuss the anatomical
      and embryological significance of this anomaly and its associated vascular
      system.

PMID- 12418096
TI  - Muscle-fiber characteristics in adult mouse-tongue muscles.
AB  - To clarify functions of the mouse-tongue muscles, proteins such as myocin heavy
      chain (MHC) 2a and MHC-2b, which are isoforms of the fast-twitch fiber type
      myosin heavy chain, in the lateral margin of the tongue were observed by reverse
      transcription polymerase chain reaction and immunohistochemical analyses. The
      main MHC isoform in the superior longitudinal muscle of the tongue was MHC-2b,
      with the fastest function and the main MHC isoform in the transverse muscle of
      the tongue was MHC-2a. These findings suggested that the fastest function is
      necessary for the superior longitudinal muscle of the tongue, which is useful for
      moving the tongue in and out of the mouth in the sagittal direction, showing
      different cellular biological properties of the myofibers from those of the
      transverse muscle of the tongue.

PMID- 12418097
TI  - John T. Edsall and Advances in Protein Chemistry.

PMID- 12418098
TI  - Getting to know u.

PMID- 12418099
TI  - The expanded denatured state: an ensemble of conformations trapped in a locally
      encoded topological space.

PMID- 12418100
TI  - Identification and functions of usefully disordered proteins.

PMID- 12418101
TI  - Unfolded proteins studied by Raman optical activity.

PMID- 12418102
TI  - What fluorescence correlation spectroscopy can tell us about unfolded proteins.

PMID- 12418103
TI  - Unfolded peptides and proteins studied with infrared absorption and vibrational
      circular dichroism spectra.

PMID- 12418104
TI  - Is polyproline II a major backbone conformation in unfolded proteins?

PMID- 12418105
TI  - Toward a taxonomy of the denatured state: small angle scattering studies of
      unfolded proteins.

PMID- 12418106
TI  - Determinants of the polyproline II helix from modeling studies.
AB  - Despite the fact that Tiffany and Krimm (1968a,b) formulated their hypothesis
      more than thirty years ago, it is only now that we are beginning to truly
      appreciate the importance of the PPII helical conformation. Recent experimental
      work has demonstrated that the polypeptide backbone possesses a significant
      propensity to adopt the PPII helical conformation (Kelly et al., 2001; Rucker and
      Creamer, 2002; Shi et al., 2002). The major determinant of this backbone
      propensity would appear to be backbone solvation, as was originally hinted at by
      Krimm and Tiffany (1974) and later suggested by a number of groups (Adzhubei and
      Sternberg, 1993; Sreerama and Woody, 1999; Kelly et al., 2001; Rucker and
      Creamer, 2002; Shi et al., 2002). The calculations and modeling described above
      provide data in support of this hypothesis. Each residue has its own propensity
      to adopt the PPII conformation, with the backbone propensity being modulated by
      the side chain (Kelly et al., 2001). Short, bulky side chains occlude backbone
      from solvent and thus disfavor the PPII conformation, while the lack of a side
      chain or long, flexible side chains tend to favor the conformation (Kelly et al.,
      2001). Again, the described calculations support this. Steric interactions (Pappu
      et al., 2000) and side chain conformational entropy alos contribute to the
      observed propensities. Furthermore, as suggested from surveys of PPII helices in
      proteins of known structure (Stapley and Creamer, 1999), side chain-to-backbone
      hydrogen bonds may well play a role in stabilizing PPII helices. The survey data,
      plus supporting calculations, also suggest that some polar residues may play a
      PPII helic-capping role analogous to that observed in alpha-helices (Presta and
      Rose, 1988; Aurora and Rose, 1998). Taken in sum, an atomic-level picture of the
      stabilization of PPII helices is beginning to emerge. Once the determinants of
      PPII helix formation are known in more detail, it will become possible to apply
      them, along with the known determinants of the alpha-helical conformation, to the
      understanding of protein unfolded states. If, as suggested at the beginning of
      this article, protein unfolded states are dominated by residues in the PPII and
      alpha-conformations, these data will allow for modeling of the unfolded state
      ensembles of specific proteins with a level of realism that has not been
      previously anticipated.

PMID- 12418107
TI  - Hydration theory for molecular biophysics.

PMID- 12418108
TI  - Insights into the structure and dynamics of unfolded proteins from nuclear
      magnetic resonance.

PMID- 12418109
TI  - Unfolded state of peptides.

PMID- 12418111
TI  - [Problems in primary and secondary prevention of cardiovascular diseases].

PMID- 12418110
TI  - A new perspective on unfolded proteins.

PMID- 12418112
TI  - [Monitoring myocardial infarct (diagnostic combination, prodromal period,
      behavioral characteristics) using the WHO program "Registry of Acute Myocardial
      Infarct", Monica].
AB  - AIM: A 22-year study of diagnostic categories of myocardial infarction (MI), a
      prodromal period, behavioral characteristics of the patients. MATERIAL AND
      METHODS: WHO programs Acute Myocardial Infarction Register and MONICA were
      performed in Novosibirsk population aged 25-64 years. From January 1, 1977, to
      December 31, 1998, monitoring registered 5180 cases of MI (1774 lethal outcomes).
      RESULTS: The diagnostic category "Possible" MI occurred more frequently than
      "definite" MI, this difference being more noticeable in women than in men. In
      both diagnostic categories the disease presented with a typical clinical picture.
      In the category "definite" MI there were many cases of atypical disease. Most
      cases of MI developed at home though it occurred outdoors more frequently in men
      and at home in women. Half of the patients had arterial hypertension (AH) and
      effort angina (EA), one third of the patients had survived MI before. 91% of MI
      men were heavy smokers. Alcohol intake at MI onset was insignificant. Pain
      syndrome 2 weeks before MI was the same in survivors and the deceased. Those who
      died suddenly felt extremely tied before MI, those whose death was not sudden
      experienced exacerbation of EA and dyspnea, those who survived experienced
      exacerbation of EA. CONCLUSION: Long-term monitoring showed that MI clinical
      presentation did not differ for 2 decades. A significant number of MI patients
      with a history of hypertension, effort angina, previous MI, heavy smoking
      evidenced for the lack of prophylactic education among population.

PMID- 12418113
TI  - [Clinical course of disease and prognosis in patients with ischemic heart disease
      with stable angina pectoris, caused by stenosing coronary atherosclerosis (data
      from a a 20-year study].
AB  - AIM: To study a course and prognosis of ischemic heart disease (IHD) with stable
      angina pectoris (SAP) caused by stenotic coronary atherosclerosis (SCA) by 20
      year follow-up data. MATERIAL AND DATA: Prognosis of survival was made in 318
      patients with SAP due to SCA. RESULTS: The results of a 20-year study show that
      prognosis in IHD patients depends on SAP severity (by the functional class),
      exercise tolerance (by the exercise test), severity of coronary bed affection and
      of left ventricular contractility affection as assessed by coronary- and
      ventriculography. If lethality of the test subjects was not higher than in the
      population, the patient had good prognosis associated with one-vessel lesion,
      normal myocardial contractile function, high exercise tolerance, absence of the
      leading risk factors. CONCLUSION: The multivariance analysis with stepwise
      selection enabled the design of the model of the integral prognostic index (IPI)
      for the studied patients. The IPI index under 1.86 suggests a favourable
      prognosis, 1.87-2.33--an intermediate prognosis and in IPI higher than 2.34-
      unfavourable prognosis. Early surgery is recommended for patients with high IPI.

PMID- 12418115
TI  - [Acute coronary syndrome without elevation of the ST segment: prognostic
      significance of determining the levels of troponin I and CPK-MBmass].
AB  - AIM: To assess diagnostic and prognostic role of CPK-MBmass and troponin I(TnI)
      in patients with acute coronary syndrome without persistent ST segment elevation
      (ACS). MATERIAL AND METHODS: Standard laboratory and device tests, measurements
      of CPK-MBmass and TnI levels at admission, 12 and 24 hours after hospitalization
      were performed in 51 ACS patients (33 men, 18 women, mean age 63 +/- 8.2 years).
      Early and late (1 month and 6, 12 months after hospitalization, respectively)
      complications were studied. RESULTS: The analysis of the immediate outcomes has
      revealed that treatment brought about stabilization of the condition in 45
      (88.2%) patients, 6 patients had myocardial infarction within a month since the
      disease onset, one patient died. Late MI developed in 6 patients. For 6 months 2
      more patients died. One patient died in the following 6 months. Thus ACS points
      to adverse 1-month prognosis in 12 and 1-year prognosis in 23.5% patients. TnI
      levels and CPK-MBmass are sensitive and specific for an adverse outcome in 91.7
      and 100%, 82 and 89.7%, respectively. A predictive value for positive outcomes
      was 61.1 and 75%, respectively, for negative results 96.9 and 100%, respectively.
      CONCLUSION: Estimation of CPK-MBmass and TnI is essential in diagnosis of non-Q
      wave MI and is predictable in relation to both short- and long-term prognosis.

PMID- 12418114
TI  - [Hyperinsulinemia and its contribution to the clinical course and outcome of
      myocardial infarct. Data from a 5-year prospective study].
AB  - AIM: Assessment of hyperinsulinemia (HIE) contribution to severity of clinical
      symptoms and outcomes of myocardial infarction (MI) as well as its further
      changes as shown by a 5-year follow-up. MATERIAL AND METHODS: 112 men aged 47.5
      +/- 0.8 years with recent Q-wave MI were examined. Coronary circulation,
      frequency of concomitant arterial hypertension (AH) and complications in acute
      MI, levels of insulin, hydrocortisone and somatotropin (radioimmunoassay) were
      studied in all the patients on MI day 21-26 (the subacute period) and during long
      term follow-up with a control point of 5 years after MI onset. RESULTS: 60% of
      patients who died during 5 years after MI had HIE in the subacute period
      irrespective of AH presence. If MI was complicated by acute heart failure, HIE
      rate reached 70%. After 5 years of the follow-up, 70% of patients showed a
      decreased insulin level to < 13.5 mked/ml which went up under induced ischemia.
      CONCLUSION: An elevated level of insulin in postmyocardial infarction patients is
      caused by impaired coronary blood flow and myocardial metabolism, is a dynamic
      state and is compensatory. It is an unfavourable prognostic marker for survival
      especially in combination with hypercortisolemia. Hyperinsulinemia late after MI
      frequently is frequently associated with AH and is detected at induced myocardial
      ischemia.

PMID- 12418116
TI  - [Connection between the season of year, season of birth, and trimester of the
      individual year in patients with ischemic heart disease at risk for myocardial
      infarction and its complications].
AB  - AIM: To clarify whether the periods of the individual year (from one birthday to
      another), season of the year, season of birth of patients with ischemic heart
      disease (IHD) are involved in development of myocardial infarction and its
      complications. MATERIAL AND METHODS: Case histories of 349 men hospitalized for
      acute myocardial infarction (MI) have been analysed. The analysis concerned the
      rate of MI onset in various seasons of the year, trimesters of the individual
      year (IY) and seasons of the patient's birth. RESULTS: Incidence of MI was higher
      in winter and summer. MI complications develop more frequently in spring.
      Trimester I and IV (months i-III and IX-XII since birthday) appeared more
      favourable for development of MI and its complications. Most favourable for IM
      was trimester III of IY, for MI complications--trimester II of IY. IM occurred
      more frequently in IHD patients born in autumn, complications in those born in
      summer. CONCLUSION: Development of MI and its complications is determined by a
      number of chronobiological factors: season of the year, season of the patient's
      birth and period of the individual year. This information is valuable in planning
      preventive measures.

PMID- 12418117
TI  - [Connection of geogeophysical factors and the course of unstable angina
      pectoris].
AB  - AIM: To study relationships between changes in solar and geomagnetic activity and
      a course of unstable angina pectoris with neuron nets. MATERIAL AND METHODS:
      Heliogeophysical variables were studied in 67 male patients at the age of 42 to
      75 years with unstable angina pectoris. RESULTS: The neuronetwork analysis has
      revealed marked non-linear relations between angina episodes and heliogeophysical
      factors. CONCLUSION: Small-amplitude changes in solar and geomagnetic activity
      may influence the course of unstable angina pectoris.

PMID- 12418118
TI  - [Decrease in the sensitivity to the anti-ischemic effect of propranolol and
      prospects for correcting it in patients with stable angina pectoris].
AB  - AIM: To study incidence of low sensitivity to an antiischemic effect of
      propranolol and feasibility of its correction with a metabolic drug-
      trimetazidine. MATERIAL AND METHODS: Paired treadmill and bicycle exercise tests
      were made until depression of segment ST > 1 mm and a typical angina episode. The
      trial included 147 men with ischemic heart disease, stable angina pectoris
      (functional class II-III). The antiischemic effect of propranolol single doses 40
      or 80 mg were assessed in 117 patients. Single doses of propranolol 40 mg,
      trimetazidine 20 mg and their combination were examined for an antiischemic
      effect in 30 patients. The absence of the above effect of propranolol was stated
      in 20 patients who participated in a double blind, randomised, placebo-controlled
      study with conduction of 2-week courses of regular administration of propranolol
      in a dose 120 mg/day, trimetazidine 60 mg/day and their combination. Echo-CG was
      made initially and in the end of each course. RESULTS: Propranolol's antiischemic
      effect of a single dose 40 mg was not found in 45.3% patients, 40-80 mg--in 21%.
      Among 20 patients without effect of the single propranolol dose, an increment of
      the threshold load made up 20.7 +/- 15.7 s, after intake of trimetazidine 16.3 +/
      18.6 s. The combination of these drugs significantly increases the increment of
      the threshold load duration to 90.8 +/- 80.4 s. The same picture was observed in
      the course treatment. The above increment in the course administration of
      propranolol was 46.3 +/- 15.3 s, of trimetazidine 22.8 +/- 20.2 s, of their
      combination 122.7 +/- 21.8 s (p = 0.02). In the absence of propranolol effect,
      echo-CG registered deterioration of disorder of left ventricular diastolic
      function. 10 patients with effect of the single propranolol dose this
      deterioration was not observed in combined use of propranolol and trimetazidine.
      CONCLUSION: The antiischemic effect of propranolol in a single dose 40 mg was not
      recorded in about half of the examined anginal patients. Combined use of
      propranolol and trimetazidine in cases with no propranolol effect provides a
      synergetic effect both in single and course administration.

PMID- 12418119
TI  - [Effect of superhigh frequency electromagnetic fields and physical exercise on
      physical performance and extrasystole in myocardial ischemia patients with stable
      angina pectoris].
AB  - AIM: To study impact of UHF electromagnetic fields in combination with bicycle
      exercise on muscular performance (MP) and extrasystole (ES) in IHD patients with
      stable angina of functional class 1 and 2 (SA). MATERIAL AND METHODS: The trial
      included 112 IHD patients with SA and ES. 36 of them were exposed to coursed
      electromagnetic fields (40 W, on heart area). The other 42 patients received the
      same treatment and exercised on bicycle ergometer. 34 patients received placebo
      procedures and did therapeutic exercises. The effect was assessed with
      spiroveloergometry and ECG Holter ambulatory monitoring. RESULTS: It was found
      that 40 W UHF electromagnetic fields in combination with exercise on
      veloergometer exert a training effect in IHD patients with extrasystole
      manifesting with higher physical performance and coronary heart reserve. The
      antiarrhythmic effect consisted in a significant daily fall in mean ventricular
      ES number by 48.2%, supraventricular EX by 54.8%. CONCLUSION: Combined
      application of 40 W UHF electromagnetic fields on heart area with bicycle
      exercise is effective in IHD patients with ES.

PMID- 12418120
TI  - [Early postoperative complications and prevention of them in ischemic heart
      disease patients after direct myocardial revascularization].
AB  - AIM: To specify risk factors affecting development and frequency of complications
      early after the bypass operation in direct myocardial revascularization. MATERIAL
      AND METHODS: 455 patients with ischemic heart disease (IHD) of whom 392 (86.2%)
      had stable angina pectoris class III-IV, 25 (5.5%) had unstable angina pectoris
      (UAP) and 38 (8.5%) had survived myocardial infarction (MI) underwent autovenous
      coronary artery bypass operation. IHD combined with arterial hypertension in 103
      (22.6%), diabetes mellitus type II in 67 (14.7%), cardiac failure (CF) stage IIa
      in 97 (21.3%) patients. The ejection fraction (EF) was 37.8 +/- 3.3% in 113
      (24.8) patients, in the others it was 46.7 +/- 2.7%. RESULTS: Early postoperative
      complications arose more frequently in patients with UAP, MI, CF and low EF.
      Postoperative acute cardiovascular failure was registered in 132 (29.5%)
      patients, arrhythmia--in 60 (13.4%), perioperative MI--in 13 (2.9%) patients.
      CONCLUSION: The most significant risk factors of postoperative complications in
      the above patients are the following: UAP, MI, CF, low EF. These risk factors
      should be allowed for in preparation of patients for coronary bypass surgery.

PMID- 12418121
TI  - [Structural-functional changes in the myocardium in arterial hypertension and
      their prognostic value].

PMID- 12418122
TI  - [Long-term ambulatory follow-up of hypertension patients with low renin activity
      in blood].
AB  - AIM: To characterize a clinical course of arterial hypertension in patients with
      low activity of blood renin. MATERIAL AND METHODS: 44 hypertensive patients with
      low activity of blood renin participated in the trial. They were divided into
      three groups consisting of 18, 14 and 12 patients (group 1, 2 and 3 with adrenal
      adenoma, adrenal hyperplasia and hypertension, respectively). RESULTS: Baseline
      hypertension was higher in group 1. The clinical picture did not differ much
      between the groups. Long-term follow-up has revealed that mean arterial pressure
      tended to lowering in groups 1 and 2 while in group 3 it tended to rise.
      Incidence of arrhythmia increased thrice though myasthenia became less frequent.
      CONCLUSION: Group 1 patients had a more severe clinical course of hypertension
      with high lethality and many associated diseases. To achieve a clinical effect,
      they had to take higher doses of antihypertensive drugs.

PMID- 12418123
TI  - [Arterial hypertension in patients with undifferentiated adrenal tumors].
AB  - AIM: To study clinical and laboratory manifestations of hormonal activity in
      hypertensive patients with undifferentiated adrenal tumors. MATERIAL AND METHODS:
      40 patients (19 males and 21 females aged 16-60 years) with undifferentiated
      adrenal tumors were examined. They were treated surgically. The results of the
      examination were compared with histological evidence on the resected adrenals.
      Clinical and laboratory signs of hormonal activity of the tumor were ascertained.
      RESULTS: Clinical symptoms in patients with adrenal tumors differed from those of
      typical symptoms of Icenko-Cushing, Cohn syndromes, pheochromocytoma.
      Hypertension in patients with cortical tumor may arise because of high synthesis
      of hydrocortisone, in patients with medullary tumor--of catecholamines. However,
      the level of hormones was not high enough for development of classic syndromes.
      That's why these tumors were named undifferentiated. CONCLUSION: Adrenal cortical
      tumors have signs of mixed androgeno-mineral-glucocorticoid activity. In
      medullary adrenal tumors hypersecretion of catecholamines is associated with
      cortical hyperfunction.

PMID- 12418124
TI  - [Assessment of cardiovascular system status in patients with primary
      hyperaldosteronism using polyfunctional monitoring at stages of combination
      therapy].

PMID- 12418126
TI  - [Prognosis of patients with chronic cardiac insufficiency (from materials of the
      XIX-XXII Congress of the European Society of Cardiologists].

PMID- 12418125
TI  - [Perpetual cardiac fibrillation and predictors of sudden cardiac arrhythmic death
      in patients with ischemic stroke].
AB  - AIM: To study predictors of sudden cardiac arrhythmic death in patients with
      perpetual cardiac fibrillation (PCF) and ischemic stroke. MATERIAL AND METHODS:
      230 patients with ischemic stroke were examined. 22 (9.6%) patients of them
      (group 1) had PCF, 208 (90.4%) patients (group 2) had sinus rhythm. The groups
      were matched by sex, stage of ischemic stroke, presence of ischemic heart
      disease. Echocardiography and Holter monitoring were made in all the examinees.
      RESULTS: Zones of left ventricular dyskinesia and high-grade extrasystoles
      occurred more frequently in group 1. Ventricular extrasystoles were also frequent
      in this group. A close correlation was found between the zones of left
      ventricular dyskinesis and ventricular extrasystoles of high gradations.
      CONCLUSION: Thus, most of the patients with ischemic stroke and PCF have
      ventricular arrhythmia resultant from systolic dysfunction of the left ventricle
      and related to the risk of sudden cardiac death.

PMID- 12418127
TI  - [Cardiovascular diseases and modern prospects for preventing stroke].

PMID- 12418128
TI  - [Does pulmonary arterial hypertension exist?].

PMID- 12418129
TI  - [Molecular genetic aspects of nonspecific aortoarteritis].

PMID- 12418130
TI  - [A case of successful use of broncholytic nebulizer therapy in the complex
      treatment of chronic obstructive lung disease with a severe course in an elderly
      patient].

PMID- 12418131
TI  - [Prognostic factors in the acute phase of haemorrhagic stroke].
AB  - The aim of the study was establishing which parameters play a significant
      prognostic role in acute haemorrhagic stroke in its acute phases (during 30 days
      from stroke onset). The material included 110 patients with haemorrhagic stroke
      (HS) treated in the years 1997-1999 at the II Neurology Department, Institute of
      Psychiatry and Neurology in Warsaw or at the Neurology Department, Hospital in
      Pila. The analysis of risk factors, fitness before stroke and on the first day of
      the disease was based on history data. On the first day of the disease the
      assessment included state of consciousness, brain stem signs, vomiting, stroke
      type on the basis of clinical condition (according to Oxford classification,
      OCSP), blood pressure, body temperature measurements, intensity of neurological
      signs according to Scandinavian scale (SSS). In the blood glucose level,
      fibrinogen, leucocyte count and ESR were determined. In the first week
      consciousness state, blood pressure and miction were checked repeatedly. It was
      found that serious consciousness disturbances, stroke type TACS, POCS and severe
      not classified stroke, presence of brain stem involvement, low SSS score, high
      body temperature, high leucocyte count and glucose level were more frequent in
      patients who died within 30 days after stroke onset. Prognostically important
      were also instability of blood pressure and urinary incontinence in the first
      week. All clinical observation and laboratory analyses of prognostic importance
      in the acute phase of HS can be done in typical hospital settings.

PMID- 12418132
TI  - [The value of motor latency difference measurements between the second lumbrical
      muscle and second interosseous muscle in the diagnosis of carpal tunnel
      syndrome].
AB  - The aim of the study was to evaluate the sensitivity of a new
      electrophysiological test determining the difference between distal motor
      latencies of the second lumbrical and the second interosseous muscles (2LIDML
      test) in patients with carpal tunnel syndrome (CTS). We examined 161 nerves of
      100 patients with clinical CTS symptoms, including 68 women and 32 men, aged from
      20 to 84, as well as 60 nerves in the healthy control group. The 2LI-DML test
      examination results were compared with standard test results and an additional
      D4M-D4U test. The 2LI-DML test is based on the comparison between the median
      motor distal latency in the motor fibres, at the distance wrist-second lumbrical
      muscle, and the ulnar nerve latency, at the distance wrist-second interosseous
      muscle, maintaining identical distances during nerve stimulation and placing the
      recording electrode between the second and third metacarpal. The mean latency
      difference in 2LI-DML test in the control group was 0.15 ms + 0.12 (mean +/- SD),
      while the upper range limit was established at 0.4 ms (mean + 2SD). Abnormal 2LI
      DML test result was found in 89% of patients, that of D4M-D4U in 88% of patients,
      and that of standard tests in 74% of patients. Our evaluation of results
      demonstrates that the 2LI-DML test is a very sensitive and useful method for the
      diagnosis of a severe damage of median nerve, when the application of standard
      methods does not allow to obtain sensory and motor responses.

PMID- 12418133
TI  - [Surgical treatment after cervical spine and spinal cord injuries of the C3-C7
      level].
AB  - The authors report the methods and results of the treatment of 83 patients with
      lower cervical spine (C3-C7) injuries, who were treated in the Neurosurgery
      Department in Elblag in a period of 11 years. Lesions ranged from fractures
      mainly of vertebral C5 and C6 bodies, and dislocations--mostly at levels C4-C5
      and C5-C6. Most lesions were the consequence of a headlong jump into water
      (38.5%) and traffic accidents (29%). In admission sensory disturbances (38.5%)
      and tetraplegia or paresis of the upper limbs with paralysis of lower limbs
      (together 44.6%) were most frequently observed. The state of the patients was
      evaluated according to the ASIA-Frankel's scale. 148 surgical procedures were
      carried out. Decompression and autogenic and/or plate stabilization--from the
      anterior approach using Caspar's system and Crutchfield's traction--were the
      preferred methods. The post-surgical follow up extends from 9 years to 3 months.
      The most satisfying result was the improvement observed in the patients from
      groups A and B according to ASIA-Frankel's scale. Among 36 such patients, the
      medullary functions of 17 patients improved. 14 patients died from 5 days to 3
      months after surgery. The authors also present an overview of contemporary
      management of lower cervical spine injuries. The emphasis is placed on the
      importance of factors making the treatment of spine and spinal cord injuries more
      difficult and delaying the beginning of early and efficient surgery.

PMID- 12418134
TI  - [Results of treatment of non-traumatic cerebellar haemorrhages].
AB  - AIM: Presentation of experiences in the treatment and tentative determination of
      factors of prognostic importance which could be useful in the selection of
      appropriate treatment of patients with non-traumatic cerebellar haemorrhage.
      MATERIAL AND METHOD: 35 consecutive patients treated in the years 1987-1996 were
      analysed retrospectively. Their condition on admission was assessed using Glasgow
      Coma Scale and the treatment results were assessed using the Glasgow Outcome
      Scale at the time of discharge. All patients had CT which was repeated, as
      necessary, and in some cases angiography was done. Ten patients were treated
      surgically and 25 only conservatively (in six of them temporary external
      ventricular drainage was performed due to hydrocephalus). The analysis included
      the influence of localisation and volume of haemorrhage, presence of
      hydrocephalus, intraventricular extension of haemorrhage fourth ventricle and
      quadrigeminal cistern appearance on the state of the patients and on treatment
      results. Non-parametric tests: Mann-Whitney and variance analysis of Kruskal
      Wallis were used for determination of statistical significance (p < 0.05).
      RESULTS: Six patients were in coma (4-7 GCS score), 6 had GCS score 8-12, 6 had
      GCS score 13-14, and 17 patients had no consciousness disturbances. Haematoma
      involved only cerebellar hemisphere in 21 cases, hemisphere and vermis in 12,
      cerebellum with brain stem extension in 2 cases. Haematoma volume was below 20 ml
      in 25 cases, over 20 ml in 5 cases, and in 5 case the volume could not have been
      determined. Hydrocephalus was present in 12 patients being related to CSF outflow
      block in 7 and to intraventricular haemorrhage in 5 cases. Intraventricular
      extension of haemorrhage occurred in 9 cases. Hydrocephalus presence (p = 0.005)
      and haematoma volume (p < 0.03) influenced significantly consciousness level on
      admission. In the surgically treated group 2 patients died and in 7 cases the
      result was satisfactory (GOS:MD + GR). In the group treated conservatively 4
      patients died, 2 became disabled, and 19 left the hospital in good or very good
      condition (GOS:MD + GR). The total mortality was 17.2%, consciousness level on
      admission (p = 0.001), haematoma volume (p < 0.05), hydrocephalus presence (p <
      0.008), intraventricular extension of haemorrhage (p < 0.008) had significant
      influence on treatment results. CONCLUSIONS: In the light of our experience it is
      suggested that patients in coma should be operated on for haematoma evacuation
      with or without temporary external ventricular drainage. In conscious patients
      with stable course of disease medical treatment can be considered.

PMID- 12418135
TI  - [Brachial plexus tumors].
AB  - The brachial plexus is a primary site of tumours originating from peripheral
      nervous system, such as neurilemmoma and neurofibroma. Moreover, the brachial
      plexus is affected by various neoplasms spreading from the neighbouring anatomic
      structures. Surgical treatment of neoplasms provoking plexopathy is often
      realised by multidisciplinary teams. The authors present the series of 7 patients
      operated on for brachial plexus affection between 1993-2000, the pathologic
      findings were as follows: neurofibroma, neurilemmoma, lymphogranulomatosis,
      neurofibrosarcoma, lipoma, chordoma, sarcoma neurogenes. The analysis of clinical
      course includes: main symptoms, diagnostic procedures and results of treatment.
      Surgical technique is also described.

PMID- 12418136
TI  - [Neuroendoscopy in the treatment of third ventricular hydrocephalus accompanying
      tumors of the posterior part of the third ventricle in children].
AB  - OBJECTIVE: The aim of the study was to evaluate the effectiveness of endoscopic
      third ventriculostomy (ETV) in non-communicating hydrocephalus secondary to
      tumour of the posterior part of the third ventricle tumours in children. MATERIAL
      AND METHODS: The study group consisted of 32 patients (13 girls and 19 boys)
      treated at the Department of Neurosurgery Children's Memorial Health Institute in
      Warsaw in the years 1996-2000. In 22 cases benign tectal mass (BTM) and 10
      malignant neoplasms (including 9 germ cell tumours and 1 ependymoma) were
      diagnosed. The follow-up period after ETV ranged from 5 months to 4 years (mean
      21 months). The retrospective analysis of medical reports and control CTs, MRs,
      and PC MR-cine studies was performed. RESULTS: In all the patients the early (up
      to 3 months postop) outcomes were good. 8 patients with malignant neoplasms after
      initial chemotherapy underwent residual tumor excision (more than 3 months after
      ETVs) and in two of them the CFS meningeal tumor spreads were detected. In 26
      (81%) of the patients permanent control of hydrocephalus was achieved. The
      recurrence of active hydrocephalus was observed in 6 cases (19%). 3 of them were
      children with benign tectal masses and 3 with malignant tumours. The reason of
      failure in 2 cases was associated with meningeal tumor dissemination, and in one
      with postoperative bleeding after surgical tumor excision (communicating
      hydrocephalus). In 2 cases with benign tumours reasons of failures were not clear
      (patent stomies on PC MR-cine) and in 1 case late stomy occlusion on PC-MR flow
      study was diagnosed. Five out of 6 patients underwent shunt placements and in 1
      case with late ventriculostomy occlusion another endoscopic procedure (after 26
      months) was successfully performed. CONCLUSIONS: The endoscopic third
      ventriculostomy was an efficient method to control non-communicating
      hydrocephalus in children with posterior part of the third ventricle brain
      tumours. The PC MR flow study was a useful diagnostic tool in the stomy patency
      evaluation and in further treatment planning in cases of failures. It seems that
      recurrence of active hydrocephalus can be successfully treated with repeated ETV
      when the stomy occlusion is detected on MR flow studies. Other cases of failures
      ought to be treated by shunt implantations.

PMID- 12418137
TI  - [Endoscopic ventriculostomy of the third ventricle in adults. Own experience].
AB  - Only few reports can be found on endoscopic third ventriculostomy (ETV) in the
      Polish literature, and the majority of other reports concern paediatric or mixed
      population. This has induced the authors to report their experience with ETV in
      adults, reporting the results and discussing the usefulness and effectiveness of
      this procedure, causes of complications and failure. ETV was carried out in 20
      patients aged over 18 years in a two-year period, beginning in 1999. In 13 cases
      (64%) the cause was external compression of CSF system by tumour leading to
      hydrocephalus. In 3 cases aqueduct stenosis was producing hydrocephalus, in 3
      cases arachnoid cyst, perisellar or situated in posterior part of the third
      ventricle, was the cause, and in one case colloidal cyst of the third ventricle.
      The outcome were analysed according to clinical and radiological criteria finding
      that the ETV was successful in 90% of cases by clinical criteria, and in 88% by
      radiological criteria. Only unimportant clinical complications were reported
      without major consequences. It is concluded that ETV is a very useful method for
      hydrocephalus treatment in adults, especially if caused by blockade of CSF
      pathways by tumour or arachnoid cysts in the vicinity of the third ventricle.

PMID- 12418138
TI  - [Evaluation of blood supply dynamics and possibilities of cerebral arteriovenous
      malformations (AVM) imaging by means of transcranial color-coded duplex
      sonography (TCCS)].
AB  - The present study was carried out in 12 patients (7 males and 5 females) aged 16
      56 years (mean age 35.9) with arteriovenous malformation diagnosed in cerebral
      angiography. The examination was performed by means of ATL ULTRAMARK 9 with low
      frequency (2MHz to 3MHz) transducer. Assessment was made of possibilities of
      imaging arteriovenous malformations by transcranial colour-coded duplex
      sonography and of blood flow values in the studied intracranial arteries.
      Statistical analysis was applied of the following blood flow parameters: mean
      velocity, peak systolic velocity, end diastolic velocity, pulsatility index (PI),
      resistance index (RI), pulsatility transmission index (PTI) and relative flow
      velocity (RFV). The malformations were imaged using TCCS in 9 (75%) patients. In
      two-dimensional B mode image the angiomas displayed echogenicity similar to the
      surrounding brain parenchyma and could not be precisely delineated. The colour
      coded imaging made possible depicting the image of the vessel loops in the AVM
      nidus. In two other patients the presence of angiomas was confirmed by blood flow
      disturbances in the feeder vessel: increased blood flow, decreased pulsatility
      and resistance indices, and collateral circulation. Collateralization by the
      contralateral internal carotid artery via the anterior communicating artery was
      disclosed in 9 cases. The TCCS results corresponded closely to angiographic
      findings. Collateral circulation via the posterior communicating artery
      ipsilateral to the AVM was found in 3 of 5 patients in whom it was diagnosed in
      cerebral angiography. Doppler findings in the patients were similar to the
      conventional TCD examination. In the feeding vessels significant increase in
      blood flow velocity and decreased pulsatility and resistance indices was
      observed. RFV value for the end diastolic velocity was higher than RFV for the
      peak systolic velocity (p < 0.001) and mean velocity. These findings suggest that
      the increased end diastolic velocity in the feeding vessel is higher than the
      mean velocity and peak systolic velocity. It is thought that the TCCS can be
      successfully used in early diagnosis of cerebral arterio-venous malformations and
      as an instrument in follow-up examination.

PMID- 12418139
TI  - [Current perspectives in the treatment of Huntington's chorea].
AB  - Huntington's chorea (HD) is a degenerative condition of the central nervous
      system of genetic origin, inherited as an autosomal dominant trait. The mechanism
      of the genetic defect is already known, it is a dynamic mutation in the ITI5 gene
      situated on chromosome 4 p 16.3 coding the protein huntington. The disease is
      progressive and leading to lethal outcome and effective treatment is unknown.
      Methods of treatment of various disturbances developing in this disease are
      described with stress laid on neuroprotective methods which could perhaps give
      better results in not so far future.

PMID- 12418140
TI  - [Decreased antioxidant-defence mechanisms in cerebrospinal fluid (CSF) in
      patients with tick-borne encephalitis (TBE)].
AB  - 14 patients with Tick-borne Encephalitis (TBE) aged 21-64 (mean = 42.3) were
      analysed. The activity of superoxide dismutase (SOD), glutathione reductase (GSSG
      R), glutathione peroxidase (GSH-Px), concentrations of malondialdehyde (MDA) and
      total sulphydryl groups (-SH) were measured in cerebrospinal fluid (CSF). Control
      group consisted of 10 patients whose CSF parameters remained in normal range. The
      CSF examination was performed twice: before and 3 weeks after treatment. The
      analysed activity of SOD, GSH-Px, GSSG-R, MDA and total sulphydryl groups (-SH)
      during the acute stage of the disease was significantly lower comparing to the
      control group. Despite the treatment, GSSG-R activity, MDA concentration and
      total sulphydryl groups--SH further lowered significantly. Although the SOD
      activity in CSF was higher in the second examination, it remained significantly
      lower comparing to the control group. We showed that the GSH-Px and GSSG-R
      activity in CSF after the acute stage of the TBE remained significantly lower
      than in the control group. Our examinations prove that during the TBE an
      increased generation of oxygen-derived free radicals occurs what shows decreased
      activity of the antioxidant parameters (SOD, GSH-Px, GSSG-R) and decreased
      concentration of total sulphydryl groups--SH in CSF. Our results suggest that
      during TBE, molecular structures injury of enzymes and antioxidative reactive
      cofactors may occur.

PMID- 12418141
TI  - [Axonal degeneration in the pathogenesis of multiple sclerosis].
AB  - Axonal degeneration plays an important role in the cumulation of disability in
      patients with multiple sclerosis (MS). Pathological studies have demonstrated
      axonal damage, particularly in area of acute inflammation and demyelination, and
      in chronic lesions. The mechanism of axonal loss is uncertain, but may involve
      axonal degeneration which is secondary to demyelination. Mediators of
      inflammation, including cytokines and proteolytic enzymes may be responsible for
      axonal damage, as may be nitric oxide. Moreover, axonal destruction might be due
      to immune cells attack directed to axonal components. The method to evaluate the
      intensity of cerebral and spinal cord atrophy, both reflecting axonal damage, is
      still searched. It is thought that therapy affecting the axonal destruction would
      possibly reduce progression of disability in MS patients.

PMID- 12418142
TI  - [Detection of cerebral microemboli by transcranial doppler. Technical aspects].
AB  - The technical aspects of microemboli detection are summarised in this paper. The
      physical principles of the microembolus signals detection, their ultrasound
      characteristics, the possibility of identification of microembolus signals in
      Doppler spectral wave and advised equipment settings have been reviewed. Then the
      methods of automatic microemboli detection are described, problems concerned with
      identification of the nature of the microembolic material and an advised time of
      monitoring patients with various indications. Technical progress in microembolus
      signals detection, especially improved methods of their automatic both detection
      and recording make a good prognosis for full explanation of the clinical
      relevance of this phenomenon.

PMID- 12418143
TI  - [The role of platelet activating factor (PAF) in physiology and pathology of the
      central nervous system].
AB  - This review describes the role of platelet activating factor (PAF) in the central
      nervous system injury. Cerebral ischaemia, traumatic injury of central nervous
      system, metabolic, toxic and degenerative neuropathy, and also the increase in
      Ca2+ concentration in the cell, are strong stimulators of PAF synthesis and its
      release from cell membranes. Neurons, glial and microglial cells, monocyte cell
      populations, macrophages and endothelial cells of blood vessels are the targets
      of platelet activating factor. The release of PAF leads to ischaemia of nervous
      tissue, acute traumatic or nontraumatic injuries, degenerative and metabolic
      nervous system disorders in adults. The use of PAF receptor antagonists prevents
      partially cell injury in central nervous system and leukocyte adhesion to
      endothelial cells.

PMID- 12418145
TI  - [Lateral approach to an extramedullary, intrameningeal C1-C2 meningioma].
AB  - This article describes an innovative approach to the excision of extramedullary
      meningioma located in the vicinity of the cranio-cervical junction, a tumour very
      rarely encountered in clinical practice. The primary innovation consists in the
      use of the lateral approach, with the addition of partial resection of the
      lateral mass of Cl. The authors present the case of a patient with a meningioma
      located at the level of the dens of the epistropheus, on the anterior surface of
      the spinal cord. The lateral approach used in this case allowed for complete
      resection of the tumour with minimum operative risk, and the patient's recovery
      has been excellent.

PMID- 12418144
TI  - [Internal carotid artery wall dissection as a cause of stroke in 19 year old
      patient. Case report].
AB  - The authors report a case of stroke in a young adult patient caused by
      intracranial internal carotid artery dissection--result of rapid neck movement.
      The patient developed hemiparesis, but all neurologic symptoms completely
      regressed after rehabilitation and now (18 months) after stroke there are no
      neurological symptoms.

PMID- 12418146
TI  - [Percutaneous transluminal angioplasty of extracranial vertebral artery stenosis-
      a case report].
AB  - Due to improvement in intravascular therapeutic procedures significant stenoses
      of vertebral and basilar arteries can presently be treated by means of
      percutaneous transluminal angioplasty (PTA). The reported case was a 34-year-old
      man with symptomatic stenosis of the distal left vertebral artery and hypoplastic
      right vertebral artery. The patient underwent PTA and the lesion was sufficiently
      dilated. No complications occurred during or after the procedure. After a year
      duplex Doppler follow-up examination showed normal blood flow and patency of both
      vertebral arteries. PTA may prove to be a useful therapeutic option in patients
      with symptoms of vertebro-basilar insufficiency.

PMID- 12418147
TI  - [Report from the International Interdisciplinary Course "Cranial Basis
      Navigation: Tumors, Injuries, Malformations, Reconstruction." September 27-29,
      2001, Freiburg, Germany].

PMID- 12418148
TI  - "A real tone": professionalizing nursing in nineteenth-century London.

PMID- 12418149
TI  - Midwifery and the construction of an image in nineteenth-century Brazil.

PMID- 12418150
TI  - Science and ritual: the hospital as medical and sacred space, 1865-1920.

PMID- 12418151
TI  - Nuns and GUNS: Holy Wars at Georgetown, 1903-1947.

PMID- 12418152
TI  - "Trained brains are better than trained muscles": scientific management and
      Canadian nurses, 1910-1939.

PMID- 12418153
TI  - From weakling to fighter: changing the image of premature infants.

PMID- 12418154
TI  - The nadir of nursing: nurse-perpetrators of the Ravensbruck concentration camp.

PMID- 12418155
TI  - Mennonite nurses in World War II: maintaining the thread of pacifism in nursing.

PMID- 12418156
TI  - Sparks to wildfires: the emergence and impact of nurse practitioner education at
      Virginia Commonwealth University 1974-1991.

PMID- 12418157
TI  - Developing a sustainable energy strategy for a water utility. Part I: A review of
      the UK legislative framework.
AB  - Increasing political effort to improve water quality across the UK and Europe has
      led to water and sewerage companies investing heavily in high-tech wastewater
      treatment plants capable of producing high quality effluents. Consequently,
      amounts of bought-in electricity used for wastewater treatment has and will
      continue to increase significantly over coming years, while greater provision of
      enhanced sewage treatment also produces greater volumes of sewage sludge
      requiring treatment and disposal. Over the same period, tougher controls on the
      quality of biosolids applied to agricultural land have also been introduced,
      while there has been an international attempt to reduce the use of fossil-fuel
      derived power sources because of concerns over global warming. The latter has
      brought about the introduction of financial instruments, such as the Climate
      Change Levy, to curb energy use, promote energy efficiency and encourage the
      development of renewable energy technologies. These factors are set to drive-up
      the costs of providing adequate sewage treatment services, while at the same
      time, a tough regulatory line taken to control profits on regional monopolies
      held by the UK water companies will significantly reduce their revenues over the
      period 2000-05. The result is that, financially, UK water and sewerage companies
      face their most challenging period since privatisation in 1989. This paper
      briefly outlines the current regulations relating to water quality and energy use
      that will affect water company operations over coming years.

PMID- 12418158
TI  - Developing a sustainable energy strategy for a water utility. Part II: A review
      of potential technologies and approaches.
AB  - Environmental legislation is increasing the amounts of bought-in electricity
      required for sewage treatment, and generating larger volumes of sewage sludge to
      be treated and disposed of. Concurrently, concerns over global warming and food
      safety from sewage sludge recycling on agricultural land is augmenting the costs
      of conventional sewage and sludge treatment technologies and practices. This
      paper reviews some emerging technologies and practices that may assist in
      mitigating these problems in the future. In addition, a number of potential
      renewable energy technologies available to water companies are reviewed. Results
      suggest that through the take-up of new technologies, current and future water
      quality standards could be delivered in a more sustainable way. However, this
      series of papers also highlights that institutional and political conflicts may
      have inadvertently failed to recognise the wider effects of improving water
      quality and lessened the financial support necessary for their widespread take
      up. It is also suggested that through the use of a Strategic Environmental
      Assessment (SEA) approach, stakeholders could gain a better understanding of the
      broader environmental effects of achieving certain water quality standards and
      develop policy and long-term investment strategies accordingly. However, to
      fulfill the information requirements of an SEA, an appropriate appraisal tool
      that considers many of these factors in unison is required, and a possible
      technique is suggested.

PMID- 12418159
TI  - Assessing state-wide biodiversity in the Florida Gap analysis project.
AB  - The Florida Gap (Fl-Gap) project provides an assessment of the degree to which
      native animal species and natural communities are or are not represented in
      existing conservation lands. Those species and communities not adequately
      represented in areas being managed for native species constitute 'gaps' in the
      existing network of conservation lands. The United States Geological Survey Gap
      Analysis Program is a national effort and so, eventually, all 50 states will have
      completed it. The objective of Fl-Gap was to provide broad geographic information
      on the status of terrestrial vertebrates, butterflies, skippers and ants and
      their respective habitats to address the loss of biological diversity. To model
      the distributions and potential habitat of all terrestrial species of mammals,
      breeding birds, reptiles, amphibians, butterflies, skippers and ants in Florida,
      natural land cover was mapped to the level of dominant or co-dominant plant
      species. Land cover was classified from Landsat Thematic Mapper (TM) satellite
      imagery and auxiliary data such as the national wetlands inventory (NWI), soils
      maps, aerial imagery, existing land use/land cover maps, and on-the-ground
      surveys. Wildlife distribution models were produced by identifying suitable
      habitat for each species within that species' range. Mammalian models also
      assessed a minimum critical area required for sustainability of the species'
      population. Wildlife species richness was summarized against land stewardship
      ranked by an area's mandates for conservation protection.

PMID- 12418161
TI  - Estimating recreational trout fishing damages in Montana's Clark Fork River
      basin: summary of a natural resource damage assessment.
AB  - This paper summarizes a natural resource damage assessment for the State of
      Montana. Mining wastes have caused significant reductions in trout stocks in a
      145-mile stretch of Montana's Silver Bow Creek and Clark Fork River. To estimate
      economic damages from decreases in catch rates, we develop and estimate an
      individual-based utility-theoretic model of where and how often an angler will
      fish as a function of travel costs, catch rates, and other influential
      characteristics of the site and individuals. The model includes resident and
      nonresident anglers who currently fish in Montana, and allows them to have
      different preferences. Demand parameters and expected catch rates are
      simultaneously estimated. The value of time is endogenously estimated as a
      proportion of the wage rate. Catch rates are linked to trout stocks through a
      stock-catch function. Collection of the angler data involved a three-step
      process: anglers were intercepted at 26 study sites, a subsample of anglers was
      selected to reflect the population trip-taking proportions to the study sites,
      and these anglers received follow-up surveys through the fishing season. Avidity
      weights are used to correct for the higher level of avidity inherent in intercept
      samples.

PMID- 12418160
TI  - Cost effective policies for alternative distributions of stochastic water
      pollution.
AB  - This study investigates the role for cost effective coastal water management with
      regard to different assumptions of probability distributions (normal and
      lognormal) of pollutant transports to coastal waters. The analytical results
      indicate a difference in costs for a given probability of achieving a certain
      pollutant load target whether a normal or lognormal distribution is assumed. For
      low standard deviations and confidence intervals, the normal distribution implies
      a lower cost while the opposite is true for relatively high standard deviations
      and confidence intervals. The associated cost effective charges and permit prices
      are higher for lognormal distributions than for normal distributions at
      relatively high confidence intervals and probabilities of achieving the target.
      An application to Himmerfjarden--an estuary south of Stockholm, Sweden--shows
      that the minimum costs of achieving a 50 per cent reduction in nitrogen load to
      the coast varies more for a lognormal than normal probability distribution. At
      high coefficient of variation and chosen probability of achieving the target, the
      minimum cost under a lognormal assumption can be three times as high as for a
      normal distribution.

PMID- 12418162
TI  - Analysis of changes in a shelterbelt network landscape in central Jutland,
      Denmark.
AB  - This paper investigates the changes in a shelterbelt network between 1950 and
      1997 in a study area in central Jutland, Denmark. The analysis consists of two
      parts. Firstly, the changes in key parameters which are of landscape ecological
      importance (shelterbelt density, connectivity, node type and landscape grain
      size) are examined. The results of this analysis show that shelterbelt density
      varied considerably during the period due to changes in biophysical and
      socioeconomic factors. A GIS analysis shows that landscape grain size decreased
      in 45 percent of the area. A major change of shelterbelt type occurred in the
      area with landscape ecological and visual scenery implications. It appears that
      public-subsidised shelterbelt planting programmes were the most important factors
      influencing changes in the shelterbelt network in the study area while
      differences in soil type were less important. Secondly, data from a questionnaire
      survey were used to examine the driving forces behind shelterbelt activities over
      a 10 year period. Hobby farmers were the most active farmer group in shelterbelt
      planting and agronomic reasons were the most important motives for shelterbelt
      planting in the study area during this period. Furthermore, it appeared that
      microclimate effects and aesthetical considerations have become important reasons
      for shelterbelt planting.

PMID- 12418163
TI  - Heavy equipment maintenance wastes and environmental management in the mining
      industry.
AB  - Maintenance wastes, if not managed properly, represent significant environmental
      issues for mining operations. Petroleum hydrocarbon liquid wastes were studied at
      an Australian site and a review of the literature and technology vendors was
      carried out to identify oil/water separation technologies. Treatment technologies
      and practices for managing oily wastewater, used across the broader mining
      industry in the Asia-Pacific region, were also identified. Key findings from the
      study were: (1) primary treatment is required to remove grease oil contamination
      and to protect secondary oily wastewater treatment systems from being overloaded;
      (2) selection of an effective secondary treatment system is dependent on influent
      oil droplet size and concentration, suspended solids concentration, flow rates
      (and their variability), environmental conditions, maintenance schedules and
      effectiveness, treatment targets and costs; and (3) oily wastewater treatment
      systems, based on mechanical separation, are favoured over those that are
      chemically based, as they simplify operational requirements. Source reduction,
      through housekeeping, equipment and reagent modifications, and segregation and/or
      consolidation of hydrocarbon waste streams, minimizes treatment costs, safety and
      environmental impact.

PMID- 12418164
TI  - Management practices that concentrate visitor activities: camping impact
      management at Isle Royale National Park, USA.
AB  - This study assessed campsite conditions and the effectiveness of campsite impact
      management strategies at Isle Royale National Park, USA. Protocols for assessing
      indicators of vegetation and soil conditions were developed and applied to 156
      campsites and 88 shelters within 36 backcountry campgrounds. The average site was
      68 m2 and 83% of sites lost vegetation over areas less than 47 m2. We believe
      that management actions implemented to spatially concentrate camping activities
      and reduce camping disturbance have been highly successful. Comparisons of
      disturbed area/overnight stay among other protected areas reinforces this
      assertion. These reductions in area of camping disturbance are attributed to a
      designated site camping policy, limitation on site numbers, construction of sites
      in sloping terrain, use of facilities, and an ongoing program of campsite
      maintenance. Such actions are most appropriate in higher use backcountry and
      wilderness settings.

PMID- 12418165
TI  - ABA urges equal access to courts for individuals with disabilities.

PMID- 12418166
TI  - I tell you, some days I could grab a pick and shovel and go back to digging
      ditches!

PMID- 12418167
TI  - Where the prairie meets the pine. The Minnesota Dental Association's Northwestern
      District.

PMID- 12418168
TI  - Well made. Interview.

PMID- 12418169
TI  - Walking humbly. Minnesota's DMORT team members remember 9-11.

PMID- 12418170
TI  - All for one, or one of a few?

PMID- 12418171
TI  - It's only money: but be careful out there.

PMID- 12418172
TI  - Changes in the dental workforce.

PMID- 12418173
TI  - The light at the end of the tunnel may be an opening door. Interview by Keith
      Erickson.

PMID- 12418174
TI  - Galactose oxidase.
AB  - The free radical-coupled copper catalytic motif has emerged as the unifying
      feature of a new family of enzymes, the radical copper oxidases. Their highly
      evolved active sites include a novel amino acid modification, the Tyr-Cys dimer,
      that forms spontaneously through self-processing of the protein during its
      maturation. The active site is remarkable in the extent to which metal ligands
      participate in the catalytic process. Rather than simply coordinating the metal
      ion, the ligands perform essential redox and proton-transfer functions in the
      chemistry of the active site, directed by their interactions with the copper
      center in the protein. The wide phylogenetic distribution and range of functions
      represented within the family hint of a fundamental role for these enzymes in the
      biology of oxygen. The roles for these enzymes are further expanding through a
      variety of biotechnological applications.

PMID- 12418175
TI  - Copper metalloregulation of gene expression.

PMID- 12418176
TI  - Bacterial copper transport.

PMID- 12418177
TI  - Understanding the mechanism and function of copper P-type ATPases.

PMID- 12418178
TI  - Copper chaperones.

PMID- 12418179
TI  - FET3P, ceruloplasmin, and the role of copper in iron metabolism.

PMID- 12418180
TI  - Blue copper-binding domains.

PMID- 12418181
TI  - Cytochrome c oxidase.

PMID- 12418182
TI  - Nuclear magnetic resonance spectroscopy studies on copper proteins.

PMID- 12418183
TI  - Comparison of current equipment.

PMID- 12418185
TI  - Going in vivo with laser microdissection.

PMID- 12418184
TI  - Laser capture microdissection and its applications in genomics and proteomics.

PMID- 12418186
TI  - Use of laser capture microdissection to selectively obtain distinct populations
      of cells for proteomic analysis.

PMID- 12418187
TI  - Optimized tissue processing and staining for laser capture microdissection and
      nucleic acid retrieval.

PMID- 12418188
TI  - Fluorescence in situ hybridization of LCM-isolated nuclei from paraffin sections.

PMID- 12418189
TI  - Immunoblotting of single cell types isolated from frozen sections by laser
      microdissection.

PMID- 12418190
TI  - Noncontact laser catapulting: a basic procedure for functional genomics and
      proteomics.

PMID- 12418191
TI  - Internal standards for laser microdissection.

PMID- 12418192
TI  - Methacarn: a fixation tool for multipurpose genetic analysis from paraffin
      embedded tissues.

PMID- 12418193
TI  - Use of laser capture microdissection for clonal analysis.

PMID- 12418194
TI  - Laser capture microdissection in carcinoma analysis.

PMID- 12418195
TI  - Laser capture microdissection to assess development.

PMID- 12418196
TI  - Application of laser capture microdissection to proteomics.

PMID- 12418197
TI  - Laser capture microdissection of mouse intestine: characterizing mRNA and protein
      expression, and profiling intermediary metabolism in specified cell populations.

PMID- 12418198
TI  - Laser capture microdissection in pathology.

PMID- 12418199
TI  - Use of laser capture microscopy in the analysis of mouse models of human
      diseases.

PMID- 12418200
TI  - Use of laser microdissection in complex tissue.
AB  - Concomitant with the rapid development in biomedical knowledge, including the
      methods of molecular biology and proteomics, and the manufacture of ever more
      precise optical instruments, powerful lasers, and sophisticated microcomputing
      hardware and software, laser microdissection systems have emerged which are now
      entering the field of routine research. Today, several devices are commercially
      available, congresses devoted to the latest advances in laser microdissection are
      now held on regular occasions, and the number of publications based on the use of
      these techniques has risen to over 250. With laser microdissection, histological
      treatment, such as chemical or immunological fixation and staining, can readily
      be combined with methods suitable for molecular biology or proteomics. As the
      optical, technical, and methodological resolution of polymerase chain reaction
      (PCR) and microdissection increases, genetic and phenotypic studies of biological
      material are possible even at the level of single cells and subcellular elements.
      Moreover, questions such as the paracrine interaction of cells within complex
      tissues, the development of cancer, and the role of single cells in tissue
      remodeling or development on the microscopic and molecular level can now be
      addressed precisely at the molecular level. This chapter reviewed the development
      of laser microdissection platforms, its potential impact on the future of
      research, and how, in particular, these technologies can be successfully
      integrated into modern research and routine histopathological studies of complex
      tissue.

PMID- 12418201
TI  - Assessment of clonal relationships in malignant lymphomas.
AB  - DNA sequencing of the antigen receptor genes remains the gold standard for the
      establishment of clonal relationships between samples. However, a variety of
      strategies may be employed as surrogates for the determination of the actual
      sequence of the clonally rearranged antigen receptor genes. The methods described
      in this chapter provide a framework for the rapid determination of clonal
      relationships between (microdissected) lymphoid populations. All of the methods
      described are PCR-based because of its versatility and ability to utilize very
      small amounts of DNA. For illustration purposes, the descriptions have been
      confined to B-cell populations. Although not described here, Ig kappa or Ig
      lambda PCR may also be utilized for determination of B-cell clonality and clonal
      relationships in the same manner. Similarly, the principles utilized may be
      extended to T-cell populations and T-cell receptor chain genes. Regardless of the
      methodology or targets involved, it is strongly recommended that all assays on
      microdissected material be run on parallel replicates of each sample to ensure
      reproducibility of results. The information about clonal relationships obtained
      by LCM has more than an academic significance and has utility in routine
      diagnostics for the establishment of minimal residual disease and the
      determination of microscopic disease recurrence vs the development of a secondary
      malignancy.

PMID- 12418202
TI  - Comparison of normal and tumor cells by laser capture microdissection.

PMID- 12418204
TI  - Analysis of gene expression.

PMID- 12418203
TI  - Analysis of folliculostellate cells by laser capture microdissection and reverse
      transcription-polymerase chain reaction (LCM-RT/PCR).

PMID- 12418205
TI  - Analysis of specific gene expression.

PMID- 12418206
TI  - Gene discovery with laser capture microscopy.

PMID- 12418207
TI  - DNA fingerprinting from cells captured by laser microdissection.

PMID- 12418208
TI  - Single cell PCR in laser capture microscopy.

PMID- 12418209
TI  - Assessment of genetic heterogeneity in tumors using laser capture
      microdissection.

PMID- 12418210
TI  - Gene mutations: analysis in proliferative prostatic diseases using laser capture
      microdissection.

PMID- 12418211
TI  - Use of laser capture microdissection-generated targets for hybridization of high
      density oligonucleotide arrays.

PMID- 12418212
TI  - Single cell gene mutation analysis using laser-assisted microdissection of tissue
      sections.

PMID- 12418213
TI  - Methylation in gene promoters: assessment after laser capture microdissection.

PMID- 12418214
TI  - Covalent enzyme-substrate compounds: detection and catalytic competence.

PMID- 12418215
TI  - Rapid mix-quench MALDI-TOF mass spectrometry for analysis of enzymatic systems.

PMID- 12418216
TI  - Pre-steady-state kinetics of enzymatic reactions studied by electrospray mass
      spectrometry with on-line rapid-mixing techniques.

PMID- 12418217
TI  - Trapping of alpha-glycosidase intermediates.

PMID- 12418218
TI  - Trapping covalent intermediates on beta-glycosidases.
AB  - The mechanism-based inactivation and subsequent identification of the
      nucleophilic residue using mass spectrometry have been successfully applied and
      used to identify the active-site nucleophile in numerous beta-glycosidases, as
      illustrated using C. fimi exoglycanase. Evidence for a covalent glycosyl-enzyme
      intermediate has come from X-ray crystallographic analysis of trapped complexes,
      the first being that of the trapped fluoroglycosyl-enzyme intermediate of Cex.
      The crystal structure of the trapped fluorocellobiosyl-enzyme complex for Cex has
      provided useful insights into catalysis and the roles of specific residues at the
      active site. In addition, information about the conformation of the natural sugar
      in the covalently bound state and the interactions at the active site was
      obtained using a mutant form of Cex.

PMID- 12418219
TI  - 2-hydroxy-6-keto-nona-2,4-diene 1,9-dioic acid 5,6-hydrolase: evidence from 18O
      isotope exchange for gem-diol intermediate.

PMID- 12418220
TI  - Nucleoside-diphosphate kinase: structural and kinetic analysis of reaction
      pathway and phosphohistidine intermediate.

PMID- 12418221
TI  - Galactose-1-phosphate uridylyltransferase: kinetics of formation and reaction of
      uridylyl-enzyme intermediate in wild-type and specifically mutated
      uridylyltransferases.

PMID- 12418222
TI  - Kinetic evidence for covalent phosphoryl-enzyme intermediate in
      phosphotransferase activity of human red cell pyrimidine nucleotidases.

PMID- 12418223
TI  - Characterization of alpha(2-->6)-sialyltransferase reaction intermediates: use of
      alternative substrates to unmask kinetic isotope effects.

PMID- 12418224
TI  - Use of sodium borohydride to detect acyl-phosphate linkages in enzyme reactions.

PMID- 12418225
TI  - Evidence for phosphotransferases phosphorylated on aspartate residue in N
      terminal DXDX(T/V) motif.

PMID- 12418226
TI  - MurC and MurD synthetases of peptidoglycan biosynthesis: borohydride trapping of
      acyl-phosphate intermediates.

PMID- 12418227
TI  - Transaldolase B: trapping of Schiff base intermediate between dihydroxyacetone
      and epsilon-amino group of active-site lysine residue by borohydride reduction.

PMID- 12418228
TI  - T4 endonuclease V: use of NMR and borohydride trapping to provide evidence for
      covalent enzyme-substrate imine intermediate.

PMID- 12418229
TI  - Detection of covalent tetrahedral adducts by differential isotope shift 13C NMR:
      acetyl-enzyme reaction intermediate formed by 3-hydroxy-3-methylglutaryl-CoA
      synthase.

PMID- 12418231
TI  - Protein tyrosine phosphatases: X-ray crystallographic observation of cysteinyl
      phosphate reaction intermediate.

PMID- 12418230
TI  - Detection of intermediates in reactions catalyzed by PLP-dependent enzymes: O
      acetylserine sulfhydrylase and serine-glyoxalate aminotransferase.

PMID- 12418232
TI  - GTP:GTP guanylyltransferase: trapping procedures for detecting and characterizing
      chemical nature of enzyme-nucleotide phosphoramidate reaction intermediate.

PMID- 12418233
TI  - gamma-Glutamyl thioester intermediate in glutaminase reaction catalyzed by
      Escherichia coli asparagine synthetase B.

PMID- 12418234
TI  - gamma-Glutamyltranspeptidase and gamma-glutamyl peptide ligases:
      fluorophosphonate and phosphonodifluoromethyl ketone analogs as probes of
      tetrahedral transition state and gamma-glutamyl-phosphate intermediate.

PMID- 12418235
TI  - Stoichiometric redox titrations of complex metalloenzymes.

PMID- 12418236
TI  - Urate oxidase: single-turnover stopped-flow techniques for detecting two discrete
      enzyme-bound intermediates.

PMID- 12418237
TI  - Nitric oxide synthase: use of stopped-flow spectroscopy and rapid-quench methods
      in single-turnover conditions to examine formation and reactions of heme-O2
      intermediate in early catalysis.

PMID- 12418238
TI  - Myeloperoxidase: kinetic evidence for formation of enzyme-bound chlorinating
      intermediate.

PMID- 12418239
TI  - Time-resolved resonance Raman spectroscopy of intermediates in cytochrome
      oxidase.

PMID- 12418240
TI  - Porphobilinogen deaminase: accumulation and detection of tetrapyrrole
      intermediates using enzyme immobilization.

PMID- 12418241
TI  - Adenosylcobalamin-dependent glutamate mutase: pre-steady-state kinetic methods
      for investigating reaction mechanism.

PMID- 12418242
TI  - Ribonucleotide reductase: kinetic methods for demonstrating radical transfer
      pathway in protein R2 of mouse enzyme in generation of tyrosyl free radical.

PMID- 12418243
TI  - Galactose oxidase: probing radical mechanism with ultrafast radical probe.

PMID- 12418244
TI  - Kinetic characterization of transient free radical intermediates in reaction of
      lysine 2,3-aminomutase by EPR lineshape analysis.

PMID- 12418246
TI  - A survey of covalent, ionic, and radical intermediates in enzyme-catalyzed
      reactions.

PMID- 12418245
TI  - Demonstration of peroxodiferric intermediate in M-ferritin ferroxidase reaction
      using rapid freeze-quench Mossbauer, resonance Raman, and XAS spectroscopies.

PMID- 12418247
TI  - [Characteristics of vegetation, soil, and their coupling of degraded grasslands].
AB  - This paper presented the characteristics of the vegetation, soil, and their
      coupling in the gradient of grazing pressure of the degraded alpine grassland in
      Sunan county and of the typical arid grassland in Huanxian county, Gansu
      province. The abundance index of species, Simpson index, Shannon-Wiener index,
      Cody index, nutrient functional diversity index and life type diversity index
      increased, while the Bray-Curtis index and nitrogen fixation diversity index
      decreased with the reduced grazing intensity in both types of degraded grassland.
      With reduced grazing pressure, the contents of total nitrogen, available nitrogen
      and organic matter in both grasslands and the content of available phosphorus in
      arid grassland at 0-40 cm soil depth were increased, and that of total phosphorus
      in alpine grassland was decreased, while phosphorus concentration in arid
      grassland showed no regular pattern of change. The total and available nitrogen,
      available phosphorus and the ratio of available phosphorus to total phosphorus
      and of organic carbon to nitrogen were all higher in alpine grassland than in
      arid grassland. The grey correlativity of vertical distribution pattern between
      soil elements and living root biomass was positively related to grazing pressure,
      while the coupling intensity of soil-herbage subsystem was increased with
      decreased grazing pressure. There existed a significant correlation between poor
      soil elements and abundance of poisonous and poor-nutritional plants in both
      degraded grasslands. The degradation process of grassland resulted not only from
      the degeneration of vegetation and soil subsystems, but also from the
      disappearance of coupling between both subsystems and the development of their
      discordance. The ecological process could be quantified by coupling intensity and
      discordance intensity. It is concluded that the studied arid grassland was
      degraded more seriously than alpine grassland.

PMID- 12418248
TI  - [Eco-restoration of abandoned farmland in the Loess Plateau].
AB  - The vegetation on abandoned farmland was succeeded from Agriophyllum arenarium
      community to Lespedeza davurica community under cutting conditions. More plant
      species was recruited at the initial stage of restoration. The new plant species
      established earlier were annual Agriophyllum arenarium and perennial Pennisetum
      flaccidum which could be the dominant species or sub-dominant species. The
      perennial Artemisia capillaris established in early-middle stage could be the sub
      dominant species, and leguminous plants appeared in late-middle stage could only
      be the associated species. The aboveground biomass of annual species reduced by
      8.8% annually, while the perennial species increased with the similar rate. The
      aboveground biomass of leguminous species increased continuously. As the
      restoration proceeded, more underground biomass was distributed in upper soil
      layer. In 1-7 years of restoration of abandoned land, the clay and silt in 0-30
      cm soil profile reduced, while grit increased, but the inverse trend occurred
      after 7 years. The water content in 0-100 cm soil profile increased continuously,
      especially during middle stage. Total and available nitrogen in 0-100 cm soil
      profile reduced in early stage, but increased in late stage. Total and available
      phosphorus and organic carbon in soil profile reduced continuously under cutting
      conditions. For the restoration of abandoned farmland to the current stable
      community, it would take 8-9 years for dominant population, 9-11 years for
      vegetative community and 11-12 years for soil system.

PMID- 12418249
TI  - [Regrowth of different plant populations in mixed pasture].
AB  - The number of tillers and leaf regrowth of perennial ryegrass (Lolium perenne)
      and that of branches and stolon growth of white clover (Trifolium repens) in
      mixed ryegrass/white clover pastures under different cutting frequency were
      monitored from 1998 to 2000, and the herbage yields and the proportion of each
      component in total yields were also determined. The results showed that cutting
      could stimulate perennial ryegrass leaf regrowth and white clover branching,
      maintain proper proportions of perennial ryegrass and white clover in the mixed
      pasture, and create the environments for the coexistence of the two species.
      Therefore, the total annual dry matter yields of the pasture was increased.
      However, cutting frequency had no significant effects on herbage yields and
      vegetative composition (P > 0.05). More leaf regrowth of perennial ryegrass was
      found in the plots cut in June than in August, whereas white clover exhibited an
      inverse trend. The herbage yield of perennial ryegrass depended on its leaf
      regrowth, while the dry matter accumulation of white clover relied on its stolon
      branching numbers. During the period of three year experiment, the proportion of
      perennial ryegrass and white clover in total herbage yields obtained from the
      plots under cutting was 50% and 15%, respectively, approximately 10% or 5% lower
      than its initial value, while CK was 39% and 6%, respectively.

PMID- 12418250
TI  - [Effect of soil compaction on Vicia faba of growth in the Loess Plateau].
AB  - The effect of soil compaction on the growth of Vicia faba was studied by pot
      experiment, field plot experiment, and farmers' field production during two
      consecutive years. The results showed that increasing soil bulk density at 0-7 cm
      depth significantly decreased the root and shoot dry weight per plant, increased
      plant mortality caused by Fusarium species, and decreased seed yields. Field
      experiments indicated that compared to the plants grown on the plots with soil
      bulk density of 1.55 and 1.64 g.cm-3, the root and shoot dry weight of plants
      grown on the plots with soil bulk density of 1.84 g.cm-3 decreased by 30.8% and
      27.9%, respectively, while the plant mortality rate increased by 21.0-48.7%, and
      seed yields decreased by 19.8%. The trials conducted on eight farmers' land
      illustrated that there existed significant negative correlations between soil
      bulk density in Spring and root and shoot dry weight of Vicia faba seedlings, and
      between soil bulk density in Autumn and seed yields. The causes of high soil
      compaction were discussed, and suggestions for improving soil quality were
      presented.

PMID- 12418251
TI  - [Regulation of fertilizer application on yield and root growth of spring wheat
      faba bean intercropping system].
AB  - The effects of N and P fertilizer application on the multiple population yield
      and root growth of spring wheat (Triticum aestivum)--spring faba bean(Vicia
      sativa)intercropping system were studied by two field experiments with 0, 150 and
      225 kgN.hm-2, three pot and pool experiments with 2 N applications (0, 100 mg
      N.kg-1 soil) and 3 P applications (0, 100 and 200 mg P.kg-1 soil). The results
      showed that this intercropping system had a significant advantage of yield and
      beneficial effects. Compared to Po supply, P fertilization increased the seed
      yield by 48.39% for intercropped spring wheat and 16.69% for intercropped faba
      bean in field experiment. Furthermore, the total seed yield of both crops was
      increased by 20.07% to 43.14% in pool culture, and the grain yield of
      intercropped faba bean was increased by 58.46% to 78.78%. In the intercropping
      system, the growth peak of root density of both crops was appeared alternately,
      the peak of wheat root growth being earlier than that of faba bean. The maximum
      root weight of intercropped wheat was in its early heading periods, whereas that
      of faba bean appeared at its maturity periods, which reduced the competition for
      water and nutrients between the crops, and resulted in yield increase. The
      weight, length and surface area of wheat roots in P supply were increased by
      54.33%, 48.88% and 47.00%, and in N supply, they were increased by 15.25%, 11.61%
      and 11.46%, respectively. About 57.61% of wheat root weight and 69.20% of faba
      bean root weight were distributed at 0-30 cm soil depths in the treatments of
      receiving P fertilizer at various rates, which indicated that P supply increased
      root weight and length of both crops in the intercropping system.

PMID- 12418252
TI  - [Effect of pesticides on field-controlling root rot of Vicia faba].
AB  - The effect of pesticides on field-controlling root rot of Vicia faba was studied
      in two consecutive years by seed treatment of fungicides and their combination.
      The results of the first year field experiments showed that among the 11
      treatments tested, triadimefon of 0.01 g a.i.kg-1 seeds was more effective than
      other fungicides applied singly or in combinations. The other test fungicides
      included thiophanate-methyl, thiram, oxadixyl and metalaxyl. Compared to the
      control, triadimefon treatment reduced the root rot index of 6-week-old seedlings
      by 51.5%, and plant accumulated percent mortality by 36%. Consequently, the
      treatment increased seed yield/plant by 21% and seed yield/ha by 97.6%. In the
      trials carried out in the following year, the plant percent mortality was reduced
      by 31.9% and seed yield increased by 19.6% under triadimefon seed treatment. It
      is demonstrated that seed treatment by triadimefon effectively controlled root
      rot, promoted plant growth, and increased seed yield of faba bean in the fields.

PMID- 12418253
TI  - [Variation in seed yield components among varieties of Poa pratensis].
AB  - Seed yield and its characteristics of 28 varieties of Poa pratensis in field
      plots at Lanzhou, China were evaluated in 2001. The results showed that the seed
      yields among the varieties were significantly different (P < 0.01) by LSD test.
      The highest yield was 643.4-650.2 kg.hm-2 obtained from varieties of Balin and
      Monoply, the lowest was 90.1 kg.hm-2 obtained from Elysee, and the other
      varieties were in the middle groups with the yields varied from 114.7 kg.hm-2 to
      435.1 kg.hm-2. Correlation analysis between seed yield and yielding
      characteristics indicated that the main factors affecting seed yield were the
      number of fertile tillers per plant (r = 0.785), the height of fertile tiller (r
      = 0.712), the length of inflorescence (r = 0.743), and the number of
      spikelets/fertile tiller (r = 0.786). Cluster analysis for seed production
      capacity based on seed yield and above-mentioned 4 main characteristics showed
      that the 28 varieties could be divided into 6 grades.

PMID- 12418254
TI  - [Response of seed germination of three xeromorphic shrubs to drought stress].
AB  - The seed germination, seedling growth and water absorption characteristic of
      Caragana korshinskii, Hedysarum scoparium, and Artemisia sphearocephala were
      investigated under different osmotic potentials (PEG 6000, -0.3(-) -2.7 MPa). The
      results showed that under drought stress, C. korshinskii had the highest
      germination rate, while A. sphearocephala had the lowest one. Under -0.3(-) -0.6
      MPa, the root length of 10-day-old A. sphearocephala seedling was significantly
      longer than that of H. scoparium and Caragana korshinskii(P < 0.05), and the
      length reached 7.9, 4.5 and 3.1 cm, respectively. There existed a significant
      positive correlation between seed germination rate and 72 h water absorption rate
      of the three shrub seeds(P < 0.01). The relationships among germination
      characteristics, root length, and survive percentage of seedlings were also
      discussed.

PMID- 12418255
TI  - [Response of alfalfa seed to stress storage conditions].
AB  - The seed germination rate, seed mortality, seedling length, and infection rate of
      alfalfa (Medicago sativa L. cv. 'Longdong') were measured at constant temperature
      20 degrees C every 60 days during one year storage period after inoculated or no
      inoculated by Fusarium avenaceum under room temperature (RT), 35 degrees C, and
      35 degrees C and +10% seed moisture content (SMC) conditions. Field emergence
      rates of seeds under above treatments were also observed, and seed-borne fungi
      were detected under the conditions mentioned above and controlled deterioration
      (CD) as well. The results showed that the percentage of isolated alfalfa seed
      borne fungi was increased from 10% under room temperature and 35 degrees C to 29%
      under 35 degrees C + 10% SMC. Disease resistance was declined, and seed mortality
      and seedling infection rate under 35 degrees C + 10% SMC were significantly
      higher than those under room temperature and 35 degrees C respectively (P <
      0.05). The seed germination rate and field emergence rate were also decreased
      significantly (P < 0.05). Seedling shoot and root length under 35 degrees C + 10%
      SMC were significantly less than those under RT and 35 degrees C respectively (P
      < 0.05). The percentages of both seed-borne fungi isolated and field emergence
      were decreased, and that of seedling infection was increased with storage period
      extending from 60 to 360 days. Compared to no inoculated control, the percentage
      of seed germination, seedling shoot and root length were decreased, and seed
      mortality and seedling infection rate were increased after inoculated by F.
      avenaceum.

PMID- 12418256
TI  - [Water distribution patterns in different degraded desert grasslands of Reaumuria
      soongorica].
AB  - Water distribution pattern and water use-efficiency in soil-plant-atmosphere
      system for light, medium, and heavy degraded Reaumuria soongorica grasslands were
      studied in Alashan region of Inner Mongolia. The total precipitation in 2001 was
      124.3 mm, of which 119.4 mm occured during experimental period. Soil water
      content (SWC) in 10-40 cm layer was greatly affected by the evapotranspiration.
      The SWC in 10-20 cm layer of medium degraded grassland paddock was significantly
      lower (P < 0.05), and the SWC in 20-40 cm layer of light degraded paddock was
      lower than that of other paddocks due to different transpiration rate and root
      distribution depth between the main co-existing plant species of R. soongorica
      and Cleistogenes soongorica in the paddocks. The annual average bare land
      evaporation and R. soongorica population transpiration were 30.6 mm and 11.9 mm,
      respectively. As the grassland further degraded, the bare land evaporation and
      transpiration through Peganum nigellastrum population, a degradation indicating
      plant species, increased, while the transpiration of R. soongorica decreased. In
      addition, the water use-efficiency of the grassland and dominant plant species
      markedly decreased with the increasing grassland degradation. Compared to the
      light degraded paddocks, for instance, the water use-efficiency of medium and
      heavy degraded paddocks were reduced by 14.6% and 46.1% for total biomass
      production, and by 37.8% and 73.8% for R. soongorica, respectively.

PMID- 12418257
TI  - [Dynamics of forage supplement and nutrition requirements of grazing sheep in
      alpine grasslands].
AB  - The dynamics of forage supply and nutrition requirements of sheep were monitored
      for a whole year under alpine grassland conditions in Sunan County, Gansu
      Province. The digestion and metabolism of grazed sheep were determined in
      different seasons. The results showed that the DE(9.76 MJ), CP(21.53%) and the
      ratio of crude protein to digestible energy (22.06 g.MJ-1) of forage were the
      highest in Spring, while the herbage dry matter yield and dry matter intake
      (60.51 +/- 3.42 g.W0.75kg-1.d-1) by grazed sheep were the lowest. Supplementary
      DM especially in energy should be provided. The ratio of crude protein to
      digestible energy was 17.62 g.MJ-1 in Summer, and was somewhat higher. The
      nitrogen utility of the forage would be improved, if energy feed was
      supplemented. Both the quality and quantity of forage produced in grasslands in
      Autumn could meet the sheep requirement. Whereas during Winter, neither forage
      yield nor nutritive value was sufficient for sheep, and the contents of the DE
      and CP of forage were the lowest in the year, which were 4.30 MJ and 4.63%,
      respectively. The nitrogen metabolism of sheep was negative. Therefore, DM,
      especially DE and CP, should be supplemented. To improve the conditions, it was
      necessary to develop seasonal animal husbandry, and combine the subsystems into
      coupling systems.

PMID- 12418258
TI  - [Change of moisture retention in sandy soil after planting mixed forest of
      Populus spp. and Robinia pseudoacacia].
AB  - The change of soil moisture retention after planting mixed forest of Populus spp.
      and Robinia pseudoacacia was studied by comparative method. The results showed
      that soil moisture retention, spatial distribution of soil pore, and soil water
      capacity were improved and increased in sandy soil after Populus spp. and Robinia
      pseudoacacia being planted, and the improvement in the mixed forest of Populus
      spp. and R. pseudoacacia was greater than that in the pure forest of Populus spp.
      or R. pseudoacacia. The basic reason of soil moisture retention being improved
      was the increment of soil organic matter, which improved soil pore condition.

PMID- 12418259
TI  - [Landscape pattern and productivity characteristics of the oasis landscape
      ecosystem in Linze, Gansu, China].
AB  - Oasis landscape ecosystem is composed of 10 landscape elements, i.e., residence
      land, cultivated land, grassland, forestland, water area, water system, road,
      rocky desert, sandy desert, and gravel desert. Among the elements, cultivated
      land formed by human being production covers the most of the area, is most
      connected, and hence, is the matrix of the oasis landscape ecosystem. Residence
      land, grassland, forestland, water area, rocky desert, sandy desert, and gravel
      desert are patches. Residence land and forestland generate from human being
      production, while rocky desert, gravel desert and sandy desert are the remnant
      with the human being disturbance. Water region and grassland are the
      environmental resources remnant after natural disturbance. Water system and road
      are corridors. Cultivated land dominated in plant production should be utilized
      with more productive layers through developing animal production other than
      expanding used-area to maintain the landscape heterogeneity and diversity of the
      oasis landscape ecosystem. For remnant and environmental resource patches, it
      should be profitable in preserving and stabilizing landscape heterogeneity and
      diversity, exploiting the functions of water and soil conservation, tourism,
      windbreak and sand fixation. For landscape elements remnant only, it should be
      fruitful in avoiding degeneration of the landscape pattern to explore their
      preceding plant production with moderate plant production.

PMID- 12418260
TI  - [Landscape ecological mechanism on system coupling of the meta-ecosystem
      consisted of mountain, desert and oasis in Hexi corridor, Gansu, China].
AB  - The fundament of system coupling is heterogeneity, and the basic prerequisite is
      that there are connective corridors in the same type between ecosystems. The
      landscape ecological mechanism of system coupling is the spatial difference of
      non-biotic environment and the heterogeneity caused by disturbances. The force or
      energy of system coupling is disturbances. From in the view of landscape ecology,
      system coupling is the merging process of different landscape elements between
      different landscape ecosystems followed by the process of character changing of
      landscape elements with scale changing. Based on the essence of disturbances,
      system coupling can be divided into two types as natural system coupling and
      artificial system coupling. Natural system coupling is the base of artificial
      system coupling, and hence, the enhance of eco-productivity of coupling system is
      based on the optimization of artificial system coupling.

PMID- 12418261
TI  - [Influence of saltwater irrigation on the yield and quality of Cynodon dactylon
      under desert conditions].
AB  - Responses of six varieties (Suwannee, Coast cross, Tifton44, Tifton68, Tifton78
      and Tifton85) of Cynodon dactylon to irrigation-water salinity were investigated
      in field by means of a double line source experimental design. The digestibility
      of the grass by goat was analyzed using the rumen gastric justice digestion
      method. The results showed that the six varieties grew well, and had a high yield
      of fresh grass when eletro-conductivity (Eci) < 10 ds.m-1. Particularly when Eci
      = 4.4 ds.m-1, the fresh grass yield of Coast cross, Suwannee, Tifton44, Tifton68,
      Tifton78 and Tifton85 was respectively increased by 142.1%, 61.1%, 136%, 121.1%,
      202.3% and 109.7%, in comparison with fresh water (Eci = 1.2) irrigation. Dry
      matter yield was also elevated with the increasing salinity of irrigated water.
      There was no obvious effect of salinity on crude protein, fiber and ash contents
      in the six varieties. Goats were fond of eating the hay irrigated by saline
      water, perhaps because of its higher digestibility. At least, the yield and
      quality of Cynodon dactylon were not effected by saltwater irrigation.

PMID- 12418262
TI  - [Temporal pattern of arthropod community on cultivated alfalfa grassland].
AB  - The variation of species and diversities of the arthropod community on cultivated
      alfalfa grassland was investigated and studied. Principal component analysis and
      optimal sorting method were used to study its temporal patterns. The results
      showed that the difference and regularity of species richness, and the diversity
      and evenness of the arthropod community at different time were obvious. The
      numbers of the species of insect pests and their natural enemies were the most in
      the last ten days of June, but the peak period of individual numbers of the
      natural enemies was later than that of insect pests. The main factors and
      temporal patterns of arthropod community in the course of seasons were obvious.
      Based on the results, the temporal patterns of arthropod community on cultivated
      alfalfa grassland could be divided into four stages: before the first ten days of
      May, the middle ten days of May to the first ten days of June, the middle ten
      days of June to the middle ten days of July, and after the middle ten days of
      July. Considering the climatic and phenological development, the characteristics
      of the pests and the natural enemies occurring in each stage were analyzed, and
      the corresponding management tactics were discussed.

PMID- 12418263
TI  - [Spatial pattern of Tetranychus urticae population in apple tree garden].
AB  - Spatial pattern of insect population is an important aspect of insect ecology. It
      reveals the spatial structure characteristics of populations, and provides a
      basis for relevant sampling techniques and data transformation. Tetranychus
      urticae Koch is a serious pest of apple tree. Its spatial pattern and time-series
      dynamics were analyzed by calculating four indices of aggregation, and parameters
      of Iwao model. The results showed that the spatial pattern of T. urticae in apple
      tree garden belonged to an aggregated distribution pattern. The aggregation
      intensity was the highest in upper and southern part of crown, and the lowest in
      its lower and inner part. The aggregation was due to the biological habits of T.
      urticae and environmental heterogeneity. No matter T. urticae was in the upper,
      middle, or lower crown of apple tree, its aggregation intensity was higher before
      first ten days of June, and then gradually decreased after the middle ten days of
      June.

PMID- 12418264
TI  - [Effect of seedling stage shading on cotton yield and its quality formation].
AB  - The effect of shading during symbiotic stage of inter-cropped cotton and wheat on
      cotton yield and its quality formation was examined by simulated shading at the
      seedling stage of cotton. The results showed that the effect of shading on the
      cotton boll formation depended upon the position of fruiting branch and fruiting
      bud. For the bolls at low(1-3 fruiting branches) and middle(4-6 fruiting
      branches) parts and the inside bolls(1-2 fruiting buds) on upper(7-9 fruiting
      branches) fruiting branch, shading favored boll formation, but for the outside
      bolls (> or = 3 fruiting buds), especially at the top fruiting branch position,
      shading was unfavorable to boll formation. The effect of shading on the weight of
      individual boll also depended upon the position of fruiting branch and fruiting
      bud, but shading did not affect the mean boll weight per plant. For seed cotton
      yield per plant, the inside boll yield of shaded low and middle fruiting branches
      was higher than the control, but that of the upper and top fruiting branches was
      just contrary, the yield of outside bolls of all branches was lower than the
      control. For the distribution of the inside and outside bolls, shaded cotton was
      1:0.36, versus 1:0.58 for the control. For the yield distribution, shaded cotton
      was 1:0.42, versus 1:0.72 for the control. The effect of shading on the cotton
      fiber and seed quality was mainly restricted on the bolls of top fruiting
      branches and the outside bolls of upper fruiting branches. The results also
      showed that different cotton varieties were different in their shade-tolerance,
      according to comprehensive analysis of the yield and quality formation, and the
      shade-tolerance of variety Zh9418 was stronger than that of Zh19 and CAZ.

PMID- 12418265
TI  - [Element contents of biofilm and suspended particulate in natural aquatic
      ecosystem].
AB  - The element contents of biofilms and suspended particulates in the natural
      aquatic ecosystem were studied, and the samples were collected in Kunming Lake of
      the Summer Palace in July and October 1999. The biofilm samples were observed
      through microscope and scanning electron microscope. Various inhabitants such as
      sessile bacteria, algae, and protozoa existed in the biofilms. The dry weights of
      biofilms increased with the longer growth period. The dry weight of biofilm at 1
      m depth of water reached to 5.19 mg.cm-2 after the growth time of 78 days. The
      element contents in biofilm, suspended particulate, and lake water were analyzed
      by ICP-AES, and the results indicated that the element contents in biofilms were
      higher than those in the particulates. There was not an evident trend in the
      element contents of biofilms at the different water depth in the same site and
      growth time. At three sampling sites, the contents of Ca, Mg, K, Na, Al, Fe, and
      S in the biofilm samples were similar between 1 m and 1.5 m depth of water, but
      the contents of Mn, Sr, Ti, P, La, Co, Cu, Pb, Li, Ni, B, Ce, V, Be, and Cr were
      different in the biofilm samples of 1 m and 1.5 m depth of water. The element
      contents of biofilms increased with the longer growth time.

PMID- 12418266
TI  - [Bio-geological temporal zonation and its agricultural significance].
AB  - Bio-geological temporal zonation can be defined as a subsistent spatial-temporal
      style that the organisms clip from a geographical zone to break through its
      limit, and extend their survival extent with the strategy of excluding the
      environmental period of time which is not suitable to live and intercepting it
      which is suitable. It is the consequence that organisms temporally adapt the heat
      distribution pattern caused by the rotation and revolution of the Earth. Bio
      geological temporal zonation relies on spatial zone, and the zonation spectrum
      changes in different spatial zones and has different basal heat zone. It appears
      as spiral loop based on its own spatial zone, and implies temporally seasonal
      change of the heat. Similarly, bio-geological temporal zonation relies on the
      distribution process of water and heat under spatial and temporal scale. The
      component, range and hierarchy of zonation spectrum change with spatial and
      temporal scale, and organisms adapt this kind of change with different ecological
      strategy depended on different ecological strategy. Human being can tune up bio
      geological temporal zonation only in small scale.

PMID- 12418267
TI  - [Research progress and trend on grassland agroecology].
AB  - The connotation, progress, research frontiers and developmental trend of
      grassland agroecology are discussed in this paper. The interface theory,
      structure and function, coupling and discordance, and health assessment of
      grassland agroecosystems were recognized as the four research frontiers of the
      discipline. There exist three primary interfaces in a grassland agroecosystem,
      i.e., vegetation-site, grassland-animal and production-management. Research into
      a series of the ecological processes that occurred at these interfaces is the key
      to revealing the features of the system behavior. There are four sections in a
      grassland agroecosystem, i.e., pre-plant, plant, animal and post-biotic sections.
      System coupling and discordance are the two important concepts to describe
      interactions among the production sections. System coupling among the sections
      can lead to system improvement by exerting the potential of system capacity.
      Health of an ecosystem is a reflection of its structure and function, and health
      assessment is a measurement of its orderliness and service value.

PMID- 12418268
TI  - [Research directions of agroecosystem health in the early 21st century].
AB  - Agroecosystem health refers to the state of an agroecosystem where it is free
      from 'distress syndrome' and to cope with stress, or capability to produce
      agricultural products in a sustainable way. At present, the research of
      agroecosystem health focuses on assessment methods, soil and water quality, human
      health, ecologically based pest management, integrated weed management,
      ecopathology, nematode communities, transgenic crops, agricultural input policy,
      landscape ecology and green food development. Firstly, the present state of
      agroecosystem health research was described; then a case study of agroecosystem
      health, biological indicators of soil health, was introduced; finally, the
      research directions of agroecosystem health were put forward. This paper could
      provide a basis for ensuring agricultural product security and increasing human
      health.

PMID- 12418269
TI  - [Development of APSIM (agricultural production systems simulator) and its
      application].
AB  - Soil-crop simulator model is an effective tool for providing decision on
      agricultural management. APSIM (Agricultural Production Systems Simulator) was
      developed to simulate the biophysical process in farming system, and particularly
      in the economic and ecological features of the systems under climatic risk. The
      current literatures revealed that APSIM could be applied in wide zone, including
      temperate continental, temperate maritime, sub-tropic and arid climate, and
      Mediterranean climates, with the soil type of clay, duplex soil, vertisol, silt
      sandy, silt loam and silt clay loam. More than 20 crops have been simulated well.
      APSIM is powerful on describing crop structure, crop sequence, yield prediction,
      and quality control as well as erosion estimation under different planting
      pattern.

PMID- 12418270
TI  - [Advance in researches on vegetation cover and management factor in the soil
      erosion prediction model].
AB  - Vegetation cover and land management are the main limiting factors of soil
      erosion, and quantitative evaluation on the effect of different vegetation on
      soil erosion is essential to land use and soil conservation planning. The
      vegetation cover and management factor (C) in the universal soil loss equation
      (USLE) is an index to evaluate this effect, which has been studied deeply and
      used widely. However, the C factor study is insufficient in China. In order to
      strengthen the research of C factor, this paper reviewed the developing progress
      of C factor, and compared the methods of estimating C value in different USLE
      versions. The relative studies in China were also summarized from the aspects of
      vegetation canopy coverage, soil surface cover, and root density. Three problems
      in C factor study were pointed out. The authors suggested that cropland C factor
      research should be furthered, and its methodology should be unified in China to
      represent reliable C values for soil loss prediction and conservation planning.

PMID- 12418271
TI  - [Molecular response of plant to drought stress].
AB  - Drought stress is a bottleneck factor for plant growth and development. Synthesis
      and accumulation of osmoprotectants, up-regulation of gene expression implicated
      in repair of desiccation injury, free radical-scavenging enzymes and late
      embryogenesis-abundant(LEA) protein could increase the drought tolerance of
      plant. There are at least for pathways of signal transduction in plant subjected
      to drought stress, two are abscisic acid(ABA)-dependent, and two are ABA
      independent. In the signal transduction of plants encountered drought stress, two
      component His protein kinase could act as an osmosensor, and Ca2+ and inositol
      triphosphate(IP3) could be the second messenger for dehydration signaling.
      Transgenic plant is an excellent system in evaluating function of encoded
      protein.

PMID- 12418272
TI  - [Review on water eco-environment in vegetation restoration in Loess Plateau].
AB  - Water is the crucial factor influencing vegetation restoration and eco
      environmental reconstruction in Loess Plateau region. In this paper, the previous
      studies on water eco-environment under vegetation construction were summarized
      from seven aspects, i.e., soil water resource, background of soil water, dynamics
      of soil water, dry soil layer, relationship between soil water and vegetarian
      productivity, classification of soil water position, and strategy for vegetation
      construction. Meanwhile, some problems in the relevant researches were pointed
      out and discussed.

PMID- 12418273
TI  - [Physiological indices of grazed grassland under health management].
AB  - Evaluation of the function and health of grazed grassland is an important aspect
      of grazing ecology. Based on analyzing the physiological response of grassland to
      grazing, a double-factor method of physiological threshold was developed.
      Physiological low limit (PLL), physiological ultimate limit (PUL), and duration
      ratio of regrowth to grazing stage (R/G ratio) were feasible to evaluate the
      sustainable management on the function and health of grazed grasslands. The
      reasonable threshold values of PLL, PUL and R/G ratio could play an important
      role on the complete recovery of the function and health of grassland after
      grazing, which was the goal of sustainable management of grassland ecosystems.

PMID- 12418274
TI  - [Application of fuzzy cluster in analyzing population dynamics of Chorthippus
      fallax].
AB  - The population dynamics includes quantity dynamics, space dynamics and temporal
      dynamics. They are interdependent and mutually influential. Fuzzy cluster
      analysis was carried out with the data of mean densities, indices of patchiness
      and occupied plot rates of Chorthippus fallax(Zubovsky) on Ganjia High Mountain
      Grassland in Xia-he County, Gansu Province. The results showed that the
      population dynamics of this grasshopper could be divided into four distinct
      periods, i.e., the initial stage of hatching and the last stage of adult, the
      peak stage of nymph, the initial stage of adult, and the peak stage of first
      nymph and the adult. The peak period of nymph was in the middle ten days to the
      last ten days of July. In this period, the eggs were completely hatched, the
      population was mainly composed of nymphs of 2 and 3 instars, and the population
      size was related to the numbers and harmful levels of this grasshopper in the
      same year. Therefore, this period was the key time for population prediction and
      chemical control.

PMID- 12418275
TI  - [Influence of soil humidity and vegetation coverage on wind erosion].
AB  - Wind erosion is becoming a constraining factor to agriculture and animal
      husbandry in the arid and semiarid area of Luanhe River. In this paper, wind
      erosion process was studied through simulation experiments. The results showed
      that soil humidity and vegetation coverage were the main factors affecting wind
      erosion. The wind erosion rate was decreased with increasing soil humidity and
      vegetation coverage, and hence, wind erosion process was reduced by modulating
      soil humidity and vegetation coverage in human activities.

PMID- 12418276
TI  - [Oral allergy syndrome (OAS)--diagnostic values of skin prick test].
AB  - The authors presented results of allergological investigation concerning 58
      patients with OAS and tree pollenosis versus 27 persons with isolated tree
      pollenosis. Commercial skin prick tests presented lower diagnostic usefulness, in
      comparison to test with fresh or boiled crude foods.

PMID- 12418277
TI  - [Risk factors for atopy in schoolchildren from Cracow].
AB  - The aim of the study was to assess atopy and its risk factors in school children
      from Cracow. A survey of atopy in the 223 children, aged 12-14 years, in relation
      to developmental, environmental and social factors, was conducted in the three
      districts of Cracow. Atopic sensitization (SPT > 3 mm) was more prevalent in
      children from highly polluted district of the Stare Miasto than in children
      living in Prokocim and Nowa Huta (34.7%-26.1%-22.1%). Good and very good
      socioeconomical status was an important risk factor for development of atopy.
      Prevalence of atopy was also related to place of residence, living conditions and
      diseases in early childhood.

PMID- 12418278
TI  - [Prevalence of allergic diseases in primary school children in Cracow and
      surroundings--risk factors].
AB  - Prevalence of allergic diseases has been increasing over recent decades,
      especially in developed countries. The aim of this study was to assess prevalence
      of bronchial asthma and allergic rhinitis in children of Krakow at school age,
      depending on home and school environment conditions. The study was carried out in
      two stages: questionnaire based on ISAAC questionnaire and skin prick tests in
      children with symptoms suggesting allergic disease were performed. Altogether 532
      children from 4 primary schools (2 in central and 2 in peripheral parts of the
      city) were included. Symptoms suggestive of allergic disease were reported by 304
      children (57.1%), including asthma in 145 (27.2%) and allergic rhinitis in 288
      children (54.1%). Asthma and allergic rhinitis was previously diagnosed in 19
      (4%) and 138 (26%) children respectively. In younger age groups more children
      reported symptoms suggestive of asthma. Pupils from schools in the center of
      Krakow exposed to high level of traffic significantly more frequently reported
      asthma and had diagnosed allergic rhinitis. Increased prevalence of allergic
      rhinitis symptoms was observed in children exposed to passive smoking. Skin prick
      tests were positive only in 29.7% of children qualified for them. The results of
      the study suggest that in pupils with allergic rhinitis in whom skin prick tests
      are weakly positive for inhaled allergens, environmental factors may play an
      important role in the development of clinical symptoms.

PMID- 12418279
TI  - [Immunoglobulin E and complement in patients with contact allergy to nickel
      suffering from atopic and contact eczema].
AB  - The aim of the study was estimation of the IgE value, circulating immunocomplexes
      and the activity of complement system in allergic contact as well as atopic
      dermatitis in patients with skin nickel hypersensitivity. The study was done in
      30 patients in the age range of 18-53 yrs suffering from allergic contact
      dermatitis (15 patients) and atopic dermatitis (15 patients) with positive skin
      patch test to nickel. The concentration of total IgE as well as specific IgE to
      mites, Phleum, Betula, Artemisia and the concentration of circulating complexes
      in the serum of patients were estimated. The activity of C1inh and CH50 was
      estimated in plasma of the patients. The results of the study indicated an
      increase of concentration of circulating immuno-complexes in 80% of the patients
      of both groups, an increase of total IgE in 50% of patients with atopic
      dermatitis and in 25% of the patients with contact dermatitis. There were no
      changes in the activity of C1inh and the value of CH50 in both groups of
      patients.

PMID- 12418280
TI  - [Complement system in patients with IgE related and non IgE related bronchial
      asthma].
AB  - The studies were performed in 32 patients in the age range of 17-58 years
      suffering from bronchial asthma in the exacerbation period of their illness. 16
      patients suffered from IgE related/atopic and 16 from IgE non IgE
      related/nonatopic bronchial asthma. The complement haemolytic activity (CH50) and
      the activity of C1 inhibitor (C1 INH) were measured in the plasma. In 60% of
      patients with IgE related asthma and in 45% of patients with non IgE related
      asthma we stated decrease of CH50. The activity of C1INH also was decreased in
      80% of patients with atopic asthma and in 40% of patients with nonatopic asthma.
      The observed changes were not related to aspirin tolerance as well as to IgE
      mediation of their illness. Control examinations of these parameters repeated
      during remission of asthma symptoms in 11 patients with low values during the
      exacerbation of the illness (in 5 patients with atopic and in 6 with non-atopic
      asthma) revealed an increase of their values; however without features of
      normalisation.

PMID- 12418281
TI  - [Social support and proper human relations in high school pupils in relation to
      psychosomatic disease prevention].
AB  - The examination concerned 313 girls and boys from the second and third class of
      the secondary schools in Krakow. The translated German version questionnaire
      "Woman Self Image and Social Ideal" was used in the examination; mainly its parts
      such as: 1. "The social support" which includes 22 questions. 2. "Human
      Relations" which includes 64 questions. The five step scale of feeling was
      applied. One of the five possibilities was chosen by the examined persons and
      analysed. Stepwise regression was performed. More than half of the examined
      pupils have a good friend, who is helpful any time and who has never lets them
      down. They are relaxed with him, may discuss important problems and can give him
      charge over their home in their absence. 5% of the examined pupils could not
      share psychological problems with any friends and 10% could not count on house or
      flat care. 10% of pupils often felt as outsiders among other young people, while
      1/3 did not experience such a feeling. The need of better understanding, care and
      support in the family and from close acquaintances was observed by 15%.
      Simultaneously only 14% claimed that relation in this matter were satisfactory.
      19% of examined persons wanted more safety and friendship. Only 14% had a feeling
      of full safety. Juveniles most often claimed, that it is not difficult for them
      to buy a gift for another person (71% vs 2%), or cherish happiness of other
      people (67% vs 0.3%), and to express sympathy to others (65% vs 2.8%). More than
      half of the respondents judge themselves as non-aggressive against others, that
      they do not place their own needs above other peoples' needs, and that they are
      not afraid of contact with others. The frequency of choosing opposite extreme did
      not exceed 5% of the respondents. With the majority of questions we found a
      number of answers regarding discussed problem, ex. accepting orders from
      superiors (never--28%, sometimes--28%, average--21%, often--12%, very often-
      11%). In analogical proportions we found answers regarding such facts as a being
      strong and steady person, without bothering of hurting somebody's feelings or
      taking care of their own goals when anyone else is in need. We showed very
      differentiated, individual approach of examined adolescents to matters regarding
      their relations with people important for shaping their attitude towards life. It
      was also shown, that most of the 16-17 year old adolescents from Krakow enjoy a
      satisfactory relationship with people important in their lives, on the other
      hand, it is distressing that almost 20% of the examined pupils do not get enough
      support, care, safety and understanding either from their peers, families or
      adults.

PMID- 12418282
TI  - [C1 inhibitor deficiency. Heredity and acquired forms. Symptoms, diagnostic and
      therapeutic problems].
AB  - C1 inhibitor deficiency can be hereditary (Type I and II) or acquired (Type I and
      II). Clinically it is manifested by recurrent attacks of angioedema which may
      involve skin, airways and digestive tract. The acquired form of C1 inhibitor
      deficiency is associated with lymphoproliferative or connective tissue disorders
      as well as with autoimmunization. Clinical symptoms are similar in all forms of
      C1 inhibitor deficiencies and they are connected with low serum level of C4 as
      well as with decreased activity of C1 inhibitor. In acquired angioedema
      additionally they are also decreased C1 and C1q and in type II C3 serum
      concentration is diminished. The drugs of choice are anabolics (danazol,
      stanazolol). Antifibrinolitic drugs are also used, especially in acquired forms
      of C1 inhibitor deficiency. The infusion of C1 inhibitor concentrate is used in
      acute emergency treatment.

PMID- 12418283
TI  - [Exercise-induced asthma and anaphylaxis].
AB  - The main discussed issues in the study are: epidemiology and the most important
      conceptions explaining pathomechanism of exercise-induced bronchospasm. Presented
      recommendations concern physical activities, prophylactic and pharmacological
      treatment in exercise-induced asthma. The study contains description of
      diagnostic exercise challenge tests principles and performance procedures.
      Problem of exercise-induced bronchial asthma related to practice sports is
      underlined. Reasons and symptoms of exercise-induced anaphylaxis are presented.

PMID- 12418284
TI  - [Inhalation challenges with agents in diagnosis of occupational asthma].
AB  - Inhalation challenges with agents causing occupational asthma are presented. We
      discuss their meaning among other diagnostic method, safety requirements,
      indications and contraindications. The study contains the description of most
      frequent delivery procedures as well as rules of assessment of bronchial response
      and result interpretation.

PMID- 12418285
TI  - [Immunomodulatory properties of ribosomal vaccine in the prevention of recurrent
      infections].
AB  - The therapeutic approach of immuno-prophylaxis by means of ribosomal
      immunotherapy in the prevention of recurrent ENT and airway infections was
      discussed. Immunomodulatory mode of action of ribosomal bacterial vaccines is
      presented.

PMID- 12418287
TI  - [Sleep related breathing disorders in allergology practice].
AB  - 1/3 of the contemporary population suffers from sleep disorders. Sleep related
      breathing disorders are very important from the clinical point of view, because
      they markedly contribute to high morbidity and mortality of this population.
      Pharyngeal and upper airway obstruction is the main cause of these disorders.
      Obstructive sleep apnoea (OSA) may be isolated or co-exist with different
      disorders of the respiratory or other systems. Prevalence of OSA is also reported
      in allergic diseases: allergic rhinitis, asthma and atopic dermatitis. The author
      presents and discusses 5 basis problems practically important from the point of
      view of the allergist, from the moment when his allergic patients complains of
      sleep disorders: 1. rough diagnosis of character of sleep and respiratory
      disorders; 2. their objective confirmation and severity classification; 3.
      etiology and differential analysis of causes; 4. patient education; 5. choice of
      individual therapeutic option.

PMID- 12418286
TI  - [The contribution of food and airborne allergens in the pathogenesis of atopic
      dermatitis].
AB  - Food hypersensitivity and airborne allergens may play a role in the pathogenesis
      of atopic dermatitis (AD). The aim of this study was to evaluate the kind of food
      and airborne allergens which may most often induce and intensify AD lesions and
      also to assess the variability and the kind of allergens leading to AD. The
      subjects of this study were 610 persons, aged 3 months-70 years. The clinical
      status of the patients was estimated by an atopic dermatitis symptom score scale
      (SCORAD). The laboratory examinations differentiated inflammatory processes from
      allergic reactions. The skin prick tests (SPT), serum total IgE and specific IgE
      antibody levels to chosen food products and standard airborne allergens with the
      immuno-enzymes method ELISA-DPC were performed. The elevated values of the total
      IgE were proved in 46.1% children from group 0-15 years and in 31.4% of
      adolescents and adult persons (above 15 year of age). On the basis of positive
      SPT and positive specific IgE values it was shown, that most frequent food
      allergens were: egg protein (13.0%), cow milk (9.5%), egg yolk (8.4%), wheat
      (3.6%) and chocolate (1.8%). The most often airborne allergens connected with AD
      were: grass (11.6%), moulds (10.2%), house dust mites (9.3%), pollen like hazel
      (8.0%) and weeds (6.7%), animal allergens coming from cats (7.2%) and dogs
      (6.1%). The food hypersensitivity was particularly manifested in children. It may
      be the predictor of potential future development of allergic disease as well as
      the indicator of the allergic march.

PMID- 12418288
TI  - [Air pollution--impact on the human respiratory system].
AB  - Authors present the problem of air-pollution in Central Europe at the turn of
      centuries. The main sources (natural & antropogenic), main types of pollutants
      (particularly SO2 and O3), WHO atmospheric air quality Guidelines, outdoor &
      indoor air pollution, episodic and chronic consequences and mechanisms with
      clinical effects of air pollution on the respiratory system (function, self
      defence) were shortly performed).

PMID- 12418289
TI  - [Immunologic methods in diagnosis of inflammatory bowel disease].
AB  - Chronic inflammatory bowel disease is included into autoimmune diseases, which is
      proved by presence of inflammatory lesions, circulating autoantibodies and the
      deposits of immune complexes in tissues. Coeliac disease (classic and atypical
      form), Crohn's Disease and ulcerative colitis are considered as chronic
      autoimmune bowel diseases. The auto-antibodies can be detected with indirect
      immunofluorescence, ELISA and immunoblotting methods. In coeliac disease the
      autoantibodies against endomysium (tissue transglutaminase) and antibodies
      against gliadin are found in patient's sera. The auto-antibody detecting is
      helpful in establishing diagnosis, controlling gluten-free diet effectiveness and
      during gluten challenge. In Crohn's disease and ulcerative colitis immunological
      laboratory tests are helpful to confirm the clinical diagnosis. The following
      auto-antibodies are tested: against cytoplasm of exocrinal pancreatic cells, and
      products of these cells, against the neutrophile cytoplasm and against goblet
      cells. The antibodies against Saccharomyces cerevisiae are also investigated. The
      clinical relevance of above autoantibodies is not clear, but it is suggested that
      their presence correlates with exacerbations and severe clinical outcome. In the
      present study the pictures of autoantibodies from fluorescent microscope were
      shown.

PMID- 12418290
TI  - [Common variable immunodeficiency concomitant with liver cirrhosis--case report].
AB  - The authors present a report of a seventeen year old girl with common variable
      immunodeficiency (CVID) and liver cirrhosis. A child of healthy, non
      consanguineous parents was diagnosed at the age of 13 years to have immune
      deficiency and an early stage of liver cirrhosis. Patient revealed the following
      signs of immune deficiency: decreased level of serum immunoglobulins,
      considerably decreased number of B cells and CD4 cells and a lack of
      proliferative response to mitogen stimulation. The USG, scintigraphy and biopsy
      of liver confirmed the diagnosis of liver cirrhosis. The patient has been
      receiving intravenous immunoglobulins (IVIG) as substitutional treatment of CVID.

PMID- 12418291
TI  - [A case of para-cerebral abscess as a complication of middle ear purulent
      inflammation].
AB  - We reported the case of para-cerebral abscess in the left temporal region, being
      a complication of exacerbation of chronic middle ear inflammation with
      cholesteatoma. Computed tomography was performed, which helped in the diagnosis.
      The patient was treated conservatively by aimed antibiotic therapy. We performed
      surgery of the middle ear, with abscess removal through trepan apertura attaining
      good results. We have presented principles of diagnostic and therapeutic
      procedures which help in prevention of intracranial complications in ear
      diseases.

PMID- 12418292
TI  - [Interferences in immunoassay].
AB  - Use of immunochemical methods for hormonal determinations makes endocrinologic
      diagnosis faster and easier; but insufficient information on possible false
      elevated or falsely low values may lead to potentially harmful and irreversible
      effects for the patient. In addition to the well known negative effects on all
      laboratory determinations of pre-analytical errors, the occurrence of abnormal
      concentrations of some proteins or the presence of therapeutic drugs is well
      known. Immunochemical methods are negatively influenced by cross-reactions, as
      well as by the interference caused by the presence of heterophilic antibodies and
      the "effect of high dose". Such effects not only make the results obtained by
      different laboratories incomparable, but also may lead to obtaining results of
      hormonal determinations completely inconsistent with clinical observations.

PMID- 12418293
TI  - [50th anniversary of the first aortic valve implantation].
AB  - This year marks the 50th anniversary of the first aortic valve prosthesis
      implanted in the descending aorta on September 11, 1952 by Dr. Charles A.
      Hufnagel at the Georgetown University Hospital in Washington, D.C. At this time,
      before the era of the heart-lung machines with extracorporeal circulation, there
      was no surgical therapy for patients with aortic insufficiency. Hufnagel
      implanted his plexiglas ball valve prosthesis, providing a significant
      hemodynamic improvement to the patients and opening the field of cardiac valve
      replacement.

PMID- 12418294
TI  - [Obstruction of outflow tracts in complete transposition of great arteries].
AB  - The obstructive lesions in the outflow tracts of hearts with complete
      transposition of the great arteries determine the clinical evolution, prognosis,
      and the selection of surgical procedures. Their knowledge is basic to interpret
      the imaging findings. From the pathologic specimens collection of the Instituto
      Nacional de Cardiologia "Ignacio Chavez", seventy-tree hearts with this
      cardiopathy were studied morphologically with the sequential segmental system.
      Thirty-two hearts had outflow tracts anomalies, being obstructive twenty-eight;
      among these lesions were: malposition of the infundibular septum, hipertrophyc
      left infundibulum, prolapse of tricuspid valve tissue through a ventricular
      septal defect, accessory mitral valve tissue, septal hipertrophy at the left
      outflow tract level, abnormal insertion of cord tendinae of the mitral valve,
      anticlockwise malposition of the mitral valve (first report in the literature).
      The left outflow tract presented obstructive lesions (92.85%) more frequently
      than the right one. These lesions produce left ventricular hipertrophy, a
      fundamental feature for the anatomic surgical procedures to be made.

PMID- 12418295
TI  - [Brugada's syndrome: experience in Cuba in 2001].
AB  - The Brugada syndrome is the most frequent electrical cause of sudden death in
      patients with structurally normal heart. It is characterized by ST segment
      elevation in V1-V3 leads, pseudo right bundle branch block and proneness for
      episodes of life-threatening ventricular cardiac arrhythmias. The aim of this
      study was to characterize patients with Brugada syndrome identified in Cuba
      between 1995 and 2001. Fourteen patients with these electrical signs (13 male and
      1 female, mean age 42.8) were studied. Seven of them were symptomatic and seven
      were not. The pharmacological test with sodium channel blockers was very useful
      (it was positive for all the patients). HV interval was normal. Programmed
      ventricular stimulation was performed. Ventricular arrhythmia was inducible in 3
      symptomatic patients and 2 asymptomatic. All the symptomatic patients and those
      asymptomatic in whom ventricular arrhythmia was inducible received automatic
      defibrillators. One clinical recurrence of ventricular arrhythmias was observed.
      Antiarrhythmic drugs were only used rarely. Clinical history and
      electrocardiographic tracings were very important to diagnose this syndrome.
      There were light, transient or masked electrical signs. The treatment of choice
      is the implantable cardioverter-defibrillator.

PMID- 12418296
TI  - [Decrease of total hemorrhage with reduced doses of enoxaparin in high risk
      unstable angina. ENHNFAI study. (Enoxaparin vs non-fractionated heparin in
      unstable angina). Preliminary report].
AB  - In this prospective, randomized and controlled study, we compare complications in
      2 groups of patients: group 1, enoxaparin 0.8 mg/kg, subcutaneous every 12 hours
      during 5 days, and group 2, intravenous unfractionated heparin during 5 days, by
      infusion treated to activate partial tromboplastin time 1.5-2 the upper limit of
      normal. Blood samples were obtained at 4, 12, 24 hours and at day 5 of treatment,
      to measure anti-Xa levels, and also, evaluated end points at 30 days, between
      groups. Univariate and multivariate logistic regression analyses were performed
      with clinical and angiographic variables between groups, with p < 0.05. RESULTS:
      203 consecutive patients, average age of 60.5 +/- 11.2 years, and 80% men, were
      included. There were no differences in clinical and angiographic characteristics.
      All patients with enoxaparin had therapeutic levels of anti-Xa, of 0.5 to 0.67
      U/mL. There was increasing risk of total bleeding in group 2 (18.7%) than in
      group 1 (5.6%), with RR = 1.72 (95% CI 1.29, 2.29), p = .003. Also, there was
      33.3% of MACE in group 2, and only 17.8% in group 1, with RR = 1.88 (CI 95% 1.29,
      2.29), p = .011. CONCLUSIONS: 1) Low doses of enoxaparine achieve therapeutic
      levels, since the first 4 hours of treatment. 2) A significant reduction of total
      bleeding occurred with the low doses of enoxaparin, with the same efficacy to
      reduce MACE during follow-up.

PMID- 12418297
TI  - [Follow-up of a group of patients with automatic implantable defibrillator].
AB  - The automatic implantable defibrillator (AID) is the treatment of choice for
      primary and secondary prevention of sudden death. At the Instituto Nacional de
      Cardiologia, since October 1996 until January 2002, 25 patients were implanted
      with 26 AID. There were 23 men (92%) and the mean age of the whole group, was
      51.4 years. Twenty-three patients (92%) presented structural heart disease, the
      most common was ischemic heart disease in 13 patients (52%), with a mean ejection
      fraction of 37.8%. One patient without structural heart disease had Brugada
      Syndrome. The most frequent clinical arrhythmia was ventricular tachycardia in 14
      patients (56%). The mean follow-up was of 29.3 months during which a total of 30
      events of ventricular arrhythmia were treated through AID; six of them were
      inappropriate due to paroxismal atrial fibrillation; 10 AID patients (34%) have
      not applied for therapy. Three patients (12%) of the group died due to congestive
      heart failure refractory to pharmacologic treatment. CONCLUSION: The implant of
      the AID is a safe and effective measure for primary and secondary prevention of
      sudden death. World-wide experience evidences, that this kind of device has not
      modified the mortality rate due to heart failure in these patients, but it has
      diminished sudden arrhythmic death.

PMID- 12418298
TI  - [Usefulness of adenosine to detect advanced paroxysmal atrioventricular block as
      a cause of syncope].
AB  - We present the case of a 66 years old man with recurrent episodes of syncope, up
      to three times during the last two months without previous symptoms. An ECG after
      the syncope showed a bilateral block (left anterior fascicle block and right
      bundle branch block) and first grade atrioventricular block. The exercise test
      did not demonstrate either AV conduction disorders or tachyarrhythmia episodes.
      Holter monitoring showed premature ventricular complexes; tilt testing and
      carotid sinus massage were normal. The electrophysiologic study revealed no
      alteration in the conduction system. Throughout atrial and ventricular
      stimulation documented no tachyarrhythmias. However, intravenous administration
      of 12 mg of adenosine induced complete AV infra-His block with ventricular
      asystolia of 7.2 sec duration. Adenosine testing can identify patients with
      syncope due to paroxysmal AV block even when the electrophysiological findings
      and other conventional tests are not conclusive.

PMID- 12418299
TI  - [Alternatives to chronic cardiac stimulation in patients with mechanical
      tricuspid prosthesis and atrioventricular block].
AB  - One of the complications of tricuspid valve replacement (TVR) is the complete
      heart block (CHB). In these patients an epicardial permanent pacemaker is
      frequently used but its insertion is another major operation and higher
      thresholds are needed. Two patients are reported, both women, with rheumatic
      heart disease and TVR who required a permanent pacemaker because they developed
      CHB. The first patient underwent mitral valve replacement with a disc valve
      seventeen years before and TVR recently. A single chamber pacemaker was
      implanted. Left ventricular pacing was achieved through the great cardiac vein.
      The acute and chronic pacing thresholds were adequate. The second patient
      underwent tricuspid and mitral replacement with a Starr-Edwards (SE) valve.
      Eighteen years later this patient had atrial fibrillation with slow ventricular
      response and heart failure. The pacemaker lead had to be inserted across the
      tricuspid SE valve because ventricle pacing through the coronary veins was
      unsuccessful. The endocardial pacing resulted in mild tricuspid regurgitation and
      has continued the same way for four years. To conclude, ventricle pacing through
      the coronary veins is safe, produces excellent results and fewer complications.
      On the other hand, ventricle pacing across a prosthetic tricuspid valve remains
      questionable because of possible damage to the prosthesis itself leading to valve
      insufficiency and because of damage to the pacing lead.

PMID- 12418300
TI  - [Non-complicated and complicated polyfascicular blocks].
AB  - Septal necrosis + Peripheral blocks. Because of an extensive septal necrosis, the
      manifestation of the initial ventricular activation forces decreases in the
      precordial leads. With left bifascicular block, first ventricular activation
      forces become evident, and the electrical signs of a sepatal necrosis are
      concealed. In the presence of a trifascicular block, the manifestation of the
      first ventricular electromotive forces diminishes again and the electrical signs
      of septal necrosis become evident once more. Small Q waves are present in leads
      V1 to V4. Extensive anterior necrosis + Peripheral blocks. Such a necrosis is
      manifested by QS complexes from V2 to V6. An associated left bifascicular block
      reduces the electrical manifestation of dead tissue: QS complexes persist only in
      V3 and V4. A trifascicular block determines the presence of QS complexes from V2
      to V5. Posteroinferior necrosis + Peripheral blocks. Electromotive forces of the
      ventricular activation shift upward, due to a posteroinferior necrosis. QS or QR
      complexes are recorded in leads a VF, II, and III. A left bifascicular block
      displaces the main electromotive forces downward, posteriorly and to the left,
      due to a delay of the posteroinferior activation. QRS complexes become positive
      and wider in all leads, the reflect the potential variations of the inferior
      portions of the left ventricle: aVF, II, and III, sometimes V5 and V6. The
      electrical signs of necrosis are reduced or abolished. With a trifascicular
      block, wide and slurred QS complexes appear in aVF, II, III, and sometimes in V5
      and V6 too.

PMID- 12418301
TI  - [Vasopressin: uses in cardiovascular practice].
AB  - Vasopressin is secreted by the neurohypophysis influenced by many variables;
      among them the most important and known is the osmotic pressure (osmotic
      regulation) of body fluid. Other factors that modify this hormone's secretion are
      changes in blood volume and blood pressure, which contribute significantly to
      hemodynamic recovery. Vasopressin receptors are located in different sites, and
      their stimulation generate also generates different physiological responses. The
      receptors are of two types, V1 and V2. The usefulness of exogenous vasopressin
      has been proven in many clinical situations, refractory cardiac arrest, septic
      shock, vasodilator shock, postcardiotomy shock, and vasoplegic shock, with
      promising results. At present, enough scientific support exists for the use of
      this antidiuretic hormone (vasopressin) in clinical practice.

PMID- 12418302
TI  - [PET of the heart. First case in Mexico].

PMID- 12418303
TI  - [Internal cardioversion with low-energy shock in atrial fibrillation].

PMID- 12418304
TI  - [PET in diagnostic nuclear medicine--cost/use aspects].

PMID- 12418305
TI  - Rapid evaluation of FDG imaging alternatives using head-to-head comparisons of
      full ring and gamma camera based PET scanners--a systematic review.
AB  - AIM: While FDG full ring PET (FRPET) has been gradually accepted in oncology, the
      role of the cheaper gamma camera based alternatives (GCPET) is less clear. Since
      technology is evolving rapidly, "tracker trials" would be most helpful to provide
      a first approximation of the relative merits of these alternatives. As difference
      in scanner sensitivity is the key variable, head-to-head comparison with FRPET is
      an attractive study design. This systematic review summarises such studies.
      METHODS: Nine studies were identified until July 1, 2000. Two observers assessed
      the methodological quality (Cochrane criteria), and extracted data. RESULTS: The
      studies comprised a variety of tumours and indications. The reported GC- and
      FRPET agreement for detection of malignant lesions ranged from 55 to 100%, but
      with methodological limitations (blinding, standardisation, limited patient
      spectrum). Mean lesion diameter was 2.9 cm (SD 1.8), with only about 20% < 1.5
      cm. The 3 studies with the highest quality reported concordances of 74-79%, for
      the studied lesion spectrum. Contrast at GCPET was lower than that of FRPET,
      contrast and detection agreement were positively related. Logistic regression
      analysis suggested that pre-test indicators might be used to predict FRPET-GCPET
      concordance. CONCLUSION: In spite of methodological limitations, "first
      generation" GCPET devices detected sufficient FRPET positive lesions to allow
      prospective evaluation in clinical situations where the impact of FRPET is not
      confined to detection of small lesions (< 1.5 cm). The efficiency of head-to-head
      comparative studies would benefit from application in a clinically relevant
      patient spectrum, with proper blinding and standardisation of acquisition
      procedures.

PMID- 12418306
TI  - Excretion of FDG into saliva and its significance for PET imaging.
AB  - AIM: Assessment of the salivary excretion of FDG and its significance during PET
      imaging. METHODS: Salivary samples from 16 patients were obtained during the
      first three hours after FDG injection and their activity concentrations were
      measured. Furthermore, regional FDG accumulations in whole body PET scans (60 min
      p.i., ROI technique) were determined in the following locations: vestibulum oris,
      floor of the mouth, hypopharynx, parotid gland, submandibular gland. This ROI
      analysis was repeated after drinking water (0.2 l) and a second scan (120 min
      p.i.). RESULTS: The salivary FDG concentrations (SUV) at the first, second and
      third hour p.i. were 0.2 +/- 0.1, 0.4 +/- 0.2, and 0.3 +/- 0.2, respectively. The
      FDG uptake in the investigated cranial and cervical sites ranged from SUV 1.2 +/-
      0.5 in the major salivary glands to 2.1 +/- 0.5 in the floor of the mouth. These
      values remained unchanged after drinking of water. CONCLUSION: The salivary FDG
      concentration is higher than expected from the low physiologic content of
      glucose. This may--similarly to renal excretion--reflect a different behavior of
      FDG and glucose during reabsorption processes. Nevertheless, the salivary
      concentration of FDG is so low that no relevant influence on PET imaging is to be
      expected. Accordingly, the drinking of water prior to the scan is of no benefit
      for FDG PET imaging of the head and the neck.

PMID- 12418307
TI  - [Optimization of radiotherapy planning for non-small cell lung cancer (NSCLC)
      using 18FDG-PET].
AB  - AIM: In recent years, FDG-PET examinations have become more important for
      problems in oncology, especially in staging of bronchogenic carcinoma. In the
      retrospective study presented here, the influence of PET on the planning of
      radiotherapy for patients with non-small-cell lung cancer (NSCLC) was
      investigated. METHODS: The study involved 39 patients with NSCLC who had been
      examined by PET for staging. They received radiotherapy on the basis of the
      anterior/posterior portals including the primary tumour and the mediastinum
      planned according to CT- and bronchoscopic findings. The results of the PET
      examination were not considered in initial radiotherapy planning. The portals
      were retrospectively redefined on the basis of FDG uptake considering the size
      and localization of the primary tumour; and FDG activities outside the
      mediastinal part of the portals. RESULTS: In 15 out of 39 patients, the CT/PET
      planned portals differed from the CT-planned ones. In most causes (n = 12) the
      CT/PET field was smaller than the CT field. The median geometric field size of
      the portals was 179 cm2, after redefinition using PET 166 cm2. In 20 patients
      with disturbed ventilation caused by the tumour (atelectasis, dystelectosis), a
      correction of the portal was suggested significantly more frequently than in the
      other patients (p = 0.03). CONCLUSIONS: Our results demonstrate the synergism of
      topographical (CT) and metabolic (FDG-PET) information, which could be helpful in
      planning radiotherapy of bronchial carcinoma, especially for patients with
      disturbed ventilation.

PMID- 12418308
TI  - [Radiation exposure around patients after administration of 123-MIBG].
AB  - AIM: Estimation of the radiation exposure to neighbouring patients, personnel and
      relatives deriving from patients undergoing 123I-MIBG scintigraphy. METHODS: For
      scintigraphic studies, 16 patients with suspected pheocromocytoma were injected
      with 340 +/- 30 MBq 123I-MIBG. Dose rates were measured at a distance of 0.5 m, 1
      m, and 2 m after 10 min, 3 h, 21 h, 45 h, and 68 h using three calibrated
      portable radiation detectors. The emasured values were background corrected.
      RESULTS: Ten minutes after injection the dose rate was 10.5 microS/h at a
      distance of 0.5 m, 3.78 microS/h at 1 m, and 0.95 microS/h at 2 m. The effective
      half-life was estimated to 8.68 +/- 0.15 h. The maximum dose in a distance of 1 m
      for neighbouring patients was 46 microS/h, for personnel in a ward 27 microS/h,
      and to relatives in a distance of 2 m 12 microS/h. CONCLUSION: This study
      demonstrates that the calculated exposure to people around patients after 123I
      MIBG injection is well below the maximum permissible annual dose limit of 1 mSv
      for not professionally exposed persons.

PMID- 12418309
TI  - A new technique of 99mTc-ciprofloxacin kit preparation.
AB  - AIM: Development of a simple and reproducible method for preparing a
      ciprofloxacin kit using a redox polymer, which would meet the requirements for an
      easy and reliable technique of labelling with 99mTc and diagnostic efficiency in
      scintigraphic imaging of infections. MATERIAL AND METHODS: To prepare the kit, an
      insoluble redox polymer containing an end alpha(beta)-alanine-N,N'-diacetate
      group anchored to the dextran matrix was used. The redox polymer synthesised by
      the authors was incubated at room temperature (10 h) with a solution of
      ciprofloxacin (1%) in a suspension (5%). The mixture was then filtered and
      dispensed into sterile vials (0.2 ml each). The kit was labelled with 99mTc for
      10 min at room temperature. The radiochemical purity of the ciprofloxacin-99mTc
      complex was determined by ITLC and paper chromatography in relation to the
      following factors: pH, total content of ciprofloxacin, volume of sodium 99mTc
      pertechnetate. Ciprofloxacin biodistribution was evaluated in Wistar rats with
      Staphylococcus aureus infection in the left inguinal region 24 h after abscess
      induction. Accumulation of 99mTc activity was determined both using external
      gamma camera imaging and counting dissected tissues 1 h after administration.
      RESULTS: Radiochemical purity is > 95% for kit-labelling (pH 3.3-3.7). With pH
      3.45, labelled ciprofloxacin shows the highest stability and radiochemical
      purity. The 99mTc-ciprofloxacin complex is stable for at least 8 h. In
      experimentally induced inflammation, the amount of accumulated 99mTc
      ciprofloxacin activity is five times higher than in controls. CONCLUSION: The
      developed method of 99mTc-ciprofloxacin kit preparation employs a redox polymer
      in a new procedure, which enables the preparation of a stable kit with a high
      99mTc-labelling efficiency. The labelled kit is suitable for scintigraphic
      imaging of infection.

PMID- 12418310
TI  - [Angioleiomyoma: nuclear medical-radiologic diagnosis of a rare soft tissue
      tumor].

PMID- 12418311
TI  - [Barrett-adenocarcinoma of the esophagus: false negative finding in a surgeon
      using FDG-PET].

PMID- 12418312
TI  - [Combination PET/CT with 124I positron rays in metastatic follicular thyroid
      carcinoma].

PMID- 12418313
TI  - [Diagnosis and treatment of syndrome of multiple endocrine neoplasia type 2].
AB  - Since 1969 to 2000 twenty one patients from 16 families with syndrome of multiple
      endocrine neoplasia (MEN) type 2 were examined. Medullary cancer of the thyroid
      gland (MCTG) was diagnosed in 18 patients, pheochromocytoma--in 15 (in 13 of them
      -two-sided), primary hyperparathyroidism--in 2. In 9 patients from 5 families
      syndrome MEN 2 was confirmed genetically (mutation in codon 634 of 11th exon RET
      in 7 patients with MEN 2a and in codon 918 in 2 patients with MEN 2b). None of
      the patients had extraadrenal pheochromocytoma, in 9 (60%) patients multicentric
      tumors within one adrenal gland were diagnosed. All the 18 patients with MCTG
      underwent extrafascial thyroidectomy with removal of fat and lymph nodes of
      paratracheal zone, 9 patients--one-sided (6) or two-sided (3) removal of fat and
      lymph nodes of lateral triangle of neck. Prophylactic thyreoidectomy was
      performed in 11-year old patient with genetically verified MEN 2a and without
      topical data of MCTG, 2 patients of 3 and 19 years of age with genetically
      verified MEN 2 are to undergo prophylactic thyroidectomy. Prophylactic
      thyroidectomy is necessary in the presence of genetic disorders in members of
      families with MEN 2 despite absence of structural changes in thyroid gland. Level
      of basal and stimulated calcitonin may be used as marker of recurrence or
      metastatic growth only. In MEN 2 after organ-saving operation rate of true
      recurrence of tumor is high because of genetic damage of medullary layer of
      adrenal gland.

PMID- 12418314
TI  - [Ultrasound investigation and mini-invasive ultrasound-assisted technologies in
      diagnosis and treatment of extra-organ separate fluid formations in abdominal
      cavity].
AB  - The authors discuss the use of ultrasound-assisted percutaneous puncture and
      drainage for diagnosis and treatment of extraorganic separate fluid formations in
      abdominal cavity (abscess, limited non-infected fluid formation, hematoma with
      clotted blood), determination of their sizes and obtaining material for
      laboratory study. 307 patients with various extraorganic separate fluid in
      formations in abdominal cavity were examined. Ultrasonic symptoms of abscess were
      described in 54 patients, of limited non-infected fluid formation--in 234, of
      hematoma with clotted blood in 19 patients. 146 patients were cured
      conservatively, 75 patients underwent US-assisted puncture, 76--US-assisted
      drainage. Mean time of drainage was 14 days (ranged from 10 to 20). There were
      neither complications nor lethal outcomes. Ultrasound examination and US-assisted
      mini-invasive surgery permit to detect precisely the nature of fluid formation,
      to perform timely and low-traumatic treatment.

PMID- 12418315
TI  - [A simple method of creation of invaginated esophago-intestinal and esophago
      gastric anastomoses].
AB  - Creation of invaginated esophageal anastomosis is easier by Tsatsanidi method,
      but this is accompanied by certain discomforts. In particular, there is
      inescapable contamination of intestinal serosa by ligature which fixes esophageal
      stump from inside and is taken out through intestinal wall. The author proposes
      to put this ligature into the side hole of the thick gastric tube and to fix it
      there with bougie. The tube is moved deeplier, ligature and esophageal stump are
      pulled up. This facilitates creation of invaginated anastomosis. Then bougie is
      removed from the thick tube and fixed ligature is freed. This method was used in
      19 patients. There were no lethal outcomes due to insufficiency of esophageal
      anastomosis. This method permits to simplify creation of invaginated anastomosis,
      to increase asepsis of surgery and to dicrease the risk of anastomosis
      insufficiency.

PMID- 12418316
TI  - [Vagotomy in surgical treatment of duodenal ulcer].
AB  - Results of organo-saving operations in 807 patients (72% men, 28% women) with
      duodenal ulcers were analyzed. Bilateral truncal vagotomy (with pyloro-,
      duodenoplasty, gastroenterostomy, gastroduodenostomy, economical stomach
      resection) were performed in 27.1% patients, selective--in 1.4%, selective
      proximal--in 65.5%, anterior selective and posterior truncal vagotomy--in 6.0%.
      Lethality was 1.6%, long-term results were excellent and good in 75.6% cases.
      Satisfactory results were seen in 8.6% patients, bad results--in 15.8%.

PMID- 12418317
TI  - [Lithogenecity of bile in patients with cholelithiasis with different morphologic
      changes in hepatic tissue].
AB  - Lithogenecity of bile was studied in patients with cholelithiasis and
      choledocholithiasis. It is demonstrated that synthesis of lithogenic bile depends
      on morphologic state of hepatic cells; chronic disease of the liver is the risk
      of the cholelithiasis.

PMID- 12418318
TI  - [Minimally invasive method in the treatment of liver trauma complications].
AB  - 78 patients aged from 14 to 73 years (57 men, 21 women) with complications after
      trauma of the liver were studied. Minimally invasive operations (puncture,
      drainage, puncture + drainage) were performed in 62 (79%) patients. 8 patients
      with small bilema received conservative treatment under visual follow-up. 8
      patients with middle and big posttraumatic lesions not treated with minimally
      invasive surgery entered control group. Intracavitary prolonged proteolysis with
      immobilized proteinases (imosimase Literum, Novosibirsk) was used. Imosimase
      injection led to lysis of thick inflammation products, intensified sanation of
      focus. There were neither complications nor lethal outcomes. 2 (2.6%) patients
      were operated. Tissue sequestrum and bleeding were indications for surgery.
      Efficacy of minimally invasive treatment of posttraumatic lesion of the iver was
      96%.

PMID- 12418319
TI  - [Variants of Botkin's biliary-cardiac syndrome in acute cholecystitis].
AB  - 4 cases of little-known syndromes in acute cholecystitis are described.
      Cholecystic-pericardial and syncopal-cardiac syndrome are seen in 1.33 and 1.78%
      cases of acute cholecystitis, respectively, and are the variants of Botkin's
      biliary-cardiac syndrome. These syndromes disappear after surgery on biliary
      tract, therefore they must be indications for surgical treatment of
      cholecystitis.

PMID- 12418320
TI  - [Prophylaxis of recurrences in herniotomy with P-like suture].
AB  - Rate of recurrences of hernias reaches 6%. Dislocation of elements of spermatic
      cord promotes hernia recurrence. Dislocation of membranes was studied on cadavers
      and during operations, and also after Postempsky's plastic surgery with
      additional [symbol: see text]-suture, which divides ostium and cord into three
      equal parts. Dislocation decreases 3-fold. 42 men were operated with [symbol: see
      text]-suture, there were no recurrences during 4 years of follow-up.

PMID- 12418321
TI  - [Temporal decompressive laparoscopy-assisted colostomy].
AB  - Morphofunctional changes in intestinal wall above the obstruction were studied
      experimentally in 112 rats with low intestinal obstruction. Treatment with
      antioxidants and lasertherapy was developed. After removal of obstruction this
      complex permits to eliminate its negative local and general consequences 1.5
      times faster than without it. Laparoscopic decompressive colostomy was performed
      in 65 patients with sub- and decompensated colonic obstruction. The developed
      therapeutic scheme was included in combined treatment before surgery. There were
      no lethal outcomes, purulent-inflammatory complications were seen in 24 (39.6%)
      patients.

PMID- 12418322
TI  - [Anaerobic paraproctitis].
AB  - Anaerobic paraproctitis (AP) was seen in 8.6% of 1057 cases with acute
      paraproctitis. Severe general condition of the patient, vast damage, fetid wound
      secretion, extensive detachment and necrosis of tissues were the main AP
      symptoms. Radical excision of affected tissues with daily revision and sanatation
      in combination with intensive general therapy permits to reduce mortality to
      4.3%. In early postoperative period reversible insufficiency of anal sphincter
      developed in 16.1% AP patients. It is necessary to close wounds as early as
      possible. Perforated cutaneous pedicle flap from posterior wall of the scrotum
      may be successfully used for plastic repair of perineum wound.

PMID- 12418323
TI  - [Use of gas flow with nitrogen oxide (NO-therapy) in combined treatment of
      purulent wounds].
AB  - NO-therapy was used in 40 patients with purulent wounds of soft tissues.
      Bacteriological, cytological and morphological examinations demonstrated
      acceleration of wound process compared with control group (40 patients without NO
      therapy). Laser doppler flowmetry demonstrated significant improvement of
      microcirculation in wound zone during NO-therapy. This method shortens by 3-5
      days the time of preparation of wound surface for surgical closure.

PMID- 12418324
TI  - [Anesthesiologic aspects of ambulatory surgery].
AB  - Experience of 2841 anesthesias during surgery performed in one-day hospital was
      analyzed. Anesthesiology service of the outpatient clinic consists of
      anesthesiologist, nurse-anesthesist, nurse of postoperative ward. Multicomponent
      anesthesia with tracheal intubation and artificial ventilation (386), combined
      (709), intravenous (511), inhalation (264), complex (473), neuroleptanalgesia
      (119), epidural (11), spinal (4), sacral (3), conduction (53) anesthesias were
      used during general, proctology, urology, oncology and gynecology surgeries.

PMID- 12418325
TI  - [Modern glue compositions in thoracic surgery].

PMID- 12418326
TI  - [Anesthesia during surgery for chronic venous insufficiency].

PMID- 12418327
TI  - [A rare variant of early postoperative intestinal obstruction].

PMID- 12418328
TI  - [Actual problems of donation in liver transplantation. Part 1].

PMID- 12418329
TI  - [Gynecomastia--symptoms, diagnosis and treatment].

PMID- 12418330
TI  - [Doctor of medicine and surgery V.I. Dal'].

PMID- 12418331
TI  - Management of prolonged pregnancy.

PMID- 12418332
TI  - When drug samples expire.

PMID- 12418333
TI  - Optimizing statin drug therapy.

PMID- 12418334
TI  - Testing for lupus.

PMID- 12418335
TI  - Evaluation & management of lower extremity ulcers. Adherence to prescribed
      therapy can save limbs.

PMID- 12418336
TI  - Home apnea monitoring for infants. A discussion of primary care issues.

PMID- 12418337
TI  - Medication use by 'healthy' midlife women. A revealing study of polypharmacy.

PMID- 12418339
TI  - Patient information. Understanding premenstrual dsyphoric disorder.

PMID- 12418338
TI  - Quality control. Ensuring that new grads measure up.

PMID- 12418340
TI  - Working with underserved populations. A module for nurse practitioner students.

PMID- 12418341
TI  - Immune recovery syndrome with HAART therapy. A clinical perspective.

PMID- 12418342
TI  - Growth hormone therapy. Determining appropriate use.

PMID- 12418343
TI  - Chronic fatigue syndrome. Symptom relief is primary goal.

PMID- 12418344
TI  - Managing the spiritual needs of patients. Simple steps to enhance well-being.

PMID- 12418345
TI  - Cardiovascular disease and exercise stress testing.

PMID- 12418346
TI  - An opportunity of a lifetime.

PMID- 12418347
TI  - Hypogonadism in men. A review of diagnosis and treatment.

PMID- 12418348
TI  - Time for results: a better way to reduce cardiovascular risk.

PMID- 12418349
TI  - Erectile dysfunction. Primary care treatment is appropriate and essential.

PMID- 12418350
TI  - Lower urinary tract symptoms in men. Differential diagnosis is main challenge.

PMID- 12418351
TI  - Prevent shock. Learn to recognize severe feeding intolerance early.

PMID- 12418352
TI  - Asthma in toddlers and young children. Airway remodeling should be primary focus.

PMID- 12418353
TI  - Management and treatment of genital herpes. A practical approach to patient care.

PMID- 12418354
TI  - Ludwig's angina: a compelling reason to check your patients' oral hygiene.

PMID- 12418355
TI  - Grief: a personal perspective.

PMID- 12418356
TI  - New directions in the pharmacotherapy of posttraumatic stress disorder.
AB  - Advances in psychopharmacology of PTSD are presented, focusing on
      antidepressants, adrenergic agents, antianxiety agents, and mood stabilizers.
      Treatment recommendations are related to recent advances in the understanding of
      the biology of PTSD. Pharmacotherapy of PTSD in children and adolescents is
      discussed, including recommended dose ranges. Recommendations are specified for
      pharmacotherapy of trauma survivors in the immediate aftermath of traumatic
      exposure, and for those with acute and chronic posttraumatic stress disorders.

PMID- 12418358
TI  - Safety and tolerability: how do newer generation "atypical" antipsychotics
      compare?
AB  - Previously, clinicians worked with antipsychotic drugs that almost invariably
      caused extrapyramidal side effects (EPS) at the dose at which they were
      clinically effective. By definition, all newer generation atypical antipsychotic
      agents are significantly better than conventional agents with regard to EPS;
      i.e., they are clinically effective at doses at which they do not cause EPS. This
      EPS advantage of atypical antipsychotics translates into several important
      clinical benefits, including better negative symptom efficacy, lesser dysphoria,
      less impaired cognition, and a lower risk of tardive dyskinesia; in fact, this
      "EPS advantage" is the principal basis of the many clinical advantages provided
      by the class of atypical antipsychotics. While all atypical agents share this
      "EPS advantage," there are important differences between these agents with regard
      to the ease and consistency with which this EPS advantage can be realized.
      Pharmacologically, different atypical antipsychotics differ; these differences
      translate into differences in their side effect profiles. Five atypical
      antipsychotics are currently available: clozapine, risperidone, olanzapine,
      quetiapine, and ziprasidone. Meaningful differences between these agents with
      regard to weight gain, sedation, anticholinergic side effects, cardiovascular
      issues, endocrine side effects, hepatic and sexual issues, will be considered and
      their clinical implications discussed.

PMID- 12418357
TI  - The cultural formulation: a method for assessing cultural factors affecting the
      clinical encounter.
AB  - The growing cultural pluralism of US society requires clinicians to examine the
      impact of cultural factors on psychiatric illness, including on symptom
      presentation and help-seeking behavior. In order to render an accurate diagnosis
      across cultural boundaries and formulate treatment plans acceptable to the
      patient, clinicians need a systematic method for eliciting and evaluating
      cultural information in the clinical encounter. This article describes one such
      method, the Cultural Formulation model, expanding on the guidelines published in
      DSM-IV. It consists of five components, assessing cultural identity, cultural
      explanations of the illness, cultural factors related to the psychosocial
      environment and levels of functioning, cultural elements of the clinician-patient
      relationship, and the overall impact of culture on diagnosis and care. We present
      a brief historical overview of the model and use a case scenario to illustrate
      each of its components and the substantial effect on illness course and treatment
      outcome of implementing the model in clinical practice.

PMID- 12418360
TI  - Personality disorders in prison: aren't they all antisocial?
AB  - The provision of mental health services in the correctional system is challenging
      at best for various clinical, administrative, and structural reasons. Among the
      complicating factors is the assessment and management of character pathology
      which either confounds the treatment of more "serious" mental illnesses, e.g.
      Axis I disorders, and/or presents itself as the primary focus for intervention.
      In this paper we review the prevalence of personality disorders on the prison
      mental health services caseload in New York State. We compare inpatient and out
      patient rates among the various disorders documented in the prison system, as
      well as look at these rates within the context of the rates of personality
      disorder in the state mental health system generally. Assessment of personality
      disorder will be addressed with particular attention to the confounding influence
      of the prison environment. Finally, treatment options will be discussed,
      including discussion of new initiatives that attempt to address inmates with
      serious mental illness and personality traits that lead to disciplinary housing.

PMID- 12418359
TI  - Heterosexual male perpetrators of childhood sexual abuse: a preliminary
      neuropsychiatric model.
AB  - This paper presents data from a series of preliminary neuropsychiatric studies,
      including neuropsychological, personality, sexual history, plethysmographic and
      neuroimaging investigations, on a sample of 22 male, heterosexual, nonexclusive
      pedophiles and 24 demographically similar healthy controls. A psychobiological
      model of pedophilia is proposed, positing that early childhood sexual abuse leads
      to neurodevelopmental abnormalities in the temporal regions mediating sexual
      arousal and erotic discrimination and the frontal regions mediating the cognitive
      aspects of sexual desire and behavioral inhibition. In this way, pedophiles
      develop deviant pedophilic arousal. Subsequently, if there is comorbid
      personality pathology, specifically sociopathy and cognitive distortions, there
      will be failure to inhibit pedophilic behavior.

PMID- 12418361
TI  - Computers in psychiatry: a review of past programs and an analysis of historical
      trends.
AB  - In a variety of clinical settings, computers are playing an increasing role in
      managing or retrieving clinical information. A recent survey of physician
      computer use suggests that psychiatrists, in comparison to other types of medical
      specialists, may be using computers less in routine care. In this paper, we
      present a literature review of 57 articles on computer programs in psychiatry
      that were published since 1966 in five major peer-reviewed journals. We divide
      the types of programs that have been developed into four categories: (1)
      diagnostic and decision support, (2) patient screening and therapy, (3) data
      collection and management, and (4) data modeling. Among the first three
      categories, we found trends in publications during the past three decades of
      research. We provide a discussion of representative computer programs. Our
      analysis of past programs reveals a number of design problems that may be a
      barrier to the more widespread use of computers in psychiatry.

PMID- 12418363
TI  - Equilibrium's fragility.

PMID- 12418362
TI  - A primer of complementary and alternative medicine and its relevance in the
      treatment of mental health problems.
AB  - The use of complementary and alternative medicine (CAM) is widespread. Those with
      psychiatric disorders are more likely to use CAM than those with other diseases.
      There are both benefits and limitations to CAM. Many controlled studies have
      yielded promising results in the areas of chronic pain, insomnia, anxiety, and
      depression. There is sufficient evidence, for example, to support the use of a)
      acupuncture for addiction problems and chronic musculoskeletal pain, b) hypnosis
      for cancer pain and nausea, c) massage therapy for anxiety, and the use of d)
      mind-body techniques such as meditation, relaxation, and biofeedback for pain,
      insomnia, and anxiety. Large doses of vitamins, herbal supplements, and their
      interaction with conventional medications are areas of concern. Physicians must
      become informed practitioners so that they can provide appropriate and meaningful
      advice to patients concerning benefits and limitations of CAM.

PMID- 12418364
TI  - Analytic framework for clinician provision of end-of-life care.
AB  - Four dimensions for the provision of end-of-life care by clinicians were
      identified from a review and synthesis of the Canadian family physician and
      palliative care literatures. These dimensions are: clinician-patient continuity,
      timing and location of care, community-centred services, and multidisciplinary
      care. Indicators of each dimension are presented along with criteria for
      indicator selection. The analytic framework was refined during the linkage of
      population-based administrative databases to identify patterns of family
      physician service provision in the last months of life for persons dying from
      cancer in Nova Scotia, Canada. Data analysis was framed to inform palliative care
      policy and programs, as well as to enable comparison among geographic areas
      within and beyond Canada.

PMID- 12418365
TI  - Patterns of symptom distress in adults receiving treatment for lung cancer.
AB  - Knowledge of the patterns of symptom distress in adults receiving treatment for
      lung cancer is an important first step in developing interventions that can
      potentially lessen symptom distress. The purposes of this secondary analysis were
      to describe the changes in patterns of symptom distress over time in adults
      receiving treatment for lung cancer, and to examine the relationship of selected
      demographic and clinical characteristics to symptom distress. Complete data were
      available for 117 patients. The patterns of symptom distress in adults receiving
      treatment for lung cancer varied between treatment groups and over time. Symptom
      distress scores were moderate to high on entry into the study, indicating that
      symptom management in newly diagnosed lung cancer patients is essential and
      should begin early in the course of illness. Moreover, clinical interventions
      should be tailored to the type of treatment. Various demographic and clinical
      variables were weak and inconsistent predictors of symptom distress, underscoring
      the importance of examining the role of psychosocial factors in mediating symptom
      distress.

PMID- 12418366
TI  - Impact of a hospital palliative care service: perspective of the hospital staff.
AB  - The first New Zealand hospital palliative care support service was established in
      1985. Different service models have now been adopted by various major hospitals.
      In 1998, a palliative care service, funded by Mary Potter Hospice, was piloted at
      Wellington Public Hospital. Twelve months post-implementation, the hospital
      staff's views of the service were evaluated. It was found that referrals to
      palliative care from hospital specialities outside the Cancer Centre increased.
      While most doctors, nurses and social workers strongly agreed or agreed that the
      service positively influenced patients' care and effectively addressed their
      symptom management needs, spiritual needs were less often met. Over 90 percent of
      each discipline strongly agreed or agreed that the service had assisted them in
      caring for patients, but, only about a half agreed that useful discharge planning
      advice and staff support was provided. Significant differences in responses were
      found between different disciplines and specialities. One fifth of the staff
      identified palliative care education needs. Recommendations are made concerning
      the development of a future hospital palliative care service.

PMID- 12418367
TI  - A palliative approach to existential issues and death in end-stage dementia care.
AB  - The aim of this study was to investigate how, in relation to the palliative
      philosophy of care, municipal staff caring for patients with dementia deal with
      existential issues, the dying process, and bereavement follow up with next of
      kin. METHODS: Thirty-one semi-structured interviews were performed and analyzed
      using a modified phenomenographic method. RESULTS: Those interviewed experienced
      existential issues as difficult to handle, and they felt lost. Three patterns of
      answers emerged: 1) attempting to minimize or ignore the issue, 2) pleading, in
      relation to the patient, that no one has control over issues concerning life and
      death, and 3) showing affection for the patient. When faced with dying patients,
      they made things easier for the family, and their goal was that the patient
      should not be left alone. No systematic bereavement follow up of next of kin
      occurred. DISCUSSION: Suggestions are made for improving municipal care, and
      applying palliative care principles for patients dying of dementia.

PMID- 12418368
TI  - A needs assessment for southern Manitoba physicians for palliative care
      education.
AB  - Recent calls for increased palliative care education of physicians and a need to
      improve the effectiveness of palliative care delivery in rural areas are the
      stimuli for this study. The needs assessment evaluated educational needs and
      preferences of physicians practicing in three Regional Health Authorities in
      southern Manitoba in 2000, as well as semi-structured interviews with health care
      workers in seven rural communities. Physicians report their knowledge of symptom
      management issues as adequate, although for other issues in palliative care such
      as bereavement, psychosocial aspects of dying, and professional issues, they have
      less confidence. Physicians prefer learning through case studies, lectures, and
      self-directed learning, in settings close to their community, on the weekend.
      Qualitative analysis from the semi-structured interviews revealed themes related
      to the role of physicians in rural palliative care: i) a need for physician
      education, ii) physician participation within the palliative care team, and iii)
      physician involvement in patient-centered care.

PMID- 12418369
TI  - Meeting existential needs in palliative care--who, when, and why?
AB  - Existential concerns are of great importance to those who are terminally ill.
      However, these matters are seldom brought into focus in the care of the patients.
      One crucial question is: who should take care of the patient's existential needs?
      The present study focuses on possible alternatives for dealing with such
      concerns, including the staff or significant others. A focus group was set up to
      gather and examine reflections from people having first-hand experience with this
      problem. The results of this study indicate that, with regard to existential
      needs, there are no general solutions. On the other hand, under specific
      conditions, several solutions can be satisfactory. Possible ways of handling the
      problem are suggested. Moreover, staff should pay attention to constraints
      operating in care settings, such as continuity and time, competent organization,
      and personal prerequisites.

PMID- 12418370
TI  - Attention: a potential vehicle for spiritual care.

PMID- 12418371
TI  - A place for psychostimulants in palliative care?

PMID- 12418372
TI  - Empty hands.

PMID- 12418373
TI  - Colonic pseudo-obstruction in a patient with advanced small cell carcinoma.

PMID- 12418374
TI  - [Correlations of low birth weight and diseases in adulthood. The hypothesis, the
      facts and the doubts].
AB  - During the past 15 years more than hundred studies confirmed the association
      between low birth weight and the cardiovascular morbidity and mortality. The
      association is explained, at least partly, by the fact, that low birth weight is
      inversely related to type 2 diabetes, hypertension and dyslipidemia in adulthood.
      Several pathophysiological mechanism are implicated in the higher susceptibility
      of individuals born with low birth weight. Data suggest that in addition to the
      intrauterine retardation the sudden break of fetal development and the
      accelerated pace of early postnatal growth might also play a role in the
      pathogenesis of these chronic diseases. The authors summarize their conclusions
      based on the available results of epidemiological and experimental studies. They
      also introduce the data suggesting an association between altered bone metabolism
      and low birth weight. Finally, the authors present those data, that cast doubts
      on the reliability of associations between low birth weight and adulthood chronic
      diseases.

PMID- 12418375
TI  - [Treatment of malignant liver tumors with radio-frequency ablation (RFA)].
AB  - INTRODUCTION: A lot of different methods exist for the treatment of liver primary
      and secondary tumours. Nowadays surgery is the method of choice. If operation is
      not possible and other conditions are available, local tumour ablation is
      applicable. One of these methods is the radio-frequency (RF) thermal ablation.
      AIMS: This method is effective on the base of literature, albeit the indications
      are not uniform. Authors by the own experience wanted to get dates to define the
      indication and to study the effectivity of this method in the therapy of liver
      tumour. PATIENTS/METHODS: Between the 1 January 2000 and 31 January 2002, 86
      tumors of 40 patients were treated with RF thermal tumour ablation. This method
      was applied first in Hungary by our workgroup. RF ablation was performed with
      generator Cosman CC-1, Radionics, Burlington and cooled-tip single or cluster
      electrodes. RESULTS: Complete response was achieved in 56 percent. Results of
      primary tumour necrosis was better when the diameter of the tumour was 3.5-4 cm
      or less or the treatment was achieved by cluster electrode. 20 patients became
      tumour free (5 have breast cancer). Tumour spread came into existence in the
      spite of therapy in ten patients, 8 patients died. The average observation time
      was one year. In conclusion, the results of this study show that RF ablation with
      a cooled-tip electrode needle is a safe and effective technique for local
      treatment of hepatic lesions 4 cm or less in diameter and if the number of lesion
      less than 4-5. CONCLUSIONS: Authors suggest to use widely the RF technique with
      other methods in the treatment of hepatic tumours.

PMID- 12418376
TI  - [Investigation of the delayed type hypersensitivity reaction in atopic patients].
AB  - INTRODUCTION: In the last decades the prevalence of atopic diseases has increased
      highly in developed countries. Although the reasons for this increase are not
      clear, it has been hypothesized that a reduction in infections and immunization
      programs may contribute to the increased prevalence of atopic diseases. AIM: In
      the present study the relationship between tuberculin response and atopic disease
      was investigated. METHODS: A total of 1012 children vaccinated with BCG were
      included in the study. All the children were given five tuberculin units PPD, and
      PPD indurations were recorded after 72 h. The test result was considered to be
      positive if the induration size was greater than 9 mm. The atopic anamnesis
      (atopic dermatitis, rhinitis, conjunctivitis, asthma, urticaria) in the children
      and their families were investigated using a questionnaire. RESULTS: 608
      individual (60.1%) had positive and 404 (39.9%) had negative tuberculin test.
      Positive atopic personal anamnesis was found in 31.74% in children with positive
      tuberculin skin test, whereas 39.85% was found in children with negative
      tuberculin test (p < 0.009, Fischer-test). Similarly more positive family
      anamnesis for atopic diseases was found among children with negative tuberculin
      test. In children with negative tuberculin test the prevalence of allergic
      conjunctivitis and rhinitis was significantly higher as compared to the group
      with positive tuberculin test. CONCLUSIONS: The authors found an inverse
      correlation between tuberculin response and atopy status. The observed decreased
      tuberculin sensitivity in atopic individuals is, however, probably not the cause,
      but rather the consequence of the disturbed immune regulation in atopic diseases.

PMID- 12418377
TI  - [Management of third-trimester low-risk pregnancies--European survey].
AB  - AIM: Main objective of pregnancy care is to provide health both for the mother
      and baby. Two main points of this care are to preselect high and low risk
      pregnancies and to determine the timing of delivery in case of fetal jeopardy or
      maternal emergency situations in the third trimester. Although we have evidence
      based techniques that are effective in reducing perinatal mortality in selected
      high-risk groups, the content of routine pregnancy care in low-risk third
      trimester pregnancies is not well defined yet. Management of these patients
      differs from center to center and from country to country and is mainly
      determined by obstetrical traditions of different geographical areas.
      PATIENTS/METHODS: Based on the data of questionnaires about recent practice of 28
      European obstetrical departments in 10 countries participating in EuroGRIT trial
      the authors sketch out current management of third trimester low risk
      pregnancies. CONCLUSIONS: In spite of current discrepancy in applying functional
      tests it is absolutely required to introduce new methods in the future only
      within the framework of evidence based medicine.

PMID- 12418378
TI  - [Fasting or post-challenge blood glucose values for detection of glucose
      intolerance in screening for metabolic syndrome?].
AB  - INTRODUCTION: The normal-pathological threshold of fasting blood glucose values
      was modified by the new WHO diagnostic criteria (1999) and, in addition, impaired
      fasting glucose (IFG) was introduced as a new clinical entity. Nevertheless, the
      2-h post-glucose challenge criteria and the concept of the impaired glucose
      tolerance (IGT) remained unchanged. There is no unequivocal agreement whether new
      fasting or unchanged post-challenge blood glucose criteria should be used for
      classification of glucose intolerance. AIMS: To assess the clinical-laboratory
      characteristics of metabolic syndrome a screening procedure was performed in
      hypertensive or obese subjects registered within primary health care and the
      reliability of the new fasting blood glucose criteria was analysed. PATIENTS AND
      METHODS: For inclusion, subjects of both sexes aged from 20 to 65 years exhibited
      at least one of the following clinical characteristics: hypertension (ongoing
      antihypertensive treatment or raised (> or = 140/90 mmHg) actual blood pressure),
      abnormal (> 30.0 kg/m2) body mass index [BMI] or elevated waist-hip ratio (> 0.85
      in women, > 0.90 in men). Subjects with known diabetes were not involved. An oral
      glucose tolerance test (OGTT) with 75 g glucose was performed in each subject.
      Subjects with complete clinical and laboratory findings were statistically
      analysed (n = 944; women/men: 545/399; age: 46.1 +/- 7.3 years; BMI 32.2 +/- 5.4
      kg/m2; waist-hip ratio 0.90 +/- 0.09; x +/- SD). RESULTS: In the total cohort
      newly diagnosed diabetes mellitus (based on the 120 min post-challenge glucose
      values) was found in 87 subjects (9.2%), IGT was detected in 136 cases (14.4%)
      while normal glucose tolerance was documented in 721 subjects (76.4%). Using
      fasting blood glucose values for classification, diabetes mellitus was detected
      in 79 subjects (8.4%), IFG was found in 124 cases (13.1%) while 741 subjects
      (78.5%) had normal glucose tolerance. Impaired glucoregulation (IGT + IFG) was
      found in 223 subjects (IGT alone 99 cases [44.4%], IFG alone 87 cases [39.0%],
      IGT and IFG in combination 37 cases [16.6%]). The sensitivity and specificity of
      fasting blood glucose criteria for detecting diabetes were 63.2% and 97.1%,
      respectively, while those for detecting glucose intolerance (IFG and diabetes as
      well as IGT and diabetes) were 52.9% and 88.2%, respectively. Clinical
      characteristics of subjects with abnormal post-challenge but normal fasting blood
      glucose values (n = 105) did not differ significantly from those of subjects with
      normal post-challenge but abnormal fasting blood glucose values (n = 85) (age:
      46.7 +/- 6.9 years vs 46.7 +/- 6.1 years; BMI: 33.1 +/- 5.4 kg/m2 vs 32.3 +/- 4.5
      kg/m2; waist-hip ratio: 0.91 +/- 0.09 vs 0.92 +/- 0.07; p > 0.05). CONCLUSION:
      OGTT and 2-h post-glucose challenge criteria should be used for the diagnosis of
      different categories of glucose intolerance in screening for metabolic syndrome.

PMID- 12418379
TI  - Reverse mortgage decision-making.
AB  - Reverse mortgages have been suggested as a promising financial tool to help low
      income older homeowners who want to remain in their houses. However, actual use
      of this option has been much below early estimates of potential demand. This
      study explored response to the new option through open-ended interviews of
      homeowners who had received reverse mortgage counseling. Decision-making was
      influenced by attachment to home, family input, and financial attitudes,
      including desire to leave a legacy. In general, homeowners took reverse mortgages
      only as a "last resort" that enabled them to maintain their independence.

PMID- 12418380
TI  - Constructing deservingness: federal welfare reform, supplemental security income,
      and elderly immigrants.
AB  - On August 22, 1996, President Clinton signed the welfare reform law that ended
      eligibility for all immigrants to federal means tested entitlements. Poor elderly
      immigrants on Supplemental Security Income were specifically targeted. This
      article documents how the print media responded to these policy changes. The
      following are the major research questions: (1) How were older immigrants on
      Supplemental Security Income portrayed in the print media before and after
      federal welfare reform? (2) Who was involved in the print media coverage of older
      immigrants on Supplemental Security Income before and after federal welfare
      reform? (3) What types of statements were made by those involved in the print
      media coverage of older immigrants on Supplemental Security Income, before and
      after federal welfare reform? The approach used was an in-depth content analysis
      of newspaper articles from major U.S. newspapers. The findings demonstrate that
      older immigrants were constructed as "undeserving" in news articles prior to the
      passage of the federal welfare reform bill. However, after the passage of the
      federal welfare reform bill the coverage of older immigrants on Supplemental
      Security Income started to change, and older immigrants were portrayed as
      "deserving." In advancing aging policy for poor, vulnerable elderly, such as
      elderly immigrants, advocates, health and social service providers can play an
      influential role in bringing their voices to the print media.

PMID- 12418381
TI  - Resource effects on access to long-term care for frail older people.
AB  - Access to long-term care depends primarily on personal resources, including
      family members and income, and on external resources, including Medicaid and
      Medicare. This study investigates how resources affect frail older individuals'
      access to long-term care, with a focus on Black and White widows. Data from the
      1989 National Long-Term Care Survey is used, in conjunction with state-level
      Medicaid and Medicare reimbursement rates for nursing home and home health care,
      to estimate the likelihood of five types of care arrangements. Results show that
      children are a primary resource for unmarried individuals in maintaining access
      to informal care. Income effects are nonlinear in relation to nursing home care:
      increasing incomes below the mean income are associated with decreasing
      probabilities of nursing home care, while increasing incomes above the mean are
      associated with increasing probabilities of nursing home care. Income and
      Medicaid effects are interrelated, with nonlinearities associated with income
      having the potential to adversely affect some older persons' ability to access
      nursing home care.

PMID- 12418382
TI  - Telemedicine, rural elderly, and policy issues.
AB  - Historically, rural America has had a difficult time providing health care to its
      residents, particularly its frail elderly population. Rural health care is often
      faced with a shortage of health care specialists, facilities with inferior
      equipment, and insufficient resources compared to health care in more urban
      areas. It is anticipated that the use of telemedicine will help address many of
      the problems facing the delivery of health care services to rural elderly. This
      paper reviews some innovative projects delivering services to the elderly. Also,
      the paper discusses several issues that need to be addressed before telemedicine
      can reach its full potential in improving access to health care, including
      reimbursement policies, patient and provider liability and confidentiality, and
      the infrastructure supporting telemedicine. Although telecommunications has
      tremendous potential to address the care needs of frail isolated elderly, without
      comprehensive reimbursement policies, guidelines for ethical conduct of a
      teleconsultation, acceptable security measures of patient records, and adequate
      as well as compatible infrastructure, that potential cannot be completely
      realized.

PMID- 12418383
TI  - A review of private residential care in Hong Kong: implications for policy and
      practice.
AB  - Hong Kong government policy encourages and facilitates families to care for their
      older members as long as possible by providing families and their older relatives
      with community support services. Residential care for the elderly is viewed as a
      last resort. Due to the inadequate supply of community support services, the long
      period of care required, and the gradual breakdown of values of filial support,
      families may increasingly give up their caring roles and seek residential care
      for their dependent elderly relatives. A shortfall in subsidized residential care
      may lead to needy elderly persons' being cared for in private residential
      facilities. The demand for private residential care is projected to increase,
      despite criticism about the standard of care provided. Although an Ordinance, a
      Regulation, and a Code of Practice for residential care homes are in place to
      control, monitor, and upgrade private residential care in Hong Kong, problems
      remain that put the elderly at risk of receiving substandard services. These
      include the existence of substandard private aged care homes operating either
      with or without a license; the provision of substandard "places" to the elderly
      under the government's "bought place" scheme and "enhanced bought place" scheme;
      ineffective inspection; a lack of grading to indicate the quality of private aged
      care homes; and a general neglect of the quality of care. We provide
      recommendations to address these concerns. This requires paying attention to both
      the quality of care, as well as to the physical environment of homes.

PMID- 12418384
TI  - Extending private pension coverage in a middle-income country: the case of
      Brazil.
AB  - Government policies can play an important role in the development of private
      pensions. These policies can be divided into three groups: (1) policies that are
      essential to providing a favorable economic environment for pensions; (2)
      policies that encourage the development of private pensions, given that a
      favorable economic environment for them exists; and (3) policies that deal with
      weaknesses of private pension systems. While the policies discussed are generally
      applicable for middle-income countries, the economic and legal environments for
      pensions differ across countries. This article focuses in particular on the
      situation in Brazil.

PMID- 12418385
TI  - [Epidemiological characteristics of multiple sclerosis in Russia].
AB  - An increase in multiple sclerosis (MS) frequency was registered in several
      countries including Russia. This may be associated with better MS diagnosis and
      treatment, better data collection and real increase in MS incidence. Previous
      local studies sometimes were based on mainly hospital cases, so the real
      prevalence was underestimated. Several population-based studies showed that
      Russia is in the zone of medium MS risk. In 1999-2000, 24 local medical
      committees collected the "official" data on the number of resident MS patients,
      which varied greatly. Statistical analyses showed a significant negative
      association (R = -0.68) between estimated level of MS prevalence and the percent
      of severe cases among these MS patients. It is proposed that in several regions
      the number of mild MS cases had been underestimated and thus the percent of
      severe cases was high. Using the rates, received in large population-based
      studies in different countries, we re-calculated the data using the 33% rate of
      severe MS cases as a model. The calculated "model" indexes using "official" data
      in two Russian cities Moscow and Orel (40.8 and 64.8 cases per 100,000 of
      population) were very close to what had been found in these populations in
      population-based epidemiological studies (37.8 and 66.1 cases, respectively).
      Recalculation of the "official" data from all 24 regions showed, that the "model"
      MS prevalence in different regions of Russia varied from 35 till 70 cases per
      100,000 of population, which seems real taking into consideration the
      geographical factor and the ethnic origin of these populations (percents of
      European residents). These "model" numbers may be used before the already started
      all-over-country epidemiological study will be finished.

PMID- 12418386
TI  - [The laboratory diagnosis of multiple sclerosis].
AB  - The importance of laboratory methods for multiple sclerosis (MS) diagnosis and
      differential diagnosis is often overestimated now. The role of several methods
      including MRI, evoked potentials, examination of the cerebrospinal fluid and some
      others methods are discussed in this review. Several conditions may in some
      patients mimick the appearance of MS and it is easy to understand why there is a
      tendency among many clinicians to embark on extensive- and expensive-laboratory
      investigations to establish the correct diagnosis at early stages of the disease.
      Disorders like cerebrovascular diseases, vasculitis, Lyme disease,
      neurosarcoidosis, acute disseminated encephalomyelitis, progressive multifocal
      leukoencephalopathy, HIV-associated encephalitis may cause very close changes of
      the results of these examinations. A detailed, exhaustive history and the
      neurological examination, along with a careful scrutiny of the actual MRI films
      by the neurologist experienced in the diagnosis of MS, will obviate the need for
      additional tests in the overwhelming majority of cases. So, the MS diagnosis and
      differential diagnosis is still based mainly of the data of clinical observation.

PMID- 12418387
TI  - [Mechanisms of lability of neurological symptoms in multiple sclerosis].
AB  - Pathophysiological peculiarities of demyelinated axons determine their high
      sensitivity to different exogenous factors and are the reason of instability of
      neurological signs in MS. One of the typical MS sing is high sensitivity to
      elevated temperature of the body. Even temporary elevation in body temperature
      may cause changes in impulse conduction in demyelinated fibres, which was proved
      by studies of evoked potentials and stabilometric studies. These disturbances may
      be associated with disorder of ions channels function. The role of other factors
      (metabolic and immunological disturbances, levels of cytokines and
      neurotransmitters) in temporary block of nerve conduction in MS is discussed.
      Further studies of the mechanisms of the lability of neurological sings in MS may
      lead to elaboration of new approaches to MS treatment.

PMID- 12418388
TI  - [Complex evaluation of neuropsychological cognitive and emotional personality
      disorders in multiple sclerosis].
AB  - 30 patients with definite MS and mild or moderate disability were tested with
      expended neuropsychological, psychiatric, psychological, neurological,
      neurophysiological, MRI methods. The aim of the study was to analyse the role of
      cognitive, emotional and personal peculiarities in MS clinical picture and its
      influence on patients adaptation and quality of life. It was found, that patients
      with MS had high level of personal anxiety, emotional ways of coping and low
      scores in constructive reasoning, narrowing of motivation sphere.
      Neuropsychological test performance revealed low level in activation, regulatory
      and operation brain processing connected with dysfunction in relations of
      profound structures with frontal brain and dysfunction of temporal-occipital
      zones of right hemisphere and also with connections between hemispheres.
      CONCLUSION: All changes had relationship with brain MRI abnormalities and
      neurophysiological characteristics.

PMID- 12418389
TI  - [Progressive course of multiple sclerosis].
AB  - The mechanisms of MS progression are now studied with great attention and the
      treatment strategies at this stage of MS are widely discussed. The clinical
      peculiarities, genetic profile, immunological and biochemical changes, data of
      pathomorphological and MRI studies are discussed in this review. The data of own
      original immunological, biochemical and MRI studies, comparing relapsing
      remitting and progressive MS course are presented. The role of axonal
      degeneration in the disease progression and data of the last trial of beta
      interferons in secondary progressive MS are also discussed.

PMID- 12418390
TI  - [Possibilities of magnetic resonance visualization in the diagnosis of multiple
      sclerosis].
AB  - Magnetic-resonance imaging (MRI) is considered to be the most informative non
      invasive method in diagnosis, differential diagnosis and estimation of activity
      of multiple sclerosis (MS). MRI data of 270 patients with clinically and
      laboratory definite MS were analyzed to assess diagnostic MRI-criteria for MS,
      MRI presentations at the time of first clinical manifestation of the disease,
      neuroimaging patterns in children and elderly persons with MS. The MRI variants
      of MS are substantiated. Neuroimaging data of cervical spinal cord in 28 patients
      with MS are presented in parallel with corresponding clinical data. The most
      typical patterns are singled out. The data of brain 1H-magnetic-resonance
      spectroscopy (MRS) in 20 patients with MS and 8 patients with inflammatory and
      vascular disorders were analyzed to reveal biochemical distinction between MS and
      non-MS lesions as well as changes in normal appearing white matter in MS. The
      differential-diagnostic value of MRS is limited although decreased N-acetyl
      aspartate peak is characteristic for MS lesions and in some cases in normal
      appearing white matter in primary-progressive MS.

PMID- 12418391
TI  - [Antiphospholipid syndrome and multiple sclerosis: differential-diagnostic
      aspects].
AB  - A comparative study of 5 patients with definite multiple sclerosis who have
      abnormally high titer of anticardiolipin IgG-antibodies [MS aCL(+)] and 9
      patients with antiphospholipid syndrome (APS) aged 22-43 was carried out. The
      results of this study are reported. The investigation has shown that some
      clinical and magnetic resonance imaging (MRI) sings in patients with APS imitate
      the course of MS. This situation makes differentiation of two conditions quite
      difficult. The peculiarities of course of MS aCL(+) such as progressive myelitic
      pattern, nontypical for MS articular, cutaneous (livedo, ecchymoses) and
      vasospastic lesions have been shown. The differential diagnostic clinical,
      immunological and MRI-criteria of two diseases have been found out. The
      investigation reveals that APS has not only cerebrovascular manifestation but
      polyneuropathy (in preference of demyelinating type) and autoimmune myopathy.

PMID- 12418392
TI  - [Multiple sclerosis with early onset: pathogenesis, clinical characteristics,
      possibilities in the treatment of its pathogenesis].
AB  - Early onset multiple sclerosis (MS) has some peculiarities in the disease course.
      56 patients with definite MS with the onset at the age under 15 years were
      included in this clinical, immunogenetical and neurophisiological study. The
      analyses of the relations between different clinical characteristics of MS in
      children has shown, that patients with onset under 10 years, had rare relapses,
      but more progressive development of disability in contrast to the patients with
      MS onset at the age of 11-15 years. Duration of the first remission was
      associated with the time to sustained disability in children with MS. The number
      and volume of MRI T2-positive lesions in the white matter of the brain was
      associated with the age of onset, duration of the disease and with the number of
      relapses. In several cases the phenomena of clinical-MRI dissociation was
      observed. Generic HLA-DRB1 genomic typing was performed in all the patients. High
      frequency of DR2(15) genotype in MS-affected children in comparison with the
      group of healthy controls was more expressed as compared with MS-affected adults.
      The comparison of frequencies of DRB1 alleles in transmitted, i.e. appeared in
      the affected child haplotypes and in non-transmitted haplotypes confirmed results
      of the case-control study showing the very significant association of MS with DR2
      alleles and extremely significant--with its DR15 subtype in children. The data of
      transmission/disequilibrium test (TDT) analysis provide strong evidence for
      linkage of DR15 alleles and susceptibility to sporadic MS in patients with
      disease onset before 15 years. The positive experience of management (beta
      interferon-1a) was shown in MS-affected children in three cases.

PMID- 12418393
TI  - [Mechanisms of glatiramer acetate action in demyelinating diseases: antigen
      specific, organ-specific or process-specific treatment].
AB  - Use of the "disease modifying" medicines is a significant success in multiple
      sclerosis (MS) treatment. These ways of MS treatment were scientificantly based
      and proved in large well-designed randomized studies, while direct mechanisms of
      their action is still under investigation. This review is discussing the
      mechanisms of action of glutiramer acetate (GA)--one of these medicines,
      modifying MS course. Its positive clinical effects in relapsing-remitting MS were
      shown in large clinical studies, confirmed by MRI and supported by extension
      trials. Immunomodulative effects of GA in MS and its experimental model (EAE) may
      be associated with induction of GA-specific cells clone, which have several
      positive for MS features, for example producing anti-inflammatory Th2-cytokines.
      Other characteristics of these cell clones should be studied further.

PMID- 12418394
TI  - [Results of open post-registration clinical trials of copaxone in patients with
      multiple sclerosis].
AB  - Results of the 2-year open postregistration study of Copaxone (glatiramer
      acetate), conducted in 3 Moscow leading medical centres are given. 32 MS patients
      with remitting-relapsing MS were investigated in accordance with international
      requirements (neurological scales, MRI of the brain, multimodal evoked
      potential). Significant reduction of annual relapse rate for 70.3%, stabilization
      of neurological status and benign safety profile were demonstrated during
      Copaxone treatment. Practical recommendations for Copaxone use are given.

PMID- 12418395
TI  - [Beta-interferons in multiple sclerosis: comparative trials and potential
      individual selection in different types of the disease course].
AB  - Beta-interferons (beta-IFN) are effective treatment of relapsing-remitting
      multiple sclerosis (MS). Recent comparative studies showed significantly higher
      efficacy of high doses of beta-IFN used every other day. In secondary progressive
      MS data of beta-IFN trials are not so promising. This may be due to mechanisms of
      action of this medicine: it can effectively block neurodegeneration associated
      with inflammation, while in secondary progressive MS other mechanisms of
      degeneration may be present. Own original studies showed, that the level of MMP9
      in serum can be used as an informative biological marker of beta-IFN activity in
      MS, this treatment could be more effective in DR2(15)-positive individuals and
      the presence of severe brain atrophy at baseline MRI can be used as a predictor
      of less effective results of treatment with beta-IFN. Future studies must define
      the methods, which may be used for selecting the subgroup of MS patients with the
      best response to beta-IFN. Data of pharmacogenetic and pharmacoeconomic studies
      must be helpful.

PMID- 12418397
TI  - [Quality of life in multiple sclerosis and pharmaco-economic studies].
AB  - Early disability and its rapid progression emphasize the medico-social importance
      of MS. The widely used disease-modifying treatments allowed to delay the time of
      severe disability, but this way of treatment is very expensive. The cost of MS is
      discussed based on literature data. The level of the cost of MS greatly depends
      on the disease severity and activity. Thus the studies of quality of life (QL)
      and pharmacoeconomical analysis, besides neurological scales, can give important
      additional information for clinical trials. First such studies in Europe in
      patients with secondary progressive MS showed a delay in progression of QL
      indexes in patients under Betaferon treatment in comparison to placebo. We
      studied changes in MOS SF-36 and WHO QL scales in groups of 60 MS patients,
      receiving Rebif or Copaxone. After 3 months of Rebif significant positive changes
      in scales, reflecting physical and social activity of MS patients, were found. At
      the same time negative changes in the "Pain" scale might reflect the presence of
      local side effects of beta-interferons treatment. No statistically significant
      changes in QL indexes under treatment with Copaxone were seen. The results of QL
      testing were associated with data of neuropsychological tests, characterizing
      chronic fatigue and depression. Thus the measurement of QL indexes may be a
      source of significant additional information, estimating the effecis of treatment
      and is the basic for pharmacoeconomical analysis.

PMID- 12418396
TI  - [New approaches to antioxidant therapy in multiple sclerosis].
AB  - For study of antioxidant therapy efficiency in relapsing-remitting multiple
      sclerosis we investigated group 1 (18 patients) treated with alpha-lipoic acid
      and group 2 (14 patients) who received complex of antioxidants and
      neuroprotectors with various mechanisms of action (oc-lipoic acid, Nicotinamide,
      Acetylcysteine, Triovit Beta-carotine, Alpha-tocopheryl acetate, Ascorbic acid,
      Selenium, Pentoxifylline, Cerebrolysin, Amantadine hydrochloride) during 1 month,
      2 times a year. The treatment resulted in significant reduction (2-3 times) of
      relapse frequency in multiple sclerosis patients (especially in group 2) and
      decrease of required corticosteroid courses. After antioxidant therapy the
      content of lipid peroxide products was significantly reduced (most expressed in
      group 2). The improved method of multicomponent antioxidant and neuroprotective
      therapy can be considered as pathogenic threatment in relapsing-remitting
      multiple sclerosis.

PMID- 12418398
TI  - [Results of treatment of congenital clubfoot with modified Goldner's technique].
AB  - The authors present the results of surgical treatment of resistant idiopathic and
      recurrent clubfoot (type IV according to Dimeglio classification). In the group
      who underwent a primary procedure, results were noted according to the Magone
      classification: 35.7% very good results, 11.9% good results, 9.52% satisfactory
      and 42.5% bad results (recurrent clubfeet accounts for 37.5%). The authors noted
      that the Goldner technique yields results comparable to the peri-talar release
      technique.

PMID- 12418399
TI  - [Long-term clinical and radiological assessment of talocrural joint stability
      after acute traumatic injury of ligamentous-capsular apparatus].
AB  - The author presents an assessment of clinical and radiological talocrural joint
      stability after acute traumatic ankle sprain treated non-operatively.
      Radiological evaluation of joint stability was performed using a special stand
      designed by the author. Joint stability was evaluated in both the sagittal and
      frontal planesusing Zwipp's technique, along with the author's own technique. I
      degree and II degree lateral and antero-lateral instability were found most often
      found in the 368 patient series that was examined. Joint instability was
      recognised more frequently radiologically than clinically.

PMID- 12418400
TI  - [The pathomorphology of congenital spinal defects in relation to future clinical
      development of the disease].
AB  - The authors categorised congenital malformations of the spine into five different
      pathomorphologic groups basing on a series of 61 cases (age ranging from 1 to 50
      years): defects of the vertebra, of the vertebral body, intervertebral
      synostosis, rib synostosis, and defects of the vertebral arch. A total of over 30
      different kinds of malformations were obtained in this classification. In the
      analysed series 34 patients had a predominant kind of malformation, while in 27
      cases mixed malformations were noted. These malformations lead to spine
      deformities: 21 cases with arch scoliosis, 15 cases with kyphoscoliosis, 13 cases
      with angular scoliosis and 12 cases with kyphosis. Deformities had a tendency to
      progress with age. In 20 patients neurological deficits (increased spasticity,
      spastic paresis, spastic and flaccid paralysis) increased after reaching skeletal
      maturity. Prognosis as to deformity regression was made difficult be the large
      variety of different pathomorphologic types of deformity. Only general patterns
      were visible e.g. a tendency to progress in cases were hemivertebra were found.
      In cases were more than one type of deformity was noted, growth balance of the
      spine was not a rule. On the contrary, even small mixed deformities of ten
      progressed. This paper indicates that most congenital deformities of the spine
      should be treated operatively, either to correct the deformity or to attain spine
      growth balance.

PMID- 12418401
TI  - [Early abductor muscle strength after total hip replacement performed by antero
      lateral approach].
AB  - Between November 2000 and April 2001 31 patients with unilateral coxarthrosis
      were assessed in order to determine strength of the hip abductors and hip
      mobility 2 days prior surgery, 10 and 14 days post surgery. All patients
      underwent total hip replacement though an antero-lateral approach. It was found
      that maximal and average muscle strength decreased during the first 2 weeks post
      op, with concomitant increase in time needed to achieve full muscle strength and
      hip mobility.

PMID- 12418402
TI  - [Supporting stabilising plate in treatment of fractures of the distal epiphysis
      of the radius].
AB  - The authors present a modified plate for stabilisation of compound fractures of
      the distal radius. The main advantages are: the simplicity of the operative
      technique and the possibility of early rehabilitation without any external
      fixation. The satisfactory results encourage further application of this
      technique.

PMID- 12418403
TI  - [Gel derived bioactive ceramic as bone substitute--an in vivo study].
AB  - The paper presents the histopathological and radiological study performed on a
      series of male, mixed-race rabbits. All rabbits had a 20 x 4 x 4 mm-bone fragment
      extracted from the radial bone according to a modified technique by Scmitt and
      Weller. In the right radius bone the bone defect was filled with approximately
      0.5 cm3 bioglass S2. In the left rius, which served as control, allogenic bone
      graft (the size of the defect) collected from the tibia and femur was implanted.
      Rabbits were sacrificed 3, 6 and 12 weeks after the procedure and
      histopathological and radiological studies were performed. These studies revealed
      a heterogeneous increase of new bone regeneration in all three phases of the
      study. The S2 biomaterial both stimulated and accelerated bone regeneration in
      the rabbits.

PMID- 12418404
TI  - [Modern biomechanical poroeslatic model of bone tissue. Part II--structure of
      pore space in cortical and trabecular bone].
AB  - In modern bone biomechanics the bone tissue is treated as a porous elastically
      deformed solid filled with a viscous newtonian fluid (two-phase poroelastic
      model) [41]. Traditional one-phase biomechanical model of bone tissue is still
      valid and it can be considered as an approximate model in comparison with the
      more realistic two-phase model of bone tissue. Hierarchical biostructure of the
      pore space of cortical and trabecular bone is presented, including the
      compartments of bone pore space after Cowin [12, 13]. Examples of clinical
      amplications of the poroelastic model of bone tissue such as: osteoporosis,
      porous coated implants, bone electromagnetostimulation in rehabilitation are
      indicated.

PMID- 12418405
TI  - [Lumbar intervertebral herniation. The composition of free sequesters--a
      morphologic study].
AB  - Since 1934 when surgery for lumbar disc herniation was first performed various
      forms of disc herniation have been described. It is generally accepted that disc
      herniations can be classified as follows: disc protrusion, disc prolapse, and
      free sequestration. Histological evaluations of protruded and prolapsed disc have
      been presented in literature, revealing degenerative changes. No special
      attention was given to free sequestered disc elements. The aim of this paper was
      to analyse the frequency of freely sequestered intervertebral disc fragments and
      to investigate the morphologic nature of sequestered discs. The free sequesters
      were observed in 15.5% of all operated cases (N = 187). In 16 (55.2%) of these
      cases the sequester was composed of nucleus pulposus material, in 12 (41.4%)
      cases end-plate elements were noted and in one case (3.4%) anulus fibrosus
      elements were found.

PMID- 12418406
TI  - [The influence of patient age and duration time of symptoms on the long-term
      outcome of surgical treatment].
AB  - The paper presents the influence of patient age and duration time of symptoms on
      the long-term outcome of surgical treatment of cubital tunnel syndrome. The
      material consisted of 57 patients treated at the Department of Hand Surgery
      between 1971 and 1997. Evaluation of the material revealed that there is no
      significant correlation between the age of onset of the symptoms and the result
      of treatment. Significantly better results were observed in post operative
      assessment in patients who have had the neuropathy for a shorter time. Patients
      over 40 years of age should be operated earlier. Results were better when
      assessed in a subjective score system, compared to an objective one.

PMID- 12418407
TI  - [Ulnar nerve stabilisation after anterior transposition].
AB  - The paper presents certain aspects of surgical procedures in the treatment of
      ulnar nerve entrapment syndrome. Eaton's technique is presented, with the use of
      non-compressing fasciodermal sling for anterior transposition of the ulnar nerve.

PMID- 12418408
TI  - [Bilateral simultaneous limb lengthening of patients with short stature using the
      Ilizarov method].
AB  - Limb lengthening of patients with short stature is a complex orthopaedic problem.
      In these cases treatment is a long-term, multistage procedure. This paper
      presents the results of lower limb lengthening using the Ilizarov technique. The
      material consists of 5 cases, in which 10 stages of bilateral simultaneous
      lengthening of the femur and opposite tibia were performed. Follow-up was on
      average 3.1 years. Problems, obstacles and complications were typical for limb
      lengthening procedures and did not differ from the results presented by other
      authors. Success of treatment depends on the patient's full co-operation,
      adequate motivation and knowledge of the principles of therapy.

PMID- 12418409
TI  - [Protocol of lower limb lengthening with the Ilizarov method].
AB  - The aim of this study is simplification of treatment monitoring, along with
      assessment of the passed and present state of the therapeutic process. Strategy
      of treatment with Ilizarov technique is presented. It is based on a short stay on
      the ward after performing the Ilizarov procedure (about 2 weeks), with most of
      the therapeutic process realised at home with support from the outpatient clinic.
      During the distraction phase patients are checked up at the outpatient clinic
      once a week, while during the consolidation phase once every 3-6 weeks. An
      original patient monitoring technique is presented. The protocol allows
      collecting the most important information in a comprehensive way for fast
      clinical evaluation and research.

PMID- 12418410
TI  - [Contemporary possibilities of thumb reconstruction. Part one--"classical"
      methods].
AB  - Loss of the thumb accounts for a 60% decrease of functional value of the hand,
      thus making its reconstruction a priority in the field of hand surgery. Basing on
      available literature and the author's own experiences classical methods (no
      microsurgery) are presented. The following methods are discussed: phalangisation,
      progressive lengthening (of the stump of the proximal phalanx and/or the first
      metacarpal bone), osteoplastic reconstruction, island flaps (Chinese flaps),
      pollicisation, vascular rein technique, along with respective indications,
      operative techniques, results and complications.

PMID- 12418411
TI  - [Fibroma chondromyxoides in two children--a case study].
AB  - The authors present the results of treatment of 2 cases of fibroma
      chondromyxoides in children. In Polish orthopaedic literature only 2 other cases
      have been presented. The first case--a 13-year-old boy--was referred to our
      centre because of a recurrent tumour in the 1st metatarsal bone and surrounding
      soft tissues. The boy had received treatment 3 years earlier outside our centre,
      where curettage of the tumour was performed. The bone cavity was then filled with
      bone grafts. The tumour was removed again and autogenous bone grafts were
      applied. On follow-up 7 years after surgery no recurrence was noted, along with
      full remodelling of the bone grafts. The second case was a 9-year-old child. The
      tumour was localised in the proximal phalanx of the thumb. During curettage and
      application of autogenous bone grafts for the tibia, transplantation of the
      tumour site occurred to the donor site. Two years after surgery tumour recurrence
      was observed. A re-operation was performed, with complete resection of the basal
      phalanx, with a fibular graft implantation. The tumour in the tibia was also
      removed. Two and a half years after surgery both tumour sites remain free of
      signs of recurrence.

PMID- 12418412
TI  - [ABO blood-group system: past and present].
AB  - The ABO blood group system was discovered one hundred years ago; the respective
      ABH antigens were found in the protein and lipid membrane components of various
      cells (most importantly, erythrocytes) and soluble blood group substances. The
      genetics of the ABO system was also elucidated. This old knowledge is still
      useful, bringing new applications. Although we do not really know the complete
      biological role of blood group systems, including that of the major ABO system,
      data, which is still being accumulated, ensure scientists and physicians of its
      importance in research and the diagnosis and therapy of diseases. For example,
      susceptibility to some diseases has been shown to be connected with the blood
      group of the patient, or the phenotype changes of the ABH determinants may
      indicate the presence of defined form of cancer. The data presented in this
      article clearly suggest the validity of the ABO blood group system in medical and
      biological sciences.

PMID- 12418413
TI  - [Molecular characteristics of antibodies recognizing human glycophorin A].
AB  - Glycophorin A, the major sialoglycoprotein of human erythrocytes and carrier of
      MN blood group antigens, is a good model to study immune response against
      glycopeptide antigens. Molecular analysis of several monoclonal antibodies
      recognizing GPA revealed that the immune response against N, but not M, antigen
      is restricted. It was shown that the recombinant Fab fragments expressed in the
      phage display system may provide novel reagents with application in
      immunohematology. The new recombinant Fab fragments revealed increased affinity
      toward GPA. Introduction of dimer-inducing peptides causes creation of bivalent
      Fab fragments revealing increased avidity.

PMID- 12418414
TI  - [Repair of DNA damage using nucleotide excision repair (NER)--relationship with
      cancer risk].
AB  - DNA damage repair, responsible for maintaining the genome integrity, plays a
      central role in cancer biology. Individual DNA repair capacity is genetically
      determined. Inherited defect in nucleotide excision repair (NER) genes leads to
      three distinct and extremely rare disorders: xeroderma pigmentosum, associated
      with high risk of skin cancer, Cockayne syndrome, and trichothiodystrophy. The
      recently identified common polymorphism in several NER genes may also influence a
      risk of cancer in general population. The review presents current knowledge about
      a role of genetic variation of NER genes in cancer predisposition.

PMID- 12418415
TI  - [Antiatherogenic effect of high density lipoprotein].
AB  - Epidemiological studies show the existence of the negative linear correlation
      between low plasma high density lipoprotein (HDL) and frequency of coronary heart
      disease (CHD). The low HDL concentration is connected also with the increasing
      risk of vascular crash in central nervous system. Probably the main mechanism of
      antiatherogenic action of HDL is its participate in the reserve cholesterol
      transport. Four stages are included in this process: the transport of free
      cholesterol from cells to extracellular acceptors (HDL); estrification of HDL
      cholesterol; transport of cholesterol esters from HDL to VLDL and LDL and uptake
      of these lipoproteins and cholesterol esters in the liver. The key role in
      selective uptake in liver and its transport to cells plays scavenger receptor BI.
      It seems probably that it is also applied in mechanism of efflux of cholesterol
      from cells. To other properties of antiatherogenic action of HDL belongs its
      antithrombotic effect: inhibition of adhesion and aggregation of platelets and
      inactivation of plasma Va and VIIIa factors resulting from participation of HDL
      as cofactor in protein C activation. HDL prevents also atherogenic modification
      of LDL by connected with paraoxonase (PON1) activity.

PMID- 12418416
TI  - [Glutathione in therapy].
AB  - It has been commonly accepted that oxidative stress is involved in pathogenesis
      of many serious and even lethal health disturbances, including neurodegenerative
      diseases, diabetes, alcoholic disease, viral and bacterial infections. In this
      paper we discuss the protective antioxidative role of glutathione, the
      predominant non-protein thiol in mammalian cells. We also emphasize the
      perspectives of glutathione therapy i.e. application of both cysteine and
      glutathione precursors.

PMID- 12418417
TI  - [Analysis of gene expression at the entire genome scale--applications in
      biological sciences and medicine].
AB  - Microarrays are one of the latest breakthroughs in experimental molecular
      biology, which allow monitoring of gene expression for tens of thousands of genes
      in parallel and are already producing huge amounts of valuable data. Microarray
      RNA expression on a genome-wide range is now a proven technology, although the
      idea of analysis of expression many genes in one sample is not new. Since the
      development of clone printing technology and oligonucleotide synthesis allowed to
      produce high density microarray. In this publication we provide the information
      about the technology, available detection systems and data analysis software.
      Comprehensive review of current or fundamental papers using microarray technology
      application in immunology, rheumatoid arthritis, oncology, cystis fibrosis
      research, primary pulmonary hypertension, psychiatry, and allergic airways
      inflammation is also included.

PMID- 12418418
TI  - [Multilevel regulation of tyrosine hydroxylase. I. Posttranscriptional levels].
AB  - The tyrosine hydroxylase plays a key role in the catecholamine synthesis
      responding to many stimuli disturbing homeostasis. In this part we described the
      posttranscriptional levels of the gene and the protein regulation including:
      alternative splicing, isoform specificity, feedback inhibition, protein
      phosphorylation and dephosphorylation, protein stability, translational
      regulation.

PMID- 12418419
TI  - Vasomotor reactivity evaluation in cardiac rehabilitation.
AB  - Endothelial dysfunction is a generalized phenomenon detectable at various levels
      in the vasculature, and is evident very early in the atherosclerotic process.
      These peculiarities have stimulated the introduction of new non-invasive
      techniques dedicated to evaluate the vasomotor response of arteries or districts
      in favourable position in the body (forearm, hand) that may reflect the response
      of inner arteries otherwise requiring invasive procedures (i.e. coronary
      arteries). Moreover, these techniques can be theoretically used to detect
      abnormalities of vasomotor response before a clinical adverse event may occur in
      subjects prone to vascular accidents with risk factors for atherosclerosis. Of
      physical stimuli inducing e-NOS activation and subsequent nitric oxide synthesis,
      the shear stress produced by pulsatile blood flow is the most important. This
      property is actually used in clinical practice to study the flow-mediated
      vasodilation (FMD) of the brachial artery. Any condition that reduces the ability
      of endothelial cells to produce nitric oxide causes endothelial dysfunction,
      which is directly reflected into a depressed FMD. There is evidence that brachial
      artery flow-mediated dilation is improved after local as well as systemic
      exercise, suggesting that the improvement in endothelial function is generalized
      and documentable in different arterial districts with similar results. Aerobic
      exercise induces e-NOS expression and improves the endothelial-dependent
      relaxation in normal as well as cardiac patients. The endothelium-independent
      vasorelaxation is generally unchanged after chronic conditioning, but this result
      is not evident in all studies. The improved endothelial vasoreactivity is
      correlated with enhanced functional capacity after moderate aerobic exercise,
      suggesting an important pathophysiological role of oxygen transport in exercise
      tolerance. These beneficial effects has been described in patients with stable
      heart failure in II and III NYHA functional class and in patients with coronary
      artery disease with programs different for frequency, duration and intensity. The
      evaluation of vasomotor reactivity gives promising results in explaining the
      effects of medications and exercise training. The demonstration that flow
      mediated dilation may quantify endothelial dysfunction in subjects with a variety
      of conditions can be used in clinical practice not only to assess the effects of
      interventions, but also to provide a preliminary screening in apparently healthy
      subjects who have an underlying silent coronary artery disease. In cardiac
      rehabilitation, there are promising results from FMD evaluation in selecting
      patients who take major benefits in terms of functional capacity and endothelium
      dependent vasodilation.

PMID- 12418420
TI  - Left atrial function: bridge to central and hormonal determinants of exercise
      capacity in patients with chronic heart failure.
AB  - The stroke volume response to exercise is a critical determinant in meeting
      peripheral metabolic demands in patients with chronic hear failure. The Left
      atrium, by its position, is important in coupling right and left ventricles, to
      left preload reserve and to modulate sympathetic activity. We performed this
      study to investigate the relationship between exercise capacity and diastolic and
      systolic left atrium function in patients with chronic heart failure. METHODS: We
      considered 128 consecutive patients with severe chronic heart failure (EF < 35%)
      due to ischemic or idiopathic dilated cardiomyopathy. Cardiac output, right
      atrial pressure, pulmonary artery pressures and mean pulmonary wedge pressure (A,
      X, V, Y wedge pressures) were determined during right cardiac catheterization. By
      Echocardiography evaluation, we measured atrial pressures and volume during early
      and late left atrial systolic filling and we calculated left atrial chamber
      stiffness by this equation P = A*eKV1. (P = left atrial pressure; A = elastic
      constant (mmHg*ml); e = the base of the natural logarithm; V1 = left atrial
      volume (ml); K = left atrial chamber stiffness constant (ml-1) = ln
      (V/X)/(maximal--minimal left atrial volumes)). All patients performed
      cardiopulmonary exercise test with modified Noughton protocol. Plasma
      norepinephrine and Atrial natriuretic factor levels were determined. RESULTS:
      Maximal and minimal left atrial volumes were inversely related to oxygen
      consumption (r = -.44, p < .001; r = -.61, p < .001). At rest, no differences
      were found in plasma norepinephrine concentrations (309 +/- 152 pg/ml vs 309 +/-
      394 pg/ml; p = ns) and systemic vascular resistance (1706 +/- 435 vs 1771 +/- 524
      dynes/cm sec-5; p = ns) in patients with large or normal left atrial volumes.
      During exercise the chronotropic response increased less in patients with large
      atrial volumes (56 +/- 13 vs 45 +/- 14; p = .001). The left atrial chamber
      stiffness constant was inversely related to peak oxygen consumption and exercise
      time. Patients with different chamber stiffness showed statistical difference in
      peak VO2 (16 +/- 4 vs 11 +/- 3 ml/kg/min; p = .0001). Left atrial ejection
      fraction was directly related to peak oxygen consumption (r = 0.55), but the most
      strongly correlation was with atrial filling fraction (r = .67). CONCLUSIONS:
      This study demonstrates a strong relationship between left atrial function and
      exercise capacity in patients with chronic heart failure.

PMID- 12418421
TI  - [Management of chronic heart failure: clinical features and resource utilization
      among patients managed by the general practitioner. Pilot project in the province
      of Udine (Italy)].
AB  - RATIONALE: In the management of heart failure the general practitioner (GP) plays
      an important role. However, international studies proved that the GP differs in
      the management of these patients from the cardiologist. This pilot study aims at
      investigating if such differences persist in the Italian community. MATERIALS AND
      METHODS: Seventy patients with heart failure have been enrolled prospectively by
      10 GPs in the Udine district (ASL 4). All of them have been evaluated at the
      first and subsequent visits, both with respect to clinical and instrumental
      parameters, overall resource consumption and quality of life. RESULTS: We
      observed a high degree of heterogeneity in the follow up patterns; a low
      coordination between GP and cardiologists in managing patients; several co
      morbidities; high social burden; a good adherence to treatment guidelines; a
      moderate workload, subjectively evaluated from the GP. CONCLUSIONS: This
      experience motivated the need of further research in the field, and, from the
      point of view of the daily practice, the need of integrating hospital and
      community management of patients with heart failure.

PMID- 12418422
TI  - Clinical validation of an anxiety and depression screening test for intensive in
      hospital rehabilitation.
AB  - Routine hospital psychological care must necessarily make use of a clinically
      reliable screening instrument for the identification of the patients to be
      referred for a clinical interview with a psychologist. This study compared two
      tests for the evaluation of anxiety and depression that are widely used in the
      hospital setting: the Hospital Anxiety and Depression Scale (HADS) and Form A-D,
      consisting of the State-Trait Anxiety Inventory (STAI-X1) for the evaluation of
      anxiety, and the Depression Questionnaire (DQ) for measuring depression. The aim
      of the study was to identify which of these instruments is the most suitable for
      screening a population admitted at in-hospital intensive rehabilitation using the
      clinical interview-based psychological evaluation as the gold standard. Both of
      the tests showed a concordance with the clinical opinion expressed by the
      psychologist, whose judgement was guided by the use of the validation study
      evaluation form. The analyses confirmed the good correlation of the two
      instruments in measuring anxiety and depression. The sensitivity of the STAI-X1
      (52%) was less than that of HADS section A (72%), but its specificity (99%) was
      greater than that observed with the application of the HADS Anxiety subscale
      (84%). Analysis of the ROC curves showed that the STAI-X1 percentages of
      sensitivity and specificity tended to balance at higher level with a cut-off
      point equal to the 80th percentile. The results of the analysis of the DQ
      demonstrated equivalence with the results obtained using HADS section D, with a
      cut-off point of the 90th percentile. On the basis of these results, and given
      that both the STAI-X1 and the DQ have a broadly based Italian normative
      population, we feel that they can be recommended for psychological screening of
      patients in an in-hospital intensive rehabilitation.

PMID- 12418423
TI  - [Integrated clinical record: unique document for diverse uses].
AB  - Technological and scientific development and changes in the health system have
      led to modifications and greater complexity in health documents and clinical
      records, without there being at the same time definition of guidelines on their
      correct compilation and formulation. The present study was designed to develop a
      single Integrated Clinical Record that combines, on the one hand, data of all
      medical, nursing and technical interventions and, on the other, involves the
      patient in all decisional processes of diagnosis and treatment during the
      hospitalization period. All phases of the project related to development of the
      Integrated Clinical Record are discussed. The data of 240 new clinical records
      regarding patients admitted consecutively over a period of 6 months are reported.
      The results show a progressive reduction of compilation errors and an improved
      management of the patient's clinical course. The innovative aspects of the new
      clinical record are discussed, with particular reference to the system of quality
      management, within which context the clinical record has to function, and to the
      modalities of check, audit and improvement.

PMID- 12418424
TI  - [Use of nitrates after recent myocardial infarction: when, how, and why].
AB  - Nitrates are useful drugs in patients affected by recent myocardial infarction:
      they have an anti-ischemic and anti-anginal effect; moreover they are effective
      on left ventricular remodeling, with few side-effects. Meta-analysis studies
      performed on patients treated with nitrates intravenously for acute myocardial
      infarction in the pre-thrombolytic era showed a reduction of the necrotic area
      and of the global mortality. On the contrary experimental studies conducted using
      nitrates orally showed no significant clinical effects. Two post-thrombolytic
      studies, ISIS-4 and GISSI-3, enrolling large numbers of patients after an acute
      myocardial infarction, randomized to assume placebo or nitrates, administered
      orally and/or transdermally, demonstrated moderate and significant reductions in
      mortality only in some subgroups of patients treated with the active drug
      compared to placebo. Nitrates as drugs are "imperfect imitators" of endogenous
      nitrates and so can produce some negative effects. In this review the different
      modes of drug administration and the respective posologies of the various
      sublingual, spray, and oral formulations in standard, long-acting or transdermal
      preparations are considered. Three problems should be considered by clinicians
      using nitrates: resistance, tolerance and rebound. The strategies to counteract
      these phenomena, as well as the clinical indications and the favorable effects
      that can be obtained using nitrates in post-infarct patients are also discussed.

PMID- 12418425
TI  - [Anticoagulation in patients with heart valve prosthesis].
AB  - The growing number of recipients of artificial heart valves draws ever more
      frequent attention to the problem of anticoagulant therapy, not only in its daily
      management but also in the event of specific conditions such as pregnancy, extra
      cardiac surgery and invasive cardiac procedures in which specific measures must
      be adopted. In each case it is necessary to take into account not only the
      characteristics of the individual prosthesis but also those of the individual
      patient, each time making an overall assessment of the specific thromboembolic
      risk without forgetting possible complications of hemorrhage. This review
      examines the various mechanisms underlying the thromboembolic risk and, in the
      light of the leading literature on the topic, seeks to identify the most
      appropriate behaviors to adopt in the management of each individual case.

PMID- 12418426
TI  - [Advantages and limitations of the cardiovascular risk charts].
AB  - The absolute risk of cardiovascular events depends on the individual's global
      risk profile, obtained from estimating the effects of multiple risk factors in
      the subject. Several risk charts have been prepared by National Societies to
      calculate the probability of an individual to suffer coronary events during a 10
      year follow-up period. In 1998 the Joint Task Force of the European Society of
      Cardiology published a risk chart which was diffused to promote primary
      prevention in the general population. However, some limitations apply to this
      model in Italy because the Framingham Study equation, which was implemented
      jointly by AHA/ACC for the assessment of cardiovascular risk, works in high risk
      North American populations but may overestimate risk in Mediterranean countries.
      On the other hand, the Carta Italiana del Rischio Cardiovascolare, derived
      successively from 3 different heterogeneous clinical studies to describe the risk
      profile, calculates the total cardiovascular burden in our population. The main
      advantage of introducing risk charts is the spread of prevention in the general
      population to reduce excess risk (> 20%) through suitable treatment. Thus, the
      assessment of high risk subjects warrants significant economic resources, and so
      it is important that it be appropriate. The Osservatorio Epidemiologico
      Cardiovascolare has collected data on the prevalence of cardiovascular risk
      factors in Italy, which could be easily integrated for a risk calculation
      appropriate to our country.

PMID- 12418427
TI  - [Telecardiology: a new way to manage the relation between hospital and primary
      care].
AB  - In medicine, computer-applied technology enables the performance of many
      diagnostic investigations with their transfer to a receiving station for
      referral. The use of telemedicine appears particularly promising in
      cardiovascular disease, because the cost/effectiveness ratio of an early,
      tailored intervention, in terms of life-saving and functional recovery, is
      demonstrated. The development of telemedicine represents an advantage for the
      individual patient in terms of the interaction between primary and secondary
      care. In addition, general practitioners can gain educationally and so be
      equipped to handle more advanced medical problems, thus reducing the number of
      hospital follow-up appointments. Economic savings for the health service are a
      driving force. Evidence to date is that the patient seems satisfied and the
      general practitioner gains competence, but the extent to which telemedicine
      results in reduced follow-up appointments and economic savings is not yet
      established. The findings of studies, even if preliminary, have important
      implications for the design and implementation of the telemedicine service center
      within the health care system. Selection of patients, significant service
      reorganization and provision of logistic support for the setting up and
      functioning of the telemedicine center will be required for it to operate
      efficiently. Future research in this subject needs to be more scientifically
      organized, in order to achieve informed decisions about the appropriate use of
      this technology.

PMID- 12418428
TI  - [Integrated models between hospital and field for patients with heart failure].
AB  - Chronic heart failure is a major health problem, which is growing parallel to the
      increasing proportion of elderly in the population. Recurrent hospitalizations
      occur in about half of the subjects within 6 months after the initial admission.
      Several co-morbidities usually coexist in these patients and influence resource
      utilization and outcome. The high re-admission rates and low proportion of
      patients who are currently enrolled in specific follow-up programs underscore the
      existing pitfalls in outpatient care, and the lack of co-operation between
      hospital departments and out-of-hospital clinics or general practitioners. As a
      consequence, up to half of the hospital admissions may be caused by potentially
      preventable factors. As worldwide health-care cost-containment escalates, it
      becomes crucial to develop new cost-effective strategies to improve the quality
      of care of more severe patients. The implementation of clinic-based heart failure
      programs showed some evidence of an improvement in functional status and in the
      frequency of hospital readmissions. However, patients referred to Heart Failure
      Clinics represent a selected population of patients compared to the overall
      population of "real-world" elderly patients with incapacitating symptoms, serious
      co-morbidities and frequent inability to attend an outpatient clinic. Few trials
      are currently available to verify the efficacy of a clinic-based approach in such
      patients, with discordant results. Other studies have extended the
      multidisciplinary program to the patient's home. These strategies might be
      particularly appropriate and cost-effective if targeted to elderly and higher
      risk patients, and appear to be of particular relevance given the phenomenon of
      progressive aging of the general population. The results of our intensive, nurse
      monitored, homecare surveillance on quality of life and hospitalization rate in
      elderly patients with refractory heart failure who previously failed to reach the
      goal of clinical stability with a clinic-based program extend the effectiveness
      of heart failure programs, in terms of quality of life and hospital readmission,
      to terminally ill subjects with short life expectancy and very high resource
      utilization.

PMID- 12418429
TI  - ["Bad" sleepers... Causes, effects, and diagnosis of sleep-related breathing
      disorders in cardiac patients].
AB  - Cardiovascular and cerebrovascular disease are the most common life-threatening
      disease in the industrialized world. There is high interest in sleep apnea and
      cardiovascular disease: several studies have demonstrated an association between
      sleep apnea and cardiovascular and cerebrovascular events. The aim of this review
      is to critically appraise the possible adverse physiological consequences of
      sleep apnea on the cardiovascular system and to assess whether such adverse
      effects constitute a risk for the development of cardiovascular disease.

PMID- 12418430
TI  - [Implantable defibrillators and prevention of sudden death: clinical and economic
      implications in the light of the MADIT II study].
AB  - The cardioverter-defibrillator is the most effective strategy to prevent sudden
      death in patients with previous episodes of ventricular tachyarrhythmia
      (secondary prevention of sudden death). In recent years the possibility of
      primary prevention of sudden death in selected groups of high risk patients has
      raised great interest. The MADIT II study highlighted the possibility of
      preventing sudden death in patients with coronary artery disease. According to
      this trial, identification of such patients can be performed by means of few
      clinical data and without expensive screenings (i.e. electrophysiological study).
      Indeed, patients with a previous myocardial infarction and low left ventricular
      ejection fraction (< 30%) may benefit from the implant of a cardioverter
      defibrillator, with a reduction of the mortality risk by about 31% in the
      following two years. In the light of these data, implant of a cardioverter
      defibrillator should be proposed in such patients, even if the problem of limited
      economic resources to meet the cost of the devices has to be considered even in
      the richest country of the world. Despite the positive scientific result, MADIT
      II has raised the problem of the effective possibility of adopting this
      therapeutic strategy in clinical practice and this question is still open.
      Strategies to reduce the theoretically high costs implicated by the MADIT II
      study include a reduction in the cost of defibrillators through dynamic market
      forces, the identification of subgroups at higher risk of sudden death, and the
      use of cheap defibrillators with limited diagnostic and therapeutic options. A
      long-term evaluation of the cost-effectiveness for western countries of these
      strategies is necessary to identify in which patient subgroups implant of a
      cardioverter-defibrillator is acceptable, i.e. cost-effective, in terms of
      primary prevention.

PMID- 12418431
TI  - [Role of echocardiography in the different stages of natural history of heart
      failure].
AB  - The prognostic value of echocardiographic findings in patients with heart failure
      is well known. In contrast, few studies have addressed the changing significance
      of echocardiographic findings during the natural history of heart failure.
      Ejection fraction is useful for stratifying the cardiac risk in the early phase
      of the disease, but a further risk stratification among patients with ejection
      fraction < 30%, < 25%, or < 20% has not been observed. On the other hand, the
      identification of a "restrictive" left ventricular filling pattern allows to
      select patients with poor prognosis among those with advanced heart failure. In
      patients with mild to moderate heart failure, the prognostic risk should be
      assessed by ejection fraction and left ventricular filling pattern integrated
      with other echocardiographic findings such as pulmonary venous flow pattern,
      right ventricular function, and transmitral flow pattern changes after exercise.
      In conclusion, the prognostic significance of echocardiographic findings varies
      during the natural history of heart failure, and therefore may differ in the way
      it influences the management and therapeutic approach.

PMID- 12418432
TI  - [Organizational and managerial model for the patient with chronic heart failure].
AB  - Patients with chronic heart failure show a range of care and global therapeutic
      management problems. The main elements for an efficient management are: hospital
      territory integration based on a structured mode of operating and on the
      healthcare professional/patient relationship; rational continuity in the
      treatment; multi-disciplinarity of the interventions; the patient's active
      participation. In the light of these considerations the authors report their own
      direct experience describing the organizational and management model for patients
      with chronic heart failure during the various phases of treatment, from the
      global functional evaluation and treatment program to homecare management
      integrated with the general practitioner.

PMID- 12418433
TI  - [Clinical evaluation of smokers].
AB  - The number of patients who continue to smoke after a major cardiac event is high.
      More and more often the patients ask the cardiologist to help them quitting
      smoking. In the last few years the rapid developments in the neuropharmacological
      field set up the bases for a more effective and evidence based treatment of
      nicotine dependence. Thus a number of reviews, guidelines and original articles
      has been published in internal medicine, cardiology and pneumology journals and
      their main purpose was to increase as much as possible the number of physicians
      able to set up a "specialistic" nicotine dependence treatment. The aim of this
      article is instead to review the stages of the smoker clinical evaluation in a
      "specialistic" environment and to translate them in practical tips ready to be
      used in the cardiological daily practice. Three issues are specifically reviewed:
      motivation to quit, degree of nicotine dependence and the role of mood
      disturbances.

PMID- 12418434
TI  - [Psychological intervention and heart failure: from theory to clinical practice].
AB  - The management of chronic heart failure patients is complicated by the presence
      of multiple comorbid conditions, polypharmacy, psychosocial concerns and
      difficulties with adherence to complex medication, dietary regimen, smoking
      cessation and correct physical activity. Taken together, these factors contribute
      to the persistently high hospitalization and mortality rates as well as to the
      poor quality of life of these patients. In fact the progressive worsening of
      symptoms such as fatigue, breathlessness, anxiety and depression may have a
      negative impact on the patient's quality of life. Nevertheless a psychological
      intervention may contribute positively to enhance functional capacity and quality
      of life, and potentially to improve survival in patients with heart failure. On
      the basis of our experience and the scientific literature, we describe in this
      paper a psychological program for such patients. The psychometric tests used in
      the assessment, the psychological interventions to improve emotional reactions
      and the educational programs for disease management are analysed.

PMID- 12418435
TI  - [Growing complexity of cardiologic intensive rehabilitation: motor rehabilitation
      resources and programs of physical training].
AB  - In the last few years the population referred to cardiac rehabilitation centers
      has changed profoundly: the number of survivors of acute cardiac events has
      increased and heart surgery is being proposed to ever greater numbers of elderly
      patients with frequent and greater comorbidities, which make the management of
      physical training programs more complex. Consequently, just as rehabilitation
      cardiologists have had to expand their field of analyses and professional skills
      and nurses have had to integrate their care protocols, physiotherapists too have
      had to adapt the management of motor rehabilitation programs to the various needs
      and problems of each patient in the different phases of recovery. The aim of this
      paper is to present and discuss the procedures followed in our center concerning
      both the mode and contents of a standard course of motor rehabilitation for
      patients without complications and those for patients with complications. The
      paper analyzes the various assessments, the training program, the instruments of
      control and verification of the results, and discusses the instruments of
      intervention in patients affected by complications such as respiratory
      disturbances, musculoskeletal impairment, complications arising from injury,
      neurological deficit and severe deconditioning. Finally, the role of the
      physiotherapist in the active, propositive management of a recovery program is
      discussed.

PMID- 12418436
TI  - [Cardiovascular risk factors in a population of Southern Lombardy].
AB  - AIM: The aim of this study was to collect data on the incidence of risk factors
      in the population of the province of Cremona. The study is based on findings
      gathered in the course of meetings with the local populace termed "Giornate del
      Cuore" ("Heart Days") promoted by a voluntary association to sensitize the
      population concerning prevention and the ways one can achieve a more appropriate
      lifestyle. MATERIALS AND METHODS: Six risk factors for cardiovascular disease
      were investigated: hypercholesterolemia, hypertension, diabetes, overweight,
      smoking, and hereditary predisposition. RESULTS: A total of 3,618 subjects, 1,783
      males (49.3%) and 1,835 females (50.7%), participated in the study. The number of
      subjects resulting with hypercholesterolemia was: 1249 M and 1426 F; with
      hypertension: 788 M, 783 F; with diabetes: 105 M, 100 F; overweight: 941 M, 892
      F; smoking: 389 M, 253 F; with hereditary predisposition: 593 M, 735 F; 81 males
      and 94 females did not show any risk factor (slightly less than 5%). The scarce
      presence of younger and middle age-groups confirms the low sensitivity of
      individuals at such ages to occasions for information and education on health
      issues. In general it emerged that, regarding the values of cholesterolemia,
      almost all subjects without health problems had never been interested to know the
      value of their own cholesterol; concerning hypertension, on the other hand, a
      more widely diffused awareness of one's own health status was found. CONCLUSIONS:
      Findings confirm how necessary it continues to be to inform and educate to a
      health-oriented lifestyle. Prevention thus constitutes a commitment of the
      greatest importance at both the individual and social level.

PMID- 12418437
TI  - [Epidemiology of ischemic cardiopathy in Tuscany].
AB  - In Italy, parallel to the reduction of mortality due to myocardial infarction
      over the last 20 years there has been an increase in the overall number of
      ischemic cardiac patients. The reason for this is that the decline in incidence
      has been outweighed by an increase both in the number of "survivors" of acute
      events and in the mean age of the population. In Tuscany in 1997 the principal
      cause of death, for both sexes, was cardiovascular disease (39.2% of total deaths
      in males, 23.7% in females). Considering the specific pathologies, in males the
      principal cause of death was ischemic heart disease (13.5%), while in females it
      was cerebrovascular disease (17.4%). For the different age-groups, both in males
      and females cardiovascular disease was the principal cause of death only in the >
      74 year age-group, which accounts for by far the greatest number of deaths and
      thus conditions the statistics, making cardiovascular disease the major cause of
      death in general. In the period 1987-1998 a progressive reduction in the
      mortality due to cardiovascular disease and myocardial infarction was observed in
      both sexes: a comparison of Tuscany with Italy as a whole in 1994 showed lower
      mortality rates in Tuscany across all the subgroups. Finally, the annual rates of
      incidence and mortality concerning myocardial infarction in 1998 are analyzed by
      age-group and, standardized for 100,000 inhabitants, for each of the local
      healthcare zones in Tuscany.

PMID- 12418438
TI  - Rheumatologic diseases in the intensive care unit: epidemiology, clinical
      approach, management, and outcome.
AB  - Patients with systemic rheumatic diseases may be admitted to the ICU because of
      worsening of or development of a new manifestation of the rheumatic disease,
      infections caused by immunosuppression, or adverse effects of drugs used to treat
      rheumatic diseases. Sometimes an unrelated, acute disorder may become life
      threatening because of the underlying rheumatic disorder. Rheumatoid arthritis is
      the most common rheumatic disease seen in ICU patients, followed by systemic
      lupus erythematosus and scleroderma. These three conditions together account for
      up to 75% of rheumatic cases admitted to the ICU. The respiratory system is the
      organ system most commonly affected in the acute process, followed by the renal,
      gastrointestinal, and nervous systems. More than 50% of admissions result from
      infections, and 25% to 35% result from exacerbation of the underlying rheumatic
      condition. In about 20% of patients, the rheumatic disorder may be diagnosed for
      the first time in the ICU. An aggressive approach should be pursued to establish
      the diagnosis of either disease exacerbation or infection. Delay in instituting
      appropriate immunosuppressive or antimicrobial therapy may result in multiple
      organ system failure and a poor outcome. The mortality rate in patients with
      rheumatic disease exceeds that predicted by the APACHE II or SAPS II scores and
      is higher than that in nonrheumatologic ICU admissions. The mortality may exceed
      50% in patients admitted for infection; the prognosis is comparatively better for
      patients with exacerbations of disease activity. Renal failure, coma, and acute
      abdomen are predictors of poor outcome. Early recognition of abdominal
      complications requiring surgical intervention may help reduce mortality.

PMID- 12418439
TI  - Airway problems in patients with rheumatologic disorders.
AB  - The intensivist should be aware of the upper airway manifestations of the common
      rheumatologic disorders which may lead to ICU admission or which may potentially
      pose a problem during airway management. Information should be obtained from the
      patient, the patient's family, and the patient's primary physician, if possible.
      One should be fully prepared with various options in case a problem arises with
      an airway. Equipment for managing a difficult airway should be available.
      Alternate methods of managing the airway (e.g., the laryngeal mask airway,
      fiberoptic scopes, and the WU Scope) (Achi Corporation, Fremont, CA) are of great
      help in dealing with airway problems. The potential for cervical spine
      instability exists in patients with rheumatologic disorders. Intubating with care
      and avoiding spinal movement both seem to be more important than any particular
      mode of intubation in preserving neurologic function. One should make a
      concentrated and serious effort to be as gentle as possible and to avoid even
      minimal trauma to the mucosa in these patients, because they are at risk for
      mucosal edema and subsequent postextubation stridor. In cases of stridor, helium
      oxygen mixtures may be of help and may eliminate the need for reintubation. When
      difficulty in establishing an airway is anticipated, it is prudent to attempt
      airway control in the operating room with surgical assistance standing by should
      cervical tracheotomy is required.

PMID- 12418440
TI  - Arthritis in the intensive care unit.
AB  - Acute arthritis in critically ill patients may be caused by local or systemic
      infection, by a flare of chronic joint disease such as rheumatoid or crystal
      associated arthritis, or by less common entities such as hemarthrosis. Diagnosis
      requires analysis of synovial fluid, and appropriate treatment is based on its
      findings. Prompt diagnosis and treatment are usually necessary to prevent the
      significant morbidity associated with these conditions.

PMID- 12418441
TI  - Systemic lupus erythematosus in the intensive care unit.
AB  - SLE causes significant morbidity and mortality by multisystem organ involvement.
      Infections are the leading cause of morbidity and mortality in patients with SLE.
      Meticulous exclusion of infection is mandatory in patients with SLE, because
      infections may masquerade as exacerbation of underlying disease; and the
      immunosuppression used to treat severe forms of exacerbation of lupus can have
      catastrophic consequences in patients with infections. Corticosteroids are the
      first-line therapy for most noninfectious complications of SLE, with various
      adjuvant immunosuppressive agents such as cyclophosphamide being increasingly
      used in combination with plasmapheresis. Some recent series have shown an
      improved survival rate, but this improvement needs to be confirmed by further
      studies. Controlled trials comparing various therapeutic options are lacking, and
      optimal therapy has not been defined.

PMID- 12418442
TI  - Catastrophic antiphospholipid syndrome in the intensive care unit.
AB  - CAPS is characterized by development of widespread microvascular thrombosis.
      Patients at risk are those with positive aCL or LA factor. Precipitating events,
      such as infection, trauma, surgical procedures, or reduction in anticoagulation
      therapy, may contribute to the development of CAPS. Presentation to the ICU can
      be dramatic, with progressive multiorgan failure and need for rapid institution
      of life-supporting measures. Cardiopulmonary failure has been the major
      contributor to mortality. A variety of therapeutic modalities have been used in
      an attempt to offset the widespread thrombosis and organ damage from high aCL
      levels. Anticoagulation therapy and high dosages of steroids seem to have a
      positive effect on survival.

PMID- 12418443
TI  - Life-threatening complications of systemic sclerosis.
AB  - Pulmonary arterial hypertension is common in patients with SSc. Fig. 1 shows the
      diagnostic and therapeutic approach to PAH in SSc. Doppler echocardiography may
      suggest the diagnosis, but RHC is necessary to confirm PAH and to measure
      vasoreactivity. Therapy is directed at the underlying connective tissue disease.
      Vasoreactive patients often benefit from therapy with high-dose calcium-channel
      [figure: see text] blockers, but most patients are not vasoreactive. Intravenous
      epoprostenol and oral endothelin-1 receptor antagonists improve hemodynamic
      measurements and symptoms in SSc-associated PAH. The therapy of right ventricular
      failure is focused on vasodilators, inotropes, and diuretics with careful
      attention to avoiding systemic hypotension. The scleroderma pulmonary-renal
      syndrome and the scleroderma renal crisis are distinct syndromes with different
      clinical presentations, histopathologic manifestations, treatments, and outcomes.
      The scleroderma pulmonary renal syndrome is an autoimmune vasculitis of kidney
      and lung associated with normal blood pressure. Treatment is supportive, and
      prognosis is dismal. In contrast, scleroderma renal crisis is associated with
      systemic hypertension, onion skinning of afferent arterioles, and response to ACE
      inhibition and renal replacement therapy. Pericardial effusions are common but
      only occasionally lead to tamponade. Esophageal dysmotility is often associated
      with aspiration, leading to pulmonary fibrosis, pneumonia, or ARDS. Diffuse bowel
      involvement may result in pseudo-obstruction, bacterial overgrowth, or
      malabsorption. Prokinetic agents, antibiotics, and parenteral nutrition may be
      required.

PMID- 12418444
TI  - Vasculitis: Wegener granulomatosis, Churg-Strauss syndrome, microscopic
      polyangiitis, polyarteritis nodosa, and Takayasu arteritis.
AB  - Identification, diagnosis, and management of the primary vasculitides and their
      attendant complications is a challenging task for the critical care physician.
      However, with appropriate therapy, the morbidity and mortality of these diseases
      can be markedly improved and allow the individual patient to return to their
      previous functional state.

PMID- 12418445
TI  - Pulmonary-renal syndromes in the intensive care unit.
AB  - Renal disease associated with pulmonary hemorrhage is seen in a variety of
      clinical disorders and is a common cause of admission to intensive care units.
      Recent advances in the understanding of the pathogenesis of these disorders have
      improved the therapeutic options significantly and have favorably influenced the
      course of many of these disorders. This article discusses rheumatologic diseases
      that involve both the kidney and lungs, with emphasis on pathogenesis and
      therapeutic options. Common pulmonary-renal syndromes including anti-glomerular
      basement membrane disease and anti-neutrophil cytoplasmic autoantibodies
      associated vasculitis.

PMID- 12418446
TI  - Central nervous system vasculitis in the intensive care unit.
AB  - Intensivists are sometimes faced with unexplained neurologic defects in ICU
      patients. A subacute presentation over weeks or months characterized by headache
      and mental status change with focal deficits in the absence of evidence of
      secondary vasculitis or other diseases mentioned in the differential diagnosis
      should arouse suspicion of PACNS. Delay in diagnosis of this rare condition may
      lead to additional morbidity and prolong ICU stay. There is also a risk of
      permanent cognitive dysfunction with untreated PACNS. A reactive CSF picture,
      ischemic changes on MR imaging, and alterations in vessel caliber on cerebral
      angiography are not diagnostic but strengthen the evidence for PACNS. A brain
      biopsy may be required to confirm the diagnosis. High-dose steroid therapy with a
      prolonged course and gradual taper controls the disease in most cases. Additional
      immunosuppressive therapy is needed in some patients.

PMID- 12418447
TI  - Neuromuscular disorders in the intensive care unit.
AB  - Neuromuscular disorders encountered in the ICU can be categorized as muscular
      diseases that lead to ICU admission and those that are acquired in the ICU. This
      article discusses three neuromuscular disorders can lead to ICU admission and
      have a putative immune-mediated pathogenesis: the Guillian-Barre syndrome,
      myasthenia gravis, and dermatomyositis/polymyositis. It also reviews critical
      care polyneuropathy and ICU acquired myopathy, two disorders that, alone or in
      combination, are responsible for nearly all cases of severe ICU acquired muscle
      weakness.

PMID- 12418448
TI  - Infections in the immunocompromised rheumatologic patient.
AB  - Immunocompromised patients with rheumatic diseases have an increased risk of
      infections. A major risk factor for infection seems to be the immunosuppressive
      therapy used. Newer therapies for RA may lead to increased rates of infection by
      opportunistic pathogens such as Mycobacteria tuberculosis. Because disease
      manifestation may mimic signs and symptoms of infection, prompt diagnosis may be
      difficult. Familiarity with the likely infections and their causes should aid in
      obtaining the appropriate culture specimens.

PMID- 12418449
TI  - New therapies: plasmapheresis, intravenous immunoglobulin, and monoclonal
      antibodies.
AB  - Rheumatologic emergencies may pose a serious threat to life, and the treatment of
      patients with these illnesses continues to be challenging. In the last decade
      extensive animal and human research has led to development of new therapies.
      Considerable progress has been made in the therapy for RA. Newly developed
      biologic therapies have shown promising results in clinical studies, and two
      agents have already been approved by the FDA. These drugs are currently available
      for therapy and are under close postmarketing scrutiny to assess long-term
      efficacy and safety. Similar therapies are under investigation for SLE.
      Plasmapheresis, once used for many diseases, is now restricted mostly to
      conditions for which its use has been shown to be beneficial in randomized,
      controlled studies. Immunoadsorption is used to target specific disease-producing
      pathogens for removal during extracorporeal therapy. Evidence is accumulating for
      the use of IVIGs in several immune-mediated conditions. The outlook for some
      emergencies continues be grim, however, and various therapies are used based on
      evidence from anecdotal case reports and case series. The new therapies are
      relatively safe, but careful monitoring is needed, because there is potential for
      serious adverse events.

PMID- 12418450
TI  - Heart rhythm problems. New treatment methods are available.

PMID- 12418451
TI  - Stable and long-lasting immune response in horses after DNA vaccination against
      equine arteritis virus.
AB  - Equine arteritis virus (EAV) is the causative agent of the equine viral
      arteritis. It is a small RNA virus with a linear, non-segmented plus RNA genome.
      EAV is a member of the Arteriviridae family that includes porcine reproductive
      and respiratory syndrome virus (PRSSV), simian haemorrhagic fever virus (SHFV)
      and lactate dehydrogenase virus (LDV). The viral transmission is via respiratory
      and reproductive routes. Clinical signs in horses vary, and severe infection can
      lead to abortions in pregnant mares or neonatal foal death. The aim of this study
      was to investigate the development of the immune response in horses after
      immunization with a DNA vaccine harbouring and expressing EAV Open Reading Frames
      (ORF) 2, 5, and 7, in combination with equine interleukin 2 (eqIL2). Three
      boosters followed the basic immunization in two-week intervals. Each immunization
      was a combination of gene gun and intramuscular injection. All horses developed a
      high titer of neutralizing antibodies after basic immunization within 2 weeks.
      Remarkably, this immune response was found to be independent of the age of
      animals. The youngest horse was six-years old, and the oldest twenty-two years
      old. A remarkable difference in the immune response between the young and old
      were not observed. The duration of immunity was investigated during a period of
      one year. After 12 months, neutralizing antibodies were still detectable in all
      the vaccinated horses.

PMID- 12418452
TI  - Early or delayed surgical treatment of supracondylar humeral fractures in
      children.

PMID- 12418453
TI  - International orthopaedic journals: a 15-year review.

PMID- 12418454
TI  - Chronic disease in former college students. VIII. Characteristics in youth
      predisposing to hypertension in later years.

PMID- 12418455
TI  - VirRAD-a "virtual" radiopharmacy learning community: your input needed.

PMID- 12418456
TI  - Central nervous system manifestations after steroid pulse therapy in systemic
      lupus erythematosus.

PMID- 12418457
TI  - Sturge-Weber syndrome in a 14-year-old girl without facial naevus.

PMID- 12418458
TI  - Genetic polymorphism of interleukin-1beta is associated with risk of type 1
      diabetes mellitus in children.

PMID- 12418459
TI  - Advances in orthopaedic oncology.

PMID- 12418460
TI  - Oesophageal scintigraphy for the investigation of dysphagia: in ans out of favour
      - underused when available.
AB  - Oesophageal scintigraphy has been used for more than 25 years and allows
      quantifiable, safe, rapid, non-invasive and well-tolerated assessment of
      oesophageal transit time and function. As technology improves, more complex image
      analysis is becoming possible. Many studies have addressed its usefulness in
      assessing oesophageal dysmotility using manometry as the gold standard: this
      literature is reviewed with reference to both the sensitivity and the specificity
      of the test as well as its application and effectiveness in various disease
      states. The use of scintigraphy in oesophageal cancer is specifically addressed -
      including in co-existing dysmotility.

PMID- 12418461
TI  - Imaging of dopamine transporters in rats using high-resolution pinhole single
      photon emission tomography.
AB  - To date, the vast majority of investigations on the dopaminergic system in small
      animals have been in vitro studies. In comparison with in vitro studies, single
      photon emission tomography (SPET) or positron emission tomography (PET) imaging
      of the dopaminergic system in small animals has the advantage of permitting
      repeated studies within the same group of animals. Dopamine transporter imaging
      is a valuable non-invasive tool with which to investigate the integrity of
      dopaminergic neurons. The purpose of this study was to investigate the
      feasibility of assessing dopamine transporter density semi-quantitatively in rats
      using a recently developed high-resolution pinhole SPET system. This system was
      built exclusively for imaging of small animals. In this unique single-pinhole
      system, the animal rotates instead of the collimated detector. The system has
      proven to have a high spatial resolution. We performed SPET imaging with
      [(123)I]FP-CIT to quantify striatal dopamine transporters in rat brain. In all
      seven studied control rats, symmetrical striatal binding to dopamine transporters
      was seen 2 h after injection of the radiotracer, with striatal-to-cerebellar
      binding ratios of approximately 3.5. In addition, test/retest variability of the
      striatal-to-cerebellar binding ratios was studied and found to be 14.5%. Finally,
      in unilaterally 6-hydroxydopamine-lesioned rats, striatal binding was only
      visible on the non-lesioned side. Quantitative analysis revealed that striatal-to
      cerebellar SPET ratios were significantly lower on the lesioned (mean binding
      ratio 2.2 +/- 0.2) than on the non-lesioned (mean ratio 3.1 +/- 0.4) side. The
      preliminary results of this study indicate that semi-quantitative assessment of
      striatal dopamine transporter density using our recently developed high
      resolution single-pinhole SPET system is feasible in living rat brain.

PMID- 12418462
TI  - The outcome of perioperative wound infection after total hip and knee
      arthroplasty.

PMID- 12418464
TI  - Radiological Society of North America 88th Annual Meeting. December 1-6, 2002.
      Chicago, Illinois, USA. Abstracts.

PMID- 12418463
TI  - Whole-body skeletal imaging in mice utilizing microPET: optimization of
      reproducibility and applications in animal models of bone disease.
AB  - The aims were to optimize reproducibility and establish [(18)F]fluoride ion bone
      scanning in mice, using a dedicated small animal positron emission tomography
      (PET) scanner (microPET) and to correlate functional findings with anatomical
      imaging using computed tomography (microCAT). Optimal tracer uptake time for
      [(18)F]fluoride ion was determined by performing dynamic microPET scans.
      Quantitative reproducibility was measured using region of interest (ROI)-based
      counts normalized to (a) the injected dose, (b) integral of the heart time
      activity curve, or (c) ROI over the whole skeleton. Bone lesions were
      repetitively imaged. Functional images were correlated with X-ray and microCAT.
      The plateau of [(18)F]fluoride uptake occurs 60 min after injection. The highest
      reproducibility was achieved by normalizing to an ROI over the whole skeleton,
      with a mean percent coefficient of variation [(SD/mean) x 100] of <15%-20%.
      Benign and malignant bone lesions were successfully repetitively imaged.
      Preliminary correlation of microPET with microCAT demonstrated the high
      sensitivity of microPET and the ability of microCAT to detect small osteolytic
      lesions. Whole-body [(18)F]fluoride ion bone imaging using microPET is
      reproducible and can be used to serially monitor normal and pathological changes
      to the mouse skeleton. Morphological imaging with microCAT is useful to display
      correlative changes in anatomy. Detailed in vivo studies of the murine skeleton
      in various small animal models of bone diseases should now be possible.

PMID- 12418465
TI  - Is high-dose radioimmunotherapy needed in non-Hodgkin's lymphoma? For.

PMID- 12418467
TI  - [Ultraschall 2002. 26th Three-country meeting of the Swiss, German, and Austrian
      Societies for Ultrasound in Medicine. 23-26 October 2002, Basel. Abstracts].

PMID- 12418466
TI  - Abstracts of the 53rd Annual Meeting of the Irish Cardiac Society. 11-12 October
      2002, Galway.

PMID- 12418468
TI  - Abstracts of the 15th Congress of the European College of
      Neuropsychopharmacology. Barcelona, Spain, 5-9 October 2002.

PMID- 12418470
TI  - Somatostatin receptor scintigraphy using (99m)Tc-EDDA/HYNIC-TOC in graves'
      disease.

PMID- 12418473
TI  - Florida Dental Association membership directories.

PMID- 12418471
TI  - Waterford Surgical October Club and Surgical Section, Royal Academy of Medicine
      Joint Surgical Symposium. 19 October 2002. Abstracts.

PMID- 12418474
TI  - Symposium on Gastrointestinal, Liver and Pancreatic Cancer. Venice, Italy, 6-8
      June 2002.

PMID- 12418475
TI  - Attitude of Czech physicians to adverse drug reaction reporting.
AB  - This survey was carried out to test physicians' knowledge of the principles of
      adverse drug reaction (ADR) reporting. Structured interviews were carried out
      with 500 physicians in all regions of the Czech Republic. The questions were
      aimed at observing ADR, the obligation and the means of reporting, and the source
      of drug information used in practice. Ninety percent (n=448) reported that they
      faced ADR in their practice, and 92% (n=458) were aware of the obligation to
      report, but most (180 general practitioners, 138 specialists) were unclear as to
      what should be reported. Knowledge of the subject of ADR reporting was
      significantly lower (18.4%) among physicians who used primarily the drug
      information provided by pharmaceutical companies than among those who used other
      information sources (38.4%). The low level of knowledge of ADR spontaneous
      reporting system found in our study is one of the reasons for the substantial
      underreporting of ADR in the Czech Republic compared to other European countries.

PMID- 12418477
TI  - Missouri State Medical Association 2002-2003 membership directory.

PMID- 12418476
TI  - Abstracts from the 11th North American International Society for the Study of
      Xenobiotics (ISSX) Meeting. 27-31 October 2002, Orlando, Florida, USA.

PMID- 12418478
TI  - Is high-dose radioimmunotherapy needed in non-Hodgkin's lymphoma? Against.

PMID- 12418479
TI  - [Immunologic disturbance in blood and lymphoid system disorders. Proceedings of
      the VIII Hematologic Conference of the Polish Society of Internal Medicine].

PMID- 12418480
TI  - Lipofuscinosis of the urinary bladder: a complication of chronic interstitial
      cystitis.

PMID- 12418481
TI  - Microscopic polyangiitis with massive myocardial necrosis ans diffuse pulmonary
      hemorrhage.

PMID- 12418482
TI  - [55th Annual meeting of the Japanese Association for Thoracic Surgery. Fukuoka,
      Japan. October 9-11, 2002. Program and Abstracts].

PMID- 12418483
TI  - Poison prevention packaging requirements; exemption of hormone replacement
      therapy products. Final rule.
AB  - The Commission is amending its child-resistant packaging requirements to exempt
      hormone replacement therapy ("HRT") products containing one or more progestogen
      or estrogen substances. Current exemptions cover some HRT products, but not
      others. This rule would uniformly exempt from child resistant packaging
      requirements all HRT products that rely solely on the activity of one or more
      progestogen or estrogen substances.

PMID- 12418484
TI  - Medicare program; changes to the hospital outpatient prospective payment system
      and calendar year 2003 payment rates; and changes to payment suspension for
      unfiled cost reports. Final rule with comment period.
AB  - This final rule with comment period revises the Medicare hospital outpatient
      prospective payment system to implement applicable statutory requirements and
      changes arising from our continuing experience with this system. In addition, it
      describes changes to the amounts and factors used to determine the payment rates
      for Medicare hospital outpatient services paid under the prospective payment
      system. These changes are applicable to services furnished on or after January 1,
      2003. This rule also allows the Secretary to suspend Medicare payments "in whole
      or in part" if a provider fails to file a timely and acceptable cost report. In
      addition, this rule responds to public comments received on the November 2, 2001
      interim final rule with comment period (66 FR 55850) that set forth the criteria
      the Secretary will use to establish new categories of medical devices eligible
      for transitional pass-through payment under the Medicare's hospital outpatient
      prospective payment system. Finally, this rule responds to public comments
      received on the August 9, 2002 proposed rule for revisions to the hospital
      outpatient prospective payment system and payment rates (67 FR 52092). CMS finds
      good cause to waive proposed rulemaking for the assignment of new codes to
      Ambulatory Payment Classifications and for the payment of influenza and
      pneumococcal vaccines under reasonable cost; justification for the waiver will
      follow in a subsequent Federal Register notice.

PMID- 12418485
TI  - [Regional meeting of the Japanese Society of Otolaryngology. Japan. 2001.
      Abstracts].

PMID- 12418486
TI  - Images in neuroscience. Spinal arteriovenous malformation.

PMID- 12418487
TI  - Beta-2 microglobulins in postmenopausal osteoporosis.

PMID- 12418489
TI  - The tetrapeptide N-acetyl-seryl-aspartyl-lysl-proline and angiotensin-converting
      enzyme.

PMID- 12418490
TI  - [Chin Junso--founder of the medical lineage Uirou].
AB  - Chin Junso was an excellent doctor with expertise in the medical sciences gained
      from teachings that originated in the Kin and Gen dynasties. He devised and used
      unique prescriptions with various aromatics, which he collectively called Hoyaku
      (fragrant medication). Although he did not desire to enter government service
      because of his old age, his knowledge and wishes were handed down to his
      descendants. He led a quiet life in his later years by practicing meditation at a
      Zen temple of the Rinzai-shu order. Uirou in Odawara incidentally belongs to the
      Nichiren-shu order and not to the lineage of Junso. Nichiren-shu was a Buddhism
      order popular among townspeople in Kyoto at that time. It may be of interest to
      note the second master Souju and the third master Jouyu contributed to the trade
      between Japan and Korea.

PMID- 12418491
TI  - [Psychoanalysis and sexology in Rio de Janeiro between the two world wars:
      between science and self improvement].
AB  - The beginning of psychoanalysis and sexology in Brazil takes place in the 1920's.
      It develops along the 30's and 40's. During this period, there is also a
      remarkable increase in the number of papers by other kind of specialists in sex,
      as well as translations and publications of European and North American authors
      that are considered today as the founders of such areas of studies. We have tried
      to go deeper into this intellectual mist, which began to surround the issue of
      sex in Brazil during that period of time. In order to do so, we have analyzed the
      publishing industry of the time, focusing the publications on this topic.
      Starting with the different relations these new subjects established with
      medicine, we have tried to understand the different trends they produced in
      Brazilian intellectual domains.

PMID- 12418492
TI  - S-Adenosylmethionine: molecular, biological, and clinical aspects--an
      introduction.
AB  - In clinical research, a novel approach has emerged: some of the essential
      nutrients are being used to treat pathologic conditions. Many of these nutrients,
      including methionine, must first be activated in the liver or in other tissues
      before they can exert their key functions. However, this activating process is
      impaired in disease states and, as a consequence, nutritional requirements
      change. For instance, for methionine to act as the main cellular methyl donor, it
      must first be activated to S-adenosylmethionine (SAMe; also known as
      ademethionine). SAMe is required and is of fundamental importance for the
      metabolism of nucleic acids and polyamines, the structure and function of
      membranes, and as a precursor of glutathione. These processes are often seriously
      altered in various pathologic states addressed in this symposium, but they cannot
      be restored by simply administering methionine. For instance, in liver disease
      associated with impairment of the enzyme that activates methionine to SAMe,
      supplementation with methionine is useless and may even become toxic as it
      accumulates because it is not used. Accordingly, one must correct the lack of
      SAMe by bypassing the deficiency in enzyme activation; this is done by providing
      the product of the defective reaction, namely SAMe. Under these pathologic
      conditions, SAMe becomes crucial for the functioning of the cell. Thus SAMe,
      which is found in all living organisms, becomes the essential nutrient instead of
      methionine. This symposium reviewed the biological and corresponding molecular
      aspects of SAMe metabolism and the clinical consequences of its deficiency or
      supplementation in various tissues.

PMID- 12418493
TI  - S-Adenosyl-L-methionine (SAMe): from the bench to the bedside--molecular basis of
      a pleiotrophic molecule.
AB  - S-Adenosyl-L-methionine (SAMe), a metabolite present in all living cells, plays a
      central role in cellular biochemistry as a precursor to methylation,
      aminopropylation, and transsulfuration pathways. As such, SAMe has been studied
      extensively since its chemical structure was first described in 1952. Decades of
      research on the biochemical and molecular roles of SAMe in cellular metabolism
      have provided an extensive foundation for its use in clinical studies, including
      those on depression, dementia, vacuolar myelopathy, liver disease, and
      osteoarthritis. This article provides an overview of the biochemical, molecular,
      and therapeutic effects of this pleiotrophic molecule.

PMID- 12418494
TI  - Management service organizations closer to breaking even.

PMID- 12418495
TI  - Expression of Tbx6, a muscle lineage T-box gene, in the tailless embryo of the
      ascidian Molgula tectiformis.

PMID- 12418496
TI  - Pseudo torsades de pointes.

PMID- 12418498
TI  - Health care executives honor book and article of year.

PMID- 12418497
TI  - Electrophysiological neuroimaging of the central effects of S-adenosyl-L
      methionine by mapping of electroencephalograms and event-related potentials and
      low-resolution brain electromagnetic tomography.
AB  - BACKGROUND: S-Adenosyl-L-methionine (SAMe, or ademetionine) is a naturally
      occurring molecule used as both a nutraceutical and a pharmaceutical to treat
      depression. OBJECTIVE: The central mode of action of SAMe was investigated in 20
      healthy volunteers by mapping of electroencephalograms (EEGs) and event-related
      potentials (ERPs) and low-resolution brain electromagnetic tomography (LORETA).
      DESIGN: In an acute and subacute, double-blind, placebo-controlled, crossover
      study, subjects received in random order infusions of 800 mg SAMe and placebo for
      7 d, with a washout period of 3 wk between the 2 treatment periods. EEG
      recordings were made 0, 1, 3, and 6 h after and ERP recordings were made 0 and 1
      h after the drug infusions on days 1 and 7. RESULTS: Multivariate analyses of
      variance and Hotelling T2 tests showed significant acute and subacute
      encephalotropic effects of SAMe compared with placebo. Acute pharmaco-EEG changes
      were typical of classic antidepressants of the thymoleptic type; subacute
      alterations were typical of cognition enhancers. Regarding ERPs, standard N1 and
      P2 latencies were shortened, and target P300 latencies were lengthened. N1
      amplitudes increased after subacute treatment, and temporooccipital P300
      amplitudes increased after the acute dose. Similar changes were described for
      antidepressants. LORETA showed that the N2 source strength increased in both the
      left and the right temporal lobes, whereas the P300 source strength increased in
      the dorsolateral prefrontal regions and decreased in the ventral limbic regions.
      CONCLUSION: EEG-ERP mapping identified SAMe as an antidepressant. LORETA targeted
      brain regions crucial in the therapeutic efficacy of antidepressants.

PMID- 12418499
TI  - Efficacy and tolerability of oral and intramuscular S-adenosyl-L-methionine 1,4
      butanedisulfonate (SAMe) in the treatment of major depression: comparison with
      imipramine in 2 multicenter studies.
AB  - BACKGROUND: S-Adenosyl-L-methionine (SAMe), a natural compound, is the most
      important methyl donor in the central nervous system. In several clinical trials,
      SAMe showed antidepressant activity. OBJECTIVE: Two multicenter studies were
      conducted in patients with a diagnosis of major depressive episode [baseline
      score on the 21-item Hamilton Depression Rating Scale (HAM-D) >or=18] to confirm
      the efficacy and safety of SAMe in the treatment of major depression. In the
      first study (MC3), 1600 mg SAMe/d was given orally; whereas, in the second study
      (MC4), 400 mg SAMe/d was given intramuscularly. In both studies, the effects of
      SAMe were compared with those of 150 mg imipramine/d given orally in a double
      blind design. DESIGN: In MC3, 143 patients received oral SAMe and 138 patients
      received imipramine for 6 wk. In MC4, 147 patients received SAMe intramuscularly
      and 148 patients received imipramine for 4 wk. In both studies the 2 main
      efficacy measures were the final HAM-D score and the percentage of responders to
      Clinical Global Impression at the endpoint. Secondary efficacy measures were the
      endpoint Montgomery-Asberg Depression Rating Scale scores and the percentage of
      responders, responders being those patients showing a decrease in HAM-D score of
      >or=50% from baseline. RESULTS: In both studies, the results of SAMe and
      imipramine treatment did not differ significantly for any efficacy measure.
      However, significantly fewer adverse events were observed in the patients treated
      with SAMe. CONCLUSIONS: The antidepressive efficacy of 1600 mg SAMe/d orally and
      400 mg SAMe/d intramuscularly is comparable with that of 150 mg imipramine/d
      orally, but SAMe is significantly better tolerated.

PMID- 12418500
TI  - Genetic testing explored in Congressional briefing.

PMID- 12418501
TI  - Importance of a deficiency in S-adenosyl-L-methionine synthesis in the
      pathogenesis of liver injury.
AB  - One of the features of liver cirrhosis is an abnormal metabolism of methionine--a
      characteristic that was described more than a half a century ago. Thus, after an
      oral load of methionine, the rate of clearance of this amino acid from the blood
      is markedly impaired in cirrhotic patients compared with that in control
      subjects. Almost 15 y ago we observed that the failure to metabolize methionine
      in cirrhosis was due to an abnormally low activity of the enzyme methionine
      adenosyltransferase (EC 2.5.1.6). This enzyme converts methionine, in the
      presence of ATP, to S-adenosyl-L-methionine (SAMe), the main biological methyl
      donor. Since then, it has been suspected that a deficiency in hepatic SAMe may
      contribute to the pathogenesis of the liver in cirrhosis. The studies reviewed
      here are consistent with this hypothesis.

PMID- 12418502
TI  - ACHCA membership and certification linked to high-quality care.

PMID- 12418503
TI  - S-adenosyl-L-methionine: its role in the treatment of liver disorders.
AB  - S-Adenosyl-L-methionine (SAMe) exerts many key functions in the liver, including
      serving as a precursor for cysteine, 1 of 3 amino acids of glutathione--the major
      physiologic defense mechanism against oxidative stress. SAMe is particularly
      important in opposing the toxicity of free oxygen radicals generated by various
      pathogens, including alcohol, which cause oxidative stress largely by the
      induction of cytochrome P4502E1 (CYP2E1) and by its metabolite acetaldehyde. SAMe
      also acts as the main methylating agent in the liver. The precursor of SAMe is
      methionine, one of the essential amino acids, which is activated by SAMe
      synthetase (EC 2.5.1.6). Unfortunately, the activity of this enzyme is
      significantly decreased as a consequence of liver disease. Because of decreased
      utilization, methionine accumulates and, simultaneously, there is a decrease in
      SAMe that acquires the status of an essential nutrient and therefore must be
      provided exogenously as a supernutrient to compensate for its deficiency.
      Administration of this innocuous supernutrient results in many beneficial effects
      in various tissues, mainly in the liver, and especially in the mitochondria. This
      was shown in alcohol-fed baboons and in other experimental models of liver injury
      and in clinical trials, some of which are reviewed in other articles in this
      issue.

PMID- 12418504
TI  - Leukemia incidence in the world.

PMID- 12418505
TI  - Where does your practice keep its medical records?

PMID- 12418506
TI  - Big future in tiny spaces. Nanotechnology is moving from labs to business.

PMID- 12418507
TI  - Meet the khat-heads.

PMID- 12418508
TI  - Technology and patient safety.

PMID- 12418509
TI  - Motor-vehicle occupant injury: strategies for increasing use of child safety
      seats, increasing use of safety belts, and reducing alcohol-impaired driving.
AB  - The Task Force on Community Preventive Services has conducted systematic reviews
      of interventions designed to increase use of child safety seats, increase use of
      safety belts, and reduce alcohol-impaired driving. The Task Force strongly
      recommends the following interventions: laws requiring use of child safety seats,
      distribution and education programs for child safety seats, laws requiring use of
      safety belts, both primary and enhanced enforcement of safety belt use laws, laws
      that lower the legal blood alcohol concentration (BAC) limit for adult drivers to
      0.08%, laws that maintain the minimum legal drinking age at 21 years, and use of
      sobriety checkpoints. The Task Force recommends communitywide information and
      enforcement campaigns for use of child safety seats, incentive and education
      programs for use of child safety seats, and a lower legal BAC for young drivers
      (in the United States, those under the minimum legal drinking age). This report
      provides additional information regarding these recommendations, briefly
      describes how the reviews were conducted, and provides information to help apply
      the interventions locally.

PMID- 12418510
TI  - Network of veterinary diagnostic laboratories would strengthen nation's
      biosecurity.

PMID- 12418511
TI  - "Puppy mill" bill: intentions, good; implementation, another story.

PMID- 12418512
TI  - Communicating in a crisis: making the best of a bad situation.

PMID- 12418513
TI  - More thoughts on calf roping, steer tripping.

PMID- 12418514
TI  - More thoughts on calf roping, steer tripping.

PMID- 12418515
TI  - What is your diagnosis? Supernumerary premolars and molars (cheek teeth).

PMID- 12418516
TI  - Employment of male and female graduates of US veterinary medical colleges, 2001.
AB  - Among graduates who received employment offers, 89.5% of males and 84.1% of
      females accepted an offer. Mean starting salary was $39,120 for females and
      $40,052 for males.

PMID- 12418517
TI  - Animal behavior case of the month. Attention-getting behavior.

PMID- 12418518
TI  - The ethical content of veterinary medical practice acts.

PMID- 12418519
TI  - Pituitary ACTH and adrenocortical secretion in critically ill dogs.
AB  - OBJECTIVE: To evaluate pituitary-adrenal function in a population of critically
      ill dogs by measuring serial plasma concentrations of basal cortisol, ACTH
      stimulated cortisol, and endogenous ACTH. DESIGN: Prospective study. ANIMALS: 20
      critically ill dogs admitted to an intensive care unit (ICU). PROCEDURE: Basal
      plasma cortisol, ACTH-stimulated cortisol, and endogenous ACTH concentrations
      were measured for each dog within 24 hours of admission and daily until death,
      euthanasia, or discharge from the ICU. Established reference ranges for healthy
      dogs were used for comparison. Survival prediction index (SPI) scores were
      calculated for each dog within 24 hours of admission. RESULTS: No significant
      difference was found between initial concentrations of basal cortisol, ACTH
      stimulated cortisol, and endogenous ACTH in 13 dogs that survived and those in 7
      dogs that died. High initial basal endogenous ACTH concentrations were correlated
      with subsequent high values. Low basal ACTH-stimulated cortisol concentrations
      were predictive of higher subsequent values. All basal and ACTH-stimulated
      cortisol concentrations were within or above the reference range in the 52 plasma
      samples collected from the 20 dogs during hospitalization. The SPI scores
      correlated with outcome (ie, alive or dead), but none of the plasma hormone
      concentrations correlated with SPI score or outcome. CONCLUSIONS AND CLINICAL
      RELEVANCE: Results indicate that none of the critically ill dogs in our study
      population developed adrenal insufficiency during hospitalization in the ICU.

PMID- 12418520
TI  - Prevalence of feline leukemia virus infection and serum antibodies against feline
      immunodeficiency virus in unowned free-roaming cats.
AB  - OBJECTIVE: To determine prevalence of FeLV infection and serum antibodies against
      feline immunodeficiency virus (FIV) in unowned free-roaming cats. DESIGN: Cross
      sectional serologic survey. ANIMALS: 733 unowned free-roaming cats in Raleigh,
      NC, and 1,143 unowned free-roaming cats in Gainesville, Fla. RESULTS: In Raleigh,
      overall prevalence of FeLV infection was 5.3%, and overall seroprevalence for FIV
      was 2.3%. In Gainesville, overall prevalence of FeLV infection was 3.7%, and
      overall seroprevalence for FIV was 4.3%. Overall, FeLV prevalence was 4.3%, and
      seroprevalence for FIV was 3.5%. Prevalence of FeLV infection was not
      significantly different between males (4.9%) and females (3.8%), although
      seroprevalence for FIV was significantly higher in male cats (6.3%) than in
      female cats (1.5%). CONCLUSIONS AND CLINICAL RELEVANCE: Prevalence of FeLV
      infection and seroprevalence for FIV in unowned free-roaming cats in Raleigh and
      Gainesville are similar to prevalence rates reported for owned cats in the United
      States. Male cats are at increased risk for exposure to FIV, compared with female
      cats.

PMID- 12418521
TI  - Large-bodied Demodex mite infestation in 4 dogs.
AB  - Large-bodied Demodex mites were detected in 4 dogs. The mites were readily
      detected in material obtained via deep skin scrapings and were most commonly
      found on the trunk. The mites were distinguishable from D. canis, because adult
      males were approximately 100% longer and adult females were approximately 50%
      longer than adult male and female D. canis mites, respectively. The large-bodied
      mites were found in the hair follicles, sebaceous ducts, and sebaceous glands in
      histologic sections of skin from 2 dogs. All dogs had adult-onset generalized
      demodicosis. Two dogs had coexistent iatrogenic hypercortisolism, 1 dog had
      hypothyroidism, and 1 dog did not have coexistent disease. Infestations responded
      to miticidal therapy, control of the coexistent disease, or both.

PMID- 12418522
TI  - Radiographic evidence of degenerative joint disease in geriatric cats: 100 cases
      (1994-1997).
AB  - OBJECTIVE: To determine prevalence of radiographic evidence of degenerative joint
      disease (DJD) in geriatric cats. DESIGN: Retrospective study. POPULATION: 100
      cats > 12 years of age. PROCEDURE: One investigator reviewed radiographs and for
      each articulation (or group of articulations) that was visible assigned a grade
      of severity (0, 1, 2, 3) for DJD. Another investigator reviewed medical records
      and recorded signalment, environment, previous disease, diseases evident at time
      of radiography, FeLV vaccination and infection status, feline immunodeficiency
      virus serologic status, serum creatinine concentration, serum globulin
      concentration, and any other important findings. Associations between DJD of
      grade 2 or 3 and variables recorded from the medical record were determined.
      RESULTS: Radiographic evidence of DJD was evident in 90% of cats. Neurologic
      disease was associated with lesions in the lumbosacral portion of the vertebral
      column. Severe lesions were found in 17% of the elbow joints, but an underlying
      cause was not determined. CONCLUSIONS AND CLINICAL RELEVANCE: Degenerative joint
      disease was detected radiographically in most geriatric cats and may be an
      overlooked cause of clinical disease. Clinicians should be alert to the
      possibility that DJD is associated with neurologic signs.

PMID- 12418523
TI  - Dysautonomia in dogs: 65 cases (1993-2000).
AB  - OBJECTIVE: To determine signalment, history, clinical findings, results of
      autonomic function testing and other antemortem diagnostic tests, and pathologic
      findings in dogs with dysautonomia. DESIGN: Retrospective study. ANIMALS: 65 dogs
      with dysautonomia. PROCEDURE: Case records of 68 dogs with a diagnosis of
      dysautonomia were reviewed; inclusion criteria included histologic confirmation
      of dysautonomia or clinical signs and results of pharmacologic testing consistent
      with dysautonomia. RESULTS: 65 dogs fulfilled all criteria for dysautonomia. Dogs
      from rural environments were overrepresented, and cases of dysautonomia were
      reported for every month, although the highest number of cases was reported in
      February and March. Vomiting was the most common clinical sign, followed by
      diarrhea, signs of anorexia and depression, weight loss, and dysuria. The most
      common physical examination finding was decreased or absent anal tone, followed
      by absent pupillary light reflexes and elevated nictitating membrane. Results of
      pharmacologic testing were consistent with dysautonomia, although no single test
      was 100% sensitive. Histologic lesions consistent with dysautonomia were found in
      the autonomic ganglia, brainstem nuclei, and ventral horns of the spinal cord.
      CONCLUSIONS AND CLINICAL RELEVANCE: Dysautonomia is an endemic disease in Kansas,
      and a high index of suspicion of the disease can be made by combining clinical
      signs, physical examination findings, and results of pharmacologic testing.

PMID- 12418524
TI  - Effect of lameness on milk yield in dairy cows.
AB  - OBJECTIVE: To examine the relationship between lameness and milk yield in dairy
      cows. DESIGN: Cohort study. ANIMALS: 531 dairy cows. PROCEDURE: Cows affected
      with lameness were classified into 1 of 3 groups on the basis of type of diseases
      or lesions observed, including interdigital phlegmon (foot rot), papillomatous
      digital dermatitis (foot warts), or claw lesions. Cows not affected with lameness
      were classified as healthy. From Dairy Herd Improvement Association records, 305
      day mature equivalent milk yield data were collected at the end of lactation or
      when the cow left the herd. Milk yield was compared between cows affected with
      lameness and healthy cows. RESULTS: 167 (31%) cows were affected with lameness
      during lactation. Lame cows had claw lesions (60%), papillomatous digital
      dermatitis (31%), or interdigital phlegmon (9%). Milk yield in lame cows with
      interdigital phlegmon (mean, 17,122 lb) was significantly less, compared with
      healthy cows (19,007 lb). CONCLUSIONS AND CLINICAL RELEVANCE: In this herd,
      interdigital phlegmon was associated with a 10% decrease in milk production. Lame
      cows with claw lesions or papillomatous digital dermatitis produced less milk
      than healthy cows, but the difference was not significant.

PMID- 12418525
TI  - Prevalence of fecal shedding of Salmonella spp in dairy herds.
AB  - OBJECTIVE: To estimate prevalence of Salmonella spp in Ohio dairy farms and to
      identify potential risk factors for fecal shedding of salmonellae. DESIGN: Cross
      sectional study. SAMPLE POPULATION: 105 Ohio dairy farms. PROCEDURE: Individual
      fecal samples from all mature cows in study herds were tested for Salmonella spp
      by use of standard bacteriologic culture procedures. Herds were identified as
      infected if at least 1 cow was shedding Salmonella spp. Information regarding
      herd characteristics, management practices, and health history were collected.
      Potential risk factors for herd-level Salmonella infection were identified.
      RESULTS: In 31% of the study herds (95% confidence interval, 22 to 40%), at least
      1 cow was shedding Salmonella spp. Six percent of 7,776 fecal samples contained
      Salmonella organisms; prevalence within infected herds ranged from < 1 to 97%.
      Herd size, use of free stalls for lactating and nonlactating cows, and use of
      straw bedding in nonlactating cows were significantly associated with fecal
      shedding of Salmonella spp, as determined by use of univariate analysis. By use
      of multivariate analysis, large herds were more likely to be infected than
      smaller herds; however, no other factors were associated with Salmonella
      infection after adjustment for herd size. CONCLUSIONS AND CLINICAL RELEVANCE:
      Subclinical shedding of Salmonella spp is common in Ohio dairy herds, although we
      could not identify specific interventions that may influence the prevalence of
      Salmonella spp on dairy farms. It appears that large herd size and intensive
      management may provide an environment conducive to Salmonella shedding and
      chronic dairy herd infection.

PMID- 12418526
TI  - Persistent fecal Salmonella shedding in five dairy herds.
AB  - OBJECTIVE: To monitor patterns of Salmonella fecal shedding in naturally infected
      dairy herds, determine the association between fecal shedding and individual
      animal production measures, and evaluate potential risk factors for shedding of
      Salmonella organisms among cattle in dairy herds. DESIGN: Longitudinal study.
      SAMPLE POPULATION: 5 Ohio dairy herds. PROCEDURE: For 3 herds, fecal samples were
      collected from all mature cows and unweaned calves 7 times during an 18-month
      period. For the remaining 2 herds, fecal samples were collected from 50 lactating
      cows 6 times during a 12-month period. Individual animal production records for 3
      herds were used to examine associations between individual fecal Salmonella
      shedding status and 305-day mature-equivalent milk production, somatic cell
      count, milk fat content, and milk protein content. Multivariable logistic
      regression was used to test for associations between fecal shedding status and
      breed, lactation status, lactation number, and duration of lactation. RESULTS:
      None of the adult animals had clinical signs of salmonellosis, but prevalence of
      fecal Salmonella shedding at individual collection times ranged from 0 to 99% for
      cows and from 0 to 67% for unweaned calves. Mature cows were more likely to be
      shedding Salmonella organisms than were unweaned calves. Within herds, lactation
      status and duration of lactation for individual animals were associated with
      Salmonella shedding status. Salmonella fecal shedding status was not associated
      with individual cow production measures. CONCLUSIONS AND CLINICAL RELEVANCE:
      Results suggest that subclinical fecal Salmonella shedding can persist in dairy
      herds for up to 18 months with no measurable effects on health or production of
      individual cows.

PMID- 12418527
TI  - Prevalence of Mycobacterium bovis infection in cervids on privately owned
      ranches.
AB  - OBJECTIVE: To determine prevalence of tuberculosis caused by infection with
      Mycobacterium bovis in cervids on privately owned ranches in northeastern lower
      Michigan. DESIGN: Epidemiologic survey. ANIMALS: Cervids on 96 privately owned
      ranches. PROCEDURES: A combination of slaughter and skin tuberculin testing was
      used to collect data. Infection with M. bovis was confirmed by use of standard
      necropsy and bacteriologic culture techniques. RESULTS: Cervids with tuberculosis
      were detected on 1 of the 96 ranches. The apparent prevalence of tuberculosis in
      cervids from the 96 ranches was 1.1 cases/100 cervids (21 cases/1,867 cervids
      tested). For the ranch with infected cervids, prevalence of infection with M.
      bovis was 12.1 cases/100 cervids (21 cases/174 cervids tested). No obvious gross
      lesions were seen in 8 of 21 white-tailed deer and 1 coyote with culture
      confirmed M. bovis infection. CONCLUSIONS AND CLINICAL RELEVANCE: The lack of
      visible lesions in a substantial proportion of infected animals should be taken
      into consideration in studies involving detection and prevalence of tuberculosis.

PMID- 12418528
TI  - Farming, disease control and the environment: an increasingly complex area.

PMID- 12418529
TI  - Geographical clustering of cases of bovine spongiform encephalopathy (BSE) born
      in Switzerland after the feed ban.
AB  - Over one-third of the cases of BSE in Switzerland have been born after the feed
      ban of December 1, 1990. Evidence for the geographical clustering of these cases
      emerged in two distinct regions. All the 354 BSE cases recorded until June 30,
      2000 (set A), and the 376 cases recorded up to May 14, 2001 (set B), were
      georeferenced to the centres of the communities in which the herds of origin were
      located, and control populations were georeferenced to the centres of the
      communities in which these herds were located at the time of the census. The
      latitudes and longitudes of these centres were used in the statistical analysis
      of the spatial clustering. The Cuzick-Edwards test and the spatial scan
      statistics were applied to assess the significance of the clusters, while
      controlling for the spatial distribution of the underlying cattle population.
      There was global clustering of the cases born after the ban, and distinct and
      significant (P<0.05) spatial clusters were repeatedly identified in the two case
      datasets, and in several control populations (all cases born before the feed ban
      on a random sample of control farms) in terms of cattle density by region or cow
      density by region. Differential reporting was excluded as the underlying reason
      for the observed clusters.

PMID- 12418530
TI  - Isolation of mycoplasma species from the lower respiratory tract of healthy
      cattle and cattle with respiratory disease in Belgium.
AB  - Between 1997 and 2000, a total of 150 healthy cattle and 238 animals with
      respiratory disease were examined for six Mycoplasma species. Attempts were made
      to detect Mycoplasma canis, Mycoplasma dispar and Ureaplasma diversum in calves
      with recurrent disease, and all three of these species were identified in calves
      with recurrent disease and in healthy lungs. In healthy calves, 84 per cent of
      bronchoalveolar lavage fluids were mycoplasma free; when cultures were positive,
      Mycoplasma bovirhinis was the only species isolated. Mycoplasmas were isolated
      from 78 per cent of animals suffering recurrent respiratory disease and from 65
      per cent of acute respiratory cases. Mycoplasma bovis was isolated from
      bronchoalveolar lavages from 35 per cent of calves suffering recurrent
      respiratory disease, and from 50 per cent of acute cases, and from 20 per cent of
      pneumonic cases examined postmortem. M bovis was associated with other Mycoplasma
      species in 44 per cent of cases. M dispar was also isolated from 45.5 per cent of
      calves suffering recurrent respiratory disease, often in association with M
      bovis. M canis was identified for the first time in diseased Belgian cattle.
      Other mycoplasmas, including Mycoplasma arginini, Mycoplasma alkalescens and U
      diversum, were isolated less frequently. Associations between mycoplasmas and
      other pathogens were often observed. Among lungs infected with Pasteurella and/or
      Mannheimia species, more than 50 per cent were mixed infections with M bovis.

PMID- 12418531
TI  - Evaluation of glucose as a cryoprotectant for boar semen.
AB  - Fertility parameters of boar spermatozoa were evaluated in vitro, after freeze
      thawing the semen in three different extenders containing permeable and non
      permeable cryoprotectants: A (111.0 mM Tris, 31.4 mM citric acid, 185.0 mM
      glucose, 20 per cent egg yolk, 3 per cent glycerol and 100 iu/ml penicillin G); B
      (200 mM Tris; 70.8 mM citric acid, 55.5 mM glucose, 20 per cent egg yolk, three
      per cent glycerol and 100 iu/ml penicillin G); C (200 mM Tris, 70.8 mM citric
      acid, 55.5 mM fructose, 20 per cent egg yolk, 3 per cent glycerol and 100 iu/ml
      penicillin G). The freeze-thawing techniques were the same for each extender.
      Eight ejaculates from four boars were obtained; the sperm-rich fraction of each
      ejaculate was extended in each of the three media at a final concentration of 400
      x 106 sperm/ml, loaded into 0.5 ml straws and frozen at a rate of 30 degrees
      C/minute to -196 degrees C. The straws were thawed at 60 degrees C for eight
      seconds. Sperm motility, acrosomal integrity and in vitro sperm penetration
      through the zona pellucida of gilt oocytes matured in vitro were evaluated. The
      motility of unfrozen spermatozoa was 93.1 per cent compared with 60.7 per cent,
      48.2 per cent and 35 per cent for sperm frozen in extenders A, B and C
      respectively; these values were all significantly different (P<0.05). There was
      no significant decline in sperm motility after incubation for 30 minutes in
      extender A, but there were significant decreases in sperm motility after 30
      minutes of incubation in B and C. The percentage acrosomal integrities were 97.2
      per cent for the control and 45.5 per cent, 30.3 per cent and 16.8 per cent for
      the frozen-thawed spermatozoa in extenders A, B and C respectively. The results
      of the in vitro penetration assay were 80.7 per cent when using control
      spermatozoa, and 42.2 per cent, 18.4 per cent and 3.3 per cent when using frozen
      thawed spermatozoa in extenders A, B and C respectively

PMID- 12418532
TI  - The BSE-susceptible proportion of UK sheep.

PMID- 12418533
TI  - Disease investigation into free-ranging Kafue lechwe (Kobus leche kafuensis) on
      the Kafue Flats in Zambia.

PMID- 12418534
TI  - Concurrent outbreak of PMWS and PDNS in a herd of pigs in Korea.

PMID- 12418535
TI  - Malignant catarrhal fever in cattle with suspected bracken poisoning.

PMID- 12418536
TI  - Testing for maedi-visna.

PMID- 12418537
TI  - Controlling movement to control disease.

PMID- 12418539
TI  - Future of the BVA.

PMID- 12418538
TI  - Competition Commission inquiry into POMs.

PMID- 12418540
TI  - Nocardia otitidiscaviarum infection in a cat.

PMID- 12418541
TI  - Screening tests to detect Chlamydia trachomatis and Neisseria gonorrhoeae
      infections--2002.
AB  - Since publication of CDC's 1993 guidelines (CDC, Recommendations for the
      prevention and management of Chlamydia trachomatis infections, 1993. MMWR
      1993;42[No. RR-12]:1-39), nucleic acid amplification tests (NAATs) have been
      introduced as critical new tools to diagnose and treat C. trachomatis and
      Neisseria gonorrhoeae infections. NAATs for C. trachomatis are substantially more
      sensitive than previous tests. When using a NAAT, any sacrifice in performance
      when urine is substituted for a traditional swab specimen is limited, thus
      reducing dependence on invasive procedures and expanding the venues where
      specimens can be obtained. NAATs can also detect both C. trachomatis and N.
      gonorrhoeae organisms in the same specimen. However, NAATs are usually more
      expensive than previous tests, making test performance from an economic
      perspective a key consideration. This report updates the 1993 guidelines for
      selecting laboratory tests for C. trachomatis with an emphasis on screening men
      and women in the United States. (In this report, screening refers to testing
      persons in the absence of symptoms or signs indicating C. trachomatis or N.
      gonorrhoeae infection.) In addition, these guidelines consider tests from an
      economic perspective and expand the previous guidelines to address detection of
      N. gonorrhoeae as well as C. trachomatis infections. Because of the increased
      cost of NAATs, certain laboratories are modifying manufacturers' procedures to
      improve test sensitivity without incurring the full cost associated with
      screening with a NAAT. Such approaches addressed in these guidelines are pooling
      of specimens before testing with a NAAT and additional testing of specimens whose
      non-NAAT test result is within a gray zone. This report also addresses the need
      for additional testing after a positive screening test to improve the specificity
      of a final diagnosis. To prepare these guidelines, CDC staff identified pertinent
      concerns, compiled the related literature published during 1990 or later,
      prepared tables of evidence, and drafted recommendations. Consultants, selected
      for their expertise or disciplinary and organizational affiliations, reviewed the
      draft recommendations. These final guidelines are the recommendations of CDC
      staff who considered contributions from scientific consultants. These guidelines
      are intended for laboratorians, clinicians, and managers who must choose among
      the multiple available tests, establish standard operating procedures for
      collecting and processing specimens, interpret test results for laboratory
      reporting, and counsel and treat patients.

PMID- 12418542
TI  - Iron deficiency--United States, 1999-2000.
AB  - Iron deficiency, the most common nutritional deficiency worldwide, has negative
      effects on work capacity and on motor and mental development in infants,
      children, and adolescents, and maternal iron deficiency anemia might cause low
      birthweight and preterm delivery. Although iron deficiency is more common in
      developing countries, a significant prevalence was observed in the United States
      during the early 1990s among certain populations, such as toddlers and females of
      childbearing age. One of the national health objectives for 2010 is to reduce
      iron deficiency in these vulnerable populations by 3-4 percentage points
      (objective no. 19-12). CDC has published recommendations to prevent iron
      deficiency in the United States. To characterize the iron status of persons in
      the United States, CDC calculated the prevalence of iron deficiency and iron
      deficiency anemia by applying a multiple-indicator model to data from the 1999
      2000 National Health and Nutrition Examination Survey (NHANES 1999-2000). These
      values were compared with those observed in the third National Health and
      Nutrition Examination Survey (NHANES III [1988-1994]) using the same multiple
      indicator model. This report summarizes the results of this analysis, which
      indicate that iron deficiency remains 2-5 percentage points above the 2010
      national health objectives. To prevent iron deficiency, vulnerable populations
      should be encouraged to eat iron-rich foods and breast-feed or use iron-fortified
      formula for infants.

PMID- 12418543
TI  - Usual sources of cigarettes for middle and high school students--Texas, 1998
      1999.
AB  - Persons often begin smoking when they are minors (aged <18 years), and easy
      access to cigarettes might contribute to this behavior. Laws and regulations were
      in place in Texas during 1998-1999 to reduce minors' access to cigarettes by 1)
      prohibiting the sale and distribution of tobacco products to minors; 2) imposing
      fines against retailers caught selling cigarettes to minors; 3) prohibiting
      minors from purchasing, possessing, or using tobacco products; 4) limiting
      vending machines to adult-only locations; and 5) requiring tobacco retailers to
      ask for proof of identification from anyone attempting to purchase tobacco who
      appeared to be aged <27 years. To measure progress in reducing access to
      cigarettes among middle and high school students in Texas, CDC analyzed self
      reported data from the 1998 and 1999 Texas Youth Tobacco Survey (TYTS). This
      report summarizes the results of that survey, which indicate that during 1998
      1999, reported access to cigarettes from stores and vending machines (commercial
      sources) decreased among middle school students from 13.2% to 5.3% and from 7.6%
      to 1.7%, respectively, but access from noncommercial and other sources (e.g.,
      stealing cigarettes and "getting them some other way") increased from 8.3% to
      12.3% and from 16.6% to 23.3%, respectively. Among high school students, most
      sources did not change. Educating retailers and actively enforcing laws governing
      youth access to tobacco as part of a comprehensive tobacco-control approach are
      required to reduce youth access to cigarettes.

PMID- 12418544
TI  - Vancomycin-resistant Staphylococcus aureus--Pennsylvania, 2002.
AB  - Staphylococcus aureus is one of the most common causes of hospital- and community
      acquired infections. Since the recognition of vancomycin-resistant enterococci in
      1988, the emergence of vancomycin-resistant S. aureus (VRSA) (minimum inhibitory
      concentration [MIC] > or = 32 microg/mL) has been anticipated. The transfer of
      the genetic element containing the vanA vancomycin resistance gene from
      Enterococcus faecalis to S. aureus was demonstrated in the laboratory in 1992;
      the first clinical infection with VRSA was reported in July 2002. This report
      describes the second documented clinical isolate of VRSA from a patient.

PMID- 12418546
TI  - Recommended adult immunization schedule--United States, 2002-2003.
AB  - Although the childhood immunization program in the United States has reduced the
      burden of vaccine-preventable disease substantially among children, substantial
      vaccine-preventable morbidity and mortality from diseases such as hepatitis A,
      hepatitis B, influenza, and pneumococcal infections continue to occur among
      adults. In February 2002, the Advisory Committee on Immunization Practices (ACIP)
      approved for the first time a schedule for the routine vaccination of persons
      aged > or = 19 years. The Adult Immunization Schedule has been accepted by the
      American Academy of Family Physicians (AAFP) and the American College of
      Obstetricians and Gynecologists (ACOG). ACIP will review and approve annually
      both the recommended adult and childhood immunization schedules. Together, these
      schedules provide a comprehensive summary of recommendations for prevention of
      vaccine-preventable diseases during the life span of persons in the United
      States.

PMID- 12418547
TI  - Complex I and the cAMP cascade in human physiopathology.
AB  - A cAMP-dependent protein kinase (PKA) is localized in mammalian mitochondria with
      the catalytic site at the matrix side of the membrane where it phosphorylates a
      number of proteins. One of these is the 18 kDa(IP) subunit of the mammalian
      complex I of the respiratory chain, encoded by the nuclear NDUFS4 gene.
      Mitochondria have a Ca(2+)-inhibited phosphatase, which dephosphorylates the 18
      kDa phosphoprotein of complex I. In fibroblast and myoblast cultures cAMP
      dependent phosphorylation of the 18 kDa protein is associated with stimulation of
      complex I and overall respiratory activity with NAD-linked substrates. Mutations
      in the human NDUFS4 gene have been found, which in the homozygous state are
      associated with deficiency of complex I and fatal neurological syndrome.

PMID- 12418548
TI  - Thyroid hormones and mitochondria.
AB  - Because of their central role in the regulation of energy-transduction,
      mitochondria, the major site of oxidative processes within the cell, are
      considered a likely subcellular target for the action that thyroid hormones exert
      on energy metabolism. However, the mechanism underlying the regulation of basal
      metabolic rate (BMR) by thyroid hormones still remains unclear. It has been
      suggested that these hormones might uncouple substrate oxidation from ATP
      synthesis, but there are no clear-cut data to support this idea. Two
      iodothyronines have been identified as effectors of the actions of thyroid
      hormones on energy metabolism: 3',3,5-triiodo-L-thyronine (T3) and 3,5-diiodo-L
      thyronine (T2). Both have significant effects on BMR, but their mechanisms of
      action are not identical. T3 acts on the nucleus to influence the expression of
      genes involved in the regulation of cellular metabolism and mitochondria
      function; 3,5-T2, on the other hand, acts by directly influencing the
      mitochondrial energy-transduction apparatus. A molecular determinant of the
      effects of T3 could be uncoupling protein-3 (UCP-3), while the cytochrome-c
      oxidase complex is a possible target for 3,5-T2. In conclusion, it is likely that
      iodothyronines regulate energy metabolism by both short-term and long-term
      mechanisms, and that they act in more than one way in affecting mitochondrial
      functions.

PMID- 12418549
TI  - Reconstitution of novel mitochondrial uncoupling proteins UCP2 and UCP3.
AB  - Reconstitution of novel mitochondrial uncoupling proteins, human UCP2 and UCP3,
      expressed in yeast, was performed to characterize fatty acid (FA)-induced H+
      efflux in the resulted proteoliposomes. We now demonstrate for the first time
      that representatives of physiologically abundant long chain FAs, saturated or
      unsaturated, activate H+ translocation in UCP2- and UCP3-proteoliposomes.
      Efficiency of lauric, palmitic or linoleic acid was roughly the same, but oleic
      acid induced faster H+ uniport. We have confirmed that ATP and GTP inhibit such
      FA-induced H+ uniport mediated by UCP2 and UCP3. Coenzyme Q10 did not further
      significantly activate the observed H+ efflux. In conclusion, careful instant
      reconstitution yields intact functional recombinant proteins, UCP2 and UCP3, the
      activity of which is comparable with UCP1.

PMID- 12418550
TI  - Bcl-2 family of proteins: life-or-death switch in mitochondria.
AB  - An increase in the permeability of outer mitochondrial membrane is central to
      apoptotic cell death, and results in the release of several apoptogenic factors
      such as cytochrome c into the cytoplasm to activate downstream destructive
      programs. The voltage-dependent anion channel (VDAC or mitochondrial porin) plays
      an essential role in disrupting the mitochondrial membrane barrier and is
      regulated directly by members of the Bcl-2 family proteins. Anti-apoptotic Bcl-2
      family members interact with and close the VDAC, whereas some, but not all,
      proapoptotic members interact with VDAC to open protein-conducting pore through
      which apoptogenic factors pass. Although the VDAC is involved directly in
      breaking the mitochondrial membrane barrier and is a known component of the
      permeability transition pore complex, VDAC-dependent increase in outer membrane
      permeability can be independent of the permeability transition event such as
      mitochondrial swelling followed by rupture of the outer mitochondrial membrane.
      VDAC interacts not only with Bcl-2 family members but also with proteins such as
      gelsolin, an actin regulatory protein, and appears to be a convergence point for
      a variety of cell survival and cell death signals.

PMID- 12418551
TI  - Yeast as a model to study apoptosis?
AB  - Programmed cell death (PCD) serves as a major mechanism for the precise
      regulation of cell numbers, and as a defense mechanism to remove unwanted and
      potentially dangerous cells. Despite the striking heterogeneity of cell death
      induction pathways, the execution of the death program is often associated with
      characteristic morphological and biochemical changes termed apoptosis. Although
      for a long time the absence of mitochondrial changes was considered as a hallmark
      of apoptosis, mitochondria appear today as the central executioner of programmed
      cell death. This crucial position of mitochondria in programmed cell death
      control is not due to a simple loss of function (deficit in energy supplying),
      but rather to an active process in the regulation of effector mechanisms. The
      large diversity of regulators of apoptosis in mammals and their numerous
      interactions complicate the analysis of their individual functions. Yeast,
      eukaryotic but unicellular organism, lack the main regulators of apoptosis
      (caspases, Bcl-2 family members, ...) found in mammals. This absence render them
      a powerful tool for heterologous expression, functional studies, and even cloning
      of new regulators of apoptosis. Great advances have thus been made in our
      understanding of the molecular mechanisms of Bcl-2 family members interactions
      with themselves and other cellular proteins, specially thanks to the two hybrid
      system and the easy manipulation of yeast (molecular biology and genetics). This
      review will focus on the use of yeast as a tool to identify new regulators and
      study function of mammalian apoptosis regulators.

PMID- 12418552
TI  - Molecular investigations on tRNAs involved in human mitochondrial disorders.
AB  - Over the last decade, human neurodegenerative disorders which correlate with
      point mutations in mitochondrial tRNA genes became more and more numerous. Both
      the number of mutations (more than 70) and the variety of phenotypes
      (cardiopathies, myopathies, encephalopathies as well as diabetes, deafness or
      others) render the understanding of the genotype/phenotype relationships very
      complex. Here we first summarize the efforts undertaken to decipher the initial
      impact of various mutations on the structure/function relationships of tRNAs.
      This includes several lines of research, namely (i) investigation of human
      mitochrondrial tRNA structures, (ii) comparison of disease-related and
      polymorphic mutations at a theoretical level, and (iii) experimental
      investigations of affected tRNAs in the frame of mitochondrial protein synthesis.
      A new approach aimed at searching for long-range effects of mitochondrial tRNA
      mutations on a broader global mitochondrial level will also be presented. Initial
      results obtained by comparative mitochondrial proteomics turn out to be very
      promising for deciphering unexpected molecular partners involved in the
      pathological status of the mitochondria.

PMID- 12418553
TI  - Mitochondrial dysfunction in sepsis: evidence from bacteraemic baboons and
      endotoxaemic rabbits.
AB  - Mitochondria, that provide most of the ATP needed for cell work, and that play
      numerous specific functions in biosyntheses and degradations, as well as
      contributing to Ca2+ signaling, also play a key role in the pathway to cell
      death. Impairment of mitochondrial functions caused by mutations of mt-genome,
      and by acute processes, are responsible for numerous diseases. The involvement of
      impaired mitochondria in the pathogenesis of sepsis is discussed. By means of the
      skinned fiber technique and high resolution respirometry, we have detected
      significantly reduced rates of mitochondrial respiration in heart and skeletal
      muscle of endotoxaemic rabbits. Mitochondria from heart were more affected than
      those from skeletal muscle. Decreased respiration rates were accompanied by
      reduced activities of complex I + III of the respiratory chain. Endotoxin-caused
      impairment was also detectable at the level of the Langendorff perfused heart,
      where the coronary vascular resistance was significantly increased. For an
      investigation of the influence of bacteraemia on the mitochondrial respiratory
      chain, baboons were made septic by infusion of high and low amounts of E. coli.
      For complex I + III and II + III, a clear dose-dependent decrease was detectable
      and in animals which died in septic shock, a further decrease of enzyme
      activities in comparison to the controls were found. These results are discussed
      in the light of current knowledge on the role of mitochondria in cell pathology
      in respect to sepsis. In conclusion, we present evidence that mitochondrial
      function is disturbed during sepsis. Besides ischaemic and poison-induced
      disturbances of mitochondrial function, sepsis is a further example of an acute
      disease where impaired mitochondria have to be taken into account.

PMID- 12418554
TI  - Rat hindlimb unloading: Soleus and Extensor Digitorum Longus histochemistry,
      mitochondrial DNA content and mitochondrial DNA deletions.
AB  - Mitochondrial phenotypic alterations, mitochondrial DNA content and mitochondrial
      DNA deletions in a slow, Soleus, and a fast, Extensor Digitorum Longus, skeletal
      muscle of 3- and 15-month-old hindlimb suspended rats have been studied.
      Cytochrome c oxidase-negative fibers appeared after unloading in all examined
      animals and their percentage increased with increasing unloading time. After 14
      days of suspension the mitochondrial DNA content did not change in 3-month-old
      but decreased significantly in 15-month-old rats. Soleus was much more affected
      by unloading than Extensor Digitorum Longus. The mitochondrial DNA deletion of
      4834 bp as well as other mtDNA deletions, researched with Long Distance-PCR, were
      absent in both studied muscles before and after unloading.

PMID- 12418555
TI  - Introduction: PROTEKT against respiratory tract infection.

PMID- 12418556
TI  - Global surveillance through PROTEKT: the first year.
AB  - The increasing antimicrobial resistance amongst bacterial pathogens causing
      community-acquired respiratory tract infections (CARTIs) necessitates
      surveillance at the local, regional, national and international levels to provide
      information to guide empiric antimicrobial therapy. PROTEKT (Prospective
      Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin) is a
      longitudinal, global, multicenter surveillance study designed to monitor the
      worldwide development of antimicrobial resistance and disseminate up-to-date
      information via the internet to assist in the choice of empiric therapy at the
      local level. In this paper, the results for the first year of PROTEKT are
      presented from a global perspective. Streptococcus pneumoniae, followed by
      Haemophilus influenzae and Moraxella catarrhalis, are the principal organisms
      responsible for the majority of CARTIs. The global prevalence of penicillin G
      resistance in S. pneumoniae has risen to an alarming 36.3% (high-level resistance
      22.1%, intermediate-level 14.2%) with the highest prevalence found in Asia (68%).
      In all regions, macrolide resistance is greater than penicillin G resistance with
      a global prevalence rate of 31.2%. High resistance rates were also found for
      tetracycline (30.5%) and co-trimoxazole (43.9%), and multiresistance was found
      between penicillin G, macrolides, tetracycline and co-trimoxazole. The prevalence
      of beta-lactamase-producing H. influenzae and M. catarrhalis was found to be
      similar to previous reports. Macrolide resistance in S. pyogenes was 0.3%
      overall. Telithromycin demonstrated excellent in vitro activity against all
      organisms and is a potential new candidate for the empiric therapy of CARTIs. The
      first year of PROTEKT has provided valuable information on the prevalence of
      antimicrobial resistance of bacterial agents causing CARTIs that can be used for
      guiding empiric therapy and policies. The rapidly developing and geographically
      varying resistance observed in this study further emphasizes the need for
      accurate up-to-date surveillance data.

PMID- 12418557
TI  - What can PROTEKT tell us at a local level?
AB  - Because of increasing antimicrobial resistance in bacterial pathogens causing
      community-acquired respiratory tract infections (CARTIs), surveillance at local,
      regional, national and international levels is necessary to provide information
      to guide empiric antimicrobial therapy. PROTEKT (Prospective Resistant Organism
      Tracking and Epidemiology for the Ketolide Telithromycin) is a longitudinal,
      global, multicenter surveillance study designed to monitor the worldwide
      development of antimicrobial resistance, and disseminate up-to-date information
      via the internet to assist in the choice of empiric therapy at the local level.
      In this paper, the results for the first year of PROTEKT are presented from a
      local perspective. In examples from Japan, USA and Europe, great variation was
      observed between antimicrobial susceptibility patterns for Streptococcus
      pneumoniae, Streptococcus pyogenes and Haemophilus influenzae in countries and
      cities in close proximity to each other. Telithromycin demonstrated excellent in
      vitro activity against all organisms and is a potential new candidate for the
      empiric therapy of CARTIs. The first year of PROTEKT has provided valuable
      information on the prevalence of antimicrobial resistance of bacterial agents
      causing CARTIs that can be used for guiding empiric therapy and policies.
      Variation in local resistance observed in this study further emphasizes the need
      for accurate up-to-date surveillance data at the local level.

PMID- 12418558
TI  - Prevalence and characterization of macrolide resistance in clinical isolates of
      Streptococcus pneumoniae and Streptococcus pyogenes from North America.
AB  - Resistance to macrolides is not a new phenomenon but it deserves attention
      because of the widespread use of these agents and their inclusion in many
      clinical guidelines for respiratory tract infections. The most common mechanisms
      by which Streptococcus pneumoniae and Streptococcus pyogenes develop resistance
      to macrolides is by target site modification (erythromycin ribosome methylase,
      erm) and efflux of the drug out of the organisms (macrolide efflux, mef). Target
      site modification may be of greater concern because it confers high-level
      resistance to all antimicrobials in the macrolide-lincosamide-streptograminB
      (MLSB) group. The genotype profiles of macrolide-resistant S. pneumoniae and S.
      pyogenes differ somewhat across regions in the US and between the US and Canada
      and other countries. There is some evidence for an association between macrolide
      resistance and treatment failure but this must be researched more fully. S.
      pneumoniae and S. pyogenes isolates resistant to macrolides are generally
      susceptible to ketolide antimicrobials because these agents bind more strongly to
      the relevant domain of the ribosomal subunit (withstanding erm resistance) and
      are less vulnerable to efflux compared to the macrolides.

PMID- 12418559
TI  - The rise of fluoroquinolone resistance: fact or fiction.
AB  - Fluoroquinolone antibiotics have been available since the 1980s when
      ciprofloxacin and norfloxacin were licensed. Structural revisions of the
      quinolone molecule have provided new compounds that were well suited to the
      treatment of upper and lower community-acquired respiratory tract infections,
      having good activity against Streptococcus pneumoniae. Nevertheless, it was only
      a matter of time before the pneumococcus developed effective resistance against
      these new agents. There are populations of fluoroquinolone-resistant S.
      pneumoniae and, more worryingly, many of these strains are also resistant to
      penicillin and to macrolides. Surveillance studies such as PROTEKT (Prospective,
      Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin) can
      provide an early warning system and, with the provision of global surveillance on
      a local level, can assist in the selection of empirical antibiotic treatment. The
      new ketolide antibiotic, telithromycin, has excellent activity against the major
      community-acquired respiratory pathogens (including atypical/intracellular
      organisms), and has the advantage of retaining its activity against strains of S.
      pneumoniae that are resistant to penicillin, macrolides and fluoroquinolones.

PMID- 12418560
TI  - Clinical and public health implications of macrolide-resistant Streptococcus
      pneumoniae.
AB  - Macrolide resistance among Streptococcus pneumoniae is a growing global concern,
      although its specific impact on public health is not currently well defined. A
      Consensus Working Group was convened in March 2001 to address whether credible,
      scientific data substantiate macrolide resistance in S. pneumoniae as: (i)
      producing significant morbidity; (ii) creating attendant health and economic
      burdens; (iii) constituting a public health threat; and (iv) warranting
      intervention, including development of new antibiotics with efficacy against
      these strains. Despite the limitations of available clinical data, concern about
      the possibility of treatment failure with macrolides is being expressed in
      clinical practice and in formal treatment guidelines, threatening the important
      role of these agents in the treatment of respiratory tract infections. Further
      studies are required to monitor and control macrolide resistance and evaluate
      settings in which macrolide treatment failures are occurring, and new therapeutic
      interventions are needed.

PMID- 12418561
TI  - Bone growth factors in maxillofacial skeletal reconstruction.
AB  - A literature review was performed to survey the available information on the
      potential of bone growth factors in skeletal reconstruction in the maxillofacial
      area. The aim of this review was to characterize the biological and developmental
      nature of the growth factors considered, their molecular level of activity and
      their osteogenic potential in craniofacial bone repair and reconstruction. A
      total of 231 references were selected for evaluation by the content of the
      abstracts. All growth factors considered have a fundamental role in growth and
      development. In postnatal skeletal regeneration, PDGF plays an important role in
      inducing proliferation of undifferentiated mesenchymal cells. It is an important
      mediator for bone healing and remodelling during trauma and infection. It can
      enhance bone regeneration in conjunction with other growth factors but is
      unlikely to provide entirely osteogenic properties itself. IGFs have an important
      role in general growth and maintenance of the body skeleton. The effect of local
      application of IGFs alone in craniofacial skeletal defects has not yet shown a
      clear potential for enhancement of bone regeneration in the reported dosages. The
      combination of IGF-I with PDGF has been effective in promoting bone regeneration
      in dentoalveolar defects around implants or after periodontal bone loss. TGFbeta
      alone in skeletal reconstruction appears to be associated with uncertain results.
      The presence of committed cells is required for enhancement of bone formation by
      TGFbeta. It has a biphasic effect, which suppresses proliferation and
      osteoblastic differentiation at high concentrations. BMPs, BMP2, BMP4 and BMP7 in
      particular, appear to be the most effective growth factors in terms of
      osteogenesis and osseous defect repair. Efficacy of BMPs for defect repair is
      strongly dependent on the type of carrier and has been subject to unknown factors
      in clinical feasibility trials resulting in ambiguous results. The current lack
      of clinical data may prolong the period until this factor is introduced into
      routine clinical application. PRP is supposed to increase proliferation of
      undifferentiated mesenchymal cells and to enhance angiogenesis. There is little
      scientific evidence about the benefit of PRP in skeletal reconstructive and
      preprosthetic surgery yet and it is unlikely that peri-implant bone healing or
      regeneration of local bone into alloplastic material by the application of PRP
      alone will be significantly enhanced.

PMID- 12418562
TI  - Endoscopically assisted zygomatic fracture reduction and osteosynthesis
      revisited.
AB  - In comminuted fractures of the zygoma open reduction of the malar arch is
      essential for correct anatomic repair. Avoiding exposure of this landmark may
      result in severe functional and aesthetic impairment. Exposure of the malar arch
      necessitated traditionally a coronal incision. However, recently several authors
      reported good results in malar fracture repair with minimal incisions and
      endoscopic assistance. To establish this technique a cadaver study was performed.
      Different approaches to the malar arch, fracture reduction and internal fixation
      were evaluated. After establishment of a satisfactory technique 12 patients with
      comminution of the zygoma were treated with endoscopic assistance. Repositioning
      of the fragments was excellent in nine cases, minimal remaining dislocation was
      seen in two cases and in one case revision was necessary. Postoperatively the
      frontal branch of the facial nerve was intact in all patients. Scarring was
      minimal. In three patients plating of the malar arch on a side table resulted in
      arch necrosis and resorption in the long-term follow-up. Operating time was
      remarkably longer than in conventional procedures due to the difficult technique.

PMID- 12418563
TI  - Partial inferior turbinectomy during secondary alveolar bone grafting.
AB  - This study examined the characteristics and outcome of patients undergoing
      partial inferior turbinectomy during secondary alveolar bone grafting. Thirty
      three of 55 patients with cleft lip and palate or cleft lip and alveolus who
      underwent secondary alveolar bone grafting concurrently received partial inferior
      turbinectomy to ensure that the height of the nasal floor was similar on the
      cleft side and non-affected side. At the time of surgery, patients who underwent
      turbinectomy were significantly older than those who did not undergo the
      procedure. The proportion of patients who underwent turbinectomy was
      significantly higher among patients with cleft lip and palate than among those
      with cleft lip and alveolus. These differences apparently reflected the
      developmental stage of the inferior turbinate and the relative severity of
      alveolar and palatal defects. In most patients who underwent partial inferior
      turbinectomy, postoperative X-ray films revealed excellent bone formation at the
      graft site. Our findings suggest that partial inferior turbinectomy during
      secondary alveolar bone grafting is a very useful procedure that facilitates
      dissection to the height of the nasal floor, reconstruction of the mucosal nasal
      floor, and formation of a sufficient bone bridge. It also promotes alveolar cleft
      closure, especially in patients with wide bone defects.

PMID- 12418564
TI  - Circulating levels of vascular endothelial growth factor in patients with oral
      squamous cell carcinoma.
AB  - Angiogenesis is a crucial step in tumour growth, progression, and metastasis.
      Recently, many angiogenic factors have been identified. Vascular endothelial
      growth factor (VEGF) is thought to be one such angiogenic factor and is also
      thought to be a selective mitogen for vascular endothelial cells. The present
      study was designed to determine the circulating levels of VEGF in human oral
      squamous cell carcinoma (OSCC) and to investigate its correlation with the
      clinicopathologic features and prognosis. The study consisted of 10 healthy
      volunteers and 31 patients with OSCC. A quantitative sandwich enzyme immunoassay
      technique was used to measure the concentrations of VEGF in the sera. The data
      obtained from the experiment were analysed with independent-samples t-test. The
      mean concentrations of serum VEGF were 148.80 +/- 64.17 pg x ml(-1) (range, 59
      231 pg x ml(-1)) in normal controls and 567.97 +/- 338.17 pg x ml(-1) (range, 136
      1,892 pg x ml(-1)) in OSCC group. Statistical analysis showed that the mean VEGF
      level in sera of OSCC patients was significantly higher than that in healthy
      controls (P<0.001). The serum VEGF levels of OSCC patients correlated with
      condition of nodal metastasis (P<0.05) and clinical stage (P<0.05) but not with
      sex (P>0.05) and degree of differentiation (P>0.05). Our study showed that OSCC
      was associated with significantly elevated serum VEGF concentration. Higher level
      of serum VEGF also correlated with lymph node metastasis and clinical stage of
      OSCC. Determination of serum VEGF concentration may be helpful to distinguish
      OSCC patients from the normal individuals.

PMID- 12418565
TI  - Factors influencing the therapeutic effect of muscle afferent block for
      oromandibular dystonia and dyskinesia: implications for their distinct
      pathophysiology.
AB  - Oromandibular dystonia (OMD) is a focal dystonia manifested by involuntary
      masticatory and/or lingual muscle contractions. Muscle afferent block (MAB) by
      injecting anaesthetic and alcohol intramuscularly is recently used for the
      treatment of OMD. To study the factors affecting the efficacy of MAB, 44 patients
      with OMD were treated by local injection of lidocaine and ethanol. They were
      divided into four groups (spastic, rhythmic, dyskinetic, and task-specific)
      according to the pattern of incisal movement and involuntary contraction. We used
      a clinical scaling protocol in terms of four parameters (mastication, speech,
      pain, and discomfort) to evaluate the change of symptoms objectively. The
      relationship of improvement in clinical scores with various parameters was
      assessed statistically. The overall objective improvement was 60.2 +/- 29.5%. The
      scores decreased significantly (P<0.0001, paired t-test) after MAB. The maximal
      incisal velocity significantly correlated inversely with the clinical
      improvement, and MAB was particularly effective for spastic contraction.
      Dyskinetic and rhythmic groups showed variable and significantly less
      improvements than the spastic group. MAB is highly effective for OMD, but not for
      the patients with dyskinetic symptoms. The jaw movement pattern is an important
      factor for predicting the outcome. The difference in the response to MAB in OMD
      and oral and/or orofacial dyskinesia suggests the distinct pathophysiology
      between the two.

PMID- 12418566
TI  - A comparative study of sevoflurane sedation with nitrous oxide sedation for
      dental surgery.
AB  - This study compares the use of inhalation sedation using sevoflurane (group S)
      with inhalation sedation using nitrous oxide (group N) in patients undergoing
      bilateral extraction of third molar teeth under local anaesthesia. The study was
      designed as a cross-over study. Seventeen ASA I, day surgery patients were
      studied. Patients were randomly allocated to receive either 8 l/min 50% nitrous
      oxide in oxygen (group N) or same flow of 1% sevoflurane (group S) for the first
      procedure. Each patient then had the alternate method of sedation for the second
      procedure. There were no significant differences between the methods in patient
      co-operation and surgeon's satisfaction with sedation. Psychomotor tests were
      comparable in both groups. The patients were significantly more sedated in the
      group S compared to group N (P=0.004). Significantly more patients complained of
      an unpleasant odour group S (P<0.01) but none withdrew from the study for this
      reason. No adverse cardiorespiratory effects resulted from sevoflurane or nitrous
      oxide sedation. Both methods gave good amnesia during the procedure. There was
      high acceptance of both methods and the patients rated the technique as equally
      satisfactory. We conclude that inhalation sedation with sevoflurane is a suitable
      alternative method to nitrous oxide sedation.

PMID- 12418567
TI  - Surface analysis of titanium maxillofacial plates and screws retrieved from
      patients.
AB  - This investigation is a controlled human plate-retrieval study. The surface
      appearances and elemental composition of 50 titanium maxillofacial plates and
      associated screws retrieved from 39 patients were compared with a control sample
      of unused plates and screws using stereomicroscopy, scanning electron microscopy
      and energy dispersive X-ray analysis. There were two surface finishes, either
      anodized or non-anodized. Surface contamination was detected on both retrieved
      and control plates consisting of aluminium and silica and was more commonly
      present on non-anodized specimens. Manufacturing defects comprising rough metal
      edges and protuberances were identified on the unused controls and surgical
      damage was evident on the retrieved specimens. There were no signs of corrosion
      or surface deterioration on the retrieved plates and screws which had been in the
      tissues for between 1 month and 13 years. There was no evidence from this study
      to support the routine removal of titanium maxillofacial miniplates plates due to
      corrosion up to a period of 13 years.

PMID- 12418568
TI  - Osteodistraction of a previously irradiated mandible with or without adjunctive
      hyperbaric oxygenation: an experimental study in rabbits.
AB  - The purpose of this study was to analyse the effects of irradiation and
      hyperbaric oxygenation (HBO) on mandibular osteodistraction (OD). Eighteen
      rabbits were divided into three groups: 1. Irradiation (R), 2. Irradiation+HBO (R
      HO), and 3. Control group (C). Animals of groups R and R-HO received in the
      mandible irradiation 22.4 Gy in four 5.6 Gy fractions (equivalent to 50 Gy/25
      fractions). In addition, group R-HO was given HBO at 2.5 ATA for 90 min per day
      18 times preoperatively. Unilateral osteotomy was made 1 month after completion
      of radiotherapy. After a 1 week latency period bone distraction was started at
      rate of 1 mm per day, continued for 2 weeks, and left to consolidate for 4 weeks.
      Amount of new bone was measured histomorphometrically from midsagittal sections.
      Area of new bone was equal in all groups. Bone was more mature and bone spicules
      better organized in group C than in groups R and R-HO. Cartilaginous cells were
      found in distracted bone in all groups but larger chondroid islands were evident
      only in group R. It seems that despite delayed bone formation, OD can be
      performed after radiotherapy. HBO had a beneficial effect on bone quality of a
      previously irradiated mandible.

PMID- 12418569
TI  - Allogeneic bone grafting of calvarial defects: an experimental study in the
      rabbit.
AB  - The purpose of this study was to investigate the incorporation of fresh frozen
      irradiated membranous allogeneic bone grafts into critical size calvarial defects
      in the rabbit. Fifteen rabbits had calvarial defects prepared. Twelve rabbits
      received allogeneic grafts and three received autogenous bone grafts. The rabbits
      were sacrificed at 9 and 12 months postoperatively, and the specimens were
      examined radiologically, histopathologically and with fluorescence microscopy.
      Neovascularization, bone marrow regeneration and new bone formation was evident
      throughout the grafts however revitalization of the entire graft was incomplete
      at 12 months. This study revealed that the FFI membranous grafts were well
      incorporated into rabbit calvarial defects.

PMID- 12418570
TI  - The expression of fibroblast growth factor-2 and fibroblast growth factor
      receptor-1 in chondrocytes in synovial chondromatosis of the temporomandibular
      joint. report of two cases.
AB  - Synovial chondromatosis (SC) is a rare, benign condition characterized by the
      formation of metaplastic cartilaginous nodules. The expression of fibroblast
      growth factor-2 (FGF-2) and fibroblast growth factor receptor-1 (FGFR-1) in two
      cases of SC of the temporomandibular joint (TMJ) were immunohistochemically
      studied. The possible roles of FGF-2 and FGFR-1 in SC of the TMJ are discussed.

PMID- 12418571
TI  - Referral letters in oral medicine: standard versus non-standard letters.
AB  - Usually referral letters are the only means of communication between general
      practitioners and specialists in the health area. However, they are inadequate if
      important basic data are omitted. The aim of this study was to compare the
      content of standard and non-standard letters. A total of 1956 files from the Oral
      Medicine Service were consecutively evaluated (March 1996 to September 2000). Key
      items were considered for analysis and the results were stored in a database
      using the Epinfo 6.04 program. The chi2 test (alpha=0.05) was applied to the
      results. Of the 1956 files examined, 34% (662) had a referral letter, 31% of them
      being standard letters and 69% non-standard letters. Most standard letters (87%)
      were from professionals of public health institutions. Most percent discrepancies
      between standard and non-standard letters were observed for patient address
      (14.90 vs 1.32%), patient age (54.81 vs 9.47%), chief complaint (32.21 vs 8.37%),
      fundamental lesion (29.33 vs 13.66%), and symptoms (27.81 vs 15.42%).
      Statistically significant differences were observed for patient age, professional
      referring the patient, chief complaint, and site of the lesion. The quality and
      quantity of the information differed significantly between the two types of
      letters. The standard letters were more complete and contained information
      commonly absent in the non-standard letters. We suggest the use of standard
      letters for improving the quality of communication among professionals.

PMID- 12418572
TI  - Intraoral mandibular distraction osteogenesis in facial asymmetry patients with
      unilateral temporomandibular joint bony ankylosis.
AB  - Gap arthroplasty and costochondral rib bone graft are commonly performed by oral
      and maxillofacial surgeons to reconstruct the temporomandibular joint with
      ankylosis. However, unpredictable and unsatisfactory results such as re
      ankylosis, growth disturbance, and facial asymmetry often occur. Even if the
      costochondral graft is successful, donor-site morbidity is inevitable. More
      recently, surgeons have become interested in distraction osteogenesis as a means
      of temporomandibular joint reconstruction. This case series presents the results
      of intraoral mandibular distraction osteogenesis and gap arthroplasty in two
      patients with facial asymmetry and unilateral temporomandibular joint bony
      ankylosis. Both patients had experienced failed gap arthroplasty and
      costochondral graft for the reconstruction of the temporomandibular joint.
      Distraction osteogenesis with gap arthroplasty proved successful in these two
      patients with follow-up of longer than 2 years.

PMID- 12418573
TI  - Mandibular reconstructive surgery in a patient with median cleft of the lower lip
      and mandible.
AB  - A patient 15 years and 11 months of age with median cleft of the lower lip and
      mandible underwent mandibular reconstructive surgery using autogenous iliac bone
      and a titanium mesh tray. Functional and morphological results are satisfactory 4
      years after surgery.

PMID- 12418574
TI  - Real-time endoarticular ultrasound imaging of the TMJ--a new diagnostic
      possibility? A cadaver study.
AB  - Recent advances in ultrasound imaging suggested endoarticular ultrasound imaging
      of the temporomandibular joint (TMJ) in combination with TMJ-arthroscopy as a new
      diagnostic method. Our investigations were performed on human cadavers, in
      combination with traditional TMJ-arthroscopy. During our investigations, the main
      articular structures were identified: the glenoid fossa of the temporal bone,
      articular disc, condyle of the mandible, and retrodiscal tissue. The combination
      of arthroscopy and ultrasound imaging provides more information on position,
      movement, and pathological changes in joint structures. Although all of the
      advantages, disadvantages, indications, and complications of this new diagnostic
      procedure are not yet clear, the authors consider this new method a useful
      diagnostic procedure for TMJ imaging.

PMID- 12418575
TI  - Posterior segmental osteotomy of maxillary edentulous ridge: an alternative to
      vertical reduction.
AB  - The posterior segmental maxillary osteotomy (PSMO) can be used as an alternative
      procedure to vertical reduction of the edentulous posterior maxilla. Surgical
      intrusion of the segment resulted in an adequate interarch space for prosthetic
      restoration without cortical bone loss and widening of the edentulous ridge and
      the mobilized keratinized mucosa as would be the case if vertical alveolar
      reduction had been performed.

PMID- 12418576
TI  - Focal acantholytic dyskeratosis arising in an intraoral skin flap.
AB  - A case is described of a patient with a myocutaneous pectoralis major flap who
      presented with an oral lesion of focal acantholytic dyskeratosis that was
      clinically suspicious of recurrent tumour.

PMID- 12418577
TI  - Multiple sialoliths in sublingual gland: report of a case.
AB  - We describe a 28-year-old woman with multiple sialoliths in the left sublingual
      gland. The sialoliths were removed by transoral sublingual sialadenectomy. A
      total of 22 calculi were found.

PMID- 12418578
TI  - Atherosclerosis and cancer: common pathways on the vascular endothelium.
AB  - This article reviews experimental and clinical data on atherosclerosis and cancer
      showing common pathogenic mechanisms. It is suggested that common pathways follow
      dysfunction of the vascular endothelium. The activation of the haemostatic system
      and the overexpression of cytokines and adhesion molecules by the endothelial
      cells represent important features of this dysfunction. These mechanisms can be
      responsible for progression of both diseases and explain the higher incidence of
      thromboembolic events in cancer patients, the occurrence of similar laboratory
      findings and the effect of many drugs on the course of the two diseases. Our
      article confirms that atherosclerosis and cancer share common mechanisms, and we
      hope it will stimulate further clinical trials on the use of drugs active on the
      haemostatic system in cancer patients.

PMID- 12418579
TI  - Controlling the lateral distribution and alignment of human gingival fibroblasts
      by micropatterned polysaccharide surfaces.
AB  - Adhesion and alignment of primary human gingival fibroblast to Petri dishes were
      controlled by proper modification of the surface chemistry of the solid
      substrate. In particular, air plasma (glow-discharge) treatment, coupled to a
      masking technique, was used to pattern cell-adhesive areas on a cell-adhesion
      resistant alginate coated surface. Fibroblasts were successfully confined to the
      air plasma-treated areas, which show a much greater growth rate and cell density
      as compared to the original alginate coated surface. Beside the implications for
      the study of the mechanisms of bio-adhesion at hydrophilic surfaces, these
      systems can be of interest for a number of applications in dental surgery and
      materials.

PMID- 12418580
TI  - Phalangeal ultrasonography in forearm fracture discrimination.
AB  - Over the last decade, the use of ultrasounds has been developed into an effective
      tool for investigating bone tissue and predicting the risk of fracture in
      osteoporosis. Studies have focused on hip and vertebral fractures while no
      information is available on the use of phalangeal ultrasonography to identify
      patients with forearm fractures. Thus, the current authors decided to compare 50
      postmenopausal women with low energy forearm fractures (Fractured Group) with a
      control age-matched group of 94 women (Control Group). Measurements were taken at
      the distal metaphysis of the proximal phalanxes of the hand of the non-fractured
      arm using the DBM Sonic Bone Profiler. The reproducibility of the method was
      assessed by amplitude-dependent speed of sound (AD-SoS) CV% = 0.64 and by
      Ultrasound Bone Profiler Index (UBPI) CV% = 2.38. In the Control Group, the AD
      SoS and UBPI mean values and standard deviations were significantly higher
      compared to the group with fractures (P < 0.0005). The receiver operating
      characteristic (ROC) curves were calculated and the areas under the curve (AUC)
      were 0.78 +/- 0.04 for AD-SoS and 0.77 +/- 0.05 for UBPI, respectively. Logistic
      regression analysis adjusted to age revealed that both AD-SoS (78.2%, ORAD-SoS =
      12.03, P < 0.0005) and UBPI (76.0%, ORAD-SoS = 7.39, P < 0.0005) parameters
      discriminated correctly between fractured and non-fractured control women whereas
      the association of both parameters could not allow better discrimination. The
      present results showed that ultrasound investigation at the phalanxes is
      reproducible and efficiently discriminates between subjects with forearm
      fractures and those in the control subjects.

PMID- 12418581
TI  - Long-term monitoring of cell-mediated immunity in disease-free breast cancer
      patients: a preliminary retrospective study.
AB  - In 102 N- and 44 N+ disease-free breast cancer patients, lymphocytic populations
      and skin reaction of delayed hypersensitivity (SRDH) were monitored up to 266
      months after mastectomy to find out whether they were similar or different from
      control values. In two selected groups of 34 N- and 11 N+ breast cancer patients,
      the whole 10 year follow-up was divided into three subintervals, each of them
      lasting 40 months and the time course of lymphocytic populations was evaluated.
      In the 102 N- patients, mean CD4+, CD8+, CD3+ values were lower (P < 0.01, P <
      0.001, P < 0.01, respectively) while CD4+/CD8+ ratio was higher (P < 0.05) than
      in controls. Fifteen N- breast cancer patients (16%) were anergic compared to
      30(32%) of controls (P < 0.05). In the 34 selected N- breast cancer patients soon
      after mastectomy the mean value of CD4+, CD8+, CD3+ T subpopulations was lower (P
      < 0.01, P < 0.001, P < 0.01, respectively) than in controls. Successively their
      mean value increased so that in the last subinterval they were not or were only
      slightly lower (P n.s., P < 0.05, P < 0.05, respectively) than in controls. In
      the 44 N+ patients, mean CD4+, CD8+, CD3+ values were lower (P < 0.001, v < 0.05,
      P < 0.01, respectively) and CD19+ lymphocytes higher (P < 0.001) than in
      controls. Five N+ breast cancer patients (13%) were anergic compared to 32% of
      controls (P < 0.05). In the 11 selected N+ breast cancer patients soon after
      mastectomy, the mean value of CD4+, CD8+ T subpopulations and CD16+56+ cells was
      significantly lower (P < 0.001, P < 0.001, P < 0.01, respectively) than in
      controls. Successively their mean value constantly increased so that in the last
      subinterval, no or slight (P n.s., P < 0.05, P n.s., respectively) significant
      difference compared to controls occurred. The mean CD4+/CD8+ ratio value of N-
      patients was significantly higher than in controls. However in the last
      subinterval, the significance was lower than in the first one (P < 0.05 and P <
      0.01, respectively). In the N+ patients, the mean value of CD4+/CD8+ ratio was
      constant, although not significantly, lower than in controls; however it
      progressively increased from the first to the last subinterval. Therefore the
      significance of the difference of the mean CD4+/CD8+ ratio between N- and N+
      patients strongly decreased from the first to the last subinterval (P < 0.001 and
      P < 0.05, respectively). These data indicate that in breast cancer patients,
      following mastectomy, a significant activation of memory and CD4+ T cells and
      long-term decrease of the circulating immunocompetent CD4+, CD8+ and CD16+56+
      cells occurs. The prolonged disease-free interval observed in the 34 N- and 11 N+
      breast cancer patients can be correlated with the restoration of the normal state
      of cell-mediated immunity.

PMID- 12418583
TI  - Telithromycin is as effective as amoxicillin/clavulanate in acute exacerbations
      of chronic bronchitis.
AB  - This randomized, double-blind study evaluated the efficacy and safety of a short,
      5-day course of telithromycin, a new ketolide antibacterial, compared with a
      standard 10-day course of amoxicillin/clavulanate, in the treatment of acute
      exacerbations of chronic bronchitis (AECB). The study enrolled 325 adult patients
      with AECB and a history of chronic obstructive pulmonary disease (COPD). Patients
      received either telithromycin 800 mg once daily (qd) for 5 days (followed by
      placebo for 5 days) or amoxicillin/clavulanate 500/125 mg three times daily (tid)
      for 10 days. Clinical cure rates for telithromycin post-therapy (Days 17-21, test
      of-cure) and late post-therapy (Days 31-36) were 86.1 and 78.1%, respectively;
      82.1 and 75.0% for amoxicillin/clavulanate. Excellent clinical cure rates were
      also observed for high-risk patients. Bacteriologic outcome was satisfactory for
      69.2% of telithromycin recipients vs 70.0% for amoxicillin/clavulanate
      recipients. Both treatments were generally well tolerated, although the frequency
      of drug-related adverse events was almost two-fold higher for
      amoxicillin/clavulanate (25.0 vs. 13.1%). Thus, a 5-day course of telithromycin
      800 mg qd is an effective and well-tolerated alternative to a standard 10-day
      course of amoxicillin/clavulanate 500/125 mg tid for first-line empiric treatment
      of AECB in adults with COPD.

PMID- 12418582
TI  - Evaluation of different inhaled combination therapies (EDICT): a randomised,
      double-blind comparison of Seretide (50/250 microg bd Diskus vs. formoterol (12
      microg bd) and budesonide (800 microg bd) given concurrently (both via
      Turbuhaler) in patients with moderate-to-severe asthma.
AB  - The aim of this study was to compare the efficacy safety and cost of Seretide
      (salmeterol/fluticasone propionate (Salm/FP), 50/250 microg bd) via Diskus with
      formoterol (Form; 12 microg bd) and budesonide (Bud; 800 microg bd) given
      concurrently (Form+Bud) via Turbuhaler in patients with moderate-to-severe asthma
      who were uncontrolled on existing corticosteroid therapy. The study used a
      randomised, double-blind, double-dummy, parallel-group design, consisting of a 2
      week run-in period on current corticosteroid therapy (1000-1600 microg/day of BDP
      or equivalent) and a 12-week treatment period. Symptomatic patients (n = 428)
      with FEV1 of 50-85% predicted and increased symptom scores or reliever use during
      run-in were randomly allocated to receive either Salm/FP (50/250 microg bd) via a
      single Diskus inhaleror Form+Bud (12+800 microg bd) via separate Turbuhalers.
      Clinic, diary card and asthma-related health-care resource utilisation data were
      collected. Improvement in mean morning peak expiratory flow (PEFam was similar in
      the Salm/FP and Form+Bud groups. Both PEFam and mean evening PEF (PEFpm)
      increased by a clinically significant amount (>20 L/min) from baseline in both
      treatment groups. The mean rate of exacerbations (mild, moderate or severe) was
      significantly lower in the Salm/FP group (0.472) compared with the Form+Bud group
      (0.735) (ratio = 0.64; P < 0.001), despite the three-fold lower microgram inhaled
      corticosteroid dose in the Salm/FP group. Patients in the Salm/FP group also
      experienced significantly fewer nocturnal symptoms, with a higher median
      percentage of symptom-free nights (P = 0.04), nights with a symptom score <2 (P =
      0.03), and nights with no awakenings (P = 0.02). Total asthma-related health-care
      costs were significantly lower in the Salm/FP group than the Form+Bud group
      (P<0.05). Both treatments were well tolerated, with a similar low incidence of
      adverse events. This study showed that in symptomatic patients with moderate-to
      severe asthma, Salm/FP (50/250 microg bd), administered in a single convenient
      device (Diskus), was at least as effective as an approximately three-fold higher
      microgram corticosteroid dose of Bud (800 microg bd) given concurrently with Form
      (12 microg bd) in terms of improvement in PEFam, and superior at reducing
      exacerbations and nights with symptoms or night-time awakenings. Salm/FP was also
      the less costly treatment due primarily to lower hospitalisation and drug costs.

PMID- 12418584
TI  - Alpha-1-antitrypsin deficiency: smoking, decline in lung function and
      implications for therapeutic trials.
AB  - BACKGROUND: Alpha-1-antitrypsin (AT) deficiency is a hereditary disorder
      associated with pulmonary emphysema. AT replacement therapy has been available
      for many years with only one randomised controlled trial, showing no improvement
      in the rate of decline in lung function. We aimed to obtain further data on the
      natural history of the disorder and thus to refine the criteria for future
      clinical trials. METHODS: Homozygotes for Pi type Z were identified among chest
      clinic patients and close relatives. Clinical and lung function data were
      obtained by means of a standardised questionnaire administered yearly for a
      maximum of 15 years. RESULTS: Baseline study: forced expiratory volume in 1 s
      (FEV1) and vital capacity (VC) were studied in 194 Pi type Z patients at
      registration. Past or present smoking history had the strongest relationship to
      reduction in FEV1 (P < 0.001), but among those who had smoked, estimated total
      lifetime tobacco consumption (kg) was not significantly related to FEV1. No
      effecton FEV1 was produced by gender, age of starting to smoke, asthma,
      occupation or intra-family factors in sib pairs concordant for smoking. Follow-up
      study: In 71 patients, the average number of annual lung function assessments per
      subject was 8.0 (range 6-13) and average follow-up time 97 years (range 4.2
      14.9). FEV1 slope tended to be steeper in current smokers than in ex-smokers
      (0.05 < P < 0.1) and greatest in patients with initial FEV1 in the range 30-65%
      predicted. Effects on VC were less severe. Much deterioration takes place before
      emphysematous patients come to clinical attention. FEV1 slopes calculated using
      only the first four assessments have a significantly greater variance than when
      calculated on all assessments (F = 3.79; P < 0.01). FEV1 and VC slopes using post
      bronchodilator values are greater than when using pre-bronchodilator values.
      CONCLUSIONS: Future trials of AT replacement therapy need rigorous
      standardisation of lung function testing (including bronchodilator protocol)
      together with an adequate period of assessment. Only randomised controlled trials
      should be considered valid. Therapy should ideally be started earlier than
      normally envisaged and before the onset of clinical emphysema.

PMID- 12418585
TI  - Efficacy and safety of oxitropium bromide, theophylline and their combination in
      COPD patients: a double-blind, randomized, multicentre study (BREATH Trial).
AB  - We compare the efficacy including spirometry, peak expiratory flow (PEFR) and
      quality of life and safety of an 8-week treatment with inhaled oxitropium,
      theophylline or their combination in patients with mild-to-severe chronic
      obstructive pulmonary disease (COPD). We conducted a multicentre, double-blind,
      double-dummy randomized, parallel-group study at 29 Italian outpatients clinics.
      A group of 236 patients with mild-to-severe COPD (baseline FEV1 < or = 70% of
      predicted value) were recruited. Treatments were as follows: Inhaled oxitropium
      bromide 200 microg (N=75), sustained-release oral theophylline 300 mg (N=81) or
      their combination (N=80), taken twice daily. Spirometry (FEV1 and FVC) was
      evaluated every 4 weeks, and morning and evening PEFR (before and 2-4 h after
      drug intake) was measured daily. Symptoms, cough and dysponea, were recorded
      daily. Health status was evaluated at baseline and week 8 using the disease
      specific St George' Respiratory Questionnaire (SGRQ). Any adverse event occurring
      during the treatment period was recorded on a diary card. FEV1 and FVC improved
      in all the groups at 4 and 8 weeks, but the difference between treatment groups
      did not reach statistically significant levels. Differences between groups in pre
      dosing morning and evening PEFR were not significant. Post-dosing morning and
      evening PEFR were increased and the largest increase was seen in patients treated
      with both drugs. However, differences between groups was significant only for
      evening values (P=0.008). The proportion of patients who experienced a decrease
      in symptoms was high in all groups but no differences among groups were observed.
      SGRQ total scores decreased in all treatment groups after 8 weeks, particularly
      in the oxitropium and combination groups. Clinically significant change (> or = 4
      units) was only observed in patients treated with oxitropium bromide whether with
      or without theophylline. Adverse events related to treatments were higher in the
      group treated with theophylline alone (P < 0.02). We conclude that inhaled
      oxitropium bromide alone was associated with an improvement in FEV1, PEFR and
      symptoms in patients with COPD that was not statistically different from that of
      oral theophylline alone or of the combination of both drugs. Oxitropium bromide
      in combination with theophylline provided a greater improvement in evening post
      dosing PEFR. Oxitropium bromide alone or in combination with theophylline
      improved the quality of life better than theophylline alone.

PMID- 12418586
TI  - Closed pleural needle biopsy: predicting diagnostic yield by examining pleural
      fluid parameters.
AB  - OBJECTIVE: Pleural fluid parameters that predict a diagnostic closed pleural
      needle biopsy were investigated. DESIGN: A retrospective analysis. SETTING: The
      Institute of Pulmonology, Hadassah University Hospital. PATIENTS AND METHODS:
      Forty-four patients who underwent closed pleural needle biopsies were included in
      this study. Pleural fluid values of protein, glucose, lactate dehydrogenase
      (LDH), pH, and white blood cell count with differential cell counts, from
      patients with diagnostic and non-diagnostic pleural biopsies were compared.
      RESULTS: Thirteen patients (29%) had diagnostic biopsies. Malignancy was
      identified in 10 patients (23%), of whom 70% had adenocarcinoma. Three other
      patients had non-malignant specific diagnosis. LDH levels in pleural fluid from
      patients with diagnostic pleural biopsy were higher than in patients with non
      diagnostic pleural biopsies (1436 +/- 333 U l(-1) vs. 775 +/- 109 U l(-1); P <
      0.05). LDH levels less than 510 U l(-1) were highly predictive of a negative
      biopsy (negative predictive value of 86.6%). Follow up revealed malignancy
      including mesothelioma and lymphoma, in 10 of 30 (33%) patients with non
      diagnostic biopsies, and one patient died of unrelated cause, while the pleural
      effusion either resolved, remained stable or an alternative benign process was
      identified in 19 patients (63%). CONCLUSIONS: Low levels of LDH (< 510 U l(-1))
      were highly predictive of a negative pleural needle biopsy. Thus, LDH may serve
      as a useful guide in deciding whether to perform closed pleural biopsy or to
      proceed to thoracoscopically guided biopsy.

PMID- 12418587
TI  - Short-term variability of exhaled nitric oxide in young male patients with mild
      asthma and in healthy subjects.
AB  - BACKGROUND: Exhaled nitric oxide (NOexp) is an indicator of eosinophilic airways
      inflammation. This study evaluated short-term variability of NOexp in 13 healthy
      subjects (19-41 years, eight males) and in 31 patients with asthmatic respiratory
      symptoms (19-21 years, all male) to obtain data for assessment of short-term
      changes of NOexp in clinical situations. METHODS: Mild asthma was confirmed in 10
      patients (Group = asthma). Twenty-one patients with asthmatic respiratory
      symptoms did not fulfill the functional criteria of asthma (Group = respiratory
      symptoms). The procedure to determine NOexp followed the European Respiratory
      Society (ERS) guidelines; the mean expiratory flow used during sampling was 0.09
      0.12 l/s. NOexp for each subject was determined as the mean of at least three
      successive measurements at the baseline, followed by determinations at 10 min, 6
      h and 24 h after the baseline. RESULTS: At the baseline, the mean (SD) value of
      NOexp was 6.6 (2.3) parts per billion (ppb) in the healthy controls, and
      significantly higher both in patients with respiratory symptoms (14.6 (11) ppb, P
      = 0.0076) and in those with asthma (34.2 (43) ppb, P < 0.001). Intraclass
      correlation coefficient of NOexp measured at baseline and after an interval of 10
      min was 0.959 in healthy subjects, 0.986 in patients with respiratory symptoms
      and 0.936 in asthma patients, respectively. Short-term variability in terms of
      coefficient of variation (CoV) of repeated measurements of NOexp at 10 min, 6
      hand 24 h was 5.1, 10.8 and 11.7% in healthy subjects, 71, 16.4 and 22.2% in
      patients with respiratory symptoms and 13.5, 19.4 and 26.4% in asthma patients,
      respectively. CONCLUSIONS: Reproducibility of NOexp using standardized methods
      was good both in healthy subjects and in asthmatic patients. However, in
      asthmatics the short-term variation of NOexp was over two times as high as in
      healthy subjects. The level of NOexp was elevated, except in asthma, also in
      patients with asthmatic respiratory symptoms who did not fulfill the functional
      criteria of asthma.

PMID- 12418588
TI  - Leukotriene antagonism reduces the generation of endothelin-1 and interferon
      gamma and inhibits eosinophilic airway inflammation.
AB  - The cysteinyl leukotrienes (cysLTs) and the peptide hormone endothelin (ET)-1 are
      potent bronchoconstrictor substances, and these mediators are also claimed to be
      implicated in the development of eosinophilic airway inflammation. In the present
      study, we have investigated the effect of the cysLT1 receptor antagonist
      montelukaston the development of an eosinophilic airway inflammation 24 h after
      intratracheal Sephadex (SDX) provocation in rats. Furthermore, the effect of
      montelukast treatment on the generation of ET-1 and other pro-inflammatory
      mediators has been studied. The inflammatory response was significantly reduced
      in the animals receiving SDX + montelukast compared to animals receiving solely
      SDX, as evaluated by a decrease in bronchoalveolar lavage fluid total cell count
      (10.3 +/- 1.2 vs. 18.5 +/- 1.8 x 10(4) ml(-1), P<0.001), number of eosinophils
      (299.7 +/- 43.8 vs. 577.6 +/- 46.6 x 10(2) ml(-1), P<0.001), and lymphocytes
      (116.8 +/- 20 vs. 222.0 +/- 34.8 x 10(2) ml(-1), P<0.05), as well as the degree
      of tissue inflammation (P<0.05). Montelukast also inhibited the increase in the
      concentration of the pro-inflammatory mediators ET-1 (28.5 +/- 75 vs. 40.9 +/-
      7.3 x pg ml(-1), P<0.05) and interferon (IFN)-gamma (4.3 +/- 2.2 vs. 15.6+/-8.7 x
      pg ml(-1), P<0.05), but not tumor necrosis factor-gamma or interleukin-8. In
      summary, treatment with the cysLT1 receptor antagonist montelukast reduced the
      inflammatory response during development of an eosinophilic airway inflammation,
      possibly by inhibiting the release of pro-inflammatory mediators like ET-1 and
      IFN-gamma.

PMID- 12418589
TI  - Ambient level of NO2 augments the inflammatory response to inhaled allergen in
      asthmatics.
AB  - Air pollution constitutes an important factor for asthma aggravation, and there
      is increased concern about respiratory health effects of common air pollutants.
      The purpose of this study was to examine how exposure to a high ambient
      concentration nitrogen dioxide (NO2) prior to a bronchial allergen challenge
      modulated the inflammatory response in the bronchi. Thirteen subjects with mild
      asthma and allergy were exposed at rest to either purified air or 500 microg x m
      3 NO2 for 30 min, followed 4 h later by an allergen inhalation challenge. The
      exposures (NO2 or air) were performed in random order and at least 4 weeks apart.
      Lung function during NO2/air exposure and allergen challenge was measured by
      plethysmography, and then hourly by portable spirometry after exposures.
      Subjective symptoms were recorded during and after exposure. Bronchoscopy with
      bronchial wash (BW) and bronchoalveolar lavage (BAL) was performed 19 h after
      allergen challenge. NO2+allergen enhanced the percentage of neutrophils in both
      BW and BAL compared to air+allergen (BW 19 vs. 11, P=0.05; BAL 3 vs. 1, P=0.02
      median values). The levels of eosinophil cationic protein (ECP) in BW was higher
      after NO2+allergen compared to air+allergen (90 vs. 3.6 microg/l; P=0.02, median
      values). There was no NO2-associated effect on symptoms or pulmonary function.
      These data suggest that ambient NO2 can enhance allergic inflammatory reaction in
      the airways without causing symptoms or pulmonary dysfunction.

PMID- 12418590
TI  - Identification of intracellular markers in induced sputum and bronchoalveolar
      lavage samples in patients with respiratory disorders and healthy persons.
AB  - Induced sputum and bronchoalveolar lavage (BAL) are widely used for retrieving
      cells and soluble materials for studies of airway inflammation. Centrifuged cell
      samples are suitable for immunochemical identification of cellular products. The
      aim was to determine the optimal fixation procedure to detect intracellular
      antigens in situ. In immunocytochemistry, an appropriate choice of fixation
      method is a prerequisite for identification of cells and, consequently, for
      reliability results. We compared eight fixation and permeabilization methods to
      detect intracellular antigens in cytocentrifuged cell samples. Four granular
      proteins specific to eosinophils (eosinophil cationic protein, ECP; eosinophil
      peroxidase, EPO) and neutrophils (human neutrophil lipocalin, HNL;
      myeloperoxidase, MPO) were the antigens studied. We found that the organic
      solvents often used in immunocytochemistry are unsuitable fixatives for detection
      of these intracellular low-molecular-weight proteins. Treatment with crosslinking
      fixatives alone resulted in incomplete penetration of antibodies into the cell
      interiors. Best results were obtained using a commercial reagent Ortho PermeaFix
      (OPF) for flow cytometry. With this, fixation and permeabilization take place
      simultaneously OPF-treated cells retained their structural characteristics, and
      the antibodies studied penetrated both cellular and granule membranes. With OPF
      treatment, ECP EPO, HNL, and MPO were fixed on their places in granules, and
      their antigenicity was retained. Correct identification of intracellular proteins
      is important in characterization of the respiratory inflammatory response in
      clinical work and research.

PMID- 12418591
TI  - Natural allergen exposure does not diminish the sensitivity of cytokine
      production to glucocorticosteroids in blood cells of seasonal allergic asthma and
      rhinitis patients.
AB  - Glucocorticosteroid (GCS) inhibition of cytokine production is a major anti
      inflammatory mechanism. However, increased production of pro-inflammatory
      cytokines during allergic airway inflammation has been proposed to reduce GCS
      effects. This study aimed to investigate whether allergic airway inflammation due
      to natural allergen exposure might decrease the sensitivity of granulocyte
      macrophage colony-stimulating factor (GM-CSF) production to GCS in blood cells.
      Blood samples were collected from patients with seasonal allergic asthma (n = 10)
      and rhinitis (n = 8) and healthy subjects (n = 9), before, during, and after the
      birch pollen season. Whole blood cultures were stimulated with LPS (10 ng/ml) and
      treated with budesonide (10(-11)-10(-7) M) for 20 h. GM-CSF levels were analysed
      using immunoassay. Birch pollen exposure did not alter LPS-stimulated GM-CSF
      production, although disease symptoms and blood eosinophils increased in the
      patients. There were no significant differences in budesonide inhibition of GM
      CSF production by blood cells of asthma and rhinitis patients compared with cells
      of healthy subjects before, during or after the birch pollen season and no change
      in response to allergen exposure. A concentration of 1 nM budesonide inhibited GM
      CSF production by more than 50% at all time points. In conclusion, natural
      allergen exposure did not reduce the sensitivity of GM-CSF production to GCS
      inhibition in blood cells of seasonal allergic asthma and rhinitis patients.

PMID- 12418592
TI  - Relationship between lung function, ventilation-perfusion inequality and extent
      of emphysema as assessed by high-resolution computed tomography.
AB  - The development of the high-resolution computed tomography (HRCT) has improved
      the ability to detect and quantify emphysema in various groups of patients with
      chronic airflow obstruction (COPD). Significant correlations have previously been
      found between indices of air flow obstruction, hyperinflation, reduced diffusing
      capacity for carbon monoxide (DLCO), and the extent of emphysema (emph.%)
      assessed by HRCT. However, the relationship between emph.% and ventilation
      perfusion (V(A)/Q) inequality in COPD is unknown. Twenty COPD patients with a
      mean forced expiratory volume in 1 s (FEV1) of 38.2 (+/- 15.5)% in percent of
      predicted value (%P), a mean PaO2 value of 9.6 (+/- 1.3) kPa, and a mean
      diffusing capacity of 43.6 (+/- 23.0)%P, were subjected to measurements by the
      multiple elimination inert gas technique (MIGET). The extent of emphysema was
      determined by HRCT at both full inspiration, emph.I(%) and at full expiration,
      emph.E(%), with a cut-off limit of -910 Hounsfield Units (HU) using the "Density
      Mask" method. The ventilation directed towards high V(A)/Q areas was 73 (+/-
      10.2)% and the mean ventilation (V-mean) was elevated about three times compared
      to normal. The mean emph.(I)% and emph.(E) was 45.6 (+/- 16.9) and 32.7 (+/-
      190)%, respectively. Significant correlations were shown between the emphysema
      extent and several lung function parameters, but no correlation was found between
      the emphysema extent and the V(A)/Q relationships or the blood gas values.
      Reduced DLCO%P correlated with less high V(A)/Q ventilation (r=0.73, P < 0.05)
      for the subgroup of COPD patients with DLCO(%P) less than 50% (n=12).
      CONCLUSIONS: In COPD patients, suffering from moderate to severe emphysema
      without severe blood gas impairment, no correlation was shown between the extent
      of emphysema, as assessed by HRCT, and the severity of ventilation-perfusion
      inequality. A substantial collateral ventilation in severe emphysema may be a
      mechanism that prevents a deterioration in V(A)/Q relationships and in blood gas
      levels.

PMID- 12418593
TI  - Long-term oxygen therapy and quality of life in elderly patients hospitalised due
      to severe exacerbation of COPD. A 1 year follow-up study.
AB  - The aim of this study was (1) to evaluate the effects of long-term oxygen
      treatment (LTOT) in elderly patients with severe exacerbations of chronic
      obstructive pulmonary disease (COPD) and hypoxaemia, (2) to study the health
      related quality of life (QOL) during hospital stay and at follow-up, (3) to study
      the safety of an oxygen withdrawal test performed a few days after admission to
      hospital and the possibility to predict the future need for LTOT from that test.
      Patients > 70 years with COPD-exacerbations with hypoxaemia were included after 5
      7 days treatment in hospital. Inclusion was based on results of a standardised
      oxygen withdrawal test. After 1, 3, 6 and 12 months a new oxygen withdrawal test
      was performed. Health-related QOL was evaluated with SF-36 and the St George's
      Respiratory Questionnaire at inclusion and after 3,6 and 12 months. Forty-seven
      patients were screened for participation and 29 patients, mean age 79 years,
      participated in the study. Only one patient could not tolerate the oxygen
      withdrawal test. Eighteen patients survived to the follow-up after 12 months,
      8/19 women and 2/10 men died. After 1 month LTOTwas needed (PaO2 without oxygen
      was < or = 75 k Pa) in only 6/20 patients. The effect of LTOT could therefore not
      be studied. Most components of SF-36 were very low at inclusion, but tended to
      increase after 3 months and were among the surviving patients after 12 months
      similar to that of healthy people of the same age for psychic well being and
      functioning. Especially, the symptom score of the SGRQ improved after 3 months.
      In conclusion, the future need for LTOT cannot be judged after a few days
      treatment in hospital due to exacerbations with hypoxaemia in elderly patients
      with COPD. A standardised oxygen withdrawal test can be safely done. Health
      related QOL is low in patients during the stay in hospital, but improves after
      returning home.

PMID- 12418595
TI  - Small toys contained in chocolate eggs--good or bad surprise?

PMID- 12418594
TI  - Prospective, placebo-controlled trial of 5 vs 10 days of oral prednisolone in
      acute adult asthma.
AB  - BACKGROUND: The optimal duration of oral steroid treatment in the management of
      acute adult asthma is unclear. We prospectively studied the effect of 5 vs. 10
      days of oral prednisolone in patients with acute asthma requiring hospital
      admission. METHODS: Each patient received 40 mg of enteric-coated prednisolone
      daily for 5 days, followed by 5 days of 40 mg prednisolone daily (n=24) or
      placebo (n=20). All were given their usual inhaled asthma therapy including
      inhaled corticosteroids. Patients kept PEF and symptom diaries for 21 days.
      RESULTS: For the 5-day treatment group mean (95% CI) early morning PEF was 6 (
      47,+36) l/min lower to day 21 (P=0.78). There was no evidence of differences in
      other PEF measures (morning post-bronchodilator, evening or worst of day). One
      patient in each group had an exacerbation requiring further oral steroids during
      the 21-day observation period. Asthma symptom scores were worse in the 5-day
      group on days 6-21 but the significance of this finding was uncertain, as a
      difference had emerged by day 5 (prior to trial entry). CONCLUSIONS: It may be
      possible to reduce the standard steroid course to 5 days in acute adult asthma,
      provided all patients receive inhaled steroids and a personal asthma management
      plan.

PMID- 12418596
TI  - Clinical equivalence between salbutamol hydrofluoroalkane pMDI and salbutamol
      Turbuhaler at the same cumulative microgram doses in paediatric patients.
AB  - This study aimed to demonstrate equivalent efficacy and safety between salbutamol
      delivered via the HFA134a pMDI (Hydrofluoroalkane 134a pressurised Metered Dose
      Inhaler) and the Turbuhaler dry powder inhaler in asthmatic children. This was a
      randomised, double-blind, double-dummy, placebo-controlled, crossover study in 10
      asthmatic children aged 6-15 years who demonstrated at least 10% reversibility of
      FEV1 after inhaling 400 microg of salbutamol. On 5 single study days subjects
      received either placebo or cumulative doses of 100, 200, 400 and 800 microg of
      salbutamol at 30 minute intervals. Both devices were placebo on one study day
      while each device was active on two study days. FEV1 was measured before and 20
      minutes after each dose. Heart rate was measured before spirometry. Mean FEV1 and
      heart rate at each time point and the area under the dose response time curve
      (AUC) were analysed using ANOVA. FEV1 increased similarly after cumulative doses
      of salbutamol on each of the study days, irrespective of device. Mean treatment
      difference in AUC was 0.01 L. min (95%CI -0.05 to 0.08 L). Heart did not differ
      at any dose. It is concluded that salbutamol delivery from a HFA pMDI and
      Turbuhaler is equivalenton a microgram basis in asthmatic children for efficacy
      and safety.

PMID- 12418597
TI  - Dental aid organisations: baseline data about their reality today.
AB  - AIM: To collect basic data about non-governmental dental aid organisations on a
      global scale and thus contribute to a better understanding of their diversity,
      activities and limitations. METHODS: Data was collected through a mailed
      questionnaire to all organisations listed by the FDI World Dental Federation. A
      second questionnaire was e-mailed to those organisations identified as non
      governmental organisations (NGO) by the first questionnaire. FINDINGS: The
      response rate to the first questionnaire to detect NGOs was 36.2%, to the second
      e-mailed form 84.4%. About two thirds of NGOs originated in developed countries,
      one third responded from developing countries. The majority had been established
      after 1980. Developed countries dental NGOs tended to have larger membership and
      disposed of greater budgets. In general, income was generated predominantly from
      donations and own resources. The workforce was primarily based on volunteers.
      High priority activities: service provision, education and training, technical
      assistance, community development. Measures for quality assurance showed low
      complexity. Frequent areas of problems were associated with funding and staff.
      Collaborative links with other stakeholders in development were weak and focussed
      on information exchange. CONCLUSIONS: Recommendations for NGOs, donors, FDI and
      future research are developed.

PMID- 12418598
TI  - Caries reductions related to the use of fluorides: a retrospective cohort study.
AB  - AIM: To test whether topical fluoride regimes provided additional caries
      protection to the first molar teeth of children exposed to fluoridated toothpaste
      and optimally fluoridated water supplies. PARTICIPANTS AND METHODS: This two-year
      retrospective cohort study included 660, 8-year-old-children. A cluster sampling
      technique was used to select three groups of 220 children. Group 1 was selected
      from schools using fluoride mouthrinses (Programme 1). Group 2 was selected from
      schools applying fluoride gel (APF 1.23%) in addition to the weekly fluoride
      mouthrinse (Programme 2). Oral health education and oral hygiene instruction were
      provided to both groups. The control group was selected from schools in the same
      area that had not adopted any oral health preventive programme. All children were
      exposed to optimally fluoridated water and fluoridated toothpaste for the last
      two years or more. Participants were examined for DMFS scores of their first
      molars using WHO criteria by one examiner (MLRS). RESULTS: The percentage caries
      free children in Control, Programme 1 and Programme 2 were 55%, 65% and 65.5%,
      respectively. The differences between Programme 1 and 2 in relation to the
      Control Group were statistically significant (P < 0.05). There was no difference
      between Programme 1 and 2 (P = 0.92). CONCLUSIONS: Weekly fluoride rinsing
      combined whether or not with fluoride gel applications once every three months,
      provided additional caries-preventive benefits to children with high levels of
      caries and exposed to optimally fluoridated drinking water and toothpaste. There
      was no difference in caries levels between children having fluoride rinses and
      those having fluoride rinses and fluoride gel.

PMID- 12418599
TI  - The working practices and job satisfaction of dental nurses in Trinidad and
      Tobago: findings of a national survey.
AB  - OBJECTIVE: To describe the working practices and level of job satisfaction of
      dental nurses in Trinidad and Tobago. DESIGN: Postal survey. PARTICIPANTS: Fifty
      enrolled and practising dental nurses in Trinidad and Tobago were surveyed, 38
      replied (76%). OUTCOMES MEASURES: Current working practice, career breaks,
      continuing education, job satisfaction. RESULTS: All dental nurses were employed
      by the Ministry of Health or Regional Health Authorities. Most performed a wide
      range of clinical and administrative duties along with delivering dental health
      education. Forty five per cent of respondents had taken a career break since
      qualifying with maternity and child rearing being the most common reason (94%).
      Sixty six per cent had attended a continuing education course in the previous
      year, with this most frequently being a dental refresher course. Satisfaction
      with pre-qualification training was high but current job satisfaction was low.
      Concerns with working conditions and career paths were identified. CONCLUSION:
      Dental nurses in Trinidad and Tobago expressed confidence in their ability to
      perform their current duties and showed interest in continuing education. Job
      satisfaction was low.

PMID- 12418600
TI  - Clinical and microbiological effects of local chlorhexidine applications.
AB  - AIM: To study the effects of an application of chlorhexidine varnish (40%) on
      dental plaque. DESIGN: Randomised controlled clinical trial. SUBJECTS: 40
      patients (50% females), aged 25-34 years after undergoing any necessary
      restorative treatment. Exactly one half of these individuals practiced good oral
      hygiene, the efforts of the others were poor. METHOD: Test groups received a
      chlorhexidine varnish application, the control group received a placebo varnish.
      Initially and after 2 and 6 weeks, a modified Dentocult SM-test, bleeding on
      probing, and a plaque index (Quigley-Hein) were recorded. RESULTS: In contrast to
      the control group, improvements in plaque index and bleeding on probing scores
      were found in patients with poor oral hygiene. The results of the Dentocult SM
      tests showed a considerable reduction of streptococcus colonisation. The test
      group with good oral hygiene showed only slight improvement of the examined
      indices after chlorhexidine application. The index parameters of all patients of
      the placebo groups remained unchanged over the examination time period.
      CONCLUSION: The application of a chlorhexidine varnish reduced the quantity of
      the Streptococcus mutans colonies significantly and improved clinical parameters
      in patients with elevated plaque accumulation.

PMID- 12418601
TI  - Re-emergence of tuberculosis and its variants: implications for dentistry.
AB  - Tuberculosis is one of the deadliest scourges of mankind and, overall, one third
      of the global population is infected with this mycobacterium or its variants. The
      advent of the human immunodeficiency virus (HIV) pandemic has accelerated its
      spread inexorably whilst the multi-drug resistant strains of the bacillus have
      hampered disease management. Given the alarming spread of the disease, there
      appears to be a significant potential for occupationally acquired tuberculous
      infection amongst health care workers, including dental care workers. This review
      addresses the basic microbiology and the pathogenesis of tuberculosis, its oral
      manifestations, mycobacteria other than tuberculosis (MOTT), multi-drug resistant
      tuberculosis (MDR-TB), management including aspects of the global programme on
      tuberculosis (DOTS programme), the potential for occupationally acquiring the
      disease and finally, the infection control measures that are available for dental
      and other health care workers.

PMID- 12418602
TI  - Mouthrinses and dental caries.
AB  - Mouthrinsing for the prevention of dental caries in children and adolescents was
      established as a mass prophylactic method in the 1960s and has shown average
      efficacy of caries reduction between 20-50%. Commonly, weekly or twice monthly
      rinsing procedures using neutral 0.2% NaF solutions have been used in schools or
      institutions in areas with low fluoride concentrations in the drinking water.
      Today, when dental caries has declined substantially in the western countries,
      and relatively few individuals are suffering from caries, the efficiency of large
      scale mouthrinsing is questioned and more individual approaches of caries
      prevention strategies are needed. For this reason individual caries risk
      assessments are necessary, utilising diagnostic tools with the aim of explaining
      the main causes of the caries disease. Therefore in high risk patients, daily
      mouthrinses using 0.05% NaF can be recommended combined with other selective
      preventive measures such as sugar restriction, improved oral hygiene,
      antibacterial treatments, and so forth. Mouthrinsing solutions have therefore
      been combined with antiplaque agents like chlorhexidine and other agents which
      can improve the caries preventive effect not only in high caries risk patients,
      including those with dry mouth problems and root caries. Other agents than sodium
      fluoride have been used, such as stannous and amine fluoride with proven clinical
      effects. However, although a series of new formulas of mouthrinses containing
      fluoride combined with different antiplaque agents have shown promising
      antibacterial and antiplaque efficacy, their long-term clinical effects are
      sparsely documented. Acute and chronic side effects from established and
      recommended mouthrinsing routines are extremely rare but ethanol containing
      products should not be recommended to children for long-term use or to
      individuals with alcohol problems. Patients with dry mouth problems should avoid
      mouthrinses containing high concentration of detergent components which reduce
      the substantivity of the agent and worsen the dry mouth effect. For the future,
      patients, dentists and public health officials will welcome new and safe,
      controlled and self-administrated mouthrinsing procedures with not only high
      efficacy, but also high effectivity and efficiency.

PMID- 12418603
TI  - Mouthrinses and periodontal disease.
AB  - It is known that mouthwashes can influence gingivitis; however, their role in the
      three different kinds of periodontitis is unclear. Some solutions have
      demonstrated some effect on necrotising periodontitis, yet none have been shown
      to influence early onset periodontitis. The literature provides us with a wide
      range of in vitro concentrations of substances used pure or in various mixtures
      in mouthwashes. Although only a few solutions can be used in a curative approach,
      most mouthwashes represent an essential tool in prophylaxis and thus also in post
      periodontal treatment (maintenance phase). However, severe qualitative
      differences exist between the diverse families of mouthwashes. Many studies have
      shown that the use of a mouthwash associated with regular tooth cleaning was more
      beneficial than the utilisation of mouthrinse alone.

PMID- 12418604
TI  - The minimally invasive and aesthetic bonded porcelain technique.

PMID- 12418605
TI  - Clinical implications of dopamine research in schizophrenia.
AB  - One of the most stimulating problems posed by second generation antipsychotics is
      the question of whether their ability to act on the negative, as well as the
      positive, symptoms of schizophrenia relies on the same neurochemical mechanisms
      as those responsible for their lack of extrapyramidal symptoms (EPS). Amisulpride
      is a substituted benzamide antipsychotic, which is known to be efficacious
      against both the positive and the negative symptoms of schizophrenia and to have
      a lower propensity to induce EPS than conventional antipsychotics. Amisulpride
      preferentially blocks the D2 and D3 subtypes of dopamine receptors, both
      presynaptically in the frontal cortex, enhancing dopaminergic transmission, and
      postsynaptically in subcortical areas such as the nucleus accumbens, so reducing
      dopaminergic transmission. Given that dopaminergic under-activity in the frontal
      cortex is thought to produce negative symptoms, and over-activity in the limbic
      system to produce positive symptoms, it is proposed that these are the mechanisms
      by which amisulpride produces its atypical profile.

PMID- 12418606
TI  - Efficacy review of antipsychotics.
AB  - Antipsychotic drugs have been available for more than 40 years. The invention of
      neuroleptics changed the overall treatment of schizophrenia dramatically.
      Nevertheless, the discussion on the importance and role of antipsychotic therapy
      still goes on. In the public as well as in the media, there remains a great deal
      of scepticism about the role of psychopharmacotherapy in the treatment of
      schizophrenia. The best way to handle this is an evidence-based approach. The
      efficacy of neuroleptic treatment has been proven in over 150 double-blind,
      controlled clinical trials. The second generation of antipsychotic drugs show
      similar antipsychotic properties as the classical agents, but with fewer side
      effects such as extrapyramidal symptoms (EPS). The atypical antipsychotic agents
      have improved the quality of therapy and can also improve and support other
      aspects of treatment. When used with other treatment strategies, atypical
      antipsychotic agents could improve the overall outcome of this usually chronic
      disease. It is now necessary to implement these strategies as effectively as
      possible.

PMID- 12418607
TI  - Impact on cognition of the use of antipsychotics.
AB  - Cognitive dysfunction is recognised as one of the more enduring deficits in
      schizophrenia. The syndrome is associated with impairment of the temporal and
      frontal regions of the brain that are concerned with cognitve function, as well
      as subcortical regions that are closely interconnected with them. Cognitive
      dysfunction may underpin some of the psychopathology of schizophrenia, as well as
      contribute to the patient's impaired social and vocational functioning. Cognitive
      deficits are relatively independent of psychotic symptoms in schizophrenia, and
      are probably central and enduring features of the disorder. It must also be
      considered that cognitive disability may be rate-limiting to the schizophrenic
      patient's rehabilitation and impairs quality of life. Although there is a general
      consensus that neuroleptic drugs are able to improve the psychopathology of
      schizophrenia, there is continued debate concerning their impact on cognitve
      function. Chronic treatment with classical neuroleptics has been reported to
      produce only minimal improvement in, and may actually impair, cognitive function
      in schizophrenia. In contrast, novel antipsychotics seem to cause less cognitive
      impairment than classical antipsychotic medication and may improve cognitive
      function. Whilst in the past research focused on the development of clinically
      effective antipsychotic drugs with a reduced propensity to cause extrapyramidal
      symptoms (EPS), it is now being recognised that maintaining and enhancing
      cognitive function and improving quality of life should be the goal in the
      treatment of schizophrenia.

PMID- 12418608
TI  - Amisulpride: progress and outcomes.
AB  - Amisulpride is a unique atypical antipsychotic that selectively blocks D2 and D3
      receptors presynaptically in the frontal cortex, possibly enhancing dopaminergic
      transmission, and postsynaptically in the limbic areas, possibly reducing it.
      Thus dopaminergic over-activity in the frontal cortex, and under-activity in the
      limbic areas, can be treated simultaneously, alleviating both positive and
      negative symptoms of schizophrenia, respectively. In acute schizophrenia,
      amisulpride is at least as effective as haloperidol, with a greater number of
      patients responding to treatment as determined by Clinical Global Impression (CGI
      scores (p = 0.014). In addition, amisulpride is associated with a lower incidence
      of extrapyramidal symptoms (EPS) as determined by Simpson-Angus scores (SAS) when
      compared with haloperidol (p = 0.0053). Amisulpride showed similar efficacy to
      risperidone as determined by the Brief Psychiatric Rating Scale (BPRS) and the
      Positive and Negative Symptom Score (PANSS) positive subscale; a trend towards
      greater improvement of negative symptoms as determined by PANSS negative subscale
      compared with risperidone; and similar levels of EPS. Amisulpride uniquely
      benefits patients with negative symptoms and is the only antipsychotic to
      demonstrate efficacy in patients with predominantly negative symptoms.
      Amisulpride maintains its efficacy when used for medium/long-term treatment as
      demonstrated in studies of up to 12 months. Amisulpride demonstrates greater
      improvement in controlling symptoms compared to haloperidol. In terms of the
      relevance of the effects, a superiority is observed for quality of life, social
      adaptation and functioning as measured by the Quality of Life Scale (QLS),
      Clinical Glocal Impression scale (CGI) and Functional Status Questionnaire (FSQ)
      scales. Amisulpride also has one of the lowest potentials of all the
      antipsychotic agents for weight gain. The clinical evidence for amisulpride
      supports its earlier pre-clinical potential, showing it to be an atypical
      antipsychotic agent with specific clinical advantages.

PMID- 12418609
TI  - Switching to amisulpride.
AB  - The introduction of atypical antipsychotics represents an important advance in
      the treatment of schizophrenia. As their therapeutic efficacy, tolerability and
      safety profiles are clearly superior to classical neuroleptics, atypical
      antipsychotic agents are considered to be the treatment of choice in first
      episode patients. In addition, an increasing number of patients are being
      switched from classical to atypical antipsychotic agents. Switching is especially
      relevant in patients with a poor therapeutic response to classical neuroleptics
      and persistent symptoms (positive symptoms, negative symptoms, depressive
      syndromes, cognitive deficit); in patients with a psychotic relapse despite
      compliance; in patients with important side-effects (not only acute and tardive
      extrapyramidal symptoms [EPS] and general side-effects, but also dysphoria or
      neuroleptic-induced deficit syndrome [NIDS]); and in patients who are non
      compliant due to side-effects. Switching to atypical antipsychotics should be
      performed with extreme care in stabilised patients; or in patients who present a
      danger to themselves or others at relapse; or in patients who are on depot
      neuroleptics who were non-compliant to previous oral treatment. Switching
      requires careful planning to reduce the risk of withdrawal effects (neuroleptic
      withdrawal syndrome, cholinergic rebound, exacerbation of symptoms or relapse,
      rebound of parkinsonism, dystonia, akathisia, dyskinesia), which may mask the
      beneficial effects and lead to early discontinuation of the new treatment.
      Patients, family and carers should be actively involved at all stages, and
      educated about the possible benefits and problems associated with switching
      therapy. Cross-tapering old and new treatment is the preferred method for
      switching and this involves tapering off the previous antipsychotic agent and any
      adjunctive treatment (sedatives, anticholinergic medication), while gradually
      titrating the new atypical antipsychotic agent to the established therapeutic
      dose. Switching patients to amisulpride treatment offers effective antipsychotic
      therapy, with a positive effect on negative and depressive symptoms. Amisulpride
      treatment also results in improved quality of life and social functioning in
      addition to fewer relapses and days of hospitalisation during long-term follow
      up.

PMID- 12418610
TI  - Re-thinking the brain: a frog leaps.

PMID- 12418611
TI  - Epilepsy in fragile X syndrome.
AB  - Epilepsy is reported to occur in 10 to 20% of individuals with fragile X syndrome
      (FXS). A frequent seizure/EEG pattern in FXS appears to resemble that of benign
      focal epilepsy of childhood (BFEC, benign rolandic epilepsy). To evaluate seizure
      frequency and type in a Chicago FXS cohort, data regarding potential seizure
      history were reviewed for 136 individuals with FXS (age range 2 to 51 years: 113
      males and 23 females). Seizures occurred in 15 males (13.3%) and one female
      (4.8%): of these, 12 had partial seizures. EEG findings were available for 35
      individuals (13 of 16 with seizures and 22 of 120 without seizures) and showed an
      epileptiform abnormality in 10 (77%) individuals with seizures and five (23%)
      individuals without seizures--the most common epileptiform pattern being
      centrotemporal spikes. Seizures were easily controlled in 14 of the 16
      individuals with seizures. Many individuals, including all with centrotemporal
      spikes, had remission of seizures in childhood. The most common seizure syndrome
      resembled BFEC and this pattern had the best prognosis for epilepsy remission.
      Deficiency of FMRP (fragile X mental retardation protein) appears to lead to
      increased neuronal excitability and susceptibility to epilepsy, but particularly
      seems to facilitate mechanisms leading to the BFEC pattern.

PMID- 12418612
TI  - Developmental outcome and types of chronic-stage EEG abnormalities in preterm
      infants.
AB  - The aims of this study were to determine the types of chronic-stage EEG
      abnormalities that exist and to clarify their relation to neurodevelopmental
      outcome in preterm infants. We evaluated 183 preterm infants with gestational
      ages of less than 33 weeks (mean age 29.2 weeks) and weighing less than 2000 g
      (mean weight 1275 g). The first EEG was performed within 72 hours of life;
      thereafter, EEG was performed once every 1 to 4 weeks until the infant reached a
      post-conceptional age of 40 to 42 weeks. Two kinds of EEG abnormalities, acute-
      and chronic-stage abnormalities, were evaluated and we assessed mainly the
      latter. Chronic-stage EEG abnormalities were divided into two patterns:
      disorganized and dysmature. Periventricular leukomalacia (PVL) and
      intraventricular haemorrhage (IVH) were diagnosed on the basis of ultrasound
      findings. Psychomotor development was examined every 3 months after discharge
      until at least 18 months of the infants' corrected age. Disorganized and
      dysmature patterns were observed in 52 and 28 infants respectively. Among the 52
      infants with disorganized patterns, PVL was observed in 31 and IVH in seven
      infants. Thirty-nine infants had cerebral palsy (CP). Twenty-six achieved normal
      cognitive development. Of the 28 infants with dysmature patterns, PVL was seen in
      one and IVH in 11 infants. CP was seen in five infants. Only eight infants
      achieved normal cognitive development. Gestational age and birthweight were
      significantly lower in infants with dysmature patterns than in those with
      disorganized ones. Results indicate that types of chronic-stage EEG abnormalities
      are related to types of neurological sequelae and are useful for assessing the
      mode of brain injury in preterm infants.

PMID- 12418613
TI  - Muscle power development in preterm infants with periventricular flaring or
      leukomalacia in relation to outcome at 18 months.
AB  - Periventricular flaring (PVF) or periventricular leukomalacia (PVL) was diagnosed
      by brain ultrasound during the neonatal period in 44 infants (34 males, 10
      females; mean gestational age 31 weeks 2 days, SD 2 weeks 1 day) admitted between
      1995 and 1997. The infants were divided into three groups according to the
      severity of their condition. At 0, 3, and 6 months' corrected age an age-adequate
      neurological examination with special emphasis on the relation between active and
      passive muscle power was performed and symmetry between right and left sides was
      assessed. Results for the whole body, as well as for the shoulders, trunk, and
      legs were classified as optimal, suspect, or abnormal. Motor outcome at 18
      months' corrected age was graded in the same way. An overall optimal muscle power
      regulation was found in one infant at 0, two at 3, and one at 6 months. Suspect
      outcome was found at all ages in the three groups. At 0 months muscle power
      regulation did not differ between the three groups. At 3 and 6 months overall
      poor muscle power, primarily caused by poor muscle power regulation in the
      shoulders and trunk, was found in infants with PVL grades III or IV. At 18
      months' corrected age 24 infants showed no neurological impairment, eight infants
      had minor impairment, and 12 infants had severe impairment, including all 10
      infants categorized as having PVL grades II or IV. The best predictors of
      impairment at 18 months were the combined results of muscle power in the
      shoulders and trunk at 3 months with those of the shoulders at 6 months.

PMID- 12418614
TI  - Evaluation of therapeutic electrical stimulation to improve muscle strength and
      function in children with types II/III spinal muscular atrophy.
AB  - The study aimed to evaluate the effect of low-intensity night-time therapeutic
      electrical stimulation (TES) on arm strength and function in children with
      intermediate type spinal muscular atrophy (SMA). The design was a randomized
      controlled trial with a 6-month baseline control period. Children were evaluated
      at baseline, 6, and 12 months. TES was applied from 6 to 12 months to the deltoid
      and biceps muscle, of a randomly selected arm with the opposite arm receiving a
      placebo stimulator. Thirteen individuals with SMA between 5 to 19 years of age
      were recruited into the study and eight completed the 12-month assessment. No
      statistically significant differences between the treatment and control arm were
      found at baseline, 6, and 12 months for elbow flexors, or shoulder abductors on
      quantitative myometry or manual muscle testing. There was no significant change
      in excitable muscle mass assessed by M-wave amplitudes, nor function on the
      Pediatric Evaluation of Disability Inventory (self-care domain). Therefore, in
      this study there was no evidence that TES improved strength in children with SMA.

PMID- 12418615
TI  - Early postnatal doppler assessment of cerebral blood flow velocity in healthy
      preterm and term infants.
AB  - The aim of the present study was to generate normal reference data for anterior
      and middle cerebral artery blood flow velocity and resistance index in preterm
      and term infants during the first 8 hours of life. The study population
      longitudinally included 120 healthy preterm and term infants (gestational age 24
      to 41 weeks), all of appropriate weight for gestational age. The following
      parameters were studied: peak-systolic velocity, end-diastolic velocity, mean
      velocity, and resistance index. All parameters were measured in the anterior
      cerebral artery, in the left middle cerebral artery, and in the right middle
      cerebral artery with the use of Doppler colour ultrasonography. In addition, we
      studied the ratio of mean arterial blood pressure to mean velocity in the three
      cerebral arteries as a further estimate of cerebral relative vascular resistance.
      We found that cerebral blood flow velocities increased significantly with
      increasing gestational age and birthweight, both in the anterior cerebral artery
      and in the right and left middle cerebral arteries. Resistance index, both in the
      anterior cerebral artery and in the middle cerebral arteries, increased
      significantly only with increasing gestational age. Relative vascular resistance
      decreased significantly with increasing gestational age and birthweight in the
      three cerebral arteries. Significant differences were found (p<0.05) in these
      values between the anterior cerebral artery and the middle cerebral arteries. The
      narrow time frame (2 to 8 hours) that we used to evaluate cerebral blood flow
      velocity often represents a significant moment at which decisions are made that
      can be fundamental for the outcome of the newborn infant.

PMID- 12418616
TI  - Quality of movement as predictor of ADHD: results from a prospective population
      study in 5- and 6-year-old children.
AB  - The aims of this prospective study were (1) to examine whether quantitative
      and/or qualitative aspects of motor performance in 5- to 6-year-old children can
      predict attention-deficit-hyperactivity disorder (ADHD) 18 months later; (2) to
      investigate whether this relation is also present in oppositional defiant
      disorder and conduct disorder (ODD/CD). Quantitative and qualitative aspects of
      motor performance were tested in a selected community sample (n=401; 232 males,
      169 females; mean age 6 years 4 months, SD 6 months, range 5 years 4 months to 7
      years 11 months) using the Maastricht Motor Test. Eighteen months later,
      standardized psychiatric information was obtained with the Amsterdam Diagnostic
      Interview for Children and Adolescents: 35 children were classified as having
      ADHD, and 92 children as having ODD/CD. Weighted analyses were used in logistic
      regression analyses to investigate predictive values. Unlike quantitative aspects
      of motor performance, qualitative aspects were predictive of ADHD. Motor
      performance was not predictive of ODD/CD.

PMID- 12418617
TI  - Development of early motor skills and language in children at risk for familial
      dyslexia.
AB  - Differences in motor development and the relationship between motor and language
      development were studied in 88 children with familial risk for dyslexia (43
      females, 45 males; at-risk group) and 88 children without familial risk for
      dyslexia (35 females, 53 females; control group; n=176) during the first two
      years of life. A structured parental questionnaire was used to assess motor
      development. Expressive language skills were assessed at the age of 18 months
      with the Reynell Developmental Language Scales and at 18 and 24 months with the
      MacArthur Communicative Development Inventories. At group level, the motor
      development of children in both the at-risk and control groups was similar.
      However, motor development showed a different pattern in these groups. Cluster
      analyses revealed three clusters in the control group: 'fast motor development',
      'slow fine motor development', and 'slow gross motor development'. In the at-risk
      group, only two clusters were found: 'slow motor development' and 'fast motor
      development'. A significant difference (p=0.03) was found between the clusters in
      the MacArthur Communicative Development Inventories. Children with familial risk
      for dyslexia and slow motor development had a smaller vocabulary and produced
      shorter sentences than the all other children. Associations between motor and
      language difficulties are discussed.

PMID- 12418618
TI  - Epilepsy with reversible bulbar dysfunction.
AB  - In patients with focal epilepsy, focal neurological dysfunction can occur due to
      status epilepticus and also as a post-ictal phenomenon. Bulbar dysfunction as
      evident by drooling, dysarthria, swallowing difficulties, and palatal
      glossalpharyngeal weakness has been reported in conjunction with epilepsy. This
      is non-progressive and is correlated in its severity with the frequency of
      seizures. Accompanying EEG discharges are often localized to rolandic areas that
      cortically represent oral movements and salivation. We report a 6-year-old male
      and a 6 1/2-year-old female with progressive bulbar dysfunction resulting from
      epilepsy. Ictal EEGs in patient 1 did not confirm a diagnosis of epilepsy. With
      no evidence of a cortical or brainstem focus from EEG or MRI, it is very
      difficult to explain the mechanism of bulbar dysfunction. The complete
      restoration of bulbar function after treatment with antiepileptic drugs
      demonstrates the need to consider epilepsy in similar clinical situations.

PMID- 12418619
TI  - Importance of outcome determination in pediatric rehabilitation.

PMID- 12418620
TI  - Management of drooling: 10 years after the Consortium on Drooling, 1990.

PMID- 12418621
TI  - Visual impairment in infancy: impact on neurodevelopmental and neurobiological
      processes.

PMID- 12418622
TI  - Epileptic blindness in tuberous sclerosis complex.

PMID- 12418623
TI  - Surveillance for influenza--United States, 1997-98, 1998-99, and 1999-00 seasons.
AB  - PROBLEM/CONDITION: In the United States, influenza epidemics occur nearly every
      winter and are responsible for substantial morbidity and mortality, including an
      average of approximately 114,000 hospitalizations and 20,000 deaths/year.
      REPORTING PERIOD: This report summarizes both actively and passively collected
      U.S. influenza surveillance data from October 1997 through September 2000.
      DESCRIPTION OF SYSTEM: During each October-May in the period covered, CDC
      received weekly reports from 1) approximately 120 World Health Organization (WHO)
      and National Respiratory and Enteric Virus Surveillance System (NREVSS)
      collaborating laboratories in the United States regarding influenza virus
      isolations; 2) approximately 230, 375, and 430 sentinel physicians during 1997
      98, 1998-99, and 1999-00, respectively, regarding their total number of patient
      visits and the number of visits for influenza-like illness (ILI); and 3) state
      and territorial epidemiologists regarding estimates of local influenza activity.
      WHO collaborating laboratories also submitted influenza isolates to CDC for
      antigenic analysis. Throughout the year, the vital statistics offices in 122
      cities reported weekly on deaths related to pneumonia and influenza (P&I).
      RESULTS: During the 1997-98 influenza season, influenza A(H3N2) was the most
      frequently isolated influenza virus type/subtype. Influenza A(H1N1) and B viruses
      were reported infrequently. The proportion of respiratory specimens testing
      positive for influenza peaked at 28% in late January. The longest period of
      sustained excess mortality (when the percentage of deaths attributed to P&I
      exceeded the epidemic threshold) was 10 consecutive weeks. P&I mortality peaked
      at 9.8% in January. Visits for ILI to sentinel physicians exceeded baseline
      levels for 7 weeks and peaked at 5% in mid-January through early February. A
      total of 45 state epidemiologists reported regional or widespread activity at the
      peak of the season. During the 1998-99 season, influenza A(H3N2) viruses
      predominated; however, influenza B viruses were also identified throughout the
      United States. Influenza A(H1N1) viruses were identified rarely. The proportion
      of respiratory specimens testing positive for influenza peaked at 28% in early
      February. P&I mortality exceeded the epidemic threshold for 12 consecutive weeks
      and peaked at 9.7% in early March. Visits for ILI to sentinel physicians exceeded
      baseline levels for 7 weeks and peaked at 5% in early through mid-February. Forty
      three state epidemiologists reported regional or widespread activity at the peak
      of the season. During the 1999-00 season, influenza A(H3N2) viruses predominated,
      but influenza A(H1N1) and B viruses also were identified. The proportion of
      respiratory specimens testing positive for influenza peaked at 31% in mid- to
      late December. The proportion of deaths attributed to P&I exceeded the epidemic
      threshold for 13 consecutive weeks and peaked at 11.2% in mid-January. Visits to
      sentinel physicians for ILI exceeded baseline levels 4 consecutive weeks and
      peaked at 6% in late December. Forty-four state epidemiologists reported regional
      or widespread activity at the peak of the season. INTERPRETATION: Influenza
      A(H1N1), A(H3N2), and B viruses circulated during 1997-2000, but influenza
      A(H3N2) was the most frequently reported virus type/subtype during all three
      seasons. Influenza A(H3N2) is the virus type/subtype most frequently associated
      with excess P&I mortality. Influenza activity during all three seasons occurred
      at moderate to severe levels, and excess P&I mortality was reported during > or =
      10 weeks each year. PUBLIC HEALTH ACTIONS: CDC conducts active national
      surveillance during each October-May to detect the emergence and spread of
      influenza virus variants and to monitor influenza-related morbidity and
      mortality. Surveillance data are provided weekly throughout the influenza season
      to public health officials, WHO, and health-care providers and are used to guide
      vaccine strain selection, prevention and control activities, and patient care.
      Influenza vaccination is the most effective means for reducing the yearly effect
      of influenza. Typically, one or two of the influenza vaccine component viruses
      are updated each year so that vaccine strains will closely match circulating
      viruses. Surveillance data will continue to be used to select vaccine strains and
      to monitor the match between vaccine strains and the currently circulating
      viruses.

PMID- 12418624
TI  - Guideline for Hand Hygiene in Health-Care Settings. Recommendations of the
      Healthcare Infection Control Practices Advisory Committee and the
      HICPAC/SHEA/APIC/IDSA Hand Hygiene Task Force. Society for Healthcare
      Epidemiology of America/Association for Professionals in Infection
      Control/Infectious Diseases Society of America.
AB  - The Guideline for Hand Hygiene in Health-Care Settings provides health-care
      workers (HCWs) with a review of data regarding handwashing and hand antisepsis in
      health-care settings. In addition, it provides specific recommendations to
      promote improved hand-hygiene practices and reduce transmission ofpathogenic
      microorganisms to patients and personnel in health-care settings. This report
      reviews studies published since the 1985 CDC guideline (Garner JS, Favero MS. CDC
      guideline for handwashing and hospital environmental control, 1985. Infect
      Control 1986;7:231-43) and the 1995 APIC guideline (Larson EL, APIC Guidelines
      Committee. APIC guideline for handwashing and hand antisepsis in health care
      settings. Am J Infect Control 1995;23:251-69) were issued and provides an in
      depth review of hand-hygiene practices of HCWs, levels of adherence of personnel
      to recommended handwashing practices, and factors adversely affecting adherence.
      New studies of the in vivo efficacy of alcohol-based hand rubs and the low
      incidence of dermatitis associated with their use are reviewed. Recent studies
      demonstrating the value of multidisciplinary hand-hygiene promotion programs and
      the potential role of alcohol-based hand rubs in improving hand-hygiene practices
      are summarized. Recommendations concerning related issues (e.g., the use of
      surgical hand antiseptics, hand lotions or creams, and wearing of artificial
      fingernails) are also included.

PMID- 12418625
TI  - Epilepsy--an optimistic overview.

PMID- 12418626
TI  - Review of breast cancer cases in Jaipur region.
AB  - Breast cancer forms the commonest cancer in females in Jaipur region. Two hundred
      cases of breast malignancy were recorded in a single year (1990). This
      constituted 8.30% of total cancers and 19.40% of all female cancers. The
      commonest age group was 45-54 years (37.0%) followed by 35-44 years (24.50%).
      Only 13.50% were below the age of 35 years. Majority of the patients (97.50%)
      were married and 76.0% got married below the age of 20 years, 26.50% got married
      below the age of 15 years. Most (75.0%) has menarche between the age of 13 and 16
      years. Menstrual irregularities were present in only 17.50% of the cases. More
      than 6 pregnancies had in 33.50% patients and 50.50% had 3-5 pregnancies. Only
      4.50% had no issue. Most of the women (68.50%) had their first live child between
      18 and 25 years and 13.50% had below 18 years. Majority reported having breastfed
      their children for 1-2 years. Only 12.0% and 5.0% women reported having any
      problem with breast during lactation and otherwise respectively. A family history
      of cancer was present in 10.0% of the cases. A personal delay of more than two
      years in seeking medical help was observed in only 6.0% of the cases while 22.50%
      sought medical advice within a week time. Risk factors which are implicated in
      the aetiology of breast cancer in the western setting might not necessarily hold
      true in our country. More epidemiological studies are required to elicit
      correlation, if any, in the Indian context.

PMID- 12418627
TI  - Refractory epilepsy: diagnosis and management.
AB  - Persistence of seizures despite appropriate medical treatment is called
      refractory epilepsy. Persistent seizures have enormous psychosocial, behavioural
      and cognitive effects in addition to effects on mortality. Almost 2,40,000 to
      3,20,000 patients of refractory epilepsy in India are potential candidates for
      epilepsy surgery. Causes of refractory or intractable epilepsy are inadequate
      anti-epileptic treatment, difficulty in treating some epileptic syndromes and
      difficulty in controlling seizures due to structural brain diseases. Careful
      evaluation of historical details, especially based on an eyewitness account is
      the most important aspect in establishing the diagnosis of epilepsy. Raised serum
      prolactin level helps in differentiating convulsive seizures from non-epileptic
      convulsions. Video electroencephalographic monitoring is proved effective and
      efficient mean to establish the rightful diagnosis. Recent developments in neuro
      imaging have revolutionised the diagnosis of underlying pathology in patients
      with refractory epilepsies. Patients with refractory epilepsy should be referred
      to a specialised epilepsy centre where facilities for epilepsy surgery are
      available. When medical therapy fails, other options are helpful like use of
      newer anti-epileptic drugs, vagus nerve stimulation or consideration of epilepsy
      surgery.

PMID- 12418628
TI  - Psychosocial aspects of epilepsy.
AB  - Social attitudes towards epilepsy cause more distress to the patient and his/her
      near and dear ones, than the disease itself. The major psychosocial issues
      related to epilepsy are: Quality of medical management, overprotection,
      education, employment, marriage and pregnancy. Inadequate treatment is the major
      reason involved in psychosocial issues. Constant overprotection and pampering
      leads to behavioural pattern which makes epileptic patient dependent for ever.
      Education is hampered in epileptic persons. Teachers and students should have
      proper information regarding seizures. If seizures are well controlled, job
      opportunities increase. Employers and employees need to be educated about
      epilepsy. Self-employment is the best in epileptic patients. Regarding marriage,
      each patient is to be judged on individual merits and type of epilepsy. Society
      needs to be educated about the facts and consequences of epilepsy. Risk of anti
      epileptic drug's usage is very insignificant compared to risk of seizures in
      pregnancy. So girls are advised to seek medical advice before pregnancy and
      during follow-up. With more and more support from the society, persons with
      epilepsy will have the courage and confidence to speak about themselves and their
      illness. It is only then that we will realise that persons with epilepsy are
      'normal' or 'near-normal' and this will break the vicious cycle of stigma.

PMID- 12418629
TI  - Management of status epilepticus.
AB  - Status epilepticus is a medical emergency, if not treated in time and effectively
      may cause significant mortality and morbidity. Medical therapy has been the
      mainstay of treatment but in refractory status surgical resection, multiple
      subpial transection, electroconvulsive therapy, caudate stimulation and
      acupuncture play important role. The present operational definition for adults
      and older children considers status as > or = 5 minutes of continuous seizure or
      two or more discrete seizures without regaining of full consciousness. Status
      epilepticus accounts for 1-8% of all hospital admissions for epilepsy.
      Physiological changes in generalised convulsive status epilepticus include
      transient or early (0-30 minutes) and late (after 30 minutes) changes. Temporal
      changes occur as tonic-clonic status epilepticus progresses. Management can be
      considered in two ways--out hospital management and inpatient management.
      Benzodiazepine is considered 1st line of treatment outside hospital.
      Emergency/inpatient management includes basic life support (0-10 minutes) and
      pharmacological management (10-60 minutes). Drugs used in pharmacological
      management are lorazepam, midazolam, propofol, phenobarbital, phenytoin,
      fosphenytoin, i.v. valproate, rectal diazepam, etc. The classical definition of
      refractory status epilepticus includes seizure that has not responded to
      sequential treatment of lorazepam, phenytoin or phenobarbitone or seizure
      continuing > 60-90 in spite of adequate treatment.

PMID- 12418630
TI  - Anti-epileptic drugs.
AB  - As a sizeable population is affected by epilepsy, so its effective management is
      a matter of concern. Newer anti-epileptic drugs are now in use, aimed at controls
      of seizure with fewer side-effects over and above the conventional anti-epileptic
      drugs. The anti-epileptic drugs can be divided in two groups--conventional anti
      epileptic drugs and newer anti-epileptic drugs. The drugs which fall in the first
      group are--phenytoin, phenobaibitone, valproic acid, carbamazepine, ethosuximide
      and clonazepam. The second group of drugs are--lamotrigine, clobazam,
      oxcarbazepine, topiramate and gabapentin. The pharmacology of the drugs are
      described in a nutshell in this article.

PMID- 12418631
TI  - Prospective evaluation of modified Alvarado score for diagnosis of acute
      appendicitis.
AB  - Modified Alvarado scoring system was evaluated regarding its usefulness in the
      early diagnosis of acute appendicitis and in reduction of the incidence of
      negative appendicectomies. One hundred and ten patients with a provisional
      diagnosis of acute appendicitis were studied prospectively at R G Kar Medical
      College and Hospital, Calcutta over a period of 10 months. High score was found
      to be a dependable aid both in the pre-operative diagnosis of acute appendicitis
      and in the reduction of negative appendicectomies in men and children but the
      same was not true for women who had a high false positive rate for acute
      appendicitis.

PMID- 12418632
TI  - Jaundice in falciparum malaria--some prospective observations.
AB  - The present prospective study of slide positive Plasmodium falciparum patients
      revealed a higher (17%) incidence of jaundice. This is much higher than reported
      earlier. Serum transaminases were raised by two to three times the normal value.
      Histologically the most conspicuous finding was reticulo-endothelial cell
      proliferation in the liver along with mononuclear cell infiltration. Malarial
      parasites were not found in the biopsy specimens. Mortality was high especially
      amongst the late presenters. In areas endemic for malaria, awareness of this
      entity is important. In a patient with fever and jaundice with or without altered
      sensorium, disproportionate hyperbilirubinaemia but with only mild elevation of
      liver enzymes could help differentiate these cases from viral hepatitis. The
      diagnosis can be confirmed by peripheral blood examination, done if required. As
      the mortality in late presenters is high, early diagnosis in such cases with
      institution of specific therapy may be life saving.

PMID- 12418633
TI  - AgNORs in squamous cell carcinoma of head and neck.
AB  - The number of AgNORs per nucleus correlates with cellular proliferation and
      independently with malignant change. AgNOR number was studied in 200 cases of
      squamous cell carcinoma of head and neck, the count increased with increasing
      grade and the size became smaller and irregular with increasing grade of
      carcinoma. This study seems to suggest that this method has utility in grading of
      squamous cell carcinoma of head and neck.

PMID- 12418634
TI  - Febrile convulsion--an overview.
AB  - Febrile convulsion is the most frequently occurring epilepsy syndrome,
      experienced in infants/children between 6 months and 5 years of age associated
      with fever >38 degrees C. Children having first or second degree relative with
      history of febrile convulsion, neonatal nursery stay of more than 30 days,
      developmental delay or attendance at day care centre are at increased risk of
      developing febrile convulsion. Single febrile convulsion does not increase the
      risk of epilepsy and there is no causal relationship between febrile convulsion
      and subsequent epilepsy. It has been recognised that there is significant genetic
      component for susceptibility to febrile seizures. To make the diagnosis of
      febrile convulsion, meningitis, encephalitis, serious electrolyte imbalance and
      other acute neurologic illnesses are to be excluded. While managing acute attack
      the steps to be taken are--airway management, a semi-prone position to avoid
      aspiration, monitoring vital signs and other supportive care. Diazepam or
      lorazepam is the drug to be used. There is no reason to expect phenobarbitone
      administered at the time of fever to be effective in prevention of febrile
      convulsion. The parents should be counselled about the benign nature of the
      convulsion. Although the febrile convulsion a frightening event, still it is a
      benign condition.

PMID- 12418635
TI  - Paediatric immunisation: special emphasis on measles and MMR vaccinations.
AB  - The dictum, 'prevention is better than cure', is applicable to all ailments but
      it can be most easily followed for infectious diseases, increasing numbers of
      which are being contained by specific vaccinations since the first discovery of
      smallpox vaccine by Edward Jenner in 1796. Advances in immunology and laboratory
      techniques including cell culture, genetic engineering and animal experiments
      have contributed significantly to the production of more and more vaccines, used
      successfully in preventive programmes. Infectious diseases are widely prevalent
      in the developing countries. The child population is specially vulnerable to many
      of them. These infections contribute to high morbidity and mortality and
      immunisation programmes have been undertaken as preventive measures against them
      at the national level. Paediatricians and experts are actively engaged in
      formulating and improving these programmes as problems are faced in their
      implementation. Much new information is continuously being available in the
      literature, mostly in specialised journals. The general practitioners,
      particularly those serving in the remote and vast rural areas, are not likely to
      have access to these recent developments which they need for self-motivation in
      initiating the parents with confident advice to have their children properly
      immunised and also for tackling effectively any problem arising out of
      immunisation. This paper attempts to discuss the subject of paediatric
      immunisation with special emphasis being laid on measles and MMR vaccinations.

PMID- 12418636
TI  - Epidemiology of epilepsy--Indian perspective.
AB  - There are about 20 epidemiological studies on epilepsy from different parts of
      India. They include both rural and urban studies. The prevalence rate stands at
      around 5/1000 population (at this rate present estimate of total epileptics in
      this country is about 5 million) and incidence rate varies from 38 to 49.3 per
      100,000 population per year from two community-based studies in India. Case
      control studies indicate that febrile seizures, family history of epilepsy and
      head trauma are significant risk factors. Type of seizure pattern showed maximum
      number of cases belonged to generalised seizures which is different from Western
      countries where partial seizure is the commonest variety. Treatment gap, which is
      a measure of per cent of patient populations not receiving the treatment,
      estimated to be up to 73.7% to 78% in India. Aetiology is unknown in about two
      thirds of cases. Hot water epilepsy is unique in South India and single solitary
      ring enhancing lesion in brain imaging is a common feature in Indian
      subcontinent. Evaluation of prevalence study indicates that more case-control
      studies to find out the aetiology, pharmaco-economic study to find out the
      affordable drug for general public and mass health education should be undertaken
      to dispel the social stigma and to bring about change in the attitude about the
      disease.

PMID- 12418637
TI  - Hydatid disease: an unusual breast lump.
AB  - Hydatid disease of the breast is rare, but it should be included under
      differential diagnosis of a breast lump especially in endemic areas of this
      disease. Fine needle aspiration cytology can provide a safe pre-operative
      diagnosis, although mammogram, ultrasonography of breast, magnetic resonance
      imaging and serological tests like Casoni's test can also be done. Complete
      excision of the cyst without spillage can be a curative procedure for primary
      hydatid cyst of the breast. It is important to explore other common sites like
      liver and lung by means of ultrasonography and chest x-ray and treat accordingly.
      Here in this report, a lady of 27 years old presented with a painless lump of the
      left breast. Fine needle aspiration cytology was inconclusive. Lumpectomy was
      done. Histopathological examination confirmed it to be a case of hydatid disease
      involving the left breast.

PMID- 12418638
TI  - Rmyoplasia congenita.
AB  - Amyoplasia congenita is a rare congenital disorder. Here such a case along with
      right sided inguinal hernia in 3-day-old male baby is presented with a brief
      review of literature. A 3-day-old male baby was presented with multiple bony
      deformities with right sided inguinoscrotal swelling since birth. It was
      diagnosed as a case of amyoplasia congenita along with a right sided inguinal
      hernia. The baby was managed with physiotherapy and right sided herniorrhaphy was
      done at 2 months and 2 days of age.

PMID- 12418639
TI  - Bite by a dog under provocation: is it free from risk?
AB  - There is a common belief that rabid dogs bite without provocation, hence a dog
      bite under provocation is free from the risk of rabies. This is not always true
      as is evident from the case report narrated below. Here in this article, a man of
      38 years was bitten by a dog under provocation. He developed rabies 4 months
      after the bite and subsequently died. Autopsy revealed Negri bodies from the
      brain tissue.

PMID- 12418640
TI  - The prescribing habits.

PMID- 12418641
TI  - Needless interventions in medicine.

PMID- 12418642
TI  - Special issue on diabetes.

PMID- 12418643
TI  - Diabetes and skin diseases.

PMID- 12418644
TI  - Antibiotic associated diarrhoea: a controlled study comparing plain antibiotic
      with those containing protected lactobacilli.
AB  - Antibiotic associated diarrhoea is known to occur with broad spectrum
      antibiotics. Lactobacillus has been used for prophylaxis and therapy of this
      condition. In a double blind controlled study, the antibiotic containing
      ampicillin (250 mg) and cloxacillin (250 mg) with or without protected
      lactobacilli was evaluated in 740 patients undergoing cataract surgery. The
      incidence of diarrhoea in patients receiving plain antibiotic was 13.3% compared
      to 0.0% in patients receiving antibiotic with protected lactobacilli (p<0.001).
      The study demonstrates that antibiotic formulations containing protected
      lactobacilli maintain prophylactic effect of lactobacilli.

PMID- 12418645
TI  - Oxcarbamazepine, the new effective anti-epileptic drug for add-on as well as
      monotherapy in partial epilepsies.

PMID- 12418646
TI  - Literature review--efficacy of various disinfectants against Legionella in water
      systems.
AB  - There have been reported outbreaks of Legionnaires' disease at hospitals and
      industrial facilities, which prompted the development of various preventive
      measures. For example, Ford has been developing and implementing such a measure
      at its facilities worldwide to provide technical guidance for controlling
      Legionella in water systems. One of the key issues for implementing the measure
      is the selection of a disinfectant(s) and optimum conditions for its use.
      Therefore, available publications on various disinfectants and disinfection
      processes used for the inactivation of Legionella bacteria were reviewed. Two
      disinfection methods were reviewed: chemical and thermal. For chemical methods,
      disinfectants used were metal ions (copper and silver), oxidizing agents (halogen
      containing compounds [chlorine, bromine, iodine, chlorine dioxide, chloramines,
      and halogenated hydantoins], ozone, and hydrogen peroxide), non-oxidizing agents
      (heterocyclic ketones, guanidines, thiocarbamates, aldehydes, amines,
      thiocyanates, organo-tin compounds, halogenated amides, and halogenated glycols),
      and UV light. In general, oxidizing disinfectants were found to be more effective
      than non-oxidizing ones. Among oxidizing agents, chlorine is known to be
      effective and widely used. Among non-oxidizing agents, 2,2-dibromo-3
      nitropropionamide appears to be the most effective followed by glutaraldehyde.
      Isothiazolin (known as Kathon), polyhexamethylene biguanide, and 2-bromo-2
      nitropropionamide (known as Bronopol) were found to be less effective than
      glutaraldehyde. Thermal disinfection is effective at > 60 degrees C (140 degrees
      F).

PMID- 12418647
TI  - Enzyme production activity of Phanerochaete chrysosporium and degradation of
      pentachlorophenol in a bioreactor.
AB  - Lignin peroxidase production by a white rot fungus, Phanerochaete chrysosporium,
      was experimentally investigated using a batch system and a reactor system with
      various carriers. Immobilization of mycelia cell culture was more effective in
      promoting cell growth and lignin peroxidase production compared to conventional
      stationary liquid culture. Biostage carrier, commonly used for biochemical
      treatment in a fluidized bed disposal system, greatly improved production of
      lignin peroxidase up to 8.1 U/mL in the batch system. The packed bed reactor
      system was operated using a repeated batch technique, consisting of alternating
      growth and production phases, to sustain lignin peroxidase growth and production
      during the entire experiment period. Steady-state continuous PCP degradation over
      an extended period was accomplished with a mineralization ratio exceeding 80%.
      These systems and operation methods are promising techniques for the treatment of
      hazardous waste.

PMID- 12418648
TI  - Use of semi-permeable membrane devices and solid-phase extraction for the wide
      range screening of microcontaminants in surface water by GC-AED/MS.
AB  - An automated GC-MS-based screening method was developed for over 400 industrial,
      agrochemical and household chemicals. Extracted ion chromatograms were used and
      the method was aimed at creating a minimum number of false positives. The
      compound polarity range usually associated with solid-phase extraction was
      extended to include very apolar, bioaccumulative, compounds by using the
      complementary semi-permeable membrane device technique. Real-life samples were
      taken at four locations in the main Dutch river systems and one in an
      agricultural area. Some 150 compounds were detected in the low-ng/l to low
      microg/l range. Next to the target compounds, several brominated and chlorinated
      non-target compounds were detected by means of GC with atomic emission detection
      and tentatively identified using mass spectral library searching.

PMID- 12418649
TI  - Nitrite inhibition of aerobic growth of Acinetobacter sp.
AB  - Nitrite inhibition of Acinetobacter sp. growing under aerobic conditions was
      studied. Specific growth rates under non-limiting concentrations of acetate and
      dissolved oxygen averaged 0.62h(-1). Growth and phosphate uptake by Acinetobacter
      sp. were both inhibited by increasing nitrite concentrations. The median
      inhibitory concentration (IC50) of free nitrous acid (FNA) was 0.10 mg/L and the
      IC10 of FNA was 0.05 mg/L. Removing nitrite from cultures reversed the inhibitory
      effect. Comparison of the IC10 of FNA for Acinetobacter sp. to inhibitory
      concentrations for other wastewater heterotrophic bacteria suggests that
      Acinetobacter sp. are relatively sensitive to this compound.

PMID- 12418650
TI  - Bulk water phase and biofilm growth in drinking water at low nutrient conditions.
AB  - In this study, the bacterial growth dynamics of a drinking water distribution
      system at low nutrient conditions was studied in order to determine bacterial
      growth rates by a range of methods, and to compare growth rates in the bulk water
      phase and the biofilm. A model distribution system was used to quantify the
      effect of retention times at hydraulic conditions similar to those in drinking
      water distribution networks. Water and pipe wall samples were taken and examined
      during the experiment. The pipes had been exposed to drinking water at
      approximately 13 degrees C, for at least 385 days to allow the formation of a
      mature quasi-stationary biofilm. At retention times of 12 h, total bacterial
      counts increased equivalent to a net bacterial growth rate of 0.048 day(-1). The
      bulk water phase bacteria exhibited a higher activity than the biofilm bacteria
      in terms of culturability, cell-specific ATP content, and cell-specific leucine
      incorporation rate. Bacteria in the bulk water phase incubated without the
      presence of biofilm exhibited a bacterial growth rate of 0.30 day(-1). The
      biofilm was radioactively labelled by the addition of 14C-benzoic acid.
      Subsequently, a biofilm detachment rate of 0.013 day(-1) was determined by
      measuring the release of 14C-labelled bacteria of the biofilm. For the quasi
      stationary phase biofilm, the detachment rate was equivalent to the net growth
      rate. The growth rates determined in this study by different independent
      experimental approaches were comparable and within the range of values reported
      in the literature.

PMID- 12418651
TI  - Evaluation of different approaches to quantify strong organic acidity and acid
      base buffering of organic-rich surface waters in Sweden.
AB  - The role of organic acids in buffering pH in surface waters has been studied
      using a small brownwater stream (26mg L(-1) TOC) draining a forested catchment in
      Northern Sweden. Under the conditions of elevated pressure of CO2 stream field pH
      was changed between 3.5 and 6.1 during the acidification and alkalinization
      experiment. Acid-base characteristics of the natural organic matter were also
      determined using a high precision potentiometric method for a concentrated sample
      from the same stream. We compared the predictions from the Windermere Humic
      Aqueous Model (WHAM Model V), a model derived from the potentiometric titration
      (diprotic/monoprotic acid model) and a previously derived triprotic acid model
      which only uses alkalinity and TOC as input variables. The predicted buffering
      characteristics of all three models are very similar in the pH range 4.5-7 which
      suggests that during routine analysis alkalinity and TOC are sufficient to give a
      good estimate of organic acid anion charge contribution in a large range of
      surface waters. A slightly adjusted version of WHAM V successfully describes the
      organic charge contribution in a large number of sampled surface water lakes,
      which were previously used to calibrate the triprotic model.

PMID- 12418652
TI  - Assessment of bioavailability and effects of chemicals due to remediation actions
      with caging mussels (Anodonta anatina) at a creosote-contaminated lake sediment
      site.
AB  - A study was conducted at Lake Jamsanvesi in Central Finland, to identify the
      potential ecotoxicological risks of the remediation operation of a creosote-/PAH
      contaminated lake sediment, made by capping during the years 1998-1999. Mussels
      (Anodonta anatina) were deployed to the lake at the same time as the remediation
      operation was started in November 1998. The contaminated area (0.5 ha) was
      covered by a filter geotextile (polypropylene), gravel and sand (1-1.5m) which
      were spread out on the ice and let to sink onto the bottom of the lake when the
      ice melted in May 1999. The possible impacts of capping to the adjacent
      environment were assessed from mussels exposed and particulate material settled
      (SPM) to collectors placed on the lake bottom. Mussel tissue, SPM, the water
      inside the collector were analyzed for polycyclic aromatic compounds (PAH)
      compounds. Biological endpoints included body condition, glycogen and protein
      contents of adductor muscle. Mussels and SPM exposed downstream to the
      contaminated site (Site 3) contained the highest total PAH concentrations. Biota
      sediment accumulation factors of acenaphthene, phenanthrene, anthracene,
      fluoranthene, pyrene and benzo(a)anthracene of mussels varied from 0.79 to 1.45.
      The glycogen and protein concentrations were lowest in adductor muscle from
      mussels exposed to conditions at Site 3. Concentrations of some PAH-compounds
      were found distinctly increased adjacent to the remediated area, possibly due to
      the agitation of contaminated sediment due to the capping. It is also possible
      that resuspension of sediment around remediated area (containing some PAHs)
      spread the deposited PAH-compounds.

PMID- 12418653
TI  - Use of a chemical sensor array for detecting pollutants in domestic wastewater.
AB  - A chemical sensor array (consisting of 8 conducting polymers) was used to
      continuously monitor for the presence or absence of industrial pollutants in the
      headspace of wastewater generated from an on-line flow-cell. A domestic
      wastewater (Cranfield University sewage works) was dosed with diesel to stimulate
      the presence of an intermittent discharge in a wastewater influent. Response
      patterns between the sensors were used to detect for the presence of organic
      compounds in the wastewater. Correlations between the sensor response patterns or
      fingerprints were also analysed using principal component analysis. The results
      clearly demonstrate that a chemical sensor array can rapidly identify the
      presence of organic compounds (such as diesel) in a wastewater matrix and could
      be further developed to monitor for industrial pollutants at the inlet of a
      sewage works.

PMID- 12418654
TI  - Laboratory septic tank performance response to electrolytic stimulation.
AB  - This research investigated the effects of electrolytic stimulation on the
      performance of two laboratory-scale septic tanks. The tanks were fed a synthetic
      solution that included cellulose, peptone trypticase, beef extract, and urea.
      After a baseline period with no passed current, currents ranging from 100 to 500
      mA were passed through the electrodes. The chemical oxygen demand (COD) removal
      efficiency from the tanks improved when a current was passed, with higher removal
      efficiencies observed at higher levels of passed current. Hydrolytic reactions
      resulted in ammonia and phosphate levels in the tanks that were higher than the
      influent. At currents > 300 mA, these hydrolytic reactions were suppressed,
      resulting in phosphate levels similar to the influent and ammonia levels lower
      than the influent because of the settling of ammonia-containing components of the
      feed solution. A slight increase in nitrate levels was observed when a current
      was passed, indicating minimal stimulation of nitrification activity. Abiotic
      studies confirmed that the COD can be removed via electrolysis and the removal
      was proportional to the passed current. Under the conditions of this study, the
      primary benefit of electrolytic stimulation of the septic tank is enhanced COD
      removal.

PMID- 12418655
TI  - Phosphorus reduction in a shallow hypereutrophic reservoir by in-lake dosage of
      ferrous iron.
AB  - In Bautzen Reservoir (Germany), a technique of internally dosing iron compounds
      in combination with a local water column destratification was developed in order
      to control Microcystis blooms. In this paper, experimental results concerning the
      phosphorus (P) precipitation by iron application are reported. First, preliminary
      studies were conducted serving the choice of an appropriate precipitant.
      Subsequently, a whole-lake experiment was carried out. Fe2+ salts displayed a
      delayed oxidation and flocculation behaviour when injected into an ascending
      water jet. Nevertheless, the efficiency of soluble reactive phosphorus (SRP)
      elimination was equal to experiments with Fe3 + compounds both in laboratory and
      field experiments. During Fe2+ application, a large P-binding potential remained
      during the horizontal spreading of the treated water, since the proportion of the
      dissolved iron fraction near the dosage point was still high. Thus, measurements
      at a greater distance from the dosage point revealed higher amounts of P
      eliminated by Fe2+ than by Fe3+ dosage. Compared to the preceding year 1995,
      during the treatment periods in May-August 1996 and 1997 the SRP contents in the
      whole water body dropped by 72% and 54%, respectively, while the total phosphorus
      contents dropped by 45% at each period. We conclude that in-lake dosage of Fe2+
      is an appropriate method to reduce the P loading of hypereutrophic reservoirs.

PMID- 12418656
TI  - A possible new disinfection by-product--2-chloro-5-oxo-3-hexene diacyl chloride
      (COHC)--in formation of MX by chlorinating model compounds.
AB  - MX was widely considered as one of the most important disinfection by-products
      (DPBs) and as the strong carcinogen in the chlorinated drinking water. Some model
      compounds which have been classified into four families were chlorinated at
      laboratory conditions. MX was produced only in the chlorinated substituted
      aromatic aldehydes and amino acids, while a possible new compound (COHC) was
      found in some substituted aromatic aldehydes, chlorinated substituted aromatic
      acids and phenols. Through the analysis of the peaks presented in mass spectrum,
      the composition and structure of the new compound are proposed as 2-chloro-5-oxo
      3-hexene diacyl chloride (COHC) which could cause interference in the detection
      of MX. COHC has also been found in drinking water and extracted chlorinated
      fulvic acid solution from the sediment and water of Tai Lake, so it should bring
      about more attention.

PMID- 12418657
TI  - Biomass development in slow sand filters.
AB  - Microbial biomass development in the sand and schmutzdecke layer was determined
      in two full-scale slow sand filters, operated with and without a light excluding
      cover. A standard chloroform fumigation-extraction technique was adapted to
      routinely measure microbial biomass concentrations in the sand beds. Sand was
      sampled to a depth of 10 cm and schmutzdecke was also collected at the same
      random positions on the uncovered filter. Interstitial microbial biomass in the
      uncovered sand bed increased with time and decreased with sampling depth. There
      was a small accumulation of sand biomass with time in the covered filter, but no
      relationship was apparent between biomass concentration and depth in this filter.
      Schmutzdecke did not develop on the covered filter and was spatially highly
      variable in the uncovered condition compared to the consistent patterns observed
      in interstitial biomass production. It is speculated that microbial biomass in
      the sand of uncovered filters is largely related to carbon inputs from
      photosynthetic activity in the schmutzdecke and involves mechanisms that
      spatially distribute carbon substrate from the schmutzdecke to the sand. However,
      total organic carbon and dissolved organic carbon removals were similar in both
      filters suggesting that relatively small biomass populations in covered filters
      are sufficient to remove residual labile carbon during advanced water treatment
      and little further advantage to water purification and organic carbon removal is
      gained by the increased production of biomass in uncovered slow sand filter beds.

PMID- 12418658
TI  - Characterization, differentiation and classification of aquatic humic matter
      separated with different sorbents: synchronous scanning fluorescence
      spectroscopy.
AB  - Aquatic humic solutes were separated by the non-ionic macroporous XAD-8 and DAX-8
      resins and a weakly basic DEAE cellulose anion exchanger from seven different
      fresh water sources. Synchronous fluorescence spectroscopy was applied for
      characterization, differentiation and classification of the different humic
      solute aggregates. Fluorescence properties verified that humic-solute fractions
      isolated parallelly with the non-ionic XAD-8 and DAX-8 resins resembled very
      closely each other speaking strongly for their structural similarities. DAX-8
      resin separated ca. 19% more aquatic humic matter than did the analogous XAD-8
      resin. It was possible to tentatively differentiate the untreated water samples
      according to their fluorescent materials. Several distinct classes of
      chromophores were detected in both DOM and isolated humic fractions by the
      synchronous technique: lambda(ex)/lambda(em) 280/298, 330/348, 355/373, 400/418,
      427/445, 460/478, 492/510 and 516/534 nm.

PMID- 12418659
TI  - Trophic transfer of heavy metals from freshwater zooplankton Daphnia magna to
      zebrafish Danio reiro.
AB  - The trophic transfer of metals along the food chain has been recognized as an
      important issue in the study of water quality in recent years. Feeding
      experiments were conducted to examine the assimilation of three metals (Cd, Cr
      and Zn) by the zebrafish Danio reiro feeding on the freshwater zooplankton
      Daphnia magna. The zooplankton were exposed to radiotracers from both the aqueous
      and dietary phases for different duration, and then pulse-fed to the zebrafish
      for measurements of metal assimilation efficiency (AE). The calculated AEs were 3
      8% for Cd, 2-39% for Cr, and 17-36% for Zn in the zebrafish. For Cd and Zn, there
      was no statistically significant difference between the two different
      radiolabeling routes (aqueous and dietary exposure). For Cr, the AEs were higher
      when it was accumulated by D. magna from the dietary source than when it was
      accumulated from the aqueous phase. The gut passage time (GPT) was 6-10 h for all
      metals, with less variation for Zn among the different treatments. There was no
      obvious relationship between metal GPT and metal AE, presumably due to the narrow
      range of variation of metal gut passage. About 5-36%, 20-31%, and 8-30% of the
      total Cd, Cr and Zn was found in the soft tissue of D. magna after the
      radiolabeling. A much higher fraction of Cd and Zn was found in the soft tissue
      of D. magna when the metals were accumulated from the dietary phase. No
      significant relationship between the metal AE and the metal distribution in the
      soft tissue of D. magna was however documented in this study. Our results
      demonstrated that there was major difference in metal AE in freshwater fish among
      different metals. Metal localization in prey organisms and GPT appear to have
      little influence on metal assimilation by the zebrafish.

PMID- 12418660
TI  - Optimal design for dispersion experiment.
AB  - The dispersion coefficient (D) is a very important parameter for the management
      of water quality and pollution control. Conventional sampling methods are based
      on tracer studies. Sampling periods and intervals are often subjective and left
      to the choice of the experimenter. Sometimes several observations are made to
      determine D. Yet, making several observations does not necessarily ensure
      accurate estimation of the parameters. Sampling of tracer concentrations at poor
      times will result in inaccurate estimates of D and the flow velocity (u).
      Therefore, the main aim of the study in question was to investigate the optimal
      sampling times for conducting fixed position variable-time sampling for tracer
      concentration experiments. This objective was achieved by the minimization of the
      least square criterion and applying the method proposed by Box and Lucas. The
      relative efficiency of each experimental design is predicted before data
      collection and analysis and confidence regions plotted. Results, on optimal
      sampling times for experiments are presented and illustrated. The application of
      these findings will harmonize results and reduce cost and labour expended on
      dispersion experiments.

PMID- 12418661
TI  - A study of coagulation mechanisms of polyferric sulfate reacting with humic acid
      using a fluorescence-quenching method.
AB  - A fluorescence-quenching method is developed to assess the effect of pH on the
      coagulation mechanism of humic acids (HA) reacting with metal ions. A polyferric
      sulfate (PFS) synthesized in our laboratory is adopted as the coagulant to
      simplify the hydrolysis process and increase the experimental precision. The
      following results are discovered. When the concentration of PFS increases from 2
      to 10 mg/L, the effective pH range of HA removal changes from 4.0-5.0 to 4.0-7.5.
      At increased coagulation pH, the ferric ions may still react with HA but unable
      to neutralize the surface charge completely. The residual concentrations of HA
      measured by fluorescence spectrophotometer are lower than those by TOC, as a
      consequence of the fluorescence-quenching effect. This demonstrates that the
      coagulation of HA by PFS at low pH is mainly due to charge-neutralization. The
      adsorption of the HA on the pre-formed iron hydroxide flocs is accompanied by the
      dissociation of Fe ions from the floc structure until the equilibrium has been
      reached, which is evidenced by the presence of the Fe-HA complexes in the
      solution during adsorption experiment. This is quite different from the
      characteristics of flocs formed by PFS associated with HA in the coagulation.
      Within the pH range investigated, the complex-formation and the hydrolysis are
      the two competitive reactions happened between the hydroxide ions in solution and
      the functional groups of HA. Therefore, the removal of HA is not caused by
      adsorbing onto the iron hydroxide resulted from PFS hydrolysis, but through the
      complex-formation between the PFS and the HA.

PMID- 12418662
TI  - Factors affecting the adsorption capacity of dissolved organic matter onto
      activated carbon: modified isotherm analysis.
AB  - Effects of aqueous phase Ca(II) concentrations and pH levels on the adsorption
      capacity of dissolved organic matters (DOMs) as well as the capacity dependency
      on the sources and types of DOMs and activated carbons (ACs) were examined. The
      Ca(II) effect was studied for three coal-based ACs having different pore size
      distributions (PSDs) and for three DOMs contained in three water samples. For
      each water sample, four working solutions prepared by adding different dosages of
      Ca(II) (0-1.5 mM) were used. For the water sample whose adsorption capacity was
      least affected by Ca(II), the effect of pH was subsequently examined for four
      water pH levels (pH = 5.5-10) and these three ACs. Isotherm data were analyzed in
      terms of a modified isotherm model selected from three models developed for
      normalizing isotherms of heterogeneous organic mixtures. The Ca(II) effect
      depended obviously on the DOMs used. For all three ACs, increasing Ca(II) greatly
      enhanced the adsorption capacity of a commercial humic acid. However, the
      capacity of the DOM in a naturally colored surface water source was much less
      affected and that of the DOM remaining after precoagulation was not affected. The
      DOM-Ca(II) interactions, rather than the AC-Ca(II) interactions, seemed to be the
      predominant mechanism that controlled the extent of the Ca(II)'s impact. Water pH
      greatly affected the adsorption of the surface water DOM remaining after
      precoagulation. This effect seemed to be attributed to pH's capability in
      changing ACs' charge characteristics reflected by zeta-potentials. The adsorption
      capacity increased as the water pH decreased and was well correlated as a
      function of pH and the volume of AC pores in sizes of 30-100 A. ACs having more
      pores in this size region generally exhibited larger adsorption capacities.

PMID- 12418663
TI  - Predicting oxygen transfer and water flow rate in airlift aerators.
AB  - Water flow rate, gas-phase holdup, and dissolved oxygen (DO) profiles are
      measured in a full-scale airlift aerator as a function of applied air flow rate.
      A model that predicts oxygen transfer based on discrete-bubble principles is
      applied. The riser DO profiles are used to calculate the initial bubble size. The
      range of calculated bubble diameters obtained using the model is 2.3-3.1 mm. The
      Sauter-mean diameter of bubbles measured in the laboratory ranged from 2.7 to 3.9
      mm. The riser and downcomer DO profiles and gas holdups predicted by the model
      are in close agreement with the experimental results. A model that predicts water
      flow rate based on an energy balance is used to calculate Kt, the frictional loss
      coefficient for the air-water separator. Excluding the data at the very lowest
      air flow rate, the range of calculated values for Kt (3-8) is close to a
      literature value of 5.5 proposed for hydrodynamically similar external airlift
      bioreactors. The models should prove useful in the design and optimization of
      airlift aerators.

PMID- 12418664
TI  - Hydrodynamic control of nitrogen and phosphorus turnover in an eutrophicated
      estuary in the Baltic.
AB  - The turnover of phosphorus and nitrogen have been studied in a low salinity
      estuary in the Bothnian Sea. The estuary, Gardsfjarden, has a high loading of
      nutrients from a pulp and paper mill which supplies the estuary with three times
      the annual natural input of phosphorus and nitrogen, respectively. The turnover
      of nutrients was to a great extent determined by hydrodynamic variations. During
      periods of intense resuspension there was a net export of particulate bound
      nutrients from the estuary to the sea but since these periods were short there
      was an overall net retention of particulate nutrients. The estuary was a source
      for dissolved phosphorus to the sea. The major source of phosphorus export was
      release of dissolved P from anoxic sediments. Gardsfjarden was a sink for
      dissolved nitrogen which most likely escaped the estuary by denitrification.
      Nitrate was supplied by degradation of particulate organic nitroge'n but the main
      source was import from the sea.

PMID- 12418665
TI  - Predicting diffused-bubble oxygen transfer rate using the discrete-bubble model.
AB  - A discrete-bubble model that predicts the rate of oxygen transfer in diffused
      bubble systems is evaluated. Key inputs are the applied gas flow rate and the
      initial bubble size distribution. The model accounts for changes in the volume of
      individual bubbles due to transfer of oxygen and nitrogen (and hence changing
      partial pressure), variation in hydrostatic pressure, and changes in temperature.
      The bubble-rise velocity and mass-transfer coefficient, both known functions of
      the bubble diameter, are continually adjusted. The model is applied to predict
      the results of diffused-bubble oxygen transfer tests conducted in a 14-m deep
      tank at three air flow rates. All of the test data are predicted to within 15%.
      The range of bubble diameters (0.2-2 mm) spans the region of greatest variation
      in rise velocity and mass-transfer coefficient. For simplicity, the Sauter-mean
      diameter is used rather than the full bubble size distribution without loss of
      accuracy. The model should prove useful in the design and optimization of
      hypolimnetic oxygenation systems, as well as other diffused-bubble applications.

PMID- 12418666
TI  - Aminopolyphosphonate removal during wastewater treatment.
AB  - Phosphonates are used in large quantities in industry and household products as
      scale inhibitors and chelating agents. They are not biodegraded during wastewater
      treatment but are removed by adsorption processes. Field measurements from
      different wastewater treatment plants affirm that they are removed almost
      completely during wastewater treatment. Adsorption of
      nitrilotrismethylenephosphonic acid onto activated sludge, amorphous iron oxide
      and humic acids (HAs) was studied under controlled conditions. The adsorption
      onto HAs decreases sharply with increasing pH with negligible adsorption at pH
      above 6.5. Adsorption onto amorphous iron oxide follows a Langmuir behavior. The
      presence of 1 mM Ca doubles the maximum surface capacity at pH 7. Adsorption onto
      activated sludge is not very pH sensitive and is explained to a large extent by
      adsorption onto amorphous iron oxides, but the contribution of organic matter or
      other mineral phases cannot be ruled out.

PMID- 12418667
TI  - Off-line particle size analysis of digested sludge.
AB  - Particle size analysis was carried out on six samples of digested sludge using
      laser diffraction. The digested sludge was produced in laboratory-scale reactors
      under different feed regimes based on a mixture of primary and waste activated
      sludge (WAS). Laser diffraction proved capable of providing rapid, reproducible
      results of the particle size distribution of each sample, and highlighted
      differences between the different treatments. An increase in the level of WAS in
      the digester feed sludge led to a shift in the size distribution, with a decrease
      in the number of smaller sized particles.

PMID- 12418668
TI  - Methanogenic population dynamics during startup of a full-scale anaerobic
      sequencing batch reactor treating swine waste.
AB  - Changes in methanogenic population levels were followed during startup of a full
      scale, farm-based anaerobic sequencing batch reactor (ASBR) and these changes
      were linked to operational and performance data. The ASBR was inoculated with
      anaerobic digester sludge from a municipal wastewater treatment facility. During
      an acclimation period of approximately 3 months, the ASBR content was diluted to
      maintain a total ammonia-N level of approximately 2000mg l(-1). After this
      acclimation period, the volatile solids loading rate was increased to its design
      value of 1.7g l(-1) day(-1) with a 15-day hydraulic retention time, which
      increased the total ammonia-N level in the ASBR to approximately 3,600 mg l(-1).
      The 16S ribosomal RNA (rRNA) levels of the acetate-utilizing methanogens of the
      genus Methanosarcina decreased from 3.8% to 1.2% (expressed as a percentage of
      the total 16S rRNA levels) during this period, while the 16S rRNA levels of
      Methanosaeta concilii remained low (below 2.2%). Methane production and reactor
      performance were not affected as the 16S rRNA levels of the hydrogen-utilizing
      methanogens of the order Methanomicrobiales increased from 2.3% to 7.0%. Hence,
      it is likely that during operation with high ammonia levels, the major route of
      methane production is through a syntrophic relationship between acetate-oxidizing
      bacteria and hydrogen-utilizing methanogens. Anaerobic digestion at total ammonia
      N levels exceeding 3500mg l(-1) was sustainable apparently due to the acclimation
      of hydrogen-utilizing methanogens to high ammonia levels.

PMID- 12418669
TI  - Delayed incubation as an alternative method to sample storage for enumeration of
      E. coli and culturable bacteria in water.
AB  - The effects of sample storage on enumeration of Escherichia coli in marine
      bathing water and culturable bacteria in drinking water were evaluated. Results
      showed that overnight storage at 0-5 degrees C significantly reduced the counts
      of E. coli in bathing water (p = 0.0001) with a mean reduction of 25%. A similar
      effect of sample storage was observed for the enumeration of culturable bacteria
      in drinking water at 22 +/- 2 degrees C for 66 +/- 4 h (p = 0.0074; mean
      reduction = 25%) or at 36 +/- 2 degrees C for 44 +/- 4h (p = 0.0353; mean
      reduction = 6%). The use of a delayed incubation method, i.e. overnight storage
      at 0-5 degrees C of inoculated agar plates prior to incubation, did not
      significantly affect the counts of culturable bacteria when plates were incubated
      at 22 + 2 degrees C for 66 +/- 4 h, whereas it resulted in a significant increase
      of the bacterial numbers when plates were incubated at 36 +/- 2 degrees C for 44
      +/- 4 h (p = 0.0002; mean increase = 32%). Based on these results, it is
      suggested to avoid the use of overnight or longer sample storage for the
      enumeration of E. coli in bathing water samples, as well as for the enumeration
      of culturable bacteria in drinking water. The delayed incubation method appears
      to be a reliable procedure for the enumeration of culturable bacteria and could
      represent a valid alternative to sample storage in order to overcome problems
      associated with the performance of bacteriological counts during weekends or
      statutory holidays. However, a multi-laboratory study is needed to evaluate the
      reproducibility of the delayed incubation method for the enumeration of
      culturable bacteria and its possible use for the enumeration of E. coli by
      membrane filtration.

PMID- 12418670
TI  - HPLC-PDA detection of cylindrospermopsin--opportunities and limits.
AB  - The cyanobacterial hepatotoxic alkaloid cylindrospermopsin (CYL) is of increased
      concern to public health due to the spreading of its main producer,
      Cylindrospermopsis raciborskii, around the globe. Here we present results of an
      evaluation of the possibility to analyse environmental samples for their content
      of CYL based on HPLC with photo diode array detection as an alternative to costly
      LC-MS approaches. A gradient from 0% to 50% aqueous methanol (+0.05%
      trifluoroacetic acid) in 20 min proved to be highly reproducible with respect to
      peak height, peak area, and retention time of purified CYL. Good linearity of
      peak area response was found for 1-300 ng CYL on column. For a good performance
      the duration of equilibration prior to individual runs was crucial. Extraction
      from cell material (culture and bloom) was efficiently done with pure water in
      one extraction step and CYL contents determined matched well with results
      previously obtained by LC-MS. When different seston matrices were added to
      cultured cells to mimic realistic environmental samples, however, peaks eluting
      close to CYL in chromatograms restrained the performance. The data presented show
      a limitation of HPLC-PDA analysis for trace amounts of CYL in environmental
      samples but also underline the potential of an inexpensive and fast analysis for
      various purposes.

PMID- 12418671
TI  - Comments to the use of water quality indices to verify the impact of Cordoba City
      (Argentina) on Suquia river.

PMID- 12418672
TI  - Rationale and prospects of combination therapy as a strategy for delaying
      antimalarial drug resistance.

PMID- 12418673
TI  - Safety and immunogenicity of two Haemophilus influenzae type b polysaccharide
      tetanus toxoid conjugate vaccines (PRP-T) given with diphtheria-tetanus-pertussis
      vaccine to young Papua New Guinean children.
AB  - BACKGROUND: In view of high mortality and morbidity from Haemophilus influenzae
      type b (Hib) in young Papua New Guinean children, the incorporation of a Hib
      conjugate vaccine into a nationwide immunization program would be of major public
      health benefit. METHODS: We evaluated the safety and immunogenicity of a
      lyophilized and a liquid form of Hib polysaccharide-tetanus toxoid conjugate
      vaccines (PRP-T) given in the same syringe as diphtheria-tetanus-pertussis (DTP)
      vaccine to children in Goroka, Eastern Highlands Province. In Part 1 of the study
      209 children were randomized to receive at ages 1, 2 and 3 months either DTP
      alone or a liquid formulation of DTP/PRP-T or lyophilized PRP-T dissolved in DTP
      suspension. A further 75 children were given the liquid DTP/PRP-T formulation at
      ages 2, 3 and 4 months (Part 2). 54 children aged 15-18 months were given a
      booster of the same preparation of PRP-T/DTP as they had received during Part 1.
      Blood for antibody assays was collected at enrolment, before (Part 1 only) and
      one month after the third dose, then just before and 3 weeks after the booster
      dose. RESULTS: Follow-up to age of 12 months showed that PRP-T was safe with no
      evidence of impaired response to individual vaccine components when combined with
      DTP. Geometric mean titres (GMTs) of anti-PRP antibody before vaccination (n =
      64, mean age 41 days), after 2 doses (mean age 99 days) and after 3 doses (mean
      age 132 days) of the lyophilized formulation were 0.21, 1.48 and 5.04 microg/ml,
      respectively, with 58% and 89% having anti-PRP antibody titres > or = 1.0
      microg/ml after 2 and 3 doses, respectively. Anti-PRP antibody responses to the
      liquid Hib vaccine formulation were lower (GMT post-dose 3 = 0.48 microg/ml) than
      to the lyophilized formulation, but better responses were elicited from older
      children (Part 2; GMT post-dose 3 = 0.78 microg/ml, with 79% > or = 0.15
      microg/ml). Both PRP-T preparations elicited excellent booster responses
      suggesting that children are likely to be protected if exposed to Hib infection.
      CONCLUSIONS: Lyophilized PRP-T given together with DTP is safe and immunogenic
      when given to young infants. The liquid DTP/PRP-T formulation showed a lower
      immunogenicity than in earlier studies with this vaccine, which might have been
      due to exposure to low temperature during shipment or the younger age at
      immunization.

PMID- 12418674
TI  - Towards a malaria vaccine for Papua New Guinea.
AB  - Malaria is a major problem in Papua New Guinea, where it accounts for a high
      proportion of sickness and death. In addition to the human suffering, malaria
      also puts severe stress on the health services, and may directly hinder economic
      growth. A malaria vaccine would be the best, most cost-effective and safest
      public health measure to reduce the burden of malaria. Though considerable
      technical challenges are present, much natural and scientific evidence suggests a
      vaccine is achievable. Through the malaria vaccine program at the Papua New
      Guinea Institute of Medical Research, Papua New Guinea is playing a significant
      role in the global effort to develop a malaria vaccine, and ensuring that the
      malaria patterns of the Asia-Pacific region figure strongly in vaccine
      development strategies. Discussed here are some of the major issues to be
      considered as we work towards a malaria vaccine for Papua New Guinea.

PMID- 12418675
TI  - Physiotherapy in Mount Hagen General Hospital: an audit of activity over a six
      month period.
AB  - There is a lack of a sustainable physiotherapy service in most hospitals in Papua
      New Guinea. Many clinicians, managers and senior administrators appear unaware of
      the benefits that such a service can provide. This survey uses an audit tool, a
      modified Korner form, to evaluate the impact of a physiotherapy service within a
      provincial hospital during a six-month period. The audit measures number of
      patients seen, types of diagnosis, time spent with individual patients and number
      of treatment sessions provided. 571 patients were seen in the 6 months, of whom
      308 were outpatients and 263 were inpatients. Inpatients received an average of 3
      hours of treatment per patient, outpatients received 1 hour. Most patients seen
      were those who suffer disability as a result of their condition and who would
      traditionally have a poor prognosis without physiotherapy intervention. The most
      common conditions seen were neurological disability in adults and children,
      conditions requiring orthopaedic rehabilitation, burns, arthritic conditions and
      those requiring respiratory physiotherapy techniques. The physiotherapy
      department at the hospital was the only establishment in the district able to
      provide a rehabilitation service for these patients. Hence physiotherapy greatly
      improved the services available to the most sick and disabled patients within the
      community. The fact that outpatient follow-ups proved problematic for so many
      patients suggests that patients should be kept in hospital until their
      rehabilitation needs have been fully met.

PMID- 12418676
TI  - Abdominal trauma in urban Papua New Guinea.
AB  - BACKGROUND: Trauma is the commonest cause of surgical admission in Papua New
      Guinea, accounting for around 30% of cases in Port Moresby and over 40% in the
      highlands. The abdomen is traumatized in about 10-15% of trauma cases. In
      malarial endemic areas the enlarged spleen is particularly prone to rupture
      although earlier studies showed that this injury can often be managed
      conservatively. AIM: To determine the pattern and outcome of abdominal injury in
      the two largest cities, Port Moresby and Lae, in the 1990s. METHODS: A
      retrospective study of 213 adult admissions for abdominal trauma in Port Moresby
      and a prospective study of 98 adult abdominal trauma patients in Lae. In both
      centres malaria is endemic. Statistical analysis where appropriate was made using
      the chi2 test. RESULTS: Abdominal trauma was more likely to affect men outside
      the home and women in the home. Assault was responsible for 72% of cases of
      abdominal trauma. Women were assaulted by their husbands in two-thirds of cases.
      The spleen was the most likely organ to be injured, particularly in blunt trauma.
      Road traffic accidents caused only 10% of admissions with abdominal trauma. Most
      patients were admitted with a single injury. Splenic injury was managed
      nonoperatively in over 60% of cases. The negative laparotomy rate was 7% in Port
      Moresby and 20% in Lae, but negative laparotomy did not cause any deaths or extra
      morbidity. 17 patients (5.5%) died, the highest case fatality rate being 29% in a
      group of 31 patients with an injury severity score of 25 or greater. CONCLUSION:
      The pattern of abdominal trauma reflects the culture of Papua New Guinea and the
      different spectrum of risks to men and women. Once patients reach hospital they
      tend to do reasonably well although there is room for improvement, particularly
      with early assessment of the extent of the injury. The enlarged spleen is prone
      to injury and in those cases requiring laparotomy it is difficult to conserve.
      Many cases of ruptured spleen can be treated nonoperatively.

PMID- 12418678
TI  - Perinatal outcome and associated factors of persistent breech presentation at the
      Port Moresby General Hospital, Papua New Guinea.
AB  - A study of 502 singleton persistent breech presentations and 502 controls of
      cephalic presentations during labour, at the Port Moresby General Hospital, was
      carried out from January 1988 to July 1993. In 76 (15%) of the cases, at least
      one attempt was made at external cephalic version. Backward logistic regression
      analysis showed that Momase or Islands region ethnicity, previous breech
      delivery, lack of antenatal care, preterm delivery, low birthweight and
      congenital anomalies were significantly associated with persistent breech
      delivery. The perinatal outcome of babies with breech presentation was worse than
      among babies with cephalic presentation.

PMID- 12418677
TI  - Solomon Islands dengue seroprevalence study--previous circulation of dengue
      confirmed.
AB  - Since there were no confirmed outbreaks of dengue on record an extensive search
      of available records and a seroprevalence study were undertaken to determine if
      there was evidence of past dengue virus infections in the Solomon Islands.
      Hospital and Health Department records revealed a suspected dengue outbreak in
      1982 and deaths attributed to dengue in 1995 and 1996. Serum samples from blood
      donors were analyzed for the presence of IgG antibodies specific for flavivirus
      and dengue virus. A total of 39% of the 515 samples, predominantly from adult
      males from Honiara, demonstrated IgG antibodies specific for dengue; 28% (26 of
      93) were monotypically positive by plaque reduction neutralization test for
      dengue 2 antibody and the remaining samples had antibodies to more than one
      dengue serotype. A good correlation was found between the presence of flavivirus
      and dengue IgG confirming that dengue virus had circulated in the past in the
      Solomon Islands.

PMID- 12418679
TI  - Systemic lupus erythematosus in children: a case report and review.
AB  - A 12-year-old Papua New Guinean female presented initially with nonspecific
      clinical symptoms, fever of unknown origin and anaemia. She subsequently
      developed multisystem disease involving the respiratory, gastrointestinal,
      central nervous, musculoskeletal and cutaneous systems. She was diagnosed to have
      systemic lupus erythromatosus (SLE) and started on treatment. Unfortunately the
      patient defaulted from follow-up after treatment, which covered seven months
      only, to present with acute respiratory distress from which she died within 24
      hours. A relevant literature review with the clinical features of systemic lupus
      erythematosus in children is described.

PMID- 12418680
TI  - Managing severe head injuries in Papua New Guinea.

PMID- 12418681
TI  - Guidelines for medical research projects in Papua New Guinea.

PMID- 12418682
TI  - Deluge of questions prompts AAFP to develop FIV vaccine brief. American
      Association of Feline Practitioners.

PMID- 12418683
TI  - Some costs of animal disease outbreaks cannot be counted.

PMID- 12418684
TI  - Human, animal cases of West Nile continue to climb. Virus identified in small
      number of new animal species.

PMID- 12418685
TI  - Do manatees hold the key to understanding papillomaviruses?

PMID- 12418686
TI  - Thoughts on bowel treatment in cattle.

PMID- 12418687
TI  - What is your diagnosis? Mixed lytic-proliferative lesion in the left tibia.

PMID- 12418688
TI  - What is your neurologic diagnosis? Parenchymal bleeding, irritation of the
      meninges and nerve roots, prior hemorrhage, and hemophilia A.

PMID- 12418689
TI  - Return-to-sensibility problems after penetrating captive bolt stunning of cattle
      in commercial beef slaughter plants.
AB  - OBJECTIVE: To evaluate efficacy of penetrating captive bolt stunning of cattle in
      commercial beef slaughter plants and identify potential causes of a return to
      sensibility among stunned cattle. DESIGN: Observational study. SAMPLE POPULATION:
      21 federally inspected commercial beef slaughter plants. PROCEDURE: In each
      plant, stunning of at least 100 cattle (19 large plants) or a minimum of 1 hour
      of production (2 small plants) was observed, and cattle were evaluated for signs
      of returning to sensibility on the bleed rail. Cattle with a limp, flaccid head,
      a lack of spontaneous blinking, and an absence of a righting reflex were
      considered insensible. RESULTS: In 17 of the 21 (81%) plants, all cattle were
      rendered insensible before they were hoisted onto the bleed rail. The remaining 4
      plants had cattle that had signs of returning to sensibility; these cattle were
      restunned prior to skinning or leg removal. Of 1,826 fed steers and heifers, 3
      (0.16%) had signs of returning to sensibility, whereas 8 of 692 (1.2%) bulls and
      cows did. Return-to-sensibility problems were attributed to storage of stunner
      cartridges in damp locations, poor maintenance of firing pins, inexperience of
      the stunner operator (ie, shooting cattle too high on the forehead), misfiring of
      the stunner because of a dirty trigger, and stunning of cattle with thick, heavy
      skulls. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that efficiency of
      captive bolt stunning of cattle in commercial slaughter plants can be safely and
      objectively assessed. Care should be taken to maintain stunners correctly,
      particularly when stunning bulls and cows with heavy skulls.

PMID- 12418690
TI  - Use of an objective, structured clinical examination as a component of the final
      year examination in small animal internal medicine and surgery.

PMID- 12418691
TI  - Effects of preoperative administration of ketoprofen on anesthetic requirements
      and signs of postoperative pain in dogs undergoing elective ovariohysterectomy.
AB  - OBJECTIVE: To determine the effects of preoperative administration of ketoprofen
      on anesthetic requirements and signs of postoperative pain in dogs undergoing
      elective ovariohysterectomy. DESIGN: Randomized, controlled clinical trial.
      ANIMALS: 22 clinically normal client-owned dogs. PROCEDURE: 60 minutes before
      induction of anesthesia, 11 dogs were given ketoprofen (2 mg/kg [0.9 mg/lb],
      i.m.), and the other 11 were given saline (0.9% NaCl) solution. Dogs were
      premedicated with glycopyrrolate, acepromazine, and butorphanol and anesthetized
      with thiopental; anesthesia was maintained with isoflurane. Ovariohysterectomy
      was performed by an experienced surgeon, and butorphanol was given 15 minutes
      before completion of the procedure. Objective behavioral scores and numerical
      pain scores at rest and with movement were recorded every 2 hours for 12 hours
      after surgery and then every 4 hours for an additional 12 hours. RESULTS:
      Preoperative administration of ketoprofen did not reduce the dose of thiopental
      required to induce anesthesia or the end-tidal concentration of isoflurane
      required to maintain anesthesia. Activity levels and median objective behavioral
      scores were significantly higher 4 and 6 hours after surgery in dogs given
      ketoprofen than in dogs given saline solution. However, mean numerical pain
      scores in dogs given ketoprofen were not significantly different from scores for
      dogs given saline solution at any time. CONCLUSIONS AND CLINICAL RELEVANCE:
      Results suggest that preoperative administration of ketoprofen does not reduce
      anesthetic requirements in dogs undergoing elective ovariohysterectomy but may
      reduce signs of pain after surgery. Results also suggest that the objective
      behavioral score may be a more sensitive measure of acute postoperative pain than
      traditional numerical pain scores.

PMID- 12418692
TI  - Doppler echocardiographic effects of medetomidine on dynamic left ventricular
      outflow tract obstruction in cats.
AB  - OBJECTIVE: To evaluate the effects of medetomidine on dynamic left ventricular
      outflow tract (LVOT) obstruction in cats with left ventricular hypertrophy.
      DESIGN: Clinical trial. ANIMALS: 6 domestic shorthair cats with echocardiographic
      evidence of dynamic LVOT obstruction. PROCEDURE: Cats were restrained in lateral
      recumbency, and baseline M-mode and Doppler echocardiographic examinations were
      performed. An ECG was recorded continuously, and blood pressure was measured
      indirectly with Doppler instrumentation. Medetomidine (20 microg/kg 19.1
      microg/lb]) was then administered i.m., and examinations were repeated 15 minutes
      later. RESULTS: Significant decreases in heart rate, LVOT velocity, and the LVOT
      pressure gradient were documented following medetomidine administration. After
      adjusting for the effects of heart rate by ANCOVA, there were no significant
      differences in any other systolic or diastolic indices of left ventricular
      function. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that administration
      of medetomidine to cats with dynamic LVOT obstruction may result in elimination
      of outflow tract obstruction; medetomidine may be a suitable sedative and
      analgesic agent in this subpopulation of cats.

PMID- 12418693
TI  - Evaluation of urine marking by cats as a model for understanding veterinary
      diagnostic and treatment approaches and client attitudes.
AB  - OBJECTIVE: To obtain information regarding diagnostic and treatment approaches of
      veterinarians and attitudes and beliefs of clients about a common clinical
      problem, urine marking in cats. DESIGN: Cohort study. STUDY POPULATION: 70
      veterinarians providing care for urine-marking cats and 500 owners of urine
      marking cats. PROCEDURE: Veterinarians were interviewed via telephone regarding
      criteria for diagnosis of urine marking and recommended treatments. Cat owners
      who responded to recruitment efforts for a clinical trial for urine-marking cats
      were interviewed via telephone regarding whether and from what sources they
      sought help to resolve the marking problem. RESULTS: Almost a third of
      veterinarians did not seem to correctly distinguish between urine marking
      (spraying) and inappropriate urination. Those that did make this diagnostic
      distinction reported recommending environmental management and prescribing
      medication significantly more often that those that did not make this
      distinction. Seventy-four percent of cat owners sought help from their
      veterinarians for urine marking; other common sources of information were the
      Internet and friends. Among those who did not consult a veterinarian, the most
      frequently cited reason was that they did not think their veterinarian could
      help. Among cat owners who consulted their veterinarians, 8% reported receiving
      advice on environmental hygiene and 4% on environmental management (limiting
      intercat interactions), although veterinarians who correctly diagnosed urine
      marking reported giving such advice 100 and 83% of the time, respectively.
      CONCLUSIONS AND CLINICAL RELEVANCE: Results may serve as a model for obtaining
      information critical to developing veterinary continuing education and public
      outreach programs for animal owners for various diseases.

PMID- 12418695
TI  - Use of a condylar screw plate for repair of a Salter-Harris type-III fracture of
      the femur in a 2-year-old horse.
AB  - A 2-year-old sexually intact male Paint horse weighing 427 kg (940 lb) was
      admitted for examination and treatment of intermittent non-weight-bearing
      lameness of the right hind limb of 1 week's duration. Radiography revealed a
      displaced Salter-Harris type-III fracture of the right femoral condyle with the
      sagittal component of the fracture line located in the intercondylar space and
      the transverse component exiting on the medial aspect of the femur. The fracture
      was repaired with a condylar screw plate designed for repair of femoral condylar
      fractures in humans. The owner reported by telephone 9 months after surgery that
      the horse was sound. To our knowledge, use of this particular implant system for
      fixation of a Salter-Harris type-III fracture on the medial side of the femur in
      a horse has not been described. Results in this horse suggest that this implant
      can be successfully used for repair of femoral condylar fractures in selected
      adult horses.

PMID- 12418694
TI  - Transjugular coil embolization of an intrahepatic portosystemic shunt in a cat.
AB  - A 4-month-old male domestic shorthair cat was evaluated for intermittent tremors,
      ptyalism, and signs of depression. The cat was small, thin, and unthrifty.
      Clinically important serum biochemical abnormalities included low blood urea
      nitrogen concentration and high baseline bile acids concentration. Abdominal
      ultrasonography and jejunal portography identified an intrahepatic portosystemic
      shunt. The cat was anesthetized, and a transjugular approach was used for
      percutaneous coil embolization of the shunt. Guidewires, catheters, and coils
      were inserted under fluoroscopic guidance to locate the shunt and define its
      anatomy, measure portal vein pressures before and after temporary balloon
      occlusion, and place thrombogenic coils to completely attenuate the anomalous
      vessel. The cat recovered without complications and was weaned from medical
      management. Ten weeks following the procedure, clinical signs had completely
      resolved, and baseline bile acids concentration was near reference range. Results
      in this cat illustrate that interventional radiology techniques can be safely
      used in small animals and may reduce the morbidity and mortality rates associated
      with traditional surgical procedures.

PMID- 12418696
TI  - Common variable immunodeficiency in a horse.
AB  - A 12-year-old Quarter Horse mare that was nonresponsive to medical treatment was
      evaluated for chronic respiratory disease and hepatobiliary disease. Serum
      immunoglobulin concentrations were measured by use of radial immunodiffusion that
      revealed trace to nondetectable concentrations of IgG, IgG(T), IgM, and IgA. Use
      of serum protein electrophoresis confirmed agammaglobulinemia by the absence of
      the expected peak in the gamma region. In addition, vaccination with tetanus
      toxoid did not result in specific immunoglobulin production. Flow cytometric
      analysis of blood lymphocyte subpopulations revealed the absence of B cells in
      blood. Immunohistochemical analysis of tissue sections revealed the absence of B
      lymphocytes in bone marrow and spleen, with occasional B cells in the peripheral
      lymph nodes. Blood lymphocyte proliferation assays revealed weak responses to
      pokeweed mitogen and no response to stimulation with lipopolysaccharide.
      Considering the age and sex of the horse, results of the immunologic tests
      suggested a diagnosis of common variable immunodeficiency.

PMID- 12418697
TI  - Findings in cerebrospinal fluids of horses infected with West Nile virus: 30
      cases (2001).
AB  - OBJECTIVE: To evaluate CSF in horses with confirmed West Nile virus
      encephalomyelitis. DESIGN: Retrospective study. ANIMALS: 30 horses. PROCEDURE:
      Results of CSF analyses from horses with acute neurologic signs attributed to
      West Nile virus infection that was confirmed by immunoglobulin M antibody capture
      ELISA were reviewed and analyzed. RESULTS: Among 30 CSF samples, findings in 8
      (27%) were within reference ranges and in 22 (73%) were abnormal. Among the 22
      abnormal samples, mononuclear pleocytosis was found in 16 (73%) and high protein
      concentration with nucleated cell count within reference range was found in 6
      (27%) samples. A predominance of lymphocytes was found in 11 of 16 samples with
      mononuclear pleocytosis, and a predominance of large mononuclear cells was found
      in 5 of 16 samples. Sensitivities of analyses of CSF obtained from the
      lumbosacral and atlanto-occipital regions of the spinal cord were 89 and 50%,
      respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that in horses
      with acute onset of neurologic signs caused by West Nile virus encephalomyelitis,
      findings in the CSF are likely to be abnormal, mononuclear pleocytosis with
      lymphocytic predominance may be most commonly observed, and CSF collected from
      the lumbosacral region may be abnormal more commonly than CSF collected from the
      atlanto-occipital region.

PMID- 12418698
TI  - Postoperative infection with Actinobacillus spp in horses: 10 cases (1995-2000).
AB  - OBJECTIVE: To determine features of postoperative wound infection caused by
      Actinobacillus spp in horses undergoing clean, elective surgery and to evaluate
      bacterial susceptibility profiles of bacteria isolated. DESIGN: Retrospective
      study. ANIMALS: 10 horses. PROCEDURE: Data were retrieved from medical records
      and the microbiology laboratory database. RESULTS: 1,604 horses underwent clean,
      elective surgical procedures during the study period. Of these, 23 (1.43%) had
      postoperative wound infections, and Actinobacillus spp was isolated from 10 of
      these 23 (43%). Surgical procedures in these 10 horses included laryngoplasty
      with ventriculocordectomy (n = 3), arthroscopy (3), desmotomy of the accessory
      ligament of the superficial digital flexor tendon (2), removal of laryngoplasty
      prostheses (1), and hygroma resection (1). Seven horses survived, and 3 were
      euthanatized. All 10 Actinobacillus isolates were resistant to penicillin, and 6
      were resistant to trimethoprim-sulfamethoxazole. All isolates were susceptible to
      ceftiofur and gentamicin. During the 5-year period of the study, Actinobacillus
      organisms were isolated from 35 of 513 (6.8%) samples from the general hospital
      population submitted for bacterial culture and antimicrobial susceptibility
      testing. CONCLUSIONS AND CLINICAL RELEVANCE: During the study period,
      Actinobacillus spp was isolated from a higher than expected percentage of horses
      that developed postoperative wound infections after clean, elective surgery.
      Susceptibility profiles for these isolates were different from typical
      susceptibility profiles for Actinobacillus isolates, suggesting that a pattern of
      resistance may be emerging.

PMID- 12418699
TI  - Public health policy for women in Israel.

PMID- 12418700
TI  - Women's health in perspective: progressing or regressing?

PMID- 12418701
TI  - The special health needs of Israeli women: gender and culture. Panel chaired by
      Dr. Revital Gross.

PMID- 12418702
TI  - Women's health services delivery in Israel: organizational and managerial
      analysis.

PMID- 12418704
TI  - Health knowledge, attitudes, and practice (KAP)--a basis for health promotion
      policy in Israel.
AB  - OBJECTIVE: To review how health promotion policy can be based on research data.
      DATA SOURCES: The Department of Health Promotion, Ministry of Health, Israel, in
      collaboration with Midgam Research and Consultation Company and the Israel Center
      for Disease Control have conducted ongoing research on health knowledge,
      attitudes, and practice in Israel as a basis for health policy. MAIN FINDINGS:
      Based on data from 1995 to 2000: 1. There is a positive trend in healthy dietary
      habits. 2. There is no decrease in smoking rates. 3. There is an increase in
      drinking rates of wine. 4. There is an increase in aerobic exercise. More
      Israelis declare they eat healthy foods, but currently this is only for 50% of
      the population. There is a need for health promotion efforts to further increase
      positive dietary habits. There is an immediate need for extensive health
      promotion efforts to decrease smoking rates in Israel. Also, there is a need for
      health promotion campaigns to decrease drinking in Israel. Although more people
      are participating in aerobic physical exercise, there is a need to further
      increase this number. CONCLUSION: Data on health knowledge, attitudes, and
      practice is an important source for health promotion policy. By trends seen in a
      national survey of health knowledge, attitudes, and practice conducted every two
      years, additional health promotion policy can be shaped.

PMID- 12418705
TI  - A national survey as a basis of public health policy: a case study with folic
      acid.

PMID- 12418706
TI  - Smoking prevention campaign for youth in Israel.
AB  - BACKGROUND: Smoking rates among teenagers have increased in many countries
      including Israel. Youth smoking prevention programs have developed considerably
      in recent years and the present study examines results of mass media anti-smoking
      campaign in Israel. METHODS: Two telephone interviews were conducted one moth and
      9 months after exposure to TV advertisements. The two surveys consisted of random
      samples of Israeli adolescents aged 12-18 years. RESULTS: After one month, 77% of
      the survey participants remembered the slogan of the TV ads, and 30% used it.
      After 9 months, 32% remembered it and 6% used it. 28% said they were affected by
      the TV ads. After 9 months, 25% increased their awareness about anti-smoking
      behaviors, 2% claimed to have stopped smoking, and 1% claimed to have decreased
      smoking). Significant changes in anti-smoking awareness were found in survey
      participants who were exposed to TV ads and also participated in a school
      program.

PMID- 12418707
TI  - Unease about disease.

PMID- 12418708
TI  - Scientific evaluations of interventions to improve the adequate use of
      pharmaceuticals in Third World countries.
AB  - The inadequate use of pharmaceuticals continues to be a severe problem in most
      parts of the world. Developing nations waste very large amounts of scarce health
      resources on medicines of doubtful therapeutic value, and many persons do not
      comply with physicians advice or engage in risky self-medication practices
      contributing to additional misuse of resources and iatrogenia. This paper
      examines the few scientifically designed interventions at the community and
      patient s levels to improve the appropriate use of pharmaceuticals in developing
      nations. The authors analyze the contribution made by these studies and identify
      several limitations including the absence of independent evaluations of outcomes,
      lack of sufficient information to judge the quality and adequacy of the
      instruments used, problems relating to replicability of interventions at regional
      or country level, or outside the cultural context within which they took place,
      lack of information on costs of interventions, a crucial variable in poor
      countries, and the absence of standardized outcome measures that makes
      comparative analysis very difficult.

PMID- 12418709
TI  - To screen or not to screen: the issue of breast cancer screening in older women.
AB  - INTRODUCTION: The United States Preventive Services Task Force (USPSTF)
      recommends that women aged 50-69 receive timely breast cancer screening, but does
      not make a recommendation for women aged 70 and older. Our purpose is to assess
      the relationship between age and breast cancer screening trends, and to consider
      the issue of breast cancer screening of women 70 years of age and older in light
      of demographics, disease burden, life expectancy, and activity level. METHODS:
      Data were analyzed from the state-based Behvioral Risk Factor Surveillance System
      (BRFSS) and the National Health Interview Survey (NHIS) on breast cancer
      screening practices and activity limitation status of women 50 and older.
      RESULTS: The percentage of women who reported receiving mammography and clinical
      breast examination within two years was lower among older women compared with
      younger women, and the gap has widened over time. In 1991-92, 61.4% of women 50
      69 received screening within two years, compared to 49.5% of women 70 and above,
      while in 1997-98, the percentages were 71.1 and 56.7, respectively. Among both
      age groups and in both time periods, those unable to perform a major activity of
      daily living were less likely to report receiving mammography within two years
      than those with no limitation, and the gap was much wider in the elderly. Most
      (62.7%) women 70 and older reported having no activity limitation; only 5.5%
      reported being unable to perform a major activity. DISCUSSION: These results
      suggest that elderly women are less likely than younger women to receive timely
      breast cancer screening. The USPSTF does not recommend continued screening in
      elderly women because most studies of breast cancer efficacy included inadequate
      numbers of these women. Few, if any, studies have yielded evidence that screening
      is ineffective in women 70 and over. Given the higher breast cancer incidence and
      mortality seen in elderly women, as well as the increased life expectancy with
      little or no activity limitation seen among today's elderly, consideration should
      be given to including elderly women in the recommendation to receive timely
      breast cancer screening. Since surgical and adjuvant therapy for breast cancer in
      older women has less complications than therapy for other cancers of the elderly,
      the cost-benefit ratio for breast cancer screening in this age group may prove to
      be more promising.

PMID- 12418710
TI  - A call for an international ban on asbestos.

PMID- 12418711
TI  - A review of environmental and occupational exposure to asbestos in Israel.
AB  - The case for a total ban on manufacture and use of asbestos products is stated by
      the history of asbestos use, exposures, and risks in Israel. Manufacture and use
      of asbestos began in Israel in the 1950s, rising to a peak in the mid-1970s, and
      dropping gradually thereafter until reaching minimal levels in the 1990s.
      Following heightened public concern regarding the carcinogenic effects of
      asbestos products, there were reductions in use, manufacture, and persons
      exposed. Since the 1960s, asbestos-related diseases have been diagnosed in
      hundreds patients nationwide, including asbestos workers and users, as well as
      individuals living proximally to the manufacturing facilities. Exposures to
      asbestos in place remain, and patients with asbestos-related disease from
      environmental exposure are expected to appear for at least another 20-30 years.
      In the 1980s, an advisory committee appointed by the Ministry of Health of Israel
      outlined a comprehensive approach towards prevention, control, management, and
      compensation for health risks from asbestos exposures. As certain areas are still
      contaminated with asbestos waste and as environmental exposure persists,
      continued and improved medical monitoring and compensation programs are urgently
      needed in order to reduce the suffering of exposed individuals and their
      families. The ban on asbestos prevents risks from new exposures, but does not
      undo the damage from past manufacture, use, disposal, and dumping. In this paper,
      we review the history of Israel's import and use of asbestos, and the management
      of occupational and environmental exposures. We also address policy, practice,
      and the need to protect future victims of asbestos-related disease.

PMID- 12418712
TI  - Bibliography of research and policy regarding asbestos in Israel.

PMID- 12418713
TI  - The emotional impact of injury following an international terrorist incident.
AB  - BACKGROUND: Terrorism represents a major public health threat throughout the
      world. Bombings of the United States Embassies in East Africa in 1998 resulted in
      extensive physical and emotional casualties. METHODS: This study examined
      posttraumatic stress reactions, worry, and feelings of safety in the workplace in
      the context of injury in a convenience sample of 21 individuals directly exposed
      to the bombing in Dar es Salaam, Tanzania. Eight months postbombing, participants
      completed a self-report instrument examining demographics, exposure, injury,
      initial reaction, posttraumatic stress, worry, and feelings of safety in the
      workplace. Descriptive statistics and multiple regression were used to analyze
      the data. The "Impact of Event Scale-Revised" measured current posttraumatic
      stress. RESULTS: Report of injury predicted posttraumatic stress, intrusion, and
      arousal but not avoidance/numbing. Injury and intrusion were significant
      predictors of ongoing worry. CONCLUSIONS: Even relatively minor injury may be
      associated with ongoing posttraumatic stress and worry. The participants in the
      sample were all highly exposed which, along with the small sample size, may have
      limited the ability to establish other expected relationships.

PMID- 12418714
TI  - Effect of pregnancy on periodontal and dental health.
AB  - Clinical studies have shown that oral tissues can be affected by pregnancy.
      Pregnancy-related changes are most frequent and most marked in gingival tissue.
      Pregnancy does not cause gingivitis, but may aggravate pre-existing disease. The
      most marked changes are seen in gingival vasculature. Characteristic of pregnancy
      gingivitis is that the gingiva is dark red, swollen, smooth and bleeds easily.
      Women with pregnancy gingivitis may sometimes develop localized gingival
      enlargements. The gingival changes usually resolve within a few months of
      delivery if local irritants are eliminated. The inflammatory changes are usually
      restricted to the gingiva and probably do not cause permanent changes in
      periodontal tissues more often than those in the non-pregnant state. Although it
      is widely believed that pregnancy is harmful to the teeth, the effect of
      pregnancy on the initiation or progression of caries is not clear. Previous
      studies, however, indicate that the teeth do not soften, i.e. no significant
      withdrawal of calcium or other minerals occurs in the teeth. It is mainly the
      environment of the tooth that is affected. The number of certain salivary
      cariogenic microorganisms may increase in pregnancy, concurrently with a decrease
      in salivary pH and buffer effect. Changes in salivary composition in late
      pregnancy and during lactation may temporarily predispose to dental caries and
      erosion. Although their underlying mechanisms of action are not fully understood,
      pregnancy-related changes in the oral environment may have some untoward
      temporary or permanent effects on oral health. Most of these effects could be
      avoided by practising good oral hygiene.

PMID- 12418716
TI  - Skin surface temperature over the temporomandibular joint and masseter muscle in
      healthy children and adolescents.
AB  - Skin surface temperature (SST) measurements were carried out over the
      temporomandibular joint (TMJ) and masseter muscle (MM) of 159 healthy children
      and adolescents aged 7, 11, 15 and 18 years. No current symptoms were found of
      impaired general health or from the masticatory system or recurrent headache. The
      recordings were done with a thermocouple in contact with the skin. The mean SST
      over the TMJ and MM increased with age, and from the youngest to the oldest group
      regarding the TMJ by 1.3 degrees C (right) and 1.6 degrees C (left), and for MM
      by 2.1 degrees C (right) and 2.5 degrees C (left). Variation in the mean
      difference between sides of the TMJ was 0.0-0.2 degrees C and for the MM 0.1-0.3
      degrees C. The variation in SST between sides was reduced with increasing age,
      but was higher for MM than for TMJ in all age groups. In the 7-years group, there
      was a significant difference between right and left SST over TMJ and MM. It is
      concluded that SST increases with growth during childhood and that the SST for
      the TMJ is higher than MM in all age groups. The finding of a high degree of
      thermal symmetry between sides in all age groups may have diagnostic potential
      for pathological conditions involving blood flow and in evaluation of treatment
      of these conditions.

PMID- 12418715
TI  - Treatment time of traumatic dental injuries in a cohort of 16-year-olds in
      northern Sweden.
AB  - The aim of the present study was to account for treatment time and number of
      visits required for treatment of traumatic dental injuries in a cohort of 16-year
      olds, born in 1975, and residing in the county of Vasterbotten, Sweden, and to
      analyze the correlation between total treatment time and background factors. The
      study material comprised 1012 dental records from the Public Dental Health
      Service containing information on dental injuries to primary and/or permanent
      incisors or canines. The mean total treatment time per individual was 1.3 h, with
      a range of 0.1 to 27.5 h. For injuries to the primary dentition, the mean number
      of visits per individual was 2.2. One visit was sufficient in 21% of the trauma
      episodes. In the permanent dentition, each trauma episode required a mean of 3.4
      visits, and 90% of the patients had to return for follow-up visits. The
      correlation between explanatory variables and total treatment time was described
      and analyzed by linear multiple regression analyses. Degree of severity and
      number of injured teeth were two parameters of major significance to treatment
      time. Treatment by a specialist had an impact on time in the permanent but not in
      the primary dentition. In the permanent dentition, the treatment time increased
      if the dental injury occurred before the age of 11 years. Treatment time was not
      dependent on where the clinic was located or on gender of the injured child.
      Different diagnoses could explain 33% of the variation in treatment time in the
      permanent dentition.

PMID- 12418717
TI  - Utilization of dental health services among middle-aged people in Sweden and
      Denmark.
AB  - In 1999, questionnaires were sent to random samples of 1001 Swedish citizens aged
      55-79 years and 1175 Danish citizens aged 45-69 years. Various questions were
      asked concerning dental conditions, dental visit frequency per year, and money
      spent annually on dental care, etc. The objectives were to assess differences in
      the utilization of dental services and to compare out-of-pocket costs for dental
      care in Sweden and Denmark with control for age, gender, dental conditions and
      income. More than 80% of the subjects reported that a dentist had examined them
      less than 1 year previously. However, 77% of the Danes reported dental visits
      twice a year or more compared to 28% of the Swedes. Although the Danes reported a
      more frequent use of dental services, they had poorer dental conditions compared
      to the Swedes. Even though the Swedes used dental services less often than the
      Danes did, more subjects reported high 12-month out-of-pocket costs. In the
      present study, separate models were constructed for the two countries because
      there could be different mechanisms at play, as indicated by the results. The
      different insurance systems along with different degrees of commercialization in
      the two countries might be the most decisive factors in this context.

PMID- 12418718
TI  - Analyses of the caries decline and incidence among Norwegian adolescents 1985
      2000.
AB  - Since most studies of caries decline are descriptive time-trend analyses, the
      purpose of this article was to identify factors statistically associated with the
      caries decline among Norwegian adolescents after 1985. The DMFT scores for the
      age groups 12 and 18 years reported annually by 19 counties were analysed. The
      average caries-free proportions of 18-year-olds increased from 2% to 15% between
      1985 and 2000, while the DMFT declined by 49%; 10.2 +/- 0.75 to 5.2 +/- 0.78. The
      decline for the 12-year-olds was 53%. The mean DT at the dentinal level remained
      at about 0.8 for 12-year-olds and 1.5 for 18-year-olds throughout the observation
      period. There was no significant difference in DMFT increment from age 12 to 18
      between the birth cohorts 1973 (3.8 +/- 0.46) and 1982 (3.0 +/- 0.52) when
      controlling for counties. The variables migration and children per dentist were
      significantly associated with the DMFT decline in multivariate analyses. The
      caries decline for 18-year-olds was significantly steeper before than after 1990.
      The decline among the 18-year-olds may be attributed to fluoride and more
      restrictive criteria for placement of fillings in teenagers in the 1980s and
      fewer filled teeth before the age of 12 years in the 1990s.

PMID- 12418719
TI  - Changes in employers' image of ideal dentists and managers in the Swedish public
      dental sector.
AB  - Earlier studies have shown that employers are keen to have employees whose
      attitudinal and behavioral traits are consistent with the employers' ideology.
      One way of ascertaining the image of ideal individuals is to analyze the required
      qualifications in job advertisements. The aim of this study was to explore
      possible changes in the employers' view of the ideal manager and dentist in the
      Swedish Public Dental Health Service (PDHS). The study investigated the kinds and
      frequencies of manifestly required qualifications concerning vacancies in the
      PDHS from January 1990 to December 1998. All job advertisements intended for
      dentists and managers on different hierarchical levels in general dentistry were
      included (n = 1152); 5705 qualification demands were analyzed by content analysis
      permitting quantitative descriptions of the textual material as well as an
      analysis of the underlying characteristics over time. The study indicates that,
      for dentists, dental professional qualifications or qualifications in accordance
      with the official objective of dental care were insufficient. While requests for
      qualifications relating to the economic organizational goals of the PDHS
      increased during the latter part of the period under study, requests relating to
      the dental profession decreased. For managers, too, the demands for dental
      professional qualifications had decreased at the end of the studied period
      compared to the demands for managerial qualifications and non-professional
      qualifications, which had increased. In conclusion, the job advertisement
      portrays the ideal dentist and manager primarily as an economic organizational
      asset.

PMID- 12418720
TI  - Relationship between children's first dental visit and their dental anxiety in
      the Veneto Region of Italy.
AB  - The aim of this study was to explore the association between negative experiences
      during children's first dental visit and any subsequent dental anxiety and
      related factors in three dental clinics in the Veneto Region of Italy. For this
      purpose, parents of 378 children filled out a questionnaire. Factors related to
      child dental anxiety (none-some/fairly much-very much) were explored by means of
      logistic regression analysis. The independent variables were: problems with tht
      first dental visit (no/yes), parental dental anxiety (none-some/fairly much-very
      much), number of previous visits (0-3/4 < or =) site visited (public/private) and
      age of the child (< 10 years/10 < or = years). Parental anxiety was associated
      with child's anxiety (OR = 2.3, 95% CI = 1.1-4.9). A problematic first visit was
      a strong predictor of dental anxiety. However, this effect was modified by the
      number of subsequent visits. Children with 4 or more visits after the first visit
      were less likely to be anxious after a problematic first visit (OR = 4.6, 95% CI
      = 1.5-14.1) than children with 3 visits or less after the first visit (OR = 19.8,
      95% CI = 7.2-54.5). Thus, the negative effect of a problematic first visit may
      fade during subsequent dental visits.

PMID- 12418721
TI  - Gold concentration in blood in relation to the number of gold restorations and
      contact allergy to gold.
AB  - Previous studies have demonstrated an association between gold allergy and the
      presence of dental gold restorations. The aim of the present study was to
      investigate the relationship between the concentration of gold in blood (B-Au)
      and the number of tooth surfaces with gold alloys in subjects with and without
      contact allergy to gold. In 80 patients referred for patch testing because of
      eczematous disease, blood samples were taken and analyzed for B-Au using
      inductively coupled plasma mass spectrometry. The detection limit for the Au
      determination was 0.04 microg/L. In addition, a dentist made a clinical and
      radiological examination of the patients and registered the number of dental gold
      surfaces. Patients with dental gold restorations had a statistically
      significantly higher B-Au in Mann-Whitney U test (P = 0.025), (range < 0.04-1.07
      microg/L) than patients without (range < 0.04-0.15 microg/L). Furthermore, a
      positive correlation was found between B-Au and the number of dental gold
      surfaces (P < 0.01). There was no statistically significant difference in B-Au
      between persons with and without contact allergy to gold. The study thus
      indicates that gold is released from dental restorations and taken tip into the
      circulation.

PMID- 12418722
TI  - Betaine reduces the irritating effect of sodium lauryl sulfate on human oral
      mucosa in vivo.
AB  - Our aim was to evaluate whether betaine has a protective effect during exposure
      of the human oral mucosa in vivo to sodium lauryl sulfate (SLS) or
      cocoamidopropylbetaine (CAPB) as measured with a multifrequency electrical
      impedance spectrometer (EI). Both detergents were used at the concentration of
      2.0% w/v with and without 4.0% w/v betaine in distilled water in 20 volunteers,
      and 0.5% and 1.0% w/v SLS combined with 4.0% w/v betaine in 5 volunteers. EI
      measurements were taken before application of the test solutions, after their
      removal, and every 15 min up to 45 min. Both 0.5% and 1% SLS solutions showed a
      significant reduction in 3 of the 4 indices, indicating mucosal irritation after
      the 15-min exposure (P < 0.05), whereas 2% SLS did so in all 4 indices (P <
      0.001). Betaine had no effect on the detergent-induced decline with either the 2%
      or the 0.5% SLS solutions. However, when combined with the 1% SLS solution,
      betaine significantly (P < 0.05) reduced mucosal irritation by abolishing
      decreases in indices MIX (magnitude index) and IMIX (imaginary part index) and
      lowering it for PIX (phase index). The 2% CAPB solution showed a significant (P <
      0.05) reduction in all 4 indices after the 15-min exposure, but the effect was
      significantly weaker than that of 2% SLS (P < 0.05). Betaine did not reduce the
      irritating effect of 2% CAPB. These findings can be used in the development of
      less irritating products for oral health care.

PMID- 12418723
TI  - Fluoride concentration in supragingival dental plaque after a single intake or
      habitual consumption of fluoridated milk.
AB  - The aim of this study was to evaluate the fluoride concentration in supragingival
      dental plaque after single and repeated intakes of fluoridated milk. The study
      group consisted of 22 schoolchildren, young adults and adults of both sexes, 8-41
      years of age. After a 2-week fluoride depletion period and 3 days of plaque
      accumulation, 200 ml of fluoridated milk (1g F) was ingested along with a
      standardized lunch meal. Plaque samples were collected immediately before the
      intake and after 30, 120 and 240 min. From the adult participants (n = 9)
      additional samples were collected after 12 and 18 h. After a fluoride-free
      washout period of at least 2 weeks, the whole experimental procedure was repeated
      after 4 consecutive daily intakes of fluoridated milk. The fluoride concentration
      was determined after micro-diffusion with a fluoride selective electrode. The
      results showed a statistically significant 3-fold increase of the plaque fluoride
      levels up to 4 h after the intake. At 12 and 18 h after the intake, the recorded
      levels went gradually back to baseline. There was no significant difference
      between the fluoride concentrations in the supragingival plaque after the single
      intake compared with the repeated intakes. In conclusion, the findings support
      the suggestion that milk is a suitable vehicle for local fluoride administration
      into the oral cavity, also when consumed together with a meal.

PMID- 12418724
TI  - Nordic dentists' knowledge and attitudes on dental amalgam from health and
      environmental perspectives.
AB  - The aim of this study was to identify differences and similarities between the
      Nordic countries in dentists' use of dental amalgam as a restorative material,
      and also their knowledge and attitudes about amalgam from health, environmental,
      ethical, economic and social points of view. Procedures for handling amalgam
      waste were also studied. A random sample of 250 dentists was drawn from the
      national registers of authorized dentists in each country in late autumn 1997. At
      the beginning of 1998, a questionnaire was sent to all the dentists in the study
      group. The response rate was 77.6% in Denmark, 73.2% in Finland, 78.8% in Norway,
      and 84.0% in Sweden. In Finland and Sweden the use of dental amalgam had almost
      ceased, particularly for younger patients, while in Norway and especially in
      Denmark it was still widely used. Dentists' knowledge of the environmental
      effects of amalgam was confused, but most dentists had installed amalgam
      separators in their dental units by 1998. The majority of dentists in each
      country wanted to keep dental amalgam as a restorative material even in the
      future, and they did not want to ban the import of mercury to their home
      countries. Most dentists considered amalgam to be a health risk for at least some
      patients, and a great majority (from 76% in Sweden to 94% in Norway) considered
      composite as a possible odontological risk to patients. Since a majority of the
      dentists considered both amalgam and composites possibly harmful to patients,
      efforts to develop better alternatives to amalgam should continue.

PMID- 12418725
TI  - Indoor pollutant levels from the use of unvented natural gas fireplaces in
      Boulder, Colorado.

PMID- 12418726
TI  - A novel design for anaerobic chemical oxygen demand and nitrogen removal from
      leachate in a semiaerobic landfill.
AB  - The removal capacity of carbon and nitrogen from an artificial leachate was
      evaluated by using laboratory-scale columns, and a design was proposed to remove
      nitrogen more efficiently from a semiaerobic landfill. Five columns (i.e., two
      artificial municipal waste columns under anaerobic and semiaerobic conditions, an
      artificial construction waste column under semiaerobic conditions, and two
      crushed stone columns under anaerobic and semiaerobic conditions) were used. The
      influent load rates of organics [g chemical oxygen demand (COD)/m3 x day], NH4+,
      NO3- and aeration conditions for the columns were varied, and the removal
      capacities of the columns for COD, NH4+-N, and NO3--N were measured. Among the
      packed column materials, crushed stone was shown to be most effective in removing
      COD, NH4+ N, and NO3--N from artificial leachate. Average removal rates of
      crushed column under the semiaerobic condition (column D) for COD and NH4+-N were
      estimated at about 150 g COD/m3 x day and 20 g COD/m3 x day, while those of
      crushed column under anaerobic condition (column E) for COD and NO3--N at about
      400 and 150 g COD/m3 x day, respectively. It also was found that denitrification
      and nitrification reactions in column D occurred at the same time, and the ratio
      of denitrification to nitrification was estimated to be about 80%. Therefore, an
      anaerobic structure, which could be attached to the bottom of a main pipe in a
      semiaerobic landfill, is suggested to remove nitrogen and organic substances more
      effectively.

PMID- 12418727
TI  - The catalytic incineration of styrene over an Mn2O3/Fe2O3 catalyst.
AB  - In this study, styrene monomer (SM) was treated by a commercial catalyst,
      Mn2O3/Fe2O3, in a fixed-bed reactor. The study can be classified into two major
      parts. First, the effects of operating factors, such as temperature, SM
      concentration, space velocity, and O2 concentration, on the performance of the
      catalyst were investigated. Second, two catalyst life tests were carried out to
      characterize the deactivation effect of SM. The results show that the catalyst
      results in higher conversion of SM at a higher inlet temperature and higher O2
      concentrations. The conversion of SM decreases with increasing SM concentration
      and space velocity. From the statistical analysis of the data, we find that
      temperature is the most important factor on the catalytic incineration. Oxygen
      concentration, SM concentration, and space velocity are significant parameters as
      well. This paper also provides information on the deactivation effect of SM. The
      catalysts were characterized by surface and pore-size analysis, X-ray diffraction
      (XRD), scanning electron microscopy (SEM), and electron spectroscopy for chemical
      analysis (ESCA) before and after the tests. The results show that the catalytic
      deactivation may be caused by carbon coating, and the pore size and surface area
      of the catalyst are smaller after deactivation.

PMID- 12418728
TI  - Estimation of ambient PM2.5 concentrations in Maryland and verification by
      measured values.
AB  - In 1997, Maryland had no available ambient Federal Reference Method data on
      particulate matter less than 2.5 microm in aerodynamic diameter (PM23), but did
      have annual ambient data for PM smaller than 10 microm (PM10) at 24 sites. The
      PM10 data were analyzed in conjunction with local annual and seasonal zip-code
      level emission inventories and with speciated PM2.5 data from four nearby
      monitors in the IMPROVE network (located in the national parks, wildlife refuges,
      and wilderness areas) in an effort to estimate annual average and seasonal high
      PM2.5 concentrations at the 24 PM10 monitor sites operating from 1992 to 1996.
      All seasonal high concentrations were estimated to be below the 24-hr PM2.5
      National Ambient Air Quality Standards (NAAQS) at the sites operating in Maryland
      between 1992 and 1996. The estimates also indicated that 12 monitor sites might
      exceed the 3-year annual average PM2.5 NAAQS of 15 microg/m3, but Maryland's air
      quality shows signs that it has been improving since 1992. The estimates also
      were compared with actual measurements after the PM2.5 monitor network was
      installed. The estimates were adequate for describing the chemical composition of
      the PM2.5, forecasting compliance status with the 24-hr and annual standards, and
      determining the spatial variations in PM2.5 across central Maryland.

PMID- 12418729
TI  - Online hourly determination of 62 VOCs in ambient air: system evaluation and
      comparison with another two analytical techniques.
AB  - This paper presents results of the processing and validation of data collected by
      an automatic gas chromatograph (AGC). This system was used to monitor 62 volatile
      organic compounds (VOCs) in urban air in the Basque Country, Spain. The nonpolar
      compounds (C2-C10) identified-paraffins, olefins, aromatics, and chlorinated
      compounds-accounted for 88% of the mass of total non-methane hydrocarbons
      (TNMHCs) in ambient air. The evaluation of linearity, precision, detection limits
      (DLs), and stability of retention times (RTs) indicates that the equipment is
      suitable for measuring ambient air automatically for prolonged periods (6
      months). The calibration of the equipment using response factors calculated on
      the basis of the effective carbon number (ECN) showed variations of over 10% for
      acetylene, isoprene, and n-hexane. The results provided by the automatic
      chromatograph correlated significantly with simultaneous results from other
      widely used techniques for determining VOCs in ambient air: (1) portable GC,
      equipped with photoionization detector (PID), and (2) active adsorption on Tenax
      TA followed by thermal desorption and chromatographic analysis.

PMID- 12418730
TI  - Identification of sources contributing to Mid-Atlantic regional aerosol.
AB  - Source types or source regions contributing to the concentration of atmospheric
      fine particles measured at Brigantine National Wildlife Refuge, NJ, were
      identified using a factor analysis model called Positive Matrix Factorization
      (PMF). Cluster analysis of backward air trajectories on days of high- and low
      factor concentrations was used to link factors to potential source regions.
      Brigantine is a Class I visibility area with few local sources in the center of
      the eastern urban corridor and is therefore a good location to study Mid-Atlantic
      regional aerosol. Sulfate (expressed as ammonium sulfate) was the most abundant
      species, accounting for 49% of annual average fine mass. Organic compounds (22%;
      expressed as 1.4 x organic carbon) and ammonium nitrate (10%) were the next
      abundant species. Some evidence herein suggests that secondary organic aerosol
      formation is an important contributor to summertime regional aerosol. Nine
      factors were identified that contributed to PM2.5 mass concentrations: coal
      combustion factors (66%, summer and winter), sea salt factors (9%, fresh and
      aged), motor vehicle/mixed combustion (8%), diesel/Zn-Pb (6%),
      incinerator/industrial (5%), oil combustion (4%), and soil (2%). The aged sea
      salt concentrations were highest in springtime, when the land breeze-sea breeze
      cycle is strongest. Comparison of backward air trajectories of high- and low
      concentration days suggests that Brigantine is surrounded by sources of oil
      combustion, motor vehicle/mixed combustion, and waste incinerator/industrial
      emissions that together account for 17% of PM2.5 mass. The diesel/Zn-Pb factor
      was associated with sources north and west of Brigantine. Coal combustion factors
      were associated with coal-fired power plants west and southwest of the site.
      Particulate carbon was associated not only with oil combustion, motor
      vehicle/mixed combustion, waste incinerator/industrial, and diesel/Pb-Zn, but
      also with the coal combustion factors, perhaps through common transport.

PMID- 12418731
TI  - Microfibrous mesh coated with titanium dioxide: a self-sterilizing, self-cleaning
      filter.
AB  - The utility of metal microfibrous mesh coated with titanium dioxide as a self
      sterilizing, self-cleaning filter for air is explored. The low-cost mesh is
      produced via a roll-to-roll process similar to paper manufacturing. The titanium
      dioxide is applied by spraying an aqueous suspension of the photocatalyst on the
      surface of the mesh using an airbrush. Photocatalytic activity comparable to a
      powder layer is achieved at one quarter of the mass loading. The coating enhanced
      the separation of Escherichia coli (E. coli) from aqueous suspension, but also
      led to an increase in pressure drop in an air stream flowing through the mesh.
      The self-cleaning property of the coated mesh is established by recovery of
      pressure drop performance lost due to biofilm buildup. This is accomplished via a
      photocatalytic regeneration process involving exposing the mesh to ultraviolet
      light in air. Oxidation is confirmed by monitoring CO2 evolution during the
      regeneration. Scanning electron photomicrographs also provide visual evidence of
      successful regeneration via photocatalysis.

PMID- 12418732
TI  - Volatilization of contaminants from suspended sediment in a water column during
      dredging.
AB  - Remedial dredging of contaminated bed sediments in rivers and lakes results in
      the suspension of sediment solids in the water column, which can potentially be a
      source for evaporation of hydrophobic organic compounds (HOCs) associated with
      the sediment solids. Laboratory experiments were conducted in an oscillating grid
      chamber to simulate the suspension of contaminated sediments and flux to air from
      the surface of the water column. A contaminated field sediment from Indiana
      Harbor Canal (IHC) and a laboratory-inoculated University Lake (UL) sediment,
      Baton Rouge, LA, were used in the experiments, where water and solids
      concentration and particle size distribution were measured in addition to
      contaminant fluxes to air. A transient model that takes into account contaminant
      desorption from sediment to water and evaporation from the water column was used
      to simulate water and sediment concentrations and air fluxes from the solids
      suspension. In experiments with both sediments, the total suspended solids (TSS)
      concentration and the average particle diameter of the suspended solids decreased
      with time. As expected, the evaporative losses were higher for compounds with
      higher vapor pressure and lower hydrophobicity. For the laboratory-inoculated
      sediment (UL), the water concentrations and air fluxes were high initially and
      decreased steadily implying that contaminant release to the water column from the
      suspended solids was rapid, followed by evaporative decay. For the field
      sediments (IHC), the fluxes and water concentrations increased initially and
      subsequently decreased steadily. This implied that the initial desorption to
      water was slow and that perhaps the presence of oil and grease and aging
      influenced the contaminant release. Comparison of the model and experimental data
      suggested that a realistic determination of the TSS concentration that can be
      input into the model was the most critical parameter for predicting air emission
      rates.

PMID- 12418733
TI  - Development and laboratory performance evaluation of a personal cascade impactor.
AB  - This paper presents the design and laboratory evaluation of a personal cascade
      impactor. The system is compact, lightweight, and uses a single battery-operated
      sampling pump. It operates at a flow rate of 5 L/min and consists of four
      impaction stages, each equipped with slit-shaped acceleration nozzles, and a
      backup filter. The impactor was calibrated using polydisperse particles. The 50%
      cut points of the four stages were 9.6, 2.6, 1.0, and 0.5 microm, respectively.
      The backup filter is placed downstream of the fourth stage and is used to collect
      the particles with an aerodynamic diameter smaller than 0.5 microm (dp < 0.5
      microm). The major feature of this novel sampler is its ability not only to
      fractionate the particles with an aerodynamic diameter smaller than 10 microm to
      the various size fractions, but also to collect them onto relatively small
      polyurethane foam substrates without using adhesives. Although the impaction
      substrates are not coated with adhesives such as grease or mineral oil, particle
      bounce and re-entrainment losses were found to be insignificant. Interstage
      losses of particles smaller than 0.5 microm were less than 10%; for fine
      particles, less than 5%; and for coarse particles, less than 12%. The pressure
      drop across the four stages and the backup filter were 0.015 kPa (0.153 cm
      H2O),0.025 kPa (0.255 cm H2O), 0.274 kPa (2.794 cm H2O), 0.323 kPa (3.294 cm
      H2O), and 0.370 kPa (3.773 cm H2O), respectively. Particles can be easily
      recovered from the foam substrates using aqueous extraction.

PMID- 12418734
TI  - Just-noticeable differences in atmospheric haze.
AB  - This article examines the only available experimental data taken in the natural
      environment on the ability of an observer to perceive small, incremental changes
      in the colorfulness of objects seen through atmospheric haze and estimates an
      appropriate just-noticeable difference (JND) from these data. This experimentally
      determined threshold of perception is compared to changes in the deciview scale.
      Based on these experimental results, the deciview scale is found to not be
      uniform over a wide range of visibility conditions, as has been previously
      claimed. In addition, a 1-deciview change never produces a perceptible change in
      haze, as defined by a 95% probability of producing a measurable change in the
      colorfulness of an object seen through the haze.

PMID- 12418735
TI  - Atrial oversensing in biventricular devices: shocked? (or inhibited?).

PMID- 12418736
TI  - Temporary disturbances of the QT interval precede the onset of ventricular
      tachyarrhythmias in patients with structural heart diseases.
AB  - An increase in sinus rate prior to ventricular tachyarrhythmias has been
      demonstrated in previous studies. There is no clear data available concerning
      changes in ventricular de- and repolarization prior to ventricular
      tachyarrhythmias, especially in patients with structural heart disease.
      Therefore, the aim of this study was to analyze the QT and QTc interval (Bazett's
      formula immediately before the onset of ventricular tachyarrhythmias in stored
      electrograms of patients with ICDs. The study analyzed 228 spontaneous
      ventricular tachyarrhythmia episodes in 52 patients (mean age 64 +/- 10 years, 49
      men, 3 women) and compared them with 146 electrograms of baseline rhythm recorded
      during regular ICD follow-up. Mean ventricular cycle length (CL), QT interval,
      and QTc were measured before the onset of ventricular tachyarrhythmia and during
      baseline rhythm. Prior to ventricular tachyarrhythmias onset, CL was
      significantly shorter than during baseline rhythm (714 +/- 139 vs 828 +/- 149 ms,
      P < 0.0001). By contrast, the QT interval (430 +/- 67 ms) and QTc interval (518
      +/- 67 ms) were significantly prolonged before the onset of ventricular
      tachyarrhythmias as compared to baseline rhythm (QT 406 +/- 67 ms, QTc 450 +/- 61
      ms; P < 0.0001). CL, QT, and QTc changes were independent of concomitant
      treatment with antiarrhythmic drugs. Ventricular tachyarrhythmias are preceded by
      a significant prolongation of the QT and QTc intervals. This phenomenon may
      represent a greater than normal disparity of repolarization recovery times
      possibly facilitating the development of ventricular tachyarrhythmias.

PMID- 12418737
TI  - Pacemaker reed switch behavior in 0.5, 1.5, and 3.0 Tesla magnetic resonance
      imaging units: are reed switches always closed in strong magnetic fields?
AB  - MRI is established as an important diagnostic tool in medicine. However, the
      presence of a cardiac pacemaker is usually regarded as a contraindication for MRI
      due to safety reasons. The aim of this study was to investigate the state of a
      pacemaker reed switch in different orientations and positions in the main
      magnetic field of 0.5-, 1.5-, and 3.0-T MRI scanners. Reed switches used in
      current pacemakers and ICDs were tested in 0.5-, 1.5-, and 3.0-T MRI scanners.
      The closure of isolated reed switches was evaluated for different orientations
      and positions relative to the main magnetic field. The field strengths to close
      and open the reed switch and the orientation dependency of the closed state
      inside the main magnetic field were investigated. The measurements were repeated
      using two intact pacemakers to evaluate the potential influence of the other
      magnetic components, like the battery. If the reed switches were oriented
      parallel to the magnetic fields, they closed at 1.0 +/- 0.2 mT and opened at 0.7
      +/- 0.2 mT. Two different reed switch behaviors were observed at different
      magnetic field strengths. In low magnetic fields (< 50 mT), the reed switches
      were closed. However, in high magnetic fields (> 200 mT), the reed switches
      opened in 50% of all tested orientations. No difference between the three
      scanners could be demonstrated. The reed switches showed the same behavior
      whether they were isolated or an integral part of the pacemakers. The reed switch
      in a pacemaker or an ICD does not necessarily remain closed in strong magnetic
      fields at 0.5, 1.5, or 3.0 T and the state of the reed switch may not be
      predictable with certainty in clinical situations.

PMID- 12418738
TI  - The relative lymphocyte count predicts death in patients receiving implantable
      cardioverter defibrillators.
AB  - Although the survival benefit conveyed by the automatic defibrillator has been
      well established for several subsets of patients, some patients who receive the
      device still die early. The relative lymphocyte count (%L), a portion of the
      white blood cell count differential, which is decreased in states of excess
      systemic stress, has prognostic value in patients with coronary artery disease
      and advanced heart failure. This study assessed the association of %L with
      survival in patients receiving automatic defibrillators. A total of 136
      consecutive patients (81% men; mean age 64 +/- 12 years) who were using automatic
      defibrillators were followed for 29.6 months. The mean ejection fraction was 0.36
      +/- 0.17, the mean %L was 22.7 +/- 8%, and 55 (40%) patients had decreased %L (<
      20.3%). There were 20 deaths, for a 4-year survival of 71.5%. The association of
      %L with time to death was assessed by Cox proportional hazards analysis. Ejection
      fraction (P = 0.005), %L (P = 0.01), and diagnosis (P = 0.03) were independently
      associated with time to death on multivariate analysis. One-year and 4-year
      survival rates were 93% and 54%, respectively, for the 55 patients with abnormal
      %L, compared with 99% and 84%, respectively, for the 81 with normal %L (P =
      0.03). This suggests that the %L is a readily accessible prognostic marker in
      patients using automatic defibrillators. This association is independent of age,
      sex, diagnosis, and ejection fraction.

PMID- 12418739
TI  - ST-segment deviation following implantable cardioverter defibrillator shocks:
      incidence, timing, and clinical significance.
AB  - ST-segment analysis is frequently used during surgical procedures, while ST
      deviation is considered a sign of myocardial injury. ST deviations were reported
      following transthoracic and epicardial electrical shocks. The prevalence, timing,
      and clinical significance of ST-segment deviation following endocardial ICD
      shocks are discussed in this article. Twenty-eight patients undergoing 125 shock
      episodes during ICD implantation or testing were included. A 12-lead ECG was
      recorded at baseline, continuously during the first 3-10 seconds, 1 minute after
      test shocks, 3-10 seconds and 1 and 5 minutes after each shock given to terminate
      VF. ST deviation was diagnosed when the ST-segment was displaced > or = 1 mm in
      at least one lead compared to baseline. ST-segment deviations were observed after
      49 (39%) of all shock episodes in 17 (61%) of patients. ST elevation was observed
      after 30 (24%) of all shock episodes, and ST depression after 31 (25%). Following
      13 shock episodes in seven patients, ST-elevation and depression were observed.
      ST depressions occurred more frequently after shocks given to terminate VF than
      after lower energy test shocks (28% vs 18% respectively, P = 0.045). However,
      there was no significant difference in the prevalence of ST elevations between
      the lower or higher energy shocks. No adverse clinical events were observed in
      patients with or without postshock ST-segment deviation. ST-segment deviation
      following endocardial ICD shocks is a frequent phenomenon, occurring acutely and
      resolving during the first few minutes postshock. It mayhave no prognostic
      implications.

PMID- 12418740
TI  - Dual chamber pacing in hypertrophic cardiomyopathy: long-term effects on
      diastolic function.
AB  - To assess the effects of chronic dual chamber pacing (DDD) on LV diastolic
      function in obstructive hypertrophic cardiomyopathy (HCM), 21 patients with
      obstructive HCM paced for refractory symptoms were studied at baseline and at 3
      and 12 months. HCM patients were matched to 21 patients with obstructive HCM on
      conventional treatment. Left atrial fractional shortening was calculated by M
      mode echocardiography; this index reflects LV end-diastolic pressure. LV outflow
      tract gradient decreased 65 +/- 21% with DDD pacing and the NYHA class improved
      (P = 0.033). Left atrial fractional shortening worsened with DDD pacing (P <
      0.001). Patients with abnormal baseline left atrial fractional shortening (< 16%)
      were older, had a higher NYHA class, and had more severe mitral regurgitation. In
      this subgroup, left atrialfractional shortening did not worsen with DDD pacing
      and the NYHA class improved more than in patients with normal left
      atrialfractional shortening (P = 0.033). In conclusion, chronic DDD pacing
      reduces obstruction but impairs diastolic function in HCM. In patients with
      normal diastolic function, the untoward effects of pacing on diastolic function
      are more evident than in patients with abnormal diastolic function at baseline.
      This suggests that DDD pacing might be beneficial in a subgroup of patients with
      obstructive HCM and abnormal diastolic function.

PMID- 12418741
TI  - Long-term follow-up results of tilt training therapy in patients with recurrent
      neurocardiogenic syncope.
AB  - Tilt twining therapy is considered as a first choice treatment for
      neurocardiogenic syncope in the Department of Cardiology, University of Leuven.
      However, long-term compliance to therapy may be difficult when patients become
      asymptomatic. In a single center uncontrolled study, the long-term clinical
      outcome of 38 patients was studied after a follow-up period of 43 +/- 7.8 months.
      At the time of assessment 29 patients had abandoned tilt twining therapy, while 9
      still continued on a regular basis. In this series, 31 (82%) of 38 patients were
      free from syncope and 25 (66%) of 38 were completely asymptomatic. During follow
      up, seven patients reported the recurrence of at least one syncope. Of these
      seven patients, six had discontinued tilt training therapy. The number of
      syncopes after discontinuation was significantly lower as compared with the
      period before initiation of tilt twining. In only one patient syncope recurrence
      was observed during rather irregular tilt training therapy. Moreover, in 19
      patients who abandoned tilt training after about 1 year, no syncope recurrence
      was reported during daily life, which suggests that the disturbed autonomic
      reflex activity in these patients may have been restored.

PMID- 12418742
TI  - P wave signal-averaged electrocardiography to identify risk for atrial
      fibrillation.
AB  - AF is the most common sustained cardiac arrhythmia, and this prevalence is
      increasing. The impact of AF on morbidity and mortality is substantial, as are
      the socioeconomic consequences like higher health care costs, chronic disease
      management, and disabilities. Early recognition of patients at high risk for AF,
      combined with effective management, may help prevent AF from becoming chronic,
      helping to minimize potential health risks, costs, and other complications. P
      wave signal-averaged electrocardiography (SAECG) has been shown to have a
      potential role in identifying patients at risk of developing paroxysmal AF and
      those likely to change from paroxysmal AF to chronic AF. The theoretical
      rationale of P wave SAECG in patients with AF is delay in the intraatrial and
      interatrial conduction. Intraatrial conduction delays can be seen on the surface
      electrocardiogram as P wave prolongation, which is more visible with averaging
      techniques and high resolution recording devices. Averaging followed by
      amplification after proper filtering of the electrical signal allows more precise
      measurements of duration and amplitude of the P wave. Data on reproducibility,
      filter settings, number of beats to be averaged, and definitions of the onset and
      offset depend on the system used, which can be QRS or, preferably, P wave
      triggered. A prolonged P wave duration is one of the best predictors of
      perioperative AF, but the role of P wave SAECG in the paroxysmal form is less
      well defined. Combining P wave duration with other predictors for AF improves the
      diagnostic value of P wave SAECG.

PMID- 12418743
TI  - Usefulness of orthostatic self-training for the prevention of neurocardiogenic
      syncope.
AB  - To clarify the effectiveness of an orthostatic self-training program for the
      prevention of neurocardiogenic syncope, twenty-four consecutive head-up tilt
      induced syncopal patients (12 men, 12 women; mean age 34 +/- 20 years) were
      treated with an orthostatic self-training program. The syncope was induced by
      head-up tilt testing (+ 80 degrees for 30 minutes) with or without the use of
      isoproterenol in all patients reproducibly. The hemodynamics during the syncope
      were of the cardioinhibitory type in 4, vasodepressor type in 7, and mixed type
      in 13 patients. The onset time of the tilt induced syncope was 16 +/- 10 minutes
      after the upright position. The orthostatic self-training included standing
      against a wall without moving twice a day every day for a planned duration of up
      to 30 minutes at home. The head-up tilt response was reevaluated with the same
      protocol as the initial study after 22 +/- 6 days based on the patient's daily
      recording of the self-training, and the clinical effect of the training program
      performed only once a day at home was noted over a mean follow-up of 9.5 +/- 3.4
      months (range 5-18 months). Tilt induced syncope after the self-training was
      observed in 2 of 24 patients. However, spontaneous syncope was not observed in
      any of the patients during follow-up. In conclusion, orthostatic self-training
      significantly improved the symptoms in patients with neurocardiogenic syncope.
      Once a day training for up to 30 minutes was effective and easily accepted by the
      patients for the prevention of neurocardiogenic syncope.

PMID- 12418744
TI  - Application of right atrial contiguous linear lesions: an in vivo efficacy
      validation of multipolar ablation catheters in an animal model.
AB  - Catheter ablation of atrial flutter and catheter Maze procedures require the
      creation of linear lesions. The efficacy of different multipolar catheters to
      create linear contiguous transmural lesions was studied in a sheep model. In 19
      sheep a multipolar ablation catheter was inserted into the right atrium. In nine
      sheep a steerable 7 Fr catheter (C1) with six 6-mm electrodes and in five sheep a
      steerable 7 Fr catheter (C2) with four 5-mm electrodes were placed. In five sheep
      a 3.7 Fr catheter (C3) with eight electrodes of 6-mm length was deployed
      (steerable sheath). A total of 72 linear lesions were created and evaluated.
      Catheter types C1, C2, and C3 produced continuous lesions with at least two
      adjacent electrodes in 45%, 79%, and 87% of the lesions. The mean lesion length
      achieved by C3 was longer compared to C1 and C2 (27 +/- 14 vs 10 +/- 5 and 11 +/-
      6 mm; P < 0.05). The ability to produce contiguous lesions by all available
      electrodes was low: C1, 5%; C2, 5%; and C3, 6%. C3 was most effective in exerting
      transmural lesions (93% vs C1 75% and C2 57%; P < 0.0001). Microscopic
      endocardial fibrinous adhesions and macroscopic mild electrode carbonizations
      were caused by all catheter types. In conclusion, (1) all three catheter types do
      not create contiguous lesions along all electrodes. Gaps of viable tissue remain
      in most instances; (2) lesion depths and transmurality varies with different
      catheters; and (3) potentially hazardous thrombotic material was observed during
      radiofrequency ablation with all three catheters.

PMID- 12418745
TI  - Atrial premature beats in patients with focal atrial fibrillation: incidence at
      baseline and impact of provocative maneuvers.
AB  - This study evaluated the incidence of atrial premature beats (APBs) and the
      impact of various provocative maneuvers in patients with focally initiated AF.
      Fifty patients (39 men, 57 +/- 0.4 years) with focally initiated, paroxysmal AF
      underwent Holter recording and a standardized protocol of provocative maneuvers:
      vagomechanical stimulation, adenosine 12 mg i.v., esmolol 500 ng/kg i.v.,
      orciprenaline i.v. 5 mg/50 mL saline 0.9%, and atropine 0.01 mg/kg i.v. A surface
      ECG was recorded for 20 minutes at baseline and following each part of the
      protocol. High focal activity was defined as > or = 1 APB/minute. During Holter
      ECG, 29 (58%) patients had an amount of < 200 APBs, 12 (24%) patients < 700 > or
      = 200, and 9 (18%) patients > or = 700 APBs. Less than 1 hour of high focal
      activity was observed in 34 (68%) of the 50 patients. Before starting provocative
      maneuvers 15 (30%) patients had high focal activity whereas 35 (70%) presented <
      1 APB/minute. In 29 (58%) patients APBs increased by > or = 1/min during
      provocative maneuvers: by vagomechanical stimulation in 11 patients, after
      adenosine in 15, esmolol in 12, orciprenaline in 15, and after atropine in 9
      patients. In all patients with > or = 1 APB/min at baseline, focal activity
      decreased or disappeared during some single provocative maneuvers. AF occurred in
      eight patients under provocative maneuvers. No predictive factors of a successful
      provocative maneuver were detected with regard to the baseline patients
      characteristics and Holter results. In conclusion, patients with focally
      initiated AF have a low incidence of spontaneous APBs. Various provocative
      maneuvers successfully increase APBs in more than half of the patients;
      orciprenaline had the highest efficacy. Some provocative maneuvers may suppress
      APBs in the setting of high focal activity at baseline.

PMID- 12418746
TI  - Estimation of noise level and signal to noise ratio of laplacian
      electrocardiogram during ventricular depolarization and repolarization.
AB  - Body surface Laplacian ECG (LECG) has demonstrated its enhanced capability to
      localize cardiac electrical sources closest to the recording site. The aim of the
      present study was to evaluate the noise level and signal to noise ratio (SNR) in
      the LECG as compared to the potential ECG (PECG). Such evaluation is important to
      determine the applicability of the LECG to localizing and imaging of cardiac
      electrical activity in an experimental setting. Experimental studies were
      conducted in six healthy men. A 150-channel PECG was recorded from the
      anterolateral chest and the LECG was estimated using the finite difference
      algorithm. The noise level in the PECG and LECG was evaluated using multiple
      estimation protocols. The signal level during ventricular depolarization and
      repolarization was also estimated, and the corresponding SNR was calculated.
      Different filtering techniques were examined to evaluate their effects on the
      noise level and SNR of the LECG and PECG. The experimental results indicate that
      with basic signal processing techniques (baseline adjustment, three-point moving
      average filter, and Wiener spatial filter), the SNR of the LECG is about 30-40%
      of that of the PECG. Furthermore, the SNR estimated during ventricular
      depolarization is about three times that obtained during ventricular
      repolarization for the PECG and LECG. The present study indicates that the LECG
      derived from the PECG using a local finite difference estimation procedure has
      satisfactory SNR during the periods of ventricular depolarization and
      repolarization, and suggests the feasibility of estimating the LECG from the
      recorded PECG in human subjects in an experimental setting.

PMID- 12418747
TI  - Effects of radiofrequency pulses delivered in the vicinity of the coronary
      arteries: implications for nonsurgical transthoracic epicardial catheter ablation
      to treat ventricular tachycardia.
AB  - This study evaluates the effects of epicardial RF ablation on the coronary
      vessels in a canine model. Nonsurgical epicardial catheter ablation is a
      minimally invasive procedure that has proven to be efficacious for the treatment
      of VT. This approach is limited by concern regarding the potential adverse
      effects of RF ablation on the epicardial coronary arteries. After lateral
      thoracotomy, a multipolar linear ablation catheter was sewn adjacent to or
      crossing the LAD in nine mongrel dogs. Five of these dogs also had a standard 4
      mm tip ablation catheter sewn adjacent to the LAD. RF pulses were delivered using
      temperature control. Animals were sacrificed 14 days after ablation for
      histological analyses. Using the 4-mm tip catheter, 22 consecutive single lesions
      of 2.67 +/- 0.35 mm depth were studied. The only coronary arterial change seen
      was replacement of the media with extracellular matrix. Using the linear ablation
      catheter, 117 pulses were applied to generate 24 linear lesions (3.8 +/- 1 mm
      depth). Replacement of the coronary arterial media with extracellular matrix
      proliferation was commonly seen, and severe hyperplasia occurred in one artery.
      Intravascular thrombosis occurred in six arteries. The internal perimeter of the
      vessel (0.78 +/- 0.49 mm vs 1.79 +/- 0.83 mm) was the only variable associated
      with severe arterial damage. The effects of RF ablation delivered adjacent to the
      LAD were limited to the media but when delivered above the artery, severe intimal
      hyperplasia and intravascular thrombosis may occur. Susceptibility to damage is
      inversely proportional to the vessel size.

PMID- 12418748
TI  - Interference in implanted cardiac devices, part II.

PMID- 12418749
TI  - An abnormal electrocardiogram in a young man: what is the etiology?

PMID- 12418750
TI  - Inhibition of bradycardia pacing and detection of ventricular fibrillation due to
      far-field atrial sensing in a triple chamber implantable cardioverter
      defibrillator.
AB  - Oversensing of intracardiac signals or myopotentials may cause inappropriate ICD
      therapy. Reports on far-field sensing of atrial signals are rare, and
      inappropriate ICD therapy due to oversensing of atrial fibrillation has not yet
      been described. This report presents a patient with a triple chamber ICD and a
      history of His-bundle ablation who experienced asystolic ventricular pauses and
      inappropriate detection of ventricular fibrillation due to far-field oversensing
      of atrial fibrillation. Several factors contributed to the complication, which
      resolved after reduction of the ventricular sensitivity.

PMID- 12418751
TI  - Inhibition of biventricular pacing by far-field left atrial activity sensing:
      case report.
AB  - This case report describes a patient with biventricular pacemaker in whom a far
      field sensing of left atrial activity by the pacemaker's ventricular channel
      resulted in ventricular pacing inhibition. Placing of the left ventricular pacing
      electrode in the proximal part of the coronary sinus tributary resulted in this
      far-field sensing problem, which was resolved following decreasing the
      ventricular sensitivity. The authors suggest that the far-field sensing of the
      left atrial activity should be kept in mind for troubleshooting of an atrio
      biventricular pacing system.

PMID- 12418752
TI  - Catecholaminergic polymorphic ventricular tachycardia in a 3-year-old with occult
      myocarditis.
AB  - Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare clinical
      entity in children. Occult myocarditis has not been previously implicated as an
      etiologic agent. A 3-year-old female presents with a presumed breath-holding
      spell and is found to have ventricular fibrillation requiring DC cardioversion.
      An invasive electrophysiological study was performed demonstrating the absence of
      inducible ventricular arrhythmias. Low dose epinephrine confirmed the presence
      CPVT. Right ventricular endomyocardial biopsies sent for polymerase chain
      reaction (PCR) analysis demonstrated the presence of adenoviral DNA. The authors
      hypothesize that occult myocarditis may be the inciting agent for CPVT in
      children.

PMID- 12418753
TI  - Simultaneous epicardial and endocardial mapping of a left-sided posteroseptal
      accessory pathway associated with a large coronary sinus diverticulum: successful
      ablation by transection of the diverticulum's neck.
AB  - Transcutaneous pericardial instrumentation in a patient with a left-sided
      posteroseptal accessory pathway associated with a large coronary sinus
      diverticulum was performed after three previous unsuccessful ablations. The
      earliest ventricular activation site was recorded epicardially using a catheterin
      the pericardial space, but energy delivery at this site was not possible due to
      high impedances. Intravascular linear lesions transecting the neck of the large
      coronary sinus diverticulum using the pericardial catheter as a target allowed
      successful radiofrequency catheter ablation of the accessory pathway. This case
      outlines potential problems with ablations in the pericardial space and provides
      an alternative solution that can spare patients from open surgical procedures.

PMID- 12418754
TI  - Usefulness of atrial pacing for prevention and termination of atrial
      tachyarrhythmias in a patient with persistent atrial fibrillation.
AB  - Atrial pacing with dedicated algorithms for prevention and termination of atrial
      tachyarrhythmias is under clinical evaluation. A patient is described with
      persistent symptomatic AF. After cardioversion and implantation of a DDDRP
      pacemaker before planned AVN ablation, the patient was free of symptoms. Early
      after implant, one cardioversion of AF was necessary. Over the course of 12
      months, only five episodes of atrial tachyarrhythmia occurred, all automatically
      pace terminated within 24 hours. Thus, selected patients with persistent AF may
      benefit from preventive atrial pacing since the tachyarrhythmia can organize
      intermittently to a degree sufficient for pace termination.

PMID- 12418755
TI  - Macroreentrant atrial flutter around a common atrioventricular canal in an infant
      with complicated congenital heart anomaly.
AB  - This report describes a 2-year-old male infant after repair of complicated
      congenital heart anomalies including common atrioventricular canal (CAVC), in
      which macroreentrant atrial flutter around the CAVC was demonstrated by
      electroanatomic mapping (CARTO) using a single catheter. Radiofrequency catheter
      ablation at the isthmus between the CAVC and the inferior vena cava eliminated
      the atrial flutter successfully.

PMID- 12418756
TI  - Fish pond electromagnetic interference resulting in an inappropriate implantable
      cardioverter defibrillator shock.

PMID- 12418757
TI  - Complications due to abandoned noninfected pacemaker leads.

PMID- 12418758
TI  - Complications due to abandoned noninfected pacemaker leads.

PMID- 12418759
TI  - Biventricular pacing using two pacemakers and the triggered VVT mode.

PMID- 12418761
TI  - Parametric imaging of rat mammary tumors in vivo for the purposes of tissue
      characterization.
AB  - OBJECTIVE: To estimate the average scatterer properties from ultrasonic
      backscatter in tissues for evaluating differences between neoplastic and healthy
      tissues. METHODS: Parametric images of 8 retired breeder rats in which
      spontaneous mammary tumors had developed were created by superimposing color
      coded pixels related to the estimated average scatterer properties on
      conventional gray scale B-mode images. RESULTS: The images showed a distinct
      difference between the tumors and surrounding healthy tissues. Analysis of the
      average scatterer diameters and acoustic concentrations showed a statistically
      significant difference (P < .05) between estimates inside and outside the tumors
      for most of the cases. Scatterer sizes inside the tumors were on average 30%
      larger than scatterer sizes in surrounding normal tissues. A feature analysis
      plot showed that there was a distinct difference between results obtained inside
      and outside the tumors. CONCLUSIONS: Parametric imaging that uses estimates of
      scatterer properties in tissues may lead to detection and characterization
      (diagnosis) of diseased tissues on conventional sonographic scanning systems.

PMID- 12418760
TI  - Pulse inversion sonography in the early phase of the sonographic contrast agent
      Levovist: differentiation between benign and malignant focal liver lesions.
AB  - OBJECTIVE: To determine whether examination of focal liver lesions by pulse
      inversion sonography in the early perfusion phase of the contrast agent Levovist
      (SH U 508A; Schering AG, Berlin, Germany) enables distinction between benign and
      malignant lesions. METHODS: Seventy-two patients were examined. The cause of the
      lesion was confirmed by liver biopsy, computed tomography, or both or by hepatic
      iminodiacetic acid-enhanced scintigraphy. Forty-two patients had malignant liver
      lesions, and 30 had benign liver lesions. After injection of 2 g of Levovist
      intravenously, analysis of Levovist arrival was performed by the interval delay
      imaging technique for 60 seconds. RESULTS: The early arrival of Levovist less
      than 30 seconds after injection was used as an indicator for malignancy and had
      specificity of 67% and sensitivity of 60% (P < .05). The central starlike fill-in
      as a sign for focal nodular hyperplasia had specificity of 100% and sensitivity
      of 67% (P < .001). The rimlike pattern followed by centripetal fill-in as a sign
      for hemangioma had specificity of 100% and sensitivity of 18% (P < .01). In
      contrast, the early diffuse stippled arrival pattern was found in 60% of
      malignant lesions and also in 33% of cases of focal nodular hyperplasia and in 1
      patient with an adenoma. CONCLUSIONS: Analysis of Levovist arrival time cannot
      distinguish between a malignant or benign lesion in individual cases. However,
      the central starlike arrival pattern is characteristic of focal nodular
      hyperplasia.

PMID- 12418762
TI  - Prospective evaluation of the value of negative sonographic and mammographic
      findings in patients with palpable abnormalities of the breast.
AB  - OBJECTIVE: To evaluate the value of combined negative sonographic and
      mammographic findings in patients with palpable breast abnormalities. METHODS:
      One hundred seventy-two patients with 186 palpable abnormalities who had combined
      negative sonographic and mammographic findings were prospectively studied.
      Patients who did not undergo biopsy had imaging and clinical follow-up; the mean
      follow-up period was 28.9 months (range, 24-33 months). RESULTS: Twelve patients
      underwent biopsy; benign histologic diagnoses were reported in all 12 (12 [6.9%]
      of 172). In the remaining 160 patients who were followed, there was no interval
      development of breast cancer at the site of the palpable abnormality. The
      negative predictive value of combined negative mammographic and sonographic
      findings in a patient with a palpable abnormality of the breast was 100%.
      CONCLUSIONS: Our findings suggest that in a patient with a palpable abnormality
      of the breast, the negative predictive value of combined normal sonographic and
      mammographic findings is very high and is therefore reassuring to the patient.

PMID- 12418764
TI  - Correlation between color power Doppler sonographic measurement of breast tumor
      vasculature and immunohistochemical analysis of microvessel density for the
      quantitation of angiogenesis.
AB  - OBJECTIVE: To record the correlation between color power Doppler sonographic
      measurement of breast tumor vasculature and immunohistochemical analysis of
      microvessel density for the quantitation of angiogenesis. METHODS: Women with
      palpable breast masses scheduled for excision biopsy were scanned with two- and
      three-dimensional color power Doppler sonography before and after the
      administration of a sonographic contrast agent. Vessel counts were performed on
      two- and three-dimensional sonographic images before and after contrast agent
      administration. All tumors were surgically removed and underwent
      immunohistochemical analysis for microvessel density assessment. The sonographic
      measure of tumor vascularity was correlated with microvessel density. RESULTS:
      Pathologic examination showed 43 breast cancers and 14 benign breast masses.
      Higher microvessel density was noted in malignant than benign breast masses (P <
      .0005). Color power Doppler sonographic measurement of tumor vessel number showed
      a significant positive correlation with tumor size (P < .05) and progesterone
      receptor negativity (P < .05). A significant positive correlation was observed
      between microvessel density and the number of intratumoral blood vessels assessed
      by both two- and three-dimensional color power Doppler sonography (P < .05).
      Regression models showed three-dimensional color power Doppler sonography to have
      a significantly higher correlation with microvessel density when compared with
      two-dimensional color power Doppler sonography at baseline (P < .005). The
      administration of a sonographic contrast agent did not improve correlation with
      microvessel density. CONCLUSIONS: A significant correlation was shown between
      color power Doppler sonographic measurement of tumor vascularity and microvessel
      density by immunohistochemical analysis. Further improvement in Doppler
      sonographic techniques to map capillary vessel flow should be explored to improve
      the current association with pathologic findings.

PMID- 12418763
TI  - Preferential use of sonographically guided biopsy to minimize patient discomfort
      and procedure time in a percutaneous image-guided breast biopsy program.
AB  - OBJECTIVE: To determine whether preferential use of sonographic guidance for
      percutaneous biopsy of breast masses results in a subset of patients with a
      shorter procedure time and less discomfort compared with patients undergoing
      stereotactic biopsy. METHODS: A prospective observational study was performed on
      193 women undergoing percutaneous image-guided breast biopsy between 1997 and
      1999. Data were collected on room time, physician time, and patient comfort
      levels for 122 stereotactic and 71 sonographically guided biopsies. Differences
      between stereotactic and sonographically guided biopsy for all lesions and for
      masses were analyzed for statistical significance. RESULTS: Mean room times were
      62.2 minutes for stereotactic biopsy and 39.4 minutes for sonographically guided
      biopsy (P < .0001). Mean physician times were 23.0 minutes for stereotactic
      biopsy and 15.8 minutes for sonographically guided biopsy (P < .0001). When we
      limited our analyses to women undergoing biopsy for masses, the difference in
      physician time largely disappeared, but the difference in room time remained (P <
      .0001). Women undergoing stereotactic biopsy were more likely to report
      discomfort due to body positioning than were women undergoing sonographically
      guided biopsy (P < .001). These differences existed whether we included all
      lesions or restricted our analyses to masses. CONCLUSIONS: Preferential use of
      sonographically guided breast biopsy for masses results in shorter procedure
      times and less patient discomfort compared with prone stereotactic biopsy.

PMID- 12418765
TI  - Ovarian and uterine findings in pelvic sonography: comparison between prepubertal
      girls, girls with isolated thelarche, and girls with central precocious puberty.
AB  - OBJECTIVE: To describe pelvic sonographic findings in girls as old as 7 years, to
      compare prepubertal girls with girls who had isolated thelarche or central
      precocious puberty, and to verify the accuracy of sonographic variables for
      distinguishing prepubertal girls from girls with central precocious puberty.
      METHODS: Ninety-six prepubertal girls and 2 reference groups (8 girls with
      isolated thelarche and 8 with idiopathic central precocious puberty) were
      included. Ovaries were classified morphologically as homogeneous, paucicystic,
      macrocystic, multicystic, and having isolated cysts. Receiver operating
      characteristic curves were used to choose the best cutoff points. RESULTS:
      Chronologic and bone age were correlated with uterine length, area, and volume
      and ovarian volume in prepubertal girls (P < .0001). Ovarian morphologic
      characteristics in prepubertal girls differed significantly from those of the
      reference groups (P < .0001). The best cutoff points were uterine length of 4.0
      cm, uterine area of 4.5 cm2, uterine volume of 3.0 cm3, and ovarian volume of 1.0
      cm3. CONCLUSIONS: Uterine and ovarian growth are proportional to age in
      prepubertal girls. Mean ovarian volume greater than 1 cm3 showed 100% sensitivity
      and specificity for discriminating between prepubertal girls and girls with
      central precocious puberty. Microcysts are common in prepubertal girls, but the
      presence of 6 or more follicles up to 10 mm in diameter may suggest central
      precocious puberty in girls younger than 8 years.

PMID- 12418766
TI  - Discrimination of bladder disorders in female lower urinary tract symptoms on
      ultrasonographic cystourethrography.
AB  - OBJECTIVE: To evaluate morphologic features of bladder disorders in female lower
      urinary tract symptoms using ultrasonographic cystourethrography and to elucidate
      the anatomic association of these morphologic characteristics. METHODS:
      Ultrasonographic cystourethrography was performed in 1049 women with lower
      urinary tract symptoms and 1 single urodynamic diagnosis, including 764 patients
      with genuine stress incontinence, 190 with detrusor instability, and 95 with a
      hypersensitive bladder. Thirty-six women with no lower urinary tract symptoms
      served as control subjects. Ultrasonographic assessment included measurement of
      the bladder neck position at rest and during stress and observation of the
      development of bladder neck funneling and cystocele during the Valsalva maneuver.
      RESULTS: Hypersensitive bladder and control groups had a significantly higher
      bladder neck position at rest and during stress, a lesser rotational angle of the
      bladder neck, a lower prevalence of bladder neck funneling and cystocele
      formation, and lesser mean bladder wall thickness than the other diagnostic
      groups. In the study groups, age, parity, and menopause may have effects on the
      cystourethrographic parameters except rotational angle and funneling of the
      bladder neck. With control of the confounding factors, bladder wall thickness at
      the trigone and dome was negatively correlated with the resting bladder neck
      angle (P = .006 and 0.019, respectively). Bladder wall thickness at the dome was
      positively associated with the rotational angle of the bladder neck (P = .022).
      Funneling of the bladder neck and development of cystocele during stress were
      positively associated with the resting and straining bladder neck angles as well
      as the rotational angle of the bladder neck. CONCLUSIONS: Ultrasonographic
      manifestation of a hypersensitive bladder is significantly different from that of
      genuine stress incontinence and detrusor instability.

PMID- 12418767
TI  - Fetal therapy: state of the art.
AB  - OBJECTIVE: To review our experience with the use of sonography in evaluating
      potential candidates for in utero fetal therapy performed at The Center for Fetal
      Diagnosis and Treatment at The Children's Hospital of Philadelphia. METHODS: This
      review article was designed to discuss open hysterotomy for the 4 fetal surgical
      procedures that have been performed at our institution. The procedures included
      surgical repair of myelomeningocele, resection of sacrococcygeal teratoma in
      fetuses with nonimmune hydrops, resection of an enlarging congenital cystic
      adenomatoid malformation that is not amenable to thoracoamniotic shunting, and
      tracheal clip occlusion for severe left congenital diaphragmatic hernia. RESULTS:
      For each surgical procedure, the use of sonography in the prenatal diagnosis of
      the congenital anomaly was detailed, as were indications for surgery and surgical
      procedures, postoperative monitoring and finally delivery, postnatal treatment,
      and long-term follow-up. Three of the procedures have been reasonably successful
      with rather dramatic results in some cases such that these techniques are still
      being performed. The 1 exception was open hysterotomy for the tracheal clip
      procedure for congenital diaphragmatic hernia, which has been abandoned.
      CONCLUSIONS: Fetal therapy is a rapidly evolving specialty, which is being
      practiced at several centers in this country. Sonography is an integral part of
      this specialty practice and has been used extensively in the diagnosis of some
      congenital anomalies that have debilitating or lethal consequences for the fetus.
      Technologic improvements in both sonography and magnetic resonance imaging have
      assisted tremendously in the many advances herein reported in the diagnosis and
      treatment of the above-described 4 congenital anomalies.

PMID- 12418768
TI  - Ultrasonographic appearance of supinator syndrome.
AB  - OBJECTIVE: To describe ultrasonographic findings in 4 patients with supinator
      syndrome (i.e., deep branch of the radial nerve). METHODS: Four patients with
      weakness and pain in their forearm underwent ultrasonographic examination with
      subsequent electroneurographic testing and surgical nerve inspection. Normal
      measurements of the deep branch of the radial nerve in 10 healthy volunteers
      served as comparison for measurements in the patients. RESULTS: An enlarged deep
      branch of the radial nerve was found in all 4 patients at the affected side.
      Electroneurographic testing and surgical inspection confirmed the
      ultrasonographic findings. The mean transverse diameter was 4.2 mm (range, 3.8
      4.5 mm), and the anteroposterior diameter was 3.3 mm (range, 2.5-3.8 mm). In
      volunteers, the mean transverse diameter was 2.13 mm (range, 1.7-2.6 mm), and the
      mean anteroposterior diameter was 1.3 mm (range, 1.0-1.5 mm). CONCLUSIONS: The
      deep branch of the radial nerve appears enlarged in patients with supinator
      syndrome.

PMID- 12418769
TI  - Sonographic diagnosis of traumatic gallbladder rupture.
AB  - Gallbladder injuries after blunt abdominal trauma are rare and often follow a
      vague and insidious clinical course. Consequently, gallbladder injuries commonly
      go undiagnosed until exploratory laparotomy. Early diagnosis is essential,
      because trauma to the gallbladder is typically treated surgically, and delay in
      treatment can result in considerable mortality and morbidity. With sonography
      emerging as a first-line modality for evaluation of intra-abdominal trauma,
      sonographers may wish to become more familiar with the appearance of gallbladder
      injury on sonography to facilitate earlier diagnosis and to improve treatment and
      prognosis. We report a case of gallbladder perforation after blunt abdominal
      trauma diagnosed on the basis of computed tomography (CT) and sonography.

PMID- 12418770
TI  - Sonographically guided percutaneous radio frequency ablation of a renal cell
      carcinoma in a transplanted kidney.
AB  - Radio frequency ablation is an effective treatment for focal renal cell carcinoma
      (RCC). We report a patient with RCC in a transplanted kidney that was
      successfully treated with percutaneous sonographically guided radio frequency
      ablation.

PMID- 12418771
TI  - Sonographic appearance of a bladder calculus secondary to a suture from a bladder
      neck suspension.
AB  - About 2% of all bladder calculi occur in women. Their presence necessitates a
      careful assessment of the cause. Most bladder calculi secondary to female pelvic
      surgery result from either obstruction or foreign objects. The presence of
      nonabsorbable suture material in the bladder is a well-known cause of urinary
      tract infection and stone formation. We present the sonographic findings in a
      case of a bladder stone forming around nonabsorbable sutures after a Marshall
      Marchetti-Krantz operation for stress urinary incontinence.

PMID- 12418772
TI  - Diagnosis of umbilical cord entanglement of monoamniotic twins by first-trimester
      color Doppler imaging.
AB  - Monoamniotic twins occur in approximately 5% of monochorionic twin gestations as
      a result of splitting of the inner cell mass at 8 or more days after
      fertilization, and they are associated with high perinatal mortality rates,
      ranging between 28% and 47%. These gestations have unique pathologic conditions,
      including conjoined twins, a high prevalence of discordancy for fetal structural
      anomalies (the former and possibly also the latter resulting from consequences of
      the twinning process), and cord entanglement. We present a case in which
      monoamniotic twins at first-trimester transvaginal sonography were confirmed by
      color Doppler imaging as having entangled umbilical cords.

PMID- 12418773
TI  - Juvenile polyposis of the colon: sonographic diagnosis.
AB  - Juvenile polyposis is an uncommon condition characterized by development of
      multiple juvenile polyps, predominantly in the colon but also in the rest of the
      gastrointestinal tract. The condition usually appears in childhood. The rarer and
      often fatal form, occurring in infancy, is typified by diarrhea, protein-losing
      enteropathy, bleeding, and rectal prolapse. The more common form of juvenile
      polyposis (affecting the colon, stomach, and small bowel) occurs in the first or
      second decade with rectal bleeding and anemia. We report a case of juvenile
      polyposis detected on sonography, which had been treated as severe anemia for 1
      year.

PMID- 12418774
TI  - Sonography of pancreatic ductal anatomic characteristics in annular pancreas.
AB  - Annular pancreas is a rare developmental anomaly of the pancreas. The sonographic
      feature of this condition has been described as circumferential pancreatic tissue
      around the duodenum. Diagnosis of this condition by the sonographic visualization
      of ductal anatomic characteristics is described here.

PMID- 12418775
TI  - Sonographic features of tubular duplication of the small bowel.
AB  - Tubular duplication of the small bowel is a very rare anomaly of the
      gastrointestinal system. The sonographic features of this condition are described
      in this report.

PMID- 12418776
TI  - Sequence analysis of old and new strains of porcine circovirus associated with
      congenital tremors in pigs and their comparison with strains involved with
      postweaning multisystemic wasting syndrome.
AB  - The entire genomes of 7 isolates of porcine circovirus (PCV) from pigs with
      congenital tremors (CT), type A2, or postweaning multisystemic wasting syndrome
      (PMWS) were cloned and sequenced. One isolate (CT-PCV-P7) originated from the
      late 1960s from a neonatal pig with CT, type A2. Two recent PCV isolates (CT-PCV
      P5, CT-PCV-P6) were from 2 affected neonatal pigs, from different farms, with
      unrelated outbreaks of CT; type A2. Four isolates (PMWS-PCV-P1, PMWS-PCV-P2, PMWS
      PCV-P3, PMWS-PCV-P4) originated from pigs with PMWS from 4 different farms. A
      comparative analysis of these PMWS and PCV isolates demonstrated 99% sequence
      identity with each other, and over 96% sequence identity with previously
      sequenced PCV2 isolates. The CT-PCV-P5 and CT-PCV-P6 isolates, however, shared
      99% of the same identity with each other, and interestingly also with PMWS PCV
      isolates. There were no consistent genomic differences between PMWS and recent CT
      isolates. The CT-PCV-P7 showed 98% identity similarity to PK-15-derived PCV1 and
      demonstrated only 72% identity similarity to either CT-PCV-P5 or CT-PCV-P6.
      Phylogenetic analysis confirmed that the old isolate (CT-PCV-P7), and the new
      isolates (CT-PCV-P5, CT-PCV-P6, PMWS-PCV-P1, PMWS-PCV-P2, PMWS-PCV-P3, PMWS-PCV
      P4) were correctly classified as PCV1 and PCV2, respectively.

PMID- 12418777
TI  - Seroprevalence of porcine circovirus type 2 in swine populations in Canada and
      Costa Rica.
AB  - Porcine circovirus (PCV) was recently divided into 2 antigenically distinct types
      that differ (65% amino acid identity) in the protein encoded by open reading
      frame 2 (ORF2). Porcine circovirus 1 is apparently non-pathogenic and, in
      contrast, PCV2 is associated with porcine multisystemic wasting syndrome (PMWS).
      Our objective was to determine the extent of exposure of normal pigs in Canada
      and Costa Rica to PCV2. Recombinant DNA techniques were used to produce an
      antigen from ORF2 of PCV2 that was suitable for the detection of antibody in
      swine sera. The presence of PCV2 nucleotide sequences was detected using
      polymerase chain reaction (PCR) techniques. Using these tests, specific antibody
      and nucleotide sequences were demonstrated in sera from a cohort of pigs during a
      PMWS outbreak. Antibody was detected in normal, healthy hogs slaughtered in
      Canada (82.4% of 386) and in Costa Rica (14.6% of 322). This is the first report
      indicating the presence of PCV2 in Latin America. More than 50% of these sera
      also contained PCV2 nucleotide sequence. Although these hogs were healthy when
      slaughtered, they were infected with PCV2 and may have previously been ill. The
      widespread occurrence of PCV2 in swine suggests that this virus is adapted to
      replication in porcine tissue.

PMID- 12418778
TI  - Mechanical transmission of porcine reproductive and respiratory syndrome virus
      throughout a coordinated sequence of events during cold weather.
AB  - Using a field-based model, mechanical transmission of porcine reproductive and
      respiratory syndrome virus (PRRSV) wa assessed throughout a coordinated sequence
      of events that replicated common farm worker behavior during cold weather (< 0
      degrees C). The model involved fomites (boots and containers), vehicle
      sanitation, transport, and the movement of personnel. A field strain of PRRSV was
      inoculated into carriers consisting of snow and water, and carriers were adhered
      to the undercarriage of a vehicle. The vehicle was driven approximately 50 km to
      a commercial truck washing facility where the driver's boots contacted the
      carriers during washing, introducing the virus to the vehicle interior. The
      vehicle was then driven 50 km to a simulated farm site, and the driver's boots
      mechanically spread virus into the farm anteroom. Types of containers frequently
      employed in swine farms (styrofoam semen cooler, metal toolbox, plastic lunch
      pail, and cardboard animal health product shipping parcel) contacted drippings
      from footwear on the anteroom floor. The truck wash floor, vehicle cab floor
      mats, boot soles, anteroom floor, and the ventral surface of containers were
      sampled to track the virus throughout the model. Ten replicates were conducted,
      along with sham-inoculated controls. At multiple sampling points PRRSV nucleic
      acid was detected in 8 of 10 replicates. In each of the 8 PCR-positive
      replicates, infectious PRRSV was detected on the surfaces of containers by virus
      isolation or swine bioassay. All sham-inoculated controls were negative. These
      results indicate that mechanical transmission of PRRSV can occur during
      coordinated sequence of events in cold weather.

PMID- 12418779
TI  - Genetic diversity of Streptococcus suis serotypes 2 and 1/2 isolates recovered
      from carrier pigs in closed herds.
AB  - The aim of this study was to compare, by randomly amplified polymorphic DNA
      (RAPD), the diversity of Streptococcus suis serotypes 1/2 and 2 isolates
      recovered at slaughter houses from the tonsils of clinically healthy pigs. The
      pigs belonged to herds with or without clinical signs of S. suis disease.
      Overall, a low diversity was observed among isolates of serotype 1/2. A
      representative isolate recovered from a diseased animal presented a relatively
      high similarity (85%), with most isolates recovered from carrier pigs, from herds
      either with or without clinical signs of S. suis disease. For serotype 2
      isolates, a relatively high degree of heterogeneity was observed in the whole
      population. Two subpopulations were observed for serotype 2 isolates, which arose
      from herds with clinical signs. Interestingly, the representative isolate coming
      from the diseased pig was included in a small closed cluster, with 2 isolates
      recovered from carrier pigs belonging to the same herd. On the other hand, most
      of the S. suis serotype 2 isolates originating from herds with no history of S.
      suis disease, were closely related (90% similarity). Furthermore, they presented
      different RAPD patterns from those originating from animals from the herd
      presenting S. suis clinical signs due to this serotype. Results suggest that, in
      the herds studied, clinical manifestations due to serotype 2 are probably related
      to the virulence of a specific isolate. Conversely, for the herd affected with
      serotype 1/2, clinical manifestations of the disease were more likely to be the
      result of inherent herd factors than the virulence of the specific isolate.

PMID- 12418781
TI  - Serologic follow-up of a repopulated swine herd after an outbreak of
      proliferative hemorrhagic enteropathy.
AB  - Lawsonia intracellularis is an obligate intracellular organism that causes
      porcine proliferative enteropathy, a widespread infectious disease. Very little
      is known about the immune response and the epidemiologic features of the disease
      in the field. The aims of this study were to evaluate the duration and titers of
      antibody specific for L. intracellularis in gilts after an outbreak of
      proliferative hemorrhagic enteropathy (PHE), to evaluate maternal antibodies in
      piglets, and to evaluate seroconversion and fecal shedding in growing-finishing
      pigs. Thirty-six gilts in a herd that had recently experienced an outbreak of
      PHE, including 13 that had recovered, were bled 3 wk after the beginning of the
      outbreak and then every 3 wk until they became seronegative in 2 consecutive
      tests. Fourteen piglets from 5 gilts seropositive at farrowing and 5 piglets from
      2 sows that remained seronegative were bled once or twice at the farrowing house
      and then every 3 wk until they reached market age. Fecal samples from these pigs
      were tested by polymerase chain reaction at 7 wk of age and then on the days of
      blood collection. After the PHE outbreak, the gilts had high serum antibody
      levels; the levels decreased over time, but antibody was still detectable for up
      to 3 mo in some animals. Four piglets from sows that were seropositive at
      farrowing had detectable passive antibodies up to 5 wk of age. Some nursery pigs
      started shedding L. intracellularis around 7 wk of age; peak shedding was
      observed between 13 and 16 wk. Antibody was not detected until 16 wk of age and
      was more often detected between 19 and 22 wk.

PMID- 12418780
TI  - The use of negative binomial modelling in a longitudinal study of
      gastrointestinal parasite burdens in Canadian dairy cows.
AB  - The epidemiology of bovine gastrointestinal nematodes was investigated through a
      1-year (October 1999 to September 2000) longitudinal study in 38 Canadian dairy
      herds from 4 different provinces (Prince Edward Island, Quebec, Ontario,
      Saskatchewan). For each herd, fecal egg counts from 8 randomly selected animals
      were performed on a monthly or quarterly basis. Larval cultures were performed
      once, to determine the species breakdown of the parasites. All producers were
      interviewed regarding herd management practices. The observed fecal egg counts
      were low in this study, with a range from 0 to 419 nematode eggs per 5 g of
      feces. The mean count was 9.8 and the median was 1. Standard transformations
      failed to normalize the data, which followed an over-dispersed Poisson
      distribution. A zero inflated negative binomial model was applied to assess
      factors that would influence the fecal egg counts. Identified associations were:
      egg counts were lowest in the winter and highest in the late spring; first
      lactation cattle had higher counts than older cows; if manure was spread
      mechanically on pastures used by lactating cattle the egg counts were higher; and
      if manure was spread on heifer-pastures, the adult cows had lower counts. In
      herds where pasture use was more extensive, the cattle had higher fecal egg
      counts. The difference in pasture exposure was found to be a main contributor to
      an observed difference in fecal egg counts among herds in the 4 provinces.

PMID- 12418782
TI  - Validation of 2 commercial Neospora caninum antibody enzyme linked immunosorbent
      assays.
AB  - This is a validation study of 2 commercially available enzyme linked
      immunosorbent assays (ELISA) for the detection of antibodies against Neospora
      caninum in bovine serum. The results of the reference sera (n = 30) and field
      sera from an infected beef herd (n = 150) were tested by both ELISAs and the
      results were compared statistically. When the immunoblotting results of the
      reference bovine sera were compared to the ELISA results, the same identity score
      (96.67%) and kappa values (K) (0.93) were obtained for both ELISAs. The
      sensitivity and specificity values for the IDEXX test were 100% and 93.33%
      respectively. For the Biovet test 93.33% and 100% were obtained. The
      corresponding positive (PV+) and negative predictive (PV-) values for the 2
      assays were 93.75% and 100% (IDEXX), and 100% and 93.75% (Biovet). In the 2nd
      study, competitive inhibition ELISA (c-ELISA) results on bovine sera from an
      infected herd were compared to the 2 sets of ELISA results. The identity scores
      of the 2 ELISAs were 98% (IDEXX) and 97.33% (Biovet). The K values calculated
      were 0.96 (IDEXX) and 0.95 (Biovet). For the IDEXX test the sensitivity and
      specificity were 97.56% and 98.53%, whereas for the Biovet assay 95.12% and 100%
      were recorded, respectively. The corresponding PV+ and PV- values were 98.77% and
      97.1% (IDEXX), and 100% and 94.44% (Biovet). Our validation results showed that
      the 2 ELISAs worked equally well and there was no statistically significant
      difference between the performance of the 2 tests. Both tests showed high
      reproducibility, repeatability and substantial agreement with results from 2
      other laboratories. A quality assurance based on the requirement of the ISO/IEC
      17025 standards has been adopted throughout this project for test validation
      procedures.

PMID- 12418783
TI  - Flaxseed (Linum usitatissimum) supplementation associated with reduced skin test
      lesional area in horses with Culicoides hypersensitivity.
AB  - The purpose of this study was to quantify the effect of flaxseed (Linum
      usitatissimum) supplementation on the skin test response of atopic horses. Six
      horses that displayed a positive skin test for allergy to extract from Culicoides
      sp. participated in the 42-day, placebo-controlled, double-blind, cross-over
      trial. Results showed that supplementation with flaxseed for 42 days in our
      experimental horses reduced the mean skin test response to Culicoides sp. This
      observation was concurrent with a significant decrease in the long-chain
      saturated fatty acids; behenic acid (22:0) and lignoceric acid (24:0), in the
      hair of horses receiving flaxseed. There was also a significant decrease in
      aspartate aminotransferase, and increase in serum glucose in the treatment
      animals at specific sampling points. It was concluded that; in this small pilot
      study, flaxseed was able to reduce the lesional area of the skin test response of
      atopic horses, alter the fatty acid profile of the hair, reduce inflammation, and
      did not elicit any negative side-effects in the experimental horses.

PMID- 12418784
TI  - Field study of bovine coronavirus vaccine enriched with hemagglutinating antigen
      for winter dysentery in dairy cows.
AB  - A field study of a vaccine; prepared by solubilizing cells infected with bovine
      coronavirus, Triton X-100, and mixing with an oil adjuvant, was performed at 9
      farms over 4 prefectures. The cattle tested were Holstein dairy cows aged 2 to 10
      years. A vaccination group consisted of 157 animals (including 132 pregnant cows)
      and a non-vaccinated control group consisted of 50 animals. The cows received 2
      intramuscular injections of vaccine (2 mL) at 3-week intervals. Vaccinated cows
      did not develop abnormalities, such as a decrease in milk production volume, and
      all pregnant animals calved normally. The geometric mean of the hemagglutination
      inhibition antibody titer was 34.2 before vaccination in test cows. The titer had
      increased to 105.6, 3 weeks after the 1st injection and peaked at 755.6, 1 month
      after the 2nd injection. A high antibody titer persisted at 396.0; 241.0; and
      201.5, at 3, 6, and 9 months after the 2nd injection, respectively. This confirms
      the safety and high antibody-response induced by this prototype vaccine.
      Therefore, this vaccine may be useful for the prevention of winter dysentery
      caused by bovine coronavirus infection.

PMID- 12418785
TI  - Improved immunobinding test using monoclonal antibodies for detection of
      Mycoplasma bovis in milk.
AB  - The aim of this study was to evaluate an improved immunobinding test (IBT) using
      monoclonal antibodies to identify Mycoplasma bovis in naturally infected milk.
      The IBT and the improved IBT were highly specific and had an immunologic
      sensitivity of 5 x 10(3) colony-forming units per milliliter. The results for the
      2 methods agreed in the 130 milk samples tested. However, the IBT required 158
      min, whereas the improved IBT required only 110 min. In addition, the improved
      IBT used smaller quantities of antibodies and conjugates.

PMID- 12418786
TI  - Bovine and rabbit models for the study of a Staphylococcus aureus avirulent
      mutant strain, RC122.
AB  - Staphylococcus aureus is the main etiological agent of bovine mastitis.
      Intramammary infections are difficult to cure and vaccination appears to be an
      alternative to prevent the disease. Research has focused on the development of
      mutants affected in the synthesis of pathogenicity determinants. We constructed a
      mutant strain (RC122) after chemical mutagenesis. In a mouse model, the strain
      was shown to be 1500 times less virulent, showed similar kinetics of
      disappearance in the kidney as its parental strain, and a good degree of
      protection against a challenge from homologous and heterologous strains. The
      objective of the present report was to study the avirulent RC122 S. aureus mutant
      strain in rabbit and bovine infection models. The results clearly show that RC122
      was less virulent than its parental strain in a rabbit skin model, and was also
      correlated with its avirulence as an udder pathogen. These traits make the RC122
      mutant strain interesting as a potential strain for an experimental vaccine trial
      in dairy herds.

PMID- 12418787
TI  - Failure to detect abnormal prion protein and scrapie-associated fibrils 6 wk
      after intracerebral inoculation of genetically susceptible sheep with scrapie
      agent.
AB  - Detection of the scrapie-associated protease-resistant prion protein (PrPres) in
      sheep brains in the early phase after intracerebral inoculation of the scrapie
      agent has not been documented. Fourteen 4-mo-old, genetically susceptible lambs
      (QQ homozygous at codon 171 of the PrP gene) were obtained for this study. Twelve
      lambs were inoculated intracerebrally with a brain suspension from sheep
      naturally affected with scrapie, and 2 served as uninoculated controls. Two
      inoculated animals were euthanized at each of 6 times postinoculation (1 h to 6
      wk), and their brains were collected for histopathological study, for detection
      of PrPres by the Western blot technique and an immunohistochemical (IHC) method,
      and for the detection of scrapie-associated fibrils (SAF) by negatively stained
      electron microscopy (EM). Microscopic lesions associated with introduction of the
      inoculum were seen in the brains of inoculated animals at all 6 times. However,
      both the Western blot and IHC techniques did not detect PrPres after the initial
      3 d postinoculation, nor did EM detect SAF in any of the samples. From these
      findings, it is presumed that until host amplification has occurred, the
      concentration of PrPres in inoculum is insufficient for detection by currently
      available techniques.

PMID- 12418788
TI  - Natural history and treatment of disabilities.

PMID- 12418789
TI  - Fluoxetine response in children with autistic spectrum disorders: correlation
      with familial major affective disorder and intellectual achievement.
AB  - One hundred and twenty-nine children, 2 to 8 years old, with idiopathic autistic
      spectrum disorder diagnosed by standard instruments (Childhood Austim Ratings
      Scale and Autism Diagnostic Observation Schedule) were treated with fluoxetine
      (0.15 to 0.5mg/kg) for 5 to 76 months (mean 32 to 36 months), with
      discontinuation trials. Response criteria are described. Family histories were
      obtained using the family history method in repeated interviews. Fluoxetine
      response, family history of major affective disorder, and unusual intellectual
      achievement, pretreatment language, and hyperlexia were used to define a coherent
      subgroup of autistic spectrum disorder. Statistical analyses were post hoc. Of
      the children, 22 (17%) had an excellent response, 67 (52%) good, and 40 (31%)
      fair/poor. Treatment age did not correlate with response. Fluoxetine response
      correlated robustly with familial major affective disorder and unusual
      intellectual achievement, and with hyperlexia in the child. Family history of
      bipolar disorder and of unusual intellectual achievement correlated strongly.
      Five children developed bipolar disorder during follow-up. Fluoxetine response,
      family history of major affective disorder (especially bipolar), unusual
      achievement, and hyperlexia in the children appear to define a homogeneous
      autistic subgroup. Bipolar disorder, unusual intellectual achievement, and
      autistic spectrum disorders cluster strongly in families and may share genetic
      determinants.

PMID- 12418790
TI  - Long-term safety and efficacy of continuous intrathecal baclofen.
AB  - Long-term continuous intrathecal baclofen (CITB) infusion is a treatment option
      used to manage otherwise intractable spasticity and is delivered via an
      implantable pump. The purpose of this single-center multidisciplinary review was
      to report on the long-term safety and efficacy of CITB in the treatment of 21
      children with intractable severe spasticity of cerebral origin. Nineteen
      recipients had spastic quadriplegia and two had spastic diplegia. Seven
      recipients had level IV severity on the Gross Motor Functional Classification
      System and 14 had level V. Median age at implantation was 12 years (range 4 to
      20). Fifteen recipients were male, 6 were female. Seventeen recipients were alive
      at the end of the follow-up period (31 to 78 months; mean 53, SD 4). The Ashworth
      scale showed a substantial decrease in spasticity in the upper and lower
      extremities at 6 months and at the most recent follow-up. The Gross Motor
      Function Measure and Pediatric Evaluation of Disability Inventory showed no
      functional change. Most treatment goals were at least partly achieved. Caregivers
      reported a reduction in use of oral medication for spasticity, and improvements
      in comfort, function, and ease of care. Caregiver satisfaction was high. During
      80 recipient-years of pump operation, 153 treatment-associated adverse events
      occurred: 27 of these were device-related. There were four deaths unrelated to
      CITE, including one from acute pancreatitis. Our findings might assist in
      establishing patient selection criteria and treatment goals, improving patient
      follow-up, and monitoring adverse events.

PMID- 12418791
TI  - Botulinum toxin treatment of spasticity in diplegic cerebral palsy: a randomized,
      double-blind, placebo-controlled, dose-ranging study.
AB  - This study evaluated the efficacy and safety of three doses of botulinum toxin A
      (BTX-A; Dysport) in 125 patients (mean age 5.2 years, SD 2; 54% male)with dynamic
      equinus spasticity during walking. Participants were randomized to receive
      Dysport (10, 20, or 30 units/kg) or placebo to the gastrocnemius muscle of both
      legs. Muscle length was calculated from electrogoniometric measurements and the
      change in the dynamic component of gastrocnemius shortening at four weeks was
      prospectively identified as the primary outcome measure. All treatment groups
      showed statistically significant decreases in dynamic component compared with
      placebo at 4 weeks. Mean improvement in dynamic component was most pronounced in
      the 20 units/kg group, being equivalent to an increase in dorsiflexion with the
      knee extended at 19 degrees, and was still present at 16 weeks. The safety
      profile of the toxin appears satisfactory.

PMID- 12418792
TI  - Correlation of SPECT with pathology and seizure outcome in children undergoing
      epilepsy surgery.
AB  - SPECT can be used to image regional cerebral blood flow (rCBF) and has been shown
      to help localize the seizure focus in partial epilepsies as part of the
      presurgical evaluation. Few studies have explored the possible relation between
      preoperative SPECT and underlying pathology, or any relation to postsurgical
      outcome. In this study preoperative ictal and interictal rCBF in relation to the
      histopathological diagnosis and outcome in a series of 35 children (24 females,
      11 males; mean age 9.6 years, age range 11 months to 18 years) who had undergone
      resective surgery for epilepsy were retrospectively evaluated. A correlation
      between ictal hyperperfusion and the underlying responsible pathology was shown,
      with a consistent ictal increase in perfusion in developmental pathologies and
      Rasmussen's encephalitis, and consistent interictal hypoperfusion in hippocampal
      sclerosis (HS). No rCBF study parameter appeared to relate to outcome but in the
      group with HS the best outcome was seen in those with localizing ictal rCBF. The
      varied group of pathologies from hemispherectomy had excellent outcome but the
      SPECT findings had little to contribute over the abnormalities detected on MRI.
      In conclusion, rCBF studies remain a useful presurgical investigation in children
      with partial epilepsy, especially where HS, cortical dysplasia, or inflammatory
      disease are the underlying pathology. However, rCBF studies add little to the
      investigation of children with seizures secondary to benign tumours or cerebral
      infarcts, or where hemispherectomy is the likely preferred surgical option.

PMID- 12418793
TI  - Adjustment in children with intractable epilepsy: importance of seizure duration
      and family factors.
AB  - Seventy-five families of children with intractable epilepsy but without a severe
      learning disability (mean age 7 years 1 month, SD 2 years 6 months; range 2 to 12
      years) who attended a regional paediatric neurology service, were surveyed. A
      postal questionnaire was used which included standardized measures of child and
      family adjustment; forty-eight families responded (64%; 31 males, 17 females).
      There was no significant difference between responders and non-responders in
      terms of age, sex, number of other chronic illnesses and disabilities, age at
      epilepsy diagnosis, seizure type, nor number of antiepileptic drugs currently
      prescribed (p > 0.05). The importance of including multidimensional measures of
      outcome was highlighted by the finding that epilepsy, pharmacological, and
      psychosocial factors were differentially associated with specific adjustment
      difficulties. Two factors appeared to be most pervasively implicated across a
      range of adjustment problems: frequency of rectal diazepam administration and
      family patterns of relating to each other (p < 0.05). It appeared that duration
      of seizures (as indicated by frequency of rectal diazepam administration), rather
      than the frequency of seizures per se, was more pernicious in terms of poor
      adjustment. Intrafamilial relations (degree of conflict/cohesion and soon) were
      not only associated with adjustment difficulties in the child, but also with the
      frequency of seizures themselves. Implications for psychological interventions in
      intractable epilepsy in childhood are highlighted.

PMID- 12418794
TI  - Cerebellar abnormalities in infants and toddlers with Williams syndrome.
AB  - One commonly observed neuroanatomical abnormality in adults with Williams
      syndrome is an enlarged cerebellum relative to a small cerebrum. Our study is the
      first to examine neuroanatomy in young children with Williams syndrome. Clinical
      brain MRI was examined in nine young children with Williams syndrome (mean age 21
      months, range 7 to 43 months) relative to nine age- and sex-matched normally
      developing control children (mean age 29 months, range 20 to 42 months), and two
      children with undiagnosed developmental disorders (6 and 41 months). Two
      neuroradiologists who were blinded to participant classification, hypotheses, and
      regions of interest for the study, sorted the brain scans into two groups on the
      basis of six neuroanatomical criteria. The raters placed more of the MR scans
      from children with Williams syndrome into a separate group when they analyzed
      features of the cerebellum, but not when they analyzed other brain regions. Based
      on their written comments, the raters focused on the large size of the cerebellum
      in the children with Williams syndrome. The results lead us to suggest that
      abnormal cerebellar enlargement is evident in those with Williams syndrome at an
      early age. Our results are discussed relative to the cognitive delays observed in
      Williams syndrome versus other disorders such as autism, leading us to suggest
      that the cerebellum may play a role in cognition.

PMID- 12418795
TI  - Fracture prevalence in Duchenne muscular dystrophy.
AB  - The objective of this study was to determine the prevalence, circumstances, and
      outcome of fractures in males with Duchenne muscular dystrophy (DMD) attending
      neuromuscular clinics. Three hundred and seventy-eight males (median age 12
      years, range 1 to 25 years) attending four neuromuscular centres were studied by
      case-note review supplemented by GP letter or by interview at the time of clinic
      attendance. Seventy-nine (20.9%) of these patients had experienced fractures.
      Forty-one percent of fractures were in patients aged 8 to 11 years and 48% in
      independently ambulant patients. Falling was the most common mechanism of
      fracture. Upper-limb fractures were most common in males using knee-ankle-foot
      orthoses (65%) while lower-limb fractures predominated in independently mobile
      and wheelchair dependent males (54% and 68% respectively). Twenty percent of
      ambulant males and 27% of those using orthoses lost mobility permanently as a
      result of the fracture. In a substantial proportion of males, the occurrence of a
      fracture had a significant impact on subsequent mobility.

PMID- 12418796
TI  - Performance of gesture in children with and without DCD: effects of sensory input
      modalities.
AB  - This study aimed to investigate the extent to which gesture performance depends
      on input modality and whether gestural development patterns differ in children
      with and without developmental coordination disorder (DCD). Therefore,
      development of limb gesture was studied in 140 children--105 control children (94
      males, 11 females) and in 35 children with DCD (29 males, six females) divided
      into three age bands: 5 to 6 years, 7 to 8 years, and 9 to 10 years. Transitive
      gestural skills were investigated through four input modalities: Imitation,
      Visual plus Tactile, Visual, and Verbal. Results indicate that limb gestural
      skills in normally developing children follow a progressive maturation pattern:
      Imitation, Visual plus Tactile, and visual routes appear to mature before the
      verbal route and appear to be available earlier to enable the child to perform a
      correct gesture. The performance of children with DCD throughout the four
      modalities suggested a general maturational delay. When gestures were required
      through the Verbal modality, there was a specific deficit in using sensory-motor
      information and in integrating it into a motor representation. In the Verbal
      modality, children with DCD performed consistently worse than their control peers
      and the difference in performance tended to increase rather than improve with
      age.

PMID- 12418797
TI  - Enlarged vestibular aqueduct in two male siblings.
AB  - This report describes the case history of two male siblings with sensorineural
      hearing loss and an enlarged vestibular aqueduct (EVA). Sibling 1 presented with
      a history of intermittent self-limiting ataxia and hearing loss at the age of 25
      months and sibling 2 presented with a similar history at the age of 18 months.
      MRI showed an enlarged endolymphatic duct and sac bilaterally in both children.
      Perchlorate discharge tests were positive in both infants leading to a diagnosis
      of Pendred syndrome. A number of conditions associated with EVA are discussed
      with a view to devising management strategies.

PMID- 12418798
TI  - Pitfalls in the diagnosis of glycine encephalopathy (non-ketotic
      hyperglycinemia).

PMID- 12418799
TI  - Third World adversity: African infant precocity and the role of environment.
AB  - The war against illiteracy has not been won. The number of illiterates approaches
      a billion. Most reside in Third World countries--former colonies--where they are
      caught in a poverty trap of disease, low agricultural production and
      environmental adversity requiring technology beyond their means. I argue against
      the commonly held view that this is mainly attributable to the four hundred years
      of traffic in men. According to the late K.O. Dike, middle men along the African
      coast barred foreign merchants from the hinterland, and because of this the
      social, political structure and sovereignty of the African states remained
      fundamentally unchanged during the period 1400-1807, whereas a few decades after
      colonisation the socio-political system collapsed and was replaced by a small
      rich elite and many poor, while resources were taken out of Africa. Present
      poverty and underdevelopment represent as great a challenge as the trade in
      slaves. As did the African Middle-Men of that time, African leaders now must
      unite in an ambitious and confident Pan-African Union demonstrating strength.
      Western countries should focus on reducing poverty and improving nutrition. This
      also makes terrorism and legal and illegal migration less likely. Education is
      important, but the West should not limit its effort to fighting illiteracy but
      should also support the establishment of institutions for higher education.
      Africa possessed optimal conditions and an enriched environment for human
      evolution. African Infant Precocity is a persistent example. The human brain,
      like other brains, consists 60% of poly-unsaturated fatty acids (Marine-Fat), the
      rest being water. A sufficient amount is required to secure optimal brain growth.
      It normalizes brain function, and prevents sudden cardiac and infant death, which
      have been increasing in Western societies. Humans are unique in having a mismatch
      between the need for brain food--marine fat--and our common high protein diet.
      Nowhere is the neglect of the brain greater than in pregnancy when protein is the
      only major nutrient considered. Declining levels of polyunsaturated fatty acids
      have been observed in human milk. Deficient intake could, if not corrected,
      gradually impair brain function as has been seen in animal experiments.

PMID- 12418800
TI  - Iron deficiency anaemia among children and pregnant women in the Arab Gulf
      countries: the need for action.
AB  - Anaemia, especially iron deficiency anaemia, has been considered one of the main
      public health problems in the Arab Gulf countries. This paper explores the
      magnitude of the problem and factors that contribute to the high prevalence of
      anaemia in these countries. The prevalence of iron deficiency anaemia among
      preschool children ranged from 20% to 67%, while that among school children
      ranged from 12.6% to 50%. The percentage of pregnant women who suffered from this
      anaemia ranged from 22.7% to 54%. Infant feeding practices, food habits,
      parasitic infection, parity, early age at marriage, and geographical location are
      among the most important factors associated with iron deficiency anaemia in this
      region. Programmes to prevent and control this anaemia, are urgently needed.

PMID- 12418801
TI  - Effect of probiotic fermentation on antinutrients and in vitro protein and starch
      digestibilities of indigenously developed RWGT food mixture.
AB  - Indigenously developed RWGT food mixture which contained rice flour, whey,
      sprouted green gram paste and tomato pulp (2:1:1:1 w/w) was autoclaved 1.5
      kg/cm2, 15 min, 121 degrees C), cooled and fermented with 2% liquid culture
      (containing 10(6) cells/ml broth). Two types of fermentations were carried out
      i.e. single culture fermentation [L. casei, L. plantarum (37 degrees C, 24 hr.)]
      and sequential culture fermentation [S. boulardii (25 degrees C, 24 hr.) + L.
      casei (37 degrees C, 24 hr.)]; S. boulardii [(25 degrees C, 24 hr.) + L.
      plantarum (37 degrees C, 24 hr.)]. All the fermentations drastically reduced the
      contents of phytic acid, polyphenols and trypsin inhibitor activity while
      significantly improving the in vitro digestibilities of starch and protein.
      Sequential culture fermentations brought about higher changes as compared to
      single culture fermentations.

PMID- 12418802
TI  - Physico-chemical and nutritional properties of cereal-pulse blends for bread
      making.
AB  - Supplementation of soy (full fat and defatted) and barley flours to wheat flour
      at 51 10, 15 and 20% levels were carried out to see their effect on physico
      chemical and nutritional properties of blends for bread making. The gluten
      content and sedimentation value of flour blends decreased and water absorption
      capacity increased with increase in the level of soybean and barley flour
      separately and in combinations to bread flour. All the blends at 20% levels were
      found nutritionally superior but breads prepared from them found organoleptically
      unacceptable. However, addition of 15% barley flour, 10% full fat soy flour, 10%
      defatted soy flour, 15% full fat soy flour + barley flour and 15% defatted soy
      flour + barley flour to wheat flour not only increased the total protein,
      glutelin (protein fraction), total lysine, dietary fibre and beta-glucan contents
      of cereal-pulse blends for bread making, but could also produce a product of
      acceptable quality.

PMID- 12418803
TI  - Prediction of nutritional status by chemical analysis of urine and anthropometric
      methods.
AB  - A combination of anthropometric and chemical indices was used to investigate the
      nutritional status of 26 healthy (H) and kwashiorkor (K) children aged 2-5 years
      and possibly predict the onset of malnutrition. The healthy children had
      significantly (p>0.05) higher values for weight, height, middle upper arm
      circumference and weight/height ratio than kwashiorkor children. The healthy
      children had significantly higher urinary concentrations of urea, inorganic
      sulphate and sulphate relative to creatinine, but significantly lower thiocyanate
      and thiocyanate relative to creatinine than the kwashiorkor children. The results
      of the present study would tend to indicate that a chemical analysis especially
      of urea, inorganic sulphate or thiocyanate alone or the urea/creatinine,
      inorganic sulphate/creatinine or thiocynate/creatinine ratio could be used to
      predict malnutrition after the initial anthropometric measurements. This study
      should however be repeated with a large population of volunteers to determine the
      specific cut-off points for each anthropometric and chemical analysis.

PMID- 12418804
TI  - Inter-relationships between lifestyle and diabetes mellitus, overweight/obesity
      and hypertension in Nigeria.
AB  - This study of inter-relationship between life styles and diabetes mellitus,
      overweight/obesity and hypertension was carried out to determine the life styles
      of the bank workers and the nutritional related diseases. A total sample of 570
      was systematically drawn from workers of the United Bank for Africa Plc in Lagos
      for this study, with the following results. Not surprisingly the level of
      education influenced life style (P<0.05). There was also a statistically
      significant relationship between life style and the consumption of alcohol and
      diabetes, but no relationship was found between smoking and diabetes. There was a
      significant correlation with their consumption of fatty foods and vegetables. A
      relationship between increased protein intake and an increase in educational
      status (P<0.05) was found. There was association between obesity and hypertension
      (P<0.05), and between increase in frequency of clinic visitation and hypertension
      which was statistically significant (Chi square P<.05).

PMID- 12418805
TI  - The relationship between dietary habits and body-mass index using the Federal
      Airport Authority of Nigeria as the sample.
AB  - This was a cross sectional survey of selected sample of staff of the Federal
      Airport Authority of Nigeria, Lagos, conducted in July to August, 2000. Feeding
      patterns observed among the sampled population showed that most (74.4%) ate three
      meals while 11.2% ate more than three meals daily. However, lunch was the most
      common meal eaten away from home by most (59.0%) of the respondents. Most of the
      respondents were observed to substitute snacks for their lunch (84.3%). Their
      food consumption pattern revealed that 23.2% consumed cereals daily while only
      5.6% of the respondents consumed fruits and only 10.9% affirmed to consuming
      vegetables daily. Consumption pattern of other foods revealed that 15.6% consumed
      dairy products daily, meat/fish was daily consumed by only 16.2% and only 10.0%
      consumed fats and oils daily in the meals. Gender was also observed to influence
      feeding patterns of the sampled population studied. Most of the men consumed more
      meals per day than females. Only 46.4% of all the respondents had BMI values
      within normal acceptable range. Most of the respondents that were underweight
      were men (91.4%). Blood pressure measurements revealed that most of them had
      normal systolic (78.3%) and diastolic blood pressure (81.8%). Though 3.9% had
      severely high systolic blood pressure and 0.7% had severely high diastolic blood
      pressure. Only 20.5% of the study population had acceptable blood cholesterol
      levels of which only 61.1% had BMI values within the normal acceptable range.
      Only 0.8% of the study population had very high blood cholesterol levels with
      majority of the population 72.7% on the borderline. It is recommended that health
      and nutrition education be mounted and that periodic anthropometric measurements
      be used to evaluate the risk of some non-communicable diseases.

PMID- 12418806
TI  - Anthropometric measurements of infants and under five children in Riyadh City.
AB  - The data presented in this paper are part of the ongoing pediatric nutrition
      surveillance in ten primary health centers from Riyadh City. A total of 21,507
      infants and children under five were included. The mean birth weight was 3027 g,
      and 8.6% of the children had low birth weights. The measurements showed that
      there had been no obvious change in the weights and heights of children during
      the past 13 years. In our results the children classified as moderate and
      severely underweight were 4.5% and 0.8% respectively. The data showed the average
      growth of all infants, regardless of feeding pattern, was same or faster than the
      NCHS reference population, up to approximately six months of age after which
      their growth became slower than that of the NCHS standards. The prevalence of
      malnutrition in Saudi Arabia is moderately high, in spite of the high per capita
      income, and the fact that the government subsidizes locally produced and imported
      food items. The malnutrition among this age group may be attributed to
      reproductive or social behavior and genetic factors. The reduction of
      malnutrition in the last ten years could be largely due to the nutrition and
      health education programs. There is a need for more comprehensive nutritional
      health education among the local population.

PMID- 12418807
TI  - Nutritional status assessment of pregnant women from Hisar city of Haryana.

PMID- 12418808
TI  - Snack Shack or snack shock?

PMID- 12418809
TI  - Trichodinid ectoparasites (Ciliophora: Peritrichia) of freshwater fishes of the
      family Anabantidae from the Okavango River and Delta (Botswana).
AB  - During parasitological surveys in the Okavango Delta and Panhandle in Botswana,
      two species of climbing perches belonging to the family Anabantidae were
      investigated for ectoparasites. The fishes were the blackspot climbing perch,
      Microctenopoma intermedium (Pellegrin) and the manyspined climbing perch,
      Ctenopoma multispine Peters. Five trichodinid species were found from the skin,
      fins and gills of these anabantids. One is a known species, i.e., Trichodina
      microspina Van As et Basson, 1992, for which a comparative description is
      provided. Four other species are described as new species using silver
      impregnation, i.e., Trichodina labyrinthipiscis sp. n., Trichodina anabantidarum
      sp. n., Tripartiella microctenopomae sp. n., and Tripartiella ctenopomae sp. n.

PMID- 12418810
TI  - The role of blood vessels and lungs in the dissemination of Naegleria fowleri
      following intranasal inoculation in mice.
AB  - Primary amoebic meningoencephalitis (PAM) was induced in mice by intranasal
      inoculation of Naegleria fowleri (Singh et Das, 1970) to study the role of the
      blood vessels and lungs in the early and later stages in this disease. Upon
      culturing blood and lung tissue obtained at 24-, 36-, 48-, 72-, 96-, and 120-hour
      time periods, it was found that amoebae grew only from blood and lung tissue
      obtained at the 96 and 120 hour time periods. Paraffin sections of the head
      revealed small foci of acute inflammation and amoebae within the olfactory bulb
      of the central nervous system (CNS) at 24 hours. Amoebae were not observed within
      blood vessels of the CNS until 96 and 120 hours. Also, amoebae were observed
      within the connective tissue surrounding blood vessels and sutures of the skull,
      bone marrow, and venous sinusoids between the skull bone tables at 96 and 120
      hours. No amoebae or acute inflammatory reactions were observed in the lung
      sections from any time period and indirect immunofluorescence microscopy was
      negative for N. fowleri. This study provides evidence that neither blood vessels
      nor lungs provide routes for N. fowleri to the CNS during the early stages of PAM
      and that amoebae enter veins of the CNS and bone marrow during later stages of
      the disease.

PMID- 12418811
TI  - Survey of actinosporean types (Myxozoa) belonging to seven collective groups
      found in a freshwater salmon farm in Northern Scotland.
AB  - A study of the actinosporean fauna of oligochaetes from a freshwater salmon farm
      in Northern Scotland was carried out from October 1996 to August 1998. Following
      the examination of 28,387 oligochaete worms belonging to the families
      Tubificidae, Lumbriculidae, Naididae and Enchytraeidae, five types of
      echinactinomyxon (four previously described), six types of raabeia (five
      previously described), three types of synactinomyxon (all previously described),
      four types of aurantiactinomyxon (three previously undescribed), one type of
      triactinomyxon (previously described), one type of neoactinomyxum (previously
      undescribed) and one type of siedleckiella (previously undescribed) were
      identified. The triactinomyxon type was released from unidentified immature
      oligochaetes. Of the twenty-one types of actinosporeans found, thirteen types
      were released from Tubifex tubifex (Muller), three types were released from
      Lumbriculus variegatus (Muller), three types from both L variegatus and T.
      tubifex and two types from immature oligochaetes.

PMID- 12418812
TI  - External morphological differences between Crepidostomum farionis and
      Crepidostomum metoecus (Trematoda: Allocreadiidae), parasites of salmonids, as
      revealed by SEM.
AB  - Scanning electron microscopy examinations of trematode specimens belonging to
      Crepidostomum farionis (O.F. Muller, 1784) and C. metoecus Braun, 1900, collected
      from brown trout, Salmo trutta fario L., in the Czech Republic, made it possible
      to study their surface morphology including details not described previously. The
      tegument of both species bears numerous characteristic papillae around the oral
      sucker (in C. metoecus also around the ventral sucker) and the ventral and dorsal
      surfaces of the forebody, exhibiting a high degree of variability in numbers and
      arrangement, with tegumental bosses forming lateral fields on the forebody and
      minute sensory receptors with submerged cilia scattered on the surface of the
      dorsal part of the oral sucker. In addition to marked differences in the size,
      shape and position of the oral muscular lobes, both species distinctly differ in
      the number of genital pores: two separate pores in C. farionis and a single pore
      in C. metoecus.

PMID- 12418813
TI  - Gibsonnema nom. n., a new name for the nematode genus Paraseuratoides moravec,
      Salgado-Maldonado et Aguilar-Aguilar, 2002.

PMID- 12418814
TI  - Lasiotocus lizae sp. n. (Digenea: Monorchiidae), a new trematode from marine fish
      in the Taiwan Straits, China.
AB  - Lasiotocus lizae sp. n. (Digenea: Monorchiidae) was collected from the intestine
      of Liza carinata (Valenciennes) (Mugilidae, Perciformes) in the Taiwan Straits,
      China. L. lizae is most similar to Lasiotocus glebulentus Overstreet, 1971 from
      the intestine of Mugil cephalus from the Northern Gulf of Mexico in having
      tightly compacted vitellaria, a genital pore sinistral to the midline, the ovary
      usually dextral to the acetabulum, the similar sucker ratio, and in the presence
      of both a canalicular and uterine seminal receptacle. It differs from L
      glebulentus in its cirrus sac ending anterior to rather than posterior to
      acetabulum, in the ending position of caeca, in smaller eggs, and in having a
      single rather than several conspicuous concretions in excretory vesicle.

PMID- 12418815
TI  - Some specific and non-specific phosphatases of the sporocyst of Fasciola
      hepatica. II. Enzymes associated with the membrane transport.
AB  - Using histochemical and cytophotometric methods, enzymes responsible for the
      membrane transport (alkaline phosphatase, adenosine triphosphatase, and 5
      nucleotidase) in the developing sporocyst of Fasciola hepatica (L., 1758) were
      studied. The most active metabolism occurred in the germ balls of sporocysts on
      the 8th and 15th days of development, which is associated with intensive
      proliferation and subsequently differentiation of embryos within the germ balls.

PMID- 12418816
TI  - A new atractid nematode, Atractis vidali sp. n. (Nematoda: Atractidae), from
      cichlid fishes in southern Mexico.
AB  - A new nematode species, Atractis vidali sp. n., is described from the intestine
      of cichlid fishes, Vieja intermedia (Gunther) (type host) and Cichlasoma pearsei
      (Hubbs), from specimens collected in three localities in the Mexican states of
      Campeche (Santa Gertrudis Creek) and Chiapas (Cedros and Lacanja Rivers). It
      differs from the only other atractid species reported in fishes of Mexico,
      Atractis bravoae, mainly in possessing two very unequal spicules. In contrast to
      the 10 species parasitising amphibians and reptiles in America, the new species
      has a longer body, spicules and a gubernaculum, and a different distribution of
      the caudal papillae. This is the second species of the genus Atractis recorded
      from freshwater fishes.

PMID- 12418817
TI  - Post-embryonic development of Camallanus cotti (Nematoda: Camallanidae), with
      emphasis on growth of some taxonomically important somatic characters.
AB  - In this paper, the quantitative post-embryonic development of the Asian
      freshwater fish nematode Camallanus cotti Fujita, 1927, is described. Larval and
      adult morphometrics were obtained by following the parasite's life cycle
      experimentally using copepods Macrocyclops albidus (Jurine) as intermediate host
      and guppies Poecilia reticulata (Peters), southern platyfish Xiphophorus
      maculatus (Gunther) and paradise fish Macropodus opercularis (L.) as definitive
      host. Additionally, adult worms were obtained from heavily infected paradise fish
      imported from Singapore. It is suggested that the gradual change in proportions
      of the worm's somatic body parts reflects the specific ecological role of each
      developmental stage. The free-living infective first-stage larva seems to be
      adapted for transmission, as indicated by its relatively long tail, designed to
      generate host-attracting movements, and its non-functional intestine. The second-
      and third-stage larvae from the copepod intermediate host seem mainly to invest
      in trophic functionality, i.e., the development of the buccal capsule and the
      oesophagus, which are crucial structures for the worm's successful establishment
      in the definitive fish host. Once in the fish intestine, the larvae enter a
      period of considerable growth. After the fourth (i.e., last) moult, a 72%
      increase in average female body length occurs. This is accompanied by doubling
      the average vulva-tail tip distance and the average tail length. The length of
      the female hind body expands in an accelerating allometric fashion, and seems to
      be closely linked to the posterior-wards expansion of the uterus. In the males
      however, growth seems to cease after the final moult. We conclude that female
      post-maturational body size, but especially the length of the hind body and the
      tail, are closely related to reproductive state, i.e., the developmental stage of
      the offspring in the uterus, and, probably, the worms' age. Any future
      taxonomical studies of camallanids in general, and C. cotti in particular, should
      thus be aware of the reproductive state of the females used.

PMID- 12418818
TI  - The enzymes of glycogen and trehalose catabolism from Hysterothylacium aduncum
      (Nematoda: Anisakidae).
AB  - The activity of alpha-amylase, glucoamylase, maltase, trehalase, glycogen
      phosphorylase and trehalose phosphorylase was measured in extracts from larval
      and adult Hysterothylacium aduncum (Rudolphi, 1802), parasitic nematode of marine
      fish. The content of glycogen and trehalose in the worm's body was also
      determined. Both the hydrolytic and phosphorolytic paths of sugar decomposition
      are present in H. aduncum. In the larvae glycogen was utilised mainly via the
      hydrolytic path. In the adults the activities of phosphorolytic enzymes were
      higher than in the larvae. In both stages the activity of trehalose phosphorylase
      is present. In adult nematodes it is uncommonly high. The dominating sugars in
      the adults were glucose and glycogen, while in the larvae it was trehalose.

PMID- 12418819
TI  - Experimental study on pathogenic potential of six Acanthamoeba strains isolated
      from fish.

PMID- 12418821
TI  - A prophylactically implanted cardioverter defibrillator reduced all-cause
      mortality in myocardial infarction.

PMID- 12418820
TI  - Intestinal helminths of Italian barbel, Barbus tyberinus (Cypriniformes:
      Cyprinidae), from the Tiber River and first report of Acanthocephalus clavula
      (Acanthocephala) in the genus Barbus.

PMID- 12418822
TI  - Cardiac resynchronization was effective for moderate-to-severe heart failure with
      intraventricular conduction delay.

PMID- 12418823
TI  - Nicorandil reduced coronary events in stable angina.

PMID- 12418824
TI  - Epidural anesthesia and analgesia did not reduce most comorbid outcomes in high
      risk patients having major abdominal surgery.

PMID- 12418825
TI  - Review: oral glycoprotein IIb/IIIa inhibitors increase mortality and myocardial
      infarction.

PMID- 12418826
TI  - Losartan reduced strokes and new-onset diabetes more than atenolol in essential
      hypertension.

PMID- 12418827
TI  - Losartan reduced cardiovascular morbidity and mortality more than atenolol in
      patients with diabetes and essential hypertension.

PMID- 12418828
TI  - Review: metformin does not increase fatal or nonfatal lactic acidosis or blood
      lactate levels in type 2 diabetes mellitus.

PMID- 12418829
TI  - A split regimen of regular insulin at dinner and NPH insulin at bedtime reduced
      nocturnal hypoglycemia in type 1 diabetes.

PMID- 12418830
TI  - Review: advice on low-fat diets is not better than other weight-reducing diets
      for sustaining weight loss in obesity.

PMID- 12418831
TI  - Review: infliximab increases response and remission rates in fistulizing or
      treatment-resistant Crohn disease.

PMID- 12418832
TI  - Maintenance infliximab delayed loss of response in active Crohn disease.

PMID- 12418833
TI  - Review: Somatostatin analogues reduce blood products used in acute bleeding
      esophageal varices but do not reduce mortality.

PMID- 12418834
TI  - Review: antibiotic prophylaxis reduces mortality and bacterial infection in
      cirrhosis and gastrointestinal bleeding.

PMID- 12418835
TI  - Review: probiotics are effective in preventing antibiotic-associated diarrhea.

PMID- 12418837
TI  - Review: oral antifungal drugs promote cure of fungal foot infections.

PMID- 12418836
TI  - Review: Lactobacillus is safe and effective for treating children with acute
      infectious diarrhea.

PMID- 12418838
TI  - Review: antifungal agents do not reduce mortality in neutropenia caused by
      chemotherapy or bone marrow transplantation.

PMID- 12418839
TI  - Review: organizational change and patient involvement may increase the use of
      prevention cancer screening services.

PMID- 12418840
TI  - Review: screening for depression reduces persistent depression.

PMID- 12418841
TI  - Review: venlafaxine is more effective than selective serotonin-reuptake
      inhibitors for depression.

PMID- 12418842
TI  - Galantamine improved cognition and global functioning in vascular dementia or
      Alzheimer disease with cerebrovascular disease.

PMID- 12418844
TI  - Review: cardioselective beta-blockers did not reduce respiratory function in
      chronic obstructive pulmonary disease.

PMID- 12418843
TI  - Review: several drugs, especially triptans, are effective for pain relief in
      acute migraine.

PMID- 12418845
TI  - Effects of hormone therapy on quality of life in postmenopausal women with CAD
      differed according to menopausal symptoms.

PMID- 12418846
TI  - Review: lack of evidence exists for effectiveness of over-the-counter cough
      preparations for children with URTI.

PMID- 12418847
TI  - Oral dexamethasone improved respiratory distress in children < 2 years of age
      with acute bronchiolitis.

PMID- 12418848
TI  - Ibuprofen was more protective against asthma morbidity than acetaminophen in
      asthmatic children with fever.

PMID- 12418849
TI  - Review: aerobic exercise reduces systolic and diastolic blood pressure in adults.

PMID- 12418850
TI  - Review: magnetic resonance angiography is accurate for detecting high-grade
      carotid artery stenosis that is suitable for surgery.

PMID- 12418852
TI  - Ultrasonography plus radiography was as effective as intravenous urography for
      detecting abnormalities in men with proven UTI.

PMID- 12418851
TI  - Magnetic resonance angiography had high specificity but moderate sensitivity for
      detecting pulmonary emboli.

PMID- 12418853
TI  - Children's drawings of headache pain were accurate for diagnosing migraine.

PMID- 12418854
TI  - Predictors of poor outcome in acute stroke included dependence before stroke,
      severe hemiparesis, and recurrent stroke.

PMID- 12418855
TI  - Review: one tenth of patients with Crohn disease have prolonged remission.

PMID- 12418856
TI  - Delayed prescription reduced antibiotic use in the common cold.

PMID- 12418857
TI  - Arterial blood lactate measurements quickly identified risk for death from
      paracetamol-induced liver failure.

PMID- 12418858
TI  - Incorporating economic analysis into clinical practice guidelines: a guide for
      users.

PMID- 12418859
TI  - Dysinosin A: a novel inhibitor of Factor VIIa and thrombin from a new genus and
      species of Australian sponge of the family Dysideidae.
AB  - A new marine natural product dysinosin A 1 has been isolated from a new genus and
      species of sponge of the family Dysideidae found near Lizard Island, North
      Queensland, Australia. Dysinosin A is a potent inhibitor of the blood coagulation
      cascade factor VIIa and an inhibitor of the serine protease thrombin. Among the
      distinctive features of dysinosin A are the presence of a 5,6-dihydroxy
      octahydroindole-2-carboxylic acid, 3-amino-ethyl 1-N-amidino-Delta-3-pyrroline, a
      sulfated glyceric acid, and d-leucine, assembled through three peptidic linkages.
      Dysinosin A inhibited factor VIIa at a Ki of 108 nM and thrombin at a Ki of 452
      nM. The identification of the 1-N-amidino-Delta-3-pyrroline and 5,6-dihydroxy
      octahydroindole-2-carboxylic acid as P1 and P2 moieties respectively, should pave
      the way for the design and synthesis of new structure-based inhibitors.

PMID- 12418860
TI  - Total synthesis and structural confirmation of the marine natural product
      Dysinosin A: a novel inhibitor of thrombin and Factor VIIa.
AB  - The structure and absolute configuration of the marine antithrombotic product
      dysinosin A was confirmed by total synthesis. The strategy involved
      disconnections to three subunits, of which two were synthesized from the readily
      available l-glutamic acid, d-leucine, and d-mannitol. The Grubbs olefin
      metathesis carbocyclization reaction was utilized to prepare two intermediates.

PMID- 12418861
TI  - Separate-local-field NMR spectroscopy on half-integer quadrupolar nuclei.
AB  - New approaches to the characterization of resonances in the solid-state NMR
      spectroscopy of half-integer quadrupolar nuclei are explored, on the basis of the
      acquisition of heteronuclear separate-local-field spectra on rotating solids. In
      their two-dimensional version, these experiments correlate for each chemical site
      a second-order quadrupolar MAS powder pattern with the dipolar MAS sideband
      pattern to nearby heteronuclei. As 3D NMR sequences, such 2D anisotropic
      correlation spectra become separated for inequivalent chemical sites along a
      third, isotropic dimension. Extending in such manner separate-local-field NMR
      approaches to quadrupoles facilitates the assignment of inequivalent resonances
      to specific structural environments, and provides new tools for the investigation
      of dynamics in solids. Details about these 2D and 3D NMR experiments are given,
      and their application is illustrated with 1H-23Na recoupling experiments on
      mononucleotides possessing multiple bound cations.

PMID- 12418862
TI  - Macrocyclic aromatic ether-imide-sulfones: versatile supramolecular receptors
      with extreme thermochemical and oxidative stability.
AB  - Macrocyclic receptors having extreme thermo-oxidative stability, and which bind a
      wide range of electron-donor substrates via pi-stacking donor-acceptor
      interactions, are accessible by cycloimidization of an amine-functionalized aryl
      ether-sulfone with pyromellitic dianhydride or 1,4,5,8-naphthalenetetracarboxylic
      dianhydride. The potential of these receptors in supramolecular chemistry is
      illustrated, for example, by the spontaneous self-assembly and crystallization of
      a five-component [3]pseudorotaxane from a solution of its constituents.

PMID- 12418863
TI  - Pseudotetrahedral polyhaloadamantanes as chirality probes: synthesis, separation,
      and absolute configuration.
AB  - Pseudotetrahedral, conformationally as well as configurationally stable 1-bromo-3
      chloro-5-fluoro- (4) and 1-bromo-3-chloro-5-fluoro-7-iodoadamantane (5) (and some
      related compounds) were prepared by our recently devised phase-transfer catalytic
      halogenation protocol; the optical antipodes of 4 were separated by HPLC on
      chiral phase in ee > 99%, and the absolute configurations were assigned by
      matching observed and computed circular dichroism spectra. Structure 5 is the
      first chiral aliphatic hydrocarbon containing all stable (nonradioactive)
      halogens; its structure was proven by NMR spectroscopy and by X-ray crystal data.
      We emphasize that the combination of experiment and theory is very powerful in
      assigning absolute configurations even for molecules without typical chromophors,
      with small values for the optical rotation, and without an atom at the
      stereogenic center.

PMID- 12418864
TI  - The first structural and spectroscopic characterization of a neptunyl
      polyoxometalate complex.
AB  - The reaction between PW9O349- and NpO2+ has yielded the first structurally
      characterized neptunyl(V) polyoxometalate complex, [Na2(NpO2)2(A-PW9O34)2]14-.
      This complex is isostructural with the uranyl(VI) analogue, and there is also
      spectroscopic evidence for its existence in solution. The complex is readily
      extracted into toluene, and this may have significance in the sequestering and/or
      separation of the neptunyl ion in terms of nuclear waste management.

PMID- 12418865
TI  - High-affinity mu opioid receptor ligands discovered by the screening of an
      exhaustively stereodiversified library of 1,5-enediols.
AB  - In this communication, we report the synthesis of an exhaustively
      stereodiversified library of 16 1,5-enediols (2) and the screening of these
      compounds for mu opioid receptor (MOR) binding. The stereochemical configuration
      of 2 strongly impacted the binding affinity, and (S,S,S,R)-2 exhibited a Ki of
      8.8 nM for MOR, comparable to that of endomorphin-2 (Ki = 1.2 nM). Moreover,
      compounds 2 exhibited 5-86-fold selectivity for MOR over delta opioid receptor
      (DOR) and 16-150-fold selectivity for MOR over kappa opioid receptor (KOR).
      Additionally, analogues of 2 were synthesized which showed the importance of the
      trans olefin for receptor binding but that modifications of the C-terminal amino
      acid were well tolerated. Ligand 11 is noteworthy because it retains only one of
      the amide bonds present in 1, but binds MOR with an affinity of 10 nM and 110-
      and 600-fold selectivity for MOR over DOR and KOR. These results demonstrate the
      utility of stereochemical diversity in the discovery of bioactive small
      molecules.

PMID- 12418866
TI  - Packings of uniform microspheres with ordered macropores fabricated by double
      templating.
AB  - Highly uniform 3-D ordered macroporous spheres in regular arrays were produced by
      a double templating process. The first template of larger silica balls produced
      the polymer skeleton for guiding the shape and size of the self-assembled
      superstructure of smaller polymeric balls, which are introduced subsequently into
      the internal space of the skeleton. The second templating with inorganic
      precursors has created novel superstructured materials, which could open up
      significant opportunities in a variety of areas ranging from absorbents/catalysts
      to novel photonic crystals.

PMID- 12418867
TI  - Palladium-catalyzed asymmetric phosphination: enantioselective synthesis of a p
      chirogenic phosphine.
AB  - The racemic secondary phosphine PH(Me)(Is) (1, Is = 2,4,6-(i-Pr)3C6H2) was
      coupled with PhI in the presence of NaOSiMe3 and the catalyst Pd((R,R)-Me
      Duphos)(Ph)(I) (3) to give P(Ph)(Me)(Is) (2) in up to 78% ee. The intermediate
      phosphido complex Pd((R,R)-Me-Duphos)(Ph)(P(Me)(Is)) (5a,b) was observed as a
      mixture of diastereomers by low-temperature 31P NMR. The rate of interconversion
      of 5a,b by phosphorus inversion is greater than or equal to that of reductive
      elimination, which suggests that the enantiodetermining step occurs after Pd-P
      bond formation.

PMID- 12418868
TI  - Controlled fabrication of cross-linked nanoparticles/polymer composite thin films
      through the combined use of surface-initiated atom transfer radical
      polymerization and gas/solid reaction.
AB  - A promising strategy for the controlled synthesis of inorganic/polymeric
      nanocomposites may be sustained by fabricating cross-linked PbS
      nanoparticles/polymer composite thin films through combining surface-initiated
      atom transfer radical polymerization (ATRP) and gas/solid reaction. The
      introduction of Pb ions through the extension of surface-initiated ATRP to the
      monomers containing metal ions provides an opportunity for generating
      nanoparticles on the substrate.

PMID- 12418869
TI  - Efficient mixing and reactions within microfluidic channels using microbead
      supported catalysts.
AB  - A strategy for efficiently mixing solutions and carrying out multistep catalytic
      reactions in microfluidic systems is described. The approach involves
      immobilizing catalysts on microbeads, placing the beads into well-defined
      microreactor zones, and then passing reactants through one or more of the reactor
      zones to yield products. The catalyst-modified beads effectively mix reactants
      and increase the effective surface area of the channel interior, both of which
      improve reaction velocities compared to open channels. This approach is
      demonstrated using two sequential reactions catalyzed by glucose oxidase and
      horseradish peroxidase. In addition to providing a general route to chemical
      synthesis within microfluidic systems, this design strategy may also be
      applicable to modeling reaction pathways within cells and to bio/chemical sensing
      applications.

PMID- 12418870
TI  - Efficient cu-catalyzed asymmetric conjugate additions of alkylzincs to
      trisubstituted cyclic enones.
AB  - The first examples of efficient catalytic asymmetric conjugate addition (ACA) of
      alkylzincs to trisubstituted cyclic enones is disclosed. These Cu-catalyzed
      reactions proceed efficiently with five- and seven-membered ring substrates to
      afford the desired products in >/=95% ee. Intermediate enolates can be trapped
      with alkyl halides to generate a quaternary stereogenic center. The requisite
      chiral ligand is prepared from commercially available materials and can be used
      in situ without further purification in the presence of commercial grade
      (CuOTf)2.PhMe.

PMID- 12418871
TI  - Large substituent effect on the photochemical rearrangement of 1,6-(N-Aryl)aza
      [60]fulleroids to 1,2-(N-Arylaziridino)-[60]fullerenes.
AB  - Large substituent effects were observed in the rates and reaction mechanisms of
      the photochemical rearrangement of N-arylaza-[60]fulleroid 1 to N-arylaziridino
      [60]fullerene 2, in which the difference of the rates between the fastest and the
      slowest (>2160-fold) was attained only by changing the aryl group from 1-naphthyl
      to 2-naphthyl. The decreasing order of the reaction rates in relation to the
      substituents was 1-naphthyl (1b) > 1-pyrenyl (1d) > phenyl (1a) > 2-naphthyl
      (1c). The reactions proceeded via triplet states of the fulleroids and a triplet
      sensitization of the reaction by rearranged product 2b was observed in the case
      of 1b. The slow reactions of 1a,c were interpretated by the participation of
      charge-separated species in the excited triplet states, which was supported by
      nanosecond transient absorption spectra.

PMID- 12418872
TI  - Organization of microcrystals on glass by adenine-thymine hydrogen bonding.
AB  - Shaking of adenine-tethering glass plates in an aqueous suspension of micrometer
      sized, thymine-tethering zeolite crystals such as ZSM-5 (0.6 mum x 1.7 mum x 2.5
      mum) or zeolite-A (1.7 mum x 1.7 mum x 1.7 mum) for 3 h at room temperature leads
      to facile assembly of monolayers of the zeolite microcrystals on the glass plates
      through the hydrogen-bonding interaction between the tethered adenine and
      thymine. Control experiments show that the presence of adenine and thymine on the
      respective solid surface is essential for the monolayer assembly. This
      establishes that even the micrometer-sized building blocks can be organized by a
      large number of well-defined weak hydrogen bonding. Increase in the assembly
      temperature to annealing temperatures leads to a marked increase in the rate of
      monolayer assembly and in the size of the domain in which zeolite crystals are
      closely packed in the same three-dimensional orientation.

PMID- 12418873
TI  - Site chirality as a messenger in chain-end stereocontrolled propene
      polymerization.
AB  - The origin of stereoselectivity in the chain-end controlled syndiospecific
      polymerization of propene with octahedral Ti-catalysts is unclear. We present a
      possible mechanism which is based on the site chirality as a messenger of
      information between the chirality of the chain-end and the chirality of monomer
      insertion which can operate for secondary propagation. This mechanism could be
      operative also for the industrially relevant V-based homogeneous catalysts.

PMID- 12418874
TI  - Imaging as-grown [60]fullerene nanotubes by template technique.
AB  - In this contribution we have developed a useful and experimentally easy way to
      use C60 powder to directly fabricate C60 nanotubes with a mondisperse size
      distribution and uniform orientation. The structure of C60 nanotubes was
      confirmed by SEM, TEM, and FT-IR.

PMID- 12418875
TI  - C-C bond formation via C-H bond activation: catalytic arylation and alkenylation
      of alkane segments.
AB  - A new system for catalytic arylation and alkenylation of alkane segments has been
      developed. The ortho-tert-butylaniline substrates and 2-pivaloylpyridine may be
      arylated and alkenylated at the tert-butyl group, while no functionalization
      occurred at more reactive C-H and other bonds. Arylation and alkenylation of
      these substrates are achieved in the presence of Ph2Si(OH)Me and Ph-CH=CH
      Si(OH)Me2, respectively, and the catalytic amount of Pd(OAc)2 and stoichiometric
      oxidant (Cu(OAc)2, 2 equiv) in DMF. In contrast, the ortho-i-propylaniline
      substrate underwent cyclopalladation, but no arylation product was obtained.
      Complex compound 14 was synthesized via tandem arylation-alkenylation of tert
      butylaniline 11. We hypothesize that the high selectivity of this system stems
      from the confluence of directing effect of the Schiff base or pyridine moiety and
      unique reactivity properties of a phenyl-palladium acetate species (Ph-Pd
      OAc.Ln).

PMID- 12418877
TI  - Detecting ligand binding to a small RNA target via saturation transfer difference
      NMR experiments in D(2)O and H(2)O.
AB  - A small RNA motif is used as a target for ligand-based NMR-screening by
      saturation transfer difference (STD) NMR experiments. The prerequisites for using
      a small RNA target in STD experiments, such as saturation time, frequency, and
      pulses, are discussed. We also show that it is of advantage to use D2O as solvent
      instead of H2O due to the reduced R1 relaxation rate in D2O. The 27-nucleotide
      model of the ribosomal A-site was known to bind the aminoglycoside paromomycin
      with high affinity. This binding interaction could be detected easily, proving
      the effectiveness of STD NMR experiments as a screening tool for RNA-ligand
      interactions.

PMID- 12418876
TI  - Aqueous phase separation in giant vesicles.
AB  - We report the synthesis and initial characterization of approximately 10 mum
      diameter lipid vesicles that contain two distinct aqueous phases. The aqueous two
      phase system is a dextran/poly(ethylene glycol) solution that exhibits
      temperature-dependent phase behavior. Vesicles were prepared above the phase
      transition temperature of the polymer solution. Upon cooling to room temperature,
      the polymer solution phase separated both within the vesicles and in the bulk
      solution. The location of poly(ethylene glycol)-rich and dextran-rich phases was
      determined by fluorescence microscopy. These structures are exciting in that they
      enable for the first time the interior volume of liposomes to be structured.

PMID- 12418878
TI  - Cooperative host/guest interactions via counterion assisted chelation:
      pseudorotaxanes from supramolecular cryptands.
AB  - Addition of di- or tritopic hydrogen bond accepting anions to solutions of bis(5
      hydroxymethyl-1,3-phenylene)-32-crown-10 and paraquat di(hexafluorophosphate)
      serves to enhance host/guest interaction. In particular, addition of Et4N+CF3COO-
      effectively boosts Ka 14-fold, as estimated by 1H NMR studies. Similar increases
      in apparent Ka values are observed upon addition of n-Bu4N+OTs-. Evidenced by
      crystal structures, the increased association results from chelation of the OH
      moieties of the crown by the di- or tritopic anions, forming supramolecular
      bicyclic macrocycles and stabilizing the complex in a cooperative manner.

PMID- 12418879
TI  - Deprotonation of a histidine residue in aqueous solution using constrained ab
      initio molecular dynamics.
AB  - The dissociation of a weak acid - a histidine residue - in water was investigated
      by means of constrained Car-Parrinello ab initio molecular dynamics. Both linear
      and coordination constraints were employed, and the structural, electronic, and
      dynamical transformations along the respective reaction coordinates were
      analyzed. The calculated potentials of mean force for the dissociation of a
      hydrogen atom from the Nepsilon and Ndelta positions of the imidazole ring reveal
      that protonated forms are approximately 9.0-9.5 kcal/mol more stable than the
      deprotonated. This result seems to agree well with the experimental estimate
      based on pKa. A possible transition state for the deprotonation has also been
      identified. Analysis of the electron localization function indicates that the
      proton transfer along the selected reaction path is not a fully concerted
      process.

PMID- 12418880
TI  - Oligocarbamate molecular transporters: design, synthesis, and biological
      evaluation of a new class of transporters for drug delivery.
AB  - Molecular transporters have the ability to deliver drugs and probe molecules into
      cells and tissues irrespective of their physical properties. We now report the
      design, synthesis, and biological evaluation of a new family of molecular
      transporters, guanidinylated oligocarbamates that enable exceptionally efficient
      uptake into cells and tissues. The synthesis features a solid-phase stepwise
      oligomerization to obtain the oligocarbamates and a single step
      perguanidinylation for the facile introduction of up to nine guanidinium groups.
      The oligocarbamate 9-mer is found to be among the most efficient transporters
      known, entering cells faster than even d-Arg9 and HIV-1 Tat49-57. Significantly,
      this new family of transporters also enables uptake into the formidable skin
      barrier of a probe molecule that by itself does not penetrate skin.

PMID- 12418881
TI  - Fullerenes as a tert-butylperoxy radical trap, metal catalyzed reaction of tert
      butyl hydroperoxide with fullerenes, and formation of the first fullerene mixed
      peroxides C(60)(O)(OO(t)Bu)(4) and C(70)(OO(Bu)(10).
AB  - tert-Butylperoxy radicals generated by TBHP and Ru(PPh3)3Cl2 or other catalysts
      adds to C60 and C70 to form stable multiadducts, C60(O)(OOtBu)4 and C70(OOtBu)10.
      The four tert-butylperoxy groups in the C60 mixed peroxide are located around a
      pentagon, and the epoxy O occupies the remaining 6,6-bond connected to the same
      pentagon. The C70 decaadduct shows an unprecedented C2 symmetry with the 10 tert
      butylperoxy groups added around the central part of C70 by consecutive 1,4
      addition. The compounds are fully characterized by spectroscopic data.

PMID- 12418882
TI  - The effect of HMPA on the reactivity of epoxides, aziridines, and alkyl halides
      with organolithium reagents.
AB  - A kinetic study of the effect of added HMPA cosolvent on the reaction of 2-lithio
      1,3-dithiane (1), bis(phenylthio)methyllithium (2), and bis(3,5
      bistrifluoromethylphenylthio)methyllithium (3) with methyloxirane (propylene
      oxide), N-tosyl-2-methylaziridine, and the several alkyl halides (BuCl, BuBr,
      BuI, allyl chloride) was carried out. Widely varied rate effects of HMPA on these
      SN2 substitutions were observed, ranging from >108 rate increases for 1 and butyl
      chloride to >103 rate decreases for 3 and methyloxirane. These reactions appear
      to go through separated ion pair intermediates, so a key effect is the ease of
      ion pair separation of the lithium reagent (3 > 2 > 1). Because 3 is already
      almost fully separated in THF, HMPA has no effect on the rate of halide
      substitution, but a large reduction is observed with the epoxide as substrate, a
      consequence of strong lithium assistance to the ring opening which is suppressed
      when excess HMPA is present. When ion pair separation is difficult (1), modest
      rate increases (104) are seen for epoxide opening, but very large increases are
      seen for aziridine (106) and alkyl halide reactions (108), for which lithium
      assistance is much less important. Reagent 2 shows more complicated behavior in
      reaction with the epoxide: 1-2 equiv of HMPA causes a small rate increase, while
      larger amounts cause a large rate decrease. Here the rate-accelerating effects of
      SIP formation are more nearly balanced with the rate-retarding effects of
      suppression of lithium catalysis.

PMID- 12418884
TI  - New tandem catalysis: preparation of cyclic enol ethers through a ruthenium
      catalyzed ring-closing metathesis-olefin isomerization sequence.
AB  - Tandem reactions that proceed with a single metal catalyst precursor offer novel
      opportunities for developing efficient new reaction sequences. In this regard,
      reaction conditions have been identified that allows for a tandem ring-closing
      metathesis-olefin isomerization sequence catalyzed by a common ruthenium
      precursor. Specifically, the tandem process generates cyclic enol ethers from a
      variety of readily available acyclic dienes in a single reaction vessel using
      Grubbs' ruthenium alkylidene.

PMID- 12418883
TI  - Polymerized bicontinuous cubic nanoparticles (cubosomes) from a reactive
      monoacylglycerol.
AB  - Bicontinuous cubic phases of monoacylglycerides/Poloxamer 407
      (PEO98PPO67PEO98)/water can be dispersed into submicron particles, which are
      termed "cubosomes". Technological applications of these nanoparticles may be
      possible, if their nonlamellar architecture can be rendered more robust. To
      accomplish this goal, a polymerizable heterobifunctional monoacylglycerol, 3
      (2,4,13-(E,E)-tetradecatrienoyl)-sn-glycerol (1), was synthesized and combined
      with water to form an optically transparent gel. In the presence of Poloxamer 407
      and excess water the cubic phase of 1 was dispersed by ultrasonication into 300
      nm diameter nanoparticles. The polymerization of these reactive cubosomes could
      be initiated either by the use of a photoinitiator or with redox chemistry. The
      polymerized cubosomes remained stable even after the addition of excess Triton X
      100, in a manner consistent with executing cross-linking in the nanostructures.

PMID- 12418886
TI  - Enantioselective Michael additions of nitromethane by a catalytic double
      activation method using chiral lewis Acid and achiral amine catalysts.
AB  - Reactions of nitromethane with 1-(2-alkenoyl)-3,5-dimethylpyrazoles can be
      effectively catalyzed by R,R-DBFOX/Ph.Ni(ClO4)2.3H2O and achiral amine bases,
      each in a catalytic loading of 10 mol %, to give 1-(3-substituted 4
      nitrobutanoyl)-3,5-dimethylpyrazoles in high chemical yields. Excellent
      enantioselectivities up to 98% ee have been achieved. The nitro moiety can be
      easily reduced on Raney nickel at atmospheric pressure, followed by concurrent
      cyclization, to give enantiomers of 4-substituted 2-pyrrolidinone derivatives
      after usual workup. This method can be successfully applied to a short step
      synthesis of (R)-(-)-rolipram.

PMID- 12418885
TI  - Component B binding to the soluble methane monooxygenase hydroxylase by
      saturation-recovery EPR spectroscopy of spin-labeled MMOB.
AB  - Spin-labeled Cys89 of the soluble methane monooxygenase regulatory protein (MMOB)
      from Methylococcus capsulatus (Bath) binds within 15 +/- 4 A of the hydroxylase
      (MMOH) diiron center, placing the MMOB docking site in the MMOH "canyon" region
      on iron-coordinating helices E and F of the alpha-subunit.

PMID- 12418887
TI  - Nickel-catalyzed asymmetric grignard cross-coupling of dinaphthothiophene giving
      axially chiral 1,1'-binaphthyls.
AB  - Asymmetric cross-coupling of dinaphtho[2,1-b:1',2'-d]thiophene with ArMgBr (Ar =
      Ph, 4-MeC6H4, 4-MeOC6H4) proceeded with high enantioselectivity in THF at 20
      degrees C in the presence of 3 mol % of a nickel catalyst generated from Ni(cod)2
      and a chiral oxazoline-phosphine ligand to give high yields of axially chiral 2
      mercapto-2'-aryl-1,1'-binaphthyls, whose enantiomeric excesses are over 93%. The
      mercapto group in the chiral binaphthyl was converted into iodo, boryl, and
      phosphino groups without racemization.

PMID- 12418888
TI  - Total synthesis of (+)-aspidospermidine: a new strategy for the enantiospecific
      synthesis of aspidosperma alkaloids.
AB  - A new strategy was developed for the enantiospecific synthesis of aspidosperma
      alkaloids. The key steps involve a novel ketene-lactonization reaction of a
      chiral vinyl sulfoxide to efficiently set up the quaternary carbon center, and a
      tandem Michael addition-alkylation reaction sequence to form the polycyclic core
      structure. This new strategy was employed in the total synthesis of natural
      product (+)-aspidospermidine.

PMID- 12418889
TI  - Highly enantioselective Ag(i)-catalyzed [3 + 2] cycloaddition of azomethine
      ylides.
AB  - A highly reactive Ag(I)-catalyzed [3 + 2] cycloaddition of azomethine ylides is
      founded using AgOAc as the catalytic precursor and phosphines as ligands. Using a
      new bis-ferrocenyl amide phosphine (FAP) as the ligand, we found that high
      enantioselectivities (up to 97% ee) have been achieved in the [3 + 2]
      cycloaddition of azomethine ylides. Up to four stereogenic centers can be
      established in this multicomponent coupling reaction from readily available
      materials such as aldehydes, aminoesters, and dipolarophiles.

PMID- 12418890
TI  - Skeletal diversity via a branched pathway: efficient synthesis of 29 400
      discrete, polycyclic compounds and their arraying into stock solutions.
AB  - We report the synthesis and arraying of 29 400 structurally diverse and complex
      polycyclic carbocycles using diversity-oriented synthesis (DOS) and the "one bead
      one stock solution" technology platform. Skeletal diversity, a difficult
      challenge in DOS, was achieved with a branching reaction pathway using one or two
      Diels-Alder reactions. This pathway yields small molecules having 10 different
      skeletons.

PMID- 12418891
TI  - Lewis base activation of lewis acids. Addition of silyl ketene acetals to
      aldehydes.
AB  - The weak Lewis acid silicon tetrachloride can be activated by catalytic amounts
      of the chiral bisphosphoramide (R,R)-3 to form a highly reactive, chiral
      trichlorosilyl cation which is an extremely effective promoter of aldol addition
      reactions between aldehydes and silyl ketene acetals. The tert-butyldimethylsilyl
      ketene acetal of methyl acetate adds nearly instantaneously to aromatic and
      olefinic aldehydes as well as aliphatic aldehydes (albeit more slowly) with
      excellent enantioselectivity. The homologous tert-butyldimethylsilyl ketene
      acetal of tert-butyl propanoate adds with nearly exclusive anti
      diastereoselectivity to a similar range of aldehydes also with excellent
      enantioselectivity. The origin of the slower reaction rate with aliphatic
      aldehydes is revealed to be the formation of chlorosilyl ether adducts.

PMID- 12418892
TI  - Membrane affinity of the amphiphilic marinobactin siderophores.
AB  - Marinobactins are a class of newly discovered marine bacterial siderophores with
      a unique amphiphilic structure, suggesting that their functions relate to
      interactions with cell membranes. Here we use small and large unilamellar L-alpha
      dimyristoylphosphatidylcholine vesicles (SUVs and LUVs) as model membranes to
      examine the thermodynamics and kinetics of the membrane binding of marinobactins,
      particularly marinobactin E (apo-M(E)) and its iron(III) complex, Fe-M(E).
      Siderophore-membrane interactions are characterized by NMR line broadening,
      stopped-flow spectrophotometry, fluorescence quenching, and ultracentrifugation.
      It is determined that apo-M(E) has a strong affinity for lipid membranes with
      molar fraction partition coefficients K(x)()(apo)(-)(M)E = 6.3 x 10(5) for SUVs
      and 3.6 x 10(5) for LUVs. This membrane association is shown to cause only a 2
      fold decrease in the rate of iron(III) binding by apo-M(E). However, upon the
      formation of the iron(III) complex Fe-M(E), the membrane affinity of the
      siderophore decreased substantially (K(x)()(Fe)(-)(M)E = 1.3 x 10(4) for SUVs and
      9.6 x 10(3) for LUVs). The kinetics of membrane binding and dissociation by Fe
      M(E) were also determined (k(on)(Fe)(-)(M)E = 1.01 M(-)(1) s(-)(1); k(off)(Fe)(
      )(M)E = 4.4 x 10(-)(3) s(-)(1)). The suite of marinobactins with different fatty
      acid chain lengths and degrees of chain unsaturation showed a range of membrane
      affinities (5.8 x 10(3) to 36 M(-)(1)). The affinity that marinobactins exhibit
      for membranes and the changes observed upon iron binding could provide unique
      biological advantages in a receptor-assisted iron acquisition process in which
      loss of the iron-free siderophore by diffusion is limited by the strong
      association with the lipid phase.

PMID- 12418893
TI  - Synthesis of the DNA-[Ru(tpy)(dppz)(CH(3)CN)](2+) conjugates and their photo
      cross-linking studies with the complementary DNA strand.
AB  - We here report our studies on the conjugation of photoreactive Ru(2+) complex to
      oligonucleotides (ODNs), which give a stable duplex with the complementary target
      DNA strand. These functionalized DNA duplexes bearing photoreactive Ru(2+)
      complex can be specifically photolyzed to give the reactive aqua derivative,
      [Ru(tpy)(dppz)(H(2)O)](2+)-ODN (tpy = 2,2':6',2' '-terpyridine; dppz =
      dipyrido[3,2-a:2',3'-c]phenazine), in situ, which successfully cross-links to
      give photoproduct(s) in the duplex form with the target complementary DNA strand.
      Thus, the stable precursor of the aquaruthenium complex, the monofunctional
      polypyridyl ruthenium complex [Ru(tpy)(dppz)(CH(3)CN)](2+), has been site
      specifically tethered to ODN, for the first time, by both solid-phase synthesis
      and postsynthetic modifications. (i) In the first approach, pure 3'
      [Ru(tpy)(dppz)(CH(3)CN)](2+)-ODN conjugate has been obtained in 42% overall yield
      (from the monomer blocks) by the automated solid-phase synthesis on a support
      labeled with [Ru(tpy)(dppz)Cl](+) complex with subsequent liberation of the crude
      conjugate from the support under mild conditions and displacement of the Cl(-)
      ligand by acetonitrile in the coordination sphere of the Ru(2+) label. (ii) In
      the second approach, the single-modified (3'- or 5'- or middle-modified) or 3',5'
      bis-modified Ru(2+)-ODN conjugates were prepared in 28-50% yield by an amide bond
      formation between an active ester of the metal complex and the ODNs conjugated
      with an amino linker. The pure conjugates were characterized unambiguously by
      ultraviolet-visible (UV-vis) absorption spectroscopy, enzymatic digestion
      followed by HPLC quantitation, polyacrylamide gel electrophoresis (PAGE), and
      mass spectrometry (MALDI-TOF as well as by ESI). [Ru(tpy)(dppz)(CH(3)CN)](2+)
      ODNs form highly stabilized ODN.DNA duplexes compared to the unlabeled
      counterpart (DeltaT(m) varies from 8.4 to 23.6 degrees C) as a result of
      intercalation of the dppz moiety; they undergo clean and selective
      photodissociation of the CH(3)CN ligand to give the corresponding aqua complex,
      [Ru(tpy)(dppz)(H(2)O)](2+)-ODNs (in the aqueous medium), which is evidenced from
      the change of their UV-vis absorption properties and the detection of the naked
      Ru(2+)-ODN ions generated in the course of the matrix-assisted laser desorption
      ionization time-of-flight (MALDI-TOF) mass spectrometric analysis. Thus, when
      [Ru(tpy)(dppz)(CH(3)CN)](2+)-ODN conjugate was hybridized to the complementary
      guanine (G)-rich target strand (T), and photolyzed in a buffer (pH 6.8), the
      corresponding aqua complex formed in situ immediately reacted with the G residue
      of the opposite strand, giving the cross-linked product. The highest yield (34%)
      of the photo cross-linked product obtained was with the ODN carrying two reactive
      Ru(2+) centers at both 3'- and 5'-ends. For ODNs carrying only one Ru(2+)
      complex, the yield of the cross-linked adduct in the corresponding duplex is
      found to decrease in the following order: 3'-Ru(2+)-ODN (22%) > 5'-Ru(2+)-ODN
      (9%) > middle-Ru(2+)-ODN (7%). It was also found that the photo cross-coupling
      efficiency of the tethered Ru(2+) complex with the target T strand decreased as
      the stabilization of the resulting duplex increased: 3'-Ru(2+)-ODN (VI.T)
      (DeltaT(m)(b) = 7 degrees C) < 5'-Ru(2+)-ODN (V.T) (DeltaT(m)(b) = 16 degrees C)
      < middle-Ru(2+)-ODN (VII.T) (DeltaT(m)(b) = 24.3 degrees C, Table 2). This shows
      that, with the rigidly packed structure, as in the duplex with middle-Ru(2+)-ODN,
      the metal center flexibility is considerably reduced, and consequently the
      accessibility of target G residue by the aquaruthunium moiety becomes severely
      restricted, which results in a poor yield in the cross-coupling reaction. The
      cross-linked product was characterized by PAGE, followed by MALDI-TOF MS.

PMID- 12418894
TI  - Rapid synthesis of a glycosylphosphatidylinositol-based malaria vaccine using
      automated solid-phase oligosaccharide synthesis.
AB  - Described is an automated synthesis of hexasaccharide malarial toxin 1, currently
      under development as a malaria vaccine candidate. Using a combination of
      automated solid-phase methods and solution-phase fragment coupling, the target
      glycosylphosphatidylinositol was assembled in a matter of days, compared with
      several weeks for a comparable solution-phase synthesis.

PMID- 12418895
TI  - Photostabilized chlorophyll a in mesoporous silica: adsorption properties and
      photoreduction activity of chlorophyll a.
AB  - Chlorophyll a was adsorbed to mesoporous silica (FSM, folded-sheet mesoporous
      material) to form a chlorophyll-FSM conjugate, in which a nanometer-scale
      interaction between chlorophyll a molecules resembles a living plant leaf. The
      mesopores of FSM acted as nanoscale spaces not only for an interaction between
      chlorophyll molecules and the silica support but also for a nanoscale interaction
      between the absorbed chlorophyll molecules. These interactions contribute to
      photostability. An increase in the amount of chlorophyll adsorbed to the pores of
      FSM leads to an enhancement of the photostability accompanied by a shift in the
      absorbance maximum to a longer wavelength. The physiological function of the
      chlorophyll-FSM conjugate was explored as chlorophyll-FSM exhibited the
      photoinduced ability to catalyze the reduction of methyl viologen (an electron
      carrier). The evolution of hydrogen gas was observed for 14 h without
      deterioration when an aqueous suspension containing chlorophyll-FSM, methyl
      viologen, 2-mercaptoethanol (an electron donor), and platinum was illuminated
      with visible light.

PMID- 12418896
TI  - Diastereoselective addition of gamma-substituted allylic nucleophiles to ketones:
      highly stereoselective synthesis of tertiary homoallylic alcohols using an
      allylic tributylstannane/stannous chloride system.
AB  - The diastereoselective addition of gamma-substituted allylic nucleophiles to
      ketones has been accomplished to give tertiary homoallylic alcohols. The reaction
      of tributylcinnamyltin 1a with simple ketones 2 in the presence of stannous
      chloride (SnCl(2)) gave the tertiary homoallylic alcohols 3, which include the
      anti form (based on Ph and OH), with high diastereoselectivity. In the reaction
      course, transmetalation of tributylcinnamyltin 1a with SnCl(2) proceeds to form
      an active nucleophile which is tentatively considered to be a cinnamyltin(II)
      species. A cyclic transition state A is favorable because the chlorinated tin(II)
      center is highly capable of accepting ligands. The other diastereomers (syn form)
      4 were obtained in the reaction of tributylcinnamyltin 1a with ketones 2 by the
      use of BF(3) x OEt(2) instead of SnCl(2). This reaction proceeds through an
      acyclic transition state in which BF(3) acts as a Lewis acid for activation of
      ketones. When 3-tributylstannylcyclohexene 1b or 3-tributylstannylcyclopentene 1c
      was used with SnCl(2), high diastereoselective formation of the corresponding
      homoallylic alcohols 6 which have the syn form (based on ring chain and OH) was
      observed. The selectivity was also explained by the cyclic transition state B.
      When tributylcrotyltin 1d or 1e was used, the stereochemistry of the products
      depends on the additives (SnCl(2) or BF(3) x OEt(2)), substituents of ketones,
      and reaction temperature. It is interesting that those additives compensate for
      each other in terms of diastereoselective alkylation. The alkylation of alpha
      alkoxy, aryloxy, or hydroxyketones 16 was achieved in extremely high selectivity
      using an allylic tributyltin 1a-c/SnCl(2) system. The chelation by carbonyl and
      beta-oxygens provides a rigid transition state (E or F) for selective reactions.
      It is noted that the hydroxyketone can be used without protection in this
      reaction system. The relative stereochemistry of the produced tertiary
      homoallylic alcohols was determined on the basis of X-ray analyses.

PMID- 12418897
TI  - Chemosensors for the marine toxin saxitoxin.
AB  - Eleven anthracylmethyl crown ethers have been synthesized and evaluated as
      fluorescence sensors for the marine toxin saxitoxin. Fluorescence enhancement
      data are consistent with a 1:1 binding complex for all crowns. The binding
      constants are in the range of 10(4) M(-)(1) in ammonium phosphate buffer (pH 7.1)
      in 80% ethanol solvent. Selectivity for sensing saxitoxin versus several organic
      analytes has been demonstrated for the first time. Possible modes of binding are
      presented, and relevance to saxitoxin monitoring programs are discussed.

PMID- 12418898
TI  - Cascade of coil-globule conformational transitions of single flexible
      polyelectrolyte molecules in poor solvent.
AB  - We show that hydrophobic flexible polyelectrolyte molecules of poly(2
      vinylpyridine) and poly(methacryloyloxyethyl dimethylbenzylammonium chloride) are
      trapped and frozen due to adsorption on the mica surface, and the observed AFM
      single molecule structures reflect the molecular conformation in solution. An
      increase of the ionic strength of the solution induces the cascade of abrupt
      conformational transitions due to the intrachain segregation from elongated coil
      to compact globule conformations through intermediate pearl necklace-globule
      conformations with different amounts of beads per chain. The length of the
      necklaces and the number of beads decrease, while the diameter of beads increases
      with the increase of ionic strength. Coexistence at the same time of extended
      coils, necklaces with different amounts of beads, and compact globules indicates
      the cascade of the first-order-type phase transitions.

PMID- 12418899
TI  - Deciphering the mechanistic dichotomy in the cyclization of 1-(2-ethynylphenyl)
      3,3-dialkyltriazenes: competition between pericyclic and pseudocoarctate
      pathways.
AB  - The mechanistic aspects of the cyclization of (2-ethynylphenyl)triazenes under
      both thermal and copper-mediated conditions are reported. For cyclization to an
      isoindazole, a carbene mechanistic pathway is proposed. The carbene intermediate
      can react with oxygen, dimerize to give an alkene, or be trapped either
      intermolecularly (using 2,3-dimethyl-2-butene to generate a cyclopropane) or
      intramolecularly (using a biphenyl moiety at the terminus of the acetylene to
      form a fluorene). Density-functional theory (DFT) calculations support a
      pseudocoarctate pathway for this type of cyclization. Thermal cyclization to give
      a cinnoline from (2-ethynylphenyl)triazenes is proposed to occur through a
      pericyclic pathway. DFT calculations predict a zwitterionic dehydrocinnolinium
      intermediate that is supported by deuterium trapping studies as well as
      cyclizations performed using a 2,2,6,6-tetramethylpiperidine moiety at the 3
      position of the triazene.

PMID- 12418900
TI  - Quinoxaline-bridged porphyrinoids.
AB  - Quinoxaline-bridged porphyrinoids (3), the first macrocycles containing
      dipyrrolylquinoxaline (DPQ, 1) subunits, were synthesized from the condensation
      of the diformyl-substituted DPQ derivatives (2) and 1,8-diaminoanthracene. The
      resulting structures were confirmed by X-ray analyses, which showed encapsulation
      of CHCl(3) molecules within the columnar channels established by the stacked
      arrangement of the individual macrocycles. The solution phase interactions with
      fluoride and dihydrogenphosphate anions were studied in the case of the
      unsubstituted system 3a in CH(2)Cl(2). The binding affinities for these anions,
      studied at the tetrabutylammonium salts, were found to be enhanced relative to
      those of the simple, unsubstituted monomeric DPQ "parent" system (1a), presumably
      as the result of the combined effects of preorganization and cooperative binding
      permitted by the pyrrole NH donor groups. Positive homotropic allosteric anion
      binding was observed and is ascribed to the structurally coupled nature of the
      two binding cavities present in the macrocycles. Support for this latter
      contention came from energy minimization studies.

PMID- 12418901
TI  - Three-dimensional nonlinear optical chromophores based on through-space
      delocalization.
AB  - Six permutations of 4-fold donor and/or acceptor substitution of paracyclophane
      at the 4, 7, 12, and 15 positions were synthesized to probe the phenomenon of
      three-dimensional delocalization on the nonlinear optical properties of organic
      materials. The interplay between through-bond intramolecular charge transfer
      (ICT) as well as three-dimensional, or through-space, ICT processes gives rise to
      large quadratic hyperpolarizability values. The determination of dipolar
      (beta(J)(=1)) and octupolar (beta(J)(=3)) irreducible tensor contributions to the
      overall beta tensor value is made possible by the polarized harmonic light
      scattering technique at 1.32 microm. The electric field-induced second-harmonic
      generation technique was also used at 1.91 microm for comparison. Significant
      experimental beta values for members of the series made of two centrosymmetric
      benzene-like units are a clear signature of a purely through-space ICT between
      two aryl subunits. The two configurational isomers that pair two dipolar donor
      acceptor chromophores also exhibit octupolar character. Analysis of these two
      with an additive model for beta(J)(=1) and beta(J)(=3) reveals a strong three
      dimensional inter-ring charge transfer.

PMID- 12418902
TI  - From chiral counterions to twisted membranes.
AB  - In membranes, the chirality of the amphiphile constituents is sometimes expressed
      at a supramolecular scale of nanometers or micrometers. We have recently reported
      that membranes of nonchiral dicationic n-2-n amphiphiles can also be chirally
      twisted upon interacting with chiral tartrate counterions. Here, we demonstrate
      that the mechanism of the chiral induction by counterions involves specific anion
      cation recognition and the induction of conformationally labile chirality in the
      cations. Single-crystal X-ray diffraction shows that the amphiphilic cations
      exist as a mixture of chiral conformers. (1)H NMR data establish a specific
      recognition between tartrate and n-2-n cations and show that chiral conformers
      also exist in solution. Circular dichroism (CD) in the UV-vis shows a sharp
      conformational change of tartrate ions from anti to gauche when bound to the
      chiral cationic membranes. This is confirmed by CD in the infrared region which
      also shows concomitant induced CD bands in the vibrations of the n-2-n
      amphiphiles. These results represent the first example of the so-called Pfeiffer
      effect in a membrane. They provide a general framework for designing new tunable
      membrane systems. Our work also includes the first application of vibrational
      circular dichroism in the study of chiral conformations of amphiphiles in
      membranes and demonstrates the very high potential of this technique.

PMID- 12418903
TI  - A theoretical and experimental scale of aromaticity. The first nucleus
      independent chemical shifts (NICS) study of the dimethyldihydropyrene nucleus.
AB  - Nucleus-independent chemical shift (NICS) values were calculated at several
      locations for a series of dimethyldihydropyrenes (DDPs). These NICS values were
      used to assess the relative aromaticities of the dimethyldihydropyrene nucleus
      (DDPN) of these DDPs and to construct a NICS scale of aromaticity. The NICS and
      experimentally determined relative aromaticities of these DDPNs are in complete
      agreement, verifying that NICS can be used not only to classify a compound as
      aromatic but also to determine the degrees of aromaticity of structurally related
      systems.

PMID- 12418904
TI  - Dihapto coordination of carboxylic acid derivatives with an asymmetric rhenium pi
      base: a new mechanism for amide isomerization?
AB  - The asymmetric pi basic metal fragment [TpRe(CO)(MeIm)] (Tp =
      hydridotris(pyrazolyl)borate, MeIm = 1-methylimidazole) forms thermally stable
      complexes with ethyl acetate, acetic anhydride, N-methylsuccinimide, N
      acetylpyrrole, and N-methylmaleimide in which the metal binds a carbonyl group in
      a pi fashion. In all cases a single diastereomer is observed, indicating that one
      enantioface of the carbonyl is selectively coordinated. X-ray and NMR data for
      the compound TpRe(CO)(MeIm)(eta(2)-N-methylsuccinimide) indicate that metal
      coordination effectively removes the pi interaction between the bound carbonyl
      and the nitrogen of the succinimide ring.

PMID- 12418905
TI  - Detection of chiral perturbations in ferroelectric liquid crystals induced by an
      atropisomeric biphenyl dopant.
AB  - The atropisomeric dopant 2,2',6,6'-tetramethyl-3,3'-dinitro-4,4'-bis[(4
      nonyloxybenzoyl)oxy]biphenyl (1) induces a ferroelectric SmC phase when doped
      into the SmC liquid crystal hosts 2-(4-butyloxyphenyl)-5-octyloxypyrimidine
      (PhP1) and (+/-)-4-[(4-methylhexyl)oxy]phenyl 4-decyloxybenzoate (PhB). The
      propensity of dopant 1 to induce a spontaneous polarization (polarization power)
      is much higher in PhP1 than in PhB (1555 nC/cm(2) vs <35 nC/cm(2)), which is
      attributed to a greater propensity of 1 to undergo chirality transfer via core
      core interactions with PhP1. In previous work, we postulated that a chiral
      perturbation exerted by 1 in PhP1 amplifies the polarization power of the dopant
      by causing a chiral distortion of the mean field potential (binding site)
      constraining the dopant in the SmC host, as described by the Chirality Transfer
      Feedback (CTF) model. To test the validity of the CTF model, and to provide a
      more direct assessment of the chiral perturbation exerted by dopant 1 on
      surrounding host molecules, we measured the effect of 1 on the polarization power
      of other chiral dopants acting as probes. In one series of experiments, (S,S)-5
      (2,3-difluorooctyl)-2-(4-octylphenyl)pyridine (MDW950) and (S)-4-(1
      methylheptyloxy)phenyl 4-decyloxybenzoate (4), which mimic the structures of PhP1
      and PhB, were used as probes. In another series of experiments, the atropisomeric
      dopant 2,2',3,3',6,6'-hexamethyl-4,4'-bis[(4-nonyloxybenzoyl)oxy]biphenyl (2) was
      used as probe in PhP1. The results of the probe experiments suggest that dopant 1
      exerts a much stronger chiral perturbation in PhP1 than in PhB. More
      significantly, the results of experiments using 2 as probe show that the chiral
      perturbation exerted by 1 can amplify the polarization power of another
      atropisomeric dopant, thus providing the first experimental evidence of the CTF
      effect.

PMID- 12418906
TI  - Very large breathing effect in the first nanoporous chromium(III)-based solids:
      MIL-53 or Cr(III)(OH) x [O(2)C-C(6)H(4)-CO(2)] x [HO(2)C-C(6)H(4)-CO(2)H](x) x
      H(2)O(y).
AB  - The first three-dimensional chromium(III) dicarboxylate, MIL-53as or Cr(III)(OH)
      x [O(2)C-C(6)H(4)-CO(2)].[HO(2)C-C(6)H(4)-CO(2)H](0.75), has been obtained under
      hydrothermal conditions (as: as-synthesized). The free acid can be removed by
      calcination giving the resulting solid, MIL-53ht or Cr(III)(OH) x [O(2)C-C(6)H(4)
      CO(2)]. At room temperature, MIL-53ht adsorbs atmospheric water immediately to
      give Cr(III)(OH) x [O(2)C-C(6)H(4)-CO(2)] x H(2)O or MIL-53lt (lt: low
      temperature form, ht: high-temperature form). Both structures, which have been
      determined by using X-ray powder diffraction data, are built up from chains of
      chromium(III) octahedra linked through terephthalate dianions. This creates a
      three-dimensional structure with an array of one-dimensional large pore channels
      filled with free disordered terephthalic molecules (MIL-53as) or water molecules
      (MIL-53lt); when the free molecules are removed, this leads to a nanoporous solid
      (MIL-53ht) with a Langmuir surface area over 1500 m(2)/g. The transition between
      the hydrated form (MIL-53lt) and the anhydrous solid (MIL-53ht) is fully
      reversible and followed by a very high breathing effect (more than 5 A), the
      pores being clipped in the presence of water molecules (MIL-53lt) and reopened
      when the channels are empty (MIL-53ht). The thermal behavior of the two solids
      has been investigated using TGA and X-ray thermodiffractometry. The sorption
      properties of MIL-53lt have also been studied using several organic solvents.
      Finally, magnetism measurements performed on MIL-53as and MIL-53lt revealed that
      these two phases are antiferromagnetic with Neel temperatures T(N) of 65 and 55
      K, respectively. Crystal data for MIL-53as is as follows: orthorhombic space
      group Pnam with a = 17.340(1) A, b = 12.178(1) A, c = 6.822(1) A, and Z = 4.
      Crystal data for MIL-53ht is as follows: orthorhombic space group Imcm with a =
      16.733(1) A, b = 13.038(1) A, c = 6.812(1) A, and Z = 4. Crystal data for MIL
      53lt is as follows: monoclinic space group C2/c with a = 19.685(4) A, b =
      7.849(1) A, c = 6.782(1) A, beta = 104.90(1) degrees, and Z = 4.

PMID- 12418907
TI  - Application of a new color detection based method for the fast parallel screening
      of DeNO(x) catalysts.
AB  - A new fast parallel detection method for stage I screening of solid catalysts has
      been developed. This method is based on the color change of organic dyes in the
      presence of either educts or reaction products in a reaction gas flow. As an
      example, NO decomposition and NO reduction with propylene under lean or rich
      conditions were studied. The presence of NO in a gas stream was detected by the
      color change from colorless to blue-green of filter paper impregnated with an
      organic dye, 2,2'-azinobis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS), which
      was placed in the gas stream after the catalyst bed. The catalyst library was
      made up of mixed metal oxides, synthesized by impregnation of activated carbon
      with metal oxide precursor solutions and subsequent combustion of the carbon
      matrix. Catalytic activity of these metal oxides was compared to platinum on
      gamma-alumina as a reference catalyst. The most active compounds were then
      studied in detail for their DeNO(x)properties in a high precision parallel flow
      test rig under a stationary and cyclic lean/reach operation. A new promising
      NO(x) storage catalyst was discovered.

PMID- 12418908
TI  - Dissociative electron transfer to haloacetonitriles. An example of the dependency
      of in-cage ion-radical interactions upon the leaving group.
AB  - The reductive cleavage of the haloacetonitriles (Cl, Br, I) in DMF provides
      additional examples of the formation of a fragment cluster upon dissociative
      electron transfer, which is able to survive in this polar solvent thanks to the
      electron-withdrawing character of the cyano group. The remarkable sensitivity of
      the activation energy to small changes of the interaction energies allows, with
      help of the "sticky" dissociative electron-transfer model, the precise
      determination of interaction energies down to a few millielectronvolts from the
      cyclic voltammetric data. The interaction energy rapidly decreases from Cl to Br
      and to I, correlated with the increase of the halide radius. These observations
      add to the previously gathered evidence to confirm the existence of such
      interactions and to highlight their electrostatic character. This is further
      corroborated by the quantum chemical computation of the potential energy
      profiles, which exhibit a long-distance energy minimum. This revisiting of the
      notion of sigma-ion radicals and of their status in a polar medium makes them
      appear as an electrostatic radical-ion pair rather than covalently bound
      molecules. Their stability is a function of the Lewis acid-base properties of
      both the radical and the leaving ion and is strongly influenced by the nature of
      the solvent.

PMID- 12418909
TI  - Solvent-induced modulation of collective photophysical processes in fluorescent
      silica nanoparticles.
AB  - In this paper we show how it is possible to control the nature and the efficiency
      of collective photophysical processes in a network composed of two different
      fluorescent units organized on the surface of silica nanoparticles. Such a
      structure is obtained by covering nanoparticles with a layer of dansyl moieties
      (Dns) and by partially protonating them in solution. The two fluorophores Dns and
      Dns.H(+) have very different photophysical properties and can be selectively
      excited and detected. The interaction between the two units Dns and Dns.H(+) has
      been first investigated in a reference compound obtained by derivatizing 1,6
      hexanediamine with two dansyl units. The photophysical characterization of this
      compound (absorption spectra, fluorescence spectra, quantum yield, and lifetime)
      showed that the two moieties can be involved both in energy and electron-transfer
      processes. Dansylated nanoparticles were prepared by modifying preformed silica
      nanoparticles with dansylated (3-aminopropyl)trimethoxysilane. Photophysical
      studies indicated that protonation has a dramatic effect on the fluorescence of
      the nanoparticles, leading to the quenching of both the protonated units and the
      surrounding nonprotonated ones. This amplified response to protonation, due to
      charge-transfer interactions, is solvent-dependent and is less efficient in pure
      chloroform with respect to acetonitrile/chloroform (5/1 v/v) mixtures. The
      reduced efficiency of the electron-transfer processes responsible for the
      quenching makes energy transfer competitive to such an extent that in pure
      chloroform excitation energy migration takes place from Dns.H(+) to Dns with
      great efficiency.

PMID- 12418910
TI  - Oxysulfide Sm(2)Ti(2)S(2)O(5) as a stable photocatalyst for water oxidation and
      reduction under visible light irradiation (lambda < or = 650 nm).
AB  - A Ti-based oxysulfide, Sm(2)Ti(2)S(2)O(5), was studied as a visible light-driven
      photocatalyst. Under visible light (440 nm < or = lambda < or = 650 nm)
      irradiation, Sm(2)Ti(2)S(2)O(5) with a band gap of approximately 2 eV evolved
      H(2) or O(2) from aqueous solutions containing a sacrificial electron donor
      (Na(2)S-Na(2)SO(3) or methanol) or acceptor (Ag(+)) without any noticeable
      degradation. This oxysulfide is, therefore, a stable photocatalyst with strong
      reduction and oxidation abilities under visible-light irradiation. The electronic
      band structure of Sm(2)Ti(2)S(2)O(5) was calculated using the plane-wave-based
      density functional theory (DFT) program. It was elucidated that the S3p orbitals
      constitute the upper part of the valence band and these orbitals make an
      essential contribution to the small band gap energy. The conduction and valence
      bands' positions of Sm(2)Ti(2)S(2)O(5) were also determined by electrochemical
      measurements. It indicated that conduction and valence bands were found to have
      satisfactory potentials for the reduction of H(+) to H(2) and the oxidation of
      H(2)O to O(2) at pH = 8. This is consistent with the results of the
      photocatalytic reactions.

PMID- 12418911
TI  - The nature of solid-state N-H triplebondO/O-H triplebond N tautomeric competition
      in resonant systems. Intramolecular proton transfer in low-barrier hydrogen bonds
      formed by the triplebond O=C-C=N-NH triple bond --> <-- triplebond HO-C=C-N=N
      triplebond Ketohydrazone-Azoenol system. A variable-temperature X-ray
      crystallographic and DFT computational study.
AB  - The tautomeric.O=C-C=N-NH triplebond --> <-- HO-C=C-N=N triplebond ketohydrazone
      azoenol system may form strong N-H triplebond O/O-H triplebond N intramolecular
      resonance-assisted H-bonds (RAHBs) which are sometimes of the low-barrier H-bond
      type (LBHB) with dynamic exchange of the proton in the solid state. The problem
      of the N-H triplebond O/O-H triplebond N competition in these compounds is
      studied here through variable-temperature (100, 150, 200, and 295 K) crystal
      structure determination of pF = 1-(4-F-phenylazo)2-naphthol and oF = 1-(2-F
      phenylazo)2-naphthol, two molecules that, on the ground of previous studies
      (Gilli, P; Bertolasi, V.; Ferretti, V.; Gilli, G. J. Am. Chem. Soc. 2000, 122,
      10405), were expected to represent an almost perfect balance of the two
      tautomers. According to predictions, the two molecules form remarkably strong
      bonds (d(N triplebond O) = 2.53-2.55 A) of double-minimum or LBHB type with
      dynamic N-H triplebond O/ O-H triplebond N exchange in the solid state. The
      enthalpy differences between the two minima, as measured by van't Hoff methods
      from the X-ray-determined proton populations, are very small and amount to DeltaH
      degrees = -0.120 and DeltaH degrees = -0.156 kcal mol(-)(1) in favor of the N-H
      triplebond O form for pF and oF, respectively. Successive emulation of pF by DFT
      methods at the B3LYP/6-31+G(d,p)//B3LYP/6-31+G(d,p) level has shown that both
      energetic and geometric experimental aspects can be almost perfectly reproduced.
      Generalization of these results was sought by performing DFT calculations at the
      same level of theory along the complete proton-transfer (PT) pathway for five
      test molecules designed in such a way that the RAHB formed changes smoothly from
      weak N-H triplebond O to strong O-H.N through very strong N-H triplebond O/O-H
      triplebond N bond of LBHB type. A systematic correlation analysis of H-bond
      energies, H-bond and pi-conjugated fragment geometries, and H-bond Bader's AIM
      topological properties performed along the PT-pathways leads to the following
      conclusions: (a) any X-H triplebond Y H-bonded system is fully characterized by
      its intrinsic PT-barrier, that is, the symmetric barrier occurring when the
      proton affinities of X and Y are identical; (b) the intrinsic X-H triplebond Y
      bond associated with the symmetric barrier is the strongest possible bond in that
      system and will be single-minimum (single-well, no-barrier) or double-minimum
      (double-well, low-barrier) according to whether the intrinsic PT-barrier is lower
      or slightly higher than the zero-point vibrational level of the proton; (c) with
      reference to the intrinsic H-bond, the effect of chemical substitution can only
      be that of making more and more dissymmetric the PT-barrier, while the two H
      bonds split in a higher-energy bond which is stronger because closer to the
      transition-state structure and in a lower-energy one (the stable form) which is
      weaker because farther from it; (d) complete dissymmetrization of the PT-barrier
      will increasingly weaken the more stable H-bond until the formation of an extreme
      dissymmetric single-minimum or dissymmetric single-well H-bond.

PMID- 12418912
TI  - Controlling the conductance of atomically thin metal wires with electrochemical
      potential.
AB  - We report on the study of quantum transport in atomically thin Au wires suspended
      between two Au electrodes by modulating the electrochemical potential of the
      wires in various electrolytes. The potential modulation induces a conductance
      modulation with a phase shift that is always approximately 180 degrees, meaning
      that an increase in the potential always causes a decrease in the conductance.
      The amplitude of the induced conductance modulation, however, depends on several
      parameters. First, it depends on the atomic configurations of the individual
      wires. Second, the relative amplitude, defined as the ratio of the conductance
      modulation amplitude to the conductance, decreases as the diameter of the wire
      increases. Third, it depends on whether anion adsorption is present. In the
      absence of anion adsorption, it is approximately 0.55G(0) (G(0) = 2e(2)/h) per V
      of potential modulation, for a wire with conductance quantized near 1G(0). This
      double layer charging-induced conductance modulation can be attributed to a
      change in the effective diameter of the wire. In the presence of anion
      adsorption, the amplitude is much larger (e.g., approximately 1.6G(0)/V when I(-)
      adsorption takes place) and correlates well with the strength of the adsorption,
      which is due to the scattering of conduction electrons by the adsorbed anions.

PMID- 12418913
TI  - Self-assembled M(6)L(4)-type coordination nanocage with 2,2'-bipyridine ancillary
      ligands. Facile crystallization and X-ray analysis of shape-selective
      enclathration of neutral guests in the cage.
AB  - Hollow and roughly spherical cage 1 (ca. 2 nm in diameter) is self-assembled from
      2,4,6-tri(4-pyridyl)-1,3,5-triazine (2) and Pd(diamine)(ONO(2))(2) (3). This cage
      compound enclathrates a variety of neutral organic molecules in an aqueous phase.
      Unlike cage 1a, which possesses ancillary ethylenediamine ligands on the metal
      centers, 2,2'-bipyridine(bipy)-protected cage 1b is easily crystallized, making
      possible the detailed analysis of the enclathration geometry of guests by X-ray
      crystallographic study. It is found that guests are enclathrated in three
      different manners, depending upon the shape and the size of the guests:
      tetrahedral 1:4 complexation, orthogonal 1:2 complexation, and a simple 1:1
      complexation. The solution structures elucidated by NMR are in good accordance
      with the solid structure, showing that the enclathration geometries in the solid
      state are kept even in solution.

PMID- 12418914
TI  - Decal transfer microlithography: a new soft-lithographic patterning method.
AB  - A new soft-lithographic method for micropatterning polymeric resists, Decal
      Transfer Microlithography (DTM), is described. This technique is based on the
      transfer of elastomeric decal patterns via the engineered adhesion and release
      properties of a compliant poly(dimethylsiloxane) (PDMS) patterning tool. An
      important feature of the DTM method is the exceptionally broad spectrum of design
      rules that it embraces. This procedure is capable of transferring micron to
      submicron-sized features with high fidelity over large substrate areas and
      potentially simplifies to a significant degree the requirements for effecting
      multiple levels of registration. The DTM method offers some potential advantages
      over other soft-lithographic patterning methods in that it is amenable to
      transferring resist patterns with both open and closed forms, negative and
      positive image contrasts, and does so for a wide variety of aspect ratios and a
      significant range of pattern pitches that can be accommodated without degradation
      due to mechanical distortions of the pattern transfer tool. The most significant
      advance embodied in the DTM method, however, is that it offers useful new
      capabilities for the design and fabrication of advanced planar and 3D
      microfluidic assemblies and microreactors.

PMID- 12418915
TI  - Steric and electronic effects on the reactivity of rh and ir complexes containing
      P-S, P-P, and P-O ligands. Implications for the effects of chelate ligands in
      catalysis.
AB  - Kinetic studies of the reactions of [M(CO)(L-L)I] [M = Rh, Ir; L-L =
      Ph(2)PCH(2)P(S)Ph(2) (dppms), Ph(2)PCH(2)CH(2)PPh(2) (dppe), and
      Ph(2)PCH(2)P(O)Ph(2) (dppmo)] with methyl iodide have been undertaken. All the
      chelate ligands promote oxidative addition of methyl iodide to the square planar
      M(I) centers, by factors of between 30 and 50 compared to the respective
      [M(CO)(2)I(2)](-) complexes, due to their good donor properties. Migratory CO
      insertion in [Rh(CO)(L-L)I(2)Me] leads to acetyl complexes [Rh(L-L)I(2)(COMe)]
      for which X-ray crystal structures were obtained for L-L = dppms (3a) and dppe
      (3b). Against the expectations of simple bonding arguments, methyl migration is
      faster by a factor of ca. 1500 for [Rh(CO)(dppms)I(2)Me] (2a) than for
      [Rh(CO)(dppe)I(2)Me] (2b). For M = Ir, alkyl iodide oxidative addition gives
      stable alkyl complexes [Ir(CO)(L-L)I(2)R]. Migratory insertion (induced at high
      temperature by CO pressure) was faster for [Ir(CO)(dppms)I(2)Me] (5a) than for
      its dppe analogue (5b). Reaction of methyl triflate with [Ir(CO)(dppms)I] (4a)
      yielded the dimer [[Ir(CO)(dppms)(mu-I)Me](2)](2+) (7), which was characterized
      crystallographically along with 5a and [Ir(CO)(dppms)I(2)Et] (6). Analysis of the
      X-ray crystal structures showed that the dppms ligand adopts a conformation which
      creates a sterically crowded pocket around the alkyl ligands of 5a, 6, and 7. It
      is proposed that this steric strain can be relieved by migratory insertion, to
      give a five-coordinate acetyl product in which the sterically crowded quadrants
      flank a vacant coordination site, exemplified by the crystal structure of 3a.
      Conformational analysis indicates similarity between M(dppms) and M(2)(mu-dppm)
      chelate structures, which have less flexibility than M(dppe) systems and
      therefore generate greater steric strain with the "axial" ligands in octahedral
      complexes. Ab initio calculations suggest an additional electronic contribution
      to the migratory insertion barrier, whereby a sulfur atom trans to CO stabilizes
      the transition state compared to systems with phosphorus trans to CO. The results
      represent a rare example of the quantification of ligand effects on individual
      steps from catalytic cycles, and are discussed in the context of catalytic
      methanol carbonylation. Implications for other catalytic reactions utilizing
      chelating diphosphines (e.g., CO/alkene copolymerization and alkene
      hydroformylation) are considered.

PMID- 12418916
TI  - Coordination chemistry of silver cations.
AB  - While in pure solvents Ag(+) is known to be tetrahedrally coordinated, in the
      presence of ligands such as ammonia it forms linear complexes, usually explained
      by the ion's tendency toward sd-hybridization. To explore this disparity, we have
      investigated the reaction of ammoniated silver cations Ag(+)(NH(3))(n)(), n = 11
      23, with H(2)O as well as the complementary process, the reaction of
      Ag(+)(H(2)O)(n)(), n = 25-45, with NH(3) by means of FT-ICR mass spectrometry. In
      both cases, ligand exchange reactions take place, leading to clusters with a
      limited number of NH(3) ligands. The former reaction proceeds very rapidly until
      only three NH(3) ligands are left, followed by a much slower loss of an
      additional ligand to form Ag(+)(NH(3))(2)(H(2)O)(m)() clusters. In the
      complementary process, the reaction of Ag(+)(H(2)O)(n)() with NH(3) five ammonia
      ligands are very rapidly taken up by the clusters, with a much less efficient
      uptake of a sixth one. The accompanying DFT calculations reveal a delicate
      balance between competing effects where not only the preference of Ag(+) for sd
      hybridization, but also its ability to polarize the ligands and thus affect the
      strength of their hydrogen bonding, as well as the ability of the solvent to form
      extended hydrogen-bonded networks are important.

PMID- 12418917
TI  - Electroluminescence in ruthenium(II) complexes.
AB  - We have investigated the electrochemical, spectroscopic, and electroluminescent
      properties of a family of diimine complexes of Ru featuring various aliphatic
      side chains as well as a more extended pi-conjugated system. The performance of
      solid-state electroluminescent devices fabricated from these complexes using
      indium tin oxide (ITO) and gold contacts appears to be dominated by ionic space
      charge effects. Their electroluminescence efficiency was limited by the
      photoluminescence efficiency of the Ru films and not by charge injection from the
      contacts. The incorporation of di-tert-butyl side chains on the dipyridyl ligand
      was found to be the most beneficial substitution in terms of reducing self
      quenching of luminescence.

PMID- 12418918
TI  - Geometry for self-assembling of spherical hydrocarbon cages with methane
      thiolates on au(111).
AB  - An organodisulfide with a pair of adamantane moieties was synthesized, and its
      self-assembled monolayer (SAM) was formed on Au(111). The adamantane moieties are
      almost spherical and much bulkier than alkyl chains. The structure was
      characterized by scanning tunneling microscopy. Two-dimensional crystals of the
      SAM were found to be four orientationally different hexagonals with almost the
      same lattice constant with 4 radical 3a/3 and 7a/3 (a = 0.2884 nm, the Au lattice
      constant). The structure is assigned to four of the high-order commensurate
      adlayers. The present study of geometry and energetics for self-assembling of
      such an organosulfur compound with spherical cages provides a new insight into
      the probable SAM structure of various thiolate derivatives on Au(111).

PMID- 12418920
TI  - Long-term in vitro generation of amoebocytes from the Indian horseshoe crab
      Tachypleus gigas (Muller).
AB  - Amoebocyte is the single type of cell circulating in the horseshoe crab
      hemolymph, which plays a major role in the defense system of the animal. Granules
      present in these cells are sensitive to nanogram quantities of bacterial
      endotoxins, which form the basis of the Limulus amoebocyte lysate (LAL) test.
      Normally, amoebocytes for the production of the LAL are collected by cardiac
      puncture; hence, development of the in vitro culture system for amoebocytes will
      reduce the variability of the lysate and help to conserve the 400 million-yr-old
      living fossil. In the present investigation we have attempted organ culture of
      gill flaps that have been shown to be the source of amoebocytes. The gill flaps
      were cultured at 28 degrees C on a rocker platform in a modified L-15 medium
      supplemented with 10% v/v horseshoe crab serum. This led to the release of
      amoebocytes outside the gill flaps for a period of 6-8 wk with a more or less
      steady number of amoebocytes during the weekly harvest. No significant difference
      was seen in the yield of amoebocytes from male and female horseshoe crabs.
      Confocal laser microscopy studies revealed significant difference in the size of
      amoebocytes released in vitro as compared with those obtained in vivo. Thus, we
      have optimized the culture conditions for the long-term generation of amoebocytes
      in vitro from the Indian horseshoe crab Tachypleus gigas by reducing the
      incidence of contamination, simulating in vivo conditions for the organ culture
      of gill flaps, and improvising the nutritional status using the modified L-15
      medium, providing the desired osmolarity and pH.

PMID- 12418921
TI  - A kidney epithelial cell line from a Bolivian squirrel monkey.
AB  - Squirrel monkeys are the most commonly used New World primates in biomedical
      research, but in vitro studies are restricted by the limited number of cell lines
      available from this species. We report here the development and characterization
      of a continuous, kidney epithelial cell line (SQMK-FP cells) derived from a
      newborn squirrel monkey. Karyotype was consistent with Bolivian squirrel monkey
      (submetacentric chromosome pair 15 and acrocentric chromosome pair 16). All cells
      examined were hyperdiploid with chromosome numbers ranging from 52 to 57.
      Ultrastructural analysis of SQMK-FP cells revealed the presence of cell junctions
      with radiating filaments, indicating desmosomes and numerous surface projections
      containing longitudinally oriented filaments typical of tubular epithelium.
      Biochemically, SQMK-FP cells exhibit glucocorticoid resistance typical of the
      squirrel monkey. Glucocorticoid receptor (GR) binding is low in SQMK-FP cells
      because of high expression of the FK506-binding immunophilin FKBP51 that inhibits
      GR binding. SQMK-FP cells constitute a tubular epithelial cell line that has
      biochemical properties characteristic of squirrel monkeys and represents an
      alternate cell model to B-lymphoblast SML cells to study the biology of the
      squirrel monkey in vitro.

PMID- 12418922
TI  - A new cell line from the embryonic tissue of Helicoverpa armigera HBN.
      (Lepidoptera: Noctuidae).
AB  - A new cell line from the embryonic tissue of Helicoverpa armigera was established
      and designated as NIV-HA-197. It was maintained in TNM-FH medium supplemented
      with 10% fetal bovine serum. The cell line at passage 20 had a heterogeneous
      population of cells consisting of mainly epithelial-like cells (70%), followed by
      fibroblast-like (27%), and multinucleated giant (3%) cells. The chromosome number
      ranged from 45 to 185. The growth curve at passage 40 showed a fivefold increase
      in cell number with a population-doubling time of approximately 60 h. The cell
      line was found infected with the microsporidium Nosema heliothids at passage 9.
      Using the antiprotozoan drug Metrogyl 400 and simultaneous heat treatment, the
      parasite was removed from the culture. The cell line can be cryopreserved for 30
      mo. The species specificity of the new cell line was determined by studying the
      isoenzyme profile of four enzymes, viz., lactate dehydrogenase, malate
      dehydrogenase, isocitrate dehydrogenase, and glucose 6-phosphate dehydrogenase,
      and by heteroduplex analysis. Heteroduplex analysis was used to analyze the
      mitochondrial 16S ribosomal ribonucleic acid gene sequences along with the host
      insect gene sequences, and 100% homology was obtained, confirming the
      conspecificity of the cell line. The cell line was found to be susceptible to the
      baculoviruses Autographa californica multiple nucleopolyhedrovirus, Spodoptera
      litura multiple nucleopolyhedrovirus, and H. armigera single nucleopolyhedrovirus
      (HaSNPV). More than 90% of the cells were infected by HaSNPV on the seventh post
      infection day (PID), and 28.8 x 10(6) NPV/ml was yielded on the 10th PID. The in
      vitro-grown HaSNPV caused 100% mortality, when fed to the second instar H.
      armigera larvae, in 6 d. Cessation of feeding was observed on the second PID.

PMID- 12418923
TI  - Simultaneous isolation of endothelial and smooth muscle cells from human
      umbilical artery or vein and their growth response to low-density lipoproteins.
AB  - In the pathogenesis of atherosclerosis the interplay of endothelial cells (ECs)
      and smooth muscle cells (SMCs) is disturbed. Oxidatively modified low-density
      lipoproteins (oxLDLs), important stimulators of atherosclerotic plaque formation
      in vessels, modify the growth response of both cell types. To compare growth
      responses of ECs and SMCs of the same vessel with oxLDLs, we developed a method
      to isolate both cell types from the vessel walls of umbilical cords by enzymatic
      digestion. The method further allowed the simultaneous isolation of venous and
      arterial cells from a single umbilical cord. In culture, venous ECs showed an
      elongated appearance compared with arterial ECs, whereas SMCs of artery and vein
      did not look different. Smooth muscle cells of both vessel types responded to
      oxLDLs (60 microg/ml) with an increase in their [(3)H]-thymidine incorporation
      into DNA. On the contrary, ECs of artery or vein decreased [(3)H]-thymidine
      incorporation and cell number in the presence of oxLDLs (60 microg/ml) of
      increasing oxidation grade. Thus, human umbilical SMCs and ECs of the same vessel
      show a disparate growth response toward oxLDLs. But the physiologically more
      relevant minimal oxLDLs did not decrease proliferation in venous ECs but only in
      arterial ECs. This difference in tolerance toward minimal oxLDLs should be taken
      into account while using venous or arterial ECs of umbilical cord for research in
      atherosclerosis. Further differences of venous and arterial ECs in tolerance
      toward minimal oxLDLs could be of clinical relevance for coronary artery bypass
      grafts.

PMID- 12418924
TI  - Isolation and molecular characterization of brain microvascular endothelial cells
      from human brain tumors.
AB  - Brain tumor formation and growth is accompanied by the proliferation and
      infiltration of blood capillaries. The phenotypes of endothelial cells that make
      up capillaries are known to differ not only in the tissues in which endothelial
      cells are located but also as a result of the microenvironment to which they are
      exposed. For this reason, primary cultures of brain endothelial cells were
      isolated from human brain tumors removed by surgery and compared with cells from
      normal tissue. The primary confluent monolayers that grew out of isolated
      capillary fragments consisted of closely associated, elongated, fusiform-shaped
      cells. But brain tumor-derived endothelial cells in culture exhibited
      significantly less expression of endothelial-specific Factor VIII-related antigen
      compared with cells isolated from normal tissue. Cultured cells that exhibited
      binding of Ulex europaeus lectin were shown to take up Dil-Ac-Ldl and formed
      continuous monolayers that were joined together by tight junctions. The cells
      also exhibited characteristics of the cells of the brain microvasculature in
      vitro as seen by the presence of large numbers of mitochondria and few
      pinocytotic vesicles and by the absence of Weibel-Palade bodies within the cells.
      The expression of vascular cell adhesion molecule-1, E-Selectin, and the tight
      junction associated protein ZO-1 but not intercellular adhesion molecule-1 was
      demonstrated by immunohistological staining or reverse transcriptase-polymerase
      chain reaction methodologies. Comparative studies of these endothelial cells with
      endothelial cells from normal tissue will be useful for determining and
      understanding how the blood-brain barrier differs and functions in tumor and
      healthy tissues and may lead to strategies for brain tumor therapeutic
      approaches.

PMID- 12418925
TI  - Characterization of an epithelial cell line from bovine mammary gland.
AB  - Elucidation of the bovine mammary gland's unique characteristics depends on
      obtaining an authentic cell line that will reproduce its function in vitro.
      Representative clones from bovine mammary cell populations, differing in their
      attachment capabilities, were cultured. L-1 cells showed strong attachment to the
      plate, whereas H-7 cells detached easily. Cultures established from these clones
      were nontumorigenic upon transplantation to an immunodeficient host; they
      exhibited the epithelial cell characteristics of positive cytokeratin but not
      smooth muscle actin staining. Both cell lines depended on fetal calf serum for
      proliferation. They exhibited distinct levels of differentiation on Matrigel in
      serum-free, insulin-supplemented medium on the basis of their organization and
      beta-lactoglobulin (BLG) secretion. H-7 cells organized into mammospheres,
      whereas L-1 cells arrested in a duct-like morphology. In both cell lines,
      prolactin activated phosphorylation of the signal transducer and activator of
      transcription, Stat5-a regulator of milk protein gene transcription, and of PHAS
      I-an inhibitor of translation initiation in its nonphosphorylated form. De novo
      synthesis and secretion of BLG were detected in differentiated cultures: in L-1
      cells, BLG was dependent on lactogenic hormones for maximal induction but was
      less stringently controlled than was beta-casein in the mouse CID-9 cell line. L
      1 cells also encompassed a near-diploid chromosomal karyotype and may serve as a
      tool for studying functional characteristics of the bovine mammary gland.

PMID- 12418926
TI  - Histological and ultrastructural regulation in rabbit endometrial explants by
      estrogen in serum-free culture.
AB  - A repertoire of hormonal signals including estrogen regulate the growth,
      differentiation, and functioning of diverse target tissues, including the ovary,
      the mammary gland, and skeletal tissue. A serum-free culture system derived from
      rabbit endometrium explants has been devised and is reported here to explore
      estrogen action in vitro. The system involves aseptically harvesting the uterus
      from a virgin rabbit, dissecting the endometrium, explanting it into 1- to 2
      mm(3) pieces weighing approximately 1-2 mg each, and incubating these pieces in
      serum-free Medium-199. The culture is carried out for a period of 4 d in a
      humidified CO(2) incubator at 37 degrees C with 5% CO(2). The effect of
      extraneously added estrogen (1 microg/ml) was investigated by histological and
      ultrastructural procedures. It was observed that estrogen could induce specific
      changes, such as abundant mitochondria, rough endoplasmic reticulum, golgi
      complex, and intracellular collagen deposition, in both the epithelial and the
      fibroblast cell components of the explanted tissue. The study, therefore,
      indicates that the proposed system is an ideal tool for exploring and
      demonstrating estrogen responsiveness under in vitro conditions.

PMID- 12418927
TI  - Beta blockade induces apoptosis in cultured capillary endothelial cells.
AB  - Continuous beta blockade stimulates deposition of collagen in the pulmonary
      alveolar interstitium of adult rats. It also causes changes to the capillary
      endothelial cell compartment reminiscent of programmed cell death. To test
      whether beta blockade results in endothelial cell apoptosis, cultures of
      capillary endothelial cells were treated with both a wide-spectrum beta blocker
      and a beta-2-specific antagonist. Apoptosis was measured in these cultures using
      both terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate
      nick end labeling and annexin-V assays. Both forms of beta blockade stimulated
      programmed cell death in these cultures. To test whether the apoptotic effect of
      beta blockade was related to interstitial collagen deposition, capillary
      endothelial cells were cocultured with beta-blocked pulmonary fibroblast
      monolayers. Cocultured endothelial cells were substantially protected from
      apoptosis after beta blockade; coculture over plain tissue culture plastic or
      over exogenous collagen films had no effect on programmed cell death in
      endothelial cells. These results suggest that both pulmonary endothelial and
      interstitial cells are vulnerable to injury from beta blockade but that paracrine
      interactions between these cells may protect the peripheral lung from substantive
      damage.

PMID- 12418928
TI  - Oxygen modulates the growth of skin fibroblasts.
AB  - Elevated oxygen tensions are inhibitory to the growth of skin fibroblasts. Skin
      fibroblasts grow better at oxygen tensions below 137 mm Hg regardless of seeding
      density. A wide range of oxygen tensions, including those in the physiological
      range, strongly modulate the growth of human skin fibroblasts. There were no
      significant differences between the responses of fetal and postnatal cell lines
      to changes in ambient oxygen tension. In all cases, higher oxygen tensions
      significantly impeded cell growth. Seeding cells at 10(4) cells/cm(2) afforded
      some protection from the deleterious effects of hyperoxia. Oxygen tensions
      exceeding the amount present in ambient room air also impeded cell growth at this
      higher seeding density, but the effect did not become significant until the
      oxygen partial pressure reached 241 mm Hg. At lower oxygen tensions, cells seeded
      at 10(3) cells/cm(2) grew more rapidly than did cells seeded at 10(4)
      cells/cm(2). These findings may have implications for the treatment of poorly
      healing wounds with hyperbaric oxygen.

PMID- 12418929
TI  - A continuing commitment to excellence.

PMID- 12418930
TI  - The Starry Night (La Nuit Etoilee).

PMID- 12418931
TI  - Forty years of neurotransmitters: a personal account.
AB  - All drugs in psychiatry act by influences on neurotransmitter systems. Hence, an
      appreciation of neurotransmitter disposition helps clarify our understanding of
      therapeutic actions as well as adverse effects of psychotropic drugs. Moreover,
      understanding the nuances of neurotransmitters facilitates efforts to develop
      novel agents. Currently available psychoactive drugs exert their effects through
      3 or 4 of the longest-known neurotransmitters. Over the past few decades, up to
      100 novel neurotransmitter candidates have been identified, each of them as
      interesting as traditional biogenic amines. It is likely that totally new classes
      of therapeutic agents will emerge based on these transmitter molecules.

PMID- 12418932
TI  - The interplay of nature, nurture, and developmental influences: the challenge
      ahead for mental health.
AB  - This article succinctly reviews research achievements in the fields of
      psychiatric genetics, psychosocial influences on mental disorder, and
      developmental processes. The challenges for the future are discussed in relation
      to finding and understanding the following: (1) susceptibility genes; (2)
      environmentally mediated causal risk processes; (3) nature-nurture interplay; (4)
      the effects of psychosocial adversity on the organism; (5) the causal processes
      responsible for group differences in rates of disorder; and (6) age-related
      changes in psychopathological characteristics.

PMID- 12418933
TI  - Brain volume changes in first-episode schizophrenia: a 1-year follow-up study.
AB  - BACKGROUND: Imaging studies of patients with schizophrenia have demonstrated that
      brain abnormalities are largely confined to decreases in gray matter volume and
      enlargement of the lateral and third ventricles. Global gray matter volume has
      been reported to progressively decrease in childhood-onset and chronic
      schizophrenia. Global gray matter volumes have not been examined longitudinally
      in patients with first-episode schizophrenia. One would expect global gray matter
      to decrease progressively, particularly in first-episode patients, because
      clinical deterioration is greatest in the early stages of the disease. METHODS:
      Patients with first-episode schizophrenia who had taken antipsychotic medication
      for 0 to 16 weeks (n = 34) and matched healthy comparison subjects (n = 36) were
      included in the study. For all subjects, magnetic resonance imaging scans of the
      whole brain were obtained at inclusion and after 1 year (mean [SD], 12.7 [1.1]
      months). Outcome was measured 2 years after inclusion. To compare morphological
      changes over time between patients and healthy comparison subjects, multiple
      repeated-measures analyses of variance were conducted with intracranial volume as
      a covariate. Outcome and cumulative antipsychotic medication were related to
      changes in patients' brain volumes. RESULTS: Total brain volume (-1.2%) and gray
      matter volume of the cerebrum (-2.9%) significantly decreased and lateral
      ventricle volume significantly increased (7.7%) in patients. The decrease in
      global gray matter volume significantly correlated with outcome and,
      independently of that, with higher cumulative dosage of antipsychotic medication.
      CONCLUSIONS: The loss of global gray matter in schizophrenia is progressive,
      occurs at an early stage of the illness, and is related to the disease process
      and antipsychotic medication.

PMID- 12418934
TI  - Impaired visual object recognition and dorsal/ventral stream interaction in
      schizophrenia.
AB  - BACKGROUND: Schizophrenia is associated with well-documented deficits in high
      order cognitive processes such as attention and executive functioning. The
      integrity of sensory-level processing, however, has been evaluated only to a
      limited degree. Our study evaluated the ability of patients with schizophrenia to
      recognize complete objects based on fragmentary information, a process termed
      perceptual closure. Perceptual closure processes are indexed by closure
      negativity (N(cl)), a recently defined event-related potential (ERP) component
      that is generated within the visual association cortex. This study assessed the
      neural integrity of perceptual closure processes in schizophrenia by examining
      N(cl) generation. Generation of the preceding positive (P1) and negative (N1) ERP
      components was also examined. METHODS: We evaluated 16 patients with chronic
      schizophrenia and 16 healthy comparison subjects. Successively less fragmented
      images were presented during high-density ERP recording, which permitted the
      monitoring of brain activity during perceptual closure processes prior to object
      recognition. Analyses were performed at parieto-occipital and occipitotemporal
      sites consistent with dorsal and ventral stream generators of P1, N1, and N(cl).
      RESULTS: Patients with schizophrenia showed significant impairment in the ability
      to recognize fragmented objects, along with impaired generation of N(cl). The
      amplitude of visual P1 was significantly reduced, particularly over dorsal stream
      sites. In contrast, the generation of visual N1 was intact. CONCLUSIONS: Patients
      with schizophrenia are profoundly impaired in perceptual closure as indicated by
      both impaired performance and impaired N(cl) generation. The selective impairment
      in dorsal stream P1 is consistent with prior reports of impaired magnocellular
      processing in schizophrenia. By contrast, intact ventral N1 generation suggests
      that the initial stages of ventral stream processing are relatively preserved and
      that impaired magnocellular dorsal stream functioning in schizophrenia may lead
      to secondary dysregulation of ventral stream object recognition processing.

PMID- 12418935
TI  - An assessment of the independent effects of olanzapine and risperidone exposure
      on the risk of hyperlipidemia in schizophrenic patients.
AB  - BACKGROUND: The newer antipsychotic agents exhibit a superior safety profile
      compared with conventional antipsychotic agents in terms of extrapyramidal
      symptoms. Previous studies have suggested an association between olanzapine
      treatment and hyperlipidemia. We evaluated this association using a large health
      care database. METHODS: The study was derived from the England and Wales-based
      General Practice Research Database, composed of 3.5 million subjects followed up
      between June 1, 1987, and September 24, 2000. A total of 18 309 individuals
      diagnosed as having schizophrenia were identified. A 6:1 matched nested case
      control design was used. Conditional logistic regression was used to derive
      adjusted odds ratios (ORs), controlling for sex, age, and other medications and
      disease conditions influencing lipid levels. Antipsychotic drug exposure was
      defined as the receipt of at least 1 prescription for an antipsychotic medication
      within the 3 months before the date of diagnosis of hyperlipidemia. RESULTS:
      There were 1268 incident cases of hyperlipidemia in the cohort, matched to 7598
      control subjects. Olanzapine use was associated with nearly a 5-fold increase in
      the odds of developing hyperlipidemia compared with no antipsychotic exposure
      (OR, 4.65; 95% confidence interval [CI], 2.44-8.85) (P<.001) and more than a 3
      fold increase compared with those receiving conventional agents (OR, 3.36; 95%
      CI, 1.77-6.39) (P<.001). Risperidone was not associated with increased odds of
      hyperlipidemia compared with no antipsychotic exposure (OR, 1.12; 95% CI, 0.60
      2.11) (P =.72) or conventional antipsychotic exposure (OR, 0.81; 95% CI, 0.44
      1.52) (P =.52). CONCLUSIONS: We observed a strong association between olanzapine
      exposure and hyperlipidemia in schizophrenic patients. The possible metabolic
      consequences of olanzapine use should be given serious consideration by treating
      physicians.

PMID- 12418936
TI  - Increased amygdala activation to angry and contemptuous faces in generalized
      social phobia.
AB  - BACKGROUND: Generalized social phobia (GSP) is characterized by fear of social
      interactions and sensitivity to disapproval by others. Given the established role
      of the amygdala as part of a distributed neural system for the processing of
      emotional cues, we hypothesized that subjects with GSP would exhibit greater
      amygdala activation in response to harsh (angry, fearful, and contemptous) vs
      accepting (happy) facial emotional expressions compared with healthy control
      subjects (HCs). METHODS: Fifteen subjects with DSM-IV GSP and 15 age-, sex-,
      handedness-, and education-matched HCs, free of psychotropic medication for at
      least 12 weeks, viewed 60 color photographs from a standardized set of human
      facial stimuli, during which the task was to identify the sex of the person in
      the photograph. Data were collected across 3 functional (echo-planar) runs using
      a Siemens 1.5-T magnet, and analyzed using Analysis of Functional Neuroimaging
      software (Medical College of Wisconsin, Milwaukee). RESULTS: In the left
      allocortex (including the amygdala, uncus, and parahippocampal gyrus), subjects
      with GSP produced a significantly greater percent blood oxygen level-dependent
      signal change than did HCs for contemptous compared with happy faces (GSP: 0.72%
      vs HC: -0.01%; F(1,29) = 9.56, P =.004, Cohen d = 1.15) and for angry compared
      with happy faces (GSP: 0.45% vs HC: -0.09%; F(1,29) = 6.78, P =.02, Cohen d =
      1.00). Subjects with GSP and HCs did not produce a statistically different
      percent signal change for fearful or nonexpressive faces compared with the happy
      faces in this region. CONCLUSIONS: These findings are consistent with a role for
      differential amygdala (and associated limbic) functioning in GSP. The pronounced
      response to contemptuous and angry facial expressions suggests that the amygdala
      in GSP may be particularly active in the processing of disorder-salient stimuli.

PMID- 12418937
TI  - Drug use and the risk of major depressive disorder, alcohol dependence, and
      substance use disorders.
AB  - BACKGROUND: The Children in the Community Study is a prospective longitudinal
      study investigating the association between early drug use (childhood,
      adolescence, and early 20s) and later psychiatric disorders (in the late 20s).
      METHODS: Using data from a community-based sample of 736 adults (50% female) from
      upstate New York, the subjects were interviewed at the mean ages of 14, 16, 22,
      and 27 years. Psychiatric disorders, measured by age-appropriate versions of the
      University of Michigan Composite International Diagnostic Interview, and
      participant's drug use were assessed. RESULTS: Adolescent and young adult tobacco
      use was significantly associated with an increased risk of alcohol dependence and
      substance use disorders at a mean age of 27 years, but not with new episodes of
      major depressive disorder. Earlier alcohol use significantly predicted later
      major depressive disorder, alcohol dependence, and substance use disorders in the
      late 20s, as did early marijuana use and other illicit drug use. Except for the
      effect of tobacco use on major depressive disorder, early drug use was
      significantly related to later psychiatric disorders, even after statistically
      controlling for age, sex, parental educational level, family income, and prior
      episodes of major depressive disorder and substance use disorders. CONCLUSIONS:
      Our results suggest that early drug use is associated with and predicts later
      psychiatric disorders. Preventive implications stem from the importance of
      studying a range of psychiatric disorders in the context of substance use
      assessed over a wide age range.

PMID- 12418938
TI  - Rates and predictors of mortality in an aging, rural, community-based cohort: the
      role of depression.
AB  - CONTEXT: Depression, functional disability, cognitive impairment, and self-rated
      health all predict mortality in the elderly population. There is no consensus on
      their relative contributions when examined together. OBJECTIVES: To measure rates
      and identify predictors of mortality in an aging community-based cohort. DESIGN:
      Ten-year prospective epidemiological study. Predictor variables examined in Cox
      proportional hazards models were self-rated health, ability to perform
      instrumental activities of daily living (IADLs), depressive symptoms, and
      cognitive functioning, controlling for age, sex, education, and number of
      prescription drugs. SETTING: A largely blue-collar rural community in
      southwestern Pennsylvania. PARTICIPANTS: A population-based cohort of 1064
      adults, 67 years or older at the beginning of follow-up. MAIN OUTCOME MEASURES:
      Mortality at 3, 5, and 10 years (133, 218, and 482 deaths, respectively).
      RESULTS: Mortality rates were similar to those of the 1990 US population. Older
      age, male sex, IADL disability, and number of prescription drugs measured at
      baseline were significant predictors of mortality at all 3 follow-up end points.
      Depression at baseline predicted earlier (3- and 5-year) mortality but not later
      (10-year) mortality. The interaction between self-rated health and depression
      independently and strongly predicted mortality at all end points. Cognitive
      functioning predicted mortality only when IADL disability was excluded from the
      model. CONCLUSIONS: Age, sex, depression, and functional disability are strong
      and consistent independent predictors of mortality in older adults in the
      community, in addition to objective medical burden (prescription drugs).
      Depression alone predicts mortality in the shorter rather than longer term, but
      in combination with poor self-rating of health, it strongly predicts mortality at
      all end points.

PMID- 12418939
TI  - Neurocognitive impairments in nonpsychotic parents of children with schizophrenia
      and attention-deficit/hyperactivity disorder: the University of California, Los
      Angeles Family Study.
AB  - BACKGROUND: We tested the hypotheses that certain neurocognitive impairments
      index genetic liability to schizophrenia and that childhood-onset schizophrenia
      (COS) is a variant of adult-onset schizophrenia (AOS) by determining whether
      parents of COS probands show the types of neurocognitive impairments found in
      relatives of AOS probands. METHODS: Parents of COS probands (n = 79) were
      compared with parents of attention-deficit/hyperactivity disorder (ADHD; n = 190)
      and community control (CC; n = 115) probands on 3 neurocognitive tasks shown in
      previous research to detect impairments in patients with AOS and ADHD and in the
      relatives of patients with AOS. Parents with a diagnosis of psychosis were
      excluded from the study. RESULTS: On the Degraded Stimulus-Continuous Performance
      Test and the Trail-Making Test B-Adolescent Version, the parents of COS probands
      performed significantly worse than the parents of CC and ADHD probands, who did
      not differ significantly from each other. On the Span of Apprehension, we found
      no significant group differences. Using rigorous cutoffs, a combination of scores
      on the 3 neurocognitive tests identified 16 (20%) of the mothers and fathers of
      COS probands compared with 0% of the mothers and fathers of CC probands. There
      was diagnostic specificity of the neurocognitive impairments. A combination of
      neurocognitive scores identified 6 (12%) of the mothers of COS probands vs 0% of
      the mothers of ADHD probands. A cutoff that identified 2 (2%) of the fathers of
      ADHD probands classified 5 (17%) of the fathers of COS probands. We found no
      significant differences in neurocognitive functions between the parents of ADHD
      and CC probands. CONCLUSIONS: The aggregation of neurocognitive impairments in
      the parents of COS probands provides further evidence of etiologic continuity
      between COS and AOS. A substantial subgroup of parents of COS probands had a
      worse neurocognitive performance than that of any of the parents of ADHD and CC
      probands. Receiver operating characteristic curves showed that when rigorous
      cutoffs define neurocognitive impairments, the combination of scores on certain
      neurocognitive tasks produced a level of diagnostic accuracy in the parents of
      COS probands that is sufficient for use in genetic linkage studies.

PMID- 12418940
TI  - A cohort study of behavioral problems and intelligence in children with high
      prenatal polychlorinated biphenyl exposure.
AB  - BACKGROUND: In 1978, about 2000 persons in Taiwan were poisoned when their
      cooking oil was contaminated during manufacture with heat-degraded
      polychlorinated biphenyls, which are toxic, very widespread pollutant chemicals.
      The chemicals cannot be metabolized or excreted, and 8 of the first 39 children
      born to affected women died. When examined in 1985, 117 surviving children were
      found to have ectodermal defects, developmental delay, and disordered behavior.
      We have continued to observe the children. METHODS: From 1992 through 1995, 118
      children born between 1978 and 1985 (during or after their mothers' exposure) and
      118 matched neighborhood control children had cognitive function measured yearly
      with the Wechsler Intelligence Scale for Children-Revised and behavioral problems
      measured with the Achenbach Child Behavior Checklist and the Rutter Child
      Behavior Scale A. RESULTS: The exposed children scored 3 points (P =.05) lower
      than control children for IQ; 3 points (P =.002) higher on the Child Behavior
      Checklist (an effect size similar to the sex difference); and 6 points (P<.001)
      higher on the Rutter scale (3 times the sex difference). Birth year x exposure
      interactions, testing whether children born long after the exposure were as
      affected as those born soon after, were small and not significant. Age x exposure
      interactions, testing whether the children improved relative to control children
      as they got older, were significant only for the Rutter scale. CONCLUSIONS:
      Prenatal exposure to these compounds produces long-lasting cognitive and
      behavioral damage, but there is some evidence of recovery.

PMID- 12418941
TI  - Prevalence, expenditures, and complications of multiple chronic conditions in the
      elderly.
AB  - BACKGROUND: The prevalence, health care expenditures, and hospitalization
      experiences are important considerations among elderly populations with multiple
      chronic conditions. METHODS: A cross-sectional analysis was conducted on a
      nationally random sample of 1 217 103 Medicare fee-for-service beneficiaries aged
      65 and older living in the United States and enrolled in both Medicare Part A and
      Medicare Part B during 1999. Multiple logistic regression was used to analyze the
      influence of age, sex, and number of types of chronic conditions on the risk of
      incurring inpatient hospitalizations for ambulatory care sensitive conditions and
      hospitalizations with preventable complications among aged Medicare
      beneficiaries. RESULTS: In 1999, 82% of aged Medicare beneficiaries had 1 or more
      chronic conditions, and 65% had multiple chronic conditions. Inpatient admissions
      for ambulatory care sensitive conditions and hospitalizations with preventable
      complications increased with the number of chronic conditions. For example,
      Medicare beneficiaries with 4 or more chronic conditions were 99 times more
      likely than a beneficiary without any chronic conditions to have an admission for
      an ambulatory care sensitive condition (95% confidence interval, 86-113). Per
      capita Medicare expenditures increased with the number of types of chronic
      conditions from $211 among beneficiaries without a chronic condition to $13 973
      among beneficiaries with 4 or more types of chronic conditions. CONCLUSIONS: The
      risk of an avoidable inpatient admission or a preventable complication in an
      inpatient setting increases dramatically with the number of chronic conditions.
      Better primary care, especially coordination of care, could reduce avoidable
      hospitalization rates, especially for individuals with multiple chronic
      conditions.

PMID- 12418942
TI  - Osteoporosis and fractures in postmenopausal women using estrogen.
AB  - BACKGROUND: Previous studies demonstrate that postmenopausal women who use
      estrogen are somewhat protected from bone loss and fractures compared with
      nonusers, but the extent to which estrogen users remain at risk for osteoporosis
      and fractures is uncertain. OBJECTIVE: To determine long-term probabilities for
      incident fractures among postmenopausal estrogen users. METHODS: We examined data
      from the Study of Osteoporotic Fractures, a prospective cohort study with 10
      years of follow-up (1986-1999). This cohort includes 8816 women 65 years and
      older from community settings in 4 areas of the United States. MAIN OUTCOME
      MEASURES: Hip, wrist, vertebral, and nonvertebral fractures. RESULTS: At
      baseline, using criteria developed by the World Health Organization, 40% of
      continuous estrogen users were osteopenic and 13% were osteoporotic at the hip or
      spine. Although women currently using estrogen lost less bone density than past
      users or those who never used estrogen, all user groups on average lost bone from
      the hip and calcaneus. During 10 years of observation, the adjusted probability
      of nonvertebral fractures was 19.6% for continuous estrogen users, similar to
      current partial users and lower than past users and those who never used estrogen
      (P<.05). These comparisons were similar for hip, wrist, and vertebral fractures.
      CONCLUSIONS: Although estrogen use is associated with reduced prevalence of low
      bone density, less bone loss, and lower probabilities for fractures, osteoporosis
      and fractures are common in older women who used estrogen continuously since
      menopause. Estrogen users should be considered in strategies designed to detect,
      prevent, and treat osteoporosis.

PMID- 12418943
TI  - Postponed development of disability in elderly runners: a 13-year longitudinal
      study.
AB  - BACKGROUND: The magnitude and duration of the benefit of running and other
      aerobic exercise on disability and mortality in elderly persons are not well
      understood. We sought to quantify the benefits of aerobic exercise, including
      running, on disability and mortality in elderly persons and to examine whether
      morbidity can be compressed into later years of life by regular exercise.
      METHODS: A 13-year prospective cohort study of 370 members of a runners' club for
      persons aged 50 and older and 249 control subjects initially aged 50 to 72 years
      (mean, 59 years), with annual ascertainment of the Health Assessment
      Questionnaire disability score, noting any deaths and their causes. Linear mixed
      models were used to compute postponement in disability, and survival analysis was
      conducted to determine the time to and causes of death. RESULTS: Significantly
      (P<.001) lower disability levels in runners' club members vs controls and in ever
      runners vs never runners were sustained for at least 13 years. Reaching a Health
      Assessment Questionnaire disability level of 0.075 was postponed by 8.7 (95%
      confidence interval [CI], 5.5-13.7) years in runners' club members vs controls.
      Running club membership and participation in other aerobic exercise protected
      against mortality (rate ratio, 0.36 [95% CI, 0.20-0.65] and 0.88 [95% CI, 0.77
      0.99], respectively), while male sex and smoking were detrimental (rate ratio,
      2.4 [95% CI, 1.4-4.2] and 2.2 [95% CI, 1.1-4.6], respectively). Controls had a
      3.3 times higher rate of death than runners' club members, with higher death
      rates in every disease category. Accelerated rates of disability and mortality
      were still not seen in the runners' club members; true compression of morbidity
      was not yet observable through an average age of 72 years. CONCLUSION: Running
      and other aerobic exercise in elderly persons protect against disability and
      early mortality, and are associated with prolongation of a disability-free life.

PMID- 12418944
TI  - Parathyroid hormone for treatment of osteoporosis.
AB  - BACKGROUND: Osteoporosis is a common condition associated with multiple
      deleterious consequences. No therapy entirely abolishes fracture risk. METHODS: A
      MEDLINE database (1966 to the present) search was performed for randomized
      controlled trials in humans using the keywords osteoporosis and parathyroid
      hormone (PTH) or parathyroid hormone and fracture. The Cochrane database was
      searched using the search terms osteoporosis and parathyroid hormone. RESULTS:
      Parathyroid hormone (usually subcutaneous) dosages varied markedly across the 20
      randomized controlled trial studies retrieved. In the range of 50 to 100 micro
      g/d, effects may be dose-related. Results of larger trials (up to 1637 patients)
      were conflicting as to whether effects were limited to the spine and suggested
      detrimental effects on radius bone mineral density. Little data analyzed the
      effects of PTH in older vs younger subjects or directly compared the effects by
      sex. Increases in spine bone mineral density are induced by PTH in postmenopausal
      osteoporosis, glucocorticoid-induced osteoporosis, and idiopathic osteoporosis.
      Parathyroid hormone may protect against gonadotropin-releasing hormone agonist
      related bone loss. Effects are less clear at nonspine sites when PTH is used as
      part of combination or sequential therapies or for treatment of glucocorticoid
      induced osteoporosis. Parathyroid hormone decreased the incidence of
      radiographically detected spinal fractures. The numbers of nonvertebral fractures
      were too low to be broken down by individual site. Parathyroid hormone injections
      were difficult for some patients to comply with. Occasionally, PTH-associated
      hypercalcemia may be dose-dependent, often manifesting early in treatment. An
      increase in cancer risk from PTH is not reported in humans. CONCLUSIONS:
      Parathyroid hormone decreases vertebral fractures and increases spinal bone
      density in postmenopausal osteoporosis and glucocorticoid-induced osteoporosis,
      but at the expense of a decrease in radius bone density. The long-term safety and
      nonvertebral fracture efficacy are unknown.

PMID- 12418945
TI  - Predictive value of clinic and ambulatory heart rate for mortality in elderly
      subjects with systolic hypertension.
AB  - OBJECTIVE: To examine the association of clinic and ambulatory heart rate with
      total, cardiovascular, and noncardiovascular death in a cohort of elderly
      subjects with isolated systolic hypertension from the Systolic Hypertension in
      Europe Trial. METHODS: A total of 4682 patients participated, whose untreated
      blood pressure on conventional measurement at baseline was 160 to 219 mm Hg
      systolic and lower than 95 mm Hg diastolic. Clinic heart rate was the mean of 6
      readings during 3 visits. Ambulatory heart rate was recorded with a portable
      intermittent technique in 807 subjects. RESULTS: Raised baseline clinic heart
      rate was positively associated with a worse prognosis for total, cardiovascular,
      and noncardiovascular mortality among the 2293 men and women taking placebo.
      Subjects with heart rates higher than 79 beats/min (bpm) (top quintile) had a
      1.89 times greater risk of mortality than subjects with heart rate lower than or
      equal to 79 bpm (95% confidence interval, 1.33-2.68 bpm). In a Cox regression
      analysis, predictors of time to death were heart rate (P<.001), age (P<.001),
      serum creatinine level (P =.001), presence of diabetes (P =.002), previous
      cardiovascular disease (P =.01), triglyceride readings (P =.02), smoking (P
      =.04), and elevated systolic blood pressure (P =.05), while total cholesterol
      level was found to be nonsignificant in the model. In the ambulatory monitoring
      subgroup, clinic and ambulatory heart rates predicted noncardiovascular but not
      cardiovascular mortality. However, in a Cox regression analysis in which clinic
      and ambulatory heart rates were included, a significant association with
      noncardiovascular mortality was found only for clinic heart rate (P =.004). In
      the active treatment group, the weak predictive power of clinic heart rate for
      mortality disappeared after adjustment for confounders. CONCLUSIONS: In untreated
      older patients with isolated systolic hypertension, a clinic heart rate greater
      than 79 bpm was a significant predictor of all-cause, cardiovascular, and
      noncardiovascular mortality. Ambulatory heart rate did not add prognostic
      information to that provided by clinic heart rate.

PMID- 12418946
TI  - Time trends in high blood pressure control and the use of antihypertensive
      medications in older adults: the Cardiovascular Health Study.
AB  - BACKGROUND: Control of high blood pressure (BP) in older adults is an important
      part of public health efforts at prevention. OBJECTIVE: To assess recent time
      trends in the awareness, treatment, and control of high BP and in the use of
      medications to treat high BP. METHODS: In the Cardiovascular Health Study, 5888
      adults 65 years and older were recruited from 4 US centers. At baseline,
      participants underwent an extensive examination that included the measurement of
      BP, use of medications, and other risk factors. Participants were followed up
      with annual visits that assessed BP and medication use from baseline in 1989-1990
      through the examination in 1998-1999. The primary outcome measures were control
      of BP to levels lower than than 140/90 mm Hg and the prevalence of use of various
      classes of antihypertensive medications. RESULTS: The awareness, treatment, and
      control of high BP improved during the 1990s. The proportions aware and treated
      were higher among blacks than whites, though control prevalences were similar.
      For both groups combined, the control of high BP to lower than 140/90 mm Hg
      increased from 37% at baseline to 49% in 1999. The 51% whose BP was not
      controlled generally had isolated mild to moderate elevations in systolic BP.
      Among treated persons, the improvement in control was achieved in part by a mean
      increase of 0.2 antihypertensive medications per person over the course of 9
      years. Improved control was also achieved by increasing the proportion of the
      entire Cardiovascular Health Study population that was treated for hypertension,
      from 34.5% in 1990 to 51.1% in 1999. Time trends in antihypertensive drug use
      were pronounced. Among those without coronary disease, the use of low-dose
      diuretics and beta-blockers decreased, while the use of newer agents, such as
      calcium channel blockers, angiotensin-converting enzyme inhibitors, and alpha
      blockers increased. CONCLUSIONS: While control of high BP improved in the 1990s,
      about half the participants with hypertension had uncontrolled BP, primarily mild
      to moderate elevations in systolic BP. Low-dose diuretics and beta-blockers--the
      preferred agents since 1993 according to the recommendations of the Joint
      National Committee on the Detection, Evaluation and Treatment of High Blood
      Pressure--remained underused. More widespread use of these agents will be an
      important intervention to prevent the devastating complications of hypertension,
      including stroke, myocardial infarction, and heart failure.

PMID- 12418947
TI  - Frailty and activation of the inflammation and coagulation systems with and
      without clinical comorbidities: results from the Cardiovascular Health Study.
AB  - BACKGROUND: The biological basis of frailty has been difficult to establish owing
      to the lack of a standard definition, its complexity, and its frequent
      coexistence with illness. OBJECTIVE: To establish the biological correlates of
      frailty in the presence and absence of concurrent cardiovascular disease and
      diabetes mellitus. METHODS: Participants were 4735 community-dwelling adults 65
      years and older. Frail, intermediate, and nonfrail subjects were identified by a
      validated screening tool and exclusion criteria. Bivariate relationships between
      frailty level and physiological measures were evaluated by Pearson chi2 tests for
      categorical variables and analysis of variance F tests for continuous variables.
      Multinomial logistic regression was performed to evaluate multivariable
      relationships between frailty status and physiological measures. RESULTS: Of 4735
      Cardiovascular Health Study participants, 299 (6.3%) were identified as frail,
      2147 (45.3%) as intermediate, and 2289 (48.3%) as not frail. Frail vs nonfrail
      participants had increased mean +/- SD levels of C-reactive protein (5.5 +/- 9.8
      vs 2.7 +/- 4.0 mg/L), factor VIII (13 790 +/- 4480 vs 11 860 +/- 3460 mg/dL),
      and, in a smaller subset, D dimer (647 +/- 1033 vs 224 +/- 258 ng/mL) (P< or
      =.001 for all, chi2 test for trend). These differences persisted when individuals
      with cardiovascular disease and diabetes were excluded and after adjustment for
      age, sex, and race. CONCLUSIONS: These findings support the hypothesis that there
      is a specific physiological basis to the geriatric syndrome of frailty that is
      characterized in part by increased inflammation and elevated markers of blood
      clotting and that these physiological differences persist when those with
      diabetes and cardiovascular disease are excluded.

PMID- 12418948
TI  - The risk of the development of aortic stenosis in patients with "benign" aortic
      valve thickening.
AB  - BACKGROUND: Aortic valve thickening (AVT) without aortic stenosis (AS) is common
      and was often considered benign. However, it has recently been found to be
      associated with increased morbidity and mortality. It is unknown whether patients
      with AVT are at risk for the development of AS. METHODS: Our echocardiography
      database from 1987 to 1993 was searched for cases of AVT with at least 1 year of
      echocardiographic follow-up. The risk of the development of AS was compared in
      patients with and without AVT. RESULTS: There were 2131 patients with AVT and at
      least 1 year of echocardiographic follow-up. Aortic stenosis developed in 338
      patients (15.9%) (mild, 10.5%; moderate, 2.9%; and severe, 2.5%). Multivariate
      analysis, including age, left ventricular hypertrophy, and mitral annular
      calcification, revealed that only mitral annular calcification was independently
      and significantly associated with progression to AS. CONCLUSIONS: Aortic valve
      thickening without stenosis is common, and it may progress to significant AS. It
      is possible that this development of AS may be responsible for some of the
      increased morbidity and mortality in patients with AVT.

PMID- 12418949
TI  - Failure to vaccinate Medicare inpatients: a missed opportunity.
AB  - BACKGROUND: Hospitalized elderly patients are at risk for subsequent influenza
      and pneumococcal disease. Despite this risk, they are often not vaccinated in
      this setting. METHODS: We reviewed the medical records of a national sample of
      107 311 fee-for-service Medicare patients, 65 years or older, discharged from
      April 1, 1998, through March 31, 1999, with a principal diagnosis of acute
      myocardial infarction, heart failure, pneumonia, or stroke. We linked patient
      identifiers to Medicare Part B claims to identify influenza and pneumococcal
      vaccines paid for before, during, or after hospitalization. The main outcome
      measures were documentation by chart review or paid claim of influenza or
      pneumococcal vaccination. RESULTS: Of the 104 976 patients with a single
      hospitalization, 35 169 (33.5%; 95% confidence interval [CI], 33.2%-33.8%)
      received pneumococcal vaccination prior to admission, 444 (0.4%; 95% CI, 0.4%
      0.5%) were vaccinated in the hospital, and 1076 (1.0%; 95% CI, 1.0%-1.1%) were
      vaccinated within 30 days of discharge. In the subgroup of 40 488 patients
      discharged from October through December, 12 782 (31.6%; 95% CI, 31.1%-32.0%)
      received influenza vaccination prior to admission, 755 (1.9%; 95% CI, 1.7%-2.0%)
      were vaccinated in the hospital, and 4302 (10.6%; 95% CI, 10.3%-10.9%) were
      vaccinated after discharge. Of patients who were unvaccinated prior to admission,
      97.3% (95% CI, 97.1%-97.5%) did not receive influenza vaccine and 99.4% (95% CI,
      99.3%-99.4%) did not receive pneumococcal vaccine before hospital discharge.
      CONCLUSION: National recommendations for inpatient vaccination against influenza
      and pneumococcal disease are not being followed for the vast majority of eligible
      Medicare patients admitted to the hospital.

PMID- 12418950
TI  - The risk of recurrent venous thromboembolism in heterozygous carriers of factor V
      Leiden and a first spontaneous venous thromboembolism.
AB  - BACKGROUND: Factor V (FV) Leiden is a risk factor for venous thrombosis (VT).
      Data on its influence on the risk of recurrent venous thromboembolism (VTE) are
      controversial owing to different study designs and patient cohorts. METHODS: We
      reevaluated the risk of recurrence among heterozygous carriers and noncarriers of
      FV Leiden with a first spontaneous proximal VT of the leg and/or pulmonary
      embolism. Patients with secondary VTE, homozygous FV Leiden, natural inhibitor
      deficiencies, lupus anticoagulant, cancer, or long-term anticoagulation were
      excluded. The study end point was objectively documented, symptomatic, recurrent
      VTE. RESULTS: After discontinuation of oral anticoagulant therapy for a first
      VTE, we prospectively observed 287 patients, 83 (29%) of whom were heterozygous
      for FV Leiden. Recurrent VTE was seen in 17 (20%) of 83 patients with and 44
      (21.6%) of 204 without FV Leiden. The probability of recurrence among
      heterozygotes was 12% (95% confidence interval [CI], 8%-16%), 27% (95% CI, 21%
      33%), and 27% (95% CI, 21%-33%) after 2, 4, and 6 years, respectively, and was
      not higher than that among patients without the mutation (16%, 23%, and 34%,
      respectively). The relative risk of recurrence in heterozygotes was 0.9 (95% CI,
      0.5-1.6; P =.60) after adjustment for confounding variables. The risk of
      recurrence among patients with and without FV Leiden was not different when sex
      distribution or duration of anticoagulation therapy was taken into account.
      CONCLUSIONS: The risk of recurrence is similar among carriers and noncarriers of
      FV Leiden. Heterozygous patients should receive secondary thromboprophylaxis for
      a similar length of time as patients without FV Leiden.

PMID- 12418951
TI  - Patterns of pharmacotherapy and counseling for osteoporosis management in visits
      to US ambulatory care physicians by women.
AB  - BACKGROUND: Women experience rapid bone loss following menopause. Currently
      available guidelines recommend lifestyle counseling and pharmacotherapy for
      osteoporosis prevention and treatment in postmenopausal women. METHODS: We
      analyzed 2 years of National Ambulatory Medical Care Survey data (1997-1998), a
      national representative survey evaluating recent national patterns of
      antiosteoporosis medication (AOM) use and lifestyle counseling among office
      visits made by nonpregnant women 40 years and older. RESULTS: Women 40 years and
      older made an estimated 267 million office visits annually. Of those visits,
      about 10% were associated with AOM therapy. Estrogen replacement therapy was the
      most prevalent form of AOM therapy (80%) followed by therapy with calcium and/or
      cholecalciferol (vitamin D) supplements (15%). Visits for AOM were more likely to
      be associated with women in their 50s and 60s, white race, and having private
      insurance or Medicare. Women at AOM visits were twice as likely to receive
      concurrent lifestyle counseling than women at visits without AOM therapy.
      CONCLUSIONS: Women are particularly at risk for osteoporosis as they experience
      menopause, with estimates of 20 million women with osteoporosis or osteopenia.
      Despite the high prevalence, our study showed that only 10% of all visits were
      associated with 1 or more AOM therapy prescribed, provided, or continued in 1997
      and 1998. These data also suggest that women with Medicaid or self-pay status
      were less likely to receive AOMs than women with other forms of insurance. The
      status of AOM therapy and lifestyle counseling in ambulatory care practice in the
      United States during 1997 and 1998 was less than optimal.

PMID- 12418952
TI  - Orthostatic hypotension in acute geriatric ward: is it a consistent finding?
AB  - BACKGROUND: Orthostatic hypotension (OH) is a common finding among older
      patients. We designed a study to examine the prevalence and consistency of OH
      during the day. METHODS: A total of 502 inpatients (241 men and 261 women) with a
      mean age of 81.6 years were included in the study. Orthostatic tests were
      performed 3 times during the day, 30 minutes after meals. In 13 patients only 2
      sets of measurements were obtained, and they were omitted from some of the
      calculations. Orthostatic hypotension was defined as a fall of at least 20 mm Hg
      in systolic blood pressure and/or 10 mm Hg in diastolic blood pressure on
      assuming an upright posture. RESULTS: Three hundred thirty-two (67.9%) of 489
      patients experienced OH at least once during the day. Of these, 170 patients
      (34.8% of the 489) had OH at least twice (persistent OH) and 162 patients (33.1%)
      experienced OH only once (variable OH). Diastolic OH was more prevalent than
      systolic OH (57.3% vs 43.4%; P<.001). The intraindividual consistency of OH was
      low (kappa = 0.2). Orthostatic hypotension was observed less frequently during
      the evening than during the morning and afternoon (P<.05 vs morning and P =.003
      vs afternoon). The difference between meals' constituents (light vs heavy meals)
      did not affect the prevalence of OH. CONCLUSIONS: Orthostatic hypotension is very
      common in the elderly, and diastolic OH is more common than systolic OH. The
      prevalence of OH is the lowest during the evening, and meals do not increase the
      prevalence of OH. The intraindividual consistency of OH during the day is poor.
      Thus, in elderly patients, more attention should be paid to diastolic OH and the
      diagnosis should be based on repeated measurements.

PMID- 12418953
TI  - Zinc deficiency leading to intractable vomiting.

PMID- 12418954
TI  - Percentage set straight.

PMID- 12418956
TI  - Statin use and fracture risk.

PMID- 12418958
TI  - Falls and 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors.

PMID- 12418959
TI  - Integrative medicine is a trojan horse.

PMID- 12418961
TI  - Mad4 is regulated by a transcriptional repressor complex that contains Miz-1 and
      c-Myc.
AB  - Myc and Mad family proteins are central regulators of cellular proliferation and
      differentiation. We show that various Mad family genes have distinct patterns of
      expression during the chemically induced differentiation of mouse
      erythroleukaemia (MEL) cells, suggesting that they each serve a different
      function. Mad4 RNA is highly induced and persists in terminally differentiated
      cells, in agreement with observations in other systems. Using reporter gene
      assays in stably transfected MEL cells, we show that induction of Mad4 is
      mediated by a 49 nt core promoter region. We demonstrate that the initiator
      element is required for Mad4 activation, and show that induction is associated
      with the loss from the initiator of a complex that contains Miz-1 and c-Myc. Miz
      1 activates the Mad4 promoter in transient transfection assays, and this effect
      is antagonized by c-Myc. We therefore identify Mad4 as a novel target of
      transcriptional repression by c-Myc. These data suggest that the expression of
      Mad4 in proliferating undifferentiated cells is suppressed by the binding of a c
      Myc-Miz-1 repressor complex at the initiator, and that the activation of Mad4
      during differentiation results, at least in part, from a decrease in c-Myc
      mediated repression.

PMID- 12418962
TI  - Identification of HTF (HER2 transcription factor) as an AP-2 (activator protein
      2) transcription factor and contribution of the HTF binding site to ERBB2 gene
      overexpression.
AB  - The ERBB2 gene is overexpressed in 30% of human breast cancers and this is
      correlated with poor prognosis. Overexpression of the ERBB2 gene is due to
      increased transcription and gene amplification. Our previous studies have
      identified a new cis element in the ERBB2 promoter which is involved in the
      gene's overexpression. This cis element, located 501 bp upstream from the main
      ERBB2 transcription initiation site, binds a transcription factor called HTF
      (HER2 transcription factor). We report here the identification of HTF as an AP-2
      (activator protein-2) transcription factor. The new cis element is bound by AP-2
      with high affinity, compared with a previously described AP-2 binding site
      located 284 bp downstream. Co-transfection of an AP-2alpha expression vector with
      a reporter vector containing the newly identified AP-2 binding site in front of a
      minimal ERBB2 promoter induced a dose-dependent increase in transcriptional
      activity. We examined the contribution of the new AP-2 binding site to ERBB2
      overexpression. For this purpose we abolished the new and/or the previously
      described AP-2 binding sequence by site-directed mutagenesis. The results show
      that the two functional AP-2 sites in the first 700 bp of the ERBB2 promoter co
      operate to achieve maximal transcriptional activity.

PMID- 12418963
TI  - A novel splice variant of mouse interleukin-1-receptor-associated kinase-1 (IRAK
      1) activates nuclear factor-kappaB (NF-kappaB) and c-Jun N-terminal kinase (JNK).
AB  - Interleukin-1 (IL-1)-receptor-associated kinase (IRAK) is an indispensable
      signalling molecule for host-defence responses initiated by a variety of ligands
      that bind to members of the Toll/IL-1 receptor family. Here we report a novel
      splice variant of mouse IRAK-1, IRAK-1-S, which is generated by utilizing a new
      splicing acceptor site within exon 12. IRAK-1-S cDNA is shorter than the
      originally reported IRAK-1 (IRAK-1-W) cDNA by 271 nucleotides, and the subsequent
      frameshift causes a premature termination of translation after 23 amino acids,
      which are unique to the IRAK-1-S protein. To elucidate the physiological function
      of IRAK-1-S, we overexpressed it in 293T cells and studied the effects on the IL
      1 signalling cascade. As it lacks the C-terminal region of IRAK-1-W that has been
      reported to contain the TRAF6 (tumour necrosis factor receptor-associated factor
      6) binding domain, IRAK-1-S was unable to bind TRAF6 protein, which is a proposed
      downstream signalling molecule. However, IRAK-1-S overexpressed in 293T cells
      induced constitutive activation of nuclear factor-kappaB (NF-kappaB) and c-Jun N
      terminal kinase (JNK) independent of stimulation by IL-1, as did IRAK-1-W. To
      clarify the mechanism of NF-kappaB activation by IRAK-1-S in the absence of
      binding to TRAF6, we demonstrated that IRAK-1-S binds to IRAK-1-W through its
      death domain; the findings suggested that overexpressed IRAK-1-S may bind
      endogenous IRAK-1-W and activate TRAF6 through IRAK-1-W. These results also
      indicate that this novel variant may play roles in the activation of NF-kappaB
      and JNK by IL-1 and other ligands whose signal transduction is dependent on IRAK
      1 under physiological conditions.

PMID- 12418964
TI  - Identification of amino acid residues critical for catalysis and stability in
      Aspergillus niger family 1 pectin lyase A.
AB  - Site-directed-mutagenesis studies were performed on family 1 pectin lyase A
      (PL1A) from Aspergillus niger to gain insight into the reaction mechanism for the
      pectin lyase-catalysed beta-elimination cleavage of methylesterified
      polygalacturonic acid and to stabilize the enzyme at slightly basic pH. On the
      basis of the three-dimensional structures of PL1A [Mayans, Scott, Connerton,
      Gravesen, Benen, Visser, Pickersgill and Jenkins (1997) Structure 5, 677-689] and
      the modelled enzyme-substrate complex of PL1B [Herron, Benen, Scavetta, Visser
      and Jurnak (2000) Proc. Natl. Acad. Sci. U.S.A. 97, 8762-8769], Asp154, Arg176,
      Arg236 and Lys239 were mutagenized. Substituting Arg236 with alanine or lysine
      rendered the enzyme completely inactive, and mutagenesis of Arg176 and Lys239
      severely affected catalysis. The Asp154-->Arg and Asp154-->Glu mutant enzymes
      were only moderately impaired in respect of catalysis. The results strongly
      indicate that Arg236, which is sandwiched between Arg176 and Lys239, would
      initiate the reaction upon enzyme-substrate interaction, through the abstraction
      of the proton at C5 of the galacturonopyranose ring. The positively charged
      residues Arg176 and Lys239 are responsible for lowering the p K a of Arg236.
      Arg176 and Lys239 are maintained in a charged state by interacting with Asp154 or
      bulk solvent respectively. The deprotonation of the Asp186-Asp221 pair was
      proposed to be responsible for a pH-driven conformational change of PL1A [Mayans,
      Scott, Connerton, Gravesen, Benen, Visser, Pickersgill and Jenkins (1997)
      Structure 5, 677-689]. Substitution of Asp186 and Asp221 by Asn186 and Asn221 was
      expected to stabilize the enzyme. However, the Asp186-->Asn/Asp221-->Asn enzyme
      appeared less stable than the wild-type enzyme, even at pH 6.0, as evidenced by
      fluorescence studies. This demonstrates that the pH-dependent conformational
      change is not driven by deprotonation of the Asp186-Asp221 pair.

PMID- 12418965
TI  - Gene expression patterns vary in clonal cell cultures from Rett syndrome females
      with eight different MECP2 mutations.
AB  - BACKGROUND: Females with the neurological disorder Rett syndrome are heterozygous
      for mutations in X-linked MECP2 that encodes methyl-CpG binding protein 2 (MeCP2)
      thought to act as a transcriptional repressor. To identify target genes for MeCP2
      modulation, we studied global gene expression in single cell-derived wild-type
      and mutant MECP2 expressing fibroblast clones with four common mutations (R106W,
      R306C, 705delG, 1155del32) and in lymphoblastoid cell lines (LCLs) that included
      four mutant MeCP2 (T158M, 803delG, R168X and 1159del28) expressing, and five
      (1159del28, R106W, R255X, 803delG, 803delG) wild-type MeCP2 expressing lines.
      METHODS: Clonality and mutation status were verified by androgen receptor
      methylation assays for X-inactivation and by sequencing MECP2 transcripts.
      Expression studies were done with oligonucleotide microarrays (Affymetrix U95)
      and verified with real-time quantitative RT-PCR using Sybr Green. RESULTS:
      Expression of 49 transcripts was increased, and expression of 21 transcripts was
      decreased, in at least 3 of 4 mutant/wild-type fibroblast comparisons. Transcript
      levels of 11 genes, determined by quantitative RT-PCR, were highly correlated
      with the microarray data. Therefore, multiple additional clones from two Rett
      individuals were tested by RT-PCR only. Striking expression differences were
      found in both mutant and wildtype MeCP2 expressing clones. Comparing expression
      profiles of lymphoblastoid cell lines yielded 16 differentially expressed genes.
      CONCLUSIONS: MeCP2 deficiency does not lead to global deregulation of gene
      expression. Either MeCP2's in vivo function does not involve widespread
      transcriptional repression, or its function is redundant in cell types that also
      express other methyl-CpG binding proteins. Our data suggest that clonal
      fibroblast strains may show substantial inter-strain variation, making them a
      difficult and unstable resource for genome-wide expression profiling studies.

PMID- 12418966
TI  - Identification of two SNPs in the 5' flanking region of the ACP1 gene and
      evaluation of disequilibrium among polymorphic sites.
AB  - We have studied the 5' flanking region of the ACP1 gene looking for new
      polymorphisms. Two SNPs, DdeI and FokI restricted, have been found in this
      region. We determined the genotype of DdeI and FokI SNPs, as well as of three
      other known SNPs, codon 43 (CfoI restricted), codon 41 and codon 105 (TaqI
      restricted), located respectively in exons 3, 4 and 6 in 62 unrelated subjects
      from the Italian population. Haplotype distribution for the ten possible pairs of
      loci were determined by a maximum likelihood procedure. Overall, statistically
      significant deviations from expected frequencies assuming equilibrium have been
      observed for the following pairs: FokI/codon 41, FokI/TaqI, codon 41/TaqI
      (complete association), DdeI/FokI, DdeI/codon 41 and DdeI/TaqI. The data suggest
      that the FokI area could include sequences operating in strict functional
      association with sequences included in the codon 41/TaqI area, possibly in order
      to regulate the F/S isoforms ratio of the A* and *B alleles. Since the ratio
      between the concentration of the two F and S isoforms is different for the three
      ACP1 alleles, we suggest that the ACP1 locus has been subjected to strong
      selective pressure to obtain an optimal alternative splicing mechanism of the *A
      and *B alleles. The *C variant, on the other hand, seems completely independent
      from sequences in the FokI/codon 41/TaqI areas, resulting in an inverted F/S
      ratio compared to that found for *A and *B alleles.

PMID- 12418968
TI  - Mitochondrial DNA variability in Poles and Russians.
AB  - Mitochondrial DNA (mtDNA) sequence variation was examined in Poles (from the
      Pomerania-Kujawy region; n = 436) and Russians (from three different regions of
      the European part of Russia; n = 201), for which the two hypervariable segments
      (HVS I and HVS II) and haplogroup-specific coding region sites were analyzed. The
      use of mtDNA coding region RFLP analysis made it possible to distinguish parallel
      mutations that occurred at particular sites in the HVS I and II regions during
      mtDNA evolution. In total, parallel mutations were identified at 73 nucleotide
      sites in HVS I (17.8%) and 31 sites in HVS II (7.73%). The classification of
      mitochondrial haplotypes revealed the presence of all major European haplogroups,
      which were characterized by similar patterns of distribution in Poles and
      Russians. An analysis of the distribution of the control region haplotypes did
      not reveal any specific combinations of unique mtDNA haplotypes and their
      subclusters that clearly distinguish both Poles and Russians from the
      neighbouring European populations. The only exception is a novel subcluster U4a
      within subhaplogroup U4, defined by a diagnostic mutation at nucleotide position
      310 in HVS II. This subcluster was found in common predominantly between Poles
      and Russians (at a frequency of 2.3% and 2.0%, respectively) and may therefore
      have a central-eastern European origin.

PMID- 12418967
TI  - Y-chromosome biallelic polymorphisms and Native American population structure.
AB  - It has been proposed that women had a higher migration rate than men throughout
      human evolutionary history. However, in a recent study of South American natives
      using mtDNA restriction fragment polymorphisms and Y-chromosome microsatellites
      we failed to detect a significant difference in estimates of migration rates
      between the sexes. As the high mutation rate of microsatellites might affect
      estimates of population structure, we now examine biallelic polymorphisms in both
      mtDNA and the Y-chromosome. Analyses of these markers in Amerinds from North,
      Central and South America agree with our previous findings in not supporting a
      higher migration rate for women in these populations. Furthermore, they underline
      the importance of genetic drift in the evolution of Amerinds and suggest the
      existence of a North to South gradient of increasing drift in the Americas.

PMID- 12418969
TI  - Distribution of HLA alleles in Portugal and Cabo Verde. Relationships with the
      slave trade route.
AB  - HLA-A, -B, and -DR frequencies were analysed in populations from Portugal and the
      Madeira and Cabo Verde Archipelagos, aiming to characterize their genetic
      composition. Portuguese settlers colonized both Archipelagos in the 15th and 16th
      centuries. Madeira received many sub-Saharan slaves to work in the sugar
      plantations, and Cabo Verde served as a pivotal market in the Atlantic slave
      trade and was populated by individuals coming from the Senegambia region of the
      West African coast. The population of Madeira shows the highest genetic diversity
      and the presence of alleles and haplotypes usually linked to sub-Saharan
      populations, the haplotypes accounting for 3.5% of the total. Cabo Verde presents
      typical markers acknowledged to be of European or Ibero-Mediterranean origin,
      thus revealing the admixture of European settlers with Sub-Saharan slaves.
      Altogether the number of European haplotypes reaches 15% of the total. The
      Portuguese population shows a perceivable and significant heterogeneity both in
      allele and haplotype frequencies, unveiling a differential input of peoples from
      different origins. A PCA of the populations studied, plus other relevant ones,
      clearly shows gene heterogeneity in mainland Portugal as well as the differences
      and relationships between these populations and Madeira and Cabo Verde.

PMID- 12418970
TI  - The expected power of genome-wide linkage disequilibrium testing using single
      nucleotide polymorphism markers for detecting a low-frequency disease variant.
AB  - The expected power of genome-wide linkage disequilibrium (LD) testing for a low
      frequency disease variant was examined using a simple genetic model in which the
      degree of LD between the disease variant and the adjacent single nucleotide
      polymorphism (SNP) marker decreases in proportion to the number of generations
      since the LD-generating event. In this study, the frequency of the SNP marker
      being in complete LD with a low-frequency disease variant at the LD-generating
      event was regarded as the random variable having the probability distribution
      expected from the neutral infinite sites model, which enables us to derive the
      formula for calculating the expected power of genome-wide LD testing without
      determining the allele frequency of the associated SNP marker. Such a treatment
      is essential for the evaluation of the power of LD testing, because the frequency
      of the associated marker allele is always unknown. The main results obtained are
      as follows: (1) genome-wide LD testing with a case-control design could identify
      a disease variant with a high penetrance, while a low-frequency disease variant
      showing a low penetrance is difficult to detect; (2) although the degree of LD
      increases as the number of markers increases, the power of LD testing does not
      necessarily increase after the significance level is adjusted by the Sidak
      correction or the Bonferroni correction based on the number of testings; (3) the
      use of SNP markers with only high-frequency minor alleles is more powerful for
      detecting LD even with a low-frequency disease variant than the use of SNP
      markers with both high- and low-frequency minor alleles. Thus, the study design
      of LD testing must be evaluated prior to the investigation. The present study
      will provide a guideline for determining the number of SNP markers and the range
      of SNP allele frequencies suitable for genome-wide LD testing.

PMID- 12418971
TI  - Accurate power approximations for chi2-tests in case-control association studies
      of complex disease genes.
AB  - A popular method for the analysis of case-control association studies is to
      compare the frequencies of the alleles between cases and controls by means of
      Pearson's chi2-statistic. Here, an approach for computing the power of this test
      is presented, which by computer simulation is shown to be more reliable than a
      previously published power approximation. Since the test based on Pearson's chi2-
      statistic can be anti-conservative if there is an excess of homozygotes for the
      susceptibility allele in the general population, it has been proposed to analyze
      case-control association studies by means of a trend test based on genotypes
      instead of alleles. We present an accurate power approximation for the trend
      test. The power approximations are implemented in an available computer program
      'GenOdyPower', which in addition has an option to determine the empirical power
      of these tests by simulations.

PMID- 12418972
TI  - On calculating the power of a TDT study--comparison of methods.
AB  - We show that the methods for calculating the power of the TDT of Risch &
      Merikangas (1996), McGinnis (1998, 2000), Tu & Whittemore (1999) and Knapp (1999)
      consist of three distinct approaches. The differences between the methods arise
      either by treating parental transmissions independently or not, and either
      conditioning on parental heterozygosity or not. Transmissions are only truly
      independent when the mode of inheritance of the disease is multiplicative, making
      this assumption invalid and the methods that assume them (Risch & Merikangas,
      1996; McGinnis, 1998, 2000) inappropriate. We demonstrate a basic model that
      allows analytical comparisons of the methods, and suggest a new method that
      calculates power at least as accurately as any of the three previously published.

PMID- 12418974
TI  - Jordanian men's attitudes and views of birth-spacing and contraceptive use (a
      qualitative approach).
AB  - This qualitative study was carried out to understand the meaning that Jordanian
      men attach to birth-spacing/family planning and to identify their attitudes and
      practices regarding contraceptives. Six focus group discussions were conducted
      over a 3-month period starting April 1996, with each group containing 6-10 men.
      The sample consisted of Jordanian men residing in Amman. Education, social class,
      and marital status stratified men's selection. The discussions were moderated by
      a social psychologist of the same sex. With respondents' consent, data gathered
      in the discussion groups were tape-recorded, transcribed, and critically analyzed
      using the content analysis method. The researchers found that there was a
      consensus among all men about the link between the concept of birth
      spacing/family planning and the concept of better health for the mother and the
      child. Yet, the practice of contraception was influenced by some religious and
      cultural beliefs including that of "RIZK" (or fortune) which comes when the child
      is born. Moreover, some knowledge deficits concerning modern methods of
      contraception, and their side effects in particular, were noted. Some unfavorable
      attitudes of men for themselves using male contraceptives were also noted. Most
      men in the study indicated that spousal communication takes place on issues
      related to family planning, but the final decision is, in most cases, left to the
      husband alone (the head of the house). The demand for an increasing number of
      male children and the resistance of males to use condoms were among the most
      prevalent unexpected phenomena noticed in this study. The study concludes by
      recommending that special attention be directed to males when delivering family
      planning services.

PMID- 12418975
TI  - Development of healthy public policy: feminist analysis of conflict,
      collaboration and social change.
AB  - In the past two decades, the need for economic restructuring has served as a
      rationale for dismantling social programs in Canada. As it has been enacted, such
      social restructuring has disproportionately affected marginalized people,
      particularly women. In this article we explore the schism between the principles
      that underlie the development of healthy public policy and those that are driving
      current social policy development. Through this analysis we discuss the
      implications of policy development that is based upon principles of inequity, and
      we suggest that implementation of healthy public policy requires transformational
      change in the underlying principles of the social system. A policy shift based
      upon principles of equity and social justice has been espoused throughout the
      health promotion literature. We suggest that such a shift will be facilitated by
      strengthening collaborative relations among points of conflict within society and
      among policy makers and women's organizations.

PMID- 12418976
TI  - Choosing therapies: a Senegalese woman's experience with infertility.
AB  - In this article I examine a Senegalese woman's experience in selecting treatments
      for infertility. A critical-interpretive approach is employed to place in context
      this woman's therapy selection process. Treatments are revealed through illness
      narrative, interviews, and participant observation. This case study illustrates
      the variability of choices available and the factors influencing the selection of
      different therapies over time. These factors include availability of different
      therapies as well as the meanings of infertility and the therapies. The social,
      economic, and political access to treatments permitted this individual to seek
      therapies that gave meaning to why she was experiencing infertility. The decision
      maker predominantly chose a traditional form of treatment, gris-gris, amulets
      worn about the body. After continual use, she found them ineffective and then
      used allopathic medicine with various other treatments including prayer, plants,
      and spirit divination. Overall, this decision-maker's strategies are rooted in
      the belief that she must ardently search for a solution to Allah's challenge of
      infertility. (To ensure the confidentiality of all individuals mentioned in this
      research, I have changed their names in this article.)

PMID- 12418977
TI  - Women's reflections on divorce-- 10 years later.
AB  - Ten years after divorce 95 women who participated in an earlier study of divorce
      were asked to reflect on their lives since their divorce. They were mailed a
      questionnaire to describe demographic data, self-esteem, control, life
      assessment, and their lives since divorce. Fewer than half remarried and of those
      who did, 10 divorced a second time. Slightly more women partnered than married.
      Their overall assessment of their lives was reported positively. However, 25%
      felt the same or worse than they had 10 years earlier. Income was the only
      demographic variable correlated with self-esteem, control, and life assessment.
      Women used a variety of self-care actions to improve their lives and only six
      women went to professional therapy. Their lives and some of the actions taken are
      described.

PMID- 12418978
TI  - Barriers to cancer screening amongst women with mental health problems.
AB  - The involvement of women with mental health problems in cancer screening was
      examined in order to explore service delivery options among this particular
      group. Structured interviews were used to identify the utilization of cancer
      screening and barriers experienced in accessing such screening among this group.
      The sample of women reported similar utilization rates of cancer screening as the
      general female population of the same Australian state. However, they identified
      a number of barriers to effective access to cancer screening. In response to the
      interview finding that consumers valued screening services from a well-known
      provider in a familiar environment, a series of women's health clinics were
      offered within a mental health service. This experience is described and was used
      to try to better understand barriers to cancer screening experienced by women
      with mental health problems. The women's health clinics were most efficiently
      offered in conjunction with hospital-based psychiatric services.

PMID- 12418979
TI  - Adherence to cultural practices following childbirth in migrant Chinese women and
      relation to postpartum mood.
AB  - Chinese women (N = 102) who had migrated to Sydney, Australia, were interviewed
      about traditional cultural practices they had followed in the first six weeks of
      the postpartum period. The majority (90.2%) of these women had adhered to some
      form of practice, with the most frequent being eating warm ('yang') food (78%),
      following confinement for one month (55%), and using warm water for washing
      themselves (19%). Of note was that 18% of these women felt ambivalent about
      following such practices, with the impression being that the adoption of such
      practices was more a result of family or in-law expectations than the wishes of
      the woman. Of the 9.8% who did not follow any form of traditional Chinese
      postpartum practice, only half felt ambivalent or negative about not doing so.
      There was no relationship between the women's mood at six weeks postpartum and
      how she felt about following or not following such practices. The adherence to
      traditional cultural practices was not related to length of time in Australia,
      nor to whether the woman was residing with her parents or in-laws. There was some
      indication that more educated women were less likely to follow cultural practices
      following the birth.

PMID- 12418980
TI  - Women who smoke crack and their family substance abuse problems.
AB  - Toward the goal of understanding African American women who smoke crack cocaine
      and the family context in which their drug use occurs, this descriptive
      investigation aimed to characterize the relationship between the participants'
      substance abuse problems and that of their family members. We used previously
      collected data from interviews of 208 women and examined whether participants'
      substance abuse would closely parallel that of their family members, particularly
      male family members. Indeed, participants' drug use was highly correlated with
      partners' substance use (X(2) = 12.6; p < or =.001), father's substance use (X(2)
      = 11.9; p < or =.001), brothers' drug use (X(2) = 6.2; p < or =.05), and uncles'
      alcohol and drug abuse (X(2)= 5.3; p <=.05). Among female family members, only
      aunts' drug and or alcohol abuse (X(2) = 5.3; p < or =.05) was significantly
      correlated with that of the participants. These findings clearly support the
      hypothesis that the participants' substance use patterns are significantly
      correlated with that of male family members.

PMID- 12418981
TI  - Holistic Obstetrical Problem Evaluation (HOPE): testing a theory to predict birth
      outcomes in a group of women from appalachia.
AB  - The purpose of this study was to test the Holistic Obstetrical Problem Evaluation
      (HOPE) theory by determining the effects of prenatal factors from the
      biophysical, psychosocial, spiritual, and perceptual domains of the HOPE theory
      with infant birth outcomes. Face-to-face interviews were conducted using standard
      and reliable questionnaires with a convenience sample of 120 pregnant women
      between the ages of 14 and 44 years and 16-28 weeks gestation, and attending
      three prenatal clinics in East Tennessee. Based on the multiple regression
      analysis, absence of maternal partner support during pregnancy and African
      American race predicted variance for infant birth weight (p <.05), while lower
      levels of self-esteem, use of drugs and alcohol, and active religiosity predicted
      shorter length of gestation at birth (p <.05). The multiple logistic regression
      analysis model revealed that the HOPE theory was significantly related to a
      greater incidence of preterm birth (p =.03), Chi(2) = 28.16, R(2) =.22. Within
      this model, lower levels of self-esteem and a woman's negative perception of her
      pregnancy, were significant predictors for preterm birth (p <.05). Although there
      was preliminary support for this holistic theory, further research with a larger
      and more diverse population of women is needed.

PMID- 12418982
TI  - Social network and role demands in women's Type 2 diabetes: a model.
AB  - Type 2 diabetes is a common chronic disease in middle-aged and older women. The
      social network, although an important source of support, can place conflicting
      demands on women who cope with a chronic disorder. Because this paradoxical
      situation can be a burden for many women a model was constructed to
      systematically investigate social network demands in women's Type 2 diabetes. In
      developing the model, network theory provided the framework and an extensive
      literature review determined which network components should be included.
      Material from our individual and focus group interviews was used to clarify the
      model. Traditional gender roles in the home, obligation profiles at the
      workplace, cultural expectations on women's bodies, and prejudice about the
      psychological etiology of women's diseases in health care, could all contribute
      to women's experiencing role conflict in their daily diabetes management. To
      systematically investigate potential deterrents to women's self-care, questions
      that address the different components of women's social networks are proposed.

PMID- 12418983
TI  - The Ohio Midlife Women's Study.
AB  - The Ohio Midlife Women's Study was longitudinal with measurements occurring at
      three, 9-month intervals. Our purpose in doing this research was to examine
      predictors, moderators, and outcome variables associated with the transition to
      midlife in Caucasian and African American women. Predictor variables included
      loss and gain of resources. Moderators included menopause symptoms, menopausal
      status, attitude toward menopause, coping, and demographic characteristics.
      Outcome variables included anxiety, depression, and health promoting activities.
      To obtain the proposed final sample of 160 midlife women, an initial sample of
      103 African American and 105 Caucasian "healthy" women were recruited in the
      community. Consistent predictors of anxiety were loss of resources, coping
      effectiveness, and education. Consistent predictors of depression were loss of
      resources and education. Health promoting activities were consistently predicted
      by attitude toward menopause and coping effectiveness. Stress is a better
      predictor of negative health outcomes than menopausal status.

PMID- 12418984
TI  - Eliciting qualitative information about induced abortion: lessons from Northeast
      Thailand.
AB  - Obtaining reliable information about induced abortion is notoriously difficult,
      especially where abortion is illegal. This article describes methods used in a
      study of illegal induced abortion among village women in Northeast Thailand. A
      variety of methods were used to gather in-depth qualitative data on abortion
      experiences including a randomized interview survey on reproductive health, in
      depth interviews with women who had experienced an induced abortion in the last
      two years, and the use of vignettes in focus group discussions with men and
      women. The survey provided a broad overview of the extent of the experience of
      abortion. In-depth interviews through social networks proved more successful for
      obtaining reliable accounts of abortions and suggest that survey results were
      underestimates. Focus groups discussed the situational ethics involved in
      abortion decisions. Within an appropriate context and study design, it is
      possible to obtain highly sensitive information while respecting the privacy of
      informants.

PMID- 12418985
TI  - Crossing the border for abortion services: the Tijuana-San Diego connection.
AB  - In this study we created a profile of women living on both sides of the US-Mexico
      border who terminated pregnancies in San Diego at the largest clinic providing
      abortion services in California. Sociodemographic and reproductive history data
      were collected on all 1558 women terminating pregnancies in 1996. Using country
      of residence, language use, and surname, the sample was stratified into four
      comparison groups: Tijuana residents, U.S. Non-Latinas, U.S. English-speaking
      Latinas, and U.S. Spanish-speaking Latinas. These data were supplemented by
      interviews with field experts. Compared to U.S. residents, crossborder abortion
      seekers were older, had healthier habits, were less likely to terminate in the
      second trimester, and more likely to pay cash for their procedure. While
      crossborder abortion seekers in San Diego face multiple barriers to access
      abortions, they posed no increased risk for complications, nor did they represent
      a financial burden on California.

PMID- 12418986
TI  - The relationship of contextual factors to women's perceptions of medical
      abortion.
AB  - This study explores how personal values and the social context of women's lives
      influence their perceptions of a new reproductive technology, medical abortion.
      The major objective is to examine the interrelationship between perceived
      attributes of medical abortion (number of clinic visits, availability early in
      pregnancy, seeing the expelled products of conception, and unfamiliar method) and
      the context of a woman's life. Data were collected in eight focus group
      interviews with a demographically diverse sample of 73 women who were potential
      users of mifepristone and were analyzed using content analysis techniques.
      Findings indicate that a woman's perceptions and choice of an abortion method are
      grounded in the circumstances of her life, and multiple factors enter into the
      decision-making process. Contextual and personal factors (residence, social
      support, cultural background, religion, ambivalence towards abortion, and
      employment) interact with specific attributes of the method to determine
      acceptability and choice.

PMID- 12418987
TI  - Japanese women's experience of childbirth in the United States.
AB  - While Japanese people represent a significant and growing cultural group within
      the United States, little is known about the culture-specific needs of Japanese
      women who experience pregnancy and childbirth in this country. Five women
      participated in a study of Japanese women's experience of pregnancy and
      childbirth in the United States. The following thematic clusters emerged from the
      interview data: issues related to the maintenance of Japanese birth-related
      practices and traditions; comparison of the Japanese and U.S. health systems;
      language difficulties; and the need for support systems. This group of well
      educated, medically sophisticated women regarded their experiences overall to be
      positive. Still, they identified areas of uncertainty and unfamiliarity of which
      health professionals should be aware in order to facilitate the negotiation of
      culturally congruent care.

PMID- 12418988
TI  - A longitudinal study of bone density in midlife women.
AB  - A longitudinal study of 386 healthy Black and White women aged 35-60 years was
      conducted to determine the effects of physical activity and other related factors
      on lumbar bone mineral density over 24 months. Bone mineral density of the lumbar
      spine, L2-L4, was measured using dual energy x-ray (Hologic 1000). Physical
      activity levels in three dimensions (leisure, household, and occupational) from
      both a lifelong and current perspective were obtained by questionnaire. Body mass
      index was calculated from measured weight in kilograms divided by measured height
      in meters squared. Calcium, caffeine, and alcohol intake was estimated using a
      food frequency questionnaire. Age, race, and smoking were determined by self
      report. Radioimmunoassays of follicle stimulating hormone (FSH) and estradiol
      were used to validate self-reports of menopausal status. Multiple regression
      analysis revealed that race, age, weight, FSH, calcium, and years of tobacco
      intake formed the best model at baseline (r(2) = 0.32) and at 24 months (r(2) =
      0.303). Physical activity was not a significant predictor for bone mineral
      density at either time point. There were cross-sectional changes of bone mineral
      density with race, age, and menopausal status. Black women had significantly
      higher bone mineral density than White women. However, an age-related decline in
      bone mineral density was exhibited in both Black and White women. Perimenopausal
      women had significantly lower bone mineral density as compared with premenopausal
      women. Furthermore 37 (9.6%) women at baseline and 34 (11%) at 24 months were
      designated at risk for fracture.

PMID- 12418989
TI  - Caring for themselves: facilitators and barriers to women home care workers who
      are chronically ill following their care plan.
AB  - Compliance literature has paid little attention to the ability of patients to
      carry out their care plan. Indeed, throughout this literature, the voices of
      patients are disturbingly absent. In this paper, I report a study of compliance
      issues among women home care workers who were chronically ill. Twenty-nine women
      participated in five focus groups. They were asked to share perspectives on what
      helps, what hinders, and how their health care providers were either facilitators
      or barriers to their care plan. Key findings were identified through a
      qualitative content analysis. My findings suggest that perspectives on
      compliance, which do not begin with an understanding of factors affecting
      compliance within the individual's control, are unrealistic. For these women,
      following a care plan required being sufficiently motivated and having necessary
      supports. Supports were identified as good doctor-patient communication, adequate
      financial resources, time and ability to attend to their care, and spirituality.
      Yet, even if all supports were in place, if participants did not have a stated
      motivation (i.e. sufficient reason to follow their care plan), they continued to
      go through the motions. My study suggests that recognizing the personal context
      of chronic illness may be what motivates patients to follow their care plan. This
      finding can be used by providers for patient assessment, and may help to form a
      foundation for empathic communication.

PMID- 12418990
TI  - Effects of shiftwork on sleep and menstrual function in nurses.
AB  - Evidence suggests that shiftwork is associated with menstrual irregularities,
      reproductive disturbances, risk of adverse pregnancy outcome, and sleep
      disturbances in women, yet little has been done to evaluate the effects of
      shiftwork on menstrual function and fertility. The purpose of this study was to
      evaluate menstrual function, fertility, and pregnancy outcome in nurses working
      shiftwork, and to examine the relationship of sleep to menstrual function. Sixty
      eight nurses < 40 years old completed a survey evaluating sleep, menstrual
      function, and pregnancy outcome. Fifty-three percent of the women noted menstrual
      changes when working shiftwork. Women noting menstrual changes reported more
      physiological symptoms (p < 0.003), slept approximately one hour less when
      working nights, and reported lengthened time to fall asleep (p < 0.01) when
      working nights. Findings suggest that sleep disturbances may lead to menstrual
      irregularities, and changes in menstrual function may be a marker of shiftwork
      intolerance.

PMID- 12418991
TI  - Being female: the portrayal of women's health in print media.
AB  - In this article, we examine the portrayal of women's health issues in two of
      Melbourne's print media: The Age and the Herald Sun. In particular, we aim to
      examine the patterns of coverage of women's health and the underlying message in
      articles on women's health issues. We employed an unobtrusive method, and the
      study was conducted over a three-month period: May to July 1998. We found that
      many of the articles and public reactions centred on women and reproduction. This
      implies that women are still seen in relation to their reproductive role in
      Australian society. In addition, there are many issues regarding women and their
      health missing from the media's publication during the research period. The
      message emerging from the analysis implies that if women do not fit into the
      "ideal women" framework of the society, their health needs are given little
      attention by the print media and, therefore, their health is likely to suffer.
      This can be interpreted as one form of women's oppression in Australian society.

PMID- 12418992
TI  - Factors that promote and prevent preparation for future care needs: perceptions
      of older Canadian, German, and US. women.
AB  - The risk of needing help with household tasks or of requiring care in old age
      increases. Using semi-structured, qualitative interviews, beliefs about the
      usefulness versus uselessness of planning ahead for future care needs (FCN) were
      investigated in 23 East German, 10 U.S., and 10 Canadian elderly-community
      dwelling women (> or= 65 years). Primary reasons in favor of planning for FCN
      were: gaining a feeling of security regarding the future, avoiding being a burden
      to potential helpers, and coping with one's present health conditions. Factors
      that prevent planning for FCN were: the difficulty foreseeing FCN, the lack of
      resources to plan, and low levels of perceived vulnerability. The women dealt
      with the contradictions between these factors that promote and prevent
      preparation by making general plans which could be adapted in the case of needing
      help by developing alternative plans or by avoidance of thinking about possible
      future health crises.

PMID- 12418993
TI  - Man works from sun to sun, but woman's work is never done: insights on research
      and policy.
AB  - Gender equity and equality in health and human development are key national and
      international goals. To achieve these goals, the androcentric definition of work
      needs to be addressed. The current definition is driven by the globalized
      capitalistic model, which equates "work" with generating income or the production
      of goods. Indeed, employment in the formal labor force has become the de facto
      definition of work. Women's work, unpaid and reflecting the gendered role of
      caring for others, does not fit the economic mold and is, therefore, devalued.
      The health and social welfare sectors rely heavily on the unremunerated work of
      women to reduce their budgets, ignoring the unequal burden of care shouldered by
      women worldwide. Research on women's health has also been hampered by the
      dichotomous nature of work as employment. Changing the definition of work to
      value explicitly women's work could significantly impact social, health, and
      research policies.

PMID- 12418994
TI  - A winning combination: women, literacy, and participation in health care.
AB  - Health information materials written at the appropriate reading level help
      individuals manage their own health care. In this study, we assessed the reading
      ability of clients and readability of the patient information materials at a
      rural women's health clinic. We administered a reading comprehension test to 50
      subjects and tested the patient education materials using a readability formula.
      More than one in six women could not read all of the patient information, which
      could limit their understanding, and achievement of good health care.
      Commercially available materials can be checked readily for reading level using
      software installed in most computers. This software also allows clinicians who
      prepare their own materials for their patients to generate versions that are
      appropriate for different reading levels.

PMID- 12418995
TI  - The quality of life of families of female-headed households in Botswana: a
      secondary analysis of case studies.
AB  - Previous studies note a positive relationship between female-headed households
      (FHHs) and poverty in urban and rural areas of Botswana. To explore this further,
      data were collected from 7 FHHs through participant observation and open-ended
      interviews. A secondary analysis of data described the quality of life (QOL) of
      members of the households according to one's ability to meet basic human needs
      (food, water, shelter, safety, and health). FHHs ranged in age from 40-91 years,
      with family size ranging from 1-11 members. Monthly income for 6 of the 7
      families was 30 dollars (U.S.) per month or less. Physical living environments
      were overcrowded, with poorly maintained latrines and unsafe refuse disposal.
      Family illnesses included hypertension, cataracts, mental illness, knee pain,
      ringworm, leg sores, and tonsillitis. Health risk behaviours included unprotected
      sex, alcohol abuse, and breastfeeding among potentially HIV positive mothers.
      Although Botswana claims rapidly rising levels of national income after
      independence, the QOL of FHHs remains poor. We suggest that, to alleviate
      poverty, governments in developing African countries should explore strategies
      that effectively target families headed by women.

PMID- 12418996
TI  - Patient education services as oppressor?
AB  - The education provided to women patients has been used historically to deliver
      messages of social and medical control. I suggest ethical standards of practice
      to tilt the balance toward use of education to serve women's perceived needs.
      Specific steps include standards and guidelines that specifically address
      appropriate gender differences in educational messages, regular elicitation from
      women of educational needs and satisfaction with educational services, and
      research that specifically tests the impact of patient education services on
      women and on men. More broadly, patient education must be legitimated as an
      essential service for which providers and institutions are accountable, and the
      predominately nonphysician providers who deliver it must be empowered to
      challenge current practice. Current work on health care as a gendered system
      suggests that patient education practice can rid itself of only some of the
      gender bias that exists.

PMID- 12418997
TI  - Brain injury: quality of life's greatest challenge.
AB  - The objectives of this investigation were to (1) identify elements that comprise
      an acceptable quality of life (Q-L) post-traumatic brain injury (TBI) from the
      perspectives of patients and families, and (2) explore patient and family
      satisfaction with treatment decisions relevant to QoL. The authors created,
      tested, and administered two forms (patient; family) of a 35-question interview
      to 33 participants in a longitudinal TBI study (14 women, 19 men) and 33
      associated family members. Men associated ratings of QoL with numerous variables,
      while women's responses revealed no significant relationships shared by QoL and
      other variables. Women reported a poorer QoL than did men. Older patients
      reported a better QoL than did younger patients. Families emphasized the family
      relationship, emotional control, and ability to concentrate when considering
      overall QoL. Patients did not. The majority of patients and families expressed
      satisfaction with decisions made about acute treatment. QoL research is essential
      to illuminate best practice models.

PMID- 12418998
TI  - Increasing functional rehabilitation in acquired brain injury treatment:
      effective applications of behavioural principles.
AB  - This paper investigated ways to increase the participation of direct care staff
      in the functional rehabilitation activities (FRAs) of adults with acquired brain
      injuries (ABIs). FRAs were rehabilitation agendas written by clinical staff for
      delivery by paraprofessionals. Increases in FRA completion were believed to be
      directly related to clinical success. These FRAs had been identified as key
      components in the rehabilitation programmes of the adults living within the
      residential facilities. Increases in FRAs were crucial in improving the quality
      of the rehabilitation programmes of the participants involved. The study observed
      four residential settings serving adults with ABIs using a multiple baseline
      design. The treatment approach consisted of public posting of weekly FRA
      documentation, incorporation of staff input, and reinforcement for documentation
      of FRAs. The results indicated a positive impact on the participation of staff in
      all of the residences in the study, consistent with implementation of the
      treatment package.

PMID- 12418999
TI  - The development of awareness and the use of compensatory strategies for cognitive
      deficits.
AB  - BACKGROUND: Cognitive rehabilitation often involves teaching individuals with
      acquired brain injuries (ABI) to use compensatory strategies for cognitive
      deficits. The use of compensatory strategies is frequently limited by reduced
      awareness of deficits. The process through which a person with ABI develops
      awareness and begins to use compensatory strategies is rarely explored from the
      clients' perspectives. OBJECTIVE: To explore the development of awareness and the
      use of compensatory strategies by adults with ABI. SETTING: A cognitive
      rehabilitation day treatment programme. METHOD: A critical incidents, qualitative
      inquiry was conducted with three clients who had made good recovery. The
      development of awareness and the use of compensatory strategies is examined from
      the clients' perspectives. Their perspectives are compared to the perspectives of
      the therapists with whom they worked during the cognitive rehabilitation process.
      RESULTS: Clients described the development of deficit awareness as a slow process
      with occasional 'aha' moments. These moments involved a comparison of current
      performance to pre-morbid performance on functional tasks. There was agreement
      among clients and therapists on the cognitive deficits manifested and on the
      strategies used to compensate for those deficits. The description of the process
      of developing awareness, however, was different. CONCLUSION: In-depth qualitative
      exploration of the experiences of clients has the potential to provide guidance
      for more effective cognitive rehabilitation interventions.

PMID- 12419000
TI  - Cognitive profile for Chinese patients with stroke.
AB  - PRIMARY OBJECTIVE: This study aimed to investigate the usefulness of the Chinese
      version of Cognistat for patients with stroke in a Chinese community. METHODS AND
      PROCEDURES: A total of 53 patients and 34 normal elderly with age, gender and
      literacy level matched were tested with the Chinese translated version of
      Cognistat. OUTCOMES AND RESULTS: The results suggest that the patients performed
      significantly lower than their normal counterparts on the test. The Orientation,
      Attention and Calculation sub-tests were the most significant contributors to its
      high sensitivity (0.79) and specificity (0.85), which is largely consistent with
      the original English version. A two-factor structure was confirmed with the 10
      sub-tests clustered into the areas of fluid and crystallized abilities, which
      indicates that the translation of the test content did not alter the structure of
      the instrument. However, the low level of literacy of the local elderly
      population and language structure tends to slightly alter the cognitive profile
      of the patients. CONCLUSIONS: Further studies are recommended to further explore
      the cross-cultural issues and clinical implications on establishing cognitive
      profile for patients with stroke with Cognistat.

PMID- 12419001
TI  - Impulse control differences between abstinent heroin users and matched controls.
AB  - OBJECTIVE: Heroin use has been associated with increased impulsive behaviour.
      This study examined the lasting effect of heroin use on impulse control in a
      group of ex-heroin addicts. RESEARCH DESIGN AND METHOD: Twenty-eight men, 14 ex
      heroin addicts and 14 matched controls, participated in this study. The impulse
      control ability between the two groups was compared. Each participant was
      individually interviewed for demographic data and testing of their impulse
      control ability using the Porteus Maze Test. RESULTS: The findings indicated that
      the ex-heroin addicts performed significantly more poorly on the measure of
      impulse control than the matched controls. CONCLUSIONS: This observation suggests
      that the adverse effect of heroin on impulse control may be long lasting.
      Alternative explanations for the findings were also discussed.

PMID- 12419002
TI  - Lack of apoptosis in the hypoxic brain of a rat model mimicking cyanotic heart
      disease.
AB  - OBJECTIVE: To assess the effect of chronic hypoxia on brain neuronal apoptosis,
      an animal model mimicking cyanotic heart disease was utilized. METHODS: Rats were
      placed in an hypoxic environment at birth and oxygen levels were maintained at
      10% in an air-tight Plexiglass chamber. Controls remained in room air. Animals
      were sacrificed and the brains were harvested at 1 and 4 weeks, respectively.
      RESULTS: Significant polycythemia developed in the hypoxic rats at 1 and 4 weeks.
      Indexed brain mass to body weight was significantly increased in the hypoxic
      groups by 18% (p < 0.01) and 38% (p < 0.01) as compared to controls at 1 and 4
      weeks, respectively. There was no difference in the number of apoptotic neurons
      between the chronically hypoxic rats and controls, as assayed by TUNEL labelling
      and Hoechst staining. The role of the sphingolipid ceramide was then examined
      because of its reported role in stress response, growth suppression and
      apoptosis. It was found that the brain ceramide accumulation was not
      significantly different in the hypoxic and control groups at 1 and 4 weeks.
      CONCLUSION: A protective adaptive response to chronic hypoxia in the neonatal
      brain may exist.

PMID- 12419003
TI  - Using counterconditioning to treat behavioural distress during subcutaneous
      injections in a paediatric rehabilitation patient.
AB  - A counterconditioning-based intervention was conducted to supplement topical
      anaesthesia during repeated parent-administered subcutaneous injections performed
      on a 7-year-old girl for anticoagulation post-stroke. Preferred activities were
      paired with in vivo exposure to medical stimuli, first during simulated, then
      actual injections. Differential positive reinforcement was provided contingent on
      engagement with preferred activities, button pressing in response to an auditory
      stimulus, and general compliance with adult instructions. Child distress was
      measured by direct observations and intervention effects examined using an A-B,
      single-subject case study design with an interrupted time-series statistical
      analysis for brief single-subject data. Child distress decreased significantly
      when behavioural intervention was provided. Parent ratings indicated that
      treatment effects were maintained after the intervention was turned over to the
      mother and continued at home. Heart rate data provided physiological evidence of
      counterconditioning. The results are discussed in relation to the application of
      conditioning and counterconditioning theory in the paediatric rehabilitation
      setting.

PMID- 12419004
TI  - The neurobehavioural consequences of St. Louis encephalitis infection.
AB  - BACKGROUND: St. Louis encephalitis (SLE) is a relatively common cause of
      neurological illness, yet little is known about its cognitive and psychosocial
      consequences. PURPOSE: To describe the cognitive, emotional, psychophysiological,
      and psychosocial consequences of SLE infection. METHOD: A comprehensive
      neuropsychological and psychophysiological evaluation of a high functioning woman
      6 weeks and 1 year after acute SLE infection is presented. The focus and course
      of rehabilitation is also examined. RESULTS: The primary cognitive consequences
      of SLE infection involved attention, working memory, speed of processing, and
      cognitive efficiency. Depression was also observed. Psychometric testing
      suggested that these deficits largely resolved after 1 year. CONCLUSIONS: SLE
      produces neurocognitive deficits which are reflected in both psychometric and
      psychophysiologic measures and functional status. Psychometric and vocational
      improvement were observed over 1 year. However, the normal vocational return came
      at a significant psychosocial cost. This case emphasizes the importance of a
      comprehensive neuropsychological evaluation and illustrates the importance of an
      integrated rehabilitation programme.

PMID- 12419006
TI  - Collective symbolic coping with new technology: Knowledge, images and public
      discourse.
AB  - Using data from policy analyses, media analyses and a European-wide survey about
      public perceptions of biotechnology conducted in 1996 and again in 1999, it is
      shown how a country's public develops an everyday understanding of a new
      technology (genetic modification) construed as potentially harmful by the media.
      To understand the reliance on images and related beliefs, we propose a theory of
      collective symbolic coping. It identifies four steps: first, the creation of
      awareness; second, production of divergent images; third, convergence upon a
      couple of dominant images in the public sphere; fourth, normalization. It is
      suggested that symbolic coping occurs in countries where a recent increase in
      policy activity and of media reporting has alerted the public; that this public
      show a high proportion of beliefs in menacing images; that these beliefs are
      relatively independent of pre-existing popular science knowledge; and that they
      are functionally equivalent to scientific knowledge in providing judgmental
      confidence and reducing self-ascribed ignorance. These propositions are shown to
      be true in Austria and Greece. Several implications of the theory are discussed,
      including social representation theory and public understanding of science.

PMID- 12419007
TI  - Manufacturing individual opinions: market research focus groups and the
      discursive psychology of evaluation.
AB  - This article addresses a paradox. On the one hand, discourse and rhetorical
      studies have provided evidence that evaluative talk is both variable and
      rhetorically organized. On the other hand, a wide range of social psychological
      research is produced that both presupposes and finds evidence of enduring
      underlying attitudes. One explanation for this may be that, on some occasions at
      least, the results of attitude research are a consequence of procedures that
      restrict and refine from everyday evaluative practices in a way that ensures the
      'discovery' of underlying attitudes. The article explores this explanation in one
      domain where there is a major practical concern with attitudes and opinions,
      namely market research focus groups. Detailed analysis of transcripts of eight
      market research focus groups identifies three procedures that moderators use to
      produce freestanding opinion packages: (a). they display rhetorically embedded
      evaluations as inconsequential; (b). they provide formal guidance for
      participants to produce freestanding opinions; and (c). they formulate
      participants' talk as freestanding opinions, stripping off rhetorical elements.
      The findings are supported by considering deviant cases. This illustrates one way
      in which evaluations are transformed into freestanding attitudes. More broadly,
      it contributes to a body of work that studies how social science methods work in
      practice.

PMID- 12419008
TI  - Protecting the ingroup stereotype: ingroup identification and the management of
      deviant ingroup members.
AB  - In two experiments, we investigated the impact of the presentation of a deviant
      ingroup member on the perception of the ingroup among participants who differed
      in their degree of identification with the ingroup. In Study 1, we measured
      psychology students' level of identification with the group of psychologists
      (i.e. the ingroup) and presented them with an anti-norm versus a pro-norm
      psychologist. Results showed that in the anti-norm condition (but not in the pre
      norm condition), identification predicted the ratings of psychologists as a group
      and the perception of typicality of the deviant psychologist. Also, in this
      condition, the impact of the level of identification on the ratings of
      psychologists proved to be mediated by the perceived typicality of the deviant.
      In Study 2, group measures were taken both before and after presentation of a
      deviant among members of an environmentalist group who differed in their level of
      identification with the ingroup. The level of identification had an impact on the
      modification of the ratings of environmentalists as a group, and this effect was
      mediated by the perceived typicality of the deviant environmentalist. The results
      are discussed in terms of their implications for the black sheep effect and the
      stereotype change literature.

PMID- 12419009
TI  - A meta-analysis of sex differences in romantic attraction: do rating contexts
      moderate tactic effectiveness judgments?
AB  - Although a number of studies have explored perceived sex differences in romantic
      attraction effectiveness, no research has systematically examined whether
      different rating contexts might moderate effectiveness judgments. In a meta
      analytic review of romantic attraction research, four potential moderating
      variables were examined: temporal context (unspecified, long-term, short-term),
      manipulation form (self-promotion, competitor derogation), attraction type
      (general, retention, poaching), and sex of rater (mixed, same, opposite).
      Although perceived sex differences in physical appearance and resource-related
      tactics remained stable across most moderating variables, sex differences did
      vary across some rating contexts. For example, perceptions of sex differences in
      the effectiveness of appearance-related attraction tactics were much stronger in
      the context of self-promotion (d = -.77) compared with the competitor derogation
      context (d = -.17). Resource-related tactics of attraction displayed the opposite
      pattern, with significantly larger perceived sex differences in the context of
      competitor derogation (d =.93) than in self-promotion (d =.68). Discussion
      focused on the implications of sex difference variability and stability across
      rating contexts for evolutionary theories of romantic attraction.

PMID- 12419010
TI  - What properties of talk are associated with the generation of spontaneous iconic
      hand gestures?
AB  - When people talk, they frequently make movements of their arms and hands, some of
      which appear connected with the content of the speech and are termed iconic
      gestures. Critical to our understanding of the relationship between speech and
      iconic gesture is an analysis of what properties of talk might give rise to these
      gestures. This paper focuses on two such properties, namely the familiarity and
      the imageability of the core propositional units that the gestures accompany. The
      study revealed that imageability had a significant effect overall on the
      probability of the core propositional unit being accompanied by a gesture, but
      that familiarity did not. Familiarity did, however, have a significant effect on
      the probability of a gesture in the case of high imageability units and in the
      case of units associated with frequent gesture use. Those iconic gestures
      accompanying core propositional units variously defined by the properties of
      imageability and familiarity were found to differ in their level of idiosyncrasy,
      the viewpoint from which they were generated and their overall communicative
      effect. This research thus uncovered a number of quite distinct relationships
      between gestures and speech in everyday talk, with important implications for
      future theories in this area.

PMID- 12419011
TI  - The effects of mortality salience on relationship strivings and beliefs: the
      moderating role of attachment style.
AB  - This series of studies examined mortality salience effects on relationship
      strivings, while exploring the moderating role of attachment style. In the three
      studies, Israeli university students completed an attachment style scale, were
      assigned to a mortality salience or neutral condition, and then completed scales
      tapping specific relationship strivings and beliefs. Study 1 (N = 104) examined
      participants' willingness to initiate social interactions with a hypothetical
      same-sex person; Study 2 (N = 100) examined appraisals of interpersonal
      competence; and Study 3 (N = 108) examined reports of rejection sensitivity.
      Findings revealed that mortality salience led to more willingness to initiate
      social interactions, lower rejection sensitivity and more positive appraisals of
      interpersonal competence than a control condition. These mortality salience
      effects were found mainly among persons who scored low on attachment anxiety or
      attachment avoidance. Findings were discussed in light of the terror management
      function of close relationships.

PMID- 12419012
TI  - Constructions of equality and discrimination in professional men's talk.
AB  - The contradiction between support for egalitarian employment practices and the
      maintenance of occupational androcentrism was examined by discursively analysing
      constructions of equality and discrimination from 46 interviews with professional
      men. Accounts of equality were produced through the interpretative repertories of
      'interchangeability', 'individual ability' and 'pragmatism'. This enables, first,
      an understanding of discrimination as 'non-individualism', a term used to
      describe the treatment of social group memberships as salient, and second,
      defined interventions based on a structural analysis of equality as
      discrimination. These repertoires minimized the gendered nature of men and
      women's experiences and negated the use of context in favour of an abstract
      principle of individualism. Participants warranted their accounts through
      feminist arguments, two-sided argument formulations, and the construction of a
      dichotomy between individualist-equality and structuralist-discrimination
      supporting the material practice of 'affirmative non-action', the active support
      of non-action. Relating the findings to equal opportunity policy, occupational
      cultural analyses and the discursive production of 'new sexism', the article
      identifies the absence of an account that conceptualizes both individual and
      structural facets of equality.

PMID- 12419013
TI  - Cognitive and strategic processes in small groups: effects of anonymity of the
      self and anonymity of the group on social influence.
AB  - Two studies examined cognitive and strategic processes of social influence in
      small groups. A first study showed that anonymity of in-group members to the self
      cognitively enhanced the perceived unity or entitativity of the group, while the
      interpersonal attraction to group members decreased. A second study showed that
      anonymity of the self to the group strategically enhanced differentiation from
      the group on non-normative dimensions. Overall, it was found that strategic and
      cognitive processes interact to produce social influence within the group.
      Implications for theories of social influence in groups are discussed.

PMID- 12419014
TI  - Metabolism of zaleplon by human liver: evidence for involvement of aldehyde
      oxidase.
AB  - 1. The metabolism of Zaleplon (CL-284,846; ZAL) has been studied in precision-cut
      human liver slices and liver cytosol preparations. 2. Human liver slices
      metabolized ZAL to a number of products including 5-oxo-ZAL (M2), N-desethyl-5
      oxo-ZAL (M1) and N-desethyl-ZAL (DZAL), the latter metabolite being known to be
      formed by CYP3A forms. 3. Human liver cytosol preparations catalysed the
      metabolism of ZAL to M2. Kinetic analysis of three cytosol preparations revealed
      mean (+/- SEM) K(m) and V(max) of 93 +/- 18 mm and 317 +/- 241 pmol/min/mg
      protein, respectively. 4. Using 16 individual human liver cytosol preparations a
      33-fold variability in the metabolism of 80 micro M ZAL to M2 was observed.
      Correlations were observed between M2 formation and the metabolism of the
      aldehyde oxidase substrates phenanthridine (r(2) = 0.774) and phthalazine (r(2) =
      0.460). 5. The metabolism of 80 micro M ZAL to M2 in liver cytosol preparations
      was markedly inhibited by the aldehyde oxidase inhibitors chlorpromazine,
      promethazine, hydralazine and menadione. Additional kinetic analysis suggested
      that chlorpromazine and promethazine were non-competitive inhibitors of M2
      formation with K(i) of 2.3 and 1.9 micro M, respectively. ZAL metabolism to M2
      was also inhibited by cimetidine. 6. Incubations conducted with human liver
      cytosol and H(2)(18)O demonstrated that the oxygen atom incorporated into ZAL and
      DZAL to form M2 and M1, respectively, was derived from water and not from
      molecular oxygen. 7. In summary, by correlation analysis, chemical inhibition and
      H(2)(18)O incorporation studies, ZAL metabolism to M2 in human liver appears to
      be catalysed by aldehyde oxidase. With human liver slices, ZAL was metabolized to
      products dependent on both aldehyde oxidase and CYP3A forms.

PMID- 12419015
TI  - Inhibition of zaleplon metabolism by cimetidine in the human liver: in vitro
      studies with subcellular fractions and precision-cut liver slices.
AB  - 1. The effect of cimetidine on the metabolism of zaleplon (ZAL) in human liver
      subcellular fractions and precision-cut liver slices was investigated. 2. ZAL was
      metabolized to a number of products including 5-oxo-ZAL (M2), which is known to
      be formed by aldehyde oxidase, N-desethyl-ZAL (DZAL), which is known to be formed
      by CYP3A forms, and N-desethyl-5-oxo-ZAL (M1). 3. Human liver microsomes
      catalysed the NADPH-dependent metabolism of ZAL to DZAL. Kinetic analysis of
      three microsomal preparations revealed mean (+/-SEM) S(50) and V(max) of 310 +/-
      24 micro M and 920 +/- 274 pmol/min/mg protein, respectively. 4. Human liver
      cytosol preparations catalysed the metabolism of ZAL to M2. Kinetic analysis of
      three cytosol preparations revealed mean (+/-SEM), K(m) and V(max) of 124 +/- 14
      micro M and 564 +/- 143 pmol/min/mg protein, respectively. 5. Cimetidine
      inhibited ZAL metabolism to DZAL in liver microsomes and to M2 in the liver
      cytosol. With a ZAL substrate concentration of 62 micro M, the calculated mean
      (+/-SEM, n = 3) IC50 were 596 +/- 103 and 231 +/- 23 micro M for DZAL and M2
      formation, respectively. Kinetic analysis revealed that cimetidine was a
      competitive inhibitor of M2 formation in liver cytosol with a mean (+/-SEM, n =
      3) K(i) of 155 +/- 16 micro M. 6. Freshly cut human liver slices metabolized ZAL
      to a number of products including 1, M2 and DZAL. 7. Cimetidine inhibited ZAL
      metabolism in liver slices to M1 and M2, but not to DZAL. Kinetic analysis
      revealed that cimetidine was a competitive inhibitor of M2 formation in liver
      slices with an average (n = 2 preparations) K(i) of 506 micro M. 8. The results
      demonstrate that cimetidine can inhibit both the CYP3A and aldehyde oxidase
      pathways of ZAL metabolism in the human liver. Cimetidine appears to be a more
      potent inhibitor of aldehyde oxidase than of CYP3A forms and hence in vivo is
      likely to have a more marked effect on ZAL metabolism to M2 than on DZAL
      formation. 9. The results also demonstrate that precision-cut liver slices may be
      a useful model system for in vitro drug-interaction studies.

PMID- 12419016
TI  - Reversible and irreversible inhibition of CYP3A enzymes by tamoxifen and
      metabolites.
AB  - 1. Preliminary studies have identified cytochrome P450 (CYP) 3A4 and CYP1B1 as
      the human CYPs inhibited by tamoxifen. To quantify the inhibitory potency of
      tamoxifen and its major metabolites, the metabolism of three substrates of CYP3A,
      midazolam, diltiazem and testosterone, and 7-ethoxyresorufin as a substrate of
      CYP1B1 were examined in catalytic assays carried out using human liver microsomes
      and cDNA-expression systems. 2. Tamoxifen, N-desmethyltamoxifen, 4
      hydroxytamoxifen and 3-hydroxytamoxifen reversibly inhibited midazolam 1'
      hydroxylation, diltiazem N-demethylation and testosterone 6beta-hydroxylation
      with K(i) ranging from 3 to 37 micro M in human liver microsomes. Tamoxifen, N
      desmethyltamoxifen, 4-hydroxytamoxifen and 3-hydroxytamoxifen also reversibly
      inhibited the activity of cDNA-expressed CYP3A4, CYP3A5 and CYP1B1. 3. Tamoxifen
      and N-desmethyltamoxifen exhibited time-dependent inactivation of testosterone
      6beta-hydroxylation by cDNA-expressed CYP3A4 (+ cytochrome b5) yielding k(inact)
      and K(i) of 0.04 min(-1) and 0.2 micro M for tamoxifen and 0.08 min(-1) and 2.6
      micro M for N-desmethyltamoxifen. A metabolic intermediate complex (MIC) was also
      formed by tamoxifen and N-desmethyltamoxifen with CYP3A4 (+ cytochrome b5) and
      CYP3A4 but not with CYP3A5 or CYP3A7. Pre-incubation with 4-hydroxytamoxifen and
      3-hydroxytamoxifen did not result in any CYP3A inactivation or detectable MIC
      formation. There was no detectable time-dependent inactivation or MIC formation
      with tamoxifen or metabolites with CYP1B1. 4. These data indicate that tamoxifen
      and its three major metabolites are effective inhibitors of CYP3A in vitro and
      that tamoxifen and N-desmethyltamoxifen are effective mechanism-based inhibitors.
      Thus, caution should be exercised when tamoxifen is coadministered with other
      CYP3A substrates.

PMID- 12419017
TI  - Pharmacokinetic evaluation of high pulmonary disposition of clarithromycin after
      systemic administration.
AB  - 1. The distribution characteristics of clarithromycin to the lung were
      investigated in vivo and in isolated lung perfusion experiments. The in-vivo
      integration plot analysis showed that the pulmonary uptake and extracellular
      distribution in the lung were significantly higher for clarithromycin than for
      erythromycin. 2. In the rat lung single-pass perfusion study, the pulmonary
      extraction ratio (E(ss)) of clarithromycin at steady-state was significantly
      higher than that of erythromycin, and the E(ss) of clarithromycin tended to
      decrease as the inflow concentration increased, suggesting the involvement of
      carrier-mediated transport in the pulmonary disposition of clarithromycin. 3. The
      outflow patterns of clarithromycin or erythromycin at various inflow
      concentrations were simultaneously analysed based on a pharmacokinetic model,
      which consists of the non-specific binding site, the specific binding site and
      the subsequent uptake process. The parameters obtained suggested that
      clarithromycin would have the higher affinity and higher capacity for the
      specific binding site, and the higher equilibrium constant for the non-specific
      binding site than erythromycin. 4. The simulation study using those parameters
      demonstrated that clarithromycin could be bound to the specific binding site and
      subsequently taken up more extensively than erythromycin. 5. A multiple-indicator
      dilution study also indicated that clarithromycin was more readily associated and
      extracted with the lung than with erythromycin. In the inhibition study, it was
      suggested that the pulmonary uptake of clarithromycin could be ascribed not only
      to the non-specific binding depending on its lipophilic nature, but also in part
      to some specialized mechanisms such as organic cation transporters.

PMID- 12419018
TI  - Modelling the loss of metabolic capacities of cultured hepatocytes: application
      to measurement of Michaelis-Menten kinetic parameters in in vitro systems.
AB  - 1. The loss of metabolic capacities during culture time constitutes a major
      limitation for the use of hepatocyte primary cultures in in vitro metabolism
      measurements. A new strategy is presented that permits one to calculate the
      Michaelis-Menten parameters V(max) and K(m) from extended experiments, by
      modelling V(max) as a variable dependent on time using exponential or sigmoidal
      equations. 2. This method was tested with cortisol depletion in cultured rat
      hepatocytes. V(max) and K(m) were used to calculate intrinsic clearance, and
      comparisons were made with methods already described in the literature. Intrinsic
      clearances given by our method were scaled to in vivo hepatic clearances that
      were close to those reported in the literature. 3. Our method could quantify the
      V(max) decrease with culture time from estimates of time parameters, t(1/2) or
      t(50). In our system, this V(max) decrease was in agreement with P450 cytochrome
      inactivation rates published for the rat liver. 4. In conclusion, we propose a
      convenient, simple and useful general method for both Michaelis-Menten parameter
      estimation and modelling of variations in the metabolic capacities observed in in
      vitro systems. Such an approach should improve the usefulness of hepatocytes in
      primary cultures for long-term metabolism experiments.

PMID- 12419019
TI  - Pharmacokinetics, toxicokinetics, distribution, metabolism and excretion of
      linezolid in mouse, rat and dog.
AB  - 1. Linezolid (ZYVOX), the first of a new class of antibiotics, the
      oxazolidinones, is approved for treatment of Gram-positive bacterial infections.
      2. The aim was to determine the absorption, distribution, metabolism and
      excretion (ADME) of linezolid in mouse, rat and dog in support of preclinical
      safety studies and clinical development. 3. Conventional replicate study designs
      were employed in animal experiments, and biofluids were assayed by HPLC or HPLC
      MS. 4. Linezolid was rapidly absorbed after p.o. dosing with an p.o.
      bioavailability of > 95% in rat and dog, and > 70% in mouse. Twenty-eight-day
      i.v./p.o. toxicokinetic studies in rat (20-200mg kg(-1) day(-1)) and dog (10-80
      mg kg(-1) day(-1)) revealed neither a meaningful increase in clearance nor
      accumulation upon multiple dosing. 5. Linezolid had limited protein binding
      (<35%) and was very well distributed to most extravascular sites, with a volume
      of distribution at steady-state (V(ss)) approximately equal to total body water.
      6. Linezolid circulated mainly as parent drug and was excreted mainly as parent
      drug and two inactive carboxylic acids, PNU-142586 and PNU-142300. Minor
      secondary metabolites were also characterized. In all species, the clearance rate
      was determined by metabolism. 7. Radioactivity recovery was essentially complete
      within 24-48 h. Renal excretion of parent drug and metabolites was a major
      elimination route. Parent drug underwent renal tubular reabsorption,
      significantly slowing parent drug excretion and allowing a slow metabolic process
      to become rate-limiting in overall clearance. 8. It is concluded that ADME data
      were relatively consistent across species and supported the rat and dog as the
      principal non-clinical safety species.

PMID- 12419020
TI  - Pharmacokinetic scaling of bisphenol A by species-invariant time methods.
AB  - 1. The study was performed to predict the pharmacokinetic disposition of
      bisphenol A in humans using simple allometry and several species-invariant time
      methods based on animal data. Bisphenol A was injected intravenously to mouse,
      rat, rabbit and dog (1-2 mg kg(-1) doses). 2. The obtained serum concentration
      time profiles were best described by bi-exponential equations in all these animal
      species, with the mean Cl, V(ss) and t(1/2) of 0.3 l h(-1), 0.1 litres and 39.9
      min in mouse, 1.9 l h(-1), 1.3 litres and 37.6 min in rat, 12.6 l h(-1), 7.1
      litres and 40.8 min in rabbit, and 27.1 l h(-1), 20.0 litres and 43.7 min in dog,
      respectively. 3. The human pharmacokinetic parameters of Cl, V(ss) and t(1/2)
      were predicted by simple allometry as well as by normalization according to
      species-invariant times of kallynochrons, apolysichrons and dienetichrons. 4. The
      simple allometric scaling and different time transformation methods predicted the
      human Cl, V(ss) and t(1/2) ranging from 46.0 to 127.1 l h(-1), 125.3 to 229.7
      litres and 43.6 to 196.2 min, respectively. Species-invariant time
      transformations showed that all animal data from the four species were
      superimposable. These preliminary parameter values may be useful in interpreting
      toxicity data in humans on environmental exposure to bisphenol A.

PMID- 12419021
TI  - Telemedicine and the ATA.

PMID- 12419022
TI  - Cost effectiveness of telemedicine for the delivery of outpatient pulmonary care
      to a rural population.
AB  - The objective of this study was to determine the cost effectiveness of outpatient
      pulmonary subspecialty consultations via telemedicine. A decision-analytic model
      was used to compare the cost effectiveness of providing outpatient telemedicine
      pulmonary consultations with alternative treatment methods. Model options
      included: (1) telemedicine, (2) routine care (patients travel from a remote site
      to the hub site to receive care), and (3) on-site care (patients receive care at
      the remote site). Cost and effectiveness data from the Milwaukee and Iron
      Mountain Veterans Affairs Medical Centers (VAMC) telepulmonary program were
      collected for a period of 1 year. The cost-effectiveness analysis was conducted
      from a societal perspective. Average and incremental cost-effectiveness ratios
      were calculated together with sensitivity analysis. Telemedicine was found to be
      more cost effective ($335 per patient/year) compared to routine care ($585 per
      patient/year) and on-site care ($1,166 per patient/year). Sensitivity analysis
      revealed that cost effectiveness of telemedicine was sensitive to changes in the
      values for the number of patients, probability of successful telemedicine
      consultation, telemedicine equipment cost, utility of telemedicine, and
      percentage effort assigned to the on-site pulmonary physician. Telemedicine is a
      cost-effective alternative for the delivery of outpatient pulmonary care for
      rural populations with limited access to subspecialty services. Cost
      effectiveness of telemedicine is related to three major factors: cost sharing,
      i.e., adequate patient volume and sharing of telemedicine infrastructure amongst
      various clinical users; effectiveness of telemedicine in terms of patient utility
      and successful clinical consultations; and indirect cost savings accrued by
      decreasing cost of patients' lost productivity.

PMID- 12419023
TI  - A comparative cost analysis of an integrated military telemental health-care
      service.
AB  - The National Naval Medical Center, Bethesda, Maryland, integrated telemental
      health care into its primary behavioral health-care outreach service in 1998. To
      date, there have been over 1,800 telemental health visits, and the service
      encounters approximately 100 visits per month at this time. The objective of this
      study was to compare and contrast the costs to the beneficiary, the medical
      system, and the military organization as a whole via one of the four methods
      currently employed to access mental health care from remotely located military
      medical clinics. The four methods include local access via the military's
      civilian health maintenance organization (HMO) network, patient travel to the
      military treatment facility, military mental health specialists' travel to the
      remote clinic (circuit riding) and TeleMental Healthcare (TMH). Interactive video
      conferencing, phone, electronic mail, and facsimile were used to provide
      telemental health care from a military treatment facility to a remote military
      medical clinic. The costs of health-care services, equipment, patient travel,
      lost work time, and communications were tabulated and evaluated. While the
      purpose of providing telemental healthcare services was to improve access to
      mental health care for our beneficiaries at remote military medical clinics, it
      became apparent that this could be done at comparable or reduced costs.

PMID- 12419024
TI  - A prospective evaluation of ENT telemedicine in remote military populations
      seeking specialty care.
AB  - This study evaluated telemedicine use in remote military treatment facilities
      (MTFs) ashore over a 4-month period to help guide telemedicine applications for
      shipboard medical departments. A prospective study design was used to evaluate
      specialty care provided by an ear/nose/throat (ENT) physician via
      videoconferencing (VC) for patients at remote MTFs in TRICARE Region 9. The study
      provided a complete and continuous sample of ENT consultations during a planned 4
      month period. Data sources included a telemedicine database and telephone
      interviews to assess attitudes of physician and nonphysician medical personnel. A
      total of 193 VC consultations (hereafter referred to as teleconsultations) were
      conducted following referrals from primary providers. Patients were mostly young,
      male, active-duty personnel. Forty-five percent of the 193 teleconsultations
      resulted in changed diagnosis by the ENT specialist relative to initial diagnosis
      by the referring provider. This rate of clinical impact was substantial, and it
      generalized across various ENT conditions, demographics, and MTFs. Medical
      personnel reported generally positive attitudes about telemedicine technologies
      and the telemedicine process in TRICARE Region 9. Nonphysician providers reported
      slightly more favorable attitudes compared to physicians. These results suggest
      that ENT telemedicine has substantial clinical impact in the military populations
      treated at MTFs. A high rate of changed diagnoses (45%) was observed across age,
      gender, military status, ENT conditions, and treatment facilities. Medical
      personnel reported positive attitudes about using the telemedicine system. These
      results support the use of telemedicine in shipboard medical departments.

PMID- 12419025
TI  - Teledermatology's impact on time to intervention among referrals to a dermatology
      consult service.
AB  - The aim of this study was to determine if a teledermatology consult system, using
      store-and-forward digital imaging technology, results in patients achieving a
      shorter time from referral date to date of initial definitive intervention when
      compared to a traditional referral process. Patients being referred to the
      dermatology consult service from the primary care clinics at the Durham VA
      Medical Center were randomized to either a teledermatology consultation or usual
      care. A usual care consultation consisted of a text-based electronic consult
      request. A teledermatology consultation included digital images and a
      standardized history, in addition to the text-based electronic consult. Time to
      initial definitive intervention was defined as the time between referral date and
      the date the patient was scheduled for a clinic visit for those patients that the
      consultant requested a clinic-based evaluation, or the time between referral date
      and the date the consult was answered by the consultant if a clinic visit was not
      required. Patients in the teledermatology arm of the study reached a time to
      initial definitive intervention significantly sooner than did those patients
      randomized to usual care (median 41 days versus 127 days, p = 0.0001, log-rank
      test). Additionally, 18.5% of patients in the teledermatology arm avoided the
      need for a dermatology clinic-based visit compared to zero patients avoiding a
      dermatology clinic visit in the usual care arm of the study (p < 0.001, z-test).
      Teledermatology consult systems can result in significantly shorter times to
      initial definitive intervention for patients compared to traditional consult
      modalities, and, in some cases, the need for a clinic-based visit can be avoided.

PMID- 12419026
TI  - Web site for training nonmedical health-care workers to identify potentially
      malignant skin lesions and for teledermatology.
AB  - The development of a Web site to enable nonmedical health professionals to screen
      skin potentially malignant skin lesions is described. A nurse assistant and a
      dermatologist tested the Web site. An electronic clinical form was developed to
      allow a nurse assistant to send case reports and photographs for remote diagnosis
      by a dermatologist. The nurse assistant photographed the lesions of 92 patients
      who presented some kind of dermatological condition. The images were then sent
      for evaluation by the dermatologist followed by in person examination by the same
      physician. The diagnoses, which resulted from the examination in person and, in
      some cases, the biopsy results, were compared with the diagnostic impressions of
      the nurse assistant and with the diagnostic hypothesis of the dermatologist at a
      distance. The lesions were classified as either malignant or nonmalignant. Kappa
      statistics showed a high association between the suspected malignity and
      nonmalignity of the lesions between the dermatologist (p = 6.01 x 10(-9)) and the
      nurse assistant and between the diagnosis at distance and in person (p < 1.0 x
      10(-14)). The Web site allowed a nurse assistant to screen for potentially
      malignant skin lesions and, thus, proved to be appropriate for a large-scale
      test.

PMID- 12419027
TI  - Store-and-forward diagnostic telepathology of small biopsies by e-mail
      attachment: a feasibility pilot study with a view for future application in
      Thailand diagnostic pathology services.
AB  - Diagnostic telepathology by electronic mail (e-mail) attachment is relatively
      simple and incurs minimal cost. We assessed its accuracy and practical aspects in
      routine diagnostic pathology. Using 100 small biopsy specimens, a total of 1,488
      images were digitized by one pathologist and sent as e-mail attachments from Nara
      Medical University, Japan, to a pathologist at Rajavithi Hospital, Thailand. His
      diagnoses were compared with his conventional light microscopy interpretation at
      a later date. The average total turnaround time spent on each case was 215
      minutes, far less than the several days required by conventional post. There were
      two clinically significant errors. One was a diagnostically difficult case of
      colonic dysplasia, which was called carcinoma with telepathology. The other was a
      signet ring cell carcinoma of the stomach which was undetected with
      telepathology. Microscopy objective magnification and digital image quality may
      have played a role in impairing interpretation in both cases. Store-and-forward
      telepathology provides acceptable efficacy, a comparatively faster turnaround
      time than post and could be applied in routine work within Thai pathology
      services.

PMID- 12419028
TI  - Usability of multimedia technology to help caregivers prepare for a crisis.
AB  - The objective of the research was to evaluate the usability of a multimedia
      software application that provides information on coping with difficult
      situations, dealing with everyday caring problems, and first aid for emergency
      situations. Casual users (family caregivers, professional caregivers, and older
      people) were invited to use the software application and complete a questionnaire
      measuring quality and efficiency in utility and usability. Quantitative data were
      analyzed using the Statistical Package for the Social Sciences (SPSS) and
      qualitative data were analyzed by content analysis. Findings indicated the
      software application to have high global usability, correspond to user
      expectations, respond quickly, and be visually pleasant and easily understood.
      The authors conclude that software applications of this type have the potential
      to increase the quality of life of family caregivers, enhance their coping
      capacity, and enable them to continue for a longer period in their caring role.

PMID- 12419030
TI  - Human chimaeras and understanding early development.

PMID- 12419031
TI  - Human experimental chimaerism: Chimaeras as a source of stem cells.

PMID- 12419032
TI  - Use of recombinant LH in a group of unselected IVF patients.
AB  - The aim of this study was to evaluate the use of recombinant luteinizing hormone
      (rLH) supplementation in an unselected group of IVF patients undergoing
      follicular stimulation with recombinant follicle stimulating hormone (rFSH) after
      pituitary down-regulation. Group A comprised 122 cycles administered rFSH and rLH
      while group B included 331 cycles using rFSH only during the same period of
      treatment. There was no significant difference in any of the endocrine,
      embryological and outcome parameters measured. The implantation rate of 14.2% for
      group A compared with 9.8% for group B showed a positive trend (P = 0.055), but
      for patients in whom LH concentration was <1.0 IU/l at down-regulation or
      required excessive FSH stimulation, there was an increased incidence of
      implantation if rLH was supplemented. It was concluded that the addition of
      exogenous rLH to an unselected group of 'down-regulated' patients stimulated with
      rFSH appears to offer little benefit, but in the event of profound LH down
      regulation or requirement for excessive exogenous FSH (>2500 IU), the rate of
      implantation might be improved.

PMID- 12419033
TI  - Clomiphene-induced LH surges and cetrorelix.
AB  - The following rat pituitary cell culture experiments were carried out to find an
      explanation for the increased premature LH surges in stimulation protocols using
      clomiphene citrate (CC) and subsequent gonadotrophin with mid-cycle
      administration of the GnRH antagonist cetrorelix (Cetrotide(R)) in IVF cycles.
      Rat pituitary cells were pretreated with CC, then stimulated with GnRH with and
      without co-administration of different concentrations of GnRH antagonist and
      compared with non-CC-pretreated controls. While lower concentrations of
      cetrorelix suppressed LH in CC-non-pretreated cells, but not in CC-pretreated
      cells, higher concentrations of cetrorelix suppressed LH in both groups. CC
      pretreatment increased the sensitivity of the pituitary for GnRH and reduced the
      efficacy of subsequent GnRH antagonist. Thus, the elevated risk of premature LH
      surges in clinical protocols using CC, gonadotrophin and GnRH antagonist could be
      overcome by increasing the antagonist dose.

PMID- 12419034
TI  - Impact of metformin therapy on ovarian stimulation and outcome in 'coasted'
      patients with polycystic ovary syndrome undergoing in-vitro fertilization.
AB  - This study was designed to determine if metformin therapy improves ovarian
      stimulation and IVF outcomes in coasted patients with clomiphene-resistant
      polycystic ovarian syndrome (PCOS). A retrospective data analysis was performed
      on women with clomiphene citrate-resistant PCOS treated with or without
      metformin, who underwent 72 cycles of IVF-embryo transfer with intracytoplasmic
      sperm injection (ICSI). In 59 cycles, patients were coasted to allow oestradiol
      concentrations to drop before human chorionic gonadotrophin administration. In
      patients undergoing coasting, the outcome of IVF with ICSI was compared in those
      who were treated and untreated. In patients treated with metformin, follicular
      fluid concentrations of testosterone and insulin were significantly lower (60.5
      +/- 5 versus 79.1 +/- 6 ng/dl; P < 0.05 and 18 +/- 2.5 versus 22 +/- 2.4 micro
      IU/ml; P < 0.05 respectively), and the mean number of oocytes retrieved (22.3 +/-
      2.4 versus 19.7 +/- 1.6) did not differ. The metformin-treated group showed an
      increase in the mean number of mature oocytes, oocytes fertilized and cleaving
      embryos (4-cell or greater by 72 h). However, in the group of patients undergoing
      coasting, maximum oestradiol concentrations and number of days of coasting were
      all lower in the metformin-treated group with increased clinical pregnancy rates
      (71 versus 30%, P < 0.05). Therefore, metformin use appears beneficial in
      improving IVF outcomes in clomiphene citrate-resistant PCOS patients.

PMID- 12419035
TI  - Manipulation of the oocyte: possible damage to the spindle apparatus.
AB  - Oocytes are structured, polarized cells. For high developmental potential, it is
      essential that the distribution of organelles and molecules, and the function of
      meiotic spindles remain intact during handling of oocytes in assisted
      reproduction. Spindles are dynamic cell organelles. Spindle formation depends on
      activity of motor proteins, energy supply and temperature. Disturbances in
      spindle function may predispose oocytes to aneuploidy or maturation arrest. Thus,
      perturbation of the cytoskeletal integrity of oocytes may critically influence
      the fate of the embryo. Recently, enhanced polarizing microscopy has been
      developed for non-invasive analysis of spindle morphology in living mammalian
      oocytes. Chemically induced dynamic alterations have been characterized in the
      spindle in individual mouse oocytes and it has been shown that spindle
      aberrations are predictive of risks for non-disjunction. Spindle imaging
      identified adverse, irreversible effects of handling in living human oocytes (for
      instance, the extreme susceptibility of human oocytes to cooling). Also, oocyte
      immaturity may be detected. Selection of metaphase II oocytes and an injection
      site for intracytoplasmic sperm injection (ICSI) that avoids spindle damage may
      increase the yield of euploid embryos. The detection of genetic, environmentally
      induced, or treatment-related defects in oocyte maturation by non-invasive
      spindle imaging can improve quality control and assist in the selection of
      morphologically normal oocytes for assisted reproduction.

PMID- 12419036
TI  - Maturational and developmental competence of cumulus-free immature human oocytes
      derived from stimulated and intracytoplasmic sperm injection cycles.
AB  - The present experiments compared the maturational and developmental competence of
      immature oocytes derived from stimulated cycles, following culture in a newly
      designed in-vitro maturation medium (IVM-medium) or in standard tissue culture
      medium (TCM-199; control). The results indicated that maturation and
      fertilization rates were comparable when the cumulus-free M-I stage oocytes were
      matured in the IVM-medium (78.6%) or the control medium (70.8%). However, there
      was a significant difference in blastocyst development (P < 0.05) when M-I
      oocytes were matured in these two media (19.6 versus 7.7%). Both maturation and
      early embryonic development rates of GV-stage oocytes were significantly higher
      (P < 0.01) in the IVM-medium (maturation: 75.7%; blastocyst: 12.9%) compared with
      control (maturation 55.7%; blastocyst: 0.0%). Moreover, embryos developed to the
      blastocyst stage at a higher rate in both media if GV-stage oocytes had matured
      within 24 h compared with 48 h of culture. These results demonstrate that
      immature human oocytes derived from stimulated ovaries can achieve maturation and
      early embryonic development in vitro, especially in the new IVM-medium, which may
      allow additional embryos to be produced for clinical use at embryo transfer.

PMID- 12419038
TI  - Fertilization, embryonic development and pregnancy losses with intracytoplasmic
      sperm injection for surgically-retrieved spermatozoa.
AB  - Prior to the development of intracytoplasmic sperm injection (ICSI), azoospermic
      and severely oligozoospermic men had little to no chance of having a biological
      child. In this study, ICSI outcome in 454 transfers with ejaculated spermatozoa
      and 59 transfers with surgically retrieved spermatozoa were evaluated. Normal
      fertilization rate using ejaculated spermatozoa was 75% of 5995 oocytes, and 73%
      of 751 oocytes for surgically retrieved spermatozoa; with ongoing pregnancy rates
      of 53% (242/454) and 61% (36/59) respectively. Surgically retrieved spermatozoa
      significantly (P < 0.05) impacted 1PN oocytes (6.1%, 46/751), severely fragmented
      embryos (8.8%, 46/550) and incidence of pregnancy loss (11%, 4/36). When using
      ejaculated spermatozoa, incidence of 1PN oocytes, severely fragmented embryos and
      pregnancy loss was 2.9% (177/5995), 4.5% (200/4365), 2.4% (6/242) respectively.

PMID- 12419037
TI  - The development of fertilized human ova to the blastocyst stage in KSOM(AA)
      medium: is a two-step protocol necessary?
AB  - Current protocols for the culture of human zygotes to blastocysts use two-step
      sequential media systems. The efficacy of a one-step system involving potassium
      simplex optimized medium (KSOM(AA)) has been investigated. In study 1,
      development of zygotes from days 1 to 3 in KSOM(AA) was compared with that for
      medium P-1. In study 2, embryos were cultured from days 1 to 3 in P-1 followed by
      culture from days 3 to 5 either in KSOM(AA) or medium CCM. In study 3, the
      ability of KSOM(AA) to support development of embryos from days 1 to 5, without
      medium renewal, was compared with the sequential media system P-1-->CCM. The cell
      numbers and fragmentation scores of day 3 embryos were distributed similarly
      following culture in KSOM(AA) or P-1. Significantly more KSOM(AA) embryos
      exhibited cytoplasmic pitting. Blastocyst formation rates were not significantly
      different whether embryos were cultured in the P-1-->KSOM(AA) or the P-1-->CCM
      systems, or when cultured from days 1 to 5 in KSOM(AA) without medium renewal or
      in P-1-->CCM. Five babies have been born from nine blastocysts transferred after
      extended culture in KSOM(AA). A one-step protocol involving KSOM(AA) can be used
      successfully to culture human zygotes to the blastocyst stage.

PMID- 12419039
TI  - Preimplantation genetic diagnosis for cancer predisposition.
AB  - Preimplantation genetic diagnosis (PGD) has recently been offered for couples
      with an inherited predisposition for late onset disorders. This paper presents
      the results of PGD for a group of couples at risk for producing children with
      cancer predisposition. Using a standard IVF procedure, oocytes or embryos were
      tested for different mutations predisposing to cancer, preselecting and
      transferring only mutation-free embryos back to the patients. The procedure was
      performed for patients with predisposition to familial adenomatous polyposis coli
      (FAP), Von Hippel-Lindau syndrome (VHL), retinoblastoma, Li-Fraumeni syndrome,
      determined by p53 tumour suppressor gene mutations, neurofibromatosis types I and
      II and familial posterior fossa brain tumour (hSNF5). Overall, 20 PGD cycles were
      performed for 10 couples, resulting in preselection and transfer of 40 mutation
      free embryos, which resulted in five unaffected clinical pregnancies and four
      healthy children born by the present time. Despite the controversy of PGD use for
      late onset disorders, the data demonstrate the usefulness of this approach as the
      only acceptable option for at-risk couples to avoid the birth of children with an
      inherited predisposition to cancer, and to have a healthy child.

PMID- 12419040
TI  - Assessment of beta-HCG, beta-LH mRNA and ploidy in individual human blastomeres.
AB  - In human embryos, blastomeres differentiate into trophectoderm (TE) cells and
      inner cell mass (ICM) cells of blastocysts. Although morphologically
      indistinguishable, blastomeres at early cleavage stages are likely to undergo
      changes on a molecular level that make them destined to become ICM or TE cells.
      While the transcription factor Oct-4 might serve as a marker for totipotent ICM
      cells, human chorionic gonadotrophin might be used as the equivalent for TE
      cells. This study reports a reverse transcription-polymerase chain reaction
      procedure to assess human beta-HCG mRNA concentrations as well as ploidy in
      individual blastomeres from normally and abnormally fertilized human embryos.
      beta-HCG mRNA was detected in both euploid and aneuploid cells and in oocytes.
      Surprisingly, beta-LH mRNA was also detected in some euploid blastomeres. In
      regard to preimplantation genetic diagnosis, assessment of expression levels of
      beta-HCG and Oct-4 mRNA in individual biopsied cells might serve as a tool to
      identify embryogenic blastomeres in combination with testing for chromosome and
      single gene abnormalities.

PMID- 12419041
TI  - Effects of previous ovarian surgery for endometriosis on the outcome of assisted
      reproduction treatment.
AB  - Endometriosis affects 2-50% of women at reproductive age. Surgery is an option
      for treatment, but there is no convincing evidence that it promotes a significant
      improvement in fertility. Also, the removal of ovarian endometrioma might lead to
      a reduction in the follicular reserve and response to stimulation. Therefore, the
      aim of this study was to evaluate the effect of previous ovarian surgery for
      endometriosis on the ovarian response in assisted reproduction treatment cycles
      and its pregnancy outcome. A total of 61 women, with primary infertility and
      previously having undergone ovarian surgery for endometriosis, who had received
      74 IVF/intracytoplasmic sperm injection (ICSI) cycles, were studied (study
      group). A further 74 patients with primary infertility who underwent 77 IVF/ICSI
      cycles within#10; the same period of time, at the same clinic and without
      previous ovarian surgery or endometriosis were studied as a control group.
      Patients were matched for age and treatment performed. Patients </=35 years with
      previous ovarian surgery had fewer retrieved oocytes than the patients in the
      control group (P = 0.049). The number of ampoules used for ovulation induction,
      duration of folliculogenesis; (days), number of follicles and fertilization rate
      was similar in both groups. The same was observed for pregnancy rates, with 24
      patients (53.3%) having had previous ovarian surgery and 27 (56.2%) in the
      control group becoming pregnant. Patients >35 years with previous ovarian surgery
      needed more ampoules for ovulation induction (P = 0.017) and had fewer follicles
      and oocytes than women in the control group (P = 0.001). Duration of
      folliculogenesis was similar in both groups, as was fertilization rate. A total
      of 10 patients achieved pregnancy in the study group (34.5%) and 14 (48.3%) in
      the control group. Although a lower pregnancy rate was observed in patients who
      had undergone previous ovarian surgery, this difference was not statistically
      significant (P = 0.424). In conclusion, ovarian surgery for the treatment of
      endometriosis reduces the ovarian outcome in IVF/ICSI cycles in women >35 years
      old, and might also decrease pregnancy rates. Therefore, for infertile patients,
      non-surgical treatment might be a better option to avoid reduction of the ovarian
      response.

PMID- 12419042
TI  - Recurrent early pregnancy loss and consanguinity.
AB  - The present authors have studied the possible relationship between recurrent
      miscarriage and consanguinity in the Qatari population, where the prevalence of
      first cousin marriage is 47%. The maternal of three or more early pregnancy
      losses were compared with those of 92 non-consanguineous women from the same
      population and with the same obstetrical history, matched for maternal age. The
      retrospective investigation showed no difference in the rate of previous
      pregnancy loss and maternal disorders, including diabetes, thyroid dysfunction
      and immunity, abnormal uterine and ovarian anatomy or thrombophilia. There was
      also no evidence of familial clustering of recurrent miscarriage in both groups.
      The prospective study showed no difference in the rate of subsequent pregnancy
      loss and the median gestational age and fetal weight at delivery in ongoing
      pregnancies. The absence of a relationship between recurrent miscarriage and
      consanguinity in Qatar could be due to the particular characteristics of the
      native Qatari population, in which rare recessive genes are uncommon, or overall
      to the absence of an association between recurrent miscarriage and consanguinity.

PMID- 12419044
TI  - A special path to parenthood: parent-child relationships in families giving birth
      to singleton infants through IVF.
AB  - Infertility and its treatment are increasingly viewed as public issues as well as
      a private concern. Treatments such as IVF draw on public resources and pose
      psychological and ethical dilemmas for the community. The current paper
      integrates findings from a prospective longitudinal study that assessed the
      quality of parenting in families conceiving through IVF from an attachment theory
      perspective. Seventy families who conceived singleton infants through IVF and a
      naturally conceiving control group of 63 couples were seen during pregnancy and
      at 4 and 12 months postpartum. Two observational procedures were used to assess
      maternal sensitivity to the baby, infant responsiveness and security of
      attachment at 4 and 12 months respectively. There were no IVF control group
      differences in maternal sensitivity at 4 months or in security of attachment at
      12 months. Implications of the findings for clinicians and contemporary
      controversies requiring further research are discussed.

PMID- 12419043
TI  - Malformation rate in fetuses and children conceived after ICSI: results of a
      prospective cohort study.
AB  - There is an ongoing discussion regarding conflicting data on malformation rate in
      children born after intracytoplasmic sperm injection (ICSI). A prospective,
      multicentric, control cohort study was done in Germany. Fifty-nine centres
      prospectively recruited pregnancies before the 16th week of gestation, which were
      included in the study if they were ongoing beyond this time. Children were
      examined according to a standardized procedure. A control cohort of children
      conceived spontaneously was taken from a prospective birth registry (Mainzer
      Modell), where children were examined according to the exact same criteria as the
      ICSI cohort. Major malformation rate was calculated, based on data of all
      liveborn and stillborn children, as well as on all spontaneous and induced
      abortions, beginning with the 16th week of gestation. In the ICSI cohort, 8.6% of
      infants (291/3372), and in the control cohort 6.9% of infants (2140/30940), had a
      major malformation. This resulted in a crude relative risk (RR) of 1.25 (95%
      confidence interval 1.11-1.40). There was no influence of sperm origin on major
      malformation rate in children born after ICSI. There is an increased risk for a
      child born after ICSI to have a major malformation compared with a child that has
      been spontaneously conceived. Based on knowledge of the early developmental steps
      following ICSI, as well as on data of conventional IVF in general, it is assumed
      that this increased risk is due to parental factors causing the infertility,
      which has led to ICSI in the first place.

PMID- 12419045
TI  - Introduction to methods for collecting human gametes in assisted reproduction.
AB  - The first objective of IVF is the collection of oocytes and spermatozoa. This
      article reviews the methods of choice for each sex. Collecting oocytes involves
      laparoscopic puncture and ultrasonographic puncture via
      transabdominal/transvesical and periurethral/transvesical, transvaginal methods.
      Male gametes are collected by masturbation, or by aspirating spermatozoa from the
      epididymis or from the testicle. Sperm collections can be taken from patients
      with disorders of ejaculation. A brief review of each approach is presented, with
      a critical analysis of each method.

PMID- 12419046
TI  - Diagnostics in assisted human reproduction.
AB  - The World Health Organization (WHO) estimates that 50-80 x 10(6) couples in the
      world are infertile, i.e. 7-15% of all couples of reproductive age (15-45 years
      old). The term infertility refers to couples who have been unable to conceive
      children for at least 1 year of regular unprotected intercourse. Although the
      frequency and origin of infertility varies, approximately 40-60% of the aetiology
      of infertility in the population studied is due to female causes. The
      introduction of assisted reproduction techniques, which offer couples the best
      opportunities for pregnancy, has opened a vast field of knowledge in reproductive
      biology. The medical history must be taken meticulously, with enough time to
      obtain the largest possible amount of relevant information. It is recommended
      that both partners be included in the initial work-up. In recent decades,
      technological progress has been favoured with the development of a great variety
      of diagnostic tests. Moreover, a very valuable tool helping to solve this problem
      has gained strength and is available to everybody - so-called 'evidence-based
      medicine'. There are three categories in infertility diagnostic tests. The first
      category includes tests showing a well-established correlation with pregnancy,
      e.g. semen analysis, tubal patency with hysterosalpingography or laparoscopy, and
      ovulation detection. The second category includes patients whose results are not
      consistently related to pregnancy. Here, these tests include sperm penetration
      assay in the zona-free hamster oocyte, post-coital tests, sperm penetration into
      cervical mucus, and tests to detect anti-sperm antibodies. The third group
      includes patients whose tests are not correlated with pregnancy. The relevant
      tests include endometrial biopsy, the presence of varicocele, and Chlamydia
      detection tests. Tests for infertility are often expensive. Since these patients
      are usually anxious and eager and will do almost anything to have a child, care
      must be taken to avoid exploitation of their hopes with unnecessary procedures.
      This text now reviews and updates the procedures used to investigate infertility.

PMID- 12419047
TI  - Laboratory techniques for human embryos.
AB  - This review is concerned with laboratory techniques needed for assisted
      conception, particularly the handling of gametes and embryos. Such methods are
      being increasingly refined. Successive stages of fertilization and embryogenesis
      require especial care, and often involve the use of micromanipulative methods for
      intracytoplasmic sperm injection (ICSI) or preimplantation genetic diagnosis.
      Embryologists must take responsibility for gamete collection and preparation, and
      for deciding on the means of insemination or ICSI. Embryos must be assessed in
      culture, during the 1-cell, cleaving and morula/blastocyst stages, and classified
      according to quality. Co-culture methods may be necessary. The best embryos for
      transfer must be selected and loaded into the transfer catheter. Embryos not
      transferred must be cryopreserved, which demands the correct application of
      current methods of media preparation, seeding and the correct speed for cooling
      and warming. Before too long, methods of detecting abnormal embryos and avoiding
      their transfer may become widespread.

PMID- 12419048
TI  - Two immensely complex and difficult ethical cases of IVF.

PMID- 12419049
TI  - Molecular genetics analyses in basic and clinical embryology.

PMID- 12419050
TI  - Endometrial angiogenesis: physiology and clinical implications.

PMID- 12419051
TI  - A woman's right to choose...counselling!

PMID- 12419053
TI  - A new Clinical Effectiveness Unit for the Faculty of Family Planning and
      Reproductive Health Care.

PMID- 12419054
TI  - Bleeding problems and progestogen-only contraception.

PMID- 12419056
TI  - Management of bleeding problems with hormone replacement therapy.

PMID- 12419057
TI  - Provision of Chlamydia trachomatis screening in family planning clinics and
      emergency contraception in genitourinary medicine clinics: a collaborative cross
      speciality survey.
AB  - Two surveys were undertaken to review (1) provision of Chlamydia trachomatis
      screening by family planning (FP) clinics in the London region and (2) access to
      emergency contraception (EC) from genitourinary#10; medicine (GUM) clinics within
      the former North Thames region. The findings from the first survey suggest that
      there is insufficient screening (and treatment) in vulnerable groups attending FP
      clinics. Results#10; from the second survey show that hormonal EC is widely
      available from within GUM clinics, and those clinics also provide a range of
      other contraception services. However, these details may not be widely#10;
      recognised either by policymakers or the general public. #10;

PMID- 12419058
TI  - Oves contraceptive cap: short-term acceptability, aspects of use and user
      satisfaction.
AB  - OBJECTIVE: To assess the short-term acceptability, aspects of use and user
      satisfaction with the Oves cap. DESIGN, SETTING AND SUBJECTS: A multicentre
      observational study, commissioned by Veos Ltd, manufacturers of the Oves cap, was
      carried out by the UK Family Planning and Reproductive Health Research Network in
      collaboration with the Institute of Population Studies, University of Exeter,
      Exeter, UK. Women from ten Network centres and one collaborating centre were
      invited to participate. Following an assessment by vaginal examination women were
      fitted with the cap and taught self-fitting by a doctor. The women were asked to
      use the cap six times in 8 weeks. Participants were asked to complete four
      questionnaires on various aspects of cap use including Likert-type measures and
      open-ended questions on experiences with the cap. Doctors were asked to complete
      a first visit and follow-up questionnaires. Women were self-selected clients in
      the participating centres. Women aged 18 years and over, gynaecologically
      healthy, using hormonal contraception or sterilised were eligible for the study.
      Thirty-five women were enrolled and fitted with the cap; 20 chose to participate
      in the study. MAIN OUTCOME MEASURES: Ease of fitting and removal of the cap
      expressed in structured and open-ended questions by both cap users and doctors;
      satisfaction of women and partners with the cap, measured by desire to use the
      cap in the future and by premature withdrawal from the trial. RESULTS: Twenty
      women used the cap on a total of 84 occasions. Four women completed the trial of
      six uses. While most doctors did not have difficulty with fittings or removals,
      10/20 Oves cap users reported some difficulty in fitting it over the cervix and
      12 reported some difficulty removing it in the first three uses. Fewer women had
      difficulty in fitting in uses 4-6 but nearly half continued to have some
      difficulty with removals. CONCLUSIONS: Few women indicated that they would use
      the cap in the future. However, most women were satisfied with their current
      method of contraception. The study raises the question whether women using non
      barrier methods of contraception and satisfied with their current method of
      contraception are the appropriate target recruits for a trial such as this, even
      in the absence of robust efficacy data.

PMID- 12419059
TI  - An assessment of the use of Implanon in three community services.
AB  - AIMS: The aims of the study were three-fold, namely to assess continuation rates
      with Implanon fitted in clients from three contraception and sexual health
      services; to identify factors associated with early removal of Implanon; and to
      assess clinician compliance with recommended practice in counselling and
      insertion. METHODS: Retrospective review of client records, and comparison with
      audit criteria. Postal survey. MAIN FINDINGS: One hundred and ninety women had
      Implanon inserted in the study period. Continuation rates were between 84% and
      88% at 6 months and 67% and 78% at 12 months. There were no pregnancies or
      procedure complications. The main reasons for removal were identified as
      intolerance of recognised side effects or a change of mind about wanting
      contraception. Younger women were more likely to have the device removed early.
      There was evidence of excellent or good recording of many criteria for best
      practice in counselling and insertion. The assessment highlighted certain issues
      around counselling and insertion that services needed to consider further.
      CONCLUSIONS: The three services have been reassured that they are providing a
      good standard of care to clients requesting Implanon and that their 'real life' 6
      and 12-month continuation rates are reasonable.

PMID- 12419060
TI  - A study on the knowledge and practice of contraception among men in the United
      Arab Emirates.
AB  - OBJECTIVE: To determine the knowledge and practice of contraception among United
      Arab Emirates (UAE) men. DESIGN: Cross-sectional survey. PARTICIPANTS: Four
      hundred UAE monogamously married men with children. METHOD: The participants were
      randomly selected from the community and interviewed about knowledge and practice
      of contraception using a structured questionnaire. RESULTS: A total of 348 men
      (87%) gave consent to participate in the study. Two hundred and ninety-four
      participants (84.5%) were aware of the availability of male contraceptive methods
      but only 94 (27%) were currently using these methods; 39 (41.5%) used condoms, 30
      (31.9%) practised coitus interruptus, 24 (25.5%) practised the rhythm method and
      only one (1.1%) had been sterilised. Male contraception was accepted by 116
      (33.3%) subjects of the total study population. The reasons for the objections
      were: religious 133 (57.3%), cultural barriers 47 (20.3%), personal beliefs 29
      (12.5%), medical disorders 18 (7.8%) and economical factors five (2.2%). Of 54
      users of condoms and coitus interruptus, 16 (29.6%) reported to have experienced
      adverse effects that included testicular pain in six (37.5%), decreased libido in
      six (37.5%) and diminished orgasm in four (25%). There were significant
      associations between using male contraception and levels of education of the
      partners (male p < 0.007, female p < 0.01), low family size (p = 0.0001) and
      family income (p < 0.05). Fifty-seven subjects (19.4%) thought that a 'male
      contraceptive pill' is available and 44 (15.0%) believed that a monthly injection
      is available for men. CONCLUSIONS: The level of awareness of contraception among
      men attending primary care in UAE is moderate. Two-thirds of the study subjects
      objected to the use of contraception by their wives and less than 20% practise
      contraception themselves. This is partly due to sociocultural traditions,
      religious beliefs and poor knowledge.

PMID- 12419062
TI  - Public and private collaboration in establishing a young person's sexual health
      clinic in a commercial setting.
AB  - OBJECTIVE: To define the key factors and constraints in public-private sector
      collaboration in establishing and delivering a young person's sexual health
      clinic within an existing commercial establishment. CONSULTATION, PLANNING AND
      IMPLEMENTATION PHASES: Consultations were held between the Health Promotion
      Department, family planning and commercial outlets, resulting in the
      establishment of the UK's first sexual health service within commercial premises.
      Once the clinic had been operational for 6 months, a single researcher carried
      out semi-structured interviews with 13 staff representing all levels within the
      partner organisations. POST-IMPLEMENTATION INTERVIEWS: There was agreement by all
      interviewees on the objectives of the clinic. The problems encountered during the
      establishment of the service were with the legislation pertaining to pharmacies
      and the adverse press coverage of a minority public view of the provision of
      sexual health services to young people. No respondent identified conflict between
      the aims of the clinic and the strategic objectives of their organisation.
      RECOMMENDATIONS: Common aims are imperative for successful interagency working.
      Wider initial consultations may have helped to identify potential problems and
      confirm common aims at an earlier stage of the development of the project. The
      involvement of senior management may also have improved the smooth running of the
      project.

PMID- 12419063
TI  - Evaluation of a young person's sexual health service in a commercial setting.
AB  - OBJECTIVE: To determine the acceptability and accessibility of a sexual health
      service for young people in a city centre pharmacy. DESIGN: Prospective
      qualitative survey of clients attending a new sexual health service, including
      client characteristics and semi-structured interviews. PARTICIPANTS: Clients
      attending the service between January and May 1999. MAIN OUTCOME MEASURES: Social
      demographics, reasons for attendance and consultation outcomes for clients
      together with their views of the service. RESULTS: A total of 98 clients (average
      of three clients per session) attended from January to May 1999, ranging from 14
      to 39 years of age. Clients came from 41 postcode areas of the city (which has
      over 80 postcode areas) and neighbouring districts, covering all social strata.
      Only four clients had never been sexually active; 53 clients attended for
      emergency contraception, with 26 attending for hormonal contraception. A total of
      93% of those asked were either satisfied or very satisfied with the opening
      times. All clients were satisfied or very satisfied with the clinic location.
      CONCLUSIONS: The setting of a sexual health service for young people in a city
      centre pharmacy allows access from a wide area. The timing and location of the
      service were the most commonly quoted reasons for attendance. All clients were
      asked to participate in a semi-structured interview, unless the interviewer was
      already engaged; results were obtained for 66 clients (67% of attendees).

PMID- 12419064
TI  - Persistent vaginal bleeding in a patient with a broken Implanon.
AB  - A 29-year-old woman with an Implanon contraceptive device in situ presented with
      persistent and prolonged vaginal bleeding. The implant had been inserted 2 years
      previously; the patient had been happy with it and had been mainly amenorrhoeic
      with the occasional light period. She was concerned that the implant had broken
      during a game of 'rough and tumble' with her son in August 2000. Since the trauma
      to her arm her bleeding pattern had changed, and she began bleeding heavily for 3
      weeks every month. The rod was removed and found to be fractured halfway across
      its width. A new Implanon device was inserted and the bleeding settled.

PMID- 12419066
TI  - Training for reproductive health: beyond apprenticeship.

PMID- 12419065
TI  - Intra-vas deferens injection of styrene maleic anhydride gel for male
      contraception: is it safe?

PMID- 12419067
TI  - Great balls of fire and the vicious cycle: a study of the effects of cycling on
      male fertility.
AB  - Over the past few years we have been bombarded with publicity telling us to do
      more exercise in order to reduce our risk of developing heart disease. Also, as
      commuter traffic increases and petrol prices rise, workers are constantly looking
      for quicker, cheaper and greener ways of travelling short distances. As a result
      of this, bicycle sales have risen exponentially. However, as the popularity of
      cycling increases, so do the fears that spending hours in the saddle every day
      may not be as beneficial as first thought. For many years now reports in the
      literature have suggested that exercise in general, and cycling specifically, may
      actually increase an individual's risk of developing problems in the male
      reproductive system. In this report I will review the evidence available in the
      literature, paying special attention to cycling and the risks of developing
      testicular cancer, secondary impotence and, most importantly, the effects on male
      fertility.

PMID- 12419068
TI  - Sexual health provision for young people.

PMID- 12419077
TI  - Primum non nocere.

PMID- 12419078
TI  - The view of The International Menopause Society on the Women's Health Initiative.

PMID- 12419080
TI  - Effects of progestogens on the postmenopausal breast.
AB  - The potential for an increased risk of breast cancer linked to the use of
      synthetic progestins combined with oral estrogens is one of the main putative
      reasons for discouraging postmenopausal women from using any type of hormone
      replacement therapy (HRT) for more than a few years. Because no definitive proof
      exists, the available epidemiological results can be interpreted according to
      what seems biologically plausible to each investigator, including potential
      differences between various schedules of various steroids in various species and
      in vitro models. More than 60 years after the discovery of progesterone, the main
      effects of this endogenous steroid on the physiopathology of the breast during a
      normal luteal phase are still controversial. The lack of consensus on such basic
      knowledge concerning one of the most important targets of a natural ovarian
      hormone discovered in 1934 is amazing. In the most cited studies, nothing has
      been done to measure progesterone in plasma and to correlate the extremely
      disparate cytological results with extremely erratic steroid levels at the time
      of surgical stress. In a recent study, with a better design, the physiological
      rise of endogenous progesterone during the luteal phase coincided with a drop in
      proliferation of breast epithelial cells, which appears to be only slightly
      delayed in comparison with what is described in the endometrium. Differences in
      doses and schedules of treatments with various synthetic progestins have largely
      contributed to the inconsistency in clinical recommendations. Based on the
      analysis of proliferation markers in surgical biopsies from normal human
      postmenopausal breast tissue, it is plausible that mitogenic activity is not
      identical during therapy with unopposed estrogens versus estrogens combined with
      progestogens, and is higher during HRT that combines oral conjugated equine
      estrogens with medroxyprogesterone acetate than during HRT that combines
      transdermal estradiol and progesterone. It is misleading to put all progestogens
      in the same bag irrespective of their chemical structure, and, more important,
      their effect may vary according to whether it is estrone or estradiol that is
      mainly accumulated in the breast tissue. The hypothesis of progesterone
      decreasing the proliferative effect of estradiol in the postmenopausal breast
      remains highly plausible.

PMID- 12419081
TI  - What is tibolone--and is it a SPEAR?

PMID- 12419082
TI  - Lipids and antioxidative effects of estradiol and sequential norethisterone
      acetate treatment in a 3-month randomized controlled trial.
AB  - OBJECTIVE: To determine the influence of hormone replacement therapy on serum
      lipids and antioxidative factors associated with the risk of coronary heart
      disease. METHODS: The effect of a sequential estradiol-norethisterone acetate
      regimen or placebo on lipid metabolism, antioxidative variables and fatty acid
      composition in serum was measured during the peak-estrogen phase in a randomized,
      double-blind, placebo-controlled study of 42 healthy postmenopausal women for 3
      months. RESULTS: Active treatment significantly reduced lipoprotein(a) by 15% (p
      = 0.005, compared with placebo), low-density lipoprotein (LDL) cholesterol by 10%
      (p = 0.005) and the LDL cholesterol/high-density lipoprotein (HDL) cholesterol
      ratio by 11% (p = 0.016). Serum triglycerides increased by 21% (p = 0.045). No
      effect was observed on HDL cholesterol, on apolipoproteins apo A(1) or apo B, or
      on non-esterified fatty acids in serum. No treatment effect was seen in the
      proportions of monounsaturated and polyunsaturated fatty acids. The concentration
      of malondialdehyde in serum did not change with the estrogen-progestin treatment.
      CONCLUSIONS: This sequential estrogen-progestin therapy has a beneficial effect
      on apolipoprotein(a) and LDL cholesterol, but no effect on non-esterified fatty
      acids or the level of lipid peroxidation products in serum.

PMID- 12419083
TI  - Efficacy and tolerability of pulsed estrogen therapy: a 12-week double-blind
      placebo-controlled study in highly symptomatic postmenopausal women.
AB  - OBJECTIVE: To confirm the efficacy and safety of pulsed estrogen therapy, a
      transient daily hormone exposure, for climacteric symptoms in highly symptomatic
      postmenopausal women. PATIENTS AND METHODS: In this multicenter, double-blind,
      parallel-group study, early postmenopausal women with at least seven moderate to
      severe vasomotor symptoms per day were randomized to receive intranasal
      estradiol, 150 or 300 microg/day, or placebo, for 12 weeks. The primary outcome
      measure was the mean daily number of moderate to severe vasomotor symptoms, as
      recorded in patient diaries. RESULTS: A total of 165 patients were randomized.
      The mean daily number of moderate to severe vasomotor symptoms decreased
      significantly more (p < 0.001) in the 150-microg/day (-7.86) and 300-microg/day (
      9.39) groups than in the placebo group (-5.22). The decrease reached significance
      more rapidly with the 300-microg/day dose (from week 2) than with the 150
      microg/day dose (from week 8). The rate of emergent adverse events with both
      doses was similar to that with placebo. CONCLUSIONS: Pulsed estrogen therapy,
      achieved by intranasal estradiol 150 microg/day and 300 microg/day,
      significantlyreduced the incidence of moderate to severe vasomotor symptoms,
      compared with placebo. The 300-microg/day dose demonstrated a greater and more
      rapid therapeutic effect, with no clinically significant difference in
      tolerability, compared with the 150-microg/day dose, and therefore offers the
      best efficacy/safety ratio when initiating treatment with intranasal estradiol.

PMID- 12419084
TI  - Flow resistance in carotid and middle cerebral arteries in postmenopausal women:
      a comparative study of tibolone and continuous combined hormone replacement
      therapy.
AB  - OBJECTIVE: The study sought to compare the vascular resistance and serum lipids
      of postmenopausal women assigned to tibolone therapy or continuous combined
      hormone replacement therapy. DESIGN: This was a 6-month, prospective, single
      blind, single-center, randomized study. A total of 50 healthy postmenopausal
      women were enrolled. At study end, 40 women had completed a 6-month follow-up.
      The first group (23 subjects) received conjugated equine estrogens (CEE) 0.625
      mg/day and medroxyprogesterone acetate (MPA) 5 mg/day. The second group (17
      subjects) received tibolone 2.5 mg/day. The pulsatility and resistance indexes of
      the carotid and middle cerebral arteries, and serum lipid profiles were
      monitored. RESULTS: Comparisons demonstrated that there were no significant
      differences between the groups in terms of changes in the pulsatility index (PI)
      and the resistance index (RI) of the common carotid artery (CCA), internal
      carotid artery (ICA), and middle cerebral artery (MCA) within the study period.
      Both treatments effectively reduced the total cholesterol level and with no
      significant differences found between the two regimens. However, in comparing the
      two groups, we found that high-density lipoprotein (HDL) cholesterol levels were
      significantly lower in the tibolone group at either 3 months or 6 months after
      treatment, whereas a significantly higher triglycerides level was observed in the
      CEE + MPA group after 3 months of treatment. Low-density lipoprotein (LDL)
      cholesterol levels indicated no significant differences between the two groups
      after treatment. CONCLUSIONS: The study demonstrated that major neck and cerebral
      vascular impedance was not influenced significantly by either regimen.
      Nonetheless, lipid profiles were affected differently by tibolone and by
      continuous combined CEE + MPA. However, whether or not these findings might
      modify cardiovascular risk is still unknown.

PMID- 12419085
TI  - Quality of life of breast cancer survivors: the impact of hormonal replacement
      therapy.
AB  - OBJECTIVES: The aims of this non-randomized qualitative study were to compare the
      quality of life (QOL) of breast cancer survivors who received hormone replacement
      therapy (HRT) and those who did not, and to describe the impact of breast cancer
      on their social, physical, psychological and spiritual domains. A QOL self
      evaluation questionnaire was used to determine the most important concerns and
      changes described by women that affected, or were likely to affect, their QOL as
      a result of breast cancer. METHODS: In total, 220 patients who had finished
      treatment for breast cancer were contacted; 190 agreed to participate, of whom
      123 (64.8%) completed and returned their questionnaires, which comprised
      demographic data, Quality of Life Breast Cancer Version Questionnaire and Quality
      of Life Self Evaluation Questionnaire. The results for women taking HRT were
      compared with results for those who were not. RESULTS: There were no significant
      differences in time between surgery for breast cancer and the survey, age at last
      birthday, number of pregnancies and live births, employment, breast cancer
      surgery and adjuvant therapy between HRT and non-HRT groups. No differences were
      found in the social, physical, psychological and spiritual domains between the
      two groups; however, significant differences were found between survival time and
      quality of life in some domains. During the study, none of the 123 women
      developed a recurrence of their breast cancer. CONCLUSION: There were no
      significant differences in any demographic variables between the users of HRT and
      the non-users. The same level of QOL was observed between HRT and non-HRT groups
      in the four domains of well-being. The majority of women with breast cancer
      recovered to a near normal level of QOL after a 4-year adjustment period, and
      lead fulfilling lives. This adjustment period cannot be quantified, as individual
      factors such as emotional, social and financial concerns will differ for each
      individual.

PMID- 12419086
TI  - Influence of pregnancy and breast-feeding on quantitative ultrasonometry of bone
      in postmenopausal women.
AB  - OBJECTIVE: Reproductive factors such as parity and breast-feeding may be
      associated with low bone mass and osteoporotic fractures in later years. In this
      study, os calcis quantitative ultrasonometry was used to elucidate the
      relationship between parity, lactation and bone mass in postmenopausal women.
      DESIGN: This was a comparison study using subsequent matched pairs analysis as
      well as multiple linear regression analysis. The study was carried out at five
      centers in Germany. The study included 2,080 postmenopausal women (age (mean +/-
      SD) 58.8 +/- 8.2 years), who were attending for routine check-up and in whom
      diseases and drug treatments known to affect bone metabolism had been excluded.
      METHODS AND OUTCOME MEASURES: Women underwent quantitative ultrasonometry (QUS)
      measurement at the heel. Values of the ultrasonometry variables -speed of sound,
      broadband ultrasound attenuation and stiffness index -were calculated and
      compared for nulliparous and parous women and for women who had and had not
      breast-fed. Because of some significant intergroup differences, and to determine
      any effect of the number of live births and the duration of breast-feeding on
      ultrasonometry results, second analyses were undertaken using equally sized
      samples, matched for possible confounding variables such as age and body mass
      index (matched pairs). In these analyses, nulliparous women were compared with
      parous women, grouped according to number of live births, and women who had never
      breast-fed were compared with women who had breast-fed, grouped according to
      duration of breast-feeding. Furthermore, a multiple linear regression analysis
      was performed to examine the combined effects of reproductive factors on QUS
      variables. RESULTS: No statistically significant associations were found between
      ultrasonometry variables and parity or breast-feeding, even after controlling for
      confounding variables in matched-pairs analysis or in a multiple linear
      regression analysis.

PMID- 12419087
TI  - Effects of transdermal and oral estrogen replacement on lipids and glucose
      metabolism in postmenopausal women with type 2 diabetes mellitus.
AB  - OBJECTIVE: To compare the effects of oral and transdermal estrogen replacement on
      lipid and glucose metabolism in postmenopausal women with diabetes mellitus type
      2. DESIGN AND METHODS: In an open, randomized, cross-over study, 21 diabetic
      postmenopausal women were treated with transdermal 17beta-estradiol 50 microg or
      oral conjugated equine estrogens (CEE) 0.625 mg daily, both associated with 300
      mg/day of oral micronized progesterone for 12 days monthly during 6 months each.
      After a 12-h overnight fasting period, blood glucose, insulin, glycosylated
      hemoglobin (HbA1c) and lipoprotein profile were evaluated, at baseline and after
      6 months of each schedule of hormone replacement therapy (HRT). Insulin
      sensitivity was determined by homeostasis model assessment (HOMA). RESULTS: HRT
      had no negative influence on glucose metabolism. After 6 months of CEE treatment,
      there was a significant increase in high-density lipoprotein (HDL) cholesterol,
      but also in triglycerides, of 9.0% and 20.7%, respectively (p = 0.04). The levels
      of total cholesterol and low-density lipoprotein (LDL) cholesterol were
      unaffected. Transdermal estradiol did not affect the lipid profile. CONCLUSIONS:
      Hormone replacement therapy with either oral or transdermal estrogen plus
      micronized progesterone has no harmful influence on glucose metabolism in type 2
      diabetic postmenopausal women; whether the increase in HDL cholesterol, but also
      in triglyceride levels, makes oral CEE the better choice remains an open
      question.

PMID- 12419088
TI  - Effect of transdermal estrogen therapy on some vasoactive humoral factors and 24
      h ambulatory blood pressure in normotensive postmenopausal women.
AB  - BACKGROUND: Mechanisms of the vasoprotective effect of hormone replacement
      therapy (HRT) are not completely understood, and they may involve direct actions
      on blood vessels through modulation of endogenous vasoconstrictors and
      vasodilators. Most studies have focused on estrogen action on prostacyclin and
      nitric oxide, while insufficient data exist concerning the effect of estrogen
      replacement therapy (ERT) on vascular endothelial growth factor (VEGF) and
      prostaglandin E(2). OBJECTIVE: The aim of this study was to examine the effect of
      transdermal estrogen therapy on VEGF, prostaglandin E(2) and active renin in
      normotensive postmenopausal women. METHODS: Transdermal estrogen (Climara)
      (Schering): 50 microg 17beta-estradiol) was given for 3 months to normotensive
      women with a surgically induced menopause, and serum levels of VEGF, active renin
      and prostaglandin E(2) were measured before and after treatment. In addition, 24
      h ambulatory blood pressure monitoring was carried out to determine the estrogen
      action on mean diurnal and nocturnal systolic and diastolic blood pressure
      levels. RESULTS: Estradiol treatment resulted in a significant increase in both
      VEGF and prostaglandin E(2). There was no significant change in active renin
      levels. However, out-patient monitoring showed a significant fall in systolic
      blood pressure (daytime, night-time and total 24-h). The stimulating action of
      ERT on VEGF and prostaglandin E(2) suggests that both factors can elicit estrogen
      vasodilatory effects. CONCLUSION: The estrogen-mediated increase in serum VEGF
      and prostaglandin E(2) concentrations may be a mechanism by which HRT benefits
      the cardiovascular system.

PMID- 12419089
TI  - Assessment of bleeding patterns.

PMID- 12419090
TI  - Production of prostaglandin e(2) by iridial melanocytes exposed to latanoprost
      acid, a prostaglandin F(2 alpha) analogue.
AB  - Several prostaglandin analogues used for glaucoma treatment cause increased
      pigmentation of the iris. The purpose of the present study was investigate
      whether latanoprost, a PGF(2 alpha) analogue, has any effect on the production of
      endogenous prostaglandins in iridial melanocytes, which could be important in the
      mechanism leading to increased pigmentation. Bovine and human iridial melanocytes
      in culture were used for the experiments. Production of endogenous prostaglandins
      was measured by enzyme immunoassay, and the melanin content was measured
      spectrophotometrically. In bovine iridial melanocytes, latanoprost acid caused a
      significant increase of the PGE(2) production, which could be blocked by
      indomethacin and NS398, indicating an involvement of cyclo-oxygenase 2. In order
      to study the selectivity of the phenomenon other endogenous substances/drugs were
      tested, e.g., acetylcholine, carbachol, noradrenaline, neuropeptide Y, substance
      P and alpha-MSH, but none was found to have any significant effect. Human iridial
      melanocytes also responded to latanoprost acid with increased production of
      PGE(2) and in 1 out of 5 individuals increased melanogenesis coincided with
      increased PGE(2) production. In bovine iridial melanocytes, latanoprost acid did
      not stimulate melanogenesis. These results indicate that latanoprost acid cause
      enhanced formation of endogenous prostaglandins that may have auto- and/or
      paracrine effects in the melanocytes, possibly associated with melanogenesis.

PMID- 12419091
TI  - Causes of non-compliance with drug regimens in glaucoma patients: a qualitative
      study.
AB  - The purpose of this study was to gain insights into why patients are not
      compliant with their glaucoma medications. Patients were recruited from lists
      provided by two ophthalmologists. Each patient had seen a minimum of two
      ophthalmologists for their glaucoma, and was taking at least two topical
      medications for glaucoma. Qualitative methodology was utilized, including two
      focus groups and eleven in-depth interviews in patients' homes. The results
      showed that forgetfulness was the number one reported reason for non-compliance.
      Patients did not claim to be non-compliant specifically because of side effects,
      but they did complain about them. Communication between physicians and patients
      is a key factor in compliance for glaucoma patients. Specifically, patients would
      like their physicians to teach them how to instill their eye drops, tell them
      about new/alternate medications and procedures as they become available, and
      offer new ways to make their regimen easier. Patients often do not tell their
      physician if they experience a side effect unless it is intolerable to them, yet
      they do realize the seriousness of glaucoma, and the consequences of not
      following their doctor's orders. Finally, while cost was not a reported
      deterrence to compliance, some patients would prefer less expensive alternatives.

PMID- 12419092
TI  - Blood concentrations of cyclosporin a during long-term treatment with cyclosporin
      a ophthalmic emulsions in patients with moderate to severe dry eye disease.
AB  - To quantify blood cyclosporin A (CsA) concentrations during treatment with CsA
      topical ophthalmic emulsions, blood was collected from 128 patients enrolled in a
      Phase 3, multicenter, double-masked, randomized, parallel-group study of CsA
      eyedrops for treatment of moderate to severe dry eye disease. Patients received
      0.05% CsA, 0.1% CsA, or vehicle b.i.d. for 6 months; vehicle-treated patients
      then crossed over to 0.1% CsA b.i.d. for 6 months. CsA concentrations were
      measured using a validated LC/MS-MS assay (quantitation limit = 0.1 ng/mL). No
      patient receiving 0.05% CsA had any quantifiable CsA in the blood (n = 96
      samples). All but 7 of 128 (5.5%) trough blood samples from the 0.1% CsA group
      were below the quantitation limit for CsA; none exceeded 0.3 ng/mL. CsA was also
      below the limit of quantitation in 205 of 208 (98.6%) of serial postdose blood
      samples collected from 26 patients during 1 dosing interval between months 9 and
      12. The highest C(max) measured, 0.105 ng/mL at 3 hours postdose, occurred in a
      0.1% CsA-treated patient. These results indicate that long-term use of topical
      CsA ophthalmic emulsions at doses that are clinically efficacious for treating
      dry eye will not cause any system-wide effects.

PMID- 12419093
TI  - Comparative permeability of human and rabbit corneas to cyclosporin and tritiated
      water.
AB  - Diffusion of cyclosporin A (CsA) and water through fresh and frozen (liquid
      nitrogen, -85 degrees C) human and rabbit corneas was compared to establish the
      appropriateness of using the latter tissue as a model for its human counterpart
      for in vitro permeability studies. Permeation of CsA in the presence of three
      penetration enhancers, 0.01% benzalkonium chloride (BZCl), 20% dimethylsulfoxide
      (DMSO), 10% and 20% Cremophor-EL was also studied. Permeability was determined
      using a flow-through diffusion apparatus (20 degrees C, 24 hours). ANOVA,
      Duncan's multiple range test, and an unpaired t-test were used to determine
      steady state kinetics and flux differences over time intervals. No statistically
      significant differences in flux values of CsA and water could be detected between
      fresh and frozen/thawed human and rabbit corneas. The diffusion of water was
      significantly lower across frozen/thawed rabbit cornea than across the same human
      tissue. CsA flux rates across frozen/thawed rabbit cornea in the presence of all
      three enhancers increased significantly when compared to the same tissues without
      enhancer, except in the presence of 20% Cremophor-EL after 18 hours. The rabbit
      cornea appears to be an appropriate in vitro model for studying human
      transcorneal penetration of drugs. Smaller M(w) substances, however, may have
      higher diffusion rates across frozen/thawed human corneal tissue.

PMID- 12419094
TI  - Nitric oxide and cyclic GMP-mediated protein secretion from cultured lacrimal
      gland acinar cells.
AB  - PURPOSE: Nitric oxide (NO) donors and NO synthase (NOS) substrates were tested
      for their use to stimulate protein secretion from cultured lacrimal gland acinar
      cells, through activation of guanylate cyclase. METHOD: Rabbit lacrimal gland
      epithelial cells (RLG cells) were incubated with NO donors and/or NOS substrates
      and the protein released into culture medium was determined with bicinchoninic
      acid assay. Guanylate cyclase activation by NO precursors was determined by
      measurement of c-GMP produced. RESULTS: Both NO donors and NOS substrates were
      able to stimulate protein release from RLG cells. Among 6 compounds studied,
      sodium nitroprusside, isosorbide dinitrate and N(a)-benzoyl L-arginine ethyl
      ester (BAEE) were most potent to release protein over 100% of the basal release.
      The guanylate cyclase activity was stimulated by these NO precursors and was
      inhibited by guanylate cyclase inhibitor, [1,2,4]oxadiazolo-[4,3-a]quinoxalin-1
      one (ODQ). CONCLUSION: NO donors and NOS substrates were able to stimulate
      protein release from RLG cells via activation of guanylate cyclase and c-GMP
      release, which was blocked by guanylate cyclase inhibitor, ODQ. It indicates that
      NO donors and NOS substrates could be used for the treatment of dry eye syndrome
      if the same holds true in dry eye animal models.

PMID- 12419095
TI  - Penetration of topically administered ofloxacin and trimethoprim into aqueous
      humor.
AB  - Ocular penetration of two topical antibiotics used to treat bacterial
      conjunctivitis was assessed in adult volunteers scheduled for cataract surgery.
      In this randomized, parallel-group study, patients instilled trimethoprim sulfate
      0.1%/polymyxin B (n = 23) or ofloxacin 0.3% (n = 25) QID for 3 days, plus 4
      instillations in the hour before surgery. Analysis of aqueous humor samples
      obtained during surgery showed a 2.4-fold greater concentration of ofloxacin over
      trimethoprim (1.135 micro g/ml vs 0.470 micro g/ml; P <.0001). The greater
      concentration of ofloxacin in ocular tissue coupled with its superior
      antibacterial activity profile supports its use as an alternative to
      trimethoprim/polymyxin B for treatment of bacterial conjunctivitis.

PMID- 12419096
TI  - Pilocarpine permeability across ocular tissues and cell cultures: influence of
      formulation parameters.
AB  - In vitro permeation studies of drugs across biological barriers are promising
      tools for estimating the quality and quantity of drug transport in vivo. The
      objective of this work was to compare the permeability of the hydrophilic model
      drug pilocarpine-HCl (P-HCl) through different ocular tissues and cell cultures:
      isolated pig cornea (PCr) and sclera (PSc), rabbit conjunctiva (RCo), and rabbit
      conjunctival (RCoEC) or corneal epithelial cell culture (RCrEC). Furthermore, the
      study included investigations about the influence of the excipients benzalkonium
      chloride (BAC) and ethylene diamine tetra acetic acid disodium salt (EDTA) on the
      permeability of the small drug. In general, BAC caused a facilitated drug
      transport, while EDTA hardly influenced the P-HCl concentration on the acceptor
      side, except for RCoEC. Additionally, the impact of variation in buffer solution
      pH and tonicity on drug transport in both cell cultures was tested. The higher
      the tonicity of the buffer solution (80, 300, and 600 mOsm/kg) the lower the
      permeability coefficient (P(eff)). At different pH values (6.4, 7.4, and 8.4) the
      P(eff) showed a directly proportional demeanor. In summary, a good correlation
      between the isolated tissues and cell cultures with regard to P-HCl transport
      could be observed.

PMID- 12419097
TI  - Effects of intraocular epinephrine on the corneal endothelium of rabbits.
AB  - Epinephrine is frequently used in the phacoemulsification to dilate pupils. To
      determine the effects of different concentration of epinephrine on the corneal
      endothelial cells, twenty-eight rabbit eyes were equally divided into four
      groups. Solutions, which contained normal saline, 1:1000 epinephrine, 1:5000
      epinephrine and 1:10000 epinephrine respectively, were injected into the anterior
      chambers of the eyes of four groups of rabbits. In vivo morphological changes of
      corneal endothelium and changes of thickness were checked with specular
      microscopy. In vitro morphological evaluation of corneal endothelium was observed
      in excised corneal buttons stained with alizarin red with trypan blue, and with
      scanning electron microscopy. Our results showed that there was no significant
      difference in cell density and corneal thickness among the four groups. Alizarin
      red with trypan blue stain and SEM exam revealed smooth and distinct cell borders
      of endothelial cells in each group. Intracameral injection of epinephrine does
      not produce toxic effect on corneal endothelial cells in rabbits.

PMID- 12419098
TI  - Pemirolast potassium 0.1% ophthalmic solution is an effective treatment for
      allergic conjunctivitis: a pooled analysis of two prospective, randomized, double
      masked, placebo-controlled, phase III studies.
AB  - Patients with allergic conjunctivitis may experience several debilitating
      symptoms, particularly ocular itching. The objective of this study was to
      evaluate the efficacy and safety of pemirolast potassium 0.1% ophthalmic solution
      (Alamast trade mark ), a novel mast-cell stabilizer, for preventing ocular
      manifestations of seasonal allergic conjunctivitis. A pooled analysis was
      performed of data derived from 2 prospective, randomized, double-masked, placebo
      controlled, multicenter phase III clinical trials of pemirolast potassium 0.1% in
      patients with a history of allergic conjunctivitis. Patients having a positive
      bilateral response to conjunctival allergen challenge (CAC) with ragweed antigen
      (N = 274) were randomized to receive pemirolast potassium 0.1% or placebo QID,
      beginning approximately 1-2 weeks before the onset of ragweed season and
      continuing until after the first killing frost (12-17 weeks duration). Patients
      recorded their daily evaluations of ocular itching in a diary. After the allergy
      season, patients underwent a second CAC. Evaluable patients (n = 265) recorded a
      total of 21,491 patient-days of ocular itching data during allergy season. In
      every 7-day or 14-day period, patients treated with pemirolast potassium 0.1%
      reported more days without any ocular itching compared with patients receiving
      placebo. Differences favoring pemirolast potassium 0.1% were statistically
      significant in 63% (10/16) of all 7-day periods (p < or = 0.046) and 88% (7/8) of
      all 14-day periods (p < or = 0.016). After the allergy season, pemirolast
      potassium 0.1% was significantly superior to placebo in relieving CAC-induced
      ocular itching, with relief occurring as early as 3 minutes after allergen
      challenge (p < or = 0.034). Pemirolast potassium 0.1% was well tolerated and had
      a safety profile similar to that of placebo. In conclusion, pemirolast potassium
      0.1% is effective and safe in preventing ocular itching in patients with allergic
      conjunctivitis during allergy season.

PMID- 12419099
TI  - A pilot study on the effects of two ventilation methods on weld fume exposures in
      a shipyard confined space welding task.

PMID- 12419100
TI  - Potential exposure to arsenic and other highly toxic chemicals when handling
      museum artifacts.

PMID- 12419101
TI  - Chemical exposure and risk assessment at workplaces--modeling approach.

PMID- 12419103
TI  - Attributions, stress, and work-related low back pain.
AB  - Occupational low back pain (LBP) is a major cause of morbidity and cost. Efforts
      to control LBP are largely unsuccessful, and better understanding of risks is
      needed, especially psychological factors. The purpose of this research was to
      assess the association between worker attributions and LBP. Attributing LBP to
      internal causes may increase the worker's perceived control, whereas external
      attribution may cause distress. A new model was developed to explore these
      associations. A cross-sectional design was used in this study of 278 garment
      workers. Data were gathered by a self-administered questionnaire and through
      direct observation. Responses to questions on worker attributions of LBP cause
      and knowledge of back safety were subjected to factor analysis and other
      psychometric evaluation to develop scales. Six hypotheses were tested using
      multivariate logistic regression. Workers who scored high in internal attribution
      were more likely to be knowledgeable of back safety (OR = 3.7, 95% CI = 2.0-6.7).
      Workers reporting high demand were more likely to report LBP (OR = 2.3, 95% CI =
      1.2-4.4). Workers attributing LBP to job tasks were more likely to report LBP (OR
      = 3.2, 95% CI = 1.5-6.9), and those reporting high supervisor support were less
      likely to report LBP (OR = 0.23, 95% CI = 0.08-0.66). Workers with annual incomes
      above 15,000 dollars were more likely to report LBP in the test of both the
      Demand-Control-Support and Attribution models (OR = 2.8, 95% CI = 1.2-6.9 and OR
      = 4.1, 95% CI = 1.5-11.1, respectively). While both models appeared to be useful
      for the study of low back pain, the R(2)(L) of the Demand-Control-Support model
      equaled only 11.9 percent, whereas the Attribution model equaled 26.2 percent.
      This study provides evidence that attribution theory is useful in the study of
      LBP, including in future interventions in the prevention of LBP.

PMID- 12419104
TI  - Exposure to cyclic anhydrides in welding: a new allergen-chlorendic anhydride.
AB  - Respiratory effects associated with welding fumes have been manifested in welders
      as occupational asthma. Previous studies have concerned mainly the effects of
      metal fume exposure, although it has also been suggested that asthma may develop
      as a result of exposure to contaminants generated from painted metals. To
      determine whether welding fumes contain irritating and sensitizing anhydrides,
      air samples were collected during the repair welding of forest harvesters, which
      were painted with chlorinated polyester paint. Samples were collected with an
      assembly of a spiral glass trap inserted between a filter holder with a Teflon
      filter and a Tenax sampling tube. Sample analyses were with GC-MS and GC-ECD.
      Sensitizing anhydrides released from the paint into the air were primarily
      chlorendic anhydride (<2-44 microg/m(3)) and phthalic anhydride (11-21
      microg/m(3)). Hydrogen chloride (HCl) and hexachlorocyclopentadiene were also
      found. Airborne HCl was measured with Drager tubes. Since paint films are
      electrical insulators, the film around the welding seam was removed before arc
      welding. Removal of paint with an abrasive wheel caused the least exposure to HCl
      (<0.5 ppm) in contrast to burning with a gas fuel torch, (HCl approximately 5
      ppm). HCl exposure was the highest (<0.5-20 ppm) during welding. It is
      recommended that dry paint coating be removed from an area around the seam with
      an abrasive wheel, not by burning, before welding.

PMID- 12419105
TI  - Reproducibility of survey results from a study of occupation-related respiratory
      health in the aluminum industry.
AB  - Confidence in dose-response relationships arising from occupational studies is
      dependent upon the reliability and validity of relevant exposure and morbidity
      estimates. Often self-reported occupational histories are a surrogate for direct
      exposure measures, and self-report of symptoms serves a similar purpose in place
      of more objective measures of morbidity. Unfortunately, there are few methods for
      validating either of these sources of information. This study attempts to
      evaluate the reproducibility of a survey instrument, and resulting cumulative
      exposure estimates, utilized in a study of work-related respiratory morbidity in
      the aluminum industry. The survey instrument comprised measures of pulmonary
      function, atopic status, smoking, occupational history, and respiratory symptoms.
      A Task Exposure Matrix was used to estimate exposure categories and cumulative
      exposure scores. Two groups of employees were administered the survey instrument
      on two separate occasions. Group A (n = 74) completed their two surveys more than
      ten weeks apart and Group B (n = 43) completed their surveys less than two weeks
      apart. Reproducibility was assessed using Cohen's Kappa for categorically
      measured outcome measures and intraclass correlation coefficients for
      continuously measured outcomes. Agreement across most variables, for both groups,
      was generally high. Repeatability of self-reported respiratory symptoms ranged
      from 70 to 98 percent (Group A) and 88 to 100 percent (Group B). Cumulative
      exposure scores were highly reproducible, despite some discrepancies in the self
      reported occupational histories across interviews, with most of the calculated
      intraclass r scores exceeding 0.8. These results give strength to studies
      reporting dose-response relationships derived from similarly collected data.
      Reproducibility of the survey data was enhanced by use of standardized
      questionnaire material, consistent interview structure, and calibrated equipment
      for objective observation. In particular the authors recommend use of a company
      job dictionary to optimize reproducibility of self-reported occupational
      information.

PMID- 12419106
TI  - Determinants of dust exposure in tunnel construction work.
AB  - In tunnel construction work, dust is generated from rock drilling, rock bolting,
      grinding, scaling, and transport operations. Other important dust-generating
      activities are blasting rock and spraying wet concrete on tunnel walls for
      strength and finishing work. The aim of this study was to identify determinants
      of dust exposure in tunnel construction work and to propose control measures.
      Personal exposures to total dust, respirable dust, and alpha-quartz were measured
      among 209 construction workers who were divided into 8 job groups performing
      similar tasks: drill and blast workers, shaft drilling workers, tunnel boring
      machine workers, shotcreting operators, support workers, concrete workers,
      outdoor concrete workers, and electricians. Information on determinants was
      obtained from interviewing the workers, observation by the industrial hygienist
      responsible for the sampling, and the job site superintendent. Multivariate
      regression models were used to identify determinants associated with the dust
      exposures within the job groups. The geometric mean exposure to total dust,
      respirable dust, and alpha-quartz for all tunnel workers was 3.5 mg/m(3) (GSD =
      2.6), 1.2 mg/m(3) (GSD = 2.4), and 0.035 mg/m(3) (GSD = 5.0), respectively. A
      total of 15 percent of the total dust measurements, 5 percent of the respirable
      dust, and 21 percent of the alpha-quartz exceeded the Norwegian OELs of 10
      mg/m(3), 5 mg/m(3), and 0.1 mg/m(3), respectively. Job groups with highest
      geometric mean total dust exposure were shotcreting operators (6.8 mg/m(3)),
      tunnel boring machine workers (6.2 mg/m(3)), and shaft drilling workers (6.1
      mg/m(3)). The lowest exposed groups to total dust were outdoor concrete workers
      (1.0 mg/m(3)), electricians (1.4 mg/m(3)), and support workers (1.9 mg/m(3)).
      Important determinants of exposure were job group, job site, certain tasks (e.g.,
      drilling and scaling), the presence of a cab, and breakthrough of the tunnel. The
      use of ventilated, closed cabs appeared to be the single most important control
      measure for lowering exposures.

PMID- 12419107
TI  - Musculoskeletal disorders among floor layers: is prevention possible?
AB  - The purpose of this study was to describe possibilities for the prevention of
      work-related musculoskeletal disorders among floor layers and to analyze the
      factors that promote or constrain innovation in prevention. A questionnaire study
      included 102 floor layers and 180 apprentice floor layers. Questionnaires were
      used to register musculoskeletal complaints, psychosocial factors, and proposals
      for prevention. Interviews were carried out of key persons from the trade,
      selected from the floor layers, employers, and their trade association, with the
      purpose of getting more knowledge about the barriers to innovation. The results
      indicate that musculoskeletal disorders are still a great problem in skilled
      floor layers, and also in apprentices. Primary prevention of work-related knee
      disorders and accompanying stress requires a reduction in work tasks performed in
      kneeling positions. Tools that can be used in standing positions for floor laying
      work tasks are considered useful for prevention of musculoskeletal disorders.
      Throughout their training, young apprentice floor layers slowly become socialized
      into the group, and absorb the same identity, attitude to problem-solving, and
      use of tools and working methods as the adult floor layers. Deep-rooted habits
      are very resistant to change. The intensity of the work, time pressures, frequent
      changes of work locations, and the trade's pattern of working in small firms are
      also factors that make it difficult to introduce good practice innovations in the
      floor laying trade. Work-related strain can be decreased in the trade by
      combining changes in tools, materials, and working methods. It is necessary to
      include educational training of apprentices and skilled floor layers, and also
      foremen and employers. Breaking down the barriers to change demands education and
      instruction by people who know the trade well, who can communicate effectively
      with the floor layers, and who are accepted by the trade.

PMID- 12419108
TI  - A good death: a qualitative study of patients with advanced AIDS.
AB  - The objective of this study was to identify and describe the domains that define
      a "good" versus "bad" death from the perspective of patients with advanced AIDS.
      We analyzed qualitative data from face-to-face interviews with 35 patients with
      C3 AIDS. An experienced research interviewer asked the patients to describe a
      good and bad death. Investigators used the principles of grounded theory to
      analyze the interview transcripts and identify the major domains defining a
      "good" versus a "bad" death. We identified 15 domains, of which 12 were mentioned
      by at least two participants. The 12 domains include: symptoms, quality of life,
      people present, dying process, location, a sense of resolution, patient control
      of treatment, issues of spirituality, death scene, physician-assisted suicide,
      aspects of medical care, and acceptance of death. Within these, we identified 38
      sub-categories representing specific aspects of the domains that shape a "good"
      versus "bad" death for the patients in this study. The identified 12 major
      domains encompass the major determinants of a "good" versus "bad" death from the
      perspective of patients with advanced AIDS. A better understanding of these
      domains may enable clinicians to more fully appreciate the experiences of their
      dying patients and identify ways to improve the care they provide at the end of
      life.

PMID- 12419109
TI  - Use of alternative therapies by people living with HIV/AIDS in Australia.
AB  - Few studies of use of complementary and alternative medicine (CAM) among people
      living with HIV/AIDS (PLWHA) have been conducted since combination antiretroviral
      (ARV) drug therapy became widespread. In the context of changing ARV treatment
      options, it is important to consider the prevalence and correlates of use of CAM.
      In this study, a sample of 924 Australian PLWHA completed a self-administered
      survey that included questions on use of CAM. Half (55%) of the respondents
      reported using CAM. Most PLWHA did not choose CAM as an alternative to ARV drugs,
      but use CAM to complement ARV drugs. Use of CAM was not related to measures of
      progression of HIV/AIDS disease. In contrast, CAM use was related to
      characteristics of the ways respondents live with HIV/AIDS, and their attitudes
      toward treatment. The popularity of CAM among PLWHA highlights a need to ensure
      that PLWHA can make informed choices about CAM use.

PMID- 12419110
TI  - Patient-perceived barriers to antiretroviral adherence: associations with race.
AB  - New antiretroviral (ARV) regimens require strict adherence if optimal suppression
      of HIV is to be maintained. This study is a theory-based examination of racial
      differences in patient-perceived barriers and reported ARV adherence.
      Participants (N=149) completed the Patient Medication Adherence Questionnaire
      (PMAQ), measuring adherence and perceived barriers to adherence. Adherence was
      defined as a self-report of 100% adherence in the past four weeks. Odds ratios
      were calculated to determine the relation of reported barriers to adherence for
      race and gender groups, and for the sample overall. For every ten-point increase
      in barrier score, there was an 86% increased risk of being non-adherent (OR=1.86;
      95% CI: 1.19, 2.91). Adherence was not different between racial and gender
      groups, nor was total barrier score. However, individual barriers were
      differentially endorsed across groups. Rather than relying on demographic
      predictors, which may be only an indirect marker of adherence, evaluations of
      adherence should examine the psychological and social barriers to positive
      adherence outcomes in individual patients. Our findings support the use of theory
      based behavioural interventions that address perceived barriers to adherence and
      other health promotion activities.

PMID- 12419111
TI  - Self-reported physical health among older surrogate parents to children orphaned
      and affected by HIV disease.
AB  - Around the globe, older relatives, largely grandparents, have become the
      surrogate parents to children and adolescents orphaned by parental death from
      HIV/AIDS and to those whose infected parents are too ill to serve as their
      primary caregivers. Largely invisible to research, programme and policy
      initiatives, these older surrogate parents face compounded stress and the risk of
      neglected and compromised health. An exploratory study of third- and fourth
      generation relatives (n=20, mean of 59 years) found an average of 3.3 chronic
      health conditions. Fifty-five per cent rated their own health as "fair" or "poor"
      and 70% reported having insufficient time to attend to their own health.
      Supportive services are needed to address the health needs of these "hidden
      patients".

PMID- 12419112
TI  - Infant feeding practices and attitudes among women with HIV infection in northern
      Thailand.
AB  - Knowledge and attitudes towards infant feeding among women in northern Thailand
      were examined. Face-to-face interviews using structured questionnaires were
      undertaken in three districts of Chiang Rai province. Subjects included postnatal
      women with HIV infection (group 1, n=80), antenatal women with HIV infection
      (group 2, n=36) and antenatal women with unknown HIV status (group 3, n=86).
      Advantages of breastfeeding and formula feeding according to several
      characteristics (convenience, cleanliness, cheapness and safety) were rated using
      a four-point (0-3) scale. Overall, breastfeeding was rated much higher (11.4/12)
      than formula feeding (6.1/12)(p < 0.0005). Formula feeding rating was highest
      among postnatal women with HIV infection (6.8/12); however, it was lower than the
      rating for breastfeeding (11.3/12). The vast majority of women with HIV infection
      were either formula feeding (group 1, 94%) or intended to formula feed (group 2,
      72%) their infants. In contrast, the vast majority of antenatal women of unknown
      HIV status planned to breastfeed (group 3, 83%). All women, regardless of HIV
      status, consider breastfeeding to be more advantageous than formula feeding.
      However, once women with HIV infection are informed of the risk of HIV
      transmission through breastfeeding, they are able to make their own decision to
      follow the Thai Ministry of Public Health's recommendation to formula feed.

PMID- 12419113
TI  - Mothers living with HIV/AIDS: mental, physical, and family functioning.
AB  - There has been little work assessing the psychological condition of mothers
      living with HIV, their home life, and how these women function as caretakers with
      a chronic illness. In this study, interviews were conducted with 135 HIV
      symptomatic or AIDS diagnosed mothers of young, well children aged 6-11. White
      mothers were less likely to be severely ill (CD4 counts of <500) than all other
      race/ethnic groups. The mean level of depression was elevated among this sample,
      and was associated with poorer cohesion in the family, and with poorer family
      sociability. Depression also was associated with the mothers being less able to
      perform tasks that they typically do; children of more depressed mothers had
      increased responsibilities for household tasks.

PMID- 12419114
TI  - Assessing effectiveness of home care for persons with AIDS: analysis of
      methodological problems.
AB  - The aim of this paper is to assess the methodological problems of an unsuccessful
      randomized controlled trial (RCT) conducted to evaluate the effectiveness, in
      terms of survival and quality of life, of the early offer of home care (HC) to
      persons with AIDS (PWA). The study carried out was an intention-to-treat RCT.
      Persons in the treatment group (TG) received the offer of HC at the moment of
      AIDS diagnosis; those in the control group (CG) received it six months from
      diagnosis. Many problems have hindered the progress of the study: particularly,
      the low compliance to the offer and the failure to enroll the required sample
      size have made the results unreliable. Analogous problems have been reported
      within other trials evaluating HC in different fields. The present study
      thoroughly evaluates the specific ethical and methodological problems encountered
      in designing and conducting a RCT on HC for PWA. We conclude that, before
      designing and conducting a RCT in this field, it is advisable to examine some
      main issues carefully, such as the acceptability of the offer of treatment, the
      expected compliance and the required size of the study population. If one or more
      of these elements prove to be problematic, the results of the trial risk being
      seriously compromised, and alternative approaches should be considered.

PMID- 12419115
TI  - How HIV infected haemophiliacs in Japan were informed of their HIV-positive
      status.
AB  - The purpose of this study is to find out how HIV-infected haemophiliacs were
      informed and notified of their HIV infection. Self-reporting questionnaires were
      mailed to approximately 500 patients, about one half of the haemophiliac patients
      with HIV in Japan. The response rate was about 57% (n=283); and 270 (male=269)
      patients, apart from secondary and tertiary infected patients, were eligible as
      subjects for the study. The mean age was 31.2 +/- 9.9 years. Of these subjects,
      approximately 60% did not receive explanation regarding the risk of HIV infection
      via unheated blood products. More than 60% did not receive notification until
      1990, or five years after the test became available in Japan. Contents of the
      explanations being given at the time of notifications were poor. In this paper,
      some problems of notifications of medically induced HIV are discussed, and the
      lack or delay of explanation/notification is concluded to be a consequence of the
      paternalistic attitudes of Japanese physicians and the iatrogenic nature of HIV
      infection.

PMID- 12419116
TI  - Gay men's HIV testing behaviour in Scotland.
AB  - This paper reports on the social and demographic factors associated with HIV
      testing in gay men in Scotland. Trained sessional research staff administered a
      short self-complete questionnaire to men in gay bars during January and February
      1999 in Glasgow and Edinburgh, Scotland. Questionnaires were completed by 2,498
      men (response rate of 77.5%). Half (1,190; 50%) reported ever having been HIV
      antibody tested, with men in Edinburgh more likely to report testing. Testing was
      associated with being older (26 years plus), higher education, reporting one
      unprotected anal intercourse (UAI) partner, or six or more UAI partners, in the
      last year, genitourinary medicine clinic service use, and lifetime experience of
      sexually transmitted infections. There was no relationship between HIV testing
      and treatment optimism, or evidence of a "post-Vancouver" effect. Over a fifth of
      men who said that they knew their own HIV status at last UAI had never been
      tested. Current testing policy needs to be challenged if there is to be an
      increase in the number of gay men who know their HIV status and, if tested HIV
      positive, to then access antiretroviral treatments.

PMID- 12419117
TI  - What happened to home HIV test collection kits? Intent to use kits, actual use,
      and barriers to use among persons at risk for HIV infection.
AB  - Through sequential cross-sectional surveys, we examined intent to use home HIV
      test collection kits, actual use and barriers to use among persons at high risk
      for HIV infection. Interest in kits was assessed in the 1995-96 HIV Testing
      Survey (HITS, n=1683). Kit use, knowledge of kits and barriers to use were
      assessed in the 1998-99 HITS (n=1788), after kits had become widely available.
      When asked to choose among future testing options, 19% of 1995-96 participants
      intended to use kits. Untested participants were more likely than previously
      tested HIV-negative participants to choose kits for their next HIV test (p <
      0.001). Among 1998-99 participants, only 24 (1%) had used kits; 46% had never
      heard of kits. Predictors of not knowing about kits included never having been
      HIV tested and black or Latino race. Common reasons for not using kits among
      participants aware of home test kits were concerns about accuracy, lack of in
      person counselling and cost. Despite high rates of anticipated use, kits have had
      minimal impact on the testing behaviour of persons at high risk for HIV
      infection. Increasing awareness of kits, reducing price and addressing concerns
      about kit testing procedures may increase kit use, leading to more HIV testing by
      at-risk individuals.

PMID- 12419118
TI  - Perception of voluntary screening for paediatric HIV and response to post-test
      counselling by Nigerian parents.
AB  - Nigeria may be taken to represent countries with an evolving HIV/AIDS epidemic.
      With particular reference to paediatric HIV, the voluntary testing of young
      children and their parents may provide an important entry point for the
      institution of control measures. However, there is a paucity of knowledge about
      how individuals perceive voluntary testing. This knowledge is important to the
      development of guidelines for counselling. To reduce this gap, 258 parents of
      hospitalized children (> 1 month to 15 years of age) were interviewed using a
      structured questionnaire. In addition, to complement the data, four examples of
      seropositive mother's responses during post-test counselling are presented and
      analyzed. In the survey, 223 (86%) parents were HIV/AIDS aware but only 88 (39%)
      of these parents could describe one or more route(s) of transmission and none
      described vertical transmission. Among the respondents, 153 (62%) of 248 would
      consent to the screening of self, and 195 (85%) of 230 to the screening of a
      hospitalized child if based on his/her clinical condition. Perceptions of good
      health and lack of exposure, and despair owing to lack of a specific treatment,
      were the common reasons for refusing consent. These represent some of the issues
      which would need to be addressed to increase the acceptance of voluntary testing.
      The fear of a break up of families with seropositive mothers but seronegative
      fathers was a major concern expressed during post-test counselling. HIV
      discordance among couples may be frequent and should be considered in the
      formulation of policies on counselling and voluntary testing.

PMID- 12419119
TI  - Use of UNAIDS tools to evaluate HIV voluntary counselling and testing services
      for mineworkers in South Africa.
AB  - HIV voluntary counselling and testing (VCT) is now an integral part of many HIV
      care and control programmes. However, very little work has been done to assess
      the quality of VCT services. An evaluation of VCT services for mineworkers in
      Welkom, South Africa was conducted to assess client and counsellor satisfaction,
      the quality of the services and to identify barriers to uptake of VCT. A cross
      sectional survey was carried out using tools developed by UNAIDS, consisting of
      semi-structured interviews and observation of counselling sessions. Twenty-two
      nurse counsellors and six community volunteers were interviewed. Twenty-four
      counselling sessions were observed and 24 client exit interviews were conducted.
      Although nine of the 22 nurse counsellors had only in-service rather than formal
      training for HIV counselling whereas all community volunteers had been formally
      trained, nurse counsellors demonstrated better interpersonal skills than did
      community volunteers. Both clients and counsellors identified fear of a positive
      result as a major barrier to HIV testing. Clients also raised concerns about
      confidentiality. UNAIDS evaluation tools were a feasible and an acceptable method
      of assessing VCT in this operational setting. The study identified areas where
      training needs to be strengthened and suggested ways of improving the services,
      and changes to the service have now been implemented in line with these
      recommendations.

PMID- 12419121
TI  - WHO global AIDS statistics. AIDS cases reported to the World Health Organization
      as at 7 December 2001.

PMID- 12419122
TI  - Electroencephalographic activity in a flanker interference task using Japanese
      orthography.
AB  - The neural activities for color word interference effects were investigated using
      event-related brain potentials (ERPs) recorded in a flanker-type interference
      task. Kanji words (Japanese morphograms) and kana words (Japanese phonograms)
      were used as the flanker stimuli to obtain insights about hemispheric
      specialization for processing two types of Japanese orthographies. Interference
      effects in reaction time were larger when kanji words were presented in the left
      visual field and when kana words were in the right visual field. ERPs were
      modulated by the incongruent flankers, which generated a negative ERP component
      with the different onset and offset depending on flanker attributes. Consistent
      with the behavioral data, the interference-related negativity was observed for
      kanji words presented in the left visual field and for kana words in the right
      visual field. The negativity distributed maximally over the fronto-central site.
      The early part of the negativity distributed strongly over the frontal midline
      area, whereas it extended bilaterally over the frontal area in the late phase.
      The present results support the view of preferential processing of kanji in the
      right hemisphere and that of kana in the left hemisphere. The temporal profile of
      scalp topographies for the interference-related neural activity suggests that the
      medial and dorsolateral prefrontal regions may be involved in maintaining
      attentional set and conflict resolution.

PMID- 12419123
TI  - Serial attention mechanisms in visual search: a direct behavioral demonstration.
AB  - In visual search, inefficient performance of human observers is typically
      characterized by a steady increase in reaction time with the number of array
      elements-the so-called set-size effect. In general, set-size effects are taken to
      indicate that processing of the array elements depends on limited-capacity
      resources, that is, it involves attention. Contrasting theories have been
      proposed to account for this attentional involvement, however. While some
      theories have attributed set-size effects to the intervention of serial attention
      mechanisms, others have explained set-size effects in terms of parallel,
      competitive architectures. Conclusive evidence in favor of one or the other
      notion is still lacking. Especially in view of the wide use of visual search
      paradigms to explore the functional neuroanatomy of attentional mechanisms in the
      primate brain, it becomes essential that the nature of the attentional
      involvement in these paradigms be clearly defined at the behavioral level. Here
      we report a series of experiments showing that highly inefficient search indeed
      recruits serial attention deployment to the individual array elements. In
      addition, we describe a number of behavioral signatures of serial attention in
      visual search that can be used in future investigations to attest a similar
      involvement of serial attention in other search paradigms. We claim that only
      after having recognized these signatures can one be confident that truly serial
      mechanisms are engaged in a given visual search task, thus making it amenable for
      exploring the functional neuroanatomy underlying its performance.

PMID- 12419124
TI  - Electrophysiological measures of language processing in bilinguals.
AB  - The aim of the present study was to investigate how multiple languages are
      represented in the human brain. Event-related brain potentials (ERPs) were
      recorded from right-handed polyglots and monolinguals during a task involving
      silent reading. The participants in the experiment were nine Italian monolinguals
      and nine Italian/Slovenian bilinguals of a Slovenian minority in Trieste; the
      bilinguals, highly fluent in both languages, had spoken both languages since
      birth. The stimuli were terminal words that would correctly complete a short,
      meaningful, previously shown sentence, or else were semantically or syntactically
      incorrect. The task consisted in deciding whether the sentences were well formed
      or not, giving the response by pressing a button. Both groups read the same set
      of 200 Italian sentences to compare the linguistic processing, while the
      bilinguals also received a set of 200 Slovenian sentences, comparable in
      complexity and length, to compare the processing of the two languages within the
      group. For the bilinguals, the ERP results revealed a strong, left-sided
      activation, reflected by the N1 component, of the occipitotemporal regions
      dedicated to orthographic processing, with a latency of about 150 msec for
      Slovenian words, but bilateral activation of the same areas for Italian words,
      which was also displayed by topographical mapping. In monolinguals, semantic
      error produced a long-lasting negative response (N2 and N4) that was greater over
      the right hemisphere, whereas syntactic error activated mostly the left
      hemisphere. Conversely, in the bilinguals, semantic incongruence resulted in
      greater response over the left hemisphere than over the right. In this group, the
      P615 syntactical error responses were of equal amplitude on both hemispheres for
      Italian words and greater on the right side for Slovenian words. The present
      findings support the view that there are interand intrahemispheric brain
      activation asymmetries when monolingual and bilingual speakers comprehend written
      language. The fact that the bilingual speakers in the present study were highly
      fluent and had acquired both languages in early infancy suggests that the brain
      activation patterns do not depend on the age of acquisition or the fluency level,
      as in the case of late, not-so-proficient L2 language learners, but on the
      functional organization of the bilinguals' brain due to polyglotism and based on
      brain plasticity.

PMID- 12419125
TI  - Stereoscopic illusory contours--cortical neuron responses and human perception.
AB  - In human perception, figure-ground segregation suggests that stereoscopic cues
      are grouped over wide areas of the visual field. For example, two abutting
      rectangles of equal luminance and size are seen as a uniform surface when
      presented at the same depth, but appear as two surfaces separated by an illusory
      contour and a step in depth when presented with different retinal disparities.
      Here, we describe neurons in the monkey visual cortex that signal such illusory
      contours and can be selective for certain figure-ground directions that human
      observers perceive at these contours. The results suggest that these neurons
      group stereoscopic cues over distances up to 8 degrees. In addition, we compare
      these results with human perception and show that the mean stimulus parameters
      required by these neurons also induce optimal percepts of illusory contours in
      human observers.

PMID- 12419126
TI  - Auditory peripersonal space in humans.
AB  - In the present study we report neuropsychological evidence of the existence of an
      auditory peripersonal space representation around the head in humans and its
      characteristics. In a group of right brain-damaged patients with tactile
      extinction, we found that a sound delivered near the ipsilesional side of the
      head (20 cm) strongly extinguished a tactile stimulus delivered to the
      contralesional side of the head (cross-modal auditory-tactile extinction). By
      contrast, when an auditory stimulus was presented far from the head (70 cm),
      cross-modal extinction was dramatically reduced. This spatially specific cross
      modal extinction was most consistently found (i.e., both in the front and back
      spaces) when a complex sound was presented, like a white noise burst. Pure tones
      produced spatially specific cross-modal extinction when presented in the back
      space, but not in the front space. In addition, the most severe cross-modal
      extinction emerged when sounds came from behind the head, thus showing that the
      back space is more sensitive than the front space to the sensory interaction of
      auditory-tactile inputs. Finally, when cross-modal effects were investigated by
      reversing the spatial arrangement of cross-modal stimuli (i.e., touch on the
      right and sound on the left), we found that an ipsilesional tactile stimulus,
      although inducing a small amount of cross-modal tactile-auditory extinction, did
      not produce any spatial-specific effect. Therefore, the selective aspects of
      cross-modal interaction found near the head cannot be explained by a competition
      between a damaged left spatial representation and an intact right spatial
      representation. Thus, consistent with neurophysiological evidence from monkeys,
      our findings strongly support the existence, in humans, of an integrated cross
      modal system coding auditory and tactile stimuli near the body, that is, in the
      peripersonal space.

PMID- 12419127
TI  - Masking interrupts figure-ground signals in V1.
AB  - In a backward masking paradigm, a target stimulus is rapidly (<100 msec) followed
      by a second stimulus. This typically results in a dramatic decrease in the
      visibility of the target stimulus. It has been shown that masking reduces
      responses in V1. It is not known, however, which process in V1 is affected by the
      mask. In the past, we have shown that in V1, modulations of neural activity that
      are specifically related to figure-ground segregation can be recorded. Here, we
      recorded from awake macaque monkeys, engaged in a task where they had to detect
      figures from background in a pattern backward masking paradigm. We show that the
      V1 figure-ground signals are selectively and fully suppressed at target-mask
      intervals that psychophysically result in the target being invisible. Initial
      response transients, signalling the features that make up the scene, are not
      affected. As figure-ground modulations depend on feedback from extrastriate
      areas, these results suggest that masking selectively interrupts the recurrent
      interactions between V1 and higher visual areas.

PMID- 12419128
TI  - Models of functional organization of the lateral prefrontal cortex in verbal
      working memory: evidence in favor of the process model.
AB  - Research on the functional organization of the lateral prefrontal cortex (PFC) in
      working memory continues to be fairly equivocal between two major frameworks:
      organization-by-process or organization-by-material. Although there is fairly
      strong evidence for organization-by-process models from event-related fMRI
      studies, some investigators argue that the nature of the stimulus material better
      defines the functional organization of the lateral PFC, particularly in more
      ventral regions (BA 47/45/44). Specifically, the anterior region of the
      ventrolateral PFC (BA 47/45) is hypothesized to subserve semantic processing
      while the posterior region (BA 44) may subserve phonological processing. In the
      current event-related fMRI study, we directly compared process-related versus
      material-related organizational principles in a verbal working memory task.
      Subjects performed a modified delayed response task in which they (1) retained a
      list of five words or five nonwords during the delay period ("maintenance"), or
      (2) performed a semantic (size reordering) or phonological (alphabetical
      reordering) task on the word or nonword lists, respectively ("manipulation"). We
      did not find evidence during the delay period of our task to support claims of
      anterior-posterior specializations in the ventrolateral PFC for semantic versus
      phonological processing. Subjects did, however, display greater neuronal activity
      during the delay period of manipulation trials than maintenance trials in both
      the dorsolateral PFC and posterior ventrolateral regions. These data are more
      consistent with the process model of the organization of lateral PFC in verbal
      working memory.

PMID- 12419129
TI  - Neural correlates of British sign language comprehension: spatial processing
      demands of topographic language.
AB  - In all signed languages used by deaf people, signs are executed in "sign space"
      in front of the body. Some signed sentences use this space to map detailed "real
      world" spatial relationships directly. Such sentences can be considered to
      exploit sign space "topographically." Using functional magnetic resonance
      imaging, we explored the extent to which increasing the topographic processing
      demands of signed sentences was reflected in the differential recruitment of
      brain regions in deaf and hearing native signers of the British Sign Language.
      When BSL signers performed a sentence anomaly judgement task, the occipito
      temporal junction was activated bilaterally to a greater extent for topographic
      than nontopographic processing. The differential role of movement in the
      processing of the two sentence types may account for this finding. In addition,
      enhanced activation was observed in the left inferior and superior parietal
      lobules during processing of topographic BSL sentences. We argue that the left
      parietal lobe is specifically involved in processing the precise configuration
      and location of hands in space to represent objects, agents, and actions.
      Importantly, no differences in these regions were observed when hearing people
      heard and saw English translations of these sentences. Despite the high degree of
      similarity in the neural systems underlying signed and spoken languages,
      exploring the linguistic features which are unique to each of these broadens our
      understanding of the systems involved in language comprehension.

PMID- 12419130
TI  - A cross-linguistic FMRI study of spectral and temporal cues underlying
      phonological processing.
AB  - It remains a matter of controversy precisely what kind of neural mechanisms
      underlie functional asymmetries in speech processing. Whereas some studies
      support speech-specific circuits, others suggest that lateralization is dictated
      by relative computational demands of complex auditory signals in the spectral or
      time domains. To examine how the brain processes linguistically relevant spectral
      and temporal information, a functional magnetic resonance imaging study was
      conducted using Thai speech, in which spectral processing associated with lexical
      tones and temporal processing associated with vowel length can be differentiated.
      Ten Thai and 10 Chinese subjects were asked to perform discrimination judgments
      of pitch and timing patterns presented in the same auditory stimuli under two
      different conditions: speech (Thai) and nonspeech (hums). In the speech
      condition, tasks required judging Thai tones (T) and vowel length (VL); in the
      nonspeech condition, homologous pitch contours (P) and duration patterns (D). A
      remaining task required listening passively to nonspeech hums (L). Only the Thai
      group showed activation in the left inferior prefrontal cortex in speech minus
      nonspeech contrasts for spectral (T vs. P) and temporal (VL vs. D) cues. Thai and
      Chinese groups, however, exhibited similar fronto-parietal activation patterns in
      nonspeech hums minus passive listening contrasts for spectral (P vs. L) and
      temporal (D vs. L) cues. It appears that lower level specialization for acoustic
      cues in the spectral and temporal domains cannot be generalized to abstract
      higher order levels of phonological processing. Regardless of the neural
      mechanisms underlying low-level auditory processing, our findings clearly
      indicate that hemispheric specialization is sensitive to language-specific
      factors.

PMID- 12419131
TI  - Testing for dual brain processing routes in reading: a direct contrast of chinese
      character and pinyin reading using FMRI.
AB  - Chinese offers a unique tool for testing the effects of word form on language
      processing during reading. The processes of letter-mediated grapheme-to-phoneme
      translation and phonemic assembly (assembled phonology) critical for reading and
      spelling in any alphabetic orthography are largely absent when reading
      nonalphabetic Chinese characters. In contrast, script-to-sound translation based
      on the script as a whole (addressed phonology) is absent when reading the Chinese
      alphabetic sound symbols known as pinyin, for which the script-to-sound
      translation is based exclusively on assembled phonology. The present study aims
      to contrast patterns of brain activity associated with the different cognitive
      mechanisms needed for reading the two scripts. fMRI was used with a block design
      involving a phonological and lexical task in which subjects were asked to decide
      whether visually presented, paired Chinese characters or pinyin "sounded like" a
      word. Results demonstrate that reading Chinese characters and pinyin activate a
      common brain network including the inferior frontal, middle, and inferior
      temporal gyri, the inferior and superior parietal lobules, and the extrastriate
      areas. However, some regions show relatively greater activation for either pinyin
      or Chinese reading. Reading pinyin led to a greater activation in the inferior
      parietal cortex bilaterally, the precuneus, and the anterior middle temporal
      gyrus. In contrast, activation in the left fusiform gyrus, the bilateral cuneus,
      the posterior middle temporal, the right inferior frontal gyrus, and the
      bilateral superior frontal gyrus were greater for nonalphabetic Chinese reading.
      We conclude that both alphabetic and nonalphabetic scripts activate a common
      brain network for reading. Overall, there are no differences in terms of
      hemispheric specialization between alphabetic and nonalphabetic scripts. However,
      differences in language surface form appear to determine relative activation in
      other regions. Some of these regions (e.g., the inferior parietal cortex for
      pinyin and fusiform gyrus for Chinese characters) are candidate regions for
      specialized processes associated with reading via predominantly assembled
      (pinyin) or addressed (Chinese character) procedures.

PMID- 12419132
TI  - Modality-specific deterioration in naming verbs in nonfluent primary progressive
      aphasia.
AB  - A longitudinal study of oral and written naming and comprehension of nouns and
      verbs in an individual (M. M. L.) with nonfluent primary progressive aphasia
      (PPA) is reported. M. M. L. showed progressive deterioration of oral naming of
      verbs well before deterioration of written naming of verbs and before
      deterioration of oral or written naming of nouns. Her comprehension of both nouns
      and verbs remained intact, at least relative to oral naming of verbs. Her
      performance is compared to that of two other individuals with nonfluent PPA, who
      were tested at two time points. These patients showed similar patterns with
      respect to grammatical word class (verbs more impaired than nouns) and modality
      (spoken production more impaired than written production), but somewhat different
      courses of deterioration. The modality-specific nature of the observed verb
      production deficits rules out a semantic locus for the grammatical class effects.
      The results provide a new source of evidence for the hypothesis that there are
      distinct neural mechanisms for accessing lexical representations of nouns and
      verbs in language production.

PMID- 12419133
TI  - Transcranial magnetic stimulation of the human frontal eye field: effects on
      visual perception and attention.
AB  - When looking at one object, human subjects can shift their attention to another
      object in their visual field without moving the eyes. Such shifts of attention
      activate the same brain regions as those involved in the execution of eye
      movements. Here we investigate the role of one of the main cortical oculomotor
      area, namely, the frontal eye field (FEF), in shifts of attention. We used
      transcranial magnetic stimulation (TMS), a technique known to disrupt transiently
      eye-movements preparation. We hypothesized that if the FEF is a necessary element
      in the network involved in shifting attention without moving the eyes, then#10;
      TMS should also disrupt visuospatial attention. For each volunteer, we positioned
      the TMS coil over the probabilistic anatomical location of the FEF, and we
      verified that single pulses delayed eye movements. We then applied TMS during a
      visuospatial attention task. In this task, a central arrow directed shifts of
      attention and the subject responded by a keypress to a subsequent visual
      peripheral target without moving the eyes from the central fixation point. In a
      few trials, the cue was invalid or uninformative, yielding slower responses than
      when the cue was valid. We delivered single pulses either 53 msec before or 70
      msec after target onset. Contrary to our prediction, the main effect of the
      stimulation was a decrease in reaction time when it was applied 53 msec before
      target onset. TMS over the left hemisphere facilitated responses to targets in
      the right hemifield only and for all cueing conditions, whereas TMS over the
      right hemisphere had a bilateral effect for valid and neutral but not invalid
      cueing. Thus, TMS interfered with shift of attention only in the case of right
      hemisphere stimulation: it increased the cost of invalid cueing. Our results
      suggest that TMS over the FEF facilitates visual detection, and thereby reduces
      reaction time. This finding provides new insights into the role of the human FEF
      in processing visual information. The functional asymmetry observed for both
      facilitation of visual detection and interference with shifts of attention
      provides further evidence for the dominance of the right hemisphere for those
      processes. Our results also underline that the disruptive or facilitative effect
      of TMS over a given region depends upon the behavioral context.

PMID- 12419134
TI  - Establishment of immortalized ameloblastoma cell line TAM-1.
AB  - OBJECTIVE: To establish an immortalized ameloblastoma cell line. METHODS: The
      primary cultured ameloblastoma cells were transfected with pRSV-Tag using
      Transfect AMINE kit. Tansfected cells were passaged to pass through crisis period
      and immortalize. RESULTS: Cultured ameloblastoma cells were composed
      predominantly of closely packed small polygonal cells with epithelial morphology.
      They had limited life-span of 51 days in vitro. The small polygonal cells were
      eventually replaced by large flattened cells and subsequently became senescent
      and dead. On the other side, those tumor cells transfected with SV40Tag could
      live for a longer time. The majority of them died in crisis period while the
      survived cells from crisis period gained the ability to proliferate. There was no
      morphological change in TAM-1 compared with original cultured cells. A cell clone
      was harvested which was alive and keeping on proliferating after having been
      subcultured for 25 times. It was named TAM-1. The epithelial origin of TAM-1 was
      confirmed by strong immunoreactivity for cytokeratin in contrast to negative
      vimentin expression. It was detected that SV40Tag had been transfected into TAM-1
      genesome and expressed continuously by PCR and RT-PCR. CONCLUSIONS: TAM-1 is
      immortalized ameloblastoma cell line in vitro.

PMID- 12419135
TI  - A study of the ultrastructure and gene location of hereditary gingival
      fibromatosis.
AB  - OBJECTIVE: To ascertain histology changes of hereditary gingival fibromatosis
      (HGF) and the location of HGF gene. METHODS: A pedigree analyses of HGF; and the
      ultrastructure of gingival overgrowth tissue was observed with electron
      microscopy. The overgrowth of the HGF gene was defined with microsatellite
      markers. RESULTS: The connective tissue of HGF consisted of coarse collagen
      bundles and several kinds of cells arranged abnormally, such as: epithelial
      cells, smooth muscle cells and so on; the HGF locus had been mapped to chromosome
      5q13-q22. CONCLUSIONS: The gingival pathologic changes resemble "hamartoma"; the
      findings has implications for identification of the underlying genetic basis of
      HGF.

PMID- 12419136
TI  - Effects of non-surgical treatment modalities on peri-implantitis.
AB  - OBJECTIVE: To evaluate the effects of local-delivery of 25% metronidazol gel and
      mechanical cleaning using ultrasonic carbon fiber tip on dental implants with
      peri-implantitis. METHODS: 27 implants with peri-implantitis were randomly
      assigned to receiving either 25% metronidazol gel treatment or carbon fiber tip
      ultrasonic scaling. All parameters including plaque index (PLI), probing depth
      (PD) of pocket, sulcular bleeding index (SBI), and BANA enzyme analysis were
      measured at baseline, 1, 2, 6 and 12 weeks after treatment. RESULTS:
      Statistically significant decrease (P < 0.05) in SBI, BANA test and PLI occurred
      in both treatment groups at all time intervals compared to baseline. PD had a
      decreasing tendency in both groups, but only metronidazole group reached
      statistically significant level (P < 0.05) at 2 and 6 week intervals compared to
      baseline. None of the treatment modalities produced any side effects on the
      implant and peri-implant tissues. CONCLUSIONS: Both 25% metronidazol gel and
      mechanical cleaning using ultrasonic carbon fiber tip can be safely and
      effectively used in the treatment of peri-implant diseases.

PMID- 12419137
TI  - Plane measurement of three-dimensional CT images on the diagnosis of zygomatic
      fractures.
AB  - OBJECTIVE: To investigate an available method for quantitative diagnosis of
      zygomatic fractures to quantitatively classify and diagnose the deformities of
      zygomatic fractures. METHODS: Traditional X-ray, two and three dimensional CT
      images of 96 patients with zygomatic fractures were measured and analysed by
      computer-assisted measuring system before and after operation to diagnose the
      displacement and deformity of the fractures. RESULTS: 1. Using anthropology
      points and computer assisted measuring system, a new method was established to
      assess the displacement of the zygomatic fractures. 2. Displacement of the
      zygomatic fractures was approximately diagnosed by measuring different angle of
      3D CT photographs. 3. A classification was proposed based on the deformities of
      the zygomatic fractures. CONCLUSIONS: Computer-assisted 3D CT measuring system is
      accurate, reliable and feasible in clinic for diagnosing zygomatic fractures.

PMID- 12419138
TI  - The compensation of dental arch and teeth in patients with skeletal protrusion
      and deviation of mandible.
AB  - OBJECTIVE: To investigate the compensation of dental arch and teeth in patients
      with skeletal protrusion and deviation of mandible. METHODS: Measurement of 11
      dental models was performed, midline of palate was defined as central line, the
      distance of every contact point to the midline was measured in each side. The
      dental arch symmetry was observed. Occlusion plane was defined as conference
      plane, the buccal or lingual inclination of posterior teeth in upper and lower
      arch was measured. RESULTS: Upper arch was asymmetry in these patients, the arch
      width of deviated side (the side that the chin was deviated to) was broader than
      the other side. The posterior teeth of upper and lower arch were more buccally
      and lingually inclined respectively. CONCLUSIONS: Skeletal protrusion and
      deviation of mandible may result in compensation of dental arch and teeth, the de
      compensation is important in pre-operative orthodontic treatment.

PMID- 12419139
TI  - The application of infinite element method to endodontic endosseous implant
      stress analysis.
AB  - OBJECTIVE: To study the precise stress distribution of the apical foramen area of
      endodontic endosseous implant, in order to improve the prosthetics of endodontic
      endosseous implant. METHODS: After analysis of the two-dimensional endodontic
      endosseous implants model with finite element method, left and right areas beside
      the apical foramen were selected as infinite domains to calculate. D-N
      interactive method was used to connect the finite and infinite domains. RESULTS:
      Under 45 degrees axial right oblique loading, the stress concentration occurred
      in both infinite domains of the apical foramen. The infinite domain nearing the
      load side was tension stress concentration, but the other side was compressive
      stress concentration. Two stress concentration points were just at the central
      points, which were intersections between implant and dentin. The stress reduced
      in all directions from these two stress concentration points, but in the
      ligament, the result was contrary. CONCLUSIONS: The change of the tooth
      rotational center is helpful to the tooth stability and carrying capacity after
      restoration. In the implant area, the diameter of implant at the apical foramen
      of root shall not be reduced to protect root in clinical work. It is very
      important to preserve the tissue of periodontal ligament for endodontic
      endosseous implants.

PMID- 12419140
TI  - The changes of cytokeratin 19 during oral carcinogenesis.
AB  - OBJECTIVE: To investigate the changes of cytokeratin 19 during oral
      carcinogenesis. METHODS: 53 specimens including normal oral mucosa, oral
      epithelial hyperplasia, oral epithelial dysplasia and oral squamous cell
      carcinoma were investigated by immunohistochemistry, SDS-PAGE and Western
      blotting. RESULTS: CK19 was detectable in suprabasal cell layers in epithelial
      dysplasia and in oral cancer, especially in poor-differentiated cancerous cells.
      With the lesions getting worse, the positive rate, the intensity and the
      constituent ratio of CK19 raised significantly. CONCLUSIONS: The results suggest
      that the CK19 expression in suprabasal cell layers of oral mucosa can be used as
      a marker of diagnosis of oral precancerous lesions and CK19 expression is the
      initial events during oral carcinogenesis.

PMID- 12419141
TI  - The phonological characteristics and correction of glottal stop after cleft
      palate surgery.
AB  - OBJECTIVE: To investigate the phonological characteristics of glottal stop on the
      patients with speech disorders following cleft palate surgery or pharyngoplasty,
      and to determine the effects of a new method of speech training for glottal stop
      in chinese. METHODS: Using the methods of listening judge and sound spectrograph
      in acoustic analyses to investigate the category and frequency of glottal stop on
      consonants in Chinese. A new method of speech therapy was used for 12 patients
      with glottal stop. RESULTS: The frequency of glottal stop on the unaspirating
      affricates and unaspirating plosives were the highest in Chinese consonants.
      Secondly, the aspirating affricates and aspirating plosives, and then, the
      fricatives, but the nasal consonants were not effected by glottal stop
      completely. The score of articulations of the 12 patients whom trained through
      the methods increased from 32% to 85.5%. CONCLUSIONS: The glottal stop is one of
      the main causes to impair the articulations of consonants and speech. The new
      methods of speech training for glottal stp are effective.

PMID- 12419142
TI  - The comparison of two-dimensional and three-dimensional methods in the evaluation
      of the secondary alveolar bone grafting.
AB  - OBJECTIVE: To determine the agreement between two-dimensional radiograph and
      three-dimensional CT in the evaluation of the secondary alveolar bone grafting.
      METHODS: Nine complete cleft lip and palate patients (8 UCLP, 1 BCLP) at least 6
      months post secondary alveolar bone grafting were selected. The mean age of the
      patients was 15.5 years with a range of 12 to 26 years. Occlusal radiographs were
      taken and the interdental septal height was determined using Bergland criteria.
      There were 2 type I sites, 2 type II sites, 5 type III sites and 1 type IV site.
      All the patients had undergone CT scan of the cleft within two months after the
      radiograph was taken. The plane of scan was parallel to the occlusal plane. Cuts
      of 2 mm were taken from the infraorbital rim to the gingival third of the crown
      of the teeth. Three-dimensional reconstruction was performed. RESULTS: The
      interdental septal height on the occlusal radiograph was conformed by the CT
      scan. Labial and palatal notch was found on CT scan at two grafting sides.
      CONCLUSIONS: The study provided some evidence to support the continued cautious
      use of anterior occlusal radiograph in the evaluation of bone-graft success
      before the orthodontic treatment. When the X-ray examination is not in line with
      the clinical examination, CT scan is indicated.

PMID- 12419143
TI  - Effect of human serum albumin on cell attachment of human gingival epithelial
      cells.
AB  - OBJECTIVE: To investigate the effect of human serum albumin (HSA) on cell
      attachment of human gingival epithelial cells (HGE). METHODS: HGE were primary
      cultured with keratinocyte serum-free medium (KSFM) and dispase. The cultured
      cells were immunohistochemically stained by monoclonal anti-pan cytokeratin. MTT
      test was employed to investigate the influence of HSA on the cell attachment on
      polystyrene surface. The cell growth curve of HGE which were cultured in KSFM
      with 50 g/L HSA was observed. RESULTS: The results showed significant decrease in
      cell numbers within 8 hours after HGE were inoculated, in which the polystyrene
      surface was preincubated with 50 g/L HSA. But it did not prove to be the case
      from 10 hours to 24 hours after HGE were inoculated. There were no significant
      difference within 24 hours in cell numbers between cultured in KSFM with 50 g/L
      HSA and control. The cell numbers in cell growth curve of HGE in KSFM with and
      without 50 g/L HSA did not show significant difference. CONCLUSIONS: HSA
      preincubation on polystyrene were produce inhibitory effect of HGE attachment in
      early stage.

PMID- 12419144
TI  - Chondrocyte apoptosis in rabbit temporomandibular joint after anterior disc
      displacement.
AB  - OBJECTIVE: To study the chondrocyte apoptosis in rabbit temporomandibular joint
      after anterior disc displacement. METHODS: Experimental anterior disc
      displacement was induced surgically in 20 Japanese rabbits without opening their
      temporomandibular joint bursas. Histopathologic and apoptotic (TUNEL) analysis
      was used to evaluate the changes in articular cartilage, disc and synovium.
      RESULTS: Condyle chondrocyte showed apoptosis most obviously at 1 or 2 weeks
      after surgery, and apoptotic cells concentrated in proliferative zone and
      hypertrophic zone. 4 or 6 weeks after surgery, the joint went into a remodelling
      period. CONCLUSIONS: Chondrocyte apoptosis in temporomandibular joint will be
      activated after anterior disc displacement, which initiates the remodelling in
      temporomandibular joint.

PMID- 12419145
TI  - Relationship between the facial nerve root and its surrounding vessels.
AB  - OBJECTIVE: To study relationship between facial nerve root and its surrounding
      vessels. METHODS: 49 sides facial nerve root and its surrounding vessel were
      dissected and observed. RESULTS: Facial nerve root and its surrounding vessels
      forming compression was found to be 24.5% (12/49), creating contact was found to
      be 14.3% (7/49). The main vessels compressed or (and) contacted facial nerve root
      were anterioinferior cerebellar artery (68.4%), posterioinferior cerebellar
      artery (4.1%), malformed vertebral artery (4.1%) and anterioinferior cerebellar
      vein. CONCLUSIONS: Facial nerve root compressed by offending vesselsare was
      mainly cause of hemifacial spasm.

PMID- 12419146
TI  - Effect of layering feldspathic porcelain on resulting veneer color with aluminum
      oxide core.
AB  - OBJECTIVE: To evaluate the resulting color of veneers affected by adding a layer
      of veneering porcelain on Procera aluminium oxide core. METHODS: Fifteen
      aluminium oxide disks were randomized into three groups. Each of five disks was
      veneered with porcelain of the Vita shade Al, A2 and B4 respectively. The color
      of the substrate covered with non-veneered disks and the veneered disks was
      measured separately and the color differences were calculated. RESULTS:
      Statistically significant differences (P < 0.01) in color coordinates of dark
      substrate were recorded between the substrate covered by an aluminium oxide disks
      and the addition of veneering porcelain to aluminium oxide disks. Mean
      coordinates color difference (DeltaE, DeltaL *, Deltaa *, Deltab *) after adding
      the three shades of veneering porcelain showed increase from Al (2.311) to A2
      (4.313) to B4 (8.778) in DeltaE, decrease from Al (-1.530) to A2 (-3.369) and B4
      (-3.358) in DeltaL *, and increase from Al (-1.440) to A2 (2.198) to B4 (7.955)
      in Deltab *. The direction of the color modification correlated with values
      obtained from the liberation. The resulting color was also affected by the color
      of the underlying structure. CONCLUSION: This study illustrates that color of
      aluminium oxide shell could be modified with feldspathic veneering porcelain,
      which may be used by practitioners to alter the esthetic outcome of porcelain
      veneers.

PMID- 12419147
TI  - Clinicopathological features of unicystic ameloblastoma with special reference to
      its recurrence.
AB  - OBJECTIVE: To clarify the clinicopathological spectrum and biologic behavior of
      unicystic ameloblastomas (UA). METHODS: Retrospective analysis of 33 UA was
      undertaken to relate clinicopathological variables to recurrence. RESULTS: The
      clinical features of this series were in general agreement with that of the
      previous reports. UA tended to occur at an earlier age (mean 25.3 years), with a
      male predilection and predominant mandibular involvement (90.9%).
      Microscopically, the tumors demonstrated a generally monocystic growth pattern,
      with 8 being simple cystic, 10 comprising intraluminal nodules, and 15 exhibiting
      a conspicuous component of infiltrative tumor islands in the cyst capsule. Follow
      up of 29 patients revealed 6 recurrences with an average interval of 7 years.
      Recurrence also related to histologic subtypes of UA, with those invading the
      fibrous wall having a rate of 35.7% but others 6.7%. CONCLUSIONS: Despite the
      fact that unicystic ameloblastoma may, in general, compare favorably with its
      solid or multicystic counterpart in terms of clinical behavior and response to
      treatment, the subsets of the maxillary lesions or tumors exhibiting mural
      invasion could have a high risk of recurrence.

PMID- 12419148
TI  - A longitudinal study of vertical growth of craniofacial complex in female
      children with normal occlusion from 7 to 12 years old.
AB  - OBJECTIVE: To find the laws of vertical growth of craniofacial complex in
      children with mixed dentition. METHODS: 19 female children were annually observed
      with cephalometric film in 4 successive years, of whom 10 started at 7 years
      while the others at age of 9. The two groups were longitudinally studied. All
      data were analyzed by SPSS 8.0 software. RESULTS: In the observation period, the
      height of most craniofacial regions continually grew. In anterior face, the
      middle facial height increased most (increased 4.7 mm from 7 to 10 years old, P <
      0.01; increased 3.9 mm from 10 to 12 years old, P < 0.01), while the lower facial
      height nearly unchanged (increased 1.3 mm from 7 to 10 years old, P > 0.05;
      increased 1.4 mm from 10 to 12 years old, P > 0.05). Some other regions had their
      own growing characters. CONCLUSIONS: Once the occlusal relationships of permanent
      incisors are established, it is difficult to control the anterior lower facial
      height with orthodontic treatments.

PMID- 12419149
TI  - Long-term stability of orthodontic treatment out of retention.
AB  - OBJECTIVE: To investigate the correlative factors influencing the stability of
      orthodontic treatment out of retention. METHODS: Pre-treatment, post-treatment
      and 2 approximately 8 years out of retention study models of 74 cases with
      malocclusion were assessed by the PAR (Peer Assessment Rating) index. RESULTS:
      (1) Out of retention, the relapse rate was 13.01% in weighted PAR total scores
      and the relapse rate was 6.38%, 15.56%, 28.86%, 22.41% in alignment, overjet,
      overbite and transverse buccal occlusion respectively. (2) The rate of great
      improvement was decreased from 77.03% after treatment to 64.86% out of retention.
      The PAR score increased in 53 cases (71.62%), unchanged in 6 cases (8.11%) and
      reduced in 15 cases (20.27%) out of retention. (3) The weighted total scores in
      the Begg appliance were higher than that in Edgewise out of retention (P < 0.05).
      (4) The alignment and PAR total scores out of retention were higher in class II
      malocclusion than in class I malocclusion (P < 0.05). (5) The weighted PAR total
      scores post-retention were higher in unilateral extraction than in other groups
      (P < 0.01). CONCLUSIONS: (1) There was a trend that teeth relapsed to original
      position out of retention. The relapse rate was greater in alignment, overjet,
      overbite and transverse buccal occlusion. (2) The stability out of retention was
      not related to patient's age and sex, but was related to the types of appliance,
      malocclusion and extraction.

PMID- 12419150
TI  - The crystallographic properties of the mineral phases of enamel and dentin in
      normal deciduous and permanent teeth.
AB  - OBJECTIVE: To investigate the crystallographic properties of the mineral phases
      of normal enamel and dentin (dental apatite) in deciduous and permanent teeth.
      METHODS: Three kinds of physical methods including X-ray diffraction (XRD),
      infrared absorption spectroscope (IR) and electron probe micro-analysis (EPMA)
      were utilized in this study. RESULTS: Dental apatite was not uniphase, but
      multiphase, which could be described as carbonate-substituted hydroxyapatite.
      Compared to dentin apatite, the higher crystallinity and expanded a-axis lattice
      parameters were found in enamel. Chemical analyses demonstrated that higher
      concentrations of Mg and CO(3)(2-) were found in dentin than those of enamel. But
      enamel had higher Cl content. CONCLUSIONS: The differences among enamel and
      dentin, in terms of lattice parameter and crystallinity may be partially
      attributed to the incorporation of Mg, CO(3)(2-) and Cl minor elements.

PMID- 12419151
TI  - The relativity between Streptococcus sanguis group and coronary heart disease.
AB  - OBJECTIVE: To study the relativity between Streptococcus sanguis group (SSG) and
      coronary heart disease (CHD). METHODS: 41 individuals were diagnosed with CHD and
      18 normals served as controls. All of them had undergone coronary angiography.
      Their social class (including education and wages), smoking, drinking, blood
      lipids and oral health were also recorded. SSG in saliva and subgingival plaque
      were cultivated in NAYS-B agar plates and counted. SSG were identified into
      species with routine biochemical reaction and AP-PCR. RESULTS: In the multiple
      step regression analysis, the amount of SSG in saliva and subgingival plaque were
      positively associated with severe coronary atheromatosis after adjusting the
      classical risk factors of CHD. The average amount of SSG in saliva was (435 +/-
      422) x 10(8) CFU/L in CHD group and (358 +/- 540) x 10(8) CFU/L in control group,
      F = 2.72, P = 0.08; the average amount of SSG in incisor was (331 +/- 484) x
      10(7) CFU/L in CHD group and (98 +/- 164) x 10(7) CFU/L in control group, F =
      5.54, P = 0.02; the average amount of SSG in molar was (352 +/- 381) x 10(7)
      CFU/L in CHD group and (185 +/- 232) x 10(7) CFU/L in control group, F = 2.86, P
      = 0.10. S. sanguis and S. gordonii were more in CHD group than in control group
      (P < 0.05), whereas S. mitis and S. oralis were the same in two groups (P >
      0.05). CONCLUSION: The increase of SSG in oral floras may play an important role
      in the occurrence of CHD.

PMID- 12419152
TI  - Clinical evaluation of bioactive glass in the treatment of periodontal intrabony
      defects.
AB  - OBJECTIVE: To evaluate the effect of a new product of bioactive glass,
      Perioglas((R)) on human periodontal intrabony defects. METHODS: Twenty
      periodontal intrabony defects in 10 healthy adults were selected. Four weeks
      after an initial therapy, they were randomly assigned to either a BAG
      experimental (open flap debridement with BAG, totally 13 defects) or a control
      OFD (simple open flap debridement, totally 7 defects) group. For both groups,
      routine flap procedure was performed, but the Perioglas((R)) was implanted only
      in the BAG group. The followings were recorded before the operation and repeated
      at the 3rd and 6th month evaluations: plaque index (PLI), bleeding index (BI),
      gingival recession (REC), probing depth (PD) and clinical attachment loss (CAL).
      RESULTS: At the 3rd and 6th months after operation, both groups showed
      significant reduction in PD and CAL. PD and CAL in BAG group at baseline were
      6.19 mm and 6.31 mm, which were 3.23 mm and 3.65 mm at 6th after surgery,
      respectively. PD and CAL in OFD group at baseline were 6.86 mm and 7.71 mm, which
      were 4.50 mm and 5.35 mm at 6 th after surgery, respectively. And the BAG group
      showed significant reduction in BI, which from 2.77 at baseline to 0.65 at 6th
      month post-operation. BI, PD and CAL in BAG group were significantly lower than
      those in OFD group. The reduction of BI in BAG group was significantly more than
      that in OFD group. CONCLUSIONS: The bioactive glass is effective as an adjunct to
      conventional surgery in the treatment of intrabony defects.

PMID- 12419153
TI  - Effects and mechanism of hyperbaric oxygen on prostaglandins in alveolar bone and
      gingival of experimental periodontitis in animal.
AB  - OBJECTIVE: To study the effects and the therapeutic mechanism of hyperbaric
      oxygen (HBO) on prostaglandin E(2) (PGE(2)) in alveolar bone and gingiva of
      experimental periodontitis in animal. METHODS: Experimental periodontitis was
      produced by silk thread sutures combined with high content sugar diet. For HBO
      therapy, they were exposed to a pressure of 0.25 MPa (2.5ATA), breathing pure
      oxygen one session a day for 60 min. The treatment course was 2 weeks. The value
      of PGE(2) in gingiva and alveolar bone was analyzed by enzyme immunoassay (EIA).
      RESULTS: The value of PGE(2) in gingiva of control group was 3.21 ng/g, and that
      of PGE(2) in alveolar bone was 3.22 ng/g. The contents of PGE(2) in gingiva
      (13.96 ng/g) and alveolar bone (13.32 ng/g) of periodontitis group increased
      markedly than control group (P < 0.01). The contents of PGE(2) in gingiva (5.21
      ng/g) of HBO group were 62.7% which was lower than that of periodontitis group,
      and the value of PGE(2) in alveolar bone (4.05 ng/g) were 69.6% lower than that
      of periodontitis group. The difference of PGE(2) in gingiva or alveolar bone was
      significant for the HBO group and periodontitis group (P < 0.01). CONCLUSIONS:
      The contents of PGE(2) in alveolar bone and gingiva increased markedly when
      experimental periodontitis has formed. The value of PGE(2) in alveolar bone and
      gingiva reduce markedly after HBO exposure, and the decreased rate of PGE(2) in
      alveolar bone is more evident than that of PGE(2) in gingiva after HBO therapy.

PMID- 12419154
TI  - Clonality of multiple uterine leiomyomas.
AB  - OBJECTIVE: To study the clonality of uterine leiomyomas, especially the
      relationship between different nodules in multinodular cases. METHODS: Genomic
      DNA was extracted from fresh tissue samples and digested through incubation with
      Hpa II and amplified through nested polymerase chain reaction for
      phosphoglycerate kinase (PGK) gene. The products were treated with Bst XI and
      resolved on agarose gels. RESULTS: Among the 103 cases examined, 32 (31%) carried
      the polymorphic Bst XI site at the PGK locus. Eighty-nine tumors from the 29
      cases were subjected to the cloning assay. Loss of polymorphism at the PGK locus
      was found in all tumor nodules, indicating the monoclonality of the tumor. The
      relationship between multiple tumors was also assessed by comparing their
      inactivated alleles. Seven nodules from a leiomyosarcoma were found to have
      originated from a single cell. However, the relationship was found to be more
      complicated, as demonstrated in 15 cases of multiple leiomyomas. The same
      inactivated allele was found in all nodules of 8 cases and in most nodules in 2
      cases, while totally different inactivation patterns were observed in 5 cases.
      The difference was not associated with cell proliferation. CONCLUSIONS: Clonality
      analysis can be applied to define the clonality of focal or nodular lesions.
      Uterine leiomyomas are of clonal origin. Multiple uterine leiomyomas may be
      subtyped into fully independent and aggressive types as well as a mixed type of
      both.

PMID- 12419155
TI  - A clinicopathologic and immunohistochemical study of diffuse large B-cell
      lymphoma.
AB  - OBJECTIVE: To study the clinicopathologic and immunohistochemical features of
      diffuse large B-cell lymphoma (DLBCL) and the significance of
      immunohistochemistry in diagnosis and differential diagnosis of DLBCL. METHODS:
      60 cases of DLBCL were studied and immunohistochemical staining for LCA, L26, BLA
      36, CD30, bcl-6 were carried out with the EnVision 2 step method. RESULTS: The
      age range of 76.7% (46/60) patients was 40 - 70 years. The location of the lesion
      includes nodal and extranodal sites. 90.0% (54/60) were in clinical stages of II
      (24/54), III (21/54), IV (9/54). Histopathologic morphology presented as
      centroblastic (88.3%, 53/60), immunoblastic (3.3%, 2/60), anaplastic large B cell
      type (3.3%, 2/60) and T cell rich B cell type (5.0%, 3/60). Immunostaining showed
      100% (60/60) DLBCL were positive for LCA, L26, BLA36, 3.3% (2/60) DLBCL positive
      for CD30, 95% (57/60) expressed bcl-6 protein. CONCLUSIONS: DLBCL is an
      aggressive lymphoma which shows cytologic variability from case to case. The
      evaluation of pathologic features and immunohistochemistry in DLBCL are useful
      and practical for diagnostic purposes, but cannot delineate distinctive
      morphologic subtypes.

PMID- 12419156
TI  - A comparative study of esophageal stromal tumors and smooth muscle tumors.
AB  - OBJECTIVE: To explore the clinicopathological, immunohistochemical, and molecular
      biologic characteristics of esophageal stromal tumors and smooth muscle tumors.
      METHODS: Twenty four cases of esophageal mesenchymal tumors were reclassified by
      a panel of antibodies such as CD117, CD34 etc. The sequence of 11 exon of c-kit
      gene were detected in some cases. RESULTS: There were 3 cases of esophageal
      stromal tumors, 20 leiomyomas, and 1 leiomyosarcoma. The 3 esophageal stromal
      tumors occurred in 3 men aged 71, 56 and 60 years respectively. The tumors
      originated from muscularis propria with the size of 4 cm, 8 cm and 14 cm in
      diameter. Microscopically, the tumor cells were spindle and epithelioid shaped
      with slightly basophilic appearance, arranged in intersecting fascicles,
      diffusing and palisading patterns. Immunohistochemically, the tumors were
      positive for CD117 and CD34. The mutation of 11 exon of c-kit gene was detected
      in one case. In comparison, esophageal leiomyomas occurred in a younger
      population. The age ranged from 30 to 60 years (mean age 41.6 years), 12 male
      cases, 8 female cases. 15 cases of esophageal leiomyomas were intramural tumors
      with a diameter of 0.8 - 10.5 cm (mean 4.5 cm) originating from muscularis
      propria and 5 cases which were intraluminal polyps with a diameter of 0.2 - 1.0
      cm originating from muscularis mucosae. Leiomyomas were strongly eosinophilic in
      appearance, diffuse positivity for alpha-SMA, MSA, and desmin, and no c-kit gene
      mutation. One male case of leiomyosarcoma had a diameter of 5 cm and originated
      from muscularis mucosae and displayed a sausage-shaped polyp. CONCLUSIONS:
      Leiomyoma is still the most common mesenchymal tumor of the esophagus, the
      stromal tumor can be similar to gastrointestinal stromal tumors. Typical
      esophageal leiomyosarcoma is very rare and has different clinicopathologic and
      molecular biologic features.

PMID- 12419157
TI  - Expanded T cell clones and cytokines expression in human gastric carcinomas of
      different histological types.
AB  - OBJECTIVE: To study the characteristics of host immune response against human
      gastric carcinoma of different histological types. METHODS: The expression of 24
      families of T cell receptor beta chain variable region (TCRVbeta) and cytokine
      profiles in isolated CD4(+) and CD8(+) subsets, as well as the cytokine profiles
      in purified epithelial cells from the tumor tissue and the residual benign tissue
      of patients with gastric carcinoma, was detected by a highly sensitive
      radioactivity labeled semi-quantitative RT-PCR technique. RESULTS: The number of
      expanded T cell clones in CD8(+) subset from tumor tissue of the intestinal-type
      carcinoma was larger than that of diffuse-type (P = 0.046). The mRNA levels of IL
      6, IL-8 in CD8(+) T subset, as well as the level of TNF-alpha in CD4(+) T subset
      from the tumor tissue of the diffuse type (0.61 +/- 0.29, 0.56 +/- 0.22, 0.09 +/-
      0.03) were significantly higher than that from the residual benign tissue (0.14
      +/- 0.05, 0.27 +/- 0.09, 0.04 +/- 0.02; P = 0.028, P = 0.043, P = 0.046).
      However, the mRNA level of IL-8 in CD8(+) subset and epithelial tumor cells of
      the intestinal-type (0.57 +/- 0.25, 0.27 +/- 0.07) was significantly higher than
      that from the residual benign tissue (0.21 +/- 0.07, 0.14 +/- 0.06; P = 0.028, P
      = 0.028). CONCLUSIONS: The characteristics of host immune response against tumor
      are different between intestinal-type and diffuse-type gastric carcinoma. Both
      fewer expanded T cell clones and more suppressive cytokines suggest a more
      suppressive immune status in the local tumor lesion of diffuse-type than in the
      intestinal-type of the gastric carcinoma.

PMID- 12419158
TI  - Loss of fragile histidine triad expression in colorectal carcinoma.
AB  - OBJECTIVE: To investigate the expression of fragile histidine triad (FHIT) gene
      protein, FHIT and the possible relationship between FHIT expression and
      clinicopathological indices in colorectal carcinoma. METHODS: Detecting FHIT
      protein expression in 60 cases of formalin-fixed, paraffin-embedded colorectal
      carcinoma by citrate-microwave-SP immunohistochemical method, and analyzing its
      relationship to histological grade, Dukes' stage and 5-year survival rate.
      RESULTS: 55% of the carcinomas showed a marked loss or absence of FHIT expression
      compared with their matched normal mucosa. Carcinomas with reduced expression of
      FHIT correlated with their histological grade, Dukes' stage (P < 0.05) and 5-year
      survival rate. The distribution of decreased expression of FHIT was 7/16 in grade
      I carcinoma, 14/30 in grade II, 12/14 in grade III, respectively. The correlation
      between decreased expression of FHIT and Dukes' staging was 5/11 in stage A,
      12/28 in stage B, and 16/21 in stage C. The difference between stage A, B with no
      lymph nodes metastases and the stage C with lymph nodes metastases was of
      significance (P < 0.05). The follow-up data of 39 cases showed that in the 5-year
      survival group, 13/25 were of the low FHIT expression carcinomas, while in 5-year
      deceased group 12/14 were of the low FHIT expression carcinomas (P < 0.05).
      CONCLUSIONS: The reduced expression of FHIT may be associated with decreasing
      differentiation, metastasis and 5-year survival rate in colorectal carcinoma. It
      is suggested that decreased FHIT expression plays an important role in the
      development and progression of the tumor, and thus may become a new prognostic
      marker in colorectal carcinoma.

PMID- 12419159
TI  - Gene expression of osteoprotegerin and osteoclast differentiation factor in giant
      cell tumor.
AB  - OBJECTIVE: To investigate the gene expression of osteoprotegerin (OPG) and
      osteoclast differentiation factor (ODF/TRANCE/RANKL), two new members of the TNF
      receptor superfamily, in giant cell tumor (GCT); to discuss the molecular
      mechanism of extensive bone resorption caused by GCT. METHODS: Using TRIzol
      reagent to prepare total RNA from GCT sample and normal bone tissue. By a first
      strand complementary DNA (cDNA) synthesis kit, cDNA was synthesized from 2.0
      micro g RNA according to the manufacturer's instructions. cDNA was then amplified
      by PCR. Amplification products were resolved by electrophoresis on a 1.5% agarose
      gel and stained with EB. The relative quantity of the PCR products were
      determined and the mRNA levels of OPG, ODF, M-CSF (cofactor of ODF), and RANK
      (receptor of ODF) were compared with that of the normal bone. RESULTS: GCT
      contained highly expressed mRNA of ODF, OPG, M-CSF and RANK. There was mRNA
      expression of OPG, M-CSF and RANK and less expression of ODF in normal bone. The
      ODF mRNA and RANK mRNA in GCT were more abundant than that in normal bone. In
      GCT, the ratio of ODF mRNA exceeded OPG expression. But in normal bone, the OPG
      mRNA exceeded ODF expression. CONCLUSIONS: The results suggest that GCT contains
      all signals including OPG, ODF, M-CSF and RANK that are essential for inducing
      osteoclastogenesis and promoting bone resorption.

PMID- 12419160
TI  - Rapid tissue microarray assay of p16 protein expression for different stage
      nasopharyngeal carcinoma.
AB  - OBJECTIVE: To effectively screen p16 protein expression of different clinical
      stage nasopharyngeal carcinoma (NPC) by constructing and applying high-throughput
      tissue microarray/tissue chip. METHODS: A series of tissue chips were prepared by
      using tissue arrayer with samples from different clinical stage NPC tumors and
      noncancerous nasopharynx tissue. Specimens from 259 cases of nasopharyngeal
      lesions were detected immunohistochemically on a tissue chip for p16 protein
      expression and the correlation of p16 protein expression to clinical stage of NPC
      was analyzed statistically. RESULTS: p16 protein expression was detected in all
      18 histologically normal nasopharyngeal epithelia. No p16 protein was detected in
      3 of 3 (100%) stage I NPC, 38 of 44 (86.3%) stage II NPC, 59 of 68 (86.8%) stage
      III NPC, 23 of 28 (82.1%) stage IV NPC, 87 of 98 (88.8%) unclear stage NPC. The
      efficiency of p16 protein expression in NPC tissues was significantly lower than
      that in normal nasopharyngeal epithelia (chi(2) = 82.58, P < 0.001), and there
      was no apparent relationship between p16 protein expression and clinical stages
      (chi(2) = 0.09, P = 0.769). CONCLUSIONS: The frequent deletion of p16 protein in
      NPC suggests that p16 gene has an important role in the development and
      progression of NPC. The consistency of p16 protein deletion in different stages
      of NPC suggests that the deletion of p16 protein is an early event in the
      development of NPC, and it is feasible to utilize tissue microarray for a rapid,
      economic and accurate screening of clinical tissue specimens on a large scale.

PMID- 12419161
TI  - Effects of tetracycline-controlled antisense bcl-2 expression on the growth and
      apoptosis of human neuroblastoma cell line SK-N-MC.
AB  - OBJECTIVE: To study the effects of tetracycline-controlled antisense bcl-2
      expression on the growth and apoptosis of human neuroblastoma cell line SK-N-MC
      and the related mechanisms. METHODS: The tetracycline-controlled antisense bcl-2
      expressing vector PUCCOMB1(CMV)/Asbcl-2 was constructed by inserting a 0.6 kb
      fragment antisense bcl-2 cDNA sequence into the plasmid PUCCOMB1(CMV). SK-N-MC
      cells were transfected with PUCCOMB1(CMV)-Asbcl-2 or PUCCOMB1(CMV) by
      Lipofectamine( trade mark ). The transfectant cells were further studied for
      growth viability and apoptosis induced by antisense bcl-2 expression controlled
      by tetracycline. The expression of bcl-x(L)/bcl-x(S) mRNA was examined by RT-PCR
      and the changes of expression of proteins caspase-3, bcl-2 and PARP were examined
      by Western-blot. RESULTS: The cell viability of the antisense bcl-2 transfected
      cells decreased significantly, and the apoptotic cells and DNA ladder could be
      found earlier in the antisense bcl-2 cells than in the empty vector transfected
      cells. We also found a decrease of non-activated caspase-3, cleavages of PARP and
      bcl-2 protein after treatment without fetal bovine serum (FBS) by Western-blot,
      but there was no change in the expression of bcl-x(L)/bcl-x(S) mRNA examined by
      RT-PCR during apoptosis. CONCLUSIONS: The results suggested that tetracycline
      controlled expression of antisense bcl-2 can effectively inhibit the cell
      viability of SK-N-MC cells, increase the sensitivity to apoptosis-inducing
      factor, as well as facilitate cell apoptosis after treatment of culture without
      FBS. Except bcl-x(L)/bcl-x(S) mRNA expression, activation of caspase-3, cleavage
      of protein PARP and bcl-2 were all associated with apoptosis.

PMID- 12419162
TI  - Expression of hypoxia-inducible factor-1 alpha and endothelin-1 gene in hypoxic
      pulmonary hypertension.
AB  - OBJECTIVE: To investigate the expression of hypoxia-inducible factor-1 alpha (HIF
      1alpha) and endothelin-1 (ET-1) gene in hypoxic pulmonary hypertension (HPH).
      METHODS: The animal model of HPH was replicated. The elastic fiber staining was
      applied to show the intraacinar pulmonary artery (IAPA). Radioimmunoassay (RIA)
      and in situ hybridization (ISH) were used for detection of HIF-1a and. ET-1.
      RESULTS: ISH showed that HIF-1alpha mRNA was expressed in the IAPA of all hypoxic
      rat. The expression was stronger in the H14 d (0.256 9 +/- 0.046 8) and H28 d
      (0.225 8 +/- 0.045 3) groups than in the H5 d (0.1455 +/- 0.072 2) and control
      (0.110 9 +/- 0.022 4) groups (P < 0.05), the expression of ET-1 mRNA in the H14 d
      (0.412 2 +/- 0.078 3) and H28 d (0.368 4 +/- 0.072 9) groups was also stronger
      than that in the H5 d (0.201 7 +/- 0.034 9) and control (0.185 5 +/- 0.036 1)
      groups (P < 0.05). The amount of ET-1 in pulmonary arteial blood in the H14 d
      [(158.78 +/- 25.14) pg/ml] and H28 d [(142.93 +/- 23.38) pg/ml] groups was
      significantly higher than that in the H5 d [(79.68 +/- 12.54) pg/ml] and control
      [(65.37 +/- 10.82) pg/ml] groups (P < 0.05). The mean pulmonary arterial pressure
      (mPAP) in the H14 d [(34.0 +/- 5.8) mm Hg] and H 28 d [(29.0 +/- 4.7) mm Hg]
      groups was markedly higher than that in the H5 d [(19.0 +/- 3.5) mm Hg] and
      control [(17.0 +/- 2.8) mm Hg] groups (P < 0.05). A positive rank correlation
      existed between the mPAP and the amount of ET-1 (rs = 0.747, P < 0.05).
      CONCLUSIONS: Expression of HIF-1alpha and ET-1 mRNA in IAPA increase under long
      term hypoxic condition and both show consistent expression, indicating that the
      expression of HIF-1a and ET-1 gene contribute to pathogenesis of HPH.

PMID- 12419163
TI  - Single domain antibody to human telomerase catalytic subunit: preparation and
      characterization.
AB  - OBJECTIVE: To develop a recombinant single domain antibody against hTERT, human
      telomerase catalytic subunit. METHODS: A previously prepared His-tagged hTERT
      fusion protein was used as the antigen, and the variable regions in heavy chain
      (VH) of immunized mice were RT-PCR amplified and cloned into the pCANTAB 5E, a
      phagemid vector. By transfection, the display library of mouse VH was developed.
      The candidate clones were selected by affinity panning, and soluble VH were
      obtained after expression in E. coli, HB2151. The resultant single VH antibodies
      were characterized on their binding potentials by western blotting. RESULTS: An
      about 350 bp VH fragment was amplified from spleen cells of mice immunized by His
      tagged hTERT and expressed by phage displayed as VH library. The size of the
      library was 8 x 10(4). After three rounds of affinity panning, 4 independent
      clones were chosen and consequently expressed as soluble single domain antibodies
      (Mr = 16 000). In Western blot analysis, the single domain antibody from 2 of 4
      clones proved to react with the His-tagged hTERT fusion protein (Mr = 167 000)
      without dependence of His-tags and also detect the native hTERT (Mr = 127 000)
      extracted from the human HeLa cancer cell line. DNA sequencing showed both of the
      single domain antibodies were encoded by the heavy chain variable region of the
      mouse. CONCLUSIONS: The single domain antibodies developed were hTERT
      recognizable and hTERT specific, thus providing a basis for application of
      recombinant single domain antibody in inhibition of telomerase activity and
      anticancer therapy.

PMID- 12419164
TI  - Development and identification of monoclonal antibodies against c-erbB-2 p185
      intracellular domain.
AB  - OBJECTIVE: To develop and identify the monoclonal antibodies (mAb) against c-erbB
      2 p185 intracellular domain for detection of c-erbB-2 protein overexpression in
      breast tumor cells. METHODS: BALB/C mice were immunized with a synthesized p185
      peptide of intracellular domain. The biological characteristics and
      immunoactivities were identified by different techniques. RESULTS: Three
      hybridoma cell strains secreting mAbs to c-erbB-2 protein were established and
      one of the mAbs, No. 035-E61 was tested for c-erbB-2 protein immunostaining on 39
      breast carcinoma sections, 30 breast fibroadenoma sections and 16 sections from
      various normal organs. The results showed that the positive detection frequency
      of protein expression was 26% (10/39) in breast cancer, none (0/30) in
      fibroadenoma and 3 sections from normal organs were positively stained. The
      consistency between the 035-E61 and the DAKO reagent approved by FDA was 74%.
      CONCLUSIONS: No. 035-E61 mAb can specifically recognize the p185 intracellular
      domain and may be useful in guiding clinical Herceptin treatment.

PMID- 12419165
TI  - An economic evaluation of atenolol vs. captopril in patients with type 2 diabetes
      (UKPDS 24).

PMID- 12419166
TI  - Efficacy and safety of a therapeutic interchange from high-dose calcium channel
      blockers to a fixed-dose combination of amlodipine/benazepril in patients with
      moderate-to-severe hypertension.

PMID- 12419167
TI  - Pharmacoeconomic evaluation of a pharmacist-managed hypertension clinic.

PMID- 12419168
TI  - Pharmacoutilization of antihypertensive drugs: a model of analysis.

PMID- 12419169
TI  - Cost of treating hypertension in the elderly.
AB  - Hypertension is a common disease among the elderly, a population that will
      continue to grow over the next decade. Untreated hypertension can lead to
      cardiovascular events and mortality. Given the seriousness of this disease and
      the increase in the number of elderly with hypertension, this review focuses on
      the cost of treating hypertension in the elderly as described in recent
      publications. We found a limited number of articles related to the treatment of
      hypertension in the elderly. One publication provided insightful information
      pertaining to expenditures in the United States for hypertension in 1998. This
      article was the first to examine age distribution among persons 65 years and
      older. It has been shown that antihypertensive pharmacologic treatment
      significantly reduces the incidence of cardiovascular events. Without any other
      medical conditions, thiazide-like diuretics are recommended for the treatment of
      hypertension in the elderly due to their beneficial effects, low risk for side
      effects, and low cost. In general, it was found that the elderly have higher
      expenditures per capita for hypertension and per hypertensive condition.

PMID- 12419170
TI  - Compliance and persistence with newer antihypertensive agents.
AB  - Individuals with hypertension need to stay on therapy with antihypertensive
      medication to obtain the full benefits of blood pressure reduction. There are
      important differences in tolerability across antihypertensive drug classes, and
      these differences influence the extent to which patients are willing to continue
      taking their drugs. Three separate sources of evidence--postmarket surveillance
      studies, medical/prescription database studies, and discontinuation of study
      medication in long-term endpoint clinical trials--support the proposition that
      angiotensin II antagonists, the newest class of antihypertensives, are well
      tolerated, and that patients whose initial treatment is an angiotensin II
      antagonist are more likely to persist with therapy than patients who use other
      classes of antihypertensives. Recent landmark trials with losartan in
      hypertensive patients with left ventricular hypertrophy (Losartan Intervention
      For Endpoint reduction [LIFE]) and in diabetes (Reduction of Endpoints in NIDDM
      with the Angiotensin II Antagonist Losartan [RENAAL]) demonstrated excellent
      tolerability, a high level of persistence, and clinical benefits exceeding those
      provided by blood pressure control alone for the prototype angiotensin II
      antagonist in clinical settings.

PMID- 12419171
TI  - Autoregulated glomerular filtration rate during candesartan treatment in
      hypertensive type 2 diabetic patients.

PMID- 12419172
TI  - Screening for genetic causes of hypertension.
AB  - Monogenic or single-gene forms of human hypertension result from mutations
      involving regulatory elements of the renin-angiotensin-aldosterone system (RAAS)
      or occur in syndromes associated with hereditary pheochromocytoma. RAAS gain-of
      function mutations result in sodium retention, suppression of plasma renin
      activity, and often, but not invariably, hypokalemia. Hereditary RAAS syndromes
      result from intrinsic renal abnormalities (apparent mineralocorticoid excess and
      Liddle's syndromes) or from mineralocorticoid excess states (congenital adrenal
      hyperplasia and glucocorticoid-remediable aldosteronism). In the hereditary
      pheochromocytoma syndromes many asymptomatic individuals are identified because
      they are at-risk individuals in kindreds with a pheochromocytoma-predisposing
      syndrome. On the other hand, up to 25% of subjects with presumed "sporadic"
      pheochromocytoma have germline mutations in one of four pheochromocytoma
      susceptibility genes (the RET proto-oncogene, von Hippel-Lindau gene,
      neurofibromatosis F1 gene, and succinate dehydrogenase subunit D and succinate
      dehydrogenase subunit B genes). Hereditary pheochromocytomas are typically intra
      adrenal and bilateral and patients typically present at younger ages compared
      with sporadic pheochromocytoma.

PMID- 12419173
TI  - Blood pressure-independent impact of antihypertensive agents on cardiovascular
      and renal disease.
AB  - Reduction of elevated blood pressure clearly protects against target organ
      damage, but the different targets do not necessarily benefit to the same degree.
      There is considerable debate over whether or not there is a drug-specific benefit
      above and beyond that conferred by blood pressure reduction alone. We performed a
      Medline search to identify recent randomized clinical trials including 300 or
      more patients who were followed for at least 2 years. We critically reviewed
      these papers to find like trials for comparisons. There was too much
      dissimilarity to perform a meaningful meta-analysis. We found that the literature
      does not support a definitive conclusion either in favor of or against an overall
      drug-specific protective effect. However, by grouping like trials, it is possible
      to support an additional protective effect by angiotensin-converting enzyme
      inhibitors and angiotensin II receptor blockers on reducing the rate of decline
      in renal function and in reducing proteinuria.

PMID- 12419174
TI  - Impact of dietary sodium on cardiovascular disease morbidity and mortality.
AB  - Many public health agencies recommend universal restriction of dietary sodium to
      100 mmol/L or less per day. This reflects the belief that because sodium
      restriction reduces blood pressure, it will therefore also reduce cardiovascular
      disease morbidity and mortality. Although large (100 mmol/L/24 h) reductions in
      sodium intake do produce a measurable decline in aggregate blood pressure, there
      is great heterogeneity in individual response, probably reflecting differing
      genetic, environmental, and behavioral characteristics. Moreover, sodium
      depletion has multiple other effects including activation of the renin
      angiotensin system and the sympathetic nervous system, and increase in insulin
      resistance. Since the health effect will be the sum of these multiple good and
      bad effects of sodium reduction, outcome trials are needed to determine the
      benefit or harm of alteration in sodium intake. Unfortunately, no clinical trial
      has addressed the question of whether a lower sodium diet would improve or extend
      life. The best available data derives from six prospective cohort studies. In
      sum, the scant available observational data do not rule out the possibility of
      benefit for some and increased risk for others. Considerable experience--most
      recently the hormone replacement study--underscores the hazards of extrapolating
      clinical recommendations from observational data alone. In the absence of any
      evidence from randomized trials of morbidity and mortality outcomes, and in the
      face of inconsistent observational studies, a universal recommendation for sodium
      restriction is unwarranted and inconsistent with the principles of evidence-based
      medicine.

PMID- 12419175
TI  - Hypertension and lipids: lipid factors in the hypertension syndrome.
AB  - Cardiovascular risk factors are identified as physiologic, biochemical, and
      behavioral, and include hypertension, lipid abnormalities, and hyperglycemia.
      These factors constitute the "cardiovascular dysmetabolic syndrome" and damage
      the vascular endothelium by increasing concentrations of reactive molecular
      species, ultimately increasing cardiovascular morbidity and mortality. Multiple
      risk factors, particularly hypertension and hypercholesterolemia, often coexist
      in the same individual. Low-density lipoprotein cholesterol has been demonstrated
      to upregulate the AT(1) receptor, leading to increases in blood pressure.
      Treatment of hypercholesterolemia with medications, such as the
      hydroxymethylglutaryl coenzyme A reductase inhibitors or statins that decrease
      AT(1) receptor expression and activation, reduce not only cholesterol but blood
      pressure as well. Treatment of hypertension with angiotensin-converting enzyme
      inhibitors may also reduce cholesterol. Recognition and identification of
      multiple risk factors and appropriate treatment in a manner that minimizes
      excessive oxidative stress is critical to the maintenance of normal endothelial
      cell function and cardiovascular risk reduction.

PMID- 12419176
TI  - Systemic hypertension in postmenopausal women: a clinical approach.
AB  - Gender-specific differences in the incidence of cardiovascular disease have long
      been known, and estrogens have been considered to be responsible for this
      dissimilarity. Recently, the steep increase in cardiovascular risk in the no
      longer fertile woman has become evident. The postmenopausal metabolic syndrome is
      very frequent, with obesity, insulin resistance, and hyperinsulinemia, which
      convey increased sodium reabsorption, stimulation of the sympathetic nervous
      system, and smooth muscle growth. The clinical corollary of these overall changes
      is hypertension. Gender differences in components of the renin-angiotensin system
      have been shown to exist, and may play a central role in blood pressure control.
      In normotensive populations, plasma renin activity is significantly higher in men
      than in women, and is higher in postmenopausal versus premenopausal women. Two
      angiotensin-converting enzyme inhibitors, ramipril and moexipril, have undergone
      trials aimed specifically at older people with cardiovascular risk and with
      postmenopausal hypertension, and could be the first therapeutic choice. However,
      a comprehensive treatment should include nonpharmacologic measures with strong
      emphasis on weight normalization and regular physical activity, prevention of
      osteoporosis, as well as decisions on the use of estrogen replacement therapy and
      treatment of the menopausal metabolic syndrome. Finally, education of both
      patients and physicians on the nature and prognosis of untreated hypertension is
      crucial.

PMID- 12419177
TI  - Hypertension and the eye.
AB  - In addition to being the chief cause of death in developed countries, systemic
      hypertension is also a leading cause of visual impairment. The eye is an end
      arteriolar system and is therefore susceptible to changes in blood pressure. It
      is also the only place where blood vessels can be clearly viewed by noninvasive
      techniques. This paper reviews current research into premalignant and malignant
      retinal signs of systemic hypertension. Previous methods of classifying retinal
      hypertensive signs are identified, along with more recent image analysis
      techniques. The need for observing the retinal vasculature as well as measuring
      blood pressure for monitoring systemic hypertensive patients is discussed in
      relation to current research.

PMID- 12419179
TI  - DNA damage during mitosis in human cells delays the metaphase/anaphase transition
      via the spindle-assembly checkpoint.
AB  - BACKGROUND: DNA damage during mitosis triggers an ATM kinase-mediated cell cycle
      checkpoint pathway in yeast and fly embryos that delays progression through
      division. Recent data suggest that this is also true for mammals. Here we used
      laser microsurgery and inhibitors of topoisomerase IIalpha to break DNA in
      various mammalian cells after they became committed to mitosis. We then followed
      the fate of these cells and emphasized the timing of mitotic progression, spindle
      structure, and chromosome behavior. RESULTS: We find that DNA breaks generated
      during late prophase do not impede entry into prometaphase. If the damage is
      minor, cells complete mitosis on time. However, more significant damage
      substantially delays exit from mitosis in many cell types. In human (HeLa, CFPAC
      1, and hTERT-RPE) cells, this delay occurs during metaphase, after the formation
      of a bipolar spindle and the destruction of cyclin A, and it is not dependent on
      a functional p53 pathway. Pretreating cells with ATM kinase inhibitors does not
      abrogate the metaphase delay due to chromosome damage. Immunofluorescence studies
      reveal that cells blocked in metaphase by chromosome damage contain one or more
      Mad2-positive kinetochores, and the block is rapidly overridden when the cells
      are microinjected with a dominant-negative construct of Mad2 (Mad2deltaC).
      CONCLUSIONS: We conclude that the delay in mitosis induced by DNA damage is not
      due to an ATM-mediated DNA damage checkpoint pathway. Rather, the damage leads to
      defects in kinetochore attachment and function that, in turn, maintain the
      intrinsic Mad-2-based spindle assembly checkpoint.

PMID- 12419178
TI  - Hypertension and insulin disorders.
AB  - Insulin resistance and/or compensatory hyperinsulinemia are associated with
      hypertension, obesity, dyslipidemia, and glucose intolerance. Insulin resistance
      and hyperinsulinemia are considered to increase blood pressure through
      sympathetic nervous system activation, renin-angiotensin system stimulation, and
      vascular smooth muscle cell proliferation. Leptin, magnesium ions, nitric oxide,
      endothelin, peroxisome proliferator-activated receptor gamma, and tumor necrosis
      factor-alpha also modulate blood pressure. Decreasing insulin resistance by
      lifestyle modification including diet, weight loss, and physical exercise has
      been shown to reduce blood pressure. Angiotensin-converting enzyme inhibitors
      have a beneficial effect on insulin resistance. On the other hand, the
      angiotensin II antagonist, losartan, does not affect insulin sensitivity. The
      selective alpha1-blockers have a favorable metabolic profile producing increases
      in insulin sensitivity. A short-acting type calcium channel blocker seems to
      decrease insulin sensitivity. On the other hand, long-acting type calcium channel
      blockers improve insulin sensitivity. Thiazide diuretics and most of the beta
      blockers decrease insulin sensitivity. Vasodilatory beta-blockers have been
      reported to improve insulin sensitivity. Use of low-dose diuretics avoids the
      adverse effects seen with conventional doses.

PMID- 12419180
TI  - FGF8 acts as a right determinant during establishment of the left-right axis in
      the rabbit.
AB  - BACKGROUND: FGF8 has been implicated in the transfer of left-right (L-R)
      asymmetry from the embryonic midline (node) to the lateral plate mesoderm (LPM).
      Surprisingly, opposite roles have been described in chick and mouse. In mouse,
      FGF8 is required for the left-asymmetric expression of nodal, lefty2, and Pitx2.
      In chick, FGF8 represses nodal and Pitx2 on the right side. This discrepancy
      could reflect evolutionary differences between birds and mammals. Alternatively,
      the right-asymmetric expression of fgf8, which is not found in mouse, at the
      chick node may be a prerequisite of right-sided function. Finally, chick
      (blastodisc) and mouse (egg cylinder) differ with respect to the topology of the
      early gastrula/neurula embryo. RESULTS: The rabbit blastodisc was investigated as
      an additional mammalian L-R model system. While nodal, lefty, and Pitx2 showed
      asymmetric expression in the left LPM, fgf8 and all other midline marker genes
      were symmetrically expressed at the node like in mouse. Left-sided application of
      FGF8 repressed the endogenous transcription of nodal as well as ectopic
      expression induced by the parallel administration of BMP4. Right-sided inhibition
      of FGF8 signaling induced bilateral marker gene expression, demonstrating that,
      in rabbit, FGF8 acts as a right determinant like in chick. CONCLUSIONS: These
      findings suggest that the anatomy of the early embryo (blastodisc versus egg
      cylinder) rather than taxonomical differences or asymmetry in expression
      constitutes an important determinant of FGF8 function in L-R axis formation. The
      rabbit may provide a useful model for early human embryogenesis, as human embryos
      develop via a blastodisc as well.

PMID- 12419181
TI  - p53 and p21 form an inducible barrier that protects cells against cyclin E-cdk2
      deregulation.
AB  - BACKGROUND: Cyclin E, in conjunction with its catalytic partner cdk2, is rate
      limiting for entry into the S phase of the cell cycle. Cancer cells frequently
      contain mutations within the cyclin D-Retinoblastoma protein pathway that lead to
      inappropriate cyclin E-cdk2 activation. Although deregulated cyclin E-cdk2
      activity is believed to directly contribute to the neoplastic progression of
      these cancers, the mechanism of cyclin E-induced neoplasia is unknown. RESULTS:
      We studied the consequences of deregulated cyclin E expression in primary cells
      and found that cyclin E initiated a p53-dependent response that prevented excess
      cdk2 activity by inducing expression of the p21Cip1 cdk inhibitor. The increased
      p53 activity was not associated with increased expression of the p14ARF tumor
      suppressor. Instead, cyclin E led to increased p53 serine15 phosphorylation that
      was sensitive to inhibitors of the ATM/ATR family. When either p53 or p21cip1 was
      rendered nonfunctional, then the excess cyclin E became catalytically active and
      caused defects in S phase progression, increased ploidy, and genetic instability.
      CONCLUSIONS: We conclude that p53 and p21 form an inducible barrier that protects
      cells against the deleterious consequences of cyclin E-cdk2 deregulation. A
      response that restrains cyclin E deregulation is likely to be a general
      protective mechanism against neoplastic transformation. Loss of this response may
      thus be required before deregulated cyclin E can become fully oncogenic in cancer
      cells. Furthermore, the combination of excess cyclin E and p53 loss may be
      particularly genotoxic, because cells cannot appropriately respond to the cell
      cycle anomalies caused by excess cyclin E-cdk2 activity.

PMID- 12419182
TI  - Responses of four yeast genes to changes in the transcriptional machinery are
      determined by their promoters.
AB  - Many yeast genes are distinguished by their specific requirements for different
      components of the transcriptional machinery. Here we examine four genes that fall
      into two classes as defined by their dependence on specific components of the
      transcriptional machinery. We describe a series of hybrid constructs, each of
      which bears activator binding sites that are associated with a promoter other
      than that with which they are usually affiliated. We examine expression of these
      reporters in strains bearing three modifications of the transcriptional
      machinery. Our results indicate that, in each of these cases, the promoter (and
      not the activator) determines which components of the transcriptional machinery
      are required. These and additional results, including those of others, clarify
      how disparate activators can work at many different promoters.

PMID- 12419183
TI  - Tissue-type plasminogen activator is a multiligand cross-beta structure receptor.
AB  - Tissue-type plasminogen activator (tPA) regulates fibrin clot lysis by
      stimulating the conversion of plasminogen into the active protease plasmin.
      Fibrin is required for efficient tPA-mediated plasmin generation and thereby
      stimulates its own proteolysis. Several fibrin regions can bind to tPA, but the
      structural basis for this interaction is unknown. Amyloid beta (Abeta) is a
      peptide aggregate that is associated with neurotoxicity in brains afflicted with
      Alzheimer's disease. Like fibrin, it stimulates tPA-mediated plasmin formation.
      Intermolecular stacking of peptide backbones in beta sheet conformation underlies
      cross-beta structure in amyloid peptides. We show here that fibrin-derived
      peptides adopt cross-beta structure and form amyloid fibers. This correlates with
      tPA binding and stimulation of tPA-mediated plasminogen activation. Prototype
      amyloid peptides, including Abeta and islet amyloid polypeptide (IAPP)
      (associated with pancreatic beta cell toxicity in type II diabetes), have no
      sequence similarity to the fibrin peptides but also bind to tPA and can
      substitute for fibrin in plasminogen activation by tPA. Moreover, the induction
      of cross-beta structure in an otherwise globular protein (endostatin) endows it
      with tPA-activating potential. Our results classify tPA as a multiligand receptor
      and show that cross-beta structure is the common denominator in tPA binding
      ligands.

PMID- 12419184
TI  - Galactose biosynthesis in Arabidopsis: genetic evidence for substrate channeling
      from UDP-D-galactose into cell wall polymers.
AB  - The biosynthesis of plant cell wall polysaccharides requires the concerted action
      of nucleotide sugar interconversion enzymes, nucleotide sugar transporters, and
      glycosyl transferases. How cell wall synthesis in planta is regulated, however,
      remains unclear. The root epidermal bulger 1 (reb1) mutant in Arabidopsis
      thaliana is partially deficient in cell wall arabinogalactan-protein (AGP),
      indicating a role for REB1 in AGP biosynthesis. We show that REB1 is allelic to
      ROOT HAIR DEFICIENT 1 (RHD1), one of five ubiquitously expressed genes that
      encode isoforms of UDP-D-glucose 4-epimerase (UGE), an enzyme that acts in the
      formation of UDP-D-galactose (UDP-D-Gal). The RHD1 isoform is specifically
      required for the galactosylation of xyloglucan (XG) and type II arabinogalactan
      (AGII) but is not involved either in D-galactose detoxification or in
      galactolipid biosynthesis. Epidermal cell walls in the root expansion zone lack
      arabinosylated (1-->6)-beta-D-galactan and galactosylated XG. In cortical cells
      of rhd1, galactosylated XG is absent, but an arabinosylated (1-->6)-beta-D
      galactan is present. We conclude that the flux of galactose from UDP-D-Gal into
      different downstream products is compartmentalized at the level of cytosolic UGE
      isoforms. This suggests that substrate channeling plays a role in the regulation
      of plant cell wall biosynthesis.

PMID- 12419185
TI  - NBS1 localizes to gamma-H2AX foci through interaction with the FHA/BRCT domain.
AB  - DNA double-strand breaks represent the most potentially serious damage to a
      genome; hence, many repair proteins are recruited to nuclear damage sites by as
      yet poorly characterized sensor mechanisms. Here, we show that NBS1, the gene
      product defective in Nijmegen breakage syndrome (NBS), physically interacts with
      histone, rather than damaged DNA, by direct binding to gamma-H2AX. We also
      demonstrate that NBS1 binding can occur in the absence of interaction with hMRE11
      or BRCA1. Furthermore, this NBS1 physical interaction was reduced when anti-gamma
      H2AX antibody was introduced into normal cells and was also delayed in AT cells,
      which lack the kinase activity for phosphorylation of H2AX. NBS1 has no DNA
      binding region but carries a combination of the fork-head associated (FHA) and
      the BRCA1 C-terminal domains (BRCT). We show that the FHA/BRCT domain of NBS1 is
      essential for this physical interaction, since NBS1 lacking this domain failed to
      bind to gamma-H2AX in cells, and a recombinant FHA/BRCT domain alone can bind to
      recombinant gamma-H2AX. Consequently, the FHA/BRCT domain is likely to have a
      crucial role for both binding to histone and for relocalization of hMRE11/hRAD50
      nuclease complex to the vicinity of DNA damage.

PMID- 12419186
TI  - Dynamin2 and cortactin regulate actin assembly and filament organization.
AB  - The GTPase dynamin is required for endocytic vesicle formation. Dynamin has also
      been implicated in regulating the actin cytoskeleton, but the mechanism by which
      it does so is unclear. Through interactions via its proline-rich domain (PRD),
      dynamin binds several proteins, including cortactin, profilin, syndapin, and
      murine Abp1, that regulate the actin cytoskeleton. We investigated the
      interaction of dynamin2 and cortactin in regulating actin assembly in vivo and in
      vitro. When expressed in cultured cells, a dynamin2 mutant with decreased
      affinity for GTP decreased actin dynamics within the cortical actin network.
      Expressed mutants of cortactin that have decreased binding of Arp2/3 complex or
      dynamin2 also decreased actin dynamics. Dynamin2 influenced actin nucleation by
      purified Arp2/3 complex and cortactin in vitro in a biphasic manner. Low
      concentrations of dynamin2 enhanced actin nucleation by Arp2/3 complex and
      cortactin, and high concentrations were inhibitory. Dynamin2 promoted the
      association of actin filaments nucleated by Arp2/3 complex and cortactin with
      phosphatidylinositol 4,5-bisphosphate (PIP2)-containing lipid vesicles. GTP
      hydrolysis altered the organization of the filaments and the lipid vesicles. We
      conclude that dynamin2, through an interaction with cortactin, regulates actin
      assembly and actin filament organization at membranes.

PMID- 12419187
TI  - GTP binding induces filament assembly of a recombinant septin.
AB  - The septins are a family of GTPases involved in cytokinesis in budding yeast,
      Drosophila, and vertebrates (see for review). Septins are associated with a
      system of 10 nm filaments at the S. cerevisiae bud neck, and heteromultimeric
      septin complexes have been isolated from cell extracts in a filamentous state. A
      number of septins have been shown to bind and hydrolyze guanine nucleotide.
      However, the role of GTP binding and hydrolysis in filament formation has not
      been elucidated. Furthermore, several lines of evidence suggest that not all the
      subunits of the septin complex are required for all aspects of septin function.
      To address these questions, we have reconstituted filament assembly in vitro by
      using a recombinant Xenopus septin, Xl Sept2. Filament assembly is GTP dependent;
      moreover, the coiled-coil domain common to most septins is not essential for
      filament formation. Septin polymerization is preceded by a lag phase, suggesting
      a cooperative assembly mechanism. The slowly hydrolyzable GTP analog, GTP-gamma
      S, also induces polymerization, indicating that polymerization does not require
      GTP hydrolysis. If the properties of Xl Sept2 filaments reflect those of native
      septin complexes, these results imply that the growth or stability of septin
      filaments, or both, is regulated by the state of bound nucleotide.

PMID- 12419188
TI  - Rho1 directs formin-mediated actin ring assembly during budding yeast
      cytokinesis.
AB  - In eukaryotic cells, dynamic rearrangement of the actin cytoskeleton is critical
      for cell division. In the yeast Saccharomyces cerevisiae, three main structures
      constitute the actin cytoskeleton: cortical actin patches, cytoplasmic actin
      cables, and the actin-based cytokinetic ring. The conserved Arp2/3 complex and a
      WASP-family protein mediate actin patch formation, whereas the yeast formins
      (Bni1 and Bnr1) promote assembly of actin cables. However, the mechanism of actin
      ring formation is currently unclear. Here, we show that actin filaments are
      required for cytokinesis in S. cerevisiae, and that the actin ring is a highly
      dynamic structure that undergoes constant turnover. Assembly of the actin ring
      requires the formin-like proteins and profilin, but is not Arp2/3-mediated.
      Furthermore, the formin-dependent actin ring assembly pathway is regulated by the
      Rho-type GTPase Rho1 but not Cdc42. Finally, we show that the formins are not
      required for localization of Cyk1/Iqg1, an IQGAP-like protein previously shown to
      be required for actin ring formation, suggesting that formin-like proteins and
      Cyk1 act synergistically but independently in assembly of the actin ring.

PMID- 12419189
TI  - A PI3-kinase signaling code for insulin-triggered insertion of glucose
      transporters into the plasma membrane.
AB  - Activation of phosphatidyl-inositol-3'-OH-kinase (PI3K) and the resulting
      production of phosphatidyl-inositol-3,4,5-trisphosphate (PIP3) are ubiquitous
      signaling steps that link various cell surface receptors to multiple
      intracellular targets. In fat and muscle cells, the same PI3K pathway that
      regulates metabolic enzymes, proliferation, and differentiation has also been
      shown to be involved in insulin-triggered insertion of glucose transporter GLUT4
      into the plasma membrane. The multiple PI3K functions raise the question of how
      the same PI3K pathway can be selectively used for different cell functions. Here
      we developed a dual-color evanescent wave microscopy method to simultaneously
      measure PIP3 production and GLUT4 insertion in individual 3T3L1 adipocytes.
      Activation of PI3K was found to be both necessary and sufficient for triggering
      GLUT4 insertion, but transporter insertion was markedly suppressed for small
      amplitude, persistent PIP3 signals and for large-amplitude, short PIP3 signals.
      The rejection of these common PI3K signaling responses may explain the selective
      advantage of insulin over platelet-derived growth factor and other stimuli for
      inducing GLUT4 insertion. Our study suggests that the same PI3K pathway can
      control specific cell functions by relying on effector systems that respond to
      particular receptor-encoded time courses and amplitudes of PIP3 signals.

PMID- 12419190
TI  - Genetically expressed cameleon in Drosophila melanogaster is used to visualize
      olfactory information in projection neurons.
AB  - Complex external stimuli such as odorants are believed to be internally
      represented in the brain by spatiotemporal activity patterns of extensive
      neuronal ensembles. These activity patterns can be recorded by optical imaging
      techniques. However, optical imaging with conventional fluorescence dyes usually
      does not allow for resolving the activity of biologically defined groups of
      neurons. Therefore, specifically targeting reporter molecules to neuron
      populations of common genetic identity is an important goal. We report the use of
      the genetically encoded calcium-sensitive fluorescence protein cameleon 2.1 in
      the Drosophila brain. We visualized odorant-evoked intracellular calcium
      concentration changes in selectively labeled olfactory projection neurons both
      postsynaptically in the antennal lobe, the primary olfactory neuropil, and
      presynaptically in the mushroom body calyx, a structure involved in olfactory
      learning and memory. As a technical achievement, we show that calcium imaging
      with a genetically encoded fluorescence probe is feasible in a brain in vivo.
      This will allow one to combine Drosophila's advanced genetic tools with the
      physiological analysis of brain function. Moreover, we report for the first time
      optical imaging recordings in synaptic regions of the Drosophila mushroom body
      calyx and antennal lobe. This provides an important step for the use of
      Drosophila as a model system in olfaction.

PMID- 12419191
TI  - The microtubule-destabilizing kinesin XKCM1 is required for chromosome
      positioning during spindle assembly.
AB  - Xenopus kinesin catastrophe modulator-1 (XKCM1) is a Kin I kinesin family member
      that uses the energy of ATP hydrolysis to depolymerize microtubules. We
      demonstrated previously that XKCM1 is essential for mitotic-spindle assembly in
      vitro and acts by regulating microtubule dynamics as a pure protein, in extracts
      and in cells. A portion of the XKCM1 pool is specifically localized to
      centromeres during mitosis and may be important in chromosome movement. To
      selectively analyze the function of centromere-bound XKCM1, we generated
      glutathione-S-transferase (GST) fusion proteins containing the N-terminal
      globular domain (GST-NT), the centrally located catalytic domain (GST-CD), and
      the C-terminal alpha-helical tail (GST-CT) of XKCM1. The GST-NT protein targeted
      to centromeres during spindle assembly, suggesting that the N-terminal domain of
      XKCM1 is sufficient for centromere localization. Addition of GST-NT prior to or
      after spindle assembly replaced endogenous XKCM1, indicating that centromere
      targeting is a dynamic process. Loss of endogenous XKCM1 from centromeres caused
      a misalignment of chromosomes on the metaphase plate without affecting global
      spindle structure. These results suggest that centromere bound XKCM1 has an
      important role in chromosome positioning on the spindle.

PMID- 12419192
TI  - Genes in behaviour scrutiny.

PMID- 12419193
TI  - The worm's turn.

PMID- 12419194
TI  - Darwin's pickles.

PMID- 12419195
TI  - More eggs less.

PMID- 12419196
TI  - Effective population size.

PMID- 12419197
TI  - Fitness.

PMID- 12419198
TI  - Gametophyte development.

PMID- 12419199
TI  - Developmental signaling: shrimp and strawberries help flies make cones.
AB  - EGF receptor and Notch signaling are involved in a wide variety of developmental
      processes. A new study has revealed a serial linkage between them, via Ebi and
      Strawberry Notch, which is important in determining the cone cell fate in the
      Drosophila eye.

PMID- 12419201
TI  - Chromosome segregation: pushing plasmids apart.
AB  - The ParM ATPase from Escherichia coli plasmid R1 assembles into F-actin-like
      filaments which appear to push replicated copies of the plasmid to opposite ends
      of the cell, ensuring partitioning into daughter cells. Might bacterial
      chromosomes use a similar mitotic strategy for segregation?

PMID- 12419200
TI  - Immunoglobulin genes: generating diversity with AID and UNG.
AB  - Somatic hypermutation and switch recombination of immunoglobulin genes require
      the activity of the activation-induced deaminase, AID. Recent studies of mice
      deficient for the uracil-DNA glycosylase UNG, which removes U from DNA, suggest
      that AID catalyses the deamination of dC to dU during antibody diversification.

PMID- 12419202
TI  - Innate immunity: the worm fights back.
AB  - Innate immunity is an evolutionarily ancient defense system that enables animals
      and plants to resist invading microorganisms. Recent studies have demonstrated
      the existence of innate immune responses in Caenorhabditis elegans.

PMID- 12419203
TI  - Cell cycle: new functions for Cdc14 family phosphatases.
AB  - The Cdc14 phosphatase was identified by its requirement for mitotic exit in
      budding yeast. Cdc14 homologs exist throughout the eukaryotic kingdom, but it was
      unclear whether their function would also be conserved. Recent analyses in
      fission yeast, humans and now C. elegans suggest numerous other functions for
      this family of proteins.

PMID- 12419204
TI  - Language acquisition: do as you hear.
AB  - It is not uncommon to recognize a specific action by the sound it creates.
      Neurons have been discovered in monkey premotor cortex that may contribute to
      this ability; they respond to both performing an action and hearing its action
      related sound, and may be critical for communicating with others, learning
      gestures and even acquiring language.

PMID- 12419205
TI  - Telomeres: the molecular events driving end-to-end fusions.
AB  - Recent data indicate that loss of the protective telomeric capping function leads
      to active degradation of the telomeric G-strand overhang and DNA ligase IV
      mediated non-homologous end joining. These molecular events may contribute to
      genomic instability early in tumorigenesis.

PMID- 12419206
TI  - Axon guidance: Comm hither, Robo.
AB  - In the developing CNS, commissural axons are initially attracted to the midline,
      but after crossing they acquire sensitivity to midline repellent cues which
      prevent re-crossing. Recent studies have shed new light on the mechanism by which
      commissural axons change their sensitivity to guidance cues after crossing the
      midline.

PMID- 12419207
TI  - Vertebrate development: wnt signals at the crest.
AB  - Neural crest cells, a defining feature of vertebrate embryos, form at the neural
      plate border in response to inductive signals from the ectoderm. Recent studies
      have shown that Wnt signals are essential mediators of this induction.

PMID- 12419208
TI  - Just the beginning: novel functions for angiotensin-converting enzymes.
AB  - Cardiovascular disease is predicted to be the commonest cause of death worldwide
      by the year 2020. Diabetes, smoking and hypertension are the main risk factors.
      The renin-angiotensin system plays a key role in regulating blood pressure and
      fluid and electrolyte homeostasis in mammals. The discovery of specific drugs
      that block either the key enzyme of the renin-angiotensin system, angiotensin
      converting enzyme (ACE), or the receptor for its main effector angiotensin II,
      was a major step forward in the treatment of hypertension and heart failure. In
      recent years, however, the renin-angiotensin system has been shown to be a far
      more complex system than initially thought. It has become clear that additional
      peptide mediators are involved. Furthermore, a new ACE, angiotensin-converting
      enzyme 2 (ACE2), has been discovered which appears to negatively regulate the
      renin-angiotensin system. In the heart, ACE2 deficiency results in severe
      impairment of cardiac contractility and upregulation of hypoxia-induced genes. We
      shall discuss the interplay of the various effector peptides generated by
      angiotensin-converting enzymes ACE and ACE2, highlighting the role of ACE2 as a
      negative regulator of the renin-angiotensin system.

PMID- 12419209
TI  - Two pathways to NF-kappaB.
AB  - NF-kappaB is a transcription factor that is critical for innate and adaptive
      immunity. Recently, a noncanonical pathway for NF-kappaB activation has emerged.
      Four recent papers provide physiological roles for this pathway and expand our
      understanding of lymphoid development and organogenesis with potential
      applications in the treatment of autoimmune disease.

PMID- 12419210
TI  - Deamidation of Bcl-X(L): a new twist in a genotoxic murder mystery.
AB  - Bcl-2 proteins are critical regulators of apoptosis following DNA damage. Recent
      studies have shown that genotoxic stress induces the deamidation of Bcl-X(L),
      inhibiting its antiapoptotic activities. Remarkably, Rb and p53 are important
      regulators of this novel modification of Bcl-X(L).

PMID- 12419211
TI  - Targeting and beyond: new roles for old signal sequences.
AB  - Signal sequences, once considered degenerate hydrophobic elements whose sole task
      is to target proteins to the secretory pathway, are increasingly being recognized
      as playing roles beyond targeting. Recent work is beginning to shed light on some
      of the ways the cell decodes and exploits additional functions encoded within
      signal sequences.

PMID- 12419212
TI  - Anaerobic biofilm infections in cystic fibrosis.
AB  - Pseudomonas aeruginosa is an important pathogen that infects the lungs of cystic
      fibrosis patients. A paper published in the October issue of Developmental Cell
      proves that the bacterial cells in the lung live in anaerobic biofilms and adopt
      a metabolic pattern and a phenotype that differ significantly from those of test
      tube-grown cells, and even from those of aerobic biofilms.

PMID- 12419213
TI  - Replicating past lesions in DNA.
AB  - Replication of damaged DNA is essential in all organisms and is potentially
      achieved by several mechanisms. How Escherichia coli employs these different
      mechanisms to effect efficient, accurate replication of a damaged template is
      revealed in this issue of Molecular Cell.

PMID- 12419214
TI  - Ribozymes: the first 20 years.
AB  - Twenty years have passed since the first reports that certain RNAs mediate self
      splicing and precursor tRNA processing reactions in the absence of proteins. An
      entire field emerged to learn how RNAs that lack the chemical versatility of
      amino acids nonetheless assemble into enzymes that accelerate chemical reactions
      with efficiencies that rival those of their protein counterparts.

PMID- 12419215
TI  - Did tRNA synthetase classes arise on opposite strands of the same gene?
AB  - Structural homology of class II aminoacyl-tRNA synthetases to the HSP70 family
      and the existence of a gene whose sense and antisense strands code for a
      dehydrogenase and an HSP70 chaperonin justify reconsideration of a possible sense
      antisense ancestry for the two synthetase classes.

PMID- 12419216
TI  - The docking protein FRS2alpha controls a MAP kinase-mediated negative feedback
      mechanism for signaling by FGF receptors.
AB  - The docking protein FRS2alpha functions as a major mediator of signaling by FGF
      and NGF receptors. Here we demonstrate that, in addition to tyrosine
      phosphorylation, FRS2alpha is phosphorylated by MAP kinase on multiple threonine
      residues in response to FGF stimulation or by insulin, EGF, and PDGF,
      extracellular stimuli that do not induce tyrosine phosphorylation of FRS2alpha.
      Prevention of FRS2alpha threonine phosphorylation results in constitutive
      tyrosine phosphorylation of FRS2alpha in unstimulated cells and enhanced tyrosine
      phosphorylation of FRS2alpha, MAPK stimulation, cell migration, and proliferation
      in FGF-stimulated cells. Expression of an FRS2alpha mutant deficient in MAPK
      phosphorylation sites induces anchorage-independent cell growth and colony
      formation in soft agar. These experiments reveal a novel MAPK-mediated, negative
      feedback mechanism for control of signaling pathways that are dependent on FRS2
      and a mechanism for heterologous control of signaling via FGF receptors.

PMID- 12419217
TI  - Antiapoptotic role of PPARbeta in keratinocytes via transcriptional control of
      the Akt1 signaling pathway.
AB  - Apoptosis, differentiation, and proliferation are cellular responses which play a
      pivotal role in wound healing. During this process PPARbeta translates
      inflammatory signals into prompt keratinocyte responses. We show herein that
      PPARbeta modulates Akt1 activation via transcriptional upregulation of ILK and
      PDK1, revealing a mechanism for the control of Akt1 signaling. The resulting
      higher Akt1 activity leads to increased keratinocyte survival following growth
      factor deprivation or anoikis. PPARbeta also potentiates NF-kappaB activity and
      MMP-9 production, which can regulate keratinocyte migration. Together, these
      results provide a molecular mechanism by which PPARbeta protects keratinocytes
      against apoptosis and may contribute to the process of skin wound closure.

PMID- 12419218
TI  - Requirements for signal peptide peptidase-catalyzed intramembrane proteolysis.
AB  - The presenilin-type aspartic protease signal peptide peptidase (SPP) can cleave
      signal peptides within their transmembrane region. SPP is essential for
      generation of signal peptide-derived HLA-E epitopes in humans and is exploited by
      Hepatitis C virus for processing of the viral polyprotein. Here we analyzed
      requirements of substrates for intramembrane cleavage by SPP. Comparing signal
      peptides that are substrates with those that are not revealed that helix-breaking
      residues within the transmembrane region are required for cleavage, and flanking
      regions can affect processing. Furthermore, signal peptides have to be liberated
      from the precursor protein by cleavage with signal peptidase in order to become
      substrates for SPP. We propose that signal peptides require flexibility in the
      lipid bilayer to exhibit an accessible peptide bond for intramembrane
      proteolysis.

PMID- 12419219
TI  - Grb2 is a key mediator of helicobacter pylori CagA protein activities.
AB  - CagA delivered from Helicobacter pylori into gastric epithelial cells undergoes
      tyrosine phosphorylation and induces host cell morphological changes. Here we
      show that CagA can interact with Grb2 both in vitro and in vivo, which results in
      the activation of the Ras/MEK/ERK pathway and leads to cell scattering as well as
      proliferation. Importantly, this ability of CagA is independent from the tyrosine
      phosphorylation, which occurs within the five repeated EPIYA sequences (PY
      region) of CagA. However, the PY region appears to be indispensable for the Grb2
      binding and induction of the cellular responses. Thus, intracellular CagA via its
      binding to Grb2 may act as a transducer for stimulating growth factor-like
      downstream signals which lead to cell morphological changes and proliferation,
      the causes of H. pylori-induced gastric hyperplasia.

PMID- 12419220
TI  - The crystal structure and mode of action of trans-sialidase, a key enzyme in
      Trypanosoma cruzi pathogenesis.
AB  - Trans-sialidases (TS) are GPI-anchored surface enzymes expressed in specific
      developmental stages of trypanosome parasites like Trypanosoma cruzi, the
      etiologic agent of Chagas disease, and T. brucei, the causative agent of sleeping
      sickness. TS catalyzes the transfer of sialic acid residues from host to parasite
      glycoconjugates through a transglycosidase reaction that appears to be critical
      for T. cruzi survival and cell invasion capability. We report here the structure
      of the T. cruzi trans-sialidase, alone and in complex with sugar ligands. Sialic
      acid binding is shown to trigger a conformational switch that modulates the
      affinity for the acceptor substrate and concomitantly creates the conditions for
      efficient transglycosylation. The structure provides a framework for the
      structure-based design of novel inhibitors with potential therapeutic
      applications.

PMID- 12419221
TI  - Protein folding during cotranslational translocation in the endoplasmic
      reticulum.
AB  - To test how far into the protein-conducting channel of the translocon complex a
      nascent polypeptide domain must move before it can fold, we analyzed the folding
      of in vitro translated products of truncated mRNAs encoding the Semliki Forest
      virus capsid protease domain (Cp) during translocation into microsomes. Cp folded
      when the C-terminal linker connecting it to the peptidyltransferase center was 64
      amino acids or longer. This means that to fold, Cp must exit the translocon
      channel. With an uncleaved signal sequence, about one out of four of the Cp
      domains could undergo folding with a C-terminal linker of only 38-66 amino acids.
      This suggested that the constraint imposed on folding by the translocon complex
      may be less stringent for signal-anchored membrane proteins.

PMID- 12419222
TI  - Dissection of the mechanism for the stringent factor RelA.
AB  - During conditions of nutrient deprivation, ribosomes are blocked by uncharged
      tRNA at the A site. The stringent factor RelA binds to blocked ribosomes and
      catalyzes synthesis of (p)ppGpp, a secondary messenger that induces the stringent
      response. We demonstrate that binding of RelA and (p)ppGpp synthesis are
      inversely coupled, i.e., (p)ppGpp synthesis decreases the affinity of RelA for
      the ribosome. RelA binding to ribosomes is governed primarily by mRNA, but
      independently of ribosomal protein L11, while (p)ppGpp synthesis strictly
      requires uncharged tRNA at the A site and the presence of L11. A model is
      proposed whereby RelA hops between blocked ribosomes, providing an explanation
      for how low intracellular concentrations of RelA (1/200 ribosomes) can synthesize
      (p)ppGpp at levels that accurately reflect the starved ribosome population.

PMID- 12419223
TI  - Release of peptide promoted by the GGQ motif of class 1 release factors regulates
      the GTPase activity of RF3.
AB  - E. coli mutants of RF1 and RF2, in which the universal GGQ motif is changed to
      GAQ, are slow in peptide release from ribosomes. Other kinetic properties are
      unchanged, suggesting that the GGQ motif is in contact with the peptidyl
      transferase center. Deacylated tRNA terminates protein synthesis codon
      specifically, indicating that the CCA end of tRNA and the GGQ motif operate
      similarly. Addition of a mutant factor to a pretermination ribosomal complex
      stimulates exchange of RF3-bound GDP with free GDP, but binding of GTP to RF3 and
      GTP hydrolysis requires peptide chain release. Therefore, the sequence of steps
      during termination of translation is regulated by removal of the polypeptide, an
      event that might trigger a conformational change in the ribosome.

PMID- 12419224
TI  - Universally conserved interactions between the ribosome and the anticodon stem
      loop of A site tRNA important for translocation.
AB  - The iterative movement of the tRNA-mRNA complex through the ribosome is a
      hallmark of the elongation phase of protein synthesis. We used synthetic
      anticodon stem-loop analogs (ASL) of tRNA(Phe) to systematically identify ribose
      2'-hydroxyl groups that are essential for binding and translocation from the
      ribosomal A site. Our results show that 2'-hydroxyl groups at positions 33, 35,
      and 36 in the A site ASL are important for translocation. Consistent with the
      view that the molecular basis of translocation may be similar in all organisms,
      the 2'-hydroxyl groups at positions 35 and 36 in the ASL interact with
      universally conserved bases G530 and A1493, respectively, in 16S rRNA.
      Furthermore, these interactions are also essential for the decoding process,
      indicating a functional relationship between decoding and translocation.

PMID- 12419225
TI  - The role of RNA editing by ADARs in RNAi.
AB  - Adenosine deaminases that act on RNA (ADARs) are RNA-editing enzymes that
      deaminate adenosines to create inosines in double-stranded RNA (dsRNA). Here we
      demonstrate that ADARs are not required for RNA interference (RNAi) and that they
      do not antagonize the pathway to a detectable level when RNAi is initiated by
      injecting dsRNA. We find, however, that transgenes expressed in the somatic
      tissues of wild-type animals are silenced in strains with deletions in the two
      genes encoding ADARs, adr-1 and adr-2. Transgene-induced gene silencing in adr
      1;adr-2 mutants depends on genes required for RNAi, suggesting that a dsRNA
      intermediate is involved. In wild-type animals we detect edited dsRNA
      corresponding to transgenes, and we propose that editing of this dsRNA prevents
      somatic transgenes from initiating RNAi in wild-type animals.

PMID- 12419227
TI  - SUMO-1 modification represses Sp3 transcriptional activation and modulates its
      subnuclear localization.
AB  - The GC box binding transcription factor Sp3 both activates and represses
      transcription. We have found that Sp3 activity is regulated by SUMO-1
      modification. Endogenous Sp3 is sumoylated and localized to the nuclear periphery
      and in nuclear dots. Removal of SUMO-1 from Sp3 by mutation of the SUMO acceptor
      lysines or expression of the SUMO-1 protease SuPr-1 converted Sp3 to a strong
      activator with a diffuse nuclear localization. Covalent attachment of SUMO-1 to
      Sp3 by gene fusion was sufficient to repress Sp3-dependent transcription and
      relocalize Sp3 to the nuclear periphery and nuclear dots. These studies reveal a
      direct effect of SUMO-1 modification on activity of a dual function transcription
      factor and provide a mechanism for functional specificity within the Sp
      transcription factor family.

PMID- 12419226
TI  - CSB is a component of RNA pol I transcription.
AB  - Mutation in the CSB gene results in the human Cockayne's syndrome (CS). Here, we
      provide evidence that CSB is found not only in the nucleoplasm but also in the
      nucleolus within a complex (CSB IP/150) that contains RNA pol I, TFIIH, and XPG
      and promotes efficient rRNA synthesis. CSB is active in in vitro RNA pol I
      transcription and restores rRNA synthesis when transfected in CSB-deficient
      cells. We also show that mutations in CSB, as well as in XPB and XPD genes, all
      of which confer CS, disturb the RNA pol I/TFIIH interaction within the CSB
      IP/150. In addition to revealing an unanticipated function for CSB in rRNA
      synthesis, we show that the fragility of this complex could be one factor
      contributing to the CS phenotype.

PMID- 12419228
TI  - SUMO-1 protease-1 regulates gene transcription through PML.
AB  - During a screen to identify c-Jun activators, we isolated a cysteine protease,
      SuPr-1, that induced c-Jun-dependent transcription independently of c-Jun
      phosphorylation. SuPr-1 is a member of a new family of proteases that hydrolyze
      the ubiquitin-like modifier, SUMO-1. SuPr-1 hydrolyzed SUMO-1-modified forms of
      the promyelocytic leukemia gene product, PML, and altered the subcellular
      distribution of PML in nuclear PODs (PML oncogenic domains). SuPr-1 also altered
      the distribution of other nuclear POD-associated proteins, such as CBP and Daxx,
      that act as transcriptional regulators. SuPr-1 action on transcription was
      enhanced by PML, and SuPr-1 failed to activate transcription in PML-deficient
      fibroblasts. Our studies establish an important role for SUMO proteases in
      transcription.

PMID- 12419229
TI  - Transcription corepressor CtBP is an NAD(+)-regulated dehydrogenase.
AB  - Transcriptional repression is based on the selective actions of recruited
      corepressor complexes, including those with enzymatic activities. One well
      characterized developmentally important corepressor is the C-terminal binding
      protein (CtBP). Although intriguingly related in sequence to D2 hydroxyacid
      dehydrogenases, the mechanism by which CtBP functions remains unclear. We report
      here biochemical and crystallographic studies which reveal that CtBP is a
      functional dehydrogenase. In addition, both a cofactor-dependent conformational
      change, with NAD(+) and NADH being equivalently effective, and the active site
      residues are linked to the binding of the PXDLS consensus recognition motif on
      repressors, such as E1A and RIP140. Together, our data suggest that CtBP is an
      NAD(+)-regulated component of critical complexes for specific repression events
      in cells.

PMID- 12419230
TI  - Interplay of TBP inhibitors in global transcriptional control.
AB  - The TATA binding protein (TBP) is required for the expression of nearly all genes
      and is highly regulated both positively and negatively. Here, we use DNA
      microarrays to explore the genome-wide interplay of several TBP-interacting
      inhibitors in the yeast Saccharomyces cerevisiae. Our findings suggest the
      following: The NC2 inhibitor turns down, but not off, highly active genes.
      Autoinhibition of TBP through dimerization contributes to transcriptional
      repression, even at repressive subtelomeric regions. The TAND domain of TAF1
      plays a primary inhibitory role at very few genes, but its function becomes
      widespread when other TBP interactions are compromised. These findings reveal
      that transcriptional output is limited in part by a collaboration of different
      combinations of TBP inhibitory mechanisms.

PMID- 12419231
TI  - The yeast capping enzyme represses RNA polymerase II transcription.
AB  - Using a highly pure transcription system derived from Saccharomyces cerevisiae,
      we have purified an activity in yeast whole-cell extracts that represses RNA
      polymerase II transcription. Mechanistic studies suggest that this repressor
      specifically targets transcriptional reinitiation. The two polypeptides that
      constitute the repressor have been identified as Ceg1p and Cet1p, the two
      subunits of the yeast pre-mRNA capping enzyme. A purified recombinant capping
      enzyme is able to reconstitute repressor activity. Cet1p is necessary for and
      capable of this repression. Transcriptional run-on experiments indicate that the
      capping enzyme also serves as a repressor in vivo. Efficient pre-mRNA capping
      relies on interactions between the capping enzyme and transcription apparatus.
      Repression by the capping enzyme suggests a bidirectional flow of information
      between capping and transcription.

PMID- 12419232
TI  - Design, activity, and structure of a highly specific artificial endonuclease.
AB  - We have generated an artificial highly specific endonuclease by fusing domains of
      homing endonucleases I-DmoI and I-CreI and creating a new 1400 A(2) protein
      interface between these domains. Protein engineering was accomplished by
      combining computational redesign and an in vivo protein-folding screen. The
      resulting enzyme, E-DreI (Engineered I-DmoI/I-CreI), binds a long chimeric DNA
      target site with nanomolar affinity, cleaving it precisely at a rate equivalent
      to its natural parents. The structure of an E-DreI/DNA complex demonstrates the
      accuracy of the protein interface redesign algorithm and reveals how catalytic
      function is maintained during the creation of the new endonuclease. These results
      indicate that it may be possible to generate novel highly specific DNA binding
      proteins from homing endonucleases.

PMID- 12419233
TI  - Increased recombination intermediates and homologous integration hot spots at DNA
      replication origins.
AB  - We have studied the relationship between DNA replication and recombination in
      Schizosaccharomyces pombe using two-dimensional gel electrophoresis and
      functional analysis. Our results indicate that the activation of replication
      origins (ORIs) during the mitotic cell cycle is associated with the generation of
      joint DNA molecules between sister chromatids. The frequency of integration by
      homologous recombination was up to 50-fold higher than the genomic average within
      a narrow window overlapping the ars1 replication initiation site. The S. pombe
      rad22Delta, rhp51Delta, and rhp54Delta mutants, deficient in mitotic
      recombination, activate ORIs very inefficiently and accumulate abnormal
      replication intermediates. These results focus on the general link between
      replication and recombination previously found in several systems and suggest a
      role for recombination in the initiation of eukaryotic DNA replication.

PMID- 12419234
TI  - Error-free recombinational repair predominates over mutagenic translesion
      replication in E. coli.
AB  - Tolerance mechanisms are important in the ability of cells to cope with DNA
      damage. In E. coli, the two main damage tolerance mechanisms are recombinational
      repair (RR) and translesion replication (TLR). Here we show that RR effectively
      repairs gaps opposite DNA lesions. When both mechanisms are functional, RR
      predominates over TLR, being responsible for 86% of the repair events. This
      predominance of RR is determined by the high concentration of RecA present under
      SOS conditions, which causes a differential inhibition of TLR. Further inhibition
      of TLR is caused by the RecA-catalyzed strand exchange reaction of RR. This
      molecular hierarchy in the tolerance of DNA lesions ensures that the nonmutagenic
      RR predominates over the mutagenic TLR, thereby contributing to genetic
      stability.

PMID- 12419235
TI  - Transcriptional inhibition of genes with severe histone h3 hypoacetylation in the
      coding region.
AB  - Changes in histone acetylation at promoters correlate with transcriptional
      activation and repression, but whether acetylation of histones in the coding
      region of genes is important for transcription is less clear. Here, we show that
      cells lacking the histone acetyltransferases Gcn5 and Elp3 have widespread and
      severe histone H3 hypoacetylation in chromatin. Surprisingly, severe
      hypoacetylation in the promoter does not invariably affect the ability of TBP to
      bind the TATA element, or transcription of the gene. By contrast, similar
      hypoacetylation of the coding region correlates with inhibition of transcription,
      and inhibition correlates better with the overall charge of the histone H3 tail
      than with hypoacetylation of specific lysine residues. These data provide
      insights into the effects of histone H3 hypoacetylation in vivo and underscore
      the importance of the overall charge of the histone tail for transcription.

PMID- 12419236
TI  - Essential role for the SANT domain in the functioning of multiple chromatin
      remodeling enzymes.
AB  - The SANT domain is a novel motif found in a number of eukaryotic transcriptional
      regulatory proteins that was identified based on its homology to the DNA binding
      domain of c-myb. Here we show that the SANT domain is essential for the in vivo
      functions of yeast Swi3p, Ada2p, and Rsc8p, subunits of three distinct chromatin
      remodeling complexes. We also find that the Ada2p SANT domain is essential for
      histone acetyltransferase activity of native, Gcn5p-containing HAT complexes.
      Furthermore, kinetic analyses indicate that an intact SANT domain is required for
      an Ada2p-dependent enhancement of histone tail binding and enzymatic catalysis by
      Gcn5p. Our results are consistent with a general role for SANT domains in
      functional interactions with histone N-terminal tails.

PMID- 12419237
TI  - RNAi-mediated PTB depletion leads to enhanced exon definition.
AB  - Mutually exclusive use of exons IIIb or IIIc in FGF-R2 transcripts requires the
      silencing of exon IIIb. This repression is mediated by silencer elements upstream
      and downstream of the exon. Both silencers bind the polypyrimidine tract binding
      protein (PTB) and PTB binding sites within these elements are required for
      efficient silencing of exon IIIb. Recruitment of MS2-PTB fusion proteins upstream
      or downstream of exon IIIb causes repression of this exon. Depletion of
      endogenous PTB using RNAi increases exon IIIb inclusion in transcripts derived
      from minigenes and from the endogenous FGF-R2 gene. These data demonstrate that
      PTB is a negative regulator of exon definition in vivo.

PMID- 12419238
TI  - Nonsense-associated altered splicing: a frame-dependent response distinct from
      nonsense-mediated decay.
AB  - Nonsense-associated altered splicing (NAS) is a putative correction response that
      upregulates alternatively spliced transcripts that have skipped offending
      premature termination codons (PTCs). Here, we examined whether NAS has
      characteristics in common with nonsense-mediated decay (NMD), a surveillance
      mechanism that degrades PTC-bearing mRNAs. We discovered that although NAS shared
      the need for a Kozak AUG to define frame, it differed from NMD. NAS was not
      affected by depletion of the NMD protein hUPF2, and it functioned independently
      of RNA stabilization. We identified an alternatively spliced transcript acted
      upon by both NAS and NMD, indicating that these two mechanisms are not mutually
      exclusive. Our results suggest that NAS and NMD are distinct mechanisms despite
      being triggered by the same signal.

PMID- 12419239
TI  - Epigenetic consequences of nucleosome dynamics.
AB  - Current models for epigenetic gene silencing envision a static relationship
      between histone modifications and transcription. However, evidence for nucleosome
      mobility and replacement favors a dynamic model that may explain phenomena
      ranging from variegation to the neural restriction of Rett syndrome.

PMID- 12419240
TI  - Cellular memory and the histone code.
AB  - The histone tails on the nucleosome surface are subject to enzyme-catalyzed
      modifications that may, singly or in combination, form a code specifying patterns
      of gene expression. Recent papers provide insights into how a combinatorial code
      might be set and read. They show how modification of one residue can influence
      that of another, even when they are located on different histones, and how
      modifications at specific genomic locations might be perpetuated on newly
      assembled chromatin.

PMID- 12419241
TI  - PKB binding proteins. Getting in on the Akt.
AB  - Protein kinase B (PKB) has emerged as the focal point for many signal
      transduction pathways, regulating multiple cellular processes such as glucose
      metabolism, transcription, apoptosis, cell proliferation, angiogenesis, and cell
      motility. In addition to acting as a kinase toward many substrates involved in
      these processes, PKB forms complexes with other proteins that are not substrates,
      but rather act as modulators of PKB activity and function. In this review, we
      discuss the implications of these data in understanding the multitude of
      functions predicted for PKB in cells.

PMID- 12419242
TI  - Leptin regulates bone formation via the sympathetic nervous system.
AB  - We previously showed that leptin inhibits bone formation by an undefined
      mechanism. Here, we show that hypothalamic leptin-dependent antiosteogenic and
      anorexigenic networks differ, and that the peripheral mediators of leptin
      antiosteogenic function appear to be neuronal. Neuropeptides mediating leptin
      anorexigenic function do not affect bone formation. Leptin deficiency results in
      low sympathetic tone, and genetic or pharmacological ablation of adrenergic
      signaling leads to a leptin-resistant high bone mass. beta-adrenergic receptors
      on osteoblasts regulate their proliferation, and a beta-adrenergic agonist
      decreases bone mass in leptin-deficient and wild-type mice while a beta
      adrenergic antagonist increases bone mass in wild-type and ovariectomized mice.
      None of these manipulations affects body weight. This study demonstrates a leptin
      dependent neuronal regulation of bone formation with potential therapeutic
      implications for osteoporosis.

PMID- 12419243
TI  - The Drosophila Wnt, wingless, provides an essential signal for pre- and
      postsynaptic differentiation.
AB  - At vertebrate neuromuscular junctions (NMJs), Agrin plays pivotal roles in
      synapse development, but molecules that activate synapse formation at central
      synapses are largely unknown. Members of the Wnt family are well established as
      morphogens, yet recently they have also been implicated in synapse maturation.
      Here we demonstrate that the Drosophila Wnt, Wingless (Wg), is essential for
      synapse development. We show that Wg and its receptor are expressed at
      glutamatergic NMJs, and that Wg is secreted by synaptic boutons. Loss of Wg leads
      to dramatic reductions in target-dependent synapse formation, and new boutons
      either fail to develop active zones and postsynaptic specializations or these are
      strikingly aberrant. We suggest that Wg signals the coordinated development of
      pre- and postsynaptic compartments.

PMID- 12419244
TI  - Bid, Bax, and lipids cooperate to form supramolecular openings in the outer
      mitochondrial membrane.
AB  - Bcl-2 family proteins regulate the release of proteins like cytochrome c from
      mitochondria during apoptosis. We used cell-free systems and ultimately a
      vesicular reconstitution from defined molecules to show that outer membrane
      permeabilization by Bcl-2 family proteins requires neither the mitochondrial
      matrix, the inner membrane, nor other proteins. Bid, or its BH3-domain peptide,
      activated monomeric Bax to produce membrane openings that allowed the passage of
      very large (2 megadalton) dextran molecules, explaining the translocation of
      large mitochondrial proteins during apoptosis. This process required cardiolipin
      and was inhibited by antiapoptotic Bcl-x(L). We conclude that mitochondrial
      protein release in apoptosis can be mediated by supramolecular openings in the
      outer mitochondrial membrane, promoted by BH3/Bax/lipid interaction and directly
      inhibited by Bcl-x(L).

PMID- 12419245
TI  - Structural basis of chemokine sequestration by a herpesvirus decoy receptor.
AB  - The M3 protein encoded by murine gamma herpesvirus68 (gamma HV68) functions as an
      immune system saboteur by the engagement of chemoattractant cytokines, thereby
      altering host antiviral inflammatory responses. Here we report the crystal
      structures of M3 both alone and in complex with the CC chemokine MCP-1. M3 is a
      two-domain beta sandwich protein with a unique sequence and topology, forming a
      tightly packed anti-parallel dimer. The stoichiometry of the MCP-1:M3 complex is
      2:2, with two monomeric chemokines embedded at distal ends of the preassociated
      M3 dimer. Conformational flexibility and electrostatic complementation are both
      used by M3 to achieve high-affinity and broad-spectrum chemokine engagement. M3
      also employs structural mimicry to promiscuously sequester chemokines, engaging
      conservative structural elements associated with both chemokine homodimerization
      and binding to G protein-coupled receptors.

PMID- 12419246
TI  - Structural mechanism of Smad4 recognition by the nuclear oncoprotein Ski:
      insights on Ski-mediated repression of TGF-beta signaling.
AB  - The Ski family of nuclear oncoproteins represses TGF-beta signaling through
      interactions with the Smad proteins. The crystal structure of the Smad4 binding
      domain of human c-Ski in complex with the MH2 domain of Smad4 reveals specific
      recognition of the Smad4 L3 loop region by a highly conserved interaction loop (I
      loop) from Ski. The Ski binding surface on Smad4 significantly overlaps with that
      required for binding of the R-Smads. Indeed, Ski disrupts the formation of a
      functional complex between the Co- and R-Smads, explaining how it could lead to
      repression of TGF-beta, activin, and BMP responses. Intriguingly, the structure
      of the Ski fragment, stabilized by a bound zinc atom, resembles the SAND domain,
      in which the corresponding I loop is responsible for DNA binding.

PMID- 12419247
TI  - Function and selectivity of bromodomains in anchoring chromatin-modifying
      complexes to promoter nucleosomes.
AB  - The functions of the SAGA and SWI/SNF complexes are interrelated and can form
      stable "epigenetic marks" on promoters in vivo. Here we show that stable promoter
      occupancy by SWI/SNF and SAGA in the absence of transcription activators requires
      the bromodomains of the Swi2/Snf2 and Gcn5 subunits, respectively, and nucleosome
      acetylation. This acetylation can be brought about by either the SAGA or NuA4 HAT
      complexes. The bromodomain in the Spt7 subunit of SAGA is dispensable for this
      activity but will anchor SAGA if it is swapped into Gcn5, indicating that
      specificity of bromodomain function is determined in part by the subunit it
      occupies. Thus, bromodomains within the catalytic subunits of SAGA and SWI/SNF
      anchor these complexes to acetylated promoter nucleosomes.

PMID- 12419248
TI  - Deciphering the transcriptional histone acetylation code for a human gene.
AB  - We report the results of experiments designed to test the histone code
      hypothesis. We found that only a small subset of lysines in histones H4 and H3
      are acetylated in vivo by the GCN5 acetyltransferase during activation of the IFN
      beta gene. Reconstitution of recombinant nucleosomes bearing mutations in these
      lysine residues revealed the cascade of gene activation via a point-by-point
      interpretation of the histone code through the ordered recruitment of bromodomain
      containing transcription complexes. Acetylation of histone H4 K8 mediates
      recruitment of the SWI/SNF complex whereas acetylation of K9 and K14 in histone
      H3 is critical for the recruitment of TFIID. Thus, the information contained in
      the DNA address of the enhancer is transferred to the histone N termini by
      generating novel adhesive surfaces required for the recruitment of transcription
      complexes.

PMID- 12419249
TI  - BRCA1 supports XIST RNA concentration on the inactive X chromosome.
AB  - BRCA1, a breast and ovarian tumor suppressor, colocalizes with markers of the
      inactive X chromosome (Xi) on Xi in female somatic cells and associates with XIST
      RNA, as detected by chromatin immunoprecipitation. Breast and ovarian carcinoma
      cells lacking BRCA1 show evidence of defects in Xi chromatin structure.
      Reconstitution of BRCA1-deficient cells with wt BRCA1 led to the appearance of
      focal XIST RNA staining without altering XIST abundance. Inhibiting BRCA1
      synthesis in a suitable reporter line led to increased expression of an otherwise
      silenced Xi-located GFP transgene. These observations suggest that loss of BRCA1
      in female cells may lead to Xi perturbation and destabilization of its silenced
      state.

PMID- 12419250
TI  - The SR protein SRp38 represses splicing in M phase cells.
AB  - SR proteins constitute a family of pre-mRNA splicing factors that play important
      roles in both constitutive and regulated splicing. Here, we describe one member
      of the family, which we call SRp38, with unexpected properties. Unlike other SR
      proteins, SRp38 cannot activate splicing and is essentially inactive in splicing
      assays. However, dephosphorylation converts SRp38 to a potent, general repressor
      that inhibits splicing at an early step. To investigate the cellular function of
      SRp38, we examined its possible role in cell cycle control. We show first that
      splicing, like other steps in gene expression, is inhibited in extracts of
      mitotic cells. Strikingly, SRp38 was found to be dephosphorylated specifically in
      mitotic cells, and we show that dephosphorylated SRp38 is required for the
      observed splicing repression.

PMID- 12419251
TI  - Stable association of mitotic cyclin B/Cdc2 to replication origins prevents
      endoreduplication.
AB  - We show that in fission yeast the mitotic B type cyclin Cdc13/Cdc2 kinase
      associates with replication origins in vivo. This association is dependent on the
      origin recognition complex (ORC), is established as chromosomes are replicated,
      and is maintained during G2 and early mitosis. Cells expressing an orp2 (ORC2)
      allele that reduces binding of Cdc13 to replication origins are acutely prone to
      chromosomal reduplication. In synchronized endoreduplicating cells, following
      Cdc13 ablation, replication origins are coordinately licensed prior to each
      successive round of S phase with the same periodicity as in a normal cell cycle.
      Thus, ORC bound mitotic Cyclin B/Cdc2 kinase imposes the dependency of S phase on
      an intervening mitosis but not the temporal licensing of replication origins
      between each S phase.

PMID- 12419252
TI  - LINEs mobilize SINEs in the eel through a shared 3' sequence.
AB  - We characterized members of the LINE (UnaL2) and SINE (UnaSINE1) families from
      the eel genome and found that these LINE/SINE partners share similar 3' tails. A
      retrotransposition assay in HeLa cells demonstrated that the 3' conserved tail of
      UnaL2 is necessary for its retrotransposition. This 3' tail is recognized in
      trans by the UnaL2 reverse transcriptase at a surprisingly high rate, and that of
      UnaSINE1 can also be recognized, thus providing experimental evidence that a SINE
      can be mobilized by the retrotransposition machinery of a partner LINE. We also
      demonstrated that short repeats at the 3' end of UnaL2 are required for
      retrotransposition suggesting that UnaL2 retrotransposes in a manner reminiscent
      of the reverse transcriptase activity of telomerases.

PMID- 12419253
TI  - Definition of transcriptional promoters in the human beta globin locus control
      region.
AB  - Our previous studies on the human beta globin gene cluster revealed the presence
      of intergenic transcripts throughout the locus, and demonstrated that
      transcription of the locus control region (LCR) initiates within an ERV9
      endogenous retroviral long-terminal repeat (LTR) upstream of DNase I
      hypersensitive site 5. We show, using a combination of assays, that there are
      additional sites of transcription initiation within the LCR at hypersensitive
      sites 2 and 3. We have defined sites of transcription initiation, which occurs at
      discrete positions in a direction towards the globin genes. In addition, we show
      that mutation of specific transcription factor binding sites within HS2 leads to
      a reduction in transcription levels from within this site. We propose that these
      initiation events within the LCR can account for the observed orientation
      dependence of LCR function, and contribute to the open chromatin configuration of
      the beta globin locus. In addition, transcription from within the LCR
      hypersensitive sites could compensate for the absence of the ERV9 LTR in many
      transgenic mice lines, which nevertheless regulate their globin clusters
      correctly.

PMID- 12419254
TI  - Modulation of homo- and heterodimerization of Harvey sarcoma virus RNA by GACG
      tetraloops and point mutations in palindromic sequences.
AB  - Retroviruses harbour a diploid genome of two plus-strand RNAs linked non
      covalently at the dimer linkage structure. Co-packaging of two parental RNAs is a
      prerequisite for recombination in retroviruses, but formation of heterodimers has
      not been demonstrated directly in vivo. Here, we explore elements in Harvey
      sarcoma virus (HaSV) RNA involved in homodimerization and heterodimerization with
      RNA of Moloney (Mo) and Akv murine leukemia viruses (MLV). By an in vitro assay,
      we found that HaSV dimerization specificity could be modulated by mutations in a
      decanucleotide palindrome (Pal) probably folded into a kissing-loop.
      Autocomplementary and non-autocomplementary sequences introduced into the
      putative loop directed the specificity towards formation of homodimers and
      heterodimers, respectively. Two stem-loop (SL) structures, both exposing a GACG
      tetraloop, enhanced the formation of stable HaSV dimers.A similar decanucleotide
      palindrome has been implicated in homodimerization of MLVs. Heterodimers between
      HaSV RNA and Mo- or Akv MLV were unstable, but could be stabilized by
      introduction of two point mutations in the putative HaSV kissing-loop, creating
      exact complementarity with Mo/Akv MLV palindromes. Moreover, such changes
      increased the HaSV RNA affinity for the two MLV RNAs. Similar to HaSV RNA
      homodimers, formation of heterodimers with Mo- or Akv MLV RNAs was induced by the
      presence of GACG loops. On the basis of these results, we propose that
      palindromic sequences act as variable determinants of specificity and GACG
      tetraloops as conserved determinants in the formation of homodimers and
      heterodimers of gamma-retrovirus retroviral RNAs in vivo. The complementarity of
      loop sequences in the packaging signal upstream of the GACG tetraloops might
      therefore determine homo- and heterodimerization specificity and recombination
      activity of these viruses.

PMID- 12419255
TI  - A Janus splicing regulatory element modulates HIV-1 tat and rev mRNA production
      by coordination of hnRNP A1 cooperative binding.
AB  - Retroviral protein production depends upon alternative splicing of the viral
      transcript. The HIV-1 acceptor site A7 is required for tat and rev mRNA
      production. Production of the Tat transcriptional activator is highly controlled
      because of its apoptotic properties. Two silencer elements (ESS3 and ISS) and two
      enhancer elements (ESE2 and ESE3/(GAA)3) were previously identified at site A7.
      hnRNP A1 binds ISS and ESS3 and is involved in the inhibitory process, ASF/SF2
      activates site A7 utilisation. Here, by using chemical and enzymatic probes we
      established the 2D structure of the HIV-1(BRU) RNA region containing site A7 and
      identified the RNA segments protected in nuclear extract and by purified hnRNP
      A1. ISS, ESE3/(GAA)3 and ESS3 are located in three distinct stem-loop structures
      (SLS1, 2 and 3). As expected, hnRNP A1 binds sites 1, 2 and 3 of ISS and ESS3b,
      and oligomerises on the polypurine sequence upstream of ESS3b. In addition, we
      discovered an unidentified hnRNP A1 binding site (AUAGAA), that overlaps
      ESE3/(GAA)3. On the basis of competition experiments, hnRNP A1 has a stronger
      affinity for this site than for ESS3b. By insertion of (GAA)3 alone or preceded
      by the AUA trinucleotide in a foreign context, the AUAGAA sequence was found to
      modulate strongly the (GAA)3 splicing enhancer activity. Cross-linking
      experiments on these heterologous RNAs and the SLS2-SLS3 HIV-1 RNA region, in
      nuclear extract and with recombinant proteins, showed that binding of hnRNP A1 to
      AUA(GAA)3 strongly competes the association of ASF/SF2 with (GAA)3. In addition,
      disruption of AUA(GAA)3 demonstrated a key role of this sequence in hnRNP A1
      cooperative binding to the ISS and ESS3b inhibitors and hnRNP A1 oligomerisation
      on the polypurine sequence. Thus, depending on the cellular context
      ([ASF/SF2]/[hnRNP A1] ratio), AUA(GAA)3 will activate or repress site A7
      utilisation and can thus be considered as a Janus splicing regulator.

PMID- 12419256
TI  - Protein-protein interactions between human exosome components support the
      assembly of RNase PH-type subunits into a six-membered PNPase-like ring.
AB  - The exosome is a complex of 3'-->5' exoribonucleases, which functions in a
      variety of cellular processes, all requiring the processing or degradation of
      RNA. Here we present a model for the assembly of the six human RNase PH-like
      exosome subunits into a hexameric ring structure. In part, this structure is on
      the basis of the evolutionarily related bacterial degradosome, the core of which
      consists of three copies of the PNPase protein, each containing two RNase PH
      domains. In our model three additional exosome subunits, which contain S1 RNA
      binding domains, are positioned on the outer surface of this ring. Evidence for
      this model was obtained by the identification of protein-protein interactions
      between individual exosome subunits in a mammalian two-hybrid system. In
      addition, the results of co-immunoprecipitation assays indicate that at least two
      copies of hRrp4p and hRrp41p are associated with a single exosome, suggesting
      that at least two of these ring structures are present in this complex. Finally,
      the identification of a human gene encoding the putative human counterpart of the
      bacterial PNPase protein is described, which suggests that the exosome is not the
      eukaryotic equivalent of the bacterial degradosome, although they do share
      similar functional activities.

PMID- 12419257
TI  - Interchange of DNA-binding modes in the deformed and ultrabithorax homeodomains:
      a structural role for the N-terminal arm.
AB  - The deformed (Dfd) and ultrabithorax (Ubx) homeoproteins regulate developmental
      gene expression in Drosophila melanogaster by binding to specific DNA sequences
      within its genome. DNA binding is largely accomplished via a highly conserved
      helix-turn-helix DNA-binding domain that is known as a homeodomain (HD). Despite
      nearly identical DNA recognition helices and similar target DNA sequence
      preferences, the in vivo functions of the two proteins are quite different. We
      have previously revealed differences between the two HDs in their interactions
      with DNA. In an effort to define the individual roles of the HD N-terminal arm
      and recognition helix in sequence-specific binding, we have characterized the
      structural details of two Dfd/Ubx chimeric HDs in complex with both the Dfd and
      Ubx-optimal-binding site sequences. We utilized hydroxyl radical cleavage of DNA
      to assess the positioning of the proteins on the binding sites. The effects of
      missing nucleosides and purine methylation on HD binding were also analyzed. Our
      results show that both the Dfd and Ubx HDs have similar DNA-binding modes when in
      complex with the Ubx-optimal site. There are subtle but reproducible differences
      in these modes that are completely interchanged when the Dfd N-terminal arm is
      replaced with the corresponding region of the Ubx HD. In contrast, we showed
      previously that the Dfd-optimal site sequence elicits a very different binding
      mode for the Ubx HD, while the Dfd HD maintains a mode similar to that elicited
      by the Ubx-optimal site. Our current methylation interference studies suggest
      that this alternate binding mode involves interaction of the Ubx N-terminal arm
      with the minor groove on the opposite face of DNA relative to the major groove
      that is occupied by the recognition helix. As judged by hydroxyl radical
      footprinting and the missing nucleoside experiment, it appears that interaction
      of the Ubx recognition helix with the DNA major groove is reduced. Replacing the
      Dfd N-terminal arm with that of Ubx does not elicit a complete interchange of the
      DNA-binding mode. Although the position of the chimera relative to DNA, as judged
      by hydroxyl radical footprinting, is similar to that of the Dfd HD, the missing
      nucleoside and methylation interference patterns resemble those of the Ubx HD.
      Repositioning of amino acid side-chains without wholesale structural alteration
      in the polypeptide appears to occur as a function of N-terminal arm identity and
      DNA-binding site sequence. Complete interchange of binding modes was achieved
      only by replacement of the Dfd N-terminal arm and the recognition helix plus 13
      carboxyl-terminal residues with the corresponding residues of Ubx. The position
      of the N-terminal arm in the DNA minor groove appears to differ in a manner that
      depends on the two base-pair differences between the Dfd and Ubx-optimal-binding
      sites. Thus, N-terminal arm position dictates the binding mode and the
      interaction of the recognition helix with nucleosides in the major groove.

PMID- 12419258
TI  - Crp1p, a new cruciform DNA-binding protein in the yeast Saccharomyces cerevisiae.
AB  - A synthetic cruciform DNA (X-DNA) was used for screening cellular extracts of
      Saccharomyces cerevisiae for X-DNA-binding activity. Three X-DNA-binding proteins
      with apparent molecular mass of 28kDa, 26kDa and 24kDa, estimated by SDS-PAGE,
      were partially purified. They were identified as N-terminal fragments originating
      from the same putative protein, encoded by the open reading frame YHR146W, which
      we named CRP1 (cruciform DNA-recognising protein 1). Expression of CRP1 in
      Escherichia coli showed that Crp1p is subject to efficient proteolysis at one
      specific site. Cleavage leads to an N-terminal subpeptide of approximately 160
      amino acid residues that is capable of binding specifically X-DNA with an
      estimated dissociation constant (K(d)) of 800nM, and a C-terminal subpeptide of
      approximately 305 residues without intrinsic X-DNA-binding activity. The N
      terminal subpeptide is of a size similarly to that of the fragments identified in
      yeast, suggesting that the same cleavage process occurs in the yeast and the
      E.coli background. This makes the action of a site-specific protease unlikely and
      favours the possibility of an autoproteolytic activity of Crp1p. The DNA-binding
      domain of Crp1p was mapped to positions 120-141. This domain can act autonomously
      as an X-DNA-binding peptide and provides a new, lysine-rich DNA-binding domain
      different from those of known cruciform DNA-binding proteins (CBPs). As reported
      earlier for several other CBPs, Crp1p exerts an enhancing effect on the cleavage
      of X-DNA by endonuclease VII from bacteriophage T4.

PMID- 12419259
TI  - Probabilistic code for DNA recognition by proteins of the EGR family.
AB  - A recognition code for protein-DNA interactions would allow for the prediction of
      binding sites based on protein sequence, and the identification of binding
      proteins for specific DNA targets. Crystallographic studies of protein-DNA
      complexes showed that a simple, deterministic recognition code does not exist.
      Here, we present a probabilistic recognition code (P-code) that assigns energies
      to all possible base-pair-amino acid interactions for the early growth response
      factor (EGR) family of zinc-finger transcription factors. The specific energy
      values are determined by a maximum likelihood method using examples from in vitro
      randomisation experiments (namely, SELEX and phage display) reported in the
      literature. The accuracy of the model is tested in several ways, including the
      ability to predict in vivo binding sites of EGR proteins and other non-EGR zinc
      finger proteins, and the correlation between predicted and measured binding
      affinities of various EGR proteins to several different DNA sites. We also show
      that this model improves significantly upon the prediction capabilities of
      previous qualitative and quantitative models. The probabilistic code we develop
      uses information about the interacting positions between the protein and DNA, but
      we show that such information is not necessary, although it reduces the number of
      parameters to be determined. We also employ the assumption that the total binding
      energy is the sum of the energies of the individual contacts, but we describe how
      that assumption can be relaxed at the cost of additional parameters.

PMID- 12419260
TI  - Bcl-2 and porin follow different pathways of TOM-dependent insertion into the
      mitochondrial outer membrane.
AB  - The bcl-2 gene encodes a 26kDa protein which functions as a central regulator of
      apoptosis. Here we investigated the pathway of Bcl-2alpha into the mitochondrial
      outer membrane using the yeast Saccharomyces cerevisiae as a model organism. We
      found that interactions of Bcl-2alpha with the mitochondrial import receptor
      Tom20 are dependent on two positively charged lysine residues in the immediate
      vicinity of the carboxy-terminal hydrophobic membrane anchor. The targeting
      function of these residues is independent of Tom22. Subsequent insertion of Bcl
      2alpha into the mitochondrial outer membrane does not require Tom5 or Tom40,
      indicating that Bcl-2alpha bypasses the general import pore (GIP). Bcl-2alpha
      shows a unique pattern of interactions with the components of the mitochondrial
      TOM complex, demonstrating that at least two different pathways lead from the
      import receptor Tom20 into the mitochondrial outer membrane.

PMID- 12419261
TI  - Structural effects of cofilin on longitudinal contacts in F-actin.
AB  - Structural effects of yeast cofilin on skeletal muscle and yeast actin were
      examined in solution. Cofilin binding to native actin was non-cooperative and
      saturated at a 1:1 molar ratio, with K(d)<or=0.05 microM for both CaATP-G-actin
      and F-actin. Cofilin binding enhanced the fluorescence of dansyl ethylenediamine
      (DED) attached to Gln41 on the DNase I binding loop of skeletal muscle F-actin
      and decreased the fluorescence of AEDANS at Cys41 on yeast Q41C/C374S mutant F
      actin. However, cofilin had no effect on the spectral properties of DED or AEDANS
      on CaATP-G-actin. Fluorescence energy transfer (FRET) from tryptophan residues to
      DED at Gln41 on skeletal muscle actin and to AEDANS at Cys41 on yeast Q41C/C374S
      actin was decreased by cofilin binding to F- but not to G-actin. Cofilin
      inhibited strongly the rate of interprotomer disulfide cross-linking of Cys41 to
      Cys374 on yeast Q41C mutant F-actin. Binding of cofilin enhanced excimer
      formation between pyrene probes attached to Cys41 and Cys374 on Q41C F-actin.
      These results indicate that cofilin alters the interface between subdomains 1 and
      2 and shifts the DNase I binding loop away from subdomain 1 of an adjacent actin
      protomer. Cofilin reduced FRET from tryptophan residues to 4-azido-2-nitrophenyl
      putrescine (ANP) at Gln41 in skeletal muscle F-but not in G-actin. However,
      following the interprotomer cross-linking of Gln41 to Cys374 in F-actin by ANP,
      cofilin binding did not change FRET from the tryptophan residues to ANP. This
      suggests that cofilin binding and the conformational effect on F-actin are not
      coupled tightly. Overall, this study provides solution evidence for the weakening
      of longitudinal, subdomain 2/1 contacts in F-actin by cofilin.

PMID- 12419262
TI  - Calorimetric dissection of thermal unfolding of OspA, a predominantly beta-sheet
      protein containing a single-layer beta-sheet.
AB  - Outer surface protein A (OspA) from Borrelia burgdorferi is a predominantly beta
      sheet protein comprised of beta-strands beta1-beta21 and a short C-terminal alpha
      helix. It contains two globular domains (N and C-terminal domains) and a unique
      single-layer beta-sheet (central beta-sheet) that connects the two domains. OspA
      contains an unusually large number of charged amino acid residues. To understand
      the mechanism of stabilization of this unique beta-sheet protein, thorough
      thermodynamic investigations of OspA and its truncated mutant lacking a part of
      the C-terminal domain were conducted using calorimetry and circular dichroism.
      The stability of OspA was found to be sensitive to pH and salt concentration. The
      heat capacity curve clearly consisted of two components, and all the
      thermodynamic parameters were obtained for each step. The thermodynamic
      parameters associated with the two transitions are consistent with a previously
      proposed model, in which the first transition corresponds to the unfolding of the
      C-terminal domain and the last two beta-strands of the central beta-sheet, and
      the second transition corresponds to that of the N-terminal domain and the first
      beta-strand of the central beta-sheet in the second peak. The ratio of
      calorimetric and van't Hoff enthalpies indicates that the first peak includes
      another thermodynamic intermediate state. Large heat capacity changes were
      observed for both transitions, indicative of large changes in the exposure of
      hydrophobic surfaces associated with the transitions. This observation
      demonstrates that hydrophobic parts are buried efficiently in the native
      structure in spite of the low content of hydrophobic residues in OspA. By
      decomposing the enthalpy, entropy, and Gibbs free energy into contributions from
      different interactions, we found that the enthalpy changes for hydrogen bonding
      and polar interactions are exceptionally large, indicating that OspA maintains
      its stability by making full use of its unique beta-sheet and high content of
      polar residues. These thermodynamic analyses demonstrated that it is possible to
      maintain protein tertiary structure by making effective use of an unusual amino
      acid composition.

PMID- 12419263
TI  - Prediction, assessment and validation of protein interaction maps in bacteria.
AB  - High-throughput proteomics technologies, especially the yeast two-hybrid system,
      produce large volumes of protein-protein interaction data organized in networks.
      The complete sequencing of many genomes raises questions about the extent to
      which such networks can be transferred between organisms. We attempted to answer
      this question using the experimentally derived Helicobacter pylori interaction
      map and the recently described interacting domain profile pair (IDPP) method to
      predict a virtual map for Escherichia coli. The extensive literature concerning
      E.coli was used to assess all predicted interactions and to validate the IDPP
      method, which clusters protein domains by sequence and connectivity similarities.
      The IDPP method has a much better heuristic value than methods solely based on
      protein homology. The IDPP method was further applied to Campylobacter jejuni to
      generate a virtual interaction map. An in-depth comparison of the chemotaxis
      pathways predicted in E.coli and C.jejuni led to the proposition of new
      functional assignments. Finally, the prediction of protein-protein interaction
      maps across organisms enabled us to validate some of the interactions on the
      original experimental map.

PMID- 12419264
TI  - The RTP site shared by the HIV-1 Tat protein and the 11S regulator subunit alpha
      is crucial for their effects on proteasome function including antigen processing.
AB  - The human immunodeficiency virus-1 Tat protein inhibits the peptidase activity of
      the 20S proteasome and competes with the 11S regulator/PA28 for binding to the
      20S proteasome. Structural comparison revealed a common site in the Tat protein
      and the 11S regulator alpha-subunit (REGalpha) called the REG/Tat-proteasome
      binding (RTP) site. Kinetic assays found amino acid residues Lys51, Arg52 and
      Asp67 forming the RTP site of Tat to be responsible for the effects on
      proteasomes in vitro. The RTP site identified in REGalpha consists of the
      residues Glu235, Lys236 and Lys239. Mutation of the REGalpha amino acid residues
      Glu235 and Lys236 to Ala resulted in an REGalpha mutant that lost the ability to
      activate the 20S proteasome even though it still forms complexes with REGbeta and
      binds to the 20S proteasome. The REGalpha RTP site is needed to enhance the
      presentation of a cytomegalovirus pp89 protein-derived epitope by MHC class I
      molecules in mouse fibroblasts. Cell experiments demonstrate that the Tat amino
      acid residues 37-72 are necessary for the interaction of the viral protein with
      proteasomes in vivo. Full-length Tat and the Tat peptide 37-72 suppressed 11S
      regulator-mediated presentation of the pp89 epitope. In contrast, the Tat peptide
      37-72 with mutations of amino acid residues Lys51, Arg52 and Asp67 to Ala was not
      able to reduce antigen presentation.

PMID- 12419265
TI  - Post-discharge surveillance: can patients reliably diagnose surgical wound
      infections?
AB  - Post-discharge surgical wound infection surveillance is an important part of many
      infection control programs. It is frequently undertaken by patient self
      assessment, prompted either by a telephone or postal questionnaire. To assess the
      reliability of this method, 290 patients were followed for six weeks
      postoperatively. Their wounds were photographed and also covertly assessed for
      signs of infection by two experienced infection control nurses (ICNs). Patients
      also responded to a postal questionnaire seeking evidence of infection at both
      week four and week six post-surgery. Correlation between the patient's assessment
      of their wound and the ICNs diagnosis was poor (r = 0.37) with a low positive
      predictive value (28.7%), although negative predictive value was high (98.2%).
      Assessment of photos for signs of infection by two experienced clinicians also
      correlated poorly with the ICNs diagnosis of infection (r = 0.54). The patient's
      recall of prescription of an antibiotic by their general practitioner (GP) for
      wound infection during the postoperative period correlated best with the ICNs
      diagnosis (r = 0.76). This latter measure, particularly when confirmed by the GP
      in those patients reporting an infection, appears to provide the most valid and
      resource efficient marker of post-discharge surgical wound infection.

PMID- 12419266
TI  - Comparison of hospital-acquired infection rates in paediatric burn patients.
AB  - The objective of the present study was to determine risk factors for development
      of the most common hospital-acquired infections in paediatric burn patients in
      order to give recommendations for surveillance. The prospective cohort study in a
      paediatric burn centre was conducted over a period of two years using uni- and
      multivariate analysis for risk factor identification. In a group of 41 children
      with an mean total burn surface area (TBSA) of 18.9% 42 hospital-acquired
      infections were observed. The overall infection rate was 59.7 nosocomial
      infections per 1000 patient days, the device-associated nosocomial infection
      rates per 1000 device days were 55.2 for pneumonia, 8.9 for primary bloodstream
      infections and 41.7 for urinary tract infections. The incidence density of burn
      wound infections was 18.5 per 1000 patient days. The percentage of TBSA was a
      significant risk factor for burn wound infections, but percentage of TBSA was not
      a risk factor for the device-associated infections. Duration of urinary catheter
      use and ventilation were identified as risk factors for the corresponding
      hospital-acquired infection. Surveillance of hospital-acquired infections in burn
      intensive care units should be performed in the same way as other intensive care
      unit types, as recommended by the National Nosocomial Infections Surveillance
      system, without consideration of the percentage of TBSA. In addition, burn wound
      infections should be recorded using the percentage of TBSA for stratification of
      burn wound infection rates.

PMID- 12419267
TI  - Epidemiology and control of nosocomial infections in paediatric surgery.
AB  - The purpose of this study was to determine the epidemiology and control of
      hospital-acquired infections (HAI) in paediatric surgery. We reviewed 2844
      hospitalized children in a paediatric surgical clinic between January 1997 and
      December 2000. The diagnosis of HAI was made based on criteria proposed by
      Centers for Disease Control and Prevention (CDC). The incidence, type of micro
      organisms and infections, age, sex, risk factors, and the economic aspects were
      recorded. The mortality, duration of hospitalization and economic aspects of
      patients were compared with 78 control patients matured for age, sex and primary
      illness and free of HAI. There were 78 children with HAI, the overall incidence
      was 2.74% (4.99% in 1997, 3.89% in 1998, 1.33% in 1999, 1.44% in 2000). The most
      frequent infections were surgical wound (28 patients) and urinary tract (25
      patients). The most frequent risk factors were urethral catheterization (10.26%),
      trauma (9.25%), and parenteral nutrition (8.70%). Mean hospitalization was 16
      days (range 4-28 days) in patients with infection compared with nine days (range
      2-22 days) in control group. Eight patients died in the infection group, while
      two died in the control group. HAI caused a significant increase in mortality,
      prolonged hospitalization and increased costs (P < 0.05, P < 0.001, P < 0.001,
      respectively).

PMID- 12419268
TI  - Convection warmers--a possible source of contamination in laminar airflow
      operating theatres?
AB  - This work results from concerns that forced-air convection heaters applied to
      patients in the operating theatre might interfere with ultra-clean ventilation
      system and thus be a potential source of wound contamination. Air samples were
      taken in the operative field and the bacterial load calculated by estimating the
      number of colony forming units per cubic metre of air (cfu/m(3)). Six tests were
      carried out, two in empty theatres and four during standard orthopaedic operating
      lists. Differences were seen between empty theatres and those standing empty for
      short periods during busy operating lists. Increases were seen on entry to
      theatre of staff and patients with the convection heaters off. A further small
      rise was seen after the convection heaters were turned on when applied to
      patients. This study showed that use of warm air convection heaters on patients
      produced a small increase in the number of colony forming units in ultra-clean
      air theatres but the levels were unlikely to have clinical significance. By far
      the greatest effect on numbers was movement and presence of the patient and
      theatre staff in the theatre.

PMID- 12419269
TI  - An outbreak of Serratia marcescens infection in a special-care baby unit of a
      community hospital in United Arab Emirates: the importance of the air conditioner
      duct as a nosocomial reservoir.
AB  - We report an outbreak of Serratia marcescens infection in a special-care baby
      unit (SCBU) of a university-affiliated community hospital in the United Arab
      Emirates. The outbreak involved 36 infants and lasted for 20 weeks. Seven of the
      colonized infants developed invasive illnesses in the form of bacteraemia (four
      cases), bacteraemic meningitis (two) and clinical sepsis (one). Three other term
      infants had purulent conjunctivitis. There were five deaths with an overall
      mortality of 14%. S. marcescens was cultured from airflow samples from the air
      conditioning (AC) which was the reservoir of infection in this outbreak.
      Elimination of the nosocomial source and outbreak containment were eventually
      achieved by specialized robotic cleaning of the entire AC duct system of the
      SCBU. Strict adherence to the infection control policies was reinforced to
      prevent transmission of cross-infection.

PMID- 12419270
TI  - Strain relatedness of endemic MRSA isolates in a burns unit in South India--a
      five year study.
AB  - Methicillin-resistant Staphylococcus aureus (MRSA) is an important hospital
      acquired pathogen in healthcare centres worldwide. The strain characteristics
      vary widely from country to country, although some strains have the propensity to
      spread globally. E-MRSA 15 and 16 have been established as epidemic strains in
      the UK and Europe. MRSA is widely prevalent in the Indian sub-continent and is
      endemic in the Burns Unit of St Johns Medical College Hospital, Bangalore, India.
      The purpose of the study was to investigate the predominance of one or more
      epidemic strains within an endemic situation. A representative selection of 65
      isolates of MRSA over a period spanning five years (1994-1998) was subjected to
      antibiogram comparison, phage-typing and pulsed field gel electrophoresis (PFGE)
      using SmaI. The antibiogram comparison was not a discerning method of strain
      discrimination. At least 11 different phage-types were seen among these 65
      isolates; 35.4% belonged to phage-types A and SM-A. PFGE studies showed 12
      distinct patterns, with a single pattern accounting for over half of the
      isolates. The study showed that the isolates from India were diverse and distinct
      from strains of MRSA such as E-MRSA reported from many studies in the UK.
      Molecular characterization of isolates is a source of valuable information that
      could enhance global surveillance; more work is needed across the Indian sub
      continent to establish the nature of MRSA strain diversity.

PMID- 12419271
TI  - Environmental surveillance of filamentous fungi in three tertiary care hospitals
      in Greece.
AB  - The environmental fungal load (FL) of three hospitals was studied in
      representative regions in Greece (Thessalonika, Northern Greece, Athens, Central
      Greece and Heraklion, Southern Greece). Air, surfaces and tap water from high
      risk departments were sampled monthly during one year. Air FL was [median
      (range)] 10.6 (1.2-37), 5.5 (3-28.8) and 7.7 (3.1-12.1) cfu/m(3) at Thessalonika,
      Athens and Heraklion, respectively. Air FL was lower in winter and higher in
      summer and autumn but seldom above acceptable levels. Aspergillus spp.
      constituted 70.5% of the filamentous fungi isolated. Aspergillus niger was the
      most prevalent species in the air of all the hospitals followed by Aspergillus
      flavus and Aspergillus fumigatus. The least contaminated departments were the
      intensive care units, whilst most contaminated were the solid organ
      transplantation in Athens and haematology departments in Thessalonika. No
      correlation between fungal species, season, hospital or departments was observed.
      Sixty per cent of all surfaces examined yielded filamentous fungi and/or
      blastomycetes. While no fungi were recovered from water in Thessalonika and
      Athens, one-third of the samples in Heraklion (apart from those of ICU) yielded
      multiple fungal species. The higher air FL in Thessalonika and Athens was
      recorded in departments located close to renovation works. These findings suggest
      that the air and surface FL fluctuates over the year, is due to varying fungal
      species, but does not differ greatly among hospitals. The variation among
      hospitals, as well as the role of hospital water fungal contamination and
      appropriate measures to eliminate it, need further study.

PMID- 12419272
TI  - Effective control of dental chair unit waterline biofilm and marked reduction of
      bacterial contamination of output water using two peroxide-based disinfectants.
AB  - Bacterial biofilm in dental unit waterlines (DUWs) is a widespread problem, and
      poses a potentially significant risk of infection to dental staff and patients,
      particularly those who are medically compromised or immunocompromised. The
      purpose of the present study was to investigate the level of bacterial
      contamination of dental chair unit output water in the Dublin Dental Hospital,
      and to investigate the efficacy of two hydrogen peroxide-based disinfectants in
      reducing bacterial loads to < or =200 cfu/mL as recommended by the American
      Dental Association. The chemical quality of dental chair unit input and output
      water was well within the limits recommended for potable water. Water supplied to
      the units yielded an average aerobic heterotrophic bacterial cell density of 184
      cfu/mL. However, the corresponding density in output water was considerably
      higher; the average cell density in water from the three-in-one air/water
      syringes and cup fillers in 12 chairs was 8200 and 4300 cfu/mL, respectively.
      Dental unit water obtained from 18 separate reservoir-supplied units in general
      practices in the Dublin area yielded an average of 66000 cfu/mL. The bacterial
      species found were predominantly environmental organisms, which were also present
      at low levels in the input water. Some of the species identified (e.g.,
      Burkholderia cepacia and Pseudomonas fluorescens) are known opportunistic
      pathogens. The capacity of two disinfectants, Sterilex Ultra and Sanosil, to
      reduce bacterial contamination to safe levels was compared. In a controlled
      study, once weekly overnight (15 h) disinfection using either agent reduced the
      bacterial density to below the American Dental Association recommended level of
      200 cfu/mL. However, once disinfection ceased the bacterial loads increased to
      unacceptably high levels within three weeks. Electron microscopic analysis showed
      that both disinfectants markedly reduced biofilm in the DUWs, but the biofilm
      rapidly became extensive again when once weekly disinfection ceased. While both
      disinfectants were equally effective in lowering the bacterial counts to
      acceptable levels, Sterilex Ultra was associated with clogging of DUWs in some
      dental chair units after repeated usage, suggesting that Sanosil is a more
      suitable agent for routine use.

PMID- 12419273
TI  - Cleaning efficacy of nine different cleaners in a washer-disinfector designed for
      flexible endoscopes.
AB  - Studies on processing endoscopes usually involve the combined cleaning and
      disinfecting activity. We compared nine cleaning agents designed for automatic
      processing for cleaning efficacy alone using soft and hard water as controls in
      12 different processes in a washer-disinfector. Experiments were performed
      according to the German Endoscopy Working Group recommendations using transparent
      Teflon tubes (internal diameter 2mm, length 2m) as test pieces. For each test
      three pieces contaminated with a blood/test soil containing Enterococcus faecium
      were used; two for the test and one as a control; each test was repeated three
      times. Tests were run according to the manufacturer's instructions. Test pieces
      were assessed visually and microbiologically [log(10) reduction factors (RF) vs.
      untreated controls]. Soft water alone gave poor visible cleanliness and an RF of
      0.3 (SD 0.2), while hard water produced adequate visible cleanliness and an RF of
      1.2 (SD 1.0). Five processes gave better visible cleanliness than soft water, but
      only three were better than hard water. Six processes were worse than soft water
      and five worse than hard water. Nine processes gave a better microbiological
      reduction factor than soft water, but the difference was only statistically
      significant in three. Only one process yielded a significantly higher RF than
      hard water; three were significantly worse. None of the cleaning processes
      reached the RF of 4 specified in the US regulations. This study confirms the
      variability of cleaning processes to dissolve blood residues and reduce the
      bioburden. We do not recommend abandoning cleaning agents, but suggest that
      further research is needed to clarify the relationships between washer
      disinfectors, cleaning agents, and cleaning performance.

PMID- 12419274
TI  - Environmental regulation of biofilm formation in intensive care unit isolates of
      Staphylococcus epidermidis.
AB  - Staphylococcus epidermidis is a common cause of prosthetic device-related
      infection in the intensive care unit (ICU). The environmentally regulated ica
      operon encodes a polysaccharide adhesin which is a key virulence determinant in
      the development of S. epidermidis biofilms. To evaluate the capacity of ICU S.
      epidermidis isolates to form biofilm, we measured biofilm production by 18
      isolates associated with device-related infection and 20 contaminating isolates
      that were not associated with clinically diagnosed infection. Biofilm assays were
      performed in brain-heart infusion (BHI) medium and in BHI supplemented with salt,
      ethanol or subinhibitory tetracycline, all of which have the potential to promote
      biofilm formation. Polymerase chain reaction (PCR) was used to screen for the
      presence of the ica genes. A significant proportion of S. epidermidis strains
      associated with device-related infections (89%) were found to contain the ica
      locus compared with 50% of contaminating isolates (P = 0.01). However only four
      of 26 (15.3%) of all ica-positive isolates were biofilm-positive when grown in
      BHI medium, indicating that no significant association existed between the
      presence of the ica locus and biofilm-forming capacity, under standard growth
      conditions. In contrast the number of ica-positive isolates that were biofilm
      positive under stress-inducing growth conditions or in the presence of
      subinhibitory tetracycline increased significantly to 73% (P = 0.02). These
      findings suggest that the presence of the ica locus alone is not sufficient for
      biofilm formation and that regulation of biofilm formation under altered growth
      conditions, which may exist in the in vivo environment, also plays a possible
      role in the pathogenesis of biomaterial-related S. epidermidis infections.

PMID- 12419275
TI  - Intra-laboratory reproducibility of the hand hygiene reference procedures of EN
      1499 (hygienic handwash) and EN 1500 (hygienic hand disinfection).
AB  - The bactericidal efficacy of hand antiseptic products is determined in Europe
      using two norms--EN1499 (hygienic handwash), and EN 1500 (hygienic hand
      disinfection) based on reducing the counts of bacteria on artificially
      contaminated hands. Each requires 12-15 data sets per test and comparison with a
      reference procedure. Recent research using EN 1500 suggested that most alcohol
      based hand gels are significantly less effective than the reference alcohol (2
      propanol 60%), whereas liquid alcohol-based rubs are not. However concerns about
      the accuracy and reproducibility of the norm reference procedures have been
      raised. We therefore analysed 23 experiments carried out using EN 1500
      representing 342 hand disinfection procedures, and 12 experiments using EN 1499
      representing 178 handwashes, all performed in the same laboratory for
      reproducibility of the reference procedures. The reference alcohol gave a mean
      log(10) reduction factor (RF) of 4.64 +/- 0.93; only one data set gave a
      significantly higher result (5.14, P = 0.034), and one significantly lower (4.05;
      P = 0.034). Analysis of all 23 means revealed no significant difference (P =
      0.188; ANOVA model). The reference soap gave a mean reduction of 2.82 +/- 0.49.
      Two data sets were significantly higher than this (3.35,P < 0.001; 3.12, P <
      0.001) and two significantly lower (2.55, P = 0.031; 2.47,P = 0.004). Analysis of
      all the means did reveal a significant difference (P < 0.001, ANOVA model), which
      is probably explained by the smaller standard deviations of these results. Pre
      values (bacteria recovered from fingers before a reference procedure) correlated
      significantly with RFs for both hand disinfection (correlation coefficient:
      0.291;P = 0.01) and handwash (correlation coefficient: 0.372, P = 0.01). Overall
      both procedures gave accurate and reproducible results.

PMID- 12419276
TI  - An outbreak Acinetobacter baumannii that mimics MRSA in its environmental
      longevity.

PMID- 12419277
TI  - Not all super-oxidized waters are the same.

PMID- 12419278
TI  - Increased costs due to inappropriate surgical antibiotic prophylaxis in a
      university hospital.

PMID- 12419279
TI  - Molecular identification of pathogenetic IdLNF+1 autoantibody idiotypes derived
      from the NZBxSWR F1 model for systemic lupus erythematosus.
AB  - The acceleration of nephritis in SNF(1) mice by CD4(+) T-cell clones reactive
      with a nephritogenic idiotype, Id(LN)F(1) [1], as well as the ability of anti
      Id(LN)F(1) antisera to down-regulate the production of Id(LN)F(+)(1)
      immunoglobulin (Ig) in vivo and delay nephritis [2], suggests that dysregulation
      of this idiotype may contribute to the development of SNF(1) nephritis. Herein,
      we show that a monoclonal Id(LN)F(1)-expressing antibody, 540, significantly (P<
      or = 0.01) stimulated Id(LN)F(1)-reactive T-cell clones B6 and D2 to proliferate,
      while other Id(LN)F+1 antibodies did not. Further, injection of 540-producing
      hybridoma cells into nonautoimmune (SWRxBalb/c)F(1) mice resulted in the
      deposition of Id(LN)F(+)(1) Ig in the kidneys, in a pattern indicative of early
      nephritis. To identify the pathogenetic Id(LN)F(1) epitope(s) at the molecular
      level, we compared the deduced amino acid sequences of the heavy and light chain
      variable regions of pathogenetic and non-pathogenetic Id(LN)F(1)-expressing Igs
      540, 317, and 533. Two overlapping peptides derived from the V(H) sequence of 540
      (aa 54-66 and 62-73), which both contain the triple basic amino acid motif
      K(X)K(X)K, stimulated SNF(1) T cells and T-cell clones B6 and D2. These results
      further support the involvement of a subset of Id(LN)F(1)-expressing Ig in SNF(1)
      nephritis.

PMID- 12419280
TI  - Phosphorylation abnormalities: NZB mice exhibit a B-cell signalling defect.
AB  - NZB mice demonstrate common and consistent abnormalities in B-cell activation and
      signalling. One of the hallmark characteristics of lupus disease is the prevalent
      hypergammaglobulinaemia, composed primarily of anti-nuclear antibodies. In
      addition to the hyperproliferation seen in mice exhibiting disease, the B cells
      also demonstrate a marked degree of hyperactivity in response to B-cell receptor
      occupancy. This points to an intrinsic defect in the signalling pathways
      regulating the response to an activation event. Correspondingly, B cells of NZB
      mice exhibit a significant lack of phosphatase activity, both at baseline and in
      response to stimulation. This is directly reflected by a higher level of
      phosphorylation of tyrosine residues. Individually, SAPK and SHIP-1, both players
      in the B-cell receptor signalling cascade, are also found to be abnormally
      phosphorylated in the NZB mouse.

PMID- 12419281
TI  - Spontaneous peripheral T-cell responses to the IA-2beta (phogrin) autoantigen in
      young nonobese diabetic mice.
AB  - Phogrin (IA-2beta), a major autoantigen in type 1 diabetes in man is recognized
      by peripheral T cells in the nonobese diabetic (NOD) mouse. CD4(+) T-cell clones
      derived from immunized NOD animals elicit islet destruction in a disease transfer
      model. Spontaneous proliferative responses to the protein and derived peptide
      epitopes were detected in peripheral lymph node cells (LNC) of unprimed NOD mice
      but not BALB/c controls as early as 4 weeks of age at a time point when insulitis
      in NOD animals is minimal. Responses to irradiated NOD islet cells but not
      irradiated NOD spleen cells were observed for both male and female NOD animals.
      Insulin, phogrin and phogrin-peptide 7 (aa 755-777) but not phogrin-peptide 2 (aa
      640-659) or tetanus toxin peptide were recognized as antigens. Islet cell
      reactive and phogrin peptide 7-specific CD4(+) T-cell lines were generated from
      splenocytes of unprimed 4-week-old NOD females and shown to secrete Th1-type
      cytokines. The results show that the phogrin molecule is targeted early in the
      course of disease in NOD animals at a time when circulating autoantibodies are
      absent and insulitis is minimal.

PMID- 12419282
TI  - NKT cell defects in NOD mice suggest therapeutic opportunities.
AB  - Recent studies have reported that immunoregulatory NKT cells are defective in NOD
      mice and that treatment of mice with alpha-galactosylceramide that selectively
      stimulate NKT cells, is anti-diabetogenic. The objective of this study was to
      document the natural history of changes in NKT cells in various organs in NOD
      mice in the period up to the time of diabetes onset so that novel intervention
      therapies could be devised. We found that NKT cell-specific receptor (NKT-TCR)
      Valpha14Jalpha281 expressions by quantitative (RealTime) RT-PCR in thymus, spleen
      and liver of NOD male and female mice were low at 1-3 months of life compared to
      BALB/c and C57BL/6 mice, albeit a transient spike in levels occurred in female
      NOD livers at 2 months. Female pancreases showed low levels of these transcripts
      despite their active and destructive insulitis. In contrast, NOD males exhibited
      high expression of this invariant TCR in pancreas, where their insulitis was less
      destructive. A survey of NKT-TCR expressions in a battery of congenic, non
      diabetes prone NOD strains indicated that this NKT phenotype was quite variable
      but higher than diabetes prone NOD. Bone marrow transplantation of NOD females
      from B6.NOD-H2(g7) donors raised their NKT-TCR expressions. Tuberculin
      administrations in the forms of BCG and CFA in a manner known to protect NOD mice
      from diabetes both raised NKT-TCR levels, as did the anti-inflammatory PPAR-gamma
      agonist rosiglitazone. These findings provide exciting therapeutic avenues to be
      explored in the treatment of human immune mediated type-1 diabetes where there
      are similar immunoregulatory lesions.

PMID- 12419283
TI  - Gamma interferon paradoxically inhibits the development of diabetes in the NOD
      mouse.
AB  - Gamma interferon (IFN-gamma) has been thought to play an important role in the
      pathogenesis of diabetes. This report determines if rIFN-gamma administration to
      NOD mice paradoxically inhibits the development of diabetes. Injections of
      recombinant rIFN-gamma of 5 x 10(3), 20 x 10(3), and 100 x 10(3) units, dose
      dependently inhibited the development of diabetes. The maximal rIFN-gamma dose
      decreased the incidence of diabetes from 74% in control animals to 42%. 100x10(3)
      unit rIFN-gamma dose significantly decreased insulitis score, and increased islet
      number. The development of diabetes in irradiated NOD mice was slower in animals
      injected with spleen cells from rIFN-gamma treated than from saline treated NOD
      mice suggesting that rIFN-gamma decreases anti-islet effector cell activity. The
      susceptibility to apoptosis was increased in splenic cells of rIFN-gamma treated
      mice. The expressions of the co-stimulatory molecules B7-2 and ICAM-1 were
      significantly increased in spleen cells of rIFN-gamma treated mice while the
      expression of MHC class I was decreased. In vitro studies demonstrated that NOD
      mouse mononuclear spleen cells preincubated with rIFN-gamma and subsequently
      cocultured with responder cells, potently inhibited responder T-cell
      proliferative responses. rIFN-gamma administration decreased IL-12 and IL-2 mRNA
      expression in spleen cells while increasing IL-1 expression. In conclusion, rIFN
      gamma inhibits the diabetic process in NOD mice by decreasing anti-islet effector
      activity and in turn decreasing insulitis and islet destruction. The suppression
      of Th1 cell related cytokines and/or augmentation of the macrophage cytokine IL-1
      may play a role in the diabetes sparing effect of rIFN-gamma.

PMID- 12419284
TI  - Prevention of autoimmune diabetes in the DRBB rat by CD40/154 blockade.
AB  - The autoimmune diabetes of the DRBB rat shares important similarities with
      autoimmune diabetes in humans. We have tested the ability of CD40/154 blockade
      using an anti-CD154 antibody (AH.F5) to prevent autoimmune diabetes in DRBB rats.
      The rats were treated with two intravenous doses/wk of AH.F5 (15mg/kg/dose)
      starting at 2-6wks of age. RT6.1 T-cell depletion and poly I/C was started at
      4wks of age. Control rats developed diabetes within 25 days after start of
      depletion therapy. Six of 7, 11 of 13, 7 of 12, and 4 of 11 rats treated with
      AH.F5 did not develop diabetes when treatment was started at 2-3, 4, 5, and 6wks
      of age, respectively. The rats that did not develop diabetes were maintained for
      a minimum of 72 days to >150 days following the last dose of AH.F5. Eleven rats
      maintained for >150 days underwent an additional depletion and 5/11 developed
      diabetes within 8-19 days following start of depletion.Histological examination
      indicated that AH.F5 prevented and possibly reversed insulitis. Islets in about
      50% of the treated rats remained free of inflammation following a second course
      of RT 6.1 T-cell depletion after the serum concentration of AH.F5 was negligible.
      In summary, CD40/154 blockade with AH.F5 prevents development of autoimmune
      diabetes if treatment is started prior to overt signs of beta cell destruction.
      The results indicate that the CD40/154 blockade can prevent diabetes by modifying
      the expansion or effector phase of the autoimmune diabetes.

PMID- 12419285
TI  - Serum amyloid P component and C-reactive protein opsonize apoptotic cells for
      phagocytosis through Fcgamma receptors.
AB  - Serum amyloid P component (SAP) and C-reactive protein (CRP) are opsonins that
      react with nuclear autoantigens targeted in systemic autoimmunity. CRP and SAP
      bind to apoptotic and necrotic cells, which are potential sources of these
      autoantigens. We have recently determined that the receptors for CRP on
      phagocytic cells are Fcgamma receptors. The goal of this study was to determine
      whether CRP and SAP promote phagocytosis of apoptotic cells and to identify the
      receptors involved. Apoptosis was induced in human neutrophils (PMN) and the
      Jurkat T-cell line by UV-irradiation. SAP treatment of apoptotic human PMN
      increased ingestion by autologous macrophages. Both SAP and CRP increased
      ingestion of apoptotic, but not normal Jurkat cells by J-774 macrophages and
      mouse peritoneal macrophages. Neither SAP nor CRP increased ingestion of
      apoptotic Jurkat cells by macrophages from FcR gamma-chain deficient mice, which
      lack FcgammaRI and FcgammaRIII. Inhibition of FcgammaRIII-mediated uptake using
      mAb 2.4G2 eliminated opsonization by SAP, but not by CRP. These results indicate
      that pentraxins promote uptake of apoptotic cells through FcgammaRI and/or
      FcgammaRIII. Ingestion through these receptors is expected to alter the pattern
      of cytokine production and antigen presentation in response to apoptotic cells.

PMID- 12419286
TI  - Autoantibodies to C-reactive protein is a common finding in SLE, but not in
      primary Sjogren's syndrome, rheumatoid arthritis or inflammatory bowel disease.
AB  - The occurrence of antibodies to human C-reactive protein (CRP) was analysed by
      enzyme-linked immunosorbent assay (ELISA) in 56 patient sera known to contain
      antibodies to double-stranded DNA (dsDNA) and in 16 sera from patients with
      primary Sjogren's syndrome (SS), 15 rheumatoid arthritis, 31 Crohn's disease, and
      37 ulcerative colitis. Eighty-seven per cent of the patients with anti-dsDNA
      antibodies had systemic lupus erythematosus (SLE) and the remaining had
      autoimmune hepatitis. The cut-off for positive anti-CRP test was set at the 95th
      percentile of 100 healthy blood donors. Twenty of 56 anti-dsDNA sera (36%) and
      two of 16 SS sera (13%) had antibodies reactive with human CRP, whereas all other
      samples were negative. Thirteen of 27 SLE patients (48%) were positive on at
      least one occasion. The sera containing anti-CRP antibodies only reacted with
      surface-bound antigen, but not with native CRP in solution. In conclusion, we
      found that autoantibodies to CRP are common in sera from patients with anti-dsDNA
      antibodies. It is not likely that this explains the relative failure of CRP
      response in patients with active SLE. However, it cannot be excluded that anti
      CRP autoantibodies have other biological potentials of pathophysiological
      interest in SLE, for instance by binding to CRP deposited on cell and tissue
      surfaces.

PMID- 12419287
TI  - Functional analysis of discoidin domain receptor 2 in synovial fibroblasts in
      rheumatoid arthritis.
AB  - In order to know whether any protein tyrosine kinase (PTK) is involved in the
      over-proliferation and erosiveness of synovial fibroblasts (SF) of rheumatoid
      arthritis (RA) patients, RT-PCR and RNA dot blotting were done to analyse PTKs
      profile in RA SF. Platelet-derived growth factor receptor A (PDGFRA), insulin
      like growth factor 1 receptor (IGF-1R), Janus kinase 1 (JAK1), TYK2, discoidin
      domain receptor 2 (DDR2), and Lyn were expressed in SF, and the expression of
      PDGFRA, IGF-1R, and DDR2 in SF of RA were higher than that of osteoarthritis (OA,
      as control). Immunoblotting and gelatinase zymography showed that DDR2 in RA SF,
      which still secreted active matrix metalloproteinase 1 (MMP-1) in vitro, were in
      active form. Stimulation of collagen II could make NIH-3T3 cells (as control)
      produce MMP-1, which could be inhibited by soluble extracellular part of DDR2.
      These results indicated that the over-expression of MMP-1 in RA SF might be
      related to the activation of DDR2, and collagen II, act as DDR2 ligand, might be
      one of the stimulators of the over-expression of MMP-1 of RA SF.

PMID- 12419288
TI  - How socioeconomic status may "get under the skin" and affect the heart.

PMID- 12419289
TI  - Is measuring endothelial function a good idea for prediction of coronary heart
      disease complications?

PMID- 12419290
TI  - A partial CURE for acute coronary syndromes--but how did it happen?

PMID- 12419291
TI  - A novel use of cardiac pacing to improve cardiac function, quality of life and
      (hopefully) survival in patients with heart failure and permanent atrial
      fibrillation.

PMID- 12419292
TI  - Surrogate markers to monitor efficacy of anticoagulants or antiplatelet drugs in
      atrial fibrillation.

PMID- 12419293
TI  - Coronary atherogenic risk factors in women.

PMID- 12419294
TI  - Biointerventional cardiovascular therapy.

PMID- 12419295
TI  - Stress responsivity and socioeconomic status: a mechanism for increased
      cardiovascular disease risk?
AB  - AIMS: Low socioeconomic status is associated with increased cardiovascular
      disease risk. We hypothesized that psychobiological pathways, specifically slow
      recovery in blood pressure and heart rate variability following mental stress,
      partly mediate social inequalities in risk. METHODS AND RESULTS: Participants
      were 123 men and 105 women in good health aged 47-58 years drawn from the
      Whitehall II cohort of British civil servants. Grade of employment was the
      indicator of socioeconomic status. Cardiovascular measures were monitored during
      performance of two behavioural tasks, and for 45 min following stress. Post
      stress return of blood pressure and heart rate variability to resting levels was
      less complete after 45 min in the medium and low than in the high grade of
      employment groups. The odds of failure to return to baseline by 45 min in the low
      relative to the high grade of employment groups were 2.60 (95% CI 1.20-5.65) and
      3.85 (1.48-10.0) for systolic and diastolic pressure, respectively, and 5.19
      (1.88-18.6) for heart rate variability, adjusted for sex, age, baseline levels
      and reactions to tasks. Subjective ratings of task difficulty, involvement and
      stress did not differ by socioeconomic status. CONCLUSIONS: Lower socioeconomic
      status is associated with delayed recovery in cardiovascular function after
      mental stress. Impaired recovery may reflect heightened allostatic load, and
      constitute a mechanism through which low socioeconomic status enhances
      cardiovascular disease risk.

PMID- 12419296
TI  - von Willebrand factor and coronary heart disease: prospective study and meta
      analysis.
AB  - AIMS: To determine whether circulating von Willebrand factor concentrations are
      prospectively related to risk of coronary heart disease in the general
      population. METHODS AND RESULTS: We measured baseline von Willebrand factor
      values in the stored serum samples of 625 men with major coronary events and in
      1266 controls 'nested' in a prospective study of 5661 men aged 40-59 years,
      recruited from general practices in 18 British towns in 1978-1980 and followed up
      for 16 years for fatal coronary heart disease and non-fatal myocardial
      infarction. We conducted a meta-analysis of previous relevant studies to place
      our results in context. Men in the top third of baseline von Willebrand factor
      values (tertile cutoff >126 IU.dl(-1)) had an odds ratio for coronary heart
      disease of 1.83 (95% confidence interval 1.43-2.35; 2P <0.0001) compared with
      those in the bottom third (tertile cutoff <90 IU.dl(-1)), after adjustments for
      age and town. The odds ratio was little changed after further adjustment for risk
      factors (1.82, 95% CI 1.37-2.41), and was not significantly different in an
      analysis restricted to the 404 cases and 1007 controls without baseline evidence
      of coronary heart disease (odds ratio 1.53, 95% CI 1.10-2.12). A meta-analysis of
      all relevant population-based prospective studies (including the present study)
      yielded a combined odds ratio of 1.5 (95% CI 1.1-2.0). von Willebrand factor
      values were strongly correlated with Helicobacter pylori seropositivity and
      circulating concentrations of C-reactive protein (2 P<0.0001 for each), but not
      with smoking, blood lipids, or most other measured risk factors. CONCLUSION:
      Though circulating von Willebrand factor concentrations may be associated with
      incident coronary heart disease, further studies are needed to determine the
      extent to which this is causal.

PMID- 12419297
TI  - Clopidogrel does not suppress blood markers of coagulation activation in aspirin
      treated patients with non-ST-elevation acute coronary syndromes.
AB  - AIMS: The Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) Study
      demonstrated that clopidogrel plus aspirin was superior to aspirin alone for
      prevention of recurrent vascular events in patients with acute coronary
      syndromes. The aim of this study was to compare the effect of these two regimens
      on biochemical markers of platelet and coagulation activation. METHODS AND
      RESULTS: We studied 485 patients with non-ST-elevation acute coronary syndrome
      who were randomized to clopidogrel (300 mg loading dose followed by 75 mg daily)
      or placebo for a period of 3-12 months. All patients also received aspirin
      (recommended dose 75-325 mg daily). Blood levels of P-selectin, prothrombin
      fragment F1.2, D-dimer, and von Willebrand factor were measured at baseline, day
      7 (or hospital discharge), and at day 30 after randomization. Patients receiving
      clopidogrel plus aspirin compared with aspirin alone had similar baseline
      geometric mean plasma levels of P-selectin (50.2 vs 51.7 ng.ml(-1), P=0.45),
      prothrombin fragment F1.2 (1.13 vs 1.12 nmol.l(-1), P=0.94), D-dimer (467 vs 460
      ng.ml(-1), P=0.85), and von Willebrand factor levels (1.89 vs 1.85 U.ml(-1),
      P=0.59) and there also were no significant differences at day 7, or day 30.
      However, compared with baseline, there was a significant rise in prothrombin
      fragment F1.2 at day 7 (from 1.12 to 1.39 nmol.l(-1), P<0.0001) and day 30 (from
      1.12 to 1.44 nmol.l(-1), P<0.0001), and D-dimer at day 7 (from 464 to 539 nmol.l(
      1), P<0.0001) and day 30 (from 464 to 576 nmol.l(-1), P<0.0001). The magnitude of
      this rise appeared to be greatest in patients who experienced the primary
      outcome, a composite of cardiovascular death, myocardial infarction, stroke, or
      refractory ischaemia by the end of the study. P-selectin levels were not elevated
      at any time point but von Willebrand factor values were elevated at baseline and
      remained elevated at days 7 and 30. CONCLUSION: Our results indicate that the
      clinical benefits of clopidogrel are not associated with a parallel reduction in
      markers of coagulation activation. Early suppression of coagulation markers most
      likely reflects the effects of heparin. The persistence of thrombin generation
      despite long-term clopidogrel and aspirin therapy suggests that even more
      intensive antithrombotic therapy may be required in these patients.

PMID- 12419298
TI  - Comparative effects of permanent biventricular and right-univentricular pacing in
      heart failure patients with chronic atrial fibrillation.
AB  - BACKGROUND: One third of chronic heart failure patients have major
      intraventricular conduction and uncoordinated ventricular contraction. Non
      controlled studies suggest that biventricular pacing may improve haemodynamics
      and well-being by reducing ventricular asynchrony. The aim of this trial was to
      assess the clinical efficacy and safety of this new therapy in patients with
      chronic atrial fibrillation. METHODS: Fifty nine NYHA class III patients with
      left ventricular systolic dysfunction, chronic atrial fibrillation, slow
      ventricular rate necessitating permanent ventricular pacing, and a wide QRS
      complex (paced width >or=200 ms), were implanted with transvenous biventricular
      VVIR pacemakers. This single-blind, randomized, controlled, crossover study
      compared the patients' parameters, as monitored during two 3-month treatment
      periods of conventional right-univentricular vs biventricular pacing. The primary
      end-point was the 6-min walked distance, secondary end-points were peak oxygen
      uptake, quality-of-life, hospitalizations, patients' preferred study period and
      mortality. RESULTS: Because of a higher than expected drop-out rate (42%), only
      37 patients completed both crossover phases. In the intention-to-treat analysis,
      we did not observe a significant difference. However, in the patients with
      effective therapy the mean walked distance increased by 9.3% with biventricular
      pacing (374+/-108 vs 342+/-103 m in univentricular;P =0.05). Peak oxygen uptake
      increased by 13% (P=0.04). Hospitalizations decreased by 70% and 85% of the
      patients preferred the biventricular pacing period (P<0.001). CONCLUSION: As
      compared with conventional VVIR pacing, effective biventricular pacing seems to
      improve exercise tolerance in NYHA class III heart failure patients with chronic
      atrial fibrillation and wide paced-QRS complexes. Further randomized controlled
      studies are required to definitively validate this therapy in such patients.

PMID- 12419299
TI  - A study of platelet activation in atrial fibrillation and the effects of
      antithrombotic therapy.
AB  - BACKGROUND: Platelet function may be abnormal in patients with atrial
      fibrillation (AF) and could be related to abnormal thrombogenesis. The aim of
      this cross-sectional study was to investigate new aspects of platelet biology in
      AF, predominantly focusing on platelet activation and the effects of concomitant
      antiplatelet and anticoagulant therapy. PATIENTS AND METHODS: The study group of
      238 patients were (i). 93 patients on no antithrombotic therapy, (ii). 60
      patients taking 75-325 mg aspirin/day, and (iii). 85 patients on dose-adjusted
      warfarin (International Normalised Ratio [INR] range 2.0-3.0). Results were
      compared with those from 50 age- and sex-matched normal subjects. Platelet
      markers (plasma beta-thromboglobulin, soluble glycoprotein V [both ELISA]),
      coagulation markers (fibrin D-dimer [ELISA] and fibrinogen [Clauss]), and
      platelet aggregation in response to standard platelet agonists were studied.
      RESULTS: beta-thromboglobulin (P=0.01), soluble glycoprotein V (P<0.001) and
      fibrin D-dimer (P=0.002) were higher in untreated AF patients compared to healthy
      controls. AF patients on warfarin had lower fibrin D-dimer (P<0.001) when
      compared to AF patients on no therapy. Plasma fibrinogen and platelet aggregation
      was no different between patients with AF and healthy controls. Aspirin use was
      associated with reduced platelet aggregation response to epinephrine (P=0.01),
      whilst patients established on warfarin had significantly lower plasma fibrin D
      dimer levels. CONCLUSION: AF patients exhibit changes in plasma markers of
      platelet function but no significant abnormalities of platelet aggregation.
      However, treatment with warfarin or aspirin failed to demonstrate any significant
      benefit on platelet activation, although warfarin use was associated with reduced
      thrombogenesis (fibrin D-dimer). We suggest that platelet activation may not play
      an important role in the pathogenesis of thromboembolism in AF.

PMID- 12419300
TI  - Surface plasmon resonance for measuring TBP-promoter interaction.
AB  - A procedure was developed for real-time measurement of the interaction between an
      archaeal TATA-binding protein (TBP) with stress-gene promoters from the archaeon
      Methanosarcina mazeii using surface plasmon resonance (SPR), the BIACORE 3000
      equipment, and the SA (streptavidin) Sensor Chip. Measurements were based on the
      SPR optical phenomenon, which resulted in light extinction when TBP bound a
      promoter. This process, detected as a change in a particular angle, was recorded
      in a sensorgram. The BIA-evaluation program allowed the calculation of the
      equilibrium constant (K(A)) of the interaction of M. mazeii TBP with the
      promoters of the stress genes grpE, hsp70(dnaK), and hsp40(dnaJ) (0.47, 0.26, and
      1.21x10(7)M(-1), respectively) and, for comparison, with the promoter of a non
      heat-shock gene, orf16 (0.08x10(7)M(-1)). The association rate (k(a)) of the non
      heat-shock gene orf16 was 0.4x10(4)M(-1)s(-1) and those for the stress genes,
      grpE, hsp70(dnaK), and hsp40(dnaJ) were higher: 2.8, 1.5, and 3.5x10(4)M(-1)s(
      1), respectively. The new procedure will allow a comparative analysis of
      different TPBs and promoters (wild type and mutants) under physiologic and stress
      conditions, and a correlation of TBP binding parameters with constitutive and
      stress-induced gene expression.

PMID- 12419301
TI  - Thermostable aldehyde dehydrogenase from psychrophile, Cytophaga sp. KUC-1:
      enzymological characteristics and functional properties.
AB  - We found the occurrence of NAD(P)(+)-dependent aldehyde dehydrogenase (EC1.2.1.5)
      in the cells of a psychrophile from Antarctic seawater, Cytophaga sp. KUC-1, and
      purified to homogeneity. About 50% of the enzyme activity remained even after
      heating at 50 degrees C for 65min and the highest activity was observed in the
      range of 55-60 degrees C. The enzyme was thermostable and thermophilic, although
      it was derived from a psychrophile. The circular dichroism at 222nm of the enzyme
      showed a peak at 32 degrees C. This temperature was closely similar to the
      transition temperature in the Arrhenius plots. The stereospecificity for the
      hydride transfer at C4-site of nicotinamide moiety of NADH was pro-R. The gene
      encoding the enzyme consisted of an open reading frame of 1506-bp encoding a
      protein of 501 amino acid residues. The significant sequence identity (61%) was
      found between the Cytophaga and the Pseudomonas aeruginosa enzymes, although
      their thermostabilities are completely different.

PMID- 12419302
TI  - Molecular cloning and expression of a functional dermonecrotic and haemolytic
      factor from Loxosceles laeta venom.
AB  - The bite of spiders of the genus Loxosceles can induce a variety of biological
      effects, including dermonecrosis and complement-dependent haemolysis. The aim of
      this study was to generate recombinant proteins from the Loxosceles spider gland
      to facilitate structural and functional studies in the mechanisms of loxoscelism.
      Using "Expressed Sequencing Tag" strategy of aleatory clones from, L. laeta venom
      gland cDNA library we have identified clones containing inserts coding for
      proteins with significant similarity with previously obtained N-terminus of
      sphingomyelinases from Loxosceles intermedia venom [1]. Clone H17 was expressed
      as a fusion protein containing a 6x His-tag at its N-terminus and yielded a 33kDa
      protein. The recombinant protein was endowed with all biological properties
      ascribed to the whole L. laeta venom and sphingomyelinases from L. intermedia,
      including dermonecrotic and complement-dependent haemolytic activities. Antiserum
      raised against the recombinant protein recognised a 32-kDa protein in crude L.
      laeta venom and was able to block the dermonecrotic reaction caused by whole L.
      laeta venom. This study demonstrates conclusively that the sphingomyelinase
      activity in the whole venom is responsible for the major pathological effects of
      Loxosceles spider envenomation.

PMID- 12419303
TI  - 4-Methylumbelliferone induces the expression of membrane type 1-matrix
      metalloproteinase in cultured human skin fibroblasts.
AB  - Human skin fibroblasts were cultured in the presence of 4-methylumbelliferone, an
      inhibitor of hyaluronan synthesis. Gelatinolytic activity excreted in the medium
      was examined by zymography and gelatinase assay using a fluorogenic substrate. 4
      Methylumbelliferone added to the medium activated the latent form of matrix
      metalloproteinase-2 in a dose- and time-dependent manner. Immunoblot analysis
      also showed the conversion of the latent form of matrix metalloproteinase-2 to
      its active form. This activation was observed even when the cells were cultured
      with both 4-methylumbelliferone and hyaluronan. Addition of Streptomyces
      hyaluronidase to the medium during cultivation did not activate the latent form
      of matrix metalloproteinase-2. Reverse transcription-polymerase chain reaction
      revealed that 4-methylumbelliferone markedly increased the level of mRNA for
      membrane type 1-matrix metalloproteinase, whereas levels of mRNA for matrix
      metalloproteinase-2 and tissue inhibitor of metalloproteinase-2 were little
      affected. These results suggest that 4-methylumbelliferone induces the expression
      of membrane type 1-matrix metalloproteinase, resulting in activation of matrix
      metalloproteinase-2, in cultured human skin fibroblasts.

PMID- 12419304
TI  - Functional studies of human skin disease- and deafness-associated connexin 30
      mutations.
AB  - Connexin 30 (Cx30) is a component of the gap junction complex. Dominant and
      recessive mutations in the GJB6 gene encoding Cx30 are associated with a variety
      of human inherited diseases primarily affecting the epidermis, hair, nail, and/or
      the inner ear. The underlying mechanism of disease associated with different GJB6
      mutations such as the disruption of gap junction mediated intercellular
      communication is unknown. Towards understanding these disease mechanisms,
      transfection studies were performed in a keratinocyte cell line and in HeLa cells
      using EGFP tagged wildtype Cx30 and mutant Cx30 constructs harbouring dominant
      disease-associated GJB6 mutations. For all three of the skin disease-associated
      Cx30 mutations investigated, impaired trafficking of the protein to the plasma
      membrane was observed thus preventing the formation of functional Cx30 gap
      junctions. In contrast, the deafness-associated mutation T5M-Cx30/EGFP trafficked
      to the membrane but defective channel activity was observed following dye
      transfer studies.

PMID- 12419305
TI  - Gene expression of the tight junction protein occludin includes differential
      splicing and alternative promoter usage.
AB  - Occludin is an integral membrane protein located at the tight junctions of
      epithelial cells. Multiple domains of occludin are involved in the regulation of
      paracellular permeability as well as in the targeting of the protein to the tight
      junction. In this study, different occludin variants were identified on the mRNA
      level. Four differentially spliced occludin-specific mRNA transcripts were
      detected. Expression of the resulting proteins revealed an altered subcellular
      distribution and a loss of co-localization with zonula occludens protein ZO-1 in
      the tight junction for two of the four splice variants. Our findings demonstrate
      that the fourth transmembrane domain of occludin is important for targeting
      occludin to the tight junction. Loss of the fourth transmembrane domain leads to
      a relocation of the C-terminal domain to the extracellular space. The structural
      diversity of natural occludin variants is further increased by an additional
      promoter and transcription start giving rise to an alternative exon 1. Gene
      expression mediated by this promoter is influenced by the pro-inflammatory
      cytokine tumor necrosis factor alpha.

PMID- 12419306
TI  - Docosahexaenoic acid suppresses the activity of peroxisome proliferator-activated
      receptors in a colon tumor cell line.
AB  - Fatty acids are generally considered as agonists for peroxisome proliferator
      activated receptors (PPARs). Fatty acids have been shown to bind to and
      transactivate PPARs; it is not known whether fatty acids act as generalized
      agonists for PPARs in different cell types, and thus, stimulate the expression of
      PPAR-regulated target genes. Here, we investigated the potency of unsaturated
      fatty acids on transactivation of PPRE, DNA-binding activity of PPARs, and the
      expression of a PPAR-regulated gene product, CD36. Docosahexaenoic acid (DHA)
      suppressed the basal and PPAR agonist-induced transactivation of PPRE, and DNA
      binding of PPARs in colon tumor cells (HCT116). The suppression of PPAR
      transactivation by DHA leads to reduced expression of CD36 in HCT116 cells and
      human monocytic cells (THP-1) as determined by promoter reporter gene assay and
      flow cytometric analysis. Our results demonstrate that DHA and other unsaturated
      fatty acids act as antagonists instead of agonists for transactivation of PPRE
      and PPAR-regulated gene expression in the cell lines tested. These results
      suggest that PPAR-mediated gene expression and cellular responses can be
      dynamically modulated by different types of dietary fatty acids consumed.

PMID- 12419307
TI  - Gene expression profile analysis of the mouse liver during bacteria-induced
      fulminant hepatitis by a cDNA microarray system.
AB  - Fulminant hepatic failure (FHF) is a disease characterized by sudden and severe
      impairment of liver function. To elucidate the mechanism involved in FHF, we
      adopted a murine model of FHF by administrating mice with heat-killed
      Propionibacterium acnes (P. acnes), followed by a low dose of lipopolysaccharide
      (LPS), and analyzed the dynamic change of gene expression profile of the murine
      liver using an in-house cDNA microarray system which contained most of the cDNAs
      encoding chemokines/cytokines and their receptors (33 chemokines/21 chemokine
      receptors, 28 cytokines/35 cytokine receptors) as well as 230 liver related
      proteins mostly selected by serial analysis of gene expression (SAGE). Among
      them, 335 genes were found to differ by more than 2-fold in at least one time
      point comparing with normal liver. Hierarchical cluster analysis revealed that
      except for a few genes, such as heme oxygenase (HO)-1 and nicotinamide N
      methyltransferase (NNMT) of which expression increased, the expression of most of
      the genes encoding drug metabolizing enzymes decreased with the progress of the
      disease. The expression of the genes encoding chemokines/cytokines was
      dramatically changed, such as Mig, IP-10, RANTES, TNF-alpha, and IFN-gamma. In
      addition, the expression of those that were not previously linked to this murine
      model was also identified to be changed. These include endogenous IL-18 binding
      protein (IL-18BP), CXCL16 (the ligand of Bonzo, CXCR6) as well as ESTs. Taken
      together this study has shown the systemic and comprehensive gene expression
      profile during FHF and may contribute to better understanding of the mechanism of
      FHF.

PMID- 12419308
TI  - Modulation of CYP3A4 expression by ceramide in human colon carcinoma HT-29 cells.
AB  - Cytochrome P450 3A4 (CYP3A4) enzyme is responsible for the metabolic activation
      and inactivation of the majority of clinically used drugs in human liver and
      intestines. Recent studies have increasingly implicated various inflammatory
      stimuli to cause changes in the activities and expression levels of CYPs.
      However, the underlying mechanisms are largely unknown. In the present study, our
      studies investigated the effects of ceramide on CYP3A4 expression in human colon
      carcinoma HT-29 cells. Treatment with the cell-permeable ceramide analog C(6)
      ceramide to the cells significantly decreased the expression of CYP3A4. By
      contrast, C(6)-dihydroceramide, a biologically inactive analog of C(6)-ceramide,
      did not affect CYP3A4 expression. We found that bacterial sphingomyelinase
      (SMase) and tumor necrosis factor-alpha (TNF), which are known to increase
      intracellular ceramide levels, also markedly suppressed the synthesis of CYP3A4.
      To elucidate whether nitric oxide (NO) participates in suppression of CYP3A4
      expression by ceramide, the effects of NO modulators were determined. Treatment
      with N(G)-monomethyl-L-arginine, a competitive inhibitor of inducible nitric
      oxide synthase (iNOS), was able to protect ceramide-dependent CYP3A4 suppression.
      In contrast, the addition of S-nitroso-N-acetylpenicillamine, a NO donor, to HT
      29 cells reduced CYP3A4 expression. The addition of iNOS antisense
      oligonucleotide prevented ceramide-mediated induction of iNOS expression and
      restored CYP3A4 expression. Wortmannin which is known to inhibit
      phosphatidylinositol 3-kinase (PI3-K) blocked CYP3A4 suppression by ceramide.
      Taken together, our results demonstrate that ceramide-mediated suppression of
      CYP3A4 is due to production of NO, which might result from activation of PI3-K.

PMID- 12419309
TI  - Cleavage of the cyclin-dependent kinase 5 activator p35 to p25 does not induce
      tau hyperphosphorylation.
AB  - Hyperphosphorylated tau protein is the primary component of neurofibrillary
      tangles observed in several neurodegenerative disorders. It has been hypothesized
      that in certain pathological conditions, the calcium activated protease, calpain,
      would cleave the cyclin-dependent kinase 5 (cdk5) activator p35 to a p25
      fragment, which would lead to augmented cdk5 activity, and cdk5-mediated tau
      hyperphosphorylation. To test this hypothesis, we induced calpain-mediated p35
      cleavage in rat hippocampal neuronal cultures and studied the relationship
      between p25 production, cdk5 activity, and tau phosphorylation. In glutamate
      treated cells p35 was cleaved to p25 and this was associated with elevated cdk5
      activity. However, tau phosphorylation was concomitantly decreased at multiple
      sites. The calpain inhibitor MDL28170 prevented the cleavage of p35 but had no
      effect on tau phosphorylation, suggesting that calpain-mediated processes, i.e.,
      the cleavage of p35 to p25 and cdk5 activation, do not contribute to tau
      phosphorylation in these conditions. Treatment of the neuronal cultures with N
      methyl-D-aspartic acid or with calcium ionophores resulted in an outcome highly
      similar to that of glutamate. We conclude that, in neuronal cells, the cleavage
      of p35 to p25 is associated with increased activity of cdk5 but not with tau
      hyperphosphorylation.

PMID- 12419310
TI  - Carnosine is a quencher of 4-hydroxy-nonenal: through what mechanism of reaction?
AB  - The aim of this study was to understand the mechanism of action through which
      carnosine (beta-alanyl-L-histidine) acts as a quencher of cytotoxic alpha,beta
      unsaturated aldehydes, using 4-hydroxy-trans-2,3-nonenal (HNE) as a model
      aldehyde. In phosphate buffer solution (pH 7.4), carnosine was 10 times more
      active as an HNE quencher than L-histidine and N-acetyl-carnosine while beta
      alanine was totally inactive; this indicates that the two constitutive amino
      acids act synergistically when incorporated as a dipeptide and that the beta
      alanyl residue catalyzes the addition reaction of the histidine moiety to HNE.
      Two reaction products of carnosine were identified, in a pH-dependent
      equilibrium: (a) the Michael adduct, stabilized as a 5-member cyclic hemi-acetal
      and (b) an imine macrocyclic derivative. The adduction chemistry of carnosine to
      HNE thus appears to start with the formation of a reversible alpha,beta
      unsaturated imine, followed by ring closure through an intra-molecular Michael
      addition. The biological role of carnosine as a quencher of alpha,beta
      unsaturated aldehydes was verified by detecting carnosine-HNE reaction adducts in
      oxidized rat skeletal muscle homogenate.

PMID- 12419311
TI  - An approach for reducing unwanted oligomerisation of DsRed fusion proteins.
AB  - Oligomerisation of the red fluorescent protein, DsRed, can interfere with the
      localisation and function of proteins to which it is fused. We demonstrate an
      approach that may help to reduce significantly the impact of oligomerisation on
      the biology of the protein fusion partner. Growth of yeast (Saccharomyces
      cerevisiae) cells expressing ATP synthase containing subunit gamma-DsRed fusion
      was compromised relative to control cells. Furthermore, ATP synthase was found to
      exist as oligomeric structures when isolated under conditions where monomers
      would normally be present. The compromised growth phenotype was partially
      reversed and the oligomerisation of the ATP synthase reduced when a non
      fluorescent variant of DsRed not fused to another protein was targeted to the
      mitochondrion in addition to the gamma-DsRed fusion protein. This strategy may
      also be applicable to the reduction of unwanted interactions between fusion
      proteins that contain the normally dimeric fluorescent proteins HcRed or Renilla
      GFP.

PMID- 12419312
TI  - Identification of membrane-type receptor for bile acids (M-BAR).
AB  - Bile acids play an essential role in the solubilization and absorption of dietary
      fat and lipid-soluble vitamins. Bile acids also modulate the transcription of
      various genes for enzymes and transport proteins for their own and cholesterol
      homeostasis through binding to nuclear receptors. Here we report a novel category
      of bile acid receptor, a membrane-type G protein-coupled receptor (GPCR), BG37.
      Bile acids induced rapid and dose-dependent elevation of intracellular cAMP
      levels in BG37-expressing cells, but not in mock-transfected cells, independently
      of nuclear receptor expression. The rank order of potency of various bile acids
      for BG37-expressing cells was different from that for the nuclear receptor
      mediated response. These observations demonstrate the presence of two independent
      signaling pathways for bile acids; membrane-type GPCR for rapid signaling and
      nuclear receptors for delayed signaling. Expression of BG37 was detected in
      various specific tissues, suggesting its physiological role, although it remains
      to be further characterized.

PMID- 12419313
TI  - The beta2-adaptin clathrin adaptor interacts with the mitotic checkpoint kinase
      BubR1.
AB  - The adaptor AP2 is a heterotetrameric complex that associates with clathrin and
      regulatory proteins to mediate rapid endocytosis from the plasma membrane. Here,
      we report the identification of the mitotic checkpoint kinase BubR1 as a novel
      binding partner of beta2-adaptin, one of the AP2 large subunits. Using two-hybrid
      experiments and in vitro binding assays, we show that beta2-adaptin binds to
      BubR1 through its amino-terminal beta2-'trunk' domain, while the beta2-binding
      region of BubR1 maps to the carboxy-terminal kinase domain. Subcellular
      immunolocalization studies suggest that the interaction between BubR1 and beta2
      adaptin could take place in the cytosol at any time during the cell cycle. In
      addition, we found that BubR1 and the BubR1-related kinase, Bub1, also bind to
      beta-adaptins of other AP complexes. Together, these results support a model in
      which the mitotic checkpoint kinases BubR1 and BuB1, by binding to beta-adaptins,
      may play novel roles in the regulation of vesicular intracellular traffic.

PMID- 12419314
TI  - Analysis of human TIE2 function on hematopoietic stem cells in umbilical cord
      blood.
AB  - To investigate the behavior of hematopoietic stem cells (HSCs) in cord blood
      (CB), we analyzed the expression and function of TIE2, a tyrosine kinase
      receptor. A subpopulation of Lineage (Lin)(-/low)CD34(+) cells in CB expressed
      TIE2 (18.8%). Assays for long-term culture-initiating cells (LTC-IC) and cobble
      stone formation revealed that Lin(-/low)CD34(+)TIE2(+) cells showed to have a
      capacity of primitive hematopoietic precursor cells in vitro. When Lin(
      /low)CD34(+)TIE2(+) cells were cultured on the stromal cells, they transmigrated
      under the stromal layers and kept an immature character for a few weeks. By
      contrast, Lin(-/low)CD34(+)TIE2(-) cells differentiated immediately within a few
      weeks. Finally, we confirmed that 1x10(4)Lin(-/low)CD34(+)TIE2(+) cells were
      engrafted in non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice,
      while 1x10(4)Lin(-/low)CD34(+)TIE2(-) cells were not. Taken together, we conclude
      that TIE2 is a marker of HSCs in CB. A ligand for TIE2, Ang-1 promoted the
      adhesion of sorted primary Lin(-/low)CD34(+)TIE2(+) cells to fibronectin (FN),
      and this adhesion may play a critical role in keeping HSCs in an immature status
      under the stromal cells.

PMID- 12419315
TI  - Subtype- and species-specific knockdown of PKC using short interfering RNA.
AB  - RNA interference (RNAi), the targeted mRNA degradation induced by double-stranded
      RNA (dsRNA), is a powerful tool for analyzing gene function in many organisms.
      Recently, it has been shown that RNAi is also applicable to cultured mammalian
      cells by using short interfering RNA (siRNA) [Nature 411 (2001) 494]. To examine
      whether this siRNA method is useful for analyzing the subtype-specific functions
      of protein kinase C (PKC), we first prepared siRNAs which target human alphaPKC
      and human deltaPKC and applied them into mammalian cells to suppress the
      expression of endogenous alphaPKC and deltaPKC, respectively. Each siRNA for
      alpha or deltaPKC specifically suppressed the endogenous expression of
      corresponding PKC subtype in human-derived cell lines such as HEK-293 and HeLa
      cells, but not in cells derived from rat species. The suppression level of
      deltaPKC reached maximum 48-72h after the transfection of siRNA. In addition, the
      siRNA targeting rat deltaPKC suppressed endogenous and exogenous rat deltaPKCs
      but not human deltaPKC, suggesting that siRNAs targeting PKCs effectively knocked
      down endogenous/exogenous PKCs in mammalian cells, in subtype- and species
      specific manner. Furthermore, we also developed the method to discriminate the
      siRNA-transfected cells using the antibody recognizing thymine dimer. Our present
      results strongly suggest that siRNA method enable us to examine the subtype
      specific function of PKC, not only by knockdown of the endogenous target PKC
      subtype, but also by subsequent compensation with the exogenous corresponding
      wild/mutant PKC derived from other species.

PMID- 12419316
TI  - Direct evidence for membrane pore formation by the apoptotic protein Bax.
AB  - Direct imaging of the interaction of the apoptotic protein, Bax, with membrane
      bilayers shows the presence of toroidal-shaped pores using atomic force
      microscopy. These pores are sufficiently large to allow passage of proteins from
      the intermitochondrial space. Both the perturbation of the membrane and the
      amount of protein bound to the bilayer are increased in the presence of calcium.
      The results from the imaging are consistent with leakage studies from liposomes
      of the same composition. The work shows that Bax by itself can form pores in
      membrane bilayers.

PMID- 12419317
TI  - High-throughput measurement of mitochondrial membrane potential in a neural cell
      line using a fluorescence plate reader.
AB  - Mutations in mitochondrial genes cause mitochondrial genetic disease, which is
      often associated with deficiency of the mitochondrial membrane potential (MMP).
      We present a high-throughput method for measuring MMP in intact neural cells
      using TMRM, a well-known potentiometric dye, in a 48-well plate format. Addition
      of known MMP depolarizing agents, FCCP or DNP, resulted in a time- and
      concentration-dependent decrease in fluorescence, which was saturable, whereas
      the addition of drugs that affect non-mitochondrial properties did not. A cell
      line deficient in mtDNA had decreased fluorescence, which was not further
      depleted by a depolarizing agent. The high-throughput results are similar to
      those produced by more time-consuming and low-throughput flow cytometry or
      microscopy methods. This plate-based system could facilitate the identification
      of cell-permeant small molecules (i.e., drugs) that modify MMP, which could be
      used to enhance mitochondrial function, and also for screening small populations
      of neural cells for mutations in nuclear or mtDNA genes that decrease MMP.

PMID- 12419318
TI  - Function of the lectin domain of polypeptide N-acetylgalactosaminyltransferase 1.
AB  - All UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferases cloned to date
      contain a lectin domain at the C-terminus, consisting of three tandem repeat
      sequences (alpha,beta, and gamma). We previously reported that the alpha repeat
      of one of the most ubiquitous isozymes, GalNAc-T1, is a functional lectin that
      recognizes O-linked GalNAc residues on the acceptor polypeptides with multiple
      acceptor sites; the domain appears not to be involved in the glycosylation of
      acceptors with a single acceptor site. In this report, we studied the function of
      the beta and gamma repeats in the GalNAc-T1 lectin domain, by site-directed
      mutagenesis and analysis of the catalytic properties of mutant enzymes. We found
      that the beta repeat recognizes GalNAc and is involved in glycosylation of
      acceptors with multiple glycosylation sites. The gamma repeat, on the other hand,
      showed no significant GalNAc-binding activity. These results indicate that the
      lectin domain of GalNAc-T1 has at least two functional repeats, allowing the
      possibility of multivalent interactions with GalNAc residues on the acceptor
      polypeptide during glycosylation.

PMID- 12419319
TI  - Shedding of the luminal domain of the neurotensin receptor-3/sortilin in the HT29
      cell line.
AB  - The neurotensin (NT) receptor-3/sortilin (NTR3) belongs to the new receptor
      family of VPS10P domain containing receptors. The NTR3 is expressed in all cancer
      cells on which NT activates cell growth and its cellular location is mainly
      intracellular within the endoplasmic reticulum and the trans-Golgi network.
      However, the NTR3 is also present at the cell surface of the HT29 cell line from
      which it is released by a mechanism activated by phorbol 12-myristate 13-acetate
      (PMA). The shedding of the NTR3 is sensitive to protein kinase C (PKC) and
      mitogen-activated protein (MAP) kinase inhibitors and to 1,10-phenanthroline and
      BB3103, suggesting the activation of zinc-metalloproteases and the ADAM10 (a
      desintegrin and metalloprotease). The shedding of the membrane NTR3 leads to a
      soluble protein able to bind exogenous NT, suggesting a role of this process in
      the biological activity of the peptide.

PMID- 12419320
TI  - Activation of p38 MAPK induces cell cycle arrest via inhibition of Raf/ERK
      pathway during muscle differentiation.
AB  - Cell cycle arrest is essential for initiation of muscle differentiation in
      myoblasts. Given the previously described essential role for p38 MAPK in
      myogenesis, we undertook the present study to investigate the role of p38 MAPK in
      the cell cycle arrest that initiates muscle differentiation. p38 MAPK activity
      increased during, and was required for, muscle differentiation. Inhibition of p38
      MAPK stimulated Raf and ERK activities, and induced cell proliferation in
      differentiation medium. The concomitant inhibition of p38 MAPK and ERK, however,
      failed to induce differentiation or proliferation. In conclusion, inhibition of
      the Raf/ERK pathway and the consequent cell cycle arrest is one of the major
      functions of p38 MAPK during muscle differentiation.

PMID- 12419321
TI  - Oligonucleotide microarray data mining: search for age-dependent gene expression.
AB  - Information on gene expression in colon tumors versus normal human colon was
      recently generated by an oligonucleotide microarray study. We used the associated
      database to search for genes that display age-dependent variations in expression.
      Statistically significant evidence was obtained that such genes are present in
      both the tumor and normal tissue databases. Besides the analysis of all genes
      included in the database, three subsets of genes were analyzed separately: genes
      controlled by p53, and genes coding for ribosomal proteins and for nuclear
      encoded mitochondrial proteins. Among the genes controlled by p53 some show an
      age-dependent change in expression in tumor tissues, in the sense compatible with
      an activation of p53 at higher age. A decreased expression of some ribosomal
      genes at advanced age was detected both in tumor and normal tissues. No
      significant age-dependent expression could be detected for genes encoding
      mitochondrial proteins.

PMID- 12419322
TI  - Enhanced secretion of glucagon-like peptide 1 by biguanide compounds.
AB  - Metformin was reported to increase plasma active glucagon-like peptide-1 (GLP-1)
      in humans. There are two possible mechanisms for this effect: (1) metformin
      inhibits dipeptidyl peptidase IV (DPPIV), an enzyme degrading GLP-1, and (2)
      metformin enhances GLP-1 secretion. To elucidate the mechanism(s), we examined
      (1) IC(50) of metformin for DPPIV inhibition, (2) plasma active GLP-1 changes
      after oral biguanide (metformin, phenformin, and buformin) treatment in fasting
      DPPIV-deficient F344/DuCrj rats, and (3) plasma intact GLP-1 excursions after
      oral administration of metformin and/or valine-pyrrolidide, a DPPIV inhibitor, in
      fasting DPPIV-positive F344/Jcl rats. Our in vitro assay showed that metformin at
      up to 30mM has no inhibitory activity towards porcine or rat DPPIV. Metformin
      treatment (30, 100, and 300mg/kg) increased plasma active GLP-1 levels dose
      dependently in DPPIV-deficient F344/DuCrj rats (approximately 1.6-fold at 3 and
      5h after administration of 300mg/kg). This treatment had no effect on blood
      glucose levels. Similarly, phenformin and buformin (30 and 100mg/kg) elevated
      plasma intact GLP-1 levels in F344/DuCrj rats. In DPPIV-positive F344/Jcl rats,
      coadministration of metformin (300mg/kg) and valine-pyrrolidide (30mg/kg)
      resulted in elevation of plasma active GLP-1, but neither metformin nor valine
      pyrrolidide treatment alone had any effect. These findings suggest that metformin
      has no direct inhibitory effect on DPPIV activity and that metformin and the
      other biguanides enhance GLP-1 secretion, without altering glucose metabolism.
      Combination therapy with metformin and a DPPIV inhibitor should be useful for the
      treatment of diabetes.

PMID- 12419323
TI  - A transient surge of ghrelin secretion before feeding is modified by different
      feeding regimens in sheep.
AB  - Ghrelin is a recently identified orexigenic hormone secreted by the stomach and
      has been implicated in meal-time hunger. Several experiments demonstrate a
      transient surge in ghrelin secretion shortly before a scheduled meal, suggesting
      from the involvement of cephalic mechanisms. If ghrelin secretion is stimulated
      by hunger in sheep, plasma levels of ghrelin should be modified by different
      feeding regimens that affect hunger drive. To test this hypothesis, we
      investigated changes in plasma ghrelin concentrations in fed Suffolk rams ad
      libitum and in rams either twice or four times daily. Plasma ghrelin levels
      increased (P<0.05) abruptly just before every feeding period in sheep fed twice
      and four times daily and then fell shortly after feeding. Peak levels of the pre
      prandial ghrelin surge were higher (P<0.01) in animals fed twice daily than in
      animals fed four times daily, leading to greater (P<0.05) areas under response
      curves over 12h. In contrast, the plasma ghrelin levels remained relatively low
      and constant in sheep fed ad libitum, with no evidence of surges in plasma
      ghrelin levels. These results confirm that the transient surge in plasma ghrelin
      levels occurs just before feeding and demonstrate that this can be modified by
      the feeding regimen in sheep.

PMID- 12419324
TI  - Molecular cloning of a splicing variant of human RECQL helicase.
AB  - A cDNA was isolated from the human heart library. This cDNA variant was produced
      by the deletion of 176 bases at the 5(') end of human RecQL gene, presumably by
      an alternative mRNA splicing. The cDNA contains two open reading frames and so
      may encode two isoforms of human RECQL. The first isoform is a 105 amino acid
      protein with the first 53 N-terminal amino acids identical to the known sequence
      of RECQL protein and followed by 52 amino acids introduced by in-frame premature
      stop codon. The second isoform is a 537 amino acid protein that has the same
      sequence as the published human RECQL helicase, except the first 112 amino acids
      at the N-terminal end were absent. The possible roles of both of these proteins
      are discussed.

PMID- 12419325
TI  - Expression of V-1, a novel catecholamine biosynthesis regulatory protein, is
      enhanced by hypertension in atrial myocytes of Dahl salt-sensitive rats.
AB  - V-1 positively controls catecholamine synthetic gene transcription to promote
      catecholamine production in PC12D cells. In this study, immunohistochemical
      analysis revealed that in Wistar rats, V-1 immunoreactivity was localized not
      only in sympathetic axons but also in the cytoplasm of cardiomyocytes, and that
      the immunoreactivity in atrial myocytes was more intense than that in ventricular
      myocytes. Western blot analysis also showed that V-1 expression level in the
      atrium was higher than that in the ventricle of Wistar rat hearts. When Dahl salt
      sensitive (DS) rats were fed an 8% NaCl diet after the age of 6 weeks, blood
      pressure was raised 230mm Hg at 18 weeks. V-1 expression was shown to be
      increased in the atrial myocytes of these DS rats, but not in the sympathetic
      axons, when assayed by immunohistochemistry. These results suggest that in
      normotensive rats, V-1 is preferentially expressed in the cytoplasm of
      cardiomyocytes in the atrium rather than in the ventricle. It is also suggested
      that V-1 expression is increased by hypertension in DS rat atrium.

PMID- 12419326
TI  - Different isoforms of the soluble leptin receptor in non-pregnant and pregnant
      mice.
AB  - Leptin circulates in murine serum in a free and a bound form. As shown in humans,
      a soluble leptin receptor (sOB-R), which modulates the effects of its ligand,
      circulates in murine blood. The aim of our study was to determine abundance and
      biochemical nature of this protein. For the quantification of sOB-R we developed
      a ligand-immunofunctional assay (LIFA) which is based on both, leptin binding and
      immunological recognition. The use of this LIFA revealed that during late
      gestation sera of pregnant mice had a approximately 290-fold higher level of sOB
      R than non-pregnant animals. As investigated by size exclusion chromatography
      these mice sera demonstrated a co-elution of their leptin binding activity with
      leptin immunoreactivity and levels of sOB-R measured by LIFA. Therefore, it has
      to be concluded that sOB-R represents the major leptin binding activity in murine
      circulation. The molecular analysis of sOB-R by Western blot and by cross-linking
      with 125I-leptin in sera of pregnant and non-pregnant mice demonstrated two
      different isoforms of sOB-R, which were capable of leptin binding. The sOB-R in
      serum migrated at a molecular weight of 150kDa in pregnant and only of 120kDa in
      non-pregnant animals. Deglycosylation of these isoforms led to sOB-R molecules
      which were found at the same molecular weight in SDS-PAGE. This finding indicates
      that both isoforms differ only in the degree of their glycosylation. In
      conclusion, the non-pregnant and the pregnant states are accompanied by
      differently glycosylated isoforms of sOB-R whose physiological relevance remains
      to be determined.

PMID- 12419327
TI  - Recombinant adenovirus encoding H-ras ribozyme induces apoptosis in laryngeal
      cancer cells through caspase- and mitochondria-dependent pathways.
AB  - Previously, we designed a ribozyme that targets the H-ras oncogene at the 12th
      codon mutation site (Chang et al., 1997). Ribozymes have antisense molecule and
      site-specific ribonuclease potential. In this study, an adenoviral vector was
      used to transduce the H-ras ribozyme into laryngeal cancer cells (HEp-2). This
      served to downregulate the H-ras gene expression in which this ribozyme performed
      antisense activity due to HEp-2 cells containing wild-type alleles in the 12th H
      ras codon. Together, our data demonstrated that the recombinant adenovirus
      encoding H-ras ribozyme can be broadly regarded as a cytotoxic gene therapy in
      laryngeal cancer cells regardless of containing wild-type or mutant ras gene. In
      addition, the mechanism through which the H-ras ribozyme inhibited tumor growth
      was apoptosis and involved both caspase- and mitochondria-mediated pathways. The
      activators caspase-8 and -9 as well as the effector caspase-3 in the induction
      phase of apoptosis and the substrate PARP of caspase-3 in the execution phase
      were activated 48h following the H-ras ribozyme treatment. Mitochondrial events
      characterized by the production of superoxide anion and the release of cytochrome
      c started at 24h. Mitochondrial transmembrane potential loss occurred 48h after
      the ribozyme treatment. However, Bcl-2 delayed cytochrome c release to the
      cytosol, but it could not protect the apoptosis effect, suggesting that
      cytochrome c release from mitochondria may not play a role in H-ras ribozyme
      induced apoptosis.

PMID- 12419328
TI  - Transcriptional regulation of Xbr-1a/Xvent-2 homeobox gene: analysis of its
      promoter region.
AB  - Xvent homeobox proteins are induced by BMP-4 signaling and have been known to
      mediate many BMP-4 activities as key downstream transcriptional factors. In order
      to investigate the regulatory mode of Xvent transcription, we isolated genomic
      DNA of the Xbr-1a/Xvent-2 containing the promoter region responsive to BMP-4
      signaling. The cis-acting elements located within the Xbr-1a/Xvent-2 promoter and
      the regulation modes by BMP-4 signaling were analyzed by serial deletion and site
      directed mutagenesis experiments. The upstream -235bp of the promoter retained
      the full transcriptional activity and BMP-4-response when compared with the
      longest promoter construct. Further analysis indicated that two separated 15bp
      regions contained a strong positive element and BMP-4-response element. Site
      directed mutagenesis of those regions suggests that those two regions cooperate
      for the promoter activity and BMP-4-response. Moreover, we found that the
      transcription factors, Oaz and PEBP2alphaA, were able to elicit additive effects
      with BMP-4 signaling on Xbr-1a/Xvent-2 reporter activities. These results
      indicate that transcriptional regulation of the Xbr-1a/Xvent-2 gene occurs in a
      complex mode through the cooperation of various transcription factors.

PMID- 12419329
TI  - Efficient adenylyl cyclase activation by a beta2-adrenoceptor-G(i)alpha2 fusion
      protein.
AB  - The G-protein G(i)alpha can activate adenylyl cyclase (AC), but the relevance of
      this AC activation is unknown. We used receptor-G protein co-expression and
      receptor-G protein fusion proteins to investigate G(i)alpha(2) regulation of AC
      in Sf9 cells. G(i)alpha(2) was fused to the beta(2)-adrenoceptor (beta(2)AR), a
      preferentially G(s)-coupled receptor, or the formyl peptide receptor (FPR), a
      G(i)-coupled receptor. The FPR co-expressed with, or fused to, G(i)alpha(2),
      reduced AC activity. In contrast, the beta(2)AR fused to G(i)alpha(2) was a
      highly efficient AC activator, while the beta(2)AR co-expressed with G(i)alpha(2)
      was not. Agonist efficiently stimulated incorporation of [alpha-32P]GTP
      azidoanilide into beta(2)AR-G(i)alpha(2). We explain AC activation by beta(2)AR
      G(i)alpha(2) by a model in which there is interaction of the beta(2)AR and AC,
      preventing tethered G(i)alpha(2) from interacting with the inhibitory G(i)alpha
      site of AC. The postulated beta(2)AR/AC interaction brings G(i)alpha(2) into
      close proximity of the G(s)alpha site of AC, enabling G(i)alpha(2) to activate
      AC.

PMID- 12419330
TI  - Modified carbon paste electrodes for flow injection amperometric determination of
      isocitrate dehydrogenase activity in serum.
AB  - A carbon paste electrode modified with the adsorbed products of the
      electrochemical oxidation of adenosine triphosphate is described. The electrode
      was applied to the amperometric electrocatalytic detection of the reduced form of
      both nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide
      phosphate. The catalytic oxidation current shows a linear dependence on the
      concentration of the reduced form of nicotinamide adenine dinucleotide up to
      1x10(-4)M, with a detection limit of 5x10(-9)M. Modified carbon paste electrodes
      were coated with an electrogenerated film of nonconducting poly(o
      phenylenediamine) to obtain a stable amperometric response for at least 150h. In
      addition to static measurements, determination of both reduced cofactors was
      carried out in a flow injection analysis system with a thin-layer amperometric
      detection cell. The electrocatalytic monitoring of reduced nicotinamide adenine
      dinucleotide phosphate was applied to flow injection measurement of isocitrate
      dehydrogenase activity in serum. The results were in good agreement with those
      for the standard spectrophotometric test kit. The proposed method consumed less
      time and reagents and provided better precision than the standard method.

PMID- 12419331
TI  - Direct determination of tryptophan using high-performance anion-exchange
      chromatography with integrated pulsed amperometric detection.
AB  - Here we present a new method to rapidly quantify tryptophan (Trp) in proteins,
      animal feed (Mehaden fishmeal), cell cultures, and fermentation broths. Trp is
      separated from common amino acids by anion-exchange chromatography in 12min and
      directly detected by integrated pulsed amperometry. The estimated lower detection
      limit for this method is 1pmol. Alkaline (4M NaOH) hydrolysates can be directly
      injected, and therefore we used this method to determine the optimum alkaline
      hydrolysis conditions for the release of Trp from a model protein, bovine serum
      albumin (BSA). This method accurately determined the Trp content of BSA and
      fishmeal. High levels of glucose (2%, w/w) do not interfere with the
      chromatography or decrease recovery of Trp. We used this method to monitor free
      Trp during an Escherichia coli fermentation.

PMID- 12419332
TI  - Quantitation of repetitive epitopes in glycosaminoglycans immobilized on
      hydrophobic membranes treated with cationic detergents.
AB  - Glycosaminoglycans (GAGs) are linear carbohydrate polymers containing repetitive
      sequences of differently sulfated uronic acid and glycosamine residues that are
      recognized by antibodies raised against proteoglycans. We have developed a method
      to demonstrate such repetitive sequence motifs in isolated GAG chains immobilized
      on hydrophobic membranes derivatized with cationic detergents. Six monoclonal
      antibodies directed against Cs (2B6, 3B3, Cs56, and 1B5), Hs (HepSS), and Ks
      (5D4) were used to detect native and chondroitinase-generated epitopes in the
      immobilized GAGs. All antibodies, except 1B5, were able to detect epitopes in
      both proteoglycans and isolated GAGs. Type of detergent and buffer composition
      affected the accessibility and the retention of immobilized GAGs. The epitope
      density, i.e., the number of repetitive epitopes per GAG mass, was estimated as
      the ratio between antibody (epitope) and Alcian blue (mass) staining measured
      simultaneously. The epitope profiles, using six antibodies, were different for
      each sample (CsA, CsC, Ds, Hs, intact cartilage, and human serum). The epitope
      profile may be used as a structural characteristic of a GAG population.
      Electrophoretic separation of GAGs based on their glucuronic/ioduronic acid
      content and O-sulfate/N-sulfate ratio was performed using a diethylene glycol
      diaminobutanol agarose gel. The electrophoretic populations were characterized by
      immunoblotting to detergent-treated membranes.

PMID- 12419333
TI  - An evaluation of fluorescence polarization and lifetime discriminated
      polarization for high throughput screening of serine/threonine kinases.
AB  - We used two kinases, c-jun N terminal kinase (JNK-1) and protein kinase C (PKC),
      as model enzymes to evaluate the potential of fluorescence polarization (FP) for
      high-throughput screening and the susceptibility of these assays to compound
      interference. For JNK-1 the enzyme kinetics in the FP assay were consistent with
      those found in a [gamma-33P]ATP filter wash assay. Determined pIC(50)s for
      nonfluorescent JNK-1 inhibitors were also consistent with those found in the
      filter wash assay. In contrast, fluorescent compounds were found to interfere
      with the JNK-1 FP assay, appearing as false positives, defined by their lack of
      activity in the filter wash assay. We also developed a second assay using a
      different kinase, protein kinase C, which was used to test a 5000 compound
      diversity set. As for JNK-1, interference from fluorescent compounds caused a
      high false positive rate. The Molecular Devices Corporation 'FLARe' instrument is
      capable of discriminating between fluorophores on the basis of their fluorescence
      (excited state) lifetime, and may assist in reducing compound interference in
      fluorescent assays. In both model FP kinase assays described here some, although
      not complete, reduction in interference from fluorescent compounds was achieved
      by the use of FLARe.

PMID- 12419334
TI  - A technique for isolation of rubella virus-like particles by sucrose gradient
      ultracentrifugation using Coomassie brilliant blue G crystals.
AB  - An improved method for the isolation of rubella virus-like particles (RVLP) from
      cell culture supernatant of transfected Chinese hamster ovary (CHO24S) cells is
      described. It employs a combination of membrane filtration with sucrose gradient
      ultracentrifugation. It was found that staining the RVLP band with Coomassie
      brilliant blue G (CBB) resulted in the CBB crystals adsorbing RVLP. After
      ultracentrifugation (25,000 rpm, 3h, 4 degrees C) a sharp blue band with crystals
      (diameter 30-40 microm) was observed (at a density of 1.250 g/ml at 25 degrees C)
      in a 30-60% sucrose gradient. Using a combination of SDS-PAGE and Western
      blotting techniques, E1 rubella virus structural protein was detected only in the
      solutions derived from the sharp blue band. A decrease in crystal concentration a
      few millimeters above or below the main band was associated with a decrease in
      protein concentration. By dilution with a saturated ice-cold 30% sucrose solution
      it was possible to pellet the crystals by centrifugation (15,000 rpm, 10 min).
      SDS-PAGE showed a much higher concentration of RVLP structural protein in the
      pellet than in the supernatant. This RVLP-containing material is especially
      suitable for the preparation of rubella virus immunoblot stripes.

PMID- 12419335
TI  - Analysis of peptide affinity to major histocompatibility complex proteins for the
      two-step binding mechanism.
AB  - A novel approach to the analysis of an equilibrium two-step peptide-protein
      binding is developed and applied to the experimental data. The first step of the
      process is the release of an endogenous peptide from a binding groove and the
      second is the binding of an added peptide. The method developed enables us to
      determine consequently the maximum protein occupancy level (protein-binding
      capacity), the dissociation constant of an endogenous peptide, and the
      dissociation constant of a binding (antigenic) peptide. It is shown and confirmed
      by experimental data that the value of an equilibrium dissociation constant of a
      binding peptide could be much less than the experimental value of ED(50)
      (concentration of added peptide required to bind half of the protein), but not
      equal to that commonly assumed for major histocompatibility complex (MHC)-peptide
      binding. The model considered gives a clear understanding of why some peptides
      may be good binders to MHC protein in vitro, but do not exhibit anticipated
      activity on the cellular level and vice versa.

PMID- 12419336
TI  - Homogeneous time-resolved fluorescence assay for identifying p53 interactions
      with its protein partners, directly in a cellular extract.
AB  - The p53 protein is a tumor suppressor that protects the organism against
      malignant consequences of DNA damage. Interaction of p53 with numerous cellular
      or viral proteins regulates its functional activity either positively or
      negatively. An approach leading to identification of such protein interactions
      directly in a cell extract could be of help in the development of screening
      assays to search for drugs acting on p53 in its cellular environment, either by
      disrupting its association with inhibitory proteins or by increasing its affinity
      for activating proteins. We show that the homogeneous time-resolved fluorescence
      (HTRF) assay based on the time-resolved amplified cryptate emission (TRACE)
      technology allows identification of such an interaction by simply adding a
      mixture of two labeled monoclonal antibodies, directly in a cellular extract. We
      validate this assay by studying p53/SV40-LTAg interactions. The antibodies
      directed against genuine p53 and SV40-LTAg epitopes were labeled with europium
      cryptate (donor) and XL665, a crosslinked allophycocyanin (acceptor),
      respectively. We demonstrated that a nonradiative energy transfer occurs between
      labeled antibodies only when p53 interacts with SV40-LTag, which opens up the
      possibility of extending this approach to other p53 partners to search for drugs
      that restore p53 tumor-suppressor activity.

PMID- 12419337
TI  - Measurement of high-molecular-weight hyaluronan in solid tissue using agarose gel
      electrophoresis.
AB  - The size of hyaluronan in solid tissue was measured using a combination of
      agarose gel electrophoresis and a radiometric assay. Radiolabeled hyaluronan
      binding proteins, used in the radiometric assay, were also used to detect
      hyaluronan after transfer to a nylon membrane following gel electrophoresis. Lane
      intensity on the autoradiograph was linearly related to the amount applied to the
      gel between 10 and 100ng. The intensity was independent of the hyaluronan
      molecular weight for standards with molecular weights equal to or greater than
      790,000. The radiometric assay was used to measure hyaluronan irrespective of
      size, while gel electrophoresis was used to measure hyaluronan with molecular
      weights greater than 0.79x10(6) or 4x10(6). Deferoxamine was used to inhibit
      depolymerization during the digestion of tissue samples with protease. The
      molecular weight pattern was similar for skin, skeletal muscle, heart, lung,
      small intestine, and large intestine despite large differences in hyaluronan
      content. For all tissues, 58% of the hyaluronan had a molecular weight greater
      than 4million. All tissues showed an absence of hyaluronan with a molecular
      weight below 790,000. The procedure can be used to study changes in hyaluronan
      size in tissue during inflammation and other pathological states.

PMID- 12419338
TI  - A device for the high-pressure oxygenation of protein crystals.
AB  - A system has been developed for subjecting protein crystals to hyperbaric
      pressures of oxygen gas in order to promote enzymatic reaction. Crystals of an
      oxygenase or oxidase enzyme are grown anaerobically by hanging drop vapor
      diffusion, under crystallization conditions modified to eliminate combustible
      materials such as plastic coverslips and grease. The crystalline enzyme:substrate
      complex can then be exposed to oxygen gas at pressures up to 60 bar using a
      custom-built device or "bomb." In this way, reaction is initiated synchronously
      throughout the crystal and subsequent flash freezing allows the trapping of
      enzyme:product complexes in high occupancy. These complexes can then be
      structurally characterized by conventional monochromatic X-ray crystallography.
      The bomb is furnished from naval brass and lubricated with Fomblin RT15
      perfluorinated polyether grease in order to ensure compatibility with the highly
      oxidizing environment.

PMID- 12419339
TI  - Generation of anticalins with specificity for a nonsymmetric phthalic acid ester.
AB  - A set of engineered lipocalins, so-called anticalins, that bind benzyl butyl
      phthalate, a potential pollutant of environmental and food samples or medical
      plastic ware, has been generated. To this end, the synthesis of a derivative of
      the target analyte carrying an activatable carboxylate group at the end of an
      aliphatic spacer arm was established. This compound was covalently coupled to
      amino-functionalized paramagnetic beads. Using phage display technology three
      variants were selected from a random library of the bilin-binding protein (BBP),
      a prototypic lipocalin, which exhibit binding activity toward the nonsymmetric
      phthalic acid ester. These anticalins (denominated PhtA, PhtB, and PhtC) possess
      dissociation constants of 9.1, 6.2, and 11.6 microM, respectively. Specificity
      for the binding of other phthalic acid esters was studied. No cross-reactivity
      was found for diethyl phthalate, while binding to dibutyl phthalate was observed
      with higher dissociation constants. Interestingly, two differing types of binding
      behavior were observed among the three selected anticalins. Sequence comparison
      of these engineered lipocalins with the wild-type BBP revealed that all of the 16
      randomized positions carried an amino acid exchange and that a certain sequence
      pattern had been selected, thus pointing toward a peculiar mode of structural
      interaction. Our data suggest that the generation of anticalins may provide an
      alternative to antibodies for the creation of stable receptor proteins against
      haptens with bioanalytical relevance.

PMID- 12419340
TI  - On-line drug-metabolism system using microsomes encapsulated in a capillary by
      the sol-gel method and integrated into capillary electrophoresis.
AB  - A novel microsome-encapsulation technique using the sol-gel method was developed
      for the on-line drug-metabolism analytical system integrated into capillary
      electrophoresis. This analytical system allows both the metabolism of drugs and
      the determination of the metabolites in a single capillary simultaneously.
      Microsomes isolated from rat liver were encapsulated in tetramethoxysilane-based
      silica matrices within a capillary in a single step under mild conditions. The
      availability of this system was evaluated using UDP-glucuronyltransferase, which
      is one of the most important microsomal enzymes. 4-Nitrophenol and testosterone,
      which were metabolized by the different isoforms of UDP-glucuronyltransferase,
      were used as substrates. The resultant monolithic reactor showed enzymatic
      activity at the same level as that of the soluble form. The following separation
      of the unreacted substrates and metabolites in the same capillary also showed
      high selectivity. Furthermore, the sample amount required for one analysis
      decreased more than 3 orders of magnitude from conventional reaction schemes in
      free solution. This on-line system could largely simplify the laborious
      procedures which were needed in conventional analytical schemes.

PMID- 12419341
TI  - Importance of product inhibition in the kinetics of the acylase hydrolysis
      reaction by differential stopped flow microcalorimetry.
AB  - The hydrolysis of N-acetyl-L-methionine, N-acetylglycine, N-acetyl-L
      phenylalanine, and N-acetyl-L-alanine at 298.35K by porcine kidney acylase I (EC
      3.5.1.14) was monitored by the heat released upon mixing of the substrate and
      enzyme in a differential stopped flow microcalorimeter. Values for the Michaelis
      constant (K(m)) and the catalytic constant (k(cat)) were determined from the
      progress of the reaction curve employing the integrated form of the Michaelis
      Menten equation for each reaction mixture. When neglecting acetate product
      inhibition of the acylase, values for k(cat) were up to a factor of 2.3 larger
      than those values determined from reciprocal initial velocity-initial substrate
      concentration plots for at least four different reaction mixtures. In addition,
      values for K(m) were observed to increase linearly with an increase in the
      initial substrate concentration. When an acetate product inhibition constant of
      600+/-31M(-1), determined by isothermal titration calorimetry, was used in the
      progress curve analysis, values for K(m) and k(cat) were in closer agreement with
      their values determined from the reciprocal initial velocity versus initial
      substrate concentration plots. The reaction enthalpies, Delta(r)H(cal), which
      were determined from the integrated heat pulse per amount of substrate in the
      reaction mixture, ranged from -4.69+/-0.09kJmol(-1) for N-acetyl-L-phenylalanine
      to -1.87+/-0.23kJmol(-1) for N-acetyl-L-methionine.

PMID- 12419342
TI  - A nonradioactive method for the assay of polyphosphate kinase activity and its
      application in the study of polyphosphate metabolism in Burkholderia cepacia.
AB  - Studies of polyphosphate (polyP) metabolism in microorganisms have been hampered
      by the lack of a convenient method for the assay in cell extracts of the activity
      of polyphosphate kinase (PPK), the enzyme principally responsible for microbial
      polyP biosynthesis. We report the development of such an assay, based on the well
      established metachromatic reaction, with toluidine blue, of the polyP formed
      during the PPK-catalyzed reaction. The method was successfully used in the
      characterization of PPK activity in crude extracts of an environmental
      Burkholderia cepacia isolate. The development of a protocol for the physical
      recovery of polyP from solution is also reported.

PMID- 12419343
TI  - Quantification of histamine in blood plasma and cell culture supernatants: a
      validated one-step gas chromatography-mass spectrometry method.
AB  - A novel one-step ethylchloroformate (ECF) derivatization of histamine in
      biological liquid matrices that allows the sensitive quantification by gas
      chromatography and mass spectroscopic detection (GC-MS) from small volumes of
      blood plasma or cell culture supernatants within 15 min is described. After
      addition of ECF/chloroform directly to the crude sample, histamine has been found
      to be quantitatively derivatized within seconds. Following centrifugation, the
      organic phase is transferred to a fresh vial, dried by addition of anhydrous
      sodium sulfate, and subjected to GC-MS analysis. The reliability of the results
      is verified by use of two different ion pairs for detection. The method is
      validated according to DIN 38402. Linearity is given from 0.0054 to 13 microg/ml
      and the limit of detection is 2 ng/ml (10 pg absolute, at a signal to noise ratio
      of 3:1). The limit of quantification, as calculated at a confidence level of 95%,
      is 15.6 ng/ml. Practical application is exemplified by the determination of the
      histamine content in blood plasma of birch pollen-sensitized mice and in the
      culture supernatant of rat basophil leukemia cells after Ca(2+) ionophore
      mediated degranulation.

PMID- 12419344
TI  - Gas chromatographic-mass spectrometric method for the determination of
      alkylresorcinols in human plasma.
AB  - Alkylresorcinols can be found in high amounts in whole grain cereals, especially
      in rye. Previously it has not been possible to measure alkylresorcinols in
      plasma. In this paper a validated gas chromatographic-mass spectrometric method
      for the quantitative determination of alkylresorcinols with chain lengths of
      C15:0, C17:0, C19:0, C21:0, and C23:0 in human plasma samples is presented. Other
      alkylresorcinols may be measured with the method as well, but their assay was not
      validated in this work. In this work also the amount of alkylresorcinol C25:0 was
      measured. The pretreatment of plasma samples consists of a simple incubation, an
      extraction with diethyl ether and a chromatographic purification before the GC-MS
      analysis. As internal standard an alkylresorcinol C20:0 was used. The validation
      of the method showed that it fulfilled the reliability criteria. Calibration
      graphs were linear over the range of 4.1-660pg per injection. The mean recovery
      percentage was 112+/-10.8%. Our results show that the alkylresorcinols are found
      in plasma in the same ratio, as found in rye grains, according to literature. The
      alkylresorcinols were in the unconjugated form. The total amounts of
      alkylresorcinols in two plasma samples analyzed here were 333 and 381nmol/L.

PMID- 12419345
TI  - A radiometric assay for aspartoacylase activity in cultured oligodendrocytes.
AB  - Recent studies have shown that aspartoacylase (ASPA), the defective enzyme in
      Canavan disease, is detectable in the brain only in the oligodendrocytes.
      Studying the regulation of ASPA is central to the understanding the pathogenesis
      of Canavan disease and to the development of therapeutic strategies. Toward this
      goal, we have developed a sensitive method for the assay of ASPA in cultured
      oligodendrocytes. The method involves: (a) chemical synthesis of [14C]N
      acetylaspartate (NAA) from L-[14C]Asp; (b) use of [14C]NAA as substrate in the
      assay; and (c) separation and quantitation of the product L-[14C]Asp using a TLC
      system. This method can detect as low as 10pmol of product and has been optimized
      for cultured oligodendrocytes. Thus, this method promises to be a valuable tool
      for understanding the biochemical mechanisms involved in the cell-specific
      expression and regulation of ASPA in oligodendrocytes.

PMID- 12419346
TI  - High-performance liquid chromatography determination of pipecolic acid after
      precolumn ninhydrin derivatization using domestic microwave.
AB  - A novel procedure to specifically quantify low amounts of pipecolic acid and
      structurally related compounds in several types of biological materials has been
      characterized. From crude extracts of various types of biological material, the
      first step was to clear all low-molecular-weight compounds containing primary
      amino groups by a treatment of nitrous acid. Using a microwave-assisted reaction,
      the remaining substances containing secondary amino groups were then derivatized
      with ninhydrin and made soluble in glacial acetic acid. The derivatives produced
      were resolved by reverse-phase HPLC and detected by spectrophotometry at 570nm.
      This procedure allowed more rapid determination of pipecolic acid since microwave
      heating shortened the time needed for derivatization compared with heating at 95
      degrees C in a water bath. The complete analysis of the chromogens for pipecolic
      acid and related substances was achieved in 20min. Under such conditions, the
      detection threshold for pipecolic acid was about 20pmol. The suitability of the
      technique was assessed in various biological matrices known to contain
      significant amounts of this amino acid. The data obtained are in accordance with
      those available in the literature. To our knowledge, this is the first method
      using the ninhydrin reaction in a precolumn, microwave-assisted derivatization
      procedure for detection and determination of heterocyclic alpha-amino acids.

PMID- 12419347
TI  - Two-dimensional separation of the membrane protein sarcoplasmic reticulum Ca
      ATPase for high-performance liquid chromatography-tandem mass spectrometry
      analysis of posttranslational protein modifications.
AB  - For the characterization of posttranslational modifications of the
      sarcoplasmic/endoplasmic reticulum Ca-ATPase (SERCA), we developed a two
      dimensional separation protocol based on reversed-phase HPLC followed by SDS-PAGE
      and LC-MS/MS analysis of in-gel tryptic digests. Representative experiments are
      shown for the rabbit fast-twitch skeletal muscle isoform SERCA1. Matrix-assisted
      laser desorption-ionization and electrospray ionization-mass spectrometry
      analyses of SERCA1 tryptic digests revealed ca. 66% coverage of the protein
      sequence. This approach was used for the detection and quantitation of
      nitrotyrosine formation after exposure of SERCA1 to peroxynitrite in vitro. At
      molar ratios of nitrotyrosine to protein of 0.23 we confirmed by LC-MS/MS the
      nitration of predominantly Tyr(122) in the SERCA1 sequence.

PMID- 12419348
TI  - Analysis method for lipoproteins by high-performance liquid chromatography with
      sulfopropyl-ligand column and magnesium ion-containing eluents.
AB  - We have developed a new analysis method for lipoproteins in serum by high
      performance liquid chromatography using a sulfopropyl-ligand column with eluents
      containing magnesium nitrate. The magnesium ion anchors lipoproteins to the
      ligands on the column gel. Lipoproteins are eluted from the column with a
      magnesium nitrate concentration gradient and detected by postcolumn reaction
      using a reagent containing cholesterol esterase and cholesterol oxidase. High
      density lipoprotein, low-density lipoprotein, and very-low-density lipoprotein
      were eluted in order from the column. The within-assay and between-assay
      coefficients of variation for cholesterol concentration in lipoproteins were 1.1
      3.7 and 1.3-5.8%, respectively. The correlation coefficients between the values
      of total cholesterol, high-density lipoprotein cholesterol, and low-density
      lipoprotein cholesterol obtained by the new method and those obtained by an
      enzymatic method using an automated chemical analyzer were 0.940, 0.979, and
      0.909, respectively. The new method was successfully applied to the analysis of
      plasma lipoproteins of patients with hyperlipidemia.

PMID- 12419349
TI  - Easily reversible desthiobiotin binding to streptavidin, avidin, and other biotin
      binding proteins: uses for protein labeling, detection, and isolation.
AB  - The high-affinity binding of biotin to avidin, streptavidin, and related proteins
      has been exploited for decades. However, a disadvantage of the biotin/biotin
      binding protein interaction is that it is essentially irreversible under
      physiological conditions. Desthiobiotin is a biotin analogue that binds less
      tightly to biotin-binding proteins and is easily displaced by biotin. We
      synthesized an amine-reactive desthiobiotin derivative for labeling proteins and
      a desthiobiotin-agarose affinity matrix. Conjugates labeled with desthiobiotin
      are equivalent to their biotinylated counterparts in cell-staining and antigen
      labeling applications. They also bind to streptavidin and other biotin-binding
      protein-based affinity columns and are recognized by anti-biotin antibodies.
      Fluorescent streptavidin conjugates saturated with desthiobiotin, but not biotin,
      bind to a cell-bound biotinylated target without further processing. Streptavidin
      based ligands can be gently stripped from desthiobiotin-labeled targets with
      buffered biotin solutions. Thus, repeated probing with fluorescent streptavidin
      conjugates followed by enzyme-based detection is possible. In all applications,
      the desthiobiotin/biotin-binding protein complex is easily dissociated under
      physiological conditions by either biotin or desthiobiotin. Thus, our
      desthiobiotin-based reagents and techniques provide some distinct advantages over
      traditional 2-iminobiotin, monomeric avidin, or other affinity-based techniques.

PMID- 12419350
TI  - A stereospecific colorimetric assay for (S,S)-adenosylmethionine quantification
      based on thiopurine methyltransferase-catalyzed thiol methylation.
AB  - S-Adenosyl-L-methionine (AdoMet) which is biologically synthesized by AdoMet
      synthetase bears an S configuration at the sulfur atom. The chiral sulfonium
      spontaneously racemizes to form a mixture of S and R isomers of AdoMet under
      physiological conditions or normal storage conditions. The chirality of AdoMet
      greatly affects its activity; the R isomer is not accepted as a substrate for
      AdoMet-dependent methyltransferases. We report a stereospecific colorimetric
      assay for (S,S)-adenosylmethionine quantification based on an enzyme-coupled
      reaction in which (S,S)-AdoMet reacts with 2-nitro-5-thiobenzoic acid to form
      AdoHcy and 2-nitro-5-methylthiobenzoic acid. The transformation is catalyzed by
      recombinant human thiopurine S-methyltransferase (TPMT, EC 2.1.1.67) and is
      associated with a large spectral change at 410 nm. Accumulation of the S
      adenosylhomocysteine (AdoHcy) product, a feedback inhibitor of TPMT, slows the
      assay. AdoHcy nucleosidase (EC 3.2.2.9) irreversibly cleaves AdoHcy to adenine
      and S-ribosylhomocysteine, significantly shortening the assay time to less than
      10 min. The assay is linear from 5 to at least 60 microM (S,S)-AdoMet.

PMID- 12419351
TI  - An integrated vector system for cellular studies of phage display-derived
      peptides.
AB  - Peptide phage display is a method by which large numbers of diverse peptides can
      be screened for binding to a target of interest. Even when successful, the rate
      limiting step is usually validation of peptide bioactivity using living cells. In
      this paper, we describe an integrated system of vectors that expedites both the
      screening and the characterization processes. Library construction and screening
      is performed using an optimized type 3 phage display vector, mJ(1), which is
      shown to accept peptide libraries of at least 23 amino acids in length. Peptide
      coding sequences are shuttled from mJ(1) into one of three families of mammalian
      expression vectors for cell physiological studies. The vector pAL(1) expresses
      phage display-derived peptides as Gal4 DNA binding domain fusion proteins for
      transcriptional activation studies. The vectors pG(1), pG(1)N, and pG(1)C express
      phage display-derived peptides as green fluorescent protein fusions targeted to
      the entire cell, nucleus, or cytoplasm, respectively. The vector pAP(1) expresses
      phage display-derived peptides as fusions to secreted placental alkaline
      phosphatase. Such enzyme fusions can be used as highly sensitive affinity
      reagents for high-throughput assays and for cloning of peptide-binding cell
      surface receptors. Taken together, this system of vectors should facilitate the
      development of phage display-derived peptides into useful biomolecules.

PMID- 12419352
TI  - Accurate nucleic acid concentrations by nuclear magnetic resonance.
AB  - Determination of the concentration of biochemical samples often yields values
      with uncertainties of 10-20% or more. This paper details a protocol for use with
      500- to 600-MHz NMR spectrometers to measure approximately 1mM concentrations
      within +/-1-3% accuracy. With suitable precautions, all compounds have equal NMR
      "absorption coefficients" for protons. About 2mg of sample are needed for
      proteins and nucleic acids with MW=5000, although less accurate determinations
      could be made with smaller amounts. The technique utilizes standardized internal
      reference reagent compounds, cacodylic acid or 3-(trimethylsilyl)propionic
      2,2,3,3-d(4) acid sodium salt. Spectra were signal-averaged using long interpulse
      delays so that integrals of nonexchangeable protons could be quantified relative
      to the reference standard. Accurate determinations require careful optimization
      of the homogeneity of the magnetic field and meticulous attention to sample
      preparation and spectral processing. The main source of error is usually the
      accuracy of micropipets. If sample preparation errors could be eliminated, the
      lower limit of accuracy with the current generation of NMR spectrometers is
      probably near 0.4%. However, this would require >99.5% sample purity. Methods are
      described to establish the concentration of the standards, and applications are
      illustrated with DNA mono- and oligonucleotides. Similar procedures should apply
      to proteins, polysaccharides, and other biomolecules, with about the same
      accuracy and precision.

PMID- 12419353
TI  - A colloidal silver staining--destaining method for precise assignment of
      immunoreactive spots in two-dimensional protein patterns.
AB  - The characterization of protein expression patterns by two-dimensional gel
      electrophoresis depends on efficient and reliable identification strategies for
      target spots. In addition to sophisticated techniques, such as microsequencing
      and peptide mass spectrometry, immunodetection of membrane-immobilized proteins
      is a valuable method with which to identify the corresponding spots for a given
      set of candidate proteins. To precisely assign immunoreactive spots, this
      approach requires specific immunodetection and staining of total protein to be
      performed on the same membrane. Here, we describe a highly sensitive, colloidal
      silver-based method for the assignment of immunoreactive spots in two-dimensional
      protein patterns. This simple and rapid procedure involves a destaining step
      after staining of nitrocellulose-bound proteins with colloidal silver. We show
      that destaining of proteins is a prerequisite for subsequent immunodetection
      using enhanced chemiluminescence. Several types of antibodies were successfully
      employed for antigen detection after the staining-destaining procedure. Our
      results demonstrate that the colloidal silver-based method is generally
      applicable for the unambiguous identification of candidate proteins in complex
      two-dimensional patterns.

PMID- 12419354
TI  - Direct monitoring of extracellular protease activities in microbial cultures.

PMID- 12419355
TI  - Semi-quantitative estimation of heme/hemoprotein with dichlorodihydrofluorescin
      diacetate.

PMID- 12419356
TI  - An assay for cytidine 5(')-triphosphate synthetase glutaminase activity using
      high performance liquid chromatography.

PMID- 12419357
TI  - A method for isolating alternatively spliced isoforms: isolation of murine Pax6
      isoforms.

PMID- 12419358
TI  - Specific and instantaneous one-step chemodetection of histidine-rich proteins by
      Pauly's stain.

PMID- 12419359
TI  - An alternative derivation of the binding equation for multivalent ligands.

PMID- 12419361
TI  - Design and synthesis of ethyl pyrrolidine-5,5-trans-lactams as inhibitors of
      hepatitis C virus NS3/4A protease.
AB  - Using a pyrrolidine-5,5-trans-lactam template, we have designed small, neutral,
      mechanism-based inhibitors of hepatitis C NS3/4A protease. Compound 11a, with an
      alpha-ethyl P1 substituent and a Boc-valine substituent at the pyrrolidine
      nitrogen, has an IC(50)=30 microM.

PMID- 12419363
TI  - Novel 2,5-dideoxystreptamine derivatives targeting the ribosomal decoding site
      RNA.
AB  - The ribosomal decoding site is the target of aminoglycoside antibiotics that
      specifically recognize an internal loop RNA structure. We synthesized RNA
      targeted 2,5-dideoxystreptamine-4-amides in which a sugar moiety in natural
      aminoglycosides is replaced by heterocycles.

PMID- 12419362
TI  - Chemical modification of reveromycin A and its biological activities.
AB  - Various derivatives of reveromycin A, a novel inhibitor of eukaryotic cell
      growth, were prepared and their inhibitory effects on both isoleucyl-tRNA
      synthetase activity and in vitro protein synthesis, and activities on the
      morphological reversion of src(ts)-NRK cells were assayed. The C5 hydroxyl group
      and C24 carboxyl group are particularly important for these activities.

PMID- 12419364
TI  - A glucose-selective fluorescence sensor based on boronic acid-diol recognition.
AB  - A glucose selective diphenylboronic acid fluorescent sensor (10a) with a K(a) of
      1472M(-1) has been synthesized and evaluated. This sensor shows a 43- and 49-fold
      selectivity for glucose over fructose and galactose, respectively. The binding
      affinity improvement is about 300-fold and the selectivity improvement for
      glucose over fructose is about 1400-fold compared with the monoboronic acid
      compound, phenylboronic acid. 1H NMR studies indicate that sensor 10a binds with
      alpha-D-glucofuranose in a bidentate manner (1:1 ratio).

PMID- 12419365
TI  - Structure-activity relationships for a series of thiobenzamide influenza fusion
      inhibitors derived from 1,3,3-trimethyl-5-hydroxy-cyclohexylmethylamine.
AB  - The anti-influenza activity of a series of thiobenzamide fusion inhibitors
      derived from 1,3,3-trimethyl-5-hydroxy-cyclohexylmethylamine is profiled. Axial
      disposition of the thioamide moiety is essential for potent influenza inhibitory
      activity.

PMID- 12419366
TI  - Pyrrolidine and piperidine analogues of SC-57461A as potent, orally active
      inhibitors of leukotriene A(4) hydrolase.
AB  - The synthesis and biological evaluation of a series of functionalized pyrrolidine
      and piperidine-containing analogues of our lead LTA(4) hydrolase inhibitor, SC
      57461A, is described. A number of compounds showed excellent potency in our in
      vitro screens and several demonstrated good oral activity in a mouse ex vivo
      assay. These efforts led to the identification of SC-56938 (14) as a potent,
      orally active inhibitor of LTA(4) hydrolase.

PMID- 12419367
TI  - Natural PTP1B inhibitors from Broussonetia papyrifera.
AB  - Two new compounds, 8-(1,1-dimethylallyl)-5'-(3-methylbut-2-enyl)-3',4',5,7
      tetrahydroxyflanvonol (1), 3'-(3-methylbut-2-enyl)-3',4',7-trihydroxyflavane (2)
      and three known compounds 3,3',4',5,7-pentahydroxyflavone (3), uralenol (4),
      broussochalcone A (5) were isolated from the roots of Broussonetia papyrifera,
      and their structures determined by spectroscopic methods. Compounds 1, 3, 4 and 5
      significantly show the inhibitory activities against the PTP1B enzyme.

PMID- 12419368
TI  - in vitro inhibition of the measles virus by novel ring-expanded ('fat')
      nucleoside analogues containing the imidazo[4,5-e]diazepine ring system.
AB  - The synthesis and in vitro anti-measles virus (anti-MV) activity of a class of
      ring-expanded ('fat') nucleoside analogues (1-4) containing the title
      heterocyclic ring system are reported. The target compounds were synthesized by
      base-catalyzed condensations of 4,5-dicarboxylic acid esters of the appropriately
      substituted imidazole-1-ribosides with suitably substituted guanidine
      derivatives. Compounds were screened for anti-MV activity in African green monkey
      kidney cells (CV-1), employing ribavirin as the control standard. While the
      parent compound 1 itself failed to show any significant antiviral activity
      against MV, its analogues containing hydrophobic substituents at the 2-position
      (2) or the 6-position (4) showed promising antiviral activity at submicromolar or
      micromolar concentration levels with no apparent toxicity to the host cell line.
      Both compounds showed higher anti-MV activity than the control drug ribavirin.

PMID- 12419369
TI  - The aggregation and G-quadruplex DNA selectivity of charged 3,4,9,10
      perylenetetracarboxylic acid diimides.
AB  - Two N,N'-disubstituted perylene diimide G-quadruplex DNA ligands, Tel11 (N,N'-bis
      [3-(4-methyl-morpholin-4-yl)-propyl]-3,4,9,10-perylenetetracarboxylic acid
      diimide diiodide) and Tel12 (N,N'-bis-[(3-phosphono)-propyl]-3,4,9,10
      perylenetetracarboxylic acid diimide tetrapotassium salt) were synthesized and
      studied. Visible absorbance spectroscopy, resonance light scattering, and
      fluorescence spectroscopy were utilized to explore the aggregation state,
      affinity for various DNA structures, and G-quadruplex selectivity of these
      ligands. The water-soluble ligands exist in a monomer-dimer equilibrium with the
      cationic Tel11 exhibiting a greater affinity for various DNA structures than the
      anionic Tel12. Tel12 has greater selectivity for G-quadruplex DNA over double
      stranded DNA than Tel11.

PMID- 12419370
TI  - Design and synthesis of a beta-amino phosphotyrosyl mimetic suitably protected
      for peptide synthesis.
AB  - Mimetics of phosphotyrosine (pTyr) such as phosphonomethylphenylalanine (Pmp)
      have traditionally retained alpha-amino functionality. However, beta-amino acids
      represent isomeric variants, which may exhibit properties that are distinct from
      the parent. Reported herein is the first beta-amino pTyr mimetic (Pmp(beta))
      bearing protection suitable for peptide synthesis. Preparation of Pmp(beta) was
      accomplished enantioselectively in 43% overall yield from commercially available
      4-vinylbenzyl chloride.

PMID- 12419371
TI  - Core-modified sordaricin derivatives: synthesis and antifungal activity.
AB  - Core-modified sordaricin derivatives were prepared via biotransformation followed
      by chemical modification and tested for antifungal activity. The antifungal
      activity proved to be very sensitive to modifications in the sterics and/or
      lipophilicity of the diterpene skeleton. Introduction of polar groups such as
      hydroxyl in the diterpene core results in loss of potency while small and
      lipophilic groups such as fluorine and the 7,8-olefin are well tolerated.

PMID- 12419372
TI  - Anticancer activity for 4,4'-dihydroxybenzophenone-2,4-dinitrophenylhydrazone (A
      007) analogues and their abilities to interact with lymphoendothelial cell
      surface markers.
AB  - The structure of the anticancer agent 4,4'-dihydroxybenzophenone-2,4
      dinitrophenylhydrazone (A-007) has been modified through SAR and by incorporating
      barbituric acid, pyridine, quinoline, and alkylcarboxylic acids into A-007's
      moieties. Analogue anticancer activity and interacting with CD surface markers on
      a T-cell leukemia cell line were evaluated and the correlation between SAR and
      biological properties are discussed.

PMID- 12419373
TI  - Design and synthesis of 6-substituted amino-4-oxa-1-azabicyclo[3,2,0]heptan-7-one
      derivatives as cysteine proteases inhibitors.
AB  - A series of 6-substituted amino-4-oxa-1-azabicyclo[3,2,0]heptan-7-one compounds
      was designed and synthesized as a new class of inhibitors for cysteine proteases
      cathepsins B, L, K, and S. One compound (5S,6S)-6-(N-benzyloxycarbonyl-L
      phenylalanyl) amino-4-oxa-1-azabicyclo[3,2,0]heptan-7-one showed excellent
      cathepsin L and K inhibition activity with IC(50) at a low nanomolar range.

PMID- 12419374
TI  - 6-Acylamino-penam derivatives: synthesis and inhibition of cathepsins B, L, K,
      and S.
AB  - The synthesis of a new series of 6-acylamino penam derivatives and their
      inhibition of cysteine proteases cathepsins B, L, K, and S is described. The 6
      acylamino-penam sulfone compounds showed excellent cathepsin L, K, and S
      inhibition activity with IC(50) values in the nanomolar and subnanomolar range.

PMID- 12419375
TI  - Integration of optimized substituent patterns to produce highly potent 4-aryl
      pyridine glucagon receptor antagonists.
AB  - Optimized substituent patterns in 4-aryl-pyridine glucagon receptor antagonists
      were merged to produce highly potent derivatives containing both a 3-[(1R)
      hydroxyethyl] and a 2'-hydroxy group. Due to restricted rotation of the phenyl
      pyridine bond, these analogues exist as four isomers. A diastereoselective
      methylcopper reaction was developed to facilitate the synthesis, and single
      isomers were isolated with activities in the range IC(50)=10-25 nM.

PMID- 12419376
TI  - Design, synthesis, and neuraminidase inhibitory activity of GS-4071 analogues
      that utilize a novel hydrophobic paradigm.
AB  - Structure-based design has led to the synthesis of a novel analogue of GS-4071,
      an influenza neuraminidase inhibitor, in which the basic amino group has been
      replaced by a hydrophobic vinyl group. An X-ray co-crystal structure of the new
      inhibitor (K(i)=45 nM) bound to the active site shows that the vinyl group
      occupies the same subsite as the amino group in GS-4071.

PMID- 12419377
TI  - Novel spirocyclic pyrrolidones as P2/P1 mimetics in potent inhibitors of HIV-1
      protease.
AB  - We have developed concise and efficient syntheses of novel spirocyclic
      pyrrolidones 1-3, which involve the alkylation of pyrrolidone precursor 13 with
      1,5-dibromopentane, 16 and 15, followed by an in situ lactamization. Conjugates
      of 1 and 2 with P1'/P2' hydroxy-indanolamine moiety resulted in novel and potent
      inhibitors of HIV-1 protease 25 and 26, suggesting that 1 and 2 are novel P2/P1
      HIV-PI mimetics.

PMID- 12419378
TI  - Prodrugs of 4'-demethyl-4-deoxypodophyllotoxin: synthesis and evaluation of the
      antitumor activity.
AB  - A series of prodrugs of 4'-demethyl-4-deoxypodophyllotoxin (DDPT) including
      carbamates (3-8), a carbonate (9) and water-soluble amino acid derivatives (10
      17) were prepared and tested for their antitumor activity. The carbamate 6 (2
      hydroxyethylcarbamoyl-DDPT), carbonate 9 (2-chloroethyloxycarbonyl-DDPT), and
      most of amino acid prodrugs (12-17) showed enhanced antitumor activity.

PMID- 12419379
TI  - Synthesis and stability study of a modified phenylpropionic acid linker-based
      esterase-sensitive prodrug.
AB  - An esterase-sensitive amide prodrug 1 with a modified phenylpropionic acid linker
      was synthesized. The prodrug can be converted to the drug using isolated porcine
      esterase and human plasma. Paraoxon, an esterase inhibitor, can inhibit prodrug
      to-drug conversion. The conversion of prodrug 1 was via phenol intermediate 9
      followed by a lactonization reaction to give lactone 2 and the drug.

PMID- 12419380
TI  - Trifluoromethyl ketones as inhibitors of histone deacetylase.
AB  - Trifluoromethyl ketones were found to be inhibitors of histone deacetylases
      (HDACs). Optimization of this series led to the identification of submicromolar
      inhibitors such as 20 that demonstrated antiproliferative effects against the
      HT1080 and MDA 435 cell lines.

PMID- 12419381
TI  - Alpha(1)-adrenoceptor activation: a comparison of 4-(anilinomethyl)imidazoles and
      4-(phenoxymethyl)imidazoles to related 2-imidazolines.
AB  - Literature reports suggest that disruption of an interhelical salt bridge is
      critical for alpha(1)-adrenoceptor activation, and the basic amine found in
      adrenergic receptor ligands is responsible for the disruption. Novel 4
      (anilinomethyl)imidazoles and 4-(phenoxymethyl)imidazoles are agonists of the
      cloned human alpha(1)-adrenoceptors in vitro, and potent, selective alpha(1A)
      adrenoceptor agonists have been identified in this series. These imidazoles
      demonstrate similar potencies and alpha(1)-subtype selectivities as the
      corresponding 2-substituted imidazolines. The extremely close SAR suggests that,
      in spite of the large difference in basicity, these imidazoles and imidazolines
      may establish the same interactions to activate alpha(1)-adrenoceptors.

PMID- 12419382
TI  - Six-membered cyclic ureas as HIV-1 protease inhibitors: a QSAR study based on
      CODESSA PRO approach. Quantitative structure-activity relationships.
AB  - Quantitative structure-activity relationships (QSAR) for HIV-1 protease
      inhibitory activity of substituted tetrahydropyrimidinones have been produced
      using CODESSA PRO methodology and software. The best four-parameter equation
      (R(2)(cv)=0.847) allowed us to reveal two main structural factors which are
      strongly correlated with the title activity: molecular hydrophobicity and ability
      to form hydrogen bonds with the target enzyme.

PMID- 12419383
TI  - Understanding the unique mechanism of L-FMAU (clevudine) against hepatitis B
      virus: molecular dynamics studies.
AB  - The molecular dynamics simulation of HBV-polymerase.DNA.L-FMAU-TP complex
      demonstrated that L-FMAU-TP may not serve as a substrate for HBV polymerase
      because the appropriate binding of L-FMAU-TP to the active site of HBV polymerase
      may not take place without the unfavorable conformational adjustment, which
      prevents L-FMAU-TP from being incorporated into the growing viral DNA chain.

PMID- 12419384
TI  - Inhibitors of NF-kappaB signaling: design and synthesis of a biotinylated
      isopanepoxydone affinity reagent.
AB  - A number of inhibitors of NF-kappaB signaling arising from our recent syntheses
      of isopanepoxydone and panepoxydone have been identified. Structure-activity data
      have been correlated to allow the design and synthesis of an affinity reagent for
      the isolation and identification of any relevant cellular target.

PMID- 12419385
TI  - The discovery of novel small molecule non-peptide gonadotropin releasing hormone
      (GnRH) receptor antagonists.
AB  - A novel series of non-peptide derivatives 1, 14, and 15 that bind with high
      affinity to the human GnRH receptors is discussed. The discovery was made from
      screening our in-house libraries that contained the active structure 2 along with
      a trace amount of a second active structure 1 that was derived from an acid
      induced rearrangement. From this structure type 1, a series of guanidine and non
      guanidine containing analogues were prepared and tested as GnRH receptor
      antagonists. Compounds derived from this series bind to both human and rat GnRH
      receptors and antagonize GnRH-mediated increases in inositol phosphate production
      in cells containing recombinant human receptors. These compounds or their
      analogues may be useful as therapeutic agents for the treatment of hormone
      dependent pathologies including prostate, breast and ovarian cancers.

PMID- 12419386
TI  - Synthesis of [difluoro-(3-alkenylphenyl)-methyl]-phosphonic acids on non
      crosslinked polystyrene and their evaluation as inhibitors of PTP1B.
AB  - A series of [difluoro-(3-alkenylphenyl)-methyl]-phosphonates were prepared on non
      crosslinked polystyrene, a soluble polymer support. After cleavage from the
      support, the resulting phosphonic acids were examined for inhibition with protein
      tyrosine phosphatase 1B. Compound 20, bearing an alpha,beta-unsaturated allyl
      ester moiety, was the most potent of this series of compounds, being a
      reversible, competitive inhibitor with a K(i) of 8.0+/-1.4 microM.

PMID- 12419387
TI  - Synthesis and in vitro antiprotozoal activity of 5-nitrothiophene-2
      carboxaldehyde thiosemicarbazone derivatives.
AB  - Several thiosemicarbazone derivatives of 5-nitrothiophene-2-carboxaldehyde were
      prepared by the simple process in which N(4)-thiosemicarbazone moiety was
      replaced by aliphatic, arylic and cyclic amine. Among these thiosemicarbazones
      compound 11 showed significant antiamoebic activity whereas compound 3 was more
      active antitrichomonal than the reference drug.

PMID- 12419388
TI  - Enhancement of pharmacokinetic properties and in vivo efficacy of benzylidene
      ketal M(2) muscarinic receptor antagonists via benzamide modification.
AB  - We previously reported the initial discovery of a novel class of stabilized
      benzylidene ketal M(2) receptor antagonists. This paper discusses new analogues
      consisting of benzamide modifications which not only improved M(2) receptor
      affinity and selectivity, but also enhanced the pharmacokinetic properties of the
      series. These changes led to the discovery of a highly potent and selective M(2)
      antagonist, which demonstrated in vivo efficacy and had good bioavailability in
      multiple species.

PMID- 12419389
TI  - Non-peptide alpha(v)beta(3) antagonists. Part 5: identification of potent RGD
      mimetics incorporating 2-aryl beta-amino acids as aspartic acid replacements.
AB  - A series of novel, highly potent alpha(v)beta(3) receptor antagonists with
      favorable pharmacokinetic profiles has been identified. In this series of
      antagonists, 2-aryl beta-amino acids function as potent aspartic acid
      replacements.

PMID- 12419390
TI  - New progesterone receptor antagonists: 3,3-disubstituted-5-aryloxindoles.
AB  - A new series of 3,3-disubstituted-5-aryloxindoles has been synthesized and
      evaluated for progesterone receptor antagonist (PR) activity in a T47D cell
      alkaline phosphatase assay and for their ability to bind PR in competition
      binding studies. In this communication, the synthesis and structure-activity
      relationships (SARs) of various 3,3-substituents are discussed where it is clear
      that small alkyl and spiroalkyl groups are required to achieve better PR
      antagonist activity.

PMID- 12419391
TI  - A novel synthesis of 7-aryl-8-fluoro-pyrrolo[1,2-a]pyrimid-4-ones as potent,
      stable GnRH receptor antagonists.
AB  - A new class of small molecule GnRH antagonists, the 7-aryl-8-fluoro-pyrrolo[1,2
      a]pyrimid-4-ones, was designed and a novel synthesis for these compounds was
      developed. The synthesis utilizes a base-catalyzed intramolecular cyclization of
      fluoromethyl pyrimidone 5 to generate the bicyclic core. Amongst the compounds
      synthesized, we discovered some highly potent GnRH receptor antagonists (e.g.,
      12, K(i)=9 nM), which showed enhanced stability towards acidic physiological
      conditions compared to the des-fluoro analogues.

PMID- 12419393
TI  - Effects of hippocampal lesions on conditional spatial discrimination in pigeons.
AB  - Pigeons were trained on a conditional spatial discrimination with a three-key
      operant chamber. The position of the correct key was left when all the keys were
      red, center when all the keys were green, and right when all the keys were white.
      Pigeons with hippocampal damages could learn the task, as well as intact birds
      and those that received hippocampal lesions after acquisition of the task. These
      results suggest that the pigeon hippocampus does not play a role in conditional
      spatial discrimination.

PMID- 12419392
TI  - Effects of prior apparatus experience and novelty of testing environment on
      locomotor activity following MK-801.
AB  - Robust increases in locomotor activity are observed following administration of
      dizocilpine maleate (MK-801). The present study investigated the effects of prior
      apparatus experience and manipulation of the testing environment on locomotor
      activity following peripheral MK-801. Gerbils were given zero or nine sessions of
      apparatus exposure prior to testing with MK-801 (0.1 mg/kg ip) or saline.
      Sessions were 10 min in duration and separated by 24 h. As previously reported,
      naive animals treated with MK-801 were significantly more active relative to
      controls. Exposure to the apparatus for nine sessions resulted in a significant
      reduction in MK-801-induced activity, but did not alter the activity levels of
      control animals. To evaluate the effect of changes to the testing environment,
      animals previously evaluated in the familiar condition were retested in the
      identical apparatus relocated to a novel experimental room. MK-801-treated
      animals exhibited a significant increase in activity when tested in this novel
      environment while the locomotor activity of control gerbils was not significantly
      altered. The results illustrate the importance of repetitive testing and
      environmental changes as moderating variables in studies that evaluate locomotor
      activity. These data also indicate that the effects of MK-801 on activity are
      sensitive to prior experience with the apparatus and the novelty of the testing
      environment.

PMID- 12419394
TI  - THC aggravates rat muricide behavior induced by two levels of magnesium
      deficiency.
AB  - A severe magnesium deprivation induces an interspecific aggressive behavior
      (muricidal behavior, MB) in different strains of rats. Delta9
      tetrahydrocannabinol (THC) is also known to induce MB even after a single
      injection (11 mg/kg) in starving, isolated rats. In the present work, we
      investigated the MB behavior, for six successive assays 1 h delayed, of two
      groups of male Long-Evans rats fed 50- or 150-ppm Mg(2+)-deficient diets, for 42
      days after a single injection of THC at doses (2, 4 or 8 mg/kg) that did not
      induce aggressiveness in control rats. This treatment led to Mg(2+) plasma levels
      of 5+/-0.3 and 12.3+/-0.9 mg/ml vs. 21+/-1.5 mg/ml initially. In the 50-ppm Mg
      deficient rat group, all the rats were muricidal but the MB pattern was severely
      aggravated by THC. In the 150-ppm Mg-deficient rat group, no rat was muricidal
      but all doses of THC induced a 100% MB. In addition, by quantifying the three
      phases of MB, we showed through six consecutive hourly muricidal assays, that the
      two first phases (attack latency and attack on the living mouse) decreased
      progressively, whereas the third phase (attack on the dead mouse) increased
      dramatically. This indicates firstly that Mg-deprivation decreases the
      responsiveness threshold of rats to THC. Secondly, these very low doses of THC
      induced an aggravation of MB and an acquired hyper-aggressiveness in both 50- and
      150-ppm Mg-deficient rats, probably involving different neurotransmitters, mainly
      serotonin, which is decreased by both treatments.

PMID- 12419395
TI  - Role of maternal behavior on aggression, fear and anxiety.
AB  - Concomitant to the expression of maternal behavior, the lactating female develops
      anxiolysis in the elevated plus maze test, aggression towards intruders and
      reduced fear in response to a sudden auditory stimulus. This study aims to
      determine if these behavioral changes are associated with maternal behavior
      independently of the endocrine status that characterizes gestation, parturition
      and lactation. To assess this purpose, the behavior of lactating females was
      compared to that exhibited by maternal and nonmaternal ovariectomized rats
      untreated with steroid hormones. In contrast with lactating dams, sensitized
      animals (rats that displayed maternal behavior after a continuous contact with
      young pups) did not display reduced anxiety in the plus maze test. However, the
      sensitized females showed behaviors characteristic of lactating rats, such as
      some components of maternal aggression and reduced fear, though much less
      intensely than dams. These results suggest that aggression and reduced fear, but
      not anxiolysis, partially depend on the development of maternal behavior.

PMID- 12419396
TI  - Effects of prenatal stress on stress-induced changes in behavior and macrophage
      activity of mice.
AB  - The present study analyzed the effects of maternal stress on behavior and
      macrophage activity of mice. Pregnant mice received a daily footshock (0.2 mA)
      from gestational days 15 (GD15) to 19. Experiments were performed on male
      offspring, challenged or not with another footshock (0.2 mA) on postnatal day 30
      (PND30) or 60. The following results were obtained for maternal stress: (1)
      increment in locomotor activity of juvenile but not of adult mice observed in
      both open-field and plus-maze; (2) increment in rearing frequency of juvenile but
      not of adult mice observed in the open-field; (3) decrement in macrophage
      spreading of adult but not of juvenile mice; (4) abolishment of postnatal
      footshock effects in both macrophage spreading on PND30 and macrophage nitric
      oxide (NO) production on PND60; (5) reversion of postnatal footshock effects on
      H(2)O(2) spontaneous and PMA-induced release by macrophage on PND30; (6)
      modification of postnatal stress effects on macrophage phagocytosis on PND60.
      These changes were unrelated to differences in gestational parameters and did not
      reflect altered maternal-pup interactions or nutritional factors. The observed
      data provide experimental evidence that maternal stress alters behavior, and
      macrophage activity at the same time and in the same litter. These data were
      discussed in the light of possible neuroimmune interactions that involve
      catecholaminergic pathways.

PMID- 12419397
TI  - High levels of estradiol impair spatial performance in the Morris water maze and
      increase 'depressive-like' behaviors in the female meadow vole.
AB  - The present study investigated sex differences and the effect of a high level of
      estradiol in the female meadow vole on performance in the forced swim test (FST)
      and the Morris water maze in meadow voles. Female meadow voles were
      ovariectomized (OVX) and administered either vehicle (sesame oil) or estradiol
      for 2 days prior to performing the FST. Four days following the FST, all animals
      were run in the Morris water maze. Results indicated that estradiol-injected
      female meadow voles showed more 'depressive-like' behaviors in the FST (greater
      time spent immobile and less time spent swimming) than vehicle-treated female or
      male meadow voles. In addition, estradiol-treated females had impaired
      performance (greater latencies and distance swam to reach the hidden platform)
      than both vehicle-treated female and male meadow voles, consistent with previous
      data. Despite the fact that estradiol administration increased 'depressive-like'
      behaviors in the FST and impaired performance in the Morris water maze, there was
      no correlation between the two behaviors indicating that 'depressive-like'
      behaviors did not account for the differences seen in spatial performance in the
      Morris water maze. To our knowledge, this is the first demonstration in rodents
      indicating that estradiol-mediated changes in behavior in the FST is not
      indicative of subsequent performance in the Morris water maze.

PMID- 12419398
TI  - Male-induced estrus synchronization in the female Siberian hamster (Phodopus
      sungorus sungorus).
AB  - Olfactory cues play an integral role in the organization of events that mediate
      reproductive success. In a variety of species, priming pheromones, in particular,
      are important for ensuring reproductive fitness. To date, very little research
      has focused on how male-emitted priming pheromones, such as those that regulate
      the onset of puberty and estrus synchronization in females, affect the
      reproductive physiology of the female Siberian hamster (Phodopus sungorus
      sungorus). This lack of research may be due to the physiology of the Phodopus
      genus; vaginal cytology cannot be used as a reliable indicator of estrus or
      ovulation. Using a jugular cannulation technique to determine estrous stage by
      blood analysis of prolactin and luteinizing hormone, we sought to determine if
      male priming pheromones affect estrous cyclicity in the female Siberian hamster
      and, if so, whether the production of these priming pheromones is androgen
      dependent. Our results showed that females exposed to bedding from mature, intact
      males showed a significantly higher incidence of proestrus 3 days later than did
      females exposed to the bedding of mature, gonadectomized males. Therefore, we
      found that not only do male Siberian hamsters emit chemical signals that induce
      estrus synchronization, but also that this ability is likely to be androgen
      dependent.

PMID- 12419399
TI  - Hypothalamic implants of dilute estradiol fail to reduce feeding in
      ovariectomized rats.
AB  - To investigate further the site where estradiol (E(2)) inhibits food intake, we
      tested the effects on feeding of subcutaneous and intrahypothalamic implants of
      10% E(2) benzoate in cholesterol (CHOL) or CHOL alone. E(2) was implanted
      subcutaneously in Silastic tubes, and intrahypothalamically via bilateral 29
      gauge cannulas into the paraventricular nucleus (PVN) or the medial preoptic area
      (MPA) of ovariectomized (OVX) Sprague-Dawley and Long-Evans rats. Three-day
      implant periods followed 3-day baseline periods. Rats were allowed ad libitum
      access to chow and tap water, and food intake and body weight were measured each
      day. Subcutaneous 10% E(2) implants in Sprague-Dawley rats reduced food intake
      21% on Day 2 and 34% on Day 3 (P's<.01) and decreased 3-day body weight gain 11 g
      (P<.05). In contrast, 10% E(2) implants in the PVN of Sprague-Dawley rats did not
      change food intake or body weight. Implants of 10% or 20% E(2) in the MPA also
      failed to decrease food intake. MPA implants of 10% E(2) decreased body weight
      gain 8 g (P<.05), but MPA implants of 20% E(2) decreased weight gain only 4 g
      (P>.05). To determine whether the strain of rat affected our negative results on
      food intake, we implanted 10% E(2) into the PVN of Long-Evans rats. Again, PVN
      E(2) did not decrease food intake significantly in comparison to the pretest
      baseline. PVN E(2) did, however, decrease body weight gain 5 g and decreased food
      intake 6% compared to rats with implants of CHOL (both P<.05), but these effects
      appeared to be due to an increase in feeding in the CHOL group in comparison to
      their baseline. Finally, CHOL and E(2) implants did not impair the responsivity
      of the PVN because acute implants of norepinephrine (NE) into the PVN of E(2)- or
      CHOL-treated Long-Evans rats significantly increased food intake. Our results do
      not support the hypothesis that E(2)'s actions in either the PVN or the MPA are
      sufficient to account for its inhibitory effects on feeding.

PMID- 12419400
TI  - Vagotomy attenuates effects of L-glucose but not of D-glucose on spontaneous
      alternation performance.
AB  - Two peripheral signaling routes have been proposed to account for the ability of
      peripheral substances such as glucose to modulate memory processing in the brain.
      One possible signaling route is by crossing the blood-brain barrier to act
      directly on brain. A second route involves activation of peripheral nerves with
      resulting changes in neural activity carried by peripheral nerves to the brain.
      Because the vagus nerve is a major neural pathway between the periphery and
      brain, peripherally acting modulators of memory modulators may act via vagal
      afferents to the brain to enhance memory processing. In the present experiments,
      systemic injections of either D-glucose or L-glucose, a metabolically inactive
      enantiomer, facilitated performance of rats on a four-arm alternation task, but
      at very different doses (D-glucose, 250 mg/kg; L-glucose, 3,000 mg/kg). The
      enhanced performance seen with L-glucose, but not that seen with D-glucose, was
      attenuated by vagotomy. These findings suggest that the mechanisms by which these
      enantiomers act to enhance memory are quite different, with L-glucose acting via
      vagal afferents but D-glucose acting by other means, including direct modulation
      of central nervous system (CNS) processes by D-glucose.

PMID- 12419401
TI  - Orexin-mediated feeding behavior involves both leptin-sensitive and -insensitive
      pathways.
AB  - Orexin-A and -B are neuropeptides that are implicated in the regulation of
      vigilance states and energy homeostasis. Orexins are specifically produced by
      neurons located within the lateral hypothalamic area (LHA), a region implicated
      in the regulation of feeding behavior. Here, we examined the functional
      interactions between orexins and anorectic factors [leptin, alpha-melanocyte
      stimulating hormone (alpha-MSH) and glucagon-like peptide-1 (GLP-1)] in rats.
      Intracerebroventricular injection of orexin-A (10 nmol) potently augmented food
      intake in rats. Neuropeptide Y (NPY) (0.3 nmol) and galanin (3 nmol) also induced
      a transient increase in food intake. Both NPY- and galanin-induced feeding
      behaviors were completely inhibited by preadministration of leptin (3 microg),
      while the same or a higher dose (10 microg) of leptin only partially inhibited
      orexin-A or -B-induced increase of food intake. Preadministration of anorectic
      peptides (alpha-MSH and GLP-1), which are shown to be regulated by leptin,
      abolished NPY-induced feeding; however, orexin-induced feeding was only partially
      inhibited by these anorectic peptides. These observations suggest that NPY- and
      galanin-induced increases of feeding involve a leptin-sensitive pathway, while
      orexin-induced feeding involves both leptin-sensitive and -insensitive pathways.

PMID- 12419402
TI  - Instrumental learning within the spinal cord. II. Evidence for central mediation.
AB  - Rats spinally transected at the second thoracic vertebra can learn to maintain
      their leg in a flexed position if they receive legshock for extending the limb.
      These rats display an increase in the duration of a flexion response that
      minimizes net shock exposure. The current set of experiments was designed to
      determine whether the acquisition of this behavioral response is mediated by the
      neurons of the spinal cord (i.e., is centrally mediated) or reflects a peripheral
      modification (e.g., a change in muscle tension). Experiment 1 found that
      preventing information from reaching the spinal cord by severing the sciatic
      nerve blocked the acquisition of this behavioral response. Spinalized rats also
      failed to learn if the spinal cord was anesthetized with lidocaine during
      exposure to response-contingent shock (Experiment 2). Experiment 3 demonstrated
      that prior exposure to response-contingent shock on one hindleg facilitated
      acquisition of the response when subjects were later tested on the opposite leg.
      These findings suggest that acquisition of the instrumental response depends on
      neurons within the spinal cord.

PMID- 12419403
TI  - Fetal exposure to nicotine does not alter the core temperature response of 7- to
      8-week-old rats to intracerebroventricular administration of PGE(1).
AB  - Prenatal exposure to nicotine attenuates stress-induced hyperthermia in adult
      male and female rats upon exposure to a novel environment. Given that
      prostaglandins play an important role in mediating stress-induced hyperthermia,
      our current experiments were carried out to determine if prenatal exposure to
      nicotine alters the thermogenic response of adult rats to an E-series
      prostaglandin. Forty-eight chronically instrumented adults rats (24 males and 24
      females) received an intracerebroventricular injection of prostaglandin E(1)
      (PGE(1); 0.2 microg in 10 microl of artificial cerebrospinal fluid [aCSF]) or
      vehicle (10 microl aCSF) at 7-8 weeks of postnatal life (i.e. adulthood as
      defined by the ability to reproduce) following prenatal exposure to nicotine (6
      mg of nicotine tartrate per kilogram of maternal body weight per day) or vehicle
      via a maternally implanted osmotic mini-pump from Day 6 or 7 of gestation to
      term. In female rats, intracerebroventricular injection of PGE(1) following
      prenatal exposure to vehicle produced a monophasic fever with a magnitude of
      approximately 1.5 degrees C and a duration of approximately 66 min. In male rats,
      however, intracerebroventricular injection of PGE(1) following prenatal exposure
      to vehicle produced a monophasic fever with a magnitude of only approximately 0.9
      degrees C and a duration of approximately 42 min. Prenatal exposure to nicotine
      did not significantly alter the febrile responses of male or female rats to
      intracerebroventricular injection of PGE(1) as compared to that observed
      following prenatal exposure to vehicle. Thus, prenatal exposure to nicotine does
      not significantly alter the thermogenic response of adult rats to central
      administration of the pyrogen PGE(1). It is unlikely, therefore, that an altered
      thermoregulatory effector response to E-series prostaglandins is responsible for
      mediating the attenuated stress-induced hyperthermia in adult male and female
      rats upon exposure to a novel environment following prenatal exposure to
      nicotine.

PMID- 12419404
TI  - Rearing on basal or high dietary NaCl modifies chorda tympani nerve responses in
      rats.
AB  - Two experiments were conducted to determine the influence of dietary NaCl level
      on the integrated responses of the chorda tympani (CT) nerve to salt stimulation
      alone and mixed with the sodium-channel blocker, amiloride hydrochloride. Five
      groups of adult male rats were reared on regular chow containing either basal
      0.1%, intermediate 1.0%, or high 3.0% NaCl from conception to postnatal day (PD)
      30 or from conception to adulthood. Adult rats reared from conception to
      adulthood on basal dietary NaCl demonstrated a reduction in the CT nerve response
      to NaCl due to a decrease in the amiloride sensitive transduction mechanism.
      However, the CT nerve responses of adult rats reared on basal dietary NaCl to
      PD30 and then switched to intermediate dietary NaCl were similar to those of rats
      reared for a lifetime on intermediate dietary NaCl. Similarly, the CT nerve
      responses to NaCl in animals reared on high dietary NaCl from conception to PD30
      and then switched to an intermediate NaCl diet were comparable to animals reared
      on intermediate and basal dietary NaCl. However, we found that exposure to high
      dietary NaCl led to a greater amiloride inhibition of NaCl responses. Thus, there
      is critical association between dietary NaCl level over two different exposure
      periods and CT nerve responsiveness to NaCl specifically regarding the degree of
      amiloride inhibition.

PMID- 12419405
TI  - Acute stress decreases inflammation at the site of infection. A role for nitric
      oxide.
AB  - Exposure to acute stress modulates immune function. Most research regarding
      stress and immunity has described the deleterious effects of stress. Recent
      studies, however, indicate that acute stress enhances many features of innate
      immunity. For example, exposure to acute stress reduced the time required to
      resolve inflammation produced by subcutaneous injection of streptomycin-killed,
      benign bacteria. It is unclear if this change in inflammation would be
      advantageous to the organism if challenged with living, infectious bacteria.
      Thus, the current experiments examined the effect of acute stressor exposure on
      inflammation development and resolution after a naturalistic, live bacterial
      challenge. In addition, nitric oxide (NO), an important bactericidal mediator,
      was measured at the inflammatory site. Rats (F344) were exposed to acute stress
      (100, 5-s, 1.6 mA tailshocks) and subcutaneously injected with live Escherichia
      coli ( approximately 2.5 x 10(9) colony forming units [CFU]). Stressed rats
      attained their peak inflammatory size quicker, resolved their inflammation 10-14
      days faster, experienced less bacterial-induced weight loss and released 300%
      greater NO at the inflammatory site than nonstressed controls. Thus, acute stress
      improved recovery from bacterially induced inflammation possibly due to local
      elevations in NO.

PMID- 12419406
TI  - Contrasting phenotypes of C57BL/6JOlaHsd, 129S2/SvHsd and 129/SvEv mice in two
      exploration-based tests of anxiety-related behaviour.
AB  - Knockout mice are typically generated on a mixed genetic background and, as such,
      detailed behavioural characterisation of these background strains is essential to
      the valid interpretation of mutant phenotypes. In this context, recent research
      has revealed significant differences in anxiety-like behaviour among the most
      commonly used background strains (C57BL/6J and various 129 substrains), leading
      to the possibility that at least certain mutant phenotypes may not after all be
      due to the targeted mutation. However, these findings derive largely from
      behavioural test batteries in which there may well be an experiential confound,
      while the widely reported hypolocomotor profile of most 129 substrains may
      compromise the principal indices of anxiety-like behaviour. In the present study,
      we have compared the behavioural profiles of three commonly used background
      strains (C57BL/6JOlaHsd, 129/SvEv and 129S2/SvHsd) in two of the most popular
      animal models of anxiety-the elevated plus-maze (EPM) and light/dark exploration
      (LDE) tests. Naive animals were used for each procedure, ethological scoring
      methods were employed throughout, and the inbred phenotypes were also compared
      with that of an outbred strain (Swiss-Webster) widely employed in test validation
      and behavioural pharmacology. Our results show that, despite their hypolocomotor
      profile, both 129 substrains display higher levels of anxiety-like behaviour
      (conventional and/or ethological measures) relative to the C57BL/6JOlaHsd strain.
      Furthermore, all three inbred strains were less active in both tests when
      compared with the outbred Swiss-Webster strain. However, whereas C57BL/6JOlaHsd
      mice displayed lower levels of anxiety-like behaviour than their Swiss-Webster
      counterparts (both tests), 129S2/SvHsd (but not 129/SvEv) mice exhibited evidence
      of higher anxiety, particularly in the LDE test. The implications of these
      findings are discussed in relation to both the behavioural and pharmacological
      phenotyping of mutant mice.

PMID- 12419407
TI  - Medial olivocochlear bundle activation and perceived auditory intensity in
      humans.
AB  - In order to test the hypothesis of a role of cochlear efferent activity in
      intensity perception in humans, loudness functions, loudness integration, and
      loudness summation were measured in the absence and in the presence of
      contralateral noise in normal-hearing subjects. Additionally, relationships with
      the effect of the noise on evoked otoacoustic emissions (EOAEs) were tested, and
      comparisons with vestibular neurotomy patients were performed. Overall, the
      results failed to demonstrate significant effects of contralateral noise
      stimulation on loudness functions and loudness integration. Furthermore, no
      significant differences were found in vestibular neurotomy patients. A
      significant effect of contralateral noise on loudness summation was noted, but
      was not related to the effect on otoacoustic emissions. The present results fail
      to support the notion that efferent influences onto the cochlear compression have
      a significant perceptual effect.

PMID- 12419408
TI  - Sour taste stimulation facilitates reflex swallowing from the pharynx and larynx
      in the rat.
AB  - Chemical stimulation of the pharynx and larynx is effective in eliciting reflex
      swallowing. A sour taste bolus facilitates the onset of swallowing in patients
      with neurogenic dysphagia, but the mechanism of the facilitation has not been
      clarified. We investigated the effect of sour solutions on the elicitation of
      reflex swallowing in anesthetized rats. The main ducts of salivary glands were
      ligated to avoid the effect of saliva. A small amount of water, sour solutions,
      and other taste solutions were applied to the mucosa of the pharyngolaryngeal
      region. Acetic acid and citric acid, which provide a sour taste, had a stronger
      effect on evoking reflex swallowing as compared with other taste solutions. The
      effectiveness of these acids increased with increasing concentrations. We also
      examined the contribution of the superior laryngeal nerve (SLN) and the
      pharyngeal branch of the glossopharyngeal nerve (GPNph) to reflex swallowing.
      Acetic acid was greatly effective in evoking swallowing in both the region
      innervated by the SLN and the GPNph. On the other hand, water was effective in
      the SLN region but only slightly effective in the GPNph region. The results
      indicate that stimulation of the pharyngolaryngeal region with sour solutions
      facilitates reflex swallowing, suggesting that the facilitation may be due to
      increases of sensory inputs via the SLN and GPNph.

PMID- 12419409
TI  - Stress-induced social avoidance: a new model of stress-induced anxiety?
AB  - We have studied the long-term behavioral effects of a single stressor in male
      rats by using an approach/avoidance situation as the behavioral endpoint. A
      single exposure to social defeat or electric shocks was used as stressors.
      Behavioral testing was performed in a two-compartment cage divided by an opaque
      wall and connected by a short tunnel. The larger compartment contained an
      unfamiliar male rat that was separated from the rest of the compartment by a
      transparent, perforated Plexiglas wall. The subject was placed in the small
      compartment and allowed to explore the cage for 5 min. The test was performed on
      Days 1, 5, or 10 after stress application. Unstressed rats spent 90% of time in
      the large compartment that contained the unfamiliar male. Social defeat
      dramatically reduced the exploration of the large compartment, without time
      related changes in this response. A mild electric shock had a similar effect that
      lasted more than 5 days but less than 10 days. The exploration of an empty cage
      was significantly less inhibited by stress than the exploration of a cage that
      contained the stimulus rat. The test could be applied repeatedly in the same rat,
      without major changes in the response. Chlordiazepoxide applied 1 h before
      behavioral testing abolished completely the stress-induced behavioral deficit. We
      suggest that the model can be used for studying the effects of various compounds
      on stress-induced anxiety.

PMID- 12419410
TI  - The effects of a confectionery snack on attention in young boys.
AB  - The relationship between consumption of a confectionery snack after an overnight
      fast and cognitive function was examined using a variety of cognitive tasks,
      including spatial memory, verbal memory, attention, visual perception and short
      term memory, in a sample of 21 boys, ages 9-12 years. Performance on the
      vigilance attention task was significantly improved when the participants
      consumed a confectionery snack compared to consumption of a noncalorie snack.
      Participants had significantly higher hit rates and significantly lower miss
      rates after the confectionery snack. In addition, false alarm rates increased as
      a function of time for the placebo condition and decreased for the confectionery
      condition. Thus, the confectionery snack enhanced ability to stay on task for an
      extended period of time, enabling the children to more accurately identify target
      information, as well as correctly reject nontarget information. Analysis of the
      types of errors made also revealed that when the children were in the
      confectionery condition they were less likely to make more glaring errors. No
      significant differences were found in tests of digit span, verbal memory, spatial
      memory or visual perception.

PMID- 12419411
TI  - Is the nonREM-REM sleep cycle reset by forced awakenings from REM sleep?
AB  - In selective REM sleep deprivation (SRSD), the occurrence of stage REM is
      repeatedly interrupted by short awakenings. Typically, the interventions
      aggregate in clusters resembling the REM episodes in undisturbed sleep. This
      salient phenomenon can easily be explained if the nonREM-REM sleep process is
      continued during the periods of forced wakefulness. However, earlier studies have
      alternatively suggested that awakenings from sleep might rather discontinue and
      reset the ultradian process. Theoretically, the two explanations predict a
      different distribution of REM episode duration. We evaluated 117 SRSD treatment
      nights recorded from 14 depressive inpatients receiving low dosages of
      Trimipramine. The alarms were triggered by an automatic mechanism for the
      detection of REM sleep and had to be canceled by the subjects themselves. The REM
      episodes were determined as in undisturbed sleep-they had to include the
      remaining REM activity and were separated by 30 min without REM epochs. The
      frequency histogram of REM episodes declined exponentially with episode duration
      for each of the first four sleep cycles. The duration of nonREM intervals
      revealed bimodal distributions. These results were found consistent with the
      model assuming a reset of the ultradian cycle upon awakening. Whether REM or
      nonREM activity is resumed on return to sleep can be modeled by a random decision
      whereby the probability for REM sleep might depend on the momentary REM pressure.

PMID- 12419412
TI  - Central 5-HT(3) receptors and water intake in rats.
AB  - In the present paper, we studied in rats the effect of third ventricle
      administration of m-chlorophenylbiguanide hydrochloride (1-(3
      chlorophenyl)biguanide (m-CPBG), a selective 5-HT(3) agonist, on water intake
      induced by three different physiological stimuli: water deprivation, acute salt
      load and hypovolemia. Central acute m-CPBG injections in the doses of 80 and 160
      nmol significantly reduced water intake elicited by an acute salt load. Third
      ventricle injections of m-CPBG in the dose of 160 nmol significantly inhibited
      water intake in hypovolemic animals, whereas third ventricle injections of m-CPBG
      in a higher dose (320 nmol) were necessary to decrease water intake in water
      deprived rats. Pretreatment with 1-methyl-N-[8-methyl-8-azabicyclo(3.2.1)-oct-3
      yl]-1H-indazole-3-carboxamide (LY-278,584), a selective 5-HT(3) antagonist,
      abolished the inhibitory effect on water intake seen after central administration
      of m-CPBG in all groups studied. The central administration of m-CPBG was also
      able to inhibit water intake induced by pharmacological activation of central
      cholinergic and angiotensinergic pathways. Third ventricle injections of m-CPBG
      in the highest dose employed in this study (320 nmol) were unable to modify food
      intake in food-deprived rats. An aversion test has shown that acute third
      ventricle injections of m-CPBG do not induce illness-like effects that could
      explain the water intake inhibition here observed. Also, central administration
      of m-CPBG did not modify the intake of a "dessert" meal consisting of diluted
      condensed milk. It is concluded that central 5-HT(3) receptor activation exerts a
      specific inhibitory effect on water intake.

PMID- 12419413
TI  - Removal of polysialic acid from the SCN potentiates nonphotic circadian phase
      resetting.
AB  - The adult suprachiasmatic nucleus (SCN) expresses a polysialylated form of neural
      cell adhesion molecule (PSA-NCAM) that modulates cell interactions. Previous
      studies have shown that PSA is important for photic entrainment of the SCN
      circadian clock, suggesting that changes in cell-cell interactions may contribute
      to the phase-resetting capacity of this system. A possible role for PSA in
      nonphotic circadian phase resetting was evaluated using the enzyme
      endoneuraminidase (endo N) to selectively remove PSA from the SCN. Pretreatment
      of rat brain slices containing the SCN with endo N enhanced the daytime phase
      advancing effects of the serotonin agonist, 8-hydroxy-2-dipropylaminotetralin [8
      OH-DPAT] (41% greater than inactivated enzyme controls; P<.05). Similarly,
      removal of PSA from the Syrian hamster SCN in vivo potentiated the daytime phase
      advancing effects of behavioral arousal (sleep deprivation) and of systemic
      application of 8-OH-DPAT (61% and 220% greater, respectively, than inactivated
      enzyme controls; both P<.05). While endo N perturbation of both photic and
      nonphotic phase resetting suggests that PSA plays a central role in clock
      regulation, it is striking that the effects on the two inputs are opposite in
      direction. This difference could reflect the antagonistic relationship between
      photic and nonphotic signaling pathways. It could also be explained by a
      permissive role of PSA common to both inputs, which in and of itself would not
      specify direction of response. Such a bidirectional control mechanism, based on
      PSA's attenuation of cell-cell interactions, is well documented in the developing
      nervous system, and may be retained in plastic regions of the adult brain.

PMID- 12419414
TI  - Estrogen restores cognition and cholinergic phenotype in an animal model of Down
      syndrome.
AB  - Estrogen maintains normal function of basal forebrain (BF) cholinergic neurons
      and estrogen replacement therapy (ERT) has therefore been proposed as a therapy
      for Alzheimer's disease (AD). We provide evidence to support this hypothesis in
      an animal model of Down syndrome (DS), a chromosome 16 segmental trisomy (Ts65Dn)
      mouse. These mice develop cholinergic degeneration similar to young adults with
      DS and AD patients. ERT has not been tested in women with DS, even though they
      are more likely than normosomic women to develop early menopause and AD. Female
      Ts65Dn and normosomic mice (11-15 months) received a subcutaneous estrogen pellet
      or a sham operation. After 60 days, estrogen treatment improved learning of a T
      maze task and normalized behavior in the Ts65Dn mice in reversal learning of the
      task, a measure of cognitive flexibility. Stereological evaluation of choline
      acetyltransferase (ChAT) immunopositive BF neurons showed that estrogen increased
      cell size and total number of cholinergic neurons in the medial septum of Ts65Dn
      mice. In addition, estrogen increased NGF protein levels in the BF of trisomic
      mice. These findings support the emerging hypothesis that estrogen may play a
      protective role during neurodegeneration and cognitive decline, particularly in
      cholinergic BF neuronal systems underlying cognition. The findings also indicate
      that estrogen may act, at least partially, via endogenous growth factors.
      Collectively, the data suggest that ERT may be a viable therapeutic approach for
      women with DS coupled with dementia.

PMID- 12419415
TI  - Reduced voluntary activity precedes adult-onset obesity in Nhlh2 knockout mice.
AB  - Targeted deletion of the neuronal basic helix-loop-helix transcription factor
      Nhlh2 results in adult-onset obesity in mice. Measurement of body weight and body
      composition in animals aged 3-25 weeks indicates that while male and female Nhlh2
      knockout (N2KO) animals both show adult-onset obesity, the time frame for
      development of obesity is different, with females becoming obese by 7 weeks of
      age and males becoming obese by 10 weeks of age. Heterozygous (HET) animals also
      become obese but with a slower onset, indicating a dosage effect for the activity
      of the Nhlh2 transcription factor. Food intake, body temperature, and voluntary
      activity were measured in both preobese and obese N2KO, HET, and wild-type (WT)
      animals to determine which factors contributed to weight gain. While increased
      food intake and decreased body temperature were found in older obese N2KO
      animals, only reduced physical activity preceded the onset of obesity in N2KO
      mice. N2KO animals had no deficit in either circadian rhythm or balance and motor
      control, indicating that reduced voluntary activity is the result of a behavioral
      change. These data demonstrate a role for the Nhlh2 transcription factor in
      controlling genes important to energy expenditure, and more specifically
      voluntary physical activity of animals.

PMID- 12419416
TI  - The effects of piracetam on cognitive performance in a mouse model of Down's
      syndrome.
AB  - Piracetam is a nootropic agent that has been shown to improve cognitive
      performance in a number of animal model systems. Piracetam is reported to be used
      widely as a means of improving cognitive function in children with Down's
      syndrome (DS). In order to provide a preclinical assessment of the potential
      efficacy of piracetam, we examined the effects of a dose range of piracetam in
      the Ts65Dn mouse model of DS. Ts65Dn mice are trisomic for a region of mouse
      chromosome 16 with homology to human chromosome 21. Daily piracetam treatment at
      doses of 0, 75, 150, and 300 mg/kg ip was initiated in 6-week-old male Ts65Dn and
      euploid control mice. Following 4 weeks of treatment, mice were tested in the
      visible and hidden-platform components of the Morris water maze and were placed
      overnight in computerized activity chambers to assess effects on overall
      activity. Piracetam treatment was continued through the 4 weeks of testing. In
      control mice, 75 and 150 mg/kg/day piracetam improved performance in both the
      visible- and hidden-platform tasks. Although low doses of piracetam reduced
      search time in the visible-platform component in Ts65Dn mice, all piracetam doses
      prevented trial-related improvements in performance in Ts65Dn mice. The 300
      mg/kg/day-piracetam dose was associated with a reversal of the nocturnal
      spontaneous hyperactivity in Ts65Dn. These data do not provide support for
      piracetam treatment for individuals with DS.

PMID- 12419417
TI  - Central melanocortin receptor agonist reduces spontaneous and scheduled meal size
      but does not augment duodenal preload-induced feeding inhibition.
AB  - Central melanocortin (MC) receptor agonists inhibit food intake and may be
      downstream mediators of the effects of central leptin, which (1) reduces food
      intake by selectively decreasing meal size and (2) augments the feeding
      inhibitory effects of gastrointestinal food stimuli. Central administration of
      the MC-3/4 receptor (MC-3/4R) agonist, MTII, inhibits feeding in rats, but its
      effects on meal pattern and potential interactions with gastrointestinal controls
      of food intake remain unclear. We examined meal patterns and intake in male
      Sprague-Dawley rats following central intracerebroventricular administration of
      MTII (0.01-1.0 nmol) in two situations: (1) during daytime 60-min scheduled
      access to liquid glucose (12.5%) in combination with a duodenal preload of 12.5%
      glucose or physiological saline (4.4 ml/10 min), and (2) during subsequent
      overnight access to 45 mg of solid chow pellets. Both duodenal glucose preloads
      and MTII reduced subsequent glucose intake. However, no dose of MTII augmented
      the reductions in food intake produced by duodenal glucose alone. During
      overnight access to pelleted chow, the 0.1- and 1.0-nmol doses of MTII reduced
      food intake, meal size, meal duration, and body weight, and increased the satiety
      ratio (duration of intermeal interval/preceding meal size) but did not change
      meal frequency. The present data (1) demonstrate that MTII, like leptin, reduces
      food intake by a selective reduction in meal size and not meal frequency, and (2)
      suggest that MTII increases the feeding-inhibitory potency of negative feedback
      signals critical to the control of meal size during spontaneous chow access, but
      not scheduled access to palatable liquid nutrient solutions.

PMID- 12419418
TI  - The effects of adrenalectomy and aldosterone replacement in transgenic mice
      expressing antisense RNA to the type 2 glucocorticoid receptor.
AB  - Bilateral adrenalectomy (ADX) either prevents or attenuates obesity in several
      animal models. Mice that express an antisense RNA to the glucocorticoid receptor
      (GCR) are obese. The present study was conducted to examine the effects of ADX
      and aldosterone (ALDO) replacement on the rate of weight gain and body
      composition of mice bearing an antisense GCR gene construct. Twenty-eight male
      transgenic mice bearing the antisense GCR construct and 16 male B6C/3F1 mice were
      either bilaterally ADX or given sham operations. At the time of surgery, some of
      the ADX mice and all of the sham-operated mice were implanted with 100-mg
      cholesterol (CHOL) pellets inserted subcutaneously in the subscapular region. The
      remaining ADX mice were implanted with 100-mg 1% w/w ALDO pellets using CHOL as
      vehicle. All mice were returned to their home cages for 2 weeks. They were then
      decapitated and the blood was collected for corticosterone, ALDO, insulin, and
      leptin radioimmunoassay. Carcasses were eviscerated and prepared for gravimetric
      analyses, including bomb calorimetry. ADX resulted in a significant drop in
      carcass fat in both transgenic and wildtype groups. ALDO prevented the decrease
      in carcass fat in both groups. Two weeks after ADX, transgenic mice were as fat
      as sham-operated wildtype controls, whereas both sham-operated and ALDO-treated
      transgenic groups were significantly fatter. Despite observing a reliable
      decrease in carcass fat following ADX, no corresponding decrease in circulating
      leptin was found.

PMID- 12419419
TI  - Copulation-contingent aversive conditioning and sexual incentive motivation in
      male rats: evidence for a two-stage process of sexual behavior.
AB  - Male rats were tested for sexual incentive motivation and for copulatory behavior
      during acquisition of a copulation-malaise association. One group received an
      injection of 20 ml/kg of 0.15 M LiCl 1 min after ejaculation with a capelin oil
      scented female and the other group received saline. LiCl was administered
      independently of copulation to this group. The subjects in the conditioned group
      showed reduced sexual motivation after two conditioning sessions, and copulation
      was almost extinguished after five sessions. At a postconditioning test with an
      unscented female, there was no group difference with regard to sexual motivation
      but the conditioned group still showed suppression of copulatory behavior. These
      data show that sexual incentive motivation and copulatory behavior can vary
      independently and that the associations copulation-malaise and scented female
      malaise had been established during conditioning.

PMID- 12419420
TI  - Brain NGF and EGF administration improves passive avoidance response and
      stimulates brain precursor cells in aged male mice.
AB  - Nerve growth factor (NGF) has been shown to improve damage in spatial cognition
      following aging, whereas epidermal growth factor (EGF) is important in brain cell
      proliferation. It is also known that the adult mammalian central nervous system
      contains persistent progenitor cells with characteristics of stem cells. These
      studies suggest that under appropriate external stimuli progenitor cells may
      generate neuronal and glial cells promoting recovery of the injured nervous
      system. However, little is known about the presence and responsiveness of
      progenitor cells in the aged brain. In the present investigation, we studied the
      effect of brain intracerebroventricular injections of EGF and/or NGF on
      progenitor cells of the subventricular area (SVZ) in aged male mice to test
      learning performances in the passive avoidance apparatus. We found that neither
      NGF nor EGF improved learning responses. However, combined NGF and EGF
      administration in the brain improved learning responses of aged mice in the
      passive avoidance when compared with aged matched nontreated controls. These
      findings resulted to be associated with increased immunopositivity to progenitor
      cells in the SVZ. The possible functional implications of these data are
      discussed.

PMID- 12419421
TI  - Effects of subcutaneous administration of the gamma-aminobutyric acid(A) receptor
      agonist muscimol on water intake in water-deprived rats.
AB  - The effects of the gamma-aminobutyric acid(A) (GABA(A)) receptor agonist muscimol
      were investigated on water intake in rats that had been deprived of water for 16
      h. Muscimol (0.5-2.0 mg/kg sc) produced a dose-related inhibition of water
      consumption in both male (n=8) and female (n=8) rats, with maximal suppression of
      drinking occurring during the first 30 min after administration. Doses of 1 and 2
      mg/kg produced significant decreases in water intake (P<.01), while a lower dose
      of 0.5 mg/kg was without effect. The hypodipsic effect of muscimol (1.0 mg/kg sc)
      was abolished by pretreatment of the animals with the GABA(A) receptor antagonist
      bicuculline (1 mg/kg sc). Furthermore, muscimol (2 mg/kg sc) did not produce
      aversion in a two-bottle conditioned taste aversion test, indicating that the
      suppressant effects of muscimol on water intake are not due to drug-induced
      malaise. The results suggest that systemic administration of muscimol produces a
      behaviourally specific suppression of primary drinking in rats by a GABA(A)
      receptor-mediated mechanism. Moreover, this action of muscimol appears to be
      independent of the gender of the animals.

PMID- 12419422
TI  - Individual differences in behavioral and physiological responses to restraint
      stress in pigs.
AB  - Several recent studies on pigs have demonstrated a relationship between the
      degree of resistance displayed early in life in a so-called backtest and a
      variety of behavioural and physiological responses in piglets and young fattening
      pigs. To study whether pigs with diverging responses in the backtest, i.e., high
      resisting (HR) and low-resisting (LR) pigs, differ also in adulthood in their
      responses to an acute stressor, adult nulliparous HR (n=36) and LR gilts (n=36)
      housed in groups or stalls were challenged by 5-min fixation with a nose sling.
      During the first minute of restraint, HR gilts vocalised significantly more than
      LR gilts. Over the whole 5-min period, HR gilts tended to vocalise more than LR
      gilts. Housing or backtest type did not affect immediate cortisol increase
      (Delta(-5 min; 15 min)). At t=45 min, cortisol concentrations in HR gilts but not
      in LR gilts were still higher than at t=-5 min. Heart rate quickly decreased
      during the first min of restraint and remained fairly constant thereafter.
      Estimated heart rate after 5 min of nose sling was significantly lower in HR
      gilts compared to LR gilts. Housing or backtest type did not affect heart rate
      variability indices. The results support the idea that the backtest relates to
      individual characteristics, which at an adult age also seem to play a role in the
      regulation of certain behavioral and physiological responses to short-term
      stress.

PMID- 12419423
TI  - The hidden persuaders: subtle advertising in radiation oncology.

PMID- 12419424
TI  - Clinical research in neutron capture therapy.

PMID- 12419425
TI  - Can elective nodal irradiation be omitted in stage III non-small-cell lung
      cancer? Analysis of recurrences in a phase II study of induction chemotherapy and
      involved-field radiotherapy.
AB  - PURPOSE: To establish the recurrence patterns when elective mediastinal
      irradiation was omitted, patients with Stage III non-small-cell lung cancer were
      treated with sequential chemotherapy (CHT) and involved-field radiotherapy (RT).
      METHODS AND MATERIALS: Fifty patients were treated with either two or four cycles
      of induction CHT, followed by once-daily involved-field RT to 70 Gy, delivered
      using three-dimensional treatment planning. The contoured gross tumor volume
      consisted of the pre-CHT tumor volume and nodes with a short-axis diameter of >
      or = 1 cm. Patients were reevaluated at 3 and 6 months after RT using
      bronchoscopy and chest CT. Elective nodal failure was defined as recurrence in
      the regional nodes outside the clinical target volume, in the absence of in-field
      failure. RESULTS: Of 43 patients who received doses > or = 50 Gy, 35% were
      disease free at last follow-up; in-field recurrences developed in 27% (of whom
      16% had exclusively in-field recurrences); 18% had distant metastases
      exclusively. No elective nodal failure was observed. The median actuarial overall
      survival was 18 months (95% confidence interval 14-22) and the median progression
      free survival was 12 months (95% confidence interval 6-18). CONCLUSION: Omitting
      elective mediastinal irradiation did not result in isolated nodal failure. Future
      studies of concurrent CHT and RT for Stage III non-small-cell lung cancer should
      use involved-field RT to limit toxicity.

PMID- 12419426
TI  - Failure of T stage to predict survival in patients with non-small-cell lung
      cancer treated by radiotherapy with or without concomitant chemotherapy.
AB  - PURPOSE: Because T stage does not consistently reflect tumor size in non-small
      cell lung cancer (NSCLC), we hypothesized that T stage may be of limited
      prognostic value in patients with locoregional NSCLC treated by nonsurgical
      means. METHODS AND MATERIALS: The study population consisted of 243 patients with
      histologically or cytologically proven NSCLC treated in three consecutive
      prospective trials between 1989 and 1998. The eligibility criteria for this
      analysis included planned for and began treatment at 60 Gy; Eastern Cooperative
      Oncology Group (ECOG) performance status 0 or 1; weight loss < or = 10%; no prior
      treatment; and no supraclavicular nodes, pleural effusion, or distant metastases.
      In the first study, 204 patients were randomized to receive conventional or
      accelerated radiotherapy (RT) with or without concomitant carboplatin. In the
      second, 15 patients were treated with concomitant cisplatin, etoposide, and RT in
      a single-arm study. In the third, 24 patients were treated with concomitant
      carboplatin, 5-fluorouracil, and RT in a dose-escalation study. RESULTS: A total
      of 231 patients for whom the T and N stage were known met the eligibility
      criteria. The patient characteristics were 77% male, 64% squamous histologic
      features, 33% ECOG status of 0, and 69% no weight loss. The nodal status was 36%
      N0, 7% N1, 52% N2, and 5% N3. The estimated median survival for all patients was
      1.4 years (95% confidence interval 1.2-1.6), with an estimated 10% surviving 5
      years (95% confidence interval 7-15). No significant difference was found in
      survival among the three trials (p = 0.16). The estimated median survival time
      and 5-year survival rate according to T stage were as follows: T1 (n = 29), 1.6
      years and 16%; T2 (n = 88), 1.3 years and 9%; T3 (n = 59), 1.4 years and 9%; and
      T4 (n = 55), 1.4 years and 9%. No significant trend was found in overall survival
      according to T stage (p = 0.85, log-rank). To test whether a significant effect
      of T stage on overall survival existed after adjusting for N stage, trial, ECOG
      status, and weight loss, a multifactor analysis using Cox proportional hazards
      regression analysis was carried out. There was still no significant effect of T
      stage on survival (p = 0.66) when all factors were taken into account.
      CONCLUSION: Although there is some evidence that T stage is an independent
      prognostic factor in patients with NSCLC treated surgically, it did not appear to
      be of value in this series of patients treated with RT with and without
      concomitant chemotherapy.

PMID- 12419427
TI  - Accelerated hypofractionation for early-stage non-small-cell lung cancer.
AB  - PURPOSE: To describe the outcome of treating early-stage non-small-cell lung
      cancer (NSCLC) with an accelerated hypofractionated course of radiotherapy.
      METHODS AND MATERIALS: A policy of treating early-stage NSCLC with a dose of 48
      Gy in 12 once-daily fractions without elective irradiation of radiologically
      uninvolved regional nodes was adopted in 1996. We describe the outcome in 33
      patients with NSCLC treated with this dose-fractionation schedule. RESULTS: The
      median patient age was 72.0 years. Most patients (75.8%) were not surgical
      candidates because of medical comorbidities or old age. For staging, 97.0%
      underwent CT of the thorax, and mediastinoscopy was performed in 6.1%. All
      patients had Stage T1-T2N0, except for 4 patients with positive nodes based on
      pathologically involved or clinically enlarged lymph nodes adjacent to the
      primary tumor. The overall survival rate was 80.1% at 1 year and 46.0% at 2
      years. The median survival was 22.6 months. The cause-specific survival rate was
      89.8% at 1 year and 54.1% at 2 years. The recurrence-free survival rate was 66.4%
      at 1 year and 40.0% at 2 years. Lateral radiotherapy field margins of <2 cm
      predicted for inferior overall survival, cause-specific survival, and recurrence
      free survival on univariate and multivariate analyses (p <0.05). The most
      commonly reported toxicities were acute dermatitis (30.3%) and late
      cutaneous/subcutaneous fibrosis (24.2%). CONCLUSION: Accelerated
      hypofractionation for early-stage NSCLC appears to be safe and produces promising
      early results. Very small radiotherapy field margins may lead to an inferior
      outcome. Prospective studies are needed to determine the optimal dose
      fractionation schedule.

PMID- 12419428
TI  - Dose-response relationship between probability of pathologic tumor control and
      glucose metabolic rate measured with FDG PET after preoperative chemoradiotherapy
      in locally advanced non-small-cell lung cancer.
AB  - PURPOSE: To determine the dose-response relationship between the probability of
      tumor control on the basis of pathologic tumor response (pTCP) and the residual
      metabolic rate of glucose (MRglc) in response to preoperative chemoradiotherapy
      in locally advanced non-small-cell lung cancer and to define the level of
      residual MRglc that corresponds to pTCP 50% and pTCP > or = 95%. METHODS AND
      MATERIALS: Quantitative dynamic 18F-2-fluoro-2-deoxy-D-glucose (18F-FDG) positron
      emission tomography was performed to measure regional MRglc at the primary lesion
      before and 2 weeks after preoperative chemoradiotherapy in an initial group of 13
      patients with locally advanced NSCLC. A simplified kinetic method was developed
      subsequently from the initial dynamic study and used in the subsequent 16
      patients. The preoperative radiotherapy programs consisted of (1) a split course
      of 42 Gy in 28 fractions within a period of 28 days using a twice-daily treatment
      schedule for Stage IIIA(N2) NSCLC (n = 18) and (2) standard once-daily radiation
      schedule of 45-63 Gy in 25-35 fractions during a 5-7-week period (n = 11). The
      preoperative chemotherapy regimens included two cycles of cisplatin, vinblastine,
      and 5-fluorouracil (n = 24), cisplatin and etoposide (n = 2), and cisplatin,
      Taxol, and 5-fluorouracil (n = 3). Patients free of tumor progression after
      preoperative chemoradiotherapy underwent surgery. The degree of residual MRglc
      measured 2 weeks after preoperative chemoradiotherapy and 2 weeks before surgery
      was correlated with the pathologic tumor response. The relationship between MRglc
      and pTCP was modeled using logistic regression. RESULTS: Of 32 patients entered
      into the study, 29 (16 men and 13 women; 30 lesions) were evaluated for the
      correlation between residual MRglc and pathologic tumor response. Three patients
      did not participate in the second study because of a steady decline in general
      condition. The median age was 60 years (range 42-78). One of the 29 patients had
      two separate lesions, and MRglc was measured in each separately. The tumor
      histologic types included squamous cell carcinoma (n = 9), adenocarcinoma (n =
      13), large cell carcinoma (n = 6), and poorly differentiated carcinoma (n = 2).
      The extent of the primary and nodal disease was as follows: Stage IIB (T3N0M0),
      Pancoast tumor (n = 2); Stage IIIA, T2-T3N2M0 (n = 18); Stage IIIB: T1-T3N3M0 (n
      = 5) and T4N0M0 (n = 2); a second lesion, T1 (n = 1); and localized stump
      recurrence (n = 2). A pathologically complete response was obtained in 14 (47%)
      of the 30 lesions. The remaining 16 lesions had residual cancer. The mean
      baseline value of the maximal MRglc was 0.333 +/- 0.087 micromol/min/g (n = 16),
      and it was reduced to 0.0957 +/- 0.059 micromol/min/g 2 weeks after
      chemoradiotherapy (p = 0.011). The correlation between residual MRglc and pTCP
      was made using an increment value of 0.02 micromol/min/g between the maximal and
      minimal values of MRglc. A pathologically complete response was obtained in 6 of
      6 patients with residual MRglc of < or = 0.050 micromol/min/g, 3 of 4 with < or =
      0.070, 4 of 7 with < or = 0.090, 0 of 4 with < or = 0.110, 1 of 3 with < or =
      0.130, and 0 of 6 with > or = 0.130 micromol/min/g. The fitted logistic model
      showed that residual MRglc corresponding to pTCP 50% and pTCP > or = 95% was
      0.076 and < or = 0.040 micromol/min/g, respectively. CONCLUSION: The correlation
      between the gradient of residual MRglc after chemoradiotherapy and pTCP is an
      inverse dose-response relationship. Residual MRglc of 0.076 and < or = 0.040
      micromol/min/g, representing pTCP 50% and pTCP > or = 95%, respectively, may be
      useful surrogate markers for the tumor response to radiotherapy or
      chemoradiotherapy in lung cancer.

PMID- 12419429
TI  - Interim report of toxicity from 3D conformal radiation therapy (3D-CRT) for
      prostate cancer on 3DOG/RTOG 9406, level III (79.2 Gy).
AB  - PURPOSE: A prospective Phase I dose escalation study was conducted to determine
      the maximally tolerated radiation dose in men treated with three-dimensional
      conformal radiotherapy (3D-CRT) for localized prostate cancer. This is a
      preliminary report of toxicity at Level III (79.2 Gy) on 3D Oncology
      Group/Radiation Therapy Oncology Group (RTOG) 9406. METHODS AND MATERIALS:
      Between November 26, 1996 and October 1, 1998, 173 patients with clinically organ
      confined prostate cancer (T1 and T2) were accrued to a Level III dose of 79.2 Gy.
      One hundred sixty-nine patients were available for analysis of toxicity. Patients
      were registered to two groups according to the risk of seminal vesicle invasion
      (SVI) on the basis of presenting PSA and Gleason score. Group 1 patients had a
      calculated risk of SVI <15%, and Group 2 patients had a risk of SVI > or = 15%.
      For Group 1 patients, the planning target volume (PTV) margins were 5-10 mm
      around the prostate only. For Group 2 patients, the same margins were applied to
      the prostate and seminal vesicles (PTV(1)) for the initial 55.8 Gy; then
      treatment volume was reduced to the prostate only (PTV(2)). To reduce the rectal
      dose on dose Level III, the minimum PTV dose was limited to 73.8 Gy, whereas the
      minimum gross target volume dose was 79.2 Gy, both in 44 fractions. The incidence
      of > or = 3 Grade late effects was compared to that in a similar group of
      patients treated on RTOG 7506 and 7706 studies. RESULTS: Acute tolerance to 79.2
      Gy was excellent with no patients experiencing > or = Grade 3 acute toxicity. The
      acute toxicity rate was comparable to that reported for previous lower dose
      levels. With the median follow-up of 3.3 years (range: 0.4-4.4 years), a total of
      4 patients (2.4%) experienced Grade 3 late toxicity, three cases of which were
      related to the bladder, and one related to the rectum. There were no Grade 4 or 5
      late complications noted during the period of observation. These results are also
      comparable to those reported at dose Levels I and II. The expected incidence of >
      or = 3 Grade 3 late toxicity was calculated using historical data from two
      previous RTOG prostate cancer trials, 7506 and 7706. The calculated risk
      accounted for the difference in follow-up duration between patients in this study
      and the historical experience. The observed rate of > or = Grade 3 late effects
      for Group 1 (two cases) is significantly lower (p = 0.0002) than the 17.6 cases
      that would have been expected from the historical control. The observed rate for
      Group 2 (two cases) was also significantly lower (p = 0.0037) than the 12.1 cases
      expected. CONCLUSION: Based on excellent tolerance of 3D-CRT for stages T1 and T2
      prostate cancer, further biological dose escalation has been pursued to Levels IV
      and V, 74 Gy and 78 Gy, respectively, at 2 Gy per day, in an attempt to reduce
      the total treatment duration. This trial has closed. A Phase III comparative RTOG
      trial is being developed to determine whether high-dose 3D-CRT improves efficacy.

PMID- 12419430
TI  - Biochemical disease-free survival following adjuvant and salvage irradiation
      after radical prostatectomy.
AB  - PURPOSE: To present the biochemical cure rates (biochemically no evidence of
      disease) after external irradiation (RT) in patients with high-risk prostate
      cancer after radical prostatectomy. METHODS AND MATERIALS: Seventy-six patients
      who underwent radical prostatectomy and subsequent RT were included in this
      analysis. No patient received hormonal therapy. Adjuvant RT was administered in
      35 patients (46%), and 41 patients (54%) underwent salvage RT. After
      prostatectomy, the Gleason score was <7 in 87%, and 24% had seminal vesicle
      invasion. The median RT dose in the adjuvant RT and salvage RT groups was 60 Gy
      and 65 Gy, respectively. The biochemical cure rate was defined as a serum
      prostate-specific antigen of < or =0.2 ng/mL. RESULTS: The overall 5-year Kaplan
      Meier biochemical control rate from the end of RT was 70%. The 5-year biochemical
      cure rate for adjuvant RT was significantly superior to that after salvage RT
      (86% vs. 57%). The significant predictors of biochemical failure were seminal
      vesicle invasion in the adjuvant RT group and the presence of Gleason grade 4 or
      5 in the salvage RT group. The clinical local control rate in the prostate bed
      was 100%. CONCLUSION: This report demonstrates the efficacy of RT in achieving
      high biochemical cure rates after radical prostatectomy. Additional clinical
      studies are required to determine the optimal treatment of patients at high risk
      of biochemical failure after postprostatectomy RT.

PMID- 12419431
TI  - The importance of radiation doses to the penile bulb vs. crura in the development
      of postbrachytherapy erectile dysfunction.
AB  - PURPOSE: Recent studies have implicated the proximal penis as a potential site
      specific structure for radiation-related erectile dysfunction (ED). In this
      study, we evaluated by means of a validated patient-administered questionnaire
      whether radiation doses to the bulb of the penis and/or the proximal corporeal
      bodies were predictive for the development of brachytherapy-induced ED. METHODS
      AND MATERIALS: Thirty patients who underwent permanent prostate brachytherapy
      between April 1995 and October 1999 and developed brachytherapy-induced ED were
      paired with 30 similar men who maintained potency after implantation. None of the
      60 patients received supplemental external beam radiation therapy, either before
      or after implantation. Potency was assessed by patient self-administration of the
      specific erectile questions of the International Index of Erectile Function. The
      questionnaire consisted of 5 questions with a maximum score of 25. Postimplant
      potency was defined as an International Index of Erectile Function score > or
      =11. Mean and median follow-up was 48.3 +/- 14.4 months and 48.0 months,
      respectively (range: 26.6-79.3 months). The bulb of the penis and the proximal
      crura were outlined at 0.5-cm intervals on the Day 0 postimplant CT scan. The
      radiation dose distribution to the bulb of the penis and adjacent crura was
      defined in terms of the minimum dose delivered to 25%, 50%, 70%, 75%, 90%, and
      95% of the bulb (D(25), D(50), D(70), D(75), D(90), and D(95)). RESULTS: The
      radiation dose delivered to the bulb of the penis and the proximal crura in men
      with brachytherapy-induced ED was statistically greater for all evaluated
      dosimetric parameters (D(25), D(50), D(70), D(75), D(90), and D(95)). Stepwise
      linear regression analysis indicated that penile bulb dose parameter D(50), the
      postimplant prostate CT volume, and patient age at implant were predictive of
      postimplant ED, whereas the crura dose D(25) approached statistical significance.
      Seventy-five percent of the impotent men had a bulb D(25) >60% of prescribed
      minimum peripheral dose (mPD), whereas 80% of potent men had a bulb D(25) < or
      =60% mPD. Using the D(50) bulb parameter, 70% of ED men had a dose >40% mPD,
      whereas 90% of potent men had a dose < or =40% mPD. Similar cut points for D(25)
      and D(50) crura doses were 40% and 28% mPD. The crura D(25) cut point was
      exceeded by 50% of the ED patients and only 7% of the potent patients.
      CONCLUSION: This is the first study to evaluate potency preservation and
      radiation doses to the proximal penis by means of a validated patient
      administered quality-of-life instrument. Our data confirm prior reports that
      radiation doses to the proximal penis are predictive of brachytherapy-induced ED.
      In a stepwise linear regression analysis, the strongest predictors of potency
      preservation were bulb D(50), postimplant prostate CT volume, and patient age.
      With Day 0 dosimetric evaluation, the penile bulb D(50) and D(25) should be
      maintained below 40% and 60% mPD, respectively, whereas the crura D(50) and D(25)
      should be maintained below 40% and 28% mPD, respectively, to maximize
      posttreatment potency.

PMID- 12419432
TI  - Meta-analysis of rates of erectile function after treatment of localized prostate
      carcinoma.
AB  - PURPOSE: The results of a 1997 meta-analysis of the rates of erectile function
      after external beam radiotherapy (EBRT) and radical prostatectomy have been
      widely used in patient and professional education materials and as a reference
      against which new findings are compared. With a number of recent publications, it
      is now possible to update this analysis and compare brachytherapy with or without
      EBRT with EBRT alone, standard and nerve-sparing radical prostatectomy, and
      cryotherapy. METHODS: A comprehensive literature review and subsequent meta
      analysis of the rates of erectile dysfunction associated with the treatments of
      localized prostate carcinoma was conducted. A simple logistic regression analysis
      was used to combine the data from the 54 articles that met the selection
      criteria. RESULTS: The predicted probability of maintaining erectile function
      after brachytherapy was 0.76, after brachytherapy plus EBRT 0.60, after EBRT
      0.55, after nerve-sparing radical prostatectomy 0.34, after standard radical
      prostatectomy 0.25, and after cryotherapy 0.13. When only studies reporting > or
      = 2 years follow-up were considered, the only significant change was a decline in
      the probability for nerve-sparing radical prostatectomy. No brachytherapy studies
      had a follow-up of > or = 2 years. When the probabilities were adjusted for age,
      the spread between the RT methods and surgical approaches was greater.
      CONCLUSION: The differences in the probability of maintaining erectile function
      after different treatments of localized prostate cancer are significant.

PMID- 12419433
TI  - Postoperative adjuvant chemoradiation in completely resected locally advanced
      gastric cancer.
AB  - BACKGROUND: The 5-year survival of patients with completely resected node
      positive gastric cancer ranges from 15% to 25%. We explored the feasibility of a
      chemoradiation regime consisting of concomitant hyperfractionated radiotherapy
      and 5-fluorouracil protracted venous infusion (5-FU PVI). MATERIALS AND METHODS:
      Forty patients received a total or partial gastrectomy operation and D2 nodal
      resection for Stage III gastric cancer; they were then irradiated by linac with 6
      15-MV photons. The target included the gastric bed, the anastomosis, stumps, and
      regional nodes. A total dose of 55 Gy was given in 50 fractions using 1.1 Gy
      b.i.d. All patients received a concomitant 200 mg/m2/day 5-FU PVI. Patients were
      examined during the follow-up period as programmed. Toxicity was recorded
      according to RTOG criteria. RESULTS: After a median follow-up of 75.6 months
      (range: 22-136 months), 24 (60%) patients had died, and 16 (40%) were alive and
      free of disease. The 5-year actuarial incidence of relapse was 39%, 22%, and 2%
      for distant metastases, out-field peritoneal seeding, and in-field local regional
      recurrences, respectively. The 5-year actuarial cause-specific survival was 43%.
      Three patients survived more than 11 years. Acute > or = Grade 3 toxicity
      consisted of hematologic (22.5%) and gastrointestinal toxicity (nausea and
      vomiting 22.5%, diarrhea 2.8%, and abdominal pain 2.6%). No late toxicity was
      observed. CONCLUSION: This regime of concomitant 5-FU PVI and hyperfractionated
      radiotherapy was well tolerated and resulted in successful locoregional control
      and satisfactory survival.

PMID- 12419434
TI  - Preoperative hyperfractionated radiotherapy for locally advanced rectal cancers:
      a phase I-II trial.
AB  - PURPOSE: To assess the toxicity, pathologic response rates, type of surgery, and
      oncologic results in a prospective Phase I-II trial using pure hyperfractionated
      radiotherapy (RT) preoperatively in locally advanced rectal cancer. METHODS AND
      MATERIALS: Between September 1997 and April 2000, 50 patients with T3-T4 or N1
      rectal cancers were treated preoperatively with 50 Gy (45 Gy to the pelvis and a
      5-Gy tumor boost) in 40 fractions of 1.25 Gy during 4 weeks. The pretreatment
      tumor stage as determined by CT and endorectal ultrasonography (80% of patients)
      included 1 Stage T2 (2%), 45 T3 (90%), and 4 T4 (8%). Nodal involvement (N1) was
      documented in 26 patients (52%). Surgery was performed at a median interval of 45
      days (range 26-114 days) after RT completion. Seventeen patients who presented
      with pT4 or pN1 and/or pM1 received 5-fluorouracil-based chemotherapy
      postoperatively. RESULTS: All patients completed the RT schedule as planned.
      Severe acute toxicities included two Grade 3 skin reactions (4%) that did not
      require a break. The other acute toxicities were Grade 2 or less (skin, diarrhea,
      urinary, rectal tenesmus, and fatigue). A complete pathologic response was
      observed in 7 patients (14%), and microscopic residual cancer was found in 10
      (20%). Of the 20 patients presenting with tumor located < or = 6 cm from the anal
      verge, sphincter-saving surgery was performed in 14 (70%). At 3 years, the
      actuarial locoregional control rate was 90.5%, and the disease-free survival rate
      was 74.6%. At a median follow-up of 32 months, 4 patients (8%) presented with
      severe late complications (Grade 3-4) that might have been RT related (one
      rectovaginal fistula, two chronic perineal fistulas, and one bilateral ureteral
      stenosis). CONCLUSION: In locally advanced rectal cancer, preoperative
      hyperfractionated RT to a total dose of 50 Gy is feasible, with acceptable acute
      and late toxicity and an objective downstaging effect. In view of these results,
      this schedule might be used as a basis for additional investigation regarding RT
      dose escalation or the addition of concomitant chemotherapy.

PMID- 12419435
TI  - Effects on functional outcome after IORT-containing multimodality treatment for
      locally advanced primary and locally recurrent rectal cancer.
AB  - PURPOSE: In the treatment of patients with locally advanced primary or locally
      recurrent rectal cancer, much attention is focused on the oncologic outcome.
      Little is known about the functional outcome. In this study, the functional
      outcome after a multimodality treatment for locally advanced primary and locally
      recurrent rectal cancer is analyzed. METHODS AND MATERIALS: Between 1994 and
      1999, 55 patients with locally advanced primary and 66 patients with locally
      recurrent rectal cancer were treated with high-dose preoperative external beam
      irradiation, followed by extended surgery and intraoperative radiotherapy. To
      assess long-term functional outcome, all patients still alive (n = 97) were asked
      to complete a questionnaire regarding ongoing morbidity, as well as functional
      and social impairment. Seventy-six of the 79 patients (96%) returned the
      questionnaire. The median follow-up was 14 months (range: 4-60 months). RESULTS:
      The questionnaire revealed fatigue in 44%, perineal pain in 42%, radiating pain
      in the leg(s) in 21%, walking difficulties in 36%, and voiding dysfunction in 42%
      of the patients as symptoms of ongoing morbidity. Functional impairment consisted
      of requiring help with basic activities in 15% and sexual inactivity in 56% of
      the respondents. Social handicap was demonstrated by loss of former lifestyle in
      44% and loss of professional occupation in 40% of patients. CONCLUSIONS: As a
      result of multimodality treatment, the majority of these patients have to deal
      with long-term physical morbidity, the need for help with daily care, and
      considerable social impairment. These consequences must be weighed against the
      chance of cure if the patient is treated and the disability eventually caused by
      uncontrolled tumor progression if the patient is not treated. These potential
      drawbacks should be discussed with the patient preoperatively and taken into
      account when designing a treatment strategy.

PMID- 12419436
TI  - Postoperative radiotherapy for adenocarcinoma of the ethmoid sinuses: treatment
      results for 47 patients.
AB  - PURPOSE: Ethmoid sinus cancer is a rare malignancy. Treatment results are mostly
      reported together with other sinonasal tumors, grouping a wide range of different
      histologies and treatment approaches. This study reports on the treatment outcome
      of 47 patients diagnosed with adenocarcinoma of the ethmoid sinuses and treated
      with surgery and high-dose postoperative radiation therapy. METHODS AND
      MATERIALS: Between September 1985 and October 2001, 51 patients with
      adenocarcinoma of the ethmoid sinuses were referred to the Ghent University
      Hospital. Four patients were treated with low-dose palliative radiation because
      of very extended inoperable disease or distant metastasis at the time of
      diagnosis. They were not included in this analysis. The other 47 patients, all
      staged as N0M0, were treated with surgery and postoperative high-dose radiation
      therapy. The median follow-up was 32 months. The T-stages were T1 for 2, T2 for
      17, T3 for 11, and T4 for 17 patients. All 47 patients were staged as N0M0.
      RESULTS: The 3-year, 5-year, and 7-year overall survival are respectively 71%,
      60%, and 38%. The 3-year and 5-year disease-free survival are respectively 62%
      and 36%. The 3-year and 5-year disease-free survival for T1-T2 stages are
      respectively 87% and 55%, for T3 stages 57% and 28%, and for T4 stages 41% and
      25%. The locoregional tumor control was 70% and 59% at respectively 3 and 5
      years. Patients presenting with intracranial tumor invasion at the time of
      diagnosis relapsed within 7 months after the end of radiotherapy. Radiation
      induced severe dry eye syndrome and optic neuropathy was observed in respectively
      7 and 2 of the 47 cases. CONCLUSION: Postoperative radiotherapy for
      adenocarcinoma of the ethmoid sinuses is associated with good local control
      rates. Crucial for a favorable prognosis is the absence of intracranial invasion.
      The rarity of these tumors makes it difficult to evaluate new therapeutic
      advances.

PMID- 12419437
TI  - Reirradiation of nasopharyngeal carcinoma with intracavitary mold brachytherapy:
      an effective means of local salvage.
AB  - PURPOSE: To assess the role of intracavitary mold brachytherapy in salvaging
      local failure of nasopharyngeal carcinoma (NPC). METHODS AND MATERIALS: The
      outcomes of 118 consecutive NPC patients with local failure treated with mold
      brachytherapy between 1989 and 1996 were retrospectively reviewed. Eleven
      patients received additional external radiotherapy. RESULTS: All molds were
      tailor-made, and the whole procedure was performed under local anesthesia.
      Pharyngeal recess dissection was routinely performed to allow direct contact of
      the radioactive source with the pharyngeal recess, a common site of local
      failure. Initially, the molds were preloaded with 192Ir wires, but since 1992,
      the sources have been manually afterloaded; the mold has also been redesigned for
      better conformity, ease of insertion, and radiation safety. Using brachytherapy
      alone, 50-55 Gy was given for recurrence in 4-7 days; for persistence, 40 Gy was
      administered. The overall complete remission rate was 97%. The rates of 5-year
      local control, relapse-free survival, disease-specific survival, overall
      survival, and major complication were 85%, 68.3%, 74.8%, 61.3%, and 46.9%,
      respectively. Major complications included nasopharyngeal necrosis with headache,
      necrosis of cervical vertebrae with atlantoaxial instability, temporal lobe
      necrosis, and palsy of the cranial nerves. The afterloaded mold was as effective
      as the preloaded version, but with fewer complications. CONCLUSIONS:
      Intracavitary mold brachytherapy was effective in salvaging NPC with early-stage
      local persistence or first recurrence.

PMID- 12419438
TI  - Fractionated stereotactic radiotherapy for craniopharyngiomas.
AB  - PURPOSE: To investigate outcome and toxicity after fractionated stereotactic
      radiation therapy (FSRT) in patients with craniopharyngiomas. METHODS AND
      MATERIALS: Twenty-six patients with craniopharyngiomas were treated with FSRT
      between May 1989 and February 2001. Median age was 33.5 years (range: 5-57
      years). Nine patients received FSRT after surgery as primary treatment, and 17
      patients were irradiated for recurrent tumor or progressive growth after initial
      surgery. Median target dose was 52.2 Gy (range: 50.0-57.6 Gy) with conventional
      fractionation. Follow-up included MRI and neurologic, ophthalmologic, and
      endocrinologic examinations. RESULTS: The median follow-up was 43 months (range:
      7-143 months). The actuarial local control rate and actuarial overall survival
      rates were 100% and 100%, respectively, at 5 years and 100% and 83%,
      respectively, at 10 years. Four patients showed complete response, 14 patients
      showed partial response, and 8 patients remained stable. In 5 patients, vision
      improved after radiation therapy. Acute toxicity was mild. One patient required
      cyst drainage 3 months after radiotherapy. Late toxicity after radiotherapy
      included impairment of hormone function in 3 out of 18 patients at risk. We did
      not observe any vision impairment, radionecrosis, or secondary malignancies.
      CONCLUSIONS: FSRT is effective and safe in the treatment of cystic
      craniopharyngiomas. Toxicity is extremely low using this conformal technique.

PMID- 12419439
TI  - Intra-arterial CT-angiography for cerebral arteriovenous malformation--initial
      experiences for treatment planning of radiosurgery.
AB  - PURPOSE: To clarify the feasibility and effectiveness of intra-arterial CT
      angiography (IACTA) for treatment planning of arteriovenous malformation
      radiosurgery. METHODS AND MATERIALS: A CT scanner installed in an angiographic
      examination room was used. Helical IACTA was performed in 22 patients during
      continuous intra-arterial infusion of contrast medium via the internal carotid or
      vertebral artery, and dynamic IACTA was performed in 20 of these patients with
      reconstruction at 0.2-s intervals. The dynamic IACTA was repeated for each 3- or
      5-mm increment to encompass the nidus. Subtractions were performed in
      postembolization cases. A retrospective review of IACTA was performed to assess
      the effectiveness of dynamic scans. RESULTS: No complications related to the
      angiographic procedure or CT imaging were detected. High contrast enhancement was
      obtained for both helical and dynamic IACTA. In 18 of the 20 cases (90%),
      draining veins were separated from the nidus by using the enhancement patterns,
      and in 13 cases (65%), feeding arteries were separated. CONCLUSION: Dynamic IACTA
      added important information for target-volume determinations. Conventional CT and
      MRI could be omitted from the protocol, and the period that patients wore the
      frame was substantially shortened. We conclude that IACTA is a practical and
      useful method for radiosurgical treatment planning of arteriovenous
      malformations.

PMID- 12419440
TI  - Radiation-induced epilation due to couch transit dose for the Leksell gamma knife
      model C.
AB  - PURPOSE: To determine the cause of epilation at the top of the head for 2
      patients with acoustic neuromas after undergoing fractionated radiosurgery with
      the Leskell Gamma Knife model C. This epilation was unexpected, because the
      treatment planning program stated the dose at this location was <0.1 Gy. METHODS
      AND MATERIALS: The radiation dose along a central axis, parallel to the couch,
      from the helmet's focus to the helmet cap was measured during couch transit.
      RESULTS: Transit doses of 4.4 cGy/shot at 10 cm and 5.6 cGy/shot at distances >15
      cm from the helmet's focus were measured. It was estimated that the 2 patients
      with epilation received approximately 6-7 Gy to the scalp. A shield was
      constructed and shown to reduce the transit dose by as much as 60%. CONCLUSION:
      The design of the helmet allows the uncollimated beams to reach areas of the
      patient, superior to the target, just before and after couch docking with the
      housing. For treatment involving a large number of shots (i.e., fractionation),
      off-target doses < or = 8 Gy can result. For these cases, the transit dose should
      be considered and some form of additional shielding should be used.

PMID- 12419441
TI  - Physiologic FDG-PET three-dimensional brachytherapy treatment planning for
      cervical cancer.
AB  - PURPOSE: To compare conventional two-dimensional (2D) orthogonal radiography
      based brachytherapy treatment planning for cervical cancer with a three
      dimensional (3D) treatment planning technique based on 18F-fluoro-deoxyglucose
      positron emission tomography (FDG-PET). METHODS AND MATERIALS: Eleven cervical
      cancer patients were included in this prospective study that evaluated one tandem
      and ovoid brachytherapy procedure for each patient. The patient underwent FDG-PET
      of the pelvis to visualize the tumor followed by a second FDG-PET scan with the
      FDG isotope placed inside the tandem and ovoid applicators to visualize the
      treatment source positions for 3D treatment planning. The tumor volumes were
      delineated using a binary threshold technique in which the threshold FDG-PET
      image intensity was 40% of the peak tumor intensity. RESULTS: FDG-PET provides a
      reliable estimate of the cervical cancer volume and 3D spatial relationship of
      the tumor to the tandem and ovoid applicators. The maximal bladder and rectal
      doses determined from the 3D FDG-PET dose-volume histograms were found to be
      higher than those obtained using 2D treatment planning. The minimal dose to the
      tumor volume defined by FDG-PET ranged from 50 to 475 cGy for treatment plans
      designed to deliver 650 cGy to Point A and exhibited an inverse correlation with
      tumor volume. CONCLUSION: Physiologic FDG-PET brachytherapy treatment planning is
      feasible and accurate relative to conventional 2D treatment planning. The use of
      FDG-PET offers a unique method for tumor visualization and identifies the
      limitations of conventional brachytherapy treatment planning for coverage of
      large tumors and estimation of the dose to normal structures. This technique has
      the potential for improving isodose tumor coverage for patients with cervical
      cancer while sparing critical structures.

PMID- 12419442
TI  - Lymphangiogram-assisted lymph node target delineation for patients with
      gynecologic malignancies.
AB  - PURPOSE: Intensity-modulated radiotherapy for gynecologic malignancies requires
      proper knowledge of the volumes to be irradiated and accurate delineation of
      these volumes on a three-dimensional projection. In this study, assisted by
      lymphangiography (LAG), we derived guidelines for delineating nodal target
      volumes on CT. METHODS AND MATERIALS: Sixteen patients with cervical cancer who
      underwent radiotherapy between 1995 and 1999 at the Mallinckrodt Institute of
      Radiology were enrolled in the study. The initial 6 patients underwent bipedal
      LAG as part of the staging workup. Cross-sectional CT images were acquired and
      analyzed, and lymph node locations were described relative to the aorta, vena
      cava, common iliac, external iliac, and femoral vessels. The greatest distance
      from lymph node to vessel wall and pelvic sidewall was determined for each nodal
      group. This served as a guideline from which the clinical target volume (CTV)
      definitions were developed. This proposed CTV was then applied to CT scans of 10
      patients to determine the amounts of normal tissues encompassed. RESULTS: Nodal
      CTV guidelines were derived to cover 100% of LAG-avid lymph nodes. This CTV
      definition encompassed an average of 58.1 +/- 22.8 cm(3) (6.8% +/- 2.8% of total
      volume) small bowel, 28.4 +/- 19.2 cm(3) (4.2% +/- 3.2%) large bowel, 8.6 +/- 8.6
      cm(3) (3.2% +/- 2.6%) bladder, and 1.6 +/- 3.1 cm(3) (1.0% +/- 1.7%) rectum. The
      absolute volume and fraction of normal tissues encompassed by CTV plus 1- or 2-cm
      margins were calculated. CONCLUSION: This study presents the first time that
      three-dimensional lymph node mapping with the aid of LAG has been used to
      generate a nodal CTV guideline. This information may assist radiation oncologists
      in properly determining nodal target volumes and selecting a margin around the
      CTV for intensity-modulated radiotherapy.

PMID- 12419443
TI  - Interstitial brachytherapy for salvage treatment of vaginal recurrences in
      previously unirradiated endometrial cancer patients.
AB  - PURPOSE: To evaluate whether interstitial brachytherapy can effectively salvage
      vaginal recurrence from endometrial carcinoma. METHODS AND MATERIALS: Between
      September 1989 and September 2000, 13 previously unirradiated patients (mean age
      70 years) with isolated vaginal recurrences from endometrial adenocarcinoma were
      treated with interstitial low-dose-rate brachytherapy with or without additional
      external beam radiotherapy. Brachytherapy was delivered using a modified perineal
      Syed template loaded with (192)Ir. The central cylinder was loaded with high
      activity (192)Ir (n = 12) or (137)Cs (n = 1). RESULTS: The patients had initially
      presented with FIGO Stage I (n = 11) or III (n = 2) cancer. Vaginal recurrences
      were diagnosed at a mean interval of 27.5 months after hysterectomy (range 2-83).
      The patients were followed for a median of 60 months (range 15-105). Ten patients
      had recurrence at the vaginal apex and three had recurrence in the lower two
      thirds of the vagina. The median time to recurrence was 22 months. The tumor size
      ranged from 1.5 to 6 cm (mean 2.2, median 2.5). Eleven of 13 patients received 45
      50-Gy pelvic external beam radiotherapy, followed by a mean interstitial
      brachytherapy boost of 28.3 Gy (range 18-35). The 2 other patients received
      brachytherapy only of 40 Gy and 50 Gy, respectively. All tumors were locally
      controlled. Three (23%) of 13 patients had a relapse at distant sites (two in the
      paraaortic region and one in the liver). The overall 8-year actuarial disease
      specific survival rate was 77%. Major (Grade 3 and 4) long-term morbidity
      occurred in 2 patients (15%) and included Grade 3 vaginal ulceration in 1
      patient, and Grade 4 colovesical fistula requiring surgical intervention in 1
      patient. Additional long-term morbidity included Grade 2 proctitis in 1 patient.
      CONCLUSION: Interstitial brachytherapy with or without supplementary external
      beam radiotherapy can effectively salvage vaginal recurrence from endometrial
      cancer with very favorable local control and overall survival and acceptable
      morbidity.

PMID- 12419444
TI  - Role of radiotherapy in the treatment of motor dysfunction due to metastatic
      spinal cord compression: comparison of three different fractionation schedules.
AB  - PURPOSE: The optimum fractionation schedule for radiotherapy (RT) of metastatic
      spinal cord compression (MSCC) is still debated in the literature. Several
      reports have compared different fractionation schedules for pain relief. To our
      knowledge, this retrospective analysis is the first to compare three different
      schedules for functional outcome. METHODS AND MATERIALS: For posttreatment
      functional and ambulatory outcome, three schedules, 30 Gy in 10 fractions (n =
      93), 37.5 Gy in 15 fractions (n = 80), and 40 Gy in 20 fractions (n = 74), were
      compared. Motor function was evaluated by a 6-point scale before and at the end
      of RT and 3, 6, and 12 months later. A multivariate analysis was performed for
      functional outcome, including fractionation schedule and the three relevant
      prognostic factors (primary tumor type, time of developing motor deficits before
      RT, and ambulatory status). RESULTS: No significant difference was observed for
      posttreatment motor function or ambulatory rates among the three schedules.
      According to the multivariate analysis, the radiation schedule had no significant
      impact on functional outcome (p = 0.223) in contrast to the three prognostic
      factors (p <0.001, p <0.001, and p = 0.012). CONCLUSION: The three fractionation
      schedules were comparable for functional outcome. The least time-consuming
      schedule (30 Gy in 10 fractions) should be considered for patients with a
      markedly reduced life expectancy.

PMID- 12419445
TI  - Renal toxicity after total body irradiation.
AB  - PURPOSE: To evaluate the incidence of renal dysfunction after total body
      irradiation (TBI). METHODS AND MATERIALS: Between 1990 and 1997, 64 patients
      (median age 50 years) received TBI as part of the conditioning regimen before
      bone marrow transplantation (BMT). Five patients with abnormal renal function at
      the beginning of treatment or with incomplete data were excluded. All patients
      received a total of 12 Gy (6 fractions twice daily for 3 consecutive days)
      prescribed to the peak lung dose (corrected for lung transmission) at a dose rate
      of 7.5 cGy/min. Renal shielding was not used. Renal dysfunction was assessed on
      the basis of the serum creatinine levels measured at the start and end of TBI and
      at 6, 12, 18, and 24 months after completion of BMT. Cox proportional hazard
      analysis was used to evaluate the various factors known to affect renal function.
      RESULTS: Only 4 patients had elevated serum creatinine levels at 12 months and
      subsequently only 2 of the 33 surviving patients had persistent elevated renal
      serum creatinine levels 24 months after BMT. A fifth patient developed
      proteinuria and mildly elevated serum creatinine levels at 2.5 years. In 2
      patients, the elevation coincided with disease relapse and normalized once
      remission was achieved. In the third patient, the elevation in serum creatinine
      levels coincided with relapse of multiple myeloma and the presence of Bence-Jones
      proteinuria. The fourth patient was the only patient who developed chronic renal
      failure secondary to radiation nephritis at 2 years. The etiology of the fifth
      patient's rise in creatinine was unknown, but may have been secondary to
      radiation nephritis. On univariate analysis, but not on multivariate analysis, a
      significant correlation was found between TBI-related renal dysfunction and
      hypertension before and after BMT. CONCLUSION: A dose of 12 Gy at 2 Gy/fraction
      resulted in only 1 case of radiation nephritis in the 59 patients studied 24
      months after the completion of TBI and BMT.

PMID- 12419446
TI  - Benefits of external beam irradiation for peripheral arterial bypass: preliminary
      report on a phase I study.
AB  - PURPOSE: To perform a Phase I study to determine the safety and feasibility of
      using external beam radiotherapy to prevent neointimal hyperplasia in patients
      after surgical bypass of occluded infrainguinal arteries. METHODS AND MATERIALS:
      All patients undergoing operative infrainguinal bypass for chronic ischemia were
      eligible for enrollment, although those requiring a prosthetic graft were
      preferentially considered. Immediately after bypass, the distal anastomosis was
      marked with clips, and the baseline anatomy of the anastomosis was documented
      with an intraoperative angiogram. The distal anastomotic site and 2 cm of
      surrounding tissues were irradiated to a total dose of 30 Gy, delivered in 10
      fractions. The first dose was given within 48 h of surgery. RESULTS: Twenty-one
      patients were enrolled in this study. No anastomotic or wound problems or any
      other short-term complications of the treatment developed. However, at a mean
      follow-up of 10 months (range 3-18), 12 (57%) of the 21 grafts had occluded.
      Angiography was performed in 2 patients after successful thrombolysis and
      demonstrated normal anastomoses without residual stenosis. Evidence of stenosis
      at the irradiated anastomosis was seen in only 1 of the 21 patients by ongoing
      ultrasound surveillance. CONCLUSION: Fractionated external irradiation to a total
      dose of 30 Gy delivered to the distal surgical anastomosis immediately after
      operative bypass has no short-term complications and was associated with an
      apparently low rate of intimal hyperplasia. However, any possible gains made by
      reducing the neointimal hyperplasia at the site of anastomosis were significantly
      diminished by the high frequency of thrombotic events.

PMID- 12419447
TI  - Treatment of pancreatic cancer xenografts with Erbitux (IMC-C225) anti-EGFR
      antibody, gemcitabine, and radiation.
AB  - PURPOSE: To investigate treatment of human pancreatic cancer cell lines and
      xenografts with combinations of Erbitux (IMC-C225) anti-epidermal growth factor
      receptor (EGFR) antibody, gemcitabine, and radiation. METHODS AND MATERIALS: BxPC
      3 and MiaPaCa-2 human pancreatic carcinoma cells were treated in vitro for 24 h
      with IMC-C225 (5 microg/mL), then exposed to epidermal growth factor (EGF) (10
      mM) for 5 min. Immunoblots were screened for EGFR expression and the ability of
      IMC-C225 to block EGF-induced tyrosine phosphorylation of EGFR. Cells were
      treated with IMC-C225 (5 microg/mL) on Day 0, the IC(50) dose of gemcitabine on
      Day 1 for 24 h, followed by 3 Gy 60Co irradiation on Day 2, or the combination of
      each agent. For cell proliferation, cells were counted on Day 4, and for
      apoptosis, cells were stained with annexin V-FITC and propidium iodide, then
      analyzed by FACS. Cells were treated with the same single or multiple treatments
      and analyzed in a clonogenic cell survival assay. The effect of IMC-C225,
      gemcitabine, and radiation on the growth of BxPC-3 and MiaPaCa-2 tumor xenografts
      was determined. Athymic nude mice bearing established s.c. tumor xenografts of 6
      8 mm diameter received 6 weeks of treatment with IMC-C225 (1 mg every 3 days x 6)
      alone or in combination with gemcitabine (120 mg/kg i.v. every 6 days x 6), and 6
      weekly fractions of 3 Gy radiation on the days after gemcitabine administration.
      Tumor growth was measured with Vernier calipers. RESULTS: BxPC-3 and MiaPaCa-2
      cell lines expressed low levels of EGFR. IMC-C225 inhibited EGF-induced tyrosine
      phosphorylation of the EGF receptor on both cell lines. Treatment of cells with a
      combination of IMC-C225 + gemcitabine + radiation produced the highest induction
      of apoptosis and inhibition of proliferation in vitro. Combination treatment with
      IMC-C225, gemcitabine, and radiation produced 100% complete regression of MiaPaCa
      2 tumors for more than 250 days, and the greatest growth inhibition of BxPC-3
      tumors compared to any single or dual treatments. CONCLUSIONS: The IMC-C225
      therapy in combination with gemcitabine chemotherapy and radiation therapy
      demonstrated statistically significantly greater efficacy over the single and
      double combination therapies. This form of multimodality treatment shows
      potential clinical application in the treatment of pancreatic cancer in humans.

PMID- 12419448
TI  - Ionizing radiation modulates the exposure of the HUIV26 cryptic epitope within
      collagen type IV during angiogenesis.
AB  - PURPOSE: The majority of the research on the biologic effects of ionizing
      radiation has focused on the impact of radiation on cells in terms of gene
      expression, DNA damage, and cytotoxicity. In comparison, little information is
      available concerning the direct effects of radiation on the extracellular
      microenvironment, specifically the extracellular matrix and its main component,
      collagen. We have developed a series of monoclonal antibodies that bind to
      cryptic epitopes of collagen Type IV that are differentially exposed during
      matrix remodeling and are key mediators of angiogenesis. We have hypothesized
      that ionizing radiation might affect the process of angiogenesis through a direct
      effect on the extracellular matrix and specifically on collagen Type IV. METHODS
      AND MATERIALS: Angiogenesis was induced in a chick chorioallantoic membrane (CAM)
      model; 24 h later, a single-dose treatment with ionizing radiation (0.5, 5, and
      20 cGy) was administered. Angiogenesis was assessed, and the exposure of two
      cryptic regulatory epitopes within collagen Type IV (HUI77 and HUIV26) was
      studied in vitro by solid-phase ELISA and in vivo by immunofluorescence staining.
      RESULTS: A dose-dependent reduction of angiogenesis with maximum inhibition (85%
      90%) occurring at 20 cGy was demonstrated in the CAM model. Exposure of the
      cryptic HUIV26 site, an angiogenesis control element, was inhibited both in vitro
      and in vivo by the same radiation dose, whereas little if any change was observed
      for the HUI77 cryptic epitope. CONCLUSIONS: A dose-dependent alteration of the
      functional exposure of the HUIV26 cryptic epitope is induced by radiation in
      vitro and in the CAM model in vivo. This radiation-induced change in protein
      structure and function may contribute to the inhibitory effects of ionizing
      radiation on new blood vessel growth and warrants further studies in other
      models.

PMID- 12419449
TI  - Effect of carbogen on tumor oxygenation: combined fluorine-19 and proton MRI
      measurements.
AB  - PURPOSE: Blood oxygen level dependent (BOLD) contrast in magnetic resonance
      imaging (MRI) has been widely used for noninvasive evaluation of the effects of
      tumor-oxygenating agents. However, there have been few tests of the validity of
      this method. The goal of the present work was to use the T(1) of fluorine-19 in
      perfluorocarbon (PFC) emulsions as a "gold standard" for comparison with BOLD
      MRI. MATHODS AND MATERIALS: Rats bearing R3230AC tumors implanted in the hind
      limb were injected with an emulsion of perfluoro-15-crown-5-ether for 2-3 days
      before experiments, which ensured that the PFC emulsion concentrated in the
      tumors. We correlated changes in tumor oxygenation caused by carbogen inhalation
      measured by (1)H BOLD MRI with quantitative (19)F measurements. The (19)F spin
      lattice relaxation rate R(1) (= 1/T(1)) was measured to determine initial oxygen
      tension (pO(2)) in each image pixel containing the PFC, and changes in pO(2)
      during carbogen (95% O(2), 5% CO(2)) breathing. In a second carbogen breathing
      period, changes in water signal linewidth were measured using high spectral and
      spatial resolution imaging. (19)F and (1)H measurements were used to classify
      pixels as responders to carbogen (pixels where oxygen increased significantly) or
      nonresponders (no significant change in tumor oxygenation). RESULTS: The (19)F
      and (1)H measurements agreed in 65% +/- 11% of pixels (n = 14). Agreement was
      even stronger among pixels where (1)H showed increased oxygenation; (19)F
      measurements agreed with (1)H measurements in over 79% +/- 11% of these pixels.
      Similarly, there was strong agreement between the two modalities in pixels where
      (19)F reported no change in pO(2); (1)H also showed no changes in 76% +/- 18% of
      these pixels. Quantitative correlation of changes T(2)* (DeltaT(2)*) in (1)H and
      changes R(1) (DeltaR(1)) in (19)F was weak during carbogen breathing, and
      averaged over the whole tumor was approximately 0.40 for 14 experiments. However,
      the spatial patterns of (1)H and (19)F changes were qualitatively very similar.
      In hypoxic regions that were identified based on long (19)F T(1) (>2.53 s), (19)F
      and (1)H MRI agreed that carbogen had relatively weak effects. CONCLUSIONS: These
      results suggest that (1)H BOLD MRI reliably identifies increases in tumor pO(2).
      In hypoxic regions where increases in pO(2) are most desirable, carbogen was
      ineffective. The data suggest that (19)F and (1)H MRI can be used individually or
      in combination to guide the design of improved tumor-oxygenating agents.

PMID- 12419450
TI  - Improvement of three-dimensional treatment planning models of small lung targets
      using high-speed multi-slice computed tomographic imaging.
AB  - PURPOSE: To improve the reliability of the patient model and reduce treatment
      volume by acquiring multi-slice computed tomographic (CT) data with the patients'
      single holding of breath at normal inhalation and exhalation. METHODS AND
      MATERIALS: Seven patients with nine small peripheral lung cancer tumors underwent
      CT scanning under three respiration conditions using multi-slice CT: free
      breathing (FB), shallow inspiration (SI), and shallow expiration (SE). To compare
      the treatment plan created using the two-respiratory-phase images (SI + SE) with
      the plans created using only SE images or using only FB images, we attempted to
      calculate the true dosimetric characteristics for three-dimensional treatment
      planning taking respiratory movement into consideration. Minimum dose to the
      gross tumor volume (GTV) and ipsilateral lung dose-volume histogram (DVH) were
      calculated for the inhalation and exhalation positions of shallow breathing.
      RESULTS: There was no significant difference between minimum doses of the GTV in
      the three treatment plans when using anteroposterior/posteroanterior parallel
      opposed fields. However, there was a significant difference between the minimum
      doses of the GTV in the two-phase treatment plan and the minimum dose in the
      other treatment plans when using the four-field technique, consisting of shaped
      anterior, posterior, right and left lateral fields (p = 0.03, 0.04). Comparison
      of the percent volume of ipsilateral lung receiving a dose exceeding 20 Gy
      (V(20)) based on inhalation and exhalation CT data revealed that the V(20) of the
      two-phase plan was the smallest of the three treatment planning fields (p <
      0.001). CONCLUSION: Two-phase planning using multi-slice CT provides an immediate
      reduction in the amount of normal tissue treated and improved reliability of
      patient data for DVH modeling.

PMID- 12419451
TI  - Application of constrained least-squares techniques to IMRT treatment planning.
AB  - PURPOSE: The purpose of this work was to apply the method of constrained least
      squares to inverse treatment planning and to explore its potential for providing
      a fast interactive planning environment for intensity-modulated radiation therapy
      (IMRT). METHODS AND MATERIALS: The description of the dose inside a patient is a
      linear matrix transformation of beamlet weights. The constrained least-squares
      method adds additional matrix operators and produces beamlet weights by a direct
      linear transformation. These matrix operators contain a priori knowledge about
      the radiation distribution. The constrained least-squares technique was applied
      to obtain IMRT plans for prostate and paraspinal cancer patients and compared
      with the corresponding plans optimized using the CORVUS inverse planning system.
      RESULTS: It was demonstrated that a constrained least-squares technique is
      suitable for IMRT plan optimization with significantly increased computing speed.
      For the two cases we have tested, the constrained least-squares method was an
      order of magnitude faster than conventional iterative techniques because of the
      avoidance of the iterative calculations. We also found that the constrained least
      squares method is capable of generating clinically acceptable treatment plans
      with less trial-and-error adjustments of system variables, and with improved
      target volume coverage as well as sensitive structure sparing in comparison with
      that obtained using CORVUS. CONCLUSIONS: The constrained least-squares method has
      the advantage that it does not require iterative calculation and thus
      significantly speeds up the therapeutic plan optimization process. Besides
      shedding important insight into the inverse planning problem, the technique has
      strong potential to provide a fast and interactive environment for IMRT treatment
      planning.

PMID- 12419452
TI  - The use of electronic portal imaging to verify patient position during intensity
      modulated radiotherapy delivered by the dynamic MLC technique.
AB  - PURPOSE: The precise shape of the three-dimensional dose distributions created by
      intensity-modulated radiotherapy means that the verification of patient position
      and setup is crucial to the outcome of the treatment. In this paper, we
      investigate and compare the use of two different image calibration procedures
      that allow extraction of patient anatomy from measured electronic portal images
      of intensity-modulated treatment beams. METHODS AND MATERIALS: Electronic portal
      images of the intensity-modulated treatment beam delivered using the dynamic
      multileaf collimator technique were acquired. The images were formed by measuring
      a series of frames or segments throughout the delivery of the beams. The frames
      were then summed to produce an integrated portal image of the delivered beam. Two
      different methods for calibrating the integrated image were investigated with the
      aim of removing the intensity modulations of the beam. The first involved a
      simple point-by-point division of the integrated image by a single calibration
      image of the intensity-modulated beam delivered to a homogeneous polymethyl
      methacrylate (PMMA) phantom. The second calibration method is known as the
      quadratic calibration method and required a series of calibration images of the
      intensity-modulated beam delivered to different thicknesses of homogeneous PMMA
      blocks. Measurements were made using two different detector systems: a Varian
      amorphous silicon flat-panel imager and a Theraview camera-based system. The
      methods were tested first using a contrast phantom before images were acquired of
      intensity-modulated radiotherapy treatment delivered to the prostate and pelvic
      nodes of cancer patients at the Royal Marsden Hospital. RESULTS: The results
      indicate that the calibration methods can be used to remove the intensity
      modulations of the beam, making it possible to see the outlines of bony anatomy
      that could be used for patient position verification. This was shown for both
      posterior and lateral delivered fields. CONCLUSIONS: Very little difference
      between the two calibration methods was observed, so the simpler division method,
      requiring only the single extra calibration measurement and much simpler
      computation, was the favored method. This new method could provide a
      complementary tool to existing position verification methods, and it has the
      advantage that it is completely passive, requiring no further dose to the patient
      and using only the treatment fields.

PMID- 12419453
TI  - Urethral and periurethral dosimetry in prostate brachytherapy: is there a
      convenient surrogate?
AB  - PURPOSE: To assess and compare two models for a surrogate urethra to be used for
      postimplant dosimetry in prostate brachytherapy. METHODS AND MATERIALS: Twenty
      men with a urinary catheter present at the time of postimplant computed
      tomographic imaging were studied. Urethral and periurethral volumes were defined
      as 5-mm and 10-mm diameter volumes, respectively. Three contours of each were
      used: one contour of the true urethra (and periurethra), and two surrogate
      models. The true volumes were centered on the catheter center. One surrogate
      model used volumes centered on the geometrical center of each prostate contour
      (centered surrogate). The other surrogate model was based on the average
      deviation of the true urethra from a reference line through the geometrical
      center of the axial midplane of the prostate (deviated surrogate). Maximum point
      doses and the D(10), D(25), D(50), D(90), V(100), V(120), and V(150) of the true
      and surrogate volumes were measured and compared (D(n) is the minimum dose [Gy]
      received by n% of the structure, and V(m) is the volume [%] of the structure that
      received m% of the prescribed dose) as well as the distances between the
      surrogate urethras and the true urethra. RESULTS: Doses determined from both
      surrogate urethral and periurethral volumes were in good agreement with the true
      urethral and periurethral doses except in the superior third of the gland. The
      deviated surrogate provided a physically superior likeness to the true urethra.
      Certain dose-volume histogram (DVH)-based parameters could also be predicted
      reasonably well on the basis of the surrogates. Correlation coefficients > or
      =0.85 were seen for D(25), D(50), V(100), V(120), and V(150) for both models. All
      the other parameters had correlation coefficients in the range of 0.73 - 0.85.
      CONCLUSIONS: Both surrogate models predicted true urethral dosimetry reasonably
      well. It is recommended that the simpler deviated surrogate would be a more
      suitable surrogate for routine clinical practice.

PMID- 12419454
TI  - Inverse planning for interstitial gynecologic template brachytherapy: truly
      anatomy-based planning.
AB  - PURPOSE: Commercially available optimization schemes generally result in an
      undesirable dose distribution, because of the particular shapes of tumors
      extending laterally from the tandem. Dose distribution is therefore manually
      obtained by adjusting relative dwell time values until an acceptable solution is
      found. The objective of this work is to present the clinical application of an
      inverse planning dose optimization tool for the automatic determination of source
      dwell time values in the treatment of interstitial gynecologic templates. METHODS
      AND MATERIALS: In cases where the tumor extends beyond the range of the tandem
      ovoid applicator, catheters as well as the tandem are inserted into the
      paravaginal and parametrial region in an attempt to cover the tumor volume. CT
      scans of these patients are then used for CT-based dose planning. Dose
      distribution is obtained manually by varying the relative dwell times until
      adequate dose coverage is achieved. This manual planning is performed by an
      experienced physician. In parallel, our in-house inverse planning based on
      simulated annealing is used to automatically determine which of all possible
      dwell positions will become active and to calculate the dwell time values needed
      to fulfill dose constraints applied to the tumor volume and to each organ at
      risk. To compare the results of these planning methods, dose-volume histograms
      and isodose distributions were generated for the target and each organ at risk.
      RESULTS: This procedure has been applied for the dose planning of 12 consecutive
      interstitial gynecologic templates cases. For all cases, once the anatomy was
      contoured, the routine of inverse planning based on simulated annealing found the
      solution to the dose constraints within 1 min of CPU time. In comparison, manual
      planning took more than 45 min. The inverse planning-generated plans showed
      improved protection to organs at risk for the same coverage compared to manual
      planning. CONCLUSION: This inverse planning tool reduced the planning time
      significantly and produced improved plans with reduced dose to the organs at
      risk. Furthermore, the inverse planning approach improves the physician's control
      over treatment. The focus becomes the physician's prescription to the target and
      his or her compromise due to dose to normal structures.

PMID- 12419455
TI  - Dosimetric comparison between high-precision external beam radiotherapy and
      endovascular brachytherapy for coronary artery in-stent restenosis.
AB  - PURPOSE: Several drawbacks of endovascular brachytherapy for the treatment of
      coronary artery in-stent restenosis may be addressed by high-precision external
      beam radiotherapy (EBRT). The dosimetric characteristics of both treatment
      techniques were compared. METHODS AND MATERIALS: The traversed volume of 10
      coronary artery stents during the cardiac cycle was determined by
      electrocardiographically gated multislice spiral CT in 10 patients. By use of
      this traversed volume, high-precision EBRT treatment plans were generated for
      stents in the left circumflex (LCx), left anterior descending (LAD), and right
      coronary artery (RCA). The maximum dose to the nontargeted major coronary
      arteries was determined and compared to similar data calculated for endovascular
      brachytherapy. RESULTS: High-precision EBRT targeted at LCx stents contributed a
      mean maximum dose (D(max)) of 83.5% (range: 71.6-95.3%) and 16.3% to the LAD and
      RCA, respectively. Targeted LAD stents contributed a mean D(max) of 39.3% (range:
      14.5-94.8%) and 5.2% (range: 0-13.4%) to the LCx and RCA, respectively. Targeted
      RCA stents contributed a mean D(max) of 6.2% (range: 0-12.4%) and 5.8% (range: 0
      11.5%) to the LCx and LAD, respectively. Endovascular brachytherapy targeted at
      LCx stents contributed a mean D(max) of 1.7% (range: 0.7-2.7%) and 1.0% (range:
      0.6-1.4%) to the LAD and RCA, respectively. Targeted LAD stents contributed a
      mean D(max) of 5.2% (range: 0.5-11.4%) and 0.7% (range: 0.4-1.1%) to the LCx and
      RCA, respectively; targeted RCA stents contributed a mean D(max) of 0.3% (range:
      0.2-0.5%) and 0.2% (range: 0.1-0.3%) to the LCx and LAD, respectively.
      CONCLUSIONS: Although the doses distributed throughout the heart were higher for
      high-precision EBRT compared to endovascular brachytherapy, they are expected to
      be clinically irrelevant when nontargeted major coronary arteries are not closely
      situated to the targeted vessel segment. These encouraging results warrant
      further investigation of high-precision EBRT as a potential alternative to
      endovascular brachytherapy for the treatment of coronary artery in-stent
      restenosis.

PMID- 12419456
TI  - Vascular targeted endoradiotherapy of tumors using alpha-particle-emitting
      compounds: theoretical analysis.
AB  - PURPOSE: To establish the theoretical framework and study the feasibility of
      (211)At-labeled anti-tenascin chimeric 81C6 monoclonal antibody (mAb) as anti
      vascular endoradiotherapy for the treatment of glioblastoma multiforme (GBM)
      tumors. METHODS AND MATERIALS: The morphology of blood vessels from histologic
      images was analyzed and used along with reaction-diffusion equations to assess
      the activity concentration of (211)At-labeled chimeric 81C6 mAb in GBM tumor and
      normal-brain tissue. Alpha particle microdosimetry was then used to assess the
      survival probability and average absorbed dose for tumor and normal tissue
      endothelial cells (ECs) per unit vascular cumulated activity concentration
      q(source) (MBq-s g(-1)). In turn, these survival probabilities were used to
      assess the probability of failure Phi for a single vessel. Furthermore, using the
      vessel density, the specific tumor control probability per unit mass of tumor
      tissue (tcp) and the specific normal-tissue complication probability per unit
      mass of normal-brain tissue (ntcp) were estimated. The specific tumor control
      probability, tcp, was used to assess the overall tumor control probability (TCP)
      as a function of tumor mass. RESULTS: The levels of (211)At-labeled ch81C6 mAb
      cumulated activity concentration in GBM tumor tissue were approximately five
      times higher than that in normal-brain tissue. Thus, the average absorbed dose to
      tumor ECs was higher than that of normal tissue ECs, and the survival probability
      for GBM ECs was lower than for normal-brain tissue ECs. Consequently, the
      resulting vessel-failure probability, Phi, for GBM tumor and for normal-brain
      tissue differ considerably, yielding a q(source) range between 10(3) and 10(4)
      MBq-s g(-1). CONCLUSIONS: This theoretical analysis demonstrated that (211)At
      labeled chimeric 81C6 is an effective anti-vascular therapy for the treatment of
      GBM tumors, yielding a tcp higher than 0.999 for vascular cumulated activity
      concentrations q(source) higher than 1 x 10(4) MBq-s g(-1), while yielding a low
      probability for normal-brain tissue damage.

PMID- 12419457
TI  - Radiotherapy dose perturbation of metallic esophageal stents.
AB  - PURPOSE: Metallic esophageal stents frequently present during the treatment of
      esophageal cancer while using either external beam radiotherapy or brachytherapy.
      The dosimetric effects due to these metallic stents have not been reported. This
      work investigates these dose effects for various stent models presented during a
      radiotherapy procedure. METHODS AND MATERIALS: Two types of representative stent
      models, shell and ring stents, with various designs (e.g., composition and shell
      thickness or ring spacing), were studied. Three Monte Carlo code systems
      (EGS4/BEAM, EGSnrc/DOSRZnrc, and MCNP) were used to calculate the dose
      distributions for 6- and 15-MV external photon beams and for a (192)Ir
      brachytherapy source with and without a metallic esophageal stent in place.
      RESULTS: For a single external beam, a dose enhancement is generally observed in
      front of the stent (upstream) in the region within 4-mm distance of the stent
      surface. The enhancement at 0.5-mm distance from the stent surface can be as high
      as 20%. The dose behind the stent (downstream) is generally reduced. For a
      parallel-opposed pair (POP), a dose enhancement is always observed in the region
      within 3-mm distance of the stent surface. The enhancement at 0.5-mm distance
      from the stent surface can be as high as 10% for the 15-MV POP and 8% for the 6
      MV POP. The dose effects depend on stent design (e.g., composition, thickness of
      shell stent, or ring spacing in ring stents). This dependence is reduced for a
      POP. In the case of the (192)Ir brachytherapy source, a dose enhancement is
      observed in the region within 1-mm distance from the stent surface. The dose
      enhancement is approximately 5% at 0.5-mm distance from the stent surface.
      CONCLUSION: The dose perturbations due to the presence of a metallic esophageal
      stent during the treatment of esophageal cancer while using either external beam
      radiotherapy or brachytherapy should be recognized. These perturbations result in
      an overdose in esophageal mucosa. The overdose is within 5%-10% at a depth of 0.5
      mm in the esophageal wall.

PMID- 12419458
TI  - Mold brachytherapy can be an optional technique for total scalp irradiation.

PMID- 12419459
TI  - Is there a predictive value for molecular markers in predicting response to
      radiation and chemotherapy in rectal cancer?

PMID- 12419460
TI  - Assessment of implant quality for prostate brachytherapy--is D(90) the best
      quality index?

PMID- 12419461
TI  - In memoriam: Professor Christiane Ferradini (1924-2002).

PMID- 12419462
TI  - Iron and the redox status of the lungs.
AB  - Iron is an element essential for the survival of most aerobic organisms. However,
      when its availability is not adequately controlled, iron, can catalyze the
      formation of a range of aggressive and damaging reactive oxygen species, and act
      as a microbial growth promoter. Depending on the concentrations formed such
      species can cause molecular damage or influence redox signaling mechanisms. This
      review describes recent knowledge concerning iron metabolism in the lung, during
      both health and disease. In the lower part of the lung a small redox active pool
      of iron is required for reasons that are at present unclear, but may be related
      to antimicrobial functions. When the concentration of iron is increased in the
      lung (usually because of environmental exposure), iron is deleterious and
      contributes to a range of chronic and acute respiratory diseases. Moreover,
      aberrant regulation of iron metabolism, and/or deficient antioxidant protection,
      is also associated with acute lung diseases, such as the acute respiratory
      distress syndrome (ARDS). Iron, with the consequent production of reactive oxygen
      species (ROS), microbial growth promotion, and adverse signaling is strongly
      implicated as a major contributor to the pathogenesis of numerous disease
      processes involving the lung. Heme oxgenase, an enzyme that produces reactive
      iron from heme catabolism, is also briefly discussed in relation to lung disease.

PMID- 12419463
TI  - Do oxidatively modified proteins cause ALS?
AB  - Over 90 individual mutations in SOD1 are known to cause familial amyotrophic
      lateral sclerosis (FALS). It is widely accepted that these mutations exert their
      toxic effects by a gain of function mechanism, but the nature of these toxic
      effects is as yet unknown. It has been proposed by several laboratories that
      reactions of FALS-mutant CuZnSOD are the source of elevated oxidative stress in
      CuZnSOD-linked FALS. It has also been proposed that aggregates of CuZnSOD are
      somehow involved in the disease. The hypothesis that aggregates of CuZnSOD cause
      ALS is particularly attractive because protein aggregates are frequently
      associated with other neurodegenerative diseases. Recent evidence increasingly
      suggests that protein aggregates containing CuZnSOD protein play a role in
      CuZnSOD-linked ALS, but it is not yet know why the aggregates form nor if the
      CuZnSOD proteins in the aggregates are cleaved, oxidized, demetallated, or
      otherwise covalently modified.

PMID- 12419464
TI  - Protective effects of rilmenidine and AGN 192403 on oxidative cytotoxicity and
      mitochondrial inhibitor-induced cytotoxicity in astrocytes.
AB  - Oxidative stress and mitochondrial dysfunction are important aspects of
      pathogenesis, particularly in the brain, which is highly dependent on oxygen, and
      the protection of astrocytes is essential for neuroprotection. In this context,
      imidazoline drugs have been reported to be neuroprotective. Our recent study
      showed that imidazoline drugs, including guanabenz, inhibit the naphthazarin
      induced oxidative cytotoxicity associated with lysosomal destabilization. We now
      report on a study into the protective effects of rilmenidine and AGN 192403,
      which have affinity for imidazoline-1 receptors, on the cytotoxicity induced by
      naphthazarin and inhibitors of mitochondrial respiration in astrocytes.
      Cytotoxicity was measured grossly by LDH release and by measuring changes in
      lysosomal membrane stability and features of mitochondrial membrane
      permeabilization. Naphthazarin-induced cytotoxicity was evidenced by the ordered
      development of lysosomal acridine orange relocation, decrease in mitochondrial
      potential, cytochrome c release, and caspase-9 activation, and was inhibited by
      guanabenz, rilmenidine, and AGN 192403. Antimycin A and rotenone induced
      mitochondrial dysfunction primarily, and their cytotoxicities were inhibited only
      by AGN 192403. Rilmenidine and guanabenz may have a lysosomal stabilizing effect,
      which underlies their protective effects. AGN 192403 might affect the
      mitochondrial cell death cascades, and had a novel protective effect on the
      cytotoxicity associated with mitochondrial dysfunction.

PMID- 12419465
TI  - Signal transduction in H2O2-induced senescence-like phenotype in human diploid
      fibroblasts.
AB  - A stress-induced senescence-like phenotype is induced by exposure of human
      diploid fibroblasts to subcytotoxic H2O2 stress. Previous studies showed that TGF
      beta1 is responsible for the induction of several biomarkers of replicative
      senescence within 72 h after stress: senescence-like morphology, senescence
      associated beta-galactosidase activity, and an increase in the mRNA steady state
      level of four senescence-associated genes. Other studies showed that the
      retinoblastoma protein is responsible for the appearance of these biomarkers in
      the same conditions. Here we show that sustained p38(MAPK) phosphorylation is
      responsible for both H2O2-induced overexpression of TGF-beta 1 and subsequent TGF
      beta 1-induced appearance of these biomarkers. p38(MAPK) phosphorylation is shown
      to be necessary for a self-sustained TGF-beta 1 overexpression after H2O2 stress
      through the activation of ATF-2 transcription factor, thereby creating a
      regulatory loop between sustained p38(MAPK) activation and sustained TGF-beta 1
      overexpression after stress. p38(MAPK) activation is also shown to be responsible
      in part for the growth arrest observed in stress-induced senescence-like
      phenotype. At 48 h after stress, ATF-2 starts to interact with hypophosphorylated
      Rb, which allows the biomarkers of stress-induced senescence-like phenotype to
      appear. This report gives an overall explanation of how a senescence-like
      phenotype is established after subcytotoxic H2O2 stress.

PMID- 12419466
TI  - Thiol-inducing and immunoregulatory effects of flavonoids in peripheral blood
      mononuclear cells from patients with end-stage diabetic nephropathy.
AB  - The cellular thiol status and its relationship to T-cell activation and cytokine
      synthesis of mononuclear cells was investigated in patients with end-stage
      diabetic nephropathy (ESDN) undergoing dialysis treatment. The functional effects
      of thiol repair by in vitro and in vivo treatment with flavonoids were
      elucidated. The thiol status of peripheral blood lymphocytes from 30 ESDN
      patients on hemodialysis and healthy controls was determined by flow cytometry. T
      cell activation in response to pokeweed mitogen was analyzed by CD69 expression;
      cytokines were determined in cell culture supernatants. In result, compared to
      age-matched healthy subjects, a significant thiol deficiency in ESDN patients was
      obvious. The lowered total intracellular thiol levels correlated directly to a
      significant diminished T-cell activation and an elevated synthesis of TNF-alpha
      in the patient group. The treatment with flavonoids led to a restoration of the
      thiol status within 72 h in vitro and in vivo. This effect showed a biphasic
      kinetic that first utilized cell surface thiols and secondly intracellular
      thiols. In parallel, the T-cell activation was improved substantially along with
      a significant decrease in TNF-alpha release. These data provide the rational for
      clinical trials using flavonoids in ESDN to normalize immunoregulatory defects
      via restoration of the cellular thiol status.

PMID- 12419467
TI  - UVR-induced oxidative stress in human skin in vivo: effects of oral vitamin C
      supplementation.
AB  - Previous studies of cultured skin cells and murine skin in vivo have indicated
      that UVR-induced damage involves the generation of reactive oxygen species and
      depletion of endogenous antioxidant systems. In order to explore the relevance of
      this to UVR-induced damage to human skin, we have undertaken a detailed
      examination of the time-course of changes in markers of oxidative stress in human
      skin following exposure to physiological amounts of UVR in vivo. In addition, we
      have examined the skin bioavailability of a common nutritional antioxidant,
      vitamin C, and have assessed the effects of supplementation on markers of
      oxidative stress. Our hypothesis was that acute exposure of human skin to UVR in
      vivo would lead to oxidation of cellular biomolecules that could be prevented by
      prior vitamin C treatment. A UVR-challenge of 120 mJ/cm2 of broadband UVB (peak
      310 nm, range 270-400 nm) was applied to buttock skin of 8 healthy volunteers.
      This caused a rapid and significant rise in activity of skin catalase at 1 h and
      an increase in the oxidized/total glutathione ratio at 6 h post-UVR. AP-1 DNA
      binding also peaked at 1-6 h post-UVR, then declined rapidly to baseline levels.
      No significant changes were seen in skin malonaldehyde content. Oral vitamin C
      supplements (500 mg/day) were taken by 12 volunteers for 8 weeks resulting in
      significant rises in plasma and skin vitamin C content. Supplementation had no
      effect on the UVR-induced erythemal response. The skin malonaldehyde content was
      reduced by vitamin C supplementation, but surprisingly, reductions in the skin
      content of total glutathione and protein thiols were also seen. We speculate that
      this apparently paradoxical effect could be due to regulation of total reductant
      capacity by skin cells, such that vitamin C may have been replacing other
      reductants in these cells. No evidence was obtained for an effect of the
      supplementary vitamin C on the mild oxidative stress seen in human skin following
      UVR exposure.

PMID- 12419468
TI  - Comparison of uric acid and ascorbic acid in protection against EAE.
AB  - Serum levels of uric acid (UA), an inhibitor of peroxynitrite- (ONOO-) related
      chemical reactions, became elevated approximately 30 million years ago in hominid
      evolution. During a similar time frame, higher mammals lost the ability to
      synthesize another important radical scavenger, ascorbic acid (AA), leading to
      the suggestion that UA may have replaced AA as an antioxidant. However, in vivo
      treatment with AA does not protect against the development of experimental
      allergic encephalomyelitis (EAE), a disease that has been associated with the
      activity of ONOO- and is inhibited by UA. When compared in vitro, UA and AA were
      found to have similar capacities to inhibit the nitrating properties of ONOO-.
      However UA and AA had different capacities to prevent ONOO- -mediated oxidation,
      especially in the presence of iron ion (Fe3+). While UA at physiological
      concentrations effectively blocked dihydrorhodamine-123 oxidation in the presence
      of Fe3+, AA did not, regardless of whether the source of ONOO- was synthetic ONOO
      , SIN-1, or RAW 264.7 cells. AA also potentiated lipid peroxidation in vivo and
      in vitro. In conclusion, the superior protective properties of UA in EAE may be
      related to its ability to neutralize the oxidative properties of ONOO- in the
      presence of free iron ions.

PMID- 12419470
TI  - Quantitative gas chromatographic-mass spectrometric assay of 4-hydroxynonenal
      bound to thiol proteins in ischemic/reperfused rat hearts.
AB  - Increasing evidence indicates that protein-aldehyde adducts involving mostly 4
      hydroxynonenal could be causally involved in both pathophysiological and adaptive
      events following an oxidative stress insult such as ischemia/reperfusion. The
      goal of this study was to assess if isotope dilution chromatography-mass
      spectrometry can be used to quantitate changes in the cardiac levels of 4
      hydroxynonenal and 1,4-dihydroxynonene, one of its major metabolites, bound to
      thiol proteins during ischemia/reperfusion. For this purpose, we modified a
      previously published method to include treatment with Raney Nickel, which
      specifically cleaves thioether linkages. Our study model was the isolated
      Langendorff-perfused rat heart subjected to various ischemia/reperfusion
      protocols. Hearts perfused under normoxia contained small amounts of protein
      bound 4-hydroxynonenal and 1,4-dihydroxynonene (1.38 +/- 0.29 and 2.69 +/- 0.17
      nmol/g wet weight, respectively). The accumulation of these adducts after global
      ischemia depended on the severity of the ischemic insult up to a plateau and was
      not exacerbated by reperfusion. In conclusion, our method allows the
      quantification of time-dependent changes in 4-hydroxynonenal and 1,4
      dihydroxynonene bound to proteins via thioether linkage in ischemic/reperfused
      heart tissues. The presence of protein-bound 1,4-dihydroxynonene in heart tissues
      suggests that this organ can detoxify protein-bound 4-hydroxynonenal.

PMID- 12419469
TI  - Oxidative stress and reduced antioxidant defenses in peripheral cells from
      familial Alzheimer's patients.
AB  - We have measured the levels of typical end products of the processes of lipid
      peroxidation, protein oxidation, and total antioxidant capacity (TAC) in skin
      fibroblasts and lymphoblasts taken from patients with familial Alzheimer's
      disease (FAD), sporadic Alzheimer's disease (AD), and age-matched healthy
      controls. Compared to controls, the fibroblasts and lymphoblasts carrying amyloid
      precursor protein (APP) and presenilin-1 (PS-1) gene mutations showed a clear
      increase in lipoperoxidation products, malondialdehyde (MDA), and 4
      hydroxynonenal (4-HNE). In contrast, the antioxidant defenses of cells from FAD
      patients were lower than those from normal subjects. Lipoperoxidation and
      antioxidant capacity in lymphoblasts from patients affected by sporadic AD were
      virtually indistinguishable from the basal values of normal controls. An
      oxidative attack on protein gave rise to greater protein carbonyl content in FAD
      patients than in age-matched controls. Furthermore, ADP ribosylation levels of
      poly(ADP-ribose) polymerase (PARP) nuclear substrates were significantly raised,
      whereas the PARP content did not differ significantly between fibroblasts
      carrying gene mutations and control cells. These results indicate that peripheral
      cells carrying APP and PS-1 gene mutations show altered levels of oxidative
      markers even though they are not directly involved in the neurodegenerative
      process of AD. These results support the hypothesis that oxidative damage to
      lipid, protein, and DNA is an important early event in the pathogenesis of AD.

PMID- 12419471
TI  - Hyperresistance to photosensitized lipid peroxidation and apoptotic killing in 5
      aminolevulinate-treated tumor cells overexpressing mitochondrial GPX4.
AB  - Antitumor photodynamic therapy (PDT) with administered 5-aminolevulinic acid
      (ALA) is based on metabolism of ALA to protoporphyrin IX (PpIX), which acts as a
      sensitizer of photo-oxidative damage leading to apoptotic or necrotic cell death.
      An initial goal of this study was to ascertain how the PpIX-sensitized death
      mechanism for a breast tumor line (COH-BR1 cells) might be influenced by the
      conditions of ALA exposure in vitro. Two different treatment protocols were
      developed for addressing this question: (i) continuous incubation with 1 mM ALA
      for 90 min; and, (ii) discontinuous incubation, i.e., 15 min with 1 mM ALA
      followed by 225 min without it. Following exposure to 2 J/cm2 of visible light,
      cell viability, death mechanism, and lipid hydroperoxide (LOOH) level were
      evaluated for each protocol using thiazolyl blue, Hoechst staining, and HPLC with
      electrochemical detection assays, respectively. PpIX was found to sensitize
      apoptosis when it existed mainly in mitochondria (protocol-1), but necrosis when
      it diffused to other sites, including plasma membrane (protocol-2). Experiments
      with a transfectant clone, 7G4, exhibiting approximately 85 times greater
      activity of the LOOH-detoxifying selenoenzyme GPX4 than parental cells, provided
      additional information about death mechanism. Located predominantly in
      mitochondria of 7G4 cells, GPX4 strongly inhibited both LOOH accumulation and
      apoptosis under protocol-1 conditions, but had no significant effect under
      protocol-2 conditions. These findings support the hypothesis that LOOHs produced
      by attack of photogenerated singlet oxygen on mitochondrial membrane lipids play
      an important early role in the apoptotic death cascade.

PMID- 12419472
TI  - Ozone-induced increase in exhaled 8-isoprostane in healthy subjects is resistant
      to inhaled budesonide.
AB  - The aim of this study was to quantify lung oxidant stress after short-term ozone
      exposure as reflected by 8-isoprostane concentrations in exhaled breath
      condensate (EBC) and to investigate the effects of inhaled budesonide on this
      response. 8-Isoprostane is a prostaglandin-F(2 alpha) isomer that is formed in
      vivo by free radical-catalyzed peroxidation of arachidonic acid. EBC is a
      noninvasive method to collect airway secretions. We undertook a double-blind,
      randomized, placebo-controlled, crossover study with inhaled budesonide (800
      microg) or placebo twice daily for 2 weeks prior to ozone exposure (400 parts per
      billion) for 2 h in nine healthy nonsmokers. Exhaled 8-isoprostane was measured
      by an enzyme immunoassay. 8-Isoprostane was increased 4 h after ozone exposure
      compared to pre-exposure values in both placebo (36.9 +/- 3.9 pg/ml, mean +/-
      SEM, vs. 16.9 +/- 0.7 pg/ml; p <.001) and budesonide groups (33.4 +/- 2.6 pg/ml
      vs. 15.8 +/- 0.3 pg/ml; p <.001). Pretreatment with budesonide did not affect the
      increases in 8-isoprostane (mean differences 3.4 pg/ml, 95% CI -8.9 to 15.7, p
      =.54). Short-term ozone exposure causes acute increase in lung oxidative stress
      as reflected by exhaled 8-isoprostane. This increase is resistant to pretreatment
      with a high dose of inhaled budesonide.

PMID- 12419473
TI  - Enhanced antioxidant defenses and resistance to TNF-alpha in a glycolysis
      depleted lung epithelial cell line.
AB  - Glycolysis-depleted cells, obtained by stable transfection of fructose 2,6
      bisphosphatase in mink lung epithelial cells (Mv1Lu), were less sensitive to
      serum withdrawal- and TNF-alpha-induced apoptosis than cells transfected with the
      empty vector pcDNA3 (control cells). We compared the differences in the redox
      status of the two transfectants and the changes produced by TNF-alpha treatment.
      The activities of the antioxidant enzymes catalase and glutathione peroxidase, as
      well as the content of reduced glutathione (GSH) and the activity of the nuclear
      transcription factor kappa B (NF-kappa B), were higher in pFBPase-2 clones than
      in control cells in all the conditions tested. TNF-alpha challenge sharpened the
      differences in glutathione peroxidase activity, GSH/GSSG ratios, and NF-kappa B
      activation between transfectants. These data indicate that glycolysis restriction
      at the PFK step protects cells against apoptotic stimuli by increasing the GSH
      content and NF-kappa B activity. This acquired feature may compromise
      antineoplastic treatments based on glycolytic depletion.

PMID- 12419474
TI  - Microarray analysis of H2O2-, HNE-, or tBH-treated ARPE-19 cells.
AB  - Oxidative stress plays a key role in aging diseases of the posterior pole of the
      eye such as age-related macular degeneration. The oxidative stress response of in
      vitro RPE cells has been studied for a small number of genes. However, a
      comprehensive transcriptional response has yet to be elucidated. The purpose of
      this study was to determine if the transcription of a common set of genes is
      altered by exposure of ARPE-19 cells to three major generators of oxidative
      stress, hydrogen peroxide (H2O2), 4-hydroxynonenal (HNE), and tert
      butylhydroperoxide (tBH). As expected, a common response was observed that
      included 35 genes differentially regulated by all three treatments. Of these,
      only one gene was upregulated, and only by one oxidant, while all other responses
      were downregulation. The majority of these genes fell into five functional
      categories: apoptosis, cell cycle regulation, cell-cell communication, signal
      transduction, and transcriptional regulation. Additionally, a large number of
      genes were differentially regulated by one oxidant only, including the majority
      of the conventional oxidative stress response genes present on the Clontech Human
      1.2 microarray. This study raises questions regarding the generality of results
      that involve the use of a single oxidant and a single cell culture condition.

PMID- 12419475
TI  - CCS knockout mice establish an alternative source of copper for SOD in ALS.

PMID- 12419476
TI  - Lipoprotein heterogeneity: diagnostic and therapeutic implications.

PMID- 12419477
TI  - Approach to lipoprotein management in 2001 National Cholesterol Guidelines.
AB  - In 2001 the National Cholesterol Education Program (NCEP) released its Adult
      Treatment Panel (ATP) III report. This was an evidence-based report that upgraded
      cholesterol management guidelines. The update was made possible by a series of
      large, cholesterol-lowering clinical trials. These trials demonstrated strongly
      the efficacy and safety of cholesterol reduction in both primary and secondary
      prevention of coronary heart disease (CHD). The major recommendations of the
      report were several. Low-density lipoprotein (LDL) cholesterol continued to be
      identified as the major target of cholesterol-lowering therapy. However, more
      emphasis was given to HDL cholesterol and triglycerides as important targets for
      management. The concept of CHD risk equivalents was introduced. A CHD risk
      equivalent represents an absolute risk for future CHD events equal to that in
      persons with established CHD. Diabetes was identified as a CHD risk equivalent,
      requiring more intensive LDL-lowering therapy. Finally, the report placed more
      emphasis on the metabolic syndrome as a major, multiplex risk factor requiring
      increased clinical attention.

PMID- 12419478
TI  - Measurement issues related to lipoprotein heterogeneity.
AB  - In clinical practice, the coronary artery disease (CAD) risk associated with high
      levels of low-density lipoprotein (LDL) or low levels of high-density lipoprotein
      (HDL) is assessed not by measuring LDL and HDL particles directly, but by
      measuring the amount of cholesterol carried by these lipoproteins. It is not
      generally appreciated how much the amount of cholesterol per particle varies from
      person to person, especially for LDL, because of differences in the relative
      amounts of cholesterol ester and triglycerides in the particle core as well as
      differences in particle diameter. As a consequence of the magnitude and
      prevalence of this lipid compositional variability, even the most accurate
      lipoprotein cholesterol measurements will, for many individuals, provide an
      inaccurate measure of the number of circulating lipoprotein particles and the CAD
      risk they confer. Nuclear magnetic resonance (NMR) spectroscopy offers an
      efficient new means of measuring lipoprotein levels in plasma, with
      quantification based not on cholesterol content, but on the amplitudes of
      spectral signals emitted by lipoprotein subclasses of different size. Because the
      subclass signal amplitudes are not influenced by cholesterol compositional
      variability, they provide a direct measure of lipoprotein particle
      concentrations. NMR data from the Framingham Offspring Study demonstrate a
      significant "disconnect" between LDL cholesterol and LDL particle concentrations
      in patients with low levels of HDL cholesterol. The results imply that a
      substantial portion of the excess CAD risk of patients with low HDL stems from an
      unrecognized excess of LDL particles containing less cholesterol than normal.
      Patients with this abnormality would benefit from LDL-lowering therapy but are
      not identified as candidates for such treatment on the basis of traditional LDL
      cholesterol tests.

PMID- 12419479
TI  - Clinical relevance of the biochemical, metabolic, and genetic factors that
      influence low-density lipoprotein heterogeneity.
AB  - Traditional risk factors for coronary artery disease (CAD) predict about 50% of
      the risk of developing CAD. The Adult Treatment Panel (ATP) III has defined
      emerging risk factors for CAD, including small, dense low-density lipoprotein
      (LDL). Small, dense LDL is often accompanied by increased triglycerides (TGs) and
      low high-density lipoprotein (HDL). An increased number of small, dense LDL
      particles is often missed when the LDL cholesterol level is normal or borderline
      elevated. Small, dense LDL particles are present in families with premature CAD
      and hyperapobetalipoproteinemia, familial combined hyperlipidemia, LDL subclass
      pattern B, familial dyslipidemic hypertension, and syndrome X. The metabolic
      syndrome, as defined by ATP III, incorporates a number of the components of these
      syndromes, including insulin resistance and intra-abdominal fat. Subclinical
      inflammation and elevated procoagulants also appear to be part of this
      atherogenic syndrome. Overproduction of very low-density lipoproteins (VLDLs) by
      the liver and increased secretion of large, apolipoprotein (apo) B-100-containing
      VLDL is the primary metabolic characteristic of most of these patients. The TG in
      VLDL is hydrolyzed by lipoprotein lipase (LPL) which produces intermediate
      density lipoprotein. The TG in intermediate-density lipoprotein is hydrolyzed
      further, resulting in the generation of LDL. The cholesterol esters in LDL are
      exchanged for TG in VLDL by the cholesterol ester tranfer proteins, followed by
      hydrolysis of TG in LDL by hepatic lipase which produces small, dense LDL.
      Cholesterol ester transfer protein mediates a similar lipid exchange between VLDL
      and HDL, producing a cholesterol ester-poor HDL. In adipocytes, reduced fatty
      acid trapping and retention by adipose tissue may result from a primary defect in
      the incorporation of free fatty acids into TGs. Alternatively, insulin resistance
      may promote reduced retention of free fatty acids by adipocytes. Both these
      abnormalities lead to increased levels of free fatty acids in plasma, increased
      flux of free fatty acids back to the liver, enhanced production of TGs, decreased
      proteolysis of apo B-100, and increased VLDL production. Decreased removal of
      postprandial TGs often accompanies these metabolic abnormalities. Genes
      regulating the expression of the major players in this metabolic cascade, such as
      LPL, cholesterol ester transfer protein, and hepatic lipase, can modulate the
      expression of small, dense LDL but these are not the major defects. New
      candidates for major gene effects have been identified on chromosome 1.
      Regardless of their fundamental causes, small, dense LDL (compared with normal
      LDL) particles have a prolonged residence time in plasma, are more susceptible to
      oxidation because of decreased interaction with the LDL receptor, and enter the
      arterial wall more easily, where they are retained more readily. Small, dense LDL
      promotes endothelial dysfunction and enhanced production of procoagulants by
      endothelial cells. Both in animal models of atherosclerosis and in most human
      epidemiologic studies and clinical trials, small, dense LDL (particularly when
      present in increased numbers) appears more atherogenic than normal LDL. Treatment
      of patients with small, dense LDL particles (particularly when accompanied by low
      HDL and hypertriglyceridemia) often requires the use of combined lipid-altering
      drugs to decrease the number of particles and to convert them to larger, more
      buoyant LDL. The next critical step in further reduction of CAD will be the
      correct diagnosis and treatment of patients with small, dense LDL and the
      dyslipidemia that accompanies it.

PMID- 12419480
TI  - How, when, and why to use apolipoprotein B in clinical practice.
AB  - The evidence is now clear that plasma apolipoprotein (apo) B is a better index of
      the risk of coronary artery disease (CAD) than total or low-density lipoprotein
      (LDL) cholesterol. Moreover, the evidence is also clear that clinical risk of apo
      B is determined not only by LDL particle number but also by whether small, dense
      LDL particles are present. The objective of this article, therefore, is to
      demonstrate how, when, and why apo B should be used in clinical practice. First,
      the evidence that apo B is superior to LDL cholesterol as an index of the risk of
      CAD and as a guide to the adequacy of statin therapy is briefly reviewed. Next,
      the biological bases for this superiority in identifying risk are outlined.
      Clinical scenarios are then outlined demonstrating the value of measuring apo B
      in hypertriglyceridemic, hypercholesterolemic, and normolipidemic subjects. The
      methodological soundness of the laboratory determinations of lipids and apo B is
      also an important issue. Concern has been raised regarding the measurement of apo
      B, but it is standardized, precise, and not expensive. Paradoxically, it is
      becoming ever more obvious that the methodological problems lie with calculated
      LDL cholesterol. To the known deficiencies must be added the fact that calculated
      LDL cholesterol systematically underestimates true LDL cholesterol at values
      close to target levels.Thus, from every perspective-pathophysiology, diagnosis,
      assessment of therapy, and methodologic soundness-there are powerful clinical
      arguments why apo B should be used in the routine diagnosis of dyslipidemias and
      assessment of the adequacy of statin therapy.

PMID- 12419481
TI  - Lipoprotein disorders associated with type 2 diabetes mellitus and insulin
      resistance.
AB  - Type 2 diabetes is associated with a marked increase in coronary artery disease
      (CAD). In subjects with type 2 diabetes, the characteristic lipoprotein
      abnormality is increased triglycerides, increased small, dense low-density
      lipoprotein (LDL) particles, and decreased concentrations of high-density
      lipoprotein (HDL) cholesterol but relatively normal absolute concentrations of
      LDL cholesterol. In observational studies, both increased LDL and decreased HDL
      cholesterol predict the development of CAD. In clinical trials, both fibric acids
      and statins have been shown to reduce CAD in subjects with diabetes. An
      interesting future clinical trial would be to assess whether fibric acids make an
      additional contribution to reduce CAD in patients already on statin therapy.

PMID- 12419482
TI  - High-density lipoproteins and atherosclerosis.
AB  - High-density lipoproteins (HDLs) are strongly related to risk of atherosclerotic
      cardiovascular disease. Low levels of HDL cholesterol are a major cardiovascular
      risk factor, and overexpression of the major HDL protein, apolipoprotein (apo) A
      I, markedly inhibits progression and even induces regression of atherosclerosis
      in animal models. Clinical data regarding the effect of increasing HDL
      cholesterol on vascular events are limited. HDL remains an important potential
      target for therapeutic intervention. A variety of gene products are involved in
      the regulation of HDL metabolism. Yet, the mechanisms by which HDL inhibits
      atherosclerosis are not yet fully understood. There remains much to be learned
      about HDL metabolism and its relation to atherosclerosis and other cardiovascular
      risk factors.

PMID- 12419483
TI  - Lipoprotein subclasses and coronary artery calcium in postmenopausal women from
      the healthy women study.
AB  - Lipoprotein subclass levels may improve the prediction of cardiovascular disease
      (CAD) in individuals beyond the risk assessment provided by conventional
      enzymatically determined lipid levels. The objective of this study was to
      evaluate the associations between nuclear magnetic resonance (NMR) spectroscopy
      determined lipoprotein subclasses and coronary calcification in postmenopausal
      women, and to determine whether the associations were independent of conventional
      lipid measures. Coronary artery calcification (CAC) was measured by electron beam
      computed tomography, and lipoprotein subclasses were determined by NMR
      spectroscopy (Liposcience, Inc., Raleigh, NC), in 286 healthy women (mean age =
      61.7), at 8 years postmenopause. CAC was analyzed as categories 0, 1 to 99, and >
      or =100. The mean CAC was 53 (range, 0 to 1,175), and 54% of the women had 0
      scores. Large high-density lipoprotein (HDL) was inversely associated with CAC
      category, but small HDL was not. All very low-density lipoprotein (VLDL)
      subclasses-small, medium, and large-were positively associated with CAC (p
      <0.01). Small low-density lipoprotein (LDL) was positively associated with CAC (p
      <0.01), but medium and large LDL were not. Smaller LDL particle size (p <0.01)
      and higher levels of LDL particles (p <0.001) were associated with higher CAC
      category. In separate ordinal logistic regression models, small LDL, LDL
      particles, and large VLDL were each positively associated (p <0.05) with higher
      CAC after adjustment for age, systolic blood pressure (SBP), current smoking, and
      conventional measures of LDL cholesterol, HDL cholesterol, and triglycerides.
      These results suggest that the measurement of lipoprotein subclasses may improve
      the prediction of CAD in postmenopausal women beyond that provided by the
      conventional lipid panel and CAD risk factors.

PMID- 12419484
TI  - Lipoprotein abnormalities related to women's health.
AB  - Although women have a greater life expectancy than men and tend to develop
      coronary artery disease (CAD) 10 to 20 years later than men, the burden of CAD in
      women is high, with a lifetime risk >20%. Beginning at puberty, women have more
      favorable lipoprotein profiles than men. High-density lipoprotein (HDL)
      cholesterol levels remain higher in women than men throughout their lifetime. Low
      density lipoprotein (LDL) cholesterol levels in women exceed those in men after
      middle age, but despite a shift toward smaller, denser LDL particles at the time
      of menopause, LDL particle number remains lower in women than in men throughout
      the lifespan. Lipoprotein levels strongly predict incident and recurrent CAD
      events in both sexes, and LDL particle size may be a better predictor of
      premature CAD in women than of CAD associated with advanced age. The effects of
      postmenopausal hormonal therapy on lipoprotein levels are complex, and the
      benefits of such therapy are not established. In contrast, lifestyle changes and
      pharmacological lipid-lowering therapy have been shown to favorably influence the
      natural course of atherosclerotic disease and reduce cardiovascular events in men
      and women.

PMID- 12419485
TI  - Human basal cortisol levels are increased in hospital compared to home setting.
AB  - The impact of study-environment on experimental outcome is mostly not realized
      and certainly not demonstrated. In the present study, a comparison was made
      between free salivary cortisol levels in healthy young men in a carefully
      controlled hospital setting versus a home setting. Cortisol levels during rest
      were increased in hospital compared to home environment: 2-fold at awakening, 3
      fold at the morning peak, and 5-fold late in the evening. Early morning light
      increased cortisol concentrations only in the home setting, while this effect was
      absent in the hospital setting. The data of the present study show that study
      environment has a major impact on basal hypothalamo-pituitary-adrenal (HPA)-axis
      activity, which is of particular relevance in future studies in which small
      changes in HPA-axis activity are subject of study.

PMID- 12419486
TI  - Increased intracortical inhibition in middle-aged humans; a study using paired
      pulse transcranial magnetic stimulation.
AB  - Using single and paired-pulse transcranial magnetic stimulation we compared the
      cortical excitability in two different age groups of healthy subjects (mean+/-SD
      age: 28.5+/-5.2 vs. 56.1+/-4.9 years). Motor evoked potentials were recorded from
      right extensor and flexor carpi radialis muscles. The effect of paired-pulse
      stimulation was assessed by the ratio conditioned/unconditioned response area
      with interstimulus intervals of 3 and 13 ms to test for intracortical inhibition
      and facilitation, respectively. To test the influence of sensory input the
      experiments were conducted without and with vibration of the extensor carpi
      radialis muscle. The intracortical inhibition was significantly greater in older
      subjects; however, during muscle vibration this difference between the two groups
      vanished. The different effect of vibration favors compensatory mechanisms to be
      responsible for a different paired-pulse excitability in middle-aged subjects.

PMID- 12419487
TI  - Differential changes of calcium binding proteins in the rat striatum after kainic
      acid-induced seizure.
AB  - It has been suggested that calcium binding proteins protect against Ca2+
      overload, thus rendering neurons more resistant against excitotoxicity. The
      influence of kainic acid, which induces status epilepticus, on the expressions of
      calbindin D28k, parvalbumin and calretinin was examined in the rat striatum by
      immunohistochemistry and microdensitometry. At 1, 3 and 6 days after kainic acid
      induced seizure, the number of calretinin-positive neurons in the striatum was
      significantly lower than in control rats. However, no significant difference was
      observed in the number of calbindin D28k- and parvalbumin-positive neurons in
      control and seizure rats. At 1, 3 and 6 days after seizure the optical densities
      of calretinin- and parvalbumin-positive neurons in the striatum were
      significantly lower than in control rats. Our finding concerning the selective
      loss of calretinin-positive neurons in seizure groups suggests that calcium
      binding proteins in the striatum have differential vulnerabilities to kainic acid
      induced seizure.

PMID- 12419488
TI  - The effects of nicotinamide on energy metabolism following transient focal
      cerebral ischemia in Wistar rats.
AB  - This study examined the effects of nicotinamide on adenosine triphosphate (ATP)
      and nicotinamide adenine (NAD) levels and poly(adenosine diphosphate-ribose)
      (poly(ADP-ribose)) polymerase activity following ischemia and reperfusion in
      ketamine pretreated rats. Nicotinamide was administered at the end of the
      ischemic period. Nicotinamide protected against the depletion of ATP and NAD at 6
      and 24 h of reperfusion. Nicotinamide is known to inhibit poly(ADP-ribose)
      polymerase at early time points, but was found to increase poly(ADP-ribose)
      polymerase activity at 24 h of reperfusion. It appears that nicotinamide can help
      maintain cellular energetics during reperfusion, thereby protecting cells from
      necrotic and apoptotic mechanisms.

PMID- 12419489
TI  - Neuronal death and tumor necrosis factor-alpha response to glutamate-induced
      excitotoxicity in the cerebral cortex of neonatal rats.
AB  - Neuronal death and lactate dehydrogenase (LDH) activity were evaluated in the
      cerebral cortices of neonatal rats after exposure to monosodium L-glutamate (MSG)
      to induce neuroexcitotoxicity. A time-response profile for tumor necrosis factor
      alpha (TNF-alpha) expression was drawn, with measurements taken every 6 h after
      the first dose of MSG during the first 8 postnatal days, and at days 10 and 14
      after birth. An increase in neuronal loss accompanied by high LDH activity and
      high TNF-alpha levels was observed at 8 and 10 days. These results indicate that
      neuronal loss may occur via an apoptosis-like mechanism directed selectively
      against neurons that express glutamate receptors, mainly the N-methyl-D
      aspartate, which it may be strengthen by high TNF-alpha levels through a feedback
      mechanism to induce cell death via apoptosis.

PMID- 12419490
TI  - The importance of head-free gaze control in humans performing a spatial
      orientation task.
AB  - The present study aimed at investigating how a specific instruction concerning
      gaze orientation, which involved active head motion, could influence the
      performance of human subjects in a self-controlled whole-body rotation task in
      the dark. Subjects were seated on a mobile robotic chair that they controlled
      using a joystick. They were asked to perform 360 degrees rotations while
      maintaining, when possible, the gaze on the estimated position of an earth-fixed
      target. Subjects performed better when gazing at this target than when no target
      was shown. Furthermore, performance was significantly related to head
      stabilization in space. The results reveal the importance of head-free gaze
      control for spatial orientation in so far as it may involve spatial reference
      cues and sensory signals of different modalities, which may be beneficial to self
      motion perception.

PMID- 12419491
TI  - In vitro inhibition of pentylenetetrazole and bicuculline-induced epileptiform
      activity in rat hippocampal pyramidal neurons by aqueous fraction isolated from
      Delphinium denudatum.
AB  - Roots of Delphinium denudatum W. are used for the treatment of epilepsy by
      traditional healers in subcontinent. Aqueous fraction (AF) isolated from D.
      denudatum has previously shown significant anticonvulsant activity in in vivo and
      in vitro models of seizures. We investigated anticonvulsant effects of AF on
      pentylenetetrazole (PTZ) and bicuculline (BIC)-induced epileptiform activity in
      primary hippocampal neuronal cultures. Electrophysiological studies on single
      pyramidal neurons were carried out by using whole-cell current clamp technique.
      Introduction of AF (0.6 mg/ml) in perfusate blocked PTZ (10 mM) and BIC (100
      micro M)-induced epileptiform activity comprising of paroxysmal depolarization
      shifts (PDS). The PDS were elicited again when AF was removed from perfusate. We
      conclude that AF contains anticonvulsant compounds that possibly interact with
      GABA(A) receptor to produce blockade of epileptiform activity. Further studies on
      isolation of compounds from AF may lead to discovery of new class of
      anticonvulsants.

PMID- 12419492
TI  - Enhancement of aromatase gene expression in the mediobasal hypothalamus during
      anestrus in the beagle bitch.
AB  - The relationships among expression of cytochrome p450 aromatase (p450arom) mRNA
      in the mediobasal hypothalamus (MBH), ovarian aromatase activity, and estrogen
      secretion were examined throughout the estrous cycle in beagle bitches. Using
      polymerase chain reaction (PCR) analysis we were able to detect p450arom gene
      transcripts in the canine MBH. The level of hypothalamic p450arom mRNA increased
      during the progression of anestrus and declined thereafter. Ovarian p450arom
      activity, as measured by a (3)H2O assay, were low in anestrus, increased in
      proestrus, and declined thereafter. Ovarian p450arom activity and plasma
      estradiol-17beta levels were positively correlated (r=0.77, P<0.05). These
      results suggest that enhancement of hypothalamic p450arom gene expression is
      associated with termination of anestrus.

PMID- 12419493
TI  - Developmental exposure to the antiretroviral drug zidovudine increases brain
      levels of brain-derived neurotrophic factor in mice.
AB  - We analyzed brain-derived neurotrophic factor (BDNF) and nerve growth factor
      (NGF) protein content in the central nervous system (CNS) of developing and adult
      mice exposed to the antiretroviral agent zidovudine (AZT) during prenatal and
      early postnatal period. Pregnant CD-1 mice received per os twice daily AZT (160
      mg/kg) or vehicle from gestation day 10 until lactation day 7. BDNF and NGF
      contents were measured by enzyme immunoassays in male and female offspring on day
      7, 21 or 60. In AZT-exposed females, BDNF levels were significantly increased in
      the hippocampus (days 7 and 21), in the cortex (day 60) and in the hypothalamus
      (day 21), while in males AZT exposure increased BDNF in the cortex on day 21.
      These findings support the hypothesis that developmental AZT exposure interferes
      with CNS development.

PMID- 12419494
TI  - Association analysis between Alzheimer's disease and the Nicastrin gene
      polymorphisms.
AB  - The biological study of the Nicastrin protein shows its crucial role in the
      pathogenesis of Alzheimer's disease (AD). We tested the hypothesis that the
      Nicastrin (NCSTN) gene might be genetically associated with AD. The association
      analysis of two single nucleotide polymorphisms (SNPs) in the coding region
      (cSNPs) of NCSTN were performed in an Italian population. No evidence of
      association was obtained between the two SNPs investigated in sporadic and
      familial AD cases under the stratification of currently known genetic risk
      factors including the apolipoprotein E (APOE), the presenilins and the beta
      amyloid precursor protein. The result suggests no apparent synergic interaction
      between the NCSTN and APOE epsilon 4 in the risk to develop the late onset
      sporadic form of AD. But considering its biological effects, the result can not
      exclude the NCSTN as candidate for genetic factor in AD. Further genetic study of
      the NCSTN would be necessary to evaluate the potential genetic involvement in AD.

PMID- 12419495
TI  - Temporal relationship of hippocampal liquor- and plasma-cortisol-concentrations
      in the domestic pig challenged with synthetical adreno-corticotrophic hormone.
AB  - The concentration of plasma and intracerebral cortisol in pigs challenged with
      0.5 IU adrenocorticotrophic hormone/kg body weight was simultaneously measured at
      a 30 min rate. The pigs (n=5) were provided with indwelling jugular vein
      catheters and guide canullas for insertion of a hippocampal microdialysis probe.
      Every five blood samples taken at 6 min intervals were pooled to simulate the 30
      min collection time of the microdialysis. Stimulation resulted in an increment of
      cortisol of roughly 200% in plasma and 190% in the dialysate compared to basal
      value. The average time lag of hippocampal to plasma peak was 48.75 min.
      Considering the temporal resolution of the protocol it is inferred that delays of
      at least 30 min occur between variations of peripheral and central nervous
      cortisol.

PMID- 12419496
TI  - Treadmill running and swimming increase cell proliferation in the hippocampal
      dentate gyrus of rats.
AB  - The effects of treadmill exercise and swimming on cell proliferation in the
      dentate gyrus and the involvement of opioid receptors were investigated via 5
      bromo-2'-deoxyuridine (BrdU) immunohistochemistry. Sprague-Dawley rats of the
      running groups were made to run on treadmill for 30 min each day, while those of
      the swimming groups were made to swim for 5 min each day over 3 consecutive days.
      In addition, intensity-dependency of the effects of running and swimming on cell
      proliferation was investigated. The present results demonstrate that both
      treadmill running and swimming increase the number of BrdU-labeled cells in the
      dentate gyrus and these increasing effects are more potent in light intensity and
      5 min swimming groups. Treatment with naloxone increases cell proliferation in
      the dentate gyrus in all groups, although this increase is statistically
      insignificant.

PMID- 12419498
TI  - Postural sway under muscle vibration and muscle fatigue in humans.
AB  - Separate studies have demonstrated that vibration and fatigue of ankle muscles
      alter postural control. The purpose of the present experiment was to investigate
      the effect of ankle muscle vibration on the regulation of postural sway in
      bipedal stance following ankle muscle fatigue. Center of foot pressure
      displacements were recorded using a force platform. Results showed a similar
      increase in postural sway under muscle fatigue as well as under muscle vibration.
      Interestingly, under muscle fatigue muscle vibration did not induce a further
      increase in postural sway. Two hypotheses could, at least, account for this
      observation: (1). fatigued muscles are less sensitive to muscle vibration and
      (2). the central nervous system relies less upon proprioceptive information
      originating from fatigued muscles for regulating postural sway.

PMID- 12419497
TI  - Neuropeptide Y inhibits in vitro epileptiform activity in the entorhinal cortex
      of mice.
AB  - Previous studies show that neuropeptide Y (NPY) inhibits in vitro seizures in
      rodent hippocampus. Here, we explored the effect of NPY application on
      epileptiform discharges induced by perfusion with magnesium-free solution in
      slices of entorhinal cortex from two different mouse strains. NPY significantly
      reduced the duration of epileptiform discharges with a peak effect of 36-50%.
      This is the first study showing anti-epileptiform effect of NPY in the entorhinal
      cortex and also the first evidence that NPY inhibits seizures in a cortical
      region in mice. The entorhinal cortex has a central role in transferring
      information between the hippocampus and the rest of the brain. Therefore our data
      further strengthen the concept of NPY and its receptors as widespread regulators
      of epileptiform activity and as a potential future target for antiepileptic
      therapy.

PMID- 12419499
TI  - Vasodilatation of muscle microvessels induced by somatic afferent stimulation is
      mediated by calcitonin gene-related peptide release in the rat.
AB  - In anesthesized rats, the effects of electrical stimulation (ES) to the saphenous
      nerve on the microcirculation of the gracilis muscle were assessed through the
      measurement of two different hemodynamic parameters: (a). the muscle blood flow
      (MBF) using a laser Doppler flowmeter; and (b). the changes in diameter of the
      muscle arterioles observed directly using an intravital microscope system.
      Ipsilateral ES (5 V, 20 Hz, for 30 s) produced increases in MBF and mean arterial
      pressure (47+/-10% and 18+/-5%) over the baseline, while no significant changes
      in MBF were observed in the contralateral muscle. Neither selective nor
      simultaneous alpha- and beta-adrenergic blockade altered the increases in MBF
      induced by ipsilateral ES. The arteriolar diameter was found to increase by
      38.9+/-5% following ipsilateral ES. This response in diameter was abolished after
      the topical application of a calcitonin gene-related peptide receptor antagonist
      (CGRP(8-37)). Contralateral ES produced a decrease in arteriolar diameter by 26+/
      14%. Thus, ipsilateral nerve ES produced vasodilative responses in the muscle
      accompanied by increases in MBF independently of the sympathetic activity.
      Furthermore, CGRP was found directly involved in the reflex neural regulation of
      the muscle microcirculation, which suggests the participation of an axon reflex
      mechanism.

PMID- 12419500
TI  - Informational constraints in human precision aiming.
AB  - Twelve human subjects performed a reciprocal precision aiming task of varying
      difficulty (index of difficulty=4, 5, or 6) while vision of the ongoing movement
      was available either continuously or intermittently. In the intermittent
      conditions, vision of the moving end-effector was available at regular intervals
      (equal to 100%, 125%, or 150% of the movement durations measured under continuous
      visibility conditions) for varying amounts of time (75%, 50%, or 25% of the
      duration of the interval). Movement time (MT) increased with both increasing task
      difficulty and decreasing availability of visual information. Increases in MT
      were brought about by the same systematic changes in the kinematic
      characteristics of movement, whether task difficulty increased or availability of
      visual information decreased. At higher levels of task difficulty, subjects
      organized their movements so as to make visual information available at
      particular instances (at the start and at the end of the aiming movement).

PMID- 12419501
TI  - Opposite modulation of regulators of G protein signalling-2 RGS2 and RGS4
      expression by dopamine receptors in the rat striatum.
AB  - The role of dopaminergic transmission on striatal mRNA levels of regulators of G
      protein signalling proteins RGS 2-12 was evaluated by quantitative in situ
      hybridisation. A single injection of L-dopa (50 mg/kg i.p.) significantly
      increased the RGS2 mRNA level (by 25%), an effect that was specifically abolished
      by the D1 dopamine receptor antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl
      2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (R(+)-SCH23390), but not
      changed by S(-)-eticlopride. Interestingly, the administration of this D2
      dopamine receptor antagonist alone markedly enhanced the expression of RGS2 (by
      71%), which suggests a constitutive inhibition of RGS2 expression by D2 dopamine
      receptors. Opposite results were obtained concerning the regulation of RGS4 since
      L-dopa alone was without effect whereas co-administration of L-dopa and R(+)
      SCH23390 significantly enhanced the RGS4 mRNA levels (by 38%). In conclusion, D1
      and D2 dopamine receptors appear to mediate opposite regulatory effects on RGS2
      and RGS4 expression in the striatum.

PMID- 12419502
TI  - Cerebrospinal fluid and plasma concentrations of nitric oxide metabolites are
      increased in dementia with Lewy bodies.
AB  - We compared cerebrospinal fluid (CSF) and plasma concentrations of nitric oxide
      metabolites (NO(-)(x)) in 22 patients with dementia with Lewy bodies (DLB) and 13
      matched controls. We found a pronounced increase in NO(-)(x) CSF and plasma
      levels in DLB patients. No changes were found in L-arginine and L-citrulline
      levels in CSF or plasma. There was no correlation between CSF and plasma levels
      and age, age of onset, duration of the disease or scores of the MiniMental State
      Examination. These findings reveal that excessive nitric oxide production may be
      related to the pathogenesis of DLB.

PMID- 12419503
TI  - Plant toxic proteins with insecticidal properties. A review on their
      potentialities as bioinsecticides.
AB  - To meet the demands for food of the expanding world population, there is need of
      new ways for protecting plant crops against predators and pathogens while
      avoiding the use of environmentally aggressive chemicals. A milestone in this
      field was the introduction into crop plants of genes expressing Bacillus
      thuringiensis entomotoxic proteins. In spite of the success of this new
      technology, however, there are difficulties for acceptance of these 'anti
      natural' products by the consumers and some concerns about its biosafety in
      mammals. An alternative could be exploring the plant's own defense mechanisms, by
      manipulating the expression of their endogenous defense proteins, or introducing
      an insect control gene derived from another plant. This review deals with the
      biochemical features and mechanisms of actions of plant proteins supposedly
      involved in defense mechanisms against insects, including lectins, ribosome
      inactivating proteins, enzymes inhibitors, arcelins, chitinases, ureases, and
      modified storage proteins. The potentialities of genetic engineering of plants
      with increased resistance to insect predation relying on the repertoire of genes
      found in plants are also discussed. Several different genes encoding plant
      entomotoxic proteins have been introduced into crop genomes and many of these
      insect resistant plants are now being tested in field conditions or awaiting
      commercialization.

PMID- 12419504
TI  - The sarafotoxins.

PMID- 12419505
TI  - Nematocyst ratio and prey in two Australian cubomedusans, Chironex fleckeri and
      Chiropsalmus sp.
AB  - This study examined differences in the nematocyst ratios between two species of
      Australian cubozoans. In Chiropsalmus sp., a species that feeds exclusively on
      shrimp, no changes in the ratio of the three groups of nematocyst present in the
      cnidome were detected with size of the individual animals. In Chironex fleckeri,
      the ratio of different types of nematocysts in the cnidome for small animals
      (less than 40 mm) was similar to that of Chiropsalmus sp. However, with an
      increase in body size in C. fleckeri, the nematocyst ratio changed, with
      mastigophores (nematocysts believed to hold the lethal venom component for prey)
      increasing in proportion. The change in cnidome ratio is correlated with a change
      in the prey of C. fleckeri with increased size. Small C. fleckeri appeared to
      feed exclusively on prawns, medium sized animals fed on fish and prawns and large
      animals fed predominantly on fish. An increase in the proportion of mastigophores
      (and presumably the lethal venom component) in the cnidome of C. fleckeri may
      also be responsible for why this species has caused numerous human fatalities,
      while the Australian Chiropsalmus sp. has not.

PMID- 12419506
TI  - Vascular endothelial cell injury induced by Bothrops jararaca venom; non
      significance of hemorrhagic metalloproteinase.
AB  - To examine the effect of Bothrops jararaca venom and its major hemorrhagic
      metalloproteinase, jararafibrase I (JF I), on vascular endothelial cells, B.
      jararaca crude venom and JF I were infused intravenously into rabbits. The degree
      of endothelial cell injury was estimated from the plasma level of soluble
      thrombomodulin (TM). The fibrinogen level, prothrombin time (PT), JF I antigen
      level and macroglobulin activity of the plasma were also measured. The TM level
      was not increased even by a large quantity of JF I, while the crude venom caused
      an increase in TM level suggesting the occurrence of endothelial cell injury. No
      alterations of fibrinogen level and PT were noted with a high amount of JF I, and
      no systemic bleeding was observed. Macroglobulin, which is the main inhibitor of
      metalloproteinase in rabbit plasma, was not significantly reduced despite a high
      dose of JF I. The elevation of TM level in the rabbit plasma after infusion of
      crude venom was totally suppressed by pretreatment with heparin. These findings
      suggest that the endothelial cell injury caused by B. jararaca venom is not due
      to the hemorrhagic metalloproteinase but to the coagulating factors in the venom.
      Plasma macroglobulin appears to be efficient enough to neutralize the circulating
      hemorrhagic metalloproteinases inoculated by B. jararaca.

PMID- 12419507
TI  - Cloning and characterization of an acidic cytolysin cDNA from sea anemone
      Sagartia rosea.
AB  - A full-length cDNA of cytolysin (Src I) was isolated from the tentacle of
      Sagartia rosea (a representative species in China) by reverse transcription
      polymerase chain reaction. The cDNA with an open reading frame of 648 bp encodes
      a precursor protein of 216 amino acids, which contains a prepropeptide of 38
      amino acids including a signal peptide of 19 amino acids and a propart of 19
      amino acids. Lys-Pro at C-terminus of propart is a cleavage site for proline
      endopeptidase-like protease. The mature cytolysin has a molecular mass of 19.6
      kDa and a pI value of 4.8. Src I is an acidic cytolysin found in sea anemone and
      shares 75% amino acid sequence similarity to equinatoxin II (Eqt II). The
      predicted secondary structure of the mature cytolysin comprises 15% alpha-helix,
      45% beta-sheet, and 40% random coil. The characteristic amphiphilic alpha-helix
      of cytolysin is located at the N-terminus of the processed Src I.

PMID- 12419508
TI  - Local inflammatory reaction induced by Bothrops jararaca venom differs in mice
      selected for acute inflammatory response.
AB  - Bothrops jararaca venom (BjV) causes severe systemic and local reactions,
      characterized by an acute inflammatory reaction with accumulation of leukocytes
      and release of endogenous mediators. The systemic and local effects of BjV were
      compared in lines of mice genetically selected for maximal (AIR(max)) or minimal
      (AIR(min)) acute inflammatory reactivity (AIR). The systemic reaction was
      evaluated by LD(50) and the local reaction by edema formation, cellular influx,
      release of PGE(2), NO and H(2)O(2) and the production of the pro-inflammatory
      cytokines IL-6, Tumor necrosis factor-alpha (TNF-alpha) and IFN-gamma. Both mouse
      lines were equally susceptible to the lethal effects of the venom showing similar
      LD(50) but differed significantly in terms of the local inflammatory reaction.
      Footpad edema and leukocyte influx in the peritoneum after BjV inoculation was
      higher in AIR(max) compared to AIR(min), BALB/c or outbred Swiss mice.
      Coincidently, higher levels of the soluble mediators PGE(2), IFN-gamma and TNF
      alpha were detected in the inflammatory exudate induced by BjV in AIR(max) mice.
      Cytokines levels were correlated to in vitro NO and H(2)O(2) production. The
      results demonstrate that the genetic factors selected in AIR(max) and AIR(min)
      lines of mice interfere in the control of the acute local reaction triggered by
      BjV venom.

PMID- 12419509
TI  - Influences on venom yield in Australian tigersnakes (Notechis scutatus) and
      brownsnakes (Pseudonaja textilis: Elapidae, Serpentes).
AB  - The rates at which venomous animals produce venoms are of obvious biological and
      medical importance, but factors influencing those rates remain poorly understood.
      We gathered data on venom yield (wet mass of venom) and percentage solids (dry
      mass of the venom divided by wet mass) for 53 eastern brownsnakes (Pseudonaja
      textilis) and 36 mainland tigersnakes (Notechis scutatus) over a 4-year period at
      Venom Supplies Pty. Ltd, a commercial venom production facility in South
      Australia. Tigersnakes yielded about threefold more venom (by wet mass) than
      brownsnakes, but with slightly lower percentage solids. Both species showed
      significant geographic variation in percentage solids. Venom yields varied as a
      function of the snake's sex and geographic origin, but these effects were
      secondary consequences of geographic and sex-based differences in body size.
      Relative head size affected venom yield in brownsnakes but not tigersnakes.
      Overall, the amount of venom that a snake produced during milking was affected by
      its species, its geographic origin, its body size and relative head size, and by
      the time of year that it was milked, as well as by interactions among these
      factors. Body size was the most important effect on venom yield, with yields
      increasing more rapidly with size in brownsnakes than in tigersnakes. Research at
      the intersection of snake ecology and venom characteristics has great potential,
      but will require a genuinely interdisciplinary approach.

PMID- 12419510
TI  - Accumulation of paralytic shellfish poisoning toxins in the edible shore crab
      Telmessus acutidens.
AB  - Several shellfishes including the crab Telmessus acutidens and its prey bivalve
      Mytilus galloprovincialis were collected at Onahama in Japan to investigate the
      accumulation of paralytic shellfish poisoning (PSP) toxins during the blooming
      season of toxic dinoflagellates. The toxicity of the viscera of T. acutidens
      collected in 1999 was 30.0 and 80.0 MU/g, and that of M. galloprovincialis was
      9.6 MU/g by mouse bioassay. PSP toxins in the crab viscera were identified by
      HPLC-FLD and ESI-MS, so this is the first observation of PSP toxins in T.
      acutidens. Carbamate toxins (GTX1-4, and STX) were the major component in the
      crab as well as in the mussels, and accounted for over 60% on a molar basis.
      However, the ratio of the N1-OH toxin to N1-H toxin of the crabs were largely
      different from that of the mussels, and a reductive conversion of the toxins in
      T. acutidens is concluded as the probable cause. In 2000, PSP toxins were also
      detected in both crabs and mussels, though the contents were very low compared
      with the levels observed in 1999. The difference in the toxin abundance suggests
      that the toxin content in the crab was affected by those of the prey.

PMID- 12419511
TI  - DSP toxin profile in the coastal waters of the central Adriatic Sea.
AB  - A monitoring program, carried out in 1996 and 1997, has confirmed that toxic
      compounds, other than the most frequently detected toxins okadaic acid (OA) and
      dinophysistoxin-1 (DTX-1), are involved in DSP phenomena in the Adriatic Sea.
      Toxicity was assessed by the mouse bioassay; the content and the nature of the
      toxic components were established through fluorometric HPLC analysis combined
      with mass spectrometry. A rare pectenotoxin-2 (PTX-2) derivative, 7-epi
      pectenotoxin-2 seco acid (7-epi-PTX-2SA), was the exclusive contaminant of
      samples collected from the central Adriatic in 1996. Contrary to its marked oral
      toxicity, intraperitoneally 7-epi-PTX-2SA displayed no toxic effects, hampering
      its detection by the mouse bioassay. In 1997, its concentration and frequency of
      appearance were lower than in 1996, with concomitant occurrence of OA, DTX-2, and
      a new unidentified component related to the DSP toxic group of compounds. This is
      the first report on the occurrence of DTX-2 in Adriatic mussels. A survey of the
      phytoplankton community in the surrounding seawater has established the presence
      of Prorocentrum micans and several potentially toxic species from the Dinophysis
      genus. A case of unexplained toxicity, associated with the occurrence of
      Gonyaulax polyedra, suggested possible shellfish contamination with yessotoxin
      (YTX).

PMID- 12419512
TI  - Intraspecific variability and pharmacokinetic characteristics of Androctonus
      mauretanicus mauretanicus scorpion venom.
AB  - We evaluated the degree of venom toxicity and protein content of several
      specimens of Androctonus mauretanicus mauretanicus. The quantity of protein of
      individual venom obtained after manual extraction from 31 different scorpions
      varied from a minimum of 0.15 mg to a maximum of 1.53 mg. We determined the venom
      toxicity, in mice, by estimating the number of LD(50)s of 20 scorpions chosen
      randomly among the 31 scorpions. It ranged from less than 40 LD(50)s to a maximum
      of 272 LD(50)s. The correlation between protein content and venom lethality is
      not systematic. We also determined the pharmacokinetics of the venom and its
      specific anti-venom in rabbits to compare their distribution and elimination
      properties. After a subcutaneous injection, high concentrations of venom were
      measured by ELISA in the vascular space rapidly after the injection (T(max) = 0.5
      h). The terminal half-life was 2.8 h, close the one determined after intravenous
      injection (t(1/2beta) = 3.2 h). The total volume of distribution (Vd(ss) or
      Vd(beta)) was between 317 and 380 ml/kg. The total body clearance was 82 ml/kg/h.
      For scorpion anti-venom, the terminal half-life, after intravenous injection, was
      20.25 h; the volume of distribution was 83 ml/kg and the total body clearance was
      3 ml/kg/h. After intramuscular administration, T(max) was reached at 36 h. The
      results show that venom lethality varies from specimen to specimen and that
      pharmacokinetic parameters of venom and anti-venom are totally different. This
      must be taken under consideration in anti-venom production (anti-venom titre) as
      well as in therapeutic protocols (dose, injection route) to improve serotherapy.

PMID- 12419513
TI  - Fluorometric assay using naphthylamide substrates for assessing novel venom
      peptidase activities.
AB  - In the present study we examined the feasibility of using the fluorometry of
      naphthylamine derivatives for revealing peptidase activities in venoms of the
      snakes Bothrops jararaca, Bothrops alternatus, Bothrops atrox, Bothrops moojeni,
      Bothrops insularis, Crotalus durissus terrificus and Bitis arietans, of the
      scorpions Tityus serrulatus and Tityus bahiensis, and of the spiders Phoneutria
      nigriventer and Loxosceles intermedia. Neutral aminopeptidase (APN) and prolyl
      dipeptidyl aminopeptidase IV (DPP IV) activities were presented in all snake
      venoms, with the highest levels in B. alternatus. Although all examined peptidase
      activities showed relatively low levels in arthropod venoms, basic aminopeptidase
      (APB) activity from P. nigriventer venom was the exception. Compared to the other
      peptidase activities, relatively high levels of acid aminopeptidase (APA)
      activity were restricted to B. arietans venom. B. arietans also exhibited a
      prominent content of APB activity which was lower in other venoms. Relatively low
      prolyl endopeptidase and proline iminopeptidase activities were, respectively,
      detectable only in T. bahiensis and B. insularis. Pyroglutamate aminopeptidase
      activity was undetectable in all venoms. All examined peptidase activities were
      undetectable in T. serrulatus venom. In this study, the specificities of a
      diverse array of peptidase activities from representative venoms were
      demonstrated for the first time, with a description of their distribution which
      may contribute to guiding further investigations. The expressive difference
      between snake and arthropod venoms was indicated by APN and DPP IV activities
      while APA and APB activities distinguished the venom of B. arietans from those of
      Brazilian snakes. The data reflected the relatively uniform qualitative
      distribution of the peptidase activities investigated, together with their
      unequal quantitative distribution, indicating the evolutionary divergence in the
      processing of peptides in these different venoms and/or the different abilities
      of the venoms examined to hydrolyze different peptides during envenomation.

PMID- 12419514
TI  - Persistent paresis of the facialis muscle after European adder (Vipera berus)
      bite on the forehead.
AB  - A case of Vipera berus (European adder) snake bite to the forehead is reported,
      which caused extensive oedema of the head and trunk and petechial haemorrhages.
      These resolved over several days but there was a persistent unilateral facial
      frontalis muscle paresis and ptosis most likely due to the location of the bite
      in the left fronto-temporal area.

PMID- 12419515
TI  - Diurnal and nocturnal rodents show rhythms in orexinergic neurons.
AB  - Orexin (ORX) A and B (hypocretins) are excitatory neuropeptides produced by
      neurons of the lateral hypothalamus that have been implicated in the regulation
      of the sleep-wake cycle. In rats, Fos (the product of the cfos gene) expression
      shows daily rhythms in areas involved in sleep and wakefulness and orexinergic
      neurons show elevated Fos expression during the night. The present study directly
      compared the daily pattern of Fos expression in orexinergic neurons in diurnal
      (A. niloticus; grass rats) and nocturnal (R. norvegicus; lab rats) rodents.
      Animals kept on a 12:12 light-dark cycle were perfused at six different Zeitgeber
      times (ZT), with lights on at ZT 0: 1, 5, 13, 17, 20 and 23. In both nocturnal
      and diurnal rodents orexinergic neurons showed rhythms in Fos expression, with
      more Fos seen during the active phase of each species. In the diurnal species,
      Fos expression in cells of the lateral hypothalamus that do not produce ORX was
      elevated at ZT 20, a time when these animals sleep, and was low at ZT 13, a time
      of peak of activity. These results provide further evidence for a link between
      activity in orexinergic neurons and wakefulness and that in grass rats, other
      neurons of the lateral hypothalamus may work in an antagonistic fashion with
      respect to orexinergic neurons to regulate wakefulness in this diurnal species.

PMID- 12419516
TI  - Acute and repeated treatment with L-DOPA increase c-jun expression in the 6
      hydroxydopamine-lesioned forebrain of rats and common marmosets.
AB  - L-DOPA was acutely or repeatedly administered to rats and common marmosets
      (Callithrix jacchus) with unilateral 6-hydroxydopamine (6-OHDA) denervation of
      the dopamine inputs to the forebrain. Using in situ hybridization it was found
      that L-DOPA-treated animals exhibited a pronounced induction in the gene
      expression of both c-jun and c-fos in striatum and cerebral cortex restricted to
      the dopamine-depleted hemisphere. In contrast, acute treatment with cocaine
      induced c-fos mRNA, but not c-jun mRNA, in the striatum of normal animals. These
      data suggest that dopamine denervation leads to neurochemical adaptations which
      enables L-DOPA to induce a sustained gene expression of c-jun. Such aberrant gene
      regulation may underlie the development of L-DOPA-induced movement disorders
      which are commonly found in patients with Parkinson's disease.

PMID- 12419517
TI  - Alterations in septohippocampal cholinergic neurons resulting from interleukin-2
      gene knockout.
AB  - Interleukin-2 (IL-2) has potent effects on acetylcholine (ACh) release from
      septohippocampal cholinergic neurons and trophic effects on fetal septal and
      hippocampal neuronal cultures. Previous work from our lab showed that the absence
      of endogenous IL-2 leads to impaired hippocampal neurodevelopment and related
      behaviors. We sought to extend this work by testing the hypotheses that the loss
      of IL-2 would result in reductions in cholinergic septohippocampal neuron cell
      number and the density of cholinergic axons found in the hippocampus of IL-2
      knockout mice. Stereological cell counting and imaging techniques were used to
      compare C57BL/6-IL-2(-/-) knockout and C57BL/6-IL-2(+/+) wild-type mice for
      differences in choline acetyltransferase (ChAT)-positive somata in the medial
      septum and vertical limb of the diagonal band of Broca (MS/vDB) and acetylcholine
      esterase (AChE)-labeled cholinergic axons in hippocampal projection fields. IL-2
      knockout mice had significantly lower numbers (26%) of MS/vDB ChAT-positive cell
      bodies than wild-type mice; however, there were no differences in striatal ChAT
      positive neurons. Although AChE-positive axon density in CA1, CA3b, the internal,
      and external blades of the dentate gyrus did not differ between the knockout and
      wild-type mice, the distance across the granular cell layer of the external blade
      of the dentate gyrus was reduced significantly in IL-2 knockout mice. Further
      research is needed to determine whether these outcomes in IL-2 knockout mice may
      be due to the absence of central and/or peripheral IL-2 during brain development
      or neurodegeneration secondary to autoimmunity.

PMID- 12419518
TI  - Swallowing-like activity elicited in vitro in neonatal rat organ attached
      brainstem block preparation.
AB  - The purpose of this study was to induce swallowing in an in vitro neonatal rat
      brainstem preparation and to analyze the circuit. When we applied GABA(A)
      receptor antagonist (bicuculine methiodide, BIC) into the the nucleus tractus
      solitarius (NTS) in the organ attached brainstem preparation of neonatal (0-3
      days after birth) rats, jaw closing movement, palatal lifting, and tongue
      peristalsis-like movement were seen, subsequent to elevation of the tip of the
      tongue and anterior movement of the larynx (closure of the trachea). The NTS has
      been proposed to be a critical locus for swallowing pattern generation in
      mammals. Electrical stimulation into the NTS or the vagal afferent nerve (X)
      following an application of BIC (10 microM) to the recording chamber initiated
      the same organ movement. This movement caused temporary inhibition of respiratory
      activity that was simultaneously recorded from the fourth cervical ventral nerve
      (C4). We were also able to elicit this activity in a whole organ (from lip to
      stomach, midline intact) preparation, whose oral cavity was filled with dye
      (pontamine sky-blue 3 mM, 50 microl), using each of the three types of
      stimulation. The esophagus, which was never stained by spontaneous respiratory
      movements, was stained only after the experimental stimulation. We concluded that
      the activity elicited was swallowing-like activity and the smallest circuit for
      swallowing pattern generation exists in this preparation.

PMID- 12419519
TI  - Aminergic projections to cochlear nucleus via descending auditory pathways.
AB  - The cochlear nucleus (CN) receives descending input from a variety of auditory
      nuclei. Descending inputs from the superior olive in particular have been well
      described, especially those of olivocochlear neurons, which terminate ultimately
      in the cochlea. It has been demonstrated that olivocochlear neurons receive
      serotonergic and noradrenergic inputs and thus form a route by which the
      aminergic system may modulate cochlear mechanisms. Since olivocochlear neurons
      send collaterals into the CN, it is possible that they also from a route by which
      the aminergic systems modulate CN processes. The goal of the current study was to
      determine if neurons in the superior olive that projected to the CN received
      serotonergic or noradrenergic inputs. The retrograde tracer WGAapoHRP-Au was
      injected into the CN of cats. The brainstems were silver-enhanced to visualize
      the tracer and then immunohistochemically processed with antibodies raised
      against serotonin or dopamine-beta-hydroxylase (DBH) to label serotonergic or
      noradrenergic fibers, respectively. The sections were viewed with high power
      light microscopy to determine if the retrogradely labeled neurons were contacted
      by serotonin- or DBH-immunoreactive varicosities. Retrogradely labeled cells were
      observed in auditory brainstem nuclei known to project to the CN including the
      superior olivary complex and inferior colliculus bilaterally and the opposite CN.
      In these regions, retrogradely labeled neurons were closely associated with
      serotonin- and/or DBH-immunoreactive varicosities. Assuming a synaptic
      relationship between the projection neurons and varicosities, these results
      indicate that the serotonergic and noradrenergic systems innervate the descending
      pathways to the CN. Since the serotonergic and noradrenergic systems modulate
      their targets based on level of arousal, these results support the theory that
      descending systems are involved in selective attention.

PMID- 12419520
TI  - Feeding induced by food deprivation is differentially reduced by G-protein alpha
      subunit antisense probes in rats.
AB  - Antisense oligodeoxynucleotide (AS ODN) probes directed against the alpha-subunit
      of different G-proteins have been used to differentiate feeding responses in rats
      elicited by different opioid agonists, including morphine, beta-endorphin and
      dynorphin. Furthermore, antisense probes directed against G(o)alpha, but not
      G(s)alpha, G(q)alpha or G(i)alpha, significantly reduced nocturnal feeding in
      rats. The present study examined whether food intake and weight changes elicited
      by 24 h of food deprivation were significantly altered by ventricular
      administration of antisense probes directed against either G(i)alpha(1),
      G(i)alpha(2), G(i)alpha(3), G(s)alpha, G(o)alpha, G(q)alpha or G(x/z)alpha as
      well as a control nonsense probe in rats. Deprivation-induced weight loss was
      significantly enhanced by antisense probes directed against G(s)alpha and
      G(x/z)alpha, whereas weight recovery 24 h following reintroduction of food was
      significantly reduced by antisense probes directed against G(i)alpha(2),
      G(q)alpha and G(o)alpha. Selective antisense probe effects were noted for
      deprivation-induced intake with G(s)alpha and G(q)alpha probes exerting the
      greatest reductions, G(x/z)alpha, G(i)alpha(2), and G(i)alpha(3) probes exerting
      lesser effects, and G(i)alpha(1) and G(o)alpha probes failing to affect
      deprivation-induced intake. Importantly, the nonsense control probe failed to
      alter deprivation-induced intake or weight. The reductions in deprivation-induced
      intake by AS ODN probes directed against G(s)alpha or G(q)alpha were not
      accompanied by any evidence of a conditioned taste aversion. These data indicate
      important distinctions between G-protein mediation of different effector
      signaling pathways mediating feeding responses elicited under natural (e.g.
      nocturnal feeding) and regulatory challenge (e.g. food deprivation) conditions.

PMID- 12419521
TI  - Gastrin-releasing peptide microinjected into the amygdala inhibits feeding.
AB  - Bombesin (BN)-like peptides including gastrin-releasing peptide (GRP) are known
      to inhibit feeding. In the amygdaloid body BN receptors have been found in
      moderate to high densities. The central part of the amygdala (ACE) is essentially
      involved in the regulation of feeding and body weight. In the present experiments
      GRP was injected into the ACE and liquid food intake, general behavioural
      activity, as well as core temperature, were examined in male CFY rats. Food
      intake was measured every 5 min for 30 min and at the 40th and the 60th min
      following GRP or vehicle microinjections. Bilateral application of 50, 100 or 150
      ng GRP resulted in transient inhibition of food intake while bilateral injection
      of 25 or 300 ng GRP did not modify feeding. Effect of GRP was eliminated by prior
      application of BN receptor antagonist [Leu(13)-psi(CH(2)NH)-Leu(14)]BN. After GRP
      or vehicle treatments animals were video-monitored and food intake, the first
      meal latency (FML), intermeal intervals (IMI), the time spent feeding (FT),
      grooming, resting and exploration were analysed at 5-min intervals for 30 min.
      However, FML did not change after GRP, the first IMI increased and intake, FT and
      intake/FT significantly decreased during the first 5 min. Duration of resting
      gradually increased after GRP and animals spent less time with exploration after
      GRP treatment than after vehicle injection. These differences were significant
      during the 25-30-min period. In body temperature, no significant changes were
      observed. Our results show that GRP in the ACE inhibits feeding and that GRP may
      decrease the efficiency of eating and may act as a satiety signal.

PMID- 12419522
TI  - Paracrine/autocrine function of adrenomedullin in peripheral nerves of rats.
AB  - The presence of adrenomedullin (AM) and of an AM receptor were investigated in
      highly enriched primary cultures of Schwann cells and perineural fibroblasts of
      newborn and adult rats. AM was released into the conditioned medium of adult
      perineural fibroblasts (1749+/-629 pgeq/10(5) cells per 24 h). mRNA encoding AM
      was also predominantly expressed in adult perineural fibroblasts. mRNA encoding
      the calcitonin receptor-like receptor (CRLR) and the receptor-activity-modifying
      proteins (RAMP) 1, -2 and -3 were demonstrated in all the primary cells, but the
      levels of RAMP1 mRNA relative to 18s rRNA were 10-fold lower than those of CRLR
      and RAMP2 and -3 encoding mRNA. The results are consistent with the expression of
      CRLR/RAMP2 and CRLR/RAMP3 heterodimeric AM receptors in all the primary cells
      examined. AM stimulated cAMP accumulation in newborn (EC(50) 0.62+/-0.29 nM) and
      adult (EC(50) 0.45+/-0.03 nM) rat Schwann cells and in newborn (EC(50) 0.79+/
      0.50 nM) and adult (EC(50) 1.06+/-0.72 nM) rat perineural fibroblasts. The EC(50)
      of calcitonin gene-related peptide stimulated cAMP production was 93- to 100-fold
      higher than those of AM in the four types of primary cells studied. The co
      expression of AM and its receptor in perineural fibroblasts and the expression of
      an AM receptor in Schwann cells suggest autocrine and/or paracrine modes of
      action of AM in peripheral nerves.

PMID- 12419523
TI  - Opioid circuits originating from the nucleus paragigantocellularis and their
      potential role in opiate withdrawal.
AB  - Neurons in the rat nucleus paragigantocellularis (PGi), located in the
      ventrolateral medulla, send collateral projections to the locus coeruleus (LC)
      and to the nucleus of the solitary tract (NTS). The present study examined
      whether neurons in the PGi that project to both the LC and NTS contain leucine(5)
      enkephalin (ENK), and also whether opioid-containing neurons in the PGi are
      activated following withdrawal from opiates. Retrograde transport of Fluoro-Gold
      (FG) from the LC and transport of a protein-gold tracer from the NTS was combined
      with detection of an antibody directed against ENK in the PGi. Using fluorescence
      and brightfield microscopy, it was established that more than half of the neurons
      containing both FG and the protein-gold tracer, also exhibited immunolabeling for
      ENK. The most frequent location of triply labeled neurons was the retrofacial
      portion of the PGi. In a separate series, rats were chronically implanted with
      morphine or placebo pellets and, on the fifth day, were subjected to an
      intraperitoneal injection of naltrexone. Two hours following initiation of
      withdrawal, rat brains were obtained and processed for detection of c-fos and in
      situ hybridization labeling of preproenkephalin (PPE) mRNA. Naltrexone injections
      into morphine-dependent rats caused a dramatic increase in c-fos as compared to
      control rats. Approximately 66% of the c-fos-labeled neurons exhibited labeling
      for PPE mRNA. These were also enriched in the retrofacial portion of the PGi.
      Taken together, the present data indicate that withdrawal from opiates engages
      opioid neurons in the PGi, some of which may coordinate activity of neurons in
      both the NTS and the LC.

PMID- 12419525
TI  - Cysteamine pre-treatment reduces pentylenetetrazol-induced plasticity and
      epileptiform discharge in the CA1 region of rat hippocampal slices.
AB  - The effects of prior treatment of cysteamine, a somatostatin inhibitor, on
      pentylenetetrazol (PTZ) induced epileptic and plastic changes in CA1 excitability
      were examined. Population spikes were evoked by activation of Schaffer
      collaterals with a range of stimulation intensities. Changes in the population
      spike and epileptiform amplitudes were used as indices to quantify the effects of
      PTZ exposure in the control and cysteamine pre-treated slices. Cysteamine pre
      treatment decreased baseline CA1 population spike amplitude following high
      intensity stimulation of Schaffer collaterals. Following PTZ application directly
      to the slices, cysteamine diminished the increased population spike and
      epileptiform amplitudes which were normally observed following collateral
      stimulation. Magnesium-free medium induced epileptiform activity was also
      significantly reduced with cysteamine pre-treatment. It is concluded that
      somatostatin may be involved in PTZ-induced epileptic and plastic changes in CA1
      excitability.

PMID- 12419524
TI  - Temporal effects of left versus right middle cerebral artery occlusion on spleen
      lymphocyte subsets and mitogenic response in Wistar rats.
AB  - The left and right neocortex of the brain has been shown to exert asymmetrical
      effects on the immune system. In the present study, we used a middle cerebral
      artery (MCA) occlusion model in Wistar rats to analyze the influence of
      unilateral CNS ischemia on spleen cell number and function. The occlusion time
      was 1 h, followed by reperfusion with survival for 0, 2, 7, 14, and 28 days.
      Changes in plasma norepinephrine levels were used as an index of peripheral
      sympathetic activity. Results showed that the total number of spleen cells
      significantly decreased after 2-28 days of survival in animals with cerebral
      ischemia compared to sham-operated controls. There was no change in the
      percentage of CD5(+)-CD4(+) T cells, MHC class II(+) cells, or ED1(+)
      macrophages. However, the percentage of CD5(+)-CD8(+) T cells decreased at 2
      days, resulting in an increased CD4/CD8 ratio, and both parameters returned to
      control levels after 7 days. Mitogen-induced T and B lymphocyte proliferation
      increased after 0-28 days post-ischemia independently of the mitogen used. There
      was no difference in immune response or norepinephrine levels between left and
      right MCA occlusions. These results are consistent with the notion that cerebral
      ischemia induces mobilization of certain immune cells from the periphery to the
      brain, where they may contribute to the local inflammatory response.
      Additionally, the data indicate that cerebral ischemia is followed by a systemic
      activation of T and B lymphocytes. Absence of asymmetric effects of left versus
      right stroke, and failure to demonstrate any suppressive effects of left-sided
      lesions on lymphocyte proliferation, probably reflects the fact that these large
      cerebral ischemic lesions affect both cortical and subcortical areas.

PMID- 12419526
TI  - Lesion of substantia nigra pars compacta by the GluR5 agonist ATPA.
AB  - Dopamine (DA) released by substantia nigra pars compacta (SNc) neurons is a key
      regulator of motor activity. A deficiency in the striatum DA content due to SNc
      degeneration is a characteristic of Parkinson's disease. The involvement of
      excitotoxic mechanisms in this pathology has been suggested. The kainate receptor
      subunit GluR5 has been identified in a few basal ganglia but it is strongly
      expressed in SNc. Here we examine whether (RS)-2-amino-3-(3-hydroxy-5
      tbutylisoxazol-4-yl) propanoic acid (ATPA), a selective agonist of GluR5, induces
      damage in dopaminergic (DAergic) neurons. ATPA (13 nmol) was administered to rat
      SNc. Immediately after recovery from surgery, the rats displayed ipsilateral
      turning. This behavior disappeared in subsequent days. The administration of the
      D1/D2 agonist, apomorphine (1 mg/kg, s.c.) 1 and 2 weeks after ATPA-infusion also
      induced ipsilateral turning. Histological studies-performed 21 days after ATPA
      infusion-showed a lesion of the lateral and central part of the SNc, where a
      significant loss (36%) of DAergic cells was detected by tyrosine hydroxylase
      immunohistochemistry. The lesion was restricted to the SNc, since no damage or
      glial reaction was observed in the substantia nigra pars reticulata as assessed
      by Nissl staining, tomato lectin staining for microglial cells and GFAP
      immunohistochemistry for astrocytes. IN CONCLUSION: (1). ATPA-infusion induces
      neuronal damage in the SNc in the rat and (2). the behavioral effects of
      unilateral infusion of ATPA are consistent with DAergic alterations in basal
      ganglia.

PMID- 12419527
TI  - Histamine H1-receptor modulation of inter-neuronal coupling among
      vasopressinergic neurons depends on nitric oxide synthase activation.
AB  - Inter-neuronal coupling is a relatively recently documented property of a wide
      variety of cell groups in the mammalian central nervous system. For many of these
      groups there is evidence that the coupling can be modulated by synaptic inputs.
      Incidence of dye coupling among vasopressin (VP) neurons of the rat supraoptic
      nucleus (SON) has been shown to increase in response to either activation of
      histamine H(1)-receptors or to increased NO production. Both of these effects
      involve activation of cGMP-dependent pathways. We tested the hypothesis that
      activation of H(1)-receptors resulted in downstream activation of NO synthase,
      which then mediated the H(1)-receptor effects. Putative VP neurons were
      intracellularly recorded and dye-injected in horizontal slices of hypothalamus,
      in which monosynaptic connections from the tuberomammillary nucleus (TM) were
      intact and electrically stimulated. Single-pulse TM stimulation evoked EPSPs and
      repetitive stimulation resulted in a nearly 3-fold increase in coupling incidence
      over unstimulated slices. TM-stimulated increased coupling was completely blocked
      by inhibitors of NO synthase (L-NAME) or of soluble guanylyl cyclase (ODQ or
      methylene blue), or pyrilamine, suggesting that the H(1)-receptor is not directly
      linked to guanylyl cyclase. Addition of the NO precursor, L-arginine or the NO
      donor, SNP, in combination with TM stimulation produced increases in coupling
      that were not significantly larger than those seen with stimulation alone,
      supporting the idea that a common pathway was used. We conclude that H(1)
      receptors activate NO synthase via G-protein-coupled pathways and that NO working
      though its receptor, induces the downstream cGMP-dependent processes that result
      in increased inter-neuronal coupling.

PMID- 12419528
TI  - Activation of NMDA receptors and L-type voltage-gated calcium channels mediates
      enhanced formation of Fyn-PSD95-NR2A complex after transient brain ischemia.
AB  - Recent studies have indicated that tyrosine phosphorylation of NMDA receptor
      subunit 2A (NR2A) by Src family kinases (Src, Fyn, etc.) up-regulates NMDA
      receptors activity and postsynaptic density protein 95 kDa (PSD95) may mediate
      the regulation. To investigate whether the above processes are involved in brain
      ischemia-induced enhancement of NMDA receptors function, we examined the effects
      of transient (15 min) brain ischemia followed by reperfusion on interactions
      involving Fyn, NR2A and PSD95 in rat hippocampus by co-immunoprecipitation.
      Transient brain ischemia was induced by the method of four-vessel occlusion in
      Sprague-Dawley rats. Association between Fyn and NR2A increased immediately after
      brain ischemia and the increase was maintained for at least 24 h during followed
      reperfusion, up to about 1.7-1.8-fold relative to sham-groups. The 15-min
      reperfusion after brain ischemia induced enhanced co-immunoprecipitation of
      PSD95, Fyn and NR2A with one another. The associations of PSD95 with Fyn and NR2A
      increased at 0-24 h, 0-1 h of reperfusion, up to 6.9- and 2.1-fold relative to
      sham groups, respectively. Inhibiting activation of NMDA receptors or L-type
      voltage-gated calcium channels (L-VGCC) by ketamine or nifedipine attenuated the
      above increases of associations. These results suggest that stimulation of NMDA
      receptors and L-VGCC facilitates formation of a ternary complex: Fyn-PSD95-NR2A
      during transient brain ischemia followed by reperfusion, which may result in
      potentiation of NMDA receptor function and contribute to ischemic neuronal cell
      death.

PMID- 12419529
TI  - Magnesium pre-treatment reduces neuronal apoptosis in newborn rats in hypoxia
      ischemia.
AB  - Hypoxic-ischemic brain damage has significant mortality and morbidity in
      newborns. Although the role of magnesium in neonatal hypoxic-ischemic brain
      injury related to N-methyl-D-aspartate receptors has been widely studied; the
      effects of magnesium on neuronal apoptosis have not been known exactly in hypoxia
      ischemia. The aim of this study was to investigate the effects of magnesium on
      neuronal apoptosis in the 7-day-old rat hypoxia-ischemia model. Seven-day-old
      rats were administered magnesium sulfate (group 1; n=9) or saline (group 2; n=9)
      intraperitoneally before hypoxia-ischemia. Additionally 18 seven-day-old rats
      were given magnesium sulfate (group 3; n=9) or saline (group 4; n=9) after
      hypoxic-ischemic insult. Neuronal apoptosis was investigated by the dUDP-biotin
      nick end-labeling (TUNEL) method following 3-day recovery in all subjects. In
      evaluating TUNEL-positive cells, we firstly calculated the areas (mm(2)) of brain
      regions, hippocampus, striatum, cortex, in right and left hemispheres in subjects
      by IMAGE analysis. The numerical density was calculated as the number of cells
      per square millimeter by counting all TUNEL-positive cells. Afterwards, the ratio
      of right side numeric density to sum of right and left side numeric densities
      (right Apoptosis Index) was calculated for every brain region in rats receiving
      magnesium and compared to vehicle groups. The right Apoptosis Index of the
      hippocampus in magnesium pre-treated rats (mean+/-S.D.; 36.6+/-22.1) was
      significantly lower than vehicle (61.0+/-16.0; P<0.05); whereas right apoptosis
      indices were not changed by magnesium pre-treatment in striatum and cortex.
      Additionally, magnesium sulfate administration following hypoxic-ischemic insult
      also had no effect on right apoptosis indices in all three brain regions. It is
      concluded that magnesium might have a role in preventing neuronal apoptosis due
      to neonatal hypoxic-ischemic brain injury.

PMID- 12419530
TI  - Loss of response to levodopa in Parkinson's disease and co-occurrence with
      dementia: role of D3 and not D2 receptors.
AB  - Previous data suggest a relationship between the loss of response to levodopa in
      Parkinson's disease (PD) patients with the co-occurrence of dementia, but the
      role of alterations in the dopamine system has not been explored. We measured the
      extent of striatal DA loss and changes in striatal DA D(2) and D(3) receptors in
      postmortem striatum of PD patients who historically had or had not lost their
      clinical response to dopaminergic drugs and/or had an additional diagnosis of
      dementia. Clinical evaluation and retrospective chart reviews for PD and
      dementia, and neuropathological diagnoses were obtained. All PD cases (+/
      dementia), regardless of response to dopaminergic drugs, exhibited a significant
      and similar degree and pattern of loss of tyrosine hydroxylase
      immunocytochemistry and DA transporter binding in striatum, and loss of tyrosine
      hydroxylase-immunoreactive neurons and brain-derived neurotrophic-immunoreactive
      neurons from the ventral midbrain. D(2) receptor concentrations were modestly
      elevated in the rostral striatum of all the PD cases (+/-dementia), whether or
      not they continued to respond to dopaminergic drugs. In contrast, loss of D(3)
      receptor concentration correlated with loss of response to dopaminergic drugs,
      independent of the presence or absence of dementia. A maintained response to
      dopaminergic drugs correlated with an elevation of D(3) receptors. Dementia with
      PD was highly correlated with a loss of response to dopaminergic drugs, and was
      also correlated with reduced D(3) receptors. The alterations in D(3) receptor
      concentrations were greatest in the nucleus accumbens, caudal striatum, and
      globus pallidus. Thus, loss of dopamine D(3) receptors may be a more important
      contributing factor to a loss of response to dopaminergic drugs than changes in
      the D(2) receptor.

PMID- 12419531
TI  - Daily exercise normalizes the number of diaphorase (NOS) positive neurons in the
      hypothalamus of hypertensive rats.
AB  - It is well known that nitric oxide (NO), within the paraventricular nucleus (PVN)
      of the hypothalamus, mediates sympatho-inhibition via an inhibitory GABA-ergic
      mechanism. Furthermore, the inhibitory GABA-ergic mechanism is impaired in the
      spontaneously hypertensive rat (SHR). These data suggest that the NO system,
      within the PVN, may also be impaired in the SHR. In addition, previous studies
      have documented that daily exercise attenuates the development of tachycardia,
      hypertension and blood pressure related cardiovascular disease risk factors in
      SHR. These data suggest that daily exercise enhances the inhibitory GABA-ergic
      and/or NO systems. Therefore, this study was designed to test the hypothesis that
      hypertension, in the SHR, is associated with a lower number of NADPH-diaphorase
      (a commonly used marker for neuronal NOS activity) positive neurons within the
      PVN and that daily exercise increases the number of NOS positive neurons. Using a
      standard histochemical protocol, NOS positive neurons were measured in the PVN,
      supraoptic nucleus, median preoptic area, lateral hypothalamus, nucleus of the
      tractus solitarius and rostral ventrolateral medulla. Results document that SHR
      have significantly fewer NOS-positive neurons in the PVN than their genetic
      control, the Wistar-Kyoto (WKY) rats (110+/-11 versus 139+/-17). Furthermore,
      daily exercise increased the number of NOS positive neurons in the SHR to levels
      seen in the WKY rats. These data demonstrate that hypertension, in the SHR, is
      associated with a lower number of NOS positive neurons within the PVN and that
      daily exercise increases the number of NOS positive neurons within the PVN.

PMID- 12419532
TI  - Decrease of 1-methyl-1,2,3,4-tetrahydroisoquinoline synthesizing enzyme activity
      in the brain areas of aged rat.
AB  - 1-Methyl-1,2,3,4-tetrahydroisoquinoline (1-MeTIQ), an endogenous monoamine, which
      prevents the neurotoxic effect of 1-methyl-4-phenylpyridinium ion (MPP(+)) and
      other endogenous neurotoxins, has been described as being enzymatically formed in
      the brain by the 1-MeTIQ synthesizing enzyme (1-MeTIQse). In this paper, we
      report the brain's regional distribution of this enzyme in 3- and 24-month-old
      rats. The results show that the activity is spread throughout the brain, the
      highest activity being in the dopaminergic areas (striatum and substantia nigra)
      and in the cortex. During aging there was a 1-MeTIQse activity reduction (
      approximately 50%) in the areas implicated in the ethyology of Parkinson disease
      (substantia nigra, striatum) and in the cerebral cortex.

PMID- 12419533
TI  - Interactions between recording technique and AMPA receptor modulators.
AB  - Whole cell recording (EPSCs) and extracellular recording (field EPSPs) were
      compared in hippocampal field CA1 with regard to the effects of experimental
      treatments that increase AMPA receptor gated currents. Cyclothiazide, which
      maintains AMPA receptors in the sensitized state, caused a rapid and pronounced
      increase in EPSCs but only minor changes in field EPSPs. This difference was
      evident in recordings carried out at 22 and 32 degrees C and with different
      solutions in the clamp pipette. The larger effect of cyclothiazide on EPSCs was
      unaffected by blockade of GABA and NMDA receptors. Two-dimensional current source
      density analyses derived from 64 recording sites were used to provide
      extracellular estimates of AMPA receptor mediated synaptic currents. With this
      method, cyclothiazide again had much smaller effects than were obtained with
      whole cell clamp. Differences between whole cell and extracellular recordings
      were present, although not as pronounced, for the ampakines, a class of drugs
      that slow both deactivation and desensitization of AMPA receptors. Additionally,
      increases in synaptic responses produced by frequency facilitation, a
      manipulation that enhances the number of bound receptors, were not qualitatively
      different between recording techniques. These results support the conclusion that
      the whole cell clamp technique may alter AMPA receptors in such a way as to
      increase the relative importance of desensitization.

PMID- 12419534
TI  - Complex partial status epilepticus induced by a microinjection of kainic acid
      into unilateral amygdala in dogs and its brain damage.
AB  - OBJECTIVE: In order to investigate kainic acid (KA)-induced amygdaloid seizure
      and seizure-induced brain damage in dogs, and to compare these findings with that
      in other species, a KA-induced seizure model in dogs was produced. MATERIAL AND
      METHODS: Normal beagle dogs were used. A Teflon cannula for KA injection was
      inserted into the left amygdala, and cortical or depth electrodes were
      positioned. One week after surgery, 1.5 microg of KA was microinjected into the
      left amygdala. EEGs and the behavior of the animals were monitored for 2 months
      after KA injection. In addition, neuron-specific enolase levels in the
      cerebrospinal fluid (CSF-NSE) were measured intermittently. At 2 months after the
      injection, histopathological studies were performed. RESULTS: KA-treated dogs
      showed limbic seizures that started from the left amygdala within 30 min after
      injection. The seizures developed into complex partial status epilepticus (CPSE),
      and started independently from the bilateral amygdala during the CPSE. The CPSE
      lasted for 1-3 days, and the animals showed no spontaneous seizures during the 2
      month observation period. A significant increase in CSF-NSE was observed
      immediately after CPSE. Histopathologically, extensive necrosis, which formed
      large cavity lesions, was observed around the bilateral amygdala. SUMMARY: A
      microinjection of KA into unilateral amygdala in dogs induced CPSE. The seizures
      elicited independently from bilateral amygdala, and bilateral limbic structures
      suffered extensive injury. In addition, CSF-NSE was demonstrated as a useful
      marker of acute neuronal damage.

PMID- 12419536
TI  - Apolipoprotein E alters the processing of the beta-amyloid precursor protein in
      APP(V717F) transgenic mice.
AB  - We have recently reported a critical role for apolipoprotein E (apoE) in the
      process of amyloid deposition and neuritic plaque formation in APP(V717F)
      transgenic (Tg) mice, an animal model of Alzheimer's disease (AD). In the present
      study, we have investigated whether the presence or absence of apoE alters the
      processing of the amyloid precursor protein (APP) to various fragments, including
      the beta-amyloid peptides (Abeta). Here we show that, in contrast to APP(V717F)
      Tg mice expressing apoE, APP(V717F) Tg mice deficient in apoE develop anti-Abeta
      immunoreactive multifocal aggregates, which contain the beta-cleaved C-terminal
      fragments (beta-CTFs) of APP. Tg mice deficient in apoE also display altered
      levels of mature full-length APP, increased amounts of beta-CTFs, as well as
      elevated levels of Abeta(1-40) and Abeta(1-42) in an age- and region-dependent
      manner when compared to Tg mice expressing apoE. Taken together, these data
      support a role for apoE in APP processing in vivo.

PMID- 12419535
TI  - Distinct usages of phospholipase C gamma and Shc in intracellular signaling
      stimulated by neurotrophins.
AB  - Nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and
      neurotrophin-3 (NT-3), members of the neurotrophin family, bind to and activate
      TrkA, TrkB and TrkC, respectively, members of the Trk receptor tyrosine kinase
      family, to exert various effects including promotion of differentiation and
      survival, and regulation of synaptic plasticity in neuronal cells. Many reports
      have suggested that different neurotrophins show distinct biological functions,
      although molecular mechanisms by which neurotrophins exert their different
      functions remain unclear. In the present study, we found distinct usages of
      phospholipase Cgamma (PLCgamma) and Shc in intracellular signaling stimulated by
      neurotrophins. BDNF stimulated much stronger interactions of PLCgamma with Trk
      than NGF and NT-3 in PC12 cells stably expressing TrkB and cultured cerebral
      cortical neurons, respectively, although BDNF, NGF and NT-3 induced similar
      levels of tyrosine phosphorylation of Trk. Furthermore, the cultured cortical
      neurons showed large PLCgamma-dependent increases in intracellular Ca(2+) levels
      in response to BDNF compared with NT-3. In Shc signaling, NGF, but not BDNF,
      displayed interactions between Trk and Shc in a phenylarsine oxide (PAO; an
      inhibitor of tyrosine phosphatase)-dependent manner in TrkB-expressing PC12
      cells. These results indicated that neurotrophins stimulate distinct kinds of
      interactions between Trk and PLCgamma and between Trk and Shc. These differences
      may lead to the distinct biological functions of neurotrophins.

PMID- 12419538
TI  - Effect of repeated administration of prolactin releasing peptide on feeding
      behavior in rats.
AB  - Prolactin releasing peptide (PrRP) has been reported to reduce food intake in
      rats. We tested the effect of i.c.v. administration of PrRP-31 on food intake in
      both food deprived and free-feeding rats. We did not find any effect of PrRP-31
      on food intake after single injections of up to an 8-nmol dose, but observed a
      marked decrease in food intake and body weight in rats that received a repeated
      twice daily administration of 8 nmol of PrRP-31. This effect was associated with
      an adverse behavioral pattern, indicating that the repeated high doses of the
      peptide caused non-specific effects inducing anorexia. We also tested several
      other behavioral parameters like locomotion and exploratory time, grooming and
      resting time, using lower doses of PrRP that did not cause the adverse behavior.
      Moreover, we carried out locomotor and sensory motor activity tests at the doses
      that exerted the most pronounced effect on the food intake. None of these tests
      suggested any specific behavioral effect of PrRP. We conclude that the behavioral
      pattern induced by PrRP is likely to be different from those induced by many
      other neuropeptides affecting food intake in rats.

PMID- 12419537
TI  - Site-specific decrease of progesterone receptor mRNA expression in the
      hypothalamus of middle-aged persistently estrus rats.
AB  - Middle-aged females gradually become acyclic and spontaneously develop a
      persistently estrus (PE) state. PE rats, acyclic for 30 days (early PE), are
      unresponsive to the positive feedback action of estrogen, but respond to a
      progesterone challenge with a luteinizing hormone (LH) surge and ovulation;
      unlike long-term PE rats, acyclic for 90 days, neither estrogen nor estrogen plus
      progesterone will elicit an LH surge [10th International Congress of
      Endocrinology, San Francisco, P3 (1996) 1061]. We hypothesize that the PE state
      may develop due to a diminished level of estrogen-induced progesterone receptor
      (PR) expression in the hypothalamus that prevents progesterone from stimulating
      LH regulating circuits. To test this hypothesis, PR mRNA levels were measured in
      hypothalamic regions of young, proestrus (2-3 months of age), early PE (10-12
      months) and long-term PE (13-15 months) rats. The anteroventral periventricular
      nucleus (AVPV), an important regulatory site of the LH surge, had decreased PR
      mRNA levels in early and long-term PE rats compared with proestrus rats. However,
      PR mRNA levels were reduced only in long-term PE rats in the ventromedial nucleus
      (VMH) and arcuate nucleus (ARH). In the medial preoptic nucleus (MPN), levels of
      PR mRNA did not change. A previous report showed that exogenous progesterone
      stimulates an LH surge in young and early PE animals, indicating that the
      expression of PR mRNA demonstrated in this study is sufficient to mediate
      progesterone facilitation of the LH surge in early PE rats. In acyclic, long-term
      PE rats, diminished estrogen-induced expression of progesterone receptors is
      correlated with a previously shown inability to respond to exogenous
      progesterone.

PMID- 12419539
TI  - Effect of the intracerebroventricular and systemic administration of L-serine on
      the concentrations of D- and L-serine in several brain areas and periphery of
      rat.
AB  - To gain further insight into the metabolic mechanism of endogenous D-serine, the
      effect of the intracerebroventricular and intraperitoneal administration of L
      serine on the concentrations of D- and L-serine in several brain areas and
      periphery was investigated. The intracerebroventricular injection of L-serine
      caused a rapid and marked increase in the L-serine levels in almost all brain
      regions of adult rats. This administration also produced a gradual increase in
      the D-serine levels in the forebrain, whereas a slight but significant elevation
      of D-serine was found in the cerebellum and pons-medulla. The intraperitoneal
      administration of L-serine caused a marked increase in the L-serine levels in all
      brain regions of both infant and adult rats. The treatment induced a significant
      augmentation of the D-serine levels in all brain regions of infant rats with
      higher concentrations in the cerebellum and cortex, whereas no significant change
      was observed in the cerebellum and pons-medulla of adult rats. These in vivo
      observation, together with the fact that immunohistochemical studies have
      indicated that both D-serine and serine racemase are highly concentrated in
      Bergmann glia of developing cerebellum, suggest that D-serine can be synthesized
      not only in the forebrain but also in the hindbrain by serine racemase.
      Furthermore, because the drastic decline in the cerebellar D-serine level
      coincides well with a dramatic increase in the cerebellar D-amino acid oxidase
      during early postnatal development, synthesized D-serine may be metabolized by D
      amino acid oxidase in the hindbrain of adult rats.

PMID- 12419540
TI  - Sleep states and sleep electroencephalographic spectral power in mice lacking the
      beta 3 subunit of the GABA(A) receptor.
AB  - Mice lacking the GABA(A) receptor beta(3) subunit exhibit a profound disruption
      in thalamic circuitry. We have studied sleep in these mice under baseline
      conditions and following treatment with the benzodiazepine midazolam. Under
      baseline conditions, NREM sleep time did not differ between beta(3) subunit
      knockout mice and wild type mice, while REM sleep time was significantly lower in
      knockout mice than in wild type mice during the light portion of a 24-h light
      dark cycle. In constant dark conditions, circadian rhythmicity remained intact in
      mutant mice for a period of at least 9 days. EEG delta power (1-4 Hz) was
      significantly greater in the knockout than in wild type mice during NREM sleep
      but not during other states. A transient increase in EEG power in the 12-16 Hz
      range that occurred in wild type mice just prior to the transition from NREM to
      REM sleep was present but significantly blunted in the knockout. Midazolam
      decreased NREM delta power and REM time in wild type mice. The former but not the
      latter response to midazolam was intact in the knockout. These results further
      support a role for GABAergic transmission in regulating REM sleep and EEG
      spectral phenomena associated with NREM sleep.

PMID- 12419541
TI  - In vitro blood-brain barrier permeability and cerebral endothelial cell uptake of
      the neuroprotective nitrone compound NXY-059 in normoxic, hypoxic and ischemic
      conditions.
AB  - The free radical trapping nitrone compounds alpha-phenyl-N-tert-butylnitrone
      (PBN), 2-sulfophenyl-N-tert-butylnitrone (S-PBN) and disodium 2,4-disulfophenyl-N
      tert-butyl nitrone (NXY-059) are effective neuroprotective agents in experimental
      models of both transient and permanent focal ischemia. A recent in vivo study
      suggested that NXY-059 had poor brain uptake in a transient ischemia model. We
      have now examined its blood-brain barrier permeability and cerebral endothelial
      uptake during hypoxic and ischemic conditions using an in vitro model of the
      blood-brain barrier. The in vitro blood-brain barrier permeability and cerebral
      endothelial uptake of NXY-059 and S-PBN were low during normoxic conditions. In
      contrast, PBN had very high blood-brain barrier penetration in vitro which
      confirmed earlier in vivo results. The permeability of [14C]NXY-059 increased 3.5
      times after 9 h of hypoxia or 3 h of ischemia. There was, respectively, a 5-fold
      and more than 10-fold increase, after 6 and 9 h of ischemia. The control molecule
      [3H]inulin (M(r) approximately 5000) showed a similar increase in permeability
      under the same experimental conditions indicating a major change in the transport
      properties of the endothelium. There was a 60% reduction in the ATP levels of
      astrocytes after 3 h of ischemia and a 90% reduction after 9 h. The reduction in
      ATP levels in endothelial cells was somewhat lower. The uptake of NXY-059 in
      cerebral endothelial cells under normoxic, hypoxic or 9 h of ischemic conditions
      was negligible. NXY-059, S-PBN and PBN showed no effects on vesicular transport
      or the integrity of the blood-brain barrier in normoxic or ischemic conditions,
      nor did the compounds induce any change in the ATP levels of the cells. In
      conclusion, it is possible that the increase in blood-brain barrier permeability
      of [14C]NXY-059 which occurs during prolonged ischemia in vitro reflects a change
      which may be of importance to the neuroprotective effects of this nitrone free
      radical trapping agent.

PMID- 12419542
TI  - Differential in vivo clearance of serotonin in rat dorsal raphe nucleus and CA3
      region.
AB  - In vivo chronoamperometric recordings were used to determine if the majority of
      serotonin transporters (SERTs) in the dorsal raphe nucleus (DRN) are functionally
      active. This was achieved by comparing the clearance of exogenously applied
      serotonin (5-HT) from the extracellular fluid (ECF) of the DRN to that in the CA3
      region of the hippocampus, an area with lower SERT density. Serotonin was
      pressure ejected into these regions in anesthetized rats and reproducible
      electrochemical signals measured by carbon fiber microelectrodes were recorded.
      Consistent with SERT density as measured by [3H]cyanoimipramine binding in these
      brain regions (DRN>>CA3), clearance of 5-HT was significantly faster in DRN
      compared to that in the CA3 region. The selective serotonin reuptake inhibitor,
      fluvoxamine, prolonged 5-HT clearance in both CA3 and DRN. It is known that the
      norepinephrine transporter (NET) contributes to clearance of 5-HT in the dentate
      gyrus (DG) but not in CA3. Given that the DRN receives noradrenergic innervation,
      it was also determined if the NET contributes to 5-HT clearance in the DRN.
      Destruction of the NET with the neurotoxin 6-hydroxydopamine failed to alter 5-HT
      clearance parameters in the DRN. These data support the hypothesis that serotonin
      transporters are functionally active in the DRN, that serotonin clearance is
      mediated primarily by the SERT in the DRN and that the faster clearance of 5-HT
      from this region is related to its greater density of functional SERTs.

PMID- 12419543
TI  - Luteinizing hormone and luteinizing hormone-releasing hormone secretion is under
      locus coeruleus control in female rats.
AB  - It has been suggested that norepinephrine (NE) from the locus coeruleus (LC)
      plays an important role in triggering the preovulatory surge of gonadotropins.
      This work intended to study the role of LC in luteinizing hormone (LH) secretion
      during the estrous cycle and in ovariectomized rats treated with estradiol and
      progesterone (OVXE(2)P) and to correlate it with LH releasing hormone (LHRH)
      content in the medial preoptic area (MPOA) and median eminence (ME). Female rats
      on each day of the estrous cycle and OVXE(2)P were submitted to jugular
      cannulation and LC electrolytic lesion or sham-operation, at 09:00 h. Blood
      samples were collected hourly from 11:00 to 18:00 h, when animals were
      decapitated and their brains removed to analyze LC lesion and punch out the MPOA
      and ME. Plasma LH levels and LHRH content of MPOA and ME were determined by
      radioimmunoassay. During metestrus, diestrus and estrus, LC lesion did not modify
      either LH plasma concentrations or LHRH content, but completely abolished the
      preovulatory LH surge during proestrus and the surge of OVXE(2)P. These blockades
      were accompanied by an increased content of LHRH in the MPOA and ME. The results
      suggest that: (1). LC does not participate in the control of basal LH secretion
      but its activation is essential to trigger spontaneous or induced LH surges, and
      (2). the increased content of LHRH in the MPOA and ME may be due to a decreased
      NE input to these areas. Thus, LC activation may be required for depolarization
      of LHRH neurons and consequent LH surges.

PMID- 12419544
TI  - Slight impairment of Na+,K+-ATPase synergistically aggravates ceramide- and beta
      amyloid-induced apoptosis in cortical neurons.
AB  - Dysfunction of the Na(+),K(+)-ATPase (Na(+),K(+)-pump), due to reduced energy
      supply or increased endogenous ouabain-like inhibitors, likely occurs under
      pathological conditions in the central nervous system. In cultured mouse cortical
      neurons, we examined the hypothesis that a mild non-toxic inhibition of the
      Na(+),K(+)-ATPase could synergistically sensitize the vulnerability of neurons to
      normally non-lethal apoptotic signals. Ouabain at a low concentration of 0.1
      microM slightly lessened the Na(+),K(+)-pump activity measured as an ouabain
      sensitive current, yet did not affect K(+) homeostasis and viability of cortical
      neurons. Co-exposure to 0.1 microM ouabain plus non-lethal C(2)-ceramide (5
      microM) or beta-amyloid 1-42 (5 microM), however, induced marked intracellular
      K(+) loss, caspase-3 cleavage, DNA laddering, and synergistically triggered
      neuronal death. The caspase inhibitor Z-Val-Ala-Asp(OMe)-fluoromethyl ketone (Z
      VAD-FMK) predominantly blocked the caspase activation and neuronal death. These
      results suggest that slight impairment of Na(+),K(+)-pump activity may amplify
      the disruption of K(+) homeostasis in the presence of a non-lethal apoptotic
      insult, leading to activation of apoptotic cascade and substantial neuronal
      injury.

PMID- 12419545
TI  - Uncoupling protein 2 in primary pain and temperature afferents of the spinal
      cord.
AB  - Uncoupling protein 2 (UCP2) is a mitochondrial protonophore that regulates
      cellular energy homeostasis. In this study, we explored the expression of UCP2 in
      the spinal cord. UCP2 was expressed in the substantia gelatinosa and ventral horn
      of the rodent and primate spinal cord. In all of these areas, UCP2 expression was
      associated with axons and axon terminals and direct appositions between UCP2
      immunoreactive fibers and NMDA glutamate receptors-containing perikarya were
      frequently detected. All of the UCP2-labeled processes were also immunoreactive
      for substance P. The expression of UCP2 in primary sensory afferents of the
      spinal cord suggests that this mitochondrial uncoupler is involved in the
      mechanism of pain and temperature sensation.

PMID- 12419546
TI  - 5-HT1A receptor antagonist administration decreases cell proliferation in the
      dentate gyrus.
AB  - This study investigated the action of 5-HT(1A) receptor antagonists on cell
      proliferation in the dentate gyrus of adult rats. Three antagonists (NAN-190, p
      MPPI and WAY-100635) all produced a statistically significant approximately 30%
      reduction in the number of BrdU-immunoreactive cells in the dentate gyrus. This
      suggests that 5-HT(1A) receptor activity is important during naturally occurring
      cell proliferation in the dentate gyrus, and perhaps neurogenesis, and is one of
      the many factors involved in its regulation.

PMID- 12419547
TI  - Comparison between survival of lazaroid-treated embryonic nigral neurons in cell
      suspensions, cultures and transplants.
AB  - Death of transplanted dopaminergic neurons is induced both during preparation of
      donor tissue and after intrastriatal grafting. Oxidative stress is thought to be
      partly responsible for this cell death. In the present study we compared the
      effects of three lipid peroxidation inhibitors, the lazaroids Tirilazad mesylate,
      U-83836E and U-101033, on survival of embryonic mesencephalic neurons in
      different paradigms. The lazaroids were equally potent in preventing serum
      deprivation-induced death of cultured dopaminergic neurons. In a second set of
      experiments, mesencephalic suspensions were pretreated with lazaroids and cell
      survival was analyzed immediately after dissociation, after 2 or 24 h in culture
      or after intrastriatal transplantation. Lazaroid pretreatment failed to protect
      mesencephalic neurons in the in vitro paradigms and U-101033E did not protect
      grafted dopaminergic neurons in contrast to the neuroprotective effects
      previously reported for U-83836E and Tirilazad. Pretreatment with the iron
      chelator deferoxamine mesylate did not protect cultured or grafted dopaminergic
      neurons, nor did it improve neuronal survival in the serum deprivation model. U
      83836E and U-101033E, but not Tirilazad, prevented cell death induced by the pro
      oxidant tert-butyl hydroperoxide in suspensions. In a final experiment, we found
      that systemic treatment of the graft recipient rat with Tirilazad mesylate
      (before and during the first 3 days after grafting) improved survival of
      transplanted dopaminergic neurons to 180% of control values. Our results show
      that systemic treatment with a lipid peroxidation inhibitor for 3 days can
      promote graft survival, but also highlights the poor correlation between
      neuroprotective effect of pharmacological compounds in vitro and in grafts.

PMID- 12419548
TI  - How to RECOVER from RENAISSANCE? The significance of the results of RECOVER,
      RENAISSANCE, RENEWAL and ATTACH.
AB  - Two trial programmes testing an anti-cytokine medication in chronic heart failure
      (CHF) have been halted. In the RENAISSANCE and RECOVER trials (the combined
      analysis being termed RENEWAL), 2048 CHF patients were randomised to placebo or
      one of 3 doses of etanercept, a fusion protein directed against TNF. Within
      RENAISSANCE and RECOVER a clinical composite score was used to assess the
      clinical effects at 24 weeks (primary endpoint: alpha 0.04). Overall, the number
      of patients who were classified to have during the trial "improved", remained
      "unchanged" or "worsened" was similar for patients on placebo or any dose of
      etanercept (RENAISSANCE: p=0.17, RECOVER: p=0.34). In RENEWAL (combined analysis
      of medium and high dose etanercept vs. placebo), the primary endpoint (death or
      CHF hospitalisation, alpha 0.01) was not different between etanercept and placebo
      (RR 1.10, 95%CI 0.91 to 1.33, p=0.33). In RENEWAL, the secondary endpoint (death
      for any cause) was not different between etanercept and placebo (RR 1.13, 95%CI
      0.86 to 1.50, p=0.39). ATTACH was a phase II, multicentre, randomised, double
      blind, placebo-controlled pilot trial that aimed to evaluate the effects of
      infliximab (an antibody against TNF given in 2 different doses) in 150 CHF
      patients with stable NYHA class III or IV (in NYHA IV: <10%). In the placebo
      group (n=49), none of the patients died during 28 weeks of follow-up. At 14 (28)
      weeks, the endpoint of death or hospitalisation was reached in 2 (5) patients on
      placebo, in 2 (4) patients in the medium dose (5 mg/kg), and in 8 (13) patients
      in the high dose (10 mg/kg) of infliximab. During follow-up, compared to placebo
      the hazard to reach this endpoint was similar in the medium dose group (RR 0.80,
      95%CI 0.22-2.99), but increased in the high dose group (RR 2.84, 95%CI 1.01-7.97,
      p<0.05). CONCLUSION: At the respective lower doses there was no safety issue with
      regards to the use of either infliximab or etanercept. High dose anti-TNF therapy
      may not be useful in CHF patients, but the situation in lower doses and in
      patients with documented inflammatory/metabolic problems or in cardiac cachexia
      has not yet been adequately assessed.

PMID- 12419549
TI  - Coronary and systemic hemodynamic effects of sildenafil citrate: from basic
      science to clinical studies in patients with cardiovascular disease.
AB  - Sildenafil citrate is the first oral phosphodiesterase type 5 inhibitor approved
      for the treatment of erectile dysfunction. The wide use of sildenafil by patients
      with erectile dysfunction and cardiovascular disease has resulted in a
      considerable number of independent studies investigating the cardiovascular
      safety and functional role of the phosphodiesterase type 5-cyclic guanosine
      monophosphate-nitric oxide pathway in the cardiovascular system. Endothelial
      dysfunction, defined as a reduction in the bioavailability of nitric oxide, is
      associated with many of the common risk factors for cardiovascular disease and
      erectile dysfunction. Sildenafil has been demonstrated to improve the vasomotor
      aspect of endothelial dysfunction in patients with heart failure and diabetes.
      Hemodynamic studies suggest that sildenafil is a modest vasodilator with the
      potential to increase coronary blood flow and coronary flow reserve. In patients
      with ischemic heart disease, sildenafil is associated with reductions in mean
      arterial and pulmonary pressure with little effect on heart rate, cardiac output,
      and systemic or pulmonary vascular resistance. The absence of an effect on
      cardiac output supports the lack of an inotropic effect of sildenafil. This is
      consistent with the finding that sildenafil has no effect on cyclic adenosine
      monophosphate levels in the vasculature. Finally, exciting reports have emerged
      from clinical experience with the use of phosphodiesterase type 5 inhibitors in
      patients with pulmonary hypertension.

PMID- 12419550
TI  - Rapid bedside measurement of brain natriuretic peptide in patients with chronic
      heart failure.
AB  - BACKGROUND: Brain natriuretic peptide (BNP) levels have been used to assess
      clinical status and predict prognosis of patients with chronic heart failure
      (CHF). However, BNP levels can only be measured in specialized laboratories which
      has hampered its use in daily clinical practice. We compared a new, rapid, BNP
      assay with a conventional BNP measurement and evaluated the applicability to
      current practice by comparing it with standard clinical parameters. METHODS: BNP
      levels were determined in 78 stable CHF patients and 20 controls. The severity of
      CHF was assessed by determination of New York Heart Association functional class
      (NYHA), left ventricular ejection fraction (LVEF) and peak oxygen consumption
      (peak VO(2)), and these parameters were compared to BNP levels. RESULTS: Overall,
      rapid BNP assessment was highly correlated with the conventional BNP assay
      (r=0.95, P<0.0001). In the higher ranges (>200 pmol/l), however, correlation was
      less accurate, and tended to overestimate. BNP levels also strongly correlated
      with both NYHA class, LVEF and peak VO(2) (all P<0.001). A cut-off value for BNP
      of 20 pmol/l yielded a sensitivity of 91% and a specificity of 92% to detect the
      presence of left ventricular systolic dysfunction. CONCLUSIONS: Rapid measurement
      of BNP levels is comparable to conventional BNP measurement and strongly
      correlated to clinical tests that are currently used to stratify CHF patients.
      Wider use of this method may yield a reduction of costly and time-consuming
      clinical tests and may reduce the medical burden of CHF.

PMID- 12419552
TI  - New insights in the transcriptional activity and coregulator molecules in the
      arterial wall.
AB  - A number of vascular diseases are associated with abnormal expression of genes
      that contribute to their pathophysiological and clinical manifestations, but at
      the same time offer potential therapeutic targets. One of the promising
      therapeutic approaches targets the pathophysiological pathways leading to
      aberrant gene activation, namely transcriptional activity and its molecular
      modulators (agonists, antagonists, coregulators, and nuclear receptors). The
      transcription factors can be divided into four classes (I-IV) classified by
      structural elements, like basic leucine zipper (bZIP) or basic helix-loop-helix
      (bHLH), which mediate their DNA binding activity but also determine the classes
      of drugs that can affect their activity. For example, statins modulate activation
      of the class-I transcription factor sterol responsive element-binding protein
      (SREBP), whose target genes including hydroxyl-methyl-glutaryl acetyl Coenzyme-A
      (HMG-CoA) reductase, HMG-CoA synthase, and the low-density lipoprotein receptor,
      all of which are involved in cholesterol and fatty acid metabolism. Similarly,
      insulin-like drugs target the nuclear receptor peroxisome-proliferator-activator
      receptor (PPAR)-gamma (class-II), several anti-inflammatory drugs inhibit
      activation of nuclear factor kappa B (NFkappaB) (class-IV), while others (e.g.
      flavopiridol, rapamycin, and paclitaxel) target regulation of cell-cycle
      proteins. Increased understanding of the genetic and molecular basis of disease
      (e.g. transcriptional activity and its coregulation) will potentially enhance
      future diagnosis, treatment, and prevention of vascular diseases.

PMID- 12419553
TI  - Chemoreflex sensitivity as a predictor of arrhythmia relapse in ICD recipients.
AB  - BACKGROUND: The chemoreflex sensitivity as a marker of a disturbed vagal reflex
      activity has proved to be a parameter of increased risk for ventricular
      tachyarrhythmias or sudden cardiac death. The sensitivity of patients with prior
      myocardial infarction concerning ventricular tachyarrhythmias amounted to about
      70%. This prospective study should evaluate the positive predictive accuracy of
      this new method in patients at risk for ventricular arrhythmias. METHODS: 42
      patients were enrolled into this study. All had a prior myocardial infarction at
      least 6 months previously; 35 patients were resuscitated from sudden cardiac
      death, and seven patients had documented monomorphic ventricular tachycardias.
      All patients were recipients of an ICD. The chemoreflex sensitivity was measured
      by determination of the venous partial pressure of oxygen and the heart rate
      before and after inhalation of pure oxygen. The difference in the RR-intervals
      before and after inhalation divided by the difference in the oxygen pressures
      were calculated as the chemoreflex sensitivity [ms/mmHg]. Furthermore, in all
      patients additional risk stratifiers used in this study were the presence of
      ventricular late potentials (LP), the short-term heart rate variability (HRV),
      the baroreflex sensitivity (BRS) and a decreased left ventricular function
      (ejection fraction<40%, EF). RESULTS: The chemoreflex sensitivity in the patient
      group as a whole amounted to 2.59+/-2.06 ms/mmHg. During follow-up, out of the 42
      patients enrolled, 20 had a documented arrhythmic event (AE: sustained
      ventricular tachycardia or ventricular fibrillation). Patients with and without
      AE showed significantly different values of chemoreflex sensitivity (1.58+/-1.09
      vs. 3.51+/-2.31 ms/mmHg, P<0.01) and EF (33.3+/-15.6 vs. 47.9+/-17.9%, P<0.05),
      but not of LP, HRV or BRS. The relative risk of reduced chemoreflex sensitivity
      concerning an AE amounted to 2.83 (95% CI 0.99-8.01). CONCLUSIONS: The
      chemoreflex sensitivity as a marker of increased risk for ventricular
      tachyarrhythmias shows a high positive predictive power in patients with prior
      myocardial infarction and who previously survived ventricular tachyarrhythmias.
      These results should be confirmed by studies in broad populations and without
      survived arrhythmic event.

PMID- 12419554
TI  - Association between left ventricular structure and cardiac performance during
      effort in two morphological forms of athlete's heart.
AB  - AIM: The aim of the study was to evaluate in 263 competitive athletes possible
      correlations between changes induced by different sport activities in left
      ventricular (LV) structure and cardiac response during maximal physical effort.
      METHODS: A total of 160 top-level endurance athletes (ATE; swimmers, runners;
      28+/-4 years; 98 male) and 103 strength-trained athletes (ATS; weight-lifters,
      body-builders; 27+/-5 years; male), selected on the basis of training protocol
      (dynamic vs. static exercise), underwent standard Doppler echocardiography, heart
      rate variability analysis and maximal exercise stress test by bicycle ergometry.
      M- and B-mode echocardiographic LV measurements were determined at rest, while
      the following functional indexes were assessed during effort: maximal heart rate
      (HR), maximal systolic blood pressure (SBP) and maximal workload (Watts reached
      by bicycle test). RESULTS: The two groups were comparable for age and sex, but
      ATS at rest showed higher HR, SBP, and body surface area (BSA). By echo analysis,
      LV mass index and ejection fraction did not significantly differ between the two
      groups. However, ATS showed increased sum of wall thickness (septum+posterior
      wall), relative wall thickness and LV end-systolic stress, while LV stroke volume
      and LV end-diastolic diameter (P<0.01) were greater in ATE. HR variability
      analysis underlined in ATE increased indexes of vagal tone (P<0.01). During
      maximal physical effort, ATE showed a better functional capacity, with greater
      maximal workload (P<0.001) reached with lower maximal HR and SBP. After adjusting
      for HR, age, sex, BSA and SBP, distinct multiple linear regression models
      evidenced in ATE independent associations of maximal effort workload with LV end
      diastolic diameter (P<0.001), HR (P<0.001) at rest and LV end-systolic stress
      (P<0.01) were found in ATE. On the other hand, independent direct correlation of
      SBP max during effort with sum of wall thickness (P<0.001), BSA (P<0.05) and LV
      end-systolic stress (P<0.001) was evidenced in ATS. CONCLUSIONS: LV structural
      changes in competitive athletes represent adaptation to hemodynamic overload
      induced by training and are consistent with different kinds of sport activity.
      Work capacity during exercise is positively influenced by preload increase in
      ATE, while increased afterload due to isometric training in ATS determines higher
      systemic resistance during physical effort.

PMID- 12419555
TI  - Cardiovascular disease and the global tobacco epidemic: a wake-up call for
      cardiologists.
AB  - The global tobacco epidemic continues unabated with the recruitment of young
      people, including women, to join the ranks of smokers. Even though cardiovascular
      diseases account for some of the major tobacco-related morbidity and mortality,
      cardiologists and their professional societies have lagged behind in the crusade
      against tobacco. A great opportunity exists for more involvement and leadership
      role by cardiologists, especially in countries where tobacco control efforts are
      not well established. For this to happen, there is a need to identify barriers to
      cardiologists' involvement in tobacco prevention and cessation efforts and to
      devise locally-relevant strategies to address them. Also, the areas where the
      contribution of cardiologists can be most fruitful must be identified.
      Considering that a substantial portion of the future burden of cardiovascular
      disease will occur among current tobacco users, treating tobacco dependence and
      supporting tobacco quitters are the most urgent tasks for cardiologists
      interested in reducing the human toll of tobacco. The cardiovascular community
      must consider the variety of needs and available resources to fight tobacco in
      different regions. Recommendations to involve more cardiologists in tobacco
      control, at the clinical, public health and policy levels, are presented.

PMID- 12419556
TI  - The effects of vasodilators on the relaxation of guinea-pig aorta during acute
      recoil.
AB  - BACKGROUND: We have investigated the effects of various vasodilators on smooth
      muscle relaxation during acute recoil with guinea-pig aorta to find effective
      therapies to prevent acute recoil at percutaneous transluminal coronary
      angioplasty (PTCA). METHODS: Muscle strips from guinea-pig aorta without
      endothelium were placed in a bath filled with modified Krebs solution. The strip
      was isotonically stretched with a tension of 9 mN for 1 min, and then isometric
      tension was measured until the tension reached a steady state. Various
      vasodilators were applied during isometric tension measurement. RESULTS: When no
      drug was applied (control), isometric tension reached a steady state within 20
      min. The steady state was approximately 10% lower (more relaxed) than the
      stretched level. When isosorbide dinitrate (ISDN, 1 mM) was applied during
      isometric measurement, 18.7+/-5.3% greater relaxation occurred than in control
      relaxation (P<0.05, n=5). When nicorandil (1 mM) was applied, the following
      relaxation was 18.6+/-5.7% greater than control (P<0.05, n=8). The simultaneous
      application of glibenclamide (1 mM) completely inhibited such additional
      relaxation by nicorandil. Application of nifedipine (10 microM) caused a 12.9+/
      2.5% greater relaxation than control (P=0.066, n=4). The first metabolite of
      sarpogrelate (BP984, 10 microM) caused much greater relaxation than control
      (23.7+/-7.9%, P<0.05, n=6). Amlodipine (10 microM), phentolamine (10 microM), and
      sarpogrelate (10 microM) had no influence on the relaxation of the strip.
      CONCLUSIONS: ISDN, nicorandil and BP984 significantly increase relaxation of the
      muscle strips after stretching compared to the control. These vasodilators may
      reduce acute recoil of the smooth muscle after PTCA.

PMID- 12419557
TI  - Beta-blocker therapy for dynamic left-ventricular outflow tract obstruction.
AB  - BACKGROUND: In a small but significant group of elderly patients who present with
      breathlessness, dynamic left-ventricular outflow tract obstruction (DLVOTO) may
      be responsible for symptom generation. The aim of our study was to investigate
      the effect of beta-blockade on ventricular physiology and symptoms in patients
      with DLVOTO. METHODS: We performed a pilot study in 15 patients (age 76+/-10
      years, mean+/-S.D., 14 female) with symptoms of exercise intolerance (New York
      Heart Association, NYHA, class 2.7+/-0.5). All patients had normal resting left
      ventricular (LV) systolic function together with DLVOTO based on the presence of
      basal septal hypertrophy and the development of high outflow tract velocities on
      stress echocardiography. All were commenced on oral atenolol (mean dose 45+/-19
      mg), but this could not be tolerated in four patients due to a deterioration in
      clinical status. RESULTS: In the remaining 11 patients who could tolerate
      atenolol therapy, the rate pressure product was significantly lower (23%,
      P=0.028) and there was a marked reduction in LV outflow tract velocity (23%,
      P=0.001) following beta-blockade. Patient symptoms improved significantly
      following atenolol therapy, with a reduction in mean NYHA class from 2.8+/-0.4 to
      1.5+/-0.5 (P<0.0001). CONCLUSIONS: Beta-blockade may represent a beneficial
      therapeutic approach in selected patients with DLVOTO as identified by stress
      echocardiography.

PMID- 12419558
TI  - Coronary anatomy in congenitally corrected transposition of the great arteries.
AB  - BACKGROUND: The advent of double switch procedures for the treatment of
      transposition of the great arteries with L-looped ventricles, e.g. typical
      congenitally corrected transposition of the great arteries, has made delineation
      of the coronary artery anatomy in these hearts important. Previous studies have
      suggested a consistently inverted coronary arterial pattern. METHODS: A
      morphologic study was conducted of the coronary arterial anatomy of all heart
      specimens in our registry of approximately 2600 hearts with segmental anatomy
      [S,L,L] (situs solitus of the viscera and atria, ventricular L-loop, and
      levoposition of the aorta), with anatomical features to permit such repair.
      RESULTS: Twenty specimens collected between 1965 and 1993 ranged in age from 1
      day to 23 years. Transposition of the great arteries or double outlet right
      ventricle was seen in 12 (60%). One had a single coronary artery that arose from
      the right anterior sinus and trifurcated. Another had the anterior descending
      artery arise from the right ventricular coronary artery while the circumflex
      arose alone, directly above the intercoronary commissure. Eccentric ostia were
      seen in another four, with one left ventricular coronary artery originating
      directly above the intercoronary commissure. Right ventricular aorta with
      pulmonary atresia was in eight of the total (40%). Three had eccentric ostia: one
      with both arteries from the left posterior sinus, and one with the left
      ventricular coronary over the intercoronary commissure. None of these specimens
      had additional coronary anomalies that would further complicate surgery.
      CONCLUSION: Nearly half of the specimens (45%) had coronary artery abnormalities
      that could have complicated, but not necessarily precluded, anatomic surgical
      repair.

PMID- 12419559
TI  - Etiology of aortic valve disease and recent changes in Japan:a study of 600 valve
      replacement cases.
AB  - BACKGROUND: Recent studies on the etiology of aortic valve disease in the US
      showed a decrease in rheumatic valve disease and an increase in age-related
      degenerative disease. The purpose of this study was to describe the etiology of
      aortic valve disease and its temporal changes in Japan, based on a large number
      of cases. METHODS: The medical charts of all patients who underwent aortic valve
      replacement at our institute between 1977 and 1999 were reviewed. Among the 600
      patients analyzed, 213 (36%) had pure aortic stenosis, 265 (44%) had pure aortic
      regurgitation, and 122 (20%) had combined stenosis and regurgitation. RESULTS:
      The causes were rheumatic change (49%), degenerative change (19%), bicuspid
      valves (18%), infective endocarditis (5%) and others (9%). Rheumatic disease
      continued to be the most common cause of aortic stenosis, but its frequency
      decreased from 100% in 1977-1979 to 37% in 1995-1999. In contrast, the frequency
      of degenerative change among stenotic valves increased recently from 11% in 1990
      1994 to 30% in 1995-1999. Similarly, rheumatic disease remained to be the leading
      cause of aortic regurgitation, with a decline in frequency from 46% in 1985-1989
      to 27% in 1995-1999. The percentage of degenerative change among regurgitant
      valves did not change appreciably. CONCLUSIONS: There was a shift in the causes
      of aortic valve disease, with a decrease in rheumatic disease and an increase in
      degenerative disease. This trend was similar to that observed in the US. These
      findings suggest the increasing importance of aortic valve disease due to
      degenerative change.

PMID- 12419560
TI  - Clinical characteristics and survival of patients with chronic heart failure and
      prolonged QRS duration.
AB  - BACKGROUND: Abnormal prolongation of QRS duration is a common finding in patients
      with chronic heart failure, and is associated with an impaired prognosis. The
      optimum QRS duration for separating chronic heart failure patients with respect
      to prognosis has not been determined. Whilst resynchronisation of ventricular
      conduction may benefit patients with QRS>150 ms, this has yet to be determined
      for patients with moderate QRS prolongation. METHODS: We evaluated 155 patients
      with chronic heart failure (New York Heart Association class 2.6+/-0.8, mean+/
      S.D.). The mean follow-up period was 838+/-748 days. Patients were sub-grouped
      according to QRS duration: <120 ms (normal QRS, n=82), 120-150 ms (moderate
      prolongation, n=44) and >150 ms (severe prolongation, n=29). RESULTS: The optimal
      QRS duration for stratifying patients for 2-year event free survival was 120 ms
      (receiver operating characteristic analysis: area under curve 0.73; 95% CI 0.64
      0.81). Moderate prolongation of QRS duration was associated with a worse New York
      Heart Association class, peak oxygen consumption and left ventricular ejection
      fraction when compared to patients with normal QRS duration (all P<0.05).
      Patients with moderate prolongation of QRS duration had similar impairment of New
      York Heart Association class and peak oxygen consumption as compared with
      patients with QRS duration >150 ms (all P>0.05). CONCLUSIONS: The optimum QRS
      duration for stratifying patients for medium to long-term event-free survival was
      120 ms. Heart failure patients with moderate QRS prolongation share similar
      impairment of exercise capacity and functional class to those with severe
      prolongation.

PMID- 12419561
TI  - Midwall myocardial shortening in athletic left ventricular hypertrophy.
AB  - BACKGROUND: Patients with pathological left ventricular hypertrophy have
      depressed midwall systolic shortening in spite of normal indices of left
      ventricular chamber function and a reduced midwall function has been observed to
      be an independent predictor of cardiovascular risk. Whether midwall shortening is
      depressed in physiological hypertrophy is unknown. METHODS: Forty-two subjects,
      27 athletes and 15 age- and sex-matched normal control subjects (group 1) were
      studied. The athletes were divided into those with eccentric hypertrophy (group
      2) and those with concentric hypertrophy (group 3). Systolic left ventricular
      function was assessed at the midwall and endocardium using two-dimensional
      echocardiography in all subjects. RESULTS: Left ventricular mass index was
      significantly greater in both athletic groups than in controls (group 1, 101+/
      5.8 g/m(2), group 2, 141+/-11.1*, group 3, 155+/-5.8*; *P<0.01 compared with
      group 1). Left ventricular systolic function assessed at the endocardium was
      similar among all three groups (ejection fraction: group 1, 66.2+/-2.38, group 2,
      66.8+/-1.44, group 3, 63.7+/-1.66%; endocardial fractional shortening: group 1,
      37.1+/-1.71, group 2, 37.6+/-1.13, group 3, 35.1+/-1.25%). However, fractional
      shortening at the midwall was reduced in the concentric hypertrophy athletes
      compared with the other two groups (midwall fractional shortening: group 1,
      21.9+/-1.1, group 2, 21.9+/-0.86, group 3, 18.4+/-0.96*%; P<0.05 compared with
      groups 1 and 2). CONCLUSION: Subjects with physiological concentric hypertrophy
      have depressed midwall fractional shortening. This suggests that the observed
      discrepancy between midwall and endocardial shortening in patients with left
      ventricular hypertrophy is likely to be a function of the geometry and not
      necessarily a reflection of pathology within the myocardium.

PMID- 12419562
TI  - Effects of lipids on thrombotic mechanisms in atherosclerosis.
AB  - Cholesterol lowering therapy markedly reduces the frequency of subsequent
      cardiovascular events and is associated with a modest degree of angiographic
      regression of atherosclerotic lesions. There is a strong association between
      lipids and fibrinogen, plasminogen activator-1, and activated factor VII levels.
      Low density lipoprotein may be thrombogenic whereas high density lipoprotein
      protects against thrombosis. Lipoprotein (a) may affect atherosclerosis and
      thrombosis mainly by binding to fibrin and attenuating the fibrin-enhanced
      plasminogen activation. Tissue factor-complex initiates coagulation by activating
      factor X and factor IX leading in the presence of calcium to the generation of
      thrombin. Lipid lowering treatment with statins stabilizes atheromatous plaque
      and has antithrombotic effects. Therefore there are links between lipids and the
      haemostatic mechanisms which affect atherosclerotic, vasomotor and thrombotic
      components of ischemic heart disease.

PMID- 12419563
TI  - Age-adjustment of HRV measures and its prognostic value for risk assessment in
      patients late after myocardial infarction.
AB  - THE AIMS OF OUR STUDY WERE: (1) to establish the normal limit of the heart rate
      variability (HRV) indices in a healthy population and in its four age-related
      subgroups, including a new HRV index, HRV fraction; and (2) to analyse the
      frequency and predictive value of abnormally low HRV in a population of post
      infarction patients in respect to the cut-points chosen (raw or age-adjusted).
      METHODS: Normal population of 296 healthy subjects (81 f, 215 m, aged 47+/-10
      years) and post-infarction population of 298 patients (>3 months after acute MI,
      65 f, 233 m, aged 56+/-10) were examined. The normal population was divided into
      4 subsets based on age at entry: <35, 35-44, 45-54 and >54 years. Based on a 24 h
      ECG the standard HRV analysis was performed to obtain the following indices: mean
      RR interval, SDNN and SDANN. A new index of HRV, HRV fraction (HRVF, %) was
      calculated based on a numerical processing of the RR intervals return map. All
      patients were followed for 24 months. The endpoints of the study were death (of
      any reason) and cardiac death. RESULTS: Means and normal limits for SDNN, SDANN
      and HRVF were: 147+/-36 ms [95% CI 89-220], 136+/-36 ms [79-212] and 53+/-9% [35
      68]. The HRV values below the lower normal limit (LNL) were observed in 20-25% of
      post-MI patients. During a 2 year follow-up there were 36 deaths (total mortality
      12.1%), while cardiac mortality was 9.1% (27 cases). The prognostic value of the
      analysed indices was similar (sens approximately 53-61%, spec approximately 79
      84%, PPV 22-26%, NPV 93-94%) irrespective of the cut-points chosen (calculated
      either for the entire population or age-related). Multivariate Cox regression
      analysis showed that a decrease of any index below the LNL was associated with a
      approximately 2.5 and approximately 4-6 times greater risk for death and cardiac
      death, irrespective of the cut-points chosen. CONCLUSIONS: The age-dependence of
      the HRV indices does not seem to significantly influence their prognostic value.
      Thus, a single cut-point of a particular HRV index, based on the entire
      population, is sufficient to be treated as a risk predictor. In the late phase of
      myocardial infarction the value of any global HRV index lying below the lower
      normal limit indicates independently an increased risk of death, especially
      cardiac death. The new index (HRV fraction) seems to be a promising substitute
      for currently used standard indices.

PMID- 12419564
TI  - Ischaemic heart failure: a new explanation of its cause and preventability.
AB  - When the heart contracts, it compresses its own arteries, so that blood flow in
      the coronary circulation comes to a standstill during systole. The heart must be
      supplied with blood from an auxiliary supply during diastole. The auxiliary pump
      is the aorta and its branches. When the stroke volume is injected into the aorta,
      it is overfilled and distended, storing energy in stretched elastic tissues.
      During diastole the contraction of these tissues maintains diastolic pressure.
      The hardest working organ in the body, the heart, therefore is supplied with
      blood only intermittently and only at diastolic pressure. In addition a layer of
      calcium tends to accumulate in the aorta, deteriorating its elasticity. It is
      suggested that this auxiliary pump is the weakest link in the circulatory system.
      If it fails, the heart dies of ischaemia. The calcium requirements of the body
      vary greatly in various age groups; 99% of the calcium content of the adult body
      is in the skeleton, which is complete by the age of 32 years. After that calcium
      requirements decrease. Catering for such varying calcium needs the gut to be
      impermeable to calcium. A special substance, 1,25,-dihydroxycholecalciferol,
      secreted by the liver and kidneys is needed to transfer calcium through the
      intestinal wall. When calcium needs are satisfied, the synthesis of
      cholecalciferol is discontinued, and the calcium in food in the intestines is
      excreted. To cater for the other extreme, when the calcification of the infant
      skeleton needs much calcium, nature produces a special nutrient, milk, not only
      rich in calcium, but containing a substance promoting its transference through
      the intestinal wall. The human habit of consuming the milk of another species is
      harmful because it invalidates the natural expedient of limiting calcium intake
      when it is not needed. The calcium excess resulting from milk consumption tends
      to calcify the aorta, deteriorating its elasticity, resulting in lower diastolic
      pressure. When that becomes inadequate, the heart dies of ischaemia.

PMID- 12419565
TI  - Expression of FHL2 and cytokine messenger RNAs in human myocardium after
      cardiopulmonary bypass.
AB  - BACKGROUND: Proinflammatory cytokines such as tumor necrosis factor alpha (TNF
      alpha), interleukin (IL)-6, and IL-8 have been implicated in myocardial injury
      following cardiopulmonary bypass (CPB). However, little evidence is currently
      available to directly confirm such a relationship. We have previously documented
      that a newly discovered 'four and a half LIM-only protein 2' (FHL2) is
      exclusively expressed in myofibres. We hypothesized that the upregulation of FHL2
      is proportional to the degree of myocardial injury and investigated the
      myocardial expression of FHL2 together with these cytokine messenger RNAs (mRNAs)
      during clinical CPB. METHODS: Intermittent hypothermic blood cardioplegia was
      used in all patients. Atrial myocardial biopsies were obtained immediately at the
      onset and at the end of CPB in 33 consecutive patients undergoing valvular or
      coronary artery surgery. TNF-alpha, IL-6, and IL-8 mRNA expressions in these
      myocardial samples were determined by semi-quantitative reverse transcription
      polymerase chain reaction. Myocardial FHL2 expression was determined by Western
      blot analysis. Serum levels of the MB isoenzyme of creatine kinase (CK-MB) and
      cardiac troponin-I (cTnI) before surgery and 24 h after the end of CPB were also
      measured. RESULTS: The duration of aortic crossclamping and CPB was 70+/-33 and
      99+/-37 min, respectively. No elevated myocardial TNF-alpha mRNA expression was
      found after CPB. IL-6 mRNA expressions were detected in 14 pairs of the
      myocardial biopsies and were elevated in 11 (33%) post-CPB biopsies. Similarly,
      IL-8 mRNA expressions were detected in 19 pairs of samples and were elevated in
      14 (42%) post-CPB biopsies. Among the 17 pairs of biopsies with positive FHL2
      expression, FHL2 levels were increased in 11 (33%) post-CPB samples. Moreover,
      the elevated FHL2 expression was associated with an increase in IL-6 (P=0.018)
      and IL-8 (P=0.024) mRNA expression after CPB. Postoperative CK-MB and cTnI levels
      were significantly higher in patients with myocardial FHL2 expressions than those
      without (CK-MB, 13.5+/-2.3 vs. 6.5+/-0.8 ng/ml, P=0.022; cTnI, 10.7+/-2.0 vs.
      3.5+/-0.6 ng/ml, P=0.0013). CONCLUSIONS: Our findings demonstrate for the first
      time that both IL-6 and IL-8 mRNAs are upregulated in human cardiac myocytes
      following CPB and these cytokines may be involved in myocardial ischemia
      reperfusion injury, as reflected by their association with an increased
      expression of FHL2.

PMID- 12419566
TI  - Oral L-arginine prevents murine coxsackievirus B3 myocarditis.
AB  - We have previously demonstrated that administration of nitric oxide (NO) synthase
      inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME), aggravated murine
      coxsackievirus B3 myocarditis. In the present study, we evaluated the effects of
      L-arginine, a precursor of NO, upon acute and chronic myocarditis. Dietary L
      arginine and L-arginine plus L-NAME (L-arginine+L-NAME group) were administered
      to coxsackievirus B3 (CB3)-infected C(3)H/He mice for 2 weeks (experiment I), and
      to CB3-infected mice from the second week until the fourth week after virus
      inoculation (experiment II). Infected control was prepared in each experiment. In
      experiment I, survival was higher in the L-arginine group compared with the other
      two groups, and cardiac damage was less. In addition, plasma concentrations of L
      arginine and NO were elevated in the L-arginine group. In experiment II,
      cardiomyopathic lesion in the L-arginine group was less prominent associated with
      lower plasma catecholamine and lower myocardial collagen concentrations compared
      with the other two groups. Thus, L-arginine treatment may be effective not only
      in preventing the development of acute CB3 myocarditis but in ameliorating
      cardiac dysfunction in chronic myocarditis.

PMID- 12419567
TI  - Marked abnormalities in heart rate variability are associated with progressive
      deterioration of renal function in type I diabetic patients with overt
      nephropathy.
AB  - BACKGROUND: Cardiac autonomic neuropathy is a common complication of long
      standing, type 1 diabetes and is associated with increased morbidity and
      mortality. Impaired heart rate variability is a sensitive and reproducible marker
      of cardiac autonomic neuropathy. We sought to examine the relationship between
      cardiac autonomic neuropathy as assessed by heart rate variability and overt
      nephropathy, with emphasis on the progression of renal dysfunction over 1 year.
      METHOD: Baseline and 12 month clinical and biochemical characteristics, as well
      as autonomic function tests, were analyzed in 23, type 1 diabetic patients (mean
      age 37+/-10 years, 65% males), who were prospectively enrolled as a part of a
      multi-center investigation. In addition, ambulatory, 24-h, 3-channel
      electrocardiograms were recorded, and heart rate variability indices were
      assessed in the time and frequency domains over the same period. RESULTS: All
      heart rate variability indices were markedly decreased in our study population.
      On univariate analysis, heart rate variability was associated with creatinine
      clearance, and to a lesser extent, mean 24-h blood pressures and cholesterol. On
      multivariate analysis, only heart rate variability was a significant and
      independent predictor of abnormalities in creatinine clearance. Severe reduction
      in heart rate variability at baseline was also significantly associated with the
      further deterioration in renal function at 1 year. CONCLUSION: Heart rate
      variability is significantly reduced in long-standing, type 1 diabetics with
      proteinuria or overt nephropathy. Marked abnormalities in heart rate variability
      are significantly associated with and predictive of progressive renal
      deterioration at 1 year. These findings may have implications for aggressive
      medical intervention to improve prognosis and survival in this population.

PMID- 12419568
TI  - Predictors of long-term success in catheter ablation of atrioventricular nodal
      reentrant tachycardia: a multivariate regression analysis.
AB  - BACKGROUND: To investigate the predictors of long-term success after catheter
      ablation of atrioventricular nodal reentrant tachycardia (AVNRT). METHODS: One
      hundred and fourteen consecutive patients underwent slow pathway ablation using
      anteroseptal (n=24), midseptal (n=65) and posteroseptal approach (n=25). The
      correlation between ablation approaches, electrophysiological characteristics
      during and after ablation and the recurrence rate of AVNRT was analyzed by a
      multivariate regression analysis. RESULTS: During ablation, transient AV block in
      the anteroseptal, midseptal and posteroseptal approach occurred in 8.3, 4.6 and
      0%, respectively (P<0.01). AVNRT recurred in seven patients after 5 years follow
      up. Five recurrences (20.8%) were from anteroseptal approach group and two (3.1%)
      were from midseptal approach group. Multivariate regression analysis revealed
      that anteroseptal ablation approach and residual dual atrioventricular nodal
      pathway following apparently successful ablation were the predictors for
      recurrence of AVNRT (R=0.645, P<0.001). CONCLUSION: Anteroseptal approach of slow
      pathway ablation is associated with a higher incidence of transient AV block and
      AVNRT recurrence than other approaches. Residual dual atrioventricular nodal
      pathway after apparently successful ablation also carries a high risk of
      recurrence.

PMID- 12419569
TI  - Unexpected eosinophilic myocarditis in a young woman with rapidly progressive
      dilated cardiomyopathy.
AB  - We present the case of 23-year-old woman with good living conditions, one year
      history of ventricular arrhythmia and 6 months history of decreased exercise
      tolerance, who was found to have dilated cardiomyopathy after aborted sudden
      death. Endomyocardial biopsy did not show specific findings. Within 3 months she
      developed profound bradycardia requiring pacemaker implantation and refractory
      heart failure, treated with heart transplantation. Intense eosinophilic
      myocarditis was found in the explanted heart. Retrospective analysis of the
      patient's blood count revealed mild eosinophilia (eosinophil count: 0.86 x 109/l)
      on one examination only. Following heart transplantation the patient had
      persistent eisinophilia (eosinophil count: 0.62 x 109/l). Although there was no
      proven parasitic infestation, based on positive family history of Enterobius
      vermicularis infestation she was treated with broad-spectrum antiparasitic agent:
      albendazole and her eosinophil count returned to normal values. This case shows
      that active eosinophilic myocarditis may present clinically as progressive
      dilated cardiomyopathy with severe involvement of conduction system. Massive
      myocardial tissue eosinophilia occurred in the setting of mild and transient
      blood eosinophilia. Favourable outcome following antiparasitic treatment suggests
      a potential parasitic infestation as a cause of the disease.

PMID- 12419570
TI  - Characterisation of isoprenaline myotoxicity on slow-twitch skeletal versus
      cardiac muscle.
AB  - BACKGROUND: Elevated catecholamines are known to be cardiotoxic, but their
      potential injurious effects on skeletal muscles are largely unknown. We have
      investigated whether isoprenaline induces in vivo myocyte necrosis in rat soleus
      muscle, and characterised the time-course, dose-response, spatial distribution
      and adrenoceptor involvement of its myotoxicity, in comparison with effects on
      cardiomyocytes in the same animals. MATERIAL AND METHODS: Myocyte necrosis in
      response to subcutaneous isoprenaline was detected in vivo using a monoclonal
      anti-myosin antibody. Secondary immunoperoxidase staining (in vitro) facilitated
      the localisation of the damage and quantitative image analysis. RESULTS: Using
      this sensitive technique we report a novel observation that isoprenaline induces
      significant myocyte necrosis (5-10%) in the soleus muscle. This toxic damage was
      initiated at lower doses of isoprenaline than in the myocardium (1 vs. 10 microg
      kg(-1) s.c.), and peaked earlier (at 12 vs. 18 h post injection). Damage was
      distributed throughout the soleus muscle, whereas cardiomyocyte necrosis was most
      marked in left ventricular subendocardium where it was approximately 10 and three
      times greater than in the subepicardium and atria, respectively. Using selective
      adrenoceptor (AR) antagonism, we found that isoprenaline myotoxicity was mediated
      via beta(2)-AR in the soleus and via beta(1)-AR in the myocardium. CONCLUSION:
      The results show that the myopathic effects of isoprenaline are not confined to
      the heart. The involvement of skeletal muscle with different characteristics and
      mechanisms may have important implications in elucidating and treating the
      generalised myopathic processes seen in heart failure patients who have elevated
      levels of circulating catecholamines.

PMID- 12419571
TI  - Peripartum cardiomyopathy: a selenium disconnection and an autoimmune connection.
AB  - BACKGROUND: Increased incidence and prevalence of peripartum cardiomyopathy
      (PPCM) have been documented in the Hospital Albert Schweitzer (HAS) District of
      Haiti. Although the basis for this increased incidence of PPCM remains unclear,
      there is growing evidence for an underlying autoimmune process. One potential
      risk factor for increased autoreactivity is a micronutrient deficiency. In
      Africa, low plasma selenium (Se) level has been reported as a possible risk
      factor for PPCM. This report details results of initial studies to test the
      hypothesis that plasma levels of Se and/or other micronutrients may be related to
      PPCM risk in this population. METHODS: Under the direction of the Institutional
      Review Board (HAS Ethics Committee) and with informed consent, levels of Se and
      other micronutrients were measured in plasma samples obtained from PPCM mothers
      and parity-matched control mothers from the HAS District of Haiti. RESULTS: Mean
      plasma Se level in 18 PPCM patients was 110 ng/ml (range 67-145) compared to mean
      plasma Se level in 34 control mothers of 121 ng/ml (range 98-172) (P=0.1748).
      These levels are substantially greater than those reported for pediatric patients
      with Keshan cardiomyopathy, which can be prevented by Se prophylaxis. No
      deficiency or significant difference was found in any other micronutrient tested
      (Vitamin A (retinol), Vitamin B(12), Vitamin C, Vitamin E, and B-Carotene) for
      these PPCM and control mothers. CONCLUSION: Although there are several possible
      mechanisms by which Se could play a role in the pathobiology of PPCM, there is no
      evidence that Se deficiency is a cause of PPCM or a risk factor for the
      development of PPCM in this district of Haiti. The results of this investigation
      indicate that future studies of PPCM in this population should focus on other
      potential etiologic and risk factors.

PMID- 12419572
TI  - Oral L-arginine improves endothelial dysfunction in patients with essential
      hypertension.
AB  - BACKGROUND: L-Arginine is a nitric oxide precursor, which augments endothelium
      dependent vasodilatation in hypercholesterolemic humans and animals. Endothelium
      dependent vasodilation is attenuated in patients with hypertension; however the
      effects of oral L-arginine on endothelial function of the conduit arteries in
      patients with essential hypertension have not previously been investigated.
      METHODS: In a prospective randomized double blind trial, 35 patients with
      essential hypertension received either 6 g L-arginine (18 subjects) or placebo
      (17 subjects). Patients were examined for flow-mediated endothelium-dependent
      dilatation of the brachial artery before and 1.5 h after administration of L
      arginine or placebo. At the end of the protocol the nitrate-induced, endothelium
      independent vasodilatation was evaluated. RESULTS: Two groups of L-arginine and
      placebo were similar regarding age, sex, blood lipids, smoking, diabetes,
      coronary artery disease, body mass index, intima-media thickness of the common
      carotid artery, clinics blood pressure and baseline brachial artery parameters.
      Administration of L-arginine or placebo did not change significantly heart rate,
      blood pressure, baseline diameter, blood flow or reactive hyperemia. L-Arginine
      resulted in a significant improvement of flow-mediated dilatation (1.7+/-3.4 vs.
      5.9+/-5.4%, P=0.008) while placebo did not significantly change this parameter
      (3.0+/-2.7 vs. 3.1+/-2.2%, P=ns). The effect of L-arginine on flow-mediated
      dilatation was significantly different from the effect of placebo (P=0.05). L
      Arginine did not significantly influence nitrate-induced dilatation (16+/-6.9 vs.
      17.7+/-6.7%, P=ns). CONCLUSIONS: Oral administration of L-arginine acutely
      improves endothelium-dependent, flow-mediated dilatation of the brachial artery
      in patients with essential hypertension. The long-term effects of L-arginine in
      these patients require further investigation.

PMID- 12419573
TI  - Angiotensin receptor blockers--finally the evidence is coming in: IDNT and
      RENAAL.

PMID- 12419574
TI  - The ECG in a mechanical obstruction of the ostium of the left main coronary
      artery.

PMID- 12419575
TI  - Mother-daughter peripartum cardiomyopathy.

PMID- 12419576
TI  - Rapidly reversible ECG abnormalities in chronic secondary adrenal insufficiency.

PMID- 12419577
TI  - Updates on the cytogenetics and molecular genetics of bone and soft tissue
      tumors. desmoplastic small round-cell tumors.

PMID- 12419578
TI  - Multiple telomeric aberrations in a telomerase-positive leukemia patient.
AB  - Bone marrow samples from a pancytopenia/leukemia patient were routinely analyzed
      at first and second admission. At the first presentation, the karyotype was
      normal, whereas 17 months later several chromosome aberrations were recognized
      including presumed additions to the short arms of chromosomes 1 and 16 in all
      cells, and numerous other aberrations in subpopulations of cells. From the
      predominance of aberrations at chromosome ends, we suspected insufficient
      telomere maintenance as an underlying mechanism behind the karyotype changes, in
      particular as an interstitial deletion in the region harboring the gene for the
      RNA component (hTERC) of the telomerase enzyme was also noticed; however, while
      molecular cytogenetic investigation confirmed the terminal aberrations, we found
      the malignant cells positive for telomerase activity and the presence of an hTERC
      gene on both chromosomes 3. A presumed chromosome 1 addition turned out to
      reflect an amplification of a tandemly repeated sequence element. Labeling of
      multiple tandem repeat sequences in situ by a novel multicolor primed in situ
      hybridization showed no evidence of instability of other repeated DNA elements.

PMID- 12419579
TI  - Duplication 15q as the sole anomaly in an acute promyelocytic leukemia patient
      without t(15;17).
AB  - We present a unique chromosomal abnormality found in a patient with acute
      myeloblastic leukemia of French-American-British subtype M3. The patient was
      referred for an evaluation of a chromosomal anomaly exclusively associated with
      FAB M3 or acute promyelocytic leukemia: a translocation between chromosomes 15
      and 17, t(15;17)(q22;q21.1). Neither t(15;17) nor rearrangement of RARalpha was
      detected by routine G-banded chromosome as well as fluorescence in situ
      hybridization analysis using the commercial dual-color PML/RARalpha translocation
      probe and the RARalpha probe, a break apart rearrangement dual-color probe.
      Instead of the typical rearrangement between chromosomes 15 and 17, all cells
      analyzed had a duplication of the segment of chromosome 15 between bands 15q15
      and 15q26.

PMID- 12419580
TI  - Identical abnormality of the short arm of chromosome 18 in two Philadelphia
      positive chronic myelocytic leukemia patients with erythroblastic transformation,
      resulting in duplication of BCR-ABL1 fusion.
AB  - Two patients with Ph-positive chronic myelocytic leukemia in erythroblastic
      transformation and rearrangement of the short arm of chromosome 18 are reported.
      Fluorescence in situ hybridization studies showed that the 18p rearrangement
      resulted from translocation of the main part of chromosome 22 long arm to 18p,
      including BCR-ABL1 fusion. The 18p abnormality resulted, thus, in loss of 18p and
      duplication of BCR-ABL1 in both patients. The possible relation to the
      erythroblastic type of blastic phase is briefly discussed. In addition an
      apparently intact germline ABL1 gene was duplicated and inserted into chromosome
      6 at band p21 in one of these patients.

PMID- 12419581
TI  - Identification of novel mutations in the RB1 gene in Mexican patients with
      retinoblastoma.
AB  - Retinoblastoma (RB) is a childhood tumor of the eye with an average incidence of
      one case in every 15,000-20,000 live births and occurs in sporadic or hereditary
      form. This cancer results from loss or inactivation of the RB1 gene located at
      13q14.1. This gene encodes for a 110 Kd nuclear phosphoprotein (pRB) that plays a
      major role in cell proliferation control. Different types of mutations in the RB1
      gene have been reported, but point mutations are the most common. There are no
      molecular studies on RB1 gene mutation in Mexican patients. In this study, 19
      patients with bilateral or unilateral RB were analyzed. Genetic and cytogenetic
      studies were carried out. Detection of RB1 gene mutations was done using single
      strand conformational polymorphism (SSCP). Five conformational polymorphisms were
      identified in different exons. In all cases, SSCP sequence showed new non
      described mutations that produced a frameshift on the open reading frame. The
      identification of mutations in the RB1 gene contributes to basic knowledge of
      this neoplasia and permits the possibility to offer adequate genetic counseling
      to relatives at risk.

PMID- 12419582
TI  - A new nonrandom unbalanced t(17;20) in myeloid malignancies.
AB  - Deletions of chromosomes 17 and 20 are well-described abnormalities in
      myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) but
      translocations involving these two chromosomes are uncommon. We present five male
      patients, one with MDS and four with AML, in whom a new, nonrandom unbalanced
      dicentric t(17;20), resulting in deletions of 17p and 20q, was identified.
      Conventional cytogenetics showed additional karyotypic abnormalities in most of
      the patients, including deletions of 5q, deletions or monosomy of chromosome 7,
      and deletions of 18q. Fluorescence in situ hybridization showed a deletion of the
      tumor suppressor gene TP53 on 17p. Of the four cases with follow-up data
      available, only two had received combination chemotherapy. Overall survival in
      these two cases was 6 and 7 weeks, respectively. Two other patients who had no
      active therapy administered died 6 weeks and 9 months after diagnosis,
      respectively. These five cases highlight a rare but recurrent abnormality in MDS
      and AML, potentially involving genes on 17p and 20q of importance in myeloid
      leukemogenesis.

PMID- 12419583
TI  - Cytogenetic studies of esophageal squamous cell carcinomas in the northern
      Chinese population by comparative genomic hybridization.
AB  - Esophageal cancer is the fourth most prevalent malignancy in China. So far, the
      genetic events involved in esophageal cancer remain largely unknown. To identify
      chromosomal alterations in this disease, comparative genomic hybridization was
      performed on 25 primary tumors of esophageal squamous cell carcinomas. Results
      exhibited nonrandom copy number changes in chromosome DNA, with higher incidence
      in gain than in loss. The average gains and losses per patient were 7.76 and 4,
      respectively. The most common gains were 3q (20/25), 1q (15/25), 8q (15/25), 20p
      (12/25), 20q (11/25), 5p (10/25), 15q (8/25), and 9q (8/25) with two minimal
      amplification loci mapped to chromosomal regions of 8q24 (2 cases) and 11q13 (7
      cases). High-level amplification was observed at 3q (8 cases), 5p (4 cases), and
      8q (4 cases). Losses at 3p (10/25), 13q (8/25), 18q (7/25), Xp (7/25), 4 (6/25),
      9p (6/25), 14q (6/25), 18p (6/25), and 21q (6/25) were identified. Remarkably,
      ten cases showed both loss of the entire 3p and overrepresentation of almost the
      whole 3q. No significant differences in stage or grade of tumor were found for
      DNA copy number changes. The results provided candidate regions for potential
      oncogenes and tumor suppressor genes related to Chinese esophageal cancer, to
      which further molecular studies should be addressed.

PMID- 12419584
TI  - Establishment and characterization of a poorly differentiated lethal human
      endometrial carcinoma cell line (NOU-1) with karyotype 46,XX.
AB  - Immortal gynecologic cell lines, especially those of endometrial origin are
      diverse with multiple chromosomal alterations, making the study of origin and
      molecular genetic characteristics of such neoplasms difficult, if not impossible.
      We have established a new epithelial, poorly differentiated endometrial
      adenocarcinoma cell line (NOU-1) with a 46,XX chromosome complement. To confirm
      the tumor characteristics, we injected this cell line subcutaneously into the
      nude mouse. The tumor grown in vivo had the identical histology and the same
      46,XX chromosome complement as the original tumor excised from the patient. The
      cells from the original tumor and those in the nude mouse shared the same
      characteristics with respect to histopathology, immunohistochemistry, steroid
      hormone receptor content, and growth characteristics. We report on the only
      established cell line of a highly aggressive, poorly differentiated endometrial
      adenocarcinoma with 46,XX chromosome complement where both estrogen and
      progesterone receptors are absent.

PMID- 12419585
TI  - HMGIC alterations in smooth muscle tumors of soft tissues and other sites.
AB  - The HMGIC gene, which codes a protein that acts as an architectural transcription
      factor, is frequently rearranged in a variety of benign or locally aggressive
      mesenchymal tumors. In tumors of smooth muscle differentiation, only uterine
      leiomyoma and lipoleiomyoma are known to be associated with the altered HMGIC. We
      investigated molecular and genetic alterations of the HMGIC in 36 benign and
      malignant smooth muscle tumors arising at various anatomical sites, including 13
      uterine leiomyomas, two leiomyomas of the kidney with a t(12;14), one pelvic
      lipoleiomyoma, one vascular leiomyoma of the foot, two uterine leiomyosarcomas,
      six retroperitoneal leiomyosarcomas, one leiomyosarcoma of the urinary bladder,
      and 10 leiomyosarcomas of external soft tissues. HMGIC gene expressions were
      detected in both uterine (73.3%) and extrauterine (57.1%) smooth muscle tumors by
      reverse transcriptase polymerase chain reaction (RT-PCR), and benign tumors
      (70.5%) more frequently expressed the HMGIC than leiomyo-sarcomas (57.8%).
      Variant transcripts of the HMGIC containing cryptic exonic sequences previously
      described were found in one renal and three uterine leiomyomas and four
      leiomyosarcomas arising in the uterus and soft tissues by RT-PCR. Southern blot
      analysis identified a rearranged HMGIC in one soft tissue leiomyosarcoma. Thus,
      the HMGIC alterations in smooth muscle tumors are not confined only to uterine
      leiomyoma or lipoleiomyoma. Our data expand the variety of mesenchymal tumors
      associated with HMGIC alterations.

PMID- 12419586
TI  - Differential induction of numerical chromosome changes by sodium butyrate in two
      transformed cell lines.
AB  - Transformed cell lines generally exhibit similar response to a given chemical.
      However, when two transformed cell lines, the Chinese hamster (CHO 9) and mouse
      (L929) were treated with sodium butyrate (SB) to investigate its effect on
      chromosome distribution, the two lines behaved differently from each other. At
      concentrations as low as 10(-7) M, the CHO 9 cells exhibited polyploidy as well
      as errors of numerical distributions resulting in aneuploidy. The majority of
      aneuploid cells were in quasitetraploid range indicating an association between
      the induction of polyploidy and aneuploidy. Upon staining with spindle antibody,
      the CHO cells exhibited a disarray of spindle microtubules as well as an abnormal
      cytoskeleton. In many instances the metaphase chromosomes were found to have a
      distorted spindle or lack an associated spindle altogether. The L929 cells,
      however, turned out to be far less sensitive to SB: a 100-fold increase in
      concentration of sodium butyrate (10(-5) M) did not result in production of
      polyploid cells. However, when the extent of aneuploidy induction was measured by
      using a marker chromosome, both loss and gain of the chromosome was noticed. The
      effect of SB on the spindle was much more modest than it was the case with CHO
      cells as only minor disarray in cytoskeleton or spindle morphology was observed.
      The L929 cells, however, showed some effect on microtubule orientation as well as
      an effect on the segmentation of midbody. The application of SB resulted in less
      intense and more diffuse phosphorylation; the chromosomes had a punctate
      appearance of the label compared with the solid appearance on untreated cells.
      This was ture for both species. In mouse, the centromeric heterochromatin, which
      generally is intensely labeled, appeared to be labeled only as intensely as
      euchromatin. The data show that different transformed cell lines do not respond
      similarly to SB.

PMID- 12419587
TI  - Combined analysis of morphology and fluorescence in situ hybridization in follow
      up of minimal residual disease in a child with Philadelphia-positive acute
      lymphoblastic leukemia.
AB  - The past decade has brought new technologies to the study of minimal residual
      disease (MRD) in leukemia. Each of them has limitations and is far from being
      accurate. Recently, a new multiparametric cell scanning system (Duet) was
      introduced to the field of MRD detection. This system has the advantage of
      automatically scanning large numbers of cells and performing combined analysis of
      morphology and fluorescence in situ hybridization (FISH) on the same cell. We
      used this system to characterize the lineage and degree of maturation of the
      cells carrying the minor m-BCR/ABL fusion, in a follow-up of an 8-year-old boy
      with Philadelphia-positive (Ph(+)) acute lymphoblastic leukemia (ALL). The boy
      was treated using a high-risk protocol and was closely monitored with FISH
      analysis for cells carrying the m-BCR/ABL fusion. Consecutive analysis along 2.5
      years from remission showed 0.2-4.5% m-BCR/ALB(+) cells in the peripheral blood
      (PB), which is within the accepted background range for this method. The combined
      analysis found that all the m-BCR/ABL(+) cells were mature lymphocytes. Because
      mature lymphocytes have a long life span in the circulation, this finding
      supports the fact that the patient is in remission. Moreover, since mature
      differentiated cells have a low proliferative capacity, there is a low risk for
      relapse.

PMID- 12419588
TI  - Cell proliferation, nuclear ploidy, and EGFr and HER2/neu tyrosine kinase
      oncoproteins in infiltrating ductal breast carcinoma.
AB  - The purpose of this work was to study if the variations in the nuclear DNA
      content and the expression of EGFr and HER2/neu transmembrane oncoproteins were
      related and if this influences the rate of cell proliferation modifying, in each
      case, the potential aggressivity of the neoplasia. Thirty-four ductal breast
      carcinoma tissue samples of tumors of up to 2 cm in diameter were analyzed by
      flow cytometry. HER2/neu and EGFr were measured by immunohistochemical methods.
      Twenty cases were diploid (DNA index of 1) and 14 cases were aneuploid (DNA index
      other than 1). The expression of EGFr and HER2/neu was significantly higher in
      aneuploid tumors compared with diploid tumors. The cell proliferation rate was
      significantly higher in tumors with an aneuploid pattern. The expression of EGFr
      was associated with a higher rate of cell proliferation. The higher expression of
      EGFr and HER 2/neu oncoproteins in aneuploid tumors suggests that the increased
      proliferative activity of aneuploid carcinomas is influenced by the activity of
      such oncoproteins, which favors a more aggressive biological behavior.

PMID- 12419589
TI  - A cluster of familial malignant mesothelioma with del(9p) as the sole chromosomal
      anomaly.
AB  - We describe a family of three sisters affected by malignant mesothelioma (MM) (2
      pleural and 1 peritoneal) and one brother affected by pleural plaques. All
      members of the family had been subjected to previous asbestos exposure of
      environmental-residential type. For 13 years, from 1951 to 1964, their housing
      was provided by the father's employer, an asbestos cement factory, and the
      factory warehouse was on the ground floor of the building they lived in. DNA
      extracted from paraffin-embedded MM samples was used to search for chromosomal
      alterations by a comparative genomic hybridization (CGH) method. In two cases, a
      loss at 9p was found to be the only change. The loss at 9p is a frequent event in
      malignant mesothelioma and the fact that this anomaly was diagnosed in two
      sisters as the only alteration suggests that this region may be the site of one
      or more oncosuppressor genes that could play an important role in the development
      of MM and in inducing greater genetic susceptibility to the carcinogenic effects
      of asbestos.

PMID- 12419590
TI  - A novel t(2;3)(q31;p13) in acute myelocytic leukemia.
AB  - We report a case of acute myelocytic leukemia without maturation exhibiting a
      novel t(2;3)(q31;p13). Conventional cytogenetics showed the concomitant
      occurrence of a single metaphase with 47,XX,+8. Nevertheless, interphase
      cytogenetics by fluorescence in situ hybridization using a chromosome 8 alpha
      satellite DNA probe showed that the percentage of cells with three hybridization
      signals was within the control range.

PMID- 12419591
TI  - Isodicentric/pseudoisodicentric chromosome 21 amplification in four cases of
      acute myelocytic leukemia or myelodysplasia.
AB  - The bone marrow karyotypes of three patients with acute myelocytic leukemia (AML)
      or myelodysplastic syndrome (MDS) were studied at diagnosis and revealed,
      multiple copies of the same chromosomal anomaly, considered as psu idic(21)(q22)
      associated with other rearrangement(s). The karyotype of a fourth patient with
      MDS in transformation showed one copy of a dicentric marker presumably derived
      from a similar psu idic(21) by (tandem?) interstitial amplification of part of
      its structure, resembling a "homogeneous staining region", and described as
      der(21)psu idic(21)(q22)hsr(21)(q22). This rearrangement, previously described in
      isolated cases only, might be considered as recurrent in AML/MDS and associated
      with an unfavorable prognosis. It is most probably a secondary change, because it
      was never observed as sole abnormality and the main association, as for trisomy
      21, was with del(5q). In the four cases, the number of partial supernumerary
      segmental 21pter-->21q22 copies, ranged from 2 to 10. The AML1 gene did not
      appear to be the common target of this amplification because this locus had been
      lost by the psu idic(21) in one patient

PMID- 12419592
TI  - Hypoplastic myelodysplastic syndrome-a clinical, morphologic, or genetic
      diagnosis?
AB  - We report a middle-aged female with an 11-year history of nonprogressive
      pancytopenia and severely hypoplastic marrow with minimal morphologic dysplasia.
      A diagnosis of hypoplastic myelodysplastic syndrome (MDS) was made because of the
      finding of a persistent clonal abnormality, del(13)(q12q14), and the subsequent
      demonstration of a single Auer rod-containing blast in the peripheral blood
      smear. The case illustrates the problems in the differentiation between aplastic
      anemia and hypoplastic MDS.

PMID- 12419594
TI  - 1q42 approximately q44 is rarely cytogenetically involved in sporadic uterine
      leiomyomata.

PMID- 12419593
TI  - PRAME gene expression in childhood acute lymphoblastic leukemia.
AB  - The gene PRAME (preferentially expressed antigen of melanoma) was found to be
      expressed at high levels in a large fraction of different tumors and adult
      leukemias. Since PRAME is only expressed at low levels in a few normal tissues
      and encodes an antigen recognized by autologous cytolytic T lymphocytes, it might
      be a good candidate for tumor immunotherapy. In this study, quantitative reverse
      transcriptase polymerase chain reaction was used to measure PRAME gene expression
      in 50 children with newly diagnosed acute lymphoblastic leukemia (ALL). Nine
      patients were also analyzed in relapse. Overexpression of PRAME was found in 42%
      (N = 21) of the patients. In accordance with our findings in acute myeloblastic
      leukemia (AML) patients, the rate of disease-free survival was higher and white
      blood cell counts at diagnosis were lower in patients with an overexpression of
      PRAME. However, in our group of ALL patients these findings were not
      statistically significant. The levels of expression at diagnosis corresponded
      well with those at relapse (P = 0.017). Although overexpression of PRAME was less
      frequent than in children with AML (62%) our results suggest that PRAME could be
      a useful target for immunotherapy in some children with ALL.

PMID- 12419596
TI  - Modelling bovine trypanosomosis spatial distribution by GIS in an agro-pastoral
      zone of Burkina Faso.
AB  - Modelling of the spatial distribution of bovine trypanosomosis prevalence in
      Sideradougou district Burkina Faso was performed by using a combination of
      spatial and statistical analysis. Based on a comprehensive and geographically
      representative census of herds and farms in the area, more than 2000 cattle were
      randomly chosen and their blood sampled during field survey. Data on livestock
      farming practices were recorded for each farm. All data were mapped within a GIS
      to generate new information on spatial constraints in the area. Surveys results
      were analysed and serological prevalence data were modelled using logistic
      regression. The model allowed identification and quantification of risk factors.
      In a second step the statistical model was used predictively on the entire farm
      population in the area. This method was successful in predicting the serological
      prevalence for each individual herd in the sample, from their livestock
      management patterns and spatial location. Predicted prevalences were represented
      within the GIS, taking daily movements of animals into account. Spatial
      distribution of prevalence would illustrate specific locations at risk from an
      epidemiological viewpoint. It gives evidence that the hydrological network and
      land occupation patterns in the savanna-type countryside are playing an important
      part when structuring a so-called "trypanosomosis space".

PMID- 12419597
TI  - A global livestock production and health atlas (GLiPHA) for interactive
      presentation, integration and analysis of livestock data.
AB  - An interactive electronic atlas has been developed with the purpose of providing
      a scaleable overview of spatial and temporal variation in animal production and
      health-related information for decision and policy makers in national and
      international institutions. The information contained in the atlas is currently
      managed and presented using the Key Indicators Mapping System (KIMS), and will
      also be integrated using the Key Indicators Database System (KIDS). Both systems
      were developed by the World Agricultural Information Centre of the FAO (FAO
      WAICENT), the former as a stand-alone application and the latter for access via
      the Internet. Components of the atlas include vector maps, livestock disease and
      production databases, rules for country-level disease risk classification and
      'disease cards' containing basic background information on diseases included in
      the atlas. The disease data is currently based primarily on Office International
      des Epizooties (OIE) disease reports, and the livestock production data on the
      FAO-WAICENT database. The atlas is highly interactive and allows visual
      presentation of information using maps, tables and charts. It also contains links
      to relevant resource information on the Internet. Diseases covered in the animal
      health layer include most OIE List A diseases and a subset of OIE List B
      diseases. Extensive analyses have been conducted to develop a set of qualitative
      and semi-quantitative criteria that allow improved disease status classifications
      based on 5-years cumulative OIE disease reports, and official disease control
      declarations. Classification rules were determined depending on the
      epidemiological features of each disease and considering spatial heterogeneity of
      disease presence in local regions.

PMID- 12419598
TI  - A point pattern model of the spread of foot-and-mouth disease.
AB  - The spatial spread of foot-and-mouth disease (FMD) is influenced by several
      sources of spatial heterogeneity: heterogeneity of the exposure to the virus,
      heterogeneity of the animal density and heterogeneity of the networks formed by
      the contacts between farms. A discrete space model assuming that farms can be
      reduced to points is proposed to handle these different factors. The farm-to-farm
      process of transmission of the infection is studied using point-pattern
      methodology. Farm management, commercial exchanges, possible airborne
      transmission, etc. cannot be explicitly taken into account because of lack of
      data. These latter factors are introduced via surrogate variables such as herd
      size and distance between farms. The model is built on the calculation of an
      infectious potential for each farm. This method has been applied to the study of
      the 1967-1968 FMD epidemic in UK and allowed us to evaluate the spatial variation
      of the probability of infection during this epidemic. Maximum likelihood
      estimation has been conducted conditional on the absence of data concerning the
      farms which were not infected during the epidemic. Model parameters have then
      been tested using an approximated conditional-likelihood ratio test. In this case
      study, results and validation are limited by the lack of data, but this model can
      easily be extended to include other information such as the effect of wind
      direction and velocity on airborne spread of the virus or the complex
      interactions between the locations of farms and the herd size. It can also be
      applied to other diseases where point approximation is convenient. In the context
      of an increase of animal density in some areas, the model explicitly incorporates
      the density and known epidemiological characteristics (e.g. incubation period) in
      the calculation of the probability of FMD infection. Control measures such as
      vaccination or slaughter can be simply introduced, respectively, as a reduction
      of the susceptible population or as a reduction of the source of infection.

PMID- 12419599
TI  - How best to geo-reference farms? A case study from Cornwall, England.
AB  - The commonest way of geo-referencing farms as single points is using the location
      of the farmhouse as either read off a map or approximated by its postcode. While
      these two methods may be adequate for small farms, they are unlikely to be
      satisfactory for large ones, or alternatively when they are comprised of several
      discrete units or holdings. In order to investigate the best representation of
      the total farm polygon(s) by a single point, we undertook a study using nearly
      500 actual farm boundaries in the county of Cornwall, England. For each farm, the
      farm boundaries were digitised, and its area and centroid determined using
      ArcView 3.2. A variety of point geo-referencing systems were tested to find the
      best single point location for a farm, as judged by the proportion of farm area
      captured. Whilst the centroid was found to capture the largest area, the main
      farm building was judged to be the best geo-referencing method for practical
      purposes. In contrast, the various systems of geo-coding using the farm postal
      address performed relatively poorly. Where there are separate parcels of land
      managed together in a single parish, they may be identified as a single unit, but
      if there are separate parcels in different parishes they should be identified as
      separate units.The implications of these results for Great Britain's national
      animal health information system (VETNET) are discussed.

PMID- 12419600
TI  - Use of spatial statistics and monitoring data to identify clustering of bovine
      tuberculosis in Argentina.
AB  - The spatial distribution of endemic bovine tuberculosis (TB) in Argentine cattle
      herds was described using recorded information on the detection of TB-like
      lesions in cattle slaughtered between March 1995 and 1997 at 126 slaughterhouses
      with federal inspection. Approximately, 47% (9472396 cattle) of the estimated
      total number of cattle slaughtered in Argentina during this period was included
      in the study. Information on the number of cattle per source herd consigned to
      slaughter, number of cattle with TB-like lesions per herd and the geographical
      location of counties from which cattle originated was used to investigate spatial
      clustering of TB. Overall, no evidence of clustering of TB prevalence by county
      was detected (Moran's autocorrelation statistic I=0.009, P=0.089). However, first
      (Cuzick and Edwards' test statistic, T(k)=87, P=0.036) and second-order
      (T(k)=170, P=0.038) nearest-neighbor case-counties (TB prevalence>median
      prevalence of all counties, 6.7%) were clustered. Using the spatial scan test
      based on a Bernoulli model, the most-likely cluster (P=0.001) identified during
      the study period included 5793 cases of TB (5.2 per 1000 km(2)) in five counties.
      This cluster coincided with Santa Fe Province, which contains 21% of all dairy
      cows in Argentina and accounts for 34% of the country's milk production. Several
      secondary clusters of TB-also located in dairy districts-were identified. Study
      results demonstrate that bovine TB is clustered in Argentina, and these clusters
      coincide with dairy cattle production. Identification of clustering can assist
      efforts to eradicate bovine TB from Argentina. Further spatial investigations
      need to focus on the reasons why TB is clustered in Argentina. In particular, the
      relationship between TB clustering and management practices-such as grazing
      density and production systems-need to be described to assist in the development
      of disease-control programs. The use of spatial statistics and geographical
      information systems could meet these needs.

PMID- 12419601
TI  - A Bayesian model for spatial wildlife disease prevalence data.
AB  - The analysis of the geographical distribution of disease on the scale of
      geographic areas such as administrative boundaries plays an important role in
      veterinary epidemiology. Prevalence estimates of wildlife population surveys are
      often based on regional count data generated by sampling animals shot by hunters.
      The observed disease rate per spatial unit is not an useful estimate of the
      underlying disease prevalence due to different sample sizes and spatial
      dependencies between neighbouring areas. Therefore, it is necessary to account
      for extra-sample variation and spatial correlations in the data to produce more
      accurate maps of disease incidence. The detection of spatial patterns is
      complicated by missing data in many of the geographical areas as the complete
      coverage of all areas is nearly impossible in wildlife surveys. For this purpose
      a hierarchical Bayesian model in which structured and unstructured over
      dispersion is modelled explicitly in terms of spatial and non-spatial components
      was implemented by Markov chain Monte Carlo methods. The model was empirically
      compared with the results of a non-spatial beta-binomial model using surveillance
      data of pseudorabies virus infections of European wild boars (Sus scrofa scrofa
      L.) in the Federal State of Brandenburg, Germany.

PMID- 12419602
TI  - Estimating the incubation period of raccoon rabies: a time-space clustering
      approach.
AB  - We used a time-space clustering approach to estimate the incubation period of
      raccoon rabies in the wild using data from the 1999-2001 invasion of raccoon
      rabies into eastern Ontario from northern New York State. The time differences
      and geographical distances between all possible pairs of rabies cases were
      computed, classified and assembled into a time-space matrix. The rows of that
      matrix represented differences in cases in weeks and the columns represent
      distances between cases in kilometers and the values in the cells of the matrix
      represent the counts of cases at specific time and distance intervals. There was
      a significant cluster of pairs 5 weeks apart with apparent harmonics at
      additional 5-week intervals. These results are explained by assuming the
      incubation period of raccoon rabies had a mode of 5 weeks. The time clusters
      appeared consistently at distance intervals of 5 km. We discuss the possibility
      that the spatial intervals were influenced by the 5 km radius of the point
      infection control depopulation process used in 1999 and the 10-15 km radial areas
      used in 2000. With the practical limits of those radii, there was an intensive
      effort to eliminate raccoons. Our procedure is easy to implement and provides an
      estimate of the shape of the distribution of incubation periods for raccoon
      rabies.

PMID- 12419603
TI  - The use of animal infection models to study the pathogenesis of melioidosis and
      glanders.
AB  - The use of animal infection models is central to the study of microbial
      pathogenesis. In combination with genetic, immunological and antigen purification
      techniques, much can be learned regarding the pathogenesis of diseases caused by
      microorganisms. This update focuses on the recent use of animal infection models
      to study the pathogenesis of melioidosis and glanders.

PMID- 12419605
TI  - Versatile persistence pathways for pathogens of animals and plants.
AB  - The glyoxylate cycle and the glycine cleavage system are part of conserved
      metabolic pathways involved in the chronic persistence of microorganisms in
      animal hosts. In the chromosome of the plant pathogen Rhodococcus fascians, the
      vic locus has been identified as a region containing genes essential for
      persistence inside induced leafy galls. Sequence analysis showed that this 18-kb
      locus is syntenic with chromosomal regions of Mycobacterium species that
      encompass the 'persistence' loci of these mammalian pathogens. Hence, the ability
      to switch diet inside the host appears to be governed by 'persistence' enzymes
      that are conserved between pathogens of animals and plants.

PMID- 12419606
TI  - Microbial genomics: spot the difference. . .

PMID- 12419611
TI  - Bacterial growth in the cytosol: lessons from Listeria.

PMID- 12419613
TI  - Manganese: elemental defence for a life with oxygen.
AB  - The presence of enzymes such as catalase, peroxidase and superoxide dismutase
      (SOD) obviates the problems associated with life in an aerobic environment by
      eliminating the harmful reactive oxygen species (ROS) that arise from
      respiration. Enzymic detoxification of ROS might not, however, be the only
      mechanism at work in bacteria. The accumulation of manganese (Mn), an abundant
      element in many environments, via several, recently identified transporters is
      thought to form the basis for an alternative, catalytic detoxification of ROS. An
      increasing body of evidence from work on the genetics and biochemistry of Mn
      accumulation and its cellular roles reveals that this overlooked defence
      mechanism is likely to be widespread among bacteria and might also contribute to
      virulence.

PMID- 12419614
TI  - A novel class of self-sufficient cytochrome P450 monooxygenases in prokaryotes.
AB  - The Bacillus cytochrome P450 BM3 integrates an entire P450 system in one
      polypeptide and represents a convenient prokaryotic model for microsomal P450s.
      This self-sufficient class II P450 is also present in actinomycetes and fungi. By
      genome analysis we have identified additional homologues in the pathogenic
      species Bacillus anthracis and Bacillus cereus, and in Ralstonia metallidurans.
      This analysis also revealed a novel class of putative self-sufficient P450s, P450
      PFOR, comprising a class I P450 that is related to Rhodococcus erythropolis
      CYP116, and a phthalate family oxygenase reductase (PFOR) module. P450 PFOR genes
      are found in a Rhodococcus strain, three pathogenic Burkholderia species and in
      the R. metallidurans strain that possesses a P450 BM3 homologue. Co-evolution of
      P450 and reductase domains is apparent in both types of self-sufficient enzymes.
      The new class of P450 enzymes is of potential interest for various
      biotechnological applications.

PMID- 12419615
TI  - Fungi, dendritic cells and receptors: a host perspective of fungal virulence.
AB  - An association between morphogenesis and virulence has long been presumed for
      dimorphic fungi that are pathogenic to humans, as one morphotype exists in the
      environment or during commensalism, and another within the host during the
      disease process. For Candida albicans, putative virulence factors include the
      ability to switch between saprophytic yeast and pathogenic, filamentous forms of
      the fungus. Dendritic cells sense either form in a specific way, resulting in
      distinct, T-helper-cell-dependent protective and non-protective immunities.
      Recent evidence suggests that the use of distinct recognition receptors
      contributes to the disparate patterns of reactivity observed locally in response
      to challenge with C. albicans. These findings offer new interpretive clues to the
      mechanisms of fungal virulence: rather than dimorphism per se, the engagement of
      different recognition receptors on dendritic cells might select the mode of
      fungal internalization and antigen presentation, condition the nature of the T
      helper response and, ultimately, favor saprophytism or infection.

PMID- 12419616
TI  - The fundamental contribution of phages to GAS evolution, genome diversification
      and strain emergence.
AB  - The human bacterial pathogen group A Streptococcus (GAS) causes many different
      diseases including pharyngitis, tonsillitis, impetigo, scarlet fever,
      streptococcal toxic shock syndrome, necrotizing fasciitis and myositis, and the
      post-infection sequelae glomerulonephritis and rheumatic fever. The frequency and
      severity of GAS infections increased in the 1980s and 1990s, but the cause of
      this increase is unknown. Recently, genome sequencing of serotype M1, M3 and M18
      strains revealed many new proven or putative virulence factors that are encoded
      by phages or phage-like elements. Importantly, these genetic elements account for
      an unexpectedly large proportion of the difference in gene content between the
      three strains. These new genome-sequencing studies have provided evidence that
      temporally and geographically distinct epidemics, and the complex array of GAS
      clinical presentations, might be related in part to the acquisition or evolution
      of phage-encoded virulence factors. We anticipate that new phage-encoded
      virulence factors will be identified by sequencing the genomes of additional GAS
      strains, including organisms non-randomly associated with particular clinical
      syndromes.

PMID- 12419617
TI  - Common themes among bacteriophage-encoded virulence factors and diversity among
      the bacteriophages involved.
AB  - There are common themes among bacteriophage-encoded virulence factors, which
      include the well-characterized bacterial toxins and proteins that alter
      antigenicity as well as several new classes of bacteriophage-encoded proteins
      such as superantigens, effectors translocated by a type III secretion system, and
      proteins required for intracellular survival and host cell attachment. These
      virulence factors are encoded by a diversity of bacteriophages, members of the
      viral families Siphoviridae, Podoviridae, Myoviridae and Inoviridae, with some
      bacteriophages having characteristics of more than one virus family. The location
      of virulence genes within the bacteriophage genomes is non-random and consistent
      with an origin via imprecise prophage excision or as either transferable
      cassettes or integral components of the bacteriophage genome.

PMID- 12419619
TI  - Bone formation after 4 weeks around blood-plasma-modified titanium implants with
      varying surface topographies: an in vivo study.
AB  - The aim of the present study was to investigate and compare the stability and
      bone ingrowth capacity to screw-shaped titanium implants with five different
      surface treatments. The implants were: (1) standard turned with a thin blood
      plasma coat (TP), (2) NaOH-etched dito with pore size 0.2-0.3 microm (E), (3)
      NaOH-etched with pore size 0.2-0.3 microm and a thin blood plasma coat (EP), (4)
      electrochemically oxidised with pore size 1-2 microm (O), (5) electrochemically
      oxidised with pore size 1-2 microm and a thin blood plasma coat (OP). A total of
      66 implants were divided into the above-described five groups and inserted for 4
      weeks into tibia and femur of 11 rabbits. The implants were evaluated by
      resonance frequency (RF) measurements at the time of insertion and removal, and
      analysed histomorphometrically at removal. The RF measurements showed that the
      implant stability was lower in soft bone compared to dense and increased with
      time. No significant differences were observed between the different surface
      modifications. The histomorphometric analysis revealed no statistically
      significant differences between the implants regarding bone-to-metal contact
      (BMC) and bone area inside the threads (BA). The above results indicate that thin
      blood plasma-coated and non-coated screw-shaped titanium implants with turned,
      NaOH-etched and electrochemically etched surface profiles integrate similarly to
      bone at 1 month of implantation.

PMID- 12419620
TI  - Tissue response to polyanionic collagen: elastin matrices implanted in rat
      calvaria.
AB  - The tissue response to polyanionic collagen matrices, prepared from bovine
      pericardium and implanted subperiosteally in rat calvaria, was studied. The
      materials were implanted in 72 male rats (Rattus norvegicus, albinus, Holtzman),
      randomly divided into four groups: GI-MBP hydrolyzed for 24 h; GII-MBP hydrolyzed
      for 36 h; GIII-MBP hydrolyzed for 48 h; GIV-native MBP. The materials were
      explanted after 15, 30 and 60 days and analyzed by routine histological
      procedures. Except for group IV (native bovine pericardium), polyanionic collagen
      from groups GI, GII and GIII showed low inflammatory reaction associated with
      bone formation, partially or completely integrated to the cranial bone; group GIV
      was characterized by an intense inflammatory reaction with occasional dystrophic
      mineralization and with occasional bone formation at 60 days when there was a
      decrease in the inflammatory reaction. Thus, the MBP from groups I, II and III
      were biologically compatible, enhancing bone formation with a slight delay at 60
      days in GII.

PMID- 12419621
TI  - Electrochemical characterization of cast titanium alloys.
AB  - A reaction layer forms on cast titanium alloy surfaces due to the reaction of the
      molten metal with the investment. This surface layer may affect the corrosion of
      the alloy in the oral environment. The objective of this study was to
      characterize the in vitro corrosion behavior of cast titanium alloys. ASTM Grade
      2 CP titanium, Ti-6Al-4V, Ti-6Al-7Nb and Ti-13Nb-13Zr alloys were cast into a MgO
      based investment. Experiments were performed on castings (N=4) with three surface
      conditions: (A) as-cast surface after sandblasting, (B) polished surface after
      removal of the reaction layer, and (C) sandblasted surface after removal of the
      reaction layer. Open-circuit potential (OCP) measurement, linear polarization,
      and potentiodynamic cathodic polarization were performed in aerated (air+10%
      CO(2)) modified Tani-Zucchi synthetic saliva at 37 degrees C. Potentiodynamic
      anodic polarization was subsequently conducted in the same medium deaerated with
      N(2)+10% CO(2) gas 2 h before and during the experiment. Polarization resistance
      (R(P)) and corrosion rate (I(CORR)) were calculated. Numerical results were
      subjected to nonparametric statistical analysis at alpha=0.05. The OCP stabilized
      for all the specimens after 6 x 10(4)s. Apparent differences in anodic
      polarization were observed among the different surfaces for all the metals. A
      passivation region followed by breakdown and repassivation were seen on specimens
      with surfaces A and C. An extensive passive region was observed on all the metals
      with surface B. The Kruskal-Wallis test showed no significant differences in OCP,
      R(p), I(CORR) or break down potential for each of the three surfaces among all
      the metals. The Mann-Whitney test showed significantly lower R(P) and higher
      I(CORR) values for surface C compared to the other surfaces. Results indicate
      that the surface condition has more effect on corrosion of these alloys than the
      surface reaction layer. Within the oxidation potential range of the oral cavity,
      all the metal/surface combinations examined showed excellent corrosion
      resistance.

PMID- 12419622
TI  - Transition element contained partial-stabilized cement (PSC) as a dental
      retrograde-filling material.
AB  - A modified silicate cement has previously been developed as a dental retrograde
      filling; it has great sealing ability, good biocompatibility, and anti-bacterial
      properties. However, its clinical application is limited by a long setting time
      and poor handling property. In the present study, the setting time has been
      shortened by raising the preparation temperature of the cement and adding
      transition elements into the partial-stabilized cement (PSC) to increase the rate
      of hydration reaction of the cement. The rate of the hydration was evaluated by
      micro-hardness measurement. Phase transformation and micro-structure were
      examined by an X-ray diffractometer and a scanning electron microscope,
      respectively.When the preparation temperature increased (1400 degrees C), the
      phase content of Ca(2)SiO(5)(C(2)S) and Ca(3)SiO(6)(C(3)S) increased but the CaO
      decreased. The setting time was shortened and the micro-hardness increased
      because the increased amplitude of vibration of the atoms about their equilibrium
      resting positions increased by increasing the heating temperature. When the
      transition elements were added to PSC, crystal defects were effectively created
      and monoclinic structure of C(3)S was favored to form, which would increase the
      hydrated reaction of PSC and shorten the setting time. Co addition is the most
      effective due to its ability to create more defects and stabilize the monoclinic
      structure. The micro-hardness of the PSC with Co 5 wt% addition was about 66 in
      the Vickers scale. It also exhibited an early setting within 20 min. We believe
      that the modified PSC will have a great potential in its application to
      perforation repair and retrograde filling in endodontic surgery.

PMID- 12419623
TI  - Effect of choice of surgical gloves on dough time measurements of acrylic bone
      cement.
AB  - In this study we investigated the effect of the brand of surgical gloves on the
      dough time determination for acrylic bone cements. Four different brands of
      powder-free latex surgical gloves were tested. Two commercial bone cements,
      Surgical Simplex P and Palacos R, were used for dough time measurement following
      standard test methods for acrylic bone cements (ASTM F-451 and ISO 5833). The
      results show that the measured dough time depended largely on the brand of gloves
      used, and could vary by nearly 250%. The surface morphological structures of
      gloves, determined by SEM, probably contribute to the differences in the measured
      dough time. This study provides experimental evidence that supports the need to
      describe the type of gloves used, in detail, when dough time is reported. It also
      illustrates the importance of the glove brand, when bone cement is to be handled
      as a dough in the clinical setting.

PMID- 12419624
TI  - The relationship between porosity and fatigue characteristics of bone cements.
AB  - In this study, the fatigue strengths of acrylic cement prepared by various
      commercially available reduced pressure mixing systems were compared with the
      fatigue strength of cement mixed by hand (control) under atmospheric conditions.
      The following observations were made from this investigation. The mean fatigue
      strength of reduced pressure mixed acrylic bone cement is double that of cement
      mixed by hand using an open bowl, 11,354+/-6,441 cycles to failure for reduced
      pressure mixing in comparison with 5,938+/-3,199 cycles for mixing under
      atmospheric conditions. However, the variability in mean fatigue strengths of
      reduced pressure mixed bone cement is greater for some mixing devices. The
      variation in fatigue strengths for the different mixing techniques is explained
      by the different porosity distributions. The design of the reduced pressure
      mixing system and the technique employed during mixing strongly contribute to the
      porosity distribution within the acrylic bone cement. The level of reduced
      pressure applied during cement mixing has an effect on the fatigue strength of
      bone cement, but the mixing mechanism is significantly more influential.

PMID- 12419625
TI  - Immuno-inflammatory tissue reaction to stainless-steel and titanium plates used
      for internal fixation of long bones.
AB  - The immuno-inflammatory responses to stainless-steel (21 implants in 20 patients)
      and titanium plates (22 implants in 20 patients) used in the treatment of long
      bone fractures were studied immunohistochemically. All fractures healed without
      complications. In the soft tissue adjacent to the surface of the implants a dark
      discolouration of the tissue was visible in 18/21 stainless-steel and 20/22
      titanium plates. Tissue specimens of all patients contained positive staining for
      macrophages (CD68-positive cells). Serial sections showed that the majority of
      cells were found to express the HLA-DR molecule indicating their activation. Many
      of the macrophages were surrounded by clusters of T-lymphocytes (CD3-positive
      cells). 17 out of 21 steel specimens and 15 out of 22 titanium specimens showed
      the infiltration of moderate amounts of cytotoxic T-lymphocytes (CD8-positive
      cells). Moderate amounts of B-lymphocytes (CD79alpha positive cells) were evident
      in four patients with steel and six patients with titanium implants. The results
      of the present study clearly demonstrate the presence of a marked inflammation
      and tissue reaction in the soft tissue covering stainless-steel and titanium
      plates used for internal fixation of fractures of long bones independently from
      the material used.

PMID- 12419626
TI  - Compactibility study of calcium phosphate biomaterials.
AB  - This study investigated the micromechanism responsible for the densification and
      consolidation of powders during dynamic compaction, an experimental process in
      which ceramic is formed without heating. Three calcium-deficient apatites (CDA:
      two powders and a fibrous compound) and a biphasic calcium phosphate (BCP) were
      studied to determine their aptitude (rheological and physical properties) for
      compactibility under various dynamic compaction pressures. Powders were
      investigated for their physicochemistry, particle size, and flow time, and
      compacts for their compaction rate, density, specific area, mechanical
      characteristics, and disintegration time. Powder particles showed different
      morphological features depending on the synthesis protocol used, specific area
      and rheological behaviour. Compacts were not obtained with BCP, regardless of the
      gas pressure used, whereas CDA produced compacts with good mechanical properties
      (high hardness and compression stress), particularly for the fibrous compound.
      The poor compressibility and compactibility of BCP powders were confirmed,
      whereas fibrous CDA powders showed good compactibility conducive to high-quality
      filling of biomaterials.

PMID- 12419627
TI  - Corrosion behaviour of commercially pure titanium shot blasted with different
      materials and sizes of shot particles for dental implant applications.
AB  - It is well known that the osseointegration of the commercially pure titanium
      (c.p. Ti) dental implant is improved when the metal is shot blasted in order to
      increase its surface roughness. This roughness is colonised by bone, which
      improves implant fixation. However, shot blasting also changes the chemical
      composition of the implant surface because some shot particles remain adhered on
      the metal. The c.p. Ti surfaces shot blasted with different materials and sizes
      of shot particles were tested in order to determine their topographical features
      (surface roughness, real surface area and the percentage of surface covered by
      the adhered shot particles) and electrochemical behaviour (open circuit
      potential, electrochemical impedance spectroscopy and cyclic polarisation). The
      results demonstrate that the increased surface area of the material because of
      the increasing surface roughness is not the only cause for differences found in
      the electrochemical behaviour and corrosion resistance of the blasted c.p. Ti.
      Among other possible causes, those differences may be attributed to the
      compressive residual surface stresses induced by shot blasting. All the materials
      tested have an adequate corrosion and electrochemical behaviour in terms of its
      possible use as dental implant material.

PMID- 12419628
TI  - Effect of fluoride and albumin concentration on the corrosion behavior of Ti-6Al
      4V alloy.
AB  - The purpose of this study was to investigate the effect of fluoride and albumin
      concentration on the corrosion behavior of Ti-6Al-4V alloy in acid artificial
      saliva (pH 5/37 degrees C) using potentiodynamic polarization and linear
      polarization test. Chemical analyses of the surface passive film were
      characterized using X-ray photoelectron spectroscopy. The results showed that
      either the NaF (0-0.5%) or the presence of albumin (0-0.2%) in 0.1% NaF
      containing media had a significant influence on the corrosion potential
      (E(corr)), corrosion rate (I(corr)), passive current density (I(pass)), and
      polarization resistance (R(p)) (p<0.01). The I(corr) and I(pass) values increased
      on increasing the NaF concentration, but decreased with the presence of albumin
      in NaF-containing media. The R(p) value decreased on increasing the NaF
      concentration, but increased with the presence of albumin in NaF-containing
      media. When the NaF concentration was higher than 0.1%, the protectiveness of
      TiO(2) passive film formed on Ti-6Al-4V alloy was destroyed by fluoride ions,
      leading to the formation of Na(2)TiF(6). The presence of albumin, regardless of
      the concentration, in 0.1% NaF-containing acid media improved the corrosion
      resistance of Ti-6Al-4V alloy.

PMID- 12419629
TI  - Bioactive calcium phosphate invert glass-ceramic coating on beta-type Ti-29Nb
      13Ta-4.6Zr alloy.
AB  - A fine, strong coating consisting of a bioactive calcium phosphate invert glass
      ceramic can be prepared easily by reaction of the glassy phase with an oxide
      layer formed on a new beta-type titanium alloy, Ti-29Nb-13Ta-4.6Zr, when the
      metal, on which the mother glass powders with a composition of 60CaO-30P(2)O(5)
      7Na(2)O-3TiO(2) in mol% are placed, is heated at 800 degrees C in air. A
      compositionally gradient layer is developed on the titanium alloy during the
      heating. Tensile bonding strength of the coating to the metal is significantly
      higher than those of the coatings to conventional metals such as Ti-6Al-4V alloy
      or pure titanium. The oxidized layer on Ti-29Nb-13Ta-4.6Zr alloy is relatively
      thinner than that on Ti-6Al-4V alloy even with heat treatment in air; large
      tensile stresses are not generated in the layer.

PMID- 12419630
TI  - Isothermal microcalorimetry: an analytical technique for assessing the dynamic
      chemical stability of UHMWPE.
AB  - In this work, isothermal microcalorimetry (IMC) was utilized to measure the
      exothermic heat flow from specimens of ultra-high-molecular-weight polyethylene
      (UHMWPE), that had been sterilized by various standard methods, under simulated
      shelf storage (air at 25 degrees C, 30% r.h.) and simulated implantation
      (phosphate buffered saline, PBS, at 37 degrees C) conditions. Gamma-radiation
      sterilized UHMWPE yielded initial heat flow rates approximately 7-10 times higher
      in simulated shelf storage and 2-3 times higher in simulated implantation (even
      after 1 month in PBS) than specimens which were unsterilized or sterilized using
      either ethylene oxide gas (ETO) or gas plasma (GP). These results show that gamma
      sterilization of UHMWPE produces many more unstable bonds in the polymer than is
      the case when ETO or GP is used, and that the net exothermic physico-chemical
      change proceeds steadily in a diffusion-limited manner in air or saline. In
      addition, gamma sterilization in nitrogen rather than in air did not prevent the
      creation of unstable bonds, but did defer physico-chemical change until the
      UHMWPE was exposed to oxygen. These results demonstrate the usefulness of IMC as
      a viable method for studying the stability of polymeric implant materials.

PMID- 12419631
TI  - In vitro calcium phosphate growth over surface modified PMMA film.
AB  - In vitro nucleation of calcium phosphate phase was studied over functionalized
      polymethyl methacrylate (PMMA) films using Fourier transform infrared
      spectroscopy, electron spectroscopy, scanning electron microscopy and energy
      dispersive X-ray analysis. PMMA films were prepared by dissolving commercial
      grade pellets in chloroform and cast into thin sheets. The films were immersed in
      a methanol solution of sodium hydroxide before treating with 1.5% solution of
      adenosine triphosphate (ATP) at a pH of 5.2 for 24 h. ATP treated films were then
      soaked in saturated lime solution for 4 days to initiate formation of calcium
      phosphate precursor phase over their surface. The above films immersed in
      simulated body fluid solution (1.5 x SBF) for more than 5 days led to the
      nucleation of apatitic calcium phosphate phase all over the film surface. The ATP
      coupled film not subjected to lime treatment did not show calcium phosphate
      nucleation behaviour upon immersion in SBF solution. The Ca/P ratio of the
      calcium phosphate phase increase with increase in soaking time in SBF solution.

PMID- 12419632
TI  - Long-term biocompatibility, chemistry, and function of microencapsulated
      pancreatic islets.
AB  - Transplantation of encapsulated living cells is a promising approach for the
      treatment of a wide variety of diseases. Large-scale application of the
      technique, however, is hampered by insufficient biocompatibility of the capsules.
      In the present study, we have implemented new as well as previously reported
      technologies to test biocompatibility issues of immunoisolating microcapsules on
      the long term (i.e. 2 years) instead of usually reported short time periods. When
      transplanted empty, the capsules proved to be highly biocompatible not only for
      short periods (i.e. 1 month) but also on the long term as evidenced by the
      absence of any significant biological response up to 2 years after implantation
      in rats. The immunoprotective properties of the capsules were confirmed by
      prolonged survival of encapsulated islet allografts up to 200 days. The surface
      of the applied capsule was analyzed and provides new insight in the chemical
      structure of true biocompatible and immunoprotective capsules applicable for
      transplantation of encapsulated islets in type I diabetes.

PMID- 12419633
TI  - Study on the effect of polybutyl-2-cyanoacrylate nanoparticles and their
      metabolites on the phagocytic activity of peritoneal exudate cells of mice.
AB  - The phagocytic activity of peritoneal exudate cells (PECs) harvested from
      peritoneal cavity of mice after a single intraperitoneal (i.p.) treatment with
      poly(butylcyanoacrylate) nanoparticles (PBCN) and their probable metabolites
      [poly(cyanoacrylic acid) (PCAA) and n-butanol] was investigated in an in vitro
      phagocytic assay. Polymer suspension of PBCN was given as a single i.p. injection
      at doses of 200 and 10 mgkg(-1), 3, 18, 72 and 120 h before the performance of
      the phagocytic assay. PCAA and n-butanol were given at the same manner at doses
      of 126.8 and 96.8 mgkg(-1), respectively (equivalent to a dose of 200 mgkg(-1) of
      intact PBCN after enzyme hydrolysis) 3, 18 and 120 h before the test performance.
      The phagocytic assay was performed in vitro in tubes with sheep red blood cells
      (SRBC). Phagocytic index (percentage of PECs ingested more than 3 sheep
      erythrocytes), phagocytic number, and ingestion capacity (number of erythrocytes
      ingested per cell) were the parameters used for evaluation of the phagocytic
      activity. The alterations of phagocytic activity of the PECs observed were
      strongly time- and dose-dependent. Administration of all tested compounds shortly
      before the test performance resulted in a considerable decrease in the capability
      of PECs to ingest SRBC. The alterations of phagocytic activity decreased when the
      time between the treatment of mice and the phagocytic assay is on the increase.
      The dose of 200 mgkg(-1) of PBCN administered 120 h before the phagocytic assay
      led to the significant increase of the phagocytic index of PECs. The phagocytic
      function of assayed PECs was temporary impeded and 5 days were completely enough
      for their restoration.

PMID- 12419634
TI  - Fibrinolysis inhibitors adversely affect remodeling of tissues sealed with fibrin
      glue.
AB  - Experiments have been carried out to determine if aprotinin and epsilon -amino
      caproic acid increases the quality of Fibrin glue. A rat model was used for
      tissues such as liver and skin while rabbits were used for application of glue in
      dura mater. Apposition of all the tissues, glued with fibrin was found to be good
      and remnants of the polymerized fibrin were seen even on the seventh day of
      application, though inhibitors were not incorporated with the glue. In skin,
      excessive amounts of fibrin remained as a result of addition of aprotinin and
      epsilon -amino caproic acid, as compared to the glue applied without any
      inhibitor. After dural sealing, the wound repair and new bone formation at
      craniotomy site progressed well in the fibrin glue applied area as compared to
      the commercially available glue that contained aprotinin. The adhesive strength
      of the glue without or with fibrinolysis inhibitors was found to be similar,
      after 1h grafts on rat back. The observations from this study suggests that the
      use of aprotinin with fibrin glue may not be required because, even liver tissue
      that is known to have high fibrinolytic activity was sealed and repaired well in
      the absence of plasminogen inhibitors. On the other hand, it was found that if
      inhibitors were added, nondegraded matrix remained in the tissue even after 15
      days and affected migration of repair cells. Thus, the inhibition of fibrinolysis
      after fibrin glue application is found detrimental to wound healing.

PMID- 12419635
TI  - Removal of dihydroxy-terminated components from monomethoxy-terminated
      poly(ethylene glycol).
AB  - A preparative method to remove dihydroxy-terminated components in a sample of
      presumably monomethoxy, monohydroxy-terminated poly(ethylene glycol) (PEG) is
      presented. Purification of the monomethoxy-terminated component allows one to
      prepare a diblock copolymer of PEG and poly(lactic acid) (PLLA) free of a PLLA
      PEG-PLLA triblock copolymer in various biomedical applications of the copolymer.
      Efficiency of the purification is compared for high osmotic pressure
      chromatography (HOPC) and preparative size exclusion chromatography (SEC). In
      HOPC, various types of porous silica particles, surfaces, solvents, polymer
      concentrations have been screened for the optimal performance. It was found that
      HOPC is more efficient than SEC, especially HOPC of 30-40 wt% solutions in water
      by a column packed with acid-washed controlled pore glass is optimal in producing
      high-purity fractions.

PMID- 12419636
TI  - Prosthetic particles modify the expression of bone-related proteins by human
      osteoblastic cells in vitro.
AB  - Loss of bone near joint prostheses is thought to be caused by activation of
      recruited osteoclasts by osteolytic mediators induced by wear particles. It is
      proposed that particles inhibit osteogenesis during bone remodelling causing a
      reduction in the levels of peri-implant bone. This study explores whether
      prosthetic particles modulate bone formation by affecting osteoblastic bone
      related mRNAs (alkaline phosphatase, pro-collagen Ialpha1, osteopontin,
      osteonectin, osteocalcin, bone sialoprotein and thrombospondin) or their
      translated proteins using titanium alloy, commercially pure titanium, and cobalt
      chrome particles. The direct effect of the particles revealed no change to the
      expression of the bone-related mRNAs in human bone-derived cells (HBDC) at the
      time points investigated; although non-collagenous translated proteins expressed
      by these HBDC were significantly effected (p<0.05). Different patterns of
      expression for bone-related proteins were induced by the different particles both
      directly and indirectly. Inflammatory mediators (interleukin-1beta, tumor
      necrosis factor alpha, interleukin-6, and prostaglandin E2) had similar effects
      on HBDC to the media obtained from monocytes incubated with particles. This study
      shows that prosthetic wear particles can significantly modify the expression of
      bone-related proteins by osteogenic cells in vitro. These alterations in
      osteogenic activity at the interface of the implant and bone may be an important
      factor in the failure of many orthopaedic implants.

PMID- 12419637
TI  - Effect of hydrothermally treated anodic oxide films on osteoblast attachment and
      proliferation.
AB  - In this study, the effect of anodization following hydrothermal treatments on
      osteoblast cell attachment and proliferation were evaluated. The anodic oxide
      films produced in this study was observed to exhibit overlapping microporous
      structures with microprojections. In addition, the anodic oxide surfaces were
      significantly rougher in comparison to control untreated titanium (Ti) surfaces.
      Following hydrothermal treatments for 2 and 4 h, hydroxyapatite (HA) crystals
      were observed on anodic surfaces. Using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl
      tetrazolium bromide (MTT) assay, no significant difference in the
      biocompatibility of the treated and untreated Ti surfaces was observed. However,
      scanning electron micrographs indicated rounded osteoblast cells on control and
      anodized Ti surfaces, with numerous microvilli after 6 h. In contract, cells
      cultured on hydrothermally treated surfaces after 6 h incubation were observed to
      exhibit polygonal shape, flattened, and fully spread. In addition, more cells
      were observed on Ti surfaces that were hydrothermally treated for 4 h as compared
      to Ti surfaces that were hydrothermally treated for 2 h. After culturing the
      cells for 24 h and 4 days, no significant difference was observed for cells
      cultured on all surfaces. It was concluded from this study that hydrothermally
      treated surfaces exhibited an effect on early osteoblast attachment.

PMID- 12419638
TI  - Enzymatic degradation behavior of porous silk fibroin sheets.
AB  - We investigated the degradation behavior of porous silk fibroin sheets by in
      vitro enzymatic experiments with alpha-chymotrypsin, collagenase IA, and protease
      XIV. With 1.0 U/ml protease XIV, 70% of a silk fibroin sheet was degraded within
      15 days at 37 degrees C. When the fibroin sheet was exposed to collagenase IA,
      the amount of Silk II crystalline structure in the sheets decreased slightly, and
      a small amount of Silk I crystalline structure was formed. When protease XIV was
      used, almost all Silk II disappeared, but the crystallinity increased overall
      because the amount of Silk I increased. During digestion with protease XIV, the
      pore size of the fibroin sheets increased with increasing degradation time, until
      the sheets finally collapsed and became totally shapeless. The average molecular
      weight of the products after degradation with the three enzymes followed the
      order protease XIV < collagenase IA < alpha-chymotrypsin. More than 50% of the
      products resulting from degradation with protease XIV were free amino acids.

PMID- 12419639
TI  - Infusing arginine vasopressin: raising red flags versus the effects of the
      underlying physiology.

PMID- 12419640
TI  - Effect of conivaptan, a combined vasopressin V(1a) and V(2) receptor antagonist,
      on vasopressin-induced cardiac and haemodynamic changes in anaesthetised dogs.
AB  - The neurohormonal factor arginine vasopressin (AVP) produces potent systemic
      vasoconstriction as well as water retention in the kidneys via the V(1a) and V(2)
      receptors, respectively. Therefore, AVP may be considered as an aggravating
      factor of cardiac failure. In the present study, the effects of intravenous
      (i.v.) infusion of AVP on cardiovascular parameters and the effect of conivaptan
      (YM087, 4'-(2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzoazepine-6-carbonyl)
      2-phenylbenzanilide monohydrochloride), a vasopressin V(1a)/V(2) receptor
      antagonist, on AVP-induced cardiac and haemodynamic changes were investigated in
      pentobarbitone-anaesthetised dogs. The i.v. infusion of AVP (0.12-4mUkg(-1)min(
      1)) dose-dependently produced decreases in the cardiac contractility indicator LV
      dP/dt(max) and cardiac output (CO) and increases in left ventricular end
      diastolic pressure (LVEDP) and total peripheral resistance (TPR). These changes
      accurately mimic the cardiovascular symptoms of congestive heart failure. The
      i.v. bolus injection of conivaptan (0.1mgkg(-1)) rapidly attenuated the AVP
      (4mUkg(-1)min(-1))-induced decrease in CO and reversed the AVP-induced elevation
      in both LVEDP and TPR. In conclusion, i.v. infusion of AVP produced cardiac
      dysfunction and vasoconstriction in pentobarbitone-anaesthetised dogs. Conivaptan
      demonstrated the ability to dramatically improve the impaired cardiovascular
      parameters induced by AVP. The results suggest the potential usefulness of
      conivaptan in treating congestive heart failure.

PMID- 12419641
TI  - Upregulation of vascular renin-angiotensin and endothelin systems in rats
      inhibited of nitric oxide synthesis.
AB  - The present study was aimed at investigating whether the regulation of vascular
      renin-angiotensin and endothelin (ET) systems is altered by a chronic blockade of
      nitric oxide (NO) synthesis. Male Sprague-Dawley rats were supplemented with N(G)
      nitro-L-arginine methyl ester (L-NAME, 100mgl(-1)) in drinking water for 4 weeks
      to inhibit the endogenous synthesis of NO. The mRNA expressions of renin,
      angiotensin converting enzyme (ACE), type-1 angiotensin II receptor (AT1R), ET-1,
      type-A ET receptor (ET(A)), and neutral endopeptidase (NEP) were determined in
      the thoracic aorta by reverse transcription-polymerase chain reaction. The
      treatment with L-NAME significantly increased the blood pressure, while it
      decreased the tissue levels of nitrite/nitrate. The mRNA expression of renin,
      ACE, and AT1R was increased in the aorta. The protein expression of AT1R assessed
      by Western blot analysis was also increased. The expression of ET-1 and ET(A)
      mRNA was increased, whereas that of NEP mRNA decreased. The increased expression
      of renin-angiotensin and ET system genes and the decreased expression of NEP may
      in part be causally related with the development of hypertension induced by a
      chronic blockade of NO synthesis.

PMID- 12419642
TI  - New insights into the pharmacological properties of potent antiplatelet 2-amino
      benzo[d]isothiazol-3-one derivatives.
AB  - A series of 2-amino-benzo[d]isothiazol-3-one derivatives (1-8), previously
      described as in vitro potent antiaggregatory agents endowed with spasmolytic
      properties, was evaluated for in vitro antiplatelet activity in guinea-pig
      platelet rich plasma and for in vivo effects on experimental thrombosis and
      bleeding time in mice. All the 2-amino-benzo[d]isothiazol-3-one derivatives 1-8
      were more potent antiplatelets against collagen than acetylsalicylic acid and,
      unlike this drug, strongly inhibited thromboxane agonist U46619-induced
      aggregation. Subacutely administered (5mgkg(-1) day i.p. for 5 days), compounds 6
      and 7 protected mice from collagen/epinephrine induced pulmonary thromboembolism
      at about 20-fold lower doses than acetylsalicylic acid and they prolonged
      bleeding time like the most part of the other derivatives. The potent
      antithrombotic activity was coupled with the absence of any lethal and
      ulcerogenic effect up to 200mgkg(-1) os.

PMID- 12419643
TI  - Adverse drug reactions to antibiotics observed in two pulmonology divisions of
      catanzaro, Italy: a six-year retrospective study.
AB  - We retrospectively analysed adverse drug reactions (ADRs) associated with
      antibiotic therapy and reported over a 6-year period, from January 1995 to
      December 2000, in clinical notes of two Pulmonology Units of "Mater Domini"
      University Hospital and "Pugliese-Ciaccio" Hospital, both located in Catanzaro,
      Italy. Antibiotics were responsible for 92 (44.9%) out of 205 episodes of ADRs.
      In particular, 22 episodes (23.9%) were observed after penicillin G
      administration, 19 episodes (20.7%) following ceftazidime and cefotaxime
      administration, 16 episodes (17.4%) after therapy with ampicillin, and 35
      reactions (38%) were further reported during treatments with other antibiotics.
      We determined that the drug-ADR relationship was certain in 63% of the reports;
      withdrawal of the suspected drug led to recovery in 95% of cases. In conclusion,
      this retrospective evaluation demonstrated that antibiotics are a common cause of
      ADRs in hospitalised patients and, therefore, drug surveillance can successfully
      identify targeted adverse events.

PMID- 12419644
TI  - Bioequivalence of ticlopidine hydrochloride administered in single dose to
      healthy volunteers.
AB  - Ticlopidine hydrochloride (CAS 55142-85-3) is an inhibitor of platelet
      aggregation used in the management and prevention of thromboembolic disorders.A
      new formulation of ticlopidine hydrochloride (test) was compared to the reference
      Tiklid, present in the market, in order to assess their bioequivalence and to
      register the new formulation as a generic according to the Abbreviated New Drug
      Application (ANDA) procedure.Twenty-four healthy male volunteers were treated
      with the two formulations (one tablet containing 250mg of active ingredient)
      according to a single-dose, balanced, crossover, double-blind design with a
      washout between the two study periods. Plasma concentration of ticlopidine was
      assayed in timed samples over a 24h-period with a well-validated HPLC method with
      UV detection, which allowed 5ngml(-1) to be assayed as the lowest quantifiable
      concentration. The double-blind key was disclosed only after having completed the
      assay of unknown samples. From plasma concentrations, C(max), t(max), AUC(0-t),
      AUC(0- infinity ) and t(1/2) were evaluated through non-compartmental
      pharmacokinetic analysis. C(max) and AUCs were log(10)- transformed and
      statistically processed using crossover ANOVA. No statistically significant
      formulation, period, or sequence effect was encountered. Ninety percent
      confidence intervals of C(max) and AUCs were comprised in the stipulated 0.80
      1.25 range. Similarly, Schuirmann's test led to statistically significant degrees
      on both the sides explored. Time to peak, t(max), processed with the non
      parametric Kruskal-Wallis' test, did not show any statistically significant
      degree. According to guidelines operating in Europe, the test formulation of
      ticlopidine hydrochloride can be declared bioequivalent with the reference, both
      formulations in 250mg tablets.

PMID- 12419645
TI  - The activation of serotonin receptors prevents glutamate-induced neurotoxicity
      and NMDA-stimulated cGMP accumulation in primary cortical cell cultures.
AB  - In the present study, we performed experiments on primary cell cultures from rat
      neocortex to assess the effects of the selective serotonergic 5HT(1A), 8-hydroxy
      2-(di-n-propylamino)tetralin (8-OH-DPAT) or 5HT(2), (+/-)-1-(2,5-dimethoxy-4
      iodophenyl)-2-aminopropane (DOI) agonists on neuronal death induced by 15min
      exposure to (-)glutamate (300 microM) as measured by 3-(4,5-dimethylthiazol-2-yl)
      2,5-diphenyl tetrazolium bromide (MTT). The results show that both drugs
      attenuated (-)glutamate-induced neurotoxicity and this effect was fully
      antagonized by the selective antagonists of 5HT(1) (NAN-190) or 5HT(2)
      (ketanserin) receptors.The effects of the selective serotonergic agonists on the
      production of cyclic GMP (cGMP) accumulation induced by N-methyl-D-aspartate
      (NMDA) in the same neuronal preparation were also evaluated. Only the 5HT(2)
      agent, but not 8-OH-DPAT, per se, decreased basal cGMP levels. In contrast, both
      drugs attenuated the NMDA-induced cGMP accumulation in this cell preparation. The
      unexpected similar behavior of 5HT(1) and 5HT(2) agonists towards glutamate
      induced neurotoxicity and NMDA-induced cGMP accumulation in primary cell cultures
      is discussed. It is concluded that primary cell cultures from rat cerebral cortex
      could represent a suitable experimental model to search novel neuroleptics which
      exert their effects via 5HT receptors.

PMID- 12419646
TI  - Influence of mianserin on the antinociceptive effect of morphine, metamizol and
      indomethacin in mice.
AB  - The influence of mianserin (5 or 3.6mgkg(-1)) on antinociceptive effect of
      morphine (10mgkg(-1)), metamizol (500mgkg(-1)) and indomethacin (10 or 1.4mgkg(
      1)) was investigated in a mouse model using the tail-flick and hot-plate tests.
      All drugs were injected intraperitoneally (i.p.). Mianserin was administered to
      mice 30min before applying the analgesic drugs. Measurement of nociception was
      performed within 2h after mianserin administration. The study was further
      conducted for 14 days with multiple drug doses. The results indicate that
      mianserin in a single dose increased the antinociceptive effect of metamizol (in
      the hot-plate and tail-flick tests) and indomethacin (only in the tail-flick
      test). Mianserin administered for 14 days together with metamizol increased the
      analgesic effect of the latter drug (in the hot-plate and tail-flick tests).
      Mianserin applied for 14 days increased the antinociceptive effect of
      indomethacin (in the tail-flick test).

PMID- 12419647
TI  - Emesis: antiemetic effect of cyclophosphamide at central receptors of
      multitransmitter system in the cat.
AB  - The antiemetic and emetic actions of the anticancer drug cyclophosphamide
      injected intracerebroventricularly (i.c.v.) and intravenously (i.v.) through
      chronically implanted cannulae were investigated in unanaesthetized cats.
      Cyclophosphamide in single doses was injected into the cerebral ventricles and
      intravenously for 5 consecutive days. The antiemetic effect was regularly
      obtained, whereas the emetic effect was unpredictable and of low incidence. The
      antiemetic effect of i.c.v. and i.v. cyclophosphamide was assessed, when the
      neurotoxic (mydriasis, restlessness, emesis, ataxia, muscular weakness) signs
      subsided, against i.c.v. noradrenaline- and clonidine-induced emesis.
      Noradrenaline-induced emesis was dose-dependently and dose-independently
      inhibited with i.c.v. and i.v. cyclophosphamide. On the other hand, i.c.v.
      cyclophosphamide inhibited the clonidine-induced emesis in dose-independent
      manner, while i.v. injection of the anticancer drug had no significant effect on
      the emesis. The inhibition of emesis was consistently obtained and no significant
      differences in the antiemetic potency were found between 1 and 5 consecutive days
      of treatment with cyclophosphamide. However, the inhibition of noradrenaline
      induced emesis was dose-dependent only after first administration of i.c.v.
      cyclophosphamide. It is assumed that noradrenaline acts at alpha-adrenoceptors
      within the area postrema and clonidine at alpha-adrenoceptors within and outside
      the area postrema as well as at muscarinic cholinoceptors, 5-hydroxytryptamine,
      dopamine and histamine H1 and H2 receptors, outside the area postrema, of
      multitransmitter system subserving the central regulation of emesis. It is
      suggested, therefore, that the antiemetic effect of cyclophosphamide at the
      receptors of the multitransmitter central emetic system is non-specific. In
      general, the antiemetic effect, even non-specific, of an anticancer drug could
      have practical implication. Namely, when a combination of two or more anticancer
      drugs are used for chemotherapy, the emesis could not occur if one of them could
      antagonize the emesis induced by other anticancer drug/s. Finally,
      cyclophosphamide injected i.c.v., but not i.v., evoked shortlasting emesis in
      about 20% of cats. Since the emesis was unpredictable and of low incidence it was
      not possible to study the mechanism/s and site/s of action of the anticancer
      drug.

PMID- 12419648
TI  - Pentoxifylline diminished acetaldehyde-induced collagen production in hepatic
      stellate cells by decreasing interleukin-6 expression.
AB  - The effect of pentoxifylline (PTX), a methylxanthine derivative, on collagen
      induction and secretion and on the production of mRNA of two fibrogenic
      cytokines: interleukin-6 and transforming growth factor-beta(1) (IL-6 and TGF
      beta(1)) in a rat hepatic stellate cell line (CFSC-2G) exposed to acetaldehyde
      was studied. CFSC-2G cells were treated with 175 microM acetaldehyde for 24h. The
      cells were then exposed to a medium containing 200 microM PTX. Collagen
      secretion, increased 2.6 times in acetaldehyde treated cells. Cells exposed to
      acetaldehyde and treated with PTX diminished collagen secretion to control values
      and decreased alpha(1)(I) collagen mRNA by 15%. Reverse transcriptase-polymerase
      chain reaction (RT-PCR) assays of TGF-beta(1) mRNA showed no variation in
      different experimental conditions. However, PTX induced a decrease of 32% in IL-6
      mRNA in acetaldehyde-treated cells. CFSC-2G cells treated with anti-IL-6
      monoclonal antibody, 15min before acetaldehyde was added, did not present an
      increase in alpha(1)(I) collagen mRNA. These results show that PTX inhibits the
      expression of alpha(1)(I) collagen via the inhibition of IL-6 in acetaldehyde
      treated cells. The effect herein reported on IL-6 and alpha(1)(I) collagen mRNA
      adds to the previously described effect of PTX, which could be useful in the
      fibrogenic process induced by acetaldehyde.

PMID- 12419649
TI  - Protective effects of oral arabic gum administration on gentamicin-induced
      nephrotoxicity in rats.
AB  - Arabic gum (AG) is a complex polysaccharide used as suspending agent. It has been
      widely used by eastern folk medicine practitioners as a restorative agent and is
      thought to be an excellent curative for renal failure patients. We therefore
      tested these folkloric claims using a rat model of gentamicin (GM)-induced
      nephrotoxicity. AG (7.5g 100ml(-1), in drinking water) was administered orally
      for 8 days concurrently with GM (80mgkg(-1) per day, i.p.). Estimation of urine
      volume, serum creatinine and urea concentrations, kidney tissue malondialdehyde
      (MDA) contents and glutathione (GSH) were carried out after the last dose of GM.
      Kidneys were also examined for histological changes. GM caused a marked
      nephrotoxicity as evidenced by significant increases in urine volume (295%),
      serum creatinine (318%) and urea (258%) and a significant decrease in creatinine
      clearance (Ccr) (26%). Treatment with AG protected the rats from GM-induced
      nephrotoxicity as evident by normalisation of these parameters. In addition there
      was about 187% increase in kidney tissue MDA contents above the control with GM
      treatment. AG totally prevented the GM-induced rise in kidney tissue contents of
      MDA. Kidney histology of the tissue from GM-treated rats showed necrosis and
      desquamation of tubular epithelial cells in renal cortex as well as interstitial
      nephritis. Whereas it was very much comparable to control when AG was co
      administered with GM. In conclusion, AG protected the rats from GM-induced
      nephrotoxicity, possibly, at least in part through inhibition of the production
      of oxygen free radicals that cause lipid peroxidation.

PMID- 12419650
TI  - Effect of Sinpo-Tang on the mast cell-mediated anaphylactic reactions.
AB  - The herbal formulation Sinpo-Tang (SPT) has long been used for various allergic
      diseases. We investigated the effect of SPT on the mast cell-mediated
      anaphylactic reactions in vivo and in vitro murine models. SPT dose dependently
      inhibited compound 48/80-induced ear swelling response and histamine release. SPT
      (0.001-0.1g/kg) significantly inhibited passive cutaneous anaphylaxis (PCA). The
      mast cell number was markedly decreased at the SPT-treated PCA site. In addition,
      SPT decreased intracellular calcium levels of activated mast cells. These results
      suggest that SPT inhibit the anaphylactic degranulation of mast cells through
      decrease of the intracellular calcium level.

PMID- 12419651
TI  - Hypoglycaemic effect of a novel insulin buccal formulation on rabbits.
AB  - Transmucosal delivery is a suitable route for insulin non-injection
      administration. In this study, the hypoglycaemic effect of INSULIN BUCCAL SPRAY
      (IBS), a formulation with soybean lecithin and propanediol combined as absorption
      enhancer for insulin on diabetic rabbits and rats, were investigated. The
      hypoglycaemic rate was calculated and the pharmacodynamics and pharmacokinetics
      of the formulation in rabbits were studied. The results show that when the
      diabetic rabbits were administrated with IBS in dosages of 0.5, 1.5 and 4.5Ukg(
      1), the blood glucose level decreased significantly compared with that of the
      control group and the hypoglycaemic effect lasted over 5h. The blood glucose
      decreasing rates are 22.4, 48.1 and 53.5%, respectively. The average
      bioavailability of IBS by buccal delivery versus subcutaneous injection is 29.2%.
      Meanwhile, the diabetic rats were administrated with IBS in dosages of 1.0, 3.0
      and 9.0Ukg(-1), the blood glucose level decreased significantly compared with
      that of the control group and the hypoglycaemic effect lasted over 4h. The blood
      glucose decreasing rates are 24.6, 47.5 and 59.6%, respectively. Furthermore, the
      penetration of fluorescein isothiocyanate (FITC)-labelled insulin through rabbit
      buccal mucosa was investigated by scanning the distribution of the fluorescent
      probe in the epithelium using confocal laser scanning microscopy. The results
      revealed that FITC-insulin can pass through the buccal mucosa promoted by the
      enhancer and the passage of insulin across the epithelium includes both
      intracellular and paracellular routes. From the rabbit and rat experimental
      results showed that IBS is an effective buccal delivery system, which is
      promising for clinical trial and the future clinical application.

PMID- 12419653
TI  - What is a suitable dosage of physical therapy treatment?

PMID- 12419652
TI  - 'In vitro' study of chemotherapeutic activity of sulphimidazole on some sensitive
      and metronidazole-resistant Trichomonas vaginalis strains.
AB  - Trichomonacidal treatment based on 5-nitroimidazoles is problematic both when
      Metronidazole, the drug of choice, is ineffective owing to the presence of
      resistant strains and when bacterial aerobic infections are present.
      Sulphimidazole (SIZ) possesses two distinct functional groups: one sulphonamide,
      the other 5-nitroimidazole. Since SIZ is active against aerobic and anaerobic
      bacteria, we set out to discover whether, in view of the presence of the 5
      nitroimidazole group, it could also be effective against Trichomonas vaginalis.
      Twelve strains of T. vaginalis were cultured in Modified Thioglycate Medium in
      anaerobic conditions; subsequently, their growth was monitored in the presence of
      Metronidazole (MZ), SIZ, Sulphamethoxazole (SMX), Trimethoprim (TMP) and their
      associations. Eight strains proved to be sensitive to Metronidazole (minimum
      lethal concentration=0.5 microgml(-1)) and four to be resistant (minimum lethal
      concentration=40-60 microgml(-1)). SIZ was active against both the sensitive and
      the Metronidazole-resistant strains (minimum lethal concentrations=0.5-1 and 10
      microgml(-1), respectively), thus showing that the chemotherapeutic activities of
      the two functional groups coexisting in SIZ remain unimpaired.

PMID- 12419654
TI  - Clinical practice guideline on the use of manipulation or mobilization in the
      treatment of adults with mechanical neck disorders.
AB  - PURPOSE: An evidence-based clinical practice guideline was developed to ascertain
      the risks and benefits for manipulation or mobilization in treating mechanical
      neck disorders with or without radicular findings or cerviogenic headache. Pain,
      function, patient satisfaction and adverse events were appraised. METHODS: The
      practice guideline development cycle/model and Cochrane reviewing process,
      critiquing past reviews, randomized trials and surveys were used. RESULTS:
      Manipulation and mobilization alone showed similar effects as placebo, wait
      period, or control group, and appeared similar in benefit for pain relief. While
      high-technology exercises were superior to manipulation alone for improving long
      term pain scores, manipulation plus low-technology exercise had the same effect.
      Patient satisfaction scores favoured manipulation plus low-technology exercise
      over manipulation alone, and high-technology exercise alone. Multi-modal care
      including some combination of manipulation or mobilizations and exercise was
      superior to control, other physical medicine methods, and rest. Based on weak
      evidence, estimates for serious complication for manipulation ranged from one in
      20,000 to five in 10,000,000. RECOMMENDATIONS: Stronger evidence suggests a multi
      modal management strategy using mobilization or manipulation plus exercise is
      beneficial for relief of mechanical neck pain. Weaker evidence suggest less
      benefit to either manipulation/mobilization done alone than when used with
      exercise. The risk rate is uncertain.

PMID- 12419655
TI  - The use and reported effects of mobilization with movement techniques in low back
      pain management; a cross-sectional descriptive survey of physiotherapists in
      Britain.
AB  - Manual therapy is the most commonly used approach in the management of low back
      pain (LBP) and encompasses a wide range of techniques. The aims of this study
      were to investigate the current use of mobilizations with movement (MWM) for LBP
      management in Britain and to inform future clinical research exploring their
      effects.A postal survey of a random sample of 3295 practising physiotherapists in
      Britain was conducted. A response rate of 72.1% (n=2357) was obtained. Of these,
      48.2% (n=1136) reported treating LBP, of whom 41.1% (n=467) reported using MWMs
      in LBP management. Therefore, the sample applicable for analysis consisted of
      these 467 therapists currently treating LBP and using MWMs. Most respondents
      (51.4%) worked in a national health service setting. Over half of the respondents
      used MWMs on at least a weekly basis, with 61.9% using MWMs primarily for
      mechanical LBP. The most commonly reported changes seen immediately after the
      application of MWMs were increases in range of movement (ROM) (54.4%) and pain
      relief (27.5%). This was also reflected in the outcomes chosen to evaluate
      improvement. On average, two spinal levels were mobilized using 2-3 sets of 4-5
      repetitions. The lower lumbar levels were treated more often. Most therapists
      indicated using a combination of other treatment approaches together with MWMs
      when treating LBP patients. In conclusion, this study is the first to describe
      the current practice of MWMs by physiotherapists in Britain, and the results will
      be used to inform the design of a clinical trial exploring the effects of MWMs
      for LBP.

PMID- 12419657
TI  - Immune response to parasitic attack: evolution of a pulsed character.
AB  - Pulsed characters are temporary biochemical, cellular, or structural changes
      produced in response to environmental or biotic challenge. For example, response
      to parasitic attack develops as a pulse of defensive chemicals or cells that
      typically decay after the parasite has been controlled. Almost all theories for
      the genetic variability of characters assume measurements on static characters.
      This paper presents theoretical tools to examine optimal control variables for
      pulsed characters and the expected level of genetic variability in those control
      variables. The example of host immune response to parasitic attack is used to
      develop the theory.

PMID- 12419658
TI  - Electrodiffusion model simulation of rectangular current pulses in a voltage
      biased biological channel.
AB  - Numerical methods are presented for simulating stochastic-in-time current pulses
      for an electrodiffusion model of the biological channel, with a fixed applied
      voltage across the channel. The electrodiffusion model consists of the parabolic
      advection-diffusion equation coupled either to Gauss' law or Poisson's equation,
      depending on the choice of boundary conditions. The TRBDF2 method is employed for
      the advection-diffusion equation. The rectangular wave shape of previously
      simulated traveling wave current pulses is preserved by the full set of partial
      differential equations for electrodiffusion.

PMID- 12419659
TI  - Possible role of contact following in the generation of coherent motion of
      Dictyostelium cells.
AB  - After aggregation by chemotaxis, cells of the cellular slime mold Dictyostelium
      discoideum form a multicellular structure and show coherent motion such as
      vortices. Here, we present a mathematical model to explain both aggregation and
      coherent motion of cells in two-dimensional space. The model incorporates
      chemotactic response of cells and the cell's property, called "contact
      following", to follow the other cells with which they are in contact. Analytical
      study and computer simulation using the model show that with contact following,
      cells form circular clusters within which cell rotation occurs. Unidirectional
      cell motion in a long belt of cells is another type of solution of the model.
      Besides, contact following has an effect to accelerate cell cluster merging. By
      considering the mechanism of cell movement, possible explanations of contact
      following are proposed.

PMID- 12419660
TI  - Optimal defense strategy: storage vs. new production.
AB  - If hosts produce defense proteins after they are infected by pathogens, it may
      take hours to days before defense becomes fully active. By producing defense
      proteins beforehand, and storing them until infection, the host can cope with
      pathogens with a short time delay. However, producing and storing defense
      proteins require energy, and the activated defense proteins often cause harm to
      the host's body as well as to pathogens. Here, we study the optimal strategy for
      a host who chooses the amount of stored defense proteins, the activation of the
      stored proteins upon infection, and the new production of the proteins. The
      optimal strategy is the one that minimizes the sum of the harm by pathogens and
      the cost of defense. The host chooses the storage size of defense proteins based
      on the probability distribution of the magnitude of pathogen infection. When the
      infection size is predictable, all the stored proteins are to be activated upon
      infection. The optimal strategy is to have no storage and to rely entirely on new
      production if the expected infection size n(0) is small, but to have a big
      storage without new production if n(0) is large. The transition from the "new
      production" phase to "storage" phase occurs at a smaller n(0) when storage cost
      is small, activation cost is large, pathogen toxicity is large, pathogen growth
      is fast, the defense is effective, the delay is long, and the infection is more
      likely. On the other hand, the storage size to produce for a large n(0) decreases
      with three cost parameters and the defense effectiveness, increases with the
      likelihood of infection, the toxicity and the growth rate of pathogens, and it is
      independent of the time delay. When infection size is much smaller than the
      expected size, some of the stored proteins may stay unused.

PMID- 12419661
TI  - The protein folds as platonic forms: new support for the pre-Darwinian conception
      of evolution by natural law.
AB  - Before the Darwinian revolution many biologists considered organic forms to be
      determined by natural law like atoms or crystals and therefore necessary,
      intrinsic and immutable features of the world order, which will occur throughout
      the cosmos wherever there is life. The search for the natural determinants of
      organic form-the celebrated "Laws of Form"-was seen as one of the major tasks of
      biology. After Darwin, this Platonic conception of form was abandoned and natural
      selection, not natural law, was increasingly seen to be the main, if not the
      exclusive, determinant of organic form. However, in the case of one class of very
      important organic forms-the basic protein folds-advances in protein chemistry
      since the early 1970s have revealed that they represent a finite set of natural
      forms, determined by a number of generative constructional rules, like those
      which govern the formation of atoms or crystals, in which functional adaptations
      are clearly secondary modifications of primary "givens of physics." The folds are
      evidently determined by natural law, not natural selection, and are "lawful
      forms" in the Platonic and pre-Darwinian sense of the word, which are bound to
      occur everywhere in the universe where the same 20 amino acids are used for their
      construction. We argue that this is a major discovery which has many important
      implications regarding the origin of proteins, the origin of life and the
      fundamental nature of organic form. We speculate that it is unlikely that the
      folds will prove to be the only case in nature where a set of complex organic
      forms is determined by natural law, and suggest that natural law may have played
      a far greater role in the origin and evolution of life than is currently assumed.

PMID- 12419662
TI  - Emerging patterns in tumor systems: simulating the dynamics of multicellular
      clusters with an agent-based spatial agglomeration model.
AB  - Brain cancer cells invade early on surrounding parenchyma, which makes it
      impossible to surgically remove all tumor cells and thus significantly worsens
      the prognosis of the patient. Specific structural elements such as multicellular
      clusters have been seen in experimental settings to emerge within the invasive
      cell system and are believed to express the systems' guidance toward nutritive
      sites in a heterogeneous environment. Based on these observations, we developed a
      novel agent-based model of spatio-temporal search and agglomeration to
      investigate the dynamics of cell motility and aggregation with the assumption
      that tumors behave as complex dynamic self-organizing biosystems. In this model,
      virtual cells migrate because they are attracted by higher nutrient
      concentrations and to avoid overpopulated areas with high levels of toxic
      metabolites. A specific feature of our model is the capability of cells to search
      both globally and locally. This concept is applied to simulate cell-surface
      receptor-mediated information processing of tumor cells such that a cell
      searching for a more growth-permissive place "learns" the information content of
      a brain tissue region within a two-dimensional lattice in two stages, processing
      first the global and then the local input. In both stages, differences in
      microenvironment characteristics define distinctions in energy expenditure for a
      moving cell and thus influence cell migration, proliferation, agglomeration, and
      cell death. Numerical results of our model show a phase transition leading to the
      emergence of two distinct spatio-temporal patterns depending on the dominant
      search mechanism. If global search is dominant, the result is a small number of
      large clusters exhibiting rapid spatial expansion but shorter lifetime of the
      tumor system. By contrast, if local search is dominant, the trade-off is many
      small clusters with longer lifetime but much slower velocity of expansion.
      Furthermore, in the case of such dominant local search, the model reveals an
      expansive advantage for tumor cell populations with a lower nutrient-depletion
      rate. Important implications of these results for cancer research are discussed.

PMID- 12419663
TI  - Evolving the division of labour: generalists, specialists and task allocation.
AB  - The evolutionary dynamics of specialization, in the context of the division of
      labour, are investigated. Individuals associate in groups in which benefits are
      shared and costs borne individually; each individual is either a generalist who
      can perform all the necessary tasks, a specialist who performs a sub-set of the
      necessary tasks, or a parasite who contributes nothing to the group. The
      implications of the model are explored analytically and through both numerical
      and Monte Carlo methods. These methods demonstrate the evolution of populations
      towards stable arrangements of specialists and generalists. The fittest
      populations are those that divide tasks fairly and associate in large, highly
      specialized groups. Generalists have a distinct advantage in small groups, but
      the presence of generalists, ironically, lowers group fitness. Parasites are able
      to invade both specialized and non-specialized populations. A basic model for the
      continuous division of labour is also presented, demonstrating a tendency for
      populations to evolve increasingly unfair divisions of labour. This last result
      implies that an evolutionary ratchet favours disparity between the workload of
      specialist populations.

PMID- 12419664
TI  - The problem of proton transfer in membranes.
AB  - Proton (H(+)) transfer has been examined in many molecular systems for more than
      50 years. General mechanistic possibilities including tunnelling have been
      recognized for proton movement from local base-to-base centres. An especially
      fast mechanism over considerable distances, the Grotthus mechanism, has been
      described in water. Proton transfer over long distances in membranes which is now
      known to occur in many protein bio-energetic devices is not understood since
      ground state structures do not provide a continuous H-bond network. Here we
      consider the possible mechanisms and propose that the most likely pathway for
      protons in membranes uses an excited conformational state, equivalent to a
      partial denaturation.

PMID- 12419665
TI  - Modelling dominance hierarchy formation as a multi-player game.
AB  - Animals who live in groups need to divide available resources amongst themselves.
      This is often achieved by means of a dominance hierarchy, where dominant
      individuals obtain a larger share of the resources than subordinate individuals.
      This paper introduces a model of dominance hierarchy formation using a multi
      player extension of the classical Hawk-Dove game. Animals play non-independent
      pairwise games in a Swiss tournament which pairs opponents against those which
      have performed equally well in the conflict so far, for a fixed number of rounds.
      Resources are divided according to the number of contests won. The model, and its
      emergent properties, are discussed in the context of experimental observations.

PMID- 12419666
TI  - Automatic frequency alignment and quantitation of single resonances in multiple
      magnetic resonance spectra via complex principal component analysis.
AB  - Several algorithms for automatic frequency alignment and quantitation of single
      resonances in multiple magnetic resonance (MR) spectra are investigated. First, a
      careful comparison between the complex principal component analysis (PCA) and the
      Hankel total least squares-based methods for quantifying the resonances in the
      spectral sets of magnetic resonance spectroscopy imaging (MRSI) spectra is
      presented. Afterward, we discuss a method based on complex PCA plus linear
      regression and a method based on cross correlation of the magnitude spectra for
      correcting frequency shifts of resonances in sets of MR spectra. Their advantages
      and limitations are demonstrated on simulated MR data sets as well as on an in
      vivo MRSI data set of the human brain.

PMID- 12419668
TI  - A 2D MAS solid-state NMR method to recover the amplified heteronuclear dipolar
      and chemical shift anisotropic interactions.
AB  - A two-dimensional solid-state NMR method for the measurement of chemical shift
      anisotropy tensors of X nuclei (15N or 13C) from multiple sites of a polypeptide
      powder sample is presented. This method employs rotor-synchronized pi pulses to
      amplify the magnitude of the inhomogeneous X-CSA and 1H-X dipolar coupling
      interactions. A combination of on-resonance and magic angle rf irradiation of
      protons is used to vary the ratio of the magnitudes of the 1H-X dipolar and X-CSA
      interactions which are recovered under MAS, in addition to suppressing the 1H-1H
      dipolar interactions. The increased number of spinning sidebands in the recovered
      anisotropic interactions is useful to determine the CSA tensors accurately. The
      performance of this method is examined for powder samples of N-acetyl-(15)N-L
      valine (NAV), N-acetyl-15N-L-valyl-15N-L-leucine (NAVL), and alpha-13C-L-leucine.
      The sources of experimental errors in the measurement of CSA tensors and the
      application of the pulse sequences under high-field fast MAS operations are
      discussed.

PMID- 12419669
TI  - An evaluation of the contributions of diffusion and exchange in relaxation
      enhancement by MRI contrast agents.
AB  - Magnetic compounds are known to enhance water proton relaxation, either by
      diffusion or by proton exchange. An experimental procedure to distinguish both
      mechanisms is proposed and validated by relaxation measurements made in water
      methanol solutions of Dy(3+), Ni(2+), Gd(3+), Tempo, and AMI-25. The test
      discriminates according to the character of the transverse relaxation in water
      methanol solutions: a mono-exponential decay corresponds to diffusion, while a bi
      exponential decay indicates the contribution of a proton exchange. The study of
      ferritin and akaganeite particle solutions confirms the occurrence of a proton
      exchange between protons belonging to hydroxyl groups of the particle surface and
      free water protons.

PMID- 12419670
TI  - Two dimensional prolate spheroidal wave functions for MRI.
AB  - The tradeoff between spatial and temporal resolution is often used to increase
      data acquisition speed for dynamic MR imaging. Reduction of the k-space sampling
      area, however, leads to stronger partial volume and truncation effects. A two
      dimensional prolate spheroidal wave function (2D-PSWF) method is developed to
      address these problems. Utilizing prior knowledge of a given region of interest
      (ROI) and the spatial resolution requirement as constraints, this method tailors
      the k-space sampling area with a matching 2D-PSWF filter so that optimal signal
      concentration and minimal truncation artifacts are achieved. The k-space sampling
      area is reduced because the shape and size of the sampling area match the
      resolution posed by the non-rectangular shape of a convex ROI. The 2D-PSWF method
      offers an efficient way for spatial and temporal tradeoff with minimal penalty
      due to truncation, and thus, it promises a wide range of applications in MRI
      research.

PMID- 12419672
TI  - 13C NMR spectral assignments for nematic liquid crystals by 2D chemical shift
      gamma-encoding NMR.
AB  - A novel method to accomplish 13C NMR spectral assignments for nematic liquid
      crystals is proposed. The two-dimensional (2D) isotropic/anisotropic chemical
      shift correlation spectrum is observed in which the anisotropic shift parameters
      are represented as sharp lines by gamma-encoding. The 13C spectral assignments
      can be made from the 2D spectrum with the aid of the 13C isotropic shift
      assignments for the same compound in the isotropic liquid state. The experiments
      were performed on p-methoxybenzilidene-p-n-butylaniline.

PMID- 12419675
TI  - In vivo magnetic resonance microscopy of brain structure in unanesthetized flies.
AB  - We present near-cellular-resolution magnetic resonance (MR) images of an
      unanesthetized animal, the blowfly Sarcophaga bullata. Immobilized flies were
      inserted into a home-built gradient probe in a 14.1-T magnet, and images of voxel
      size (20-40 microm)(3)--comparable to the diameter of many neuronal cell bodies
      in the fly's brain--were obtained in several hours. Use of applied field
      gradients on the order of 60 G/cm allowed minimally distorted images to be
      produced, despite significant susceptibility differences across the specimen. The
      images we obtained have exceptional contrast-to-noise levels; comparison with
      histology-based anatomical information shows that the MR microscopy faithfully
      represents patterns of nervous tissue and allows distinct brain regions to be
      clearly identified. Even at the highest resolutions we explored, morphological
      detail was pronounced in the apparent absence of instabilities or movement
      related artifacts frequently observed during imaging of live animal specimens.
      This work demonstrates that the challenges of noninvasive in vivo MR microscopy
      can be overcome in a system amenable to studies of brain structure and
      physiology.

PMID- 12419679
TI  - High resolution 2D 1H-13C correlation of cholesterol in model membrane.
AB  - High resolution 2D NMR MAS spectra of liposomes, in particular 1H-13C chemical
      shifts correlations have been obtained on fluid lipid bilayers made of pure
      phospholipids for several years. We have investigated herein the possibility to
      obtain high resolution 2D MAS spectra of cholesterol embedded in membranes, i.e.
      on a rigid molecule whose dynamics is characterized mainly by axial diffusion
      without internal segmental mobility. The efficiency of various pulse sequences
      for heteronuclear HETCOR has been compared in terms of resolution, sensitivity
      and selectivity, using either cross polarization or INEPT for coherence transfer,
      and with or without MREV-8 homonuclear decoupling during t1. At moderately high
      spinning speed (9 kHz), a similar resolution is obtained in all cases (0.2 ppm
      for 1H(3,4), 0.15 ppm for 13C(3,4) cholesterol resonances), while sensitivity
      increases in the order: INEPT < CP(x4) < CP + MREV. At reduced spinning speed (5
      kHz), the homonuclear dipolar coupling between the two geminal protons attached
      to C(4) gives rise to spinning sidebands from which one can estimate a H-H
      dipolar coupling of 10 kHz which is in good agreement with the known dynamics of
      cholesterol in membranes.

PMID- 12419680
TI  - Methods for studying transmembrane peptides in bicelles: consequences of
      hydrophobic mismatch and peptide sequence.
AB  - We have shown that bicelles prepared from dilauryl phosphatidylcholine (DLPC) and
      dipalmitoyl phosphatidylcholine (DPPC) align in a magnetic field under conditions
      similar to the more common dimyristoyl phosphatidylcholine (DMPC) bicelles. In
      addition, a model transmembrane peptide, P16, with a hydrophobic stretch of 24 A,
      and specific alanine-d(3) labels, was incorporated into all of the different
      bicelles. The long-chain phospholipid (DLPC, DMPC, or DPPC) remained unperturbed
      upon incorporation of the peptide while the quadrupolar splitting of the short
      chain phospholipid along the bicelle rim increased by varying degrees in the
      different bicelle systems. The change in quadrupolar splitting of the short-chain
      phospholipids was attributed to changes in either fluidity of the planar region
      of the bicelle or differences in overall lipid packing. When the hydrophobic
      stretch of the bilayer was 22.8 (DMPC) or 26.3 A (DPPC), the peptide tilt was
      found to be transmembrane (33-35 degrees with respect to the bicelle normal).
      When the hydrophobic stretch of the bilayer was 19.5 A (DLPC), the peptide
      quadrupolar splittings suggested a loss of transmembrane orientation. When
      tryptophan was incorporated in the middle of the transmembrane region, the
      transmembrane orientation was also lost.

PMID- 12419681
TI  - Soft-triple resonance solid-state NMR experiments for assignments of U-13C, 15N
      labeled peptides and proteins.
AB  - The process of obtaining sequential resonance assignments for heterogeneous
      polypeptides and large proteins by solid-state NMR (ssNMR) is impeded by
      extensive spectral degeneracy in these systems. Even in these challenging cases,
      the cross peaks are not distributed uniformly over the entire spectral width.
      Instead, there exist both well-resolved single resonances and distinct groups of
      resonances well separated from the most crowded region of the spectrum. Here, we
      present a series of new triple resonance experiments that exploit the non-uniform
      clustering of resonances in heteronuclear correlation spectra to obtain
      additional resolution in the more crowded regions of a spectrum. Homonuclear and
      heteronuclear dipolar recoupling sequences are arranged to achieve directional
      transfer of coherence between neighboring residues in the peptide sequence. A
      frequency-selective (soft) pulse is applied to select initial polarization from a
      limited (and potentially) well-resolved region of the spectrum. The pre-existing
      resolution of one or more spins is thus utilized to obtain additional resolution
      in the more crowded regions of the spectrum. A new protocol to utilize these
      experiments for sequential resonance assignments in peptides and proteins is also
      demonstrated.

PMID- 12419684
TI  - Sensitivity-enhanced E.COSY-type HSQC experiments for accurate measurements of
      one-bond 15N-1H(N) and 15N-13C' and two-bond 13C'-1H(N) residual dipolar
      couplings in proteins.
AB  - Novel E.COSY-type HSQC experiments are presented for the accurate measurement of
      one-bond 15N-1H(N) and 15N-13C(') and two-bond 13C(')-1H(N) residual dipolar
      couplings in proteins. Compared with existing experiments, the (delta,J)-E.COSY
      experiments described here are composed of fewer pulses and the resulting spectra
      exhibit 1.4 times the sensitivity of coupled HSQC spectra. Since residual dipolar
      couplings play increasingly important roles in structural NMR, the proposed
      methods should find wide spread application for structure determination of
      proteins and other biological macromolecules.

PMID- 12419685
TI  - 3D MR microscopy with resolution 3.7 microm by 3.3 microm by 3.3 microm.
AB  - The technique of magnetic resonance imaging microscopy holds promise of bringing
      the full capabilities of NMR to arbitrarily specified positions within spatially
      inhomogeneous systems, including biological cells, yet the possibilities are
      limited by the need for adequate sensitivity and spatial resolution. We report
      proton magnetic resonance images obtained by combining advances in receiver coil
      sensitivity, gradient strength, and pulse/gradient sequence design. We achieve
      resolution of 3.7 +/- 0.4 microm by 3.3 +/- 0.3 microm by 3.3 +/- 0.3 microm for
      a volume resolution approximately 40 femtoliters (corresponding to approximately
      3 x 10(12) proton spins).

PMID- 12419686
TI  - Subchronic 3-month oral toxicity study of grape seed and grape skin extracts.
AB  - Meganatural brand grape seed extract (GSE) and grape skin extract (GSKE),
      containing proanthocyanidin (PAC) polyphenolic compounds, are intended for use in
      food as functional ingredients exhibiting antioxidant activity.
      Proanthocyanidins, as well as the minor constituent phenolic compounds in GSE and
      GSKE, are present naturally in many foods such as fruits, vegetables, chocolate,
      tea, etc., and on average people consume 460-1000 mg/day of these combined
      substances. Although humans have ingested PACs for centuries without reported
      adverse effects, the current toxicology literature contains relatively little
      formal evidence regarding their safety. Accordingly, as part of a program to
      investigate the safety of GSE and GSKE, these products were incorporated into
      chow and fed to rats for at least 3 months in a GLP-compliant subchronic toxicity
      study. Groups of CD (Sprague-Dawley) Crl:CD IGS BR rats (20 males and 20 females
      per group) were fed diets containing GSE at concentrations of 0, 0.63, 1.25 or
      2.5% (w/w); GSKE was fed at 2.5% (w/w) only. Clinical observations were recorded
      and body weight and feed consumption measured throughout the study. After 1
      month, blood was obtained from 10 rats/sex/group by retrobulbar puncture for
      interim measurement of clinical pathology. At the end of the study the rats were
      subjected to a full necropsy, aortic blood samples were collected for clinical
      pathology, selected organs were weighed and a complete list of tissues was
      preserved from all animals. Histologic examination was performed on all tissues
      from control and high-dose GSE and GSKE groups. There were no treatment-related
      changes that were considered to be of toxicologic significance. Therefore, a
      dietary concentration of 2.5% GSE or 2.5% GSKE was considered to be a no-observed
      adverse effect level (NOAEL). This was equivalent to a time-weighted average dose
      over the course of the study of approximately 1.78 g/kg body weight/day GSE or
      GSKE in male rats and 2.15 g/kg body weight/day in female rats.

PMID- 12419687
TI  - Direct scavenging of nitric oxide and superoxide by green tea.
AB  - In the present study, we investigated the free radical scavenging effects of
      green tea extract and green tea tannin mixture and its components using a nitric
      oxide (NO) and superoxide (O(2)(-)) generating system in vitro. Green tea extract
      showed direct scavenging activity against NO and O(2)(-) and green tea tannin
      mixture, at the same concentration, showed high scavenging activity. Comparison
      of the activities of seven pure compounds isolated from green tea tannin mixture
      showed that (-)-epigallocatechin 3-O-gallate (EGCg), (-)-gallocatechin 3-O
      gallate (GCg) and (-)-epicatechin 3-O-gallate (ECg) had higher scavenging
      activities than (-)-epigallocatechin (EGC), (+)-gallocatechin (GC), (-)
      epicatechin (EC) and (+)-catechin (C), showing the importance of the structure of
      flavan-3-ol linked to gallic acid for this activity. Among the gallate-free
      tannins, EGC and GC were more effective O(2)(-) scavengers than EC and C,
      indicating the O-trihydroxy structure in the B ring is an important determinant
      of such activity. However, this structure did not affect the NO scavenging
      activity. These findings confirm that green tea tannin has excellent antioxidant
      properties, which may be involved in the beneficial effect of this compound.

PMID- 12419688
TI  - Effects of ergothioneine on diabetic embryopathy in pregnant rats.
AB  - The natural antioxidant ergothioneine (2-mercaptohistidine trimethylbetaine) is a
      fungal metabolite and found in most plant and animal tissues. The effect of
      ergothioneine on diabetic embryopathy in rats was assessed. Supplementation of
      diabetic pregnant rats with L-ergothioneine (1.147 mg/kg body weight) daily for
      the first 11.5 days of pregnancy reduced the rate of embryo malformations, to
      values similar to the non-diabetic animals. The ergothioneine had no effect on
      the plasma glucose levels, both in diabetic and control animals. We conclude that
      the inhibition of the glucose-mediated free radical dependent embryo malformation
      by ergothioneine is an important antioxidant prophylactic mechanism, which when
      combined with vitamin E could benefit the management of diabetic embryopathy.

PMID- 12419689
TI  - Disposition and metabolism of isoeugenol in the male Fischer 344 rat.
AB  - The primary objective of these studies was to determine the absorption,
      distribution, metabolism and excretion of isoeugenol following oral and
      intravenous administration to male Fischer-344 rats. Following a single oral dose
      of [14C]isoeugenol (156 mg/kg, 50 microCi/kg), greater than 85% of the
      administered dose was excreted in the urine predominantly as sulfate or
      glucuronide metabolites by 72 h. Approximately 10% was recovered in the feces,
      and less than 0.1% was recovered as CO(2) or expired organics. No parent
      isoeugenol was detected in the blood at any of the time points analyzed.
      Following iv administration (15.6 mg/kg, 100 microCi/kg), isoeugenol disappeared
      rapidly from the blood. The t(1/2) was 12 min and the Cl(s) was 1.9 l/min/kg.
      Excretion characteristics were similar to those of oral administration. The total
      amount of radioactivity remaining in selected tissues by 72 h was less than 0.25%
      of the dose following either oral or intravenous administration. Results of these
      studies show that isoeugenol is rapidly metabolized and is excreted predominantly
      in the urine as phase II conjugates of the parent compound.

PMID- 12419690
TI  - Estrogenic and antiproliferative properties of soy sapogenols in human breast
      cancer cells in vitro.
AB  - Two soy sapogenols, soyasapogenol A (SA) and soyasapogenol B (SB) were tested for
      their estrogenic activities in estrogen responsive MCF-7 or estrogen-insensitive
      MDA-MB-231 (MDA) human breast cancer cells. SB and SA had differential actives on
      cell proliferation with 10 microM SB being growth inhibitory to MDA cells with no
      significant effect at any concentration on MCF-7 cells. SA also inhibited MDA
      cell proliferation at 10 micro, but at this same dose stimulated a 2.5-fold
      increase in MCF-7 proliferation. SA (0.1-10 microM) induced pS2 mRNA levels and
      the induction was blocked by co-treatment of cells with the anti-estrogen ICI
      182,780. SA also induced the formation of an ER-ERE DNA complex measured by
      electrophoretic mobility shift assay. In summary, these results show that
      soyasapogenol A is estrogenic, whereas soyasapogenol B is growth inhibitory.

PMID- 12419691
TI  - Anti-genotoxic effect of aqueous extracts of sun mushroom (Agaricus blazei Murill
      lineage 99/26) in mammalian cells in vitro.
AB  - The "sun mushroom" is the popular name for the Agaricus blazei Murill fungus, a
      mushroom native to south-eastern Brazil, which has been frequently used in
      popular medicine mainly in the form of tea to treat various ailments (stress,
      diabetes, etc.). In the present study, the genotoxic and/or anti-genotoxic
      effects ofA. blazei on mammalian cells in culture was assessed by checking the
      increase or reduction of micronucleus (MN) frequency and comets. The sun mushroom
      (lineage 99/26) was used as aqueous extracts prepared (2.5%) at three different
      temperatures (60, 25 and 4 degrees C). The in vitro micronucleus (MN) test in
      binucleated cells and comet assay were used in V79 cells cultivated in HAM
      F10+DMEM medium (1:1), supplemented with 10% of fetal bovine serum. The
      experiments were divided into four treatment types: 1. Negative control; 2.
      Positive control with MMS; 3. Treatments with the three forms of extracts (60, 25
      and 4 degrees C); and 4. Treatments with the extracts in different associations
      (simultaneous, pre-treatment, post-treatment and simultaneous after pre
      incubation for 1 h) with MMS. None of the A. blazei extracts show genotoxic
      activity. In the comet assay no protecting effect was found. The results obtained
      in the MN test showed that the three forms of extracts used had protective
      activity, suggesting that the compound or active ingredients of A. blazei are
      always present in these extracts. The greater protective efficiency of the
      simultaneous treatment and simultaneous treatment with pre-incubation mixture
      with MMS suggests that the extracts have an antimutagenic action of the
      desmutagenic type.

PMID- 12419692
TI  - Sodium fluoride-induced hypoproteinemia and hypoglycemia in parental and F(1)
      generation rats and amelioration by vitamins.
AB  - Oral administration of sodium fluoride (NaF; 40 mg/kg body weight) daily from day
      6 of gestation to day 21 of lactation caused, compared with the distilled water
      control (group 2), significant reductions in body weight and feed consumption as
      well as concentration of glucose and protein in the serum of P- and F(1)
      generation rats; however, sodium and potassium concentrations in the serum were
      significantly higher than those of the vehicle control (group 2). Administration
      of either vitamins C (50 mg/kg body weight/day), D (2 ng/0.2 ml olive
      oil/animal/day) or a combination of vitamins C+D+E along with NaF caused
      significant amelioration in body weight and feed consumption, as well as glucose,
      protein, sodium and potassium concentrations in the serum of P- and F(1)
      generation rats compared with the NaF-only treated group. Withdrawal of NaF
      treatment during lactation caused significant amelioration in feed consumption
      (days 15-21 only), sodium, potassium, glucose and protein concentrations in the
      serum of both P- and F(1)-generation rats. Co- treatment with vitamin E (2 mg/0.2
      ml olive oil/animal/day) caused significant amelioration in body weight (days 15
      and 20 of gestation only), sodium, potassium, glucose (only in P-generation
      females) and protein (only in P-generation female) concentrations in the serum of
      rats than in NaF-treated rats alone. It is concluded that co-treatment with
      vitamins C, D and C+D+E were found more effective in ameliorating NaF-induced
      effects than vitamin E and withdrawal of NaF treatment during lactation.

PMID- 12419693
TI  - Host resistance to Trypanosoma cruzi infection is enhanced in mice fed Fusarium
      verticillioides (=F. moniliforme) culture material containing fumonisins.
AB  - Fumonisins, metabolites of Fusarium verticillioides (=F. moniliforme) and related
      fungi that occur naturally on corn, elicit various organ- and species-specific
      toxicities. However, immunologic effects of fumonisins are not well
      characterized. BALB/c mice were fed diets containing F. verticillioides culture
      material (CM) providing 50 (LD) or 150 (HD) ppm fumonisins (FB(1)+FB(2))
      beginning 1 week before and continuing 5 weeks after challenge with the myotropic
      Brazil strain of T. cruzi. A control group (ZD) was fed a diet lacking CM. The LD
      and HD diets caused increases in tissue sphinganine/sphingosine ratios and
      minimum to mild hepatotoxicity, both of which are typically induced by
      fumonisins. Nitric oxide (NO) production by peritoneal macrophages from HD mice
      was significantly higher than by peritoneal macrophages from ZD mice on day 14
      after challenge. NO production also was stimulated in macrophages from ZD mice,
      but the peak response did not occur until day 26 after challenge. Compared with
      ZD mice, LD and HD mice exhibited reduced parasitemia and decreased numbers of
      pseudocysts in cardiac muscle. Thus, the CM increased host resistance to T. cruzi
      by accelerating NO production by macrophages or otherwise enhancing the immune
      response. The findings provide additional evidence that fumonisins modulate
      immune function.

PMID- 12419694
TI  - Effect of sorbic acid administration on urinary trans,trans-muconic acid
      excretion in rats exposed to low levels of benzene.
AB  - Trans,trans-muconic acid (t,t-MA) is a biomarker of benzene exposure reflecting
      metabolic activation to trans,trans-muconaldehyde. t,t-MA background urinary
      levels are highly variable, thus limiting its use to exposure monitoring of
      levels over 1 ppm of benzene. Actually, sorbic acid (SA) is known to influence
      background excretion of t,t-MA in man, but only a few examples suggest that SA
      ingestion can enhance t,t-MA levels occurring together with benzene exposure. In
      this study, the effect of SA was investigated in benzene-exposed male Sprague
      Dawley rats exposed to 1 ppm benzene for 6 h. Exposed animals had a 24-h urinary
      t,t-MA excretion higher than that observed in non-exposed animals (87+/-13
      microg/kg vs 19+/-3 microg/kg body weight). The oral dose of 8 mg/kg body weight
      SA had no effect on urinary t,t-MA both in control and in benzene-exposed rats.
      Increases of t,t-MA levels in urine occurred at SA doses of 50-200 mg/kg body
      weight, and co-exposure to benzene and SA (50 and 100 mg/kg body weight) produced
      additive enhancement of t,t-MA excretion. These data demonstrate the dose
      response relationship between SA administration and t,t-MA excretion. Our study
      showed that SA ingestion at doses equal to or greater than 50 mg/kg body weight
      significantly affects the t,t-MA urinary levels in rats exposed to 1 ppm of
      benzene for 6 h. These data support the conclusion that in man t,t-MA is not
      suitable for biomonitoring of low levels of benzene exposure.

PMID- 12419695
TI  - Effects of propyl paraben on the male reproductive system.
AB  - Parabens are p-hydroxybenzoic acid ester compounds widely used as preservatives
      in foods, cosmetics, toiletries and pharmaceuticals. These compounds exert a weak
      estrogenic activity as determined by in vitro estrogen receptor assay and in vivo
      uterotrophic assay. In a previous study, it was demonstrated by the present
      author that exposure of post-weaning mammals to butyl paraben adversely affects
      the secretion of testosterone and the function of the male reproductive system.
      In the present study, it is shown that propyl paraben also adversely affects the
      hormonal secretion and the male reproductive functions. Propyl paraben was
      administered to 3-week-old rats which were divided into four groups of eight
      animals each, at doses of 0.00, 0.01, 0.10 and 1.00% with the AIN93G modified
      diet. At the end of 4 weeks, the rats were sacrificed by decapitation and the
      weights of testes, epididymides, prostates, seminal vesicles and preputial glands
      were determined. There were no treatment-related effects of propyl paraben on the
      organ weights in any of the study groups. The cauda epididymal sperm reserves and
      concentrations decreased in a dose-dependent manner and the difference was
      significant at dose of 0.10% and above. Daily sperm production and its efficiency
      in the testis of all groups receiving propyl paraben significantly decreased. The
      serum testosterone concentration decreased in a dose-dependent manner and the
      decrease was significant in the group that received the highest dose. The
      exposure level at which this effect was observed is the same as the upper-limit
      acceptable daily intake (10 mg/kg body weight/day) of parabens in the European
      Community and Japan.

PMID- 12419696
TI  - Lack of effects of oxolinic acid on spermatogenesis in young adult and aged
      Wistar rats.
AB  - Prolonged treatment with oxolinic acid is known to elevate serum luteinizing
      hormone (LH) levels, resulting in induction of Leydig cell tumors in rats. In a
      carcinogenicity study of the compound, tubular atrophy of the testis was also
      increased, suggesting that oxolinic acid might affect spermatogenesis. The
      present study was therefore performed using rats of different ages with a
      particular focus on seminiferous tubule alteration and its relation to Leydig
      cell proliferation. Young adult (7 weeks of age) and aged (52 weeks of age) males
      of the Wistar strain were administered oxolinic acid at dietary concentrations of
      0 (basal diet), 300, 1000 or 3000 ppm for 4 (all groups), 13 (0 and 3000 ppm
      groups), 26 (0 and 3000 ppm groups), or 52 weeks (0 and 3000 ppm groups of aged
      rats). Serum LH levels were elevated in both young adult and aged animals treated
      with 3000 ppm at most examined time points. While testosterone levels were also
      increased at the early time points in young adult, this was not the case in older
      animals. Elevation of the incidences of foci and/or focal hyperplasia of Leydig
      cells was noted but was only slight limited to aged rats treated with 3000 ppm
      after 26 weeks. Furthermore, it did not appear to be related to seminiferous
      tubular alteration. No treatment-related histopathological abnormalities could be
      detected in any treatment group, and morphometrical stage analysis of
      spermatogenesis conducted for the control and 3000 ppm-treated groups
      demonstrated no lesions. These results provide strong evidence that prolonged
      oxolinic treatment does not directly induce testicular toxicity or altered
      spermatogenesis in either young adult or aged rats, except for slight increase of
      Leydig cell proliferative lesions caused by elevated serum LH levels. Aged rats
      might have higher sensitivity than young adults to the effects of oxolinic acid
      on proliferative lesions of Leydig cells.

PMID- 12419697
TI  - In vitro assay of hydrolysis and chlorohydroxy derivatives of bisphenol A
      diglycidyl ether for estrogenic activity.
AB  - Bisphenol A diglycidyl ether (BADGE) is an epoxy resin monomer. Epoxy-based
      solution coatings are used in many applications as additives for a variety of
      plastic coatings in food packaging. It is well known that unreacted BADGE can
      migrate from epoxy-based packing materials into foods. Not only BADGE but also
      its derivatives can easily migrate into foods and it is likely that we intake
      BADGE and its derivatives through food or drink. Recently, endocrine disrupting
      chemicals (EDCs) have attracted attention because they have been shown to affect
      reproduction in wildlife. The estrogenic activity of BADGE derivatives has not
      previously been investigated. Therefore, we investigated the estrogenic activity
      of the BADGE derivatives, dihydrolysed BADGE (BADGE-4OH) and chlorohydroxy BADGE
      (BADGE-2Cl), using breast cancer cell (T47D) proliferation assay and estrogen
      receptor (ER) (alpha) binding assay. These chemicals exhibited T47D cell
      proliferation at concentrations of 10(-14)-10(-4) M. However, these chemicals did
      not bind to ER (alpha) in the binding assay.

PMID- 12419698
TI  - Developmental toxicity of oral n-butylamine hydrochloride and inhaled n
      butylamine in rats.
AB  - Pregnant Wistar rats were administered 0, 100, 400 or 1000 mg mono-n-butylamine
      hydrochloride/kg body weight/day by gavage on days 6 through 15 post coitum
      (sperm-positive=day 0), or inhaled mono-n-butylamine 0, 17, 50 or 152 ppm (whole
      body exposure), 6 h/day on days 6 through 19 post coitum. Oral n-butylamine HCl
      1000 mg/kg reduced maternal feed consumption, increased early post-implantation
      losses (embryonic resorptions), reduced fetal and placental weight, and retarded
      skeletal development (incomplete skull and sternebral ossification), and produced
      malformations (filiform/kinked tail, enlarged cardiac ventricular chamber(s),
      malpositioned heart, aortic arch atresia, diaphragmatic hernia); 100 mg/kg was
      the no-observed-adverse effect level (NOAEL) for prenatal developmental toxicity;
      400 mg/kg, the maternal no-effect level, produced only malformations (aortic arch
      atresia, malpositioned heart, diaphragmatic hernia). Inhaled n-butylamine
      produced concentration-dependent nasal epithelial hyperplasia and squamous
      metaplasia, inflammation and necrosis; the maternal NOAEL was less than 17 ppm.
      There were no treatment-related signs of embryo/fetotoxicity, particularly, no
      effects on fetal morphology. The developmental NOAEL was 152 ppm. The
      neutralization of n-butylamine by hydrochloride converts it from a strong alkali
      causing tissue burns into a weak acid/base which is fetotoxic. Possible
      mechanisms of fetotoxicity are free radical production, metabolic acidosis, and
      lysosomotrophy.

PMID- 12419699
TI  - The effect of calcium load and the calcium channel blocker verapamil on
      gentamicin nephrotoxicity in rats.
AB  - Gentamicin (GM) is used against serious and life-threatening Gram negative
      infections. However its use is limited by the occurrence of nephrotoxicity.
      Reports on the interaction between GM nephrotoxicity and calcium (Ca(2+)) or Ca
      blockers are conflicting. Therefore, in the present work we assessed the effect
      of treatment of rats with graded doses of calcium carbonate, CaCO(3) (0.25, 0.5
      or 1.0 g/kg) orally, or the Ca(2+) channel blocker verapamil (1.75, 3.5 or 7.0
      mg/ kg) intramuscularly (i.m.), on the nephrotoxicity induced by concomitant i.m.
      treatment with GM (80 mg /kg/day for 6 days). Nephrotoxicity was evaluated
      histopathologically by light microscopy and biochemically by measuring the
      concentrations of urea and creatinine in plasma, reduced glutathione (GSH), lipid
      peroxidation and superoxide dismutase (SOD) activity in kidney cortex. The
      results indicated that the administration of CaCO(3) produced a dose-dependent
      amelioration in the biochemical indices of nephrotoxicity in plasma and renal
      cortex, which was significant at the two higher doses used. The histological
      picture of the renal proximal tubules followed a similar pattern. Treatment with
      verapamil induced a dose-dependent potentiation in the biochemical parameters of
      nephrotoxicity that was significant only at the highest dose used (7 mg/kg). This
      dose also exacerbated the GM-induced histological necrosis. The above
      interactions may be clinically relevant in patients treated concurrently with
      these agents.

PMID- 12419700
TI  - Haemotoxicity of thiamphenicol in the BALB/c mouse and Wistar Hanover rat.
AB  - Chloramphenicol (CAP) is haemotoxic in man, inducing two forms of toxicity.
      First, a commonly-occurring, dose-related, reversible bone marrow depression,
      which develops during treatment. Second, a rarer aplastic anaemia (AA),
      developing after treatment, is irreversible, and often fatal. Thiamphenicol (TAP)
      was developed as a replacement for CAP; however, there are no toxicological
      investigations in the mouse or rat on the dose-related haemotoxicity of TAP, in
      repeat dose gavage studies. Therefore, we have conducted a comprehensive
      investigation in these species, administering TAP for 7-17 days, to define
      haematological changes. Female BALB/c mice were gavaged with TAP, daily for 7-17
      days at 400-1500 mg/kg; female Wistar Hanover rats were dosed with TAP daily at
      50-375 mg/kg for 9 or 10 days. Haematological changes were studied at 1, 7 and 14
      days post-dosing. In mice at day 1, TAP caused decreases in RBC, HCT and Hb;
      reticulocytes and platelets were reduced; changes were dose-related and
      reversible. Marrow cell counts were reduced; marrow was hypocellular, with
      erythroid depletion and progenitor cell vacuolation; the myeloid/erythroid (M:E)
      ratio was increased. In the rat, changes were not as clear-cut; there was anaemia
      with indications of reduced reticulocyte and platelet counts, and evidence of
      decreased neutrophils and lymphocytes. Marrow erythroid cells were decreased,
      precursor cells vacuolated, and the M:E ratio increased. We conclude that TAP
      induced haematological changes in the mouse and rat, parallelling the dose
      dependent, reversible marrow depression reported in man; TAP is more haemotoxic
      in the rat than in the mouse.

PMID- 12419701
TI  - Single-dose topical exposure to the pyrethroid insecticide, permethrin in
      C57BL/6N mice: effects on thymus and spleen.
AB  - Immunomodulatory effects of single topical exposure to permethrin were evaluated
      in 5-week-old female C57BL/6N mice. Mice exposed to 5-25 microl permethrin
      (equivalent to 220-1100 mg/kg body weight) on shaved interscapular skin were
      evaluated for altered body weight; splenic and thymic organ weight and
      cellularity; thymocyte cell surface expression, cellular apoptosis; splenic
      macrophage phagocytosis and hydrogen peroxide production; splenic B cell antibody
      production and T cell cytolytic activity; and mitogen-induced proliferation of
      splenocytes and thymocytes after in vivo or in vitro permethrin exposure. Topical
      permethrin application (25 microl) caused 32% inhibition of splenic T cell
      proliferation; in vitro exposure to permethrin also diminished splenocyte
      proliferation by 72% at 25 microM and 86% at 100 microM. permethrin did not
      appear to affect other leukocyte functional assays. Dose-related decreases in
      thymic cellularity of 52 and 80% were seen in mice exposed to 15 and 25 microl
      permethrin, respectively. Apoptosis was significantly increased in CD4(-)8(-) and
      CD4(-)8(+) thymocytes, and the CD4(+)CD8(+) thymocyte subpopulation was most
      severely diminished, suggesting possible chemical-induced apoptotic mechanism of
      thymic atrophy. Permethrin also caused splenic hypocellularity by 31% at 15
      microl, and by 50% at 25 microl, an effect that may relate to inhibited
      proliferation or reduced seeding from the hypocellular thymus.

PMID- 12419702
TI  - Aluminium-induced changes in the rat brain serotonin system.
AB  - Aluminium exposure, apart from producing cholinotoxicity, can include changes in
      other neurotransmitter levels since neurotransmitter levels are closely
      interrelated. Reports of aluminium (Al) effects on brain neurotransmitters are
      limited. To investigate the effect of Al on the rat brain serotonergic system,
      the present study was conducted to explore brain region-specific changes and
      duration-specific changes. Male Wistar albino rats were exposed orally to Al
      chloride (AlCl(3).6H(2)O; 320 mg/kg body weight) daily for up to 60 days and
      changes in the 5-hydroxytrytamine (5-HT) and its metabolite 5-hydroxyindole
      acetic acid (5-HIAA) levels were observed after 4, 14 and 60 days of exposure in
      olfactory lobe (OLB), cerebellum (CBL), pons (PON), medulla oblongata (MOB),
      spinal cord (SPI), hypothalamus (HYP), hippocampus (HIP), striatum (STR),
      midbrain (MBR) and cortex (COR) brain regions. Significantly increased 5-HT
      levels observed in brain regions OLB (60 days), HIP (4,14 days), STR (14 days),
      HYP (14, 60 days), MBR (4 and 14 days), PON (4 days), MOB (4 days) and SPI (4, 14
      and 60 days) following Al exposure may be due to Al deactivating 5-HT system by
      decreased release and subsequent breakdown of 5-HT. Decreased 5-HT levels
      observed in cerebral COR, HIP (60 days) and in CBL after 4 and 60 days of
      exposure suggest an inhibitory effect of Al on the 5-HT system due to withdrawal
      of cholinergic input in these brain regions. 5-HIAA level changes correlate with
      5-HT level changes in many brain regions studied. The results reveal that the
      neurochemical changes due to Al were dependent on the duration of exposure and
      are brain-region-specific. The observed changes may be related to the cholinergic
      toxicity of Al.

PMID- 12419703
TI  - Cytokine fingerprinting of chemical allergens: species comparisons and
      statistical analyses.
AB  - The cellular and molecular mechanisms that result in the induction of chemical
      respiratory sensitization are unclear, although there is evidence for the
      development of T helper (Th) 2 type responses and, in some cases, the production
      of IgE. We have compared cytokine secretion patterns stimulated by topical
      exposure of BALB/c strain mice or Brown Norway (BN) strain rats to the reference
      respiratory allergen trimellitic anhydride (TMA), or to the reference contact
      allergen 2,4-dinitrochlorobenzene (DNCB). Under conditions where TMA and DNCB
      provoke similar levels of immune activation [increases in lymph node cell (LNC)
      cellularity and proliferation] divergent cytokine expression patterns are
      elicited. TMA-activated LNC isolated from BALB/c mice or BN rats elaborated high
      levels of the Th2-type cytokines interleukin (IL)-10 and IL-13, but relatively
      little of the Th1-type cytokines IL-12 or interferon gamma. For LNC derived from
      both species there was a requirement for restimulation in vitro with the mitogen
      concanavalin A for IL-4 production. Generally, DNCB-stimulated LNC displayed the
      converse type 1 cytokine phenotype. The cytokine secretion profiles of LNC
      isolated from BN rats were considerably more variable than those observed for LNC
      from BALB/c mice. Statistically significant differences (P<0.01) between DNCB-
      and TMA-activated LNC were recorded for all cytokines in BALB/c strain mice. For
      the BN rat, differences reached statistical significance (P<0.01) only for the
      expression of IL-4 and IL-13. These data demonstrate that the intrinsic ability
      of DNCB and TMA to promote preferential Th1- and Th2-type responses,
      respectively, is species-independent and provide further evidence that chemical
      respiratory allergens are associated with polarized Th2-type responses. For the
      prospective assessment of chemical respiratory allergens as a function of induced
      cytokine secretion profiles, however, these data suggest that the use of the
      BALB/c strain mouse will provide the more robust method.

PMID- 12419704
TI  - Toxicity of dietary restriction of fat enriched diets on cardiac tissue.
AB  - The present study examines the effects of caloric restriction in cardiac tissue
      evaluation markers of oxidative stress. High-fat dietary restrictions can have a
      long-term impact on cardiac health. Dietary restriction of control diet increased
      myocardial superoxide dismutase (SOD) and catalase activities. Dietary
      restriction of fatty acid-enriched diets increased myocardial lipoperoxide
      concentrations, while SOD activity was decreased in cardiac tissue of rats with
      dietary restriction of fatty acid-enriched diets. Dietary restriction of
      unsaturated fatty acid-enriched diet induced the highest lipoperoxide
      concentration and the lowest myocardial SOD activity. Dietary restriction of
      unsaturated fatty acid decreased myocardial glycogen, and increased the lactate
      dehydrogenase/citrate synthase ratio. Dietary restriction of fatty acid-enriched
      diets were more deleterious to cardiac tissue than normal ad lib.-fed diet. In
      conclusion, the effects of caloric restriction on myocardial oxidative stress is
      dependent on which nutrient is restricted. Dietary restriction of fatty acid
      enriched diets is deleterious relative to ad lib.-fed chow diet.

PMID- 12419705
TI  - Comparison of gastrointestinal absorption between human and rat: the role of
      intestinal absorptive surface area and unstirred aqueous layer(1).

PMID- 12419707
TI  - Functions of the orexinergic/hypocretinergic system.
AB  - Orexin A and orexin B are hypothalamic peptides that act on their targets via two
      G protein-coupled receptors (OX1 and OX2 receptors). In the central nervous
      system, the cell bodies producing orexins are localized in a narrow region within
      the lateral hypothalamus and project mainly to regions involved in feeding,
      sleep, and autonomic functions. Via putative pre- and postsynaptic effects,
      orexins increase synaptic activity in these regions. In isolated neurons and
      cells expressing recombinant receptors orexins cause Ca2+ elevation, which is
      mainly dependent on influx. The activity of orexinergic cells appears to be
      controlled by feeding- and sleep-related signals via a variety of
      neurotransmitters/hormones from the brain and other tissues. Orexins and orexin
      receptors are also found outside the central nervous system, particularly in
      organs involved in feeding and energy metabolism, e.g., gastrointestinal tract,
      pancreas, and adrenal gland. In the present review we focus on the physiological
      properties of the cells that secrete or respond to orexins.

PMID- 12419708
TI  - Regulation of membrane-associated iPLA2 activity by a novel PKC isoform in
      ventricular myocytes.
AB  - Thrombin stimulation of rabbit ventricular myocytes increases membrane
      associated, Ca2+-independent phospholipase A2 (iPLA2) activity, resulting in
      accelerated hydrolysis of membrane plasmalogen phospholipids and increased
      production of arachidonic acid and lysoplasmenylcholine. This study was designed
      to investigate the signal transduction pathways involved in activation of
      membrane-associated iPLA2. Incubation of isolated membrane fractions suspended in
      Ca2+-free buffer with thrombin or phorbol 12-myristate 13-acetate resulted in a
      two- to threefold increase in iPLA2 activity. Prior treatment with the PKC
      inhibitor GF-109203X blocked iPLA2 activation by thrombin. These data suggest
      that a novel PKC isoform present in the membrane fraction modulates iPLA2
      activity. Immunoblot analysis revealed a significant portion of PKC-epsilon
      present in the membrane fraction, but no other membrane-associated novel PKC
      isoform was detected by this method. These data indicate that activation of
      membrane-associated iPLA2 is mediated by a membrane-associated novel PKC isoform
      in thrombin-stimulated rabbit ventricular myocytes.

PMID- 12419709
TI  - Modulation of the erythropoietin-induced proliferative pathway by cAMP in
      vascular smooth muscle cells.
AB  - We previously reported that erythropoietin (Epo) has a mitogenic effect on rat
      vascular smooth muscle cells (VSMC) and that activation of the mitogen-activated
      protein kinase (MAPK) cascade is an important mediator for Epo-induced
      mitogenesis. An increase in intracellular cAMP has an antiproliferative effect on
      VSMC. We therefore hypothesized that cAMP effectors inhibit Epo-induced MAPK
      activation in rat VSMC. When we exposed VSMC to recombinant human Epo (rHuEpo),
      DNA synthesis was increased. Forskolin (Fsk) or cilostazol (Cil) decreased the
      DNA synthesis stimulated by rHuEpo. Coincubation with Rp-cAMPS triethylamine
      canceled the suppression of DNA synthesis and MAPK activity by Fsk. Both rHuEpo
      and phorbol 12-myristate 13-acetate upregulated phosphorylations of MEK and MAPK.
      Pretreatment with Fsk inhibited these phosphorylations. Protein kinase C
      inhibitors also suppressed MEK and MAPK phosphorylations. Moreover, Fsk induced
      phosphorylation of Raf-1 at serine-259. These results indicated that cAMP
      inhibited Epo-induced MAPK activation and that this suppression might be
      regulated upstream or at Raf-1. The results also suggested that these agents,
      which could accumulate cAMP, might be protective for Epo-stimulated direct
      action.

PMID- 12419710
TI  - Phosphocreatine kinetics at the onset of contractions in skeletal muscle of MM
      creatine kinase knockout mice.
AB  - Phosphocreatine (PCr) depletion during isometric twitch stimulation at 5 Hz was
      measured by (31)P-NMR spectroscopy in gastrocnemius muscles of pentobarbital
      anesthetized MM creatine kinase knockout (MMKO) vs. wild-type C57B (WT) mice. PCr
      depletion after 2 s of stimulation, estimated from the difference between spectra
      gated to times 200 ms and 140 s after 2-s bursts of contractions, was 2.2 +/-
      0.6% of initial PCr in MMKO muscle vs. 9.7 +/- 1.6% in WT muscles (mean +/- SE, n
      = 7, P < 0.001). Initial PCr/ATP ratio and intracellular pH were not
      significantly different between groups, and there was no detectable change in
      intracellular pH or ATP in either group after 2 s. The initial difference in net
      PCr depletion was maintained during the first minute of continuous 5-Hz
      stimulation. However, there was no significant difference in the quasi-steady
      state PCr level approached after 80 s (MMKO 36.1 +/- 3.5 vs. WT 35.5 +/- 4.4% of
      initial PCr; n = 5-6). A kinetic model of ATPase, creatine kinase, and adenylate
      kinase fluxes during stimulation was consistent with the observed PCr depletion
      in MMKO muscle after 2 s only if ADP-stimulated oxidative phosphorylation was
      included in the model. Taken together, the results suggest that cytoplasmic ADP
      more rapidly increases and oxidative phosphorylation is more rapidly activated at
      the onset of contractions in MMKO compared with WT muscles.

PMID- 12419712
TI  - New opportunities for anesthesia research in Canada.

PMID- 12419711
TI  - PepT1-mediated fMLP transport induces intestinal inflammation in vivo.
AB  - In the present study, the effect of H(+)/peptide transporter (PepT1)-mediated N
      formylmethionyl-leucyl-phenylalanine (fMLP) transport on inflammation in vivo in
      the rat small intestine, which expresses high PepT1 levels, and in the rat colon,
      which does not express PepT1, were investigated using myeloperoxidase (MPO)
      activity and histological analysis. We found that 10 microM fMLP perfusion in the
      jejunum for 4 h significantly increased MPO activity and altered the architecture
      of jejunal villi. In contrast, 10 microM fMLP perfusion in the colon for 4 h did
      not induce any inflammation. In addition, we have shown that 50 mM Gly-Gly alone
      did not affect basal MPO activity but completely inhibited the MPO activity
      induced by 10 microM fMLP in the jejunum. Together, these experiments demonstrate
      that 1) the differential expression of PepT1 between the small intestine and the
      colon plays an important role in epithelial-neutrophil interactions and 2) the
      inhibition of fMLP uptake by jejunal epithelial cells (expressing PepT1) reduces
      the neutrophil ability to move across the epithelium, in agreement with our
      previously published in vitro study. This report constitutes the first in vivo
      study showing the implication of a membrane transporter (PepT1) in intestinal
      inflammation.

PMID- 12419713
TI  - Towards the regulation of research ethics boards.

PMID- 12419714
TI  - Sevoflurane and isoflurane, but not propofol, decrease mivacurium requirements
      over time.
AB  - PURPOSE: Volatile anesthetic agents potentiate neuromuscular blockade, but the
      magnitude of potentiation appears to be time dependent. The time course of this
      interaction was studied by measuring mivacurium infusion rates during
      sevoflurane, isoflurane and propofol anesthesia. METHODS: After informed consent,
      anesthesia was induced in 48 ASA physical status I-II adults with propofol,
      fentanyl and mivacurium 0.25 mg.kg(-1) and maintained with N(2)O (60%) and one of
      the three agents chosen at random: sevoflurane 1.9%; isoflurane 1.2%; or propofol
      100-150 microgram.kg(-1).min(-1). Train-of-four stimulation was applied every 15
      sec to the ulnar nerve. Neuromuscular blockade was monitored with accelerometry.
      At 5% recovery of the first twitch (T1), a mivacurium infusion was started and
      adjusted every five minutes to maintain 90-95% T1 depression. RESULTS: The time
      to 5% T1 recovery after the initial dose was similar in all groups (13-15 min).
      Fifteen minutes after the start of the infusion mivacurium requirements were
      greater (P < 0.05) in the propofol group (7.5 +/- 1.7 microgram.kg(-1).min(-1);
      mean +/- SD) than in either isoflurane (4.7 +/- 1.6 microgram.kg(-1).min(-1)) or
      sevoflurane (4.5 +/- 1.5 microgram.kg(-1).min(-1)) group. Then, the rate remained
      stable for propofol (6.2 +/- 1.4 microgram.kg(-1).min(-1) after 90 min of
      infusion) while it decreased with isoflurane to 2.9 +/- 1.6 microgram.kg(-1).min(
      1) at 90 min (P < 0.05 vs propofol) and to 1.4 +/- 1.0 microgram.kg(-1).min(-1)
      in the sevoflurane group (P < 0.05 vs propofol and isoflurane). CONCLUSION:
      Sevoflurane and isoflurane do not prolong the effect of a bolus dose of
      mivacurium, but potentiation increases with time from 30-105 min of exposure.
      This interaction is greater with sevoflurane than isoflurane.

PMID- 12419715
TI  - Duration of control stimulation does not affect onset and offset of neuromuscular
      blockade at the corrugator supercilii muscle measured with phonomyography or
      acceleromyography.
AB  - PURPOSE: Phonomyography (PMG) is a novel technique for measuring neuromuscular
      blockade (NMB). The effect of the duration of control stimulation on the onset
      and duration of blockade was investigated using PMG and acceleromyography (AMG).
      METHODS: After induction of anesthesia, a microphone was placed above the middle
      portion of the left eyebrow, and an acceleromyographic probe was placed above the
      middle portion of the right eyebrow. Twenty patients were randomized to receive
      bilateral, single-twitch, facial nerve stimulation (0.1 Hz, 20 mA) with three
      minutes (n = 10) or ten minutes (n = 10) of supramaximal stimulation before
      mivacurium 0.2 mg.kg(-1) was administered. Onset, maximum effect, and offset of
      NMB were measured. RESULTS: Using PMG, lag time, onset time, maximum effect, and
      time to reach 75% of control twitch height (mean +/- SD) were 36 +/- 27 sec, 136
      +/- 35 sec, 89 +/- 10%, and 12.1 +/- 4.5 min, respectively, after three minutes
      of control stimulation and were 40 +/- 22 sec, 122 +/- 40 sec, 93 +/- 3%, and
      12.4 +/- 4.9 min, after ten minutes. Using AMG, the values were 38 +/- 23 sec,
      106 +/- 28 sec, 79 +/- 6%, and 14.3 +/- 5.9 min, respectively, after three
      minutes and were 34 +/- 22 sec, 106 +/- 28 sec, 76 +/- 10%, and 14.9 +/- 3.7 min,
      after ten minutes. Compared to PMG, AMG revealed significant bias for onset time
      (-30 sec), maximum effect (-16%) and time to reach 75% of control twitch height
      (1.5 min), with wide limits of agreement of 66 sec, 22%, and 5.6 min,
      respectively. CONCLUSION: The duration of control stimulation did not influence
      the time course of blockade measured by either method. Three minutes of
      supramaximal stimulation is sufficient to measure pharmacodynamic parameters. AMG
      measures a shorter onset and longer recovery time and reduced anesthesiology the
      maximum effect compared to PMG.

PMID- 12419716
TI  - Systolic blood pressure, not BIS, is associated with movement during laryngoscopy
      and intubation.
AB  - OBJECTIVE: To compare bispectral index (BIS) values to hemodynamic variations, in
      order to evaluate adequacy of anesthesia during orotracheal intubation with
      muscle relaxants. METHODS: Forty-one patients ASA I-II, scheduled for elective
      peripheral surgery under general anesthesia with tracheal intubation were
      enrolled in the study. Fentanyl/thiopental followed by vecuronium were used for
      induction. Onset of relaxation was monitored at the orbicularis occuli (OO)
      muscle using train-of-four stimulation. Intubation was performed when no response
      at the OO was detected visually. Intubating conditions were noted. The "isolated
      forearm" technique was used to detect movement during laryngoscopy/intubation.
      BIS values, pulse rate (PR), and systolic pressure were recorded before
      induction, during laryngoscopy/intubation and 60 sec after intubation. RESULTS:
      Although intubating conditions were clinically adequate for all patients, ten out
      of 41 had movement of the isolated arm during laryngoscopy/intubation. BIS values
      were not significantly different for these patients: 67 (55-83) compared to those
      who had no movement: 60 (35-80), P = 0.6. During laryngoscopy, PR increased for
      all patients while systolic pressure increased significantly only in patients who
      moved: 125 (100-136) mmHg vs those who did not: 108 (67-140), P < 0.05.
      CONCLUSION: Systolic pressure elevations were associated with inadequate
      anesthesia as evaluated by the "isolated forearm" technique, during
      laryngoscopy/intubation. BIS values were not different between groups, suggesting
      that systolic blood pressure may be a better predictor of inadequate anesthesia
      under the circumstances described.

PMID- 12419717
TI  - Dexamethasone 8 mg in combination with ondansetron 4 mg appears to be the optimal
      dose for the prevention of nausea and vomiting after laparoscopic
      cholecystectomy.
AB  - PURPOSE: The combination of antiemetic drugs could be a solution to prevent
      severe postoperative nausea and vomiting (PONV). The aim of this randomized
      double blind, dose-ranging study was to determine the minimum single effective
      dose of dexamethasone combined with ondansetron for the prevention of PONV in
      patients undergoing laparoscopic cholecystectomy. METHODS: One hundred eighty
      patients were allocated randomly to one of six groups to receive saline (P
      group), ondansetron 4 mg (O group), or ondansetron 4 mg and dexamethasone at
      doses of 2 mg (OD2 group), 4 mg (OD4 group), 8 mg (OD8 group), and 16 mg (OD16
      group). A standardized general anesthetic was used. All episodes of PONV during
      the intervals of zero to six hours, 6-12 hr and 12-24 hr after surgery were
      evaluated using a numeric scoring system. Mean visual analogue scale pain scores
      at rest and on movement, the time to first demand of analgesia, total analgesic
      consumption in 12 hr epochs, duration of hospital stay, and side effects were
      recorded. RESULTS: The incidence of PONV in the OD8 (16%) and OD16 (16%) groups
      was lower than in the 83% (P < 0.001) and O groups (50%) at the 12-24 hr epoch (P
      < 0.05). There were no differences in antiemetic effect between the O, OD2 and
      OD4 groups and between the OD8 and OD16 groups. Pain scores, total analgesic
      consumption, duration of hospital stay and side effects were similar among
      groups. CONCLUSION: Our results suggest that 8 mg is the minimum dose of
      dexamethasone that, combined with ondansetron 4 mg will effectively prevent PONV
      in patients undergoing laparoscopic cholecystectomy.

PMID- 12419718
TI  - Recovery of psychomotor function after propofol sedation is prolonged in the
      elderly.
AB  - PURPOSE: To assess the effects of age on recovery of psychomotor function for
      propofol sedation during spinal anesthesia. METHODS: Propofol was continuously
      infused during surgery and spinal anesthesia in 15 elderly patients (65-85 yr
      old) and 15 younger patients (20-50 yr-old). Infusion rates were adjusted to
      maintain an appropriate level of sedation using the bispectral index (range 60
      70). The sedative infusion was discontinued at the end of surgery. The early
      recovery times from the end of propofol infusion to opening of eyes on command,
      sustaining a hand grip, and recall of name were noted. Psychomotor function, as
      measured by the Trieger's dot test, was evaluated before anesthesia and 30, 60,
      90, 120 min after the end of propofol infusion. RESULTS: The duration of
      anesthesia was 142 +/- 55 min and 134 +/- 61 min in the elderly and younger
      patients, respectively. No differences were observed in early recovery times
      between elderly and younger patients (opened their eyes on command, 6.3 +/- 4.0
      min and 5.2 +/- 2.6 min; sustained a hand grip, 7.2 +/- 3.9 min and 6.1 +/- 3.5
      min and recalled their name, 8.0 +/- 4.5 min and 6.5 +/- 3.8 min, P > 0.05 ). The
      recovery of psychomotor function in the elderly took longer compared with the
      younger patients, and psychomotor function in the elderly recovered at 120 min
      after the end of propofol infusion. CONCLUSION: Early recovery times following
      propofol sedation is similar between elderly and younger patients, but recovery
      of psychomotor function in the elderly is delayed compared with younger patients.

PMID- 12419719
TI  - Benzodiazepine premedication may attenuate the stress response in daycase
      anesthesia: a pilot study.
AB  - PURPOSE: Patients undergoing daycase surgery suffer from varying degrees of fear
      and anxiety. There is conflicting evidence in the literature regarding the
      benefit of benzodiazepine premedication in daycase surgery. We carried out a
      prospective, double-blind, randomized pilot study investigating the effect of
      benzodiazepine premedication on the stress response in patients undergoing
      daycase anesthesia and surgery. METHODS: Group I (n = 16) received diazepam 0.1
      mg*kg(-1) orally 60 min preoperatively; Group II (n = 15) received diazepam 0.1
      mg*kg(-1) orally 90 min preoperatively; Group III (n = 30) received a placebo.
      The stress response was measured by analyzing urinary catecholamine and cortisol
      levels and by scoring anxiety levels using state-trait anxiety inventory (STAI)
      scores and visual analogue scores (VAS). RESULTS: Anxiety scores (VAS and STAI
      scores) were not different between groups. We found a statistically significant
      reduction in urinary cortisol and noradrenaline levels in the groups receiving
      diazepam vs placebo. DISCUSSION: The reduction in stress hormones following
      diazepam premedication, in patients undergoing daycase surgery may support the
      role for benzodiazepine premedication in this setting. However, further studies
      are warranted to determine the clinical significance of these findings.

PMID- 12419720
TI  - [Autonomic hyperreflexia induced by sacral root stimulation is detected by
      spectral analysis of the EEG].
AB  - PURPOSE: To compare spectral analysis of the electrocardiogram (ECG) with mean
      arterial pressure (MAP) and heart rate (HR) monitoring in the detection of
      autonomic hyperreflexia (AHR) induced by sacral root stimulation. METHODS: Ten
      spinal cord injured patients scheduled for implantation of a sacral root
      stimulator for bladder retention were included. Under target controlled
      anesthesia with propofol 4 micro g*mL(-1) and remifentanil 4 ng*mL(-1), the
      patients were placed in the knee chest position. The sacral roots were exposed by
      laminectomy (L2-S1) and their function assessed by electrostimulation under
      urodynamic and cardiovascular monitoring. Online power spectrum densities were
      calculated from the ECG R-R interval by the MemCalc(TM) software using the
      maximum entropy method. Low frequency (LF: 0.04-0.15 Hz) and high frequency (HF:
      0.15-0.4 Hz) spectra were associated with sympathetic and parasympathetic
      activities respectively. The most extreme value of each variable was noted before
      and during each stimulation. A difference ( triangle up ) of more than 10%
      signified AHR. The comparison ( triangle up LF vs triangle up MAP and triangle up
      HF vs triangle up HR) was done by a concordance test with a kappa coefficient
      (k): -1 = total discordance to 1 = total concordance. RESULTS: AHR was detected
      in six patients as an increase in LF and MAP (n = 4); an increase in LF, HF, MAP
      with a decrease in HR (n = 2). The detection delay was 5.3 +/- 1 sec (LF, HF) and
      10.4 +/- 1.2 sec (MAP and HR). Concordance was 85% (LF vs MAP: k = 0.7) and 90%
      (HF vs HR: k = 0.8). CONCLUSION: AHR induced by sacral root stimulation is
      detected by spectral analysis of the ECG earlier than MAP and HR. Other studies
      are needed to confirm these results.

PMID- 12419721
TI  - Xenon preserves neutrophil and monocyte function in human whole blood.
AB  - PURPOSE: Most volatile anesthetics are known to inhibit the oxidative and
      phagocytic function of neutrophils. In the present study, we investigated the
      effect of xenon on phagocytosis and respiratory burst activity of neutrophils and
      monocytes in human whole blood. METHODS: Heparinized whole blood from 22 healthy
      volunteers was incubated for 60 min in the presence of 65% xenon. Sixty-five
      percent nitrous oxide was used as a positive control to prove the reliability of
      our in vitro system. Phagocytosis of fluorescein isothiocyanate labelled,
      opsonized Escherichia coli (E. coli) by neutrophils and monocytes was measured
      using flow cytometry. After induction with either N-formyl-methionyl-leucyl
      phenylalanine (FMLP), phorbol-12-myristate-13-acetate or opsonized E. coli,
      respiratory burst activity was assessed by measuring the oxidation of
      dihydrorhodamine 123 to rhodamine 123 with a flow cytometer. RESULTS: Exposure of
      human whole blood to xenon increased the percentage of neutrophils showing
      phagocytosis (94 +/- 3% vs 92 +/- 4%; P < 0.01), and the amount of ingested
      bacteria (P < 0.01). Respiratory burst activity in neutrophils and monocytes was
      not affected by xenon. Nitrous oxide significantly reduced the percentage of
      neutrophils showing respiratory burst after FMLP stimulation. Furthermore, E.
      coli-induced stimulation resulted in a decreased number of reacting neutrophils
      (84 +/- 15% vs 95 +/- 5%; P < 0.05) and monocytes (70 +/- 22% vs 83 +/- 11%; P <
      0.05) as well as a reduced production of hydrogen peroxide in both cell lines
      compared to control. CONCLUSION: In contrast to nitrous oxide, xenon preserves
      neutrophil and monocyte antibacterial capacity in vitro.

PMID- 12419722
TI  - Combined paravertebral lumbar plexus and parasacral sciatic nerve block for
      reduction of hip fracture in a patient with severe aortic stenosis.
AB  - PURPOSE: To report the use of a combined paravertebral lumbar plexus and
      parasacral sciatic nerve block for reduction of hip fracture in an elderly
      patient with severe aortic stenosis. CLINICAL FEATURES: In an 87-yr-old lady with
      severe aortic stenosis and fracture of the right trochanter due to a fall, a
      combined right-sided paravertebral lumbar plexus and parasacral sciatic nerve
      block was used successfully for operative reduction of the fracture. A moderate
      amount of phenylephrine was required to maintain adequate systemic blood pressure
      despite the largely unilateral nature of the blocks. CONCLUSION: Combined
      paravertebral lumbar plexus and parasacral sciatic nerve block can be a viable
      alternative to general anesthesia and epidural or spinal block for hip surgery in
      patients with severe aortic stenosis.

PMID- 12419723
TI  - Continuous mandibular nerve block for pain relief. A report of two cases.
AB  - PURPOSE: Mandibular nerve block allows surgery to be performed on the mandible.
      However, pain in the postoperative period needs to be treated with opioids or non
      steroidal anti-inflammatory agents which have undesirable side effects. We
      examine the feasibility of continuous mandibular nerve block with 0.25%
      bupivacaine top-ups using a catheter for intraoperative and postoperative pain
      relief in two patients with a fracture of the mandible. METHODS: Using the
      lateral extraoral approach, the mandibular nerve was approached with an 18-gauge
      indwelling iv cannula in two patients undergoing repair of a fractured mandible
      under general anesthesia. After removing the needle, an 18-gauge epidural
      catheter was inserted into the cannula which was then removed. The catheter was
      tunnelled subcutaneously to emerge at the lateral aspect of the forehead. Two to
      4 mL bupivacaine 0.25% were injected on a 12-hr basis and the catheter was kept
      in place for seven days. RESULTS: Both patients had excellent pain relief and no
      parenteral or oral analgesics were required throughout the postoperative period.
      No side effects were noted. CONCLUSIONS: Continuous mandibular nerve block with 2
      4 mL 0.25% bupivacaine top-ups injected twice a day through a catheter provides
      excellent pain relief in patients with a fracture of the mandible. This method
      may have implications for the management of pain of other etiology in the
      mandibular region.

PMID- 12419724
TI  - Hospital practice more than specialty influences the choice of regional or
      general anesthesia for Cesarean section.
AB  - PURPOSE: Describe the influence of specialty certification and practice style
      upon the anesthetic technique used for Cesarean deliveries. METHODS: Alberta
      physician claims and hospital abstracts between April 1, 1998 to March 31, 2000
      were used to determine the technique of anesthesia (regional or general). The
      influence of practice (volume of deliveries, geographic location, presence of
      regional analgesia providers) and specialty (anesthesiologist or family/general
      practice) is explored by logistic regression. RESULTS: Hospital abstracts of
      13,884 Cesarean sections were analyzed. Anesthesiologists performed 76% of the
      anesthetics: epidural (33%), spinal (45%), and general anesthesia (22%).
      Comparing only regional and metropolitan hospitals, the percent of general
      anesthesia performed by anesthesiologists varied between 5% to 50%. After
      adjusting for other factors, we found, in order of importance, the following
      determined the use of general anesthesia for Cesarean sections: 1) hospitals with
      more epidural procedure providers during labour were 3% less likely to have
      providers choose general anesthesia; 2) larger, regional and metropolitan
      hospitals were less likely to have providers choose general anesthesia; 3)
      hospitals with a high volume epidural procedure provider during labour were 64%
      less likely to have providers choose general anesthesia; 4) anesthesiologists
      were 32% less likely to choose general anesthesia. CONCLUSION: The overall use of
      regional anesthesia for Cesarean sections in Alberta is high. The chance of
      receiving a general anesthetic for a Cesarean delivery varies across the province
      and was more related to practice environment than specialty.

PMID- 12419725
TI  - The anesthetic management of ventricular septal defect (VSD) repair in a child
      with mitochondrial cytopathy.
AB  - PURPOSE: To present the anesthetic management for the correction of a ventricular
      septal defect (VSD) in a patient with multiple acyl CoA dehydrogenase deficiency
      (glutaric aciduria type II; GAII). A review of the literature about anesthetic
      management of patients with mitochondrial diseases undergoing cardiopulmonary
      bypass (CPB) is also included. CLINICAL FEATURES: An 11-yr-old girl with GAII
      manifested as severe hypoglycemia since she was a newborn and generalized muscle
      weakness. She underwent open-heart surgery for VSD correction with CPB. The
      anesthetic management avoided inhalational anesthetics, maintained the blood
      sugar within normal limits and continued normothermia during CPB in order to
      avoid the stress of hypothermia for her abnormal mitochondria. The patient
      tolerated the procedure well and experienced a good recovery. CONCLUSION: The
      anesthetic management of patients with any mitochondrial disease requires
      normoglycemia, normothermia and the avoidance of metabolic stress in order to
      preserve energy production by the diseased mitochondria.

PMID- 12419726
TI  - Inhaled iloprost controls pulmonary hypertension after cardiopulmonary bypass.
AB  - PURPOSE: Severe pulmonary hypertension (PH) is a major cause of right ventricular
      (RV) dysfunction. Various iv vasodilator modalities have been used with limited
      results because of lack of pulmonary selectivity. The aim of the present
      controlled study was to evaluate the efficacy of inhaled iloprost, a synthetic
      prostacyclin analogue, in patients with elevated pulmonary vascular resistance
      (PVR) immediately after separation from cardiopulmonary bypass (CPB). METHODS:
      Twelve patients with persistent PH after discontinuation of CPB were included in
      the study. In all patients standard hemodynamic monitoring was used. Inhaled
      iloprost was administered via nebulized aerosol at a cumulative dose of 0.2 micro
      g*kg(-1) for a total duration of 20 min. Complete sets of hemodynamic
      measurements were performed before inhalation (baseline), during and after
      cessation of the inhalation period. Echocardiographic monitoring of RV function
      was also used. RESULTS: Inhaled iloprost induced a reduction in the
      transpulmonary gradient at the end of the inhalation period in comparison to
      baseline (9.33 +/- 3.83 mmHg vs 17.09 +/- 6.41 mmHg, P < 0.05). The mean
      pulmonary artery pressure to systemic artery pressure ratio decreased over this
      period (0.28 +/- 0.08 vs 0.45 +/- 0.17, P < 0.05). A statistically significant
      decrease of the PVR to systemic vascular resistance ratio was also observed (0.15
      +/- 0.05 vs 0.21 +/- 0.05, P < 0.05). Improved indices of RV function were
      observed in echocardiographic monitoring. CONCLUSION: Inhaled iloprost appears to
      be a selective pulmonary vasodilator and may be effective in the initial
      treatment of PH and the improvement of RV performance in the perioperative
      setting.

PMID- 12419727
TI  - Dopamine may preserve the myocardial oxygen balance better than dobutamine when
      administered with milrinone.
AB  - PURPOSE: To compare the hemodynamic effects of dopamine with those of dobutamine
      when administered with milrinone in patients undergoing non-cardiac surgery.
      METHODS: In 14 patients undergoing major surgery during anesthesia with
      isoflurane, milrinone (50 microgram*kg(-1) followed by 0.25 microgram*kg(-1)*min(
      1)) was administered. Hemodynamic baseline values were assessed 50 min after
      continuous infusion of milrinone. Additional infusion of either dopamine or
      dobutamine, randomly selected, was started at the rate of 4 and later 8
      microgram*kg(-1)*min(-1); each hemodynamic variable was measured 20 min after
      changing the infusion rate. One hour after ceasing the infusion of one
      catecholamine (dopamine or dobutamine), the other was infused at the rate of 4
      and 8 microgram*kg(-1)*min(-1). RESULTS: Milrinone increased heart rate (HR), but
      decreased mean arterial pressure (MAP) and systemic vascular resistance (SVR) (P
      < 0.05 for each). Dopamine administered with milrinone significantly increased
      MAP and cardiac output (CO), whereas dobutamine significantly increased HR and
      CO, but decreased SVR. By comparison between dopamine and dobutamine administered
      at the rate of 8 microgram*kg(-1)*min(-1), there was a significant difference in
      HR, MAP, and SVR (P < 0.01, 0.01, and 0.05, respectively). CONCLUSION: Dopamine
      and dobutamine administered with milrinone induce different hemodynamic changes:
      dopamine increases MAP without affecting HR, whereas dobutamine increases HR. Our
      data suggest that the myocardial oxygen balance might be better preserved with
      dopamine than with dobutamine when administered with milrinone.

PMID- 12419728
TI  - Propofol for electrical storm; a case report of cardioversion and suppression of
      ventricular tachycardia by propofol.
AB  - PURPOSE: To present a case report where propofol abolished recurrent ventricular
      tachycardia (VT) and to suggest a mechanism by which this may have occurred.
      CLINICAL FEATURES: A 65-yr-old male was admitted to the intensive care unit (ICU)
      with electrical storm. Recurrent episodes of VT persisted despite maximal anti
      arrhythmic therapy and resulted in a prolonged ICU course and the need for intra
      aortic balloon pump support. This was complicated by an ischemic limb,
      necessitating an anesthetic for femoral thrombectomy. On several occasions while
      in the ICU, episodes of VT had resolved with boluses of propofol prior to planned
      cardioversion. In the operating room, episodes of non-sustained VT resolved after
      a bolus of propofol and remained suppressed for the duration of the case with the
      use of a propofol infusion. CONCLUSION: The effects of propofol on cardiac
      conduction and on the autonomic nervous system have been studied but its effects
      on arrhythmias are not well documented. In this case report, propofol was
      associated with the resolution and suppression of VT. Recent evidence suggests
      that sympathetic blockade may be an effective treatment for electrical storm.
      This may be the mechanism by which propofol can abolish this arrhythmia
      intraoperatively.

PMID- 12419729
TI  - Similar long-term cardiovascular effects of propofol or isoflurane anesthesia
      during ischemia/ reperfusion in dogs.
AB  - PURPOSE: To compare the long-term functional and metabolic effects of propofol or
      isoflurane general anesthesia in a canine model of ischemia/reperfusion. METHODS:
      Using magnetic resonance (MR) techniques, we monitored both regional metabolism
      ((31)P MR spectroscopy) and systolic function of the heart ((1)H MR imaging)
      throughout a two-hour occlusion of the left anterior descending coronary artery
      and ten days of reperfusion. Twenty-two beagles were randomized into isoflurane
      and propofol general anesthesia groups (n = 10, n = 12 respectively). Contrast
      enhanced MR imaging was used to measure infarct size (% of left ventricle that
      was necrotic) and coronary blood flow was determined using radioactively labelled
      microspheres. RESULTS: Cardiac metabolism, as monitored by intracellular pH and
      high-energy phosphate ratios, was not significantly different between the two
      groups throughout the protocol. Relative to propofol, isoflurane reduced the
      depression of left ventricular ejection fraction (EF) during the ischemic period
      [isoflurane 68.5% +/- 4.2%, propofol 58.3% +/- 2.0% of baseline (B); P = 0.04],
      propofol increased the recovery of EF at day three (isoflurane 63.9% +/- 4.3%,
      propofol 74.0% +/- 2.5% of B; P = 0.05). By day ten, EF in both groups was
      similar. Infarct sizes were also similar at day ten (isoflurane 15.7% +/- 3.0%,
      propofol 13.2% +/- 2.2%). Normalizing these by the region at risk (volume of
      tissue with low blood flow during the occlusion) to assess infarct ratios was
      also not significant (isoflurane 0.58% +/- 0.08%, propofol 0.54% +/- 0.07%).
      CONCLUSIONS: There were no significant differences between the two anesthetic
      groups at day ten, suggesting that any apparent dissimilarities in early
      cardiovascular effects were short-term only. These results indicate that
      isoflurane and propofol produce equivalent long-term cardiovascular effects
      following ischemia/reperfusion.

PMID- 12419730
TI  - PVC tracheal tubes exert forces and pressures seven to ten times higher than
      silicone or armoured tracheal tubes--an in vitro study.
AB  - PURPOSE: Many types of tracheal tubes (TT) including silicone, polyvinylchloride
      (PVC) and armoured have been used for blind tracheal intubation (TI) via the
      intubating laryngeal mask airway (ILMA) and may cause trauma to the airway. We
      examined the maximal in vitro forces and pressures exerted by the tip of various
      TT as it exits the ILMA. METHODS: Silicone, PVC and armoured TT were studied. A
      #5 ILMA was secured on a wooden platform. With the use of a Harvard pump, force
      was applied to push the TT through the ILMA at 0.34 cm*sec(-1). Forces exerted to
      push the TT and forces exerted by the TT tips on distal objects were calculated
      using proximal and distal pressure manometres. The areas of contact between the
      distal TT tips and the distal objects were measured by planimetry of an imprint.
      The final pressures exerted by the TT tips on a fixed distal object were
      calculated by dividing the forces exerted by the areas of contact. RESULTS: When
      compared to silicone and armoured TT, PVC TT exerted seven to ten times higher
      forces and pressures on distal objects. (P < 0.05). Heating PVC TT and inserting
      PVC TT with reverse curvature to the ILMA did not decrease the forces and
      pressures exerted by the distal tip. CONCLUSION: The high forces and pressures
      exerted by PVC TT may theoretically contribute to increased morbidity to
      patients' airway and esophagus. Caution should be exercised before attempting
      blind TI via the ILMA with a PVC TT.

PMID- 12419731
TI  - Complete separation of the tube from the mask during removal of a disposable
      laryngeal mask airway.
AB  - PURPOSE: To describe a complication of the disposable laryngeal mask airway
      (LMA). CLINICAL FEATURES: A 23-yr-old woman underwent a wide local excision of a
      chest wall melanoma and sentinel node biopsy under general anesthesia. During use
      of a single-use LMA-Unique(TM), the airway tube became completely separated from
      the distal mask (backplate). No sequelae resulted from failure of the airway
      apparatus. The LMA was examined by LMA North America, and the company stated "no
      definitive explanation can be made to explain the cause for separation of the
      airway from the backplate." CONCLUSION: Although the use of the LMA is associated
      with rare and minimal complications, each airway should be carefully inspected
      before its use for loss of integrity resulting from sterilization or for defects
      in manufacturing.

PMID- 12419732
TI  - Canadian Anesthesiologists' Society Gold Medal.

PMID- 12419733
TI  - CD-ROM Review: ACLS HeartCode.

PMID- 12419734
TI  - Web page evaluation in medical education.

PMID- 12419735
TI  - On the proper sterile technique for handling of propofol.

PMID- 12419736
TI  - The lightwand: a useful aid in the difficult tracheostomy.

PMID- 12419737
TI  - Another report of obstruction of a heat and moisture exchange filter.

PMID- 12419738
TI  - The appropriateness of the pulmonary artery catheter in cardiovascular surgery.

PMID- 12419740
TI  - Prospective clinical trials as a model for patient-centred care.

PMID- 12419741
TI  - New paradigms in oncological therapeutics: redefining combination chemotherapy.

PMID- 12419742
TI  - DNA methyltransferase inhibitors-state of the art.
AB  - BACKGROUND: DNA methylation is the addition of a methyl group to the 5 position
      of cytosine. It is an epigenetic process with several effects, including
      chromatin structure modulation, transcriptional repression and the suppression of
      transposable elements. In malignancy, methylation patterns change, resulting in
      global hypomethylation with regional hypermethylation. This can lead to genetic
      instability and the repression of tumor suppressor genes. DESIGN: A review of the
      DNA methyltransferase inhibitor literature was conducted. RESULTS: DNA
      methylation inhibitors have demonstrated the ability to inhibit hypermethylation,
      restore suppressor gene expression and exert antitumor effects in in vitro and in
      vivo laboratory models. Four inhibitors, which are analogs of the nucleoside
      deoxycitidine, have been clinically tested: 5-azacytidine, 5-aza-2'
      deoxycytidine, 1-beta-D-arabinofuranosyl-5-azacytosine and dihydro-5-azacytidine.
      The first two have demonstrated encouraging antileukemic activity but little
      activity in solid tumors, while the latter two are no longer under study due to
      lack of efficacy. A fifth agent, MG98, is an antisense oligodeoxynucleotide
      directed against the 3' untranslated region of the DNA methyltransferase-1 enzyme
      mRNA, and is now under phase II study. CONCLUSIONS: While some positive clinical
      results with DNA methyltransferase inhibitors have been seen, a definitive
      clinical role for these agents will most likely require combination therapy, and
      good phase III studies are needed.

PMID- 12419743
TI  - Is first-line single-agent mitoxantrone in the treatment of high-risk metastatic
      breast cancer patients as effective as combination chemotherapy? No difference in
      survival but higher quality of life were found in a multicenter randomized trial.
AB  - BACKGROUND: To determine whether patients with high-risk metastatic breast cancer
      draw benefit from combination chemotherapy as first-line treatment. PATIENTS AND
      METHODS: A total of 260 women with measurable metastatic breast cancer fulfilling
      high-risk criteria, previously untreated with chemotherapy for their metastatic
      disease, were randomized to receive either mitoxantrone 12 mg/m(2) or the
      combination of fluorouracil 500 mg/m(2), epirubicin 50 mg/m(2) and
      cyclophosphamide 500 mg/m(2) (FEC) every 3 weeks. Treatment was continued until
      complete remission plus two cycles, or until disease progression. In the case of
      partial remission or stable disease, treatment was stopped after 12 cycles.
      Second-line treatment was vindesine, mitomycin and prednisolone. Gain from
      treatment was estimated using a modified Brunner's score composed of time to
      progression, patients' rating of the treatment benefit, alopecia, vomiting and
      performance status. RESULTS: After recruitment from 1992 to 1997 and observation
      from 1997 to 1999, the final evaluation showed that single-agent treatment with
      mitoxantrone does not differ significantly from combination treatment with FEC in
      terms of response, objective remission rate, remission duration, time to
      response, time to best response, time to progression or overall survival. There
      was, however, a significant difference in gain from treatment using a modified
      Brunner's score favoring the single-agent treatment arm. There was no evidence
      that any subgroup would fare better with combination treatment. CONCLUSIONS: No
      significant difference was detected between the treatment with mitoxantrone as a
      single agent and the combination of low-dose FEC in terms of response or
      survival; therefore, the imperative of the necessity of first-line combination
      chemotherapy for patients with high-risk metastatic breast cancer may be
      questioned. Since toxicity and quality of life score favored the single-agent
      mitoxantrone treatment arm, this treatment may be offered to patients preferring
      quality of life to a potential small prolongation of survival.

PMID- 12419744
TI  - A phase II study of cisplatin and vinorelbine in patients with metastatic breast
      cancer.
AB  - BACKGROUND: To evaluate the efficacy and safety of the combination of cisplatin
      and vinorelbine in metastatic breast cancer. PATIENTS AND METHODS: Cisplatin (80
      mg/m(2) day 1) and vinorelbine (25 mg/m(2) days 1 and 8) were administrated every
      3 weeks to 52 patients (mean age 57 years; range 35-75 years) with metastatic
      breast cancer. Thirty-two patients were previously untreated for metastatic
      disease. Treatment was repeated for a maximum of six cycles. RESULTS: Objective
      responses were obtained in 27 patients (52.9%; complete response 9.8%). The
      response rate was similar in pretreated and untreated patients (50% and 54.7%,
      respectively; P = 0.7). ECOG performance status was good (grade 0 or 1) in 55.7%
      of patients at baseline assessment and in 90.3% at the end of treatment (P =
      0.0001). Median time to progression was 8.5 months (8.5 months in first-line and
      8.7 months in second-line patients). Median survival was 16.6 months (21.2 months
      in first-line and 16.1 months in second-line patients). Grade 3/4 toxicity
      included neutropenia (44% in first-line, 60% in second-line patients), nausea
      (17.3%), anemia (17%), asthenia (3.8%) and thrombocytopenia (1.9%). There were no
      cases of febrile neutropenia or treatment-related deaths. Alopecia did not
      develop in any of the patients. CONCLUSIONS: Cisplatin plus vinorelbine is active
      and tolerable in metastatic breast cancer, in untreated and pretreated patients.

PMID- 12419745
TI  - Neoadjuvant chemotherapy with a combination of pegylated liposomal doxorubicin
      (Caelyx) and paclitaxel in locally advanced breast cancer: a phase II study by
      the Hellenic Cooperative Oncology Group.
AB  - BACKGROUND: To determine the activity and safety of the combination of paclitaxel
      and pegylated liposomal doxorubicin (Caelyx) in patients with locally advanced
      breast cancer. PATIENTS AND METHODS: This was a multicenter phase II study.
      Thirty-five newly diagnosed patients with locally advanced breast cancer were
      included in the study. Histological or cytological diagnosis was necessary for
      inclusion. Median age was 54 years (range 26-73 years). Fifteen patients were
      premenopausal and 20 postmenopausal. Paclitaxel was administered at a dose of 175
      mg/m(2) and pegylated liposomal doxorubicin 35 mg/m(2) every 3 weeks for six
      cycles. RESULTS: Twenty-five patients (71%) responded. Six (17%) had a complete
      response, 19 (54%) had a partial response, four remained stable, two progressed
      and four were not evaluated for response due to discontinuation of chemotherapy.
      Three patients had a pathologically complete response. A total of 173 cycles were
      administered. The primary toxicity observed was skin toxicity. Grade 3 skin
      toxicity was noted in four patients (11%). Palmar-plantar erythrodysesthesia
      (PPE) grade 3 was experienced by three (9%). Two patients presented with PPE and
      skin toxicity. Hematological toxicities included grade 3 leukopenia in four
      patients (3%). Other grade 3 toxicities were uncommon and included only alopecia
      in 29 patients (83%). Grade 3 or 4 neurotoxicity was not observed in any patient.
      Dose reduction was necessary in seven patients; in six due to skin toxicity and
      in one due to neutropenia. Four patients discontinued treatment due to skin
      toxicity. There were no treatment-related deaths. CONCLUSIONS: The combination of
      pegylated liposomal doxorubicin and paclitaxel was active in locally advanced
      breast cancer. The primary toxicity was cutaneous toxicity and it was manageable.

PMID- 12419746
TI  - In vitro comparative evaluation of trastuzumab (Herceptin) combined with
      paclitaxel (Taxol) or docetaxel (Taxotere) in HER2-expressing human breast cancer
      cell lines.
AB  - BACKGROUND: Trastuzumab (Herceptin) has clinical indication in association with
      paclitaxel (Taxol) for the treatment of human epidermal growth factor receptor 2
      (HER2)-expressing breast cancer. Synergistic interactions have been reported with
      taxane derivatives in HER2-expressing breast cancer cells. However, no direct
      comparison of the potential interest in combining trastuzumab with either
      paclitaxel or docetaxel (Taxotere) has been reported. MATERIALS AND METHODS: The
      present study was designed to evaluate in a comparative way the interaction of
      trastuzumab with paclitaxel or docetaxel in HER2-overexpressing human breast
      cancer cell lines. HER2 expression was documented in MCF-7, MDA-MB453 and SK-BR3
      cell lines using immunocytochemistry with purified mouse anti-human monoclonal
      antibody. Cytotoxicity assays were performed using the sulforhodamine B assay and
      in vitro interactions between trastuzumab and taxanes were analyzed using the
      median-effect principle. RESULTS: Trastuzumab cytotoxicity was confirmed to be
      directly related to HER2 expression level. At the IC(50), the combination of
      trastuzumab with either paclitaxel or docetaxel led to synergism in all cell
      lines. However, considering mean values calculated in the IC(30)-IC(70) range of
      concentrations, trastuzumab interacted additively with docetaxel in SK-BR3 and
      MDA-MB453 cell lines while additive and synergistic interactions were achieved
      with paclitaxel in SK-BR3 and MDA-MB453, respectively. On the same basis,
      trastuzumab yielded synergistic interaction with both taxanes in the MCF-7 cell
      line. CONCLUSIONS: The present study shows that at least additive interactions
      are observed when trastuzumab is combined with either paclitaxel or docetaxel in
      weak to moderate or more than moderate HER2-expressing cells. Some interesting
      results were achieved in cells displaying weak HER2 expression which could
      suggest some further potential interest in trastuzumab.

PMID- 12419747
TI  - A phase II study of topotecan plus gemcitabine in the treatment of patients with
      relapsed ovarian cancer after failure of first-line chemotherapy.
AB  - BACKGROUND: Second-line chemotherapy for patients with ovarian cancer who failed
      platinum and paclitaxel treatment remains a therapeutic challenge. We
      investigated the toxicity profile and therapeutic efficacy of a novel combination
      regimen, topotecan plus gemcitabine, in a clinical phase II study. PATIENTS AND
      METHODS: Women with relapsed epithelial ovarian cancer after platinum and
      paclitaxel treatment were eligible to participate in this trial. Topotecan was
      given at an initial dose of 0.5 mg/m(2) daily (days 1-5), combined with
      gemcitabine 800 mg/m(2) and 600 mg/m(2) on days 1 and 8, respectively. Precluding
      good tolerability, this protocol facilitated subsequent dose increases of
      topotecan up to 1.0 mg/m(2). The primary objective was to determine the dose
      limiting toxicity, whereas secondary objectives comprised measurable and CA-125
      response rates, disease-free and overall survival. RESULTS: The twenty-one
      patients (median age 57 years, range 37-70 years) who were allocated to this
      trial received a total of 94 courses of chemotherapy. Median follow-up was 20.5
      months. Topotecan dosage could be escalated to 0.75 mg/m(2) in nine patients and
      1 mg/m(2) in another two patients. Dose reduction was not necessary in any case.
      There were no episodes of neutropenic fever, sepsis or chemotherapy-related
      fatalities. Only one patient developed CTC grade 4 leukopenia after the first
      treatment cycle, whereas three patients showed grade 3/4 anaemia. Five patients
      experienced thrombocytopenia grade 4 without clinical sequelae. Non-hematological
      toxicities were mild and rare. Eleven patients could be evaluated for clinical
      tumour response, with three complete, and four partial remissions. Two patients
      each had stable and progressive diseases. The median progression-free survival
      rate was 8.8 months [95% confidence interval (CI) 6.3-13.4 months]. The median
      overall survival rate was 21.1 months (95% CI 14.8-22.1 months). CONCLUSIONS:
      Topotecan combined with gemcitabine has a favourable toxicity profile and
      encouraging efficacy in patients with recurrent ovarian cancer.

PMID- 12419748
TI  - Phase II study of a fixed dose-rate infusion of gemcitabine associated with
      uracil/tegafur in advanced carcinoma of the pancreas.
AB  - BACKGROUND: The objectives of this study were to evaluate the efficacy and
      toxicity of a fixed dose-rate infusion of gemcitabine associated with
      uracil/tegafur (UFT) in patients with advanced adenocarcinoma of the pancreas.
      PATIENTS AND METHODS: Forty-three chemotherapy-naive patients with adenocarcinoma
      of the pancreas were included in this phase II study. All of whom had a Karnofsky
      performance status >or=50 and bi-dimensionally measurable disease (either
      advanced non-resectable or metastatic); median age 59 years (range 39-77);
      male:female ratio 29:14. Eight patients (19%) had locally advanced disease and 35
      (81%) distant metastases. Treatment consisted of gemcitabine 1200 mg/m(2) given
      as a 120-min infusion weekly for 3 consecutive weeks, plus oral UFT 400
      mg/m(2)/day (in 2-3 doses per day) on days 1-21, cycles were given every 28 days.
      Measurements of efficacy included response rate, clinical benefit response, time
      to disease progression and overall survival. RESULTS: A total of 192 cycles of
      chemotherapy were delivered with a median of four per patient. There were two
      complete responses (5%) and 12 partial responses (28%), producing an overall
      response rate of 33% [95% confidence interval (CI) 16% to 49%]. Thirteen patients
      (30%) had stable disease, whereas 16 (37%) had a progression. The median time to
      progression was 6 months and the median overall survival was 11 months. Twenty
      five patients (64%, 95% CI 47% to 78%) experienced a clinical benefit response.
      Grade 3-4 WHO toxicities were: neutropenia in nine patients (21%);
      thrombocytopenia in four (9%); anaemia in five (12%); diarrhoea in four (9%); and
      asthenia in one (2%). CONCLUSIONS: A fixed dose-rate infusion of gemcitabine
      associated with UFT was well tolerated and showed promising activity in patients
      with locally advanced or metastatic carcinoma of the pancreas. This is an
      appropriate palliative treatment in this setting.

PMID- 12419749
TI  - A multicentre phase II trial of primary chemotherapy with cisplatin and
      protracted venous infusion 5-fluorouracil followed by chemoradiation in patients
      with carcinoma of the oesophagus.
AB  - BACKGROUND: We undertook a multicentre phase II trial to evaluate the safety and
      efficacy of primary chemotherapy followed by chemoradiation for localised
      adenocarcinoma or squamous carcinoma of the oesophagus. PATIENTS AND METHODS:
      Chemotherapy comprised five 3-weekly cycles of cisplatin and protracted
      continuous infusion 5-fluorouracil, with conformally planned radiotherapy
      commencing at the start of the fifth cycle. RESULTS: The planned treatment
      programme was completed by 39 of 72 patients (54%), and a further 13% completed
      chemotherapy and proceeded to surgical oesophagectomy. Response rates to
      chemotherapy and to the entire treatment programme were 47% [95% confidence
      interval (CI) 34% to 60%] and 56% (CI 43% to 68%). The dysphagia score improved
      in 54% of patients. The median survival duration was 14.6 months with 1- and 2
      year survival rates of 58.7% and 44.1%, respectively. Grade III/IV chemotherapy
      related toxicity occurred in 38% of patients, and there were no treatment-related
      deaths. CONCLUSIONS: This is a feasible and active treatment regimen providing
      palliative benefits for patients with poor-prognosis localised oesophageal
      cancer.

PMID- 12419750
TI  - Gemcitabine and doxorubicin for the treatment of patients with advanced
      hepatocellular carcinoma: a phase I-II trial.
AB  - BACKGROUND: We determined the maximum tolerated dose (MTD) and then further
      evaluated the response rate and safety profile of gemcitabine (Gem) plus
      doxorubicin (Dox) in chemonaive patients with advanced hepatocellular carcinoma
      (HCC). PATIENTS AND METHODS: Dose escalation was tested over four dose levels in
      each 21-day cycle: level 1 (Gem 1000 mg/m(2) on days 1 and 8, Dox 30 mg/m(2) on
      day 1), level 2 (Gem/Dox 1250/30), level 3 (Gem/Dox 1250/45) and level 4 (Gem/Dox
      1250/60). The MTD was further evaluated in phase II. RESULTS: Patients'
      characteristics were: 47 men, three women; median age 53 years (range 28-70);
      Zubrod performance status (PS) scores 0-1 (74%), PS 2 (26%); Okuda stage I (24%)
      and stage II (76%). Fifteen patients were enrolled in phase I: level 1 (n = 3),
      level 2 (n = 6), level 3 (n = 6), level 4 (n = 0). Level 2 was identified as the
      MTD. Dose-limiting toxicities included esophageal bleeding, grade 4 neutropenia
      and neutropenic fever. Of the 34 patients evaluable for response in phase II (of
      35 total), there were four (11.8%) partial responses (95% CI, 0.8% to 22.8%) and
      six (17.6%) minor responses; nine (26.5%) had stable disease and 15 (44.1%)
      progressed. Sixteen per cent of patients had a decline of >or=50% in alpha
      fetoprotein levels after treatment. Median survival and progression-free survival
      were 4.6 months (range 0.3-19.2) and 2.5 months (range 0.2-7.8), respectively,
      for 35 patients. Grade 3/4 hematological toxicities included anemia (45.7%),
      neutropenia (51.4%), thrombocytopenia (25.7%); febrile neutropenia (11.8%) and
      non-hematological toxicities were mild to moderate. CONCLUSIONS: Gemcitabine plus
      doxorubicin produces modest activity and moderate toxicity in this cohort of
      Chinese patients with advanced HCC.

PMID- 12419751
TI  - A phase III randomized trial of 5-fluorouracil, doxorubicin, and mitomycin C
      versus 5-fluorouracil and mitomycin C versus 5-fluorouracil alone in curatively
      resected gastric cancer.
AB  - BACKGROUND: A phase III single-center randomized trial was performed in order to
      determine whether the addition of mitomycin C (MMC) and/or doxorubicin to 5
      fluorouracil (5-FU) as adjuvant chemotherapy could influence survival in patients
      with curatively resected gastric cancer. PATIENTS AND METHODS: A total of 416
      patients who had undergone curative resection for stage IB-IIIB gastric
      adenocarcinoma were stratified according to the stage and type of surgery, and
      then randomized to receive one of the three chemotherapy regimens, 5-FU alone (F)
      or 5-FU and MMC (FM) or 5-FU, doxorubicin and MMC (FAM) within 5 weeks after
      surgery. RESULTS: Of 416 patients registered, 395 (133 in F, 131 in FM and 131 in
      FAM) were assessable. Median follow-up duration was 91 months. Five-year overall
      survival rates were 67.2% for F, 67.0% for FM and 66.7% for FAM (P = 0.97). Five
      year disease-free survival rates were 62.1% for F, 63.3% for FM and 62.5% for FAM
      (P = 0.83). Hematological toxicities were more frequent in the FM and FAM groups,
      whereas stomatitis was more common in the F group. CONCLUSIONS: Compared with
      adjuvant 5-FU alone, the addition of MMC and/or doxorubicin to 5-FU did not
      influence survival in patients with resected gastric cancer.

PMID- 12419752
TI  - Long-term risk of second malignancy after treatment of Hodgkin's disease: the
      influence of treatment, age and follow-up time.
AB  - BACKGROUND: To quantify the long-term risk of second cancers (SCs) up to 30 years
      after primary treatment for Hodgkin's disease (HD) Material and methods In the
      period 1968 to 1985, an unselected population of 1024 patients started treatment
      for HD at the Norwegian Radium Hospital (NRH) and were followed for SC from 1969
      through 1998 by The Norwegian Cancer Registry. The median age at diagnosis of HD
      was 40 years, and the median time at follow-up was 14 years. RESULTS: Of 197 SCs,
      14 were acute non-lymphocytic leukemia (ANLL), 31 non-Hodgkin's lymphoma (NHL)
      and 152 solid cancers. The standardized incidence ratio (SIR) was significantly
      increased for SCs as a group, and for the subgroups ANLL, NHL, lung cancer,
      breast cancer, stomach cancer and melanoma. ANLL was related to heavy treatment
      with chemotherapy (CT) and combined CT and radiotherapy (RT), NHL was not
      treatment related, and solid tumors were related to radiotherapy only or combined
      RT and CT. The SIR of ANLL and NHL reached a peak between 5 and 10 years after
      treatment. Solid and non-solid tumors increased with young age at diagnosis of HD
      and solid tumors increased with follow-up time up to 28 years CONCLUSION: In a
      long-term follow-up study of HD patients of all ages, the SIR of solid tumors was
      high in patients treated at young age and decreased with increasing age. Most
      solid tumors had started within or at the edge of the irradiated field, and SIR
      of solid tumors increased even 20-30 years after diagnosis.

PMID- 12419753
TI  - Gamma delta T-cell neoplasms: a clinicopathological study of 11 cases.
AB  - BACKGROUND: The majority of T-cell neoplasms express T-cell antigen receptor
      (TCR) alpha beta on their cell surface, and a few cases show the TCR gamma delta
      phenotype. Recently, a variety of gamma delta T-cell neoplasm was recognized;
      however, its clinicopathological features have not been extensively analyzed.
      Here we report the results of a clinicopathological study of 11 cases of gamma
      delta T-cell neoplasm. PATIENTS AND METHODS: During the 11-year period from 1989
      to 1999, 104 patients with T-cell neoplasms were examined by flow cytometric
      analysis and/or immunohistochemical analysis. Tumor cells from all 104 patients
      expressed one or more of the T-cell antigens-CD2, CD3, CD5 and CD7. Forty-nine of
      the 104 cases of T-cell neoplasms were examined immunophenotypically for TCR
      alpha beta/gamma delta subsets. RESULTS: Expression of TCR gamma delta on tumor
      cells was found in five (33%) of 15 patients with precursor T-cell lymphoblastic
      leukemia/lymphoma, one (25%) of four with T-cell granular lymphocytic leukemia
      and five (26%) of 19 with peripheral T-cell lymphoma (PTCL), whereas no
      expression was found in 11 patients with adult T-cell leukemia-lymphoma. Primary
      sites of the five patients with gamma delta PTCL were as follows: lymph node,
      three; skin, one and liver, tonsil and skin, one. The courses of the three
      patients with gamma delta PTCL of nodal onset were very short (3, 5 and 9 months,
      respectively), and they were all resistant to combination chemotherapies.
      CONCLUSIONS: Although gamma delta T-cell neoplasm constitutes a heterogeneous
      population, it is important to examine the expression of TCR with the view to
      identifying possible poor prognostic subgroups, such as primary nodal gamma delta
      T-cell lymphoma.

PMID- 12419754
TI  - Phase II trial of branched peginterferon-alpha 2a (40 kDa) for patients with
      advanced renal cell carcinoma.
AB  - BACKGROUND: Peginterferon-alpha 2a (40 kDa), PEGASYS(TM) (PEG-IFN), is a modified
      form of recombinant human interferon (IFN)-alpha 2a with sustained absorption and
      prolonged half-life after subcutaneous administration. A phase II trial was
      conducted in previously untreated patients with advanced renal cell carcinoma
      (RCC) to assess efficacy, toxicity and pharmacokinetic profile. PATIENTS AND
      METHODS: Forty previously untreated patients with advanced RCC were enrolled on
      this multicenter trial. The median age was 60 years and 63% had prior
      nephrectomy. PEG-IFN was administered at a dose of 450 micro g/week on a weekly
      basis by subcutaneous injection. Serial venous blood samples were drawn to assess
      concentrations of PEG-IFN. RESULTS: Five (13%) patients achieved a major response
      (four partial and one complete). The median time to progression was 3.8 months,
      and 63% of patients were alive at 1 year. The toxicity profile was mostly mild to
      moderate in intensity. Toxicity higher than grade 2 included neutropenia (six
      patients), fatigue/asthenia (four patients), nausea/vomiting (three patients) and
      elevated hepatic transaminase concentrations (four patients). Serum drug levels
      were studied in all patients; mean C(max) at week 1 was 19 ng/ml, and levels were
      sustained at close to peak over 1 week. With chronic dosing, drug concentration
      was increased 3-fold, and steady state was achieved in 5-9 weeks. CONCLUSIONS:
      The sustained maintenance of serum levels of PEG-IFN allows once-weekly dosing.
      The efficacy and tolerability profile was qualitatively similar to standard IFN
      alpha, and adverse events were mostly mild to moderate in nature.

PMID- 12419755
TI  - Use of a topoisomerase I inhibitor (irinotecan, CPT-11) in metastatic
      adrenocortical carcinoma.
AB  - BACKGROUND: Complete responses are rare after medical treatment of adrenocortical
      tumors. We performed a single center prospective study of the antitumor effect of
      irinotecan (CPT-11) in patients with metastatic adrenocortical cancer. PATIENTS
      AND METHODS: Since 1999, all patients with advanced progressive adrenocortical
      carcinoma, referred to the Institut Gustave-Roussy, have been enrolled
      prospectively in this study. CPT-11 (250 mg/m(2)) was administered intravenously
      on day 1 in a 2-h infusion, every 14 days. World Health Organization (WHO)
      criteria were used to evaluate tumor response and toxicity. RESULTS: During
      treatment, no dose or schedule modifications were made. A median of three courses
      were given (range 1-8), and all but two patients received at least three complete
      chemotherapy courses. No objective or complete responses were observed. The best
      response achieved was stabilization in three patients, lasting from 1.5 to 4
      months. Significant toxicity occurred in two patients. CONCLUSIONS: Our results
      do not support a major role of CPT-11 in adrenocortical carcinoma.

PMID- 12419756
TI  - Phase I and pharmacokinetic study of docetaxel in combination with epirubicin and
      cyclophosphamide in advanced cancer: dose escalation possible with granulocyte
      colony-stimulating factor, but not with prophylactic antibiotics.
AB  - BACKGROUND: The objective of this phase I trial was to determine the maximally
      tolerated doses of the combination of docetaxel, epirubicin and cyclophosphamide.
      PATIENTS AND METHODS: Patients with advanced cancer, World Health Organization
      (WHO) performance status 0 to 2, who had received up to one prior chemotherapy
      regimen were treated with docetaxel, epirubicin and cyclophosphamide repeated
      every 21 days. The cyclophosphamide dose was fixed at 600 mg/m(2) and the dose
      levels studied were: docetaxel/epirubicin; 60/60, 75/60, 75/75, 75/90, 85/90 and
      85/105 mg/m(2). There was provision for the addition of prophylactic
      ciprofloxacin and granulocyte colony-stimulating factor (G-CSF) in separate steps
      if dose-limiting toxicity (DLT) was neutropenia related. RESULTS: Forty-three
      patients were entered and all were assessable for toxicity. Dose-limiting
      toxicity, predominantly febrile neutropenia, was surprisingly seen at the first
      dose level. The addition of prophylactic ciprofloxacin did not permit dose
      escalation, but dose escalation was possible with the addition of G-CSF. The
      highest administered dose level with G-CSF was docetaxel 85 mg/m(2) and
      epirubicin 105 mg/m(2) with DLTs in five of six patients. Treatment was well
      tolerated in 10 patients treated at the recommended dose level (85/90) with only
      one patient experiencing DLT. Responses were seen in a range of malignancies
      including breast and anaplastic thyroid cancers. No significant pharmacokinetic
      interaction was observed, but a transient increase in epirubicinol plasma
      concentration occurred during and after docetaxel infusion. CONCLUSIONS: The
      recommended dose level of docetaxel 85 mg/m(2), epirubicin 90 mg/m(2) and
      cyclophosphamide 600 mg/m(2) with G-CSF support has a favorable toxicity profile
      and is suitable for further investigation in phase II and III trials.

PMID- 12419757
TI  - Phase I study of rubitecan and gemcitabine in patients with advanced
      malignancies.
AB  - BACKGROUND: Rubitecan (9-nitrocamptothecin, 9-NC, Orathecin) and gemcitabine have
      single-agent activity in pancreatic and ovarian carcinoma. We conducted a phase I
      trial to evaluate the maximum tolerated dose (MTD) and toxicities of this
      combination in advanced malignancies. PATIENTS AND METHODS: Twenty-one patients
      with refractory or recurrent malignancies were enrolled in this dose escalation
      trial. Dose escalation proceeded from a starting level of rubitecan at 0.75
      mg/m(2)/day administered orally on days 1-5 and 8-12 in combination with
      gemcitabine 1000 mg/m(2) administered intravenously on days 1 and 8 of a 21-day
      cycle. RESULTS: The MTD was defined as rubitecan 1 mg/m(2) administered orally
      days 1-5 and 8-12, and gemcitabine 1000 mg/m(2) administered intravenously over
      30 min days 1 and 8, given every 21 days. Dose-limiting toxicity was
      myelosuppression including neutropenia and thrombocytopenia. Other side effects
      included diarrhea, nausea, vomiting and fatigue. Five patients with stable
      disease were observed among 18 evaluable patients. CONCLUSIONS: The recommended
      phase II dose is rubitecan 1 mg/m(2) given orally on days 1-5 and 8-12 in
      combination with gemcitabine 1000 mg/m(2) as a 30-min intravenous infusion on
      days 1 and 8 of a 21-day cycle.

PMID- 12419758
TI  - Primary brain CD30+ ALK1+ anaplastic large cell lymphoma ('ALKoma'): the first
      case with a combination of 'not common' variants.
AB  - BACKGROUND: Primary central nervous system lymphomas (PCNSLs) are rare tumors,
      mostly represented by diffuse large B cells. PCNSLs with a T phenotype are less
      frequently reported; even rarer are anaplastic large cell lymphomas (ALCLs).
      PCNSL ALCLs are commonly represented, like their systemic counterpart, by a
      variably prevalent amount of large pleomorphic tumor cells ('hallmark cells'),
      and this feature enhances their recognition. Patient and methods We report the
      first case of primary brain CD30+ ALK-1+ ALCL with a T-cell phenotype, showing
      the combination of both the 'lymphohistiocytic' and the 'small cell' variants of
      the disease. A few elements consistent with 'hallmark cells' were recognizable.
      However, these cells were never prominent, increasing diagnostic difficulties.
      Immunohistochemistry results were critical for the correct interpretation. Our
      findings also differ from the majority of PCNSL ALCLs for the absence of tumor
      necrosis and the lack of prominent mitotic activity. The neuroimaging picture was
      not specific. A comparison with literature data concerning the
      clinical/instrumental features shows a very frequent meningeal involvement in
      PCNSL ALCLs, in contrast to the majority of PCNSLs. CONCLUSION: The occurrence of
      such a rare form of ALCL may widen the spectrum of differential diagnoses in
      PCNSL and their recognition may allow a rapid diagnosis, thus encouraging
      adequate treatment, which should take into account the high rate of meningeal
      involvement observed in these cases.

PMID- 12419759
TI  - Severe tumor lysis syndrome during treatment with STI 571 in a patient with
      chronic myelogenous leukemia accelerated phase.

PMID- 12419760
TI  - Obstructive sleep apnea secondary to chronic lymphocytic leukemia.

PMID- 12419761
TI  - Mismatch repair genes hMLH1 and hMSH2 and colorectal cancer: a HuGE review.
AB  - Evidence to support a role for the mismatch repair genes human mutL homolog 1
      (hMLH1) and human mutS homolog 2 (hMSH2) in the etiology of colorectal cancer has
      come from linkage analysis, segregation studies, and molecular biologic analysis.
      More recently, carriers of potentially pathogenic mutations in the hMLH1/hMSH2
      genes have consistently been shown to be at a greatly increased risk of
      developing colorectal cancer compared with the general population. When
      considered together, the available evidence shows a strong, consistent, and
      biologically plausible association between mismatch repair gene mutations and
      colorectal cancer. The penetrance of mutations in hMLH1/hMSH2 is incomplete and
      is significantly higher in males (approximately 80%) than in females
      (approximately 40%). To date, evidence for gene-gene or gene-environment
      interactions is limited, although preliminary studies have revealed a number of
      avenues that merit exploration. Population screening for mutation carriers is not
      currently a feasible option, and mutation analysis remains restricted to either
      relatives of mutation carriers or colorectal cancer cases selected on the basis
      of phenotype.

PMID- 12419762
TI  - Who should be screened for postpartum anemia? An evaluation of current
      recommendations.
AB  - The authors evaluated the utility of selective screening criteria for postpartum
      anemia developed by the Centers for Disease Control and Prevention (CDC) versus
      criteria developed among low-income women using prevalence-based screening
      principles. Pregnant women in Raleigh, North Carolina, were followed up to the
      postpartum visit in 1997-1999 (n = 345). Prevalence of postpartum anemia was
      19.1%. Independent risk markers, arrived at through multivariate logistic
      regression, were multiparity (odds ratio (OR) = 1.5, 95% confidence interval
      (CI): 0.8, 2.9), obesity (OR = 3.0, 95% CI: 1.6, 5.5), anemia at 24-29 weeks'
      gestation (OR = 2.3, 95% CI: 1.2, 4.4), anemia before delivery (OR = 3.4, 95% CI:
      1.8, 6.7), and not exclusively breastfeeding (OR = 2.8, 95% CI: 1.0, 7.7). Risk
      scores were calculated by counting risk markers present. Likelihood ratios were
      determined for all possible risk scores of our algorithm and CDC's algorithm.
      Anemia screening decisions differed depending on clinic anemia prevalence. For
      example, if low test thresholds are assumed, when clinic prevalence is 10%, women
      with risk scores >3 on the authors' algorithm and >0 on CDC's algorithm should be
      screened. The authors' algorithm, in combination with prevalence information, can
      save clinics more money than CDC's current algorithm because a broader range of
      likelihood ratios was obtained, indicating a better ability to distinguish high-
      from low-risk women. However, if resources are available, universal screening
      should be considered in high-prevalence settings.

PMID- 12419763
TI  - Occupational magnetic field exposure and cardiovascular mortality in a cohort of
      electric utility workers.
AB  - In electric utility workers, occupational exposure to magnetic fields has
      previously been associated with mortality from acute myocardial infarction (AMI)
      and arrhythmia but not from chronic coronary heart disease (CCHD) or
      atherosclerosis. To investigate these health endpoints further, the authors
      examined mortality from AMI (n = 407) and CCHD (n = 369) in a cohort of 35,391
      male workers at the Southern California Edison Company between 1960 and 1992.
      Exposure was estimated according to duration of employment in occupations
      associated with high levels of magnetic field exposure and was calculated as
      cumulative exposure to magnetic fields expressed in micro-Tesla-years. Adjustment
      was made for age, calendar time, socioeconomic status, race, and worker status
      (active or inactive). The authors found that men working longer in high-exposure
      occupations or working as electricians, linemen, or power plant operators had no
      increased risk of dying from either AMI or CCHD compared with men who never
      worked in high-exposure occupations. For cumulative exposure, no association was
      observed with mortality from AMI (rate ratio per 1 micro T-year = 1.01, 95%
      confidence interval: 0.99, 1.02) or CCHD (rate ratio per 1 micro T-year = 1.00,
      95% confidence interval: 0.99, 1.02). These results, indicating no exposure
      related risk increase for AMI mortality, do not confirm previous results.

PMID- 12419764
TI  - Cardiovascular disease mortality in Hispanics and non-Hispanic whites.
AB  - Despite a worse cardiovascular disease (CVD) risk profile, Hispanics have lower
      CVD mortality than non-Hispanic Whites in studies based on death certificates.
      This study examined 310 deaths that occurred between 1984 and 1998 among 1,862
      Hispanic and non-Hispanic White participants in the San Luis Valley Diabetes
      Study, using medical records to classify cause of death. Among persons without
      diabetes, the age-adjusted all-cause mortality rate was 6.1/1,000 person-years in
      non-Hispanic Whites and 7.4/1,000 person-years in Hispanics. Among persons with
      diabetes, it was 24.3/1,000 person-years in non-Hispanic Whites and 21.9/1,000
      person-years in Hispanics. Among nondiabetics, the age-adjusted CVD mortality
      rate was 2.5/1,000 person-years in non-Hispanic Whites and 1.6/1,000 person-years
      in Hispanics. Among diabetics, it was 12.9/1,000 person-years in non-Hispanic
      Whites and 8.8/1,000 person-years in Hispanics. Among nondiabetics, the adjusted
      hazard ratio for CVD death in Hispanics compared with non-Hispanic Whites was
      0.65 (95% confidence interval (CI): 0.34, 1.23). The hazard ratio for coronary
      heart disease death was 0.95 (95% CI: 0.35, 2.59). Among diabetics, the hazard
      ratio for CVD death, after adjustment for conventional and diabetes risk factors,
      was 0.44 (95% CI: 0.26, 0.74), and for coronary heart disease death it was 0.43
      (95% CI: 0.21, 0.91). A statistically significant decreased risk of CVD death was
      observed only in male Hispanics with diabetes. Competing mortality or factors
      that interact with diabetes may explain these differences.

PMID- 12419765
TI  - Fifteen-year trends in cardiovascular risk factors (1980-1982 through 1995-1997):
      the Minnesota Heart Survey.
AB  - The objective was to describe trends in cardiovascular risk factors between 1980
      1982 and 1995-1997 in metropolitan Minneapolis-St. Paul, Minnesota. Four
      population-based surveys of 4,000-6,000 adults aged 25-74 years were conducted in
      1980-1982, 1985-1987, 1990-1992, and 1995-1997 using consistent sampling
      strategies and protocols. The authors completed interviews and examinations to
      characterize cardiovascular risk factors. Blood samples were drawn and assayed
      for several analytes including total cholesterol. Although total cholesterol
      decreased 7-9 mg/dl during the 1980s, no further reduction was noted between 1990
      1992 and 1995-1997. Hypercholesterolemia prevalence (total cholesterol of >240
      mg/dl and/or use of lipid-lowering medication) fell between 1980-1982 and 1990
      1992 but increased thereafter. Current cigarette smoking, systolic blood
      pressure, and hypertension prevalence decreased significantly between 1980-1982
      and 1995-1997. Body mass index increased substantially across the four surveys.
      Although there was little change in the mean leisure-time physical activity, the
      proportion of the population not engaging in regular exercise increased between
      1990-1992 and 1995-1997. Dietary fat decreased consistently from 1980-1982 to
      1995-1997, while overall caloric intake rose 8% in women but not men. To
      conclude, the favorable trends in hypertension, cigarette smoking, and dietary
      fat consumption observed in Minneapolis-St. Paul from 1980-1982 to 1995-1997 were
      paralleled by less favorable recent trends in total cholesterol,
      hypercholesterolemia, adiposity, and physical activity.

PMID- 12419766
TI  - Cigarette smoking and alcohol consumption in relation to cognitive performance in
      middle age.
AB  - In the elderly, cigarette smoking has been related to reduced cognitive
      performance and moderate alcohol consumption to increased cognitive performance.
      It is not clear whether these associations also exist in middle age. The authors
      examined these relations in a population-based cohort study of 1,927 randomly
      selected, predominantly middle-aged subjects aged 45-70 years at the time of
      cognitive testing and living in the Netherlands. From 1995 until 2000, an
      extensive cognitive battery was administered, and compound scores were
      calculated. Risk factors had been assessed approximately 5 years previously.
      Multiple linear regression analyses (in which one unit of the cognitive score =
      one standard deviation) showed that, after the authors adjusted for age, sex,
      education, alcohol consumption, and cardiovascular risk factors, current smokers
      had reduced psychomotor speed (beta = -0.159, 95% confidence interval: -0.071, 
      0.244; p = 0.0003) and reduced cognitive flexibility (beta = -0.133, 95%
      confidence interval: -0.035, -0.230; p = 0.008) compared with never smokers. This
      effect was similar to that of being approximately 4 years older. Alcohol
      consumption was related to increased speed and better flexibility, especially
      among women who drank 1-4 alcoholic beverages a day. In conclusion, among middle
      aged subjects, current smoking was inversely and alcohol consumption positively
      related to psychomotor speed and cognitive flexibility. This finding suggests
      that actions to prevent cognitive decline can be taken in middle age.

PMID- 12419767
TI  - Vigorous leisure activity through women's adult life: the Women's Health
      Initiative Observational Cohort Study.
AB  - This study described differences in vigorous activity participation recalled
      across the life span, assessed whether reports of past vigorous activity were
      associated with current participation, and examined factors associated with
      participation in current vigorous activity among women. After the exclusion of
      women aged 50-54 years, the study population included 71,837 multiethnic
      postmenopausal women aged 55-79 years who were participating in the Women's
      Health Initiative Observational Cohort Study, 1993-1998. Vigorous activity was
      assessed retrospectively for ages 18, 35, and 50 years and currently at
      enrollment into the study (median age, 65 years). Current participation in
      vigorous activity (>3 days/week) was low and consistent across racial/ethnic
      groups (13-16%). The prevalence of vigorous activity declined with age, with the
      largest decrease in vigorous activity occurring after age 50 years for all
      racial/ethnic groups. Current vigorous activity was generally higher among women
      with a lower body mass index, not currently smoking, in excellent general health,
      and of higher socioeconomic status across racial/ethnic groups. These data
      suggest that a lower prevalence of vigorous activity in the postmenopausal period
      is part of a complex of health-related attitudes and behaviors that transcends
      race/ethnicity. The perimenopausal period may be a critical juncture at which
      targeted and tailored interventions may help to achieve maintenance of physical
      activity into the postmenopausal period.

PMID- 12419768
TI  - Maternal smoking during pregnancy and childhood obesity.
AB  - A recent cohort study suggested that maternal smoking during pregnancy might be a
      risk factor for childhood obesity. Data from the obligatory school entry health
      examination in six Bavarian (Germany) public health offices in 1999-2000 were
      used to assess the relation between maternal smoking during pregnancy and
      childhood obesity (n = 6,483 German children aged 5.00-6.99 years). A body mass
      index greater than the 90th percentile was defined as overweight, and a body mass
      index greater than the 97th percentile was defined as obesity. The main exposure
      was maternal smoking during pregnancy. The prevalences of overweight and obesity,
      expressed as percentages, increased in the following order: never smoked
      (overweight: 8.1, 95% confidence interval (CI): 7.2, 9.0; obesity: 2.2, 95% CI:
      1.7, 2.7); less than 10 cigarettes daily (overweight: 14.1, 95% CI: 11.1, 17.7;
      obesity: 5.7, 95% CI: 3.7, 8.2); and 10 or more cigarettes daily (overweight:
      17.0, 95% CI: 10.1, 26.2; obesity: 8.5, 95% CI: 3.7, 16.1). The adjusted odds
      ratios for maternal smoking during pregnancy were 1.43 (95% CI: 1.07, 1.90) for
      overweight and 2.06 (95% CI: 1.31, 3.23) for obesity. A dose-dependent
      association between overweight/obesity and maternal smoking during pregnancy was
      observed that could not be explained by a wide range of confounders, suggesting
      that intrauterine exposure to inhaled smoke products rather than lifestyle
      factors associated with maternal smoking accounts for this finding.

PMID- 12419769
TI  - Dietary quality and lifestyle factors in relation to 10-year mortality in older
      Europeans: the SENECA study.
AB  - The single and combined effects of three healthy lifestyle behaviors-nonsmoking,
      being physically active, and having a high-quality diet-on survival were
      investigated among older people in the SENECA Study. This European longitudinal
      study started with baseline measurements in 1988-1989 and lasted until April 30,
      1999. The study population consisted of 631 men and 650 women aged 70-75 years
      from Belgium, Denmark, Italy, The Netherlands, Portugal, Spain, and Switzerland.
      A lifestyle score was calculated by adding the scores of the lifestyle factors
      physical activity, dietary quality, and smoking habits. The single lifestyle
      factors and the lifestyle score were related to mortality. Even at ages 70-75
      years, the unhealthy lifestyle behaviors smoking, having a low-quality diet, and
      being physically inactive were singly related to an increased mortality risk
      (hazard ratios ranged from 1.2 to 2.1). The risk of death was further increased
      for all combinations of two unhealthy lifestyle behaviors. Finally, men and women
      with all three unhealthy lifestyle behaviors had a three- to fourfold increase in
      mortality risk. These results underscore the importance of a healthy lifestyle,
      including multiple lifestyle factors, and the maintenance of it with advancing
      age.

PMID- 12419770
TI  - Alcohol intake and sickness absence: a curvilinear relation.
AB  - Little is known about the U-shaped relation between alcohol intake and health
      beyond findings related to cardiovascular disease. Medically certified sickness
      absence is a health indicator in which coronary heart disease is only a minor
      factor. To investigate the relation between alcohol intake and sickness absence,
      records regarding medically certified sick leaves from all causes were assessed
      for 4 years (1997-2000) in a cohort of 1,490 male and 4,952 female municipal
      employees in Finland. Hierarchical Poisson regression, adjusted for self-reported
      behavioral and biologic risk factors, psychosocial risk factors, and
      cardiovascular diseases, was used to estimate the rate ratios and their 95%
      confidence intervals, relating sickness absence to each level of alcohol
      consumption. For both men and women, a significant curvilinear trend was found
      between level of average weekly alcohol consumption and sickness absence. The
      rates of medically certified sickness absence were 1.2-fold higher (95%
      confidence interval: 1.1, 1.3) for never, former, and heavy drinkers compared
      with light drinkers. The U-shaped relation between alcohol intake and health is
      not likely to be explained by confounding due to psychosocial differences or
      inclusion of former drinkers in the nondrinkers category. Moderate alcohol
      consumption also may reduce health problems other than cardiovascular disease.

PMID- 12419771
TI  - Childhood asthma in Beijing, China: a population-based case-control study.
AB  - China is the most populous country in the world. Few studies, however, have been
      conducted there to investigate the risk factors for childhood asthma. A
      population-based case-control study was conducted in Shunyi County, People's
      Republic of China, in January 1999 and March 2001 to investigate the issue. An
      increased risk of childhood asthma was associated with smoking by relatives in
      front of the mother while she was pregnant with the child (odds ratio (OR) = 1.3,
      95% confidence interval (CI): 1.0, 1.6) and with smoking by relatives in front of
      the child (OR = 1.4, 95% CI: 1.1, 1.9). The risk increased with the increasing
      number of smokers and the total minutes of smoking by relatives in front of both
      the child and the mother while she was pregnant with the child. An increased risk
      was observed for use of coal for heating (OR = 1.5, 95% CI: 1.1, 1.9). Those who
      reported using coal for cooking without ventilation also had an increased risk
      (OR = 2.3, 95% CI: 1.5, 3.5). An increased risk was observed for those who
      reported having molds or fungi on the ceilings of their houses (OR = 1.8, 95% CI:
      1.1, 2.9) or inside the child's room (OR = 1.8, 95% CI: 1.0, 3.2). An increased
      risk was also found for those having both a dog and a cat as pets (OR = 1.5, 95%
      CI: 1.0, 2.3) or for finding both cockroaches and rats inside their houses (OR =
      1.8, 95% CI: 1.2, 2.8).

PMID- 12419772
TI  - Molecular cloning, expression, and function of osteoclastic calcineurin Aalpha.
AB  - This study explores the role of the calmodulin- and Ca(2+)-sensitive phosphatase
      calcineurin A in the control of bone resorption by mature osteoclasts. We first
      cloned full-length calcineurin Aalpha and Abeta cDNA from a rabbit osteoclast
      library. Sequence analysis revealed an approximately 95 and 86% homology between
      the amino acid and the nucleotide sequences, respectively, of the two isoforms.
      The two rabbit isoforms also showed significant homology with the mouse, rat, and
      human homologs. In situ RT-PCR showed evidence of high levels of expression of
      calcineurin Aalpha mRNA in freshly isolated rat osteoclasts. Semiquantitative
      analysis of staining intensity revealed no significant difference in calcineurin
      Aalpha expression in cells treated with vehicle vs. those treated with the
      calcineurin (activity) inhibitors cyclosporin A (8 x 10(-7) M) and FK506 (5 x 10(
      9) and 5 x 10(-7) M). We then constructed a fusion protein comprising calcineurin
      Aalpha and TAT, a 12-amino acid-long arginine-rich sequence of the human
      immunodeficiency virus protein. Others have previously shown that the fusion of
      proteins to this sequence results in their receptor-less transduction into cells,
      including osteoclasts. Similarly, unfolding of the TAT-calcineurin Aalpha fusion
      protein by shocking with 8 M urea resulted in its rapid influx, within minutes,
      into as many as 90% of all freshly isolated rat osteoclasts, as was evident on
      double immunostaining with anti-calcineurin Aalpha and anti-TAT antibodies. Pit
      assays performed with TAT-calcineurin Aalpha-positive osteoclasts revealed a
      concentration-dependent (10-200 nM) attenuation of bone resorption in the absence
      of cell cytotoxicity or changes in cell number. TAT-hemaglutinin did not produce
      significant effects on bone resorption or cell number. The study suggests the
      following: 1) the 61-kDa protein phosphatase calcineurin Aalpha can be
      effectively tranduced into osteoclasts by using the TAT-based approach, and 2)
      the transduced protein retains its capacity to inhibit osteoclastic bone
      resorption.

PMID- 12419773
TI  - High glucose promotes mesangial cell apoptosis by oxidant-dependent mechanism.
AB  - Reactive oxygen species are recognized as important mediators of biological
      responses. Hyperglycemia promotes the intracellular generation of superoxide
      anion and hydrogen peroxide. In several cell lines, oxidant stress has been
      linked to the activation of death programs. Here, we report for the first time
      that high ambient glucose concentration induces apoptosis in murine and human
      mesangial cells by an oxidant-dependent mechanism. The signaling cascade
      activated by glucose-induced oxidant stress included the heterodimeric redox
      sensitive transcription factor NF-kappaB, which exhibited an upregulation in
      p65/c-Rel binding activity and suppressed binding activity of the p50 dimer.
      Recruitment of NF-kappaB and mesangial cell apoptosis were both inhibited by
      antioxidants, implicating oxidant-induced activation of NF-kappaB in the
      transmission of the death signal. The genetic program for glucose-induced
      mesangial cell apoptosis was characterized by an upregulation of the Bax/Bcl-2
      ratio. In addition, phosphorylation of the proapoptotic protein Bad was
      attenuated in mesangial cells maintained at high-glucose concentration, favoring
      progression of the apoptotic process. These perturbations in the expression and
      phosphorylation of the Bcl-2 family were coupled with the release of cytochrome c
      from mitochondria and caspase activation. Our findings indicate that in mesangial
      cells exposed to high ambient glucose concentration, oxidant stress is a
      proximate event in the activation of the death program, which culminates in
      mitochondrial dysfunction and caspase-3 activation, as the terminal event.

PMID- 12419774
TI  - Chemical anoxia of tubular cells induces activation of c-Src and its
      translocation to the zonula adherens.
AB  - Cyanide (CN)-induced chemical anoxia of cultured mouse proximal tubular (MPT)
      cells increased the kinase activity of c-Src by approximately threefold. 4-Amino
      5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2), a specific
      inhibitor of c-Src, prevented Src activation. CN also increased the permeability
      of MPT cell monolayers, an event ameliorated by PP2. During CN treatment, the
      proteins of the zonula adherens (ZA; E-cadherin and the catenins) disappeared
      from their normal location at cell-cell borders and appeared within the cytosol.
      CN also resulted in the appearance of c-Src at cell-cell borders. PP2 prevented
      these CN-induced alterations in the distribution of ZA proteins and c-Src. CN
      also increased the association of c-Src with beta-catenin and p120 and induced a
      substantial increase in tyrosine phosphorylation of both catenins. PP2 prevented
      the CN-induced phosphorylation of these catenins. In summary, we show that CN
      induced chemical anoxia activates c-Src and induces its translocation to cell
      cell junctions where it binds to and phosphorylates beta-catenin and p120. Our
      findings suggest that these events contribute to the loss of the epithelial
      barrier function associated with chemical anoxia.

PMID- 12419775
TI  - Renal arterial 20-hydroxyeicosatetraenoic acid levels: regulation by
      cyclooxygenase.
AB  - 20-HETE, a potent vasoconstrictor, is generated by cytochrome P-450 omega
      hydroxylases and is the principal eicosanoid produced by preglomerular
      microvessels. It is released from preglomerular microvessels by ANG II and is
      subject to metabolism by cyclooxygenase (COX). Because low-salt (LS) intake
      stimulates the renin-angiotensin system and induces renal cortical COX-2
      expression, we examined 20-HETE release from renal arteries (interlobar and
      arcuate and interlobular arteries) obtained from 6- to 7-wk-old male Sprague
      Dawley rats fed either normal salt (0.4% NaCl) or LS (0.05% NaCl) diets for 10
      days. With normal salt intake, the levels of 20-HETE recovered were similar in
      arcuate and interlobular arteries and interlobar arteries: 30.1 +/- 8.5 vs. 24.6
      +/- 5.3 ng. mg protein(-1). 30 min(-1), respectively. An LS diet increased 20
      HETE levels in the incubate of either arcuate and interlobular or interlobar
      renal arteries only when COX was inhibited. Addition of indomethacin (10 microM)
      to the incubate of arteries obtained from rats fed an LS diet resulted in a two-
      to threefold increase in 20-HETE release from arcuate and interlobular arteries,
      from 39.1 +/- 13.2 to 101.8 +/- 42.6 ng. mg protein(-1). 30 min(-1) (P < 0.03),
      and interlobar arteries, from 31.7 +/- 15.1 to 61.9 +/- 29.4 ng. mg protein(-1).
      30 min(-1) (P < 0.05) compared with release of 20-HETE when COX was not
      inhibited. An LS diet enhanced vascular expression of cytochrome P-4504A and COX
      2 in arcuate and interlobular arteries; COX-1 was unaffected. Metabolism of 20
      HETE by COX is proposed to represent an important regulatory mechanism in setting
      preglomerular microvascular tone.

PMID- 12419776
TI  - pH is decreased in transplanted rat pancreatic islets.
AB  - Recent studies of transplanted pancreatic islets have indicated incomplete
      revascularization. We investigated the pH, in relation to oxygen tension (Po(2)),
      in endogenous islets and islets syngeneically transplanted to the renal
      subcapsular site of nondiabetic and streptozotocin-diabetic recipients. Tissue pH
      and Po(2) were measured using microelectrodes. In the endogenous islets, tissue
      pH was similar to that in arterial blood. In the transplanted islets, tissue pH
      was 0.11-0.15 pH units lower. No differences in islet graft pH were seen between
      nondiabetic and diabetic animals, and none if the islet grafts were investigated
      1 day or 1 mo posttransplantation. The Po(2) in the endogenous islets was
      approximately 35 mmHg. Transplanted islets had a markedly lower tissue Po(2) both
      1 day and 1 mo after transplantation. A negative correlation between the tissue
      Po(2) and the hydrogen ion concentration was seen in the 1-mo-old islet
      transplants in diabetic animals. In conclusion, decreased Po(2) in transplanted
      islets is associated with a decreased tissue pH, suggesting a shift toward more
      anaerobic glucose metabolism after transplantation.

PMID- 12419777
TI  - Chronic inflammation and the effect of IGF-I on muscle strength and power in
      older persons.
AB  - Deregulation of the inflammatory response plays a major role in the age-related
      decline of physical performance. The causal pathway leading from inflammation to
      disability has not been fully clarified, but several researches suggest that
      interleukin-6 (IL-6) causes a reduction of physical performance in elderly
      through its effect on muscle function. In vitro studies demonstrated that IL-6
      inhibits the secretion of insulin-like growth factor I (IGF-I) and its biological
      activity, suggesting that the negative effect of IL-6 on muscle function might be
      mediated through IGF-I. We evaluated the joint effect of IGF-I and IL-6 on muscle
      function in a population-based sample of 526 persons with a wide age range (20
      102 yr). After adjusting for potential confounders, such as age, sex, body mass
      index, IL-6 receptor, and IL-6 promoter polymorphism, IL-6, IGF-I, and their
      interaction were significant predictors of handgrip and muscle power. In analyses
      stratified by IL-6 tertiles, IGF-I was an independent predictor of muscle
      function only in subjects in the lowest IL-6 tertile, suggesting that the effect
      of IGF-I on muscle function depends on IL-6 levels. This mechanism may explain
      why IL-6 is a strong risk factor for disability.

PMID- 12419778
TI  - Are genital infections and inflammation cofactors in the pathogenesis of invasive
      cervical cancer?

PMID- 12419779
TI  - Treatment of nasopharyngeal cancer: raising the "Barr".

PMID- 12419780
TI  - Despite concerns, FDA panel backs EGFR inhibitor.

PMID- 12419781
TI  - Tobacco programs wither as states divert settlement revenue.

PMID- 12419782
TI  - States' allocation of tobacco settlement revenue, 2000 and 2001.

PMID- 12419783
TI  - Whatever happened to...? Looking back 10 years.

PMID- 12419784
TI  - Entire family faces consequences of lack of insurance, report finds.

PMID- 12419785
TI  - Recruitment begins for lung cancer screening trial.

PMID- 12419786
TI  - Herpes simplex virus-2 as a human papillomavirus cofactor in the etiology of
      invasive cervical cancer.
AB  - BACKGROUND: Human papillomavirus (HPV) infection is the main cause of invasive
      cervical cancer, but cofactors may act in conjunction with HPV. We performed a
      pooled analysis of seven case-control studies to examine the effect of one
      possible HPV cofactor, herpes simplex virus-2 (HSV-2) infection, in the etiology
      of invasive cervical cancer. METHODS: Blood and exfoliated cervical specimens
      were obtained from 1263 case patients with invasive cervical cancer (1158 with
      squamous-cell carcinomas and 105 with adeno- or adenosquamous-cell carcinomas)
      and 1117 age-matched control subjects. Western blot analysis and/or an enzyme
      linked immunosorbent assay were used to detect type-specific serum antibodies to
      HSV-2 and HSV-1, and Chlamydia trachomatis serum antibodies were detected using a
      micro-immunofluorescence assay. HPV DNA was detected using a polymerase chain
      reaction assay. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were
      computed from unconditional logistic regression models. RESULTS: Overall, HSV-2
      seropositivity was higher among case patients with squamous-cell carcinoma
      (44.4%, 95% CI = 41.5% to 47.3%) or adeno- or adenosquamous-cell carcinoma
      (43.8%, 95% CI = 34.2% to 53.5%) than among control subjects (25.6%, 95% CI =
      23.0% to 28.2%). Cervical specimens from 1098 (94.8%) squamous-cell carcinoma
      case patients, 95 (90.5%) adeno- or adenosquamous carcinoma case patients, and
      164 (14.7%) control subjects were positive for HPV DNA. Among the HPV DNA
      positive women, HSV-2 seropositivity was associated with increased risks of
      squamous-cell carcinoma (OR = 2.19, 95% CI = 1.41 to 3.40) and adeno- or
      adenosquamous-cell carcinoma (OR = 3.37, 95% CI = 1.47 to 7.74) after adjustment
      for potential confounders. A similar association between HSV-2 seropositivity and
      squamous-cell carcinoma risk was observed after further controlling for markers
      of sexual behavior (OR = 1.96, 95% CI = 1.24 to 3.09). Among control subjects,
      HSV-2 seropositivity was associated with markers of sexual behavior, but not with
      cervical HPV DNA positivity. CONCLUSION: HSV-2 infection may act in conjunction
      with HPV infection to increase the risk of invasive cervical carcinoma.

PMID- 12419787
TI  - Plasma Epstein-Barr virus DNA and residual disease after radiotherapy for
      undifferentiated nasopharyngeal carcinoma.
AB  - BACKGROUND: Epstein-Barr virus (EBV) DNA can be detected and quantified in the
      plasma of patients with EBV-related tumors, such as nasopharyngeal carcinoma
      (NPC). Although NPC at early stages can be cured by radical radiotherapy, there
      is a high recurrence rate in patients with advanced NPC. The pretreatment level
      of circulating EBV DNA is a prognostic factor for NPC, but the prognostic value
      of post-treatment EBV DNA has not been studied. We designed a prospective study
      in Hong Kong, China, to investigate the value of plasma EBV DNA as a prognostic
      factor for NPC. METHODS: One hundred seventy NPC patients, without metastatic
      disease at presentation, were treated with a uniform radiotherapy protocol.
      Circulating EBV DNA was measured by real-time quantitative polymerase chain
      reaction before treatment and 6-8 weeks after radiotherapy was completed. Risk
      ratios (RRs) were determined with a Cox regression model, and associations of
      various factors with progression-free and overall survival and recurrence rates
      were determined with a stepwise Cox proportional hazards model. All statistical
      tests were two-sided. RESULTS: Ninety-nine percent of patients achieved complete
      clinical remission. Levels of post-treatment EBV DNA dominated the effect of
      levels of pretreatment EBV DNA for progression-free survival. The RR for NPC
      recurrence was 11.9 (95% confidence interval [CI] = 5.53 to 25.43) for patients
      with higher post-treatment EBV DNA and 2.5 (95% CI = 1.14 to 5.70) for patients
      with higher pretreatment EBV DNA. Higher levels of post-treatment EBV DNA were
      statistically significantly associated with overall survival (P<.001; RR for NPC
      recurrence = 8.6, 95% CI = 3.69 to 19.97). The positive and negative predictive
      values for NPC recurrence for a higher level of post-treatment EBV DNA were 87%
      (95% CI = 58% to 98%) and 83% (95% CI = 76% to 89%), respectively. CONCLUSION:
      Levels of post-treatment plasma EBV DNA in patients with NPC appear to strongly
      predict progression-free and overall survival and to accurately reflect the post
      treatment residual tumor load.

PMID- 12419788
TI  - Baseline dietary fiber intake and colorectal adenoma recurrence in the wheat bran
      fiber randomized trial.
AB  - BACKGROUND: The Wheat Bran Fiber (WBF) trial was a double-blind, high-fiber
      versus low-fiber phase III intervention trial in which participants were randomly
      assigned to receive a cereal fiber supplement of either 2.0 g/day or 13.5 g/day
      to assess whether a high-fiber supplement could decrease risk of recurrent
      colorectal adenomas. Although no effect of the supplement on polyp recurrence was
      observed, participants consumed a baseline average of 17.5 grams of fiber per
      day, which may have been sufficient to protect against adenoma recurrence.
      Therefore, we examined whether baseline fiber intake affected colorectal adenoma
      recurrence or modified the effect of treatment group in the WBF trial
      participants. METHODS: Quartiles of baseline fiber intake were calculated on the
      basis of the distribution in the study population. Odds ratios (ORs) for adenoma
      recurrence were calculated using the lowest quartile of fiber intake as the
      reference. The effect of fiber from specific food sources on adenoma recurrence
      was also assessed. All statistical tests were two-sided. RESULTS: Adjusted ORs
      (95% confidence intervals) for adenoma recurrence were 0.79 (0.56 to 1.12), 0.76
      (0.54 to 1.08), and 0.83 (0.57 to 1.19) for the second, third, and fourth
      quartiles, respectively. Fiber from the three primary food sources (fruits;
      breads, cereals and crackers; and vegetables) had no appreciable effect on
      adenoma recurrence. Baseline fiber intake also had little effect on adenoma
      recurrence when the population was stratified by treatment group. In addition,
      there was no interaction between treatment group and quartile of baseline fiber
      intake. CONCLUSIONS: No association was found between amount of fiber consumed at
      baseline and adenoma recurrence in the WBF trial participants. The baseline fiber
      intake, whether considered as a whole or from specific sources, did not modify
      the effect of treatment group.

PMID- 12419789
TI  - Trends in use of adjuvant multi-agent chemotherapy and tamoxifen for breast
      cancer in the United States: 1975-1999.
AB  - BACKGROUND: Understanding trends in the dissemination of findings from clinical
      research can help in estimating their population-level benefits. We evaluated
      trends in the use of adjuvant multi-agent chemotherapy, tamoxifen, and the
      combination of both treatments for early-stage breast cancer in the United States
      from 1975 through 1999. METHODS: Data on treatment of 217 508 patients diagnosed
      from 1975 through 1999 with stages I, II, and IIIA breast cancer were obtained
      from eight registries of the Surveillance, Epidemiology, and End Results (SEER)
      Program. Models of dissemination were developed from these data after adjustment
      based on information from a series of population-based Patterns of Care (POC)
      studies that randomly selected case patients from the SEER registries. The POC
      studies included 7116 patients diagnosed from 1987 through 1991 and in 1995 who
      were eliminated from the SEER data used in this analysis. RESULTS: The modeled
      disseminations were generally compatible with the POC-observed proportions of
      each treatment. The use of multi-agent chemotherapy was higher among
      premenopausal women, and the use of tamoxifen was higher among postmenopausal
      women. The use of multi-agent chemotherapy for postmenopausal women diagnosed
      with lymph node-positive stage II+ or stage IIIA cancer reached a peak in 1983
      and then decreased through 1986, indicating its substitution with tamoxifen.
      After 1986, the combined use of multi-agent chemotherapy and tamoxifen increased
      for almost all stages and ages. After the early 1990s, tamoxifen use in
      postmenopausal women with stage II+ or stage III breast cancer declined.
      CONCLUSIONS: The observed dissemination patterns suggest that the results of
      clinical trials are disseminated fairly rapidly to community-based physicians and
      their patients.

PMID- 12419790
TI  - Association between sulfotransferase 1A1 genotype and survival of breast cancer
      patients receiving tamoxifen therapy.
AB  - BACKGROUND: Human sulfotransferase 1A1 (SULT1A1) catalyzes the sulfation of a
      variety of phenolic and estrogenic compounds, including 4-hydroxytamoxifen (4-OH
      TAM), the active metabolite of tamoxifen. A functional polymorphism in exon 7 of
      the SULT1A1 gene (SULT1A1*2) has been described that generates an enzyme that has
      approximately twofold lower activity and is less thermostable than that of the
      common allele SULT1A1*1. We investigated the hypothesis that that high sulfation
      activity would increase the elimination of 4-OH TAM by examining whether the
      presence of this polymorphism affects the efficacy of tamoxifen therapy. METHODS:
      We examined the relationship between the SULT1A1*2 allele and survival in a
      cohort of 337 women with breast cancer who received tamoxifen (n = 160) or who
      did not (n = 177). SULT1A1 genotype was determined by restriction fragment
      polymorphism analysis. Patient survival was evaluated according to SULT1A1
      genotype using Kaplan-Meier survival functions. Hazard ratios (HRs) were
      calculated from adjusted Cox proportional hazards modeling. All statistical tests
      were two-sided. RESULTS: Among tamoxifen-treated patients, those who were
      homozygous for the SULT1A1*2 low-activity allele had approximately three times
      the risk of death (HR = 2.9, 95% confidence interval [CI] = 1.1 to 7.6) as those
      who were homozygous for the common allele or those who were heterozygous
      (SULT1A1*1/*2). Among patients who did not receive tamoxifen, there was no
      association between survival and SULT1A1 genotype (HR = 0.7, 95% CI = 0.3 to
      1.5). CONCLUSIONS: Sulfation of 4-OH TAM provides a previously unanticipated
      benefit, possibly due to alterations in the bioavailability of the active
      metabolite or to undefined estrogen receptor-mediated events. These data
      alternatively suggest that variability in the metabolism of tamoxifen may affect
      its efficacy.

PMID- 12419791
TI  - Effects of the herbal extract PC-SPES on microtubule dynamics and paclitaxel
      mediated prostate tumor growth inhibition.
AB  - BACKGROUND: PC-SPES is a botanical preparation shown to have efficacy in patients
      with androgen-dependent and androgen-independent prostate carcinoma. Several
      herbal constituents in PC-SPES inhibit tumor growth through cell cycle arrest and
      apoptosis, although the mechanisms of these activities are poorly defined. We
      sought to identify PC-SPES-induced changes in gene expression, specifically in
      those genes encoding cytoskeletal proteins that could be associated with PC-SPES
      induced cytoxicity. METHODS: LNCaP prostate carcinoma cells were treated with PC
      SPES, and changes in gene expression were determined by complementary DNA (cDNA)
      microarray hybridization and northern blot analyses. PC-SPES and paclitaxel, a
      microtubule-stabilizing drug, effects on microtubules were assessed by
      immunofluorescence of treated cells and by in vitro tubulin polymerization
      assays. In vivo effects of PC-SPES and paclitaxel were assessed using CWR22R
      androgen-independent prostate cancer xenografts. All statistical tests were two
      sided. RESULTS: PC-SPES treatment of LNCaP cells for 24 hours altered the
      expression of 17 cytoskeletal genes. mRNA levels of alpha-tubulin decreased
      sevenfold. Although paclitaxel stabilized and PC-SPES treatment disrupted
      microtubule architecture in LNCaP cells, the combination of both agents had an
      intermediate effect. PC-SPES inhibited tubulin polymerization in vitro, even in
      the presence of paclitaxel. Compared with tumors in control mice (mean tumor
      volume = 2983 mm(3), 95% confidence interval [CI] = 2380 to 3586 mm(3)), tumors
      were statistically significantly smaller in mice that received PC-SPES (mean
      tumor volume = 2018 mm(3), 95% CI = 1450 to 2568 mm(3); P =.028), paclitaxel
      (mean tumor volume = 1340 mm(3), 95% CI = 697 to 1983 mm(3); P<.001), or the
      combination of PC-SPES and paclitaxel (mean tumor volume = 1955 mm(3), 95% CI =
      1260 to 2650 mm(3); P =.034). CONCLUSION: PC-SPES may interfere with microtubule
      polymerization. This activity has implications for the clinical management of
      patients with advanced prostate cancer who may be taking PC-SPES concurrently
      with microtubule-modulating chemotherapeutic agents, such as paclitaxel.

PMID- 12419792
TI  - Allium vegetables and risk of prostate cancer: a population-based study.
AB  - Epidemiologic and laboratory studies suggest that allium vegetables and garlic
      constituents have antitumor effects. In a population-based, case-control study
      conducted in Shanghai, China, we investigated the association between intake of
      allium vegetables, including garlic, scallions, onions, chives, and leeks, and
      the risk of prostate cancer. We administered in-person interviews and collected
      information on 122 food items from 238 case subjects with incident,
      histologically confirmed prostate cancer and from 471 male population control
      subjects. Men in the highest of three intake categories of total allium
      vegetables (>10.0 g/day) had a statistically significantly lower risk (odds ratio
      [OR] = 0.51, 95% confidence interval [CI] = 0.34 to 0.76; P(trend)<.001) of
      prostate cancer than those in the lowest category (<2.2 g/day). Similar
      comparisons between categories showed reductions in risk for men in the highest
      intake categories for garlic (OR = 0.47, 95% CI = 0.31 to 0.71; P(trend)<.001)
      and scallions (OR = 0.30, 95% CI = 0.18 to 0.51; P(trend)<.001). The reduced risk
      of prostate cancer associated with allium vegetables was independent of body
      size, intake of other foods, and total calorie intake and was more pronounced for
      men with localized than with advanced prostate cancer.

PMID- 12419794
TI  - Multidrug-resistant MCF-7 cells: an identity crisis?

PMID- 12419795
TI  - Re: Adherence to therapy with oral antineoplastic agents.

PMID- 12419797
TI  - Survivin enhances Aurora-B kinase activity and localizes Aurora-B in human cells.
AB  - Survivin, one of the most tumor-specific gene products, has been implicated in
      both anti-apoptosis and cytokinesis. However, the mechanism by which survivin
      regulates these two different processes is still elusive. Here, we show that
      survivin binds to the catalytic domain of Aurora-B. We demonstrate that in the
      presence of survivin, Aurora-B phosphorylates histone H3 much more efficiently
      than in the absence of survivin in a cell-free system. Furthermore, we confirm
      that cells lacking survivin due to survivin antisense oligonucleotide-treatment
      have lower Aurora-B kinase activity, whereas cells overexpressing survivin have
      higher Aurora-B kinase activity. We also provide evidence that depletion of
      survivin by survivin antisense oligonucleotide treatment causes significant
      reduction of endogenous phosphorylated histone H3 and mislocalization of Aurora
      B. These results indicate that survivin stimulates Aurora-B kinase activity and
      helps correctly target Aurora-B to its substrates during the cell cycle, thus
      providing a mechanism as to how survivin exerts its function in human cells.

PMID- 12419798
TI  - Calmodulin regulates the transcriptional activity of estrogen receptors.
      Selective inhibition of calmodulin function in subcellular compartments.
AB  - The steroid hormone estrogen elicits biological effects in cells by binding to
      and activating the estrogen receptor (ER). Estrogen binding induces a
      conformational change in the receptor, inducing nuclear translocation and
      transcriptional activation of ER. The ubiquitous Ca(2+)-binding protein
      calmodulin has been shown to interact directly with ER and enhance its stability.
      To further elucidate the functional sequelae of the association between
      calmodulin and ER, we examined the effect on ER transcriptional activation of
      specifically inhibiting calmodulin. The cell-permeable calmodulin antagonist
      CGS9343B prevented estrogen-induced transcriptional activation by ER, without
      altering basal transcription. The inhibition was dose-dependent and independent
      of the time of estrogen stimulation. To validate these findings, calmodulin
      function was also neutralized by targeted expression of a specific inhibitor
      peptide. By inserting localization signals, the inhibitor peptide was selectively
      targeted to different subcellular domains. Inactivation of calmodulin function in
      the nucleus virtually eliminated estrogen-stimulated ER transcriptional
      activation. By contrast, when membrane calmodulin was specifically neutralized,
      estrogen-stimulated transcriptional activation by ER was only slightly
      attenuated. Importantly, the inhibitor peptides did not significantly reduce the
      amount of ER in the cells. Together, these data demonstrate that calmodulin is a
      fundamental component of ER transcriptional activation.

PMID- 12419799
TI  - Human T-lymphotropic virus type I tax activates I-kappa B kinase by inhibiting I
      kappa B kinase-associated serine/threonine protein phosphatase 2A.
AB  - I-kappa B kinase (IKK) is a serine/threonine kinase that phosphorylates I-kappa B
      alpha and I-kappa B beta and targets them for polyubiquitination and proteasome
      mediated degradation. IKK consists of two highly related catalytic subunits,
      alpha and beta, and a regulatory gamma subunit, which becomes activated after
      serine phosphorylation of the activation loops of the catalytic domains. The
      human T-lymphotropic retrovirus type-I trans-activator, Tax, has been shown to
      interact directly with IKK gamma and activates IKK via a mechanism not fully
      understood. Here we demonstrate that IKK binds serine/threonine protein
      phosphatase 2A (PP2A), and via a tripartite protein-protein interaction, Tax, IKK
      gamma, and PP2A form a stable ternary complex. In vitro, PP2A down-regulates
      active IKK prepared from Tax-producing MT4 cells. In the presence of Tax,
      however, the ability of PP2A to inactivate IKK is diminished. Despite their
      interaction with IKK gamma, PP2A-interaction-defective Tax mutants failed to
      activate NF-kappa B. Our data support the notion that IKK gamma-associated PP2A
      is responsible for the rapid deactivation of IKK, and inhibition of PP2A by Tax
      in the context of IKK x PP2A x Tax ternary complex leads to constitutive IKK and
      NF-kappa B activation.

PMID- 12419800
TI  - Isolation, structure, and activity of GID, a novel alpha 4/7-conotoxin with an
      extended N-terminal sequence.
AB  - Using assay-directed fractionation of Conus geographus crude venom, we isolated
      alpha-conotoxin GID, which acts selectively at neuronal nicotinic acetylcholine
      receptors (nAChRs). Unlike other neuronally selective alpha-conotoxins, alpha-GID
      has a four amino acid N-terminal tail, gamma-carboxyglutamate (Gla), and
      hydroxyproline (O) residues, and lacks an amidated C terminus. GID inhibits alpha
      7 and alpha 3 beta 2 nAChRs with IC(50) values of 5 and 3 nm, respectively and is
      at least 1000-fold less potent at the alpha 1 beta 1 gamma delta, alpha 3 beta 4,
      and alpha 4 beta 4 combinations. GID also potently inhibits the alpha 4 beta 2
      subtype (IC(50) of 150 nm). Deletion of the N-terminal sequence (GID Delta 1-4)
      significantly decreased activity at the alpha 4 beta 2 nAChR but hardly affected
      potency at alpha 3 beta 2 and alpha 7 nAChRs, despite enhancing the off-rates at
      these receptors. In contrast, Arg(12) contributed to alpha 4 beta 2 and alpha 7
      activity but not to alpha 3 beta 2 activity. The three-dimensional structure of
      GID is well defined over residues 4-19 with a similar motif to other alpha
      conotoxins. However, despite its influence on activity, the tail appears to be
      disordered in solution. Comparison of GID with other alpha 4/7-conotoxins which
      possess an NN(P/O) motif in loop II, revealed a correlation between increasing
      length of the aliphatic side-chain in position 10 (equivalent to 13 in GID) and
      greater alpha 7 versus alpha 3 beta 2 selectivity.

PMID- 12419801
TI  - Human type 3 iodothyronine selenodeiodinase is located in the plasma membrane and
      undergoes rapid internalization to endosomes.
AB  - The type 3 iodothyronine selenodeiodinase (D3) is an integral membrane protein
      that inactivates thyroid hormones. By using immunofluorescence cytochemistry
      confocal microscopy of live or fixed cells transiently expressing FLAG-tagged
      human D3 or monkey hepatocarcinoma cells expressing endogenous D3, we identified
      D3 in the plasma membrane. It co-localizes with Na,K-ATPase alpha, with the early
      endosomal marker EEA-1 and clathrin, but not with two endoplasmic reticulum
      resident proteins. Most of the D3 molecule is extracellular and can be
      biotinylated with a cell-impermeant probe. There is constant internalization of
      D3 that is blocked by sucrose or methyl-beta-cyclodextrin-containing medium.
      Exposing cells to a weak base such as primaquine increases the pool of
      internalized D3, suggesting that D3 is recycled between plasma membrane and early
      endosomes. Such recycling could account for the much longer half-life of D3 (12
      h) than the thyroxine activating members of the selenodeiodinase family, type 1
      (D1; 8 h) or type 2 (D2; 2 h) deiodinase. The extracellular location of D3 gives
      ready access to circulating thyroid hormones, explaining its capacity for rapid
      inactivation of circulating thyroxine and triiodothyronine in patients with
      hemangiomas and its blockade of the access of maternal thyroid hormones to the
      human fetus.

PMID- 12419802
TI  - Endosome-to-Golgi transport is regulated by protein kinase A type II alpha.
AB  - Studies of RII alpha-deficient B lymphoid cells and stable transfectants
      expressing the type II alpha regulatory subunit (RII alpha) of cAMP-dependent
      protein kinase (PKA), which is targeted to the Golgi-centrosomal area, reveal
      that the presence of a Golgi-associated pool of PKA type II alpha mediates a
      change in intracellular transport of the plant toxin ricin. The transport of
      ricin from endosomes to the Golgi apparatus, measured as sulfation of a modified
      ricin (ricin sulf-1), increased in RII alpha-expressing cells when PKA was
      activated. However, not only endosome-to-Golgi transport, but also retrograde
      ricin transport to the endoplasmic reticulum (ER), measured as sulfation and N
      glycosylation of another modified ricin (ricin sulf-2), seemed to be increased in
      cells expressing RII alpha in the presence of a cAMP analog, 8-(4
      chlorophenylthio)-cAMP. Thus, PKA type II alpha seems to be involved in both
      endosome-to-Golgi and Golgi-to-ER transport. Because ricin, after being
      retrogradely transported to the ER, is translocated to the cytosol, where it
      inhibits protein synthesis, we also investigated the influence of RII alpha
      expression on ricin toxicity. In agreement with the other data obtained, 8-(4
      chlorophenylthio)-cAMP and RII alpha were found to sensitize cells to ricin,
      indicating an increased transport of ricin to the cytosol. In conclusion, our
      results demonstrate that transport of ricin from endosomes to the Golgi apparatus
      and further to the ER is regulated by PKA type II alpha isozyme.

PMID- 12419803
TI  - Pneumocystis carinii cell wall beta-glucan induces release of macrophage
      inflammatory protein-2 from alveolar epithelial cells via a lactosylceramide
      mediated mechanism.
AB  - Infiltration of the lungs with neutrophils promotes respiratory failure during
      severe Pneumocystis carinii (PC) pneumonia. Recent studies have shown that
      alveolar epithelial cells (AECs), in addition to promoting PC attachment, also
      participate in lung inflammation by the release of cytokines and chemokines.
      Herein, we demonstrate that a PC beta-glucan rich cell wall isolate (PCBG)
      stimulates the release of macrophage inflammatory protein-2 (MIP-2) from isolated
      AECs through a lactosylceramide-dependent mechanism. The results demonstrate that
      MIP-2 mRNA and protein production is significantly increased at both early and
      late time points after PCBG challenge. Although CD11b/CD18 (Mac-1, CR3) is the
      most widely studied beta-glucan receptor, we demonstrate that CD11b/CD18 is not
      present on AECs. This study instead demonstrates that preincubation of AECs with
      an antibody directed against the membrane glycosphingolipid lactosylceramide
      (CDw17) results in a significant decrease in MIP-2 secretion. Preincubation of
      the anti-CDw17 antibody with solubilized lactosylceramide reverses this effect.
      Furthermore, incubation of AECs with inhibitors of glycosphingolipid
      biosynthesis, including N-butyldeoxyno jirimycin and d-threo-1-phenyl-2
      decanoylamino-3-morpholino-1-propanol-HCl, also results in a significant decrease
      in AEC MIP-2 production following challenge with PCBG. These data demonstrate
      that PC beta-glucan induces significant production of MIP-2 from AECs and that
      CDw17 participates in the glucan-induced inflammatory signaling in lung
      epithelial cells during PC infection.

PMID- 12419804
TI  - Inactivation of Kex2p diminishes the virulence of Candida albicans.
AB  - Deletion of the kexin gene (KEX2) in Candida albicans has a pleiotropic effect on
      phenotype and virulence due partly to a defect in the expression of two major
      virulence factors: the secretion of active aspartyl proteinases and the formation
      of hyphae. kex2/kex2 mutants are highly attenuated in a mouse systemic infection
      model and persist within cultured macrophages for at least 24 h without causing
      damage. Pathology is modest, with little disruption of kidney matrix. The
      infecting mutant cells are largely confined to glomeruli, and are aberrant in
      morphology. The complex phenotype of the deletion mutants reflects a role for
      kexin in a wide range of cellular processes. Taking advantage of the specificity
      of Kex2p cleavage, an algorithm we developed to scan the 9168 open reading frames
      in Assembly 6 of the C. albicans genome identified 147 potential substrates of
      Kex2p. These include all previously identified substrates, including eight
      secreted aspartyl proteinases, the exoglucanase Xog1p, the immunodominant antigen
      Mp65, and the adhesin Hwp1p. Other putative Kex2p substrates identified include
      several adhesins, cell wall proteins, and hydrolases previously not implicated in
      pathogenesis. Kexins also process fungal mating pheromones; a modification of the
      algorithm identified a putative mating pheromone with structural similarities to
      Saccharomyces cerevisiae alpha-factor.

PMID- 12419805
TI  - Exogenous Nef protein activates NF-kappa B, AP-1, and c-Jun N-terminal kinase and
      stimulates HIV transcription in promonocytic cells. Role in AIDS pathogenesis.
AB  - The human immunodeficiency virus (HIV) Nef protein plays a critical role in AIDS
      pathogenesis by enhancing replication and survival of the virus within infected
      cells and by facilitating its spread in vivo. Most of the data obtained so far
      have been in experiments with endogenous Nef protein, so far overlooking the
      effects of exogenous soluble Nef protein. We used recombinant exogenous Nef
      proteins to activate nuclear transcription factors NF-kappaB and AP-1 in the
      promonocytic cell line U937. Exogenous SIV and HIV-1 Nef proteins activated NF
      kappaB and AP-1 in a dose- and time-dependent manner. Activation of NF-kappaB by
      exogenous Nef was concomitant to the degradation of the inhibitor of NF-kappaB,
      IkappaBalpha. In agreement with increased AP-1 activation, a time- and dose
      dependent increase in JNK activation was observed following treatment of U937
      cells with exogenous Nef. Since exogenous Nef activates the transcription factors
      NF-kappaB and AP-1, which bind to the HIV-1 long terminal repeat (LTR), we
      investigated the effect of exogenous Nef on HIV-1 replication. We observed that
      exogenous Nef stimulated HIV-1 LTR via NF-kappaB activation in U937 cells and
      enhanced viral replication in the chronically infected promonocytic cells U1.
      Therefore, our results suggest that exogenous Nef could fuel the progression of
      the disease via stimulation of HIV-1 provirus present in such cellular reservoirs
      as mononuclear phagocytes in HIV-infected patients.

PMID- 12419806
TI  - Post-activation turn-off of NF-kappa B-dependent transcription is regulated by
      acetylation of p65.
AB  - NF-kappaB represents a family of eukaryotic transcription factors participating
      in the regulation of various cellular genes involved in the immediate early
      processes of immune, acute-phase, and inflammatory responses. Cellular
      localization and consequently the transcriptional activity of NF-kappaB is
      tightly regulated by its partner IkappaBalpha. Here, we show that the p65 subunit
      of NF-kappaB is acetylated by both p300 and PCAF on lysines 122 and 123. Both
      HDAC2 and HDAC3 interact with p65, although only HDAC3 was able to deacetylate
      p65. Acetylation of p65 reduces its ability to bind kappaBeta-DNA. Finally,
      acetylation of p65 facilitated its removal from DNA and consequently its
      IkappaBetaalpha-mediated export from the nucleus. We propose that acetylation of
      p65 plays a key role in IkappaBetaalpha-mediated attenuation of NF-kappaBeta
      transcriptional activity which is an important process that restores the latent
      state in post-induced cells.

PMID- 12419807
TI  - Posttranslational modification of serine to formylglycine in bacterial
      sulfatases. Recognition of the modification motif by the iron-sulfur protein
      AtsB.
AB  - Calpha-formylglycine is the catalytic residue of sulfatases. Formylglycine is
      generated by posttranslational modification of a cysteine (pro- and eukaryotes)
      or serine (prokaryotes) located in a conserved (C/S)XPXR motif. The modifying
      enzymes are unknown. AtsB, an iron-sulfur protein, is strictly required for
      modification of Ser(72) in the periplasmic sulfatase AtsA of Klebsiella
      pneumoniae. Here we show (i) that AtsB is a cytosolic protein acting on newly
      synthesized serine-type sulfatases, (ii) that AtsB-mediated FGly formation is
      dependent on AtsA's signal peptide, and (iii) that the cytosolic cysteine-type
      sulfatase of Pseudomonas aeruginosa can be converted into a substrate of AtsB if
      the cysteine is substituted by serine and a signal peptide is added. Thus,
      formylglycine formation in serine-type sulfatases depends both on AtsB and on the
      presence of a signal peptide, and AtsB can act on sulfatases of other species.
      AtsB physically interacts with AtsA in a Ser(72)-dependent manner, as shown in
      yeast two-hybrid and GST pull-down experiments. This strongly suggests that AtsB
      is the serine-modifying enzyme and that AtsB relies on a cytosolic function of
      the sulfatase's signal peptide.

PMID- 12419808
TI  - Characterization of the DNA-unwinding activity of human RECQ1, a helicase
      specifically stimulated by human replication protein A.
AB  - The RecQ helicases are involved in several aspects of DNA metabolism. Five
      members of the RecQ family have been found in humans, but only two of them have
      been carefully characterized, BLM and WRN. In this work, we describe the
      enzymatic characterization of RECQ1. The helicase has 3' to 5' polarity, cannot
      start the unwinding from a blunt-ended terminus, and needs a 3'-single-stranded
      DNA tail longer than 10 nucleotides to open the substrate. However, it was also
      able to unwind a blunt-ended duplex DNA with a "bubble" of 25 nucleotides in the
      middle, as previously observed for WRN and BLM. We show that only short DNA
      duplexes (<30 bp) can be unwound by RECQ1 alone, but the addition of human
      replication protein A (hRPA) increases the processivity of the enzyme (>100 bp).
      Our studies done with Escherichia coli single-strand binding protein (SSB)
      indicate that the helicase activity of RECQ1 is specifically stimulated by hRPA.
      This finding suggests that RECQ1 and hRPA may interact also in vivo and function
      together in DNA metabolism. Comparison of the present results with previous
      studies on WRN and BLM provides novel insight into the role of the N- and C
      terminal domains of these helicases in determining their substrate specificity
      and in their interaction with hRPA.

PMID- 12419809
TI  - 3-Mercaptopyruvate sulfurtransferase of Leishmania contains an unusual C-terminal
      extension and is involved in thioredoxin and antioxidant metabolism.
AB  - Cytosolic 3-mercaptopyruvate sulfurtransferases (EC ) of Leishmania major and
      Leishmania mexicana have been cloned, expressed as active enzymes in Escherichia
      coli, and characterized. The leishmanial single-copy genes predict a
      sulfurtransferase that is structurally peculiar in possessing a C-terminal domain
      of some 70 amino acids. Homologous genes of Trypanosoma cruzi and Trypanosoma
      brucei encode enzymes with a similar C-terminal domain, suggesting that this
      feature, not known in any other sulfurtransferase, is a characteristic of
      trypanosomatid parasites. Short truncations of the C-terminal domain resulted in
      misfolded inactive proteins, demonstrating that the domain plays some key role in
      facilitating correct folding of the enzymes. The leishmanial recombinant enzymes
      exhibited high activity toward 3-mercaptopyruvate and catalyzed the transfer of
      sulfane sulfur to cyanide to form thiocyanate. They also used thiosulfate as a
      substrate and reduced thioredoxin as the accepting nucleophile, the latter being
      oxidized. The enzymes were expressed in all life cycle stages, and the expression
      level was increased under peroxide or hypo-sulfur stress. The results are
      consistent with the enzymes having an involvement in the synthesis of sulfur
      amino acids per se or iron-sulfur centers of proteins and the parasite's
      management of oxidative stress.

PMID- 12419810
TI  - Inhibition of protein kinase CK2 by anthraquinone-related compounds. A structural
      insight.
AB  - Protein kinases play key roles in signal transduction and therefore are among the
      most attractive targets for drug design. The pharmacological aptitude of protein
      kinase inhibitors is highlighted by the observation that various diseases with
      special reference to cancer are because of the abnormal expression/activity of
      individual kinases. The resolution of the three-dimensional structure of the
      target kinase in complex with inhibitors is often the starting point for the
      rational design of this kind of drugs, some of which are already in advanced
      clinical trial or even in clinical practice. Here we present and discuss three
      new crystal structures of ATP site-directed inhibitors in complex with "casein
      kinase-2" (CK2), a constitutively active protein kinase implicated in a variety
      of cellular functions and misfunctions. With the help of theoretical
      calculations, we disclose some key features underlying the inhibitory efficiency
      of anthraquinone derivatives, outlining three different binding modes into the
      active site. In particular, we show that a nitro group in a hydroxyanthraquinone
      scaffold decreases the inhibitory constants K(i) because of electron-withdrawing
      and resonance effects that enhance the polarization of hydroxylic substituents in
      paraposition.

PMID- 12419811
TI  - Development of novel fluorescence probes that can reliably detect reactive oxygen
      species and distinguish specific species.
AB  - We designed and synthesized 2-[6-(4'-hydroxy)phenoxy-3H-xanthen-3-on-9-yl]benzoic
      acid (HPF) and 2- [6-(4'-amino)phenoxy-3H-xanthen-3-on-9-yl]benzoic acid (APF) as
      novel fluorescence probes to detect selectively highly reactive oxygen species
      (hROS) such as hydroxyl radical (*OH) and reactive intermediates of peroxidase.
      Although HPF and APF themselves scarcely fluoresced, APF selectively and dose
      dependently afforded a strongly fluorescent compound, fluorescein, upon reaction
      with hROS and hypochlorite ((-)OCl), but not other reactive oxygen species (ROS).
      HPF similarly afforded fluorescein upon reaction with hROS only. Therefore, not
      only can hROS be differentiated from hydrogen peroxide (H(2)O(2)), nitric oxide
      (NO), and superoxide (O2*-) by using HPF or APF alone, but (-)OCl can also be
      specifically detected by using HPF and APF together. Furthermore, we applied HPF
      and APF to living cells and found that HPF and APF were resistant to light
      induced autoxidation, unlike 2',7'-dichlorodihydrofluorescein, and for the first
      time we could visualize (-)OCl generated in stimulated neutrophils. HPF and APF
      should be useful as tools to study the roles of hROS and (-)OCl in many
      biological and chemical applications.

PMID- 12419812
TI  - 5' stem-loop of collagen alpha 1(I) mRNA inhibits translation in vitro but is
      required for triple helical collagen synthesis in vivo.
AB  - The 5' stem-loop is a conserved sequence element found around the translation
      initiation site of three collagen mRNAs, alpha1(I), alpha2(I), and alpha1(III).
      We show here that the 5' stem-loop of collagen alpha1(I) mRNA is inhibitory to
      translation in vitro. The sequence 5' to the translation initiation codon, as a
      part of the 5' stem-loop, is also not efficient in initiating translation under
      competitive conditions. This suggests that collagen alpha1(I) mRNA may not be a
      good substrate for translation. Since the 5' stem-loop binds protein factors in
      collagen-producing cells, this binding may regulate its translation in vivo. We
      studied in vivo translation of collagen alpha1(I) mRNA after transfecting
      collagen alpha1(I) genes with and without the 5' stem-loop into Mov 13
      fibroblasts. The mRNA with the alpha1(I) 5' stem-loop was translated into pepsin
      resistant collagen, which was secreted into the cellular medium. This mRNA also
      produced more disulfide-bonded high molecular weight collagen found
      intracellularly. The mRNA in which the 5' stem-loop was mutated, but without
      affecting the coding region of the gene, was translated into pepsin-sensitive
      collagen and produced only trace amounts of disulfide-bonded collagen. This
      suggests that the 5' stem-loop is required for proper folding or stabilization of
      the collagen triple helix. To our knowledge this is the first example that an RNA
      element located in the 5'-untranslated region is involved in synthesis of a
      secreted multisubunit protein. We suggest that 5' stem-loop, with its cognate
      binding proteins, targets collagen mRNAs for coordinate translation and couples
      translation apparatus to the rest of the collagen biosynthetic pathway.

PMID- 12419813
TI  - A retrograde signal from calsequestrin for the regulation of store-operated Ca2+
      entry in skeletal muscle.
AB  - Calsequestrin (CSQ) is a high capacity Ca(2+)-binding protein present in the
      lumen of sarcoplasmic reticulum (SR) in striated muscle cells and has been shown
      to regulate the ryanodine receptor Ca(2+) release channel activity through
      interaction with other proteins present in the SR. Here we show that
      overexpression of wild-type CSQ or a CSQ mutant lacking the junction binding
      region (amino acids 86-191; Delta junc-CSQ) in mouse skeletal C2C12 myotube
      enhanced caffeine- and voltage-induced Ca(2+) release by increasing the Ca(2+)
      load in SR, whereas overexpression of a mutant CSQ lacking a Ca(2+) binding,
      aspartate-rich domain (amino acids 352-367; Delta asp-CSQ) showed the opposite
      effects. Depletion of SR Ca(2+) by thapsigargin initiated store-operated Ca(2+)
      entry (SOCE) in C2C12 myotubes. A large component of SOCE was inhibited by
      overexpression of wild-type CSQ or Delta junc-CSQ, whereas myotubes transfected
      with Delta asp-CSQ exhibited normal function of SOCE. These results indicate that
      the aspartate-rich segment of CSQ, under conditions of overexpression, can
      sustain structural interactions that interfere with the SOCE mechanism. Such
      retrograde activation mechanisms are possibly taking place at the junctional site
      of the SR.

PMID- 12419814
TI  - Glucosamine inhibits inositol acylation of the glycosylphosphatidylinositol
      anchors in intraerythrocytic Plasmodium falciparum.
AB  - Glycosylphosphatidylinositol (GPI) anchors are crucial for the survival of the
      intraerythrocytic stage Plasmodium falciparum because of their role in membrane
      anchoring of merozoite surface proteins involved in parasite invasion of
      erythrocytes. Recently, we showed that mannosamine can prevent the growth of P.
      falciparum by inhibiting the GPI biosynthesis. Here, we investigated the effect
      of isomeric amino sugars glucosamine, galactosamine, and their N-acetyl
      derivatives on parasite growth and GPI biosynthesis. Glucosamine, but not
      galactosamine, N-acetylglucosamine, and N-acetylgalactosamine inhibited the
      growth of the parasite in a dose-dependent manner. Glucosamine specifically
      arrested the maturation of trophozoites, a stage at which the parasite
      synthesizes all of its GPI anchor pool and had no effect during the parasite
      growth from rings to early trophozoites and from late trophozoites to schizonts
      and merozoites. An analysis of GPI intermediates formed when parasites incubated
      with glucosamine indicated that the sugar interferes with the inositol acylation
      of glucosamine-phosphatidylinositol (GlcN-PI) to form GlcN-(acyl)PI. Consistent
      with the non-inhibitory effect on parasite growth, galactosamine, N
      acetylglucosamine, and N-acetylgalactosamine had no significant effect on the
      parasite GPI biosynthesis. The results indicate that the enzyme that transfers
      the fatty acyl moiety to inositol residue of GlcN-PI discriminates the
      configuration at C-4 of hexosamines. An analysis of GPIs formed in a cell-free
      system in the presence and absence of glucosamine suggests that the effect of the
      sugar is because of direct inhibition of the enzyme activity and not gene
      repression. Because the fatty acid acylation of inositol is an obligatory step
      for the addition of the first mannosyl residue during the biosynthesis of GPIs,
      our results offer a strategy for the development of novel anti-malarial drugs.
      Furthermore, this is the first study to report the specific inhibition of GPI
      inositol acylation by glucosamine in eukaryotes.

PMID- 12419815
TI  - Identification of the active site residues of Pseudomonas aeruginosa protease IV.
      Importance of enzyme activity in autoprocessing and activation.
AB  - Protease IV is a lysine-specific endoprotease produced by Pseudomonas aeruginosa
      whose activity has been correlated with corneal virulence. Comparison of the
      protease IV amino acid sequence to other bacterial proteases suggested that amino
      acids His-72, Asp-122, and Ser-198 could form a catalytic triad that is critical
      for protease IV activity. To test this possibility, site-directed mutations by
      alanine substitution were introduced into six selected residues including the
      predicted triad and identical residues located close to the triad. Mutations at
      any of the amino acids of the predicted catalytic triad or Ser-197 caused a loss
      of enzymatic activity and absence of the mature form of protease IV. In contrast,
      mutations at His-116 or Ser-200 resulted in normal processing into the
      enzymatically active mature form. A purified proenzyme that accumulated in the
      His-72 mutant was shown in vitro to be susceptible to cleavage by protease IV
      purified from P. aeruginosa. Furthermore, similarities of protease IV to the
      lysine-specific endoprotease of Achromobacter lyticus suggested three possible
      disulfide bonds in protease IV. These results identify the catalytic triad of
      protease IV, demonstrate that autodigestion is essential for the processing of
      protease IV into a mature protease, and predict sites essential to enzyme
      conformation.

PMID- 12419816
TI  - Conformational changes in Kir2.1 channels during NH4+-induced inactivation.
AB  - We have shown previously that NH(4)(+) binding to the external pore of a Kir2.1
      channel induces channel inactivation possibly through conformational changes. In
      this study, we performed further biophysical analyses of the NH(4)(+)-induced
      inactivation modeled by a refined kinetic scheme. Also, we investigated the
      conformational change hypothesis by examining whether the chemical modification
      of single-cysteine substitution of amino acids located at the internal pore
      alters the kinetics of the NH(4)(+)-induced inactivation. In addition, we
      examined whether the mutation of amino acids located at various parts of a Kir2.1
      channel influences the NH(4)(+)-induced inactivation. Kir2.1 channels were
      expressed in Xenopus oocytes and studied using patch-clamp techniques. The gating
      of the NH(4)(+)-induced inactivation was affected by mutation of several amino
      acids located at various regions of the Kir2.1 channel. These results suggest
      that amino acids from different parts of a Kir2.1 channel are involved in the
      channel closure. Furthermore, internal chemical modification of several cysteine
      mutants resulted in the block of inward currents and changes in the on and off
      rate for the NH(4)(+)-induced inactivation, suggesting that the internal pore
      mouth is involved in the closure of a Kir2.1 channel. Taken together these
      results provide new evidence for conformational changes affecting the NH(4)(+)
      induced inactivation in the Kir2.1 channel.

PMID- 12419817
TI  - The NF-kappa B activation in lymphotoxin beta receptor signaling depends on the
      phosphorylation of p65 at serine 536.
AB  - NF-kappaB-inducing kinase (NIK) has been shown to play an essential role in the
      NF-kappaB activation cascade elicited by lymphotoxin beta receptor (LTbetaR)
      signaling. However, the molecular mechanism of this pathway remains unclear. In
      this report we demonstrate that both NIK and IkappaB kinase alpha (IKKalpha) are
      involved in LTbetaR signaling and that the phosphorylation of the p65 subunit at
      serine 536 in its transactivation domain 1 (TA1) plays an essential role. We also
      found that NF-kappaB could be activated in the LTbetaR pathway without altering
      the level of the phosphorylation of IkappaB and nuclear localization of p65. By
      using a heterologous transactivation system in which Gal4-dependent reporter gene
      is activated by the Gal4 DNA-binding domain in fusion with various portions of
      p65, we found that TA1 serves as a direct target in the NIK-IKKalpha pathway. In
      addition, mutation studies have revealed the essential role of Ser-536 within TA1
      of p65 in transcriptional control mediated by NIK-IKKalpha. Furthermore, we found
      that Ser-536 was phosphorylated following the stimulation of LTbetaR, and this
      phosphorylation was inhibited by the kinase-dead dominant-negative mutant of
      either NIK or IKKalpha. These observations provide evidence for a crucial role of
      the NIK-IKKalpha cascade for NF-kappaB activation in LTbetaR signaling.

PMID- 12419818
TI  - Is the glutamate residue Glu-373 the proton acceptor of the excitatory amino acid
      carrier 1?
AB  - Glutamate transport by the neuronal excitatory amino acid carrier (EAAC1) is
      accompanied by the coupled movement of one proton across the membrane. We have
      demonstrated previously that the cotransported proton binds to the carrier in the
      absence of glutamate and, thus, modulates the EAAC1 affinity for glutamate. Here,
      we used site-directed mutagenesis together with a rapid kinetic technique that
      allows one to generate sub-millisecond glutamate concentration jumps to locate
      possible binding sites of the glutamate transporter for the cotransported proton.
      One candidate for this binding site, the highly conserved glutamic acid residue
      Glu-373 of EAAC1, was mutated to glutamine. Our results demonstrate that the
      mutant transporter does not catalyze net transport of glutamate, whereas
      Na(+)/glutamate homoexchange is unimpaired. Furthermore, the voltage dependence
      of the rates of Na(+) binding and glutamate translocation are unchanged compared
      with the wild-type. In contrast to the wild-type, however, homoexchange of the
      E373Q transporter is completely pH-independent. In line with these findings the
      transport kinetics of the mutant EAAC1 show no deuterium isotope effect. Thus, we
      suggest a new transport mechanism, in which Glu-373 forms part of the binding
      site of EAAC1 for the cotransported proton. In this model, protonation of Glu-373
      is required for Na(+)/glutamate translocation, whereas the relocation of the
      carrier is only possible when Glu-373 is negatively charged. Interestingly, the
      Glu-373-homologous amino acid residue is glutamine in the related neutral amino
      acid transporter alanine-serine-cysteine transporter. The function of alanine
      serine-cysteine transporter is neither potassium- nor proton-dependent.
      Consequently, our results emphasize the general importance of glutamate and
      aspartate residues for proton transport across membranes.

PMID- 12419819
TI  - Human fibroblast growth factor-23 mutants suppress Na+-dependent phosphate co
      transport activity and 1alpha,25-dihydroxyvitamin D3 production.
AB  - The human fibroblast growth factor 23 (hFGF23) and its autosomal dominant
      hypophosphatemic rickets (ADHR) mutant genes were incorporated into animals by
      naked DNA injection to investigate the action on phosphate homeostasis in vivo.
      The hFGF23 mutants (R176Q, R179Q, and R179W) markedly reduced serum phosphorus
      (6.2-6.9 mg/dl) compared with the plasmid MOCK (8.5 mg/dl). However, native
      hFGF23 did not affect serum phosphorus (8.6 mg/dl). Both hFGF23 and hFGF23R179Q
      mRNAs were expressed more than 100-fold in the liver 4 days after injection,
      however, the C-terminal portion of hFGF23 was detected only in the serum from
      hFGF23R179Q-injected animals (1109 pg/ml). hFGF23R179Q mutant was secreted as a
      32-kDa protein, whereas, native hFGF23 was detected as a 20-kDa protein in the
      cell-conditioned media. These results suggest the hFGF23R179Q protein is
      resistant to intracellular proteolytic processing. The hFGF23R179Q suppressed
      Na/P(i) co-transport activities both in kidney and in small intestine by 45 and
      30%, respectively, as well as serum 1alpha,25-dihydroxyvitamin D(3) to less than
      15 pg/ml. However, it had little effect on serum parathyroid hormone (PTH).
      Infusion of hFGF23R179Q protein normalized serum phosphorus in
      thyroparathyroidectomized rats without affecting serum calcium. Taken together,
      the FGF23 mutants reduce both phosphate uptake in intestine and phosphate
      reabsorption in kidney, independent of PTH action.

PMID- 12419820
TI  - Molecular basis of bone morphogenetic protein-15 signaling in granulosa cells.
AB  - Bone morphogenetic protein-15 (BMP-15), an oocyte growth factor belonging to the
      transforming growth factor-beta superfamily, has recently been shown to be
      necessary for normal female fertility in mammals. We have previously demonstrated
      that BMP-15 regulates granulosa cell (GC) proliferation and differentiation;
      namely, BMP-15 promotes GC mitosis, suppresses follicle-stimulating hormone (FSH)
      receptor expression, and stimulates kit ligand expression. Although the role of
      BMP-15 in female reproduction has progressively deserved much attention, there is
      nothing known to date about the signaling pathway and receptors for BMP-15. Using
      rat primary GCs and a human GC cell line, COV434, we have now found that
      administration of BMP-15 causes a rapid and transient phosphorylation, thus
      activation, of the Smad1/5/8 pathway. BMP-15 also stimulated promoter activity of
      a selective BMP-responsive reporter construct, further demonstrating the
      stimulation of Smad1/5/8 signaling by BMP-15. In contrast, BMP-15 stimulation of
      Smad2 phosphorylation was very weak. To identify the receptors for BMP-15, we
      utilized recombinant extracellular domains of individual transforming growth
      factor-beta superfamily receptors and found that activin receptor-like kinase-6
      extracellular domain most effectively co-immunoprecipitates with BMP-15, whereas
      BMP receptor type II extracellular domain was most effective in inhibiting BMP-15
      bioactivity on FSH-induced progesterone production and GC thymidine
      incorporation. We also investigated whether activation of the MAPK pathway is
      necessary for BMP-15 biological activity and found that the addition of U0126, an
      inhibitor of ERK1/2 phosphorylation, suppresses BMP-15 activity on GC mitotsis
      but not on FSH-induced progesterone production, suggesting a selective signaling
      cascade in GC proliferation and differentiation.

PMID- 12419821
TI  - Thyroid hormone receptor DNA binding is required for both positive and negative
      gene regulation.
AB  - The beta isoform of thyroid hormone receptor (TR-beta) has a key role in the
      feedback regulation of the hypothalamic-pituitary-thyroid (H-P-T) axis. The
      mechanism of trans-repression of the hypothalamic thyrotropin-releasing hormone
      (TRH) and pituitary thyroid-stimulating hormone (TSH) subunit genes, however,
      remains poorly understood. A number of distinct mechanisms for TR-beta-mediated
      negative regulation by thyroid hormone have been proposed, including those that
      require and do not require DNA binding. To clarify the importance of DNA binding
      in negative regulation, we constructed a DNA-binding mutant of TR-beta in which
      two amino acids within the P box were altered (GSG for EGG) to resemble that
      found in the glucocorticoid receptor (GR). We termed this mutant GS125, and as
      expected, it displayed low binding affinities for positive and negative thyroid
      hormone-response element (pTRE and nTRE, respectively) in gel-mobility shift
      assays. In transient transfection assays, the GS125 mutant abolished
      transactivation on three classic pTREs (DR+4, LAP, and PAL) and all negatively
      regulated promoters in the H-P-T axis (TRH, TSH-beta, and TSH-alpha). However,
      GS125 TR-beta bound to a composite TR/GR-response element and was fully
      functional on this hybrid TR/GR-response element. Moreover, the GS125 TR-beta
      mutant displayed normal interactions with transcriptional cofactors in mammalian
      two-hybrid assays. These data do not support a DNA-binding independent mechanism
      for thyroid hormone negative regulation in the H-P-T axis.

PMID- 12419822
TI  - Identification of Dss1 as a 12-O-tetradecanoylphorbol-13-acetate-responsive gene
      expressed in keratinocyte progenitor cells, with possible involvement in early
      skin tumorigenesis.
AB  - This study identifies genes expressed early in 12-O-tetradecanoylphorbol-13
      acetate (TPA)-induced skin carcinogenesis in genetically initiated Tg.AC v-Ha-ras
      transgenic mice. Keratinocyte progenitor cells from TPA-treated Tg.AC mice were
      isolated with fluorescence-activated cell sorting and expression was analyzed
      using cDNA microarray technology. Eleven genes were identified whose expression
      changed significantly in response to carcinogen treatment. Deleted in split
      hand/split foot 1 (Dss1) is a gene associated with a heterogeneous limb
      developmental disorder called split hand/split foot malformation. cDNA microarray
      expression analysis showed that the mouse homologue of Dss1 is induced by TPA.
      Dss1 overexpression was detected by Northern blot analysis in early TPA-treated
      hyperplastic skins and in JB6 Cl 41-5a epidermal cells. Interestingly, Dss1
      expression was also shown to be elevated in skin papillomas relative to normal
      skins, and further increased in squamous cell malignancies. Functional studies by
      ectopically constitutive expression of Dss1 in JB6 Cl 41-5a preneoplastic cells
      strongly increased focus formation and proliferation of these cells and enhanced
      efficiency of neoplastic transformation of the cells in soft agar. These results
      strongly suggest that Dss1 is a TPA-inducible gene that may play an important
      role in the early stages of skin carcinogenesis.

PMID- 12419823
TI  - JAK/STAT but not ERK1/ERK2 pathway mediates interleukin (IL)-6/soluble IL-6R down
      regulation of Type II collagen, aggrecan core, and link protein transcription in
      articular chondrocytes. Association with a down-regulation of SOX9 expression.
AB  - Signal transducers and activators of transcription (STAT) factors are cytoplasmic
      proteins that can be activated by Janus kinases (JAK) and that modulate gene
      expression in response to cytokine receptor stimulation. STAT proteins dimerize,
      translocate into the nucleus, and activate specific target genes. In the present
      study, we show for the first time that interleukin-6 (IL), in the presence of its
      soluble receptor (sIL-6R), induces activation of JAK1, JAK2, and STAT1/STAT3
      proteins in bovine articular chondrocytes. Western blotting and mobility shift
      assays demonstrated that this effect is accompanied by the DNA binding of the
      STAT proteins. The mitogen-activated protein kinase pathway was also activated in
      response to IL-6/sIL-6R association, as reflected by phosphorylation of ERK1 and
      ERK2 proteins. In these conditions, the expression of cartilage-specific matrix
      genes, type II collagen, aggrecan core, and link proteins was found to be
      markedly down-regulated. This negative effect was abolished by addition of
      parthenolide, an inhibitor of the STAT activation, whereas blockade of the MAP
      kinases with PD098059 was without significant effect. Thus, activation of the
      STAT signaling pathways, but not ERK-dependent pathways, is essential for down
      regulation of the major cartilage-specific matrix genes by IL-6. In addition, a
      parallel reduction of Sox9 expression, a key factor of chondrocyte phenotype, was
      found in these experimental conditions. These IL-6 effects might contribute to
      the phenotype loss of chondrocytes in joint diseases and the alteration of
      articular cartilage associated with this pathology.

PMID- 12419824
TI  - Migrating colonic crypt epithelial cells: primary targets for transformation.
AB  - It is widely believed that stem cells are the relevant target cells for colonic
      cell transformation. Evidence is presented that a proliferative transit daughter
      cell acquiring a mutant adenomatous polyposis coli gene during upward migration
      from the crypt base can develop retention abnormalities and permanence in the
      crypt, thus qualifying as a transformed clone which is retained in the colonic
      epithelium.

PMID- 12419825
TI  - The major lipid peroxidation product, trans-4-hydroxy-2-nonenal, preferentially
      forms DNA adducts at codon 249 of human p53 gene, a unique mutational hotspot in
      hepatocellular carcinoma.
AB  - Trans-4-hydroxy-2-nonenal (4-HNE), a major electrophilic by-product of lipid
      peroxidation, is able to interact with DNA to form exocyclic guanine adducts. 4
      HNE is a mutagen and a significant amount of 4-HNE-guanine adduct has been
      detected in normal cells. Recently, it has been reported that exposure of the
      wild-type p53 human lymphoblastoid cell line to 4-HNE causes a high frequency of
      G to T transversion mutations at the third base of codon 249 (-AGG*-) in the p53
      gene, a mutational hotspot in human cancers, particularly hepatocellular
      carcinoma. These findings raise a possibility that 4-HNE could be an important
      etiological agent for human cancers that have a mutation at codon 249 of the p53
      gene. However, to date, the sequence specificity of 4-HNE-DNA binding remains
      unclear due to the lack of methodology. To address this question, we have
      developed a method, using UvrABC nuclease, a nucleotide excision repair enzyme
      complex isolated from Escherichia coli, to map the distribution of 4-HNE-DNA
      adducts in human p53 gene at the nucleotide sequence level. We found that 4-HNE
      DNA adducts are preferentially formed at the third base of codon 249 in the p53
      gene. The preferential binding of 4-HNE was also observed at codon 174, which has
      the same sequence and the same nearest neighbor sequences (-GAGG*C-) as codon
      249. These results suggest that 4-HNE may be an important etiological agent for
      human cancers that have a mutation at codon 249 of the p53 gene.

PMID- 12419826
TI  - Changes in expression of the human homologue of the Drosophila discs large tumour
      suppressor protein in high-grade premalignant cervical neoplasias.
AB  - The Drosophila tumour suppressor discs large (Dlg) is a cell-junction localized
      protein that is required for the maintenance of epithelial cyto-architecture and
      the negative control of cell proliferation. The mammalian homologue is likely to
      have a similar mode of action, and therefore functional perturbation of this
      protein may be linked to the development of epithelial-derived cancers. The
      finding that several unrelated viral oncoproteins, including the E6 protein of
      oncogenic human papillomaviruses, bind to the human homologue of Dlg (hDlg)
      supports this proposition. Employing immunohistochemistry, we show that in
      uterine cervical squamous epithelia, prominent localization of hDlg at sites of
      intercellular contact occurs in cells that have left the proliferating basal cell
      layers and begun maturation. The presence of hDlg at sites of cell:cell contact
      diminishes, whilst intracellular cytoplasmic levels increase significantly in
      high-grade, but not low-grade, cervical neoplasias. In invasive squamous cell
      carcinomas, total cellular hDlg levels are greatly reduced. Our data suggest that
      loss of hDlg at sites of intercellular contact may be an important step in the
      development of epithelial cancers.

PMID- 12419827
TI  - Erythropoietin is involved in growth and angiogenesis in malignant tumours of
      female reproductive organs.
AB  - The accumulating evidence that erythropoietin and erythropoietin receptor are
      expressed in various non-haematopoietic organs suggests that erythropoietin
      signalling might be involved in the growth of tumours, but this possibility has
      never been examined. We found that mRNAs for erythropoietin and erythropoietin
      receptor are expressed in malignant tumours of female reproductive organs, where
      erythropoietin levels are higher than in normal tissues. Furthermore, tumour
      cells and capillary endothelium showed erythropoietin receptor immunoreactivity.
      To investigate the role of the erythropoietin/erythropoietin receptor pathway in
      these tumours, we injected mouse monoclonal antibody against erythropoietin or
      the soluble form of erythropoietin receptor into blocks of tumour specimens and
      cultured the blocks. After 12 h of injections, these blocks were examined and
      compared with control blocks injected with mouse monoclonal antibody, heat
      denatured soluble form of erythropoietin receptor, mouse serum or saline. Tumour
      cells and capillaries were markedly decreased in a dose-dependent manner after
      either injection. A marked increase of the cells containing fragmented DNA and
      the histopathological characteristics of these cells suggest that the decrease in
      tumour cells and capillary endothelial cells was due to apoptotic cell death. The
      co-existence of JAK2 and phosphorylated-JAK2, and STAT5 and phosphorylated STAT5,
      all of which are involved in the mitogenic signalling of erythropoietin, was
      found frequently in tumour cells and capillary endothelial cells in the untreated
      blocks. In contrast, most of the phosphorylated-JAK2- or phosphorylated-STAT5
      positive cells had disappeared in the experimental blocks. Moreover, reduced
      tyrosine phosphorylation of STAT5 in the experimental blocks was confirmed by
      western blotting analysis. The results strongly indicate that erythropoietin
      signalling contributes to the growth and/or survival of both transformed cells
      and capillary endothelial cells in these tumours. Thus, deprivation of
      erythropoietin signalling may be a useful therapy for erythropoietin-producing
      malignant tumours.

PMID- 12419828
TI  - Diet, cancer and aging in DNA mismatch repair deficient mice.
AB  - Diet is an important risk factor for many cancers. High fat/low calcium (HFLC)
      diets are associated with increased tumorigenesis, whereas caloric restriction
      (CR) reproducibly increases lifespan and decreases tumors. Mutations are involved
      in aging and cancer, and different diets may alter mutagenesis. However, a number
      of repair pathways normally counteract mutations by correcting errors before they
      can be fixed in the genome. To further understand interactions between diet,
      aging and cancer, mice deficient in a major repair pathway called DNA mismatch
      repair (MMR) were fed HFLC, CR or control diets. Mlh1 deficient mice are prone to
      lymphomas and intestinal adenomas and carcinomas. No significant changes in
      adenocarcinoma or lymphoma incidence were observed with HFLC or CR diets.
      Significantly more (2.2-fold) adenomas occurred with HFLC diets although adenoma
      numbers were unchanged with CR. Only a small increase in lifespan (116% of
      control) was achieved with CR. In addition, levels of microsatellite mutations in
      the small and large intestines were unchanged with the different diets. Our
      studies indicate that MMR deficiency may be epistatic to certain otherwise strong
      environmental influences on carcinogenesis or aging.

PMID- 12419829
TI  - Multiple pulmonary adenomas in the lung of transgenic mice overexpressing the RON
      receptor tyrosine kinase. Recepteur d'origine nantais.
AB  - The receptor tyrosine kinase RON (recepteur d'origine nantais), a member of the
      MET proto-oncogene family, has been implicated in the pathogenesis of certain
      epithelial cancers including lung adenocarcinomas. To determine the oncogenic
      potential of RON, transgenic mice were generated using the surfactant protein C
      promoter to express human wild-type RON in the distal lung epithelial cells. The
      mice were born normal without morphological defects in the lung, however,
      multiple lung adenomas with distinct morphology and growth pattern were observed.
      Tumors appeared as a single mass in the lung around 2 months of age and gradually
      developed into multiple nodules throughout the lung. Most of the tumors were
      characterized as cuboidal epithelial cells with type II cell phenotypes. They
      grew along the alveolar walls and projected into the alveolar septa. A transition
      from pre-malignant adenomas to adenocarcinomas was observed. The RON transgene is
      highly expressed and constitutively activated in the tumors as evident by
      immunohistochemical staining and western blot analyses. Moreover, we found that
      Ras expression was dramatically increased in the majority of tumors. However, no
      mutation in the 'hot spots' of the K-Ras or p53 gene was observed, although
      limited genomic instability occurs in individual tumors. Taken together, this is
      a mouse lung tumor model with unique biological characteristics. The model may
      provide an opportunity to study the role of RON in lung tumors and to elucidate
      the mechanisms underlying this distinct lung tumor.

PMID- 12419830
TI  - Human melanomas of fibroblast and epithelial morphology differ widely in their
      ability to synthesize retinyl esters.
AB  - Reduced retinyl ester synthesis has been associated with several forms of cancer;
      we therefore proposed studying melanoma development from the perspective of this
      biochemical pathway. Cultures of human melanoma cells with fibroblastoid
      morphology showed negligible retinyl ester synthesis; in sharp contrast, those
      with epithelioid morphology were capable of retinol esterification. Further,
      isolated proliferating epidermal melanocytes (HFSC/2) esterified retinol, whereas
      proliferating normal skin fibroblasts (F:CCD-1121.Sk) did not. A primary site
      cutaneous melanoma and its metastatic match (both of epithelioid morphology) were
      capable of retinol esterification, while a matched fibroblastoid tumor pair did
      not synthesize retinyl esters; nevertheless, LRAT (lecithin:retinol
      acyltransferase) protein was found in microsomal fractions from all four tumors.
      A mutation screen in the LRAT coding region and adjacent intronic sequences
      revealed several novel mutations in these melanomas as well as in HFSC/2 and
      F:CCD-1121.Sk cells: a single nucleotide polymorphism in exon 1(37A-->G), a
      silent mutation in exon 2a (188 A-->G/186 G-->A), and an insertion in the 5'UTR
      (9-10insC). CRBP-1 basal expression was present in the HFSC/2, and in both sets
      of matched tumor pairs; however, steady-state levels in the fibroblastoid
      melanoma pair were one-third that found in the epithelioid matched tumor pair. Co
      culture of human primary site epithelioid melanoma with proliferating normal
      human skin fibroblasts abrogated retinol esterification within 96 h and increased
      the expression of the active form of TGFbeta-1 by 2.4-fold. A concomitant 3.2
      fold downregulation of CRBP-1 expression took place. This is the first study to
      (1) demonstrate an association between retinyl ester synthesis and cutaneous
      melanoma morphological phenotypes; (2) suggest the existence of a soluble,
      diffusible inhibitor of the retinol esterification pathway; (3) report the
      ability of the isolated, proliferating human epidermal melanocyte to esterify
      retinol; and (4) provide evidence of DNA variants in the coding region of LRAT.

PMID- 12419831
TI  - The role of MAPK pathways in the action of chemotherapeutic drugs.
AB  - In this study we have investigated the role of mitogen-induced and stress
      activated MAP kinase pathways in the cellular response to taxol, etoposide and
      ceramide in three different human cancer cell lines: HeLa cervical carcinoma,
      MCF7 breast cancer and A431 squamous carcinoma cells. The mitogen-induced ERK
      MAPKs were linked to cell proliferation and survival, whereas the stress
      activated MAPKs, p38 and JNK, were connected with apoptosis. Our results show
      that all drugs activated MAPKs, but that the extent and kinetics of activation
      were different. In order to assay the biological consequences of drug-induced
      MAPK activation we employed selective MAPK inhibitors and measured both long-term
      clonogenic survival as well as short-term parameters including apoptosis,
      mitochondrial metabolic integrity and cell cycle progression. Our results show
      that drug induced toxicity is not correlated with any singular parameter, but
      rather a combination of effects on cell cycle and apoptosis. In certain
      constellations the modulation of MAPK pathways could enhance or decrease drug
      efficacies. These effects mainly pertained to the regulation of apoptosis and
      clonogenic survival, but they were highly dependent on the combination of drug
      and cell line without any clear patterns of correlations emerging. These results
      suggest that the modulation of MAPK pathways to enhance the efficacy of
      chemotherapeutic drugs is of limited value unless it is tailored to the specific
      combination of drug and cancer.

PMID- 12419832
TI  - A pharmacogenetic study to investigate the role of dietary carcinogens in the
      etiology of colorectal cancer.
AB  - Susceptibility to colorectal cancer, one of the most common forms of cancer in
      the Western world, has been associated with several environmental and dietary
      risk factors. Dietary exposure to food derived heterocyclic amine carcinogens and
      polycyclic aromatic hydrocarbons have been proposed as specific risk factors.
      Many polymorphic Phase I and Phase II drug metabolizing enzymes are responsible
      for the metabolism and disposition of these compounds and it is therefore
      possible that inheritance of specific allelic variants of these enzymes may
      influence colorectal cancer susceptibility. In a multicenter case-control study,
      490 colorectal cancer patients and 593 controls (433 matched case-control pairs)
      were genotyped for common polymorphisms in the cytochrome P450 (CYP1A1, CYP1A2,
      CYP1B1, CYP2A6, CYP2C9, CYP2C19 and CYP2D6), glutathione S-transferase (GSTM1,
      GSTP1 and GSTT1), sulfotransferase (SULT1A1 and SULT1A2), N-acetyl transferase 2
      (NAT2), NAD(P)H:quinone oxidoreductase (NQO1), methylenetetrahydrofolate
      reductase (MTHFR), and microsomal epoxide hydrolase (EPHX1) genes. Matched case
      control analysis identified alleles associated with higher colorectal cancer risk
      as carriage of CYP1A1*2C (OR = 2.15, 95% CI 1.36-3.39) and homozygosity for
      GSTM1*2/*2 (OR = 1.53, 95% CI 1.16-2.02). In contrast, inheritance of the
      CYP2A6*2 (OR = 0.51, 95% CI 0.28-1.06), CYP2C19*2 (OR = 0.72, 95% CI 0.52-0.98)
      and the EPHX1(His113) alleles were associated with reduced cancer risk. We found
      no association with colorectal cancer risk with NAT2 genotype or any of the other
      polymorphic genes associated with the metabolism and disposition of heterocyclic
      amine carcinogens. This data suggests that heterocyclic amines do not play an
      important role in the aetiology of colorectal cancer but that exposure to other
      carcinogens such as polycyclic aromatic hydrocarbons may be important
      determinants of cancer risk.

PMID- 12419833
TI  - Genetic polymorphisms of alcohol and aldehyde dehydrogenases and glutathione S
      transferase M1 and drinking, smoking, and diet in Japanese men with esophageal
      squamous cell carcinoma.
AB  - The genetic polymorphisms of aldehyde dehydrogenase-2 (ALDH2), alcohol
      dehydrogenase-2 (ADH2), ADH3, and glutathione S-transferase M1 (GSTM1) influence
      the metabolism of alcohol and other carcinogens. The ALDH2*1/2*2 genotype, which
      encodes inactive ALDH2, and ADH2*1/2*1, which encodes the low-activity form of
      ADH2, enhance the risk for esophageal cancer in East Asian alcoholics. This case
      control study of whether the enzyme-related vulnerability for esophageal cancer
      can be extended to a general population involved 234 Japanese men with esophageal
      squamous cell carcinoma and 634 cancer-free Japanese men who received annual
      health checkups. The GSTM1 genotype was not associated with the risk for this
      cancer. Light drinkers (1-8.9 units/week) with ALDH2*1/2*2 had an esophageal
      cancer risk 5.82 times that of light drinkers with ALDH2*1/2*1 (reference
      category), and their risk was similar to that of moderate drinkers (9-17.9
      units/week) with ALDH2*1/2*1 (odds ratio = 5.58). The risk for moderate drinkers
      with ALDH2*1/2*2 (OR = 55.84) exceeded that for heavy drinkers (18+ units/week)
      with ALDH2*1/2*1 (OR = 10.38). Similar increased risks were observed for those
      with ADH2*1/2*1. A multiple logistic model including ALDH2, ADH2, and ADH3
      genotypes showed that the ADH3 genotype does not significantly affect the risk
      for esophageal cancer. For individuals with both ALDH2*1/2*2 and ADH2*1/2*1, the
      risk of esophageal cancer was enhanced in a multiplicative fashion (OR = 30.12),
      whereas for those with either ALDH2*1/2*2 or ADH2*1/2*1 alone the ORs were 7.36
      and 4.11. In comparison with the estimated population-attributable risks for
      preference for strong alcoholic beverages (30.7%), smoking (53.6%) and for lower
      intake of green and yellow vegetables (25.7%) and fruit (37.6%), an
      extraordinarily high proportion of the excessive risk for esophageal cancer in
      the Japanese males can be attributed to drinking (90.9%), particularly drinking
      by persons with inactive heterozygous ALDH2 (68.5%). Education regarding these
      risky conditions in connection with ALDH2 and ADH2 is vitally important in a new
      strategic approach aimed at preventing esophageal cancer in East Asians.

PMID- 12419834
TI  - Indolo[3,2-b]carbazole inhibits gap junctional intercellular communication in rat
      primary hepatocytes and acts as a potential tumor promoter.
AB  - Indole-3-carbinol (I3C) is a naturally occurring substance that shows anti
      carcinogenic properties in animal models. Besides its clear anti-carcinogenic
      effects, some studies indicate that I3C may sometimes act as a tumor promoter.
      Indolo[3,2-b]carbazole (ICZ), which is formed in the acidic environment of the
      stomach after intake of I3C, has a similar structure to, and shares biological
      effects with, the well-known tumor promoter 2,3,7,8-tetrachlorodibenzo-p-dioxin
      (TCDD). Therefore, we hypothesized that ICZ could be responsible for the
      potential tumor-promoting activity of I3C. The aim of the present study was to
      investigate the effect of ICZ on gap junctional intercellular communication
      (GJIC) in primary cultured rat hepatocytes co-cultured with the rat liver
      epithelial cell line WB-F344. Indolo[3,2-b]carbazole inhibited GJIC in the rat
      hepatocytes in a dose- and time-dependent manner. Significant inhibition was
      observed after 8 and 12 h of treatment with 1 and 0.1 micro M ICZ, respectively.
      Maximum GJIC inhibition (cell-cell communication only 5% of control values) was
      observed after 24-48 h of ICZ treatment. Continued exposure to 1 micro M ICZ
      suppressed GJIC until approximately 120 h. Both ICZ and TCDD treatment reduced
      the Cx32 mRNA level as well as the plasma membrane Cx32 staining. Indolo[3,2
      b]carbazole increased the Cyp1a1, Cyp1a2 and Cyp1b1 mRNA levels concurrently with
      an increase in 7-ethoxyresorufin O-deethylase (EROD) activities. Maximum EROD
      activity and Cyp1a1 mRNA levels were observed after approximately 12 h, whereas
      Cyp1a2 and Cyp1b1 mRNA levels peaked after 48 h. This study shows that ICZ may
      possess tumor promoter activity down-regulating GJIC by mechanisms, which seem to
      include activation of the Ah receptor and/or Cyp1 activity. Further studies are
      needed in order to clarify the anticarcinogenic/carcinogenic effects of I3C and
      ICZ before high doses of I3C may be recommended as a dietary supplement.

PMID- 12419835
TI  - Grape seed extract induces apoptotic death of human prostate carcinoma DU145
      cells via caspases activation accompanied by dissipation of mitochondrial
      membrane potential and cytochrome c release.
AB  - Grape seed extract (GSE), rich in the bioflavonoids commonly known as
      procyanidins, is one of the most commonly consumed dietary supplements in the
      United States because of its several health benefits. Epidemiological studies
      show that many prostate cancer (PCA) patients use herbal extracts as dietary
      supplements in addition to their prescription drugs. Accordingly, in recent
      years, we have focused our attention on assessing the efficacy of GSE against
      PCA. Our studies showed that GSE inhibits growth and induces apoptotic death of
      human PCA cells in culture and in nude mice. Here, we performed detailed studies
      to define the molecular mechanism of GSE-induced apoptosis in advanced human PCA
      DU145 cells. GSE treatment of cells at various doses (50-200 micro g/ml) for 12
      72 h resulted in a moderate to strong apoptotic death in a dose- and time
      dependent manner. In the studies assessing the apoptotic-signaling pathway
      induced by GSE, we observed an increase in cleaved fragments of caspases 3, 7 and
      9 as well as PARP in GSE-treated cells after 48 and 72 h of treatment. Pre
      treatment of cells with general caspases inhibitor, z-Val-Ala-Asp(OMe)-FMK or
      caspase 3-like proteases inhibitor [z-Asp(OMe)-Glu(OMe)-Val-Asp(OMe)-FMK], almost
      completely (approximately 90%) inhibited the GSE-induced apoptotic cell death. In
      a later case, GSE-induced caspase-3 activity was completely inhibited. Selective
      caspase 9 inhibitor [z-Leu-Glu(OMe)-His-Asp(OMe)-FMK] showed only partial
      inhibition of GSE-induced apoptosis whereas GSE-induced protease activity of
      caspase 9 was completely inhibited. Upstream of caspase cascade, GSE showed
      disappearance of mitochondrial membrane potential and an increase in cytochrome c
      release in cytosol. Together, these results suggest that GSE possibly causes
      mitochondrial damage leading to cytochrome c release in cytosol and activation of
      caspases resulting in PARP cleavage and execution of apoptotic death of human PCA
      DU145 cells. Furthermore, GSE-caused caspase 3-mediated apoptosis also involves
      other pathway(s) including caspase 9 activation.

PMID- 12419836
TI  - Stable expression of rat sulfotransferase 1B1 in V79 cells: activation of
      benzylic alcohols to mutagens.
AB  - We have constructed Chinese hamster V79-derived cell lines (V79-rSULT1B1-A and 
      B) that express rat sulfotransferase 1B1 (rSULT1B1). Sulfotransferase activity
      towards 1-naphthol was 1020 +/- 220 pmol/min/mg cytosolic protein in V79-rSULT1B1
      A cells and 57 +/- 9 pmol/ min/mg in V79-rSULT1B1-B cells. These activities were
      similar over 100 population doublings and at varying cell densities.
      Immunostaining indicated a cytoplasmatic localization of rSULT1B1. Expression
      usually was homogeneous within colonies but showed some variation between
      colonies. The level of rSULT1B1 protein in V79-rSULT1B1-B cells was similar to
      that in rat liver but higher than in colon mucosa. The cytotoxicity of the
      benzylic alcohols 4H-cyclopenta[def]chrysen-4-ol and 6-hydroxymethylbenzo
      [a]pyrene was enhanced >100-fold in V79-rSULT1B1-A cells compared with SULT
      deficient cells (V79p). Likewise, these compounds showed mutagenic effects (at
      the hprt locus) in V79-rSULT1B1-A cells starting at a concentration of 0.02 and
      0.01 micro M, respectively, but were inactive in V79p cells even at a
      concentration of 1 micro M. The cell line with the lower expression level, V79
      rSULT1B1-B, showed only marginal toxification of the compounds investigated,
      indicating an important role of the expression level in the test system. A
      thoroughly characterized mammalian cell system, including positive controls, is
      now available for studying rSULT1B1-mediated bioactivation of promutagens and
      protoxicants.

PMID- 12419837
TI  - Overexpression of an ectopic H19 gene enhances the tumorigenic properties of
      breast cancer cells.
AB  - The maternally expressed H19 gene is transcribed as an untranslated RNA that
      serves as a riboregulator. We have previously reported that this transcript
      accumulates in epithelial cells in approximately 10% of breast cancers. To gain
      further insight on how the overexpression of the H19 gene affects the phenotype
      of human breast epithelial cells, we investigated the oncogenic potential of RNA
      that was abundantly expressed from MDA-MB-231 breast cancer cells stably
      transfected with the genomic sequence of the human H19 gene. The amount of H19
      RNA did not affect cell proliferation capacity, timing of cell cycle phases or
      anchorage-dependent ability of H19-transfected clones in vitro. But in anchorage
      independent growth assays the H19-recombined cells formed more and larger
      colonies in soft-agar versus control cells. To explore this phenotypic change, we
      analysed tumour development after subcutaneous injection of H19-recombined cells
      into scid mice. Results showed that H19 overexpression promotes tumour
      progression. These data support the hypothesis that an overload of H19 transcript
      is associated with cells exhibiting higher tumorigenic phenotypes and therefore
      we conclude that the H19 gene has oncogenic properties in breast epithelial
      cells.

PMID- 12419838
TI  - Identification of human CYP forms involved in the activation of tamoxifen and
      irreversible binding to DNA.
AB  - This study investigates which CYP forms are responsible for the conversion of
      tamoxifen to its putative active metabolite alpha-hydroxytamoxifen and
      irreversible binding to DNA. We have used eight different baculovirus expressed
      recombinant human CYP forms and liquid chromatography-mass spectrometry to show
      that only CYP3A4 is responsible for the NADPH-dependent alpha-hydroxylation of
      tamoxifen. Surprisingly, this CYP did not catalyse the formation of 4
      hydroxytamoxifen. We demonstrate for the first time, by means of accelerator mass
      spectrometry, that CYP3A4 also catalysed the activation of [(14)C]tamoxifen to
      intermediates that irreversibly bind to exogenous DNA. Incubation of
      [(14)C]tamoxifen (20.6 kBq, 100 micro M) with CYP3A4, in the presence of NADPH
      for 60 min led to levels of DNA binding of 39.0+/-9.0 adducts/10(8) nucleotides
      (mean +/- SE, n = 6). While CYP3A4 converted tamoxifen to N-desmethyltamoxifen
      (38.3 +/- 7.20 pmol/20 min/pmol CYP, n = 4), the polymorphic CYP2D6 showed the
      highest activity for producing this metabolite (48.6+/-1.52pmol/20 min/pmol CYP).
      CYP2D6 was also the most active in catalysing 4-hydroxylation of tamoxifen,
      although an order of magnitude lower level was also detected with CYP2C19. With
      tamoxifen as substrate, no 3,4-dihydroxytamoxifen could be detected with any CYP
      form. CYP2B6 did not catalyse the metabolism or the binding of tamoxifen to DNA.
      It is concluded that CYP3A4 is the only P450 of those tested that converts
      tamoxifen to alpha-hydroxytamoxifen and the only one that results in appreciable
      levels of irreversible binding of tamoxifen to DNA.

PMID- 12419839
TI  - Ethylation and methylation of hemoglobin in smokers and non-smokers.
AB  - Two previous studies demonstrated elevated levels of 3-ethyladenine in smokers'
      urine, suggesting that cigarette smoke may contain a DNA ethylating agent. We
      hypothesized that such an agent would also lead to elevated levels of N-terminal
      N-ethylvaline in hemoglobin. N-terminal N-alkylated valines in hemoglobin can be
      measured using a modified Edman degradation, which employs pentafluorophenyl
      isothiocyanate to produce a pentafluorophenylthiohydantoin. The latter is
      quantified by gas chromatography-negative ion chemical ionization-mass
      spectrometry (GC-NICI-MS). We modified the published method to increase its
      sensitivity and selectivity, thereby allowing quantification of N-terminal N
      ethylvaline. Modifications included the use of a deuterated peptide as the
      internal standard, the introduction of an HPLC purification step, and the use of
      tandem mass spectrometry (MS/MS) for detection and quantification of the analyte,
      1-ethyl-5-isopropyl-3-pentafluorophenyl-2-thiohydantoin. We also quantified N
      terminal N-methylvaline in the same samples. The mean level of N-terminal N
      ethylvaline in the hemoglobin of smokers was 3.76 +/- 2.77 pmol/g globin (n =
      39), significantly higher than in non-smokers, 2.50 +/- 1.65 pmol/g globin (n =
      28), P = 0.023. The difference remained significant after correction for gender
      and age. The mean level of N-terminal N-methylvaline in smokers was 997 +/- 203
      pmol/g globin (n = 45) compared with 904 +/- 149 pmol/g globin in non-smokers (n
      = 29); these values were not significantly different when corrected for gender
      and age. As levels of hemoglobin and DNA adducts often correlate, the results of
      this study support the proposal that cigarette smoke contains an as yet
      unidentified ethylating agent, which might be involved in DNA damage and tumor
      initiation.

PMID- 12419840
TI  - Cellular background level of 8-oxo-7,8-dihydro-2'-deoxyguanosine: an isotope
      based method to evaluate artefactual oxidation of DNA during its extraction and
      subsequent work-up.
AB  - The measurement of oxidative damage to cellular DNA is a challenging analytical
      problem requiring highly sensitive and specific methods. In addition, artefactual
      DNA oxidation during its extraction and subsequent work-up may give rise to
      overestimated levels of oxidized DNA bases. In the present study, we have used
      (18)O-labelled 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo) as an internal
      standard to evaluate the extent of artefactual DNA oxidation during the critical
      steps preceding the measurement. The labelled oxidized purine nucleoside was
      specifically generated in cellular DNA using the recently available generator of
      (18)O-labelled singlet oxygen. Artefactual DNA oxidation that could take place
      during the work-up increases the level of 8-oxodGuo but not of the (18)O-oxidized
      nucleoside. Therefore, the ratio between the two compounds, as measured by high
      performance liquid chromatography coupled to tandem mass spectrometry, allows an
      unambiguous comparison of different methodologies. The comparison of different
      DNA extraction protocols led to the conclusion that artefactual DNA oxidation
      during the extraction step could be minimized if: (i) nuclei are isolated after
      cell lysis; (ii) desferrioxamine, a transition metal chelator is added to the
      different extraction buffers; and (iii) sodium iodide (or alternatively guanidine
      thiocyanate) is used for DNA precipitation. It was also demonstrated that sodium
      iodide does not decompose the targeted oxidized purine nucleoside. In addition,
      three different DNA digestion protocols were evaluated and they were found to
      give rise to similar results. Using the best-studied protocol, the steady-state
      cellular background level of 8-oxodGuo, in a lymphocyte cell line, was determined
      to be approximately 0.5 lesions/10(6) DNA nucleosides.

PMID- 12419841
TI  - Fish oil increases mitochondrial phospholipid unsaturation, upregulating reactive
      oxygen species and apoptosis in rat colonocytes.
AB  - We have shown that a combination of fish oil (high in n-3 fatty acids) with the
      butyrate-producing fiber pectin, upregulates apoptosis in colon cells exposed to
      the carcinogen azoxymethane, protecting against colon tumor development. We now
      hypothesize that n-3 fatty acids prime the colonocytes such that butyrate can
      initiate apoptosis. To test this, 30 Sprague-Dawley rats were provided with diets
      differing in the fatty acid composition (corn oil, fish oil or a purified fatty
      acid ethyl ester diet). Intact colon crypts were exposed ex vivo to butyrate, and
      analyzed for reactive oxygen species (ROS), mitochondrial membrane potential
      (MMP), translocation of cytochrome C to the cytosol, and caspase-3 activity
      (early events in apoptosis). The fatty acid composition of the three major
      mitochondrial phospholipids was also determined, and an unsaturation index
      calculated. The unsaturation index in cardiolipin was correlated with ROS levels
      (R = 0.99; P = 0.02). When colon crypts from fish oil and FAEE-fed rats were
      exposed to butyrate, MMP decreased (P = 0.041); and translocation of cytochrome C
      to the cytosol (P = 0.037) and caspase-3 activation increased (P = 0.032). The
      data suggest that fish oil may prime the colonocytes for butyrate-induced
      apoptosis by enhancing the unsaturation of mitochondrial phospholipids,
      especially cardiolipin, resulting in an increase in ROS and initiating apoptotic
      cascade.

PMID- 12419842
TI  - Comparative analysis of Helicobacter DNAs and biliary pathology in patients with
      and without hepatobiliary cancer.
AB  - Several Helicobacter species have recently been isolated from the bile and
      hepatobiliary systems of murine species, and are well recognized as a pathogen of
      the hepatobiliary disorder. This study was planned to investigate whether
      Helicobacter species possess a causative potential for human hepatobiliary
      disease, especially for hepatobiliary carcinogenesis. Bile and hepatobiliary
      tissue samples from 19 patients with hepatobiliary cancer and 19 patients with
      benign biliary diseases were subjected to polymerase chain reaction analyses for
      the detection of Helicobacter DNAs. Using a proliferating cell nuclear antigen
      (PCNA) staining technique, we also investigated the biliary epithelial cell
      kinetics with special reference to the presence of Helicobacter DNAs in the
      hepatobiliary system. We found that Helicobacter DNAs were positive in 10 (52.6%)
      of the 19 patients with hepatobiliary cancer. The incidence was significantly
      higher than that (15.7%) in the benign cases (P = 0.03). The PCNA labeling index
      in the biliary epithelium in Helicobacter DNA-positive patients was statistically
      higher than that in Helicobacter DNA-negative ones, regardless of whether the
      patient was suffering from hepatobiliary cancer and/or biliary inflammation. A
      close correlation between the presence of Helicobacter DNAs and an elevation of
      the PCNA labeling index in the biliary epithelium was demonstrated by multiple
      regression analysis. Our findings suggest that Helicobacter species may play a
      role in the pathogenesis of hepatobiliary cancer through an acceleration of
      biliary cell kinetics.

PMID- 12419843
TI  - Stearoyl-CoA desaturase 1 (Scd1) gene overexpression is associated with genetic
      predisposition to hepatocarcinogenesis in mice and rats.
AB  - The stearoyl-CoA desaturase 1 (Scd1) gene is involved in the synthesis and
      regulation of unsaturated fatty acids. Its expression is increased by several
      treatments/conditions that are associated with hepatocarcinogenesis (peroxisome
      proliferators, iron overload, dichloroacetic acid). We found that the Scd1 gene
      is differentially expressed, showing >10-fold higher mRNA levels in the normal
      liver tissue of C3H/He mice, which are genetically susceptible to
      hepatocarcinogenesis, than of BALB/c mice, which are resistant. Similarly, Scd1
      mRNA expression was approximately 4-fold higher in the normal liver of F344 rats,
      which are susceptible to hepatocarcinogenesis, than in Brown Norway (BN) rats,
      which are resistant. The chromosomal location of the Scd1 locus, both in mice and
      rats, excludes Scd1 candidacy as a hepatocellular tumor-modifier gene, as the
      Scd1 locus did not show allele-specific effects in a BALB/cxC3H/He intercross or
      in a BNxF344 backcross and intercross. No Scd1 coding polymorphisms were detected
      in the mouse and the rat strains showing elevated Scd1 expression. These results
      suggest that the Scd1 gene represents a downstream target of hepatocellular tumor
      modifier loci in two rodent species.

PMID- 12419844
TI  - Metabolic activation of the environmental contaminant 3-nitrobenzanthrone by
      human acetyltransferases and sulfotransferase.
AB  - 3-Nitrobenzanthrone (3-NBA) an extremely potent mutagen and suspected human
      carcinogen identified in diesel exhaust and in airborne particulate matter was
      shown to form multiple DNA adducts in vitro and in vivo in rats. In order to
      investigate whether human N,O-acetyltransferases (NATs) and sulfotransferases
      (SULTs) contribute to the metabolic activation of 3-NBA we used a panel of newly
      constructed Chinese hamster lung fibroblast V79MZ derived cell lines expressing
      human NAT1, human NAT2 or human SULT1A1, as well as TA1538-derived Salmonella
      typhimurium strains expressing human NAT1 (DJ400) or human NAT2 (DJ460) and
      determined DNA binding and mutagenicity. The formation of 3-NBA-derived DNA
      adducts was analysed by (32)P-postlabelling after exposing V79 cells to 0.01
      micro M 3-NBA or 0.1 micro M N-acetyl-N-hydroxy-3-aminobenzanthrone (N-Ac-N-OH
      ABA), a potential metabolite of 3-NBA. Similarly up to four major and two minor
      adducts were detectable for both compounds, the major ones being identical to
      those detected previously in DNA from rats treated with 3-NBA. Comparison of DNA
      binding between different V79MZ derived cells revealed that human NAT2 and, to a
      lesser extent, human NAT1 and human SULT1A1, contribute to the genotoxic
      potential of 3-NBA and N-Ac-N-OH-ABA to form DNA adducts. However, the extent of
      DNA binding by 3-NBA was higher in almost all V79 cells at a 10-fold lower
      concentration than by N-Ac-N-OH-ABA, suggesting that N-Ac-N-OH-ABA is not a major
      intermediate in the formation of 3-NBA-derived adducts. 3-NBA showed a 3.8-fold
      and 16.8-fold higher mutagenic activity in Salmonella strains expressing human
      NAT1 and human NAT2, respectively, than in the acetyltransferase-deficient
      strain, whereas N-Ac-N-OH-ABA was only clearly (but weakly) mutagenic in
      Salmonella DJ460 expressing human NAT2. This finding suggests that N-Ac-N-OH-ABA
      is not a major reactive metabolite responsible for the high mutagenic potency of
      3-NBA in Salmonella. Collectively our results indicate that O-acetylation and O
      sulfonation by human NATs and SULTs may contribute significantly to the high
      mutagenic and genotoxic potential of 3-NBA. Moreover, the yet-unidentified four
      major 3-NBA-derived adducts may be DNA adducts without an N-acetyl group.

PMID- 12419845
TI  - The mutational signature of alpha-hydroxytamoxifen at Hprt locus in Chinese
      hamster cells.
AB  - The anti-oestrogen tamoxifen is very effective in the treatment and prevention of
      breast cancer. Tamoxifen is not a pure antagonist, but possesses weak oestrogenic
      activity that may contribute to a slightly increased risk of endometrial cancer.
      Whilst this can be incorporated into risk-benefit analysis for the use of the
      drug, residual concerns exist over the exact mechanism of formation of these
      tumours. Tamoxifen is a potent hepatocarcinogen in the rat, probably via a
      genotoxic mechanism. Whilst tamoxifen does not appear to cause liver tumours in
      humans, DNA adducts have been found in endometrial tissue of women receiving the
      drug. Hence, there is still a need to establish the mechanism of formation of
      these tumours. We have therefore determined the molecular nature of mutations
      induced in vitro by alpha-hydroxytamoxifen, the putative proximate genotoxic
      metabolite, in a mammalian cell line (V79-rHSTa) with stable expression of rat
      hydroxysteroid sulfotransferase a, which catalyses the further metabolism of
      alpha-hydroxytamoxifen to its ultimate genotoxic product. DNA sequence
      alterations were examined at the Hprt gene in 50 mutant clones. Simple base
      substitutions, mainly GC-->TA transversions, predominated. However, single G:C
      base pair deletions and partial/complete exon skippings were also observed. All
      but one of the mutations involved guanine bases on the non-transcribed strand,
      probably indicating preferential repair of alpha-hydroxytamoxifen-induced guanine
      adducts from the transcribed strand. Nearest neighbour analysis of the mutations
      (on the non-transcribed strand) indicated that thymines (20/40) followed by
      guanines (13/40) were the most frequent 5' neighbours, with adenines or guanines
      the most frequent 3' neighbours. Many of the mutations occurred at TTGA/G
      sequences. Three mutational hot spots accounted for 11 GC-->TA transversions and
      another site for two single G:C base pair deletions. A search for these
      characteristic mutations in tumour-related genes of treated rats and humans
      should help in understanding the mechanism(s) of tamoxifen-induced
      carcinogenicity.

PMID- 12419846
TI  - Antitumorigenic activity of the prebiotic inulin enriched with oligofructose in
      combination with the probiotics Lactobacillus rhamnosus and Bifidobacterium
      lactis on azoxymethane-induced colon carcinogenesis in rats.
AB  - Prebiotics such as fructans, and probiotics such as Lactobacilli or
      Bifidobacteria, or a combination of prebiotics and probiotics (synbiotics) are
      thought to be protective against colon cancer. Therefore, we studied whether the
      prebiotic inulin enriched with oligofructose (Raftilose-Synergy1, briefly,
      Synergy1, 10% of the diet), probiotics [Bifidobacterium lactis (Bb12) and
      Lactobacillus rhamnosus (LGG), each at 5x10(8) c.f.u./g diet] or synbiotics (a
      combination of the two) protect rats against azoxymethane (AOM)-induced colon
      cancer. Male F344 rats were divided into: Controls; PRE, which were fed a diet
      containing Synergy1; PRO, fed a diet containing LGG and Bb12; PREPRO, fed a diet
      containing Synergy1, LGG and BB12. Ten days after beginning the diets, rats were
      treated with AOM (15 mg/kg s.c. two times); dietary treatments were continued for
      the entire experiment. Thirty-one weeks after AOM, rats treated with Synergy1
      (PRE and PREPRO groups) had a significantly lower (P < 0.001) number of tumours
      (adenomas and cancers) than rats without Synergy1 (colorectal tumours/rat were
      1.9 +/- 1.7, 1.1 +/- 1.1, 2.2 +/- 1.4 and 0.9 +/- 1.2 in Controls, PRE, PRO and
      PREPRO groups, respectively, means +/- SD). A slight, not significant effect of
      probiotics in reducing malignant tumours was also observed (P = 0.079). Caecal
      short-chain fatty acids (SCFA) were higher (P < 0.001) in the groups treated with
      Synergy1. Apoptosis was increased in the normal mucosa of the PRO group, while no
      variation was observed in the tumours. Colonic proliferation was lower in the PRE
      group as compared with Controls. Glutathione S-transferase placental enzyme pi
      type expression, and to a lesser extent, inducible NO synthase were depressed in
      the tumours from rats in the PRE and PREPRO groups. Cycloxygenase-2 expression
      was increased in the tumours of control rats but not in those from PRE, PRO or
      PREPRO rats. In conclusion, prebiotic administration in the diet decreases AOM
      induced carcinogenesis in rats.

PMID- 12419847
TI  - Redox-regulated mechanism may account for zerumbone's ability to suppress cancer
      cell proliferation.
AB  - A recent report shows that zerumbone (ZER) inhibits the proliferation of, and
      induces apoptosis in, colon cancer cells. We suggest a mechanism for these
      phenomena, based on our recently proposed redox model of cell proliferation which
      stresses the importance of intracellular redox potential E in the control of
      proliferation of normal and cancer cells.

PMID- 12419849
TI  - OxyR: a molecular code for redox sensing?
AB  - Helmann discusses the controversy surrounding the activation of the bacterial
      redox-regulated transcription factor OxyR. Evidence from different sources,
      including crystallographic data, has led to opposing models for the chemical
      changes that activate OxyR. Is it an intramolecular disulfide-linkage? Is it
      oxidation of a single cysteine residue to a sulfenic acid? Are there different
      active forms depending on the type of cysteine modification: intramolecular
      disulfide bond, sulfenic acid, S-nitrosothiol, or mixed disulfide with
      glutathione? These issues are discussed in the broader context of transcriptional
      regulation and how particular regulators may activate distinct genetic programs
      depending on the precise state of the regulator produced in response to
      environmental cues.

PMID- 12419850
TI  - Human CD8+ T cells do not require the polarization of lipid rafts for activation
      and proliferation.
AB  - Lipid rafts are important signaling platforms in T cells. Little is known about
      their properties in human CD8(+) T cells. We studied polarization of lipid rafts
      by digital immunofluorescence microscopy in primary human T cells, using beads
      coated with anti-CD3 and anti-CD28 mAbs (CD3/28 beads). Unlike CD4(+) T cells,
      CD8(+) T cells did not polarize lipid rafts when stimulated with CD3/28 beads,
      when the anti-CD28 antibody was substituted with B7.2Ig, or if an anti-CD8
      antibody was added to the CD3/28 beads. This phenomenon was also observed in
      human antigen-specific CD8(+) T cells. On stimulation with CD3/28 beads, the T
      cell antigen receptor clustered at the cell/bead contact area in both CD4(+) and
      CD8(+) T cells. Examination of lipid rafts isolated by sucrose density gradient
      centrifugation revealed the constitutive expression of p(56)Lck in the raft
      fractions of unstimulated CD8(+) T cells, whereas p(56)Lck was recruited to the
      raft fraction of CD4(+) T cells only after stimulation with CD3/28 beads.
      Stimulation with CD3/28 beads induced marked calcium flux, recruitment of PKC
      theta and F-actin to the cell/bead contact site, and similar proliferation
      patterns in CD4(+) and CD8(+) T cells. Thus, polarization of lipid rafts is not
      essential for early signal transduction events or proliferation of human CD8(+)
      lymphocytes. It is possible that the lower stringency of CD8(+) T cell activation
      obviates a requirement for raft polarization.

PMID- 12419851
TI  - Transcriptional profiles associated with aging and middle age-onset caloric
      restriction in mouse hearts.
AB  - To provide a global analysis of gene expression in the aging heart, we monitored
      the expression of 9,977 genes simultaneously in 5- and 30-month-old male B6C3F(1)
      mice by using high-density oligonucleotide microarrays and several statistical
      techniques. Aging was associated with transcriptional alterations consistent with
      a metabolic shift from fatty acid to carbohydrate metabolism, increased
      expression of extracellular matrix genes, and reduced protein synthesis. Caloric
      restriction (CR) started at 14 months of age resulted in a 19% global inhibition
      of age-related changes in gene expression. Interestingly, CR also resulted in
      alterations in gene expression consistent with preserved fatty acid metabolism,
      reduced endogenous DNA damage, decreased innate immune activity, apoptosis
      modulation, and a marked cytoskeletal reorganization. These observations provide
      evidence that aging of the heart is associated with specific transcriptional
      alterations, and that CR initiated in middle age may retard heart aging by
      inducing a profound transcriptional reprogramming.

PMID- 12419852
TI  - Reorganization of the cochleotopic map in the bat's auditory system by
      inhibition.
AB  - The central auditory system of the mustached bat shows two types of
      reorganization of cochleotopic (frequency) maps: expanded reorganization
      resulting from shifts in the best frequencies (BFs) of neurons toward the BF of
      repetitively stimulated cortical neurons (hereafter centripetal BF shifts) and
      compressed reorganization resulting from the BF shifts of neurons away from the
      BF of the stimulated cortical neurons (hereafter centrifugal BF shifts).
      Facilitation and inhibition evoked by the corticofugal system have been
      hypothesized to be respectively related to centripetal and centrifugal BF shifts.
      If this hypothesis is correct, bicuculline (an antagonist of inhibitory GABA-A
      receptors) applied to cortical neurons would change centrifugal BF shifts into
      centripetal BF shifts. In the mustached bat, electric stimulation of cortical
      Doppler-shifted constant-frequency neurons, which are highly specialized for
      frequency analysis, evokes the centrifugal BF shifts of ipsilateral collicular
      and cortical Doppler-shifted constant-frequency neurons and contralateral
      cochlear hair cells. Bicuculline applied to the stimulation site changed the
      centrifugal BF shifts into centripetal BF shifts. On the other hand, electric
      stimulation of neurons in the posterior division of the auditory cortex, which
      are not particularly specialized for frequency analysis, evokes centripetal BF
      shifts of cortical neurons located near the stimulated cortical neurons.
      Bicuculline applied to the stimulation site augmented centripetal BF shifts but
      did not change the direction of the shifts. These observations support the
      hypothesis and indicate that centripetal and centrifugal BF shifts are both based
      on a single mechanism consisting of two components: facilitation and inhibition.

PMID- 12419853
TI  - New insights and new approaches toward the study of age-related macular
      degeneration.

PMID- 12419854
TI  - Head to head with Boas: did he err on the plasticity of head form?

PMID- 12419855
TI  - Effects of creatine supplementation on housekeeping genes in human skeletal
      muscle using real-time RT-PCR.
AB  - The present study examined the validity and reliability of measuring the
      expression of various genes in human skeletal muscle using quantitative real-time
      RT-PCR on a GeneAmp 5700 sequence detection system with SYBR Green 1 chemistry.
      In addition, the validity of using some of these genes as endogenous controls
      (i.e., housekeeping genes) when human skeletal muscle was exposed to elevated
      total creatine levels and exercise was also examined. For all except 28S, linear
      relationships between the logarithm of the starting RNA concentrations and the
      cycle threshold (C(T)) values were established for beta-actin, beta2
      microglobulin (beta2M), cyclophilin (CYC), and glyceraldehyde-3-phosphate
      dehydrogenase (GAPDH). We found a linear response between C(T) values and the
      logarithm of a given amount of starting cDNA for all the genes tested. The
      overall intra-assay coefficient of variance for these genes was 1.3% and 21% for
      raw C(T) values and the linear value of 2(-C(T)), respectively. Interassay
      variability was 2.3% for raw C(T) values and 34% for the linear value of 2(
      C(T)). We also examined the expression of various housekeeping genes in human
      skeletal muscle at days 0, 1, and 5 following oral supplementation with either
      creatine or a placebo employing a double-blind crossover study design. Treatments
      were separated by a 5-wk washout period. Immediately following each muscle
      sampling, subjects performed two 30-s all-out bouts on a cycle ergometer.
      Creatine supplementation increased (P < 0.05) muscle total creatine content above
      placebo levels; however, there were no changes (P > 0.05) in C(T) values across
      the supplementation periods for any of the genes. Nevertheless, 95% confidence
      intervals showed that GAPDH was variable, whereas beta-actin, beta2M, and CYC
      were the least varying genes. Normalization of the data to these housekeeping
      genes revealed variable behavior for beta2M with more stable expressions for both
      beta-actin and CYC. We conclude that, using real-time RT-PCR, beta-actin or CYC
      may be used as housekeeping genes to study gene expression in human muscle in
      experiments employing short-term creatine supplementation combined with high
      intensity exercise.

PMID- 12419856
TI  - Large-scale, high-throughput screening for coagulation and hematologic phenotypes
      in mice.
AB  - The Mouse Phenome Project is an international effort to systematically gather
      phenotypic data for a defined set of inbred mouse strains. For such large-scale
      projects the development of high-throughput screening protocols that allow
      multiple tests to be performed on a single mouse is essential. Here we report
      hematologic and coagulation data for more than 30 inbred strains. Complete blood
      counts were performed using an Advia 120 analyzer. For coagulation testing, we
      successfully adapted the Dade Behring BCS automated coagulation analyzer for use
      in mice by lowering sample and reagent volume requirements. Seven automated assay
      procedures were developed. Small sample volume requirements make it possible to
      perform multiple tests on a single animal without euthanasia, while reductions in
      reagent volume requirements reduce costs. The data show that considerable
      variation in many basic hematological and coagulation parameters exists among the
      inbred strains. These data, freely available on the World Wide Web, allow
      investigators to knowledgeably select the most appropriate strain(s) to meet
      their individual study designs and goals.

PMID- 12419857
TI  - Gene expression profile of human endothelial cells exposed to sustained fluid
      shear stress.
AB  - Biomechanical forces can modulate endothelial phenotype through changes in gene
      expression. We hypothesized that physiological laminar shear stresses (LSS) act
      as differentiative stimuli on endothelial cells (EC) to alter gene expression,
      creating an antioxidant, anti-apoptotic and anti-proliferative environment. The
      transcriptional profile of cultured human umbilical vein endothelial cells
      (HUVEC) exposed to LSS was evaluated by GeneCalling; 107 genes demonstrated at
      least a twofold change in expression at 24 h (LSS vs. static). These flow
      responsive genes represent a limited number of functional clusters that include
      transcription factors, antioxidants, signaling molecules, cell cycle regulators,
      and genes involved in cellular differentiation. Immunohistochemistry and in situ
      hybridization confirmed that many of these flow-responsive genes, including the
      novel basic helix-loop-helix transcription factor Hath6, are expressed in EC in
      vivo. Thus these data identify a limited set of flow-responsive genes expressed
      in the endothelium that may be responsible for the establishment and maintenance
      of the flow-adapted endothelial phenotype in vivo.

PMID- 12419858
TI  - Genomic analysis of alachlor-induced oncogenesis in rat olfactory mucosa.
AB  - Alachlor induces olfactory mucosal tumors in rats in a highly ordered temporal
      process. We used GeneChip analysis to test the hypothesis that histological
      progression and oncogenic transformation are accompanied by gene expression
      changes that might yield clues as to the molecular pathogenesis of tumor
      formation. Acute alachlor exposure caused upregulation of matrix
      metalloproteinases (MMP)-2 and -9, tissue inhibitor of metalloproteinase-1,
      carboxypeptidase Z, and other genes related to extracellular matrix homeostasis.
      Heme oxygenase was upregulated acutely and maintained elevated expression.
      Expression of ebnerin, related to the putative human tumor suppressor gene DMBT1,
      progressively increased in alachlor-treated olfactory mucosa. Progression from
      adenomas to adenocarcinoma was correlated with upregulation of genes in the wnt
      signaling pathway. Activated wnt signaling was confirmed by immunohistochemical
      localization of beta-catenin to nuclei of adenocarcinomas, but not earlier
      lesions. These observations suggest that initiation and progression of alachlor
      induced olfactory mucosal tumors is associated with alterations in extracellular
      matrix components, induction of oxidative stress, upregulation of ebnerin, and
      final transformation to a malignant state by wnt pathway activation.

PMID- 12419859
TI  - Distinct gene-sex interactions regulate adult rat cardiomyocyte width and length
      independently.
AB  - Wistar-Kyoto (WKY) and WKY-derived hyperactive (WKHA) rats are two genetically
      related inbred strains of rats that are both normotensive yet exhibit differences
      in left ventricular mass (LVM). We had shown previously that cardiomyocytes from
      male WKHA are wider than that of male WKY, and that there was genetic linkage
      between LVM and a locus on chromosome 5 (RNO5) in the male progeny of a F2
      WKHA/WKY cross. We show here that cardiomyocyte width is linked to the same RNO5
      locus in male reciprocal congenic rats derived from WKHA and WKY. Contrary to
      males, we found no genetic linkage between LVM and the RNO5 locus in female rats.
      However, ventricular hypertrophy in females might be of a different nature,
      because cardiomyocytes from female WKHA were shorter than their WKY counterparts
      (with no difference in width). The RNO5 locus contains that of the natriuretic
      peptide precursor A (Nppa) gene. In male congenic rats, changes in cardiomyocyte
      width always correlated with reciprocal changes in the LV concentration of atrial
      natriuretic factor (ANF, i.e., the peptide product of Nppa). Taken together with
      other functional data, the small size of the RNO5 locus (approximately 63 cR)
      increased the likelihood that both cardiomyocyte width and LV ANF concentration
      could be linked to only one gene (possibly Nppa) in male rats. Moreover, our
      results support the notion that genes and sex interact to regulate cardiomyocyte
      width and length independently from one another.

PMID- 12419861
TI  - Influence of canine cumulus oophorus on homologous sperm motility.
AB  - Sperm ejaculated by 8 beagle dogs and the cumuli oophori collected from 3 estrous
      beagle bitches were co-incubated, and penetration of the sperm into cumuli was
      observed to investigate the influence of cumuli on homologous sperm. The
      percentages of hyperactivated sperm and acrosome-reacted sperm were calculated
      after incubation with homogenized cumuli. The hyaluronic acid content of the
      incubated cumuli was measured, and hyperactivation and the acrosome reaction of
      the sperm were evaluated in medium containing hyaluronic acid. The mean
      percentage of hyperactivated sperm (33.0%) and number (3.0) of sperm that had
      penetrated a cumulus among sperm incubated for 7 hr were significantly higher
      than the values for sperm incubated for 0.5 hr (P<0.01). Almost all sperm that
      had penetrated the cumuli had intact acrosome, as though they were
      hyperactivated. The percentages of motile sperm (77.3%) and hyperactivated sperm
      (23.6%) after 2 hr incubation in the medium containing homogenized cumuli were
      significantly higher than in control medium (P<0.01), but there was no difference
      between cumulus and control media in the percentages of acrosome-reacted sperm.
      The hyaluronic acid content of a cumulus increased after 24 hr incubation. After
      2 and 4 hr of incubation the percentages of hyperactivated sperm in the medium
      containing hyaluronic acid were significantly higher than in the control medium
      (P<0.01). These results suggest that canine hyperactivated sperm with intact
      acrosome can penetrate homologous cumuli and that the sperm are able to pass
      through the cumulus because the hyperactivated movement is maintained by
      hyaluronic acid secreted by the cumulus cells.

PMID- 12419862
TI  - Effects of bovine lactoferrin by the intramammary infusion in cows with
      staphylococcal mastitis during the early non-lactating period.
AB  - To evaluate the clinical effects of bovine lactoferrin on staphylococcal mastitis
      in Holstein cows during the early non-lactating period, 41 mammary quarters were
      selected randomly from 36 cows on 3 dairy farms. Twelve quarters were infused
      intramammarily with bovine lactoferrin. Twenty-nine quarters were infused with
      antibiotic as a control. In the bovine lactoferrin-infused group, 91.7% of
      mastitic quarters were cured at 7 days after calving, compared with 48.3% in the
      control group. Furthermore, the changes in mammary secretion induced by the
      infusion of bovine lactoferrin were investigated. Mean numbers of staphylococci
      in mammary gland secretions were significantly decreased in both 5 bovine
      lactoferrin-infused quarters and 5 antibiotic-infused control quarters (p<0.05).
      Unlike in the control quarters, the mean total cell concentration in the mammary
      gland secretions increased in bovine lactoferrin-infused quarters. Similar
      results were obtained in 6 healthy quarters which were infused with bovine
      lactoferrin. In these quarters, the cell population contained mainly phagocytes
      such as polymorphonuclear leukocytes and cells positive for CD11b which is known
      as a complement receptor. The mean concentration of C3 in mammary gland
      secretions was significantly increased in 5 mastitic quarters infused with bovine
      lactoferrin (p<0.05), but showed no significant change in 5 mastitic control
      quarters. These results suggested that bovine lactoferrin treatment for
      staphylococcal mastitis in the early non-lactating period might increase the rate
      of cure through the induction of innate immunity in the host.

PMID- 12419863
TI  - Relationship among insulin-like growth factor-I, blood metabolites and postpartum
      ovarian function in dairy cows.
AB  - The relationship among nutritional status, systemic insulin-like growth factor-I
      (IGF-I) and ovarian function early postpartum were investigated. A total of 27
      Holstein-Friesian cows, 10 that cycled normally within 20 days postpartum, 5
      diagnosed with follicular cysts, 8 with persistent corpus luteum (CL) after the
      first ovulation postpartum and 4 with inactive ovaries were used for the study.
      Blood samples were collected 1-3 times per week, for 60 days pre- and postpartum,
      for IGF-I, progesterone, estradiol, free fatty acids (FFA), blood urea nitrogen
      (BUN), and aspartate aminotransferase (AST) determination. Inactive ovary and
      cystic cows had a higher body condition score before calving and lost more
      condition than normal or persistent CL cows. Immediately postpartum, IGF-I levels
      were higher and rose sharply in cows that cycled normally than in cystic,
      inactive ovary or persistent CL cows. At calving and early postpartum, FFA was
      higher in inactive ovary and cystic than in normal and persistent CL cows. There
      was a significant strong positive relationship between IGF-I and BUN, and strong
      negative relationships between IGF-I and FFA and AST in all groups. There was a
      positive relationship between serum IGF-I and estradiol in normal cystic and
      inactive ovary cows. This study found that overconditioned cows during the dry
      period or at calving, lost more body condition postpartum. These cows also had a
      deeper and longer period of negative energy balance (NEB), poor liver function
      and low circulating IGF-I concentrations early postpartum. Such cows were likely
      to have poor reproductive function as seen in development of cystic ovaries,
      persistent CL and inactive ovary. Changes in serum IGF-I early postpartum may
      help predict both nutritional and reproductive status in dairy cattle.

PMID- 12419864
TI  - Different factors affect developmental competence and cryotolerance in in vitro
      produced bovine embryo.
AB  - The present study was conducted to examine the effects of culture systems and
      culture media on developmental competence and freezability of bovine embryos
      obtained by in vitro culture of in vitro matured and fertilized (IVM-IVF)
      oocytes. No significant difference was observed in the proportions of oocytes
      developed to blastocysts, the speed at which the oocytes reached the blastocyst
      stage and the number of cells, when the IVM-IVF oocytes were cultured in CR1aa
      with or without cumulus cells. Nevertheless, more of the IVM-IVF oocytes cultured
      either with or without cumulus cells in CR1aa were seen to reach the blastocyst
      stage much sooner than those cultured with cumulus cells in TCM199 (P<0.05). The
      proportion of embryos developed to the blastocyst stage by day 7 in CR1aa culture
      was significantly higher than embryos cultured in TCM199. Viability after frozen
      thawed blastocysts were obtained in vitro, was seen in a significantly higher
      percentage of embryos cultured in TCM199 and developed to the hatched blastocysts
      than in those cultured in CR1aa (P<0.05). These results indicate that CR1aa was
      superior to TCM199 for the potential developmental of IVM-IVF oocytes to
      blastocysts during in vitro culture regardless of co-culture with or without
      cumulus cells. But the freezability of blastocysts developed in CR1aa was
      inferior to those developed in TCM199.

PMID- 12419865
TI  - A gross and histopathological study of an ectopic white line development in
      equine laminitis.
AB  - In horses with chronic laminitis, an abnormal horny structure called lamellar
      wedge, is generated between the hoof wall and the laminar epidermis. To be able
      to manage horses with chronic laminitis correctly, more information about the
      pathological state of this abnormal horn is required. The aim of this study was
      to collect and analyze objective morphological data about the abnormal horn in
      order to understand its morphology and development. In the study, the abnormal
      horn was grossly visible on the sagittal hoof section from approximately 20 days
      after the onset of disease. In the histological observations, the structural
      characteristics of this abnormal horn were similar to the white line tissue,
      suggesting it is an ectopic white line. Mean value of the cross-sectional area of
      the abnormal horn against the distal phalanx section area (A/D) was 0.29 cm(2) SD
      +/- 0.14 and it finally showed an eight-fold increase over the mean value of
      normal white line section area against the distal phalanx section area. In
      conclusion, a large amount of the ectopic white line is thought to be finally
      able to inhibit normal hoof wall growth, so that it should be resected at the
      optimum time when would be after one month from the onset of the disease.

PMID- 12419866
TI  - Functional morphology of the mastication muscles in the lesser and greater mouse
      deer.
AB  - The mastication muscles were examined in the lesser (Tragulus javanicus) and
      greater mouse deer (Tragulus napu) to clarify the form of the mastication muscles
      in these primitive artiodactyls. The M. masseter was well-developed in both
      species, however the attachment area of its origin was not confirmed in the
      rostral facial part. The masseter bundles were not observed on the lateral side
      of the maxilla bone, and their origin was restricted to the zygomatic arch area.
      This suggests that the M. masseter may not act as a motor raising the mandible
      rostro-dorsally, but pull the insertion vertically unlike the highly derived
      grazer of Bovidae. The Crista temporalis was weak and the M. temporalis was thin
      in the mouse deer, and this indicates that the M. temporalis may not be important
      in the mastication in the primitive artiodactyls. These findings suggest that the
      browser such as mouse deer has been adapted for the feeding on soft leaves, and
      functional-morphologically different in mastication strategy from the grazer such
      as developed Bovidae species. The architecture of the mastication muscles was not
      different between the two species. However, in the muscle weight ratios per body
      weight, the M. temporalis and the M. digastricus were significantly smaller in
      greater mouse deer than in lesser mouse deer.

PMID- 12419867
TI  - Passage of equine herpesvirus-1 in suckling mouse brain enhances extraneural
      virus growth and subsequent hematogenous neuroinvasion.
AB  - Intracerebral inoculation of field-isolates as well as established strains of
      equine herpesvirus-1 (EHV-1) in suckling mice results in viral replication in
      neurons and glial cells and induces encephalitis. By intraperitoneal (i.p.)
      inoculation, no histological lesion was observed in the central nervous system
      (CNS) in suckling mice with the EHV-1 HH1 strain (HH1), whereas a neuroadapted
      variant (NHH1) produced by serial passage of HH1 in the mouse brain caused severe
      encephalomyelitis after i.p. inoculation. The purpose of this study was to
      determine the route of neuroinvasion after i.p. inoculation of NHH1 and to
      clarify the effects of the brain passage on viral neuroinvasion. NHH1, but not
      HH1, targeted splenic and pulmonary macrophages and omental fat cells on days 1
      and 2 post-inoculation (p.i.). From days 1 to 3 p.i., cell-associated viremia was
      occurred in NHH1-infected mice, but not in HH1-infected mice. On day 4 p.i.,
      viral antigen was detected in a few endothelial cells, perivascular glial cells
      and neurons in the CNS in NHH1-infected mice. The number of viral antigen
      positive cells increased markedly after day 5 p.i. In contrast, no viral antigen
      positive cell was detected in the CNS in HH1-infected mice, except for a few
      nerve cells in the thoracic cord on day 4 p.i. These results suggest that NHH1
      neuroinvasion is hematogenous and is correlated with enhanced extraneural virus
      growth.

PMID- 12419868
TI  - No apoptotic cell death of erythroid cells of erythroblastic islands in bone
      marrow of healthy rats.
AB  - A possibility of apoptotic cell death in erythropoietic regulation was examined
      by means of detailed light microscopical histoplanimetry, electron microscopy,
      the in situ nick-end labeling method, and an immunohistological method in the rat
      bone marrow. Serum erythropoietin concentrations were shown at normal levels. The
      erythroid series on a mature process presented several morphological features of
      apoptosis, i.e. the shrinkage of both nuclei and cytoplasm and the chromatin
      condensation. In the light microscopical histoplanimetry, however, morphological
      signs of final apoptotic cell death were never found in any erythroid cell within
      the erythroblastic islands. This finding was also supported by detailed
      ultrastructural observation: No erythroid cell bodies were trapped and degraded
      by the central macrophages of the erythroblastic islands, while the denucleated
      nuclei with small amount of cytoplasm of late erythroblasts were often trapped
      and degraded in the macrophages. Nuclear DNA fragmentation was not detected in
      any erythroblasts, but was detected in the lysosomes of the central macrophages.
      These findings suggest that erythropoiesis is regulated by other regulatory
      mechanisms than apoptotic cell death. An additional ultrastructural finding shows
      that the reticulocytes anchored to the central macrophages are transported into
      the peripheral blood circulation.

PMID- 12419869
TI  - Gonadosomatic index and testis morphology of common carp (Cyprinus carpio) in
      rivers contaminated with estrogenic chemicals.
AB  - To study the effect of estrogenic chemicals on fish, the gonadosomatic index (GSI
      = [testis weight/body weight] x 100) and testis histology of mature common carp
      (Cyprinus carpio) from 2 contaminated sites (Ishizu and Wada rivers, Osaka) and a
      control site were examined between June 1998 and March 2001. The concentration of
      nonylphenol, bisphenol A and 17beta-estradiol in the Ishizu river was 3-4 times
      higher than in the Wada river. In the pre-breeding and breeding seasons, there
      were no significant differences in body weight among carp from the 3 sites, the
      body weight of Ishizu river carp being significantly lower (p<0.05) than that of
      Wada river fish only in the post-breeding season. The GSI and testis weight in
      fish from the Ishizu river were significantly lower (p<0.05) than in control fish
      during all phases of gonadal cycle and lower than in Wada river fish in the pre
      breeding and post-breeding season. No histological abnormalities were found in
      the testes of the males examined. Histological observation of the testes revealed
      a delay in the onset of spermatogenesis in fish from the Ishizu river compared
      with those from the other sites. These results clearly imply that the estrogenic
      chemicals in the Ishizu river adversely affect the testis development of the
      fish.

PMID- 12419870
TI  - Long-term excretion of Shiga toxin-producing Escherichia coli (STEC) and
      experimental infection of a sheep with O157.
AB  - To investigate a long-term shedding of Shiga toxin (Stx)-producing Escherichia
      coli (STEC) from sheep, a fifteen-month study for STEC isolation from a sheep,
      which had yielded STEC before, was attempted. The sheep continued to shed STEC
      and 39 STEC were isolated. The number of STEC in the feces was estimated at 1.7 x
      10(3) per gram. In addition, although Stx1-negative O157 and stx2-encoding
      bacteriophage were experimentally infected to the sheep, Stx-positive O157 or
      Stx2- producing bacterial cells were not detected. The genetical and biochemical
      characterization of those 39 STEC strains showed that all STEC strains produced
      Shiga toxin 1 (Stx1) and were divided into three classes (I to III). From
      phylogenetic analysis of their amino acid sequences, class-I STEC was classified
      as group 1 comprising mainly human STEC, and classes II/III were as group 2
      comprising sheep STEC. Our results suggest that STEC easily colonized in sheep
      and that the sheep continued to shed STEC, showing that sheep might be an
      important reservoir for human STEC infection.

PMID- 12419871
TI  - Changes of hip joint congruity after triple pelvic osteotomy in the dog with hip
      dysplasia.
AB  - Changes in hip joint congruity was evaluated in dogs with hip dysplasia before
      and after triple pelvic osteotomy by computed tomography examination in the
      standing position. Lateral center edge angle significantly increased, and center
      distance (CD) significantly decreased after surgery compared to the values before
      surgery, respectively. There was an inverse proportion between the postoperative
      period and the change in the ratio of CD. These results suggested that joint
      laxity was improved with time after surgery, providing evidence of the clinical
      usefulness of this surgery.

PMID- 12419872
TI  - Congenital chondrodysplastic dwarfism with dyshematopoiesis in a holstein calf.
AB  - A holstein calf with congenital chondrodysplastic dwarfism was
      histopathologically examined. The head of the calf was relatively flat giving a
      dog-like appearance with its short nose and sloping forehead. Limb bones were
      dumbbell-like with short diaphysis and hypertrophied metaphyses. Bone marrow was
      pale, whitish and fatty. In the metaphyseal plates most of chondrocytes were
      pyknotic with swollen and ghost-like cytoplasm, and were irregularly arranged.
      Column of calcified cartilage were poorly formed losing comb-like structure. Bone
      marrow was ischemic with poor hematopoiesis and was moderately replaced by
      adipose tissue. In articular cartilage, most of chondrocytes were degenerated
      with ghost-like cytoplasm. Many cartilage canals and occasional bone marrow-like
      structure were formed. The characteristics lesions of the calf were
      chondrodysplasia and dyshematopoiesis.

PMID- 12419873
TI  - Prevalence of antibodies to Neospora caninum in Korean native beef cattle.
AB  - A total of 438 sera from Korean native beef cattle in 9 provinces were tested for
      Neospora caninum antibodies using an immunofluorescent antibody test (IFAT).
      Eighteen (4.1%) cattle were positive by IFAT. The titers ranged from 1:200 (10
      animals), 1:400 (5 animals), 1:800 (2 animals) to 1:1,600 (1 animal). Although
      the seroprevalence was slightly higher in Chungnam (8.9%), this was not
      significantly different from those noted in Kyunggi, Kangwon, Kyungbuk, Kyungnam,
      and Cheju provinces. Sera obtained from beef cattle in the provinces of Chungbuk,
      Jeonbuk and Jeonnam were all negative. Neospora positive sera were also tested
      for anti-Toxoplasma gondii antibodies using a commercial latex agglutination test
      (LAT). Antibody to T. gondii was detected in only 1 (5.6%) of 18 N. caninum
      positive sera. These results indicate that N. caninum and T. gondii infection are
      present at a low level in the Korean native beef cattle.

PMID- 12419874
TI  - Localization of cytokines in tendinocytes of the superficial digital flexor
      tendon in the horse.
AB  - Although inflammatory activation of cytokines have been analyzed in various
      tissues, there have only been a few and as-yet-inconclusive studies on cytokines
      in equine tendons. In this study, the localizations of 4 cytokines (IL-1alpha, IL
      1beta, TNFalpha and IFNgamma) in tendinocytes of the equine superficial digital
      flexor tendon (SDFT) were analyzed by the use of an immunohistochemical method.
      In inflamed tendons positive staining for all 4 cytokines antibodies were
      detected in endotedinieum cells and vascular epithelial cells. In contrast,
      negative or trace immunoreactions were obtained in many tendinocytes in the
      normal tendon. The variation in cellular immune responses depending on the kind
      of cytokine may reflect the physiological/pathological condition of the SDFT.

PMID- 12419875
TI  - The expression of sialyl Lewis X in canine and feline mammary gland tumors.
AB  - The expression of sialyl Lewis X (sLe(x)) in 93 canine and 15 feline mammary
      gland tumors (MGT) obtained by surgical resection at Veterinary Medical Center,
      the University of Tokyo was examined by immunohistochemistry. Their
      clinicopathological features and prognosis were also reviewed. Approximately 60%
      of MGT tissues showed sLe(x) positive expressions, while all normal mammary gland
      tissues were negative. However, its expression was not correlated with
      clinicopathological features and prognosis significantly. This study suggests
      that sLe(x) may be a tumor-associated antigen in canine and feline MGTs.

PMID- 12419876
TI  - Development of a shuttle polymerase chain reaction for the detection of bovine
      herpesvirus 2.
AB  - Three different polymerase chain reaction (PCR) protocols were evaluated for
      their ability to detect bovine herpesvirus 2 (BoHV-2): single-step PCR with 3
      reaction stages (denaturation, annealing and extension), 2 reaction stages
      (denaturation and annealing/extension; shuttle PCR), and semi-nested PCR with 3
      reaction stages. All the PCR protocols showed the same sensitivity (detection
      limit of 0.4 TCID(50)). A non-specific band sometimes appeared in mock cell DNA
      at annealing temperatures below 64 degrees C. The shuttle PCR was found to be
      superior to the other protocols under consideration because of the speed of its
      application. Furthermore, no non-specific band was detected in DNAs of eight
      other DNA viruses. Thus, the shuttle PCR seems to be an excellent diagnostic tool
      for BoHV-2 infections.

PMID- 12419877
TI  - A unique isolate of Malassezia from a cat.
AB  - An isolate of Malassezia from a cat with otitis externa was examined
      mycologically as well as molecularly. The isolate was similar to M. sympodialis
      in morphological and biochemical characteristics. In molecular analysis, however,
      it differed from the 7 species of Malassezia previously reported. Therefore, this
      clinical isolate from a cat might be a new species of Malassezia.

PMID- 12419878
TI  - Orphan G protein-coupled receptors and beyond.
AB  - Since the first discovery of mammalian receptors for adrenaline (beta(2)) and
      acetylcholine (M(1)) in 1986, many G protein-coupled receptors for known ligands
      have been cloned by protein purification, PCR (polymerase chain reaction) and low
      stringency hybridization, and they have been identified by expression cloning
      techniques. Now we are almost out of the known ligands pool. However, through the
      achievement of the Human Genome Project, numerous orphan receptors (whose natural
      ligands are not yet found) are also available for analysis. In this review, I
      would like to review recent achievements in the discovery of natural ligands, to
      describe useful orphan receptor strategies, and to predict the future of reverse
      pharmacology.

PMID- 12419879
TI  - Effects of meluadrine tartrate and ritodrine hydrochloride on oxytocin-induced
      uterine contraction, uterine arterial blood flow and maternal cardiovascular
      function in pregnant goats.
AB  - This study was designed to elucidate the effects of meluadrine tartrate on
      oxytocin-induced uterine contraction and maternal hemodynamics in unanesthetized,
      chronically instrumented pregnant goats. After the administration of meluadrine
      tartrate or ritodrine hydrochloride to pregnant goats, changes in heart rate
      (HR), arterial blood pressure (AOP), and arterial blood pH and gasses (P(O2) and
      P(CO2)) in the mother, as well as changes in intrauterine pressure (IUP) and
      uterine arterial blood flow (UBF), were measured. The escalating administration
      of meluadrine tartrate (0.03, 0.1, 0.3 and 1 micro g. kg(-)(1). min(-)(1)) or
      ritodrine hydrochloride (1, 3, 10 and 30 microg. kg(-)(1). min(-)(1)) to the
      maternal femoral vein caused a marked and similar inhibition in oxytocin-induced
      uterine contraction (a rise in IUP). By these escalating dosings, maternal HR was
      increased dose-dependently in both treatment groups; however, the degree of the
      HR increase in the meluadrine tartrate-treatment group was significantly less
      than that in the ritodrine hydrochloride-treatment group. Furthermore, the degree
      of the UBF decrease in the meluadrine tartrate-treatment group was significantly
      less than that in the ritodrine hydrochloride-treatment group. The present study
      suggests that meluadrine tartrate has a mild influence on the maternal
      cardiovascular function relative to the effects of ritodrine taking the potent
      efficacy on oxytocin-induced uterine contraction into account.

PMID- 12419880
TI  - Effects of meluadrine tartrate on maternal metabolic responses and fetal
      hemodynamics in pregnant goats.
AB  - This study was designed to elucidate the effects of meluadrine tartrate on
      maternal metabolic responses and fetal hemodynamics in unanesthetized,
      chronically instrumented pregnant goats. After the administration of meluadrine
      tartrate to pregnant goats or directly to fetuses, changes in heart rate (HR),
      arterial blood pressure and arterial blood pH, gasses, electrolytes and metabolic
      responses were measured. The constant administration of meluadrine tartrate (0.1
      microg. kg(-)(1). min(-)(1)) to pregnant goats resulted in the increases of
      maternal HR, glucose and free fatty acid and the decrease of maternal blood K(+)
      concentration. The direct escalating administration of meluadrine tartrate (0.01,
      0.03 and 0.1 microg. kg(-)(1). min(-)(1)) did not increase the fetal HR, while
      ritodrine hydrochloride (0.3, 1 and 3 microg. kg(-)(1). min(-)(1)) to fetuses
      increased the fetal HR dose-dependently. The present study suggests that
      meluadrine tartrate has a mild influence relative to the effects of ritodrine to
      the maternal metabolic responses and fetal cardiovascular function.

PMID- 12419881
TI  - Effect of betaxolol on aspartate aminotransferase activity in hypoxic rat retina
      in vitro.
AB  - We investigated the effect of betaxolol on the decrease of mitochondrial
      aspartate aminotransferase (mAAT) activity in rat retinas induced by hypoxia in
      vitro. It is reported that mAAT decreases in ischemic or hypoxic retina and that
      the decrease is caused by Ca(2+)-dependent proteases such as calpain. Betaxolol
      is a compound that has beta(1)-adrenergic receptor blocking and voltage-dependent
      calcium channel blocking properties. The rat eye cups were maintained with
      Locke's solution saturated with 95% air - 5% CO(2). The eye cups were immersed in
      glucose-free Locke's solution saturated with 95% N(2) / 5% CO(2) (hypoxic
      solution). Ninety minutes of hypoxia caused a 20% decrease in mAAT activity. The
      eye cups incubated with the hypoxic solution containing 1 mM EGTA, 10 micro M MK
      801 or 100 micro M betaxolol were protected from the decrease in mAAT activity,
      so that the residual mAAT activity was 50%, 45% or 40%, respectively, compared to
      the eye cups incubated in hypoxic solution alone, which had a 100% decrease in
      mAAT activity. In addition, co-incubation with EGTA and betaxolol had a greater
      protective effect against the mAAT decrease than a single application. This
      additive effect of betaxolol was dose-dependent. These results suggested that
      betaxolol had a protective effect against the decrease of mAAT caused by hypoxia
      and indicated that betaxolol might inhibit the Ca(2+) release from intracellular
      Ca(2+) stores.

PMID- 12419882
TI  - Modulation by mibefradil of the histamine-induced Ca2+ entry in human aortic
      endothelial cells.
AB  - The effect of mibefradil, known as a T- and L-type Ca(2+) channel antagonist, on
      the histamine-induced Cl(-) current and Ca(2+) entry was investigated in human
      aortic endothelial cells by the fluorescence measurement of intracellular Ca(2+)
      concentration ([Ca(2+)](i)) combined with the patch clamp method. Mibefradil (10
      micro M) inhibited both the Cl(-) current and Ca(2+) entry in a concentration
      dependent manner with an IC(50) value of 4.8 and 2.6 micro M for the Cl(-)
      current and [Ca(2+)](i), respectively. These values were comparable to those
      reported for the inhibition of the T-type Ca(2+) channel and other Cl(-)
      channels. The suppression of Ca(2+) entry is not caused by the inhibition of the
      Cl(-) current and the resulting depolarization since the inhibition was still
      observed under the voltage clamp condition. These results suggest that mibefradil
      is a potent blocker not only for the agonist-induced Cl(-) current but also
      Ca(2+) entry channels in vascular endothelial cells.

PMID- 12419883
TI  - Effects of KMD-3213, a uroselective alpha 1A-adrenoceptor antagonist, on the tilt
      induced blood pressure response in normotensive rats.
AB  - KMD-3213 ((-)-1-(3-hydroxypropyl)-5-((2R)-2-[[2-([2-[(2,2,2
      trifluoroethyl)oxy]phenyl]oxy)ethyl]amino]propyl)-2,3-dihydro-1H-indole-7
      carboxamide), an alpha(1A)-adrenoceptor antagonist with potency similar to that
      of tamsulosin, is under development for the treatment of bladder outlet
      obstruction in patients with benign prostatic hypertrophy. In the present study,
      we investigated the effects of KMD-3213 on the tilt-induced blood pressure
      response in anesthetized normotensive rats. Male normotensive Sprague-Dawley rats
      were placed in the supine position on a board under cocktail anesthetization
      (alpha-chloralose, urethane and sodium pentobarbital). The arterial blood
      pressure was measured from the carotid artery. The animals were given consistent
      45 degrees head-up tilt from the horizontal position, following the transient
      decrease in the blood pressure, and then recovery of the blood pressure to the
      normal level. Significant orthostatic hypotension was seen with intravenous
      administration of both prazosin and tamsulosin at doses over 3 micro g/kg, and
      these drugs completely blocked the tilt-induced blood pressure responses at 30
      micro g/kg. On the other hand, these responses were still retained when KMD-3213
      was administered intravenously at a dose up to 75 micro g/kg of KMD-3213.
      Moreover, KMD-3213 showed the highest uroselectivity of the test drugs. These
      results indicate that KMD-3213 is not likely to induce orthostatic hypotension
      and would be a useful compound for the treatment of urinary outlet obstruction in
      patients with benign prostatic hyperplasia.

PMID- 12419884
TI  - The mRNA expression of serotonin 2C subtype receptors uncoupled with inositol
      hydrolysis in NG108-15 cells.
AB  - Cell culture systems seem to be useful for clarifying the cellular physiological
      mechanisms of serotonin 2C subtype receptors (5-HT2CR) and related drug action
      mechanisms. However, there are still few reports about cells that contain
      intrinsic 5-HT2CR. This report demonstrates by using RT/PCR that 5-HT2CR mRNA
      exists in splicing variant forms in NGI08-15 cells. The PCR results using a pair
      of primers that recognized sequences near the third intracellular loop site
      showed two neighboring bands at about 500 bp upon electrophoresis in acrylamide
      gels. The sequence analysis demonstrated that one band was the rat 5-HT2CR
      sequence and the other one was that of the mouse. Serotonin, however, did not
      enhance the inositol phosphates formation in NG108-15 cells. It has been reported
      that post-translational modifications of RNA, splicing and editing, occur at the
      site of the second intracellular loop domain in 5-HT2CR mRNA. Accordingly, a pair
      of primers that recognized this site were designed. The molecular size of the PCR
      product was shorter than that expected based on the sequence of the native 5
      HT2CR. The fragment lacked the 95 nucleotides of native 5-HT2CR mRNA. This seems
      to be the reason why serotonin did not enhance inositol phosphates formation in
      NG108-15 cells.

PMID- 12419885
TI  - Involvement of the NMDA-nitric oxide pathway in the development of
      hypersensitivity to tactile stimulation in dental injured rats.
AB  - To investigate mechanisms in pathological pain conditions as the hyperalgesia and
      allodynia observed after dental surgery, we employed a rat dental-injury model
      involving the simultaneous pulpectomy to a lower incisor and extraction of an
      ipsilateral upper incisor. We found that hypersensitivity to tactile stimulation
      developed on both ipsilateral and contralateral sides in the dental-injured rats
      5 days after the surgery and that this lasted for at least 30 days. Recovery from
      hypersensitivity to tactile stimulation was achieved by the intraperitoneal
      (i.p.) administration of MK-801 (0.05 mg/kg) or N(G)-monomethyl-L-arginine
      monoacetate (L-NMMA: 10 - 100 mg/kg), but not attained by N(G)-monomethyl-D
      arginine monoacetate (D-NMMA: 100 mg/kg). This recovery effect of L-NMMA (50
      mg/kg) was inhibited by pretreatment with L-arginine (600 mg/kg). In the
      trigeminal nucleus caudalis (SpVc), the changes in nitric oxide (NO) levels
      invoked by the intravenous (i.v.) administration of N-methyl-D-aspartate (NMDA;
      10 mg/kg) were found to be significantly larger in the dental-injured rats than
      in sham-operated rats. The number of neuronal NO synthase (nNOS)-positive neurons
      increased in layers I-II and III-IV in the SpVc on both sides of the dental
      injured rats. These results suggest that hypersensitivity to tactile stimulation
      developed following dental injury, and that NMDA receptor/NOS/NO production
      pathways in the SpVc may be involved in pathological conditions.

PMID- 12419886
TI  - Responses of exposure to cigarette smoke at three dosage levels on soleus muscle
      fibers in Wistar-Kyoto and spontaneously hypertensive rats.
AB  - Fiber type distributions, cross-sectional areas (CSAs) and succinate
      dehydrogenase (SDH) activities in the soleus (SOL) muscle in normotensive Wistar
      Kyoto (WKY) and spontaneously hypertensive (SHR) rats were determined after
      exposure to cigarette smoke at three different dosage levels using a smoking
      machine. The rats were exposed to cigarette smoke at a rate of 15 puffs/min, for
      20 min/day with 23 cigarettes (low-dosage), 26 cigarettes (medium-dosage) or 30
      cigarettes (high-dosage) for 8 weeks. There were no effects on the body weight,
      SOL weight, fiber type distribution, CSA or SDH activity of WKY after exposure to
      cigarette smoke, irrespective of the dosage level. In contrast, the body weights
      of SHR were lower after exposure to cigarette smoke, irrespective of the dosage
      level. The SOL weights of SHR were lower after exposure to cigarette smoke at the
      medium- and high-dosage levels. A lower percentage of type I fibers, a higher
      percentage of type IIA fibers and a smaller CSA of both type I and type IIA
      fibers were observed in SHR after exposure to cigarette smoke at the high-dosage
      level, but not at the low- and medium-dosage levels. These results indicate that
      heavy cigarette smoke causes changes in the enzyme histochemical properties with
      a reduced CSA of the SOL in SHR, but not in WKY.

PMID- 12419887
TI  - Antisense-inhibition of plasma membrane Ca2+ pump induces apoptosis in vascular
      smooth muscle cells.
AB  - The effect of antisense oligodeoxynucleotides (ODNs) of plasma membrane Ca(2+)
      pumping ATPase (PMCA) on rat aortic vascular smooth muscle cells (VSMCs) in
      primary culture was examined. More than 80% of the PMCA expressed in cultured
      VSMCs was the PMCA-1B subtype. Exposed to antisense ODNs against PMCA-1, not only
      the expression of the PMCA protein but also mRNA of PMCA-1B was diminished in a
      concentration-dependent manner. Extracellular Na(+)-independent (45)Ca(2+) efflux
      catalyzed via PMCA was inhibited with antisense ODNs. Both the resting and
      ionomycin- or ATP-stimulated levels of intracellular Ca(2+) were increased by
      antisense ODNs. Furthermore, prolonged treatment with antisense ODNs caused
      apoptosis in VSMCs. The occurrence of apoptosis was inhibited by FK506, a potent
      immunosuppressant. These results demonstrate that the PMCA was specifically
      inhibited by antisense ODNs and suggest that PMCA plays an important role in
      regulation of intracellular Ca(2+) concentrations, especially at the resting
      condition to prevent an occurrence of apoptosis that may be induced through the
      activation of calcineurin.

PMID- 12419888
TI  - Effects of minoxidil on ischemia-induced mechanical and metabolic dysfunction in
      dog myocardium.
AB  - Effects of minoxidil on ischemia-induced myocardial mechanical and metabolic
      dysfunction were examined in anesthetized open-chest dogs. A regional portion of
      the left ventricle was made ischemic for 20 min by ligating the left anterior
      descending coronary artery, and then reperfused for 120 min. Dimethylsulfoxide or
      minoxidil (0.3, or 1.0 mg/kg) was injected intravenously 10 min before ligation.
      Ischemia decreased regional myocardial contraction, and reperfusion recovered it
      but incompletely. Myocardial metabolic derangement was observed during ischemia,
      such as decreases in the myocardial levels of ATP and creatine phosphate. These
      metabolic changes caused by ischemia were restored by reperfusion. Minoxidil
      injection at 0.3 and 1.0 mg/kg significantly decreased blood pressures but
      increased coronary flow. Pretreatment with minoxidil significantly enhanced the
      recovery of myocardial contraction during reperfusion after ischemia. The levels
      of ATP and creatine phosphate in the ischemic myocardium were significantly
      preserved by minoxidil at 0.3 mg/kg. No significant effect of minoxidil on the
      metabolism was observed in the 120 min reperfused myocardium. In conclusion,
      minoxidil improved the mechanical dysfunction in the reperfused heart and the
      drug at low dose preserved high-energy phosphates during ischemia.

PMID- 12419889
TI  - Effects of radical scavengers, TA248 and TA276, on stunned myocardium in dogs:
      involvement of K ATP channels.
AB  - TA248 (7-(beta-D-glucopyranosyloxy)-4-hydroxy-3-octyloxy-2H-1-benzopyran-2-one)
      and TA276 (sodium 7-hydroxy-3-octyloxy-2H-1-benzopyran-2-one-4-oxide) were newly
      developed as radical scavengers. In vitro, TA276 scavenged both superoxide anions
      (. O(2)(-)) and hydroxyl radicals (. OH). TA248 also trapped. O(2)(-), but had
      less activity on. OH. In vivo, left ventricular contractile functions were
      determined in pentobarbital-anesthetized open-chest dogs. A regional portion of
      the left ventricular wall was made ischemic for 20 min by ligating the left
      anterior descending coronary artery and then reperfused for 60 min. TA248 (3
      mg/kg) and TA276 (3 mg/kg) injected i.v. 10 min before occlusion significantly
      improved myocardial stunning that is contractile dysfunction observed after
      reperfusion following brief ischemia. Glibenclamide (1 mg/kg) injected i.v. 20
      min before occlusion significantly worsened the myocardial stunning. Pretreatment
      with glibenclamide completely abolished the beneficial effect of TA276 on
      myocardial stunning, whereas it only partially attenuated that of TA248, showing
      some improvement even in the presence of glibenclamide. Because of the incomplete
      scavenging activity of TA248, residual. OH may play some roles in improvement of
      myocardial stunning with TA248 in the presence of glibenclamide. We speculate
      that the. OH may eject glibenclamide from its binding site on K(ATP) channels,
      leading to opening of the channels.

PMID- 12419890
TI  - Administration of Folium mori extract decreases nitric oxide synthase expression
      in the hypothalamus of streptozotocin-induced diabetic rats.
AB  - Folium mori, the leaves of Morus alba L., has traditionally been used for the
      treatment of diabetic hyperglycemia. It has been shown to induce enhanced NOS
      expression in the hypothalamus of rats with streptozotocin (STZ)-induced
      diabetes. In the present study, the effect of Folium mori on the expression of
      nitric oxide synthase (NOS) in the hypothalamus of STZ-induced diabetic rats was
      investigated via nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d)
      histochemistry. Enhanced NAPDH-d expression was detected in the paraventricular
      nucleus, ventromedial hypothalamic nucleus, and lateral hypothalamic area of the
      hypothalamus in the STZ-induced diabetes group. Administration of the aqueous
      extract of Folium mori to rats with STZ-induced diabetes resulted in decreased
      NADPH-d positivity. These results suggest that Folium mori treatment is effective
      in curbing the desire for food under diabetic conditions via modulation of NO
      expression in the hypothalamus.

PMID- 12419892
TI  - Effect of YM992, a novel antidepressant with selective serotonin re-uptake
      inhibitory and 5-HT 2A receptor antagonistic activity, on a marble-burying
      behavior test as an obsessive-compulsive disorder model.
AB  - YM992 ((S)-2-[[(7-fluoroindan-4-yl)oxy]methyl]morpholine) monohydrochloride is a
      novel antidepressant with selective serotonin (5-hydroxytryptamine, 5-HT) re
      uptake inhibition and 5-HT(2A) receptor antagonistic activity. The effects of
      YM992 and two selective 5-HT re-uptake inhibitors (SSRIs) were studied in a
      marble-burying behavior test as a model of an obsessive-compulsive disorder (OCD)
      in mice at doses of 5, 10 and 15 mg/kg, i.p. YM992 and fluoxetine significantly
      inhibited marble-burying behavior at a dose of 15 mg/kg (i.p.) without affecting
      spontaneous locomotor activities. Citalopram also significantly inhibited the
      behavior at doses of 5, 10 and 15 mg/kg (i.p.) without affecting spontaneous
      locomotor activities. These results suggest that YM992, as well as SSRIs, may
      exhibit anti-OCD activity in addition to an antidepressive effect in clinical
      use.

PMID- 12419891
TI  - Effects of naltrexone on spontaneous itch-associated responses in NC mice with
      chronic dermatitis.
AB  - The effects of the opioid antagonist naltrexone on spontaneous itch-associated
      behaviors and cutaneous nerve activities were examined to determine whether it
      inhibits pruritus through peripheral action in NC mice with chronic dermatitis.
      Their rostral-back scratching and caudal-back biting were 19 and 3.4 times more,
      respectively, than those of control mice. The activities of cutaneous nerves
      innervating the rostral and caudal back were 9.5 and 5.4 times more,
      respectively, in affected mice than in control mice. Subcutaneous injections of
      naltrexone significantly inhibited the scratching and biting, without effects on
      the nerve activities. The results suggest that the peripheral action does not
      play a central role in inhibiting chronic itch-associated behaviors.

PMID- 12419893
TI  - Time-dependent effect of glutamate on long-term potentiation in the
      suprachiasmatic nucleus of rats.
AB  - The effect of glutamate on optic nerve stimulation-evoked field potentials in rat
      suprachiasmatic nucleus (SCN) was examined in vitro. Glutamate application for 20
      min induced long-term potentiation (LTP) of the field potentials in the SCN at
      nighttime, whereas that induced a weak LTP at daytime. On the other hand,
      application for 40 min induced LTP in the SCN during the daytime, whereas it
      induced a weak one at nighttime. These results indicate that the effect of
      glutamate is dependent on the application time and that the effect is influenced
      by the duration of glutamate exposure.

PMID- 12419894
TI  - Scarce adenylation in bacteriophage T4 mRNAs.
AB  - The degradation of mRNA is crucial for the rapid shift of bacteriophage T4 gene
      expression from early to late. The present study was conducted to investigate
      whether T4 mRNA is polyadenylated or not, because polyadenylation is known to
      facilitate the degradation of mRNA in Escherichia coli cells. Total RNA extracted
      from T4-infected cells was subjected to self-circularization or intermolecular
      ligation by T4 RNA ligase, and a region containing the 3'-5' junction was
      amplified by RT-PCR. Cloning and sequencing as well as the length distribution of
      amplified DNA fragments revealed no adenines at the 3'-ends of uvsY and soc RNAs.
      The present result suggests that T4 mRNA is not significantly adenylated.

PMID- 12419895
TI  - Novel endonuclease in Archaea cleaving DNA with various branched structure.
AB  - We identified a novel structure-specific endonuclease in Pyrococcus furiosus.
      This nuclease contains two distinct domains, which are similar to the DEAH
      helicase family at the N-terminal two-third and the XPF endonuclease superfamily
      at the C-terminal one-third of the protein, respectively. The C-terminal domain
      has an endonuclease activity cleaving the DNA strand at the 5'-side of nicked or
      flapped positions in the duplex DNA. The nuclease also incises in the proximity
      of the 5'-side of a branch point in the template strand for leading synthesis in
      the fork-structured DNA. The N-terminal helicase may work cooperatively to change
      the fork structure suitable for cleavage by the C-terminal endonuclease. This
      protein, designated as Hef (helicase-associated endonuclease for fork-structured
      DNA), may be a prototypical enzyme for resolving stalled forks during DNA
      replication, as well as working at nucleotide excision repair.

PMID- 12419896
TI  - Evidence of paternal transmission of mitochondrial DNA in a nucleus-cytoplasm
      hybrid of timopheevi wheat.
AB  - Structural heterogeneity depicted as heteroplasmy of the mitochondrial (mt)
      transcriptional unit of nad3-orf156 (atp8) was studied in a nucleus-cytoplasm
      (NC) hybrid of Triticum timopheevi with the D plasmon from the maternal Aegilops
      squarrosa and compared with that of the parental lines. The tetraploid NC hybrid
      and the parental lines both showed varying degrees of heteroplasmy in this mtDNA
      region. The G plasmon of the paternal T. timopheevi possessed five sequence
      types, while two sequence types were detected in the D plasmon of Ae. squarrosa.
      The NC hybrid possessed all the five sequence types identical to those of the
      paternal parent in a 30% relative stochiometry. The remaining 70% comprised only
      one of the two maternal sequence types, suggestive of strong and selective NC
      interaction. No novel sequence types were detected and the relative
      stoichiometries of the paternal sequence types were conserved in the NC hybrid.
      No paternal-identical or -related sequences were detected in the maternal D
      plasmon. These results provide evidence of the paternal transmission of the mtDNA
      and possibly account for the origin of the observed mtDNA heteroplasmy in the NC
      hybrid.

PMID- 12419897
TI  - Single-strand conformation polymorphism of sequence-tagged site markers based on
      partial sequences of cDNA clones in Cryptomeria japonica.
AB  - Sixty-seven sequence-tagged site (STS) markers were identified from partial
      sequences of cDNA clones obtained from the inner bark of Cryptomeria japonica.
      Polymorphisms of the STSs were investigated for the parental clones of a mapping
      population, Haara and Kumotooshi, using both single-strand conformation
      polymorphism (SSCP) and sequencing analysis. Twenty-two STSs showed nucleotide
      differences between Haara and Kumotooshi, of which 19 STS differences were
      detectable under the electrophoresis conditions we used here. We also analyzed
      SSC-polymorphism in 10 additional clones derived from various Japanese regions to
      evaluate the usefulness of the STSs developed here among other populations of C.
      japonica. Twenty-five, about 40%, of the STSs showed polymorphism under selected
      electrophoresis conditions. The genotype segregation for 19 STSs was investigated
      among the Haara x Kumotooshi F(1) population, and these STS markers were mapped
      on a linkage map. SSCP analysis of STSs was efficient in terms of cost and time,
      and it allows detection of a sufficiently high proportion of polymorphisms to
      provide a convenient means for mapping of expressed sequences on a linkage map
      and for studying various aspects of population genetics.

PMID- 12419898
TI  - Full-size P and KP elements predominate in wild Drosophila melanogaster.
AB  - We analyzed the genomic P elements of 57 wild-derived Drosophila melanogaster
      isofemale lines from Africa, Australia and Asia. All carried many P sequences per
      genome, and the full-size P and the internally deleted KP elements were very
      common or predominant in the populations. The genomic content of full-size P and
      KP elements does not correlate well with the P transposition-inducing and 
      repressing abilities of a line. Our results show that a large majority of type I
      repressor elements are full-size P elements, and almost all type II repressor
      elements are KP elements in the natural populations of D. melanogaster from these
      parts of the world.

PMID- 12419899
TI  - Developmental abnormalities in mouse embryos tetrasomic for chromosome 11:
      apparent similarity to embryos functionally disomic for the x chromosome.
AB  - Adopting a mating system involving two different Robertsonian translocations with
      monobrachial homology, we studied the early development of mouse embryos trisomic
      or tetrasomic for chromosome 11. A developmental delay of 12-24 hours was evident
      in trisomic embryos at embryonic day (E)7.5, whereas tetrasomic embryos
      apparently had stopped growth by E6.5 without formation of extraembryonic
      structures. This extremely severe developmental abnormality found in tetrasomic
      embryos is similar to that reported in embryos having two active X chromosomes in
      extraembryonic cell lineages. Autosomal tetrasomy, but not autosomal trisomy, can
      lead to such early developmental errors. Thus, a reasonable inference would be
      that the X chromosome is twice as active as the autosome. Probably, the X
      chromosome became upregulated in response to the evolutionary necessity of
      minimizing haplo-insufficiency brought about by miniaturization of the Y
      chromosome.

PMID- 12419900
TI  - Generation of 919 expressed sequence tags from immature flower buds and gene
      expression analysis using expressed sequence tags in the model plant Lotus
      japonicus.
AB  - Lotus japonicus has received increased attention as a potential model legume
      plant. In order to study gene expression in reproductive organs and to identify
      genes that play a crucial function in sexual reproduction, we constructed a cDNA
      library from immature flower buds containing anthers at the stage of developing
      tapetum cells in L. japonicus, and characterized 919 expressed sequence tags
      (ESTs) randomly selected from a cDNA library of the immature flower buds. The 919
      ESTs analyzed were clustered into 821 non-redundant EST groups. As a result of a
      database search, 436 groups (53%) out of the 821 groups showed sequence
      similarity to genes registered in the public database. Out of these 436 groups,
      109 groups showed similarity to genes encoding hypothetical proteins whose
      function had not yet been estimated. Three hundred eighty five groups (47%)
      showed no significant homology to known sequences and were classified as novel
      sequences. A comparison of 821 non-redundant EST sequences and EST sequences
      derived from the whole plant L. japonicus revealed that 474 EST sequences derived
      from immature flower buds were not found in the EST sequences of the whole plant.
      In order to confirm the expression pattern of potential reproductive-organ
      specific EST clones, nine clones, which were not matched to ESTs derived from the
      whole plant, were selected, and RT-PCR analysis was performed on these clones. As
      a result of RT-PCR, we found two novel anther specific clones. One clone was
      homologous to a gene encoding human cleft lip and palate associated transmembrane
      protein (CLPTM1) like protein, and the other clone did not show a significant
      similarity to any genes deposited in the public database. These results indicate
      that ESTs analyzed here represent a valuable resource for finding reproductive
      organ specific genes in Lotus japonicus.

PMID- 12419901
TI  - Construction of BAC libraries derived from the ascidian Ciona intestinalis.
AB  - Large insert genomic bacterial artificial chromosome (BAC) libraries were
      constructed from a basal chordate, the ascidian Ciona intestinalis. Insert
      analyses of randomly selected clones indicated that in the first library the mean
      insert size was 135 kb and predicted a 15-fold coverage of the Ciona genome, and
      in the second library the mean insert size was 165 kb and predicted a 5-fold
      coverage of the genome. These first large insert genomic libraries of the
      ascidian should increase the speed of genomic analyses of basal chordates.

PMID- 12419902
TI  - New cholinesterase inhibiting steroidal alkaloids from the leaves of Sarcococca
      coriacea of Nepalese origin.
AB  - From the leaves of Sarcococca coriacea two new steroidal alkaloids,
      epoxynepapakistamine-A [(20S)-20-(N-methylamino)-3beta-(tigloylamino)-5alpha
      pregna-16alpha,17alpha-epoxy-2beta,4beta-di-O-acetate] (1), and
      epoxysarcovagenine-D [(20S)-20-(N-methylamino)-3beta-(tigloylamino)-5alpha-pregna
      2-en-16alpha,17alpha-epoxy-4-one] (2), and two known compounds funtumafrine C
      [(20S)-20-(N,N-dimethylamino)-5alpha-pregna-3-one] (3) and N-methylfuntumine (4)
      were isolated. Their structures were elucidated on the basis of their spectral
      properties. The compounds 1, 3 and 4 were found to have cholinesterase inhibitory
      activity when tested for the inhibition of electric eel acetylcholinesterase and
      horse serum butyrylcholinesterase. They inhibited both enzymes in a concentration
      dependent fashion.

PMID- 12419903
TI  - Microbial transformation of rubijervine.
AB  - Preparative-scale fermentation of rubijervine (1), the known 22,26
      epiminocholestane Veratrum alkaloid, with Cunninghamella echinulata ATCC 9244 has
      resulted in the isolation of the new metabolites 7alpha-hydroxyrubijervine (2)
      and solanid-5-ene-3beta,12alpha-diol-1-one (3). Structure elucidation of these
      metabolites was based primarily on 1D- and 2D-NMR analyses. The microbe C.
      echinulata ATCC 9244 was able to metabolize rings A and B of rubijervine but
      failed to metabolize rings C, D or its N-containing side chain, a finding which
      is analogous to the results of previous fermentation studies of steroidal
      alkaloids.

PMID- 12419904
TI  - Determination of optimum processing temperature for transformation of glyceryl
      monostearate.
AB  - The purpose of this study was to clarify the mechanism of transformation from
      alpha-form to beta-form via beta'-form of glyceryl monostearate (GM) and to
      determine the optimum conditions of heat-treatment for physically stabilizing GM
      in a pharmaceutical formulation. Thermal analysis repeated twice using a
      differential scanning calorimeter (DSC) were performed on mixtures of two crystal
      forms. In the first run (enthalpy of melting: DeltaH1), two endothermic peaks of
      alpha-form and beta-form were observed. However, in the second run (enthalpy of
      melting: DeltaH2), only the endothermic peak of the alpha-form was observed. From
      a strong correlation observed between the beta-form content in the mixture of
      alpha-form and beta-form and the enthalpy change, (DeltaH1-DeltaH2)/DeltaH2, beta
      form content was expressed as a function of the enthalpy change. Using this
      relation, the stable beta-form content during the heat-treatment could be
      determined, and the maximum beta-form content was obtained when the heat
      treatment was carried out at 50 degrees C. An inflection point existed in the
      time course of transformation of alpha-form to beta-form. It was assumed that
      almost all of alpha-form transformed to beta'-form at this point, and that
      subsequently only transformation from beta'-form to beta-form occurred. Based on
      this aspect, the transformation rate equations were derived as consecutive
      reaction. Experimental data coincided well with the theoretical curve. In
      conclusion, GM was transformed in the consecutive reaction, and 50 degrees C was
      the optimum heat-treatment temperature for transforming GM from the alpha-form to
      the stable beta-form.

PMID- 12419905
TI  - Synthesis of water-soluble polymeric prodrugs possessing 4-methylcatechol
      derivatives by mechanochemical solid-state copolymerization and nature of drug
      release.
AB  - In this study we synthesized the water-soluble polymeric prodrugs possessing a 4
      methylcatechol (4MC) derivative as a side chain by mechanochemical solid-state
      copolymerization. 1-benzoyl-4-methylcatechol (Bz4MC) was selected as a model
      compound of 4MC, and its methacryloyl derivative (1) was synthesized. 6-O
      methacryloyl-D-galactose (2) was also prepared as a water-soluble monomer. The
      mechanochemical solid-state copolymerization of 1 and 2 was carried out to obtain
      the water-soluble polymeric prodrug possessing the Bz4MC as a side chain. The
      mechanochemical copolymerization of 1 and 2 proceeded to completion, and the
      polymeric prodrug produced possessed a narrow molecular weight distribution.
      Three kinds of polymeric prodrugs, whose compositions were different from one
      another, were hydrolyzed in vitro. The hydrolysis of these polymeric prodrugs
      proceeded to completion. The rate constants of hydrolysis decreased with
      increasing the mole fraction of 1 in polymeric prodrug. It was suggested that the
      rate constant of hydrolysis could be controlled by the composition, the mole
      fraction of 1 in the polymeric prodrug.

PMID- 12419906
TI  - Analysis of the release process of phenylpropanolamine hydrochloride from
      ethylcellulose matrix granules.
AB  - The release properties of phenylpropanolamine hydrochloride (PPA) from
      ethylcellulose (EC, ethylcellulose 10 cps (EC#10) and/or 100 cps (EC#100)) matrix
      granules prepared by the extrusion granulation method were examined. The release
      process could be divided into two parts, and was well analyzed by applying square
      root time law and cube root law equations, respectively. The validity of the
      treatments was confirmed by the fitness of the simulation curve with the measured
      curve. At the initial stage, PPA was released from the gel layer of swollen EC in
      the matrix granules. At the second stage, the drug existing below the gel layer
      dissolved, and was released through the gel layer. Also, the time and release
      ratio at the connection point of the simulation curves was examined to determine
      the validity of the analysis. Comparing the release properties of PPA from the
      two types of EC matrix granules, EC#100 showed more effective sustained release
      than EC#10. On the other hand, changes in the release property of the EC#10
      matrix granule were relatively more clear than that of the EC#100 matrix granule.
      Thus, it was supposed that EC#10 is more available for controlled and sustained
      release formulations than EC#100.

PMID- 12419907
TI  - Beta-N-cyanoethyl acyl hydrazide derivatives: a new class of beta-glucuronidase
      inhibitors.
AB  - Eight new beta-N-substituted acyl hydrazides along with their corresponding acyl
      derivatives were synthesized and screened for in vitro beta-glucuronidase
      inhibition and found to be active against the enzyme. All of these compounds were
      found to be noncompetitive inhibitors except for N'-(2-cyanoethyl)-4-hydroxy
      benzohydrazide (10), which was found to be an uncompetitive inhibitor. Structure
      activity relationship studies indicated that the benzyloxy group present in
      compounds 12 and 13 is responsible for the beta-glucuronidase inhibition
      activity.

PMID- 12419908
TI  - 5 Alpha-reductase inhibitory and antiandrogenic activities of novel steroids in
      hamster seminal vesicles.
AB  - The pharmacological activity of several 16-bromosubstituted trienediones 4 and 5,
      16-methyl substituted dienediones 6 and 7 and the 16-methyl substituted
      trienedione 8 was determined on gonadectomized hamster seminal vesicles by
      measuring the in vitro conversion of testosterone (T) to dihydrotestosterone
      (DHT) as 5alpha-reductase inhibitors and also the ability of these steroids to
      bind to the androgen receptor. Steroids 6 and 7 when injected together with T
      decreased the weight of the seminal vesicles thus showing an antiandrogenic
      effect. Compounds 5 and 6 reduced substantially the conversion of T to DHT and
      therefore can be considered good inhibitors for the enzyme 5alpha-reductase;
      however both steroids failed to form a complex with the androgen receptor. On the
      other hand compound 7 which showed a very small inhibitory activity for the
      enzyme 5alpha-reductase, exhibited a very high affinity for the androgen receptor
      and thus can be considered an effective antiandrogen. This compound also reduced
      substantially the weight of the seminal vesicles. Steroids 4 and 8 did not reduce
      the weight of the seminal vesicles and exhibited a low affinity for the androgen
      receptor; 8 showed a weak 5alpha-reductase inhibitory activity, whereas 4
      exhibited a weak androgenic effect.

PMID- 12419909
TI  - Phosphorylation of disaccharides with inorganic cyclo-triphosphate in aqueous
      solution.
AB  - The phosphorylation of disaccharides by inorganic cyclo-triphosphate (P(3m)) with
      a six-membered ring was examined in aqueous solution. In the phosphorylation of
      cellobiose, lactose, and alpha,alpha-trehalose with P(3m), beta-D-glucopyranosyl
      (1-->4)-beta-D-glucopyranosyl 1-triphosphate, beta-D-galactopyranosyl-(1-->4)
      beta-D-glucopyranosyl 1-triphosphate, and 3-O-triphospho-alpha-D-glucopyranosyl
      (1-->1)-alpha-D-glucopyranoside were synthesized with maximum yields of 28%, 35%,
      and 20%, respectively. In the reactions of maltose and sucrose with P(3m), two
      phosphorylated products were obtained in yields of 42% and 58%, respectively. The
      main phosphorylated products were assigned to alpha-D-glucopyranosyl-(1-->4)-beta
      D-glucopyranosyl 1-triphosphate and beta-D-fructofuranosyl-(2-->1)-2-O-triphospho
      alpha-D-glucopyranoside by heteronuclear multiple bond correlation (HMBC) NMR.
      The phosphorylation mechanism of disaccharides with P(3m) is discussed.

PMID- 12419910
TI  - Water-soluble constituents of anise: new glucosides of anethole glycol and its
      related compounds.
AB  - From the water-soluble portion of the methanolic extract of the fruit of anise
      (Pimpinella anisum L.), which has been used as a spice and medicine since
      antiquity, twelve new and five known glucosides of phenylpropanoids, including
      four stereoisomers of anethole glycol 2'-O-beta-D-glucopyranoside and four
      stereoisomers of 1'-(4-hydroxyphenyl)propane-1',2'-diol 2'-O-beta-D
      glucopyranoside were isolated together with anethole glycols and guaiacyl
      glycerol. The structures of the new compounds were clarified by spectral
      investigation.

PMID- 12419911
TI  - Constituents of holothuroidea, 12. Isolation and structure of glucocerebrosides
      from the sea cucumber Holothuria pervicax.
AB  - Ten glucocerebrosides, HPC-3-A-HPC-3-J, have been isolated from their obtained
      parent glucocerebroside molecular species HPC-3, together with other
      glucocerebroside molecular species HPC-1 and HPC-2, from the less polar lipid
      fraction of a chloroform/methanol extract of the sea cucumber Holothuria
      pervicax. The structures of these glucocerebrosides have been determined on the
      basis of chemical and spectroscopic evidence. Reversed-phase HPLC, including a
      recycling system, was effective in isolating these glucocerebrosides, revealing a
      very close resemblance in structure, though the problem due to regio-isomers
      remains.

PMID- 12419912
TI  - Water-soluble constituents of cumin: monoterpenoid glucosides.
AB  - From the water-soluble portion of the methanol extract of cumin (fruit of Cuminum
      cyminum L.), which has been used as a spice and medicine since antiquity, sixteen
      monoterpenoid glucosides, including twelve new compounds, were isolated. Their
      structures were clarified by spectral investigation.

PMID- 12419913
TI  - 1,5-dimethyl-6H-pyridazino[4,5-b]carbazole, a 3-aza bioisoster of the antitumor
      alkaloid olivacine.
AB  - A series of b-fused carbazoles structurally related to pyrido[4,3-b]carbazole
      type alkaloids was prepared, utilizing the Diels-Alder reaction of 1
      methylpyrano[3,4-b]indol-3(9H)-one with electron-deficient acetylenic dienophiles
      as the key step. The title compound (14) thus obtained in only four steps
      represents a new 3-aza analog of the antitumor natural product, olivacine.

PMID- 12419914
TI  - Ardisiphenols and other antioxidant principles from the fruits of Ardisia
      colorata.
AB  - Novel alkylphenols, ardisiphenols A-C (1-3) and a novel bergenin derivative,
      demethoxybergenin (10) were isolated from the fruits of Ardisia colorata
      (Myrsinaceae), together with known alkylresorcinols (4-6), embelin (7), myricetin
      (8), quercetin (9), bergenin (11), norbergenin (12), kaempferol (13), quercetin-3
      O-beta-D-glucopyranoside (14) and gallic acid (15). Their structures were
      determined by NMR, MS(/MS) analyses and other spectroscopic methods.
      Ardisiphenols showed moderate scavenging activities toward 1,1-diphenyl-2
      picrylhydrazyl (DPPH) radicals and showed cytotoxicity against the murine breast
      cancer cell line, FM3A.

PMID- 12419915
TI  - Two new rearranged taxoids from Taxus wallichiana ZUCC.
AB  - Two new rearranged taxane diterpenoids, 5alpha,7beta,10beta,13alpha-tetrahydroxy
      2alpha,9alpha,15-triacetoxy-11(15-->1)-abeo-taxa-4(20), 11-diene (1) and
      5alpha,9alpha,10beta,13alpha-tetraacetoxy-15-hydroxy-11(15-->1)-abeo-taxa-4(20),
      11-diene (2) have been isolated from the barks of Taxus wallichiana. The
      structures of these compounds have been confirmed by modern spectroscopic
      techniques.

PMID- 12419916
TI  - Synthesis of symmetrical 1,5-bis-thio-substituted anthraquinones for cytotoxicity
      in cultured tumor cells and lipid peroxidation.
AB  - The synthesis of a series of anthraquinone moieties bearing symmetrical sulfur
      linked substituents in the 1 and 5 positions is described. These compounds were
      evaluated for their ability to inhibit the growth of suspended rat glioma C6
      cells and human hepatoma G2 cells, respectively. In addition, the redox property
      of the compounds was determined based on the inhibition of lipid peroxidation in
      model membranes. Compounds 2a and 2h in this series compared favorably and
      exhibited the most potent cytotoxicity (0.02, 0.05 microM) against C6 cells in
      the XTT colorimetric assay. As far as redox properties are concerned, all bis
      thio-anthraquinones show potential lipid peroxidation in model membranes very
      close to that of mitoxantrone (MX), and 2a, 2d, 2e, 2i, 2j, and 2k have more
      potential than that of MX. The lack of cytotoxicity of compound 2i cannot be
      related to lipid peroxidation, but the steric and electronic properties of the
      side-chain substituent maybe impair effective recognition of the cleavable
      complex. In contrast to MX, 2a and 2h are cytotoxic in rat glioma C6 cells and do
      not enhance lipid peroxidation in model membranes.

PMID- 12419917
TI  - Eudragit NE30D based metformin/gliclazide extended release tablets: formulation,
      characterisation and in vitro release studies.
AB  - Metformin/Gliclazide extended release tablets were formulated with Eudragit NE30D
      by wet granulation technique. Two batches were prepared in order to study
      influence of drug polymer ratio on the tablet formation and in vitro drug
      release. The formulated tablets were characterized by disintegration time,
      hardness, friability, thickness, weight variation, and in vitro drug release. The
      percentage of polymer, with respect to Metformin/Gliclazide, required to produce
      tablets with acceptable qualities was 9 to 13.45. The percentage of polymer below
      this range released the drug immediately and above this range produced granules
      not suitable for tablet formation. The quantity of Metformin/Gliclazide present
      in the tablets and the release medium were estimated by a validated HPLC method.
      The formulated tablets had acceptable physicochemical characters and released the
      drug over 6-8 h. The data obtained from in vitro release studies were fitted with
      various kinetic models and was found to follow Higuchi kinetics.

PMID- 12419918
TI  - Cytotoxic compounds from Polygala vulgaris.
AB  - To search for antitumor agents from plants, we studied Polygala vulgaris since
      cytotoxic lignans are known to occur in some Polygala species. Preliminary data
      on plant petrol ether, chloroform, and methanol extracts from the roots and
      aerial parts, showed in vitro cytotoxic activity against the solid tumor LoVo
      cell line. Fractionation of the active extracts led to the isolation of three new
      compounds, a derivative of aucuparine and two xanthones, as well as a known
      methylsinapate. All compounds were tested for in vitro cytotoxic activity using
      two cell lines, LoVo and its strain, which express resistance to common antitumor
      agents.

PMID- 12419919
TI  - Ab initio molecular orbital study of the reactivity of active alkyl groups. V.
      Nitrosation mechanism of acetone with syn-form of methyl nitrite.
AB  - The mechanisms of nitrosation of acetone through sodium enolate [CH3CO1CH2]-Na+
      (1) or naked enolate [CH3CO1CH2]- (2) with methyl nitrite CH3O3NO2 (3), and the
      reactivity of the syn-form of 3 (syn-3) during the C-N bond formation process
      were investigated using ab initio molecular orbital (MO) methods. Our results
      have demonstrated the predominant formation of E-1-hydroxyimino-2-oxo-propane
      CH3COCH=NOH (4E) when the complex [CH3CO1CH2NO2(O3CH3)]-Na+ was produced
      kinetically via a metal-chelated pericyclic transition state (TS(CHELATED)), in
      which the O3 atom of syn-3 was coordinated to the Na+ atom of 1.

PMID- 12419920
TI  - Constituents with radical scavenging effect from Opuntia dillenii: structures of
      new alpha-pyrones and flavonol glycoside.
AB  - The aqueous ethanolic extract from the fresh stems of Opuntia dillenii HAW.
      showed potent radical scanvenging activity. Three new compounds, opuntioside I, 4
      ethoxyl-6-hydroxymethyl-alpha-pyrone, and kaempferol 7-O-beta-D-glucopyranosyl-(1
      ->4)-beta-D-glucopyranoside, were isolated from the extract. The structures of
      the new compounds were determined on the basis of chemical and physicochemical
      evidence and the radical scavenging effects of principal constituents were
      examined.

PMID- 12419921
TI  - The improved synthesis of OPC-29030, a platelet adhesion inhibitor via
      diastereoselective oxidation of chiral non-racemic sulfide.
AB  - An improved synthetic route of OPC-29030, the platelet adhesion inhibitor, was
      established via the diastereoselective oxidation of a chiral non-racemic sulfide
      (R)-5 to (S(S))-6 by the catalytic oxidation using VO(acac)(2) and cumene
      hydroperoxide (CHP) in the presence of MS4A. Under the current condition, the
      diastereoselectivity was not influenced by the presence of moisture, and moderate
      to high selectivity (72% de) was obtained at -30 degrees C. The obtained
      sulfoxide, which diastereomeric excess was easily raised by the
      recrystallization, could successfully lead to OPC-29030.

PMID- 12419922
TI  - Trypanocidal terpenoids from Laurus nobilis L.
AB  - Trypanocidal constituents of dried leaves of Laurus nobilis L. (Lauraceae) were
      examined. Activity-guided fractionation of the methanol extract resulted in the
      isolation of two guaianolides, dehydrocostus lactone (1) and zaluzanin D (2), and
      a new p-menthane hydroperoxide, (1R,4S)-1-hydroperoxy-p-menth-2-en-8-ol acetate
      (3). The minimum lethal concentrations of these compounds against epimastigotes
      of Trypanosoma cruzi were 6.3, 2.5, and 1.4 microM, respectively.

PMID- 12419923
TI  - Novel and efficient synthesis of 4-dimethylamino-2-glycosylaminoquinazolines by
      cyclodesulfurization of glycosyl thioureas with dimethylcyanamide.
AB  - 4-dimethylamino-2-glycosylaminoquinazoline derivatives were synthesized by
      cyclodesulfurization of N-aryl-N'-glycosyl thioureas with dimethylcyanamide in
      the presence of silver triflate in good yields.

PMID- 12419924
TI  - A novel push-pull Diels-Alder diene: reactions of 4-alkoxy- or 4-phenylsulfenyl-5
      chalcogene-substituted 1-phenylpenta-2,4-dien-1-one with electron-deficient
      dienophiles.
AB  - 5-(phenylselenenyl)- and 5-(phenylsulfenyl)-4-ethoxy-1-phenyl-2,4-pentadien-1
      ones (2) and (3) underwent [4+2] cycloaddition with N-methyl and N
      phenylmaleimides and successive isomerization to give the 7-benzoyl-3a,4,5,7a
      tetrahydro-1H-isoindole-1,3(2H)-diones 5, 8 and 9 in good yields. The 4-ethoxy
      group on the 2,4-pentadien-1-one was found to be effective to facilitate the
      cycloaddition with dienophiles. We also performed other [4+2] cycloadditions of
      2,4-pentadien-1-ones with DMAD or naphthoquinone.

PMID- 12419925
TI  - Cascade reaction of imines with phenylsulfinylallene. X-ray structure of the
      product and its formation mechanism.
AB  - The structure of the product derived from the reaction of a dihydropyridine
      derivative with phenylsulfinylallene has been clarified by a single crystal X-ray
      analysis and the formation mechanism is discussed on the basis of the reaction
      path calculations by semiempirical and ab initio molecular orbital methods.

PMID- 12419926
TI  - Collision-induced dissociation actualized the H+-promoted reaction as observed in
      vitro; harman formation from beta-carboline-type monoterpenoid glucoindole
      alkaloids.
AB  - The fragmentation from beta-carboline-type monoterpenoid glucoindole alkaloids to
      harman, which is a hypothetical pathway to generate simple beta-carbolines, was
      actualized in the collision-induced dissociation in MS.

PMID- 12419927
TI  - New criteria for 'obesity disease' in Japan.
AB  - The present study was designed to establish adequate criteria for categorizing
      'obesity disease' in Japan in relation to obesity-related complications. The
      subjects were 1,193 Japanese subjects (775 men, 418 women; age: 20-84 years old,
      body mass index (BMI): 14.9-56.4 kg/m(2)) including subjects undergoing a health
      examination and obese subjects visiting an obesity clinic. Visceral fat area
      (VFA) and subcutaneous fat area (SFA) were determined by computed tomography (CT)
      at the umbilical level. Anthropometric parameters, including BMI, waist
      circumference (W), waist/hip circumference (W/H), ratio and waist
      circumference/body height (W/BH) ratio, were measured. Hyperglycemia,
      dyslipidemia, and hypertension were evaluated as obesity-related complications.
      The relationship between each parameter and the prevalence of the complications
      was investigated. The number of complications increased in accordance with BMI
      and the average value was greater than 1.0 at a BMI of 25. The best combination
      of the sensitivity and specificity for detecting subjects with multiple risk
      factors was a BMI of 25. BMI showed a close positive correlation with SFA
      (r=0.82), even for BMI > or =25 (r=0.77), but had a weaker correlation with VFA
      (r=0.54). The obese subjects with a BMI > or =25 had no correlation between BMI
      and VFA because of the wide individual variation of VFA. The number of disorders
      was greater than 1.0 at 100 cm(2) of VFA and the best combination of the
      sensitivity and specificity for determining subjects with multiple risk factors
      was 100 cm(2) of VFA. Between the simple anthropometric values and measurement of
      VFA, it was proven that W had the closest relationship with VFA in both men
      (r=0.68) and women (r=0.65). The regression line obtained from simple correlation
      analyses indicated that the W corresponding to 100 cm(2) of VFA was 84.4 cm in
      men and 92.5 cm in women. These data suggest that obesity is adequately specified
      as a BMI > or =25 in Japan where the prevalence and degree of obesity remains
      mild. It is reasonable to establish the cut-off point of VFA at 100 cm(2) as
      indicative of the risk of obesity-related disorders and a waist circumference of
      85 cm in men and 90 cm in women approximates to this visceral fat mass.

PMID- 12419928
TI  - Candesartan cilexetil improves left ventricular function, left ventricular
      hypertrophy, and endothelial function in patients with hypertensive heart
      disease.
AB  - Patients with hypertension often develop left ventricular (LV) hypertrophy and
      deterioration of the cardiac and endothelial functions. Recent clinical trials
      have shown the added benefits of angiotensin II receptor blockers in hypertensive
      patients. Twenty-nine patients with hypertensive heart disease (HHD) underwent
      echocardiography, radionuclide ventriculography and the measurement of
      endothelial function before and after administration of candesartan (8 mg/day).
      The subjects were divided into poorly controlled blood pressure (BP) (group P,
      n=6) and well controlled BP (group C, n=23). Endothelial function was evaluated
      from flow-dependent dilation, which was calculated as the percent change of the
      radial artery diameter during reactive hyperemia after upper arm occlusion,
      measured with a high-resolution ultrasound system. In group C, LV diastolic
      function and endothelial function were significantly (p<0.05) improved at 3
      months after administration, LV systolic function and hypertrophy were
      significantly (p<0.05) improved after 6 months and these effects were maintained
      at 12 months. Even in group P, LV function, LV hypertrophy, endothelial function
      and brain natriuretic peptide were significantly (p<0.05) improved at 6 months
      after administration. In patients with HHD, candesartan improves LV systolic and
      diastolic function, LV hypertrophy and endothelial function within 6 months of
      administration, regardless of the control of BP.

PMID- 12419929
TI  - Usefulness of the Symphony Nitinol Stent for arteriosclerosis obliterans.
AB  - The Symphony Peripheral Stent is a self-expanding stent made of thermal memory
      Nitinol wire. Stents were implanted in 39 lesions of 32 patients (26 men, 6
      women) with atherosclerosis obliterans (ASO). The ankle-arm index (AAI), and
      vessel diameters evaluated by quantitative angiography were compared before and 6
      months after treatment. Symphony Peripheral Stent implantation significantly
      improved the AAI from 0.50+/-0.4 to 0.9+/-0.2 (p<0.01), the minimum lumen
      diameter (MLD) from 2+/-1.5 to 5+/-1.4 mm (p<0.01) and percent diameter stenosis
      (% DS) from 69+/-20% to 16.5+/-8% (p<0.01). Re-evaluation of 33 of the 39 lesions
      6 months after treatment revealed a low restenosis rate of 15%, an AAI of 0.8+/
      0.3, MLD of 4.5+/-2 mm and %DS of 30+/-22%, so the Symphony Peripheral Stent is
      thus a promising choice for patients with ASO.

PMID- 12419930
TI  - Serum hepatocyte growth factor predicts ventricular remodeling following
      myocardial infarction.
AB  - Hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF)
      stimulate endothelial cell proliferation and induce angiogenesis, but the timing
      and significance of their release in patients with acute myocardial infarction
      (AMI) are unknown in relation to future left ventricular remodeling. Venous blood
      samples were obtained at admission and up to 3 weeks later in 40 patients with
      AMI and in 40 age- and sex-matched control subjects. Blood samples were also
      taken from the coronary sinus (CS) in 20 patients on day 7 following AMI. Left
      ventricular end-diastolic volume in the subacute (1 week) and chronic (3 months)
      phases was assessed by left ventriculography to identify the remodeling group
      (n=15), which was defined as an increase in left ventricular end-diastolic volume
      index > or =5 ml/m(2) relative to the baseline value. Serum HGF and VEGF
      concentrations were higher in newly admitted patients with AMI than in the
      controls (HGF, 0.33 +/-0.09 vs 0.24+/-0.08 ng/ml, p<0.01; VEGF, 92.2+/-43.1 vs
      67.2+/-29.8 pg/ml, p<0.01), peaking on day 7 (HGF, 0.41+/-0.12; VEGF, 161.7+/
      76.9), and gradually decreasing between days 14 and 21. The HGF concentration in
      the CS did not differ from the concentration in the periphery, but the VEGF
      concentration was significantly more abundant in the CS than in the peripheral
      sample on day 7 (p<0.05). The serum HGF concentration on day 7 was higher in the
      remodeling group than in the nonremodeling group (0.47 +/-0.13 vs 0.36+/-0.09
      ng/ml, p<0.01), but there was no difference between the groups on admission, day
      14 and day 21. The serum VEGF concentration did not differ between the remodeling
      and nonremodeling groups at any time. Thus, the serum HGF concentration on day 7
      after AMI is mostly from noncardiac sources and predicts left ventricular
      remodeling.

PMID- 12419931
TI  - Trends in the clinical and morphological characteristics of cardiac myxoma: 20
      year experience of a single tertiary referral center in Japan.
AB  - The purpose of this study was to clarify whether or not a change in the clinical
      characteristics of cardiac myxoma has occurred during the past 2 decades. The
      clinical records of 57 patients (22 men, 35 women; age, 52+/-14 years) with
      myxoma that had been surgically treated between May 1978 and July 1997 at the
      National Cardiovascular Center in Japan were reviewed. All myxomas were
      discovered by transthoracic echocardiography. They were divided into an early
      group (n=30) treated in the first decade (1978-1987) and a late group (n=27)
      treated in the second decade (1988-1997). The incidence of myxoma, patient
      characteristics, preoperative symptoms and echocardiographic features did not
      differ between the 2 groups. In contrast, the maximal dimensions of myxoma in the
      early group were significantly larger than those in the late group (6.3 +/-2.7 cm
      vs 4.3+/-1.3 cm, p=0.012). The weight of myxoma in the early group tended to be
      heavier than that in the late group (76+/-80 g vs 25+/-18 g, p=0.054). The
      incidence of patients with asymptomatic myxoma also tended to increase in the
      late group (7% vs 26%, p=0.07). Although there was no difference in the incidence
      of myxoma, smaller and asymptomatic myxomas were more frequent during the last
      decade, probably as a result of the development of cardiac imaging, particularly
      echocardiography.

PMID- 12419932
TI  - Lack of association between angiotensin-converting enzyme gene polymorphism and
      peripheral vascular disease in type 2 diabetic patients in Taiwan.
AB  - A total of 361 Chinese patients with type 2 diabetes were studied for the
      association between peripheral vascular disease (PVD) and the insertion/deletion
      polymorphism involving a 287-bp alu repeat sequence at intron 16 of the
      angiotensin-converting enzyme (ACE) gene. The patients were divided into PVD (+)
      (n=45) and PVD (-) (n=316) based on an ankle-brachial index <0.9 and > or =0.9,
      respectively. Polymerase chain reaction was used to identify gene polymorphism.
      Results showed that D allele frequency in the patients without and with PVD was
      31.8% and 33.3%, respectively (p=NS). The prevalence rates of II, ID and DD
      genotypes in the PVD (-) group were 45.6%, 45.3% and 9.2%, respectively; and the
      respective values for the PVD (+) group were 44.4%, 44.4% and 11.1% (p=NS).
      Prevalence rates of PVD in genotypes II, ID, and DD were 12.2%, 12.3% and 14.7%,
      respectively (p=NS). In logistic regression analyses, the unadjusted and adjusted
      odds ratios for DD vs II and ID vs II genotypes for PVD were not statistically
      significant. The respective adjusted odds ratios were 1.88 (0.56-6.29) and 1.33
      (0.63-2.80). In conclusion, there was not a significant association between the
      ACE genotype and PVD in Chinese type 2 diabetic patients. However, a type 2 error
      can not be ruled out.

PMID- 12419933
TI  - Sialic acid or troponin T to detect perioperative myocardial damage in patients
      undergoing elective coronary artery bypass grafting.
AB  - Sialic acid (SA), a family of acetylated derivatives of neuraminic acid, is
      elevated in patients with coronary heart disease. Cardiac troponin T (cTnT),
      myoglobin (Mb), and creatine kinase-MB (CK-MB) are specific markers of myocardial
      injury and are, at present, widely used to detect perioperative myocardial damage
      during coronary artery bypass grafting (CABG) surgery. The present study
      investigated the net myocardial release of SA and the cardiac markers (cTnT, Mb,
      CK-MB) during reperfusion after hypothermic cardioplegic cardiac arrest in 25
      patients undergoing elective CABG. Additional paired arterial, central venous,
      and coronary sinus blood samples were obtained after atrial cannulation before
      aortic cross-clamping (preischemic sample) and at 1 and 10 min after aortic
      declamping (reperfusion samples). There were no increase in the SA, cTnT, Mb and
      CK-MB concentrations before aortic cross-clamping, but there was considerable
      release of these markers within 10 min after aortic declamping: cTnT release was
      significantly higher compared with baseline values before aortic cross-clamping.
      In contrast to SA, Mb, and CK-MB, the difference between baseline and release
      values for cTnT at 1 min after aortic declamping was not significant. The rate of
      increase for SA was significantly higher than for Mb, CK-MB and cTnT. SA is a
      unique and novel marker that could be particularly useful in assessing myocardial
      cell damage in patients undergoing cardiac surgery.

PMID- 12419934
TI  - Beta-blocker decreases the increase in QT dispersion and transmural dispersion of
      repolarization induced by bepridil.
AB  - Bepridil is effective for intractable cardiac arrhythmia, but in rare cases will
      induce torsades de pointes (TdP) associated with QT interval prolongation. Beta
      blockers will effectively prevent TdP in some clinical settings, so the effect of
      beta-blocker on the change in QT interval, QT dispersion and transmural
      dispersion of repolarization (TDR) induced by bepridil was investigated in 10
      patients (7 male, 3 female; 62+/-6 years old) with intractable paroxysmal atrial
      fibrillation. The QTc interval, QTc dispersion and TDR were measured before and
      after 1 month of administration of bepridil, and then a beta-blocker was added
      and the QTc interval, QTc dispersion and TDR re-measured 1 month later. Bepridil
      significantly prolonged the QTc interval (0.42+/-0.05 to 0.50+/-0.08; p<0.01),
      and increased both the QT dispersion (0.07+/-0.05 to 0.14+/-0.08; p<0.01) and TDR
      (0.10+/-0.04 to 0.16+/-0.05; p<0.01). The addition of a beta-blocker decreased
      the QTc interval (0.50+/-0.08 to 0.47+/-0.04; p=0.09) and significantly decreased
      both the QTc dispersion (0.14 +/-0.08 to 0.06+/-0.02; p<0.01) and TDR (0.16+/
      0.05 to 0.11+/-0.04; p<0.001). Compared with the control, the combination therapy
      significantly prolonged the QTc interval, but did not increase either QTc
      dispersion or TDR, and so was effective in all patients with intractable AF. The
      findings suggest that beta-blocker reduces the increase in QT dispersion and TDR
      induced by bepridil, and combined therapy with bepridil and beta-blocker might
      thus be useful for intractable atrial fibrillation.

PMID- 12419935
TI  - Long-term (3-5 years) clinical and angiographic follow-up results of coronary
      stenting in elderly patients.
AB  - The early and late results of percutaneous transluminal coronary angioplasty in
      elderly patients are well known, but although stent implantation has become the
      most frequent percutaneous coronary intervention in many centers, little
      information exists about its long-term outcome in elderly patients. The aim of
      this study was to evaluate the long-term clinical and angiographic follow-up
      results of intracoronary stenting in a study cohort of 120 patients (92 male)
      over 65 years of age, who underwent successful coronary stenting between June
      1995 and December 1997. The target coronary artery was 48% left anterior
      descending, 21% circumflex and 31% right coronary artery. Stent implantation was
      elective in 54%, suboptimal in 32% and bailout in 14% of the patients. Long-term
      (34+/-14 months) clinical and angiographic follow-up was completed in 78% and 56%
      of the patients, respectively. The following end-points were considered: death,
      non-fatal myocardial infarction (MI), target and non-target lesion
      revascularization. Angiographic restenosis was detected in 31% of the patients.
      During the long-term follow-up period, 14% of the patients died and 11% developed
      a new MI. Target lesion revascularization was done in 19.4%, non-target lesion
      revascularization was done in 21%, and the survival rate was 86%. Although the
      restenosis rates did not deviate greatly from the expected long-term figures in
      younger populations, they do indicate that the potential for major cardiac events
      is still high among elderly subjects, in spite of developments in stent
      technology and medication.

PMID- 12419936
TI  - Detection of angiotensin-converting enzyme gene insertion/deletion polymorphism
      from paraffin-embedded tissues: the Hisayama study.
AB  - Previous studies have suggested that archival materials from formalin-fixed
      paraffin-embedded blocks are unsuitable for most molecular techniques because the
      extracted DNA can be severely degraded. Therefore, the present study was designed
      to investigate the accuracy of genotyping for the insertion (I)/deletion (D)
      polymorphism of the angiotensin-converting enzyme (ACE) gene from paraffin
      embedded tissues of autopsy cases from Hisayama Town, Japan. The genotype was
      determined using the double polymerase chain reaction method and to test the
      accuracy of the method, the polymorphism was investigated using paraffin-embedded
      tissues from 18 cases whose ACE genotypes (6 cases for each genotype) were known
      in advance from analysis of fresh-frozen tissue samples. Genotyping using
      paraffin-embedded tissues was then determined for 968 autopsy subjects. The
      genotype could be determined in 16 of the 18 test samples (88.9%) and there was
      no discrepancy with the results obtained from the fresh-frozen tissues. Of the
      968 autopsy cases, the frequency of the DD, ID, and II genotypes was 12.4%,
      47.3%, and 40.3%, respectively, a distribution that did not deviate from the
      Hardy-Weinberg equilibrium (chi(22df )= 0.67, p=0.72). These findings suggest the
      accuracy of the present method of ACE genotyping from paraffin-embedded tissues.

PMID- 12419937
TI  - High-density lipoprotein cholesterol and the role of statins.
AB  - Low levels of high-density lipoprotein cholesterol (HDL-C) are currently
      considered to be a major risk factor for the development of coronary artery
      disease (CAD). Deficiencies in the HDL metabolic pathway promote atherosclerosis
      and contribute to CAD. Low HDL-C levels are included in the Framingham 10-year
      risk assessment for CAD although they are not yet targeted for therapy. Recent
      clinical trials have shown benefits from raising HDL-C, particularly in patients
      with lower baseline levels. The statin class of drugs, used primarily to lower
      the level of low-density lipoprotein-cholesterol, may be able to raise the HDL-C
      level as well. Statins could potentially affect HDL-C by different modes of
      action, most importantly by altering reverse cholesterol transport. Among the
      currently available statins, simvastatin has demonstrated the most consistent
      ability to raise HDL-C level, but further large-scale studies at an early stage
      will be needed to prove the antiatherogenic effects of this class of drugs.

PMID- 12419938
TI  - Inhibition of angiotensin-converting enzyme reduces susceptibility of
      hypertrophied rat myocardium to ventricular fibrillation.
AB  - Left ventricular (LV) hypertrophy increases susceptibility to reperfusion
      arrhythmias and the angiotensin-converting enzyme inhibitor, ramipril, may reduce
      that susceptibility via regression of LV hypertrophy. Rats (n=12 per group) were
      subjected to abdominal aortic constriction (AC) or sham-operation (SH) and from 3
      to 6 weeks after surgery, 3 AC groups received ramipril (0.01, 0.1, or 1 mg/kg
      per day p.o.) while the SH and 1 AC group received vehicle. Six weeks after
      surgery (ie after 3 weeks of treatment), the hearts were excised and subjected to
      independent Langendorf perfusion of left and right coronary beds. The left
      coronary bed was then subjected to ischemia (7 min) and reperfusion (5 min).
      Hypertrophied hearts from the vehicle AC group showed a significant increase in
      the incidence of reperfusion-induced ventricular fibrillation (VF) compared with
      control hearts from the SH group (92%* vs 33%: *p<0.05); this difference was
      abolished by ramipril (42%, 50%, and 42%, at 0.01, 0.1, or 1 mg/kg per day,
      respectively). The LV weight/body weight ratio was significantly increased in all
      AC groups (regardless of ramipril treatment) relative to the SH group. At the
      cellular level, myocyte length was significantly increased in the vehicle AC
      group, but was normalized by ramipril treatment (1 mg/kg per day). At the
      molecular level, atrial natriuretic factor (ANF) mRNA expression was also
      significantly increased in the vehicle AC group, but was again normalized by
      ramipril treatment (1 mg/kg per day). In conclusion, short-term treatment with
      ramipril reduced susceptibility to severe ventricular arrhythmias in
      hypertrophied rat hearts. This protection was achieved in the absence of a
      significant reduction in LV weight, but was accompanied by regression of myocyte
      hypertrophy, as reflected by reductions in cell size and ANF expression.

PMID- 12419939
TI  - Transfer of antisense oligodeoxynucleotides against endothelin receptors A and B
      into human coronary smooth muscle cells and endothelial cells by apolipoprotein E
      peptide: an in vitro study.
AB  - Antisense oligodeoxynucleotides (AS-ODNs) are a new generation of therapeutic
      agents for gene therapy. To develop a new approach in regulating the expression
      of endothelin (ET) receptor, N,N-dipalmitylglycyl-apolipoprotein E (129-169)
      peptide (dpGapoE), an efficient gene delivery system, was used to transfect
      phosphorothioated AS-ODNs against nucleotides of human ET type A (ETA) receptors
      in human coronary smooth muscle cells (HCSMCs) and type B (ETB) receptors in
      human coronary endothelial cells (HCECs). After transfection, translocation to
      the nuclei and concentration in nuclear structures were observed in approximately
      40% of HCSMCs and 60% of HCECs, respectively, at 48 h by fluorescence microscopy.
      Both the cellular ETA mRNA concentration in HCSMCs and ETB mRNA concentration in
      HCECs significantly declined. This approach may enable gene regulation in vivo
      and could be used to regulate vascular tone and constriction through ET
      receptors.

PMID- 12419940
TI  - In vivo angiographic detection of vascular lesions in apolipoprotein E-knockout
      mice using a synchrotron radiation microangiography system.
AB  - Genetically modified hyperlipidemic mice provide important information on the
      pathogenesis of atherosclerosis, but most experimental designs are limited to in
      vitro or ex vivo examinations. The present study was designed to detect
      atherosclerotic lesions in situ in apolipoprotein E-knockout (apoE-KO) mice using
      a newly developed angiography system, synchrotron radiation (SR)
      microangiography, which uses monochromatic SR as an X-ray source and a high
      definition camera or video system as a detector. Digital microangiography with 7
      mm pixel sizes was carried out and atherosclerotic lesion in small arteries less
      than 500 microm in diameter were detected. Moreover, the coronary artery stenotic
      lesion of an apoE-KO mouse was detected in situ with the angiography system. The
      new SR microangiography system is a powerful tool for investigating
      atherosclerotic lesions in situ in genetically engineered mice and will promote
      the basic study of atherosclerotic disease.

PMID- 12419942
TI  - A case of cardiomyopathy induced by premature ventricular complexes.
AB  - Tachycardia-induced cardiomyopathy is a well-known and reversible condition, but
      the left ventricular dysfunction caused by frequent isolated premature
      ventricular complexes (PVCs) has been rarely reported. Apparent dilated
      cardiomyopathy was resolved in a patient after the focal source of PVCs was
      eliminated by radiofrequency catheter ablation. Echocardiography showed
      progressive improvement of the abnormal wall motion. Frequent PVCs could be the
      cause of left ventricular dysfunction in a subset of patients with dilated
      cardiomyopathy and radiofrequency ablation should be the choice of therapy in
      those patients.

PMID- 12419941
TI  - Oxidized low density lipoprotein potentiation of Fas-induced apoptosis through
      lectin-like oxidized-low density lipoprotein receptor-1 in human umbilical
      vascular endothelial cells.
AB  - Under normal conditions, vascular endothelial cells are resistant to Fas-mediated
      apoptosis, although they express detectable Fas on their cell surface. Because
      oxidized Low density lipoprotein (Ox-LDL) is thought to promote atherogenesis,
      the potential role that Ox-LDL may play in Fas-mediated apoptosis was
      investigated in human umbilical vascular endothelial cells (HUVECs), focusing
      particularly on the involvement of the lectin-like Ox-LDL receptor-1 (LOX-1).
      HUVECs were treated with agonistic anti-Fas antibody (CH11) and Ox-LDL and then
      the degree of apoptosis was determined by cell death ELISA. Ox-LDL concentration
      dependently sensitized Fas-mediated apoptosis. Flow cytometry demonstrated that
      Ox-LDL dose-dependently up-regulated cell surface Fas expression. On the other
      hand, treating HUVECs with Ox-LDL did not lead to any significant change in the
      expression of death mediators, including Fas, Fas ligand (FasL), FADD, and FLICE
      as assessed by multiplex polymerase chain reaction amplification. More
      importantly, these effects of Ox-LDL on Fas-mediated apoptosis were significantly
      blocked by a neutralizing LOX-1 monoclonal antibody, which can block LOX-1
      mediated cellular uptake of Ox-LDL. Ox-LDL may be an important factor involved in
      the regulation of Fas-induced apoptosis via Ox-LDL/LOX-1 interaction in vascular
      endothelial cells. The results may provide insights into the pathogenesis of
      accelerated atherosclerosis in patients with hyperlipidemia.

PMID- 12419943
TI  - Surgical experience with right atrial-aortic fistula and penetration of the
      superior vena cava by a protruding Accufix atrial J-shaped retention wire.
AB  - A 57-year-old woman who had a dual chamber pacemaker implanted in June 1990 for
      sick sinus syndrome had developed heart failure since 1993. Although fluoroscopy
      revealed that the proximal J-shaped retention wire of the lead had fractured and
      had protruded through the outer insulation in 1994, and also that the distal J
      shaped retention wire of the lead had protruded through the outer insulation in
      1997, a transthoracic echocardiographic examination diagnosed tricuspid valve
      regurgitation, suggesting that the right atrial-aortic fistula might have been
      overlooked. In an attempt to avoid migration of the J-shaped retention wire from
      the lead and to repair the tricuspid regurgitation, it was decided that an
      operation be performed; however, intraoperative transesophageal echocardiography
      showed a right atrial-aortic fistula. Intraoperative inspection also revealed
      that the right atrial-aortic fistula and penetration of the superior vena cava
      had been caused by the Accufix atrial J-shaped retention wire. Under total
      cardiopulmonary bypass and induced cardiac arrest, a right atriotomy was
      performed and the atrial and ventricular leads were removed from the tips. The
      atrial orifice of the fistula and the aortic orifice were closed. Finally, a new
      dual-chamber pacing system with bipolar epicardial pacing leads was implanted.
      Postoperative inspection revealed that the proximal retention wire had fractured,
      the tip of the retention wire had protruded through the outer insulation, and the
      distal J-shaped outer insulation was damaged.

PMID- 12419944
TI  - Shoshin beriberi with vasospastic angina pectoris possible mechanism of mid
      ventricular obstruction: possible mechanism of mid-ventricular obstruction.
AB  - A 73-year-old heavy drinker was admitted to hospital in a state of shock. He had
      been suffering from frequent angina at rest, causing him to drink more heavily in
      an effort to overcome his anginal chest pain. He had been drinking hard each day
      and had not eaten for 4 weeks. His hemodynamic state on admission showed high
      output heart failure. Echocardiography revealed hyperkinesis of the left
      ventricle and mid-ventricular obstruction with peak intraventricular gradients of
      30 mmHg. Although no improvement was seen despite administering the maximal dose
      in catecholamine therapy, his condition improved rapidly after vitamin B(1) was
      administered. Cardiac catheterization revealed mid-ventricular obstruction with
      an apical aneurysm. Coronary artery spasm was induced by injecting acetylcholine
      in the distal site of the left anterior descending artery, which perfused the
      area of the apical aneurysm. In the present case, both left ventricular
      hyperkinesis caused by shoshin beriberi and apical myocardial infarction caused
      by frequent coronary spasms produced mid-ventricular obstruction with an apical
      aneurysm.

PMID- 12419945
TI  - Transient complete atrioventricular block occurring 1 week after radiofrequency
      ablation for the treatment of atrioventricular nodal re-entrant tachycardia.
AB  - Atrioventricular (AV) block following radiofrequency (RF) ablation for the
      treatment of AV nodal re-entrant tachycardia (AVNRT) is a rare but serious
      complication of this procedure. Almost all such cases occur during or immediately
      after radiofrequencey (RF) energy application, followed by prompt recovery. The
      present report describes a 22-year-old woman with first-degree AV block on
      electrocardiography, who developed complete AV block 1 week after RF ablation for
      the treatment of the uncommon form of AVNRT (slow/slow). The patient's complete
      AV block persisted for another 1 week before she recovered.

PMID- 12419946
TI  - MDR1 genotype-related pharmacokinetics and pharmacodynamics.
AB  - The multidrug resistant transporter MDR1/P-glycoprotein, the gene product of
      MDR1, is a glycosylated membrane protein of 170 kDa, belonging to the ATP-binding
      cassette superfamily of membrane transporters. MDR1 acts as an energy-dependent
      efflux pump that exports its substrates out of cells. MDR1 was originally
      isolated from resistant tumor cells as part of the mechanism of multidrug
      resistance, but over the last decade, it has been elucidated that human MDR1 is
      also expressed throughout the body to confer intrinsic resistance to the tissues
      by exporting unnecessary or toxic exogeneous substances or metabolites. A number
      of structurally unrelated drugs are substrates for MDR1, and MDR1 and other
      transporters are recognized as an important class of proteins for regulating
      pharmacokinetics and pharmacodynamics. In 2000, Hoffmeyer et al. performed a
      systemic screening for MDR1 polymorphisms and detected 15 single nucleotide
      polymorphisms (SNPs). They also indicated that a polymorphism in exon 26 at
      position 3435 (C3435T), a silent mutation, affected the expression level of MDR1
      protein in duodenum, and thereby the intestinal absorption of digoxin. To date,
      the genotype frequencies of C3435T have been investigated extensively using a
      larger population and interethnic difference has been elucidated, and a total of
      28 SNPs have been found at 27 positions on the MDR1 gene. Clinical studies on
      MDR1 genotype-related MDR1 expression and pharmacokinetics have also been
      performed around the world; however, results were not always consistent with
      Hoffmeyer's report. In this review, published reports are summarized for the
      future individualization of pharmacotherapy based on MDR1 genotyping. In
      addition, recent investigations have raised the possibility that MDR1 and related
      transporters play a fundamental role in regulating apoptosis and immunology, and
      in fact, there are reports of MDR1-related susceptibility to inflammatory bowel
      disease, HIV infection and renal cell carcinoma. Herein, these issues are also
      summarized, and the current status of the knowledge in the area of
      pharmacogenomics of other transporters is briefly introduced.

PMID- 12419947
TI  - Further characterization of galloyl pedunculagin as an effective
      autophosphorylation inhibitor of C-kinase in vitro.
AB  - The inhibitory effect of galloyl pedunculagin (GP) isolated from Platycarya
      strobilacea on the activity and autophosphorylation of Ca(2+)- and phospholipid
      dependent protein kinase (C-kinase) was examined in vitro. It was found that (i).
      GP inhibited the activity (phosphorylation of complement C3 from guinea pig) of C
      kinase alpha (rat brain) in a dose-dependent manner with an ID(50) of approx.
      0.12 micro M (ii). GP at lower doses (ID(50)=approx. 6 nM) inhibited
      autophosphorylation of C-kinase alpha; and (iii). the GP-induced inhibition of
      autophosphorylation of C-kinase alpha and its enzyme activity was a manner non
      competitive to ATP. Similar inhibitory effect of GP on autophosphorylation of
      recombinant human C-kinase eta (rhC-kinase eta) and its phosphorylating activity
      was observed. These results suggest that GP is an effective autophosphorylation
      inhibitor of these two C-kinase isoforms (alpha and eta) in vitro. In addition,
      the CD analysis suggests that the proline-containing six amino acid residues
      (PVLTPP) including a threonine residue (autophosphorylation site) at the C
      terminal region (positions 635-640) of C-kinase alpha may be one of the GP
      binding sites.

PMID- 12419948
TI  - Activins A, AB, and B inhibit hepatocyte growth factor synthesis by MRC-5 human
      lung fibroblasts.
AB  - The effect of activins A, AB, and B on hepatocyte growth factor (HGF) synthesis
      stimulated by 12-O-tetradecanoylphorbol beta-acetate (TPA) was studied in MRC-5
      human lung fibroblasts. Activins A, AB, and B inhibited the increase in HGF
      secretion induced by TPA in different dose-dependent manners and potencies. At 5
      ng/ml, activins A and AB inhibited the increase approximately 30% and 10%,
      respectively, and at 25 ng/ml both activins produced almost maximal inhibition,
      i.e., approximately 40%. Activin B caused 10% inhibition at 12 ng/ml, and at 25
      ng/ml produced almost maximal inhibition, approximately 30%. Further analysis
      with activin A indicated that the inhibition was caused by decreased HGF mRNA
      levels, followed by decreased cellular HGF levels. At 25 ng/ml, activin A
      inhibited the increase in HGF in the cellular lysate and the increase in HGF mRNA
      level approximately 80% and 40%, respectively.

PMID- 12419949
TI  - Differentiation-inducing effects of verticinone, an isosteroidal alkaloid
      isolated from the bulbus of Fritillaria ussuriensis, on human promyelocytic
      leukemia HL-60 cells.
AB  - The inducer of differentiation of human promyelocytic leukemia HL-60 cells is
      commonly accepted to have potential therapeutic importance. Verticinone, one of
      the major isosteroidal alkaloids from the bulbus of Fritillaria ussuriensis, was
      found to inhibit the growth of HL-60 cells by inducing these cells to
      differentiate toward granulocytes. Importantly, the combination of verticinone
      with all-trans retinoic acid (ATRA), a well-known inducer of HL-60 cells into
      granulocytic lineages, was more effective than either alone, suggesting its
      therapeutic use in minimizing the effective dose of ATRA.

PMID- 12419950
TI  - Nateglinide suppresses postprandial hypertriglyceridemia in Zucker fatty rats and
      Goto-Kakizaki rats: comparison with voglibose and glibenclamide.
AB  - Postprandial hypertriglyceridemia, as well as postprandial hyperglycemia, are
      important factors contributing to the development of cardiovascular disease in
      patients with type 2 diabetes. Nateglinide is a recently approved antidiabetic
      that suppresses postprandial hyperglycemia by stimulating the early phase of
      insulin secretion. In the present study, we investigated the effects of
      nateglinide on postprandial hypertriglyceridemia in obese Zucker fatty (ZF) rats
      and non-obese diabetic Goto-Kakizaki (GK) rats. Administration of an oral fat
      load caused marked hypertriglyceridemia with a peak at 2 h in ZF and GK rats.
      Nateglinide (50 mg/kg) significantly suppressed the increase of plasma
      triglycerides after fat loading in both types of rat (delta AUC [0-4 h]: 15+/-69
      mg.h/dl for nateglinide vs. 838+/-100 mg.h/dl for vehicle in ZF rats; p<0.01,
      81+/-22 mg x h/dl for nateglinide vs. 164+/-17 mg.h/dl for vehicle in GK rats;
      p<0.01). In contrast, other antidiabetic agents (voglibose and glibenclamide) did
      not show a significant effect on the increase of triglycerides after fat loading.
      The triglyceride components suppressed by nateglinide were mainly at the origin
      and in the pre beta subfraction on agarose gel electrophoresis, suggesting that
      chylomicrons and very low density lipoproteins were decreased. Plasma insulin
      levels were significantly increased at 30 min in nateglinide-treated rats, but
      not in voglibose- or glibenclamide-treated rats. These results suggest that
      nateglinide not only suppresses postprandial hyperglycemia, but also suppresses
      postprandial hypertriglyceridemia, by promoting rapid and pulsatile insulin
      secretion in patients with type 2 diabetes.

PMID- 12419951
TI  - Effect of Sho-saiko-to extract on hepatic inflammation and fibrosis in
      dimethylnitrosamine induced liver injury rats.
AB  - Sho-saiko-to extract, a Chinese herbal medicine, is widely used for treatment of
      chronic hepatitis in Japan. However, it is not clear what conditions Sho-saiko-to
      extract improves hepatic inflammation and fibrosis. We therefore induced various
      stages of liver injury in model rats and administered Sho-saiko-to extract. We
      then evaluated the liver inflammation and liver fibrosis-improving effects of Sho
      saiko-to extract. The liver injury model rats were produced by administration of
      various doses of dimethylnitrosamine (DMN) and Sho-saiko-to extract was
      administered to these rats. Then the liver inflammation and fibrosis-improving
      effects of Sho-saiko-to extract were evaluated according to L-asparate
      aminotransferase (AST), L-alanine aminotransferase (ALT), liver retinoid levels,
      levels of hydroxyproline, Transforming Growth Factor-beta (TGF-beta), and the
      liver fibrosis area. These indicators depended on the total doses of DMN. The
      ability of Sho-saiko-to extract to improve liver inflammation and fibrosis was
      limited to the following levels of the respective parameters: AST levels (234-264
      U/l), ALT levels (208-232 U/l), TGF-beta levels (1102-1265 pg/g liver tissue),
      hydroxyproline levels (633-719 nmol/g liver tissue), and liver fibrosis area (9.7
      10.6 times for normal rat). These findings suggested that Sho-saiko-to extract is
      effective in the treatment of liver inflammation and fibrosis up to a certain
      degree of severity, but it produces no improvement in more severe cases.

PMID- 12419953
TI  - Protective effect of moutan cortex extract on acetaminophen-induced cytotoxicity
      in human Chang liver cells.
AB  - The aim of this study was to investigate the effect of Moutan Cortex on
      acetaminophen (AAP)-induced toxicity in human Chang liver cells. Cells were
      incubated with AAP (0-30 mM) to evaluate the drug's ability to reduce
      cytoviability. For the cells treated with 10, 20 and 30 mM AAP, LDH leakage was
      39.8%, 49.0% and 57.6%, respectively. Administration of Moutan Cortex reduced
      cytotoxicity in a dose-dependent manner. Glutathione (GSH) concentration in human
      liver cells decreased significantly after exposure to 20 (p<0.05) and 30 mM
      (p<0.01) AAP, and increased (p<0.05) if incubated with AAP and Moutan Cortex. The
      ability of AAP to inhibit mitochondrial function and its counteraction by Moutan
      Cortex was also evaluated. Moutan Cortex showed dose-dependent increases in MTT
      metabolism and ATP levels in AAP-treated cells. The DNA content of AAP-treated
      cells increased with the treatment of Moutan Cortex. These observations
      demonstrate that Moutan Cortex may significantly attenuate AAP-induced toxicity.
      It can be considered a cytoprotective agent in this in vitro model of drug
      toxicity.

PMID- 12419952
TI  - Acute and chronic effects of T-1032, a novel selective phosphodiesterase type 5
      inhibitor, on monocrotaline-induced pulmonary hypertension in rats.
AB  - We examined the hemodynamic property of T-1032 (methyl 2-(4-aminophenyl)-1,2
      dihydro-1-oxo-7-(2-pyridylmethoxy)-4-(3,4,5-trimethoxy-phenyl)-3-isoquinoline
      carboxylate sulfate), a novel selective phosphodiesterase type 5 (PDE5)
      inhibitor, and evaluated the chronic effect of T-1032 on cardiac remodeling and
      its related death in monocrotaline (MCT)-induced pulmonary hypertensive rats. T
      1032 (1, 10, 100 micro g/kg, i.v.) significantly reduced mean arterial pressure
      (MAP) and right ventricular systolic pressure (RVSP) without a change in heart
      rate. The change in RVSP was more potent than that in MAP with 1 micro g/kg T
      1032 treatment (RVSP: -8.2+/-1.2%, mean arterial pressure: -5.7+/-1.2%), and
      reductions in RVSP and MAP reached a peak at doses of 1 and 10 micro g/kg,
      respectively. In contrast, nitroglycerin (0.1, 1, 10 micro g/kg, i.v.) and
      beraprost (0.1, 1 micro g/kg, i.v.) did not cause a selective reduction in RVSP
      at any dose. When T-1032 (300 ppm in diet) was chronically administered, it
      delayed the death, and significantly suppressed right ventricular remodeling (T
      1032-treated: 0.318+/-0.021 g, control: 0.401+/-0.013 g, p<0.05). Our present
      results suggest that T-1032 selectively reduces RVSP, and resulting in the
      suppression of right ventricular remodeling with a delay of the death in MCT
      induced pulmonary hypertensive rats.

PMID- 12419954
TI  - Synthesis, analgesic, anti-inflammatory and antibacterial activities of some
      novel 2-phenyl-3-substituted quinazolin-4(3H) ones.
AB  - A series of novel 2-phenyl-3-substituted quinazolin-4(3H)-ones have been
      synthesized by treating methyl-N-(2-phenyl quinazolin-3-yl-4(3H)-one)
      dithiocarbamate with different amines, the starting material dithiocarbamate was
      synthesized from anthranilic acid. The title compounds were investigated for
      analgesic, anti-inflammatory and antibacterial activities. All the test compounds
      exhibited significant activity, the compounds A1, A2 and A3 shown more potent
      analgesic activity, and the compound A3 shown more potent anti-inflammatory
      activity than the reference standard diclofenac sodium.

PMID- 12419955
TI  - Anti-inflammatory and anti-allergic activities of hydroxylamine and related
      compounds.
AB  - The anti-inflammatory activities of several novel oximes and O-acyl oximes that
      we synthesized have been reported based on carrageenan-induced rat foot-pad
      swelling assay and histamine-induced rat vascular permeability assay. A
      cyclooxygenase (COX)-1 inhibitory effect has also been reported for 4'
      piperidinoacetophenone and 4'-morpholinoacetophenone oximes and their O-acyl
      derivatives. To further search for more effective non-steroidal anti-inflammatory
      or anti-allergic drugs, 1-hydroxylamino-1-(4'-piperidinophenyl) ethane (P-HA) and
      1-hydroxylamino-1-(4'-morpholinophenyl) ethane (M-HA) were synthesized from the
      corresponding oximes with sodium cyanoborohydride, and N,O-diacetyl
      hydroxylamines (P-HA-Ac and M-HA-Ac) were prepared from these hydroxylamines
      using acetyl chloride. These hydroxylamines and N,O-diacetyl hydroxylamines
      clearly exhibited inhibitory effects on mouse carrageenan-induced foot-pad
      swelling induced by oral administration (150, 37.5 mg/kg). An oral dose of P-HA
      Ac (150 mg/kg) significantly inhibited the mouse anaphylactic reaction to
      ovalbumin measured by the abdominal wall (AW) method. Percutaneous administration
      of P-HA and M-HA significantly inhibited 2,4-dinitrofluorobenzene (DNFB)-induced
      contact hypersensitivity reaction (type IV) in mice at a dose of 0.5 and 0.1
      mg/ear, respectively. All tested hydroxylamines and N,O-diacetyl hydroxylamines
      clearly inhibited both COX-1 and COX-2 enzyme activities with IC(50) values of
      1.9-28.7 and 1.6-2.9 micro M against COX-1 and COX-2, respectively.
      Hydroxylamines (P-HA and M-HA) also showed a 5-lipoxygenase inhibitory effect.

PMID- 12419956
TI  - Daio-Orengedokuto inhibits HMG-CoA reductase and pancreatic lipase.
AB  - To evaluate the antihyperlipidemic activities of Orengedokuto (OT) and Daio
      Orengedokuto (DOT), the inhibitory effects of these polyprescriptions on HMG-CoA
      reductase and pancreatic lipase and on the rat hyperlipidemic model induced by
      Triton WR-1339 were measured. OT potently inhibited HMG-CoA reductase but did not
      inhibit lipase. Among their ingredients, Coptidis Rhizoma was the most potent
      inhibitor, followed by Rhei Rhizoma. The HMG-CoA reductase-inhibitory activity of
      80% EtOH extract was superior to that of water extract. However, DOT potently
      inhibited HMG CoA-reductase as well as pancreatic lipase. In the rat
      hyperlipidemic model induced by Triton WR-1339, OT and DOT decreased serum total
      cholesterol and low-density lipoprotein cholesterol levels. DOT also decreased
      serum triglyceride levels, but OT did not decrease it. These results suggest that
      the antihyperlipidemic activity of DOT may originate from the inhibition of
      pancreatic lipase as well as HMG-CoA reductase.

PMID- 12419957
TI  - Taraxinic acid, a hydrolysate of sesquiterpene lactone glycoside from the
      Taraxacum coreanum NAKAI, induces the differentiation of human acute
      promyelocytic leukemia HL-60 cells.
AB  - The present work was performed to elucidate the active moiety of a sesquiterpene
      lactone, taraxinic acid-1'-O-beta-D-glucopyranoside (1). from Taraxacum coreanum
      NAKAI on the cytotoxicity of various cancer cells. Based on enzymatic hydrolysis
      and MTT assay, the active moiety should be attributed to the aglycone taraxinic
      acid (1a). rather than the glycoside (1). Taraxinic acid exhibited potent
      antiproliferative activity against human leukemia-derived HL-60. In addition,
      this compound was found to be a potent inducer of HL-60 cell differentiation as
      assessed by a nitroblue tetrazolium reduction test, esterase activity assay,
      phagocytic activity assay, morphology change, and expression of CD 14 and CD 66 b
      surface antigens. These results suggest that taraxinic acid induces the
      differentiation of human leukemia cells to monocyte/macrophage lineage. Moreover,
      the expression level of c-myc was down-regulated during taraxinic acid-dependent
      HL-60 cell differentiation, whereas p21(CIP1) and p27(KIP1) were up-regulated.
      Taken together, our results suggest that taraxinic acid may have potential as a
      therapeutic agent in human leukemia.

PMID- 12419958
TI  - Saeng-Maek-San, a medicinal herb complex, protects liver cell damage induced by
      alcohol.
AB  - The effect of treatment with Saeng-Maek-San (SMS) Complex (SMS1 or SMS2) upon rat
      hepatocytes exposed to alcohol was investigated. We compared the serum
      biochemistry and liver histology of rats administered both alcohol and SMS to
      control rats treated with alcohol alone. SMS treatment resulted in a significant
      reduction in the levels of aspartate aminotransferase (AST), alanine
      aminotransferase (ALT) and triglycerides (TG) compared to the control rats. In
      contrast, expression levels of alcohol dehydrogenase (ADH) were increased.
      Electron microscopy indicated that administration of SMS preserved the structure
      of organelles, including the nucleus and mitochondria. In addition, lipid
      droplets and secondary lysosomes were observed in the control rats. These data
      suggest that SMS represents an excellent candidate for protection of rat
      hepatocytes from alcohol-mediated damage.

PMID- 12419959
TI  - Evaluation of skin barrier function using direct current I: effects of
      conductivity, voltage, distance between electrodes and electrode area.
AB  - The objective of this study was to evaluate the reduction in skin barrier
      function caused by direct current iontophoresis by measuring resistance in the
      short term. The experiments were carried out using rat abdominal skin in vivo.
      The resistance was measured every 125 ms and analyzed using a two-compartment
      model consisting of surface and skin resistance. Moreover, the initial value and
      the rate constant of each resistance were calculated with the non-linear
      approximation program. The proposed method could evaluate the reduction in
      barrier function from the initial value and the rate constant of surface
      resistance with high sensitivity and accuracy. Using this proposed method, the
      effects of the conductivity of an adhesive pad, voltage, the distance between
      electrodes and the area of electrode were examined. The increase in conductivity
      of the adhesive pad decreased the initial value since the rate constant
      increased. The reduction in barrier function depends on voltage. Although the
      barrier function decreased up until an electrode distance of 1 cm, it increased
      beyond 1 cm. These phenomena contributed to the current pass portion in the skin
      because the resistance was in the order of the stratum corneum, epidermis and
      dermis. The initial value decreased with increasing electrode area. However, the
      rate constant was little affected since the current density of a topical
      electrode adjacent to the other electrode was high.

PMID- 12419960
TI  - Studies on interactions between traditional herbal and western medicines. V.
      effects of Sho-saiko-to (Xiao-Cai-hu-Tang) on the pharmacokinetics of
      carbamazepine in rats.
AB  - The possibility of pharmacokinetic interactions between Sho-saiko-to extract
      powder (TJ-9), the most widely used traditional Chinese herbal (Kampo) medicine
      in Japan, and carbamazepine (CBZ), an important anti-epileptic drug, was examined
      in rats. There was no significant difference in the protein binding of CBZ in
      serum obtained before and after the single oral administration of TJ-9. The
      addition of TJ-9 to normal hepatic microsomes inhibited CBZ-10,11-epoxylase
      activity in a concentration-dependent manner. Liver weight, amounts of P450 and
      cytochrome b(5) in hepatic microsomes and the formation of carbamazepine-10,11
      epoxide (CBZ-E), an active metabolite of CBZ, by microsomes were not influenced
      by 2-week repeated oral pretreatment with TJ-9 (1 g/kg/d), although pretreatments
      with phenobarbital (80 mg/kg/d, i.p.) significantly increased these parameters.
      The simultaneous oral administration of TJ-9 (1 g/kg) significantly decreased the
      peak plasma concentration of CBZ and the area under the concentration-time curve
      of CBZ-E, and lengthened the time to reach the peak concentration of CBZ after
      oral administration of CBZ. Two-week repeated oral pretreatment with TJ-9,
      however, did not affect the plasma concentration-time profile or any
      pharmacokinetic parameter of CBZ or CBZ-E. Also, a single oral administration of
      TJ-9 (1 g/kg) significantly delayed gastric emptying. These results indicated
      that the simultaneous oral administration of TJ-9 with CBZ to rats decreased the
      gastrointestinal absorption of CBZ, at least in part, by delaying gastric
      emptying, without affecting the metabolism of CBZ.

PMID- 12419961
TI  - Increased urinary hydrogen peroxide levels caused by coffee drinking.
AB  - Experiments with volunteers in Singapore have demonstrated that coffee drinking
      increases urinary hydrogen peroxide levels (Long, Halliwell, Free Rad. Res., 32,
      463-467 (2000)). We re-examined the effect of coffee drinking of healthy Japanese
      subjects on urinary hydrogen peroxide levels. A cup of brewed or canned coffee
      commercially available in Japan generated 120-420 micro mol hydrogen peroxide in
      incubation in a neutral medium at 37 degrees C for 6 h. The increased levels were
      higher than those obtained from a cup of green tea extract or a glass of red
      wine. After the subject drank a cup of coffee, apparent hydrogen peroxide levels
      (micro mol/g creatinine) in urine collected 1-2 h after coffee drinking increased
      3-10-fold compared to the levels before coffee drinking. The increased urinary
      hydrogen peroxide levels are likely derived mainly from 1,2,4-benzenetriol
      excreted in urine, because the major component that generates hydrogen peroxide
      is found to be 1,2,4-benzenetriol, and storing urine collected after coffee
      drinking increased hydrogen peroxide levels in a time-dependent fashion. Total
      hydrogen peroxide equivalent levels excreted in 3 h-urine after coffee drinking
      were estimated to be 0.5-10% that of coffee consumed. A residual amount of
      hydrogen peroxide may be retained or consumed in human bodies.

PMID- 12419962
TI  - Adhesive defect in extracellular matrix tenascin-X-null fibroblasts: a possible
      mechanism of tumor invasion.
AB  - Extracellular matrix tenascin-X (TNX)-null mice, generated by disruption of the
      Tnx gene, display augmented invasion and metastasis of B16-BL6 melanoma tumor
      cells due to increased activities of matrix metalloproteinase (MMP)-2 and MMP-9.
      In this study, we investigated cell-matrix and cell-cell adhesions using TNX-null
      fibroblasts and wild-type fibroblasts. TNX-null fibroblasts exhibited a decreased
      attachment to fibronectin compared with that of wild-type fibroblasts. B16
      melanoma cells were cocultured with wild-type or TNX-null fibroblasts, and the
      adhesion of B16 melanoma to the fibroblasts was assessed. B16 melanoma cells on
      wild-type fibroblasts proliferated and spread out in a horizontal direction,
      whereas those on TNX-null fibroblasts overlapped each other rather than migrating
      horizontally. These overlapping B16 melanoma cells on TNX-null fibroblasts peeled
      off faster than those on wild-type fibroblasts. To determine whether the
      decreased cell-matrix and cell-cell adhesions on TNX-null fibroblasts were due to
      increased MMP activity, the activities of MMPs in wild-type and TNX-null
      fibroblasts were compared by gelatinolytic assays. The analysis of MMPs from
      conditioned media demonstrated that almost the same levels of MMP activities were
      detected between wild-type and TNX-null fibroblasts. However, contrary to our
      expectations the activities of MMPs from conditioned media of B16 melanoma cells
      cocultured on TNX-null fibroblasts were rather reduced than those of B16 melanoma
      cells cocultured on wild-type. We concluded that the absence of TNX in the
      extracellular environment might play an important role in enhancement of the
      detachment of B16 melanoma cells.

PMID- 12419963
TI  - Structural and functional analysis of a new upstream promoter of the human
      FAT/CD36 gene.
AB  - FAT/CD36 is involved in various processes including uptake of fatty acid into the
      heart and of oxidized low density lipoprotein (LDL) into macrophages. Expression
      of the FAT/CD36 gene is regulated in a tissue-specific manner, and loss or
      inadequately regulated expression of FAT/CD36 is thought to be one of the causes
      of some diseases such as cardiomyopathy and atherosclerosis. We recently found
      that the mouse and human FAT/CD36 genes have two independent promoters. To
      elucidate the physiological significance of the two promoters, we characterized
      the peroxisome proliferator-activated receptor ligand-responsive new promoter
      that is located 14 kb upstream of the previously reported promoter of the human
      gene. We found several SNPs in this region some of which were found only when
      analyzing DNA samples from the patients lacking FAT/CD36 totally or in a cell
      type-specific manner. However, we could not detect any negative effect of these
      SNPs on the transcription by transient transfection analysis, suggesting that the
      identified SNPs alone are not directly linked to low transcriptional activities.

PMID- 12419964
TI  - The 5-HT2 receptor antagonist reduces immobility of mice treated with the
      atypical antidepressant mianserin in the forced swimming test.
AB  - Effects of co-administration with the 5-HT(2) receptor antagonist LY 53857 and
      the antidepressant mianserin on immobility time in the forced swimming test were
      investigated in mice. Mianserin did not affect the immobility time at ranges from
      1-10 mg/kg, although it elicited anti-immobility effects at 20 mg/kg. Co
      administration of the 5-HT(2) receptor antagonist LY 53857 and a subactive dose
      of mianserin induced apparent anti-immobility effects. Since mianserin
      facilitates noradrenaline (NA) release from nerve terminals via inhibition of
      alpha(2) receptors, the blockade of the 5-HT(2) receptor may increase the
      antidepressant effect of drugs modifying NA levels in the synaptic cleft.

PMID- 12419965
TI  - Hepatic mitochondrial prooxidant and antioxidant status in ethanol-induced liver
      injury in rats.
AB  - In this study, prooxidant and antioxidant status in liver homogenates and their
      mitochondrial fractions were investigated in both chronic and chronic plus acute
      ethanol-treated rats. Increases in serum transaminase activities, as well as
      increases in total lipid, triglyceride, malondialdehyde (MDA) and diene conjugate
      (DC) levels and decreases in glutathione (GSH), vitamin E and vitamin C levels,
      have been observed in liver homogenates following chronic ethanol treatment (20%
      ethanol, v/v as drinking water for 3 months), but CuZn-superoxide dismutase
      (CuZnSOD), glutathione peroxidase (GSH-Px) and glutathione transferase (GST)
      activities remained unchanged in postmitochondrial fractions. When an acute dose
      of ethanol (5 g/kg, i.p.) was given rats which had received ethanol chronically,
      serum transaminase activities and hepatic lipid and MDA and DC levels increased
      further, but GSH levels and antioxidant enzymes decreased more compared to the
      chronic ethanol-treated rats. There were no significant differences in the levels
      of MDA, DC and protein carbonyl and the activities of GSH-Px and GST in the
      hepatic mitochondrial fraction of rats following both chronic and chronic plus
      acute treatments. Mn-superoxide dismutase (MnSOD) activities increased in both
      groups, but mitochondrial GSH levels decreased only after chronic plus acute
      treatment. Therefore, we suggest that the increase in MnSOD activity may play an
      important role in the regulation of mitochondrial susceptibility against ethanol
      induced oxidative stress.

PMID- 12419966
TI  - Ursolic acid as a trypanocidal constituent in rosemary.
AB  - The MeOH extract of the leaves of rosemary (Rosmarinus officinalis L.) completely
      inhibited the motility of cultured epimastigotes of Trypanosoma cruzi at the
      concentration of 2 mg/ml after 2 h of incubation. Activity-guided fractionation
      of the MeOH extract has resulted in the isolation of three triterpene acids,
      betulinic, oleanolic and ursolic acids. Ursolic acid stopped the movement of all
      T. cruzi epimastigotes at the minimum concentration (MC(100)) of 40 micro g/ml
      (88 micro M) after 48 h of incubation. Oleanolic acid was less active (MC(100):
      250 micro g/ml, 550 micro M) and betulinic acid was practically inactive.

PMID- 12419967
TI  - Inhibitory effect of stevioside on tumor promotion by 12-O-tetradecanoylphorbol
      13-acetate in two-stage carcinogenesis in mouse skin.
AB  - Four steviol (ent-kaurene-type diterpenoid) glycosides, stevioside, rebaudiosides
      A and C, and dulcoside A, have been isolated from Stevia rebaudiana BERTONI.
      These compounds showed strong inhibitory activity against 12-O
      tetradecanoylphorbol-13-acetate (TPA)-induced inflammation in mice. The 50%
      inhibitory dose of these compounds for TPA-induced inflammation was 54.1-291.6
      micro g/ear. Furthermore, at 1.0 and 0.1 mg/mouse of stevioside mixture, the
      mixture of these compounds markedly inhibited the promoting effect of TPA (1
      micro g/mouse) on skin tumor formation initiated with 7,12
      dimethylbenz[a]anthracene (50 micro g/mouse).

PMID- 12419968
TI  - Anti-invasive and metastatic activities of evodiamine.
AB  - We have recently reported that evodiamine can suppress in vitro invasion and lung
      metastasis by colon 26-L5 carcinoma cells. To extend our study, we examine here
      the anti-invasive and metastatic effects of evodiamine on Lewis lung carcinoma
      (LLC) and B16-F10 melanoma in addition to colon 26-L5 carcinoma. Critical
      structures of evodiamine for the activities were also evaluated by comparison
      with compounds possessing structures similar to that of evodiamine. Evodiamine
      concentration-dependently inhibited the invasion of B16-F10, LLC and colon 26-L5
      cells with IC(50) values of 2.4 micro M, 4.8 micro M and 3.7 micro M,
      respectively. Pre-treatment of colon 26-L5 cells with evodiamine before
      inoculation into mice caused significant suppression of the liver metastasis as
      well as the lung metastasis. Lung metastasis by LLC is also inhibited
      significantly by pre-exposure to evodiamine. When the anti-migratory activity of
      evodiamine was compared with that of evodiamine-like compounds, rutaecarpine
      lacking a methyl group at N-14 and a hydrogen at C-13 b exhibited much less
      effect than evodiamine. In addition, reserpine, having beta-configurated hydrogen
      at C-13 b, inhibited tumor cell migration more potently than yohimbine, having
      alpha-configurated hydrogen at the same position. These results suggest that
      evodiamine may be useful as a leading compound for agents in tumor metastasis
      therapy. Also, the presence of a methyl group at N-14 and the configuration of
      hydrogen at C-13 b may be responsible for the inhibitory activities of
      evodiamine.

PMID- 12419969
TI  - A novel method for preparation of animal models of liver damage: liver targeting
      of carbon tetrachloride in rats.
AB  - Animal models prepared by treatment with toxic compounds such as a carbon
      tetrachloride have been used to examine drug disposition in hepatic diseases.
      However, it is possible that these compounds accumulate and cause damage to other
      organs as they are administered systemically. In this study, we used the liver
      surface application technique to deliver a toxic compound to the liver to prepare
      an appropriate animal model in which only the liver is significantly damaged. To
      restrict the absorption area in the liver, a cylindrical diffusion cell was
      attached to the liver surface of male Wistar rats. Twenty-four hours after direct
      addition of carbon tetrachloride to the diffusion cell, plasma levels of glutamic
      oxaloacetic transaminase (GOT) and glutamic-pyruvic transaminase (GPT), and
      hepatic malondialdehyde (MDA) concentration were increased, while there were no
      changes in plasma creatinine or renal MDA level. On the other hand, not only GOT,
      GPT and hepatic MDA, but also creatinine and renal MDA levels were markedly
      increased by p.o. and i.p. administration of carbon tetrachloride, suggesting
      renal damage. These results indicated that the animal models of liver damage
      prepared by utilizing drug delivery techniques to accumulate toxic compounds in
      the liver would enable us to investigate the precise effects of hepatic disorder
      on drug disposition.

PMID- 12419971
TI  - Long-term radical scavenging activity of AA-2G and 6-acyl-AA-2G against 1,1
      diphenyl-2-picrylhydrazyl.
AB  - Stoichiometric evaluation of the radical scavenging activity of O-substituted
      derivatives at the C-2 position of ascorbic acid (AA) was conducted. Their
      reaction with a stable radical, 1,1-diphenyl-2-picrylhydrazyl (DPPH), under an
      acidic condition was assessed by the colorimetric method. 2-O-alpha-D
      Glucopyranosyl-L-ascorbic acid (AA-2G) and a series of 6-O-acyl-2-O-alpha-D
      glucopyranosyl-L-ascorbic acids (6-Acyl-AA-2G) had long-term radical scavenging
      activity against DPPH. The reaction of AA-2G or 6-Acyl-AA-2G with DPPH was very
      slow when compared with AA. However, one molecule of these derivatives consumed
      approximately three molecules of DPPH radicals at the end of the experiment (2
      h). In contrast, one molecule of AA scavenged two molecules of DPPH radicals, and
      the reaction ended in the short time (<10 min). The quantity of radicals quenched
      by AA-2G and 6-Acyl-AA-2G was superior to that of AA in a long-term reaction.

PMID- 12419970
TI  - Prolonged intestinal absorption of cephradine with chitosan-coated ethylcellulose
      microparticles in rats.
AB  - Cephradine-containing ethylcellulose microparticles (MPC) were prepared by the
      solvent evaporation method. Chitosan-coated MPC (Chi-MPC) were prepared by doping
      MPC with viscous chitosan solution and subsequently drying. When fluorescein
      isothiocyanate (FITC)-labeled chitosan-coated ethylcellulose microparticles
      without drug were administered intraduodenally, they moved slowly in the
      intestine, that is, most of them were retained at the upper and middle parts of
      the small intestine for more than 8 h, which is considered due to mucoadhesive
      properties of coated chitosan. When MPC and Chi-MPC was incubated at 37 degrees C
      in the JP 14 second fluid, pH 6.8, both released the drug slowly with similar
      release rates. Cephradine solution and suspension, MPC and Chi-MPC were
      administered intraduodenally to investigate intestinal drug absorption. Only Chi
      MPC suppressed the initial plasma level and maintained the plasma concentration
      for a long time up to 24 h, suggesting Chi-MPC would be useful for prolonged
      intestinal absorption of cephradine.

PMID- 12419972
TI  - Production of interleukin-1 activity of Kupffer cells from mice treated with the
      acidic mannan fraction of baker's yeast.
AB  - We investigated the production of interleukin-1 (IL-1) activity by Kupffer cells
      (KC) from mice treated with a neutral mannan fraction (WNM) or an acidic mannan
      fraction (WAM025) from baker's yeast (Saccharomyces cerevisiae) in vivo and in
      vitro. The mice administered WAM025 showed an increase in the number of KC and
      the IL-1 production compared with mice administered WNM. In an in vitro
      stimulation assay using KC from a normal mouse, it was also found that WAM025
      displayed an increase in IL-1 production. Diisopropyl fluorophosphate completely
      inhibited the production of IL-1 by KC from the mice administered WAM025.

PMID- 12419973
TI  - A metabolic switching hypothesis for the first step in the hypolipidemic effects
      of fibrates.
AB  - Pyruvate dehydrogenase kinase 4 (PDK4) mRNA was identified as a transcript that
      was rapidly and generally induced by fibrates in various tissues of the mouse.
      The time course of induction was much faster than those of typical peroxisome
      proliferator-activated receptor alpha (PPAR alpha)-regulated peroxisomal mRNAs.
      Rapid and efficient induction of PDK4 mRNA in various tissues would inactivate
      pyruvate dehydrogenase and stimulate fatty acid oxidation at the whole body
      level, leading to enhanced utilization of serum fatty acids and triglycerides.
      This metabolic switching mechanism can explain the early phase of the fibrate
      induced decrease in the serum levels of triglycerides. Furthermore, the muscle in
      the fibrate-induced early state with limited activity of pyruvate dehydrogenase
      and low levels of fatty acids will utilize proteins as an energy source and
      extensive degradation of proteins may lead to myopathy or rhabdomyolysis.

PMID- 12419974
TI  - The nursing profession must be more assertive over pay.

PMID- 12419975
TI  - Challenge of raising the status of gerontological nursing.

PMID- 12419976
TI  - Nurse in charge who walked out on an understaffed ward.

PMID- 12419977
TI  - Pain in venous leg ulceration: aetiology and management.
AB  - Leg ulceration is a common chronic recurring condition which affects a
      significant percentage of the UK population. There has been much written about
      the management of leg ulcers; yet despite this, pain in venous aetiology remains
      poorly understood. This article will discuss some of the factors that contribute
      to pain in venous aetiology as well as offering clinical management strategies.

PMID- 12419978
TI  - The role and power of safety representatives and committees.
AB  - Case Scenario: Doreen, who had been a union member for many years and more
      recently had become a union officer in her local branch, was asked by the union
      if she would like to take on the role of being a health and safety
      representative. She was hesitant to accept as she was not sure what would be
      involved.

PMID- 12419980
TI  - National Service Framework for Older People: stroke coordinators.
AB  - The National Service Framework (NSF) for Older People aims to develop integrated
      stroke services with specialized treatment, carer involvement, secondary
      prevention and rehabilitation. There is an emphasis upon the role of stroke
      coordinators. The aim of this study was to examine the relationships between
      stroke coordinators and other agencies involved in stroke care, and to describe
      stroke coordinators' current roles. Interviews with 11 stroke coordinators across
      the West Midlands region took place and were evaluated using a grounded theory
      approach. The roles of stroke coordinators and the perceived levels of
      integration among stroke services varied between localities. In a few areas, a
      number of 'adhesive' factors helped bond the coordinator role to successful
      integration, while in most areas the absence of all or some of these factors made
      the role less effective. To meet the demands of the NSF, a stroke coordinator's
      role needs to be a high profile, corporate function, requiring a higher level of
      autonomy, accountability and responsibility, and demanding creativity and
      innovation from post holders.

PMID- 12419979
TI  - Venous thromboprophylaxis in acutely ill patients: nursing role.
AB  - Venous thromboembolism (VTE) is a serious medical problem and is one of the most
      important preventable causes of mortality and morbidity in hospitalized patients.
      This article reviews the prevention of VTE with thromboprophylaxis in acutely ill
      general medical patients. We review recent studies which show that general
      medical patients are at moderate risk of VTE and that low-molecular-weight
      heparin reduces this risk. Nurses have a key role to play in changing clinical
      practice by increasing awareness of the risk of VTE in medical patients, helping
      in the process of risk assessment and ensuring appropriate prophylaxis.

PMID- 12419981
TI  - The professional standard of care in clinical negligence.
AB  - The general principle of law relating to breach of duty in the tort of negligence
      has been discussed during this series of articles. This article continues that
      discussion in relation to healthcare professionals such as nurses and doctors,
      and how the law affects their case. The issue of the expanded role of the nurse
      is also discussed.

PMID- 12419982
TI  - Teaching the stoma care routine to a patient with low vision.
AB  - Teaching the patient with a newly formed stoma but who also has low vision to
      manage his/her stoma independently can be a difficult task. This case study shows
      how a nurse taught a patient with low vision to become independent in relation to
      his newly formed stoma, with a view to being discharged home successfully. At the
      time the stoma care nurse used her past experience and common sense in achieving
      this aim. After the event the stoma care nurse researched the literature and
      discovered that there are accessories/devices available to assist patients with
      low vision to manage their stoma and help improve their vision. On reflection,
      the stoma care nurse felt she did not have sufficient time preoperatively with
      the patient, which prevented her from being able to change the course of action.
      She has now improved her knowledge, which will assist her in the future if she
      has to care for another patient with low vision who has had a newly formed stoma.

PMID- 12419983
TI  - Cutinova Hydro: a modern alternative to hydrocolloids.
AB  - Since the 1960s, moist wound healing has been accepted as the scientific approach
      to wound care. The White Paper 'Making a Difference' (Department of Health (DoH),
      1999) stated that nursing practice should be supported by research and that
      current evidence should be utilized to improve information used to support care
      and treatment decisions. Wound care products, both the traditional and the new,
      are under increasing scrutiny as the physiology of the wound healing process is
      understood with more clarity, assisting the clinician to reappraise current
      practice in the light of new information. The following study considers such
      physiological responses when reporting the effects of Cutinova Hydro (Smith and
      Nephew) in treating exuding wounds.

PMID- 12419984
TI  - Modernization of the NHS is shrouded in spin.

PMID- 12419985
TI  - Complementary therapies--patient demand.

PMID- 12419986
TI  - Containing families' grief: therapeutic group work in a hospice setting.
AB  - This article explores the literature relating to the needs of bereaved children
      and families and describes the course of a family bereavement group run in a
      hospice. The interventions involved dramatherapy and other creative arts media.
      The group comprised of four families all of whom had had a parent die in the
      hospice. Their ages ranged from 6-46 years. Two one-day workshops were followed
      by six closed-group evening sessions. The aims and interventions for each session
      are outlined and a short commentary on the process given. Significant aspects of
      containing families' grief through the use of therapeutic group work is
      highlighted.

PMID- 12419987
TI  - Joe's story: reflection on a difficult interaction between a nurse and a
      patient's wife.
AB  - Unfortunately, not all nursing interactions are positive. Incidents can occur
      that leave nurses with a variety of negative emotions. This paper examines one
      such interaction that occurred between the author, a dying patient, and the
      patient's wife. The author reflects on and attempts to explain the feelings
      aroused by the situation through the use of psychodynamic theories. The
      characteristic personality and coping styles of the main participants are
      discussed. Issues relating to staff support are also highlighted.

PMID- 12419988
TI  - Reflexology audit: patient satisfaction, impact on quality of life and
      availability in Scottish hospices.
AB  - Complementary therapies are being accessed increasingly by cancer patients. The
      aims of this audit were to investigate the impact of reflexology on the quality
      of life of 20 cancer patients, to determine their satisfaction with the service
      provided and to investigate the availability of this therapy within Scottish
      hospices. The audit findings suggest that the clients were satisfied with the
      service received. Respondents noted that their quality of life was improved
      through a reduction in physical and emotional symptoms. It was found that the
      provision of reflexology within Scottish hospices varied, with less than half
      providing this service. The results of this audit suggest that reflexology may be
      a worthwhile treatment for other cancer patients and requires further research to
      evaluate the benefits.

PMID- 12419989
TI  - Cancer patients' experiences and evaluations of aromatherapy massage in
      palliative care.
AB  - Many patients suffering from cancer make use of complementary therapies, with
      aromatherapy being a popular choice. Quantitative studies, using questionnaire
      data, have shown that aromatherapy may reduce psychological distress and enhance
      symptom control in cancer patients. However, little is known about the personal
      meanings patients associate with the therapy. This study explored the patients'
      experiences of aromatherapy using of a focus group interview. Eight themes
      emerged from the analysis, six of which have been acknowledged to some extent by
      previous authors: de-stressing effects of aromatherapy, the counselling role of
      the aromatherapist, aromatherapy as a reward, patient empowerment, communication
      through touch, and negative aspects of the service. Two apparently new themes
      emerged concerned with security of context (where the aromatherapy took place)
      and preconceived perceptions of the value of aromatherapy as a treatment of
      cancer patients. The implications of the findings are discussed in relation to
      the perceived role of counselling, collaborative practice and training in
      complementary therapies.

PMID- 12419990
TI  - Holism and a health-promoting approach to palliative care.
AB  - This article draws on Illich's definition of health and explores the perspective
      of facing death as a process of adaptation. Research into psychoneuroimmunology
      is discussed. This focuses on using one's own resources, which the author sees as
      a central tenet of holism. A key aspect of this approach is not only empowerment
      of patients, but also of nurses, allowing them to be self-aware, self-valuing and
      to practise self-care. The article mentions an educational strategy to encourage
      a health-promoting approach. This course uses the concept of holism as a
      framework for teaching and practice of palliative care.

PMID- 12419991
TI  - Fulfilling patients' wishes: palliative care at home.

PMID- 12419992
TI  - An audit of subcutaneous syringe drivers in a non-specialist hospital.
AB  - The use of syringe drivers as a method of drug delivery to control symptoms in
      palliative care is a common and accepted practice, but one which has evolved
      rather than been subject to close multiprofessional scrutiny and guideline
      formation. There is evidence that adverse incidents may arise as a result of
      syringe driver use (Medical Devices Agency (MDA), 1998), for example, errors in
      drug calculations, drug stability, equipment failure (including disconnection)
      and the wrong rate of infusion. Inadequate user training, poor servicing of
      equipment and inadequate documentation and record keeping are all thought to be
      contributing factors (MDA, 1998). In the hospital where this audit was carried
      out, syringe drivers are used to administer drugs to patients with cancer during
      the palliative phase of illness. The purpose of this clinical audit was to
      establish the standard of current practice in wards where syringe drivers were
      being used. A retrospective study of 13 cases of syringe driver use is presented.
      The results highlight many areas of unregulated practice with regard to setting
      up, monitoring and maintenance of syringe drivers. The choice of drugs and doses
      prescribed, evaluation of treatment responses and review of treatment regimens
      were also areas of concern. Guidelines for the use of syringe drivers in non
      specialist hospitals are put forward.

PMID- 12419993
TI  - Primary care services received during terminal illness.
AB  - The World Health Organization (1990) provides guidelines on what constitutes
      effective palliative care. However, it remains unclear whether people with a
      terminal illness living in their own homes have access to the services they need.
      This article reports on a study carried out in the United Kingdom on the views of
      people with a terminal illness (n = 15), their lay carers (n = 10) and bereaved
      carers (n = 19). Participants were asked about the primary care services they had
      received and their views on both helpful and unhelpful aspects of service
      provision. All terminally ill people in the study (except one) had cancer, which
      raises questions about access to palliative care services for non-cancer
      populations. Participants had contact primarily with district nurses, general
      practitioners and Macmillan nurses (specialist nurses). Few other services were
      received. A number of important issues arose from the data, indicating that lay
      carers in particular were not always receiving the information and support they
      needed in order to be effective caregivers.

PMID- 12419994
TI  - Pilocarpine for radiation-induced xerostomia in head and neck cancer.
AB  - This article examines the use of pilocarpine hydrochloride for radiation-induced
      xerostomia in patients with head and neck cancer. Four randomized controlled
      trials involving 401 patients met the authors' predefined inclusion criteria and
      were critically appraised. Three studies used topical pilocarpine as a mouthwash.
      Outcome measurements were both quantitative and qualitative. The studies reported
      statistically significant differences in favour of pilocarpine-stimulated
      treatment groups. Subjective improvements in feelings of oral dryness, speaking
      and chewing were reported in all studies. However, sample sizes varied and in all
      cases sampling methods were poorly defined. The pilocarpine doses tested produced
      side effects, but those reported were easily tolerated. The persistent findings
      of symptomatic improvement following pilocarpine use merit consideration, but
      there is insufficient evidence from these studies alone to generalize results to
      the wider population.

PMID- 12419995
TI  - A study of the experiences of women living with HIV/AIDS in Uganda.
AB  - This small descriptive study investigated the experiences of Ugandan women living
      with a diagnosis of human immunodeficiency virus/acquired immunodeficiency
      syndrome (HIV/AIDS), exploring what assisted them to cope and identifying their
      future concerns. A purposeful sample of seven HIV-positive women was accessed
      through two indigenous non-governmental organizations in Eastern Uganda. Single
      semi-structured interviews were conducted on location. Following analysis of the
      narrative data, three principal aspects of their experiences emerged: loss and
      adversity, constructive living, and future uncertainties. Loss and adversity
      encompassed bereavements, multiple psychosocial losses and physical suffering.
      Constructive living related to the ability to adopt positive living activities,
      rebuilding shattered lives, sometimes from the brink of despair. Since the
      participants were all mothers, future concerns focused on child care anxieties.
      Stress and uncertainty surrounding HIV testing of children was also evident.
      Despite the cultural contrast, many of the findings were remarkably similar to
      those documented in Western literature. The women related their experiences with
      an absence of self-pity or resentment. Resilience, resourcefulness and hope were
      typically, perhaps instinctively, demonstrated.

PMID- 12419996
TI  - Nurses' responses to death and dying: a need for relentless self-care.
AB  - This article examines the lived experiences of nurses responsible for
      administering care to dying patients. To achieve this, the article explores the
      notion of 'relentless self-care' and why this is an important feature of
      palliative nursing practice (Renzenbrink, 1998), even though for many nurses,
      their feelings of loss must remain hidden (Doka, 1989). Because of this, nurses
      try to protect themselves from distressing symptoms by distancing themselves from
      death. Consequently, nurses may locate dying patients in side-rooms and hand over
      part of their caring role to relatives (Sudnow, 1967; Wakefield, 1996, 1999). In
      view of these responses, the final part of the article will attempt to offer a
      way forward for the nursing profession, by examining why nurses should treat
      their own feelings of loss as being analogous to those of a bereaved relative.

PMID- 12419997
TI  - The interaction and phosphorylation of tropomodulin by protein kinase Calpha in
      N/N 1003A lens epithelial cells.
AB  - PURPOSE: Tropomodulin, a tropomyosin and actin-binding protein stabilizes
      tropomyosin-actin filaments and is important in maintaining the elongated shape
      of lens fiber cells. In this study the role of PKCalpha-catalyzed phosphorylation
      of tropomodulin is determined. METHODS: The interaction of PKCalpha and
      tropomodulin was measured by immunoprecipitation after activation with either
      phorbol ester at 200 nM for 60 min or 10 ng/ml EGF for 15 min. Tropomodulin
      phosphorylation was determined after co-immunoprecipitation using an in vitro
      [gamma-32P] PKC activity assay and by specific reaction with antiphosphothreonine
      antisera. Changes in tropomodulin interaction with tropomyosin or with the
      cytoskeleton were measured in a gel overlay assay and by association with a
      "Triton-insoluble" fraction. RESULTS: Both phorbol ester and EGF caused an
      increased interaction of PKCalpha with tropomodulin. Following activation of
      PKCalpha by phorbol ester or by EGF there was an increased phosphorylation of
      tropomodulin on threonine residues. The phosphorylation of tropomodulin did not
      affect interaction with tropomyosin as measured by a gel overlay assay. However,
      there was an increased association of tropomodulin with the "Triton-insoluble"
      cytoskeletal fraction. CONCLUSIONS: Activation of PKCalpha by EGF causes an
      increased phosphorylation of tropomodulin which results in an increase in
      tropomodulin association with cytoskeletal components. This establishes a signal
      pathway by which EGF induced activation of PKCalpha alters the interaction of
      lens cytoskeletal proteins.

PMID- 12419998
TI  - Brachial plexus: normal anatomy and pathological conditions.

PMID- 12419999
TI  - Miliary lung disease revisited.
AB  - This article reviews the high-resolution computed tomography imaging features of
      miliary pattern, a characteristic radiologic manifestation of diffuse
      micronodular lung disease. The most common entities with this pattern are miliary
      tuberculosis, pneumoconiosis, sarcoidosis, metastases, and hypersensitivity
      pneumonia. According to the distribution of the nodules in relation to the
      secondary lobule, high-resolution computed tomography findings divide miliary
      patterns into 3 groups: centrilobular, perilymphatic, and random presentation.
      The radiologic features that help in the differential diagnosis are discussed.

PMID- 12420000
TI  - Pericardium: anatomy and spectrum of disease on computed tomography.

PMID- 12420001
TI  - Current status of multidetector computed tomography urography in imaging of the
      urinary tract.

PMID- 12420002
TI  - Understanding people who smoke and how they change: a foundation for smoking
      cessation in primary care, part 2.
AB  - The purpose of this 2-part article is to develop an understanding of people who
      smoke and how they change as a foundation for the delivery of smoking cessation
      interventions in primary care. Central to our approach is the transtheoretical
      model of change (TMC). The TMC is an evidence-based model of behavior change that
      has been developed and tested during the past 2 decades by Prochaska and his
      colleagues in the context of smoking cessation. We use a review of the
      literature, in-depth interviews of people who successfully quit smoking, and our
      experience applying the TMC in the context of primary care and a smoking
      cessation clinic to explore the clinical work of smoking cessation. This is part
      2 of the article "Understanding People Who Smoke and How They Change: A
      Foundation for Smoking Cessation in Primary Care." Part 1 describes the
      theoretical information known about smoking cessation: why smoking is a powerful
      behavior, the scientific background of the TMC, and the building-block constructs
      of the TMC. The first section of part 2 is a review of the Public Health Service
      clinical practice guideline, Treating Tobacco Use and Dependence, published in
      2000. The second chapter of part 2 is a discussion of clinical assessments and
      strategies for working with smokers grounded in the Public Health Service
      practice guideline, our understanding of people who smoke, and the TMC. Woven
      throughout are transcripts of interviews with 4 people in which they describe
      their experiences smoking and their pathways to cessation.

PMID- 12420003
TI  - Hobson's choice?

PMID- 12420004
TI  - Bilateral maxillary and mandibular fourth molars.

PMID- 12420007
TI  - Further statistics in dentistry: Part 1: Research designs 1.
AB  - This new series of articles is designed to supplement, rather than replace, the
      material contained in the earlier series on statistics in dentistry published in
      the British Dental Journal and subsequently made available in book form.(1) With
      the increasing availability of calculators, personal computers and computer
      statistical software packages, the need for details of the 'nuts and bolts' of
      statistical theory has diminished, but the need for an understanding of how and
      when such theory should be applied, and how studies should be designed to make
      best use of it, has probably increased. It is with these thoughts in mind that
      this new series is being offered.

PMID- 12420008
TI  - Gardner's syndrome - a case report.
AB  - Gardner's syndrome is the association of multiple colonic polyps (familial
      adenomatous polyposis coli - FAP) with sebaceous cysts and jaw osteomas. The
      significance of this dominantly inherited condition to the dentist is that the
      colonic polyps usually undergo malignant change by the fourth decade and the
      extra-intestinal lesions may be apparent before those in the bowel. As such,
      early detection of multiple jaw osteomas and/or multiple sebaceous cysts
      (particularly on the scalp) may lead to appropriate further investigation and
      treatment which might be life saving. Diagnosis of this condition also has
      implications for other family members.

PMID- 12420013
TI  - Inter- and intra-operator reliability of the recording of occlusal contacts using
      'occlusal sketch' acetate technique.
AB  - OBJECTIVES: To develop a simple way of recording occlusal contacts with proven
      inter- and intra-operator reliability. SETTING: Clinical skills laboratory in the
      University Dental Hospital of Manchester. MATERIALS AND METHODS: The marked
      static occlusal contacts of 20 sets of models were recorded in a pseudo-clinical
      situation, by three dentists and in addition by one dentist on two occasions
      using a schematic representation of the dental arch - the 'occlusal sketch'.
      RESULTS: The median of Kappa agreement for inter- and intra-operator reliability
      was almost perfect. CONCLUSIONS: The occlusal sketch is a simple, inexpensive and
      easy way of recording the results of an occlusal examination using marking
      papers.

PMID- 12420014
TI  - Patient preferences in a preliminary study comparing an intra-oral lubricating
      device with the usual dry mouth lubricating methods.
AB  - OBJECTIVE: To compare an intra-oral device to relieve oral dryness with the other
      methods of lubricating the mouth at night. DESIGN: Multidisciplinary single blind
      randomised cross over study. SETTING: The subjects were drawn from patients
      attending a dry mouth clinic. MATERIALS AND METHODS: Thirty-four dentate subjects
      attended on five occasions at intervals of 4 weeks. At the first visit the teeth
      were scaled and impressions were recorded. The device was fitted either on the
      second or the fourth visit. At all visits samples were taken of the resting and
      stimulated saliva for volumetric analysis and the dry mouth score recorded. Data
      were collected from the lubrication timings and the questionnaire. RESULTS: Ten
      water, nine saliva substitute and ten sugar-free chewing gum lubricators
      completed the study. There were 27 female and two male subjects with an average
      age of 62 years. Nine out of 10 of those lubricating with chewing gum preferred
      wearing the device (P = 0.037). After the device wearing period the subjects'
      self assessment of mouth dryness (P = 0.056), speech (P = 0.009) and swallowing
      (P = 0.031) were more favourable when compared with the alternative lubrication
      with 66% preferring the intra-oral device to their alternative method of
      lubrication. CONCLUSIONS: The majority of the subjects preferred wearing the
      device at night compared with their normal method of lubrication. Subjects'
      perception of dryness, speech and swallowing became closer to the clinician's
      assessment after wearing the device.

PMID- 12420015
TI  - Factors associated with amalgam restorations in Taiwan.
AB  - OBJECTIVE: This study investigated the prevalence of and factors associated with
      amalgam restorations of posterior teeth in Taiwan. METHOD: The authors analyzed
      the dental data regarding direct restorations of posterior teeth from the
      National Health Insurance Research Database of 1997, which was the first
      nationwide data available. The chi-square test and analysis of variance was used
      to compare the characteristics of the teeth, patients, dentists, and dental
      treatment settings between amalgam and composite restorations. The multivariate
      analysis was applied to obtain the Generalized Estimating Equation estimation for
      associations of multiple factors with amalgam restorations, taking into account
      the intra-individual correlation of teeth restored. RESULTS: Amalgam was used in
      53.3% of the direct restorations of posterior teeth. When all the important
      factors were assessed simultaneously, characteristics significantly associated
      with more amalgam restorations were: dentists aged 43 years and above, patients
      aged 1-22 years, primary molars, two- or three-surface cavity, regions with
      higher number of population served per dentist, and dental clinic. CONCLUSION:
      Doctors' age, patients' age, type of dental treatment settings, population served
      per dentist, type of tooth, and number of surfaces restored were significantly
      associated with amalgam restorations in Taiwan.

PMID- 12420020
TI  - Perceived cognitive deficits, emotional distress and disability following
      whiplash injury.
AB  - OBJECTIVES: To describe the pattern of perceived cognitive deficits in patients
      with whiplash injury, to examine the relation between perceived cognitive
      deficits and disability, and to examine the determinants of perceived cognitive
      deficits in patients with whiplash injury. PARTICIPANTS: A total of 81
      individuals participated in the study. There were 29 patients (13 men, 16 women)
      with a diagnosis of whiplash, grade I or II. Patients with work-related soft
      tissue injuries (n=24) and nonclinical controls (n=28) were included as
      comparison groups. METHODS: Participants completed measures of perceived
      cognitive deficits, pain severity, depression, anxiety and pain-related
      disability. RESULTS: Both patient groups scored significantly higher than the
      nonpatient control group on the measure of perceived cognitive deficits, but did
      not differ significantly from each other. Perceptions of cognitive deficits were
      significantly correlated with pain-related disability. A hierarchical regression
      examining the relative contribution of anxiety, depression and pain showed that
      only anxiety and depression contributed significant unique variance to the
      prediction of perceived cognitive deficits. DISCUSSION: The potential benefits of
      focusing interventions on the management of anxiety and depression in the
      rehabilitation of patients with whiplash injuries are discussed.

PMID- 12420021
TI  - The role of health anxiety among patients with chronic pain in determining
      response to therapy.
AB  - Considerable research suggests that health anxiety (HA) influences the response
      of patients with chronic pain to pain and treatment. The present investigation
      extends the current understanding of HA and explores whether it affects how
      patients respond to a common therapeutic intervention, namely instructions to
      reduce pain behaviour. Sixty-five patients with chronic pain completed measures
      of pain, anxiety and cognition following an active occupational therapy session
      in which they were specifically instructed either to inhibit or reduce pain
      behaviour, or to carry out the session as they normally would. Regression
      analyses revealed that those with higher levels of HA experienced greater
      anxiety, somatic sensations and catastrophic cognitions during therapy than those
      with lower levels of HA. The regression analyses also revealed a consistent trend
      for an interaction between HA and instructional set; when those with higher HA
      reduced their pain behaviour, they subsequently reported greater anxiety, and
      more somatic sensations and catastrophic thoughts than when they carried out the
      session as they normally would. In contrast, only those with lower HA had a
      tendency to benefit from reducing pain behaviour, reporting lower state anxiety
      and fewer somatic sensations during the session than those who did not reduce
      their pain behaviour. The results suggest that HA should be taken into
      consideration during treatment.

PMID- 12420022
TI  - Pain in patients with panic disorder: relation to symptoms, cognitive
      characteristics and treatment outcome.
AB  - OBJECTIVE: Although there has been a link between certain types of pain, notably
      chest pain, and panic disorder, the relation between pain and panic disorder has
      not been systematically evaluated. In the present study, the relation between
      pain symptoms (headache, chest pain, stomach pain, joint pain) and the clinical
      presentation of patients with panic disorder was evaluated. HYPOTHESES: Pain was
      generally hypothesized to be related to increased symptoms of anxiety, panic
      relevant cognitive domains and treatment outcome. In terms of specific pain
      domains, headache and chest pain were expected to be more closely related to
      anxiety-related symptoms. PARTICIPANTS AND METHODS: Patients (n=139) meeting the
      criteria of the Diagnostic and Statistical Manual of Mental Disorders - Fourth
      Edition for panic disorder completed a set of standardized clinician-rated and
      self-reported measures. Moderator analyses were used in a subset of these
      patients completing a treatment outcome study. RESULTS: Approximately two-thirds
      of the participants endorsed at least one current pain symptom. The hypotheses
      were partially supported, with pain being associated with higher levels of
      anxiety and depression symptoms, as well as panic frequency. Pain was also
      related to several cognitive features, including anxiety sensitivity and panic
      appraisals. Headache and chest pain were more highly associated with anxiety
      symptoms than was joint pain. Cognitive measures did not mediate the relation
      between anxiety and pain, and pain did not significantly moderate outcome in
      response to cognitive-behavioural therapy. CONCLUSIONS: Co-occurring pain
      symptoms appear to be more highly related to phenomenology than to treatment
      response in patients with panic disorder.

PMID- 12420023
TI  - Can pain-related fear be reduced? The application of cognitive-behavioural
      exposure in vivo.
AB  - Although cognitive-behavioural treatments of patients with chronic pain generally
      are reported to be effective, customization might increase their effectiveness.
      One possible way to customize treatment is to focus the intervention on the
      supposed mechanism underlying the transition from acute to chronic pain
      disability. Evidence is accumulating in support of the conjecture that pain
      related fear and associated avoidance behaviours are crucial in the development
      and maintenance of chronic pain disability. It seems timely to apply this
      knowledge to the cognitive-behavioural management of chronic pain. Two studies
      are presented here. Study 1 concerns a secondary analysis of data gathered in a
      clinical trial that was aimed at the examination of the supplementary value of
      coping skills training when added to an operant-behavioural treatment in patients
      with chronic back pain. The results show that, compared with a waiting list
      control, an operant-behavioural treatment with or without pain-coping skills
      training produced very modest and clinically negligible decreases in pain-related
      fear. Study 2 presents the effects of more systematic exposure in vivo treatment
      with behavioural experiments in two single patients reporting substantial pain
      related fear. Randomization tests for AB designs revealed dramatic changes in
      pain-related fear and pain catastrophizing. In both cases, pain intensity also
      decreased significantly, but at a slower pace. Differences before and after
      treatment revealed clinically significant improvements in pain vigilance and pain
      disability.

PMID- 12420024
TI  - Etiology and outcome of acute liver failure: experience from a liver
      transplantation centre in Montreal.
AB  - BACKGROUND: Acute liver failure is a rare condition in which massive liver injury
      is associated with the rapid development of hepatic encephalopathy. Although
      viral hepatitis and drug-induced liver injury are the most common causes, no
      specific etiology is found in a substantial proportion of cases reported from
      Europe and the United States. AIM: To determine the etiology and outcome of
      patients with acute liver failure in the authors' institution. PATIENTS AND
      METHODS: The charts of 81 consecutive patients admitted to Saint-Luc between 1991
      and 1999 were reviewed. RESULTS: The etiology was viral in 27 cases (33.2%),
      toxic or drug-induced in 22 (27.2%), of unknown origin in 22 (27.2%) and due to
      various causes in 10 (12.3%) (autoimmune, vascular, cancer). Of the 81 patients,
      16% survived without liver transplantation, and 84% died or underwent liver
      transplantation. Survival without liver transplantation differed according to the
      mode of presentation: the survival rate was 27% in patients with hyperacute liver
      failure, 7% in those with acute liver failure and 0% in those with subacute liver
      failure. Among the 38 patients who underwent liver transplantation, survival one
      year after transplantation was 71%. In the 30 patients who died without liver
      transplantation, the main causes of death were cerebral edema and sepsis.
      CONCLUSIONS: Acute liver failure is associated with a high mortality, and liver
      transplantation is the treatment of choice. In a significant proportion of cases,
      the etiology remains undetermined and is probably related to yet unidentified
      hepatotropic viruses.

PMID- 12420025
TI  - Resource utilization for acute lower gastrointestinal hemorrhage: the Ontario GI
      bleed study.
AB  - OBJECTIVES: Acute lower gastrointestinal hemorrhage (LGIH) is a common indication
      for hospitalization. However, there are few published studies of related health
      care resource utilization. Resource utilization, length of stay (LOS) and direct
      medical costs were characterized in a cohort of patients admitted for
      nonmalignant LGIH to centres in Ontario. METHODS: Consecutive admissions for LGIH
      were identified at four Ontario hospitals. Profiles of resource utilization, LOS
      and estimates of direct medical costs were compiled through detailed chart review
      and adaptation of an administrative database. All centres were participants in
      the Ontario Case Cost Project. Linear regression models of log-transformed data
      were constructed to identify demographic variables predictive of LOS and case
      cost. RESULTS: Among 124 patients enrolled (mean age 58.8 years) the average case
      cost was dollars 4832 (SD dollars 7187) for 7.5 days in hospital (SD 12.0).
      Diverticular disease was the bleeding source most often identified (34.6%),
      followed by hemorrhoids (13.7%) and ischemic colitis (9.7%). Older age and
      comorbid illness, specifically coronary artery disease (CAD), were associated
      with both increased LOS and higher case cost in univariate regression analyses.
      Age persisted as the lone independent predictor of LOS in the multivariate model
      (P<0.05, R2=0.076), and age and CAD were both independent predictors of cost
      (P<0.05, R2=0.109) in a stepwise multiple linear regression analysis. Neither sex
      nor nonsteroidal anti-inflammatory drug use predicted LOS or cost. CONCLUSIONS:
      Admissions for acute LGIH are associated with significant resource utilization,
      particularly among elderly patients with CAD.

PMID- 12420026
TI  - Systemic amyloidosis: a rare presentation of mesenteric angina.
AB  - A 64-year-old man presented with an eight-month history of increasing
      postprandial epigastric pain and a 15 kg weight loss. Computed tomography of the
      abdomen, panendoscopy and mesenteric angiography failed to explain the cause of
      the patient's mesenteric angina. Systemic amyloidosis involving intestinal small
      vasculature without larger arterial involvement was diagnosed at autopsy after
      the patient died of an asystolic cardiac arrest. Mesenteric angina without
      evidence of ischemic enteritis or pseudo-obstruction is a rare manifestation of
      amyloidosis.

PMID- 12420027
TI  - What can we learn from cost-of-illness studies?

PMID- 12420028
TI  - Motion - prophylactic banding of esophageal varices is useful: arguments for the
      motion.
AB  - Variceal hemorrhage is a frequent complication of cirrhosis and is associated
      with a high mortality rate, especially in patients with decompensated liver
      disease. Endoscopy is useful in identifying factors that predict a high
      likelihood of bleeding, including large varices and red colour signs. Endoscopic
      rubber band ligation has superseded sclerotherapy in the prevention of both
      recurrent hemorrhage and the first episode of bleeding, because it causes fewer
      complications and requires fewer sessions to eradicate varices. It has been
      proven to be more effective than nontreatment in the primary prophylaxis against
      variceal hemorrhage. There is extensive literature that has found that band
      ligation is more effective than beta-adrenergic receptor antagonists at
      preventing the first variceal hemorrhage. There is ongoing debate about the
      relative merits of these two approaches, but the available evidence supports the
      conclusion that band ligation is the treatment of choice in the primary
      prevention of variceal bleeding. Trials of combined medical and endoscopic
      therapy are eagerly awaited, and the author suspects that it may prove to be more
      effective than either modality alone.

PMID- 12420029
TI  - Motion - prophylactic banding of esophageal varices is useful: arguments against
      the motion.
AB  - Bleeding from esophageal varices leads to substantial morbidity and mortality.
      Despite advances in pharmacological and endoscopic therapy, as well as general
      supportive care, the mortality rate associated with acute variceal hemorrhage has
      not improved significantly over the past two decades. Prophylactic therapy with
      nonselective beta-blockers or long acting nitrates reduces the incidence of
      variceal bleeding in patients with cirrhosis, is cost effective and may improve
      survival. Surgical portosystemic shunting reduces the risk of bleeding but is
      associated with significant operative mortality and a high risk of portosystemic
      encephalopathy. Endoscopic sclerotherapy causes adverse effects in a large
      proportion of patients and is, therefore, not suitable for primary prophylaxis of
      bleeding. Although variceal band ligation is effective in reducing the rate of
      bleeding and is safer than sclerotherapy, it has not been shown to provide a
      survival advantage compared with beta-blockers. A significant reduction in the
      rate of variceal bleeding with band ligation, compared with beta-blockers, was
      shown in only one study. Beta-blockers offer several advantages, including low
      cost, ease of use and safety. The available data do not yet support the
      prophylactic use of variceal band ligation, and this procedure should be reserved
      for patients who are either unwilling or unable to take beta-blockers. It is
      hoped that additional large, multicentre trials of band ligation versus beta
      blockers will examine the efficacy, cost effectiveness and impact on quality of
      life among patients with cirrhosis.

PMID- 12420030
TI  - Motion - patients with primary sclerosing cholangitis should undergo early liver
      transplantation: arguments for the motion.
AB  - Primary sclerosing cholangitis (PSC) is a condition of unknown etiology that
      causes progressive inflammation, fibrosis and obliteration of the intrahepatic
      and extrahepatic biliary tree. There is no medical cure, and ursodeoxycholic acid
      and other drugs have not been shown to affect the natural history of the disease.
      Endoscopic dilation is of value only in the relief of symptoms and complications
      related to dominant strictures. Cholangio- carcinoma occurs in a substantial
      minority of cases, especially those with ulcerative colitis and cirrhosis, and is
      often not clinically apparent before surgery. There are no good serologic tests
      for early cancers. Because this tumour has such a dismal prognosis, some
      authorities recommend that liver transplantation be undertaken before its
      development. This procedure is the only curative option for PSC, and excellent
      survival rates have been reported. There is evidence that early transplantation,
      before end stage liver disease or cholangiocarcinoma have developed, improves the
      survival and quality of life of patients with PSC. Because it is the only
      procedure of proven benefit, patients with PSC should be considered for liver
      transplantation early in the course of the disease.

PMID- 12420031
TI  - Motion - patients with primary sclerosing cholangitis should undergo early liver
      transplantation: arguments against the motion.
AB  - Liver transplantation is an accepted form of treatment for patients with primary
      sclerosing cholangitis (PSC) and can provide long term survival.
      Cholangiocarcinoma occurs in 10% to 20% of patients with PSC, is difficult to
      diagnose and has a poor prognosis. It has been proposed that liver
      transplantation be undertaken early in the course of the PSC, before cancer
      develops. Such a proposal would have significant implications for the method of
      assigning priority to patients awaiting liver transplantation. Other patients on
      the waiting list would experience further delays, while there is no proven
      benefit for PSC patients. Few patients with this disease are removed from the
      waiting list because they developed cancer. If one were to state that PSC
      patients warrant special consideration because of the hypothetical risk of
      cholangiocarcinoma, the same argument could be applied to patients with hepatitis
      C and other causes of cirrhosis, who are at increased risk of hepatocellular
      carcinoma. The transplant allocation system is applied in an equitable fashion to
      patients with a large variety of liver diseases. Alteration of this system to
      benefit a small number of patients with PSC would violate the principles on which
      it was created, and cannot be justified.

PMID- 12420032
TI  - Motion - the available treatments for hepatitis C are cost effective: arguments
      for the motion.
AB  - The treatment of hepatitis C has evolved over the past decade, and a combination
      of interferon (IFN), pegylated or standard type, and ribavirin is now
      acknowledged as the therapy of choice. Questions remain, however, about the
      duration of treatment and which patients are the most likely to benefit from
      therapy. Cost effectiveness analyses (CEAs) have been employed to answer these
      questions. Before the results can be interpreted appropriately, however,
      clinicians must make themselves aware of the underlying assumptions and the
      nature of the 'reference' case. Moreover, certain parameters, including quality
      of-life evaluations, may not be easily translated from one jurisdiction to
      another. The costs and benefits of treatment are often very sensitive to such
      factors as patient age, viral load, histological severity and the viral genotype.
      Randomized controlled clinical trials, and the CEAs on which they are based, have
      shown that combination therapy is more cost effective than IFN monotherapy, and
      that both are cost effective compared with no treatment. Ongoing research on the
      use of pegylated IFN, weight-adjusted dosing of ribavirin, and the treatment of
      relapsers and nonresponders will provide valuable data that could be incorporated
      into future CEAs. Health care resources are vast, but not limitless. Therefore,
      health care providers need to become aware of how best to allocate resources to
      the general population. CEAs can facilitate this process by determining which
      treatment strategies are likely to yield the greatest clinical benefits without
      excessive expenditures.

PMID- 12420033
TI  - Motion - the available treatments for hepatitis C are cost effective: arguments
      against the motion.
AB  - Hepatitis C is a prevalent infection in North America. However, the natural
      history of hepatitis C virus (HCV) infection in the general population is not
      fully understood. Available cohort-based studies suggest that only a relative
      minority of patients develop significant liver disease, such as cirrhosis and/or
      hepatocellular carcinoma. Other studies, mostly conducted based on referral
      patients with established disease, portray much more serious consequences of HCV
      infection. Although a substantial improvement has been made in the treatment for
      HCV, the overall impact of antiviral therapy in altering the natural course of
      HCV infection remains uncertain. Therapeutic trials involve narrow selection
      criteria that would exclude the majority of hepatitis C patients in the
      community, and are conducted in ideal settings that may not be generalizable to
      the average practice setting. Demographic groups that are at high risk of
      developing severe liver disease include older male patients who consume alcohol.
      In contrast, antiviral therapy is more effective in young and female patients and
      those who do not drink alcohol. Thus, patients who appear to be successfully
      treated may not be those for whom clearance of the virus would be beneficial.
      Cost-effectiveness studies published to date have not been able to fully address
      the complex and heterogeneous matrix of the factors that influence the natural
      history of HCV infection and treatment response. In summary, there is a
      significant degree of uncertainty about many assumptions that are necessary in
      creating computer models to estimate the cost-effectiveness of HCV therapy. When
      interpreting the results of cost effectiveness analyses regarding the treatment
      of HCV infection, it is important to be aware of the underlying assumptions that
      are incorporated in the model and the data on which they are based. Given these
      limitations, vis- -vis the expense, toxicity and yet limited effectiveness of the
      currently available antiviral agents, one should not blindly accept a conclusion
      that treatment for hepatitis C is cost effective.

PMID- 12420034
TI  - Motion - all patients with NASH need to have a liver biopsy: arguments for the
      motion.
AB  - Previously regarded as an obscure disorder, nonalcoholic steatohepatitis (NASH)
      has recently emerged as an important chronic liver disease. NASH is within a
      spectrum of disorders characterized by excessive accumulation of fat in the
      liver, including simple hepatic steatosis (fatty liver), inflammation and
      necrosis (steatohepatitis), and fibrosis. Collectively, the disorders are called
      nonalcoholic fatty liver disease (NAFLD). Estimates of the prevalence of these
      individual conditions are suspect because liver biopsy is required for definitive
      diagnosis and is not generally performed. Although these conditions have
      traditionally been thought of as diseases of obese women, and are frequently
      associated with diabetes mellitus and hypertriglyceridemia, they have also been
      identified in lean men. Insulin resistance appears to be a common factor. These
      conditions are difficult to distinguish from each other clinically, and no
      biochemical or radiological test reliably establishes the diagnosis. A ratio of
      serum aspartate to alanine aminotransferase levels of less than one can
      distinguish NAFLD from alcoholic liver disease, but this is a nonspecific
      finding. Fatty infiltration imparts a diffuse echogenicity to the liver at
      ultrasonography, but this test cannot easily distinguish fat from fibrous tissue
      or identify cases of NASH. Only histological examination can establish the
      diagnosis of NASH, grade its severity, determine the prognosis and guide
      treatment.

PMID- 12420035
TI  - Motion - all patients with NASH need to have a liver biopsy: arguments against
      the motion.
AB  - Most cases of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic
      steatohepatitis (NASH) are suspected on the basis of the exclusion of viral,
      autoimmune, metabolic and genetic causes of chronic liver disease in patients
      with chronic elevation of aminotransferase enzymes. However, the definitive
      diagnosis of NASH requires liver biopsy. Valuable blood tests include hepatitis B
      and C serology, iron profile, alpha 1-antitrypsin phenotype, ceruloplasmin,
      antinuclear antibody and antismooth muscle antibody, and serum protein
      electrophoresis. If these tests are negative or normal, and if there are no
      symptoms or signs of chronic liver disease, it is unlikely that a specifically
      treatable liver disease would be discovered at biopsy. The prevalence of NAFLD in
      the general population appears to be approximately 20%, and 2% to 3% of people
      have NASH. There is no proven specific therapy for the spectrum of nonalcoholic
      liver disease; therefore, the management of the patient with NASH is not likely
      to be changed after histological assessment. Bleeding, sometimes fatal, and other
      complications requiring hospitalization can occur, and liver biopsies should not
      be undertaken without clear clinical indications. The high cost of undertaking
      histological assessment of all persons with asymptomatic elevations of liver
      enzymes cannot be justified in view of the risks and limited clinical benefits.

PMID- 12420039
TI  - The price of life.

PMID- 12420040
TI  - Coenzyme Q(10) and congestive heart failure: what is the verdict?

PMID- 12420041
TI  - Functional status and quality of life following non-Q wave myocardial infarction.
AB  - OBJECTIVE: To review the literature on the management of non-Q wave myocardial
      infarction (NQWMI) with regard to functional status and quality of life outcomes.
      BACKGROUND: Recent trials have raised the question of whether all patients with
      NQWMI should undergo an early routine invasive investigation versus a noninvasive
      ischemia-driven approach. Previous studies examined the management of NQWMI and
      focused on mortality and recurrent myocardial infarctions. Little is known about
      whether a routine invasive approach affects functional status and quality of
      life. METHODS: A MEDLINE search of the English-language literature from 1981 to
      2001 was performed using the terms myocardial infarction, NQWMI, risk
      stratification, prognosis and management. This search was supplemented by
      narrowed searches of subheadings and surveys of references cited in review
      articles and book chapters. Emphasis was placed on those studies that included
      information on the outcomes of quality of life and functional status. RESULTS:
      Earlier studies suggest that there is little benefit to a routine invasive
      strategy. These studies demonstrated an increase in mortality and periprocedural
      complications. In older studies there is some evidence that suggests routine
      revascularization improves the secondary end points of quality of life,
      functional status and patient satisfaction. Two recent trials have suggested that
      with newer technology, including stenting and the use of antithrombotic and
      antiplatelet agents, there may be a mortality advantage to a routine invasive
      approach. Substantial functional status and quality of life advantages to this
      strategy are possible and expected, but little data exists to support this in the
      literature. CONCLUSION: The optimal strategy for the management of patients with
      NQWMI is still unclear despite recent studies suggesting improved outcomes with a
      routine invasive strategy. There is a growing body of literature on the impact of
      therapy on functional status and quality of life in many disciplines. The impact
      of routine revascularization on functional status and quality of life requires
      evaluation in specific, randomized, controlled trials.

PMID- 12420042
TI  - Regional variation in the management of acute myocardial infarction in the
      province of Quebec.
AB  - BACKGROUND: Previous studies have shown that there are differences in acute
      myocardial infarction (AMI) management in Canada and in the United States.
      However, there has been little research to evaluate regional variations in AMI
      treatment and outcomes for Canadian patients. OBJECTIVE: To determine whether
      regional variation in the management of AMI in Quebec has an impact on patient
      mortality and morbidity. PATIENTS AND METHODS: Discharge summary and physician
      claims databases for 76,012 patients with AMI were used between January 1, 1988
      and December 31, 1995 to build 16 cohorts for the administrative regions of the
      province of Quebec. The clinical characteristics, prescription medications,
      cardiac procedure use, readmissions for cardiac complications and mortality
      across the different regions were compared. RESULTS: After adjusting for age and
      sex, discharge prescriptions resulted in the following ranges: angiotensin
      converting enzyme inhibitors 34% to 46% of patients, acetylsalicylic acid 49% to
      77%, beta-blockers 32% to 54%, calcium channel blockers 25% to 48%, lipid
      lowering drugs 4% to 16% and nitrates 76% to 86%. Procedure use varied
      considerably across the province during the initial 10 days post-AMI
      (catheterization 3% to 28%; percutaneous coronary intervention 1% to 8%, and
      coronary artery bypass surgery 0 to 2%), as well as one year after discharge (27%
      to 47%, 8% to 17%, and 6% to 12%, respectively). Some variation was observed for
      cardiac complications after one year (unstable angina 9% to 21%; congestive heart
      failure and recurrent myocardial infarction, no major variation). However, there
      was no significant regional variation observed for one-year and three-year
      mortality rates (19% to 22% and 27% to 31%, respectively). CONCLUSIONS: There was
      marked regional variation in the rates of discharge prescriptions for cardiac
      medications and cardiac procedures in patients who have had an AMI in Quebec.
      These results suggest that the type of treatment received for an AMI depends on
      the region in which the patient lives. This variation appeared to affect
      readmission rates for unstable angina, but had no impact on mortality or other
      cardiac complications post-AMI.

PMID- 12420043
TI  - The sympathoadrenal system mediates the blood pressure and cardiac effects of
      human coagulation factor XII-related "new pressor protein".
AB  - OBJECTIVE: To investigate the major cardiovascular effects of human plasma "new
      pressor protein" (NPP) and how the adrenal medulla contributes to these effects.
      METHODS: NPP was injected into bioassay rats intravenously, and the effects on
      blood pressure and cardiac function were investigated. Acute adrenal medullectomy
      (2MDX), alpha- and beta-adrenergic blockade and plasma catecholamine levels were
      also used to evaluate the role of the sympathoadrenal system in mediating the NPP
      effects. RESULTS: NPP significantly raised systolic blood pressure (SBP) and mean
      arterial pressure but not diastolic blood pressure (DBP), with no significant
      change in total peripheral resistance. Heart rate, cardiac output and stroke
      volume rose by 16%, 53% and 36%, respectively. Plasma catecholamines increased
      massively, notably adrenaline, raising the adrenaline to noradrenaline ratio from
      about 4:1 to 18:1. 2MDX attenuated the increments of SBP and heart rate by more
      than 90% and more than 70%, respectively, implicating the adrenal medulla. Beta
      adrenergic blockade (propranolol) potentiated the NPP-induced increase of SBP and
      DBP, but not that of heart rate. Combined alpha- and beta-adrenergic blockade
      (phentolamine and propranolol) blocked the rise in SBP, DBP and heart rate.
      CONCLUSIONS: NPP's hypertensive action is attributable mainly to increases in
      systolic blood pressure, heart rate and cardiac output (an increase in heart rate
      and stroke volume) with massive release of adrenal medullary catecholamines. Such
      effects suggest a novel axis between coagulation factor XII and the
      sympathoadrenal system, the cardiovascular effects of which are controlled by
      combined alpha- and beta-adrenergic blockade, but not by angiotensin-converting
      enzyme inhibition. Clinical relevance depends on whether NPP is formed in vivo in
      thrombotic states.

PMID- 12420044
TI  - Human coagulation factor XII-related "new pressor protein": role of PACAP in its
      cardiovascular and sympathoadrenal effects.
AB  - OBJECTIVE: To investigate the role of pituitary adenylate cyclase-activating
      polypeptide (PACAP)-38 and -27 as possible mediators of the actions of "new
      pressor protein" (NPP), which is related to coagulation factor XIIa, on blood
      pressure (systolic and diastolic blood pressure) and heart rate, and on the
      release of adrenal medullary catecholamines. METHODS: Adult male Wistar bioassay
      rats (n=8 to 18 per group) were anesthetized with inactin (100 mg/kg
      intraperitoneally), ganglion-blocked with pentolinium (19.2 mg/kg subcutaneously)
      and treated with captopril (2.5 mg/kg intravenously). Human NPP was injected at
      20 L plasma equivalent per approximately 300 g of rat intravenously, and both
      PACAPs were injected at 10 g/kg intravenously. The systolic and diastolic blood
      pressure and heart rate responses to all of these agonists were determined using
      a MacLab/8 system. Arterial plasma adrenaline and noradrenaline were determined
      by high performance liquid chromatography with fluorimetric detection. Responses
      to NPP, the PACAPs and a specific PACAP antagonist were compared to assess the
      PACAPs as potential mediators of the cardiovascular effects of NPP. RESULTS:
      PACAP-38 mimicked the effects of NPP on systolic and diastolic blood pressure and
      heart rate more closely than did PACAP-27. Generally, NPP raised diastolic blood
      pressure and heart rate, and especially plasma adrenaline and noradrenaline, more
      impressively in degree and duration than that achieved by the PACAPs. The
      antagonism of PACAP receptors (PAC-1) significantly reduced the cardiovascular
      effects of NPP by 30% to 50%. CONCLUSIONS: PACAP-38, especially, may qualify as a
      potential mediator of the cardiovascular and sympathoadrenal effects of NPP but
      incomplete inhibition of NPP activity by PAC-1 receptor antagonism and the
      observed differences all suggest that PACAP is not the only peptide involved.
      Such peptidic mediation of the effects of NPP may explain the potentiation of NPP
      by captopril and why NPP remains effective after cholinergic blockade. These data
      suggest that PACAP is involved in a novel axis between NPP, cardiac function and
      blood pressure that resists angiotensin-converting enzyme inhibition. Any
      endogenous production of NPP could raise clinically relevant issues pertaining to
      therapy with ACE inhibitors.

PMID- 12420045
TI  - Increased AT(2)R protein expression but not increased apoptosis during
      cardioprotection induced by AT(1)R blockade.
AB  - BACKGROUND: The angiotensin II type 2 receptor (AT2R) is considered to be
      antigrowth and to mediate apoptosis in several cell types. Whether AT2R
      upregulation, associated with angiotensin II type 1 receptor (AT1R) blockade and
      cardioprotection after ischemia-reperfusion (IR), might not result in increased
      cardiomyocyte (CM) apoptosis has not been documented. OBJECTIVES: To determine
      whether increased AT2R protein expression, during AT1R blockade after acute IR,
      is associated with no increase in CM apoptosis. MATERIALS AND METHODS: The
      recovery of left ventricular (LV) mechanical function after acute IR (30 min of
      ischemia, 40 min of reperfusion) was measured in isolated Langendorff rat hearts
      following pretreatment with the AT1R antagonist candesartan (CN) (CN 10 nmol/L)
      for 40 min before ischemia. The authors established with an initial dose-response
      curve using escalating concentrations of CN that 10 nmol/L abrogated
      vasoconstriction induced by angiotensin II (0.1  mol/L). AT1R and AT2R protein
      expression (Western immunoblot), CM apoptosis (terminal deoxynucleotidyl
      transferase-mediated 2'-deoxyuridine 5'-triphosphate nick end-labelling assay and
      nuclear morphology) and apoptotic markers (Bax, Bcl-2, caspase-3, p53) were
      assessed in LV tissue. RESULTS: Compared with IR controls, CN improved peak
      systolic pressure, LV developed pressure and positive dp/dt, and increased AT2R
      (not AT1R) protein, but did not change the level of apoptosis or the expression
      of Bax, Bcl-2, caspase-3 or p53. CN also increased AT2R protein after ischemia
      alone but did not change CM apoptosis or expression of the markers. CONCLUSIONS:
      Increased AT2R protein expression during AT1R blockade after IR in the isolated
      Langendorff rat heart is associated with cardioprotection but no increase in CM
      apoptosis.

PMID- 12420046
TI  - Left ventricular pseudoaneurysm.

PMID- 12420047
TI  - Heart failure--are we making progress?

PMID- 12420048
TI  - Role of S2 receptors in the stimulatory effect of serotonin on hemopoietic bone
      marrow stem cells.
AB  - Studies by the method of splenic exocolonies with serotonin receptor blockers
      methysergide and cyproheptadine showed that S2 receptors are involved in the
      stimulatory effect of serotonin on hemopoietic bone marrow stem cells.

PMID- 12420049
TI  - Doxorubicin modulates biological effects of ATP in bone marrow cells in vitro.
AB  - ATP activity in mouse bone marrow cells was studied in in vitro experiments. ATP
      in physiological and supraphysiological concentrations stimulated blebbing of the
      plasma membrane. Subacute administration of doxorubicin (inductor of oxidative
      stress) decreased cell sensitivity to ATP, which corresponded to changes in
      membrane lipid peroxidation.

PMID- 12420050
TI  - Blockade of hyperpolarization-activated channels modifies the effect of beta
      adrenoceptor stimulation.
AB  - Experiments on rats showed that blockade of hyperpolarization-activated currents
      moderates tachycardia induced by beta-adrenoceptor agonist isoproterenol and
      potentiates the increase in stroke volume produced by this agonist. Electrical
      stimulation of the vagus nerve against the background of isoproterenol treatment
      augmented bradycardia and increased stroke volume. Blockade of hyperpolarization
      activated currents followed by application of isoproterenol moderated vagus
      induced bradycardia and had no effect on the dynamics of stroke volume.

PMID- 12420051
TI  - Mechanisms underling the effects of adaptogens on erythropoiesis during
      paradoxical sleep deprivation.
AB  - We studied the effects of adaptogens extracts of Siberian ginseng, Rhodiola
      rosea, bergenia, and ginseng and pantohematogen, on erythropoiesis after
      paradoxical sleep deprivation. Adaptogens stimulated bone marrow erythropoiesis
      in the early stage, but decreased the count of bone marrow erythrokaryocytes 3-7
      days after treatment. The effect of adaptogens on erythropoiesis is associated
      with modulation of the state of brain neurotransmitter systems followed by
      changes in functional activity of cells in the hemopoiesis-inducing
      microenvironment.

PMID- 12420052
TI  - Correction of L-NAME-induced disturbances in DNA synthesis and free radical
      oxidation in respiratory organs of newborn albino rats with dalargin.
AB  - Intraperitoneal injections of L-NAME (5 injections, 9.3 x 10(-5) mol/kg each) to
      albino rats from the 2nd to 6th day of life inhibited DNA synthesis in epithelial
      cells, stimulated this process in bronchial smooth muscle cells, and intensified
      free radical oxidation in the lungs. Dalargin administered in a dose of 1.4 x 10(
      7) mol/kg 30 min after treatment with NG-nitro-L-arginine methyl ester abolished
      its effect on epithelial cells and attenuated changes in smooth muscle cells.
      Correcting activity of dalargin is associated with its antiradical and
      antioxidant properties.

PMID- 12420053
TI  - Immunotropic effects of gonadotropin-releasing hormone analog under conditions of
      emotional painful stress.
AB  - Surfagon, a synthetic analog of gonadotropin-releasing hormone injected before
      emotional painful stress dose-dependently changed the number of antibody
      producing cells in rats and phagocytic and functional activities of neutrophils
      in mice. In castrated animals this peptide increased all studied parameters. This
      suggests that sex steroids are not involved in the realization of these effects.

PMID- 12420054
TI  - Osteovisceral afferent interrelations.
AB  - The effects of stimulation of intraosseus receptors on visceral afferent
      reactions were studied in experiments on anesthetized cats. Stimulation of
      intraosseus receptors decreased the thresholds of evoked potentials recorded in
      the cerebral cortex in response to stimulation of the heart, stomach, and
      duodenum. It was concluded that stimulation of intraosseus receptors during
      osteopathy (e. g. increased intraosseus pressure) increases sensitivity of
      visceral sensory systems and can provoke the development of pain syndromes. It is
      important that visceral pain in such cases should be considered as a symptom of
      organ pathology, but not as a manifestation of vertebrovisceral syndrome.

PMID- 12420055
TI  - Glutathione-dependent system of antioxidant defense in the placenta in preterm
      delivery.
AB  - Components of the antioxidant defense system in placental tissues were studied in
      women with normal pregnancy and full-term delivery and women with spontaneous
      abortions at 28-36 weeks. In women with spontaneous abortions glutathione
      peroxidase activity in placental tissues increased and the content of SH
      compounds decreased, which led to exhaustion of the antioxidant defense system.
      Glutathione-S-transferase activity also decreased, which attests to impaired
      detoxifying function of the placenta.

PMID- 12420056
TI  - Structural modification of collagen during nonenzymatic glycosylation in vitro.
AB  - We studied changes in collagen resistance to proteases and formation of new
      fluorescent compounds during in vitro nonenzymatic glycosylation. The inhibitory
      effects of guanidine chloride and catalase were different: guanidine chloride
      inhibited cross-linking in collagen molecules, while catalase inhibited the
      formation of chromophore-containing compounds.

PMID- 12420057
TI  - Effect of fibrinogen on functional activity of blood leukocytes.
AB  - Fibrinogen intensified luminol-dependent chemiluminescence of blood leukocytes
      stimulated with opsonized zymosan. It is hypothesized that fibrinogen stimulates
      and prolongs functional activity of leukocytes during inflammation.

PMID- 12420058
TI  - Mechanisms of hemopoiesis in athymic mice.
AB  - Cell elements of peripheral blood and bone marrow and splenic hemopoiesis were
      studied in athymic BALB/c mice (nude or thymectomized animals). In athymic
      animals lympho- and erythropoiesis were suppressed, while granulocyto- and
      monocytopoiesis were activated. These changes were more pronounced in nude mice.

PMID- 12420059
TI  - Possible involvement of aqueous medium in distant signal transmission from
      immunoactive dipeptides.
AB  - Possible involvement of aqueous medium in distant signal transmission to target
      cells through solitons without formation of the ligand-receptor complexes is
      discussed. Temperature dependence of IR spectra for dipeptide and amino acid
      solutions in the far and near IR regions are presented, which prove principal
      possibility of such processes.

PMID- 12420061
TI  - Modulation of orientation and exploratory behavior in mice during development of
      humoral immune response.
AB  - We demonstrated opposite changes in the orientation and exploratory behavior of
      (CBAxC57Bl/6)F(1) mice in the open field test during the formation of primary
      humoral immune response. These changes depended on initial behavioral activity:
      the exploratory behavior was suppressed in animals with initially high activity,
      stimulated in animals with medium reaction, and remained unchanged in mice with
      initially low activity. The detected changes in the exploratory behavior during
      the formation of immune response were leveled in the total population (not
      divided by initial behavioral status).

PMID- 12420060
TI  - Pine resin and Biopin ointment: effects on repair processes in tissues.
AB  - The effects of Biopin (ointment containing pine resin) used in the treatment of
      burns, wounds, and pyoinflammatory processes on cell composition of the wound
      surface (smears) and granulation tissue were studied on rats. In vitro
      antibacterial activity of the drug was also evaluated. At the early stage of
      inflammation Biopin modulated the nonspecific and inhibited specific cell immune
      response, normalized hemodynamics in the inflammation focus, activated synthetic
      processes in the wound, and was effective towards anaerobes and bacilli.

PMID- 12420062
TI  - Long-term self-maintenance of hemopoietic precursors in bone marrow culture
      derived from tumor necrosis factor-deficient mice is not a result of neoplastic
      transformation.
AB  - In long-term bone marrow cultures derived from tumor necrosis factor-deficient
      mice the total cell production and the total duration of hemopoiesis are
      increased (the latter is comparable with mouse life span). Telomerase activity in
      cells of nonadherent fraction of long-term bone marrow cultures from tumor
      necrosis factor-deficient mice increases with time and peaks after 1-year
      culturing. Karyotyping of nonadherent and adherent cells of long-term bone marrow
      cultures revealed instability of nonadherent cells and hyperploidy of the stromal
      sublayer cells, which attested to the presence of a neoplastic transformation.
      However, cell differentiation is not blocked in long-term bone marrow cultures.
      The nonadherent fraction of long-term bone marrow cultures from tumor necrosis
      factor-deficient mice cannot be cultured without exogenous growth factors; in the
      presence of growth factors the cells proliferate, but cannot be passaged; stromal
      sublayer cells cannot be passaged as well. Intraperitoneal and intravenous
      injections of nonadherent cells to recipients with normal and radiation
      attenuated immunity induced no tumor growth. Hence, peculiar dynamics of long
      term bone marrow cultures from tumor necrosis factor-deficient mice cannot be
      explained by neoplastic transformation.

PMID- 12420063
TI  - Functional asymmetry of the brain and bone marrow in hemopoiesis in
      (CBAxC57Bl/6)F(1) mice.
AB  - The role of functional asymmetry of the brain and bone marrow in the formation of
      exogenous 8-day splenic CFU was studied in (CBAxC57Bl/6)F(1) mice. The intensity
      of hemopoiesis depended on the motor asymmetry of donors and recipients of bone
      marrow cells and differed for bone marrow transplantations from the right and
      left femoral bones.

PMID- 12420064
TI  - Effect of hydrocortisone on spontaneous and mitogen-dependent activity of
      peripheral blood lymphocytes in some vertebrates.
AB  - The effect of hydrocortisone on functional activity of peripheral blood
      lymphocytes in different vertebrates during ontogeny was studied by the blast
      transformation test. Hydrocortisone in a dose of 100 mg/kg inhibited functional
      activities of T and B lymphocytes in vitro stimulated by mitogens. This
      inhibitory effect was observed in both young and adult animals. However
      proliferative activity of concanavalin A-dependent blood T suppressors in rats
      increased, especially in adult animals (by 3.5 times). Hence, hydrocortisone
      produced different effects on functional activity of peripheral blood lymphocytes
      in the studied species, and these effects are dose- and species-dependent.

PMID- 12420065
TI  - Effect of genotype on behavioral and hormonal components of sexual activation of
      male mice.
AB  - Possible relationship between changes in behavior and hormone response to a sex
      stimulus was studied by comparing these parameters in mice of 10 genotypes. All
      males spent more time near the wall during the very first 5 min after appearance
      of the female. Strains with the minimum (DBA/2, C57Bl/6J) and maximum (SWR, CBA)
      time spent near the wall were distinguished. Genotypical differences in hormone
      response during sexual activation were detected. Considerable increase in
      testosterone concentration in the peripheral blood was observed in males of 6 of
      the 10 mouse strains 30 min after appearance of the female. Mouse strains with
      contrast sexual activation were distinguished. No correlation between behavioral
      and hormonal response was detected. The detected genetically determined
      variability of the behavioral and hormonal components of sexual activation is
      determined by hereditary peculiarities of central mechanisms regulating the
      studied functions.

PMID- 12420066
TI  - Diagnostic value of tumor markers Cyfra 21-1 and neuron-specific enolase in
      analysis of pleural fluid.
AB  - The diagnostic value of tumor markers Cyfra 21-1 and neuron-specific enolase in
      blood serum and pleural fluid in differential diagnosis of pleural exudation in
      cancer patients and patients with nontumor pleurisy was evaluated. The most
      pronounced changes were characteristic of Cyfra 21-1. In patients with pleurisy
      caused by malignant tumors the degree and incidence of increased Cyfra 21-1
      concentrations in the serum and pleural fluid were higher than in patients with
      pleural exudation of nontumor origin. These data attest to high diagnostic
      sensitivity and specificity of Cyfra 21-1. Complex measurements of the marker in
      the serum and pleural fluid will improve diagnosis of pleural exudation of
      tumorous etiology.

PMID- 12420067
TI  - Antioxidant activity of blood plasma in individuals with neoplasms.
AB  - In 3 groups of patients with neoplasms plasma antioxidant activity was measured
      by the yield of TBA-reactive products generated in lecithin-Fe(2+) model system.
      Patients with laryngeal, tongue, oropharyngeal, oral, and laryngopharyngeal
      tumors showed lower plasma antioxidant activity compared to patients with breast,
      lung, and bronchial cancer (p<0.005). In women with breast cancer plasma
      antioxidant activity increased with age (p<0.05). Possible mechanisms underlying
      these fluctuations are discussed. It is assumed that plasma antioxidant activity
      is relatively stable and modulates body resistance to tumor process.

PMID- 12420068
TI  - Some biochemical characteristics and water exchange in human articular cartilage
      in osteoarthrosis.
AB  - Rearrangement of intra- and intermolecular bonds in collagen molecule,
      disaggregation of proteoglycans and their elimination from cartilage involved in
      osteoarthrosis are responsible for water accumulation and its increased mobility
      in cartilage.

PMID- 12420069
TI  - Proliferative processes in the epidermis of patients with atopic dermatitis
      treated with thymodepressin.
AB  - Proliferative activity of the epidermis in skin biopsy specimens from patients
      with atopic dermatitis before and during therapy with thymodepressin
      (immunosuppressant) was studied by immunohistochemical method (by expression of
      Ki-67 antigen). The number of Ki-67-positive keratinocyte nuclei in atopic
      dermatitis considerably surpassed the corresponding parameter in intact skin
      (32.46 +/- 3.06% vs. 8.73 +/- 1.28%, p<0.05). Two 10-day courses of
      thymodepressin (0.1% solution, 1 ml intramuscularly) for 30 days reduced the
      number of Ki-67-positive keratinocyte nuclei to 20.78 +/- 3.36%. Clinical
      improvement was also achieved (sleep became normal, itching decreased, erythema
      and desquamation also decreased or disappeared). These findings suggest that
      disorders in keratinocyte proliferation are an important component in the
      pathogenesis of atopic dermatitis and confirm high efficiency of thymodepressin
      in the treatment of this condition.

PMID- 12420070
TI  - Dyshormonal disorders in gout: experimental and clinical studies.
AB  - A total of 107 patients with primary gout were examined. The pituitary-gonadal
      system is imbalanced in male patients with gout, which manifests by
      hyperproduction of progesterone and suppressed production of testosterone and
      estradiol. These changes are more pronounced in patients with chronic arthritis
      and proteinuric nephropathy. Similar dyshormonal changes are experimentally
      simulated in rats by induction of purine metabolism disorders. Exogenous
      injection of androgens in experimental hyperuricemia led to normalization of
      purine metabolism and hormonal homeostasis.

PMID- 12420071
TI  - Effect of Vilon and Epithalon on glucose and glycine absorption in various
      regions of small intestine in aged rats.
AB  - Vilon (Lys-Glu) and Epithalon (Ala-Glu-Asp-Gly) administered orally for 1 month
      improved transport characteristics of the small intestine in aged rats. Vilon
      enhanced passive glucose accumulation in the serous fluid in inverted sac made
      from the distal region of the small intestine, while Epithalon enhanced this
      process in the medial region. Vilon stimulated active glucose accumulation in the
      serous sac of the medial small intestine, Epithalon - in the proximal and distal
      small intestinal segments. Glycine absorption increased only in the proximal
      intestinal segment under the effect of Epithalon.

PMID- 12420072
TI  - Effects of short peptides on thymocyte blast transformation and signal
      transduction along the sphingomyelin pathway.
AB  - Immunomodulating effects of synthetic peptides Vilon (Lys-Glu), Epithalon (Ala
      Glu-Asp-Gly), and Cortagen (Ala-Glu-Asp-Pro) and possible involvement of the
      sphingomyelin signal transduction pathway in their effects in mouse thymocytes
      were studied. Vilon produced the most potent comitogenic effect on thymocyte
      proliferation and modulated comitogenic activity of interleukin-1b. Epithalon was
      less potent, while Cortagen produced no such effects. Vilon produced a more
      pronounced stimulatory effect on sphingomyelinase activity in mouse thymocyte
      membranes compared to Epithalon and Cortagen.

PMID- 12420073
TI  - Circadian variations of melatonin concentration in saliva and blood content of
      immunocompetent cells in healthy individuals.
AB  - Salivary content of melatonin and parameters of the immune status were studied in
      young healthy individuals. Morning and evening levels of melatonin showed
      different correlations with some immunity parameters. It was assumed that the
      degree and type of correlation between the immune system and melatonin depend on
      the phase of circadian cycle, which should be considered during evaluation of
      immunoendocrine status.

PMID- 12420074
TI  - Chronoenterography: monitoring of circadian rhythm of the intestinal evacuatory
      function.
AB  - A new method for studies of circadian rhythm of the bowel evacuatory function in
      humans is proposed: chronoenterography. The existence of optimal and pessimal
      phases in the circadian rhythm of enteral evacuatory activity was proven using
      this method. The optimal phase is associated with 3-4-fold reduced chronorisk of
      enteral arrhythmia. A new classification of enteral arrhythmia and its stages and
      severity is proposed.

PMID- 12420075
TI  - Directional left-sided asymmetry of adrenals in experimentally domesticated
      animals.
AB  - Directional left-sided asymmetry of the adrenals was typical of black and silver
      foxes, American minks, and gray rats selected by their behavior. In domesticated,
      but to a greater extent, in aggressive animals, the weight of the left adrenal
      and the width of its medulla and cortex markedly surpassed the corresponding
      parameters of the right adrenal. In aggressive animals enlargement of the left
      adrenal cortex was associated with widening of the zona reticularis, while in
      domesticated animals with enlargement of the zona fasciculata.

PMID- 12420076
TI  - Ultrastructural peculiarities of intranuclear inclusions in some target cells
      during endotoxin shock.
AB  - Intranuclear inclusions detected in hepatic, renal, and cerebral cells during
      endotoxemia can be subdivided into true and pseudo inclusions. True inclusions
      have filamentous and crystalline structure and are rarely found in control
      animals. However, the number of true inclusions increases during pathology and
      can serve as a marker of molecular pathology in the cells provoked by endotoxin.

PMID- 12420078
TI  - A new method for evaluation of safety of antiarrhythmic drugs.
AB  - A new method for preclinical evaluation of safety of antiarrhythmic drugs is
      proposed. During chronic stress, class I antiarrhythmic preparations increased
      mortality of test animals. By contrast, class II-IV antiarrhythmic agents and
      antioxidants produced no significant effect on mortality of experimental mice.
      These data agree with published results of multicenter studies.

PMID- 12420077
TI  - Mathematical analysis of subtypes of muscarinic receptors modulating heart and
      respiratory rhythms in rats.
AB  - Mathematical analysis of the data obtained in experiments on the whole organism
      revealed that blockade of M(2)-cholinergic receptors increased both heart and
      respiratory rates. Blockade of M(1)-cholinergic receptors alleviated tachycardia
      induced by M(2)-receptor blockade.

PMID- 12420079
TI  - The epidemiology of salt and hypertension.
AB  - The relationship between salt intake and blood pressure was once highly
      controversial. Early comparisons of populations did support the salt hypothesis
      but were difficult to interpret because of unmeasured confounding variables.
      However, the INTERSALT project, published in 1988 overcame many of these problems
      and reported within - and between - population gradients of sodium excretion and
      blood pressure or the rise in blood pressure with advancing age. Of the five long
      term follow-up studies of salt intake and cardiovascular disease, two suggested
      that a low salt intake might be harmful. These studies are however open to much
      criticism. The three other studies reported positive relationships between salt
      intake and stroke or heart attack. Whilst there is little doubt that salt
      restriction lowers blood pressure in hypertensive patients, there remains some
      uncertainty whether any effect is seen in normotensives. The effects, if present,
      are small (reducing systolic pressure by about 2 mmHg) and not clinically useful,
      although if applied on a population-wide basis they might reduce the prevalence
      of hypertension by about 17 %. In many countries food producers and food
      standards agencies are beginning to respond by cutting the salt content of
      processed foods.

PMID- 12420080
TI  - Hypoglycemia associated autonomic failure.
AB  - Intensively treated patients with diabetes have a three-fold increased risk of
      severe hypoglycemic episodes with an attendant four percent mortality. These
      findings, unfortunately undermine attempts to achieve normoglycemia in diabetic
      patients. It has been proven that antecedent hypoglycemia is a major factor
      responsible for blunting metabolic, neuroendocrine and also autonomic responses
      to subsequent hypoglycemia. Diabetic patients with good glycemic control become
      unable to recognize symptoms of hypoglycemia. Lack of symptoms, or hypoglycemia
      unawareness, is part of the syndrome called hypoglycemia associated autonomic
      failure. This syndrome also includes inadequate neuroendocrine hormonal responses
      and reduced glycemic thresholds for counterregulatory hormonal secretion. Factors
      regulating the magnitude of hypoglycemia associated autonomic failure include
      antecedent duration and frequency of hypoglycemia, prior episodes of exercise,
      and autonomic neuropathy. Understanding the pathophysiology of this syndrome will
      provide a foundation for therapy aimed at preventing severe hypoglycemia during
      intensive metabolic control. This article will review our current understanding
      of the mechanisms responsible for hypoglycemia associated autonomic failure.

PMID- 12420081
TI  - QT prolongation in patients with Type 2 diabetes and microalbuminuria.
AB  - The link between microalbuminuria and premature death in Type 2 diabetes is not
      fully explained by conventional cardiovascular risk factors. We aimed to
      determine if QT prolongation and/or dispersion are linked to microalbuminuria in
      patients with Type 2 diabetes and to investigate their associations with other
      risk factors. We have studied asymptomatic patients with Type 2 diabetes with no
      clinical evidence of coronary disease (43 with microalbuminuria matched with 43
      normoalbuminuric patients). Rate-corrected maximum QT interval (QT(c) max) was
      greater in the microalbuminuric group [mean (SD): 450 (23) vs 440 (20) ms(1/2), p
      = 0.046] as was the proportion of patients with QT(c) max > 440 ms (67 % vs 38 %,
      p = 0.01). Rate-corrected QT dispersion (QT(cd)) was similar in the two groups
      [57 (21) vs 53 (23) ms(1/2), p = 0.41]. Linear regression analysis showed that
      QT(c) max and/or QT(cd) were not strongly linked to albumin excretion rate but
      more strongly to factors associated with microalbuminuria such as blood pressure
      and factor XIIa. Our findings support the hypothesis that QT prolongation and
      microalbuminuria have common determinants in Type 2 diabetes. QT prolongation may
      contribute to the increased mortality observed in microalbuminuric subjects with
      Type 2 diabetes.

PMID- 12420082
TI  - Prospective investigation of autonomic cardiac neuropathy in diabetes mellitus.
AB  - Forty-five patients with clinically manifest diabetes mellitus were investigated
      (25 male, 20 female, 48 +/- 10 yrs, 14 diabetes type 1, 31 type 2). Duration of
      manifestation was 12.2 +/- 9.7 yrs.Vibration thresholds and thermal thresholds
      were assessed. Respiratory sinus arrhythmia (RSA) was measured during deep
      respiration at 6/min. The QTc-interval was assessed according to Bazett's
      formula. MIBG-SPECT was carried out in all 45 cases. Patients with abnormal MIBI
      perfusion scintigraphy had previously been excluded from the study. RSA was
      abnormal in 12/45 patients. The MIBG-SPECT was abnormal in 28/45 cases with dorso
      septal lack of activity. No difference was seen between type 1 and 2 diabetics
      with regard to either vibration and thermal thresholds or RSA and MIBG-SPECT.
      Abnormal MIBG-SPECT was correlated with vibration threshold and abnormal heart
      RSA tests but not with abnormality in QTc. The mean QTc-interval was 419 +/- 24
      ms (QTc normal in 36, abnormal > or = 440ms in 9). It was longer in female than
      in male patients. There exists no significant correlation of QTc-interval results
      with either heart rate variability or MIBG-SPECT. The QTc-interval is not a
      sensitive parameter of autonomic cardiac denervation.

PMID- 12420083
TI  - Continuous cardiac baroreceptor measurement during tilt in healthy elderly
      subjects.
AB  - INTRODUCTION: Abnormalities of cardiac baroreceptor sensitivity (BRS) may
      contribute towards the high prevalence of orthostatic hypotension and falls in
      the elderly. Most mathematical analyses used to determine BRS in the time or
      frequency domains assume a stationary physiological state and cannot be performed
      under dynamic change and therefore are not valid during tilt. We describe a new
      method of estimating BRS during tilt. METHODS: Twenty-five healthy elderly
      volunteers with a mean age of 69 +/- 3 years underwent head-up tilt to 70
      degrees, within 5 s, 3 times on 2 separate visits. Blood pressure (BP) and heart
      rate were recorded continuously using a Finapres beat-to-beat BP monitor and
      surface ECG. A continuous estimate of BRS was obtained by combining beat-to-beat
      linear regression with Legendre polynomial interpolation. RESULTS: The values for
      supine BRS prior to tilt on the two visits, calculated using the new regression
      method (10.4 +/- 8.2 ms/mmHg and 12.5 +/- 9.7 ms/mmHg) were similar to those
      using fast Fourier analysis (10.7 +/- 6.7 ms/mmHg and 12.4 +/- 7.1 ms/mmHg). A
      rapid fall in BP and pulse interval along with cardiac BRS values occurred with
      tilt within the first 20 s of onset on both visits and remained reduced up to 90
      s post tilt (p < 0.01). CONCLUSIONS: The values for cardiac BRS obtained using
      continuous time domain analysis agree well with those calculated using spectral
      methods and can be used to assess the dynamic changes in BRS to rapid
      perturbations in BP such as that occur with tilt.

PMID- 12420084
TI  - Valsalva maneuver suggests increased rigidity of cerebral resistance vessels in
      familial dysautonomia.
AB  - In familial dysautonomia (FD), cerebral autoregulation (CA) must adjust cerebral
      blood flow to extreme and rapid fluctuations in systemic blood pressure.
      Compromised CA during systemic blood pressure (BP) fluctuations might contribute
      to central autonomic dysfunction in FD. To evaluate CA during rapid BP changes,
      we monitored heart rate (HR), radial artery BP and middle cerebral artery blood
      flow velocity (CBFV), using transcranial Doppler sonography, in eight FD patients
      and twelve age-matched controls in supine position at baseline and during a
      Valsalva maneuver (VM, 40 mmHg expiratory pressure for 15 seconds). The best of
      four VM recordings was analyzed. We calculated two autoregulation parameters.
      CA(II) reflects BP related autoregulatory CBFV increase in late phase II of VM.
      CA(II) = [(CBFV(II late)-CBFV(II early))/CBFV(II early)]/[(BP(II late)-BP(II
      early))/BP(II early)]. CA(IV) reflects BP and HR related autoregulatory CBFV
      increase in phase IV of VM. CA(IV) =
      (CBFV(IV)/CBFV(I))/(BP(IV)/BP(I))/(HR(IV)/HR(I)). Baseline systemic BP, but not
      CBFV, was higher in the patients than the controls. During VM, both groups had
      similar CBFV and BP values, but CAIV and especially CA(II) were significantly
      lower in the patients than the controls. We have documented that FD patients
      maintain stable CBFV during rapid BP fluctuations associated with early and late
      phase II and phase IV of VM suggesting that small intracerebral vessels of FD
      patients are less responsive to rapid systemic blood pressure fluctuations. To
      compensate for decreased sympathetic vascular innervation, we propose that FD
      patients may alter the myogenic component of CA by vessel wall thickening
      resulting in increased rigidity of intracerebral resistance vessels. The
      resulting vasoconstriction would allow maintenance of normal baseline CBFV in
      spite of chronic recumbent hypertension.

PMID- 12420085
TI  - Serum prolactin levels in Parkinson's disease and multiple system atrophy.
AB  - The hypothalamic-pituitary axis (HPA) may be involved early in multiple system
      atrophy (MSA), whereas in idiopathic Parkinson's disease (IPD) its impairment
      seems to be correlated with motor disability. The release of prolactin (PRL) is
      mediated through the HPA and an increase in PRL levels is documented during
      stress. In this study, we investigated basal and erect PRL levels to assess
      whether basal PRL or changes in PRL levels after 60 degrees head-up tilt (HUT;
      orthostatic stress) could distinguish between MSA and IPD patients. We studied
      five patients with MSA on levodopa treatment, five levodopa-naive MSA patients,
      nine IPD patients on dopaminergic treatment, six drug-naive IPD patients and six
      normal individuals. PRL levels were measured in the supine position after 30
      minutes rest and during 60 degrees HUT after 5 and 15 minutes. Baseline PRL
      values were significantly lower for patients with IPD than for those with MSA,
      both for levodopa-treated and naive patients ( p < 0.004, estimated decrease 55.1
      %, 95 % CI from 29.4 % to 71.52 %). After orthostatic stress PRL levels were
      increased in healthy individuals after 15 minutes of HUT ( p = 0.044, estimated
      increase 11.5 %, 95 % CI from 0.4 % to 23.8 %), whereas there was no evidence for
      a change of PRL levels in patients with MSA or IPD after 5 and 15 minutes of HUT.
      We also did not find any evidence for a difference in PRL change after HUT
      between MSA and IPD patients. Baseline PRL levels might differentiate between
      early MSA and IPD, being higher in MSA. However, orthostatic stress using HUT
      appears unable to differentiate between MSA and IPD.

PMID- 12420086
TI  - Eye examination-induced syncope Role of trigeminal afferents.
AB  - The role of trigeminal afferents in a patient with eye examination - induced
      syncope was investigated. A head-up tilt test precipitated presyncope with a
      reduced blood pressure. On a separate day, the application of Schirmer's
      lacrimation test strips in each conjunctival sac caused vasodepression and
      cardioinhibition. Topical administration of 0.5 % proparacaine hydrochloride
      produced ocular anesthesia and loss of corneal reflexes. Schirmer's test
      following anesthesia again caused presyncope with reductions in blood pressure
      and heart rate. The supramaximal stimulus to a supraorbital nerve before and
      after topical anesthesia did not affect blood pressure or heart rate. It is
      concluded that trigeminal afferents did not induce vasodepressive syncope in this
      patient. Instead, corticohypothalamic centers may have played an important role.

PMID- 12420087
TI  - Skeletal muscle channelopathies.
AB  - Ion channelopathies have common clinical features, recurrent patterns of
      mutations, and almost predictable mechanisms of pathogenesis. In skeletal muscle,
      disorders are associated with mutations in voltage-gated Na(+), K(+), Ca(2+), and
      Cl(-) channels leading to hypoexcitability, causing periodic paralysis and to
      hyperexcitabilty, resulting in myotonia or susceptibility to malignant
      hyperthermia.

PMID- 12420088
TI  - Cerebral ischemic preconditioning. An experimental phenomenon or a clinical
      important entity of stroke prevention?
AB  - Neurons can be preconditioned by various procedures to resist ischemic events.
      The preconditioning mechanism induced is characterized by a brief episode of
      ischemia that renders the brain more resistant against subsequent longer ischemic
      events. This ischemic tolerance has been shown in numerous experimental models of
      cerebral ischemia. The basic molecular mechanisms of ischemic tolerance are
      largely unknown. During the induction phase N-methyl-O-aspartate and adenosine
      receptors and, possibly, oxygen free radicals and conservation of energy
      metabolism are required. Protein kinases, transcription factors, and immediate
      early genes appear to transduce the signal into a tolerant response. Although the
      mechanism of ischemic tolerance remains uncertain, its discovery provides the
      focus for further understanding of the mechanism of endogenous neuroprotection
      and the potential of novel therapeutic strategies for neuroprotection. Such
      neuroprotective strategies may extend beyond ischemic tolerance to include other
      brain injury states as well.

PMID- 12420089
TI  - Myasthenia mimicking vertebrobasilar stroke.
AB  - The advent of thrombolysis has offered a remarkable opportunity for treatment of
      acute ischemic stroke. Other therapies involving neuro-protection may be
      forthcoming. These treatments, however, are not without risk, making accurate
      diagnosis of stroke all the more important. Several conditions may mimic stroke
      in the emergency department, with myasthenia being an uncommon stroke mimic. We
      present two cases of myasthenia presenting as posterior circulation stroke. In
      one case, the tempo suggested basilar thrombosis. Treatment decisions regarding
      thrombolysis for stroke must be made rapidly. Stroke mimics continue to present a
      diagnostic challenge, myasthenia included. Accurate diagnosis is essential to
      avoid unnecessary hazard, as well as to implement effective treatment for the
      appropriate diagnosis.

PMID- 12420090
TI  - Episodic ataxia type 2. Three novel truncating mutations and one novel missense
      mutation in the CACNA1A gene.
AB  - We analysed the CACNA1A gene, located on chromosome 19p13, in three unrelated
      families and one sporadic case with episodic ataxia type 2 (EA-2). In two of the
      families and the sporadic patient, novel truncating mutations, which disrupt the
      reading frame and result in a premature stop of the CACNA1A protein, were
      identified in exons 14, 16 and 26. In the remaining family, a novel missense
      mutation (H253Y) was found. Of the twenty two EA-2 mutations identified thus far,
      including those of the present study, seventeen are truncating mutations and five
      are missense mutations, all resulting in an EA-2 clinical phenotype.

PMID- 12420091
TI  - Transient Global Amnesia. Evidence against vascular ischemic etiology from
      diffusion weighted imaging.
AB  - The etiology of Transient Global Amnesia (TGA) is still obscure. Diffusion
      Weighted-Imaging (DWI) provides conflicting evidence concerning a possible
      vascular ischemic cause in mesiotemporal structures including the hippocampal
      region. The question remains open whether conflicting observations resulted from
      different observation times. DWI was performed at a time interval with known
      sensitivity for detection of ischemia. Ten patients (5 male, 5 female; mean age
      of 63 +/- 9, range 41-71 years) with typical TGA were investigated at an average
      delay of 18 hours (range 6 to 44 hours) between onset of symptoms and magnetic
      resonance imaging (transversal DW-, T1W- and T2W-MRI). Five patients received
      apparent-diffusion-coefficient (ADC)-mapping. Cerebrovascular studies (ECG, TTE
      and extra/transcranial dopplersonographic and duplexultrasonic investigation) and
      EEG were normal in all patients. DW-MRI-sequences and ADC-maps, if performed,
      were normal in all patients. Conventional T2W-MRI in 3 out of 10 patients showed
      microangiopathic subcortical changes and lacunar strokes of older origin. We
      conclude that TGA does not result from a vascular ischemic etiology in the
      majority of cases.

PMID- 12420092
TI  - Antidisialosyl antibodies in chronic idiopathic ataxic neuropathy.
AB  - Antidisialosyl antibodies were found in two out of 13 patients with chronic
      idiopathic ataxic neuropathy (CIAN) and not in 32 patients with different sensory
      neuropathies of known cause. This finding confirms the association of
      antidisialosyl antibodies and CIAN regardless of the absence of the M band. These
      antibodies may have pathogenic relevance; however, larger series are needed to
      establish their clinical significance.

PMID- 12420093
TI  - Alzheimer's disease and brain infarcts in the elderly. Agreement with
      neuropathology.
AB  - Clarifying the etiology of dementia is one of the most difficult diagnostic
      challenges, especially in the elderly. We examined the accuracy of clinical
      criteria to distinguish Alzheimer's disease (AD) and dementia associated with
      infarcts of the brain, either isolated (vascular dementia) or associated with
      degenerative lesions (mixed dementia). We carried out a prospective clinico
      neuropathological study in a selected series of hospitalized patients. We
      evaluated the clinical aspects of 33 patients aged over 75 years by use of the
      criteria and scores of DSMIII, NINCDS-ADRDA, Loeb and Gandolfo, ADDTC and NINDS
      AIREN and the Hachinski Ischemic Score. The neuropathological diagnosis was
      considered to be the gold standard. When comparing clinical criteria and
      neuropathology, the agreement was moderate for Hachinski's score (0.50) and
      Loeb's score (0.43) and substantial for the ADDTC (0.63) and the NINDS-AIREN
      (0.67). When mixed dementias were excluded, the agreement between all clinical
      criteria and scores and the pathological diagnosis rose to 0.88. Hachinski's
      score was the most sensitive (0.89) and the NINDS-AIREN the most specific (0.86)
      for the diagnosis of vascular dementia. In conclusion, all sets of clinical
      criteria distinguished pure AD from vascular dementia with a high accuracy
      whereas mixed dementia was clinically under-recognized. The NINDS-AIREN criteria
      were the most discriminating for the accurate identification of patients with
      mixed dementia.

PMID- 12420094
TI  - Circadian heart rate variability in Parkinson's disease.
AB  - Parkinson's disease is known to affect the reflex cardiovascular control systems,
      resulting in a suppressed heart rate variability, but present knowledge
      concerning the long-term characteristics of heart rate and heart rate
      variability, e. g. circadian regulation, is limited. We investigated the
      circadian fluctuation of the time domain, frequency domain and some non-linear
      measures of heart rate variability in 44 untreated patients with Parkinson's
      disease and 43 age- and sex-matched control subjects.In the parkinsonian
      patients, the measured power spectral components of heart rate variability (low
      frequency power and high-frequency power) and the SD(1) value of the Poincare two
      dimensional vector analysis, that quantifies the short term beat-to-beat
      variability, were suppressed at night. During the daytime only the SD1 of the
      Poincare was suppressed. The night-to-day-ratios of the heart rate variability
      measures did not differ significantly between the patients and the controls. The
      results indicate that the long-term parasympathetic cardiovascular regulation is
      impaired in untreated patients with Parkinson's disease. The dysfunction is more
      pronounced at night.

PMID- 12420095
TI  - Predictors of cognitive level and depression severity are different in patients
      with left and right hemispheric stroke within the first year of illness.
AB  - Causes of cognitive impairment after stroke are not yet clear because a large
      number of sociodemographic and clinical variables complicate the understanding of
      the phenomenon. We aim to evaluate sociodemographic and clinical predictors of
      cognitive level and depression in subjects with different lesion laterality. We
      assessed 153 right (n = 87) and left (n = 66) unilateral first-ever stroke
      patients within the first year of illness with the Structured Clinical Interview
      for DSM-IV-Patient Edition, the Hamilton Depression Rating Scale, the Hamilton
      Anxiety Rating Scale, the State Trait Anger Expression Inventory, the Barthel
      Index, and the Mini Mental State Examination (MMSE). Sociodemographic variables
      were also measured. Sixty-two (41 %) patients suffered from Major Depression
      (MDD), and 26 (17 %) suffered from Minor Depression (MIND). An univariate
      analysis of variance showed that MMSE scores were different throughout the groups
      of left and right stroke patients with MDD, MIND and without depression. Left
      stroke patients with MDD were more cognitively impaired than all the other
      groups. This result was valid after controlling for the effect of lesion location
      on cognitive level difference between the groups. A series of stepwise multiple
      regression analyses indicated that depression severity was a predictor of
      cognitive level and vice-versa in left hemispheric stroke patients only.
      Moreover, educational level in right hemispheric stroke patients and state-anger
      and number of regions affected in left hemispheric stroke patients were other
      predictors of cognitive level. The study confirms the hypothesis that predictors
      of cognitive level and depression severity are different in subjects with
      different laterality of lesion and that MDD is associated with cognitive
      impairment in left stroke patients.

PMID- 12420096
TI  - Lack of evidence for a role of the myelin basic protein gene in multiple
      sclerosis susceptibility in Sardinian patients.
AB  - A link between myelin basic protein (MBP) polymorphism and multiple sclerosis
      (MS) has been reported in some populations but not in others. We analysed two
      polymorphisms in the 5' flanking region of the MBP exon 1 gene in MS patients
      from the founder population of Sardinia. Using the transmission disequilibrium
      test (TDT), MBP polymorphisms were analysed in 363 singleton MS families. No
      distortion in transmission of the tetranucleotide repeat (ATGG)12 and of the 1116
      1540 nt alleles was found. Moreover, we discovered no epistatic effect of the MBP
      gene on the HLA/MHC DRB1,DQB1, DPB1 loci or on alleles defined by D6S1683 marker
      found to be associated with MS in Sardinians. We concluded that the MBP gene does
      not play a role in MS susceptibility in Sardinians.

PMID- 12420097
TI  - Seventh nerve palsies may be the only clinical sign of small pontine infarctions
      in diabetic and hypertensive patients.
AB  - BACKGROUND: Small brainstem infarctions are increasingly recognized as a cause of
      isolated ocular motor and vestibular nerve palsies in diabetic and/or
      hypertensive patients. This raises the question whether there are also isolated
      7(th) nerve palsies due to pontine infarctions in patients with such risk factors
      for the development of cerebrovascular diseases. METHODS: Over an 11-year-period,
      we retrospectively identified 10 diabetic and/or hypertensive patients with
      isolated 7(th) nerve palsies and electrophysiological abnormalities indicating
      pontine dysfunction. All patients had examinations of masseter and blink
      reflexes, brainstem auditory evoked potentials, direct current electro
      oculography including bithermal caloric testing, and T1- and T2-weighted MRI
      (slice thickness: 4-7 mm). RESULTS: Electrophysiological abnormalities on the
      side of the 7(th) nerve palsy included delayed masseter reflex latencies (4
      patients), slowed abduction saccades (4 patients), vestibular paresis (2
      patients), and abnormal following eye movements (2 patients).
      Electrophysiological abnormalities were always improved or normalized at re
      examination, which was always associated with clinical improvement. MRI revealed
      an ipsilateral pontine infarction in 2 patients. Another 2 had bilateral
      hyperintense intrapontine lesions, and one an ipsilateral cerebellar infarction.
      CONCLUSIONS: Simultaneous improvement or recovery of abnormal clinical and
      electrophysiological findings strongly indicated that both were caused by the
      same actual pontine lesions. A 7(th) nerve palsy may be the only clinical sign of
      a pontine infarction in diabetic and/or hypertensive patients. Such mechanism may
      be underestimated if based on MRI only.

PMID- 12420098
TI  - Posterior reversible encephalopathy syndrome due to severe hypercalcemia.
AB  - Posterior reversible encephalopathy syndrome (PRES) is a leukoencephalopathy
      clinically characterized by headache, altered mental status, visual loss and
      seizures. Neuroimaging demonstrates symmetrical posterior cortical and
      subcortical lesions. The exact pathophysiology is unknown but there is a strong
      association with immunosuppressants and hypertension. We report two cases of PRES
      in normotensive patients with severe hypercalcemia as the only identifiable
      cause. Possible pathophysiological mechanisms are discussed.

PMID- 12420099
TI  - Mutations of the prion protein gene phenotypic spectrum.
AB  - Prion diseases are inherited in 5-15 % of cases. They are classified according to
      changes in the prion protein gene ( PRNP) or conventionally according to
      phenotype as Gerstmann-Straussler-Scheinker disease (GSS), fatal familial
      insomnia (FFI), or familial Creutzfeldt-Jakob disease (fCJD). Point mutations and
      insertions within PRNP form the genetic background. We report the results of a
      systematic analysis of over 500 case reports of patients with PRNP abnormalities.
      We compare clinical, neuropathological and molecular data in five groups, namely
      GSS, FFI, fCJD, base pair insertion (BPI), and all cases collectively. Clinical
      presentation overlaps between mutations, but some have characteristic features
      (e. g. P105L, D178N-129M, T183A). Some mutations, especially in the lack of
      sufficient family history, in earlier phases tend to resemble other
      neurodegenerative disorders like multiple system atrophy, corticobasal
      degeneration or familial diseases such as late-onset spinocerebellar ataxia,
      spastic paraparesis, frontotemporal dementia, or Alzheimer's disease. The codon
      129 polymorphism has a phenotypic influence in inherited prion diseases, as in
      non-genetic forms, but additional factors might be considered as background for
      phenotypic variability.

PMID- 12420100
TI  - Friedreich's ataxia mimicking hereditary motor and sensory neuropathy.
AB  - Four patients from three unrelated families, with clinical and
      electrophysiological findings compatible with the diagnosis of hereditary motor
      and sensory neuropathy, are presented. The molecular analysis showed that the
      affected individuals were homozygous for the mutation in the X25 gene,
      characteristic of Friedreich's ataxia. These patients seem to represent a form of
      Friedreich's ataxia mimicking Charcot-Marie-Tooth disease.

PMID- 12420101
TI  - Immunological assay for assessing the efficacy of glatiramer acetate (Copaxone)
      in multiple sclerosis. A pilot study.
AB  - Recently we described an enzyme-linked immunoadsorbent spot (ELISPOT) assay
      allowing us to define an immunological response profile observed in multiple
      sclerosis patients treated with Copaxone (glatiramer acetate; GA) but not
      untreated subjects [4]. The profile encompasses three criteria, a) reduced
      proliferative response to GA (as observed with a standard primary proliferation
      assay); b) strong in vitro activation of interferon-gamma-producing T cells at
      high concentrations of GA (as detected by interferon-gamma ELISPOT); and c)
      activation of interleukin-4-producing T cells over a wider range of
      concentrations of GA (as detected by interleukin-4 ELISPOT). It is at present
      unknown whether the immunological response to GA correlates with the clinical
      response. To address this question we performed the pilot study reported here. We
      asked the major German multiple sclerosis centres to send us blood samples from
      all GA-treated patients who were going to discontinue treatment because of
      treatment failure. The clinical nonresponders either had an unchanged or
      increased exacerbation rate, or developed a secondary progressive course during
      GA treatment. Over more than one year, we prospectively collected 9 samples from
      clinical non-responders. We compared the immune response to GA of peripheral
      blood mononuclear cells from the 9 clinical nonresponders with 15 clinical
      responders, using a standard proliferation assay combined with ELISPOT assays for
      detection of interferon-gamma and interleukin-4 secreting cells. Thirteen (86 %)
      of the 15 clinical responders met at least 2 of the immunological response
      criteria mentioned above. In contrast, only 2 (22 %) of the 9 clinical
      nonresponders met two of the immunological criteria (p = 0.0006). We conclude
      that the ELISPOT assay may provide a promising additional tool for monitoring the
      treatment response in multiple sclerosis patients treated with GA.

PMID- 12420102
TI  - Apoptosis and leucocyte-endothelium interactions contribute to the delayed
      effects of cryotherapy on tumours in vivo.
AB  - In dermatology, cryotherapy is commonly used to treat benign and malignant skin
      lesions. However, studies investigating the time-course of the direct and delayed
      effects on the microvasculature and subsequent tissue destruction are lacking.
      Amelanotic melanomas (A-Mel-3) were implanted into the dorsal skinfold chamber of
      Syrian Golden hamsters (n=51). Tumour and normal tissue were frozen to -20
      masculine C (cooling rate 150 masculine C/min). Intravital fluorescence
      microscopy was performed to assess microvascular changes and leucocyte
      endothelium interactions up to 24 h. The relative degrees of necrosis and
      apoptosis and the accumulation of leucocytes were investigated by histology and
      immunohistochemistry. Apoptosis was quantified using the TUNEL assay in
      combination with computer-assisted image analysis. After cryotherapy, red blood
      cell velocity (RBCV) decreased in postcapillary venules and tumour vessels,
      whereas functional vessel density (FVD) was significantly reduced in tumour
      vessels as compared with postcapillary venules. Leucocyte-endothelium interaction
      increased first in normal and tumour tissue, and then after 24 h leucocytes
      accumulated in normal tissue close to the tumour margin. Necrosis was induced in
      the cryolesions directly after freezing and remained constant over the entire
      observation period. In contrast, apoptosis increased in the periphery of the
      tumour tissue up to 24 h following cryotherapy. In conclusion, tissue destruction
      by cryotherapy is not only induced by direct necrosis and microvascular stasis,
      but also by the inflammatory infiltrate and subsequent apoptosis. This could be
      an important finding regarding the generation of an immune response.

PMID- 12420103
TI  - Antimelanogenic activity of hydrocoumarins in cultured normal human melanocytes
      by stimulating intracellular glutathione synthesis.
AB  - The antimelanogenic activity of six hydrocoumarins and alpha-tocopherol (alpha
      Toc) in normal human melanocytes was evaluated in both cell culture systems and
      cell homogenates. The inhibitory effects of hydrocoumarins depended upon their
      substituent groups. alpha-Toc and some of the hydrocoumarins inhibited
      melanogenesis in cultured normal human melanocytes, although they did not
      influence melanin synthesis in enzyme solution prepared as cell homogenates. In
      addition, alpha-Toc and the hydrocoumarins stimulated intracellular glutathione
      (GSH) synthesis. In particular, 7-allyl-6-hydroxy-4,4,5,8
      tetramethylhydrocoumarin strongly inhibited melanogenesis and intracellular GSH
      synthesis in normal human melanocytes, more so than alpha-Toc. Furthermore,
      hydrocoumarins exhibited higher scavenging and quenching activities against with
      tert-butyl peroxyl radicals and singlet oxygen species. These results suggest
      that 7-allyl-6-hydroxy-4,4,5,8-tetramethyl hydrocoumarin would be useful as an
      antimelanogenic agent for the prevention or improvement of skin pigmentation
      induced by reactive oxygen compounds and free radicals, and may inhibit
      melanogenesis, including tyrosinase transfer and melanosome differentiation, by
      interrupting melanization by increasing the intracellular GSH content.

PMID- 12420104
TI  - Differential TNFalpha mRNA regulation detected in the epidermis of leprosy
      patients.
AB  - The epidermis is an important site of the immunoinflammatory response in the
      skin. In the present study, the expression of cytokine and ICAM-1 (intercellular
      adhesion molecule-1) genes was evaluated by RT-PCR in the epidermis isolated from
      biopsies from 25 reactional leprosy patients. TNFalpha and IL-6 mRNAs were
      detected in all individuals during the reactional state (reversal reaction or
      erythema nodosum leprosum), IL-8 message was detected in 66.6% and 62.5% of the
      patients, IL-12 mRNA was present in 91.6% and 62.5% and ICAM-1 in 100% and 71.4%,
      respectively. In addition, when skin biopsies were obtained from the same
      patients before and during the reactional episode, an enhancement in cytokine
      mRNA, but not in ICAM-1 mRNA, was observed. Seven patients were also evaluated at
      the onset of reaction and during antiinflammatory treatment. In contrast to a
      preferential decrease in the TNFalpha gene detected in the dermis, during the
      treatment phase, persistent/enhanced TNFalpha mRNA expression was detected in the
      epidermis in six out of the seven patients assessed. This peculiar pattern of
      expression might reflect a differential impact that in vivo antiinflammatory
      therapy has on the epidermis. The present findings indicate that the epidermis
      plays an important role in the local inflammatory response in leprosy and that
      the profile of response detected in the epidermis during the reactions may be
      regulated differently from that in the dermis.

PMID- 12420105
TI  - Natural killer and natural killer-T cells in psoriasis.
AB  - Psoriasis is characterized by a dermal and epidermal infiltrate comprised
      predominantly of CD4(+) and CD8(+) T cells, respectively. These cells behave in
      an antigen-dependent manner, which suggests that psoriasis may be a T-cell
      mediated autoimmune disease. Psoriasis shares certain immunological features with
      recognized autoimmune conditions such as type I diabetes mellitus and multiple
      sclerosis, in both of which a pathogenic role is postulated for natural killer
      (NK) cells and natural killer-like T (NK-T) cells. However, there are few studies
      assessing the role of NK and NK-T cells in psoriasis. We sought to determine
      whether NK and NK-T cells are present in psoriasis. Skin biopsies were taken from
      the active edge of a psoriasis plaque and from uninvolved skin at least 5 cm away
      from involved skin of ten patients with chronic plaque psoriasis. Skin from four
      normal subjects was used as controls. Using an immunoperoxidase technique,
      cryostat sections were stained using antibodies to T-cell markers CD2, CD3, CD4
      and CD8; cutaneous leucocyte associated antigen; NK cell markers CD16, CD56,
      CD57, CD94 and CD158a; and the NK-T cell marker CD161. There were significantly
      more cells expressing T cell markers, NK cell markers CD16, CD57, CD94 and CD158a
      and NK-T cell marker CD161 in involved skin than in uninvolved or normal skin (
      P<0.01). There was no difference in the number of cells expressing CD56. Cells
      expressing NK markers were found most commonly in the papillary dermis
      immediately subjacent to the dermoepidermal junction. Cells expressing CD57 were
      found in significantly higher numbers in the epidermis and reticular dermis of
      involved skin. This study demonstrates that cells expressing NK markers and NK-T
      cell markers are present in plaques of psoriasis. The exact roles of NK and NK-T
      cells in psoriasis are unclear, although they may modulate autoimmune
      inflammation and act as a source of Th(1) cytokines important in the psoriatic
      process.

PMID- 12420107
TI  - IL-10 is unable to downregulate VEGF expression in human activated keratinocytes.

PMID- 12420106
TI  - Upregulation of interleukin-18 expression in mouse primary keratinocytes induced
      to differentiate by calcium.
AB  - Interleukin-18 (IL-18) is an immunomodulatory cytokine that stimulates interferon
      gamma production by T helper cells. Recently, basal keratinocytes have been shown
      to constitutively express IL-18, and IL-18 expression increases in the suprabasal
      keratinocytes in psoriatic lesions. In the study reported here we showed that in
      mouse epidermis, IL-18 immunoreactivity was markedly increased in the granular
      and cornified layers. To further investigate whether differentiated keratinocytes
      synthesize more IL-18, we examined the expression of mouse IL-18 in primary mouse
      keratinocytes induced to differentiate by calcium, an in vitro cell culture
      system mimicking keratinocyte differentiation in the epidermis. We demonstrated
      that IL-18 mRNA and protein in cultured keratinocytes were increased by calcium
      treatment in a time- and dose-dependent manner. The upregulation of IL-18 was
      associated with an increase in keratinocyte differentiation markers, and was
      dependent on the synthesis of new RNAs and proteins. However, the IL-18 protein
      in the cytoplasm was predominantly in the precursor form, and no increase in IL
      18 activity was detected in the culture medium treated with calcium. Furthermore,
      blocking the calcium-induced keratinocyte differentiation with protein kinase C
      inhibitor inhibited the upregulation of IL-18 expression. These findings suggest
      that IL-18 is synthesized in keratinocytes mainly in the inactive precursor form,
      and its expression is upregulated as basal keratinocytes differentiate in the
      epidermis.

PMID- 12420108
TI  - Absent or low expression of T-cell receptor zeta-chain in T cells infiltrating
      human pathological skin conditions.
AB  - The T-cell receptor (TCR) zeta-chain is involved in signal transduction necessary
      for T-cell activation and subsequent proliferation. Expression of the TCR zeta
      chain in vivo has been studied by a variety of technical approaches on different
      cell and tissue specimen. However, the in situ situation concerning the
      expression of the TCR zeta-chain has not yet been investigated on infiltrating T
      lymphocytes in neoplastic and inflammatory cutaneous diseases. In this study, we
      analysed the expression of the TCR zeta-chain in a number of skin tissues
      affected by established inflammatory and neoplastic conditions. Serial sections
      of different tissue specimens were stained immunoenzymatically for CD3 and TCR
      zeta-chain expression. No or at most scarce expression of TCR zeta-chain was
      detectable in the inflammatory and neoplastic skin conditions investigated as
      compared to CD3-positive cells. It is possible that this TCR zeta-chain deletion
      is induced by the skin microenvironment as an effect of local immunoregulatory
      influences. Alternatively, lymphocytes located in the skin may generally not
      express this molecule. In our study, tumour-infiltrating T lymphocytes of CTCL
      were negative for TCR zeta-chain expression. It has been hypothesized that
      downregulation of the TCR zeta-chain on tumour-infiltrating T lymphocytes is a
      mechanism by which neoplastic cells escape the cellular immune response. Our
      findings showing the absence or reduction of TCR zeta-chain expression also in
      inflammatory skin lymphocytic infiltrates is not consistent with a pivotal role
      of the TCR zeta-chain in the process of immune escape of tumour cells.

PMID- 12420109
TI  - Enhancement effects of (R) and (S) enantiomers and the racemate of a model
      enhancer on permeation of theophylline through human skin.
AB  - The conformation of a permeation enhancer, given their mechanism of action, could
      influence its enhancing properties, since the stratum corneum components form
      essentially a chiral environment. The racemate and both enantiomers of 6
      aminohexanoic acid 2-octylester as model enhancers with one chiral center were
      synthesized and their ability to enhance in vitro theophylline permeation through
      human skin was tested. The MTMT concept could not be applied in this study (the
      melting points of the substances were lower than 20 masculine C) and we observed
      no significant difference in enhancement ratios (ERs) of racemic 6-aminohexanoic
      acid 2-octylester and that of each enantiomer. However, differences in permeation
      rates between enantiomers and their racemates do not have to be related to
      stereoselective interactions, since they may also be explained by differences in
      physicochemical properties. The study also showed that there was no difference in
      the permeation enhancement ability between the (R)-(-) and (S)-(+) isomers of 6
      aminohexanoic acid 2-octylester (the ERs were 2.72+/-0.42 and 2.79+/-0.60 for (R)
      and (S) enantiomers, respectively), suggesting that the enhancing properties of
      the compounds are not dependent on their spatial arrangement. Although
      stereoselective interactions between an enhancer and stratum corneum components
      may exist, they seem not to be important for the enhancer action.

PMID- 12420110
TI  - The physiology of colonic metabolism. Possibilities for interventions with pre-
      and probiotics.
AB  - The awareness is increasing that in the colon many metabolic processes take place
      in relation to the fermentation of our food, which might be relevant for health
      and disease. However, the relation between food, colon metabolism and health or
      disease is far from clear. In this overview, the physiology of colonic metabolism
      and possibilities for its modification by the use of pre- and probiotics are
      discussed. Results of in vitro and animal studies indicate a beneficial impact of
      probiotics on adverse metabolic processes in the colon, but confirmation in human
      studies has to be extended. The administration of prebiotics seems to be
      promising with regard to their capacity to modulate the bacterial composition in
      the colon and there are indications that prebiotics can beneficially influence
      colonic metabolism. Whether these modulations brought about by pre- or probiotics
      have an effect on the health of the host, however, needs to be established in
      most cases.

PMID- 12420111
TI  - Relationship of prebiotics and food to intestinal microflora.
AB  - Dietary carbohydrates that escape digestion in the small intestine, undergo
      bacterial fermentation in the colon. This process affects the microbial ecology
      of the gastrointestinal tract and influences gut metabolism and function.
      Prebiotics are non-digestible but fermentable oligosaccharides that are
      specifically designed to change the composition and activity of the intestinal
      microbiota with the prospect to promote the health of the host. Dietary fiber and
      non-digestible oligosaccharides are the main growth substrates of gut
      microorganisms. Their fermentation results in the acidification of the colonic
      contents and the formation of short chain fatty acids which serve as fuels in
      different tissues and may play a role in the regulation of cellular processes.
      Prebiotics specifically stimulate the growth of endogenous microbial population
      groups such as bifidobacteria and lactobacilli which are perceived as being
      beneficial to human health. In spite of the interesting nutritional properties of
      prebiotics it is questionable whether a wholesome diet rich in fruit and
      vegetables needs to be supplemented with prebiotics for optimal health effects.

PMID- 12420112
TI  - Medical, nutritional and technological properties of lactulose. An update.
AB  - The undigestable disaccharide lactulose has been in medical use for over 40
      years, mainly in the treatment of portosystemic encephalopathy and of
      constipation. Pharmacodynamics of lactulose make it an efficacious and safe drug
      in these indications. But the reason for its numerous potential benefits are
      under research now. The major principle of action is the promotion of growth and
      activity of lactic acid bacteria in the gut which counteract detrimental species
      such as clostridia or salmonellae. This shows that prebiotic action, if used
      accordingly, can have medically significant effects. The mechanism of action,
      medical and prebiotic effects, veterinary uses, and technological properties of
      lactulose, e. g. in yoghurt production are reviewed.

PMID- 12420113
TI  - Effects of lactulose on the intestinal microflora of periparturient sows and
      their piglets.
AB  - The periparturient period of animals (and humans) is very stressful and
      influenced by the microecosystem of the gastrointestinal tract (GIT). Performance
      and productivity of animal husbandry depend on the health of animal mothers and
      their offspring. We investigated the influence of prebiotic amounts of lactulose
      in sows and their piglets. Two experimental trial sows received daily 30 ml
      lactulose, 71 field trial sows received daily 45 ml lactulose during their
      periparturient period (10 days before until 10 days after parturison). The
      weaners of trial sows received 15 ml lactulose per 1 kg baby food 10 days before
      and 10 days after weaning.The effect of lactulose was recorded by performance
      parameters like number of piglet born alive, losses until weaning, body mass of
      piglets, daily weight gain of weaners until 35 days after weaning. The effect of
      lactulose on GIT microflora was estimated by bacterial counts of faeces of sows
      (total aerobic bacteria, Gram-negative bacteria, Clostridium (C.) perfringens).
      In order to show a previously unknown effect of lactulose we investigated the
      levels of antibodies to phospholipase C (PLC) of C. perfringens in plasma of
      experimental sows and in colostral and ripe milk of field sows. Lactulose
      influenced the performance parameters of sows in a non-significant way. In case
      of weaners we recorded significant daily weight gains. Lactulose significantly
      influenced total aerobic bacterial counts, C. perfringens counts in faeces of
      sows 20 days after parturison. Under experimental conditions it was shown that
      trial sows and their piglets had higher IgG-antibody levels to C. perfringens
      PLCs than the control animals. Similar results were found under field conditions.
      Trial sows had significant higher IgG-anti LPS (J5) antibodies in milk 10 days
      after birth.

PMID- 12420114
TI  - The role of the intestinal microflora for the development of the immune system in
      early childhood.
AB  - The intestinal tract performs many different functions; in addition to absorption
      and digestion it is also the body's largest organ of host defence. Part of the
      intestinal mucosal barrier function is formed by a common mucosal immune system
      which provides communication between the different mucosal surfaces of the body.
      The intestine also contains a microbial ecosystem with a large body of microbes,
      1-11/2 kg in an adult. The microbes and their activity have a major impact on the
      development and functioning of the intestinal immune system and vice versa. This
      mutual influence also affects the host beyond the intestine. The intestinal
      colonisation with a balanced microflora is of main importance for the correct
      development of the immune system. The importance of the intestinal microflora is
      most clearly seen in germfree animals, but also diseases like atopy are
      associated with disturbances in the intestinal microflora. This often manifests
      itself in a low number of bifidobacteria. The use of probiotics or prebiotics to
      correct this imbalance and modulate the immune activity has received increasing
      scientific documentation. The precise mechanisms behind these immune modulatory
      activities are not well understood and require further investigation.

PMID- 12420115
TI  - Rapid enlargement of a residual craniopharyngioma during short-term growth
      hormone replacement.

PMID- 12420116
TI  - Neuropathology of sudden infant death (syndrome): literature review and evidence
      of a probable apoptotic degenerative cause.
AB  - BACKGROUND: The agonizing enigma of sudden infant death syndrome (SIDS) endures.
      Contemporary research concentrates on the central nervous system (CNS) as the
      prime cause. REVIEW AND DISCUSSION: What follows is a review of the
      neuropathology of SIDS. A persuasive, but as yet unproved, hypothesis is that the
      lethal pathophysiologic derangement or mechanism in SIDS involves dysfunction of
      sleep-related cardiorespiratory homeostatic controls or failure to arouse or
      both. Neuropathological investigation of SIDS continues to be closely linked to
      the study of specific anatomic structures and regions of the CNS. The structures
      in these regions underpin and regulate normal cardiorespiratory function. It
      follows that dysfunction of one or more of these loci probably precipitates SIDS.
      Under this large umbrella review we include histological, immunohistochemical,
      and biochemical markers in the cerebrospinal fluid (CSF), cerebrum, cerebellum,
      brain stem, pituitary gland, and pineal gland. With variable effect, these
      regions are deemed to mediate the functionality of cardiorespiratory activity and
      the diurnal rhythms of sleep/arousal. The following factors, which (a) are
      associated with altered electrochemical or neural transmission and biochemical
      changes in the CNS and (b) predispose to systemic derangements that most probably
      precipitate SIDS, are subjects of ongoing investigation: evidence of delayed
      development; ischemic insult; degenerative changes; and synaptic alterations.
      CONCLUSION: On the basis of current data, we add to these theoretical constructs
      by postulating that apoptotic neurodegeneration constitutes the anatomic
      substrate accounting for the pathophysiologic mechanism and proximate cause of
      SIDS.

PMID- 12420117
TI  - Clinical-etiological and therapeutic profile of 719 Mexican epileptic children.
AB  - RATIONALE: We performed this study with the intention of describing the clinical
      etiological characteristics and therapeutic responses in a group of epileptic
      children seen at the Instituto Nacional de Pediatria (INP), a tertiary facility
      in Mexico City. METHODS: All patients who attended the Epileptic Clinic between
      March and June 1998 and fulfilled the selection criteria were enrolled in the
      study. Clinical and therapeutic response data were recorded. Three groups were
      formed by etiology. Statistical tests were two-tailed, with alpha=0.05. RESULTS:
      In all, 719 patients were studied. The distribution by etiology was as follows:
      group I, idiopathic (123 patients); group II, cryptogenic (132); and group III,
      symptomatic (464). In group I, 56% of the patients were female. Mean age at onset
      was 5 years 2 months (SD: 3 years 8 months) in group I; 1 year 11 months (SD: 2
      years 5 months) in group II; and 2 years 10 months (SD: 3 years 1 month) in group
      III. The mean evolution time was 5 years 4 months (SD: 4 years) in all groups.
      The most frequent variety of epilepsy in the three groups was generalized
      epilepsy, followed by partial epilepsy. The following epileptic syndromes were
      identified: in group I, 28 patients had epilepsy with generalized tonic-clonic
      seizures, 15, absence epilepsy, and 6, benign rolandic seizures; in group II, all
      32 patients had focal cryptogenic epilepsy; in group III, 235 had generalized
      symptomatic and 192, focal symptomatic epilepsy. The main etiologies were hypoxic
      ischemic encephalopathy (24%) and neural infections (22%). Appropriate seizure
      control was achieved in 108 (87%) patients in group I; 84 (64%) in group II; and
      315 (68%) in group III. In group I, no patient needed more than two antiepileptic
      drugs and 90% had normal psychomotor development. CONCLUSION: When the three
      groups were compared in terms of appropriate epileptic control and normal
      psychomotor development, group I differed from the other groups and the
      difference was statistically significant.

PMID- 12420118
TI  - Case management of hydrocephalus associated with the progression of childhood
      brain stem gliomas.
AB  - OBJECT: Most patients diagnosed with brain stem glioma become bedridden because
      of deteriorating brain stem function. Many brain stem glioma patients develop
      hydrocephalus. Both of these outcomes greatly detract from the quality of life of
      these patients. We have analyzed the occurrence of hydrocephalus in diffuse brain
      stem gliomas in children, and we discuss the management of advanced cases.
      METHODS: Eighteen patients diagnosed with brain stem glioma while under 15 years
      of age, including 1 with dissemination, were studied retrospectively. The average
      overall survival was 11.8 +/- 6.5 months (mean +/- SD). Hydrocephalus occurred in
      16 (88.9%) of the 18 cases. The patients diagnosed with hydrocephalus all
      exhibited a rapid decline in consciousness. The average time to onset of
      hydrocephalus after tumor diagnosis was 5.1 +/- 3.3 months. Twelve of the 16
      patients with hydrocephalus were treated with cerebrospinal fluid (CSF)
      diversion, by means of a Torkildsen shunt, a ventriculoperitoneal shunt, or third
      ventriculostomy. The level of consciousness and patient performance status
      improved after CSF diversion except in 2 patients who had received Torkildsen
      shunts. The patients treated for hydrocephalus survived significantly longer than
      those patients who did not undergo any intervention for hydrocephalus. CSF
      diversion may be a therapeutic intervention that significantly improves the
      quality of life and survival of patients. CONCLUSION: Our results suggest that
      patients diagnosed with brain stem glioma should be closely monitored for signs
      of hydrocephalus and be examined by neuroimaging rapidly when indicated. Our
      results also suggest that once hydrocephalus is diagnosed CSF diversion should be
      performed promptly.

PMID- 12420119
TI  - Is the success rate of endoscopic third ventriculostomy age-dependent? An
      analysis of the results of endoscopic third ventriculostomy in young children.
AB  - INTRODUCTION: Different opinions exist in the literature about the effectiveness
      of endoscopic third ventriculostomy (ETV) in the treatment of hydrocephalus in
      young children. Therefore we made a retrospective evaluation of our own success
      rates of performing ETVs in children less than 2 years of age. MATERIALS AND
      METHODS: In a series of 275 ETVs 66 procedures were performed in children less
      than 2 years of age. RESULTS: The overall success rate in this young age group
      was 53%, lower than the success rates of ETVs reported in literature (72-92%).
      But further analysis of these results and a comparison of the results in
      subgroups with different etiologies of the hydrocephalus showed that the success
      rates varied between 20 and 88%. CONCLUSION: We conclude that the success of ETV
      depends mainly on the etiology of the hydrocephalus and not on the age of the
      patient alone.

PMID- 12420120
TI  - Arachnoid cyst rupture with subdural hygroma: report of three cases and
      literature review.
AB  - INTRODUCTION: Arachnoid cysts are believed to account for about 1% of all
      intracranial expansive lesions, some remain inactive throughout life, others lie
      dormant for many years before clinical manifestation. In a few cases, arachnoid
      cysts have ruptured after cranial trauma or more rarely, spontaneously, with
      resultant subdural haemorrhage or CSF collection. CASE REPORT: We report three
      cases with traumatic rupture of arachnoid cyst into the subdural space in
      children, which is an extremely unusual complication. DISCUSSION: A review of the
      literature revealed only 18 previously reported cases.

PMID- 12420121
TI  - The significance of the percentage of the defect size in spina bifida cystica in
      determination of the surgical technique.
AB  - AIM: Our aim was to classify meningoceles and meningomyeloceles in terms of
      defect area as a percentage of the thoracolumbar region to make it possible to
      select the surgical technique accordingly. MATERIALS AND METHODS: Thirty-two
      cases were included in the study program. Any defect smaller than 8% of the
      thoracolumbar region was primarily sutured and classed as grade 1. RESULTS: The
      defects that it was not possible to handle with primary suture because of the
      broad base and thereby closed with muscle-skin flaps were those occupying more
      than 8% of the thoracolumbar region and these were classed as grade 2. It was not
      possible to perform primary repair of any defect occupying more than 8% of the
      thoracolumbar area. CONCLUSION: The use of combined latissimus dorsi+gluteus
      maximus muscle-skin flaps was found to be safe in broad-based meningomyelocele
      defects, as they provide wider closures and permanent bolstering of the
      meningomyelocele defect, thus protecting the region against multiple trauma.

PMID- 12420122
TI  - Clinical features and neuroradiological findings of mitochondrial pathology in
      six neonates.
AB  - OBJECTS: We hoped to itemize the clinical and neuroradiological features of six
      neonates with mitochondrial disorders. METHODS: We examined a case series of six
      neonates. The diagnosis of mitochondrial cytopathy was made on the basis of
      spectrophotometric measurements of respiratory chain enzyme activities in
      skeletal muscle biopsy specimens. Magnetic resonance (MR) imaging was performed
      in all cases. CONCLUSIONS: The antenatal onset in five cases and the lack of any
      symptom-free interval are suggestive of fetal expression of the disease. No
      specific symptoms were found: arthrogryposis congenita multiplex in one,
      progressive hepatocellular dysfunction in three, encephalomyelopathy and
      cardiomyopathy in four. Complex I deficiency was found in three patients, while
      one patients had a defect of complex IV and the last a combined defect of
      complexes I and IV. Neuroradiological findings were either cerebral atrophy or
      white matter abnormalities of the brain stem in all cases but one and gave
      additional information, because clinical symptoms are not quite specific. The
      combination of clinical and MRI findings in neonatal cases can rule out hypoxic
      ischemic encephalopathy, which suggests an additional screening method to look
      for mitochondrial disorder.

PMID- 12420123
TI  - Neuroendoscopic placement of Ommaya reservoir into a cystic craniopharyngioma.
AB  - INTRODUCTION: Total removal of the tumor is the most acceptable therapeutic
      modality in the management of craniopharyngioma; however, there are innumerable
      factors that can upset treatment plans. Unresectable lesions are often treated
      with gamma knife surgery (GKS). Reduction of the cystic volume is necessary, to
      decrease the area to be treated with GKS. An Ommaya reservoir system is usually
      placed during open surgery or by stereotactic access. MATERIALS AND METHODS: The
      authors use a neuroendoscope for safer and less invasive placement of the Ommaya
      reservoir into deep-seated cystic lesions. The cystic component is aspirated, and
      the Ommaya reservoir tube is precisely guided and placed into the cyst cavity
      under neuroendoscopic control with a newly developed two-burr-hole technique.
      This neuroendoscopic procedure could make it easier to reduce cystic volume prior
      to GKS as the final procedure. This technique may also be used for instillation
      of chemotherapeutic agents and for repeat aspirations, making the achievement of
      cystic control more likely. This type of neuroendoscopic management is a safe and
      effective procedure and could be considered as an alternative management
      technique for some stubborn cystic craniopharyngiomas.

PMID- 12420124
TI  - Aplasia cutis congenita of the scalp.
AB  - CASE REPORT: We report the case of a newborn baby who presented with scalp
      aplasia cutis congenita and an underlying skull defect. DISCUSSION: We discuss
      the diverse options for the management of this condition and the feasibility of
      early surgical repair in the light of the current literature. We also comment on
      the possible role of benzodiazepines in the genesis of this lesion.

PMID- 12420126
TI  - No chromosomal imbalances detected by comparative genomic hybridisation in a case
      of fetal immature teratoma.
AB  - CASE REPORT: We present the first application of comparative genomic
      hybridisation (CGH) in fetal brain tumours in the case of a fetal immature
      teratoma. The tumour was discovered in a female fetus at 22 weeks gestation after
      presentation with significant craniomegaly of such degree that the head size
      measured by sonography was found to correspond to a gestational age of 37 weeks,
      and the pregnancy was terminated. RESULTS: Neuropathological examination showed
      an immature teratoma measuring 1.7 x 1.6 x 0.5 cm and containing tissue from all
      three germinal layers. CGH was successfully performed and, in contrast to earlier
      results in both cerebral and extracerebral teratomas also investigated with the
      same technique, it revealed no chromosomal imbalances. CONCLUSION: This indicates
      that mono- or trisomies did not have a role in the pathogenesis in this
      particular case and that a fetal immature teratoma may contain aberrations
      smaller than the detection threshold of CGH. However, it remains to be seen in
      larger cohorts whether fetal teratomas follow a different pathogenetic pathway
      and may be triggered by different molecular events than teratomas occurring in
      later life.

PMID- 12420127
TI  - Mixed malignant germ cell tumour of the lateral ventricle in an 8-month-old girl:
      case report and review of the literature.
AB  - CASE REPORT: We report a huge intracerebral malignant germ cell tumour (GCT)
      which appeared in the lateral ventricles of an 8-month-old girl. Due to extensive
      tumour vascularisation only partial resection was achieved. Histology revealed an
      embryonal carcinoma mixed with a teratoma. The MIB-1 staining index was >20%.
      Chemotherapy induced a marked regression of the tumour. After chemotherapy
      complete resection of the tumour remnant was easily achieved. Histology showed
      only mesenchymal differentiated tumour tissue and the embryonal carcinoma could
      no longer be detected. More than 2 years after the second operation and 31 months
      after diagnosis the child remains tumour-free. CONCLUSION: The majority of
      cranial mixed malignant GCTs affects patients older than 4 years of age. To our
      knowledge this is the youngest patient in whom an intracranial malignant GCT
      containing an embryonal carcinoma has been diagnosed and successfully treated.

PMID- 12420128
TI  - Primary intracranial fibrosarcoma.
AB  - INTRODUCTION: Primary fibrosarcomas of the brain are very rare tumors, so that
      information regarding the treatment is scarce. We report the contributions that
      different therapeutic options made to the treatment of a child with one of these
      aggressive tumors. CASE REPORT: A 13-year-old boy underwent a complete resection
      of a left temporo-parietal mass that had been diagnosed as a fibrosarcoma by two
      independent pathologists. Adjuvant chemotherapy with vincristine, actinomycin-D,
      ifosfamide and Adriamycin was started, but after 3 months tumor relapse was
      evident. The boy subsequently received radiation therapy during which there was
      evidence of progressive tumor shrinkage. A second surgery was performed 6 months
      after radiotherapy and a small enhancing lesion, revealed to be gliosis, was
      resected. The child remains alive and well 44 months after diagnosis. CONCLUSION:
      Our experience supports the importance of total resection followed by radiation
      therapy, and radiotherapy should be started as soon as possible after surgical
      resection, rather than administering chemotherapy first.

PMID- 12420129
TI  - Diverticular enlargement of the foramina of Luschka and congenital hydrocephalus.
AB  - CASE REPORT: We report on a 9-month-old boy with congenital hydrocephalus
      involving cystic lesions in the bilateral cerebellopontine angle cisterns.
      Sequential CT cisternography demonstrated congenital obstruction of the fourth
      ventricular outlet and diverticular enlargement of the foramina of Luschka.
      DISCUSSION: The possibility of neuroendoscopic third ventriculostomy as a
      treatment for these pathologies is discussed.

PMID- 12420130
TI  - An RCAS-TVA-based approach to designer mouse models.

PMID- 12420131
TI  - Confirmation and high resolution mapping of an atherosclerosis susceptibility
      gene in mice on Chromosome 1.
AB  - Previously, we demonstrated that Ath1 is a quantitative trait locus for aortic
      fatty streak formation, located on Chromosome (chr) 1, with susceptibility in
      C57BL/6J mice and resistance in C3H/HeJ and BALB/cJ mice fed an atherogenic diet.
      In this study, we find an atherosclerosis susceptibility locus in the same region
      of Chr 1 by constructing two congenic strains with the resistance phenotype
      transferred from different resistant strains, PERA/EiJ or SPRETUS/EiJ. By
      backcrossing one congenic strain to C57BL/6J and testing recombinant animals, we
      reduced the distance of the atherosclerosis susceptibility region to 2.3 cM
      between D1Mit14 and D1Mit10. Further testing of nine recombinant animals showed
      that eight of the nine were consistent with a further narrowing between D1Mit159
      and D1Mit398 a distance of 0.66 cM. This region encompasses a number of potential
      candidate genes including the thiol-specific antioxidant gene Aop2, also known as
      peroxiredoxin 5 (Prdx5). AOP2 is capable of reducing hydroperoxides and lipid
      peroxides in the cell. To investigate Aop2 as a potential candidate, we mapped
      Aop2 in our backcross and localized it to the atherosclerosis susceptibility
      interval. We determined that Aop2 is highly expressed in atherosclerosis-related
      tissues including liver and heart. We also found an inverse correlation between
      Aop2 mRNA in liver and atherosclerosis phenotype for strains C57BL/6 and the
      resistant congenic derived from SPRETUS/EiJ. Since LDL oxidation has been
      implicated in the pathogenesis of this disease, and AOP2 possesses antioxidant
      activity, we suggest the role of Aop2 in atherosclerosis susceptibility needs to
      be further explored.

PMID- 12420132
TI  - SNPs in putative regulatory regions identified by human mouse comparative
      sequencing and transcription factor binding site data.

PMID- 12420133
TI  - Examination of OLETF-derived non-insulin-dependent diabetes mellitus QTL by
      construction of a series of congenic rats.
AB  - The Otuska Long-Evans Tokushima Fatty (OLETF) rat is one of the well
      characterized animal models for the study of type 2 diabetes. Our previous QTL
      mapping identified 11 loci responsible for non-insulin-dependent diabetes
      mellitus (NIDDM) susceptibility in the OLETF rat. Here we generated a series of
      congenic animals by individually introgressing all 11 OLETF-derived NIDDM loci
      into a normoglycemic F344 background. Subsequent oral glucose tolerance test
      revealed that the congenic strains for Nidd1/of, Nidd2/of, Nidd3/of Nidd4/of,
      Nidd7/of, and Nidd10/of showed significantly higher levels of blood glucose in
      comparison with parental host strain F344. Furthermore, simultaneously made
      heterozygote animals for Nidd1/of and Nidd2/of did not increase blood glucose
      levels, indicating that these loci are recessively inherited as predicted by the
      QTL analysis. Congenic strains for the other five loci-Nidd5/of, Nidd6/of,
      Nidd8/of, Nidd9/of, and Nidd11/of-were apparently normoglycemic, presumably owing
      to heterosis or because the effect of these loci may not be detected unless
      interactions with other OLETF genes exist. We believe that these congenic strains
      should provide useful agents for decomposing complex diabetic traits and for
      positional cloning.

PMID- 12420134
TI  - Tissue localization of the copper chaperone ATOX1 and its potential role in
      disease.
AB  - ATOX1 is a cytoplasmic copper chaperone that interacts with the copper-binding
      domain of the membrane copper transporters ATP7A and ATP7B. ATOX1 has also been
      suggested to have a potential anti-oxidant activity. This study investigates the
      tissue-specific localization of the mouse homolog, Atox1, in mouse liver and
      kidney. Immunohistochemical studies in the liver localize the copper chaperone to
      hepatocytes surrounding both hepatic and central veins. In the kidney, Atox1 is
      localized to the cortex and the medulla. Cortex immunostaining is specific to
      glomeruli in both the juxtamedullary and cortical nephrons. Expression in the
      medulla appears to be associated with the loops of Henle. These data suggest that
      localized regions in the liver and kidney express Atox1 and have a role in copper
      homeostasis and/or anti-oxidant protection. Twenty-seven patients with Wilson
      disease-like phenotypes and two patients with Menkes disease-like phenotypes were
      screened for ATOX1 mutations with no alterations detected. The human phenotype
      resulting from mutations in ATOX1 remains unidentified.

PMID- 12420135
TI  - A large duplication associated with dominant white color in pigs originated by
      homologous recombination between LINE elements flanking KIT.
AB  - The Dominant White (I/KIT) locus is one of the major coat color loci in the pig.
      Previous studies showed that the Dominant White (I) and Patch (IP) alleles are
      both associated with a duplication including the entire KIT coding sequence. We
      have now constructed a BAC contig spanning the three closely linked tyrosine
      kinase receptor genes PDGFRA-KIT-KDR. The size of the duplication was estimated
      at about 450 kb and includes KIT, but not PDGFRA and KDR. Sequence analysis
      revealed that the duplication arose by unequal homologous recombination between
      two LINE elements flanking KIT. The same unique duplication breakpoint was
      identified in animals carrying the I and IP alleles across breeds, implying that
      Dominant White and Patch alleles are descendants of a single duplication event.
      An unexpected finding was that Pietrain pigs carry the KIT duplication, since
      this breed was previously assumed to be wild type at this locus. Comparative
      sequence analysis indicated that the distinct phenotypic effect of the
      duplication occurs because the duplicated copy lacks some regulatory elements
      located more than 150 kb upstream of KIT exon 1 and necessary for normal KIT
      expression.

PMID- 12420136
TI  - A first-generation EST RH comparative map of the porcine and human genome.
AB  - We have constructed a first-generation EST radiation hybrid comparative map of
      the porcine genome by assigning 1,058 markers to the IMpRH(7000) panel.
      Chromosomal localization was determined with a 2pt LOD of 4.8 for 984 markers,
      using the IMpRH mapping tool. Annotated ESTs represent 46.2% or 489 of the
      markers. Marker distribution was not stochastic and ranged from 0.41 for SSC8 to
      1.77 for SSC12, respectively. Two hundred fifty-one markers assigned to the
      physical map of the pig did not find a homologous sequence in V22 of the human
      genome assembly, indicative of gaps in the assembled human genome sequence. The
      comparative porcine/human map covers 3,290 MB, or 98.3% of the presumed size of
      the human genome. However, 60 breakpoints were identified between chromosomes, as
      well as 90 micro-rearrangements within synteny groups. Six porcine chromosomes
      SSC2, 5, 6, 7, 12, and 14-correspond to the three gene-richest human chromosomes,
      HSA17, 19, and 22, and show above average marker density. Porcine Chrs 1, 8, 11,
      and X display a low DNA/marker ratio and correspond to the 'genome deserts' on
      HSA 18, 4, 13, and X.

PMID- 12420137
TI  - A mapping and evolutionary study of porcine sex chromosome genes.
AB  - A combination of FISH and RH mapping was used to study the evolution of sex
      chromosome genes in the pig. In total, 19 genes were identified, including 3 PAR
      genes (STS, KAL, PRK). The gene order of the porcine X Chromosome (Chr) closely
      resembled the human X Chr (PRK/STS/KAL-AMELX-EIF2s3X/ZFX-USP9X-DBX-SMCX),
      suggesting that the porcine X has undergone very little rearrangement during
      evolution. For the porcine Y Chr, two linkage groups of 10 NRY genes were found,
      and the following order was established: Ypter-(AMELY-EIF2S3Y/ZFY-USP9Y-DBY/UTY)
      (TSPY-SMCY-UBE1Y-SRY)-CEN. This gene order showed greater conservation with the
      murine Y than with the human Y Chr. In addition, all porcine Y Chr genes mapped
      to Yp, which is similar to the mouse and included EIF2s3Y and UBE1Y, which are
      not present in humans. Interestingly, complete conservation of X/Y homologous
      gene order was found between the pig X and Y Chrs, indicating that the porcine Y
      Chr has not undergone extensive reorganisation with respect to the X. This
      suggests that the order of the X/Y homologous genes of the porcine X and Y Chrs
      may closely resemble the ancestral gene order of the eutherian sex chromosomes.

PMID- 12420138
TI  - Novel phenotypes identified by plasma biochemical screening in the mouse.
AB  - We used ENU mutagenesis in the mouse for the rapid generation of novel mutant
      phenotypes for both gene function studies and use as new animal models of human
      disease (Nolan et al. 2000b). One focus of the program was the development of a
      blood biochemistry screen. At 8-12 weeks of age, approximately 300 ml of blood
      was collected from F1 offspring of ENU mutagenized male mice. This yielded
      approximately 125 ml of plasma, used to perform a profile of 17 standard
      biochemical tests on an Olympus analyzer. Cohorts of F1 mice were also aged and
      then retested to detect late onset phenotypes. In total, 1,961 F1s were screened.
      Outliers were identified by running means and standard deviations. Of 70 mice
      showing consistent abnormalities in plasma biochemistry, 29 were entered into
      inheritance testing. Of these, 9 phenotypes were confirmed as inherited, 10 found
      not to be inherited, and 10 are still being tested. Inherited mutant phenotypes
      include abnormal lipid profiles (low total and HDL cholesterol, high
      triglycerides); abnormalities in bone and liver metabolism (low ALP, high ALP,
      high ALT, and AST); abnormal plasma electrolyte levels (high sodium and
      chloride); as well as phenotypes of interest for the study of diabetes (high
      glucose). The gene loci bearing the mutations are currently being mapped and
      further characterized. Our results have validated our biochemical screen, which
      is applicable to other mutagenesis projects, and we have produced a new set of
      mutants with defined metabolic phenotypes.

PMID- 12420140
TI  - Meiotic differentiation during colony maturation in Saccharomyces cerevisiae.
AB  - As yeast colonies ceased growth, cells at the edge of these colonies transited
      from the cell division cycle into meiosis at high efficiency. This transition
      occurred remarkably synchronously and only at late stages of colony maturation.
      The transition occurred on medium containing acetate or low concentrations of
      glucose, but not on medium containing high glucose. The repression by high
      glucose was overcome when IME1 was overexpressed from a plasmid. Experiments with
      different growth media imply that meiosis in colonies is triggered by changes in
      the nutrient environment as colonies mature. HAP2 is required to sporulate in any
      carbon source, whereas GRR1 is required for glucose repression of sporulation.
      CLN3 is required to repress meiosis in colonies but not in liquid cultures,
      indicating that the regulators that mediate the transition to meiosis in colonies
      are not identical to the regulators that mediate this transition in liquid
      cultures.

PMID- 12420141
TI  - Proteolysis of a nucleotide excision repair protein by the 26 S proteasome.
AB  - The 26 S proteasome degrades a broad spectrum of proteins and interacts with
      several nucleotide excision repair (NER) proteins, including the complex of Rad4
      and Rad23 that binds preferentially to UV-damaged DNA. The rate of NER is
      increased in yeast strains with mutations in genes encoding subunits of the 26 S
      proteasome, indicating that it could negatively regulate a repair process. The
      specific function of the 26 S proteasome in DNA repair is unclear. It might
      degrade DNA repair proteins after repair is completed or act as a molecular
      chaperone to promote the assembly or disassembly of the repair complex. In this
      study, we show that Rad4 is ubiquitylated and that Rad23 can control this
      process. We also find that ubiquitylated Rad4 is degraded by the 26 S proteasome.
      However, the interaction of Rad23 with Rad4 is not only to control degradation of
      Rad4, but also to assist in assembling the NER incision complex at UV-induced
      cyclobutane pyrimidine dimers. We speculate that, following the completion of DNA
      repair, specific repair proteins might be degraded by the proteasome to regulate
      repair.

PMID- 12420142
TI  - Isolation, heterological cloning and sequencing of the RPL28 gene in
      Kluyveromyces lactis.
AB  - By virtue of heterologous functional complementation of the Saccharomyces
      cerevisiae Delta pdr5 mutant strain, using a Kluyveromyces lactis genomic
      library, three different K. lactis chromosomal inserts were obtained.
      Transformation of the S. cerevisiae Delta pdr1 Delta pdr3 mutant strain,
      hypersensitive to drugs, with isolated plasmids resulted in resistance to
      cycloheximide and fluconazole. Transformation of K. lactis host strains, using
      the cloned chromosomal fragments, led to an increased level of resistance to some
      mitochondrial inhibitors and azole antifungals. The nucleotide sequence of the
      cloned inserts revealed that two of them contain the drug efflux transporter gene
      Kl-PDR5 and the third contains a DNA segment homologous to chromosome VII of S.
      cerevisiae. Along with three novel ORFs, encoding two proteins of unknown
      molecular function and one putative hexose transporter, this segment also
      contained the Kl-RPL28 gene, found to be responsible for the cycloheximide
      resistance of heterologous transformants. This gene codes for the large subunit
      ribosomal protein (149 amino acids) that shares 89.9% identity with its S.
      cerevisiae counterpart. The coding region of Kl-RPL28 was found to be interrupted
      with one intron near the 5' end. The nucleotide sequence data reported in this
      paper were submitted to GenBank and assigned the accession number AF493565.

PMID- 12420143
TI  - Genetic manipulation of the pathogenic yeast Candida parapsilosis.
AB  - Candida parapsilosis is an important human pathogen, responsible for severe cases
      of systemic candidiasis and one of the leading causes of mortality in neonates.
      In this report, we describe the first system for genetic manipulation of C.
      parapsilosis. We isolated and subsequently determined DNA sequences of genes
      encoding galactokinase ( CpGAL1) and orotidine-5'-phosphate decarboxylase (
      CpURA3) from a genomic DNA library of C. parapsilosis by functional
      complementation of corresponding mutations in Saccharomyces cerevisiae. The
      predicted protein products, Gal1p and Ura3p, displayed a high degree of homology
      with corresponding sequences of C. albicans and S. cerevisiae, respectively. A
      collection of galactokinase-deficient ( gal1) strains of C. parapsilosis was
      prepared using direct selection of mutagenized cells on media containing 2-deoxy
      galactose. Additionally, we constructed a plasmid vector carrying CpGAL1 as a
      selection marker and a genomic DNA fragment with an autonomously replicating
      sequence activity that transforms the C. parapsilosis gal1 mutant strain with
      high efficiency. This system for genetic transformation of C. parapsilosis may
      significantly advance the study of this human pathogen, greatly improving our
      understanding of its biology and virulence, with implications for drug
      development.

PMID- 12420144
TI  - New insights in the regulation of the afp gene encoding the antifungal protein of
      Aspergillus giganteus.
AB  - The antifungal protein (AFP) secreted by the mould Aspergillus giganteus is a
      small, highly basic polypeptide with antifungal activity. Previous work has shown
      that transcription of the corresponding afp gene is regulated by ambient pH,
      being suppressed under acidic and strongly induced under alkaline conditions.
      This observation suggested that the afp gene is regulated by the wide-domain
      transcriptional factor PacC. Here, we show that two putative PacC binding sites
      within the afp promoter, denoted afpP1 and afpP2, are efficiently recognised in
      vitro by a PacC fusion protein of A. nidulans. In addition, we found that
      phosphate, which was used as a buffering agent during cultivation, plays an
      important role in regulating afp expression. AFP production was nearly completely
      inhibited in the presence of external phosphate. The results of Northern analysis
      indicate that the inhibitory effect of phosphate is mediated at the
      transcriptional level.

PMID- 12420145
TI  - Isomaltose formed by alpha-glucosidases triggers amylase induction in Aspergillus
      nidulans.
AB  - Among various alpha-glucobioses examined, isomaltose was the most effective
      inducer for amylase synthesis in Aspergillus nidulans. Amylase induction by
      maltose was completely inhibited by addition of castanospermine or cycloheximide,
      while induction by isomaltose was not affected by the inhibitors, suggesting that
      amylase induction by maltose requires inducible alpha-glucosidases. Disruption of
      the alpha-glucosidase A gene ( agdA), the alpha-glucosidase B gene ( agdB), or
      both genes did not abolish maltose-dependent induction, although amylase
      production induced by maltose decreased about 2-fold in the agdA/ agdB double
      disruptant, compared with that in the agdB disruptant at all concentrations
      tested. Upon induction by isomaltose, amylase synthesis was enhanced considerably
      in the agdB and agdA/ agdB disruptants. Even at 3 nM, isomaltose induced amylase
      production in the double disruptant, supporting the suggestion that isomaltose is
      a physiological inducer for amylase. Therefore, maltose must be converted to
      isomaltose by alpha-glucosidases prior to triggering amylase synthesis, but no
      specific alpha-glucosidase is required for amylase induction by maltose. Probably
      any alpha-glucosidases having isomaltose-forming activity, including AgdA and
      AgdB, may participate in amylase induction by maltose.

PMID- 12420146
TI  - Different functions of the class I and class II chitin synthase genes, chsC and
      chsA, are revealed by repression of chsB expression in Aspergillus nidulans.
AB  - The filamentous fungus, Aspergillus nidulans, genome contains at least five
      chitin synthase-encoding genes. chsB is essential for normal hyphal growth. chsA
      and chsC are likely to be cooperatively required for hyphal wall integrity. In
      this study, we constructed chsA chsB and chsC chsB double mutants, in which chsB
      expression was under a repressible promoter [ alcA(p)]. While chsA or chsC single
      mutants did not show obvious growth defects, the chsA chsB and chsC chsB double
      mutants showed different phenotypes from the chsB single mutant and from each
      other under alcA(p)-repressing conditions. The chsA chsB double mutant produced
      fewer aerial hyphae and the chsC chsB double mutant showed reduced cell mass.
      These observations support the idea that chsA and chsC each play a different role
      in hyphal morphogenesis. In addition, the chitin contents of these double mutants
      were higher than those of the chsB single mutant. When chsA was expressed
      ectopically under the chsB promoter in the chsB mutant, the growth defects caused
      by chsB repression were not remedied at all, although an increased level of chsA
      mRNA was observed. Thus, it is suggested that the gene products of chsA and chsB
      themselves have different functions in hyphal morphogenesis.

PMID- 12420147
TI  - Suppression of tandem-multimer formation during genetic transformation of the
      mycotoxin-producing fungus Penicillium paxilli by disrupting an orthologue of
      Aspergillus nidulans uvsC.
AB  - An orthologue of Aspergillus nidulans uvsC and Saccharomyces cerevisiae RAD51 was
      cloned from the filamentous fungus, Penicillium paxilli. A mutation in uvsC
      causes UV sensitivity during germination. The product of RAD51 is involved in
      meiotic recombination and DNA damage repair. The deduced amino acid sequence of
      the product of this gene (Pprad51) shared 92% identity with UVSC. Site-specific
      disruption of pprad51 showed a significant effect for extra-cellular DNA
      integration. Transformation of the null mutant with pII99, which confers
      geneticin resistance, resulted in a shift from a predominance of direct repeats
      at a single site to single copies when compared with a control strain. A copy
      number effect of integrated pII99 for geneticin selection was suggested as the
      frequency of direct repeat formation was less when selected at a lower
      concentration in the control strain. However, such an effect was not observed in
      the null mutant, further supporting an involvement of Pprad51 in direct repeat
      formation.

PMID- 12420148
TI  - Evolution of heteroplasmy at a mitochondrial tandem repeat locus in cultured
      rabbit cells.
AB  - Surveys of animal mitochondrial DNA (mtDNA) polymorphism reveal that mtDNA length
      variation is common. Much of this variation involves non-coding tandem repeat
      arrays in the main control region of the molecule. Despite a high mutation rate,
      generating systematic individual mtDNA length heteroplasmy, the number of repeats
      in a tandem array is maintained within a narrow range in lagomorphs. To
      investigate the basis for this apparent paradox, we studied the evolution of
      mtDNA length polymorphism in several rabbit cell clones containing different
      proportions of mtDNA, with four or five 153-bp repeats. Our data show that
      equivalent amounts of two mtDNA molecular types are not stable (evolution towards
      a predominant type being the rule) and that other types remain represented,
      maintaining the length polymorphism. The data suggest that mtDNA molecules with a
      longer array of repeats have a replicative advantage that could depend on the
      nuclear background.

PMID- 12420150
TI  - Double dissociation of serotonergic and dopaminergic mechanisms on attentional
      performance using a rodent five-choice reaction time task.
AB  - RATIONALE: Converging evidence suggests that dopaminergic and serotonergic
      mechanisms affect distinct aspects of cognitive performance. Experiments using
      the rodent five-choice reaction time task have established a critical role for
      dopaminergic mechanisms in the rat medial prefrontal cortex (mPFC), but have
      yielded only incomplete evidence regarding the specific functions of serotonin
      receptors. OBJECTIVES: To contrast the effects of systemic or intra-mPFC
      administration of dopamine or serotonin agents on performance of the five-choice
      reaction time task. METHODS: Two groups of rats trained on the five-choice
      reaction time task received systemic administration of either the dopamine D(1)
      receptor partial agonist SKF 38393 (0, 1, 3 or 10 mg/kg IP) or the serotonin 5
      HT(2A/C) receptor antagonist ketanserin (0, 0.3, 0.6 or 1 mg/kg SC) prior to
      testing; a further group was implanted with chronic guide cannulae and received
      ketanserin (0, 0.025, 0.1 or 0.4 micro g/side) infused into the mPFC prior to
      testing. RESULTS: SKF 38393 affected aspects of accuracy and vigour of
      responding, while regardless of the route of administration ketanserin reduced
      premature responding without any effect on choice accuracy. CONCLUSIONS: Together
      with our previous findings of increased choice accuracy following intra-mPFC SKF
      38393 (Granon et al. 2000), the present results support the notion that the
      functions of dopamine and serotonin receptors in the mPFC relate to two distinct
      domains of executive control. Dopamine D(1) receptors are critical to optimise
      response selection in skilled non-automatic tasks, while serotonin 5-HT(2A)
      receptors regulate the execution of primed responses.

PMID- 12420151
TI  - Local injections of the 5-hydroxytryptamine antagonist mianserin into substantia
      nigra pars reticulata block tremulous jaw movements in rats: studies with a
      putative model of Parkinsonian tremor.
AB  - RATIONALE: Atypical antipsychotics such as clozapine and olanzapine have a low
      liability for producing motor side effects. In addition to being D2 antagonists,
      these drugs have a complex binding profile that includes affinity for muscarinic,
      alpha, H1, and various serotonin receptors. Previous work in rats has shown that
      atypical antipsychotics suppress tremulous jaw movements induced by the
      anticholinesterase tacrine in rats. Cholinomimetic-induced jaw movements are a
      putative model of parkinsonian tremor, and the ability of antipsychotic drugs to
      suppress these movements in rats is correlated with motor side-effect liability
      in humans. OBJECTIVE: The present work was undertaken to study the role of
      central serotonin receptors in the generation of cholinomimetic-induced jaw
      movements. RESULTS: Systemic injections of the serotonin antagonist mianserin
      suppressed tacrine-induced jaw movements, with an ED(50) of 2.77 mg/kg. Local
      injections of mianserin directly into substantia nigra pars reticulata (SNr) also
      suppressed tacrine-induced jaw movements. Injections into ventrolateral
      neostriatum, or a control site dorsal to SNr, failed to have any effects on jaw
      movement activity. CONCLUSIONS: These studies suggest that atypical
      antipsychotics may act both on striatal muscarinic receptors and nigral serotonin
      receptors to suppress jaw movement activity. It is possible that the unique motor
      properties of atypical antipsychotics result from actions on multiple receptors
      in several brain areas. The precise serotonin receptor subtype involved in these
      effects is unknown, and future work will examine the effects of drugs that act
      selectively on 5-HT(2A) and 5-HT(2C) receptors.

PMID- 12420152
TI  - Neurosteroids in depression: a review.
AB  - RATIONALE: A deregulation in concentrations of the neurosteroids
      (allo)pregnanolone and 3alpha,5alpha-tetrahydrodeoxycorticosterone (3alpha,5alpha
      TH DOC) has been found in depressed patients. These levels normalize following
      treatment with selective serotonin reuptake inhibitors (SSRIs). Furthermore,
      administration of the neurosteroid dehydroepiandrosterone (DHEA) to depressed
      patients is associated with an improvement in the symptoms of depression.
      OBJECTIVE: The aim of the present review is to clarify the mechanisms whereby
      neurosteroids, particularly allopregnanolone and DHEA, are involved in depression
      and to discuss the effect of SSRIs on allopregnanolone concentration. METHODS:
      Literature on preclinical and clinical research has been analyzed in relation to
      the pathophysiology of depression. RESULTS: Decreased plasma and cerebrospinal
      fluid concentrations of allopregnanolone in depressed patients increase to normal
      levels following effective psychopharmacological treatment. This might either be
      a physiological aspect of improvement in the symptoms of depression or a
      pharmacologically induced alteration. Several findings support the hypothesis of
      an antidepressant effect of allopregnanolone. These include an antidepressant
      effect demonstrated in an animal model of depression and a suppressing effect on
      corticotropin-releasing hormone (CRH) and arginine-vasopressin (AVP) gene
      expression. SSRIs increase levels of allopregnanolone, but this effect is not
      confined to this class of drugs alone. The beneficial effect of DHEA
      administration in depressed patients might result from its sigma 1 receptor
      mediated enhancement of noradrenaline and serotonin neurotransmission,
      antiglucocorticoid effects, and cognition enhancing effects. CONCLUSIONS:
      Indirect genomic (allopregnanolone) and non-genomic (allopregnanolone and DHEA)
      mechanisms are involved in the neurosteroidogenic pathophysiology of depression.
      Clinical studies in homogeneous groups of non-pharmacologically treated depressed
      patients are required to elucidate this relationship further.

PMID- 12420153
TI  - Effects of haloperidol on cue-induced autonomic and behavioral indices of heroin
      reward and motivation.
AB  - RATIONALE: Most theoretical conceptions of motivation presume an internal state
      of sympathetic nervous system activation that precedes and accompanies goal
      seeking behavior. OBJECTIVES: The present study investigates the animals'
      physiological and behavioral response to presentation of environmental cues
      predictive of availability (S+) or non-availability (S-) of heroin in the goal
      box of a straight-arm alley. METHODS: Animals were trained to discriminate
      between two olfactory cues, one predictive of the delivery of i.v. heroin (0.1
      mg/kg) upon the rat's entry into the goal box of the runway (the S+) and another
      cue (the S-) predictive of i.v. saline upon goal-box entry. Once discriminative
      performance had stabilized, animals were challenged with each of four haloperidol
      treatments in a counterbalanced manner (0.0, 0.075, 0.15, 0.3 mg/kg i.p.). Run
      times and heart rates (measured via radiotelemetry) served as the dependent
      variables on every trial. RESULTS: Both behavioral and physiological measures of
      motivation responded differentially to S+ and S- cues. Haloperidol had no effect
      during or immediately following S- trials, nor prior to reinforcer delivery on S+
      trials. However, the behavioral and physiological consequences of heroin delivery
      during dopamine receptor antagonism were reliable - animals ran more slowly and
      showed less activation (lower heart rates) on the first S+ trial following a
      heroin + haloperidol experience. CONCLUSIONS: The current data demonstrate that
      physiological and behavioral indices of cue-induced motivation remained intact
      during haloperidol challenge, while the reinforcing consequences of heroin appear
      to have been attenuated by dopamine receptor antagonism.

PMID- 12420154
TI  - Discriminative stimulus effects of zolpidem in squirrel monkeys: role of
      GABA(A)/alpha1 receptors.
AB  - RATIONALE: The discriminative stimulus effects of zolpidem in squirrel monkeys
      trained at doses greater than or equal to 3.0 mg/kg differ from those of
      conventional benzodiazepines (BZs), but the extent to which these effects reflect
      the selectivity of zolpidem for GABA(A)/alpha(1) receptors is not known.
      OBJECTIVES: The present study investigated the ability of GABA(A)/alpha(1)
      preferring agonists to substitute for training doses of zolpidem greater than or
      equal to 3.0 mg/kg and the ability of GABA(A)/alpha(1)-preferring antagonists to
      block zolpidem's discriminative stimulus effects. METHODS: Squirrel monkeys were
      trained to discriminate intravenous injections of zolpidem (3.0 or 5.6 mg/kg)
      from saline and tested with BZ agonists differing in selectivity and efficacy at
      GABA(A)/alpha(1) receptors. Antagonism of the effects of zolpidem was studied
      using the GABA(A)/alpha(1)-preferring antagonists beta-carboline-3-carboxylate-t
      butyl ester (beta-CCT) and 3-propyloxy-beta-carboline (3-PBC). RESULTS: Zolpidem
      and quazepam (GABA(A)/alpha(1)-preferring agonist) engendered full substitution
      for zolpidem, whereas CL 218,872 (GABA(A)/alpha(1)-preferring partial agonist)
      and the non-selective BZ agonists alprazolam and flunitrazepam engendered low and
      variable levels of zolpidem-lever responding (35-58%). Both beta-CCT and 3-PBC
      antagonized the discriminative stimulus effects of zolpidem in a surmountable
      fashion. CONCLUSIONS: Our findings provide evidence for a key role of
      GABA(A)/alpha(1) receptors in the discriminative stimulus effects of zolpidem at
      relatively high training doses, and suggest that selectivity and relatively high
      efficacy at GABA(A)/alpha(1) receptors is required for BZ agonists to reproduce
      these discriminative stimulus effects.

PMID- 12420155
TI  - Effects of SCH 23390 and eticlopride on cocaine-seeking produced by cocaine and
      WIN 35,428 in rats.
AB  - RATIONALE: Exposure to a small amount of cocaine can trigger relapse, and so an
      understanding of the mechanisms underlying cocaine-seeking are important for the
      development of effective anti-relapse treatments. OBJECTIVES: The present study
      sought to compare the contributions of dopamine D(1)- and D(2)-like receptors in
      drug-seeking produced by cocaine and WIN 35,428. METHODS: Reinstatement of
      extinguished cocaine self-administration was measured for rats that received
      injections of cocaine (5.0-20.0 mg/kg) or WIN 35,428 (0.1-1.0 mg/kg) following
      extinction. Prior to the injection of cocaine or WIN 35,428, rats received an
      injection of the D(1)-like antagonist, SCH 23390 (0.001-0.010 mg/kg) or the D(2)
      like antagonist, eticlopride (0.01-0.30 mg/kg). Effects of SCH 23390 (0.01 mg/kg)
      on cocaine-produced locomotor activation were also measured in separate groups of
      rats. RESULTS: The ability of both cocaine and WIN 35,428 to produce cocaine
      seeking was dose-dependent. Within the range of doses tested, SCH 23390 failed
      significantly to attenuate the ability of either cocaine or WIN 35,428 to
      reinstate extinguished cocaine self-administration, although cocaine-produced
      locomotor activation was significantly attenuated by pretreatment with the
      highest dose of SCH 23390. Eticlopride attenuated both cocaine and WIN 35,428
      produced cocaine-seeking but lower doses were required to decrease WIN 35,428
      produced cocaine-seeking. CONCLUSIONS: These results suggest that dopamine D(2)
      mechanisms are involved in cocaine-seeking produced by both cocaine and WIN
      35,428. The lower potency of eticlopride in attenuating cocaine-produced cocaine
      seeking suggest that cocaine's effects at sites other than the dopamine
      transporter contribute to its ability to elicit drug-seeking.

PMID- 12420156
TI  - Buspirone decreases physiological reactivity to unconditioned and conditioned
      aversive stimuli.
AB  - RATIONALE: Serotonergic pathways are thought to be important in mediating the
      effects of aversive events. OBJECTIVE: To investigate the effects of buspirone, a
      5-HT(1A) partial agonist, on habituation and extinction in an aversive classical
      conditioning model. METHODS: Forty healthy male volunteers were randomly assigned
      to a single dose of buspirone (10 mg) or placebo. They filled in questionnaires
      of anxiety and depression at baseline and visual analogue scales of tension and
      anxiety before and at 60, 120 and 150 min after drug administration. Their skin
      conductance responses to auditory stimuli were measured on the conditioning model
      2 h after drug intake. RESULTS: There were no differences between groups on
      depression or anxiety. Buspirone decreased the amplitude of the skin conductance
      response and the number of spontaneous fluctuations in both the habituation and
      extinction phases but had no effect on skin conductance level. Buspirone also
      attenuated the unconditioned response to the white noise and the response to the
      first tone. Visual analogue ratings of tension and anxiety decreased after
      buspirone. CONCLUSIONS: Buspirone decreased physiological reactivity in an
      aversive classical conditioning model. It had anxiolytic effects on both
      conditioned and unconditioned anxiety. This might be due to its multiple actions
      on 5-HT receptors.

PMID- 12420157
TI  - Mycothiol biochemistry.
AB  - Mycothiol (MSH) is a novel thiol comprised of N-acetylcysteine amide-linked to
      GlcN-alpha(1-1)-Ins. It is the major thiol in most actinomycetes and is produced
      at millimolar levels in mycobacteria and streptomycetes. MSH biosynthesis occurs
      by linkage of GlcNAc to Ins, deacetylation to GlcN-Ins, ligation of the latter to
      L-cysteine, and transacetylation of the cysteinyl residue by CoASAc to produce
      MSH. The genes encoding the respective enzymes have been designated mshA, mshB,
      mshC, and mshD; all but mshA have been identified. Mycobacterium smegmatis
      mutants deficient in mshA, mshC, and mshD have been characterized. MSH plays a
      significant role in the detoxification of thiol-reactive substances, including
      formaldehyde, various electrophiles, and antibiotics. Mycothiol S-conjugates
      derived from electrophiles and antibiotics are cleaved by mycothiol S-conjugate
      amidase to release GlcN-Ins, used to resynthesize MSH, and a mercapturic acid
      which is excreted from the cell. A mycothiol-disulfide-selective reductase has
      been identified and likely helps to maintain cellular MSH in the reduced state.
      Mycothiol biochemistry has characteristics similar to those of glutathione but
      also has a variety of unique features.

PMID- 12420158
TI  - Cellular differentiation in the cyanobacterium Nostoc punctiforme.
AB  - Nostoc punctiforme is a phenotypically complex, filamentous, nitrogen-fixing
      cyanobacterium, whose vegetative cells can mature in four developmental
      directions. The particular developmental direction is determined by environmental
      signals. The vegetative cell cycle is maintained when nutrients are sufficient.
      Limitation for combined nitrogen induces the terminal differentiation of
      heterocysts, cells specialized for nitrogen fixation in an oxic environment. A
      number of unique regulatory events and genes have been identified and integrated
      into a working model of heterocyst differentiation. Phosphate limitation induces
      the transient differentiation of akinetes, spore-like cells resistant to cold and
      desiccation. A variety of environmental changes, both positive and negative for
      growth, induce the transient differentiation of hormogonia, motile filaments that
      function in dispersal. Initiation of the differentiation of heterocysts, akinetes
      and hormogonia are hypothesized to depart from the vegetative cell cycle,
      following separate and distinct events. N. punctiforme also forms nitrogen-fixing
      symbiotic associations; its plant partners influence the differentiation and
      behavior of hormogonia and heterocysts. N. punctiforme is genetically tractable
      and its genome sequence is nearly complete. Thus, the regulatory circuits of
      three cellular differentiation events and symbiotic interactions of N.
      punctiforme can be experimentally analyzed by functional genomics.

PMID- 12420159
TI  - mRNA-mediated detection of environmental conditions.
AB  - Bacteria inhabit an amazing variety of ecological niches and readily adapt to
      changing environmental conditions. Precise monitoring of external and internal
      parameters is a prerequisite for the induction of appropriate stress responses.
      Proteins are often used as sensing devices. However, there is now accumulating
      evidence that the 5' end of mRNA can be responsive to environmental stimuli. The
      folding of certain mRNA species is thermally controlled. RNA-based thermosensors
      modulate the efficiency of translation by controlling the accessibility of
      translation initiation signals that are captured in hairpin structures under
      repressing conditions. Recently, it has been recognized that mRNA can also sense
      physiological signals other than temperature. The overall structure of several
      vitamin-regulated leader mRNAs depends on the availability of the respective
      effector molecule. Binding of the vitamin or its precursor to the transcript
      impairs ribosome binding. Most likely, detection of environmental conditions by
      sensory RNAs is an emerging concept that is likely to extend much beyond the
      presently known examples.

PMID- 12420160
TI  - Identification of Salmonella enterica serovar Typhimurium genes associated with
      growth suppression in stationary-phase nutrient broth cultures and in the chicken
      intestine.
AB  - Over 2,800 Tn 5 insertion mutants of Salmonella enterica sv. Typhimurium were
      screened for the loss of ability to suppress the multiplication of a
      spectinomycin-resistant (Spc(r)) but otherwise isogenic S. enterica sv.
      Typhimurium strain, when the Spc(r) mutant was added to 24-h LB broth cultures of
      the mutants. Selected "growth non-suppressive" (GNS) mutants were defective in
      respiration (insertions in arcA and fnr), amino acid biosynthesis (aroA and
      aroD), nutrient uptake and its regulation (tdcC and crp), and chemotaxis (fliD).
      In the last GNS mutant, the transposon inactivated yhjH, an ORF with unknown
      function which shows sequence similarity to di-guanylate cyclase and to novel two
      component signal transduction proteins. In newly hatched chickens, all of the
      mutants, with the exception of the fliDmutant, were also unable to suppress
      colonization of the alimentary tract by the parent strain inoculated 1 day later.
      Defined mutations in luxS or sdiA,genes which contribute to quorum sensing in S.
      enterica sv. Typhimurium, had no effect on the stationary-phase growth
      suppression. Analysis of a transcriptional fusion construct indicated that yhjH
      was moderately expressed in the exponential phase of growth and up-regulated upon
      entry into stationary phase. Expression of yhjH was also considerably suppressed
      by the addition of supernatant from a 24-h stationary-phase S. enterica sv.
      Typhimurium culture, suggesting that the gene belongs to a new sensing and
      signaling regulatory pathway in S. enterica sv. Typhimurium.

PMID- 12420161
TI  - Detection of hepatotoxic Microcystis strains by PCR with intact cells from both
      culture and environmental samples.
AB  - Microcystins are small hepatotoxic peptides produced by a number of
      cyanobacteria. They are synthesized non-ribosomally by multifunctional enzyme
      complex synthetases encoded by the mcy genes. Primers deduced from mcy genes were
      designed to discriminate between toxic microcystin-producing strains and non
      toxic strains. Thus, PCR-mediated detection of mcy genes could be a simple and
      efficient means to identify potentially harmful genotypes among cyanobacterial
      populations in bodies of water. We surveyed the distribution of the mcyB gene in
      different Microcystis strains isolated from Chinese bodies of water and confirmed
      that PCR can be reliably used to identify toxic strains. By omitting any DNA
      purification steps, the modified PCR protocol can greatly simplify the process.
      Cyanobacterial cells enriched from cultures, field samples, or even sediment
      samples could be used in the PCR assay. This method proved sensitive enough to
      detect mcyB genes in samples with less than 2,000 Microcystis cells per ml. Its
      accuracy, specificity and applicability were confirmed by sequencing selected DNA
      amplicons, as well as by HPLC, ELISA and mouse bioassay as controls for toxin
      production of every strain used.

PMID- 12420162
TI  - Validation of Cdc68p as a novel antifungal target.
AB  - Candida albicans is the main cause of systemic fungal infections for which there
      is an urgent need for novel antifungal drugs. The CP (Cdc68p-Pob3p) complex,
      which is involved in transcription elongation, was evaluated as a putative
      antifungal target. In order to predict the consequences of inhibition of this
      complex, the largest CP subunit in Saccharomyces cerevisiae, Cdc68p, was the
      first novel target to be tested in GATE, a recently described, quantitative
      target inactivation system. Depletion of the cell's pool of Cdc68p led to rapid
      cell death. Subsequently, the C. albicans orthologue of CDC68, CaCDC68, was
      cloned. Attempts to disrupt both alleles were unsuccessful, thus suggesting an
      essential role of CaCDC68 in this fungus also. Furthermore, CDC68 was proven to
      be present in Neurospora crassa and Aspergillus nidulans, thus suggesting that
      the CP complex is widespread among fungi and could serve as a broad range
      antifungal target. Analysis of Cdc68p and Pob3p sequences indicated significant
      structural differences between fungal CP complexes and those present in higher
      eukaryotes. These results predict that, in principle, fungal-specific ligands of
      CP complexes could be identified that could subsequently serve as chemical
      starting points towards the development of new antifungal therapeutic agents.

PMID- 12420163
TI  - Effect of redox potential on activity of hydrogenase 1 and hydrogenase 2 in
      Escherichia coli.
AB  - This report elucidates the distinctions of redox properties between two uptake
      hydrogenases in Escherichia coli. Hydrogen uptake in the presence of mediators
      with different redox potential was studied in cell-free extracts of E. coli
      mutants HDK103 and HDK203 synthesizing hydrogenase 2 or hydrogenase 1,
      respectively. Both hydrogenases mediated H(2) uptake in the presence of high
      potential acceptors (ferricyanide and phenazine methosulfate). H(2) uptake in the
      presence of low-potential acceptors (methyl and benzyl viologen) was mediated
      mainly by hydrogenase 2. To explore the dependence of hydrogen consumption on
      redox potential of media in cell-free extracts, a chamber with hydrogen and redox
      ( E(h)) electrodes was used. The mutants HDK103 and HDK203 exhibited significant
      distinctions in their redox behavior. During the redox titration, maximal
      hydrogenase 2 activity was observed at the E(h) below -80 mV. Hydrogenase 1 had
      maximum activity in the E(h) range from +30 mV to +110 mV. Unlike hydrogenase 2,
      the activated hydrogenase 1 retained activity after a fast shift of redox
      potential up to +500 mV by ferricyanide titration and was more tolerant to O(2).
      Thus, two hydrogenases in E. coli are complementary in their redox properties,
      hydrogenase 1 functioning at higher redox potentials and/or at higher O(2)
      concentrations than hydrogenase 2.

PMID- 12420164
TI  - A non-dechlorinating strain of Dehalospirillum multivorans: evidence for a key
      role of the corrinoid cofactor in the synthesis of an active tetrachloroethene
      dehalogenase.
AB  - A strain of Dehalosprillum multivorans, designated strain N, was isolated from
      the same source as the formerly described tetrachloroethene (PCE)-dechlorinating
      D. multivorans, herein after referred to as strain K. Neither growing cells nor
      cell extracts of strain N were able to dechlorinate PCE. The pceA and pceB genes
      encoding for the PCE-reductive dehalogenase were detected in cells of strain N;
      and they were 100% homologous to the corresponding genes of strain K. Since the
      PCE dehalogenase of D. multivorans strain K contains a corrinoid cofactor, the
      corrinoids of strain N cells were extracted. Analysis of the corrinoids revealed
      the absence of the specific corrinoid, which is the cofactor of the PCE
      dehalogenase of strain K cells. RT-PCR of mRNA indicated that the pceA gene was
      transcribed in strain N cells to a far lower extent than the pceA gene of strain
      K under the same experimental conditions. Western blot analysis of crude extracts
      of strain N showed that, if at all, an insignificant amount of the apoprotein of
      the PCE dehalogenase was present. The results indicate that the inability of
      strain N to dechlorinate is due to the absence of the corrinoid cofactor of the
      enzyme mediating PCE dechlorination.

PMID- 12420165
TI  - Localization of Mn(II)-oxidizing activity and the putative multicopper oxidase,
      MnxG, to the exosporium of the marine Bacillus sp. strain SG-1.
AB  - Dormant spores of the marine Bacillus sp. strain SG-1 catalyze the oxidation of
      manganese(II), thereby becoming encrusted with insoluble Mn(III,IV) oxides. In
      this study, it was found that the Mn(II)-oxidizing activity could be removed from
      SG-1 spores using a French press and recovered in the supernatant following
      centrifugation of the spores. Transmission electron microscopy of thin sections
      of SG-1 spores revealed that the ridged outermost layer was removed by passage
      through the French press, leaving the remainder of the spore intact. Comparative
      chemical analysis of this layer with the underlying spore coats suggested that
      this outer layer is chemically distinct from the spore coat. Taken together,
      these results indicate that this outer layer is an exosporium. Previous genetic
      analysis of strain SG-1 identified a cluster of genes involved in Mn(II)
      oxidation, the mnx genes. The product of the most downstream gene in this
      cluster, MnxG, appears to be a multicopper oxidase and is essential for Mn(II)
      oxidation. In this study, MnxG was overexpressed in Escherichia coli and used to
      generate polyclonal antibodies. Western blot analysis demonstrated that MnxG is
      localized to the exosporium of wild-type spores but is absent in the non
      oxidizing spores of transposon mutants within the mnx gene cluster. To our
      knowledge, Mn(II) oxidation is the first oxidase activity, and MnxG one of the
      first gene products, ever shown to be associated with an exosporium.

PMID- 12420166
TI  - Influence of nitrate on oxalate- and glyoxylate-dependent growth and acetogenesis
      by Moorella thermoacetica.
AB  - Oxalate and glyoxylate supported growth and acetate synthesis by Moorella
      thermoacetica in the presence of nitrate under basal (without yeast extract)
      culture conditions. In oxalate cultures, acetate formation occurred concomitant
      with growth and nitrate was reduced in the stationary phase. Growth in the
      presence of [(14)C]bicarbonate or [(14)C]oxalate showed that CO(2) reduction to
      acetate and biomass or oxalate oxidation to CO(2) was not affected by nitrate.
      However, cells engaged in oxalate-dependent acetogenesis in the presence of
      nitrate lacked a membranous b-type cytochrome, which was present in cells grown
      in the absence of nitrate. In glyoxylate cultures, growth was coupled to nitrate
      reduction and acetate was formed in the stationary phase after nitrate was
      totally consumed. In the absence of nitrate, glyoxylate-grown cells incorporated
      less CO(2) into biomass than oxalate-grown cells. CO(2) conversion to biomass by
      glyoxylate-grown cells decreased when cells were grown in the presence of
      nitrate. These results suggest that: (1) oxalate-grown cells prefer CO(2) as an
      electron sink and bypass the nitrate block on the acetyl-CoA pathway at the level
      of reductant flow and (2) glyoxylate-grown cells prefer nitrate as an electron
      sink and bypass the nitrate block of the acetyl-CoA pathway by assimilating
      carbon via an unknown process that supplements or replaces the acetyl-CoA
      pathway. In this regard, enzymes of known pathways for the assimilation of two
      carbon compounds were not detected in glyoxylate- or oxalate-grown cells.

PMID- 12420167
TI  - Evidence for MoeA-dependent formation of the molybdenum cofactor from molybdate
      and molybdopterin in Escherichia coli.
AB  - The function of the MoeA protein in the biosynthesis of the molybdenum cofactor
      (MoCo) was analyzed in vitro, using purified His(6)-MoeA from Escherichia coli,
      molybdopterin (MPT) isolated from buttermilk xanthine oxidase and molybdate. The
      formation of MoCo was monitored by the reconstitution of nitrate reductase
      activity in extracts of the Neurospora crassa nit-1 mutant. Formation of MoCo
      from MPT and molybdate required MoeA and L-cysteine or glutathione. The reaction
      proceeded at micromolar molybdate levels and was time- and MoeA concentration
      dependent. A physical interaction between MoeA and MPT was demonstrated by HPLC
      analysis of MoeA-bound MPT.

PMID- 12420168
TI  - The roles of the three gene copies encoding hydroxylamine oxidoreductase in
      Nitrosomonas europaea.
AB  - The nitrifying bacterium Nitrosomonas europaea contains three copies of the gene
      (hao) encoding hydroxylamine oxidoreductase (HAO), the second enzyme in the
      nitrification pathway which oxidizes NH(2)OH to NO(2)(-). The nucleotide
      sequences of the hao genes differ by only one nucleotide. Two of the three gene
      copies have identical promoter sequences, while the third promoter has a
      different nucleotide sequence. Mutant strains with two of the three copies of hao
      inactivated were created by insertional inactivation, using DNA cassettes
      containing kanamycin- and gentamycin-resistance genes. All three double-mutant
      combinations were obtained. These double mutants were phenotypically identical
      under the conditions tested. Two of these double mutants were similar to wild
      type cells or cells having a single hao copy inactivated regarding growth rates
      or hydroxylamine-dependent O(2) uptake activity, but had only about 50% of the
      wild-type level of in vitro HAO activity and hao mRNA. The third hao double
      mutant had an unstable genotype, resulting in recombination of the gentamycin
      marker into another copy of hao. The N. europaea genomic sequence was recently
      completed, revealing the locations of the copies of hao and other nitrification
      genes. Comparison with the arrangement of hao genes in the closely related
      strain, Nitrosomonas sp. strain ENI-11, showed a similar organization.

PMID- 12420169
TI  - Different effectors of dimorphism in Yarrowia lipolytica.
AB  - Yarrowia lipolytica is an ascomycete with biotechnological potential. In common
      media, the fungus grows as a mixture of yeast-like and short mycelial cells. The
      environmental factors that affect dimorphism in the wild-type strain, W29, and
      its auxotrophic derivative, PO1a, were analyzed. In both strains, pH was the most
      important factor regulating the dimorphic transition. Mycelium formation was
      maximal at pH near neutrality and decreased as pH was lowered to become almost
      null at pH 3. Carbon and nitrogen sources, namely glucose and ammonium, were also
      important for mycelium formation; and their effect was antagonized by some
      alternative carbon and nitrogen sources. Citrate was an important positive
      effector of mycelium growth. Anaerobic stress induced formation of mycelial
      cells. The importance of the protein kinase A pathway was suggested by the
      inhibition of mycelium growth by cAMP. We propose that the interplay of these
      factors regulates the adaptation of the fungus, to better exploit its natural
      ecological niches.

PMID- 12420170
TI  - Characterisation, genome size and genetic manipulation of the myxobacterium
      Sorangium cellulosum So ce56.
AB  - In this study, Sorangium cellulosum So ce56 was phenotypically and genotypically
      analysed in order to evaluate whether this strain can be used in a comprehensive
      genome project as a representative of the secondary metabolite-producing
      myxobacteria. In contrast to many other strains of S. cellulosum, strain So ce56
      was found to have various advantageous features, including fast and homogeneous
      growth in submerged cultures and the ability to complete its morphological
      differentiation cycle on agar, even when the inoculant originates from a liquid
      culture. Two groups of secondary metabolites isolated from the culture broth were
      identified, the polyketides etnangien and chivosazole. The presence of polyketide
      synthase-encoding genes in the genome of strain So ce56 was demonstrated via PCR.
      The phenotypic classification was confirmed by comparison of 16S rDNA sequences
      which showed that S. cellulosum So ce56 clusters within a separate lineage
      together with S. cellulosum ATCC 25531 and the epothilone producer S. cellulosum
      So ce90. The genome of S. cellulosum So ce56 belongs to the largest bacterial
      genomes described so far. It is estimated to be 12.2 Mb in size, by pulsed-field
      gel electrophoresis. In order to demonstrate that S. cellulosum So ce56 is a
      convenient strain for molecular biological studies, a genetic manipulation system
      was developed. Using triparental mating, polyketide synthase-encoding genes were
      inactivated, leading to chivosazole-negative mutants.

PMID- 12420171
TI  - Intracellular pyruvate flux in the methane-producing archaeon Methanococcus
      maripaludis.
AB  - During growth of the methanogenic archaeon Methanococcus maripaludis on alanine
      as the sole nitrogen source under H(2)/CO(2), alanine was incorporated into amino
      acids derived from pyruvate including leucine, isoleucine, and valine. Thus,
      growth with alanine was an efficient means of labeling intracellular pools of
      pyruvate in this lithotroph. Cells were grown with 18% [U-(13)C]alanine, and the
      distribution of the isotope in the branched-chain amino acids was determined by
      (13)C-NMR. Carbons derived from pyruvate contained 14.5% (13)C, indicating that
      most of the cellular pyruvate was obtained from alanine. In contrast, carbons
      derived from acetyl-CoA contained only 3-5% (13)C, indicating that only small
      amounts of acetyl-CoA were formed from pyruvate. Thus, autotrophic acetyl-CoA
      biosynthesis continued even in the presence of an organic carbon source.
      Moreover, the labeling of acetyl-CoA was lower than would be predicted if
      pyruvate was a C-1 donor for acetyl-CoA biosynthesis. Carbon derived from the C-1
      of acetyl-CoA contained less (13)C than carbon derived from the C-2 of acetyl
      CoA, and this difference was attributed to the acetyl-CoA:CO(2) exchange activity
      of acetyl-CoA synthase. No enrichment was detected for the C-1 of valine, which
      was derived from the C-1 of pyruvate. This result was attributed to the
      pyruvate:CO(2) exchange activity of pyruvate oxidoreductase and may have
      important implications for isotope tracer studies utilizing pyruvate. Lastly,
      these results demonstrate that the breakdown of pyruvate by methanococci is very
      limited even under conditions where it is the sole nitrogen and major carbon
      source.

PMID- 12420172
TI  - Tricarboxylic acid cycle aconitase activity during the life cycle of Streptomyces
      viridochromogenesTu494.
AB  - Previously, it was shown that inactivation of the tricarboxylic acid cycle
      aconitase gene acnA impairs the morphological and physiological differentiation
      of Streptomyces viridochromogenes Tu494, which produces the herbicide
      phosphinothricin tripeptide (PTT). In order to further characterize the role of
      the aconitase in the Streptomyces life cycle, aconitase activity was analyzed
      during growth of S. viridochromogenes in liquid culture. Two prominent maxima
      were measured in cell-free crude extracts. The first maximum was found at an
      early stage of growth, which is correlated with a decrease in pH when rapid
      glucose consumption is initiated. The second, lower maximum was detected at the
      beginning of the expression of the PTT-specific biosynthetic gene phsA,implying
      the onset of secondary metabolism. These results were confirmed by examining
      transcription of the acnA promoter in time-course experiments. The highest
      transcription rate was found during the early growth phases. In order to identify
      putative regulatory mechanisms, the transcriptional start site of the acnA
      transcript and subsequently the promoter were identified. Several putative,
      regulatory protein binding sites (e.g. regulators of oxygen stress or iron
      metabolism) were detected in the promoter region of acnA, which suggested complex
      regulation of acnA.

PMID- 12420173
TI  - Genes involved in the anaerobic degradation of ethylbenzene in a denitrifying
      bacterium, strain EbN1.
AB  - Genes involved in anaerobic degradation of the petroleum hydrocarbon ethylbenzene
      in the denitrifying Azoarcus-like strain EbN1 were identified on a 56-kb DNA
      contig obtained from shotgun sequencing. Ethylbenzene is first oxidized via
      ethylbenzene dehydrogenase to (S)-1-phenylethanol; this is converted by (S)-1
      phenylethanol dehydrogenase to acetophenone. Further degradation probably
      involves acetophenone carboxylase forming benzoylacetate, a ligase forming
      benzoylacetyl-CoA, and a thiolase forming acetyl-CoA and benzoyl-CoA. Genes of
      this pathway were identified via N-terminal sequences of proteins isolated from
      strain EbN1 and by sequence similarities to proteins from other bacteria.
      Ethylbenzene dehydrogenase is encoded by three genes (ebdABC), in accordance with
      the heterotrimeric enzyme structure. Binding domains for a molybdenum cofactor
      (in subunit EbdA) and iron/sulfur-clusters (in subunits EbdA and EbdB) were
      identified. The previously observed periplasmic location of the enzyme was
      corroborated by the presence of a twin-arginine leader peptide characteristic of
      the Tat system for protein export. A fourth gene (ebdD) was identified, the
      product of which may act as an enzyme-specific chaperone in the maturation of the
      molybdenum-containing subunit. A distinct gene (ped) coding for (S)-1
      phenylethanol dehydrogenase apparently forms an operon with the ebdABCD genes.
      The ped gene product with its characteristic NAD(P)-binding motif in the N
      terminal domain belongs to the short-chain dehydrogenase/reductase (SDR)
      superfamily. A further operon apparently contains five genes (apc1-5) suggested
      to code for subunits of acetophenone carboxylase. Four of the five gene products
      are similar to subunits of acetone carboxylase from Xanthobacter autotrophicus.
      Upstream of the apc genes, a single gene (bal) was identified which possibly
      codes for a benzoylacetate CoA-ligase and which is co-transcribed with the apc
      genes. In addition, an apparent operon containing almost all genes required for
      beta-oxidation of fatty acids was detected; one of the gene products may be
      involved in thiolytic cleavage of benzoylacetyl-CoA. The DNA fragment also
      included genes for regulatory systems; these were two sets of two-component
      systems, two LysR homologs, and a TetR homolog. Some of these proteins may be
      involved in ethylbenzene-dependent gene expression.

PMID- 12420174
TI  - (R)-Benzylsuccinyl-CoA dehydrogenase of Thauera aromatica, an enzyme of the
      anaerobic toluene catabolic pathway.
AB  - The first intermediate of anaerobic toluene catabolism, (R)-benzylsuccinate, is
      formed by enzymic addition of the methyl group of toluene to a fumarate
      cosubstrate and is subsequently activated to (R)-2-benzylsuccinyl-CoA. This
      compound is then oxidised to benzoyl-CoA and succinyl-CoA by a specific beta
      oxidation pathway. The enzyme catalysing the first oxidation step of this
      pathway, (R)-benzylsuccinyl-CoA dehydrogenase, is encoded by the bbsG gene in
      Thauera aromatica. It was functionally overproduced in Escherichia coli, purified
      and characterised. The enzyme is a homotetramer with a subunit size of 45 kDa and
      contains one FAD per subunit. It is highly specific for (R)-benzylsuccinyl-CoA
      and is inhibited by (S)-benzylsuccinyl-CoA. An apparent K(m) value of 110+/-10
      micro M was obtained for (R)-benzylsuccinyl-CoA. The reaction product of (R)
      benzylsuccinyl-CoA dehydrogenase was identified as (E)-benzylidene-succinyl-CoA
      by comparison with the chemically synthesised compound, which was obtained via a
      new synthetic procedure. (R)-Benzylsuccinyl-CoA dehydrogenase was detected as a
      specifically substrate-induced protein in toluene- and m-xylene-grown cells of
      several bacterial species, using enzyme activity and immunological detection.

PMID- 12420175
TI  - Amino acid replacements in transmembrane domain 1 influence osmosensing but not
      K+ sensing by the sensor kinase KdpD of Escherichia coli.
AB  - Expression of the kdpFABC operon coding for the high affinity K+ -translocating
      KdpFABC complex of Escherichia coli is induced by K+ limitation or high
      osmolality. This process is controlled by the sensor kinase/response regulator
      system KdpD/KdpE. To study the importance of the transmembrane domains of KdpD
      for stimulus perception, each amino acid residue of the transmembrane domain 1
      and Asp-424 of the adjacent periplasmic loop were replaced with Cys in a KdpD
      derivative devoid of native Cys residues. In vivo analysis of KdpD proteins with
      a single Cys residue revealed that 14 out of 18 amino acid replacements caused an
      altered response towards an osmotic upshift imposed by NaCl, whereby only four
      replacements also altered the response towards changes in the K+ concentration.
      The in vitro activities of most of the KdpD derivatives were in the range of KdpD
      devoid of native Cys residues. The results reveal that the osmosensing and K+ 
      sensing properties of KdpD can be dissected. Furthermore, the data support the
      hypothesis that osmosensing involves amino acid residues of the transmembrane
      domains.

PMID- 12420176
TI  - Genetic groups of the insect-pathogenic fungus Beauveria bassiana are associated
      with habitat and thermal growth preferences.
AB  - A persistent paradigm in insect pathology is one that relates the insect host to
      certain genetic groups of insect-pathogenic fungi. This paradigm assumes that the
      genotype of an insect-pathogenic fungus coevolves with a certain taxon of insect
      host that it infects. The insect-pathogenic fungus Beauveria bassiana shows a
      wide host range and is considered to be a facultative insect pathogen. In this
      study, a population genetics analysis of B. bassiana from forested and
      agricultural habitats as well as from the Canadian Arctic showed distinct genetic
      groups associated with the three different habitats. Within each group,
      recombining population structures and clonally reproducing lineages were
      observed. The B. bassiana isolates were also assessed for their abilities to grow
      at 8, 15, 25 and 37 degrees C and for their tolerances to UV exposure. The
      genetic groups from the Arctic and from the forested habitats grew at lower
      temperatures, while the genetic group from the agricultural habitat grew at 37
      degrees C and was tolerant to UV exposure. There were no clear associations
      between the genetic group and the ability to infect coleopteran or lepidopteran
      insect larvae. There is increasing evidence that such studies represent a
      significant paradigm shift; habitat selection, not insect host selection, drives
      the population structure of deuteromycetous insect-pathogenic fungi. We suggest
      that adaptation to a certain habitat type is an important criterion for
      identifying insect-pathogenic fungal strains for use in insect biocontrol
      efforts.

PMID- 12420177
TI  - Native-feather degradation by Fervidobacterium islandicum AW-1, a newly isolated
      keratinase-producing thermophilic anaerobe.
AB  - A native-feather-degrading thermophilic anaerobe was isolated from a geothermal
      hot stream in Indonesia. Isolate AW-1, identified as a member of the species
      Fervidobacterium islandicum, was shown to degrade native feathers (0.8%, w/v)
      completely at 70 degrees C and pH 7 with a maximum specific growth rate (0.14 h(
      1)) in Thermotoga- Fervidobacterium(TF) medium. After 24 h of culture, feather
      degradation led to an increase in free amino acids such as histidine, cysteine
      and lysine. Moreover, nutritionally essential amino acids such as tryptophan and
      methionine, which are rare in feather keratin, were also produced as microbial
      metabolites. A homomultimeric membrane-bound keratinolytic protease (>200 kDa; 97
      kDa subunits) was purified from a cell extract of F. islandicum AW-1. The enzyme
      exhibited activity toward casein and soluble keratin optimally at 100 degrees C
      and pH 9, and had a half-life of 90 min at 100 degrees C. The enzyme showed
      higher specific activity for the keratinous substrates than other proteases and
      catalyzed the cleavage of peptide bonds more rapidly following the reduction of
      disulfide bridges in feather keratin by 10 mM dithiothreitol. Therefore, the
      enzyme from F. islandicum AW-1 is a novel, thermostable keratinolytic serine
      protease.

PMID- 12420178
TI  - In vivo assessment of the Tat signal peptide specificity in Escherichia coli.
AB  - Tat- and Sec-targeting signal peptides are specific for the cognate Tat or Sec
      pathways. Using two reporter proteins, the specificity and convertibility of a
      Tat signal peptide were assessed in vivo. The specific substitutions by RK, KR
      and KK for the RR motif of the TorA signal peptide had no effect on the exclusive
      Tat-dependent export of colicin V (ColV). By introducing multiple substitutions
      in a typical Tat signal peptide, altered signal peptides lacking the twin
      arginine motif were obtained. Interestingly, some of these signal peptides
      preserved Tat-pathway targeting capacity, but resulted in a loss of exclusivity.
      In addition, further increasing the hydrophobicity of the n-region without
      modifying the h-region converted the Tat signal peptides to Sec signal peptides
      in the ColV transport. Replacement of positively charged residues in the c-region
      also abolished the Tat-exclusive targeting of ColV or green fluorescent protein
      (GFP), but the folded GFP could be transported only through the Tat pathway.
      These results strongly suggest that the overall hydrophobicity of the n-region is
      one of the determinants of Tat-targeting exclusivity.

PMID- 12420179
TI  - Inducible aluminum resistance of Acidiphilium cryptum and aluminum tolerance of
      other acidophilic bacteria.
AB  - Aluminum ions are highly soluble in acidic environments. Toxicity of aluminum
      ions for heterotrophic, facultatively and obligately chemolithoautotrophic
      acidophilic bacteria was examined. Acidiphilium cryptum grew in glucose-mineral
      medium, pH 3, containing 300 mM aluminum sulfate [Al(2)(SO(4))(3)] after a lag
      phase of about 120 h with a doubling time of 7.6 h, as compared to 5.2 h of
      growth without aluminum. Precultivation with 1 mM Al(2)(SO(4))(3) and transfer to
      a medium with 300 mM Al(2)(SO(4))(3) reduced the lag phase from 120 to 60 h, and
      immediate growth was observed when A. cryptum was precultivated with 50 mM
      Al(2)(SO(4))(3), suggesting an aluminum-induced resistance. Aluminum resistance
      was not induced by Fe(3+) ions and divalent cations. Upon exposure of A. cryptum
      to 300 mM Al(2)(SO(4))(3), the protein profile changed significantly as
      determined by SDS-PAGE. When other acidophiles were cultivated with 50-200 mM
      aluminum sulfate, no lag phase was observed while the growth rates and the
      cellular yields were significantly reduced. This growth response was observed
      with Acidobacterium capsulatum, Acidiphilium acidophilum, Acidithiobacillus
      ferrooxidans, and Acidithiobacillus thiooxidans. Precultivation of these strains
      with aluminum ions did not alter the growth response caused by aluminum. The
      content of A. cryptum cultivated with 300 mM Al(2)(SO(4))(3)was 0.44 microg Al/mg
      cell dry weight, while that of the other strains cultivated with 50 mM
      Al(2)(SO(4))(3) ranged from 0.30 to 3.47 microg Al/mg cell dry weight.

PMID- 12420180
TI  - [Therapy concepts in chronic tinnitus retraining and/or group behavioral
      therapy?]].

PMID- 12420181
TI  - [Early cancer detection in persons exposed to asbestos dust. Is integration of
      ENT examination into the prevention program according to occupational directive G
      1.2 necessary?].

PMID- 12420182
TI  - [Clinical manifestations of diffuse idiopathic skeletal hyperostosis (DISH)].
AB  - BACKGROUND: Diffuse idiopathic skeletal hyperostosis (DISH, Forestier disease) is
      in most cases a harmless, asymptomatic disease characterized by a massive,
      noninflammatory ossification with intensive formation of osteophytes affecting
      ligaments, tendons, and fasciae, especially of the spinal column. If the disease
      becomes symptomatic at all, the leading complaints will usually be dysphagia in
      the sense of a lump in the throat and difficulty in swallowing. However, in rare
      cases the osteophytes may influence the laryngeal function ranging from
      hoarseness and immobility of the vocal cord to life-threatening inspiratory
      stridor. Such laryngeal manifestations are almost unknown. PATIENTS AND METHOD:
      We report on three patients, two female and one male, suffering not only from
      chronic dysphagia but also from increasing inspiratory stridor and difficult
      breathing. RESULTS: Especially one case illustrates how difficult it can be to
      establish the etiological relationship between a cancer-like ulcer in the
      postcricoid region and a bilateral inactivity of the vocal cord on the one hand
      and DISH on the other hand. Only the resistance of the ulceration to any therapy
      as well as rare case reports in the literature confirmed our suspicion that the
      ulcer and disturbance of laryngeal function were caused by chronic pressure
      exerted by the huge vertebral osteophytes. In all three patients surgical
      resection of the osteophytes resulted in complete relief of complaints.
      CONCLUSION: Uni- or bilateral immobility of the arytenoids, possibly associated
      with chronic inflammatory hyperplasia of the tissue of the arytenoids and the
      postcricoid region, may be a symptom of an unusual manifestation of DISH.

PMID- 12420183
TI  - [The influence of bioceramics on phagocytosis of human leukocytes].
AB  - BACKGROUND: After implantation of biomaterials in the regions of head and neck
      with resident microbial contamination the interaction between the implant and
      microbes play an important role for the success of the implantation. The host
      immune defence is important for the outcome after implantation, too. Phagocytosis
      plays an important role in the human immune response on infections. MATERIAL AND
      METHODS: The method described by Suess was used to investigate and measure the
      influence of the bioceramics Bioverit((R)) and Al(2)O(3)-ceramic on phagocytosis
      of yeast by human leukocytes. RESULTS: The bioceramics showed no statistically
      significant influence on phagocytosis function by human leukocytes. There was a
      tendency towards lower phagocytosis rates in all samples with bioceramics.
      CONCLUSIONS: The bioceramics Bioverit((R)) and Al(2)O(3) ceramic have no
      influence on phagocytosis of human leukocytes. In conclusion these biomaterials
      did not cause any inhibition of this important part of the human immune response
      on microbial infections after alloplastic implantation in head and neck regions.

PMID- 12420184
TI  - [Findings in a high-risk group following asbestos exposure. Benefit of ENT
      examinations in patients with long-term exposure to asbestos].
AB  - BACKGROUND AND OBJECTIVE: Laryngeal diseases caused by exposure to asbestos are
      listed in the current German list of occupational diseases under number 4104.
      Parallel to a multicenter study to evaluate whether a CT scan should be included
      in the examinations for occupational diseases according to the German
      surveillance guidelines, an additional ENT examination was evaluated. PATIENTS
      AND METHODS: One hundred workers with a mean exposure time to asbestos of 20.9
      years were given a complete ENT examination in 4 consecutive years (1993-1996).
      Radiological signs for asbestosis were observed in 21 cases and 58 participants
      had pleural affections caused by asbestos. Significant nicotine abuse was
      reported by 15 persons: 61 participants were ex-smokers and 24 had never smoked.
      Regular alcohol consumption was reported by 90% (11% more than 80 g/day).
      RESULTS: As documented in the literature, we found a high prevalence of
      laryngitis, especially in smoking patients. One patient had early laryngeal
      cancer (T1). CONCLUSION: The integration of an ENT examination into the German
      surveillance guidelines for occupational diseases should be discussed for
      patients with a high exposure to asbestos.

PMID- 12420186
TI  - ["Childhood illnesses" 2002].

PMID- 12420185
TI  - [Evaluation of the tinnitus retraining therapy as combined with a cognitive
      behavioral group therapy].
AB  - BACKGROUND: The study evaluates the effectiveness of a Tinnitus Retraining
      Therapy as combined with a cognitive behavioral group therapy. PATIENTS AND
      METHODS: 95 patients suffering from chronic tinnitus (mean age 49,3 years) were
      included. 16 of these 95 participants served as a waiting list control group. The
      participants were divided into 3 treatment groups. Group 1 was fitted with
      wideband noise generators, group 2 with hearing aids. The 3rd group was not
      supplied with any device. After a detailed audiological and psychological
      examination and tinnitus counseling all patients took part in a cognitive
      behavioral therapy for a period of 3 months. RESULTS: 64,5% of our patients
      improved significantly after the initial group therapy. In contrast, the patients
      of the waiting list control group showed no significant improvement. This initial
      treatment effect could be maintained over the period of control. We were unable
      to show significant advantages of noise generators as compared to cognitive
      behavioural group therapy alone. CONCLUSION: The Tinnitus Retraining Therapy
      combined with a cognitive behavioral group therapy is an effective treatment in
      patients with chronic tinnitus.

PMID- 12420187
TI  - [Cervical cystic hygroma] ].
AB  - We report the case of a 27-year-old patient suffering from a cystic hygroma of
      unknown etiology. She presented with an asymptomatic fluctuant mass in the right
      posterior triangle of the neck. NMR-scans revealed a cystic tumor in the above
      mentioned area without enhancement after administration of gadolinium. The cystic
      hygroma was surgically excised. Three and six months after surgery there was no
      sign of recurrence. By means of the presented case report and review of
      literature we discuss diagnosis and treatment of cystic hygromas.

PMID- 12420188
TI  - [Vesicular diseases of mouth and oropharyngeal mucosa].

PMID- 12420189
TI  - Secular trends in cardiovascular disease.

PMID- 12420190
TI  - Hypertension and the eye: changing perspectives.
AB  - Systemic hypertension is a common condition associated with significant morbidity
      and mortality. Hypertension confers cardiovascular risk by causing target-organ
      damage that includes retinopathy in addition to heart disease, stroke, renal
      insufficiency and peripheral vascular disease. The recognition of hypertensive
      retinopathy is important in cardiovascular risk stratification of hypertensive
      individuals. This review reevaluates the changing perspectives in the
      pathophysiology, classification and prognostic significance of fundal lesions in
      hypertensives.

PMID- 12420191
TI  - Secular changes in blood pressure in childhood, adolescence and young adulthood:
      systematic review of trends from 1948 to 1998.
AB  - One plausible reason for the decline in cardiovascular disease (CVD), and in
      particular stroke, in the last century is population reductions in blood
      pressure. Blood pressure tracks from childhood into adulthood, and early-life
      blood pressure is associated with increased cardiovascular risk but few studies
      have reported on blood pressure trends among young individuals who are free of
      CVD and not taking antihypertensive medication. Knowledge of such trends may
      improve understanding of the causes of hypertension and enhance prevention. We
      report that declines in blood pressure have been taking place in high-income
      countries in 5 to 34-year-olds of both sexes and from a range of ethnic groups
      for at least the last 50 years, indicating that exposures acting in early life
      are important determinants of blood pressure. Possible explanations for these
      favourable trends include improvements in early-life diet and there is also
      intriguing evidence suggesting that blood pressure may be programmed by sodium
      intake in infancy. Occurring throughout the blood pressure distribution, these
      trends may have made important contributions to declining CVD rates. There may
      therefore be scope for intervening in early life to prevent high blood pressure
      in adulthood, and the downward trends reported in several recent studies suggest
      that the prevalence of adult hypertension and cardiovascular risk will continue
      to decline. However, persisting high rates of CVD in the developed world, the
      impending CVD epidemic in developing countries, along with increasing childhood
      obesity, and the possibility that favourable blood pressure trends may be
      plateauing point to the need for enhanced measures to control blood pressure, and
      for further research to improve understanding of its determinants.

PMID- 12420192
TI  - Are we negating the benefits of CABG by forgetting secondary prevention?
AB  - The objective of the study was to examine medically managed secondary prevention
      at one year after coronary artery bypass grafting (CABG). In all, 214 consecutive
      patients undergoing isolated elective CABG seen four weeks preoperatively and one
      year post-operatively. Preoperative systolic blood pressure averaged 135+/-20
      mmHg, which increased to 148+/-25 mmHg (P<0.0001) as did diastolic pressure (81+/
      12 to 87+/-13 mmHg; P<0.0001). Anginal symptoms were reported by 45.1% (P<0.0001)
      although median severity scored lower (4.0 [3.0-5.4] vs 0 [0-2.0]; P<0.0001).
      Breathlessness decreased from 93% to 64% (P<0.0001) and was scored less severely
      (4.0 [2.0-5.0] vs 2.0 [0-4.0]; P<0.0001. In all, 88% with postoperative angina
      reported dyspnoea against 44% of those without (P<0.0001). Calcium antagonist use
      was more common in patients with angina (27.2% vs 5.1%; P<0.0001), but not
      nitrates (P=0.8695), diuretics (P=0.4218), digoxin (P=0.2565), beta-blockers
      (P=0.0820), or ACE inhibitors (P=0.7256). Preoperatively 166 patients (80.2%)
      took aspirin vs 69.2% afterwards (P=0.0131). Twelve patients (6.5%) received
      warfarin after operation vs none preoperatively. Two took digoxin (0.97%)
      preoperatively and 14 (7.7%) postoperatively (P=0.001) for chronic atrial
      fibrillation. One of these took warfarin. Long-acting nitrate use fell from 63.4%
      to 15.8% (P <0.0001). Short-acting nitrate use fell similarly (P<0.0001).
      Preoperatively 37 patients (17.9%) took ACE inhibitors vs 44 postoperatively
      (24.2%); 39 had not received them before. Preoperatively 48 (23.2%) took
      diuretics vs 30 (16.5%) postoperatively (P=0.127); 24 had not previously taken
      diuretics. More patients took HMGCoA inhibitors postoperatively (P=0.0068) and
      total cholesterol was significantly reduced with a concomitant increase in HDL
      fraction. Smoking habit was virtually unchanged from 17.8% to 15.1% (P=0.5023).
      IN CONCLUSION: angina was common. Apart from statin prescribing, postoperative
      secondary prevention measures were poorly applied, less widespread and less
      effective than preoperatively. The implications are disturbing.

PMID- 12420193
TI  - Compliance to hypertension guidelines in clinical practice: a multicentre pilot
      study in Italy.
AB  - The aim of this study was to investigate the diagnostic approach to recently
      diagnosed hypertensive patients by primary care physicians in Italy and to find
      out whether general practitioners manage these patients according to 1999 WHO/ISH
      guideline recommendations. In total, 228 consecutive patients (117 men and 111
      women, mean age 51+/-12 years) with recently diagnosed hypertension (<2 years)
      referred for the first time to six outpatient hypertension centres throughout
      Italy were included in the study. The primary care physicians' approach was
      evaluated during the specialist visit by a specific questionnaire containing
      detailed questions about diagnostic work-up and treatment made at the time of the
      first diagnosis of hypertension. At the study visit, 71% of the patients were on
      treatment with antihypertensive drugs and 18.7% of them had blood pressure (BP)
      values lower than 140/90 mmHg. A complete clinical and laboratory evaluation
      according to the minimum work-up suggested by the guidelines had been carried out
      in only 10% of the patients. A full physical examination had been performed in
      60% of the patients, electrocardiogram in 54%, serum total cholesterol in 53%,
      glucose in 49%, creatinine in 49%, urine analysis in 46%, potassium in 42%, and
      fundus oculi in 19%. Additional investigations such as ambulatory BP monitoring,
      echocardiogram, carotid ultrasonogram, and microalbuminuria had been carried out
      in a minority of patients (21, 18, 9, and 3%, respectively). The impact on
      hypertension guidelines on patients' management in everyday primary care practice
      appears marginal. Thus, our findings indicate that the majority of general
      practitioners manage hypertensive patients according to a simple BP-based
      approach rather than a more integrated approach based on global risk
      stratification.

PMID- 12420194
TI  - Effects of atorvastatin on aortic pulse wave velocity in patients with
      hypertension and hypercholesterolaemia: a preliminary study.
AB  - As statins may contribute to plaque stabilisation, it is important to evaluate
      whether these drugs may modify arterial stiffness. In 23 patients, aged 32-70
      years, with hypertension and hypercholesterolaemia, a double-blind randomised
      study vs placebo was performed to evaluate whether atorvastatin was able to
      modify aortic stiffness, measured from aortic pulse wave velocity (PWV), after a
      12-week treatment. The results revealed that atorvastatin did not change blood
      pressure, significantly lowered (P<0.003; <0.002) plasma total and LDL
      cholesterol, and increased aortic PWV by +8% (vs -2% under placebo) (P<or=0.05).
      The percentage changes in plasma total and LDL cholesterol and in PWV were
      significantly and negatively correlated, independent of blood pressure level. The
      finding of increased aortic PWV after 12-week statin treatment agrees with
      studies in monkeys, indicating that, at the early phase of hypolipidaemic diet
      but not later, aortic PWV increases transiently as a consequence of the
      significant reduction of lipid vascular content. In conclusion, the present
      results support the possibility that statins might contribute to a change in
      arterial stiffness independent of blood pressure level, and suggest that long
      term studies in humans are needed to evaluate the contribution of arterial
      elasticity to statin-induced vascular remodelling.

PMID- 12420195
TI  - Age-related changes in peripheral pulse timing characteristics at the ears,
      fingers and toes.
AB  - It is accepted that older subjects have increasing arterial stiffness, which
      results in increasingly faster pulse transmission to the periphery. However, this
      age association is less clear in younger subjects and for different peripheral
      measurement sites. The aims of this study were to determine the association
      between age and pulse timing characteristics over a five decade age range at the
      ears, fingers and toes, and to compare these with any additional effects
      associated with differences in subject height, systolic blood pressure and heart
      rate. Photoplethysmography pulse wave-forms were recorded noninvasively from the
      right and left sides at the ears, fingers and toes of 116 normal healthy human
      subjects. Their median age was 42 years (range 13-72 years). Systolic blood
      pressure, height and heart rate were also measured. Pulse transit times (PTTs)
      were determined and referenced to the electrocardiogram R wave. The results
      revealed that age was the strongest contributor to PTT differences at all sites
      (P<0.0001). The decrease with ageing was greatest at the toes: -1.6, -0.6, -0.4
      ms/year for the toes, fingers, and ears, respectively. Changes for the right and
      left body sides at each level were highly similar. Blood pressure was also an
      important contributor to PTT at all sites (P<0.0001); -1.0, -0.4, -0.3 ms/mm Hg,
      respectively, with approximately half of the effect explained by age. Height was
      significantly and independently related to PTT at the fingers and toes
      (P<0.0001); +1.1, +0.7 ms/cm, respectively. The fraction of PTT variability
      explained by these relationships was 0.65, 0.48, 0.26 for the toes, fingers and
      ears, respectively (P<0.0001). Finally, we concluded that the age effect
      decreased linearly from the second to the seventh decades, demonstrating that the
      effect of changes in arterial stiffness can be detected noninvasively from an
      early age at three main peripheral sites. Age is the dominant factor in
      contributing to PTT, and is greatest at the toes, followed by the fingers and
      then the ears.

PMID- 12420196
TI  - Clinic and ambulatory pulse pressure segregate a cluster of cardiovascular risk
      factors.
AB  - Office pulse pressure (PP) has been found to be independently associated with
      cardiovascular morbidity and mortality. While there is evidence that 24 h blood
      pressure (BP) is a better marker of the cardiovascular complications of
      hypertension than office BP, this information is still lacking in regard to PP.
      The aim of the present study was, therefore, to evaluate possible differences
      between office and 24 h PP in their relationship with cardiovascular risk
      profile. This cross-sectional study was performed in a group of 175 (104 M, 71 F)
      hypertensives (43 never treated before the study) free of clinical evidence of
      target organ disease. BP was measured at rest and during 24 h monitoring; cardiac
      structure and function was studied by ultrasounds; biochemical analyses were
      performed to evaluate some parameters of lipid and carbohydrate metabolism.
      Patients were divided into tertiles of office PP and of 24 h PP. Those in the
      highest tertile of PP had a significantly higher office and 24 h systolic BP
      along with a reduction in peripheral insulin sensitivity. Regarding cardiac
      structure and function, a significantly higher prevalence of concentric left
      ventricular hypertrophy (23 vs 55%; P=0.05) and an initial impairment of
      diastolic function with increase of the A wave was detected in hypertensives with
      higher PP. No difference between office and 24 h PP in detecting patients at
      higher cardiovascular risk was observed. In conclusion, office and 24 h pulse
      pressures were both able to segregate patients with a cluster of cardiovascular
      risk factors.

PMID- 12420197
TI  - Janus faces of the white coat effect: blood pressure not only rises, it may also
      fall.
AB  - For reliable control of hypertension, it is essential to know the prevalence of
      the white coat effect (WCE), which is defined as either a difference of 10 mmHg
      or more in systolic blood pressure (BP) and/or a difference of 5 mmHg or more in
      diastolic BP measured by a general practitioner (GP), a nurse, or the patient
      him/herself. The objective was to assess the WCE in hypertensive patients
      visiting GPs in primary healthcare centres. A blinded, randomised study in six
      primary healthcare centres was conducted, where eight GPs, nine nurses and 210
      patients (92 men and 118 women) on a hypertension control regimen participated.
      Heart rate and BP in GPs', nurses' and self-service rooms were measured twice
      using a sphygmomanometer and an automatic device. Altogether, 148 patients (70%)
      performed the self-measurements of BP and heart rate perfectly successfully in
      all the three rooms. These were included in the final analyses. One out of three
      patients (33%) showed a marked alerting WCE in the GP's room (systolic BP rose by
      at least 10 mmHg and/or diastolic BP by at least 5 mmHg). On the contrary, one
      out of 10 (10%) showed a marked relaxing WCE in the GP's room (systolic BP
      decreased by at least 10 mmHg and/or diastolic BP by at least 5 mmHg). It can be
      concluded that the WCE in general practice has two faces: an alerting reaction
      and a relaxing reaction. This should be taken into account in hypertension
      control.

PMID- 12420198
TI  - Assessment of drug effects on blood pressure and pulse pressure using clinic,
      home and ambulatory measurements.
AB  - This study investigated the differences in the effect of an angiotensin
      converting enzyme inhibitor (ACEI) compared with an angiotensin receptor blocker
      (ARB) on blood pressure (BP) and pulse pressure (PP) measured in the clinic (CBP
      and CPP, respectively), at home (HBP, HPP) and with ambulatory monitoring (ABP,
      APP). Twenty-seven hypertensive patients were randomised to receive lisinopril
      (20 mg) or losartan (50 mg) for 5 weeks, and were subsequently crossed-over to
      the alternative treatment for a second 5-week period. Measurements of CBP, 24-h
      ABP and 5-days HBP were performed before randomisation and at the end of each
      treatment period. All measurement methods showed that lisinopril was more
      effective than losartan in reducing BP. However, the difference between the two
      drugs was demonstrated with greater precision using HBP (P<0.001) than 24-h ABP
      (P<0.01), whereas the poorest precision for demonstrating this difference was
      provided by CBP (P<0.05). Lisinopril was also found more effective than losartan
      in reducing HPP (P=0.01) and 24-h APP (P=0.03) whereas no such a difference was
      detected using measurements of CPP. It was concluded that the antihypertensive
      drugs may differ in their effects not only on BP, but also on PP. HBP monitoring
      appears to be as reliable as 24-h ABP monitoring in detecting differences in the
      effect of drugs on both BP and PP. Clinic measurements seem to be the least
      reliable method, particularly in the detection of differences in PP.

PMID- 12420200
TI  - Treatment of gonadal damage in recipients of allogeneic or autologous
      transplantation for haematological malignancies.
AB  - Management of iatrogenic gonadal reproductive failure and sexual morbidity
      assumes a priority, especially in young recipients of high-dose chemotherapy and
      stem cell transplantation (SCT). Hormone replacement treatment (HRT) is
      beneficial for correction of sexual symptoms and osteoporosis in both sexes,
      especially in females. Sperm banking is the standard technique for preservation
      of fertility in adult and sexually mature adolescent males. Testicular tissue
      cryopreservation has a place in well-selected azoospermic adults and in mentally
      and sexually competent adolescents. In vitro fertilisation using superovulation
      with embryo-cryopreservation (for future embryo transfer) is the most tried
      method in female SCT recipients with good results. In mentally and sexually
      competent adolescents and adults without a partner, ovarian cortical tissue
      cryopreservation has a place for subsequent re-implantation to orthotopic or
      heterotopic sites. Gonadotrophin releasing hormone (GnRH) co-treatment during
      chemotherapy, is a promising method for the future. Although generally
      reassuring, continued monitoring of the offspring of SCT survivors and follow-up
      of all recipients of SCT is important for return of spontaneous or induced
      fertility.

PMID- 12420201
TI  - Outcome of 5651 hematopoietic stem cell transplants for hematological
      malignancies carried out in Europe in 1993: a reliability study of the registry.
AB  - Outcome results of observational databases are frequently criticized as relying
      on incomplete information from incomplete patient populations. Few data are
      available to dispute these arguments of selection bias. The European Group for
      Blood and Marrow transplantation (EBMT) decided to address this question by
      evaluating the hematopoietic stem cell transplants performed in 1993. A
      comprehensive survey was launched in an effort to collect informations on all
      transplants for hematological malignancies performed throughout Europe during the
      year 1993. The main goals of this effort were to compare the group of
      spontaneously reported patients with the group of retrospectively solicited
      patients, and to give an accurate estimate of the outcome of all patients. For
      the year 1993, the annual EBMT activity survey indicated 6336 transplants
      performed for hematological malignancies in Europe. A total of 5651 transplants
      could be analyzed; 2595 were reported spontaneously by the teams (group A) and
      3056 were retrieved on solicitation (group B). Patients and transplant
      characteristics for group A and B were very similar for most parameters with a
      few exceptions. There was no statistical difference for outcome at 3 years
      between groups A and B: disease-free survival (DFS) was 45 +/- 1% and 44 +/- 1%,
      relapse incidence (RI) 41 +/- 1% and 42 +/- 1%, transplant-related mortality
      (TRM) 23 +/- 1% and 23 +/- 1%, and overall survival (OS) 54 +/- 1% and 55 +/- 1%,
      respectively, for group A and group B. The real outcome at 3 years for the 5651
      patients (group A + group B) transplanted in 1993 was 44 +/- 1%, 41 +/- 1%, 23 +/
      1%, and 54 +/- 1%, for DFS, RI, TRM and OS, respectively. The outcome at 3 years
      by transplant modality, autologous or allogeneic transplants, and by disease
      categories showed no difference between groups A and B.

PMID- 12420202
TI  - A phase I dose-escalation study of etoposide continuous infusion added to
      busulphan/cyclophosphamide as conditioning prior to autologous or allogeneic stem
      cell transplantation.
AB  - Relapse of the primary disease remains the predominant cause of death following
      bone marrow transplantation for high-risk haematological malignancies. Improved
      supportive care and patient selection have resulted significant improvements in
      toxicity with standard conditioning regimens. Further dose intensification to
      reduce the risk of relapse may therefore be feasible. We determined the maximal
      tolerated dose (MTD) of a 5-day continuous infusion (CI) of etoposide when added
      to oral busulphan 16 mg/kg and intravenous cyclophosphamide 120 mg/kg (Bu/Cy) as
      conditioning in 44 autograft and 18 allograft recipients at high risk of relapse.
      The major toxicity of escalating doses of etoposide was oral and gastro
      intestinal mucositis, reflected by a statistically significant increase in the
      requirement for total parenteral nutrition in both autografts and allograft
      recipients. Time to neutrophil and platelet recovery, opiate analgesia
      requirements, and duration of hospitalization were not affected by etoposide dose
      escalation. The MTD in autograft recipients was 300 mg/m(2)/day (1500 mg/m(2)
      total dose), and 100 mg/m(2)/day (500 mg/m(2) total dose) for allograft
      recipients. Mucositis and hepatotoxicity were more frequent in allograft
      recipients, suggesting that methotrexate may have contributed to the lower
      tolerable dose in these patients. As a consequence, further dose escalation may
      not be possible in heavily pre-treated patients undergoing allogeneic
      transplantation. Conversely, high dose CI etoposide can be added with relative
      safety to Bu/Cy in autograft recipients.

PMID- 12420203
TI  - Reduced intensity preparative regimens for allogeneic hematopoietic stem cell
      transplantation: a single center experience.
AB  - According to recent reports, fast engraftment with minimal transplant-related
      toxicity and mortality (TRT, TRM) can be achieved by using reduced-intensity
      preparative regimens in allogeneic hematopoietic stem cell transplantation
      (HSCT). We report our experience with related (39%) and unrelated (61%) HSCT in
      44 high risk patients (AML, ALL, CML, CLL) receiving either busulfan/fludarabine
      or busulfane/fludarabine/ATG or TBI/fludarabine as reduced-intensity preparative
      regimens. Organ toxicity was minimal with mild mucositis and no major bleeding.
      Acute GVHD was recorded in 64% of the patients. Twenty-three patients achieved
      complete remission after transplantation, and complete chimerism was obtained in
      all patients with stable engraftment (35 patients). Twenty-nine patients died: 15
      due to relapse/progression, 14 due to TRM. Survival with median follow-up of 18.5
      months was significantly better in patients with matched related transplants
      compared to patients with other transplants. However, there was no difference
      between related and unrelated transplants with regard to engraftment, TRM and
      GVHD. In conclusion, our results in high-risk patients transplanted in CR or with
      smoldering leukemia from a related donor are encouraging, although a longer
      follow-up and a larger group of patients is needed in order to evaluate the role
      of different reduced-intensity preparative regimens in unrelated and related
      HSCT.

PMID- 12420204
TI  - Long-term follow-up of normal peripheral blood progenitor cell donors treated
      with filgrastim: no evidence of increased risk of leukemia development.
AB  - Data on the long-term safety of filgrastim administration in peripheral blood
      progenitor cell (PBPC) donors are scarce. The main theoretical risk is believed
      to be the possible development of leukemia. We conducted a survey of filgrastim
      treated related donors to determine the incidence of leukemia after PBPC
      donation. Of the 343 PBPC donors eligible for inclusion in the survey, 281 (82%)
      were interviewed by telephone between December 1998 and February 2000. The mean
      age at donation was 44 years. The median time elapsed after PBPC donation was 39
      months, and in 278 (99%) of the interviewed donors it was at least 1 year. At the
      time of the interview none of the donors had been diagnosed with acute or chronic
      leukemia. Although the sample size is small and the follow-up duration is
      limited, these data suggest that exposure to filgrastim is not associated with
      any notable risk of leukemia development in PBPC donors.

PMID- 12420205
TI  - Polymorphisms of transforming growth factor-beta1 and transforming growth factor
      beta1 type II receptor genes are associated with acute graft-versus-host disease
      in children with HLA-matched sibling bone marrow transplantation.
AB  - The aim of this study was to determine whether the gene polymorphisms of Th1/Th2
      and immunoregulatory cytokines were associated with aGVHD in Japanese children
      receiving allogeneic bone marrow transplantation (allo BMT). We investigated
      polymorphisms of genes encoding interleukin (IL)-4, IL-4 receptor (IL-4 R), IL
      10, transforming growth factor (TGF)-beta1, TGF-beta1 type II receptor (TGF-beta1
      RII), interferon (IFN)-gamma, IFN-gamma type 2 receptor (IFN-gamma R2), and IFN
      regulatory factor (IRF)-1. Sixty-seven patients were treated with allo BMT from
      HLA-identical siblings, and aGVHD was observed in 38. TGF-beta1 codon 10 leucine
      (Leu) /proline (Pro) polymorphism in donors was associated with the development
      of aGVHD. Patients having donors with the Pro allele had aGVHD more frequently
      than those without Pro allele (30/45 vs 8/20, odds ratio = 3.00; P = 0.04). TGF
      beta1 RII 1167 C/T polymorphism in recipients was also associated with the
      development of aGVHD. The incidence was significantly higher in recipients with T
      allele than in those without T allele (21/27 vs 16/35, odds ratio = 4.16; P =
      0.01). In conclusion, genetic backgrounds of TGF-beta1 and TGF-beta1 RII may be
      involved in the development of aGVHD in HLA-matched sibling BMT in Japanese
      children.

PMID- 12420206
TI  - Response to induction chemotherapy is not essential to obtain survival benefit
      from high-dose melphalan and autotransplantation in myeloma.
AB  - Two hundred and twenty-two myeloma patients autografted after 200
      mg/m(2)melphalan were studied to examine the relationship between response to
      induction chemotherapy and outcome. Induction comprised cyclophosphamide,
      vincristine, doxorubicin and methylprednisolone (C-VAMP) every 3 weeks for one
      cycle beyond maximum response. 81% responded to C-VAMP (chemosensitive) with 40
      complete (CR) and 139 partial (PR) remissions, and 43 did not respond (NR; <50%
      reduction in paraprotein; primary refractory). Overall, 130 patients (59%)
      attained or remained in CR post-transplant; including 40% of NR, 53% of PR, and
      97% of CR after C-VAMP (P < 0.0001). Amongst these 130 patients, the 5-year OS
      was independent of response to C-VAMP (NR 79%, PR 74%, CR 60%; P = 0.69).
      Similarly, among the 69 patients in PR post-transplant, the 5-year OS was
      independent of response to C-VAMP. In Cox analysis, lack of response to C-VAMP
      did not affect outcome significantly. These data show that lack of response to
      induction therapy does not automatically predict poor long-term outcome in
      myeloma, since a substantial proportion of these patients attain CR after
      autograft and enjoy extended survival. Myeloma patients should not be
      disqualified from an autograft based upon lack of response to induction
      chemotherapy.

PMID- 12420207
TI  - Unrelated donor BMT recipients given pretransplant low-dose antithymocyte
      globulin have outcomes equivalent to matched sibling BMT: a matched pair
      analysis.
AB  - Fifty-seven patients receiving unrelated donor (UD) BMT were matched for disease
      and stage with 57 recipients of genotypically matched related donor (MRD) BMT.
      All UD recipients were matched serologically for A and B and by high resolution
      for DR and DQ antigens. All patients received CsA and 'short course' methotrexate
      with folinic acid. Unrelated donor BMT patients also received thymoglobulin 4.5
      mg/kg (6 mg/kg if <30 kg) in divided doses over 3 days pretransplant. For UD and
      RD BMT, respectively, incidence of acute GVHD grade II-IV was 19 +/- 6% vs 36 +/-
      8%, grade III-IV 10 +/- 6% vs 18 +/- 7%, chronic GVHD 44 +/- 8% vs 51 +/- 8%, non
      relapse mortality 15 +/- 5% vs 8 +/- 4% at 100 days, 28 +/- 8% vs 36 +/- 7% at 3
      years. At 3 years, relapse was 45 +/- 7% vs 42 +/- 7%, and disease-free survival
      39 +/- 7% vs 37 +/- 7%. None of these differences are significant. Three-year
      overall survival was identical at 42 +/- 7%. For 29 patients with
      low/intermediate risk leukemia, disease-free survival was 68 +/- 10% after UD BMT
      vs 59 +/- 9% for RD BMT recipients (P = NS). Corresponding figures for high risk
      patients were 14 +/- 7% and 21 +/- 8%, respectively. We conclude that UD BMT
      recipients matched as above and given pretransplant ATG have similar outcomes to
      recipients of MRD BMT using conventional drug prophylaxis. Unrelated donor BMT
      should be considered in any circumstance where MRD BMT is routine.

PMID- 12420208
TI  - Generation of alloreactive anti-leukemic cytotoxic T lymphocytes with attenuated
      GVHD properties from haploidentical parents in childhood acute lymphoblastic
      leukemia.
AB  - We sought to generate alloreactive leukemia-reactive cytotoxic T lymphocytes from
      haploidentical parents by culture of peripheral blood mononuclear cells in vitro
      with irradiated leukemic blasts and IL-2 from children with ALL. After 21 days in
      culture the mean cytotoxicity of haploidentical lymphocytes against ALL blasts
      was 38% (n = 11). Cultured parental CTL were not leukemia specific but
      alloreactive as evidenced by equivalent cytotoxicity against stimulating ALL
      blasts and ConA-stimulated blasts from the other parent. The cultures yielded
      primarily CD8(+) T cells (59%). Irradiation of CTL limited proliferation by 96%
      but had no short-term effects on leukemia reactive cytotoxicity, suggesting a
      means to limit GVHD potential in vivo. One patient was treated for relapse of ALL
      post-haploidentical transplant with CTL generated from the original donor. A
      total of nine infusions were given: the first three were irradiated, while the
      last six were not due to disease progression. The patient experienced clearance
      of peripheral blasts, and despite concomitant infusion of IL-2 with the last
      three CTL infusions, did not experience immediate GVHD reactions. We conclude
      that ALL blasts are sufficiently immunostimulatory to generate in vitro CTL with
      provision of exogenous IL-2, and that these CTL could exert an anti-leukemia
      effect in vivo.

PMID- 12420209
TI  - Successful bone marrow transplantation from an unrelated donor in a patient with
      adult T cell leukemia.
AB  - We report a 51-year-old male with adult T cell leukemia (ATL) who received a BMT
      from an HLA-identical unrelated donor. The ATL proved refractory to chemotherapy,
      and he underwent BMT conditioned with CY/TBI. Complications of encephalitis of
      unknown origin were successfully treated with steroid therapy and the patient has
      been in CR for 16 months after BMT. Human T cell leukemia virus type 1 proviral
      DNA loads were reduced to undetectable levels in PBMC sampled 12 months after
      BMT. This encouraging result suggests that BMT from an unrelated donor should be
      considered for ATL even if the disease is refractory to chemotherapy.

PMID- 12420210
TI  - The effect of post-transplant spironolactone on daily potassium requirements in
      patients undergoing autologous stem cell transplantation.

PMID- 12420211
TI  - Rapid-onset leucodrema associated with graft-versus-host disease.

PMID- 12420213
TI  - BCL-x(L) and BCL2 delay Myc-induced cell cycle entry through elevation of p27 and
      inhibition of G1 cyclin-dependent kinases.
AB  - The anti-apoptotic molecules BCL-x(L) and BCL2 delay cell cycle entry from
      quiescence. We used serum induction and induction of a Myc-estrogen receptor
      fusion protein (MycER) in quiescent fibroblasts to investigate the mechanisms
      underlying the cell cycle activity of BCL-x(L) and BCL2. We demonstrate for the
      first time that BCL-xL and BCL2 delayed serum-induced and Myc-induced, but not
      E2F-induced, cell cycle entry. The cyclin-dependent kinase inhibitor p27 was
      elevated during serum deprivation and cell cycle entry in BCL-x(L) or BCL2
      expressing NIH3T3 cells and a Rat1MycER cell line. Activation of cyclin-dependent
      kinase 2 (cdk2) and cyclin-dependent kinase 4 (cdk4) were delayed during
      progression to S phase, while the induction of cyclin D1 protein, as well as the
      levels of cyclin E, cdk2, and cdk4 were unaltered by BCL-x(L) or BCL2. Inhibition
      of cyclin/cdk activities in BCL-x(L) or BCL2 expressing cells was associated with
      excess p27 in the cyclin/cdk complexes. Neither BCL-x(L) nor BCL2 delayed S phase
      entry in cells deficient in p27, thus p27 is required for the cell cycle function
      of BCL-x(L) and BCL2. The cell cycle effects of BCL-x(L) and BCL2 were more
      profound in Myc-induced than in serum-induced cell cycle entry. Our results
      suggest that one possible mechanism by which BCL-x(L) and BCL2 delay cell cycle
      entry may be the inhibition of Myc activity through the elevation of p27.

PMID- 12420214
TI  - Regulation of the IRF-1 tumour modifier during the response to genotoxic stress
      involves an ATM-dependent signalling pathway.
AB  - The mechanism by which genotoxic stress induces IRF-1 and the signalling
      components upstream of this anti-oncogenic transcription factor during the
      response to DNA damage are not known. We demonstrate that IRF-1 and the tumour
      suppressor protein p53 are coordinately up-regulated during the response to DNA
      damage in an ATM-dependent manner. Induction of IRF-1 protein by either ionizing
      radiation (IR) or etoposide occurs through a concerted mechanism involving
      increased IRF-1 expression/synthesis and an increase in the half-life of the IRF
      1 protein. A striking defect in the induction of both IRF-1 mRNA and IRF-1
      protein was observed in ATM deficient cells. Although ATM deficient cells failed
      to increase IRF-1 in response to genotoxic stress, the induction of IRF-1 in
      response to viral mimetics remained intact. Re-expression of the ATM kinase in AT
      cells restored the DNA damage inducibility of IRF-1, whilst the PI-3 kinase
      inhibitor wortmannin inhibited IRF-1 induction by DNA damage in ATM-positive
      cells. The data highlight a role for the ATM kinase in orchestrating the
      coordinated induction and transcriptional cooperation of IRF-1 and p53 to
      regulate p21 expression. Thus, IRF-1 is controlled by two distinct signalling
      pathways; a JAK/STAT-signalling pathway in viral infected cells and an ATM
      signalling pathway in DNA damaged cells.

PMID- 12420215
TI  - Human Dbf4/ASK promoter is activated through the Sp1 and MluI cell-cycle box
      (MCB) transcription elements.
AB  - Dbf4 is the regulatory subunit of Cdc7 kinase, which is essential for entry into
      and traversing through S phase. The level of Dbf4, which is critical for the
      activation of Cdc7, is regulated by transcription and protein degradation. To
      gain a better understanding as to how the transcription of human Dbf4 (HuDbf4) is
      regulated, we have cloned and characterized its promoter. We found that HuDbf4
      core promoter is localized within (-)211 to -285 of the translation start-codon.
      This 75 bp DNA segment contains, among others, a putative MluI Cell-cycle Box
      (MCB). A point mutation within the MCB dramatically reduced the promoter
      activity. This is the first example that an MCB element plays an essential role
      in the activation of a core promoter in mammalian cells. The auxiliary elements
      required for the full promoter activity are present within 162-bp upstream from
      the core promoter (i.e., -286/-447). A point mutation within the Sp1 element at 
      353/-361 resulted in a decrease of promoter activity to the basal level, while
      the deletion of the putative HES-1 at -326/-331 dramatically increased the
      promoter activity. Taken together, our data suggests that the MCB element is
      essential for the core promoter activation, while the Sp1 positive regulator and
      the HES-1 repressor coordinately determine the efficiency of the HuDbf4 promoter.
      We have also found: (i) that the major transcription initiations occur at -220, 
      235 and -245; (ii) that HuDbf4 gene consists of 12 exons, which spread over a 33
      kb region.

PMID- 12420217
TI  - The bovine papillomavirus oncoprotein E5 retains MHC class I molecules in the
      Golgi apparatus and prevents their transport to the cell surface.
AB  - During papillomavirus infection, the E5 protein localizes in the cell Golgi
      apparatus and other endomembrane compartments. Cells transformed by E5 do not
      express major histocompatibility class I complex (MHC I) on the cell surface,
      while cells transformed by the other transforming proteins E6 and E7 do. In
      addition, the total amount of both MHC I protein and mRNA is reduced in E5
      transformed cells. Here we show that expression of bovine papillomavirus E5
      causes the retention of MHC I in the Golgi apparatus, thus preventing its
      transport to the cell surface. We ascribe this effect to a failure of
      acidification of the Golgi apparatus, as similar effects are observed in control
      cells treated with the ionophore monensin. Treatment of E5-transformed cells with
      either beta- or gamma-interferon increases the synthesis of MHC I, showing that
      inhibition of MHC I expression by E5 is not irreversible. However, even after
      interferon treatment, MHC I, although increased in quantity, is not transported
      to the cell surface. E5 therefore affects MHC I at several levels, but prevention
      of MHC I transport to the cell surface appears to be the dominant effect. Lack of
      surface MHC I would have profound consequences for presentation of viral peptides
      to the immune system.

PMID- 12420216
TI  - Src activation regulates anoikis in human colon tumor cell lines.
AB  - Src is a non-receptor protein tyrosine kinase, the expression and activity of
      which is increased in >80% of human colon cancers with respect to normal colonic
      epithelium. Previous studies from this and other laboratories have demonstrated
      that Src activity contributes to tumorigenicity of established colon
      adenocarcinoma cell lines. Src participates in the regulation of many signal
      transduction pathways, among which are those leading to cellular survival. In
      this study, we addressed the potential role of Src activation to a specific
      aspect of tumor cell survival, resistance to detachment-induced apoptosis
      (anoikis). Using five colon tumor cell lines with different biologic properties
      and genetic alterations, we demonstrate that expression and activity of Src
      corresponds with resistance to anoikis. Enforced expression of activated Src in
      subclones of SW480 cells (of low intrinsic Src expression and activity) increases
      resistance to anoikis; whereas decreased Src expression in HT29 cells (of high
      Src expression and activity) by transfection with anti-sense Src expression
      vectors increases susceptibility to anoikis. In contrast, increasing or
      decreasing Src expression had no effect on susceptibility to staurosporine
      induced apoptosis in attached cells. PD173955, a Src family-specific tyrosine
      kinase inhibitor, increases the susceptibility of HT29 cells to anoikis in a dose
      and time-dependent manner. Increasing Src expression and activity led to
      increased phosphorylation of Akt, a mediator of cellular survival pathways,
      whereas decreasing Src activity led to decreased Akt phosphorylation. In colon
      tumor cells with high Src activity, the PI3 kinase inhibitor LY 294002 sensitized
      cells to anoikis. These results suggest that Src activation may contribute to
      colon tumor progression and metastasis in part by activating Akt-mediated
      survival pathways that decrease sensitivity of detached cells to anoikis.

PMID- 12420219
TI  - Modulation of invasive properties of human glioblastoma cells stably expressing
      amino-terminal fragment of urokinase-type plasminogen activator.
AB  - The binding of urokinase-type plasminogen activator (uPA) to its receptor (uPAR)
      on the surface of tumor cells is involved in the activation of proteolytic
      cascades responsible for the invasiveness of those cells. The diffuse, extensive
      infiltration of glioblastomas into the surrounding normal brain tissue is
      believed to rely on modifications of the proteolysis of extracellular matrix
      components; blocking the interaction between uPA and uPAR might be a suitable
      approach for inhibiting glioma tumorigenesis. We assessed how expression of an
      amino-terminal fragment (ATF) of uPA that contains binding site to uPAR affects
      the invasiveness of SNB19 human glioblastoma cells. SNB19 cells were transfected
      with an expression plasmid (pcDNA3-ATF) containing a cDNA sequence of ATF-uPA.
      The resulting ATF-uPA-expressing clones showed markedly less cell adhesion,
      spreading, and clonogenicity than did control cells. Endogenous ATF expression
      also significantly decreased the invasive capacity of transfected glioblastoma
      cells in Matrigel and spheroid-rat brain cell aggregate models. ATF-uPA
      transfectants were also markedly less invasive than parental SNB19 cells after
      injection into the brains of nude mice, suggesting that competitive inhibition of
      the uPA-uPAR interaction on SNB19 cells by means of transfection with ATF cDNA
      could be a useful therapeutic strategy for inhibiting tumor progression.

PMID- 12420218
TI  - Differential expression of carcinoembryonic antigen (CEA) splice variants in
      whole blood of colon cancer patients and healthy volunteers: implication for the
      detection of circulating colon cancer cells.
AB  - Quantification of circulating cancer cells in whole blood samples by real time
      quantitative RT-PCR might be of clinical value for monitoring therapeutic
      effectiveness. In colon cancer patients, carcinoembrynic antigen (CEA) and
      cytokeratin 20 (CK20) have been frequently used for RT-PCR based tumor cell
      detection, but the specificity in particular for CEA has been questioned. In this
      study, we compared real-time RT-PCR for CEA and CK20 and analysed patients with
      metastatic disease (n=32) and healthy volunteers (n=17). CK20 mean values were
      elevated in cancer patients (P<0.001) and defined a subgroup (38%) who showed
      CK20 levels at least 100-fold above the highest value of the healthy control
      group. In contrast, only two cancer patients (6%) showed elevated CEA levels.
      Samples of the healthy control group showed exclusively a CEA-PCR product of 79
      degrees C melting temperature. Thirty per cent of the colon cancer patients
      showed an additional product of 82 degrees C melting temperature. The 82 degrees
      C product was identical with the amplification product of CEA-cDNA and cDNA from
      different colon cancer cell lines. Colon cancer cells were spiked into normal
      blood in 10-fold dilutions that resulted in a dose dependent shift of the melt
      curve from 79 degrees C to the 82 degrees C. Sequencing of the PCR products
      showed that white blood cells express a splice variant of CEA, which hinders
      detection of tumor cell cDNA in whole blood samples. Our findings have
      implications for the use of CEA as a diagnostic molecule (e.g. by RT-PCR). The
      discovery of a physiologically expressed CEA splice variant might lead to a
      better understanding of the biological function of CEA and its family members.

PMID- 12420220
TI  - Lung-specific expression of human mutant p53-273H is associated with a high
      frequency of lung adenocarcinoma in transgenic mice.
AB  - To investigate the tumorigenic potential of mutant p53 when selectively expressed
      in lung tissue, a transgenic mouse model was developed in which a mutant form of
      p53 (p53-273H) was placed under the transcriptional control of the lung-specific
      human surfactant protein C (SP-C) promoter. Two founder mice were identified, and
      a line of SP-C/p53-273H transgenic mice was established from one of the founders.
      Human p53-273H protein was detected specifically in lung tissue from transgenic
      mice. Malignant tumors, which were histologically characterized as
      adenocarcinomas, were observed in transgenic mice, with the earliest onset
      documented at 4 months of age. To further evaluate incidence and onset of tumor
      formation, transgenic mice (n=113) were sacrificed at age intervals ranging from
      4-15 months. At 13-15 months of age, transgenic mice were significantly more
      likely to have lung tumors at necropsy than age-matched non-transgenic
      littermates (9 out of 39 (23%) versus 2 out of 35 (5.7%), chi(2) test, P=0.036).
      The SP-C/p53-273H transgenic mice described here thus represent a genetically
      defined model with which to study the role of p53 mutations in lung
      tumorigenesis, as well as the potential complementary contributions of other
      genetic alterations or environmental carcinogens to lung tumor development.

PMID- 12420221
TI  - Mitochondrial stress-induced calcium signaling, phenotypic changes and invasive
      behavior in human lung carcinoma A549 cells.
AB  - We have investigated mechanisms of mitochondrial stress-induced phenotypic
      changes and cell invasion in tumorigenic but poorly invasive human pulmonary
      carcinoma A549 cells that were partly depleted of mitochondrial DNA (mtDNA).
      Depletion of mtDNA (genetic stress) caused a markedly lower electron transport
      coupled ATP synthesis, loss of mitochondrial membrane potential, elevation of
      steady state [Ca(2+)](c), and notably induction of both glycolysis and
      gluconeogenic pathway enzymes. Markers of tumor invasion, cathepsin L and
      TGFbeta1, were overexpressed; calcium-dependent MAP kinases (ERK1 and ERK2) and
      calcineurin were activated. The levels of anti-apoptotic proteins Bcl2 and Bcl
      X(L) were increased, and the cellular levels of pro-apoptotic proteins Bid and
      Bax were reduced. Both mtDNA-depleted cells (genetic stress) and control cells
      treated with carbonyl cyanide m-chlorophenylhydrazone (metabolic stress)
      exhibited higher invasive behavior than control cells in a Matrigel basement
      membrane matrix assay system. MtDNA-depleted cells stably expressing anti-sense
      cathepsin L RNA, TGFbeta1 RNA, or treated with specific inhibitors showed reduced
      invasion. Reverted cells with 80% of control cell mtDNA exhibited marker protein
      levels, cell morphology and invasive property closer to control cells. Our
      results suggest that the mitochondria-to-nucleus signaling pathway operating
      through increased [Ca(2+)](c) plays an important role in cancer progression and
      metastasis.

PMID- 12420222
TI  - RAR agonists stimulate SOX9 gene expression in breast cancer cell lines: evidence
      for a role in retinoid-mediated growth inhibition.
AB  - Retinoic acid receptors (RARs) are ligand-dependent transcription factors which
      are members of the steroid/thyroid hormone receptor gene family. RAR-agonists
      inhibit the proliferation of many human breast cancer cell lines, particularly
      those whose growth is stimulated by estradiol (E2) or growth factors. PCR
      amplified subtractive hybridization was used to identify candidate retinoid
      regulated genes that may be involved in growth inhibition. One candidate gene
      identified was SOX9, a member of the high mobility group (HMG) box gene family of
      transcription factors. SOX9 gene expression is rapidly stimulated by RAR-agonists
      in T-47D cells and other retinoid-inhibited breast cancer cell lines. In support
      of this finding, a database search indicates that SOX9 is expressed as an EST in
      breast tumor cells. SOX9 is known to be expressed in chondrocytes where it
      regulates the transcription of type II collagen and in testes where it plays a
      role in male sexual differentiation. RAR pan-agonists and the RARalpha-selective
      agonist Am580, but not RXR agonists, stimulate the expression of SOX9 in a wide
      variety of retinoid-inhibited breast cancer cell lines. RAR-agonists did not
      stimulate SOX9 in breast cancer cell lines which were not growth inhibited by
      retinoids. Expression of SOX9 in T-47D cells leads to cycle changes similar to
      those found with RAR-agonists while expression of a dominant negative form of
      SOX9 blocks RA-mediated cell cycle changes, suggesting a role for SOX9 in
      retinoid-mediated growth inhibition.

PMID- 12420223
TI  - The emergence of protocadherin-PC expression during the acquisition of apoptosis
      resistance by prostate cancer cells.
AB  - In order to identify gene products associated with the development of acquired
      therapeutic resistance by prostate cancer cells, we created two novel apoptosis
      resistant prostate cancer cell lines, LNCaP-TR (phorbol-ester [TPA]-Resistant)
      and LNCaP-SSR (Serum Starvation-Resistant) by repeated transient exposure of
      cultured human LNCaP cells to apoptotic stimuli followed by expansion of
      surviving cell populations. These cell lines were found to be cross-resistant to
      the alternative selective agent and also hormone-resistant when xenografted into
      castrated male immunodeficient mice. RNA from the LNCaP-TR line was comparatively
      screened using a subtractive hybridization-PCR procedure. This allowed us to
      identify a 249 bp cDNA fragment that hybridized to a 4.8 kb mRNA preferentially
      expressed by the apoptosis-resistant cells. Using RACE procedures, we cloned and
      sequenced the complete 4.8 kb cDNA. It is an unusual member of the protocadherin
      gene family containing two large overlapping open reading frames encoding
      homologous polypeptides, one having a signal sequence and the other lacking a
      signal sequence and we refer to it as protocadherin-PC. LNCaP cells directly
      transformed with protocadherin-PC cDNA were comparatively resistant to phorbol
      ester induced apoptosis. Antibody recognition studies demonstrating the
      cytoplasmic nature of the protcadherin-PC translation product and its propensity
      to bind beta-catenin suggest that it might influence the apoptotic sensitivity of
      prostate cancer cells through a unique mechanism.

PMID- 12420224
TI  - c-MYC activates protein kinase A (PKA) by direct transcriptional activation of
      the PKA catalytic subunit beta (PKA-Cbeta) gene.
AB  - The c-MYC proto-oncogene encodes a ubiquitous transcription factor involved in
      the control of cell growth and differentiation and broadly implicated in
      tumorigenesis. Understanding the function of c-MYC and its role in cancer depends
      upon the identification of c-MYC target genes. Here we show that c-MYC induces
      the activity of Protein Kinase A (PKA), a key effector of cAMP-mediated signal
      transduction, by inducing the transcription of the gene encoding the PKA
      catalytic subunit beta (PKA-Cbeta). c-MYC-mediated induction of PKA-Cbeta gene
      transcription occurs in multiple tissues, is independent of cell proliferation
      and is mediated by direct binding of c-MYC to the PKA-Cbeta gene promoter
      sequences. Constitutive expression of PKA-Cbeta in Rat1A cells induces their
      transformation, and c-MYC-induced transformation can be reverted by
      pharmacological inhibition of PKA, suggesting that up-regulation of PKA is
      critical for c-MYC-associated tumorigenesis. These results indicate that, by
      activating PKA, c-MYC can provide endogenous activation of the cAMP signal
      transduction pathway independently of extracellular signals.

PMID- 12420225
TI  - Farnesyltransferase inhibitor (L-744,832) restores TGF-beta type II receptor
      expression and enhances radiation sensitivity in K-ras mutant pancreatic cancer
      cell line MIA PaCa-2.
AB  - Activated ras is known to dysregulate TGF-beta signaling by altering the
      expression of TGF-beta type II receptor (RII). It is well documented that tumor
      cells harboring mutant ras are more resistant to radiation than cells with wild
      type ras. In this study, we hypothesized that the use of farnesyltransferase
      inhibitor (FTI, L-744,832) may directly restore TGF-beta signaling through RII
      expression via ras dependent or independent pathway leading to induction of
      radiation sensitivity. Two pancreatic cancer cell lines, BxPC-3 and MIA PaCa-2
      were used in this study. FTI inhibited farnesylation of Ras protein more
      significantly in MIA PaCa-2 than BxPC-3 cells. In contrast, MIA PaCa-2 cells were
      resistant to radiation when compared to BxPC-3 cells. BxPC-3 cells were more
      resistant to FTI than MIA PaCa-2 cells. In combination treatment, no significant
      radiosensitizing effect of FTI was observed in BxPC-3 cells at 5 or 10 microM.
      However, in MIA PaCa-2 cells, a significant radiosensitizing effect was observed
      at both 5 and 10 microM concentrations (P>0.004). The TGF-beta effector gene
      p21(waf1/cip1) was elevated in combination treatment in MIA PaCa-2 but not in
      BxPC-3 cells. In MIA PaCa-2 cells, FTI induced TGF-beta responsive promoter
      activity as assessed by 3TP-luciferase activity. A further induction of
      luciferase activity was observed in MIA PaCa-2 cells treated with radiation and
      FTI. Induction of TGF-beta signaling by FTI was mediated through restoration of
      the RII expression, as demonstrated by RT-PCR analysis. In addition, re
      expression of RII by FTI was associated with a decrease in DNA methyltransferase
      1 (DNMT1) levels. Thus, these findings suggest that the L-744,832 treatment
      restores the RII expression through inhibition of DNMT1 levels causing induction
      of TGF-beta signaling by radiation and this forms a novel molecular mechanism of
      radiosensitization by FTI.

PMID- 12420226
TI  - The Rb-family protein p107 inhibits translation by a PDK1-dependent mechanism.
AB  - The Rb family of proteins, which consists of Rb, p107 and p130, are critical
      regulators of cell proliferation. In addition to their inhibitory effects on cell
      cycle progression, Rb-family proteins repress transcription by RNA polymerases I
      and III, and may therefore restrain cell growth. However, it is not known if Rb,
      p107 or p130 have direct effects on protein synthesis. Here we report that
      ectopic expression of p107 in rat fibroblasts markedly attenuates the stimulation
      of mRNA translation and global protein synthesis by serum growth factors. This
      effect is associated with a reduction in the phosphorylation and activation of
      the serine-threonine kinases Akt1 and p70 S6 kinase (S6K1), two downstream
      targets of phosphoinositide-dependent kinase 1 (PDK1). We show that
      overexpression of p107 interferes with the recruitment of PDK1 to the plasma
      membrane in response to growth factors. Overexpression of PDK1 restores the
      defect in translation elicited by p107. These results suggest that p107 restricts
      cell growth by interfering with the phosphoinositide 3-kinase (PI3K) signaling
      pathway.

PMID- 12420227
TI  - p16(INK4a) inactivation is not required to immortalize human mammary epithelial
      cells.
AB  - Using standard culture conditions, primary human mammary epithelial cells (HMECs)
      undergo a premature, transient growth arrest termed M0 (mortality stage 0) after
      10-15 population doublings in vitro. It has been reported that emergence from
      this growth arrest by the abrogation of p16(INK4a), a cyclin-dependent kinase
      inhibitor, and expression of the catalytic component of human telomerase (hTERT)
      are necessary for HMEC immortalization. Here we show that primary HMECs, grown on
      feeder layers, do not undergo this growth arrest and can be immortalized without
      abrogating p16. These findings support the concept that the so-called M0 stage
      represents a cell culture stress-induced growth arrest and that hTERT is
      sufficient to immortalize HMECs when cultured under adequate conditions.

PMID- 12420228
TI  - Groups of p53 target genes involved in specific p53 downstream effects cluster
      into different classes of DNA binding sites.
AB  - The tumor suppressor protein p53, once activated, can cause either cell cycle
      arrest or apoptosis through transactivation of target genes with p53 DNA binding
      sites (DBS). To investigate the role of p53 DBS in the regulation of this
      profound, yet poorly understood decision of life versus death, we systematically
      studied all known and potential p53 DBS. We analysed the DBS separated from
      surrounding promoter regions in yeast and mammalian assays with and without DNA
      damage. p53 efficiently utilized the DBS of MDM2 and of genes connected to cell
      cycle arrest, DNA repair and the death receptor pathway of apoptosis. However,
      p53 was unable to utilize two-thirds of the isolated DBS, a subset that included
      almost all DBS of apoptosis-related genes. Neither ASPP2, a p53-interacting
      protein reported to specifically stimulate p53 transcriptional activity on
      apoptosis-related promoters, nor DNA damage resulted in p53 utilization of
      isolated DBS of apoptosis-related genes. Thus, a major regulation of p53 activity
      occurs at the level of p53 DBS themselves by posing additional requirements for
      the successful utilization of apoptosis-related DBS.

PMID- 12420235
TI  - Hirudin as alternative anticoagulant--a historical review.
AB  - Advances in separation techniques and biotechnology have contributed to the
      development of anticoagulant agents from hematophagous animals. The most potent
      known natural thrombin inhibitor from blood-sucking leeches ( Hirudo
      medicinalis), hirudin has served as a standard for designing the natural
      coagulation inhibitors as an anticoagulant drug. The search for the development
      of hirudin from leech extract to genetically engineered products as an
      alternative anticoagulant has been resumed. The pharmacological profiling of the
      isolated thrombin inhibitor has shown that native hirudin is an antithrombotic
      agent of high quality. However, its clinical use has remained limited, because
      the substance has not been available in adequate amounts. The progress in
      molecular biology has stimulated the interest in the structure and function of
      hirudin. This development resulted in the production of recombinant hirudins (r
      hirudins) through gene technology. The biological properties of hirudin combined
      with the ready availability of recombinant forms make the specific thrombin
      inhibitor well-suited for use as an antithrombotic drug. Its use should lead to a
      decisive progress in the management of thromboembolic diseases of both arterial
      and venous origin. Clinical trials, especially in diseases in which thrombin
      plays a crucial role, are in progress.

PMID- 12420236
TI  - Pharmacology of recombinant hirudin.
AB  - Hirudin is the anticoagulative product of the salivary glands of the medical
      leech Hirudo medicinalis. It is characterized by a direct, bifunctional
      inhibition mechanism and a high, exclusive specificity and a strong ability to
      bind to thrombin (tight binding). Further characteristics are the organic
      chemical structure of hirudin (peptide), which allows only parenteral
      administration; the missing metabolism in the organism; and the exclusive
      glomerular filtration of hirudin in kidneys as the effective elimination
      mechanism. Recombinant hirudin (r-hirudin) is a product of genetic engineering
      that is identical to the hirudin found in nature and has the same biochemical and
      pharmacological characteristics as natural hirudin.

PMID- 12420237
TI  - Methods for the monitoring of direct thrombin inhibitors.
AB  - Direct thrombin inhibitors are available for prophylactic as well as therapeutic
      purposes. Application of hirudin in therapeutic doses has been shown to require
      drug monitoring. Currently, most experience is available for recombinant hirudin,
      but the principle aspects of drug monitoring are the same for all direct thrombin
      inhibitors. Most frequently, activated partial thromboplastin time (aPTT) and
      modifications of the activated clotting time (ACT) have been used for the
      monitoring of hirudin therapy. However, these methods are insensitive at plasma
      levels higher than 0.6 mg/L of hirudin, so that overdoses may be missed despite
      monitoring. Correlations between ecarin clotting time (ECT), enzyme immunoassays,
      and chromogenic substrate assays on one side and global tests on the other side
      are poor. Fully automated chromogenic substrate-based assays, also available as
      point-of-care tests (POCT), are more precise and sensitive and are not disturbed
      by interferents such as heparin and antithrombin. Good correlations can be
      observed between chromogenic assays and the ECT performed in plasma or whole
      blood samples. ECT can also be determined with POCT systems. Test characteristics
      such as imprecision and measuring range are comparable to those of the
      chromogenic assays. In conclusion, therapy with direct thrombin inhibitors should
      be monitored with chromogenic assays or ECT.

PMID- 12420238
TI  - Hirudin in heparin-induced thrombocytopenia.
AB  - Heparin-induced thrombocytopenia (HIT), a serious side effect of heparin
      treatment, requires alternative anticoagulation in most affected patients. The
      recombinant hirudin (r-hirudin) lepirudin has been approved for this purpose
      after two prospective trials in laboratory-confirmed HIT patients. Other drugs
      available for this purpose are danaparoid sodium (a heparinoid) and argatroban, a
      synthetic direct thrombin inhibitor. In this article, recommendations for optimal
      use of r-hirudin in HIT are given, covering therapy in uncomplicated patients as
      well as in special situations such as heparin reexposure of HIT patients. Because
      lepirudin's half-life depends on renal function, it may vary between 1 and 200
      hours, which requires individual dose adjustments. Lepirudin compares favorably
      with danaparoid, based on retrospective data. No direct comparisons of lepirudin
      with argatroban are available, but argatroban might offer advantages in patients
      with renal failure, because it is mainly eliminated hepatically. Major
      hemorrhage, the main risk of lepirudin treatment, occurring in about 15% of
      patients, makes close monitoring important. New monitoring tools, such as the
      ecarin clotting time (ECT), might further reduce bleeding risks. Antihirudin
      antibodies, which can alter the pharmacokinetics as well as the pharmacodynamics
      of hirudin, can also be countered by close monitoring and appropriate dose
      adjustments. Whereas hirudins have not yet managed to gain importance in non-HIT
      indications such as unstable coronary syndromes, they have a major role to play
      in the treatment of HIT. The choice between the available drugs for HIT, namely
      lepirudin, danaparoid, and argatroban, has to be made according to the clinical
      presentation of the patient.

PMID- 12420239
TI  - Heparin-induced thrombocytopenia-alternative anticoagulation in pregnancy and
      lactation.
AB  - Heparin-induced thrombocytopenia (HIT) appears rarely in pregnant patients who
      are being treated with heparin. When HIT is suspected, heparin treatment should
      be discontinued and alternative anticoagulation should be started. The heparinoid
      danaparoid appears to be the drug of choice for acute treatment and prophylaxis
      because of its low placental permeability. Between the 12th and 36th weeks of
      pregnancy, either danaparoid may be continued or warfarin may be used after
      recovery of platelet counts. Before and during delivery, danaparoid should be
      preferred over warfarin in order to avoid bleeding complications in mother and
      infant. Hirudin should only be used when either cross-reactivity with heparin
      induced antibodies or cutaneous allergy against heparinoids are observed.
      Postpartum warfarin seems to be the treatment of choice because breast-feeding
      can be continued. Alternative treatment with either danaparoid or hirudin is
      possible, but data on treatment with these reagents in lactating mothers are very
      limited.

PMID- 12420240
TI  - Anticoagulation with recombinant hirudin and danaparoid sodium in pediatric
      patients.
AB  - Patients receiving heparin are at risk of developing heparin-induced
      thrombocytopenia (HIT). Whereas in HIT I only reversible mild thrombocytopenia
      occurs within the first days of heparin treatment, HIT II may lead to potentially
      life-threatening thromboembolic events. Pediatric patients suffering from HIT II
      have been reported in a study on newborns and in a few reports on children and
      adolescents. However, thrombotic complications can be as severe in children as
      they are in adults. In the case of HIT II, the withdrawal of heparin is required
      and alternative anticoagulation should be started. In contrast to numerous
      investigations in adult patients, including prospective studies, experience with
      alternative anticoagulants in pediatric patients is limited. The available data
      were analyzed according to HIT II complications, alternative anticoagulation, and
      clinical outcome. In conclusion, HIT II represents a potentially dangerous
      complication of heparin therapy in pediatric patients also. Alternative
      anticoagulation applied in pediatric patients mainly included danaparoid sodium
      and recombinant hirudin. In most patients treated with these anticoagulants,
      effective anticoagulation and clinical improvement were observed. Because of
      limited experience, more data are required for optimal management of HIT II in
      young patients.

PMID- 12420241
TI  - Hirudin for prophylaxis and treatment of deep vein thrombosis.
AB  - Since recombinant hirudin (r-hirudin) has become available, several studies have
      been published on hirudin for prophylaxis and treatment of thromboembolic
      complications. Vr-hirudin was shown to be superior even to low-molecular-weight
      heparin (LMWH) for prophylaxis of deep venous thrombosis (DVT), especially in
      high-risk patients. Consequently, r-hirudin was expected to be more effective
      than heparins are in the treatment of thromboembolic events. Vr-hirudin was
      proved to be safe and efficacious in the therapy of thromboembolic events.
      However, no benefit could be shown in comparison with heparin. In contrast, in
      patients suffering from HIT type II, r-hirudin is the drug of choice for the
      therapy of thromboembolic complications.

PMID- 12420242
TI  - Hirudin in acute coronary syndromes.
AB  - Acute coronary syndromes are a major cause of morbidity and mortality in Western
      societies. The term describes a spectrum from unstable angina, the recently
      defined non-Q wave infarction (the Non ST-Elevation Myocardial Infarction
      [NSTEMI]), to acute transmural myocardial infarction. With regard to treatment, a
      series of recently published studies compared the specific direct thrombin
      inhibitor hirudin with standard unfractionated heparin. Initial small studies
      showed promising results and led to the initiation of large-scale clinical trials
      addressing patients with acute coronary syndromes. However, in these studies, an
      unacceptably high incidence of serious hemorrhagic complications prompted safety
      boards to stop trials. In those studies carried out according to the protocol, no
      significant clinical benefit of hirudin over standard heparin was proved. Here,
      hirudin has been shown to be equivalent to unfractionated heparin for the
      treatment of unstable coronary syndromes with or without ST elevation and as an
      adjunct to percutaneous coronary balloon angioplasty. Because of its narrow
      therapeutic window between clinical benefit and increased bleeding hazards,
      hirudin should be used cautiously. For patients with heparin-induced
      thrombocytopenia, hirudin is accepted as an important therapeutic alternative.

PMID- 12420243
TI  - Hirudin in renal insufficiency.
AB  - Recombinant hirudins (r-hirudins) are potent direct thrombin inhibitors
      increasingly used for alternative anticoagulation, especially in heparin-induced
      thrombocytopenia. R-hirudins are almost exclusively eliminated by the kidneys,
      and a close correlation between r-hirudin clearance and endogenous creatinine
      clearance has been observed. Accordingly, the pharmacokinetics of r-hirudin are
      altered in patients with renal insufficiency. A decline of renal r-hirudin
      clearance is associated with an increase of r-hirudin half-life and the area
      under the curve (AUC). Therefore, renal impairment necessitates reduction of r
      hirudin dose to avoid overdose or inadequate accumulation of the thrombin
      inhibitor. To this end, close monitoring of r-hirudin anticoagulation is
      required, which at best is performed by measuring r-hirudin blood levels by
      ecarin clotting times (ECT) or chromogenic assays, in addition to activated
      partial thromboplastin time (aPTT). Recent studies showed that r-hirudin
      anticoagulation is feasible in acute or chronic renal failure treated with
      continuous or intermittent renal replacement therapy, if appropriate r-hirudin
      dosing and adequate monitoring are warranted. High-volume hemofiltration with r
      hirudin-permeable hemodialyzers constitutes a valuable means to markedly reduce r
      hirudin blood concentration and total r-hirudin body content in case of r-hirudin
      overdose or r-hirudin-associated bleeding. In the future, the hepatically
      eliminated direct thrombin inhibitor argatroban may facilitate alternative
      anticoagulation in patients with renal insufficiency.

PMID- 12420244
TI  - Biological relevance of anti-recombinant hirudin antibodies--results from in
      vitro and in vivo studies.
AB  - This article provides an overview of the clinically relevant characteristics of
      antibodies directed toward recombinant (r) hirudin, with emphasis on the
      different ways in which these antibodies may influence pharmacokinetics and
      pharmacodynamics of r-hirudin. A high incidence of anti-hirudin antibody (AHAb)
      formation, mainly of the immunoglobulin G (IgG) subclass, was reported in up to
      74% of patients treated with r-hirudin for more than 5 days. Like other drug
      induced antibodies, AHAb may be responsible for accumulation or neutralization of
      the drug. Current clinical data support this assumption with reports on reduced
      metabolism, enhanced activity, and accumulation and neutralization of r-hirudin
      in the presence of AHAb. By examining AHAb developed in patients, we were able to
      demonstrate that AHAbs are capable of neutralizing r-hirudin in vitro. In
      addition, the anticoagulant activity of r-hirudin administered to Sprague-Dawley
      rats was almost completely abolished when a monoclonal mouse AHAb with known r
      hirudin neutralizing capacity in vitro was injected intravenously. Because r
      hirudin is mainly eliminated via the kidneys, formation of r-hirudin-AHAb
      complexes may, due to their size, result in accumulation of r-hirudin. We
      investigated filtration of r-hirudin incubated with monoclonal mouse AHAb by
      using high-flux hemodialyzers in a suitable in vitro model. Whereas sieving
      coefficients (SC) were high in the absence of AHAb, they were minimal (SC < 0.05)
      in the presence of AHAb. These findings may also be important when AHAb-positive
      patients treated with r-hirudin undergo hemofiltration procedures, which have
      recently been described as a rescue measure in case of r-hirudin overdosage. In
      vivo, the influence of a non-neutralizing monoclonal mouse AHAb on r-hirudin
      pharmacokinetics was examined in rats. Pharmacokinetic data compared with those
      of a control group without AHAb administration revealed that r-hirudin
      elimination half-life was significantly prolonged (59 +/- 25 minutes versus 142
      +/- 25 minutes). This was accompanied by a decrease of total plasma clearance of
      r-hirudin. The volume of distribution of r-hirudin was significantly decreased
      (275 +/- 112 mL/kg versus 35 +/- 3 mL/kg), indicating that r-hirudin bound by
      AHAb is mainly distributed to the intravascular compartment. Taken together, both
      the half-life prolongation and the decrease of the volume of distribution
      contribute to r-hirudin accumulation and may explain respective findings in
      patients. In summary, two different effects of AHAbs seem to be clinically
      relevant: decreasing anticoagulant activity of r-hirudin by neutralization and
      accumulation of r-hirudin by reducing renal clearance. Formation of AHAbs has not
      yet been correlated with enhanced major bleeding complications. However, close
      monitoring of coagulation parameters is recommended in AHAb-positive patients
      during r-hirudin treatment.

PMID- 12420246
TI  - [Alexithymia--return of a repression].

PMID- 12420247
TI  - [Evidence of validity of the German version of the TAS-20. Contribution to the
      52nd conference of the German Board of Psychosomatic Medicine in Bad Honnef
      (2001)].
AB  - 419 patients (psychosomatic-C/L-service unit; neurotic spectrum, somatoform and
      personality disorders) were investigated by collecting data of clinical and
      psychometrical variables (SCL-90-R, NEO-FFI, IIP-D). The aim was to evaluate
      whether the sum score and the three factors of the German 20-item-version of the
      Toronto-Alexithymia-Scale (TAS-20) postulated by Bagby correlate with other
      clinical variables in a convergent way. The TAS-20 sum score and the factors (F1)
      "Difficulties identifying feelings" and (F2) "Difficulties describing one's
      feelings" correlated convergently with the NEO-FFI-scales "neuroticism" and
      "openness for new experiences", with numerous scales of the SCL-90-R, as well as
      with the scales "cool/repelling" and "introverted/social avoiding" interaction
      style of the IIP-D. Factor (F3) "Externally oriented thinking" correlated with
      "Extraversion" but was not related to clinical impairment (SCL-90 R). The results
      could be interpreted in terms of convergent validity of the TAS-20. In addition,
      alexithymic patients seem to be impaired with respect to interpersonal
      communication and they are subjectively able to perceive appreciate this
      restriction.

PMID- 12420248
TI  - [Distribution of alexithymia as a personality-trait in psychosomatically ill in
      patients--measured with TAS 20 and LEAS].
AB  - Preliminary findings of an ongoing study of the distribution of alexithymia in
      different diagnostic-groups of psychosomatically ill in-patients (n = 240, will
      be increased to n = 400) are reported. Alexithymiea is measured simultaneousely
      by the Levels of Emotional Awareness Scale (LEAS, a performance-test) and the 20
      item Toronto Alexithymia Scale (TAS 20, a self-report-scale). Measured by the
      LEAS and compared with other diagnostic groups (affective, anxiety and compulsive
      obsessive disorders; adjustment disorders; eating disorders), patients with
      somatoform disorders showed a decreased ability to be aware of and to communicate
      their emotional states. This finding which meets theoretical considerations about
      the origin of alexithymia could not be found with the TAS 20. The TAS 20 did not
      differentiate between the diagnostic groups, but showed - in accordance with two
      other self-report-scales (STAI for self reported anxiety as a personality trait
      and SCL-90-R for self reported somatic und psychic complaints) - higher mean
      scores at the onset than at the end of treatment. Methodical implications of the
      different findings of the two alexithymia scales are discussed.

PMID- 12420249
TI  - [Increased level of tonic sympathetic arousal in high-vs. low-alexithymic
      cervical dystonia patients].
AB  - The purpose of this study was to assess whether alexithymia is a risk factor for
      autonomic dysregulation in cervical dystonia (spasmodic torticollis, ST).
      Alexithymia was assessed by an authorized German version of the TAS-20. In a
      first step, we recruited 10 ST-patients with high alexithymia scores (> 62; M =
      69.2, SD = 3.0) and compared them with 10 ST-patients with low alexithymia scores
      (< 35; M = 28.7, SD = 4.3) on physiological and subjective responses to a
      cognitive and an emotional laboratory stressor. High-alexithymic ST-patients
      generally showed increased levels of autonomic arousal (higher SCL, more NS.SCF
      and lower T; 0.016 </= p </= 0.065) under all experimental conditions. In a
      second step, we used a less extreme alexithymia-definition (high >/= 57 vs. low
      </= 36) in a sample of 2 x 20 probands and found no significant differences. Our
      results suggest a chronically increased level of sympathetic activation in high
      alexithymic patients with spasmodic torticollis.

PMID- 12420250
TI  - [Different patterns of regional brain activation during emotional stimulation in
      alexithymics in comparison with normal controls].
AB  - OBJECTIVE: This study was designed to determine patterns of regional brain
      activation during emotional stimulation in alexithymics as compared with normal
      controls. METHOD: We used 15O-water positron emission tomography and an emotional
      stimulation paradigm based upon autobiographic recall of either happy, sad or
      emotionally neutral situations. 10 normal subjects without medical or
      psychiatrical history were compared with 9 patients with somatoform disorder
      without any other DSM-IV diagnosis. TAS-20 was used as a measure for alexithymia,
      depression was measured using BDI. RESULTS: Normal controls showed significantly
      greater activation than alexithymics in cingulate areas, corpus callosum, and
      right superior and inferior frontal gyrus. Alexithymics activated significantly
      more in cuneus and precuneus, thalamus (pulvinar), left medial frontal, right
      inferior temporal, left superior temporal regions, left precentral gyrus, and the
      cerebellum. CONCLUSIONS: During emotional autobiographic recall, alexithymia,
      either trait or state, is characterized by utilization of different brain regions
      when compared to normal controls. The areas activated by alexithymic persons
      largely comprise of language related regions, leaving out limbic and paralimbic
      areas.

PMID- 12420251
TI  - [Psychodynamic and neurobiological influences in the etiology of alexithymia].
AB  - This article discusses modern theories about the influence of developmental
      factors on the genesis of alexithymia and about its influence on maturing
      neurobiological structures. Against this background it becomes clear that core
      concepts of psychodynamic psychotherapy, like the concept of a unconscious level
      of experience, are confirmed by modern neurobiological research. Thus, modern
      psychosomatic research should strive to validate clinical core concepts by the
      use of empirical studies which also consider neurobiological parameters.

PMID- 12420253
TI  - Periodontal pathology associated with asymptomatic third molars.
AB  - PURPOSE: We report the prevalence of periodontal probing depth (PD) as a clinical
      measure of the extent of periodontitis associated with asymptomatic third molars
      at the initial examination in a cohort of patients enrolled in an institutional
      review board-approved longitudinal clinical trial. PATIENTS AND METHODS: Three
      hundred twenty-nine healthy patients were enrolled during a 30-month period. Full
      mouth periodontal probing that included third molars was conducted to determine
      periodontal status. Panoramic radiographs were taken to assess the degree of
      eruption of the third molars and the angulation of third molars compared with the
      adjacent second molar. Vertical bitewing radiographs were analyzed to detect
      alveolar bone levels relative to the cementoenamel junction on the distal of
      second molars. RESULTS: Twenty-five percent (82 of 329) of all enrolled patients,
      and 34% (14 of 41) of black patients, had at least one PD equal to or greater
      than 5 mm on the distal of a second molar or around a third molar. PD equal to or
      greater than 5 mm was associated with periodontal attachment loss of at least 1
      mm in every patient; PD equal to or greater than 5 mm was associated with
      attachment loss equal to or greater than 2 mm in 80 of 82 patients. A higher
      proportion of patients 25 years old or older had a PD equal to or greater than 5
      mm on the distal of second molars or around third molars compared with patients
      younger than 25 years (33% vs 17%, P =.002). The distals of second molars and
      third molars in the mandible were affected more often than in the maxilla (25% vs
      5%, P =.0001). CONCLUSIONS: Our data indicating that 25% of patients with
      retained asymptomatic third molars have considerable periodontal pathology in the
      third molar region were unexpected. National epidemiologic surveys indicate a
      much lower rate of periodontitis in the population younger than 35 years.

PMID- 12420254
TI  - Microbial complexes detected in the second/third molar region in patients with
      asymptomatic third molars.
AB  - PURPOSE: Our goal was to report the detection and levels of pathogenic bacteria
      in subgingival plaque samples taken from the distal of all second molars in 295
      patients with asymptomatic third molars. PATIENTS AND METHODS: Data assessing
      oral health were collected from each of these healthy patients (ASA Classes I and
      II). Probing depth (PD), at 6 sites per tooth, including third molars, was
      obtained to determine periodontal status. Subgingival plaque samples were taken
      from the distal of all second molars before periodontal probing. The presence and
      levels of 11 bacterial species were determined using whole chromosomal DNA probes
      and checkerboard DNA-DNA hybridization. Detected bacterial species were grouped
      into clusters of periodontal pathogens designated as "red" or "orange" complex
      microorganisms as described by Socransky et al (J Clin Periodontal 25:134, 1998)
      who found an association of these specific microorganisms with periodontitis.
      RESULTS: As a group these relatively young patients were periodontally healthy.
      "Orange and red" complex microorganisms were detected at levels equal to or
      greater than 10(5) more often if patients had a PD equal to or greater than 5 mm
      with periodontal attachment loss at the distal of second molars or around third
      molars at their entry examination. In patients with no PD equal to or greater
      than 5 mm in the third molar region, "orange and red" complex microorganisms were
      detected at levels equal to or greater than 10(5) more frequently than would be
      anticipated in patients with little clinical evidence of periodontal disease.
      CONCLUSIONS: The clinical findings of increased periodontal PDs and periodontal
      attachment loss coupled with colonization of periodontal pathogens support the
      concept that clinical and microbial changes associated with the initiation of
      periodontitis may present first in the third molar region in young adults.

PMID- 12420255
TI  - Inflammatory mediators and periodontitis in patients with asymptomatic third
      molars.
AB  - PURPOSE: Our goal was to report the detection and levels of gingival crevicular
      fluid (GCF) inflammatory mediators, sampled at the mesial of 4 first molars and
      distal of 4 second molars, in 316 patients with asymptomatic third molars.
      PATIENTS AND METHODS: Levels of GCF inflammatory mediators, interleukin (IL)-1
      beta and prostaglandin (PG)E(2), were determined and log transformed for each
      patient. Z scores were calculated using the mean and standard deviation of the
      log values for the entire sample of 316 patients. The log mediator levels and Z
      scores of patients who had probing depths (PDs) less than 5 mm (n = 238) were
      compared with patients with at least 1 PD equal to or greater than 5 mm (n = 78)
      on the distal of second molars or around third molars. A periodontal Composite
      GCF Inflammation Score was calculated for each patient by summing the Z scores
      obtained for IL-1 beta and PGE(2) for that patient. RESULTS: The levels of GCF IL
      1 beta and PGE(2) were higher if a patient had a PD equal to or greater than 5 mm
      in the third molar region. The Composite GCF Inflammation Score indicated
      "elevated inflammation" if a PD equal to or greater than 5 mm was found in the
      third molar region as well. CONCLUSIONS: These data suggest that asymptomatic
      patients with PD equal to or greater than 5 mm in the third molar region with
      associated periodontal attachment loss have increased levels of biochemical
      mediators of inflammation compared with patients with PD less than 5 mm. These
      findings are consistent with the concept that early periodontitis in young adults
      that initiates in the third molar region is associated with increases in key
      inflammatory mediators.

PMID- 12420256
TI  - Small dose of propofol for preventing nausea and vomiting after third molar
      extraction.
AB  - PURPOSE: The study goal was to evaluate the efficacy and safety of a small dose
      of propofol for the prevention of nausea and vomiting following third molar
      extraction. PATIENTS AND METHODS: In a prospective, randomized, double-blinded,
      placebo-controlled trial, 90 women received placebo or propofol at 2 different
      doses (0.25 mg/kg, 0.5 mg/kg) (n = 30 of each) intravenously at the end of
      surgery. A standard general anesthetic technique, including sevoflurane and
      nitrous oxide in oxygen, was employed throughout the surgical procedure. Emetic
      episodes and safety assessments were performed during 0 to 3 hours and 3 to 24
      hours after after anesthesia. RESULTS: The rate of patients experiencing emesis
      free (no nausea, retching, or vomiting) during 0 to 3 hours after anesthesia was
      60% with placebo, 66% with propofol 0.25 mg/kg (P =.395), and 90% with propofol
      0.5 mg/kg (P =.001); the corresponding rate during 3 to 24 hours after anesthesia
      was 60%, 63% (P = 0.5), and 87% (P =.02) (P values compared with placebo). No
      clinically serious adverse effects due to the study drug were observed in any
      group. CONCLUSIONS: Prophylactic therapy with a small dose (0.5 mg/kg) of
      propofol is effective for preventing postoperative nausea and vomiting in female
      patients undergoing general anesthesia for third molar extractions.

PMID- 12420257
TI  - Mechanosensory and thermosensory changes across the border of impaired
      sensitivity to pinprick after mandibular nerve injury.
AB  - PURPOSE: The study goal was to determine how sensory function varies across the
      border of impaired sensitivity to pinprick in patients with mandibular nerve
      injuries. PATIENTS AND METHODS: Borders of decreased sensitivity to pinprick were
      mapped in 15 patients who reported altered sensation. Four mechanoreceptive, 2
      thermoreceptive, and 2 thermonociceptive functions were studied at 5 sites
      separated by 0.6 cm across the border. The tests were repeated to evaluate day-to
      day consistency in the pattern of variation for each sensory measure. RESULTS:
      The estimates of sensory function were not found to vary in a systematic manner
      from outside to inside the pinprick-impaired area for all patients for any of the
      8 tests. However, for every test, some patients exhibited large variations. On
      average, the magnitudes of loss in contact detection, subjective intensity of
      light touch, and direction discrimination were greatest; the magnitudes of loss
      in 2-point perception and in heat and cold pain perception were least. Some
      patients provided no evidence of impairment on certain tests. For some patients,
      the estimates suggested increased sensitivity within the pinprick-impaired area
      (eg, to noxious cold stimuli). CONCLUSIONS: Although certain patients exhibit
      impairment, there is no obligatory loss in light touch, 2-point perception,
      direction discrimination, or temperature perception across the border of
      decreased sensitivity to pinprick. The differences among patients suggest that
      the data from individual patients should be evaluated in clinical studies and in
      clinical practice. Researchers should not rely solely on average values and
      summary statistics.

PMID- 12420258
TI  - Evaluation of computer-based area and volume measurement from coronal computed
      tomography scans in isolated blowout fractures of the orbital floor.
AB  - PURPOSE: In this retrospective study, we evaluated isolated blowout fractures of
      the orbital floor by region-of-interest measurements from coronal computed
      tomography (CT) scans and their relationship to ophthalmologic findings. PATIENTS
      AND METHODS: Fracture area and volume of displaced tissue of blowout fractures in
      38 patients were measured from coronal CT scans. Measurement was performed by
      identifying distances (for area calculation) of the fracture and identifying
      areas (for volume calculation) of the displaced tissue in each CT slice. The
      calculated data were then compared with the amount of enophthalmos, presence of
      diplopia, and limitation of ocular motility. RESULTS: Orbital floor area (mean +/
      SD) was 5.72 +/- 1.07 cm(2); fracture area, 2.63 +/- 1.20 cm(2); and the volume
      of displaced tissue, 1.15 +/- 0.91 mL. The average proportion of the fracture
      within the orbital floor was 45.3 +/- 17.6%. Fracture area and volume of
      displaced tissue were significantly positively correlated with enophthalmos and
      diplopia and not correlated with the limitation of ocular motility. For
      enophthalmos of 2 mm or greater, mean fracture area (mean +/- SD) was 4.08 +/-
      1.09 cm(2) and volume of displaced tissue was 1.89 +/- 1.19 mL; for less than 2
      mm enophthalmos, 1.98 +/- 0.83 cm(2) and 0.83 +/- 0.58 mL, respectively.
      Enophthalmos of 2 mm can be expected with 3.38 cm(2) of fracture area and 1.62 mL
      of displaced tissue. CONCLUSIONS: Region-of-interest measurement from coronal CT
      scan has an application in the assessment of patients with pure blowout fractures
      of the orbital floor and adds useful information in posttraumatic evaluation of
      orbital fractures.

PMID- 12420260
TI  - Navigation-guided resection of temporomandibular joint ankylosis promotes safety
      in skull base surgery.
AB  - PURPOSE: Computer-assisted surgery (CAS) has not been a routine part of
      craniomaxillofacial surgery to date. This report investigates the use of CAS to
      promote the safe removal of ankylosed temporomandibular joint bone in the skull
      base. PATIENTS AND METHODS: Out of a total pool of experience with 102 navigation
      guided CAS procedures between January 1998 and December 2000, we report on 2
      cases of navigation-aided resection of severe ankylosis of the mandibular condyle
      with a predetermined safety margin of the resection toward the middle cranial
      fossa, and identification of the foramen ovale. RESULT: The use of CAS with
      navigation resulted in the promotion of safe surgical excision of the ankylosed
      skull base tissue. CONCLUSIONS: We regard navigation-aided resection of an
      ankylosis fo the mandibular condyle as a valuable additional technique in this
      potentially complicated procedure.

PMID- 12420261
TI  - Temporoparietal fascia flaps and superficial musculoaponeurotic system plication
      in parotid surgery reduces Frey's syndrome.
AB  - PURPOSE: The purpose of this retrospective study was to evaluate the incidence of
      Frey's syndrome after parotid gland surgery with elevation of a skin flap versus
      the interposition of musculoaponeurotic tissue between the skin and the facial
      nerve. MATERIALS AND METHODS: The standard skin flap was used in 122 patients
      (1981 to 1989), whereas interposition of temporoparietal galea or superficial
      musculoaponeurotic system was performed in 146 consecutive patients (1989 to
      1998). RESULTS: The incidence of Frey's syndrome was reduced from 33% to 4% with
      the use of a musculoaponeurotic layer, and the mean duration of postoperative
      facial nerve paresis decreased from 3 months to 6 weeks. CONCLUSIONS:
      Consideration should be given to the use of an interpositional layer of tissue
      between the facial nerve and the skin flap to reduce the incidence of Frey's
      syndrome after parotid gland surgery.

PMID- 12420263
TI  - Peripheral osteoma of the oral and maxillofacial region: a study of 35 new cases.
AB  - PURPOSE: The purpose of this article was to present 35 new cases of peripheral
      osteoma of the oral and maxillofacial region with an analysis of the literature.
      PATIENTS AND METHODS: We performed a search of our files for the past 5 years for
      peripheral osteoma of the oral and maxillofacial region. The criteria used to
      diagnose osteoma included the radiographic and histologic features. RESULTS: The
      35 patients, which included 23 males (65%) and 12 females (35%), ranged in age
      from 14 to 58 years, with a mean age of 29.4 years. Most of the osteomas were
      located in frontal bone (28.57%), mandible (22.85%), and maxilla (14.28%).
      CONCLUSION: Peripheral osteomas of the jaw bones are uncommon, and accordingly,
      patients with osteoma should be evaluated for Gardner's syndrome. In addition, it
      is appropriate to provide both clinical and radiographic follow-up after surgical
      excision of a peripheral osteoma.

PMID- 12420264
TI  - Analysis of temporomandibular joint synovial fluid using Fourier
      transform/infrared spectroscopy.
AB  - PURPOSE: In recent years infrared spectroscopy has been increasingly used for the
      analytical determination of biologic fluids and tissues. With the help of this
      method it was possible to investigate the various types of arthritis affecting
      the knee joint, among others. The aim of our study was to show that infrared
      spectroscopy can also be used as a method to analyze the synovial fluid of the
      temporomandibular joint to differentiate between inflammatory and noninflammatory
      disorders. MATERIALS AND METHODS: Using Fourier transform/infrared spectroscopy
      analysis, comparable absorption spectra with characteristic signals in the
      corresponding range of wavelength were shown and used to prove pathologic
      alterations in the synovial fluid. Samples of 22 patients with arthritis of the
      temporomandibular joint and 12 patients with noninflammatory internal derangement
      were investigated and compared with each other. RESULTS: Our measurements
      presented a distinct intensity difference between the absorption spectra of
      patients who had arthritis and those without signs of an inflammatory change but
      with an internal derangement as control specimens. Due to the small number of
      undiluted samples it was not possible to follow up with a multivariant analysis,
      necessary for a differential diagnostic evaluation between the individual types
      of arthritis. CONCLUSIONS: A certain differentiation between arthritic and
      noninflamed temporomandibular joints can be noted with infrared spectroscopy of
      the synovial fluid. This represents a valuable option for minimally invasive
      diagnostic proof of inflammation in cases of joint disorders.

PMID- 12420265
TI  - The effect of a unilateral costochondral graft on the growth of the marmoset
      mandible.
AB  - PURPOSE: The purpose of the investigation was to examine growth of the mandible
      after costochondral grafting with special reference to the amount of cartilage
      included in the grafts. MATERIALS AND METHODS: The material consisted of 5
      growing and 3 adult marmoset monkeys, Callithrix jacchus, in which the condylar
      process was removed unilaterally and replaced with a costochondral graft (CCG)
      containing either a short or long cartilage end. Growing animals were followed
      for 15 months until they attained maturity; and adult animals were followed for
      13 months. Measurements made on frontal radiographs performed bimonthly, and
      direct measurements made on dry mandibles and crania at the end of the
      experiment, were used to evaluate the growth of the mandible and glenoid fossa.
      RESULTS: Longitudinal cephalometric evaluation revealed a gradual deviation of
      the lower dental midline to the unoperated side in growing monkeys with a long
      cartilage transplant. In all other animals, virtually no midline deviation
      occurred. Measurements on dry mandibles showed that the length and ramus height
      were longer in growing animals with long cartilage transplants compared with
      those with short cartilage transplants. In adult animals, the amount of cartilage
      did not make any difference with regard to the mandibular measurements.
      Enlargement of the articulating head on the grafted side was recorded in all
      animals. A morphologic change in the glenoid fossa of growing monkeys with a long
      cartilage transplant was also noted. CONCLUSIONS: The findings of this
      investigation indicate that depending on the amount of cartilage in a unilateral
      CCG, a tissue-separating force is generated in growing monkeys, capable of
      propelling the mandible to the unoperated side. This gradual overgrowth occurs
      during the entire growth period, indicating a strong hormonal and growth factor
      influence on the growth process. Jaw function may have an effect on the
      articulating surface of the CCG, seen as enlarged articulating head on the
      grafted side in all animals.

PMID- 12420267
TI  - The ascending ramus of the mandible as a donor site in maxillofacial bone
      grafting.
AB  - PURPOSE: The goal of this study was to quantify the amount of bone graft material
      present in the anterior part of ascending ramus while avoiding the inferior
      alveolar neurovascular bundle injury. MATERIALS AND METHODS: This study was made
      on 16 samples of dry skull. Osteotomies were made in front of the mandibular
      canal from the mandibular notch to 3 mm posterior of the root of the third molar.
      The dimensions, the surface area, and the volume of the bone grafts were measured
      and evaluated. RESULTS: The average dimensions of the graft material obtained
      from the anterior part of ascending ramus were 37.60 x 33.17 x 22.48 x 9.15 mm;
      the average bone volume was 2.36 mL; and the average surface area of the graft
      material was 495.13 mm(2). CONCLUSION: The results of the present study show that
      the anterior part of ascending ramus can be used as the donor site for
      reconstruction of small bone defects in the oral and maxillofacial region.

PMID- 12420268
TI  - Does plate adaptation affect stability? A biomechanical comparison of locking and
      nonlocking plates.
AB  - PURPOSE: The purpose of this investigation was to determine whether the degree of
      plate adaptation and effects of locking influenced the mechanical behavior of the
      plate/screw/substrate system for 2.0-mm monocortical superior border plates and
      2.4-mm reconstruction plates secured at the inferior border intended to stabilize
      simulated mandibular angle fractures. MATERIALS AND METHODS: A total of 130
      polyurethane synthetic mandible replicas (Synbone, Landquart, Switzerland) were
      used in this investigation. Five controls each, for incisal edge and molar
      loading, as well as 5 samples each for 2.4-mm locking and nonlocking
      reconstruction plates and 2.0-mm locking and nonlocking monocortical superior
      border plates, intimately adapted (0.0-mm offset), 1.0-mm offset and 2.0-mm
      offset were subjected to loading at the incisal edge and molar region with an
      Instron 1331 (Instron Corp, Canton, MA) servohydraulic mechanical testing unit.
      Load/displacement data were recorded, and yield load, yield displacement, and
      stiffness were determined. Mean and standard deviation values were calculated.
      Statistically significant differences were determined for the effects of locking
      and degree of plate adaptation using a 1-way analysis of variance (P <.05). For
      differences within categories and among groups, a Sheffe multiple-comparison test
      was performed. First-order polynomial best-fit curves were created for each group
      to further evaluate and compare the mechanical behavior. RESULTS: There were no
      statistically significant differences (P <.05) for yield load, yield
      displacement, and stiffness within the 2.4 and the 2.0 locking categories for
      both molar and incisal edge loading. For the 2.4 nonlocking category, there were
      statistically significant differences for yield load, yield displacement, and
      stiffness between the 0.0-mm offset group and both the 1.0-mm and 2.0-mm offset
      groups for both molar and incisal edge loading but not between the 1.0-mm and 2.0
      mm groups. For the 2.0 nonlocking category, there were statistically significant
      differences for yield load, yield displacement, and stiffness between both the
      0.0-mm and 1.0-mm offset groups and the 2.0-mm offset group for both molar and
      incisal edge loading but not between the 0.0-mm and 1.0-mm groups. CONCLUSIONS:
      The degree of adaptation (amount of offset) affected the mechanical behavior of
      the nonlocking systems evaluated. It did not affect the locking systems. Failure
      occurred as an "all-or-nothing" pattern.

PMID- 12420269
TI  - Changes in the condyle and disc in response to distraction osteogenesis of the
      minipig mandible.
AB  - PURPOSE: Distraction osteogenesis (DO) is a commonly used technique for
      mandibular lengthening, but changes in the temporomandibular joint have not been
      well documented. The purpose of this study was to evaluate the effect of DO, at
      varying rates, on the mandibular condyle and articular disc. MATERIALS AND
      METHODS: Semiburied distractors were placed via submandibular incisions in 15
      minipigs. Two unoperated animals served as controls. The protocol consisted of 0
      day latency and rates of 1, 2, or 4 mm/d for a 12-mm gap. After the animals were
      killed (0, 24, or 90 days), ipsilateral and contralateral condyles and discs were
      harvested and evaluated to determine changes in 1) condylar form and size, 2)
      condylar surface, and 3) the articular disc. RESULTS: Articular surfaces of the
      condyles in control animals were smooth, with no irregularities or erosions. In
      animals undergoing distraction, ipsilateral condyles showed increasing changes in
      morphology and AP dimension, and surface contour irregularities as the DO rate
      increased. These changes were present, but to a lesser degree, in the
      contralateral condyles. Articular discs of both ipsilateral and contralateral
      sides showed variable thinning at the medial aspect at end DO. After 90 days,
      changes in the condyles and discs were reduced by remodeling except in the 4 mm/d
      DO groups. CONCLUSIONS: Results of this preliminary study indicate that gross
      changes occur in condyles and discs after unilateral mandibular DO. These changes
      are more severe at faster distraction rates (4 mm/d) and tend to resolve during
      neutral fixation when a rate of 1 mm/d is used.

PMID- 12420270
TI  - Management of severe mandibular retrognathia in the adult patient using
      traditional orthognathic surgery.

PMID- 12420271
TI  - Management of severe mandibular retrognathia in the adult patient using
      distraction osteogenesis.

PMID- 12420272
TI  - Streptococcal infection of the temporomandibular joint of hematogenous origin: a
      case report and contemporary therapy.

PMID- 12420273
TI  - Osteochondroma of the coronoid process (Jacob's disease).

PMID- 12420274
TI  - Destructive aneurysmal bone cyst of the mandibular condyle: report of a case and
      review of the literature.

PMID- 12420275
TI  - Reconstruction of a nasomaxillary defect with traditional and infraorbital
      zygomaticus implants: report of a case.

PMID- 12420276
TI  - Superolateral dislocation of the mandibular condyle: report of 2 cases and review
      of the literature.

PMID- 12420277
TI  - Uvular paralysis after dental anesthesia.

PMID- 12420278
TI  - Alteration of chin sensibility due to damage of the cutaneous branch of the
      mylohyoid nerve during genioplasty.

PMID- 12420279
TI  - Restoration of the temporal defect using laser stereolithography technique.

PMID- 12420280
TI  - The Le Fort island approach: an alternative access for partial maxillectomy.

PMID- 12420281
TI  - Ultrasonography of the temporomandibular joint: where is the disc?

PMID- 12420282
TI  - Granule changes of human and murine endocrine cells in the gastrointestinal
      epithelia are characteristic of piecemeal degranulation.
AB  - Piecemeal degranulation is a unique pattern of cell secretion that consists of a
      slow release of granule contents from cytoplasmic secretory granules, which
      leaves empty chambers that do not fuse with each other or with the plasma
      membrane. To our knowledge, no cell types other than mast cells, basophils, and
      eosinophils have been reported in the literature to show morphological features
      of piecemeal degranulation. In the present study we provide evidence for
      ultrastructural morphologies characteristic of piecemeal degranulation in entero
      endocrine cells of the human and murine gastrointestinal epithelia. Human biopsy
      samples were taken from the mucosa of the distal duodenum, proximal jejunum, and
      colon in 10 patients undergoing endoscopic examination for malabsorption,
      diarrhea, and/or abdominal pain. Murine gastrointestinal samples were obtained
      from 10 adult C57 mice. All specimens were prepared for transmission electron
      microscopy (TEM) according to standard protocols. Results showed that different
      types of gastrointestinal entero-endocrine cells, in both humans and mice, were
      recognizable with ultrastructural features diagnostic for piecemeal
      degranulation, including specific granule and cytoplasmic changes. In the
      granules, the content was found to be loosely packed or diminished. Notably,
      altered granules did not fuse with each other or with the plasma membrane, and
      were characteristically intermingled with normal, resting granules. At times, the
      release events transformed the granules into enlarged, empty containers. Numerous
      entero-endocrine cells presented a rich supply of membrane-bound vesicles (50-200
      nm in diameter) that were free in the cytoplasm or attached to granules. This
      finding of piecemeal degranulation in gastrointestinal entero-endocrine cells
      suggests that such a secretory model might be a general degranulation pattern in
      cells involved in paracrine-endocrine secretion.

PMID- 12420283
TI  - Variation in Langerhans cell number and morphology between the upper and lower
      regions of the human esophageal epithelium.
AB  - Langerhans cells (LCs) are dendritic components of stratified epithelia,
      presenting antigens to other cells of the immune system that play a crucial role
      in local defense. The paucity of information about their significance in the
      esophageal mucosa was addressed by studying their distribution and morphology in
      this particular location. LCs were identified by immunohistochemical detection of
      CD1a, a cell-specific marker, using a monoclonal antibody, as well as by electron
      microscopic identification of characteristic Birbeck granules, among other
      typical morphological features. Cell counts carried out at 25 and 35 cm distal to
      the dental arch demonstrated significant differences in number and size between
      the two locations. The upper region contained 10.4 +/- 0.8 cells (mean +/- SEM)
      vs. 18.4 +/- 1.4 cells in the lower region. Also, cells in the lower region were
      larger and appeared to have longer dendritic processes. To our knowledge this is
      the first report of regional differences in number and morphology of LCs in human
      esophageal mucosa.

PMID- 12420284
TI  - Microvascularization of the hypermineralized calcified fibrocartilage and
      cortical bone in the sheep proximal femur.
AB  - It is well known that the incidence of hip fractures is increasing as the
      population ages, and that vascularity is one of the most important
      characteristics for any tissue (the proximal femur being no exception).
      Additionally, calcified fibrocartilage from tendon and ligament insertions
      comprises a significant portion of the fractional area of the proximal femur's
      cortical shell. The goal of the present investigation was to quantify and compare
      the microvascularity of the cortical bone and calcified fibrocartilage of the
      proximal femur in a sheep model. There were no regional differences in the
      vascular density of the cortical bone. However, the calcified fibrocartilage from
      tendon and capsular insertions were determined to be avascular, and regions of
      the proximal femur with insertions lacked a vascularized periosteum. If a vessel
      was present in the calcified fibrocartilage, it was located within an isolated
      region of bone tissue or osteoid. Since blood vessels appear to be a significant
      contributor to the health and remodeling of mineralized tissue, it is
      hypothesized that the large areas of avascular calcified fibrocartilage present
      on the elderly femoral neck may predispose these regions to damage accumulation.
      Therefore future research should examine the role of the vascularity to the
      proximal femur in the mechanisms of numerous pathological conditions, such as
      avascular necrosis, osteopenia, and hip fractures.

PMID- 12420285
TI  - Enhanced immunocytochemical expression of antioxidant enzymes in rat
      submandibular gland after normobaric oxygenation.
AB  - In order to clarify the role of antioxidant enzymes in the male rat submandibular
      gland against short-term normobaric oxygenation, we performed immunocytochemical
      staining of manganese-containing superoxide dismutase (Mn-SOD), copper- and zinc
      containing SOD (Cu/Zn-SOD), catalase (CAT), glutathione peroxidase, and
      glutathione S-transferases (GST alpha, GST mu, and GST pi) between days 1 and 7
      after normobaric oxygenation. Ultrastructural alterations and immunoreactivities
      for malondialdehyde (MDA), a lipid peroxidation-related molecule, of the acinar
      and ductal cells after the oxygenation were also investigated. Immunoreactivity
      for MDA was exhibited in the acinar cells throughout the experiment. On the other
      hand, immunoreactivity for the SODs, CAT, and GSTs was not altered, when compared
      to that of controls, but was significantly elevated in the granular, striated,
      and excretory ductal cells. Since an increase of lipid peroxidation as indicated
      by enhanced immunoreactivity for MDA was detected in the acinar and intercalated
      ductal cells, the results indicate that the enhanced antioxidant enzymes in the
      granular, striated, and excretory ductal cells play a crucial role in the self
      defense system of the male rat submandibular gland against normobaric
      oxygenation.

PMID- 12420286
TI  - Polarized light microscopic analyses of collagen fibers in the rat incisor
      periodontal ligament in relation to areas, regions, and ages.
AB  - We prepared decalcified sagittal sections (20 microm thick) from the incisal,
      middle, and basal regions of the mandibular incisor of male Wistar rats aged 2,
      6, 12, and 24 months, and examined the sections using polarized light microscopy.
      Most of the birefringent fibers appeared to run obliquely across the periodontal
      ligament. Birefringent fibers running parallel to the long axis of the incisor
      were also found in the intermediate area of the ligament. Similar fiber
      architecture was observed in all four age groups. Quantitative analysis showed
      that the retardation values of collagen were higher in the bone- and tooth
      related areas and lower in the intermediate area of the ligament. The values for
      the bone- and tooth-related areas increased from the basal toward the incisal
      regions in all four age groups. Age-related changes in the retardation values
      were found only in the incisal region of the incisor. In the incisal region, the
      values for the bone- and tooth-related areas increased markedly from 2-24 months
      of age, whereas those for the intermediate area increased slightly but
      significantly with age. Our findings indicate that the degrees of molecular
      organization and alignment of collagen fibers in the bone- and tooth-related
      areas of the ligament are higher than those in the intermediate area and increase
      near the incisal region and with age. It is also suggested that the collagen
      fibers in the intermediate area remain immature along the long axis of the
      incisor throughout the life span of the animal.

PMID- 12420287
TI  - The structure of the conus arteriosus of the sturgeon (Acipenser naccarii) heart:
      II. The myocardium, the subepicardium, and the conus-aorta transition.
AB  - Sturgeons constitute a family of living "fossil" fish whose heart is related to
      that of other ancient fish and the elasmobranches. We have undertaken a
      systematic study of the structure of the sturgeon heart aimed at unraveling the
      relationship between the heart structure and the adaptive evolutionary changes.
      In a related paper, data were presented on the conus valves and the
      subendocardium. Here, the structure of the conus myocardium, the subepicardial
      tissue, and the conus-aorta transition were studied by conventional light,
      transmission, and scanning electron microscopy. In addition, actin localization
      by fluorescent phalloidin was used. The conus myocardium is organized into
      bundles whose spatial organization changes along the conus length. The variable
      orientation of the myocardial cell bundles may be effective in emptying the conus
      lumen during contraction and in preventing reflux of blood. Myocardial cell
      bundles are separated by loose connective tissue that contains collagen and
      elastin fibers, vessels, and extremely flat cells separating the cell bundles and
      enclosing blood vessels and collagen fibers. The ultrastructure of the myocardial
      cells was found to be very similar to that of other fish groups, suggesting that
      it is largely conservative. The subepicardium is characterized by the presence of
      nodular structures that contain lympho-hemopoietic (thymus-like) tissue in the
      young sturgeons and a large number of lymphocytes after the sturgeons reach
      sexual maturity. This tissue is likely implicated in the establishment and
      maintenance of the immune responses. The intrapericardial ventral aorta shows a
      middle layer of circumferentially oriented cells and internal and external layers
      with cells oriented longitudinally. Elastin fibers completely surround each
      smooth muscle cell, and the spaces between the different layers are occupied by
      randomly arranged collagen bundles. The intrapericardial segment of the ventral
      aorta is a true transitional segment whose structural characteristics are
      different from those of both the conus subendocardium and the rest of the ventral
      aorta.

PMID- 12420288
TI  - Qualitative and quantitative morphology of renal nerves in C57BL/6J mice.
AB  - The detailed morphology of the renal nerves in mice has not been reported
      previously. The aims of this study were to describe the general morphology of the
      extrinsic renal nerve in C57BL/6 mice, and determine its morphometric parameters.
      The major renal nerve innervating the left kidney was isolated in five mice. Thin
      sections of the nerve segments were then examined by transmission electron
      microscopy. The renal nerve averaged 35.4 +/- 3.6 (S.E.M.) microm in diameter and
      741 +/- 104 microm in area. The renal nerve contained an average of 830 +/- 169
      unmyelinated fibers and only 4.6 +/- 1.7 myelinated fibers. The axon diameter of
      myelinated and unmyelinated fibers averaged 2.2 +/- 0.3 microm and 0.76 +/- 0.02
      microm, respectively. The diameter of the unmyelinated fibers ranged from 0.3 to
      2.0 microm, and the distribution histogram was unimodal. The majority of fibers
      (85%) had diameters of 0.6-1.0 microm. These results are similar to those
      obtained for renal nerves of rats with respect to the predominance of
      unmyelinated fibers. However, the diameter of unmyelinated fibers is larger in
      rats and the distribution histogram of rat unmyelinated fibers is bimodal, in
      contrast to the unimodal distribution in mice. The morphological description of
      the renal nerves in mice provides baseline data for further investigations of the
      structural basis of altered autonomic reflexes. The results will be useful in
      analyses of genes that influence the development and structure of sympathetic and
      sensory innervation of the kidney in genetically manipulated mice.

PMID- 12420289
TI  - Urorectal septum malformation sequence: Insights into pathogenesis.
AB  - We characterize the urorectal septum malformation sequence (URSMS) in discordant
      fetal lambs and relate it to the human syndromes with which URSMS is associated.
      We found abnormal external genitalia, imperforate anus, and fistulous connections
      between the rectum, bladder, and vagina. Discordance among the dizygous twins
      eliminated teratogens as a likely etiologic factor. We summarize the relevant
      literature and propose a molecular model for the pathogenesis of the URSMS, in
      which alterations in sonic hedgehog and homeobox genes lead to caudal mesodermal
      deficiency during blastogenesis.

PMID- 12420290
TI  - Neuroanatomy of the common dolphin (Delphinus delphis) as revealed by magnetic
      resonance imaging (MRI).
AB  - In this study, magnetic resonance (MR) images of the brain of an adult common
      dolphin (Delphinus delphis) were acquired in the coronal plane at 66 antero
      posterior levels. From these scans a computer-generated set of resectioned
      virtual images in orthogonal planes was constructed using the programs VoxelView
      and VoxelMath (Vital Images, Inc., Michigan State Univ.). Sections in all three
      planes reveal major neuroanatomical structures. These structures in the adult
      common dolphin brain are compared with those from a fetal common dolphin brain
      from a previously published study as well as with MR images of adult brains of
      other odontocetes. This study, like previous ones, demonstrates the utility of MR
      imaging (MRI) for comparative neuroanatomical investigations of dolphin brains.

PMID- 12420291
TI  - Distribution of the elastic fiber and associated proteins in flexor tendon
      reflects function.
AB  - The elastic fiber is known to be an important component of skin, lung, and
      vasculature. Much less is known about the distribution of elastin and elastic
      fiber-related proteins in connective tissues, yet genetic defects of elastic
      fiber constituents can lead to deficiencies in these tissues. For the first time,
      we determine the distribution of elastin, fibrillins 1 and 2, and microfibril
      associated glycoproteins (MAGPs) 1 and 2 in the flexor digitorum profundus (FDP)
      tendon. Three functionally distinct regions of the FDP tendon, the
      fibrocartilagenous (FC) region, avascular/tensional (AV/T) region, and insertion
      region, were evaluated by immunohistochemical methods for these five proteins.
      Biochemical analysis of desmosine content, an elastin-specific cross-link,
      demonstrated the presence of elastin in each region, and this was verified
      histochemically. The fibrillins were found with elastin and also pericellularly
      with internal fibroblasts where elastin was not detected. Although there was
      overlapping distribution, fibrillin 2 was more prominent in the interior of the
      tendon while fibrillin 1 was prominent in outer cell layers that contained
      elastic fibers. Both MAGP-1 and -2 were found throughout the tendon, although the
      greatest abundance was near the tendon insertion to bone. Surprisingly, MAGP-1
      demonstrated a filamentous appearance within the fibrocartilage that did not
      correspond to the fibrillin 1 or 2 or MAGP-2 staining pattern. Lastly, we have
      shown that a vincular membrane located along the dorsal surface of the tendon
      near the insertion has a very high elastin content and a unique interface with
      the tendon that consists of an elastic anchor within the tendon body.

PMID- 12420292
TI  - Description of a poorly differentiated carcinoma within the brainstem of a white
      whale (Delphinapterus leucas) from magnetic resonance images and histological
      analysis.
AB  - In this study we used magnetic resonance imaging (MRI) to investigate
      neuroanatomical structure in the brain of a white whale (Delphinapterus leucas)
      that died from a large tumor within the brainstem. This specimen was also
      compared with a normal white whale brain using MRI. MRI scans of the white whale
      specimen show how the tumor deformed surrounding brain structure.
      Histopathological analysis indicated a poorly differentiated carcinoma of
      uncertain origin. These analyses demonstrate the usefulness of supplementing
      histological analyses of pathology with studies of gross morphology facilitated
      by MRI.

PMID- 12420293
TI  - Epididymal G protein-coupled receptor (GPCR): two hats and a two-piece suit
      tailored at the GPS motif.
AB  - G protein-coupled receptors (GPCRs) are involved in cell recognition and
      signaling and their function has been experimentally determined by ligand
      activation and site-directed mutagenesis. Structurally, GPCRs consist of an
      extracellular N-terminus and an intracellular C-terminus separated by seven
      helical transmembrane domains (TM7). The extracellular region is highly
      glycosylated. The intracellular region binds to G proteins. An epididymal GPCR,
      designated HE6 (for human epididymis-specific protein 6), is present in the
      stereocilia projecting from the apical domain of principal cells into the
      epididymal lumen. In conceptual terms, HE6 wears two hats: an unusually long
      extracellular region characteristic of cell adhesion proteins, and an
      intracellular region with binding affinity to G protein. The binding partner to
      the long extracellular region has not been identified. HE6 has another remarkable
      feature comparable to the GPCR calcium-independent receptor of alpha-latrotoxin,
      designated CIRL. Both HE6 and CIRL are endogenously cleaved into two pieces at
      the GPCR proteolytic site (GPS) located adjacent to TM1, the first of the seven
      transmembrane helices. One fragment of the heterodimer wears the cell adhesion
      hat; the other retains the typical characteristics of GPCRs. This proteolytic
      processing may be regarded as a mechanism of molecular compartmentalization of
      cell adhesion and G protein activation functions. The latter may engage a beta
      arrestin-driven endocytic trafficking mechanism independent from the adhesive
      properties of the mucin extracellular domain. It is also conceivable that events
      taking place in the epididymal lumen can be surveyed by the long adhesive rod and
      subsequently coupled inside principal cells to a signaling cascade.

PMID- 12420295
TI  - HE6, a two-subunit heptahelical receptor associated with apical membranes of
      efferent and epididymal duct epithelia.
AB  - Human Epididymis-specific protein 6 [HE6 (GPR64)] is a highly conserved, tissue
      specific seven-transmembrane receptor of the human epididymis. The rodent
      counterparts were cloned and 5'-inverse PCR employed to confirm that the cDNA
      sequences were full length. Downstream from the highly conserved signal peptide
      coding sequence, the 5'-regions contained at least six mini-exons of less than 50
      nucleotides. Multiple splice variants involving these mini-exons were cloned in
      the human, the majority of which was also found in rodents. Northern blot
      analysis showed that the tissue distribution of the mRNA was very similar in
      human and rodents. The human HE6 gene was assigned to the X chromosome in a
      region, which is syntenic to the mouse. The HE6 sequence predicted a two-subunit
      receptor of the LNB-TM7 subfamily. A membrane preparation and protein
      solubilization method was adopted to identify the endogenous epididymal proteins.
      Two sets of peptides were chosen for antibody production, assuming that protein
      scission had occurred within the conserved GPS-motif. Western blot analysis
      revealed abundant two-subunit proteins in human and rodents, comprising an
      approximately 180 kDa hydrophilic ectosubunit and a <40 kDa hydrophobic
      endosubunit. Deglycosylation experiments showed that the large ectosubunits were
      highly glycosylated, the carbohydrate side chains dramatically increasing the
      apparent molecular mass. Immunohistochemical studies revealed that both subunits
      were associated with apical membranes of efferent ductule and proximal epididymal
      duct epithelia.

PMID- 12420294
TI  - Chromosomal location, structure, and temporal expression of the platelet
      activating factor receptor (PAFr) gene in porcine endometrium and embryos
      relative to estrogen receptor alpha gene expression.
AB  - Although platelet-activating factor receptor (PAFr) gene was well characterized
      in the human, little was known about it in domestic animals. Porcine PAFr gene
      was mapped using fluorescence in situ hybridization (FISH). The structure of this
      gene was investigated using a 5' rapid amplification of cDNA ends (RACE)
      technique. Temporal expression of PAFr and estrogen receptor alpha genes (ER),
      and distribution of the PAFr transcripts in porcine endometrial and embryonic
      tissues on days 0, 10, 12, 14, 16, and 18 were analyzed using DNA competitors and
      reverse transcription and polymerase chain reaction (RT-PCR). The porcine PAFr
      gene was mapped to SSC6q26-27. Alternative splicing of primary transcripts of the
      PAFr gene produced two different transcripts. Transcript 1 was expressed in all
      tissues and cells, and transcript 2 was detected in all tissues but white blood
      cells. The temporal expression of the PAFr gene in endometrial (P > 0.05) and
      embryonic (P < 0.05) tissues of pregnant sows increased from day 10 to 16. The
      temporal expression of ER genes in endometrial tissues of pregnant sows decreased
      from day 10 to 18 (P < 0.05). In addition, ER expression was detectable in 20-60%
      of embryonic tissue samples, which generally decreased. In combination with
      previously obtained data on PAF and estradiol-17beta (E(2)) concentrations in
      pregnant uterine luminal fluids (pULF), endometrial and embryonic tissues, the
      present results indicated that the increasing PAFr transcripts were positively
      associated with increasing levels of PAF. Both ER transcripts and E(2) found in
      pULF decreased correspondingly from day 13 to 16. These results indicate that via
      PAFr, PAF could play a dominant role in peri-implantation development in pigs as
      compared to E(2).

PMID- 12420296
TI  - Expression patterns of pituitary adenylate cyclase activating polypeptide and its
      type I receptor mRNAs in the rat placenta.
AB  - Pituitary adenylate cyclase activating polypeptide (PACAP) was first isolated
      from ovine hypothalamus and is known to act as a tropic factor in various cells.
      Recent report revealed the expression of PACAP and the PACAP type I (PAC(1))
      receptor in human and rat placentas at term. Placenta is a critical organ that
      synthesizes several growth and angiogenic factors for its own growth as well as
      fetal development. However, there is little information regarding the expression
      pattern and cellular localization of PACAP and PAC(1) during pregnancy. The aim
      of this study was to define the expression and distribution of PACAP and PAC(1)
      receptor mRNAs in the rat placenta during pregnancy. PACAP and PAC(1) receptor
      mRNAs were expressed in decidual cells, chorionic vessels, and stromal cells of
      the chorionic villi. Interestingly, the expression of these genes varied with the
      day of gestation. For example, PACAP and PAC(1) receptor mRNAs expressed in
      decidual cells on day 13.5 and 15.5, their expression was strong in chorionic
      vessels and stromal cells of the chorionic villi within the labyrinth zone on day
      17.5, 19.5, and 21.5. In fact, as gestation advanced, the expression of PACAP and
      PAC(1) receptor mRNAs in the decidua cells disappeared, as their high expression
      became evident in the chorionic vessels and stromal cells of the chorionic villi.
      Our finding that PACAP and the PAC(1) receptor are co-localized and their genes
      seemingly co-regulated within specific placental areas, strongly suggest that
      this peptide may play an important role, as an autoregulator or pararegulator via
      its PAC(1) receptor, in physiological functioning of the placenta for gestational
      maintenance.

PMID- 12420297
TI  - Differential expression of the two GH genes during embryonic development of
      rainbow trout Oncorhynchus mykiss in relation with the IGFs system.
AB  - The Growth hormone (GH)/insulin-like growth factor (IGF) system promotes
      embryonic growth in higher vertebrates. Such a system exists in salmonids, but
      exhibits an additional level of complexity resulting from a recent whole genome
      tetraploidisation. Thus, two nonallelic GH genes are present in the trout genome.
      Although the two GH genes are similar, the possibility remains that the two genes
      have evolved separately, acquiring a distinct expression pattern. In this study,
      using whole mounted in situ hybridisation, we observed a one stage delay between
      the appearance of GH-2 (Stage 22) and GH-1 (Stage 23) soon after pituitary
      formation (Stage 21). In addition, by double in situ hybridisation, we clearly
      evidenced two types of somatotroph, one expressing only GH-2 and the other type
      both GH-1 and GH-2 at Stage 24. Consequently, at this stage more cells expressed
      GH-2 than GH-1 as confirmed by quantitative RT-PCR. However at hatching, as in
      adult, the difference between the expression of the two GH genes was no longer
      observed. In addition, our immunohistochemical studies did not show any delay
      between the expression of the mRNA and its translation as a protein at Stage 24.
      A comparison of the expression pattern of the IGF system components (IGF-1, IGF
      2, and the receptor type I) determined by real time RT-PCR, have shown an IGF-1
      mRNA increase concomitantly to the appearance of GH expression. On the whole, our
      results demonstrate a differential regulation of GH-1 and GH-2 genes in rainbow
      trout embryo. The relationship observed between the expression of different
      component of the GH/IGF system seems to indicate that this system could be
      functional early on during embryonic development.

PMID- 12420298
TI  - Differential pattern of Xist RNA accumulation in single blastomeres isolated from
      8-cell stage mouse embryos following laser zona drilling.
AB  - Xist gene expression begins at the late 2-cell stage in female mouse embryos and
      by the third division results in the accumulation of an average 100 copies of
      Xist RNA per cell, as measured by real-time reverse transcription-polymerase
      chain reaction (RT-PCR). In the blastocyst, the trophectoderm maintains the
      paternally imprinted pattern of Xist expression present during early development,
      while either the maternal or the paternal X chromosome can express Xist among
      cells of the inner mass. Fluorescent in situ hybridization (FISH) has previously
      established that Xist transcripts are localized on the silenced X chromosome,
      forming aggregates of variable dimensions in blastomeres of 8-cell embryos. This
      observation and the fact that Xist RNA accumulation per cell sharply decreases
      after morula stage raise the possibility that cells of cleaving embryos contain
      different levels of Xist RNA, perhaps linked to their subsequent developmental
      fates. We show here that Xist RNA is efficiently recovered from single
      blastomeres isolated from 8-cell embryos following laser zona drilling. Sexing of
      the samples and simultaneous quantification of Xist RNA in individual cells is
      achieved with a multiplex Xist/Sry real-time RT-PCR assay sensitive to the single
      copy level. This analysis reveals that Xist RNA is indeed accumulated to
      substantially different levels in individual blastomeres of the same 8-cell
      embryo and that two blastomeres contain most of the molecules per embryo. These
      results support the conclusion that cells of the early mammalian embryo are not
      all functionally equivalent. Differential Xist gene expression could arise from
      differences in DNA methylation, or the order in which cells divide.

PMID- 12420299
TI  - Display of different modes of transcription by the promoters of an early
      embryonic gene, Zfp352, in preimplantation embryos and in somatic cells.
AB  - We have previously reported a Krupple-like finger protein gene, Zfp352, which is
      expressed temporarily in two- to eight-cell mouse embryos. The Zfp352 gene is
      intron-less in the coding region but carries a solitary 4.3-kb intron in the 5'
      untranslated region. In this study, we have analyzed the Zfp352 promoter activity
      in early embryos and in somatic cells. We determined that the major Zfp352
      promoter, designated P1 and located upstream of exon 1, is utilized in both early
      embryos and in somatic cells. A TATA-like box and a transcription initiator
      element are discernible in the P1 promoter. We uncovered an alternative promoter,
      designated P2, in the intron. 5'-Rapid amplification of cDNA ends and real-time
      RT-PCR experiments indicated that the P2 promoter is weak and is probably
      fortuitous in early embryos. In somatic cells, however, transfection experiments
      showed that P2 is as active as P1 as a promoter. Furthermore, P2 appears to be
      composed of two different subdomains used differentially for transcription
      initiation in embryos and in somatic cells. Our observations may bear relevance
      in explaining developmental deficiencies associated with somatic cell cloning
      experiments.

PMID- 12420300
TI  - Epidermal growth factor regulation of connexin 43 in cultured granulosa cells
      from preantral rabbit follicles.
AB  - Connexin 43 (Cx43), a gap junction protein expressed in differentiated granulosa
      cells, is necessary for normal follicular development. Cx43 expression and
      regulation by epidermal growth factor (EGF) were characterized in immature rabbit
      granulosa cells. Cx43 mRNA was expressed in the granulosa cells of primary
      follicles, but was undetectable in primordial follicles. Abundant expression of
      Cx43 mRNA was maintained in the granulosa cells of growing follicles through
      maturity. Granulosa cells were isolated from early preantral follicles and
      maintained in monolayer cultures for 72 hr. After the first 24 hr of culture,
      they were maintained for 48 hr in serum-free medium supplemented with 0, 1, 5, or
      10 ng/ml of mouse EGF. Granulosa cell proteins were isolated, solubilized, and
      evaluated for Cx43 by Western blot analysis using antibodies to rat Cx43.
      Relative amounts of Cx43 protein (both phosphorylated and nonphosphorylated) were
      increased (P < 0.05) by EGF in a dose-dependent manner. Northern blot analysis of
      RNA from cultured granulosa cells demonstrated increased amounts of Cx43 mRNA in
      the EGF treated cultures (10 ng EGF/ml) relative to controls (P < 0.03). In
      summary, Cx43 gap junctions are synthesized in granulosa cells following the
      onset of folliculogenesis in vivo and their expression is enhanced by EGF in
      vitro.

PMID- 12420301
TI  - Cryo-survival and development of bovine blastocysts are enhanced by culture with
      recombinant albumin and hyaluronan.
AB  - Recombinant albumin can be used to supplement culture medium for the maturation
      and fertilization of bovine oocytes and subsequent embryo development to the
      blastocyst stage. Recombinant albumin was able to support blastocyst development
      at rates equivalent to that of bovine serum albumin (BSA) supplemented media.
      Supplementation of media containing recombinant albumin and citrate stimulated
      blastocyst expansion. Culture with recombinant albumin and citrate significantly
      increased the ability of the resultant blastocysts to re-expand and hatch
      following cryopreservation. The further addition of the glycosaminoglycan
      hyaluronan to the culture medium containing either BSA or recombinant albumin
      also increased the ability of blastocysts to survive cryopreservation. Inclusion
      of recombinant albumin and hyaluronan in culture media facilitates the
      development of physiological defined culture conditions. For bovine embryos this
      has implications for both research and commercial applications where defined
      reproducible conditions are desirable.

PMID- 12420302
TI  - Interferon-tau in bovine blastocysts following parthenogenetic activation of
      oocytes: pattern of secretion and polymorphism in expressed mRNA sequences.
AB  - A series of experiments were conducted to examine the pattern of production and
      secretion of interferon-tau (IFN-tau) by blastocysts following parthenogenetic
      activation of bovine oocytes. In the first experiment, 36.8, 24.1, and 33.2% of
      IVF-derived and parthenogenetically activated oocytes cultured in the presence or
      absence of a monolayer of buffalo rat liver cells, respectively, reached the
      blastocyst stage. Following individual culture of blastocysts, IFN-tau
      concentration in medium droplets was similar among the three groups, although IVF
      derived blastocysts contained significantly more cells. In the second experiment,
      156 IVF-derived blastocysts were sexed by PCR with 75 and 81, respectively, being
      male and female. IFN-tau secretion of these was compared to that of 70
      parthenogenetic blastocysts. Female and parthenogenetic blastocysts produced
      significantly more IFN-tau than their male counterparts. In the third experiment,
      the ability of hatched blastocysts to form outgrowths and the pattern of their
      IFN-tau secretion were examined. Of the 48 IVF-derived blastocysts, 44 formed
      outgrowths compared to 41 of the 42 hatched parthenotes. Parthenogenetic
      outgrowths were significantly larger after 7 days, but this difference had
      disappeared after 14 days. IFN-tau secretion did not differ between the two
      groups. Lastly, sequence analyses of expressed mRNA from individual
      parthenogenetic blastocyst outgrowths showed four different transcript types
      which, based on their predicted amino acid sequence, belong to two subgroups, IFN
      tau1 and IFN-tau3. In addition, one new transcript sequence was identified,
      encoding a new protein isoform.

PMID- 12420303
TI  - Meiosis in the golden hamster: a confocal microscopy and flow cytometric
      analysis.
AB  - In this study, confocal microscopy and flow-cytometry were utilized to follow
      meiosis in hamster spermatogenesis. Confocal microscopy was used as an analytical
      tool to observe spermatocytes inside the tubules following meiotic progression
      consecutively at defined spermatogenic stages. To study spermatocyte
      differentiation, the structure of the synaptonemal complex was studied in detail
      at various stages of hamster spermatogenesis using the antibody against SC3 (the
      protein of axial/lateral element). The synaptonemal complex was observed from the
      leptotene stage until the first meiotic division with maximal staining in mid
      pachytene spermatocytes, suggesting a role for SC3 at this postrecombinational
      stage. In addition, 3-dimensional (3D) images of synaptonemal complex were
      observed, providing information about spatial distribution of the chromosomes
      within the nuclei of spermatocytes at different stages of meiosis. Changes in
      spermatocyte sizes and DNA condensation allowed assessment of meiosis by flow
      cytometry. Changes in chromatin condensation at different stages of hamster
      meiosis were followed, revealing decondensation from early to late pachytene
      stages. The analysis also allowed a comparing of chromatin status of mitotic and
      meiotic chromosomes, confirming the less compact structure of the latter,
      possibly connected to increased transcriptional activity during meiosis.

PMID- 12420304
TI  - Glycogen synthase kinase-3 regulates mouse oocyte homologue segregation.
AB  - Intracellular regulation of oocyte meiosis is not completely understood. However,
      reversible phosphorylation, which involves serine/threonine protein kinases and
      phosphatases (PP), is an important mediator. Glycogen synthase kinase-3 (GSK-3)
      is a highly conserved serine/threonine protein kinase. Currently no reports exist
      on presence or function of GSK-3 in mammalian oocytes. The aim of this study was
      to determine GSK-3 presence/absence, transcript and protein expression,
      intracellular protein distribution, and to investigate the functional importance
      of GSK-3 in mouse oocyte meiosis. Germinal vesicle-intact (GVI) oocytes contained
      both GSK-3 transcript and protein. Although GSK-3 beta-isoform is the only
      transcript identifiable in GVI oocytes, both alpha- and beta-isoforms were
      recognized by Western blot analysis. In growing, meiotic-incompetent oocytes GSK
      3 was present, diffusely located throughout the cytoplasm and absent in the
      nucleus, whereas in meiotic-competent oocytes this cytoplasmic GSK-3 displays a
      predominant peri-oolemma staining. Treatment of mouse GVI oocytes with lithium
      chloride (LiCl), which inhibits both inositol monophosphatase (IMPase) and GSK-3,
      had no significant influence on oocyte viability, morphology, or development to
      metaphase II (MII). However, LiCl caused abnormal spindle formation and
      significantly increased incidence of abnormal homologue segregation during the
      first meiotic division. L690,330, which is a specific IMPase inhibitor, had no
      significant effect on oocyte viability, morphology, MII development, or homologue
      segregation. This is the first report of GSK-3 in mammalian oocytes. LiCl
      inhibition of mouse oocyte GSK-3 modified organization of microtubules and/or
      function of meiotic spindles thus compromising segregation of condensed bivalent
      chromosomes.

PMID- 12420305
TI  - Glutathione (GSH) concentrations vary with the cell cycle in maturing hamster
      oocytes, zygotes, and pre-implantation stage embryos.
AB  - Glutathione (GSH) is thought to play critical roles in oocyte function including
      spindle maintenance and provision of reducing power needed to initiate sperm
      chromatin decondensation. Previous observations that GSH concentrations are
      higher in mature than immature oocytes and decline after fertilization, suggest
      that GSH synthesis may be associated with cell cycle events. To explore this
      possibility, we measured the concentrations of GSH in Golden Hamster oocytes and
      zygotes at specific stages of oocyte maturation and at intervals during the first
      complete embryonic cell cycle. Between 2 and 4 hr after the hormonal induction of
      oocyte maturation, GSH concentrations increased significantly (approximately
      doubling) in both oocytes and their associated cumulus cells. This increase was
      concurrent with germinal vesicle breakdown and the condensation of metaphase I
      chromosomes in the oocyte. GSH remained high in ovulated, metaphase II (MII)
      oocytes, but then declined significantly, by about 50%, shortly after
      fertilization, as the zygote progressed back into interphase (the pronucleus
      stage). GSH concentrations then plummeted by the two-cell embryo stage and
      remained at only 10% of those in MII oocytes throughout pre-implantation
      development. These results demonstrate that oocyte GSH concentrations fluctuate
      with the cell cycle, being highest during meiotic metaphase, the critical period
      for spindle growth and development and for sperm chromatin remodeling. These
      observations raise the possibility that GSH synthesis in maturing oocytes is
      regulated by gonadotropins, and suggest that GSH is more important during
      fertilization than during pre-implantation embryo development.

PMID- 12420306
TI  - Sorting specificity of spermatogenic cell specific region of mouse hexokinase-s
      (mHk1-s).
AB  - Hexokinase is the first enzyme involved in the glycolysis process that produces
      glucose phosphorylate. Our previous study reported on our cloning of mouse Hk1-s
      (mHk1-s) cDNA, which were expressed only in testis cells, and noted that this
      cDNA has a spermatogenic cell-specific region (SSR) that replaces the porin
      binding domain (PBD) in the Hk1of somatic cells. Although we know that PBD binds
      to the outer membrane of a mitochondrion, the role of the SSR is not yet
      understood. To investigate the intracellular localization of SSR, we constructed
      expression vectors with the epitope tag (GFP-, HA-), subcloned SSR, or PBD cDNA.
      We transfected these vectors in mouse fibroblast, NIH3T3 cells, after which we
      observed the localization of the SSR and PBD in the NIH3T3 cells. Our current
      study using the immunocytochemical method revealed that PBD is concentrated
      around the mitochondrion. However, the SSR could not be ascribed to the
      mitochondrion, ER, or nuclear colocalization. Moreover, subcellular fractionation
      analysis showed that PBD was detected in the mitochondrial fraction, and that SSR
      was detected in the cytosolic fraction. Our findings suggest that PBD of Hk1
      targets mitochondrion, but the SSR of mHk1-s targets some specific organellae.

PMID- 12420307
TI  - Progesterone induces acrosome reaction in stallion spermatozoa via a protein
      tyrosine kinase dependent pathway.
AB  - Progesterone (P(4)) is a physiological inducer of the acrosome reaction (AR) in
      stallion spermatozoa. However, the capacitation-dependent changes that enable
      progesterone binding, and the nature of the signaling cascade that is triggered
      by progesterone and results in induction of the AR, are poorly understood. The
      aim of the current study was, therefore, to investigate the protein kinase
      dependent signaling cascades involved in progesterone-mediated induction of the
      AR in stallion spermatozoa. In addition, we aimed to determine whether
      bicarbonate, an inducer of sperm capacitation, acted via the same pathway as P(4)
      or whether it otherwise synergized P(4)-mediated induction of the AR. We examined
      the effect on AR progression of specific inhibitors and stimulators of protein
      kinase A (PKA), protein kinase C (PKC), protein kinase G (PKG), and protein
      tyrosine kinase (PTK), in the presence or absence of 15 mM bicarbonate and/or 1
      microg/ml progesterone. Progression of the AR was assessed using the Pisum
      sativum agglutinin conjugated to fluorescein iso thiocyanate (PSA-FITC) staining
      technique. Bicarbonate specifically activated a PKA-dependent signaling pathway,
      whereas the effect of P(4) was independent of PKA. Conversely, while P(4)
      mediated AR induction was dependent on PTK, the effects of bicarbonate were PTK
      independent. Finally, although the AR inducing effects of both P(4) and
      bicarbonate were sensitive to staurosporin, a potent blocker of PKC activity at
      moderate (50 nM) concentrations, the effect of P(4) was completely blocked at 50
      nM staurosporin, whereas that of bicarbonate was only completely inhibited by
      much higher concentrations (2 microM) where staurosporin also inhibits PKA
      activity. In conclusion, P(4)-mediated activation of the AR is dependent on a
      pathway that includes both PTK and PKC. While the effects of bicarbonate on the
      AR are mediated via a separate PKA-dependent signaling pathway, P(4) and
      bicarbonate have synergistic effects on the AR.

PMID- 12420308
TI  - Activation of PP2A-like phosphatase and modulation of tau phosphorylation
      accompany stress-induced apoptosis in cultured oligodendrocytes.
AB  - In a number of neurodegenerative diseases, tau-positive glial cytoplasmic
      inclusions (GCIs), immunochemically labeled with antibodies to the small heat
      shock protein (HSP) alphaB-crystallin, occur in oligodendrocytes. The microtubule
      associated protein tau is functionally modulated by phosphorylation. We have
      shown previously that oxidative stress (OS) and heat shock (HS) induce apoptotic
      cell death in oligodendrocytes. The present study was undertaken to test whether
      stress responses in oligodendrocytes cause abnormalities in the expression and
      posttranslational modification of tau proteins, and whether the dynamic
      phosphorylation and dephosphorylation of tau are involved in the pathogenesis of
      glial cells. Cultured rat brain oligodendrocytes were subjected to OS, exerted by
      hydrogen peroxide, or HS (44 degrees C, 30 min). Immunoblot analysis with a panel
      of phosphorylation-dependent antibodies shows that OS and HS caused the rapid
      dephosphorylation of tau proteins at multiple sites, before characteristic
      features of apoptosis were observed. Concomitantly, ERK1,2 (extracellular signal
      regulated kinase) was activated. Tau phosphorylation and rephosphorylation after
      stress was mediated by glycogen synthase kinase 3beta (GSK-3beta), and not by
      ERK1,2 and could be suppressed by lithium chloride, a specific inhibitor of GSK
      3beta. Stress-induced dephosphorylation could be mimicked by alkaline phosphatase
      and suppressed by the protein phosphatase inhibitor okadaic acid (OA), indicating
      that PP2A in oligodendrocytes is activated by stress. OA at low concentrations
      could prevent stress-induced DNA fragmentation, but eventually exerted cytotoxic
      effects. Hence, stress-induced activation of PP2A in oligodendrocytes and tau
      dephosphorylation constitute a major feature of the response to injury in these
      cells, which eventually undergo apoptotic cell death.

PMID- 12420309
TI  - Catecholamine-induced oligodendrocyte cell death in culture is developmentally
      regulated and involves free radical generation and differential activation of
      caspase-3.
AB  - Oligodendrocyte cultures were used to study the toxic effects of catecholamines.
      Our results showed that catecholamine-induced toxicity was dependent on the dose
      of dopamine or norepinephrine used and on the developmental stage of the
      cultures, with oligodendrocyte progenitors being more vulnerable. A role for
      oxidative stress and apoptosis on the mechanism of action of catecholamines on
      oligodendrocyte cell death was next assessed. Catecholamines caused a reduction
      in intracellular glutathione levels, an accumulation in reactive oxygen species
      and in heme oxygenase-1, the 32 kDa stress-induced protein. All these changes
      were prevented by N-acetyl-L-cysteine, a thiocompound with antioxidant activity
      and a precursor of glutathione, and were more pronounced in progenitors than
      mature cells, which could contribute to their higher susceptibility. Apoptotic
      cell death, as assessed by activation of caspase-9 and -3 and cleavage of
      poly(ADP-ribose) polymerase (a substrate of caspase-3), was only observed in
      oligodendrocyte progenitors. Pretreatment with zVAD, a general caspase inhibitor,
      prevented activation of caspase-9 and -3, DNA fragmentation, and decreased
      progenitors cell death. Furthermore, the expression levels of procaspase-3 and
      the ratio of the proapoptotic protein bax to antiapoptotic protein bcl-xl were
      several folds higher in immature than mature oligodendrocytes. Taken together,
      these results strongly suggest that the catecholamine-induced cytotoxicity in
      oligodendrocytes is developmentally regulated, mediated by oxidative stress, and
      have characteristics of apoptosis in progenitor cells.

PMID- 12420310
TI  - Trafficking of PLP/DM20 and cAMP signaling in immortalized jimpy
      oligodendrocytes.
AB  - The synthesis, transport, and insertion of jimpy proteolipid protein and DM20
      were studied in normal (158N) and jimpy (158JP) immortalized oligodendrocyte
      lines. Four different expression vectors encoding fusion proteins composed of
      native PLP and DM20 or jimpy PLP or DM20 were linked to enhanced green
      fluorescent protein (EGFP). All four transfected fusion proteins had similar
      distributions in the cell bodies and processes of the two cell types. Both normal
      and jimpy PLP-EGFP and DM20-EGFP were detected in both cell lines as far as 200
      microM from the cell body, indicating synthesis and transport of mutated PLP and
      DM20 toward the plasma membrane. Immunocytochemistry of fixed normal and jimpy
      cells with the O10 antibody, which recognizes a conformationally sensitive
      PLP/DM20 epitope, confirmed that normal and jimpy PLP and DM20 were transported
      to the plasma membrane. Live staining of normal and jimpy cells transiently
      transfected with the native PLP showed positive staining, indicating PLP was
      correctly inserted into the membrane of both normal and jimpy oligodendrocytes.
      However, live staining of normal and jimpy cells transiently transfected with
      jimpy PLP showed no positive staining, indicating the mutated protein is
      abnormally inserted into the plasma membrane. Electrophysiological recordings of
      the resting membrane potential measured in the whole cell mode of the patch-clamp
      technique showed the absence of a developmentally regulated negative shift in the
      membrane potential in jimpy cells compared to normal native or immortalized
      oligodendrocytes. Treatment of 158N cells and native oligodendrocytes with
      dibutyryl cAMP (dbcAMP) caused morphological and biochemical differentiation, but
      failed to do so in 158JP cells, suggesting an abnormal signaling pathway in
      jimpy. The defect in cAMP signaling in jimpy oligodendrocytes was associated with
      the suppression of increase in mRNA level of the inducible cAMP early repressor
      (ICER). When the jimpy oligodendrocyte line was transfected with normal PLP or
      DM20 and exposed to dbcAMP, the cells failed to differentiate. This finding
      suggests that improper insertion of jimpy protein into the plasma membrane alters
      the membrane in such a way that certain signaling pathways are permanently
      altered. The abnormal insertion of jimpy PLP/DM20 into the plasma membrane may be
      the basis for the lack of cell signaling and abnormal resting potential in jimpy
      oligodendrocytes.

PMID- 12420311
TI  - Nitric oxide induces rapid, calcium-dependent release of vesicular glutamate and
      ATP from cultured rat astrocytes.
AB  - Nitric oxide (NO; 1 microM) or an NO donor (500 microM diethylenetriamine-nitric
      oxide, DETA-NONOate) caused rapid glutamate and ATP release from cultured rat
      cortical astrocytes. NO-induced glutamate release was prevented by calcium
      chelators (EGTA or BAPTA-AM) and an inhibitor of vesicular exocytosis (botulinum
      neurotoxin C, BoTx-C), but not by a glutamate transport inhibitor, L-trans
      pyrrolidine-2,4-dicarboxylate (t-PDC), a cyclooxygenase inhibitor (indomethacin),
      or an inhibitor of soluble guanylate cyclase 1H-[1,2,4]oxadiazolo-[4,3
      a]quinoxalin-1-one (ODQ), and was not induced by mitochondrial respiratory
      inhibitors (myxothiazol or azide). Similarly to glutamate, NO-induced ATP release
      was also completely blocked by BAPTA-AM and BoTx-C, suggesting again a vesicular,
      calcium-dependent mechanism of release. Addition of DETA-NONOate (500 microM) to
      fura-2-loaded astrocytes induced a rapid, transient increase in intracellular
      calcium levels followed by a lower, sustained level of calcium entry. The latter
      was blocked by gadolinium (1 microM), an inhibitor of capacitative Ca(2+) entry.
      Thus, NO appears to cause rapid exocytosis of vesicular glutamate and ATP from
      astrocytes by raising intracellular calcium levels. Astrocytes activated by
      lipopolysaccharide/endotoxin and interferon-gamma to express inducible NO
      synthase (iNOS) maintained substantially higher extracellular glutamate levels
      than nonactivated cells or activated cells treated with an iNOS inhibitor
      (1400W), but the rate of glutamate uptake by these cells was similar. This
      suggests that NO from inflammatory-activated astrocytes causes release of
      astrocytic glutamate. NO-induced release of astrocytic glutamate and ATP may be
      important in physiological or pathological communication between astrocytes and
      neurons.

PMID- 12420312
TI  - Ammonia-induced heme oxygenase-1 expression in cultured rat astrocytes and rat
      brain in vivo.
AB  - Ammonia is a key factor in the pathogenesis of hepatic encephalopathy (HE), which
      is a major complication in acute and chronic liver failure and other
      hyperammonemic states. The molecular mechanisms underlying ammonia neurotoxicity
      and the functional consequences of ammonia on gene expression in astrocytes are
      incompletely understood. Using cDNA array hybridization technique we identified
      ammonia as a trigger of heme oxygenase-1 (HO-1) mRNA levels in cultured rat
      astrocytes. As shown by Northern and Western blot analysis, HO-1 mRNA levels were
      upregulated by ammonia (0.1-5 mmol/L) after 24 h and protein expression after 72
      h in astrocytes. These ammonia effects on HO-1 are probably triggered to a minor
      extent by ammonia-induced glutamine synthesis or by astrocyte swelling, because
      HO-1 expression was not inhibited by the glutamine synthetase inhibitor
      methionine sulfoximine (which abrogated ammonia-induced cell swelling in cultured
      astrocytes), and ammonia-induced HO-1 expression could only partly be mimicked by
      hypoosmotic astrocyte swelling. Hypoosmotic (205 mOsm/L) exposure of astrocytes
      led even to a decrease in HO-1 mRNA levels within 4 h, whereas hyperosmotic (405
      mOsm/L) exposure increased HO-1 mRNA expression. After 24 h, hypoosmolarity
      slightly raised HO-1 mRNA expression. Taurine and melatonin diminished ammonia
      induced HO-1 mRNA or protein expression, whereas other antioxidants
      (dimethylthiourea, butylated hydroxytoluene, N-acetylcysteine, and reduced
      glutathione) increased HO-1 mRNA levels under ammonia-free conditions. An in vivo
      relevance is suggested by the finding that increased HO-1 expression occurs in
      the brain cortex from acutely ammonia-intoxicated rats. It is concluded that
      ammonia-induced HO-1 expression may contribute to cerebral hyperemia in
      hyperammonic states.

PMID- 12420313
TI  - Selective blockade of astrocytic glutamate transporter GLT-1 with dihydrokainate
      prevents neuronal death during ouabain treatment of astrocyte/neuron cocultures.
AB  - Glutamate (Glu) is a major excitatory neurotransmitter of the mammalian central
      nervous system and under normal conditions plays an important role in information
      processing in the brain. Therefore, extracellular Glu is subject to strong
      homeostasis. Astrocytes in the brain have been considered to be mainly
      responsible for the clearance of extracellular Glu. In this study, using mixed
      neuron/astrocyte cultures, we investigated whether astrocytic Glu transporter GLT
      1 is crucial to the survival of neurons under various conditions. Treatment of
      the mixed cultures with a low concentration of Glu did not produce significant
      death of neurons. However, cotreatment with dihydrokainate (DHK), a specific
      blocker of GLT-1, resulted in significant neuronal death that was suppressed by
      an antagonist of N-methyl-D-aspartate (NMDA) receptors. These results suggested
      that astrocytic GLT-1 participated in the clearance of extracellular Glu and
      protected neurons from NMDA receptor-mediated toxicity. When the cultures were
      treated with ouabain, an inhibitor of Na(+)/K(+)-ATPase, a low concentration of
      Glu resulted in massive neuronal death that was also suppressed by cotreatment
      with an antagonist of NMDA receptors. In this case, however, cotreatment with DHK
      significantly protected neurons from death, suggesting that GLT-1 was responsible
      for the death of neurons. The present study provides evidence suggesting that
      astrocytes use their Glu transporter GLT-1 to protect neurons from Glu toxicity,
      but, ironically, also use GLT-1 to kill neurons through Glu toxicity depending on
      their status.

PMID- 12420314
TI  - The tetraspanin protein, CD9, is expressed by progenitor cells committed to
      oligodendrogenesis and is linked to beta1 integrin, CD81, and Tspan-2.
AB  - Previous studies identified the tetraspanin protein CD9 in myelinating
      oligodendrocytes. The present report extends these observations by identifying
      CD9 in a subpopulation of oligodendrocyte progenitor cells (OPCs) and in
      premyelinating oligodendrocytes in rodents. NG2-positive cells expressed CD9 in a
      temporal and spatial pattern during development that was consistent with CD9
      expression in OPCs just prior to their differentiation into premyelinating
      oligodendrocytes. NG2-positive cells in mature brains were CD9-negative. CD9
      expression during oligodendrocyte development in vitro supported this hypothesis,
      as all CD9-positive cells became O4-positive when switched to oligodendrocyte
      differentiating media. CD9 immunoreactivity was enriched in myelinating
      oligodendrocytes and their processes, and the outer aspects of myelin internodes.
      Immunoprecipitation of CD9 from postnatal rat cerebrum coprecipitated beta1
      integrin, CD81, and Tspan-2, another tetraspanin protein recently identified in
      oligodendrocytes. Following surface biotinylation of oligodendrocytes in vitro,
      biotinylated beta1 integrin was identified in a CD9 immunoprecipitate. These data
      support a molecular link between surface integrins and a CD9, Tspan-2 molecular
      web during the differentiation of oligodendrocytes. Oligodendrocyte production
      and myelination appears to be normal in CD9-deficient mice. These data support
      the hypothesis that CD9 helps form the tetraspanin web beneath the plasma
      membranes of progenitor cells committed to oligodendrogenesis, but that CD9 is
      not essential for oligodendrogenesis and myelination.

PMID- 12420315
TI  - Selective inflammatory stimulations enhance release of microglial response factor
      (MRF)-1 from cultured microglia.
AB  - The mrf-1 gene has been isolated from microglia exposed to cultured cerebellar
      granule neurons undergoing apoptosis. We have shown that mrf-1 is upregulated in
      response to neuronal death and degeneration both in vitro and in vivo. However,
      the exact role of MRF-1 remains unknown. Here we show that MRF-1 is released from
      cultured rat microglia, and its release is greatly enhanced under inflammatory
      conditions. When microglia were treated with ATP, the amount of MRF-1 that was
      released increased 10-fold compared to the basal level of release. Enhanced MRF-1
      release was induced within 10 min and peaked within 1 h; after approximately 4 h,
      the MRF-1 release had returned to normal. MRF-1 release was stimulated by 2
      methyl-thio-ATP (five-fold) and a P2X(7) selective agonist, 2'- and 3'-O-(4
      benzoylbenzoyl)-ATP (ten-fold). Moreover, the ATP-stimulated MRF-1 release was
      inhibited by a P2X(7) selective antagonist, oxidized ATP (oATP), and also under a
      Ca(2+)-free condition. These results indicate that the effects of ATP are
      dependent on Ca(2+) influx through P2X(7) receptors. MRF-1 release was enhanced
      by Ca(2+)-ionophore A23187 (sixfold), thapsigargin (threefold); however, it was
      not enhanced by glutamate or lipopolysaccharide. Moreover, a platelet-activating
      factor enhanced microglial MRF-1 release in a dose-dependent manner. We also
      showed that a conditioned medium from cerebellar granule neurons undergoing
      apoptosis markedly increased MRF-1 release from microglia; that effect was
      significantly inhibited by oATP. These results indicate that selective
      inflammatory stimulations, including ATP and PAF, enhance MRF-1 release from
      microglia through a Ca(2+)-dependent mechanism and suggest that MRF-1 may play a
      role in cell-cell interactions under inflammatory conditions.

PMID- 12420316
TI  - Regulation of the kinetics of intracerebral chemokine gene expression in murine
      Toxoplasma encephalitis: impact of host genetic factors.
AB  - The expression and kinetics of a panel of chemokines during Toxoplasma
      encephalitis (TE) were analyzed in a comparative study of genetically resistant
      BALB/c and susceptible C57BL/6 mice. In parallel with disease activity and the
      number of postinfection (p.i.) leukocytes, C57BL/6 mice induced CRG-2/IP-10,
      MuMIG, RANTES, MCP-1, MIP-1alpha, and MIP-1beta earlier and reached increased
      levels, as compared with BALB/c mice. These differences in the kinetics of
      intracerebral (i.c.) chemokines may serve as a compensatory mechanism to prevent
      death from necrotizing TE in C57BL/6 mice; in contrast, BALB/c mice downregulated
      i.c. chemokines with efficient parasite control in the chronic latent phase.
      Furthermore, this study showed that the pattern of i.c. chemokines and the
      cellular sources were identical in both strains of mice, with astrocytes and
      microglia expressing CRG-2/IP-10 and MCP-1 or RANTES and MuMIG, respectively, and
      leukocytes transcribing CRG-2/IP-10, MCP-1, and RANTES. Thus, the present study
      demonstrates that host genetic factors exert a strong impact on i.c. chemokines
      in experimental murine TE.

PMID- 12420318
TI  - Head development in the onychophoran Euperipatoides kanangrensis with particular
      reference to the central nervous system.
AB  - The neuroectoderm of the Euperipatoides kanangrensis embryo becomes
      distinguishable during germ band formation when the antennal segment is evident
      externally. During later stages of development, the neuroectoderm proliferates
      extensively and, at the anterior part of the head, newly-formed neuron precursor
      cells occupy most of the volume. The antenna forms from the dorsolateral side of
      the anterior somite. The antenna has no neuroectoderm of its own at the onset of
      its formation, but instead, neurons migrate out to the appendage from the nearby
      region of the developing brain. When the antennal tract is formed it is
      positioned horizontally in the brain, in line with the antennal commissure. Only
      later, and coincidentally with the anterior repositioning of the antenna, is the
      tract's distal part bent anteriorly and positioned laterally. The eye starts to
      develop posteriorly to the antenna and the antennal commissure. This suggests
      that the segment(s) associated with the onychophoran eye and antenna are not
      serially homologous with segments carrying equivalent structures within the
      Euarthropoda. Evidence is presented to further support the presence of a terminal
      mouth in the ground plan of the Onychophora and, hence, an acron may not exist in
      the arthropod clade.

PMID- 12420319
TI  - Structure of the tarsi in some Stenus species (Coleoptera, Staphylinidae):
      external morphology, ultrastructure, and tarsal secretion.
AB  - SEM studies show that the differentiation among Stenus species with respect to
      the formation of the tarsi (wide bilobed vs. slender tarsomeres) takes place with
      a considerable augmentation of tarsal ventral setae in wide bilobed tarsomeres.
      The structural diversity of ventral tarsal setae among and within species is
      discussed with respect to 1) their different roles as mechanosensilla and tenent
      setae, respectively, and 2) the different selection pressures in terms of
      adhesive requirements along the longitudinal tarsus axis. The tarsi are provided
      with four groups of tarsal mechanosensilla, comprising hair and bristle sensilla,
      campaniform sensilla, and scolopidia. The tarsus wall is supported by an
      epidermis, which forms three different types of glands pouring their secretion
      via different exit paths onto the outer cuticle. The organization and
      ultrastructure of each of these glands is described. Only one (unicellular) gland
      is directly associated with the ventral tenent setae and is thus considered to
      form the main part of the adhesive secretion. The beetles appear to release the
      tarsal secretion through mediation of the tenent setae, which contains a lipid
      and a proteinaceous fraction. I propose that the secretion is discharged to the
      outside via a system of very fine pore canals in the wall of the setal shaft. Gas
      chromatography and infrared spectroscopy revealed that the lipid fraction of the
      secretion is a mixture of unsaturated fatty acid glycerides and aliphatic
      hydrocarbons whose spectra are similar to those of extractions of the superficial
      lipid coating of the body surface.

PMID- 12420317
TI  - cAMP-dependent reorganization of the Cajal bodies and splicing machinery in
      cultured Schwann cells.
AB  - It is well established that forskolin-induced elevation of cAMP results in
      activation of DNA synthesis in Schwann cell cultures. This promitotic response is
      partially mediated by the Cdk2, which is required for the transition from the G1
      to the S phase of the cell cycle. In the present study, we analyze the effects of
      cAMP elevation in cultured Schwann cells on the transcriptional activity and on
      the organization of two nuclear compartments involved in pre-mRNA processing:
      Cajal bodies (CBs) and splicing factor compartments. Our immunofluorescence and
      quantitative studies show that forskolin treatment induces a 5.6-fold increase in
      the proportion of S phase Schwann cells, detected by a short pulse (20 min) of
      BrdU incorporation. This increase in DNA synthesis correlates with an activation
      of global transcription, as is indicated by the higher nuclear incorporation of
      BrU in nascent RNA. Forskolin treatment significantly increases the percentage of
      Schwann cells containing typical CBs, which concentrate spliceosomal snRNPs and
      the survival motor neuron (SMN) protein. This increase in the number of CBs
      closely correlates with the activation of transcription. Moreover, the occurrence
      of CBs is significantly higher in BrdU (+) cells than in BrdU (-) cells,
      indicating that entry in the S phase promotes the formation of CBs. During the S
      phase, Schwann cell nuclei display higher Cdk2 nuclear staining and concentrate
      this kinase in CBs. Forskolin also induces a redistribution of the pre-mRNA
      splicing factors in Schwann cells. Primary cultures of Schwann cells provide an
      excellent physiological model to demonstrate that the assembly of CBs is a
      transcription- and replication-dependent cellular event. Moreover, the S phase
      accumulation of Cdk2 observed in Schwann cells supports a functional link between
      CBs and DNA replication, which is mediated by the possible participation of CBs
      in the regulatory control of histone gene expression.

PMID- 12420320
TI  - Development of the supraorbital and mandibular lateral line canals in the
      cichlid, Archocentrus nigrofasciatus.
AB  - The development of two of the cranial lateral line canals is described in the
      cichlid, Archocentrus nigrofasciatus. Four stages of canal morphogenesis are
      defined based on histological analysis of the supraorbital and mandibular canals.
      "Canal enclosure" and "canal ossification" are defined as two discrete stages in
      lateral line canal development, which differ in duration, an observation that has
      interesting implications for the ontogeny of lateral line function. Canal
      diameter in the vicinity of individual neuromasts begins to increase before
      ossification of the canal roof in each canal segment; this increase in canal
      diameter is accompanied by an increase in canal neuromast size. The mandibular
      canal generally develops later than the supraorbital canal in this species, but
      in both of these canals development of the different canal segments contained
      within a single dermal bone is asynchronous. These observations suggest that a
      dynamic process requiring integration and interaction among different tissues, in
      both space and time, underlies the development of the cranial lateral line canal
      system. The supraorbital and mandibular canals appear to demonstrate a "one
      component" pattern of development in Archocentrus nigrofasciatus, where the walls
      of each canal segment grow up from the underlying dermal bone and then fuse to
      form the bony canal roof. This is contrary to numerous published reports that
      describe a "two-component" pattern of development in teleosts where the bony
      canal ossifies separately and then fuses with an underlying dermal bone. A survey
      of the literature in which lateral line canal development is described using
      histological analysis suggests that the occurrence of two different patterns of
      canal morphogenesis ("one-component" and "two-component") may be due to
      phylogenetic variation in the pattern of the development of the lateral line
      canals.

PMID- 12420321
TI  - Synthesis and secretion of molecules exhibiting the HL1 epitope during
      development of the hyaline layer of the asteroid Pisaster ochraceus.
AB  - A complex ECM layer called the hyaline layer (HL) surrounds embryos and larvae of
      the starfish Pisaster ochraceus. When preserved by freeze substitution, the HL of
      a bipinnaria larva consists of six sublayers. From the plasmalemma outwards these
      are the intervillous layer (iv), the H3, H2, H1 sublayers that make up the
      supporting layer, a boundary layer (b) and the coarse outer meshwork (cm). HL
      development begins at fertilization when exocytosis of the cortical granules
      releases ECM into the perivitelline space and elevates the fertilization
      membrane. Over the course of early development the layers are added in a
      sequential manner and by hatching the embryo is surrounded by a thin HL
      containing most if not all of the layers. The layers thicken over the next few
      days. By the bipinnaria stage the larvae are surrounded by a thick six-layered
      HL. HL1 is a monoclonal antibody that reacts against an epitope found in all
      regions of the HL of the bipinnaria larva except the H2 sublayer. Western blots
      show that it is present on several molecules during HL development. The number
      and pattern of the HL1-labeled molecules change during development, suggesting
      that either new molecules are being produced or that some molecules are
      precursors of others. Light (immunofluorescence) and TEM (immunogold) studies
      using HL1 in the early stages of development show that HL1-positive material is
      not present in the corticle granules and that it only begins to be manufactured
      and secreted in quantity in the blastula stage at 18-20 h. Following this it
      continues to be secreted at least as far as the bipinnaria stage. Molecules
      containing the HL1 antigen therefore do not appear to play a major role in early
      development of the HL but are necessary for later events. The results suggest
      that, like the sea urchin HL, the starfish HL undergoes a sequential organization
      of the different HL layers from ECM components, which are released into the
      perivitelline space.

PMID- 12420322
TI  - Caste morphology and development in Termitogeton nr. planus (Insecta, Isoptera,
      Rhinotermitidae).
AB  - The termite family Rhinotermitidae displays a wide diversity in its patterns of
      social organization in castes. The genus Termitogeton probably branched off early
      in the evolution of this family. We studied the developmental pathways of a
      putative undescribed species from New Guinea, Termitogeton nr planus. The
      development begins with two white inactive instars (larvae), the second of which
      possesses small wing buds. These are followed by a relatively homogenous group of
      active immature stages (pseudergates) among which a biometric study revealed the
      presence of four instars. The first of these instars possesses wing buds that
      regress at subsequent molts. The external morphology of older instars resembles
      that of higher termite workers. Older pseudergates can differentiate into
      presoldiers and then into soldiers, but they are also able to molt into a unique
      stage with long wing pads (nymph), preceding the imago. Colony maturity can be
      reached with about 10(3) individuals. The sex ratio is near 1:1 in all castes
      except soldiers, among which females are more numerous than males. The caste
      pattern of T. nr. planus is reminiscent of those of the Kalotermitidae and
      Termopsidae, and of Prorhinotermes among the Rhinotermitidae. None of these taxa
      possess a true worker caste, permanently diverted from imaginal development:
      social tasks are done by unspecialized immatures that retain a full array of
      developmental options, including that of proceeding to the imago. The most
      remarkable trait of T. nr. planus is the presence in all second-instar
      individuals of wing buds that later regress to reappear in the single nymphal
      stage. We suggest that the traditional definitions of the terms larvae, nymphs,
      and pseudergates should be revised because they cannot be satisfactorily applied
      to the castes of Termitogeton.

PMID- 12420323
TI  - Complex genital structures indicate cryptic female choice in a haplogyne spider
      (Arachnida, Araneae, Oonopidae, Gamasomorphinae).
AB  - Female genital structures with their allied muscles of the haplogyne spider
      Opopaea fosuma are described. A functional explanation of this system is given,
      which indicates that cryptic female choice may occur in these spiders: the
      anterior wall of their spermatheca is strongly sclerotized and possesses a cone
      shaped hole in its upper part. A transverse sclerite that serves as muscle
      attachment bears a nail-like structure and lies in a chitinized area of the
      anterior wall of the uterus externus. Muscle contraction presses this nail into
      the hole of the spermatheca. In this way, the uterus externus gets both locked
      and fixed. Furthermore, as this occurs the copulatory orifice is enlarged and the
      resulting suction probably leads to previously deposited sperm being drawn from
      the spermatheca and dumped. This is a common mechanism used by females to
      influence a male's chances of fathering their offspring in a process known as
      cryptic female choice.

PMID- 12420324
TI  - Cranial osteology of the Andean lizard Stenocercus guentheri (Squamata:
      Tropiduridae) and its postembryonic development.
AB  - In spite of the great diversity of iguanian lizards, detailed descriptions of
      their osteocrania and postembryonic development are rare. Herein, the adult
      cranial osteology of the tropidurid lizard Stenocercus guentheri and its
      postembryonic development are described based on cleared and double-stained and
      dry skeletal specimens from a single Ecuadorian population. The amphikinetic
      skull of S. guentheri is short and elevated and bears teeth on the premaxilla,
      maxillae, and pterygoids. Mandibular teeth are present on the dentaries.
      Ossification of the articular from Meckel's cartilage and growth of the parietal
      (ossification and investment of the frontoparietal fontanelle) are the most
      significant ontogenetic changes of the splanchnocranium and dermatocranium,
      respectively. The ossification of the cartilage separating the bones of the
      braincase is the most relevant postembryonic ontogenetic event of the
      neurocranium. The number of teeth does not vary ontogenetically and replacement
      teeth are present throughout postembryonic life. This study includes a list of
      the osteocranial characters of Stenocercus that have been used in systematic
      studies, as well as a discussion of functional morphology and kinesis.

PMID- 12420325
TI  - Biflagellate spermatozoon of the poison-dart frogs Epipedobates femoralis and
      Colostethus sp. (Anura, Dendrobatidae).
AB  - This study describes the spermatozoa of the dendrobatids Epipedobates femoralis
      and Colostethus sp. using light and transmission electron microscopy. Both
      species possess a biflagellate spermatozoon, an unusual characteristic only
      previously reported in two anuran species belonging to the families
      Leptodactylidae and Racophoridae. The acrosomal complex of both species consists
      of a conical acrosomal vesicle and a subacrosomal cone, both of which cover the
      anterior portion of the nucleus, but to differing extents. In the midpiece, the
      centrioles are disposed parallel to each other and to the cell axis and give rise
      to two axonemes. Two paraxonemal rods were also seen entering the nuclear fossa.
      Both flagella are surrounded by a single mitochondrial collar. Each flagellum is
      formed by an axial fiber connected to the axoneme by an axial sheath; juxta
      axonemal fibers are absent. Our data seem to support that Epipedobates femoralis
      should be placed in a separate clade possibly related to Colosthetus and that
      these two genera may not be monophyletic.

PMID- 12420326
TI  - Developmental origin of the frontoparietal bone in Bombina variegata (Anura:
      Discoglossidae).
AB  - Development of the frontoparietal bone in the European yellow-bellied toad,
      Bombina variegata, was followed on the basis of histological analysis of
      transverse serial sections through the larval skulls to recognize early stages of
      ossification represented by osteoid (uncalcified bone matrix) and on cleared and
      stained specimens to investigate more advanced stages. Ossification of the
      frontal begins as three tiny areas of osteoid (F(1), F(2), F(3)) adjoining the
      dorsal surface of the orbital cartilage, which are separated by areas without
      osteoid. F(3) is the largest (most advanced). Prior to calcification, F(3)
      extends to fuse with F(2) and then with F(1), but it does not expand over the
      prootic fissure posteriorly. As calcification begins the strip of bone is joined
      posteromedially by F(4). Only then does a single ossification center
      corresponding to the parietal arise on the anterodorsal surface of the otic
      capsule. This ossification sequence corresponds to those observed in the
      Actinopterygii and in caudate amphibians.

PMID- 12420327
TI  - IOM study: minorities receive inferior care.

PMID- 12420328
TI  - Californian authorities want ban on cleaning fluid to reduce smog.

PMID- 12420329
TI  - Novelty contact lenses are banned in the United States.

PMID- 12420330
TI  - Outbreak of legionnaires' disease in the United Kingdom. Official cleaning and
      disinfection procedures must be adhered to.

PMID- 12420331
TI  - Outbreak of legionnaires' disease in the United Kingdom. Extracorporeal membrane
      oxygenation should be considered in severe cases.

PMID- 12420332
TI  - Antenatal screening policies for Down's syndrome. Serum screening for Down's
      syndrome is better than age screening.

PMID- 12420333
TI  - Myopia. Convergence might cause myopia.

PMID- 12420334
TI  - Growth hormone in growth hormone deficiency. Deficiency cannot be diagnosed
      solely on the results of stimulation tests.

PMID- 12420335
TI  - [Immunizations against viral hepatitis B in patients with chronic liver disease].
AB  - Hepatitis B virus still remains the main etiological factor of acute hepatitis in
      Poland. The review presents the immunogenicity of the vaccine and indications for
      immunizing patients with chronic liver disease against hepatitis B. Recommended
      vaccine dosages and schedules are presented.

PMID- 12420336
TI  - [Increased incidence of hepatocellular carcinoma].
AB  - Increased incidence of hepatocellular carcinoma related to hepatitis C virus
      (HCV) infection has been noted recently. Only in year 2000 seven new cases of HCC
      in HCV-positive patients were diagnosed. In all cases liver tumors were found in
      cirrhotic patients and they were at advanced stage (multiple or large in size)
      precluding successful therapy. More than half of HCC cases related to HCV
      infection were connected with blood transfusion(s) in the past. Patients
      transfused a few decades ago should be screened for HCV infection and those with
      liver cirrhosis require careful and regular monitoring including ultrasound and a
      fetoprotein examinations in order to detect focal lesions at less advanced stage
      making medical intervention possible.

PMID- 12420337
TI  - [Helicobacter pylori infection in gastric cancer patients].
AB  - The aim of the study was to evaluate the role of Helicobacter pylori infection in
      gastric cancer development. MATERIAL AND METHODS: 475 patients were included into
      the study (270 gastric cancer patients and 205 controls). Helicobacter pylori
      status was determined by enzyme linked immunoabsorbent assay (ELISA). The
      frequency of H. pylori infection in gastric cancer patients and the control group
      was compared. The relationship between the presence of anti-H. pylori antibodies
      and selected clinical and pathomorphological parameters was analysed. RESULTS: H.
      pylori infection was statistically more frequent in gastric cancer patients than
      in controls (94.4% vs. 86.3%, p = 0.0039). Subjects infected with H. pylori were
      about 2.5-fold more likely to develop gastric cancer than uninfected individuals
      (OR = 2.69; 95% CI = 0.93-4.45) and the risk depended on age. A positive
      relationship between H. pylori infection and family history of cancer was found
      (p = 0.045). H. pylori status was irrespective of patient's age, sex, duration of
      symptoms, AB0 blood group, tumour site, stage, histology and p53 status in cancer
      tissue. CONCLUSION: Our study confirms a positive relationship between H. pylori
      infection and gastric cancer, however, in contrast to previous reports fails to
      demonstrate that bacteria protect the host from cardia cancer. Our results
      suggest also that in gastric cancer H. pylori does not induce p53 mutations.

PMID- 12420338
TI  - [Flow cytometric analysis of peripheral blood lymphocytes in children with
      chronic gastroduodenitis with and without Helicobacter pylori infection].
AB  - The immune system plays an important role in chronic gastroduodenitis. A group of
      70 children with chronic gastroduodenitis were subjected to examinations,
      including 42 children with H. pylori infection (group I) and 28 children without
      H. pylori infection (group II). Applying the method of flow cytometry, the per
      cent values of peripheral blood lymphocytic subpopulations were determined before
      and after treatment. The obtained results of examinations in group I were
      compared with those obtained in group II and were also compared with the
      standards given by Zeman for healthy children. On the basis of analysis of own
      material it was found that in both studied groups before and after the treatment
      lower per cent values were observed of CD3 and CD8 T-cells, NK CD56 cells and
      higher value of CD4 to CD8 T-cell ratio was disclosed as compared to healthy
      children. Comparing the per cent values of lymphocytic subpopulations in children
      with and without H. pylori infection it was found that in group I a higher per
      cent of CD4 T-cells, lower per cent of CD8 T-cells and, therefore, higher value
      of CD4 to CD8 T-cell ratio were present.

PMID- 12420339
TI  - [Evaluation of the usefulness examination of IgG avidity for serodiagnosis of
      toxoplasmosis].
AB  - An assay measuring the avidity of T. gondii-specific IgG is a useful serological
      indicator of toxoplasmosis which in many cases allows on the basis of single
      serum sample testing to confirm or exclude acute infection. IgG antibodies
      against T. gondii produced in the recent primary infection are of low-avidity
      while IgG antibodies in the chronic toxoplasmosis are of high-avidity. In the
      present study 80 sera: 47 sera of patients with suspected acute toxoplasmosis, 23
      sera of pregnant women and 10 sera of healthy blood donors, were evaluated for
      the presence of IgM, IgA and IgG antibodies and for the avidity of IgG. Among the
      80 tested sera IgM antibodies were present in 34 (42.5%) cases of which 22
      (64.7%) showed low-avidity of IgG and the presence of IgA antibodies confirming
      acute toxoplasmosis. In the rest of these 34 sera three of them showed low
      avidity index and nine other high avidity in spite of the presence of IgM
      antibodies. In these 12 sera IgA antibodies were not present. In 46 (57.5%)
      examined sera IgM or IgA antibodies were not detectable and the present the IgG
      antibodies showed high-avidity what is characteristic of chronic infection. An
      assay for evaluation of avidity of IgG antibodies specific for T. gondii is
      valuable in complementing existing tests and in many cases it has decisive value
      for interpretation of results.

PMID- 12420340
TI  - [Value of pH-metric examination in diagnosing gastroesophageal reflux in children
      and youth with typical and atypical clinical symptoms of gastroesophageal reflux
      disease].
AB  - AIM: The aim of work was an estimation of pH-metric examination in diagnosing of
      gastroesophageal reflux in children with typical and atypical symptoms of the
      gastroesophageal reflux disease. MATERIAL AND METHODS: 121 children were analysed
      with suspected to gastroesophageal reflux disease. Depending on reported ailments
      they were divided into 2 groups. Group I patients with typical symptoms of
      gastroesophageal reflux disease were including: heartburn, rebounding; while the
      second group consisted of those with atypical symptoms: nausea, vomiting, chest
      pain, abdominal pain. 24-hour pH-metric examination was performed in each
      patient. RESULTS: On the basis of pH-metric examination gastroesophageal reflux
      was diagnosed in 85.2% patients from I group and 44.8% patients from group II.
      CONCLUSION: The most important examination determining diagnosis of
      gastroesophageal reflux in children with both typical and atypical symptoms of
      this illness should be pH-metric examination of the esophagus. In children with
      atypical symptoms in consideration of differential diagnosis we should take into
      account a possibility of gastroesophageal reflux.

PMID- 12420341
TI  - [Antithrombin III, protein C and thrombin/antithrombin III complexes (TAT) in
      patients suffering from chronic cholecystolithiasis treated by classical and
      laparoscopic cholecystectomy].
AB  - Surgery is the basic treatment method of cholecystolithiasis. Traditional methods
      have been replaced laparoscopy. The aim of the study was the evaluation of
      haemostasis after classical and laparoscopic cholecystectomy. The studies were
      conducted in 48 patients suffering from chronic cholecystolithiasis--29 of them
      were operated on by laparoscopy, 19 patients were operated on by classical way.
      We revealed, that classical and laparoscopic cholecystectomy cause a similar
      increase of thrombin generating in vascular bed and are risk factors for
      occurrence of thrombo-embolic complications.

PMID- 12420342
TI  - [Markers of oxidative damage in blood of children with cystic fibrosis].
AB  - In cystic fibrosis (CF), as a result of chronic pulmonary infections and
      digestive malabsorption, an imbalance between the production of reactive oxygen
      species and their inactivation by protective systems is observed. This may cause
      impairment of cell metabolism and oxidative injury. The aim of this study was to
      examine whether markers of oxidative damage to protein (protein carbonyls) and
      lipids (malondialdehyde) may be modified in cystic fibrosis patients with
      pancreatic insufficiency. We have found that mean concentration of plasma protein
      carbonyls was 0.835 nmol/mg protein (the range of 0.31-1.71 nmol/mg protein) in
      CF patients (n = 57) and was higher by 30% than that in controls (n = 20). Plasma
      concentration of malondialdehyde (MDA) was 2.98 mumol/l in the range of 1.23-4.77
      mumol/l. Among fifty seven patients studied, in 30 children MDA level was
      elevated above the highest values observed in the healthy group (2.80 mumol/l).
      Total radical-trapping antioxidant parameters (TRAP) amounted to 629 mumol/l and
      735 mumol/l in CF patients and control, respectively. The difference was
      statistically significant (p < 0.005). The obtained results indicated that in CF
      patients oxidative stress caused oxidative modification of proteins and
      peroxidation of lipids which was accompanied by lowering of antioxidant
      protection. These results indicate that certain CF patients (especially those
      with exocrine pancreatic insufficiency) are susceptible to oxidative damage,
      therefore it seems that an adequate and balanced diet is essential for achieving
      and maintaining normal antioxidant defenses.

PMID- 12420343
TI  - [Serum neopterin and beta2-microglobulin concentration as "prognostic markers" of
      AIDS].
AB  - The aim of the study was evaluation of serum neopterin and beta 2-microglobulin
      concentrations as "prognostic markers" of AIDS natural history. MATERIAL AND
      METHODS: Investigations was performed in 68 patients (48 hiv-infected and 20
      without hiv-infection), who were divided into 3 groups according to HIV CDC
      classification. RESULTS: The highest serum concentrations of neopterin and beta 2
      microglobulin were detected in patients with AIDS. In a non-symptomatic HIV
      infected patients p24 Ag was absent. It was detected in patients with AIDS.
      Negative correlation between neopterin and beta 2-microglobulin serum
      concentration and CD4 count was detected in sera from all patients. Positive
      correlation was observed between p24 Ag, serum neopterin and beta 2-microglobulin
      concentration in patients with AIDS. CONCLUSIONS: Progression of HIV infection
      was connected with an increase of serum neopterin and beta 2-microglobulin serum
      concentrations. Neopterin serum concentration seems to be a more sensitive marker
      of HIV infection than beta 2-microglobulin.

PMID- 12420345
TI  - [Prevalence of HLA class I and II antigens and extra-bowel manifestations in
      ulcerative colitis].
AB  - HLA class I and II antigens are common among patients with ulcerative colitis.
      They can be involved in the autoaggressive mechanisms of the disease. The aim of
      the study was to evaluate the prevalence of HLA B and HLA DR antigens and
      estimate the correlation to extra-bowel manifestations of the disease. 50
      patients with ulcerative colitis and 20 healthy controls were examined. HLA-B27, 
      B7, -B40, -DR1, -DR2, -DR3, -DR4 and -DR7 were determined using monoclonal
      antibodies in microlymphocytotoxic method. HLA I and/or HLA II antigens were
      detected in 36% of patients: HLA I in 28% and HLA II 16%. 46% of the patients
      were demonstrating joint changes, with 65% of them presenting HLA molecules. 16%
      of the examined patients presented symptoms of intrahepatic cholestasis; with 67%
      having HLA I/II molecules. The difference from the control group was
      statistically significant, only 25% of healthy persons presented HLA I/II
      antigens. The incidence of joint involvement and cholestasis was higher in
      ulcerative colitis patients with HLA class I and/or HLA II.

PMID- 12420344
TI  - [Effect of chitosan in complex management of obesity].
AB  - The aim of the present study was to verify the effect of chitosan as a possible
      adjuvant in the complex management of obesity. METHOD: Fifty obese women (22-59
      years, BMI > 30) participated in the study. A six months program consisted of 2
      hour meetings with a physician, psychologist and dietitian, in a group of about
      20 persons, every two weeks. Low calorie diet (1000 kcal/day), physical activity
      and behaviour modification were recommended. Supplementation with chitosan was
      evaluated in a randomized, placebo-controlled, double-blind study. In the
      chitosan group, participants received ChitininN (Primex Ingredients ASA,
      Avaldsnes, Norway) i.e. 750 mg pure chitosan per tablet, two tablets three times
      daily before each main meal. The placebo group received identical placebo
      tablets. RESULTS: Significantly higher body weight loss was noted in the chitosan
      supplemented group (15.9 kg) than in the placebo group (10.9 kg) Also a greater
      decrease of systolic and diastolic blood pressure was observed in the chitosan
      group. There was no difference between the groups in the decrease of LDL and
      total cholesterol. No adverse effects were noted but the number of drop-outs was
      higher in the placebo group than in the chitosan group. CONCLUSION: Chitosan can
      be used as a valuable and safe adjuvant in long-term dietary treatment of
      obesity. Chitosan seems to accentuate the reduction of blood pressure associated
      with weight reduction.

PMID- 12420346
TI  - [Insulin receptor gene polymorphism in myocardial infarction patients].
AB  - The aim of this study was the assessment of the association of human insulin
      receptor gene Nsil polymorphism with myocardial infarction in 100 patients and
      140 healthy individuals. The polymorphism was studied using polymerase chain
      reaction. An association was found between N2 allele and myocardial infarction,
      particularly in patients with normal body weight and/or with positive family
      history.

PMID- 12420347
TI  - [A case of otogenic cerebellar abscess].
AB  - Cerebellar abscess is a serious complication of ear disease that requires early
      diagnosis and treatment. Computerized axial tomography with contrast enhancement
      is very useful for the diagnosis of these abscesses. This fact is illustrated by
      a case report of a cerebellar abscess secondary to chronic otitis media with
      cholesteatoma detected in one of our patients. On examination otorrhoea, fever,
      headache, vomiting and had hemilateral conductive hearing loss. The therapy
      included radical operation, excision of the abscess and antibiotic therapy.

PMID- 12420348
TI  - [Skin patch test with nickel sulphate--an attempt of broader interpretation of
      the results].
AB  - Skin patch test with nickel sulphate provides grounds for distinguishing 10%
      females with hypersensitivity to ions of this metal. The literature data
      published as yet indicate that in these women an alteration takes place in
      conditions of the inner environment of their organisms. The alteration may result
      in an absence of adaptive capacities of the women to altered conditions of the
      outer environment (occasional, transient elevation in nickel ion level in the
      environment). Such an approach to the problem opens discussion on the accepted as
      yet, egocentric pattern of thinking, related to effects of metal ions on the
      organism and described as the physiological mechanism of the type I and IV
      hypersensitivity. The author suggests that nickel ions, acting at subtoxic levels
      but markedly exceeding the doses defined as physiological ones, which may develop
      locally, transiently in the outer environment, may exert unfavourable effects on,
      depending upon the level of conducted studies, molecular, cellular, tissue or
      body levels. The absence of skin adaptive capacity to, i.a., neutralize the
      excess of ions at the site of their application disturbs in a dose-related manner
      the normally functioning immune system, what is manifested with an inflammatory
      reaction of various intensity.

PMID- 12420349
TI  - [Current trends in diagnostic imaging of the pancreas].
AB  - Imaging techniques play a key role the diagnosis of pancreas diseases. This paper
      is intended to review the current status of various, modern imaging modalities
      and discuss the technical aspects, advantages and drawbacks of ultrasonography,
      spiral CT, endoscopic retrograde cholangiography and MR imaging in the diagnosis
      of pancreatic diseases.

PMID- 12420350
TI  - [Liver failure and neurotransmitters of central nervous system].
AB  - There is increasing evidence that alternations of glutamatergic function are
      implicated in the pathogenesis of central nervous system consequences of
      hyperammonemia in liver failure. Concentrations of ammonium ion are increased and
      it leads to uncontrolled production of glutamine from these ions, so it is
      responsible for damage of the brain. Increasing concentrations of glutamine in
      the brain have a direct effect on glutamatergic neurotransmission, because number
      of binding sites for glutamatergic receptors changes. A number of binding sites
      for glutamatergic receptors: non-NMDA, AMPA and kainate is decreased in
      hippocampus, cerebral cortex, hypothalamus and cerebellum, while the binding
      sites for the NMDA receptor were within normal limits. Diminished expression of
      glutamatergic receptors leads to hypofunction of these receptors. So we can say
      about correlation between hyperammonemia in liver failure to distribution and
      activity of glutamine and glutamate as a neurotransmitter of CNS.

PMID- 12420351
TI  - [Diagnostic tests of alcohol consumption].
AB  - Alcoholism is one of the most frequent dependences. In the cases of excessive
      alcohol consumption laboratory tests become abnormal and, therefore, may have
      ability to detect alcohol-dependent subjects. We present the biological markers
      for recent alcohol intake such as ethanol, methanol and 5-hydroxytryptophol and
      the most obvious and specific tests for chronic alcohol consumption including
      gamma-glutamyltransferase, aspartate and alanine aminotransferase, carbohydrate
      deficient transferrin, macrocytosis, beta-hexosaminidase and erythrocytic
      aldehyde dehydrogenase.

PMID- 12420352
TI  - [Autonomic neuropathy in diabetic patients. Part I. Pathogenesis and clinical
      problems].
AB  - Diabetic neuropathy is one of the most common and serious complications of
      diabetes both type 1 and type 2. Damage to autonomic nerves in the course of
      diabetes mellitus leads to diabetic autonomic neuropathy. There are three
      hypotheses explaining the pathogenetic mechanism of polyneuropathy: metabolic,
      vascular and immunological. Many diabetic patients have demonstrable
      abnormalities of autonomic function without any evidence of clinical disease.

PMID- 12420353
TI  - [Autonomic neuropathy in diabetic patients. Part II. Diagnosis and treatment].
AB  - Many diabetic patients have demonstrable abnormalities of autonomic function
      without any evidence of clinical disease. Tests of autonomic function are assumed
      to be a measure of "neurological" state and may be important methods of assessing
      therapy of diabetic complications.

PMID- 12420354
TI  - [Fungal infection in the course of acute liver failure].
AB  - Fungal infection is a common, serious and underestimated complication, which
      contributes significantly to high mortality in patients with acute liver injury.
      The features accounting for the incidence of fungal infection include defects of
      immune response, routine use of H2 antagonists, frequent use of broad-spectrum
      antibiotics and invasive monitoring. Clinical deterioration characterized by
      increasing coma grade after initial improvement, increasing prothrombin time,
      pyrexia unresponsive to antibiotics, renal failure and elevated white cell count
      make up the clinical picture of the disease which suggests coexistence of fungal
      infection in acute liver injury. Candida albicans is the principal etiological
      agent of fungal infection and this pathogen is frequently isolated from the
      respiratory tract within a week of admission. The mortality among untreated
      patients with acute liver injury complicated with mycotic infection reaches 100%.
      The early application of the specific treatment in cases suspected of mycotic
      infection in patients with liver injury could markedly reduce mortality in this
      group of patients.

PMID- 12420355
TI  - [Twentieth anniversary of the Pneumology Department of the Medical Academy in
      Warsaw].

PMID- 12420356
TI  - [Medical dilemmas related to issuing a driver license].

PMID- 12420357
TI  - Energy metabolism in the brain.

PMID- 12420358
TI  - The cerebral glucose-fatty acid cycle: evolutionary roots, regulation, and
      (patho)physiological importance.

PMID- 12420359
TI  - Expression, regulation, and functional role of glucose transporters (GLUTs) in
      brain.

PMID- 12420360
TI  - Insulin-like growth factor-1 promotes neuronal glucose utilization during brain
      development and repair processes.

PMID- 12420361
TI  - CNS sensing and regulation of peripheral glucose levels.
AB  - It is clear that the brain has evolved a mechanism for sensing levels of ambient
      glucose. Teleologically, this is likely to be a function of its requirement for
      glucose as a primary metabolic substrate. There is no question that the brain can
      sense and mount a counterregulatory response to restore very low levels of plasma
      and brain glucose. But it is less clear that the changes in glucose associated
      with normal diurnal rhythms and feeding cycles are sufficient to influence either
      ingestive behavior or the physiologic responses involved in regulating plasma
      glucose levels. Glucosensing neurons are clearly a distinct class of metabolic
      sensors with the capacity to respond to a variety of intero- and exteroceptive
      stimuli. This makes it likely that these glucosensing neurons do participate in
      physiologically relevant homeostatic mechanisms involving energy balance and the
      regulation of peripheral glucose levels. It is our challenge to identify the
      mechanisms by which these neurons sense and respond to these metabolic cues.

PMID- 12420362
TI  - Glucose transporter protein syndromes.

PMID- 12420363
TI  - Glucose, stress, and hippocampal neuronal vulnerability.

PMID- 12420364
TI  - Glucose/mitochondria in neurological conditions.
AB  - Impairments of glucose and mitochondrial function are important causes of brain
      dysfunction and therefore of brain disease. Abnormalities have been found in
      association with disease of the nervous system in most of the components of
      glucose/mitochondrial metabolism. In many, molecular genetic abnormalities have
      been defined. Brain glucose oxidation is abnormal in common diseases of the
      nervous system, including Alzheimer disease and other dementias, Parkinson
      disease, delirium, probably schizophrenia and other psychoses, and of course
      cerebrovascular disease. Defects in a single component and even a single mutation
      can be associated with different clinical phenotypes. The same clinical phenotype
      can result from different genotypes. The complex relationship between biological
      abnormality in brain glucose utilization and clinical disorder is similar to that
      in other disorders that have been intensively studied at the genetic level. Genes
      for components of the pathways of brain glucose oxidation are good candidate
      genes for disease of the brain. Preliminary data support the proposal that
      treatments to normalize abnormalities in brain glucose oxidation may benefit many
      patients with common brain diseases.

PMID- 12420365
TI  - Energy utilization in the ischemic/reperfused brain.

PMID- 12420366
TI  - Diabetes mellitus and the central nervous system.

PMID- 12420367
TI  - Diabetes, the brain, and behavior: is there a biological mechanism underlying the
      association between diabetes and depression?
AB  - In summary, our review of the literature suggests that diabetes, especially type
      1 diabetes, may place patients at risk for a depressive disorder through a
      biological mechanism linking the metabolic changes of diabetes to changes in
      brain structure and function. Further studies are warranted examining these
      relationships in order to better understand the impact of diabetes on brain
      functioning and structure as well as one potential manifestation of such changes-
      affective disorder. Moreover, such studies could play a useful role in better
      understanding mechanisms that commonly underlie the development of depression in
      individuals without diabetes but with other medical problems or conditions.

PMID- 12420368
TI  - Schizophrenia and diabetes.

PMID- 12420369
TI  - Psychoactive drugs affect glucose transport and the regulation of glucose
      metabolism.

PMID- 12420370
TI  - [Advances in the treatment of macular degeneration].

PMID- 12420371
TI  - [The effect of phosphodiesterase type 3 inhibitor on chorio-retinal blood flow in
      rabbits eyes].
AB  - PURPOSE: To investigate the ocular effect of intravenous administration of a
      phosphodiesterase type 3 inhibitor (NSP-805) and to compare the effect of NSP-805
      with that of a calcium antagonist (nicardipine hydrochloride) on chorio-retinal
      blood flow in anesthetized albino rabbits. METHODS: Twenty-four female albino
      rabbits (weighting 2.0-4.0 kg) were anesthetized with intravenous injection. NSP
      805(40 micrograms/kg and 100 micrograms/kg) and nicardipine of 40 micrograms/kg
      were intravenously administrated to the anesthetized rabbits. Intravenously
      administration of 20% dimethyl sulfoxide (DMSO) was used as a vehicle. Chorio
      retinal blood flow was measured with a laser Doppler flowmeter at baseline and
      every 20 minutes after intravenous administration for 120 minutes. Heart rates
      and systemic blood pressure were monitored. Baseline measurements were compared
      with every 10 minutes after intravenous administration. Differences between the
      drug groups and vehicle group were analyzed. RESULTS: After administration of a
      low dose of NSP--805 (40 micrograms/kg) and nicardipine (40 micrograms/kg), the
      chorio-retinal blood flow was significantly increased (p < 0.05). A high dose NSP
      805(100 micrograms/kg) reduced systemic blood pressure significantly, but the
      increase of chorio-retinal blood flow was less than that at the low dose of NSP
      805(40 micrograms/kg) and nicardipine (40 micrograms/kg). Chorio-retinal blood
      flow in the NSP 805(40 micrograms/kg) and nicardipine (40 micrograms/kg) groups
      was significantly increased over that in the control group (20% DMSO) (p < 0.05).
      CONCLUSION: The results suggest that the NSP-805 has the potential of increasing
      chorio-retinal blood flow in rabbit eyes.

PMID- 12420372
TI  - [Utility of indocyanine green angiography guided laser photocoagulation of
      choroidal neovascularization in age-related macular degeneration].
AB  - PURPOSE: The efficacy of photocoagulating choroidal neovascularization (CNV) of
      age-related macular degeneration with indocyanine green angiography(ICG) was
      evaluated. 1. The utility of ICG-guided laser photocoagulation for juxtafoveal
      and extrafoveal CNV, 2. The utility of photocoagulating feeder vessels of
      subfoveal CNV. METHODS: 1. We compared 139 eyes undergoing ICG-guided laser
      photocoagulation (IA group), with 85 eyes treated with fluorescein angiography
      (FAG)-guided laser photocoagulation(FA group), of juxtafoveal and extrafoveal
      CNV. 2. We treated 35 eyes of 35 patients in which feeder vessels detected by ICG
      served as targets of photocoagulation. RESULTS: 1. The success rate of laser
      photocoagulation was 81% in the IA group and 82% in the FA group. There was no
      statically significant difference between the IA and FA groups in terms of
      distance from the fovea, CNV size, or lesion type. The rates of maintained or
      improved visual acuity in groups of IA and FA at the final follow-up as compared
      with those before treatment, were 71% (61/86 eyes) and 65% (36/55 eyes),
      respectively. 2. The feeder vessels were obliterated in 66%. The percentage of
      eyes with maintained or improved visual acuity at six months and at final follow
      up as compared to visual acuity before treatment was 64% and 58%, respectively.
      Thirteen(81%) of 16 eyes which had shown extrafoveal feeder vessel ingrowth sites
      and small CNV of 1-disc area or less showed feeder vessel closure. CONCLUSION: 1.
      ICG-guided laser photocoagulation of juxtafoveal and extrafoveal CNV should be
      performed actively in the same way as FAG-guided laser photocoagulation. 2. It is
      best to attempt to coagulate feeder vessels when they are extrafoveal and when
      the CNV is small.

PMID- 12420373
TI  - [TPD ophthalmic solution (mixture of tropicamide, phenylephrine hydrochloride,
      and diclofenac sodium) for cataract surgery].
AB  - PURPOSE: We made a TPD ophthalmic solution by combining tropicamide
      solution(Mydrin-P: T), phenylephrine hydrochloride(Neosynesin Kowa: P) and
      diclofenac sodium(Diclod: D), and evaluated its efficiency in mydriasis during
      cataract surgery compared to T, P, and D. SUBJECTS AND METHODS: Twenty-five
      eyes(19 patients) were given either TPD solution(10 eyes) or T, P, and D
      solution(15 eyes), and the treatment was given six times before surgery. Pupil
      diameters were measured before and after surgery. RESULT: The operation time was
      10.0 +/- 5.2(mean +/- standard deviation) minutes in the TPD group, and 9.0 +/-
      3.6 minutes in the T, P and D group. The preoperative and postoperative one pupil
      diameter was 8.65 +/- 0.34 mm and 8.20 +/- 0.35 mm in the TPD group and 8.80 +/-
      0.49 mm and 8.37 +/- 0.61 mm in the T, P, and D group, respectively. The rate of
      miosis was 5.1 +/- 4.2% in the TPD group and 4.8 +/- 5.1% in the T, P, and D
      group, respectively. There was no statistically significant difference between
      the two groups. CONCLUSION: TPD ophthalmic solution maintains the mydriasis as
      potent by as T, P and D solution.

PMID- 12420374
TI  - [Effects on eyestrain of outward stimuli for accommodation].
AB  - PURPOSE: We investigated experimentally the effect on eyestrain of outward-shift
      stimuli for accommodation. METHODS: Six female students fixed optical outward
      shift stimuli for accommodation during 2 min immediately after 15 min of a
      sustained task on a 3-D display. Before and after the trial, their ocular
      functions were measured and their subjective symptoms were assessed. The outward
      shift stimuli were applied by moving the targets of scenery images from far to
      near and near to far repetitively at around both eyes' far point position. As a
      control, stationary targets at the position of 0 D were used instead of moving
      targets. The same experiment was repeated twice for each subject. RESULTS: In the
      first experiment, there were significant changes in the accommodative contraction
      time, the accommodation lag, and the myopic shift, and the subjective symptoms of
      "eyestrain" and "eye dryness" in the control group, but in the stimulus group
      there were only increases of the complaint of "eyestrain". In the second
      experiment, the changed items were the contraction time and the complaints of
      "eyestrain" and "eye dryness" in both groups. The outward-shift stimuli caused a
      tendency in the far point to shift outward in the first experiment, and there was
      a statistically significant inward shift in the second experiment. CONCLUSION:
      From these results, it is suggested that the outward-shift stimuli for
      accommodation are effective in relieving eyestrain following the deterioration of
      ocular functions except when the far point is shifted inward.

PMID- 12420375
TI  - [Visual prognosis in polypoidal choroidal vasculopathy associated with subretinal
      hematoma].
AB  - PURPOSE: Although it is reported that the prognosis for polypoidal choroidal
      vasculopathy(PCV) is better than that for age-related macular degeneration,
      visual acuity is not always good in eyes with subfoveal hemorrhage. We evaluated
      the factors that may affect the visual prognosis after subfoveal hematoma
      associated with PCV. SUBJECT: We examined retrospectively the records of 37 eyes
      in 34 patients that were diagnosed as PCV by indocyanine green angiography from
      January 1998 to July 2000 at Kyoto University Hospital. Among the 37 eyes, we
      chose 15 eyes in 15 patients that had subfoveal hematoma of more than 1 disk
      diameter, and evaluated the area of hematoma, period required for absorption of
      the hematoma, association of choroidal neovascularization(CNV), treatment, and
      visual acuity change. RESULTS: The area and the absorption period of the hematoma
      did not correlate with the visual prognosis. Association of CNV strongly
      influenced the visual outcome after the absorption of subretinal hemorrhage. Four
      eyes with CNV received various treatments, but no restoration of visual acuity
      was observed. CONCLUSION: CNV association mostly affected the prognosis of PCV
      with hematoma. Early detection of CNV appeared important to predict visual
      prognosis.

PMID- 12420376
TI  - [Availability of TPD ophthalmic solution (mixture of Mydrin-P solution,
      Neosynesin Kowa solution, and Diclod solution) in regard to the corneal barrier
      function--clinical evaluation for vitrectomy in patients with diabetic
      retinopathy].
AB  - PURPOSE: We made TPD ophthalmic solution by combining Tropicamide solution(Mydrin
      P: T), Phenylephrine Hydrochloride(Neosynesin Kowa solution: P) and Diclofenac
      Sodium(Diclod solution: D), and evaluated its efficiency in terms of corneal
      epithelial damage in patients with diabetic retinopathy. SUBJECTS AND METHODS:
      Five patients(10 eyes) who were to undergo vitrectomy were enrolled in this
      study. They each received T, P, and D 6 times and TPD solution in the same way.
      Before and after the instillation, superficial punctate keratopathy (SPK) was
      evaluated and corneal epithelial permeability was determined by anterior
      fluorophotometry. RESULTS: After the instillation of T, P, and D, corneal damage
      increased in all eyes. After the instillation of TPD, three eyes showed only one
      grade change up in AD(A: area, D: density) classification of SPK. The fluorescein
      uptake change between pre- and post-instillation was 457.5 +/- 468.8 (mean +/-
      standard deviation) ng/ml with T, P, and D and 100.5 +/- 235.6 ng/ml with TPD(p <
      0.01). CONCLUSION: TPD solution decreases both corneal epithelium damage and
      barrier function change of corneal epithelium.

PMID- 12420377
TI  - [Program for continuing professional education in ophthalmology. A review. 12.
      Neuro-ophthalmologic examination].

PMID- 12420378
TI  - "What's a woman to do?".

PMID- 12420380
TI  - Valuing labor support. A doula's perspective.

PMID- 12420379
TI  - From Iowa to Boston: renewing the spirit of nursing.

PMID- 12420381
TI  - Premature menopause raises risks of fatal adrenal condition. Early diagnosis can
      lead to effective treatment for women.

PMID- 12420382
TI  - Newborn hearing screening. Making the case for national minimum standards.

PMID- 12420384
TI  - Promoting breastfeeding. A useful algorithm for nurses on a mother/baby unit.

PMID- 12420383
TI  - What's a woman to do? Exploring HRT questions raised by the women's health
      initiative.

PMID- 12420385
TI  - Exploring calcium level disorders. Looking through the genetic window for new
      treatment clues.

PMID- 12420386
TI  - Managing PMS & PMDD. Exploring new treatment options.

PMID- 12420387
TI  - Nurses as lobbyists. Individual and collective strategies for influencing others.

PMID- 12420388
TI  - Exploring Latino rituals in birthing. Understanding the need to bury the
      placenta.

PMID- 12420389
TI  - Experiencing grandparent grief. 'A piece of my heart died twice'.

PMID- 12420390
TI  - A review of the argument in favor of state law remedies under the patients' bill
      of rights.

PMID- 12420391
TI  - Medicare establishes new payment system for long-term care hospitals.

PMID- 12420392
TI  - HHS issues final regulation on Medicare-endorsed Prescription Drug Card
      Initiative.

PMID- 12420393
TI  - Balancing community benefits with practical solutions--the rules remain gray.

PMID- 12420394
TI  - A vacated appellate opinion begs the question: are municipalities liable to
      provide competent EMT services?

PMID- 12420395
TI  - HHS publishes final privacy modifications.

PMID- 12420396
TI  - Pharmaceutical manufacturers seek OIG comfort.

PMID- 12420397
TI  - A summary of HIPAA's administrative regulations--Part III.

PMID- 12420398
TI  - Medicare announces increase in nursing home payments.

PMID- 12420399
TI  - High court upholds independent physician reviews under state law.

PMID- 12420400
TI  - A summary of HIPAA's administrative regulations--Part II.

PMID- 12420401
TI  - Legal issues involving economic credentialing.

PMID- 12420402
TI  - Nursing homes of Oklahoma.

PMID- 12420403
TI  - Re: Nursing homes in Oklahoma.

PMID- 12420404
TI  - Re: Dental insurance premiums as a valid medical expense.

PMID- 12420405
TI  - Facts about oral cancer.

PMID- 12420407
TI  - Dentistry's "Jungle Jim".

PMID- 12420406
TI  - Avoiding your greatest fear--malpractice.
AB  - This article discusses ten clinically based behavioral approaches to minimizing
      the risk of a malpractice claim. Suggestions are stated in both a positive and
      negative way and ranked from least significant to most significant.
      Recommendations include the need to develop effective listening skills; learning
      to communicate with patients verbally and in writing; keeping patient
      expectations realistic; being thorough when examining and diagnosing; and knowing
      one's limitations. Also included is the need to inform patients concerning
      adverse events; keeping written records of what was said and done; discussing
      alternatives, risks, complications, and fees in advance; and developing a
      relationship with patients based on mutual respect and trust. Case examples are
      presented for each approach.

PMID- 12420408
TI  - Sluggish economy has little impact on dentistry.... There's no better time than
      now to be in the health care profession!

PMID- 12420409
TI  - Oral pathology.

PMID- 12420410
TI  - What is this HIPAA thing?

PMID- 12420411
TI  - The lump.

PMID- 12420412
TI  - The future of breast cancer screening and treatment.

PMID- 12420413
TI  - The evolution of breast cancer risk assessment.
AB  - Breast cancer risk assessment is in the process of refinement, largely due to the
      potential for pharmacologic risk reduction. In the 1970s, benign tissue changes
      were assigned relative risk (RR) values. The 1980s witnessed the introduction of
      mathematical models for calculating risk. Genetic counseling and testing appeared
      in the 1990s. Now in 2002, we are witnessing efforts to improve risk assessment
      by actively searching for cellular 'atypia' through nipple aspirate fluid (NAF),
      ductal lavage, and random fine needle aspiration (FNA). One deficiency plagues
      any approach to predicting breast cancer based on historical risk factors-
      exclusion of the 70% majority of women who develop breast cancer without any
      identifiable risk factors. Realizing that the long-term goal of breast cancer
      risk assessment should be tissue and/or serum-based strategies, the authors
      introduce the Oklahoma Breast Cancer Project, a tissue bank designed to augment
      research devoted to molecular biologic markers of risk.

PMID- 12420414
TI  - Self-reported mammography screening among Oklahoma women age 50 and older:
      Oklahoma Behavioral Risk Factor Surveillance System 1997-2001.
AB  - PURPOSE: To examine which factors were associated with mammography screening
      among women age 50 and older in Oklahoma from 1997-2001. METHODS: Using data from
      4,338 women age 50 and older interviewed for the 1997-2001 Oklahoma Behavioral
      Risk Factor Surveillance System, this study examines the proportion of women
      receiving mammography screening services and assesses the associations between
      covariates of interest and mammography screening. RESULTS: Among Oklahoma women
      age 50 and older, 17.5% had never received a mammogram and 14.9% of those who had
      received a mammogram had not done so in the past two years. Women without health
      insurance coverage, those of lower socioeconomic status and those engaging in
      risky health behaviors were more likely to never have had a mammogram and, if
      they were screened, to have not had a mammogram in the past two years.
      CONCLUSIONS: These results show a need to focus mammography screening programs on
      women with lower socioeconomic status.

PMID- 12420415
TI  - Screening mammography for Oklahoma Medicare beneficiaries: a national priority
      for quality improvement.
AB  - Breast cancer is one of the most common malignancies diagnosed in women in the
      United States. It is estimated that more than 2,700 new cases of female breast
      cancer will be diagnosed in Oklahoma this year. Using the Medicare mammography
      denominator file and Medicare claims data (October 1999 through September 2001),
      we assessed the utilization of mammography for this population. The overall
      biennial mammography rate for Oklahoma Medicare patients was 46.9% (95% CI 46.7
      47.1) and was 54.7% (95% CI 54.3-55.2) for Medicare patients aged 50-67 years.
      There were significant racial disparities in utilization of mammography. In
      addition, there was substantial county-to-county variation in the utilization of
      mammography in Oklahoma. When compared to other states and territories, Oklahoma
      mammography rates for this population were in the lowest quartile nationally,
      ranking 47th in the nation. Increasing the use of mammography services for
      Medicare patients is a national priority for healthcare quality improvement.

PMID- 12420416
TI  - Breast cancer risk: evaluating the risk and role of genetic testing.
AB  - Identifying women who might have an increased risk for breast and ovarian cancer
      due to family history can be difficult for physicians and patients alike. All
      physicians can identify those women who might be at an increased risk for
      familial or hereditary breast cancer. Gene testing can refine the estimate of the
      risk after thorough discussion of the benefits and limitations of current testing
      for BRCA1 and BRCA2. Exploring options for prevention and detection may benefit
      high-risk women.

PMID- 12420417
TI  - Tularemia.

PMID- 12420418
TI  - A mammogram could save your life--a personal testimony.

PMID- 12420419
TI  - [The homeless alcoholic: who cares?].
AB  - Two homeless alcoholics, males aged 58 and 40 years, suffered from multiple
      health problems. Sleeping outdoors, excessive drinking and incompetence refrained
      them from seeking proper assistance. The patients were assessed on many occasions
      at primary care services provided in shelters in Amsterdam, at police stations
      and in the streets. They were also frequently admitted to shelter infirmaries,
      alcohol clinics and general hospitals. Despite substantial individual health
      damage, community costs and extreme care consumption, coercive treatment was not
      applied to prevent the death of the first patient and to stabilise the situation
      of the second. It is stated that a specific group such as homeless alcoholics can
      hardly be treated except during moments of crisis. Coercive treatment should be
      applicable in order to stabilise these patients so as to prevent early mortality
      among the alcoholic homeless with comparable health problems. Outreach primary
      care services for the alcoholic homeless should actively cooperate with addiction
      and mental health services in providing adequate care.

PMID- 12420420
TI  - [Repetitive strain injury (RSI); a report from the Health Council of the
      Netherlands].
AB  - The Health Council of the Netherlands has published its advisory report on
      Repetitive Strain Injury (RSI). The report provides clear information on the
      state of this syndrome, including the definition of the problem, the
      epidemiology, various hypothetical pathophysiological mechanisms, occupational
      and personal risk factors, and possible methods of treatment. The council states
      that with regard to the last aspect, too few data are available to draw any
      conclusion as to the most promising therapy. Nevertheless, patients should get
      consistent advice from their GP or company doctor. The council emphasises that
      encouraging physical exercise and eliminating any possible causative strain
      should be part of an integrated approach, embracing work-related psychosocial and
      personal issues. Of particular interest is the council's advice to prevent RSI by
      improving the physical condition and by selective training of muscle function.
      The report recommends that more research be carried out in order to provide
      insight into the effectiveness of the treatment of RSI.

PMID- 12420421
TI  - [Repetitive strain injury (RSI): occurrence, etiology, therapy and prevention].
AB  - In the Netherlands, work related upper-limb disorders are called Repetitive
      Strain Injuries (RSI). RSI is not a diagnosis but a catch-all term for symptoms
      and signs located in the neck, upper back, shoulder, arm, elbow, hand, wrist and
      fingers. These symptoms may include pain, stiffness, tingling, clumsiness, loss
      of co-ordination, loss of strength, skin discoloration and temperature
      differences. Each year, 8% of working Dutch citizens take time off work due to
      RSI symptoms. Although the number of people claiming disability benefit due to
      RSI is limited, this figure has risen consecutively over the last three years.
      There is consensus that repetitive work at a high frequency and possibly
      accompanied by exertion of force is accompanied by RSI symptoms. There are
      indications of a relation between visual display unit use and these symptoms.
      However, these relations have not been established in a longitudinal study of
      adequate quality. High perceived job stress and a high workload are thought to be
      related to RSI, and women report more symptoms than men. There is insufficient
      information available on the role of different coping styles, perfectionism and
      dealing with symptoms. There is little information on the underlying mechanisms
      in the development of RSI, the diagnostics, therapy and prevention. In view of
      the lack of clear diagnostic criteria, suggestions have been made for a
      standardised description of the symptoms involved in the syndrome. A
      multidisciplinary treatment is likely to have the most effect. In terms of
      prevention, an integrated approach aimed at improving the working posture,
      reduction of static load and job stress and at individual factors is assumed to
      be the most effective.

PMID- 12420422
TI  - [Adipose tissue: an innervated endocrine gland].
AB  - Until recently, adipose tissue was considered to function as a passive store of
      triglycerides and therefore of calories. Fascinating research over the past ten
      years has altered this traditional perspective. Adipose tissue has been shown to
      produce hormones. Leptin was discovered in 1994; one of its main functions is to
      adapt the organism to starvation. Sympathetic nerve fibres were shown to
      innervate adipose tissue and to facilitate lipolysis leading to the release of
      glycerol and free fatty acids. In addition, parasympathetic innervation of
      adipose tissue was recently demonstrated, with anabolic effects. Different sets
      of autonomic neurons in the brain stem appear to innervate either the abdominal
      or the subcutaneous fat compartment. This may be the anatomical substrate for the
      hitherto unexplained regulation of body fat distribution (subcutaneous versus
      intra-abdominal). Moreover, fat distribution under physiological conditions (sex
      steroids, glucocorticoids) and pathological conditions (e.g., AIDS lipodystrophy,
      Cushing syndrome) might be mediated via the central nervous system. The
      developments in this research area have the potential to increase our insights
      into the pathogenesis of metabolic disorders such as hypertriglyceridaemia and
      type-2 diabetes mellitus.

PMID- 12420423
TI  - [Nifedipine first choice in management of threatening preterm labor].
AB  - Preterm birth is the most important cause of perinatal mortality in Europe and
      North America. Tocolytic agents named beta 2-sympathicomimetics postpone delivery
      for 24-48 hours, but do not reduce perinatal mortality or morbidity. Calcium
      antagonists, in particular nifedipine, are more effective tocolytic agents than
      beta 2-sympathicomimetics in terms of delaying delivery. Meta-analyses have found
      that calcium antagonists statistically significantly reduced perinatal morbidity
      and that the number of maternal side effects was statistically significantly
      lower compared with beta 2-sympathicomimetics. Nifedipine also has the benefit of
      oral administration, in contrast with beta 2-sympathicomimetics which are
      administered intravenously. Nifedipine is therefore the first choice in the
      management of threatening preterm labour.

PMID- 12420424
TI  - [Diagnostic image(110). An elderly woman with micturition problems. Caruncle
      urethrae in genital prolapse].
AB  - In a 72-year-old woman with micturition problems, in whom a genital prolapse had
      been diagnosed earlier, a urethral caruncle was diagnosed, i.e. a prolapse of the
      dorsal mucosa of the urethra.

PMID- 12420425
TI  - [Strong relationship between the course of the first pregnancy, delivery and
      puerperium and that of the following].
AB  - OBJECTIVE: To evaluate the significance of the course of a first pregnancy,
      delivery and puerperium (episode) for the course of a second episode. DESIGN:
      Retrospective cohort analysis. METHOD: Data from 3591 pregnancies, deliveries
      (3624 children) and puerperium of women from the Dutch town of Urk in the period
      1986-1995 were analysed. RESULTS: The study group consisted of 910 nulliparous
      women. Of these, 387 (group 1) had experienced an uncomplicated first pregnancy
      delivery-puerperium episode and 523 (group 2) a complicated one. In the study
      period, 77.3% of the women in group 1 and 59.8% of the women in group 2 gave
      birth for a second time. The course of the second episode was uncomplicated in
      74.6% of group 1 and 46.3% of group 2. This difference was significant (p <
      0.0001). The percentage of home deliveries in groups 1 and 2 was 80.3% and 50.5%
      respectively (p < 0.0001). The percentage of operative deliveries (vaginal and
      abdominal) was 1.3% and 8.6% respectively (p = 0.0008). No significant
      differences in perinatal outcome and postpartum referrals were found. Sixty-two
      of the 313 women with a complicated first episode had a primary indication for
      hospital delivery for a second partus, based on the outcome of the first episode.
      Even when these women were excluded, the differences in outcome as described were
      significant. CONCLUSION: An uncomplicated versus complicated first pregnancy
      delivery-puerperium episode was an important prognostic factor with respect to an
      uncomplicated or complicated secondary episode respectively.

PMID- 12420426
TI  - [Serious frostbite in a homeless psychiatric patient].
AB  - A 22-year-old homeless male psychiatric patient of Ghanaian origin was diagnosed
      with severe frostbite in both lower legs. The lesion consisted of haemorrhagic
      blistering with already visible demarcation. When sepsis developed both lower
      legs had to be amputated as a matter of urgency.

PMID- 12420427
TI  - [Centenary of the Health Council of the Netherlands. VI. Coordination mechanisms
      and the authority of the Health Council of the Netherlands].
AB  - What do scientific advisory boards such as the Health Council of the Netherlands
      get their authority from? How does the Council ensure that its advice is
      incorporated into policy and into the practices at which the advice is directed?
      A frequently heard answer to this question is: by describing 'the state of
      knowledge' as optimally as possible. However, case studies on advisory work by
      the Health Council have shown that this explanation is too simplistic. It is more
      likely that the explanation lies in the use of 'co-ordination tools'--such as
      problem definition, the committee process and a specific use of language--that
      enable the Council to both separate and bridge science and policy. The authority
      of the Council is based on the hybrid nature of its work.

PMID- 12420428
TI  - [One hundred years of the Association of Surgeons in the Netherlands. IX.
      Pediatric surgery].

PMID- 12420429
TI  - A numbers game. Still no consensus on the true NP population.

PMID- 12420430
TI  - Playing in the big leagues.

PMID- 12420431
TI  - FAQs on NP certification.

PMID- 12420432
TI  - Heading off antibiotic resistance.

PMID- 12420433
TI  - Men and osteoporosis. Preventing fracture and disability.

PMID- 12420434
TI  - Prostate-specific antigen testing. An essential guide to its use and meaning.

PMID- 12420435
TI  - Patient information. Caring for ankle sprains.

PMID- 12420436
TI  - Beyond heart attacks and prostate cancer. Is it time for a men's health
      specialty?

PMID- 12420437
TI  - Gender blindness and gender differences. Clinical implications of both.

PMID- 12420438
TI  - The lifelong lurker. A clinical review of hypothyroidism.

PMID- 12420439
TI  - Amiodarone for cardiac arrhythmias. Key management issues for NPs.

PMID- 12420441
TI  - Autoimmune hepatitis. Essential information for managing this clinical challenge.

PMID- 12420440
TI  - Paired for life? Controlling allergic rhinitis can improve pediatric asthma.

PMID- 12420442
TI  - Preventive care for adolescents. A review of clinical guidelines.

PMID- 12420443
TI  - To market, to market. The nuts and bolts of prescription drug approval.

PMID- 12420444
TI  - Disease state management.... Is it coming to a pharmacy near you?

PMID- 12420445
TI  - Nephropathic cystinosis. Recognizing this rare disorder.

PMID- 12420446
TI  - Facts about Web pharmacies.

PMID- 12420447
TI  - Clinical knowledge to the test.

PMID- 12420448
TI  - Dealing with prejudice in the ED.

PMID- 12420449
TI  - Stool specimen testing.

PMID- 12420450
TI  - Diabetes in the elderly. Treatment goals depend on age-related issues.

PMID- 12420452
TI  - Patient information. Preventing heat-related illness.

PMID- 12420451
TI  - The postmenopausal woman. Complex issues require NP touch.

PMID- 12420453
TI  - Oropharyngeal dysphagia in the elderly. Identifying and managing patients at
      risk.

PMID- 12420454
TI  - Comprehensive primary care for the elderly. Key concepts for meeting the goal.

PMID- 12420455
TI  - The DASH diet. A practical tool for hypertension management in the elderly.

PMID- 12420456
TI  - Structured treatment interruption. An update on current research findings.

PMID- 12420457
TI  - Soothing the burn. Modern management of GERD.

PMID- 12420458
TI  - Breastfeeding education. Keep it simple.

PMID- 12420459
TI  - Give patients an Rx for joy.

PMID- 12420460
TI  - NM judgment raises red flag. State law mandates nationwide action by NPs.

PMID- 12420461
TI  - Unlicensed personnel issues.

PMID- 12420462
TI  - St. John's wort for depression.

PMID- 12420463
TI  - Diagnosis and management of repetitive strain injury.

PMID- 12420464
TI  - Gastroesophageal reflux in children. Primary care management.

PMID- 12420465
TI  - Postprandial blood glucose. Keeping increases in check for cardiovascular health.

PMID- 12420466
TI  - Patient information. Preventing repetitive strain injuries.

PMID- 12420467
TI  - Pap smear screening during pregnancy. Necessary component of the first prenatal
      visit.

PMID- 12420468
TI  - Got questions? PDAs put answers in the palm of your hand.

PMID- 12420469
TI  - Medical information online. A medical librarian's guide to the Web.

PMID- 12420470
TI  - IT to the rescue? Technology's role in preventing medical errors.

PMID- 12420471
TI  - Get the specifics. Consider underlying conditions when evaluating ED.

PMID- 12420472
TI  - Addressing spiritual concerns.

PMID- 12420475
TI  - Additional points for apnea discussion.

PMID- 12420477
TI  - Medicare myths and realities.

PMID- 12420478
TI  - Lessons learned in Maryland.

PMID- 12420479
TI  - Urinalysis: the great detective.

PMID- 12420480
TI  - Infectious mononucleosis. A clinical review.

PMID- 12420481
TI  - Wasting syndrome in HIV/AIDS patients. A guide to prevention and management.

PMID- 12420482
TI  - Close-up on reimbursement. Key elements of reimbursement coding. A guide for
      nurse practitioners.

PMID- 12420483
TI  - Close-up on reimbursement. Who needs a Medicare number? You do! Why and how to
      get one.

PMID- 12420484
TI  - Platelet-derived growth factor for foot ulcerations. An effective adjunct to good
      wound care.

PMID- 12420485
TI  - Patient information.  Nighttime bruxism.

PMID- 12420486
TI  - Debridement for chronic wounds. A review of common uses.

PMID- 12420487
TI  - Safe school zone? To stay healthy, students must stay smart.

PMID- 12420488
TI  - Emergency contraception. Why you should prescribe it before it's needed.

PMID- 12420489
TI  - And the poor get ... children.

PMID- 12420491
TI  - Ground zero: 'it felt like hell'.

PMID- 12420492
TI  - Sleepless in New York.

PMID- 12420493
TI  - Don't be afraid to blow the whistle.

PMID- 12420494
TI  - Professional liability insurance.

PMID- 12420495
TI  - Mammography: choices.

PMID- 12420496
TI  - Curing long-lasting hiccups.

PMID- 12420497
TI  - Pain: the fifth vital sign. Comprehensive assessment leads to proper treatment.

PMID- 12420498
TI  - Vitamin B12 deficiency in the elderly. A major contributor to falls.

PMID- 12420499
TI  - Evaluating growth in children. Distinguishing between normal and worrisome.

PMID- 12420500
TI  - Therapy choices beyond antihistamines. Vasomotor rhinitis.

PMID- 12420501
TI  - Turning the tide. Drawing teens away from tobacco.

PMID- 12420502
TI  - Rethinking asthma. New ways of looking at an old problem.

PMID- 12420503
TI  - The enigma of prostatitis. Recent advances in classification and management.

PMID- 12420504
TI  - Patient information. Identifying and treating hypothermia.

PMID- 12420505
TI  - In search of a magic bullet.

PMID- 12420506
TI  - Group visits for diabetes care.

PMID- 12420507
TI  - The complete blood count.

PMID- 12420508
TI  - Dissecting an exam question.

PMID- 12420510
TI  - What are you worth? An enlightening investigation of salary formulation.

PMID- 12420509
TI  - The climb continues. NP salaries increase, but at a slower pace.

PMID- 12420511
TI  - The heart of the matter. National guidelines urge more aggressive cholesterol
      treatment.

PMID- 12420512
TI  - Vomiting in children. A comprehensive review.

PMID- 12420513
TI  - Medical complications of modern art. What you need to know about body piercing.

PMID- 12420515
TI  - Retroviruses and opportunistic infection. An update.

PMID- 12420516
TI  - Patient information. Staying healthy during flu season.

PMID- 12420514
TI  - Informed choices. Your most valuable role in menopause care is education.

PMID- 12420517
TI  - Nocturnal asthma. Strategies that put it to rest.

PMID- 12420519
TI  - Yoga as a clinical intervention.

PMID- 12420518
TI  - Cardiac rehabilitation. Increased referrals can decrease mortality, morbidity and
      costs.

PMID- 12420520
TI  - Pressure sores: a guide.

PMID- 12420521
TI  - The root of NP practice.

PMID- 12420524
TI  - More on polycythemia.

PMID- 12420525
TI  - Open-access scheduling.

PMID- 12420526
TI  - The difference between negligence and malpractice.

PMID- 12420527
TI  - Using modifier -25.

PMID- 12420528
TI  - Lipoprotein analysis.

PMID- 12420529
TI  - CT scans for the worried well.

PMID- 12420530
TI  - Oropharyngeal cancer. Tobacco and alcohol are main culprits.

PMID- 12420531
TI  - Sweetening the toxic cocktail. Managing the side effects of HIV medications.

PMID- 12420532
TI  - Healing with homeopathy. An introduction to basic tenets.

PMID- 12420533
TI  - Clinical aromatherapy. Therapeutic uses for essential oils.

PMID- 12420534
TI  - The energetic language of therapeutic touch. A holistic tool for nurse
      practitioners.

PMID- 12420535
TI  - Achieving bladder control. Treatment in the primary care setting.

PMID- 12420536
TI  - Persistent molluscum contagiosum. Case study in a 6-year-old girl with asthma and
      eczema.

PMID- 12420537
TI  - Wants vs. needs. A case study in polypharmacy and drug advertising.

PMID- 12420538
TI  - Patient information. Soybeans: good for your heart.

PMID- 12420544
TI  - Curbing test anxiety.

PMID- 12420545
TI  - Bad behavior, bad kid?

PMID- 12420546
TI  - The Pap smear.

PMID- 12420547
TI  - The complete neurological examination: what every nurse practitioner should know.

PMID- 12420548
TI  - Constipation in the elderly. Routine equals regularity.

PMID- 12420549
TI  - Changed lives. The hidden impact of falls in the elderly.

PMID- 12420550
TI  - Preventing osteoporosis. Lifelong nutrition and exercise habits are the most
      powerful weapons.

PMID- 12420551
TI  - Metabolic complications in HIV infection. In search of underlying mechanisms.

PMID- 12420552
TI  - Does provider gender matter in sexual assault treatment? An enlightening review
      of practice and research.

PMID- 12420553
TI  - Patient information. Understanding menopause.

PMID- 12420554
TI  - Hypnosis for habit disorders. Helping children help themselves.

PMID- 12420555
TI  - Ensuring home safety for your Alzheimer's patients.

PMID- 12420556
TI  - The 'invisible people'.

PMID- 12420561
TI  - The effect of miswak and tooth brush filaments end-surface texture on enamel. A
      SEM pilot study.
AB  - OBJECTIVE: The aim of the study was to compare the abrasive effect of miswak and
      toothbrush filaments on enamel tooth surface. MATERIAL AND METHODS: Ten maxillary
      central incisors were obtained from Division of Maxillofacial Surgery, King Saud
      University, College of Dentistry. Twenty specimen were prepared, they were
      divided into 4 groups (1) Butler toothbrush; (2) Aquafresh toothbrush; (3)
      Miswak; (4) Control group. Miswak, Aquafresh 311 and Butler 311 tooth brush were
      used with light pressure in one direction motion for 60 seconds on enamel
      surface. The specimens were prepared for Scanning Electron Microscopy (SEM)
      examination. The middle filament from toothbrushes and miswak were also prepared
      for SEM. RESULTS: Showed that filaments end-surface texture play a major role in
      abrasive active activity and enamel tooth surface loss. CONCLUSION: The Butler
      311 toothbrush and miswak showed lesser effect on enamel as compared to Aquafresh
      311 toothbrush.

PMID- 12420562
TI  - Tooth exfoliation, osteonecrosis and neuralgia following herpes zoster of
      trigeminal nerve.
AB  - A case of herpes zoster of the trigeminal nerve with complications of
      osteonecrosis and neuralgia in the absence of local or systemic predisposing
      factors is presented. The literature is reviewed and the role of varicella zoster
      virus in the pathology of tooth exfoliation and osteonecrosis is discussed.

PMID- 12420563
TI  - Prevalence of periodontal disease in endemically flourosed areas of Davangere
      Taluk, India.
AB  - Success of fluoride in combating dental caries led to study of fluoride on
      periodontal disease, but studies are less reported in literature and results are
      varied in nature. To address this issue, the study was conducted to assess
      severity of periodontal disease among (n = 283) 36-45 years old adults residing
      in area of different concentration of fluoride in drinking water. The villages
      selected were having fluoride concentration in their drinking water are Shamnur
      (0.5 PPMF), Kundawada (1.1 ppmF) and Halebathi (3.17 ppm). Ion Selective
      Electrode Method (OrionUSA) estimated fluoride in drinking water. Community
      Periodontal Index (WHO, 1997) and Plaque Index (Silness and Loe, 1967) was used
      to assess periodontal status. There was consistent decrease in mean plaque score
      from 1.45+ _0.024 at 0.51 ppm, 1.21+ _0.009 at 1.1 ppm, and 1.12+ _0.08 at 3.17
      ppm fluoride area. This difference was significant statistically (P < 0.001). As
      the fluoride concentration in drinking water increased there was decrease in
      severity of prevalence of periodontitis. This difference in observation was
      significant statistically (P < 0.05). There were no effects of fluoride on
      calculus, since little variability was found in three different fluoride areas.
      Thus it was concluded from the study results that the increase in fluoride
      concentration decreased the plaque accumulation. decreased the shallow and deep
      pockets. Hence lower prevalence and severity of periodontal disease.

PMID- 12420564
TI  - Classification and management of dental caries. New concepts.
AB  - There has been a tremendous change in the understanding of carious lesion in all
      aspects from pathogenesis to prevention. The profession has also seen a
      revolutionary change in the material science and technology. In spite of these
      changes, the caries classification provided by Dr. G. V. Black remains unchanged,
      deterring the radical changes needed in the understanding of caries as a disease
      process. This article propose a new classification of dental caries to suit the
      present day changes in the related area. The article opens by highlighting the
      changes and limitations in the existing classification. The logical and
      advantageous outcome of the new classification is projected at the end
      emphasizing the need to change in conservative dentistry and education.

PMID- 12420565
TI  - A qualitative and quantitative estimation of AgNORS in dysplastic and non
      dysplastic leukoplakias.
AB  - Using a silver staining technique, nucleolar organizer region--associated
      proteins (AgNORS) were studied in formalin, fixed paraffin embedded tissue blocks
      of normal oral buccal mucosa epithelium, leukoplakia with dysplasias and
      leukoplakia without dysplasias. Fifty cases, that comprised of 10 cases of normal
      oral buccal mucosa epithelium and 40 cases, of leukoplakia without dysplasia and
      with mild, moderate and severe leukoplakia were examined with respect to the
      relationship between AgNOR counts and histologic grading. The mean AgNOR count
      per nucleus increased from normal oral buccal mucosa epithelium to leukoplakia
      without dysplasia to leukoplakia with dysplasia. Higher counts, wider scatter and
      smaller size of AgNOR in the nuclei were seen as the grading of dysplasia
      increased from mild to severe. It is suggested that this method has potential in
      distinguishing between dysplastic and non dysplastic leukoplakias and for early
      diagnosis, prognosis and treatment planning of dysplastic lesions.

PMID- 12420566
TI  - A comparative evaluation of sealing ability of rootcanal sealers.
AB  - The importance of apical seal has always been stressed in endodontic therapy.
      Root canal sealers have been used along with gutta percha to enhance the seal.
      The apical sealing ability of AH26/silverfree, a modified version of AH26, a
      resin based sealer was compared with tubliseal, a zincoxide eugenol based sealer
      using methylene blue dye penetration method. AH26/silverfree showed superior
      sealing ability.

PMID- 12420567
TI  - Clinical evaluation of guided tissue regeneration procedure in the treatment of
      grade II mandibular molar furcations.
AB  - The management of furcation defects remains a challenge in periodontal therapy,
      Traditionally, furcation therapy involved scaling, rootplaning, furcation plasty
      and resective techniques. The purpose of this study was to clinically evaluate
      the potential of guided tissue regeneration in the treatment of mandibular molar
      grade II furcations using a nonresorbable barrier, TefGen-GTR and compare it with
      open flap debridement alone. Ten patients with similar bilateral grade II
      furcation lesions participated in the study. TefGen-GTR was placed in the
      experimental sites while the contralateral sites served as controls. Treatment
      effects were evaluated at six months reentry. Both groups showed gain in vertical
      and horizontal open probing attachment and defect depth reduction when compared
      to baseline values, with experimental sites showing statistically significant
      improvement over the controls. The results suggest that the nonresorbable Teflon
      barrier, TefGen-GTR, may be used as an alternative for treatment of grade II
      furcation invasions.

PMID- 12420568
TI  - A comparative evaluation of four adhesive tooth coloured restorative materials.
      An invitro study.
AB  - Four adhesive tooth colored restorative materials, Fuji II, Fuji II LC, Dyract
      and TPH composite resin were evaluated for the amount of microleakage in enamel
      and cementum. The TPH composite resin showed maximum microleakage, significantly
      higher than Fuji II, which showed least microleakage. All the four materials
      showed more micro leakage in cementum when compared to enamel.

PMID- 12420569
TI  - A study on cryopreservation of cultured rabbit periodontal ligament cells.
AB  - Cultured rabbit periodontal ligament cells were subjected to short term
      cryopreservation in liquid nitrogen, for a period of 84 hours and 168 hours, to
      study the effect of cryopreservation on coll viability and culturing ability. The
      vital cell count performed by Trypan Blue exclusion was 14.93 x 10(0) cells/ml in
      vial A and 9.11 x 10(6) cell/ml in vial B, before cryopreservation. The loss of
      viability was minimal--vital cell count being 14.64 x 10(6) cells/ml in vial A
      and 8.87 x 10(6) cells/ml in vial B after 84 hrs of cryopreservation and 14.6 x
      10(6) cells/ml in vial A and 8.82 x 10(6) cells/ml in vial B after 168 hours of
      cryopreservation. The cryopreserved cells after thawing could grow again in
      cultured.

PMID- 12420570
TI  - Surgical treatment of melanin-pigmented gingiva; an esthetic approach.
AB  - The aim of this clinical article is to review the methods of depigmentation of
      melanin pigmentation of gingiva and explain scalpel surgical technique for
      depigmentation of gingiva.

PMID- 12420571
TI  - Further on the causation of oral submucous fibrosis.
AB  - Oral submucous fibrosis is perhaps a disease of multifactorial aetiology, of
      which areca nut usage is definitely a causative factor. We disagree with the
      previous reports in that the action of areca quid on the oral mucosa is not that
      simplistic and is not dictated solely by the duration of exposure to it or by
      simple process of passive diffusion. We noted that the role of copper cannot be
      segregated from that of zinc, the biochemical relatedness of these two elements
      is well elucidated. The transport of copper in to the oral epithelium may be
      dictated more by the composition of the quid rather than the time of exposure.
      Zinc is implicated in the modulation of mucosal metallothionein, thereby
      interfering with copper absorption. The bioavailability of zinc in its turn
      depends on elements like calcium and iron present in oral fluid. The usage of
      slaked lime(calcium hydroxide) as as ingredient of betel quid, thereby causing an
      interference with zinc bioavailability is a matter of concern. Of practical
      importance is the processing of raw areca nut and the various proprietary forms
      (sachets) available in the market, the toxic effects of which varies depending on
      its contents. Studies on the role of geochemical factors in modulating the
      chemical composition of the various nut forms, thereby altering its toxic effects
      will be an interesting pursuit.

PMID- 12420572
TI  - Hemifacial microsomia. A case report and review.
AB  - Hemifacial microsomia (HFM) is a variable asymmetric craniofacial malformation
      resulting in hypoplasia of the components of the first and second branchial
      arches. Because of the extremely variable expressively of the HFM, treatment
      measures also vary considerably from the use of activator to total reconstruction
      of TM joint and management of secondary deformities of maxilla, nose, orbit and
      zygomatic bone. We present a case of HFM type I of mild deformity treated with
      onlay bone grafting.

PMID- 12420573
TI  - Etiology, pathogenesis and treatment of habitual dislocations of the T.M. Joints
      [original work].
AB  - Definite treatment of any pathological condition, is based on the understanding
      of its correct pathogenesis and etiology. Without this basic understanding
      correct and lasting treatment is not possible. When there is no knowledge of
      exact pathogenesis and etiology, various theories and treatments are suggested by
      various workers. This is what exactly happened in the case of habitual
      dislocations of the T.M. Joints. This in term has happened because the dental
      surgeons and so called oral surgeons, never expanded their vision, beyond their
      restricted field of 20 deciduous teeth and 32 permanent teeth. Lack of
      understanding of basic physiological functions, of various tissues in the body
      and their effects on various systems as a whole was neglected. For this study
      four patients were selected from many, who could visit my clinic regularly and co
      operate to follow all the instructions over a period of at least 5 years. The
      analysis of their symptoms and signs, had a different story to tell than what was
      described in the literature so far.

PMID- 12420574
TI  - Determination of the morphological irregularities in the middle and apical 1/3rd
      region of the root canal system of permanent maxillary incisors.
AB  - A thorough knowledge of the root canal anatomy and an understanding of its
      variations from the normal are mandatory for the successful root canal therapy.
      The assessment and exploration of the accessory canal and apical delta is
      necessary to combat the persistent infection at the periapical area. The purpose
      of this study is to determine the morphological irregularities in the middle and
      apical 1/3rd region of the root canal system of maxillary incisors. A total of
      100 maxillary incisors were decalcified, processed, sectioned at the middle and
      apical 1/3rd region and observed under an ordinary microscope. The frequency of
      accessory canals, apical delta and type of canal configuration were studied.
      Accessory canals were found in 5% of the teeth. There was absence of apical delta
      in all the specimens. Total specimens showed single canal extended from the pulp
      chamber to the apex (Type 1 canal configuration).

PMID- 12420575
TI  - A study on the isolation of anaerobic bacteria from the root canal infections in
      anterior non-vital teeth with special reference to Bacteroides species.

PMID- 12420576
TI  - Biochemical changes of saliva in tobacco chewers tobacco smokers, alcohol
      consumers, leukoplakia and oral cancer patients.
AB  - Normal salivary function is considered to be critical for the maintenance of
      healthy oral mucosa. Oral fluids provide an easily available non-invasive for the
      diagnosis of a wide range of diseases and clinical situations. The present study
      evaluated the variations in the biochemical constituents of saliva of leukoplakia
      and oral cancer patients when compared with that of the control group. 90
      individuals were grouped into 6 categories with 15 individuals in each group. The
      groups included individuals without tobacco or alcohol habits, tobacco smokers,
      tobacco chewers, alcohol consumers, leukoplakia and oral cancer patients. There
      was significant alteration in the salivary biochemical composition of leukoplakia
      and oral cancer patients which could be attributed to the impairment of salivary
      gland function caused by tobacco and alcohol usage or by the disease process
      itself.

PMID- 12420577
TI  - Comparison of impact strength of acrylic resin reinforced with kevlar and
      polyethylene fibres.
AB  - The present study was done to evaluate the impact strengths of heat-activated
      acrylic resins reinforced with Kevlar fibres, polyethylene fibres and
      unreinforced heat activated acrylic resin. Each of three groups had 25 specimens.
      Brass rods of uniform length of 40 mm and diameter of 8 mm were used to prepare
      the moulds. A combination of long fibres (40 mm length) and short fibres (6 mm
      length) were used. The total amount of fibres incorporated was limited to 2% by
      weight of the resin matrix. Short and long fibres of equal weight were
      incorporated. The short fibres were mixed with polymer and monomer and packed
      into the mould, while, the long axis of the specimen, perpendicular to the
      applied force. The specimens were then processed. Impact strength testing was
      done on Hounsfield's impact testing machine. Kevlar fibre reinforced heat
      activated acrylic resin specimens recorded higher mean impact strength of 0.8464
      Joules, while polyethylene fibres reinforced heat activated acrylic resin
      recorded mean impact strength of 0.7596 joules. The unreinforced heat activated
      acrylic resin recorded mean impact strength of 0.3440 Joules.

PMID- 12420579
TI  - Supernumerary roots.
AB  - Supernumerary roots are one of the development anomalies pertaining to the tooth
      root morphology. It is generally well known that the deciduous and permanent
      anterior teeth have a single root. Maxillary molars have three roots and
      mandibular molars have two roots. Pertaining to the premolars, except for the
      maxillary first premolars all other premolars have a single roots. These
      supernumerary roots may be due to the disturbances of the Hertwig's epithelial
      root sheath forming the root. Cases have been reported where in both the
      deciduous and permanent dentition exhibiting supernumerary roots. Here with we
      are presenting cases of supernumerary roots in permanent teeth involving
      maxillary third molars, mandibular first, second molars and mandibular second
      premolars.

PMID- 12420578
TI  - Determination of mode of fracture of adhesive restorative materials. An invitro
      study.
AB  - In the present invitro study, four adhesive restorative materials were evaluated
      for the determination of mode of fracture. The four materials chosen were TPH
      composite resin, Dyract, Fuji II LC and Fuji II. The mode of fracture was
      determined at a magnification of 10X. The TPH composite resin and Dyract showed
      adhesive fracture whereas the glass ionomer group showed cohesive fracture.

PMID- 12420580
TI  - [Looking back on past decades of vaccinology].
AB  - Author makes a survey upon the progress of vaccinology from the Jennerian times
      up to the modern vaccines of our ages, particularly as far as Hungary is
      concerned. Some pictures of the vaccinology to come are dealt with, too, e.g.
      genetic methods, mucosal immunization etc. Some changes in vaccinology caused by
      either favourable (polio) or unfavourable (pertussis) impacts and by introduction
      of new vaccines are described. The activity of the "Clinical vaccination service"
      (clinical consultation, teaching) is detailed.

PMID- 12420581
TI  - [Diurnal changes in blood pressure and their consequences].
AB  - Author analyses the daily blood pressure and heart rate alterations due to
      circadian rhythm and their effects to development of dangerous clinical
      situations (sudden death, stroke, myocardial infarct, ischaemic episodes) in
      hypertension with or without ischemic heart disease. The most dangerous time
      period is the morning hours, but serious problems are the sudden increases in
      blood pressure in any time of day as well. The daily changes in blood pressure
      (rise in blood pressure variability) are often associated with the alteration in
      heart rate (decrease in heart rate variability) and loss of dipp at night. The
      main cause of this "death-three" is the overactivity of the sympathetic nervous
      system. An antihypertensive drug with good quality can be capable to depress the
      high blood pressure continuously during the whole day inhibiting the rapid rise
      periods of blood pressure. The best measure of this effect is the high
      through/peak ratio.

PMID- 12420582
TI  - [Gynecologic and endocrinologic sequelae of bulimia--hormonal changes].
AB  - INTRODUCTION: Gynecological problems are one of the most frequent somatic
      complications of eating disorders. AIMS: The purpose of the present study was to
      assess the role of improper eating habits causing menstrual disturbances,
      anovulation and related hormonal changes. Latent bulimia nervosa is in the focus
      of attention since amenorrhea is considered as a diagnostic criterion of anorexia
      nervosa. METHOD: Subjects of the BITE (Bulimia Investigation Test, Edinburgh)
      test were infertile patients (n = 34) of the gynecological outpatient departments
      after medical examination, blood-test (LH, FSH, androstenedione, DHEAS,
      progesterone, testosterone, SHBG, prolactin) and ultrasonic examination (uterus
      and ovaries). RESULTS: Symptoms and severity subscales of the BITE test and body
      mass index (BMI) were close correlation (p = 0.003, p = 0.033). In comparison
      with previous results, EDNOS (Eating Disorders Not Otherwise Specified)
      prevalence was 48%. Of hormonal changes, low LH and FSH levels (6/6) and
      hyperandrogenism (5/6) were significant in patients with subclinical eating
      disorders (n = 6) by infertile women as compared with the "normal" infertile
      group (n = 18; 7/18, 8/18). CONCLUSION: The recent results suggests that
      unsatisfactory nutrition (bulimic binges, "crash diet") is as relevant in
      hormonal dysfunction, menstrual disturbances and infertility as pathologically
      low weight in anorexia nervosa. Excessive application of contraceptives in
      therapy has to be taken into consideration.

PMID- 12420584
TI  - [Janos Arany--the demographer and epidemiologist].

PMID- 12420583
TI  - [Frequency of the Connexin26/35delG mutation and its characteristic phenotype in
      patients with hearing impairment and controls in Northeastern Hungary].
AB  - INTRODUCTION: Hereditary hearing impairment is a heterogeneous disorder showing
      different pattern of inheritance and involving a multitude of different genes.
      Mutations in the GJB2 gene, especially the 35delG mutation, have been established
      as a major cause of inherited and sporadic non-syndromic deafness in different
      populations. Mutations in GJB2 gene, encoding gap junction protein (Connexin 26),
      may be responsible for up to 50% of cases of autosomal recessive non-syndromic
      hearing impairment and in 15-30% of sporadic cases. STUDY DESIGN: The authors
      analyzed 15 north east Hungarian families and 30 sporadic cases with nonsyndromic
      hearing impairment for the 35delG mutation. METHODS: DNA were tested for the
      common 35delG mutation by a polymerase chain reaction based restriction enzyme
      assay (BsiYl). RESULTS: Fifty two patients showing a homozygous 35delG mutation
      were audiological examined. Ordinarily these patients showed a prelingual,
      sensorineural, bilateral, symmetric hearing loss without progression. The
      audiograms were characterized by sloping or flat patterns. The carrier frequency
      of the 35delG mutation among control group was 5.1%. CONCLUSION: The phenotypic
      manifestation varied in 30% of all analyzed patients, making genetic counseling
      extremely difficult. Due to this knowledge mutation analysis of GJB2 cannot
      distinctly predict the degree of hearing impairment.

PMID- 12420585
TI  - [Hungarian physicians in Vienna].

PMID- 12420586
TI  - [Inhibition of lectin induced peripheral blood lymphocyte proliferation by
      colorectal cancer extract: a preliminary report of three cases].
AB  - BACKGROUND: Tumor infiltrating lymphocytes (TIL) in colorectal cancer are a
      manifestation of local, cell mediated immune response to the malignant tumor.
      Tumor progression is due to impairment of the host ability to control tumor
      growth. Several studies suggested possible causes for such impairment, however,
      the precise factor(s) underlying such malfunction is uncertain. AIM: To compare
      the possible effects of colorectal cancer (CRC) and normal colonic mucosa
      extracts on lectin induced blastogenesis of the same patients' peripheral blood
      lymphocytes (PBL) proliferation. METHODS: CRC and normal mucosa extracts were
      obtained from 3 patients undergoing curative surgery for colon adenocarcinoma.
      Proliferation assays used PBL from the CRC patients, incubated with Concanavalin
      A (ConA) and Phytohemoglobin (PHA) in the presence of CRC or normal mucosa
      extract and in medium alone. Proliferation was measured by H3 Thymidine
      incorporation following 48 hours on incubation. RESULTS: Exposure of ConA induced
      PBL proliferation assay to CRC extract yielded a 98.7% inhibition measured by
      counts/minute (cpm) of incorporated H3 Thymidine compared to normal colonic
      mucosa extract (1,214 +/- 594 cpm vs. 95,335 +/- 6,997 cpm respectively, p =
      0.0018). PHA stimulated proliferation exposed to CRC extract showed a 99.7%
      decrease in blastogenic activity compared to normal mucosa extract (362 +/- 175
      cpm vs. 62,375 +/- 16,591 cpm respectively, p = 0.0234). CONCLUSIONS: These
      preliminary results suggest that CRC extract contain factor(s) capable of
      profoundly inhibiting lectin induced proliferation of PBL. Shedding of suppressor
      substances may be one of the possible mechanisms by which the tumor evades the
      effector arm of the cell-mediated immune response. Characterization of such
      factors may aid in intratumor, local and systemic cellular immune response
      reconstitution.

PMID- 12420587
TI  - [The relation between the perception of dyspnea and beta 2-agonists consumption
      in patients with mild-moderate asthma].
AB  - It is well documented that, in patients with asthma, there is a considerable
      variation in the severity of breathlessness for any particular degree of airflow
      obstruction. The factors underlying this variability are still to be explored.
      The consumption of beta 2-agonists and the perception of dyspnea were assessed in
      eighty asthmatic patients, with mild-moderate asthma, attending the asthma
      clinic. The perception of dyspnea was compared to sixty normal subjects. All
      patients received treatment with inhaled corticosteroid and beta 2-agonists as
      needed. Nine patients were excluded from the study, hence the data reported
      relates to 71 patients. In 55% of the patients the mean score of the perception
      of dyspnea during breathing against resistance was normal, it was low in 20 (28%)
      and high in the remaining 12 (17%). There was no correlation between the FEV1 and
      the perception of dyspnea. The mean +/- SEM beta 2-agonists consumption was 2.9
      +/- 0.4 puffs/day (range 0-7.2). There was a statistically significant difference
      in beta 2-agonists consumption between the mid asthmatic and the moderate
      asthmatic groups (p < 0.01). In both groups the mean beta 2-agonists consumption
      was significantly higher in the high preception of dyspnea group than in the
      normal (p < 0.05) and the low (p < 0.01) perception of dyspnea groups. We
      conclude that about half of mild-moderate asthmatic patients have normal
      perception of dyspnea while the other half have either high or low perception of
      dyspnea. More obstructed patients have higher beta 2-agonists consumption.
      However, in every degree of severity there is a close relation between the
      perception of dyspnea and the beta 2-agonists consumption.

PMID- 12420588
TI  - [Angioedema of the tongue and oropharynx after treatment with sublingual
      captopril].
AB  - Angioedema of the tongue and oropharynx is a rare and potentially life
      threatening adverse reaction related to the use of angiotensin converting enzyme
      inhibitors. We report a case of a patient who suffered angioedema of the tongue
      following sub-lingual Captopril treatment and discuss the prevalence, prevention
      and treatment of this adverse event. This case report is an addition to a limited
      number of similar cases and denotes the severity of this phenomenon and the need
      to be aware of its existence.

PMID- 12420589
TI  - [Upper respiratory tract manifestations in yellow nail syndrome].
AB  - Yellow Nail Syndrome (YNS) is characterized by a triad of ankle edema, pleural
      effusion and yellow nails. A close association was also found between YNS and
      rhinitis and sinusitis ranging from 25% to 83%. Although usually other symptoms
      precede rhinosinusitis, we describe three cases in which the onset of the upper
      respiratory tract manifestations predated nail changes and other characteristics
      of YNS. Our aim is to emphasize the importance of upper respiratory tract
      diseases in this uncommon syndrome.

PMID- 12420590
TI  - [The prevalence of positive allergy skin tests among children with asthma in the
      Ashkelon Region, Israel].
AB  - BACKGROUND: Asthma is the most common chronic disease amongst children.
      OBJECTIVE: To find the prevalence of positive allergy skin tests amongst children
      having asthma attending the asthma clinic in Barzilai Medical Center in Ashkelon
      Israel. STUDY DESIGN: Retrospective study. All medical files of the asthmatic
      children attending the asthma clinic in Barzilai Medical Center in Ashkelon,
      Israel, were reviewed. Data regarding their clinical status, past medical
      history, socioeconomic and familial medical history were collected. RESULTS: One
      thousand three hundred and fifty three medical files including all the
      information necessary for the study were reviewed. Amongst the children 1,238
      lived in urban areas and towns and 115 lived in rural areas. It was found that
      most of the children have positive allergy skin tests for house dust mite and
      mold. Among the urban children 86.2% were found to have positive allergy skin
      tests for house dust mite compared with 48% of the rural children (P < 0.02).
      Positive allergy skin tests for mold were found among 63.1% of the urban children
      compared with 44% of the rural children (p < 0.04). Positive allergy skin tests
      for most allergens were found to be more prevalent amongst the children living in
      urban areas compared with the children living in rural areas. The positive
      allergy skin tess are not related to parental smoking habits or house pets
      amongst these findings. CONCLUSION: Most of the children living in the Ashkelon
      region and positive allergy skin tests for house dust mite. This tendency is more
      common among the children living in urban areas as compared with children living
      in rural areas. The reason for this difference has to be studied.

PMID- 12420591
TI  - [Fracture of the supracondylar process of the humerus associated with Monteggia
      fracture].
AB  - Fractures of the supracondylar process of the humerus have been rarely described
      in the medical literature. This is a bony projection that arises from the
      anteromedial surface of the distal humerus, and present in only one per cent of
      the population. We present a patient with this rare injury associated with a
      Monteggia fracture of the forearm. The proximity of neurovascular structures to
      the process makes them vulnerable to injury associated with this fracture. We
      present a review of the literature and treatment guidelines.

PMID- 12420592
TI  - [Child abuse--undiagnosed].
AB  - We present the case of a 2 1/2 year old child brought to the emergency room by
      his mother, a nurse at that hospital, and her companion, because of a fractured
      clavicle. Over the next 14 days the child was seen by a variety of physicians in
      different sites (3 different emergency rooms, pediatricians' offices, orthopedic
      clinics) for various injuries. Each individual injury was treated separately, and
      the diagnosis of a battered child syndrome was not entertained. The child was not
      undressed completely and numerous clues to the diagnosis went undetected. A
      greater sensitivity to the diagnosis of child abuse is essential. More careful
      history-taking, more thorough physical examination and better interinstitutional
      communication are essential if child abuse is to be detected in its earliest
      phases.

PMID- 12420593
TI  - [Family practitioners' knowledge and attitudes towards various fields of non
      conventional medicine].
AB  - BACKGROUND: The common feature of the different varieties of non-conventional
      medicine (NCM) is the lack of recognition, complete or partial, given to them by
      the institutions of conventional medicine. Treating all varieties in the same way
      can cause confusion. AIM: To investigate the knowledge and attitudes of family
      practitioners (FP) in the methods of NCM that are most commonly practiced in
      Israel. METHODS: Anonymous questionnaires were used that tested knowledge and
      probed attitudes about FP about acupuncture, homeopathy, shiatsu and reflexology.
      RESULTS: 130 FP participated in the study (response rate 91%). In-depth training
      of any one of the NCM methods was rare (3-7%). Overall, a very minimal level of
      knowledge of all four methods was found--58% did not manage to answer even one
      knowledge question correctly, and the best result was five correct answers out of
      eight. Most of the doctors recognized NCM as legitimate, and thought that
      conventional and non-conventional medicine should co-exist side by side. Over 30%
      saw the possibility of integrating all four NCM methods within the institutions
      of conventional medicine. No significant difference was found in the doctors'
      attitudes towards the different methods. Better knowledge was associated with
      more positive attitudes towards NCM (p < 0.05), and a greater likelihood of
      referring patients (p < 0.1). CONCLUSION: Since attitudes towards NCM seem to be
      shaped by knowledge to a certain extent, educators should consider teaching more
      about these treatments both in medical schools and as part of CME.

PMID- 12420594
TI  - [Hormonal replacement therapy summer 2002--much ado about what?].
AB  - Hormonal replacement therapy, in use for years, gained popularity as a result of
      many published studies indicating the major positive effects it had on women's
      health. Today, new evidence in recently published studies (mainly HERS and WHI
      trials), present the pros and cons of the treatment including the risk of breast
      cancer and cardiovascular disease, reinstating the controversial subject on to
      the public agenda.

PMID- 12420595
TI  - [Allergy and asthma].
AB  - Asthma often appears early in life as one of the target organs in the allergic
      process. Allergic rhinitis and asthma are linked by epidemiologic, histologic,
      physiologic, and immunopathologic characteristics. Identifying risk factors for
      sensitization and subsequent development of wheezing has significant implications
      for the prevention and treatment of asthma. A family history of atopy and early
      sensitization to house dust mites especially increase the risk, while early
      exposure to infections may reduce the risk. Inner city children have generally
      increased risk for asthma compared to children raised in rural areas. In a recent
      study in Israel inner city asthmatic children were more allergic to both indoor
      and outdoor allergens than rural asthmatic children. A further study is indicated
      to examine the prevalence of asthma among allergic children. The allergic part of
      the evaluation of risk factors in asthmatic patients should be examined. The
      elimination of the offending trigger or decreased exposure can be very helpful in
      reducing the symptoms requiring medication and long-term effects of the
      inflammatory process in asthma.

PMID- 12420596
TI  - [Nutritional supplements and cancer].
AB  - According to recent data more than half of cancer patients are looking for
      alternative and complementary therapies to add to their regimen of care.
      Nutritional supplements are one of the common complementary methods that cancer
      patients are using. This mode of therapy is being used independently by the
      patients or being prescribed by physicians or alternative practitioners. The use
      of these supplements raises questions concerning the efficacy and safety of those
      products and the proper way to utilize them. In this article questions are raised
      regarding the integration of nutritional supplements in the care of cancer
      patients, as well as reviewing some evidence regarding possible therapeutic
      options of phytoestrogens and green tea as common examples of nutritional
      supplements that have undergone some scientific research relating to cancer
      prevention and treatment.

PMID- 12420597
TI  - [The psychological (long-term) sequelae of abortion].
AB  - This article aims to review the available literature on the short and long-term
      psychological sequelae of abortion. This subject remains controversial. The most
      common reactions women experienced after pregnancy loss were grief, depression
      and anxiety. From the reviewed literature it seems that those reactions are more
      common following spontaneous abortion than after therapeutic abortion. Risk
      factors for these reactions include past psychiatric history, social and cultural
      attitude, poor social support, history of previous therapeutic abortion, the fact
      that the current abortion is the result of medical or genetic problem, no living
      children, or being a single woman. Most of the reviewed papers deal with short
      term reactions and raise the need for long term research (more than 2 years).
      Only one such paper was found. It is recommended that all those who treat women
      that had an abortion should be aware of its psychological consequences and help
      identify and refer high-risk women for treatment.

PMID- 12420598
TI  - [Eating disturbances in adolescent girls with type 1 diabetes mellitus].
AB  - Eating disorders that meet DSM-IV criteria, especially bulimia nervosa and EDNOS
      are more than twice as common in adolescent girls with Type 1 Diabetes (DM) than
      in their nondiabetic peers. The prevalence of subthreshold eating disorders is
      especially high in this group and may be found in 14% of girls with DM. Insulin
      omission is a common weight loss behavior in girls with DM and eating disorders.
      Insulin omission and binge eating inevitably contribute to the increased rate of
      hyperglycemia and increased risk of long-term diabetes related medical
      complications, including retinopathy and nephropathy. The weight gain and dietary
      restrictions associated with diabetes treatment and the ready availability of
      insulin omission to promote weight loss are most likely responsible for this
      increased prevalence of eating disorders. A high index of suspicion for eating
      disorders is recommended in the diabetes clinic setting to enable early
      identification of disordered eating attitudes and behavior before they progress
      to clinical eating disorders. Clinic-based psychoeducational programs may be
      effective for prevention or early intervention. Severe eating disorders require
      more intensive intervention, tailored to address the DM context.

PMID- 12420599
TI  - [Management of primary intracerebral hemorrhage].
AB  - BACKGROUND: Primary intracranial hemorrhage (PICH) is responsible for about 10%
      of all strokes and is associated with a grave prognosis with high morbidity and
      mortality rates. OBJECTIVES: To familiarize the reader with new insights gained
      in the field of PICH over recent years. METHODS: The authors conducted a MEDLINE
      search on studies related to the diagnosis and therapy of PICH. The authors also
      formed an expert committee of the Israeli Neurological Society that discussed the
      epidemiology, prevention, diagnosis and therapy of PICH and present their
      conclusions herein. RESULTS AND DISCUSSION: PICH is a common and serious disorder
      with ominous prognosis. A large proportion of all PICH could theoretically be
      prevented if appropriate therapeutic interventions would be applied in advance.
      This holds especially true for lowering systolic and diastolic blood pressure.
      Conservative therapy continues to be the most appropriate therapy form to date
      although it only marginally improves patient outcome and survival. Surgical
      interventions have not proved to be superior to conservative therapy thus far,
      except for certain forms of PICH as detailed in the article. However, newer
      surgical techniques that are currently undergoing randomized studies could
      perceivably improve patients survival and outcome.

PMID- 12420600
TI  - [Subglottic carcinoma].
AB  - Subglottic malignancies are rare. They constitute about 1% of laryngeal cancer.
      Most of these malignancies are squamous cell carcinoma. In this article were
      describe various definitions concerning the borders of the subglottic region. A
      summary of pathophysiology and behavior of cancer in this location is presented.
      The incidence of primary subglottic carcinoma is low. The origin of most cancers
      in this area is the glottic cancer that extends into the subglottic region. The
      tumor tends to spread through lymphatic channels to the paraglottic and
      preglottic (delphian) nodes and secondary to the jugular chain. The delayed
      diagnosis is due to the lack of symptoms in the early stage of the disease and
      the hidden location of the tumor. The presenting symptoms are usually dyspnea and
      stridor. Direct laryngoscopy is essential for early detection of the tumor and
      the use of CT and MRI is advocated. Therapy is usually radical. Total
      laryngectomy and radiation therapy have both been advocated. Between 1995 and
      2000, 126 patients with laryngeal squamous cell carcinoma were presented to our
      department. Our experience in diagnosing and treating subglottic cancer in 4
      patients is hereby described. The latest literature on the subject is reviewed.

PMID- 12420601
TI  - [The use of non-steroidal anti inflammatory drugs (NSAIDs)--COX-2 inhibitors].

PMID- 12420602
TI  - [The cardiovascular safety of cyclooxygenase-2 (COX-2) inhibitors].

PMID- 12420603
TI  - [Chemotherapy in the elderly patient].

PMID- 12420604
TI  - The prevalence of autoimmune hepatitis in Hashimoto's thyroiditis in a Turkish
      population.
AB  - PURPOSE: Hashimoto's thyroiditis (HT) is an autoimmune thyroid disorder. Although
      its etiopathogenesis is obscure, there are many findings about the relationship
      between other autoimmune diseases and HT. The reason for this association is a
      topic of interest, but in our study we searched for the concurrence of autoimmune
      hepatitis (AH) with HT, which is a relatively new autoimmune disorder for this
      association. METHODS: Forty-six patients (44 female, 2 male) with HT were
      included in the study. Liver function tests, viral hepatitis markers,
      autoantibody panels, ultrasonography and liver biopsy were performed in certain
      cases. RESULTS: All patients were hepatitis B negative, only two patients were
      hepatitis C positive (4.3%). Smooth muscle antibody (SMA) was 21.7% positive, ANA
      was 26% positive, Anti-Liver kidney microsomal antibody-1 (LKM-1) was 13.4%
      positive. Anti-mitochondrial antibody (AMA) was not detected. Liver biopsy
      performed on six patients. Two of them had (+++) positive LKM-1 antibody titer,
      the other two had ANA and SMA positive results respectively and the last two had
      chronic hepatitis C infection. The pathology revealed AH in first four patients.
      We found four out of forty-six patients with HT as AH (8.69%). CONCLUSION: HT
      patients should be searched for autoimmune diseases and AH might be one of them.

PMID- 12420606
TI  - Influence of L-NAME and L-Arg on ischaemia-reperfusion induced gastric mucosa
      damage.
AB  - OBJECTIVE: The aim of this study was to investigate effects of L-NAME and L
      Arginine on gastric mucosal injury induced by ischaemia-reperfusion. METHODS: In
      the experiment, 20 New Zealand rabbits were used (2700-3000 g). Celiac artery was
      clamped for 30 min for ischaemia and then 60 min of reperfusion followed this
      after all rabbits were anaesthetized. In the Sham-control group (G 1, n = 5),
      laparotomy was performed, and the celiac artery was prepared without clipping.
      Group 2 (Untreated, n = 5) rabbits were only subjected to ischaemia-reperfusion.
      Group 3 (n = 5) rabbits had L-Arginine Methyl Ester (L-Arg) 3 mg/kg/min as i.v.
      infusion during the first 15 min of the reperfusion. Group 4 (n = 5) rabbits had
      a nitric oxide inhibitor NG-nitro-L-arginine methyl ester (L-NAME) 100
      micrograms/kg/min i.v. during the first 15 min of the reperfusion. After 60 min
      of reperfusion, the rabbits were killed, and their stomachs were removed for
      histopathologic evaluation and determination of malondialdehyde (MDA) level.
      RESULTS: After ischaemia-reperfusion, Untreated group had macroscopic necrosis
      involving 50 +/- 6% of total gastric mucosa area and deep mucosal necrosis
      involving 10 +/- 5% of mucosal strips. In the group treated with L-NAME,
      macroscopic mucosal necrosis involved 52 +/- 6% of total gastric mucosa area and
      deep mucosal necrosis involved 11 +/- 3% of mucosal strips (both p > 0.05 versus
      Untreated group). L-Arg treatment significantly reduced macroscopic mucosal
      necrosis area to 20 +/- 6% and deep mucosal necrosis to 3 +/- 1% (both p < 0.05
      versus Untreated group and L-NAME group). MDA level in the L-Arg group was
      significantly lower when compared to control and L-NAME group MDA level (p <
      0.05). CONCLUSION: These results suggest that NO increase induced by L-Arginine
      injection is involved in the protection of gastric mucosa after ischaemia
      reperfusion.

PMID- 12420605
TI  - Morphological characteristics of chronic hepatitis: a comparative study on
      Turkish patients.
AB  - BACKGROUND: Chronic hepatitis caused by hepatitis B and hepatitis C virus have
      characteristic histological features. We aimed to compare these histological
      features between two groups. METHODS: We worked on two groups each contains 50
      patients, that are serologically proven, have hepatitis B and hepatitis C. These
      patients were analysed according to the histological features which are more
      often seen in chronic hepatitis C. RESULTS: We found higher percentage of
      lymphoid follicles and aggregates in portal tracts, bile duct damage or loss and
      lymphoreticular reaction in patients with chronic hepatitis C than chronic
      hepatitis B (44%-12%, 96%-14%, 84%-40%, respectively). We recorded most patients
      with severe portal tract inflammation were in group of chronic hepatitis C (86%).
      Bile duct loss wasn't observed in any patients with chronic hepatitis B, while it
      was present in 44% of chronic hepatitis C group. There was no significant
      difference between two hepatitis groups with regard to fatty change. 13 out of 14
      patients, having all those above mentioned histological findings, diagnosed with
      chronic hepatitis C whereas only one patient had chronic hepatitis B.
      CONCLUSIONS: Aggregates and follicles forming portal inflammation,
      lymphoreticular reaction together with bile duct damage, especially with bile
      duct loss strongly indicates presence of chronic hepatitis C.

PMID- 12420607
TI  - Is surgical portosystemic shunt the treatment of choice in Budd-Chiari syndrome?

PMID- 12420608
TI  - Gastric cancer: the French survey.
AB  - Presentation of a multicentric retrospective french study concerning 4,655 cases
      of gastric cancer operated between 1980 and 1996. The mean age was 67.4 years old
      with a male predominance of 63.1%. Pains was the predominant presenting symptom
      (60%) followed by alteration of the general condition (44%) and anaemia (20%).
      35.5% of tumors were of distal, 18.8% of middle and 18.6% of proximal
      localisation. As regard cancer stages, 40% were of stage I,-II and 60% of stages
      III,-IV. Subtotal gastrectomy was realised in 44%, total radical gastrectomy in
      42.1% and other surgical procedures in 14% of cases (proximal gastric resection
      or atypical resection). D1 lymphadenectomy was associated in 58.4% and D2 in
      41.6%. Morbidity was of 23% and mortality of 11.9% which passed from 19% during
      the first (1980,-85) to 8% in the last interval of time (1990,-96). The 5 years
      survival was 41% in case of gastric resection. In univariate analysis the 5 years
      relative survival was better in female patients (44% at 5 years), in patients
      younger than 50 years old (46%), when pain was the only clinical symptom (52.7%),
      in middle and distal third localisation (47%), in case of subtotal distal
      resection (47%) and in less advanced stages (79% at 5 years for stage I cancer).
      In multivariate analysis the 5 years survival was essentially correlated to the
      stage of the tumor and no real prognosis improvement was shown during the period
      of the study.

PMID- 12420609
TI  - Radical resection for pancreatic cancer.
AB  - Ductal adenocarcinoma of the pancreas is still characterized by (1) poor
      prognosis after surgery and (2) extreme difficulty in early diagnosis, and we
      need a breakthrough. For the first problem, we have performed a wide range of
      lymphatic and connective tissue clearance (extended pancreatectomy) which has
      succeeded in improving the 5-year survival rate from 8% to 24% via decreasing the
      incidence of locoregional recurrence. When liver perfusion chemotherapy via the
      hepatic artery and the portal vein was added to the patients who had received
      extended pancreatectomy, the 5-year survival rate was further elevated to 40% via
      decreasing the incidence of hepatic metastasis. We conclude that pancreatic
      cancer should be treated by the better-balanced treatments between locoregional
      control and prevention of hepatic metastasis. For the second problem, we have
      more actively collected pancreatic juice to perform cytodiagnosis even though no
      obvious tumor was delineated by the conventional imaging diagnoses. When cancer
      cells were detected in the pancreatic juice, our method of intraoperative
      cytology was very useful in precisely locating the occult lesion indicating an
      appropriate range of pancreatectomy. The resected pancreas was proven to have
      included borderline malignancy and in situ or minimally-invasive carcinoma by the
      postoperative histology, and disease-free 5-year survival rate was 100%. In the
      future, we need to detect patients with a high risk of pancreatic cancer and
      develop a less-painful method to collect the pancreatic juice.

PMID- 12420610
TI  - Palliative treatment in "peri"-pancreatic carcinoma: stenting or surgical
      therapy?
AB  - Mostly, patients with peri-pancreatic cancer (including pancreatic, ampullary and
      distal bile duct tumors) are diagnosed in a stage in which curative resection is
      not possible. The median survival rate of patients with non resectable peri
      pancreatic cancer varies between 6 and 12 months. During this period palliative
      treatment is necessary, which should focus on major symptoms as obstructive
      jaundice, duodenal obstruction and pain. Controversy exists about how to provide
      optimal palliative treatment. Both surgical and non surgical palliative
      procedures relief obstructive jaundice. From early retrospective and prospective
      randomized studies it is known that in the early phase after treatment, more
      complications are found after surgical palliation, whereas in the late phase more
      complications are seen after endoscopic palliation. Because more recent studies
      clearly showed improved results after surgical palliation, current
      recommendations probably should be that patients with a suspected poor short-term
      survival (< 6 months) should be offered non surgical palliative therapy and those
      with a longer life expectancy may best be treated with bypass surgery.
      Unfortunately, valid criteria for estimating the remaining survival time are not
      available, except for the presence of metastases. The use of a prognostic score
      chart might assist in estimating the prognosis. Literature does not give
      sufficient information to make a well deliberated (evidence based) selection
      between the different types of surgical bypasses, but a choledochojejunostomy is
      generally preferred. After stenting, a correlation is found between survival and
      the development of duodenal obstruction, and between 9% and 21% of the patients
      who underwent a surgical biliary bypass without a prophylactic gastric bypass,
      will develop gastric outlet obstruction. Therefore, in patients with a relatively
      good prognosis it is recommended to perform routinely a double--biliary and
      gastric--bypass. Pain is a frequent symptom and is related with poor survival.
      Pain management aside from pain medication can be performed by means of a celiac
      plexus blockade or a thorascopic splanchnicectomy, and also radiotherapy seems to
      have a positive result on pain.

PMID- 12420611
TI  - Symptomatic ileocolic fistula as a complication of endoscopic laser therapy. A
      case report.
AB  - Since 1973, laser photo therapy is used in the treatment of gastrointestinal
      neoplasms as well as in various forms of intestinal hemorrhage. Complications
      including hemorrhage, stenosis and perforation are well documented but ileocolic
      fistulas after laser therapy for a villous adenoma have been rarely reported. We
      report the case of a patient with diarrhea related to an ileocecal fistula. This
      fistula appeared 1 year after laser therapy for a villous tumor of the cecum.

PMID- 12420612
TI  - Non-tumoral elevation of alpha-fetoprotein (AFP): a 10 year follow-up in two
      subjects.
AB  - Elevation of serum alpha-fetoprotein (AFP) in the absence of any liver disease or
      malignancy, likely of genetic origin, is an uncommon observation which may be the
      source of diagnostic difficulties in routine clinical practice, especially in
      cases without available familial data. Animal studies suggest that the anomaly
      may be related to a mutation located in a regulatory gene different from that
      mapped for AFP. The transmission pattern of the defect is unknown with a strong
      suggestion for an autosomal dominant inheritance. We report the cases of two
      patients in whom a stable elevation of unknown origin of the tumoral marker for
      up to 10 years, has been observed in the absence of any detectable liver and/or
      malignancy and in whom the lack of familial data was the source of diagnostic
      difficulties.

PMID- 12420613
TI  - [Molecular diagnosis of synovial sarcoma].

PMID- 12420614
TI  - [Fortunato Liceti: a turning point in the study of "monsters" and the beginning
      of modern teratology].

PMID- 12420615
TI  - [Denatured ethyl alcohol in histopathology].

PMID- 12420616
TI  - [The ThinPrep Pap test in population screening].
AB  - The ThinPrep technique has been applied to Pap tests in a population screening
      program in Imola, Italy. A significative decrease in the number of inadequate
      tests has been observed, while the distribution of the Bethesda diagnostic
      categories was not different in comparison to the previous year, when
      conventional Pap tests were used with the adoption of the ThinPrep technique, the
      productivity of the screening program increased without any need to modify the
      screening protocol.

PMID- 12420617
TI  - [Deflation of breast implants, pre-filled with saline or hydrogel. Results and
      analysis of 650 treated patients].
AB  - SUBJECT: The main mechanical side effect of saline or hydrogel filled implants is
      deflation. The aim of this study was to analyse the prosthetic deflation rate in
      the last 7 years in the plastic surgery unit of Toulouse. PATIENTS AND METHODS:
      We tracked 650 patients operated on between july 1993 and july 2000 (representing
      1117 primary implants) which we separated in two groups: the first group
      contained patients in need of breast reconstruction; the second group contained
      all the patients with implants placed for aesthetic or breast asymMetry reasons.
      For each of the two groups we determined the number and the type of implants, as
      well as the rate and the mean delay after which deflation occurred. RESULTS:
      During this period, we've determined that: rate of deflation of group 1
      (reconstruction) is highest than group 2 (aesthetic), despite sort of implant;
      rates of deflation of pre-filled hydrogel implants are highest than rates of
      deflation of pre-filled saline implants. DISCUSSION: Only a few series concerning
      implants deflation have been described in the literature. We can find a large
      difference in results which vary from 2 to 76%. We were surprised by the result
      of our series with a rate of deflation up to 15% with a medium follow-up 5 years
      in both groups and a mean delay before the fourth year. Deflation's factors are
      numerous: type of sterilisation, rippling, texture, valve's incompetence,
      prosthetic patch, guarantee control and iatrogenic causes. Because the silicone
      gel implants (the one uncomplicated by deflation) were taken off the french
      market, the saline implants tried to supplant them but without satisfactory
      results. CONCLUSIONS: With the unacceptable rate deflation of implants in our
      study, the return in the french market of silicone gel implants seems us an
      acceptable alternative.

PMID- 12420618
TI  - [Protocol of cleft lip and palate by Saint-Vincent-de-Paul team].
AB  - The treatment of cleft lip and palate at Saint-Vincent-de-Paul hospital is
      realized by a multidisciplinary team. The calendar of the primary treatment is
      adapted according to the eventual antenatal diagnosis: it may be early and in two
      sessions, or late at 4 months but in one session. The calendar of the secondary
      treatment is more classical.

PMID- 12420619
TI  - [Efficacy and tolerance of Algosteril (calcium alginate) versus Jelonet (paraffin
      gauze) in the treatment of scalp graft donor sites in children. Results of a
      randomized study].
AB  - Split skin graft is frequently needed in the treatment of burned patients. Scalp
      is often free of burns. Due to its good skin quality and important surface, scalp
      is a very interesting skin donor site, specially in case of children. A
      controlled, randomised clinical trial was carried out in 10 French Plastic
      Surgery or Burns Units. It assessed the efficacy and the acceptability of calcium
      alginate dressing (Algosteril) versus paraffin gauze dressing (Jelonet) in the
      treatment of scalp donor sites in children. 67 children (mean age 54 months)
      entered the study, 34 in the alginate group and 33 in the control group. Follow
      up visits were on day 2/d3, d5/d6, Day complete healing, d30 and d60 after
      surgery. The two groups were comparable on inclusion (demographic
      characteristics, burn nature and surface, donor site surface and thickness of
      split skin graft). The mean healing time was 10 and 11 days for Algosteril and
      Jelonet group respectively (ns). The quality of the newly formed tissue was
      estimated to permit a sooner skin reharvesting in the Algosteril group than in
      the control group (p = 0.003). Bleeding through dressing was significantly less
      important in the Algosteril group (p = 0.02). Changes were considered by
      investigators less painful with Algosteril on day complete healing (p = 0.0096).
      Hair growth is homogenous in both groups on day 30 and day 60 (ns). These results
      showed that scalp is a very interesting skin donor site and that Algosteril is of
      a real interest in donor site treatment.

PMID- 12420620
TI  - [The Marjolin's ulcer, destiny of a unstable scar. About 54 cases of burn's
      sequelae].
AB  - Through a study of 54 cases of malignant transformation on burn's scar, collected
      during a period of 8 years, the authors underline the particularities of this
      tumor, reported at the literature such as the preponderance of spinocellular
      carcinoma as histological type, the high rate of lymphatic metastasis and
      recurrence, and also the poor prognosis. In addition, the authors underline the
      non-rare character of this affection, whose incidence is correlated to the level
      of medication; it's occurring in younger patients, and its short delay of
      transformation. The treatment is based on prevention by a correct management of
      the initial burns, the cure of any instable scar, and a regular surveillance. The
      biopsy should be realised in case of suspicion of degeneration. The radical
      treatment must be initially aggressive, consisting on large excision associated
      eventually to radiotherapy. This treatment must be integrated in an elaborating
      therapeutic strategy, taking on consideration the evolutive potentiality of these
      tumors in order to improve chances of recovery and survival.

PMID- 12420621
TI  - [Reconstruction of large scalp and calvarium defects by using the semi-free
      latissimus dorsi flap associated with methylmethacrylate implant for
      cranioplasty].
AB  - The semi free latissimus dorsi flap is characterized by a temporary vascular
      anastomosis on a pedicle not belonging to the loco-regional anatomy of the skin
      defect; after a period of autonomy, the section of the flap pedicle is
      obligatory. Its advantage compared to the classic free flap is the great
      microsurgical security avoiding complex, and stressful supervision in the
      postoperative period. From June 1998 to January 2001, 7 patients ranging from 18
      to 65 years old and suffering from large scalp defects going between 20 x 13 cm
      and 27 x 18 cm have benefited from this surgical method. The etiology of these
      defects was: in 4 cases dermatofibrosarcoma protuberans involving the periost, in
      1 case destruction of the near entirety of the scalp and calvarium by electrical
      burn, in 1 case an instable scar of burn with osteomyelitis and in the last case
      an osteomyelitis on a frontal cranioplasty. Three stages have been used:--The
      thoraco-dorsal artery was anastomosed on the wrist to the radial artery in a
      termino-lateral way and the thoraco-dorsal vein to the superficiel radial vein in
      a termino-terminal way;--The flap was fixed to the forearm for 2 weeks, then, the
      debridement which has always exposed the dura was done; The flap was sutured to
      the defect after reconstruction of calvarial defect with the methylmetacrylate
      implant;--After 3 weeks the pedicle was sectioned and the flap tailored exactly
      to the defect. No postoperative complications were reported. With a mean follow
      up of 18 months, the scalp coverage was very satisfactory.

PMID- 12420622
TI  - [Foot reconstruction with the "bi-Masquelet" procedure].
AB  - A case of complex injury of the dorsal aspect of the foot is reported, the
      reconstruction of which combined two procedures described by A.C. Masquelet. The
      induced membrane and spongy autograft technique was used to reconstruct the
      metatarsal arch. The first stage was the insertion into the defect of a cement
      spacer which was responsible for the formation of a pseudosynovial membrane. The
      second stage was the reconstruction by a fresh autologous cancellous bone graft
      combined with hydroxyapatite. The membrane induced by the spacer prevents from
      the resorption of the graft and favors its vascularity and its corticalization.
      Soft tissue reconstruction was achieved by the mean of a supramalleolar island
      flap. Although bone healing occurred by the ninth month, the authors describe and
      discuss the possible mistakes when using this technique. Despite the many
      technical problems reported in this clinical case, bone reconstruction with the
      induced membrane and spongy autograft technique has proved to be easily handable
      and effective under adverse conditions.

PMID- 12420623
TI  - [Familial pyoderma gangrenosum following a mammoplasty reduction: a case report].
AB  - The authors report a case of familial pyoderma gangrenosum following a
      mammoplasty reduction. This disease should be known by all surgeons, because its
      occurrence may follow all surgical procedure. The only efficient treatment is
      based on steroids and large surgical excisions must be contraindicated.

PMID- 12420624
TI  - [Distal radial-ulnar arthrosis and radial-carpal arthrosis: evaluation on a
      population from the end of the 15th century to the beginning of the 18th
      century].
AB  - The authors report on a study on the wrists from a medieval population (end of
      the 15th-century, beginning of the 18th century). The distal radio-ulnar
      arthrosis and the radio-carpal arthrosis were assessed after a macroscopic
      examination of the wrist bones. Statistical treatment of the data led to
      correlations with age, sex and bilateral nature of injuries. The distal radio
      ulnar arthrosis has statistic correlation with age (P < 0.05). There is no
      relationship between sex and bilateral nature of injuries. For the radio-carpal
      arthrosis, injuries are often present for elderly woman (P < 0.01) and young man
      (P < 0.05). The bilateral nature of arthrosis increases with age (P < 0.05). The
      wrists which are damaged by the distal radio-ulnar arthrosis are often associated
      with radio-carpal injuries (P < 0.05). The absence of any obvious osseous
      traumatic aetiology suggests a bilateral ligamentous distension for women and
      elderly men. A traumatic ligament rupture can be incriminated for young men maybe
      related to repeated microtraumatic activities.

PMID- 12420626
TI  - [Emerging and reemerging infectious diseases].

PMID- 12420625
TI  - [Look and nasal ventilation].
AB  - Ophthalmic manifestations of nasal obstruction can involve palpebral, orbital and
      ophthalmic disturbances. They can be the consequence of: directly with the nasal
      obstruction because the orbital cavity drains partly in the nasal fossae: rings,
      lipoptosis, blepharochalasis, fat protrusions, aggravation of exophthalmy in
      Grave's disease, enophthalmia. Oral breathing: there are modifications in the
      shape of the palpebral fissure ("round eye") by stretching of the facial mask and
      modifications of the orbital rims ("sad eye") due to lack of naso-sinusal
      expansion, often associated to malocclusion, there is a biomechanical correlation
      between the dental occlusion and the orbital area because of the presence of the
      maxillary sinus. Every occlusal disorder have an influence on projections of the
      supra and infraorbital rims.

PMID- 12420627
TI  - [Appropriateness of emergency hospital admissions].
AB  - INTRODUCTION: The aim of this work is to know the proportion of inadequate urgent
      admissions in a general hospital. MATERIAL AND METHODS: A retrospective and
      descriptive study of patients admitted during 1,999 was performed. The
      Appropriatness Evaluation Protocol (AEP) was used in order to evaluate the
      appropriatness of the admissions. RESULTS: Eighteen admissions (4.5%) were
      inadecuated. There was a higher proportion of inappropriate admission (IA) when
      the physician responsible of the admission was a medical specialist (internal
      medicine, hematology or nephrology): odds ratio 5.3 in opposite to emergency
      physicians (p < 0.03). CONCLUSIONS: There was a low proportion of inadequate
      admissions (4.5%) and the risk of inappropriatness of the admission was major
      when it was ordered by a medical specialist.

PMID- 12420628
TI  - [Alkaline phosphatase isoenzymes in the serum of patients with renal
      insufficiency].
AB  - OBJECTIVE: The aim of this study was to test the utility of serum alkaline
      phosphatase isoenzymes determination from patients with renal insufficiency.
      MATERIAL AND METHODS: Serum levels of alkaline phosphatase isoenzymes were
      determined in a group of 58 patients: 22 of them suffering acute renal
      insufficiency (ARI) and 36 with chronic renal failure (CRF) undergoing regular
      hemodialysis, results obtained were compared from a population of 30 healthy
      adults. Intestinal, bone, liver, macromolecular and intestinal variant
      isoenzymes, were separated by electrophoresis on agarose gel and quantified using
      a densitometer. RESULTS: Were found a significant increase the total alkaline
      phosphatase activity in both pathologic groups (p < 0.05 in ARI and p < 0.01 in
      CRF). Isoenzymatic profiles showed: increase of the bone fraction (p < 0.05 in
      ARI and p < 0.001 in CRF), decrease of the liver isoenzyme (p < 0.001) in both
      groups, macromolecular fraction elevated in acute patients (p < 0.05) and a
      significant increase of the intestinal and intestinal variant isoenzyme in the
      chronic patients (p < 0.001). CONCLUSION: The renal insufficiency modified the
      normal distribution of alkaline phosphatase isoenzymes and the study of their
      serum levels could be an effective non-invasive marker, for the evaluation of
      bone disease and intestinal disorders associated with renal failure.

PMID- 12420629
TI  - [Prevalence of obesity in hospitalized internal medicine patients].
AB  - OBJECTIVE: We describe the weight's distribution in a sample of medical patients
      in hospital. We estimate the global prevalence and the presence between other
      different clinical variables. MATERIAL AND METHODS: A prevalence cross-sectional
      study was carried out. We determine weight, stature and several clinical
      variables in 101 patients admit in the internal medicine department of Juan Ramon
      Jimenez hospital in Huelva. The patients were admitted from 6th to 7th of june in
      2000. The Body Mass Index (BMI) > or = 30 Kg/m2 was used to define the obesity.
      RESULTS: The prevalence of obesity was 32.2% [0.236-0.416]. In the study we find
      an association with female (prevalente rate -PR- 3.22), HTA (PR 4.72), dislipemia
      (RP 4.40) and hyperuricacemia (RP 4.28). CONCLUSIONS: The prevalence of obesity
      in our patients was between 23.41%, it was greater than others estimations in
      general people. We find association with women and classic cardiovascular risk
      factors.

PMID- 12420630
TI  - [Primary intestinal T lymphoma: a report of two cases and a review of the
      literature].
AB  - Lymphomas of the gastrointestinal tract are the most common type of primary
      extranodal lymphomas and about 15-20% of these are primary intestinal lymphomas.
      They may be or B or T- cell. Intestinal T-cell lymphomas are much less common and
      they can be enteropathy-associated. This disease occurs in adults with abdominal
      pain often associated with intestinal perforation. The course is aggressive. The
      major problem is to distinguish this disease from a benign ulcer. Two cases with
      differents clinical and pathologic features are reported with a review in the
      literature of this uncommon entity.

PMID- 12420631
TI  - [Primary ciliary dyskinesia, presentation of an atypical case].
AB  - Primay ciliary dyskinesia is a rare autosomal recessive disorder, characterized
      by abnormal ciliary structure and function and chronic lung, sinus and middle ear
      disease. A 45-year-old man with a history of recurrent respiratory infections,
      which was developped in the adult age, and was presented with moderate clinical
      involvement, and spermatic hypomotility in seminogram. Diagnosis and differential
      diagnosis was based on the typical clinical picture and the electron
      microscopical demonstration of ultrastructural abnormalities. We found abnormal
      number of cilia on the bronchial mucosa cells and the ciliary structure was
      abnormal too. We observed abnormally short dynein arms and defective radial
      spokes.

PMID- 12420633
TI  - [Spinal pseudoarthrosis in ankylosing spondylitis].
AB  - Spinal pseudoarthrosis is an uncommon complication in patients with advanced
      ankylosing spondylitis which consists in destruction of the discovertebral
      junction. Two cases of spinal pseudoarthrosis at the thoracolumbar level after a
      spontaneous fall are reported. Because of the neural arch involvement and the
      spinal cord compression a stabilization was required. Different imaging
      techniques are complementaries in the study of this entity, conventional
      radiographs and computed tomography may depicte bone abnormalities, but magnetic
      resonance allows a correct evaluation of spinal cord and soft tissue involvement.

PMID- 12420632
TI  - [Pneumonia caused by Corynebacterium pseudodiphteriticum, an entity worth
      knowing].
AB  - Respiratory infections are challenging for clinicians and new microbes or those
      considered previously as normal flora or less virulent forms seen responsible for
      some cases. Thus, the case reported here is a nosocomial pneumonia caused by
      Corynebacterium pseudodiphteriticum in a man suffering chronic obstructive
      pulmonary disease and resolved with cefotaxime. This microorganism is part of the
      oropharingeal bacterial flora and is therefore associated mainly with respiratory
      disease an less commonly with endocarditis, prostheses or wound infections.
      Susceptibility testing found uniform susceptibility to b-lactamases,
      aminoglycosides, rifampin and tetracycline. Susceptibility to ciprofloxacine is
      variable and resistance to macrolides (erythromycin and clindamycin) was
      frequent.

PMID- 12420634
TI  - [Camptocormia: an infrequent muscular disease].
AB  - The camptocormia is an entity characterized by a kyphosis lumbar reductible in
      supine decubitus, associated to dysfunctions in computed tomography scans and
      histologics in the paravertebrals muscles of the lumbar segment. We contribute a
      new case corresponding to a 70 year-old woman with chronic lumbar pain and
      kyphosis dorsolumbar reductible, in who the on-line tomography showed compatible
      images with fatty degeneration and atrophy of the lumbar musculature, discoveries
      that were confirmed in the histologic study.

PMID- 12420635
TI  - [Infections by Arcanobacterium haemolyticum: an emerging pathogen].
AB  - Arcanobacterium haemolyticum is a grampositive rod wich belonged, until a short
      time ago, to Corynebacterium genus, and recently classified in a new genus, with
      only one specie. Human is the main reservoir. It has been isolated from the skin
      and pharinx of healthy individuals, but also it is cause of infection, specially
      pharingitis, in children, and chronic cutaneous ulcus, in diabetic patients. Less
      frequently, it is cause of osteomyelitis, meningitis, pneumonia, abscess,
      endocarditis and sepsis. Diagnosis is difficult because its double quality:
      comensal and pathogen. There are not established guidelines for the treatment of
      these infections, although most of isolated strains are susceptibles to
      penicillin, erythromicin, clindamycin and tetracycline. High doses of penicillin,
      with or without gentamicin, it is recommended for the treatment of deep
      infections.

PMID- 12420636
TI  - [P-glycoprotein, a membrane pump that represents a barrier to chemotherapy in
      cancer patients].
AB  - Multidrug resistance (MDR) in oncology is considered to be the main cause of
      chemotherapy failure in the treatment of patients with cancer. The resistance
      mechanism consists in decrease intracellular drug accumulation by P-glycoprotein
      (Gp-P) overexpression. This protein acts as a drug-extracting pump that needs
      energy in the process. The efflux takes place by mean of a pore in the cell
      membrane that consist in twelve segments. The activity of this pump is regulated
      by protein kinase C and shows homology with other transport systems. The analysis
      of the presence of Gp-P and the characterization of MDR phenotype in biopsy
      material could be important in the overcome of the resistance to cancer
      chemotherapy.

PMID- 12420637
TI  - [Piperacillin-tazobactam also at home].

PMID- 12420638
TI  - [Pulmonary hypoplasia: an infrequent disease in adults].

PMID- 12420639
TI  - [Solitary pancreatic metastasis occurring twenty years after nephrectomy for
      renal cell carcinoma].

PMID- 12420640
TI  - [Sternal metastasis of hepatocarcinoma].

PMID- 12420641
TI  - [Muscle infarction in patients with diabetes mellitus].

PMID- 12420642
TI  - [Charles Bonnet syndrome].

PMID- 12420643
TI  - [Enalapril induced cholestasic hepatitis].

PMID- 12420644
TI  - [Review articles should take into account the Spanish publications].

PMID- 12420645
TI  - [Methanol intoxication].

PMID- 12420646
TI  - [Myelodysplastic syndrome, diabetes insipidus, and progressive deficit of
      hypothalamic dysfunction].

PMID- 12420647
TI  - [Intraportal hydatidosis as manifestation of portal hypertension].

PMID- 12420648
TI  - Geriatric psychiatry: complex challenges, promising treatments.

PMID- 12420649
TI  - Cognitive pharmacotherapy of Alzheimer's disease and other dementias.
AB  - OBJECTIVE: The objective of this paper is to review the randomized controlled
      trials (RCTs) on the pharmacotherapy of Alzheimer's disease and other dementias
      and to provide evidence-based recommendations for treatment of the cognitive
      impairment associated with these disorders. METHOD: A Medline search was
      conducted for RCTs, using the following key words: Alzheimer's disease, dementia,
      therapy, cholinesterase inhibitor, donepezil, rivastigmine, and galantamine.
      Studies were critically appraised, followed by a review of published major
      clinical practice guidelines. Recommendations for treatment were made based on
      best available evidence. RESULTS: The pharmacotherapy of Alzheimer's disease
      should include the meticulous management of vascular risk factors (for example,
      hypertension, diabetes, cholesterol, and stroke prophylaxis) and consideration
      for supplementation with folate, vitamin B complex, and vitamin E. Patients
      should be offered at least 1 trial of a cholinesterase inhibitor, with the
      possibility of another trial if the first is poorly tolerated or ineffective.
      Patients with vascular dementia and dementia with Lewy bodies should also be
      offered treatment with cholinesterase inhibitors. At this time, we lack
      sufficient data to recommend the use of hormone replacement or antiinflammatory
      therapy for treatment of dementia as the primary indication. CONCLUSION:
      Reasonable evidence exists to provide recommendations for the pharmacotherapy of
      dementia. Treatment will likely result in modest but important benefits to
      patients, caregivers, and society.

PMID- 12420650
TI  - Brief screening tests for dementia.
AB  - OBJECTIVE: To compare brief dementia screening tests as candidates for routine
      use in primary care practice. METHOD: We selected screening tests that met 2
      criteria: 1) administration time of 10 minutes or less in studies including
      individuals with, and without, dementia; and 2) performance characteristics
      evaluated in at least 1 community or clinical sample of older adults. We compared
      tests for face validity, sensitivity, and specificity in a clearly defined
      subject sample; for vulnerability to sociodemographic biases unrelated to
      dementia; for direct comparison with an accepted standard; for acceptability to
      patients and doctors; and for brevity and ease of administration, scoring, and
      interpretation by nonspecialists. RESULTS: Thirteen instruments met our inclusion
      criteria. Very short tests (1 minute or less) proved unacceptable by several
      criteria. Standard instruments requiring more than 5 minutes to complete,
      including the best-studied Mini-Mental State Examination (MMSE), were found to be
      too long for routine application. Several failed other performance tests or could
      not be adequately assessed. Short tests taking between 2 and 5 minutes that can
      be administered by nonspecialists with little or no training and are relatively
      unbiased by language and education level appear to be superior to both shorter
      and longer instruments. CONCLUSIONS: Three tests showed the most promise for
      broad application in primary care settings: the Mini-Cog, the Memory Impairment
      Screen, and the General Practitioner Assessment of Cognition (GPCOG). Formal
      practice intervention trials are now needed to validate the utility of short
      screens with regard to implementation, effect on rates of diagnosis and treatment
      of dementia patients, and outcomes for patients, families, and health care
      systems.

PMID- 12420651
TI  - Effective use of electroconvulsive therapy in late-life depression.
AB  - OBJECTIVE: To review literature pertaining to the efficacy, safety, and
      tolerability of electroconvulsive therapy (ECT) in treating late-life depression.
      METHOD: We undertook a literature review with an emphasis on research studies
      published in the last 10 years. RESULTS: There is a positive association between
      advancing age and ECT efficacy. Age per se does not necessarily increase the risk
      of cognitive side effects from ECT, but this risk is increased by age-associated
      neurological conditions such as Alzheimer's dementia and cerebrovascular disease.
      With appropriate evaluation and monitoring, ECT can be used safely in patients of
      very advanced age and in those with serious medical conditions. Several technical
      factors, including dose of electricity relative to a patient's seizure threshold,
      position of electrodes, frequency of administration, and total number of
      treatments, have an impact on the efficacy and cognitive side effects of ECT and
      need to be taken into account when administering ECT. Naturalistic studies have
      found that 50% of more of patients have a relapse of depression within 6 to 12
      months of discontinuing acute ECT. CONCLUSIONS: In recent years, there has been
      substantial progress in our understanding of the effect of technical factors on
      the efficacy and cognitive side effects of ECT. When administered in an optimal
      manner, ECT is a safe, well-tolerated, and effective treatment in older patients.
      Relapse of depression after response to ECT remains a significant problem, and
      there is a need for further research into the prediction and prevention of post
      ECT relapse.

PMID- 12420652
TI  - Are leptin and cytokines involved in body weight gain during treatment with
      antipsychotic drugs?
AB  - OBJECTIVE: To critically review published literature on the causal association
      between leptin, cytokines, and excessive body weight gain (BWG) induced by
      antipsychotic drugs (APs). METHODS: We completed a Medline search using the words
      leptin, cytokines, antipsychotic drugs, neuroleptics, psychotropic drugs, weight
      gain, and obesity. We also included our empirical research on this topic in the
      discussion. We examined the relation between leptin, cytokines (mainly tumour
      necrosis factor alpha [TNF-alpha] and its soluble receptors), and AP-induced BWG,
      using the biological sciences' current theories of causality. RESULTS: In the
      general field of weight regulation, there is scarce experimental evidence that
      leptin or TNF-alpha by themselves can induce obesity. Serum levels of leptin and
      TNF-alpha rather increase simultaneously as BWG occurs. This has also been
      reported during AP-induced BWG, with the equivocal exception of a study with
      clozapine. Some researchers have suggested that the absence of the expected
      correlation between leptin and body mass index (BMI) or serum insulin levels, and
      the lack of sex-related differences in leptin levels in AP-treated patients, may
      point to a causal relation. This contention requires more experimental support.
      In addition, future clinical studies must carefully control for sex and BMI.
      CONCLUSIONS: No conclusive evidence has been provided that leptin or TNF-alpha
      may induce obesity either in drug-free subjects or in AP-treated patients. In
      most cases, the elevated serum levels of these hormones appear to be a
      consequence rather than a cause of obesity. That does not mean that such an
      elevation is innocuous, since it may impair blood pressure and also carbohydrate
      and lipid metabolism regulation. Hence, all efforts should be made to prevent or
      attenuate BWG during treatment with APs.

PMID- 12420653
TI  - Strategies of collaboration between general practitioners and psychiatrists: a
      survey of practitioners' opinions and characteristics.
AB  - BACKGROUND: The description of collaboration models and the key underlying
      principles provide important information for designing services. However, to
      apply this broad corpus of information to clinical services and policymaking, we
      need to know which key principles (or strategies) of collaboration are the most
      accepted by local physicians. METHOD: In this context, we designed a survey that
      included 2 objectives: 1) to collect the opinions of practising general
      practitioners (GPs) and psychiatrists in Montreal with respect to strategies for
      improving collaboration between these 2 groups and 2) to identify demographic and
      practice characteristics of those physicians associated with the acceptance of
      such strategies. We designed a questionnaire to specifically elicit physicians'
      opinions about strategies involving communication, continuing medical education
      (CME) for GPs in psychiatry, and access to consulting psychiatrists, as well as
      to identify the profiles of the respondent physicians. We mailed the
      questionnaire to 203 GPs and 203 psychiatrists who were randomly selected.
      RESULTS: The response rate was 86% for GPs and 87% for psychiatrists. Physicians
      expressed favourable opinions about most strategies involving 1) the improvement
      of communication and 2) the organization of CME activities concerning GP
      practices in the field of psychiatry. On the other hand, they did not indicate
      acceptance of the strategies involving on-site collaboration between GPs and
      psychiatrists. Physician age, sex, place of practice, type of practice (such as
      seeing patients with or without appointments), and responsibility for
      administrative duties associated significantly with the degree of acceptance of
      the proposed strategies. CONCLUSION: Communication and CME strategies for GPs in
      psychiatry can be an option to improve collaboration between GPs and
      psychiatrists. However, strategies of access to consulting psychiatrists require
      significant alterations to established clinical routines and professional roles.

PMID- 12420654
TI  - A test of the phase model of psychotherapy change.
AB  - OBJECTIVE: A comparative trial of 2 forms (interpretive and supportive) of short
      term, time-limited individual (STI) therapy provided data that were used to test
      the propositions of the Howard and others phase model of psychotherapy change.
      METHOD: Patients completed the Integra Outpatient Tracking Assessment Form on 5
      occasions during the 20-session treatments. The measure assesses 3 dimensions:
      subjective well-being, current symptoms, and current life dysfunction. Howard and
      others regard these as dimensions that represent successive phases in the therapy
      change process (that is, well-being improves first, followed by resolution of
      symptoms, and finally by change in long-standing life dysfunction). We conducted
      a test of their model, using their approach to data analysis. RESULTS: The
      comparative trial data provided no support for the phase model. CONCLUSIONS:
      Possible explanations for the absence of confirmatory findings are considered.

PMID- 12420655
TI  - Lamotrigine use in geriatric patients with bipolar depression.
AB  - OBJECTIVE: To study the effectiveness of adding lamotrigine to the treatment of
      inpatient geriatric patients with bipolar disorder (BD) who were in the depressed
      phase and had been on lithium and valproate for at least 3 months. METHOD:
      Lamotrigine was started at 25 mg given at bedtime, with weekly incremental
      increases of 12.5 mg daily until a total dosage of either 75 mg or 100 mg was
      obtained. Improvement was measured by clinical interview and Hamilton Depression
      Rating Scale (HDRS) scores. Patients were reassessed at 6 weeks, and if their
      HDRS score had decreased by at least 50%, they were considered to have improved.
      RESULTS: The study group comprised 5 women with an average age of 71.5 years
      (range 65 to 85). Four had rapid-cycling BD, and 1 had mixed BD. All patients had
      early age of onset, as judged by their first contact with a psychiatrist or their
      first hospitalization. The average initial HDRS score was 27 (range 20 to 35). Of
      the patients, 3 out of the 5 had remission of symptoms, as judged by clinical
      interview and reduction of their HDRS score by 50%. At 3 months follow-up, these
      3 patients had not required rehospitalization and were doing well. Lamotrigine
      was well tolerated, and none of the patients developed a rash. One patient did
      develop coarse hand tremor that improved when the lamotrigine dosage was
      decreased. CONCLUSIONS: Lamotrigine in conjunction with lithium and valproate may
      be effective in treating geriatric patients with BD and depression.

PMID- 12420656
TI  - Dissolution profile, tolerability, and acceptability of the orally disintegrating
      olanzapine tablet in patients with schizophrenia.
AB  - OBJECTIVE: This pilot study investigates the dissolution profile, tolerability,
      and acceptability of an orally disintegrating olanzapine tablet in patients with
      schizophrenia. METHOD: Eleven patients with schizophrenia stabilized on oral
      olanzapine (mean dosage 12.7 mg daily [SD5.2]) were given an orally
      disintegrating olanzapine tablet, rather than their usual tablet, daily for 7
      days. At each visit, visual assessments were made for elapsed time to initial
      disintegration (every 15 seconds) and complete disintegration (every 1 minute).
      At the end of the study, patients completed a drug-acceptance questionnaire.
      RESULTS: The mean time to initial disintegration was 15.78 seconds, and mean time
      to complete disintegration was 0.97 minutes. All patients found the orally
      disintegrating tablet acceptable and expressed positive comments. Nonserious
      clinically significant adverse events, asthenia, purpuric rash, headache,
      depression, and insomnia (preexisting, except for asthenia and insomnia) were
      reported in 3 patients. CONCLUSION: The orally disintegrating olanzapine tablet
      disintegrates rapidly and is a well-tolerated and acceptable alternative to
      standard olanzapine tablets in patients with schizophrenia.

PMID- 12420657
TI  - Progress against major depression in Canada.
AB  - BACKGROUND: Generally, public health strategies for major depression have focused
      on case-finding, public and professional education, and disease-management
      strategies. In principle, increased rates of treatment utilization and improved
      treatment outcomes should lead to improved mental health at the population level.
      Progress of this sort, however, has been difficult to confirm. METHODS: The
      National Population Health Survey (NPHS) is a large-scale longitudinal study of a
      representative sample drawn from the Canadian population. To date, Statistics
      Canada has released data from 3 NPHS cycles: 1994-1995, 1996-1997, and 1998-1999.
      Treatment utilization and major depression measures were employed in the NPHS
      survey, providing a unique source of longitudinal Canadian data. In this study,
      major depression point prevalence (defined using a predictive instrument for
      annual major depressive episode [MDE] prevalence and responses from a distress
      scale) and associated treatment utilization were evaluated over time. RESULTS:
      Between 1994-1995 and 1995-1996, the proportion of persons with depression
      receiving antidepressant treatment increased dramatically, from 18.2% (12.3% to
      22.1%) in 1994-1995 to 32.6% (23.0% to 42.2%) in 1998-1999. Point prevalence of
      major depression was 2.4%, 1.8%, and 1.9% in the 3 NPHS iterations. CONCLUSIONS:
      Data from the NPHS suggest public health progress against major depression in
      Canada. More people with major depression in Canada are receiving treatment, and
      these changes may have been associated with improved population health status.
      However, both random variation and extraneous societal factors could account for
      the observed trends in prevalence. It is impossible to relate changes in
      utilization directly to population health status using the NPHS data.

PMID- 12420658
TI  - Re: Atypical antipsychotic use in treating adolescents and young adults with
      developmental disabilities.

PMID- 12420659
TI  - Evidence supports validity of seasonal affective disorder.

PMID- 12420660
TI  - Seasonal affective disorder: the latitude hypothesis revisited.

PMID- 12420661
TI  - Treatment of posttraumatic stress disorder with tiagabine.

PMID- 12420662
TI  - Assessing pain tolerance in a patient with acute psychosis.

PMID- 12420663
TI  - Musical hallucinations during a treatment with benzodiazepine.

PMID- 12420664
TI  - Bupropion-methylphenidate combination and grand mal seizures.

PMID- 12420665
TI  - The association of depressed affect and stroke in institutionalized Canadians.

PMID- 12420666
TI  - Quetiapine and neuroleptic malignant syndrome.

PMID- 12420667
TI  - [Serial assessment of right ventricular function in the acute and convalescent
      stages after successful reperfusion: relationship to infarct-related coronary
      artery].
AB  - OBJECTIVES: To elucidate the relationship between the infarct-related coronary
      artery and the right ventricular function before and after successful
      recanalization. METHODS: Hemodynamics and right ventricular function were
      measured using a REF-1 thermodilution catheter before and shortly after
      recanalization and during the convalescent stage in 35 patients, 17 with
      anteroseptal and 18 with inferior acute myocardial infarction. RESULTS: Pulmonary
      arterial pressure significantly decreased in both anteroseptal and inferior
      myocardial infarction patients after recanalization. Right ventricular volume
      index in patients with anteroseptal myocardial infarction increased after
      recanalization, but again decreased during convalescence. The right ventricle
      became enlarged in patients with inferior myocardial infarction to maintain the
      right ventricular stroke volume constant. Right ventricular ejection fraction
      (RVEF) did not significantly change in patients with inferior myocardial
      infarction during convalescence (38 +/- 13%, 38 +/- 13%, 46 +/- 9%), whereas RVEF
      in patients with anteroseptal myocardial infarction temporarily decreased after
      recanalization, and then increased during convalescence (37 +/- 10%, 31 +/- 12%,
      41 +/- 7%). Patients with inferior myocardial infarction were divided into two
      groups, patients with increased RVEF (n = 6) and decreased RVEF (n = 12) shortly
      after recanalization. Patients with increased RVEF showed significantly improved
      RVEF during convalescence (49 +/- 7% vs 37 +/- 6%, p < 0.05). The increase in
      RVEF shortly after recanalization in patients with inferior myocardial infarction
      was an independent factor for predicting RVEF during convalescence. CONCLUSIONS:
      Patients with anteroseptal myocardial infarction showed a different pattern of
      change in the right ventricular function during the acute and convalescent
      stages. An early change in RVEF in patients with inferior myocardial infarction
      can predict RVEF in the convalescent stage.

PMID- 12420668
TI  - Myocardial enhancement on magnetic resonance imaging with gadolinium
      diethylenetriamine pentaacetic acid and improvement of left ventricular function
      in patients with dilated cardiomyopathy.
AB  - OBJECTIVES: This study evaluated the significance of myocardial gadolinium
      diethylenetriamine pentaacetic acid (Gd-DTPA) enhancement on magnetic resonance
      imaging for the improvement of left ventricular function in patients with dilated
      cardiomyopathy. METHODS: Twenty-seven patients with dilated cardiomyopathy (mean
      age 59 +/- 11 years) were studied. The magnitude of myocardial Gd-DTPA
      enhancement was quantitatively assessed using signal intensity ratio and compared
      to changes in left ventricular function and adverse cardiac events during a
      relatively long follow-up period. RESULTS: Regional high signal intensity ratio,
      defined as > or = mean + 2SD in seven normal subjects, was found in 14 patients:
      in three or more regions out of five myocardial regions analyzed in six patients
      (extensive enhancement) and in only one or two regions in eight patients (limited
      enhancement). The remaining 13 patients had no high signal ratio in any of the
      five regions analyzed (no enhancement). During the follow-up period of 3.9 +/-
      1.9 years, four patients died of cardiac causes. The incidence of cardiac death
      was 33.3% in patients with extensive enhancement, 12.5% in those with limited
      enhancement and 7.7% in those without enhancement, but there was no statistical
      difference. Mild improvement in fractional shortening was observed in patients
      without enhancement during the follow-up (19 +/- 4%-->27 +/- 10%, p = 0.03).
      CONCLUSIONS: Evaluation of myocardial Gd-DTPA enhancement on magnetic resonance
      imaging may provide useful prognostic information for patients with dilated
      cardiomyopathy.

PMID- 12420669
TI  - [Clinical evaluation of the cause of left ventricular dysfunction in type 2
      diabetes without significant cardiac disease].
AB  - OBJECTIVES: The relationship between left ventricular dysfunction and
      hypertension or proteinuria was evaluated in type 2 diabetic patients without
      significant cardiac disease to investigate the cause of diabetic cardiac
      dysfunction. METHODS: Twenty-one patients with type 2 diabetes mellitus (mean age
      63.8 +/- 7.4 years) underwent left ventriculography and Doppler echocardiography
      to calculate the ejection fraction and E/A ratio (E/A). RESULTS: Thirteen
      patients had hypertension (61.9%) and six patients had proteinuria (28.6%). The
      E/A was 0.82 +/- 0.21 in all patients. The E/A in patients with hypertension or
      proteinuria was significantly less than in those without these diseases (0.74 +/-
      0.18 vs 0.97 +/- 0.18, p = 0.011; 0.65 +/- 0.10 vs 0.89 +/- 0.20, p = 0.010,
      respectively). The ejection fraction was 73.3 +/- 7.2% in all patients. The
      ejection fraction in patients with proteinuria was significantly less than in
      those without proteinuria (67.6 +/- 10.0% vs 75.5 +/- 4.4%, p = 0.019), but there
      was no significant difference in ejection fraction between patients with and
      without hypertension. The duration of diabetes was significantly related to the
      ejection fraction (r = -0.436, p = 0.048) but not to the E/A. CONCLUSIONS: In
      patients with type 2 diabetes without significant cardiac disease, left
      ventricular diastolic function may be related to both hypertension and
      proteinuria and left ventricular systolic function may be related to proteinuria
      and duration of diabetes. Therefore, in addition to hypertension, complications
      of nephropathy or long duration of diabetes may be related to the cause of the
      diabetic cardiac dysfunction.

PMID- 12420670
TI  - [Headache due to nitroglycerin administration and its clinical significance].
AB  - OBJECTIVES: This study assessed the side effects of nitroglycerin administration
      and their clinical significance. METHODS: Adverse reactions associated with
      sublingual nitroglycerin administration were investigated in 103 patients, 71 men
      and 32 women (mean age 56 +/- 11 years), 32 patients with coronary artery
      stenosis and 71 without coronary artery stenosis. RESULTS: Fifty-one percent of
      patients experienced headache and 30% experienced other adverse reactions,
      whereas 19% experienced no adverse reactions. The relationship was investigated
      between headache, the most common adverse reaction, and the following eight
      clinical background factors: coronary angiographic findings, sex, age,
      hyperlipidemia, hypertension, diabetes mellitus, smoking and drinking. Multiple
      regression analysis was conducted by treating sublingual nitroglycerin-induced
      headache as an object variable and the clinical background factors as explanatory
      variables. Statistically, the onset of headache correlated most closely to
      coronary angiographic findings, followed by smoking, hypertension, diabetes
      mellitus and drinking. The first four factors suppressed the onset of headache,
      whereas drinking facilitated the onset of headache. CONCLUSIONS: There is a close
      relationship between the onset of headache following sublingual nitroglycerin
      administration and coronary angiographic findings. Sublingual nitroglycerin
      induced headache as a predictor of coronary angiographic findings has a
      sensitivity and specificity of 81% and 66%, respectively, for patients without
      coronary artery stenosis based on the absence of headache.

PMID- 12420671
TI  - [Sigmoid shaped ventricular septum causing hemodynamic deterioration during
      lumbar anesthesia: a case report].
AB  - A 73-year-old woman with a left femoral neck fracture underwent an operation for
      femoral caput replacement. Twenty-five minutes after induction of spinal
      anesthesia, ST depression emerged followed by shock. Although the ST depression
      indicated an ischemic event, Levine grade IV systolic murmur was noticed at the
      aortic valve area. Echocardiography revealed narrowing of the left ventricular
      outflow tract with a pressure gradient of 170 mmHg. Rapid fluid infusion (1,000
      ml) stabilized her blood pressure and the patient recovered without adverse
      sequelae. Echocardiography and magnetic resonance imaging suggested the presence
      of sigmoid shaped ventricular septum rather than obstructive hypertrophic
      cardiomyopathy. There was no significant pressure gradient at rest. Sigmoid
      shaped ventricular septum is usually considered as a normal aging process and has
      little clinical importance, but several cases associated with outflow obstruction
      have been reported. As the patient had no abnormal findings on
      electrocardiography or chest radiography and had no abnormal symptom on physical
      examination, the sequelae were impossible to predict.

PMID- 12420672
TI  - [Prolonged deep vein thrombosis after radical prostatectomy].

PMID- 12420673
TI  - Can we become a "ministry engaged"?

PMID- 12420674
TI  - Breaking through the ceiling at CHI.

PMID- 12420675
TI  - Literacy issues in patient care.

PMID- 12420676
TI  - Trustees and canon law. An increasingly lay leadership in Catholic health care
      must remember its responsibilities to the church.

PMID- 12420677
TI  - Toward a theology of wellness. Health, in the Judeo-Christian tradition, is
      understood holistically and connected to the state of one's relationship to God.

PMID- 12420678
TI  - The physician leader in health care. What qualities does a doctor need to be an
      effective organizational leader?

PMID- 12420679
TI  - Assessing medical error in health care. Developing a "culture of safety".

PMID- 12420680
TI  - Part Six of the directives. Preserving integrity in partnerships directives
      requires an objective moral analysis of cooperative arrangements.

PMID- 12420681
TI  - Responsibility and cooperation. Evaluating partnerships among health care
      providers.

PMID- 12420682
TI  - Catholic health care and sterilization. The "principle of cooperation" provides
      the necessary ethical guidelines.

PMID- 12420683
TI  - Institutional cooperation: the ERDs. This principle of cooperation can guide
      collaboration with other-than-Catholic partners.

PMID- 12420684
TI  - Treasure chest or Pandora's box?

PMID- 12420685
TI  - Researchers race for Alzheimer's cure.

PMID- 12420686
TI  - Getting real about risk management.

PMID- 12420687
TI  - Study views visiting patterns.

PMID- 12420688
TI  - Drawing a blueprint for succession.

PMID- 12420689
TI  - Risks of claims-made insurance.

PMID- 12420690
TI  - Caring for multiple medical problems. Increasingly, cardiologists must deal with
      more than heart disease.

PMID- 12420691
TI  - Safe treatment for depression after heart attack.

PMID- 12420693
TI  - Medicare to cover new "super stents" if the FDA approves them.

PMID- 12420692
TI  - Miami police handle arrests with sirens, radios--and defibrillators.

PMID- 12420694
TI  - The next generation of stents. Thinner stents in the devices may be easier on
      vessel walls.

PMID- 12420695
TI  - Protecting the heart's protective inner lining. When bacteria of fungi breach a
      defensive coating of cells, doctors today can fight back.

PMID- 12420696
TI  - Double-duty drugs vs. strokes. Serendipitous benefits from medications are saving
      lives.

PMID- 12420698
TI  - I have just been diagnosed with an overactive thyroid. What are the risks to my
      heart?

PMID- 12420697
TI  - I have arthritis and take ibuprofen. Can ibuprofen cause heart failure?

PMID- 12420699
TI  - I have congested heart failure and I was recently diagnosed with sleep apnea. Are
      the two connected?

PMID- 12420700
TI  - cDNA cloning, sequencing, and differential expression of a heart-type fatty acid
      binding protein in the mummichog (Fundulus heteroclitus).
AB  - A heart fatty acid-binding protein (H-FABP) cDNA was isolated from the liver of
      the mummichog (Fundulus heteroclitus) and the complete cDNA sequence and
      predicted amino acid sequence was determined. This cDNA binds to a mRNA product
      of 0.95 kb with the highest level of RNA expression in the male liver, gills, and
      gonads. Exposure of mummichogs to the polycyclic aromatic hydrocarbon (PAH)
      pyrene significantly down-regulated H-FABP expression at the highest
      concentration. This study provides evidence that environmentally relevant
      toxicants can modulate H-FABP expression.

PMID- 12420701
TI  - Correlates of exercise adherence in an African American church community.
AB  - This study identified correlates of attendance to a community-based exercise
      program in an African American church congregation. After medical clearance, 48
      participants completed measures of social support, health-related quality of
      life, depression, exercise self-efficacy, and exercise motivation and then
      participated in an exercise program for 6 months (attendance rate = 27%). Age, a
      sense of affiliation as a motivator to exercise, and weekly caloric expenditure
      derived from yard work were positively associated with program attendance, and
      full- or part-time employment was negatively associated with attendance. The
      authors concluded that exercise adherence is a complicated phenomenon that is
      influenced by a variety of environmental, personal, and social factors. Social
      factors, in particular, may be important in promoting adherence to an exercise
      program in African Americans.

PMID- 12420702
TI  - Role of S-adenosyl-L-methionine in the treatment of depression: a review of the
      evidence.
AB  - Major depression remains difficult to treat, despite the wide array of registered
      antidepressants available. In recent years there has been a surge in the
      popularity of natural or alternative medications. Despite this growing
      popularity, there is limited evidence for the effectiveness of many of these
      natural treatments. S-adenosyl-L-methionine (SAMe) is one of the better studied
      of the natural remedies. SAMe is a methyl donor and is involved in the synthesis
      of various neurotransmitters in the brain. Derived from the amino acid L
      methionine through a metabolic pathway called the one-carbon cycle, SAMe has been
      postulated to have antidepressant properties. A small number of clinical trials
      with parenteral or oral SAMe have shown that, at doses of 200-1600 mg/d, SAMe is
      superior to placebo and is as effective as tricyclic antidepressants in
      alleviating depression, although some individuals may require higher doses. SAMe
      may have a faster onset of action than do conventional antidepressants and may
      potentiate the effect of tricyclic antidepressants. SAMe may also protect against
      the deleterious effects of Alzheimer disease. SAMe is well tolerated and
      relatively free of adverse effects, although some cases of mania have been
      reported in bipolar patients. Overall, SAMe appears to be safe and effective in
      the treatment of depression, but more research is needed to determine optimal
      doses. Head-to-head comparisons with newer antidepressants should help to clarify
      SAMe's place in the psychopharmacologic armamentarium.

PMID- 12420703
TI  - Mycotic cerebral vasculitis in a paediatric cardiac transplant patient excludes
      misadventure.
AB  - We present the case of a 10-year-old girl with cardiomyopathy who received a
      heart transplant. Due to organ rejection, the dosage of immunosuppressive agents
      was increased postoperatively. The patient complained of intermittent headaches
      in the following days and developed a haemorrhagic necrosis of the left thalamus.
      A week later, an oral dose of cyclosporin A was accidentally given intravenously,
      and 2 weeks later a recurrent subarachnoid haemorrhage of unknown origin was
      diagnosed. The clinical course was then characterised by progressive
      deterioration resulting in coma, fluctuating brain stem symptoms and the
      development of a massive cerebral oedema with subsequent brain death. A coroner's
      autopsy was instigated to investigate a claim of medical misadventure.
      Neuropathological investigations found a focal infiltration of fungal hyphae in
      the left posterior cerebral artery resulting in necrosis of the vascular wall and
      thus explaining the source of the recurrent subarachnoid haemorrhage which
      eventually resulted in the girl's death. Medical misadventure due to the
      administration of cyclosporin was not directly responsible for the death of this
      patient. This case illustrates that it is of paramount importance to copiously
      sample and investigate the basal cerebral arteries in cases of subarachnoid
      haemorrhage of unknown origin, in particular in a medico-legal context.

PMID- 12420704
TI  - JC virus genotyping offers a new means of tracing the origins of unidentified
      cadavers.
AB  - There has been no reliable means of tracing the origins of unidentified cadavers
      but the recent finding that JC virus (JCV) can serve as a means of elucidating
      human migrations suggested that this virus may also be useful to trace the
      origins of unidentified cadavers. DNA samples extracted from renal tissue and
      urine were used as the template for PCR amplification of a 610 bp region (IG
      region) of the viral genome. We detected JCV DNA in 45% of the renal samples and
      in 33% of the urine samples and was detectable even 10 days after death. The
      sequences of the amplified IG regions could be used to determine the genotypes.
      We conclude that the JC virus genotype is a new marker useful for tracing the
      origins of unidentified cadavers.

PMID- 12420705
TI  - Allele frequency data for 16 STR loci in the Vietnamese population.
AB  - The short tandem repeat systems ACTBP2, D3S1358, TH01, D21S11, D18S51, Penta E,
      D5S818, D13S317, D7S820, D16S539, CSF1PO, Penta D, VWA, D8S1179, TPOX and FGA
      were studied in a population sample from Vietnam (178 individuals, mainly from
      the Hanoi area). The 16 loci met Hardy-Weinberg expectations and possess a
      combined power of discrimination greater than 0.9999999999999999998 and a
      combined power of exclusion greater than 0.99999994 in this Vietnamese
      population.

PMID- 12420706
TI  - Whiplash sine whiplash.

PMID- 12420707
TI  - Placebo whiplash data need cautious interpretation.

PMID- 12420708
TI  - MRI in isolated sixth nerve palsies.

PMID- 12420709
TI  - Surprising article in Neuroradiology.

PMID- 12420710
TI  - [The Internet and self treatment: how to put them together?].
AB  - Information and communication technology through the Internet has brought about
      elements/processes/objects produced in order to be used by humane bio-sciences
      related to bio-medicine activities, such as public health. ICT has been covering
      larger domains of medical information, producing fields of specialization known
      as telemedicine, cyber-medicine and consumers' health information. It tries to
      meet consumers' need of information, by apparently creating something similar to
      self-treatment with some expertise. This way, consumers would be able to make
      more 'educated' decisions in terms of their acquisitions in the area of health.
      In order to reach this objective, computer programs have come up with health
      decision aids software. It is clear the mingling of three powers that participate
      in the mechanisms that organize present day life - instrumental reasoning and its
      technical production, the power created by the union of institutions and
      ideologies, and the belief in the myths, symbols and rites of scientific
      technology. As a possible result, we may have the colonization of societies by
      authorities that produce specialized knowledge, by professionals that apply such
      knowledge to produce technological items or pack them in technological cases, by
      industrial systems and by information, distribution and commercial nets.

PMID- 12420711
TI  - Neurocysticercosis and the global world.

PMID- 12420712
TI  - MR brain changes following terpentine oil ingestion.

PMID- 12420713
TI  - Severe acute cerebrovascular disease revealing hepatitis C virus infection:
      effectiveness of alpha-interferon.

PMID- 12420714
TI  - Quetiapine in Huntington's disease: a first case report.

PMID- 12420715
TI  - Elevated striatal dopamine transporter in a drug naive patient with Tourette
      syndrome and attention deficit/ hyperactivity disorder: positive effect of
      methylphenidate.

PMID- 12420716
TI  - Internuclear ophthalmoplegia as the first sign of neuroborreliosis.

PMID- 12420717
TI  - Remission of a CNS inflammatory disease accompanied by newly developed ANA and
      arthropathy during treatment with IFN-beta.

PMID- 12420718
TI  - Cerebral venous thrombosis: correlation between recanalization and clinical
      outcome--a long-term follow-up of 40 patients.

PMID- 12420719
TI  - Assessment of CSF homovanillic acid levels distinguishes dementia with Lewy
      bodies from Alzheimer's disease.

PMID- 12420720
TI  - Exclusion of the Nurr1 gene in autosomal recessive Parkinson's disease.

PMID- 12420722
TI  - Hans Berger (1873-1941).

PMID- 12420721
TI  - [Health concepts in current science-oriented discourse].
AB  - This article analyzes health as a concept in some science-oriented discourses by
      representative authors of functional sociology, anthropology and epistemology, by
      focusing their notions of illness and procedures. In the field of sociology, the
      ideas of normality, labeling, and deviation from labeling patterns stand out.
      Additionally, we present the main health models in North American health
      anthropology and evaluate the proposition of a new perspective that intends to
      overcome the duality between culture and society - the theory of signal, meaning
      and practice systems. We also analyze the Canguilhemian difference between
      normality and health, as well as the notion of health as normative capacity.
      Finally, we propose the distinctive concepts of primary, secondary and tertiary
      health as the first step of a theoretical construction that can guide health
      policies and social procedures based on a positive notion of health.

PMID- 12420723
TI  - HIV-1 associated encephalopathy and myelopathy.
AB  - HIV-1-associated encephalopathy (HIVE) remains an important manifestation of
      advanced HIV infection despite recent advances in antiretroviral therapy. Special
      pharmacological and virological conditions predominate in the central nervous
      system (CNS). HIVE is characterized by "subcortical" dementia which becomes
      manifest as psychomotors lowing as well as memory and concentration deficits.
      Deficits of central motor function are an invariable finding. Enhanced viral
      replication in immunocompetent CNS cells is believed to be the pathogenic basis
      of CNS disease. This process leads to neurotoxic effects elicited directly by
      viral products as well as indirectly by the immune response to the virus. HIV-1
      associated myelopathy (HIVM) is the other CNS manifestion of advanced HIV-1
      infection. The present consensus paper recommends diagnostic and therapeutic
      procedures in HIVE and HIVM and outlines the state of current research.

PMID- 12420724
TI  - [Mental illness in Brazilian penal law: legal irresponsibility, potentiality for
      danger/aggressiveness and safety policies].
AB  - Psychiatric information and practice are closely related with the field of
      criminal law, questioning classical penal law premises, such as responsibility
      and freewill. We have analyzed the articles related to mental health in Brazilian
      penal laws, since Codigo Criminal do Imperio do Brazil (Brazilian Empire criminal
      laws) from 1830. Our objective is to describe the structuring of a legal status
      for the mentally ill in Brazil, as well as the model of penal intervention in the
      lives of those considered as 'dangerous' and 'irresponsible'. In order to do so,
      we have analyzed not only specific articles on penal law, but also texts by
      specialized analysts. In addition, we have discussed the concepts that keep
      mentally-ill criminals in a rather ambiguous situation, i.e. legal
      irresponsibility, potential aggressiveness and safety policies.

PMID- 12420725
TI  - A need assessment for telehealth in the South Pacific.

PMID- 12420726
TI  - Telemedicine in Europe--the TELEPLANS project.

PMID- 12420727
TI  - Molecular therapies in Crohn's disease: coming of age.

PMID- 12420728
TI  - A 33-year-old woman from Nigeria with eosinophilia.

PMID- 12420729
TI  - [Escola Tropicalista Baiana (Bahia Tropical School): the mystical origin of
      tropical medicine in Brazil].
AB  - This article aims at presenting the polemic current views on the genesis of
      tropical medicine in Brazil, by analyzing medical agents, concepts and procedures
      during the 18th century, which are generally understood as opposed to the
      institutionalization of this field of studies. It is our objective to revise the
      rigid boundaries between the pre-scientific and the scientific periods medical
      practice underwent during the Empire.

PMID- 12420730
TI  - Single-dose metronidazole versus 5-day multi-drug antibiotic regimen in excision
      of pilonidal sinuses with primary closure: a prospective randomised controlled
      double-blinded study.
AB  - BACKGROUND AND AIMS: This pilot study examines whether single-dose intravenous
      metronidazole preoperatively is at least as effective as a broad-spectrum multi
      drug regimen in preventing infection-related wound complications following
      excision of pilonidal sinuses with primary closure. PATIENTS AND METHODS: A
      double-blinded study with 50 patients randomised to receiving either a single
      drug (intravenous metronidazole 500 mg) prophylaxis preoperatively or multi-drug
      cover (intravenous cefuroxime 1.5 g and metronidazole 0.5 g preoperatively, and
      oral co-amoxiclav 375 mg 8-hourly postoperatively). They will be reviewed 1, 2
      and 4 weeks postoperatively. The wound will be graded as: I, healthy; II, redness
      and swelling of edges; III, abscess related to a suture; IV, spreading wound
      infection; V, wound breakdown. Other factors considered are the distance from the
      lowest wound margin to the anal verge, and previous pilonidal sinus surgery.
      RESULTS: Results awaited. CONCLUSION: Single-dose metronidazole seems an
      appropriate and low-cost antibiotic to consider for prophylaxis in pilonidal
      sinus surgery. This study will form the base for a trial to be conducted in
      larger numbers as a randomised controlled trial in order to have statistical
      power.

PMID- 12420731
TI  - Metastatic renal cell carcinoma involving the rectum.
AB  - BACKGROUND AND AIMS: Metastatic spread of a distant tumor to the rectum is
      extremely rare. To our knowledge, there have been no published reports of
      hematogenic metastasis from a renal cell carcinoma to the rectum. PATIENTS AND
      METHODS: A patient with a renal cell carcinoma was initially treated by a radical
      right nephrectomy. RESULTS: Nine months after the surgery he started to have
      multiple episodes of hematochezia. Colonoscopy showed a nodular lesion located in
      the distal rectum, and biopsy revealed an undifferentiated carcinoma. The patient
      then underwent abdominoperineal resection of the rectum, and histological
      examination showed metastatic renal clear cell carcinoma. CONCLUSION: This case
      represents an exceedingly rare condition, which has never been reported before.

PMID- 12420732
TI  - Stapled hemorrhoidectomy: a word of caution.

PMID- 12420733
TI  - Importance of gravity in determining the distribution of pulmonary blood flow.

PMID- 12420734
TI  - [Abstracts of the VII Meeting of the National Association for the Study of the
      Pancreas].

PMID- 12420735
TI  - Clinical quiz. Disseminated dermatitis.

PMID- 12420736
TI  - Treating hepatitis C in HIV-HCV coinfected patients.
AB  - As the natural history of HIV infection has changed following the introduction of
      highly active antiretroviral therapy (HAART), morbidity and mortality in the
      afflicted patients could be significantly reduced. The decreasing risk of
      suffering from opportunistic infections and tumors, however, is at the cost of
      antiretroviral drug-related toxicities. Today, mortality by liver disease is the
      major cause of death in HIV-infected patients from industrial countries. In the
      US and Europe about 30% of HIV-positive individuals are also infected with
      hepatitis C virus (HCV), and approximately 50-90% of persons who acquired HIV
      from injecting drugs are coinfected with HCV. In these dually infected
      individuals the presence of each viral infection impacts the natural history of
      the other one, and worsening of associated liver disease and complications within
      this population are increasing. The management of chronic hepatitis C (cHC) in
      HCV-HIV coinfection has become a major challenge, since possible interactions
      with antiretroviral therapies, increased risk of special side effects and
      compromises in adherence in patients already taking several drugs have to be
      taken into account. On the other hand, treatment strategies to fight HCV have
      been essentially ameliorated during the past 2 years by using pegylated
      interferon-alpha2b (Peg-IFN-alpha2b) combined with ribavirin, and there is hope
      that the successful therapeutic outcome in HCV-monoinfected individuals may beat
      least partly translated into benefits for the difficult-to-treat population of
      HCV-HIV dually infected persons. During the 15th International AIDS Conference in
      July 2002 in Barcelona, a satellite symposium, as well as a session in the main
      program and a number of poster presentations focussed on HCV-HIV coinfection and
      addressed the urgent problems and therapeutic challenges in managing cHC in the
      situation of underlying HIV disease.

PMID- 12420737
TI  - Employment contracts for NPs.

PMID- 12420738
TI  - Postnatal gender-dependent maturation of cellular cysteine uptake.
AB  - BACKGROUND: In view of the functional capacity of glutathione synthesis in
      premature infants, and because the availability of cysteine is one the rate
      limiting steps in glutathione synthesis, we hypothesized that the low glutathione
      levels in premature infants may be due to immaturity of the active cellular
      uptake of cysteine. OBJECTIVE: To document in cells from newborn infants the
      effect of maturity and gender on cysteine uptake and consequently on glutathione
      levels. METHODS: Incorporation of L-[35S] cysteine was measured in leukocytes
      from cord blood and from tracheal aspirates (TAC) of newborn infants of varying
      (gestational as well as postnatal) ages and gender. Cysteine uptake was
      correlated with glutathione in TAC. RESULTS: The maturity of newborn girls
      positively influences cysteine uptake, which is responsible for 78% of the
      variation in their glutathione content. However, in newborn boys, gestational and
      postnatal ages did not influence the cysteine uptake. DISCUSSION: Cysteine uptake
      appears to be the limiting step explaining the reported gender-related
      differences in glutathione as well as the low levels of this central antioxidant
      found in premature infants. The immature cysteine uptake found in cells from
      premature infants raises questions about the bioavailability of this
      conditionally essential amino acid in regimens of parenteral nutrition for human
      neonates.

PMID- 12420739
TI  - Activin, a grape seed-derived proanthocyanidin extract, reduces plasma levels of
      oxidative stress and adhesion molecules (ICAM-1, VCAM-1 and E-selectin) in
      systemic sclerosis.
AB  - This study evaluated whether a new generation antioxidant Activin derived from
      the grape seed proanthocyanidins, could reduce the induction of the adhesion
      molecules as a result of inflammatory response in the plasma of systemic
      sclerosis (SSc) patients. SSc patients were divided into two groups: one group
      was treated with Activin, a grape seed-derived proanthocyanidins, while the other
      group served as control. Patients were given Activin 100 mg/day orally for one
      month after which the blood samples were withdrawn from both groups of the
      patients. Blood was also taken from normal human volunteers. Plasma was obtained
      in fasting state between 8 to 9 A.M. from two groups of SSc patients and
      controls. Soluble adhesion molecules including ICAM-1, VCAM-1, E-selectin and P
      selectin as well as malonaldehyde, a marker for oxidative stress, were measured.
      The results of our study demonstrated up-regulation of these soluble adhesion
      molecules except for P-selectin, in the plasma of the SSc patients compared to
      those obtained from human volunteers. Activin significantly attenuated the
      increased expression of these adhesion molecules. In addition, there was a
      significant increase in the amount of malondialdehyde formation in the plasma of
      the SSc patients, which was also attenuated by Activin. The results of this study
      demonstrated that Activin could reduce the inflammatory response and the
      oxidative stress developed in SSc patients.

PMID- 12420740
TI  - A glycomic approach to hepatic tumors in N-acetylglucosaminyltransferase III (GnT
      III) transgenic mice induced by diethylnitrosamine (DEN): identification of
      haptoglobin as a target molecule of GnT-III.
AB  - A glycomic approach to the identification of target molecules in
      glycosyltransferase gene targeting mice is a promising strategy to understand the
      biological significance of glycosyltransferase genes in vivo. In order to
      understand the biological effects of N-acetylglucosaminyltransferase III (GnT
      III) on tumor formation in the liver, diethylnitrosamine (DEN) induced tumor
      formation in the GnT-III transgenic mice was examined. Our findings show that the
      incidence of hepatic tumor could be dramatically suppressed. A glycomic approach
      using two-dimensional gel electrophoresis followed by lectin blot analysis and
      sequence analysis revealed that haptoglobin, a radical scavenger molecule in
      serum was heavily glycosylated in hepatic tumor-bearing GnT-III transgenic mice
      that had been treated with DEN. Immunoprecipitation followed by E4-PHA lectin
      blot analysis also confirmed that the bisecting GlcNAc, a product of GnT-III was
      added to haptoglobin molecules. Since the use of DEN is known to lead to the
      production of lipid peroxidation products which facilitate this reaction and
      haptoglobin is an acute phase reactant, acting as a radical scavenger against
      hemoglobin or iron stimulated lipid peroxidation, a relationship between the
      glycosylation of haptoglobin and the suppression of hepatoma development can not
      be ruled out. This paper is the first report that shows a relationship between
      the sugar chains of glycoproteins with radical scavenger activity and
      hepatocarcinogenesis.

PMID- 12420741
TI  - Management of oxidative stress by heme oxygenase-1 in cisplatin-induced toxicity
      in renal tubular cells.
AB  - Induction of heme oxygenase-1 (HO-1) may serve as an immediate protective
      response during treatment with the cytostatic drug cisplatin (CDDP). Oxidative
      pathways participate in the characteristic nephrotoxicity of CDDP. In the present
      study, cultured tubular cells (LLC-PK1) were used to investigate whether
      induction of HO provided protection against CDDP by maintaining the cellular
      redox balance. The antioxidants, alpha-tocopherol (TOCO) and N-acetylcysteine
      (NAC), were used to demonstrate that elevation of ROS levels contribute to the
      development of CDDP-induced cytotoxicity. Chemical modulators of HO activity were
      used to investigate the role of HO herein. Hemin was used to specifically induce
      HO-1, while exposure of the cells to tin-protoporphyrin (SnPP) was shown to
      inhibit HO activity. Hemin treatment prior to CDDP-exposure significantly
      decreased the generation of ROS to control levels, while inhibition of HO
      increased the ROS levels beyond the levels measured in cells treated with CDDP
      alone. Furthermore, HO induction protected significantly against the cytotoxicity
      of CDDP, although this protection was limited. Similar results were obtained when
      the cells were preincubated with TOCO, suggesting that mechanisms other than
      impairment of the redox ratio are important in CDDP-induced loss of cell
      viability in vitro. In addition, SnPP treatment exacerbated the oxidative
      response and cytotoxicity of CDDP, especially at low CDDP concentrations. We
      therefore conclude that HO is able to directly limit the CDDP-induced oxidative
      stress response and thus serves as safeguard of the cellular redox balance.

PMID- 12420742
TI  - Monochloramine inhibits the expression of E-selectin and intercellular adhesion
      molecule-1 induced by TNF-alpha through the suppression of NF-kappaB activation
      in human endothelial cells.
AB  - Reactive oxygen species have various effects on the expression of cell adhesion
      molecules induced by proinflammatory cytokines, such as tumor necrosis factor a
      (T-NF-alpha). We studied the effects of monochloramine (NH2Cl), a physiological
      oxidant derived from activated neutrophils, on the TNF-alpha-induced expression
      of E-selectin and intercellular adhesion molecule-1 (ICAM-1) in human umbilical
      vein endothelial cells (HUVEC). HUVEC were pretreated with or without NH2Cl (20
      90 microM for 20 min), then stimulated with TNF-alpha (10 ng/ml), and the
      expression of E-selectin and ICAM-1 was measured. Without NH2Cl, TNF-alpha
      induced marked expression of e-selectin and ICAM-1. Pretreatment with NH2Cl
      resulted in a significant, but transient inhibition of the expression of adhesion
      molecules. Higher dose of NH2Cl showed more pronounced inhibition, and the
      inhibitory effect lasted for 8h when 70 microM of NH2Cl was added. TNF-alpha
      stimulation also induced marked activation of nuclear factor KB (NF-kappaB).
      Notably, NH2Cl also inhibited this NF-kappaB activation in a dose- and time
      dependent manner, which was similar to the inhibition of E-selectin and ICAM-1
      expression. In addition, IkappaB-alpha phosphorylation and degradation were also
      inhibited by NH2Cl pretreatment. These observations indicated that NH2Cl
      inhibited TNF-alpha-induced expression of E-selectin and ICAM-1 through the
      inhibition of NF-kappaB activation. We speculate that neutrophil-derived
      chloramines may have a regulatory role in the recruitment of leukocytes.

PMID- 12420743
TI  - Spaciotemporal alteration of 8-hydroxy-2'-deoxyguanosine levels in cardiomyocytes
      after myocardial infarction in rats.
AB  - Temporary or persistent heart failure is one of the major complications after
      myocardial infarction (MI). In order to elucidate the pathogenesis of MI, we
      studied the spaciotemporal alteration of 8-hydroxy-2'-deoxyguanosine (8-OHdG)
      levels in cardiomyocytes in a rat model of ligation of the left anterior
      descending branch of the coronary artery. The lethality in this model was 18%.
      Hearts were dissected at 0, 3, 6, 12, 24, 48 h, and 1, 2, 4, 6 weeks after the
      operation. The cardiac level of 8-OHdG was evaluated biochemically as well as by
      immunohistochemistry with monoclonal antibody N45.1. Three to 6h after ligation,
      the 8-OHdG levels were increased in the cardiomyocytes of MI (six-fold) and peri
      MI (four-fold) areas. After 24 h, the myocardium in the MI area was necrotized,
      and thereafter the 8-OHdG level decreased. 8-OHdG levels in the myocardium of
      peri-MI areas returned once to a normal level, but were significantly increased
      at 2-4 weeks along with the appearance of apoptotic cardiomyocytes in this area.
      The heart after MI has been generally considered as clinically stable after four
      weeks. However, cardiomyocytes near the infarcted area were oxidatively stressed
      even after four weeks when the affected lesion was extensive. The present data
      support the use of supplementary antioxidant therapies to save functional
      myocardium after MI. (213 words)

PMID- 12420744
TI  - Quinones as free-radical fragmentation inhibitors in biologically important
      molecules.
AB  - Effects of a number of quinones and diphenols of various structures on free
      radical fragmentation processes taking place in alpha-diols, glycerol, 2
      aminoethanol, glycero-1-phosphate, ethylene glycol monobutyrate, maltose, and
      some lipids were investigated. Quinone additions have been found to change the
      direction of free-radical transformations of the compounds cited above by
      inhibiting formation of the respective fragmentation products owing to oxidation
      of radicals of the starting compounds. The results obtained and literature data
      available allow a suggestion to be made that the system quinone/diphenol is able
      to not only deactivate or generate such active species as O2.- but also control
      the realization probability of free-radical processes of peroxidation and
      fragmentation in biologically important molecules.

PMID- 12420745
TI  - Use of N,N-dimethyl-p-phenylenediamine to evaluate the oxidative status of human
      plasma.
AB  - Oxidative stress has been clearly implicated in human disease by a growing body
      of scientific evidences. There is no ideal method for the measurement of this
      parameter. A possible strategy would be to measure simultaneously several
      biomarkers representing damage to different cellular components or,
      alternatively, a method able to evaluate the hydroperoxides, intermediate
      products of oxidation originating from different classes of molecules, such as
      lipids, peptides, amino acids, etc. can be used. We are introducing a simple,
      rapid and inexpensive assay to measure the oxidative status of human plasma. It
      is based on the properties of N,N-dimethyl-p-phenylenediamine (DMPD), a compound
      able to produce a fairly long-lived radical cation. The absorbance at 505 nm of a
      DMPD solution in the presence of plasma, which is proportional to the amount of
      hydroperoxyl compounds, is related to the oxidative status of the sample and
      could be expressed as hydrogen peroxide equivalents (HPE). This assay was not
      influenced by freezing-thawing and storage time of the plasma samples. The assay
      can be automated, performed in a kinetic mode, and used for routine analyses. The
      DMPD assay alone or in combination with analytical methods for assessing
      antioxidant capacity is suggested as a reliable tool to obtain information in
      pathologies related to oxidative stress.

PMID- 12420746
TI  - Independent and interactive association of blood antioxidants and oxidative
      damage in elderly people.
AB  - Oxidative stress is recognized as one of the major contributors to the increased
      risk of several diseases. Many recent population studies have established a close
      link between antioxidant defense and lowered risk of morbidity and mortality from
      cancer and heart disease, but little is known about the cooperative interactions
      of antioxidants. We examined the cross-sectional independent and interactive
      association of serum lipid-soluble antioxidant levels and free radical scavenging
      enzymes to serum malondialdehyde (MDA) levels, as a marker of oxidative damage.
      The participants were 160 nonsmoker institutionalized elderly. Upper tertile
      values of erythrocyte-superoxide-dismutase (E-SOD) constituted the strongest
      associated single compound with a 74% decreased risk of high MDA. Upper tertiles
      of carotenoids and alpha-tocopherol independently showed a similar lowering of
      risk of about 57%. The highest tertiles of lycopene and either beta-carotene or
      alpha-tocopherol simultaneously reveal a higher decreased risk for oxidative
      damage (74 and 71%, respectively), very similar to those in the upper tertiles of
      all these three vitamins (75%). This study represents one of the few attempts to
      date to understand the interactive effect between antioxidants and suggests that
      lipid-soluble antioxidants act not individually, but rather cooperatively with
      each other. The efficacy of this interaction is more effective when lycopene is
      present.

PMID- 12420747
TI  - Observation of protein-derived (BSA) oxygen-centered radicals by EPR spin
      trapping techniques.
AB  - Electron paramagnetic resonance (EPR) spin-trapping experiments, employing the
      novel spin-trap DEPMPO, provide evidence for the formation of protein-peroxyl
      radicals from the reaction of bovine serum albumin (BSA) or lysozyme with HO. in
      the presence of O2. Spin-trapping leads to the detection of anisotropic spectra
      of partially immobilized protein-peroxyl spin-adducts; positive identification is
      based on a novel spectrum simulation approach (through which broadened
      anisotropic spectra are simulated and compared with experiment) and by comparison
      of results with those obtained when MeO2. is trapped and the adduct frozen in a
      solid matrix.

PMID- 12420748
TI  - Differential role of CYP2E1 binders and isoniazid on CYP2E1 protein modification
      in NADPH-dependent microsomal oxidative reactions: free radical scavenging
      ability of isoniazid.
AB  - We evaluated the effect of "weak" CYP2E1 binders (ethanol, acetone and glycerol)
      "tight" CYP2E1 binders (4-methylpyrazole, imidazole, isoniazid and pyridine) and
      CCl4 (suicide substrate of CYP2E1) on the NADPH-dependent production of
      microsomal reactive oxygen species (ROS), lipid peroxidation (LPO), and
      subsequent modification of microsomal and CYP2E1 proteins. The oxidation of 2',7'
      dichlorofluorescin diacetate (DCFHDA) was used as an index of formation of
      microsomal ROS and LPO-derived reactive species. Microsomal LPO was determined by
      malondialdehyde (MDA) HPLC measurement. Addition of NADPH to rat liver microsomes
      initiated DCFHDA oxidation and MDA formation, leading to further selective
      modification of microsomal proteins and proteases-independent degradation of
      CYP2E1 protein. Iron chelators prevented these processes whereas hydroxyl radical
      scavengers showed weak effects, suggesting an important role of LPO. Among the
      tested CYP2E1 binders, only isoniazid strongly inhibited NADPH-dependent DCFHDA
      oxidation, LPO and modification of microsomal proteins. Other CYP2E1 binders
      showed weak inhibitory effects of these processes. Concerning NADPH-dependent
      modification of CYP2E1 protein, all of the tested CYP2E1 binders, except
      glycerol, prevented this process with a different potency (isoniazid > 4
      methylpyrazole = imidazole = pyridine 3 >> acetone > ethanol). "Tight" binders
      were more effective than "weak" binders. The CCl4 stimulated the DCFHDA
      oxidation, LPO and CYP2E1 protein modification. Among the tested CYP2E1 binders,
      only isoniazid effectively scavenged 2,2-diphenyl-1-picrylhydrazyl (DPPH) free
      radicals. In microsomes isolated from CYP2E1 transfected HepG2 cells, isoniazid
      inhibited the CYP2E1-dependent DCFHDA oxidation whereas other CYP2E1 binders did
      not inhibit this reaction although these compounds strongly inhibited CYP2E1
      activity. The present study demonstrates that CYP2E1 binders and isoniazid
      differentially inhibit LPO-catalyzed oxidative modification of CYP2E1 protein in
      NADPH-dependent microsomal reactions. It seems that CYP2E1 binders protect CYP2E1
      from the oxidative modification mainly by binding to the active site of the
      enzyme, rather than by blocking the reactive species production. The strong
      protective effect of isoniazid can be attributed to its ability to scavenge free
      radicals. These effects of CYP2E1 binders are considered to contribute to the
      regulation of hepatic CYP2E1 protein levels via stabilization of the protein.

PMID- 12420749
TI  - Antioxidant alpha-keto-carboxylate pyruvate protects low-density lipoprotein and
      atherogenic macrophages.
AB  - Oxidative modification of low-density lipoprotein (oxLDL) plays a pathogenic role
      in atherogenesis. Classical antioxidants such as L-ascorbic acid can inhibit
      formation of oxLDL. Alpha-Keto-carboxylates such as pyruvate and congeners also
      display antioxidant properties in some cell-free and intact cell systems. We
      tested the hypothesis that pyruvate or alpha-keto-glutarate may function as
      antioxidants with respect to LDL incubated with 5 or 10 microM Cu2+ alone or in
      combination with THP-1-derived macrophages. alpha-Hydroxy-carboxylates (L
      lactate), linear aliphatic monocarboxylates (acetate/caprylate) and L-ascorbic
      acid served as controls. The oxLDL formation was ascertained by electrophoretic
      mobility and oxLDL cytotoxicity was judged by macrophage viability and
      thiobarbituric acid reactive substances (TBARS) formation. Cu2+ alone was not
      cytotoxic but increased electrophoretic mobility of cell-free LDL, stimulating
      TBARS. Millimolar pyruvate, alpha-ketoglutarate, or micromolar L-ascorbic acid
      partially inhibited oxLDL formation, while alpha-hydroxy-carboxylate or the
      aliphatic mono-carboxylates had no measurable antioxidant properties in cell-free
      LDL. Co-culture of LDL with macrophages and Cu2+ augmented TBARS release and
      resulted in 95% macrophage death. Pyruvate improved macrophage viability with 5
      microM Cu2+ up to 60%. L-Ascorbic acid (> or = 100 microM) protected macrophages
      up to 80%. When > or = 100 microM L-ascorbic acid was combined with pyruvate,
      oxLDL formation and macrophage death were fully prevented. Thus, alpha-keto
      carboxylates, but not physiological alpha-hydroxy-carboxylates or aliphatic
      monocarboxylates qualify as antioxidants in LDL systems. Since alpha-keto
      carboxylates enhanced the antioxidant power of L-ascorbic acid, our findings may
      have implications for strategies attenuating atherosclerosis.

PMID- 12420750
TI  - In vitro antioxidant activity of 2,5,7,8-tetramethyl-2-(2'-carboxyethyl)-6
      hydroxychroman (alpha-CEHC), a vitamin E metabolite.
AB  - 2,5,7,8-tetramethyl-2-(2'-carboxyethyl)-6-hydroxychroman (alpha-CEHC) has been
      identified as a major water-soluble metabolite of vitamin E, which circulates in
      the blood and is excreted with the urine. The aim of this study was to assess the
      antioxidant activity of alpha-CEHC using several methods with different
      prooxidant challenges. In the Oxygen Radical Absorbance Capacity assay, a
      fluorescent protein acts as a marker for oxidative damage induced by peroxyl
      radicals. In the Trolox Equivalent Antioxidant Capacity (TEAC) assay, a stable
      free radical, 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid (ABTS.+) is
      reduced directly by antioxidants. Scavenging properties vs. reactive nitrogen
      species were studied measuring the effects on tyrosine nitration after reaction
      with peroxynitrite. Trolox, alpha-tocopherol, ascorbic acid, and (-)-epicatechin
      were simultaneously tested in order to compare their antioxidant activities. In
      all mentioned systems, alpha-CEHC exhibited antioxidant properties similar to
      those of Trolox. We conclude that alpha-CEHC is a molecule with good antioxidant
      activity, having the advantage over Trolox of being a naturally occurring
      compound. These properties might be useful for research or industrial purposes.

PMID- 12420751
TI  - Tetrahydro-beta-carboline alkaloids that occur in foods and biological systems
      act as radical scavengers and antioxidants in the ABTS assay.
AB  - Tetrahydro-beta-carboline alkaloids that occur in foods such as wine, seasonings,
      vinegar and fruit products juices, jams) acted as good radical scavengers
      (hydrogen- or electron donating) in the ABTS (2,2'-Azinobis-(3
      ethylbenzothiazoline-6-sulfonic acid)) assay, and therefore, they could
      contribute to the beneficial antioxidant capacity attributed to foods. In
      contrast, the fully aromatic beta-carbolines norharman and harman did not show
      any radical scavenger activity in the same assay. During the reaction with ABTS.+
      radical cation, tetrahydro-beta-carboline-3-carboxylic acid such as 1-methyl
      1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid (MTCA) and 1-methyl-1,2,3,4
      tetrahydro-beta-carboline-1,3-dicarboxylic acid (MTCA-COOH) were converted to
      harman, whereas 1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid (THCA) and
      1,2,3,4-tetrahydro-beta-carboline-1,3-dicarboxylic acid (THCA-COOH) afforded
      norharman. These results suggest that food and naturally-occurring tetrahydro
      beta-carboline alkaloids if accumulated in tissues, as reported elsewhere, might
      exhibit antioxidant activity.

PMID- 12420752
TI  - Non-peptidic chemokine receptors antagonists as emerging anti-HIV agents.
AB  - HIV entry within the cell involves the presence of at least two chemokine co
      receptors, the CCR5 and CXCR4 receptors. Viral entry can be inhibited by the
      natural ligands for CXCR4, the CXC chemokine SDF-1 and CCR5, the CC chemokines
      RANTES, MIP-1alpha and MIP-1beta, respectively. Much research has been devoted
      ultimately to the development of small molecule chemokine antagonists that
      inhibit virus entry within the cell, and constitute in this way novel antiviral
      medications. The most potent and specific CXCR4 antagonists reported up to now
      are the bicyclam derivatives, which also potently block X4 HIV replication. One
      such compound, AMD3100 has proved to be a highly specific CXCR4 antagonist, which
      consistently blocks the outgrowth of all X4 HIV and dual-tropic (R5/X4) variants
      that use CXCR4 for entering the cells. From such bicyclam analogues, AMD3100 was
      selected as the clinical candidate, which, after initial Phase I studies,
      proceeded to Phase II trials, but unfortunately showed significant cardiac side
      effects which lead to its withdrawal from further development. The first
      nonpeptidic compound that interacts with CCR5, but not with CXCR4, is a
      quaternary ammonium derivative, TAK-779, which also shows potent but variable
      anti-HIV activity. A large number of potent CCR5 antagonists from several classes
      of polycyclic derivatives have been recently disclosed. Many such derivatives
      showed nanomolar binding affinity to the receptor, and at least one of them, the
      oxime-piperidine derivative SCH-351125 has progressed to clinical evaluation. The
      development of such agents for clinical use may constitute an additional approach
      for the treatment of HIV infection, in addition to the classical one involving
      reverse transcriptase and protease inhibitors.

PMID- 12420753
TI  - Direct measurement of local and global contributions in the binding of coformycin
      to bovine adenosine deaminase.
AB  - A general method is outlined that determines quantitatively the extent to which
      tight ligand binding to an enzyme active site is facilitated by the adoption of a
      stabler macromolecular conformation in the complex. The method therefore rejects
      the general assumption that competitive inhibitor binding to enzyme active sites
      involves only local (active site) interactions. The procedure involves comparing
      the unfolding transition state free energies of the free and complexed enzyme
      from physiological conditions. For the interaction of the transition state analog
      coformycin with bovine adenosine deaminase we observed that the binding free
      energy by the physiological enzyme was approximately 92% due to the assumption of
      a stabler enzyme conformation in the complex. The significance of these findings
      in terms of general enzyme catalysis is discussed.

PMID- 12420754
TI  - Transition metal acetylsalicylates and their anti-inflammatory activity.
AB  - Mononuclear and binuclear transition metal [Co(II), Cu(II), Ni(II) and Zn(II)]
      acetylsalicylates of the type [M(L)2], [M(L)2Cl2] and [(M)2(L)4] have been
      prepared and characterized on the basis of their physical, spectral and
      analytical data. The complexes have been investigated in an in vivo animal model
      for anti-inflammatory activity and show a better effect and a more potent action
      than acetylsalicylic acid.

PMID- 12420755
TI  - Some coumarins and triphenylethene derivatives as inhibitors of human testes
      microsomal 17beta-hydroxysteroid dehydrogenase (17beta-HSD type 3): further
      studies with tamoxifen on the rat testes microsomal enzyme.
AB  - The 7-hydroxycoumarins, umbelliferone and 4-methylumbelliferone (IC50 = 1.4 and
      1.9 microM, respectively) were potent inhibitors of human testes microsomal
      17beta-HSD (type 3) enzyme whereas 7-methoxycoumarin, 4-hydroxycoumarin and 7
      ethoxycoumarin had little or no inhibitory activity. Analogues of the weak
      inhibitory triphenylethenes tamoxifen and clomiphene but lacking the basic
      substituent, were weak inhibitors of the human microsomal enzyme. Inhibitory
      activity was improved by replacement of the triphenylethene structure with a
      triphenylmethyl (17, 52.6% inhibition) or phenylpropyl (16, 94.8%, IC50 = 42.1
      microM) skeleton. Further studies on tamoxifen using rat testes microsomal 17beta
      HSD showed that the inhibition was time-dependent and irreversible but not
      specifically mechanism-based.

PMID- 12420756
TI  - Antibacterial cobalt(II), nickel(II) and zinc(II) complexes of nicotinic acid
      derived Schiff-bases.
AB  - Nicotinic acid derived Schiff bases and their transition metal [cobalt(II),
      nickel(II) and zinc(II)] complexes have been prepared and characterized by
      physical, spectral and analytical data. The Schiff bases act as deprotonated
      tridentate ligands for the complexation of the above mentioned metal ions. These
      complexes, possessing the general formula [M(L)2] [where M = Co(II), Ni(II) and
      Zn(II) and L = HL1-HL4] showed an octahedral geometry of the metal ions. For
      determining the effect of metal ions upon chelation, the Schiff bases and their
      complexes have been screened for antibacterial activity against several
      pathogenic strains of Escherichia coli, Staphylococcus aureus and Pseudomonas
      aeruginosa. The new metal derivatives reported here were more bactericidal
      against one or more bacterial species as compared to the uncomplexed Schiff
      bases.

PMID- 12420757
TI  - Sensitive detection of organophosphorus pesticides using a needle type
      amperometric acetylcholinesterase-based bioelectrode. Thiocholine
      electrochemistry and immobilised enzyme inhibition.
AB  - An acetylcholinesterase (AChE) based amperometric bioelectrode for a selective
      detection of low concentrations of organophosphorus pesticides has been
      developed. The amperometric needle type bioelectrode consists of a bare cavity in
      a PTFE isolated Pt-Ir wire, where the AChE was entrapped into a photopolymerised
      polymer of polyvinyl alcohol bearing styrylpyridinium groups (PVA-SbQ). Cyclic
      voltammetry, performed at Pt and AChE/Pt disk electrodes, confirmed the
      irreversible, monoelectronic thiocholine oxidation process and showed that a
      working potential of +0.410 V vs. Ag/AgCl, KCl(sat) was suitable for a selective
      and sensitive amperometric detection of thiocholine. The acetylthiocholine
      detection under enzyme kinetic control was found in the range of 0.01-0.3 U cm(
      2) of immobilised AChE. The detection limit, calculated for an inhibition ratio
      of 10%, was found to reach 5 microM for dipterex and 0.4 microM for paraoxon. A
      kinetic analysis of the AChE-pesticide interaction process using Hanes-Woolf or
      Lineweaver-Burk linearisations and secondary plots allowed identification of the
      immobilised enzyme inhibition process as a mixed one (non/uncompetitive) for both
      dipterex and paraoxon. The deviation from classical Michaelis Menten kinetics
      induced from the studied pesticides was evaluated using Hill plots.

PMID- 12420758
TI  - Antibacterial Co(II), Cu(II), Ni(II) and Zn(II) complexes of thiadiazole derived
      furanyl, thiophenyl and pyrrolyl Schiff bases.
AB  - 2-Amino-1,3,4-thiadiazole undergoes a condensation reaction with furane-,
      thiophene- and pyrrole-2-carboxaldehyde to form tridentate NNO, NNS and NNN donor
      Schiff bases. These Schiff bases were further used to obtain complexes of the
      type [M(L)2]X, where M = Co(II), Cu(II), Ni(II) or Zn(II), L = L1, L2 or L3 and X
      = Cl2. The new compounds described here have been characterized by their
      physical, spectral and analytical data, and have been screened for antibacterial
      activity against several bacterial strains such as Escherichia coli,
      Staphylococcus aureus, and Pseudomonas aeruginosa. The antibacterial potency of
      the Schiff bases increased upon chelation/complexation in comparison to the
      uncomplexed Schiff bases against the tested bacterial species thus, opening new
      approaches to find new ways in the fight against antibiotic-resistant strains.

PMID- 12420759
TI  - Proteinaceous inhibitor versus fructose as modulators of Pteris deflexa invertase
      activity.
AB  - An acid invertase from the fern Pteris deflexa Link was purified and the effect
      of reaction products on enzyme activity was studied. Fructose and glucose were
      competitive and non-competitive inhibitors of the enzyme, respectively. Since
      proteins suppressed glucose and fructose inhibition of the enzyme, an invertase
      modulation by reaction products is unlikely; nevertheless, an invertase
      proteinaceous inhibitor previously reported could have a role in this respect.
      The purified enzyme was an heterodimer Mr 90,000 Daltons composed of subunits of
      66,000 and 30,000 Daltons. The enzyme had beta-fructofuranosidase activity and
      hydrolyzed mainly sucrose but also raffinose and stachyose, with Km of 3.22,
      10.80 and 38.50 mM, respectively. Invertase activity with an optimum pH at 5.0
      was present in almost every leaf fern tissue. Pinnas (sporophyll leaflets) had
      the higher enzyme levels. Invertase histochemical and immunochemical localization
      studies showed the enzyme mainly in phloem cells. Epidermis, collenchyma and
      parenchyma cells also showed invertase protein.

PMID- 12420760
TI  - Pyrrolylbenzothiazole derivatives as aldose reductase inhibitors.

PMID- 12420761
TI  - Structure-activity relationships of new NAPAP-analogs.
AB  - Several new analogs of the known thrombin inhibitor NAPAP were synthesized, in
      which the P2 glycine residue was substituted by natural and unnatural amino
      acids. The thrombin inhibitory potency was comparable to that of NAPAP. Several
      of the compounds had inhibition constants lower than 10 nM and a very high
      selectivity compared to trypsin, factor Xa and plasmin. In addition, analogs were
      prepared by alkylation of the N(alpha)-atom of the 4-amidinophenylalanine in P1
      position, which showed a more than 10-fold lower thrombin inhibition.
      Furthermore, azaglycine was introduced instead of P2 glycine. For most of the
      inhibitors similar fast elimination rates were seen in rats after intravenous
      dosing, as found previously for NAPAP. Only some compounds, which contained a
      second basic group showed a slightly decreased cumulative biliary clearance.

PMID- 12420762
TI  - Talks bridge AVMA, AAVSB relations, but not dual programs. American Veterinary
      Medical Association. American Association of Veterinary State Boards.

PMID- 12420763
TI  - Is the carbon-copy cat causing questions from your clients?

PMID- 12420764
TI  - Confiscated Asian turtles treated in marathon rescue effort.

PMID- 12420765
TI  - Global influenza laboratory on the horizon.

PMID- 12420766
TI  - Pleased to see clinical experience highlighted.

PMID- 12420767
TI  - Giving credit to university's contributions.

PMID- 12420768
TI  - Questions regarding article on pet relinquishments, euthanasias.

PMID- 12420769
TI  - Development of a mental wellness program for animals.

PMID- 12420770
TI  - What is your diagnosis? Splenic torsion.

PMID- 12420771
TI  - Developing a curriculum to improve the skills, knowledge, aptitudes, and
      attitudes of veterinary students.

PMID- 12420772
TI  - ECG of the month. Sinus tachycardia with left bundle branch block.

PMID- 12420773
TI  - Anesthesia case of the month. A suitable choice for anesthetic management of a
      green iguana for an orchidectomy.

PMID- 12420774
TI  - Veterinarians and administrative law.

PMID- 12420775
TI  - Potential revenue impact of an outbreak of foot-and-mouth disease in the United
      States.
AB  - OBJECTIVE: To estimate potential revenue impacts of an outbreak of foot-and-mouth
      disease (FMD) in the United States similar to the outbreak in the United Kingdom
      during 2001. DESIGN: Economic analysis successively incorporating quarantine and
      slaughter of animals, an export ban, and consumer fears about the disease were
      used to determine the combined impact. SAMPLE POPULATION: Secondary data for
      cattle, swine, lambs, poultry, and products of these animals. PROCEDURE: Data for
      1999 were used to calibrate a model for the US agricultural sector. Removal of
      animals, similar to that observed in the United Kingdom, was introduced, along
      with a ban on exportation of livestock, red meat, and dairy products and a
      reduction and shift in consumption of red meat in the United States. RESULTS: The
      largest impacts on farm income of an FMD outbreak were from the loss of export
      markets and reductions in domestic demand arising from consumer fears, not from
      removal of infected animals. These elements could cause an estimated decrease of
      $14 billion (9.5%) in US farm income. Losses in gross revenue for each sector
      were estimated to be the following: live swine, -34%; pork, -24%; live cattle 
      17%; beef, -20%; milk, -16%; live lambs and sheep, -14%; lamb and sheep meat, 
      10%; forage, -15%; and soybean meal, -7%. CONCLUSIONS AND CLINICAL RELEVANCE:
      Procedures to contain an outbreak of FMD to specific regions and allow
      maintenance of FMD-free exports and efforts to educate consumers about health
      risks are critical to mitigating adverse economic impacts of an FMD outbreak.

PMID- 12420776
TI  - External and internal influences on disease risk in cats.

PMID- 12420777
TI  - Selected methods of animal carcass disposal.

PMID- 12420778
TI  - Cyclosporine and ketoconazole for the treatment of perianal fistulas in dogs.
AB  - OBJECTIVE: To evaluate efficacy and cost of using cyclosporine and ketoconazole
      for the treatment of perianal fistulas in dogs. DESIGN: Clinical trial. ANIMALS:
      12 dogs with perianal fistulas. PROCEDURE: Dogs received cyclosporine and
      ketoconazole orally (target whole blood trough cyclosporine concentrations of 400
      to 600 ng/ml). Study endpoints were resolution of clinical signs, remission, and
      recurrence of disease. Adverse effects and cost of medications were reported.
      Results were compared with those from previous studies in humans and in dogs in
      which single agent cyclosporine treatment for perianal fistulas was used.
      RESULTS: All dogs had resolution of clinical signs. Eight dogs went into
      remission; however, 5 of those 8 had recurrence of fistulas. Adverse effects of
      treatment were minimal and well tolerated. Cost of treatment was comparable to
      traditional surgical options and less than single agent cyclosporine treatment.
      CONCLUSIONS AND CLINICAL RELEVANCE: Administration of cyclosporine with
      ketoconazole is an effective and cost-comparable treatment for perianal fistulas
      in dogs.

PMID- 12420779
TI  - Use of prostaglandins and bromocriptine mesylate for pregnancy termination in
      bitches.
AB  - OBJECTIVE: To assess the efficacy and safety of 2 protocols using bromocriptine
      mesylate and prostaglandins to terminate unwanted pregnancy in bitches. DESIGN:
      Prospective randomized single-blind controlled study. ANIMALS: 34 crossbred and
      purebred bitches referred for possible pregnancy termination. Seven additional
      pregnant bitches were used as controls. PROCEDURE: Pregnancy was assessed by
      ultrasonographic examination from day 25 after mating in all bitches. Of the 34
      bitches, 25 were pregnant and were randomly allocated to a treatment group. Group
      1 dogs (n = 12) received a combination of increasing amounts of bromocriptine
      mesylate (15 to 30 microg/kg [6.8 to 13.6 microg/lb], p.o., q 12 h) and dinoprost
      tromethamine (0.1 to 0.2 mg/kg [0.045 to 0.09 mg/lb], s.c., q 24 h). Group-2 dogs
      (n =13) received a combination of increasing amounts of bromocriptine mesylate
      (the same schedule as group-1 dogs) and cloprostenol sodium (1 microg/kg [0.45
      microg/lb], s.c., q 48 h). Both groups were treated until pregnancy termination.
      Results-Treatment success was 100% in both groups. Days of treatment required for
      pregnancy termination did not significantly differ between groups (5.0 +/- 0.6 vs
      3.7 +/- 0.6 days, group-1 and group-2 dogs, respectively) although adverse
      effects only developed in group-1 dogs. At the end of the protocols,
      pseudopregnancy was observed in 3 of 12 and 6 of 13 group-1 and group-2 dogs,
      respectively. Pregnancy termination was followed by a mucoid sanguineous vulvar
      discharge for 3 to 10 days. CONCLUSIONS AND CLINICAL RELEVANCE: Results of this
      study indicate that protocols that combine the use of bromocriptine mesylate and
      prostaglandins for the termination of unwanted pregnancy in bitches are efficient
      and safe. The use of bromocriptine mesylate and cloprostenol had the best results
      and could be easily used on an outpatient basis.

PMID- 12420780
TI  - Comparison of transdermal administration of fentanyl versus intramuscular
      administration of butorphanol for analgesia after onychectomy in cats.
AB  - OBJECTIVE: To compare postoperative discomfort assessed by subjective pain score
      and plasma cortisol concentrations in cats undergoing onychectomy that received
      analgesia by use of transdermal fentanyl (TDF) patches or an i.m. injection of
      butorphanol. DESIGN: Randomized prospective clinical trial. ANIMALS: 22 client
      owned cats weighing 2.2 to 5 kg (4.84 to 11 lb) undergoing onychectomy.
      PROCEDURE: Researchers were blinded to which cats received a TDF patch (25
      microg/h) 18 to 24 hours prior to surgery or an i.m. injection of butorphanol
      (0.2 mg/kg (0.09 mg/lb]) at the time of sedation, immediately following
      extubation, and at 4-hour intervals thereafter for 12 hours. Clinical variables,
      plasma cortisol concentration, and pain scores were evaluated and recorded 24
      hours prior to surgery, at extubation, and 2, 4, 8, 12, 24, 36, and 48 hours
      after surgery. RESULTS: The TDF group had a lower pain score than the butorphanol
      group only at 8 hours after surgery. Both groups had significantly lower mean
      plasma cortisol concentrations 0, 24, 36, and 48 hours after surgery, compared
      with mean plasma cortisol concentrations prior to surgery. No significant
      differences in appetite or response to handling the feet were observed between
      the 2 groups. CONCLUSIONS AND CLINICAL RELEVANCE: Our data did not reveal a
      difference in pain relief between administration of TDF and butorphanol. Plasma
      cortisol concentrations were not different between groups. Fentanyl appeared to
      provide equivalent analgesia to butorphanol in cats undergoing onychectomy. The
      primary advantage of using a TDF patch is that repeated injections are not
      required.

PMID- 12420781
TI  - Intra-abdominal botryomycosis in a dog.
AB  - A 6-year-old 41.8-kg (92-lb) sexually intact male German Shepherd Dog used as an
      attack and pursuit dog by the local police department was examined because of
      general malaise and sudden onset of ataxia. Abnormal findings included a high WBC
      count, fever, and ongoing weight loss. Physical examination was unrevealing
      initially, in part because of the aggressive nature of the dog. Following
      treatment with antibiotics, an abdominal mass was detected during a second
      physical examination, and was confirmed radiographically. Subsequent ultrasound
      examination revealed a walled mass of mixed echogenicity, with areas of
      detectable fluid movement. A laparotomy was performed to remove the mass, which
      weighed 2.2 kg (4.5 lb). Histologic findings were consistent with botryomycosis,
      and Staphylococcus intermedius was isolated on bacteriologic culture.
      Postoperative treatment consisted of intravenous, intra-abdominal, and oral
      administration of antibiotics. Diagnosis of botryomycosis requires histologic
      examination and bacteriologic culture of the lesion. Treatment consists of
      surgical intervention and administration of antimicrobials. Botryomycosis is a
      poorly understood and rarely reported disease found in many species. A computer
      search of the literature failed to reveal any previous reports of intra-abdominal
      botryomycosis in dogs.

PMID- 12420782
TI  - Separation anxiety syndrome in cats: 136 cases (1991-2000).
AB  - OBJECTIVE: To determine whether cats develop clinical signs typical of separation
      anxiety syndrome (SAS) and the type and frequency of applicable clinical signs in
      affected cats. DESIGN: Retrospective study. ANIMALS: 136 cats with clinical signs
      typical of SAS in dogs. Subjects were evaluated during home visits. PROCEDURE:
      Medical records of pet cats evaluated for behavior problems during a 10-year
      period were reviewed. Medical records of cats that displayed behaviors typical of
      dogs with SAS (eg, inappropriate elimination, excessive vocalization,
      destructiveness, or self-mutilation) were more extensively examined, and cats
      that displayed these behaviors only when separated from an apparent attachment
      figure were included in the study. RESULTS: Behavior problems triggered by
      separation anxiety included inappropriate urination (96 cats), inappropriate
      defecation (48), excessive vocalization (16), destructiveness (12), and
      psychogenic grooming (8). Inappropriate defecation was identified in a
      significantly higher percentage of the neutered females in the study than in the
      neutered males. Seventy-five percent of the cats that urinated inappropriately
      urinated exclusively on the owner's bed. Psychogenic grooming was identified in 8
      of the 40 neutered females but in none of the neutered males, whereas
      destructiveness was observed in 12 of the 92 neutered males but in none of the
      neutered females. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that cats
      can develop SAS. Sex and breed differences in the frequency of particular signs
      of SAS in cats may exist. Feline SAS should be considered in the differential
      diagnosis of anxiety-related misbehavior in cats.

PMID- 12420783
TI  - Clinicopathologic evidence of disseminated intravascular coagulation in horses
      with acute colitis.
AB  - OBJECTIVE: To detect subclinical disseminated intravascular coagulation (DIC) in
      horses with colitis and to determine any association between the diagnosis of
      subclinical DIC and outcome or occurrence of complications in horses with
      colitis. DESIGN: Prospective study. ANIMALS: 37 horses admitted to a veterinary
      teaching hospital for treatment of acute colitis. PROCEDURE: Coagulation profiles
      were obtained on each horse 0, 24, and 48 hours after admission. Six tests were
      performed: platelet count, plasma fibrinogen concentration, prothrombin time,
      activated partial thromboplastin time, antithrombin activity, and serum fibrin
      degradation products concentration. RESULTS: A clinicopathologic diagnosis of
      subclinical DIC was made if 3 of the 6 tests had abnormal results at any 1 sample
      period. No horse had clinical signs of DIC at the time of sampling. Twelve of 37
      (32%) horses met the criteria for diagnosis of subclinical DIC within a 1-year
      period. Outcome was defined as survival or nonsurvival. Five of 12 horses with
      subclinical DIC and 2 of 25 horses without subclinical DIC did not survive. Crude
      odds ratio analysis revealed a horse with acute colitis was 8 times as likely to
      die or be euthanatized if a diagnosis of subclinical DIC was made. CONCLUSIONS
      AND CLINICAL RELEVANCE: Clinicopathologic evidence of DIC is common and is
      significantly associated with a poor outcome in horses with acute colitis.
      Treatment of subclinical DIC may influence outcome in horses with acute colitis.

PMID- 12420784
TI  - Use of biphasic electrical cardioversion for treatment of idiopathic atrial
      fibrillation in two horses.
AB  - Rectilinear biphasic cardioversion was used in 2 horses with idiopathic sustained
      atrial fibrillation; 1 horse converted to sustained sinus rhythm. Variables that
      potentially affected outcome of the electrical cardioversion procedures in these
      horses included duration of arrhythmia, placement of cardioverter pads and
      paddles, serum electrolyte concentrations, and treatment with quinidine. Serum
      cardiac troponin I concentration, measured to determine whether the myocardium
      was damaged from the electrical shocks, was within the reference range in both
      horses after the procedure. Biphasic electrical cardioversion may provide an
      alternative to pharmacologic cardioversion with quinidine in horses. The
      rectilinear biphasic defibrillator-cardioverter uses a unique biphasic waveform
      to deliver constant current to the myocardium during cardioversion, regardless of
      transthoracic impedance. Biphasic cardioversion is safer and more effective than
      traditional monophasic cardioversion in humans and animals.

PMID- 12420785
TI  - Evaluation of a cranial arthroscopic approach to the stifle joint for the
      treatment of femorotibial joint disease in horses: 23 cases (1998-1999).
AB  - OBJECTIVE: To describe a single-portal cranial arthroscopic approach to the
      stifle joint in horses and to determine the clinical outcome in horses with
      femorotibial joint disease in which this approach was used. DESIGN: Retrospective
      study. ANIMALS: 23 adult horses. PROCEDURE: Medical records were reviewed to
      obtain information on clinical outcome in horses in which the single-portal
      cranial arthroscopic approach was used. RESULTS: Twenty-nine stifle joints of 23
      horses were examined arthroscopically, using the described approach. Subchondral
      bone cysts were treated in 19 medial femoral condyles of 12 horses. Unilateral
      cruciate ligament desmitis (4 horses), meniscal tearing (3), or both (2) were
      identified in 9 horses. Evidence of degenerative joint disease without cystic
      lesions or soft tissue trauma was found in 2 horses. Information on clinical
      outcome was obtained for 21 of 23 horses. A successful outcome was obtained in 15
      of 21 horses and was defined as return to sound performance at a degree equal to
      or better than that prior to injury and lameness. Eight of 12 horses treated for
      medial femoral condylar cysts had a successful outcome. Four show horses treated
      for cruciate ligament lesions alone successfully returned to showing activity.
      None of the 3 horses with meniscal tearing were able to perform successfully.
      CONCLUSIONS AND CLINICAL RELEVANCE: The femorotibial joint was evaluated through
      a single-portal cranial arthroscopic approach, using the femoropatellar joint as
      the point of access. This approach was easy to perform, allowed controlled access
      to the femorotibial joint, avoided accidental damage to articular structures, and
      required fewer access portals.

PMID- 12420786
TI  - Sensitivity of test strategies used in the Voluntary Johne's Disease Herd Status
      Program for detection of Mycobacterium paratuberculosis infection in dairy cattle
      herds.
AB  - OBJECTIVE: To evaluate sensitivities at the herd level of test strategies used in
      the Voluntary Johne's Disease Herd Status Program (VJDHSP) and alternative test
      strategies for detecting dairy cattle herds infected with Mycobacterium
      paratuberculosis. DESIGN: Nonrandom cross-sectional study. SAMPLE POPULATION: 64
      dairy herds from Pennsylvania, Minnesota, Colorado, Ohio, and Wisconsin. Fifty
      six herds had at least 1 cow shedding M. paratuberculosis in feces; the other 8
      herds were free from paratuberculosis. PROCEDURE: For all adult cows in each
      herd, serum samples were tested for antibodies to M. paratuberculosis with an
      ELISA, and fecal samples were submitted for bacterial culture for M.
      paratuberculosis. Sensitivities at the herd level (probability of detecting
      infected herd) of various testing strategies were then evaluated. RESULTS:
      Sensitivity at the herd level of the testing strategy used in level 1 of the
      VJDHSP (use of the ELISA to test samples from 30 cows followed by confirmatory
      bacterial culture of feces from cows with positive ELISA result) ranged from 33
      to 84% for infected herds, depending on percentage of cows in the herd with
      positive bacterial culture results. If follow-up bacterial culture was not used
      to confirm positive ELISA results, sensitivity ranged from 70 to 93%, but
      probability of identifying uninfected herds as infected was 89%. CONCLUSIONS AND
      CLINICAL RELEVANCE: Results suggest that the testing strategy used in the VJDHSP
      will fail to identify as infected most dairy herds with a low prevalence of
      paratuberculosis. A higher percentage of infected herds was detected if follow-up
      bacterial culture was not used, but this test strategy was associated with a high
      probability of misclassifying uninfected herds.

PMID- 12420787
TI  - Myotropic peptides in Drosophila melanogaster and the genes that encode them.
AB  - Myotropic peptides are structurally dissimilar; thus, they comprise different
      families. The cellular expressions of myotropins suggest they act as hormones,
      transmitters, and modulators of numerous biological processes. Drosophila
      melanogaster allatostatin (AST), FMRFamide-containing, dromyosuppressin (DMS),
      and drosulfakinin (DSK) peptides represent four different myotropin families. A
      different gene encodes each of these four myotropin families. D. melanogaster
      AST, FMRFamide-containing, DMS, and DSK peptides are present in neural and gut
      tissue, but are not all expressed in the same cells. These four families of
      myotropins affect spontaneous contractions of gut, heart, and/or reproductive
      tissue, but their effects are dissimilar in magnitude and time course. Based on
      their structures, genes, distributions, and activities, the synthesis and release
      of these D. melanogaster myotropins are likely governed by different sensory
      inputs and regulatory mechanisms. The differences in structures, precursors,
      cellular expressions, and activities are consistent with the conclusion that they
      do not play redundant roles in their effects on the frequency of muscle
      contractions. Orthologs of these D. melanogaster myotropins exist in other animal
      species; thus, research on the mechanisms involved in their production and
      processing, functions, and signaling may be widely applicable. Here, we review
      research on D. melanogaster AST, FMRFamide-containing, myosuppressin, and
      sulfakinin peptides.

PMID- 12420788
TI  - A mutant exhibiting abnormal habituation behavior in Caenorhabditis elegans.
AB  - The acquisition and retention of information by the nervous system are major
      processes of learning. Habituation is a simple learning process that occurs
      during repeated exposure to harmless stimuli. C. elegans is habituated when
      repeatedly given mechanical stimuli and recover from the habituation when the
      stimuli are stopped. A habituation abnormal mutant was isolated and assigned to a
      new gene hab-1 whose mutation causes slow habituation. The hab-1 mutant phenotype
      is remarkable at short time interval stimuli. However, hab-1 mutant worms show
      normal dishabituation. Ablations of neurons constituting the neural circuit for
      mechanical reflexes did not abolish abnormalities caused by the hab-1 mutation.

PMID- 12420789
TI  - Morphometric description of the wandering behavior in Drosophila larvae: a
      phenotypic analysis of K+ channel mutants.
AB  - Genetic dissection in Drosophila has provided insights into the molecular
      mechanisms of K+ channel subunits that underlie various physiological functions.
      The involvement of these subunits in animal behavior, however, is not well
      understood. Mutations of the Shaker (Sh), Hyperkinetic (Hk), ether a go-go (eag)
      and quiver (qvr) genes have been found to affect the IAK+ channel in different
      ways. The influence of individual K+ channel subunits on complex larval
      locomotion behavior can be quantified utilizing the computer-assisted Dynamic
      Image Analysis System (DIAS), a motion analysis system that allows morphometric
      assessments. Different aspects of larval locomotion in mutants of these four
      genes were contrasted to those modified by the Na+ channel mutations
      paralytic(ts) (para(ts)) and no-action-potential(ts) (nap(ts)). Genetic
      interactions among these K+ channel mutations and the counter-balancing effects
      of nap(ts) were studied in double and triple mutant combinations. An animal at
      the wandering stage was allowed to crawl spontaneously on an agar substrate to
      extract features of the crawling pattern by DIAS. To quantify locomotion,
      characteristic parameters, including time spent in forward locomotion and
      direction change, and stride length and frequency, were computed by DIAS. Sh, Hk,
      and qvr mutant larvae were found to spend more than 80% of their crawling time on
      forward locomotion (i.e., less than 20% in direction change), in contrast to 70
      74% in wild-type larvae, and less than 60% in eag mutant larvae. The synergistic
      effects of double and triple K+ channel mutations on these parameters of
      locomotion suggest that each K+ channel subunit contributes in a specific manner
      to the efficiency of locomotion.

PMID- 12420790
TI  - A novel mutation in the gene encoding noggin is not causative in human neural
      tube defects.
AB  - Neural tube defects (NTD) are a common birth defect, with both genetic and
      environmental contributions to their etiology. In mouse, null mutations in Noggin
      result in fully-penetrant NTDs. We investigated Noggin for mutations that may
      predispose to human NTDs in 202 NTD cases. One variant allele was identified in a
      male patient with myelomeningocele. The patient's father and a sibling also
      carried the variant allele, but neither was affected with an open NTD. DNA
      sequencing confirmed a C1064A missense mutation predicted to result in the
      conversion of residue 84 from proline to histidine. The variant found in the NTD
      patient is a newly identified variant, the role of which is uncertain.

PMID- 12420791
TI  - The public health potential of aspirin.

PMID- 12420792
TI  - The role of myocardial KATP-channel blockade in the protective effects of
      glibenclamide against ischaemia in the rat heart.
AB  - Glibenclamide preserves postischaemic myocardial function in the isolated,
      erythrocyte perfused, working rat heart model. This study addresses the possible
      involvement of KATP channels in this beneficial action of glibenclamide. We
      hypothesized that if glibenclamide improved postischaemic cardiac function by
      blocking of KATP channels, opening of these KATP channels should result in the
      opposite, namely detrimental effects on postischaemic heart function.
      Postischaemic functional loss and coronary blood flow were recorded during
      treatment with glibenclamide (4 micromol x l(-1); n = 5), the KATP channel
      openers pinacidil (1 micromol x (l-1); n = 5) and diazoxide (30 micromol x l(-1);
      n = 5), the combination of glibenclamide with pinacidil (n = 5) and glibenclamide
      with diazoxide (n = 5), and vehicle (n = 8). Both pinacidil and diazoxide
      significantly increased coronary blood flow 2-3 times, which was abolished by
      glibenclamide pre- and postischaemically. This confirms that under both flow
      conditions glibenclamide significantly blocks KATP channels in the coronary
      vasculature. The 12 min. global ischaemic incident resulted in a cardiac
      functional loss of 22.2 +/- 2.9% during vehicle. Glibenclamide reduced the
      cardiac functional loss to 4.3 +/- 1.2% (P < 0.01). Interestingly, both pinacidil
      and diazoxide reduced the cardiac functional loss to 4.0 +/- 1.5% (P < 0.01) and
      2.9 +/- 1.4% (P < 0.001), respectively. The combination pinacidil+glibenclamide
      resulted in additional protection compared with the individual components (0.6 +/
      0.1 versus 4.0 +/- 1.5%, P < 0.05). Thus, in contrast to its effect on coronary
      vascular tone, the glibenclamide-induced improvement of postischaemic cardiac
      function may not be mediated through blockade of the KATP channel. Alternative
      mechanisms may be operative, such as uncoupling of the mitochondrial respiratory
      chain, thereby preconditioning the hearts against stunning.

PMID- 12420793
TI  - Affinities of dihydrocodeine and its metabolites to opioid receptors.
AB  - Dihydrocodeine is metabolized to dihydromorphine, dihydrocodeine-6-O-,
      dihydromorphine-3-O- and dihydromorphine-6-O-glucuronide, and nordihydrocodeine.
      The current study was conducted to evaluate the affinities of dihydrocodeine and
      its metabolites to mu-, delta- and kappa-opioid receptors. Codeine, morphine, d,1
      methadone and levomethadone were used as controls. Displacement binding
      experiments were carried out at the respective opioid receptor types using
      preparations of guinea pig cerebral cortex and the specific opioid agonists
      [5H]DAMGO (mu-opioid receptor), [3H]DPDPE (delta-opioid receptor) and [3H]U69,593
      (K-opioid receptor) as radioactive ligands at concentrations of 0.5, 1.0 and 1.0
      nmol/l, respectively. All substances had their greatest affinity to the mu-opioid
      receptor. The affinities of dihydromorphine and dihydromorphine-6-O-glucuronide
      were at least 70 times greater compared with dihydrocodeine (Ki 0.3 micromol/l),
      whereas the other metabolites yielded lower affinities. For the delta-opioid
      receptor, the order of affinities was similar with the exception that
      dihydrocodeine-6-O-glucuronide revealed a doubled affinity in relation to
      dihydrocodeine (Ki 5.9 micromol/l). In contrast, for the K-opioid receptor,
      dihydrocodeine-6-O- and dihydromorphine-6-O-glucuronide had clearly lower
      affinities compared to the respective parent compounds. The affinity of
      nordihydrocodeine was almost identical to that of dihydrocodeine (Ki 14
      micromol/l), whereas dihydromorphine had a 60 times higher affinity. These
      results suggest that dihydromorphine and its 6-O-glucuronide may provide a
      relevant contribution to the pharmacological effects of dihydrocodeine. The O
      demethylation of dihydrocodeine to dihydromorphine is mediated by the polymorphic
      cytochrome P-450 enzyme CYP2D6, resulting in different metabolic profiles in
      extensive and poor metabolizers. About 7% of the caucasian population which are
      CYP2D6 poor metabolizers thus may experience therapeutic failure after standard
      doses.

PMID- 12420794
TI  - Ebselen protects against the reduction in levels of drug-metabolizing enzymes in
      livers of rats with deoxycholic acid-induced liver injury.
AB  - Ebselen is a seleno-organic compound that inhibits oxidative stress by lipid
      peroxidation through a glutathione peroxidase-like activity. We studied the
      effect of ebselen on the expression of hepatic drug-metabolizing enzymes in rats
      with deoxycholic acid-induced liver injury. Hydrophobic bile acids, such as
      deoxycholic acid, are known to cause cholestatic liver injury, and it was
      reported that expression of hepatic cytochrome P-450 (CYP) was reduced by
      deoxycholic acid administration in rats. Hydrophobic bile acids induce lipid
      peroxidation in the liver, and this may be one mechanism of the development of
      liver injury. In the present study, we investigated the effect of ebselen (30
      mg/kg/day for 10 days) on rats ingesting deoxycholic acid (1% of diet for 10
      days). Deoxycholic acid decreased levels of CYP1A1, 2B1, 2E1 and 3A2 to 34, 58,
      62 and 37% of control values, respectively, and increased serum alkaline
      phosphatase (ALP) and alanine aminotransferase (ALT) activities to 1.8 and 8.6
      times the levels of controls, respectively. Administration of ebselen with
      deoxycholic acid prevented the decreases in levels of CYP1A1 and 3A2 (86 and 65%
      of control, respectively) and the increases in serum ALP and ALT activities (1.4
      and 1.9 times of control, respectively) caused by deoxycholic acid. These results
      indicate that ebselen may have a protective effect against hydrophobic bile acid
      induced liver injury.

PMID- 12420795
TI  - Behavioural effects in rodents of methyl angolensate: a triterpenoid isolated
      from Entandrophragma angolense.
AB  - Behavioral effects of methyl angolensate were investigated in mice and rats.
      Spontaneous motor activity, pentobarbital sleeping time, amphetamine-stereotyped
      behaviour, exploratory activity and apomorphine-induced climbing studies in mice
      were evaluated. The results revealed that methyl angolensate reduced spontaneous
      motor activity in mice, prolonged the duration of pentobarbital sleeping time in
      rats and attenuated amphetamine-induced stereotype behaviour in rats. Methyl
      angolensate also decreased exploratory activity in mice and reduced the rate of
      apomorphine-induced climbing in mice at the doses tested. It is suggested that
      methyl angolensate possesses some biologically active principles that are
      sedative in nature.

PMID- 12420796
TI  - Regional differences in the effect of oestrogen on vascular tone in isolated
      rabbit arteries.
AB  - The aim of the study was to assess how oestrogen acutely affects the tone of
      isolated artery segments from different vascular beds in rabbit. Cumulative
      concentrations of 17beta-oestradiol were added to ring segments of thoracic
      aorta, pulmonary artery, ear artery and coronary arteries from adult male
      rabbits. Coronary arteries precontracted with potassium or the thromboxane
      agonist, U46619, relaxed to oestrogen (10(-7) to 10(-4) M), whereas oestrogen
      (10(-8) to 10(-4) M) only caused additional contraction in segments of thoracic
      aorta and pulmonary artery precontracted with phenylephrine. In the thoracic
      aorta both the phospholipase C inhibitor NCDC (10(-4) M) and the cyclooxygenase
      inhibitor indomethacin (10(-5) M) almost completely blocked the contractile
      effect of oestrogen. In segments of the ear artery, oestrogen caused relaxation
      only at higher concentrations of oestrogen (10(-5) to 10(-4) M). In conclusion,
      oestrogen may cause both relaxation and vasoconstriction in different vascular
      beds, and in the thoracic aorta the contractile effects of oestrogen may be
      mediated via inositol phosphate-dependent pathways and release of prostaglandins.

PMID- 12420797
TI  - Dose response of carboplatin-induced nephrotoxicity in rats.
AB  - Abstract: Carboplatin, a second-generation platinum-containing anticancer drug,
      is currently being used against a variety of cancers. High-dose carboplatin
      chemotherapy can cause renal tubular injury in cancer patients. However, the
      biochemical mechanism of carboplatin-induced renal injury has not been well
      studied. This study investigated the dose response of carboplatin-induced changes
      in endogenous antioxidants, lipid peroxidation and platinum content in rat
      kidney. Male Wistar rats (250-300 g) were divided into five groups and treated as
      follows: (1) control (saline, intraperitoneally); (2) carboplatin (64 mg/kg,
      intraperitoneally); (3) carboplatin (128 mg/kg, intraperitoneally); (4)
      carboplatin (192 mg/kg, intraperitoneally); and (5) carboplatin (256 mg/kg,
      intraperitoneally). The animals were sacrificed four days after treatment. The
      blood and kidneys were isolated and analyzed. Plasma creatinine and blood urea
      nitrogen levels were increased significantly in response to carboplatin in a dose
      dependent manner. Renal superoxide dismutase and catalase activities were
      decreased significantly due to carboplatin at dosages of 128 mg/kg and above. The
      protein expressions of renal copper/zinc-superoxide dismutase and manganese
      superoxide dismutase significantly depleted after carboplatin. Carboplatin (192
      and 256 mg/kg) significantly increased lipid peroxidation (malondialdehyde
      concentration) in rat kidneys. Carboplatin dose-dependently increased the renal
      platinum concentration, with significance at dosages of 128 mg/kg and above.
      Carboplatin (256 mg/kg) significantly increased renal xanthine oxidase activity,
      while ratio of reduced to oxidized glutathione depleted significantly. The data
      suggested that carboplatin caused dose-dependent oxidative renal injury, as
      evidenced by renal antioxidant depletion, enhanced lipid peroxidation, platinum
      content, plasma creatinine and blood urea nitrogen levels in rats.

PMID- 12420798
TI  - Beneficial effects of trandolapril in uninephrectomized spontaneously
      hypertensive rats: role of cyclooxygenase pathway.
AB  - The antihypertensive efficacy of the angiotensin-converting enzyme inhibitor
      trandolapril was evaluated in uninephrectomized spontaneously hypertensive rats.
      After 5 weeks of treatment, blood pressure, cardiac and aortic mass, as well as
      the functional status of the aortic endothelium, and the role played by the
      cyclooxygenase pathway were investigated. In addition, the effect of a sub
      antihypertensive dose of the calcium antagonist verapamil, in combination with
      trandolapril, was also investigated. As compared to placebo, trandolapril
      returned blood pressure and aortic lamina media cross sectional area to
      normotensive values, significantly reduced the heart-to-body weight, and improved
      the acetylcholine-induced relaxation of aortic rings. This latter effect is
      thought to be mediated by the elimination of a substance derived from the
      cyclooxygenase pathway. Verapamil, in single therapy, did not reduce blood
      pressure, or heart-to-body weight, increased aortic lamina media cross sectional
      area and impaired acetylcholine-induced relaxation. When combined with
      trandolapril in dual therapy, some of the beneficial effects of trandolapril
      remained, whereas others were counterbalanced by verapamil. In conclusion,
      trandolapril proved to be an effective therapeutic drug in this animal model of
      hypertension. Combination of trandolapril with a sub-antihypertensive dose of
      verapamil did not show any positive synergistic effect; on the contrary, it
      outweighed some of the beneficial effects of trandolapril.

PMID- 12420799
TI  - Glutamate uptake in synaptic plasticity: from mollusc to mammal.
AB  - A great deal of research has been directed toward understanding the cellular
      mechanisms underlying synaptic plasticity and memory formation. To this point,
      most research has focused on the more "active" components of synaptic
      transmission: presynaptic transmitter release and postsynaptic transmitter
      receptors. Little work has been done characterizing the role neurotransmitter
      transporters might play during changes in synaptic efficacy. We review several
      new experiments that demonstrate glutamate transporters are regulated during
      changes in the efficacy of glutamatergic synapses. This regulation occurred
      during long-term facilitation of the sensorimotor synapse of Aplysia and long
      term potentiation of the Schaffer-collateral synapse of the rat. We propose that
      glutamate transporters are "co-regulated" with other molecules/processes involved
      in synaptic plasticity, and that this process is phylogenetically conserved.
      These new findings indicate that glutamate transporters most likely play a more
      active role in neurotransmission than previously believed.

PMID- 12420800
TI  - LTP, memory and structural plasticity.
AB  - Our current understanding of the mechanisms of information processing and storage
      in the brain, based on the concept proposed more than fifty years ago by D. Hebb,
      is that a key role is played by changes in synaptic efficacy induced by
      coincident pre- and postsynaptic activity. Decades of studies of the properties
      of long-term potentiation (LTP) have shown that this form of plasticity
      adequately fulfills these requirements and is likely to contribute to several
      models of learning and memory. Recent analyses of the molecular events implicated
      in LTP are consistent with the view that modifications of receptor properties or
      insertion of new receptors account for the potentiation of synaptic transmission.
      These experiments, however, have also uncovered an unexpected structural
      plasticity of synapses. Dendritic spines appear to be dynamic structures that can
      be formed, modified in their shape or eliminated under the influence of activity.
      Furthermore, recent studies suggest that LTP, in addition to changes in synaptic
      function, is also associated with mechanisms of synaptogenesis. We review here
      the evidence pointing to this activity-dependent remodeling and discuss the
      possible role of this structural plasticity for synaptic potentiation, learning
      and memory.

PMID- 12420801
TI  - Gene control of synaptic plasticity and memory formation: implications for
      diseases and therapeutic strategies.
AB  - There has been nearly a century of interest in the idea that information is
      stored in the brain as changes in the efficacy of synaptic connections between
      neurons that are activated during learning. The discovery and detailed report of
      the phenomenon generally known as long-term potentiation opened a new chapter in
      the study of synaptic plasticity in the vertebrate brain, and this form of
      synaptic plasticity has now become the dominant model in the search for the
      cellular and molecular bases of learning and memory. Accumulating evidence
      suggests that the rapid activation of the genetic machinery is a key mechanism
      underlying the enduring modification of neural networks required for the laying
      down of memory. Here we briefly review these mechanisms and illustrate with a few
      examples of animal models of neurological disorders how new knowledge about these
      mechanisms can provide valuable insights into identifying the mechanisms that go
      awry when memory is deficient, and how, in turn, characterisation of the
      dysfunctional mechanisms offers prospects to design and evaluate molecular and
      biobehavioural strategies for therapeutic prevention and rescue.

PMID- 12420802
TI  - Stress, metaplasticity, and antidepressants.
AB  - A large body of evidence has established a link between stressful life events and
      development or exacerbation of depression. At the cellular level, evidence has
      emerged indicating neuronal atrophy and cell loss in response to stress and in
      depression. At the molecular level, it has been suggested that these cellular
      deficiencies, mostly detected in the hippocampus, result from a decrease in the
      expression of brain-derived neurotrophic factor (BDNF) associated with elevation
      of glucocorticoids. Thus, an increase in expression of BDNF, facilitating both
      neuronal survival and neurogenesis, is thought to represent a converging
      mechanism of action of various types of antidepressant treatments (e.g.,
      antidepressant drugs and transcranial magnetic stimulation). However, as also
      revealed by converging lines of evidence, high levels of glucocorticoids down
      regulate hippocampal synaptic connectivity ('negative' metaplasticity), whereas
      an increase in expression of BDNF up-regulates connectivity in the hippocampus
      ('positive' metaplasticity). Therefore, antidepressant treatments might not only
      restore cell density but also regulate higher-order synaptic plasticity in the
      hippocampus by abolishing 'negative' metaplasticity, and thus restore hippocampal
      cognitive processes that are altered by stress and in depressed patients. This
      antidepressant regulatory effect on hippocampal synaptic plasticity function,
      which may, in turn, suppress 'negative' metaplasticity in other limbic
      structures, is discussed.

PMID- 12420803
TI  - A comparative review of rodent prefrontal cortex and working memory.
AB  - The prefrontal cortex is critical to working memory processes. Current theories
      of prefrontal function are largely based on primate behavioural and
      electrophysiological data. As molecular genetic techniques advance in mice, so
      investigations into the rodent prefrontal cortex should expand, such that rodent
      models of prefrontal function during working memory may be used to study the
      synaptic and molecular basis of the phenomenon. This review attempts to summarize
      aspects of published data that pertain to working memory and suggest directions
      that will allow a coherent comparison of prefrontal function and interaction in
      monkey, rat and mouse.

PMID- 12420804
TI  - Cellular mechanisms of striatum-dependent behavioral plasticity and drug
      addiction.
AB  - The striatum has long been known to be involved in the control of motor behavior,
      since disruption of dopamine-mediated function in this brain structure is
      directly linked to Parkinson's disease and other disorders of movement. However,
      it is now accepted that both dorsal and ventral striatal nuclei are also
      essential for a variety of cognitive processes, which depend on reward-based
      stimulus-response learning. Since the neuroanatomical and neurochemical
      organization of dorsal and ventral striatum is only partially overlapping, it is
      likely that both common and nucleus-specific cellular and molecular events
      contribute to synaptic plasticity, learning and memory processes mediated by
      these cerebral structures. Alterations in cell signaling in the striatum may be
      particularly important in the response to both acute and chronic administration
      of drugs of abuse, resulting in maladaptive changes in the reward-based
      associative learning involved in addiction, withdrawal and relapse.

PMID- 12420805
TI  - Synaptic plasticity in drug reward circuitry.
AB  - Drug addiction is a major public health issue worldwide. The persistence of drug
      craving coupled with the known recruitment of learning and memory centers in the
      brain has led investigators to hypothesize that the alterations in glutamatergic
      synaptic efficacy brought on by synaptic plasticity may play key roles in the
      addiction process. Here we review the present literature, examining the
      properties of synaptic plasticity within drug reward circuitry, and the effects
      that drugs of abuse have on these forms of plasticity. Interestingly, multiple
      forms of synaptic plasticity can be induced at glutamatergic synapses within the
      dorsal striatum, its ventral extension the nucleus accumbens, and the ventral
      tegmental area, and at least some of these forms of plasticity are regulated by
      behaviorally meaningful administration of cocaine and/or amphetamine. Thus, the
      present data suggest that regulation of synaptic plasticity in reward circuits is
      a tractable candidate mechanism underlying aspects of addiction.

PMID- 12420806
TI  - Avian influenza S T R I K E S Virginia poultry farms.

PMID- 12420807
TI  - Veterinarians help protect soldiers in Operation Enduring Freedom.

PMID- 12420809
TI  - Officials fine-tune salmon virus response.

PMID- 12420808
TI  - Commendations for service veterinarians, induced molting among 2002 resolutions.

PMID- 12420810
TI  - And coming around the track, looking promising ... the horse genome map.

PMID- 12420811
TI  - What's in the water?

PMID- 12420812
TI  - Debate over trap-neuter-release programs for feral cats to continue in Nashville.

PMID- 12420813
TI  - NASA veterinarian treats Hubble Space Telescope.

PMID- 12420814
TI  - Thinks transdermal fentanyl patches are dangerous.

PMID- 12420815
TI  - Examining intestinal biopsy specimens.

PMID- 12420816
TI  - Stray voltage in a poultry facility.

PMID- 12420817
TI  - In favor of docking tails for cows in confinement facilities.

PMID- 12420818
TI  - Reactions to FMD scare.

PMID- 12420819
TI  - Reactions to FMD scare.

PMID- 12420820
TI  - What is your diagnosis? An oval gas lucency.

PMID- 12420821
TI  - Product liability and livestock feed.

PMID- 12420822
TI  - Biological terrorism against animals and humans: a brief review and primer for
      action.

PMID- 12420823
TI  - Compendium of animal rabies prevention and control, 2002.

PMID- 12420824
TI  - Evaluation of a routine diagnostic fecal panel for dogs with diarrhea.
AB  - OBJECTIVES: To assess the diagnostic yield of a routine fecal panel and determine
      whether Clostridium perfringens or C difficile toxin production is associated
      with acute hemorrhagic diarrheal syndrome (AHDS) in dogs. DESIGN: Case-control
      study. ANIMALS: 260 dogs with diarrhea and 177 dogs with normal feces. PROCEDURE:
      Medical records were reviewed for results of culture for C difficile,
      Campylobacterspp, and Salmonella spp; C perfringens fecal enterotoxin (CPE) assay
      via ELISA or reverse passive latex agglutination (RPLA) assay; fecal endospore
      enumeration; C difficile toxin A assay; and parasite evaluation. RESULTS:
      Prevalence of CPE in dogs with diarrhea was 22/154 (14.3%) via ELISA and 47/104
      (45.2%) via RPLA assay, versus 9/74 (12%) via ELISA and 26/103 (25%) via RPLA
      assay in control dogs. Prevalence of C difficile was 47/260 (18%) in dogs with
      diarrhea and 41/74 (55%) in control dogs. Prevalence of C difficile toxin A was
      26/254 (10.2%) in dogs with diarrhea and 0/74 in control dogs. Diagnosis of AHDS
      was made in 27 dogs; 8 had positive results for CPE, 7 had positive results for
      toxin A, and 1 had positive results for both toxins. Campylobacter spp were
      isolated from 13 of 260 (5%) dogs with diarrhea and 21 of 74 (28.4%) control
      dogs. Salmonella spp were isolated from 3 (1.2%) dogs with diarrhea. CONCLUSIONS
      AND CLINICAL RELEVANCE: Diagnostic value of a fecal panel in dogs with diarrhea
      appears to be low.

PMID- 12420825
TI  - Correlation between severity of clinical signs and motor evoked potentials after
      transcranial magnetic stimulation in large-breed dogs with cervical spinal cord
      disease.
AB  - OBJECTIVE: To evaluate use of transcranial magnetic motor evoked potentials for
      assessment of the functional integrity of the cervical spinal cord in large-breed
      dogs with cervical spinal cord disease. DESIGN: Randomized, controlled, masked
      study. ANIMALS: 10 healthy large-breed control dogs and 25 large-breed dogs with
      cervical spinal cord diseases. PROCEDURE: Affected dogs were allocated to 3
      groups on the basis of neurologic status: signs of neck pain alone, ambulatory
      with ataxia in all limbs, or nonambulatory. Transcranial magnetic stimulation was
      performed on each dog with the same standard technique. Motor evoked potentials
      (MEP) were recorded from electrodes inserted in the tibialis cranialis muscle.
      Following the procedure, each dog was anesthetized and cervical radiography, CSF
      analysis, and cervical myelography were performed. The MEP latencies and
      amplitudes were correlated with neurologic status of the dogs after correction
      for neuronal path length. RESULTS: Mean MEP latencies and amplitudes were
      significantly different between control dogs and dogs in each of the 3 neurologic
      categories, but were not significantly different among dogs in the 3 neurologic
      categories. A linear association was evident between MEP latencies and amplitudes
      and severity of neurologic deficits; the more severe the neurologic deficits, the
      more prolonged the latencies and the more decreased the amplitudes. CONCLUSIONS
      AND CLINICAL RELEVANCE: Transcranial magnetic MEP are useful to assess severity
      of cervical spinal cord disease in large-breed dogs. Impairment of the functional
      integrity of the cervical spinal cord was found even in dogs with neck pain
      alone.

PMID- 12420826
TI  - Effects of a program of human interaction and alterations in diet composition on
      activity of the hypothalamic-pituitary-adrenal axis in dogs housed in a public
      animal shelter.
AB  - OBJECTIVE: To determine whether a program of human interaction or alterations in
      diet composition would alter activity of the hypothalamic-pituitary-adrenal (HPA)
      axis in dogs housed in an animal shelter. DESIGN: Prospective study. ANIMALS: 40
      dogs. PROCEDURE: Dogs were (n = 20) or were not (20) enrolled in a program of
      regular supplemental human interaction (20 min/d, 5 d/wk, for 8 weeks) involving
      stroking, massaging, and behavioral training. In addition, half the dogs in each
      group were fed a typical maintenance-type diet, and the other half were fed a
      premium diet. Plasma cortisol and ACTH concentrations were measured during weeks
      0, 2, 4, and 8 and before and after exposure to a battery of novel situations
      during weeks 0 and 8. RESULTS: Plasma cortisol concentration was significantly
      decreased by week 2, but plasma ACTH concentration was not significantly
      decreased until week 8 and then only in dogs fed the premium diet. Following
      exposure to novel situations, plasma cortisol and ACTH concentrations were
      significantly increased. However, during week 8, dogs enrolled in the program of
      human interaction had significantly lower increases in cortisol concentration
      than did dogs not enrolled in the program. CONCLUSIONS AND CLINICAL RELEVANCE:
      Results suggest that both a program of human interaction and alterations in diet
      composition have moderating effects on activity of the HPA axis in dogs housed in
      an animal shelter and that activity of the HPA axis may be increased for a longer
      period during shelter housing than measurement of plasma cortisol concentration
      alone would suggest.

PMID- 12420827
TI  - Use of low doses of ketamine administered by constant rate infusion as an adjunct
      for postoperative analgesia in dogs.
AB  - OBJECTIVE: To compare indicators of postoperative pain and behavior in dogs with
      and without a low-dose ketamine infusion added to usual perioperative management.
      DESIGN: Prospective, randomized, blinded clinical study. ANIMALS: 27 dogs
      undergoing forelimb amputation. PROCEDURE: Dogs were anesthetized with
      glycopyrrolate, morphine, propofol, and isoflurane. Thirteen dogs were treated
      with ketamine IV, as follows: 0.5 mg/kg (0.23 mg/lb) as a bolus before surgery,
      10 microg/kg/min (4.5 microg/lb/min) during surgery, and 2 microg/kg/min (0.9
      microg/lb/min) for 18 hours after surgery. Fourteen dogs received the same volume
      of saline (0.9% NaCl) solution. All dogs received an infusion of fentanyl (1 to 5
      microg/kg/h [0.45 to 2.27 pg/lb/h]) for the first 18 hours after surgery. Dogs
      were evaluated for signs of pain before surgery, at the time of extubation, and
      1, 2, 3, 4, 12, and 18 hours after extubation. Owners evaluated their dogs'
      appetite, activity, and wound soreness on postoperative days 2, 3, and 4.
      RESULTS: Dogs that received ketamine infusions had significantly lower pain
      scores 12 and 18 hours after surgery and were significantly more active on
      postoperative day 3 than dogs that received saline solution infusions.
      CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that perioperative
      administration of low doses of ketamine to dogs may augment analgesia and comfort
      in the postoperative surgical period.

PMID- 12420828
TI  - Measurement of the cardiac silhouette in psittacines.
AB  - OBJECTIVE: To determine reference values for size of the radiographic cardiac
      silhouette in healthy adult medium-sized psittacines. DESIGN: Prospective case
      series. ANIMALS: 46 African grey parrots (Psittacus erythacus), 7 Senegal parrots
      (Poicephalus senegalis), and 6 orange-winged Amazon parrots (Amazona amazonica).
      PROCEDURE: Birds were anesthetized, and ventrodorsal radiographic projections
      were obtained. Maximum width of the cardiac silhouette, width of the thorax at
      the level of the maximum width of the cardiac silhouette, and width of the
      coracoid were measured on the radiographs. Sternum length was directly measured
      on individual birds. Results of physical examination, electrocardiography, and
      echocardiography were normal in all birds. RESULTS: Mean cardiac silhouette width
      to-sternum length ratio was 38%, mean cardiac silhouette width-to-thorax width
      ratio was 55%, and mean cardiac silhouette width-to-coracoid width ratio was
      600%. Width of the cardiac silhouette was strongly correlated with length of the
      sternum, width of the coracoid, and width of the thorax. No significant
      differences between species were detected. CONCLUSIONS AND CLINICAL RELEVANCE:
      Results suggest that in healthy adult medium-sized psittacines, the cardiac
      silhouette on a ventrodorsal radiographic projection should be 35 to 41 % of the
      length of the sternum, 51 to 61 % of the width of the thorax, and 545 to 672% of
      the width of the coracoid.

PMID- 12420829
TI  - Clinical features of avian vacuolar myelinopathy in American coots.
AB  - OBJECTIVE: To characterize clinical features of avian vacuolar myelinopathy (AVM)
      in American coots. DESIGN: Case-control study. ANIMALS: 26 AVM-affected American
      coots and 12 unaffected coots. PROCEDURES: Complete physical, neurologic,
      hematologic, and plasma biochemical evaluations were performed. Affected coots
      received supportive care. All coots died or were euthanatized, and AVM status was
      confirmed via histopathologic findings. RESULTS: 3 severely affected coots were
      euthanatized immediately after examination. Seventeen affected coots were found
      dead within 7 days of admission, but 5 affected coots survived > 21 days and had
      signs of clinical recovery. Abnormal physical examination findings appeared to be
      related to general debilitation. Ataxia (88%), decreased withdrawal reflexes
      (88%), proprioceptive deficits (81%), decreased vent responses (69%), beak or
      tongue weakness (42%), and head tremors (31%), as well as absent pupillary light
      responses (46%), anisocoria (15%), apparent blindness (4%), nystagmus (4%), and
      strabismus (4%) were detected. Few gross abnormalities were detected at necropsy,
      but histologically, all AVM-affected coots had severe vacuolation of white matter
      of the brain. None of the control coots had vacuolation. CONCLUSIONS AND CLINICAL
      RELEVANCE: Although there was considerable variability in form and severity of
      clinical neurologic abnormalities, clinical signs common in AVM-affected birds
      were identified. Clinical recovery of some AVM-affected coots can occur when
      supportive care is administered. Until the etiology is identified, caution should
      be exercised when rehabilitating and releasing coots thought to be affected by
      AVM.

PMID- 12420830
TI  - Medical and surgical treatment of pyothorax in dogs: 26 cases (1991-2001).
AB  - OBJECTIVE: To compare outcomes of dogs with pyothorax treated medically versus
      surgically and to identify prognostic indicators for dogs with pyothorax. DESIGN:
      Retrospective study. ANIMALS: 26 dogs. PROCEDURE: Medical records were reviewed
      to obtain information regarding signalment, results of physical and laboratory
      evaluations at the time of initial examination, results of bacterial culture of
      pleural fluid, radiographic abnormalities, treatment (surgical vs medical),
      complications, whether the disease recurred, disease-free interval, survival
      time, and cause of death. RESULTS: Calculated proportions of dogs free from
      disease 1 year after treatment were 25 and 78%, respectively, for dogs treated
      medically and surgically. Treatment was 5.4 times as likely to fail in dogs
      treated medically as in dogs treated surgically. Two regression models relating
      treatment group (medical vs surgical) to disease-free interval were found to be
      significant. The first contained terms for medical treatment and isolation of
      Actinomyces spp from pleural fluid; the second contained terms for medical
      treatment and radiographic detection of mediastinal or pulmonary lesions at the
      time of initial examination. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest
      that surgical treatment is associated with a better outcome than medical
      treatment in dogs with pyothorax. In addition, surgery should be considered if
      radiographic evidence of mediastinal or pulmonary lesions is detected or if
      Actinomyces spp is isolated from the pleural fluid.

PMID- 12420831
TI  - Primary pure red cell aplasia in dogs: 13 cases (1996-2000).
AB  - OBJECTIVES: To examine clinical features, laboratory test results, treatment, and
      outcome of dogs with pure red cell aplasia (PRCA). DESIGN: Retrospective study.
      ANIMALS: 13 dogs with severe nonregenerative anemia and bone marrow erythroid
      aplasia. PROCEDURES: Medical records of dogs determined to have PRCA on the basis
      of results of blood and bone marrow analysis between 1996 and 2000 were reviewed.
      Criteria for inclusion in the study were severe nonregenerative anemia (Hct <
      20%; reticulocyte count < 1.0%), selective erythroid aplasia in bone marrow, and
      lack of underlying diseases that may have caused the anemia. RESULTS: Median age
      of dogs was 6.5 years. Females were significantly overrepresented. Median Hct was
      10%, and median reticulocyte count was 0.1%. Direct Coombs' test results were
      negative for all dogs tested, and spherocytosis was evident in 2 dogs. All dogs
      were treated with prednisolone, and 2 dogs were treated with prednisolone and
      cyclophosphamide. Responses to treatment were complete, partial, and poor in 10,
      1, and 2 dogs, respectively. Median time required to achieve an increase of 5% or
      more in Hct was 38 days, and median time to complete remission was 118 days. Of
      10 dogs for which follow-up information was available, only 1 required long-term
      immunosuppressive treatment. CONCLUSIONS AND CLINICAL RELEVANCE: Dogs with PRCA
      appear to respond readily to treatment with immunosuppressive drugs; however,
      hematologic responses may not be observed for weeks to months after initiation of
      treatment.

PMID- 12420832
TI  - Use of a hemoglobin-based oxygen-carrying solution in cats: 72 cases (1998-2000).
AB  - OBJECTIVE: To determine clinical features and outcome associated with use of a
      hemoglobin-based oxygen-carrying (HBOC) solution in cats. DESIGN: Retrospective
      study. ANIMALS: 72 cats. PROCEDURE: Medical records of cats that received an HBOC
      solution were reviewed. RESULTS: The most common clinical signs and physical
      examination findings prior to infusion of the HBOC solution were associated with
      anemia; vomiting, neurologic signs, and respiratory abnormalities were also
      detected. The HBOC solution was given as a supportive measure in treatment of
      anemia in 70 cats, most often because compatible blood was not readily available.
      There were 80 separate HBOC solution infusion events (mean dose, 14.6 ml/kg [6.6
      mg/lb]; mean rate of infusion, 4.8 ml/kg [2.2 ml/lb] per hour). Improvements in
      37 of 43 of the more closely monitored cats included increased rectal
      temperature, blood hemoglobin concentration, blood pressure, appetite, and
      activity. Adverse events in 44 cats included pulmonary edema (n = 8), pleural
      effusion (21), mucous membrane discoloration (21), pigmenturia (11), vomiting
      (4), and neurologic abnormalities (4). Twenty-three cats were discharged from the
      hospital, and 49 cats died or were euthanatized. Necropsy examination of 23 cats
      did not reveal evidence of renal or hepatic toxicosis associated with HBOC
      administration. CONCLUSIONS AND CLINICAL RELEVANCE: Although administration of an
      HBOC solution may provide temporary support to anemic cats, the development of
      pulmonary edema or pleural effusion potentially associated with rapid infusion
      rate and large volume of infusion of the HBOC solution should be investigated
      further before use of the solution can be recommended in cats.

PMID- 12420833
TI  - Use of antimicrobial susceptibility testing of bacterial pathogens isolated from
      the milk of dairy cows with clinical mastitis to predict response to treatment
      with cephapirin and oxytetracycline.
AB  - OBJECTIVE: To determine whether results of antimicrobial susceptibility testing
      of bacterial pathogens isolated from the milk of dairy cows with clinical
      mastitis were associated with duration of clinical signs or bacteriologic cure
      rate following treatment with cephapirin and oxytetracycline. DESIGN:
      Observational study on a convenience sample. ANIMALS: 58 dairy cows with 121
      episodes of clinical mastitis. PROCEDURE: Cows that only had abnormal glandular
      secretions were treated with cephapirin alone. Cows with an inflamed gland and
      abnormal glandular secretions were treated with oxytetracycline and cephapirin.
      Cows with systemic signs of illness, an inflamed gland, and abnormal glandular
      secretions were treated with oxytetracycline and flunixin meglumine and frequent
      stripping of the affected glands. The Kirby-Bauer method was used for
      antimicrobial susceptibility testing, and current guidelines were used to
      categorize causative bacteria as susceptible or resistant to the treatment
      regimen. RESULTS: Median durations of episodes of clinical mastitis caused by
      susceptible (n = 97) and resistant (24) bacteria were not significantly
      different. Bacteriologic cure rates at 14 and 28 days were similar for episodes
      caused by susceptible and resistant bacteria; however, for 56 episodes of
      clinical mastitis caused by gram-positive bacteria and treated with cephapirin
      alone, bacteriologic cure rate at 28 days was significantly higher for
      susceptible than for resistant bacteria. CONCLUSIONS AND CLINICAL RELEVANCE:
      Results suggest that antimicrobial susceptibility testing was of no value in
      predicting duration of clinical signs or bacteriologic cure rate in dairy cows
      with mastitis, except for episodes caused by gram-positive organisms treated with
      intramammary administration of cephapirin alone.

PMID- 12420834
TI  - Evidence-based medicine: its relevance in maternal, fetal and neonatal medicine.

PMID- 12420835
TI  - The term, singleton, vaginal breech delivery controversy.

PMID- 12420836
TI  - Second-trimester uterine artery Doppler screening in unselected populations: a
      review.
AB  - OBJECTIVE: Doppler ultrasound provides a non-invasive method for the study of the
      uteroplacental circulation. In normal pregnancy, impedance to flow in the uterine
      arteries decreases with gestation, which may be the consequence of trophoblastic
      invasion of the spiral arteries and their conversion into low-resistance vessels.
      Pre-eclampsia and fetal growth restriction are associated with failure of
      trophoblastic invasion of spiral arteries, and Doppler studies, in these
      conditions, have shown that impedance to flow in the uterine arteries is
      increased. A series of screening studies involving assessment of impedance to
      flow in the uterine arteries have examined the potential value of Doppler in
      identifying pregnancies at risk of the complications of impaired placentation.
      This review examines the findings of Doppler studies in unselected populations.
      METHODS: Searches of a computerized medical database were performed to identify
      relevant studies. Only those studies that provided sufficient data to allow
      calculation of the performance of the test were included in the analysis.
      Likelihood ratios were calculated for each study and are reported for pre
      eclampsia, fetal growth restriction and perinatal death as well as for more
      severe forms of pre-eclampsia and fetal growth restriction. RESULTS: The
      literature search identified 19 relevant studies, four of which were excluded
      from the further analysis. The main characteristics and results of the 15
      remaining studies provided discrepant results, which may be the consequence of
      differences in Doppler technique for sampling, the definition of abnormal flow
      velocity waveform, differences in the populations examined, the gestational age
      at which women were studied and different criteria for the diagnosis of pre
      eclampsia and fetal growth restriction. Nevertheless, the studies provided
      evidence that increased impedance to flow in the uterine arteries is associated
      with increased risk for subsequent development of pre-eclampsia, fetal growth
      restriction and perinatal death. In addition, women with normal impedance to flow
      in the uterine arteries constituted a group that have a low risk of developing
      obstetric complications related to uteroplacental insufficiency. CONCLUSIONS: The
      review suggests that increased impedance to flow in the uterine arteries in
      pregnancies attending for routine antenatal care identifies about 40% of those
      who subsequently develop pre-eclampsia and about 20% of those who develop fetal
      growth restriction. Following a positive test, the likelihood of these
      complications is increased by about 6 and 3.5 times, respectively.

PMID- 12420837
TI  - Screening for trisomy 21 by maternal age, fetal nuchal translucency and maternal
      serum biochemistry at 11-14 weeks: a German multicenter study.
AB  - OBJECTIVE: To examine the effectiveness of screening for trisomy 21 by a
      combination of maternal age, fetal nuchal translucency (NT) thickness and
      maternal serum biochemistry using free beta-human chorionic gonadotropin (hCG)
      and pregnancy-associated plasma protein-A (PAPP-A) at 11-14 weeks of gestation.
      METHODS: This was a multicenter study of screening for trisomy 21 by a
      combination of maternal age, fetal NT and maternal serum free beta-hCG and PAPP-A
      at 11-14 weeks of gestation, using the methodology developed by the Fetal
      Medicine Foundation. The distribution of estimated risks for trisomy 21 was
      determined and the sensitivity and false-positive rate for a risk cut-off of 1 in
      300 were calculated. RESULTS: In total, 3864 singleton pregnancies with live
      fetuses at 11-14 weeks were examined and the fetal NT and maternal serum free
      beta-hCG and PAPP-A were successfully measured in all cases. The median maternal
      age was 33 (range 15-46) years and, in 1271 (35.8%), the age was 35 years or
      more, the median gestation at screening was 12 (11-14) weeks and the median fetal
      crown-rump length was 64 (range 45-84) mm. The fetal NT was above the 95th
      centile in 73.7% (14 of 19) of trisomy 21 and in 4.8% (169 of 3505) of normal
      pregnancies. The estimated risk for trisomy 21 based on maternal age, fetal NT
      and maternal serum free beta-hCG and PAPP-A was 1 in 300 or greater in 6.6% (233
      of 3505) of normal pregnancies, in 84.2% (16 of 19) of those with trisomy 21 and
      88.9% (24 of 27) of those with other chromosomal defects. CONCLUSIONS: In
      Germany, the results of screening for chromosomal defects by measurement of fetal
      NT and maternal serum biochemistry, in centers with appropriately qualified
      sonographers, are similar to those reported in the UK using the same methodology.

PMID- 12420838
TI  - Optimal thresholds of the lecithin/sphingomyelin ratio and lamellar body count
      for the prediction of the presence of phosphatidyl glycerol in diabetic women.
AB  - OBJECTIVE: To assess the optimal thresholds of the lecithin/sphingomyelin (L/S)
      ratio and lamellar body count for the prediction of the presence of phosphatidyl
      glycerol (PG) in diabetic pregnant women. METHODS: We accessed a database of
      clear amniotic fluid specimens obtained by transabdominal amniocentesis in
      diabetic women with singleton non-malformed fetuses. PG results were classified
      as 'absent' or 'present'. Receiver operating characteristic (ROC) curve analysis
      was constructed of different L/S ratios and lamellar body counts to identify the
      optimal threshold for prediction of the presence of PG. Sensitivity was defined
      as the rate of L/S ratio and lamellar body count above specific thresholds among
      cases with present PG. The false-positive rate was that of L/S ratios or lamellar
      body counts above specific thresholds among cases with absent PG. Statistical
      analysis included one-way analysis of variance with post-hoc analysis, with p <
      0.05 considered significant. RESULTS: A total of 76 consecutive women were
      included in the analysis, 74% (n = 56) using insulin and the remainder treated by
      diet alone. L/S and PG results were both available in 72 women. PG was reported
      as 'present' in 70% (51/73) of specimens. As expected, there was a significant
      relationship between L/S ratios and presence of PG (area under the curve = 0.932,
      p < 0.001). An L/S ratio of > or = 3.0 represented the optimal trade-off between
      sensitivity (68%) and false-positive rate (6%) in the prediction of present PG.
      Similarly, there was a significant relationship between lamellar body count
      values and presence of PG (area under the curve = 0.976, p < 0.001). A lamellar
      body count of > or = 50 000 represented the optimal trade-off between sensitivity
      (92%) and false-positive rate (0%) in the prediction of present PG. CONCLUSION:
      In diabetic pregnant patients, the presence of PG in the amniotic fluid more
      closely corresponded to an L/S ratio of > or = 3.0 or to a lamellar body count of
      > or = 50,000.

PMID- 12420839
TI  - Central nervous system lupus and pregnancy: 11-year experience at a single
      center.
AB  - OBJECTIVE: To describe the pregnancy outcomes in women with central nervous
      system (CNS) manifestations of lupus. METHODS: Between 1991 and 2002, the outcome
      of five pregnancies in four patients with CNS lupus were retrospectively
      reviewed. All patients had an established history of systemic lupus erythematosus
      (SLE), and either a history of CNS lupus or active CNS lupus. Pregnancy outcomes
      assessed included term and preterm birth, intrauterine growth restriction,
      abnormal antepartum testing, perinatal mortality, pre-eclampsia and other
      maternal morbidities. RESULTS: Evidence of active CNS lupus symptoms developed in
      three of the five pregnancies. Two pregnancies were complicated by early onset
      pre-eclampsia, abnormal antepartum testing and extreme prematurity, with one
      subsequent neonatal death. The remaining three pregnancies had good neonatal
      outcomes, but were complicated by severe maternal post-pregnancy exacerbations,
      and the eventual death of one patient. CONCLUSIONS: CNS lupus in pregnancy
      represents an especially severe manifestation of SLE, and may involve great
      maternal and fetal risks.

PMID- 12420840
TI  - Umbilical vein and middle cerebral artery blood flow response to partial
      occlusion by external compression of the umbilical vein (pressure test).
AB  - OBJECTIVES: We studied the responses of flow in the umbilical vein and of the
      circulation in the proximal segment of the middle cerebral artery (MCA) during
      partial external compression of the umbilical vein. METHODS: Partial occlusion of
      the umbilical vein was achieved by the pressure test, consisting of applying
      external pressure on the maternal abdominal wall for 1-2 s. RESULTS: During 60
      pressure tests in 45 fetuses with nuchal cords, we observed complete cessation of
      the umbilical vein flow, while blood flow in the umbilical arteries was
      preserved, and proximal MCA flow was moderately or markedly decreased. Blood flow
      in other segments of the MCA was unchanged. This effect, which was more
      pronounced before the 32nd week of gestation, was also observed in association
      with spontaneous fetal movements. CONCLUSION: The pressure test decreases flow in
      the proximal MCA, and interrupts umbilical vein blood flow. Further analysis of
      this response suggested the presence of associated vasoconstriction of the
      proximal MCA.

PMID- 12420841
TI  - Heat shock protein 70 expression in neonatal rats after hypoxic stress.
AB  - OBJECTIVES: The tissue damage due to hypoxia in newborns is to some extent age
      dependent; organs of premature babies are more vulnerable to hypoxic insult than
      full-term neonates. The aim of this immunohistochemical study was to investigate
      the role of heat shock protein 70 (HSP70), a stress-inducible protein, in
      developing the response to hypoxia in premature newborns. METHODS: Postnatal day
      7 rats (corresponding to a human fetus of 32-34 weeks' gestation) and day-12 rats
      (corresponding to a full-term newborn infant) (n = 7) were subjected to mild
      hypoxia at 33 degrees C. Control rats (n = 7) for each group breathed room air
      for 4 h. After 4 h of recovery, the animals were killed, and brains, hearts and
      kidneys were removed for immunohistochemical staining. RESULTS:
      Immunohistochemically, HSP70 expression was found to be induced in the
      hippocampus and myocardium after exposure to hypoxia. The level of HSP70
      expression in the hippocampus after hypoxic stress was significantly higher in
      the 12-day rats than in the 7-day rats (p = 0.03). However, HSP70 expression in
      the myocardium did not show any significant difference between the two groups. In
      addition, no significant induction of HSP70 expression was apparent in the kidney
      of rats exposed to hypoxia or in any organ of the control animals. CONCLUSIONS:
      We conclude that diminished HSP70 expression in the hippocampus of premature
      newborns may play a critical role in developing the response to hypoxic stress.
      However, HSP70 expression in the heart and the kidney after exposure to hypoxia
      did not appear to be related to fetal maturity.

PMID- 12420842
TI  - Magnesium sulfate and neonatal outcomes of preterm neonates.
AB  - OBJECTIVE: To determine whether in utero exposure to magnesium sulfate was
      associated with increased neonatal morbidity and mortality among premature
      neonates, and secondarily to determine the relationship, if any, between duration
      of magnesium sulfate exposure and neonatal morbidity and mortality. METHODS: We
      studied 401 neonates at our institution who were born between 23 and 34 weeks'
      gestation following preterm labor or preterm premature rupture of membranes. The
      population was stratified by exposure to magnesium sulfate and compared by
      various neonatal outcome variables. Similarly, the magnesium-exposed population
      was stratified by duration of exposure and compared for various neonatal outcome
      variables. Student's t test, chi2 test, Fisher's exact test and logistic
      regression were used for analysis. RESULTS: A total of 190 neonates were exposed
      to magnesium sulfate, while 211 neonates were not. The magnesium-exposed neonates
      were delivered at a significantly lower gestational age compared to the unexposed
      neonates (28.2 +/- 3.0 vs. 29.3 +/- 3.1 weeks, p = 0.001). Univariate analysis
      revealed no differences between groups with regard to rates of respiratory
      distress syndrome, intraventricular hemorrhage, periventricular leukomalacia,
      necrotizing enterocolitis, patent ductus arteriosus, histological and clinical
      chorioamnionitis, neonatal sepsis or neonatal death. However, magnesium-exposed
      neonates were more likely to have received antibiotics (71.6% vs. 45.0%, p =
      0.0001) and antenatal steroids (95.8% vs. 61.6%, p = 0.0001), factors known to
      affect perinatal morbidity and mortality. Controlling for antenatal confounding
      factors, magnesium sulfate use was not independently associated with neonatal
      mortality (odds ratio (OR) = 0.66; 95% confidence interval (CI) = 0.28, 1.54; p =
      0.34). Seventy-nine neonates were exposed to magnesium sulfate therapy for more
      than 24 h, while 111 neonates were exposed for 24 h or less. There were no
      significant differences between groups with respect to neonatal outcomes, with
      the exception of an increased rate of clinical chorioamnionitis in the group
      exposed to magnesium for more than 24 h (22% vs. 8.2%, p = 0.005). After
      adjusting for gestational age at delivery, magnesium sulfate exposure for over 24
      h was independently associated with a 2.8-fold increased rate of clinical
      chorioamnionitis (OR = 2.8, 95% CI = 1.14, 6.90; p = 0.02). CONCLUSION: Prenatal
      exposure to magnesium sulfate was not associated with increased neonatal
      morbidity or mortality. However, prolonged exposure to magnesium sulfate may be
      associated with an increased risk of clinical chorioamnionitis.

PMID- 12420843
TI  - Evidence of intrapartum hypoxia-ischemia is not present in the majority of cases
      of neonatal seizures.
AB  - OBJECTIVE: To determine the extent to which neonatal seizures are associated with
      intrapartum hypoxia-ischemia. METHODS: In this case-control study, all neonates
      diagnosed with seizures at a single institution from 1988 to 1999 were compared
      to a control group without seizures matched in a 2:1 fashion for gestational age
      at delivery, birth weight and mode of delivery. Data were abstracted from the
      maternal and neonatal charts. Parametric variables were compared using an
      independent samples t test, and non-parametric variables were compared using a
      Fisher exact test, with p < 0.05 being considered significant. RESULTS: There
      were 13 cases of neonatal seizures identified, of which one was chromosomally
      abnormal and excluded from further analysis. For the cases, the mean gestational
      age at delivery was 34.8 +/- 6.9 weeks, with four preterm and eight term
      deliveries. The mean birth weight for the cases was 2684 +/- 1369 g (range 590
      4350 g). For both cases and controls, 83% were delivered vaginally and 17% by
      Cesarean section. For term neonates with seizures, the mean length of stay was
      11.6 +/- 5.0 days, as compared to 2.5 +/- 0.9 days in the control group (p <
      0.001). A 1-min Apgar score of < 7 was found in six of 12 (50%) cases and seven
      of 24 (29%) controls, and a 5-min Apgar score of < 7 was found in four of 12
      (33%) cases and four of 24 (17%) controls (non-significant). In the controls, the
      mean base excess was -2.8 +/- 2.6 mEq/l, and the mean umbilical arterial pH was
      7.28 +/- 0.09. In the case group, two infants born at 24 weeks did not have an
      umbilical arterial blood gas obtained; in the remaining cases, the mean base
      excess was -7.6 +/- 6.9 mEq/l (p = 0.02), and the mean cord pH was 7.17 +/- 0.23
      (p = 0.065), with only three of ten (30%) having a pH < 7.00 (p = 0.02).
      CONCLUSION: Clinically significant acidosis was found in only 30% of neonates who
      developed seizures, and only one of 12 cases (8%) could possibly have met the
      criteria of the American College of Obstetricians and Gynecologists for
      neurological morbidity linked to intrapartum asphyxia. The majority of cases of
      neonatal seizures were not associated with evidence of intrapartum hypoxia
      ischemia.

PMID- 12420844
TI  - The relationship between pacifier use, bottle feeding and breast feeding.
AB  - OBJECTIVE: To investigate the influence of pacifier use and the introduction of
      formula milk on breast feeding. METHODS: The mothers of 356 healthy newborn
      infants who initiated breast feeding while in-patients were interviewed within 3
      days of birth and later at 2 and 6 months postpartum. Information regarding
      previous birth, breast-feeding frequency, pacifier use and the adoption of
      formula milk were obtained. The data were analyzed using chi2 and Kruskal-Wallis
      tests. RESULTS: At the end of the second month, 264 (74%) of the mothers were
      still breast feeding; by the end of the sixth month this had fallen to 236 (66%).
      Among the 356 mothers, 152 had at least one previous infant, and 132 (86.8%) of
      them had breast fed a previous infant. Of the women who breast fed their previous
      infant for more than 2 months, 112 (84.8%) breast fed the current child until the
      end of the second month and 104 (78.7%) until the end of the sixth month after
      delivery. Of all investigated patients, 204 were primiparous (57.3%). Of these,
      152 (74.5%) breast fed until the end of the second month, and 132 (64.7%) until
      the end of the sixth month after delivery. Amongthe 204 primiparae, 92 (45%) gave
      formula to their newborn infants. Forty-four of these 92 mothers (47.8%) had
      discontinued breast feeding by the end of the second month. Among the 356 newborn
      infants, 220 used pacifiers at the end of the second month. Within this group, 72
      (33%) of the infants did not breast feed, while 148 (67%) did breast feed. Of all
      investigated mothers, 136 did not give pacifiers to their infants and only eight
      of these mothers (6%) had stopped breast feeding at the end of the second month.
      CONCLUSIONS: We found an inverse correlation between pacifier usage and breast
      feeding. Breast feeding was most common among multiparous mothers.

PMID- 12420845
TI  - Limb-body wall complex: a case series.
AB  - OBJECTIVE: Limb-body wall complex (LBWC) is a rare fetal polymalformation of
      uncertain etiology, but it has been regarded as sporadic in nature with a low
      recurrence risk. We review a case series in light of recent evidence about
      possible genetic and environmental associations. METHODS: All abortions or births
      coded as limb-body wall defect or fetal acrania/exencephaly or with unclassified
      polymalformation between January 1996 and January 2001 were audited. RESULTS:
      During the 5-year period there were 33,286 live births in our region. Eleven
      cases met the criteria of LBWC giving an incidence of 0.33/1000 live births. In
      50%, 50% and 30% of women a history of cigarette, alcohol and marijuana use,
      respectively, was noted. Furthermore, 40% of the women had a history of a
      previous infant with a congenital anomaly. One patient delivered two consecutive
      male infants with LBWC. CONCLUSIONS: Whilst the majority of cases of LBWC are
      sporadic, some women may have an underlying genetic predisposition. It may be
      prudent to advise against the use of alcohol, cigarettes and other drugs and to
      offer an ultrasound scan in a tertiary referral center in a subsequent pregnancy.

PMID- 12420846
TI  - Twin-twin transfusion syndrome with only superficial placental anastomoses:
      endoscopic and pathological evidence.
AB  - Deep arteriovenous placental anastomoses in monochorionic placentas have been
      considered an essential etiological factor in twin-twin transfusion syndrome
      (TTTS). Moreover, some investigators have suggested that superficial anastomoses
      have a protective role. We report on confirmed cases of TTTS with only
      superficial anastomoses.

PMID- 12420847
TI  - Resistance surveillance in Italy: four-year results from the MYSTIC program.
AB  - The MYSTIC program is an international, multicenter surveillance study that
      compares the activity of meropenem, in centers that are prescribers, with that of
      imipenem, ceftazidime, piperacillin/tazobactam, ciprofloxacin and gentamicin.
      These Italian data are from 3 centers (neutropenia, cystic fibrosis and intensive
      care units). A total of 2,072 (238 Gram-positive and 1,834 Gram-negative) aerobic
      microorganisms were collected during the study. Pseudomonas aeruginosa (33.4%)
      was the most isolated species followed by Escherichia coli (14.4%). All except
      one Enterobacteriaceae strain isolated were fully susceptible to meropenem.
      Moreover, the activity of meropenem against Enterobacteriaceae was about eight
      fold greater than that of imipenem and four- to eight-fold more active than that
      of ceftazidime. Meropenem was highly active against non-fermentative Gram
      negative microorganisms, exceeding the activity of most of the other
      antimicrobial agents tested. Moreover, meropenem showed increasing activity
      during the 4 years of study (starting from 86.2% in 1997 to 94.0% in 2000). In
      conclusion, our results indicate that meropenem has excellent potency and
      spectrum of activity despite being prescribed for the treatment of seriously ill
      patients, and appears to be a reliable option for the initial empirical treatment
      of serious nosocomial infections.

PMID- 12420848
TI  - Antibiotic use in an Italian university hospital.
AB  - The aim of this retrospective observational study was to investigate: a)
      expenditure for antibiotics with respect to the total pharmacy drug budget and to
      costs of other medical devices; b) the most frequently used antimicrobial classes
      and molecules; c) the clinical units that most frequently use antimicrobial
      therapy; d) the preferred route of administration; e) consumption patterns of
      antibiotics over two periods (January-September 1999 and January-September 2000).
      The consumption of a single antimicrobial agent was expressed as daily defined
      doses (DDD) per 100 bed days. In 1999 drugs accounted for 56% of the total costs
      but decreased to 46% in 2000. Antibiotics accounted for 15% of the pharmacy's
      overall acquisition costs in 1999 and dropped to 13% in 2000. In both 1999 and
      2000, penicillins were used most, followed by cephalosporins and aminoglycosides.
      In 1999, the most frequently used antibiotic was amoxicillin (4.02 DDD per 100
      bed days) followed by ceftazidime, ampicillin, ceftriaxone, and co-amoxiclav. In
      2000 ceftriaxone was the most commonly used antibiotic (4.35 DDD per 100 bed
      days) followed by co-amoxiclav, amoxicillin, ceftazidime. The general surgery,
      medical therapy and infectious diseases units accounted for the majority of
      penicillin consumption, while cephalosporins were most widely used in general
      surgery, orthopedics and neurosurgery units. Parenteral administration was the
      most widely used route in both years.

PMID- 12420849
TI  - Daptomycin morphostructural damage in Bacillus cereus visualized by atomic force
      microscopy.
AB  - Daptomycin is a novel, rapidly bactericidal in vitro antibiotic that is under
      investigation for the treatment of serious Gram-positive infections. Although
      daptomycin appears to disrupt membrane function, the precise mechanism of action
      has not been fully elucidated. Atomic force microscopy (AFM) is an innovative
      technique that allows high-resolution visualization and digital image
      manipulation of cell surface structures in 3 dimensions without the use of
      photons and electrons. The aim of this study was to use AFM to investigate the
      morphostructural changes in Bacillus cereus that occur upon daptomycin
      administration. The effects of daptomycin at 4x and 8x the minimal inhibitory
      concentration were visualized during an 8-hour incubation period. Atomic force
      microscopy images showed aberrant bacterial surface formations, including
      flattening and shrinking of cells and leakage of cytoplasm through the membrane.
      In addition to structural changes, the destabilization of flagella was also
      observed. These results support previous data suggesting that daptomycin disrupts
      membrane function.

PMID- 12420850
TI  - Antibiotic susceptibility patterns of Helicobacter pylori strains isolated from
      northeastern Mexico.
AB  - There are reports of increased antibiotic resistance rates in Helicobacter pylori
      strains around the world. The aim of this study was to determine the
      susceptibility patterns in H. pylori strains isolated in Monterrey, Mexico. We
      studied 62 strains isolated from the same number of symptomatic adult patients.
      Metronidazole (Mtz), clarithromycin (Cla), amoxicillin (Amx) and tetracycline
      (Tet) were tested by the E-test method. We observed that 37.1% of the strains
      were resistant to Mtz (MIC > or = 8 mg/L), and 8.1% to Cla (MIC > or = 8 mg/L),
      but we did not observe resistance to Amx (MIC > or = 2 mg/L) or Tet (MIC > or = 4
      mg/L). In northeastern Mexico, the percentage of resistant strains was similar to
      that observed in developed countries. These results confirm that it is necessary
      to evaluate the susceptibility patterns of H. pylori strains by geographic area.

PMID- 12420851
TI  - Antimicrobial-resistant Salmonella enterica serovars isolated from chickens in
      Spain.
AB  - In order to analyze the antibiotic resistance of Salmonella enterica serovars, a
      total of 112 Salmonella strains were tested (54 S. enteritidis, 32 S.
      typhimurium, 11 S. heidelberg, 7 S. infantis, 4 S. virchow and 4 S. hadar). The
      bacteria were isolated from 691 samples of frozen and fresh chicken meat.
      Identification of microorganisms and antimicrobial sensitivity testing were
      undertaken by means of the automated MicroScan AutoScan 4 method (Baxter in
      Spain). 45.5% of 112 strains tested were susceptible to all antibiotics. The
      highest percentage of resistance was found to: chloramphenicol (44.6%),
      ampicillin (34.8%) and tetracycline (33.9%). Multiple resistance was observed in
      49 strains (43.7%), whereas single resistance was seen in 12 isolates (10.7%). We
      found 12 different patterns of resistance in Salmonella enterica serovar
      enteriditis. Resistance to chloramphenicol was the most common single resistance.
      The most frequent patterns of multiresistant strains were ampicillin +
      amoxicillin/clavulanate + cefazolin + imipenem and chloramphenicol + impipenem.
      In this serotype, 49 isolates belonged to phagetype 4. Salmonella typhimurium
      showed the highest percentages of resistance to the tested drugs, with six
      different resistance patterns found. 25 strains out of 32 S. typhimurium isolates
      belonged to phagotype 120 and 13 of these showed the same resistance pattern:
      chloramphenicol + tetracycline + ampicillin. The high incidence of antibiotic
      resistant salmonellae found in chickens in our study suggests the need for public
      health interventions to decrease selective pressure on bacterial strains by
      antimicrobial agents.

PMID- 12420852
TI  - Effects of fluconazole singly and in combination with 5-fluorocytosine or
      amphotericin B in the treatment of cryptococcal meningoencephalitis in an
      intracranial murine model.
AB  - In this study we developed a highly reproducible intracranial murine model of
      cryptococcosis. Mice (Balb/c, 5-7 weeks old) were challenged intracranially and
      treated with intermediate (30 mg/kg) or high (90 mg/kg) dose fluconazole, and
      amphotericin B (0.75 mg/kg), administered singly or in combination with
      flucytosine (100 mg/kg). Survival and brain CFU analyses were performed. Effect
      of fluconazole prophylaxis was also determined. Our data show that the developed
      model mimics clinical signs of cryptococcal meningitis. In single treatment,
      fluconazole (30 mg/kg) was more efficacious than amphotericin B or flucytosine (P
      < 0.0001). Combination treatment led to significantly increased anticryptococcal
      activity, which was highest for high dose fluconazole + flucytosine (P < 0.0001).
      However, no significant difference was observed between high dose fluconazole
      treatment with and without flucytosine (P >0.05). Fluconazole prophylaxis led to
      a significant decrease in brain CFU. In conclusion, high dose fluconazole
      administered post-infection, or as prophylaxis, may be highly efficacious in the
      treatment and prevention of meningoencephalitis.

PMID- 12420853
TI  - Diffusion of isepamicin into cancellous and cortical bone tissue.
AB  - The degree of penetration of an antibiotic into the infection site is an
      important factor in its therapeutic efficacy, particularly in bone and joint
      infections. In the present study, we examined the bone tissue penetration of
      isepamicin at a dose of 15 mg/Kg, and the results were correlated to
      microbiologic data to estimate the clinical efficacy of isepamicin in bone
      infections. In this open-label, single-arm, noncomparative study, subjects of
      similar age, body weight, height and creatinine clearance who were undergoing
      elective total hip replacement received a single, parenteral 15 mg/Kg dose of
      isepamicin. Plasma and bone tissue samples were collected a mean 1.3 hours later
      and analyzed by a high-pressure liquid chromatography method. Twelve patients (3
      men and 9 women; mean age, 73.5 years; mean body weight, 53.5 Kg, mean creatinine
      clearance, 58.5 mL/min) were enrolled. The mean +/- SD plasma concentration of
      isepamicin at the time of bone removal was 43.0 +/- 10.4 microg/mL. The mean +/-
      SD isepamicin concentrations were 11.6 +/- 7.1 microg/mL in cancellous bone
      tissue and 12.0 +/- 7.3 microg/mL in cortical bone tissue. The mean +/- SD ratios
      of isepamicin concentration in bone and plasma (bone/plasma) were 0.28 +/- 0.14
      for cancellous bone tissue and 0.31 +/- 0.20 for cortical bone tissue. The
      concentrations achieved in both cancellous and cortical bone tissue were greater
      than the minimum concentrations required to inhibit the growth of 90% of strains
      (MIC90) of most of the susceptible pathogens commonly involved in bone
      infections.

PMID- 12420854
TI  - Amoxicillin/clavulanic acid versus cefotaxime for antimicrobial prophylaxis in
      abdominal surgery: a randomized trial.
AB  - Amoxicillin/clavulanic acid (amoxicillin 2 g/clavulanic acid 200 mg) has been
      administered in comparison to cefotaxime (2 g) for antimicrobial prophylaxis in
      476 evaluable patients undergoing abdominal surgery at high risk of septic
      complications. Both antibiotics were administered as a single infusion. 205
      evaluable patients (110 in amoxicillin/clavulanic acid group and 95 in cefotaxime
      group) underwent upper gastrointestinal surgery (including gastroduodenal and
      biliary surgery). The wound infection rate was 4.5% for amoxicillin/clavulanic
      acid and 7.4% for cefotaxime, with no significant differences. Intra-abdominal
      abscesses were observed in 3 patients in the amoxicillin/clavulanic acid group
      and in 1 patient in the cefotaxime group. 271 evaluable patients (135 in
      amoxicillin/clavulanic acid group and 136 in cefotaxime group) underwent lower
      gastrointestinal surgery (including colorectal surgery). The wound infection rate
      was 11% for amoxicillin/clavulanic acid and 13% for cefotaxime, with no
      significant differences. A purulent discharge was present in 3 patients in both
      groups. Intra-abdominal abscesses were observed in 3 patients in the
      amoxicillin/clavulanic acid group and in 4 patients in the cefotaxime group. No
      serious adverse events and no cases of diarrhea were observed. In conclusion, in
      our experience amoxicillin/clavulanic acid proved to be as effective as
      cefotaxime in protecting patients from surgical infections in abdominal surgery.
      Its use in surgical prophylaxis may help decrease the cost of treatment and
      reduce the risk of resistance to antibiotics and superinfections.

PMID- 12420855
TI  - Surgical antibiotic prophylaxis in a Turkish university hospital.
AB  - A prospective study was performed to assess the practice of antibiotic
      prophylaxis for surgical procedures in Pamukkale University Hospital, Denizli,
      Turkey. All surgical procedures performed between April 1 and July 31, 2001, were
      included. During the study period 897 operations were reviewed. 96% of all
      procedures were elective, 4% emergencies. Approximately 70.7% were clean surgery,
      25.3% clean-contaminated, 2.8% contaminated, and 1.2% dirty. 98% of patients
      (879) received antibiotic prophylaxis. Although timing of prophylaxis was
      appropriate in all procedures, the duration of prophylaxis was optimal in only
      47.7% of all cases. Sulbactam/ampicillin (SAM), cefazolin and cefepime were the
      most commonly used antibiotics during the study period. The results of our study
      suggest that the choice of prophylactic antimicrobial agent was inappropriate in
      most cases. In conclusion, we think that compliance regarding the optimal choice,
      frequency, and duration of perioperative antibiotic prophylaxis is not adequate
      in our hospital, and that more education on the subject is necessary.

PMID- 12420856
TI  - Conservative medical therapy of infections following osteosynthesis: a
      retrospective analysis of a six-year experience.
AB  - The conventional therapeutic approach to bone infection associated with
      osteosynthesis is based on the idea that microbial eradication is most readily
      achieved by removal of the foreign material together with adequate antimicrobial
      therapy. This strategy usually requires implantation of external fixation devices
      with additional discomfort to the patient. We report our experience with
      conservative medical and antimicrobial therapy without removal of the
      osteosynthesis until adequate bone callus deposition is documented by bone
      radiography scan. Twenty patients with infections associated with intramedullary
      nailing (9 patients), screws and plate (9 patients) or screws (2 patients) were
      treated between 1995 to 2000. Osteosynthesis implantation sites were tibia (7
      patients), femur (6 patients), femur and tibia (1 patient), humerus (1 patient),
      others (5 patients). Diagnosis of infection was based on clinical-microbiological
      evidence and confirmed by 99Tc-labeled leukocyte scan studies. Offending
      pathogens were Staphylococcus aureus 17 cases, Staphylococcus aureus +
      Escherichia coli, Staphylococcus epidermidis, unknown, 1 case each. Most
      infections were initially treated with intravenous or intramuscular teicoplanin
      +/- ciprofloxacin or rifampin followed by oral antimicrobial therapy usually with
      ciprofloxacin or minocycline plus rifampin. Mean duration of antimicrobial
      therapy was 27.7 weeks (range 12-64 weeks). All patients (100%) were cured, and
      none complained of side-effects requiring antibiotic therapy discontinuation. We
      conclude that conservative medical therapy is feasible for osteosynthesis
      associated bone infection.

PMID- 12420857
TI  - Comparative analysis of azithromycin and clarithromycin efficacy and tolerability
      in the treatment of chronic prostatitis caused by Chlamydia trachomatis.
AB  - A total of 123 patients, older than 18 years of age, with symptoms of chronic
      prostatitis and inflammatory findings as well as the presence of Chlamydia
      trachomatis confirmed by DNA/RNA DIGENE hybridization method in expressed
      prostatic secretion or in voided bladder urine collected immediately after
      prostatic massage, were examined. The patients were randomized to receive a total
      of 4.5 g of azithromycin for 3 weeks, given as a 3-day therapy of 1 x 500 mg
      weekly or clarithromycin 500 mg b.i.d. for 15 days. Patients' sexual partners
      were treated at the same time. Clinical and bacteriological efficacy were
      evaluated 4-6 weeks after the end of therapy. In the group of patients with
      chronic chlamydial prostatitis the eradication rates (azithromycin 37/46,
      clarithromycin 36/45) and the clinical cure rates (azithromycin 32/46,
      clarithromycin 32/45) were not significantly different with regards to the
      administered drug (p > 0.05). In the group of patients with asymptomatic
      chlamydial prostatitis the eradication rates (azithromycin 11/16, clarithromycin
      10/15) were not significantly different with regards to the administered drug (p
      = 1.00, OR = 1.1).

PMID- 12420858
TI  - Comparison of 5-fluorouracil and 5-fluoro-2'-deoxyuridine as an effector in
      radiation-activated prodrugs.
AB  - The purpose of this study was to clarify whether 5-fluoro-2'-deoxyuridine (FdUrd)
      is superior to 5-fluorouracil (5-FU) as an effector in the radiation-activated
      prodrugs which we have been developing. The in vitro cytotoxicity of 5-FU and
      FdUrd was compared in two murine tumor and four human pancreatic cancer cell
      lines using a colony assay and in vivo efficacy was compared with SCCVII tumor
      using a growth delay time assay. FdUrd was slightly more hydrophilic than 5-FU.
      In vitro, FdUrd was more efficient than 5-FU in two lines, whereas 5-FU was more
      efficient in two lines and the two drugs were almost equal in efficacy in the
      remaining two. The concentration to reduce tumor cell survival to 50% after 24-h
      drug exposure was 5-32 microM for both 5-FU and FdUrd in murine lines, while it
      was 30-210 microM in human pancreatic cancer cell lines. The difference in
      relative efficacy of the two drugs among these cell lines could not be attributed
      to the rate of intracellular uptake of the compounds. FdUrd was less toxic than 5
      FU in C3H/He mice, and FdUrd was less efficient than 5-FU in SCCVII tumors in
      vivo. These results suggest that FdUrd is not necessarily more potent than 5-FU,
      and development of the FdUrd prodrugs may not necessarily turn out to be
      fruitful.

PMID- 12420859
TI  - Vitamin E protection from/potentiation of the cytogenetic toxicity of cisplatin
      in Swiss mice.
AB  - Possible protection from or potentiation of the cytogenetic toxic effects of
      cisplatin (CP) 5 mg/kg b.w. in mouse bone marrow, spermatogonia by three
      different doses of alpha-tocopheryl acetate (vitamin E) 100, 200 and 300 mg/kg,
      and the transmission of such effects in the male germline, were assessed. CP
      induced chromosomal aberrations (CAs) in bone marrow were decreased in vitamin E
      pretreated mice, but significantly (P < or = 0.05) only with vitamin E 300 mg/kg.
      The percentages of dividing cells in bone marrow were increased in vitamin E
      pretreated groups of mice, but not significantly. However, the frequency of CP
      induced micronuclei (MN) in polychromatic erythrocytes (PCEs) declined
      significantly (P < or = 0.01) in all the vitamin E-pretreated groups of mice. In
      spermatogonia the CP-induced CAs were also decreased significantly by vitamin E
      200 mg/kg (P < or = 0.01), and 100 and 300 mg/kg (P < or = 0.05). However,
      transmission of CP-induced cytogenetic toxic effects from spermatogonia to
      spermatocyte, resulting in the formation of aberrant primary spermatocytes, was
      enhanced significantly in the mice pretreated with vitamin E 100 mg/kg (P < or =
      0.05) and 200 mg/kg (P < or = 0.01). But the enhancement in the transmission of
      such effects was not significant in the mice pretreated with vitamin E 300 mg/kg.
      Besides, there was no significant change in vitamin E-pretreated groups of mice
      in the transmission of cytogenetic toxicity of CP from spermatogonia to sperm
      with the manifestation of abnormal sperm morphology. Thus, vitamin E protected
      bone marrow and spermatogonia from the cytogenetic toxic effects of CP,
      particularly efficiently at the highest tested dose (300 mg/kg), but it failed to
      protect from the transmission of such effects in the male germline of mouse and
      rather potentiated them to some extent. Treatment with vitamin E, an antioxidant,
      might be capable of protecting noncancerous cells from the oxidative damage
      caused by cisplatin but it might also reduce the effects of cisplatin on
      cancerous cells. Thus, the benefits of antioxidant treatment during cancer
      chemotherapy is yet to be demonstrated clearly.

PMID- 12420860
TI  - Etoposide, leucovorin (LV) and 5-fluorouracil (5-FU) in 5-FU+LV pre-treated
      patients with advanced colorectal cancer.
AB  - In the present study, we evaluated the efficacy and safety of the weekly
      combination of etoposide, leucovorin (LV) and 5-fluorouracil (5-FU) when
      administered as second-line chemotherapy in patients with relapsed/refractory
      advanced colorectal cancer (ACC), previously treated with weekly LV+5-FU.
      Etoposide was administered at 3 different dose levels (DLs), in 3 groups of 20
      patients each (total: 60); DL-I: etoposide 80 mg/m2, DL-II: etoposide 120 mg/m2,
      and DL-III: etoposide 180 mg/m2, in 45 min i.v. infusion, and followed in all
      levels by LV 100 mg/m2 i.v. over 1 hour and 5-FU 500 mg/m2 i.v. bolus. Treatment
      was administered weekly until disease progression or unacceptable toxicity. No
      patients at DL-I responded, while 2 patients at DL-II and 3 at DL-III had a
      partial response (PR). Stable disease (SD) rates were as follows; at DL-I: 2, DL
      II: 8 and DL-III: 9. More patients in DL-I progressed (n = 19) compared to DL-II
      (n=10) and DL-II (n = 8) (p < 0.0007). Time to progression was for DL-I, -II, 
      III: 17, 15, and 14 weeks, respectively. Median survival was DL-I, -II, -III: 30,
      30, and 32.5 weeks, respectively. Toxicity consisted mainly of neutropenia,
      diarrhea and mucositis at all DLs, and was significantly more severe in DL-III.
      No difference was noted in responses between DL-II and DL-III. The authors
      conclude that the combination of etoposide with LV+5-FU has limited activity when
      administered after failure of weekly LV+5-FU in patients with ACC and should not
      be recommended for further evaluation.

PMID- 12420861
TI  - A novel method for monitoring response to chemotherapy based on the detection of
      circulating cancer cells: a case report.
AB  - We describe a novel method for detecting micrometastasis in the blood stream of
      cancer patients based on RT-PCR amplification of tumor-associated
      carcinoembryonic antigen (CEA) mRNA. To increase sensitivity and specificity of
      RT-PCR, CEA transcript was selectively up-regulated in cancer cells by exposure
      of peripheral blood to non-toxic concentrations of staurosporine (ST).
      Thereafter, polyA(+) RNA was extracted from tumor cells captured by means of
      magnetic beads coated with a monoclonal antibody against a common human
      epithelial antigen. Finally, RNA was subjected to RT-PCR analysis of CEA
      transcript. Using this approach, we demonstrated an ST-mediated increase in CEA
      transcript in blood specimens collected from a patient with metastatic colon
      cancer before receiving treatment with 5-fluorouracil/leucovorin. After a few
      cycles of chemotherapy, CEA-positive tumor cells were no longer detected.
      Clinical follow-up of this patient indicated that treatment with chemotherapy
      induced a dramatic reduction in liver metastasis. Therefore, it can be
      hypothesized that lack of CEA transcript detection might be consistent with
      disappearance or at least marked reduction of circulating tumor cells.

PMID- 12420862
TI  - Superior vena cava syndrome caused by chemotherapy-induced fibrosis.
AB  - We report a case of a 51-year old man with small cell lung cancer who developed
      superior vena cava syndrome due to obstruction of the superior vena cava at the
      junction of the brachiocephalic vein by a fibrotic band, 2 months after
      completing six cycles of chemotherapy with cisplatin and etoposid. Superior vena
      cava syndrome caused by chemotherapy-induced pulmonary fibrosis should be kept in
      mind during follow-up.

PMID- 12420863
TI  - The triad of weight loss, fever and night sweating: isolated bone marrow
      tuberculosis, a case report.
AB  - Extrapulmonary tuberculosis is known to be the infection in an organ with or
      without pulmonary involvement. The infection in extrapulmonary tuberculosis is
      insidious and the symptoms and signs are generally nonspecific. We describe a 56
      year-old male patient complaining of weight loss, fever, and night sweats.
      Although there were no signs and symptoms attributable to pulmonary tuberculosis,
      polymerase chain reaction (PCR), microscobical and cultural examination of bone
      marrow aspirate revealed isolated bone marrow tuberculosis. A treatment protocol
      of isoniazid, rifampicin, pyrazinamide, and streptomycin was administered. After
      9 months of treatment, re-examination of the bone marrow revealed no signs of
      tuberculosis. Tuberculosis should be kept in mind especially in endemic areas and
      bone marrow should be examined in case of suspected tuberculosis infection.

PMID- 12420864
TI  - Efficacy of ivermectin delivered via a controlled-release capsule against small
      lungworms (Protostrongylidae) in sheep.
AB  - To evaluate the efficacy of an ivermectin controlled-release capsule (CRC), which
      delivers 1.6 mg ivermectin per day intraruminally for 100 days to sheep weighing
      40-80 kg (IVOMEC Maximizer CR Capsule for adult sheep, Merial), against small
      lungworms two studies with 48 naturally infected adult female Merino Landrace
      sheep were conducted. The sheep were allocated by restricted randomization based
      on bodyweight to untreated controls or received an ivermectin CRC. Eight sheep
      per group were necropsied 35, 70 or 105 days post-treatment. Lungworms were
      recovered by dissection or peptic digestion of the lungs. Baermann/Wetzel
      technique was used for faecal lungworm larval counts at weekly intervals. The
      efficacy of treatment was 100% against Dictyocaulus filaria and Protostrongylus
      rufescens (P < 0.05) at each necropsy day. The efficacy against Protostrongylus
      brevispiculum, Cystocaulus ocreatus and Neostrongylus linearis increased from 35
      to 105 days after administration of the CRC and was found to be 100% (P < 0.01),
      96.6% (P < 0.01) or 99% (P < 0.01), respectively, at 105 days post-treatment. The
      reductions of Muellerius capillaris counts varied and were 96.2% (P < 0.05) at 70
      days post-treatment and 44.6% (P > 0.1) at 105 days post-treatment. Faecal
      lungworm larvae disappeared nearly completely from at least 3 weeks after the
      ivermectin CRC administration for all protostrongylid species including M.
      capillaris so that pasture infectivity will be subsequently significantly
      reduced.

PMID- 12420865
TI  - Field evaluation of the effect of in-feed doxycycline for the control of ileitis
      in weaned piglets.
AB  - The aim of this trial was to evaluate the effect of in-feed doxycycline (DOXY) on
      the control of ileitis in weaned piglets. On a farm with a previous history of
      ileitis outbreaks, 288 piglets at the age of weaning (25 +/- 2 days old) were
      divided into four experimental groups, each group comprising three pens with 24
      piglets in each pen. Non-medicated animals served as negative control (NC) group,
      whereas groups DOXY-50, DOXY-125 and DOXY-250 received doxycycline via feed at
      50, 125 and 250 ppm, respectively. Therapy lasted for 14 days followed by an
      observation period of 28 days. In conclusion, administration of doxycycline at a
      dose rate of 125 or 250 ppm had beneficial effect compared with the NC group. in
      terms of the reduction of diarrhoea prevalence, the enhancement of growth
      performance and the reduction of prevalence of Lawsonia intracellularis in the
      intestine, as shown either by the PCR method or by specific histopathological
      examinations. Treatment with 250 ppm of doxycycline for a fortnight interval post
      weaning seems to be beneficial leading to better growth rates of piglets not only
      during treatment period, but also throughout the whole nursery phase.

PMID- 12420866
TI  - Development of PCR assay for differentiation of some important wild animal meat
      of Sri Lanka.
AB  - A polymerase chain reaction (PCR) assay was developed to differentiate meat of
      Ceylon spotted deer (Axis axis ceylonensis), Ceylon hog deer (A. porcius oryzus),
      Ceylon sambhur (Cervus unicolor unicolor) and barking deer (Muntiacus muntijak
      malabaricus) from meat of cattle, goat, buffalo, pig, dog and sheep. A set of
      primers was designed according to the sequence of the mitochondrial cytochrome b
      gene of C. elaphus canadensis and by PCR amplification about 450 bp band was
      observed for all four animal species and these primers were not cross reacted
      with DNA of other animal species tested in the study under the tested reaction
      conditions. A band of 649 bp size was observed for all animal species when DNA
      was amplified with the universal primers and that indicated the presence of
      mitochondrial DNA in the samples. Further, the results indicated that this
      technique was sensitive enough to differentiate rotten meat, at least 5 days
      after the killing of an animal. Under these PCR conditions, the DNA of bacteria,
      which is involved in decomposition of meat, was not amplified with both universal
      and specific primers. However, the method was not sensitive enough in
      differentiating cooked meat of these species. Slaughtering of these four wild
      animal species is banned, but the animals are being killed illegally. Lack of
      meat identification methods has been identified as one of the major constraints
      to implement legal procedures and conserve biodiversity in the country.

PMID- 12420867
TI  - Partial sequencing of env gene of bovine leukaemia virus from Brazilian samples
      and phylogenetic analysis.
AB  - Analysis of the partial bovine leukaemia virus (BLV) env gp51 gene sequences
      obtained from three BLV strains isolated in three different regions of Brazil was
      carried out. The Brazilian BLV env gp51 sequences were compared with seven other
      corresponding sequences of BLV strains isolated in different countries and with
      consensus sequence as well. The obtained data point on qualitative and
      quantitative differences among the analysed strains as far as the occurrence of
      single point mutations is concerned. Two Brazilian strains show significantly
      higher mutation rate than other analysed strains. Amino acid analysis did not
      show, however, any substantial changes of the primary protein structure coded by
      well conserved region of BLV env gp51 gene. Based on the obtained data, the
      putative dendogram image of possible phylogenetic relations among the studied BLV
      strains is presented as well.

PMID- 12420868
TI  - Sequence analysis of the full-length cloned DNA of a chicken anaemia virus (CAV)
      strain from Bangladesh: evidence for genetic grouping of CAV strains based on the
      deduced VP1 amino acid sequences.
AB  - Chicken anaemia virus (CAV) was detected in the bursa of Fabricius of a 4-week
      old chicken obtained from an outbreak of acute infectious bursal disease in
      Bangladesh. Repeated attempts to grow this virus in MDCC-MSB1 cells were not
      successful. A full-length PCR amplicon of the genome of this strain, designated
      as BD-3 CAV, was cloned and sequenced. The complete nucleotide sequence and the
      deduced amino acid sequence were compared with those of 12 other CAV strains. The
      genetic analysis of the amino acid sequences of VP1 indicated the possible
      existence of genetic groups among CAV strains, as BD-3 CAV along with four other
      strains (CIA-1, L-028, Isolate 704 and TR-20) formed a distinct lineage. These
      strains have four signatory amino acids in VP1, such as 75I/T, 97L, 139Q and
      144Q, out of which the latter two are located in a small hydrophilic peak.

PMID- 12420869
TI  - Chemiluminescent immunoassay as a microtiter system for the detection of
      Salmonella antibodies in the meat juice of slaughter pigs.
AB  - Chemiluminescent immunoassay (CLIA) was applied in the screening of swine meat
      juice samples obtained from different laboratories in Germany, using the indirect
      enzyme linked immunosorbent assay (ELISA) as test for comparison. Out of the 1350
      samples tested, 987 were found acceptable for validation of results. A good level
      of agreement between the two tests was obtained with a kappa value of 0.824 at
      20% cut-off and 0.798 at 40% cut-off. At 20% and 40% cut-off levels, a
      sensitivity of 96.2% and 97.3%, respectively, and a specificity of 94.6% and
      95.1%, respectively, were demonstrated between CLIA and ELISA. The detecting
      lipopolysaccharide (LPS) antigen was tested for specificity and a cross-reaction
      with two Escherichia coli and Yersinia strains was found when tested with ELISA.
      This reaction was not observed in CLIA, possibly because of the broader
      measurement spectrum of this test, which allows a more distinctive definition of
      immunologic reactions. The same explanation can be given for the increased number
      of meat juice samples which were positively detected only in ELISA but not in
      CLIA. Because of the wide detection range in CLIA, a normalization scheme was
      necessary to obtain reproducible results in this test system. The samples
      positively classified in screening were further tested for reciprocal titres in
      both test systems, and a higher correlation between screening and titration
      results was obtained for CLIA. Based on the results of this study, CLIA can be
      used as a reference method in detecting Salmonella antibodies in the meat juice
      of slaughter pigs.

PMID- 12420870
TI  - Anti-microbial susceptibility for east1 + Escherichia coli isolated from
      diarrheic pigs in Korea.
AB  - The in vitro susceptibilities of 128 isolates of east1 + Escherichia coli from
      pre-weaned and post-weaned pigs with diarrhoea were tested with nine commonly
      used anti-microbial agents by an agar dilution minimal inhibitory concentration
      (MIC) procedure according to National Committee for Clinical Laboratory Standards
      guidelines. For the isolates from preweaned and post-weaned pigs, most of them
      were susceptible to low concentrations (MIC90) of tetracycline (4 and 2
      microg/ml), ceftiofur (2 and 2 microg/ml), and colistin (4 and 2 microg/ml).
      Marked resistance was found in others.

PMID- 12420871
TI  - Patterns of Mycoplasma hyopneumoniae infections in Belgian farrow-to-finish pig
      herds with diverging disease-course.
AB  - Patterns of Mycoplasma hyopneumoniae (Mh) infections were investigated in five
      clinically infected herds and in five herds subclinically infected with Mh. In
      the clinically infected herds, housing and management conditions were good
      whereas these conditions were poor in the subclinically infected herds. In each
      herd, serum antibodies against Mh were detected in pigs of different ages and
      nasal swabs were taken for Mh detection using nested PCR (nPCR). The percentage
      of seropositive pigs in the clinically infected herds increased from 8% in pigs
      of 9 weeks to 52% in pigs of 18 weeks and seroconversion was most shown between
      12 and 15 weeks. In the subclinically infected herds, the percentages increased
      from 2 to 24% and most of the pigs became seropositive between 15 and 18 weeks.
      The percentage of nPCR positive pigs at 6 weeks was 16 and 0% in the clinically
      and subclinically infected herds, respectively. The results demonstrate that the
      seroprevalences were higher in the clinically infected herds and that most of the
      pigs became infected with Mh at a younger age. It can be concluded that
      additional factors different from housing and management, like differences among
      Mh strains, may determine the infection pattern of Mh and the clinical course of
      the infection.

PMID- 12420872
TI  - Influence of Staphylococcus aureus exosecretions isolated from bovine mastitis on
      leukocyte activity in vitro.
AB  - The role of Staphylococcus aureus and coagulase-negative staphylococcal
      exosecretions was tested for its ability to elicit in vitro proliferation of
      bovine blood lymphocytes, which we determined by means of the 3H-thymidine
      proliferation assay and by flow cytometry. Exosecretions of 32 field strains of
      S. aureus isolated from bovine udder infection and one of each of S. intermedius
      (M2), S. hyicus (M5), S. xylosus (M6) and S. chromogenes (M10) were used. Of the
      32 S. aureus bacterial exosecretions, only 14 stimulated bovine mononuclear cells
      to proliferate. A high degree of association was found when the proliferation
      indexes were compared with the virulence as determined by intracisternal
      inoculation. All the six S. aureus strains that were categorized as highly
      virulent and that were tested in the proliferation assay exhibited a
      proliferation index > 20, whereas the five S. aureus strains that were
      categorized as low did not stimulate at all. Cells treated with media or Columbia
      broth supplemented with 0.1% D-glucose, yeast extract, and 0.5% NaCl (CBs) did
      not exceed 15% of the T-cells double positive with CD25+, whereas incubation with
      Con A activated the T-cells to display CD25+ up to 90%. Cells treated with one of
      the exosecretions that stimulated bovine mononuclear cells to proliferate,
      stimulated CD3+ and CD4+ T-cells to exhibit CD25+ receptor significantly higher
      (P < 0.05) than that found in media and CBs treatments, but lower than those
      found in Con A treatments. The exosecretions that did not stimulate mononuclear
      cells to proliferate also did not activate T-cells to exhibit CD25+ receptor. Con
      A activated 74% out of the total CD8+ to exhibit ACT2 receptor and 50% out of the
      total CD4+ to exhibit ACT3 receptor. A few but not all of the exosecretions that
      activated the CD25 receptor on T-cells also activated the ACT3 receptor on CD4+
      cells.

PMID- 12420873
TI  - 4-[6-(Dansylamino)hexylamino]-7-methyl-2-phenyl-1,8-naphthyridine as a new
      potential fluorescent probe for studying A1-adenosine receptor.
AB  - A new fluorescent ligand for adenosine receptors, obtained by the insertion of a
      dansylamino-moiety with a linear hexyl spacer in the N4 position of a 1,8
      naphthyridine adenosine receptor ligand, proved to possess a high affinity and
      selectivity for the A1 receptor subtype.

PMID- 12420874
TI  - Novel quinolinone-phosphonic acid AMPA antagonists devoid of nephrotoxicity.
AB  - We reported previously the synthesis and structure-activity relationships (SAR)
      in a series of 2-(1H)-oxoquinolines bearing different acidic functions in the 3
      position. Exploiting these SAR, we were able to identify 6,7-dichloro-2-(1H)
      oxoquinoline-3-phosphonic acid compound 3 (S 17625) as a potent, in vivo active
      AMPA antagonist. Unfortunately, during the course of the development,
      nephrotoxicity was manifest at therapeutically effective doses. Considering that
      some similitude exists between S 17625 and probenecid, a compound known to
      protect against the nephrotoxicity and/or slow the clearance of different drugs,
      we decided to synthesise some new analogues of S 17625 incorporating some of the
      salient features of probenecid. Replacement of the chlorine in position 6 by a
      sulfonylamine led to very potent AMPA antagonists endowed with good in vivo
      activity and lacking nephrotoxicity potential. Amongst the compounds evaluated,
      derivatives 7a and 7s appear to be the most promising and are currently evaluated
      in therapeutically relevant stroke models.

PMID- 12420875
TI  - Synthesis of N-arylsulfonyl DL-phenylserine derivatives exhibiting anti
      inflammatory activity in experimental studies.
AB  - Synthesis and evaluation of anti-inflammatory activity in rats with adjuvant
      arthritis of aryl sulfonyl derivatives of nonproteinogenic aromatic amino acids
      is reported. The studied compounds were synthesized by introducing residues of
      benzene-, p-toluene-, and p-bromobenzene sulfonic acids into threo-DL
      phenylserine and erythro-DL-p-nitrophenylserine structures. From the set of 12
      compounds tested in animal screening, N-(p-bromobenzenesulfonyl)-erythro-DL-p
      nitrophenylserine ethyl ester 12 demonstrated the most pronounced anti
      inflammatory activity. This compound inhibited inflammation process in
      polyarthritis phase by 53% (P < 0.001) though it was slightly toxic (LD50 > 6,000
      mg kg(-1) for mice).

PMID- 12420876
TI  - Synthesis and anti-microbial activity of isothiosemicarbazones and cyclic
      analogues.
AB  - It is known that some derivatives of both thiourea and thiosemicarbazide exhibit
      potent anti-microbial activity. In order to investigate the effects on the
      biological properties of structural modifications of such structures, we have
      synthesised and studied some arylidenisothiosemicarbazones. In this paper we
      report on the synthesis and structure-activity relationships of some
      isothiosemicarbazones, where the arylidene group has been replaced with a
      cycloalkyl group and the sulfur atom has been either differently substituted or
      enclosed in a thiazole ring.

PMID- 12420877
TI  - Synthesis and anti-hIV activity of 1-(2,6-difluorophenyl)-1H,3H-thiazolo[3,4
      a]benzimidazole structurally-related 1,2-substituted benzimidazoles.
AB  - The synthesis of 1,2-substituted benzimidazoles is reported. These novel
      derivatives share chemical similarities with 1-aryl-1H,3H-thiazolo[3,4
      a]benzimidazoles, a class of HIV-1 NNRTIs studied widely. All compounds prepared
      were tested in MT-4 cells to explore their potential anti-HIV activity and were
      found to be less potent than 1-(2,6-difluorophenyl)-1H,3H-thiazolo[3,4
      a]benzimidazole (TBZ).

PMID- 12420878
TI  - Synthesis and biological evaluation of new imidazo[1,2-a]pyridine derivatives
      designed as mefloquine analogues.
AB  - This paper describes the synthesis and the in vitro antimalarial profile of two
      new imidazo[1,2-a]pyridine derivatives 4HCl and 13HCl, structurally proposed as
      mefloquine (1) analogues, by exploring bioisosterism and molecular simplification
      tools. The synthetic route employed to access the title compounds used, as
      starting material, the previously described ethyl 2-methylimidazo[1,2-aJpyridine
      3-carboxylate derivative (5). These novel heterocyclic derivatives 4HCl and 13HCl
      presented modest antimalarial activity against the W-2 and D-6 clones of
      Plasmodium falciparum as well as inhibitors of in vitro heme polymerization
      compared to mefloquine.

PMID- 12420879
TI  - Compatibility between active components of a commercial drug.
AB  - A thermal and a kinetic analysis on the decomposition processes of a commercial
      drug named diamplicil (AD), obtained by an antibiotic combination of ampicillin
      (A) and dicloxacillin (D), have been carried out to find their thermal stability.
      The DSC/TG curves of this commercial drug were compared with those of its active
      components and an excipient, the magnesium stearate (M). Kinetic study was
      carried out using both isothermal and dynamic TG curves. Decomposition mechanisms
      for both active components and commercial drug tested were not found. The kinetic
      data obtained by the non-isothermal isoconversional method showed that D
      component causes a decrease of the kinetic stability of the active A component.
      Additive magnesium stearate does not decrease the stability of the two
      components. Moreover, storage time values at room temperature were calculated.

PMID- 12420880
TI  - Advanced glycation end-products/peptides: a preliminary investigation by LC and
      LC/MS.
AB  - An investigation on AGE-peptides, originating by proteolysis of in vitro glycated
      proteins, was carried out by LC methods with different detection applied to the
      mixture produced by proteinase K digestion of in vitro glycated human serum
      albumin (HSA). Classical approaches, like spectroscopic (UV, fluorescence) and
      mass spectrometric methods (MALDI, LC/ESI/MS), show that the digestion mixture is
      highly complex. However, there are clearcut differences between the digestion
      mixtures of glycated and unglycated HSA, in the former case allowing
      identification of possible glycated peptides belonging to the AGE-peptide class.
      MS/ MS experiments on selected species seem to be promising as regards structural
      information.

PMID- 12420881
TI  - Synthesis and antitumor activity of 1,3-benzodioxole derivatives.
AB  - A series of 1,3-benzodioxoles (5-19) was synthesized and evaluated for their in
      vitro antitumor activity against human tumor cell lines. Some derivatives
      exhibited tumor growth inhibition activity. In particular, 6-(4-aminobenzoyl)-1,3
      benzodioxole-5-acetic acid methyl ester 8, the most active compound of the
      series, possesses a significant growth inhibitory activity on 52 cell lines at
      concentrations ranging from 10(-7) to 10(-5) M.

PMID- 12420882
TI  - Solid-phase synthesis of combinatorial libraries based on enatiomerically pure
      (1S,2S,4R,5S)-4,5-dihydroxycyclohexan-1,2-dicarboxylic acid scaffolds.
AB  - The conditions for solid-phase functionalization of the new enantio-pure scaffold
      1 to give libraries of general formula 4 have been derived.

PMID- 12420883
TI  - Genetic epidemiology in a molecular age.

PMID- 12420884
TI  - The end of the beginning: a requiem for the categorization of mental disorder?

PMID- 12420885
TI  - A twin study of sex differences in social support.
AB  - BACKGROUND: Social support may reduce the risk of psychiatric illness. Though
      perceived as an environmental measure, genetic factors may influence levels of
      social support. A relationship between social roles and personality with social
      support suggests possible sex effects on the sources of individual differences in
      social support. METHOD: We used the responses of MZ and DZ same and opposite sex
      twins to 16 questions regarding their social life. Six factors--friend support,
      relative support, friend problem, relative problem, confidants and social
      integration were used for structural equation modelling. Factor derived scales
      were analysed for genetic, shared and unique environmental influences.
      Quantitative and qualitative gender differences were analysed using the software
      package Mx. RESULTS: Except for relative support and confidants, no qualitative
      sex differences were seen. Genetic and individual specific environmental
      influences accounted for the variance for friend support, friend problems,
      relative problems and social integration and no quantitative gender differences
      were seen. For relative support genetic factors were detected in females but not
      males, while for confidants, the shared environment was important in females but
      not males. CONCLUSIONS: Except for relative support in males, genetic factors
      influence variation in all dimensions of social support. Shared environmental
      factors influence relative support and relative problems in both sexes. Sex
      differences were detected for confidants and relative support.

PMID- 12420886
TI  - Prenatal life and post-natal psychopathology: evidence for negative gene-birth
      weight interaction.
AB  - BACKGROUND: Many studies suggest that pregnancy and birth complications (PBCs)
      are environmental risk factors for child psychopathology. However, it is not
      known whether the effects of PBCs occur independently of genetic predisposition.
      The current study examined the possibility of gene-environment interaction in a
      twin design. METHOD: The East Flanders Prospective Twin Survey prospectively
      records the births of all twin pairs born in East Flanders, Belgium. The current
      study included 760 twin pairs aged 6-17 years. Multilevel regression analysis was
      used to assess the effects of several PBCs collected around the time of birth.
      Using structural equation modelling, ACE models assuming additive genetic (A),
      shared environmental (C) and unique environmental (E) influences, were compared
      in order to examine whether the contribution of genetic factors to parent-rated
      child problem behaviour varied as a function of exposure to dichotomously and
      continuously defined PBCs. RESULTS: A main independent effect of lower birth
      weight, corrected for gestational age (small for gestational age--SGA), on child
      problem behaviour was found. In addition, there was an interaction between
      genetic influence and SGA, in that being smaller for gestational age resulted in
      less influence of additive genetic factors on individual differences in problem
      behaviour. CONCLUSIONS: Results are suggestive of negative gene-birth weight
      interaction. Children who are SGA are less sensitive to the genetic effects, and
      those with high genetic vulnerability are less sensitive to the effects of being
      SGA in bringing about post-natal mental health effects.

PMID- 12420887
TI  - Frequency and heritability of depression symptomatology in the second half of
      life: evidence from Danish twins over 45.
AB  - BACKGROUND: Self-reported depressive symptoms among the elderly have generated
      considerable interest because they are readily available measures of overall well
      being in a population often thought to be at special risk for mental disorder.
      METHOD: The heritability of depression symptoms was investigated in a sample of
      2169 pairs of Danish twins (1033 MZ and 1136 same sex DZ) ranging in age from 45
      to over 95. Twins completed an interview assessment that identified symptoms of
      depression, which were scored on Affective, Somatic and Total scales. RESULTS:
      Overall heritability estimates (a2) for the Affective (a2 = 0.27, (95% CI 0.22
      0.32)). Somatic (a2 = 0.26, (0.21-0.32)), and Total (a2 = 0.29, (0.22-0.34))
      scales were all moderate, statistically significant and similar to results from
      other studies. To assess possible variations in heritability across the wide age
      span, the sample was stratified into age groups in increments of 10 years. The
      magnitude of heritable influence did not vary significantly with age or sex.
      Somatic scale heritability tended to be greater for females than for males,
      though this difference was not statistically significant. The genetic correlation
      between the Affective and Somatic scales was 0.71, suggesting substantial common
      genetic origins. CONCLUSIONS: Though the frequency of self-reported depressive
      symptoms increased with age in this sample, their heritability did not.

PMID- 12420888
TI  - Childhood parental loss and risk for first-onset of major depression and alcohol
      dependence: the time-decay of risk and sex differences.
AB  - BACKGROUND: Whereas a number of studies have suggested that parental loss is
      associated with increased risk for major depression (MD), much less is known
      about possible gender differences, diagnostic specificity and the time course of
      the impact of loss. METHOD: First-onsets for MD and alcohol dependence (AD) were
      assessed at personal interviews in 5070 twins from same-sex (SS) and 2118 from
      opposite-sex (OS) twin pairs ascertained from a population-based registry. Cox
      Proportional Hazard (PH) and Non-Proportional Hazard (NPH) models, examining
      first onsets of MD and AD, were used with twins from SS pairs and conditional
      logistic regression for OS pairs. Parent-child separations prior to age 17 were
      divided into death and separation from other causes. RESULTS: The PH assumptions
      of constant increased risk were rejected for the impact of loss on risk for MD
      but not for AD. NPH models found significantly increased risk for MD after both
      death and separation with the risk lasting much longer for separations. For AD,
      the PH model found significantly increased risk after parental separation but not
      death. In both SS and OS twin pairs, no sex differences were seen in the impact
      of parental loss on risk for MD whereas the association between separation and
      risk for AD was significantly stronger in females than in males. CONCLUSION:
      Consistent sex differences in the association with parental loss were seen for AD
      but not MD. The analysis of the time-course of increased risk after loss suggests
      three different patterns which may reflect different relationships: parental
      death and MD (return to baseline within approximately 12 years), separation and
      MD (return to baseline within approximately 30 years) and separation and AD (no
      change in risk over time).

PMID- 12420889
TI  - Common mental disorder symptom counts in populations: are there distinct case
      groups above epidemiological cut-offs?
AB  - BACKGROUND: At the lower end of IQ distributions in general populations, there is
      a clear excess of cases, representing the distinct pathology of severe learning
      disability. This study aimed to establish whether such a subpopulation exists in
      distributions of common mental disorder and depression symptom scores, above
      epidemiological 'case' cut-offs. METHOD: Data from 9556 non-psychotic respondents
      to the 1993 OPCS (Office of Population Censuses and Surveys) National Household
      Psychiatric Morbidity Survey were analysed. The distribution of total neurotic
      symptom and depression scores from the revised Clinical Interview Schedule were
      examined. Automated least squares methods were used to fit the best single
      statistical distribution to the data. RESULTS: A single exponential curve
      provided the best fit for the whole population, but floor effects produced
      deviations at symptom counts of 0-3. After truncation, exponential distributions
      fitted excellently. Proportions of the population above conventional cut-offs of
      > or = 12 symptoms differed by < 12% from expected for a range of low and high
      prevalence groups. The single exponential model also fitted the depression score.
      CONCLUSIONS: Symptom counts for the common mental disorders fall within single
      population distributions, with little apparent numerical excess in the case
      range. High and low prevalences of these disorders appear to be population
      characteristics, with shifts in exponential means predicting proportions above
      case cut-offs.

PMID- 12420890
TI  - Exclusion criteria in the diagnostic classifications of DSM-IV and ICD-10:
      revisiting the co-occurrence of psychiatric syndromes.
AB  - BACKGROUND: Exclusion criteria are present in almost all diagnostic categories in
      both DSM-IV and ICD-10. These exclusion criteria state that one diagnosis is not
      made if it is 'due to' another disorder. However, there is little empirical
      evidence demonstrating that the hierarchy imposed by the exclusion criteria is
      meaningful. The current study examines associations between ten common mental
      disorder pairs to determine whether they are higher for disorder pairs that are
      classified in DSM-IV and/or ICD-10 as having a hierarchical relationship, than
      for those that are not hierarchically related. METHOD: Data were analysed from
      the Australian National Survey of Mental Health and Wellbeing, a large (N =
      10,641) epidemiological survey of mental disorders. Bivariate odds ratios between
      disorder pairs were calculated from logistic regression analyses. Multivariate
      odds ratios were also calculated from separate logistic regression analyses in
      which the sample was restricted to likely positive cases, and co-morbid mental
      disorders and neuroticism scores were both controlled. RESULTS: The odds ratios
      between disorder pairs related according to the exclusion criteria were higher
      than those of unrelated disorders, for both DSM-IV and ICD-10. When constraints
      were placed on the data to control for the effects of co-morbid disorders and
      neuroticism the same pattern was evident in DSM-IV, but not in ICD-10.
      CONCLUSION: The patterns of association between disorder pairs found in the
      exclusion criteria for DSM-IV appear to more closely mirror the patterns of
      association found in epidemiological data. While this does not guarantee that the
      exclusion criteria are valid it is argued that identifying significant
      associations should be the first step in establishing meaningful exclusion
      criteria.

PMID- 12420891
TI  - The effects of co-morbidity on the onset and persistence of generalized anxiety
      disorder in the ICPE surveys. International Consortium in Psychiatric
      Epidemiology.
AB  - BACKGROUND: Although it is well known that generalized anxiety disorder (GAD) is
      highly co-morbid with other mental disorders, little is known about the extent to
      which earlier disorders predict the subsequent first onset and persistence of
      GAD. These associations are examined in the current report using data from four
      community surveys in the World Health Organization (WHO) International Consortium
      in Psychiatric Epidemiology (ICPE). METHOD: The surveys come from Brazil, Canada,
      the Netherlands and the United States. The Composite International Diagnostic
      Interview (CIDI) was used to assess DSM-III-R anxiety, mood and substance use
      disorders in these surveys. Discrete-time survival analysis was used to examine
      the associations of retrospectively reported earlier disorders with first onset
      of GAD. Logistic regression analysis was used to examine the associations of the
      disorders with persistence of GAD. RESULTS: Six disorders predict first onset of
      GAD in all four surveys: agoraphobia, panic disorder, simple phobia, dysthymia,
      major depression and mania. With the exception of simple phobia, only respondents
      with active disorders have elevated risk of GAD. In the case of simple phobia, in
      comparison, respondents with a history of remitted disorder also have
      consistently elevated risk of GAD. Simple phobia is also the only disorder that
      predicts the persistence of GAD. CONCLUSIONS: The causal processes linking
      temporally primary disorders to onset of GAD are likely to be state-dependent.
      History of simple phobia might be a GAD risk marker. Further research is needed
      to explore the mechanisms involved in the relationship between simple phobia and
      subsequent GAD.

PMID- 12420892
TI  - Generalized anxiety disorder and clinical worry episodes in young women.
AB  - BACKGROUND: This article presents epidemiological data on the prevalence of DSM
      IV generalized anxiety disorder (GAD) and sub-threshold GAD (fulfilling three out
      of four GAD criteria) in young women together with data on co-morbidity and
      psychosocial functioning. The prevalence of clinically relevant worry and its
      predictive validity for the diagnosis of GAD were also examined. METHOD: Young
      women (N = 2064), aged between 18 and 25, from a representative German community
      sample were diagnosed with a structured clinical interview (ADIS-L, German
      research version). An additional interview questioned all the participants about
      the frequency/intensity and uncontrollability of diverse worry topics. RESULTS:
      Thirty-seven participants (1.8%) fulfilled the criteria of current GAD (1 week
      point prevalence) and 56 received a lifetime diagnosis (2.7%); a further 50
      participants (2.3%) were diagnosed with sub-threshold GAD. Co-morbidity between
      GAD and other disorders was high for current (68%) and lifetime GAD (91%). GAD,
      as well as sub-threshold GAD, showed clearly reduced levels of psychosocial
      functioning. Whereas worries of low intensity and high controllability were
      ubiquitous in all subsamples, clinically defined worrying was rarely present in
      healthy subjects (0.89%) and of adequate predictive accuracy for GAD.
      CONCLUSIONS: Full GAD and sub-threshold GAD were moderately frequent in young
      women. Although DSM-IV worry criteria proved to be highly useful, the strictness
      of the complete GAD-criteria should not lead to absence of attention from
      subclinical generalized anxiety states in research and practice.

PMID- 12420893
TI  - Childhood adversity and anxiety versus dysthymia co-morbidity in major
      depression.
AB  - BACKGROUND: Childhood adversity places individuals with major depression at risk
      for anxiety and dysthymia co-morbidity. The goal of the present paper is to
      broaden this area of research by examining specificity between the type of
      adversity (e.g. abuse versus neglect/indifference) and the resulting co-morbid
      disorder (e.g. anxiety versus dysthymia co-morbidity). METHOD: The volunteer
      sample consisted of 76 women meeting Diagnostic and Statistical Manual (DSM-IV)
      criteria for major depression. Of these, 28 were diagnosed with a co-morbid
      anxiety disorder and 21 were diagnosed with co-morbid dysthymia. Childhood
      physical abuse, sexual abuse, psychological abuse, antipathy and indifference
      were assessed using a contextual interview and rating system. RESULTS: Severe
      sexual abuse and psychological abuse were significantly and preferentially
      associated with co-morbid anxiety, while severe physical abuse was significantly
      and preferentially associated with co-morbid dysthymia. Indifference and
      antipathy were significantly associated with both co-morbid anxiety and
      dysthymia. Multivariate analyses revealed that severe sexual abuse was the
      adverse childhood experience most strongly associated with co-morbid anxiety.
      CONCLUSIONS: These results suggest that particular adverse experiences in
      childhood do set up specific vulnerabilities to the expression of anxiety versus
      dysthymia co-morbidity in adulthood major depression. Cognitive mediators of
      these associations are discussed as avenues of future research.

PMID- 12420894
TI  - Impairments of response conflict monitoring and resolution in schizophrenia.
AB  - BACKGROUND: It has been argued recently that the attentional dysfunction in
      schizophrenia occurs as a result of an inability to inhibit automatic attentional
      shifts to compelling external stimuli. However, this hypothesis is based on
      performance on paradigms that require overt or covert shifts of spatial
      attention. METHOD: We investigated responses to foveally presented stimuli in
      patients with schizophrenia and healthy controls as they performed unidimensional
      and bidimensional versions of the flanker task. In both tasks, centrally
      presented target stimuli were flanked by peripheral stimuli that were either
      congruent or incongruent with the behavioural goal of the subject. In the
      bidimensional task, the flanking stimuli could be congruent and incongruent on
      multiple stimulus characteristics. RESULTS: On the unidimensional flanker task,
      the behavioural goal modulated the responses of the schizophrenia group such that
      response times (RTs) to target stimuli that were flanked by congruent stimuli
      were faster than RTs to target stimuli flanked by incongruent stimuli. However,
      on the bidimensional flanker task, the responses of schizophrenia patients were
      no longer constrained by the behavioural goal and RTs to both congruent and
      incongruent stimuli were equivalent. CONCLUSIONS: It appears that the attentional
      dysfunction in schizophrenia may reflect difficulty in resolving multiple and
      simultaneous response conflicts. These findings suggest a possible role for the
      anterior cingulate cortex in the attentional impairments associated with
      schizophrenia.

PMID- 12420896
TI  - Disturbed communication in schizophrenia: the role of poor pragmatics and poor
      mind-reading.
AB  - BACKGROUND: Disturbed speech in schizophrenia may reflect pragmatic deficits of
      expressive language. Pragmatic comprehension deficits also occur in
      schizophrenia. This study investigated whether poor 'mind-reading' (i.e. a
      general difficulty with inferring and monitoring other people's thoughts) causes
      pragmatic language impairments of both expression and comprehension in patients
      with schizophrenia. METHOD: Mind-reading (or theory of mind) was tested in
      patients with schizophrenia and in healthy controls using a false-belief picture
      sequencing task. Pragmatic comprehension skills were assessed using a test of non
      literal speech interpretation. Clinical ratings of formal thought disorder (FTD)
      indexed the expressive language deficits of patients. To control for possible
      contributory effects of executive dysfunction, inhibitory control was tested
      using capture picture-sequences and executive-planning was tested using the Tower
      of London task. RESULTS: False-belief picture-sequencing, understanding of irony
      and understanding of metaphors were all selectively impaired in the patients.
      Poor mind-reading (indexed by high error rate in sequencing false-belief stories)
      was associated with poor understanding of irony, but was unrelated to poor
      understanding of metaphors. Whereas poor appreciation of irony and poor mind
      reading were associated with high ratings of positive formal thought disorder,
      high ratings of negative formal thought disorder were associated with poor
      understanding of metaphors and executive dysfunction. CONCLUSIONS: Whereas poor
      mind-reading may contribute to positive aspects of formal thought disorder and
      impaired appreciation of irony in patients with schizophrenia; negative features
      of formal thought disorder and poor understanding of metaphors appear better
      explained by abnormal semantics. Overall, the findings of this study support the
      view that the functional basis of formal thought disorder in schizophrenia is not
      unitary.

PMID- 12420895
TI  - Remembering or knowing: electrophysiological evidence for an episodic memory
      deficit in schizophrenia.
AB  - BACKGROUND: In schizophrenia, impaired conscious retrieval of past events and
      facts may represent a selective cognitive deficit of declarative memory against a
      background of a generalized neuropsychological impairment. We aimed to
      disentangle the neural subprocesses leading to this deficit applying the
      'Remember/Know procedure'. METHOD: Event-related potentials (ERPs) were recorded
      as 14 schizophrenic patients and 14 controls recognized an equal mixture of
      previously presented old and new words. For recognized old words, participants
      were required to judge whether recognition was associated with recollection
      ('Remember') or familiarity ('Know'), either reflecting episodic or semantic
      memory. RESULTS: Patients showed a lack of 'Remember responses', which led to
      more opportunities to make 'Know responses'. ERPs for 'Remember' compared to 'New
      responses' differed consistently in controls over left temporo-parietal and right
      frontal electrode sites. Although schizophrenic patients showed the same
      topography for this Remember old/new effect, it was apparent over temporoparietal
      sites for only 800 ms and over right frontal sites for 1100 ms post-stimulus. For
      controls, the Know old/new effect was elicited over temporo-parietal sites
      between 500 and 800 ms. For patients, it showed a widespread maximum over frontal
      sites between 500 and 1100 ms. CONCLUSIONS: The shorter time course of the left
      temporo-parietal Remember old/new effect suggests that the patients' episodic
      memory impairment was possibly mediated by a dysfunction of the mediotemporal
      regions. The more widespread frontal Know old/new effect in the patients suggests
      that the prefrontly mediated processes associated with retrieval of semantic
      memory may be enhanced compensatorily.

PMID- 12420897
TI  - Lower prevalence of pre-morbid neurological illness in African-Caribbean than
      White psychotic patients in England.
AB  - BACKGROUND: It has been suggested that the increased incidence of psychosis in
      African-Caribbeans living in England may be due to illnesses in which social
      stress plays an important aetiological role. If this is the case, the prevalence
      of factors associated with psychosis that predate illness onset such as obstetric
      complications, pre-morbid neurological illness and poor childhood social
      adjustment may be expected to be lower in African-Caribbean than Whites psychotic
      patients. METHOD: Details of obstetric complications, pre-morbid neurological
      illness, and pre-morbid social adjustment were obtained for 337 psychotic
      patients by patient interview, interviews of mothers and chart review. The
      proportions of patients with each 'risk factor' in the African-Caribbean (N =
      103) and White (N = 184) groups were compared using regression analysis; age,
      sex, social class, diagnosis and referral status were possible explanatory
      variables. RESULTS: African-Caribbean patients were less likely to have suffered
      a pre-morbid neurological disorder than their White counterparts (odds ratio
      0.19, 95% CI 0.06-0.61). There was no significant difference in pre-morbid social
      adjustment or obstetric complications between the two groups, though fewer
      obstetric complications were reported in the African-Caribbean group (21.5%) than
      the White group (30.9%). CONCLUSIONS: African-Caribbean patients with psychosis
      have experienced less pre-morbid neurological illness.

PMID- 12420898
TI  - Self-perception of poor health and suicidal ideation in medical patients.
AB  - OBJECTIVE: To determine the relationship between self-perceived health and
      suicidal ideation among patients in general internal medicine practice settings.
      METHOD: A representative sample of 4007 patients was assessed for current
      suicidal ideation, self-perception of health, current medical disorders and
      current mental disorders (major depression, generalized anxiety disorder, panic
      attacks and alcohol use disorder) with the PRIME-MD Patient Health Questionnaire.
      RESULTS: Patients with self-perception of poor health, compared with those who
      reported more favourable health perception, were significantly more likely to
      report current suicidal ideation (35.2% v. 8.3%; chi2 = 97.4, df = 1, P <
      0.0001). Multivariate logistic regression analyses revealed that the perception
      of poor health was associated with a significantly increased risk of suicidal
      ideation (OR = 3.1, CI 1.9, 5.0), even after adjusting for sociodemographic
      characteristics, mental disorders and common physical illnesses. CONCLUSION: Self
      perception of poor health is associated with a significantly increased risk of
      suicidal ideation among general medical patients, even in the absence of common
      mental and physical disorders. These findings add to a growing literature on the
      importance of self-perceived health in the treatment and outcomes of mental and
      physical well-being by documenting self-perceived poor health as a risk factor
      for suicidal ideation in medical patients.

PMID- 12420899
TI  - Readmission risk in schizophrenia: selection explains previous findings of a
      progressive course of disorder.
AB  - BACKGROUND: Several studies have investigated the issue of the natural course of
      schizophrenia. Our study addressed whether there is evidence for progression,
      potentially deteriorating, over the long-term course of the disorder. METHOD:
      Modern survival analysis techniques were applied to case-register data on the
      pattern of readmission to in-patient psychiatric facilities. The sample consisted
      of a total of 8953 persons with schizophrenia. RESULTS: No evidence of a
      progressive course of schizophrenia was found in the present study. The
      accelerating pattern of the course of schizophrenia described by some authors,
      including a previous analysis of an almost identical dataset, can be explained by
      selection. CONCLUSIONS: Heterogeneity reflecting the various levels of individual
      vulnerability may govern the overall individual course of schizophrenia. We
      hypothesize that the persistent deficit syndrome and negative symptoms are
      influential determinants of this heterogeneity.

PMID- 12420900
TI  - Major depressive episode among young adults: CIDI-SF versus SCAN consensus
      diagnoses.
AB  - BACKGROUND: We aimed to evaluate the diagnostic accuracy of a highly structured
      diagnostic interview in relation to a semi-structured diagnostic procedure. We
      compared the World Health Organization Composite International Diagnostic
      Interview Short Form (CIDI-SF) in diagnosing major depressive episode (MDE) to
      consensus diagnoses based on the SCAN interview (Schedules for Clinical
      Assessment in Neuropsychiatry). METHOD: Subjects comprised a follow-up sample of
      239 20-24-year-old former high-school students who were administered the SCAN and
      immediately thereafter the CIDI-SF. Concordance was estimated for 12-month MDE,
      using different cut-points of the CIDI-SF and for any affective disorders.
      RESULTS: Correspondence between instruments was moderate for MDE (kappa = 0.43,
      sensitivity 0.71, specificity 0.82), but better for any affective disorder (kappa
      = 0.60, sensitivity 0.70, specificity 0.90). Most false negatives suffered from
      their depression as much as those correctly identified by the CIDI-SF. False
      negativity was mainly due to not endorsing the stem questions of the CIDI-SF. Of
      the false positives almost half had an affective disorder other than MDE.
      CONCLUSIONS: The CIDI-SF seems to function best in identifying a broader category
      of affective disorders. It could be useful in large-scale community surveys where
      more extensive psychiatric interviews are not feasible.

PMID- 12420901
TI  - Does problem-solving treatment work through resolving problems?
AB  - BACKGROUND: A randomized controlled trial of problem-solving treatment,
      antidepressant medication and the combination of the two treatments found no
      difference in treatment efficacy for major depressive disorders in primary care.
      In addition to treatment outcome, the trial sought to determine possible
      mechanisms of action of the problem-solving intervention. METHOD: Two potential
      mechanisms of action of problem-solving treatment were evaluated by comparison
      with drug treatment. First, did problem-solving treatment work by achieving
      problem resolution and secondly, did problem-solving treatment work by increasing
      the patients' sense of mastery and self-control? RESULTS: Problem-solving
      treatment did not achieve a greater resolution in the patients' perception of
      their problem severity by comparison with drug treatment, neither did problem
      solving treatment result in a greater sense of mastery or self-control.
      CONCLUSIONS: The results from this study did not support the hypotheses that for
      patients with major depression, by comparison with antidepressant medication:
      problem-solving treatment would result in better problem resolution; or that
      problem-solving treatment would increase the patients' sense of mastery and self
      control.

PMID- 12420902
TI  - Electroconvulsive therapy (ECT) practice in Metropolitan New York community
      hospitals.

PMID- 12420903
TI  - Electroconvulsive therapy (ECT) practice in Metropolitan New York community
      hospitals.

PMID- 12420904
TI  - Surveillance for asthma--United States, 1980-1999.
AB  - PROBLEM/CONDITION: Asthma, a chronic disease occurring among both children and
      adults, has been the focus of clinical and public health interventions during
      recent years. In addition, CDC has outlined a strategy to improve the timeliness
      and geographic specificity of asthma surveillance as part of a comprehensive
      public health approach to asthma surveillance. REPORTING PERIOD COVERED: This
      report presents national data regarding self-reported asthma prevalence, school
      and work days lost because of asthma, and asthma-associated activity limitations
      (1980-1996); asthma-associated outpatient visits, asthma-associated
      hospitalizations, and asthma-associated deaths (1980-1999); asthma-associated
      emergency department visits (1992-1999); and self-reported asthma episodes or
      attacks (1997-1999). DESCRIPTION OF SYSTEMS: CDC's National Center for Health
      Statistics (NCHS) conducts the National Health Interview Survey annually, which
      includes questions regarding asthma and asthma-related activity limitations. NCHS
      collects physician office-visit data in the National Ambulatory Medical Care
      Survey, emergency department and hospital outpatient data in the National
      Hospital Ambulatory Medical Care Survey, hospitalization data in the National
      Hospital Discharge Survey, and death data in the Mortality Component of the
      National Vital Statistics System. RESULTS: During 1980-1996, asthma prevalence
      increased. Annual rates of persons reporting asthma episodes or attacks, measured
      during 1997-1999, were lower than the previously reported asthma prevalence
      rates, whereas the rates of lifetime asthma, also measured during 1997-1999, were
      higher than the previously reported rates. Since 1980, the proportion of children
      and adults with asthma who report activity limitation has remained stable. Since
      1995, the rate of outpatient visits and emergency department visits for asthma
      increased, whereas the rates of hospitalization and death decreased. Blacks
      continue to have higher rates of asthma emergency department visits,
      hospitalizations, and deaths than do whites. INTERPRETATION: Since the previous
      report in 1998 (CDC. Surveillance for Asthma--United States, 1960-1995. MMWR
      1998;47[No. SS-1]:1-28), changes in asthma-associated morbidity and death have
      been limited. Asthma remains a critical clinical and public health problem.
      Although data in this report indicate certain early indications of success in
      current asthma intervention programs (e.g., limited decreases in asthma
      hospitalization and death rates), the continued presence of substantial racial
      disparities in these asthma endpoints highlights the need for continued
      surveillance and targeted interventions.

PMID- 12420905
TI  - Malaria surveillance--United States, 1999.
AB  - PROBLEM/CONDITION: Malaria is caused by four species of intraerythrocytic
      protozoa of the genus Plasmodium (i.e., P. falciparum, P. vivax, P. ovale, or P.
      malariae). Malaria is transmitted by the bite of an infective female Anopheles
      sp. mosquito. The majority of malaria infections in the United States occur in
      persons who have traveled to areas with ongoing transmission. In the United
      States, cases can occur through exposure to infected blood products, by
      congenital transmission, or locally through mosquitoborne transmission. Malaria
      surveillance is conducted to identify episodes of local transmission and to guide
      prevention recommendations for travelers. PERIOD COVERED: Cases with onset of
      illness during 1999. DESCRIPTION OF SYSTEM: Malaria cases confirmed by blood
      films are reported to local and state health departments by health-care providers
      or laboratory staff. Case investigations are conducted by local and state health
      departments, and reports are transmitted to CDC through the National Malaria
      Surveillance System (NMSS). Data from NMSS serve as the basis for this report.
      RESULTS: CDC received reports of 1,540 cases of malaria with an onset of symptoms
      during 1999 among persons in the United States or one of its territories. This
      number represents an increase of 25.5% from the 1,227 cases reported for 1998. P.
      falciparum, P. vivax, P. malariae, and P. ovale were identified in 46.0%, 30.7%,
      4.6%, and 3.6% of cases, respectively. More than one species was present in 12
      patients (0.8% of total). The infecting species was unreported or undetermined in
      223 (14.5%) cases. The number of reported malaria cases acquired in Africa
      increased 27.6% (n = 901), compared with 1998, and an increase of 2.9% (n = 246)
      occurred in cases acquired in Asia, compared with 1998. Cases from the Americas
      increased by 19.7% (n = 274) from 1998. Of 831 U.S. civilians who acquired
      malaria abroad, 159 (19.1%) reported that they had followed a chemoprophylactic
      drug regimen recommended by CDC for the area to which they had traveled. Three
      patients became infected in the United States, all through probable local
      mosquitoborne transmission. Five deaths were attributed to malaria, all caused by
      P. falciparum. INTERPRETATION: The 25.5% increase in malaria cases in 1999,
      compared with 1998, resulted primarily from increases in cases acquired in Africa
      and the Americas. This increase is possibly related to a change in the system by
      which states report to CDC, but it could also have resulted from local changes in
      disease transmission, increased travel to these regions, improved reporting to
      state and local health departments, or a decreased use of effective antimalarial
      chemoprophylaxis. In the majority of reported cases, U.S. civilians who acquired
      infection abroad were not on an appropriate chemoprophylaxis regimen for the
      country where they acquired malaria. PUBLIC HEALTH ACTIONS: Additional
      information was obtained concerning the five fatal cases and the three infections
      acquired in the United States. The NMSS surveillance form was modified to gather
      more detailed information regarding compliance with prescribed chemoprophylaxis
      regimens. Persons traveling to a malarious area should take one of the
      recommended chemoprophylaxis regimens appropriate to the region of travel, and
      travelers should use personal protection measures to prevent mosquito bites. Any
      person who has been to a malarious area and who subsequently develops a fever or
      influenza-like symptoms should seek medical care immediately; investigation
      should include a blood-film test for malaria. Malaria infections can be fatal if
      not diagnosed and treated promptly. Recommendations concerning prevention of
      malaria can be obtained from CDC.

PMID- 12420906
TI  - Oxidized LDL metabolites with high family risk for premature cardiovascular
      disease.
AB  - OBJECTIVE: Considering the importance of primary prevention of Cardiovascular
      Disease (CVD) from childhood, especially in children with high family risk for
      premature atherosclerosis, and also the importance of oxidized LDL in the process
      of atherosclerosis, the main metabolites of ox-LDL i.e. Malondialdehyde (MDA) and
      Conjugated diene (CDE) have been measured in children of high risk families and
      compared with a control group. METHODS: Children and adolescents (6-18 years) of
      parents with premature myocardial infarction (MI < or = 55 y in men and < or = 65
      y in women), were selected as the case group. The control group included
      neighbors of the case group matched for age and socioeconomic status. All samples
      have been selected by simple random sampling. Both the case and control groups
      were divided in two subgroups: those with a total cholesterol and/or LDL-C > or =
      95th centile and those with normal lipid levels. Each subgroup consisted of 32
      subjects, so 128 subjects were studied (64 in the case and 64 in the control
      group). MDA and CDE were measured by spectrophotometry using molar absorbivity.
      Data were analyzed by SPSSv10/Win software using ANOVA, Bonferroni, Scheffe
      Duncan, Tukey-HSD, and the Student's t-test. RESULT: The mean MDA value in the
      case and control groups was significantly different (1.84 +/- 0.43 vs. 1.67 +/-
      0.41 micromol/L, p=0.03), but this difference was not significant regarding the
      mean CDE level (0.50 +/- 0.05 vs. 0.47 +/- 0.04 micromol/L, p>0.05). The mean MDA
      level in the case group with hyperlipidemia was significantly higher than that in
      the case group without hyperlipidemia (1.985 +/- 0.516 vs. 1.690 +/- 0.366,
      micromol/L, P=0.02) and also higher than control group with or without
      hyperlipidemia (1.985 +/- 0.516 vs. 1.720 +/- 0.389, 1.615 +/- 0.429 micromol/L
      respectively, P<0.05). The mean CDE level in the case group with hyperlipidemia
      was significantly higher than the case group without hyperlipidemia (0.542 +/-
      0.034 vs. 0.494 +/- 0.049 micromol/L, P=0.04) and higher than the control group
      with or without hyperlipidemia (0.542 +/- 0.034 vs. 0.464 +/- 0.051, 0.484 +/-
      0.048 micromol/L respectively, p<0.05). In case boys with hyperlipidemia, the
      mean MDA (2.03 +/- 0.2 micromol/L) and the mean of CDE (0.56 +/- 0.04 micromol/L)
      was significantly higher than other subgroups (P<0.05). CONCLUSION: Considering
      the increased susceptibility of LDL to oxidation in children with high family
      risk for premature CVD, special attention should be paid to consumption of foods
      and seasoning containing antioxidants from childhood especially in high risk
      families.

PMID- 12420907
TI  - Detecting protein losing enteropathy by Tc-99m dextran scintigraphy: a novel
      experience.
AB  - OBJECTIVE: To evaluate protien using enteropathy by Tc-99m dextran scintigraphy.
      METHODS: Methods for detecting protein loss from the intestine revolve around
      fecal nitrogen excretion, the clearance of alpha-1 antitrypsin in stools and by
      endoscopic biopsy. RESULT: The diagnosis of protein-losing enteropathy (PLE) can
      also be established by a scintigraphic method that is noninvasive, simple and
      requires no patient preparation or motivation. This diagnostic modality can also
      delineate the site of protein loss, thereby offering a targeted approach, and if
      need be, surgery. Radiolabelling of a non-protein, noncolloidal, nonparticulate
      and biofriendly molecule like dextran with Technetium-99m for imaging enteric
      protein loss was utilized in imaging eight children with PLE. CONCLUSION: The
      results were encouraging. The authors advocate the use of this diagnostic tool in
      identifying patients with PLE, particularly in the pediatric age group.

PMID- 12420908
TI  - Skin cleansing in neonates and infants--basics of cleansers.
AB  - OBJECTIVE: Using a proper cleanser for bathing neonatal and infant skin is of
      prime importance considering the anatomical differences with regard to adult
      skin. Choosing the right cleanser requires knowledge of the composition of a
      cleanser as well as the properties of the individual ingredients. METHODS: The
      article discusses the guidelines for cleansing the skin of neonates and infants.
      The characteristics of an ideal cleanser for pediatric skin have also been
      enumerated. RESULTS: In India, majority of cleansers recommended for babies do
      not mention their active ingredients. Their claims of "mildness" have not been
      substantiated with clinical studies. Cetaphil, a non-soap, lipid-free liquid
      cleanser, has been clinically proven to be non-irritating by the Chamber
      Scarification Test. Moreover, Cetaphil also has a pH of less than 7, which does
      not alter the physiological pH of skin. CONCLUSION: Hence, Cetaphil should
      definitely be considered while choosing a cleanser for neonates and infants.

PMID- 12420909
TI  - Anthropometry and moderate malnutrition in preschool children.
AB  - OBJECTIVE: For years it has been shown that more children die from moderate
      malnutrition (MM) than severe. Till yet few studies deal specifically with
      identifying these children. This study attempts to statistically determine the
      appropriate anthropometric measures and cut-off points for diagnosing moderate
      malnutrition in preschool children. METHODS: Anthropometric measurements were
      obtained from 609 preschool children from the cities of Adigrat, Ethiopia;
      Janampet, India; San Paulo, Brazil. The values were used to determine the
      sensitivity, specificity, positive predictive value (PPV) and likelihood ratio
      (LR) of each index studied. The optimum cutoff point for each index was
      considered to be the cutoff point with the maximum Kappa coefficient for
      efficiency. The McNemar Test for the significance of changes was used to
      determine if these findings were in agreement when applied to this data. RESULTS:
      Weight for height (WFH) at each site had the highest PPV and LR of 4 but was not
      signficant by the McNemar Test. Mid-upper arm circumference (MUAC) in India had
      the same PPV (77%) as WFH but a LR of 2. MUAC in India, Brazil and Ethiopia
      tested significantly for the McNemar Test. The cut-off point for MUAC in India
      and Brazil was determined to be <15.5 cm in India and Brazil but was <15 cm in
      Ethiopia. Waist circumference in India tested a significantly PPV of 64%, and a
      LR of 2. CONCLUSION: These results show that WFH and MUAC could be used with WFA
      to identify the MM child. The cut-off points for MUAC may vary per location. WC
      positive data suggests further study is warranted. The McNemar findings yielded
      significant evidence that statistically determined indicators can be established
      to identify MM. With further study these methods may prove to be an important
      component in the efforts to improve child survival.

PMID- 12420910
TI  - Nasopharyngeal carriage of Haemophilus influenzae.
AB  - OBJECTIVE: Nasopharyngeal colonization of Haemophilus influenzae (H. influenzae)
      in young children may be important in developing countries. METHOD: In this
      study, we screened school going children for carriage of H. influenzae. A total
      of 44 H. influenzae isolates out of a collection of 162 were characterized for
      biotypes, capsular serotypes and antibiotic resistance. RESULTS: A significant
      proportion of H. influenzae (25/44) isolates were serotype b. High antibiotic
      resistance was observed against commonly administered antibiotics like ampicillin
      (79%), chloramphenicol (20%), trimethoprim sulfamethoxazole (84%) and
      erythromycin (95%). Comparison of antibiotic resistance profile of nasopharyngeal
      isolates was observed to be correlated with those of H. influenzae from disease.
      CONCLUSION: Multidrug resistant nasopharyngeal H. influenzae in young healthy
      children may act as reservoir. Monitoring of antibiotic resistance among
      nasopharyngeal H. influenzae as a surrogate for invasive H. influenzae seems an
      attractive option.

PMID- 12420911
TI  - Platelet therapy.
AB  - Thrombocytopenia is a major cause of bleeding episodes at all ages. The
      pathophysiology, causes of thrombocytopenia and clinical presentation have been
      reviewed briefly. However the emphasis has been laid on various aspects of
      platelet support such as indications and amount of platelet support essential for
      management of bleeding episodes with the help of platelet concentrates, single
      donor platelets. Strategies for management of platelet transfusion refractoriness
      has also been included for effective management of bleeding episodes in these
      conditions.

PMID- 12420912
TI  - Wilson's disease.
AB  - Wilson's disease (WD), an inborn error of copper (Cu) metabolism, is now one of
      the leading liver diseases in children in India. The clinical presentation can be
      extremely varied viz.,--all forms of acute and chronic liver disease, minimal to
      severe neurological disease, psychiatric problems, bony deformities, hemolytic
      anemia and endocrine manifestations. A high index of suspicion is necessary along
      with a judicious battery of investigations for diagnosis. Hepatic copper
      estimation is the most reliable test but is not easily available in India. Liver
      biopsy may not be possible because of bleeding problems and histological features
      are often not diagnostic of WD. In the absence of hepatic Cu, a low
      ceruloplasmin, high 24 hour urinary copper and presence of KF rings aid in making
      the diagnosis. The mainstay of initial therapy is Cu-chelators like D
      Penicillamine, and Trientine for reduction in body copper to sub-toxic levels.
      Subsequent maintenance therapy is necessarily lifelong with D-Penicillamine,
      Trientine or Zinc. Children on therapy must be monitored regularly for response,
      side-effects, compliance and rehabilitation. Response to therapy may be
      unpredictable, but acute and early presentations like fulminant hepatic failures
      have a poor outcome. All siblings must be screened for WD as early diagnosis and
      treatment result in a good outcome. The identification of the WD gene on
      chromosome 13 has led to the possible use of molecular genetics (haplotype and
      mutational analyses) in the diagnosis of WD. Parent groups/associations must take
      active part in holistic management of WD.

PMID- 12420913
TI  - Non-viral infections of the liver.
AB  - The function and anatomy of the liver renders this organ peculiarly susceptible
      to bacterial and parasitic infections; fungal infections are increasingly
      recognised in the immunocompromised. As biochemical abnormalities of liver
      function can be non-specific, a high index of suspicion of liver or biliary
      infection is required. A need for prompt investigation is emphasised by the
      potentially rapid progression and poor prognosis of some bacterial and fungal
      infections, and the public health implications of parasitic diseases. This review
      encompasses the major infections of the liver and biliary tree other than viral
      hepatitis and includes aspects of pathogenicity, epidemiology, clinical
      presentation, diagnosis and management.

PMID- 12420914
TI  - Acute and chronic pancreatitis.
AB  - Pancreatitis is under appreciated during childhood although its diagnosis is
      simple and management straightforward in most cases. There is a range of possible
      causes, which is quite different to the situation in adults. The commonest
      underlying problems are probably structural abnormalities of the pancreatic and
      biliary ducts such as choledochal malformation, common pancreatobiliary channel
      and pancreas divisum. Other causes, which can be important in certain groups and
      geographical areas, are those due to drug reactions, viral infection and
      parasitic infestation, and blunt abdominal trauma. The diagnosis is established
      by showing a significantly raised plasma amylase level. Other diagnostic tools
      such as ultrasound, computed tomography (CT) scanning and endoscopic retrograde
      cholangiopancreatography (ERCP) have a major role in determining possible
      underlying causes, and hence selecting out those who require definitive
      corrective surgery. The pathophysiology of pancreatitis remains to be fully
      elucidated and, in the acute phase can affect other organs such as the renal and
      respiratory systems. Later complications include sepsis, pancreatic abscess and
      typically pseudocyst formation. Most of these can be treated using minimally
      invasive techniques such as percutaneous aspiration although open surgical
      techniques such as cystgastrostomy may be required in a few.

PMID- 12420915
TI  - Management of portal hypertension.
AB  - Portal hypertension (PHT) is common in children and a majority of cases in India
      are constituted by extrahepatic portal venous obstruction or cirrhosis of liver.
      Morbidity and mortality in this condition is related to variceal bleeding, most
      commonly from esophageal varices. Acute variceal bleeding is best controlled by
      endoscopic therapy. Somatostatin and octreotide are useful in acute variceal
      bleeding as a supplementary therapy. Acute variceal bleeding uncontrolled by
      medical therapy merits preferably a shunt surgery or devascularization depending
      upon etiology of PHT and expertise of the surgeon. Acute variceal bleeding
      originating from gastric varices can be effectively controlled by endoscopic
      injection of tissue adhesive agent (n-butyl 2 cyanoacrylate). Eradication of
      esophageal varices by endoscopic measures (sclerotherapy or band ligation) is
      successful in prevention of recurrence of bleeding. Surgical portosystemic shunts
      especially in non-cirrhotic PHT are successful in achieving portal decompression
      and significant reduction in recurrence of variceal bleeding. Role of beta
      blockers in primary prophylaxis of variceal bleeding in children still remains to
      be substantiated.

PMID- 12420917
TI  - Child with a tail.
AB  - An interesting case of a child with a tail is reported. The child had a tail like
      structure in the back since birth, increasing with age. It was 20 cm. long, the
      longest tail so far described in the English literature. There was no functional
      complain. The result was excellent after excision as the problem was only
      cosmetic.

PMID- 12420916
TI  - Alagille syndrome.
AB  - Alagille syndrome (AGS) was described more than 35 years ago as a genetic entity
      characterised by five major features: chronic cholestasis owing to paucity of
      interlobular bile ducts; peripheral pulmonary stenosis; butterfly like vertebral
      arch defect; posterior embryotoxon and peculiar facies. AGS has long been said to
      have a relative good prognosis but overall survival at twenty years averages 70%.
      Complex congenital heart disease and hepatic disease with or without liver
      transplantation contribute significantly to mortality. JAGGED1 has been
      identified as a responsible gene by demonstration of mutations in AGS patients.
      Studies of JAGGED1 expression pattern demonstrate that minor features and almost
      all the elements in the long list of manifestations described in AGS patients are
      not coincidental. This suggests that Alagille syndrome definition may be
      revisited in the light of JAGGED1 mutations.

PMID- 12420918
TI  - Importance of screening the peripheral smear.
AB  - A 5-year-old boy presented with history of failure to thrive from infancy. There
      was a history of one sibling death due to similar problems and history of severe
      abortions in the mother. Routine examination of peripheral smear revealed more
      than 50% acanthocytes. Based on this tests were streamlined to doing lipid
      profile and Lipo protein electrophoresis which revealed hypolipidemia and absent
      beta hypo protein band. Jejunal mucosal biopsy confirmed the diagnosis of A Beta
      Lipo proteinemia which revealed lipid laden enterocytes. This case illustrates
      the importance of simple tests like peripheral smear examination in streamlining
      further tests in the diagnosis of major diseases.

PMID- 12420919
TI  - Engelmann's disease with optic atrophy.
AB  - Engelman-Camurati disease is a rare Diaphyseal dysplasia, characterized by
      endosteal and periostal thickness of cortex of shaft of tubular bone sparing
      metaphysis and epiphysis. The bone of the hand, feet, ribs, scapulae and pubis
      are not affected.

PMID- 12420920
TI  - Alagille syndrome.
AB  - Syndromic paucity of bile ducts or "Alagille syndrome" is characterized by
      peculiar facies, chronic cholestasis, posterior embryotoxon, butterfly-like
      vertebral arch defects and peripheral pulmonary artery hypoplasia or stenosis. We
      present a two-year-old female child with the 'partial' or 'incomplete' Alagille
      syndrome. The child had three of the five major features of the syndrome. A brief
      review of literature of the syndrome is presented.

PMID- 12420921
TI  - Childhood sacoidosis presenting as recurrent erythema nodosum.

PMID- 12420922
TI  - Engineering properties of water/wastewater-treatment sludge modified by hydrated
      lime, fly ash and loess.
AB  - The purpose of this research was to present engineering properties of modified
      sludge from water/wastewater treatment by modifiers such as hydrated lime, loess,
      and fly ash. The proper mixing ratio was determined to hold the pH of the
      modified sludge above 12.0 for 2 h. Laboratory tests carried out in this research
      included particle analysis, compaction and CBR, SEM and X-ray diffraction,
      unconfined compression test, permeability test, and TCLP test. The main role of
      lime was to sterilize microorganisms in the sludge. The unconfined strength of
      the modified sludge by fly ash and loess satisfied the criteria for construction
      materials, which was above 100 kPa. The permeability of all the mixtures was
      around 1.0 x 10(-7) cm/s. Extraction tests for hazardous components in modified
      sludge revealed below the regulated criteria, especially for cadmium, copper, and
      lead. The present study suggested that the use of lime, fly ash, and loess be an
      another alternative to modify or stabilize water/wastewater treatment sludge as
      construction materials in civil engineering.

PMID- 12420923
TI  - Treatment of recalcitrant wastewater from ethanol and citric acid production
      using the microalga Chlorella vulgaris and the macrophyte Lemna minuscula.
AB  - Laboratory-scale experiments were performed to develop a procedure for biological
      treatment of recalcitrant anaerobic industrial effluent (from ethanol and citric
      acid production) using first the microalga Chlorella vulgaris followed by the
      macrophyte Lemna minuscula. This recalcitrant dark-colored wastewater, containing
      high levels of organic matter and low pH, prevents the growth of microalgae and
      macrophytes, and therefore, could not be treated by them. Therefore, the
      wastewater was diluted to 10% of the original concentration with wash water from
      the production line. Within 4 days of incubation in the wastewater, C. vulgaris
      population grew from 5 x 10(5) to 2 x 10(6) cells/mL. This culture reduced
      ammonium ion (71.6%), phosphorus (28%), and chemical oxygen demand (COD) (61%),
      and dissolved a floating microbial biofilm after 5 days of incubation.
      Consequently, L. minuscule was able to grow in the treated wastewater (from 7 to
      14 g/bioreactor after 6 days), precipitated the microalgal cells (by shading the
      culture), and reduced other organic matter and color (up to 52%) after an
      additional 6 days of incubation. However, L. minuscula did not improve removal of
      nutrients. This study demonstrates the feasibility of combining microalgae and
      macrophytes for bioremediation of recalcitrant industrial wastewater.

PMID- 12420924
TI  - Comparison of anaerobic dechlorinating enrichment cultures maintained on
      tetrachloroethene, trichloroethene, cis-dichloroethene and vinyl chloride.
AB  - An anaerobic mixed microbial culture was enriched from soil and groundwater taken
      from a site contaminated with trichloroethene (TCE). This enrichment culture was
      divided into four subcultures amended separately with either perchloroethene
      (PCE), TCE, cis-dichloroethene (cDCE) or vinyl chloride (VC). In each of the four
      subcultures, the chlorinated ethenes were rapidly, consistently, and completely
      converted to ethene at rates of 30-50 micromol/l of culture per day, or an
      average 160 micro-electron equivalents/l of culture per day. These cultures were
      capable of sustained and rapid dechlorination of VC, and could not dechlorinate
      1,2-dichloroethane, differentiating them from Dehalococcoides ethenogenes, the
      only known isolate capable of complete dechlorination of PCE to ethene.
      Chloroform (CF) and 1,1,1-trichloroethane, frequent groundwater co-contaminants
      with TCE and PCE, inhibited chlorinated ethene dechlorination. Most strongly
      inhibited was the final conversion of VC to ethene, with complete inhibition
      occurring at an aqueous CF concentration of 2.5 microM. Differences in rates and
      community composition developed between the different subcultures, including the
      loss of the VC enrichment culture's ability to dechlorinate PCE. Denaturing
      gradient gel electrophoresis of amplified bacterial 16S rRNA gene fragments
      identified three different DNA sequences in the enrichment cultures, all
      phylogenetically related to D. ethenogenes. Based on the PCR-DGGE results and
      substrate utilization patterns, it is apparent that significant mechanistic
      differences exist between each step of dechlorination from TCE to ethene,
      especially for the last important dechlorination step from VC to ethene.

PMID- 12420925
TI  - Kinetics and mechanisms of UV-photodegradation of chlorinated organics in the gas
      phase.
AB  - Over the last two decades, the application of photodegradation for the
      destruction of a wide spectrum of organic compounds in air has gained
      considerable interest in abating environmental pollution. This paper presents the
      results of a fundamental study conducted to evaluate the gas phase oxidation
      kinetics of volatile organic compounds (VOCs) with respect to different
      parameters pertinent to the operating conditions of air stripping and soil vapor
      extraction processes. Photodegradations of three chlorinated VOCs: chloroform,
      carbon tetrachloride (CTC) and trichloroethylene (TCE), were investigated in a
      semi-batch reactor using a low-pressure mercury UV lamp. The effects of different
      experimental parameters, such as the initial concentrations of the VOCs, the
      reaction medium, relative humidity, light intensity, temperature and the effect
      of mixture that may influence the kinetics of the gas phase photodegradation were
      evaluated. Mechanisms of photodegradation as supported by the experimental data
      are also proposed.

PMID- 12420926
TI  - Aluminum speciation in natural waters: measurement using Donnan membrane
      technique and modeling using NICA-Donnan.
AB  - The study of Al speciation is of interest for the assessment of soil and water
      quality. For the measurement of "free" aluminum (Al3+), a recently developed
      Donnan membrane technique was tested by measuring Al3+ in aluminum-fluoride
      solutions and gibbsite suspensions. It shows that the Donnan membrane technique
      can measure free Al3+ reliably up to 10(-9) M and the equilibration takes 3-4
      days. Next, Al binding to humic acid (HA) purified from a forest soil was
      measured using either the Donnan membrane technique or gibbsite suspension.
      Results were compared with those predicted with the non-ideal consistent
      competitive adsorption (NICA)-Donnan model. The predictions using the generic
      parameters without fitting were in reasonable agreement with the measured data.
      Finally, the Donnan membrane technique was used to determine Al binding to
      dissolved organic matter (DOM) in the solutions of 24 soil samples at pH interval
      of 3-7. Measurements agree well with the predictions using the NICA-Donnan model
      assuming 30% of DOM is HA and 30% is fulvic acid. With this model, the effects of
      pH and DOM changes on the concentration of Al in 81 soil solutions were predicted
      reasonably without adjustment of model parameters. The comparison between the
      results of analysis and the modeling provides a mutual validation for the two
      methods.

PMID- 12420927
TI  - Fluorescent dye labeled bacteriophages--a new tracer for the investigation of
      viral transport in porous media: 1. Introduction and characterization.
AB  - A new method for the study of pathogen transport in porous media is presented.
      The method is based on conjugation of fluorescent dyes to target bacteriophages
      and application of the modified bacteriophages for tracer studies. We demonstrate
      that the relevant transport determining properties of Rhodamine and several
      fluorescein-labeled phages are practically identical to those of the native
      bacteriophages. The advantages of the proposed method relative to direct
      enumeration of bacteriophages by plaque forming unit method, turbidity,
      fluorescent microspheres, and other alternative tracers are discussed. Notable
      advantages include simple quantitation by optical methods, unbiased signals even
      when virus aggregates are formed, and the ability to decouple inactivation
      kinetics from transport phenomena. Additionally, the signal reflects the removal
      and transport of the studied microorganism and not a surrogate.

PMID- 12420928
TI  - Fluorescent dye labeled bacteriophages--a new tracer for the investigation of
      viral transport in porous media: 2. Studies of deep-bed filtration.
AB  - Viral transport in deep-bed sand filters was studied by a new method that enables
      rapid and simple quantitation of labeled viruses. The residence time distribution
      (RTD) of viruses in the bed was compared to the RTD of a fluorescein dye under
      conditions that simulate a filter run. The characteristics of the RTD curves for
      the free dye and the labeled bacteriophages followed very different trends during
      the filter run. While the retention time of free dye was practically independent
      of the filtration stage, the average retention time of the labeled bacteriophage
      depended in a non-linear way on filtration time. Average virus retention time as
      well as virus-removal efficiency were minimal at the ripening stage, increased
      during the operational stage and then decreased again towards the turbidity
      breakthrough stage. This complex trend reflects two opposing mechanisms that
      dominate the behavior of the filter. During the ripening stage the accumulation
      of the kaolin-alum material in the filter increases the adsorption surface area
      and retards virus mobility. After sufficient kaolin-alum deposit is accumulated
      in the filter, aging and densification of the alum deposit induces size exclusion
      phenomenon giving faster apparent mobility of viruses in the filter bed.

PMID- 12420929
TI  - Degradation of pentachlorophenol by ozonation and biodegradability of
      intermediates.
AB  - The degradation pathway of pentachlorophenol (PCP) under ozonation and the
      biodegradability of the resulting intermediates were investigated. The objectives
      were to: (1) provide mechanistic details in the ozone-mediated degradation, (2)
      evaluate the biodegradability of resultant intermediates at various progressive
      stages of ozonation, and (3) thereby, assess the feasibility for a coupled
      chemical-biological treatment scheme for PCP. Tests of BOD5, COD, and E. coli
      toxicity along with qualitative and quantitative GC analyses were performed for
      aliquots withdrawn before and after various stages of ozonation and biological
      incubation. Ozonated PCP decomposed under the direct nucleophilic attack of ozone
      through an addition-elimination mechanism, resulting in tetrachloro-p
      benzoquinone and tetrachloro-p-hydroquinone intermediates that were further
      degraded by O3 and OH* to other open-ring products including ketones and acids
      that eventually led to simple oxalic acid and quantitative release of chloride
      ion. As ozonation progressed toward but prior to complete mineralization,
      reaction intermediates became increasingly more biodegradable prior to complete
      degradation, which suggested the potential of using ozonation in conjunction with
      biological treatment for the effective control of chlorinated aromatics.

PMID- 12420930
TI  - Toxicity assays: a way for evaluating AOPs efficiency.
AB  - The technical feasibility and performance of photocatalytic degradation of
      aqueous methomyl (50 mg/L) have been studied at pilot scale in two well-defined
      systems of special interest because natural-solar UV light can be used:
      heterogeneous photocatalysis with titanium dioxide and homogeneous photocatalysis
      by photo-Fenton. The pilot plant is made up of compound parabolic collectors
      specially designed for solar photocatalytic applications. Experimental conditions
      allowed pesticide disappearance, degree of mineralisation and toxicity achieved
      in the two photocatalytic systems to be compared. Total disappearance of methomyl
      is attained by photo-Fenton in 60 min and by TiO2 in 100 min. Hundred percent of
      nitrogen and sulphur are recovered as ammonium and sulphate. By contrast,
      complete mineralisation of total organic carbon (TOC) is not achieved even after
      quite a long time (more than 300 min). Three different bioassays (Vibrio
      fischeri, Daphnia magna and a Microalga) have been used for testing the progress
      of toxicity during treatment. All remained toxic down to very low-pesticide
      concentrations and in some bioassays were still toxic after total disappearance
      of the pesticide. Only if treatment is maintained throughout enough
      mineralisation (i.e. TOC disappearance), the toxicity is reduced to below the
      threshold (EC50%).

PMID- 12420931
TI  - Evaluation of 1-octanol degradation by photocatalysis and ultrasound using SPME.
AB  - Solid-phase micro-extraction has been used for identifying, quantifying and
      following the evolution of intermediate products of octanol degradation by two
      advanced oxidation treatments (AOTs), photocatalytic and ultrasound processes,
      inducing mainly the same active species. Headspace extraction enabled direct
      extraction of the organic compounds in a heterogeneous process like
      photocatalysis. The presence of a solid does not affect the extraction percentage
      of alkanes, alkenes and aldehydes while alcohols and carboxylic acids are not
      completely extracted if the extraction time is too short. To extract C3-C8
      alkanes, alkenes and aldehydes a Carboxen/PDMS fiber and an extraction time of 25
      min are used. The presence of alcohol and carboxylic acids requires the use of
      the presence of salt under acidic conditions, a longer extraction time and a
      polyacrylate fiber (PA), having a polar fiber. The in situ derivatization-
      pyrenyldiazomethane on a PA fiber--increases the carboxylic acid extraction
      containing smaller hydrocarboned chain while diazomethane derivatization is not
      as efficient due to its volatility. Whatever be the treatment, photocatalysis or
      ultrasound processes, aldehydes are the main intermediate products, which is not
      surprising since the same oxidation species (HO2(o), O2(o-), OH(o)) are formed.
      Alkanes and alkenes are also detected in both processes; however, alkane
      formation is more important in photocatalysis while alkenes are formed in higher
      amounts by ultrasound. Moreover, the presence of carboxylic acids in more
      important amounts by ultrasound than by photocatalysis is attributed to the
      presence of holes (h+) in photocatalysis which induces photo-Kolbe degradation.
      The sonochemical formation of small-chained dienes and alkynes is probably due to
      pyrolysis of hydrophobic compounds in cavitation bubbles.

PMID- 12420932
TI  - Identification of the sources of fecal coliforms in an urban watershed using
      antibiotic resistance analysis.
AB  - Bacteria such as fecal coliforms are used as indicators of fecal pollution in
      natural waters. These bacteria are found in the feces of most wild and domestic
      animals and thus provide no information as to the source of fecal contamination,
      yet identification of indicator bacteria sources allows improved risk assessment,
      remediation, and total daily maximum load (TDML) assessment of environmental
      waters. This bacterial source tracking study was initiated in order to identify
      the dominant source(s) of fecal contamination in the urban watershed of Stevenson
      Creek in Clearwater, Florida. Five sites that represent areas where routine
      monitoring has previously shown high levels of fecal coliforms were sampled over
      7 months. Fecal coliforms were enumerated by membrane filtration, and antibiotic
      resistance analysis was used to "fingerprint" a subset of randomly selected
      isolates and statistically match them to fingerprints of fecal coliforms from
      known sources (the library). A field test of the classification accuracy of the
      library was carried out by isolating fecal coliforms from the soil and waters
      surrounding a failing onsite wastewater treatment and disposal system (OSTDS).
      The vast majority of the isolates were classified into the human category. The
      major sources of fecal pollution in Stevenson Creek over the course of the study
      were wild animal, human, and, to a lesser extent, dog. Overall, wild animal feces
      were identified as the dominant source when fecal coliform levels were high, but
      when fecal coliform levels were low, the dominant source was identified as human.
      The results of this study demonstrate that the sources of fecal indicator
      bacteria within one urban watershed can vary substantially over temporal and
      spatial distances.

PMID- 12420933
TI  - Mineralization of a sorbed polycyclic aromatic hydrocarbon in two soils using
      catalyzed hydrogen peroxide.
AB  - Hydrogen peroxide (H2O2) catalyzed by soluble iron or naturally occurring soil
      minerals, (i.e., modified Fenton's reagent) was investigated as a basis for
      mineralizing sorbed and NAPL-phase benzo[a]pyrene (BaP), a hydrophobic and toxic
      polycyclic aromatic hydrocarbon, in two soils of different complexity. 14C
      Benzo[a]pyrene was added to silica sand and a silt loam soil, and mineralization
      was investigated using three-level central composite rotatable experimental
      designs. The effects of H2O2 concentration, slurry volume, and iron(II) amendment
      were investigated in the silica sand systems. In a Palouse loess silt loam soil,
      the variables included H2O2 concentration, slurry volume, and pH, with H2O2
      catalyzed by naturally occurring iron oxyhydroxides. Regression equations
      generated from the data were used to develop three-dimensional response surfaces
      describing BaP mineralization. Based on the recovery of 14C-CO2, 70% BaP
      mineralization was achieved in the sand within 24 h using 15 M H2O2 and an
      iron(II) concentration of 6.6 mM with a slurry volume of 0.3 x the field capacity
      of the sand. For the silt loam soil, 85% mineralization of BaP was observed using
      15 M H2O2, no iron amendment, and a slurry volume of 20 x the soil field
      capacity. The balance of the radiolabeled carbon remained as unreacted BaP in the
      soil fraction. Gas-purge measurements over 5 d confirmed negligible desorption
      under nontreatment conditions. However, oxidation reactions were complete within
      24 h and promoted up to 85% BaP mineralization, documenting that the natural rate
      of desorption/dissolution did not control the rate of oxidation and
      mineralization of the BaP. The results show that catalyzed H2O2 has the ability
      to rapidly mineralize sorbed/NAPL-phase BaP and that partitioning, which is often
      the rate-limiting factor in soil remediation, does not appear to limit the rate
      of vigorous Fenton-like treatment.

PMID- 12420934
TI  - A study of the evolution of the particle boundary layer in a reservoir, using
      laser particle sizing.
AB  - The dynamics of the particle boundary layer in the Boadella reservoir was studied
      using an in situ laser optical particle-sizing instrument. This layer was found
      at the bottom of the reservoir from summer until the end of the year, when the
      reservoir was fully mixed. Most of the particles in this layer are remnants of
      the summer algae bloom and are trapped in the boundary layer due to the thermal
      stratification. The phytoplankton bloom is mainly composed of diatoms, with
      diameter d approximately 5 microm and green algae with diameter d approximately
      15 microm. Inorganic particles and decomposed organic particles with d < 3 microm
      are also encountered in the boundary layer. On the other hand, particles with
      diameter between 30 and 100 microm are mostly found in the epilimnion of the
      reservoir. These are a mixture of aggregates of inorganic particles, colonies of
      phytoplankton, zooplankton, detritus, etc. Different mixing events occurring
      during autumn resuspended the small particles in the boundary layer, while the
      greater particles settled down. The extent of the resuspension has been
      parameterized with a non-dimensional number that balances the stress across the
      interface and the strength of the stratification.

PMID- 12420935
TI  - Washing powders and the environment: has TAED any influence on the complexing
      behaviour of phosphonic acids?
AB  - Complexation properties of two phosphonic acids: nitrilotris (methylenephosphonic
      acid) and 1-hydroxyethane-1,1'-diphosphonic acid, with Cu(II) and Ca(II) have
      been previously determined by pH and ionic selective electrode titrations. These
      phosphonic acids are commonly added to washing powders as polyphosphate
      substitutes and are here studied in the presence of another detergent compound:
      tetraacetylethylenediamine (TAED), a bleaching activator. Product concentrations
      were chosen in order to correspond to component concentration ratios encountered
      in washing powders. Potentiometric titrations were carried out to determine the
      possible TAED interferences; they indicate that TAED and its by-products have no
      action on phosphonic acid complexing behaviour. Under our experimental
      conditions, the action of TAED was modelled with acetic acid and ethylenediamine,
      the final by-products of TAED hydrolysis. If we take into account both phosphonic
      and acetic acids, speciation diagrams corresponding to representative fresh water
      systems showed that the acetic acid does not influence cation speciation.

PMID- 12420936
TI  - Advanced oxidation and adsorption technologies for organic micropollutant removal
      from lake water used as drinking-water supply.
AB  - The goal of this research is to evaluate the effectiveness of innovative drinking
      water treatments designed to remove toxic and mutagenic organic micropollutants
      from lake waters used for human consumption. The widely used adsorption on
      granular activated carbon (GAC) filter technique was compared with the more
      innovative resin column techniques (XAD4 and Ambersorb-563) and with the advanced
      oxidation processes (AOPs) with UV/O3 and UV/O3/ H2O2. The water samples,
      collected from lake Como, treated with these techniques were analysed for
      mutagenic activity using Ames assay, toxicity using bioluminescent bacteria and
      organic compound were characterized using the GC-MS technique. The results found
      a decrease of the mutagenic and toxic activities of the lake water after
      adsorption on GAC and resins, while the AOP process generally increased these
      parameters. The absence of mutagenic activity was found only when a GAC
      adsorption step was performed in addition to the AOP process. Similar results
      were obtained by the toxicological and chemical analyses. In addition, the GC-MS
      analysis identified some possible mutagenic agents.

PMID- 12420937
TI  - Occurrence of nitrifying bacteria and nitrification in Finnish drinking water
      distribution systems.
AB  - Microbiological nitrification process may lead to chemical, microbiological and
      technical problems in drinking water distribution systems. Nitrification activity
      is regulated by several physical, and chemical, and operational factors. However,
      the factors affecting nitrification in the distribution systems in boreal region,
      having its specific environmental characteristics, are poorly known. We studied
      the occurrence and activity of nitrifying bacteria in 15 drinking water networks
      distributing water with very different origin and treatment practices. The waters
      included chloraminated surface water, chlorinated surface water, and non
      disinfected groundwater. The networks were located in eight towns in different
      parts of Finland. Our results showed that nitrifying bacteria are common in
      boreal drinking water distribution systems despite their low temperature.
      Surprisingly high numbers and activities of nitrifiers were detected in pipeline
      sediment samples. The numbers of ammonia-oxidizing bacteria and their oxidation
      potentials were highest in chloraminated drinking water delivering networks,
      whereas the nitrite-oxidizing bacteria were present in the greatest numbers in
      those networks that used non-disinfected groundwater. The occurrence of
      nitrifying bacteria in drinking water samples correlated positively with the
      numbers of heterotrophic bacteria and turbidity, and negatively with the content
      of total chlorine. Although nitrifying bacteria grew well in drinking water
      distribution systems, the problems with nitrite accumulation are rare in Finland.

PMID- 12420938
TI  - Application of Landsat imagery to regional-scale assessments of lake clarity.
AB  - A procedure that uses Landsat imagery to estimate Secchi disk transparency (SDT)
      of lakes was developed and applied to approximately 500 lakes with surface areas
      > 10 ha in the seven-county metropolitan area of Minneapolis and St. Paul, MN,
      USA, to assess spatial patterns and temporal trends in lake clarity. Thirteen
      Landsat MSS and TM images over the period 1973-1998 were used for the analysis.
      Satellite brightness values from lake surfaces were calibrated against available
      historical data on SDT (n = approximately 20-40) measured nearly
      contemporaneously with the acquisition date of each image. Calibration regression
      equations for the late-summer TM images had a range of r2 from 0.72 to 0.93.
      Regression analysis for three late-summer MSS images yielded r2 values ranging
      from 0.60 to 0.79. Results indicate that a single late-summer image yields a
      reliable estimate of regional lake clarity and reasonably accurate estimates of
      SDT for individual lakes. An analysis of seasonal patterns on a large lake water
      quality database was used to develop a model that adjusts synoptic satellite SDT
      estimates from different dates to a common reference, making them more comparable
      from year-to-year. Analysis of long-term trends shows that in spite of the large
      land-use changes within the region over the study period, only 49 (about 10%) of
      assessed lakes in the region showed significant temporal trends in SDT over the
      period, and more lakes had increasing SDT (34) than decreasing SDT (15).

PMID- 12420939
TI  - A suite of multi-segment fugacity models describing the fate of organic
      contaminants in aquatic systems: application to the Rihand Reservoir, India.
AB  - The fugacity-based quantitative water-air-sediment interaction (QWASI) model is
      described which can be used to establish a mass balance for an organic or
      metallic contaminant in a lake ecosystem consisting of water, suspended matter,
      bottom sediments and the atmosphere. A suite of such models is described and
      discussed with various degrees of complexity including versions treating
      equilibrium and non-equilibrium situations, steady-state and dynamic conditions
      with either single or multiple segments. It is suggested that when seeking to
      apply a mass balance model to a specific lake and contaminant situation, it is
      desirable to start with a simple model and increase the complexity as
      circumstances dictate. This approach is illustrated by application of QWASI
      models to the Rihand Reservoir in India for lindane and benzo(a)pyrene. The roles
      are discussed by which such models can contribute to improved management of
      chemicals that may adversely affect aquatic systems, especially in developing
      regions.

PMID- 12420940
TI  - Solubility controls on aluminum in drinking water at relatively low and high pH.
AB  - Potential control of soluble aluminum in drinking water by formation of solids
      other than Al(OH)3 was examined. At pHs below 6.0, Al(+3) solids containing
      sulfate, silica or potassium are thermodynamically favored versus amorphous
      Al(OH)3; however, in this work no evidence could be obtained that solids other
      than Al(OH)3 would form in practice. At pHs above 9, aluminum and magnesium were
      discovered to form complex solid phases of approximate composition AlMg2(OH)7,
      AlMg2SiO2(OH)7 or Al(SiO2)2(OH)3 dependent on circumstance. Formation of these
      solids provide a mechanistic explanation for enhancements to precipitative
      softening obtained in practice by dosing Al(+3) salts; that is, improved
      flocculation/settling and removal of silica from water that interferes with
      calcium precipitation. The solids also maintain residual aluminum below
      regulatory guidelines at high pH > 9.5.

PMID- 12420941
TI  - Comparative process stability and efficiency of anaerobic digestion; mesophilic
      vs. thermophilic.
AB  - The comparative process stability and efficiency of mesophilic (35 degrees C) and
      thermophilic anaerobic digestion (55 degrees C) has been evaluated for four
      different reactor configurations, which are: daily batch-fed single-stage
      continuously stirred tank reactor (CSTR), continuously fed single-stage CSTR,
      daily batch-fed two-phase CSTR, and daily batch-fed non-mixed single-stage
      reactor. The results are discussed for three periods: (1) start-up, (2) steady
      state, and (3) organic loading rate (OLR) increase until reactor failure (pH
      below 5.5). During the start-up, the single-stage CSTRs at both temperatures
      showed the least stability, while the non-mixed single-stage reactors reached
      steady state in the shortest time with relatively stable pH and low volatile
      fatty acid (VFA). In the case of the thermophilic non-mixed reactor, efficient
      removal of propionate occurred but supplementation of nutrients (Ca, Fe, Ni, and
      Co) was required when VFA increased. The results imply the importance of
      inorganic nutrients bioavailability. The comparative results of the reactor
      performance at steady state clearly showed the superior performance of the
      thermophilic non-mixed reactor with respect to lower VFA, higher gas production
      and volatile solids removal implying that microbial consortia proximity can
      alleviate the problem of poor effluent quality in thermophilic system. During the
      OLR increase until reactor failure, all thermophilic reactors except the
      thermophilic non-mixed reactor showed increases in propionate concentrations as
      the OLR increased, while all mesophilic reactors except the mesophilic two-phase
      system showed little increase in VFA concentrations. When all reactors had the
      same conditions with OLR increase, the continuously fed reactors showed the
      lowest gas production, while the non-mixed reactors showed the highest gas
      production at both temperatures. It is hypothesized that the non-mixing reactor
      configuration has closer microbial consortia proximity than others. Therefore,
      the results in this study indicated the importance of microbial consortia
      proximity. A proposed model for the effect of the distance between two syntrophic
      bacteria reasonably matched the data in this study.

PMID- 12420942
TI  - Electrochemical treatment of cigarette industry wastewater: feasibility study.
AB  - The electrochemical treatability of wastewater from the cigarette industry has
      been investigated in this paper using cast iron electrode. The treatment
      efficiency was monitored in terms of COD, BOD and suspended solids concentration.
      The cast iron anode was found effective in treatment of the above-mentioned
      wastewater. About 56% of COD and 84% of BOD removal was observed at 3.5 A current
      for 5 h of electrolysis. The effect of increase in surface area of anode reduces
      electrolysis time and also energy consumption per kg of COD removal. The treated
      effluent was subjected to chemical coagulation studies using Ca(OH)2 as
      coagulant. The final treated effluent was found to confirm the stipulated
      standards for safe disposal into surface water bodies (Indian Standards). It was
      concluded that the electrochemical treatment followed by chemical coagulation
      could be opted as an alternate treatment scheme for the present industry.

PMID- 12420943
TI  - Chlorination of model drinking water biofilm: implications for growth and organic
      carbon removal.
AB  - The influence of chlorine on biofilm in low organic carbon environments typical
      of drinking water or industrial process water was examined by comparing biomass
      and kinetic parameters for biofilm growth in a chlorinated reactor to those in a
      non-chlorinated control. Mixed-population heterotrophic biofilms were developed
      in rotating annular reactors under low concentration, carbon-limited conditions
      (< 2 mg/L as carbon) using three substrate groups (amino acids, carbohydrates and
      humic substances). Reactors were operated in parallel under identical conditions
      with the exception that chlorine was added to one reactor at a dose sufficient to
      maintain a free chlorine residual of 0.09-0.15 mg/L in the effluent. The presence
      of free chlorine resulted in development of less biofilm biomass compared to the
      control for all substrates investigated. However, specific growth and organic
      carbon removal rates were on the average five times greater for chlorinated
      biofilm compared to the control. Observed yield values were less for chlorinated
      biofilm. Although chlorinated biofilm's specific organic carbon removal rate was
      high, the low observed yield indicated organic carbon was being utilized for
      purposes other than creating new cell biomass. The impacts of free chlorine on
      mixed-population biofilms in low-nutrient environments were different depending
      upon the available substrate. Biofilms grown using amino acids exhibited the
      least difference between control and chlorinated kinetic parameters; biofilm
      grown using carbohydrates had the greatest differences. These findings are
      particularly relevant to the fundamental kinetic parameters used in models of
      biofilm growth in piping systems that distribute chlorinated, low-carbon
      concentration water.

PMID- 12420944
TI  - Estimating the toxicities of organic chemicals to bioluminescent bacteria and
      activated sludge.
AB  - Toxicity assays based on bioluminescent bacteria have several advantages
      including a quick response and an easily measured signal. The Shk1 assay is a
      procedure for wastewater toxicity testing based on the bioluminescent bacterium
      Shk1. Using the Shk1 assay, the toxicity of 98 organic chemicals were measured
      and EC50 values were obtained. Quantitative structure-activity relationship
      (QSAR) models based on the logarithm of the octanol-water partition coefficient
      (log(Kow)) were developed for individual groups of organic chemicals with
      different functional groups. The correlation coefficients for different groups of
      organic compounds varied between 0.69 and 0.99. An overall QSAR model without
      discriminating the functional groups, which can be used for a quick estimate of
      the toxicities of organic chemicals, was also developed and model predictions
      were compared to experimental data. The model accuracy was found to be one order
      of magnitude from the observed values.

PMID- 12420945
TI  - Control of denitrification in a septage-treating artificial wetland: the dual
      role of particulate organic carbon.
AB  - We examined the factors controlling organic carbon (C) cycling and its control of
      nitrogen (N) removal via denitrification in an aerated artificial wetland
      treating highly concentrated wastewater to nutrient-removal standards. Processing
      of organic material by the septage-treating wetland affected the biological
      reactivity (half-life, or t1/2) of organic C pools through microbial degradation
      and gravity fractionation of the influent septage. Primary sedimentation
      fractionated the initial septage material (t1/2 = 8.4d) into recalcitrant waste
      solids (t1/2 = 16.7d) and highly labile supernatant (t1/2 = 5.0d), allowing this
      reactive fraction to be further degraded during treatment in aerobic wetland
      tanks until a less labile material (t1/2 = 7.3d) remained. Organic C
      contributions from in situ fixation by nitrifying bacteria or algae in these
      tanks were small, about 1% of the C degradation rate. In the aerated tanks,
      denitrification was correlated with particulate organic C loading rates, although
      the average C required (0.35 mg C L(-1)h(-1)) to support denitrification was only
      12% of the total C respiration rate (2.9 mg C L(-1)h(-1)). Additions of plant
      litter (2.5g C L(-1)) to the aerated tanks under normal operating conditions
      doubled denitrification rates to 0.58 mg N L(-1)h(-1), and reduced effluent
      nitrate levels by half, from 12.7 to 6.4 mg N L(-1). However, C degradation
      within the plant litter (0.15mg C L(-1)h(-1)) was sufficient to have accounted
      for only 35% of the additional denitrification. Evidence from laboratory and full
      scale plant litter additions as well as process monitoring indicates that the
      stimulation of denitrification is due to the respiration-driven formation of
      anaerobic microsites within particulate organic C. In this aerated highly C
      loaded septage-treating wetland, anaerobic microsite, rather than C substrate
      availability limits denitrification.

PMID- 12420946
TI  - An innovative electro-corrosion recess creation technique for improved
      microelectrode fabrication.
AB  - A new and simple electrochemical (corrosion) method for recess creation for the
      fabrication of metal and metal-metal oxide microelectrodes has been developed.
      Controlled recess was created in low melting point alloy (LMA)-filled
      micropipettes using slightly acidic 1-3 M ZnCl2 as the electro-corrosion
      solution. The current was applied from a 3 V DC source. The recess length in the
      LMA-filled micropipette can be manipulated as needed for a specific
      microelectrode by varying the electro-corrosion time. The present method is
      expected to make microelectrode fabrication a less tedious process. Dissolved
      oxygen, oxidation-reduction potential and pH microelectrodes have been made using
      the present method and the microelectrode characteristics were found to be in
      conformity with those reported by other researchers.

PMID- 12420947
TI  - Dietary risk factors for invasive and in-situ cervical carcinomas in Bangkok,
      Thailand.
AB  - OBJECTIVE: Although human papillomavirus (HPV) may be a necessary cause of
      cervical cancer, most women with HPV infections do not develop this disease. This
      study was conducted to evaluate the possible effects of specific dietary factors
      on cervical carcinogenesis. METHODS: Fifty hospitalized in-situ cases and 125
      controls were identified from family planning or gynecologic clinics associated
      with Siriraj hospital in Bangkok, Thailand, and 134 hospitalized invasive cases
      and 384 hospitalized controls from the public wards of Siriraj Hospital were
      administered a food-frequency questionnaire and tested for HPV DNA in exfoliated
      cervical cells. Odds ratios in relation to intake of foods high in vitamin C,
      folate, vitamin E, vitamin A, beta-carotene, retinol, and cruciferous vegetables
      were estimated using logistic regression in case-control comparisons and in case
      case comparisons adjusted for HPV status. RESULTS: High intake of foods rich in
      vitamin A, and particularly high-retinol foods, were associated with a reduced
      risk of in-situ disease and less strongly also with a reduced risk of invasive as
      compared to in-situ disease. No association was found between intake of
      cruciferous vegetables, foods high in vitamin C, folate, vitamin E, and beta
      carotene and risk of either in-situ or invasive cervical cancer. CONCLUSIONS:
      Increasing intake of foods rich in total vitamin A, and particularly high-retinol
      foods, may reduce risk of in-situ cervical cancer, and at the highest level of
      intake may inhibit progression to invasion. If others confirm these results they
      suggest means of reducing the risk of cervical cancer that are amenable to public
      health action.

PMID- 12420948
TI  - Association between alcohol consumption and postmenopausal breast cancer: results
      of a case-control study in Montreal, Quebec, Canada.
AB  - OBJECTIVES: To determine the association between postmenopausal breast cancer and
      prior consumption of alcoholic beverages. METHODS: This case-control study,
      conducted in all Montreal hospitals between 1996 and 1997, included 556
      postmenopausal women (age 50-75 years) who had a new histologically confirmed
      diagnosis of primary, malignant breast cancer. Control subjects (577) were
      selected from other histologically confirmed sites of cancer. A detailed history
      of alcohol consumption and other risk factors was obtained by interview. Indices
      reflecting alcohol consumption were developed and unconditional logistic
      regression was used to estimate adjusted odds ratios (OR) and 95% confidence
      intervals (CI). RESULTS: Current regular drinkers of any type of alcohol were at
      an increased risk of breast cancer (OR = 1.5; 95% CI 1.0-2.2). For all beverages
      considered, current regular drinkers showed higher risks than ever regular
      drinkers. The risk of breast cancer was highest among women who reported
      exclusive drinking of wine on a weekly or daily basis (e.g. current regular
      drinking: OR = 2.3; 95% CI 1.2-4.3). Women who started to drink wine on or before
      the age of 40 were at a 2.5 times increased risk (95% CI 1.4-4.4). CONCLUSIONS:
      Our findings provide further support for a positive association between the risk
      of postmenopausal breast cancer and alcohol consumption.

PMID- 12420949
TI  - Medical radiation, family history of cancer, and benign breast disease in
      relation to breast cancer risk in young women, USA.
AB  - OBJECTIVE: In previous studies breast cancer risk has been increased among women
      who received high doses (above 100-200 cGy) of ionizing radiation or those
      exposed to lower doses prior to age 20. Some evidence suggests that such risk may
      be distinctly elevated among women with a family history of breast or ovarian
      cancer (probably only carriers of specific gene mutations) and women with benign
      breast disease (BBD). METHODS: A population-based case-control study in Los
      Angeles County obtained interview data from 744 women who were aged 40 or younger
      and diagnosed with breast cancer during 1983-1988, and from 744 matched controls.
      Women with a positive family history of breast or ovarian cancer reported cancer
      in a mother, sister, or grandmother. Women with BBD reported a physician
      diagnosis. Radiation exposure was defined as a history of either radiation
      therapy or moderate exposure to medical radiography. RESULTS: Breast cancer risk
      was elevated among women exposed to medical radiation prior to age 20 years (odds
      ratio (OR) = 1.4, 95% confidence interval (CI) = 1.2-1.8), relative to unexposed
      women. This increased risk was observed only among women with a history of BBD
      (OR = 2.4, 95% CI = 1.6-3.7). Overall, risk was not associated with exposure to
      medical radiation after age 20 years, although among women with a positive family
      history of breast or ovarian cancer, exposed women had an increased risk (OR=
      1.8, 95% CI = 1.0-3.1). Breast cancer risk was not increased among women with a
      family history of breast/ovarian cancer exposed to medical radiation before age
      20 years or those with BBD exposed to medical radiation after age 20 years.
      DISCUSSION: Study participants may have received radiation doses that are no
      longer common, hampering study generalizability. Although differences in recall
      between cases and controls cannot be completely excluded, women with BBD or a
      family history of breast cancer appear to have greater breast cancer risk
      following relatively low ionizing radiation exposure than other women in this
      study.

PMID- 12420950
TI  - Cancer prevention behaviors and socioeconomic status among Hispanics and non
      Hispanic whites in a rural population in the United States.
AB  - OBJECTIVES: Socioeconomic status is explored as a predictor of differences
      between Hispanics and non-Hispanic Whites in cancer prevention behavior. METHODS:
      In a cross-sectional study, in-person interviews (n = 1795) were conducted in a
      population-based random sample of adults in 20 communities with a high proportion
      of Hispanics. RESULTS: Hispanics were significantly less likely than non-Hispanic
      Whites to ever have had cervical (p < 0.001), breast (p = 0.007), or colorectal
      cancer (FOBT p = 0.008; sigmoidoscopy/colonoscopy p < 0.002) screening. After
      adjusting for socioeconomic status (education and having health insurance), only
      differences in cervical cancer remained significant (p = 0.024). After adjusting
      for socioeconomic status, Hispanics had a significantly higher intake of fruits
      and vegetables per day (4.84 servings) than non-Hispanic Whites (3.84 servings)
      (p < 0.001); and fat behavior score was marginally significant after adjustment
      for socioeconomic status (p = 0.053). Significantly fewer Hispanics were current
      smokers than non-Hispanic Whites (p < 0.001). CONCLUSIONS: There is only limited
      support for the hypothesis that socioeconomic status is a major determinant of
      some cancer-related behaviors; specifically, socioeconomic status is related to
      mammography and colorectal screening, but not cervical cancer, dietary behavior,
      or smoking.

PMID- 12420951
TI  - Changes in breast cancer incidence and stage distribution in Modena, Italy: the
      effect of a mammographic screening program.
AB  - OBJECTIVE: Assessing changes in breast cancer (BC) incidence and stage
      distribution in the District of Modena, Italy, during the period 1992-1998, and
      their relationship to a mammographic screening program launched in 1995. METHODS:
      Demographic, clinical, and pathological data of all BC cases reported to the
      population-based Modena Cancer Registry between 1992 and 1998 were collected and
      linked to the screening database. RESULTS: A total of 3429 women were diagnosed
      with BC in the District of Modena between 1992 and 1998. In this period the
      incidence rate increased by 15.7% (from 134.3 in 1992 to 155.4 per 100,000 in
      1998). The increase began in 1995 and exclusively included women aged 50-69; the
      incidence rose by 30.4%. Moreover, the rise was confined to early tumors, with
      more than half (54%) of all cases reported in 1998 diagnosed as stage 0 or I
      disease, compared with 42% in 1992. Screen-detected tumors were significantly
      smaller (13.2 mm) than other tumors diagnosed in women aged 50-69 (18.5 mm), with
      46% of screen-detected tumors smaller than 10 mm. Overall, a decline in the
      average tumor diameter was shown (from 20.2 mm in 1992-1994 to 18 mm in 1996
      1998). CONCLUSIONS: Our data confirm that mammographic screening leads to an
      increase in the incidence of early-stage BC cancers.

PMID- 12420952
TI  - Correlates of vitamin supplement use in the United States: data from the
      California Teachers Study cohort.
AB  - OBJECTIVE: To describe factors associated with vitamin supplement use in a large
      cohort of adult women. METHODS: California teachers and administrators (n =
      133,479) completed a questionnaire on lifestyle factors and medical history.
      Specific supplement users regularly used at least one specific vitamin supplement
      in the past year; multivitamin users regularly used a multivitamin; and
      multivitamin and specific supplement users took a multivitamin and one or more
      specific supplements. Associations between supplement use and other variables
      were quantified using means, cross-tabulations, and age-adjusted prevalence odds
      ratios. RESULTS: Multivitamin and specific supplement users tended to be older
      and Caucasian. Compared to non-users, they were also leaner (odds ratio [OR] for
      BMI > or = 30 kg/m2 = 0.6 for specific supplement users with or without
      multivitamins, and OR = 0.7 for multivitamin only users), and were less likely to
      be current smokers (OR for current smoking = 0.8 for multivitamin plus specific
      supplement users, OR = 0.9 for specific supplement only users, and OR = 0.7 for
      multivitamin only users). Specific supplement users (with or without
      multivitamins) were more likely to use cancer screening tests, eat fruits and
      vegetables, and exercise than were multivitamin only users or non-users.
      CONCLUSIONS: A variety of demographic, dietary, and health-related factors were
      associated with different categories of supplement use.

PMID- 12420953
TI  - Obesity, body size, and risk of postmenopausal breast cancer: the Women's Health
      Initiative (United States).
AB  - OBJECTIVE: Body size is an important modifiable risk factor for breast cancer.
      Although obesity has generally been found to be associated with increased risk
      for postmenopausal breast cancer, there remain questions concerning the role of
      body fat distribution, lifetime weight history, and effects within specific
      subgroups of women. METHODS: We assessed the relationship of several
      anthropometric measures and risk of postmenopausal breast cancer in 85,917 women
      aged 50-79 at entry in the Women's Health Initiative Observational Study. Women
      were enrolled during 1993-1998 at 40 clinics in the US and 1030 developed
      invasive breast cancer by April 2000. Upon entry, trained clinical center staff
      measured each woman's height, weight, and waist and hip circumference. RESULTS:
      Anthropometric factors were not associated with breast cancer among women who had
      ever used hormone replacement therapy (HRT). Among HRT non-users, heavier women
      (baseline body mass index (BMI) >31.1) had an elevated risk of postmenopausal
      breast cancer (relative risk (RR) = 2.52; 95% confidence interval (CI) = 1.62
      3.93), compared to slimmer women (baseline BMI < 22.6). The elevation in risk
      associated with increasing BMI appeared to be most pronounced among younger
      postmenopausal women. Change in BMI since age 18, maximum BMI, and weight were
      also associated with breast cancer in HRT non-users. While both waist and hip
      circumference were associated with breast cancer risk, their ratio, a measure of
      fat distribution, was not (RR = 1.33; 95% CI = 0.88-2.01). CONCLUSIONS: Our study
      confirms previously reported findings that generalized obesity is an important
      risk factor for postmenopausal breast cancer, but only among women who have never
      taken HRT. Lifetime weight gain is also a strong predictor of breast cancer.
      Waist to hip ratio, a measure of weight distribution, does not appear to be
      related to postmenopausal breast cancer risk.

PMID- 12420954
TI  - Risk of breast cancer in women exposed to diethylstilbestrol in utero:
      prelimiinary results (United States).
AB  - BACKGROUND: A synthetic estrogen, diethylstilbestrol (DES), was widely prescribed
      to pregnant women during the 1950s and 1960s but was later discovered to be
      associated with an increased risk of clear-cell carcinoma of the vagina and
      cervix in female offspring. DES has not been linked to other cancers in female
      offspring, but studies of other prenatal factors such as twin gestation and pre
      eclampsia have indicated that in-utero estrogen levels may influence breast
      cancer risk. We evaluated the relation of in-utero DES exposure to the risk of
      adult breast cancer. METHODS: A cohort of 4821 exposed women and 2095 unexposed
      women, most of whom were first identified in the mid-1970s, were followed by
      mailed questionnaires for an average of 19 years. Reported cancer outcomes were
      validated by medical record review. Breast cancer incidence in DES-exposed
      daughters was compared with cancer incidence in unexposed daughters with use of
      Poisson regression analysis, adjusting for year of birth, age at menarche, age at
      first birth, and number of births. FINDINGS: The rate ratio for incidence of
      invasive breast cancer in exposed versus unexposed women was 1.4 (95% confidence
      interval (CI) = 0.7-2.6). DES exposure was not associated with an increased risk
      of breast cancer in women under 40 years, but among women aged 40 and older the
      rate ratio was 2.5 (95% CI = 1.0-6.3). The rate ratio for the association of DES
      exposure with estrogen receptor-positive tumors was 1.9 (95% CI = 0.8-4.5).
      INTERPRETATION: While not statistically significant, the overall 40% excess risk,
      arising exclusively from the subset of estrogen receptor-positive cases, raises a
      concern calling for continued investigation.

PMID- 12420955
TI  - Diabetes mellitus and ovarian cancer (Sweden).
AB  - OBJECTIVE: We present results from a large, population-based cohort study in
      Sweden, where we assessed ovarian cancer risk among patients hospitalized for
      diabetes mellitus. METHODS: The cohort was composed of patients identified in the
      Swedish In-Patient Register as having a hospital discharge diagnosis of diabetes
      mellitus in 1965-1994. The follow-up was done by linkages with the national
      cancer register and other population-based registers. Standardized incidence
      ratios (SIR) were used as a measure of relative risk. RESULTS: After exclusion of
      the first year of follow-up (to avoid selection bias), 141,627 women remained in
      the cohort, contributing 865,746 years of follow-up to the study. The overall SIR
      for ovarian cancer was 0.97 (95% confidence interval (CI) 0.87-1.08). We found no
      difference in the risk estimates among women who had been hospitalized for
      classic complications of diabetes and for those who had not, or according to the
      duration of follow-up. Women above 40 years of age at first hospitalization
      presented a SIR of 0.96 (95% CI 0.85-1.07). CONCLUSIONS: Our study provides
      evidence of lack of an association between diabetes mellitus and ovarian cancer.

PMID- 12420956
TI  - A pooled analysis of case-control studies of thyroid cancer. VII. Cruciferous and
      other vegetables (International).
AB  - OBJECTIVE: To investigate the association between cruciferous and other
      vegetables and thyroid cancer risk we systematically reanalyzed the original data
      from 11 case-control studies conducted in the US, Asia, and Europe. METHODS: A
      total of 2241 cases (1784 women, 457 men) and 3716 controls (2744 women, 972 men)
      were included. Odds ratios (OR) and the corresponding 95% confidence intervals
      (CI) were estimated for each study by logistic regression models, conditioned on
      age and sex, and adjusted for history of goiter, thyroid nodules or adenomas, and
      radiation. Summary ORs for all studies combined were computed as the weighted
      average of the estimates from each study. RESULTS: A decreased risk for the
      highest level of cruciferous vegetable intake, as compared to the lowest, was
      observed in Los Angeles, Hawaii, Connecticut, southeastern Sweden, Tromso, and
      Switzerland; the OR were above unity in Japan and Uppsala, whereas no material
      association was found in northern Sweden, Italy, or Greece. The OR values for all
      studies combined were 0.87 (95% CI 0.75-1.01) for moderate and 0.94 (95% CI 0.80
      1.10) for high cruciferous vegetables intake. The results were similar in studies
      from iodine-rich areas and endemic goiter areas, and were consistent when the
      analysis was restricted to papillary carcinomas and women. The summary OR values
      for vegetables other than cruciferous were 1.04 (0.88-1.22) for moderate and 0.82
      (0.69-0.98) for high consumption. CONCLUSIONS: This combined analysis indicates
      that cruciferous vegetables are not positively related to thyroid cancer risk.
      Their effect does not seem to be substantially different from that of other
      vegetables, which appear to be protective on this cancer.

PMID- 12420957
TI  - Risk assessment between silica dust and lung cancer.

PMID- 12420958
TI  - Lung cancer risks in silica-exposed workers.

PMID- 12420959
TI  - Back to school: smoking policies in US college residence halls (fall 2002).

PMID- 12420960
TI  - Trophic relations in two lakes from the Bulgarian Black Sea coast and
      possibilities for their restoration.
AB  - Based on quantitative data on nutrients, light penetration, phytoplankton,
      zooplankton and zoobenthos obtained in the period 1992-1994 the relations between
      trophic levels were studied by means of statistical analysis. The two lakes are
      distinguished by relatively high transfer efficiency between phytoplankton and
      zooplankton, which depends on the size distribution among zooplankton and
      percentage of blue-green algae. The bottom up influence seems to prevail over the
      top-down influence, water surface area and phosphorus load are large, and mean
      depth is more than 1 m. All this let us conclude that biomanipulation measures
      alone are not sufficient for a substantial lake restoration.

PMID- 12420961
TI  - Nutrient fluxes from the Danube Basin to the Black Sea.
AB  - This paper deals with the state of the art of quantification of sources, pathways
      and sinks of nutrients in the Danube Basin and their transport from the catchment
      to the Black Sea. It shows main results of emission estimates to surface waters
      and the Danube Water Quality Model approach to link these emissions estimates to
      measured water monitoring data. The current paper provides a quantitative
      synthesis of available knowledge regarding the fate of nutrients in the Danube
      Basin. Even though many knowledge gaps existed, our understanding of the system
      has increased. As such, the paper provides a vehicle to carry the discussion one
      step beyond just complaining about how much we do not know yet.

PMID- 12420962
TI  - Application of eutrophication indices for assessment of the Bulgarian Black Sea
      coastal ecosystem ecological quality.
AB  - The present paper is an attempt to test the applicability of the trophic state
      index (TRIX) for scaling the eutrophication along the Bulgarian Black Sea coastal
      zone in concert with a number of chemical and biological descriptors aimed at
      selection of relevant indicators of marine coastal area ecological quality. The
      following environmental parameters have been considered: t(o), salinity,
      nutrients--inorganic P, N and dissolved Si, dissolved oxygen and oxygen
      saturation, phytoplankton--taxonomic structure, abundance and biomass,
      chlorophyll a, zooplankton--taxonomic structure, abundance and biomass. Principal
      Component Analysis was applied in order to figure out and score the most relevant
      combination of parameters to discriminate between sites and select representative
      descriptors (pressure/state) of eutrophication. The following variables are
      defined as relevant descriptors for classification of the sites: nutrients (N, P,
      Si) and their molar ratios (N:P and Si:P), the capacity of the system to produce
      and sustain organic matter (chlorophyll a, phytoplankton biomass), phytoplankton
      taxonomic dominance (Bacilariophyceae:Dinophyceae biomass ratio), grazing
      pressure (phytoplankton:zooplankton biomass, Bacilariophyceae:Copepoda), plankton
      diversity index (Hb and Ha) and the trophic state index (TRIX). The investigated
      sites under a different anthropogenic impact are classified according to selected
      descriptors and their water quality state.

PMID- 12420963
TI  - Benthic community structure of the Bosphorus and surrounding area.
AB  - Abstract Spatial and temporal distribution of benthic communities around the
      Strait of Istanbul (Bosphorus) and the effect of lower layer discharge on these
      communities have been evaluated during studies between February-December 1999.
      Mytilus galloprovincialis was the dominant species with fasies at the Black Sea
      station that is not affected by the strait lower layer current system. On the
      other hand, another Black Sea station, influenced by the strait lower layer
      currents, has a similar biota to the strait stations. Species richness and
      diversity is highest in the strait than other areas. The dominant species is
      Maera grossimana. However, the station located at the Black Sea exit of the
      strait has a different biota, and various groups/species appeared to be dominant.
      Melinna palmata is the dominant species at the Sea of Marmara during the study
      period. Low dissolved oxygen values of lower layer and soft substratum of
      sediment resulted in wide distribution of Melinna palmata, adapted to these
      conditions. The closer stations to the strait in the Sea of Marmara have higher
      diversity as a result of hydrodynamic processes. On the other hand, coastal
      stations with low currents and inputs have lower index values, showing the
      negative effect of discharges and pollution.

PMID- 12420964
TI  - Environmetric approaches to estimate pollution impacts on a coastal area by
      sediment and river water studies.
AB  - This paper represents an effort to demonstrate the opportunities of some
      environmetric methods like regression analysis, cluster analysis and principal
      components analysis. Their role for data modeling is stressed and the basic
      theoretical principles are given. The application of the multivariate statistical
      methods is illustrated by two major examples: Assessment of metal pollution based
      on multivariate statistical modeling of "hot spot" sediments from the Black Sea;
      and a trend study of Kamchia River water quality. In the first part of the study
      the environmetric approach makes it possible to separate three zones of the
      marine environment with different levels of pollution (Bourgas gulf, Varna gulf
      and lake buffer zone). Further, the extraction of four latent factors offers a
      specific interpretation of the possible pollution sources and separates the
      natural factors from the anthropogenic ones, the latter originating from
      contamination by chemical and steel-works and an oil refinery. In the second part
      of the study nine sampling sites along Kamchia River were considered as sources
      for water quality monitoring data. Trends for all parameters are calculated by
      the use of linear regression analysis and special attention is paid to a specific
      coastal site. Then five latent factors were extracted from the monitoring data
      set in order to gain information about some structural characteristics of the
      set.

PMID- 12420965
TI  - Pollution sources identification in the "land-sea" system.
AB  - It is our opinion that the new scientific thinking and education in the 21st
      century will increase the significance of the multidisciplinary nature knowledge.
      The nature of the marine sediments as well as the biochemical features of the
      littoral organisms appear to be in close relation to the geochemical impact of
      the coastal onshore. The biogeochemical analysis of the terrestrial and marine
      biocenosis is still fragmental, without balance between the casual and sequential
      relationships. Along the Bulgarian Black Sea coast the latter necessitates the
      geological pattern clarification of the areas south of Bourgas. Even a
      superficial overview of the geological features of the region highlights the
      impact of the geochemical anomalies related to Rosen and Zidarovo volcanic
      apparatuses and intrusions, other ore deposits south and south-west as well.
      However, the intensive anthropogenic impact on the geochemical haloes should be
      pointed out in the complex of ecological damage to the coast. Through
      complementary geoecological studies a significant updating of the knowledge is
      suggested. The geoecological mapping is needed to present the ratio of the lands
      saturated with geonoxes, and anthropogenically polluted ones. The new methodology
      recommended was applied to make the distinction of such lands in the regions of
      Pirdop and Kardjali. Another key element appears to be the ecological-economic
      characteristics in the offshore-onshore balance. The marine resources will be
      studied in the alternative context: benefit-damage from the onshore polluters,
      and the biogeochemical characteristics of the littoral zone. The coastal area's
      environmental status should make a distinction between the environmentally
      undamaged, environmentally damaged by nature, anthropogenically damaged and
      complex damaged lands. Each ecological study or analysis presenting the
      ecological condition of the environment in a status quo (at a certain moment and
      at a certain location) is described in this work as a Status Geoecological
      System. For environmental management and protection of the Black Sea we refer to
      an indispensable Data File representing the Dynamic Geoecological System.

PMID- 12420966
TI  - Nutrient distribution in the Bosphorus and surrounding areas.
AB  - As part of a five years monitoring project "Water Quality Monitoring of the
      Strait of Istanbul", February-December 1999 nutrient dynamics of the Black Sea
      the Sea of Marmara transect are studied to evaluate the effect of discharges
      given by deep disposals. Through a one-year study, upper layer nutrient
      concentrations were generally under the effect of northwestern-shelf Black Sea
      originated waters. This effect was strictly observed in July, when the upper
      layer flow was the thickest. On the other hand, partly in November but especially
      in December the northwestern-shelf Black Sea originated water flow was a minimum
      resulting in similar concentrations in both layers. Nutrient fluctuations also
      affected the chlorophyll a and POC concentrations as parameters of productivity.
      The nutrient concentrations decreased with the effect of spring bloom and highest
      chlorophyll a values were detected in November at Strait stations that did not
      match to the Sea of Marmara values. This fact represents the time-scale
      difference between the Black Sea and the Sea of Marmara. On the contrary, high
      nutrient concentrations in the lower layer (especially inorganic phosphate), and
      therefore low N:P ratios reflect the effect of deep discharge. Vertical mixing
      caused by meteorological conditions of the shallow station (M3) under the effect
      of surface discharges resulted in homogenous distribution of nutrients. Nutrient
      concentrations of the stations affected by deep discharge showed that the two
      layer stratification of the system did not permit the discharge mix to the upper
      layer.

PMID- 12420967
TI  - Innovative technologies for wastewater treatment in coastal tourist areas.
AB  - The selection of appropriate wastewater treatment technologies for coastal
      tourist areas is important in the sense that they have to meet stringent effluent
      limits in a simple and easy to operate flow scheme. This paper outlines different
      effluent standards implemented in sensitive coastal areas and briefly discusses
      the merit of a number of innovative technologies, namely the sequencing batch
      reactor, the intermittent aeration process, the moving bed reactor and the biofim
      filter-sequencing batch reactor system, either as a batch or continuous flow
      process applicable in these areas.

PMID- 12420968
TI  - Retrofitting activated sludge systems to intermittent aeration for nitrogen
      removal.
AB  - The paper provides the basis and the conceptual approach of applying process
      kinetics and modelling to the design of alternating activated sludge systems for
      retrofitting existing activated sludge plants to intermittent aeration for
      nitrogen removal. It shows the significant role of the two specific parameters,
      namely, the aerated fraction and the cycle time ratio on process performance
      through model simulations and proposes a way to incorporate them into a design
      procedure using process stoichiometry and mass balance. It illustrates the effect
      of these parameters, together with the sludge age, in establishing the balance
      between the denitrification potential and the available nitrogen created in the
      anoxic/aerobic sequences of system operation.

PMID- 12420969
TI  - Polishing of secondary effluent by an algal biofilm process.
AB  - The potential in polishing secondary effluent by an algal biofilm composed of
      different green and bluegreen algae was investigated. During the photosynthesis
      process of algal biofilm oxygen was produced while dissolved carbon dioxide was
      consumed. This led to an increasing pH due to the change of the carbon dioxide
      equilibrium in water. The high pH caused precipitation of dissolved phosphates.
      The attached algae took up nitrogen and phosphorus during the growth of biomass.
      In addition to nutrient removal, an extensive removal of faecal bacteria was
      observed probably caused by adsorption of the algal biofilm and by photooxidation
      involving dissolved oxygen. The experimental results suggest that a low-cost,
      close to nature process especially for small wastewater treatment plants for
      nutrient removal and bacteria reduction can be developed with the aid of an algal
      biofilm.

PMID- 12420970
TI  - Design of SBR systems for nutrient removal from wastewaters subject to seasonal
      fluctuations.
AB  - Designing SBR systems for simultaneous biological nitrogen and phosphorus removal
      is evaluated and defined for wastewaters from small coastal areas subject to
      seasonal fluctuations in quantity and quality. A design procedure is developed
      using basic process stoichiometry and significant operating parameters. A
      stepwise approach was utilized to secure full nitrification, available nitrate
      limitation for denitrification, a mixed phase with enough anaerobic fraction for
      P removal. A fundamental relationship between the effective sludge age, the
      recycle ratio and the cycle time was developed and used for the determination of
      physical design parameters.

PMID- 12420971
TI  - Activated carbon and residual nitrification for higher quality effluents for the
      coastal areas.
AB  - Efforts for the task of modification of a nitrification/denitrification unit
      operating in a series of two fixed bed columns are outlined. The problem was
      elevated dissolved oxygen concentrations at the entrance of the denitrification
      column, resulting in an excessive consumption of methanol. The possibility of
      using a column of activated carbon for adsorption alone and in which both
      adsorption and residual nitrification take place was investigated. The results
      were observed to be very satisfactory in reducing dissolved oxygen levels to
      practically zero at the entrance of the denitrification unit especially for the
      case where both adsorption and residual nitrification were employed.

PMID- 12420972
TI  - Membrane dosing units for chemicals in water and wastewater treatment plants.
AB  - It is well known that in the practice of the drinking water as well as of the
      wastewater treatment especially for the processes of pH-regulation, flocculation,
      precipitation or disinfection, the dosing of reagents is necessary. The costs of
      the automatic dosing stations are comparatively high. For the smaller water
      treatment plants these stations are uneconomical and charged with maintenance
      problems very often. In many cases the frequently observed highly fluctuating
      reagents needs and the recess between can cause disruption of the normal
      exploitation work. These disadvantages can easily be overcome by a device based
      on permeable or semi-permeable membranes. The use of semi-permeable membranes is
      favourable especially in the cases of fluctuating water quantities or
      standstills. It can be effective because of the possibility for their self
      regulation during the dosing. When there is no inflow available some kind of
      concentration equilibrium is established between the internal and external
      membrane layers. This system is easy to install and it can be easily adapted to
      the local conditions. The device can be a canister filled with the desired
      reagent and covered with a lid of a definite semi-permeable membrane. After
      determining the permeability of the membranes made of different materials only
      the appropriate membrane area is important to be determined. Developed methods
      for defining the specific membrane permeability are discussed in the paper.
      Suggestions for the application of such devices in practice are given as well.

PMID- 12420973
TI  - A new process for the combined treatment of municipal wastewaters and landfill
      leachates in coastal areas.
AB  - One of the most convenient methods for leachate control is to treat landfill
      leachates with domestic wastewaters. In this framework, a two-stage treatment
      system including anaerobic pre-treatment combined with a chemical post-treatment
      system such as ammonia stripping and/or Magnesium Ammonium Phosphate (MAP)
      precipitation can be comparable with a conventional secondary biological
      treatment. In this study, 2.5% and 2% of leachate by volume was mixed with
      domestic wastewater as the feed for the mesophilic Upflow Anaerobic Sludge Bed
      Reactor (UASBR). pH, feed strength and hydraulic retention time (HRT) were
      monitored for the evaluation of the performance of the anaerobic process. The
      HRT's varied from 0.76 to 0.52 d and 58% and 85% COD removal efficiencies were
      obtained at Organic Loading Rates (OLR) of 0.63 and 2 kg COD/m3.d respectively.
      The average biomass (VS) concentration in the reactor increased from 40 g/l to 50
      g/l during the study. Effluents from the UASBR were further treated chemically
      either with lime for ammonia stripping or with MAP precipitation. MAP
      precipitation was applied both at the stoichiometric ratio (Mg:NH4:PO4 = 1:1:1)
      and above the stoichiometric ratio (Mg:NH4:PO4 = 1:1:1.3). Maximum NH4 removal of
      66% was achieved at the pH of 9.3 at the stoichiometric ratio, whereas 86% NH4
      removal was obtained at the pH of 9.3 above the stoichiometric ratio.
      Alternatively, ammonia stripping was applied either to the effluents directly
      taken from the anaerobic reactor or to the effluents to which MAP precipitation
      was applied stoichiometrically. Ammonia stripping was conducted for 24 h and 89%
      NH4 removal was observed at the end of 24 h. Consequently, this study indicates
      that anaerobic pre-treatment combined with chemical post-treatment (MAP) produced
      high quality of effluent comparable to the conventional biological treatment
      especially in terms of N and P levels.

PMID- 12420974
TI  - Effect of loading rate and intermittent aeration cycle on nitrogen removal in
      membrane separation activated sludge process.
AB  - The performance of the submerged membrane separation activated sludge process
      with intermittent aeration was investigated in a laboratory scale experiment by
      changing organic loading rate and intermittent aeration cycle. A rectangular PVC
      tank was used as an aeration tank, in which a flat-sheet type Micro-Filtration
      membrane made of poly-olefin with a pore size of 0.2 microm was submerged.
      Organic loading rate to the reactor was set at 0.3 and 0.8 g-TOC/L/day. C/N ratio
      in the feed was set at around 5.0 for every condition. Aeration cycle was changed
      from 10 min-10 min (aeration-stop) to 120 min-120 min in different organic
      loading conditions. Flux through the membrane was set at 0.25 m/day. Membrane
      fouling proceeded rapidly in 0.8 g-TOC/L/day conditions. However, when organic
      loading rate was 0.3 g-TOC/L/day, bacterial metabolic substances were degraded
      rapidly compared to the production, thereby decreasing viscosity in mixed liquor.
      Nitrogen removal rate was between 60% and 80% for 0.8 g-TOC/L/day loading, and
      between 50% and 65% for 0.3 g-TOC/L/day loading. And the nitrogen removal was
      highest in 40 min to 60 min aeration cycle conditions. Too short aeration cycle
      did not result in sufficiently long anoxic periods for denitrification while too
      long a cycle resulted in unnecessary anaerobic periods after depletion of
      nitrate. Intermittent aeration was effective also for decreasing viscosity in
      mixed liquor.

PMID- 12420975
TI  - Municipal wastewater treatment in the anaerobic-aerobic baffled filter reactor at
      ambient temperature.
AB  - This paper presents the pilot-scale experiments with anaerobic-aerobic treatment
      of municipal wastewater. As the anaerobic part of the pilot-scale system, the
      combination of the anaerobic baffled reactor and the anaerobic filter was used.
      The aerobic part of reactor was designed as an activated sludge system with the
      carrier of biomass (polypropylene cords). Two pilot-scale reactors (AN-I and AN
      II) under real conditions were monitored. All technological parameters were
      identical in both reactors, but the AN-I reactor was inoculated with the
      psychrophilic digested sludge. The HRT in the anaerobic and aerobic parts of
      reactors were about 15 hours and 4 hours, respectively. The temperature in both
      reactors varied during the year from 4.5 to 23 degrees C. During the yearly
      operation time both systems removed all monitored parameters with relatively high
      efficiencies (COD-78.6-83.0%, BOD5-92.5-94.0 and SS-80.9-92.7%). The intensive
      nitrification process was observed during the whole year in both reactors (under
      average temperature of 5.9 degrees C in January 2000, too). The average removal
      of the NH4-N varied during the year from 46.4 to 87.3%. In both systems the
      effective denitrification process was observed, too. In the real conditions it is
      possible to operate such systems for a long time without removing excess sludge.

PMID- 12420976
TI  - Seasonal changes of nutrients and oxygen in the Bulgarian Black Sea coastal area.
AB  - The paper discusses the seasonal dynamics of nutrients and oxygen during the
      period 1995-1998 in comparison to the previous periods. This study is based on
      monthly and seasonally monitoring in the 3-20 n. m. zone along the Bulgarian
      Black Sea area. The investigation reveals certain shifting of seasonal maximums
      (minimums) and a trend of decreasing oxygen saturation, phosphorus and silicon in
      the last few years.

PMID- 12420977
TI  - Significance of wetlands in water quality management--past and present situation
      of Kizilirmak Delta, Turkey.
AB  - Wetlands are of utmost importance in the sense of protecting the natural
      ecological balance of the environment. It is possible to improve the water
      quality of wetlands, which are located in coastal areas like river deltas and
      lakes without disturbing the ecological balance through rehabilitation and by
      controlling. However, many wetlands in the world have so far been dried and
      converted to agricultural areas due to insufficient knowledge of their ecological
      value. Such an understanding was also held as true in Turkey and most of its
      wetlands have been converted to agricultural land till recent years. An example
      of such an occurrence and modifications within years are observed in the delta of
      the Kizilirmak River, which is the longest river of Turkey ending in the Black
      Sea. The past and present situation of the Kizilirmak delta will be investigated
      in this paper together with the changes in water quality. An evaluation of the
      water quality of the river and of lakes within the delta is done based on
      available previous data and on the final findings of water quality measurements
      conducted within the framework of this study.

PMID- 12420978
TI  - The wave breaking phenomena as a tool for environmental friendly shore
      protection.
AB  - An experimental study was carried out to evaluate the rate of energy dissipation
      during wave breaking and the dependence of dissipation on the breaker type. The
      splash mechanism that occurs just after the breaking is also examined based on
      knowledge of external and macroscopic properties of breakers only. During the
      experiments, it is observed that most of the energy is dissipated while the water
      jet formed during wave breaking hits the water surface. It has been found that
      the percentage of wave energy dissipated in plunging type waves is larger than in
      spilling type waves.

PMID- 12420979
TI  - Implementing GIS to resolve environmental coastal problems in Varna.
AB  - The city of Varna, like many other coastal cities along the Black Sea and
      Mediterranean Sea, has a lot of problems related to the environmental protection
      for many years, including those with coastal zone management. Recently, the
      coastal slope problems due to land-slides appeared as very urgent and difficult
      to be solved. This paper describes a method to solve some of the problems by
      analysing the data collected. A data layer representing the complete hydrologic
      network including transport lines through slopes, lakes, streams, rivers, is a
      necessary component of many hydrologic and coastal applications. The coastal area
      of the city has significant importance--sea ports, resorts, cargo terminals. Most
      of them add environmental problems to the Black Sea in adjacent territories and
      the region as a whole. The attempt described is to solve these problems on the
      ground. This paper describes a process to analyse the area specific geographical
      data for a decision. Making a front-end application using ESRI's ArcView
      3.0a/Avenue, user-friendly procedures were prepared to automate most of the
      functions. This application generates maps using data collected during the last
      two years. The data acquisition is performed according to the Bulgarian
      standards. Converting procedures are created and tested as well. Finally, a
      technology for updating data is approved.

PMID- 12420980
TI  - Liquid waste management strategies for coastal areas.
AB  - Liquid waste management in coastal areas is a challenging issue, because recipe
      solutions applied so far have not met the expectations fully. Therefore decision
      makers, planners, engineers as well as the inhabitants of these places are
      looking for a better approach that will adequately handle the problem and perform
      reliable solutions. It is the aim of this paper to review the recent situation of
      liquid waste management for coastal areas in general, and discuss it from the
      point of view of Turkey in particular. A simple and applicable waste management
      strategy is also proposed in the paper and its merits are illustrated in a case
      study. Finally, anticipating the wide applications of such systems in coastal
      establishments, some recommendations are forwarded.

PMID- 12420981
TI  - Wastewater management in coastal urban areas: the case of Greece.
AB  - The continuously increasing quantities of municipal and industrial wastewater
      discharged into the sea environment degrade the quality of the water. In this
      paper, the recent technologies are evaluated, and the practices recommended for
      the wastewater treatment in coastal urban areas are analyzed, with respect to the
      requirements of the EU legislation. Also the principles for the disposal of the
      treated wastewater are discussed. Finally, a brief review of the current
      situation of wastewater management in Greece is given, regarding the treatment
      strategies previously presented

PMID- 12420982
TI  - Integrating river basin management and the coastal zone: the (blue) Danube and
      the (black) sea.
AB  - In order to effectively manage the wide variety of physical, chemical biological
      and ecological processes in a sensitive coastal environment such as the Black
      Sea, current environmental management objectives are no longer sufficient: a new
      management approach has to address the intimate functional linkage between the
      river basin and the costal environment. Current water quality legislation
      requires compliance to emission levels based on the chemical analysis of water
      samples taken at discharge points, such as treatment plants discharging into
      rivers. While such measures provide a relative indication of the water quality at
      the point of discharge, they fail to describe accurately and sufficiently the
      quality of the water received from the watershed or basin. As water flows through
      the catchment, rainfall run-off from urban and agricultural areas carries
      sediments, pesticides, and other chemicals into river systems, which lead to
      coastal waters. The impact of the Kosovo crisis on the Danube ecosystems provides
      a poignant example of the effects of such diffused pollution mechanisms and
      reveals a number of interesting pollution mechanisms. This paper discusses both
      the effects of diffused pollution on the Black Sea, drawing from state-of-the-art
      reports on the Danube, and proposes a framework for a decision support system
      based on distributed hydrological and pollution transport simulation models and
      GIS. The use of ecological health indicators and fuzzy inference supporting
      decisions on regional planning within this framework is also advocated. It is
      also argued that even the recently produced GEF document on Black Sea protection
      scenarios should benefit significantly if the concept of pollution reduction from
      both urban, industrial and rural areas should undergo a systematic conceptual
      update in the view of the recent recommendations of the UNEP IETC (2000)
      document.

PMID- 12420983
TI  - SeaWiFs satellite data analysis of Black Sea water discharge pattern into the
      Aegean Sea.
AB  - Satellite data from the SeaWiFS sensor has been used to determine chlorophyll-a
      contents in the North Aegean Sea using SEADAS 3.3 software. The data is used to
      extract knowledge on water movements/flow phenomena using chlorophyll as a
      "tracer" but will also indicate water quality. More than 100 SeaWiFS scenes from
      1998 up to 2001 have been analyzed in terms of hydrodynamic phenomena, mainly the
      transport and spreading pattern of Black Sea Water in the North Aegean Sea but
      also concerning the water quality and its seasonal and yearly variation at the
      mouth region of the Dardanelles. Some comparison with earlier studies using NOAA
      AVHRR thermal data and historical CZCS scenes is also made.

PMID- 12420985
TI  - Consciousness is slower than you think.
AB  - In easy serial choice reaction time tasks (CRT tasks) young adults can very
      rapidly "correct" nearly all their errors by making the responses that they
      should have made (error-correcting responses). They are much less accurate at
      signalling their errors by making the same, deliberate, response to each (error
      signalling responses), and they poorly remember errors that they have not
      signalled or corrected. When instructed to ignore errors they nevertheless
      involuntarily register them because the response immediately following them
      (responses following unacknowledged errors) are unusually slow, and they
      sometimes make involuntary error correction responses. Errors that are neither
      signalled nor remembered are registered at some level because responses following
      unacknowledged errors are slowed. Old age does not impair the accuracy of error
      correction or reduce the proportion of errors that are acknowledged because they
      are followed by unusually slow responses, but it does reduce the accuracy of
      error signalling and of recall of errors. Groups of 40 young adults (mean age
      20.1 years, SD 1.1) and 40 older adults (mean 71.2 years, SD 5.1) signalled and
      recalled their errors increasingly accurately as intervals between each response
      and the next signal were increased from 150 ms to 1000 ms. Error signalling and
      recall improved as response-signal interval (RSI) durations increased, reaching
      asymptote at RSIs of 800 ms for the young and 1000 ms for the older adults. Thus
      processes necessary for conscious and deliberate choice or error-signalling
      responses and for subsequent recall of errors require more than 150 ms to
      complete, are slowed by old age, and may be interrupted by onset of new signals
      occurring earlier than 800 to 1000 ms after completion of an incorrect response.

PMID- 12420984
TI  - The hippocampus, space, and viewpoints in episodic memory.
AB  - A computational model of how single neurons in and around the rat hippocampus
      support spatial navigation is reviewed. The extension of this model, to include
      the retrieval from human long-term memory of spatial scenes and the spatial
      context of events is discussed. The model explores the link between spatial and
      mnemonic functions by supposing that retrieval of spatial information from long
      term storage requires the imposition of a particular viewpoint. It is consistent
      with data relating to representational hemispatial neglect and the involvement of
      the mammillary bodies, anterior thalamus, and hippocampal formation in supporting
      both episodic recall and the representation of head direction. Some recent
      behavioural, neuropsychological, and functional neuroimaging experiments are
      reviewed, in which virtual reality is used to allow controlled study of
      navigation and memory for events set within a rich large-scale spatial context.
      These studies provide convergent evidence that the human hippocampus is involved
      in both tasks, with some lateralization of function (navigation on the right and
      episodic memory on the left). A further experiment indicates hippocampal
      involvement in retrieval of spatial information from a shifted viewpoint. I
      speculate that the hippocampal role in episodic recollection relates to its
      ability to represent a viewpoint moving within a spatial framework.

PMID- 12420986
TI  - Generate and test: an alternative route to knowledge elicitation in an implicit
      learning task.
AB  - Three experiments are reported, which examine generation of knowledge in the
      McGeorge and Burton (1990) invariant learning task. In this task, participants
      are exposed to 30 four-digit numbers containing an invariant "3". Following this
      participants then demonstrate a preference for novel numbers containing this
      invariant over numbers without it. Despite above-chance performance on this
      pseudo-memory test, participants appear unable to verbalize anything pertinent to
      the invariant. Here we introduce a novel version of this task, relying on
      generation of items rather than a preference test. We argue that this new task
      engages different processing resources, resulting in different patterns of
      performance. In Experiment 1, invariant learning was demonstrated using a novel
      fragment completion test. Experiment 2 found that suppressing articulation
      inhibited learning, implying that this test task accesses phonological knowledge.
      It is suggested that using the fragment completion test engages different
      processing resources during test from those in a preference test. Experiment 3
      reinforces this position by demonstrating that knowledge appears to transfer
      across surface features, a result that seems to contradict recent findings by
      Stadler, Warren, and Lesch (2000). A resolution is offered, drawing on episodic
      accounts of implicit learning.

PMID- 12420987
TI  - Evidence against hyperspecificity in implicit invariant learning.
AB  - Four experiments examined the claim that cross-format transfer in invariant
      learning is reliant solely on the presence of repetition structure in study and
      test strings (Stadler, Warren, & Lesch, 2000). Experiments 1, 2, and 3 used
      strings with no repetitions and found significant cross-format transfer in
      combination with a non-significant transfer decrement--no significant difference
      between same- and changed-format conditions. Further investigation of the basis
      of the role of repetition structure revealed an emphasis on the perceptual
      salience of test stimuli (Experiment 4). Our results contrast with those of
      Stadler et al. and suggest that under the conditions we employed invariant
      learning is not highly sensitive to changes in the perceptual characteristics of
      stimuli and therefore is inaccurately described as hyperspecific. We suggest that
      the term hyperspecific be reserved for cases in which minor format changes result
      in significant performance impairments--for example, typographical effects in
      implicit memory.

PMID- 12420988
TI  - Semantic priming in number naming.
AB  - The issue of semantic and non-semantic conversion routes for numerals is still
      debated in numerical cognition. We report two number-naming experiments in which
      the target numerals were preceded by another numeral (prime). The primes and
      targets could be presented either in arabic (digit) notation or in verbal
      (alphabetical) notation. The results reveal a semantically related distance
      effect: Latencies are fastest when the prime has the same value as the target and
      increase when the distance between prime and target increases. We argue that the
      present results are congruent with the idea that the numerals make access to an
      ordered semantic number line common to all notations, as the results are the same
      for within-notation priming (arabic-arabic or verbal-verbal) and between
      notations priming (arabic-verbal or verbal-arabic). The present results also
      point to a rapid involvement of semantics in the naming of numerals, also when
      the numerals are words. As such, they are in line with recent claims of rapid
      semantic mediation in word naming.

PMID- 12420989
TI  - The locus of semantic priming effects in person recognition.
AB  - Semantic priming in person recognition has been studied extensively. In a typical
      experiment, participants are asked to make a familiarity decision to target items
      that have been immediately preceded by related or unrelated primes. Facilitation
      is usually observed from related primes, and this priming is equivalent across
      stimulus domains (i.e., faces and names prime one another equally). Structural
      models of face recognition (e.g., IAC: Burton, Bruce, & Johnston, 1990)
      accommodate these effects by proposing a level of person identity nodes (PINs) at
      which recognition routes converge, and which allow access to a common pool of
      semantics. We present three experiments that examine semantic priming for
      different decisions. Priming for a semantic decision (e.g., British/American?)
      shows exactly the same pattern that is normally observed for a familiarity
      decision. The pattern is equivalent for name and face recognition. However, no
      semantic priming is observed when participants are asked to make a sex decision.
      These results constrain future models of face processing and are discussed with
      reference to current theories of semantic priming.

PMID- 12420990
TI  - Associative priming in a masked perceptual identification task: evidence for
      automatic processes.
AB  - Two experiments investigated the influence of automatic and strategic processes
      on associative priming effects in a perceptual identification task in which prime
      target pairs are briefly presented and masked. In this paradigm, priming is
      defined as a higher percentage of correctly identified targets for related pairs
      than for unrelated pairs. In Experiment 1, priming was obtained for mediated word
      pairs. This mediated priming effect was affected neither by the presence of
      direct associations nor by the presentation time of the primes, indicating that
      automatic priming effects play a role in perceptual identification. Experiment 2
      showed that the priming effect was not affected by the proportion (.90 vs. .10)
      of related pairs if primes were presented briefly to prevent their
      identification. However, a large proportion effect was found when primes were
      presented for 1000 ms so that they were clearly visible. These results indicate
      that priming in a masked perceptual identification task is the result of
      automatic processes and is not affected by strategies. The present paradigm
      provides a valuable alternative to more commonly used tasks such as lexical
      decision.

PMID- 12420991
TI  - Stimulus-response compatibility in intensity-force relations.
AB  - Romaiguere, Hasbroucq, Possamai, and Seal (1993) reported a new compatibility
      effect from a task that required responses of two different target force levels
      to stimuli of two different intensities. Reaction times were shorter when high
      and low stimulus intensities were mapped to strong and weak force presses
      respectively than when this mapping was reversed. We conducted six experiments to
      refine the interpretation of this effect. Experiments 1 to 4 demonstrated that
      the compatibility effect is clearly larger for auditory than for visual stimuli.
      Experiments 5 and 6 generalized this finding to a task where stimulus intensity
      was irrelevant. This modality difference refines Romaiguere et al.'s (1993)
      symbolic coding interpretation by showing that modality-specific codes underlie
      the intensity-force compatibility effect. Possible accounts in terms of
      differences in the representational mode and action effects are discussed.

PMID- 12420992
TI  - Scalar timing in temporal generalization in children with short and long stimulus
      durations.
AB  - This experiment investigated temporal generalization performance in children aged
      3, 5, and 8 years by using auditory stimulus durations where the standard was 0.4
      s or 4.0 s, and non-standard stimuli were spaced linearly around the standard. At
      all ages, generalization gradients superimposed well when plotted on the same
      relative scale, indicating conformity to scalar timing. Whatever the standard
      duration used, the principal developmental changes were the increasing steepness
      of the generalization gradient with increasing age and a shift from symmetrical
      gradients, in the 3- and 5-year-olds, to adult-like asymmetrical gradients in the
      8-year-olds.

PMID- 12420993
TI  - Expertise, attention, and memory in sensorimotor skill execution: impact of novel
      task constraints on dual-task performance and episodic memory.
AB  - Two experiments explored the attention and memory processes governing
      sensorimotor skill. Experiment 1 compared novice and experienced golf putting
      performance in single-task (putting in isolation) and dual-task conditions
      (putting while performing an auditory word search task). At specific intervals,
      participants also produced episodic descriptions of specific putts. Experiment 2
      assessed novice performance following training on the same putting task. In
      Experiment 1, experienced golfers did not differ in putting accuracy from single
      to dual-task conditions and, compared to novices, had higher recognition memory
      for words heard while putting but diminished episodic memories of specific putts.
      However, when using an s-shaped arbitrarily weighted "funny putter" designed to
      disrupt the mechanics of skill execution, experienced golfers produced extensive
      episodic memories of specific putts but showed decreased dual-task putting
      accuracy and recognition memory for secondary task words. Trained novices
      produced results intermediate between the untrained novices and experienced
      golfers. As predicted by current theories of practice-based automaticity,
      expertise leads to proceduralized control that does not require constant
      attention. Resources are free to devote to secondary task demands, yet episodic
      memory for primary task performance is impoverished. Novel task constraints
      (e.g., a funny putter) increase attention to execution, compromising secondary
      task performance but enhancing memory for skill execution.

PMID- 12420994
TI  - A quantitative model of optimal data selection in Wason's selection task.
AB  - The optimal data selection model proposed by Oaksford and Chater (1994)
      successfully formalized Wason's selection task (Wason, 1966). The model, however,
      involved some questionable assumptions and was also not sufficient as a model of
      the task because it could not provide quantitative predictions of the card
      selection frequencies. In this paper, the model was revised to provide
      quantitative fits to the data. The model can predict the selection frequencies of
      cards based on a selection tendency function (STF), or conversely, it enables the
      estimation of subjective probabilities from data. Past experimental data were
      first re-analysed based on the model. In Experiment 1, the superiority of the
      revised model was shown. However, when the relationship between antecedent and
      consequent was forced to deviate from the biconditional form, the model was not
      supported. In Experiment 2, it was shown that sufficient emphasis on
      probabilistic information can affect participants' performance. A detailed
      experimental method to sort participants by probabilistic strategies was
      introduced. Here, the model was supported by a subgroup of participants who used
      the probabilistic strategy. Finally, the results were discussed from the
      viewpoint of adaptive rationality.

PMID- 12420995
TI  - Syllogistic reasoning and cognitive ageing.
AB  - Gilinsky and Judd (1994) demonstrated that age-related impairment in syllogistic
      reasoning was in part due to reduced working-memory capacity. A total of 30 older
      (average age 66 years) and 34 younger persons (average age 24 years) were tested
      on syllogisms of various types as well as on other measures. Syllogistic
      reasoning was significantly correlated with education, processing speed, word
      span, and word fluency. Correlations with visuo-spatial processing and random
      letter generation were just short of significance. Syllogistic reasoning
      performance declined with age, although the deficit was no longer statistically
      significant following control for age-related differences in information
      processing speed. On the other hand the inclusion of word fluency as an
      additional covariate boosted the apparent age effect, returning it to statistical
      significance. Thus it is possible that cognitive processes outside of working
      memory might underpin at least part of the apparent age deficit. This possibility
      is evaluated in the light of neuropsychological evidence implicating the
      prefrontal cortex in both the processing of syllogisms and more generally in
      cognitive ageing.

PMID- 12420996
TI  - Temporal and causal order effects in thinking about what might have been.
AB  - When people think counterfactually about what might have been different for a
      sequence of events, they are influenced by the order in which the events
      occurred. They tend to mentally undo the most recent event in a temporal sequence
      of two events. But they tend to mentally undo the first event in a causal
      sequence of four events. We report the results of two experiments that show that
      the temporal and causal order effects are not dependent on the number of events
      in the sequence. Our first experiment, with 300 participants, shows that the
      temporal order effect occurs for sequences with four events as well as for
      sequences with two events. Our second experiment, with 372 participants, shows
      that the causal order effect occurs for sequences with two events as well as for
      sequences with four events. We discuss the results in terms of the mental
      representations that people construct of temporal and causal sequences.

PMID- 12420997
TI  - Parafoveal-on-foveal interactions in word recognition.
AB  - An experiment is reported in which participants read sequences of five words,
      looking for items describing articles of clothing. The third and fourth words in
      critical sequences were defined as "foveal" and "parafoveal" words, respectively.
      The length and frequency of foveal words and the length, frequency, and initial
      letter constraint of parafoveal words were manipulated. Gaze and refixation rate
      on the foveal word were measured as a function of properties of the parafoveal
      word. The results show that measured gaze on a given foveal word is
      systematically modulated by properties of an unfixated parafoveal word. It is
      suggested that apparent inconsistencies in previous studies of parafoveal-on
      foveal effects relate to a failure to control for foveal word length and hence
      the visibility of parafoveal words. A serial-sequential attention-switching model
      of eye movement control cannot account for the pattern of obtained effects. The
      data are also incompatible with various forms of parallel-processing model. They
      are best accounted for by postulating a process-monitoring mechanism, sensitive
      to the simultaneous rate of acquisition of information from foveal and parafoveal
      sources.

PMID- 12420998
TI  - 358,534 nonwords: the ARC Nonword Database.
AB  - The authors present a model of the phonotactic and orthographic constraints of
      Australian and Standard Southern British English monosyllables. This model is
      used as the basis for a web-based psycholinguistic resource, the ARC Nonword
      Database, which contains 358,534 monosyllabic nonwords--48,534 pseudohomophones
      and 310,000 non-pseudohomophonic nonwords. Items can be selected from the ARC
      Nonword Database on the basis of a wide variety of properties known or suspected
      to be of theoretical importance for the investigation of reading.

PMID- 12420999
TI  - Language familiarity effects in short-term memory: the role of output delay and
      long-term knowledge.
AB  - Four experiments examined the origins of language familiarity effects in
      bilingual short-term recall. In Experiments 1A and 1B, bilingual adults were
      tested on serial recall and probed serial recall of words and nonwords in their
      first and second languages. A first-language advantage was obtained on both
      measures, indicating that the beneficial effects of language familiarity are not
      exclusively attributable to lesser output delay during overt recall. In
      Experiments 2A and 2B, the same group of bilinguals was tested on serial recall
      and serial recognition of word lists in both languages. Although a sizeable first
      language advantage was obtained on the serial recall measure, recognition
      performance was comparable in the two languages. On the basis of these results it
      is suggested that language differences in bilingual immediate memory arise in
      large part as a consequence of the differential availability of language-specific
      long-term knowledge with which to support retrieval processes in serial recall.

PMID- 12421000
TI  - Starch-based plastic polymer degradation by the white rot fungus Phanerochaete
      chrysosporium grown on sugarcane bagasse pith: enzyme production.
AB  - In this study, starch metabolites and enzymes were determined during starch-based
      plastic polymer biodegradation by the white rot fungus Phanerochaete
      chrysosporium, grown in sugarcane bagasse pith in tubular reactors. Various
      metabolites, amylase, ligninase and cellulase production were measured during P.
      chrysosporium growth on sugarcane bagasse pith with added glucose and starch
      polymer. On-line respirometric analyses followed during 32 days confirmed the P.
      chrysosporium capability of growing on sugarcane bagasse pith with starch polymer
      degradation. Enzyme activity during secondary metabolism increased, and a 70% and
      74% starch degradation was reached with and without glucose addition, generating
      low molecular weight metabolites (e.g.) dextrin, maltotriose, maltose and glucose
      that were detected by high performance liquid chromatography.

PMID- 12421001
TI  - Impact of long-term application of industrial wastewater on the emergence of
      resistance traits in Azotobacter chroococcum isolated from rhizospheric soil.
AB  - A total of 57 (36 and 21) Azotobacter chroococcum were isolated from wheat
      (Triticum aestivum) rhizospheric soil irrigated with industrial wastewater (about
      a decade) and ground water (uncontaminated) and characterized on the basis of
      morphological, cultural and biochemical characteristics. Rhizospheric soils were
      analyzed for metal concentrations by atomic absorption spectrophotometery and the
      test soil samples were contaminated with Fe, Zn, Cu, Cr, Ni and Pb. All the
      isolates of A. chroococcum were tested for their resistance against Hg2+, Cd2+,
      Cu2+, Cr3+, Cr6+, Zn2+, Ni2+ and Pb2+. Among 36 isolates of Azotobacter from soil
      irrigated with industrial wastewater, 94.4% were resistant to Pb2+ and Hg2+ and
      86.1%, 77.5% and 63.8% were resistant to Zn2+, Cr6+ and Cr3+ respectively. The
      highest minimum inhibitory concentration of 200 microg/ml for Hg2+ and 1600
      microg/ml for other metals were observed against these bacteria from soil. The
      incidences of metal resistance and MICs of metals for A. chroococcum from
      wastewater irrigated soil were significantly different to those of uncontaminated
      soil. All A. chroococcum isolates were tested for their resistance against 11
      commonly used antibiotics/drugs. 91.6% were found to be resistant against
      nitrofurantoin while 86.4% and 80.5% were found to be resistant against polymyxin
      B and co-trimoxazole respectively. Agarose gel electrophoresis using the miniprep
      method for plasmid isolation revealed that these isolates harboured plasmids of
      molecular weights 58.8 and 64.5 kb using EcoRI and HindIII digests of X DNA and
      undigested X DNA as standard markers.

PMID- 12421003
TI  - Biodegradation of wastepaper by cellulase from Trichoderma viride.
AB  - Environmental issues such as the depletion of non-renewable energy resources and
      pollution are topical. The extent of solid waste production is of global concern
      and development of its bioenergy potential can combine issues such as pollution
      control and bioproduct development, simultaneously. Various wastepaper materials,
      a major component of solid waste, were treated with the cellulase enzyme from
      Trichoderma viride, thus bioconverting their cellulose component into fermentable
      sugars. All wastepaper materials exhibited different susceptibilities towards the
      cellulase as well as the production of non-similar sugar releasing patterns when
      increasing amounts of paper were treated with a fixed enzyme concentration. The
      hydrolysis of wastepaper with changing enzyme concentrations and incubation
      periods also resulted in dissimilar sugar-producing tendencies. A general decline
      in hydrolytic efficiency was observed when increasing sugar concentrations were
      produced during biodegradation of all wastepaper materials.

PMID- 12421002
TI  - Effects of a municipal solid waste compost and mineral fertilization on plant
      growth in two tropical agricultural soils of Mali.
AB  - A pot experiment was conducted to compare the effects of compost and mineral
      fertilization on the growth and chemical composition of ryegrass (Lolium perenne
      L.) in two Malian agricultural soils (Baguineda, abbreviated as Bgda, 12 degrees
      23' S, 7 degrees 45' W and Gao. 16 degrees 18' N, 0 degrees GM). Treatments
      included: control, NPK alone, NPK + C25, NPK + C50, NPK + C100, PK + C50, NK +
      C50, NP + C50, K + C50, P + C50, N + C50 and C50 alone, where NPK represents the
      non-modified Hoagland's solution (corresponding to 271, 95 and 172 kg/ha of N, P
      and K respectively) and C25, C50 and C100 the different rates (25, 50 and 100
      T/ha) of compost. Compost and mineral fertilization significantly increased dry
      matter production. The application of 50 T/ha of compost alone increased the dry
      matter yield by 10% and 17.5% while mineral NPK alone, by 69.7% and 65% for Gao
      and Bgda soils, respectively. The combination of compost and mineral NPK (NPK +
      C25 for Gao and NPK + C50 for Bgda) showed the highest crop yields.

PMID- 12421004
TI  - Potential of Amaranthus seeds in supplementary feed and its impact on growth in
      some carps.
AB  - Amaranthus seeds were used at three different levels (20%, 35%, 50%) in fish
      diets under a semi-intensive fish culture system and their impact on the growth
      of common carp, Cyprinus carpio, and rohu, Labeo rohita, was studied. Growth in
      terms of body weight gain was maximum in fish fed on diets containing 20%
      Amaranthus seeds, that replaced rice bran and groundnut oil cake in the feed.
      Overall, the fish fed on diets containing Amaranthus seeds at different levels
      showed better growth than the control, because of the good-quality proteins
      available in Amaranthus seeds. In the two species used, L. rohita showed better
      growth performance than C. carpio.

PMID- 12421005
TI  - Utilization of fermented silkworm pupae silage in feed for carps.
AB  - Fermented silkworm pupae (SWP) silage or untreated fresh SWP pastes were
      incorporated in carp feed formulations replacing fishmeal. The feed formulations
      were isonitrogenous (30.2-30.9% protein) and isocaloric (ME = 2905-2935 kcal/kg).
      Feeding under a polyculture system consisting of 30% each of catla (Catla catla),
      mrigal (Cirrhinus mrigala) and rohu (Labeo rohita) with 10% silver carps
      (Hypophthalmychthys molitrix) was carried out in ponds to evaluate the nutritive
      quality of SWP silage. Survival rate, feed conversion ratio and specific growth
      rate, respectively, were 84.2%, 2.10 and 2.39 for fermented SWP silage, 65.8%,
      2.98 and 2.26 for untreated SWP and 67.5%, 3.16 and 2.20 for fishmeal indicating
      clearly that the fermented SWP silage was nutritionally superior to untreated SWP
      or fishmeal. The dietary influence on the proximate composition of whole fish was
      marginal.

PMID- 12421006
TI  - Preparation and characterization of biodegradable poly-3-hydroxybutyrate-starch
      blend films.
AB  - Bacterial polyesters have attracted much attention as biodegradable biocompatible
      polymers. Poly-3-hydroxybutyrate, a microbially produced thermoplastic, has
      similar material properties to polypropylene. Its potential application as
      biodegradable and biocompatible plastics is well documented. However, due to high
      cost it is used mainly in biomaterials for medical applications. Materials with
      useful properties may result from blending bacterial polyhydroxybutyrate (PHB)
      with other polymers. In this paper, the compatibility of PHB with starch for
      improved properties and cost reduction is discussed. The thermal and mechanical
      properties of the blended films were studied by means of thermogravimetry,
      differential scanning calorimetry and an automated material testing system. The
      results revealed that blend films had a single glass transition temperature for
      all the proportions of PHB:starch tested. The nature of all combinations was
      found to be crystalline. The tensile strength was optimum for the PHB:starch
      ratio of 0.7:0.3 (wt/wt). The variation in tensile strength, Young's modulus,
      extension needed to break, thermal stability, glass transition temperature,
      melting temperature, for the different proportions of PHB:starch are discussed.

PMID- 12421007
TI  - Recycling spent larval food of Corcyra cephalonica stainton as a broiler feed
      ingredient.
AB  - In commercial insectaries, large-scale production of rice moth, Corcyra
      cephalonica Stainton in pearl millet grain medium leads to an extensive
      accumulation of spent C. cephalonica larval medium (CLM). Experiments were
      conducted to determine whether inclusion of CLM for corn in the standard broiler
      diet (SBD) could ensure normal growth and development of broilers. Chemical
      analysis revealed that CLM diets met the nutritional requirements as of SBD. CLM
      diet contained no aflatoxin as well. Biological experiments were conducted to
      study the suitability of CLM diet in different combinations with SBD at 100% +
      0%, 75% + 25%, 50% + 50%, 25% + 75% and 0% + 100% w/w without any nutritional
      change, and after nutritional modification with corn starch. CLM replacement was
      based on the corn content of the basal diet. Birds preferred SBD 100% and SBD 75%
      + CLM 25% nutritionally unchanged diets, and showed higher growth rate and weight
      gain. These parameters were significantly lower in other diet combinations.
      Modified isoenergetic CLM based diets in all the combinations, however,
      contributed higher feed intake and resulted in more weight gain as of SBD.
      Furthermore, none of treatments in both experiments yielded bird mortalities. The
      experimental CLM diets except SBD 75% + CLM 25% in both experiments were cost
      effective and contributed lower diet cost/kg weight gain.

PMID- 12421008
TI  - Identification of organic matter from peat, leonardite and lignite fertilisers
      using humification parameters and electrofocusing.
AB  - The organic matter extracted from peats (P), leonardites (Le) and lignites (Li)
      was characterised by humification parameters and electrofocusing (EF). The degree
      of humification and the humification index might be used to distinguish P from Le
      and Li, but not Le from Li because they showed overlapped values, while the
      humification rate could be used only for the identification of Le and EF profiles
      of P, Le and Li fertilisers revealed different band patterns: P samples did not
      show bands in the region with isoelectric point, pI > 4.4; Le samples showed very
      intense bands in the region with pI > 4.4; Li samples showed a very different
      band pattern with poorly resolved bands in the region with pI > 3.8. P, Le and Li
      samples can be distinguished by combining humification parameters and EF.

PMID- 12421009
TI  - Survival of Salmonella spp. in a simulated acid-phase anaerobic digester treating
      sewage sludge.
AB  - The presence of pathogenic microorganisms in municipal waste sludge may create a
      serious outbreak of water borne diseases if the sludge is used for agricultural
      purpose. An attempt to decrease the number of pathogenic microorganisms,
      Salmonella spp. using a simulated acid-phase anaerobic digester was tested in a
      laboratory-scale batch experiment. Reduction of Salmonella spp. was demonstrated
      in a mixture of sludge and organic acid, simulating an acid digester of a two
      phase anaerobic digestion process. A high concentration of organic acid at a pH
      value of 5.5-6.0 prevents a decrease in Salmonella spp. concentration. Almost
      complete destruction of Salmonella spp. is observed within two days if the pH
      value is maintained below 5.5.

PMID- 12421010
TI  - Composting of the solid fraction of olive mill wastewater with olive leaves:
      organic matter degradation and biological activity.
AB  - The flocculated solid fraction of olive mill wastewaters, obtained from two
      different olive oil extraction systems (FOMW1 and FOMW2) was composted, with
      olive leaves (OL) as bulking agent, by the static pile system (Rutgers). The
      dynamic of organic matter (OM) degradation during composting and its relationship
      with the basal respiration and fluorescein diacetate (FDA) hydrolytic activity,
      as indicators of biological activity, were studied. Two mixtures were prepared:
      C1, from 65% FOMW1 plus 35% OL; and C2, from 74% FOMW2 plus 25% OL and 1% urea.
      The biooxidative phase of composting in C1, which had a high initial C/N ratio,
      was long, leading to a high OM degradation, mainly of the lignocellulosic
      compounds. The water-soluble organic carbon content, C/N ratio and the urea
      supplied as a N source for the C2 compost make this mixture more adequate for
      composting, as it had a shorter composting time than C1, and developed a
      microbial population with a high metabolic activity. The results for basal
      respiration in C1 and C2 were correlated at a high probability level with those
      of FDA hydrolysis, and both parameters can be used for establishing the degree of
      biological stability of the composting material.

PMID- 12421011
TI  - Comparison of growth and performance in upland and lowland switchgrass types to
      water and nitrogen stress.
AB  - The objective of the study was to examine lowland (Alamo and Kanlow) and upland
      (Blackwell and Caddo) cultivars of switchgrass (Panicum virgatum L.) for
      differences in response to water deficit and nitrogen fertilizer. Cultivars were
      grown in pots with fritted clay at two water levels: well watered and deficit
      conditions (-0.1 and -1.0 MPa) and two nitrogen levels (10 and 100 kg ha(-1)).
      Nitrogen determined growth potential of the cultivars more than water
      availability. The lowland cultivars produced greater biomass yields than upland
      cultivars. However, upland cultivars showed a smaller response to drought stress.
      Under water stress conditions all cultivars exhibited a higher leaf percentage of
      total dry matter (DM), with the upland cultivars having the highest leaf
      percentage of total DM. Nitrogen proved to have more of an effect on single-leaf
      photosynthesis rates than water. Alamo demonstrated the greatest biomass
      production among all cultivars. The differences found between the two lowland
      cultivars suggest that Alamo would be better suited for forage and biomass
      production in central Texas, being a higher producer under drought and non
      drought conditions than Kanlow as well as upland cultivars.

PMID- 12421012
TI  - Effects of fly ash and Helminthosporium oryzae on growth and yield of three
      cultivars of rice.
AB  - A 120-day greenhouse experiment was conducted to study the effects of various fly
      ash concentrations (0%, 20%, 40%, 60%, 80% and 100% vol/vol) with normal field
      soil and Helminthosporium oryzae on the growth and yield of three cultivars (Pusa
      Basmati, Pant-4 and Pant-10) of rice, Oryza sativa L. Application of 20% and 40%
      fly ash with soil caused a significant increase in plant growth and yield of all
      the three cultivars. Forty percent fly ash caused a higher increase in growth and
      yield than did 20%. Sixty percent, 80% and 100% fly ash had an adverse effect on
      growth and yield of all the three cultivars, the maximum being with 100% fly ash.
      Inoculation of H. oryzae had an adverse effect on the growth and yield, Pant-10
      suffered higher damage by H. oryzae than Pusa Basmati and Pant-4. Pant-10 also
      exhibited higher infected leaf area and greater disease symptoms of H. oryzae
      than did Pusa Basmati and Pant-4. Plants grown in 100% fly ash suffered higher
      reductions in growth and yield with H. oryzae than plants grown in pure soil or
      in 20% or 40% fly ash. In general, plant growth was best in Pusa Basmati followed
      by Pant-4 and Pant-10, while yield was higher in Pant-4 followed by Pant-10 and
      Pusa Basmati.

PMID- 12421013
TI  - Nitrogen removal in an anaerobic baffled filter reactor with aerobic post
      treatment.
AB  - A new sewage treatment system was studied, which consisted of an anaerobic
      baffled filter reactor and the following aerobic post-treatment. One of the two
      studied systems (AN-I) was inoculated with psychrophilic digested sludge, the
      second one (AN-II) was operated without inoculation. The HRT in anaerobic and
      aerobic parts of the reactors were about 15 and 4 h, respectively. The
      temperature in both reactors varied during the year from 4.5 to 23 degrees C. All
      monitored parameters were removed with relatively high efficiencies (COD = 78.6
      83.0%, BOD5 = 92.5-94.0% and SS = 80.9-92.7%). An intensive nitrification process
      was observed during the whole year in both reactors (under average temperature of
      5.9 degrees C in January 2000, also). The average removal of the NH4-N varied
      during the year from 46.4% to 87.3%. In both systems a partial denitrification
      process was observed, too.

PMID- 12421014
TI  - Mesophilic biogas production from fruit and vegetable waste in a tubular
      digester.
AB  - A semi-continuously mixed mesophilic tubular anaerobic digester was tested for
      the conversion of fruit and vegetable waste (FVW) into biogas. The effect of
      hydraulic retention time (HRT) and the feed concentration on the extent of the
      degradation of the waste was examined. Varying the HRT between 12 and 20 days had
      no effect on the fermentation stability and pH remained between 6.8 and 7.6, but
      an inhibition of methanogenic bacteria was observed at HRT below 12 days. The
      overall performance of the reactor was depressed by changing the feed
      concentration from 8% to 10% TS (dry weight). By applying a feed concentration of
      6% and HRT of 20 days in the tubular digester, 75% conversion efficiency of FVW
      into biogas with a methane content of 64% was achieved.

PMID- 12421015
TI  - Enzymatic hydrolysis of molasses.
AB  - Kinetic studies of the enzymatic hydrolysis of molasses were conducted using
      glucoamylase. Central Sugar Refinery SDN BHD contains 13-20% glucose. The
      molasses was diluted and the kinetic experiments were conducted at 67 degrees C
      with 100-1000 mg/l of glucoamylase. The glucose contents of the molasses were
      enhanced after hydrolysis of molasses solution with 1000 mg/l glucoamylase. A
      Lineweaver-Burk plot was obtained based on enzyme kinetic data. The rate
      constant, Km and maximum reaction rate, Vmax for 500 mg/l of glucoamylase were
      100 mmol/l (18 g/l) and 5 mmol/l min (0.9 g/l min), respectively. The maximum
      reaction rate, Vmax for 1000 mg/l of glucoamylase was doubled, to 100 mmol/l (18
      g/l) and the rate constant, Km was the same for 500 mg/l of glucoamylase. The
      substrate inhibition model was noncompetitive based on the resulting Lineweaver
      Burk plot for enzyme concentration of 500 and 1000 mg/l.

PMID- 12421016
TI  - Simplified method for estimation of microbial activity in compost by ATP
      analysis.
AB  - A simplified method using ATP analysis was proposed to estimate the time course
      of microbial activity during composting. A compost sample was suspended in
      distilled water and its filtrate was used to estimate the ATP content in the
      compost by the luciferine-luciferase fluorescence reaction. The method permitted
      the rapid and simple determination of ATP in the compost and was successfully
      applied to monitor the time course of the microbial activity in the laboratory
      scale composting process. The analytical simplicity in this method greatly
      improved the field-applicability of the ATP analysis for the composting process
      monitoring.

PMID- 12421017
TI  - Comment on "The effect of kaolin particles on the behavior of nitrifying
      activated sludge units".

PMID- 12421018
TI  - Alcohol and hepatitis viruses B and C--double trouble?

PMID- 12421019
TI  - High seroprevalence and clinical significance of hepatitis B and C infection in
      hospitalized patients with alcoholic cirrhosis.
AB  - OBJECTIVES: Patients with alcoholic cirrhosis (AC) are frequently infected with
      hepatotropic viruses which could alter the clinical spectrum of the disease. We
      studied the seroprevalence of hepatitis B (HBV) and hepatitis C virus (HCV) and
      their impact on the clinical profile of patients with AC. METHODS: Two hundred
      and ten hospitalized patients of AC were studied and screened for markers of HBV
      and HCV infection. Clinical, biochemical and virological correlation was done.
      RESULTS: One hundred and forty (66.6%) patients had no viral infection Group I,
      50 (23.8%) were positive for HBsAg Group II and 20 (9.5%) for anti-HCV Group III.
      All patients were males with comparable ages (43.9 years, 44 years and 45.9 years
      respectively). The amount of alcohol consumed by patients in Group III (130 +/-
      115 g/d) was significantly less than Group II (204 +/- 130 g/d, P < 0.05) and
      Group I (281 +/- 188 g/d, p < 0.001). The duration of alcohol abuse was shorter
      in Group II and III, although not statistically significant. Presentation as
      jaundice was common in Group II and III (p < 0.05). The AST and ALT values (IU/L)
      were significantly higher in Group II (239 +/- 351, 197 +/- 266) and III (157 +/-
      170, 86 +/- 52) than Group I (89 +/- 78, 66 +/- 54) (P < 0.05). The serum
      alkaline phosphatase (IU/L) was higher in Group III (349 +/- 223) as compared to
      Group II (263 +/- 186) and Group I (162 +/- 62) (P < 0.05). There was however, no
      difference in Child's grade or the discriminant function between the three groups
      of patients. CONCLUSIONS: (i) One-third of the hospitalized patients with AC are
      infected with HBV or HCV infection, (ii) these infections hasten clinical
      presentation of patients with alcoholic liver disease, with lesser amount of
      alcohol consumption and (iii) jaundice, raised ALT/AST and alkaline phosphatase
      are more common with superadded viral infection.

PMID- 12421020
TI  - Panniculitides--a clinicopathologic study.
AB  - OBJECTIVES: To describe the clinical and pathologic features of panniculitides,
      an uncommon group of diseases, where the available Indian literature is sparse.
      MATERIAL AND METHODS: Prospective four years study of patients presenting with
      panniculitis to a large teaching hospital in North India. RESULTS: Erythema
      nodosum (EN) was the commonest panniculitis (79.3% cases) in our cohort. Other
      causes included erythema induratum, Weber Christian disease, cutaneous
      polyarteritis nodosa and panniculitis associated with Takayasu's arteritis and
      dermatomyositis-lupus overlap. Elevated ESR and leukocytosis were the common
      laboratory abnormalities encountered. Septal panniculitis without vasculitis was
      the most frequent histopathologic pattern observed. Patients of EN did well on
      nonsteroidal anti-inflammatory drugs while corticosteroids with or without
      azathioprine were used to treat other panniculitides. CONCLUSIONS: Physician
      awareness, clinical pattern recognition and histopathological confirmation, all
      play a key role in the identification and management of panniculitis.

PMID- 12421021
TI  - Prevalence of pathogens in diabetic foot infection in South Indian type 2
      diabetic patients.
AB  - AIM: To determine the prevalence of pathogens in diabetic foot infections, in
      relation to parameters like Wagner's grading, duration of diabetes and healing
      time. MATERIAL AND METHODS: A group of 654 (M:F, 433:221) type 2 diabetic
      patients with foot ulcers were studied. Specimens like pus, wound exudate and
      tissue were processed for smear for Gram's staining, aerobic and anaerobic
      culture, and biochemical identifications. RESULTS: In 654 diabetic patients, 728
      pathogens were isolated. Aerobic pathogens were isolated in 437 (66.8%) patients
      and anaerobic pathogens were isolated in 217 (33.2%). As Wagner's grading
      increased, the prevalence of anaerobic pathogens also increased. Neuropathy was
      common in diabetic patients infected with both aerobic and anaerobic pathogens.
      Ulcers infected with anaerobic pathogens showed a longer healing time than ulcers
      infected with aerobic pathogens. There was no significant difference in
      peripheral vascular disease (PVD) in patients selected for the study. Among
      aerobic pathogens, Enterobacteriaceae family (48%), Staphylococcus species (spp)
      (18.2%), Streptococcus spp (16.8%) and Pseudomonas spp (17%) were seen
      frequently. Among anaerobes Peptostreptococcus spp and Clostridium spp formed
      69.4%. Gram-negative anaerobes like Bacteroides spp and Fusobacterium spp were
      present in 30.6%. Healing time was longer when strict aerobic pathogen
      Pseudomonas spp and strict anaerobic pathogens were present (136.1 +/- 28.6 and
      136.4 +/- 34.7 days, respectively). CONCLUSIONS: Diabetic foot infection is
      polymicrobial in nature. The healing time of wound infected with anaerobic
      pathogens was higher than those infected with aerobic pathogens. Anaerobic
      pathogens increased with the Wagner's grading. Presence of neuropathy increased
      the risk of foot infection.

PMID- 12421022
TI  - Laser palliation of esophageal carcinoma.
AB  - OBJECTIVE: Forty-five cases of advanced esophageal carcinoma were treated with
      Nd:YAG laser, to relieve dysphagia. METHODS: There were 36 males (80%) and nine
      female (20%) patients. The mean age of the patients was 55.87 years. Thirty-nine
      patients (86.6%) were found to have squamous cell carcinoma. Middle third growths
      were found to be most common (66.6%), followed by lower third (20%) and upper
      third (13.3%) tumours. The mean dysphagia grade at presentation was 3.33 with all
      45 patients (100%) having dysphagia. RESULTS: After three months of treatment,
      the mean dysphagia grade improved to 1.73 with 39 patients being able to eat at
      least soft or solid food. Mean number of laser sessions required was 3.3. The
      mean weight of the patients also increased from 45.13 Kg to 47.71 Kg. Three
      patients developed an esophageal perforation (6.6%), out of whom two died. No
      other major complication was observed. CONCLUSION: Nd:YAG laser is thus an
      excellent means of palliation of distressful symptom of carcinoma of esophagus
      with expectable morbidity and mortality.

PMID- 12421023
TI  - Insulin sensitivity in pre-eclampsia.
AB  - OBJECTIVE: To investigate whether pre-eclampsia is associated with an
      exaggeration of the insulin resistance in normotensive pregnancy. DESIGN: Minimal
      model analysis of a frequently sampled intravenous glucose tolerance test to
      assess insulin sensitivity. SETTING: SMS Medical College, Jaipur (Raj.)
      PARTICIPANTS: Eleven women with pre-eclampsia and eleven matched normotensive
      pregnant women. RESULTS: Insulin sensitivity (S1) was increased in the group with
      pre-eclampsia compared with the normotensive women (Mean +/- SEM): 2.6 (0.4) vs
      1.6 (0.2) 10(-4) min(-1) per mU/L; P = 0.028). This was accompanied by a decrease
      in glucose effectiveness (SG) (1-1 +/- 0.1 vs 1.7 +/- 0.1 10(-2) min(-1), P =
      0.006) in the pre-eclamptic women. In the normotensive group there was a
      significant inverse correlation between S1 and mean arterial blood pressure (r = 
      0.65; P = 0.03), but no such relation existed in the group with pre-eclampsia.
      CONCLUSIONS: As with other forms of secondary hypertension, and unlike essential
      hypertension, the pathophysiology of pre-eclampsia is not associated with insulin
      resistance.

PMID- 12421024
TI  - Effects of low-dose omega-3 fatty acid substitution in type-2 diabetes mellitus
      with special reference to oxidative stress--a prospective preliminary study.
AB  - BACKGROUND: A state of increased oxidative stress has been recognised in type 2
      diabetes mellitus (DM). The present study was done to assess the effects of low
      dose omega-3 fatty acids substitution in patients with type 2 DM with special
      reference to oxidative stress. METHOD: Sixty-five patients with type 2 DM of body
      mass index (BMI) < 27 kg/m2 and thirty age and sex matched healthy controls were
      evaluated for blood glucose, blood pressure and lipid profile and oxidative
      stress was assessed in them by measuring lipid peroxides (LP), diene conjugates
      (DC) and reduced glutathione (RG) in the serum. Of the 65, 40 motivated patients
      were randomly divided into two groups--group 1 comprising of fifteen patients
      prescribed a diabetic diet along with a placebo and group 2 consisting of twenty
      five patients on the same diet with the addition of 0.6 g omega-3 fatty acids as
      one capsule Maxigard (containing 180 mg eicosapentaenoic acid and 120 mg
      docosahexaenoic acid) twice daily. All parameters were reassessed after six
      weeks. RESULTS: The levels of lipid peroxides (micromol/L), diene conjugates (OD
      units) and reduced glutathione (mmol GSH/L) were significantly altered indicating
      increased oxidative stress in the diabetics compared to the healthy controls:
      4.106 +/- 0.889, 2.751 +/- 0.424, 1.344 +/- 0.316 and 1.91 +/- 0.541, 1.735 +/-
      0.315, 1.919 +/- 0.310, respectively (p < 0.001 for all the three). Patients in
      group 1 and 2 were comparable in all respects including oxidative stress at the
      start of therapy. After six weeks, on comparing the mean % changes in the three
      parameters of oxidative stress between the two groups, it was seen that the %
      change was significantly higher in group 2 (Maxigard group) compared to group 1
      (Placebo; 5.22 +/- 1.056 (p = 0.05), 3.28 +/- 0.608 (p = 0.01), 5.27 +/- 0.585 (p
      < 0.001) and 0.82 +/- 0.123, 0.18 +/- 0.017, 0.56 +/- 0.035 (p < 0.001),
      respectively. The patients in group 2 also exhibited significantly greater
      improvement in glycemic status, blood pressure and lipid profiles. CONCLUSIONS:
      The present study documented the existence of a state of increased oxidative
      stress in type 2 diabetics. Significant beneficial effects of low dose omega-3
      fatty acids substitution for PUFA-6 were observed not only on oxidative stress
      parameters but also on blood pressure and metabolic profile.

PMID- 12421025
TI  - The activity of superoxide dismutase in hydroxyurea-treated E beta thalassemia.
AB  - AIM: To study the activity of superoxide dismutase (SOD) and the level of fetal
      hemoglobin (HbF) in hydroxyurea (HU)-treated E beta thalassaemia. METHODS: We
      have measured SOD level, HbF, mean corpuscular volume (MCV), packed cell volume
      (PCV) and hemoglobin (Hb) of E beta thalassaemia treated with HU (dose 30
      mg/kg/day) for consecutive 90 days. RESULT: The increase of HbF synthesis without
      increase of Hb was observed in HU-treated patients. CONCLUSION: The decreased SOD
      level in long term and low dose of HU therapy in E beta thalassaemia may have
      some role to inhibit superoxide radical of erythrocyte. HU may act as inhibitor
      for oxidative damage of red cell in E beta thalassaemia.

PMID- 12421026
TI  - Is increased apolipoprotein B-A major factor enhancing the risk of coronary
      artery disease in type 2 diabetes?
AB  - OBJECTIVES: An association of Apolipoprotein B (Apo B) with coronary artery
      disease (CAD) independent of LDL cholesterol (LDLc) concentrations has been
      reported in white population. This analysis was taken up to study whether the
      higher CAD risk in Asian Indians with diabetes could be explained by possible
      alterations in Apo B and Apolipoprotein A1 (Apo A1) concentrations. METHODS: The
      study group consisted of four hundred and forty seven men aged > or = 25 years,
      167 with CAD and 280 with no CAD, classified by coronary angiography. Plasma
      lipid profile including total cholesterol, LDLc, Apo A1 and Apo B were done.
      Glucose tolerance was evaluated in all. RESULTS: Age, BMI, Apo B, and Apo A1 were
      significantly associated with CAD in a multiple regression analysis. Hyper Apo B
      was more common than hyper LDLc in CAD (73.6% vs 20.4%, chi2 = 157, P < 0.001).
      Apo B concentrations were increased in diabetic subjects even in the presence of
      normal levels of LDLc and in the absence of CAD. CONCLUSIONS: The study has shown
      that the apolipoproteins B and A1 provide better information regarding the risk
      of CAD. Apo B abnormalities exist in large percentages of CAD subjects despite
      having normal levels of LDLc. Diabetes per se enhances the Apo B concentrations
      and this could probably be one of the mechanisms of accelerated CAD in diabetes.
      Hyper Apo B may be an index of CAD risk.

PMID- 12421027
TI  - A follow-up study of juvenile rheumatoid arthritis into adulthood.
AB  - AIM OF THE STUDY: To study the clinical profile of various subtypes of juvenile
      rheumatoid arthritis (JRA) in adulthood and analyse the outcome of the disease in
      terms of functional status, educational achievement, growth abnormalities,
      radiological progression and activity of the disease. METHODS: From a group of
      150 JRA cases, 26 adult patients were included in the study. All of them were
      under follow up since the onset of disease in childhood. Clinical data at the
      onset were obtained from old medical documents. Detailed clinical and laboratory
      assessment of all cases were done. RESULTS: There were 10 oligoarticular, 13
      polyarticular and three systemic onset cases. Mean age of onset of disease was
      11.7 +/- 3.39 years (range 2-15). Mean duration of follow up was 11.4 +/- 4.46
      years range (6-22). Twenty-one patients had active disease. Ninety percent of
      oligoarthritis group were in class 1 status whereas none of the systemic onset
      JRA cases were in class I. Micrognathia, short stiff neck and short stature were
      noticed among polyarticular and systemic onset JRA. Seventy percent of
      oligoarthritis group developed inflammatory low back ache. Bony ankylosis of
      tarsal and carpal bones were seen in eight cases. CONCLUSION: In our study there
      is a male predominance in JRA. Pauciarticular (oligoarthritis) JRA occurring in
      older boys had the best functional outcome. Growth abnormalities and radiological
      changes were more common in polyarticular and systemic onset JRA.

PMID- 12421028
TI  - Ultra-science.

PMID- 12421029
TI  - Theodor Bilharz--(1825-1862) Postal stamp released in Egypt, 1962. Issued on his
      100th death anniversary.

PMID- 12421030
TI  - Pictorial CME. Atrio-ventricular block.

PMID- 12421031
TI  - Hepatopulmonary syndrome.

PMID- 12421032
TI  - Pharmacoeconomics.
AB  - Today, spiraling costs of medical care coupled with limited resources have led to
      an explosive increase in the number of pharmacoeconomic analyses being carried
      out. The first step in a pharmacoeconomic analysis is to measure the costs and
      benefits of the therapeutic regimens being compared. Then one compares these
      costs and benefits by calculating a cost: benefit ratio for each regimen. Four
      types of economic analyses are commonly used for this purpose. While cost
      minimization analysis ignores the benefits and focuses only on costs of
      treatment, cost-effectiveness analysis measures costs in monetary terms and
      benefits or outcome in their natural clinical units. Cost benefit analysis on the
      other hand, places monetary values on both-costs and outcome of therapy. Finally,
      cost utility analysis measures costs in monetary terms, and outcome in a single
      utility-based unit of measurement. Utility based measures like quality adjusted
      life-years (QALY) measure the contribution made by the regimens to the patient's
      quality of life. Finally study designs generally used for generating data for a
      pharmacoeconomic analysis are mentioned, and concepts like marginal analysis,
      sensitivity analysis and discounting are explained in the context of health
      economics.

PMID- 12421033
TI  - Ethylenedibromide poisoning.

PMID- 12421034
TI  - Absence of typically described electrocardiographic changes in a patient of
      hyperkalemia who had preexisting electrocardiographic changes.

PMID- 12421035
TI  - Endoluminal treatment of infrarenal abdominal aortic aneurysm with bifurcated
      stent-graft system.
AB  - Atherosclerotic infrarenal aortic aneurysm has been traditionally treated by open
      surgical repair. We report a high risk case where the aneurysm was successfully
      treated by the new technique of endoluminal stent graft placement.

PMID- 12421036
TI  - Alopecia universalis in a case of systemic lupus erythematosus.
AB  - We report a case of systemic lupus erythematosus (SLE) who presented with
      alopecia universalis. MR, a 23 years female patient was admitted with alopecia
      universalis and other features of SLE like peripheral arthritis, fever,
      nephritis, butterfly rash over the malar regions, positive ANA and anti-ds DNA
      antibodies. There was a gap of four years between the onset of alopecia
      universalis and other clinical features of SLE. The alopecia was of non-scarry
      variety and responded to systemic and topical steroids.

PMID- 12421037
TI  - Myelopathy during treatment of autoimmune hemolytic anaemia.
AB  - A specific neurological syndrome resembling, subacute combined degeneration of
      spinal cord, has been observed to occur during treatment of autoimmune hemolytic
      anaemia (AHA). We propose that folate administration can precipitate this
      neurological syndrome in patients with subclinical deficiency of vitamin B12, a
      phenomenon more likely to occur in tropical countries. Such cases have not been
      previously reported.

PMID- 12421038
TI  - Torsade de pointes probably induced by sparfloxacin.
AB  - Sparfloxacin is a new fluoroquinolone with potent antitubercular activity. We
      report a case of a 37 year old female who was on this drug as part of modified
      antitubercular therapy and developed torsade de pointes on this drug.

PMID- 12421039
TI  - Left sided cervical and thoracic malignant extra-adrenal pheochromocytoma.
AB  - Extra-adrenal Pheochromocytomas are rare entities. High index of suspicion among
      diastolic hypertensives followed by screening test for 24-hour urinary
      catecholamine level helps in diagnosis. 123I MIBG scintigraphy is specific for
      tumour localisation and surgical debulking of tumour or 131I MIBG therapy are
      alternative modes of treatment.

PMID- 12421040
TI  - Development of carcinoma of esophagus in a treated case of breast carcinoma:
      possibly related to radiation therapy.
AB  - Radiation is well known to increase the risk of cancer. Leukemias, skin cancers,
      osteosarcomas, thyroid cancers are some examples of radiation-induced
      malignancies. Radiation-induced carcinoma of the esophagus is extremely rare. We
      present a case of 42 year old patient who received radiotherapy for breast cancer
      and subsequently developed esophageal carcinoma.

PMID- 12421041
TI  - Oral contraceptive-induced central retinal artery occlusion.
AB  - Oral contraceptives are known to have ocular complications including retinal
      vascular lesions. The authors report a case of central retinal artery occlusion
      in a young woman on oral contraceptives.

PMID- 12421043
TI  - Gonadal dysgenesis due to isochromosome formation.

PMID- 12421042
TI  - Invasive aspergillosis caused by Aspergillus terreus in a non-immunosuppressed
      patient.

PMID- 12421044
TI  - Childhood multiple sclerosis--report of two Indian cases.

PMID- 12421045
TI  - Sheehan's syndrome.

PMID- 12421046
TI  - Gabapentin for the treatment of familial erythromelalgia pain.

PMID- 12421047
TI  - Garlic and ischemic heart disease.

PMID- 12421048
TI  - Cyanosis--the right and wrong of medical teaching.

PMID- 12421049
TI  - Modern way of robbery.

PMID- 12421050
TI  - A critical evaluation of signs and symptoms in the diagnosis of Addison's
      disease.

PMID- 12421051
TI  - Flumazenil in acute benzodiazepine overdose.

PMID- 12421052
TI  - Electrocardiogram--a historical revisit.

PMID- 12421053
TI  - Why do non-color words interfere with color naming?
AB  - In the non-color-word Stroop task, university students' response latencies were
      longer for low-frequency than for higher frequency target words. Visual identity
      primes facilitated color naming in groups reading the prime silently or
      processing it semantically (Experiment 1) but did not when participants generated
      a rhyme of the prime (Experiment 3). With auditory identity primes, generating an
      associate or a rhyme of the prime produced interference (Experiments 2 and 3).
      Color-naming latencies were longer for nonwords than for words (Experiment 4).
      There was a small long-term repetition benefit in color naming for low-frequency
      words that had been presented in the lexical decision task (Experiment 5).
      Facilitation of word recognition speeds color naming except when phonological
      activation of the base word increases response competition.

PMID- 12421054
TI  - Programming of endogenous and exogenous saccades: evidence for a competitive
      integration model.
AB  - Participants were required to make a saccade to a uniquely colored target while
      ignoring the presentation of an onset distractor. The results provide evidence
      for a competitive integration model of saccade programming that assumes
      endogenous and exogenous saccades are programmed in a common saccade map. The
      model incorporates a lateral interaction structure in which saccade-related
      activation at a specific location spreads to neighboring locations but inhibits
      distant locations. In addition, there is top-down, location-specific inhibition
      of locations to which the saccade should not go. The time course of exogenous and
      endogenous activation in the saccade map can explain a variety of eye movement
      data, including endpoints, latencies, and trajectories of saccades and the well
      known global effect.

PMID- 12421055
TI  - Roles of salience and strategy in conjunction search.
AB  - In some cases, the search for a conjunction target proceeds through the smaller
      group of elements in a display, whereas in others, search is limited to those
      elements that share a particular feature with the target. In 6 experiments,
      participants searched for a conjunction target among displays consisting of
      various proportions of 2 distractor types. Smaller-group search was more
      prevalent than target-feature search with denser displays and with features that
      were highly discriminable. Explicit instructions to limit search to a specific
      feature affected performance only when the discriminability of the guiding
      feature was much greater than the other target feature. Together, these
      experiments show that bottom-up factors have more influence in guiding
      conjunction searches than previously thought.

PMID- 12421056
TI  - Top-down influences on perceptual grouping.
AB  - Observers are faster to find and discriminate a target pair of adjacent, same
      shaped objects that are within the same perceptual group (within group) versus
      within adjacent perceptual groups. Manipulating the probability of a within-group
      pair modulated this grouping effect such that it increased as the percentage of
      within-group trials (25%, 50%, or 75%) increased. This probability effect was
      stronger for extrinsic grouping factors (common region and connectedness) than
      for intrinsic factors (proximity and color similarity). Further experiments,
      however, suggested that this extrinsic-intrinsic difference was due to
      differences in overall speed with which the target pair was found. The results
      are interpreted as indicating that grouping is sensitive to top-down influences
      as long as there is sufficient time for feedback to operate.

PMID- 12421058
TI  - Perceiving curvilinear heading in the presence of moving objects.
AB  - Four experiments were directed at understanding the influence of multiple moving
      objects on curvilinear (i.e., circular and elliptical) heading perception.
      Displays simulated observer movement over a ground plane in the presence of
      moving objects depicted as transparent, opaque, or black cubes. Objects either
      moved parallel to or intersected the observer's path and either retreated from or
      approached the moving observer. Heading judgments were accurate and consistent
      across all conditions. The significance of these results for computational models
      of heading perception and for information in the global optic flow field about
      observer and object motion is discussed.

PMID- 12421057
TI  - Auditory dominance in temporal processing: new evidence from synchronization with
      simultaneous visual and auditory sequences.
AB  - Evidence that audition dominates vision in temporal processing has come from
      perceptual judgment tasks. This study shows that this auditory dominance extends
      to the largely subconscious processes involved in sensorimotor coordination.
      Participants tapped their finger in synchrony with auditory and visual sequences
      containing an event onset shift (EOS), expected to elicit an involuntary phase
      correction response (PCR), and also tried to detect the EOS. Sequences were
      presented in unimodal and bimodal conditions, including one in which auditory and
      visual EOSs of opposite sign coincided. Unimodal results showed greater
      variability of taps, smaller PCRs, and poorer EOS detection in vision than in
      audition. In bimodal conditions, variability of taps was similar to that for
      unimodal auditory sequences, and PCRs depended more on auditory than on visual
      information, even though attention was always focused on the visual sequences.

PMID- 12421059
TI  - Revisiting bias effects in word-initial phonological priming.
AB  - The phonological priming paradigm, in which participants respond to the second of
      2 consecutively presented spoken words, has the potential to be a useful tool
      with which to study lexical processing. Concerns about response biases distorting
      the results have persisted since its introduction. This study explored the
      manifestation of biases by modifying the standard priming experiment such that
      the magnitude of priming effects using the same items could be compared at
      different points during the testing session. Four experiments investigated
      whether a recent dissociation of response biases and priming effects is evidence
      of lexical inhibition when the prime and target overlap by the first 3 word
      initial phonemes (M. Hamburger & L. M. Slowiaczek, 1996). Biases were found in
      conditions previously thought to prevent their influence.

PMID- 12421060
TI  - Behavior of college baseball players in a virtual batting task.
AB  - A baseball batting simulation was used to investigate the information used to hit
      a baseball. Measures of spatial and temporal swing accuracy were used to test
      whether batters (a) use speed to estimate pitch height, (b) initiate a constant
      swing duration at a fixed time to contact, (c) are influenced by the history of
      previous pitches and pitch count, and (d) use rotation direction. Batters were
      experienced college players. Pitch speed variance led to predictable spatial
      errors, and spatial accuracy was worse than temporal accuracy. Swing duration was
      generally variable. The history of the previous 3 pitches and the pitch count had
      significant effects on accuracy, and performance improved when rotation cues were
      added. There were significant effects of expertise on hitting strategy.

PMID- 12421061
TI  - The time course of competition for attention: attention is initially labile.
AB  - Competition for attention between 2 written words was investigated by presenting
      the words briefly in a single stream of distractors (Experiment 1) or in
      different streams (Experiment 2-6), using rapid serial visual presentation at 53
      ms/item. Stimulus onset asynchrony (SOA) was varied from 0 to 213 ms. At all SOAs
      there was strong competition, but which word was more likely to be reported
      shifted markedly with SOA. At SOAs in the range of 13-53 ms the second word was
      more likely to be reported, but at 213 ms, the advantage switched to the first
      word, as in the attentional blink. A 2-stage competition model of attention is
      proposed in which attention to a detected target is labile in Stage 1. Stage 1
      ends when one target is identified, initiating a serial Stage 2 process of
      consolidation of that target.

PMID- 12421062
TI  - Recognition memory for briefly presented pictures: the time course of rapid
      forgetting.
AB  - When viewing a rapid sequence of pictures, observers momentarily understand the
      gist of each scene but have poor recognition memory for most of them (M. C.
      Potter, 1976). Is forgetting immediate, or does some information persist briefly?
      Sequences of 5 scenes were presented for 173 ms/picture; when yes-no testing
      began immediately, recognition was initially high but declined markedly during
      the 10-item test. With testing delays of 2 or 6 s, the decline over testing was
      less steep. When 10 or 20 pictures were presented, there was again a marked
      initial decline during testing. A 2-alternative forced-choice recognition test
      produced similar results. Both the passage of time and test interference (but not
      presentation interference) led to forgetting. The brief persistence of
      information may assist in building a coherent representation over several
      fixations.

PMID- 12421063
TI  - Perceptual processes in matching and recognition of complex pictures.
AB  - The role of perceptual feature sampling in speeded matching and recognition was
      explored in 4 experiments. Experiments 1-3 involved a perceptual matching task
      with pictures of various objects and scenes. In Experiments 2 and 3, same
      different judgments were given under time pressure. The main objective of the
      matching task was to obtain measures of the perceptual processing rates of
      different object features. Experiment 4 was an old-new recognition experiment, in
      which the same stimuli as those in the matching task were used. Response signals
      were used to limit processing time in the recognition task. The results
      demonstrated that it is possible to predict speeded recognition performance from
      performance in perceptual matching. A simple stochastic feature-sampling model
      provides a unified account of the data from the 4 experiments.

PMID- 12421064
TI  - Necessity of spatial pooling for the perception of heading in nonrigid
      environments.
AB  - This study examined whether the perception of heading is determined by spatially
      pooling velocity information. Observers were presented displays simulating
      observer motion through a volume of 3-D objects. To test the importance of
      spatial pooling, the authors systematically varied the nonrigidity of the flow
      field using two types of object motion: adding a unique rotation or translation
      to each object. Calculations of the signal-to-noise (observer velocity-to-object
      motion) ratio indicated no decrements in performance when the ratio was .39 for
      object rotation and .45 for object translation. Performance also increased with
      the number of objects in the scene. These results suggest that heading is
      determined by mechanisms that use spatial pooling over large regions.

PMID- 12421066
TI  - Use of parafoveally visible characters during the reading of Chinese sentences.
AB  - Chinese readers' use of parafoveal character previews was examined. In Experiment
      1, the preview of target characters consisted of targets or of graphemically
      similar, homophonic, or dissimilar characters. Each preview was replaced with the
      corresponding target when the eyes reached the target location. Oculomotor
      measures revealed preview benefits for targets, for graphemically similar
      characters, and for homophonic characters. Experiment 2 showed that parafoveal
      preview of graphemically similar characters yielded benefits primarily when they
      shared the phonetic radical with their targets. The phonological relationship
      between previewed radicals and subsequently viewed targets was ineffective.
      Chinese character processing thus involves the initial use of orthographic
      information from the phonetic radical and the activation of the character's
      phonological form.

PMID- 12421065
TI  - Dissociation between location and shape in visual space.
AB  - There are often large perceptual distortions of shapes lying on the ground plane,
      even in well-lit environments. These distortions occur under conditions for which
      the perception of location i saccurate. Four hypotheses are considered for
      reconciling these seemingly paradoxical results, after which 2 experiments are
      reported that lend further support to 1 of them--that perception of shapeand
      perception of location are sometimes dissociable. The 2 experiments show that
      whereas perception of location does not depend on whether viewing is monocular or
      binocular (when other distance cues are abundant), perception of shape becomes
      more veridical when viewing is binocular. This means that perception of shape is
      not fully constrained by the perceived locations of the vertices that define the
      shape.

PMID- 12421067
TI  - Masked priming effects with syllabic neighbors in a lexical decision task.
AB  - Four lexical decision experiments using a masked priming paradigm were conducted
      to analyze whether the previous presentation of a syllabic neighbor (a word
      sharing the same 1st syllable) influences recognition performance. The results
      showed an inhibitory effect of more frequent syllabic primes and some
      facilitation of nonword syllabic primes (Experiments 1-3). When monosyllabic
      pairs were used (Experiment 3), no priming effects of the 2 initial letters were
      found. Finally, when using only syllables as primes, latencies to words were
      shorter when preceded by primes that corresponded to the 1st syllable than by
      primes that contained 1 letter more or less than the 1st syllable (Experiment 4).
      Results are interpreted using activation models that take into account a syllabic
      level of representation.

PMID- 12421068
TI  - Cross-modal illusory conjunctions between vision and touch.
AB  - Cross-modal illusory conjunctions (ICs) happen when, under conditions of divided
      attention, felt textures are reported as being seen or vice versa. Experiments
      provided evidence for these errors, demonstrated that ICs are more frequent if
      tactile and visual stimuli are in the same hemispace, and showed that ICs still
      occur under forced-choice conditions but do not occur when attention to the felt
      texture is increased. Cross-modal ICs were also found in a patient with parietal
      damage even with relatively long presentations of visual stimuli. The data are
      consistent with there being cross-modal integration of sensory information, with
      the modality of origin sometimes being misattributed when attention is
      constrained. The empirical conclusions from the experiments are supported by
      formal models.

PMID- 12421069
TI  - Production and characterization of exopolysaccharides excreted by thermophilic
      bacteria from shallow, marine hydrothermal vents of Flegrean Ares (Italy).
AB  - Thermophilic microorganisms (4001-4014), described as aerobic or facultatively
      anaerobic, endospore forming with growth optima temperatures in the range of 60
      to 80 degrees C, have been isolated from hot marine springs around Ischia and
      from hydrothermal vents in the gulf of Naples. Mucous colonies are been selected
      for the recovery of new strains producing exopolysaccharides (EPS). To induce the
      biosynthesis of new exopolysaccharides, different sugars were tested as carbon
      sources in the media. The production of EPS in the strain 4009 reached 60 mg/l
      using trehalose as carbon source, increasing the yield of about 1000 fold. The
      4001-EPS was a mannan with a molecular weight of 380.000 D and with a complex
      primary structure. In fact, the analysis of the permethylated polysaccharide in
      GC-MS, showed the presence of mannose, glucose, galactose, mannosamine in the
      relative ratio of 1:0.1:tr :tr, respectively. Nuclear magnetic resonance spectrum
      of the exopolysaccharide confirmed the presence of a repetitive unity formed by
      seven monosaccharides, six with alpha gluco/galacto configuration and one residue
      with beta conformation.

PMID- 12421070
TI  - Analysis of phospholipids and ornithine-containing lipids from Mesorhizobium spp.
AB  - Polar lipid compositions of seven strains belonging to the four species of the
      Mesorhizobium genus were described. The lipid patterns of Mesorhizobium strains
      were very similar. Only quantitative differences were observed.
      Diphosphatidylglycerol (DPG), phosphatidylglycerol (PG), phosphatidylethanolamine
      (PE), and phosphatidylcholine (PC) were found to be the major phospholipids of
      the analysed bacteria. In addition, two methylated derivatives of PE were
      observed: phosphatidyl-N,N-dimethylethanolamine (DMPE) and phosphatidyl-N
      monomethylethanolamine (MMPE). Polar head groups of those phospholipids were
      predominately acylated with lactobacillic (19:0 cyclopropane) acid. Ornithine
      containing lipid (OL) was also identified. 3-hydroxy fatty acids found in the
      lipid preparations were derived exclusively from the ornithine lipid. 3
      hydroxylactobacillic was the main acyl residue amide linked to the ornithine.

PMID- 12421071
TI  - Biotransformation of biarylic compounds by yeasts of the genus trichosporon.
AB  - The biotransformation of biphenyl, dibenzofuran, and diphenyl ether by 24 strains
      belonging to 18 species of the genus Trichosporon was investigated to assess the
      taxonomic relevance of this property at species and genus level. With the
      exceptions of T. brassicae and T. porosum CBS 2040, all other strains were able
      to transform the parent compounds to monohydroxylated intermediates. A second
      hydroxylation on the same aromatic ring was carried out by fewer strains and
      depended on the substrate. It appears that this step is the rate-limiting one in
      the biotransformation of the biarylic compounds tested. Ring fission of
      dihydroxylated derivatives of biphenyl was observed within 12 species. The
      aromatic ring system of dihydroxylated dibenzofuran was cleaved by strains of 5
      species, while strains of 13 species were able to cleave the aromatic ring system
      of dihydroxylated diphenyl ether. Only 4 strains out of 18 species were able to
      cleave the aromatic ring system of all three parent compounds. These most active
      yeasts belong to the species T. coremiiforme, T. montevideense, T. mucoides, and
      T. sporotrichoides. In addition, strains of the species Cryptococcus curvatus and
      Cryptococcus humicola, closely related to the genus Trichosporon, were tested in
      parallel.

PMID- 12421072
TI  - Diversity of transconjugants that acquired plasmid pJP4 or pEMT1 after
      inoculation of a donor strain in the A- and B-horizon of an agricultural soil and
      description of Burkholderia hospita sp. nov. and Burkholderia terricola sp. nov.
AB  - We examined the diversity of transconjugants that acquired the catabolic plasmids
      pJP4 or pEMT1, which encode degradation of 2,4-dichlorophenoxyacetic acid (2,4
      D), in microcosms with agricultural soil inoculated with a donor strain
      (Dejonghe, W., Goris, J., El Fantroussi, S., Hofte, M., De Vos, P., Verstraete,
      W., and Top, E. M. Appl. Environ. Microbiol. 2000, p. 3297-3304). Using
      repetitive element PCR fingerprinting, eight different rep-clusters and six
      separate isolates could be discriminated among 95 transconjugants tested.
      Representative isolates were identified using 16S rDNA sequencing, cellular fatty
      acid analysis, whole-cell protein analysis and/or DNA-DNA hybridisations.
      Plasmids pJP4 and pEMT1 appeared to have a similar transfer and expression range,
      and were preferably acquired and expressed in soil by indigenous representatives
      of Ralstonia and Burkholderia. Two rep-clusters were shown to represent novel
      Burkholderia species, for which the names Burkholderia hospita sp. nov. and
      Burkholderia terricola sp. nov. are proposed. When easily degradable carbon
      sources were added together with the plasmid-bearing donor strain, also a
      significant proportion of Stenotrophomonas maltophilia isolates were found. The
      transconjugant collections isolated from A- (0-30 cm depth) and B-horizon (30-60
      cm depth) soil were similar, except for B. terricola transconjugants, which were
      only isolated from the B-horizon.

PMID- 12421073
TI  - Staphylococcus succinus subsp. casei subsp. nov., a dominant isolate from a
      surface ripened cheese.
AB  - A new subspecies of the species Staphylococcus succinus, isolated from a Swiss
      surface ripened cheese, is described. This subspecies is differentiated from the
      species Staphylococcus succinus ATCC 700337T on the basis of DNA-DNA
      hybridisation, cell wall composition and phenotypic characteristics.
      Staphylococcus succinus subsp. casei could be distinguished among other things by
      its ability to reduce nitrate, form acid from D-mannose and D-melezitose, ferment
      adenosine, inosine, D-sorbitol, and 2,3-butanediol, but not D-alanine. The type
      strain of Staphylococcus succinus subsp. casei is DSM 15096 (CIP no. pending).
      The GenBank accession numbers for the reference sequences of the 16S rDNA and the
      hsp60 gene used in this study are AJ320272 and AF527482, respectively.

PMID- 12421074
TI  - A detailed phenotypic characterisation of the type strains of Halomonas species.
AB  - We have made a detailed phenotypic characterisation of the type strains of 21
      species within the genus Halomonas and have also studied any possible
      intraspecific variation of strains within H. eurihalina, H. halophila, H. maura
      and H. salina. We used 234 morphological, physiological, biochemical, nutritional
      and antimicrobial susceptibility tests. Nutritional assays were carried out using
      both classical and miniaturized (BIOLOG system) identification methods. Two
      different numerical analyses were made using the TAXAN program; the first
      included the differential data from all the tests carried out whilst the second
      used only the 57 tests with the highest diagnostic scores (> or = 0.5). The
      results of both analyses were quite similar and demonstrated the phenotypic
      heterogeneity of the Halomonas species in question. At a 62% similarity level the
      type species were grouped into three phena, the main difference between them
      being the capacity of those included within phenon A (H. aquamarina, H.
      meridiana, H. cupida, H. pantelleriensis and H. halmophila) to produce acids from
      sugars. The species grouped in phenon C (H. campisalis, H. desiderata and H.
      subglasciescola) used fewer organic substrates than the others. The remaining
      strains were included in phenon B. H. marisflavi was clearly distinct and thus
      was not included in any of the three phena. High phenotypic similarity (more than
      88%) was found between Halomonas campisalis and Halomonas desiderata. The results
      of our work should allow researchers to minimise the tests required to arrive at
      a reliable phenotypic characterisation of Halomonas isolates and to select those
      of most use to differentiate Halomonas species from each other.

PMID- 12421075
TI  - Evaluation of tRNA intergenic length polymorphism (tDNA-pCR) for the
      differentiation of the members of the Burkholderia cepacia complex.
AB  - Nowadays, tentative identification of B. cepacia complex bacteria in routine
      diagnostic laboratories is based on a combination of selective media,
      conventional biochemical reactions, commercial test systems and PCR-based assays.
      Some of these assays have the capacity to discriminate reliably among several
      members of the B. cepacia complex, however one single method differentiating all
      B. cepacia-like organisms is not available. In this study, the applicability of
      tDNA-PCR for the differentiation and rapid identification of the different
      members of the B. cepacia complex was evaluated. For B. gladioli and most of the
      B. cepacia genomovars, differentiable patterns were obtained. For some of the
      members of the B. cepacia complex however, the tDNA-PCR patterns were very
      similar and sometimes multiple patterns existed within in a single genomovar. No
      distinction could be made between the tDNA-PCR patterns of B. vietnamiensis and
      B. pyrrocinia and of B. cepacia genomovars I and VIII respectively. We could
      conclude that, although tDNA-PCR is not sufficient as a single method to identify
      all the members of the B. cepacia complex unambiguously or to replace the
      currently used methods, it is a very fast and easily applicable method that could
      be a very useful tool for the differentiation and identification of B. cepacia
      like organisms.

PMID- 12421076
TI  - Use of predictive modeling for Propionibacterium strain classification.
AB  - Computed data analysis of biochemical or molecular profiles is currently used in
      studies of microbial taxonomy, epidemiology, and microbial diversity. We assessed
      the use of Partial Least Squares (PLS) regression for multivariate data analysis
      in bacteriology. We identified clear relationships between RAPD profiles of
      propionibacteria strains and their species classification, autolytic capacities,
      and their origins. The PLS regression also predicted species identity of some
      strains with RAPD profiles partially related to those of reference strains. The
      PLS analysis also allowed us to identify key characteristics to use to classify
      strains. PLS regression is particularly well adapted to i) describing a
      collection of bacterial isolates, ii) justifying bacterial groupings using
      several sets of data, and iii) predicting phenotypic characters of strains that
      have been classified by routine typing methods.

PMID- 12421077
TI  - Close genetic and phenotypic relatedness between mycoplasma ovine/caprine
      serogroup 11 and Mycoplasma bovigenitalium.
AB  - Strains of Mycoplasma ovine/caprine serogroup 11, isolated from infertile sheep,
      were compared to the type strain, 2D, and to strains of the cattle pathogen M.
      bovigenitalium, including the type strain, PG11. Examination of these strains by
      growth inhibition and immune fluorescence tests showed strong serological cross
      reactivity between M. serogroup 11 and M. bovigenitalium but not with other
      ruminant mycoplasmas. Substrate oxidation and growth studies did not show any
      consistent differences between M. serogroup 11 and M. bovigenitalium strains; all
      strains assigned to both groups were adapted to the utilisation of a small range
      of organic acids as energy sources. DNA:DNA hybridisation, carried out between
      DIG labelled reference strains of M. serogroup 11 and M. bovigenitalium and field
      isolates of these two mycoplasmas showed a particularly close relationship with
      hybridisation rates all greater than 70% and, mostly, closer to 90%. Sequencing
      of the 16S ribosomal RNA gene region of the M. serogroup 11 and M. bovigenitalium
      strains as well as the respective type strains revealed very high overall
      homologies of 99.5%. In summary, the results showed a very close phenotypic and
      genotypic relatedness between these two ruminant mycoplasmas which justifies
      their classification into a single species.

PMID- 12421078
TI  - New methods for the analysis of binarized BIOLOG GN data of Vibrio species:
      minimization of stochastic complexity and cumulative classification.
AB  - We apply minimization of stochastic complexity and the closely related method of
      cumulative classification to analyse the extensively studied BIOLOG GN data of
      Vibrio spp. Minimization of stochastic complexity provides an objective tool of
      bacterial taxonomy as it produces classifications that are optimal from the point
      of view of information theory. We compare the outcome of our results with
      previously published classifications of the same data set. Our results both
      confirm earlier detected relationships between species and discover new ones.

PMID- 12421079
TI  - Persistence and functional impact of a microbial inoculant on native microbial
      community structure, nutrient digestion and fermentation characteristics in a
      rumen model.
AB  - Small sub-unit (SSU) rRNA-targeted oligonucleotide probes were used to monitor
      the persistence of a genetically engineered bacterium inoculated in model rumens.
      Eight dual flow continuous culture fermenters were operated with either standard
      artificial saliva buffer or buffer with chondroitin sulfate (0.5 g/l) added.
      After 168 h of operation, fermenters were inoculated with Bacteroides
      thetaiotaomicron BTX (BTX), at approximately 1% of total bacteria. B.
      thetaiotaomicron was quantified using a species-specific probe and shown to
      persist in fermenters 144 h after inoculation (relative abundance 0.48% and 1.42%
      of total SSU rRNA with standard and chondroitin sulfate buffers, respectively).
      No B. thetaiotaomicron SSU rRNA was detected in fermenter samples prior to
      inoculation with strain BTX. Relative abundances of Bacteria, Eucarya and Archaea
      were not affected by either inoculation or buffer type. Fiber digestion, in
      particular the hemicellulose fraction, increased after strain BTX addition.
      Chondroitin sulfate addition to the buffer increased bacterial nitrogen flow in
      fermenters, but did not alter fiber digestion. Neither inoculum nor buffer type
      altered total short chain fatty acid (VFA) concentrations but proportions of
      individual VFA differed. In model rumens, B. thetaiotaomicron BTX increased fiber
      digestion when added to mixed ruminal microbes, independent of chondroitin
      sulfate addition; but further study is needed to determine effects on other fiber
      digesting bacteria.

PMID- 12421080
TI  - Analysis of genomic diversity among photosynthetic stem-nodulating rhizobial
      strains from northeast Argentina.
AB  - The genomic diversity among photosynthetic rhizobia from northeast Argentina was
      assessed. Forty six isolates obtained from naturally occurring stem and root
      nodules of Aeschynomene rudis plants were analyzed by three molecular typing
      methods with different levels of taxonomic resolution: repetitive sequence-based
      PCR (rep-PCR) genomic fingerprinting with BOX and REP primers, amplified 16S rDNA
      restriction analysis (ARDRA), and 16S-23S rDNA intergenic spacer-restriction
      fragment length polymorphism (IGS-RFLP) analysis. The in vivo absorption spectra
      of membranes of strains were similar in the near infrared region with peaks at
      870 and 800 nm revealing the presence of light harvesting complex I,
      bacteriochlorophyll-binding polypeptides (LHI-Bchl complex). After extraction
      with acetone-methanol the spectra differed in the visible part displaying peaks
      belonging to canthaxanthin or spirilloxanthin as the main carotenoid complement.
      The genotypic characterization by rep-PCR revealed a high level of genomic
      diversity among the isolates and almost all the photosynthetic ones have
      identical ARDRA patterns and fell into one cluster different from Bradyrhizobium
      japonicum and Bradyrhizobium elkanii. In the combined analysis of ARDRA and rep
      PCR fingerprints, 7 clusters were found including most of the isolates. Five of
      those contained only photosynthetic isolates; all canthaxanthin-containing
      strains grouped in one cluster, most of the other photosynthetic isolates were
      grouped in a second large cluster, while the remaining three clusters contained a
      few strains. The other two clusters comprising reference strains of B. japonicum
      and B. elkanii, respectively. The IGS-RFLP analysis produced similar clustering
      for almost all the strains. The 16S rRNA gene sequence of one representative
      isolate was determined and the DNA sequence analysis confirmed the position of
      photosynthetic rhizobia in a distinct phylogenetic group within the
      Bradyrhizobium rDNA cluster.

PMID- 12421081
TI  - 16S rRNA sequence analysis of bacteria present in foaming activated sludge.
AB  - The formation of a stable viscous foam on activated sludge aeration basin
      surfaces is a world wide problem. Foam is usually comprised of filamentous
      bacteria occurring predominantly in the mixed liquor. The lack of availability of
      pure cultures of most filaments and the limited amount of characterisation data
      available for them, means that our current understanding of their taxonomic
      position is very poor and their relationship to other bacteria are not known. 16S
      rDNA sequencing was used in an attempt to identify the bacteria in a foaming
      sample from the Centurion Waste Water Treatment Plant in Gauteng South Africa.

PMID- 12421082
TI  - Characterization of pigmented methylotrophic bacteria which nodulate Lotononis
      bainesii.
AB  - Root nodule isolates from a shrubby legume, Lotononis bainesii, were
      characterized by 16S rRNA gene sequencing and morphologically by substrate
      utilization patterns. The symbiotic genome of these isolates was analysed by
      partial sequencing of the nifH gene. Based on the results of numerical taxonomy,
      the isolates formed a closely related cluster, showing no correspondence to any
      of the known rhizobial clusters. Analysis of nearly full-length 16S rDNA
      sequences demonstrated that these isolates were related to Methylobacterium
      nodulans (SY et al., 2001). In the absence of nifH sequence data for the genus
      Methylobacterium, the nifH phylogeny showed these isolates to be related to
      Azospirillum brasilense. The facultative methylotrophic nature of these isolates
      was also demonstrated by their ability to grow in the presence of methanol as a
      sole carbon source.

PMID- 12421083
TI  - Three novel halotolerant and thermophilic Geobacillus strains from shallow marine
      vents.
AB  - During a polyphasic taxonomic analysis performed on isolates from shallow marine
      hydrothermal vents of Eolian Islands (Italy), three thermophilic, halotolerant
      bacilli, designated as strain 1bw, strain 5-2 and strain 10-1, could not be
      affiliated to any described species. Physiological and biochemical
      characteristics, membrane lipids composition, mol % G+C content, and phylogenetic
      relationships determined on the basis of the 16S rRNA gene sequence analysis,
      placed these strains within the genus Geobacillus. The three strains were only
      moderately related to species of Geobacillus and their relatives, members of
      Saccharococcus. Determination of the relatedness among each other at a higher
      taxonomic level by DNA-DNA reassociation experiments demonstrated the three
      isolates to represent three different novel Geobacillus genomospecies. The
      taxonomic novelty of these three marine strains was substantiated by their
      physiological properties and by fatty acid patterns that did not match closely
      those of any Geobacillus type strain. These three novel strains could be of
      interest to biotechnology because of their ability to produce exopolysaccharides
      and to adhere on polystirene, characteristics undescribed so far for other
      Geobacillus species. They are also able to utilise hydrocarbons such as gas oil,
      kerosene and mineral lubricating oil. Strain 5-2 is tolerant to zinc.

PMID- 12421084
TI  - Amplified fragment length polymorphism (AFLP) analysis of Listeria monocytogenes.
AB  - An agarose gel based single enzyme AFLP method using EcoR1 digestion of Listeria
      monocytogenes DNA was developed for epidemiological typing. The method was
      evaluated with 84 L. monocytogenes cultures, and results were compared with those
      obtained with serotyping, phage-typing and cadmium and arsenic resistance typing.
      The AFLP method was reproducible and 14 different banding patterns comprising
      between five and eight DNA fragments were produced. All except two of the AFLP
      patterns were serorype specific. Different AFLP patterns were recognised within
      serovar 4b (four patterns), 1/2a (two patterns), 1/2b (six patterns): single
      patterns were obtained from cultures of serovars 1/2c, 3a, 3b and 3c. There were
      associations with AFLP results and those from phage-typing and cadmium and
      arsenic resistance typing, although each method showed some independence. This
      preliminary evaluation suggests that this AFLP method will be useful for
      epidemiological typing of L. monocytogenes.

PMID- 12421085
TI  - Acetaldehyde and ethanol are responsible for mitochondrial DNA (mtDNA)
      restriction fragment length polymorphism (RFLP) in flor yeasts.
AB  - Flor yeasts grow and survive in fino sherry wine where the frequency of
      respiratory-deficient (petite) mutants is very low. Mitochondria from flor yeasts
      are highly acetaldehyde- and ethanol-tolerant, and resistant to oxidative stress.
      However, restriction fragment length polymorphism (RFLP) of mtDNA from flor yeast
      populations is very high and reflects variability induced by the high
      concentrations of acetaldehyde and ethanol of sherry wine on mtDNA. mtDNA RFLP
      increases as the concentration of these compounds also increases, but is followed
      by a total loss of mtDNA in petite cells. Yeasts with functional mitochondria
      (grande) are target of continuous variability, so that flor yeast mtDNA can
      evolve extremely rapidly and may serve as a reservoir of genetic diversity,
      whereas petite mutants are eventually eliminated because metabolism in sherry
      wine is oxidative.

PMID- 12421086
TI  - Solid echo in the slow-motion region. Effects of the finite pulse widths.
AB  - The effects of nonzero radio-frequency pulse widths on the echo signals in solids
      with molecular motions have been investigated. It has been shown that in the slow
      motion region a time position and an amplitude of the echo signal depend not only
      on the width of the pulse, but also on the shape of potential wells and the
      correlation time, describing the molecular motion. A comparison of the developed
      theory with experimental results obtained for polycrystalline NH4Cl demonstrates
      a good agreement between them.

PMID- 12421087
TI  - 1H and 13C NMR studies of molecular dynamics in the biocopolymer of glycolide and
      epsilon-caprolactone.
AB  - Copolymers of glycolide and epsilon-caprolactone were studied using differential
      scanning calorimetry and solid-state NMR. The variation of the T1 relaxation time
      with temperature reflects local disorder and can be quantified in terms of the
      distribution of correlation times predicted by the Davidson-Cole model. T,
      relaxation is dominated by trans-gauche isomerisation, with an activation energy
      of 34-35 kJ mol(-1).

PMID- 12421088
TI  - Carbonates, thiocarbonates, and the corresponding monoalkyl derivatives: III. The
      13C chemical shift tensors in potassium carbonate, bicarbonate and related
      monomethyl derivatives.
AB  - The principal values of the 13C chemical shift tensors in potassium carbonate
      (K2CO3), trithiocarbonate (K2CS3), bicarbonate (KHCO3), methylcarbonate
      (KO2COCH3), S-methyl-monothiocarbonate (KO2CSCH3), O-methyl-monothiocarbonate
      (KOSCOCH3), S-methyl-dithiocarbonate (KOSCSCH3), and O-methyl-dithiocarbonate
      (KS2COCH3), were measured in solid-state nuclear magnetic resonance experiments.
      Chemical shift tensor calculations on the corresponding isolated anions were used
      to assign the chemical shift tensor orientations in the molecular frames of all
      anions. The correlation between experimental and calculated principal values
      improves significantly when the calculations are performed on isolated anions
      with proton-optimized X-ray geometries rather than on isolated anions with fully
      optimized geometries. Further considerable improvement in the correlation is
      achieved by utilizing the embedded ion method, which was recently developed to
      include electrostatic crystal potentials in chemical shift tensor calculations on
      ionic compounds. Similarities and differences in the chemical shift tensor
      orientations and principal values of the trigonal sp2 carbon atoms in the
      carbonate and thiocarbonate anions are compared with those known for condensed
      polyaromatic hydrocarbons.

PMID- 12421089
TI  - Determination of T1rhoH relaxation rates in charred and uncharred wood and
      consequences for NMR quantitation.
AB  - The performance of three different techniques for determining proton rotating
      frame relaxation rates (T1rhoH) in charred and uncharred woods is compared. The
      variable contact time (VCT) experiment is shown to over-estimate T1rhoH.
      particularly for the charred samples, due to the presence of slowly cross
      polarizing 13C nuclei. The variable spin (VSL) or delayed contact experiment is
      shown to overcome these problems; however, care is needed in the analysis to
      ensure rapidly relaxing components are not overlooked. T1rhoH is shown to be non
      uniform for both charred and uncharred wood samples; a rapidly relaxing component
      (T1rhoH = 0.46-1.07 ms) and a slowly relaxing component (T1rhoH = 3.58-7.49) is
      detected in each sample. T1rhoH for each component generally decreases with
      heating temperature (degree of charring) and the proportion of rapidly relaxing
      component increases. Direct T1rhoH determination (via 1H detection) shows that
      all samples contain an even faster relaxing component (0.09-0.24 ms) that is
      virtually undetectable by the indirect (VCT and VSL) techniques. A new method for
      correcting for T1rhoH signal losses in spin counting experiments is developed to
      deal with the rapidly relaxing component detected in the VSL experiment.
      Implementation of this correction increased the proportion of potential 13C CPMAS
      NMR signal that can be accounted for by up to 50% for the charred samples. An
      even greater proportion of potential signal can be accounted for if the very
      rapidly relaxing component detected in the direct T1rhoH determination is
      included; however, it must be kept in mind that this experiment also detects 1H
      pools which may not be involved in 1H-13C cross-polarization.

PMID- 12421090
TI  - Impact of remote protonation on 13C CPMAS NMR quantitation of charred and
      uncharred wood.
AB  - The impact of inefficient cross polarization (long TCH values), caused by long
      13C-1H internuclear distances, on 13C CPMAS NMR spectra of charred and uncharred
      woods is determined by simultaneously fitting data from complementary variable
      spin lock and variable contact time experiments. As expected, the impact is
      minimal for uncharred woods, but is very significant for the charred woods.
      Quantification of the decrease in CPMAS signal intensity caused by both
      inefficient cross polarization and rapid T1rhoH relaxation is achieved using an
      advanced spin counting methodology, for which the term "spin accounting" is
      proposed. 13C CPMAS NMR observabilities determined using the spin accounting
      methodology were close to 100% for the uncharred samples, and 69-82% for the
      charred samples. This represents a large improvement on the 30-40%
      observabilities determined using other spin counting techniques. Furthermore, it
      is shown that remote protonation and rapid T1rhoH relaxation are roughly equally
      responsible for the low signal intensity of standard (I ms contact time) 13C
      CPMAS spectra of charcoal.

PMID- 12421091
TI  - The influence of water content on the 23Na and 31P NMR spectral parameters in
      solid Na-DNA.
AB  - 23Na and 31P MAS NMR spectra and spin-lattice relaxation times in a solid sample
      of Na-DNA were measured under very carefully controlled conditions of relative
      ambient humidity. The observed substantial changes of the NMR parameters are
      related to the water-induced transitions between the different molecular
      configurations of DNA, with the transition between A- and B-DNA occurring in the
      30-60% range of relative humidity. Our work demonstrates that the previously
      measured NMR parameters are in error because the relative humidity of the system
      had not been controlled, rendering the results irreproducible.

PMID- 12421092
TI  - Pharmacogenomics of response to anti-tumor necrosis factor therapy in patients
      with Crohn's disease.
AB  - The relatively recent development of genetically engineered agents has the
      potential to alter the treatment of Crohn's disease radically, and drugs that
      inhibit tumor necrosis factor-alpha (TNFalpha) have been introduced as a new
      therapeutic class with high efficacy, rapid onset of action, prolonged effect,
      and improved tolerance. However these agents are expensive and at least one-third
      of the eligible patients fail to show any useful response. Finding a means to
      predict those who will respond, and to anticipate relapse are, therefore, of
      obvious importance. T helper-type 1 (Th1) lymphocytes orchestrate much of the
      inflammation in Crohn's disease mainly via production of TNFalpha, which appears
      to play a pivotal role as a pro-inflammatory cytokine. It exerts its effects
      through its own family of receptors (TNFR1 and TNFR2), the end results of which
      include apoptosis, c-Jun N-terminal kinase/stress-activated protein kinase
      (JNK/SAPK) activation and NF-kappaB activation. Activated NF-kappaB enters the
      nucleus and induces transcription of genes associated with inflammation, host
      defense and cell survival. The promoter region of the TNF gene lies between
      nucleotides -1 and -1300, and encompasses numerous polymorphic sites associated
      with potential binding sites for various transcription factors. Carriers of the
      TNF allele 2 (TNF2), which contains a single base-pair polymorphism at the -308
      promoter position, produce slightly more TNFalpha in their intestinal mucosa than
      non-TNF2 carriers. TNF polymorphisms also appear to influence the nature and
      frequency of extraintestinal manifestations of inflammatory bowel disease (IBD).
      A number of routes of inhibition of TNF are being investigated. Most extensively
      evaluated is the use of monoclonal antibodies against TNFalpha (e.g. infliximab).
      Several large controlled trials indicate that infliximab has a role in treating
      patients with moderate to severely active Crohn's disease and in fistulating
      Crohn's disease. Although it would be useful to genetically differentiate
      'responders' from 'non-responders,' currently there are few published data on TNF
      polymorphisms in IBD, and often only selected polymorphisms are genotyped. Small
      studies have shown possible associations between poor response to infliximab and
      increasing mucosal levels of activated NF-kappaB, homozygosity for the
      polymorphism in exon 6 of TNFR2 (genotype Arg196Arg), positivity for perinuclear
      antineutrophil cytoplasmic antibodies (ANCA), and with the presence of increased
      numbers of activated lamina propia mononuclear cells producing interferon-gamma
      and TNFalpha. This is a rapidly changing field, and more information of greater
      direct clinical benefit can be expected soon.

PMID- 12421093
TI  - Advances in understanding the genetic basis of rheumatoid arthritis and
      osteoarthritis: implications for therapy.
AB  - Rheumatoid arthritis (RA) and osteoarthritis (OA) are polygenic diseases.
      Polymorphisms in candidate genes have been studied for possible association with
      susceptibility to disease development. Aside from HLA polymorphisms, of
      particular interest are those in genes encoding cytokines, signaling molecules,
      and enzymes involved in the production and catabolism of oxygen and nitrogen
      radicals. Cytokines are involved in the modulation of the pathological process
      and have been the target for novel therapeutic interventions. Evidence for their
      involvement in RA and OA has been provided from genetic analyses in patient
      populations as well as from animal models of disease. Intracellular signaling
      cascades control cellular responses and thus regulate many aspects of the
      pathology manifested in rheumatic diseases. Deciphering the organization and
      activity of such signaling pathways in disease is underway. Polymorphisms have
      been identified in gene promoter regions regulating efficient binding of
      transcription factors, and in coding regions of genes whose products are involved
      in signal cascades relevant to RA. Among these are the NF-kappaB pathway, steroid
      receptors and the p53 tumor suppressor gene. Both reactive oxygen species (ROS)
      and reactive nitrogen species (RNS) have also been implicated in rheumatic
      diseases. It is thought that excess, damaging, ROS/RNS may arise from an
      imbalance between the production and removal of these chemical species.
      Polymorphisms in genes that encode enzymes involved in either generating or
      degrading ROS/RNS may contribute to such an imbalance. In the last few years,
      polymorphisms in such genes have indeed been identified as risk factors for
      rheumatic diseases.

PMID- 12421094
TI  - Chromosomally-encoded resistance mechanisms of Pseudomonas aeruginosa:
      therapeutic implications.
AB  - Pseudomonas aeruginosa is an important nosocomial pathogen that presents a
      difficult therapeutic challenge. Although P. aeruginosa has been shown to acquire
      resistance mechanisms encoded on plasmids, this pathogen comes armed with
      multiple chromosomally-encoded mechanisms of resistance that can provide
      impressive intrinsic resistance, as well as the potential to mutate to high-level
      multi-drug resistance. Recent analysis of the sequenced genome of P. aeruginosa
      PAO1 suggested that we have just started to unlock the resistance potential of
      this pathogen. One of the most serious threats to the usefulness of beta-lactams
      against P. aeruginosa is the chromosomal AmpC cephalosporinase. When AmpC
      production increases through mutational events, overproduction of this
      cephalosporinase provides high-level resistance to all beta-lactams except the
      carbapenems. Carbapenem resistance typically requires down-regulation of the
      outer membrane protein (OprD), which serves as the primary route of entry for
      carbapenems. Perhaps the most threatening of the resistance mechanisms encoded on
      the P. aeruginosa chromosome are the multi-drug efflux pumps. These pumps have
      the ability to extrude multiple classes of antibiotics from the periplasmic
      space, as well as the cytoplasm. Natural expression of efflux pumps in 'wild
      type' cells plays an important role in the relatively decreased susceptibility of
      P. aeruginosa to antibiotics. However, the greatest therapeutic problems occur
      when these pumps are overproduced in mutants and high-level, multi-drug
      resistance develops. Although the development of infections with highly resistant
      strains of P. aeruginosa can present serious therapeutic challenges, the most
      troublesome threat associated with the chromosomally-encoded resistance
      mechanisms is the potential for high-level resistance to emerge during the course
      of therapy. When resistance emerges during therapy, clinical failure can occur
      and the therapeutic options for second-line therapy can become severely limited.
      Unfortunately, the emergence of resistance during therapy is not a rare event
      with P. aeruginosa and these three resistance mechanisms. Therefore, clinicians
      must be mindful of this threat when choosing an appropriate therapy, and usually
      appropriate therapy includes a combination of drugs. Since the standard
      combination of an aminoglycoside and a beta-lactam has been shown to be
      ineffective in preventing the emergence of some resistance problems, the search
      for more effective combinations must be a priority.

PMID- 12421095
TI  - Gene therapy approaches to HIV infection.
AB  - The HIV pandemic represents a new challenge to biomedical research. What began as
      a handful of recognized cases among homosexual men in the US has become a global
      pandemic of such proportions that it clearly ranks as one of the most destructive
      viral scourges in history. In the past few years new treatments and drugs have
      been developed and tested, but the development of a new generation of therapies
      remains a major priority, because of the lack of chemotherapeutic drugs or
      vaccines that show long-term efficacy in vivo. Recently, gene therapeutic
      strategies for the treatment of patients with HIV infection have received
      increased attention because they are able to offer the possibility of
      simultaneously targeting multiple sites in the HIV genome, thereby minimizing the
      production of resistant virus. Recombinant genes for gene therapy can be
      classified as expressing interfering proteins (intracellular antibodies, dominant
      negative proteins) or interfering RNAs (antisense RNAs, ribozymes, RNA decoys).
      The latter group offers the advantage of avoiding the stimulation of host immune
      response which might progressively decrease the efficacy of proteins. The
      stumbling block to achieving lasting antiviral effects is still represented by
      the lack of efficient gene transfer techniques capable of generating persistent
      transgene expression and a high number of transduced cells relative to
      untransduced cells. Novel delivery vectors, such as lentiviruses, might overcome
      some of these shortcomings. The use of recombinant genes to generate immunity is
      a very promising concept that is rapidly expanding. Since the immune system can
      significantly amplify the response to tiny amounts of antigen, DNA vaccines can
      indeed be delivered by exploiting traditional gene therapy approaches without the
      need of high transduction efficiency.

PMID- 12421096
TI  - DNA testing for familial hypercholesterolemia: improving disease recognition and
      patient care.
AB  - Cardiovascular disease is the leading cause of death worldwide and, like most
      chronic diseases, it has major genetic and environmental components. Among
      patients with coronary heart disease onset before the age of 55, about 5% of
      cases are attributable to heterozygous familial hypercholesterolemia (FH), a
      disease following autosomal dominant inheritance. About 50% of individuals with
      FH die before the age of 60 due to myocardial infarction. The frequency of FH is
      estimated to be 1 : 500. FH is related to mutations in the low-density
      lipoprotein (LDL)-cholesterol LDL-receptor gene and apolipoprotein B (apoB) gene.
      The identification of individuals with FH has been based on lipid levels and
      segregation of lipid levels within the family. However, phenotypes are
      overlapping and family history is not always informative. Therefore, a DNA-based
      genetic test for FH appears to offer the best alternative. The DNA test gives a
      simple yes/no answer. The FH test is a definitive tool for the identification of
      affected family members. The approach of targeted family genetic screening to
      find new patients is faster and more reliable compared with a biochemical form of
      screening. Early identification and efficient treatment of such patients is
      important and highly cost effective. There is evidence to suggest that the nature
      of the LDL-receptor (LDLR) mutation influences the degree of cholesterol lowering
      achieved by HMG-CoA reductase inhibitors (statins). The observed differences in
      the LDL-cholesterol (LDL-C) responses to these drugs among the various LDLR gene
      mutations are not yet completely understood. The relationships shown between LDLR
      mutation types and lipid levels, and the response of lipid levels to HMG-CoA
      reductase inhibitor treatment, will have to be investigated within the framework
      of pharmacogenetic studies. The variables, which are important in determining the
      overall atherosclerosis risk, are the result of combined activity in a dynamic
      network of numerous genes and environment. Candidate genes for atherosclerosis
      need to be further tested and validated. Future research should be directed at
      determining the significance of such targets, which patients with FH are at
      particularly high risk of premature cardiovascular disease, and which
      environmental factors are effective in modulating this risk. Genetics-based
      diagnostics will complement identification of FH while improving cardiovascular
      risk prediction, prevention of disease and treatment efficacy.

PMID- 12421097
TI  - Deductive genomics: a functional approach to identify innovative drug targets in
      the post-genome era.
AB  - The sequencing of the human genome has generated a drug discovery process that is
      based on sequence analysis and hypothesis-driven (inductive) prediction of gene
      function. This approach, which we term inductive genomics, is currently
      dominating the efforts of the pharmaceutical industry to identify new drug
      targets. According to recent studies, this sequence-driven discovery process is
      paradoxically increasing the average cost of drug development, thus falling short
      of the promise of the Human Genome Project to simplify the creation of much
      needed novel therapeutics. In the early stages of discovery, the flurry of new
      gene sequences makes it difficult to pick and prioritize the most promising
      product candidates for product development, as with existing technologies
      important decisions have to be based on circumstantial evidence that does not
      strongly predict therapeutic potential. This is because the physiological
      function of a potential target cannot be predicted by gene sequence analysis and
      in vitro technologies alone. In contrast, deductive genomics, or large-scale
      forward genetics, bridges the gap between sequence and function by providing a
      function-driven in vivo screen of a highly orthologous mammalian model genome for
      medically relevant physiological functions and drug targets. This approach allows
      drug discovery to move beyond the focus on sequence-driven identification of new
      members of classical drug-able protein families towards the biology-driven
      identification of innovative targets and biological pathways.

PMID- 12421098
TI  - Emerging ethical issues in pharmacogenomics: from research to clinical practice.
AB  - Pharmacogenomics holds much promise for the application of genetic information to
      the improvement of clinical care. Ethical issues for pharmacogenomics arise at
      the intersection of the spheres of drug development and genetic testing. Clinical
      drug trial designs which use subject selection based on genotype must consider
      the features of scientific validity, social value and risk-benefit ratio, and
      later, the impact of this strategy on post-market studies and clinical use of
      drugs. Although the testing context for pharmacogenomic tests is different from
      other genetic tests, decisions to use any new clinical tests in medical practice
      will require evaluation of not only the benefit linked to improved drug use but
      also the risks arising in part from the scale of testing, predictive value and
      collateral potential of the genetic test. Integration of pharmacogenomic
      information into clinical practice will require clinical trials to assess their
      clinical usefulness, including the impact of tests on therapeutic outcomes.
      Trials will also be needed to demonstrate the effectiveness of education,
      informed consent and counseling.

PMID- 12421099
TI  - Influenza vaccinations: who needs them and when?
AB  - Influenza vaccination programmes should aim at reducing the burden from influenza
      among those who need it most. The primary aim of this literature review is to
      identify who should receive priority in influenza vaccination programmes. Risk
      factors for severe post-influenza complications include immune-related factors,
      such as ageing or the presence of immune-suppression, respiratory tract disease,
      proneness to exacerbation of concomitant high-risk disease, potential adverse
      effects associated with long-term drug use or residence in closed communities
      with high transmission rate. When given annually in autumn, inactivated trivalent
      influenza vaccines can reduce severe complications from influenza among persons
      aged 65 years or older by 30-60%. Among children aged less than 7 years, notably
      those with asthma, the occurrence of otitis media or acute respiratory disease is
      reduced by 20-75% with vaccination. In addition, vaccination of residents of long
      term care facilities and their personnel leads to a 42% reduction in mortality
      among patients. However, uncertainty remains about whether influenza vaccination
      can reduce complications from influenza among the large group of older children
      and persons of working-age with high-risk disease. To further increase the impact
      of prevention strategies, the development and application of clinical prediction
      rules to estimate absolute risks of post-influenza complications should be
      studied in relation to optimal vaccine delivery strategies. Furthermore,
      adequately powered studies should be conducted to demonstrate possible
      effectiveness of vaccination in reducing post-influenza complications among older
      children and working-age adults.

PMID- 12421100
TI  - Statins and menopause.
AB  - During the reproductive period, women generally have lower low-density
      lipoprotein (LDL) cholesterol and higher high-density lipoprotein cholesterol
      than age- and diet-matched men. However, these possibly antiatherogenic
      characteristics of lipoproteins are changed to a potentially atherogenic profile
      after menopause. Menopause-related changes in lipoprotein profile can be
      corrected by the administration of hormone replacement therapy (HRT). However,
      the results of recent studies did not show definite benefits of HRT on coronary
      heart disease-related mortality rates. On the other hand, several large-scale,
      long-term clinical trials provide evidence for efficacy and safety of HMG-CoA
      reductase inhibitors (statins) in both men and women. The results of 19 short
      term clinical trials using simvastatin, pravastatin, fluvastatin or lovastatin in
      postmenopausal women are summarised and discussed. All these investigations
      reported significant reductions in both total and LDL cholesterol levels. The
      question of whether statin therapy results in a significant decrease in
      cardiovascular-related mortality rates along with a better quality of life in
      postmenopausal women remains to be investigated in large-scale, randomised,
      double-blind, placebo-controlled clinical trials.

PMID- 12421101
TI  - Chronic fatigue syndrome: probable pathogenesis and possible treatments.
AB  - Chronic fatigue syndrome (CFS) belongs in the medically unexplained illnesses. It
      affects approximately 0.2-0.7% of the population in Western countries. It is
      characterised by unexplained fatigue, lasting 6 months or more, impairment of
      neurocognitive functions and quality of sleep, and of somatic symptoms, such as
      recurrent sore throat, muscle aches, arthralgias, headache and postexertional
      malaise. No link between infections and CFS has been clearly established but the
      immune system is activated, there are aberrations in several hypothalamic
      pituitary axes and involvement of other parts of the central nervous system. No
      specific treatment has been found. Cognitive behavioural therapy is established
      to be of value to improve quality of life. More effective treatment should
      result, as advances in biomedical as well as psychological research continue.

PMID- 12421102
TI  - Diagnosis and management of psoriatic arthritis.
AB  - Psoriatic arthritis (PsA) is considered to be one of the spondyloarthritides, and
      as such has both spinal and peripheral joint involvement. In 80% of patients,
      psoriasis usually precedes the development of arthritis. Although there are no
      widely accepted diagnostic criteria, a number of distinct clinical features allow
      it to be distinguished from other forms of inflammatory arthritis. It affects
      both sexes equally, and the pattern of joint involvement is characteristic with
      distal interphalangeal joint involvement, asymmetry, dactylitis, flail or
      ankylotic deformities of digits, and the frequent presence of enthesitis and
      spinal involvement. It may have a pattern of joint involvement similar to
      rheumatoid arthritis (RA) but in these patients rheumatoid factor and the other
      systemic features of RA are usually absent. Radiographs frequently reveal
      evidence of asymmetric sacroiliitis and spinal disease, and peripheral joints, as
      well as showing erosions, may also demonstrate profuse new bone formation and
      ankylosis. Profound osteolysis producing the pencil-in-cup deformity can also
      occur in the same individual. It is now recognised that PsA can be a destructive
      arthritis with an increased morbidity and mortality. Studies of standard disease
      modifying therapies have been small and frequently inconclusive because of a high
      placebo response rate. This may be as a result of heterogeneity in patient
      selection, poor assessment tools, or the difference in underlying pathogenesis
      and subsequent response to therapy. In meta-analyses, sulfasalazine and
      methotrexate have been shown to be effective. Treating the skin alone seems to
      have little impact on joint disease, and the relationship between skin and joints
      is still unclear. However, recent studies with anti-tumour necrosis factor
      agents, such as etanercept and infliximab, have shown considerable significant
      clinical benefit and provided the hope that we will at last have effective
      therapies for this disease.

PMID- 12421103
TI  - Options for early therapeutic abortion: a comparative review.
AB  - Vacuum aspiration, either manual or electric, has for many years been the most
      commonly used method for termination of an early pregnancy. More recently, new
      medical methods have been developed which for many women are attractive
      alternatives to the surgical procedure. The compounds mainly used are
      prostaglandin analogues, methotrexate, and mifepristone in combination with a
      suitable prostaglandin analogue. However, only the last method has been
      registered for routine clinical use. The treatment schedule mainly used is
      mifepristone 200 to 600 mg followed 36 to 48 hours later by oral misoprostol 0.4
      to 0.6 mg in pregnancies up to 49 days and vaginal gemeprost 1.0mg or misoprostol
      0.8 mg if the treatment period is extended to 63 days of amenorrhoea. The ability
      to compare medical and surgical methods is limited by the fact that there are few
      randomised studies and the definitions of successful outcome (complete abortion),
      adverse effects and complications vary from one study to the other. Experience
      with the method used is also important for the outcome. However, it seems
      adequate to state that the medical method is equally, or almost equally, as
      effective as vacuum aspiration. Duration of bleeding and amount of blood loss is
      greater following medical abortion. Also the frequency of uterine pain, vomiting
      and diarrhoea is higher following medical abortion than following vacuum
      aspiration. On the other hand, the frequency of major complications such as
      excessive bleeding, blood transfusion and pelvic infection does not seem to
      differ between the two procedures. Surgical complications, for example, uterine
      perforation and cervical tears, are obviously not a risk associated with medical
      abortion. Both methods are equally well accepted provided the woman is allowed to
      choose. It is not possible to state which method is best. Medical termination of
      early pregnancy will not replace, but is an alternative to, vacuum aspiration and
      ideally both methods should be available to give the woman a choice.

PMID- 12421104
TI  - Bicalutamide: in early-stage prostate cancer.
AB  - Bicalutamide is an oral, once-daily nonsteroidal antiandrogen. Its efficacy in
      localised or locally advanced prostate cancer is currently being investigated as
      part of the Early Prostate Cancer (EPC) programme. In the EPC programme,
      bicalutamide 150 mg/day, as an adjunct to radiotherapy, radical prostatectomy or
      watchful waiting, significantly reduced the risk of objective disease
      progression, the incidence of bone metastases and the risk of prostate specific
      antigen progression compared with placebo (p < 0.0001 for all three parameters)
      after a median follow-up of 3 years. Survival data are currently immature, with
      an overall mortality rate of 6% in both treatment arms. On two nonblind,
      randomised trials, bicalutamide 150 mg/day monotherapy was as effective as
      medical or surgical castration in terms of overall survival in patients with
      locally advanced nonmetastatic prostate cancer. After a median follow-up of 6.3
      years, median survival was 63.5 and 69.9 months for bicalutamide and castration,
      respectively; time to disease progression was also similar between treatment
      groups. Bicalutamide recipients reported a significantly smaller loss in sexual
      interest and a better physical capacity than recipients of castration (p <or=
      0.05 for both parameters). Bicalutamide is well tolerated in studies of up to 6.3
      years' duration.

PMID- 12421108
TI  - Anastrozole: in early breast cancer.
AB  - Anastrozole, a nonsteroidal selective aromatase inhibitor, has recently been
      approved in the US and several other countries for the adjuvant treatment of
      postmenopausal women with hormone receptor-positive early breast cancer. In the
      Arimidex, Tamoxifen alone or in Combination (ATAC) trial, anastrazole 1mg was
      significantly more effective than tamoxifen 20mg or combined treatment (17 and
      19% relative risk reduction) for disease-free survival in postmenopausal women
      with early breast cancer. black triangle Anastrazole was also significantly more
      effective than tamoxifen for time to tumour recurrence and the odds of a primary
      contralateral tumour as a first event. During the first 2 years of treatment with
      anastrozole, tamoxifen or the combination, patient quality of life was similar in
      all treatment groups. Compared with tamoxifen, anastrozole was associated with a
      significantly lower incidence of vaginal bleeding, vaginal discharge, hot
      flushes, endometrial cancer, ischaemic cerebrovascular events, venous
      thromboembolic events and deep vein thrombosis including pulmonary embolism;
      tamoxifen was associated with a lower incidence of musculoskeletal disorders and
      fracture.

PMID- 12421111
TI  - Etanercept: an updated review of its use in rheumatoid arthritis, psoriatic
      arthritis and juvenile rheumatoid arthritis.
AB  - Etanercept is a subcutaneously administered biological response modifier that
      binds and inactivates tumour necrosis factor-alpha, a proinflammatory cytokine.
      In patients with early active rheumatoid arthritis, etanercept 25mg twice weekly
      was associated with a more rapid improvement in disease activity and a
      significantly greater cumulative response than methotrexate over 12 months of
      treatment in a randomised, double-blind trial. In addition, etanercept recipients
      showed a slower rate of radiographic progression and a more rapid improvement in
      quality of life than methotrexate recipients. The efficacy of etanercept was
      maintained at 3 years' follow-up. Etanercept was also significantly better than
      placebo at reducing disease activity in patients who had an inadequate response
      to previous treatment with disease-modifying antirheumatic drugs (DMARDs) in
      several well controlled trials. At study end (after 3 or 6 months' treatment),
      the percentage of patients achieving an American College of Rheumatology 20%
      (ACR20) response with etanercept (25mg or 16 mg/m(2) twice weekly) was 59 to 75%
      as monotherapy and 71% in combination with methotrexate; corresponding placebo
      response rates were 11 to 14% and 27%, respectively. Response has been maintained
      in patients who continued treatment for up to 5 years. In patients with psoriatic
      arthritis, etanercept 25mg twice weekly significantly reduced disease activity
      and improved skin lesions in two double-blind, placebo-controlled, 12- to 24-week
      trials. In the 24-week study, ACR20 response rates (50 vs 13%), psoriatic
      arthritis response rates (70 vs 23%) and the median improvement in skin lesions
      (33 vs 0%) were significantly greater in etanercept than in placebo recipients.
      In patients with polyarticular-course juvenile rheumatoid arthritis, etanercept
      resulted in improvements in all measures of disease activity and was
      significantly more effective than placebo at reducing disease flare. Eighty
      percent of patients receiving etanercept achieved a >or=30% reduction in disease
      activity over 7 months of treatment, and this was maintained for up to 2 years in
      a trial extension. Etanercept was generally well tolerated in children and adults
      in clinical trials; the most commonly occurring adverse effects included
      injection site reactions, infection, headache, rhinitis and dizziness. In
      conclusion, etanercept has emerged as an important new treatment option in
      inflammatory arthritis. Etanercept provides rapid and sustained improvements in
      disease activity in patients with early and DMARD-refractory rheumatoid arthritis
      and has been shown to inhibit radiographic progression in those with early
      disease. Well controlled studies have also demonstrated the efficacy of
      etanercept in patients with psoriatic arthritis or polyarticular-course juvenile
      rheumatoid arthritis.

PMID- 12421112
TI  - Fixed combination trandolapril/verapamil sustained-release: a review of its use
      in essential hypertension.
AB  - In well designed studies in patients with mild to moderate hypertension,
      combinations of the sustained-release (SR) formulation of the nondihydropyridine
      calcium channel antagonist verapamil 120 to 240 mg/day and the ACE inhibitor
      trandolapril 0.5 to 8 mg/day were significantly more effective in reducing
      sitting systolic blood pressure (SBP) and diastolic blood pressure (DBP) from
      baseline than placebo. In most randomised studies, combinations of verapamil SR
      120 to 240 mg/day and trandolapril 0.5 to 8 mg/day were significantly more
      effective in lowering sitting DBP and SBP than the corresponding monotherapies
      administered at the same dosage. Trandolapril/verapamil SR 2/180 mg/day provided
      significantly more effective 24-hour ambulatory blood pressure (BP) control than
      of the corresponding monotherapies. Moreover, trandolapril/verapamil SR reduced
      BP in patients inadequately controlled with either of the corresponding
      monotherapies. The antihypertensive efficacy of trandolapril/verapamil SR 2/180
      mg/day was generally similar to that of other combinations of antihypertensive
      agents (metoprolol/hydrochlorothiazide, atenolol/chlorthalidone,
      lisinopril/hydrochlorothiazide, enalapril/hydrochlorothiazide) in patients with
      hypertension, including those with type 2 diabetes mellitus.
      Trandolapril/verapamil SR reduced BP in patients with hypertension and type 2
      diabetes or primary renal disease, Black patients and elderly patients.
      Trandolapril/verapamil SR was more effective than the individual components
      administered as monotherapy in reducing proteinuria in patients with type 2
      diabetes or primary renal disease. Trandolapril/verapamil SR had a neutral or
      beneficial effect on metabolic parameters (glucose, insulin, lipids) in patients
      with hypertension, including those with type 2 diabetes. Trandolapril/verapamil
      SR preserved left ventricular function in patients with heart failure. Fewer
      cardiac events occurred after therapy with trandolapril/verapamil SR than after
      trandolapril alone in post-myocardial infarction patients with congestive heart
      failure. The incidence of adverse events in recipients of trandolapril/verapamil
      SR was similar to that of the individual components, and that of other
      combination therapies. In placebo-controlled trials conducted in the US,
      headache, upper respiratory tract infections, cough, constipation,
      atrioventricular block (first degree) and dizziness were the most commonly
      reported adverse events in recipients of combinations of verapamil SR (120 to 240
      mg/day) and trandolapril (0.5 to 8 mg/day). In conclusion, the fixed-dose
      combination of trandolapril/verapamil SR is an effective treatment for patients
      with hypertension, including those with type 2 diabetes. Trandolapril/verapamil
      SR tended to be more effective than monotherapy with either verapamil SR or
      trandolapril, and generally showed antihypertensive efficacy similar to that of
      other combination antihypertensive therapies. Current data support the use of
      trandolapril/verapamil SR as an alternative treatment when monotherapy with
      either agent is not effective. Data from large clinical trials currently being
      conducted will assist in fully defining the role of trandolapril/verapamil SR as
      a cardio- and renoprotective agent.

PMID- 12421113
TI  - Antibacterial therapy of neurosyphilis: lack of impact of new therapies.
AB  - Neurosyphilis is caused by the spirochete Treponema pallidum. These organisms
      divide slowly, requiring long exposure to antibacterials for treatment success.
      In order for an antibacterial to be effective in the therapy of neurosyphilis, it
      must achieve treponemicidal concentrations in the CSF, have a long half-life and
      be given in a treatment regimen that favours compliance. Penicillin was first
      introduced for the treatment of syphilis in 1943, and despite interest in the use
      of amoxicillin, erythromycin, tetracycline, doxycycline, ceftriaxone and
      azithromycin, penicillin remains the only recommended antibacterial agent for
      neurosyphilis.

PMID- 12421114
TI  - Parasomnias: epidemiology and management.
AB  - The category of common sleep disorders known as parasomnias includes disorders of
      arousal, rapid eye movement (REM) sleep behaviour disorder (RBD), nocturnal
      seizures, rhythmic movement disorder, and tooth grinding or 'bruxism'.
      Parasomnias are all characterised as undesirable physical or behavioural
      phenomena occurring during the sleep period. Although these conditions can be
      distressing and, in some cases, hazardous to the sleeper and his or her bed
      partner, it is important to recognise that parasomnias are diagnosable and
      treatable in the vast majority of patients. Evaluation begins with a careful
      clinical interview with the sleeper and a family member to elucidate the
      frequency, duration, description and timing after sleep onset of these
      behavioural events. Disorders of arousal are the most common type of parasomnia
      and cover a spectrum from calm sleepwalking to emotionally agitated or complex
      behaviours, such as dressing or driving, for which the patient usually has no
      memory upon awaking. 'Sleep terrors' are quite common in young children and are
      often outgrown. Disorders of arousal represent a partial, as opposed to a full,
      awakening from deep non-REM sleep, typically occurring within the first 60 to 90
      minutes after sleep onset. RBD is characterised clinically by a history of dream
      enacting behaviour, and the patient may recall dream content. REM sleep periods
      typically occur in the latter half of the night. Physiologically, RBD results
      from a lack of the normal muscle atonia that is associated with REM sleep. RBD
      has been linked to a number of other neurological conditions; thus, a careful
      review of systems and a physical examination are crucial. A formal laboratory
      sleep study or polysomnogram with an expanded electroencephalographic montage can
      help distinguish among non-REM and REM parasomnias and nocturnal seizures. The
      latter may manifest clinically as arousals from sleep associated with
      vocalisation and/or complex behaviours. Rhythmic movement disorder can include
      head banging or body rocking at sleep onset or during the night. Tooth grinding
      is a common sleep-related behaviour that, when severe, can result in dental
      injury. Hypnagogic hallucinations (experience of dream imagery at sleep onset)
      and sleep-onset paralysis (experience of muscle/body paralysis as one is falling
      asleep) are symptoms rather than diagnostic categories. These phenomena
      classically occur in many individuals with narcolepsy, but also may occur in
      healthy sleep-deprived individuals. Safety precautions and good general sleep
      hygiene measures are recommended for individuals with a parasomnia, as the
      disorder can be exacerbated by sleep deprivation and various other factors. When
      the events are frequent or particularly dramatic, medication with a long- or
      medium-acting benzodiazepine, such as clonazepam, at bedtime is effective therapy
      in most cases of non-REM disorders of arousal and RBD. A dental guard may be
      helpful in tooth grinders. Relaxation training and guided imagery may be helpful
      strategies for some patients, especially those with disorders of arousal or
      rhythm movement disorders. There is no evidence of any association between
      parasomnias and psychiatric illness. Demystification of these conditions and
      reassurance, particularly for parents of paediatric patients, is an important
      aspect of clinical intervention.

PMID- 12421118
TI  - Quantum-dot nanocrystals for ultrasensitive biological labeling and multicolor
      optical encoding.
AB  - Semiconductor nanoparticles in the size range of 2-6 nm are of great current
      interest, not only because of their size-tunable properties but also because of
      their dimensional similarity with biological macromolecules (e.g., nucleic acids
      and proteins). This similarity could allow an integration of nanomaterials with
      biological molecules, which would have applications in medical diagnostics,
      targeted therapeutics, and high-throughput drug screening. Here we report new
      developments in preparing highly luminescent and biocompatible CdSe quantum dots
      (QDs), and in synthesizing QD-encoded micro- and nano-beads in the size range of
      100 nm-10 microm. We show that the optical properties of ZnS-capped CdSe quantum
      dots are sensitive to environmental factors such as pH and divalent cations,
      leading to the potential use of quantum dots in molecular sensing. We also show
      that chemically modified proteins can be used to coat the surface of water
      soluble QDs, to restore their fluorescence, and to provide functional groups for
      bioconjugation. For multiplexed optical encoding, we have prepared large
      microbeads with sizes similar to that of mammalian cells, and small nanobeads
      with sizes similar to that of viruses.

PMID- 12421115
TI  - Non-cholinergic strategies for treating and preventing Alzheimer's disease.
AB  - The pathophysiology of Alzheimer's disease is complex and involves several
      different biochemical pathways. These include defective beta-amyloid (Abeta)
      protein metabolism, abnormalities of glutamatergic, adrenergic, serotonergic and
      dopaminergic neurotransmission, and the potential involvement of inflammatory,
      oxidative and hormonal pathways. Consequently, these pathways are all potential
      targets for Alzheimer's disease treatment and prevention strategies. Currently,
      the mainstay treatments for Alzheimer's disease are the cholinesterase
      inhibitors, which increase the availability of acetylcholine at cholinergic
      synapses. Since the cholinesterase inhibitors confer only modest benefits,
      additional non-cholinergic Alzheimer's disease therapies are urgently needed.
      Several non-cholinergic agents are currently under development for the treatment
      and/or prevention of Alzheimer's disease. These include anti-amyloid strategies
      (e.g. immunisation, aggregation inhibitors, secretase inhibitors), transition
      metal chelators (e.g. clioquinol), growth factors, hormones (e.g. estradiol),
      herbs (e.g. Ginkgo biloba), nonsteroidal anti-inflammatory drugs (NSAIDs, e.g.
      indomethacin), antioxidants, lipid-lowering agents, antihypertensives, selective
      phosphodiesterase inhibitors, vitamins (E, B12, B6, folic acid) and agents that
      target neurotransmitter or neuropeptide alterations. Neurotransmitter receptor
      based approaches include agents that modulate certain receptors (e.g. nicotinic,
      muscarinic, alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid [AMPA],
      gamma-aminobutyric acid [GABA], N-methyl-D-aspartate [NMDA]) and agents that
      increase the availability of neurotransmitters (e.g. noradrenergic reuptake
      inhibitors). Of these strategies, the NMDA receptor antagonist memantine is in
      the most advanced stage of development in the US and is already approved in
      Europe as the first treatment for moderately severe to severe Alzheimer's
      disease. Memantine is proposed to counteract cellular damage due to pathological
      activation of NMDA receptors by glutamate. Results with Ginkgo biloba have been
      mixed. Data for neurotrophic therapies and vitamin E (tocopherol) appear
      promising but require confirmation. NSAIDs and conjugated estrogens have not
      proven to be of value to date for the treatment of Alzheimer's disease. Statins
      may have a potential role in reducing the risk or delaying the onset of
      Alzheimer's disease, although this has yet to be confirmed in randomised trials.
      There are currently no data to support the use of statins as a treatment for
      dementia. This article provides an update on the current status of selected
      agents, focusing primarily on those agents with the most extensive clinical
      evidence at present.

PMID- 12421116
TI  - Glatiramer acetate: a review of its use in relapsing-remitting multiple
      sclerosis.
AB  - Glatiramer acetate is a synthetic copolymer composed of a random mixture of four
      amino acids that modifies the immune response that results in the CNS
      inflammation, demyelination and axonal loss characteristic of relapsing-remitting
      multiple sclerosis (RRMS). In three randomised, double-blind trials in patients
      with RRMS, subcutaneous glatiramer acetate 20 mg/day was significantly more
      effective than placebo for the primary outcome measure of each trial (mean
      relapse rate, proportion of relapse-free patients and number of gadolinium
      enhancing lesions on magnetic resonance imaging [MRI] scans). The mean relapse
      rate was significantly reduced at endpoint (approximately one-third less) in the
      two larger trials (the US pivotal trial [primary endpoint] and the
      European/Canadian study [tertiary endpoint]) in patients receiving glatiramer
      acetate compared with those receiving placebo. The rate was 78% less for
      glatiramer acetate than placebo patients in the pilot trial that investigated a
      slightly different patient population. Glatiramer acetate significantly decreased
      disease activity and burden of disease, as assessed in the European/Canadian
      study using a range of MRI measures. Patients with RRMS treated with glatiramer
      acetate in the US trial were significantly more likely to experience improved
      disability (whereas placebo recipients were more likely to experience worsening
      disability) and their overall disability status was significantly improved
      compared with placebo recipients. Data from the active-treatment extension of the
      US trial suggest that glatiramer acetate has sustained clinical benefits up to 8
      years. Glatiramer acetate was generally well tolerated; the most commonly
      reported treatment-related adverse events were localised injection-site reactions
      and transient post-injection systemic reactions. Both reactions were generally
      mild and self limiting but were responsible for the majority of withdrawals from
      treatment (up to 6.5 and 3.5%, respectively). Glatiramer acetate is not
      associated with the influenza-like syndrome or neutralising antibodies that are
      reported in patients treated with interferon-beta for RRMS. The cost
      effectiveness of glatiramer acetate has yet to be definitively determined as
      assessment of available data is confounded by very different models, data sources
      and assumptions. CONCLUSION: Glatiramer acetate has shown efficacy in well
      controlled clinical trials in patients with RRMS; it reduces relapse rate and
      decreases MRI-assessed disease activity and burden. It is generally well
      tolerated and is not associated with the influenza-like symptoms and formation of
      neutralising antibodies seen with the interferons-beta. Based on available data
      and current management guidelines, glatiramer acetate is a valuable first-line
      treatment option for patients with RRMS.

PMID- 12421119
TI  - Charge transfer fluorescent probes using boronic acids for monosaccharide
      signaling.
AB  - We have developed a new series of glucose sensitive fluorophores that display
      shifts in emission wavelengths and/or intensity change upon the binding of
      monosaccharides. Complexation of glucose with the boronic acid moiety changes
      both its orbital hybridization and its ability to accept and donate electrons.
      This change results in distinct emission spectra for the fluorophores when free
      in solution or complexed with monosaccharide. The spectral changes upon
      saccharide binding can be modified by substitution of electron donor or acceptor
      group on the fluorophore allowing rational design of the spectral response.

PMID- 12421120
TI  - Biocompatible semiconductor optoelectronics.
AB  - We investigate optoelectronic properties of integrated structures comprising
      semiconductor light-emitting materials for optical probes of microscopic
      biological systems. Compound semiconductors are nearly ideal light emitters for
      probing cells and other microorganisms because of their spectral match to the
      transparency wavelengths of biomolecules. Unfortunately, the chemical composition
      of these materials is incompatible with the biochemistry of cells and related
      biofluids. To overcome these limitations, we investigate functionalized
      semiconductor surfaces and structures to simultaneously enhance light emission
      and the flow of biological fluids in semiconductor microcavities. We have
      identified several important materials problems associated with the
      semiconductor/biosystem interface. One is the biofluid degradation of
      electroluminescence by ionic diffusion into compound semiconductors. Ions that
      diffuse into the active region of a semiconductor light emitter can create point
      defects that degrade the quantum efficiency of the radiative recombination
      process. In this paper we discuss ways of mitigating these problems using
      materials design and surface chemistry, and suggest future applications for these
      materials.

PMID- 12421121
TI  - Excitation ratiometric fluorescent biosensor for zinc ion at picomolar levels.
AB  - Zinc is a metal ion of increasing significance in several biomedical fields,
      including neuroscience, immunology, reproductive biology, and cancer. Fluorescent
      indicators have added greatly to our understanding of the biology of several
      metal ions, most notably calcium. Despite substantial efforts, only recently have
      zinc indicators been developed which are sufficiently selective for use in the
      complex intra- and extracellular milieus, and which are capable of quantifying
      the free zinc levels with some degree of reliability. However, these indicators
      (such as FuraZin-1 and Newport Green DCF) have only modest sensitivity, and there
      is growing evidence that significantly lower levels of free zinc may be
      biologically relevant in some instances. We have adapted the peerless selectivity
      and sensitivity of a carbonic anhydrase-based indicator system to an excitation
      ratiometric format based on resonance energy transfer: i.e., where the zinc ion
      level is transduced as the ratio of fluorescence intensities excited at two
      different excitation wavelengths, which is preferred for fluorescence microscopy.
      The system exhibits more than a 60% increase in the ratio of intensity excited at
      365 nm to that excited at 546 nm (emission observed at 617 nm). The detection
      limit is about 10 pM in zinc buffered systems, a 10-1000-fold improvement on the
      Fura indicators (which respond to Ca and Mg as well), and a 10 000-fold
      improvement on the recently described FuraZin-1.

PMID- 12421122
TI  - Hyperspectral techniques in analysis of oral dosage forms.
AB  - Pharmaceutical oral dosage forms are used in this paper to test the sensitivity
      and spatial resolution of hyperspectral imaging instruments. The first experiment
      tested the hypothesis that a near-infrared (IR) tunable diode-based remote
      sensing system is capable of monitoring degradation of hard gelatin capsules at a
      relatively long distance (0.5 km). Spectra from the capsules were used to
      differentiate among capsules exposed to an atmosphere containing 150 ppb
      formaldehyde for 0, 2, 4, and 8 h. Robust median-based principal component
      regression with Bayesian inference was employed for outlier detection. The second
      experiment tested the hypothesis that near-IR imaging spectrometry of tablets
      permits the identification and composition of multiple individual tablets to be
      determined simultaneously. A near-IR camera was used to collect thousands of
      spectra simultaneously from a field of blister-packaged tablets. The number of
      tablets that a typical near-IR camera can currently analyze simultaneously was
      estimated to be approximately 1300. The bootstrap error-adjusted single-sample
      technique chemometric-imaging algorithm was used to draw probability-density
      contour plots that revealed tablet composition. The single-capsule analysis
      provides an indication of how far apart the sample and instrumentation can be and
      still maintain adequate signal-to-noise ratio (S/N), while the multiple-tablet
      imaging experiment gives an indication of how many samples can be analyzed
      simultaneously while maintaining an adequate S/N and pixel coverage on each
      sample.

PMID- 12421123
TI  - DNA and protein applications of near-infrared dyes.
AB  - The near-infrared region of the spectrum (650-1100 nm) offers distinct advantages
      over the traditional UV/vis region for spectroscopic measurements. In the past,
      the lack of commercially available equipment capable of working in the near
      infrared limited the utility of near-infrared techniques. However, since the
      advent of photodiodes and semiconductor lasers, much progress has been made in
      the development of near-infrared techniques. This paper discusses the use of near
      infrared dyes used in DNA and protein applications.

PMID- 12421124
TI  - Single live cell imaging for real-time monitoring of resistance mechanism in
      Pseudomonas aeruginosa.
AB  - We have developed and applied single live cell imaging for real-time monitoring
      of resistance kinetics of Pseudomonas aeruginosa. Real-time images of live cells
      in the presence of a particular substrate (EtBr) provided the first direct
      insights of resistance mechanism with both spatial and temporal information and
      showed that the substrate appeared to be accumulated in cytoplasmic space, but
      not periplasmic space. Three mutants of P. aeruginosa, PAO4290 (a wild-type
      expression level of MexAB-OprM), TNP030#1 (nalB-1, MexAB-OprM over expression
      mutant), and TNP076 (DeltaABM, MexAB-OprM deficient mutant), were used to
      investigate the roles of these three membrane proteins (MexAB-OprM) in the
      resistance mechanism. Ethidium bromide (EtBr) was chosen as a fluorescence probe
      for spectroscopic measurement of bulk cell solution and single cell imaging of
      bulk cells. Bulk measurement indicated, among three mutants, that nalB-1
      accumulated the least EtBr and showed the highest resistance to EtBr, whereas
      DeltaABM accumulated the most EtBr and showed the lowest resistance to EtBr. This
      result demonstrated the MexAB-OprM proteins played the roles in resistance
      mechanism by extruding EtBr out of cells. Unlike the bulk measurement, imaging
      and analysis of bulk cells at single cell resolution demonstrated individual cell
      had its distinguished resistance kinetics and offered the direct observation of
      the regulation of influx and efflux of EtBr with both spatial and temporal
      resolution. Unlike fluorescent staining assays, live cell imaging provided the
      real-time kinetic information of transformation of membrane permeability and
      efflux pump machinery of three mutants. This research constitutes the first
      direct imaging of resistance mechanism of live bacterial cells at single cell
      resolution and opens up the new possibility of advancing the understanding of
      bacteria resistance mechanism.

PMID- 12421125
TI  - Reflectance spectroscopy for in vivo detection of cervical precancer.
AB  - Optical technologies, in particular fluorescence spectroscopy, have shown the
      potential to provide improved detection methods for cervical neoplasia that are
      sensitive and cost effective through accurate, objective, instantaneous point-of
      care diagnostic tools. The specific goals of this study were to analyze
      reflectance spectra of normal and neoplastic cervical tissue in vivo and to
      evaluate the data for use in diagnostic algorithm development. Spectroscopic
      measurements were obtained at four distinct source-detector separations from 324
      sites in 161 patients. As the source-detector separation increases, greater
      tissue depth is probed. The average spectra of each diagnostic class differed at
      all source-detector separations, with the greatest differences occurring at the
      smallest source-detector separations. Algorithms, based on principal-component
      analysis and Mahalanobis distance classification, were developed and evaluated
      for all combinations of source-detector separations relative to the gold standard
      of colposcopically directed biopsy. The diagnostic combination of squamous normal
      versus high-grade squamous intraepithelial lesions gave good discrimination with
      a sensitivity of 72% and a specificity of 81%; discrimination of columnar normal
      versus high-grade squamous intraepithelial lesions also was good, with
      sensitivity of 72% and specificity of 83%. Thus, reflectance spectroscopy appears
      promising for in vivo detection of cervical precancer. Strategies that combine
      fluorescence and reflectance spectroscopy may enhance the discrimination
      capabilities.

PMID- 12421126
TI  - Fluorescence spectroscopy for cervical precancer detection: Is there variance
      across the menstrual cycle?
AB  - This study assesses one possible cause of inter-patient variation in fluorescence
      spectroscopy of the cervix: the menstrual cycle. Ten patients with no history of
      an abnormal Pap smear were seen daily throughout 30 consecutive days of their
      cycle. Fluorescence excitation-emission matrices were measured from three
      cervical sites on each patient. Principal component analysis was used to
      determine which spectral regions varied with the day of the cycle. Classification
      was performed to assess the influence of menstrual cycle on precancer diagnosis.
      Variations in the principal component scores and the redox ratio values show that
      the fluorescence emission spectra at 340-380 nm excitation appear to correlate
      with the cell metabolism of the cervical epithelium throughout the menstrual
      cycle; these changes do not affect diagnostic classification. The menstrual cycle
      affects intra-patient variation but does not appear to cause a significant level
      of inter-patient variation. It does not need to be controlled for in optical
      detection strategies based on fluorescence spectroscopy.

PMID- 12421127
TI  - Spectroscopic analysis of the autofluorescence from human bronchus using an
      ultraviolet laser diode.
AB  - A GaN based ultraviolet (UV) laser diode (LD) was used to study the
      autofluorescence (AF) spectrum of the normal and tumor human bronchial tissues
      under ex vivo conditions. The UV LD generates a coherent short wavelength (around
      400 nm) light beam with an intensity of about a few watts. AF spectrum data can
      be obtained without interference by excitation light. A clear blue peak located
      at around 483 nm was observed along with a green peak at around 560 nm in the
      normal tissue. The peak intensities observed were very weak for the tumor
      tissues. The AF imaging and spectrum analysis were performed along with a
      histopathological study. The spatial distribution of the elastin in the bronchial
      tissue affected the intensity of the AF whereas the spectrum shape was not
      affected. Strong AF was observed from regions that include a high density of the
      elastin. Biopsy measurements were performed for ex vivo samples, and depth
      profiling of the elastin was studied along with variations of the AF spectrum. AF
      spectra excited by the UV LD for fluorescence materials including FAD, NADH, and
      elastin were measured. The spectrum shape of the elastin as well as of NADH was
      similar to that of normal bronchial tissues.

PMID- 12421128
TI  - Noninvasive fluorescent study in situ and in real time of glucose effects on the
      pharmacokinetic of calcein.
AB  - This study was undertaken to compare the effect of glucose injection on the
      pharmacokinetic behavior of a soluble dye in normal and tumoral tissues. The
      measurements were done using a noninvasive fluorescent spectroscopy in situ and
      in real time. The experiments were performed on three groups of animals with
      calcein as a soluble pH-insensitive fluorescent dye combined or not with glucose.
      Glucose solution was injected 5 or 30 min before calcein. Fluorescence emission
      intensity was recorded on normal and tumor tissues with an optical multichannel
      analyzer. Calcein concentration was also measured in blood using repetitive blood
      sampling. In the control group (without glucose injection), calcein is rapidly
      cleared from the blood, with a slow tissue clearance. Fluorescence of normal
      tissue was higher than fluorescence measured in tumor tissue. When glucose is
      injected 5 min before calcein, there was a rapid increase of tissue fluorescence
      followed by a plateau remaining during the whole experiment. No difference
      between tumor and normal tissue fluorescence intensity was observed. When glucose
      was injected 30 min before calcein, the plateau phase was reduced to 50 min in
      normal tissue. Tumor tissue fluorescence displays no distinct plateau phase.
      These results clearly showed the effect of glucose injection in situ and in real
      time, by a noninvasive method, on the pharmacokinetic of a soluble dye in a tumor
      tissue compared to a normal tissue. Differences between blood compartment and
      tissues kinetic profiles were also clearly demonstrated.

PMID- 12421129
TI  - Using two discrete frequencies within the middle infrared to quantitatively
      determine glucose in serum.
AB  - Tight glucose monitoring is essential for the reduction of diabetic
      complications. This research investigated the changes of absorption spectra
      observed in serum at three prominent glucose absorption peaks in the middle
      infrared using a demountable liquid, transmission cell. Two frequencies of light
      were used to determine the glucose absorption: one at 1193 cm(-1 ) to determine
      the background water absorption and the other at one of the characteristic peaks
      (1035, 1080, and 1109 cm(-1)). The peak at 1035 cm(-1) was best for quantitative
      determination with a standard of error of 20.6 mg/dl (1.1 mmol/L). While
      interference from other serum constituents could cause problems, urea and albumin
      two constituents known to have close absorption peaks-were determined to have no
      effect on the ability to determine the glucose levels at 1035 cm( -1).

PMID- 12421130
TI  - Imaging caries lesions and lesion progression with polarization sensitive optical
      coherence tomography.
AB  - New diagnostic tools are needed for the characterization of dental caries in the
      early stages of development. If carious lesions are detected early enough, they
      can be arrested without the need for surgical intervention. The objective of this
      study was to demonstrate that polarization sensitive optical coherence tomography
      (PS-OCT) can be used for the imaging of early caries lesions and for the
      monitoring of lesion progression over time. High-resolution polarization resolved
      images were acquired of natural caries lesions and simulated caries lesions of
      varying severity created over time periods of 1 to 14 days. Linearly polarized
      light was incident on the tooth samples and the reflected intensity in both
      orthogonal polarizations was measured. PS-OCT was invaluable for removing the
      confounding influence of surface reflections and native birefringence necessary
      for the enhanced resolution of the surface structure of caries lesions. This
      study demonstrated that PS-OCT is well suited for the imaging of interproximal
      and occlusal caries, early root caries, and for imaging decay under composite
      fillings. Longitudinal measurements of the reflected light intensity in the
      orthogonal polarization state from the area of simulated caries lesions linearly
      correlated with the square root of time of demineralization indicating that PS
      OCT is well suited for monitoring changes in enamel mineralization over time.

PMID- 12421131
TI  - Simultaneous refractive index and thickness measurements of bio tissue by optical
      coherence tomography.
AB  - This paper presents two techniques based on optical coherence tomography, the
      "focus tracking method" and the "optical path shifting method," for determining
      refractive index and thickness simultaneously, which are especially useful for
      bio tissues. From comparison of these two methods, it was found that the focus
      tracking method is suitable for in vivo measurement, but does not have high
      precision. The optical path shifting method is limited to in vitro measurement,
      but has high precision. Using the optical path shifting method, the refractive
      indices of cucumber were measured at the wavelength of 850 and 1300 nm.

PMID- 12421132
TI  - Optical coherence tomography for in situ monitoring of laser corneal ablation.
AB  - OBJECTIVE: To improve the precision of refractive surgery, a new approach for
      determination of the removed corneal thickness profile in situ with laser
      ablation by optical coherence tomography (OCT) is developed. STUDY
      DESIGN/MATERIALS AND METHODS: The traditional method for precision (less than 10
      microm) measurements of intraocular distances is based on the use of the
      reflected component of probing radiation. This component is characterized by a
      small range of operating angles between a probing beam and a normal to the
      surface under study. To enhance this range of operating angles we suggest using a
      light component backscattered from a biological object. This will enable
      precision measurements over the entire surface of the cornea without any changes
      in the orientation between a probing beam and the eye, a necessary condition for
      in situ monitoring of laser refraction correction in the eye. We suggest a
      specially developed algorithm of OCT signal processing to measure the corneal
      thickness by the backscattered light component for a single longitudinal scan (A
      scan). The corneal thickness profile is obtained by a series of such A scans
      acquired by successively scanning a probing beam along the corneal surface. The
      thickness profile of removed layer is determined by changes in the corneal
      thickness profile in the process of ablation. When the cornea is ablated by a
      beam with a fixed transverse profile, we propose using integral characteristics
      of the ablated layer profile, for example, the maximum ablation depth, as
      criteria of changes in refractive power of the eye. The measurement precision by
      these characteristics is considerably higher than by a single A scan. Since the
      cornea is a poorly scattering medium, the Fourier filtering is employed to
      increase reliability and precision of the method. Model experiments on monitoring
      the ablation process in a lavsan film and ex vivo human cornea are described.
      Preliminary experiments on in vivo measurements of human corneal thickness are
      performed. RESULTS: In model experiments the precision of measurement of laser
      ablation depth by one A scan was 5-20 microm, depending on the signal-to-noise
      ratio (SNR), whereas the precision of measurement of laser ablation depth as the
      integral characteristic of the ablated layer profile was 0.3-5 microm. The
      experimental results showed that at small SNR Fourier filtering might
      considerably increase reliability and precision of measurements. When SNR is
      high, the measurement precision does not change. The precision of measurements of
      the corneal thickness in preliminary in vivo experiments was higher than in ex
      vivo experiments. This factor is very promising for application of the method
      suggested herein in refractive surgery.

PMID- 12421133
TI  - Analysis on performance and optimization of frequency-domain near-infrared
      instruments.
AB  - Frequency-domain near-infrared techniques have been widely used to detect the
      optical properties of biological tissues noninvasively. In this paper we propose
      an analytical model to evaluate the performance of frequency-domain instruments.
      Based on the diffusion equation and the transfer properties of optoelectronic
      components, we treat all parts, including the medium, as two-port networks and
      apply systematic methods to answer questions concerning frequency-domain
      instruments. Experiments show that this method can reasonably reflect the
      properties of the instrument within an accuracy of 7%. This kind of method can be
      used to design suitable instruments for various applications. We also analyze the
      selection of the instrument parameters to achieve optimal performance at an
      efficient cost using this analytical model.

PMID- 12421134
TI  - Robustness of the Chen-Dougherty-Bittner procedure against non-normality and
      heterogeneity in the coefficient of variation.
AB  - Chen, Dougherty, and Bittner [Y. Chen, E. R. Dougherty, and M. L. Bittner, J.
      Biomed. Opt. 2(4), 364-374 (1997)] provided the derivation of a probability
      density function (PDF) for a signal ratio from a DNA microarray. This PDF is
      potentially useful for testing whether a pair of signals from the same gene has a
      common mean. The derivation of the PDF assumes the normality of all signal
      distributions and a common coefficient of variation (CV) for all signals within a
      microarray. The testing procedure requires the calculation of a common confidence
      interval for a microarray, based on a maximum likelihood estimator of the
      "common" CV, and the determination of whether or not a ratio for a particular
      gene falls within this interval. This study used Monte Carlo techniques and
      demonstrated that the procedure is robust to violations of normality and also to
      constancy in the coefficients of variation. A closer examination of the dynamics
      of the procedure found that the robustness was the result of offsetting effects.
      The size of the confidence interval was increased as a result of higher estimates
      of the common CV, as the actual CV pattern became heterogeneous. This effect
      mitigated the inflation in the size of the ratio as a result of increasing CV
      heterogeneity. These findings suggest that the Chen-Dougherty-Bittner procedure
      may be used even if underlying assumptions do not hold.

PMID- 12421135
TI  - College of American Pathologists Consensus Conference XXXVI: Diagnostic Issues in
      Thrombophilia.
AB  - OBJECTIVES: To review the state of the art relating to laboratory testing for
      thrombophilia, as reflected by the medical literature and the consensus opinion
      of recognized experts in the field, and to make recommendations regarding
      laboratory testing (whom to test, when to test, what tests to perform, rationale
      for testing, and other issues) in the assessment of thrombotic risk in individual
      patients and their family members. DATA SOURCES: Review of the medical literature
      (primarily from the last 10 years) and the experience and opinions of experts in
      the field were used as data sources. DATA EXTRACTION AND SYNTHESIS: Participating
      authors evaluated the medical literature and prepared manuscripts with specific
      proposed recommendations. Drafts of all of the manuscripts were prepared and
      circulated to every participant in the College of American Pathologists
      Conference XXXVI: Diagnostic Issues in Thrombophilia prior to the conference.
      Each of the conclusions and associated recommendations was then presented for
      discussion. Recommendations were accepted if a consensus of 70% or more of the 27
      experts attending the conference was reached. The results of the discussion were
      then used to revise the manuscripts and recommendations into final form.
      CONCLUSIONS: Consensus was reached on 179 recommendations, all of which are
      presented in articles in this issue of the Archives. Detailed discussion of the
      rationale for each of these recommendations is found in the text of the
      respective articles, along with citations to justify the level of evidence for
      the recommendations. This is an evolving area of research, and it is certain that
      further clinical studies will change many of the recommendations, cause some to
      be deleted, and add others in the future.

PMID- 12421136
TI  - Laboratory evaluation of hypercoagulability with venous or arterial thrombosis.
AB  - OBJECTIVE: To provide recommendations for hypercoagulation testing for patients
      with venous, arterial, or neurovascular thrombosis, as reflected in the medical
      literature and the consensus opinion of recognized experts in the field. DATA
      SOURCES, EXTRACTION, AND SYNTHESIS: The authors extensively examined the
      literature and current practices, and prepared a draft manuscript with
      preliminary recommendations. The draft manuscript was circulated to each of the
      expert participants (n = 30) in the consensus conference prior to the convening
      of the conference. The manuscript and recommendations were then presented at the
      conference for discussion. Recommendations were accepted if a consensus of the 28
      experts attending the conference was reached. The discussions were also used to
      revise the manuscript into its final form. CONCLUSIONS: The resulting article
      provides 17 recommendations for hypercoagulation testing in the setting of
      venous, arterial, or neurovascular thrombosis. The supporting evidence for test
      selection is analyzed and cited, and consensus recommendations for test selection
      are presented. Issues for which a consensus was not reached at the conference are
      also discussed.

PMID- 12421137
TI  - Diagnostic studies for thrombophilia in women on hormonal therapy and during
      pregnancy, and in children.
AB  - OBJECTIVE: To review the role of acquired and inherited prothrombotic risk
      factors that increase the risk of thrombosis in oral contraceptive users, during
      pregnancy, and in neonates, infants, and children; and to determine by the
      consensus opinion of recognized experts in the field which risk factors should be
      determined in which individuals at which time. DATA SOURCES: Review of the
      medical literature and current clinical practice by a panel of experts in the
      field of thrombophilia. DATA EXTRACTION AND SYNTHESIS: The experts made an
      extensive review of the published literature and prepared a draft manuscript,
      which included preliminary recommendations. The draft manuscript was circulated
      to participants in the College of American Pathologists Conference XXXVI:
      Diagnostic Issues in Thrombophilia prior to the conference. The manuscript and
      recommendations were then presented at the conference for discussion.
      Recommendations were accepted if a consensus of the 26 experts attending the
      conference was reached. The results of the discussion were used to revise the
      manuscript into its final form. CONCLUSIONS: This report reviews the options for
      testing for thrombophilic states in women using oral contraceptives, during
      pregnancy, and in neonates and children. General guidelines for testing in these
      clinical situations are provided, along with citation of the appropriate
      supporting literature.

PMID- 12421138
TI  - Clinical utility of factor V leiden (R506Q) testing for the diagnosis and
      management of thromboembolic disorders.
AB  - OBJECTIVE: To review the current state of the art regarding the role of the
      clinical laboratory in diagnostic testing for the factor V Leiden (FVL)
      thrombophilic mutation (and other protein C resistance disorders), and to
      generate, through literature reviews and opinions of recognized thought-leaders,
      expert consensus recommendations on methodology and diagnostic, prognostic, and
      management issues pertaining to clinical FVL testing. DATA SOURCES, EXTRACTION,
      AND SYNTHESIS: An initial thorough review of the medical literature and of
      current best clinical practices by a panel of 4 experts followed by a consensus
      conference review, editing, and ultimate approval by the majority of a panel of
      28 additional coagulation laboratory experts. CONCLUSIONS: Consensus
      recommendations were generated for topics of direct clinical relevance, including
      (1) defining those patients (and family members) who should (and should not) be
      tested for FVL; (2) defining the preferred FVL laboratory testing methods; and
      (3) defining the therapeutic, prophylactic, and management ramifications of FVL
      testing in affected individuals and their family members. As FVL is currently the
      most common recognized familial thrombophilia, it is hoped that these
      recommendations will assist laboratorians and clinicians caring for patients (and
      families) with this common mutation.

PMID- 12421139
TI  - Clinical and laboratory management of the prothrombin G20210A mutation.
AB  - OBJECTIVE: To make recommendations regarding the appropriate evaluation for the
      prothrombin G20210A mutation, as reflected by published evidence and the
      consensus opinion of recognized experts in the field. DAT SOURCES: Review of the
      medical literature, primarily since 1996. DATA EXTRACTION AND SYNTHESIS: After an
      initial assessment of the literature, key points defining the condition, and
      review of the clinical study design, a draft manuscript was prepared and
      circulated to every participant in the College of American Pathologists
      Conference on Diagnostic Issues in Thrombophilia before the meeting. Each of the
      key points and associated recommendations were then presented for discussion at
      the conference. Recommendations were accepted if a consensus of 70% of experts
      attending the conference was reached. The results of the discussion were used to
      revise the manuscript into its final form. CONCLUSIONS: Consensus was reached on
      several recommendations concerning the criteria for testing for the prothrombin
      G20210A mutation and for the method of testing. First, a major point of consensus
      was that the prothrombin G20210A mutation is a significant risk factor for venous
      thromboembolism (VTE) and that testing should be considered in the initial
      evaluation of suspected inherited thrombophilia. Second, although several
      analytic methods are commonly used for genetic testing for the prothrombin
      mutation, all are generally robust and reliable. The recommendations for testing
      for the prothrombin mutation parallel those for the factor V Leiden mutation and
      include patients with a history of recurrent VTE, a first episode of VTE before
      the age of 50 years, a history of an unprovoked VTE at any age, thromboses in
      unusual anatomic sites, or an affected first-degree relative with VTE. A history
      of VTE related to pregnancy or estrogen use and unexplained pregnancy loss during
      the second or third trimesters were also considered to be indications for
      testing. Other scenarios remain controversial or not recommended, including
      general population screening.

PMID- 12421140
TI  - Antithrombin deficiency: issues in laboratory diagnosis.
AB  - OBJECTIVE: To review the current understanding of the pathophysiology of
      antithrombin deficiency and its role in congenital thrombophilia. Recommendations
      for diagnostic testing of antithrombin function and concentration, derived from
      the medical literature and consensus opinions of recognized experts in the field,
      are included. These recommendations specify whom, how, and when to test. DATA
      SOURCES: Review of the published medical literature. DATA EXTRACTION AND
      SYNTHESIS: A summary of the medical literature and proposed testing
      recommendations were prepared and presented at the College of American
      Pathologists Conference XXXVI: Diagnostic Issues in Thrombophilia. After
      discussion at the conference, consensus recommendations presented in this article
      were accepted after a two-thirds majority vote by the participants. CONCLUSIONS:
      Antithrombin deficiency is an infrequent genetic abnormality that may be a
      significant contributing cause of thrombophilia. Antithrombin deficiency also may
      be observed in conjunction with other genetic or acquired risk factors. Assay of
      antithrombin plasma levels is appropriate in the laboratory evaluation of
      individuals with thrombophilia, preferably using a functional, amidolytic
      antithrombin assay. The diagnosis of antithrombin deficiency should be
      established only after other acquired causes of antithrombin deficiency, such as
      liver disease, consumptive coagulopathy, or heparin therapy, are excluded. A low
      antithrombin level should be confirmed with a subsequent assay on a fresh
      specimen, and family studies may be helpful to establish the diagnosis. Antigenic
      antithrombin assays may be of benefit in subclassification of the type of
      antithrombin deficiency and to confirm the decreased antithrombin level in
      patients with type I deficiency.

PMID- 12421141
TI  - Laboratory issues in diagnosing abnormalities of protein C, thrombomodulin, and
      endothelial cell protein C receptor.
AB  - OBJECTIVE: To review the current understanding of the pathophysiology of protein
      C deficiency and its role in congenital thrombophilia. Recommendations for
      diagnostic testing for protein C function and concentration, derived from the
      medical literature and consensus opinions of recognized experts in the field, are
      included, specifying whom, how, and when to test. The role of related proteins,
      such as thrombomodulin and endothelial protein C receptor, is also reviewed. Data
      Sources.-Review of the published medical literature. DATA EXTRACTION AND
      SYNTHESIS: A summary of the medical literature and proposed testing
      recommendations were prepared and presented at the College of American
      Pathologists Conference XXXVI: Diagnostic Issues in Thrombophilia. After
      discussion at the conference, consensus recommendations presented in this
      manuscript were accepted after a two-thirds majority vote by the participants.
      CONCLUSIONS: Protein C deficiency is an uncommon genetic abnormality that may be
      a contributing cause of thrombophilia, often in conjunction with other genetic or
      acquired risk factors. When assay of protein C plasma levels is included in the
      laboratory evaluation of thrombophilia, a functional amidolytic protein C assay
      should be used for initial testing. The diagnosis of protein C deficiency should
      be established only after other acquired causes of protein C deficiency are
      excluded. A low protein C level should be confirmed with a subsequent assay on a
      new specimen. Antigenic protein C assays may be of benefit in subclassification
      of the type of protein C deficiency. The role of thrombomodulin and endothelial
      cell protein C receptor in thrombosis has yet to be clearly established, and
      diagnostic testing is not recommended at this time.

PMID- 12421142
TI  - A review of the technical, diagnostic, and epidemiologic considerations for
      protein S assays.
AB  - OBJECTIVES: To review the state of the art relating to protein S deficiency as a
      risk factor for thrombosis and to make recommendations regarding the use of
      protein S measurements in the assessment of thrombotic risk in individual
      patients and families. DATA SOURCES, EXTRACTION, AND SYNTHESIS: Selection
      criteria were developed for the inclusion of publications from 1985 to 2001 based
      on the relevant literature concerned with the systematic review of diagnostic
      tests. Minimal selection criteria were agreed on and the articles stratified into
      level 1 if they met these criteria and level 2 if they did not meet these
      criteria. The included articles were reviewed by the authors and abstracted onto
      predetermined data collection forms. These forms were then scored and
      recommendations based on level 1 studies. As described elsewhere, results of
      discussions at the College of American Pathologists Conference XXXVI on
      Diagnostic Issues in Thrombophilia were used to revise the manuscript into its
      final form. CONCLUSIONS: Consensus was reached on 16 recommendations for the use
      of protein S assays in the assessment of thrombotic risk in individuals and
      families. Two themes run through the conclusions. First, protein S assays are the
      most technically problematic of the assays reviewed at this conference. Second,
      only 2 papers evaluating the diagnostic use of protein S assays met our level 1
      inclusion criteria. These 2 problems point out the need for better standardized
      assays and rigorous studies of the diagnostic utility of these assays.

PMID- 12421143
TI  - Hyperhomocyst(e)inemia and Thrombophilia.
AB  - OBJECTIVE: To review the role of an elevated total plasma homocysteine level
      (hyperhomocyst[e]inemia) in patients with venous or arterial thrombosis, as
      reflected by the medical literature and the consensus opinion of recognized
      experts in the field. DATA SOURCES: Review of the medical literature, primarily
      from the last 10 years. DATA EXTRACTION AND SYNTHESIS: The literature was
      reviewed to identify key points defining the condition, and the clinical study
      design of each article was examined. A draft manuscript was prepared and
      circulated prior to the conference to every participant in the College of
      American Pathologists Conference XXXVI: Diagnostic Issues in Thrombophilia. Each
      of the key points and associated recommendations was then presented for
      discussion at the conference. Recommendations were accepted if a consensus of the
      70% of the experts attending the conference was reached. The results of the
      discussion were used to revise the manuscript into its final form. CONCLUSIONS:
      Consensus was reached on 9 recommendations concerning the criteria for diagnosis,
      the method of testing, and the approach for clinical management. A major point of
      consensus was that no causal role of hyperhomocyst(e)inemia in venous or arterial
      thrombosis is yet established. Testing methods used to measure homocysteine
      directly are sensitive and reliable, and provide more information than does
      genotyping for markers linked to abnormal plasma homocysteine.

PMID- 12421144
TI  - Plasminogen and tissue-type plasminogen activator deficiency as risk factors for
      thromboembolic disease.
AB  - OBJECTIVE: To review the published evidence for an association between a
      deficiency of plasminogen or tissue-type plasminogen activator (tPA) and the risk
      of thrombosis. DATA SOURCES: Review of the medical literature, with an emphasis
      on the last 10 years. DATA EXTRACTION AND SYNTHESIS: After an initial assessment
      of the literature, including review of clinical study design and laboratory
      methods, a draft manuscript summarizing the findings was prepared and circulated
      to participants in the College of American Pathologists Conference on Diagnostic
      Issues in Thrombophilia. The key findings and each recommendation were presented
      for discussion at the conference. Recommendations were accepted if a consensus of
      the 27 experts attending the conference was reached. The results of the
      discussion were used to revise the manuscript into its final form. CONCLUSIONS:
      The consensus of the conference was that routine laboratory assessment of
      plasminogen and tPA concentration in patients with thrombophilia is not warranted
      at this time. Analysis of plasminogen and tPA gene alterations in patients with
      thrombophilia is also not warranted at this time. Determination of plasminogen
      concentration should be performed in patients suspected of having ligneous
      conjunctivitis.

PMID- 12421145
TI  - The contact system.
AB  - OBJECTIVES: To review the literature for conditions, diseases, and disorders that
      affect activity of the contact factors, and further to review the literature for
      evidence that less than normal activity of any of the contact factors may be
      associated with thrombophilia. DATA SOURCES: MEDLINE search for English-language
      articles published from 1988 to 2001 and pertinent references contained therein,
      as well as search of references in recent relevant articles and reviews. STUDY
      SELECTION: Relevant clinical and laboratory information was extracted from
      selected articles. Meta-analysis was not feasible because of heterogeneity of
      reports. DATA EXTRACTION AND SYNTHESIS: Evidence for association of altered
      levels of the contact factors and thrombophilia was sought. A wide variety of
      disorders is associated with decreased activity of the contact factors; chief
      among these disorders are liver disease, hepatic immaturity of newborns, the
      antiphospholipid syndrome, and, for factor XII, being of Asian descent. These
      disorders are more common than homozygous deficiency. The few series and case
      reports of thrombophilic events in patients homozygous for deficiency of contact
      factors are not persuasive enough to support causality. The apparent association
      between levels consistent with heterozygosity (40%-60% of normal) of any of the
      contact factors (but especially factor XII) in persons with antiphospholipid
      antibodies appears to be due to falsely decreased in vitro activity levels of
      these factors, which are normal on antigenic testing. The apparent association
      with thrombosis is better explained by the antiphospholipid syndrome than by the
      modest reduction of the levels of contact factors. CONCLUSIONS: Presently, it is
      not recommended to measure activity of contact factors during routine evaluation
      of patients who have suffered venous or arterial thromboembolism or acute
      coronary syndromes.

PMID- 12421146
TI  - Dysfibrinogenemia and thrombosis.
AB  - OBJECTIVES: To review the state of the art relating to congenital
      dysfibrinogenemia as a potential risk factor for thrombosis, as reflected by the
      medical literature and the consensus opinion of recognized experts in the field,
      and to make recommendations for the use of laboratory assays for assessing this
      thrombotic risk in individual patients. DATA SOURCES: Review of the medical
      literature, primarily from the last 10 years. DATA EXTRACTION AND SYNTHESIS:
      After an initial assessment of the literature, key points were identified.
      Experts were assigned to do an in-depth review of the literature and to prepare a
      summary of their findings and recommendations. A draft manuscript was prepared
      and circulated to every participant in the College of American Pathologists
      Conference on Diagnostic Issues in Thrombophilia. Each of the key points and
      associated recommendations were then presented for discussion at the conference.
      Recommendations were accepted if a consensus of experts attending the conference
      was reached. The results of the discussion were used to revise the manuscript
      into its final form. CONCLUSIONS: Consensus was reached on 5 conclusions and 2
      recommendations concerning the use of testing for dysfibrinogens in the
      assessment of thrombotic risk in individual patients. Detailed discussion of the
      rationale for each of these recommendations is found in the text of this article.
      Compared with the other, more common hereditary thrombophilias, dysfibrinogenemia
      encompasses a diverse group of defects with varied clinical expressions.
      Congenital dysfibrinogenemia is a relatively rare cause of thrombophilia.
      Therefore, routine testing for this disorder is not recommended as part of the
      laboratory evaluation of a thrombophilic patient. This is an evolving area of
      research, and further clinical studies may change these recommendations in the
      future.

PMID- 12421147
TI  - Factor XIII polymorphisms and venous thromboembolism.
AB  - OBJECTIVE: To review the relationship between factor XIII polymorphisms and
      venous thromboembolism. METHODS: Review of the medical literature using
      computerized databases and secondary sources identified through reviews of
      bibliographies. DATA SYNTHESIS: Plasma factor XIII is the precursor of a
      transglutaminase that cross-links fibrin, thereby altering its properties,
      including resistance to fibrinolysis. It is, therefore, biologically plausible
      that alterations in factor XIII activity could affect thrombosis risk. There are
      4 common polymorphic forms of factor XIII that differ among ethnic groups. The
      Val34Leu polymorphism results in an amino acid change near the thrombin cleavage
      site that may alter the rate of activation. Several case-control studies have
      investigated the relation of the Val34Leu polymorphism to venous thromboembolism.
      Some have shown a potentially protective effect of this polymorphism, but the
      association is not consistent. CONCLUSION: Evidence is conflicting regarding the
      association of the factor XIII Val34Leu polymorphism with risk of venous
      thromboembolism, and further studies are needed before screening for this
      polymorphism can be recommended for evaluation of thrombophilia.

PMID- 12421148
TI  - Heparin cofactor II deficiency.
AB  - OBJECTIVES: To review of the state of the art relating to congenital heparin
      cofactor II deficiency as a potential risk factor for thrombosis, as reflected by
      the medical literature and the consensus opinion of recognized experts in the
      field, and to make recommendations for the use of laboratory assays for assessing
      this thrombotic risk in individual patients. DATA SOURCES: Review of the medical
      literature, primarily from the last 10 years. DATA EXTRACTION AND SYNTHESIS:
      After an initial assessment of the literature, including review of clinical study
      design and laboratory methods, a draft manuscript was prepared and circulated to
      participants in the College of American Pathologists Conference XXXVI: Diagnostic
      Issues in Thrombophilia. Recommendations were accepted if a consensus of experts
      attending the conference was reached. The results of the discussion were used to
      revise the manuscript into its final form. CONCLUSIONS: Consensus was reached
      that there is insufficient evidence to recommend testing for heparin cofactor II
      deficiency in patients with thromboembolic disease.

PMID- 12421149
TI  - Plasminogen activator inhibitor-1 levels and polymorphisms.
AB  - OBJECTIVE: To review the published evidence of a relationship between levels of
      plasminogen activator inhibitor-1 (PAI-1) or the 4G/5G polymorphism of the PAI-1
      gene and the occurrence of venous thromboembolic disease. METHODS: Review of the
      medical literature using computerized databases and a review of secondary sources
      identified through bibliographies. DATA SYNTHESIS: Plasminogen activator
      inhibitor-1 is an important inhibitor of the fibrinolytic system, so it is
      biologically plausible that elevated levels could suppress fibrinolysis and
      result in an increased risk of thrombosis. Several small studies reported
      associations between PAI-1 levels and venous thromboembolism, some of which
      appear to be familial. Problems with these studies include variations in PAI-1
      plasma levels due to circadian changes and the acute phase response, as well as
      alterations due to common comorbid disease states. More recent investigations
      have focused on genetic polymorphisms, particularly the 4G/5G insertion/deletion
      in the promoter region, affecting transcription rates. The relation of 4G/5G to
      venous thrombosis has been investigated primarily in case-control studies, which
      have produced inconsistent findings. Most studies, however, have reported higher
      PAI-1 plasma levels in individuals with 4G/4G. CONCLUSIONS: The evidence
      regarding the relationship between an elevated PAI-1 plasma level or PAI-1
      genetic polymorphism and the risk of venous thromboembolism is conflicting. There
      is insufficient information to recommend use of PAI-1 levels or genotype in
      evaluating thrombophilia.

PMID- 12421150
TI  - Elevated hemostatic factor levels as potential risk factors for thrombosis.
AB  - OBJECTIVES: To review the state of the art relating to elevated hemostatic factor
      levels as a potential risk factor for thrombosis, as reflected by the medical
      literature and the consensus opinion of recognized experts in the field, and to
      make recommendations for the use of specific measurements of hemostatic factor
      levels in the assessment of thrombotic risk in individual patients. DATA SOURCES:
      Review of the medical literature, primarily from the last 10 years. DATA
      EXTRACTION AND SYNTHESIS: After an initial assessment of the literature, key
      points were identified. Experts were assigned to do an in-depth review of the
      literature and to prepare a summary of their findings and recommendations. A
      draft manuscript was prepared and circulated to every participant in the College
      of American Pathologists Conference XXXVI: Diagnostic Issues in Thrombophilia
      prior to the conference. Each of the key points and associated recommendations
      was then presented for discussion at the conference. Recommendations were
      accepted if a consensus of the 27 experts attending the conference was reached.
      The results of the discussion were used to revise the manuscript into its final
      form. CONCLUSIONS: Consensus was reached on 8 recommendations concerning the use
      of hemostatic factor levels in the assessment of thrombotic risk in individual
      patients. Detailed discussion of the rationale for each of these recommendations
      is presented in the article. This is an evolving area of research. While routine
      use of factor level measurements is not recommended, improvements in assay
      methodology and further clinical studies may change these recommendations in the
      future.

PMID- 12421151
TI  - Platelet count monitoring and laboratory testing for heparin-induced
      thrombocytopenia.
AB  - OBJECTIVE: Heparin-induced thrombocytopenia (HIT) is an antibody-mediated adverse
      drug reaction that paradoxically is associated with a brief but dramatically
      increased risk for thrombosis (transient acquired thrombophilia). The objective
      of this article is to provide practical recommendations for platelet count
      monitoring in patients receiving heparin, as well as for selection of laboratory
      assays to detect pathogenic HIT antibodies. STUDY SELECTION: Relevant literature
      that focused on frequency and timing of HIT in various clinical settings and that
      dealt with laboratory testing for HIT antibodies was critically appraised. DATA
      EXTRACTION AND SYNTHESIS: The author prepared a preliminary manuscript including
      recommendations that was presented to participants at the College of American
      Pathologists Conference XXXVI: Diagnostic Issues in Thrombophilia (November 10,
      2001). Support of at least 70% of conference participants was required for
      recommendations to be adopted. CONCLUSIONS: The risk of immune HIT varies
      depending on the type of heparin (unfractionated heparin greater than low
      molecular-weight heparin) and patient population (surgical greater than medical).
      Thus, the intensity of platelet count monitoring should be stratified depending
      on the clinical situation. Platelet count monitoring should focus on the period
      of highest risk (usually days 5 to 10 after starting heparin) and should use an
      appropriate platelet count baseline (generally, the highest platelet count
      beginning 4 days after start of heparin). However, earlier platelet count
      monitoring is appropriate if the patient received heparin within the past 100
      days, as already circulating HIT antibodies can cause rapid-onset HIT with
      heparin reexposure. Although both antigen and (washed platelet) activation assays
      are very sensitive for detecting clinically significant HIT antibodies,
      activation assays have greater diagnostic specificity for clinical HIT.

PMID- 12421152
TI  - Antiphospholipid antibodies.
AB  - OBJECTIVE: To review the role of lupus anticoagulants in the pathogenesis of both
      venous and arterial thromboembolic events, as well as in recurrent spontaneous
      abortions. The pathophysiology of lupus anticoagulants and associated
      antiphospholipid antibodies (eg, anticardiolipin antibodies) is also discussed.
      DATA SOURCES: Review of the recent medical literature. DATA EXTRACTION AND
      SYNTHESIS: Key articles in the recent medical literature dealing with lupus
      anticoagulants and their role in pathogenesis of thromboembolic events were
      reviewed. Plasma proteins that have an affinity for binding to "perturbed
      cellular membranes" have been identified as the antigenic targets for
      antiphospholipid antibodies. Thus, the concept of antiphospholipid antibodies
      needs to be reevaluated. Perhaps a better term is antiprotein-phospholipid
      antibodies. The principal antigenic protein targets are beta(2)-glycoprotein I,
      prothrombin, and a wide range of additional proteins that interact with activated
      cellular membranes, including protein C, protein S, annexin V, etc. Most research
      reported in the literature has focused on beta(2)-glycoprotein I and human
      prothrombin.

PMID- 12421153
TI  - Thrombotic thrombocytopenic purpura and the hemolytic uremic syndrome.
AB  - OBJECTIVE: To evaluate the usefulness and feasibility of measuring plasma von
      Willebrand factor (vWF)-cleaving metalloprotease activity (ADAMTS 13) in the
      differential diagnosis of thrombotic thrombocytopenic purpura (TTP), the
      hemolytic uremic syndrome, and other thrombotic microangiopathies. DATA SOURCES:
      Articles published in the medical literature. DATA EXTRACTION AND SYNTHESIS: In
      TTP, a multimeric form of vWF that is larger than that ordinarily found in the
      plasma may cause systemic platelet aggregation under the high-shear conditions of
      the microcirculation. ADAMTS 13 is a divalent cation-activated, vWF-cleaving
      metalloprotease that converts unusually large vWF multimers derived from
      endothelial cells into smaller vWF forms in normal plasma. ADAMTS 13 is severely
      reduced or absent in most patients with TTP. The vWF-cleaving metalloprotease is
      present in fresh-frozen plasma, cryoprecipitate-depleted plasma
      (cryosupernatant), and in plasma that has been treated with solvent and
      detergent. The enzyme is defective in children with chronic relapsing TTP.
      Infusion of any of the plasma products that contain the vWF-cleaving
      metalloprotease stops or prevents (for about 3 weeks) TTP episodes in these
      patients. An immunoglobulin (Ig) G autoantibody to the vWF-cleaving
      metalloprotease is found transiently in many adult patients with acquired acute
      idiopathic, recurrent, and ticlopidine/clopidogrel-associated TTP. Patients with
      acquired TTP require plasma exchange, that is, both infusion of a plasma product
      containing vWF-cleaving metalloprotease and removal of autoantibody and/or
      unusually large vWF multimers by plasmapheresis. The pathophysiology of platelet
      aggregation in bone marrow transplantation/chemotherapy-associated thrombotic
      microangiopathy, as well as in hemolytic uremic syndrome, is not established. In
      neither condition is there a severe decrease in plasma vWF-cleaving
      metalloprotease activity, as there is in TTP. CONCLUSIONS: The presently
      available lengthy and complicated procedure for estimation of plasma vWF-cleaving
      metalloprotease activity is not yet practical for rapid diagnostic use. This test
      has supplanted the equally lengthy and difficult, less specific analysis of
      plasma vWF multimeric pattern. If the clinical distinction between TTP and
      hemolytic uremic syndrome is uncertain, it is appropriate to acquire (before
      therapy) a citrate-plasma sample for the ultimate determination of vWF-cleaving
      metalloprotease activity.

PMID- 12421154
TI  - Hope, through a glass, darkly.

PMID- 12421155
TI  - Treatment of headache with botulinum toxin A--a review according to evidence
      based medicine criteria.
AB  - The aim of this review is to evaluate the studies available from reference
      systems and published congress contributions on the prophylactic treatment of
      idiopathic and cervicogenic headache with botulinum toxin A, and to classify
      these studies according to evidence-based medicine (EBM) criteria. The studies
      were analysed with respect to the study design, the number of patients enrolled,
      the efficacy parameters, and the significance of results. We used the following
      classification of EBM. I: randomized, controlled study with sufficient number of
      patients; II: well-designed, controlled study (or randomized, controlled study
      with insufficient number of patients, no exact diagnosis, missing data of
      botulinum toxin A dose); III: well-designed, descriptive study; IV: case reports,
      opinions of experts. For tension-type headache, two studies were found with
      negative evidence of I with respect to the primary endpoint. There are about as
      many positive as negative studies with evidence of II or III. For the therapy of
      migraine, one study with both negative and positive evidence of I, one in part
      positive study of II, and three positive studies classified as III are available.
      Two studies on cervicogenic headache with evidence of II and III are
      contradictory. In addition, we found several positive case reports. For patients
      with cluster headache, there are positive and negative case reports. We found one
      positive case report for the treatment of chronic paroxysmal hemicrania. As a
      result of this analysis, we consider no sufficient positive evidence for a
      general treatment of idiopathic and cervicogenic headaches with botulinum toxin A
      to date. Further studies are needed for a definite evaluation of subgroups with
      benefit from such treatment.

PMID- 12421156
TI  - Tinted spectacles and visually sensitive migraine.
AB  - A double-masked randomized controlled study with cross-over design compared the
      effectiveness of precision ophthalmic tints in the prevention of headache in
      migraine sufferers. Seventeen patients chose the colour of light that optimally
      reduced perceptual distortion of text and maximized clarity and comfort. They
      were later given glasses with spectral filters providing optimal colour under
      conventional white lighting ('optimal' tint) or glasses that provided a slightly
      different colour ('control' tint). The tints were supplied in random order, each
      for 6 weeks, separated by an interval of at least 2 weeks with no tints. Headache
      diaries showed that the frequency of headaches was marginally lower when the
      'optimal' tint was worn, compared with the 'control'. The trial extends to adults
      with migraine, the results of a previous double-masked study demonstrating, in
      children with reading difficulty, beneficial effects of precision tints in
      reducing symptom frequency. In the present study, however, the effects are
      suggestive rather than conclusive.

PMID- 12421157
TI  - Fatigue in chronic migraine patients.
AB  - Fatigue is a common symptom frequently reported in many disorders including
      headaches, but little is known about its nature. The objective was to determine
      the prevalence of fatigue in chronic migraine (CM) patients, to define its
      subtypes and its relationship with other conditions comorbid with CM. Sixty-three
      CM patients were analysed. The Fatigue Severity Scale (FSS), the Chalder fatigue
      scale and the CDC diagnostic criteria for chronic fatigue syndrome (CFS) were
      used. Fifty-three (84.1%) patients had FSS scores greater than 27. Forty-two
      (66.7%) patients met the CDC criteria for CFS. Thirty-two patients (50.8%) met
      the modified CDC criteria (without headache). Beck depression scores correlated
      with FSS, mental and physical fatigue scores. Trait anxiety scores also
      correlated with fatigue scales. Women had higher FSS scores than men, P < 0.05.
      Physical fatigue was associated with fibromyalgia, P < 0.05. Fatigue as a symptom
      and CFS as a disorder are both common in CM patients. Therapeutic interventions
      include a graded aerobic exercise program, cognitive behavioural therapy and
      antidepressants. Identification of fatigue and its subtypes in headache disorders
      and recognition of headaches in CFS patients has implications for the
      pathophysiology, diagnosis and treatment of these disorders.

PMID- 12421158
TI  - Atypical presentations of cluster headache.
AB  - Recently, cluster headache has been shown to occur with aura, suggesting that as
      more cluster patients are seen by headache specialists new forms of this well
      defined primary headache syndrome will be identified. This study presents three
      atypical presentations of cluster headache: persistent or unremitting cluster,
      periodic cluster, and reflex or event-related cluster. Case reports are presented
      with an explanation as to why these headaches should be considered cluster
      headache.

PMID- 12421159
TI  - Hyperbaric oxygen treatment of active cluster headache: a double-blind placebo
      controlled cross-over study.
AB  - Sixteen patients, 12 with episodic and four with chronic cluster headache (CH)
      according to the International Headache Society criteria (1), participated in the
      study. They were randomly selected to start with one out of two different
      hyperbaric treatments in a double-blind, placebo-controlled, cross-over study
      design. Both gases were administered by mask inside a multiplace hyperbaric
      chamber for 70 min at 250 kPa (2.5 ATA) in two sessions 24 h apart. Active
      treatment was 100% oxygen (HBO treatment), while placebo treatment was 10% oxygen
      in nitrogen (hyperbaric normoxic placebo = sham treatment) corresponding to
      breathing air at sea level. All patients were decompressed on air. The patients
      documented the number of headache attacks and their degree of severity according
      to a modified VAS scale (level 0-4, where level 0 = no headache and level 4 =
      very severe headache). A headache index (HI = sum of (number of attacks times
      degree of severity)) was calculated for the run-in week prior to and the week
      after each separate treatment. A treatment was regarded as effective if it
      reduced the HI by>50%. Blood samples were taken from the external jugular vein
      before and during hyperbaric treatment (after 30 and 70 min), 1 day and 1 week
      after each treatment for analyses of calcitonin gene-related peptide (CGRP),
      vasoactive intestinal peptide (VIP) and neuropeptide Y (NPY) and in a few
      patients also endotheline and nitrate. No difference between HBO and sham
      treatment on the HI or the prophylactic effect was observed in our study.
      However, 83% of the episodic CH patients and 25% of the chronic ones responded to
      either of the two treatments with at least 50% reduction of HI or remission for
      shorter or longer periods. This response rate exceeds an expected high placebo
      response due to the study procedure. Two episodic CH patients still experienced
      remission on follow-up 1 year after sham treatment. Five patients reported mild
      or moderate CH attacks during the sham treatment, and none during the HBO
      treatment. Changes in neuropeptides, endotheline and nitrate levels did not
      differ systematically when comparing the two different hyperbaric treatments or
      with respect to responders and non-responders. We conclude that two HBO sessions
      were not more effective than two sham treatments in reducing the HI and
      interrupting the CH period when given in a well-established cluster period or in
      chronic CH. The hyperbaric condition itself seems effective in reducing the HI,
      at least in patients with episodic CH, although a powerful placebo response can
      not be ruled out.

PMID- 12421160
TI  - Efficacy and safety of acetaminophen and naproxen in the treatment of tension
      type headache. A randomized, double-blind, placebo-controlled trial.
AB  - The objective of this study was to evaluate and compare the efficacy and safety
      of single doses of acetaminophen (paracetamol) 1000 mg and naproxen 375 mg vs.
      placebo over a six-hour period in the treatment of tension-type headache. The
      treatments were compared in a randomized, double-blind, multicentre, placebo
      controlled study. Efficacy was evaluated using four standard analgesic summary
      endpoints (the sum of pain intensity differences from baseline, the maximum pain
      intensity from baseline, the sum of the pain relief scores, and the maximum pain
      relief score). Both acetaminophen 1000 mg and naproxen 375 mg were significantly
      superior to placebo (P<or=0.009 and P<or=0.021, respectively) but not
      significantly different from each other (P>or=0.498) for these four endpoints.
      For example, the mean sum of pain intensity differences from baseline was 9.14+/
      0.34 for acetaminophen 1000 mg and 8.81+/-0.35 for naproxen 375 mg compared with
      7.42+/-0.34 for placebo. Other efficacy endpoints (percentage of responders (pain
      reduced to none) at two hours, onset of meaningful relief, time to use of rescue
      medication and subject's overall impression of study medication) showed similar
      trends. A significantly larger mean pain intensity difference from baseline was
      observed for acetaminophen 1000 mg (1.13) than for naproxen 375 mg (0.95)
      (P=0.036) at one hour after treatment. There was no significant difference among
      the treatment groups in the incidence of adverse events (P=0.730). In summary,
      the results of this well-controlled, double-blind study demonstrate that over-the
      counter acetaminophen 1000 mg and prescription naproxen 375 mg are effective and
      well tolerated in the treatment of tough (moderate-to-severe) tension-type
      headache.

PMID- 12421161
TI  - Brain blood flow in the nitroglycerin (GTN) model of migraine: measurement using
      positron emission tomography and transcranial Doppler.
AB  - Nitroglycerin has been widely used as a model of experimental migraine. Studies
      combining measurement of flow velocity using transcranial Doppler (TCD)
      concurrently with measures of cerebral blood flow (CBF) are uncommon. We report
      the results of a study combining TCD and positron emission tomography (PET).
      Healthy volunteers with no personal or family history of migraine underwent
      measurement of CBF using H215O PET, and velocity using TCD. Measurements were
      done at baseline, and following i.v. nitroglycerin at 0.125, 0.25 and 0.5 micro
      g/kg per min. Subcutaneous sumatriptan (6 mg) was injected, with CBF and velocity
      measured 15, 30, and 60 min later. Nitroglycerin was terminated and measurements
      obtained 30 min later. Six male and six female subjects were studied.
      Nitroglycerin increased global CBF while flow velocities decreased. Sumatriptan
      did not have a significant effect on these values. Regions of increased flow
      included the anterior cingulate, while regions of decreased flow included the
      occipital cortex. Our data suggest that nitroglycerin induces regional changes in
      CBF that are similar to changes reported in spontaneous migraine, but produces
      distinctly different effects on global CBF and velocity.

PMID- 12421162
TI  - Analysis of nitric oxide synthase genes in cluster headache.
AB  - The aetiology of cluster headache is still not yet completely understood, but the
      potential relevance of genetic factors has been recognized during recent years.
      Nitric oxide (NO) plays a critical role in the regulation of vasodilation,
      neurotransmission, inflammation and many other events throughout the body. NO
      also appears to be an important mediator of vascular headache pathophysiology. In
      this study we have performed an association analysis of five polymorphic
      microsatellite markers in the three different NO synthase (NOS) genes; nNOS
      (NOS1), iNOS (NOS2A) and eNOS (NOS3). Ninety-one cluster headache patients
      diagnosed according to International Headache Society criteria and 111 matched
      controls were studied. Phenotype and allele frequencies were similarly
      distributed in patients and controls except for an iNOS (NOS2A) pentanucleotide
      repeat allele which was significantly more common in controls. We observed a
      higher phenotype frequency of this allele in our control group compared with
      rates in control groups of other studies, whereas the frequency in our patients
      was similar to that in controls from previous reports. Thus, we conclude that it
      is unlikely that genetic variations within the NOS genes contribute greatly to
      cluster headache susceptibility.

PMID- 12421163
TI  - Cardiac cephalgia is not necessarily an exertional headache: case report.

PMID- 12421165
TI  - Monoamniotic twins: diagnosis and management.
AB  - Monoamniotic twins, although uncommon, are associated with high antenatal and
      perinatal morbidity and mortality. The associated complications include cord
      entanglement, congenital anomalies, twin-twin transfusion syndrome, intrauterine
      growth retardation and preterm delivery. A thorough literature search using
      Medline and OVID was performed to look at the current diagnostic criteria for
      monoamniotic twins and the subsequent management. Specific criteria are employed
      during ultrasonography for making the diagnosis. Different opinions in the
      literature exist regarding the proper antepartum monitoring of monoamniotic
      twins, the optimal timing and the mode of delivery. Generally, it is agreed that
      there should be regular antepartum fetal heart trace monitoring and serial
      sonograms with umbilical artery Doppler flow study. Most studies advocate
      delivery at 32 weeks to reduce the risk of intrauterine deaths related to cord
      entanglement. Cesarean section is the preferred mode of delivery even though
      cases of successful vaginal delivery have been reported.

PMID- 12421166
TI  - Power spectral analysis of heart rate variability during acute hypoxia in fetal
      lambs.
AB  - BACKGROUND: The aim of the current study was to investigate the changes in the
      power spectral pattern of the heart rate variability of fetal lambs during acute
      hypoxia and the possible value of power spectral analysis as a quantitative fetal
      monitoring method. METHODS: Acutely instrumented eight fetal lambs in the third
      trimester of gestation were subjected to reproducible hypoxia by reducing the
      maternal placental blood flow with complete obstruction of the maternal abdominal
      aorta for 60 s. Fetal electrocardiographic data 5 min prior to occlusion, 1 min
      during occlusion and 1, 5, and 10 min after the removal of occlusion were
      analyzed using power spectral analysis. Differences among the procedural steps
      were determined by the Friedman test with multiple comparisons using Duncan's
      multiple-range test. Wilcoxon's rank sum test was used for the comparison between
      low-and high-frequency power values at each step. p< 0.05 was considered
      significant. RESULTS: Low-, high-, total-frequency power and low-to-high
      frequency ratio all significantly increased with hypoxia compared with the
      baseline state (p < 0.05). High-frequency power remained higher than low
      frequency power during the resting state (baseline state, 5 and 10 min after
      hypoxia). CONCLUSIONS: Increased low-frequency power and low-to-high frequency
      ratio during hypoxia reflects increased sympathetic activity compared with the
      baseline state. Higher high-frequency power during the resting state compared
      with low-frequency power reflects active respiratory movement of the fetal lambs
      near term and increased parasympathetic activity. It appeared possible that power
      spectral analysis could serve as a useful quantitative tool to monitor the
      autonomic changes in fetal lambs during hypoxia.

PMID- 12421167
TI  - Bacterial vaginosis in early pregnancy may predispose for preterm birth and
      postpartum endometritis.
AB  - BACKGROUND: Bacterial vaginosis (BV) has been reported to be associated with
      spontaneous preterm delivery and infectious morbidity after birth in non-Swedish
      populations. Our intention was to investigate the situation in a Swedish
      population. METHODS: In this cohort study, 924 patients were enrolled
      consecutively. A Papanicolaou (Pap) smear, which included a posterior fornix
      sample, was obtained at the first visit (median: 12 weeks and 1 day) at the two
      antenatal care units in central Goteborg 1990-91. Clue cells in the Pap smear
      were considered to be consistent with BV. The principal outcome variables were
      spontaneous preterm birth (< 37 weeks) and postpartum endometritis. A relative
      risk (RR) was calculated with a 95% confidence interval. RESULTS: The prevalence
      of BV was 15.6%. An association was seen between BV in early pregnancy and
      postpartum endometritis [RR 3.26 (1.38-7.71)]. A non-significant association was
      found between BV and spontaneous preterm birth [RR 2.10 (0.90-4.94)]. A multiple
      logistic regression analysis was performed adjusting for primi-/multiparity and
      antibiotics during pregnancy and the odds ratio was 2.16 (0.87-3.64).
      CONCLUSIONS: The prevalence of BV was 15.6% in this Swedish pregnant population.
      The risk for postpartum endometritis was tripled among women with BV in early
      pregnancy. The risk for spontaneous preterm birth among women with BV was doubled
      but non-significant, although the samples were obtained early in pregnancy.

PMID- 12421168
TI  - Effect of pregnancy on trunk range of motion when sitting and standing.
AB  - BACKGROUND: During pregnancy, apposition of body segments and changes in trunk
      mobility and motion control due to increased mass and dimensions may reduce the
      functional range of motion of the trunk segments. Although static postures have
      been investigated, dynamic trunk motion during pregnancy in sitting and standing
      has had very limited investigation. METHODS: Included in the study was a
      volunteer sample of convenience of nine primiparous and multiparous women. Twelve
      nulliparous females formed a control group. The subjects were filmed while
      performing maximum seated and standing trunk forward flexion, side-to-side
      flexion and seated axial rotation. A repeated measures anova was used to
      investigate systematic changes in the motion of the pelvic and thoracic segments
      and the thoracolumbar spines during pregnancy. RESULTS: As pregnancy progressed,
      there was no significant decrease in the range of side-to-side flexion. For
      forward flexion and axial rotation, motion of the thoracic segment and the
      thoracolumbar spine was significantly reduced. Movement of the pelvis was less
      affected. Base of support width was increased for forward flexion and side-to
      side flexion. CONCLUSIONS: In late pregnancy, strategies such as increasing the
      width of the base of support and reducing obstruction from other body parts were
      used to minimize the effects of increased trunk mass and girths. Not all trunk
      segment motion was affected equally. The differing effect on individual trunk
      segment motion may lead to altered movement patterns during functional tasks.

PMID- 12421170
TI  - Response to activated protein C decreases throughout pregnancy.
AB  - BACKGROUND: The possibility that changes in activated protein C anticoagulant
      activity may contribute to the hemostatic changes associated with pregnancy has
      been previously investigated, but the results of the studies are still
      controversial. METHODS: Nine hundred and sixty-one healthy nonpregnant and 711
      normal pregnant women who were noncarriers of factor V Leiden at different weeks'
      gestation were included in a cross-sectional trial. Moreover, the APC ratio was
      repeatedly measured in 45 women throughout pregnancy. The activated protein C
      ratio was tested using the modified activated partial thromboplastin time-based
      assay. RESULTS: A significantly lower APC ratio was observed at 20-28 and 32-38
      (p = 0.0001) weeks' gestation compared with nonpregnant values. The decrease in
      the APC ratio throughout pregnancy showed a significant trend (p = 0.014). In
      none of the subjects did the APC ratio reach the cut-off values for APC
      resistance. CONCLUSIONS: Our data confirm a reduction in the APC ratio throughout
      pregnancy. In our series, an APC ratio of less than 2.0 according to the cut-off
      point of our laboratory).

PMID- 12421169
TI  - Frequency of denial of pregnancy: results and epidemiological significance of a 1
      year prospective study in Berlin.
AB  - BACKGROUND: There has been an increasing number of reports on denial of
      pregnancy. However, only very few studies have involved a large number of
      patients. To date, no reliable calculation of this condition's general frequency,
      also from an epidemiological perspective, has been available. METHODS: A
      prospective case sampling was performed between 1 July 1995 and 30 June 1996 in
      the metropolitan area of Berlin. All institutions in which deliveries have taken
      place were engaged. The lower limit for inclusion was the 20th week of gestation
      as the first physician's earliest diagnosis of pregnancy. Furthermore, the woman
      herself must not have had any subjective perception. RESULTS: Recruited women
      were divided into three groups. Altogether 62 cases and 29 462 deliveries within
      the 1-year study period were valid for the frequency calculation, leading to a
      ratio of 1 : 475 (all cases) and of 1 : 2455 for totally unexpected births with a
      viable newborn (intrapartal diagnosis of the pregnancy). CONCLUSIONS: This first
      prospective, population-based study has also certain epidemiological relevance.
      From projecting the ratio of 1 : 475 for all of Germany, approximately 1600 cases
      of denied pregnancies per year are diagnosed, at the earliest, from the 20th week
      of gestation. Totally unexpected deliveries of a viable fetus without any
      presumption of being pregnant with 300 projected yearly births would occur
      threefold more often than triplets. Occurrence of denied pregnancy seems yet to
      be similar across different socio-demographic conditions. The common view that
      denied pregnancies are exotic and rare events is no longer valid. More studies of
      similar design are needed.

PMID- 12421171
TI  - Plasma oxytocin levels in women during labor with or without epidural analgesia:
      a prospective study.
AB  - BACKGROUND: Epidural analgesia (EDA) has been reported to prolong labor. Whether
      this is by interference with endogenous oxytocin release or other mechanisms is
      unclear. With increasing numbers of women receiving an EDA, it is important to
      study its effects on labor. The aim was to study the concentration of plasma
      oxytocin and the progress of labor in women with and without EDA. METHODS: Thirty
      four full-term women in spontaneous labor were included, 17 with epidural and 17
      controls, matched for cervical dilatation and parity. Oxytocin was measured by
      radioimmunoassay before analgesia, 60 min later and after placental discharge. No
      oxytocin augmentation was given during the first hour. RESULTS: EDA during labor
      was associated with a fall in plasma oxytocin. There was no difference in plasma
      oxytocin levels between the groups at inclusion. One hour later, oxytocin
      concentrations had decreased in the epidural and increased in the control group
      (Student's t-test, p = 0049). The change in oxytocin levels between the first and
      second sample differed significantly between the groups (ancova, p = 0.028). No
      difference in cervix dilatation between the groups 1 h after inclusion was noted,
      but women with EDA had a longer labor compared with those without, especially
      those with epidural and oxytocin augmentation during the later phase of the first
      stage of labor. CONCLUSION: EDA during labor may interfere with the release of
      plasma oxytocin, which may be one mechanism behind prolongation of labor. Larger
      studies are needed to clarify the effects of epidural analgesia and the role of
      oxytocin during labor.

PMID- 12421172
TI  - Joel-Cohen or Pfannenstiel incision at cesarean delivery: does it make a
      difference?
AB  - OBJECTIVE: To evaluate whether the technique to open the abdomen might influence
      the operative time and the maternal and neonatal outcome. METHODS: All
      consecutive women who underwent a cesarean section at a gestational age greater
      than or equal to 32 weeks were randomly allocated to have either the Joel-Cohen
      or the Pfannenstiel incision. Exclusion criteria were two or more previous
      cesarean sections and previous longitudinal abdominal incision. During the study
      period 366 patients underwent a cesarean delivery. Of these patients, 56 did not
      meet the inclusion criteria. The remaining patients were allocated to the Joel
      Cohen (n = 152) group and to the Pfannenstiel (n = 158) group. Extraction time
      was defined as the time interval from skin incision to the clamping of the
      umbilical cord. RESULTS: The total operative time was similar in both groups
      [Joel-Cohen 32 min (12-60) vs. Pfannenstiel 33 min (18-70)]. The extraction time
      was shorter in the Joel-Cohen group than in the Pfannenstiel group [190 s (60
      600) vs. 240 s (50-600), p = 0.05]. This remained statistically significant after
      adjustment for confounding variables (Hazard = 1.26, p = 0.05). No difference was
      found between groups in terms of intraoperative and postoperative complications.
      No difference was found in the neonatal neurodevelopmental assessment at 6 months
      of age in relation to the abdominal incision performed. CONCLUSION: The Joel
      Cohen method of opening the abdomen at cesarean delivery is faster then the
      Pfannenstiel technique at delivering the fetus. However, considering the absence
      of benefits to the mother and the fetus there is no clear indication for
      performing a Joel-Cohen incision.

PMID- 12421173
TI  - Characterization of women with a history of recurrent vulvovaginal candidosis.
AB  - BACKGROUND: To characterize history, signs, and symptoms in women with a history
      of recurrent vulvovaginal candidosis (RVVC) and who had consulted with symptoms
      generally associated with the condition. METHODS: Eighty-three women with a
      history consistent with RVVC were interviewed regarding 32 parameters and 10
      signs found at the clinical examination were noted. Candida cultures were made
      from the introitus and the posterior vaginal fornix. RESULTS: Only in a few of
      the 43 women with and the 40 without a positive yeast culture could any of the
      many etiological factors that have been associated with RVVC be traced. Only two
      factors differed between the groups, namely yogurt intake, which was reported by
      28 (68%) and 38 (95%) women in these groups, respectively. Vaginal douching was
      performed by 10 (23%) women in the Candida-positive group and by 17 (42%) women
      in the Candida-negative group. Pruritus and burning occurred in 31 (72%) and 22
      (51%) of culture-positive patients, which was less frequent than in the culture
      negative group, i.e. reported by 19 (47%) and 9 (22%) patients, respectively (p =
      0.022 and p = 0.007). Edema (p = 0.026) of the vulva as well as erythema (p =
      0.019) and edema (p = 0.008) of the vaginal mucosa, caseous discharge (p =
      0.016), were found more often in the Candida culture-positive cases. CONCLUSIONS:
      History and results of clinical examination of patients with RVVC are not enough
      to distinguish those who are culture-positive from those who are culture-negative
      for Candida from the genital tract.

PMID- 12421174
TI  - Persistent ectopic pregnancy after linear salpingotomy: a non-predictable
      complication to conservative surgery for tubal gestation.
AB  - BACKGROUND: The drawback of conservative surgery for ectopic pregnancy (EP) is
      the risk of persistent trophoblast. The purpose was to characterize patients who
      develop persistent ectopic pregnancy (PEP) after salpingotomy for EP and to
      assess prognostic factors. METHODS: The medical records of 417 patients treated
      by salpingotomy for EP were reviewed. Forty-eight (11.5%) patients were diagnosed
      with persistent EP. The data were analyzed using the Mann-Whitney U-test,
      Fischer's exact test or the chi2-test. RESULTS: Of 417 women, 48 (11,5%) were
      treated for PEP by either repeat surgery (n = 25) or methotrexate (n = 23). Oral
      methotrexate failed in 4/19 cases while intramuscular (i.m.) methotrexate was
      successful in 4/4 cases. Women treated for PEP had a higher preoperative and a
      slower postoperative decline of serum human chorionic gonadotropin (hCG). Both
      the preoperative and the early postoperative hCG levels had a low diagnostic
      sensitivity (0.38-0.66) and specificity (0.74-0.77) for predicting PEP. In
      multivariate logistic analysis, none of the following clinical variables were
      predictive of PEP: duration of surgery, laparoscopic approach, history of
      previous EP, history of previous lower abdominal surgery, ruptured EP, pelvic
      adhesions, absence of products of conception at microscopy and hemoperitoneum.
      CONCLUSIONS: Persistent ectopic pregnancy can neither be predicted from clinical
      variables nor from single measurements of hCG with an accuracy sufficient for
      clinical use.

PMID- 12421175
TI  - Management of missed abortion: comparison of medical treatment with either
      mifepristone + misoprostol or misoprostol alone with surgical evacuation. A multi
      center trial in Copenhagen county, Denmark.
AB  - OBJECTIVE: To compare the efficacy of two different medical treatment regimens:
      mifepristone 600 mg orally + misoprostol 0.4 mg vaginally (Mf + Ms) or
      misoprostol 0.4 mg vaginally (Ms) with conventional surgical evacuation (SE) in
      women with missed abortion. MATERIALS AND METHODS: Prospective crossover study
      with alternating regimens every 4 months. The three university clinics of
      Obstetrics and Gynecology in Gentofte, Herlev and Glostrup of Copenhagen County.
      During the period October 1999 to October 2000, 176 women with missed abortion
      accepted to participate in the study. RESULTS: The proportion of women who needed
      surgical evacuation after medical treatment, number of women who needed re
      evacuation after primary surgical evacuation, duration of vaginal bleeding,
      treated infections, need of analgesics, and the subjective experiences from the
      participating women. Fifty-four, 73 and 49 patients were randomized to Mf + Ms,
      Ms and SE, respectively. Within 1 week, complete expulsion occurred in 40 (74%),
      52 (71%), 47 (96%) of the three arms, respectively. Duration of bleeding was 6.9,
      7.1 and 2.5 days in the three arms, respectively (p < 0.01). Women with an
      initial plasma chorionic gonadotrophine (p-hCG) between 2000 and 20 000 IU/l and
      a gestational age less than 75 days had a significantly better response to the
      medical treatment than those not fulfilling these two criteria. Initial p
      progesterone did not correlate with success of medical treatment. MAIN OUTCOME
      MEASURES: Proportion of women who needed surgical evacuation after medical
      treatment, and the number of women who needed re-evacuation after primary
      surgical evacuation, duration of vaginal bleeding, treated infections, the need
      of analgesics, and subjective experiences from participating women. CONCLUSION:
      Vaginal misoprostol 0.4-0.6 mg is effective in most patients with missed
      abortion. Pre-treatment with the antiprogesterone mifepristone does not increase
      the success rate. The selection of women with missed abortion for medical
      treatment based on gestational age and initial p-hCG level may increase the
      success of medical treatment significantly.

PMID- 12421176
TI  - Cost-analyzes based on a prospective, randomized study comparing laparoscopic
      colposuspension with a tension-free vaginal tape procedure.
AB  - BACKGROUND: The aim of this study was to compare laparoscopic colposuspension
      with tension-free vaginal tape (TVT) in terms of costs to the county. METHODS: In
      a prospective, randomized study, we approached 270 consecutive women presenting
      for evaluation of stress urinary incontinence symptoms at one university
      hospital. Preoperatively, and at 1-year follow-up, the women underwent urodynamic
      evaluation, an ultra-short pad-test and completed a lower urinary tract symptoms
      questionnaire. We randomized 79 consenting, eligible women to either procedure; a
      1-year follow-up examination was performed on 68/71 (96%) women that were
      available. The procedures were performed as described previously. Main outcome
      measures were all relevant costs for goods and services associated with the
      procedures. RESULTS: The baseline characteristics of the two groups were similar.
      The TVT procedure was performed significantly faster than the laparoscopic
      colposuspension, i.e. 44.9 +/- 14.2 min compared with 60.5 +/- 13.4 min (p <
      0.0001). Even so, procedural costs were significantly lower for laparoscopic
      colposuspension than for TVT (euro 1273.4 compared with euro 1342.8 p < 0.001).
      At the 1-year follow-up visit, three women operated on with TVT and one operated
      on with laparoscopic colposuspension required re-operation for continuous stress
      urinary incontinence. One women operated on with TVT had her sling cut for
      bladder-emptying problems. Total costs, including re-operations were euro 1462.6
      for a TVT procedure andeuro; 1314.5 for a laparoscopic colposuspension.
      CONCLUSION: In our hands, the laparoscopic colposuspension was less expensive to
      the county than the TVT procedure.

PMID- 12421178
TI  - Chance finding of a leiomyosarcoma in hysteroscopic resection of a myoma.

PMID- 12421177
TI  - Management of female genital mutilation in Djibouti: the Peltier General hospital
      experience.
AB  - Female genital mutilation (FGM) is still performed on 98% of Djiboutian women.
      Infibulation (FGM type 3) is the most widely used method of FGM in Djibouti. Even
      though this operation is mutilating, illegal and sometimes results in death, it
      is still practiced at approximately the same rate as in the past. Mass
      immigration of African women to Europe, Canada, Australia and the United States
      in the past decade has brought the problems of FGM to these countries. Female
      genital mutilation is a problem unfamiliar to most Western obstetrician
      gynecologists. A tight infibulation can be a high risk for the mother and fetus
      if not handled by a skilled operator. It can lead to an unnecessary cesarean
      section as a result of the fear of handling infibulated women. Therefore, Western
      physicians need to be informed. The aim of this article was to share our
      experience of FGM. It will focus on FGM in Djibouti, its types, epidemiology and
      health consequences. It will present the management of obstetric and gynecologic
      complications and discuss medico-legal and health service measures to combat
      these dangerous and unnecessary practices

PMID- 12421179
TI  - A hepatoid carcinoma of the ovary.

PMID- 12421180
TI  - Benign multicystic peritoneal mesothelioma.

PMID- 12421181
TI  - A rare case of postmenopausal bleeding due to Wegener's granulomatosis.

PMID- 12421182
TI  - Myolipoma of soft tissue: an unusual tumor with expression of estrogen and
      progesterone receptors. Report of two cases and review of the literature.

PMID- 12421186
TI  - Mortality rates among physicians -- how should the data be interpreted?

PMID- 12421183
TI  - Mode of delivery in breach presentation.

PMID- 12421187
TI  - Do anesthesiologists die younger?

PMID- 12421188
TI  - Mortality rates among Swedish physicians: a population-based nationwide study
      with special reference to anesthesiologists.
AB  - BACKGROUND: Recent studies both in the UK and in the USA have indicated a higher
      mortality rate among anesthesiologists than among other physicians. We therefore
      decided to investigate the situation in Sweden during the years 1993-99. METHODS:
      All 26086 doctors in Sweden with a specialist licence in 1993, including those
      who were retired or who received one until 1999, were identified in official
      records and followed up regarding survival until 1999; generating approximately
      179300 person-years. RESULTS: Overall, 893 deaths occurred during the 7-year
      follow up. Mean age at death was 72.9 years in the whole population, the lowest
      being 64.1 years among the anesthesiologists and the highest 77.0 among the
      pediatricians. However, there were large differences in the age and sex
      distribution among the specialties. For this reason a series of proportional
      hazard regression analyses (Cox's) of the mortality rates in the various
      specialty groups were performed, taking into account the influence of age and
      gender differences. After this procedure anesthesiologists had a 46% higher
      mortality rate and pediatricians a 24% lower mortality rate than other specialist
      groups; both deviations being statistically significant. All other specialties
      had a mortality risk within the expected range. Anesthesiologists tended to have
      higher rates than other specialists for most underlying causes of death.
      CONCLUSION: Anesthesiologists have a higher mortality rate than other
      specialties. The cause is so far unknown. However, it is unlikely to be caused by
      obvious confounders such as age, gender, or smoking habits. Other factors linked
      to occupational exposure should be investigated.

PMID- 12421189
TI  - Mortality among Finnish anesthesiologists from 1984-2000.
AB  - BACKGROUND: Previous studies have suggested increased mortality among
      anesthesiologists. We report age-standardized mortality rates and causes of death
      among Finnish anesthesiologists. METHODS: Data covering the deaths of all medical
      specialists during 1984-2000 were obtained and analyzed. There were 799 deaths,
      of which 18 involved anesthesiologists. The causes of deaths of these
      anesthesiologists were obtained from the database of Statistics Finland. RESULTS:
      The age-standardized mortality rate (SR) for the male anesthesiologists was 33.9
      years (per 1000), and that for the other male specialists was 84.6 years. The SR
      for the female anesthesiologists was 45.4 years, and that for the other female
      specialists was 77.3 years. The mean age at death among the anesthesiologists was
      63.0 years (SD 11.0), while the mean age at death among the other specialists was
      68.6 years (SD 14.7). The age structures of the anesthesiologists and other
      specialists were different, with the anesthesiologists being younger. CONCLUSION:
      The different age distributions of the anesthesiologists and other specialists
      caused the difference in age at death. The SR values for the anesthesiologists
      are clearly lower than those for other specialists. Thus, the present findings do
      not show increased mortality among Finnish anesthesiologists.

PMID- 12421190
TI  - Mortality of anesthesiologists, pediatricians, and other specialists in Norway.
AB  - BACKGROUND: Following sensational media reports, particularly from Sweden, there
      has been discussion in Scandinavia during the last couple of years about whether
      anesthesiologists have shorter life spans than other medical specialists.
      METHODS: Survival analysis (Cox regression) from the master file of the Norwegian
      Medical Association was used to compare anesthesiologists with pediatricians and
      other specialists. Data was taken from 10367 specialists, 533 anesthesiologists,
      488 pediatricians, and 9325 other specialists, with Norwegian citizenship. These
      comprised 574065 man-years, of which 171190 were lived after achieving specialty.
      CONCLUSION: No differences in mortality were found between the three groups.

PMID- 12421191
TI  - Mortality among anesthesiologists in Denmark, 1973-95.
AB  - BACKGROUND: Preliminary data from Sweden indicating that anesthesiologists have a
      high mortality risk has caused a lot of concern in Denmark. The aim of this study
      therefore was to compare mortality between consultant anesthesiologists and other
      consultants in Denmark. METHODS: A historical prospective cohort study based on
      the membership register of the Danish Medical Association from 1973 to 1992. The
      study population consisted of 6854 consultants who were members of the
      Association of Medical Specialists, 406 of whom were anesthesiologists. The all
      cause mortality between the two groups was compared during the period 1972-95
      using Cox's proportional hazard regression model. RESULTS: The study covered
      approximately 86000 person-years. A total of 1205 deaths occurred within the
      period studied, 41 of whom were anesthesiologists. The relative risk for all
      cause mortality among the anesthesiologists compared with all the other
      consultants was 1.0 (95% confidence limit: 0.7-1.4). CONCLUSION: In Denmark there
      is no evidence of a high mortality risk in consultant anesthesiologists compared
      with other consultants.

PMID- 12421192
TI  - Tranexamic acid given intraoperatively reduces blood loss after total knee
      replacement: a randomized, controlled study.
AB  - BACKGROUND: Extensive blood loss in total knee replacement (TKR) surgery is well
      known and is associated with a high transfusion rate of allogenic blood.
      Tranexamic acid (TXA) has been shown to reduce blood loss by 50% in this patient
      group, but only in cases with a perioperative loss of 1400-1800 ml. This study
      was performed to see if TXA offers any advantages in knee replacement surgery
      with blood loss at 800 ml. METHODS: Thirty consecutive patients scheduled for TKR
      in spinal anesthesia with the use of a tourniquet, were randomized to TXA or non
      TXA. Tranexamic acid 10 mg kg-1 was given at conclusion of surgery and again 3 h
      later. Blood loss was registered. RESULTS: Total blood loss was at all times
      significantly lower in the TXA group compared to the non-TXA group (409.7+/-174.9
      ml vs. 761.7+/-313.1 ml; P<0.001). There were no differences in coagulation
      parameters. No patients in the TXA group had a blood transfusion vs. 13% in the
      non-TXA group (NS). No complications were registered in the two groups.
      CONCLUSION: We conclude that TXA significantly reduces blood loss after total
      knee replacement surgery.

PMID- 12421193
TI  - Sigmoid colonic reflectance pulse oximetry and tonometry in a porcine
      experimental hypoperfusion shock model.
AB  - BACKGROUND: The objective of the present study was to determine if colonic
      endoluminal mucosal oxygen saturation, as determined by reflectance pulse
      oximetry, is an appropriate method to monitor colonic ischemia produced by a
      gradual partial constriction of the aorta in a porcine experimental model.
      METHODS: Piglets were anesthetized and mechanically ventilated. A Nellcor RS-10
      reflectance pulse oximeter probe was attached to a Foley balloon catheter and
      passed transanally to record the oxygen saturation of the sigmoid colonic mucosa.
      For comparison, a tonometry catheter was introduced into the sigmoid colon.
      Hypoperfusion shock was induced by partial gradual constriction of the aorta. The
      same measurements but no intervention was performed in the control group.
      RESULTS: During one-third reduction of the aortic blood flow, the
      plethysmographic signal disappeared suddenly and the sigmoid colonic mucosa
      oxygen saturation (ScO2) measurements showed zero in seven out of the eight pigs.
      During two-thirds flow reduction, no plethysmographic signals were observed in
      any of the piglets. During the reperfusion period, ScO2 measurements with a good
      plethysmographic signal were obtained immediately after complete release of the
      aortic constriction in all pigs. Significantly decreased intramucosal pH and
      increased difference between the arterial and regional PCO2 (PCO2 gap) were
      observed during two-thirds blood flow reduction. CONCLUSION: In contrast to the
      results of previous investigations, the sigmoid colonic pulse oximetry was not
      useful because the method proved to be overly sensitive and non-linear in
      relation to regional blood flow.

PMID- 12421194
TI  - Does dopexamine influence regional vascular tone and oxygenation during
      intestinal hypotension?
AB  - BACKGROUND: Local effects of dopexamine on intestinal vascular tone and
      oxygenation were investigated during intestinal hypotension. To this end, we
      employed an experimental model, in which the superior mesenteric arterial
      pressure (PSMA) was controlled by an adjustable perivascular clamp. This approach
      enabled us to keep the intestinal perfusion pressure (IPP) constant in the face
      of any systemic circulatory alterations. METHODS: In 11 barbiturate-anesthetized
      pigs, we instrumented the superior mesenteric circulation for assessments of
      vascular resistance (RMES), IPP, jejunal mucosal perfusion (Laser Doppler) and
      intestinal tissue oxygenation (microoximetry). Measurements were carried out
      before and during dopexamine infusions (0.5 and 1.0 micro g.kg-1.min-1) at a
      freely variable PSMA (i.e. the perivascular clamp fully open) and at a PSMA of 50
      mmHg and 30 mmHg. RESULTS: At a constant PSMA of 50 mmHg, dopexamine had no
      significant intestinal vascular effects. However, at a constant PSMA of 30 mmHg,
      both doses of dopexamine were associated with decreases in RMES. Effects of
      dopexamine on intestinal oxygen delivery and extraction were minimal during these
      procedures, while a minor decrease in intestinal tissue oxygen tension was
      observed during dopexamine administration at the lowest IPP level. CONCLUSION: At
      very low intestinal perfusion pressures (approximately 30 mmHg) dopexamine
      produces intestinal vasodilation in excess of what is produced by intrinsic
      autoregulation. This suggests that there is a vasodilatory reserve in the
      intestine under such conditions and that a pharmacological vasodilator like
      dopexamine may improve intestinal circulation during regional severe hypotension.

PMID- 12421195
TI  - Modulation of the inflammatory response to cardiopulmonary bypass by dopexamine
      and epidural anesthesia.
AB  - BACKGROUND: Cardiopulmonary bypass (CPB) induces a systemic inflammatory
      reaction. Microcirculation-dependent alteration of the gut mucosal barrier with
      subsequent translocation of endotoxins is a postulated mechanism for this
      inflammatory response. This study was designed to elucidate whether two different
      approaches to modulate splanchnic perfusion may influence systemic inflammation
      to CPB. METHODS: We examined 40 patients scheduled for elective coronary bypass
      surgery in a prospective, randomized study. One group (DPX) received dopexamine
      (1 micro g. kg-1. min-1) continuously after induction of anesthesia until 18 h
      after CPB. The control group (CON) received equal volumes of NaCl 0.9% in a time
      matched fashion. In a third group (EPI) a continuous epidural infusion of
      bupivacaine 0.25% [(body height (cm) - 100). 10-1=ml.h-1] was administered for
      the whole study period. Procalcitonin (PCT), tumor necrosis factor (TNF-alpha),
      soluble TNF receptor, human soluble intercellular adhesion molecule-1, C-reactive
      protein (CRP) and leukocyte count were measured as parameters of inflammation.
      RESULTS: All parameters significantly increased following CPB. Increases of PCT,
      TNF-alpha and leukocyte count were significantly attenuated in the DPX and EPI
      groups at different time points. However, neither splanchnic blood flow nor
      oxygen delivery and consumption were different when compared with the CON-group.
      CONCLUSION: These results do suggest that mechanisms other than an improved
      splanchnic blood flow by DPX and EPI treatment have to be considered for the anti
      inflammatory effects.

PMID- 12421196
TI  - Cerebrospinal fluid concentrations of atracurium, laudanosine and vecuronium
      following clinical subarachnoid hemorrhage.
AB  - BACKGROUND: Neuromuscular blocking agents may exert central nervous system
      effects when they reach the brain. This study assessed the concentrations and the
      time course of passage of vecuronium, atracurium, and its metabolite laudanosine
      in the cerebrospinal fluid (CSF) of patients undergoing intracranial aneurysm
      clipping. METHODS: Twenty-five patients with subarachnoid hemorrhage were
      randomly allocated to receive an intravenous infusion of vecuronium (n=13) or
      atracurium (n=12). Arterial blood and lumbar CSF were sampled before and 1, 2, 3,
      4 and 8 h after the start of the relaxant infusion. The samples were analyzed by
      liquid chromatography-electrospray ionization mass spectrometry (vecuronium) and
      high-pressure liquid chromatography (atracurium and laudanosine). RESULTS: The
      data of 20 patients (10 in both groups) were analyzed. In 11 CSF samples from
      five patients atracurium was detected in concentrations from 10 to 50 ng/ml.
      Laudanosine was retrieved in all CSF samples at 1, 2, 3, 4 and 8 h; the highest
      CSF concentration of laudanosine occurred at 3 h [38 (18-63) ng/ml: median
      (range)]. Vecuronium was not found in any CSF sample. CONCLUSION: Significant
      concentrations of atracurium and laudanosine but not of vecuronium were detected
      in the CSF of patients during and immediately after intracranial aneurysm
      surgery.

PMID- 12421197
TI  - Assessment of the respiratory exchange ratio in mechanically ventilated patients
      by a standard anaesthetic gas analyser.
AB  - BACKGROUND: The respiratory exchange ratio (R) is the CO2 production divided with
      O2 consumption. R is an essential factor included in several formulas during
      routine blood gas analysis. Instant and individual measurement of R may be of
      particular interest to improve the evaluation of each single patient. A standard
      anaesthetic gas analyser has been recommended for measurement of R among
      spontaneously breathing healthy subjects, but there is no experience using this
      method among mechanically ventilated critically ill patients. This study
      validates the assessment of R by a Bruel & Kjaer gas analyser (B & K) during
      positive pressure ventilation of intensive care patients. METHODS: The B & K
      sampled gas from 11 mechanically ventilated patients over a period of 5 min. The
      recordings of end-tidal values of O2 and CO2 based on fractions (RF) allowed for
      calculation of RF by the alveolar equation solved for R. The continuous
      recordings of corresponding values were depicted into an O2-CO2 diagram. A
      developed computer program calculated estimates of R as the slope of the
      regression lines related to the full cycle (Rfull) and the expiratory phase only
      (Rexp). Corrected values of the full respiratory cycle (Rfull*) were also
      calculated assuming changes of CO2 and O2 volumes during gas exchange. The
      different estimates of R were compared with simultaneous measurement of a
      Deltatrac indirect calorimeter (Rdelta). RESULTS: Ten values of RF were within
      the expected interval of 0.72 < R < 1.00. For the full respiratory cycles, the
      mean R-value was 0.94 +/- 0.07 and for the expiratory phase the mean R-value was
      0.82 +/- 0.08. The O2-CO2 diagram appeared as a convexo-convex loop during each
      cycle. The agreement of Rexp and Rdelta (Rexp-Rdelta: 0.01 +/- 0.13) were good.
      CONCLUSION: This study demonstrates that gas measurements by a standard
      anaesthetic gas monitor can be used for determination of R, and thereby we
      present an alternative to R calculation made by the Deltatrac monitor.

PMID- 12421198
TI  - Prospective, randomized cost analysis of anesthesia with remifentanil combined
      with propofol, desflurane or sevoflurane for otorhinolaryngeal surgery.
AB  - BACKGROUND: In the era of cost containment, cost analysis should demonstrate the
      cost-effectiveness of new anesthetic drugs. METHODS: This single-blind,
      prospective, randomized study compared the costs of three remifentanil (REM)
      based anesthetic techniques with a conventional one in 120 patients undergoing
      otorhinolaryngeal surgery. The patients were randomized (n=30 each group) to
      either receive a combination of REM with propofol, desflurane or sevoflurane, or
      a conventional anesthetic with thiopentone, alfentanil, isoflurane and N2O.
      RESULTS: The costs for anesthetic and nonanesthetic drugs and for disposables
      were twice as high in the three REM-based groups as in the conventional group
      (REM/PRO 0.51 Euro;/min, REM/DES 0.42 Euro;/min, and REM/SEVO 0.41 Euro;/min vs.
      0.18 Euro;/min in the ALF/ISO/N2O group; P<0.05). Wastage of intravenous drugs
      accounted for up to 40% of total costs. In all REM groups, early recovery was
      predictably faster and more complete (P<0.05). Patient satisfaction was equally
      high (90-97%) in all groups, with less nausea in the REM/PRO group. CONCLUSION:
      This study demonstrates that REM-based anesthetic techniques are more expensive
      than a conventional technique using alfentanil, isoflurane and N2O. This is the
      result of higher costs of anesthetic and nonanesthetic drugs and of disposables.
      The wastage of intravenous drugs contributes considerably to these costs.

PMID- 12421199
TI  - Lamotrigine monotherapy for control of neuralgia after nerve section.
AB  - BACKGROUND: We present six patients treated only with the new-generation
      anticonvulsant lamotrigine to define its sole effect on neuralgia after nerve
      section. METHODS: Previous surgical or pharmacological attempts failed to relieve
      this neuropathic pain in our patients. Before initiation of lamotrigine therapy,
      patients reported spontaneous and touch-evoked shooting pain followed by periods
      of burning pain. No breakthrough medication was needed during the maintenance
      phase of 1-23 months. Data were acquired by a pain diary on a weekly basis.
      RESULTS: With 75-300 mg of lamotrigine per day, the burning and shooting pain
      intensity was relieved by 33-100%. Most obviously, the attack frequency of the
      shooting pain was reduced by 80-100%. No adverse effects were observed.
      CONCLUSION: We conclude that lamotrigine may be beneficial in the treatment of
      neuralgia after nerve section following the failure of previous pharmacological
      or surgical attempts.

PMID- 12421200
TI  - Preoperative predictors of moderate to intense acute postoperative pain in
      patients undergoing abdominal surgery.
AB  - BACKGROUND: Pain is a sensory and emotional experience that is influenced by
      physiologic, sensory, affective, cognitive, socio-cultural, and behavioral
      factors. Consistent with the perspective to improve the postoperative pain
      control, the present study has the purpose of assessing the effect of presurgical
      clinical factors, psychological and demographic characteristics as predictors for
      reporting moderate to intense acute postoperative pain. METHODS: A prospective
      cohort study was performed with 346 inpatients undergoing abdominal elective
      surgery (ASA physical status I-III, age range 18-60 years). The measuring
      instruments were Pain Visual Analog Scale, the State-Trait Anxiety Inventory, and
      the Montgomery-Asberg Depression Rating Scale. Multivariate conditional
      regression modeling was used to determine independent predictors for moderate to
      intense acute postoperative pain. RESULTS: Moderate to intense acute
      postoperative pain was associated with status ASA III (odds ratio (OR) = 1.99),
      age (OR = 4.72), preoperative moderate to intense pain (OR = 2.96), chronic pain
      (OR = 1.75), high trait-anxiety and depressive mood moderate to intense (OR =
      1.74 and OR = 2.00, respectively). Patients undergoing surgery to treat cancer
      presented lower risk for reporting moderate to intense pain OR = 0.39, as well as
      those that received the epidural analgesia and multimodal analgesia with systemic
      opioid (OR = 0.09 and OR = 0.16, respectively). CONCLUSIONS: The identification
      of predictive factors for intense acute postoperative pain may be useful for
      designing specific preventive interventions to relieve patient suffering.
      Especially because few of these variables are accessible for medical
      intervention, which would improve the clinical outcomes and quality of life of
      patients at risk of moderate to intense acute postoperative pain.

PMID- 12421201
TI  - Intrathecal fentanyl/meperidine combined with low-dose epidural bupivacaine for
      Cesarean section in a patient with advanced Krukenberg tumors.
AB  - This case report demonstrates the anesthetic management of a 41-year-old
      primiparous parturient with massive ascites due to advanced Krukenberg tumors,
      undergoing Cesarean section. We chose a combined intrathecal-epidural technique,
      using intrathecal hypobaric fentanyl and hyperbaric meperidine, and a low dose of
      epidural bupivacaine in order to avoid hemodynamic instability in this critically
      ill patient. Surgery was carried out without difficulty under adequate regional
      anesthesia. The blood pressure was maintained with low doses of phenylephrine and
      dopamine. Opioid-related complications such as nausea-vomiting, pruritus,
      drowsiness, and respiratory depression were not observed in this patient.
      Therefore, intrathecal opioids combined with a low dose of epidural local
      anesthetics for Cesarean section is suitable for critically ill patients with
      malignant abdominal tumors, such as a Krukenberg tumor, complicated by massive
      ascites.

PMID- 12421202
TI  - An anaphylactic reaction to blood supplied from patient's mother.
AB  - We present the case of a 4-year-old girl who developed anaphylactic shock during
      general anesthesia. Symptoms appeared 80 min into the operation and may have been
      an immediate allergic reaction to the transfused blood supplied from the child's
      mother based on the clinical signs, the decrease of components of complements and
      the elevated concentrations of histamine and tryptase. The blood type was the
      same and antibody screening test and crossmatch was negative. The blood was
      irradiated and we used a white cell-reduction filter. This patient possibly has
      antibodies to her mother's plasma and this type of reaction cannot be prevented
      by these routine methods. It is reported that the risk of transfusion associated
      graft-vs.-host disease is high when a patient receives blood from a closely
      related donor. However, there are, no reports of anaphylactic reactions to blood
      supplied from mother to child. We suggest that there is a potential for
      anaphylactic reaction as well as transfusion associated graft-vs.-host disease
      when a child patient receives blood from the mother.

PMID- 12421203
TI  - Intravenous sedation and general anesthesia for a patient with Gilles de la
      Tourette's syndrome undergoing dental treatment.
AB  - Patients with Gilles de la Tourette's syndrome develop symptoms during childhood.
      Repetitive various motor tics or speech tics that are spontaneous, aimless, and
      involuntary are characteristic of the syndrome (1). Patients with the syndrome
      have been considered to have an aggressive, impulsive, and obsessive character
      (2). (3). Suicide is one of the mental symptoms of the syndrome. Routine dental
      treatment with this syndrome can be difficult.

PMID- 12421204
TI  - Lund strikes again.

PMID- 12421206
TI  - Treatment of intracranial hypertension and aspects on lumbar dural puncture in
      severe bacterial meningitis.

PMID- 12421208
TI  - Transfusion medicine illustrated. Morphologic hallmarks of Babesia.

PMID- 12421209
TI  - Approaches to selecting blood for transfusion to patients with autoimmune
      hemolytic anemia.

PMID- 12421210
TI  - Is it time for a new look at granulocyte transfusions?

PMID- 12421211
TI  - Nomenclature for neutrophil-specific antigens.

PMID- 12421212
TI  - Guidelines for assessing appropriateness of pediatric transfusion.

PMID- 12421213
TI  - Granulocyte transfusion therapy for infections in candidates and recipients of
      HPC transplantation: a comparative analysis of feasibility and outcome for
      community donors versus related donors.
AB  - BACKGROUND: Feasibility, response to granulocyte transfusion therapy, and
      clinical outcome were compared among HPC transplant recipients enrolled in a
      prospective study of a community blood bank-based unrelated donors program, a
      prospective granulocyte study using family donors, and matched control patients
      without granulocyte transfusion therapy. STUDY DESIGN AND METHODS: Overall, 40
      patients (327 collections) received granulocyte concentrates from unrelated
      donors, 34 patients (219 collections) received granulocyte concentrates from
      related donors, and 74 patients served as controls. Study entry criteria for
      patients included an absolute neutrophil count (ANC) of less than 200 per microL
      and documented invasive fungal or bacterial infections. RESULTS: There was a
      median delay of 3 days (range, 0-14) in patients receiving transfusions from
      unrelated donors between day of diagnosis of infection and start of granulocyte
      transfusion therapy as compared with a median delay of 5 days (range, 0-25) in
      patients receiving transfusions from related donors (p = 0.01). The ANC increment
      after the first, second, and seventh transfusions in patients who had community
      donors was significantly higher or comparable to patients who had family donors.
      Overall, clinical outcome was comparable between the three patient groups. Kaplan
      Meier analysis revealed no difference between all cohorts in overall 6-month
      survival (p = 0.28, log-rank) or event-free survival (p = 0.17, log-rank).
      CONCLUSION: These results suggest that future efficacy trials should consider
      inclusion of unrelated community donors for timely institution of granulocyte
      transfusion therapy.

PMID- 12421214
TI  - Polymerized human Hb use in acute chest syndrome: a case report.
AB  - BACKGROUND: Acute chest syndrome (ACS) is a complication of sickle cell disease
      that can cause significant morbidity. Transfusion therapy has been shown to
      significantly increase oxygenation in patients with ACS and RBC exchange is
      considered the standard of care in patients at high risk of respiratory failure.
      CASE REPORT: A patient with ACS and several high-risk features, including
      thrombocytopenia, profound anemia, bilateral pulmonary infiltrates,
      staphylococcal sepsis, and pulmonary embolism is presented. The patient refused
      transfusion on religious grounds and received 12 units of human polymerized Hb
      solution (poly SFH-P injection, PolyHeme, Northfield Laboratories) over the
      course of 13 days. The patient's respiratory status improved and she was
      discharged home without receiving RBC transfusions. CONCLUSION: This is the first
      reported case that describes the use of PolyHeme in a patient with sickle cell
      disease, ACS, and sepsis. This therapy is thought to have been lifesaving for
      this patient.

PMID- 12421215
TI  - RBC T activation and hemolysis in a neonatal intensive care population:
      implications for transfusion practice.
AB  - BACKGROUND: Reports of transfusion-associated hemolysis in infants with T
      activated RBCs have led to the suggestion that infants should be screened and
      provided with low-titer anti-T blood components. T-activated RBCs react with the
      lectins Arachis hypogea and Glycine soja; variants of T (Th and Tx) and Tk also
      react with A. hypogea, but not G. soja. Although Tk is not a true variant of T,
      for the purposes of this study, all RBCs that are reactive with A. hypogea but
      are not reactive with G. soja are called "T variants." STUDY DESIGN AND METHODS:
      A prospective study was carried out to examine T and T variant activation and
      transfusion-associated hemolysis in a neonatal intensive care population and to
      determine if antibodies to T and T variant are detectable in donor plasma. A
      total of 2041 samples from 375 infants were tested for T and T variant activation
      utilizing a lectin panel. Three hundred donor plasma samples were tested for
      antibodies to T and T variant. RESULTS: Forty-eight of 375 infants (12.8%) had T-
      and T-variant-activated RBCs. Of these, 13 of 48 (27%) developed at least one
      episode of sepsis and 9 of 48 (19%) developed necrotizing enterocolitis (NEC) at
      some point during their inpatient stay. T activation was not always temporally
      associated with the onset of NEC or sepsis. The remaining 26 of 48 (54%) were
      healthy infants receiving convalescent care in the neonatal intensive care units
      and showed no evidence of either NEC or sepsis. Twelve (of 375) additional
      infants (3.2%) who developed NEC and 100 (27%) who developed sepsis showed no RBC
      T activation. Twenty-three of 48 (48%) infants with T-activated RBCs received
      standard blood components, but no transfusion-associated hemolysis occurred.
      Donor plasma samples contained T but not T variant antibodies. CONCLUSION: T
      variant activation of RBCs occurs in healthy neonates as well as in infants with
      NEC and sepsis, but T activation appears rare. Transfusion- associated hemolysis
      was not seen. The provision of specially prepared blood components for infants
      with NEC is unnecessary.

PMID- 12421216
TI  - Prophylactic antigen-matched donor blood for patients with warm autoantibodies:
      an algorithm for transfusion management.
AB  - BACKGROUND: Patients with warm autoantibodies are at high risk for delayed
      hemolytic transfusion reactions due to the presence of alloantibodies. To provide
      blood safe for transfusion and to avoid adsorption studies in some cases, the
      provision of prophylactic antigen-matched donor blood where feasible for patients
      with warm autoantibodies is advocated. STUDY DESIGN AND METHODS: Twenty
      consecutive adult patients with warm autoantibodies (January 1999 to February
      2000) received chronic RBC transfusions by use of this protocol: the serology
      consistent with warm autoantibodies was confirmed; the alloantibodies were
      identified; the complete phenotype was determined (i.e., C, E, c, e, K, Jk(a),
      Jk(b), Fy(a), Fy(b), S, and s); and prophylactic antigen-matched (i.e., donor
      RBCs matched with the patient's phenotype), WBC-reduced donor RBCs were provided
      for transfusion. On subsequent admissions, samples were evaluated by panel
      studies and DATs. If the serology remained consistent with previous findings,
      prophylactic antigen-matched, WBC-reduced RBCs were transfused without further
      testing. RESULTS: Eight of 20 (40%) patients had existing, clinically significant
      alloantibodies. In 12 of 20 (60%) patients, a phenotype was determined and the
      patients received transfusion of a total of 149 prophylactic antigen-matched RBC
      units (mean, 15 units per patient) precluding adsorption studies on 51
      pretransfusion samples. In 8 of 20 (40%) cases (2 with alloantibodies),
      phenotypes were indeterminant, necessitating differential allogeneic adsorption
      studies on 39 samples before transfusion of 144 RBC units (mean, 18 units per
      patient). CONCLUSIONS: Determining complete phenotypes should be a routine
      component of the serologic evaluation of patients with warm autoantibodies. Our
      algorithm for providing prophylactic antigen-matched RBCs to these patients when
      a complete phenotype can be determined provides flexibility in their transfusion
      management while maintaining safety and circumvents or simplifies pretransfusion
      adsorption studies.

PMID- 12421217
TI  - RBC-associated IgG in patients with visceral leishmaniasis (kala-azar): a
      prospective analysis.
AB  - BACKGROUND: Despite the fact that anemia is one of the most striking clinical
      features of visceral leishmaniasis (kala-azar), the factors involved in its
      pathogenesis are not fully understood. Although the cause of the anemia seen in
      these patients is often multifactorial, sequestration and destruction of the RBCs
      in the enlarged spleen, immune mechanisms, and alterations in RBC membrane
      permeability have been implicated. STUDY DESIGN AND METHODS: To investigate
      whether RBCs of patients with kala-azar were coated with IgG, blood samples of 67
      patients were tested, prospectively, before (Day 1), during (Day 30), and after
      (Day 90) antimonial therapy, to examine the presence of RBC-associated IgG,
      circulating immune complexes (CICs), and rheumatoid factor (RF). RESULTS: The
      prevalence of a positive DAT on Day 1 was significantly greater than the
      prevalence of a positive DAT performed on Day 30 and on Day 90 (32.8 vs. 4 vs.
      0%, p < 0.001). With an enzyme-linked antiglobulin test (ELAT) to measure the
      number of IgG molecules per RBC more accurately, it was found that the amount of
      IgG molecules per RBC was increased (mean, 298 molecules of IgG per RBC) in the
      group of patients with kala-azar tested before antimonial therapy, but was
      considered normal (<50 molecules of IgG per RBC) in all patients tested 90 days
      after treatment. The prevalence of a positive eluate test was low (15.0%) in DAT
      (anti-IgG)-positive patients and the positivity of DATs and ELATs correlated with
      the presence of either RF or CICs, respectively. CONCLUSIONS: These data suggest
      that a nonspecific adsorption of CICs on the RBC surface is probably the most
      important factor involved in the increased amount of RBC-associated IgG in
      patients with untreated visceral leishmaniasis; however, further prospective
      studies are required to establish the exact role of the RBC-associated
      antibodies, CICs, and RF as contributing factors of the anemia seen in these
      patients.

PMID- 12421218
TI  - Acquired and transient RBC CD55 deficiency (Inab phenotype) and anti-IFC.
AB  - BACKGROUND: Antigens of the Cromer blood group system reside on the glycoprotein
      CD55 (decay-accelerating factor). The Inab phenotype is the null phenotype of
      this system. So far, only five propositi have been described who exhibit this
      phenotype, and single-nucleotide substitutions in the CD55 gene have been found
      in three of them. This report describes the first example of a patient with an
      acquired and transient form of the Inab phenotype. CASE REPORT: A 54-year-old
      black patient was admitted to the hospital because of abdominal pain. Multiple
      splenic infarctions were visualized in the abdominal computerized tomography
      scan, and a prophylactic splenectomy was performed. The patient's serum reacted
      by an IAT with all donor RBCs tested. RESULTS: Serologic analysis showed that the
      patient had the rare Inab phenotype and that his serum contained anti-IFC. Flow
      cytometry demonstrated the absence of CD55 on his RBCs, whereas lymphocytes,
      monocytes, granulocytes, and platelets expressed CD55, albeit at a weaker level
      than cells of common phenotypes. cDNA revealed no differences from the published
      sequences. Flow cytometry performed 12 months after splenectomy showed
      reappearance of the CD55 antigen; serologic tests performed after 17 months
      revealed that the anti-IFC had almost disappeared and that the RBCs were again
      agglutinated by various Cromer antibodies. CONCLUSION: A patient with an acquired
      and transient form of the Inab phenotype is described, in whom the CD55
      deficiency is limited to the RBCs and is associated with splenic infarctions.

PMID- 12421219
TI  - Hypotensive reaction during staphylococcal protein A column therapy in a patient
      with anomalous degradation of bradykinin and Des-Arg9-bradykinin after contact
      activation.
AB  - BACKGROUND: Hypotensive reactions have occurred in patients taking angiotensin
      converting enzyme (ACE) inhibitors after infusion of blood previously in contact
      with negatively charged surfaces capable of generating kinins, which accumulate
      when ACE, a kininase, is inhibited. A patient with anomalous bradykinin (BK)
      metabolism who experienced hypotension during extracorporeal staphylococcal
      protein A (SPA) therapy while on an ACE inhibitor was studied. CASE REPORT: A
      patient with mitomycin-associated hemolytic-uremic syndrome received SPA
      treatments after her ACE inhibitor, lisinopril, was held. Lisinopril was
      restarted before her 18th SPA treatment, and immediately after return of treated
      plasma she developed facial redness and hypotension, which resolved after the
      return stopped and recurred when restarted. To study formation and degradation of
      kinins, exposed her plasma to glass beads. We found a normal kinin formation rate
      but an abnormal degradation and accumulation of Des-Arg9-BK. The kinin
      degradation enzymes ACE, aminopeptidase P (APP), and carboxypeptidase N (CPN)
      were measured while on an ACE inhibitor, showing absence of ACE activity, low
      APP, but normal CPN. CONCLUSION: This patient's vasodilation and hypotension
      during SPA therapy was associated with a pre- existing anomaly of BK metabolism.
      Her ACE inhibitor shifted degradation toward Des-Arg9-BK formation, and her low
      APP was associated with a prolonged t50 and accumulation of the vasoactive Des
      Arg9-BK.

PMID- 12421220
TI  - Sickle Hb polymerization in RBC components from donors with sickle cell trait
      prevents effective WBC reduction by filtration.
AB  - BACKGROUND: RBC components collected from donors with sickle cell trait
      frequently occlude WBC-reduction filters. In vitro, sickle trait RBCs have the
      potential for sickle Hb (Hb S) polymerization at low oxygen saturations and high
      Hb concentrations. STUDY DESIGN AND METHOD: To determine if the low pH and high
      osmolarity of the CP2D used in the collection contributed to filter failures, the
      filterability of sickle trait donor RBCs collected in CP2D was compared with RBCs
      from the same donors collected in heparin. RESULTS: Five of six sickle trait
      components collected in CP2D did not complete filtration, but all six RBC
      components collected in heparin filtered completely. RBC components collected in
      CP2D from four other sickle trait donors were divided in two, and one-half was
      treated with carbon monoxide to convert Hb S to its liganded form to prevent Hb S
      polymerization. All four carbon monoxide-treated components filtered within 9
      minutes, but only one untreated component filtered completely. RBC components
      collected by apheresis contained less CP2D, and five of seven sickle trait
      apheresis components filtered completely; four of the five filtered rapidly (<15
      min) and one filtered in 100 minutes. Hb oxygen saturation was greater in the
      four rapidly filtering apheresis RBC components (68 +/- 9%) than in the three
      that filtered slowly or incompletely (37 +/- 5%, p = 0.03). CONCLUSIONS: Hb S
      polymerization appears responsible for RBC WBC-reduction filter failures. Citrate
      anticoagulant and low oxygen saturation are responsible in part for Hb S
      polymerization in this setting.

PMID- 12421221
TI  - Parvovirus B19 transmission by heat-treated clotting factor concentrates.
AB  - BACKGROUND: Human parvovirus B19 (B19) DNA can be frequently detected in plasma
      derived coagulation factor concentrates. The production of some clotting factor
      products includes heat treatment steps for virus inactivation, but the
      effectiveness of such steps for B19 inactivation is unclear. Moreover, detailed
      transmission case reports including DNA sequence analysis and quantification of
      B19 DNA from contaminated heat-treated blood components have not been provided so
      far. Therefore, the correlation between B19 DNA in blood components and
      infectivity remains unclear. STUDY DESIGN AND METHODS: Asymptomatic B19
      infections of two patients with hemophilia A were detected by anti-B19
      seroconversion after administration of B19-contaminated heat-treated clotting
      factors. The suitability of nucleic acid sequence analysis for confirmation of
      B19 transmission was investigated. Furthermore, the B19 DNA level in blood
      components was determined and the drug administration was reviewed to calculate
      the amount of inoculated B19 DNA. RESULTS: Both B19 transmissions from clotting
      factor products could be confirmed by identical nucleic acid sequences of virus
      DNA from patients and blood components while sequences from unrelated controls
      could be differentiated. One patient received, for 4 days, a total of 180 mL
      vapor heat-treated prothrombin complex concentrate containing 8.6 x 10(6) genome
      equivalents per mL of B19 DNA. The other patient received 966 mL of low
      contamination (4.0 x 10(3) genome equivalents/mL) dry heat-treated FVIII
      concentrate over a period of 52 days. CONCLUSION: B19 transmissions can be
      confirmed by nucleic acid sequencing. However, due to the low variability of the
      B19 genome, a large part of the B19 genome must be analyzed. The transmissions
      show that the applied heat treatment procedures were not sufficient to inactivate
      B19 completely.

PMID- 12421222
TI  - Investigation of transfusion transmission of a WA1-type babesial parasite to a
      premature infant in California.
AB  - BACKGROUND: A premature infant in California developed respiratory distress
      associated with infection with a protozoal parasite, Babesia. The infant had
      received two blood transfusions, one from the father and one from an anonymous
      donor (Donor A). This study describes the follow-up required to identify the
      source and species of Babesia that infected the infant. STUDY DESIGN AND METHODS:
      At the time of the infant's illness, whole blood from the infant, father, and
      mother was evaluated for Babesia infection. Similar evaluation of whole blood
      from Donor A was performed 2 months after the suspected donation to the infant.
      Samples were tested using blood smear examination, serology, PCR, and hamster
      inoculation. Identity of the recovered Babesia parasites was confirmed by DNA
      amplification by PCR, genetic sequencing of the 18S gene, and phylogenetic
      analysis. RESULTS: WA1-type Babesia was recovered from the infant. Neither parent
      was the source of infection. Serology and hamster inoculation confirmed WA1-type
      Babesia infection in Donor A. DNA sequences of the 18S gene from the infant and
      donor isolates were 100% identical. CONCLUSION: WA1-type Babesia infections may
      be difficult to detect among blood donors because such infections can be
      subclinical. This is the second WA1-type Babesia transmission via blood
      transfusion and the first in an infant. Physicians in the western United States
      should consider Babesia as a possible cause of nonspecific febrile illness after
      a blood transfusion.

PMID- 12421223
TI  - Identification of Babesia microti-specific immunodominant epitopes and
      development of a peptide EIA for detection of antibodies in serum.
AB  - BACKGROUND: Babesia microti is a tick-borne agent that is increasingly implicated
      in transfusion-acquired infection, especially in immunocompromised and elderly
      recipients. To develop a test that can detect antibody responses to B. microti,
      peptide epitopes identified in two serocomplementary B. microti-specific antigens
      were used in a prototype EIA. STUDY DESIGN AND METHODS: A prototype peptide EIA
      was used to detect B. microti-specific antibodies in 15 sera taken before
      infection and 107 taken after infection from 59 individuals with known tick-borne
      infections previously confirmed by other methods. Three additional groups of
      samples were also tested: a proficiency panel of 18 sera positive for B. microti
      by IFA, 38 sera from blood donors confirmed positive by IFA, and 30 sera from
      random blood donors. RESULTS: The combination peptide detected 98 out of 107 sera
      taken after infection that were IgG blot positive (4 equivocal). This included
      all 12 samples that were PCR positive and six sera from smear-negative patients
      that were confirmed positive by PCR, immunoblot, or IFA. Of the IgG blot-positive
      specimens that were equivocal (four specimens) or did not react (nine specimens)
      by EIA, most had low IFA titers consistent with previous exposure. In a second
      evaluation, 15 out of 15 Babesia IFA-positive sera and 3 out of 3 Babesia
      Ehrlichia IFA-positive sera were positive, whereas sera from 30 random donors
      were negative. Finally, of 38 IFA-positive blood-donor samples, 35 were positive
      by peptide EIA. The three EIA-negative sera were Western blot negative.
      CONCLUSION: Reactivity of the B. microti-specific peptide EIA shows a high
      correlation with IFA, PCR, and B. microti immunoblot in confirmed B. microti
      cases. The peptide EIA may be the most suitable B. microti infection test for
      adaptation to the blood bank environment if testing for B. microti is required in
      the future.

PMID- 12421224
TI  - Partitioning of human and sheep forms of the pathogenic prion protein during the
      purification of therapeutic proteins from human plasma.
AB  - BACKGROUND: Therapeutic proteins derived from human plasma and other biologic
      sources have demonstrated an excellent safety record relative to the potential
      threat of transmissible spongiform encephalopathy (TSE) transmission. Previously,
      hamster-adapted scrapie was used as a model agent to assess TSE clearance in
      purification steps leading to the isolation of biopharmaceutical proteins. The
      current study investigated the validity of hamster scrapie as a model for human
      TSE clearance studies. The partitioning of the pathogenic forms of the prion
      protein associated with human variant CJD (PrP(vCJD)), human sporadic CJD
      (PrP(sCJD)) and Gerstmann-Straussler-Scheinker (PrP(GSS)) syndrome was compared
      to the partitioning of hamster scrapie (PrP(Sc)) in three plasma protein
      purification steps. Sheep scrapie (PrP(Sc)) was similarly evaluated. STUDY DESIGN
      AND METHODS: The starting materials for three plasma protein purification steps,
      cryoseparation, 3 percent PEG separation, and 11.5 percent PEG separation, were
      spiked with brain homogenates containing human PrP(vCJD), human PrP(sCJD), human
      PrP(GSS), sheep PrP(Sc), and hamster 263K PrP(Sc). The partitioning of the
      pathogenic form of the PrP was analyzed. RESULTS: Clearance of the pathogenic
      form of the PrP was measured relative to the effluent fraction. Regardless of the
      source of the pathogenic prion, clearance was similar to hamster PrP(Sc). A
      nominal amount of clearance (approx., 1 log), an intermediate amount of clearance
      (approx., 2 log), and a substantial amount of clearance (> or = 3 log) were
      observed for the cryoseparation, 3 percent PEG separation, and 11.5 percent PEG
      separation steps, respectively. In the latter step, no PrP was detected in the
      effluents. CONCLUSIONS: These data demonstrate that human prions, including vCJD
      prions, can be removed during the purification of human therapeutic proteins and
      indicate that partitioning of human prions is similar to that observed in the
      hamster scrapie model.

PMID- 12421225
TI  - Outcome of an optional HCV screening program for blood transfusion recipients in
      Ireland.
AB  - BACKGROUND: An optional (general) HCV testing program for blood and blood
      component recipients before the introduction of routine donor anti-HCV screening
      (October 1991) was launched in Ireland in 1995 to complement the targeted
      lookback program in progress at that time and to identify transfusion-transmitted
      hepatitis C. STUDY DESIGN AND METHODS: The public were informed of the
      opportunity to avail of screening by widespread media coverage. Screening was by
      an initial ELISA (Abbott 3.0, Abbott Laboratories) at the transfusion center
      laboratories. Reactive samples were referred to a virus reference laboratory
      where two additional ELISAs (Ortho 3.0, Ortho Clinical Diagnostics; and Murex
      3.0, Murex) were performed. Confirmation of ELISA-positive samples was by a RIBA
      (RIBA 3.0, Chiron Corp.). All patients found to be anti-HCV- seropositive were
      tested for HCV RNA by PCR and were referred to a hepatologist. RESULTS: A total
      of 14,917 persons have been tested for hepatitis C in this program to date (85%
      women). Sixty-one people were confirmed positive for HCV by RIBA 3.0 (0.4%).
      Excluding persons with other risk factors (n = 15), the HCV positivity rate for
      blood component transfusion recipients (n = 46) was 0.3 percent. Of the 46
      confirmed hepatitis C-positive blood component transfusion recipients, 32 were
      women (70%), 24 of whom received transfusion for obstetric or gynecologic
      indications (75%). Thirty-eight of 46 (83%) anti-HCV seropositive transfusion
      recipients tested had detectable HCV RNA by PCR. CONCLUSION: This program
      identified 46 transfusion recipients and 10 coagulation factor concentrate
      recipients, all of whom were previously unaware of their infection. The majority
      of HCV-positive transfusion recipients identified were women. This may reflect
      that women are longer living survivors of transfusion therapy or alternatively,
      in our experience, that Irish women perceive themselves at greater risk of
      hepatitis C because of the well-publicized association of this virus with
      recipients (women) of Irish RhIG.

PMID- 12421226
TI  - Comparative yield of HCV RNA testing in blood donors screened by 2.0 versus 3.0
      antibody assays.
AB  - BACKGROUND: Two HCV antibody tests (EIA 2.0 [EIA2], Abbott; and the Version 3.0
      ELISA [EIA3], Ortho) are currently licensed for screening of US blood donors.
      Testing of donors for HCV RNA allows comparison of the sensitivities of the two
      antibody-screening assays. STUDY DESIGN AND METHODS: All allogeneic blood
      donations at 13 US test sites were screened for HCV RNA by testing plasma
      minipools using an investigational assay (COBAS AmpliScreen HCV test, v2.0, Roche
      Molecular Systems). Some sites screened for HCV antibody by EIA2 and some used
      EIA3. The frequency of RNA-positive and antibody-negative (RNA-pos and Ab-neg)
      donations among donors screened by each antibody assay was compared. Antibody
      appearance was assessed in a donor follow-up study. RESULTS: A total of 5.51 x
      10(6) donations were screened for HCV RNA. Of these, 2.27 million were screened
      for antibody by EIA2, and 3.24 million by EIA3. Twenty-three donations were HCV
      RNA-pos and Ab-neg. The frequency of RNA-pos and Ab-neg donations was higher
      among donations screened by EIA2 (1 in 134,000), compared to those screened by
      EIA3 (1 in 540,000) (p = 0.001). Of the 17 RNA-pos and Ab-neg donations
      identified by test sites that used EIA2, 14 were retested by EIA3 and 10 (71%)
      were reactive. Most RNA-pos and Ab-neg donors appear to be in the process of
      seroconversion. Donors that were initially EIA2-negative and EIA3-reactive showed
      a more prolonged pattern of seroconversion compared to those that were initially
      nonreactive by both antibody assays. Four donors were EIA2-negative, EIA3
      reactive, and RIBA-indeterminate (c33c) for at least 90 days, 1 for more than 317
      days. CONCLUSION: EIA3 would have detected the majority of RNA-positive donations
      missed by EIA2. Some RNA-positive donors are EIA2-negative and EIA3-reactive for
      a prolonged period of time.

PMID- 12421227
TI  - Predictive value of circulating immature cell counts in peripheral blood for
      timing of peripheral blood progenitor cell collection after G-CSF plus
      chemotherapy-induced mobilization.
AB  - BACKGROUND: Enumeration of CD34+ cells in peripheral blood (PB) before apheresis
      predicts the number of CD34+ cells collected, although flow cytometric techniques
      used are complex and expensive. In an attempt to determine the optimal timing for
      peripheral blood progenitor cell (PBPC) collection, the usefulness of circulating
      immature cell (CIC) counts in PB was evaluated. STUDY DESIGN AND METHODS: CIC
      counts in PB and CD34+ cell counts in the apheresis product from 249 collections
      were assessed, and the relationship between these two parameters was evaluated by
      with the Pearson rank correlation analysis, the Fisher exact test, and the U
      test. RESULTS: CIC counts were correlated significantly with the number of CD34+
      cells per kg of patient's body weight in the apheresis product (Pearson rank
      correlation analysis: r = 0.635, p < 0.0001). When a level of 1 x 10(9) CICs per
      L was selected as a cutoff value, the sensitivity and specificity for collecting
      more than 1 x 10(6) CD34+ cells per kg of body weight were 75.7 and 85.5 percent,
      respectively. CONCLUSION: The present study strongly suggests that the number of
      CICs in PB may estimate the number of CD34+ cells collected. The data indicate
      that CIC counts above 1 x 10(9) per L can be used as a good predictor for PBPC
      collections containing more than 1 x 10(6) CD34+ cells per kg of body weight in a
      single apheresis procedure.

PMID- 12421228
TI  - Human neutrophil antigens.

PMID- 12421229
TI  - Deficiency of ADAMTS13 and thrombotic thrombocytopenic purpura.

PMID- 12421231
TI  - Use of the Procleix HIV-1 and HCV discriminatory assays to detect HIV and HCV RNA
      in whole blood.

PMID- 12421234
TI  - Evidence-based respiratory medicine: why, where and how.

PMID- 12421232
TI  - ABO-mismatched platelet transfusions and clinical outcomes after cardiac surgery.

PMID- 12421236
TI  - CD4+ T cells in lung tissue predict responsiveness to cyclosporin A in
      interstitial pneumonia.
AB  - OBJECTIVE: A limited number of case studies have demonstrated the steroid-sparing
      and disease stabilization effects of cyclosporin A (CsA) combined with
      corticosteroid in patients with chronic interstitial pneumonia (IP). Although CsA
      is known to inhibit the proliferation and function of CD4+ T cells, it is not
      clear what type of IP is responsive to CsA administration. METHODOLOGY: In order
      to evaluate whether any lymphocyte subsets in alveolar tissue predict the
      responsiveness to CsA, morphometric analysis was performed on lung tissue
      obtained from six IP patients who were treated with a combination of CsA and
      steroid because the therapeutic effect of steroid alone had been limited.
      RESULTS: Cell densities of CD4+ T cells were significantly decreased in the
      alveolar tissues obtained from CsA responders (n = 3) compared to non-responders
      (n = 3) (120 +/- 86/mm2 vs 503 +/- 172/mm2, P=0.0495). CD4/CD8 ratios of CsA
      responders were also significantly lower than those of non-responders (0.315 +/-
      0.070 vs 1.975 +/- 0.965, P=0.0463). However, cell densities of CD8+ T cell and
      areas of B cells aggregates were similar in both groups. CONCLUSIONS: The present
      observations, contrary to expectation, reveal that lower cell densities of CD4+ T
      cells and lower CD4/CD8 ratios are associated with responsiveness to CsA in
      combination therapy, suggesting that pharmacological actions other than
      suppression of CD4+ T cells explain the efficacy of CsA in patients with chronic
      IP.

PMID- 12421237
TI  - Molecular mechanisms underlying human beta-defensin-2 gene expression in a human
      airway cell line (LC2/ad).
AB  - OBJECTIVE: Recently, human beta-defensin-2 (hBD-2), an inducible defensin, has
      been reported to be involved in innate immunity and host defence. To examine the
      exact roles of hBD-2 in the respiratory system, we examined the molecular
      mechanisms of hBD-2 gene expression in vitro. METHODOLOGY: Using a human airway
      cell line (LC-2/ad), lipopolysaccharide (LPS)-induced gene expression of hBD-2
      was studied in the absence or the presence of (i) dexamethasone, (ii) inhibition
      of NF-kappaB and AP-1, (iii) intracellular calcium chelator, and (iv)
      cyclooxygenase (COX) inhibitors. RESULTS: Lipopolysaccharide-induced gene
      expression of hBD-2 was down-regulated by (i) dexamethasone, (ii) inhibition of
      NF-kappaB and AP-1, and (iii) intracellular calcium chelator. However, COX
      inhibitors had no effect on LPS-induced mRNA expression of hBD-2. CONCLUSION:
      These findings suggest that glucocorticoids (GC), but not COX inhibitors, reduce
      hBD-2 gene expression, while NF-kappaB, AP-1 and intracellular calcium are
      essential for hBD-2 expression. Glucocorticoid-induced down-regulation of hBD-2
      might be involved in the GC-induced suppression of respiratory host defence
      associated with hBD-2.

PMID- 12421238
TI  - Preliminary evaluation of soluble IL-2 receptor and type III procollagen N
      terminal aminopeptide in pleural fluid for differentiating tuberculous,
      carcinomatous and parapneumonic pleural effusions.
AB  - OBJECTIVE: The aim of the study was to clarify the possibility of using pleural
      fluid levels of soluble IL-2 receptor (sIL-2R) and type III procollagen N
      terminal aminopeptide (PIIIP) for differentiating tuberculous, carcinomatous and
      parapneumonic pleural effusions. METHODOLOGY: Fifty patients with pleural
      effusions were investigated retrospectively. The pleural effusions were due to
      tuberculosis (n = 11), carcinoma (n = 22), pneumonia (n = 9) and heart failure (n
      = 8). The concentrations of sIL-2R and PIIIP were measured in pleural effusion
      using commercially available kits. RESULTS: Soluble IL-2 receptor concentrations
      were highest in the patients with tuberculosis (6,856 +/- 3,212 U/mL), followed
      by those with carcinoma (4,680 +/- 1,872 U/mL), pneumonia (2,227 +/- 525 U/mL)
      and heart failure (1,439 +/- 244 U/mL). Significant differences were found
      between tuberculosis and carcinoma (P = 0.023), carcinoma and pneumonia (P =
      0.015), and pneumonia and heart failure (P = 0.002) groups. Type III procollagen
      N-terminal aminopeptide concentrations were higher in the patients with
      tuberculosis (262.5 +/- 157.9 U/mL) and pneumonia (257.0 +/- 96.7 U/mL) than in
      those with carcinoma (48.0 +/- 27.7 U/mL) and heart failure (10.9 +/- 5.6 U/mL).
      Significant differences were found between tuberculosis and carcinoma (P < 0.001)
      and pneumonia and carcinoma (P < 0.001). To differentiate effusions, the cutoff
      points of sIL-2R (2,980 U/mL) and PIIIP (110.0 U/mL) were obtained from the
      highest concentration in the pneumonia group and in the carcinoma group,
      respectively. Using these criteria, the sensitivities for differentiating
      tuberculous, carcinomatous, and parapneumonic effusions were 90.9, 86.4 and
      88.9%, respectively, with 100, 95 and 100% specificity, respectively.
      CONCLUSIONS: The simultaneous determination of sIL-2R and PIIIP concentrations in
      pleural effusions may be clinically useful in differentiating tuberculous,
      carcinomatous, and parapneumonic effusions. Further assessments are required to
      determine the broad clinical application of this assay.

PMID- 12421239
TI  - Addition of a 2-month low-dose course of levofloxacin to long-term erythromycin
      therapy in sinobronchial syndrome.
AB  - BACKGROUND: We previously reported that a 6-month low-dose course of ofloxacin
      combined with long-term low-dose erythromycin therapy (EM therapy) was superior
      to EM therapy alone for sinobronchial syndrome (SBS), especially during the
      initial 2 months of treatment. However, there was no data as to whether
      discontinuation of low-dose ofloxacin after 2 months results in symptom relapse.
      This study was designed to clarify this issue. METHODOLOGY: Twenty-three patients
      with SBS received a 2-month course of levofloxacin (LVFX) therapy (100 mg once a
      day) concurrent with a 6-month course of EM therapy (200 mg three times a day)
      (group A). Eighteen other patients were given the EM therapy alone (group B).
      Clinical parameters, including quantity of morning sputum, were recorded in a
      daily symptom diary, and reviewed by each doctor in charge at 2-4 week intervals.
      RESULTS: The quantity of morning sputum decreased more rapidly in group A than in
      group B. No relapse of symptoms was recognized after discontinuation of LVFX in
      group A. CONCLUSIONS: A 2-month low-dose course of LVFX in conjunction with long
      term EM therapy may be efficacious for the treatment of SBS, as evidenced by
      rapid improvement of expectoration without any relapse after LVFX
      discontinuation.

PMID- 12421240
TI  - Prevalence of respiratory symptoms related to chronic obstructive pulmonary
      disease and asthma among middle aged and older adults.
AB  - OBJECTIVE: The aim of this study was to assess the prevalence of chronic
      obstructive pulmonary disease in middle aged and older adults. METHODOLOGY: A
      random sample of 7,005 adults aged between 45 and 69 years was drawn from
      electoral rolls for Melbourne, Victoria, Australia. A postal survey was conducted
      using the European Community Respiratory Health Survey respiratory screening
      questionnaire with additional questions on chronic bronchitis and emphysema.
      Participants were asked to return the survey by reply mail. Non-responders were
      sent a reminder postcard after 2 weeks, a replacement questionnaire after 4 weeks
      and then contacted by telephone. RESULTS: Completed questionnaires were returned
      by 4,906 (70.0%) participants. The commonest symptoms were exertional dyspnoea
      (27.2%) and wheezing (20.5%). Chronic bronchitis was reported by 12.0% and
      emphysema by 1.2%. Males were significantly more likely to report cough and
      sputum, while females were more likely to report asthma. The prevalence of
      exertional dyspnoea, cough and sputum, emphysema and heart disease increased with
      age. Chronic bronchitis, emphysema and most respiratory symptoms were associated
      with smoking. CONCLUSIONS: Self-reported chronic bronchitis or emphysema affect
      one in eight middle aged and older adults. Differences between men and women are
      partly explained by differences in smoking. These findings require confirmation
      with lung function tests.

PMID- 12421241
TI  - The relationship between FEV1 and PEF in the assessment of the severity of
      airways obstruction.
AB  - OBJECTIVE: International consensus guidelines suggest that in asthma and chronic
      obstructive pulmonary disease (COPD), measurements of FEV1 and PEF are equivalent
      in the assessment of the degree of airflow obstruction when expressed as the per
      cent of predicted values. METHODOLOGY: In this retrospective study, 2,587 paired
      measurements of PEF and FEV1 performed by 101 adult patients with asthma (n = 56)
      and COPD (n = 45) attending an outpatient chest clinic were obtained. The mean
      differences between FEV1 and PEF measurements when expressed as the percentage of
      predicted values was determined. The level of agreement between the two
      measurements in the classification of asthma severity (life-threatening, severe,
      moderate and mild asthma determined by PEF or FEV1 measurements of <30%, 30-60%,
      60-80%, and >80% of the predicted values, respectively) was determined. RESULTS:
      There was considerable variability between measurements of FEV1 and PEF when
      expressed as % predicted values. In both asthma and COPD, the FEV1% predicted was
      smaller than the PEF % predicted, with the mean difference being -10.9% (95% CI, 
      12.8% to -8.9%) with limits of agreement of -35.4% to +13.6%. The weighted Kappa
      statistic for agreement was 0.59 (95% CI, 48-70%) in the classification of the
      severity of airflow obstruction. CONCLUSION: When expressed as percentage of
      predicted values, PEF and FEV1 values are not equivalent. We recommend that
      guidelines be modified to state that across the spectrum of the severity of
      airflow obstruction there is considerable variability between measurements of
      FEV1 and PEF when expressed as % predicted such that the FEV1 may be as much as
      35% lower or up to 15% higher than the PEF for patients with obstructive lung
      diseases.

PMID- 12421242
TI  - Bronchial hyperresponsiveness in patients with squamous cell lung cancer.
AB  - OBJECTIVE: The aim of this study was to examine the relationship between
      bronchial hyperresponsiveness, both in vivo and in vitro, and the type of lung
      cancer (squamous cell or adenocarcinoma). METHODOLOGY: We measured airway
      responsiveness by methacholine inhalation test in 33 patients with squamous cell
      lung cancer and 44 patients with lung adenocarcinoma. In addition, airway smooth
      muscle reactivity to acetylcholine was measured in vitro in specimens from some
      patients. RESULTS: Seventeen of 33 patients with squamous cell cancer and three
      of 44 patients with adenocarcinoma showed bronchial hyperresponsiveness (BHR).
      Multiple regression analysis as used to assess the log of the minimum cumulative
      dose to decrease respiratory conductance vs six variables: cancer phenotype, FEV1
      (% predicted), FEV1/FVC (%), smoking pack years, gender and the location of
      tumour. The phenotype (squamous cell cancer) was the only factor associated with
      BHR. However, there was no significant difference in airway smooth muscle
      reactivity to acetylcholine in vitro in bronchial muscle samples from squamous
      cell cancer patients (n = 6) and adenocarcinoma patients (n = 6). CONCLUSION: The
      present findings suggest that bronchial hyperresponsiveness in patients with
      squamous cell lung cancer is not determined solely by bronchial smooth muscle
      hyperreactivity.

PMID- 12421243
TI  - Skin prick test reactivity to common aeroallergens in asthmatic patients with and
      without rhinitis.
AB  - OBJECTIVE: The aim of this study was to investigate the prevalence of skin prick
      test (SPT) reactivity to common aeroallergens among Malaysian asthmatic patients
      with and without rhinitis. METHODOLOGY: An SPT using eight aeroallergens
      (Dermatophagoides pteronyssinus, Dermatophagoides farinae, cat fur, cockroach,
      Acacia sp., Bermuda grass, Aspergillus fumigatus and Aspergillus niger) was
      performed on 206 asthmatic patients. RESULTS: One hundred and forty patients
      (68%) were reactive to at least one of the aeroallergens. Among the SPT-positive
      patients, a positive prick test reaction to the house dust mites, D.
      pteronyssinus (93.6%), and D. farinae (81.4%) was most common, followed by cat
      fur (20.0%), cockroach (7.9%), Bermuda grass (7.9%), Acacia sp. (7.9%), A.
      fumigatus (0.7%) and A. niger (0.7%). A history of rhinitis was elicited in 111
      (53.9%) patients and 95 (85.3%) of these patients were SPT-positive compared with
      only 45 (47.4%) of 95 patients with asthma symptoms alone (P < 0.001). The
      presence of rhinitis and a young age of onset of asthma were independent factors
      for positive SPT reaction to at least one of the aeroallergens. CONCLUSIONS: The
      prevalence of SPT reactivity to common aeroallergens is high among Malaysian
      asthmatics, particularly in those with an early age of onset and in those with
      coexisting rhinitis.

PMID- 12421244
TI  - What is the optimal approach for using a direct amplification test in the routine
      diagnosis of pulmonary tuberculosis? A preliminary assessment.
AB  - OBJECTIVE: The aim of this study was to determine the most appropriate strategy
      for the rapid diagnosis of pulmonary tuberculosis (PTB) using a nucleic acid
      amplification (NAA) test. METHODOLOGY: This was a prospective study of 128 adult
      patients in whom respiratory secretions were tested for Mycobacterium
      tuberculosis by the AMPLICOR assay. The basis for starting PTB treatment was
      noted for each patient. The optimal approach was determined by using Bayes'
      theorem to compare different combinations of pretest probability, smear results
      with the AMPLICOR test. RESULTS: The incidence of PTB was 15.6%. In only one
      patient was treatment for PTB commenced because of a positive AMPLICOR result.
      The rest were managed according to the conventional approach which relied upon
      clinical judgment and direct smear. The optimal approach was to treat patients
      with high or intermediate pretest risk for PTB who returned positive AMPLICOR
      tests. The overall accuracies of the conventional approach, AMPLICOR test and
      optimal approach were 89.8, 95.3 and 96.1%, respectively. CONCLUSION: This small
      study suggests that NAA testing be limited to patients with high or intermediate
      pretest risk of PTB. In this group, positive results demand treatment while the
      management of those with negative results still relies on clinical judgment.

PMID- 12421245
TI  - Clinicopathological features of chronic hypersensitivity pneumonitis.
AB  - OBJECTIVE: Only limited information exists concerning the clinical and
      pathological features of chronic hypersensitivity pneumonitis (HP) in Japan and
      elsewhere. We present data on clinicopathological features of chronic HP obtained
      through a Japanese nationwide survey. METHODOLOGY: We studied the clinical and
      pathological findings in 10 patients with chronic HP who underwent surgical lung
      biopsy or postmortem examination. RESULTS: There were three types of clinical
      course: six of the 10 patients had persistent symptoms followed by repeated acute
      episodes; two showed a subacute onset with persistent symptoms; and two exhibited
      an insidious onset. Five patients made no attempt to avoid antigen exposure and
      they all had progressive disease. Pathological findings indicated that lesions
      were mainly centrilobular with or without epithelioid cell granulomas in
      specimens obtained during the acute or subacute stage. In contrast, most patients
      in the chronic stage predominantly showed interstitial fibrosis with a usual
      interstitial pneumonia pattern. CONCLUSIONS: The pathological findings of chronic
      HP depend on the stage of the disease at tissue sampling.

PMID- 12421246
TI  - A case of refractory bilateral pleural effusion due to post-irradiation
      constrictive pericarditis.
AB  - A 51-year-old woman suffering from dyspnoea and refractory bilateral pleural
      effusions is discussed. The effusion was characterized as a transudate and
      cardiac decompensation and renal insufficiency were initially suspected. Diuretic
      agents were not effective and the patient required bilateral chest water-sealed
      drainage tubes for 4 months, after exclusion of neoplastic infiltration, collagen
      disease and other cardiac disorders. On echocardiogram, cardiac function and
      other findings were almost normal, except for shortening of deceleration time in
      transmitral flow velocity. To evaluate the reduced diastolic compliance, cardiac
      catheterization was performed, and revealed an elevated pressure in the right
      ventricle with a dip-and-plateau pattern, and constrictive pericarditis was
      diagnosed. The hydrothorax resolved after pericardiectomy and symptoms were
      alleviated. Three and a half years after surgery, the patient is well and taking
      only oral diuretics. The underlying mechanism of cardiac disorder appears to have
      been mixed restriction and constriction due to irradiation of her chest for
      breast cancer 13 years ago. Because the echocardiogram was within normal limits,
      the diagnosis was delayed. Radiation-induced constrictive pericarditis should be
      considered if there is an unexplained transudate effusion with a normal
      echocardiogram.

PMID- 12421247
TI  - Pulmonary glomus tumour: a case initially diagnosed as carcinoid tumour.
AB  - Pulmonary glomus tumours are rare lesions, with few cases reported previously.
      Herein, we present the clinical and pathological features of a case of pulmonary
      glomus tumour. A 29-year-old female patient presented to our clinic complaining
      of cough, dyspnoea and left-sided chest pain. Computed tomography (CT) of the
      thorax revealed a nodular lesion causing obstruction of the left main bronchus.
      Fibreoptic bronchoscopy demonstrated a polypoid mass occluding the left main
      bronchus 10 mm distal to the main carina. Bronchoscopic biopsy was interpreted
      histologically as carcinoid tumour. Bronchotomy plus mass extirpation was
      performed with left thoracotomy. Microscopically, a tumoral structure composed of
      uniform cells with a round centrally located nucleolus and narrow eosinophilic
      cytoplasm was seen. Thin-walled vessels lined with endothelium were interspersed
      between tumoral structures. The cells were stained chromogranin and cytokeratin
      negative and strongly vimentin positive. The pathological diagnosis for the
      thoracotomy specimen was pulmonary glomus tumour. Follow-up chest CT was negative
      for recurrent tumour and the patient remains free of disease 17 months after
      surgery.

PMID- 12421248
TI  - Fatal idiopathic acute eosinophilic pneumonia with acute lung injury.
AB  - A fatal case of idiopathic eosinophilic pneumonia with acute lung injury is
      described. The patient required treatment with mechanical ventilation and
      intravenous corticosteroids, however, she died on the third hospital day. At
      autopsy, both exudative and proliferative phases of diffuse alveolar damage were
      observed bilaterally. Marked eosinophilic infiltrate was noted in the alveolar
      wall and within the alveolar cavities with occasional abscess-like features. To
      our knowledge, this is the first report of fatal acute eosinophilic pneumonia,
      and provides important information for the management of this condition.

PMID- 12421249
TI  - Resolution of native lung pneumothorax by insertion of a nitinol stent for
      bronchostenosis in the transplanted lung.
AB  - Following single lung transplantation, the native lung remains a potential source
      of morbidity from spontaneous pneumothorax, hyperinflation, bacterial and fungal
      infection and malignancy. The case of a single lung transplant recipient for
      idiopathic pulmonary fibrosis who developed a recurrent, non-resolving,
      spontaneous multiloculated pneumothorax in the native lung following
      thoracoscopic talc pleurodesis is reported. The pneumothorax ultimately resolved
      following insertion of a nitinol stent for coexisting bronchostenosis in the
      transplanted lung. In a single lung transplantation recipient in whom a native
      lung pneumothorax reoccurs or persists despite appropriate initial management, it
      may be useful to undertake bronchoscopy to exclude the possibility of
      bronchostenosis in the transplanted lung.

PMID- 12421252
TI  - Natural progress of blood glucose in full-term low-grade low-birthweight infants.
AB  - BACKGROUND: Although various authors have suggested the risk of hypoglycemia in
      practical medicine for low-birthweight infants is exaggerated, convincing
      evidence using recent definitions of hypoglycemia is not documented. METHODS: To
      evaluate the risk of hypoglycemia in low grade low-birthweight infants (LGLBWI)
      (2100 g < birthweight < 2500 g) whose only abnormality is low-birthweight, whole
      blood glucose (BGw) was measured five times (0, 0.5, 1, and 4 h after birth and
      just before the first bottle feeding) in 49 LGLBWI and 38 normal birthweight
      infants. RESULTS: Whole blood glucose was not lower in LGLBWI with a gestational
      age of 38-40 weeks (GT38LGLBWI) than in normal birthweight individuals with a
      gestational age of 38-40 weeks at each of the five measuring times. No case of
      GT38LGLBWI, not even in small for gestational age infants, required treatment for
      hypoglycemia. The BGw was significantly lower in 37-week gestational age LGLBWI
      than in GT38LGLBWI at 0.5 h and 1 h after birth (P < 0.05). However, in all cases
      with low BGw value (below 30 mg/dL at 1 h after birth), BGw value increased
      naturally to the normal level 1.5 h after birth. No symptoms of hypoglycemia were
      observed. CONCLUSIONS: In the care of hypoglycemia in LGLBWI, attention should be
      paid first to gestational age, namely, tendency to prematurity. In this study,
      however, no hypoglycemia that required treatment was found among full-term normal
      LGLBWI, even those who were small for gestational age. Frequent blood glucose
      measurement for those infants is therefore unnecessary.

PMID- 12421253
TI  - Nucleated red blood cell counts and erythropoietin levels in high-risk neonates.
AB  - BACKGROUND: The presence of increased numbers of nucleated red blood cells (NRBC)
      and increased levels of erythropoietin (EPO) in the circulation of neonates has
      been associated with states of relative hypoxia. The aim of this study is to
      assess the pattern of NRBC counts and EPO levels in a group of high-risk neonates
      under stress conditions and determine the short-term outcome for these babies by
      using these parameters. METHODS: There were 69 high-risk neonates; 14
      intrauterine growth retarded (IUGR), 25 preterm infants, 18 term infants with
      asphyxia and 12 infants of diabetic mothers. Control groups included healthy,
      term infants delivered either vaginally (n = 18) or with cesarean section (n =
      19). Three blood samples were obtained from each infant within 12 h (initial), 3
      days and 7 days after birth to measure NRBC counts and EPO levels. Neonatal and
      short-term outcomes at 3 and 6 months of age were determined. RESULTS: There was
      no significant difference among the groups with regard to the initial serum EPO
      concentrations. The initial NRBC counts were significantly lower in the control
      groups compared with the study groups (P = 0.002). While there was no significant
      difference between patients with good and poor outcome in terms of EPO
      concentrations of initial samples, a significant difference existed in terms of
      NRBC counts (P = 0.038). CONCLUSIONS: Both serum EPO level and NRBC count provide
      limited clinical benefit in the detection of pathological conditions of the
      neonatal period, but NRBC count determination seems to be especially helpful in
      predicting short-term neurodevelopmental outcome.

PMID- 12421254
TI  - New criteria of normal serum lipid levels in Japanese children: the nationwide
      study.
AB  - AIM: To make new criteria of serum lipid levels in current Japanese children
      using the large nationwide data provided from Japan Association of Health Service
      for the analysis. METHODS: The subjects were schoolchildren who received
      screening and care programs for lifestyle related diseases since 1993-1999. Serum
      total cholesterol (TC), high-density lipoprotein cholesterol (HDLC) and
      triglyceride (TG) levels were measured, and low-density lipoprotein cholesterol
      (LDLC) levels were calculated. Serum lipid levels were analyzed by age and sex.
      For each serum lipid, we extracted age- and sex-specific group which the mean
      value was not statistically different from that in 1999 by Student's t-test
      analysis. RESULTS: The level below the 75th percentile was defined to be
      acceptable, from the 75th to 95th to be borderline and over the 95th to be high
      in TC/LDLC. The level below the fifth percentile in HDLC was defined to be low
      and the level over the 95th percentile in TG to be high. Therefore, TC level was
      categorized as follows: acceptable < 190 mg/dL; borderline 190-219 mg/dL; and
      high > 220 mg/dL. The LDLC level was also categorized into: acceptable < 110
      mg/dL; borderline 110-139 mg/dL; and high > 140 mg/dL. The cut-off value in TG
      was determined to be 140 mg/dL and in HDLC was 40 mg/dL. CONCLUSIONS: This new
      criteria should prove valuable in health strategies for rational prevention and
      intervention in children. It should be emphasized to provide some intervention
      for Japanese children immediately.

PMID- 12421255
TI  - Dyslipidemia in young Japanese children: its relation to familial
      hypercholesterolemia and familial combined hyperlipidemia.
AB  - BACKGROUND: Most cases of dyslipidemia found in adults are non-familial. However,
      in children, especially young children, dyslipidemias other than familial
      hypercholesterolemia (FH) have not yet been characterized. METHODS: From April
      1990 to March 1999, 56 181 children were screened, and 1380 showed abnormal
      levels of apolipoprotein B (more than 2.5 standard deviations above the mean).
      Among these, 1198 were re-examined and further characterized by measuring lipids
      and apolipoproteins, and by their familial histories. RESULTS: Seventy-seven
      percent of the children (928 of 1198) recalled were diagnosed as being
      dyslipidemic. Ninety-one children were FH, 423 were type IIa, 128 were type IIb,
      98 were type IV, and 188 were hypoalphalipoproteinemia. The presumed incidence of
      FH was 0.19%, IIa 0.87%, IIb 0.26%, IV 0.20%, and hypoalphalipoproteinemia 0.39%,
      taking into account the percentage of subjects who refused recall. At regular
      follow-ups, in many children with type IIb, the phenotypic expression changes
      from type IIb to IIa or IV. Thus, lipid and apolipoprotein levels were determined
      in 77 family members in 34 families of children with type IIb. Forty-five family
      members were dyslipidemic (type IIa 18, type IIb 11, type IV 16). As a result, 27
      children (79%) with type IIb met the criteria for familial combined
      hyperlipidemia. CONCLUSIONS: Children with dyslipidemia had more family or
      genetic background than adults. Unexpectedly, children with type IIb were mostly
      familial combined hyperlipidemia. Thus, setting appropriate eating patterns
      during childhood might be important for normalizing risk factors for
      atherosclerotic coronary heart disease, especially in children with FH or type
      IIb.

PMID- 12421256
TI  - Childhood idiopathic nephrotic syndrome in Turkey.
AB  - BACKGROUND: It has been reported that there are racial and regional differences
      in peak incidence age, histopathological features and response to steroid therapy
      in childhood idiopathic nephrotic syndrome. METHODS: One hundred and thirty-eight
      patients with a diagnosis of idiopathic nephrotic syndrome, followed up in 1994
      2000, were assessed retrospectively. The aim of this study was to assess the
      patients' response pattern to steroid therapy, to determine whether the duration
      of the initial steroid therapy alters the steroid response pattern of the disease
      and to assess renal biopsy results. RESULTS: One hundred and fourteen patients
      who initially received only steroid therapy and were followed up regularly were
      classified according to response pattern. Of the 114 patients, 30 children had an
      initial response, 25 children had infrequent relapse, 19 had frequent relapse, 25
      had steroid dependence and 15 children had steroid resistance. The 99 patients
      with steroid responsive nephrotic syndrome were divided into two groups with
      respect to duration of the initial steroid therapy. There was no statistically
      significant difference between standard and short therapy groups with respect to
      the steroid response patterns. Percutaneous renal biopsy was performed in 43 of
      the 138 patients. Mesengioproliferative glomerulonephritis was the most common
      histopathological lesion, followed by membranoproliferative glomerulonephritis.
      The proportions of membranous glomerulonephritis, focal segmental
      glomerulosclerosis and minimal change nephrotic syndrome were low in our group.
      CONCLUSIONS: Our study group is similar to one reported from Saudi Arabia with
      respect to the steroid response pattern and to Saudi Arabian and Nigerian reports
      with respect to the histopathology. Although it has been reported that short
      initial steroid therapy was followed by a higher rate of relapses, there was no
      statistically significant difference between standard and short therapy groups
      with respect to the relapse rate in our study group.

PMID- 12421257
TI  - Most reliable indices in differentiation between thalassemia trait and iron
      deficiency anemia.
AB  - BACKGROUND: Iron deficiency anemia (IDA) and thalassemia trait (TT) are the most
      common forms of microcytic anemia. Some discrimination indices calculated from
      red blood cell indices are defined and used for rapid discrimination between TT
      and IDA. However, there has been no study carried out in which the validity of
      all of the defined indices are compared in the same patient groups. Youden's
      index is the most reliable method by which to measure the validity of a
      particular technique, because it takes into account both sensitivity and
      specificity. METHODS: We calculated eight discrimination indices (Mentzer Index,
      England and Fraser Index, Srivastava Index, Green and King Index, Shine and Lal
      Index, red blood cell (RBC) count, red blood cell distribution width and red
      blood cell blood distribution width index (RDWI)) in 26 patients with IDA and in
      37 patients with beta TT (betaTT). We determined the number of correctly
      identified patients by using each discrimination index. We also calculated
      sensitivity, specificity, positive and negative predictive value and Youden's
      index of each discrimination index. RESULTS: None of the discrimination indices
      showed a sensitivity and specificity of 100%. Youden's indices of RBC count and
      RDWI were the highest with the value of 82 and 80%, respectively. Ninety percent
      and 92% of the patients were correctly identified with RBC and RDWI,
      respectively. CONCLUSIONS: Red blood cell count and RDWI are the most reliable
      discrimination indices in differentiation between betaTT and IDA.

PMID- 12421258
TI  - DNA damage in children treated with imipramine for primary nocturnal enuresis.
AB  - BACKGROUND: Despite the fact that primary nocturnal enuresis (PNE) is self
      limited and pathologically benign, the emotional stress and inconvenience that it
      produces, warrants treatment. Imipramine is one of the widely used drugs in PNE
      treatment. Although some mutagenic effects were suggested in imipramine
      administration, this toxicity has never been investigated in enuretic patients.
      The aim of this study was to evaluate the association of exposure to imipramine
      with DNA damage. METHODS: Thirty-five children treated with imipramine for at
      least 4.5 months who were in otherwise good health were accepted into the
      investigation. Twenty healthy sisters or brothers of the patients who did not use
      any long-term drugs were studied simultaneously as the control group. Comet assay
      was used to evaluate DNA damage. RESULTS: Damaged (limited and extensive
      migrated) cells of the enuretic children who were taking imipramine were
      statically higher than that of the control group (P < 0.05) indicating a
      detectable DNA damaging effect of imipramine in human lymphocytes. CONCLUSIONS:
      Our finding suggests that the difference in comet scores between two groups was
      induced by the imipramine treatment. The other possibility to be considered is
      the psychological stress of the children who were concerned by the symptoms and
      their parent's anxiety. As our preliminary data were based on a limited number of
      children, further research is needed considering the importance of this possible
      toxic effects which may be associated with mutagenicity.

PMID- 12421259
TI  - Factors that affect television viewing time in preschool and primary
      schoolchildren.
AB  - BACKGROUND: Excessive viewing of television (TV) has been linked to aggressive
      behavior, violence and childhood obesity. METHODS: A cross-sectional study was
      conducted among preschool children and primary schoolchildren in Ankara during
      March and April 1999 to detect the factors that affect TV viewing time and to
      evaluate their parents' knowledge, attitudes and practices with regard to TV. The
      parents were asked to fill out a questionnaire about TV habits of their family,
      the number and location of TVs in the household and the effect of TV on children.
      Of 400 questionnaires, 350 answered the questions appropriately for this study.
      Children were divided into two groups, preschool children and primary
      schoolchildren. Television viewing time was given daily, as a mean of weekday.
      RESULTS: The mean age for becoming a TV viewer was 2.7 +/- 1.6 years. Of all, 62%
      of children spent >/= 2h/day watching TV and 8.3% of children spent > 4 h. The TV
      viewing time of child was significantly and positively correlated with that of
      siblings, mother and father for both groups. Age and sleeping time of the child,
      age and the education level of mother, presence of TV in the child's room and the
      starting age watching TV did not affect the viewing time. One-half of parents
      reported that the TV programs watched included violence, and one-third thought TV
      depicts child abuse, especially emotional abuse. CONCLUSIONS: It was found that
      the TV watching habits of parents had an influence on those of their children.
      Therefore, pediatricians should take 'TV histories' of children and their parents
      and educate parents how to become good TV viewers.

PMID- 12421260
TI  - Efficacy and safety of rectal thiopental, intramuscular cocktail and rectal
      midazolam for sedation in children undergoing neuroimaging.
AB  - BACKGROUND: This study was designed to investigate the overall usefulness of
      rectal thiopental, rectal midazolam and i.m. modified cocktail (meperidine
      chlorpromazine hydrochloride-feniramin maleat) in 70 children undergoing computed
      tomography (CT) and magnetic resonance imaging (MRI). METHODS: The dosage of
      thiopental was 50 mg per kg for infants under 6 months of age, 35 mg per kg
      between six and 12 months, and 25 mg per kg for older children. The maximal dose
      did not exceed 700 mg in this study. The dosage of midazolam was 1 mg per kg for
      all children. A modified cocktail was described as a formulation including 11
      mg/mL of meperidine, 2.8 mg/mL of chlorpromazine and 2.8 mg/mL of pheniramine
      maleat. The dosage of modified cocktail was 0.1 mL per kg for all children.
      RESULTS: The mean induction time for the i.m. cocktail was significantly longer
      than that for rectal thiopental (P < 0.001). The mean duration of deep sedation
      was 60.79 +/- 27.00 min with rectal thiopental and 58.74 +/- 39.70 min with i.m.
      cocktail (P > 0.05). Although the mean duration of sleep for rectal thiopental
      and i.m. cocktail was similar, the mean discharge duration for i.m. cocktail was
      significantly longer than that for rectal thiopental (P < 0.05). Children sedated
      with the cocktail therapy also required a longer period of observation in the
      department. Significant decreases in heart rate, systolic blood pressure and
      oxygen saturation occurred in three groups (P < 0.001). Significant decreases in
      body temperature occurred after rectal thiopental and i.m. cocktail therapy (P <
      0.01). The effect of rectal midazolam was minimal. CONCLUSIONS: Rectal thiopental
      may be the drug of choice for pediatric sedation because it has a more rapid
      onset and offset of action. It is also safe and effective at the dosage studied
      in children undergoing MRI. Rectal midazolam also may be used in children
      undergoing CT imaging because of minimal side-effects.

PMID- 12421261
TI  - Dual chamber cardiac pacing in children: Single chamber pacing dual chamber
      sensing cardiac pacemaker or dual chamber pacing and sensing cardiac pacemaker?
AB  - BACKGROUND: Dual chamber pacemakers (single chamber pacing dual chamber sensing
      cardiac pacemaker (VDD) and dual chamber pacing and sensing cardiac pacemaker
      (DDD)) are being used frequently in children and adolescents. The aim of this
      study was to verify the safety and performance of the VDD and DDD pacing systems,
      and to evaluate the differences between two pacing modes with regard to atrial
      sensing and tracking functions. METHODS: In this study, we evaluated 14 patients
      with VDD pacing and 15 patients with DDD pacing between 1994 and 2000. In the
      patient group with VDD pacing, all had congenital or acquired atrioventricular
      (AV) block. In the patient group with DDD pacing, 11 had congenital or acquired
      AV block, three had sinus node dysfunction with AV conduction disturbance and one
      had idiopathic hypertrophic subaortic stenosis. Twenty-eight devices were
      implanted in the subpectoral area using the transvenous route. After implantation
      the atrial tracking capabilities of the pacing systems were analyzed by
      telemetry, Holter monitoring, and treadmill exercise testing. RESULTS: The mean
      age of patients in the VDD pacing group was younger. The percentage of congenital
      heart disease was higher in the DDD pacing group. There was no significant
      difference regarding fluoroscopy time during implantation and follow-up time
      between the two groups. During implantation, in the VDD pacing group the mean
      sensed atrial signal was 3.1 +/- 1.3 mV and this decreased to 1.37 +/- 0.68 mV (P
      < 0.05) during follow-up. This pattern was also observed in DDD group (3 +/- 2 mV
      vs 1.9 +/- 1.5 mV, P < 0.05). Although the P wave measurement at implantation did
      not differ between the two groups, it was significantly higher in the DDD pacing
      group at the last control. Three patients with VDD pacing were reprogrammed to
      VVI or single chamber pacing and sensing, rate adaptive cardiac pacemaker because
      of complete loss of AV synchrony. There was no atrial sensing problem in the DDD
      pacing group. During the follow-up, one patient with VDD pacing developed
      diaphragmatic stimulation and required lead revision. In one patient with DDD
      pacing, venous thrombosis occurred in the right subclavian vein and was treated
      with thrombolytic therapy. During treadmill exercise testing, in one patient with
      VDD and one patient with DDD pacing temporary failure of atrial sensing occurred.
      At 24 h Holter monitoring, intermittent loss of atrial sensing was documented in
      two patients with VDD pacing. CONCLUSIONS: Dual chamber pacing in children with
      DDD or VDD pacemakers is a suitable method for bradycardia treatment. Atrial
      sensing problems may occur in VDD pacemakers. Therefore, DDD pacing mode should
      be preferred whenever suitable for the patient to maintain the AV synchrony.

PMID- 12421262
TI  - Trend of neonatal group B streptococcal infection during the last 15 years.
AB  - BACKGROUND: The survey was designed to determine the trend of group B
      streptococcal (GBS) infection during the last 15 years, as well as update the
      reality of this disease. METHODS: Questionnaires were administered every 5 years
      towards neonatal intensive care unit-equipped hospitals. The first survey was
      made from 1983 to 1987, the second one from 1988 to 1992 and the third one from
      1993 to 1997. The 15-year questionnaire survey included a total of 831 patients.
      The changes in number of patients, the ages at onset, the diagnosis, the
      serotypes of causative agents, the presence or absence of complicated delivery
      and the prognosis were analyzed. RESULTS: It seems that the increasing trend of
      the number of patients has stopped in the period from 1993 to 1997 (third
      survey). The most common causative subtype was type III GBS, regardless of early
      onset type or late onset type. As to perinatal abnormality, approximately 40% of
      the early onset cases were free from risk factors. Concerning the prognosis,
      22.6% of early onset cases and 38.7% of late onset cases died or had sequelae.
      CONCLUSIONS: The number of GBS-infected cases has stopped increasing, but it is
      still necessary to carry out screenings of pregnant women for the purpose of
      decreasing the onset of the disease.

PMID- 12421263
TI  - Investigation of risk factors for tonsillopharyngitis with macrolide resistant
      Streptococcus pyogenes in Turkish children.
AB  - BACKGROUND: Streptococcus pyogenes is the most important causative agent of
      tonsillopharyngitis. Although penicillin is the drug of choice in streptococcal
      tonsillopharyngitis, macrolides are recommended drugs in patients who have an
      allergy to penicillin. However, resistance to macrolides is an important problem
      in some regions of the world. Risk factors for resistance development have not
      been investigated sufficiently. OBJECTIVES: To investigate the risk factors for
      the development of tonsillopharyngitis with macrolide resistant S. pyogenes.
      METHODS: Three hundred and forty-five children with tonsillopharyngitis caused by
      S. pyogenes were investigated for various risk factors. Streptococcus pyogenes
      isolated from children's throat culture were examined for erythromycin,
      clarithromycin and azithromycin susceptibility. RESULTS: Two hundred and sixty
      three children were found eligible for the analysis of risk factors. Resistances
      to erythromycin, clarithromycin and azithromycin were detected as 3.8, 4.2 and
      4.2%, respectively. Macrolide use of the family members in the last 3 months
      (odds ratio = 7.04, P = 0.005) has been determined to be a risk factor for the
      development of tonsillopharyngitis with macrolide resistant S. pyogenes.
      CONCLUSION: Restriction of macrolide antibiotic use appears to be the most
      important measure to prevent the development of tonsillopharyngitis with
      resistant S. pyogenes.

PMID- 12421264
TI  - Septic arthritis in patients followed-up in neonatal intensive care unit.
AB  - BACKGROUND: Septic arthritis is an uncommon, but serious disorder in neonates.
      Most patients survive with permanent handicaps. Due to the rarity of this
      condition in neonates and paucity of signs and symptoms, the diagnosis of septic
      arthritis in newborns is more difficult than in older children. METHODS: Septic
      arthritis or suppurative arthritis is an infection of the joint by a variety of
      microorganisms, including bacteria, viruses, mycobacteria and fungi. Purulent
      synovial fluid, positive culture and positive Gram stain were accepted as a gold
      standard for exact diagnosis. Fourteen neonates who were followed-up in a
      neonatal intensive care unit, with septic arthritis, were included in a study
      based on a review of medical reports and a long-term clinical and radiological
      follow-up. Clinical symptoms, bacteriology, risk factors and outcomes are
      discussed. RESULTS: Staphylococcus aureus was the predominant causative organism.
      Risk factors for septic arthritis were prematurity (4/14), umbilical
      catheterization or venous catheterization (3/14), sepsis (3/14), perinatal
      asphyxia (2/14) and difficult birth (1/14). All cases of septic arthritis in
      neonates were improved without squealae except in two patients. One patient died
      and one patient had severe squealae. In these two patients, the duration of
      disease from clinical onset to initiation of therapy was long. CONCLUSIONS: The
      most important prognostic factor in predicting a favorable outcome in neonatal
      septic arthritis is early diagnosis and therapy. When appropriate treatment is
      delayed, catastrophic sequelae are inevitable. Early diagnosis of the condition
      and rapid removal of pus are mandatory for the survival of the joint. Long-term
      follow-up may reveal effects of epiphyseal damage, early degenerative changes and
      limitation of the range of motion.

PMID- 12421265
TI  - Meatus tightly covered by the prepuce is associated with urinary infection.
AB  - BACKGROUND: Almost all newborns have phimosis, which is known as one of the risk
      factors for urinary infection. The present study analyzed which specific prepuce
      conditions correlated with the development of febrile urinary infection in
      Japanese male infants. METHODS: The subjects consisted of 100 children, 64 boys
      and 36 girls, with febrile urinary infection. Prepuces were classified by their
      retractability in the male patients and in 714 healthy boys. RESULTS: Ninety-four
      percent of first febrile urinary infections occurred before 7 months of age in
      boys, whereas only 37% of the girls had first infections by that age. The prepuce
      covered the external urethral meatus in 96% of the healthy boys aged 3 years or
      less. A gentle retraction maneuver could not uncover the urethral meatus in
      approximately 40% of the boys aged 0-6 months. The frequency started to decline
      spontaneously after that age. Male patients aged 0-6 months significantly more
      often had tightly covered meatus than did healthy neonates (85%vs 42%, P <
      0.0001). CONCLUSIONS: These findings indicate that it is specifically those boys
      whose external urethral meatus are tightly covered with foreskin who constitute
      the high-risk group for urinary infection. Awareness of this observation should
      help with diagnosing and managing urinary infection in young boys.

PMID- 12421266
TI  - Accelerated hepatitis B vaccination schedule in childhood.
AB  - BACKGROUND: For children travelling to a hepatitis B virus (HBV) endemic area or
      before a treatment by blood or blood productions, the conventional HBV
      vaccination schedule takes too long to be completed. There may be problems in the
      completion of the whole vaccination schedule in developing countries because of
      particular problems. In these situations an accelerated schedule may be useful
      for HBV vaccination. METHODS: In this study, 40 children were randomly divided
      into two groups. Groups were vaccinated according to two different schedules;
      schedule A: one dose at 0, 1, and 6 months and schedule B: one dose at 0, 10, and
      21 days (Engerix B, 10 mcg/0.5 ml, GlaxoSmithKline). Follow-up blood samples were
      obtained at 1, 6 and 12 months after the first vaccine injection. RESULTS:
      Seroconversion rates were 35 and 80% 1 month after the first vaccine injection,
      95 and 80% at 6 months, 95 and 100% at 12 months, in groups A and B respectively.
      Seroprotection rates were 20 and 65% 1 month after the first vaccine injection,
      85 and 70% at 6 months, 95 and 95% at 12 months, in groups A and B respectively.
      Seroconversion and seroprotection rates was significantly different at day 28 in
      accelerated vaccination schedule (P < 0.005). CONCLUSIONS: In conclusion, an
      accelerated vaccination course against HBV (three doses at 0, 10, and 21 days)
      elicited protective levels of anti-HBs antibodies more rapidly than a classic
      course (three doses at 0, 1, and 6 months) and without a difference in the rate
      of seroprotection after 1 year. The accelerated 3-week recombinant HBV
      vaccination schedule should be recommended for HBV prophylaxis when children,
      such as hurried travellers, who have to have blood and blood productions, or an
      estimated irregular vaccination, where they have < 1 month to complete the
      standard HBV vaccination schedule before travelling to HBV endemic areas.

PMID- 12421267
TI  - Seroepidemiology of Helicobacter pylori infection in children living in eastern
      Turkey.
AB  - BACKGROUND: The prevalence of Helicobacter pylori is higher in developing
      countries, with most infections occurring in childhood. Because the prevalence in
      eastern Turkey has not been previously reported, we carried out an investigation
      to detect the prevalence of H. pylori infection in a large city center in this
      region. METHODS: Serum samples of 466 randomly selected healthy schoolchildren
      aged 6-17 years were tested for the presence of anti-H. pylori IgG antibodies.
      RESULTS: Overall 300 (64.4%) samples were seropositive. The frequency of H.
      pylori infection was similar in males and females (P = 0.47), was correlated with
      age (P < 0.0001) and was inversely correlated with economic status (P < 0.0001).
      Those who had a larger sibship size had a higher seroprevalence (P < 0.0001).
      There was no significant difference between children whose parents of different
      educational status (P = 0.56 for fathers and P = 0.86 for mothers). CONCLUSIONS:
      This very high prevalence of H. pylori in eastern Turkey seems to depend on
      environmental factors.

PMID- 12421268
TI  - Nitric oxide further attenuates pulmonary hypertension in magnesium-treated
      piglets.
AB  - BACKGROUND: Persistent pulmonary hypertension of the newborn (PPHN) commonly
      appears as a complication of several pulmonary and non-pulmonary diseases. The
      hypoxia possibly inhibits Ca2+ +/- dependent K+ channels, thus resulting in
      membrane depolarization of pulmonary smooth muscle cells, which leads to the
      opening of Ca2+ channels and Ca2+ entry, resulting in contraction of the vascular
      smooth muscle. However, magnesium (Mg2+) is an antagonist of Ca2+. We studied the
      effect of magnesium sulfate on the treatment of hypoxia-induced pulmonary
      hypertension and compared to the site of action of nitric oxide (NO). METHODS:
      Zero-day-old piglets were used in each experiment. The effects of Mg2+ were
      tested in each hypoxic, normoxic and hyperoxic states. Once the desired physical
      state was achieved, Mg2+ was administered at a dose of 100 mg/kg approximately
      every 10 min. In order to determine the exact mechanism of the Mg2+, Nw-nitro-l
      arginine (LNNA), a NO synthase-inhibitor, was administered simultaneously with
      Mg2+ in some of the experiments. RESULTS: There was a significant correlation
      between the percent reduction of the pulmonary arterial pressure (PAP) caused by
      magnesium and the level of oxygen (O2) present in the pulmonary artery. The
      greatest amount of reduction was seen in the hypoxic condition where the least
      amount of O2 is found. A further reduction in the PAP was seen when NO was given
      at the end of the Mg2+ trials. There was no significant reduction seen in the
      systemic arterial pressure. CONCLUSIONS: Inhaled NO further reduced the PAP in
      piglets already treated with Mg2+.

PMID- 12421269
TI  - Developmental changes in cyclo-oxygenase mRNA induction by hypoxia in rat kidney.
AB  - BACKGROUND: Prostaglandins, synthesized by cyclo-oxygenase (COX), regulate renal
      hemodynamics and also epithelial water and solute transport. Developmental
      changes occur in COX-2 mRNA expression and its response to lipopolysaccharide
      stimulation in rats. We examined age-related changes in COX mRNA expression
      induced by hypoxia in the renal cortex and medulla of developing rats. METHODS:
      Total RNA was extracted from 1- and 4-week-old male Wistar rats exposed to one or
      4 h of hypoxia (8% O2). Cyclo-oxygenase mRNA was quantitatively analyzed using a
      real-time polymerase chain reaction with dual-labeled fluorogenic probes.
      RESULTS: Expression of COX-1 mRNA did not change in response to hypoxia in the
      cortex or medulla in either infantile or adult rats. In infantile rats, COX-2
      mRNA expression was not induced by one or 4 h of hypoxia. In adults, 1- and 4-h
      exposures to hypoxia induced COX-2 mRNA in the renal cortex, and 1-h of exposure
      induced COX-2 mRNA in the medulla. CONCLUSIONS: Response of expression of COX-2
      mRNA in rats exposed to acute hypoxia show age-related variability treated by
      acute hypoxia. Cyclo-oxygenase-2 might not play a major role in the hypoxic
      infantile rat kidney.

PMID- 12421270
TI  - White matter lesion due to dural sinus thrombosis in an infant with subdural
      hematoma.

PMID- 12421271
TI  - Chemotherapy-induced multiple vertebral compression fractures in a boy with acute
      lymphoblastic leukemia.

PMID- 12421272
TI  - Protein-losing enteropathy complicated with recurrent convulsions and
      developmental delay in a 4-month-old boy.

PMID- 12421273
TI  - Stenting pulmonary artery stenosis in an infant with tricuspid atresia: approach
      via the foramen ovale and ventricular septal defect using a long flexible sheath.

PMID- 12421274
TI  - Sudden death due to dissecting aortic aneurysm in an adolescent without any
      underlying disease.

PMID- 12421275
TI  - Transient pancytopenia associated with parvovirus infection in a healthy child.

PMID- 12421276
TI  - Hepatoblastoma in a low-birthweight infant complicated with cleft palate, Dandy
      Walker malformation and chronic lung disease.

PMID- 12421277
TI  - Disseminated candidiasis following prednisolone therapy in systemic lupus
      erythematosus.

PMID- 12421278
TI  - High concentration of serum nitrite/nitrate obtained from patients with influenza
      associated encephalopathy.

PMID- 12421279
TI  - New molecular methods to study gene functions in Candida infections.
AB  - Candida albicans has become a model system for human pathogenic fungi in clinical
      research, mainly due to the increasing number of Candida infections. Molecular
      techniques to study C. albicans virulence properties have been improved over the
      last few years, despite difficulties in genetic manipulation of this fungus. Some
      of the recent achievements from our own laboratory or from other groups are
      described in this article. The molecular analysis of the recently identified ATP
      dependent transporter Mlt1 using the green fluorescent protein (GFP) as reporter
      for protein localization and the dominant MPAR gene as a selection marker for
      gene inactivation provides an example for the study of gene functions in C.
      albicans.

PMID- 12421280
TI  - Histopathologic and histochemical characterization of calcified structures in
      hamsters inoculated with Paracoccidioides brasiliensis.
AB  - In pathogenicity studies of 31 Paracoccidioides brasiliensis isolates preserved
      using Castellani's method we intraperitoneally inoculated 104 young adult
      hamsters and found laminated concentric structures and calcified appearance that
      resembled Schaumann bodies, in 43 of them, especially in animals with apparently
      good condition. We characterized these structures histologically and
      histochemically using different stains (PAS, Grocott, haematoxylin-eosin, Von
      Kossa). The Von Kossa staining revealed calcium in these structures. Similar
      structures have been described in patients with sarcoidosis and also in hamsters
      inoculated with P. brasiliensis. We found no correlation between the presence of
      these calcifications and serum calcium levels.

PMID- 12421281
TI  - Invasive aspergillosis in cancer.
AB  - Ten confirmed cases of invasive aspergillosis (IA) in cancer patients were
      analysed retrospectively. Eight were pulmonary, one was sinonasal and one was
      cutaneous. The majority of patients had haematological malignancies (7), the
      remaining three were cases of solid tumours. Fever was present in all 10 cases.
      Cough and lung signs were present in all eight cases of invasive pulmonary
      aspergillosis. Haemoptysis was encountered in three of nine cases of pulmonary
      and sinonasal aspergillosis. Mortality was low (2%). While corticosteroids,
      antibiotics and anticancer chemotherapy/radiotherapy were factors predisposing
      the patients to IA, neutropenia was perhaps responsible for their mortality.
      Seven of the patients had other associated pathogens isolated in culture in
      addition to Aspergillus spp. Aspergillus fumigatus was the predominant species,
      followed by A. flavus, A. glaucus, A. nidulans and A. niger. Direct microscopic
      examination (in six of seven cases) and culture (six of seven cases) correlated
      well with radiographic and clinical findings in cases with lung involvement.
      Serology for anti-Aspergillus antibodies performed by gel diffusion precipitin
      test was positive in one case of sinonasal aspergillosis, wherein only one
      precipitin band was observed. Correlation of clinical symptoms, consistent
      radiographic findings and microbiological work-up (the latter including a triad
      of direct microscopy, culture and serology) are required to arrive at a diagnosis
      of IA, especially where histology cannot form the mainstay of diagnosis.

PMID- 12421282
TI  - Clinicopathological and mycological spectrum of allergic fungal sinusitis in
      South India.
AB  - In the present study, we describe characteristic clinicopathological and
      radiological features as well as fungal culture results in a series of 24
      patients with allergic fungal sinusitis (AFS). Nasal obstruction and discharge
      with nasal polyposis was the commonest (95.8%) clinical presentation. Allergic
      mucin was uniformly present in all patients. Aspergillus species were the
      commonest fungal isolates (95.8%). One case of mixed Aspergillus and Curvularia
      sinusitis as well as one case of Drechslera sinusitis were also identified.
      Typical computerized tomography scan features of hyperdense areas interspersed
      with soft tissue densities in the affected sinuses were seen in all patients.
      Application of appropriate diagnostic criteria is essential to establish the
      diagnosis of AFS and distinguish it from invasive fungal sinus infections.

PMID- 12421283
TI  - Immunohistochemical study of subcutaneous phaeohyphomycoses.
AB  - Immunohistochemical study of inflammatory infiltrate was carried out in five
      cases of subcutaneous phaeohyphomycosis before and after therapy. The infections
      were due to the genus Alternaria in four cases and genus Cladosporium in one. In
      four cases, infiltrating T cells with helper memory phenotype were slightly more
      abundant after therapy (70-80% versus 75-90% of T lymphocytes) and those with
      suppressor cytotoxic phenotype were slightly less abundant (20-25% versus 10
      15%). In one case, CD8+, Tia-1+ lymphocytes constituted 50% of the T-cell
      infiltrate before and after therapy. In all cases, the infiltrate contained many
      CD79 a+ plasma cells, which increased slightly after therapy, and a high CD1a
      positivity of dendritic cells (presumably Langerhans cells) before and after
      therapy. The CD1a+ cells were detected in the epidermis and in granulomatous
      infiltrate; in the dermis and subcutis, many were close to fungal structures. In
      four cases, intra-epidermal CD1a+ cell number was slightly lower than in control
      skin. CD68+ cells were not found in the epidermis.

PMID- 12421284
TI  - High prevalence of the neurotrope Exophiala dermatitidis and related oligotrophic
      black yeasts in sauna facilities.
AB  - The black yeast Exophiala dermatitidis, an agent of fatal brain infections in
      East Asia, is common in European steam baths. The related fungi Sarcinomyces
      phaeomuriformis and Exophiala mesophila were isolated from locations in these
      complexes with lower ambient temperature and/or moisture. The latter two species
      had dry, rather than slimy, colonies and lower maximum growth temperatures (38
      degrees C, 32 degrees C) than E. dermatitidis (42 degrees C). Exophiala
      dermatitidis produces abundant extracellular polysaccharide (EPS). The only E.
      dermatitidis strains lacking EPS were found outside the steam baths. Therefore it
      is likely that the extracellular polysaccharides commonly produced by E.
      dermatitidis are significant to survival under hot and moist conditions.
      Substrates sampled as controls, such as fruit surfaces and human faeces, yielded
      Exophiala dermatitidis at very low frequency.

PMID- 12421285
TI  - In vitro susceptibilities of cerebrospinal fluid isolates of Cryptococcus
      neoformans collected during a ten-year period against fluconazole, voriconazole
      and posaconazole (SCH56592).
AB  - We investigated the in vitro susceptibilities of 213 cerebrospinal fluid isolates
      of Cryptococcus neoformans isolated from 192 patients through a 10-year period,
      1990-99, against fluconazole, voriconazole and posaconazole (SCH56592) by using
      the NCCLS (National Committee for Clinical Laboratory Standards) macrodilution
      method, M27-A. The overall MICs50 and MICs90 of fluconazole, voriconazole and
      posaconazole were found to be 2 and 8 micro g ml-1, <or=0.125 micro g ml-1
      (both), and <or=0.015 and 0.06 micro g ml-1, respectively. The MIC ranges,
      MICs50, and MICs90 of three triazoles were also determined according to the
      defined year category (1990-94, 1995, 1996, 1997 and 1998-99). The MICs50 and
      MICs90 of each triazole remained almost unchanged and did not exhibit any sign of
      an upward shift during a decade (1990-99). However, a tendency for development of
      possible cross-resistance between the three triazoles was observed only in 1996.
      Meanwhile, the individual relapsing isolates (n:21) from 20 patients exhibited
      same, higher or, suprisingly, lower MICs, particularly against fluconazole and
      posaconazole.

PMID- 12421286
TI  - Ground red hot pepper agar in the isolation and presumptive identification of
      Cryptococcus neoformans.
AB  - The study compared ground red hot pepper agar (GRHP) and Guizotia abyssinica
      creatinine agar (GACA), a medium routinely used for isolation of Cryptococcus
      neoformans. In order to confirm the capacity of GRHP to support the Cr.
      neoformans growth and pigment production, 15 strains were inoculated onto GRHP
      and GACA. No significant differences in the growth and pigmentation of the tested
      strains on the two media were noted. As heavily contaminated specimens, 50
      samples of pigeon droppings were examined by plating on GRHP and GACA, which
      resulted in the isolation of 14 and nine Cr. neoformans strains, respectively.
      The results indicate that GRHP, as a result of its superior selectivity and
      significant reduction of contaminant growth, provides better conditions than GACA
      for isolation and presumptive identification of Cr. neoformans from heavily
      contaminated specimens.

PMID- 12421287
TI  - Bacterial and Candida adhesion to intact and denatured collagen in vitro.
AB  - Several recent reports imply the possibility of cariogenicity and periodontal
      disease linked to denture plaque containing Candida albicans. Adhesion of oral
      bacteria and Candida species to the extracellular matrix, such as type I
      collagen, fibronectin and denatured type I collagen, was examined by using
      adenosine triphosphate (ATP) analysis. The adhesion of C. albicans to intact and
      denatured type I collagen was significantly greater than those of oral bacteria
      and other species of Candida. This result suggests that C. albicans possesses the
      ability to adhere specifically to extracellular matrix, as compared with other
      Candida species or oral bacteria.

PMID- 12421289
TI  - Did earthworms contribute to the parasitic evolution of dermatophytes?
AB  - The survival of dermatophyte species in the gut of four species of earthworms was
      studied by feeding the fungi to the earthworms. Recovery of the dermatophyte
      species in culture from the guts was only possible for Microsporum gypseum and
      Chrysosporium keratinophilum. In the light of these findings, we presume that
      earthworms could have influenced the parasitic evolution of certain
      dermatophytes.

PMID- 12421288
TI  - Limited genetic diversity of Candida albicans in fecal flora of healthy
      volunteers and inpatients: a proposed basis for strain homogeneity in clinical
      isolates.
AB  - Molecular analysis of Candida albicans isolates from individual patients often
      yields a single strain at multiple sites. Whether this strain-limitation is due
      to virulence factors favoring the invasive strain or to lack of genetic diversity
      in the gastrointestinal reservoir is uncertain. We elected to study C. albicans
      genotypes in the fecal flora among healthy volunteers and inpatients. Self
      obtained stool swabs or stool samples were cultured on inhibitory mold agar. From
      each subject with C. albicans, nine colonies were randomly selected, individually
      propagated, and typed utilizing random amplified polymorphic DNA. Colonies were
      considered identical (all bands matched), related variants (one to three unique
      bands), or distinct strains (more than three unique bands). Analysis showed a
      single clone in 33/43 (76.7%) volunteers and 6/18 (33.3%) inpatients (P = 0.018),
      two to four related variants in eight (18.6%) volunteers and 10 (55.6%)
      inpatients, and two distinct strains in two volunteers (4.6%) and two inpatients
      (11.1%). Strain variation was more common in females (33.5 versus 5.6%; P = 0.04)
      and tended to increase with age (r = 0.245, P = 0.06). These findings illustrate
      that most healthy subjects harbor a single strain of C. albicans in the fecal
      flora. This strain may undergo genetic evolution leading to minor clonal
      variations. The mechanisms for strain selection, maintenance and possible
      evolution remain to be delineated.

PMID- 12421290
TI  - Case Report. Maxillary sinus infection due to Emericella nidulans.
AB  - Fungal infections of the maxillary sinus are frequently caused by Aspergillus
      species, particularly A. fumigatus. In otherwise healthy persons there is an
      association with overfilling of dental root canals, when zinc-containing filling
      materials were used. Below, a maxillary sinus aspergilloma is reported in a young
      immunocompetent female patient caused by Aspergillus (Emericella) nidulans.

PMID- 12421291
TI  - Aspergillus nidulans is frequently resistant to amphotericin B.
AB  - The high failure rate of amphotericin B-based therapy in patients with
      Aspergillus nidulans infections may not be entirely a result of host factors as
      suggested previously. Innate resistance of A. nidulans to polyenes may contribute
      to the poor response in patients.

PMID- 12421292
TI  - Case Report. Disseminated aspergillosis complicating pregnancy.
AB  - We report a case of disseminated aspergillosis in a hitherto healthy 24-year-old
      woman during her 24th week of pregnancy. Relevant findings at autopsy revealed
      innumerable septate, dichotomously branched (45 degrees ) hyphae compatible with
      Aspergillus in lung and liver tissues. Cerebral histology showed cerebral vessels
      occluded by hyphae causing cerebral infarction. There was no evidence of invasive
      aspergillosis in the placenta and fetal tissues. Aspergillus sp. was confirmed by
      amplification of a specific 357-base-pair amplicon from a paraffin block
      containing lung tissue. This case illustrates a previously uncharacterized
      spectrum of disseminated aspergillosis, indicating the need for a heightened
      awareness that Aspergillus species are opportunistic agents for invasive and
      disseminated infection in pregnancy.

PMID- 12421293
TI  - Case Report. Oro-facial manifestations of Penicillium marneffei infection in a
      Thai patient with AIDS.
AB  - Penicillium marneffei infection is prevalent in South-East Asia and Southern
      China and has been considered an acquired immunodeficiency syndrome (AIDS)
      defining disease. This report focuses on the oral and facial manifestations of P.
      marneffei infection in a 28-year-old Thai male patient with AIDS. The clinical,
      mycological and ultrastructural features are described.

PMID- 12421294
TI  - Case Report. Bilateral sporotrichosis.
AB  - We describe a rare case of sporotrichosis, clinically exuberant, with bilateral
      distribution.

PMID- 12421295
TI  - Case Reports. Infection due to Scedosporium apiospermum in renal transplant
      recipients: a report of two cases and literature review of central nervous system
      and cutaneous infections by Pseudallescheria boydii/Sc. apiospermum.
AB  - Two cases of infections due to Scedosporium apiospermum in renal transplant
      recipients, one localized in the central nervous system, the other in the skin,
      are presented, and a literature review of 21 cases of central nervous system and
      cutaneous infections due to Pseudallescheria boydii/Sc. apiospermum is given.

PMID- 12421296
TI  - Case Report. Bullous tinea pedis in an elderly man.
AB  - We report a case of recurrent bullous tinea pedis that had been misdiagnosed for
      a long time and treated with oral steroids. Initially, direct microscopy of
      potassium hydroxide preparations was negative and culture did not reveal any
      fungal organism. In a biopsy taken simultaneously from the edge of a bulla and
      stained with periodic acid-Schiff, septate mycelia were clearly visible.
      Trichophyton mentagrophytes was later identified in repeated cultures. The
      infection resulted in two clinical variants of tinea: initially, the
      vesiculobullous type and later - after intake of steroids because of an unrelated
      disease - the dry squamous hyperkeratotic type. The change of the clinical
      pattern indicates the important role of the host's immune response in determining
      the clinical presentation of the disease.

PMID- 12421297
TI  - Case reports. Tinea gladiatorum due to Trichophyton mentagrophytes.
AB  - Two cases of tinea gladiatorum due to Trichophyton mentagrophytes var.
      quinckeanum are described. A pet rabbit was probably the primary source of
      infection, which was then spread further by man-to-man contact. Besides these two
      patients, four other members of the same wrestling team were affected by tinea
      corporis.

PMID- 12421299
TI  - The histidine kinase Hik33 perceives osmotic stress and cold stress in
      Synechocystis sp PCC 6803.
AB  - The stress imposed on living organisms by hyperosmotic conditions and low
      temperature appears to be perceived via changes in the physical state of membrane
      lipids. We compared genome-wide patterns of transcription between wild-type
      Synechocystis sp. PCC 6803 and cells with a mutation in the histidine kinase
      Hik33 using a DNA microarray. Our results indicated that Hik33 regulated the
      expression of both osmostress-inducible and cold-inducible genes. The respective
      genes that were regulated by Hik33 under hyperosmotic and low-temperature
      conditions were, for the most part, different from one another. However, Hik33
      also regulated the expression of a set of genes whose expression was induced both
      by osmotic stress and by cold stress. These results indicate that Hik33 is
      involved in responses to osmotic stress and low-temperature stress but that the
      mechanisms of the responses differ.

PMID- 12421300
TI  - Primary and secondary metabolism, and post-translational protein modifications,
      as portrayed by proteomic analysis of Streptomyces coelicolor.
AB  - The newly sequenced genome of Streptomyces coelicolor is estimated to encode 7825
      theoretical proteins. We have mapped approximately 10% of the theoretical
      proteome experimentally using two-dimensional gel electrophoresis and matrix
      assisted laser desorption ionization time-of-flight (MALDI-TOF) mass
      spectrometry. Products from 770 different genes were identified, and the types of
      proteins represented are discussed in terms of their annotated functional
      classes. An average of 1.2 proteins per gene was observed, indicating extensive
      post-translational regulation. Examples of modification by N-acetylation,
      adenylylation and proteolytic processing were characterized using mass
      spectrometry. Proteins from both primary and certain secondary metabolic pathways
      are strongly represented on the map, and a number of these enzymes were
      identified at more than one two-dimensional gel location. Post-translational
      modification mechanisms may therefore play a significant role in the regulation
      of these pathways. Unexpectedly, one of the enzymes for synthesis of the
      actinorhodin polyketide antibiotic appears to be located outside the cytoplasmic
      compartment, within the cell wall matrix. Of 20 gene clusters encoding enzymes
      characteristic of secondary metabolism, eight are represented on the proteome
      map, including three that specify the production of novel metabolites. This
      information will be valuable in the characterization of the new metabolites.

PMID- 12421301
TI  - Fibronectin mediates Opc-dependent internalization of Neisseria meningitidis in
      human brain microvascular endothelial cells.
AB  - A central step in the pathogenesis of bacterial meningitis caused by Neisseria
      meningitidis (the meningococcus) is the interaction of the bacteria with cells of
      the blood-brain barrier. In the present study, we analysed the invasive potential
      of two strains representing hypervirulent meningococcal lineages of the ET-5 and
      ET-37 complex in human brain-derived endothelial cells (HBEMCs). In contrast to
      previous observations made with epithelial cells and human umbilical vein-derived
      endothelial cells (HUVECs), significant internalization of encapsulated
      meningococci by HBMECs was observed. However, this uptake was found only for the
      ET-5 complex isolate MC 58, and not for an ET-37 complex strain. Furthermore, the
      uptake of meningococci by HBMECs depended on the presence of human serum, whereas
      serum of bovine origin did not promote the internalization of meningococci in
      HBMECs. By mutagenesis experiments, we demonstrate that internalization depended
      on the expression of the opc gene, which is present in meningococci of the ET-5
      complex, but absent in ET-37 complex meningococci. Chromatographic separation of
      human serum proteins revealed fibronectin as the uptake-promoting serum factor,
      which binds to HBMECs via alpha 5 beta 1 integrin receptors. These data provide
      evidence for unique molecular mechanisms of the interaction of meningococci with
      endothelial cells of the blood-brain barrier and contribute to our understanding
      of the pathogenesis of meningitis caused by meningococci of different clonal
      lineages.

PMID- 12421302
TI  - Saccharomyces cerevisiae C1D is implicated in both non-homologous DNA end joining
      and homologous recombination.
AB  - C1D is a gamma-irradiation inducible nuclear matrix protein that interacts with
      and activates the DNA-dependent protein kinase (DNA-PK) that is essential for the
      repair of the DNA double-strand breaks and V(D)J recombination. Recently, it was
      demonstrated that C1D can also interact with TRAX and prevent the association of
      TRAX with Translin, a factor known to bind DNA break-point junctions, and that
      over expression of C1D can induce p53-dependent apoptosis. Taken together, these
      findings suggest that mammalian C1D could be involved in maintenance of genome
      integrity by regulating the activity of proteins involved in DNA repair and
      recombination. To obtain direct evidence for the biological function of C1D that
      we show is highly conserved between diverse species, we have analysed the
      Saccharomyces cerevisiae C1D homologue. We report that the disruption of the YC1D
      gene results in a temperature sensitivity and that yc1d mutant strains exhibit
      defects in non-homologous DNA end joining (NHEJ) and accurate DNA repair. In
      addition, using a novel plasmid-based in vivo recombination assay, we show that
      yc1d mutant strains are also defective in homologous recombination. These results
      indicate that YC1D is implicated in both homologous recombination and NHEJ
      pathways for the repair of DNA double-strand breaks.

PMID- 12421303
TI  - Two distinct regions on the surface of an RNA-binding domain are crucial for
      RNase E function.
AB  - Despite its importance for RNA processing and degradation in Escherichia coli,
      little is known about the structure of RNase E or its mechanism of action. We
      have modelled the three-dimensional structure of an essential amino-terminal
      domain of RNase E on the basis of its sequence homology to the S1 family of RNA
      binding domains. Each of the five surface-exposed aromatic residues and most of
      the 14 basic residues of this RNase E domain were replaced with alanine to
      determine their importance for RNase E function. All the surface residues
      essential for cell growth and feedback regulation of RNase E synthesis mapped to
      one end of the domain. In vitro assays indicate that these essential residues
      fall into two functionally distinct groups that form discrete clusters on
      opposite faces of the S1 domain. One group, comprising Phe-57, Phe-67 and Lys-112
      [corrected], is of general importance for the ribonuclease activity of RNase E,
      whereas the other group, comprising Lys-37 and Tyr-60, is entirely dispensable
      for catalytic activity in vitro. The side-chains of two residues previously
      identified as sites of temperature-sensitive mutations lie buried directly
      beneath the surface region defined by Phe-57, Phe-67 and Lys-112 [corrected],
      which probably enhances RNase E activity by making a crucial contribution to the
      binding of substrate RNAs. In contrast to the S1 domain, an arginine-rich RNA
      binding domain in the carboxyl half of RNase E appears to have a more peripheral
      role in RNase E function, as it is not required for feedback regulation, cell
      growth or ribonuclease activity.

PMID- 12421304
TI  - A novel Myb-related protein involved in transcriptional activation of encystation
      genes in Giardia lamblia.
AB  - Giardia lamblia is an important human intestinal parasite that survives outside
      of the host by differentiation of trophozoites into infectious cysts.
      Transcriptional regulation is key for encystation gene expression, but the
      mechanisms are unknown. Giardia genome database searches identified a myb-like
      gene (gmyb2) whose expression increased during encystation. Epitope-tagged gMyb2
      localized to both nuclei. DNA binding and mutation analysis showed that gMyb2
      binds specifically to C(T/A)ACAG, a c-Myb-like target sequence in the promoters
      of encystation-induced genes encoding gMyb2, three cyst wall proteins and G6PI-B,
      a key enzyme in cyst wall polysaccharide biosynthesis. gMyb2 binding sites were
      not found in the upstream regions of 31 other giardial genes. Deletion of the
      putative gMyb2 binding site greatly reduced encystation-specific promoter
      activity of g6pi-b. Fusion of gMyb2 binding sites to the constitutive ran
      promoter or g6pi-b promoter deletion lacking the gMyb2 binding site in-duced
      encystation-specific expression. gMyb2 may play an important role in
      transcriptional regulation of encystation genes, and may help co-ordinate
      synthesis of cyst wall proteins and polysaccharide. gMyb2 is the first giardial
      transcription factor to be functionally identified and the first that is
      associated with upregulation of encystation genes. This work provides a model for
      study of differential gene regulation in early diverging eukaryotic organisms.

PMID- 12421305
TI  - The segregation of the Escherichia coli origin and terminus of replication.
AB  - Escherichia coli chromosome replication forks are tethered to the cell centre.
      Two opposing models describe how the chromosomes segregate. In the extrusion
      capture model, newly replicated DNA is fed bi-directionally from the forks toward
      the cell poles, forming new chromosomes in each cell half. Starting with the
      origins, chromosomal regions segregate away from their sisters progressively as
      they are replicated. The termini segregate last. In the sister chromosome
      cohesion model, replication produces sister chromosomes that are paired along
      much of their length. The origins and most other chromosomal regions remain
      paired until late in the replication cycle, and all segregate together. We use a
      combination of microscopy and flow cytometry to determine the relationship of
      origin and terminus segregation to the cell cycle. Origin segregation frequently
      follows closely after initiation, in strong support of the extrusion-capture
      model. The spatial disposition of the origin and terminus sequences also fits
      this model. Terminus segregation occurs extremely late in the cell cycle as the
      daughter cells separate. As the septum begins to invaginate, the termini of the
      completed sister chromosomes are transiently held apart at the cell centre, on
      opposite sides of the cell. This may facilitate the resolution of topological
      linkages between the chromosomes.

PMID- 12421306
TI  - Subcellular localization of the Bacillus subtilis structural maintenance of
      chromosomes (SMC) protein.
AB  - The Bacillus subtilis structural maintenance of chromosomes (SMC) protein is a
      member of a large family of proteins involved in chromosome organization. We
      found that SMC is a moderately abundant protein ( approximately 1000 dimers per
      cell). In vivo cross-linking and immunoprecipitation assays revealed that SMC
      binds to many regions on the chromosome. Visualization of SMC in live cells using
      a fusion to the green fluorescent protein (GFP) and in fixed cells using
      immunofluorescence microscopy indicated that a portion of SMC localizes as
      discrete foci in positions similar to that of the DNA replication machinery
      (replisome). When visualized simultaneously, SMC and the replisome were often in
      similar regions of the cell but did not always co-localize. Persistence of SMC
      foci did not depend on ongoing replication, but did depend on ScpA and ScpB, two
      proteins thought to interact with SMC. Our results indicate that SMC is bound to
      many sites on the chromosome and a concentration of SMC is localized near
      replication forks, perhaps there to bind and organize newly replicated DNA.

PMID- 12421307
TI  - Two homologous genes, DCW1 (YKL046c) and DFG5, are essential for cell growth and
      encode glycosylphosphatidylinositol (GPI)-anchored membrane proteins required for
      cell wall biogenesis in Saccharomyces cerevisiae.
AB  - The cell wall of Saccharomyces cerevisiae consists of glucan, chitin and various
      kinds of mannoproteins. Major parts of mannoproteins are synthesized as
      glycosylphosphatidylinositol (GPI)-anchored proteins and are then transferred to
      cell wall beta-1,6-glucan. A glycosyltransferase has been hypothesized to
      catalyse this transfer reaction. A database search revealed that the products of
      YKL046c and DFG5 are homologous to bacterial mannosidase. These genes are
      homologous to each other and have primary structures characteristic of GPI
      anchored proteins. Although single disruptants of ykl046c and dfg5 were viable,
      ykl046cDelta was hypersensitive to a cell wall-digesting enzyme (zymolyase),
      suggesting that this gene is involved in cell wall biosynthesis. We therefore
      designated this gene as DCW1 (defective cell wall). A double disruptant of dcw1
      and dfg5 was synthetically lethal, indicating that the functions of these gene
      products are redundant, and at least one of them is required for cell growth.
      Cells deficient in both Dcw1p and Dfg5p were round and large, had cell walls that
      contained an increased amount of chitin and secreted a major cell wall protein,
      Cwp1p, into the medium. Biochemical analyses showed that epitope-tagged Dcw1p is
      an N-glycosylated, GPI-anchored membrane protein and is localized in the membrane
      fraction including the cell surface. These results suggest that both Dcw1p and
      Dfg5p are GPI-anchored membrane proteins and are required for normal biosynthesis
      of the cell wall.

PMID- 12421308
TI  - A site-specific recombinase (RinQ) is required to exert incompatibility towards
      the symbiotic plasmid of Rhizobium etli.
AB  - The replication/partition region of the symbiotic plasmid p42d of Rhizobium etli
      CE3 is characterized by the presence of the repABC operon. A recombinant plasmid
      containing this region is able to replicate in a R. etli derivative cured from
      p42d, with the same stability and copy number shown by the parental plasmid.
      However, when this construct is introduced into the wild-type strain, instead of
      exerting incompatibility against the p42d, it forms a stable cointegrate with it.
      In this paper, we show that a site-specific resolvase, and its action sites are
      essential factors to displace the symbiotic p42d. We propose a model for this
      novel incompatibility mechanism.

PMID- 12421309
TI  - A unique, bifunctional site-specific DNA recombinase from Mycoplasma pulmonis.
AB  - Site-specific DNA invertible elements often control the production of bacterial
      surface proteins that are subject to phase variation (ON/OFF switching).
      Inversion of the DNA element occurs as a result of the reciprocal exchange of DNA
      catalysed by a specialized enzyme (recombinase) that acts at specific sites. By
      continually switching the orientation of the invertible element in the
      chromosome, and consequently the production of the variable protein(s), the cell
      population remains continually responsive to environmental change such as
      immunological challenge. In addition to phase-variable surface proteins,
      Mycoplasma pulmonis has a family of phase-variable restriction-modification
      enzymes. We report here that a single recombinase in M. pulmonis, HvsR, catalyses
      independent DNA inversions at non-homologous loci, causing variations in surface
      lipoproteins and in the DNA recognition sequence specificity of restriction
      enzymes. Thus, HvsR is a site-specific DNA recombinase with dual substrate
      specificity.

PMID- 12421310
TI  - Elongation factor Tu and E1 beta subunit of pyruvate dehydrogenase complex act as
      fibronectin binding proteins in Mycoplasma pneumoniae.
AB  - The interactions between pathogenic bacteria and extracellular matrix (ECM)
      components markedly influence the initiation and establishment of infection. We
      have identified two surface proteins of virulent Mycoplasma pneumoniae with
      molecular masses of 45 and 30 kDa that bind to the ECM constituent, fibronectin
      (Fn). These Fn-binding proteins (FnBPs) were purified to near homogeneity using
      Fn-coupled Sepharose 4B-affinity column chromatography, and amino acid sequence
      analysis of the 45 and the 30 kDa proteins identified them as elongation factor
      Tu (EF-Tu) and pyruvate dehydrogenase E1 beta subunit (PDH-B) respectively. The
      genes for EF-Tu and PDH-B were cloned, and the entire EF-Tu gene and NH2-terminus
      of PDH-B (NPDH (pyruvate dehydrogenase E1 beta subunit from amino acid 1-244)-B)
      gene were overexpressed in Escherichia coli. The recombinant proteins, rEF-Tu and
      rNPDH-B, were purified to homogeneity by His-tag affinity column chromatography
      and used to immunize rabbits. Purified rEF-Tu and rNPDH-B bound to Fn using a
      ligand immunoblot assay and ELISA. Immunogold electron microscopy with polyclonal
      antibodies reactive against rEF-Tu (antirEF-Tu) and rNPDH-B (antirNPDH-B) and
      whole cell radioimmunoprecipitation (WCRIP) revealed the surface location of
      these proteins. Adherence of viable M. pneumoniae to immobilized Fn was inhibited
      by antirEF-Tu and antirNPDH-B antisera in a dose-dependent and cumulative manner.
      These results demonstrate that M. pneumoniae EF-Tu and PDH-B, in addition to
      their major cytoplasmic biosynthetic and metabolic roles, can be surface
      translocated, which confers additional important biological functions.

PMID- 12421311
TI  - The VirB/VirD4 type IV secretion system of Bartonella is essential for
      establishing intraerythrocytic infection.
AB  - Bartonellae are pathogenic bacteria uniquely adapted to cause intraerythrocytic
      infection in their human or animal reservoir host(s). Experimental infection of
      rats by Bartonella tribocorum revealed the initial colonization of a yet
      unidentified niche outside of circulating blood. This primary niche periodically
      seeds bacteria into the bloodstream, resulting in the invasion and persistent
      intracellular colonisation of erythrocytes. Here, this animal model was used for
      a genetic analysis of the virB locus (virB2-11) and the downstream located virD4
      gene, which together encode a putative type IV secretion system (T4SS). A generic
      method for marker-less gene replacement allowed the generation of non-polar in
      frame deletions in either virB4 or virD4. Both mutants were unable to cause
      bacteraemia, whereas complementation with the full-length genes in trans
      completely restored infectivity. Segregation analysis of the complementation
      plasmids further denoted that VirB4 and VirD4 are required at an early stage of
      the infection course before the onset of intraerythrocytic bacteraemia. This
      analysis of defined mutants in an in vivo model identified components of the
      VirB/VirD4 T4SS as the first bona fide pathogenicity factors in Bartonella.

PMID- 12421312
TI  - Overexpression of ccl1-2 can bypass the need for the putative apocytochrome
      chaperone CycH during the biogenesis of c-type cytochromes.
AB  - In Gram-negative bacteria, including Rhodobacter capsulatus, the membrane protein
      CycH acts as a putative apocytochrome chaperone during the biogenesis of c-type
      cytochromes. CycH-null mutants are unable to produce various c-type cytochromes
      and sustain photosynthetic (Ps) growth that requires the cytochromes c1 and c2 or
      cy. However, Ps+ revertants are readily obtained only on minimal, but not on
      enriched, medium. To obtain further information about the biogenesis of c-type
      cytochromes, these suppressor mutants were studied. Complementation of a CycH
      null mutant for Ps+ growth by a genomic library constructed using DNA from a Ps+
      suppressor yielded a plasmid carrying the ccl1-2 operon, the products of which,
      Ccl1 and Ccl2, are also involved in the biogenesis of c-type cytochromes. DNA
      sequence analysis revealed that the complementing activity resulted from a single
      point mutation, G488A, located upstream of the coding region of ccl1-2. This
      mutation changed the -35 region of the ccl1-2 promoter from TTGGCC to TTGACC,
      improving its similarity to the consensus sequence of Escherichia colisigma 70
      dependent promoters. That the G488A mutation indeed enhanced transcription of
      ccl1-2 was demonstrated by the use of reporter gene fusions. An appropriate ccl1
      2::lacZ transcriptional-translational fusion carrying the G488A mutation produced
      in R. capsulatus over 30-fold higher beta-galactosidase activity than a wild-type
      construct. Immunoblot analyses confirmed that Ccl1 and Ccl2 were overproduced in
      the Ps+ suppressors. Deletion of either ccl1 or ccl2, from the ccl1-2 cluster
      carrying the G488A mutation abolished the complementing ability, indicating that
      overexpression of both ccl1 and ccl2 was required to confer the Ps+ phenotype on
      a CycH-null mutant. These findings therefore demonstrate that, during R.
      capsulatus growth on minimal medium, the requirement for CycH in c-type
      cytochrome biogenesis could be bypassed by overexpressing the ccl1-2 operon.

PMID- 12421313
TI  - The third chemotaxis locus of Rhodobacter sphaeroides is essential for
      chemotaxis.
AB  - The purple photosynthetic bacterium Rhodobacter sphaeroides has three loci
      encoding multiple homologues of the bacterial chemosensory proteins: 13 putative
      chemoreceptors, four CheW, four CheA, six CheY, two CheB and three CheR.
      Previously, studies have shown that, although deletion of cheOp1 led to only
      minor changes in behaviour, deletion of cheOp2 led to a loss of taxis. The third
      locus encodes two CheA, one CheR, one CheB, one CheW, one CheY, a putative
      cytoplasmic chemoreceptor (TlpT) and a protein showing homology to the
      chromosomal partitioning factor Soj (designated Slp). Here, we show that every
      protein encoded by this locus is essential for normal chemotaxis. Phototaxis is
      also dependent upon all the components of this locus, except CheB2 and Slp. The
      two putative CheA proteins encoded in this locus are unusual. CheA3 has only the
      P1 domain and the P5 regulatory domain linked by a large internal domain, whereas
      CheA4 lacks the P1 and P2 domains required for phosphorylation and response
      regulator binding. These data indicate that the minimal set of proteins required
      for normal chemotaxis in R. sphaeroides is all the proteins encoded by cheOp2 and
      the third chemotaxis locus, and that the multiple chemosensory protein homologues
      found in R. sphaeroides are not redundant.

PMID- 12421314
TI  - The Zygosaccharomyces bailii antifungal virus toxin zygocin: cloning and
      expression in a heterologous fungal host.
AB  - Zygocin, a monomeric protein toxin secreted by a virus-infected killer strain of
      the osmotolerant spoilage yeast Zygosaccharomyces bailii, kills a broad spectrum
      of human and phytopathogenic yeasts and filamentous fungi by disrupting
      cytoplasmic membrane function. The toxin is encoded by a double-stranded (ds)RNA
      killer virus (ZbV-M, for Z. bailii virus M) that stably persists within the yeast
      cell cytosol. In this study, the protein toxin was purified, its N-terminal amino
      acid sequence was determined, and a full-length cDNA copy of the 2.1 kb viral
      dsRNA genome was cloned and successfully expressed in a heterologous fungal
      system. Sequence analysis as well as zygocin expression in Schizosaccharomyces
      pombe indicated that the toxin is in vivo expressed as a 238-amino-acid
      preprotoxin precursor (pptox) consisting of a hydrophobic N-terminal secretion
      signal, followed by a potentially N-glycosylated pro-region and terminating in a
      classical Kex2p endopeptidase cleavage site that generates the N-terminus of the
      mature and biologically active protein toxin in a late Golgi compartment. Matrix
      assisted laser desorption mass spectrometry further indicated that the secreted
      toxin is a monomeric 10.4 kDa protein lacking detectable post-translational
      modifications. Furthermore, we present additional evidence that in contrast with
      other viral antifungal toxins, zygocin immunity is not mediated by the toxin
      precursor itself and, therefore, heterologous pptox expression in a zygocin
      sensitive host results in a suicidal phenotype. Final sequence comparisons
      emphasize the conserved pattern of functional elements present in dsRNA killer
      viruses that naturally infect phylogenetically distant hosts (Saccharomyces
      cerevisiae and Z. bailii) and reinforce models for the sequence elements that are
      in vivo required for viral RNA packaging and replication.

PMID- 12421315
TI  - Autoregulation of Helicobacter pylori Fur revealed by functional analysis of the
      iron-binding site.
AB  - The ferric uptake regulator protein Fur regulates iron-dependent gene expression
      in bacteria. In Helicobacter pylori it has been shown to regulate iron-activated
      and iron-repressed genes. In this study, we show that H. pylori Fur protein
      regulates transcription from its own sigma 80 promoter P fur in response to iron.
      Footprinting analysis shows that Fur binds at three distinct operators at P fur
      overlapping and proximal to the promoter elements. Site-directed mutagenesis of
      the proposed iron-binding site of the protein results in derepression of P fur
      and the loss of iron regulation. In vivo oligomerization assays reveals that the
      C-terminus of Fur is necessary for multimerization of the protein and that the
      mutations do not affect this activity. Molecular and phenotypic analysis of the
      mutant proteins provides evidence that the iron-binding site controls the
      specific affinity of Fur for the operators at P fur and hence its repressive
      ability. In summary, the data presented are consistent with a model in which Fur
      acts as a rheostat of transcription to autoregulate its own expression in
      response to iron, which in turn controls expression of iron-induced and iron
      repressed genes, providing maintenance of homeostasis.

PMID- 12421316
TI  - ExsD is a negative regulator of the Pseudomonas aeruginosa type III secretion
      regulon.
AB  - Expression of the Pseudomonas aeruginosa type III secretion system is induced by
      contact with eukaryotic cells, serum or low Ca2+ concentrations. We report that
      ExsD, a unique protein, is a negative regulator of the type III regulon.
      Localization studies indicate that ExsD is not secreted by P. aeruginosa. To
      determine the role of exsD, a non-polar deletion was returned to the chromosome
      by allelic exchange. The delta exsD mutant is competent for type III secretion
      and translocation of the ExoU cytotoxin to eukaryotic host cells. To examine the
      effect of ExsD on transcription, lacZ transcriptional reporter fusions were
      integrated into the chromosome. Promoters controlling transcription of genes
      encoding the type III secretory, regulatory and effector proteins demonstrated
      significant derepression in the delta exsD background. Expression of ExsD from a
      multicopy plasmid completely repressed transcription of the regulon. Although a
      mutant in pscC, encoding a structural component of the type III translocase, is
      repressed for expression of the regulon, a delta exsD, pscC:: omega double mutant
      is derepressed. Bacterial two-hybrid data indicate that ExsD binds the
      transcriptional activator of the regulon, ExsA. We conclude that ExsD is a
      negative regulator and propose that ExsD functions as an ExsA antiactivator to
      regulate transcription of the regulon.

PMID- 12421317
TI  - Regulation of virulence gene expression in Vibrio cholerae by quorum sensing:
      HapR functions at the aphA promoter.
AB  - Quorum sensing negatively influences virulence gene expression in certain
      toxigenic Vibrio cholerae strains. At high cell densities, the response regulator
      LuxO fails to reduce the expression of HapR, which, in turn, represses the
      expression of the virulence cascade. A critical regulatory step in the cascade is
      activation of tcpPH expression by AphA and AphB. We show here that HapR
      influences the virulence cascade by directly repressing aphA expression. In
      strain C6706, aphA expression was increased in a delta hapR mutant and decreased
      in a delta luxO mutant, indicating a negative and positive influence,
      respectively, of these gene products on the promoter. Overexpression of HapR also
      reduced aphA expression in both C6706 and Escherichia coli. DNase I footprinting
      showed that purified HapR binds to the aphA promoter between -85 and -58.
      Although it appears that quorum sensing does not influence virulence gene
      expression in strain O395 solely because of a frameshift in hapR, overproduced
      HapR did not repress expression from the O395 aphA promoter in either Vibrio or
      E. coli, nor did the protein bind to the promoter. Two basepair differences from
      C6706 are present in the O395 HapR binding site at -85 and -77. Introducing the 
      77 change into C6706 prevented HapR binding and repression of aphA expression.
      This mutation also eliminated the repression of toxin-co-regulated pilus (TCP)
      and cholera toxin (CT) that occurs in a delta luxO mutant, indicating that HapR
      function at aphA is critical for density-dependent regulation of virulence genes.

PMID- 12421318
TI  - Strand-specific loading of DnaB helicase by DnaA to a substrate mimicking unwound
      oriC.
AB  - We analysed the enzymatic activity (strand dis-placement) of the Escherichia coli
      DnaB helicase on a mirror-image pair of oligonucleotide-based substrates
      mimicking the unwound replication origin oriC. Loading of the helicase complex
      occurred exclusively to the single-stranded 'lower strand' part of the
      substrates. Full helicase activity required DnaA bound to the double-stranded
      part of the substrates (oriC DnaA box R1) and to their single-stranded 'upper
      strand' part. We assume that in vivo DnaA also loads the first of two helicase
      complexes - required for the assembly of two replication forks - to the lower
      strand of oriC during initiation of bidirectional chromosome replication in E.
      coli.

PMID- 12421319
TI  - Expression of the glutamyl-tRNA synthetase gene from the cyanobacterium
      Synechococcus sp PCC 7942 depends on nitrogen availability and the global
      regulator NtcA.
AB  - We report here transcriptional analyses of a cyanobacterial gene encoding an
      aminoacyl-tRNA synthetase (aaRS), the gltX gene from Synechoccocus sp. PCC 7942,
      coding for the glutamyl-tRNA synthetase. We show that the transcript levels of
      gltX in Synechococcus depend on nitrogen availability and do not increase with
      the growth rate, which is at odds with observations from other bacteria. We also
      demonstrate the involvement of the cyanobacterial global regulator NtcA in
      transcriptional control of gltX according to nitrogen status. Our results support
      a regulatory model in which the gltX transcript level is finely tuned by a
      dynamic equilibrium between activation and repression relying upon the cellular
      concentration of NtcA.

PMID- 12421320
TI  - The histone deacetylase Hda1 from Ustilago maydis is essential for teliospore
      development.
AB  - In the corn smut fungus Ustilago maydis, pathogenic development is controlled by
      the b mating type locus that encodes the two homeodomain proteins bE and bW. A
      heterodimer of bE and bW controls a large set of genes, either directly by
      binding to cis regulatory sequences or indirectly via a b-dependent regulatory
      cascade. It is thought that several of the b-regulated genes contribute to
      processes involved in pathogenicity. In a screen for components of the b
      dependent regulatory cascade we have isolated Hda1, a protein with homology to
      histone deacetylases of the RPD3 class. Hda1 can substitute for the histone
      deacetylase RPD3 in Saccharomyces cerevisiae, showing that it functions as a
      histone deacetylase. Deletion of hda1 results in the expression of several genes
      that are normally expressed only in the dikaryon, among these are several genes
      that are now expressed independently from their activation by the bE/bW
      heterodimer. hda1 mutant strains are capable to infect corn, and the
      proliferation of dikaryotic hyphae within the plant appears comparable to wild
      type strains during initial developmental stages. Upon karyogamy, however, the
      proliferation to mature teliospores is blocked. The block in sporogenesis in
      Deltahda1 strains is probably a result of the deregulation of a specific set of
      genes whose temporal or spatial expression prevent the proper developmental
      progress.

PMID- 12421321
TI  - SycE allows secretion of YopE-DHFR hybrids by the Yersinia enterocolitica type
      III Ysc system.
AB  - The Ysc type III secretion system allows Yersinia enterocolitica to translocate
      virulence proteins, called Yop effectors, into the cytosol of eukaryotic cells.
      Some of the Yop effectors possess an individual chaperone called a Syc protein.
      The first 15 amino acids of the YopE effector constitute a secretion signal that
      is sufficient to promote secretion of several reporter proteins. Residues 15-50
      of YopE comprise the minimal binding domain for the SycE chaperone. In this
      study, we investigated the secretion by the Ysc system of several YopE-DHFR
      hybrid proteins with different folding properties, and evaluated the role of
      SycE, the cognate chaperone of YopE, in this context. We have analysed the
      secretion of hybrids containing 16 (YopE16), 52 (YopE52) and 80 (the complete
      region covered by the chaperone, YopE80) amino acids of YopE or full-length YopE
      (YopEFL) with wild-type DHFR and two mutants with altered folding properties. The
      hybrids containing DHFR delta77, the mutant whose folding properties are the most
      drastically affected, could be secreted in all the conditions tested, even in the
      absence of the chaperone SycE. In contrast, DHFRwt could only be secreted fused
      to the first 52 amino acids of YopE, and its secretion was strictly dependent on
      SycE. The hybrids YopE80-DHFRwt and YopEFL-DHFRwt were not secreted. YopEFL
      DHFRwt completely jammed the channel in an SycE-dependent fashion. Our
      experiments indicate that, in order to be secreted, proteins must be unfolded or
      only partially folded, and that TSS chaperones could keep their substrates in a
      secretion-competent conformation, probably by preventing their folding. In
      addition, they show that the secretion apparatus can reject folded proteins if
      they are not deeply engaged into the injectisome.

PMID- 12421322
TI  - Localization of TMJ sounds to side.
AB  - Differential diagnosis depends in cases with disk displacement on accurate
      identification of sound source. Mistakes may occur when clicking from one
      temporomandibular joint (TMJ) is heard on both sides of the head at auscultation
      and neither examiner nor patient, is sure about side. The hypothesis was that the
      head tissues affect spectral characteristics of TMJ sounds and that differences
      due to different positioning of sensors can be used in localization of source.
      The aim was to compare bilateral electronic recordings of unilateral TMJ sounds
      to obtain and compare attenuation, phase shift and time delay. Recordings were
      made from 12 subjects with unilateral clicking. Small electret condenser
      microphones, bandwidth 40-20 000 Hz, were placed at the openings of the auditory
      canals and the sounds were recorded at a sampling rate of 48 000 Hz. The head
      tissues acted as a filter causing a frequency dependent attenuation and phase
      shift. There was a time difference between the ipsi- and the contra lateral
      recordings, the latter always having a longer delay time (range 0.2-1.2 ms, group
      mean 0.68 ms, s.d. 0.292 ms). In conclusion, spectral analysis of bilateral
      electronic TMJ sound recordings is of diagnostic value when bilateral clicking is
      heard at auscultation and can help to avoid diagnosing a silent joint as
      clicking.

PMID- 12421323
TI  - Influences of social support on the oral health of older people in Britain.
AB  - A national UK study involving a random sample of 876 non-institutionalized older
      people (aged 65 or older) were recruited, to identify the association between
      social support (living alone), self-reported oral health status and oral health
      behaviour (use of services). Home interviews were undertaken exploring oral
      health behaviour (time and reason for last dental visit) and oral health status
      measures (self-reported number of teeth possessed and denture status). In
      addition, socio-demographic characteristics were collected. Bivariate analysis
      identified that social support was associated with time since last dental visit
      (P < 0.01), reason for last dental visit (P < 0.01), self-reported number of
      teeth possessed (P < 0.01) and denture status (P < 0.01). In regression analysis,
      social support emerged as an important predictor of reason for last dental visit
      and denture status having accounted for other factors in the model (age, gender,
      social class and educational attainment). Social support is associated with oral
      health status and oral health behaviour of older people in Britain and is likely
      to influence both the decision making process of when to seek dental care and
      what type of treatment to opt for.

PMID- 12421324
TI  - Oral mucosal versus cutaneous sensory testing: a review of the literature.
AB  - The innervation of skin and oral mucosa plays a major physiological role in
      exteroception. It also has a clinical interest as illustrated by sensory changes
      after neurosurgical procedures. These sensory changes often rely only on the
      patients' subjective reports, although objective assessments are possible. This
      review compares the neurophysiological features of the trigeminal sensory
      pathways with those of cutaneous sensory innervation. In this review, three
      receptor groups will be discussed: mechanoreceptors, thermoreceptors and
      nociceptors. Differences between receptors in the glabrous skin, the hairy skin
      and the oral mucosa will be highlighted. Sensory testing devices have been
      developed to quantify psychophysiological parameters such as the threshold level
      for receptor activation upon mechanical stimulation, but such devices have been
      merely developed to determine the threshold of skin receptors (tactile, thermal).
      Later on, some have been adapted to suit the particularities of the oral
      environment. This review attempts to compare the available literature on test
      devices for oral versus cutaneous tactile function. It summarizes what is common
      or rather particular to the devices used to study either cutaneous or oral
      receptors.

PMID- 12421325
TI  - Fracture resistance of pressable glass-ceramic fixed partial dentures.
AB  - The aim of the present study was to evaluate the mechanical strength of the
      Empress2 system, which is based on the use of a high-strength glass--ceramic core
      of lithium disilicate, and the fracture resistance of fixed partial dentures
      fabricated with this material. To evaluate mechanical strength, four types of
      ceramic materials were tested for four-point flexural strength and diametral
      tensile strength: Empress2 core material, Empress2 layering porcelain,
      conventional Empress material and Dicor. Then, using Empress2, conventional
      Empress and Dicor, actual clinical type anterior fixed partial dentures were
      fabricated for fracture testing. The results showed that the Empress2 core
      material, at 329 MPa, has more than twice the flexural strength of conventional
      materials and at 271 MPa, more than four times the diametral tensile strength of
      conventional materials. Furthermore, fixed partial dentures fabricated with
      Empress2 had a fracture resistance of 1424 N. That is, they were more than twice
      as fracture resistant as fixed partial dentures made with conventional materials.

PMID- 12421326
TI  - Evaluation of mastication-induced change in sympatho-vagal balance through
      spectral analysis of heart rate variability.
AB  - Mastication modulates the autonomic nervous activity of the digestive glands and
      the heart. The autonomic nervous balance is evaluated with spectral analysis of
      heart rate variability. In the present study, we investigated the effects of
      mastication of chewing gum base on heart rate variability to clarify the role of
      mastication in the sympatho-vagal balance for the regulation of the heart rate.
      Mastication of a chewing gum base stimulated the salivary secretion and shortened
      the R-R intervals in the electrocardiogram of healthy young subjects without
      swallowing of saliva at a fixed rate of respiration. Based on the analysis of
      heart rate variability, mastication increased the low-frequency band spectral
      power (LF), and decreased the high-frequency band spectral power (HF). The LF/HF
      was markedly increased by the mastication. Mastication enhances the sympathetic
      nervous activity and/or suppresses the parasympathetic nervous activity for the
      heart. Feeding behaviour with mastication might play a role in the modulation of
      the autonomic nervous activity.

PMID- 12421327
TI  - Anticipatory and reflexive neck muscle activities during voluntary rapid jaw
      opening and passive jaw depression in humans.
AB  - The characteristics of head movement during voluntary rapid jaw opening movement
      and passive jaw depression were investigated using accelerometers and
      electromyographs (EMG) on eight healthy examinees. Passive depressions were
      executed by means of load on the lower jaw, initiated either by examinees
      themselves or an experimenter. In the depression initiated by examinees, a head
      extension movement that preceded the load to the lower jaw and anticipatory
      activities in the nuchal region of the trapezius muscle were observed. In the
      depression initiated by the experimenter, the anticipatory activities were not
      observed. In both of these cases, stretch reflexes were induced in the trapezius
      muscle. During voluntary rapid jaw opening, a head-extension movement nearly
      synchronized with the opening movement in the lower jaw acceleration, and dorsal
      neck muscle activities accompanying the synchronized movement were observed. The
      peak timing of these neck-muscle activities preceded the latencies of the stretch
      reflex activities observed in the jaw-depressed tasks, but no anticipatory
      activities were observed in the dorsal-neck muscles. We conclude that neither the
      anticipatory activities nor the reflex activities observed in the passive
      depressions have effects on the initial part of the dorsal-neck muscle
      activities, which are related to the head-extension synchronized with the
      voluntary lower-jaw opening movement.

PMID- 12421328
TI  - Heterogeneity of temporomandibular disorders: cluster and case-control analyses.
AB  - Cluster analysis has been applied to the classification of temporomandibular
      disorders (TMD). The factors most often used in these classification systems are
      psychological and psychosocial. The aim of this study is to classify individuals
      diagnosed with TMD, by using cluster analysis based on their clinical condition
      and the global severity of the disease. In this study, one investigator selected
      the patients at the dental clinics located at the Jewish General and Montreal
      General hospitals, Montreal, Canada, from September 1994 to December 1997. The
      study population included 162 outpatients. The results of this study indicated
      the existence of four TMD subgroups: three TMD pain groups with localized or
      generalized disorder related to different levels of interferences in their life
      and a non-pain, but disabled group. External validation of the cluster solution
      support the replication of the four groups and allow for further interpretation
      of the patients' profiles. Clenching-grinding and depression were related to the
      groups presenting generalized TMD. Orthodontic treatment and female sex, however,
      were the factors associated with a more localized condition. This classification
      system may provide a better understanding of the TMD subgroups and clues for the
      treatment and prognosis of TMD patients.

PMID- 12421329
TI  - Influence of a bite-plane according to Jeanmonod, on bruxism activity during
      sleep.
AB  - One way to look at nocturnal oral parafunction such as bruxism, is using
      polysomnography. Although in recent years several studies have been carried out,
      it is almost impossible to compare the respective results because of the lack of
      standardization in the methodology used. The nocturnal muscular activity of m.
      Masseter and m. Temporalis Anterior has been registered in 21 patients suffering
      from bruxism, prior and after treatment with a bite-plane made according to
      Jeanmonod. A group of five persons without any dental or muscular parafunction
      has been included as a control. A computer program based on the biomechanical
      principles of muscle contraction has been developed and was used to analyse the
      raw electromyography (EMG) signal. The data shows a significant decrease (P =
      0.008) in nocturnal parafunctional muscle activity with the bite-plane in situ.
      The present study shows that by analysing the raw signal obtained via EMG using a
      specially designed computer program, it becomes possible to isolate the
      occurrence of parafunctional events in the EMG signal and to study the influence
      of a given therapy on this EMG signal.

PMID- 12421330
TI  - EMG activity of the masseter muscle in implant supported overdenture wearers
      during chewing of hard and soft food.
AB  - The influence of texture of food on the surface electromyographic (EMG) activity
      of the masseter muscle was investigated in a sample of mandibular implant
      overdenture wearers. Six experienced denture wearers (mean age 57.8 years) with
      mandibular overdentures supported by two implants, consented to participate in
      this study. Fresh raw carrots and peeled apples of similar size and weight were
      chosen as representing hard and soft food, respectively. The findings were in
      line with those earlier reported in dentate subjects and complete denture wearers
      in that harder foods require higher chewing rates, higher EMG activity and higher
      relative contraction times, accompanied by shorter cycle durations. It was also
      concluded that rehabilitation with implant retained mandibular dentures may
      result in more regular chewing patterns with higher electrical activity of the
      masseter muscles, thus providing improved chewing function and comfort.

PMID- 12421331
TI  - Effect of ageing on the bond strength of a permanent denture soft lining
      material.
AB  - Molloplast-B is a widely used, long-term, heat-cured silicone denture soft lining
      material. Adhesion failure of this material to poly (methyl methacrylate) denture
      base material is a problem that is encountered clinically. The purpose of this
      study was to investigate the effects of long-term immersion in water at 37 +/- 1
      degrees C and of accelerated ageing in water at 50 +/- 1 degrees C on the tensile
      and shear bond strength values of this denture resilient lining material bonded
      to a heat-cured denture base material. Immersion in water for 1 week at 37 +/- 1
      degrees C had no significant effect on the measured bond strength values. Longer
      immersion of specimens in water at 37 +/- 1 degrees C led to a significant
      reduction in the measured tensile and shear bond strengths. The present study has
      demonstrated that the reduction in Molloplast-B bond strength that occurs as a
      result of long-term ageing in water at 37 +/- 1 degrees C can be achieved in a
      shorter period of time by ageing the specimens in water at a higher temperature.

PMID- 12421332
TI  - Associated factors of tooth wear in southern Thailand.
AB  - The purpose of this study was to evaluate the possible risk factors connected
      with tooth wear. Using the Tooth Wear Index (TWI) and the charting of pre
      disposing factors tooth surface loss was recorded in 506 patients, of the Dental
      Hospital, Prince of Songkla University. We found that age, sex, number of tooth
      loss, frequency of alcohol, sour fruit and carbonate intake were significant risk
      factors. Regarding the tooth position, the first molar showed the greatest degree
      of wear, while the canine and premolar showed the least, respectively. The
      occlusal surface showed the greatest wear and the cervical, lingual and buccal
      surfaces showed the least, respectively.

PMID- 12421333
TI  - Scanning electron microscopic and energy dispersive spectrometric investigations
      on the effect of XeCl excimer laser on human dentin with smear layer.
AB  - The purpose of this study was to study the effect of XeCl excimer laser on smear
      layer covered dentine of extracted human teeth. Twenty-four freshly extracted
      human molar teeth were collected and randomly divided into one control group and
      three experimental groups of six teeth each (groups A-D). The teeth in the
      experimental groups were irradiated with XeCl 308-nm excimer laser at a fluence
      of 0.4 J cm-2 and a constant pulse repetition rate of 25 Hz. Group A was used as
      the control, while groups B, C and D were irradiated at different exposure times
      of 3, 5 and 7 s, respectively. Subsequently these teeth specimens were subjected
      to scanning electron microscopic (SEM) examination and energy dispersive X-ray
      (EDX) spectrometric analysis. The SEM examination revealed melting of the smear
      layer covered dentin to conceal the underlying dentinal tubules. At a longer
      exposure time (7 s), dentin melted to form large grains and this resulted in non
      uniform closure of underlying dentinal tubules. Under the conditions of this
      study, it is concluded that the pulsed XeCl 308-nm excimer laser at a fluence of
      0.4 J cm-2, with an exposure time of 5 s uniformly occluded exposed smear layer
      covered dentine with no conspicuous variation in chemical structure.

PMID- 12421334
TI  - The determination of freeway space using two different methods.
AB  - The aim of this study was to determine the average freeway space of dentate
      subjects and relate this to recommended ranges for edentulous patients, also to
      see if any differences were observed between two different methods of measuring
      freeway space. The freeway space of 72 dentate subjects was measured, first using
      a Willis gauge, and secondly using a pair of sprung dividers. The intra- and
      interoperator variability was evaluated as was the reproducibility of the
      accuracy of both techniques. The mean freeway space using the Willis gauge was
      3.3 mm, for both intra and inter operator variability, and with the sprung
      dividers 3.1 and 2.9 mm, respectively, with no significant difference being seen
      between any combination of results (P > 0.05). Individual measurements within the
      two measuring methods being assessed showed significant differences (P < 0.05).
      The mean measurements of freeway space in dentate subjects found in this study
      were within the recommended 2-4 mm range, however, 15% of the subjects in the
      study had freeway space measurements outside this range. This study would suggest
      that the range for freeway space measurement could more realistically be 2-7 mm.

PMID- 12421335
TI  - In vitro evaluation of the effect of a current bleaching agent on the
      electrochemical corrosion of dental alloys.
AB  - The nightguard bleaching of discoloured teeth is currently performed by using %
      10 carbamide peroxide. While the material is effective on the bleaching of
      natural teeth, it may deteriorate crowns, bridges and amalgam restorations placed
      in the mouth. The purpose of the present study was to investigate the effect of
      10% carbamide peroxide on the electrochemical corrosion of various dental casting
      alloys used for fixed partial dentures and dental amalgam. Tafel extrapolation
      curves were obtained by the corrosion cell that facilitated simulation of the
      oral environment and comparison of the corrosion rates of alloys and amalgam was
      accomplished. The results revealed that unpolished amalgam and nickel-chromium
      alloy samples had the most and noble alloys had the least corrosion rate.

PMID- 12421336
TI  - Demonstration of postsynaptic receptor plasticity in an amphibian neuroendocrine
      interface.
AB  - Pituitary pars intermedia melanotrope cells are often used as a model to study
      mechanisms of neuroendocrine integration. In the amphibian Xenopus laevis, the
      synthesis and release of alpha-melanophore-stimulating hormone (alpha-MSH) from
      these cells is a dynamic process dependent upon the colour of background. In
      animals on a black background, there is a higher level of synthesis and secretion
      of alpha-MSH than in animals on a white background, and, consequently, there is
      skin darkening in animals on a black background. The melanotropes are innervated
      by hypothalamic neurones that produce neuropeptide Y (NPY), a peptide that
      inhibits alpha-MSH secretion via the NPY Y1 receptor. The inhibitory neurones
      have a higher expression of NPY in animals adapted to a white background and both
      the size and the number of inhibitory synapses on the melanotrope cells are
      enhanced. The purpose of the present study was to determine if this presynaptic
      plasticity displayed by the inhibitory neurones is reciprocated by postsynaptic
      plasticity (i.e. if there is an enhanced expression of the Y1 receptor in
      melanotropes of animals adapted to a white background). For this purpose
      quantitative real-time reverse transcriptase-polymerase chain reaction was used
      to determine the level of Y1 receptor mRNA in melanotropes of animals undergoing
      the process of background adaptation. The results showed that there is a higher
      Y1 receptor mRNA expression in melanotropes of white-adapted animals. We conclude
      that the inhibitory neuroendocrine interface in the Xenopus pars intermedia
      displays postsynaptic plasticity in response to changes of background colour. To
      our knowledge, this is the first demonstration of a physiological environmental
      change leading to changes in postsynaptic receptor expression in a fully
      identified vertebrate neuroendocrine reflex.

PMID- 12421337
TI  - Lipopolysaccharide-induced oestrogen receptor regulation in the paraventricular
      hypothalamic nucleus of lewis and Fischer rats.
AB  - Oestrogen receptor (ER) regulation of gene transcription in neurosecretory and
      pituitary cells has been proposed as an important mechanism for increased
      hypothalamic-pituitary-adrenal (HPA) axis responses in females of several
      mammalian species, including humans. Inbred female Fischer (F344/N) and Lewis
      (LEW/N) rats have similar oestrogen levels, although Fischer rats exhibit hyper-
      and Lewis rats hypo-HPA axis responses. The blunted HPA axis response of Lewis
      rats has been associated with their blunted hypothalamic corticotropin releasing
      hormone (CRH) expression. To determine if the female CRH expression deficiency in
      Lewis rats is associated with defective ER expression and regulation,
      hypothalamic paraventricular nucleus (PVN) transcript levels of CRH and ER were
      determined under basal conditions and after immune challenge. Microdissected PVN
      were obtained from control and lipopolysaccharide (LPS) treated Lewis and Fischer
      rats and CRH, ERalpha and beta mRNA levels were determined by semiquantitative
      reverse-transcriptase-polymerase chain reaction. In addition, ERalpha and beta
      protein levels were determined by semiquantitative Western blots. ERalpha and
      beta mRNA and protein levels in the PVN of control Fischer rats were
      significantly higher than in control Lewis rats. ERalpha and beta mRNA and
      protein levels in Fischer rats were reduced by LPS administration at the time of
      maximal CRH mRNA levels but did not change in Lewis rats, an effect independent
      of oestrogen levels. These data indicate that defective neuroendocrine HPA axis
      responses are associated with defective ER expression and regulation in Lewis PVN
      despite oestrogen concentrations.

PMID- 12421338
TI  - Centrally administered galanin-like peptide modifies food intake in the rat: a
      comparison with galanin.
AB  - Galanin-like peptide (GALP) is a recently identified neuropeptide that shares
      sequence homology with the orexigenic neuropeptide, galanin. In contrast to
      galanin, GALP is reported to bind preferentially to the galanin receptor 2
      subtype (GalR2) compared to GalR1. The aim of this study was to determine the
      effect of GALP on feeding, body weight and core body temperature after central
      administration in rats compared to the effects of galanin.
      Intracerebroventricular (i.c.v.) injection of GALP (1 micro g-10 micro g)
      significantly stimulated feeding at 1 h in both satiated and fasted Sprague
      Dawley rats. However, 24 h after GALP injection, body weight gain was
      significantly reduced and food intake was also usually decreased. In addition,
      i.c.v. GALP caused a dose-related increase in core body temperature, which lasted
      until 6-8 h after injection, and was reduced by peripheral administration of the
      cyclooxygenase inhibitor, flurbiprofen (1 mg/kg). Similar to GALP, i.c.v.
      injection of galanin (5 micro g) significantly increased feeding at 1 h in
      satiated rats. However, there was no difference in food intake and body weight at
      24 h, and galanin only caused a transient rise in body temperature. Thus, similar
      to galanin, GALP has an acute orexigenic effect on feeding. However, GALP also
      has an anorectic action, which is apparent at a later time. Therefore, GALP has
      complex opposing actions on energy homeostasis.

PMID- 12421339
TI  - Syrian hamster and rat display developmental differences in the regulation of
      pineal arylalkylamine N-acetyltransferase.
AB  - In the Syrian hamster, the role of noradrenaline in the regulation of melatonin
      synthesis is less clear than in the rat. During pineal ontogenesis in the rat,
      noradrenaline is the major transmitter involved in the onset of melatonin
      synthesis and melatonin rhythm. We analysed the involvement of noradrenaline in
      the ontogenesis of melatonin synthesis in the Syrian hamster and compared it with
      that of the rat. We followed the developmental profile of melatonin content in
      parallel with those of mRNA expression and activity of AA-NAT, the melatonin
      rhythm-generating enzyme. In addition, we tested the effect of noradrenergic
      drugs at early steps of pineal ontogenesis. In the Syrian hamster, the night-time
      Aa-nat mRNA, first detected 3 days after birth, increases progressively up to a
      maximum reached at 30 days of age and then decreases significantly towards
      adulthood. The daytime level of Aa-nat mRNA remains always low. A significant
      day/night rhythm appears 10 days after birth, is maximal (200-fold nocturnal
      increase) 30 days after birth and decreases slowly towards adulthood. Ontogenesis
      of the AA-NAT activity rhythm is similar, although with a much lower amplitude of
      day/night variations (four-fold). The developmental pattern of melatonin content
      is similar to that of AA-NAT and could be correlated with the appearance of
      sympathetic innervation in the pineal gland. However, neither alpha- nor beta
      adrenergic antagonists inhibit the night-time Aa-nat mRNA transcription in the 9
      day-old Syrian hamster, in contrast to what is observed in the adult. For
      comparison, the beta-adrenergic antagonist propranolol inhibits Aa-nat gene
      expression in 2-day-old rat. These results show that both species are different
      in the regulation of the appearance of melatonin synthesis and that Syrian
      hamster is peculiar from birth in term of noradrenaline involvement in the
      activation of melatonin synthesis.

PMID- 12421340
TI  - Isolation and structure-bioactivity characterization of glycosylated N-pro
      opiomelanocortin isoforms.
AB  - The N-terminal fragment of mouse pro-opiomelanocortin (N-POMC) was isolated from
      AtT-20 cell-conditioned medium on the basis of immunoreactivity to an anti-POMC1
      50 monoclonal antibody by a concentration step, a cation exchange step, reversed
      phase high-performance liquid chromatography (HPLC) and size exclusion HPLC. Two
      groups of N-POMC isoforms with a molecular weight (MW) of approximately 11 kDa
      and 13 kDa, respectively, were identified by mass spectrometry and N-terminal
      amino acid sequencing. C-terminal sequencing indicated that 11 kDa isoforms
      correspond to POMC1-74 and 13 kDa isoforms to POMC1-95. Isoforms from both groups
      enhanced the prolactin mRNA content (measured by means of TaqMan real-time
      reverse transcription-polymerase chain reaction) in cultured rat pituitary cell
      aggregates in a dose-dependent manner, but not all of them showed this activity.
      POMC1-74 compounds were significantly more potent than POMC1-95 isoforms. The
      observed effects were abolished by coincubation with the monoclonal anti-POMC1-50
      antibody, showing the specificity of this biological action. Incorporation of
      bromodeoxyuridine into DNA of immunostained lactotrophs was enhanced by only a
      minor part of the isoforms. Some of these had no effect on prolactin mRNA
      expression. The N-POMC isoforms appeared to be N- and at least in part O
      glycosylated. After enzymatic N-deglycosylation of selected N-POMC isoforms, the
      stimulatory effect on the prolactin mRNA level was depressed (in case of the
      POMC1-95 isoforms) or totally abolished (in case of the POMC1-74 isoforms). The
      present findings show that N-POMC is a mixture of differentially glycosylated
      isoforms, that the isoforms of POMC1-74 are the biologically more effective forms
      and that different isoforms induce different biological responses in the same
      cell population. The data also show the essential role of N-glycosylation in the
      biological response.

PMID- 12421341
TI  - Effects of leptin on arcuate pro-opiomelanocortin and cocaine-amphetamine
      regulated transcript expression are independent of circulating levels of
      corticosterone.
AB  - In the hypothalamic arcuate nucleus, neurones that coexpress cocaine-amphetamine
      regulated transcript (CART) and alpha-melanocyte-stimulating hormone [alpha-MSH;
      pro-opiomelanocortin (POMC) derived] peptides exert catabolic actions and are
      stimulated by leptin. However, leptin treatment also affects other circulating
      factors that influence hypothalamic gene expression. Notably, the
      hypercorticosteronaemia of ob/ob mice is lowered by leptin treatment. To examine
      the interaction between glucocorticoids and leptin on POMC/CART mRNA expression,
      an experiment combining leptin and adrenalectomy (ADX) in leptin deficient ob/ob
      mice was carried out. Obese ob/ob and lean littermate Ob/? mice were ADX or sham
      operated. ADX mice received a pellet containing 25% corticosterone
      subcutaneously. Seven days postoperatively, mice were injected intraperitoneally
      for 5 days with either recombinant human leptin or vehicle. On the sixth day, the
      mice were decapitated and the brains removed and trunk blood was collected for
      corticosterone analysis. Plasma concentrations of corticosterone were elevated in
      all ob/ob groups compared to Ob/?. For both ob/ob and Ob/? groups, corticosterone
      concentrations exhibited a decline across groups: vehicle-sham>leptin-sham>ADX
      vehicle>ADX-leptin. Leptin inhibited food intake and bodyweight in ob/ob-sham and
      ob/ob-ADX to a similar extent, whereas no effect of leptin was observed in Ob/?
      mice. Similarly, leptin caused an identical increase in arcuate POMC and CART
      mRNA expression in ob/ob-sham and ob/ob-ADX compared to vehicle. The present data
      support the view that leptin influences arcuate POMC and CART mRNA expression
      directly, and that the effect is not modulated by corticosterone across a wide
      range of circulating corticosterone concentrations.

PMID- 12421342
TI  - Nutritional regulation of hypothalamic leptin receptor gene expression is
      defective in diet-induced obesity.
AB  - Leptin action in the hypothalamus plays a critical role in maintaining normal
      food intake and body weight. Hyperleptinaemia is associated with obesity in
      humans and animal models, suggesting a state of leptin resistance. Although the
      mechanism of leptin resistance is not clearly understood, alterations in leptin
      receptor (Ob-R) gene expression have been proposed as a potential mechanism
      mediating modifications in leptin action in obesity and during changes in
      nutritional status (fed/fasted). The current study examined the effects of diet
      induced obesity (DIO) made by feeding rats a high fat diet for 9 weeks, and
      nutritional status on levels of long form (Ob-Rb) and total (Ob-Rtot) Ob-R mRNA
      expression in the hypothalamus. In the fed state, hypothalamic Ob-Rb mRNA and Ob
      Rtot mRNA levels were similar in DIO and control standard chow fed rats (SC)
      despite hyperleptinaemia in DIO rats. However, although an overnight fast
      moderately increased hypothalamic Ob-Rb mRNA levels in SC rats, fasting did not
      increase Ob-Rb mRNA levels in DIO rats. To address the possibility that elevated
      leptin concentration in DIO rats may mediate an alteration in OB-R mRNA levels,
      we examined the effects of adenovirus-mediated hyperleptinaemia on Ob-R gene
      expression in SC rats. Despite substantially elevated plasma and cerebrospinal
      fluid concentrations of leptin, hypothalamic Ob-R mRNA levels were similar in
      both groups. In conclusion, the current study demonstrates that DIO is associated
      with a loss of nutritional regulation of hypothalamic Ob-R mRNA levels, and that
      hyperleptinaemia is not sufficient to alter Ob-R mRNA expression.

PMID- 12421343
TI  - Localization of oestrogen receptors in the sensory and motor areas of the spinal
      cord in Japanese quail (Coturnix japonica).
AB  - In Japanese quail, the presence of aromatase (oestrogen synthase) in the dorsal
      horn of the spinal cord suggests that spinal sensory processes might be
      controlled by local actions of oestrogens. This is supported by the presence of
      oestrogen receptors and aromatase in the dorsal horn of the spinal cord in rats,
      and by the alteration of sensitivity by oestrogens in various mammalian species
      and also in canaries. We investigated whether oestrogens that are locally
      produced in the quail spinal cord can bind to specific receptors in the vicinity
      of their site of synthesis. We demonstrate the presence of numerous oestrogen
      receptor alpha-immunoreactive (ERalpha-ir) cell nuclei, predominantly in laminae
      II and, to a lesser extent, I and III of the dorsal horn of the spinal cord (i.e.
      in the area where aromatase was previously identified). ERalpha-ir cells were
      also seen in various parts of the intermediate zone (laminae V-VII). This
      presence of ERalpha-ir cells in the dorsal horn and intermediate zone fits in
      well with the distribution of ERalpha-ir cells in homologous areas in mammals,
      including rats. Only a few labelled cells were found in the ventral horn in the
      cervical, brachial, thoracic and first lumbar segments, but a conspicuous dense
      group of large ERalpha-ir cells was identified in lamina IX of the ventral horn
      in synsacral segments 8-10, which contain the motoneurones innervating the
      muscles of the cloacal gland. The presence of ERalpha-ir cells in lamina IX of
      these synsacral segments in quail contrasts with the finding that motoneurones
      innervating penile muscles in rats contain androgen, but not oestrogen receptors,
      and are influenced by androgens rather than by oestrogens. Together, these data
      suggest that spinal actions of oestrogens may modulate the sensory and motor
      systems that participate in reproduction, as well as other nonreproductive
      functions in quail.

PMID- 12421344
TI  - Sexual differentiation of astrocyte morphology in the developing rat preoptic
      area.
AB  - The preoptic area is an important brain region controlling sex-typic behaviour
      and physiology, and astrocytes of this region are responsive to steroids
      perinatally. Utilizing glial fibrillary acidic protein immunocytochemistry, the
      morphology of astrocytes in the preoptic area of male and female rat pups was
      examined on the day of birth and on postnatal day 3. As early as the day of
      birth, astrocytes of the male preoptic area exhibit both significantly greater
      primary process length and number of primary processes, and these differences
      remain at postnatal day 3. Application of exogenous steroid to females suggested
      that gonadal steroids, in particular oestradiol, mediate the sex difference. Pups
      received 100 micro g of steroid on the day of birth and again on postnatal day 1,
      and astrocyte morphology was assessed on postnatal day 3. Both oestradiol and
      testosterone induced significant changes in process length and number compared to
      vehicle-treated controls. Astrocytes of oestradiol-treated females did not differ
      on PN3 from those of PN3-untreated males. Exposure to the nonaromatizable
      steroid, dihydrotestosterone, had no effect on any attribute of astrocyte
      morphology. This suggests the effects induced by testosterone are mediated by
      oestradiol following local aromatization of the steroid, and not through direct
      activation of the androgen receptor. Astrocytes are important in synapse
      formation and efficacy, and we hypothesize a role for astrocyte complexity and
      differentiation in the establishment of synaptic patterning.

PMID- 12421345
TI  - Functional subsets of serotonergic neurones: implications for control of the
      hypothalamic-pituitary-adrenal axis.
AB  - Serotonergic systems play an important role in the regulation of behavioural,
      autonomic and endocrine responses to stressful stimuli. This includes modulation
      of both the hypothalamic-pituitary-adrenal (HPA) axis and the hypothalamic-spinal
      adrenal (HSA) axis, which converge at the level of the adrenal cortex to regulate
      glucocorticoid secretion. Paradoxically, serotonin can either facilitate or
      inhibit HPA axis activity and stress-related physiological or behavioural
      responses. A detailed analysis of the brainstem raphe complex and its ascending
      projections reveals that facilitatory and inhibitory effects of serotonergic
      systems on glucocorticoid secretion may be due to influences of topographically
      organized and functionally diverse serotonergic systems. (i) A serotonergic
      system arising from the middle and caudal dorsal raphe nucleus and projecting to
      a distributed central autonomic control system and a lateral 'emotional motor
      system'. Evidence suggests that serotonin can sensitize this subcortical circuit
      associated with autonomic arousal, anxiety and conditioned fear. (ii) A
      serotonergic system arising from the median raphe nucleus and projecting
      extensively and selectively to a ventral subiculum projection system. Evidence
      suggests that serotonin facilitates this limbic circuit associated with
      inhibition of ultradian, circadian and stress-induced activity of both the HPA
      axis and the HSA axis. These new perspectives, based on functional anatomical
      considerations, provide a hypothetical framework for investigating the role of
      serotonergic systems in the modulation of ultradian, circadian and stress-induced
      neuroendocrine function.

PMID- 12421346
TI  - Pleiotrophin, an angiogenic and mitogenic growth factor, is expressed in human
      gliomas.
AB  - Pleiotrophin (PTN) is a mitogenic/angiogenic, 15.3 kDa heparin-binding peptide
      that is found in embryonic or early postnatal, but rarely in adult, tissues.
      Since developmentally regulated factors often re-appear in malignant cells, we
      examined PTN expression in human glioma cell lines, cell cultures derived from
      solid gliomas and glioma sections. PTN mRNA or protein was detected by reverse
      transcriptase-polymerase chain reaction, immunohistochemistry, western blot or
      enzyme-linked immunoassay in all WHO III and IV grade gliomas and cells analyzed
      in vitro or in situ. One WHO II grade glioma investigated was PTN negative. In
      vitro, PTN was synthesized in perinuclear regions of glioma cells, secreted into
      the cultivation medium, but its production varied considerably between glioma
      cells cultivated from different solid gliomas or glioma cell lines. In situ, PTN
      expression was restricted to distinct parts/cells of the tumour. PTN did not
      influence the proliferation of glioma cells themselves, but stimulated
      [3H]thymidine incorporation into DNA of microglial cells. Furthermore, in Boyden
      chamber assays, PTN showed a strong chemotactic effect on murine BV-2 microglial
      cells. PTN is supposed to be a paracrine growth/angiogenic factor that is
      produced by gliomas and contributes to their malignancy by targeting endothelial
      and microglial cells.

PMID- 12421347
TI  - Expression of interleukin-1 receptors and their role in interleukin-1 actions in
      murine microglial cells.
AB  - Interleukin (IL)-1 is an important mediator of acute brain injury and
      inflammation, and has been implicated in chronic neurodegeneration. The main
      source of IL-1 in the CNS is microglial cells, which have also been suggested as
      targets for its action. However, no data exist demonstrating expression of IL-1
      receptors [IL-1 type-I receptor (IL-1RI), IL-1 type-II receptor (IL-1RII) and IL
      1 receptor accessory protein (IL-1RAcP)] on microglia. In the present study we
      investigated whether microglia express IL-1 receptors and whether they present
      target or modulatory properties for IL-1 actions. RT-PCR analysis demonstrated
      lower expression of IL-1RI and higher expression of IL-1RII mRNAs in mouse
      microglial cultures compared with mixed glial or pure astrocyte cultures.
      Bacterial lipopolysaccharide (LPS) caused increased expression of IL-1RI, IL-1RII
      and IL-1RAcP mRNAs, induced the release of IL-1beta, IL-6 and prostaglandin-E2
      (PGE2), and activated nuclear factor kappaB (NF-kappaB) and the mitogen-activated
      protein kinases (MAPKs) p38, and extracellular signal-regulated protein kinase
      (ERK1/2), but not c-Jun N-terminal kinase (JNK) in microglial cultures. In
      comparison, IL-1beta induced the release of PGE2, IL-6 and activated NF-kappaB,
      p38, JNK and ERK1/2 in mixed glial cultures, but failed to induce any of these
      responses in microglial cell cultures. IL-1beta also failed to affect LPS-primed
      microglial cells. Interestingly, a neutralizing antibody to IL-1RII significantly
      increased the concentration of IL-1beta in the medium of LPS-treated microglia
      and exacerbated the IL-1beta-induced IL-6 release in mixed glia, providing the
      first evidence that microglial IL-1RII regulates IL-1beta actions by binding
      excess levels of this cytokine during brain inflammation.

PMID- 12421348
TI  - Dietary low linolenic acid compared with docosahexaenoic acid alter synaptic
      plasma membrane phospholipid fatty acid composition and sodium-potassium ATPase
      kinetics in developing rats.
AB  - The objective of this study was to investigate if maternal dietary 20:4n-6
      arachidonic acid (AA) and 22:6n-3 compared with adequate or low levels of 18:3n-3
      linolenic acid (LNA) increases synaptic plasma membrane (SPM) cholesterol and
      phospholipid content, phospholipid 20:4n-6 and 22:6n-3 content, and Na,K-ATPase
      kinetics in rat pups at two and five weeks of age. At parturition, Sprague-Dawley
      rats were fed semi-purified diets containing either AA + docosahexaenoic acid
      (DHA), adequate LNA (control; 18:2n-6 : 18:3n-3 ratio of 7.1 : 1) or low LNA
      (18:2n-6 : 18:3n-39 ratio of 835 : 1). During the first two weeks of life, the
      rat pups received only their dams' milk. After weaning, pups received the same
      diet as their respective dams to five weeks of age. No significant difference was
      observed among rat pups fed the diet treatments for SPM cholesterol or total and
      individual phospholipid content at two and five weeks of age. Fatty acid analysis
      revealed that maternal dietary AA + DHA, compared with feeding the dams the
      control diet or the low LNA diet, increased 20:4n-6 in phosphatidylserine and
      22:6n-3 content of SPM phospholipids. Rats fed dietary AA + DHA or the control
      diet exhibited a significantly increased Vmax for SPM Na,K-ATPase. Diet treatment
      did not alter the Km (affinity) of SPM Na,K-ATPase in rat pups at two and five
      weeks of age. It is concluded that dietary AA + DHA does not alter SPM
      cholesterol and phospholipid content but increases the 22:6n-3 content of SPM
      phospholipids modulating activity of Na,K-ATPase.

PMID- 12421349
TI  - Regulation of tyrosine hydroxylase by stress-activated protein kinases.
AB  - Recombinant human tyrosine hydroxylase (hTH1) was found to be phosphorylated by
      mitogen and stress-activated protein kinase 1 (MSK1) at Ser40 and by p38
      regulated/activated kinase (PRAK) on Ser19. Phosphorylation by MSK1 induced an
      increase in Vmax and a decrease in Km for 6-(R)-5,6,7,8-tetrahydrobiopterin
      (BH4), while these kinetic parameters were unaffected as a result of
      phosphorylation by PRAK. Phosphorylation of both Ser40 and Ser19 induced a high
      affinity binding of 14-3-3 proteins, but only the interaction of 14-3-3 with
      Ser19 increased the hTH1 activity. The 14-3-3 proteins also inhibited the rate of
      dephosphorylation of Ser19 and Ser40 by 82 and 36%, respectively. The
      phosphorylation of hTH1 on Ser19 caused a threefold increase in the rate of
      phosphorylation of Ser40. These studies provide new insights into the possible
      roles of stress-activated protein kinases in the regulation of catecholamine
      biosynthesis.

PMID- 12421350
TI  - Activation of the rat dopamine D2 receptor promoter by mitogen-activated protein
      kinase and Ca2+/calmodulin-dependent protein kinase II pathways.
AB  - To investigate regulation of D2 receptor (D2R) gene expression by protein
      kinases, we evaluated effects of constitutively active MAPK kinase kinase (MEKK),
      Ca2+/calmodulin-dependent protein kinase (CaMK) II, CaMKIV and cyclic AMP
      dependent protein kinase (PKA) on D2R promoter activity using luciferase reporter
      gene assays. A 1.5-kbp fragment containing the rat D2R promoter was cloned
      upstream of the reporter and transfected into D2R-expressing NB2A cells or
      nonexpressing NG108-15 and C6 glioma cells. MEKK and CaMKII, but not CaMKIV and
      PKA, increased promoter activity 4.5- and 1.5-fold, respectively, in NB2A cells.
      Inhibitory effects of a MEK inhibitor and lack of effect by dominant negative
      (DN)-JNK1 or DN-p38MAPK revealed that ERK but not JNK and p38MAPK is involved in
      MEKK-induced promoter activation. Deletion and mutation of the promoter revealed
      that the MEKK-responsive region was Sp1 site B between nucleotides -56 and -47.
      Overexpression of Sp1 suppressed promoter activity without affecting MEKK-induced
      activation. Interestingly, overexpression of Zif268 increased promoter activity
      through the region between nucleotides -56 and -36. Increased activity by Zif268
      was additive with CaMKII-induced activation but not with activation induced by
      MEKK. Co-transfection with CaMKII stimulated nuclear translocation of Zif268.
      These results suggest that ERK and CaMKII positively regulate the D2R promoter
      and that Zif268 is a potential transcription factor for the CaMKII-dependent
      pathway.

PMID- 12421351
TI  - Selective reduction of a PDZ protein, SAP-97, in the prefrontal cortex of
      patients with chronic schizophrenia.
AB  - Many postsynaptic density proteins carrying postsynaptic density-95/discs
      large/zone occludens-1 (PDZ) domain(s) interact with glutamate receptors to
      control receptor dynamics and synaptic plasticity. Here we examined the
      expression of PDZ proteins, synapse-associated protein (SAP) 97, postsynaptic
      density (PSD)-95, chapsyn-110, GRIP1 and SAP102, in post-mortem brains of
      schizophrenic patients and control subjects, and evaluated their contribution to
      schizophrenic pathology. Among these PDZ proteins, SAP97 exhibited the most
      marked change: SAP97 protein levels were decreased to less than half that of the
      control levels specifically in the prefrontal cortex of schizophrenic patients.
      In parallel, its binding partner, GluR1, similarly decreased in the same brain
      region. The correlation between SAP97 and GluR1 levels in control subjects was,
      however, altered in schizophrenic patients. SAP102 levels were also significantly
      reduced in the hippocampus of schizophrenic patients, but this reduction was
      correlated with sample storage time and post-mortem interval. There were no
      changes in the levels of the other PDZ proteins in any of the regions examined.
      In addition, neuroleptic treatment failed to mimic the SAP97 change. These
      findings suggest that a phenotypic loss of SAP97 is associated with the
      postsynaptic impairment in prefrontal excitatory circuits of schizophrenic
      patients.

PMID- 12421352
TI  - Intercommunications between brain capillary endothelial cells and glial cells
      increase the transcellular permeability of the blood-brain barrier during
      ischaemia.
AB  - Increased cerebrovascular permeability is an important factor in the development
      of cerebral oedema after stroke, implicating the blood-brain barrier (BBB). To
      investigate the effect of hypoxia on the permeability changes, we used a cell
      culture model of the BBB consisting of a co-culture of brain capillary
      endothelial cells and glial cells. When endothelial cells from this co-culture
      model were submitted alone to hypoxic conditions, long exposures (48 h) were
      necessary to result in an increase in endothelial cell monolayer permeability to
      [3H]inulin. When endothelial cells were incubated in presence of glial cells, a
      huge increase in permeability occurred after 9 h of hypoxic conditions. Oxygen
      glucose deprivation (OGD) resulted in a much shorter time (i.e. 2 h) required for
      an increase in permeability. We have demonstrated that this OGD-induced
      permeability increase involves a transcellular rather than a paracellular
      pathway. Conditioned medium experiments showed that glial cells secrete soluble
      permeability factors during OGD. However, endothelial cells have to be made
      sensitive by OGD in order to respond to these glial soluble factors. This work
      shows that an early cross-talk between glial and endothelial cells occurs during
      ischaemic stroke and alters BBB transcellular transport by means of glial factor
      secretions.

PMID- 12421353
TI  - Identity of adenylyl cyclase isoform determines the G protein mediating chronic
      opioid-induced adenylyl cyclase supersensitivity.
AB  - To determine the intracellular signal transduction pathway responsible for the
      development of tolerance/dependence, the ability of Gzalpha to substitute for
      pertussis toxin (PTX)-sensitive G proteins in mediating adenylyl cyclase (AC)
      supersensitivity was examined in the presence of defined AC isoforms. In
      transiently micro-opioid receptor (OR) transfected COS-7 cells (endogenous
      inhibitory G proteins: Gialpha2, Gialpha3 and Gzalpha), neither acute (1 micro
      mol/L) nor chronic morphine treatment (1 micromol/L; 18 h) influenced
      intracellular cAMP production. Coexpression of the micro -OR together with AC
      type V and VI fully restored the ability of morphine to acutely inhibit cAMP
      generation. Chronic morphine treatment further resulted in the development of
      tolerance/dependence, as assessed by desensitization of the acute inhibitory
      opioid effect (tolerance) as well as the induction of AC supersensitivity after
      drug withdrawal (dependence). Specific direction of micro -OR signalling via
      Gzalpha by both PTX treatment and Gzalpha over-expression had no effect on
      chronic morphine regulation of AC type V, but completely abolished the
      development of tolerance/dependence with AC type VI. Similar results were
      obtained in stably micro -OR-expressing HEK293 cells transiently cotransfected
      with Gzalpha and either AC type V or VI. Coprecipitation studies further verified
      that Gzalpha specifically binds to AC type V but not type VI. Taken together,
      these results demonstrate that in principle each of the OR-activated G proteins
      per se is able to mediate AC supersensitivity. However, they also indicate that
      it is the molecular nature of AC isoform that selects and determines the OR
      activated G protein mediating tolerance/dependence.

PMID- 12421354
TI  - beta-Amyloid peptide induces formation of actin stress fibers through p38 mitogen
      activated protein kinase.
AB  - Based on the critical role of actin in the maintenance of synaptic function, we
      examined whether expression of familial beta-amyloid precursor protein APP-V642I
      (IAPP) or mutant presenilin-1 L286V (mPS1) affects actin polymerization in rat
      septal neuronal cells. Expression of either IAPP or mPS1 but not wild-type
      amyloid precursor protein or presenilin-1induced formation of actin stress fibers
      in SN1 cells, a septal neuronal cell line. Treatment with beta-amyloid (Abeta)
      peptide also caused formation of actin stress fibers in SN1 cells and primary
      cultured hippocampal neurons. Treatment with a gamma-secretase inhibitor
      completely blocked formation of actin stress fibers, indicating that
      overproduction of Abeta peptide induces actin stress fibers. Because activation
      of the p38 mitogen-activated protein kinase (p38MAPK)-mitogen-associated protein
      kinase-associated protein kinase (MAPKAPK)-2-heat-shock protein 27 signaling
      pathway mediates actin polymerization, we explored whether Abeta peptide
      activates p38MAPK and MAPKAPK-2. Expression of IAPP or mPS1 induced activation of
      p38MAPK and MAPKAPK-2. Treatment with a p38MAPK inhibitor completely inhibited
      formation of actin stress fibers mediated by Abeta peptide, IAPP or mPS1.
      Moreover, treatment with a gamma-secretase inhibitor completely blocked
      activation of p38MAPK and MAPKAPK-2. In summary, our data suggest that
      overproduction of Abeta peptide induces formation of actin stress fibers through
      activation of the p38MAPK signaling pathway in septal neuronal cells.

PMID- 12421355
TI  - Increased methamphetamine-induced locomotor activity and behavioral sensitization
      in histamine-deficient mice.
AB  - We have recently suggested that the brain histamine has an inhibitory role on the
      behavioral effects of methamphetamine by pharmacological studies. In this study,
      we used the histidine decarboxylase gene knockout mice and measured the
      spontaneous locomotor activity, the changes of locomotion by single and repeated
      administrations of methamphetamine, and the contents of brain monoamines and
      amino acids at 1 h after a single administration of methamphetamine. In the
      histidine decarboxylase gene knockout mice, spontaneous locomotor activity during
      the dark period was significantly lower than in the wild-type mice.
      Interestingly, methamphetamine-induced locomotor hyperactivity and behavioral
      sensitization were facilitated more in the histidine decarboxylase gene knockout
      mice. In the neurochemical study, noradrenaline and O-phosphoserine were
      decreased in the midbrain of the saline-treated histidine decarboxylase gene
      knockout mice. On the other hand, single administration of methamphetamine
      decreased GABA content of the midbrain of the wild-type mice, but did not alter
      that of histidine decarboxylase gene knockout mice. These results suggest that
      the histamine neuron system plays a role as an awakening amine in concert with
      the noradrenaline neuron system, whereas it has an inhibitory role on the
      behavioral effects of methamphetamine through the interaction with the GABAergic
      neuron system.

PMID- 12421356
TI  - TorsinA and heat shock proteins act as molecular chaperones: suppression of alpha
      synuclein aggregation.
AB  - TorsinA, a protein with homology to yeast heat shock protein104, has previously
      been demonstrated to colocalize with alpha-synuclein in Lewy bodies, the
      pathological hallmark of Parkinson's disease. Heat shock proteins are a family of
      chaperones that are both constitutively expressed and induced by stressors, and
      that serve essential functions for protein refolding and/or degradation. Here, we
      demonstrate that, like torsinA, specific molecular chaperone heat shock proteins
      colocalize with alpha-synuclein in Lewy bodies. In addition, using a cellular
      model of alpha-synuclein aggregation, we demonstrate that torsinA and specific
      heat shock protein molecular chaperones colocalize with alpha-synuclein
      immunopositive inclusions. Further, overexpression of torsinA and specific heat
      shock proteins suppress alpha-synuclein aggregation in this cellular model,
      whereas mutant torsinA has no effect. These data suggest that torsinA has
      chaperone-like activity and that the disease-associated GAG deletion mutant has a
      loss-of-function phenotype. Moreover, these data support a role for chaperone
      proteins, including torsinA and heat shock proteins, in cellular responses to
      neurodegenerative inclusions.

PMID- 12421357
TI  - Glutamate release by an Na+ load and oxidative stress in nerve terminals:
      relevance to ischemia/reperfusion.
AB  - Previously we have reported that oxidative stress induced by hydrogen peroxide
      exacerbates the effect of an Na+ load in isolated nerve terminals, with a
      consequence of an ATP depletion, [Ca2+]i and [Na+]i deregulation, and collapse of
      mitochondrial membrane potential. In the present study, the release of glutamate
      in response to a combined effect of an [Na+] load and oxidative stress was
      measured in isolated nerve terminals over an incubation for 15 min. Exposure to
      hydrogen peroxide (100 micro m) had no effect on the release of glutamate, but
      significantly enhanced the Ca2+-independent glutamate release induced by a small
      [Na+] load achieved with 10 micro m veratridine. The effect of a larger Na+ load
      induced by 40 micro m veratridine was not further increased by hydrogen peroxide;
      in contrast the external Ca2+-dependent glutamate release was completely
      eliminated by the oxidant under this condition. The effects of oxidative stress
      superimposed on a Na+ load are consistent with at least two factors: (i) a
      relatively modest Na+ load induced by veratridine is augmented by H2O2 giving
      rise to an increased Ca2+-independent release of glutamate (ii) oxidative stress
      in combination with a larger Na+ load causes severe ATP depletion limiting the
      Ca2+-dependent vesicular glutamate release. Given the concurrent presence of an
      Na+ load and oxidative stress in ischemia/reperfusion these results indicate that
      the extent of the Na+ load developing during the ischemic period could determine
      the release of glutamate induced by an oxidative stress during reperfusion.

PMID- 12421358
TI  - Serotonin synthesis and its light-dark variation in the rat retina.
AB  - Retinal circadian rhythms are driven by an intrinsic oscillator, using chemical
      signals such as melatonin, secreted by photoreceptor cells. The purpose of the
      present work was to identify the origin of serotonin, the precursor of melatonin,
      in the retina of adult rat, where no immunoreactivity for serotonin or tryptophan
      hydroxylase had ever been detected. To demonstrate local synthesis of serotonin
      in the rat retina, substrates of tryptophan hydroxylase, the first limiting
      enzyme in the serotonin pathway, have been used. Tryptophan, in the presence of
      an inhibitor of aromatic amino acid decarboxylase, enhanced 5-hydroxytryptophan
      levels, whereas alpha-methyltryptophan, a competitive substrate inhibitor, was
      hydroxylated into alpha-methyl-5-hydroxytryptophan. Tryptophan hydroxylase
      substrate concentration was higher in the dark period than in the light period,
      and formation of hydroxylated compounds was increased. The presence of tryptophan
      hydroxylase mRNA in the rat retina was confirmed by RT-PCR. Taken together, the
      results support the local synthesis of serotonin by tryptophan hydroxylation,
      this metabolic pathway being required more critically when 5-HT is used for
      melatonin synthesis.

PMID- 12421359
TI  - Study of the nematode putative GABA type-A receptor subunits: evidence for
      modulation by ivermectin.
AB  - Two alleles of the HG1 gene, which encodes a putative GABA receptor alpha/gamma
      subunit, were isolated from Haemonchus contortus. These two alleles were shown
      previously to be associated with ivermectin susceptibility (HG1A) and resistance
      (HG1E), respectively. Sequence analysis indicates that they differ in four amino
      acids. To explore the functional properties of the two alleles, a full-length
      cDNA encoding the beta subunit, a key functional component of the GABA receptor,
      was isolated from Caenorhabditis elegans (gab-1, corresponding to the GenBank
      locus ZC482.1) and coexpressed in Xenopus oocytes with the HG1 alleles. When gab
      1 was coexpressed with either the HG1A allele or the HG1E allele in Xenopus
      oocytes, gamma-aminobutyric acid (GABA)-responsive channels with different
      sensitivity to the agonist were formed. The effects of ivermectin on the hetero
      oligomeric receptors were determined. Application of ivermectin alone had no
      effect on the receptors. However, when coapplied with 10 micro m GABA, ivermectin
      potentiated the GABA-evoked current of the GAB-1/HG1A receptor, but attenuated
      the GABA response of the GAB-1/HG1E receptor. We demonstrated that the
      coexpressed HG1 and GAB-1 receptors are GABA-responsive, and provide evidence for
      the possible involvement of GABA receptors in the mechanism of ivermectin
      resistance.

PMID- 12421360
TI  - Urotensin-II regulates intracellular calcium in dissociated rat spinal cord
      neurons.
AB  - Urotensin-II (U-II), a peptide with multiple vascular effects, is detected in
      cholinergic neurons of the rat brainstem and spinal cord. Here, the effects of U
      II on [Ca2+]i was examined in dissociated rat spinal cord neurons by fura 2
      microfluorimetry. The neurons investigated were choline acetyltransferase
      positive and had morphological features of motoneurons. U-II induced [Ca2+]i
      increases in these neurons with a threshold of 10-9 m, and a maximal effect at 10
      6 m with an estimated EC50 of 6.2 x 10-9 m. The [Ca2+]i increase induced by U-II
      was mainly caused by Ca2+ influx from extracellular space, as the response was
      markedly attenuated in a Ca2+-free medium. Omega-conotoxin GVIA (10-7 m), a N
      type Ca2+ channel blocker, largely inhibited these increases, whereas the P/Q
      Ca2+ channel blocker, omega-conotoxin GVIIC (10-7 m) and the l-type Ca2+ channel
      blocker, verapamil (10-5 m) had minimal effects. Down-regulation of protein
      kinase C by 4-alpha-phorbol 12-myristate 13-acetate (10-6 m) or enzyme inhibition
      using the specific inhibitor bisindolylmaleimide I (10-6 m) did not inhibit the
      observed effects. Similarly, inhibition of protein kinase G with KT5823 (10-6 m)
      or Rp-8-pCPT-cGMPS (3 x 10-5 m) did not modify U-II-induced [Ca2+]i increases. In
      contrast, protein kinase A inhibitors KT5720 (10-6 m) and Rp-cAMPS (3 x 10-5 m)
      reduced the response to 25 +/- 3% and 42 +/- 8%, respectively. Present results
      demonstrate that U-II modulates [Ca2+]i in rat spinal cord neurons via protein
      kinase A cascade.

PMID- 12421361
TI  - Matrix metalloproteinase mediated degradation of basement membrane proteins in
      Trembler J neuropathy nerves.
AB  - A single point mutation in peripheral myelin protein 22 (pmp22) of the Trembler-J
      (TrJ) mouse models the human peripheral neuropathy, Charcot-Marie-Tooth disease
      type 1 A (CMT1A). An unexplored aspect of this disease is the gradual remodeling
      of the extracellular matrix in affected nerves. To elucidate the mechanism
      responsible for these changes, the levels of the extracellular matrix molecules
      laminin, collagen IV, and fibronectin were determined. In TrJ nerves, laminin is
      modestly increased while full-length forms of collagen IV and fibronectin are
      decreased. Matrix metalloproteinases (MMPs) are known to degrade multiple matrix
      molecules; therefore, nerves were assayed for MMP-2 and MMP-9 proteins. In
      neuropathy nerves, elevated levels of MMP-2 and MMP-9 were detected on western
      blots, and gelatin zymography confirmed the up-regulation of gelatinalytic
      activity in affected samples. Immunostaining studies revealed an increase in the
      numbers of MMP-2- and MMP-9-expressing cells in TrJ nerves. Cell type-specific
      immunolabeling showed that infiltrating macrophages are a significant source of
      both MMP-2 and MMP-9. Finally, the degradation of exogenous collagen IV by TrJ
      nerve lysates was prevented with a specific MMP inhibitor. Together these
      observations suggest that infiltration by MMP-expressing macrophages contributes
      to the remodeling of the TrJ nerve matrix.

PMID- 12421362
TI  - Selective modifications in the nucleus accumbens of dopamine synaptic
      transmission in rats exposed to chronic stress.
AB  - Stressful events are accompanied by modifications in dopaminergic transmission in
      distinct brain regions. As the activity of the neuronal dopamine (DA) transporter
      (DAT) is considered to be a critical mechanism for determining the extent of DA
      receptor activation, we investigated whether a 3-week exposure to unavoidable
      stress, which produces a reduction in DA output in the nucleus accumbens shell
      (NAcS) and medial prefrontal cortex (mPFC), would affect DAT density and DA D1
      receptor complex activity in the NAcS, mPFC and caudate-putamen (CPu). Rats
      exposed to unavoidable stress showed a decreased DA output in the NAcS
      accompanied by a decrease in the number of DAT binding sites, and an increase in
      the number of DA D1 binding sites and Vmax of SKF 38393-stimulated adenylyl
      cyclase. In the mPFC, stress exposure produced a decrease in DA output with no
      modification in DAT binding or in DA D1 receptor complex activity. Moreover, in
      the CPu stress exposure induced no changes in DA output or in the other
      neurochemical variables examined. This study shows that exposure to a chronic
      unavoidable stress that produces a decrease in DA output in frontomesolimbic
      areas induced several adaptive neurochemical modifications selectively in the
      nucleus accumbens.

PMID- 12421363
TI  - Axin negatively affects tau phosphorylation by glycogen synthase kinase 3beta.
AB  - Glycogen synthase kinase 3beta (GSK3beta) is an essential protein kinase that
      regulates numerous functions within the cell. One critically important substrate
      of GSK3beta is the microtubule-associated protein tau. Phosphorylation of tau by
      GSK3beta decreases tau-microtubule interactions. In addition to phosphorylating
      tau, GSK3beta is a downstream regulator of the wnt signaling pathway, which
      maintains the levels of beta-catenin. Axin plays a central role in regulating
      beta-catenin levels by bringing together GSK3beta and beta-catenin and
      facilitating the phosphorylation of beta-catenin, targeting it for ubiquitination
      and degradation by the proteasome. Although axin clearly facilitates the
      phosphorylation of beta-catenin, its effects on the phosphorylation of other
      GSK3beta substrates are unclear. Therefore in this study the effects of axin on
      GSK3beta-mediated tau phosphorylation were examined. The results clearly
      demonstrate that axin is a negative regulator of tau phosphorylation by GSK3beta.
      This negative regulation of GSK3beta-mediated tau phosphorylation is due to the
      fact that axin efficiently binds GSK3beta but not tau and thus sequesters
      GSK3beta away from tau, as an axin mutant that does not bind GSK3beta did not
      inhibit tau phosphorylation by GSK3beta. This is the first demonstration that
      axin negatively affects the phosphorylation of a GSK3beta substrate, and provides
      a novel mechanism by which tau phosphorylation and function can be regulated
      within the cell.

PMID- 12421364
TI  - Neuroprotective effects of bcl-2 overexpression in hippocampal cultures:
      interactions with pathways of oxidative damage.
AB  - Overexpression of bcl-2protects neurons from numerous necrotic insults, both in
      vitro and in vivo. While the bulk of such protection is thought to arise from Bcl
      2 blocking cytochrome c release from mitochondria, thereby blocking apoptosis,
      the protein can target other steps in apoptosis, and can protect against necrotic
      cell death as well. There is evidence that these additional actions may be
      antioxidant in nature, in that Bcl-2 has been reported to protect against
      generators of reactive oxygen species (ROS), to increase antioxidant defenses and
      to decrease levels of ROS and of oxidative damage. Despite this, there are also
      reports arguing against either the occurrence, or the importance of these
      antioxidant actions. We have examined these issues in neuron-enriched primary
      hippocampal cultures, with overexpression of bcl-2 driven by a herpes simplex
      virus amplicon: (i) Bcl-2 protected strongly against glutamate, whose toxicity is
      at least partially ROS-dependent. Such protection involved reduction in
      mitochondrially derived superoxide. Despite that, Bcl-2 had no effect on levels
      of lipid peroxidation, which is thought to be the primary locus of glutamate
      induced oxidative damage; (ii) Bcl-2 was also mildly protective against the pro
      oxidant adriamycin. However, it did so without reducing levels of superoxide,
      hydrogen peroxide or lipid peroxidation; (iii) Bcl-2 protected against permanent
      anoxia, an insult likely to involve little to no ROS generation. These findings
      suggest that Bcl-2 can have antioxidant actions that may nonetheless not be
      central to its protective effects, can protect against an ROS generator without
      targeting steps specific to oxidative biochemistry, and can protect in the
      absence of ROS generation. Thus, the antioxidant actions of Bcl-2 are neither
      necessary nor sufficient to explain its protective actions against these insults
      in hippocampal neurons.

PMID- 12421365
TI  - High transcytosis of melanotransferrin (P97) across the blood-brain barrier.
AB  - The blood-brain barrier (BBB) performs a neuroprotective function by tightly
      controlling access to the brain; consequently it also impedes access of proteins
      as well as pharmacological agents to cerebral tissues. We demonstrate here that
      recombinant human melanotransferrin (P97) is highly accumulated into the mouse
      brain following intravenous injection and in situ brain perfusion. Moreover, P97
      transcytosis across bovine brain capillary endothelial cell (BBCEC) monolayers is
      at least 14-fold higher than that of holo-transferrin, with no apparent intra
      endothelial degradation. This high transcytosis of P97 was not related to changes
      in the BBCEC monolayer integrity. In addition, the transendothelial transport of
      P97 was sensitive to temperature and was both concentration- and conformation
      dependent, suggesting that the transport of P97 is due to receptor-mediated
      endocytosis. In spite of the high degree of sequence identity between P97 and
      transferrin, a different receptor than the one for transferrin is involved in P97
      transendothelial transport. A member of the low-density lipoprotein receptor
      protein family, likely LRP, seems to be involved in P97 transendothelial
      transport. The brain accumulation, high rate of P97 transcytosis and its very low
      level in the blood suggest that P97 could be advantageously employed as a new
      delivery system to target drugs directly to the brain.

PMID- 12421366
TI  - Kainate-induced excitotoxicity is dependent upon extracellular potassium
      concentrations that regulate the activity of AMPA/KA type glutamate receptors.
AB  - In addition to well-known N-methyl-d-aspartate (NMDA) receptor-mediated
      excitotoxicity, recent studies suggest that non-NMDA type ionotropic glutamate
      receptors are also important mediators of excitotoxic neuronal death, and that
      their functional expression can be regulated by the cellular environment. In this
      study, we used cerebellar granule cells (CGCs) in culture to investigate kainate
      (KA)-induced excitotoxicity. Although previous reports indicated that KA induces
      apoptosis of CGCs in culture, no KA-induced excitotoxic cell death was observed
      in CGCs treated with KA when cells were maintained in high potassium media (24 mm
      K+). In contrast, when mature CGCs were shifted into low potassium media (3 mm
      K+), KA produced significant excitotoxicity. In electrophysiological studies, the
      KA-induced inward current density was significantly elevated in CGCs shifted into
      low K+ media compared with those maintained in high K+ media. Non-desensitizing
      aspects of KA currents observed in this study suggest that these responses were
      mediated by AMPA rather than KA receptors. In immunofluorescence studies, the
      surface expression of GluR1 subunits increased when mature CGCs were shifted into
      a low K+ environment. This study suggests that KA-induced excitotoxicity in
      mature CGCs is dependent upon the extracellular potassium concentration, which
      modulates functional expression and excitability of AMPA/KA receptors.

PMID- 12421367
TI  - Synaptic concentration of type-I adenylyl cyclase in cerebellar neurons.
AB  - Specific subcellular targeting and spatial arrangement of signaling molecules are
      important for efficient signal transduction. The neuro-specific type-I adenylyl
      cyclase (AC1) is stimulated by Ca2+, and plays an essential role in
      neurodevelopment and neuroplasticity. We generated hemagglutinin (HA)-tagged AC1
      to study its subcellular localization in cultured neurons. The HA-tagged AC1 has
      similar enzymatic activity and regulatory properties to that of non-tagged
      protein. HA-AC1 targeted to both apical and basolateral domains in the epithelial
      Madin-Darby canine kidney (MDCK) cells, and it was found in both axons and
      dendrites in cultured hippocampal neurons as well as in cerebellar granule
      neurons. Interestingly, AC1 showed a distinct punctate form of immunostaining in
      MDCK cells and transfected neurons, suggesting it targets to specific subcellular
      domains. By immunostaining with different synaptic markers, we found that AC1
      puncta were located at the excitatory synapses in cerebellar granule neurons. Our
      data provide a possible cellular mechanism for the physiological role of AC1 in
      neuroplasticity.

PMID- 12421368
TI  - Human immunodeficiency virus-1 Tat protein and methamphetamine interact
      synergistically to impair striatal dopaminergic function.
AB  - The human immunodeficiency virus (HIV)-1 transactivating protein Tat may be
      pathogenically relevant in HIV-1-induced neuronal injury. The abuse of
      methamphetamine (MA), which is associated with behaviors that may transmit HIV-1,
      may damage dopaminergic afferents to the striatum. Since Tat and MA share common
      mechanisms of injury, we examined whether co-exposure to these toxins would lead
      to enhanced dopaminergic toxicity. Animals were treated with either saline, a
      threshold dose of MA, a threshold concentration of Tat injected directly into the
      striatum, or striatal injections of Tat followed by exposure to MA. Threshold was
      defined as the highest concentration of toxin that would not result in a
      significant loss of striatal dopamine levels. One week later, MA-treated animals
      demonstrated a 7% decline in striatal dopamine levels while Tat-treated animals
      showed an 8% reduction. Exposure to both MA + Tat caused an almost 65% reduction
      in striatal dopamine. This same treatment caused a 56% reduction in the binding
      capacity to the dopamine transporter. Using human fetal neurons, enhanced
      toxicity was also observed when cells were exposed to both Tat and MA.
      Mitochondrial membrane potential was disrupted and could be prevented by
      treatment with antioxidants. This study demonstrates that the HIV-1 'virotoxin'
      Tat enhances MA-induced striatal damage and suggests that HIV-1-infected
      individuals who abuse MA may be at increased risk of basal ganglia dysfunction.

PMID- 12421369
TI  - Subtype-specific regulation of the expression and function of muscarinic
      acetylcholine receptors in embryonic chicken retinal cells.
AB  - We examined the effect of long-term agonist exposure on muscarinic acetylcholine
      receptor expression and function in embryonic chicken retinal cells. Long-term
      carbachol exposure induced a time- and concentration-dependent decrease in M2, M3
      and M4 muscarinic receptor numbers. Kinetic analyses revealed a first-order
      process with similar rate constants for all three subtypes. Both the maximal
      decrease and the agonist potency for regulation of M3 were significantly higher
      than those for M2 and M4. Upon agonist removal, M2 and M4 numbers returned to
      control values, but M3 recovery after 24 h was no higher than 40%. Agonist
      treatment did not alter the levels of receptor mRNAs. Receptor inactivation with
      a covalent alkylating antagonist demonstrated that the partial M3 protein
      recovery was not due to a decreased intrinsic basal rate of synthesis, suggesting
      that it is induced by agonist treatment. Prolonged carbachol exposure induced
      concomitant decreases in muscarinic-mediated inhibition of cyclic AMP
      accumulation which were completely reversed after agonist removal. Sustained
      receptor activation also promoted significant decreases in muscarinic receptor
      stimulated phosphoinositide turnover, which were only partially reversed after
      agonist removal. These data demonstrate subtype-specific regulation of the
      expression and function of muscarinic receptors in the retina.

PMID- 12421370
TI  - Microglia enhance beta-amyloid peptide-induced toxicity in cortical and
      mesencephalic neurons by producing reactive oxygen species.
AB  - The purpose of this study was to assess and compare the toxicity of beta-amyloid
      (Abeta) on primary cortical and mesencephalic neurons cultured with and without
      microglia in order to determine the mechanism underlying microglia-mediated Abeta
      induced neurotoxicity. Incubation of cortical or mesencephalic neuron-enriched
      and mixed neuron-glia cultures with Abeta(1-42) over the concentration range 0.1
      6.0 microm caused concentration-dependent neurotoxicity. High concentrations of
      Abeta (6.0 microm for cortex and 1.5-2.0 microm for mesencephalon) directly
      injured neurons in neuron-enriched cultures. In contrast, lower concentrations of
      Abeta (1.0-3.0 microm for cortex and 0.25-1.0 microm for mesencephalon) caused
      significant neurotoxicity in mixed neuron-glia cultures, but not in neuron-
      enriched cultures. Several lines of evidence indicated that microglia mediated
      the potentiated neurotoxicity of Abeta, including the observations that low
      concentrations of Abeta activated microglia morphologically in neuron-glia
      cultures and that addition of microglia to cortical neuron-glia cultures enhanced
      Abeta-induced neurotoxicity. To search for the mechanism underlying the microglia
      mediated effects, several proinflammatory factors were examined in neuron-glia
      cultures. Low doses of Abeta significantly increased the production of superoxide
      anions, but not of tumor necrosis factor-alpha, interleukin-1beta or nitric
      oxide. Catalase and superoxide dismutase significantly protected neurons from
      Abeta toxicity in the presence of microglia. Inhibition of NADPH oxidase activity
      by diphenyleneiodonium also prevented Abeta-induced neurotoxicity in neuron-glia
      mixed cultures. The role of NADPH oxidase-generated superoxide in mediating Abeta
      induced neurotoxicity was further substantiated by a study which showed that
      Abeta caused less of a decrease in dopamine uptake in mesencephalic neuron-glia
      cultures from NADPH oxidase-deficient mutant mice than in that from wild-type
      controls. This study demonstrates that one of the mechanisms by which microglia
      can enhance the neurotoxicity of Abeta is via the production of reactive oxygen
      species.

PMID- 12421371
TI  - Preservation of extracellular glutathione by an astrocyte derived factor with
      properties comparable to extracellular superoxide dismutase.
AB  - Cultured rat and human astrocytes and rat neurones were shown to release reduced
      glutathione (GSH). In addition, GSH oxidation was retarded by the concomitant
      release of a factor from the cells. One possibility is that this factor is
      extracellular superoxide dismutase (SOD). In support of this, the factor was
      found to bind heparin, have a molecular mass estimated to be between 50 and 100
      kDa, and CuZn-type SOD protein and cyanide sensitive enzyme activity were
      demonstrated in the cell-conditioned medium. In addition, supplementation of
      native medium with exogenous CuZn-type SOD suppressed GSH oxidation. We propose
      that preservation of released GSH is essential to allow for maximal up-regulation
      of GSH metabolism in neurones. Furthermore, cytokine stimulation of astrocytes
      increased release of the extracellular SOD, and enhanced stability of GSH. This
      may be a protective strategy occurring in vivo under conditions of oxidative
      stress, and suggests that SOD mimetics may be of therapeutic use.

PMID- 12421373
TI  - Transient rise in intracellular calcium produces a long-lasting increase in
      plasma membrane calcium pump activity in rat sensory neurons.
AB  - The plasma membrane Ca2+ ATPase (PMCA) plays a major role in clearing Ca2+ from
      the neuronal cytoplasm. Calmodulin stimulates PMCA activity and for some isoforms
      this activation persists following clearance of Ca2+ owing to the slow
      dissociation of calmodulin. We tested the hypothesis that PMCA-mediated Ca2+
      efflux from rat dorsal root ganglion (DRG) neurons in culture would remain
      stimulated following increases in intracellular Ca2+ concentration ([Ca2+]i).
      PMCA-mediated Ca2+ extrusion was recorded following brief trains of action
      potentials using indo-1-based photometry in the presence of cyclopiazonic acid. A
      priming stimulus that increased [Ca2+]i to 506 +/- 28 nm (>15 min) increased the
      rate constant for [Ca2+]i recovery by 47 +/- 3%. Ca2+ clearance from subsequent
      test stimuli remained accelerated for up to an hour despite removal of the
      priming stimulus and a return to basal [Ca2+]i. The acceleration depended on the
      magnitude and duration of the priming [Ca2+]i increase, but was independent of
      the source of Ca2+. Increases in [Ca2+]i evoked by prolonged depolarization,
      sustained trains of action potentials or activation of vanilloid receptors all
      accelerated Ca2+ efflux. We conclude that PMCA-mediated Ca2+ efflux in DRG
      neurons is a dynamic process in which intense stimuli prime the pump for the next
      Ca2+ challenge.

PMID- 12421372
TI  - Identification of JNK-dependent and -independent components of cerebellar granule
      neuron apoptosis.
AB  - Cerebellar granule neurons grown in high potassium undergo rapid apoptosis when
      switched to medium containing 5 mm potassium, a stimulus mimicking
      deafferentation. This cell death can be blocked by genetic deletion of Bax, a
      member of the pro-apoptotic Bcl-2 family, cycloheximide an inhibitor of
      macromolecular synthesis or expression of dominant-negative c-jun. These
      observations suggest that Bax activation is the result of c-jun target gene(s) up
      regulation following trophic withdrawal. Candidate genes include the BH3-only Bcl
      2 family members Dp5 and Bim. The molecular mechanisms underlying granule cell
      neuronal apoptosis in response to low potassium were investigated using CEP-1347
      (KT7515), an inhibitor of the MLK family of JNKKK. CEP-1347 provided protection
      of potassium-serum-deprived granule cells, but such neuroprotection was not long
      term. The incomplete protection was not due to incomplete blockade of the JNK
      signaling pathway because c-jun phosphorylation as well as induction of c-jun RNA
      and protein were completely blocked by CEP-1347. Following potassium-serum
      deprivation the JNKK MKK4 becomes phosphorylated, an event blocked by CEP-1347.
      Cells that die in the presence of CEP-1347 activate caspases; and dual inhibition
      of caspases and MLKs has additive, not synergistic, effects on survival. A lack
      of synergism was also seen with the p38 inhibitor SB203580, indicating that the
      neuroprotective effect of the JNK pathway inhibitor cannot be explained by p38
      activation. Activation of the JNK signaling pathway seems to be a key event in
      granule cell apoptosis, but these neurons cannot survive long term in the absence
      of sustained PI3 kinase signaling.

PMID- 12421374
TI  - Selective inhibition of Abeta42 production by NSAID R-enantiomers.
AB  - Non-steroidal anti-inflammatory drugs (NSAIDs) have been associated with reduced
      risk for Alzheimer's disease (AD) and selected NSAIDs racemates suppress beta
      amyloid (Abeta) accumulation in vivo and Abeta42 production in vitro. Clinical
      use of NSAIDs for preventing or treating AD has been hampered by dose-limiting
      toxicity believed to be due to cyclooxygenase (COX)-inhibition that is reportedly
      not essential for selective Abeta42 reduction. Profens have racemates and R
      enantiomers were supposed to be inactive forms. Here we demonstrate that R
      ibuprofen and R-flurbiprofen, with poor COX-inhibiting activity, reduce Abeta42
      production by human cells. Although these R-enantiomers inhibit nuclear factor
      kappaB (NF-kappaB) activation and NF-kappaB can selectively regulate Abeta42,
      Abeta42 reduction is not mediated by inhibition of NF-kappaB activation. Because
      of its efficacy at lowering Abeta42 production and low toxicity profile, R
      flurbiprofen is a strong candidate for clinical development.

PMID- 12421375
TI  - ProSAP/Shank postsynaptic density proteins interact with insulin receptor
      tyrosine kinase substrate IRSp53.
AB  - The ProSAP/Shank family of multidomain proteins of the postsynaptic density (PSD)
      can either directly or indirectly interact with NMDA-type and metabotropic
      glutamate receptors and the actin-based cytoskeleton. In a yeast two hybrid
      screen utilizing a proline-rich domain that is highly conserved among the
      ProSAP/Shank family members, we isolated several cDNA clones coding for the
      insulin receptor substrate IRSp53. The specificity of this interaction was
      confirmed in transfected COS cells. Co-immunoprecipitation of IRSp53 and ProSAP2
      solubilized from rat brain membranes indicates that the interaction occurs in
      vivo. The C-terminal SH3 domain of IRSp53 is responsible for the interaction with
      a novel proline-rich consensus sequence of ProSAP/Shank that was characterized by
      mutational analysis. IRSp53 is a substrate for the insulin receptor in the brain
      and acts downstream of small GTPases of the Rho family. Binding of Cdc42Hs to
      IRSp53 induces actin filament assembly, reorganization and filopodia outgrowth in
      neuronal cell lines. Our data suggest that IRSp53 can be recruited to the PSD via
      its ProSAP/Shank interaction and may contribute to the morphological
      reorganization of spines and synapses after insulin receptor and/or Cdc42Hs
      activation.

PMID- 12421386
TI  - What criteria do patients use when judging the effectiveness of psoriasis
      management?
AB  - Judgements on the effectiveness of psoriasis management are based on clinical
      criteria employed by dermatologists, and how they take account of patients'
      experiences in the process of history taking. In this study the aim was to gain
      the in-depth patients' perspective and investigate the criteria that they employ
      when making judgements about the effectiveness of their therapy. These findings
      were then compared with the clinical and research literature on the clinical
      effectiveness of psoriasis treatments. The study design is exploratory
      descriptive, using a qualitative ethnographic approach. In-depth interviews were
      undertaken in an outpatient department dermatology clinic. A purposive sample of
      20 adult patients currently attending represented the following types of
      psoriasis: guttate, chronic plaque and scalp. A key comparable finding between
      the literature and the interview data is that dermatologists emphasize observable
      criteria of effectiveness, such as clearance of the lesion, whereas patients
      emphasis focuses on the subjective concerns, such as suppleness, softness and
      alleviation of itch. This discrepancy needs to be considered during history
      taking, in relation to its impact on therapy concordance and in the use and
      development of outcome measures used for clinical assessment and evaluations of
      psoriasis therapy.

PMID- 12421387
TI  - An evaluation of a domiciliary respite service for younger people with dementia.
AB  - RATIONALE, AIMS AND OBJECTIVES: There is a lack of respite services designed
      specifically for younger people with dementia. There is also a dearth of studies
      on the evaluation of domiciliary respite services for carers of people with
      dementia in general. This paper reports on the evaluation of a domiciliary
      respite service for carers of younger people with dementia, in one area in
      Northern Ireland, provided by a local branch of the Alzheimer's Society. METHODS:
      Using a qualitative approach, eight carers and their families were interviewed in
      their own homes about their views and expectations of the service, the benefits
      and problems they experienced, and other issues of relevance to them. RESULTS:
      Overall, they reported great satisfaction with the service. The way they used,
      and benefited from, the service differed for individuals. Most of them, however,
      gained respite in the form of help with bathing and dressing the person with
      dementia. Carers reported that they did not engage in social or recreational
      activities during the period of respite. Instead they used the respite time to
      catch up with household chores and shopping. DISCUSSION AND CONCLUSIONS: The
      benefits and concerns can only be understood from the perspectives of carers and
      in the context of their needs, values, beliefs and traditions. The insight gained
      can be used to inform future provision of services for this population.

PMID- 12421388
TI  - The effectiveness of cognitive-behavioural interventions provided at Outlook: a
      disfigurement support unit.
AB  - RATIONALE, AIMS AND OBJECTIVES: The establishment and evaluation of a
      disfigurement support unit (Outlook), based in a district general hospital is
      described. METHODS: The effectiveness of cognitive-behavioural interventions
      provided for 36 adults referred from a range of specialties was evaluated through
      the use of semistructured interviews, and standardized and visual analogue scales
      completed at initial assessment, at the end of intervention and at 6 months
      follow-up. RESULTS: There were significant improvements on all measures at the
      end of intervention, which were maintained at 6-month follow-up, including social
      anxiety, appearance-related distress, general anxiety and depression. Clients
      also reported significant improvements in positive affect and satisfaction with
      life. They felt more confident with strangers and in dealing with new social
      situations. In addition, their perceptions of the noticeability of their
      condition, both to themselves and to others, had significantly reduced.
      Dendograms revealed two distinct groupings of clients, with one group showing
      greater improvements following intervention. CONCLUSIONS: The results suggest
      that Outlook represents a valuable addition to the current provision of surgical
      and medical care.

PMID- 12421389
TI  - Do abnormal liver function tests predict inpatient imaging yield? An evaluation
      of clinical decision making.
AB  - RATIONALE, AIMS AND OBJECTIVES: Diagnostic abdominal imaging is frequently
      performed in hospitalized patients to assess the cause of abnormal liver function
      tests (LFTs). We undertook this study to assess whether the extent and severity
      of LFTs abnormalities predicted the yield of inpatient imaging. METHODS: We
      retrospectively reviewed inpatients' abdominal imaging studies performed for
      abnormal LFTs during a 27 month period. Imaging results were matched to LFTs
      performed during a 5 day collection window surrounding the image request date.
      Five LFTs were categorized by severity of abnormality and were then collapsed
      into three classes based on pathophysiology. RESULTS: Among 759 imaging studies
      completed for the indication of abnormal LFTs, 196 (26%) were positive (abnormal
      and explained the abnormal LFTs). Among the LFT classes, severity of laboratory
      test abnormality correlated with positive imaging examinations yield only for the
      transaminases: 18% for the normal-mildly abnormal transaminases compared with 31%
      for moderately-severely abnormal transaminases. The number of abnormal LFT
      classes per study correlated only slightly better: 21% of patients with none or
      one abnormal LFT class had a positive imaging study compared with 35% of patients
      with all three abnormal LFT classes. CONCLUSIONS: The yield of inpatient
      abdominal imaging for abnormal LFTs correlates only weakly with both the severity
      and the extent of different abnormal LFTs. Further research is needed to define
      the optimal imaging strategies for evaluating inpatients with suspected
      hepatobiliary disease.

PMID- 12421390
TI  - Prescribing pattern of antihypertensive drugs by family physicians and general
      practitioners in the primary care setting in Bahrain.
AB  - The aim was to determine whether there are differences among family physicians
      (FPs) and general practitioners (GPs) in terms of their preference for different
      classes of antihypertensives, either alone or in combinations, in uncomplicated
      cases of hypertension and to determine the extent of adherence to WHO/ISH
      guidelines. We have analysed prescribing of antihypertensives by qualified family
      physicians (FPs) (n=77) and compared this with that of general practitioners
      (GPs) (n =41) by auditing 1791 prescriptions of FPs and 914 prescriptions of GPs,
      issued to patients with uncomplicated hypertension, at 15 out of 20 health
      centres in Bahrain. The choice of antihypertensive(s) by FPs and GPs was
      comparable and conformed with the WHO/ISH guidelines as regards preference for:
      (i) beta-blockers, angiotensin converting enzyme (ACE) inhibitors and calcium
      channel blockers (CCBs) as monotherapy; (ii) two-drug combinations (diuretic-beta
      blocker; beta-blocker-CCB); (iii) three-drug combinations (diuretic-beta-blocker
      CCB; diuretic-beta-blocker-ACE inhibitor; beta-blocker- ACE inhibitor-CCBs), and
      (iv) choice of drug used for the elderly either alone (CCBs) or as combinations
      (diuretic-beta-blocker; beta-blocker-CCB and diuretic-beta-blocker-ACE inhibitor;
      diuretic-beta-blocker-CCB). In several instances prescribing by both FPs and GPs
      was not in accordance with the WHO/ISH guidelines: reluctance to prescribe
      diuretics as monotherapy; use of suboptimal combinations (beta-blocker-ACE
      inhibitor); and extensive use of beta-blockers and irrational use of immediate
      release nifedipine in elderly. A statistically significant prescribing difference
      between FPs and GPs was evident in the following: beta-blockers as monotherapy (P
      =0.01), diuretic-CCB (P=0.046), and diuretic-CCB-methyldopa (P=0.01) combination,
      and immediate-release nifedipine monotherapy in the elderly (P=0.027), were
      prescribed more often by the GPs. However, beta-blocker-ACE inhibitor-CCB
      combination was more often prescribed by FPs (P=0.046). Remarkable differences in
      prescribing pattern of antihypertensives between the FPs and GPs were evident.
      Although the general pattern supported a superior prescribing profile of the FPs
      as expected, there is a need for improved prescribing by both GPs and FPs.
      Educational programmes, both graduate and residency training, and continuing
      professional education, should specifically address these deficiencies in order
      to assure quality primary health care.

PMID- 12421391
TI  - The rising cost of health care: can demand be reduced through more effective
      health promotion?
AB  - The cost of health care continues to rise in the face of an apparently insatiable
      demand. Unless the actual need for health care can be reduced to manageable
      levels, the financial burden will probably become economically unacceptable.
      Although some illnesses are unavoidable, others that are largely due to unhealthy
      lifestyles are preventable. Circulatory diseases, diabetes and some cancers,
      which are major causes of morbidity and mortality in western societies, are
      strongly linked to physical inactivity, psychological stress, unhealthy eating,
      obesity and smoking. There is ample evidence that promotion of healthy
      lifestyles, including physical activity, healthy eating and non-smoking, are
      effective for the primary and secondary prevention of these diseases. Although
      there are examples of successful public health programmes that have encouraged
      more healthy lifestyles and reduced the burden of disease, we need to be much
      more effective in putting theory into practice. In order to improve the health of
      the nation and to prevent the economy being overwhelmed by the increasing demand
      for health care, we need a change of mindset from a consumerist approach to an
      acceptance of personal and corporate responsibility for more healthy lifestyles.
      Widespread collaboration among health care agencies, private and public
      utilities, the entertainment industry and the communications media will be
      necessary in order to provide the necessary incentives for lifestyle changes.

PMID- 12421392
TI  - The importance of audit in diagnostic imaging.

PMID- 12421393
TI  - Rationing of surgery for varicose veins based on the presence or absence of
      cosmetic symptoms.

PMID- 12421396
TI  - Ethical review of health service research in the UK: implications for nursing.
AB  - BACKGROUND: This paper examines the current systems and structures for ethical
      review of health services research in the United Kingdom (UK). Past criticisms
      and the adequacy of recent governance arrangements for Ethics Committees in
      addressing these are discussed. The implications for nurses are then considered.
      RATIONALE: This examination of the situation is prompted by the demand for more
      innovative research designs in health care evaluation, new regulations and
      guidance, and a climate of public anxiety regarding research conduct in the UK.
      FINDINGS: The evolution of Research Ethics Committees (RECs) has been slow and
      resulted in a lack in consistency. Criticisms made of RECs can be categorized
      into four main areas. New governance arrangements for RECs have emerged as
      potential solutions to these criticisms. This review identifies the limitations
      of the new governance arrangements in addressing past criticisms because of two
      factors. The first is insufficient funding. The second is confusion about the
      confidentiality and consent requirements of clinicians working in areas where
      research is conducted and on whom recruitment processes often rely. The current
      situation regarding health research ethical review has implications for nurses,
      whether they are working as researchers, members of Ethics Committees or
      clinicians where research is conducted. CONCLUSION: The new governance
      arrangements may go some way to addressing past problems. However, investment in
      RECs is required. It is also important to realize that maintaining ethical
      probity in health service research is a tripartite concern. It is reliant as it
      is on the actions of Ethics Committees and clinical research partners as well as
      those of the researchers themselves.

PMID- 12421397
TI  - Transforming loss: Taiwanese women's adaptation to stillbirth.
AB  - AIM: To explore the experiences of Taiwanese mothers of stillborn babies, their
      coping strategies, and the ways in which their subsequent human interactions are
      shaped by Taiwanese culture. BACKGROUND: Giving birth to a male family heir is
      still considered an important responsibility for Taiwanese women. The ideology of
      continuity is still at the centre of Chinese family life in which women are
      expected to deliver babies that will continue their husbands' family lines.
      Research on the connection between this responsibility and women's reaction to
      stillbirth in a cultural context is limited. Understanding Taiwanese women's
      experiences with stillbirth will add to the body of nursing knowledge, especially
      in terms of giving culturally competent nursing care. METHODS: Interpretive
      ethnographic procedures were used to locate coping strategies. Twenty mothers who
      had stillbirth experiences were interviewed periodically during the 2 years
      following their losses. Following Agar's example, data were analysed to identify
      themes representing coping strategies. FINDINGS: The four major themes identified
      were (a) transforming the meaning of death, (b) doing something for the deceased,
      (c) anticipating another pregnancy, and (d) rebuilding a social fabric.
      CONCLUSION: The processes that the mothers of stillborn babies experience
      represent transformations that involve engagement with cultural expectations for
      woman. The authors suggest that these cultural impacts should be incorporated
      into nursing assessment and treatment practices.

PMID- 12421398
TI  - Caring conversations - psychiatric patients' narratives about suffering.
AB  - AIM: The aim of this study was to increase and deepen the understanding of how
      psychiatric patients in conversations with nurses narrate their experience of
      suffering. METHODS: Data were obtained in the years 2001-2002 by audio recording
      of 20 individual caring conversations between eight patients and three
      psychiatric nurses at a psychiatric outpatient unit in Sweden. Before the data
      were gathered the study was approved by a local research ethics committee. The
      methodology is inspired by the hermeneutics of Paul Ricoeur. The data is given a
      naive reading which is followed by two structural analyses which explain the
      text. Finally, the structural analyses and the pre-understanding are confronted
      in a critical reflection. FINDINGS: In the patients' narratives, suffering was at
      first concealed under a facade that helps the patient to cope with suffering and
      with shame. As they moved along to a turning point, something happened that made
      them able to risk everything, i.e. their very selves, but also gave them the
      possibility of regaining vital parts of themselves that where lost when the
      facade was constructed. As they took the suffering upon themselves, they grew to
      be fully visible as human beings and healing was possible as a re-establishment
      of the interpersonal bridge. This not only meant that the sufferer became open
      for relationships with others or an abstract other, but also that an opening in
      the relationship with themselves occurred. CONCLUSIONS: If psychiatric patients
      are allowed to narrate freely they develop different plot structures, which can
      either hide or reveal suffering. Patients who could establish an answer to the
      why-question of suffering could also interpret their suffering in a way that
      enabled growth and reconciliation. In order to do so, they had to abandon the
      shelter of the facade and confront suffering and shame. This turning point opened
      them up to life-sustaining relationships with themselves as well as with abstract
      and concrete others.

PMID- 12421399
TI  - Governing the conduct of conduct: are restraints inevitable?
AB  - BACKGROUND: The purpose of this article is to provide an interpretation of how
      restraint use is maintained and legitimized despite negative reports on its
      efficacy and questions about its ethicality. My research examined the use of
      restraint on a patient requiring care in an acute teaching hospital in Australia.
      This article examines one case study that was part of a PhD research project. The
      literature reveals evidence of the harm that restraints cause, as well as their
      ineffectiveness as a safety measure. In addition, it indicates that the
      prevalence of restraint use is high. METHODS: The study is framed by a
      Foucauldian approach to discourse analysis. This report is an in-depth case study
      including observations of the patient, interviews with members of the
      multidisciplinary team and analysis of medical, physiotherapy and nursing
      notation. FINDINGS: Discourses from the health care team are identified by which
      restraint use is justified, and legitimized by staff. An important discursive
      practice is 'constituting the patient's inability to self govern' and their
      resulting marginalization from the services provided by the team. LIMITATIONS:
      There are certain philosophical limitations including classical arguments about
      the position of postmodernism and specifically the ideas of Michel Foucault as
      opposed to other philosophy's ability to make sense of a phenomenon. The study
      was carried out in Australia and thus the discursive practices may be dissimilar
      in other countries. CONCLUSIONS: Through these discursive practices we can
      understand how staff maintain a monopoly over the truth and perpetuate claims
      about the inevitability of restraint use.

PMID- 12421400
TI  - Exploring participation: older people on discharge from hospital.
AB  - BACKGROUND AND AIM: User participation has been a widely researched and debated
      phenomenon in the formulation and implementation of health and social care policy
      and indeed wider public sector policy in the United Kingdom (UK), yet there
      remains a vast array of definitions of the term and great variety in the findings
      of empirical studies. The aim of this paper is to discuss the main findings of an
      empirical study in order to build upon existing evidence and interpretation
      relating to user participation in health and social care. METHOD: The study
      reported here was carried out in the UK and explored the extent to which older
      people were able and willing to assume an active role in the process of using
      health and social care. Hospital discharge and the period shortly afterwards was
      the process under investigation. This study used a multi-method approach
      incorporating both quantitative and qualitative approaches; data from 260
      questionnaires and 30 interviews were included. FINDINGS: The majority of
      respondents felt that they had been involved in decisions regarding their
      discharge from hospital. All welcomed advice from professionals and some
      preferred service providers to make decisions on their behalf. DISCUSSION:
      Arnstein's ladder of citizen participation is drawn upon in analysing the
      findings and notions of 'partnership', 'relationship', 'communication' and
      'paternalism' are discussed.

PMID- 12421401
TI  - 'I'm still waiting...': barriers to accessing cardiac rehabilitation services.
AB  - BACKGROUND: The United Kingdom (UK) National Service Framework for coronary heart
      disease challenges health services to address existing problems regarding the
      quality and content of cardiac rehabilitation services. Concern also exists
      regarding inequalities in access to services. The South Yorkshire Coalfields
      Health Action Zone (SYCHAZ) funded this study to harness the views and
      experiences of staff and patients regarding existing services. The intention is
      to use the information gained to develop acceptable and accessible services for
      the future. AIMS: To explore what barriers exist for patients in accessing
      cardiac rehabilitation services within the South Yorkshire Coalfield locality.
      ETHICAL ISSUES AND APPROVAL: Patients were identified and recruited with the
      assistance of staff responsible for their care. Informed consent was obtained
      prior to participation. Approval was obtained from the relevant Ethics
      Committees. METHODS: Qualitative methods were used, including semi-structured
      interviews and Framework Analysis techniques. Purposive sampling was used to
      select participants. INSTRUMENTS: Semi-structured individual interviews of 15
      staff and 20 postmyocardial infarction patients. One group interview with seven
      health visitors and two with lay members of heart support groups. OUTCOMES:
      Barriers to accessing cardiac rehabilitation. RESULTS: This study revealed a
      limited service capacity. Big gaps exist between patches of service activity that
      most patients appear to slip through. Problems in accessing the service were
      categorized into five themes: absence, waiting, communication, understanding, and
      appropriateness. Some groups fared worse in terms of access to services, for
      example women, the elderly and those in traditional working class coalfields
      communities. Professional and more affluent participants appeared better able to
      negotiate their way around the system by seeking out advice or 'going private'.
      LIMITATIONS: The omission of medical staff and ethnic minority patients.
      CONCLUSIONS: Cardiac rehabilitation in the policy targets in UK will only be met
      with substantial investment to address the barriers identified here.

PMID- 12421402
TI  - Health promotion in palliative care: the patients' perception of therapeutic
      interaction with the palliative nurse in the primary care setting.
AB  - AIMS: To identify and describe palliative patients' perception of factors within
      the interaction with the community palliative care nurse that enhance feelings of
      health and well-being, and to begin to define health promotion in relation to
      palliative nursing in the primary care setting. BACKGROUND: Health promotion may
      seem to be of little relevance in palliative care and for patients within its
      remit, and there is no definition of health promotion in relation to palliative
      care, yet therapeutic 'new' nursing, and its core elements of holism,
      egalitarianism and a humanistic approach accord with the philosophy of palliative
      care and are recognised as health promoting nursing practice. DESIGN/METHODS: A
      qualitative methodology was used. Information was obtained from 12 patients by a
      qualitative semi-structured interview. Data were organised and analysed using
      recognised guidelines for phenomenological analysis. FINDINGS: The patients
      identified two types of therapeutic interaction with the nurse, which enhanced
      feelings of health and well-being in different ways. Psychological well-being was
      enhanced by the humanistic and egalitarian personal interaction with the nurse,
      and the professional interaction focused on the disease and addressed physical
      problems. Although recognizing the nurses' role in the relief of physical
      symptoms, the patients' perception of 'feeling better' generally focussed on
      enhancement of psychological health and well-being. CONCLUSION: For the patients,
      a combination of 'new' (therapeutic) nursing and a more traditional expert-led
      approach resulted in the promotion of an enhanced sense of physical and
      psychological health and well-being, and was an integral part of community
      palliative care nursing. Based on the study findings, the researcher offers a
      definition of health promotion relevant to palliative nursing in the primary care
      setting, which identifies that for the patients (but with caveats related to
      generalizability), the practice of holistically therapeutic palliative nursing is
      the ideal.

PMID- 12421403
TI  - Cautious caregivers: gender stereotypes and the sexualization of men nurses'
      touch.
AB  - AIM: The aim of this research was to explore the experience of men nurses and the
      ways in which gender relations structure different work experiences for women and
      men in the same profession. BACKGROUND: Men are now entering the nursing
      profession in record numbers and challenging the notion that men are
      inappropriate in caregiver roles or incapable of providing compassionate and
      sensitive care. A limitation of the current state of knowledge regarding caring
      and men nurses is that it is primarily focused on men nursing students, not
      practising nurses. Little is known about men nurses' practices of caring and how
      such practices reflect the gendered nature of nursing and nurses' caring work.
      METHODS: The theme of men nurses as cautious caregivers emerged from data that
      were collected in two rounds of semi-structured interviews with eight men nurses
      practising in Nova Scotia, Canada. Thematic analysis, informed by feminist theory
      and masculinity theory, was used as the method for analysing the data. FINDINGS:
      For men nurses, the stereotype of men as sexual aggressors is compounded by the
      stereotype that men nurses are gay. These stereotypes sexualize men nurses' touch
      and create complex and contradictory situations of acceptance, rejection and
      suspicion of men as nurturers and caregivers. They also situate men nurses in
      highly stigmatized roles in which they are subject to accusations of
      inappropriate behaviour. For men nurses, this situation is lived as a heightened
      sense of vulnerability and the continual need to be cautious while touching and
      caring for patients. Ultimately, this situation impacts on the ability of men
      nurses to do the caring work they came into nursing to do.

PMID- 12421404
TI  - Cadets and nursing students: same destination - different route.
AB  - BACKGROUND: In response to the policy initiatives in England to secure
      recruitment and retention in the nursing and midwifery professions, strategies to
      improve and extend access to preregistration education and training in England
      have been developed. The relatively recent development of modern cadet schemes is
      an example of such a strategy. Despite the increasing interest in and
      proliferation of cadet schemes, there is as yet little evidence for their
      effectiveness. Reporting on an evaluation of a scheme in England, this paper
      makes some contribution to this evidence. AIMS AND OBJECTIVES: The project
      explored former nurse cadets' experiences of the cadet scheme 9 months after
      their transition to nurse education. The aims of the project were to evaluate the
      extent to which former cadets and university staff considered the scheme to
      prepare students effectively for access to university nurse education. METHODS:
      The first cohort of former cadets entered nurse education in September 2000.
      After 9 months they were invited to contribute to an evaluation of the cadet
      scheme and their present experience. The evaluation consisted of a structured
      questionnaire sent to all the former cadets, a focus group interview with the
      former cadets, informal discussions with university staff and brief documentary
      analysis. CONCLUSION: Tensions were apparent between the worlds of education and
      clinical practice: the cadets felt better prepared clinically than academically
      and found an element of repetition in the nursing programme. They valued their
      preparation, which they felt put them at an advantage over other nursing
      students. However, some of them experienced difficulties in the transition to
      higher education and further review is therefore required to establish the
      success of cadet schemes.

PMID- 12421405
TI  - A descriptive study of registered nurses' experiences with web-based learning.
AB  - AIMS: To describe the experiences of registered nurses (RNs) who enrolled in a
      web-based course from either their home or the workplace. RATIONALE: In order to
      maintain competency in rapidly changing health care systems, and meet the
      challenge of overcoming traditional barriers to continuing education, RNs need
      access to innovative educational delivery methods. As yet, little is known about
      the web-based learners' experience, particularly when courses are accessed from
      the nursing practice setting. METHODS: The article focuses on the results from
      questionnaires conducted with 57 RNs enrolled in a web-based, postdiploma course.
      These findings emanate from a larger study using survey method and focus group
      interviews. Nurses' experiences were measured using the Online Learner Support
      Instrument which was developed and tested for use in the study. RESULTS: Most
      nurses found the course highly satisfactory. Not all experiences were positive
      however, and a number of challenges were faced. Access to the course from home
      was reported as very satisfactory for the majority, while work users encountered
      a number of serious barriers such as insufficient time and limited computer
      access. The RNs made significant gains in their learning with e-mail, Internet,
      keyboarding and word processing skills during the 16-week course. Lack of
      computer skills, erroneous perceptions of course workload and inadequate
      preparation for web learning were largely responsible for the majority of
      withdrawals. CONCLUSION: Web-based learning can be an effective mode of delivery
      for nursing education. Advance preparation by educational institutions, employers
      and prospective students is essential. Teachers, peers, technology, course design
      and the learning environment are key variables that influence the learners'
      experience and success.

PMID- 12421406
TI  - Empowering practitioners: an unrealistic expectation of nurse education?
AB  - BACKGROUND: Empowerment has become an increasingly popular theme in nurse
      education. This is evident from the growing number of courses that claim to
      enable nurses to become empowered. However, this is taking place in an
      environment with little critical debate about the assumptions and implications
      for educators and students. Consequently there is a risk of creating hegemony and
      regimes of truth. AIM: This paper sets out to review critically existing
      discourses on empowerment and to suggest a more reflexive and realistic view.
      THEMES: The origins of empowerment are established, together with its
      relationship to professional education. There is a review of the nature of power
      and autonomy, followed by an examination of the effects of expectations of
      empowering practice on educators and students. The lack of reflexivity in notions
      of empowerment is discussed. Consideration is given to the possibility of
      rehabilitating empowerment by offering an alternative conception that is
      realistic and reflexive. CONCLUSIONS: Conclusions are drawn to suggest that
      although much of the writing on empowerment in education is insufficiently self
      critical and consequently is open to censure, ideas of empowerment should not be
      rejected completely: they may serve to stimulate educators (and their students as
      future practitioners) to connect with and challenge society.

PMID- 12421407
TI  - An evaluation of the role of the Clinical Placement Coordinator in student nurse
      support in the clinical area.
AB  - PURPOSE OF THE STUDY: The purpose of this study was to evaluate the role of the
      Clinical Placement Coordinator (CPC) and the continued development of the role in
      the context of the provision of student support in the clinical area. BACKGROUND:
      Following the introduction of the Registration/Diploma in Nursing Studies
      programme in the Republic of Ireland in 1994 the post of CPC was created to
      support student nurses in the clinical area. The CPC is an experienced nurse who
      provides dedicated support to student nurses in a variety of clinical settings
      however, unlike the role of mentor/preceptor they do not have a client/patient
      caseload. To date no major evaluation of the post has taken place. Therefore the
      Department of Health and Children commissioned a national evaluation of the post
      of which part of the findings are reported in this paper. METHODOLOGY: A two
      stage study is described utilizing a mixed-methods approach. Data collection
      included individual and focus group interviews and questionnaires. Interviews
      were analysed using thematic content analysis and data collected from
      questionnaires were analysed utilizing descriptive and inferential statistics.
      FINDINGS: An analysis of the data identified the responsibilities and functions
      of CPC were multivariate, however, core elements of the role were evident. The
      core elements were identified as student support and practice development. The
      central and most frequent finding from the data collected was the individual
      support students received from CPCs throughout their clinical placement.
      CONCLUSION: The role of CPC was evaluated as a positive addition to the realm of
      student support and the clinical team. The positioning of the post in the
      clinical area also adds the dimension of a CPC being a link between student
      nurses and the various groups that provide student support, this is essential in
      light of the changing role of the nurse tutor following the full integration of
      preregistration nurse education into the third-level sector and the development
      of a formal preceptorship role for clinical nurses in the Republic of Ireland.

PMID- 12421409
TI  - Genomic organization and regulation of three cecropin genes in Anopheles gambiae.
AB  - Three cecropin genes (AgCecA-C) were identified from Anopheles gambiae, a major
      vector for malaria in sub-Saharan Africa. These genes form a cluster with AgCecA
      and AgCecB positioned in opposite orientation, while AgCecC is downstream of
      AgCecA in the same direction. One intron is present in each of these three genes.
      Motif searches of promoter regions revealed elements that could be regulated by
      the NF-kappaB family of transcriptional regulators. The divergent promoter (1186
      nucleotides in length) between CecA and CecB and the promoter for CecC were
      analysed by transfection in An. gambiae cell lines. Results showed that these
      promoters were up-regulated by lipopolysaccharide. The activity was further
      elevated when heat-inactivated microbes were used to challenge the cell line. At
      least one NF-kappaB site was required for inducible expression of both CecA and
      CecB.

PMID- 12421410
TI  - Specific developmental gene silencing in the honey bee using a homeobox motif.
AB  - Manipulating the expression of genes in species that are not currently used as
      genetic models will provide comparative insights into the evolution of gene
      functions. However the experimental tools in doing so are limited in species that
      have not served as models for genetic studies. We have examined the effects of
      double stranded RNA (dsRNA) in the honey bee, an insect with considerably basic
      scientific interest. dsRNA derived from a 300 bp stretch of the E30 homeobox
      motif was injected into honey bee embryos at the anterior pole in the
      preblastoderm stage. We found that the dsRNA fragment successfully disrupted the
      protein expression of the target gene throughout the whole embryo. The disruption
      caused deficient phenotypes similar to known loss of function mutants of
      Drosophila engrailed, whereas embryos injected with nonsense dsRNA showed no
      abnormalities. We show that the large size of the honey bee egg (D: 0.3 mm, L:
      1.6 mm) and the long preblastoderm stage (11-12 h) can be exploited to generate
      embryos with partial disruption of gene function, which may provide an elegant
      alternative to classical chimeric analyses. This is the first report of targeted
      disruption of gene function in the honey bee, and the results prove that the
      chosen target gene is a functional ortholog to engrailed in Drosophila.

PMID- 12421411
TI  - Isolation and molecular characterization of Musca domestica delta-9 desaturase
      sequences.
AB  - We have isolated fatty acyl-CoA desaturase cDNA (Mdomd9) and genomic sequences
      from the housefly, Musca domestica. Two approximately 1.66 kb cDNAs were
      recovered. They had identical coding regions and 3' untranslated regions (UTRs),
      but differed in their 5' UTRs. The open reading frame encodes a 380 amino acid
      (aa) protein with 82% identity to Drosophila melanogaster desat1, and significant
      (> 50%) identity with other insect delta-9 desaturases. Functional analyses in a
      yeast expression system confirmed the cDNA encodes a delta9 desaturase. Northern
      analysis indicated two transcripts of 1.7 and 2.9 kb that hybridized specifically
      to the open reading frame. PCR amplification of genomic templates revealed three
      intron sites that are conserved among other insect species. Southern analysis of
      genomic DNA indicated at least two desaturase gene copies per haploid genome.
      There is a high degree of polymorphism, most of which appears to be due to
      variable intron sequences; curiously, individual flies had varying morphs of
      intron II and intron III. Together, the data suggest that there are more delta9
      desaturase alleles within the population studied than there are loci within the
      genome, and support other studies suggesting that insect fatty acyl-CoA
      desaturases are a dynamically evolving gene family.

PMID- 12421412
TI  - CYP6B cytochrome p450 monooxygenases from Papilio canadensis and Papilio glaucus:
      potential contributions of sequence divergence to host plant associations.
AB  - Two groups of furanocoumarin-inducible cytochrome p450 genes, the CYP6B4 group
      and the CYP6B17 group, characterized in two closely related tiger swallowtails,
      Papilio glaucus and Papilio canadensis, are induced to different extents, with
      generally higher levels of CYP6B transcripts in P. glaucus. To investigate the
      evolutionary history of these CYP6B genes in the context of their association
      with furanocoumarin detoxification, we isolated thirteen CYP6B genes from these
      species. Each of these genes contains an intron at a conserved position (1334
      nucleotides from the translation start site), which varies in length due to three
      insertion/deletions. The proximal 5' end flanking sequence from the transcription
      initiation site is highly conserved (91-98% nt identity). The sequence 5' to -640
      is significantly variable due largely to the presence of three
      insertion/deletions. The sequence at the 3' end of this region contains a
      putative xenobiotic response element to xanthotoxin (XRE-xan), important for
      basal and xanthotoxin-inducible transcription of the P. polyxenes CYP6B1v3 gene,
      and multiple elements known to regulate vertebrate phase I and II promoters,
      including an XRE-AhR (Xenobiotic Response Element to Aryl hydrocarbon Receptor),
      an OCT-1 element (octamer protein binding site), an ARE (Antioxidant Response
      Element), an EcRE (Ecdysone Response Element), and an imperfect PXR (Pregnane X
      Receptor) responsive element (PRE). Our analyses of CYP6B genes in these two
      species indicate that these genes are in an early stage of divergence and that
      differential exposure of these two species to chemically distinct host plants
      resulting from geographical isolation has had functional impacts not only on the
      coding regions of these genes but also on their promoter regions. Thus, changes
      in p450 regulation as well as catalytic activity may play a role in the evolution
      of host plant associations in herbivorous insects.

PMID- 12421413
TI  - Developmental profiles and ecdysone regulation of the mRNAs for two ecdysone
      receptor isoforms in the Mediterranean fruit fly Ceratitis capitata.
AB  - Using 5' RACE with specific primers for the ecdysone receptor B1 isoform of the
      Mediterranean fruit fly (medfly), Ceratitis capitata, we isolated a cDNA clone
      encoding the specific region of the medfly ecdysone receptor A isoform (CcEcR-A).
      The CcEcR-A-specific region was very similar to the EcR-A-specific region of
      Drosophila melanogaster and less similar to the EcR-A-specific regions of
      Lepidoptera. The developmental expression of both CcEcR-A and CcEcR-B1 mRNAs was
      studied in whole animals, salivary glands and ovaries by RT-PCR, using isoform
      specific primers. Both CcEcR mRNAs are present in very early embryos, decrease to
      very low levels during the first hours of embryogenesis and are highly expressed
      in all consequent embryonic stages. During metamorphosis both isoforms are
      present showing two peaks; the first at the larval-prepupal transition and the
      second during the second half of prepupal development. These peaks are correlated
      with the two puffing cycles and the two major 20-hydroxyecdysone (20E) increases
      that occur during medfly metamorphosis. CcEcR-B1 mRNA was directly induced in
      larval salivary glands in vitro by 20E, even at very low concentrations of the
      hormone, while CcEcR-A mRNA was slightly induced only by high 20E concentrations
      and in the absence of a protein synthesis inhibitor. During oogenesis, the CcEcR
      mRNAs were expressed synchronously, peaking at the beginning of both
      previtellogenic and vitellogenic phases.

PMID- 12421414
TI  - Molecular cloning and characterization of the cathepsin B-like proteinase from
      the cotton boll worm, Helicoverpa armigera.
AB  - An enzyme purified from the ovaries of Helicoverpa armigera, as an active form
      with molecular mass of 30 kDa on SDS-PAGE, was identified as a cysteine
      proteinase because it could be inhibited by E-64, a specific inhibitor of
      cysteine proteinase, and required reducing conditions for activity. This enzyme
      was further identified as a cathepsin B-like cysteine proteinase by partial amino
      acid sequencing. A cDNA encoding this proteinase was cloned from H. armigera,
      using degenerate primers and RACE techniques. Results of Northern blots indicated
      that the mRNA encoding the proteinase was transcribed in the ovaries, the fat
      bodies of female and male adults, pupae and in the larvae. No mRNA was detected
      from the larval epidermis or from the midgut. Hence, transcription of the
      cathepsin B-like cysteine proteinase from H. armigera was tissue-specific, but
      not gender- or developmental stage-specific. However, proteolytic activities were
      only detected from ovaries, and adult female and male fat bodies. No activity was
      observed from pupal and larval fat bodies, from the larval epidermis or from the
      midgut. Only one form of mRNA of approximately 1100 bases was detected, and in
      situ hybridization showed that the transcripts were distributed in the adult
      female fat bodies, follicular cells and the oocytes. Since the proteinase
      expressed in ovaries was able to degrade vitellin in vitro, it may be involved in
      the degradation of vitellin during embryonic development.

PMID- 12421415
TI  - Two novel strains of Wolbachia coexisting in both species of mulberry
      leafhoppers.
AB  - Wolbachia is an intracellular symbiont that causes reproductive disorders in many
      insects. Its presence in the leafhoppers Hishimonoides sellatiformis and
      Hishimonus sellatus, vectors of mulberry dwarf-Phytoplasma, was confirmed by the
      PCR analysis of 16S rDNA, ftsZ and wsp. Sequencing of cloned PCR products
      revealed that two Wolbachia strains coexist in both leafhoppers. The phylogenetic
      analysis of wsp revealed that these strains belong in novel positions in the B
      group of Wolbachia. These strains were detected by PCR and/or PCR-RFLP in all of
      the tested non-genital organs including salivary glands, as well as in the tested
      genital organs of Hishimonoides sellatiformis. In addition, Wolbachia-like
      organisms were observed by electron microscopy in all PCR-positive organs. We
      discuss the possible horizontal transmission of Wolbachia via mulberry trees.

PMID- 12421416
TI  - Molecular cloning and sequencing of salivary gland-specific cDNAs of the blood
      sucking bug Triatoma brasiliensis (Hemiptera: Reduviidae).
AB  - Haematophagous insects produce pharmacological substances in their saliva to
      counteract vertebrate host haemostasis events such as coagulation,
      vasoconstriction and platelet aggregation. To investigate the bioactive salivary
      molecules of the triatomine bug Triatoma brasiliensis, we produced subtraction
      enriched cDNAs of salivary-gland specific genes using suppression subtractive
      hybridization. Six full-length differentially expressed cDNAs (Tb113, Tb125,
      Tb152, Tb169, Tb180 and Tb198) were selected, cloned and sequenced. Sequence
      similarity searches of the databases using the putative amino acid sequence of
      our clones gave the following results: Tb152 - Triabin, an antithrombin induced
      platelet aggregation factor found in salivary gland extracts of T. pallidipennis.
      Tb169 - Pallidipin, an anticollagen induced platelet aggregation factor also
      found in T. pallidipennis salivary homogenates. Tb180 - Procalin, the major
      allergen of T. protracta saliva. The other three salivary-gland specific cDNAs
      produced no obvious homologies. Comparison of these salivary gland-specific cDNAs
      of with those of other triatomines combined with functional studies using
      recombinant proteins will allow a better understanding of the co-evolutionary
      process occurring between these insects and their vertebrate hosts, and may also
      lead to the discovery of novel antihaemostatic agents.

PMID- 12421417
TI  - Differentially expressed midgut transcripts in Culicoides sonorensis (Diptera:
      ceratopogonidae) following Orbivirus (reoviridae) oral feeding.
AB  - Understanding the vector insect's gene expression response to a virus infection
      may aid design of control measures for arbovirus diseases. Culicoides sonorensis
      is a vector of several agriculturally important pathogens, such as epizootic
      haemorrhagic disease virus (EHDV) that causes disease in ruminants. Two
      approaches, differential display and suppression subtractive hybridization, were
      used to identify 400+ Culicoides transcripts that were more abundant in midguts 1
      day following an oral meal containing EHDV. Of these, quantitative PCR confirmed
      seven to be more abundant in virus-fed midguts than controls. One such transcript
      encodes a putative RNA editase, CsRED1, induced by dsRNA. Transcripts encoding
      putative receptors involved in cell differentiation included CsLAR, a protein
      tyrosine phosphatase, and CsFZ2, homologous to the wingless receptor in D.
      melanogaster. Transcripts encoding putative translation machinery components
      included CseIF3, CseIF5A and CsRPS6. Overall, the cDNA fragments identified in
      this study increased in the midgut at one day postfeeding; by 2 days postfeeding,
      increases in transcript levels shifted from the midgut to the remainder of the
      infected midge.

PMID- 12421418
TI  - Arrangement and structural conservation of the mitochondrial control region of
      two species of Plecoptera: utility of tandem repeat-containing regions in studies
      of population genetics and evolutionary history.
AB  - Low levels of primary sequence similarity across insect taxa have led to the
      suggestion of conserved structural elements in the insect mitochondrial control
      region. Our aim was to determine whether previously described motifs and
      secondary structures exist in stoneflies (Plecoptera). Several motifs and
      structural elements previously described in Orthoptera and Diptera were found,
      including a conserved 'hairpin' structure that may play a role in the initiation
      of mtDNA replication. The repeat region had the highest percentage similarity,
      lowest A-T content and highest transition to transversion ratio, suggesting a
      unique evolutionary pattern for the repeats. Finally, we discuss the usefulness
      of the control region in population genetic and evolutionary studies.

PMID- 12421419
TI  - Antibacterial peptide defensin is involved in midgut immunity of the soft tick,
      Ornithodoros moubata.
AB  - Two defensin genes A and B were previously demonstrated to be up-regulated by
      blood feeding in the soft tick, Ornithodoros moubata [Nakajima et al. (2001) Two
      isoforms of a member of the arthropod defensin family from the soft tick,
      Ornithodoros moubata (Acari: Argasidae). Insect Biochem Mol Biol 31: 747-751]. In
      this study, two defensin isoforms C and D similar to defensins A and B were newly
      cloned. A total of four defensins have been identified in O. moubata. All four
      Ornithodoros defensins are coded as prepro-defensins. Ornithodoros defensin genes
      consist of four exons and three introns, an organization reported in mussel
      defensins but not insect defensins. Ornithodoros defensin C and D genes are
      predominantly expressed in the midgut and up-regulated in response to blood
      feeding. The mature peptide of the previously cloned Ornithodoros defensin A was
      purified from the midgut lumen, indicating defensin is secreted into the midgut.
      These findings confirm the involvement of Ornithodoros defensin in midgut
      immunity.

PMID- 12421420
TI  - Transgenic Drosophila reveals a functional in vivo receptor for the Bacillus
      thuringiensis toxin Cry1Ac1.
AB  - The bacterium Bacillus thuringiensis synthesizes toxins (delta-endotoxins) that
      are highly specific for insects. Once ingested, the activated form of the toxin
      binds to a specific receptor(s) located on the midgut epithelial cells, inserts
      into the membrane causing the formation of leakage pores and eventual death of
      the susceptible insect larvae. Manduca sexta larvae are highly susceptible to
      Cry1Ac1, a toxin that is believed to bind M. sexta Aminopeptidase N, a
      glycoprotein located on the apical membrane. However, the binding data obtained
      to date only support the interaction of Cry1Ac1 with APN in vitro. To explore the
      in vivo role of APN, we have utilized the GAL4 enhancer trap technique to drive
      the expression of M. sexta APN in both midgut and mesodermal tissues of Cry1Ac1
      insensitive Drosophila larvae. Transgenic Drosophila fed the toxin were now
      killed, demonstrating that APN can function as a receptor for Cry1Ac1 in vivo.

PMID- 12421421
TI  - Expression of proteasome subunit isoforms during spermatogenesis in Drosophila
      melanogaster.
AB  - In this study, we sought to identify and characterize all the proteasome genes of
      Drosophila melanogaster. Earlier work led to the identification of two genes
      encoding alpha4-type 20S proteasome subunit isoforms that are expressed
      exclusively in the male germline. Here we extend these results and show that six
      of the 20S proteasome subunits, and four of the 19S regulatory cap subunits, have
      gene duplications encoding male-specific isoforms. More detailed analyses of two
      of these male-specific subunits (Prosalpha3T and Prosalpha6T), using GFP-tagged
      reporter transgenes, revealed that they are predominantly localized to the
      nucleus at later stages of spermatogenesis and are present there in mature,
      motile sperm. These results suggest a possible role of a 'spermatogenesis
      specific' proteasome in sperm differentiation and/or function.

PMID- 12421422
TI  - A novel family of anticoagulants from the saliva of Ixodes scapularis.
AB  - Using biochemical and molecular approaches, we have identified a 9.8 kDa protein
      in the saliva of Ixodes scapularis that inhibits the intrinsic pathway of
      coagulation. The 9.8 kDa anticoagulant protein was purified by reverse-phase HPLC
      and its N-terminal amino acid sequence determined. The N-terminal sequence showed
      homology with Salp14, an immuno-dominant antigen present in the saliva of
      engorging I. scapularis nymphs. Recombinant Salp14 expressed in Escherichia coli
      prolonged the activated partial thromboplastin time (APTT) of human plasma in a
      dose-dependent manner and was a specific inhibitor of factor Xa. A cDNA encoding
      a 9.3 kDa protein, Salp9Pac, was subsequently isolated from an I. scapularis
      salivary gland cDNA library. Salp9Pac showed 93% identity to the N-terminal
      sequence of the anticoagulant purified by HPLC. These data indicate that the
      anticoagulant protein purified by HPLC, Salp9Pac and Salp14 are members of a
      family of novel coagulation protease inhibitors present in tick saliva. While
      recombinant Salp9Pac did not show biological activity in the assays tested
      currently, it is likely to be mechanistically different from its paralogues. This
      raises the possibility that ticks may enhance their adaptive ability to cope with
      a wide spectrum of proteases, by transcribing such structurally related
      anticoagulant proteins with different functions.

PMID- 12421423
TI  - Intragenomic variation in ITS2 rDNA in the louse of humans, Pediculus humanus:
      ITS2 is not a suitable marker for population studies in this species.
AB  - The two internal transcribed spacers (ITS) of ribosomal DNA are often used as
      markers of populations of insects. We studied the ITS2 of the head lice and body
      lice of humans, to determine whether this gene is a suitable marker of
      populations of these insects. ITS2 sequences were amplified by PCR from lice from
      four different countries: Australia, China, Japan and the USA. Direct cycle
      sequencing of some of these PCR products gave equivocal nucleotide chromatograms.
      This indicated that some lice had more than one ITS2 sequence, so we cloned PCR
      products from these lice. Temperature gradient gel electrophoresis (TGGE)
      revealed that 50 of the 67 clones we screened had different nucleotide sequences.
      All lice had several ITS2 types, including those with unequivocal chromatograms.
      A phylogenetic tree of 15 different ITS2 sequences showed that the sequences from
      individual lice were not monophyletic. We conclude that the ITS2 is not a useful
      marker of populations for Pediculus humanus.

PMID- 12421424
TI  - The impact of atherosclerotic renovascular disease on diabetic renal failure.
AB  - Atherosclerotic renovascular disease (ARVD) is common in the general population,
      and its prevalence increases with age. Parallel studies show it is also common in
      patients with diabetes. The widespread use of angiotensin converting enzyme
      inhibitors and angiotensin receptor antagonists for heart and kidney disease
      might therefore expose arteriopathic diabetic patients to potential harm if they
      had critical renal artery stenosis. This review looks at the natural history of
      ARVD in the diabetic and non-diabetic populations: while it is common, it only
      rarely leads to renal failure. Hence intervention to revascularize ischaemic
      kidney son the basis of radiological appearances alone may subject some patients
      to unnecessary therapy. Although untested by randomized trial, a policy of
      watchful waiting may be the simplest strategy for most diabetic patients with
      suspected ARVD, reserving angiography and angioplasty (usually backed up by a
      stent) for those with an abrupt decline in renal function and no other cause for
      renal deterioration. Future clinical trials may better define subgroups of
      patients who will truly benefit from renal revascularization.

PMID- 12421425
TI  - The epidemiology of diabetic limb sepsis: an African perspective.
AB  - We review the epidemiology of foot and hand sepsis in adult diabetes patients in
      Africa. Limb sepsis in these patients is associated with significant morbidity
      and mortality. The pathogenesis of diabetic foot infections in these patient
      populations appears to be similar to that for patients in industrialized
      countries -ulcers and underlying peripheral neuropathy being the most important
      risk factors. Prevention of peripheral neuropathy through aggressive glycaemic
      control may be the most important primary control measure for foot infections.
      The tropical diabetic hand syndrome (TDHS) is being increasingly seen in diabetes
      patients in certain parts of Africa. The syndrome is acute, usually follows minor
      trauma to the hand, and is associated with a progressive synergistic form of
      gangrene. The major risk factors for TDHS are unknown but recent data suggest
      poor glycaemic control is associated with poor outcome. Treatment of TDHS
      requires aggressive surgery. Hence, preventive efforts for both foot and hand
      sepsis include aggressive glucose control, and education on hand and foot care
      and the importance of seeking medical attention promptly at the earliest onset of
      symptoms

PMID- 12421426
TI  - Autonomic neuropathy is associated with increased cardiovascular risk factors:
      the EURODIAB IDDM Complications Study.
AB  - AIMS: To assess the prevalence of and risk factors for autonomic neuropathy in
      the EURODIAB IDDM Complications Study. METHODS: The study involved the
      examination of randomly selected Type I (insulin-dependent) diabetic patients
      from 31 centres in 16 European countries. Neuropathic symptoms and two tests of
      autonomic function (changes in heart rate and blood pressure from lying to
      standing) were assessed and data from 3007 patients were available for the
      present analysis. Autonomic neuropathy was defined as an abnormality of at least
      one of the tests. RESULTS: The prevalence of autonomic neuropathy was 36% with no
      sex differences. The frequency of one and two abnormal reflex tests was 30% and
      6%, respectively. The R-R ratio was abnormal in 24% of patients while 18% had
      orthostatic hypotension defined as a fall in systolic blood pressure > 20 mmHg on
      standing. Significant correlations were observed between autonomic neuropathy and
      age (P < 0.01), duration of diabetes (P < 0.0001), HbA1c (P < 0.0001), diastolic
      blood pressure (P < 0.05), lower HDL-cholesterol (P < 0.01), the presence of
      retinopathy (P < 0.0001) and albuminuria (P < 0.0001). New associations have been
      identified from the study: the strong relationship of autonomic neuropathy to
      cigarette smoking (P < 0.01), total cholesterol/HDL-cholesterol ratio (P < 0.05)
      and fasting triglyceride (P < 0.0001). As a key finding, autonomic neuropathy was
      related to the presence of cardiovascular disease (P < 0.0001). All analyses were
      adjusted for age, duration of diabetes and HbA1c. However, data have been only
      partly confirmed by logistic regression analyses. Frequency of dizziness on
      standing up was 18%, while only 4% of patients had nocturnal diarrhoea and 5% had
      problems with bladder control. CONCLUSION: Cardiovascular reflex tests, even in
      the form of the two tests applied, rather than a questionnaire, seem to be
      appropriate for the diagnosis of autonomic neuropathy. The study has identified
      previously known and new potential risk factors for the development of autonomic
      neuropathy, which may be important for the development of risk reduction
      strategies. Our results may support the role of vascular factors in the
      pathogenesis of autonomic neuropathy.

PMID- 12421427
TI  - Familial clustering of diabetic retinopathy in South Indian Type 2 diabetic
      patients.
AB  - AIM: The aim of the study was to determine whether there is familial clustering
      of diabetic retinopathy among South Indian Type 2 diabetic subjects. METHODS:
      During the period September 1991 to September 1997, 322 families with at least
      two diabetic siblings who were registered at our centre and had undergone a
      retinal examination were selected for the study. The sibling with the longest
      duration of diabetes was defined as the proband. The prevalence of retinopathy
      was compared between the siblings of probands with and without retinopathy.
      RESULTS: Diabetic retinopathy was diagnosed in 11.2% of the siblings of the
      probands without diabetic retinopathy and in 35.3% of the siblings of the
      probands with diabetic retinopathy (P < 0.0001). The increased prevalence of
      retinopathy among siblings of probands with retinopathy represented all grades of
      retinopathy, namely non-proliferative diabetic retinopathy with and without
      maculopathy and proliferative diabetic retinopathy, although the latter did not
      reach statistical significance due to the small numbers. Hypertension, metabolic
      control and the duration of diabetes among the probands did not affect the
      clustering of retinopathy. The odds ratio for retinopathy in the siblings of
      probands with retinopathy after adjusting for age, glycosylated haemoglobin,
      duration of diabetes, proteinuria and other confounding variables was 3.37(95%
      confidence interval 1.56-7.29, P = 0.002). CONCLUSIONS: Familial clustering of
      diabetic retinopathy was three times higher in siblings of Type 2 diabetic
      subjects with diabetic retinopathy.

PMID- 12421428
TI  - Basal-bolus insulin therapy in Type 1 diabetes: comparative study of pre-meal
      administration of a fixed mixture of insulin lispro (50%) and neutral protamine
      lispro (50%) with human soluble insulin.
AB  - AIMS: To ascertain whether pre-meal administration of 50% insulin lispro and 50%
      neutral protamine lispro (NPL), given as a fixed mixture (Humalog Mix50, human
      soluble (regular) insulin as a basal-bolus regimen in people with Type 1
      diabetes. Both regimens included bedtime human isophane (NPH) insulin. METHODS:
      This was a multinational, multicentre, randomized, open-label, two-period
      crossover comparison of two insulin treatments for two 12-week periods in 109
      patients with Type 1 diabetes. The protocol provided preliminary evaluations of
      dose requirements and recommendations for insulin dose adjustment when switching
      regimens on the basis of blood glucose (BG) values. Eight-point BG profiles,
      frequency of hypoglycaemia, HbA1c, insulin dose, time of injection, and frequency
      of snacking were assessed during each treatment. RESULTS: Total daily insulin
      dose was similar for both treatments, but the total pre-meal doses were higher (P
      < 0.001) and the bedtime dose of isophane was lower (P < 0.001) with Mix50. The
      pre-meal dose before breakfast and lunch, although statistically different (P =
      0.006 and P < 0.001, respectively), was of similar magnitude, but the pre-evening
      meal dose was higher with Mix50 (P < 0.001). Median (interquartile range) time of
      insulin injection before meals was: Mix50 4.2 (25th percentile = 1.0; 75th
      percentile = 6.3) min, human soluble insulin 24.6 (25th percentile = 16.6; 75th
      percentile = 30.0) min. Pre-meal and bedtime BG concentrations did not differ
      between treatments. The BG 2 h after the evening meal was lower with Mix50 (8.40
      +/- 2.95 mmol/l vs. 9.60 +/- 3.47 mmol/l) (P = 0.049). BG after breakfast and
      lunch, mean HbA1c, frequency of hypoglycaemia, frequency of snacks, and body
      weight were not different. CONCLUSION: The use of Mix50 in a basal-bolus regimen
      achieved similar control of pre-meal BG to human soluble insulin, and overall
      glycaemic control and hypoglycaemia risk were equivalent. This suggests that
      Mix50 can provide an adequate supply of insulin to control BG between meals while
      providing the convenience of injecting immediately before meals.

PMID- 12421429
TI  - Prevalence of retinopathy differs with age at onset of diabetes in a population
      of patients with Type 1 diabetes.
AB  - AIM: The VISS study (Vascular complications in South-east Sweden) investigates
      prevalence and incidence of vascular complications in a population with Type 1
      diabetes, from a well-defined geographical area and followed from diagnosis with
      HbA1c measurement. METHOD: The study population comprised all 440 patients with
      Type 1 diabetes onset before the age of 36 years, onset during 1983-1987, and at
      the time of onset living within the counties of Jonkoping, Kalmar or
      Ostergotland. Retinopathy was examined with fundus photography 1994-1995, and
      classified according to a modified Airlie House protocol. RESULTS: Fundus
      photographs from 390 patients were evaluated. In 277 (71%) patients no
      retinopathy was seen. The prevalence of retinopathy increased from 11% among
      patients < 5 years old at diabetes onset, to 48% among those 15-19 years old at
      diabetes onset, and then decreased to 30% for patients 30-35 years old at
      diabetes onset (P for chi2 for linear trend for all ages 0.017, for age at onset
      0-19 years P = 0.0003), without corresponding differences in duration or HbA1c
      between patients with different onset age. Patients with HbA1c in the highest
      quartile (> 8.3% HbA1c) had a relative risk of 2.4 (95% confidence interval (CI)
      1.7-3.2) of having any retinopathy compared with patients with lower HbA1c, and a
      relative risk of 7.1 (95% CI 3.0-16.7) of having other forms of retinopathy than
      microaneurysms. CONCLUSION: In patients with diabetes duration of 6-13 years, the
      prevalence of retinopathy is clearly related to glycaemic control. Furthermore,
      the risk of retinopathy varies with different age at onset, independently of
      differences in duration or glycaemic control.

PMID- 12421430
TI  - Cardiovascular autonomic reactivity is decreased in adolescents with Type 1
      diabetes.
AB  - AIMS: To characterize autonomic nervous system function by means of the heart
      rate and blood pressure responses to various stimuli in relation to pubertal
      maturation in patients with Type 1 diabetes mellitus (DM). METHODS: One hundred
      out of 138 eligible patients at the Out-patient Diabetes Clinic and 100 healthy
      control subjects were examined in terms of cardiovascular parameters at rest,
      during deep breathing and when standing. Heart rate variability was analysed with
      time domain,frequency domain and fractal dimension parameters. Tanner pubertal
      staging was performed before the examinations. RESULTS: The time domain
      parameters of heart rate variability at rest or during standing did not
      significantly differ between the patients and controls in total or at pubertal
      stages. In the spectral analysis of heart rate variability the very low frequency
      band was decreased in the patients during standing (P = 0.023).The increase in
      the very low frequency (P = 0.013)and low frequency (P = 0.031) spectral powers
      upon changing from a supine position to standing was attenuated in the patients
      in total, while no significant differences were observed within the Tanner
      pubertal stages between patients and controls. Heart rate variability during deep
      breathing was decreased in the patients with distal polyneuropathy (P = 0.006).
      CONCLUSIONS: Although cardiovascular integrity is in the main well preserved in
      adolescent patients with Type 1 DM, these patients are prone to attenuated
      autonomic nervous system reactivity.

PMID- 12421432
TI  - Acute effect of orlistat on post-prandial lipaemia and free fatty acids in
      overweight patients with Type 2 diabetes mellitus.
AB  - AIMS: Post-prandial lipaemia is prolonged and exaggerated in patients with Type 2
      diabetes mellitus, with an accumulation of atherogenic triglyceride-rich
      lipoprotein remnants. We postulate that orlistat, a gastrointestinal lipase
      inhibitor, may cause changes in post-prandial lipoprotein metabolism by reducing
      dietary triglyceride absorption. METHODS: The acute effect of a single dose of
      120 mg orlistat on post-prandial glucose, lipids, remnant lipoproteins and free
      fatty acids (FFA) was evaluated in a randomized, double-blind, placebo-controlled
      cross-over study of 63 overweight patients with Type 2 diabetes mellitus (body
      mass index 30.4 +/- 3.8 kg/m2). Either a single dose of orlistat or placebo was
      given before a standard mixed meal containing 70 g of fat and plasma triglyceride
      (TG), remnant-like particles cholesterol (RLP-C) and FFA were sampled at 2-h
      intervals for 8 h. RLP-C was measured by an immunoseparation assay and FFA by an
      enzymatic colorimetric method. RESULTS: The concentrations of plasma TG (P <
      0.0001), RLP-C (P = 0.003), and FFA (P < 0.0001) were significantly lower at 2 h
      after orlistat compared with placebo. Both plasma RLP-C (P = 0.04) and FFA (P <
      0.0001) remained lower after orlistat than placebo at 4 h. The incremental area
      under the curve (iAUC) above baseline fasting level for both TG and RLP-C was
      significantly more reduced after orlistat than placebo (iAUC-TG 5.8 (3.7-8.2)
      mmol/l x h-1 vs. 5.7 (4.1-10.9), respectively, P = 0.04; iAUC-RLP-C: 0.53 (0.23
      1.04) mmol/l x h-1 vs. 0.56 (0.35-1.40), respectively, P = 0.02). The test meal
      was well tolerated by all subjects, with only three subjects reporting faecal
      urgency after orlistat. CONCLUSIONS: Orlistat has a beneficial effect on post
      prandial lipaemia in overweight Type 2 diabetic patients and lowers plasma TG,
      RLP-C and FFA in the early post-prandial period.

PMID- 12421431
TI  - C-reactive protein is more strongly related to post-glucose load glucose than to
      fasting glucose in non-diabetic subjects; the Insulin Resistance Atherosclerosis
      Study.
AB  - AIMS: It has been suggested that cardiovascular disease may be more strongly
      related to post-challenge glycaemia than to fasting glucose concentrations. We
      hypothesized that subclinical inflammation, as indicated by elevated serum levels
      of C-reactive protein (CRP), may partially explain the association of
      cardiovascular disease with post-challenge glycaemia. METHODS: We studied the
      relationship of CRP (measured with a highly sensitive immunoassay) with fasting
      glucose and 2-h glucose concentrations during an oral glucose tolerance test in
      non-diabetic subjects from the Insulin Resistance Atherosclerosis Study. RESULTS:
      Spearman correlation analyses and multiple linear regression analyses showed a
      significant association of both fasting glucose and 2-h glucose concentrations
      with CRP levels, after adjusting for demographic covariates (age, sex, ethnicity,
      clinical centre; Spearman correlation coefficients: r = 0.18 for fasting glucose,
      r = 0.27 for 2-h glucose, both P < 0.0001). However, after additional adjustment
      for body mass index and waist-hip ratio only 2-h glucose (and not fasting
      glucose) was significantly related to CRP (r = 0.03 for fasting glucose, P = NS;
      r = 0.14 for 2-h glucose, P < 0.0001). Adding insulin sensitivity to the
      multivariate models further weakened the relationship of CRP to 2-h glucose (r =
      0.07, P < 0.05). CRP mean values increased by 2-h glucose category (normal vs.
      impaired glucose tolerance vs. isolated post-challenge hyperglycaemia).
      CONCLUSIONS: Chronic, subclinical inflammation, as indicated by elevated
      circulating CRP levels, is more strongly associated with post-challenge glycaemia
      than with fasting glucose levels in non-diabetic subjects. This association is
      partially independent of body fat and insulin resistance.

PMID- 12421433
TI  - Tumour necrosis factor-alpha plasma levels in elderly patients with Type 2
      diabetes mellitus-observations over 2 years.
AB  - AIMS: The cytokine tumour necrosis factor-alpha (TNF-alpha) is involved in the
      development of obesity-linked insulin resistance. TNF-alpha plasma levels rise
      with increasing age and might thus also be related to metabolic control in Type 2
      diabetes mellitus. We have studied the relationship of TNF-alpha plasma levels to
      glycaemic control in elderly patients with Type 2 diabetes over 2 years. METHODS:
      Clinical and laboratory data of 53 patients (26 women, 27 men) with Type 2
      diabetes (mean age 71.6 +/- 5.6 years) were regularly evaluated over 2 years, and
      the relationship to anti-diabetic treatment regimens analysed. TNF-alpha plasma
      level was measured by a solid-phase enzyme amplified sensitivity immunoassay.
      RESULTS: TNF-alpha plasma levels increased significantly from 16.2 +/- 9.6 pg/ml
      at baseline to 28.0 +/- 13.8 pg/ml after 2 years (P = 0.028). HbA1c values also
      increased from 6.4 +/- 1.2% to 7.7 +/- 1.6% (P = 0.046). Mean body mass index of
      the patients remained almost constant, while a moderate increase in the
      percentage of body fat (34.5 +/- 7.0% to 35.3 +/- 6.9%; P= 0.061) and in waist
      hip ratio was observed (0.86 +/- 0.04 to 0.88 +/- 0.04; P= 0.052). After
      adjustment for covariates multivariate analysis demonstrated that TNF-alpha
      plasma levels are positively related to the HbA1c values of the whole study
      population at the baseline control and after 2 years. TNF-alpha also revealed a
      positive correlation to the percentage of body fat. CONCLUSIONS: In elderly
      patients with Type 2 diabetes TNF-alpha plasma levels revealed a continuous
      increase during an observation period of 2 years. This increase in TNF-alpha
      plasma levels might add another aspect to the worsening of glycaemic control in
      the progression of Type 2 diabetes.

PMID- 12421434
TI  - Increasing prevalence of diabetes mellitus in Oman.
AB  - AIMS: To determine the prevalence of diabetes mellitus and impaired fasting
      glucose by age, gender, and by region and compare results with the 1991 survey;
      and estimate previously undiagnosed diabetes mellitus in the Omani population.
      METHODS: Cross-sectional survey containing a probability random sample of 5838
      Omani adults aged >or= 20 years. Diabetes and impaired fasting glucose (IFG) were
      assessed by fasting venous plasma glucose using 1999 World Health Organization's
      diagnostic criteria (normoglycaemia < 6.1 mmol/l, IFG >or= 6.1 but < 7 mmol/l,and
      diabetes >or= 7 mmol/l). The 1991 survey was reanalysed using the same diagnostic
      criteria, and results were compared. RESULTS: In 2000, the age-adjusted
      prevalence of diabetes among Omanis aged 30-64 years reached 16.1% (95%
      confidence interval (CI) 14.7-17.4) compared with 12.2% (95% CI11.0-13.4) in
      1991. IFG was found among 7.1% (95% CI6.2-8.1) of males and 5.1% (95% CI 4.4-6.0)
      of females. Generally, diabetes was more common in urban then rural regions. Only
      one-third of diabetic subjects knew that they had diabetes. Nearly half of the
      study population had a body mass index > 25 kg/m2. CONCLUSIONS: The prevalence of
      diabetes is high in Oman and has increased over the past decade. The high rate of
      abnormal fasting glucose together with high rates of overweight and obesity in
      the population make it likely that diabetes will continue to be a major health
      problem in Oman. Primary prevention programmes are urgently needed to counteract
      major risk factors that promote the development of diabetes.

PMID- 12421435
TI  - The oral glucose tolerance test reveals a high frequency of both impaired glucose
      tolerance and undiagnosed Type 2 diabetes mellitus in primary
      hyperparathyroidism.
AB  - AIMS: To evaluate the frequency of impaired glucose tolerance (IGT)and
      undiagnosed diabetes mellitus together with the indices of insulin resistance
      (IR) in primary hyperparathyroidism (pHPT). METHODS: Out of 105 consecutive pHPT
      patients (F/M 78/27, asymptomatic/symptomatic 68/37, age (mean +/- s.d.) 60.7 +/-
      12.7 years,body mass index 25.2 +/- 3.8 kg/m2, ionized calcium (iCa) 1.49 +/-
      0.16 mmol/l,parathormone 200.4 +/- 233.9 pg/ml),59 without known diabetes
      mellitus and controls (n = 60) underwent an oral glucose tolerance test (OGTT, 75
      g os). As indices of IR, homeostasis model assessment (HOMAIR)or OGTT data
      (insulin sensitivity index composite (ISI comp)) were evaluated. RESULTS: In pHPT
      the prevalence of IGT (mean, 95% confidence intervals (CI), 40.7%, 27.8-53.6) was
      higher than in controls (25.0%, 13.7-36.3, P < 0.03). Similarly,the prevalence of
      undiagnosed diabetes mellitus was higher in pHPT(15.3%, 5.8-24.7) than in
      controls (5.0%, 0-10.7, P < 0.05). Moreover,the prevalence of IGT and undiagnosed
      diabetes was higher in pHPT than that previously reported in the general
      population of Northern Italy(8.5% and 3.2%, respectively). The indices showed
      that insulin resistance was higher in pHPT than in controls: HOMAIR (median, 95%
      CI,2.6, 2.5-3.9 vs. 1.7, 1.6-2.5, respectively; P < 0.003); ISI comp (3.5, 3.4
      4.6 vs. 5.1, 4.9-7.2, respectively; P < 0.002). CONCLUSIONS: Our data in a large
      and modern day pHPT series, with a preponderance of asymptomatic patients,
      confirm increased insulin resistance and pre-valence of IGT and undiagnosed
      diabetes.

PMID- 12421436
TI  - Symptom scoring systems to diagnose distal polyneuropathy in diabetes: the
      Diabetic Neuropathy Symptom score.
AB  - AIMS: To provide one of the diagnostic categories for distal diabetic
      polyneuropathy,several symptom scoring systems are available, which are often
      extensive and lack in validation. We validated a new four-item Diabetic
      Neuropathy Symptom (DNS) score for diagnosing distal diabetic polyneuropathy.
      METHODS: We compared score characteristics of the generally accepted Neuropathy
      Symptom Score (NSS) with the DNS score, and tested construct validity,predictive
      value and reproducibility with the Diabetic Neuropathy Examination score, Semmes
      Weinstein monofilaments and Vibration Perception Threshold(clinical standards) in
      73 patients with diabetes (24 Type 1, 49 Type 2;43 male/30 female; mean age 57
      years (19-90);mean diabetes duration 15 years (1-43)). RESULTS: Correlation
      between NSS and DNS score was high (Spearman r= 0.88). Patient scores were more
      differentiated on the DNS score. The relation of the NSS and DNS scores,
      respectively, with clinical standards was good (Spearman r= 0.21-0.60).
      Reproducibility of the DNS score was high (Cohen weighted kappa 0.78-0.95). The
      DNS score was easier to perform in clinical practice. CONCLUSIONS: The DNS is
      validated, fast and easy to perform, with a high predictive value when screening
      for diabetic polyneuropathy.

PMID- 12421437
TI  - Sulphonylurea-induced hypoglycaemia in institutionalized elderly in Hong Kong.

PMID- 12421438
TI  - Detection of enterovirus RNA sequences in serum samples from autoantibody
      positive subjects at risk for diabetes.

PMID- 12421439
TI  - The presence of a common mitochondrial DNA variant is associated with fasting
      insulin levels in Europeans in Auckland.

PMID- 12421441
TI  - Forgotten implications of HPV positivity for the majority of females: a clinical
      perspective.

PMID- 12421442
TI  - Borderline nuclear change; can a subgroup be identified which is suspicious of
      high-grade cervical intraepithelial neoplasia, i e CIN 2 or worse?
AB  - Borderline nuclear change; can a subgroup be identified which is suspicious of
      high-grade cervical intraepithelial neoplasia, i.e. CIN 2 or worse? Only 10% of
      first borderline smears are associated with a histological high-grade (HG)
      abnormality, i.e. CIN 2,3, invasive malignancy or glandular neoplasia on
      subsequent investigation. The advantages of highlighting this subgroup are
      obvious but is this possible? From 1996 and 1997, 242 borderline smears with
      histological follow-up were examined by two independent experienced observers
      (observer 1 and 2) without prior knowledge of further investigation results. For
      each smear a profile of nuclear details was produced, also noting the type of
      cell mainly affected by the process; then the observers were asked to assess the
      degree of worry of HG disease for each smear i.e. whether the smear fell into
      group 1 borderline changes indicative of low-grade (normal, inflammatory,
      CIN1/HPV) disease (BL/LG) or group 2 difficult borderline smear, HG disease (CIN
      2,3, invasive neoplasia or glandular neoplasia) cannot be excluded (BL/HG).
      Observer 1 selected a group of BL/HG with a PPV for HG disease of 38%, with
      observer 2 having a PPV of 50%; this compared with the overall laboratory HG
      disease PPV for borderline smears of 14%. Both observers found the most useful
      criterion to be the increase in nuclear:cytoplasmic ratio. Our results show that
      it is possible to separate a small group of borderline smears which should be
      classified as 'borderline/high grade lesion difficult to exclude' (BL/HG). Both
      observers had some success in arriving at this classification although their
      method of selecting out this group was quite different.

PMID- 12421443
TI  - Flow cytometric DNA analysis on fine needle aspiration biopsies of liver lesions.
AB  - Flow cytometric DNA analysis on fine needle aspiration biopsies of liver lesions
      The DNA cell content of 39 fine needle aspiration biopsies (FNAs) from five
      benign liver lesions, nine hepatocellular carcinomas (HCCs), and 25 metastatic
      tumours was analysed in a prospective fashion by flow cytometry (FCM). All benign
      lesions were diploid. Aneuploidy was found in five (55.6%) HCCs and in nine (36%)
      metastatic tumours. DNA index (DI) differences were not significant. The S-phase
      fraction (SPF) was higher in the malignant tumours, both combined (P < 0.02) and
      separated primary and metastatic (P < 0.05). We could not demonstrate an
      association between diploidy and percentage of benign hepatocytes in the smears
      of malignant tumours. The serum alpha-fetoprotein (AFP) level did not correlate
      with ploidy, DI, or SPF in the HCCs. In conclusion, ploidy and DI do not
      discriminate between benign and malignant liver lesions, but the SPF is higher in
      malignant tumours. DNA analysis does not help to distinguish primary from
      metastatic liver tumours. The presence of benign hepatocytes in samples from
      malignant tumours does not seem to influence the analysis of ploidy by FCM.

PMID- 12421444
TI  - Fine needle aspiration cytology of suspected tuberculous lymphadenitis.
AB  - Fine needle aspiration cytology of suspected tuberculous lymphadenitis The aims
      of this cross-sectional study were to describe the distributional patterns of
      tuberculous lymphadenitis and to assess the correlation between fine needle
      aspiration cytology (FNAC) and the Ziehl Neelsen staining technique in diagnosing
      tuberculous lymphadenitis. Romanowsky's method (Wright's stain) for cytological
      diagnosis and Ziehl Neelsen (hot method) for the identification of acid-fast
      bacilli were utilized. Out of one hundred and twenty-eight consecutive patients
      attending the cytological diagnostic service of the Department of Pathology
      within Jimma University, 89 (69.6%) of the patients were younger than 30 years of
      age. The male to female ratio was 1.3 : 1. The cervical region was the most
      common site and involved 95 cases (74.2%), followed by the axillary and inguinal
      lymph node regions (20.3% and 4.3%, respectively). The Wright's-stained cytology
      smears were grouped into three categories: epithelioid granulomas without
      necrosis, epithelioid granulomas with caseous necrosis and necrosis without
      epithelioid granulomas. The Ziehl Neelsen stains were undertaken on separate
      slides: 20.0% of the cases showing epithelioid granulomas without necrosis, 61.9%
      of those with epithelioid granulomas with necrosis/abscesses and 69.7% of those
      with necrosis without granulomas were found to be positive for acid-fast bacilli.
      The overall positivity for the ZiehlNeelsen stained cases was 59.4%. It can
      therefore be concluded that FNAC is a reliable diagnostic tool in helping to
      avert the more invasive surgical procedures undertaken in the diagnosis of
      tuberculous adenitis. The ZiehlNeelsen stain for identification of acid-fast
      bacilli should be incorporated as an adjunct to increase the diagnostic accuracy
      of tuberculous lymphadenitis.

PMID- 12421445
TI  - Archival cervical smears: a versatile resource for molecular investigations.
AB  - Archival cervical smears: a versatile resource for molecular investigations
      Archival cervical smears represent a huge resource of pathological specimens.
      This, together with long clinical follow-up data, makes archival smears the most
      valuable resource for cervical cancer research. Despite this huge potential, only
      a few molecular investigations have been carried out based on archival smears. It
      has been shown that archival smears can be used for amplification of genomic
      sequences by polymerase chain reaction (PCR). However, it is unknown whether PCR
      can be applied to minute dyskaryotic cells microdissected from archival cervical
      smears and whether these archival materials are suitable for reverse
      transcription PCR (RT-PCR). To address these issues, we prepared DNA and RNA
      samples from dyskaryotic cells microdissected from archival cervical smears with
      a storage time of 11 years and systematically tested the extent that these
      materials can be used for PCR-based molecular investigations at both DNA and RNA
      levels. Our results showed that a crude DNA preparation simply by proteinase K
      digestion was suitable for PCR amplification of genomic sequences. By targeting
      the amplified genomic sequence to 250 bp or less, most if not all archival smears
      could be used for PCR and are therefore suitable for screening gene mutations and
      loss of heterozygosity, human papillomavirus typing, etc. Purified DNA samples
      from microdissected dyskaryotic cells were adequate for restriction enzyme
      digestion and could be used for a PCR-based clonality analysis of the androgen
      receptor gene. Finally, RNA samples extracted from dyskaryotic cells
      microdissected from archival smears were adequate for RT-PCR as long as a gene
      specific primer was used for the RT reaction and the target sequence was
      restricted to 150 bp or less. In summary, our results demonstrated that archival
      cervical smears are suitable for a range of molecular investigations at both DNA
      and RNA levels. The potential gain of knowledge on cervical cancer by the
      molecular study of archival smears is immense.

PMID- 12421446
TI  - Cytomorphological spectrum in gynaecomastia: a study of 389 cases.
AB  - Cytomorphological spectrum in gynaecomastia: a study of 389 cases The objective
      of this study was to document the spectrum of cytomorphological features in
      aspirates from gynaecomastia. During a 22-year period (July 1979 to June 2001)
      fine needle aspirations (FNA) were conducted on 651 males with a breast lesion.
      Fine needle aspirate slides from 529 benign cases were reviewed along with the
      histological sections of 54 cases where available. Of the 529 FNA, 140 were
      excluded (105 unsatisfactory, five cystic fluid aspirated, 30 inflammatory
      lesions). In 134 of 389 cases reviewed florid gynaecomastia was observed while
      the remainder showed benign ductal cells (BDC) in varying quantities from less
      than five to more than 25 groups. Of the 134 cases with florid gynaecomastia, 49
      had a fibroadenoma-like picture (FLP), where a large number of BDC fragments with
      a staghorn configuration, prominent stromal fragments with contoured stroma and
      bare bipolar nuclei were seen abundantly in all cases. In 85 cases the features
      resembled fibroadenomatoid hyperplasia (FH), with only an occasional staghorn
      configuration of BDC seen in 82% of the cases. In 83% of cases stromal fragments
      of varying proportions were seen but a contoured stroma was seen in only 3.5% of
      cases. Both stromal and epithelial atypia were seen in 41% and 86% cases,
      respectively, of FLP, and in 7% and 69% cases of FH. Columnar cells, apocrine
      cells and foam cells were seen in approximately similar quantities in both the
      lesions. Vascularized stroma was seen in 22% of the cases with FLP but in only
      4.5% of cases those with FH. Cytohistological correlation performed in 54 cases
      showed marked variation. Fine needle aspirates showed florid changes in 13 of the
      41 cases of simple gynaecomastia and two of the eight cases with florid
      gynaecomastia on tissue sections. In conclusion, a wide spectrum of morphological
      features are encountered in FNA from benign male breast lesions. It is important
      to recognize these to avoid a false-positive diagnosis.

PMID- 12421447
TI  - Fine needle aspiration cytology of minor salivary gland tumours of the palate.
AB  - Fine needle aspiration cytology of minor salivary gland tumours of the palate
      This retrospective study was carried out to review aspirates from minor salivary
      gland tumours of the palate and to assess the problems encountered in their
      diagnosis, especially the cytological diagnosis of newer entities such as
      polymorphous low grade adenocarcinoma (PLGA). Fifty-five cases of palatal
      salivary gland tumours aspirated over a period of 16 years were reviewed.
      Histology was available in 26 cases. Pleomorphic adenoma (27 cases) was the most
      common benign cytodiagnosis. Eleven aspirates were malignant tumours of which
      eight cases were adenoid cystic carcinoma and three cases were mucoepidermoid
      carcinoma. Seven cases were diagnosed on fine needle aspiration as suggestive of
      PLGA. However histological confirmation was available in only one of these cases.
      Concordance between the initial and revised typings of the tumours was seen in
      only 28 cases (54%) in the present study. Initially 18 of the 51 tumours (35.3%)
      could not be typed; and after review, only three could not be typed. Three cases
      of oncocytoma could be diagnosed on review only. Palatal salivary gland tumours,
      although relatively uncommon, are difficult to diagnose cytologically. This is
      more so in cases of newer entities such as PLGA, as their cytological diagnosis
      is still not well characterized.

PMID- 12421448
TI  - Detection of bladder cancer by multitarget multicolour FISH: comparative analysis
      on archival cytology and paraffin-embedded tissue.
AB  - Detection of bladder cancer by multitarget multicolour FISH: comparative analysis
      on archival cytology and paraffin-embedded tissue We have evaluated the
      possibility of using the same specimen for both cytological diagnosis and
      multitarget multicolour FISH (MtMcFISH) analysis in order to determine whether
      the routinely processed specimens used for diagnosis were also suitable for this
      ancillary procedure. For this purpose 18 positive samples (11 voided urine and
      seven bladder washings) were selected, together with a representative section of
      the corresponding immediately previous or subsequent histological specimens. Two
      negative cytology slides were added as negative controls. FISH analysis revealed
      a normal pattern for each probe in the two negative controls and an abnormal
      pattern in the 18 positive cases. In the latter the same FISH alterations were
      found in the cytology samples and in the corresponding histological sections, and
      superimposable cytological/histological features were observed in two cases where
      two different histology samples were analyzed. The results clearly show that
      MtMcFISH may be successfully applied to destained routinely processed cytology
      slides.

PMID- 12421449
TI  - Disco dancing.

PMID- 12421450
TI  - Educational case report - self assessment.

PMID- 12421451
TI  - Bronchial epithelial atypia mimicking squamous cell carcinoma secondary to
      cyclophosphamide therapy.

PMID- 12421452
TI  - Cervical screening in older women.

PMID- 12421454
TI  - Expanding the envelope: can we increase the organ donor pool through the
      appropriate application of infectious disease principles?

PMID- 12421455
TI  - Transmission of viral hepatitis by kidney transplantation: donor evaluation and
      transplant policies (Part 1: hepatitis B virus).
AB  - This two-part article discusses serologic testing of prospective donors for viral
      hepatitis B and C, as part of the comprehensive donor evaluation, and reviews the
      current policies and practices aimed at preventing donor-to-recipient
      transmission of hepatitis B and C viruses (HBV, HBC). This first part of the
      review discusses HBV. Organs procured from HBV-infected donors can transmit the
      virus to their recipients. Because infections with HBV have been associated with
      increased morbidity and mortality among renal transplant recipients, it is
      important to prevent HBV transmission with renal transplantation. Routine
      serologic evaluation of prospective organ donors for markers of HBV infection
      includes testing for hepatitis B surface antigen (HBsAg), anti-hepatitis B
      surface antigen antibody (HBsAb), and antibody to hepatitis B core antigen (anti
      HBc). The risk of HBV transmission with kidney transplantation is a function of
      the serologic status of both donor and recipient. Knowledge of this risk is
      essential for the rational use of kidney allografts. HBsAg-positive donors are at
      high risk of transmitting HBV infection to their organ recipients, particularly
      if these donors are concurrently positive for hepatitis B e antigen (HBeAg).
      Kidneys from donors with isolated presence of HBsAb are unlikely to transmit HBV
      infection to their recipients. The risk of HBV transmission with the use of
      kidneys from IgG anti-HBc-positive, HBsAg-negative donors is low. Kidneys from
      donors negative for both HBcAg and anti-HBc are at low-to-negligible or no risk
      of transmitting HBV to their recipients. Under certain conditions, kidneys from
      HBV-infected donors can be safely used and thus prevent unnecessary discarding of
      organs. Kidneys from HBsAg-positive donors, who are negative for HBeAg, carry no
      risk or only minimal risk of transmitting HBV infection to their recipients if
      these recipients are immune to HBV or HBsAg-positive. However, the safety of
      these policies deserves further evaluation.

PMID- 12421456
TI  - Transmission of viral hepatitis by kidney transplantation: donor evaluation and
      transplant policies (Part 2: hepatitis C virus).
AB  - This two-part article discusses serologic testing of prospective donors for viral
      hepatitis B and C as part of the comprehensive donor evaluation and reviews of
      the current policies and practices aimed at preventing donor-to-recipient
      transmission of hepatitis B and C viruses (HBV, HBC). This second part of the
      review discusses HCV. Organs procured from HCV-infected donors can transmit the
      virus to their recipients. Because a number of studies have associated infections
      with HCV with increased morbidity and mortality among renal transplant
      recipients, it is important to prevent HCV transmission with renal
      transplantation. The majority of organ procurement organizations (OPOs) perform
      routine screening of organ donors for antibodies to HCV (anti-HCV). The
      prevalence of HCV infection among cadaver organ donors, ascertained based on a
      positive anti-HCV test by ELISA2, varies worldwide between 1.08% and 11.8%. The
      use of kidneys from donors negative for anti-HCV by ELISA2 carries negligible or
      no risk of transmitting HCV infection. The use of organs from anti-HCV-positive
      donors has been restricted to life-saving transplants (heart, liver or lung) by
      the majority of OPOs worldwide. However, discarding kidneys from all anti-HCV
      positive donors would lead to unnecessary waste of organs because not all anti
      HCV positive donors are infectious. Recently, the policy of unconditional
      restriction on the use of kidneys from anti-HCV positive donors has been
      challenged, and transplantation of organs from anti-HCV-positive donors into anti
      HCV-positive recipients has been found to be safe. An even better alternative
      might be a policy of transplanting kidneys from anti-HCV-positive donors only in
      HCV RNA-positive recipients. However, until more data become available, these two
      strategies remain experimental treatments.

PMID- 12421457
TI  - Efficacy and tolerability of prophylactic treatment with intravenous
      piperacillin/tazobactam in patients undergoing hematopoietic stem cell
      transplantation.
AB  - BACKGROUND: Infections remain a major cause of morbidity and mortality in
      patients undergoing autologous or allogeneic hematopoietic stem cell
      transplantation (HSCT). About 80% of patients experience fever during aplasia and
      early engraftment despite oral antibacterial chemoprophylaxis. METHODS: In a
      pilot study, 50 patients undergoing autologous or allogeneic HSCT received a
      prophylactic antibacterial treatment with intravenous piperacillin/tazobactam
      beginning on day of stem cell or bone marrow transfusion. They were analyzed
      retrospectively for frequencies of fever of unknown origin (FUO), documented
      infection, bacteremia and death because of infection. Furthermore, data from
      microbiological monitoring and tolerability were evaluated. RESULTS: Among 28
      autologous transplanted patients, 10 (36%) developed fever more than 38.5 degrees
      C; 9/10 FUO, 1/28 pulmonary infiltrates. Eighteen patients (64%) remained without
      any symptom of infection. In the allogeneic group (n = 22), there were eight
      patients (36%) with FUO, and five patients (23%) with documented infections
      (pneumonia 2, enteritis 1, pyelonephritis 1, Escherichia coli bacteremia 1). In
      nine patients (41%), escalation of antimicrobial treatment was not necessary. The
      majority of detected microbes in cultures of throat and nose secretions, blood,
      urine and stool were gram-positive bacteria (77.8%), among them Staphylococcus
      epidermidis (23.5%), streptococci (group A, B, C; 21.0%) and enterococci (10.6%).
      Incidence of gram-negative bacteria and fungi was similar with 11.8% and 10.4%,
      respectively. The most frequent gram-negative strains were Escherichia coli
      (6.5%) and Pseudomonas aeruginosa (1.7%). There was no severe toxicity or
      hypersensitivity. CONCLUSION: Compared to oral decontamination and
      chemoprophylaxis, an intravenous prophylactic regimen as described above could be
      an effective and well-tolerated approach in prevention of bacterial infections
      and related complications, with a higher acceptance in recipients of bone marrow
      or stems cell grafts. Further evaluation in comparison with fluoroquinolone
      prophylaxis regarding efficacy, development of resistances as well as cost
      benefit analyses is warranted.

PMID- 12421458
TI  - Evolving experience of hepatitis B virus prophylaxis in liver transplantation.
AB  - Passive immunoprophylaxis with hepatitis B immunoglobulin (HBIG) is important to
      prevent recurrence of hepatitis B virus (HBV) after orthotopic liver
      transplantation (OLT) for chronic HBV cirrhosis. With availability of lamivudine
      (3TC), the use of combination prophylaxis with long-term HBIG/3TC has been shown
      to prevent short-term HBV recurrence. This report compares HBV recurrence rates
      between groups receiving no/short-term HBIG, long-term HBIG alone, or HBIG/3TC
      prophylaxis, and describes HBIG requirements during the first 6 and 12 months in
      the latter two groups. This study involved patients undergoing OLT at the
      University of Tennessee-Memphis between May 1990 and July 2001. During this
      period, 388 liver transplants were performed at our center. All hepatitis B
      surface antigen (HBsAg)-positive recipients (n = 27) were included in this
      retrospective analysis. The groups were similar with regard to pre-transplant
      demographic characteristics such as age, gender, weight, and pre-transplant
      diagnosis. Owing to the retrospective study design, median follow-up was longer
      for the no-prophylaxis (5.6 years) and the HBIG-alone (6.0 years) groups compared
      to the HBIG/3TC group (4.2 years). Patient survival was 50% in the no-prophylaxis
      and 71% in the HBIG-alone groups compared to 100% in the HBIG/3TC group (P =
      0.09). When censored for death with a functioning graft, graft survival was 50%
      in the no-prophylaxis and 86% in the HBIG-alone group compared to 100% in the
      HBIG/3TC group (P = 0.07). The overall incidence of HBV recurrence in the no
      prophylaxis era was 100% and 21% in the HBIG-alone era compared to 0% in the
      HBIG/3TC era (P < 0.001), despite similar mean and median HBIG trough titers in
      the HBIG-alone and HBIG/3TC groups. The incidence of HBV recurrence in HBV DNA
      positive recipients was 100% in the no-prophylaxis era, 30% in the HBIG-alone
      era, and 0% in the HBIG/3TC era (P < 0.001). Recipients in the HBIG-alone group
      had a nearly two-fold increase in HBIG requirement at 6 and 12 months in order to
      maintain similar HBIG trough titers post-transplant compared to recipients in the
      HBIG/3TC group despite similar pre-transplant HBV serology. This increased HBIG
      requirement in the HBIG-alone group resulted in a marked increase in the mean
      overall cost of HBV prophylaxis in this group ($47,367 US dollars at 6 months;
      $84,280 US dollars at 12 months) compared to the HBIG/3TC group ($25,931 US
      dollars at 6 months; $49,599 US dollars at 12 months). These data demonstrate an
      improvement in patient and graft survival rates in the group receiving
      combination HBIG/3TC prophylaxis compared to the HBIG-alone and no-prophylaxis
      groups. There was a significant reduction in HBV recurrence in the group
      receiving combination HBIG/3TC when compared to the groups receiving HBIG alone
      or no prophylaxis. Furthermore, we demonstrated that the addition of 3TC to the
      long-term HBIG regimen led to elimination of the disparity previously described
      in HBV recurrence rates between HBV DNA-positive and HBV DNA-negative recipients.
      Importantly, our data demonstrates a complete lack of HBV recurrence in the
      HBIG/3TC group at a median follow-up of 4.2 years. Additionally, the data show
      that the addition of 3TC to the post-operative prophylaxis regimen resulted in a
      reduction in the requirement of HBIG at 6 and 12 months, which markedly reduced
      the overall cost of post-transplant HBV prophylaxis.

PMID- 12421459
TI  - Impact of HIV seropositivity on graft and patient survival after cadaveric renal
      transplantation in the United States in the pre highly active antiretroviral
      therapy (HAART) era: an historical cohort analysis of the United States Renal
      Data System.
AB  - BACKGROUND: National statistics are presented for patient survival and graft
      survival in patients seropositive for the human immunodeficiency virus (HIV+) at
      the time of renal transplantation in the era prior to highly active
      antiretroviral therapy (HAART). METHODS: Historical cohort analysis of 63, 210
      cadaveric solitary renal transplant recipients with valid HIV serology entries in
      the United States Renal Data System (USRDS) from 1 January 1987 to 30 June 1997.
      The medical evidence form was also used for additional variables but, because of
      fewer available values, was analyzed in a separate model. Outcomes were patient
      characteristics and survival associated with HIV+ status. RESULTS: Thirty-two
      patients (0.05%) in the study period were HIV+ at transplant. HIV+ patients were
      comparable to the national renal transplant population in terms of gender and
      ethnic distribution but were younger and had younger donors and better HLA
      matching than the USRDS population. Patient and graft three-year survival were
      significantly reduced in HIV+ recipients (53% graft, 83% patient survival)
      relative to the USRDS population (73% and 88%, respectively). In multivariate
      analysis, HIV+ status was independently associated with patient mortality and
      decreased graft survival in recipients of cadaveric kidney transplants.
      CONCLUSIONS: This analysis was retrospective and may underestimate the number of
      HIV+ patients transplanted in the United States. Although the clinical details of
      patient selection for transplant were unknown, these results show HIV+ patients
      can have successful outcomes after cadaveric renal transplantation, although
      outcomes are significantly different from HIV- recipients.

PMID- 12421460
TI  - Incidence of histoplasmosis following allogeneic bone marrow transplant or solid
      organ transplant in a hyperendemic area.
AB  - Questions have arisen regarding the risk of developing symptomatic Histoplasma
      capsulatum infection among patients who undergo transplant-related
      immunosuppression in areas endemic for histoplasmosis. Our medical center is
      located in a hyperendemic area for histoplasmosis, where three large outbreaks
      occurred since 1978. We undertook a retrospective chart review of 137 patients
      who received allogeneic bone marrow transplant and of 449 patients who received
      solid organ transplant from January 1994 to December 1996 in order to assess the
      incidence of active histoplasmosis. Charts were reviewed before and after
      transplantation for clinical outcomes, H. capsulatum serologies and antigen
      results, and microbiological and radiological results. After a mean follow-up
      duration exceeding 16 months, no patient was diagnosed with histoplasmosis. In
      the absence of an outbreak, histoplasmosis is a rare infection following the
      immunosuppression of allogeneic bone marrow or solid organ transplantation even
      in a hyperendemic area. Pre-transplant serologies or chest radiographs consistent
      with prior infection were not associated with post-transplant histoplasmosis.

PMID- 12421461
TI  - Endothelial injury: cause and effect of alloimmune inflammation.
AB  - This review discusses the concept that endothelial cells may facilitate
      inflammation, but are also targets of the inflammatory response. Endothelial
      cells express several molecules that promote leukocyte recruitment, and other
      molecules, such as MHC class I that enable endothelial injury. Circulating
      alloantibodies produced following transplantation may also target the endothelium
      for injury. It has been shown that the expression of select protective genes
      within endothelial cells, including anti-apoptotic genes, may provide resistance
      to immune-mediated injury. Thus, an understanding of the mechanisms by which
      endothelial cells are injured and by which endothelial cells are protected is
      important for our understanding of allograft rejection.

PMID- 12421463
TI  - Donor-transmitted parvovirus infection in a kidney transplant recipient
      presenting as pancytopenia and allograft dysfunction.
AB  - Parvovirus B19 is a nonenveloped single-stranded DNA virus that commonly causes a
      benign childhood infection typically manifesting as a "slapped-cheek" rash. In
      immunodeficient hosts, this infection can cause persistent anemia and
      occasionally pancytopenia. Recently, direct renal involvement has been reported
      in renal transplant recipients leading to various forms of glomerulopathy and
      allograft dysfunction. Most cases are primary infections and are donor
      transmitted through the transplanted organ. Clinical and virological response to
      intravenous immunoglobulin (Ig) is usually excellent. We describe a case of donor
      transmitted parvovirus infection in a 23-year-old male who received his first
      cadaver renal transplant. The patient had an uncomplicated postoperative course
      with immediate graft function. Eight weeks after transplantation, he presented
      with fever, polyarthralgia, pancytopenia, and allograft dysfunction. Serological
      studies revealed elevated IgM titers against parvovirus B19. A renal biopsy was
      performed, which showed no evidence of acute rejection but with moderate degree
      of tubular damage. Parvovirus B19 viral DNA was detected in the renal tissue via
      polymerase chain reaction (PCR). The patient received a 10-day course of
      intravenous Ig (400 mg/kg/day) with excellent response. His blood count
      normalized and the allograft improved to baseline function. The incidence of
      parvovirus infection in renal transplant patients is probably underestimated,
      because patients are not routinely screened for it and anemia and/or pancytopenia
      in these patients are often ascribed to immunosuppressive drugs. Because this
      infection is treatable, we conclude that parvovirus B19 infection should be
      actively considered in transplant patients presenting with pancytopenia and
      allograft dysfunction.

PMID- 12421462
TI  - Possible benefit of intravenous immunoglobulin therapy in a lung transplant
      recipient with West Nile virus encephalitis.
AB  - During the summer of 2000, a countrywide epidemic of West Nile fever (WNF)
      occurred in Israel, with 417 confirmed cases and 35 deaths. Immunosuppressed
      patients had a 31% case-fatality rate, which was significantly higher compared to
      non-immunosuppressed patients (13%). We describe a 42-year-old male lung
      transplant recipient with serologically confirmed West Nile virus (WNV)
      encephalitis and deteriorating level of consciousness. He was treated with 0.4
      g/kg intravenous immunoglobulin preparation from Israeli donors that contained a
      high titer of anti-WNV antibodies (1 : 1600). The patient showed rapid
      improvement within 24 h and complete disappearance of signs and symptoms within
      48 h. This is the second case of an immunosuppressed patient responding to the
      same preparation of intravenous immunoglobulins. Larger studies are required in
      order to establish the therapeutic role of immunoglobulins in patients with WNF.

PMID- 12421464
TI  - Infection of central nervous system after kidney transplantation.

PMID- 12421465
TI  - Interaction of chloramphenicol and the calcineurin inhibitors in renal transplant
      recipients.
AB  - Several case reports have described a pharmacokinetic interaction between
      chloramphenicol and the calcineurin inhibitors (CNIs). Based on these reports, we
      set out to characterize the effects of chloramphenicol on cyclosporine and
      tacrolimus trough concentrations in renal transplant recipients. We
      retrospectively evaluated daily trough CNI concentrations and compared them with
      baseline CNI concentrations prior to chloramphenicol. Six adult renal or
      pancreas/kidney transplant recipients received 11 courses of chloramphenicol. Of
      these, three received cyclosporine (6 episodes) and three received tacrolimus (5
      episodes). The mean dose and duration of chloramphenicol was not significantly
      different between groups. Chloramphenicol coadministration increased mean
      cyclosporine troughs maximally by 41.3% on day 4, though overall differences were
      not significant using analysis of variance (anova). Tacrolimus trough levels
      increased to 99% above baseline on day 2, 151% on day 3, 161% on day 4, 191% on
      day 5, and to 207% on day 6 and reached statistical significance by anova (P =
      0.001). These results confirm case reports and suggest that careful trough
      monitoring should be implemented if chloramphenicol is to be used with the CNIs.

PMID- 12421466
TI  - Perceptions about prenatal care: views of urban vulnerable groups.
AB  - BACKGROUND: In the United States, infant mortality rates remain more than twice
      as high for African Americans as compared to other racial groups. Lack of
      adherence to prenatal care schedules in vulnerable, hard to reach, urban, poor
      women is associated with high infant mortality, particularly for women who abuse
      substances, are homeless, or live in communities having high poverty and high
      infant mortality. This issue is of concern to the women, their partners, and
      members of their communities. Because they are not part of the system, these
      womens' views are often not included in other studies. METHODS: This qualitative
      study used focus groups with four distinct categories of people, to collect
      observations about prenatal care from various perspectives. The 169 subjects
      included homeless women; women with current or history of substance abuse;
      significant others of homeless women; and residents of a community with high
      infant mortality and poverty indices, and low incidence of adequate prenatal
      care. A process of coding and recoding using Ethnograph and counting ensured
      reliability and validity of the process of theme identification. RESULTS:
      Barriers and motivators to prenatal care were identified in focus groups.
      Pervasive issues identified were drug lifestyle, negative attitudes of health
      care providers and staff, and non-inclusion of male partners in the prenatal
      experience. CONCLUSIONS: Designing prenatal care relevant to vulnerable women in
      urban communities takes creativity, thoughtfulness, and sensitivity. System
      changes recommended include increased attention to substance abuse
      treatment/prenatal care interaction, focus on provider/staff attitudes, and
      commitment to inclusion of male partners.

PMID- 12421467
TI  - RanBPM interacts with psoriasin in vitro and their expression correlates with
      specific clinical features in vivo in breast cancer.
AB  - BACKGROUND: Psoriasin has been identified as a gene that is highly expressed in
      pre-invasive breast cancer, but is often downregulated with breast cancer
      progression. It is currently unknown whether psoriasin influences epithelial cell
      malignancy directly or by affecting the surrounding environment. However the
      protein is found in the nucleus, cytoplasm as well as extracellularly. In the
      present study we have sought to identify potential psoriasin-binding proteins and
      to describe their expression profile in breast tumors. METHODS: The yeast two
      hybrid method was used to identify potential binding partners for psoriasin. The
      interaction of psoriasin with RanBPM was confirmed in-vitro by co
      immunoprecipitation. The expression of RanBPM and psoriasin was measured by RT
      PCR in a series of breast cell lines, breast tumors and primary lymphocytes.
      RESULTS: We have identified RanBPM as an interacting protein by the yeast two
      hybrid assay and confirmed this interaction in-vitro by co-immunoprecipitation.
      RT-PCR analysis of RanBPM mRNA expression in cell lines (n = 13) shows that
      RanBPM is widely expressed in different cell types and that expression is higher
      in tumor than in normal breast epithelial cell lines. RanBPM expression can also
      be induced in peripheral blood mononuclear cells by treatment with PHA. RanBPM
      mRNA is also frequently expressed in invasive breast carcinomas (n = 64) and a
      higher psoriasin/RanBPM ratio is associated with both ER negative (p < 0.0001)
      and PR negative status (p < 0.001), and inflammatory cell infiltrates (p <
      0.0001) within the tumor. CONCLUSIONS: These findings support the hypothesis that
      psoriasin may interact with RanBPM and this may influence both epithelial and
      stromal cells and thus contribute to breast tumor progression.

PMID- 12421468
TI  - Evidence for non-independent gating of P2X2 receptors expressed in Xenopus
      oocytes.
AB  - BACKGROUND: P2X2 receptor is an ATP-activated ion channel which is widely
      expressed in the nervous system, and mediates synaptic transmission. RESULTS: We
      recorded currents of P2X2 receptors expressed in Xenopus oocytes from outside-out
      patches and have found that currents recorded from patches containing a single or
      multiple P2X2 channels differ in a manner suggesting positive cooperativity.
      First, the currents from multichannel patches exhibit simultaneous transitions
      more frequently than predicted from the activity of independent channels. Second,
      the mean open lifetime at the current level of a single channel in a multichannel
      burst is about six times longer than the open time of currents from single
      channel patches, a trend opposite to what is expected of independent channels.
      These results indicate that the channels have positive cooperativity and that the
      longer opening is due to a slower closing rate. Third, from kinetic analysis the
      likelihood of the cooperative model is significantly larger than that of the
      independent model. Fourth, the open channel noise of currents from patches
      containing multiple channels is less than half that from a single channel, which
      is consistent with the channel properties being different when they are active in
      groups. CONCLUSION: Taken together, our results suggest that P2X2 receptors are
      non-independent, but interact with positive cooperativity.

PMID- 12421470
TI  - Effect of morphine-induced antinociception is altered by AF64A-induced lesions on
      cholinergic neurons in rat nucleus raphe magnus.
AB  - AIM: To examine the role of cholinergic neurons in the nucleus raphe magnus (NRM)
      in noxious heat stimulation and in the effects of morphine-induced
      antinociception by rats. METHODS: After the cholinergic neuron selective toxin,
      AF64A, was microinjected into the NRM, we examined changes in the antinociceptive
      threshold and effects of morphine (5 mg/kg, ip) using the hot-plate (HP) and tail
      flick (TF) tests. RESULTS: Systemic administration of morphine inhibited HP and
      TF responses in control rats. Microinjection of AF64A (2 nmol/site) into the NRM
      significantly decreased the threshold of HP response after 14 d, whereas the TF
      response was not affected. Morphine-induced antinociception was significantly
      attenuated in rats administered AF64A. Extracellular acetylcholine was attenuated
      after 14 d to below detectable levels in rats given AF64A. Naloxone (1
      microg/site) microinjected into control rat NRM also antagonized the
      antinociceptive effect of systemic morphine. CONCLUSION: These findings suggest
      that cholinergic neuron activation in the NRM modulates the antinociceptive
      effect of morphine simultaneously with the opiate system.

PMID- 12421471
TI  - Ability of sickle cells to scavenge endothelium-derived nitric oxide is reduced.
AB  - AIM: To assess the ability of sickle cells to interfere with the release or
      transfer of endothelium-derived relaxing factor (EDRF) in comparison to normal
      erythrocytes. METHODS: A perfusion-superfusion bioassay system was used a canine
      carotid artery with endothelium (donor of EDRF) and a ring of the same vessel
      without endothelium (detector) were separated by tubing resulting in a five
      second interval for transfer of EDRF from donor to detector. Changes in isometric
      tension were monitored in both the donor and the detector preparations. Release
      of EDRF, as determined by sustained relaxations during the contractions to
      phenylephrine, was induced by infusing acetylcholine through the donor artery.
      RESULTS: Superfusion with normal and sickle erythrocytes caused impairment of the
      endothelium-dependent relaxations in both detector and donor tissues. When
      infused through the transfer line, sickle cells were less potent than normal
      erythrocytes in inhibiting relaxation in the detector tissues. In contrast,
      infusion of either normal erythrocytes or sickle cell through the donor artery
      caused similar degrees of inhibition in donor and detector arteries. Hemolysates
      from both types of erythrocytes were equieffective at either site of infusion.
      CONCLUSION: These results indicate that sickle cells are intrinsically less
      potent scavengers of EDRF than normal erythrocytes. However, exposure to the
      endothelium enhances the ability of sickle cells to inhibit lumenal release of
      endothelium-derived relaxing factor.

PMID- 12421472
TI  - Activation of astrocytes by advanced glycation end products: cytokines induction
      and nitric oxide release.
AB  - AIM: To investigate whether two kinds of in vitro prepared advanced glycation end
      products (AGE), Glu-BSA and Gal-BSA, could induce proinflammatory mediators IL
      1beta and TNF-alpha, as well as oxidative stress and nitric oxide (NO), in
      astrocytes, thus contributing to brain injury. METHODS: Radioimmunoassay and RT
      PCR technique were used to detect two cytokines' level and existence of receptor
      for AGE (RAGE). DTNB reaction was used to measure reduced glutathione (GSH)
      level. NO content was assayed using Griess reagent provided by Promega. RESULTS:
      Enhanced protein levels of both cytokines in supernatants and cell lysates of
      astroglia cultures were detected after treated with AGE-BSA 1 g/L, especially Gal
      BSA, for 72 h. The increases were also in a concentration-dependent manner.
      Changes in protein levels might be attributed to changes in transcriptional
      levels documented by semi-quantitative RT-PCR. Both AGE-BSA could also reduce
      astrocytic GSH and induce NO release. RAGE was detected in astrocytes.
      CONCLUSION: Enhanced levels of astrocytic proinflammatory mediators IL-1beta and
      TNF-alpha, and oxidative stress caused by AGE might contribute to, at least
      partially, the detrimental effects of AGE in neuronal disorders and aging brain.

PMID- 12421473
TI  - Interleukin-2-induced antinociception in morphine-insensitive rats.
AB  - AIM: To investigate interleukin-2-induced antinociception in morphine-insensitive
      rats. METHODS: Paw withdrawal latencies (PWL) to noxious radiant heat were taken
      as the measurement of pain threshold. RESULTS: Intraplantar injection of human
      recombinant interleukin-2 (1.5 x10(4) U) significantly increased PWL in normal
      rats. PWL was also markedly increased by IL-2 in 45-d-post-complete Freund's
      adjuvant (CFA)-treated rats, which have been proven morphine-insensitive. IL-2
      induced antinociception in CFA-treated rats were significantly lower than that in
      normal rats. IL-2-induced antinociception was partially blocked by naloxone (1
      mg/kg, ip) in normal rats but remained unchanged in CFA group. CONCLUSION: IL-2
      induced antinociception is partially mediated by mu-opioid receptors. Therapeutic
      applications of IL-2 may also be expanded to relieve morphine-insensitive pain.

PMID- 12421474
TI  - Apoptotic effect of As2S2 on K562 cells and its mechanism.
AB  - AIM: To investigate the apoptotic effect of As2S2 on K562 cells and its
      mechanism. METHODS: The effect of As2S2 on proliferation of K562 cells was
      determined by counting the number of cells. Apoptosis was assessed by flow
      cytometry, DNA fragmentation analysis, and morphology observation. Expression of
      protein was determined by Western blot. RT-PCR was used to evaluate changes in
      gene expression. RESULTS: As2S2 greatly inhibited the proliferation and induced
      apoptosis of K562 cells in a concentration- and time-dependent manner at the
      concentration range of 1-5 micromol/L during 24-72 h. Viable cells were decreased
      to approximately 71 % of control at the concentration of 5 micromol/L after 48-h
      incubation, 31.4 % after 72-h incubation, and 45.4 % at 3 micromol/L after 72-h
      incubation. At 3 micromol/L for 72 h, 5 micromol/L for 48 h, and 5 micromol/L for
      72 h, the apoptosis rate were 34.4 %, 21.8 %, and 46 % of the treated-cells,
      respectively. As2S2 decreased the Bcr-Abl fusion protein and protein tyrosine
      kinase (PTK) activity of c-abl and Bcr-Abl, but it did not change the
      transcription of bcr-abl assayed. As2S2 also induced apoptosis in fresh
      mononuclear cells derived from chronic myelogenous leukemia (CML) patients. CML
      Ph+ leukemia cells were more sensitive to the apoptotic effect of As2S2 than Ph-
      mononuclear cells (P<0.05). CONCLUSION: As2S2 inhibited the proliferation and
      induced apoptosis in K562 and fresh CML mononuclear cells. The decline of the Bcr
      Abl protein and its PTK activity may play an important role in the apoptotic
      effect of As2S2. As2S2 may be a useful agent for the treatment of CML.

PMID- 12421475
TI  - Effect of isoverbascoside, a phenylpropanoid glycoside antioxidant, on
      proliferation and differentiation of human gastric cancer cell.
AB  - AIM: To investigate the effects of phenylpropanoid glycoside antioxidant
      isoverbascoside on cell proliferation and differentiation of human gastric cancer
      cell line MGC 803. METHODS: MGC 803 cells were treated with isoverbascoside. Its
      effects on cell proliferation, tumorigenicity, enzymatic activities, cell cycles,
      and gene expression were respectively evaluated with cell counting, tumor
      formation assay, enzymatic assay, flow cytometer analysis, and Western blotting,
      with Me2SO as positive control. RESULTS: Isoverbascoside could markedly inhibit
      cell proliferation in dose- and time-dependent manner. Isoverbascoside 20
      micromol/L strikingly suppressed cell tumorigenicity, activities of alkaline
      phosphatase (ALP), and lactate dehydrogenase (LDH), and caused G0/G1 arrest. The
      expression of G1 S checkpoint related proteins, p53, p21/WAF1, and p16/INK4, were
      up-regulated after MGC 803 cells were treated with isoverbascoside 20 micromol/L
      for 4-8 h. Contrarily, the expression of C-myc protein was suppressed after 8 h
      treatment. CONCLUSION: Isoverbascoside inhibited cell proliferation, reversed
      cell malignant phenotypic characteristics, and consequently caused
      differentiation in MGC 803 cells. These effects might be associated with its
      activities of causing G0/G1 arrest and regulating the expression of cell cycle
      related proteins.

PMID- 12421476
TI  - Effects of resveratrol and ethanol on production of pro-inflammatory factors from
      endotoxin activated murine macrophages.
AB  - AIM: To study the interaction of resveratrol and ethanol on the production of pro
      inflammatory factors from activated murine peritoneal macrophages (MPM). METHODS:
      NO production was measured with Griess assay; IL-1 production was measured
      through thymocyte co-stimulating assay; IL-6 and TNF-alpha were detected by ELISA
      method. RESULTS: Resveratrol (6.25, 12.5, 25 micromol/L) and ethanol (0.2 %, 0.8
      %) synergistically inhibited the 24 h production of NO from lipopolysaccharide
      (LPS, 1 mg/L) and IFN-gamma (5 kU/L) stimulated MPM; resveratrol at higher dose
      (25 micromol/L) also inhibited IL-6 production. Ethanol additively strengthened
      this effect. Ethanol had no significant influence on 24 h MPM IL-1 production,
      but it promoted the ability of resveratrol on enhancing the IL-1 release from
      activated MPM. Low doses of ethanol inhibited 24 h production of TNF-alpha,
      however, both dose of ethanol enhanced the promoting effect of resveratrol on TNF
      alpha production. CONCLUSION: Resveratrol and ethanol can interact to influence
      the production of macrophage function molecules, which is noteworthy in
      evaluating the health-care effect of wine consumption.

PMID- 12421477
TI  - Intracellular calcium was involved in muscarinic currents increased by
      hypoosmotic membrane stretch in gastric myocytes of guinea pig.
AB  - AIM: To investigate the role of intracellular calcium in muscarinic currents
      increased by hypoosmotic membrane stretch in gastric antral circular myocytes of
      the guinea pig. METHODS: The whole cell patch-clamp technique was used, and the
      myocytes were isolated by collagenase. Cells were swelled by hypoosmotic solution
      (200 Osmmol/kg). RESULTS: The hypoosmotic membrane stretch markedly increased
      carbachol-induced muscarinic currents (ICCh). The ICCh and the increase of ICCh
      were completely blocked by quinidine 3 micromol/L, a specific muscarinic current
      blocker. In external calcium-free solution hypoosmotic membrane stretch could not
      increase ICCh, but in the presence of nicadipine 5 micromol/L, a L-type calcium
      channel blocker or gadolinium chloride 100 nmol/L, a stretch-activated cation
      channel blocker, the ICCh was still increased by hypoosmotic membrane stretch.
      When both nicardipine and gadolinium chloride were added into external solution,
      ICCh were not increased by hypoosmotic membrane stretch any more. Ryanodine, a
      calcium-induced calcium release (CICR) agonist completely blocked hypoosmotic
      membrane stretch-induced increase of ICCh. CONCLUSION: Hypoosmotic membrane
      stretch increased ICCh and the increment was related to influx of external
      calcium and CICR.

PMID- 12421478
TI  - Inhibition of human phosphodiesterase 4A expressed in yeast cell GL62 by
      theophylline, rolipram, and acetamide-45.
AB  - AIM: To study the inductive expression of human phosphodiesterase 4A (hPDE4A) in
      yeast cell GL62 and investigate the inhibitory effects of theophylline, rolipram,
      and acetamide-45 on PDE4A activity of the expressed product in yeast cell GL62.
      METHODS: Yeast cell GL62 were transfected with human PDE4A gene cloned in the
      expression plasmid p138NB. Expression was induced by adding CuSO4 to a final
      concentration of 150 micromol/L, and the expressed product was extracted. The
      activity of PDE4A was detected by HPLC. RESULTS: Yeast cell GL62 expressed a
      certain protein at CuSO4 150 micromol/L, the size of the expressed product was
      between 62 kDa and 83 kDa, the activity of PDE4A of the expressed product at 3 h
      was in maximum (188 23) micromol/g/min, and the Km was (17.7 2.6) micromol/L.
      Theophylline, rolipram, and acetamide-45 could inhibit the activity of PDE4A
      extracted from yeast cell GL62. The IC50 (95 % confidence limits) of
      theophylline, rolipram, and acetamide-45 were 1642 (989-2727), 4.58 (3.45-6.08),
      and 275 (170-444) micromol/L respectively. CONCLUSION: PDE4A expressed in yeast
      cell GL62 is biologically active. Theophylline, rolipram, and acetamide-45 can
      inhibit the PDE4A activity. The expressed product in yeast cell GL62 may be used
      in the research work of PDE4 and its inhibitors.

PMID- 12421479
TI  - Protective effects of polypeptide from Chlamys farreri on Hela cells damaged by
      ultraviolet A.
AB  - AIM: To study the protective effect of polypeptide isolated from Chlamys farreri
      (PCF) on Hela cells damaged by ultraviolet A (UVA) in vitro. METHODS: Cell
      proliferation was determined by MTT method; intra-cellular free calcium [Ca2+]i
      and rates of apoptosis and death were measured by flow cytometry (FCM). RESULTS:
      PCF (0.5 %-2 %) enhanced the activities of glutathione peroxidase (GSH-px),
      superoxide dismutase (SOD), and catalase (CAT), and stimulated cell
      proliferation. The concentration of [Ca2+]i was increased while the amounts of
      MDA and the rates of apoptosis and death of the cells were decreased. The
      differences between the PCF groups and control group were significant (P<0.05,
      P<0.01). CONCLUSION: PCF protected Hela cells against damage by UVA via its anti
      oxidative mechanisms.

PMID- 12421480
TI  - Protective effects of apocynin on "two-hit" injury induced by hemorrhagic shock
      and lipopolysaccharide.
AB  - AIM: To evaluate the protective effects of apocynin on "two-hit" injury in rats.
      METHODS: "Two-hit" injury model of rat was induced by hemorrhagic shock (40 mmHg
      for 45 min) followed by iv administration of lipopolysaccharide (LPS, 150
      microg/kg). Rats were randomized into seven groups: Sham, LPS, hemorrhage,
      hemorrhage/LPS, and hemorrhage/LPS+apocynin (2.5, 5.0, and 10.0 mg/kg). Apocynin
      was dissolved in the resuscitation fluid (normal saline, NS) and administered iv
      for 2 h. After LPS or NS administration, the survival rates at 8 h, 16 h, 24 h,
      and 48 h were monitored. The content of malondialdehyde (MDA) was measured in
      lung at 3 h and 6 h after iv LPS and in serum before hemorrhage, after
      hemorrhage, and at 0, 0.5, 1, 2, 4, and 6 h after iv LPS. Myeloperoxidase (MPO)
      activity in lung and liver was examined at 3 h and 6 h after iv LPS/NS. RESULTS:
      After "two-hit" injury, the survival rates of rats at 8 h, 16 h, 24 h, and 48 h
      were 64.3 %, 35.7 %, 28.6 %, and 14.3 % respectively, there were significant
      differences as compared to sham group (P<0.05 or P<0.01, respectively), the MDA
      level in lung and serum were significantly enhanced (P<0.01) as compared to sham
      group, and MPO activity in lung and liver after "two-hit" injury was also
      significantly increased (P<0.01). Apocynin treatment enhanced the mean arterial
      pressure (MAP) of hemorrhagic shock rats dose-dependently (P<0.05), increased the
      survival rate of "two-hit" injury rats, decreased the serum and lung MDA content,
      and downregulated MPO activity in lung and liver. CONCLUSION: Apocynin could
      preventively ameliorate "two-hit" injury in rats induced by hemorrhagic shock and
      LPS insult.

PMID- 12421481
TI  - Developmental toxicity of cocaine exposure in mid-pregnancy mice.
AB  - AIM: To investigate the toxic effects of mid-pregnancy cocaine exposure on embryo
      fetus. METHODS: A transplacental murine model of cocaine exposure on embryo-fetus
      mice was established, in which pregnant dams of comparable weight were assigned
      into three groups: cocaine with food ad lib (COC), saline and pair-fed with COC
      (SPF), and saline with food ad lib (SAL). From embryonic d 8 (E8) to E17,
      physiological variables of dams and offspring were recorded and concentrations of
      dopamine and serotonin in fetal striatum were examined. RESULTS: Compared with
      SAL dams, COC and SPF dams showed lower weight gain. But only COC fetuses
      demonstrated low brain weight and low striatum weight on E17, as well as small
      biparietal diameter (BPD) on postnatal d1 (P1). Surprisingly, low brain/body
      weight ratio was seen in COC offspring, which might reflect disproportionate
      growth delay in these fetuses. Neurotransmitter and histological analysis
      revealed high level of dopamine and serotonin in COC fetal striatum, as well as
      morphological alterations of liver. CONCLUSION: Mid-pregnancy cocaine exposure
      induces fetal growth delay in utero, especially disproportionate brain
      developmental retardation. Maternal undernutrition does not play a key role in
      fetal developmental retardation when exposed to cocaine in utero.

PMID- 12421482
TI  - Effects of pollen extract EA-10, P5 on chronic prostatitis or infertility with
      chronic prostatitis.
AB  - AIM: To determine the drug action mechanism of pollen extract EA-10, P5 on the
      treatment of chronic prostatitis (CP) or infertility with CP. METHODS:
      Malondiadehyde (MDA), superoxide dismutase (SOD), and nitrogen monoxide (NO) were
      measured by biochemical assay, and zinc content was assayed by atomical
      spectrophotography in the pre-treatment and post-treatment of CP or infertility
      with CP. RESULTS: Compared with control group, leukocytes in expressed protatic
      secretion (LEPS), MDA, and NO were increased, and zinc content and SOD were
      decreased significantly in the pre-treatment of CP. After the treatment, LEPS was
      improved, and MDA and NO were reduced, while zinc content were increased
      apparently and the alteration of SOD was not evident (P>0.05). In the pre
      treatment of infertility with CP, LEPS, MDA, NO, sperm viability, and seminal
      leukocytes were obviously higher and seminal plasma SOD, zinc content, and sperm
      motility were obviously lower than those in control group. After the treatment,
      LEPS, sperm motility, and sperm viability were improved, MDA, NO, and seminal
      leukocytes were decreased, SOD and zinc content were increased markedly.
      CONCLUSION: There was inter-correlation between oxygen free radicals (OFR) and
      occurrence, development, and recovery of CP; Change of OFR may be involved in the
      drug action mechanism of EA-10, P5 in the treatment of CP or infertility with CP.

PMID- 12421483
TI  - Effect of CYP2D6*10 genotype on propafenone pharmacodynamics in Chinese patients
      with ventricular arrhythmia.
AB  - AIM: To determine the effect of CYP2D6*10 genotype on propafenone
      pharmacodynamics in Chinese patients with ventricular arrhythmia. METHODS:
      Seventeen Chinese patients with ventricular premature contractions (VPC> or
      =1000/d) were recruited. They were normal in routine laboratory testing and
      administered propafenone hydrochloride 450-600 mg per day in three divided doses.
      Twelve lead cardiogram and 24 h Holter monitoring were performed before and after
      7 d treatment of propafenone. Steady-state peak and trough concentrations of
      propafenone were measured by HPLC method. CYP2D6*10 genotypes of patients were
      assayed by polymerase chain reaction (PCR) and restriction fragment length
      polymorphism (RFLP). RESULTS: Total inhibitory rate of VPC was 79.9 % in 17
      patients with ventricular arrhythmia after propafenone treatment. PR interval
      prolongation was increased from 0.146 s+/-0.018 s to 0.161 s+/-0.022 s (P<0.05).
      CYP2D6 genotypes played an important role in plasma levels and effects of
      propafenone. In 450 mg/d group, patients with homozygous mutant of CYP2D6*10 not
      only had a Cmax of propafenone two times as high as those of wild-type genotype,
      but also showed a two fold higher inhibitory rate of VPC compared with those with
      homozygous CYP2D6*1 (P<0.05). CONCLUSION: CYP2D6*10 genotype is relevant to
      decreased activity of CYP2D6 enzyme in Chinese patients. Elevated plasma
      concentration is consistent with better efficacy of propafenone in patients with
      ventricular arrhythmia.

PMID- 12421484
TI  - Identification of guanfu base A hydrochloride phase I and phase II metabolites in
      rat bile by liquid chromatography mass spectrometry.
AB  - AIM: To study metabolites of guanfu base A hydrochloride (GFA) in rat bile.
      METHODS: An analytical method was developed to identify guanfu base A and its
      metabolites by liquid chromatography mass spectrometry (LC-MS) and electrospray
      ionization tandem mass spectrum (MS-MS). Rat bile was collected after iv
      injection of GFA. Phase I metabolite was identified by comparison with authentic
      standard for their retention time, molecular ion peaks, fragment ions, and UV
      spectrums. In order to identified Phase II conjugates, the aglycones were
      identified after rat bile was treated with either glucuronidase or sulfatase
      firstly. Phase II conjugates were also separated and determined for their
      molecular ions by LC-MS, at last they were verified by identifying characteristic
      product ions or precursor ions by MS-MS. RESULTS: Phase I metabolite, guanfu base
      I (GFI), was identified in rat bile. After phase II conjugates were treated with
      glucuronidase or sulfatase, GFA and GFI occurred in chromatograms. Quasi
      molecular ions m/z 606 and 510 were separated and detected in rat bile. They were
      indicated to be GFA glucuronide and GFA sulfate, respectively. Furthermore, GFA
      glucuronide was confirmed to exist in rat bile by identifying two characteristic
      ions, m/z 177, [M+H]+ of glucuronic acid, and m/z 430, [M+H]+ of GFA, as product
      ions of m/z 606. CONCLUSION: Phase I metabolite GFI and phase II conjugates, GFA
      glucuronide and sulfate, GFI glucuronide and sulfate, were identified in rat
      bile.

PMID- 12421485
TI  - Relationship between drug effects and particle size of insulin-loaded bioadhesive
      microspheres.
AB  - AIM: To formulate and characterize insulin-loaded adhesive microspheres (MP) and
      evaluate drug effects of MP with various sizes, 120, 350, and 1000 nm in
      diameter, in the alloxan-induced diabetic rats. METHODS: Insulin-loaded MP were
      formulated by an ionotropic gelation procedure. Particle size distributions were
      determined by photon correlation spectroscopy and optical microscopy. The factors
      that influenced the particle sizes and loading capacity were investigated, and
      the release properties were assessed in vitro. The hypoglycemic effect was
      investigated by monitoring the plasma glucose level of the alloxan-induced
      diabetic rats after oral administration. RESULTS: All the MPs with three sizes
      formulated were in the desired size range, and the loading capacity was 15.3 %+/
      1.7 % (120 nm), 32.4 %+/-2.4 % (350 nm), and 53.3 %+/-2.7 % (1000 nm)
      respectively. The particle size also had an influence on the release property of
      the MPs. Half an hour later, 25 %+/-4 % (120 nm), 18.3 %+/-2.4 % (350 nm), and
      8.6 %+/-1.3 % (1000 nm) of insulin were released. MP with different sizes had
      various degree of hypoglycemic effects after 10 h (P<0.05 vs control insulin
      solution). The plasma glucose level of 350 nm size particles remarkably decreased
      15 h later (P<0.05 vs 120 nm) or 35 h later (P<0.01 vs others). The relative
      pharmacological availability was 10.2 %+/-0.5 % (120 nm), 14.9 %+/-1.3 % (350
      nm), and 7.3 %+/-0.8 % (1000 nm) respectively. Particles of 350 nm showed a
      comparatively higher availability (P<0.05). CONCLUSION: Adhesive CS-MP were
      helpful in increasing the relative pharmacological bioavailability of insulin,
      and a distinct advantage of proper particle size helped to increase the drug
      effects.

PMID- 12421486
TI  - [Clinical features of Crohn's disease: its diagnosis and treatment].
AB  - OBJECTIVE: To enhance our understanding of Crohn's disease and improve its early
      diagnostic accuracy and therapeutic efficacy. METHODS: Thirty-one patients with
      active Crohn's disease were studied. All their diagnostic and therapeutic results
      were analyzed. RESULTS: Most patients were young adults, with a 1.14:1 female
      predominance in prevalence. The disease affects any segment or a combination of
      segments of the alimentary tract from the mouth to the anus. However, the colon
      and the small bowel were the major sites involved. Recurrent episodes of
      abdominal pain and watery diarrhea were the most common symptoms. In addition,
      low grade fever, emaciation, anemia, and symptoms with skin, joints or perianal
      complications could be discovered if attention was paid. An endoscopy combined
      with histologic examination in biopsy specimens provided characteristic features
      with a diagnostic accuracy of 62.9%. Granulomas were identifiable in 30.8% of all
      biopsy specimens. Transabdominal bowel sonography (TABS) accurately detected
      intestinal complications. Factors causing misdiagnosis were: insufficient
      attention of the disease, diverse clinical presentations, or over emphasis of the
      diagnostic value of granulomas. Oral prednisone therapy for mild to moderate
      disease was more rapid to receive clinical remission when compared to oral
      aminosalicylates (SASP or 5-ASA). Nutrition support therapy was given in 20 cases
      with active disease and received beneficial effects on host nutritional status.
      Immunosuppressives were used on an individual basis, and showed variable effects
      with limited experience. Sixteen patients had operations due to intestinal
      obstruction or failure to respond to drug therapies. Rapid improvement after
      operations was achieved. CONCLUSIONS: Crohn's diseases not uncommon in China.
      Abdominal pain and watery diarrhea are two hallmark symptoms. Endoscopy (with
      biopsy), and TABS were both valuable procedures for diagnosis. Prednisone and
      SASP/5-ASA were effective as inductive therapies. Surgery, as an alternative and
      effective treatment, provided another choice in well selected patients.

PMID- 12421487
TI  - [Analysis of a family pedigree with primary shunt hyperbilirubinaemia].
AB  - OBJECTIVE: To identify whether primary shunt hyperbilirubinaemia is a genetic
      disorder or not and the pattern of the inheritance. METHOD: Clinical case data
      were studied with analysis of family pedigree of a case. RESULTS: Although the
      patient with primary shunt hyperbilirubinaemia presented an elevated unconjugated
      serum bilirubin, anemia and splenomegaly, the patient also presented decline of
      amount of peripheral white cells and normal amount of reticulocytes. The mature
      erythrocytes in peripheral blood and bone marrow were irregular in shape and
      size. There were also some target-, rod-, and mouth-shaped peripheral red cells
      in blood smear. With analysis of family pedigree, we can find that there were
      some patients with the primary shunt hyperbilirubinaemia in every generation of
      the family with equal distribution in male and female. The pattern of inheritance
      was transmitted from one generation to the next generation directly. Almost any
      manifestation of the disease may be found in adult patients, but the severity of
      the disorder was not the same among these patients. CONCLUSIONS: The primary
      shunt hyperbilirubinaemia is a genetic disease; its pattern of inheritance is
      autosomal dominant. It is suggested that the disease of primary shunt
      hyperbilirubinaemia could be renamed as hereditary shunt hyperbilirubinaemia.

PMID- 12421488
TI  - [The short term effect of rabeprazol versus omeprazole on symptom relief of
      duodenal ulcer].
AB  - OBJECTIVE: To evaluate the therapeutic effect on duodenal ulcer symptoms and
      safety of rabeprazol as compared with omeprazole. METHODS: This is a multicenter,
      randomized, double-blind, controlled trial. Patients with active duodenal ulcer
      were divided into group A treated with rabeprazole 10 mg/day and group B treated
      with omeprazole 20 mg/day. The duration of treatment was 7 days in both groups.
      All the symptoms including abdominal pain, acid regurgitation, belching and
      abdominal bloatness were evaluated before and during the treatment. RESULTS: All
      patients enrolled in group A (108 cases) and group B (103 cases) went through the
      study. Between the two groups, there were no differences in the mean time of
      partial and complete pain relief rates every day. The partial pain relief rate on
      day one was higher in group A (56%) than that in group B (33%, P < 0.05). On day
      seven, acid regurgitation relief rate was higher in group A than that in group B
      (100% and 83%, respectively, P < 0.05). No significant difference in the rate of
      partial pain relief and acid regurgitation on the other days of the treatment.
      The relief rate of abdominal bloatness and belching everyday in the two groups
      were similar. No adverse events took place in both groups. CONCLUSIONS:
      Rabeprazole (10 mg/day) has excellent therapeutic effect on the symptoms of
      duodenal ulcer patients. The effects on the relief of pain and acid regurgitation
      are better than those of omeprazole. Rabeprazole for short term using is safe.

PMID- 12421489
TI  - [A study of coronary artery involvement in aortitis].
AB  - OBJECTIVE: To investigate the clinical features, treatment and prognosis of
      coronary artery involvement resulting from aortoarteritis and discuss the
      potential difficulties in the diagnosis and treatment of the disease. METHODS: Of
      121 consecutive hospitalized patients with aortoarteritis from 1998 to 2001, the
      patients, who were found to have more than 50% diameter reduction of coronary
      artery by angiography because of clinically suspected coronary artery
      involvement, were studied retrospectively. RESULTS: In the study, there were
      totally 10 cases with coronary artery involvement of aortoarteritis, which
      accounted for 8.26% (10/121) of all the hospitalized patients with
      aortoarteritis. Nine of the 10 cases were female, aged 19 - 45 (31 +/- 9) years.
      There were evidences of peripheral arterial lesions and angina pectoris in all
      the cases. Of the 10 cases, 7 had abnormal electrocardiography and 5 abnormal
      echocardiography. Aortic root angiography or coronary angiography was the most
      useful tool for definitive diagnosis. Coronary ostia were most frequently
      involved. Coronary revascularization improved angina pectoris in most of the
      patients. However, the long-term efficacy and survival rate should be
      investigated further. CONCLUSION: Coronary artery may be involved in
      aortoarteritis. Appropriate measurements should be taken to detect and to treat
      the lesion.

PMID- 12421490
TI  - [A study on the diagnosis and etiology of cerebral venous thrombosis].
AB  - OBJECTIVE: To determine the clinical characteristic and common etiologies of
      cerebral venous thrombosis (CVT) in China. METHODS: Clinical and neuroimaging
      data of 91 cases of CVT were analyzed retrospectively. RESULTS: 91 CVT patients
      (49 men, 42 women), aged from 9 to 57 years, were diagnosed with MRI (78 cases,
      85.71%), MRA (37 cases, 40.66%) or DSA (32 cases, 35.16%). 27 cases (29.67%) had
      a clinical pattern of isolated intracranial hypertension, 56 cases (61.54%) of
      focal deficits and/or seizures, 3 cases of subacute encephalopathy and 5 cases of
      cavernous sinus thrombosis. Oral contraceptive was the most common cause, being
      found in 12 cases (13.19%). CONCLUSIONS: Understanding of the clinical
      characteristics of CVT and using of MRI and MRA examination as early as possible
      is the key in CVT diagnosis. Oral contraceptive is the most common etiology.

PMID- 12421491
TI  - [The effect of cyclin kinase inhibitor p27 on tumor necrosis factor-alpha induced
      mesangial cell proliferation].
AB  - OBJECTIVE: To investigate the role of cyclin kinase inhibitor p27 on
      proliferation of mesangial cell (MC) induced by tumor necrosis factor-alpha (TNF
      alpha). METHODS: p27 protein of MC lysate was detected with Western blotting
      analysis. The degree of MC proliferation was estimated through [(3)H] thymidine
      incorporation. The effect of reducing p27 expression on MC proliferation was
      analysed with p27 antisense oligodeoxynucleotide (ODN) phosphorothioate. RESULTS:
      TNFalpha (200 000 U/L) decreased p27 level to 0.6 +/- 0.1 from 1.1 +/- 0.1 of MC
      lysate cultured in serum-free DMEM for 24 hours (P < 0.01) and increased [(3)H]
      thymidine incorporation to 2 060 +/- 112 from 685 +/- 53 cpm/well (P < 0.01). p27
      antisense ODN transfection decreased p27 level of MC stimulated by TNF-alpha for
      24 hours (0.3 +/- 0.1 vs 0.6 +/- 0.1, P < 0.01) and increased [(3)H] thymidine
      incorporation (2 420 +/- 130 vs 2 060 +/- 112 cpm/well, P < 0.05) in 24 hours of
      culture. CONCLUSION: The decline of p27 protein may play an important role in MC
      proliferation induced by TNF-alpha. Because the cell cycle is controlled by the
      interplay between the positive cell cycle regulatory proteins (CCRP) and negative
      CCRP, further research is needed to study the expression of the positive and
      negative CCRP in MC in order to understand better the role of CCRP in MC
      proliferation.

PMID- 12421492
TI  - [Analysis of sister chromatid differentiation in myelodysplastic syndrome and its
      clinical application].
AB  - OBJECTIVE: To verify the value of sister chromatid differentiation (SCD) analysis
      of bone marrow cells in establishing the diagnosis and predicting prognosis of
      myelodysplastic syndrome (MDS). METHODS: S-bromodeoxyuridine-SCD and karyotyping
      studies were performed in 50 cases with clinically suspected MDS. RESULTS:
      Prolonged cell cycle time (CT) was found in 33 of the 50 cases (66.0%). In 13
      cases with acute myeloid leukemia (AML), all had prolonged CT. However, only 2
      (10.5%) of the 19 cases with nonmalignant hematological disorders had prolonged
      CT. There were significant differences of CT between the cases with MDS and those
      with AML, aplastic anemia (AA) and benign hypercellular anemias as well as
      healthy individuals. However, there were no significant differences between
      healthy individuals and cases with AA and, with benign hepercellular anemia. CT
      gradually prolonged during the evolution of MDS. 24 of the 50 patients (48.0%)
      were found to have clonal chromosomal abnormalities. In seven cases not
      compatible with MDS according to FAB criteria, six were found to have clonal
      chromosomal abnormalities. The mortality rates were 11.8 and 50.0% in the groups
      of normal SCD and of prolonged SCD, respectively (P < 0.05). The rates of
      leukemia transformation in both the groups were 5.9% and 16.7% (P > 0.05). The
      median survival of both the groups was 12 months and 8 months (P = 0.051).
      CONCLUSION: SCD analysis is valuable for establishing the diagnosis and
      predicting the prognosis of MDS.

PMID- 12421493
TI  - [The effect of inhibiting nuclear factor-kappa B on the diabetic nephropathy].
AB  - OBJECTIVE: To investigate the effect of inhibiting nuclear factor-kappa B (NF
      kappaB) on diabetic nephropathy (DN) and mRNA expression of fibronectin (FN) in
      diabetic kidneys. METHODS: Male Wistar rats were divided into 3 groups: group A
      (n = 11) the normal rats, group B (n = 11) the diabetic rats without any therapy,
      and group C (n = 9) the diabetic rats treated with pyrrolidine dithiocarbamate
      (an inhibitor of NF-kappaB). At the end of 18th week, the kidneys were taken out
      from all the rats to measure the NF-kappaB activity by electrophoretic mobility
      shift assays (EMSA) and the mRNA expression of FN by reverse transcript (RT)-PCR,
      as well as to observe the glomerular basement membrane (GBM) thickening and
      mesangial matrix (MM) density (MM area/mesangial area) by electronic microscope.
      24 hour urine was also collected to measure the levels of albumin (urine albumin
      excretion, UAE). RESULTS: NF-kappaB activity of renal tissue in group B [(1.85 +/
      0.54) x 10(6)] was significantly higher than that in group A [(0.07 +/- 0.11) x
      10(6), P < 0.01] and the activity in group C [(0.25 +/- 0.25) x 10(6)] lower than
      that in group B (P < 0.01). Compared with those in group A, the UAE [(2.18 +/-
      1.98) mg vs (0.41 +/- 0.47) mg, P < 0.01], the GBM thickening [(531.6 +/- 107.6)
      nm vs (312.4 +/- 25.4) nm, P < 0.01] and the MM density (56.41 +/- 6.78) in group
      B were significantly higher. The UAE [(0.56 +/- 0.72) mg], the GBM thickening
      [(315.8 +/- 21.4) nm] and the MM density (37.97 +/- 7.37) in group C were
      significantly lower than those in group B (all were P < 0.01). The renal mRNA
      expression of FN in group B (0.73 +/- 0.26) was significantly higher than that in
      group A (0.31 +/- 0.15, P < 0.01), while the expression in group C (0.26 +/-
      0.06) was lower than that in group B (P < 0.01). CONCLUSION: NF-kappaB is
      activated in the diabetic kidneys. The inhibition of NF-kappaB can slow down the
      development of DN and decrease the mRNA expression of FN in diabetic kidneys. Our
      data suggest that NF-kappaB may play an important role in the development of DN.

PMID- 12421494
TI  - [The diagnostic value of polymerase chain reaction for the detection of
      Pneumocystis carinii DNA from induced sputum samples].
AB  - OBJECTIVES: To evaluate the diagnostic value of PCR for detection of Pneumocystis
      carinii DNA from induced sputum samples. METHODS: P. carinii cysts or
      trophozoites were detected in induced sputa by Giemsa stain or Gomori Methenamine
      silver (GMS) stain. A fragment of the Pneumocystis carinii mitochondrial large
      subunit rRNA gene was amplified from sputum samples using a one-step PCR method
      with mt-rRNA primers. RESULTS: In this study, sputum samples from 16 patients
      with a clinical diagnosis of Pneumocystis carinii pneumonia (PCP) and 20 patients
      with other respiratory infections were first tested by cytochemical staining.
      Pneumocystis carinii was detected in 8 and 0 sputum samples from the two groups,
      respectively. The sensitivity and specificity of cytochemical stain were 50% and
      100%. With the one-step mt-rRNA-PCR method, Pneumocystis carinii DNA was detected
      in 14 and 0 sputum samples from 16 PCP patients and 20 non-PCP patients. The
      sensitivity and specificity of mt-rRNA-PCR was 88% and 100%, respectively.
      CONCLUSIONS: The specificity of both Giemsa and GMS staining of induced sputum
      samples is high and the methods are simple, but the sensitivity is low. The
      sensitivity of PCR for P. carinii DNA from induced sputum samples is
      significantly higher than cytochemical stains, and the method is highly specific
      when used in the clinical diagnosis of PCP.

PMID- 12421495
TI  - [Familial membranous nephropathy: an analysis of 3 kindreds and literature
      review].
AB  - OBJECTIVE: To report three kindreds of familial membranous nephropathy and
      describe its clinical and pathological characteristics. METHODS: 6 patients with
      renal biopsy proved familial membranous nephropathy from 3 kindreds were
      described. Their clinical and pathological data were compared with 33 patients
      who were also suffering from familial membranous nephropathy from 16 kindreds
      documented in PubMed and 30 sporadic patients who were collected in our hospital
      with membranous nephropathy. RESULTS: Compared with the patients documented in
      the literatures, the patients were older and the ratios of male and female
      patients in this series were equal. In both series, the pathological lesions were
      severe. Compared with sporadic patients with membranous nephropathy, the patients
      in familial form had severer pathological lesions. There were no differences
      among all patients in clinical manifestations, such as proteinuria, hypertension
      and renal function. The major clinical symptom in familial membranous nephropathy
      patients was nephritic syndrome. CONCLUSIONS: The present study first reported
      the kindreds of familial membranous nephropathy in China. The clinical
      manifestations of familial membranous nephropathy in our patients, as well as in
      other familial cases reported to date, are similar with those in the non-familial
      membranous nephropathy patients, but the pathological changes in the familial
      cases were severer than those in the non-familial. To distinguish the familial
      form from idiopathic membranous nephropathy, it is essential to understand the
      genetic factors underlying this disease.

PMID- 12421496
TI  - [Association of ecNOS 4 b/a polymorphism and end-stage chronic renal failure].
AB  - OBJECTIVE: To examine the association between insertion/deletion polymorphism in
      intron 4 of ecNOS gene (ecNOS 4 b/a) and end-stage chronic renal failure (ESCRF)
      in Han people in Tianjin, China. METHODS: The genotypes of ecNOS 4 b/a
      polymorphism were detected by PCR-minisatellite DNA detection technique. 67 CRF
      patients on hemodialysis were included in the study group, with 70 healthy
      volunteers as controls. RESULTS: (1) The genotype frequencies were 79.1%, 19.4%
      and 1.5% in the patients and 91.4%, 8.6% and 0% in the controls for bb, ba and aa
      genotypes, respectively. (2) The allele frequencies were significantly different
      between the patients and controls (chi(2) = 4.617, P < 0.05). The a/(a + b) odds
      ratio (OR, 95% confidence interval) of the patients vs controls was 2.64 (1.09,
      6.43) (Z = 2.14, P < 0.05). (3) The average age of the patients with allele a was
      47.43 +/- 11.63, while that without allele a was 58.08 +/- 13.68. The difference
      was significant, t = 2.664 (P < 0.01). (4) The frequency of allele a is lower in
      Han people of Tianjin (4.3%) than that in Japanese (10.1%) (chi(2) = 4.898, P =
      0.027). CONCLUSIONS: (1) The frequency of allele a is lower in Han people of
      Tianjin than that in Japanese and Westeners; (2) ecNOS 4 b/a polymorphism is
      associated with ESCRF in Han population of Tianjin and allele a is associated
      with the increased risk of ESCRF.

PMID- 12421497
TI  - [The role of hyperhomocysteinemia on atherosclerosis in patients with chronic
      renal failure].
AB  - OBJECTIVE: To determine whether atherosclerosis may be accelerated by
      hyperhomocysteinemia in patients with chronic renal failure (CRF). METHODS: One
      hundred and ninety-seven CRF patients and 53 healthy volunteers were included in
      this study. Plasma total homocysteine (tHcy) levels were measured by using
      fluorescence polarization immunoassay. Intima-media thickness (IMT) and
      prevalence atherosclerotic plaques of the extracranial common carotid artery were
      determined by high-resolution B-mode ultrasonography. The changes in brachial
      artery diameter during reactive hyperemia (D(h)) and after administration of
      sublingual nitroglycerin (D(n)) were analyzed during ultrasonic examination.
      RESULTS: The prevalence of hyperhomocysteinemia was 84.4% in the CRF patients.
      The mean level of tHcy (23.56 +/- 11.91) micro mol/L was significantly higher in
      the CRF patients than that in the healthy controls (7.97 +/- 2.65) micro mol/L (P
      < 0.01). The prevalence of atherosclerotic plaques and the mean IMT value of
      carotid artery were significantly increased in CRF patients compared with that in
      age-matched controls. Furthermore, arterial dilating function sush as D(h) and
      D(n) was significantly decreased in CRF patients [(D(h)) (4.05 +/- 3.81)% and
      (D(n)) (4.94 +/- 4.28)%] compared with that in controls [(D(h)) (8.81 +/- 6.15)%
      and (D(n)) (11.72 +/- 7.64)%] (P < 0.01). The levels of plasma tHcy were coherent
      with intensity of atherosclerosis in the CRF patients. Multiple stepwise
      regression analysis showed that in CRF patients, independent risk factors
      associated with value of IMT were level of tHcy, age, and duration of dialysis
      (RR = 0.484, P < 0.001), while those associated with D(h) arterial dilatation
      were plasma tHcy level, age, duration of dialysis and total cholesterol (RR =
      0.263, P < 0.001) and those associated with D(n) were age and tHcy level (RR =
      0.211, P < 0.001). CONCLUSION: The results indicate that atherosclerosis and
      dysfunction of arterial vasodilation in CRF patients are associated with increase
      of plasma tHcy. Hyperhomocysteinemia may be an independent risk factor for
      atherosclerosis seen in CRF patients.

PMID- 12421498
TI  - [Methylenetetrahydrofolate reductase gene polymorphism and plasma homocysteine
      levels in hemodialysing patients].
AB  - OBJECTIVE: To study the influence of mutation of 677 C to T in the
      methylenetetrahydrofolate reductase (MTHFR) gene on the plasma total homocysteine
      (tHcy) levels in hemodialysis patients. METHODS: The study population included 40
      healthy subjects and 53 patients with end-stage renal disease (ESRD) undergoing
      hemodialysis. C 677 T transition in the MTHFR gene was detected by Hinf 1
      restriction enzyme analysis. Plasma tHcy concentrations were determined by HPLC
      with fluorescent detection. Serum folate and vitamin B(12) levels were measured
      with chemiluminescent immunoassay. RESULTS: The allelic frequency of the 677 C to
      T transition in the MTHFR gene in hemodialysis patients was 52.8% versus 53.8% in
      healthy controls. The mean tHcy level was significantly higher in hemodialysis
      patients than that in control subjects (38.68 micro mol/L versus 15.47 micro
      mol/L, P < 0.01). The folate and vitamin B(12) concentrations were higher in
      patients than those in controls. There was a significant influence of the +/+
      genotype, folate and vitamin B(12) status on plasma tHcy level. CONCLUSION: It is
      demonstrated that the extent of hyperhomocysteinemia in hemodialysis patients is
      not only the result of impaired metabolism and elimination of Hcy in uremia, but
      is also genetically determined by the MTHFR genotype. Folate and vitamin B(12)
      status also influences the homocysteine concentration of hemodialysis patients.

PMID- 12421499
TI  - [The association between uric acid and coronary heart disease].
AB  - OBJECTIVE: To determine the association between uric acid and coronary artery
      disease (CAD) and whether the relationship is gender dependent. METHOD: A cross
      sectional study of 355 men and women with or without CAD was performed. Coronary
      artery angiography was done for all the subjects. Patients treated with
      diuretics, isopurinol, aspirin, lipid-lowering agents and heparin and patients
      with renal, hepatic, or thyroid diseases were excluded. Gender, age, body mass
      index, fasting plasma glucose, total cholesterol, triglyceride, high-density
      lipoprotein cholesterol, low-density lipoprotein cholesterol, fibrinogen,
      cigarette smoking consumption, CAD family history, essential hypertension history
      and CAD severity were analyzed. Cigarette smoking consumption was graded as
      follows: 0: no smoking, 1: </= 5 pack-year, 2: 5 to 10 pack-year, 3: greater than
      10 pack-year. CAD severity was scored angiographically as follows: 0 (absent): no
      evidence of CAD; 1 (mild): 1-vessel disease with < 50% stenosis; 2 (moderate): 1
      vessel disease with >/= 50% stenosis, or 2-vessel disease, both vessels with <
      50% stenosis or 1 with < 50% and the other with > 50% stenosis, or 3-vessel
      disease, all with < 50% stenosis; 3 (severe): 2-vessel disease, both with > 50%
      stenosis, or 3-vessel disease with >/= stenosis in one vessel > 50%. RESULTS: The
      upper uric acid qunrtiles in the women group were associated with higher CAD
      severity than the lower uric acid qunrtiles. The mean CAD severity score
      according to the uric acid qunrtiles were 2.10 (uric acid 163 approximately 217.5
      micro mol/L) 2.27, (uric acid 218.0 approximately 276.0 micro mol/L) 2.36 (uric
      acid 277.0 approximately 335.0 micro mol/L) and 2.62 (uric acid 336.0
      approximately 694.0 micro mol/L). No such relation was found in men. With
      multiple logistic regression, gender (B = 0.924, P = 0.012, OR = 2.520), fasting
      plasma glucose (B = 0.391, P = 0.006, OR = 1.478), fibrinogen (B = 0.007, P =
      0.000, OR = 1.007) and cigarette smoking consumption grading (B = 0.306, P =
      0.018, OR = 1.358) were independently associated with CAD, there was a trend
      association between age and CAD (B = 0.032, P = 0.056, OR = 1.032), Uric acid (B
      = 0.002, P = 0.349, OR = 0.998) and other variables did not have significant
      independent association with CAD. With stepwise multiple regression analysis,
      fibrinogen, fasting plasma glucose, total cholesterol, gender, age showed
      significant independent association with CAD severity, but uric acid (B = 0.004,
      beta = 0.025, t = 0.373, P = 0.709) and other variables did not. In the female
      group, CAD or CAD severity was independently associated with triglyceride and
      fibrinogen, but not with uric acid. CONCLUSIONS: The upper uric acid qunrtiles in
      the women group have higher CAD severity than the lower uric acid qunrtiles.
      However, with multiple regression, either in women or in men, uric acid was not
      independently associated with CAD or CAD severity.

PMID- 12421500
TI  - [Screening and analysis of early cardiopathology-related gene in type 2 diabetes
      mellitus].
AB  - OBJECTIVE: To screen and analyze early cardiopathology related gene in type 2
      diabetes mellitus (DM). METHODS: (1) To develop a rat model of type 2 DM, SD rats
      were injected with streptozotocin (STZ, 15 mg/kg) after high caloric diet had
      been given for two months. (2) After establishment of the model for half a month,
      one and a half month and six months respectively, dissected myocardium was
      observed under electron microscope. (3) After establishment of the model for half
      a month, myocardium was analyzed with fluorescence labelled mRNA differential
      display. Positive clones were BLAST after conformed by Northern blot. Via the
      application of bioinformatics, the function and structure of unknown sequences
      were predicted. RESULTS: (1) The model of type 2 DM developed with the character
      of lightly impaired islet function and insulin resistance. (2) Diabetic
      cardiomyopathy was verified by the ultrastructural change of myocardium which
      became serious with time. (3) Screened and conformed clones were muscle carnitine
      palmitoyltransferase 1 and 8 and novel sequences were named DCM1, 2, 5, 6, 8, 11,
      12, 16, which had been submitted to Genbank. DCM 5 was predicted to play a role
      of catalysis or signal conduction via the application of bioinformatics.
      CONCLUSIONS: The altered mRNA expression of these genes suggested that they were
      candidates for a role in the development of cardiopathy prior to the
      ultrastructural alterations of myocardium. The change of key enzyme in energy
      metabolism may be the initial factor during heart functional disorder. Further
      investigation was required for reverse intervention of diabetic cardiopathy in
      early period.

PMID- 12421501
TI  - [Antisense inhibition of cyclooxygenase-2 reduces malignant phenotype of gastric
      cancer cells].
AB  - OBJECTIVE: To investigate the role of cyclooxygenase-2 (COX-2) in tumorigenesis
      of gastric cancer, and the introduction of into human gastric cancer cells to
      suppress COX-2 expression. METHODS: The high COX-2 expressing human gastric
      cancer cell line SGC 7901 was stably transfected with the COX-2 antisense
      recombinant vector and plain vector (named as 7901-AS and 7901-P cells). The COX
      2 expression levels in transfected cells were detected by immunocytochemistry and
      dot blotting methods. Proliferation and tumorigenic ability of transfected (7901
      AS, 7901-P) and control (SGC 7901) cells were evaluated in vitro with MTT assay
      and in vivo with nude mice. RESULTS: Antisense treatment for COX-2 gene
      significantly reduced the expression level of COX-2 protein and mRNA and led
      inhibition of proliferation in 7901-AS cells. The tumor graft of 7901-AS in nude
      mice 30 days after implantation had less volume and weight than that of SGC7901
      and 7901-P [(486.67 +/- 15.28) mg vs (826.67 +/- 77.67) mg and (776.67 +/-
      300.06) mg, P < 0.01]. CONCLUSIONS: Overexpression of COX-2 in human gastric
      cancer cell line SGC 7901 was related to the malignant phenotype of cancer cells.
      Inhibition of COX-2 expression by antisense technique could reverse malignant
      phenotypes of gastric cancer cells.

PMID- 12421502
TI  - [The relationship between GSTM1, GSTT1 gene polymorphisms and susceptibility to
      sporadic colorectal adenocarcinoma].
AB  - OBJECTIVE: To analyse the association genetic polymorphisms of glutathione S
      transferase (GST) M1 and T1 with genetic susceptibility to sporadic colorectal
      adenocarcinoma (SCRAC). METHODS: All subjects are unrelated the Han people in
      Hubei province of China. Using multiple PCR, we studied the genetic polymorphisms
      of the GSTM1, GSTT1 genes of 101 healthy controls and 104 SCRAC patients.
      RESULTS: (1) All the differences of the frequency of GSTM1 null genotype between
      SCRACs and the controls, between proximal and distal SCRACs and between the elder
      and the younger SCRACs did not reach statistical significance. (2) The
      differences of the frequency of GSTT1 null genotype between SCRACs and the
      controls did not reach statistical significance too; But the null genotype for
      GSTT1 was significantly more common among distal SCRACs when compared with the
      proximals (66.2%:44.4%, chi(2) = 3.97, P < 0.05) and more common among the elder
      SCRACs when compared with younger SCRACs (70.9%:49.0%, chi(2) = 5.21, P < 0.05).
      (3) Subjects carring both of the null genotypes for GSTM1 and GSTT1 had more than
      4.33-fold risk for developing SCRACs compared with the subjects caring both of
      the nonull genotypes for GSTM1 and GSTT1 (OR = 4.33, 95% confidence interval,
      1.56 - 12.04). CONCLUSIONS: (1) There was no association the susceptibility to
      SCRAC with GSTM1 or GSTT1 null genotype alone, but the date suggests GSTT1 null
      genotype may influence the distal SCRAC, especially the elder; (2) The individual
      with both of the null genotypes of GSTM1 and GSTT1 increases markedly the risk of
      SCRAC, and this genotype is the susceptibility gene to SCRAC.

PMID- 12421503
TI  - [A clinical study of 26 cases of cryptococcal meningitis].
AB  - OBJECTIVE: To study the diagnosis and therapy of cryptococcal meningitis.
      METHODS: Retrospective review of the clinical features, treatment and outcome of
      26 patients with cryptococcal meningitis from October 1981 to September 2001 at
      Peking Union Medical College Hospital. RESULTS: The age of the patients ranged
      from 5 to 62 years (mean: 35.6 years), 12 were male and 14 were female. There
      were 16 patients with underlying diseases, 9 had systemic lupus erythematosus
      (SLE), 4 had human immunodeficiency virus (HIV) infection and/or acquired
      immunodeficiency syndrome (AIDS) and 3 had other diseases. 12 patients had
      contact with pigeons. The nonspecific clinical and laboratory findings in these
      patients led to misdiagnosis: as lupus encephalopathy in 6 cases and tuberculous
      meningitis in 5 cases. 23 of the 26 cases were positive of cryptococcus on
      cerebrospinal fluid (CSF) smear. 13 cases were positive on CSF culture, but latex
      coagulate test performed in 20 cases were all positive, 15 patients had high
      intracranial pressure (> 300 mm H(2)O), 9 patients with dilated ventricle
      received brain ventricular draining. Only 2 cases used fluconazole monotherapy.
      One patient only used amphotericin B. The rest of the patients were given
      amphotericin B in combination with flucytosine (12 patients) or fluconazole (5
      cases), or flucytosine combined with fluconazole (6 cases). The mean dose of
      amphotericin B was 2.6 g, the highest dose of amphotericin B and liposomal
      amphotericin B was 10.05 g and 20 g, respectively. The outcome of the 26 cases
      showed that 17 were cured, 4 improved, 3 patients were died and 2 patients gave
      up any further treatment. From Oct. 1981 to Sep. 1996 we found only 9 cases, but
      in recent 5 years we found 17 cases. CONCLUSIONS: The incidence of cryptococcal
      meningitis was increasing in the recent 5 years. The conditions associated with
      this disease include extensive broad spectrum antibiotics, immunosuppressive
      drugs or ligh-dose corticosteroids and increasing cases of HIV/AIDS. The early
      diagnosis and treatment of cryptococcal meningitis may reduce death rate. We
      still recommended amphotericin B plus flucytosine as the standard therapy for
      cryptococcal meningitis. Ventricular drainage and amphotericin B
      intraventricularly via an implanted tube into dilated ventricle could improve the
      clinical condition of serious cryptococcal meningitis and decrease the dosage of
      systemic use of amphotericin B, therefore, reduce the side-effects of the drugs.

PMID- 12421504
TI  - [A clinical analysis of 104 cases of acute pure and mixed organophosphate
      poisoning].
AB  - OBJECTIVE: To study the difference of the clinical manifestations between single
      and mixed acute organophosphate (OP) poisoning. METHODS: The clinical signs and
      symptoms, the activity of cholinesterase (ChE) in erythrocytes, plasma and whole
      blood, and the level of AST, CK, LDH and ALT were compared between a single OP
      poisoning group (Group S) and a mixed OP poisoning group (Group C). RESULTS:
      Group S and Group C compare with: (1) Symptoms and signs on arrival at hospital:
      Group C was found to have more cases showing, nausea and vomiting than group S
      with obvious difference (P < 0.05). (2) The rates of other symptoms and signs
      were of no significant difference between the 2 groups. The activity of
      cholinesterase of the 2 groups on arrival at hospital: Whole blood ChE < 0.30: 16
      cases and 14 cases; > 0.30 approximately : 24 cases and 19 cases; 0.50
      approximately 0.70: 14 cases and 17 cases; erythrocyte ChE < 0.30: 18 cases and
      14 cases; > 0.30 approximately : 22 cases and 21 cases; 0.50 approximately 0.70:
      14 cases and 15 cases; plasma ChE < 0.30: 28 cases and 25 cases; > 0.30
      approximately : 10 cases and 12 cases; 0.50 approximately 0.70: 16 cases and 13
      cases; chi(2) = 0.852, 1.444, 0.509. There was no obvious difference (P > 0.05).
      (3) Positive rates of serum biochemical parameters between the 2 groups within 72
      hours after arrival at hospital: Group S AST 24 cases, ALT 18 cases, CK 42 cases,
      LDH 22 cases, Tbil 21 cases; Group C AST 20 cases, ALT 11 cases, CK 32 cases, LDH
      18 cases, Tbil 17 cases. There was also no obvious difference (P > 0.05). (4)
      Positive rate of ECG: between the 2 group on arrival at hospital Group S 24
      cases, Group C 19 cases. No obvious difference was shown (P > 0.05). (5) Fatality
      rates between the 2 groups: Group S 7.41% (4/54), Group C 6.00% (3/50), chi(2) =
      0.082, P > 0.05. CONCLUSION: Acute mixed OP poisoning and single OP poisoning
      show no significant difference in clinical manifestations. The treatment measures
      for single OP poisoning also has good effect fo mixed OP poisoning.

PMID- 12421505
TI  - [An open label multi-center clinical trial to evaluate the efficacy of compound
      pseudoephedrine [corrected] hydrochloride sustained release capsules in patients
      with nasal symptoms associated with common cold].
AB  - OBJECTIVE: To evaluate the efficacy and safety of compound pseudoephedrine
      [corrected] hydrochloride (New Contact sustained release capsules) in the
      treatment of the nasal symptoms associated with common cold or influenza. METHOD:
      Open label multi-center clinical trial was adopted: one capsule twice daily with
      an interval of 12 hours, successively for 4 days to treat the nasal symptoms
      associated with common cold or influenza. RESULTS: A total of 416 patients were
      eligible for efficacy and safety analysis. The cure rates for nasal congestion
      from day 1 to day 4 were 7%, 31%, 64% and 88%, cumulatively; for runny nose were
      9%, 36%, 68% and 89%; for sneezing were 20%, 51%, 76% and 93%, and for watery
      eyes were 36%, 68%, 89% and 96%, respectively. There were no serious adverse
      events during the study. Forty adverse events (AE's) with an incidence of 8% were
      developed in 35 patients. The most frequent AE's were drowsiness (24/416, 6%) and
      dry mouth (5/416, 1%). All AE's were in mild or moderate degree. CONCLUSION: The
      results indicated that New Contact sustained released capsule was effective in
      controlling the nasal symptoms associated with common cold or influenza and it
      was well-tolerated.

PMID- 12421506
TI  - [Chronic Chlamydia pneumoniae infection in patients with coronary disease.
      Relation with increased fibrinogen values].
AB  - BACKGROUND: A number of studies have suggested that infection with Chlamydia
      pneumoniae can play a role in development of atherosclerosis. The goal of this
      study was to know the prevalence of chronic C. pneumoniae infection, evaluated
      with IgG antibodies seropositivity, in Spanish patients with coronary disease and
      its association with inflammatory markers and cardiovascular risk factors.
      PATIENTS AND METHOD: In 176 patients with coronary disease IgG and IgM antibodies
      to C. pneumoniae were determined by enzyme immunoassay. In addition, fibrinogen
      and C-reactive protein values were measured as inflammatory markers. Controls
      were 55 healthy subjects whose age was not different from patients.
      Seropositivity for C. pneumoniae was considered when indices of IgG and/or IgM
      antibodies were higher than mean plus two standard deviations of control values.
      Three patients with seropositivity for IgM were excluded. RESULTS: In 126
      patients and 2 controls a seropositivity against C. pneumoniae was proved (72.8%
      vs 4.2%; p < 0.001). Cardiovascular risk factors were not different in
      seropositive and seronegative groups of patients. Prevalence of
      hyperfibrinogenemia was higher in the former group (38.8% vs 19.1%; p = 0.01).
      The number of the patients with increased values of C-reactive protein was
      similar in both groups, although these values could be modified by treatment with
      statins. In multivariate analysis an association between seropositivity for C.
      pneumoniae and hyperfibrinogenemia was found (odds ratio [OR] = 2.42; 95%
      confidence interval, 1.07-5.48; p = 0.03) after adjusting for age, gender,
      smoking, hypertension, hypercholesterolemia and diabetes. CONCLUSIONS: Chronic
      infection with C. pneumoniae in patients with coronary disease is very prevalent,
      and it is associated with increased fibrinogen values.

PMID- 12421507
TI  - [Prevalence of Bartonella spp. seropositivity in human immunodeficiency virus
      infected and non infected intravenous drug abusers].
AB  - BACKGROUND: Serology is an useful tool in the diagnosis of Bartonella spp.
      infections in human immunodeficiency virus (HIV) seronegative patients. The value
      of this technique in HIV co-infected individuals is unknown. The aim of this
      study was to assess the prevalence of Bartonella spp. seropositivity among
      intravenous drugs abusers (IDA), both HIV-infected and non-infected. PATIENTS AND
      METHOD: A retrospective seroepidemiological study was carried out among 241 IDA.
      One hundred and forty-seven of them were infected with HIV type 1. The titer of
      serum IgG antibodies against Bartonella spp. were determined. RESULTS: Thirty
      three (14%) individuals were seropositive for Bartonella spp. Nineteen (13%)
      seropositive cases were found among HIV carriers and 14 (15%) among HIV
      uninfected people. No relationship between Bartonella spp. seropositivity and the
      CD4+ cell counts was found when HIV infected patients were analyzed. CONCLUSIONS:
      We have found a similar prevalence of Bartonella spp. seropositivity in HIV
      infected and non HIV-infected IDA.

PMID- 12421508
TI  - [Utility of arteriography with selective arterial calcium injection for the
      diagnosis of insulinoma].
AB  - BACKGROUND: Common preoperative imaging techniques for the diagnosis of
      insulinomas do not lead to an effective localization in 40% cases. We present
      here our experience with arteriography followed by selective arterial calcium
      injection (AACI). METHOD: Retrospective review of AACIs and other techniques
      performed in patients with endogenous hyperinsulinism. RESULTS: AACI either
      localized the tumor or at least conditional its surgical resection in nine out of
      11 cases. In 2 out of 11 patients, the test yielded a negative result (factitious
      hypoglycemia). Only 4 tumors were identified by other techniques. CONCLUSIONS:
      AACI is a first-choice technique for the preoperative localization of
      insulinomas. It may also help rule out other causes of hypoglycemia.

PMID- 12421509
TI  - [Effectiveness of varicella vaccine].

PMID- 12421510
TI  - [Perspectives in the eradication of the immuno-preventable diseases].

PMID- 12421511
TI  - [Potential diet carcinogenics and risk of cancer].

PMID- 12421512
TI  - [Treatment of alcoholic hepatitis with corticosteroids. Are they really
      effective?].

PMID- 12421513
TI  - [Liver transplantation in a patient infected by human immunodefficiency virus].

PMID- 12421514
TI  - [Spontaneous cerebellar haemorrhage associated with Ginkgo biloba ingestion].

PMID- 12421515
TI  - [Out-patient clinic in a single time, is the only and best solution?].

PMID- 12421517
TI  - [Acute suppurative colangitis, severe sepsis and liver abscess in a patient with
      intrahepatic stones].

PMID- 12421518
TI  - [Prevalence erectile dysfunction in patients with hypertension].
AB  - BACKGROUND: Erectile dysfunction (ED), defined as the consistent inability to
      achieve or maintain an erection sufficient for satisfactory sexual performance,
      is closely associated with hypertension. We assessed the prevalence of ED in
      patients with hypertension at the primary care level. We analyzed factors
      associated with ED in these patients. We also worked out the relationship between
      cardiovascular disease risks and ED. PATIENTS AND METHOD: This transversal
      multicenter study was carried out in educational primary care centers. A total of
      512 patients with hypertension completed the International Index of Erectile
      Function in its abridged form (IIEF-5). Their known cardiovascular risk factors,
      comorbidity, toxic habits and hypertension history were taken form their medical
      records. RESULTS: Of 512 patients, 5 were not included in the study because of
      incomplete data in the IIEF-5 questionnaire. Mean age was 63.36 years (range 30
      to 86). The prevalence of erectile dysfunction was 46.5%. Correlation of ED with
      age [OR = 1.05 (1.028-1.075)], diabetes mellitus [OR = 2.06 (1.247-3.406)] and
      ischemic heart disease [OR = 3.15 (1.429-6.947)] did reach statistical
      significance (p < 0.05). A linkage with cardiovascular disease risks, as worked
      out by the Framingham study, was not found. CONCLUSIONS: We observe a high
      prevalence of ED in patients with hypertension.

PMID- 12421519
TI  - [Glucose effectiveness and components of the metabolic syndrome in recently
      diagnosed hypertensive patients].
AB  - BACKGROUND: Glucose effectiveness (SG) is a parameter that indicates the glucose
      ability to clearing itself from the plasma independently of insulin's action. Our
      purpose was to analyze the cluster characteristics associated with the metabolic
      syndrome in a group of non-obese, recent-onset hypertensives and to test if there
      was a correlation with SG and the effectiveness of glucose at basal insulin point
      (GEZI). PATIENTS AND METHOD: We studied 36 patients with mild hypertension with
      normal basal glucose levels. We determined plasma lipid subfractions,
      apolipoproteins and urate levels. An intravenous glucose tolerance test (TTGI)
      and minimal model analysis according to Bergman was performed and SG, GEZI and
      insulin sensitivity (SI) were calculated. RESULTS: Patients with lower SG and
      GEZI had higher levels of total triglycerides (Tg) (r = 0.42; p = 0.01 and r =
      0.48; p = 0.002, respectively) and triglycerides bind to VLDL (Tg-VLDL) (r =
      0.40; p < 0.01 and r = 0.49; p = 0.002, respectively). When the cluster of
      metabolic syndrome was analyzed, SG was inversely related to uric acid levels and
      to the waist-hip index. However, SI was only related to the uric acid levels (r =
      0.38; p = 0.01). CONCLUSIONS: In non-obese, recently diagnosed hypertensive
      patients, the SG parameter seems to be an early marker for the development of
      metabolic syndrome.

PMID- 12421520
TI  - [Diagnostic concordance between emergency room and hospitalization in medical
      patients].
AB  - BACKGROUND: The purpose of this study was to know the concordance of diagnosis
      between emergency rooms amd hospitalization wards and to analyze the mistake
      index, the epidemiological characteristics and the main reasons for the mistakes.
      PATIENTS AND METHOD: We analyzed hospitalized patients and used a three-level
      concordance: exact diagnosis (A), syndromical concordance (B) and mistake (C). We
      compared age, sex, time and days of hospitalization between the groups A+B and C.
      We also analyzed the causes of mistakes in group C. RESULTS: We found 88.1% of
      patients in level A, 7.3% in level B and 4.6% in level C. There were no
      significant differences in the variables analyzed. Main mistakes were a deficient
      clinical evaluation (50%) and X-ray interpretation (28.6%). CONCLUSIONS:
      Concordance of diagnoses was the rule, with less than 5% mistakes. There is no
      clinical or epidemiological pattern for the mistake. The most frequent cause for
      it was a deficient clinical evaluation.

PMID- 12421521
TI  - [Impotence and hypertension].

PMID- 12421522
TI  - [Paget's disease of bone: study of 314 patients].
AB  - BACKGROUND: To describe the clinical and laboratory features of Paget's disease
      of bone at the time of diagnosis. PATIENTS AND METHOD: This multicenter and
      retrospective study included 314 patients. Diagnosis was performed by means of
      characteristic radiological findings and typical bone scintigraphy. The variables
      analyzed included: epidemiological variables, cause of diagnosis, bone
      involvement, disease extension (Coutris index), complications, alkaline phosphate
      (AP) levels and disease activity (Renier index). RESULTS: There were 159 (50.5%)
      males and the mean age was 64.9 years (SD 12.6). Diagnosis was casual in 228
      (72.6%) patients. Polyostotic involvement was detected in 201 (63.9%) patients.
      More common locations were pelvis, skull and lumbar spine. Sacrum was more
      frequently involved in men than in women (p < 0.05), whereas skull involvement
      was more common in women (p < 0.05). The number of bones involved was 3.1 SD 3
      and the percentage of skeletal involvement was 8.7 % (SD 6.5). One hundred ninety
      eigth (63%) patients had complications. The disease was active in 242 (77%)
      patients with a mean AP value of 377 IU/L (SD 493); the activity of the disease
      measured by the Renier index was 34 (SD 46); the activity was greater in the
      skull and the humerus. CONCLUSIONS: Paget's disease of bone is usually
      asymptomatic. Polyostotic involvement and activity are common at the time of
      diagnosis. Knowledge of the extension and activity by means of a mathematical
      model may aid to make therapeutical decisions.

PMID- 12421523
TI  - [Clinical intervention in smoking. Are specific primary health-care centers
      needed?].

PMID- 12421524
TI  - [Severe non-infectious secondary effects of blood transfusion].

PMID- 12421526
TI  - [Promotion of blood donation in a hospital: comparison of two aproaches].

PMID- 12421527
TI  - [Systematic screening of thyroid function in the hormonal evaluation of
      gynecomastia].

PMID- 12421528
TI  - [Transexualism: a challenge for moral sense].

PMID- 12421530
TI  - [Systemic capillary leak syndrome associated with lymphoproliferative disease].

PMID- 12421531
TI  - [Ergotism in a patient treated with ritonavir and ergotamine].

PMID- 12421532
TI  - [Cryoglobulinemic syndrome and autoimmune hepatitis].

PMID- 12421533
TI  - Hans H. Ussing--scientific work: contemporary significance and perspectives.
AB  - As a zoologist, Hans H. Ussing began his scientific career by studying the marine
      plankton fauna in East Greenland. This brought him in contact with August Krogh
      at the time George de Hevesy, Niels Bohr and Krogh planned the application of
      artificial radioactive isotopes for studying the dynamic state of the living
      organism. Following his studies of protein turnover of body tissues with
      deuterium-labeled amino acids, Ussing initiated a new era of studies of transport
      across epithelial membranes. Theoretical difficulties in the interpretation of
      tracer fluxes resulted in novel concepts such as exchange diffusion,
      unidirectional fluxes, flux-ratio equation, and solvent drag. Combining methods
      of biophysics with radioactive isotope technology, Ussing introduced and defined
      the phrases 'short-circuit current', 'active transport pathway' and 'shunt
      pathway', and with frog skin as experimental model, he unambiguously proved
      active transport of sodium ions. Conceived in his electric circuit analogue of
      frog skin, Ussing associated transepithelial ion fluxes with the hitherto
      puzzling 'bioelectric potentials'. The two-membrane hypothesis of frog skin
      initiated the study of epithelial transport at the cellular level and raised new
      questions about cellular mechanisms of actions of hormones and drugs. His
      theoretical treatment of osmotic water fluxes versus fluxes of deuterium labeled
      water resulted in the discovery of epithelial water channels. His discovery of
      paracellular transport in frog skin bridged studies of high and low resistance
      epithelia and generalized the description of epithelial transport. He devoted the
      last decade of his scientific life to solute-coupled water transport. He
      introduced the sodium recirculation theory of isotonic transport, and in an
      experimental study, he obtained the evidence for recirculation of sodium ions in
      toad small intestine. In penetrating analyses of essential aspects of epithelial
      membrane transport, Ussing provided insights of general applicability and
      powerful analytical methods for the study of intestine, kidney, respiratory
      epithelia, and exocrine glands-of equal importance to biology and medicine.

PMID- 12421534
TI  - Cystic fibrosis transmembrane conductance regulator in teleost fish.
AB  - The gills and intestinal epithelia of teleost fish express cystic fibrosis
      transmembrane conductance regulator (CFTR), and utilize this low conductance
      anion channel in the apical membrane for ion secretion in seawater gill and in
      the basolateral membrane for ion absorption in freshwater gill. Similarly, in the
      intestine CFTR is present in the basolateral membrane for intestinal absorption
      and also in the apical membrane of secreting intestine. The expression of CFTR
      and the directed trafficking of the protein to the apical or basolateral membrane
      is salinity-dependent. The CFTR gene has been cloned and sequenced from several
      teleost species and although all the major elements in the human gene are
      present, including two nucleotide binding domains that are common to all ATP
      binding cassette (ABC) transporters, the sequences are divergent compared to
      shark or human. In euryhaline fish adapting to seawater, CFTR, localized
      immunocytochemically, redistributes slowly from a basolateral location to the
      apical membrane while ion secretory capacity increases. The facility with which
      teleosts regulate CFTR expression and activation during salinity adaptation make
      this system an appealing model for the expression and trafficking operation of
      this labile gene product.

PMID- 12421535
TI  - Mitochondria-rich cells as experimental model in studies of epithelial chloride
      channels.
AB  - The mitochondria-rich (mr) cell of amphibian skin epithelium is differentiated as
      a highly specialised pathway for passive transepithelial transport of chloride.
      The apical membrane of mr cells expresses several types of Cl(-) channels, of
      which the function of only two types has been studied in detail. (i) One type of
      channel is gated by voltage and external chloride concentration. This intriguing
      type of regulation leads to opening of channels only if [Cl(-)](o) is in the
      millimolar range and if the electrical potential is of a polarity that secures an
      inwardly directed net flux of this ion. Reversible voltage activations of the
      conductance proceed with long time constants, which depend on V in such a way
      that the rate of conductance activation increases when V is clamped at more
      negative values (serosal bath grounded). The gating seems to involve processes
      that are dependent on F-actin localised in the submembrane domain in the neck
      region of the flask-shaped mr cell. (ii) The other identified Cl(-) pathway of mr
      cells is mediated by small-conductance apical CFTR chloride channels as concluded
      from its activation via beta-adrenergic receptors, ion selectivity, genistein
      stimulation and inhibition by glibenclamide. bbCFTR has been cloned, and
      immunostaining has shown that the gene product is selectively expressed in mr
      cells. There is cross-talk between the two pathways in the sense that activation
      of the conductance of the mr cell by voltage clamping excludes activation via
      receptor occupation, and vice versa. The mechanism of this cross-talk is unknown.

PMID- 12421536
TI  - The route of passive chloride movement across amphibian skin: localization and
      regulatory mechanisms.
AB  - Transepithelial Cl(-) conductance (G(Cl)) in amphibian skin can be activated in
      several species by serosa positive potentials. Mitochondria-rich cells (MRC) or
      tight junctions (TJ) between the epithelial cells are possible sites for this
      pathway. The properties and the techniques used to investigate this pathway are
      reviewed in the present paper. In situ techniques are preferable, since specific
      properties of the MRC are apparently not maintained in isolated cells. Volume
      measurements and electronprobe microanalysis of intracellular ions suggest the
      localization of voltage-activated G(Cl) to MRC. G(Cl) correlates poorly with the
      density of MRC. The vibrating voltage probe allows quantitative correlation of
      the local Cl(-) current through morphologically identified structures and the
      transepithelial Cl(-) current. Our analysis shows that 80% of the voltage
      activated Cl(-) current is accounted for by current through MRC or their
      immediate vicinity. The activation patterns of this current and the inhibition by
      the alpha(1)-adrenergic agonist, epinephrine, conform to those of the
      transepithelial current. However, less than 20% of the MRC are active at a
      certain moment and the activity is spontaneously variable with time. The
      molecular nature of this pathway, physiological control mechanisms and their
      relation to the temporal activity of MRC remain to be studied.

PMID- 12421537
TI  - Cloning and characterisation of amphibian ClC-3 and ClC-5 chloride channels.
AB  - Amphibians have provided important model systems to study transepithelial
      transport, acid-base balance and cell volume regulation. Several families of
      chloride channels and transporters are involved in these functions. The purpose
      of this review is to report briefly on some of the characteristics of the
      chloride channels so far reported in amphibian epithelia, and to focus on
      recently cloned members of the ClC family and their possible physiological roles.
      The electrophysiological characterisation, distribution, localisation and
      possible functions are reviewed and compared to their mammalian orthologs.

PMID- 12421538
TI  - Sodium-proton exchange in crayfish.
AB  - Recently, three proton pump inhibitors were shown to have no effect on proton
      excretion and little on Na uptake in tapwater-adapted (TW) crayfish, while all
      three reduced Na-H exchange in salt-depleted (SD) animals. It appeared that the
      exchange was mediated by the Na channel-H pump in SD crayfish but not in TW
      animals. An alternative, a 2Na-1H exchanger, might function in the latter. To
      test this, the effects of amiloride (AM) and ethylisopropyl AM (EIPA) on Na
      fluxes were observed. AM inhibits the Na channel but is a much weaker blocker of
      Na-H exchangers. In contrast, EIPA inhibits exchangers but acts weakly on the Na
      channel. If an exchanger functions in TW crayfish, we should expect EIPA to block
      Na influx in them with AM having a weaker action. The reverse should be true in
      SD animals. Experimental data showed that EIPA was a potent inhibitor of Na
      influx in TW crayfish with half-maximal inhibition at about 0.2 microM. However,
      AM proved to be equipotent. In SD crayfish, EIPA was as effective as in TW
      animals, and again AM was equally potent. The data fail to show the expected
      differential action. Therefore, AM and its analogues cannot be used to
      distinguish between the two models of Na-H exchange in crayfish.

PMID- 12421539
TI  - Cultured gill epithelia as models for the freshwater fish gill.
AB  - We review recent progress in the development of models for the freshwater teleost
      gill based on reconstructed flat epithelia grown on permeable filter supports in
      primary culture. Methods are available for single-seeded insert (SSI)
      preparations consisting of pavement cells (PVCs) only from trout and tilapia, and
      double-seeded insert (DSI) preparations from trout, containing both PVCs (85%)
      and mitochondria-rich cells (MRCs, 15%), as in the intact gill. While there are
      some quantitative differences, both SSI and DSI epithelia manifest electrical and
      passive permeability characteristics typical of intact gills and representative
      of very tight epithelia. Both preparations withstand apical freshwater exposure,
      exhibiting large increases in transepithelial resistance (TER), negative
      transepithelial potential (TEP), and low rates of ion loss, but there is only a
      small active apical-to-basolateral "influx" of Cl(-) (and not of Na(+)).
      Responses to various hormonal treatments are described (thyroid hormone T3,
      prolactin, and cortisol). Cortisol has the most marked effects, stimulating
      Na(+),K(+)-ATPase activity and promoting active Na(+) and Cl(-) influxes in DSI
      preparations, and raising TER and reducing passive ion effluxes in both epithelia
      via reductions in paracellular permeability. Experiments using DSI epithelia
      lacking Na(+) uptake demonstrate that both NH(3) and NH(4)(+) diffusion occur,
      but are not large enough to account for normal rates of branchial ammonia
      excretion, suggesting that Na(+)-linked carrier-mediated processes are important
      for ammonia excretion in vivo. Future research goals are suggested.

PMID- 12421540
TI  - Annelid epithelia as models for electrogenic Na+ transport.
AB  - The electrogenic Na(+) absorption across tight epithelia from invertebrates
      follows the principles analog to the mechanisms found in vertebrates.
      Extracellular Na(+)-ions pass the apical cell membranes through highly selective
      Na(+) channels and follow an electrochemical gradient which is sustained by the
      basolateral Na(+)/K(+)-ATPases. These apical Na(+) channels are selectively
      blocked by amiloride and represent the rate-limiting target for the control of
      transcellular Na(+) uptake. Although annelids express ADH-like peptide hormones,
      they lack the osmoregulatory mineralocorticoid system with the vertebrate
      specific key hormone aldosterone. Thus, their epithelia may represent interesting
      models for investigation of ion transport regulation. While the formation of
      urine in the nephridia of, for example, leeches had been subject to intensive
      studies, the investigation of ion transport across their body wall was largely
      neglected. We use dissected segments of integuments from the limnic leech Hirudo
      medicinalis and, recently, from the earthworm Lumbricus terrestris for Ussing
      chamber experiments. We investigate transintegumental ion transport with focus on
      control of electrogenic Na(+) uptake and the amiloride-sensitive part of it and
      identified several extracellular factors as peptide hormones, tri- and divalent
      cations or purinergic molecules with regulatory effects on it. Meanwhile, there
      exists a macroscopic view on Na(+) absorption; however, other ion transport
      mechanisms across annelid integuments still await scientific effort. Here we
      present a concise synopsis about the electrophysiology of annelid integuments to
      illustrate the state of science and to evaluate whether further studies in this
      particular field may be of interest.

PMID- 12421541
TI  - Two isoforms of the Na+/K+/2Cl- cotransporter are expressed in the European eel
      (Anguilla anguilla).
AB  - Two cDNA isoforms of the NKCC1 secretory cotransporter have been isolated from
      the European eel. The NKCC1a isoform exhibited mRNA expression in a wide range of
      tissues in a similar fashion to mammals, whereas NKCC1b was expressed primarily
      in the brain. The effect of freshwater (FW) to seawater (SW) transfer on NKCC1a
      expression was dependent on the developmental stage. In non-migratory yellow
      eels, NKCC1a mRNA expression in the gill was transiently up-regulated 4.3-fold
      after 2 days but also subsequently by 2.5-6-fold 3 weeks after SW transfer. Gill
      NKCC1a expression was localised mainly in branchial chloride cells of SW
      acclimated yellow eels. In contrast to yellow eels, NKCC1a mRNA abundance was not
      significantly different following SW acclimation in silver eel gill. NKCC1a mRNA
      abundance decreased in the kidney following SW acclimation and this may correlate
      with lower tubular ion/fluid secretion and urine flow rates in SW teleosts.
      Kidney NKCC1a mRNA expression in silver eels was also significantly lower than in
      yellow eels, suggesting some pre-acclimation of mRNA levels. NKCC1a mRNA was
      expressed at similar low levels in the middle intestine of FW- and SW-acclimated
      yellow or silver eels, suggesting the presence of an ion secretory mechanism in
      this gut segment.

PMID- 12421542
TI  - Sodium-dependent copper uptake across epithelia: a review of rationale with
      experimental evidence from gill and intestine.
AB  - The paper reviews the evidence for apparent sodium-dependent copper (Cu) uptake
      across epithelia such as frog skin, fish gills and vertebrate intestine.
      Potential interactions between Na(+) and Cu during transfer through epithelial
      cells is rationalized into the major steps of solute transfer: (i) adsorption on
      to the apical/mucosal membrane, (ii) import in to the cell (iii) intracellular
      trafficking, and (iv) export from the cell to the blood. Interactions between
      Na(+) and Cu transport are most likely during steps (i) and (ii). These ions have
      similar mobilities (lambda) in solution (lambda, Na(+), 50.1; Cu(2+), 53.6 cm(2)
      Int. ohms(-1) equiv(-1)); consequently, Cu(2+) may compete equally with Na(+) for
      diffusion to membrane surfaces. We present new data on the Na(+) binding
      characteristics of the gill surface (gill microenvironment) of rainbow trout. The
      binding characteristics of Na(+) and Cu(2+) to the external surface of trout
      gills are similar with saturation of ligands at nanomolar concentrations of
      solutes. At the mucosal/apical membrane of several epithelia (fish gills, frog
      skin, vertebrate intestine), there is evidence for both a Cu-specific channel
      (CTR1 homologues) and Cu leak through epithelial Na(+) channels (ENaC). Cu(2+)
      slows the amiloride-sensitive short circuit current (I(sc)) in frog skin,
      suggesting Cu(2+) binding to the amiloride-binding site of ENaC. We present
      examples of data from the isolated perfused catfish intestine showing that Cu
      uptake across the whole intestine was reduced by 50% in the presence of 2 mM
      luminal amiloride, with 75% of the overall inhibition attributed to an amiloride
      sensitive region in the middle intestine. Removal of luminal Na(+) produced more
      variable results, but also reduced Cu uptake in catfish intestine. These data
      together support Cu(2+) modulation of ENaC, but not competitive entry of Cu(2+)
      through ENaC. However, in situations where external Na(+) is only a few
      millimoles (fish gills, frogs in freshwater), Cu(2+) leak through ENaC is
      possible. CTR1 is a likely route of Cu(2+) entry when external Na(+) is higher
      (e.g. intestinal epithelia). Interactions between Na(+) and Cu ions during
      intracellular trafficking or export from the cell are unlikely. However, effects
      of intracellular chloride on the Cu-ATPase or ENaC indicate that Na(+) might
      indirectly alter Cu flux. Conversely, Cu ions inhibit basolateral Na(+)K(+)
      ATPase and may increase [Na(+)](i).

PMID- 12421543
TI  - Rapid responses to steroid hormones: from frog skin to human colon. A homage to
      Hans Ussing.
AB  - Fifty years ago, Hans Ussing described the mechanism by which ions are actively
      transported across frog skin. Since then, an enormous amount of effort has been
      invested in determining the cellular and molecular specifics of the transport
      mechanisms and their regulatory pathways. Ion transport in high-resistance
      epithelia is regulated by a variety of hormonal and non-hormonal factors. In
      vertebrates, steroid hormones such as mineralocorticoids, glucocorticoids and
      estrogens are major regulators of ion and water transport and hence are central
      to the control of extracellular fluid volume and blood pressure. Steroid hormones
      act through nuclear receptors to control the transcriptional activity of specific
      target genes, such as ion channels, ion transporters and ion pumps. These effects
      are observed after a latency of several hours and can last for days leading to
      cellular differentiation that allows a higher transport activity. This pathway is
      the so-called genomic phase. However, in the past 10 years, it has become
      apparent that steroid hormones can regulate electrolyte and water transport in
      tight epithelia independently of the transcription of these ion channels and
      transporters by regulating ion transporter activity in a non-genomic fashion via
      modulation of various signal transduction pathways. The molecular mechanisms
      underlying the steroid hormone-induced activation of signal transduction pathways
      such as protein kinase C (PKC), protein kinase A (PKA), intracellular calcium,
      intracellular pH and mitogen-activated protein kinases (MAPKs) and how non
      genomic activation of these pathways influences epithelial ion transport will be
      discussed in this review.

PMID- 12421544
TI  - Control of Cl- transport in the operculum epithelium of Fundulus heteroclitus:
      long- and short-term salinity adaptation.
AB  - The eurohaline fish, Fundulus heteroclitus, adapts rapidly to enhanced salinity
      by increasing the ion secretion by gill chloride cells. An increase of
      approximately 70 mOsm in plasma osmolarity was previously found during the
      transition. To mimic this in vitro, isolated opercular epithelia of seawater
      adapted Fundulus mounted in a modified Ussing chamber were exposed to an increase
      in NaCl and/or osmolarity on the basolateral side, which immediately increased
      I(SC). Various Cl(-) channel blockers as well as the K(+) channel blocker Ba(2+)
      added to the basolateral side all inhibited the steady-state as well as the
      hypertonic stimulation of I(SC). The exists -agonist isoproterenol stimulates
      I(SC) in standard Ringer solutions. In contrast, when cell volume was kept at the
      larger value by simultaneous addition of water, the stimulation with
      isoproterenol was abolished, suggesting that the key process for activation of
      the Na(+), K(+), 2Cl(-) cotransporter is cell shrinkage. The protein kinase C
      (PKC) inhibitor chelerythrine and the myosin light chain kinase (MLCK) inhibitor
      ML-7 had strong inhibitory effects on the mannitol activation of I(SC), thus both
      MLCK and PKC are involved. The two specific protein kinase A (PKA) inhibitors H
      89 and KT 5720 had no effect after mannitol addition whereas isoproterenol
      stimulation was completely blocked by H-89. This indicates that PKA is involved
      in the activation of the apical Cl(-) channel via c-AMP whereas the shrinkage
      activation of the Na(+), K(+), 2Cl(-) cotransporter is independent of PKA
      activation. The steady-state Cl(-) secretion was stimulated by an inhibitor of
      serine/threonine phosphatases of the PP-1 and PP-2A type and inhibited by a PKC
      inhibitor but not by a PKA inhibitor. Thus, it seems to be determined by
      continuous phosphorylation and dephosphorylation involving PKC but not PKA. The
      steady-state Cl(-) secretion and the maximal obtainable Cl(-) secretion were
      measured in freshwater-adapted fish and in fish retransferred to saltwater. No
      I(SC) could be measured in freshwater-adapted fish or in the fish within the
      first 18 h after transfer to saltwater. As evidenced from Western blot analysis
      using antiserine-antibodies, a heavily serine phosphorylated protein of about 190
      kDa was consistently observed in the saltwater-acclimated fish, but was only
      weakly present in freshwater-acclimated fish. This observation indicates that
      acclimatization to saltwater stimulates the expression of this 190-kDa protein
      and/or a serine/threonine kinase, which subsequently phosphorylates the protein.

PMID- 12421545
TI  - Regulation of Na-K-2Cl cotransport by phosphorylation and protein-protein
      interactions.
AB  - The Na-K-2Cl cotransporter plays important roles in cell ion homeostasis and
      volume control and is particularly important in mediating the movement of ions
      and thus water across epithelia. In addition to being affected by the
      concentration of the transported ions, cotransport is affected by cell volume,
      hormones, growth factors, oxygen tension, and intracellular ionized Mg(2+)
      concentration. These probably influence transport through three main routes
      acting in parallel: cotransporter phosphorylation, protein-protein interactions
      and cell Cl(-) concentration. Many effects are mediated, at least in part, by
      changes in protein phosphorylation, and are disrupted by kinase and phosphatase
      inhibitors, and manoeuvres that reduce cell ATP content. In some cases,
      phosphorylation of the cotransporter itself on serine and threonine (but not
      tyrosine) is associated with changes in transport rate, in others,
      phosphorylation of associated proteins has more influence. Analysis of the
      stimulation of cotransport by calyculin A, arsenite and deoxygenation suggests
      that the cotransporter is phosphorylated by several kinases and dephosphorylated
      by several phosphatases. These kinases and phosphatases may themselves be
      regulated by phosphorylation of residues including tyrosine, with Src kinases
      possibly playing an important role. Protein-protein interactions also influence
      cotransport activity. Cotransporter molecules bind to each other to form high
      molecular weight complexes, they also bind to other members of the cation
      chloride cotransport family, to a variety of cytoskeletal proteins, and to
      enzymes that are part of regulatory cascades. Many of these interactions affect
      transport and may override the effects of cotransporter phosphorylation. Cell Cl(
      ) may also directly affect the way the cotransporter functions independently of
      its role as substrate.

PMID- 12421546
TI  - Two-pore domain K+ channels-molecular sensors.
AB  - Two-pore domain K(+) (K2P) channels have been cloned from a variety of species
      and tissues. They have been characterised biophysically as a 'background' K(+)
      selective conductance and are gated by pH, stretch, heat, coupling to G-proteins
      and anaesthetics. Whilst their precise physiological function is unknown, they
      are likely to represent an increasingly important family of membrane proteins.

PMID- 12421547
TI  - Where have all the Na+ channels gone? In search of functional ENaC in exocrine
      pancreas.
AB  - Many epithelia express specific Na(+) channels (ENaC) together with the cystic
      fibrosis regulator (CFTR) Cl(-) channels. Pancreatic ducts secrete HCO(3)(-)-rich
      fluid and express CFTR. However, the question whether they possess ENaC has not
      been consistently addressed. The aim of the present study was to investigate if
      pancreatic ducts express functional ENaC. Membrane voltages (V) of ducts isolated
      from rat pancreas were measured with microelectrodes or whole-cell patch-clamp
      technique. Amiloride and benzamil given from bath or luminal sides did not
      hyperpolarize V. Lowering of extracellular Na(+) concentrations had effects that
      were not consistent with a simple Na(+) conductance, but rather with a
      Na(+)/Ca(2+) exchange. Acute or long-lasting treatment of pancreatic ducts with
      mineralocorticoids had no effect on V of unstimulated or secretin-stimulated
      preparations. Furthermore, pre-treatment of animals with glucocorticoids had no
      effect on pancreatic fluid secretion evoked from ducts, or from acini. Hence, our
      study shows that pancreas especially pancreatic ducts do not express functional
      ENaC.

PMID- 12421548
TI  - Renal organic anion transport: a comparative and cellular perspective.
AB  - A major system for net transepithelial secretion of a wide range of hydrophobic
      organic anions (OAs) exists in the proximal renal tubules of almost all
      vertebrates. This process involves transport into the cells against an
      electrochemical gradient at the basolateral membrane and movement from the cells
      into the lumen down an electrochemical gradient. Transport into the cells at the
      basolateral membrane, which is the dominant, rate-limiting step, is a tertiary
      active transport process, the final step which involves countertransport of the
      OA into the cells against its electrochemical gradient in exchange for alpha
      ketoglutarate moving out of the cells down its electrochemical gradient. The
      outwardly directed gradient for alpha-ketoglutarate is maintained by metabolism (
      approximately 40%) and by transport into the cells across both the basolateral
      and luminal membranes by separate sodium-dicarboxylate cotransporters (
      approximately 60%). The inwardly directed sodium gradient driving alpha
      ketoglutarate uptake is maintained by the basolateral Na(+)-K(+)-ATPase, the
      primary energy-requiring transport step in the total tertiary process. The
      basolateral OA/alpha-ketoglutarate exchange process now appears to be
      physiologically regulated by several factors in mammalian tubules, including
      peptide hormones (e.g., bradykinin) and the autonomic nervous system acting via
      protein kinase C (PKC) pathways and epidermal growth factor (EGF) working via the
      mitogen-activated protein kinase (MAPK) pathway.

PMID- 12421549
TI  - Intestinal bicarbonate secretion by marine teleost fish--why and how?
AB  - Intestinal fluids of most marine teleosts are alkaline (pH 8.4-9.0) and contain
      high levels of HCO(3)(-) equivalents (40-130 mM) which are excreted at a
      significant rate (>100 microEq kg(-1) h(-1)). Recent research reveals the
      following about this substantial HCO(3)(-) secretion: (1) It is not involved in
      acid-base regulation or neutralisation of stomach acid, but increases in parallel
      with drinking rate at elevated ambient salinities suggesting a role in
      osmoregulation; (2) In species examined so far, all sections of the intestine can
      secrete bicarbonate; (3) The secretion is dependent on mucosal Cl(-), sensitive
      to mucosal DIDS, and immuno-histochemistry indicates involvement of an apical Cl(
      )/HCO(3)(-) exchanger. In addition, hydration of CO(2) via carbonic anhydrase in
      combination with proton extrusion appears to be essential for bicarbonate
      secretion. The mode of proton extrusion is currently unknown but potential
      mechanisms are discussed. One consequence of the luminal alkalinity and high
      bicarbonate concentrations is precipitation of calcium and magnesium as carbonate
      complexes. This precipitation is hypothesised to reduce the osmolality of
      intestinal fluids and thus play a potential role in water absorption and
      osmoregulation. The present studies on European flounder reveal that elevated
      luminal calcium (but not magnesium) concentrations stimulate intestinal
      bicarbonate secretion both acutely and chronically, in vitro and in vivo. At the
      whole animal level, the result of this elevated bicarbonate secretion was
      increased calcium precipitation with an associated reduction in the osmolality of
      rectal fluids and plasma. These observations suggest direct functional links
      between intestinal bicarbonate secretion, divalent cation precipitation and
      osmoregulation in marine teleost fish.

PMID- 12421550
TI  - A model of HIV/AIDS with staged progression and amelioration.
AB  - An epidemic model with multiple stages of infection is studied. The model allows
      for infected individuals to move from advanced stages of infection back to less
      advanced stages of infection. A threshold parameter which determines the local
      stability of the disease free equilibrium is found and interpreted. Under
      conditions on the parameters, global stability is demonstrated using techniques
      involving compound matrices.

PMID- 12421551
TI  - Modeling the impact of random screening and contact tracing in reducing the
      spread of HIV.
AB  - Mathematical models can help predict the effectiveness of control measures on the
      spread of HIV and other sexually transmitted diseases (STDs) by reducing the
      uncertainty in assessing the impact of intervention strategies such as random
      screening and contact tracing. Even though contact tracing is one of the most
      effective methods used for controlling treatable STDs, it is still a
      controversial strategy for controlling HIV because of cost and confidentiality
      issues. To help estimate the effectiveness of these control measures, we
      formulate two models with random screening and contact tracing based on the
      differential infectivity (DI) model and the staged-progression (SP) model. We
      derive formulas for the reproductive numbers and the endemic equilibria and
      compare the impact that random screening and contact tracing have in slowing the
      epidemic in the two models. In the DI model the infected population is divided
      into groups according to their infectiousness, and HIV is largely spread by a
      small, highly infectious, group of superspreaders. In this model contact tracing
      is an effective approach to identifying the superspreaders and has a large effect
      in slowing the epidemic. In the SP model every infected individual goes through a
      series of infection stages and the virus is primarily spread by individuals in an
      initial highly infectious stage or in the late stages of the disease. In this
      model random screening is more effective than for the DI model, and contact
      tracing is less effective. Thus the effectiveness of the intervention strategy
      strongly depends on the underlying etiology of the disease transmission.

PMID- 12421552
TI  - A ratio-dependent food chain model and its applications to biological control.
AB  - While biological controls have been successfully and frequently implemented by
      nature and human, plausible mathematical models are yet to be found to explain
      the often observed deterministic extinctions of both pest and control agent in
      such processes. In this paper we study a three trophic level food chain model
      with ratio-dependent Michaelis-Menten type functional responses. We shall show
      that this model is rich in boundary dynamics and is capable of generating such
      extinction dynamics. Two trophic level Michaelis-Menten type ratio-dependent
      predator-prey system was globally and systematically analyzed in details
      recently. A distinct and realistic feature of ratio-dependence is its capability
      of producing the extinction of prey species, and hence the collapse of the
      system. Another distinctive feature of this model is that its dynamical outcomes
      may depend on initial populations levels. Theses features, if preserved in a
      three trophic food chain model, make it appealing for modelling certain
      biological control processes (where prey is a plant species, middle predator as a
      pest, and top predator as a biological control agent) where the simultaneous
      extinctions of pest and control agent is the hallmark of their successes and are
      usually dependent on the amount of control agent. Our results indicate that this
      extinction dynamics and sensitivity to initial population levels are not only
      preserved, but also enriched in the three trophic level food chain model.
      Specifically, we provide partial answers to questions such as: under what
      scenarios a potential biological control may be successful, and when it may fail.
      We also study the questions such as what conditions ensure the coexistence of all
      the three species in the forms of a stable steady state and limit cycle,
      respectively. A multiple attractor scenario is found.

PMID- 12421553
TI  - The critical vaccination fraction for heterogeneous epidemic models.
AB  - Given a population with m heterogeneous subgroups, a method is developed for
      determining minimal vaccine allocations to prevent an epidemic by setting the
      reproduction number to 1. The framework is sufficiently general to apply to
      several epidemic situations, such as SIR, SEIR and SIS models with vital
      dynamics. The reproduction number is the largest eigenvalue of the linearized
      system round the local point of equilibrium of the model. Using the Perron
      Frobenius theorem, an exact method for generating solutions is given and the
      threshold surface of critical vaccine allocations is shown to be a compact,
      connected subset of a regular (m-1)-dimensional manifold. Populations with two
      subgroups are examined in full. The threshold curves are either hyperbolas or
      straight lines. Explicit conditions are given as to when threshold elimination is
      achievable by vaccinating just one or two groups in a multi-group population and
      expressions for the critical coverage are derived. Specific reference is made to
      an influenza A model. Separable or proportionate mixing is also treated.
      Conditions are conjectured for convexity of the threshold surface and the problem
      of minimizing the amount of vaccine used while remaining on the threshold surface
      is discussed.

PMID- 12421555
TI  - A mechanistic framework for co-transcriptional folding of the HDV genomic
      ribozyme in the presence of downstream sequence.
AB  - Hepatitis delta virus (HDV) is a circular pathogenic RNA that uses self-cleavage
      by closely related 84 nt genomic and antigenomic ribozymes to facilitate the
      replication of its genome. Downstream of each ribozyme is a stretch of
      nucleotides termed the attenuator that functions to base-pair with and unfold the
      ribozyme into a rod-like fold. The competing rates of RNA synthesis, ribozyme
      folding and cleavage, and rod folding are therefore likely to affect the
      efficiency of co-transcriptional self-cleavage. In these studies, co
      transcriptional folding of the genomic ribozyme was assayed in vitro by
      monitoring co-transcriptional self-cleavage of transcripts having variable
      lengths of sequence downstream of the ribozyme. Co-transcriptional cleavage data
      were simulated successfully only with kinetic models in which cleavage-inactive
      channels were populated during transcription. Partitioning to and escape from
      these channels was influenced, in part, by whether the available attenuator
      sequence could form structures with the ribozyme, and by the stability of such
      structures. Surprisingly, only 23 nt of attenuator were needed for strong
      inactivation of cleavage. Self-cleavage of certain 3'-virus-containing sequences
      could be restored, partially, by renaturation; however, self-cleavage of
      transcripts with a full-length attenuator could not be restored efficiently by
      renaturation in vitro. This suggests that in the presence of the attenuator, the
      cleavage-active ribozyme fold is not the thermodynamically most stable species.
      In accordance with this model, the efficiency of self-cleavage of the ribozyme
      followed by a full-length attenuator was increased by decreasing the rate of
      transcription. These results suggest that, in the absence of additional factors,
      efficient co-transcriptional cleavage of the full-length genomic HDV RNA may
      require cleavage to occur prior to synthesis of the attenuator.

PMID- 12421557
TI  - Phosphotransfer in Rhodobacter sphaeroides chemotaxis.
AB  - The two-component sensing system controlling bacterial chemotaxis is one of the
      best studied in biology. Rhodobacter sphaeroides has a complex chemosensory
      pathway comprising two histidine protein kinases (CheAs) and eight downstream
      response regulators (six CheYs and two CheBs) rather than the single copies of
      each as in Escherichia coli. We used in vitro analysis of phosphotransfer to
      start to determine why R.sphaeroides has these multiple homologues. CheA(1) and
      CheA(2) contain all the key motifs identified in the histidine protein kinase
      family, except for conservative substitutions (F-L and F-I) within the F box of
      CheA(2), and both are capable of ATP-dependent autophosphorylation. While the
      K(m) values for ATP of CheA(1) and CheA(2) were similar to that of E.coli, the
      k(cat) value was three times lower, but similar to that measured for the related
      Sinorhizobium meliloti CheA. However, the two CheAs differed both in their
      ability to phosphorylate the various response regulators and the rates of
      phosphotransfer. CheA(2) phosphorylated all of the CheYs and both CheBs, whilst
      CheA(1) did not phosphorylate either CheB and phosphorylated only the response
      regulators encoded within its own genetic locus (CheY(1), CheY(2), and CheY(5))
      and CheY(3). The dephosphorylation rates of the R.sphaeroides CheBs were much
      slower than the E.coli CheB. The dephosphorylation rate of CheY(6), encoded by
      the third chemosensory locus, was ten times faster than that of the E.coli CheY.
      However, the dephosphorylation rates of the remaining R.sphaeroides CheYs were
      comparable to that of E.coli CheY.

PMID- 12421556
TI  - Protein-protein and protein-DNA interactions of sigma70 region 4 involved in
      transcription activation by lambdacI.
AB  - The cI protein of bacteriophage lambda (lambdacI) activates transcription from
      promoter P(RM) through an acidic patch on the surface of its DNA-binding domain.
      Genetic evidence suggests that this acidic patch stimulates transcription from
      P(RM) through contact with the C-terminal domain (region 4) of the sigma(70)
      subunit of Escherichia coli RNA polymerase. Here, we identify two basic residues
      in region 4 of sigma(70) that are critical for lambdacI-mediated activation of
      transcription from P(RM). On the basis of structural modeling, we propose that
      one of these sigma(70) residues, K593, facilitates the interaction between
      lambdacI and region 4 of sigma(70) by inducing a bend in the DNA upstream of the 
      35 element, whereas the other, R588, interacts directly with a critical acidic
      residue within the activating patch of lambdacI. Residue R588 of sigma(70) has
      been shown to play an important role in promoter recognition; our findings
      suggest that the R588 side-chain has a dual function at P(RM), facilitating the
      interaction of region 4 with the promoter -35 element and participating directly
      in the protein-protein interaction with lambdacI.

PMID- 12421558
TI  - The palm subdomain-based active site is internally permuted in viral RNA
      dependent RNA polymerases of an ancient lineage.
AB  - Template-dependent polynucleotide synthesis is catalyzed by enzymes whose core
      component includes a ubiquitous alphabeta palm subdomain comprising A, B and C
      sequence motifs crucial for catalysis. Due to its unique, universal conservation
      in all RNA viruses, the palm subdomain of RNA-dependent RNA polymerases (RdRps)
      is widely used for evolutionary and taxonomic inferences. We report here the
      results of elaborated computer-assisted analysis of newly sequenced replicases
      from Thosea asigna virus (TaV) and the closely related Euprosterna elaeasa virus
      (EeV), insect-specific ssRNA+ viruses, which revise a capsid-based classification
      of these viruses with tetraviruses, an Alphavirus-like family. The replicases of
      TaV and EeV do not have characteristic methyltransferase and helicase domains,
      and include a putative RdRp with a unique C-A-B motif arrangement in the palm
      subdomain that is also found in two dsRNA birnaviruses. This circular motif
      rearrangement is a result of migration of approximately 22 amino acid (aa)
      residues encompassing motif C between two internal positions, separated by
      approximately 110 aa, in a conserved region of approximately 550 aa. Protein
      modeling shows that the canonical palm subdomain architecture of poliovirus
      (ssRNA+) RdRp could accommodate the identified sequence permutation through
      changes in backbone connectivity of the major structural elements in three loop
      regions underlying the active site. This permutation transforms the ferredoxin
      like beta1alphaAbeta2beta3alphaBbeta4 fold of the palm subdomain into the
      beta2beta3beta1alphaAalphaBbeta4 structure and brings beta-strands carrying two
      principal catalytic Asp residues into sequential proximity such that unique
      structural properties and, ultimately, unique functionality of the permuted RdRps
      may result. The permuted enzymes show unprecedented interclass sequence
      conservation between RdRps of true ssRNA+ and dsRNA viruses and form a minor,
      deeply separated cluster in the RdRp tree, implying that other, as yet
      unidentified, viruses may employ this type of RdRp. The structural
      diversification of the palm subdomain might be a major event in the evolution of
      template-dependent polynucleotide polymerases in the RNA-protein world.

PMID- 12421559
TI  - The energetics of consensus promoter opening by T7 RNA polymerase.
AB  - The consensus 23 base-pair T7 DNA promoter is classically divided into two
      domains, an upstream binding domain (-17 to -5), and a downstream initiation
      domain (-4 to +6) relative to the transcription start site at +1. During
      transcription initiation, T7 RNA polymerase (T7 RNAP) melts specifically the -4
      to +2/+3 (TATAGG/G) region of the duplex DNA promoter to form a pre-initiation
      open complex. No external energy source is used and the energy for open complex
      formation is derived from the free energy of specific interactions with the
      binding domain, particularly the specificity region (-13 to -6). Using 2
      aminopurine fluorescence-based equilibrium and kinetic measurements, we have
      measured the binding affinities of various topologically modified DNA promoters
      (40 bp in length) that represent initial, final, and transition-state analogs of
      the promoter DNA in the T7 RNAP-DNA complex, to determine the energy of specific
      binding interactions, and the energy required for forming an initiation bubble.
      The results indicate that 16-16.5 kcal mol(-1) of free energy is made available
      upon T7 RNAP binding (through specificity loop) to the promoter binding domain.
      To melt the TATAGG/G sequence 7-8 kcal mol(-1) of free energy is utilized; this
      compares with approximately 6 kcal mol(-1) predicted from nearest neighbor
      analysis. The remaining 8.5-9.5 kcal mol(-1) of net free energy is retained for
      stabilization of the specific pre-initiation binary complex. Of the 7-8 kcal mol(
      1) energy that is used to generate the pre-initiation DNA bubble in the open
      complex, we estimate that one half (3.5-4 kcal mol(-1)) is utilized for
      nucleation/deformation process (through bending, untwisting, etc.) in the melting
      region (-4 to -1 TATA) of the initiation domain (-4 to +6), and appears to be
      independent of the nucleation site within this region. The other half is utilized
      in unpairing the +1 to +2/+3 GG/G sequence for initiation. The interactions of T7
      RNAP with a 20-bp non-specific DNA on the other hand are very weak (DeltaG<-5k
      cal mol(-1)), which is not sufficient to melt and stabilize an open complex of a
      non-specific DNA.

PMID- 12421560
TI  - Specificity of mammalian Y-box binding protein p50 in interaction with ss and ds
      DNA analyzed with generic oligonucleotide microchip.
AB  - p50 protein is a member of the Y-box binding transcription factor family and is a
      counterpart of YB-1 protein. The generic microchip was used to analyze the
      sequence specificity of p50 binding to single (ss) and double-stranded (ds)
      oligodeoxyribonucleotides. The generic microchip contained 4,096 single-stranded
      octadeoxyribonucleotides in which all possible core 6-mers (4(6)=4,096) were
      flanked at their 3' and 5'-ends with degenerated nucleotides. The
      oligonucleotides were chemically immobilized within polyacrylamide gel pads fixed
      on a glass slide. The binding of p50 to the generic microchip was shown to be the
      most specific to ss GGGG motif and then to ss CACC and CATC motifs. GC-rich ds
      oligonucleotides of the generic microchip, and particularly those containing
      GGTG/CACC, GATG/CATC, and GTGG/CCAC heterogeneous motifs, were most efficiently
      destabilized due to interaction with p50. Gel-shift electrophoresis has shown
      that the protein exhibits much higher binding specificity to 24-mer oligoA-TGGGGG
      oligoA containing G-rich 6-mer, in comparison with 24-mer oligoA-AAATAT-oligoA
      carrying A,T-rich 6-mer in full correspondence with the data obtained with the
      microchip. Studies of DNA-binding proteins using gel-immobilized ss and ds DNA
      fragments provide a unique possibility to detect low-affinity complexes of these
      proteins with short sequence motifs and assess the role of these motifs in
      sequence-specific interactions with long recognition sites.

PMID- 12421561
TI  - The crystal structure of the Epstein-Barr virus protease shows rearrangement of
      the processed C terminus.
AB  - Epstein-Barr virus (EBV) belongs to the gamma-herpesvirinae subfamily of the
      Herpesviridae. The protease domain of the assemblin protein of herpesviruses
      forms a monomer-dimer equilibrium in solution. The protease domain of EBV was
      expressed in Escherichia coli and its structure was solved by X-ray
      crystallography to 2.3A resolution after inhibition with diisopropyl
      fluorophosphate (DFP). The overall structure confirms the conservation of the
      homodimer and its structure throughout the alpha, beta, and gamma-herpesvirinae.
      The substrate recognition could be modelled using information from the DFP
      binding, from a crystal contact, suggesting that the substrate forms an
      antiparallel beta-strand extending strand beta5, and from the comparison with the
      structure of a peptidomimetic inhibitor bound to cytomegalovirus protease. The
      long insert between beta-strands 1 and 2, which was disordered in the KSHV
      protease structure, was found to be ordered in the EBV protease and shows the
      same conformation as observed for proteases in the alpha and beta-herpesvirus
      families. In contrast to previous structures, the long loop located between beta
      strands 5 and 6 is partially ordered, probably due to DFP inhibition and a
      crystal contact. It also contributes to substrate recognition. The protease shows
      a specific recognition of its own C terminus in a binding pocket involving
      residue Phe210 of the other monomer interacting across the dimer interface. This
      suggests conformational changes of the protease domain after its release from the
      assemblin precursor followed by burial of the new C terminus and a possible
      effect onto the monomer-dimer equilibrium. The importance of the processed C
      terminus was confirmed using a mutant protease carrying a C-terminal extension
      and a mutated release site, which shows different solution properties and a
      strongly reduced enzymatic activity.

PMID- 12421562
TI  - Analysis of catalytic residues in enzyme active sites.
AB  - We present an analysis of the residues directly involved in catalysis in 178
      enzyme active sites. Specific criteria were derived to define a catalytic
      residue, and used to create a catalytic residue dataset, which was then analysed
      in terms of properties including secondary structure, solvent accessibility,
      flexibility, conservation, quaternary structure and function. The results
      indicate the dominance of a small set of amino acid residues in catalysis and
      give a picture of a general active site environment. It is hoped that this
      information will provide a better understanding of the molecular mechanisms
      involved in catalysis and a heuristic basis for predicting catalytic residues in
      enzymes of unknown function.

PMID- 12421563
TI  - Molecular dissection, tissue localization and Ca2+ binding of the ryanodine
      receptor of Caenorhabditis elegans.
AB  - The ryanodine receptor of Caenorhabditis elegans (CeRyR) which contains 5,071
      amino acid residues, is encoded by a single gene, ryr-1/unc-68. The unc-68(kh30)
      mutation, isolated in an animal showing abnormal response to the anesthetic
      ketamine, has the substitution Ser1444Asn in CeRyR, predicted to be a
      phosphorylation site. To elucidate the function of the region of CeRyR, and to
      determine the localization of CeRyR in this animal, ten region-peptides were
      produced in Escherichia coli by using expression plasmids and eight antisera were
      raised against these fusion peptides. One antibody against the region
      corresponding to the kh30 mutation site enabled detection of CeRyR from mutant
      animals both in Western analysis and in situ. Specificity of this antiserum was
      demonstrated using Western analysis, which showed the full size and the partial
      size bands in wild-type and in the Tc1-induced deletion mutant animals,
      respectively, but no corresponding bands in unc-68 null mutant animals. CeRyR was
      detected in I-bands of muscle sarcomeres by double immunostaining. CeRyR was
      found in the body wall, pharyngeal, vulval, anal and sex muscles of adult worms
      and also found to be present in embryonic muscle, but not in non-muscle cells.
      Two EF-hand motifs and the C terminus were demonstrated to be Ca(2+) binding
      regions. On the basis of these results, we propose a model for the functional
      domains of CeRyR, which agrees well with the model of mammalian skeletal RyR,
      which is based on proteolysis and cross-linking analysis. We discuss the
      usefulness and limitations of the molecular dissection approach, which uses
      peptides and peptide-specific antibodies to determine the local structure and
      function of individual domains within a large molecule.

PMID- 12421564
TI  - Structure of prokaryotic SECIS mRNA hairpin and its interaction with elongation
      factor SelB.
AB  - In prokaryotes, the recoding of a UGA stop codon as a selenocysteine codon
      requires a special elongation factor (EF) SelB and a stem-loop structure within
      the mRNA called a selenocysteine insertion sequence (SECIS). Here, we used NMR
      spectroscopy to determine the solution structure of the SECIS mRNA hairpin and
      characterized its interaction with the mRNA-binding domain of SelB. Our
      structural and biochemical data identified the conserved structural features
      important for binding to EF SelB within different SECIS RNA sequences. In the
      free SECIS mRNA structure, conserved nucleotides are strongly exposed for
      recognition by SelB. Binding of the C-terminal domain of SelB stabilizes the RNA
      secondary structure. In the protein-RNA complex, a Watson-Crick loop base-pair
      leaves a GpU sequence accessible for SelB recognition. This GpU sequence at the
      tip of the capping tetraloop and a bulge uracil five Watson-Crick base-pairs
      apart from the GpU are essential for interaction with SelB.

PMID- 12421565
TI  - Determination of a transition state at atomic resolution from protein engineering
      data.
AB  - We present a method for determining the structure of the transition state
      ensemble (TSE) of a protein by using phi values derived from protein engineering
      experiments as restraints in molecular dynamics simulations employing a realistic
      all-atom molecular mechanics energy function. The method uses a biasing potential
      to select an ensemble of structures having phi values in agreement with the
      experimental data set. An application to acylphosphatase (AcP), a protein for
      which phi values have been measured for 24 out of 98 residues, illustrates the
      approach. The properties of the TSE determined in this way are compared with
      those of a coarse-grained model obtained using a Monte Carlo (MC) sampling method
      based on a C(alpha) representation of the structure. The two TSEs determined at
      different structural resolution are consistent and complementary. While the
      C(alpha) model allows better sampling of the conformation space occupied by the
      transition state, the all-atom model offers a more detailed description of the
      structural and energetic properties of the conformations included in the TSE. The
      combination of low-resolution C(alpha) results with all-atom molecular dynamics
      simulations provides a powerful and general method for determining the nature of
      TSEs from protein engineering data.

PMID- 12421566
TI  - The disulphide mapping, folding and characterisation of recombinant Ber e 1, an
      allergenic protein, and SFA8, two sulphur-rich 2S plant albumins.
AB  - We have cloned and expressed genes encoding the allergenic brazil nut 2S albumin
      (Ber e 1) and the sunflower albumin 8 (SFA8) in the methylotrophic yeast Pichia
      pastoris. We show that both proteins were secreted at high levels and that the
      purified proteins were properly folded. We also showed that Ber e 1 is
      glycosylated during secretion and that the glycan does not interfere with the
      folding or immunoreactivity. The disulphide map of the Ber e 1 protein was
      experimentally established and is in agreement with the conserved disulphide
      structure of other members of the 2S albumin family. A model three-dimensional
      structure of the allergen was generated. During the expression studies and
      through mutation we have also shown that alteration of the sequences around the
      Kex2 endoproteolytic processing site in the expressed fusion protein can
      compromise the secretion by targeting part of the protein for possible
      degradation. The secreted production of these properly folded sulphur-rich plant
      albumins presents an opportunity to delineate the attributes that make an
      allergen and to facilitate the diagnosis and therapy of type I allergy.

PMID- 12421567
TI  - Co-evolutionary analysis reveals insights into protein-protein interactions.
AB  - Protein-protein interactions play crucial roles in biological processes.
      Experimental methods have been developed to survey the proteome for interacting
      partners and some computational approaches have been developed to extend the
      impact of these experimental methods. Computational methods are routinely applied
      to newly discovered genes to infer protein function and plausible protein-protein
      interactions. Here, we develop and extend a quantitative method that identifies
      interacting proteins based upon the correlated behavior of the evolutionary
      histories of protein ligands and their receptors. We have studied six families of
      ligand-receptor pairs including: the syntaxin/Unc-18 family, the GPCR/G-alpha's,
      the TGF-beta/TGF-beta receptor system, the immunity/colicin domain collection
      from bacteria, the chemokine/chemokine receptors, and the VEGF/VEGF receptor
      family. For correlation scores above a defined threshold, we were able to find an
      average of 79% of all known binding partners. We then applied this method to find
      plausible binding partners for proteins with uncharacterized binding
      specificities in the syntaxin/Unc-18 protein and TGF-beta/TGF-beta receptor
      families. Analysis of the results shows that co-evolutionary analysis of
      interacting protein families can reduce the search space for identifying binding
      partners by not only finding binding partners for uncharacterized proteins but
      also recognizing potentially new binding partners for previously characterized
      proteins. We believe that correlated evolutionary histories provide a route to
      exploit the wealth of whole genome sequences and recent systematic proteomic
      results to extend the impact of these studies and focus experimental efforts to
      categorize physiologically or pathologically relevant protein-protein
      interactions.

PMID- 12421568
TI  - Interleukin-1 beta increases the BCL-2/BAX ratio in Kaposi's sarcoma cells.
AB  - Interleukin-1 (IL-1) is a multifunctional cytokine known to act as a growth
      factor for AIDS-KS cells. In addition to its mitogenic effects, we found that IL
      1 induced the protection of KS cells from apoptotic death induced by serum
      deprivation in a dose-dependent manner. AIDS-KS cells as well as cells derived
      from iatrogenic and sporadic KS exhibited a similar response to IL-1, which
      stresses the key role of this cytokine in the pathogenesis of KS regardless of
      its epidemiological form. Using both an immunohistochemical and an immunoblot
      approach, we found that IL-1 increased the expression of Bcl-2 and decreased that
      of Bax, while having no effect on the expression of Bclx(L), Fas and CD40. The
      effects of IL-1 were inhibited by IL-1ra, suggesting that imbalance between these
      two counter-acting cytokines may contribute to the altered accumulation of KS
      spindle cells. Our findings may provide a link between KS cell escape from
      apoptosis and the immune dysregulation known to be associated with KS.

PMID- 12421569
TI  - Synergism between stem cell factor and granulocyte-macrophage colony-stimulating
      factor on cell proliferation by induction of cyclins.
AB  - Synergism between stem cell factor (SCF) and granulocyte-macrophage colony
      stimulating factor (GM-CSF) has been shown to be essential for hematopoietic cell
      proliferation. Since HML-2 cells proliferate exponentially in the presence of SCF
      and GM-CSF together, we analyzed the molecular mechanism of the interaction
      between these two factors in the cells. An immediate-early gene product, c-myc,
      was additively upregulated in HML-2 cells by addition of a combination of SCF and
      GM-CSF. c-myc antisense oligonucleotides effectively suppressed cell
      proliferation and downregulated the induction of D3, E, A, and B cyclins in HML-2
      cells stimulated with the two-factor combination. HML-2 cells arrested at the
      G0/G1 phase with SCF alone and expressed modest amounts of c-myc and cyclin D3,
      but not cyclin E. With GM-CSF treatment alone, the cells could not progress to
      the G2/M phase and expressed c-myc, cyclin D3 and cyclin E but not cyclins A or
      B. The addition of the counterpart cytokine resulted in cell cycle completion by
      induction of the deficient cyclins. Taken together, it appears that the induction
      of c-myc is an indispensable event in the proliferation of HML-2 cells and that
      the cytokines SCF and GM-CSF interact reciprocally for expression of all cyclins
      required for cell cycle progression.

PMID- 12421570
TI  - Molecular cloning and functional characterization of Cynomolgus monkey (Macaca
      fascicularis) CC chemokine receptor, CCR3.
AB  - We have cloned and performed the first functional characterization of the
      chemokine receptor, CCR3, of Cynomolgus monkey (Macaca fascicularis). The deduced
      amino acid sequence of the cloned Cynomolgus CCR3 was found to be more similar to
      that of a previously-reported Rhesus (Macaca mulatta) CCR3 (99.4%) than that of a
      reported Cynomolgus CCR3 (98.0%). Stably-transfected Cynomolgus CCR3 bound human
      eotaxin (CCL11) with similar kinetics (Kd 240 pM) and was responsive to human
      CCR3 ligands (eotaxin [CCL11], eotaxin-2 [CCL24], and MCP4 [CCL13]) in Ca(2+)
      mobilization and chemotaxis assays, thus provides a useful alternative species
      model system for the analysis of modulators of eotaxin--CCR3 induced signaling
      and activation.

PMID- 12421571
TI  - Analysis of novel disease-related genes in bronchial asthma.
AB  - Bronchial asthma is a complex disease characterized by airway inflammation
      involving interleukin (IL)-4 and IL-13. We have applied microarray analyses to
      human bronchial epithelial cultures to probe for genes regulated by these
      cytokines and have identified a subset of disease-relevant genes by comparison
      with cDNA libraries derived from normal and asthmatic bronchial biopsies.
      Squamous cell carcinoma antigen-1 (SCCA1) and SCCA2, the cysteine and serine
      protease inhibitors, respectively, showed the highest expression by IL-4 and IL
      13, and particularly, SCCA1 was significantly increased in the asthmatic cDNA
      library. STAT6 was shown to be involved in expression of SCCA1 and SCCA2 in
      vitro. Furthermore, serum levels of SCCA were also elevated in asthmatic
      patients. Taken together, it was supposed that SCCA may play some role in the
      pathogenesis of bronchia asthma, and measuring its serum level may be relevant
      for diagnosing or monitoring the status of bronchial asthma. In a complex
      disorder such as asthma, this combination of in vitro and in vivo genomic
      approaches is a powerful discriminatory method enabling identification of novel
      disease-related genes and their mechanisms of regulation.

PMID- 12421572
TI  - Increased expression of B-lymphocyte chemoattractant, but not pro-inflammatory
      cytokines, in muscle tissue in rhesus chronic Lyme borreliosis.
AB  - Inflammation in skeletal muscle is a consistent feature of Lyme borreliosis, both
      in the human disease and experimental models. This study had two goals: to
      evaluate the expression of selected pro-inflammatory and chemokine genes in
      skeletal muscle in the Rhesus model of Lyme disease, and to identify unexpected
      cytokine genes involved in Lyme myositis. Two different techniques for measuring
      cytokine messenger RNA (mRNA) levels were used to achieve these goals: gene
      expression microarrays and. real-time RT-PCR (Taqman). Muscle from necropsies and
      biopsies were used, and were obtained from both infected and uninfected non-human
      primates (NHPs). Although many cytokines were found expressed in muscle tissue,
      pro-inflammatory cytokines commonly associated with inflammation were not
      consistently upregulated in infected muscles relative to uninfected muscles.
      However, B-lymphocyte chemoattractant (BLC), a chemokine implicated in the
      trafficking of B-cells into tissue, was increased in expression. This study is
      the first to extensively characterize cytokine gene expression in chronically
      inflamed tissue in Lyme borreliosis.

PMID- 12421573
TI  - The negative immunoregulatory effects of serotonin (5-HT) moduline, an endogenous
      5-HT1B receptor antagonist with anti-anxiety properties.
AB  - BACKGROUND: Serotonin (5-HT) has negative immunoregulatory effects by reducing
      the interferon-gamma (IFNgamma)/interleukin-10 (IL-10) production ratio by
      stimulated immune cells. Leukocytes have functional 5-HT1B receptors. 5-HT
      moduline, an endogenous 5-HT1B receptor antagonist, may antagonize the 5-HT1B
      agonist-induced proliferation of immune cells. AIMS: To examine the effects of 5
      HT moduline on the stimulated production of IFNgamma, tumor necrosis factor alpha
      (TNFalpha) and IL-10. RESULTS: 5-HT moduline, 10(-6) M and 10(-5)M, significantly
      reduced the production of IFNgamma and the IFNgamma/IL-10 ratio. 5-HT moduline
      10(-5)M significantly reduced the production of TNFalpha. The combination of 5
      HT, 15 microg/mL, with 5-HT moduline, 10(-6)M and 10(-5)M, further decreases the
      IFNgamma/IL-10 production ratio. INTERPRETATION: 5-HT moduline has negative
      immunoregulatory effects.

PMID- 12421574
TI  - Cell vacuolation.

PMID- 12421575
TI  - Tubular-vesicular transformation in the contractile vacuole system of
      Dictyostelium.
AB  - The contractile vacuole complex of Dictyostelium is the paradigm of a membrane
      system that undergoes tubular-vesicular transitions during its regular cycle of
      activities. This system acts as an osmoregulatory organelle in freshwater amoebae
      and protozoa. It collects fluid in a network of tubules and cisternae, and pumps
      it out of the cell through transient pores in the plasma membrane. Tubules and
      vacuoles are interconvertible. The tubular channels are associated with the
      cortical actin network and are capable of moving and fusing. The contractile
      vacuole complex is separate from vesicles of the endosomal pathway and preserves
      its identity in a dispersed state during cell division. We outline techniques to
      visualize the contractile vacuole system by electron and light microscopy.
      Emphasis is placed on GFP-fusion proteins that allow visualization of the
      dynamics of the contractile vacuole network in living cells. Proteins that
      control activities of this specialized organelle in Dictyostelium have been
      conserved during evolution and also regulate membrane trafficking in man.

PMID- 12421576
TI  - Development of periodic tension in the contractile vacuole complex membrane of
      paramecium governs its membrane dynamics.
AB  - The contractile vacuole complex is a membrane-bound osmoregulatory organelle of
      fresh water protozoa such as Paramecium. In Paramecium it consists of a central
      vacuole (the contractile vacuole) and 5-10 arms that radially extend from the
      vacuole into the cytosol (the radial arms). Excess cytosolic water, acquired
      osmotically, is segregated by the radial arms and enters the vacuole, so that the
      vacuole swells (the fluid-filling phase). The vacuole then rounds (the rounding
      phase) and the radial arms sever from the vacuole. The vacuole membrane then
      fuses with the plasma membrane at the pore region and the pore opens. The vacuole
      shrinks as its fluid is discharged through the pore (the fluid-discharging
      phase). The pore closes when the fluid has been discharged. The radial arms then
      reattach to the vacuole, so that the vacuole swells again as the fluid enters
      from the arms (the next fluid-filling phase). We found that the vacuole continued
      to show rounding and slackening even after it together with a small amount of
      cytosol had been isolated from the cell. Using a microcantilever placed on the
      surface of the vacuole the tension of the in vitro vacuole increased to 5 x 10(
      3)N m(-1) as the vacuole rounds, and its lowest value was 1 x 10(-4)N m(-1)
      during slackening. We propose a hypothesis that an increase in the spontaneous
      curvature of the organelle's membrane leads to an increase in membrane tension
      and thus to the vacuole's rounding, severing of the radial arms from the vacuole,
      and opening of the pore. Conversely, a decrease in the spontaneous curvature
      accompanied by a decrease in membrane tension could lead to the closing of the
      pore and reattachment of the radial arm at the start of the fluid-filling phase.

PMID- 12421577
TI  - Parasitophorous vacuole: morphofunctional diversity in different coccidian genera
      (a short insight into the problem).
AB  - We present a short insight into the problem of parasitophorous vacuole (PV)
      formation as a most peculiar kind of cell vacuolization occurring in the course
      of intracellular development of coccidian pathogens of the genera Eimeria,
      Isospora, Toxoplasma, Sarcocystis, Cryptosporidium, Epieimeria, and Karyolysus.
      The review focuses on the morpho-functional diversity of PVs in these parasites.
      By the present time, the PVs containing different parasite genera and species
      have been examined to different extent. The membrane of the PV (PVM) obviously
      derives from the host cell plasmalemma. But soon after parasite penetration, the
      morphofunctional organization and biochemical composition of the PVM drastically
      changes: its proteins are selectively excluded and those of the parasite are
      incorporated. As the result, the PV becomes not fusigenic for lysosomes or any
      other vacuoles or vesicles, because host cell surface markers necessary for
      membrane fusion are eliminated from the PVM during parasite invasion. The pattern
      of the PVs is parasite specific and demonstrates a broad diversity within the
      same genera and species and even at different stages of the endogenous
      development. The PV is far from being an indifferent membrane vesicle containing
      the parasite. Instead, it represents a dynamic system that reflects the innermost
      events of host-parasite relationships, thus promoting the accomplishing of the
      parasite life cycle, which, in its turn, is a necessary prerequisite of the
      parasite eventual survival as a species.

PMID- 12421578
TI  - Giant vacuoles arising during ADH-induced transcellular bulk water flow across
      the epithelium of the frog urinary bladder.
AB  - Structural changes of the cytoplasm of urinary bladder granular cells after an
      antidiuretic hormone (ADH) stimulation of water transport were studied using
      standard and cryogenic methods of electron microscopy. Numerous changes occurred
      in these cells, the cytoplasm of the granular cells becoming swollen, and the
      intercellular spaces enlarged. Most granules become fused with the apical
      membrane. Under maximal ADH action, giant vacuoles appear in the cytoplasm of
      granular cells, in association with microfilaments and microtubules. Analysis of
      ultrastructure of the granular cells has established the origin of giant vacuoles
      from the cis -cisterna of the Golgi complex. A hypothesis based on the
      morphofunctional homology of giant vacuoles in granular cells with the
      contractile vacuoles of Protozoa is proposed in which the giant vacuoles
      ('contractile-like' vacuoles) are seen as operating a osmoregulatory role in
      these cells. It is also proposed that microtubules and microfilaments participate
      in giant vacuole migration through the cytoplasm.

PMID- 12421579
TI  - Vacuole formation in mast cells responding to osmotic stress and to F-actin
      disassembly.
AB  - Fluorescent probes were used to visualize the morphology of membranes and of F
      actin in rat peritoneal mast cells, exposed to hyperosmotic medium and
      consequently reversed to isotonicity. Hypertonicity induced cell shrinkage
      followed by a regulatory volume increase, and cell alkalinization that was
      sensitive to amiloride, an inhibitor of the Na(+)/H(+) exchanger (NHE), but not
      to Latrunculin B, an inhibitor of actin polymerization. Using Bodipy
      Sphingomyelin, we have observed formation of vacuole-like dilations (VLDs),
      primarily at or close to the adhesion plane, following the reversal from hyper-
      to isotonic medium. VLD formation was not inhibited by Latrunculin B or by
      amiloride. Phalloidin staining has shown that actin filaments do not surround the
      vacuoles and latrunculin-induced depolymerization of actin has actually promoted
      vacuole formation, even in isotonic conditions. The results support the idea that
      a decrease in membrane tension promotes the internalization of the plasma
      membrane.

PMID- 12421580
TI  - Vacuolation in T-tubules as a model for tubular-vesicular transformations in
      biomembrane systems.
AB  - This review outlines the basic properties of T-tubules in skeletal muscle cells,
      and the factors that govern reversible vacuolation in T-tubules under
      experimental conditions. Comparable membranous transformations, involving the
      plasma membrane or occurring intracellularly, in non-muscle cells are then
      considered. Finally, the mechanisms of similar transformations in various model
      membrane systems are discussed. In view of the similarities between reversible
      vacuolation in the T-system and membrane transformations occurring in a variety
      of non-muscle cells, it is suggested that reversible vacuolation in T-tubules may
      be regarded as a general model for tubular-vesicular transformations in
      biomembranes.

PMID- 12421581
TI  - Osmotic processes in vacuolation and detubulation of skeletal muscle.

PMID- 12421582
TI  - Dynamic vacuolation in skeletal muscle fibres after fatigue.
AB  - Vacuoles develop after fatiguing stimulation in frog skeletal muscle fibres.
      Experiments on isolated Xenopus muscle fibres show that this vacuolation is a
      dynamic process that reaches its maximum about 20 min after the end of fatiguing
      stimulation and then recedes. Fatigue-induced vacuoles originate from the t
      tubular system. Recent data indicate that vacuoles are formed because of lactate
      accumulation in the t-tubules resulting in increased osmotic pressure and
      subsequent water influx. There is no obligatory connection between the presence
      of vacuoles and force depression, which is another common feature during the
      recovery from fatigue. Nevertheless, extensive vacuolation may exaggerate this
      force depression.

PMID- 12421584
TI  - Detection of minute virus of mice using real time quantitative PCR in assessment
      of virus clearance during the purification of Mammalian cell substrate derived
      biotherapeutics.
AB  - A real time quantitative PCR assay has been developed for detecting minute virus
      of mice (MVM). This assay directly quantifies PCR product by monitoring the
      increase of fluorescence intensity emitted during enzymatic hydrolysis of an
      oligonucleotide probe labelled covalently with fluorescent reporting and
      quenching dyes via Taq polymerase 5'-->3' exonuclease activity. The quantity of
      MVM DNA molecules in the samples was determined using a known amount of MVM
      standard control DNA fragment cloned into a plasmid (pCR-MVM). We have
      demonstrated that MVM TaqMan PCR assay is approximately 1000-fold more sensitive
      than the microplate infectivity assay with the lowest detection limit of
      approximately one particle per reaction. The reliable detection range is within
      100 to 10(9) molecules per reaction with high reproducibility. The intra assay
      variation is <2.5%, and the inter assays variation is <6.5% when samples contain
      >100 particles/assay. When we applied the TaqMan PCR to MVM clearance studies
      done by column chromatography or normal flow viral filtration, we found that the
      virus removal factors were similar to that of virus infectivity assay. It takes
      about a day to complete entire assay processes, thus, the TaqMan PCR assay is at
      least 10-fold faster than the infectivity assay. Therefore, we concluded that
      this fast, specific, sensitive, and robust assay could replace the infectivity
      assay for virus clearance evaluation.

PMID- 12421583
TI  - Properties of the vertebrate skeletal muscle tubular system as a sealed
      compartment.
AB  - Confocal imaging of impermeant fluorescent dyes trapped in the tubular (t-)
      system of skeletal muscle fibres of rat and cane toad was used to examine changes
      in the morphology of the t-system upon mechanical skinning, the time course of
      dye loss from the sealed t-system in mechanically skinned fibres and the
      influence of rapid application and removal of glycerol on the morphology of the
      sealed t-system. In contrast to intact fibres, which have a t-system open to the
      outside, the sealed t-system of toad mechanically skinned fibres consistently
      displayed local swellings (vesicles). The occurrence of vesicles in the sealed t
      system of rat-skinned fibres was infrequent. Application and removal of 200-400
      mM glycerol to the sealed t-system did not produce any obvious changes in its
      morphology. The dyes fluo-3, fura-2 and Oregon green 488 were lost from the
      sealed t-system of toad fibres at different rates suggesting that the mechanism
      of organic anion transport across the tubular wall was not by indiscriminate bulk
      transport. The rate of fluo-3 and fura-2 loss from the sealed t-system of rat
      fibres was greater in rat than in toad fibres and could be explained by
      differences in surface area: volume ratio of the t-system in the two fibre types.
      Based on the results presented here and on other results from this laboratory, an
      explanation is given for the formation of numerous vesicles in toad-skinned
      fibres and lack of vesicle formation in rat-skinned fibres. This explanation can
      also help with better understanding the mechanism responsible for vacuole
      formation in intact fibres.

PMID- 12421585
TI  - Interference of thiomersal in biologicals during protein estimation.
AB  - In the present report thiomersal was detected as interfering substance in
      hepatitis B vaccines during the total protein estimation by Lowry's protein
      assay. The thiomersal at different concentrations of 0.005%, 0.0075%, 0.01%,
      0.02%, 0.05% and 0.1% was found to reduce the Folin Ciocalteu's phenol reagent
      and produce colour development between 0.024 O.D to 1.023 O.D. values. Further,
      the thiomersal was shown to interfere between 34.55% to 52.73% with Folin
      Ciocalteu's phenol reagent, when 10 batches of different hepatitis B vaccines
      were subjected to estimation of total protein content by Lowry's protein assay.

PMID- 12421586
TI  - Detection and characterization of pestivirus contaminations in human live viral
      vaccines.
AB  - In view of the use of potentially contaminated foetal calf serum (FCS) in cell
      cultures pestiviruses may be present in live viral vaccines. Thirty-six lots of
      human live viral vaccines produced by three manufacturers were tested for the
      presence of pestiviruses. Bovine viral diarrhoea virus (BVDV) RNA was detected in
      33% of the vaccine lots. All positive results were caused by the mumps component
      of a single manufacturer. Partial sequences of the 5' untranslated region of BVD
      viral RNA were determined. The sequences were closely related to that of the NADL
      strain of BVDV. The amount of BVDV RNA in the vaccines was determined by real
      time RT-PCR using the LightCycler. Between 3.3*10(2) and 6.2*10(5) RNA copies per
      dose were found to be present in the vaccine samples.Additionally, culture tests
      were done with FCS and human diploid cells used in the vaccine production of the
      manufacturer whose vaccines were positive by PCR. All attempts to detect virus
      antigen in MRC-5 human diploid cells or to infect these cells with BVDV failed.
      This suggests that BVDV RNA detected in human live viral vaccines represents
      passive carry over of BVDV from contaminated FCS rather than active virus
      replication in human diploid cells. Our results indicate that contamination with
      BVDV of FCS used in vaccine production does not appear to be of immediate concern
      to human health. Furthermore, our results indicate that gamma-irradiation of FCS
      destroys BVDV particles and is also effective in preventing the presence of BVDV
      RNA in the vaccines.

PMID- 12421587
TI  - Chinese hamster ovary (CHO) cell clustering does not correlate with in vivo
      histamine-sensitization when measuring residual activity of aldehyde-treated
      pertussis toxin (PT).
AB  - CHO cell clustering test failed to detect a reversion to PT toxicity of a
      commercial DTaP vaccine batch that failed to pass the test for reversion to
      histamine sensitizing (HS) activity. Efficacy of CHO cell clustering assay was,
      accordingly, evaluated using purified PT treated with graded concentrations of
      formaldehyde at 37 degrees C for 24h. The formaldehyde-treated PT was shown to
      lose CHO cell clustering activity to the level of 0.01% by the mild treatment
      while retaining 3.7-20.3% of HS activity which were far over the levels of
      commercial vaccines. When a reversion to toxicity of the aldehyde-detoxified PT
      was examined by incubating at 37 degrees C for three weeks, CHO cell clustering
      test again failed to detect the reversion to toxicity of the PT which showed a
      remarkable reversion to HS activity. These findings suggested that CHO cell
      clustering test might have an efficacy limitation in predicting in vivo activity
      of aldehyde-treated PT.

PMID- 12421588
TI  - Development of Vero cell-derived inactivated Japanese encephalitis vaccine.
AB  - We have established a manufacturing system for a Vero cell-derived inactivated
      Japanese encephalitis vaccine at a 500l scale. The production system involves
      expansion of Vero cells using microcarrier, followed by virus infection. Except
      for an additional purification step, the downstream purification processes are
      similar to those used for the current mouse brain-derived vaccine; cell removal,
      concentration and removal of low-molecular weight impurities by membrane
      filtration, formalin-inactivation, sucrose density gradient ultracentrifugation,
      and Sulfate-Cellulofine column chromatography are conducted. The antigen obtained
      from the manufacturing system was highly purified and its physico-chemical and
      immunological properties were comparable with those of antigen derived from mouse
      brains. Our system is very simple and could be easily scaled-up to allow vaccine
      production at a several thousand litre scale.

PMID- 12421589
TI  - A stable lyophilized reagent for use in a potential reference assay for
      quantitation of anti-D in immunoglobulin products.
AB  - Quality control of anti-D immunoglobulins intended for in vivo clinical use
      requires in vitro assay of potency. A lyophilized biotinylated monoclonal anti-D
      (biotinylated Brad-5; 99/698) has been evaluated for its suitability to serve as
      a working reagent in a competitive enzyme-linked immunoassay (EIA) for anti-D
      quantitation. The reagent demonstrated acceptable stability in accelerated
      degradation tests and following reconstitution. Twelve international laboratories
      obtained comparable potencies for each of nine anti-D samples using 99/698 in a
      standardized assay procedure using erythrocytes fixed to microtitre plates. We
      also describe the use of trehalose for stabilization of dried erythrocyte-coated
      microtitre plates.

PMID- 12421590
TI  - Effects of chronic variate stress on feeding behavior and on monoamine levels in
      different rat brain structures.
AB  - Chronic variate stress was seen to decrease the ingestion of sweet food when
      compared to control rats. Brain monoamines are known to be involved in the
      control of food intake, serotonin appears to be involved in the mechanisms of
      satiety, and dopamine in mediating appetite or approach behaviors triggered by
      incentive stimuli associated with rewards. The effect of chronic variate stress
      on cerebral levels of monoamines was also studied in rats. Increased levels of
      DOPAC were observed in the frontal cortex and in the hippocampus and an increased
      5-HIAA/5-HT ratio was also observed in this latter structure. In the
      hypothalamus, levels of HVA and DOPAC were decreased, as well as the DOPAC/DA
      ratio, while no difference was found in amygdala. During the treatment, there
      were no differences in the consumption of water and regular food between stressed
      and control animals. An increase in the adrenal weight was observed at the end of
      the treatment. The results suggest that emotional changes, such as exposure to
      stress situations can influence feeding behavior, chronic variate stress causes
      decreased ingestion of sweet food and decreased dopaminergic neurotransmission in
      hypothalamus. Increased dopamine metabolite levels in the cortex and hippocampus
      were also observed and some of these modifications may be related to alterations
      in feeding behavior.

PMID- 12421591
TI  - Effects of 5-aminolevulinic acid on the glutamatergic neurotransmission.
AB  - The haem precursor 5-aminolevulinic acid (ALA) has been proposed to be involved
      in the neurological dysfunctions presented by patients with acute porphyrias. The
      effects of ALA on the [3H]glutamate and [3H]MK-801 (dizocilpine) binding to rat
      cortical membranes and on [3H]glutamate uptake by rat astrocyte cultures were
      evaluated in the present study in order to elucidate the interaction of ALA with
      the glutamatergic system and its possible contribution to the in vivo excitatory
      properties of ALA. ALA (0-1mM) did not affect the binding of 100 nM
      [3H]glutamate, nor the equilibrium binding constants (K(d) and B(max)) of this
      neurotransmitter in rat or human cortical membranes. The binding of the NMDA
      channel blocker, [3H]MK-801, was not affected by ALA (0-10mM) either. ALA (0-3mM)
      dose-dependently inhibited glutamate uptake by astrocyte cultures. ALA
      significantly reduced both the K(m) and V(max) of glutamate uptake indicating an
      uncompetitive inhibition. The inhibitory effect was irreversible and apparently
      related to the selective inhibition of the GLT-1 (EAAT2) subtype of glutamate
      transporter. The finding that ALA significantly increased astrocyte
      lipoperoxidation in astrocytes incubated under these conditions suggests that the
      inhibitory effect of ALA might be related to an oxidative damage of the
      transporter. We propose that the inhibition of glutamate uptake may underlie ALA
      induced convulsions.

PMID- 12421592
TI  - Hydrogen peroxide mediates higher order chromatin degradation.
AB  - Although a large body of evidence supports a causative link between oxidative
      stress and neurodegeneration, the mechanisms are still elusive. We have recently
      demonstrated that hydrogen peroxide (H(2)O(2)), the major mediator of oxidative
      stress triggers higher order chromatin degradation (HOCD), i.e. excision of
      chromatin loops at the matrix attachment regions (MARs). The present study was
      designed to determine the specificity of H(2)O(2) in respect to HOCD induction.
      Rat glioma C6 cells were exposed to H(2)O(2) and other oxidants, and the
      fragmentation of genomic DNA was assessed by field inversion gel electrophoresis
      (FIGE). S1 digestion before FIGE was used to detect single strand fragmentation.
      The exposure of C6 cells to H(2)O(2) induced a rapid and extensive HOCD. Thus,
      within 30 min, total chromatin was single strandedly digested into 50 kb
      fragments. Evident HOCD was elicited by H(2)O(2) at concentrations as low as 5
      micro M. HOCD was mostly reversible during 4-8h following the removal of H(2)O(2)
      from the medium indicating an efficient relegation of the chromatin fragments. No
      HOCD was induced by H(2)O(2) in isolated nuclei indicating that HOCD-endonuclease
      is activated indirectly by cytoplasmic signal pathways triggered by H(2)O(2). The
      exposure of cells to a synthetic peroxide, i.e. tert-butyrylhydroperoxide (tBH)
      also induced HOCD, but to a lesser extent than H(2)O(2). Contrary to the
      peroxides, the exposure of cells to equitoxic concentration of hypochlorite and
      spermine NONOate, a nitric oxide generator, failed to induce rapid HOCD. These
      results indicate that rapid HOCD is not a result of oxidative stress per se, but
      is rather triggered by signaling cascades initiated specifically by H(2)O(2).
      Furthermore, the rapid and extensive HOCD was observed in several rat and human
      cell lines challenged with H(2)O(2), indicating that the process is not
      restricted to glial cells, but rather represents a general response of cells to
      H(2)O(2).

PMID- 12421593
TI  - Inhibition of LPS-induced iNOS and NO synthesis in primary rat microglial cells.
AB  - Nitric oxide (NO) has been implicated in the etiopathology of multiple sclerosis
      (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), and
      inhibition of NO synthesis has been proposed to be a possible mechanism of action
      of drugs to treat MS. In the present study, we investigated the inhibitory effect
      on NO synthesis of various steroids, cytokines and drugs used or proposed for the
      treatment of MS. As a model system, we used primary rat microglial cells which
      produce NO synthase and subsequently release NO upon stimulation with
      lipopolysaccharide (LPS). Among the substances tested, the glucocorticoids
      prednisone, hydrocortisone, dexamethasone and progesterone as well as
      transforming growth factor-beta (TGF-beta) dose-dependently inhibited LPS-induced
      nitric oxide synthase (iNOS) and NO synthesis. In contrast, COP-1, the
      phosphodiesterase inhibitors rolipram and pentoxifylline, the cytokines
      interleukin-10 (IL-10) and interferon-beta (IFN-beta) as well as the steroids
      beta-estradiol, testosterone, and dehydroepiandrosterone (DHEA) showed no
      inhibitory effect. Cholesterol slightly, but not significantly, increased LPS
      induced nitric oxide synthesis. We conclude from the present study that with
      respect to treatment of MS, inhibition of NO synthesis may be an important
      mechanism of action of glucocorticoids and transforming growth factor-beta, but
      not of other drugs used or proposed to treat MS.

PMID- 12421594
TI  - Catechol-O-methyltransferase inhibition protects against 3,4
      dihydroxyphenylalanine (DOPA) toxicity in primary mesencephalic cultures: new
      insights into levodopa toxicity.
AB  - Inhibition of catechol-O-methyltransferase (COMT) has protective effects on
      levodopa (L-DOPA), but not D-DOPA toxicity towards dopamine (DA) neurons in rat
      primary mesencephalic cultures [Mol. Pharmacol. 57 (2000) 589]. Here, we extend
      our recent studies to elucidate the mechanisms of these protective effects. Thus,
      we investigated the effects of all main L-DOPA/DA metabolites on survival of
      tyrosine hydroxylase immunoreactive (THir) neurons in primary rat mesencephalic
      cultures. 3-O-Methyldopa, homovanillic acid, dihydroxyphenyl acetate and 3
      methoxytyramine had no effects at concentrations up to 300 micro M after 24h,
      whereas DA was more toxic than L-DOPA with toxicity at concentrations of >or=1
      micro M. The coenzyme of COMT, S-adenosyl-L-methionine (SAM), and its
      demethylated product S-adenosylhomocystein caused no relevant alteration of THir
      neuron survival or L-DOPA toxicity. In contrast, inhibition of SAM synthesis by
      selenomethionine showed time- and dose-dependent increase of THir neuron
      survival, but did not affect L-DOPA toxicity. L-DOPA-induced lipid peroxidation
      in mesencephalic cultures was not modified by the COMT inhibitor Ro 41-0960 (1
      micro M). Increased contamination of the cultures with glial cells attenuated L-
      and D-DOPA toxicity, but caused significant enhancement of protection by COMT
      inhibitors against L-DOPA toxicity only. Investigations of L-DOPA uptake in rat
      striatal cultures using HPLC revealed a significant reduction of extracellular L
      DOPA concentrations by Ro 41-0960. Our data confirm that L-DOPA toxicity towards
      DA neurons is mediated by an autooxidative process, which is attenuated by glial
      cells. In addition, we demonstrate a second mechanism of L-DOPA toxicity in vitro
      mediated by a COMT- and glia-dependent pathway, which is blocked by COMT
      inhibitors, most likely due to enhanced glial uptake of L-DOPA.

PMID- 12421595
TI  - Roles of cathepsins in reperfusion-induced apoptosis in cultured astrocytes.
AB  - Astrocytic apoptosis may play a role in the central nervous system injury. We
      previously showed that reperfusion of cultured astrocytes with normal medium
      after exposure to hydrogen peroxide (H(2)O(2))-containing medium causes
      apoptosis. This study examines the involvement of the lysosomal enzymes
      cathepsins B and D in the astrocytic apoptosis. Reperfusion after exposure to
      H(2)O(2) caused a marked increase in caspase-3 and cathepsin D activities and a
      marked decrease in cathepsin B activity. Pepstatin A, an inhibitor of cathepsin
      D, and acetyl-L-aspartyl-L-methionyl-L-glutaminyl-L-aspart-1-aldehyde (Ac-DMQD
      CHO), a specific inhibitor of caspase-3, blocked the H(2)O(2)-induced decrease in
      cell viability and DNA ladder formation in cultured rat astrocytes. The (L-3
      trans-(propylcarbamoyl)oxirane-2-carbonyl)-L-isoleucyl-L-proline methyl ester
      (CA074 Me), a specific inhibitor of cathepsin B, did not affect the H(2)O(2)
      induced cell injury. On the other hand, CA074 Me decreased cell viability with
      DNA ladder formation when cultured in the presence of Ac-DMQD-CHO. This caspase
      independent apoptosis was attenuated by the addition of the cathepsin D inhibitor
      pepstatin A. Caspase-3 like activity was markedly inhibited by Ac-DMQD-CHO and
      partially by pepstatin A. Pepstatin A and CA074 Me inhibited cathepsin B and
      cathepsin D activities, respectively, in the presence and absence of Ac-DMQD-CHO.
      These results suggest that cathepsins B and D are involved in astrocytic
      apoptosis: cathepsin D acts as a death-inducing factor upstream of caspase-3 and
      the caspase-independent apoptosis is regulated antagonistically by cathepsins B
      and D.

PMID- 12421596
TI  - P2Y(1) receptor activation inhibits NMDA receptor-channels in layer V pyramidal
      neurons of the rat prefrontal and parietal cortex.
AB  - In the 1st part of this study, monosynaptic excitatory postsynaptic potentials
      (EPSPs) in layer V of the rat prefrontal cortex (PFC) were evoked by electrical
      stimulation of layer I. Recordings with intracellular sharp, microelectrodes
      showed a concentration-dependent inhibition of the EPSP by adenosine 5'-O-(2
      thiodiphosphate) (ADP-beta-S). Pyridoxal-phosphate-6-azophenyl-2',4'-disulphonic
      acid (PPADS), when given alone depressed the EPSP and in addition antagonized the
      effect of ADP-beta-S. Exclusion of the N-methyl-D-aspartate (NMDA) component of
      the EPSP by D(.)-amino-5-phosphonopentanoic acid (AP-5) abolished the ADP-beta-S
      induced depression. The pressure-application of both NMDA and alpha-amino-3
      hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) caused reproducible
      depolarizations. ADP-beta-S inhibited the effect of NMDA, but did not alter that
      of AMPA. PPADS was also under these conditions antagonistic with ADP-beta-S. In
      the 2nd part of the study, NMDA-induced currents were measured by whole-cell
      patch-clamp pipettes. ADP-beta-S caused a concentration-dependent inhibition of
      the responses to NMDA. PPADS alone did not alter the NMDA-currents but again
      antagonized the action of ADP-beta-S; 2'-deoxy-N(6)-methyladenosine-3',5'
      diphosphate (MRS 2179) also abolished the NMDA effect. The ADP-beta-S-induced
      inhibition persisted in the presence of tetrodotoxin (TTX) or guanosine 5'-O-(3
      thiodiphosphate) (GDP-beta-S) applied to the external medium and the pipette
      solution, respectively. The 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) moderately
      decreased the ADP-beta-S effect. The inhibitory function of ADP-beta-S on EPSPs
      and the interaction with PPADS was observed also in layer V pyramidal neurons of
      the parietal somatosensory cortex. In conclusion, metabotropic P2Y(1) receptors
      appear to exert a new modulatory influence on fast excitatory amino acid
      transmission in the cerebral cortex.

PMID- 12421597
TI  - Pentylenetetrazol-induced seizures and kindling: changes in free fatty acids,
      superoxide dismutase, and glutathione peroxidase activity.
AB  - The whole brain free fatty acid (FFA) level, as well as the activities of
      superoxide dismutase (SOD) and glutathione peroxidase (GPX) were determined in
      the frontal cortex, cerebellum, hippocampus, and pons-medulla region of the
      single pentylenetetrazol (PZT)-treated and PZT-kindled Hannover-Wistar rats. PZT
      administration in the convulsive dose caused significant increase of the brain
      FFA content. Decreased SOD activity was detected in the frontal cortex of PZT
      kindled rats, whereas decreased GPX activity was found in the frontal cortex and
      cerebellum of all treated rats, as well as in the hippocampus and pons-medulla of
      PZT-kindled rats. Kindling caused distinctive change of antioxidative defense in
      the frontal cortex, hippocampus, and pons-medulla region.

PMID- 12421598
TI  - Genistein inhibits Ca2+ influx and glutamate release from hippocampal
      synaptosomes: putative non-specific effects.
AB  - The role of protein tyrosine kinases on glutamate release was investigated by
      determining the effect of broad range inhibitors of tyrosine kinases on the
      release of glutamate from rat hippocampal synaptosomes. We found that lavendustin
      A and herbimycin A did not inhibit glutamate release stimulated by 15 mM KCl, but
      genistein, also a broad range inhibitor of tyrosine kinases did inhibit the
      intracellular Ca(2+) concentration response to KCl and, concomitantly, decreased
      glutamate release evoked by the same stimulus, in a dose-dependent manner. These
      effects were not observed with the inactive analogue genistin. Therefore, we
      investigated the mechanism whereby genistein modulates Ca(2+) influx and
      glutamate release. Studies with voltage-gated Ca(2+) channel inhibitors showed
      that omega-conotoxin GVIA did not further inhibit glutamate release or the Ca(2+)
      influx stimulated by KCl in the presence of genistein. This tyrosine kinase
      inhibitor and omega-agatoxin IVA had a partially additive effect on those events.
      Nitrendipine did not reduce significantly the KCl-induced responses. Genistein
      further reduced Ca(2+) influx in response to KCl in the presence of nitrendipine,
      omega-conotoxin GVIA and omega-agatoxin IVA, simultaneously. The effect of
      tyrosine phosphatase inhibitors was also tested on the influx of Ca(2+) and on
      glutamate release stimulated by KCl-depolarization. We found that the broad range
      inhibitors sodium orthovanadate and dephostatin did not significantly affect
      these KCl-evoked events. Our results suggest that genistein inhibits glutamate
      release and Ca(2+) influx in response to KCl independently of tyrosine kinase
      inhibition, and that tyrosine kinases and phosphatases are not key regulators of
      glutamate release in hippocampal nerve terminals.

PMID- 12421599
TI  - Altered reaction of facial motoneurons to axonal damage in the presymptomatic
      phase of a murine model of familial amyotrophic lateral sclerosis.
AB  - In transgenic mice carrying the G93A human mutation of Cu/Zn superoxide dismutase
      (SOD1), which provide a model of familial amyotrophic lateral sclerosis, we
      investigated, before the onset of symptoms, two parameters of the response of
      facial motoneurons to nerve transection, i.e. nitric oxide synthase induction and
      motoneuron loss. Axotomy elicited after 2 and 3 weeks high nitric oxide synthase
      expression in facial motoneurons of wild-type mice, whereas the induction was
      very weak or absent in transgenic mice. At 1 month post-axotomy, loss of facial
      motoneurons was significantly higher in mutant mice than in wild-type
      littermates. Thus, SOD1 mutation interferes with the oxidative cascade elicited
      by axonal injury in cranial motoneurons. The results also indicate that the
      adverse gain of function of the mutant SOD1 enhances the vulnerability of
      motoneurons to peripheral stressful conditions.

PMID- 12421600
TI  - Acrolein inflicts axonal membrane disruption and conduction loss in isolated
      guinea-pig spinal cord.
AB  - We have examined the effect of acrolein, an aldehyde product of lipid
      peroxidation, on axons in isolated guinea-pig spinal cord white matter. We found
      that 200 microM acrolein, but not 50 microM, induced a time-dependent loss of
      compound action potential conduction. Such conduction loss was irreversible
      within 1 h after acrolein perfusion. Parallel anatomical assessment indicates
      membrane integrity breakdown based on a horseradish peroxidase-exclusion assay.
      This is the first report to suggest that acrolein inflicts severe axonal damage.
      Since axonal damage within white matter plays a key role in the pathology of
      traumatic spinal cord injury, we suggest that acrolein may be a critical factor
      in mediating secondary functional loss.

PMID- 12421601
TI  - Influence of sleep disturbance on steroid 5alpha-reductase mRNA levels in rat
      brain.
AB  - Sleep deprivation has been shown to affect the production of steroid hormones in
      peripheral steroidogenic organs, but little is known about the influence of sleep
      disturbance on the metabolism of steroid hormones in the brain. To elucidate a
      possible association of the sleep-wake cycle with brain neurosteroid metabolism,
      the influence of short-term sleep disturbance on the expression of mRNA encoding
      steroid 5alpha-reductase, the enzyme converting progesterone and other steroid
      hormones to their neuroactive 5alpha-reduced metabolites, was investigated. Rats
      were first subjected to non-selective disturbance of the sleep-wake cycle, and
      the expression of steroid 5alpha-reductase mRNA in rat hippocampus and brainstem
      was determined using a semi-quantitative one-step RT-PCR technique. Non-selective
      disturbance of the sleep-wake cycle resulted in the elevation of 5alpha-reductase
      mRNA levels in the brainstem, but not in the hippocampus, and the elevated mRNA
      expression returned to the basal levels after a short period of the sleep
      recovery. Further studies showed that selective REM sleep deprivation
      significantly elevated 5alpha-reductase mRNA levels in both hippocampus and
      brainstem, thus proposing the possibility that REM sleep reduction may largely
      contribute to the elevation of steroid 5alpha-reductase mRNA levels observed
      during short-term disturbance of the sleep-wake cycle. Since the enhancement of
      steroid 5alpha-reductase gene expression may result in the elevation of
      neuroactive 5alpha-reduced steroid production in the brainstem, the findings
      presented here provide further evidence for suggesting that neuroactive steroids
      may play a physiologically important role in the neuronal network for REM sleep
      initiation and maintenance.

PMID- 12421602
TI  - Quantitative autoradiographic distribution of NPFF1 neuropeptide FF receptor in
      the rat brain and comparison with NPFF2 receptor by using [125I]YVP and
      [(125I]EYF as selective radioligands.
AB  - The selectivity of two new radioligands, [(125)I]YVP ([(125)I]YVPNLPQRF-NH(2))
      and [(125)I]EYF ([(125)I]EYWSLAAPQRF-NH(2)), for neuropeptide FF (NPFF) receptor
      subtypes was determined using HEK293 cells expressing hNPFF(1) and CHO cells
      expressing hNPFF(2) receptors. Saturation binding and displacement experiments
      showed that [(125)I]YVP and [(125)I]EYF bound selectively with a very high
      affinity, K(D)=0.18 nM and 0.06 nM, to NPFF(1) and NPFF(2) receptors
      respectively. By using in vitro autoradiography with these radioligands and frog
      pancreatic polypeptide (PP) as selective unlabelled competitor of NPFF(2) binding
      sites, NPFF(1) and NPFF(2) receptor distribution was analyzed throughout the rat
      CNS. The highest densities of [(125)I]EYF binding sites were seen in the most
      external layers of the dorsal horn of the spinal cord, the parafascicular
      thalamic nucleus, laterodorsal thalamic nucleus and presubiculum of hippocampus.
      All specific binding of this radioligand was inhibited by 200 nM frog PP. The
      density of 0.1 nM [(125)I]YVP binding was much smaller in all brain areas and
      frog PP-insensitive binding sites (NPFF(1) receptor subtype) were detected in
      septal, thalamic and hypothalamic areas but were absent in the spinal cord. The
      restricted distribution of NPFF(1) receptors in the CNS supports its specific
      role in a limited number of neuronal functions. In contrast to the rat spinal
      cord where the NPFF(1) system is absent, there is no strict separation between
      NPFF(1) and NPFF(2) system at the supraspinal level.

PMID- 12421603
TI  - Extending the cerebellar Lugaro cell class.
AB  - We describe here, in Golgi-impregnated rat cerebellar cortex, a new group of
      large granular layer neurons. These cells have a globular soma located at
      variable depths in the granular layer, and three to four long radiating dendrites
      coursing through the three layers of the cortex. The axon projects more or less
      directly into the molecular layer, where it expands in a local plexus of oblique
      and tortuous thick collaterals ascending through the major part of the layer.
      Interestingly, the axons of several of these cells give off a collateral that
      courses for a long distance in the transverse direction, just above the Purkinje
      cell somata, parallel to the parallel fibers. While the granular layer location
      and the polymorphous somato-dendritic pattern of these cells is reminiscent of
      that of Golgi cells, their axonal pattern is clearly of the same type as that of
      another large granular layer interneuron, the Lugaro cell. Moreover, double anti
      calretinin and anti-calbindin immunolabellings show that Lugaro cells as well as
      some globular somata dispersed in the granular layer are both calretinin-positive
      and in close apposition with numerous calbindin-positive varicosities of Purkinje
      cell axon recurrent collaterals. These latter are known from previous
      ultrastructural studies to be pre-synaptic to Lugaro cells. The common granular
      layer location and calretinin labelling, the striking similarity in axonal
      projection pattern, and the important common recurrent afferentation by Purkinje
      cell axons strongly argue in favor of the classification of these globular
      interneurons as a subgroup of a widened Lugaro cell type.

PMID- 12421604
TI  - Action potential afterdepolarization mediated by a Ca2+-activated cation
      conductance in myenteric AH neurons.
AB  - We investigated the nature of afterdepolarizing potentials in AH neurons from the
      guinea-pig duodenum using whole-cell patch-clamp recordings in intact myenteric
      ganglia. Afterdepolarizing potentials were minimally activated following action
      potential firing under normal conditions, but after application of charybdotoxin
      (40 nM) or tetraethyl ammonium (TEA; 10-20 mM) to the bathing solution, prominent
      afterdepolarizing potentials followed action potentials. The whole-cell current
      underlying afterdepolarizing potentials (I(ADP)) in the presence of TEA (10-20
      mM) reversed at -38 mV and was not voltage-dependent. Reduction of NaCl in the
      bathing (Krebs) solution to 58 mM shifted the reversal potential of the I(ADP) to
      -58 mV, suggesting that the current underlying the afterdepolarizing potential
      was carried by a mixture of cations. The relative contributions of Na(+) and K(+)
      to this current were estimated to be about 1:5. Substitution of external Na(+)
      with N-methyl D-glucamine blocked the current while replacement of internal Cl(-)
      with gluconate did not block the I(ADP). The I(ADP) was also inhibited when CsCl
      filled patch pipettes were used. The I(ADP) was blocked or substantially
      decreased in amplitude in the presence of N-type Ca(2+) channel antagonists,
      omega-conotoxin GVIA and omega-conotoxin MVIIC, respectively, and was eliminated
      by external Cd(2+), indicating that it was dependent on Ca(2+) entry. The I(ADP)
      was also inhibited by ryanodine (10-20 microM), indicating that Ca(2+)-induced
      Ca(2+) release was involved in its activation. Niflumic acid consistently
      inhibited the I(ADP) with an IC(50) of 63 microM. Using antibodies against the
      pore-forming subunits of L-, N- and P/Q-type voltage-gated Ca(2+) channels, we
      have demonstrated that myenteric AH neurons express N- and P/Q, but not L-type
      voltage-gated Ca(2+) channels. We conclude that the ADP in myenteric AH neurons,
      in the presence of an L-type Ca(2+)-channel blocker, is generated by the opening
      of Ca(2+)-activated non-selective cation channels following action potential
      mediated Ca(2+) entry mainly through N-type Ca(2+) channels. Ca(2+) release from
      ryanodine-sensitive stores triggered by Ca(2+) entry contributes significantly to
      the activation of this current.

PMID- 12421605
TI  - Interactions between ionotropic and metabotropic glutamate receptors regulate
      cAMP response element-binding protein phosphorylation in cultured striatal
      neurons.
AB  - The striatum is a key structure of basal ganglia controlling extrapyramidal motor
      activity and processing addictive plasticity of abused substances. Glutamatergic
      transmission that is enriched in the striatum regulates a variety of striatal
      neuronal activities via selective activation of ionotropic and metabotropic
      glutamate receptors (mGluRs). In this study, the interaction between N-methyl-D
      aspartate (NMDA) receptors and group I mGluRs (mGluR1 and mGluR5 subtypes) in
      activating a phosphorylation cascade to a transcription factor cAMP response
      element-binding protein (CREB) was investigated in primary cultures of E18 or
      postnatal day 1 striatal neurons. We found that activation of NMDA receptors with
      NMDA rapidly and concentration-dependently increased the number of neurons
      expressing phosphorylated CREB (pCREB) as revealed by immunocytochemistry. The
      increased pCREB expression by NMDA was sensitive to an NMDA antagonist MK801. Co
      incubation of a subthreshold dose of a group I mGluR agonist 3,5
      dihydroxyphenylglycine (DHPG) that itself did not alter basal pCREB expression
      augmented NMDA-induced CREB phosphorylation. The mGluR5 antagonist 2-methyl-6
      (phenylethynyl)pyridine hydrochloride blocked the DHPG augmentation of NMDA
      induced CREB phosphorylation, while the mGluR1 antagonist 7
      (hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester did not.
      Interestingly, the protein kinase C inhibitors chelerythrine and Go6983 also
      prevented DHPG from enhancing CREB phosphorylation induced by NMDA. Whereas a low
      dose of the protein kinase C activator phorbol 12-myristate 13-acetate mimicked
      the DHPG potentiation. These results indicate a facilitatory regulation of an
      NMDA cascade to CREB phosphorylation by concurrent glutamatergic tone on mGluR5,
      which is probably processed via an intracellular signaling pathway involving
      protein kinase C.

PMID- 12421606
TI  - The role of the dorsal columns in neuropathic behavior: evidence for plasticity
      and non-specificity.
AB  - Despite conflicting clinical and experimental evidence, textbook description of
      somatic sensations continues to follow a rigid dichotomy based on the concept
      that pain sensation is transmitted cephalad primarily through anterolateral
      pathways, while touch is mediated through the dorsal column pathway. This study
      provides an example of the dynamic rerouting in the transmission of the
      nociceptive signals following injuries to the peripheral and central processes of
      sensory neurons. In two rat models for mononeuropathy, the chronic constriction
      injury model [Bennett, G.J., Xie, Y.K., Pain 33 (1988) 87-107] and the spared
      nerve injury model [Decosterd, I., Woolf, C.J., Pain 87 (2000) 149-158], we
      demonstrate that selective dorsal columns lesion produced significant decrease of
      tactile and cold allodynias and thermal hyperalgesia which were assessed by the
      Von Frey hair filaments, the acetone drop test and the heat-induced paw
      withdrawal, respectively. These manifestations, however, can reappear 2 weeks
      after bilateral dorsal column lesion in rats subjected to spared nerve injury
      mononeuropathy and appear also in animals sustaining chronic bilateral dorsal
      column lesion followed by either model of mononeuropathy. Lesion of the dorsal
      column on the side opposite to the neuropathic leg did not alter the neuropathic
      manifestations in both animal models. Changes in the sequence of timing of the
      dorsal column lesion and induction of mononeuropathy, suggest that the effects of
      the former last for 1 to 2 weeks. The results of this study show that the dorsal
      columns are involved in neuropathic manifestations and at the same time are not
      necessary for their full development and persistence. Furthermore, these results
      shade doubts on the validity of the concept of segregation of pathways involved
      in the transmission of neuropathic manifestations. Therefore, principles
      governing acute pain transmission are not necessarily applicable to chronic pain
      situations. The latter conditions seem to engage other available pathways to
      reestablish the pain signaling system.

PMID- 12421607
TI  - Dehydroepiandrosterone and alpha-estradiol limit the functional alterations of
      rat brain mitochondria submitted to different experimental stresses.
AB  - The effects of dehydroepiandrosterone (DHEA), dehydroepiandrosterone-sulfate
      (DHEA-S), alpha-estradiol and beta-estradiol on the main functions of purified
      rat brain mitochondria were investigated in basal conditions and after being
      submitted to various stresses including anoxia-reoxygenation, uncoupling and
      apoptosis. In basal conditions, DHEA (1 microM) and alpha-estradiol (1 microM)
      inhibited the respiratory control ratio (RCR) from 3.1 to 2.3 (25%). After anoxia
      reoxygenation, DHEA (1 microM) and alpha-estradiol (1 microM) reversed
      significantly (P<0.01) the RCR decrease from 1.4 to 2.0 (21.5%) by restoring the
      state 4. This effect was observed when DHEA was added either before anoxia or
      before reoxygenation and when alpha-estradiol was added before anoxia. The
      mitochondrial membranes damaged after the anoxia-reoxygenation were 70 and 50%,
      respectively, protected by DHEA and alpha-estradiol at 1 microM. They also
      limited by about 50%, the cytochrome c release induced by the anoxia
      reoxygenation. The oxygen consumption of mitochondria in presence of NADH (130
      microM) and cytochrome c (5 microM) was significantly inhibited by DHEA and alpha
      estradiol with high EC(50) of 30 and 22 pM, respectively. At 1 microM, they also
      inhibited the 10 microM carbonyl cyanide m-chlorophenylhydrazone-induced
      uncoupling to about 35% whereas beta-estradiol only decreased it to 9%. Our
      results indicated that DHEA and alpha-estradiol partly preserved the
      mitochondrial functions altered by an anoxia-reoxygenation with a concentration
      dependent effect. The mechanism involved was independent of the classical genomic
      effect of steroids, the antioxidant properties but implicated a direct action on
      the mitochondrial membranes.

PMID- 12421608
TI  - Cerebellar lesion up-regulates P2X1 and P2X2 purinergic receptors in
      precerebellar nuclei.
AB  - ATP released in the extracellular space by neuronal injury can influence
      neighboring neurons via activation of purinergic receptors. In vitro data suggest
      the involvement of ATP and purinergic receptors as trophic agents in different
      biological events such as neuritogenesis and cell survival. Recently, in vivo
      studies have demonstrated modifications in the glial expression of ionotropic
      purinergic receptors after CNS lesions. In the present study, we investigated the
      effects of CNS lesion on the neuronal expression of P2X(1) and P2X(2) receptor
      subunits by immunohistochemistry and western blotting techniques. In the
      precerebellar structures of normal animals the expression of P2X(1) and P2X(2)
      was lower than previously reported. P2X(1) immunostaining was confined only to
      fibers, while P2X(2) immunostaining demonstrated a neuronal expression. After
      unilateral cerebellar lesion (hemicerebellectomy) axotomized precerebellar
      neurons underwent marked cell loss; however, some precerebellar neurons did not
      degenerate. Seven to 35 days after hemicerebellectomy, a transient, time
      dependent, marked increase in the number of immunopositive P2X(1) and P2X(2)
      neurons was observed in the precerebellar nuclei of the experimental side. An
      even distribution of immunopositive neurons was present in almost all
      precerebellar nuclei examined, except for the inferior olive. In this latter
      structure, differences in the distribution of immunopositive neurons were evident
      among the subnuclei. Up-regulation of immunoreactivity over relatively long time
      periods, distribution selectivity and absence of degenerating morphological
      features in immunopositive neurons suggest that purinergic receptors may have a
      role in mediating the survival of neuronal responses to axotomy. The present
      findings are the first report in the CNS of P2X(1) and P2X(2) receptor subunit
      involvement in neuronal reaction to axotomy. They provide in vivo evidence of a
      correlation between purinergic receptor subunit up-regulation and survival of
      injured neurons.

PMID- 12421609
TI  - Calcium/calmodulin-dependent protein kinase II clusters in adult rat hippocampal
      slices.
AB  - We have previously reported the formation of calcium/calmodulin-dependent protein
      kinase II (CaMKII) clusters approximately 110 nm in diameter in hippocampal
      neurons in culture and in the intact adult brain, under conditions that simulate
      ischemic stress and increase [Ca(2+)](i) [Dosemeci et al. (2000) J. Neurosci. 20,
      3076-3084; Tao-Cheng et al. (2001) Neuroscience 106, 69-78]. These observations
      suggest that ischemia-like conditions that prevail during the dissection of brain
      tissue for the preparation of hippocampal slices could lead to the formation of
      CaMKII clusters. We now show by pre-embedding immuno-electron microscopy that,
      indeed, CaMKII clusters are present in the CA1 pyramidal neurons in hippocampal
      slices from adult rats fixed immediately after dissection, and that the number of
      CaMKII clusters increases with the delay time between decapitation and fixation.
      Moreover, CaMKII clusters are typically localized near the endoplasmic reticulum.
      When acute slices are allowed to recover in oxygenated medium for 2 h, CaMKII
      clusters mostly disappear, indicating that clustering is reversible. Also, the
      postsynaptic density, another site for CaMKII accumulation under excitatory
      conditions, becomes thinner upon recovery. Treatment of recovered slices with
      high potassium for 90 s causes the re-appearance of CaMKII clusters in nearly all
      CA1 pyramidal cells examined. On the other hand, when dissociated hippocampal
      neurons in primary culture are exposed to the same depolarizing conditions, only
      approximately 25% of neurons exhibit CaMKII clusters, indicating a difference in
      the susceptibility of the neurons in culture and in acute slices to excitatory
      stimuli. Altogether these observations indicate that the effect of CaMKII
      clustering should be considered when interpreting experimental results obtained
      with hippocampal slices.

PMID- 12421610
TI  - Expression of calcitonin gene-related peptide, substance P and protein kinase C
      in cultured dorsal root ganglion neurons following chronic exposure to mu, delta
      and kappa opiates.
AB  - The mechanisms involved in morphine tolerance are poorly understood. It was
      reported by our group that calcitonin gene-related peptide (CGRP)-like
      immunoreactivity (IR) was increased in the spinal dorsal horn during morphine
      tolerance [Menard et al. (1996) J. Neurosci. 16, 2342-2351]. More recently, we
      observed that it was possible to mimic these results in cultured dorsal root
      ganglion (DRG) neurons allowing for more detailed mechanistic studies [Ma et al.
      (2000) Neuroscience 99, 529-539]. The aim of the present series of experiments
      was to further validate the DRG cell culture model by establishing which subtypes
      of opioid receptors are involved in the induction of CGRP in cultured rat DRG
      neurons, and to examine the signaling pathway possibly involved in the induction
      of CGRP-like IR following repeated opiate treatments. Other neuropeptides known
      to be expressed in DRG neurons, such as substance P (SP), neuropeptide Y (NPY)
      and galanin, were investigated to assess specificity. Following treatment with
      any of the three opioid agonists (mu, DAMGO; delta, DPDPE; kappa, U50488H), the
      number of CGRP- and SP-IR cultured DRG neurons increased significantly, and in a
      concentration-dependent manner, with the effects of kappa agonist being less
      pronounced. NPY and galanin were not affected.Double-immunofluorescence staining
      showed that the three opioid receptors were co-localized with both CGRP- and SP
      like IR.Protein kinase C (PKC)-like IR was found to be significantly increased
      following a repetitive treatment with DAMGO. Double-immunofluorescence staining
      showed the co-localization of PKCalpha with CGRP- and SP-IR in cultured DRG
      neurons. Moreover, a combined treatment with DAMGO and a PKC inhibitor
      (chelerythrine chloride or Go 6976) was able to block the effects of the opioid
      on increased CGRP-like IR. These data suggest that the three opioid receptors may
      be involved in the induction of CGRP and SP observed following chronic exposure
      to opiates, and that PKC probably plays a role in the signaling pathway leading
      to the up-regulation of these neuropeptides. These findings further validate the
      DRG cell culture as a suitable model to study intracellular pathways that govern
      changes seen following repeated opioid treatments possibly leading to opioid
      tolerance.

PMID- 12421611
TI  - Bidirectional synaptic plasticity in intercalated amygdala neurons and the
      extinction of conditioned fear responses.
AB  - Classical fear conditioning is believed to result from potentiation of
      conditioned synaptic inputs in the basolateral amygdala. That is, the conditioned
      stimulus would excite more neurons in the central nucleus and, via their
      projections to the brainstem and hypothalamus, evoke fear responses. However,
      much data suggests that extinction of fear responses does not depend on the
      reversal of these changes but on a parallel NMDA-dependent learning that competes
      with the first one. Because they control impulse traffic from the basolateral
      amygdala to the central nucleus, GABAergic neurons of the intercalated cell
      masses are ideally located to implement this second learning. Consistent with
      this hypothesis, the present study shows that low- and high-frequency stimulation
      of basolateral afferents respectively induce long-term depression (LTD) and
      potentiation (LTP) of responses in intercalated cells. Moreover, induction of LTP
      and LTD is prevented by application of an NMDA antagonist. To determine how these
      activity-dependent changes are expressed, we tested whether LTD and LTP induction
      are associated with modifications in paired-pulse facilitation, an index of
      transmitter release probability. Only LTP induction was associated with a change
      in paired-pulse facilitation. Depotentiation of previously potentiated synapses
      did not revert the modification in paired pulse facilitation, suggesting that LTP
      is associated with presynaptic alterations, but that LTD and depotentiation
      depend on postsynaptic changes. Taken together, our results suggest that
      basolateral synapses onto intercalated neurons can express NMDA-dependent LTP and
      LTD, consistent with the possibility that intercalated neurons are a critical
      locus of plasticity for the extinction of conditioned fear responses. Ultimately,
      these plastic events may prevent conditioned amygdala responses from exciting
      neurons of the central nucleus, and thus from evoking conditioned fear responses.

PMID- 12421612
TI  - Naloxone-precipitated withdrawal jumping in 11 inbred mouse strains: evidence for
      common genetic mechanisms in acute and chronic morphine physical dependence.
AB  - Physical dependence is a widely known consequence of morphine intake. Although
      commonly associated with prolonged or repeated morphine administration,
      withdrawal symptoms can be elicited even after a single prior morphine exposure.
      What remains contentious is the extent to which physical dependence following
      acute and chronic morphine treatment is mediated by common physiological
      substrates and, accordingly, represent distinct syndromes. The genetic
      relationship between acute and chronic morphine dependence was thus presently
      studied by comparing mice of 11 inbred strains (129P3, A, AKR, BALB/c, C3H/He,
      C57BL/6, CBA, DBA/2, LP, SJL, and SWR) for naloxone-precipitated withdrawal
      jumping responses using three subcutaneous morphine administration paradigms:
      acute (single injection) or chronic (three daily morphine injections for 4 days)
      injection, or chronic infusion (7 days via implanted osmotic minipumps). Although
      there were differences in the magnitude of withdrawal jumping between the three
      different morphine administration paradigms, large and significant strain
      differences were observed for each. In addition, the same strains were unusually
      sensitive or, conversely, altogether refractory to withdrawal jumping across all
      morphine treatment conditions. Overall, strain jumping means between acute and
      chronic dependence paradigms displayed a high degree of genetic correlation
      (r=0.87-0.95). The significant correlation between chronic morphine injection and
      continuous morphine infusion discounts the possible confounding effect of
      contextual learning and spontaneous withdrawal between chronic injections on the
      assessment of naloxone-precipitated withdrawal. Substantial heritability was also
      observed for acute and both paradigms of chronic dependence, with estimates
      ranging from h(2)=0.53 to 0.70. The present demonstration of a strong genetic
      correlation between physical dependence to morphine following acute and chronic
      treatment implies that genes associated with variable sensitivity in the two
      traits are the same, and is suggestive of shared physiological substrates. The
      data also demonstrate that the differential genetic liability to morphine
      physical dependence begins with, and is predicted by, the first morphine
      exposure.

PMID- 12421613
TI  - Nitric oxide causes apparent release of zinc from presynaptic boutons.
AB  - One of us showed previously [Cuajungco and Lees (1998) Brain Res. 799, 188-129]
      that nitric oxide injected into the cerebrum in vivo causes zinc staining to
      appear in the somata of neurons and suggested that this staining of somata might
      be accompanied by a depletion (release) of zinc from axon terminals. In the
      present study, we confirm earlier results and report that there is a dramatic
      loss (apparent release) of histologically reactive zinc from the boutons of zinc
      containing axons induced by infusion of nitric oxide into the brain in vivo. Rats
      were anesthetized with halothane and a cannula was inserted into the hippocampus.
      Either nitric oxide donor (spermineNONOate, 100 mM/2 microl) or control
      (spermine, 100 mM/2 l) was infused into the hippocampus or the cerebellar cortex.
      Two hours after infusion, N-(6-methoxy-8-quinolyl)-para-toluenesulfonamide (TSQ)
      staining for zinc in the brains revealed that sperminenitric oxide, but not
      control (spermine only) produced up to 95% depletion of zinc staining from the
      zinc-containing boutons. TSQ-positive neurons were also conspicuous throughout
      injection sites, in both the cerebral cortex and in the cerebellar cortex, where
      the Purkinje neurons were especially vivid, despite the scarcity of zinc
      containing axonal boutons. It is suggested that the TSQ-stainable zinc in somata
      might represent intracellular stores mobilized from within or permeating
      extracellular stores.

PMID- 12421614
TI  - Vitamin A deficiency produces spatial learning and memory impairment in rats.
AB  - Vitamin A and its derivatives (retinoids) play important roles in many
      physiological processes. The recent finding of high levels of cellular retinol
      binding protein type 1 immunoreactivity, cellular retinoic acid-binding protein
      type 1 immunoreactivity and the presence of nuclear retinoid receptors in the
      central nervous system of adult rodents suggests that retinoids may carry out
      important roles in the adult brain. In consideration of the role of the
      hippocampus in spatial learning and memory we evaluated the effect of vitamin A
      deprivation in adult rats on these functions. Following 12 weeks of vitamin A
      free diet, rats were trained to acquire a radial-arm maze task. Results show that
      this diet induced a severe deficit in the spatial learning and memory task. The
      cognitive impairment was fully restored when vitamin A was replaced in the diet.
      We also found a significant decrease in hippocampal acetylcholine release induced
      by scopolamine, assessed using microdialysis technique, and a reduction in the
      size of hippocampal nuclei of CA1 region in vitamin-deficient rats, compared to
      rats fed with a vitamin A-sufficient diet. These results demonstrate that vitamin
      A has a critical role in the learning and memory processes linked to a proper
      hippocampal functioning.

PMID- 12421615
TI  - Heterosynaptic modulation by the octopaminergic OC interneurons increases the
      synaptic outputs of protraction phase interneurons (SO, N1L) in the feeding
      system of Lymnaea stagnalis.
AB  - We examined the cholinergic synapses between protraction phase interneurons (SO
      or N1L) and their targets (N1M interneuron, B1 motoneuron) in the buccal ganglia
      of the pond snail Lymnaea stagnalis. We have tested the hypothesis that the OC
      (octopamine-containing) interneuron, an intrinsic modulator of the feeding
      network, can increase the synaptic efficacy from the SO or N1L to their targets.
      Prestimulation of the OC interneuron, 4 s before the activation of the SO or N1L
      increases the strength of their output synapses by 75% (SO)-110% (N1L). The
      individual excitatory postsynaptic potentials evoked by SO or N1L stimulation
      increase in size. OC prestimulation also produces an increase in the firing rate
      of these presynaptic interneurons: SO 40%; N1L 33%. The facilitation lasts up to
      6 s after the end of the OC burst. The enhancement of PSPs is seen at all the
      output synapses (both excitatory and inhibitory) of the SO and N1L interneurons.
      The output synapses of the non-cholinergic swallowing phase N3p interneuron are
      not affected, even when the same postsynaptic target is selected. The SO-->N1M,
      SO-->B1 and N1L-->N1M synapses are also strengthened by bath application of 1-5
      microM octopamine (average increase 60%). The major effect is an increased
      excitability of the SO; the B1 motoneuron response to the main transmitter of the
      SO, acetylcholine, is unaffected. Increased synaptic outputs of the protraction
      phase SO and N1L interneurons is functionally significant for generation of
      feeding pattern in the Lymnaea CNS. Strengthening the connections of SO and N1L
      to the central pattern generator (N1M) interneurons enhances their ability to
      drive fictive feeding. Thus heterosynaptic facilitation by the octopaminergic OC
      interneurons in the central pattern generator network may contribute to the
      behavioral plasticity of feeding in the intact animal.

PMID- 12421616
TI  - Rat nigral xenografts survive in the brain of MHC class II-, but not class I
      deficient mice.
AB  - We have examined the role of the indirect pathway of antigen recognition and T
      cells in neural xenografts rejection by using major histocompatibility complex
      (MHC) class II-deficient mice as xenograft recipients. Dissociated embryonic
      ventral mesencephalic tissue from Sprague-Dawley rats was stereotaxically
      injected as a cell suspension into the striatum of MHC class II-deficient adult
      mice as well as MHC class I-deficient and wild-type mice as controls. All of the
      MHC class II-deficient mice had surviving grafts in the striatum 4 weeks post
      grafting. In contrast, only a few of the MHC class I-deficient mice exhibited
      very small grafts and none of the wild-type mice had any surviving grafts. The
      mean number of surviving transplanted dopamine neurons in the MHC class II
      deficient group was significantly larger than that observed in the other two
      groups. Moderate levels of MHC class I antigen expression were seen in the
      transplantation sites of some animals in the MHC class II-deficient group. No
      helper or cytotoxic T cells were observed infiltrating into the graft sites of
      this group. However, there were markedly increased levels of expression of MHC
      class I and class II antigens, and a number of T cells infiltrating in the graft
      sites in both the MHC class I-deficient and wild-type groups. These results show
      that rat embryonic nigral tissue can survive transplantation in the brain of the
      MHC class II-deficient mice for at least 4 weeks without any overt signs of
      rejection, suggesting that the indirect pathway of foreign antigen recognition
      mediated by host MHC class II molecules and helper T cells plays an important
      role in the rejection responses to intracerebral xenografts.

PMID- 12421617
TI  - Development of Drosophila larval neuromuscular junctions: maintaining synaptic
      strength.
AB  - In spite of the available information about the development of Drosophila
      neuromuscular junctions, the correlation between nerve terminal morphology and
      maintenance of synaptic strength has still not been systematically addressed
      throughout larval development. We characterized the growth of the abdominal
      longitudinal muscle 6 (m6) and the motor terminals Ib and Is that innervate it
      within segment 4. In addition, we measured the evoked excitatory junction
      potential (EJP) amplitudes while the Ib and Is axons were selectively recruited.
      Regression analysis with natural log transformation of response variables
      indicated that the developmental curves for m6 and the motor axons Ib and Is were
      best fitted as second order polynomial regressions during larval development.
      Initially Is terminals are longer and possess more synaptic varicosities at the
      first instar stage. The Is terminals also grow faster in subsequent developmental
      stages. The growth of nerve terminals and their target m6 are not proportional
      although tightly correlated. This results in a larger average muscle area
      innervated by a single varicosity as the animal develops. The amplitudes of the
      EJPs of Ib and Is neurons show no developmental difference in their amplitudes
      from the first to the late third larval instar. The Is axon consistently produced
      larger EJPs than the Ib axon at each developmental stage. The time constants for
      both rising and decay phases of EJPs increase exponentially throughout larval
      development. The results presented not only help in quantifying the normal
      development of Drosophila neuromuscular junctions, but also provide a framework
      for future investigations to properly interpret developmental abnormalities that
      may occur in various mutants.

PMID- 12421618
TI  - Transient forebrain ischemia alters the mRNA expression of methyl DNA-binding
      factors in the adult rat hippocampus.
AB  - We have examined how transient cerebral ischemia affects the mRNA expression of a
      family of methyl CpG-binding domain (MBD)-containing factors in the rat
      hippocampus. Our results show that each member of this family is affected by
      cerebral ischemia challenge, but with differing patterns of responsiveness. At 3,
      6 and 12 h following reperfusion, MeCP2 and MBD1 expression is maintained at
      control levels throughout the hippocampus. At 24 h, MeCP2 and MBD1 are induced in
      both the CA1 and CA3 subfields. This delayed pattern of induction is in contrast
      to the responses of MBD2 and MBD3. Both MBD2 and MBD3 display significant changes
      in expression at early times following reperfusion, although their changes are
      opposite in direction. MBD2 expression is induced throughout the hippocampal
      formation at 6 h, and remains elevated at 12 and 24 h. MBD3 expression decreases
      as early as 3 h following insult in the CA3 and dentate gyrus, and the decreased
      expression remains in the vulnerable CA1 subfield at 6, 12, and 24 h. Taken
      together, these results are the first to illustrate that the expression of methyl
      DNA-binding factors are affected by challenges to the brain, and they also
      illustrate that each methyl DNA-binding factor responds differently to cerebral
      ischemic challenge. As each of these family members is associated either directly
      or indirectly with the inhibition of gene transcription, our results suggest that
      following cerebral ischemia the normal pattern of transcriptional inhibition
      provided by these factors may be altered in the hippocampus.

PMID- 12421619
TI  - Role of androgens in the regulation of urotensin II precursor mRNA expression in
      the rat brainstem and spinal cord.
AB  - It has been reported that both urotensin II precursor (pro UII) mRNA and androgen
      receptors (ARs) are highly expressed in rat brainstem motor nuclei and ventral
      horn of the spinal cord. In order to determine the possible involvement of
      androgens in regulation of pro UII mRNA expression, we have studied the co
      localization of pro UII mRNA and AR immunoreactivity and the effect of castration
      and dihydrotestosterone (DHT) replacement therapy on pro UII mRNA in the rat
      facial nucleus and ventral horn of the spinal cord. By in situ hybridization, pro
      UII mRNA was only detected in motoneurons in both the facial nucleus and ventral
      horn of the spinal cord. Double-labelling studies revealed that the vast majority
      (over 95%) of motoneurons immunostained for AR also expressed pro UII mRNA in
      both areas examined. Three weeks after castration, pro UII mRNA expression, as
      measured by semi-quantitative in situ hybridization, was increased by 17% and 58%
      in the ventral horn of the spinal cord and the facial nucleus, respectively. The
      administration of DHT completely prevented the stimulating effect of castration.
      These results indicate that circulating androgens are exerting a down-regulation
      of pro UII expression possibly by a direct action at the level of motoneurons.
      The physiological relevance of these new findings remains to be fully explored.

PMID- 12421620
TI  - A 'single toxin-double lesion' rat model of striatonigral degeneration by
      intrastriatal 1-methyl-4-phenylpyridinium ion injection: a motor behavioural
      analysis.
AB  - Previous attempts to reproduce striatonigral degeneration, the core pathology
      underlying Parkinsonism in multiple system atrophy, have been impeded by
      interactions in the neurotoxins used to replicate striatal and nigral
      degeneration in rodents. To overcome these interactions, we have developed a new
      model of striatonigral degeneration which uses a single unilateral administration
      of 1-methyl-4-phenylpyridinium ion (MPP(+)) into the rat striatum. Spontaneous
      and drug-induced rotational behaviour, thigmotactic scanning, stepping adjusting
      steps and paw reaching deficits were compared in four groups of animals: group 1
      (control), group 2 (20 microg quinolinic acid), group 3 (20 microg 6
      hydroxydopamine), and group 4 (90 nmol MPP(+)). MPP(+) administration resulted in
      the absence of the amphetamine-induced ipsilateral bias observed in the 6
      hydroxydopamine group and of the apomorphine-induced ipsilateral bias observed in
      the quinolinic acid group. There was no thigmotactic scanning asymmetry in the
      MPP(+)-injected rats compared to the quinolinic acid- and the 6-hydroxydopamine
      injected rats. MPP(+) elicited a bilateral stepping adjustment deficit similar to
      that found in the quinolinic acid group when compared to controls. MPP(+) also
      elicited a more severe and significant contralateral deficit in paw reaching
      compared to controls, 6-hydroxydopamine and quinolinic acid groups.
      Histopathology revealed a significant reduction of the lesioned striatal surface
      (-47.53%) with neuronal loss and increased astrogliosis in the MPP(+) group
      grossly similar to that found in the quinolinic acid group. Contrary to the
      latter group, however, loss of intrastriatal and striatal-crossing fibre bundles
      was observed in the MPP(+) group as there was also some retrograde degeneration
      in the ipsilateral thalamic parafascicular nucleus. The mean loss of dopaminergic
      cells in the ipsilateral substantia nigra pars compacta in MPP(+) rats was less
      marked (-48.8%) than in the 6-hydroxydopamine rats (-63.6%) and was not
      significant in quinolinic acid rats (-5.2%). This study shows that a single
      unilateral intrastriatal administration of MPP(+) induces a unique motor
      behaviour resulting from both nigral and striatal degeneration, but also from
      possible extrastriatal damage. This 'single toxin-double lesion' paradigm may
      thus serve as a rat model of striatonigral degeneration.

PMID- 12421621
TI  - Estrogen replacement improves spatial reference memory and increases hippocampal
      synaptophysin in aged female mice.
AB  - Estrogen deficiency during menopause is often associated with memory dysfunction.
      However, inconsistencies regarding the ability of estrogen to improve memory in
      menopausal women highlight the need to evaluate, in a controlled animal model,
      the potential for estrogen to alleviate age-related mnemonic decline. The current
      study tested whether estrogen could ameliorate spatial reference memory decline
      in aged female mice. At the conclusion of testing, levels of the presynaptic
      protein synaptophysin, and activities of the synthetic enzymes for acetylcholine
      and GABA, were measured in the hippocampus and neocortex. Aged (27-28-month-old)
      female C57BL/6 mice were given daily subcutaneous injections of 1 microg or 5
      microg of beta-estradiol-3-benzoate dissolved in sesame oil. Control mice
      received daily injections of sesame oil or no injections. Estradiol treatment
      began 5 days prior to behavioral testing and continued throughout testing.
      Spatial and non-spatial memory were assessed in the Morris water maze. The 5
      microg dose of estradiol significantly improved spatial learning and memory in
      aged females. The performance of 5 microg females improved significantly more
      rapidly than that of control females; estradiol-treated females performed at
      asymptotic levels by session 2. Furthermore, 5 microg females exhibited a more
      robust spatial bias than controls during probe trials. In contrast, 1 microg of
      estradiol did not improve spatial task performance. Neither dose affected
      performance of the non-spatial task. In the hippocampus, synaptophysin was
      increased in 5 microg females relative to controls. Estrogen did not affect
      enzyme activities in either brain region. This study is the first to examine the
      effects of estrogen replacement on spatial reference memory and synaptophysin
      expression in aged post-estropausal female rodents. The results suggest that: (1)
      estrogen can profoundly improve spatial reference memory in aged females, and (2)
      this improvement may be related to increased hippocampal synaptic plasticity, but
      not modulation of the synthetic enzymes for acetylcholine and GABA.

PMID- 12421622
TI  - Identification of calcium-dependent and -independent signaling pathways involved
      in polychlorinated biphenyl-induced cyclic AMP-responsive element-binding protein
      phosphorylation in developing cortical neurons.
AB  - Cyclic AMP (cAMP)-responsive element-binding protein (CREB) is a transcription
      factor important in developing nervous system cells and is activated by a variety
      of signaling molecules. Aroclor 1254 (A1254), a polychlorinated biphenyl mixture,
      perturbs Ca(2+) homeostasis and increases CREB phosphorylation in rat neonatal
      cortical cell cultures in a time- and concentration-dependent manner. The present
      experiments determined that the cell type responding to A1254 with Ca(2+)
      increases and phosphorylated CREB (phospho-CREB) was predominantly of neuronal
      morphology and microtubule-associated protein (MAP2)-positive phenotype.
      Similarly, glutamate (100 microM) increased phospho-CREB immunoreactivity
      selectively in MAP2-immunopositive cells. Using Western blotting and
      immunocytochemical techniques, we identified key signal transduction pathways
      operative in phosphorylating CREB in cortical cell cultures and examined their
      participation in 3 ppm A1254-induced CREB activation. Cortical cultures treated
      with glutamate, forskolin or the phorbol ester phorbol 12-myristate 13-acetate
      exhibited robust increases in phospho-CREB. Tetrodotoxin (1 microM) completely
      inhibited CREB phosphorylation by A1254, suggesting that synaptic activity is
      involved in A1254-induced CREB activation. Buffering [Ca(2+)](i) with bis(2
      aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis(acetoxymethyl) ester in
      the absence of extracellular Ca(2+) partially inhibited A1254-induced CREB
      phosphorylation. Inhibition of mitogen-activated protein kinase (10 microM U0126)
      or protein kinase C (PKC; bisindoylmaleimide, 5 microM) activation did not
      inhibit A1254-induced CREB phosphorylation. By contrast, inhibition of protein
      kinase A (PKA) with 100 microM PKA inhibitor peptide, PKI, blocked A1254-induced
      CREB phosphorylation. Thus, we examined whether A1254 activates PKA by increasing
      cAMP; 10 microM forskolin, but not A1254, elevated intracellular cAMP levels.
      These results indicate that in neocortical cells in culture, CREB phosphorylation
      occurs via Ca(2+)-, PKA-, and PKC-dependent pathways. Furthermore, A1254-induced
      CREB phosphorylation occurs predominantly in neurons, is dependent on synaptic
      activity and mediated by Ca(2+)- and PKA-dependent pathways.

PMID- 12421623
TI  - Activation of neurokinin-1 receptors promotes GABA release at synapses in the rat
      entorhinal cortex.
AB  - We have previously shown that activation of neurokinin-1 receptors reduces
      acutely provoked epileptiform activity in rat entorhinal cortex in vitro, and
      suggested that this may result from an increase in GABA release from inhibitory
      interneurones. In the present study we have made whole cell patch clamp
      recordings of spontaneous GABA-mediated inhibitory postsynaptic currents as an
      indicator of GABA release in slices of rat entorhinal cortex, and determined the
      effects of neurokinin receptor activation on this release. The neurokinin-1
      receptor agonists septide and GR73632 provoked a robust increase in the frequency
      of GABA-mediated currents, and an increase in mean amplitude. The effects were
      mimicked by substance P, and blocked by a neurokinin-1 receptor antagonist. High
      concentrations of neurokinin A had similar effects, which were also blocked by
      the neurokinin-1 receptor antagonist, but agonists at neurokinin-2 or neurokinin
      3 receptors were ineffective. The increases in amplitude and frequency of events
      provoked by septide were prevented by prior blockade of action potential
      dependent release with tetrodotoxin. In current clamp recordings from putative
      interneurones, GR73632 evoked depolarisation and a prolonged discharge of action
      potentials. Finally, recordings from pyramidal neurones and oriens-alveus
      interneurones in CA1 of the hippocampus showed that application of GR73632 caused
      an increase in frequency and amplitude of GABA-mediated inhibitory postsynaptic
      currents in the former and persistent firing of action potentials in the latter.
      The results demonstrate that neurokinin-1 receptor activation promotes the
      release of GABA at synapses on principal neurones in both entorhinal cortex and
      hippocampus. The abolition of this effect by tetrodotoxin and the excitatory
      responses seen in interneurones clearly suggest that the neurokinin-1 receptor is
      localised on the soma-dendritic domain of the inhibitory neurones. Thus,
      substance P inputs to inhibitory neurones may have a widespread influence on
      cortical network excitability and could play a role in epileptogenesis and its
      control.

PMID- 12421624
TI  - Loss of cardiolipin and mitochondria during programmed neuronal death: evidence
      of a role for lipid peroxidation and autophagy.
AB  - Cardiolipin, a lipid of the mitochondrial inner membrane, is lost from many types
      of cells during apoptotic death. Here we show that the cardiolipin content of
      nerve growth factor (NGF)-deprived rat sympathetic neurons undergoing apoptotic
      death in cell culture decreased before extensive loss of mitochondria from the
      cells. By 18-24 h after NGF deprivation, many neurons did not stain with the
      cardiolipin-specific dye, Nonyl Acridine Orange, suggesting complete loss of
      cardiolipin. Gas chromatography confirmed the decline of cardiolipin content in
      NGF-deprived neurons. Electron microscopy and immunoblots for the mitochondrial
      specific protein, heat shock protein 60 (HSP60), revealed that there was only a
      slight decrease in mitochondrial mass at this time. Cardiolipin loss after NGF
      deprivation was concurrent with increased production of mitochondrial-derived
      reactive oxygen species [Kirkland, R.A., Franklin, J.L., 2001. J. Neurosci. 21,
      1949-1963] and increased lipid peroxidation. Compounds having antioxidant effects
      blocked peroxidation, loss of cardiolipin, and the decrease of mitochondrial mass
      in NGF-deprived neurons. These compounds also blocked an increase in the number
      of lysosomes and autophagosomes in NGF-deprived cells. The findings reported here
      show that the important mitochondrial inner membrane lipid, cardiolipin, is lost
      from mitochondria during neuronal apoptosis and that this loss occurs before
      significant loss of mitochondria from cells. They suggest that the loss of
      cardiolipin is mediated by free radical oxygen.

PMID- 12421625
TI  - Insulin-like growth factor-I inhibits endogenous acetylcholine release from the
      rat hippocampal formation: possible involvement of GABA in mediating the effects.
AB  - Evidence suggests that insulin-like growth factor-I (IGF-I) plays an important
      role during brain development and in the maintenance of normal as well as
      activity-dependent functioning of the adult brain. Apart from its trophic
      effects, IGF-I has also been implicated in the regulation of brain
      neurotransmitter release thus indicating a neuromodulatory role for this growth
      factor in the central nervous system. Using in vitro slice preparations, we have
      earlier reported that IGF-I potently inhibits K(+)-evoked endogenous
      acetylcholine (ACh) release from the adult rat hippocampus and cortex but not
      from the striatum. The effects of IGF-I on hippocampal ACh release was sensitive
      to the Na(+) channel blocker tetrodotoxin, suggesting that IGF-I might act
      indirectly via the release of other transmitters/modulators. In the present
      study, we have characterized the possible involvement of GABA in IGF-I-mediated
      inhibition of ACh release and measured the effects of this growth factor on
      choline acetyltransferase (ChAT) activity and high-affinity choline uptake in the
      hippocampus of the adult rat brain. Prototypical agonists of GABA(A) and GABA(B)
      receptors (i.e. 10 microM muscimol and 10 microM baclofen) inhibited, whereas the
      antagonists of the respective receptors (i.e. 10 microM bicuculline and 10 microM
      phaclofen) potentiated K(+)-evoked ACh release from rat hippocampal slices. IGF-I
      (10 nM) inhibited K(+)- as well as veratridine-evoked ACh release from rat
      hippocampal slices and the effect is possibly mediated via the activation of a
      typical IGF-I receptor and the subsequent phosphorylation of the insulin receptor
      substrate-1 (IRS-1). The inhibitory effects of IGF-I on hippocampal ACh release
      were not additive to those of either muscimol or baclofen, but were attenuated by
      GABA antagonists, bicuculline and phaclofen. Additionally, in contrast to ACh
      release, IGF-I did not alter either the activity of the enzyme ChAT or the uptake
      of choline in the hippocampus. These results, taken together, indicate that IGF
      I, under acute conditions, can decrease hippocampal ACh release by acting on the
      typical IGF-I/IRS receptor complex while having no direct effect on ChAT activity
      or the uptake of choline. Furthermore, the evidence that effects of IGF-I could
      be modulated, at least in part, by GABA antagonists suggest that the release of
      GABA and the activation of its receptors may possibly be involved in mediating
      the inhibitory effects of IGF-I on hippocampal ACh release.

PMID- 12421626
TI  - Cannabinoids attenuate depolarization-dependent Ca2+ influx in intermediate-size
      primary afferent neurons of adult rats.
AB  - CB1 receptors have been localized to primary afferent neurons, but little is
      known about the direct effect of cannabinoids on these neurons. The
      depolarization-evoked increase in the concentration of free intracellular calcium
      ([Ca(2+)](i)), measured by microfluorimetry, was used as a bioassay for the
      effect of cannabinoids on isolated, adult rat primary afferent neurons 20-28 h
      after dissociation of dorsal root ganglia. Cannabinoid agonists CP 55,940 (100
      nM) and WIN 55,212-2 (1 microM) had no effect on the mean K(+)-evoked increase in
      [Ca(2+)](i) in neurons with a somal area<800 microm(2), but the ligands
      attenuated the evoked increase in [Ca(2+)](i) by 35% in neurons defined as
      intermediate in size (800-1500 microm(2)). The effects of CP 55,940 and WIN
      55,212-2 were mediated by the CB1 receptor on the basis of relative effective
      concentrations, blockade by the CB1 receptor antagonist SR141716A and lack of
      effect of WIN 55,212-3. Intermediate-size neurons rarely responded to capsaicin
      (100 nM). Although cannabinoid agonists generally did not inhibit depolarization
      evoked increases in [Ca(2+)](i) in small neurons, immunocytochemical studies
      indicated that CB1 receptor-immunoreactivity occurred in this population. CB1
      receptor-immunoreactive neurons ranged in size from 227 to 2995 microm(2) (mean
      somal area of 1044 microm(2)). In double labeling studies, CB1 receptor
      immunoreactivity co-localized with labeling for calcitonin gene-related peptide
      and RT97, a marker for myelination, in some primary afferent neurons. The
      decrease in evoked Ca(2+) influx indicates that cannabinoids decrease conductance
      through voltage-dependent calcium channels in a subpopulation of primary afferent
      neurons. Modulation of calcium channels is one mechanism by which cannabinoids
      may decrease transmitter release from primary afferent neurons. An effect on
      voltage-dependent calcium channels, however, represents only one possible effect
      of cannabinoids on primary afferent neurons. Identifying the mechanisms by which
      cannabinoids modulate nociceptive neurons will increase our understanding of how
      cannabinoids produce anti-nociception in normal animals and animals with tissue
      injury.

PMID- 12421627
TI  - Immunocytochemical localization of glutamic acid decarboxylase in physiologically
      identified interneurons of hamster spinal laminae III-V.
AB  - Neurons in Rexed's laminae III-V of an isolated spinal cord-skin patch
      preparation from hamsters were recorded in whole-cell mode and stained
      intracellularly with biocytin. Evidence of inhibitory synaptic function was
      obtained via post-hoc immunofluorescent labeling with a monoclonal antibody
      directed against an axon terminal isoform of brain glutamic acid decarboxylase.
      For a subset of neurons, examination with laser scanning confocal microscopy
      revealed punctate accumulations of glutamic acid decarboxylase immunoreactivity
      within axon enlargements (1-3 microm diameter), as imaged in single optical
      sections and confirmed by subsequent optical scans in the orthogonal plane. Axons
      of glutamic acid decarboxylase-immunoreactive neurons were found to exhibit dense
      local terminations overlapping the soma and dendrites or bifurcated into lengthy
      rostrocaudal daughter branches ventral to the cell body. The degree and
      uniformity of immunolabeling in axonal enlargements varied considerably, even
      amongst boutons belonging to the same cell. Glutamic acid decarboxylase-positive
      neurons received input from myelinated (A) afferent fibers and responded to
      natural stimuli appropriate for activating responses in low threshold
      mechanoreceptors. These results provide evidence that two different populations
      of GABAergic inhibitory interneurons are involved in local and intersegmental
      circuits that mediate integration of mechanosensory information in the deep
      spinal dorsal horn.

PMID- 12421628
TI  - Orphanin FQ-induced hyperphagia is mediated by corticosterone and central
      glucocorticoid receptors.
AB  - Orphanin FQ (Nociceptin) has been reported to stimulate food intake in satiated
      rats and to stimulate corticosterone release. A large body of evidence exists to
      link central feeding systems with the regulation of corticosterone. In this
      study, we sought to determine whether or not circulating corticosterone is
      necessary for the induction of food intake by Orphanin FQ. We found that
      intracerebroventricular injection of Orphanin FQ (0.64-5 nmoles) dose dependently
      stimulated food intake and plasma corticosterone within 30 min of injection.
      Removal of corticosterone, by adrenalectomy, abolished the hyperphagic effect of
      Orphanin FQ. The stimulatory effect of Orphanin FQ on food intake was still
      negated following a low dose of corticosterone replacement (corresponding to a
      plasma corticosterone concentration of 1.86+/-0.99 microg/dl). However, following
      a larger dose of corticosterone replacement (corresponding to a plasma
      corticosterone concentration of 8.92+/-0.55 microg/dl) the feeding effect was
      fully restored. We concluded this study by testing the glucocorticoid receptor
      antagonist, RU486 (Mifepristone, 80 microg/2 microl) on Orphanin FQ-induced
      feeding. Central injection of RU486, 30 min prior to injection of Orphanin FQ,
      significantly reduced Orphanin FQ-induced food intake in comparison to vehicle
      treated controls. Overall, these data demonstrate the necessity for circulating
      corticosterone in the mediation of Orphanin-FQ-induced feeding and suggest that
      the mechanism through which the hyperphagic effect is obtained involves
      activation of central glucocorticoid receptors.

PMID- 12421629
TI  - Functional genomics of parasitic worms: the dawn of a new era.
AB  - The study of gene function in parasitic worms is technically demanding due to
      difficulties associated with life-cycle propagation and, hence, molecular
      genetics. Exploitation of the free-living nematode, Caenorhabditis elegans,
      coupled with recent major advances in molecular studies of parasitic nematodes,
      have opened up new avenues for understanding the biology of these parasites and
      present opportunities for novel strategies of therapeutic intervention and
      control.

PMID- 12421630
TI  - Monogenea of Arabian Gulf fishes. 1. Descriptions of three Capsala spp.
      (Capsalidae) including Capsala naffari n. sp. infecting mackerel tuna Euthynnus
      affinis from coasts of Emirates.
AB  - Three species of the genus Capsala including Capsala naffari n. sp., C. neothunni
      (Yamaguti, 1968) and C. nozawae (Goto, 1894) are recorded and described from the
      buccal cavity of mackerel tuna Euthynnus affinis caught from Emirate coasts.
      Capsala naffari can be differentiated by its lateral spiniform teeth, which
      extend posteriorly, small measurements compared with the closely resembled C.
      gotoi and relatively large testes. This is the first record of the genus Capsala
      from Arabian Gulf fishes and E. affinis is a new host record.

PMID- 12421631
TI  - Pseudodactylogyrus kamegaii sp. n. (Monogenea: Pseudodactylogyridae) from wild
      Japanese eel, Anguilla japonica.
AB  - The monogenean Pseudodactylogyrus kamegaii sp. n. is described, based on
      specimens collected from the gills of wild Japanese eel Anguilla japonica caught
      in Chiba Prefecture, Japan. This species is the most similar to P. anguillae (Yin
      and Sproston, 1948), but different in the shape and measurements of the male
      copulatory organ, vagina and marginal hook. This new species was collected from
      the eel in brackish waters, while P. anguillae and P. bini, the other known
      pseudodactylogyrids of Japanese eel, have been recorded only in fresh waters.

PMID- 12421632
TI  - Differential localization of processed fragments of Plasmodium falciparum serine
      repeat antigen and further processing of its N-terminal 47 kDa fragment.
AB  - The serine repeat antigen (SERA) of Plasmodium falciparum is a blood stage
      malaria vaccine candidate. It has been shown that 120 kDa SERA was
      proteolytically processed into N-terminal 47 kDa fragment (P47), central 56 kDa
      fragment (P56) that was further converted to 50 kDa (P50), and C-terminal 18 kDa
      fragment (P18). Here, we have examined the processing of SERA and the
      localization of its processed fragments by using mouse antibodies directed
      against recombinant proteins corresponding to different domains of SERA. Western
      blot analysis showed that all the processing events occurred inside parasitized
      erythrocytes at the stage just prior to the schizont rupture, that P47 was
      further processed into two 25 kDa fragments and that the two fragments, which
      were linked to P18 through disulfide bonds, were associated with the merozoite.
      In contrast, P50 was completely shed into culture medium and absent from the
      merozoite. This observation was further supported by the results of indirect
      immunofluorescence assay. These results could account for the findings that
      antibodies against P47 were inhibitory to the parasite growth in vitro but those
      against P50 were not. Finally, we demonstrated that the further processing of P47
      is allelic type-dependent. The results of the present study would help in vaccine
      designing based on SERA.

PMID- 12421633
TI  - Multidrug resistance in the protozoan parasite Entamoeba histolytica.
AB  - In this review we discuss the mechanisms and molecules involved in the multidrug
      resistance (MDR) of the protozoan parasite Entamoeba histolytica. Drug resistant
      mutants exhibited the main characteristics presented by the MDR mammalian cells.
      They showed cross-resistance to several unrelated drugs that is reverted by
      calcium channel blockers. MDR phenotype in E. histolytica is regulated at a
      transcriptional level by the EhPgp1 gene, which is constitutively expressed and
      by the EhPgp5 gene, whose expression is induced in the presence of the drug.
      Transcription factors participate in the expression regulation of these genes.
      After over transcription, the EhPgp genes are amplified, cooperating to produce
      the MDR phenotype. Post-transcriptional mechanisms such as mRNA stability seem to
      be involved in this phenomenon. As for other mdr gene products, the EhPGP5
      protein functions as a chloride current inductor or as a regulator of cellular
      regulatory volume decrease.

PMID- 12421634
TI  - Fcgamma receptor IIA and IIIB polymorphisms are associated with susceptibility to
      cerebral malaria.
AB  - Human FcgammaRIIA and FcgammaRIIIB exhibit genetic polymorphisms, FcgammaRIIA
      131H/R and FcgammaRIIIB-NA1/NA2, coding for different capacities for IgG binding
      and phagocytosis. Recently, FcgammaRIIA-131R was reported to be associated with
      protection against high-density Plasmodium falciparum infection in Kenya.
      Furthermore, FcgammaRIIIB-NA1/NA2 polymorphism was shown to influence FcgammaRIIA
      function in an allele-specific manner. In this study, we examined a possible
      association of FcgammaRIIA-131H/R and FcgammaRIIIB-NA1/NA2 polymorphisms with
      malaria severity in 107 cerebral malaria patients, 157 non-cerebral severe
      malaria patients, and 202 mild malaria controls living in northwest Thailand.
      This study reveals that, with the FcgammaRIIIB-NA2 allele, the FcgammaRIIA-131H/H
      genotype is associated with susceptibility to cerebral malaria (OR 1.85, 95% CI
      1.14-3.01; P=0.012), although these polymorphisms are not individually involved
      in the disease severity. Our results suggest that FcgammaRIIA-131H/R and
      FcgammaRIIIB-NA1/NA2 polymorphisms have an interactive effect on host defense
      against malaria infection.

PMID- 12421635
TI  - IL-10 leads to a higher parasite persistence in a resistant mouse model of
      Leishmania major infection.
AB  - IL-10 is a cytokine secreted by a wide variety of cell types and has pleiotropic
      activities, mainly as a modulator of the immune response. In this study, we
      tested in a direct way the influence of IL-10 expression on Leishmania major
      infection in resistant mice. We report that C57BL/6 mice treated with a single
      inoculation of recombinant adenovirus vector-expressing viral IL-10 (Ad-vIL-10),
      1 day before parasitic challenge, exhibited a dual effect on footpad swelling,
      characterized by a decrease on lesion size at the early stage of the infection,
      followed by a rapid increase of these lesions that attained the complete healing
      later in infection. The reduction in lesion swelling in vIL-10 treated mice was
      accompanied by a decrease cellular infiltration of lymphocytes and monocytes at
      the site of parasite inoculation. Most significantly, vIL-10 administration led
      to a higher parasite burden in the draining popliteal lymph nodes late during
      infection, when the complete healing of the lesions was already achieved. RT-PCR
      analysis showed no important modification of cytokine transcripts in vIL-10
      treated mice, early in infection, indicating no changes in mouse phenotype from
      resistant to susceptible status. Therefore, IL-10 administration influenced the
      outcome of the disease by modifying the inflammation and local cell recruitment
      at the site of parasite penetration and by leading to an enhanced residual
      parasite load in popliteal lymph nodes later in infection. The implication of IL
      10 on the host immune status and the establishment and outcome of the infection
      is discussed.

PMID- 12421636
TI  - Human African trypanosomiasis: potential therapeutic benefits of an alternative
      suramin and melarsoprol regimen.
AB  - Treatment of late-stage human African trypanosomiasis is complicated by the
      presence of trypanosomes within the central nervous system (CNS). The regimen
      commonly prescribed to treat CNS-stage disease involves the use of the
      trypanocidal drugs suramin and melarsoprol. Suramin does not cross the blood
      brain barrier efficiently and therefore, at normal dosages, will not cure CNS
      stage infections. An initial treatment with suramin is given to eliminate the
      parasites from the peripheral tissues. This is followed by a course of
      intravenous melarsoprol, which can enter the CNS. However, melarsoprol not only
      produces severe adverse reactions but also is extremely painful to administer.
      One possible method to help alleviate these problems is to reduce the total
      amount of melarsoprol in the treatment regimen. This study indicates a synergism
      between suramin and melarsoprol and demonstrates that experimental murine CNS
      trypanosomiasis can be cured with a single intraperitoneal dose of 20 mg/kg
      suramin followed almost immediately by 0.05 ml (4.5 micromol) topical
      melarsoprol. These dosages will not cure the infection when administered as
      monotherapies. Moreover, the timing of the drug administration appears to be
      crucial to the successful outcome of the regimen. If the interval between
      injection of suramin and application of topical melarsoprol is extended from 15
      min to 3 or 7 days, the infections are not cured. Although extended relapse times
      occur following these regimens when compared with monotherapy approaches. Thus,
      there is strong evidence that injected suramin and topical melarsoprol should be
      given almost simultaneously to achieve the most effective combination of the two
      drugs.

PMID- 12421637
TI  - Bell-shaped curves for prostaglandin-induced modulation of adenylate cyclase: two
      mutually opposing effects.
AB  - Each of the natural prostanoid is at least one order of magnitude more potent for
      its specific receptor (DP, EP, FP, IP and TP) than any of the other prostanoids.
      However, they are able to interact also with one or more of the other classes of
      prostanoid receptors. The concentration-response curves for modulation of
      adenylate cyclase activity in rabbit mesenteric artery smooth muscle cells by
      different prostaglandins are not always monotonic, i.e. simple sigmoidal curves
      in logarithmic scale, but they are often biphasic. Prostacyclin, iloprost and
      prostaglandin E(1) showed a convex bell-shaped curve, i.e. adenylate cyclase
      activity is stimulated at lower concentrations and inhibited at higher
      concentrations, while the curve of prostaglandin E(2) showed a concave bell
      shaped curve, i.e. adenylate cyclase is inhibited at lower concentrations and
      stimulated at higher concentrations. By selectively inhibiting one of the
      transduction mechanisms present in mesenteric smooth muscle cells, we have
      demonstrated that the observed responses to these prostanoids are likely due to
      two mutually opposing effects. Thus, the data previously published by our
      laboratory on a prostacyclin analog, 5(Z)-carbacyclin, might be reinterpreted
      more correctly in the light of this new possibility.

PMID- 12421638
TI  - P38 mitogen-activated protein kinase inhibitor SB203580 has a bi-directional
      effect on iNOS expression and NO production.
AB  - In the present study, the mediator role of p38 kinase, a member of the mitogen
      activated protein kinase (MAPK) family, was studied in lipopolysaccharide-induced
      inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO)
      production in J774 mouse macrophages and T-84 human colon epithelial cells. Two
      pyridinyl imidazole inhibitors of p38 MAPK, 4-(4-fluorophenyl)-2-(4
      methylsulfinylphenyl)-5-(4-pyridyl)-imidazole (SB203580) and 4-(4-fluorophenyl)-2
      (4-hydroxyphenyl)-5-(4-pyridyl)-imidazole (SB202190), stimulated NO production at
      low drug concentrations, maximal stimulation occurring at 1 microM drug
      concentration. In contrast, higher concentrations inhibited NO production, which
      was>90% at 30 microM drug concentration. The bi-directional effect was found in
      both cell types tested. Negative control compound SB202474, which is structurally
      related but does not inhibit p38, did not stimulate NO production but inhibited
      it at 30 microM concentration. A chemically different p38 inhibitor 2-methyl-4
      phenyl-5-(4-pyridyl)oxazole (SC68376) had only a stimulatory action on NO
      production. Western blotting and reverse transcriptase polymerase chain reaction
      (RT-PCR) analysis of iNOS showed that both stimulatory and inhibitory effects of
      SB203580 occurred at the level of iNOS expression. SB203580 did not alter
      lipopolysaccharide-induced NF-kappaB activation as detected by electrophoretic
      mobility shift assay (EMSA). The data show that pyridinyl imidazoles SB203580 and
      SB202190 have a bi-directional effect on NO production through iNOS pathway
      depending on the drug concentration used. The inhibitory effect was unrelated to
      inhibition of p38 MAPK, whereas the stimulatory effect is most likely mediated by
      p38 MAPK dependent mechanism, suggesting a novel mechanism for regulation of iNOS
      expression, which is common for murine and human cells.

PMID- 12421639
TI  - A single residue contributes sensitivity to allosteric modulation of AMPA
      receptors by LY395153.
AB  - Previous studies have shown that a single point mutation (S(750)Q) in the splice
      variant region of rat Glu(1) subunits can eliminate positive allosteric
      modulation by cyclothiazide. The present study investigated the effects of
      mutating the equivalent residue (S(776)Q) in the human Glu(4) subunit on the
      activity and binding of a novel AMPA receptor potentiator, LY395153 (N-2-(4
      benzamidophenylpropyl-2-propanesulfonamide)). The mutation markedly attenuated,
      but did not eliminate, potentiation by LY395153 and cyclothiazide. In addition,
      binding of [3H]LY395153 was significantly reduced by this mutation. These effects
      occurred in the absence of any change in the response to glutamate or the binding
      of a competitive AMPA receptor antagonist, [3H]Ro 48-8587 ([2,4,5-3H]9-imidazol-1
      yl-8-nitro-2,3,5,6-tetrahydro[1,2,4]-triazolo[1,5-c]quinazoline-2,5-dione
      triethylammonium salt). Collectively, these results demonstrate that structurally
      diverse classes of potentiators are sensitive to mutations of this single Ser
      residue, suggesting that binding to this residue may be necessary for positive
      allosteric modulation of AMPA receptors.

PMID- 12421640
TI  - Correlation between pregnanesteroid conformation, receptor affinity, and anti
      natriuretic effect.
AB  - The aim of this study was to correlate mineralocorticoid action and steroid
      structure. Inasmuch as Na(+) retention follows a parabolic dose-response curve
      for most pregnanesteroids, the second-order coefficient of the function was used
      as a representative factor for this bipartite biological effect. The C(3)=O/D
      angle of the ligands was correlated with both Na(+)-retaining activity and
      binding affinity for the mineralocorticoid receptor. Because some steroids
      exhibit identical functional groups and different conformational structure, we
      also postulate that the flat conformation of a pregnanesteroid determines its
      Na(+)-retaining capacity in vivo. No correlations were found in vitro, which
      demonstrates the multifactorial nature of the second-order coefficient determined
      in vivo under more complex and interactive conditions that include various pre
      receptor variables. These findings may allow the estimation of the putative
      biological activity of a given steroid simply by knowing its conformational
      structure, which may be important for designing compounds in a pharmaceutical
      setting.

PMID- 12421641
TI  - Effects of pharmacological manipulations of cannabinoid receptors on severity of
      dystonia in a genetic model of paroxysmal dyskinesia.
AB  - Previous studies have shown beneficial effects of the cannabinoid CB(1)/CB(2)
      receptor agonist (R)-4,5-dihydro-2-methyl-4-(4-morpholinylmethyl)-1-(1
      naphthalenylcarbonyl)-6H-pyrrolo [3,2,1-ij]quinolin-6-one mesylate (WIN 55,212-2)
      in dt(sz) mutant hamsters, a model of idiopathic paroxysmal dystonia
      (dyskinesia). To examine the pathophysiological significance of the cannabinergic
      system in the dystonic syndrome, the effect of the cannabinoid CB(1) receptor
      antagonist N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3
      pyrazole-carboxamide (SR 141716A) on severity of dystonia was investigated in
      dt(sz) mutants which exhibit episodes of dystonic and choreoathetotic
      disturbances in response to mild stress. SR 141716A (5 and 10 mg/kg i.p.) failed
      to exert any effects on the severity of dystonia. While the antidystonic efficacy
      of WIN 55,212-2 (5 mg/kg i.p.) was confirmed, cannabidiol (which has low affinity
      to cannabinoid receptors) tended to delay the progression of dystonia only at a
      high dose (150 mg/kg i.p.). The antidystonic and cataleptic effects of WIN 55,212
      2 (5 mg/kg i.p.) were completely antagonized by pretreatment with SR 141716A at
      doses of 2.5 mg/kg (catalepsy) and 10 mg/kg (antidystonic efficacy). These data
      indicate that the antidystonic efficacy of WIN 55,212-2 is selectively mediated
      via CB(1) receptors. The lack of prodystonic effects of SR 141716A together with
      only moderate antidystonic effects of WIN 55,212-2 suggests that reduced
      activation of cannabinoid CB(1) receptors by endocannabinoids is not critically
      involved in the dystonic syndrome. In view of previous pathophysiological
      findings in mutant hamsters, the antidystonic efficacy of WIN 55,212-2 can be
      explained by modulation of different neurotransmitter systems within the basal
      ganglia.

PMID- 12421642
TI  - A role for endocannabinoids in indomethacin-induced spinal antinociception.
AB  - Inhibition of prostaglandins synthesis does not completely explain non-steroidal
      anti-inflammatory drug-induced spinal antinociception. Among other mediators,
      endocannabinoids are involved in pain modulation. Indomethacin-induced
      antinociception, in the formalin test performed in spinally microdialysed mice,
      was reversed by co-administration of the cannabinoid 1 (CB(1)) antagonist, N
      (piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1-H-pyrazole-3
      carboxamide (AM-251), but not by co-infusion of prostaglandin E(2). Indomethacin
      was ineffective in CB(1) knockout mice. AM-251 also reversed the indomethacin
      induced antinociception in a test of inflammatory hyperalgesia to heat.
      Furthermore, during the formalin test, indomethacin lowered the levels of spinal
      nitric oxide (NO), which activates cellular reuptake and thus breakdown of
      endocannabinoids. The pronociceptive effect of an NO donor, 3-methyl-N-nitroso
      sydnone-5-imine (RE-2047), was abolished by co-administration of the
      endocannabinoid transporter blocker N-(4-hydroxyphenyl) arachidonoyl amide (AM
      404). Moreover, the antinociceptive activity of the NO synthase inhibitor, N
      nitro-L-arginine methyl ester (L-NAME), was reversed by AM-251. Thus we propose
      that at the spinal level, indomethacin induces a shift of arachidonic acid
      metabolism towards endocannabinoids synthesis secondary to cyclooxygenase
      inhibition. In addition, it lowers NO levels with subsequent higher levels of
      endocannabinoids.

PMID- 12421643
TI  - Regulation of N-methyl-D-aspartate cytotoxicity by neuroactive steroids in rat
      cortical neurons.
AB  - We investigated the effects of neuroactive steroids on N-methyl-D-aspartate
      (NMDA) cytotoxicity in cultured rat cortical neurons. 3alpha-hydroxy-5beta
      pregnan-20-one sulfate (3alpha5betaS) attenuated, whereas pregnenolone sulfate
      and pregnenolone hemisuccinate exacerbated, NMDA neurotoxicity in cortical slice
      cultures. These actions of steroids were not affected by inhibition of protein
      synthesis, by blockade of GABA(A) receptors, or by blockade of sigma receptors.
      In addition, the actions of steroids were not affected by manipulation of cyclic
      AMP levels or protein kinase C activity. We found that 3alpha5betaS attenuated
      and pregnenolone hemisuccinate augmented NMDA-induced currents in cortical
      neurons, whereas pregnenolone sulfate exerted no significant effect. Fluorometric
      measurements revealed that 3alpha5betaS attenuated and pregnenolone hemisuccinate
      augmented glutamate-induced increase in intracellular Ca(2+). Pregnenolone
      sulfate slowed the decay of Ca(2+) increase induced by glutamate, without
      significant effect on the peak amplitude of Ca(2+) increase. These results
      indicate that neuroactive steroids affect NMDA cytotoxicity by modulation of
      Ca(2+) influx through NMDA receptor-associated channels.

PMID- 12421644
TI  - Effects of the adenosine A1 receptor allosteric modulators PD 81,723 and LUF 5484
      on the striatal acetylcholine release.
AB  - The objective of the present study was to characterize the adenosine A(1)
      receptor allosteric enhancing and antagonistic actions of (2-amino-4,5,6,7
      tetrahydrobenzo[b]thiophen-3-yl)(3,4-dichlorophenyl)methanone (LUF 5484) and (2
      amino-4,5-dimethyl-3-thienyl)-[3-(trifluoromethyl)phenyl]methanone (PD 81,723) on
      striatal acetylcholine release. Upon local administration in conscious rats, LUF
      5484 or PD 81,723 caused a concentration-dependent increase of extracellular
      acetylcholine levels of approximately 40%, which was similar to that obtained by
      the selective adenosine A(1) receptor antagonists 8-cyclopentyl-1,3
      dimethylxanthine (8CPT) and N(6)-cyclopentyl-9-methyladenine (N0840). In
      interaction experiments, LUF 5484 or PD 81,723 did not change the inhibition of
      acetylcholine release by the adenosine A(1) receptor agonist N(6)
      cyclopentyladenosine (CPA), whereas 8CPT caused an eightfold rightward shift.
      Acetylcholine concentrations were diminished with 62+/-3%, 48+/-11% and 56+/-9%
      by CPA, CPA+LUF 5484 and CPA+PD 81,723, respectively. In conclusion, the
      antagonistic action of LUF 5484 and PD 81,723 seems to counteract the putative
      allosteric actions with respect to the reduction of striatal acetylcholine
      release.

PMID- 12421645
TI  - Comparison of the anticholinergic effects of the serotonergic antidepressants,
      paroxetine, fluvoxamine and clomipramine.
AB  - Paroxetine, a selective serotonin reuptake inhibitor, shows relatively high
      affinity for muscarinic acetylcholine receptors compared to other selective
      serotonin reuptake inhibitors. To determine whether paroxetine has
      anticholinergic effects in vivo, we examined the effects of paroxetine on
      oxotremorine-induced tremor, spontaneous defecation and passive avoidance
      performance using mice and compared the results with those using fluvoxamine,
      another selective serotonin reuptake inhibitor, and clomipramine, a tricyclic
      antidepressant with serotonin selectivity. The potency of antidepressant activity
      as determined in the tail suspension test was
      paroxetine>fluvoxamine>clomipramine. Paroxetine and clomipramine inhibited
      oxotremorine-induced tremor, reduced spontaneous defecation and impaired passive
      avoidance performance, while fluvoxamine did not have similar effects. A
      comparison of ED(50) values showed that the ratio of anticholinergic effect to
      antidepressant activity was fluvoxamine, >3.2; paroxetine, 2.1-2.6; clomipramine,
      <0.8. These results suggest that paroxetine may induce fewer adverse
      anticholinergic effects than clomipramine, but more than fluvoxamine.

PMID- 12421646
TI  - Effects of ghrelin and amylin on dopamine, norepinephrine and serotonin release
      in the hypothalamus.
AB  - Ghrelin and amylin are gut-derived hormones that stimulate and inhibit food
      intake, respectively. Feeding is modulated by aminergic neurotransmitters in the
      hypothalamus. We have evaluated the effects of ghrelin and amylin on dopamine,
      norepinephrine and serotonin release from rat hypothalamic synaptosomes. We found
      that ghrelin did not modify dopamine or norepinephrine release, but inhibited
      serotonin release. On the other hand, amylin inhibited dopamine release, without
      affecting norepinephrine or serotonin. We conclude that the appetite-stimulating
      activity of ghrelin could be mediated by inhibited serotonin release, while the
      anorectic effects of amylin could involve inhibited release of dopamine in the
      hypothalamus.

PMID- 12421647
TI  - Effects of alpha-adrenoceptor agonists and antagonists on histamine-induced
      impairment of memory retention of passive avoidance learning in rats.
AB  - The effect of alpha-adrenoceptor agents on the impairment induced by histamine
      was measured for memory retention of passive avoidance learning in rats. Post
      training intracerebroventricular (i.c.v.) injection was carried out in all the
      experiments. Histamine (5, 10 and 20 microg/rat) reduced, while a histamine H(1)
      receptor antagonist, chlorpheniramine (0.1, 1 and 10 microg/rat), increased
      memory retention. The histamine H(2) receptor antagonist, ranitidine (0.1, 1, 10
      and 20 microg/rat), did not elicit any response in this respect. Different doses
      of chlorpheniramine but not ranitidine reversed the histamine-induced impairment
      of memory. Clonidine and prazosin decreased, but yohimbine and phenylephrine
      increased, memory retention. Yohimbine decreased the inhibitory response to
      histamine. Phenylephrine, clonidine and prazosin did not alter the histamine
      effect. It is concluded that a histamine-induced impairment of memory retention
      through histamine H(1) receptors and an alpha(2)-adrenoceptor mechanism may be
      involved in the histamine response.

PMID- 12421648
TI  - Role of the vestibular nuclei in endothelin-1-induced barrel rotation in rats.
AB  - The fourth or lateral ventricular injection of endothelin-1 resulted in a dose
      dependent increase in the barrel rotation and produced marked induction of c-Fos
      positive cells in the vestibular nuclei. The doses of the former injection were
      lower and had shorter mean latent periods compared with the later injection. c
      Fos expression after endothelin-1 injection was prevented by the pretreatment
      with the endothelin ET(A) receptor antagonist, cyclo(D-alpha-aspartyl-L-propyl-D
      valyl-L-leucyl-D-tryptophyl) (BQ-123), the glutamate NMDA receptor antagonist,
      dizocilpine maleate (MK-801), or the L-type Ca(2+) channel antagonist, verapamil,
      in addition to the incidence of the rotational behavior. There was a significant
      difference in c-Fos expression between the right and left medial vestibular
      nuclei, and the number of c-Fos-labeled neurons in the medial vestibular nucleus
      was markedly increased on the opposite side of the rotational direction. These
      results suggest that the elicitation of the barrel rotation may be mediated by
      endothelin ET(A) receptors, glutamate NMDA receptors, and L-type Ca(2+) channels.
      The changes in the receptor and channel systems induced by endothelin-1
      injections appeared to exert crucial influences on the vestibular nuclei and then
      on the maintenance of equilibrium. The direction of the barrel rotation has a
      deep connection with the imbalance of neuronal activity in the left and right
      medial vestibular nuclei.

PMID- 12421649
TI  - Analysis of the time course for organ culture-induced endothelin ET B receptor
      upregulation in rat mesenteric arteries.
AB  - In contrast to the constitutively expressed endothelin ET(A) receptor, the
      distribution of endothelin ET(B) receptors is more variable. The aim of the
      present study was to investigate the kinetics of organ culture-induced
      upregulation of contractile endothelin ET(B) receptors in rat mesenteric arteries
      at both mRNA and functional levels. Assessment of mRNA expression revealed low
      levels of endothelin ET(B) receptor mRNA relative to endothelin ET(A) receptor
      mRNA after 3 h of culture, which gradually increased to reach a plateau level
      after 24 h. Correspondingly, vessels cultured for 3 h showed a negligible
      contractile response the selective endothelin ET(B) receptor agonist sarafotoxin
      6c. Subsequently, the contractile response to sarafotoxin 6c was successively
      increased during organ culture until 24 h and, thereafter, a further increase in
      potency was seen after 48 h. These results demonstrate a rapid induction of
      transcription within less than 7 h followed by an increase in the response to
      receptor stimulation.

PMID- 12421650
TI  - Acute inhibition of glutathione biosynthesis alters endothelial function and
      blood pressure in rats.
AB  - The cardiovascular and biochemical responses during acute oxidative stress
      induced by D,L-buthionine-(S,R)-sulfoximine (BSO) were investigated in Sprague
      Dawley rats. Mean arterial pressure, heart rate and vascular reactivity were
      measured after subcutaneous injection of BSO (4 mmol/kg). Control rats received
      saline. Levels of GSH and GSSG in blood and tissues as well as renal superoxide
      were determined. Nitric oxide, prostacyclin and thromboxane A(2) in plasma and
      aorta, and isoprostane in plasma were also measured. Blood pressure was elevated
      at 24 h (121+/-2 vs. 104+/-2 mm Hg), with increased reactivity to phenylephrine
      (by a 59+/-4 vs. 45+/-2 mm Hg change), and impaired response to sodium
      nitroprusside (by a -35+/-2 vs. -63+/-2 mm Hg change), P<0.05. The GSH:GSSG ratio
      was reduced at 8 and 24 h in blood (4.1+/-0.6 and 5.1+/-0.3, respectively, vs.
      8.5+/-0.2), and at 8 h in the aorta (1.0+/-0.2 vs. 2.9+/-0.5), heart (1.6+/-0.3
      vs. 2.3+/-0.1) and kidney (2.1+/-0.2 vs. 3.7+/-0.4), P<0.05. Superoxide
      fluorescence was increased at 24 h via NADH (4131+/-194 vs. 2853+/-199), NADPH
      (2874+/-272 vs.1479+/-257) and succinate (2475+/-133 vs. 1594+/-2150), P<0.05.
      Plasma prostacyclin was reduced at 8 and 24 h (36+/-4 and 52+/-13, respectively,
      vs. 310+/-44 pg/ml), P<0.001, whereas nitric oxide was reduced at 24 h (6.4+/-1
      vs. 22+/-2 microM), P<0.01. Also at 24 h, thromboxane A(2) was increased both in
      plasma (374+/-154 vs. 61+/-10 pg/ml) and the aorta (174.4+/-38 vs. 27+/-3.4
      pg/mg), P<0.05. Thus, acute BSO-induced oxidative stress alters blood pressure
      and endothelial function by mechanisms involving increased plasma levels and
      aortic release of thromboxane A(2) and reduced nitric oxide and prostacyclin.

PMID- 12421651
TI  - Inhibition by extracellular ATP of organic anion transport in the perfused rat
      liver.
AB  - The action of extracellular ATP on organic anion transport in the bivascularly
      perfused rat liver was investigated, using bromosulfophthalein as a model
      substance. Transport was measured by means of the multiple-indicator dilution
      technique. The action of portal 100 microM ATP presented the following
      characteristics: (a) inhibition of bromosulfophthalein single pass extraction;
      the inhibition degree decreased with increasing bromosulfophthalein doses; (b)
      diminution of the influx rate coefficients; (c) 86.7% decrease of the maximal
      activity of the saturable component for bromosulfophthalein transport, but 100%
      increase of the non-saturable component; (d) diminution of the
      bromosulfophthalein flow-limited distribution space; (e) no significant
      alteration of the rate coefficients for metabolic sequestration. The action of
      ATP on organic anion transport in the intact liver occurred at much lower
      concentrations (10x) than those previously reported for isolated hepatocytes.
      This reinforces the suggestion that inhibition of organic anion transport could
      be a physiologically relevant effect of extracellular ATP.

PMID- 12421652
TI  - 5-HT2A receptor antagonist properties of cyamemazine in rat and guinea pig smooth
      muscle.
AB  - 5-HT(2A) receptor antagonism seems to explain the low incidence of extrapyramidal
      side effects with atypical neuroleptics. Whether the neuroleptic cyamemazine,
      which at low doses is also devoid of extrapyramidal side effects, possesses 5
      HT(2A) receptor antagonist properties is unknown. Cyamemazine was tested for its
      ability to antagonize 5-HT(2A)-mediated responses in isolated rat aorta and
      guinea pig trachea and to displace [3H]ketanserin specifically bound to rat brain
      membranes. In isolated rat aorta, cyamemazine potently and competitively
      antagonized serotonin-dependent contractions (pA(2)=8.82+/-0.26, n=7; Schild's
      slope=1.02+/-0.29). In this test, cyamemazine was of similar potency as
      ketanserin (pA(2)=8.23). In isolated guinea pig trachea, cyamemazine reduced
      maximum contractile responses to serotonin with pIC(50)=7.92+/-0.35, (n=4),
      whereas ketanserin exhibited a pIC(50)=8.79. Finally, cyamemazine displaced
      [3H]ketanserin specifically bound to rat brain membranes with pK(i)=8.76+/-0.53
      (n=3). In conclusion, cyamemazine behaves as a potent antagonist at 5-HT(2A)
      receptors, which compares well with the reference compound, ketanserin. Whether
      this 5-HT(2A) receptor antagonist action of cyamemazine can explain its low
      incidence of extrapyramidal side effects deserves further investigation.

PMID- 12421653
TI  - Oxytocin-induced renin secretion by denervated kidney in anaesthetized rat.
AB  - The effects of oxytocin on renin secretion by denervated kidney were investigated
      in vivo, by infusing the peptide directly into the renal artery of anaesthetized
      rats. Renin secretion was calculated by the renal veno-arterial difference in
      plasma renin activity multiplied by renal plasma flow. The intra-renal arterial
      (i.r.a.) infusion of oxytocin (1.5 or 15 ng/kg/min, 10 min) induced a sixfold
      increase in renin secretion as compared to vehicle-treated controls, without
      effects on renal blood flow, mean arterial blood pressure, glomerular filtration
      rate or natriuresis. The effect of oxytocin (1.5 ng/kg/min) was prevented by
      pretreatment with an oxytocin receptor antagonist, desGly-NH(2),d(CH(2))(5)[D
      Tyr(2),Thr(4),Orn(8)]vasotocin] (5.6 microg/kg bolus i.v. 20 min before oxytocin
      infusion, followed by 2.8 microg/kg/min i.r.a.). Nadolol (2.5 mg/kg i.v.), a beta
      adrenoceptor antagonist, also blocked the oxytocin-induced increase in renin
      secretion. These results show that oxytocin is able to stimulate renin release by
      activating oxytocin receptors but that beta-adrenoceptors also seem to be
      involved.

PMID- 12421654
TI  - Evidence of conscious and subconscious olfactory information processing during
      word encoding: a magnetoencephalographic (MEG) study.
AB  - The present study was meant to distinguish between unconscious and conscious
      olfactory information processing and to investigate the influence of olfaction on
      word information processing. Magnetic field changes were recorded in healthy
      young participants during deep encoding of visually presented words whereby some
      of the words were randomly associated with an odor. All recorded data were then
      split into two groups. One group consisted of participants who did not
      consciously perceive the odor during the whole experiment whereas the other group
      did report continuous conscious odor perception. The magnetic field changes
      related to the condition 'words without odor' were subtracted from the magnetic
      field changes related to the condition 'words with odor' for both groups. First,
      an odor-induced effect occurred between about 200 and 500 ms after stimulus onset
      which was similar in both groups. It is interpreted to reflect an activity
      reduction during word encoding related to the additional olfactory stimulation.
      Second, a later effect occurred between about 600 and 900 ms after stimulus onset
      which differed between the two groups. This effect was due to higher brain
      activity related to the additional olfactory stimulation. It was more pronounced
      in the group consisting of participants who consciously perceived the odor during
      the whole experiment as compared to the other group. These results are
      interpreted as evidence that the later effect is related to conscious odor
      perception whereas the earlier effect reflects unconscious olfactory information
      processing. Furthermore, our study provides evidence that only the conscious
      perception of an odor which is simultaneously presented to the visual
      presentation of a word reduces its chance to be subsequently recognized.

PMID- 12421655
TI  - Cognitive flexibility across the sleep-wake cycle: REM-sleep enhancement of
      anagram problem solving.
AB  - Flexible or 'fluid' cognitive processes are regarded as fundamental to problem
      solving and creative ability, requiring a specific neurophysiological milieu. REM
      sleep dreaming is associated with creative processes and abstract reasoning with
      increased strength of weak associations in cognitive networks. REM sleep is also
      mediated by a distinctive neurophysiological profile, different to that of wake
      and NREM sleep. This study compared the performance of 16 subjects on a test of
      cognitive flexibility using anagram word puzzles following REM and NREM
      awakenings across the night, and waking performances during the day. REM
      awakenings provided a significant 32% advantage in the number of anagrams solved
      compared with NREM awakenings and was equal to that of wake time trials.
      Correlations of individual performance profiles suggest that REM sleep may offer
      a different mode of problem solving compared with wake and NREM. When early and
      late REM and NREM awakening data were separated, a dissociation was evident, with
      NREM task performance becoming more REM-like later in the night, while REM
      performance remained constant. These data suggest that the neurophysiology of REM
      sleep represents a brain state more amenable to flexible cognitive processing
      than NREM and different from that in wake, and may offer insights into the
      neurocognitive properties of REM-sleep dreaming.

PMID- 12421656
TI  - An electrophysiological and behavioral investigation of involuntary attention
      towards auditory frequency, duration and intensity changes.
AB  - We measured behavior and event-related brain potentials (ERPs) in 12 subjects
      performing on an audio-visual distraction paradigm to investigate the cerebral
      mechanisms of involuntary attention towards stimulus changes in the acoustic
      environment. Subjects classified odd/even numbers presented on a computer screen
      300 ms after the occurrence of a task-irrelevant auditory stimulus, by pressing
      the corresponding response button. Auditory stimuli were standard tones (600 Hz,
      200 ms, 85 dB; P=0.8) or deviant tones (P=0.2), these differing from the standard
      either in frequency (700 Hz), duration (50 ms) or intensity (79 dB), in separate
      blocks. In comparison to performance to visual stimuli following the standard
      tones, reaction time increased by 24 ms (F(1,11)=10.91, P<0.01) and hit rate
      decreased by 4.6% (F(1,11)=35.47, P<0.001) to visual stimuli following the
      deviant tones, indicating behavioral distraction. ERPs revealed the mismatch
      negativity (MMN) elicited to deviant tones, which was larger for the duration
      deviant than for the frequency and intensity deviants (F(2,22)=19.43, P<0.001,
      epsilon =0.83), and which had different scalp distribution for all three deviant
      conditions (F(16,176)=2.40, P<0.05, epsilon =0.12). As the shorter duration and
      softer intensity deviant tones were unlikely to engage fresh neurons responding
      to their specific physical features, the present results indicate that a genuine
      change detection mechanism is involved in triggering attention switching towards
      sound changes, and suggest a largely distributed neural network of the auditory
      cortex underlying such involuntary attention switching.

PMID- 12421657
TI  - Electrophysiological estimates of biological and syntactic gender violation
      during pronoun processing.
AB  - During comprehension, a personal pronoun (he, she, it) refers to a preceding
      referent (boy, girl, child). This co-reference could be established, among other
      ways, by using (i). conceptual/semantic information (biological gender agreement
      between the pronoun and its referent), (ii). syntactic information (syntactic
      gender agreement), or (iii). both. This event-related brain potential (ERP) study
      assesses this interplay of syntactic and semantic information. We focussed on the
      N400 component, related to semantic integration, and the SPS/P600 component,
      related to syntactic reanalysis. The study was conducted in German, because its
      rich syntactic gender system offers a means to dissociate between biological
      (MALE/FEMALE) and syntactic gender (masculine/feminine/neuter), especially in the
      case of diminutives (das(neuter) Bubchen(MALE) [the little boy]). German subjects
      read sentences in which a referent (Bubchen(MALE-neuter)/Bub(MALE-masculine)
      [boy]) was introduced. Later a personal pronoun was presented which either agreed
      with the referent in terms of syntactic gender, or in terms of biological gender,
      or both, or violated both agreements. Overall, results showed salient P600
      effects for pronouns. This indicates that the establishment of reference involves
      syntactic reanalysis. Furthermore, we observed N400 effects in sentences with non
      diminutives, but not with diminutives. This shows that conceptual/semantic
      integration is involved during non-diminutive but not during diminutive pronoun
      processing, or at least it could not be violated. The overall pattern of results
      supports the claim that for non-diminutives, both syntactic and conceptual
      information is used to establish co-reference, while for diminutives the process
      might be purely syntactically driven.

PMID- 12421659
TI  - Dynamic patterns make the premotor cortex interested in objects: influence of
      stimulus and task revealed by fMRI.
AB  - Research in monkey and man indicates that the ventrolateral premotor cortex (PMv)
      underlies not only the preparation of manual movements, but also the perceptual
      representation of pragmatic object properties. However, visual stimuli without
      any pragmatic meaning were recently found to elicit selective PMv responses if
      they were subjected to a perceivable pattern of change. We used functional
      magnetic resonance imaging (fMRI) to investigate if perceptual representations in
      the PMv might apply not only to pragmatic, but also to dynamic stimulus
      properties. To this end, a sequential figure matching task that required the
      processing of dynamic features was contrasted with a non-figure control task
      (Experiment 1) and an individual figure matching task (Experiment 2). In order to
      control for potential influences of stimulus properties that might be associated
      with pragmatic attributes, different types of abstract visual stimuli were
      employed. The experiments yielded two major findings: if their dynamic properties
      are attended, then abstract 2D visual figures are sufficient to trigger
      activation within premotor areas involved in hand-object interaction. Moreover,
      these premotor activations are independent from stimulus properties that might
      relate to pragmatic features. The results imply that the PMv is engaged in the
      processing of stimuli that are usually or actually embedded within either a
      pragmatic or a dynamic context.

PMID- 12421658
TI  - Functional magnetic resonance imaging of brain activity in the visual oddball
      task.
AB  - Abnormalities in the P300 ERP, elicited by the oddball task and measured using
      EEG, have been found in a number of central nervous system disorders including
      schizophrenia, Alzheimer's disease, and alcohol dependence. While
      electrophysiological studies provide high temporal resolution, localizing the
      P300 deficit has been particularly difficult because the measurements are
      collected from the scalp. Knowing which brain regions are involved in this
      process would elucidate the behavioral correlates of P300. The aim of this study
      was to determine the brain regions involved in a visual oddball task using fMRI.
      In this study, functional and high-resolution anatomical MR images were collected
      from seven normal volunteers. The data were analyzed using a randomization-based
      statistical method that accounts for multiple comparisons, requires no
      assumptions about the noise structure of the data, and does not require spatial
      or temporal smoothing. Activations were detected (P<0.01) bilaterally in the
      supramarginal gyrus (SMG; BA 40), superior parietal lobule (BA 7), the posterior
      cingulate gyrus, thalamus, inferior occipitotemporal cortex (BA 19/37), insula,
      dorsolateral prefrontal cortex (BA 9), anterior cingulate cortex (ACC), medial
      frontal gyrus (BA 6), premotor area, and cuneus (BA 17). Our results are
      consistent with previous studies that have observed activation in ACC and SMG.
      Activation of thalamus, insula, and the occipitotemporal cortex has been reported
      less consistently. The present study lends further support to the involvement of
      these structures in visual target detection.

PMID- 12421660
TI  - MEG alpha activity decrease reflects destabilization of multistable percepts.
AB  - Multistable stimuli offer the possibility to investigate visual awareness, since
      they evoke spontaneous alternations between different perceptual interpretations
      of the same stimulus and, therefore, allow to dissociate perceptual from stimulus
      driven mechanisms. In the present study, we used an ambiguous motion paradigm and
      compared endogenous reversals of perceived motion direction which occur
      spontaneously during constant ambiguous stimulation with exogenous reversals that
      were induced externally by changes of stimulation. Contrasting the two conditions
      allowed to investigate processes that trigger endogenous reversals, since the
      related activity should be absent in the exogenous reversal condition. We
      employed ambiguous dot patterns which can easily be transformed to present two
      stable motion directions in order to induce exogenous pattern reversals. Whole
      head MEG was recorded from 10 subjects. We analyzed event-related fields (ERFs)
      and oscillatory activity in the alpha and gamma ranges. The results showed P300
      like slow waves in response to both endogenous and exogenous reversals reflecting
      the conscious recognition of pattern reversals. Analyses in the gamma-band did
      not reveal any significant modulations. The alpha activity showed different time
      courses for endogenous and exogenous reversals. While the exogenous alpha
      activity decreased in temporal relation to the pattern reversal, the endogenous
      alpha activity displayed a continuous decrease starting in the time interval
      preceding the reversal. This time course of the endogenous alpha activity is
      consistent with a bottom-up approach to figure reversals, since it reflects a
      process of destabilization of the actual percept until a switch of visual
      awareness occurs.

PMID- 12421661
TI  - Volitional scaling of anticipatory ocular pursuit velocity using precues.
AB  - Human subjects cannot normally perform smooth eye movements in the absence of a
      target. However, the repeated presentation of identical, transient target motion
      stimuli, preceded by warning cues, leads to the build up of anticipatory smooth
      pursuit (ASP) eye movements several hundred milliseconds prior to stimulus onset.
      The present study sought to investigate whether subjects are able to volitionally
      scale ASP speed, as well as select pursuit direction, in advance of target motion
      stimuli of random direction (left vs. right) and speed (10, 20, 30 and 40 degrees
      /s), given stationary precues predictive of both these target parameters. The
      subjects' success at this task is discussed in terms of their ability to
      volitionally scale the internal store of target velocity information postulated
      to drive ASP.

PMID- 12421662
TI  - Second somatosensory area (SII) plays a significant role in selective
      somatosensory attention.
AB  - In order to explore human cortical areas involved in active attention toward a
      somatosensory modality, somatosensory evoked cortical magnetic fields were
      recorded in ten healthy adults with a 122-channel whole-head magnetometer while
      the subjects performed the selective attention task. Two kinds of stimulus
      modality, somatosensory and auditory, were presented independently in the same
      session. For the somatosensory modality, a randomized sequence of strong (P=0.45)
      and weak (P=0.05) electric stimuli was delivered to the right median nerve at the
      wrist. For the auditory modality, a randomized sequence of 900-Hz (P=0.45) and
      950-Hz (P=0.05) tones was delivered to both ears. Subjects were requested to pay
      attention to the specified stimulus modality (either somatosensory or auditory)
      and to count the number of rare stimuli of the attended modality (weak stimuli in
      the somatosensory or 950-Hz tone in the auditory modality). A total of 12
      sessions were performed for each subject, among which the order of attended
      modality was changed alternately and counterbalanced among subjects. In the data
      analysis, somatosensory evoked fields for frequent stimuli (strong electric
      stimuli) were compared between the two conditions; attend somatosensory condition
      (ATS) and attend auditory condition (non-attend somatosensory condition; NATS).
      In six out of the ten subjects, somatosensory evoked fields showed attention
      related change. The magnitude of the estimated generator source in SII, but not
      in SI, significantly increased from NATS to ATS while keeping the same locations.
      Moreover, a simulation study using the estimated sources in SII in NATS supported
      the enhancement of the activity in the SII rather than participation of
      additional sources in the selective attention task. These results suggest that
      the SII plays a main role in selective somatosensory attention.

PMID- 12421663
TI  - Event-related brain potential evidence for a response of inferior temporal cortex
      to familiar face repetitions.
AB  - We investigated immediate repetition effects in the recognition of famous faces
      by recording event-related brain potentials (ERPs) and reaction times (RTs).
      Participants recognized celebrities' faces that were preceded by either the same
      picture, a different picture of the same celebrity, or a different famous face.
      Face repetition caused two distinct ERP modulations. Repetitions elicited a
      strong modulation of an N250 component ( approximately 200-300 ms) over inferior
      temporal regions. The N250 modulation showed a degree of image specificity in
      that it was still significant for repetitions across different pictures, though
      reduced in amplitude. ERPs to repeated faces were also more positive than those
      to unprimed faces at parietal sites from 400 to 600 ms, but these later effects
      were largely independent of whether the same or a different image of the
      celebrity had served as prime. Finally, no influence of repetition was observed
      for the N170 component. Dipole source modelling suggested that the N250
      repetition effect (N250r) may originate from the fusiform gyrus. In contrast,
      source localisation of the N170 implicated a significantly more posterior
      location, corresponding to a lateral occipitotemporal source outside the fusiform
      gyrus.

PMID- 12421664
TI  - Visual marking for search: behavioral and event-related potential analyses.
AB  - Visual marking is an attentional mechanism of prioritizing the selection of new
      static or moving objects via top-down intentional inhibition of old objects
      [Psychol. Rev. 104 (1997) 90-122]. The present study investigated the operation
      of visual marking using event-related brain potentials (ERPs). Participants
      searched a display for one of two target letters among randomly selected letter
      distractors. Two item set sizes were used in a two-stage display. Half of the
      items appeared for 1000 ms in the first stage followed by the remainder in the
      second stage. Three blocked conditions were used. In the Preview condition,
      targets appeared as one of a set of new items in Display 2. Items in Display 1
      could thus be excluded from search by visual marking. In the Control condition,
      old items changed when new items appeared, and the target was equally likely to
      be at an old or a new position. In this condition marking is unlikely to be
      engaged since old locations could contain the target. In the Search condition,
      targets appeared either in Display 1 (80%) or Display 2 (20%), and Display 1
      items did not change. The results showed condition-contingent attentional
      modulations in the N1/N2 range. In addition, a broadly distributed centrally
      preponderant sustained negativity was obtained in the 350-750 ms time range after
      the onset of Display 1 for the Preview-Control comparison. This latter negativity
      is interpreted to reflect the processes involved in setting up and maintaining of
      visual marking. It demonstrated an effect of visual marking well prior to Display
      2 onset, thereby ruling out an account of the preview benefit solely due to
      attentional capture by Display 2 item onset.

PMID- 12421665
TI  - Auditory deprivation affects processing of motion, but not color.
AB  - Event-related potentials (ERPs) were recorded in response to color changes of
      isoluminant, high spatial frequency gratings and to motion of grayscale, low
      spatial frequency gratings in 11 normally hearing and 11 congenitally deaf
      adults. The stimuli were designed to activate preferentially the ventral and
      dorsal streams of visual processing, respectively. Color changes evoked prominent
      P1 and N1 components in the ERP; motion evoked an early, focal positivity (the P
      INZ), a minimal P1, and a prominent N1. Color changes elicited similar ERP
      components in hearing and deaf participants. In contrast, motion elicited larger
      amplitude and more anteriorly distributed N1 components in deaf than hearing
      participants. These results suggest that early auditory deprivation may have more
      pronounced effects on the functions of the dorsal visual pathway than on
      functions of the ventral pathway.

PMID- 12421666
TI  - Cytokines come of age.

PMID- 12421667
TI  - Molecular mechanisms of cytokine receptor activation.
AB  - Cytokine receptors are transmembrane proteins that transmit a signal into the
      cell upon ligand binding. Commonly, these molecules have one hydrophobic segment
      of about 20-26 amino acids that is believed to span the membrane as a helix and
      this divides these receptors into extra- and intracellular components. By
      utilizing two different epitopes, the cytokines bridge two receptor chains,
      resulting in a close proximity of the intracellular component and thereby
      initiating the intracellular signalling cascade. The dimerization event is
      believed to be the mechanism by which the signal is transmitted across a
      membrane. In the light of new results obtained for the erythropoietin receptor,
      James A. Wells questioned whether any dimer would be sufficient. This review will
      expand upon the above question by discussing the more complex signal-transducing
      receptor subunits of the Interleukin-6 type family of cytokines. Based on the
      recently solved quaternary structure of the Insulin receptor, possible analogies
      will be confronted.

PMID- 12421668
TI  - A structural template for gp130-cytokine signaling assemblies.
AB  - The gp130-cytokine system has been fertile ground for protein structure-function
      studies aimed at elucidating the basis of ligand recognition and receptor
      activation. A number of longstanding questions involve the mechanism of the
      stepwise assembly of the active signaling complexes, as well as the structure of
      the gp130-cytokine complexes. It has been clear from functional studies that the
      paradigm of gp130-cyokine recognition will differ substantially from the
      classical homo-dimeric systems, typified by human growth hormone (hGH) and its
      receptor. Recently, a crystal structure of a viral interleukin-6 (vIL-6),
      complexed with the D1D2D3 domains of the gp130 extracellular domain, has resolved
      many of these questions, and reconciled much of the functional and mutagenesis
      data which have existed for a variety of gp130-cytokines. In this review, we
      discuss the structure of the vIL-6/gp130 complex in some detail and suggest that
      the geometry of this complex will be a common structural template utilized by
      other gp130-cytokines, as well as cytokines from distinct signaling systems.

PMID- 12421669
TI  - Structure, binding, and antagonists in the IL-4/IL-13 receptor system.
AB  - Interleukin-4 (IL-4) and IL-13 are the only cytokines known to bind to the
      receptor chain IL-4Ralpha. Receptor sharing by these two cytokines is the
      molecular basis for their overlapping biological functions. Both are key factors
      in the development of allergic hypersensitivity, and they also play a major role
      in exacerbating allergic and asthmatic symptoms. Knowledge of structure and
      function of this system has allowed the development of inhibitors that block the
      interaction between the cytokines and their shared receptor. Mutational analysis
      of IL-4 has revealed variants with high-affinity binding to IL-4Ralpha but no
      detectable affinity for the second receptor subunit, which is either (gamma)c or
      IL-13Ralpha1. These IL-4 antagonists fail to induce signal transduction and block
      IL-4 and IL-13 effects in vitro. IL-4 antagonists prevent the development of
      allergic disease in vivo and an antagonistic variant of human IL-4 is now in
      clinical trials for asthma. Detailed knowledge of the site of interaction of IL-4
      and IL-4Ralpha has been gained by structure analysis of the complex of these two
      proteins and through functional studies employing mutants of IL-4 and its
      receptor subunits. Based on these new data, the hitherto elusive goal of
      designing small molecular mimetics may be feasible.

PMID- 12421670
TI  - The role of soluble receptors in cytokine biology: the agonistic properties of
      the sIL-6R/IL-6 complex.
AB  - Cytokines perform ever-increasing roles in both, the regulation of general
      homeostasis and in orchestrating the immune response during disease. To ensure
      that control of the cytokine network is tightly regulated, nature has developed a
      series of systems designed for this purpose. In this respect, researchers have
      placed considerable emphasis on identifying and characterising the regulatory
      properties of soluble cytokine receptors. These proteins bind their ligands with
      similar affinities to those of their cognate transmembrane receptors and are
      effective at prolonging the circulating half-life of cytokines they bind.
      However, it is the individual capacity of these soluble receptors to act as
      either antagonists or agonists which has been the principal focus of most
      research studies. This review provides an overview of the activities of soluble
      cytokine receptors, but primarily concentrates on those that possess agonistic
      properties.

PMID- 12421671
TI  - Summary and comparison of the signaling mechanisms of the Toll/interleukin-1
      receptor family.
AB  - The Toll/interleukin-1 (IL-1) receptor (TIR) family comprises two groups of
      transmembrane proteins, which share functional and structural properties. The
      members of the IL-1 receptor (IL-1R) subfamily are characterized by three
      extracellular immunoglobulin (Ig)-like domains. They form heterodimeric signaling
      receptor complexes consisting of receptor and accessory proteins. The members of
      the Toll-like receptor (TLR) subfamily recognize alarm signals that can be
      derived either from pathogens or the host itself. TLRs possess leucine-rich
      repeats in their extracellular part. TLRs can form dimeric receptor complexes
      consisting of two different TLRs or homodimers in the case of TLR4. The TLR4
      receptor complex requires supportive molecules for optimal response to its ligand
      lipopolysaccharide (LPS). A hallmark of the TIR family is the cytoplasmic TIR
      domain that is indispensable for signal transduction. The TIR domain serves as a
      scaffold for a series of protein-protein interactions which result in the
      activation of a unique signaling module consisting of MyD88, interleukin-1
      receptor associated kinase (IRAK) family members and Tollip, which is used
      exclusively by TIR family members. Subsequently, several central signaling
      pathways are activated in parallel, the activation of NFkappaB being the most
      prominent event of the inflammatory response. Recent developments indicate that
      in addition to the common signaling module MyD88/IRAK/Tollip, other molecules can
      modulate signaling by TLRs, especially of TLR4, resulting in differential
      biological answers to distinct pathogenic structures. Subtle differences in TLR
      signaling pathways are now becoming apparent, which reveal how the innate immune
      system decides at a very early stage the direction in which the adaptive immune
      response will develop. The creation of pathogen-specific mediator environments by
      dendritic cells defines whether a cellular or humoral response will be activated
      in response to the pathogen.

PMID- 12421672
TI  - Molecular basis of the cell specificity of cytokine action.
AB  - The molecular cloning and biological analyses of cytokines have led us to a
      general understanding of their pleiotropism and redundancy. These features have
      been ascribed to the composition of cytokine receptor complexes, which include a
      signal-transducing receptor subunit that is used by all members of a cytokine
      family and a binding subunit that is specific for each cytokine. Even though a
      given cytokine uses the same receptor complex when binding to various cell types,
      the cytokine elicits quite specific and distinct biological responses in
      different types of cells. Even in the same type of cell, the responses to a given
      cytokine could vary depending on the location of the cell and the condition of
      its microenvironment. Important mediators for the main cytokine signal
      transduction pathway are the Janus kinases (Jaks) and signal transducer and
      activator of transcription (STATs). Selective usage of members of the Jak and
      STAT families by a given cytokine receptor is partly responsible for the
      specificity of cytokine action. In addition to the Jak-STAT pathway, a cytokine
      receptor complex can simultaneously operate multiple signal-transduction
      pathways, which usually express contradictory properties. These contradictory
      signals from a single cytokine are orchestrated to evoke a unified biological
      response in the cell. Here we discuss the molecular mechanisms that regulate how
      the cell specificity of cytokine signals is regulated, especially focusing on the
      IL-6/gp130 system.

PMID- 12421673
TI  - Role of the SHP-2 tyrosine phosphatase in cytokine-induced signaling and cellular
      response.
AB  - Cytokines and growth factors are important extracellular regulatory proteins.
      They exert their biological functions through binding to their cognate receptors
      on the cell surface and triggering intracellular signaling cascades. However, the
      intracellular signaling mechanisms of cytokines and growth factors are not well
      understood. Accumulating evidence has shown that protein phosphorylation and
      dephosphorylation carried out by protein kinases and protein phosphatases are
      fundamental biochemical events in intracellular signal transduction. SHP-2, a Src
      homology (SH) 2 domain-containing protein tyrosine phosphatase (PTP), is widely
      involved in a variety of signaling pathways triggered by cytokines and growth
      factors, including the MAP kinase, Jak-Stat, and PI3 kinase pathways. Recent
      studies have clearly demonstrated that this phosphatase plays an important role
      in transducing signals relayed from the cell surface to the nucleus, and is a
      critical intracellular regulator in cytokine and growth factor-induced cell
      survival, proliferation, and differentiation.

PMID- 12421674
TI  - Cytokine regulation of liver development.
AB  - Liver development is a sequential array of distinct biological events. Each step
      of differentiation is regulated by intrinsically programmed mechanisms as well as
      by extracellular signals. The establishment of cell culture systems that
      recapitulate each stage of liver development has led to the identification of
      several extracellular signals that affect hepatocytic differentiation.
      Furthermore, studies on genetically engineered animals, especially knockout and
      transgenic mice, have highlighted a number of molecules essential for liver
      development. By applying primary culture techniques to analyses of mutant mice,
      it is now possible to link extracellular signals to intracellular pathways that
      provoke cellular responses of differentiation. Improvement in gene transfer
      technology utilizing viral vectors has further expanded the molecular analysis of
      liver development. In this review article, we summarize recent advances and
      attempt to describe the molecular basis of liver development from beginning to
      end as a sequential event.

PMID- 12421675
TI  - Ex vivo expansion of hematopoietic stem cells by cytokines.

PMID- 12421676
TI  - The role of transsignalling via the agonistic soluble IL-6 receptor in human
      diseases.
AB  - The activation of cells that do not express the membrane bound interleukin-6 6
      receptor (IL-6R) by IL-6 and the soluble IL-6 receptor (sIL-6R) is termed
      transsignalling. Transsignalling may be an pathogenetic factor in human diseases
      as diverse as multiple myeloma (MM), Castleman's disease, prostate carcinoma,
      Crohn's disease, systemic sclerosis, Still's disease, osteoporosis and
      cardiovascular diseases. IL-6 and sIL-6R may directly or indirectly enhance their
      own production on endothelial or bone marrow stromal cells. Positive feedback
      autocrine loops thus created in affected organs may either cause or maintain
      disease progression. In autoimmune or vasculitic disease, the ability of the IL
      6/sIL-6R complex to inhibit apoptosis of autoreactive T-cells may be central to
      the development of tissue specific autoimmunity. The anti-apoptotic effect of the
      IL-6/sIL-6R complex may be involved in tumour genesis and resistance to
      chemotherapy. Only in rare cases, where counterregulation has failed, there is a
      notable systemic effect of IL-6/sIL-6R. Appropriate animal models are necessary
      to establish the pathogenetic role of the IL-6/sIL-6R complex. A specific
      treatment option for diseases influenced by the sIL-6R could be based on gp130
      Fc, a soluble gp130 (sgp130) linked to the Fc-fragment of IgG1. gp130-Fc has
      shown efficacy in vivo in animal models of Crohn's disease.

PMID- 12421677
TI  - The role of cytokines in liver failure and regeneration: potential new molecular
      therapies.
AB  - The liver is a unique organ, and first in line, the hepatocytes encounter the
      potential to proliferate during cell mass loss. This phenomenon is tightly
      controlled and resembles in some way the embryonal co-inhabitant cell lineage of
      the liver, the embryonic hematopoietic system. Interestingly, both the liver and
      hematopoietic cell proliferation and growth are controlled by various growth
      factors and cytokines. IL-6 and its signaling cascade inside the cells through
      STAT3 are both significantly important for liver regeneration as well as for
      hematopoietic cell proliferation. The process of liver regeneration is very
      complex and is dependent on the etiology and extent of liver damage and the
      genetic background. In this review we will initially describe the clinical
      relevant condition, portraying a number of available animal models with an
      emphasis on the relevance of each one to the human condition of fulminant hepatic
      failure (FHF). The discussion will then be focused on the role of cytokines in
      liver failure and regeneration, and suggest potential new therapeutic modalities
      for FHF. The recent findings on the role of IL-6 in liver regeneration and the
      activity of the designer IL-6/sIL-6R fusion protein, hyper-IL-6, in particular,
      suggest that this molecule could significantly enhance liver regeneration in
      humans, and as such could be a useful treatment for FHF in patients.

PMID- 12421678
TI  - How cells of repair-deficient mice handle chromosome breaks and proliferate as
      malignant survivors.

PMID- 12421679
TI  - RNA interference: a promising approach to antiviral therapy?

PMID- 12421684
TI  - Hyperacidification in cystic fibrosis: links with lung disease and new prospects
      for treatment.
AB  - A new link between the genetic defect and lung pathology in cystic fibrosis (CF)
      has been established by the recent discovery of an abnormally acidic pH in the
      organelles of CF respiratory epithelial cells, along with an increased acidity of
      the CF airway surface liquid. The defect in cystic fibrosis transmembrane
      resistance regulator (CFTR) results in hyperacidification of the trans-Golgi
      network, an organelle responsible for glycosylation, and protein- and membrane
      sorting in mammalian cells. Hyperacidification and altered surface
      glycoconjugates might contribute to mucus thickening, bacterial adhesion and
      colonization, inflammation, and irreversible tissue damage. The increased acidity
      of the intracellular organelles and of the lung lining in CF could be linked, and
      both represent potential therapeutic targets.

PMID- 12421685
TI  - The possible role of complement activation in Alzheimer disease.
AB  - Molecular pathological studies of Alzheimer disease (AD) brain have revealed the
      presence of a spectrum of inflammatory mediators. Epidemiological studies have
      indicated that the use of anti-inflammatory agents, especially non-steroidal anti
      inflammatory drugs (NSAIDs), results in a substantially reduced risk of
      contracting the disease. It is possible that well targeted anti-inflammatory
      agents will also be useful in treating established AD. Inhibitors of
      cyclooxygenase-2 have been unsuccessful in this regard, and traditional NSAIDs
      have produced mixed results. The complement system, which is strongly activated
      in AD brain, is an attractive target for therapeutic intervention, particularly
      through inhibition of the autodestructive action of the membrane attack complex.
      The complement system works in conjunction with activated microglia, which
      express high levels of complement receptors. Overactive microglia secrete many
      toxic materials. Inhibition of microglial activation is another potential
      therapeutic target.

PMID- 12421686
TI  - A model for PKC involvement in the pathogenesis of inborn errors of metabolism.
AB  - A model for the possible involvement of Protein Kinase C (PKC) in the
      pathogenesis of inborn errors of metabolism has been proposed. According to this
      model, perturbation of PKC activity by the accumulation of naturally occurring
      compounds serves as a unifying functional link between genotype and phenotype.
      Recent reports regarding an increasing number of modulating metabolites, specific
      PKC-subtypes activities, their effect on transcription factors and gene
      expression in various diseases and additional PKC-substrates expand the model. A
      re-examination of the proposed model in view of these reports and, vice versa, a
      review of these reports in the context of the proposed model reveal some common
      phenotypic outcomes in inborn errors of fatty acid-, cholesterol- and homocystine
      metabolism as well as lysosomal and peroxisomal diseases.

PMID- 12421687
TI  - Human complement receptor type 1 (CR1) binds to a major malarial adhesin.
AB  - Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1), a major adhesin
      molecule expressed on Plasmodium-falciparum-infected erythrocytes, interacts with
      several receptors on endothelial cells and uninfected erythrocytes. This
      'stickiness', known as rosetting, is a strategy used by the parasite to remain
      sequestered in the microvasculature to avoid destruction in the spleen and liver.
      Erythrocyte rosetting causes obstruction of the blood flow in microcapillaries.
      Recent data suggest a direct interaction between PfEMP1 and a functional site of
      complement receptor type 1 (CR1; CD35) on uninfected erythrocytes. Consistent
      with the hypothesis that CR1 is important in malaria pathogenesis is a 40-70-fold
      increase in the frequency of two CR1 blood-group antigens (at least one of which
      might rosette less efficiently) in malaria-exposed African populations.
      Furthermore, structural differences in erythrocyte CR1 between human and non
      human primates are probably explained by the selective pressure of malaria.

PMID- 12421688
TI  - Genetically-modified-animal models for human infections: the Listeria paradigm.
AB  - Several human pathogens exhibit a restricted host-tropism, relying on the species
      specific interaction of microbial ligand(s) with host receptor(s). This
      specificity accounts for some of the difficulties in modeling human infections in
      animals. The discovery of L. monocytogenes host-specificity and elucidation of
      the underlying mechanism has led to the generation of transgenic mice expressing
      one of its human receptors, E-cadherin. This model is presented here as a
      paradigm of a genetically-modified-animal model for studying a human infectious
      disease.

PMID- 12421692
TI  - A2B receptor activation promotes glycogen synthesis in astrocytes through
      modulation of gene expression.
AB  - Adenosine has been proposed as a key factor regulating the metabolic balance
      between energy supply and demand in the central nervous system. Because
      astrocytes represent an important cellular element in the control of brain energy
      metabolism, we investigated whether adenosine could induce long-term changes of
      glycogen levels in primary cultures of mouse cortical astrocytes. We observed
      that adenosine increased glycogen content, up to 300%, in a time- (maximum at 8
      h) and concentration-dependent manner with an EC(50) of 9.69 microM.
      Pharmacological experiments using the broad-spectrum agonist 5'-(N
      ethylcarboxamido)adenosine (NECA) and specific agonists for the A(1), A(2A), and
      A(3) receptors [N(6)-cyclopentyladenosine (CPA), CGS-21680, and IB-MECA,
      respectively] suggest that the effect of adenosine is mediated through activation
      of the low-affinity A(2B) adenosine receptor subtype. Interestingly, adenosine
      induces in parallel the expression of the protein targeting to glycogen (PTG),
      one of the protein phosphatase-1 glycogen-targeting subunits that has been
      implicated in the control of glycogen levels in various tissues. These results
      indicate that adenosine can exert long-term control over glycogen levels in
      astrocytes and might therefore play a significant role in physiological and/or
      pathological processes involving long-term modulation of brain energy metabolism.

PMID- 12421694
TI  - Expression and functional characterization of SCaMPER: a sphingolipid-modulated
      calcium channel of cardiomyocytes.
AB  - Calcium channels are important in a variety of cellular events including muscle
      contraction, signaling, proliferation, and apoptosis. Sphingolipids have been
      recognized as mediators of intracellular calcium release through their actions on
      a calcium channel, sphingolipid calcium release-mediating protein of the
      endoplasmic reticulum (SCaMPER). The current study investigates the expression
      and function of SCaMPER in cardiomyocytes. Northern analyses and RT-PCR cloning
      and sequencing revealed SCaMPER expression in both human and rat cardiac tissue.
      Immunofluorescence and Western blot analyses demonstrated that SCaMPER is
      abundant in cardiac tissue and is localized to the sarcotubular junction. This
      was confirmed by the colocalization of SCaMPER with dihydropyridine and ryanodine
      receptors by confocal microscopy. Purified T tubules were shown to contain
      SCaMPER and immunoelectron micrographs suggested that SCaMPER is located to the
      junctional T tubules, but a junctional SR localization cannot be ruled out. The
      sphingolipid ligand for SCaMPER, sphingosylphosphorylcholine (SPC), initiated
      calcium release from the cardiomyocyte SR. Importantly, antisense knockdown of
      SCaMPER mRNA produced a substantial reduction of sphingolipid-induced calcium
      release, suggesting that SCaMPER is a potentially important calcium channel of
      cardiomyocytes.

PMID- 12421695
TI  - Transient transfection of polarized epithelial monolayers with CFTR and reporter
      genes using efficacious lipids.
AB  - Transient transfection of epithelial cells with lipid reagents has been limited
      because of toxicity and lack of efficacy. In this study, we show that more
      recently developed lipids transfect nonpolarized human airway epithelial cells
      with high efficacy and efficiency and little or no toxicity. Because of this
      success, we hypothesized that these lipids may also allow transient transfection
      of polarized epithelial monolayers. A panel of reagents was tested for transfer
      of the reporter gene luciferase (LUC) into polarized monolayers of non-cystic
      fibrosis (non-CF) and CF human bronchial epithelial cells, MDCK epithelial cell
      monolayers, and, ultimately, primary non-CF and CF airway epithelial cells. Lipid
      reagents, which were most successful in initial LUC assays, were also tested for
      transfer of vectors bearing the reporter gene green fluorescent protein (GFP) and
      for successful transfection and expression of an epithelial-specific protein, the
      cystic fibrosis transmembrane conductance regulator (CFTR). Electrophysiological,
      biochemical, and immunological assays were performed to show successful
      complementation of an epithelial monolayer with transiently expressed CFTR. We
      also present findings that help facilitate monolayer formation by these airway
      epithelial cell lines. Together, these data show that polarized monolayers are
      transfected transiently with more recently developed lipids, specifically
      LipofectAMINE PLUS and LipofectAMINE 2000. Transient transfection of epithelial
      monolayers provides a powerful system in which to express the cDNA of any
      epithelium-specific protein transiently in a native polarized epithelium to study
      protein function.

PMID- 12421697
TI  - Hephaestus encodes a polypyrimidine tract binding protein that regulates Notch
      signalling during wing development in Drosophila melanogaster.
AB  - We describe the role of the Drosophila melanogaster hephaestus gene in wing
      development. We have identified several hephaestus mutations that map to a gene
      encoding a predicted RNA-binding protein highly related to human polypyrimidine
      tract binding protein and Xenopus laevis 60 kDa Vg1 mRNA-binding protein.
      Polypyrimidine tract binding proteins play diverse roles in RNA processing
      including the subcellular localization of mRNAs, translational control, internal
      ribosome entry site use, and the regulation of alternate exon selection. The
      analysis of gene expression in imaginal discs and adult cuticle of genetic mosaic
      animals supports a role for hephaestus in Notch signalling. Somatic clones
      lacking hephaestus express the Notch target genes wingless and cut, induce
      ectopic wing margin in adjacent wild-type tissue, inhibit wing-vein formation and
      have increased levels of Notch intracellular domain immunoreactivity. Clones
      mutant for both Delta and hephaestus have the characteristic loss-of-function
      thick vein phenotype of DELTA: These results lead to the hypothesis that
      hephaestus is required to attenuate Notch activity following its activation by
      Delta. This is the first genetic analysis of polypyrimidine tract binding protein
      function in any organism and the first evidence that such proteins may be
      involved in the Notch signalling pathway.

PMID- 12421698
TI  - Cellularisation in the endosperm of Arabidopsis thaliana is coupled to mitosis
      and shares multiple components with cytokinesis.
AB  - Distinct forms of cytokinesis characterise specific phases of development in
      plants. In Arabidopsis, as in many other species, the endosperm that nurtures the
      embryo in the seed initially develops as a syncytium. This syncytial phase ends
      with simultaneous partitioning of the multinucleate cytoplasm into individual
      cells, a process referred to as cellularisation. Our in vivo observations show
      that, as in cytokinesis, cellularisation of the Arabidopsis endosperm is coupled
      to nuclear division. A genetic analysis reveals that most Arabidopsis mutations
      affecting cytokinesis in the embryo also impair endosperm cellularisation. These
      results imply that cellularisation and cytokinesis share multiple components of
      the same basic machinery. We further report the identification of mutations in a
      novel gene, SPATZLE, that specifically interfere with cellularisation of the
      endosperm, but not with cytokinesis in the embryo. The analysis of this mutant
      might identify a specific checkpoint for the onset of cellularisation.

PMID- 12421699
TI  - Mutations in spalt cause a severe but reversible neurodegenerative phenotype in
      the embryonic central nervous system of Drosophila melanogaster.
AB  - The gene spalt is expressed in the embryonic central nervous system of Drosophila
      melanogaster but its function in this tissue is still unknown. To investigate
      this question, we used a combination of techniques to analyse spalt mutant
      embryos. Electron microscopy showed that in the absence of spalt, the central
      nervous system cells are separated by enlarged extracellular spaces populated by
      membranous material at 60% of embryonic development. Surprisingly, the central
      nervous system from slightly older embryos (80% of development) exhibited almost
      wild-type morphology. An extensive survey by laser confocal microscopy revealed
      that the spalt mutant central nervous system has abnormal levels of particular
      cell adhesion and cytoskeletal proteins. Time-lapse analysis of neuronal
      differentiation in vitro, lineage analysis and transplantation experiments
      confirmed that the mutation causes cytoskeletal and adhesion defects. The data
      indicate that in the central nervous system, spalt operates within a regulatory
      pathway which influences the expression of the beta-catenin Armadillo, its ligand
      N-Cadherin, Notch, and the cell adhesion molecules Neuroglian, Fasciclin 2 and
      Fasciclin 3. Effects on the expression of these genes are persistent but many
      morphological aspects of the phenotype are transient, leading to the concept of
      sequential redundancy for stable organisation of the central nervous system.

PMID- 12421700
TI  - Kremen proteins interact with Dickkopf1 to regulate anteroposterior CNS
      patterning.
AB  - A gradient of Wnt/beta-catenin signalling formed by posteriorising Wnts and
      anteriorising Wnt antagonists regulates anteroposterior (AP) patterning of the
      central nervous system (CNS) during Xenopus gastrulation. In this process, the
      secreted Wnt antagonist Dkk1 functions in the Spemann organiser and its anterior
      derivatives by blocking Wnt receptors of the lipoprotein receptor-related protein
      (LRP) 5 and 6 class. In addition to LRP6, Dkk1 interacts with another recently
      identified receptor class, the transmembrane proteins Kremen1 (Krm1) and Kremen2
      (Krm2) to synergistically inhibit LRP6. We have investigated the role of Krm1 and
      Krm2 during early Xenopus embryogenesis. Consistent with a role in zygotic Wnt
      inhibition, overexpressed Krm anteriorises embryos and rescues embryos
      posteriorised by Wnt8. Antisense morpholino oligonucleotide (Mo) knockdown of
      Krm1 and Krm2 leads to deficiency of anterior neural development. In this
      process, Krm proteins functionally interact with Dkk1: (1) in axis duplication
      assays krm2 synergises with dkk1 in inhibiting Wnt/LRP6 signalling; (2) krm2
      rescues microcephalic embryos induced by injection of inhibitory anti-Dkk1
      antibodies; and (3) injection of krm1/2 antisense Mo enhances microcephaly
      induced by inhibitory anti-Dkk1 antibodies. The results indicate that Krm
      proteins function in a Wnt inhibition pathway regulating early AP patterning of
      the CNS.

PMID- 12421701
TI  - HrzicN, a new Zic family gene of ascidians, plays essential roles in the neural
      tube and notochord development.
AB  - Two axial structures, a neural tube and a notochord, are key structures in the
      chordate body plan and in understanding the origin of chordates. To expand our
      knowledge on mechanisms of development of the neural tube in lower chordates, we
      have undertaken isolation and characterization of HrzicN, a new member of the Zic
      family gene of the ascidian, Halocynthia roretzi. HrzicN expression was detected
      by whole-mount in situ hybridization in all neural tube precursors, all notochord
      precursors, anterior mesenchyme precursors and a part of the primary muscle
      precursors. Expression of HrzicN in a- and b-line neural tube precursors was
      detected from early gastrula stage to the neural plate stage, while expression in
      other lineages was observed between the 32-cell and the 110-cell stages. HrzicN
      function was investigated by disturbing translation using a morpholino antisense
      oligonucleotide. Embryos injected with HrzicN morpholino ('HrzicN knockdown
      embryos') exhibited failure of neurulation and tail elongation, and developed
      into larvae without a neural tube and notochord. Analysis of neural marker gene
      expression in HrzicN knockdown embryos revealed that HrzicN plays critical roles
      in distinct steps of neural tube formation in the a-line- and A-line precursors.
      In particular HrzicN is required for early specification of the neural tube fate
      in A-line precursors. Involvement of HrzicN in the neural tube development was
      also suggested by an overexpression experiment. However, analysis of mesodermal
      marker gene expression in HrzicN knockdown embryos revealed unexpected roles of
      this gene in the development of mesodermal tissues. HrzicN knockdown led to loss
      of HrBra (Halocynthia roretzi Brachyury) expression in all of the notochord
      precursors, which may be the cause for notochord deficiency. Hrsna (Halocynthia
      roretzi snail) expression was also lost from all the notochord and anterior
      mesenchyme precurosrs. By contrast, expression of Hrsna and the actin gene was
      unchanged in the primary muscle precursors. These results suggest that HrzicN is
      responsible for specification of the notochord and anterior mesenchyme. Finally,
      regulation of HrzicN expression by FGF-like signaling was investigated, which has
      been shown to be involved in induction of the a- and b-line neural tube, the
      notochord and the mesenchyme cells in Halocynthia embryos. Using an inhibitor of
      FGF-like signaling, we showed that HrzicN expression in the a- and b-line neural
      tube, but not in the A-line lineage and mesodermal lineage, depends on FGF-like
      signaling. Based on these data, we discussed roles of HrzicN as a key gene in the
      development of the neural tube and the notochord.

PMID- 12421702
TI  - A homolog of FBP2/KSRP binds to localized mRNAs in Xenopus oocytes.
AB  - A Xenopus oocyte expression library was screened for proteins that bind to the
      340-nucleotide localization element of Vg1 mRNA. Four different isolates encoded
      a Xenopus homolog of the human transcription factor, FUSE-binding protein 2
      (FBP2). This protein has been independently identified as the splicing regulatory
      factor KSRP. The only significant difference between the Xenopus protein,
      designated VgRBP71, and KSRP is the absence of a 58 amino acid segment near the N
      terminal of the former. In vivo binding assays show that VgRBP71 is associated
      with mRNAs localized to either the vegetal or animal hemispheres, but was not
      found with control mRNAs. Unlike other factors that bind to the localization
      element of Vg1 mRNA, VgRBP71 does not accumulate at the vegetal cortex with the
      mRNA; rather, it is present in the nucleus and throughout the cytoplasm at all
      stages of oogenesis. Cytoplasmic VgRBP71 appears to be most concentrated at the
      cell cortex. VgRBP71 interacts with Prrp, another protein that binds to the Vg1
      localization element; this association does not require the presence of Vg1 mRNA.

PMID- 12421703
TI  - The early topography of thalamocortical projections is shifted in Ebf1 and Dlx1/2
      mutant mice.
AB  - The prevailing model to explain the formation of topographic projections in the
      nervous system stipulates that this process is governed by information located
      within the projecting and targeted structures. In mammals, different thalamic
      nuclei establish highly ordered projections with specific neocortical domains and
      the mechanisms controlling the initial topography of these projections remain to
      be characterized. To address this issue, we examined Ebf1(-/-) embryos in which a
      subset of thalamic axons does not reach the neocortex. We show that the
      projections that do form between thalamic nuclei and neocortical domains have a
      shifted topography, in the absence of regionalization defects in the thalamus or
      neocortex. This shift is first detected inside the basal ganglia, a structure on
      the path of thalamic axons, and which develops abnormally in Ebf1(-/-) embryos. A
      similar shift in the topography of thalamocortical axons inside the basal ganglia
      and neocortex was observed in Dlx1/2(-/-) embryos, which also have an abnormal
      basal ganglia development. Furthermore, Dlx1 and Dlx2 are not expressed in the
      dorsal thalamus or in cortical projections neurons. Thus, our study shows that:
      (1) different thalamic nuclei do not establish projections independently of each
      other; (2) a shift in thalamocortical topography can occur in the absence of
      major regionalization defects in the dorsal thalamus and neocortex; and (3) the
      basal ganglia may contain decision points for thalamic axons' pathfinding and
      topographic organization. These observations suggest that the topography of
      thalamocortical projections is not strictly determined by cues located within the
      neocortex and may be regulated by the relative positioning of thalamic axons
      inside the basal ganglia.

PMID- 12421704
TI  - Regulation of Easter activity is required for shaping the Dorsal gradient in the
      Drosophila embryo.
AB  - Dorsoventral polarity of the Drosophila embryo requires maternal spatzle-Toll
      signaling to establish a nuclear gradient of Dorsal protein. The shape of this
      gradient is altered in embryos produced by females carrying dominant alleles of
      easter (ea(D)). The easter gene encodes a serine protease that generates
      processed Spatzle, which is proposed to act as the Toll ligand. By examining the
      expression domains of the zygotic genes zen, sog, rho and twist, which are
      targets of nuclear Dorsal, we show that the slope of the Dorsal gradient is
      progressively flattened in stronger ea(D) alleles. In the wild-type embryo,
      activated Easter is found in a high M(r) complex called Ea-X, which is
      hypothesized to contain a protease inhibitor. In ea(D) embryo extracts, we detect
      an Easter form corresponding to the free catalytic domain, which is never
      observed in wild type. These mutant ea(D) proteins retain protease activity, as
      determined by the production of processed Spatzle both in the embryo and in
      cultured Drosophila cells. These experiments suggest that the ea(D) mutations
      interfere with inactivation of catalytic Easter, and imply that this negative
      regulation is essential for generating the wild-type shape of the Dorsal
      gradient.

PMID- 12421705
TI  - Domain-specific olivocerebellar projection regulated by the EphA-ephrin-A
      interaction.
AB  - Neural maps in the vertebrate central nervous system often show discontinuously
      segregated, domain-to-domain patterns. However, the molecular mechanism that
      establishes such maps is not well understood. Here we show that in the chicken
      olivocerebellar system, EphA receptors and ephrin-As are expressed with distinct
      levels and combinations in mapping domains. When ephrin-A2 is retrovirally
      overexpressed in the cerebellum, the olivocerebellar map is disrupted, excluding
      axons with high receptor activity from ectopic expression domains. Conversely,
      overexpression of a truncated EphA3 receptor in the cerebellum reduces endogenous
      ligand activity to undetectable levels and causes aberrant mapping, with high
      receptor axons invading high ligand domains. In vitro, ephrin-A2 inhibits
      outgrowth of inferior olive axons in a region-specific manner. These results
      suggest that Eph receptors and ephrins constitute domain-specific positional
      information, and the spatially accurate receptor-ligand interaction is essential
      to guide inferior olive axons to their correct target domains.

PMID- 12421706
TI  - The Schmidtea mediterranea database as a molecular resource for studying
      platyhelminthes, stem cells and regeneration.
AB  - Platyhelminthes are excellent models for the study of stem cell biology,
      regeneration and the regulation of scale and proportion. In addition, parasitic
      forms infect millions of people worldwide. Therefore, it is puzzling that they
      remain relatively unexplored at the molecular level. We present the
      characterization of approximately 3,000 non-redundant cDNAs from a clonal line of
      the planarian Schmidtea mediterranea. The obtained cDNA sequences, homology
      comparisons and high-throughput whole-mount in situ hybridization data form part
      of the S. mediterranea database (SmedDb; http://planaria.neuro.utah.edu). Sixty
      nine percent of the cDNAs analyzed share similarities with sequences deposited in
      GenBank and dbEST. The remaining gene transcripts failed to match sequences in
      other organisms, even though a large number of these (approximately 80%)
      contained putative open reading frames. Taken together, the molecular resources
      presented in this study, along with the ability of abrogating gene expression in
      planarians using RNA interference technology, pave the way for a systematic study
      of the remarkable biological properties displayed by Platyhelminthes.

PMID- 12421707
TI  - The Drosophila Pox neuro gene: control of male courtship behavior and fertility
      as revealed by a complete dissection of all enhancers.
AB  - We have dissected the entire cis-regulatory region of the Drosophila Pox neuro
      gene with regard to its enhancers, and have analyzed their functions by the
      selective addition to Pox neuro null mutant flies of one or several functions,
      each regulated by a complete or partial enhancer. We have identified at least 15
      enhancers with an astounding complexity in arrangement and substructure that
      regulate Pox neuro functions required for the development of the peripheral and
      central nervous system and of most appendages. Many of these functions are
      essential for normal male courtship behavior and fertility. Two enhancers
      regulate the development of the penis, claspers and posterior lobes of male
      genitalia. Three enhancers, two of which overlap, control the development of
      chemosensory bristles in the labellum, legs and wings, some or all of which are
      required for the transmission of gustatory signals elicited by female pheromones.
      An additional enhancer regulates in the developing brain the connectivity of two
      specific neuronal clusters entrusted with processing olfactory pheromone signals
      from the antennal nerve. Finally, functions crucial for the ability of the male
      to copulate depend on an enhancer that activates Pox neuro expression in the
      embryonic ventral cord. In addition to these male courtship and fertility
      functions of Pox neuro, we have identified enhancers that regulate: (1) proper
      segmentation of tarsal segments in the leg disc and in homologous segments of the
      antennal disc; and (2) proper development of the wing hinge and hence the ability
      of the fly to fly.

PMID- 12421708
TI  - Adult and embryonic blood and endothelium derive from distinct precursor
      populations which are differentially programmed by BMP in Xenopus.
AB  - Blood and blood vessels develop in close association in vertebrate embryos and
      loss-of-function mutations suggest common genetic regulation. By the criteria of
      co-expression of blood and endothelial genes, and lineage tracing of progeny, we
      locate two distinct populations of progenitors for blood and endothelial cells in
      developing Xenopus embryos. The first population is located immediately posterior
      to the cement gland during neurula stages and gives rise to embryonic blood and
      vitelline veins in the anterior ventral blood island (aVBI), and to the
      endocardium of the heart. The second population resides in the dorsal lateral
      plate mesoderm, and contains precursors of adult blood stem cells and the major
      vessels. Both populations differentiate into endothelial cells in situ but
      migrate to new locations to differentiate into blood, suggesting that their micro
      environments are unsuitable for haematopoietic differentiation. Both require BMP
      for their formation, even the Spemann organiser-derived aVBI, but individual
      genes are affected differentially. Thus, in the embryonic population, expression
      of the blood genes, SCL and GATA2, depend on BMP signalling while expression of
      the endothelial gene, Xfli1, does not. By contrast, Xfli1 expression in the
      adult, DLP population does require BMP. These results indicate that both adult
      and the anterior component of embryonic blood in Xenopus embryos derive from
      populations of progenitors that also give rise to endothelial cells. However, the
      two populations give rise to distinct regions of the vasculature and are
      programmed differentially by BMP.

PMID- 12421709
TI  - The ubiquitin ligase Hyperplastic discs negatively regulates hedgehog and
      decapentaplegic expression by independent mechanisms.
AB  - Photoreceptor differentiation in the Drosophila eye disc progresses from
      posterior to anterior in a wave driven by the Hedgehog and Decapentaplegic
      signals. Cells mutant for the hyperplastic discs gene misexpress both of these
      signaling molecules in anterior regions of the disc, leading to premature
      photoreceptor differentiation and overgrowth of surrounding tissue. The two genes
      are independently regulated by hyperplastic discs; decapentaplegic can still be
      misexpressed in cells mutant for both hyperplastic discs and hedgehog, and a
      repressor form of the transcription factor Cubitus interruptus can block
      decapentaplegic misexpression but not hedgehog misexpression. Loss of
      hyperplastic discs causes the accumulation of full-length Cubitus interruptus
      protein, but not of Smoothened, in both the eye and wing discs. hyperplastic
      discs encodes a HECT domain E3 ubiquitin ligase that is likely to act by
      targeting Cubitus interruptus and an unknown activator of hedgehog expression for
      proteolysis.

PMID- 12421710
TI  - Molecular control of ciliary neuron development: BMPs and downstream
      transcriptional control in the parasympathetic lineage.
AB  - The generation of noradrenergic sympathetic neurons is controlled by BMPs and the
      downstream transcription factors Mash1, Phox2b, Phox2a and dHand. We examined the
      role of these signals in developing cholinergic parasympathetic neurons. The
      expression of Mash1 (Cash1), Phox2b and Phox2a in the chick ciliary ganglion is
      followed by the sequential expression of panneuronal, noradrenergic and
      cholinergic marker genes. BMPs are expressed at the site where ciliary ganglia
      form and are essential and sufficient for ciliary neuron development. Unlike
      sympathetic neurons, ciliary neurons do not express dHand; noradrenergic gene
      expression is eventually lost but can be maintained by ectopic dHand expression.
      Together, these results demonstrate a common BMP dependence of sympathetic
      neurons and parasympathetic ciliary neurons and implicate dHand in the
      maintenance of noradrenergic gene expression in the autonomic nervous system.

PMID- 12421711
TI  - Shar-pei mediates cell proliferation arrest during imaginal disc growth in
      Drosophila.
AB  - During animal development, organ size is determined primarily by the amount of
      cell proliferation, which must be tightly regulated to ensure the generation of
      properly proportioned organs. However, little is known about the molecular
      pathways that direct cells to stop proliferating when an organ has attained its
      proper size. We have identified mutations in a novel gene, shar-pei, that is
      required for proper termination of cell proliferation during Drosophila imaginal
      disc development. Clones of shar-pei mutant cells in imaginal discs produce
      enlarged tissues containing more cells of normal size. We show that this
      phenotype is the result of both increased cell proliferation and reduced
      apoptosis. Hence, shar-pei restricts cell proliferation and promotes apoptosis.
      By contrast, shar-pei is not required for cell differentiation and pattern
      formation of adult tissue. Shar-pei is also not required for cell cycle exit
      during terminal differentiation, indicating that the mechanisms directing cell
      proliferation arrest during organ growth are distinct from those directing cell
      cycle exit during terminal differentiation. shar-pei encodes a WW-domain
      containing protein that has homologs in worms, mice and humans, suggesting that
      mechanisms of organ growth control are evolutionarily conserved.

PMID- 12421712
TI  - Genomic analysis of neural crest induction.
AB  - The vertebrate neural crest is a migratory stem cell population that arises
      within the central nervous system. Here, we combine embryological techniques with
      array technology to describe 83 genes that provide the first gene expression
      profile of a newly induced neural crest cell. This profile contains numerous
      novel markers of neural crest precursors and reveals previously unrecognized
      similarities between neural crest cells and endothelial cells, another migratory
      cell population. We have performed a secondary screen using in situ hybridization
      that allows us to extract temporal information and reconstruct the progression of
      neural crest gene expression as these cells become different from their neighbors
      and migrate. Our results reveal a sequential 'migration activation' process that
      reflects stages in the transition to a migratory neural crest cell and suggests
      that migratory potential is established in a pool of cells from which a subset
      are activated to migrate.

PMID- 12421713
TI  - Beta-catenin/Tcf-regulated transcription prior to the midblastula transition.
AB  - Following fertilization, the zygotic genome in many organisms is quiescent until
      the midblastula transition (MBT), when large-scale transcription begins. In
      Xenopus embryos, for example, transcription is believed to be repressed until the
      twelfth cell division. Thus, although dorsal-ventral patterning begins during the
      first cell cycle, little attention has been given to transcriptional regulation
      in pre-MBT development. We present evidence that regulated transcription begins
      during early cleavage stages and that the beta-catenin-Tcf complex is required
      for the transcription of the Xenopus nodal genes Xnr5 and Xnr6 as early as the
      256-cell stage. Moreover, inhibition of beta-catenin/Tcf function can block
      dorsal development, but only if the inhibition begins early and is maintained
      throughout pre-MBT stages. Dorsal development can be rescued in ventralized
      embryos if Tcf-dependent transcription is activated prior to MBT, but activation
      of Tcf after MBT cannot rescue ventralized embryos, suggesting that beta
      catenin/Tcf-dependent transcription is required prior to MBT for dorsal-ventral
      patterning in Xenopus.

PMID- 12421714
TI  - Mouse dispatched mutants fail to distribute hedgehog proteins and are defective
      in hedgehog signaling.
AB  - Hedgehog (Hh) signaling plays a major role in multiple aspects of embryonic
      development, which involves both short- and long-range signaling from localized
      Hh sources. One unusual aspect of Hh signaling is the autoproteolytic processing
      of Hh followed by lipid modification. As a consequence, the N-terminal fragment
      of Hh becomes membrane anchored on the cell surface of Hh-producing cells. A key
      issue in Hh signaling is to understand the molecular mechanisms by which lipid
      modified Hh protein is transported from its sites of synthesis and subsequently
      moves through the morphogenetic field. The dispatched gene, which encodes a
      putative multipass membrane protein, was initially identified in Drosophila and
      is required in Hh-producing cells, where it facilitates the transport of
      cholesterol-modified Hh. We report the identification of the mouse dispatched
      (Disp) gene and a phenotypic analysis of Disp mutant mice. Disp-null mice
      phenocopy mice deficient in the smoothened gene, an essential component for Hh
      reception, suggesting that Disp is essential for Hh signaling. This conclusion
      was further supported by a detailed molecular analysis of Disp knockout mice,
      which exhibit defects characteristic of loss of Hh signaling. We also provide
      evidence that Disp is not required for Hh protein synthesis or processing, but
      rather for the movement of Hh protein from its sites of synthesis in mice. Taken
      together, our results reveal a conserved mechanism of Hh protein movement in Hh
      producing cells that is essential for proper Hh signaling.

PMID- 12421716
TI  - A role for midbrain arcs in nucleogenesis.
AB  - Nuclei are fundamental units of vertebrate brain organization, but the mechanisms
      by which they are generated in development remain unclear. One possibility is
      that the early patterning of brain tissue into reiterated territories such as
      neuromeres and columns serves to allocate neurons to distinct nuclear fates. We
      tested this possibility in chick embryonic ventral midbrain, where a periodic
      pattern of molecularly distinct stripes (midbrain arcs) precedes the appearance
      of midbrain nuclei. We found that midbrain arc patterning has a direct
      relationship to the formation of nuclei. Both differential homeobox gene
      expression and diagnostic axon tracing studies established that the most medial
      arc contains primordia for two major midbrain nuclei: the oculomotor complex and
      the red nucleus. We tested the relationship of the medial arc to oculomotor
      complex and red nucleus development by perturbing arc pattern formation in Sonic
      Hedgehog and FGF8 misexpression experiments. We found that Sonic Hedgehog
      manipulations that induce ectopic arcs or expand the normal arc pattern elicit
      precisely parallel inductions or expansions of the red nucleus and oculomotor
      complex primordia. We further found that FGF8 manipulations that push the medial
      arc rostrally coordinately move both the red nucleus and oculomotor complex
      anlagen. Taken together, these findings suggest that arcs represent a patterning
      mechanism by which midbrain progenitor cells are allocated to specific nuclear
      fates.

PMID- 12421715
TI  - Gene expression profiles of mouse submandibular gland development: FGFR1
      regulates branching morphogenesis in vitro through BMP- and FGF-dependent
      mechanisms.
AB  - Analyses of gene expression profiles at five different stages of mouse
      submandibular salivary gland development provide insight into gland organogenesis
      and identify genes that may be critical at different stages. Genes with similar
      expression profiles were clustered, and RT-PCR was used to confirm the
      developmental changes. We focused on fibroblast growth factor receptor 1 (FGFR1),
      as its expression is highest early in gland development. We extended our array
      results and analyzed the developmental expression patterns of other FGFR and FGF
      isoforms. The functional significance of FGFR1 was confirmed by submandibular
      gland organ culture. Antisense oligonucleotides decreased expression of FGFR1 and
      reduced branching morphogenesis of the glands. Inhibiting FGFR1 signaling with
      SU5402, a FGFR1 tyrosine kinase inhibitor, reduced branching morphogenesis.
      SU5402 treatment decreased cell proliferation but did not increase apoptosis.
      Fgfr, Fgf and Bmp gene expression was localized to either the mesenchyme or the
      epithelium by PCR, and then measured over time by real time PCR after SU5402
      treatment. FGFR1 signaling regulates Fgfr1, Fgf1, Fgf3 and Bmp7 expression and
      indirectly regulates Fgf7, Fgf10 and Bmp4. Exogenous FGFs and BMPs added to
      glands in culture reveal distinct effects on gland morphology. Glands cultured
      with SU5402 were then rescued with exogenous BMP7, FGF7 or FGF10. Taken together,
      our results suggest specific FGFs and BMPs play reciprocal roles in regulating
      branching morphogenesis and FGFR1 signaling plays a central role by regulating
      both FGF and BMP expression.

PMID- 12421717
TI  - Cell lineage analysis of the amphipod crustacean Parhyale hawaiensis reveals an
      early restriction of cell fates.
AB  - In the amphipod crustacean, Parhyale hawaiensis, the first few embryonic
      cleavages are total and generate a stereotypical arrangement of cells. In
      particular, at the eight-cell stage there are four macromeres and four
      micromeres, and each of these cells is uniquely identifiable. We describe our
      studies of the cell fate pattern of these eight blastomeres, and find that the
      eight clones resulting from these cells set up distinct cell lineages that differ
      in terms of proliferation, migration and cell fate. Remarkably, the cell fate of
      each blastomere is restricted to a single germ layer. The ectoderm originates
      from three of the macromeres, while the remaining macromere generates the
      visceral mesoderm. Two of the micromeres generate the somatic mesoderm, a third
      micromere generates the endoderm and the fourth micromere generates the germline.
      These findings demonstrate for the first time a total cleavage pattern in an
      arthropod which results in an invariant cell fate of the blastomeres, but
      notably, the cell lineage pattern of Parhyale reported shows no clear resemblance
      to those found in spiralians, nematodes or deuterostomes. Finally, the techniques
      we have developed for the analysis of Parhyale development suggest that this
      arthropod may be particularly useful for future functional analyses of crustacean
      development.

PMID- 12421718
TI  - Early patterning of the mouse embryo--contributions of sperm and egg.
AB  - The first cleavage of the fertilised mouse egg divides the zygote into two cells
      that have a tendency to follow distinguishable fates. One divides first and
      contributes its progeny predominantly to the embryonic part of the blastocyst,
      while the other, later dividing cell, contributes mainly to the abembryonic part.
      We have previously observed that both the plane of this first cleavage and the
      subsequent order of blastomere division tend to correlate with the position of
      the fertilisation cone that forms after sperm entry. But does sperm entry
      contribute to assigning the distinguishable fates to the first two blastomeres or
      is their fate an intrinsic property of the egg itself? To answer this question we
      examined the distribution of the progeny of early blastomeres in embryos never
      penetrated by sperm - parthenogenetic embryos. In contrast to fertilised eggs, we
      found there is no tendency for the first two parthenogenetic blastomeres to
      follow different fates. This outcome is independent of whether parthenogenetic
      eggs are haploid or diploid. Also unlike fertilised eggs, the first 2-cell
      blastomere to divide in parthenogenetic embryo does not necessarily contribute
      more cells to the blastocyst. However, even when descendants of the first
      dividing blastomere do predominate, they show no strong predisposition to occupy
      the embryonic part. Thus blastomere fate does not appear to be decided by
      differential cell division alone. Finally, when the cortical cytoplasm at the
      site of sperm entry is removed, the first cleavage plane no longer tends to
      divide the embryo into embryonic and abembryonic parts. Together these results
      indicate that in normal development fertilisation contributes to setting up
      embryonic patterning, alongside the role of the egg.

PMID- 12421719
TI  - Neural tube closure requires Dishevelled-dependent convergent extension of the
      midline.
AB  - In Xenopus, Dishevelled (Xdsh) signaling is required for both neural tube closure
      and neural convergent extension, but the connection between these two
      morphogenetic processes remains unclear. Indeed normal neurulation requires
      several different cell polarity decisions, any of which may require Xdsh
      signaling. In this paper we address two issues: (1) which aspects of normal
      neurulation require Xdsh function; and (2) what role convergent extension plays
      in the closure of the neural tube. We show that Xdsh signaling is not required
      for neural fold elevation, medial movement or fusion. Disruption of Xdsh
      signaling therefore provides a specific tool for uncoupling convergent extension
      from other processes of neurulation. Using disruption of Xdsh signaling, we
      demonstrate that convergent extension is crucial to tube closure. Targeted
      injection revealed that Xdsh function was required specifically in the midline
      for normal neural tube closure. We suggest that the inherent movement of the
      neural folds can accomplish only a finite amount of medial progress and that
      convergent extension of the midline is necessary to reduce the distance between
      the nascent neural folds, allowing them to meet and fuse. Similar results with
      Xenopus strabismus implicate the planar cell polarity (PCP) signaling cascade in
      neural convergent extension and tube closure. Together, these data demonstrate
      that PCP-mediated convergent extension movements are crucial to proper vertebrate
      neurulation.

PMID- 12421720
TI  - Dishevelled 2 is essential for cardiac outflow tract development, somite
      segmentation and neural tube closure.
AB  - The murine dishevelled 2 (Dvl2) gene is an ortholog of the Drosophila segment
      polarity gene Dishevelled, a member of the highly conserved Wingless/Wnt
      developmental pathway. Dvl2-deficient mice were produced to determine the role of
      Dvl2 in mammalian development. Mice containing null mutations in Dvl2 present
      with 50% lethality in both inbred 129S6 and in a hybrid 129S6-NIH Black Swiss
      background because of severe cardiovascular outflow tract defects, including
      double outlet right ventricle, transposition of the great arteries and persistent
      truncus arteriosis. The majority of the surviving Dvl2(-/-) mice were female,
      suggesting that penetrance was influenced by sex. Expression of Pitx2 and plexin
      A2 was attenuated in Dvl2 null mutants, suggesting a defect in cardiac neural
      crest development during outflow tract formation. In addition, approximately 90%
      of Dvl2(-/-) mice have vertebral and rib malformations that affect the proximal
      as well as the distal parts of the ribs. These skeletal abnormalities were more
      pronounced in mice deficient for both Dvl1 and Dvl2. Somite differentiation
      markers used to analyze Dvl2(-/-) and Dvl1(-/-);Dvl2(-/-) mutant embryos revealed
      mildly aberrant expression of Uncx4.1, delta 1 and myogenin, suggesting defects
      in somite segmentation. Finally, 2-3% of Dvl2(-/-) embryos displayed thoracic
      spina bifida, while virtually all Dvl1/2 double mutant embryos displayed
      craniorachishisis, a completely open neural tube from the midbrain to the tail.
      Thus, Dvl2 is essential for normal cardiac morphogenesis, somite segmentation and
      neural tube closure, and there is functional redundancy between Dvl1 and Dvl2 in
      some phenotypes.

PMID- 12421721
TI  - A defect in a novel Nek-family kinase causes cystic kidney disease in the mouse
      and in zebrafish.
AB  - The murine autosomal recessive juvenile cystic kidney (jck) mutation results in
      polycystic kidney disease. We have identified in jck mice a mutation in Nek8, a
      novel and highly conserved member of the Nek kinase family. In vitro expression
      of mutated Nek8 results in enlarged, multinucleated cells with an abnormal actin
      cytoskeleton. To confirm that a defect in the Nek8 gene can cause cystic disease,
      we performed a cross-species analysis: injection of zebrafish embryos with a
      morpholino anti-sense oligonucleotide corresponding to the ortholog of Nek8
      resulted in the formation of pronephric cysts. These results demonstrate that
      comparative analysis of gene function in different model systems represents a
      powerful means to annotate gene function.

PMID- 12421722
TI  - Epidemiology of colorectal cancer.
AB  - Colorectal cancer is a important public health problem: there are nearly one
      million new cases of colorectal cancer diagnosed world-wide each year and half a
      million deaths. Recent reports show that, in the US, it was the most frequent
      form of cancer among persons aged 75 years and older. Given that the majority of
      cancers occur in elder people and with the ageing of the population in mind, this
      observation gives further impetus to investigating prevention and treatment
      strategies among this subgroup of the population. Screening research,
      recommendations and implementation is an obvious priority. While there are many
      questions to be resolved, it is apparent that many facets of colorectal cancer
      are becoming increasingly understood and prospects for prevention are becoming
      apparent. Achieving colorectal cancer control is the immediate challenge.

PMID- 12421723
TI  - Genetics of colorectal cancer: hereditary aspects and overview of colorectal
      tumorigenesis.
AB  - Familial adenomatous polyposis and hereditary non-polyposis colorectal cancer are
      dominantly inherited conditions with 100% and 80% life-time risk of developing
      colorectal cancer, respectively. The genetic mutations responsible for these two
      conditions lie in the adenomatous polyposis coli (APC) and mismatch repair genes.
      These same genes also play a key role in the formation of sporadic colorectal
      cancers, which arise on a background of a similar spectrum of mutations to the
      hereditary cancers. This article examines the genetic mechanisms underlying the
      hereditary colorectal cancers, as well as genetic predisposition to colorectal
      cancer in the general population in the absence of a clear-cut genetic syndrome.
      Colorectal cancer arises as the cumulative effect of multiple mutations within
      the cell, allowing it to escape growth and regulatory control mechanisms. This
      step-wise progression of mutations facilitates the histological transition from
      normal mucosa to adenoma to carcinoma. The latter part of this paper focuses on
      the key genetic events underlying this process and provides an overview of the
      genetic mechanisms responsible for colorectal tumorigenesis.

PMID- 12421724
TI  - Genetics--cellular basis.
AB  - Colorectal carcinogenesis is a multistep process during which the specialised
      epithelial cells of intestinal mucosa surface (e.g. colonocytes) accumulate a
      series of genetic and epigenetic events which lead to a perturbation of their
      normal cellular functions and turnover. This review will address the mechanisms
      and biological effects of these abnormalities on the growth control,
      differentiation, adhesion and survival of the colonocytes.

PMID- 12421725
TI  - Pathology--a molecular prognostic approach.
AB  - Colorectal cancer affects 29,000 people and kills approximately 15,000 in England
      and Wales each year, most of these deaths resulting from the effects of local or
      distant recurrence. There is a need to give these patients accurate prognoses and
      individualised treatment regimens. At present, the best prognostic markers are
      clinicopathological. Post-genomic science and the new high throughput
      technologies offer unrivalled opportunities to understand the biology and
      molecular pathology of colorectal cancer. These technologies should be used in
      the context of large randomised controlled trials to identify new molecular
      prognostic and predictive markers and also new targets for therapy.

PMID- 12421726
TI  - Screening for colorectal cancer.
AB  - Screening for colorectal cancer is feasible and there is increasingly compelling
      evidence to show that such programmes can save lives at a cost similar to that of
      the existing breast cancer screening programme.

PMID- 12421727
TI  - New techniques for imaging colorectal cancer: the use of MRI, PET and
      radioimmunoscintigraphy for primary staging and follow-up.
AB  - Modern imaging techniques such as computed tomography (CT) and ultrasound (US)
      are in the majority of cases able to detect local and metastatic spread of
      malignancy. Increasingly, the requirement is for even more accurate pre-operative
      tumour staging to enable the use of new surgical techniques, neo-adjuvant
      therapies and, postoperatively, to enable detection of tumour recurrence on
      follow-up. Recent imaging research has focused on magnetic resonance imaging
      (MRI) for the detection of local tumour extension particularly for rectal tumours
      and on positron emission tomography (PET) and radioimmunoscintigraphy (RIS) for
      the detection of metastatic nodal and soft tissue disease. This article briefly
      describes these three imaging modalities and their role in primary staging,
      detection of hepatic metastases and local recurrence.

PMID- 12421728
TI  - Surgery for colorectal cancer.
AB  - Colorectal cancer remains the second commonest cause of cancer death in North
      America and Western Europe. Surgery remains the mainstay of treatment. The aim of
      surgery should be to achieve cure and to avoid locoregional recurrence. The
      fixity of the primary tumour determines resectability, and the extent of spread
      determines ultimate survival. Patients with rectal cancer present a particular
      problem. There is good evidence that lower local recurrence rates may be achieved
      both by improvements in surgical technique and the use of adjuvant radiotherapy.
      The importance of adequate treatment of the circumferential tumour margin cannot
      be over-emphasised; meticulous attention is required to ensure an adequate
      circumferential excision. The lowest incidences of locoregional recurrence are
      reported by surgeons who perform total mesorectal excision. Anorectal function,
      sexual and urinary dysfunction may occur after rectal excision. Both
      postoperative and pre-operative radiotherapy can reduce the incidence of local
      recurrence. However, in view of the low recurrence rates obtained with TME alone,
      the role of adjuvant radiotherapy requires further evaluation. Several aspects of
      the surgical management of colorectal cancer, for example, the role of transanal
      local excision of selected rectal cancers and laparoscopic surgery, the
      management of obstructed cases and the role of follow-up remain to be defined
      clearly.

PMID- 12421729
TI  - Outcome following surgery for colorectal cancer.
AB  - There is evidence to suggest that survival following surgery for colorectal
      cancer is improving. Audits undertaken in a single institution between 1974-1979
      and 1991-1994 provide the opportunity to evaluate the extent to which earlier
      diagnosis and better surgery contribute to the improvement in survival. There was
      little evidence that patients were presenting at an earlier stage during the
      latter period. In contrast, more patients had a potentially curative resection.
      This analysis confirmed that, over this period, there has been a substantial
      improvement in survival following surgery for colorectal cancer; this improvement
      was largely due to better surgery rather than earlier presentation.

PMID- 12421730
TI  - Surgery of liver metastases from colorectal cancer: new promises.
AB  - For a long time, patients with liver metastases from colorectal cancer were
      considered to be incurable. Over the last 30 years, the benefits of surgical
      resection and systemic chemotherapy have been established. Actually, surgical
      resections are feasible with a very low mortality and a 5-year survival that
      approaches 40%, but only 10-20% of patients are candidates for surgery. The
      others gain benefit from chemotherapy with increasingly active drugs. To improve
      this overall picture, efforts have been made to increase the number of patients
      that could be candidates for surgery and to decrease the risk of recurrence after
      surgical resection. Shrinkage of tumours after administration of pre-operative
      chemotherapy and the availability of ablative techniques now allow the treatment,
      with curative intent, of metastases initially considered as non-resectable.
      Chemotherapeutic regimens have been developed to decrease the risk of
      postoperative recurrence.

PMID- 12421731
TI  - Radiotherapy in rectal cancer.
AB  - Radiotherapy has an established role in the treatment of rectal cancer. In
      primary resectable cancer, numerous randomised trials have shown that
      particularly pre-operative, and to some extent also postoperative, radiotherapy
      substantially reduces the risk of local failure. This is seen also with total
      mesorectal excision. Secondary to the reduction in local failures, there is also
      a slight improvement in survival after pre-operative radiotherapy or
      postoperative radiochemotherapy. Using appropriate techniques, the morbidity of
      radiotherapy is low. In non-resectable cancer, radiotherapy may cause down
      staging, allow surgery, and may cure some patients. Whether radiochemotherapy is
      more efficient has yet to be firmly established. The role of pre-operative
      radio(chemo)therapy to permit more sphincter-preserving procedures with adequate
      long-term function is not defined.

PMID- 12421732
TI  - Chemotherapy in colorectal cancer: new options and new challenges.
AB  - Colorectal cancer is the second most common cause of cancer-related mortality in
      Europe and North America. Studies conducted in the last two decades have
      established the role of adjuvant therapy in stage III colon cancer. However,
      there is currently no international consensus with the role of adjuvant treatment
      in stage II disease. The introduction of irinotecan, oxaliplatin, oral
      fluoropyrimidines and raltitrexed has broadened the treatment options available
      for patients with advanced colorectal cancer. The integration of these drugs with
      the new molecular targeted therapies such as epidermal growth factor receptor,
      cyclooxygenase, angiogenesis and matrix metalloproteinase inhibition will form
      the basis of clinical research in the next few years and may, in the future,
      impact on the survival of patients with colorectal cancer. This review will focus
      on the place of chemotherapy in colorectal cancer, but not its role in
      combination with radiotherapy in rectal cancer.

PMID- 12421733
TI  - Immunotherapy of colorectal cancer.
AB  - Over the last decade, there has been a rapid expansion in the field of tumour
      immunology. There is now convincing evidence that both the cellular and humoral
      arms of the immune system are capable of interacting with tumour cells. The most
      significant advances have been in our understanding of cellular responses and the
      complex events that lead to T-lymphocyte activation, as well as in the
      identification of tumour antigens recognised by T-lymphocytes. This knowledge has
      led to the development of anticancer immunotherapies designed to produce tumour
      antigen-specific T-cell responses, adding to the earlier antibody or whole-cell
      vaccine approaches. In addition, new methods have been developed to quantify
      antigen-specific T-cell responses, and the emergent field of recombinant gene
      technology has led to an increasing number of novel methods for vaccine delivery.
      This review will explore these advances, as well as possible future directions,
      with an emphasis on colorectal cancer.

PMID- 12421734
TI  - Gene therapy for colorectal cancer.
AB  - Gene therapy has been developed as a potential novel treatment modality for
      colorectal cancer. The preclinical data have been promising and several clinical
      trials are under way for colorectal cancer. Data from many phase 1 trials have
      proven the safety of the reagents, but have not yet demonstrated significant
      therapeutic benefit. In order to refine this approach, continuing efforts should
      be made to improve the antitumour potency, efficiency of gene delivery, and
      accuracy of gene targeting. It is likely that gene therapy will be integrated
      into pre-existing therapies including surgery, chemotherapy and radiotherapy to
      establish its niche in tomorrow's medicine.

PMID- 12421736
TI  - The brain in sleep-disordered breathing: is it the chicken or is it the egg?

PMID- 12421735
TI  - Therapeutics targeting signal transduction for patients with colorectal
      carcinoma.
AB  - The cytotoxics developed for the treatment of patients with advanced colorectal
      cancer have yielded diminishing returns. Agents aimed at novel molecular targets
      are required to improve the prognosis of this disease. This review describes the
      most recent advances in the clinical development of therapies designed to block
      the function of several important signalling cellular proteins. Therapies
      discussed include agents targeting: (i) the epidermal growth factor receptor
      (EGFR) family; (ii) Ras via the inhibition of farnesyltransferase; (iii) Raf
      kinase; (iv) the mitogen-activated protein kinase pathway (MAPK, MEK, Erk); (v)
      Akt; and (vi) the apoptosis signalling pathways including NF-kappaB, Bcl-2 and
      the TRAIL receptor. The results of clinical trials of the first generation of
      such therapeutics to enter clinical evaluation in malignant diseases are
      presented. Potential advantages and disadvantages of these different therapeutic
      modalities are discussed and future challenges for the evaluation of these
      targeted agents in the clinic is presented.

PMID- 12421737
TI  - Don't lose the forest for the trees: satisfaction and success in bronchoscopy.

PMID- 12421738
TI  - Ventilator-induced cachexia.

PMID- 12421739
TI  - Therapy of pulmonary hypertension: the evolution from vasodilators to
      antiproliferative agents.

PMID- 12421740
TI  - Echo-Doppler demonstration of acute cor pulmonale at the bedside in the medical
      intensive care unit.

PMID- 12421741
TI  - Effect of design-related bias in studies of diagnostic tests for ventilator
      associated pneumonia.

PMID- 12421742
TI  - A role for vascular endothelial growth factor in acute and resolving lung injury.
AB  - We have previously reported, in patients with acute respiratory distress syndrome
      (ARDS), elevated plasma levels of vascular endothelial growth factor (VEGF) that
      became reduced in those who recovered. To examine the potential effect of VEGF on
      the epithelial side of the alveolar-capillary membrane, we compared VEGF levels
      in the epithelial lining fluid (ELF) of the same 40 patients with ARDS, and in 28
      patients at risk of ARDS. We measured intrapulmonary VEGF levels in 23 patients
      on Days 1 and 4 after admission to the intensive therapy unit and related these
      levels to recovery. ELF from subjects with ARDS contained lower levels of VEGF
      than did ELF from at-risk subjects (1,076 and 7,674 pg/ml, respectively, p =
      0.0004) and increased ELF levels at Day 4 were associated with recovery (p =
      0.001). Alveolar macrophages from subjects with ARDS produced significantly less
      VEGF than those from at-risk subjects (6.3 and 13.0 pg/ml, respectively, p =
      0.005). Similarly, alveolar neutrophils from subjects with ARDS produced
      significantly less VEGF than those at risk (13.9 and 31.5 pg/ml, respectively, p
      = 0.03). ELF VEGF levels inversely correlated with Lung Injury Score (p = 0.003).
      These studies suggest that VEGF in the alveolar space may reflect the development
      of, and recovery from, acute lung injury in a manner opposite to that in plasma.

PMID- 12421743
TI  - The Richmond Agitation-Sedation Scale: validity and reliability in adult
      intensive care unit patients.
AB  - Sedative medications are widely used in intensive care unit (ICU) patients.
      Structured assessment of sedation and agitation is useful to titrate sedative
      medications and to evaluate agitated behavior, yet existing sedation scales have
      limitations. We measured inter-rater reliability and validity of a new 10-level
      (+4 "combative" to -5 "unarousable") scale, the Richmond Agitation-Sedation Scale
      (RASS), in two phases. In phase 1, we demonstrated excellent (r = 0.956, lower
      90% confidence limit = 0.948; kappa = 0.73, 95% confidence interval = 0.71, 0.75)
      inter-rater reliability among five investigators (two physicians, two nurses, and
      one pharmacist) in adult ICU patient encounters (n = 192). Robust inter-rater
      reliability (r = 0.922-0.983) (kappa = 0.64-0.82) was demonstrated for patients
      from medical, surgical, cardiac surgery, coronary, and neuroscience ICUs,
      patients with and without mechanical ventilation, and patients with and without
      sedative medications. In validity testing, RASS correlated highly (r = 0.93) with
      a visual analog scale anchored by "combative" and "unresponsive," including all
      patient subgroups (r = 0.84-0.98). In the second phase, after implementation of
      RASS in our medical ICU, inter-rater reliability between a nurse educator and 27
      RASS-trained bedside nurses in 101 patient encounters was high (r = 0.964, lower
      90% confidence limit = 0.950; kappa = 0.80, 95% confidence interval = 0.69, 0.90)
      and very good for all subgroups (r = 0.773-0.970, kappa = 0.66-0.89).
      Correlations between RASS and the Ramsay sedation scale (r = -0.78) and the
      Sedation Agitation Scale (r = 0.78) confirmed validity. Our nurses described RASS
      as logical, easy to administer, and readily recalled. RASS has high reliability
      and validity in medical and surgical, ventilated and nonventilated, and sedated
      and nonsedated adult ICU patients.

PMID- 12421744
TI  - Relative ability of full and partial forced expiratory maneuvers to identify
      diminished airway function in infants with cystic fibrosis.
AB  - The tidal and raised volume rapid thoracoabdominal compression techniques are
      increasingly used to detect diminished airway function in infancy. The aim of
      this study was to assess the relative ability of parameters measured by these
      techniques to identify diminished airway function in infants newly diagnosed with
      cystic fibrosis (CF) with and without clinical evidence of prior lower
      respiratory illness. A cross-sectional, prospective study design was used in
      which maximal flow at functional residual capacity (VmaxFRC) from the tidal
      technique and FVC, FEV0.5, FEF75, and FEF25-75 from the raised volume technique
      were measured in 47 infants with CF and 187 healthy infants of similar body size,
      sex distribution, ethnic group, and exposure to maternal smoking. Multiple linear
      regression was used to assess group differences and to calculate SD scores for
      each parameter for the infants with CF. Airway function was also compared with
      clinical assessments of respiratory status made by pediatric pulmonologists.
      FEV0.5 was significantly diminished in 13 infants with CF, of whom 4 had been
      identified by clinicians as having normal respiratory status. Only one infant
      with CF had a VmaxFRC below the estimated normal range. Airway function is
      diminished in infants with CF irrespective of prior lower respiratory illness and
      in those whose respiratory status is considered normal by pediatric
      pulmonologists. In infants with CF, the raised volume technique identified
      diminished airway function more frequently than the tidal technique.

PMID- 12421745
TI  - Mechanical ventilation-induced diaphragmatic atrophy is associated with oxidative
      injury and increased proteolytic activity.
AB  - Prolonged mechanical ventilation (MV) results in reduced diaphragmatic maximal
      force production and diaphragmatic atrophy. To investigate the mechanisms
      responsible for MV-induced diaphragmatic atrophy, we tested the hypothesis that
      controlled MV results in oxidation of diaphragmatic proteins and increased
      diaphragmatic proteolysis due to elevated protease activity. Further, we
      postulated that MV would result in atrophy of all diaphragmatic muscle fiber
      types. Mechanically ventilated animals were anesthetized, tracheostomized, and
      ventilated with 21% O2 for 18 hours. MV resulted in a decrease (p < 0.05) in
      diaphragmatic myofibrillar protein and the cross-sectional area of all muscle
      fiber types (i.e., I, IIa, IId/x, and IIb). Further, MV promoted an increase (p <
      0.05) in diaphragmatic protein degradation along with elevated (p < 0.05) calpain
      and 20S proteasome activity. Finally, MV was also associated with a rise (p <
      0.05) in both protein oxidation and lipid peroxidation. These data support the
      hypothesis that MV is associated with atrophy of all diaphragmatic fiber types,
      increased diaphragmatic protease activity, and augmented diaphragmatic oxidative
      stress.

PMID- 12421746
TI  - Brain morphology associated with obstructive sleep apnea.
AB  - Obstructive sleep apnea (OSA) is characterized by repeated occurrences of
      hypoxic, hypercapnic, and transient blood pressure elevation episodes that may
      damage or alter neural structures. Underdeveloped structures or pre-existing
      damage in brain areas may also contribute to the genesis of the syndrome. Brain
      morphology in 21 patients with OSA and in 21 control subjects was assessed using
      high-resolution T1-weighted magnetic resonance imaging. Three-dimensional brain
      images were obtained with voxels of approximately 1 mm3. Images were spatially
      normalized and segmented into gray matter, white matter, and cerebrospinal fluid.
      For each segment, regional volumetric differences were determined relative to
      age, handedness, and group (patients with OSA versus control subjects), using
      voxel-based morphometry, with OSA effects weighted by disease severity. A
      significant age effect on total gray matter was found in control subjects but not
      in patients with OSA. Diminished regional and often unilateral gray matter loss
      was apparent in multiple sites of the brain in patients with OSA, including the
      frontal and parietal cortex, temporal lobe, anterior cingulate, hippocampus, and
      cerebellum. Unilateral loss in well-perfused structures suggests onset of neural
      deficits early in the OSA syndrome. The gray matter loss occurs within sites
      involved in motor regulation of the upper airway as well as in areas contributing
      to cognitive function.

PMID- 12421747
TI  - The male predisposition to pharyngeal collapse: importance of airway length.
AB  - Obstructive sleep apnea is an important disorder because of both its prevalence
      and its cardiovascular and neurocognitive sequelae. Despite the fact that male
      sex is a major risk factor for this disorder, the mechanisms underlying this
      predisposition are unclear. To understand the pathophysiologic basis of the male
      predisposition for pharyngeal collapse, we performed a detailed analysis of the
      anatomic and physiologic features of the upper airway in a cohort of normal and
      near-normal subjects (equal number of men and women). Although no important
      physiologic (genioglossal electromyogram, airflow resistance) differences were
      observed between sexes, a number of anatomic differences were apparent. The
      pharyngeal airway length was substantially longer in men compared with women.
      There was also an increased cross-sectional area of the soft palate and an
      increased airway volume in men compared with women. Using signal-averaged
      anatomic data from male and female subjects, we developed representative male and
      female finite element airway models. This model demonstrated the male airway to
      be substantially more collapsible than the female airway, solely on the basis of
      anatomic differences. This study suggests that the male predisposition to
      pharyngeal collapse is anatomically based, primarily as the result of an
      increased length of vulnerable airway as well as increased soft palate size.

PMID- 12421748
TI  - Bile salts potentiate adenylyl cyclase activity and cAMP-regulated secretion in
      human gallbladder epithelium.
AB  - Fluid and ion secretion in the gallbladder is mainly triggered by the
      intracellular second messenger cAMP. We examined the action of bile salts on the
      cAMP-dependent pathway in the gallbladder epithelium. Primary cultures of human
      gallbladder epithelial cells were exposed to agonists of the cAMP pathway and/or
      to bile salts. Taurochenodeoxycholate and tauroursodeoxycholate increased
      forskolin-induced cAMP accumulation to a similar extent, without affecting cAMP
      basal levels. This potentiating effect was abrogated after PKC inhibition,
      whereas both taurochenodeoxycholate and tauroursodeoxycholate induced PKC-alpha
      and -delta translocation to cell membranes. Consistent with a PKC-mediated
      stimulation of cAMP production, the expression of six adenylyl cyclase isoforms,
      including PKC-regulated isoforms 5 and 7, was identified in human gallbladder
      epithelial cells. cAMP-dependent chloride secretion induced by isoproterenol, a
      beta-adrenergic agonist, was significantly increased by taurochenodeoxycholate
      and by tauroursodeoxycholate. In conclusion, endogenous and therapeutic bile
      salts via PKC regulation of adenylyl cyclase activity potentiate cAMP production
      in the human gallbladder epithelium. Through this action, bile salts may increase
      fluid secretion in the gallbladder after feeding.

PMID- 12421749
TI  - Structural characterization of the human proteome.
AB  - This paper reports an analysis of the encoded proteins (the proteome) of the
      genomes of human, fly, worm, yeast, and representatives of bacteria and archaea
      in terms of the three-dimensional structures of their globular domains together
      with a general sequence-based study. We show that 39% of the human proteome can
      be assigned to known structures. We estimate that for 77% of the proteome, there
      is some functional annotation, but only 26% of the proteome can be assigned to
      standard sequence motifs that characterize function. Of the human protein
      sequences, 13% are transmembrane proteins, but only 3% of the residues in the
      proteome form membrane-spanning regions. There are substantial differences in the
      composition of globular domains of transmembrane proteins between the proteomes
      we have analyzed. Commonly occurring structural superfamilies are identified
      within the proteome. The frequencies of these superfamilies enable us to estimate
      that 98% of the human proteome evolved by domain duplication, with four of the 10
      most duplicated superfamilies specific for multicellular organisms. The zinc
      finger superfamily is massively duplicated in human compared to fly and worm, and
      occurrence of domains in repeats is more common in metazoa than in single
      cellular organisms. Structural superfamilies over- and underrepresented in human
      disease genes have been identified. Data and results can be downloaded and
      analyzed via web-based applications at http://www.sbg.bio.ic.ac.uk.

PMID- 12421750
TI  - Signatures of domain shuffling in the human genome.
AB  - To elucidate the role of exon shuffling in shaping the complexity of the human
      genome/proteome, we have systematically analyzed intron phase distributions in
      the coding sequence of human protein domains. We found that introns at the
      boundaries of domains show high excess of symmetrical phase combinations (i.e., 0
      0, 1-1, and 2-2), whereas nonboundary introns show no excess symmetry. This
      suggests that exon shuffling has primarily involved rearrangement of structural
      and functional domains as a whole. Furthermore, we found that domains flanked by
      phase 1 introns have dramatically expanded in the human genome due to domain
      shuffling and that 1-1 symmetrical domains and domain families are nonrandomly
      distributed with respect to their age. The predominance and extracellular
      location of 1-1 symmetrical domains among domains specific to metazoans suggests
      that they are associated with the rise of multicellularity. On the other hand, 0
      0 symmetrical domains tend to be over-represented among ancient protein domains
      that are shared between the eukaryotic and prokaryotic kingdoms, which is
      compatible with the suggestion of primordial domain shuffling in the progenote.
      To see whether the human data reflect general genomic patterns of metazoans,
      similar analyses were done for the nematode Caenorhabditis elegans. Although the
      C. elegans data generally concur with the human patterns, we identified fewer
      intron-bounded domains in this organism, consistent with the lower complexity of
      C. elegans genes. [The following individuals kindly provided reagents, samples,
      or unpublished information as indicated in the paper: Z. Gu and R. Stevens.]

PMID- 12421751
TI  - Genomic structure and evolution of the ancestral chromosome fusion site in 2q13
      2q14.1 and paralogous regions on other human chromosomes.
AB  - Human chromosome 2 was formed by the head-to-head fusion of two ancestral
      chromosomes that remained separate in other primates. Sequences that once resided
      near the ends of the ancestral chromosomes are now interstitially located in 2q13
      2q14.1. Portions of these sequences had duplicated to other locations prior to
      the fusion. Here we present analyses of the genomic structure and evolutionary
      history of >600 kb surrounding the fusion site and closely related sequences on
      other human chromosomes. Sequence blocks that closely flank the inverted arrays
      of degenerate telomere repeats marking the fusion site are duplicated at many,
      primarily subtelomeric, locations. In addition, large portions of a 168-kb
      centromere-proximal block are duplicated at 9pter, 9p11.2, and 9q13, with 98%-99%
      average sequence identity. A 67-kb block on the distal side of the fusion site is
      highly homologous to sequences at 22qter. A third ~100-kb segment is 96%
      identical to a region in 2q11.2. By integrating data on the extent and similarity
      of these paralogous blocks, including the presence of phylogenetically
      informative repetitive elements, with observations of their chromosomal
      distribution in nonhuman primates, we infer the order of the duplications that
      led to their current arrangement. Several of these duplicated blocks may be
      associated with breakpoints of inversions that occurred during primate evolution
      and of recurrent chromosome rearrangements in humans.

PMID- 12421752
TI  - Gene content and function of the ancestral chromosome fusion site in human
      chromosome 2q13-2q14.1 and paralogous regions.
AB  - Various portions of the region surrounding the site where two ancestral
      chromosomes fused to form human chromosome 2 are duplicated elsewhere in the
      human genome, primarily in subtelomeric and pericentromeric locations. At least
      24 potentially functional genes and 16 pseudogenes reside in the 614-kb of
      sequence surrounding the fusion site and paralogous segments on other
      chromosomes. By comparing the sequences of genomic copies and transcripts, we
      show that at least 18 of the genes in these paralogous regions are
      transcriptionally active. Among these genes are new members of the cobalamin
      synthetase W domain (CBWD) and forkhead domain FOXD4 gene families. Copies of
      RPL23A and SNRPA1 on chromosome 2 are retrotransposed-processed pseudogenes that
      were included in segmental duplications; we find 53 RPL23A pseudogenes in the
      human genome and map the functional copy of SNRPA1 to 15qter. The draft sequence
      of the human genome also provides new information on the location and intron-exon
      structure of functional copies of other 2q-fusion genes (PGM5, retina-specific
      F379, helicase CHLR1, and acrosin). This study illustrates that the duplication
      and rearrangement of subtelomeric and pericentromeric regions have functional
      relevance to human biology; these processes can change gene dosage and/or
      generate genes with new functions.

PMID- 12421753
TI  - Segmental polymorphisms in the proterminal regions of a subset of human
      chromosomes.
AB  - The subtelomeric domains of chromosomes are probably the most rapidly evolving
      structures of the human genome. The highly variable distribution of large
      duplicated subtelomeric segments has indicated that frequent exchanges between
      nonhomologous chromosomes may have been taking place during recent genome
      evolution. We have studied the extent and variability of such duplications using
      in situ hybridization techniques and a set of well-defined subtelomeric cosmid
      probes that identify discrete regions within the subtelomeric domain. In addition
      to reciprocal translocation and illegitimate recombination events that could
      explain the observed mosaic pattern of subtelomeric regions, it is likely that
      homology-based recombination mechanisms have also contributed to the spread of
      distal subtelomeric sequences among particular groups of nonhomologous chromosome
      arms. The frequency and distribution of large-scale subtelomeric polymorphisms
      may have direct implications for the design of chromosome-specific probes that
      are aimed at the identification of cryptic subtelomeric deletions. Furthermore,
      our results indicate that the relevance of some of the telomere closures proposed
      within the present Human Genome Sequence draft are restricted to specific allelic
      variants of unknown frequencies.

PMID- 12421754
TI  - Neighboring-nucleotide effects on single nucleotide polymorphisms: a study of 2.6
      million polymorphisms across the human genome.
AB  - We investigated substitution patterns and neighboring-nucleotide effects for
      2,576,903 single nucleotide polymorphisms (SNPs) publicly available through the
      National Center for Biotechnology Information (NCBI). The proportions of
      substitutions were A/G, 32.77%; C/T, 32.81%; A/C, 8.98%; G/T, 9.06%; A/T, 7.46%;
      and C/G, 8.92%. The two nucleotides immediately neighboring the variable site
      showed major deviation from genome-wide and chromosome-specific expectations,
      although lesser biases extended as far as 200 bp. On the 5' side, the biases for
      A, C, G, and T were 1.43%, 4.91%, -1.70%, and -4.62%, respectively. These biases
      were -4.44%, -1.59%, 5.05%, and 0.99%, respectively, on the 3' side. The
      neighboring-nucleotide patterns for transitions were dominated by the
      hypermutability effects of CpG dinucleotides. Transitions were more common than
      transversions, and the probability of a transversion increased with increasing A
      + T content at the two adjacent sites. Neighboring-nucleotide biases were not
      consistent among chromosomes, with Chromosomes 19 and 22 standing out as
      different from the others. These data provide genome-wide information about the
      effects of neighboring nucleotides on mutational and evolutionary processes
      giving rise to contemporary patterns of nucleotide occurrence surrounding SNPs.

PMID- 12421756
TI  - Identification of candidate genes regulating HDL cholesterol using a chromosomal
      region expression array.
AB  - To identify candidate genes encoding QTLs in baboons, we have developed a novel
      strategy that integrates comparative mapping, bioinformatics, and expression
      arrays. A genome-wide scan, performed previously on pedigreed baboons to localize
      QTLs for phenotypes that are known risk factors for atherosclerosis, revealed a
      QTL on chromosome 18q that influences high-density lipoprotein cholesterol (HDL
      C) phenotypes. After ruling out the only two biologically relevant positional
      candidate genes in this chromosomal region, we combined information from baboon
      pedigrees and HDL-C phenotypes with a baboon microsatellite marker map, human
      microsatellite marker maps, and human genome maps to develop a chromosomal region
      expression array (CREA). The CREA was screened with heterologous liver cDNA from
      sib-pairs of contrasting HDL-C phenotypes on two different diets, and genes were
      prioritized for further study by expression profiles. Analysis of gene expression
      in this restricted chromosomal region, combined with HDL-C phenotypic
      information, yielded a list of candidate genes for the QTL regulating HDL-C in
      baboons. Our data demonstrate the power of this strategy for identifying
      candidate genes encoding QTLs for multigenic traits. This strategy is applicable
      to many species that serve as models for human diseases and can even be used with
      human subjects.

PMID- 12421755
TI  - In silico model-driven assessment of the effects of single nucleotide
      polymorphisms (SNPs) on human red blood cell metabolism.
AB  - The completion of the human genome project and the construction of single
      nucleotide polymorphism (SNP) maps have lead to significant efforts to find SNPs
      that can be linked to pathophysiology. In silico models of complete biochemical
      reaction networks relate a cell's individual reactions to the function of the
      entire network. Sequence variations can in turn be related to kinetic properties
      of individual enzymes, thus allowing an in silico model-driven assessment of the
      effects of defined SNPs on overall cellular functions. This process is applied to
      defined SNPs in two key enzymes of human red blood cell metabolism: glucose-6
      phosphate dehydrogenase and pyruvate kinase. The results demonstrate the utility
      of in silico models in providing insight into differences between red cell
      function in patients with chronic and nonchronic anemia. In silico models of
      complex cellular processes are thus likely to aid in defining and understanding
      key SNPs in human pathophysiology.

PMID- 12421757
TI  - Systematic learning of gene functional classes from DNA array expression data by
      using multilayer perceptrons.
AB  - Recent advances in microarray technology have opened new ways for functional
      annotation of previously uncharacterised genes on a genomic scale. This has been
      demonstrated by unsupervised clustering of co-expressed genes and, more
      importantly, by supervised learning algorithms. Using prior knowledge, these
      algorithms can assign functional annotations based on more complex expression
      signatures found in existing functional classes. Previously, support vector
      machines (SVMs) and other machine-learning methods have been applied to a limited
      number of functional classes for this purpose. Here we present, for the first
      time, the comprehensive application of supervised neural networks (SNNs) for
      functional annotation. Our study is novel in that we report systematic results
      for ~100 classes in the Munich Information Center for Protein Sequences (MIPS)
      functional catalog. We found that only ~10% of these are learnable (based on the
      rate of false negatives). A closer analysis reveals that false positives (and
      negatives) in a machine-learning context are not necessarily "false" in a
      biological sense. We show that the high degree of interconnections among
      functional classes confounds the signatures that ought to be learned for a unique
      class. We term this the "Borges effect" and introduce two new numerical indices
      for its quantification. Our analysis indicates that classification systems with a
      lower Borges effect are better suitable for machine learning. Furthermore, we
      introduce a learning procedure for combining false positives with the original
      class. We show that in a few iterations this process converges to a gene set that
      is learnable with considerably low rates of false positives and negatives and
      contains genes that are biologically related to the original class, allowing for
      a coarse reconstruction of the interactions between associated biological
      pathways. We exemplify this methodology using the well-studied tricarboxylic acid
      cycle.

PMID- 12421758
TI  - Novel PAX6 binding sites in the human genome and the role of repetitive elements
      in the evolution of gene regulation.
AB  - Pax6 is a critical transcription factor in the development of the eye, pancreas,
      and central nervous system. It is composed of two DNA-binding domains, the paired
      domain (PD), which has two helix-turn-helix (HTH) motifs, and the homeodomain
      (HD), made up from another HTH motif. Each HTH motif can bind to DNA separately
      or in combination with the others. We identified three novel binding sites that
      are specific for the PD and HD domains of human PAX6 from single-copy human
      genomic DNA libraries using cyclic amplification of protein binding sequences
      (CAPBS) and electrophoretic mobility shift assays (EMSAs). One of the binding
      sites was found within sequences of repetitive Alu elements. However, most of the
      Alu sequences were unable to bind to PAX6 because of a small number of mismatches
      (mostly in CpG dinucleotide hot spots) in the consensus Alu sequences. PAX6
      binding Alu elements are found primarily in old and intermediate-aged Alu
      subfamilies. These data along with our previously identified B1-type Pax6 binding
      site showed that evolutionarily conserved Pax6 has target sites that are
      disparate in primates and rodents. This difference indicates that human and mouse
      Pax6-regulated gene networks may have evolved through these lineage-specific
      repeat elements.

PMID- 12421759
TI  - Genome-wide co-occurrence of promoter elements reveals a cis-regulatory cassette
      of rRNA transcription motifs in Saccharomyces cerevisiae.
AB  - Combinatorial regulation is an important feature of eukaryotic transcription.
      However, only a limited number of studies have characterized this aspect on a
      whole-genome level. We have conducted a genome-wide computational survey to
      identify cis-regulatory motif pairs that co-occur in a significantly high number
      of promoters in the S. cerevisiae genome. A pair of novel motifs, mRRPE and PAC,
      co-occur most highly in the genome, primarily in the promoters of genes involved
      in rRNA transcription and processing. The two motifs show significant positional
      and orientational bias with mRRPE being closer to the ATG than PAC in most
      promoters. Two additional rRNA-related motifs, mRRSE3 and mRRSE10, also co-occur
      with mRRPE and PAC. mRRPE and PAC are the primary determinants of expression
      profiles while mRRSE3 and mRRSE10 modulate these patterns. We describe a new
      computational approach for studying the functional significance of the physical
      locations of promoter elements that combine analyses of genome sequence and
      microarray data. Applying this methodology to the regulatory cassette containing
      the four rRNA motifs demonstrates that the relative promoter locations of these
      elements have a profound effect on the expression patterns of the downstream
      genes. These findings provide a function for these novel motifs and insight into
      the mechanism by which they regulate gene expression. The methodology introduced
      here should prove particularly useful for analyzing transcriptional regulation in
      more complex genomes.

PMID- 12421760
TI  - Genome dynamics in aging mice.
AB  - Random spontaneous genome rearrangements are difficult to detect in vivo,
      especially in postmitotic tissues. Using a lacZ-plasmid reporter mouse model, we
      have previously presented evidence for the accumulation of large genome
      rearrangements in various tissues, including postmitotic tissues, during aging.
      These rearrangements, which were found to be organ-specific and to increase with
      age, have one breakpoint in the lacZ-reporter locus and the second elsewhere in
      the mouse genome. In this present work, we have used a mouse genome sequence
      database to physically characterize a total of 49 genome rearrangements in the
      brain, heart, and liver from young and old mice at two lacZ-plasmid reporter
      loci. Half of all breakpoints in the mouse genome occurred in chromosomes 3 and
      4, each carrying a lacZ-reporter cluster, at distances varying from <100 kb to 66
      Mb, indicating intrachromosomal deletions or inversions. The other half of the
      breakpoints in the mouse genome was found randomly on any of the other
      chromosomes, indicating translocations. Alternatively, part of the intra- and
      extrachromosomal events could involve transpositions. Regions of extended
      homology were not found at the breakpoints. These results lead us to postulate
      potential mechanisms for the origin of large genome rearrangements in mouse
      tissues and to predict their possible impact as a potential cause of aging.

PMID- 12421761
TI  - Identification of new herpesvirus gene homologs in the human genome.
AB  - Viruses are intracellular parasites that use many cellular pathways during their
      replication. Large DNA viruses, such as herpesviruses, have captured a repertoire
      of cellular genes to block or mimic host immune responses, apoptosis regulation,
      and cell-cycle control mechanisms. We have conducted a systematic search for all
      homologs of herpesvirus proteins in the human genome using position-specific
      scoring matrices representing herpesvirus protein sequence domains, and pair-wise
      sequence comparisons. The analysis shows that approximately 13% of the
      herpesvirus proteins have clear sequence similarity to products of the human
      genome. Different human herpesviruses vary in their numbers of human homologs,
      indicating distinct rates of gene acquisition in different lineages. Our analysis
      has identified new families of herpesvirus/human homologs from viruses including
      human herpesvirus 5 (human cytomegalovirus; HCMV) and human herpesvirus 8
      (Kaposi's sarcoma-associated herpesvirus; KSHV), which may play important roles
      in host-virus interactions.

PMID- 12421762
TI  - Gene expression analysis using oligonucleotide arrays produced by maskless
      photolithography.
AB  - Microarrays containing 195,000 in situ synthesized oligonucleotide features have
      been created using a benchtop, maskless photolithographic instrument. This
      instrument, the Maskless Array Synthesizer (MAS), uses a digital light processor
      (DLP) developed by Texas Instruments. The DLP creates the patterns of UV light
      used in the light-directed synthesis of oligonucleotides. This digital mask
      eliminates the need for expensive and time-consuming chromium masks. In this
      report, we describe experiments in which we tested this maskless technology for
      DNA synthesis on glass surfaces. Parameters examined included deprotection rates,
      repetitive yields, and oligonucleotide length. Custom gene expression arrays were
      manufactured and hybridized to Drosophila melanogaster and mouse samples.
      Quantitative PCR was used to validate the gene expression data from the mouse
      arrays.

PMID- 12421763
TI  - Genomic signature tags (GSTs): a system for profiling genomic DNA.
AB  - Genomic signature tags (GSTs) are the products of a method we have developed for
      identifying and quantitatively analyzing genomic DNAs. The DNA is initially
      fragmented with a type II restriction enzyme. An oligonucleotide adaptor
      containing a recognition site for MmeI, a type IIS restriction enzyme, is then
      used to release 21-bp tags from fixed positions in the DNA relative to the sites
      recognized by the fragmenting enzyme. These tags are PCR-amplified, purified,
      concatenated, and then cloned and sequenced. The tag sequences and abundances are
      used to create a high-resolution GST sequence profile of the genomic DNA. GSTs
      are shown to be long enough for use as oligonucleotide primers to amplify
      adjacent segments of the DNA, which can then be sequenced to provide additional
      nucleotide information or used as probes to identify specific clones in
      metagenomic libraries. GST analysis of the 4.7-Mb Yersinia pestis EV766 genome
      using BamHI as the fragmenting enzyme and NlaIII as the tagging enzyme validated
      the precision of our approach. The GST profile predicts that this strain has
      several changes relative to the archetype CO92 strain, including deletion of a 57
      kb region of the chromosome known to be an unstable pathogenicity island.

PMID- 12421764
TI  - SNPSTRs: empirically derived, rapidly typed, autosomal haplotypes for inference
      of population history and mutational processes.
AB  - Each independently evolving segment of the genomes of a sexually reproducing
      organism has a separate history reflecting part of the evolutionary history of
      that organism. Uniparentally or clonally inherited DNA segments such as the
      mitochondrial and chloroplast genomes and the nonrecombining portion of the Y
      chromosome have provided, to date, most of the known data regarding compound
      haplotypic variation within and among populations. These comparatively small
      segments include numerous polymorphic sites and undergo little or no
      recombination. Recombining autosomes, however, comprise the major repository of
      genetic variation. Technical challenges and recombination have limited large
      scale application of autosomal haplotypes. We have overcome this barrier through
      development of a general approach to the assessment of short autosomal DNA
      segments. Each such segment includes one or more single nucleotide polymorphisms
      (SNPs) and exactly one short tandem repeat (STR) locus. With dramatically
      different mutation rates, these two types of genetic markers provide
      complementary evolutionary information. We call the combination of a SNP and a
      STR polymorphism a SNPSTR, and have developed a simple, rapid method for
      empirically determining gametic phase for double and triple heterozygotes. Here,
      we illustrate the approach with two SNPSTR systems. Although even one system
      provides insight into population history, the power of the approach lies in
      combining results from multiple SNPSTR systems.

PMID- 12421765
TI  - Protein-protein interactions between large proteins: two-hybrid screening using a
      functionally classified library composed of long cDNAs.
AB  - Large proteins have multiple domains that are potentially capable of binding many
      kinds of partners. It is conceivable, therefore, that such proteins could
      function as an intricate framework of assembly protein complexes. To
      comprehensively study protein-protein interactions between large KIAA proteins,
      we have constructed a library composed of 1087 KIAA cDNA clones based on prior
      functional classifications done in silico. We were guided by two principles that
      raise the success rate for detecting interactions per tested combination: we
      avoided testing low-probability combinations, and reduced the number of potential
      false negatives that arise from the fact that large proteins cannot reliably be
      expressed in yeast. The latter was addressed by constructing a cDNA library
      comprised of random fragments encoding large proteins. Cytoplasmic domains of
      KIAA transmembrane proteins (>1000 amino acids) were used as bait for yeast two
      hybrid screening. Our analyses reveal that several KIAA proteins bearing a
      transmembrane region have the capability of binding to other KIAA proteins
      containing domains (e.g., PDZ, SH3, rhoGEF, and spectrin) known to be localized
      to highly specialized submembranous sites, indicating that they participate in
      cellular junction formation, receptor or channel clustering, and intracellular
      signaling events. Our representative library should be a very useful resource for
      detecting previously unidentified interactions because it complements
      conventional expression libraries, which seldom contain large cDNAs.

PMID- 12421766
TI  - Detection of peptides, proteins, and drugs that selectively interact with protein
      targets.
AB  - Genome sequencing has been completed for multiple organisms, and pilot proteomic
      analyses reported for yeast and higher eukaryotes. This work has emphasized the
      facts that proteins are frequently engaged in multiple interactions, and that
      governance of protein interaction specificity is a primary means of regulating
      biological systems. In particular, the ability to deconvolute complex protein
      interaction networks to identify which interactions govern specific signaling
      pathways requires the generation of biological tools that allow the distinction
      of critical from noncritical interactions. We report the application of an
      enhanced Dual Bait two-hybrid system to allow detection and manipulation of
      highly specific protein-protein interactions. We summarize the use of this system
      to detect proteins and peptides that target well-defined specific motifs in
      larger protein structures, to facilitate rapid identification of specific
      interactors from a pool of putative interacting proteins obtained in a library
      screen, and to score specific drug-mediated disruption of protein-protein
      interaction.

PMID- 12421767
TI  - The automatic detection of homologous regions (ADHoRe) and its application to
      microcolinearity between Arabidopsis and rice.
AB  - It is expected that one of the merits of comparative genomics lies in the
      transfer of structural and functional information from one genome to another.
      This is based on the observation that, although the number of chromosomal
      rearrangements that occur in genomes is extensive, different species still
      exhibit a certain degree of conservation regarding gene content and gene order.
      It is in this respect that we have developed a new software tool for the
      Automatic Detection of Homologous Regions (ADHoRe). ADHoRe was primarily
      developed to find large regions of microcolinearity, taking into account
      different types of microrearrangements such as tandem duplications, gene loss and
      translocations, and inversions. Such rearrangements often complicate the
      detection of colinearity, in particular when comparing more anciently diverged
      species. Application of ADHoRe to the complete genome of Arabidopsis and a large
      collection of concatenated rice BACs yields more than 20 regions showing
      statistically significant microcolinearity between both plant species. These
      regions comprise from 4 up to 11 conserved homologous gene pairs. We predict the
      number of homologous regions and the extent of microcolinearity to increase
      significantly once better annotations of the rice genome become available.

PMID- 12421768
TI  - Trauma care in England and Wales: is this as good as it gets?

PMID- 12421769
TI  - Injuries associated with airbag deployment.

PMID- 12421770
TI  - Fluid resuscitation in prehospital trauma care: a consensus view.

PMID- 12421772
TI  - Risk reduction through skeletal scintigraphy as a screening tool in suspected
      scaphoid fracture: a literature review.

PMID- 12421773
TI  - The MRC CRASH Trial: study design, baseline data, and outcome in 1000 randomised
      patients in the pilot phase.
AB  - OBJECTIVES: To test the design and feasibility of a large scale multicentre
      randomised controlled trial evaluating the efficacy and safety of a high dose
      corticosteroid infusion after head injury. To assess whether large numbers of
      patients could be enrolled and treated within eight hours from injury and then
      followed up at six months. METHODS: Randomised placebo controlled multicentre
      trial of a 48 hour corticosteroid infusion after significant head injury. All
      head injured adults who were observed while in hospital to have GCS of 14 or less
      (out of a maximum score of 15), and who were within eight hours of the injury,
      were eligible for trial entry. Analysis of baseline and outcome data (for both
      treatment groups combined) for 1000 patients enrolled in the pilot phase of the
      MRC CRASH Trial. RESULTS: Fifty two hospitals in 14 countries participated in the
      pilot phase, recruiting an average of one patient per hospital per month. Of the
      1000 randomised patients, 330 (33%) had mild head injury, 289 (29%) had moderate
      head injury, and 381 (38%) had severe head injury. Seven hundred and nine (71%)
      patients were randomised within three hours of injury. Outcome at two weeks from
      injury was known for 991 (99%) patients, of whom 170 (17%) patients died. At the
      time of writing, six month follow up for the first 500 patients was nearly
      complete. Vital status was known for 465 (93%) of the 500 patients, of whom 97
      (21%) had died. Functional status based on the Glasgow Outcome Scale was known
      for 438 (88%) of the 500 patients: 21% were dead, 17% were severely disabled, 22%
      were moderately disabled, and 34% had made a good recovery. CONCLUSIONS: The
      trial procedures proved practicable and a wide variety of patients were recruited
      in the emergency department within eight hours of injury. Using simple outcome
      measures, large numbers of patients can be successfully followed up.

PMID- 12421771
TI  - Whiplash associated disorders: a review of the literature to guide patient
      information and advice.
AB  - OBJECTIVES: To review the literature and provide an evidence based framework for
      patient centred information and advice on whiplash associated disorders. METHODS:
      A systematic literature search was conducted, which included both clinical and
      non-clinical articles to encompass the wide range of patients' informational
      needs. From the studies and previous reviews retrieved, 163 were selected for
      detailed review. The review process considered the quantity, consistency, and
      relevance of all selected articles. These were categorised under a grading system
      to reflect the quality of the evidence, and then linked to derived evidence
      statements. RESULTS: The main messages that emerged were: physical serious injury
      is rare; reassurance about good prognosis is important; over-medicalisation is
      detrimental; recovery is improved by early return to normal pre-accident
      activities, self exercise, and manual therapy; positive attitudes and beliefs are
      helpful in regaining activity levels; collars, rest, and negative attitudes and
      beliefs delay recovery and contribute to chronicity. These findings were
      synthesised into patient centred messages with the potential to reduce the risk
      of chronicity. CONCLUSIONS: The scientific evidence on whiplash associated
      disorders is of variable quality, but sufficiently robust and consistent for the
      purpose of guiding patient information and advice. While the delivery of
      appropriate messages can be both oral and written, consistency is imperative, so
      an innovative patient educational booklet, The Whiplash Book, has been developed
      and published.

PMID- 12421774
TI  - A meta-analysis of GCS 15 head injured patients with loss of consciousness or
      post-traumatic amnesia.
AB  - OBJECTIVES: The classification of patients with "minor head injury" has relied
      largely upon the Glasgow Coma Scale (GCS). The GCS however is an insensitive way
      of defining this heterogeneous subgroup of patients. The aim of the study was to
      develop an extended GCS 15 category by meta-analysis of previously published case
      control studies that have identified symptom risk factors for an abnormal head
      tomogram. METHODS: Eligibility for the study was defined as: (1) Full papers and
      not abstracts. (2) Case-control or nested case-control studies on GCS 15 patients
      (adults or adults plus children). Outcome variable being head tomography: normal
      or abnormal. (3) Documentation of one or more symptom variables such that the
      odds ratio could be calculated. Five symptom variables were defined for the
      purpose of the study: headache, nausea, vomiting, blurred vision, and dizziness.
      RESULTS: Three articles fulfilled the criteria for the study. The Mantel-Haenszel
      test using a pooled estimate was used to calculate the common odds ratio for an
      abnormal head tomogram for each of the five symptom variables. The odds ratio for
      the symptom variables was: dizziness 0.594 (95%CI 0.296 to 1.193), blurred vision
      0.836 (95%CI 0.369 to 1.893), headache 0.909 (95% CI: 0.601 to 1.375), severe
      headache 3.211 (95% CI: 2.212 to 4.584), nausea 2.125 (95% CI 1.467 to 3.057),
      vomiting 4.398 (95% CI 2.790 to 6.932). CONCLUSION: The results of this study
      provide a framework on which GCS category 15 patients can be stratified into four
      risk categories based upon their symptoms.

PMID- 12421775
TI  - Lack of change in trauma care in England and Wales since 1994.
AB  - To demonstrate trends in trauma care in England and Wales from 1989 to 2000.
      STUDY POPULATION: Database of the Trauma Audit and Research Network that includes
      hospital patients admitted for three days or more, those who died, were
      transferred or admitted to an intensive care or high dependency area. METHOD: To
      demonstrate trends in outcome, severity adjusted odds of death per year of
      admission to hospital were calculated for all hospitals (n=99) and 20 hospitals
      who had participated since 1989 (adjustments are for Injury Severity Score, age,
      and Revised Trauma Score). The grade of doctor initially seeing the injured
      patient in accident and emergency and median prehospital times per year of
      admission were calculated to demonstrate trends in the process of care. Trend
      analyses were carried out using simple linear regression (odds ratio versus
      year). RESULTS: The analysis shows a significant reduction in the severity
      adjusted odds of death of 3% per year over the 1989-2000 time period (p=0.001).
      During the period 1989-1994 the odds of death declined most steeply (on average
      6% per year p=0.004). Between 1994 to 2000 no significant change occurred
      (p=0.35). This pattern was mirrored by the 20 permanent members where the odds of
      death also declined more steeply over the 1989-1994 period. The percentage of
      severely injured patients (ISS >15) seen by a consultant increased from 29 to 40
      from 1989-1994 but has remained static subsequently. Median prehospital times for
      severely injured patients have not changed significantly since 1994 (51 to 45
      minutes). CONCLUSION: Most of the case fatality reduction for trauma patients
      reaching hospital over the 1989-2000 time period occurred before 1995 when there
      was most marked change in the initial care of severely injured patients.

PMID- 12421776
TI  - Diagnostic peritoneal lavage analysis: should trauma guidelines be revised?
AB  - OBJECTIVES: Diagnostic peritoneal lavage (DPL) is used to detect intraperitoneal
      bleeding in patients sustaining blunt and penetrating abdominal trauma. The
      procedure should be performed by an experienced general surgeon, and the fluid
      obtained analysed by haematology technicians. Current Advanced Trauma Life
      Support guidelines are very clear on what constitutes a positive result,
      mandating laparotomy. The aim of this work was to assess whether DPL could
      actually be performed in practice. METHODS: A telephone survey was performed of a
      random selection of haematology technicians in 40 major trauma units in the UK,
      to assess whether they could actually analyse a DPL sample if it were sent to
      them. This was performed both during the day, and "out of hours". Secondly the
      experience of performing DPL was determined among 1797 general surgical trainees
      and consultants, by means of a questionnaire. RESULTS: Between 9 am and 5 pm 29
      of 40 haematology technicians questioned were able to analyse a sample of DPL
      fluid. This compared with a figure of 9 of 40 when the questionnaire was
      administered "out of hours". A total of 854 (48%) questionnaires were received
      from surgical trainees and consultants. Approximately 60% of those questioned had
      performed less than 10 DPLs throughout the whole of their careers. DISCUSSION:
      These results suggest that UK surgeons have little experience in performing DPL,
      and even if they do it is unlikely that any haematology departments will be able
      to analyse the sample, especially if performed after 5 pm. ATLS guidelines should
      be changed, and this investigation abandoned in favour of abdominal ultrasound.

PMID- 12421777
TI  - Prevention of chronic pain after whiplash.
AB  - The acute whiplash injury is a significant health burden for patients and the
      healthcare system. Traditional approaches to treatment fail to resolve this ever
      growing medicolegal and social problem. A new biopsychosocial model of whiplash
      disorder encourages new ways of treating and preventing of the chronic
      disability. This biopsychosocial model takes into account the mechanism by which
      acute pain becomes chronic pain, and how this can be prevented. Specific
      education and treatments encourage a behaviour after whiplash injury that is
      conducive to more rapid recovery, and provides the whiplash patient with insight
      into the mediators of chronic pain. The article describes in practical terms how
      to use education, reassurance, a more judicious use of therapy, and exercise to
      achieve this goal. Practical guidelines are provided on educating the patient
      about other symptoms that may cause concern.

PMID- 12421778
TI  - Temporal and demographic variations in attendance at accident and emergency
      departments.
AB  - OBJECTIVES: Little has been reported of the demographic and temporal variations
      in accident and emergency (A&E) attendances despite the importance of this
      information in planning services. The purpose of this paper to is to explore the
      variations in attendance patterns across the West Midlands region of the NHS.
      METHODS: The data were obtained from the A&E minimum dataset from a sample of 13
      hospitals. Arrival dates and times, age, and sex of all patients attending A&E in
      the year from 1 April 1999 to 31 March 2000 were analysed to look at the pattern
      of attendance by hour, day and month, age, and sex. RESULTS: No differences were
      found in attendance patterns in respect to sex. Attendances by children under 15
      years peaked in the evening between 18:00 and 19:59. In contrast, peak attendance
      in those over 15 years was between 09:00 and 11:59. The percentage of "out of
      hours" attendances in this dataset was highest in the under 1 age group (58.5%),
      the 15-24 age group (57.1%), and the 25-44 age group (54.6%). The highest
      proportion of patients attended A&E on a Monday, while the percentage of weekend
      attendances decreased with age. In children aged 1-14 years there were more
      attendances in summer than winter. In those aged under 1 and over 65 there was a
      winter peak with December having the most attendances. CONCLUSIONS: No sex
      differences were found in the temporal attendance patterns at A&E. However, many
      differences were found in the attendance of different age groups. These
      differences are of great importance in the planning of services, and further
      research is required to explain the reasons behind these variations.

PMID- 12421779
TI  - The PATRIARCH Study. Using outcome measures for league tables: can a North
      American prediction of admission score be used in a United Kingdom children's
      emergency department? PRISA And Triage In A Regional Children's Hospital.
AB  - OBJECTIVES: The use of league tables has become predominant in the healthcare
      culture of the United Kingdom. These tables are often based on measures that are
      viewed with scepticism by clinicians. This study was designed to test the
      validity of a North American risk of admission score, the PRISA, for use in a
      United Kingdom population of accident and emergency (A&E) attendees. METHODS: All
      attendees to a children's A&E department were scored using the PRISA for a single
      calendar month (November 2000) RESULTS: 701 children were studied in total. The
      results show that the PRISA applied to this population gives an area under the
      receiver operator curve of 0.76. Of the 701 patients studied, 206 (29.4%) were
      admitted. The PRISA predicted a total of 206.10 admissions. Of the 50 patients
      discharged with the highest PRISA scores (that is, with the highest likelihood of
      admission), none were admitted in the 48 hours after their original attendance.
      CONCLUSIONS: These results show that the PRISA is suitable as a measure of
      paediatric A&E department performance in the United Kingdom and it is highly
      promising as a future measure of quality.

PMID- 12421780
TI  - Dental knowledge of accident and emergency senior house officers.
AB  - OBJECTIVES: To determine the dental knowledge of accident and emergency (A&E)
      senior house officers (SHOs). METHOD: A telephone survey of A&E departments in
      England with more than 30 000 new attendances per year was conducted between
      November 1998 and July 1999. The questionnaire covered basic dental knowledge as
      well as scenarios of some common dental problems encountered in the A&E
      department. RESULTS: Most SHOs in this study saw between one and five dental
      problems each week. Of the 102 SHOs in this survey, 52% had no previous training
      in examination of the mouth. Only 52% knew the approximate date of eruption of a
      permanent upper central incisor. In the treatment of post-extraction bleeding,
      36% knew the first line of treatment. When presented with a scenario of a patient
      with a dental infection, only 29% gave the optimal empirical treatment.
      CONCLUSIONS: There is a need for better dental education among medical personnel.
      Guidelines or algorithms for the management of some common dental problems would
      also be useful as well as standard written advice sheets for patients with dental
      problems.

PMID- 12421781
TI  - A little nightclub medicine: the healthcare implications of clubbing.
AB  - OBJECTIVE: To describe the scale and range of acute medical problems among
      patients who present to an inner city accident and emergency (A&E) department
      after attending nightclubs in Liverpool. METHODS: From April 1997 to April 1998,
      all patients identified as having attended a nightclub before their arrival at
      the department were included in the study. Information regarding their attendance
      was gathered retrospectively using a standard proforma. SETTING: A large, city
      centre, teaching hospital A&E department with an annual new patient attendance
      rate of over 95,000. RESULT: 777 such patients were enrolled in the study (0.81%
      of all new attendances during the same period). This was probably an
      underestimate, as some eligible patients were not identified during the study.
      Predictably, most presentations were at the weekend between midnight and 08.00.
      Surprisingly, the commonest mode of transport to the hospital was an ambulance
      (38%, 298 of the total). Assault accounted for most presentations (57%, 443 of
      the total) and lacerations were the commonest injury (the face being most
      frequently affected). Alcohol was the commonest intoxicant overtly associated
      with the A&E department attendance. CONCLUSIONS: Injury after assault is the
      commonest precipitant of hospital care among clubbers in Liverpool. Alcohol is
      the most important contributory factor, although illegal drug misuse is a
      considerable challenge in the clubs themselves. A number of measures such as (a)
      the introduction of unbreakable glass or plastic containers; (b) the elimination
      of glass from outside clubs; (c) the provision of high quality immediate medical
      care at larger venues; (d) the curbing of over crowding and cheap drinks
      promotions; (e) registration of doormen, and (f) targeted policing of the areas
      around nightclubs are urgently required to reduce the healthcare (and civic)
      burden of clubbing. The cost for these should be borne by the highly profitable
      clubbing and brewing industries. A national code of practice for clubs-already in
      existence voluntarily-should be made mandatory.

PMID- 12421782
TI  - Overview of research designs.

PMID- 12421783
TI  - Towards evidence based emergency medicine: best BETs from Manchester Royal
      Infirmary. Swimmers view or supine oblique views to visualise the cervicothoracic
      junction.
AB  - A short cut review was carried out to establish whether swimmer's views were
      better than superior oblique views at visualising the C7/T1 junction. Eleven
      papers were found using the reported search, of which one presented the best
      evidence to answer the clinical question. The author, date and country of
      publication, patient group studied, study type, relevant outcomes, results, and
      study weaknesses of this best paper are tabulated. A clinical bottom line is
      stated.

PMID- 12421785
TI  - Towards evidence based emergency medicine: best BETs from Manchester Royal
      Infirmary. Computed tomography and the exclusion of upper cervical spine injury
      in trauma patients with altered mental state.
AB  - A short cut review was carried out to establish whether CT scans of the upper
      cervical spine are necessary in trauma patients with altered mental status and
      normal plain radiographs. A total of 572 papers were found using the reported
      search, of which six presented the best evidence to answer the clinical question.
      The author, date and country of publication, patient group studied, study type,
      relevant outcomes, results, and study weaknesses of these best papers are
      tabulated. A clinical bottom line is stated.

PMID- 12421786
TI  - Antibiotics in compound depressed skull fractures.
AB  - A short cut review was carried out to establish whether antibiotics reduce the
      incidence of meningitis in patients with compound depressed skull fracture.
      Altogether 198 papers were found using the reported search, of which one
      presented the best evidence to answer the clinical question. The author, date and
      country of publication, patient group studied, study type, relevant outcomes,
      results and study weaknesses of this best paper are tabulated. A clinical bottom
      line is stated.

PMID- 12421787
TI  - Towards evidence based emergency medicine: best BETs from Manchester Royal
      Infirmary. Antibiotics in patients with isolated chest trauma requiring chest
      drains.
AB  - A short cut review was carried out to establish whether the administration of
      antibiotics reduces the incidence of intrathoracic infection in patients who have
      had a chest drain inserted after trauma. Altogether 321 papers were found using
      the reported search, of which two presented the best evidence to answer the
      clinical question. The author, date and country of publication, patient group
      studied, study type, relevant outcomes, results, and study weaknesses of these
      best papers are tabulated. A clinical bottom line is stated.

PMID- 12421788
TI  - Towards evidence based emergency medicine: best BETs from Manchester Royal
      Infirmary. Ultrasound or computed tomography in paediatric blunt abdominal
      trauma.
AB  - A short cut review was carried out to establish whether computed tomography is
      superior to ultrasonography at identifying intra-abdominal injury in children.
      Altogether 123 papers were found using the reported search, of which six
      presented the best evidence to answer the clinical question. The author, date and
      country of publication, patient group studied, study type, relevant outcomes,
      results, and study weaknesses of these best papers are tabulated. A clinical
      bottom line is stated.

PMID- 12421789
TI  - Towards evidence based emergency medicine: best BETs from Manchester Royal
      Infirmary. Lignocaine premedication before rapid sequence induction in head
      injuries.
AB  - A short cut review was carried out to establish whether pretreatment with
      lignocaine (lidocaine) reduces the rise in intracranial pressure associated with
      intubation of head injured patients. Altogether 85 papers were found using the
      reported search, of which three presented the best evidence to answer the
      clinical question. The author, date and country of publication, patient group
      studied, study type, relevant outcomes, results, and study weaknesses of these
      best papers are tabulated. A clinical bottom line is stated.

PMID- 12421790
TI  - Towards evidence based emergency medicine: best BETs from Manchester Royal
      Infirmary. Factor VIIa for intractable blood loss in trauma.
AB  - A short cut review was carried out to establish whether factor VIIa is indicated
      in patients suffering intractable blood loss after trauma. Altogether 59 papers
      were found using the reported search, of which two presented the best evidence to
      answer the clinical question. The author, date and country of publication,
      patient group studied, study type, relevant outcomes, results, and study
      weaknesses of these best papers are tabulated. A clinical bottom line is stated.

PMID- 12421791
TI  - Towards evidence based emergency medicine: best BETs from Manchester Royal
      Infirmary. Routine use of antibiotic ointment and wound healing.
AB  - A short cut review was carried out to establish whether topical antibiotics
      improved the outcome of simple wounds. Altogether 71 papers were found using the
      reported search, of which one presented the best evidence to answer the clinical
      question. The author, date and country of publication, patient group studied,
      study type, relevant outcomes, results, and study weaknesses of this best paper
      are tabulated. A clinical bottom line is stated.

PMID- 12421792
TI  - Article 11. Capital planning, the coroner, and there is a transit van in your
      resuscitation room.

PMID- 12421793
TI  - Hitting them where it hurts? Low dose nalbuphine therapy.
AB  - OBJECTIVE: To determine if low dose nalbuphine provides an adequate reduction in
      pain with minimal side effects. METHODS: Prospective cohort of 115 patients given
      nalbuphine by paramedics in Wales and the English borders. OUTCOME MEASURES: (1)
      Mean total dose of nalbuphine administered, change in pain score, time to
      adequate pain relief (score below four), and change in respiratory rate and
      systolic blood pressure; (2) proportion of patients continuing to suffer moderate
      to severe pain on arrival at hospital; (3) incidence of adverse events. RESULTS:
      Full data were obtained for all patients. The mean total dose of nalbuphine
      administered was 6.09 mg (range 2.5 to 12.5 mg). This was significantly higher in
      trauma than ischaemic chest pain patients (7.03 versus 5.13 mg). The mean
      reduction in pain score was -3.97 (95% CI -4.38 to -3.57, p<0.001). The mean time
      to adequate pain relief (where this was achieved) was 15.7 minutes (95% CI 13.4
      to 17.9 minutes). On arrival at hospital 60% of patients (n=69, 95% CI 50.9 to
      68.5%) still met ambulance criteria for analgesia (70.7% of trauma patients and
      49.1% with ischaemic chest pain). Systolic blood pressure fell by a mean of -3.67
      (95% CI -6.76 to -0.58, p=0.02) and respiratory rate increased by a mean of 1.63
      (95% CI 1.08 to 2.17, p<0.001). Two patients complained of nausea (1.74%, 95% CI
      0.5 to 6.0%). No other adverse events were reported. CONCLUSION: Low dose
      nalbuphine results in few adverse events, but offers poor pain control for a high
      proportion of patients.

PMID- 12421794
TI  - Pattern and severity of injuries in micro-scooter related accidents.
AB  - OBJECTIVES: To examine the pattern and severity of injuries sustained by children
      following micro-scooter (MS) accidents, and to document the extent of use of
      protective clothing in these accidents. METHODS: Prospective data collection on
      all children with MS related accidents from January to June 2001. Demographic
      data were collected, including the mechanism of injury, place of accident, use of
      protective clothing, extent of injuries, and injury management. Injury severity
      score was calculated for each child. RESULTS: A total of 92 children with 104
      injuries were seen during the study period. Male and female sex distribution was
      similar. The pattern of injuries was similar to those from roller blading
      accidents. Soft tissue injuries constitute 79.8% (83 of 104) and fractures 20.1%
      (21 of 104). Injuries of the upper limb particularly the wrists were commonest
      for both soft tissue and fractures. The mean ISS (SD) was 2.08 (2.31) with a
      range of 1 to 18. No deaths were recorded during the study period and all the
      head injuries seen were minor in nature. None of our patients wore any protective
      clothing, and almost all accidents occurred in public places. CONCLUSIONS: MS
      related injuries are on the increase. Currently, the manufacturers' advice on use
      of protective clothing is being ignored. Parents and riders of the MS need be to
      be educated about the related injuries. The use of protective clothing should be
      encouraged to reduce injuries.

PMID- 12421795
TI  - Hoof kick injuries in unmounted equestrians. Improving accident analysis and
      prevention by introducing an accident and emergency based relational database.
AB  - OBJECTIVE: To assess injury patterns attributable to horse kicks, to raise the
      issue of preventive measures, and to evaluate the role of modern accident and
      emergency department computer software. METHODS: Data analysis using a new kind
      of full electronic medical record. RESULTS: Seventeen kicked equestrians were
      unmounted at the time of injury. Eight of seventeen patients sustained contusions
      of the extremities, the back, and the trunk. In nine patients an isolated facial
      injury was diagnosed. Five of nine patients needed referrals to the department of
      plastic surgery because of the complexity of the facial soft tissue wounds. Three
      underwent maxillofacial surgery. CONCLUSION: Clinical: the equestrian community
      may underestimate the risk of severe injuries attributable to hoof kicks,
      especially while handling the horse. Educational lectures and the distribution of
      educational literature should be promoted. The introduction of additional face
      shields may be protective. Software related issue: the handling of an increasing
      amount of medical data makes a development in computerisation of emergency units
      necessary. Thus the increasing utilisation of new computer technology could have
      a significant influence on accident analysis and prevention and the quality of
      research in the future.

PMID- 12421796
TI  - Golf related head injuries in children.
AB  - OBJECTIVES: To assess the incidence and severity of head injuries to children
      sustained by a blow from a golf club or ball and to highlight the potential for
      significant injury. An increase in public awareness of these risks might result
      in a reduction in morbidity. METHODS: Over a period of seven months, all children
      aged 3-13 years, attending the accident and emergency department with a head
      injury sustained from a golf club or ball had their case notes reviewed by the
      author. RESULTS: Thirty seven children, 78% of whom were boys, were identified as
      having sustained such a head injury, commonly during the school holiday months.
      Thirty three of the injuries were caused by golf clubs, the other four by a golf
      ball. Half of the injuries were to the frontal area. Twenty five children (68%)
      had skull radiographs but only one was positive--one child sustaining a compound
      depressed fracture of the frontal area. One child required cleaning and suturing
      of a wound under a general anaesthetic. A known epileptic child had a fit
      immediately after being hit on the head by a golf ball. Twenty two (60%)
      sustained lacerations that were repaired with steristrips or glue. Twelve had
      haematomas, seven complained of dizziness/drowsiness, and two had
      nausea/vomiting. CONCLUSIONS: Other authors have reported fatal head injuries,
      and it would seem that parents are unaware of the risks of serious and permanent
      head injury, with the potential for death, attributable to blows to the head from
      golf clubs and balls. The need for early tuition in the safety aspects of the
      game cannot be underestimated and parent and player education strategies are
      suggested as the main means of reducing injuries in this popular sport.

PMID- 12421797
TI  - Prehospital thrombolysis: lessons from Sweden and their application to the United
      Kingdom.
AB  - OBJECTIVE: To study the successful implementation of paramedic administered
      prehospital thrombolysis in Sweden, and to consider the implications of this for
      the UK. METHODS: A series of research visits were undertaken, including visits to
      Uppsala Hospital and dispatch centre, ambulance stations in several counties of
      Sweden and Dalarna County, which has one of the longest experiences of
      telemedicine supported prehospital thrombolysis in Europe. Data relating to
      prehospital thrombolysis, stages in successful implementation, and potential
      barriers to change were identified. RESULTS: Two thirds of the hospitals in
      Sweden now have some form of prehospital thrombolysis. A nationally agreed and
      standardised training programme and the fact that many ambulance paramedics are
      also qualified nurses has facilitated successful introduction, but Sweden's low
      population density is also an important factor. Data from Dalarna County indicate
      that the median "pain to needle" time has been reduced by 45 minutes with a
      concurrent reduction in complications from 50% to 25% (p=0.018). Inhospital
      mortality has also reduced from 12% to 6%, but with the small numbers involved
      this improvement does not achieve statistical significance (p=0.36). CONCLUSION:
      If the outcome of acute myocardial infarction in the United Kingdom is to be
      improved, and National Service Framework targets met, then prehospital
      thrombolysis is an important development. Several technical solutions already
      exist, and a single bolus thrombolytic agent is now available, but the main
      barriers to full implementation are related to the establishment of an effective
      training programme and the organisational changes that will facilitate this new
      practice. High quality research is urgently needed to guide the implementation of
      prehospital thrombolysis in a clinically and cost effective way.

PMID- 12421798
TI  - Importance of emergency identification schemes.
AB  - BACKGROUND: Millions of people worldwide may have a hidden medical condition that
      could endanger their life in an emergency. These conditions may include cardiac
      conditions, severe allergies, or diabetes. Emergency identification schemes such
      as Medic Alert produce emblems that alert health care professionals to potential
      problems and can ensure appropriate and prompt treatment. This paper uses
      mechanical failure of the Bjork-Shiley convexo-concave (BSCC) heart valve as an
      example of a hidden medical condition. These patients have been encouraged to
      carry information to alert staff in an emergency that they have a BSCC patient in
      their care and to be alert to the signs and symptoms of acute valve malfunction.
      OBJECTIVE: To establish awareness and credibility of emergency identification
      schemes among emergency personnel and to assess if information on specific
      medical conditions would influence ambulance personnel regarding destination
      hospitals. METHODS: Questionnaires were sent to senior staff (n=380) of accident
      and emergency (A&E) departments and operational directors of ambulance
      headquarters (n=39) throughout the United Kingdom. Hospitals were divided into
      regional divisions to assess differences in responses across regions. RESULTS:
      The majority of respondents (99%) had heard of emergency identification schemes
      and felt that it was important for patients with special conditions to carry some
      form of identification. Nearly all ambulance respondents (97%) indicated it was
      routine to search for body worn emblems in contrast with only 71% of A & E staff.
      However, more than half of ambulance respondents (53.9%) stated information on
      emblems/cards would not influence their choice of destination hospital.
      CONCLUSIONS: The importance of how information on pre-existing medical conditions
      can influence care, is highlighted by the BSCC valve issue, where immediate
      diagnosis is essential for patient survival. It is vital that all staff routinely
      search patients for this information and if necessary act upon the information
      provided.

PMID- 12421799
TI  - Cardiac tamponade: a case of kitchen floor thoracotomy.

PMID- 12421800
TI  - Disruption of the iliocolic artery after blunt trauma.
AB  - Injury to the superior mesenteric artery and branches is an uncommon event, which
      is typically associated with penetrating injury and high mortality. A case is
      presented of rupture of a branch of the superior mesenteric artery (iliocolic
      artery) after blunt trauma. The case illustrates the more occult presentation and
      better overall prognosis associated with this type of injury as compared with
      injury to the proximal superior mesenteric artery. In addition this case
      highlights the importance of vigilance in patients who deteriorate after initial
      resuscitation.

PMID- 12421801
TI  - Use of the Asherman chest seal as a stabilisation device for needle thoracostomy.

PMID- 12421802
TI  - Cervical spine control; bending the rules.
AB  - Cervical spine fractures associated with diffuse idiopathic hyperostosis (DISH)
      are less common than those associated with ankylosing spondylitis and can occur
      after minor trauma in patients asymptomatic of the disease process. This case
      report describes a hyperextension injury of the neck in a patient unknown to have
      DISH, which resulted in an angulated C3/C4 fracture. The position of the fracture
      was improved by placing the neck in flexion with immediate improvement in the
      patient's neurological deficit.

PMID- 12421803
TI  - Fatal anaphylactoid reaction to N-acetylcysteine: caution in patients with
      asthma.
AB  - Paracetamol overdose is a common reason for presentation to the emergency
      department and N-acetylcysteine is frequently used in the treatment of toxic
      paracetamol ingestions. Adverse reactions to N-acetylcysteine are common though
      usually mild and easily treated. Serious reactions to N-acetylcysteine however,
      are rare and there have been no previous reported fatalities with its therapeutic
      use. This report describes the case of a 40 year old brittle asthmatic patient
      who died after treatment with intravenous N-acetylcysteine. Asthma is a risk
      factor for adverse reactions to N-acetylcysteine and special caution should be
      exercised in its use in brittle asthmatic patients.

PMID- 12421805
TI  - Tricyclic antidepressant overdose.

PMID- 12421806
TI  - Drug binding in human P-glycoprotein causes conformational changes in both
      nucleotide-binding domains.
AB  - The human multidrug resistance P-glycoprotein (P-gp, ABCB1) uses ATP to transport
      many structurally diverse compounds out of the cell. It is an ABC transporter
      with two nucleotide-binding domains (NBDs) and two transmembrane domains (TMDs).
      Recently, we showed that the "LSGGQ" motif in one NBD ((531)LSGGQ(535) in NBD1;
      (1176)LSGGQ(1180) in NBD2) is adjacent to the "Walker A" sequence
      ((1070)GSSGCGKS(1077) in NBD2; (427)GNSGCGKS(434) in NBD1) in the other NBD (Loo,
      T. W., Bartlett, M. C., and Clarke, D. M. (2002) J. Biol. Chem. 277, 41303
      41306). Drug substrates can stimulate or inhibit the ATPase activity of P-gp.
      Here, we report the effect of drug binding on cross-linking between the LSGGQ
      signature and Walker A sites (Cys(431)(NBD1)/C1176C(NBD2) and
      Cys(1074)(NBD2)/L531C(NBD1), respectively). Seven drug substrates (calcein-AM,
      demecolcine, cis(Z)-flupentixol, verapamil, cyclosporin A, Hoechst 33342, and
      trans(E)-flupentixol) were tested for their effect on oxidative cross-linking.
      Substrates that stimulated the ATPase activity of P-gp (calcein-AM, demecolcine,
      cis(Z)-flupentixol, and verapamil) increased the rate of cross-linking between
      Cys(431)(NBD1-Walker A)/C1176C(NBD2-LSGGQ) and between Cys(1074)(NBD2-Walker
      A)/L531C(NBD1-LSGGQ) when compared with cross-linking in the absence of drug
      substrate. By contrast, substrates that inhibited ATPase activity (cyclosporin A,
      Hoechst 33342, and trans(E)-flupentixol) decreased the rate of cross-linking.
      These results indicate that interaction between the LSGGQ motifs and Walker A
      sites must be essential for coupling drug binding to ATP hydrolysis. Drug binding
      in the transmembrane domains can induce long range conformational changes in the
      NBDs, such that compounds that stimulate or inhibit ATPase activity must decrease
      and increase, respectively, the distance between the Walker A and LSGGQ
      sequences.

PMID- 12421807
TI  - The 2-A crystal structure of 6-oxo camphor hydrolase. New structural diversity in
      the crotonase superfamily.
AB  - 6-Oxo camphor hydrolase (OCH) is an enzyme of the crotonase superfamily that
      catalyzes carbon-carbon bond cleavage in bicyclic beta-diketones via a retro
      Claisen reaction (Grogan, G., Roberts, G. A., Bougioukou, D., Turner, N. J., and
      Flitsch, S. L. (2001) J. Biol. Chem. 276, 12565-12572). The native structure of
      OCH has been solved at 2.0-A resolution with selenomethionine multiple wave
      anomalous dispersion and refined to a final R(free) of 19.0. The structure of OCH
      consists of a dimer of trimers that resembles the "parent" enzyme of the
      superfamily, enoyl-CoA hydratase. In contrast to enoyl-CoA hydratase, however,
      two octahedrally coordinated sodium atoms are found at the 3-fold axis of the
      hexamer of OCH, and the C-terminal helix of OCH does not form a discrete domain.
      Models of the substrate, 6-oxo camphor, and a proposed enolate intermediate in
      the putative active site suggest possible mechanistic roles for Glu-244, Asp-154,
      His-122, His-45, and His-145.

PMID- 12421808
TI  - Ca2+-independent phospholipase A2 is required for agonist-induced Ca2+
      sensitization of contraction in vascular smooth muscle.
AB  - Excitatory agonists can induce significant smooth muscle contraction under
      constant free Ca(2+) through a mechanism called Ca(2+) sensitization.
      Considerable evidence suggests that free arachidonic acid plays an important role
      in mediating agonist-induced Ca(2+)-sensitization; however, the molecular
      mechanisms responsible for maintaining and regulating free arachidonic acid level
      are not completely understood. In the current study, we demonstrated that Ca(2+)
      independent phospholipase A(2) (iPLA(2)) is expressed in vascular smooth muscle
      tissues. Inhibition of the endogenous iPLA(2) activity by bromoenol lactone (BEL)
      decreases basal free arachidonic acid levels and reduces the final free
      arachidonic acid level after phenylephrine stimulation, without significant
      effect on the net increase in free arachidonic acid stimulated by phenylephrine.
      Importantly, BEL treatment diminishes agonist-induced Ca(2+) sensitization of
      contraction from 49 +/- 3.6 to 12 +/- 1.0% (p < 0.01). In contrast, BEL does not
      affect agonist-induced diacylglycerol production or contraction induced by
      Ca(2+), phorbol 12,13-dibutyrate (a protein kinase C activator), or exogenous
      arachidonic acid. Further, we demonstrate that adenovirus-mediated overexpression
      of exogenous iPLA(2) in mouse portal vein tissue significantly potentiates
      serotonin-induced contraction. Our data provide the first evidence that iPLA(2)
      is required for maintaining basal free arachidonic acid levels and thus is
      essential for agonist-induced Ca(2+)-sensitization of contraction in vascular
      smooth muscle.

PMID- 12421809
TI  - Structural analysis of Siah1 and its interactions with Siah-interacting protein
      (SIP).
AB  - Seven in absentia homologue (Siah) family proteins bind ubiquitin-conjugating
      enzymes and target proteins for proteasome-mediated degradation. Recently we
      identified a novel Siah-interacting protein (SIP) that is a Sgt1-related molecule
      that provides a physical link between Siah family proteins and the Skp1-Cullin-F
      box ubiquitin ligase component Skp1. In the present study, a structure-based
      approach was used to identify interacting residues in Siah that are required for
      association with SIP. In Siah1 a large concave surface is formed across the dimer
      interface. Analysis of the electrostatic surface potential of the Siah1 dimer
      reveals that the beta-sheet concavity is predominately electronegative,
      suggesting that the protein-protein interactions between Siah1 and SIP are
      mediated by ionic contacts. The structural prediction was confirmed by site
      directed mutagenesis of these electronegative residues, resulting in loss of
      binding of Siah1 to SIP in vitro and in cells. The results also provide a
      structural basis for understanding the mechanism by which Siah family proteins
      interact with partner proteins such as SIP.

PMID- 12421810
TI  - Observation of an arsenic adduct in an acetyl esterase crystal structure.
AB  - The crystal structures of an acetyl esterase, HerE, and its complex with an
      inhibitor dimethylarsinic acid have been determined at 1.30- and 1.45-A
      resolution, respectively. Although the natural substrate for the enzyme is
      unknown, HerE hydrolyzes the acetyl groups from heroin to yield morphine and from
      phenyl acetate to yield phenol. Recently, the activity of the enzyme toward
      heroin has been exploited to develop a heroin biosensor, which affords higher
      sensitivity than other currently available detection methods. The crystal
      structure reveals a single domain with the canonical alpha/beta hydrolase fold
      with an acyl binding pocket that snugly accommodates the acetyl substituent of
      the substrate and three backbone amides that form a tripartite oxyanion hole. In
      addition, a covalent adduct was observed between the active site serine and
      dimethylarsinic acid, which inhibits the enzyme. This crystal structure provides
      the first example of an As-containing compound in a serine esterase active site
      and the first example of covalent modification of serine by arsenic. Thus, the
      HerE complex reveals the structural basis for the broad scope inhibition of
      serine hydrolases by As(V)-containing organic compounds.

PMID- 12421811
TI  - Cytoplasmic loop connecting helices IV and V of the melibiose permease from
      Escherichia coli is involved in the process of Na+-coupled sugar translocation.
AB  - Previous photolabeling and limited proteolysis studies suggested that one of the
      four basic residues (Arg-141) of the N-terminal cytoplasmic loop connecting
      helices IV and V (loop 4-5) of the melibiose permease (MelB) from Escherichia
      coli has a potential role in its symport function (Ambroise, Y., Leblanc, G., and
      Rousseau, B. (2000) Biochemistry 39, 1338-1345). A mutagenesis study of Arg-141
      and of the other three basic residues of loop 4-5 was undertaken to further
      examine this hypothesis. Cys replacement analysis indicated that Arg-141 and Arg
      149, but not Lys-138 and Arg-139, are essential for MelB transport activity.
      Replacement of Arg-141 by neutral residues (Cys or Gln) inactivated transport and
      energy-independent carrier-mediated flows of substrates (counterflow, efflux),
      whereas it had a limited effect on co-substrate binding. R141C sugar transport
      was partially rescued on reintroducing a positive charge with a charged and
      permeant thiol reagent. Whereas R149C was completely inactive, R149K and R149Q
      remained functional. Strikingly, introduction of an additional mutation in the C
      terminal helix X (Gly for Val-343) of R149C restored sugar transport. Impermeant
      thiol reagents inhibited R149C/V343G transport activity in right-side-out
      membrane vesicles and prevented sugar binding in a sugar-protected manner. All
      these data suggest that MelB loop 4-5 is close to the sugar binding site and that
      the charged residue Arg-141 is involved in the reaction of co-substrate
      translocation or substrate release in the inner compartment.

PMID- 12421812
TI  - HIV-1 antiviral activity of recombinant natural killer cell enhancing factors,
      NKEF-A and NKEF-B, members of the peroxiredoxin family.
AB  - CD8(+) T-cells are a major source for the production of non-cytolytic factors
      that inhibit HIV-1 replication. In order to characterize further these factors,
      we analyzed gene expression profiles of activated CD8(+) T-cells using a human
      cDNA expression array containing 588 human cDNAs. mRNA for the chemokine I-309
      (CCL1), the cytokines granulocyte-macrophage colony-stimulating factor and
      interleukin-13, and natural killer cell enhancing factors (NKEF) -A and -B were
      up-regulated in bulk CD8(+) T-cells from HIV-1 seropositive individuals compared
      with seronegative individuals. Recombinant NKEF-A and NKEF-B inhibited HIV-1
      replication when exogenously added to acutely infected T-cells at an ID(50) (dose
      inhibiting HIV-1 replication by 50%) of approximately 130 nm (3 microg/ml).
      Additionally, inhibition against dual-tropic simian immunodeficiency virus and
      dual-tropic simian-human immunodeficiency virus was found. T-cells transfected
      with NKEF-A or NKEF-B cDNA were able to inhibit 80-98% HIV-1 replication in
      vitro. Elevated plasma levels of both NKEF-A and NKEF-B proteins were detected in
      23% of HIV-infected non-treated individuals but not in persons treated with
      highly active antiviral therapy or uninfected persons. These results indicate
      that the peroxiredoxin family members NKEF-A and NKEF-B are up-regulated in
      activated CD8(+) T-cells in HIV infection, and suggest that these antioxidant
      proteins contribute to the antiviral activity of CD8(+) T-cells.

PMID- 12421813
TI  - Underproduction of sigma 70 mimics a stringent response. A proteome approach.
AB  - When Escherichia coli cells enter stationary phase due to carbon starvation the
      synthesis of ribosomal proteins is rapidly repressed. In a DeltarelA DeltaspoT
      mutant, defective in the production of the alarmone guanosine tetraphosphate
      (ppGpp), this regulation of the levels of the protein synthesizing system is
      abolished. Using a proteomic approach we demonstrate that the production of the
      vast majority of detected E. coli proteins are decontrolled during carbon
      starvation in the DeltarelA DeltaspoT strain and that the starved cells behave as
      if they were growing exponentially. In addition we show that the inhibition of
      ribosome synthesis by the stringent response can be qualitatively mimicked by
      artificially lowering the levels of the housekeeping sigma factor, sigma(70). In
      other words, genes encoding the protein-synthesizing system are especially
      sensitive to reduced availability of sigma(70) programmed RNA polymerase. This
      effect is not dependent on ppGpp since lowering the levels of sigma(70) gives a
      similar but less pronounced effect in a ppGpp(0) strain. The data is discussed in
      view of the models advocating for a passive control of gene expression during
      stringency based on alterations in RNA polymerase availability.

PMID- 12421814
TI  - Promoter architecture modulates CFTR exon 9 skipping.
AB  - Using hybrid minigene experiments, we have investigated the role of the promoter
      architecture on the regulation of two alternative spliced exons, cystic fibrosis
      transmembrane regulator (CFTR) exon 9 and fibronectin extra domain-A (EDB). A
      specific alternative splicing pattern corresponded to each analyzed promoter.
      Promoter-dependent sensitivity to cotransfected regulatory splicing factor
      SF2/ASF was observed only for the CFTR exon 9, whereas that of the EDB was
      refractory to promoter-mediated regulation. Deletion in the CFTR minigene of the
      downstream intronic splicing silencer element binding SF2/ASF abolished the
      specific promoter-mediated response to this splicing factor. A systematic
      analysis of the regulatory cis-acting elements showed that in the presence of
      suboptimal splice sites or by deletion of exonic enhancer elements the promoter
      dependent sensitivity to splicing factor-mediated inhibition was lost. However,
      the basal regulatory effect of each promoter was preserved. The complex
      relationships between the promoter-dependent sensitivity to SF2 modulated by the
      exon 9 definition suggest a kinetic model of promoter-dependent alternative
      splicing regulation that possibly involves differential RNA polymerase II
      elongation.

PMID- 12421815
TI  - The farnesoid X-receptor is an essential regulator of cholesterol homeostasis.
AB  - To address the importance of the farnesoid X-receptor (FXR; NR1H4) for normal
      cholesterol homeostasis, we evaluated the major pathways of cholesterol
      metabolism in the FXR-deficient (-/-) mouse model. Compared with wild-type, FXR(
      /-) mice have increased plasma high density lipoprotein (HDL) cholesterol and a
      markedly reduced rate of plasma HDL cholesterol ester clearance. Concomitantly,
      FXR(-/-) mice exhibit reduced expression of hepatic genes involved in reverse
      cholesterol transport, most notably, that for scavenger receptor BI. FXR(-/-)
      mice also have increased: (i) plasma non-HDL cholesterol and triglyceride levels,
      (ii) apolipoprotein B-containing lipoprotein synthesis, and (iii) intestinal
      cholesterol absorption. Surprisingly, biliary cholesterol elimination was
      increased in FXR(-/-) mice, despite decreased expression of hepatic genes thought
      to be involved in this process. These data demonstrate that FXR is a critical
      regulator of normal cholesterol metabolism and that genetic changes affecting FXR
      function have the potential to be pro-atherogenic.

PMID- 12421816
TI  - Peroxisome proliferator-activated receptor gamma (PPARgamma ) as a molecular
      target for the soy phytoestrogen genistein.
AB  - The principal soy phytoestrogen genistein has an array of biological actions. It
      binds to estrogen receptor (ER) alpha and beta and has ER-mediated estrogenic
      effects. In addition, it has antiestrogenic effects as well as non-ER-mediated
      effects such as inhibition of tyrosine kinase. Because of its complex biological
      actions, the molecular mechanisms of action of genistein are poorly understood.
      Here we show that genistein dose-dependently increases estrogenic transcriptional
      activity in mesenchymal progenitor cells, but its biological effects on
      osteogenesis and adipogenesis are different. At low concentrations (< or =1
      microm), genistein acts as estrogen, stimulating osteogenesis and inhibiting
      adipogenesis. At high concentrations (>1 microm), however, genistein acts as a
      ligand of PPARgamma, leading to up-regulation of adipogenesis and down-regulation
      of osteogenesis. Transfection experiments show that activation of PPARgamma by
      genistein at the micromolar concentrations down-regulates its estrogenic
      transcriptional activity, while activation of ERalpha or ERbeta by genistein down
      regulates PPARgamma transcriptional activity. Genistein concurrently activates
      two different transcriptional factors, ERs and PPARgamma, which have opposite
      effects on osteogenesis or adipogenesis. As a result, the balance between
      activated ERs and PPARgamma determines the biological effects of genistein on
      osteogenesis and adipogenesis. Our findings may explain distinct effects of
      genistein in different tissues.

PMID- 12421817
TI  - Direct association of p300 with unmodified H3 and H4 N termini modulates p300
      dependent acetylation and transcription of nucleosomal templates.
AB  - The nature of histone acetylation events in active chromatin is an important
      issue in transcriptional regulation. We have systematically analyzed the ability
      of p300, either alone or in response to an interacting activator, to acetylate
      specific recombinant histones in the context of free histones, histone octamers,
      or nucleosomal arrays. Our results indicate that p300 has an intrinsic ability to
      acetylate all core histones but that the level and specificity of histone
      acetylation is indeed context-dependent. Thus, H3 and H4 are preferentially
      acetylated in free octamers, whereas all histones are nearly equally acetylated,
      in an activator-dependent manner, in chromatin. Moreover, H3 and H4 show H2A and
      H2B tail-independent acetylation in chromatin, whereas maximal H2A and H2B
      acetylation in this context is dependent upon H3 and H4 tails (but not their
      acetylation). In further support of an apparent intrinsic preference of p300 for
      the H3 and H4 tails, as well as an important role for direct interactions of p300
      with unacetylated H3 and H4 tails in both acetylation and transcription, we have
      shown that p300 selectively acetylates isolated H3 and H4 tails, that p300
      strongly and selectively binds to free unacetylated H3 and H4 tails, and that
      p300-mediated acetylation of nucleosomal histones and transcriptional activation
      are selectively inhibited by isolated (unacetylated) H3 and H4 tails.

PMID- 12421818
TI  - The role of the alarmone (p)ppGpp in sigma N competition for core RNA polymerase.
AB  - Some promoters, including the DmpR-controlled sigma(N)-dependent Po promoter, are
      effectively rendered silent in cells lacking the nutritional alarmone (p)ppGpp.
      Here we demonstrate that four mutations within the housekeeping sigma(D)-factor
      can restore sigma(N)-dependent Po transcription in the absence of (p)ppGpp. Using
      both in vitro and in vivo transcription competition assays, we show that all the
      four sigma(D) mutant proteins are defective in their ability to compete with
      sigma(N) for available core RNA polymerase and that the magnitude of the defect
      reflects the hierarchy of restoration of transcription from Po in (p)ppGpp
      deficient cells. Consistently, underproduction of sigma(D) or overproduction of
      the anti-sigma(D) protein Rsd were also found to allow (p)ppGpp-independent
      transcription from the sigma(N)-Po promoter. Together with data from the direct
      effects of (p)ppGpp on sigma(N)-dependent Po transcription and sigma-factor
      competition, the results support a model in which (p)ppGpp serves as a master
      global regulator of transcription by differentially modulating alternative sigma
      factor competition to adapt to changing cellular nutritional demands.

PMID- 12421819
TI  - A functional role for nicotine in Bcl2 phosphorylation and suppression of
      apoptosis.
AB  - Nicotine is not only a major component in tobacco but is also a survival agonist
      that inhibits apoptosis induced by diverse stimuli including chemotherapeutic
      drugs. However, the intracellular mechanism(s) involved in nicotine suppression
      of apoptosis is unclear. Bcl2 is a potent antiapoptotic protein and tumor
      promotor that is expressed in both small cell lung cancer (SCLC) and non-small
      cell lung cancer (NSCLC) cells. It is possible that nicotine may regulate Bcl2 to
      stimulate cell survival. Here we report that nicotine can induce Bcl2
      phosphorylation exclusively at the serine 70 site in association with prolonged
      survival of SCLC H82 cells expressing wild-type but not the phosphorylation
      deficient S70A mutant Bcl2 after treatment with chemotherapeutic agents (i.e.
      cisplatin or VP-16). Nicotine induces activation of PKC alpha and the MAPKs ERK1
      and ERK2, which are physiological Bcl2 kinases. Furthermore, ET-18-OCH3, a
      specific phospholipase C (PLC) inhibitor, blocks nicotine-stimulated Bcl2
      phosphorylation and promotes apoptosis, suggesting that PLC may be involved in
      nicotine activation of Bcl2 kinases. Using a genetic approach, the gain-of
      function S70E mutant, which mimics Ser(70) site phosphorylation in the flexible
      loop domain, potently enhances chemoresistance in SCLC cells. Thus, nicotine
      induced cell survival results, at least in part, from a mechanism that involves
      Bcl2 phosphorylation. Therefore, novel therapeutic strategies for lung cancer in
      which Bcl2 is expressed may be used to abrogate the anti-apoptotic activity of
      Bcl2 by inhibiting multiple upstream nicotine-activated pathways.

PMID- 12421820
TI  - Acetylation of p53 inhibits its ubiquitination by Mdm2.
AB  - In response to DNA damage, the activity of the p53 tumor suppressor is modulated
      by protein stabilization and post-translational modifications including
      acetylation. Interestingly, both acetylation and ubiquitination can modify the
      same lysine residues at the C terminus of p53, implicating a role of acetylation
      in the regulation of p53 stability. However, the direct effect of acetylation on
      Mdm2-mediated ubiquitination of p53 is still lacking because of technical
      difficulties. Here, we have developed a method to obtain pure acetylated p53
      proteins from cells, and by using an in vitro purified system, we provide the
      direct evidence that acetylation of the C-terminal domain is sufficient to
      abrogate its ubiquitination by Mdm2. Importantly, even in the absence of DNA
      damage, acetylation of the p53 protein is capable of reducing the ubiquitination
      levels and extending its half-life in vivo. Moreover, we also show that
      acetylation of p53 can affect its ubiquitination through other mechanisms in
      addition to the site competition. This study has significant implications
      regarding a general mechanism by which protein acetylation modulates
      ubiquitination-dependent proteasome proteolysis.

PMID- 12421821
TI  - Deletion of a single amino acid residue from different 4-coumarate:CoA ligases
      from soybean results in the generation of new substrate specificities.
AB  - Plant 4-coumarate:coenzyme A ligases, acyl-CoA ligases, peptide synthetases, and
      firefly luciferases are grouped in one family of AMP-binding proteins. These
      enzymes do not only use a common reaction mechanism for the activation of
      carboxylate substrates but are also very likely marked by a similar functional
      architecture. In soybean, four 4-coumarate:CoA ligases have been described that
      display different substrate utilization profiles. One of these (Gm4CL1)
      represented an isoform that was able to convert highly ring-substituted cinnamic
      acids. Using computer-based predictions of the conformation of Gm4CL1, a peptide
      motif was identified and experimentally verified to exert a critical influence on
      the selectivity toward differently ring-substituted cinnamate substrates.
      Furthermore, one unique amino acid residue present in the other isoenzymes of
      soybean was shown to be responsible for the incapability to accommodate highly
      substituted substrates. The deletion of this residue conferred the ability to
      activate sinapate and, in one case, also 3,4-dimethoxy cinnamate and was
      accompanied by a significantly better affinity for ferulate. The engineering of
      the substrate specificity of the critical enzymes that activate the common
      precursors of a variety of phenylpropanoid-derived secondary metabolites may
      offer a convenient tool for the generation of transgenic plants with desirably
      modified metabolite profiles.

PMID- 12421822
TI  - Targeted disruption of the osteoblast/osteocyte factor 45 gene (OF45) results in
      increased bone formation and bone mass.
AB  - We have previously described osteoblast/osteocyte factor 45 (OF45), a novel bone
      specific extracellular matrix protein, and demonstrated that its expression is
      tightly linked to mineralization and bone formation. In this report, we have
      cloned and characterized the mouse OF45 cDNA and genomic region. Mouse OF45 (also
      called MEPE) was similar to its rat orthologue in that its expression was
      increased during mineralization in osteoblast cultures and the protein was highly
      expressed within the osteocytes that are imbedded within bone. To further
      determine the role of OF45 in bone metabolism, we generated a targeted mouse line
      deficient in this protein. Ablation of OF45 resulted in increased bone mass. In
      fact, disruption of only a single allele of OF45 caused significantly increased
      bone mass. In addition, knockout mice were resistant to aging-associated
      trabecular bone loss. Cancellous bone histomorphometry revealed that the
      increased bone mass was the result of increased osteoblast number and osteoblast
      activity with unaltered osteoclast number and osteoclast surface in knockout
      animals. Consistent with the bone histomorphometric results, we also determined
      that OF45 knockout osteoblasts produced significantly more mineralized nodules in
      ex vivo cell cultures than did wild type osteoblasts. Osteoclastogenesis and bone
      resorption in ex vivo cultures was unaffected by OF45 mutation. We conclude that
      OF45 plays an inhibitory role in bone formation in mouse.

PMID- 12421823
TI  - Autocrine transforming growth factor-beta signaling mediates Smad-independent
      motility in human cancer cells.
AB  - Transforming growth factor-beta (TGF-beta) is a pleiotropic growth factor that
      plays a critical role in modulating cell growth, differentiation, and plasticity.
      There is increasing evidence that after cells lose their sensitivity to TGF-beta
      mediated growth inhibition, autocrine TGF-beta signaling may potentially promote
      tumor cell motility and invasiveness. To understand the molecular mechanisms by
      which autocrine TGF-beta may selectively contribute to tumor cell motility, we
      have generated MDA-MB-231 breast cancer cells stably expressing a kinase-inactive
      type II TGF-beta receptor (T beta RII-K277R). Our data indicate that T beta RII
      K277R is expressed, can associate with the type I TGF-beta receptor, and block
      both Smad-dependent and -independent signaling pathways activated by TGF-beta. In
      addition, wound closure and transwell migration assays indicated that the basal
      migratory potential of T beta RII-K277R expressing cells was impaired. The
      impaired motility of T beta RII-K277R cells could be restored by reconstituting
      TGF-beta signaling with a constitutively active TGF-beta type I receptor
      (ALK5(TD)) but not by reconstituting Smad signaling with Smad2/4 or Smad3/4
      expression. In addition, the levels of ALK5(TD) expression sufficient to restore
      motility in the cells expressing T beta RII-K277R were associated with an
      increase in phosphorylation of Akt and extracellular signal-regulated kinase 1/2
      but not Smad2. These data indicate that different signaling pathways require
      different thresholds of TGF-beta activation and suggest that TGF-beta promotes
      motility through mechanisms independent of Smad signaling, possibly involving
      activation of the phosphatidylinositol 3-kinase/Akt and/or mitogen-activated
      protein kinase pathways.

PMID- 12421824
TI  - Conformational switching and fibrillogenesis in the amyloidogenic fragment of
      apolipoprotein a-I.
AB  - The N-terminal portion of apolipoprotein A-I corresponding to the first 93
      residues has been identified as the main component of apolipoprotein A-I fibrils
      in a form of systemic amyloidosis. We have been able to characterize the process
      of conformational switching and fibrillogenesis in this fragment of
      apolipoprotein A-I purified directly from ex vivo amyloid material. The peptide
      exists in an unstructured form in aqueous solution at neutral pH. The
      acidification of the solution provokes a collapse into a more compact,
      intermediate state and the transient appearance of a helical conformation that
      rapidly converts to a stable, mainly beta-structure in the fibrils. The
      transition from helical to sheet structure occurs concomitantly with peptide self
      aggregation, and fibrils are detected after 72 h. The alpha-helical conformation
      is induced by the addition of trifluoroethanol and phospholipids. Interaction of
      the amyloidogenic polypeptide with phospholipids prevents the switching from
      helical to beta-sheet form and inhibits fibril formation. The secondary structure
      propensity of the apolipoprotein A-I fragment appears poised between helix and
      the beta-sheet. These findings reinforce the idea of a delicate balance between
      natively stabilizing interactions and fatally stabilizing interactions and stress
      the importance of cellular localization and environment in the maintenance of
      protein conformation.

PMID- 12421825
TI  - Proximal events in signaling by plasma membrane estrogen receptors.
AB  - Estradiol (E2) rapidly stimulates signal transduction from plasma membrane
      estrogen receptors (ER) that are G protein-coupled. This is reported to occur
      through the transactivation of the epidermal growth factor receptor (EGFR) or
      insulin-like growth factor-1 receptor, similar to other G protein-coupled
      receptors. Here, we define the signaling events that result in EGFR and ERK
      activation. E2-stimulated ERK required ER in breast cancer and endothelial cells
      and was substantially prevented by expression of a dominant negative EGFR or by
      tyrphostin AG1478, a specific inhibitor for EGFR tyrosine kinase activity.
      Transactivation/phosphorylation of EGFR by E2 was dependent on the rapid
      liberation of heparin-binding EGF (HB-EGF) from cultured MCF-7 cells and was
      blocked by antibodies to this ligand for EGFR. Expression of dominant negative
      mini-genes for Galpha(q) and Galpha(i) blocked E2-induced, EGFR-dependent ERK
      activation, and Gbetagamma also contributed. G protein activation led to
      activation of matrix metalloproteinases (MMP)-2 and -9. This resulted from Src
      induced MMP activation, implicated using PP2 (Src family kinase inhibitor) or the
      expression of a dominant negative Src protein. Antisense oligonucleotides to MMP
      2 and MMP-9 or ICI 182780 (ER antagonist) each prevented E2-induced HB-EGF
      liberation and ERK activation. E2 also induced AKT up-regulation in MCF-7 cells
      and p38beta MAP kinase activity in endothelial cells, blocked by an MMP
      inhibitor, GM6001, and tyrphostin AG1478. Targeting of only the E domain of
      ERalpha to the plasma membrane resulted in MMP activation and EGFR
      transactivation. Thus, specific G proteins mediate the ability of E2 to activate
      MMP-2 and MMP-9 via Src. This leads to HB-EGF transactivation of EGFR and
      signaling to multiple kinase cascades in several target cells for E2. The E
      domain is sufficient to enact these events, defining additional details of the
      important cross-talk between membrane ER and EGFR in breast cancer.

PMID- 12421826
TI  - Specific and potent RNA interference in terminally differentiated myotubes.
AB  - Double-stranded RNA (dsRNA) interference is a potent mechanism for sequence
      specific silencing of gene expression and represents an invaluable approach for
      investigating gene function in normal and diseased states as well as for drug
      target validation. Here, we report that skeletal muscle myoblasts and terminally
      differentiated myotubes are susceptible to RNA interference. We employed an
      approach in which dsRNA is generated by cellular transcription from plasmids
      containing long (1 kilobase) inverted DNA repeats of the target gene rather than
      using dsRNA synthesized in vitro. We show that gene silencing by this method is
      effective for endogenously expressed genes as well as for exogenous reporter
      genes. An analysis of the expression of several endogenous genes and exogenous
      reporters demonstrates that the silencing effect is specific for the target gene
      containing sequences within the inverted repeat. Our method eliminates the need
      to chemically synthesize dsRNA and is not accompanied by global repression of
      gene expression. Furthermore, we show for the first time that sequence-specific
      dsRNA-mediated gene silencing is possible in differentiated, multinucleated
      skeletal muscle myotubes. These findings provide an important molecular tool for
      the examination of protein function in terminally differentiated muscle cells and
      provide alternative approaches for generating disease models.

PMID- 12421827
TI  - Transcriptional activation of the proglucagon gene by lithium and beta-catenin in
      intestinal endocrine L cells.
AB  - The proglucagon gene encodes several peptide hormones that regulate blood glucose
      homeostasis, growth of the small intestine, and satiety. Among them, glucagon
      like peptide 1 (GLP-1) lowers blood glucose levels in patients with diabetes and
      inhibits eating and drinking in fasted rats. Although proglucagon transcription
      and GLP-1 synthesis were shown to be activated by forskolin and other protein
      kinase A (PKA) activators, deleting or mutating the cAMP-response element (CRE)
      only moderately attenuates the proglucagon gene promoter in response to PKA
      activation. Therefore, PKA may activate proglucagon transcription via a mechanism
      independent of the CRE motif. Recently, PKA was shown to phosphorylate and
      inactivate GSK-3beta, a key mediator in the Wnt signaling pathway. We show here
      that lithium, an inhibitor of GSK-3beta, activates proglucagon gene transcription
      and stimulates GLP-1 synthesis in an intestinal endocrine L cell line, GLUTag.
      The activation was also observed in primary fetal rat intestinal cell (FRIC)
      cultures, but not in a pancreatic A cell line. Co-transfection of beta-catenin, a
      downstream effector of GSK-3beta activities, activated the proglucagon gene
      promoter without a CRE. Furthermore, forskolin and 8-Br-cAMP phosphorylated GSK
      3beta at serine 9 in intestinal proglucagon-producing cells, and both lithium and
      forskolin induced the accumulation of free beta-catenin in these cell lines.
      These observations indicate that the proglucagon gene is among the targets of the
      Wnt signaling pathway.

PMID- 12421828
TI  - Cytoskeleton interactions involved in the assembly and function of glycoprotein
      80 adhesion complexes in dictyostelium.
AB  - Adhesion complexes typically assemble from clustered receptors that link to the
      cytoskeleton via cytoplasmic adapter proteins. However, it is unclear how
      phospholipid-anchored adhesion molecules, such as the Dictyostelium receptor
      gp80, interact with the cytoskeleton. gp80 has been found to form adhesion
      complexes from raftlike membrane domains, which can be isolated as a Triton X-100
      insoluble floating fraction (TIFF). We report here that the actin-binding protein
      ponticulin mediates TIFF-cytoskeleton interactions. Analysis of gp80-null cells
      revealed that these interactions were minimal in the absence of gp80. During
      development, gp80 was required to enhance these interactions as its adhesion
      complexes assembled. Whereas ponticulin and gp80 could partition independently
      into TIFF, gp80 was shown to recruit ponticulin to cell-cell contacts and to
      increase its partitioning into TIFF. However, these proteins did not co
      immunoprecipitate. Furthermore, sterol sequestration abrogated the association of
      ponticulin with TIFF without affecting gp80, suggesting that sterols may mediate
      the interactions between ponticulin and gp80. In ponticulin-null cells, large
      gp80 adhesion complexes assembled in the absence of ponticulin despite the lack
      of cytoskeleton association. We propose that such nascent gp80 adhesion complexes
      produce expanded raftlike domains that recruit ponticulin and thereby establish
      stable cytoskeleton interactions to complete the assembly process.

PMID- 12421829
TI  - Ubiquitination and proteasomal degradation of endogenous and exogenous inositol
      1,4,5-trisphosphate receptors in alpha T3-1 anterior pituitary cells.
AB  - In alphaT3-1 mouse anterior pituitary gonadotropes, chronic activation of
      gonadotropin-releasing hormone (GnRH) receptors causes inositol 1,4,5
      trisphosphate (InsP(3)) receptor down-regulation (Willars, G. B., Royall, J. E.,
      Nahorski, S. R., El-Gehani, F., Everest, H. and McArdle, C. A. (2001) J. Biol.
      Chem. 276, 3123-3129). In the current study, we sought to define the mechanism
      behind this adaptive response. We show that GnRH induces a rapid and dramatic
      increase in InsP(3) receptor polyubiquitination and that proteasome inhibitors
      block InsP(3) receptor down-regulation and cause the accumulation of
      polyubiquitinated receptors. Thus, the ubiquitin/proteasome pathway is active in
      alphaT3-1 cells, and GnRH regulates the levels of InsP(3) receptors via this
      mechanism. Given these findings and further characterization of this system, we
      also examined the possibility that alphaT3-1 cells could be used to examine the
      ubiquitination of exogenous InsP(3) receptors introduced by cDNA transfection.
      This was found to be the case, since exogenous wild-type InsP(3) receptors, but
      not binding-defective mutant receptors, were polyubiquitinated in a GnRH
      dependent manner, and agents that inhibited the polyubiquitination of endogenous
      receptors also inhibited the polyubiquitination of exogenous receptors. Further,
      we used this system to determine whether phosphorylation was involved in
      triggering InsP(3) receptor polyubiquitination. This was not the case, since
      mutation of serine residues 1588 and 1755 (the predominant phosphorylation sites
      in the type I receptor) did not inhibit polyubiquitination. In total, these data
      show that the ubiquitin/proteasome pathway is active in anterior pituitary cells,
      that this pathway targets both endogenous and exogenous InsP(3) receptors in GnRH
      stimulated alphaT3-1 cells, and that, in contrast to the situation for many other
      substrates, phosphorylation does not trigger InsP(3) receptor polyubiquitination.

PMID- 12421830
TI  - Sp1 transactivation of the TCL1 oncogene.
AB  - Cis-regions and trans-factors controlling TCL1 oncogene expression are not known.
      We identified the functional TCL1 promoter by mapping four transcriptional start
      sites 24-30 bp downstream of a TATA box. A 424-bp fragment upstream of the major
      start site showed robust promoter activity comparable with SV40 in both TCL1
      expressing and non-expressing cell lines. Additional constructs spanning 10 kb
      upstream and 20 kb downstream of the start site showed only modest increases in
      reporter activity indicating that TCL1 expression is primarily controlled by the
      promoter. Ten putative Sp1-binding sites were identified within 300 bp of the
      start site, and three of these specifically bound Sp1. A dose-dependent
      transactivation of the TCL1 promoter with Sp1 addition in Sp1-negative Drosophila
      SL2 cells was observed, and mutation of the three identified Sp1-binding sites
      significantly repressed reporter gene expression in 293T cells, confirming a key
      role for Sp1 in activating the TCL1 promoter in vivo. In TCL1 silent cell lines,
      CpG DNA methylation was rarely observed at functional Sp1 sites, and methylation
      of a previously reported NotI restriction site was associated with dense CpG
      methylation rather than endogenous TCL1 gene silencing. Together, these results
      indicate that Sp1 mediates transactivation of the TCL1 core promoter and that
      TCL1 gene silencing is not dependent on mechanisms involving Sp1 and NotI site
      methylation.

PMID- 12421831
TI  - An extremely potent inhibitor of xanthine oxidoreductase. Crystal structure of
      the enzyme-inhibitor complex and mechanism of inhibition.
AB  - TEI-6720 (2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylic acid) is an
      extremely potent inhibitor of xanthine oxidoreductase. Steady state kinetics
      measurements exhibit mixed type inhibition with K(i) and K(i)' values of 1.2 +/-
      0.05 x 10(-10) m and 9 +/- 0.05 x 10(-10) m, respectively. Fluorescence-monitored
      titration experiments showed that TEI-6720 bound very tightly to both the active
      and the inactive desulfo-form of the enzyme. The dissociation constant determined
      for the desulfo-form was 2 +/- 0.03 x 10(-9) m; for the active form, the
      corresponding number was too low to allow accurate measurements. The crystal
      structure of the active sulfo-form of milk xanthine dehydrogenase complexed with
      TEI-6720 and determined at 2.8-A resolution revealed the inhibitor molecule bound
      in a long, narrow channel leading to the molybdenum-pterin active site of the
      enzyme. It filled up most of the channel and the immediate environment of the
      cofactor, very effectively inhibiting the activity of the enzyme through the
      prevention of substrate binding. Although the inhibitor did not directly
      coordinate to the molybdenum ion, numerous hydrogen bonds as well as hydrophobic
      interactions with the protein matrix were observed, most of which are also used
      in substrate recognition.

PMID- 12421833
TI  - Unexpected down-regulation of the hIK1 Ca2+-activated K+ channel by its opener 1
      ethyl-2-benzimidazolinone in HaCaT keratinocytes. Inverse effects on cell growth
      and proliferation.
AB  - We used a combination of electrophysiological and cell and molecular biological
      techniques to study the regulation and functional role of the intermediate
      conductance Ca(2+)-activated K(+) channel, hIK1, in HaCaT keratinocytes. When we
      incubated cells with the hIK1 opener, 1-ethyl-2-benzimidazolinone (1-EBIO), to
      investigate the cellular consequences of prolonged channel activity, an
      unexpected down-regulation of channels occurred within a few hours. The same
      effect was produced by the hIK1 openers chlorzoxazone and zoxazolamine and was
      also observed in a different cell line (C6 glioma cells). After 3 days of
      treatment with 1-EBIO, mRNA levels of hIK1 were substantially diminished and no
      channel activity was detected. Down-regulation of hIK1 was accompanied by a loss
      of mitogenic activity and a strong increase in cell size. After withdrawal of 1
      EBIO, hIK1 mRNA and channel activity fully recovered and the cells resumed
      mitogenic activity. Our data present evidence for a novel feedback mechanism of
      hIK1 expression that appears to result from the paradoxical action of its
      pharmacological activator during prolonged application. Because the down
      regulation of hIK1 bears immediate significance on the biological fate of
      keratinocytes, 1-EBIO and related compounds might emerge as potent tools to
      influence the proliferation of various non-excitable cells endowed with IK
      channels.

PMID- 12421832
TI  - Complex of pregnancy-associated plasma protein-A and the proform of eosinophil
      major basic protein. Disulfide structure and carbohydrate attachment.
AB  - Pregnancy-associated plasma protein-A (PAPP-A) is a metzincin superfamily
      metalloproteinase responsible for cleavage of insulin-like growth factor-binding
      protein-4, thus causing release of bound insulin-like growth factor. PAPP-A is
      secreted as a dimer of 400 kDa but circulates in pregnancy as a disulfide-bound
      500-kDa 2:2 complex with the proform of eosinophil major basic protein (pro-MBP),
      recently shown to function as a proteinase inhibitor of PAPP-A. Except for PAPP
      A2, PAPP-A does not share global similarity with other proteins. Three lin-notch
      (LNR or LIN-12) modules and five complement control protein modules (also known
      as SCR modules) have been identified in PAPP-A by sequence similarity with other
      proteins, but no data are available that allow unambiguous prediction of
      disulfide bonds of these modules. To establish the connectivities of cysteine
      residues of the PAPP-A.pro-MBP complex, biochemical analyses of peptides derived
      from purified protein were performed. The PAPP-A subunit contains a total of 82
      cysteine residues, of which 81 have been accounted for. The pro-MBP subunit
      contains 12 cysteine residues, of which 10 have been accounted for. Within the
      2:2 complex, PAPP-A is dimerized by a single disulfide bond; pro-MBP is dimerized
      by two disulfides, and each PAPP-A subunit is connected to a pro-MBP subunit by
      two disulfide bonds. All other disulfides are intrachain bridges. We also show
      that of 13 potential sites for N-linked carbohydrate substitution of the PAPP-A
      subunit, 11 are occupied. The large number of disulfide bonds of the PAPP-A.pro
      MBP complex imposes many restraints on polypeptide folding, and knowledge of the
      disulfide pattern of PAPP-A will facilitate structural studies based on
      recombinant expression of individual, putative PAPP-A domains. Furthermore, it
      will allow rational experimental design of functional studies aimed at
      understanding the formation of the PAPP-A.pro-MBP complex, as well as the
      inhibitory mechanism of pro-MBP.

PMID- 12421834
TI  - Quantitative indicators from a food expenditure survey can be used to target the
      food insecure in South Africa.
AB  - Recent work on assessing household food insecurity has focused mainly on
      experiential-based measures using qualitative survey questions. In this paper, we
      employed two quantitative measures to estimate prevalence rates for household
      food insecurity in South Africa. One measure, termed food poverty, assessed
      whether the amount spent by a household on food was inadequate to purchase a low
      cost food plan. Low energy availability assessed whether the food energy
      available to a household, through its purchases and home production, was less
      than the sum of its members' recommended energy intakes. The 1995 Income and
      Expenditure Survey, a large representative survey of South African households (n
      = 28,704), was used for this secondary data analysis. Results showed that 43% of
      households were in food poverty in October 1995, and 55% had a low energy
      availability. These indicators allowed classification of households into four
      groups: food poverty only; low energy availability only; food insecure on both
      measures; and food secure. These groups differed on various aspects of household
      food consumption, suggesting that these indicators can be used to target
      different types of interventions to meet specific needs. Both bivariate and
      multivariate analyses showed that households that were food insecure on both
      measures were more likely to be in rural areas, have low incomes or large
      household sizes, and be headed by Africans or individuals of mixed ancestry.
      These patterns of food insecurity were corroborated by previous research on
      income poverty and nutritional status, suggesting that food poverty and low
      energy availability are useful, quantitative indicators for assessing food
      insecurity in South Africa.

PMID- 12421835
TI  - Vitamin A supplementation of women postpartum and of their infants at
      immunization alters breast milk retinol and infant vitamin A status.
AB  - Vitamin A supplementation of lactating mothers and of infants at the time of
      diphtheria-pertussis-tetanus (DPT) and oral polio vaccine (OPV) immunizations
      have both been suggested as measures to prevent deficiency among infants. This
      multicenter randomized, double-blind, placebo-controlled trial was conducted in
      Ghana, India and Peru to determine the effect of maternal vitamin A
      supplementation on breast milk retinol and of maternal and infant supplementation
      on infant vitamin A status. Mothers in the intervention group received 60 mg
      vitamin A (as retinol palmitate) at 18-42 d postpartum; their infants were given
      7.5 mg three times, i.e., at 6, 10 and 14 wk of age with DPT and OPV
      immunizations. Mothers and infants in the comparison group received a placebo.
      Maternal supplementation resulted in higher breast milk retinol at 2 mo
      postpartum [difference in means 7.1, 95% confidence interval (CI), 3.4, 10.8
      nmol/g fat] and lower proportion of mothers with breast milk retinol < or = 28
      nmol/g fat (15.2 vs. 26.6%, 95% CI of difference -16.6, -4.1%). At 6 and 9 mo,
      maternal supplementation did not affect breast milk retinol or the proportion of
      mothers with low breast milk retinol. Vitamin A supplementation of the mothers
      and their infants reduced the proportion of infants with serum retinol < or = 0.7
      micro mol/L (30.4 vs. 37%, 95% CI of difference -13.7, 0.6%) and that with low
      vitamin A stores as indicated by the modified relative dose response (MRDR) >
      0.06 (44.2 vs. 52.9%, 95% CI of difference -16.6, -0.9%) at 6 mo. Supplementation
      had no effect at 9 mo. The beneficial effect of supplementation on breast milk
      retinol and infants' vitamin A status varied by site. It was greatest in India
      followed by Ghana and Peru. At the doses used, maternal supplementation improved
      breast milk retinol status at 2 mo (P < 0.001) and maternal and infant
      supplementation modestly increased (P = 0.03) infant vitamin A status at 6 mo of
      age. Additional strategies to improve vitamin A status of 6- to 9-mo-old infants
      must be considered.

PMID- 12421836
TI  - Iron supplementation affects growth and morbidity of breast-fed infants: results
      of a randomized trial in Sweden and Honduras.
AB  - Iron supplements are often prescribed during infancy but their benefits and risks
      have not been well documented. We examined whether iron supplements affect growth
      or morbidity of breast-fed infants. Full-term infants in Sweden (n = 101) and
      Honduras (n = 131) were randomly assigned to three groups at 4 mo of age: 1)
      placebo from 4 to 9 mo; 2) placebo from 4 to 6 mo and iron supplements [1 mg/(kg.
      d)] from 6 to 9 mo; or 3) iron supplements from 4 to 9 mo. All infants were
      exclusively or nearly exclusively breast-fed to 6 mo and continued to be breast
      fed to at least 9 mo. Growth was measured monthly and morbidity data were
      collected every 2 wk. Among the Swedish infants, gains in length and head
      circumference were significantly lower in those who received iron than in those
      given placebo from 4 to 9 mo. The same effect on length was seen in Honduras, but
      only at 4-6 mo among those with initial hemoglobin (Hb) > or =110 g/L. There was
      no significant main effect of iron supplementation on morbidity, nor any
      significant interaction between iron supplementation and site, but for diarrhea
      (with both sites combined), there was an interaction between iron supplementation
      and initial Hb. Among infants with Hb < 110 g/L at 4 mo, diarrhea was less common
      among those given iron than in those given placebo from 4-9 mo, whereas the
      opposite was true among those with Hb > or = 110 g/L (P < 0.05). We conclude that
      routine iron supplementation of breast-fed infants may benefit those with low Hb
      but may present risks for those with normal Hb.

PMID- 12421837
TI  - Oxidized fatty acids promote atherosclerosis only in the presence of dietary
      cholesterol in low-density lipoprotein receptor knockout mice.
AB  - Studies suggest that heated oils contribute to the presence of oxidized
      components in the circulating lipoproteins and to the development of
      atherosclerosis in animals. We evaluated the effects of 11-13 wk of consumption
      of a well defined dietary oxidized fatty acid, 13-hydroxylinoleic acid (13-HODE)
      (8 mg), on atherosclerotic lesion development and plasma cholesterol
      concentrations in mice fed diets varying in fat and cholesterol contents. LDL
      receptor knockout mice were used in two feeding studies. In study 1, oxidized
      fatty acid consumption in association with a high fat diet increased aortic
      lesion areas by >100% (P < 0.05). Surprisingly, oxidized fatty acid intake also
      tended to increase plasma total cholesterol (P = 0.12) and LDL cholesterol (P <
      0.05) as well as oxidative stress as measured by higher levels of autoantibodies
      to oxidatively modified proteins (P = 0.008). However, in mice fed a nonpurified
      diet, oxidized fatty acids were not atherogenic and may even have been
      beneficial, as indicated by a lower plasma triglyceride (TG) concentration (P <
      0.05). In study 2, mice were fed either a high fat, medium fat or low fat diet to
      evaluate whether the increase in aortic lesions due to oxidized fatty acid
      consumption in study 1 was a result of the associated higher plasma total and LDL
      cholesterol concentrations. In study 2, 13-HODE-treated mice in the medium and
      low fat diet groups but not those fed the high fat diet had larger
      atherosclerotic lesions (P < 0.05). Additionally, plasma total and LDL
      cholesterol as well as TG were not affected by HODE treatment. However, the total
      cholesterol:HDL cholesterol ratio was higher in treated mice (P < 0.05) and HDL
      cholesterol was lower in HODE-treated mice that were fed the low fat diet (P <
      0.05). Our results suggest that, in mice fed cholesterol, oxidized fatty acids
      may be atherogenic, both in terms of increased oxidative stress (as seen in study
      1) and by increasing the atherogenicity of the plasma cholesterol profile.

PMID- 12421838
TI  - Dietary fiber down-regulates colonic tumor necrosis factor alpha and nitric oxide
      production in trinitrobenzenesulfonic acid-induced colitic rats.
AB  - Previous studies have revealed the beneficial effects exerted by dietary fiber in
      human inflammatory bowel disease, which were associated with an increased
      production of SCFA in distal colon. The aim of the present study was to elucidate
      the probable mechanisms involved in the beneficial effects of a fiber
      supplemented diet (5% Plantago ovata seeds) in the trinitrobenzenesulfonic acid
      (TNBS) model of rat colitis, with special attention to its effects on the
      production of some of the mediators involved in the inflammatory response, such
      as tumor necrosis factor alpha (TNFalpha) and nitric oxide (NO). Rats were fed
      the fiber-supplemented diet for 2 wk before TNBS colitis induction and thereafter
      until colonic evaluation 1 wk later. The results obtained showed that dietary
      fiber supplementation facilitated recovery from intestinal insult as evidenced
      both histologically, by a preservation of intestinal cytoarchitecture, and
      biochemically, by a significant reduction in colonic myeloperoxidase activity and
      by restoration of colonic glutathione levels. This intestinal anti-inflammatory
      effect was associated with lower TNFalpha levels and lower NO synthase activity
      in the inflamed colon, showing significant differences when compared with
      nontreated colitic rats. Moreover, the intestinal contents from fiber-treated
      colitic rats showed a significantly higher production of SCFA, mainly butyrate
      and propionate. We conclude that the increased production of these SCFA may
      contribute to recovery of damaged colonic mucosa because they constitute
      substrates for the colonocyte and, additionally, that they can inhibit the
      production of proinflammatory mediators, such as TNFalpha and NO.

PMID- 12421839
TI  - Conjugated linoleic acid differentially modifies fatty acid composition in
      subcellular fractions of muscle and adipose tissue but not adiposity of
      postweaning pigs.
AB  - This study examined the interaction between conjugated linoleic acid (CLA) and
      dietary fat type on the enrichment of subcellular fractions, the Delta(9)
      desaturase index and adiposity in pigs. Early weaned piglets (n = 6/group) were
      fed for 35 d diets supplemented with 15 g/100 g diet beef tallow or corn oil, or
      12 g/100 g tallow or corn oil plus 3 g CLA. There were no effects of dietary fat
      or CLA on the mass of dissected skin, bone, muscle or adipose tissue of the 7th
      to 9th thoracic rib sections. Medial subcutaneous adipose tissue of pigs fed
      tallow had smaller adipocytes than that of pigs fed corn oil. The lateral
      subcutaneous site was unaffected by dietary fat type. Microsomes accumulated <50%
      the concentration of trans-10,cis-12, cis-11,trans-13, and cis-9,trans-11 CLA as
      membrane and nonmembrane fractions of adipose tissue and longissimus muscle.
      There was no evidence of preferential incorporation of any CLA isomer into any of
      the subcellular fractions. Addition of CLA to the diets reduced adipose tissue
      nonmembrane monounsaturated fatty acids (MUFA; g/100 g total fatty acids) by 15%
      in corn oil-fed pigs and by 19% in tallow-fed pigs. Total saturated fatty acids
      (SFA) were increased by CLA commensurately in this lipid fraction. This resulted
      in a reduced Delta(9) desaturase index [MUFA/(SFA + MUFA)] in the nonmembrane
      lipid fraction of pigs fed either the corn oil or tallow diets. Thus, in spite of
      marked effects on fatty acid composition and the Delta(9) desaturase index, CLA
      had no effect on adiposity in early weaned piglets fed high fat diets.

PMID- 12421840
TI  - Zinc transporters in the rat mammary gland respond to marginal zinc and vitamin A
      intakes during lactation.
AB  - Marginal intake of zinc and vitamin A is common during lactation and a deficiency
      of one micronutrient can result in a secondary deficiency of the other. However,
      the resistance of milk zinc (Zn) concentration to changes in dietary Zn or
      vitamin A indicates tight regulation of mammary gland Zn transport. Although
      several mammalian proteins have been identified and implicated in Zn transport,
      the mechanisms responsible for mammary gland Zn transport and their regulation by
      dietary Zn and vitamin A are unknown. In this study, we identified mammary gland
      Zn transporters and determined effects of marginal Zn and vitamin A intakes on
      their levels. Rats were fed a control [25 mg Zn/kg, 4 retinol equivalents
      (RE)/g], a low Zn (10 mg Zn/kg), a low vitamin A (0.4 RE/g), or a low Zn (10 mg
      Zn/kg) and vitamin A (0.4 RE/g) diet throughout lactation. ZnT-1, ZnT-2 and ZnT-4
      were identified in the mammary gland and localized to the serosal membrane (ZnT
      1) or intracellularly (ZnT-2 and ZnT-4) by immunostaining. Rats fed a low Zn or
      low vitamin A diet had lower ZnT-1 protein and higher ZnT-4 mRNA expression and
      protein levels compared with controls. There was a significant interaction
      between dietary Zn and vitamin A on zinc transporter mRNA expression and protein
      levels. Although total mammary gland Zn was not affected, mammary gland
      metallothionein levels were lower in rats fed low Zn and higher in rats fed low
      vitamin A, suggesting different mechanisms regulating zinc transporter levels.
      These results indicate that milk Zn level is maintained through coordinated
      regulation of mammary gland zinc transporters and documents an effect of vitamin
      A on zinc homeostasis at the molecular level during lactation.

PMID- 12421841
TI  - Supplementation of N-acetylcysteine normalizes lipopolysaccharide-induced nuclear
      factor kappaB activation and proinflammatory cytokine production during early
      rehabilitation of protein malnourished mice.
AB  - Increased sensitivity to septic shock has been reported in protein malnourished
      patients. In this study, we used an animal septic shock model to investigate
      effects of glutathione (GSH) levels on nuclear factor kappaB (NFkappaB)
      activation and proinflammatory cytokine production in protein malnutrition. We
      further investigated molecular mechanisms by which protein malnutrition
      influenced inflammatory responses. CD-1 mice were fed for 3 wk a normal protein
      (150 g/kg) diet or a protein-deficient (5 g/kg) diet, or for 2 wk a protein
      deficient diet followed by 1 wk of N-acetylcysteine (NAC) supplementation.
      Lipopolysaccharide (LPS) was injected intravenously, and liver was collected at
      0, 15 min, 1, 4, 24 and 48 h after LPS administration. Protein malnutrition
      significantly increased the activation of NFkappaB and transcription levels of
      its downstream genes interleukin-1beta and tumor necrosis factor-alpha. Peak
      NFkappaB activation was inversely associated with GSH levels (r = -0.939, P <
      0.0001) but positively correlated with the GSH disulfide/2GSH reduction potential
      (r = 0.944 P < 0.0001). We noted unusual NFkappaB p50/p50 homodimer translocation
      that was significantly elevated in tissue from protein malnourished mice, along
      with decreased peak levels of normal p65/p50 heterodimer translocation.
      Interestingly, mRNA levels of IkappaB-alpha were not affected by protein
      malnutrition. However, early supplementation of NAC to protein malnourished mice
      without replenishing with dietary protein restored GSH levels and reduction
      potential, and normalized NFkappaB activation and proinflammatory cytokine
      production. Taken together, these findings provide evidence supporting the role
      of GSH in NFkappaB activation and inflammatory response in protein malnutrition,
      and the use of NAC in early rehabilitation of protein malnutrition without a high
      protein diet.

PMID- 12421842
TI  - Antigen-driven murine CD4+ T lymphocyte proliferation and interleukin-2
      production are diminished by dietary (n-3) polyunsaturated fatty acids.
AB  - This study is the first to describe the impact of consuming a diet rich in (n-3)
      polyunsaturated fatty acids (PUFA) from fish oil on antigen-driven activation of
      naive CD4+ T lymphocytes. To accomplish this, we used lymphocytes isolated from T
      cell receptor (TCR) transgenic mice (i.e., DO11.10). A large portion of the T
      lymphocytes from these mice expresses a TCR specific for a peptide within the
      ovalbumin (OVA) molecule (OVA(323-339)). When this antigen is presented in the
      context of major histocompatibility complex I-A(d) with costimulation, these
      naive CD4+ T cells become activated, produce interleukin (IL)-2 and clonally
      expand. (n-3) PUFA enrichment was accomplished by feeding DO11.10 mice one of two
      nutritionally complete experimental diets that differed only in the source of
      fat: lard or menhaden fish oil [high in (n-3) PUFA]. After 2 wk of consuming the
      experimental diets, lymphocytes were isolated from the spleen of each mouse, then
      cultured in the presence of antigen (i.e., OVA(323-339)) or concanavalin A (Con
      A), a nonspecific, polyclonal T cell stimulus. IL-2 production and lymphocyte
      proliferation were determined after 48 and 72 h, respectively. Naive CD4+ T
      lymphocytes from fish oil-fed mice stimulated with antigen produced less IL-2 (
      approximately 33%; P < 0.001) and proliferated to a lesser extent ( approximately
      50%; P < 0.0001) than the same cells from lard-fed DO11.10 mice. When stimulated
      with Con A, (n-3) PUFA did not affect either proliferation or IL-2 production. In
      summary, we report for the first time that feeding mice a diet enriched with (n
      3) PUFA reduces in vitro antigen-stimulated production of IL-2 and subsequent
      proliferation of naive CD4+ T lymphocytes.

PMID- 12421843
TI  - Zinc deficiency in mice alters myelopoiesis and hematopoiesis.
AB  - Suboptimal nutriture causes leukopenia, but whether this is related to a
      modification in hematopoiesis is unknown. A 34-d period of zinc deficiency was
      used to obtain moderate and severely zinc-deficient (ZD) young adult mice whose
      bone marrow was evaluated for alterations in hematopoiesis, myelopoiesis and
      lymphopoiesis by flow cytometry. Expressions of CD31 (PECAM-1) and Ly-6C were
      used to identify changes in marrow population composition. Identity of marrow
      cells was confirmed with TER119, CD45R, Ly-6G and CD11b. Cells of the erythroid
      lineage declined as much as 60% depending on the degree of zinc deficiency,
      providing new insight into the early observations of clinicians that anemia
      accompanied ZD in humans. The lymphoid compartment also declined 50-70% with
      preferential losses among pre-B cells, an underlying cause of the lymphopenia
      that is a part of ZD, in which loss of pre-B cells was identified by CD43,CD45R,
      and immunoglobulin M. Conversely, cells of the myeloid lineage increased
      substantially in the marrow, both in proportion and absolute numbers in all ZD
      mice. Granulocytic cells increased 40-60%, whereas monocytic cells nearly doubled
      in ZD mice. These data suggest that there are important adaptations in
      hematopoietic functions as zinc becomes limiting. In the immune system, the
      precursors of phagocytic cells, which provide innate immunity, are protected,
      whereas precursors of lymphocytes, which provide adaptive immunity, are down
      regulated. These findings illuminate the unique response of the marrow to a
      nutritional stress.

PMID- 12421844
TI  - Improved vitamin B-6 status is positively related to lymphocyte proliferation in
      young women consuming a controlled diet.
AB  - To examine the effect of increased intake levels of vitamin B-6 (B-6) on
      lymphocyte proliferation and interleukin 2 (IL-2) concentration, young women (n =
      7) consumed a constant diet containing 1 mg (5.91 micro mol) B-6/d for a 7-d
      adjustment period, followed by three 14-d experimental periods during which the
      daily B-6 intake was 1.5, 2.1 and 2.7 mg (8.86, 12.41 and 15.95 micro mol)/d,
      respectively. Weekly fasting blood and daily 24-h urine samples were collected.
      Lymphocyte proliferation and IL-2 production were measured in response to
      phytohemagglutinin. Vitamin B-6 status improved with increased B-6 intake as
      measured by plasma pyridoxal 5'-phosphate (PLP) and urinary 4-pyridoxic acid.
      When subjects consumed 2.1 mg B-6/d for 7 d, lymphocyte proliferation increased
      by 35% (P < or = 0.05) compared with the mean value after consumption of 1.5 mg B
      6/d for 14 d. There was no further enhancement after an additional week of 2.1
      and 2.7 mg B-6/d for 2 wk. Lymphocyte proliferation was correlated (P < or =
      0.01) with vitamin B-6 intake (r = 0.757), plasma PLP (r = 0.456) and erythrocyte
      aminotransferase activities (r = -0.361). Plasma IL-2 concentration and in vitro
      production did not change throughout the study, although five of seven subjects
      showed increases with intakes of 2.1 and 2.7 mg B-6/d, respectively, compared
      with the 1.5 mg/d intake. Concentrations of PLP in peripheral blood mononuclear
      cells were correlated (r = 0.357, P < or = 0.01) with plasma PLP, but not with
      proliferation. These results show that improving vitamin B-6 status by consuming
      a B-6 intake higher than the current Recommended Dietary Allowance enhances
      lymphocyte proliferation.

PMID- 12421845
TI  - Diindolylmethane alters gene expression in human keratinocytes in vitro.
AB  - Indole-3-carbinol (I3C) and its dimer 3,3'-diindolylmethane (DIM), obtained from
      dietary consumption of cruciferous vegetables, have multiple biochemical
      activities. Both compounds have been effective clinically in treating
      precancerous lesions of the cervix and laryngeal papillomas, pathologies with a
      human papillomavirus (HPV) component. Using cDNA microarrays, we examined early
      changes in gene expression after treatment with 100 micro mol/L DIM in C33A and
      CaSki cervical cancer cells and in an immortalized human epithelial cell line
      (HaCat), as well as in normal human foreskin keratinocytes (HFK). Multiple
      analyses were done after treating C33A cells for 6 h; other analyses included 4-
      and 12-h treatments of C33A and 6-h treatments of CaSki, HaCat and HFK cells. DIM
      consistently altered the expression of >100 genes at least twofold. Many of the
      stimulated genes encode transcription factors and proteins involved in signaling,
      stress response and growth. Results were comparable between transformed cells
      with and without integrated HPV sequences, and many of the same genes were
      induced in these cancer-derived cells and in noncancer cells. Eight genes
      encoding bZip proteins were among the most consistently and robustly induced,
      including the stress-associated immediate early gene GADD153 (>50 fold in C33A)
      and nuclear factor-interleukin 6 (NF-IL6), also known as c/EBPbeta, (>5 fold in
      C33A), which has been shown to reduce expression of HPV oncogenes. Induction of
      GADD153, NF-IL6 and ATF3 was confirmed by Western analysis. In functional
      analyses, DIM not only suppressed transcription of a luciferase gene driven by
      the HPV11 upstream regulatory region (URR) in C33A, CaSki, HaCat and HFK cells
      from >2-fold to 37-fold depending on the type of cells, but also reduced
      endogenous transcription of HPV16 oncogenes to undetectable levels in CaSki cells
      as determined by an RNase protection assay. Ectopic expression of GADD153 or NF
      IL6 suppressed transcription in a dose-dependent manner driven by the HPV11 URR
      in C33A, CaSki, HaCat and HFK cells. These results identify unexpected ways in
      which dietary I3C and DIM invoke cellular responses and are consistent with a
      potential antiviral effect of DIM on keratinocytes, but they do not explain the
      differential sensitivity of transformed keratinocytes to apoptosis by DIM.

PMID- 12421846
TI  - Adaptive changes in adipocyte gene expression differ in AKR/J and SWR/J mice
      during diet-induced obesity.
AB  - Obesity-prone (AKR/J) and obesity-resistant (SWR/J) mice were weaned onto low
      (LF) or high fat (HF) diets to identify adaptive changes in adipocyte gene
      expression that are associated with differences between the strains in fat
      deposition. Food consumption was monitored at weekly intervals and all mice were
      evaluated after consuming their respective diets for 4 wk for analysis of mRNA
      levels of selected metabolic genes. Despite similar food consumption, body weight
      and fat deposition were significantly greater in AKR/J than in SWR/J mice, and
      this difference was greatly accentuated by the HF diet. The HF diet produced
      distinct differences between strains in gene expression patterns among fat
      depots. In AKR/J mice, UCP1 mRNA was decreased 10-fold in interscapular brown
      adipose tissue (BAT) and four- to fivefold in retroperitoneal and inguinal white
      adipose tissue (WAT). The HF diet also decreased PGC-1 and beta(3)-adrenergic
      receptor mRNA by two- and ninefold in BAT from AKR/J mice. In contrast, the HF
      diet either increased uncoupling protein (UCP)1 in BAT or had no effect on
      expression of these genes in adipose tissues from SWR/J mice. UCP2 mRNA was
      fourfold higher in WAT from AKR/J compared with SWR/J mice and increased by an
      additional twofold in WAT from AKR/J mice fed the HF diet. UCP2 was unaffected by
      diet in SWR/J mice. These studies show that the diet-induced obesity of AKR/J
      mice is characterized by increased metabolic efficiency and is associated with
      changes in adipocyte gene expression that limit the adaptive thermogenic response
      to increased energy density.

PMID- 12421847
TI  - Dietary polyunsaturated fats regulate rat liver sterol regulatory element binding
      proteins-1 and -2 in three distinct stages and by different mechanisms.
AB  - Male Sprague-Dawley rats, trained to consume their daily energy needs in a single
      3-h meal (0900-1200 h), were used to examine the hypothesis that polyunsaturated
      fatty acids (PUFA) lowered the nuclear content of sterol regulatory element
      binding protein (SREBP)-1 and/or -2 by suppressing the proteolytic release of
      mature SREBP from the membrane-anchored precursor pool. The nuclear
      concentrations of hepatic SREBP-1 and -2 were 50 and 42% lower (P < 0.05) in rats
      that consumed a single PUFA-supplemented meal (i.e., 10 g fish oil/100 g fat-free
      diet) than in rats fed the fat-free diet alone. This was paralleled by 63 and 52%
      reductions in the expression of the SREBP-1 and -2 target genes, fatty acid
      synthase and HMG-CoA synthase, respectively; but the marked increase in the
      amount of precursor SREBP-1 and -2 resulting from meal ingestion was unaffected.
      After the consumption of a second meal of fish oil, the nuclear level of mature
      SREBP-1 was only 16% of that in rats fed the fat-free diet, but the amount of
      nuclear SREBP-2 was not different from the level in rats fed the fat-free diet.
      Again, the sizes of the SREBP-1 and -2 precursor pools were not reduced. A
      decrease in the hepatic concentration of precursor SREBP-1 did not occur until
      rats had consumed 5 meals of fish oil. At this point, the nuclear content of
      SREBP-2 was actually twofold higher (P < 0.05) in rats fed fish oil or safflower
      oil, but the amount of precursor SREBP-2 was unaffected. These data indicate that
      PUFA suppress the in vivo proteolytic release of SREBP-1 and -2, but the effect
      on SREBP-2 is transitory, possibly reflecting the ability of PUFA to enhance
      cholesterol losses via bile acid synthesis.

PMID- 12421848
TI  - Long-term effects of histidine depletion on whole-body protein metabolism in
      healthy adults.
AB  - The essentiality of histidine in healthy adults is a controversial topic. To
      study the potential metabolic effects of a lack of exogenous histidine, four
      healthy adults consumed a histidine-free diet, with adequate energy and 1.0
      g/(kg. d) of an L-amino acid mixture for 48 d. Protein metabolism was monitored
      every 4 d by using indicator amino acid (L-[1-(13)C]phenylalanine) oxidation (in
      four subjects) and [(15)N]glycine (in one subject). Urine samples (24-h) were
      collected for measurement of urea, total nitrogen, creatinine, 3-methylhistidine
      (3-MH), histidine and beta-alanine. Albumin, transferrin and hematologic
      concentrations were measured on d 0, 24 and 48. Urinary excretion of nitrogen,
      urea, creatinine and 3-MH were not affected by the histidine-free diet. However,
      there was a significant (P < 0.001) linear decline (24-28%) in whole-body protein
      turnover. Significant (P < 0.05) decreases in albumin (12%), transferrin (17%)
      and hemoglobin (Hb) (11%) concentrations occurred slowly over the histidine
      depletion period. The urinary excretion of beta-alanine (an index of carnosine
      catabolism) generally increased in the smallest subject during the consumption of
      histidine-free diet. This study demonstrates that a lack of histidine in the diet
      for a prolonged period resulted in an accommodation of protein turnover and
      phenylalanine oxidation, measured by the (13)C-phenylalanine indicator amino
      acid. The extensive metabolic accommodation, together with decreases in Hb,
      albumin and transferrin during histidine depletion, leaves unresolved the issue
      of whether histidine is a dietary essential amino acid in healthy adults.

PMID- 12421849
TI  - Naringenin from cooked tomato paste is bioavailable in men.
AB  - Naringenin has been shown to exert antiestrogenic, cholesterol-lowering and
      antioxidant activities, as well as an indirect modulation on the metabolism of
      many xenobiotics. It is one of the most abundant polyphenols in tomato. Given the
      widespread consumption of tomato (Lycopersicum esculentum) and tomato-based
      products, this study was designed to determine whether plasma levels of
      naringenin were detectable in five men after consumption of a test meal
      containing 150 mg of cooked tomato paste. Naringenin intake with the test meal
      was 3.8 mg. Blood was drawn from fasting subjects and 2, 4, 6, 8 and 24 h after
      the meal. To compare the results with a control, the same meal without tomato
      paste (control meal) was administered to the same subjects 2 wk later. Analyses
      were performed using high-performance liquid chromatography coupled with a
      CoulArray electrochemical detector. The peak plasma concentration was 0.12 +/-
      0.03 micro mol/L 2 h after the meal. Unconjugated naringenin was not detected.
      Naringenin was not detected in plasma at any time after consumption of the
      control meal. In addition to naringenin, we detected rutin and chlorogenic acid
      in tomato paste, but these polyphenols and their derivatives (quercetin and
      caffeic acid) were not detected in plasma at any time. To the best of our
      knowledge, this is the first study demonstrating naringenin bioavailability in
      humans after consumption of a meal containing cooked tomato paste.

PMID- 12421850
TI  - Increases in blood folate indices are similar in women of childbearing age
      supplemented with [6S]-5-methyltetrahydrofolate and folic acid.
AB  - The natural diastereoisomer [6S]-5-methyltetrahydrofolate ([6S]-5-MTHF) may be a
      safer fortificant than folic acid for neural tube defect (NTD) prevention because
      it is unlikely to mask vitamin B-12 deficiency. An inverse relationship between
      NTD risk and blood folate concentrations has been reported. In this randomized,
      placebo-controlled, double-blind trial, we compared the effects of [6S]-5-MTHF
      and folic acid supplementation for 24 wk on plasma folate and red cell folate
      (RCF) in women of childbearing age (18-49 y). Women (n = 104) were randomly
      assigned to receive a supplement containing [6S]-5-MTHF (113 micro g/d), folic
      acid (100 micro g/d) or placebo. The mean estimated linear increase in plasma
      folate concentration was 0.3 [95% confidence interval (CI): 0.1, 0.5], and 0.4
      (0.2, 0.6) nmol/(L. wk) in the [6S]-5-MTHF and folic acid groups, respectively.
      The mean estimated linear increase in RCF was 7.4 (95% CI: 4.5, 10.3), and 8.3
      (4.4, 12.3) nmol/(L. wk) in the [6S]-5-MTHF and folic acid groups, respectively.
      There were no differences in the slopes between the [6S]-5-MTHF group and the
      folic acid group in either plasma folate (P = 0.48) or RCF (P = 0.70). At 24 wk,
      estimated mean increases in plasma folate concentrations were 6.9 (95% CI: 1.7,
      12.2) and 9.2 (3.3, 15.1) nmol/L, and in RCF, 251 (143, 360) and 275 (148, 402)
      nmol/L, in the [6S]-5-MTHF and folic acid groups, respectively, relative to the
      placebo group. These data suggest that low dose [6S]-5-MTHF and folic acid
      supplementation increase blood folate indices to a similar extent. A steady state
      in the blood indices had not been reached by 24 wk.

PMID- 12421851
TI  - Glyceride stearic acid content and structure affect the energy available to
      growing rats.
AB  - To better understand the relative absorption of 18:0, specific structured
      triglycerides (STG) with varied ratios of 18:0 and short-chain organic acids
      (2:0, 3:0, 4:0) were compared with naturally occurring 18:0 in cocoa butter and
      to other mono- and diglycerides (DGs) containing 18:0. A bioassay for available
      fat energy was developed for growing Sprague-Dawley rats fed reduced energy from
      a control diet containing an American Heart Association (AHA) fat blend to
      generate 60 or 80% normal growth. The resulting standard growth curve was applied
      to the test fats, including cocoa butter and six glycerides, which were blended
      3:1 with the AHA blend (to ensure EFA sufficiency) and pair-fed to match intake
      of control rats (AHA diet, 80% normal growth). Available energy from test fats
      ranged from 30 to 12 kJ/g (7.1 to 2.9 kcal/g) for cocoa butter to 18:0-DG,
      respectively, with the mean of the four different STG being 22 kJ/g (5.2 kcal/g).
      Energy available from test fats was negatively related to total 18:0 in the STG
      (r = -0.90; P < 0.001) and fecal dry weight (r = -0.92; P < 0.001); the effect
      was greater for monoglyceride (monolong-18:0) than for DG (dilong-18:0) but was
      not related to fecal 18:0. Compared with monoglyceride-18:0, available energy was
      increased or decreased when short-chain organic acids (SCOA) were added to form
      triglycerides, depending on the addition of butyrate or acetate, respectively.
      The different fat sources altered the available energy without apparent changes
      in lipoproteins or body composition. Thus, the reduced energy available from a
      glyceride containing 18:0 is determined by its total 18:0 and reflects the mono-
      or dilong chain character of the glyceride, its content of SCOA and triglyceride
      structure or organization per se.

PMID- 12421852
TI  - Intestinal calcium absorption in growing dogs is influenced by calcium intake and
      age but not by growth rate.
AB  - The effects of calcium (Ca) intake (V(I)), age and growth rate on intestinal Ca
      absorption were studied in growing dogs. Two breeds of dogs differing in their
      growth rate (67 Great Danes and 23 Miniature Poodles) were raised on diets
      differing only in their Ca content (range 0.33 to 3.3 g/100 g diet on a dry
      matter basis). Repetitive Ca balance studies were performed with the aid of
      (45)Ca from 6 wk (i.e., after weaning) until 6 mo of age. Several models were
      investigated expressing true Ca absorption (V(a)) as a function of V(I), breed
      and age. V(a) was directly proportional to a function close to V(I)(0.82) being a
      continuation of the high Ca needs for mineralization of the growing skeleton.
      This curvilinear relationship between V(a) and V(I) and the inverse relationship
      between fractional Ca absorption and V(I) indicated the presence of active and
      passive Ca absorption in weaned growing dogs. A model in which these two
      components of Ca absorption can be discerned revealed that active Ca absorption
      underwent age-dependent changes, whereas passive absorption remained constant and
      accounted for 53% absorption of the V(I). At low V(I), active absorption
      contributed to a significant part of the V(a), whereas at excessive V(I) active
      absorption was negligible and passive absorption was the driving force for
      causing supra positive Ca balance. Intestinal Ca handling did not differ between
      breeds with dramatically different mature body size and growth rates.

PMID- 12421853
TI  - Enzymes and metabolites of cysteine metabolism in nonhepatic tissues of rats show
      little response to changes in dietary protein or sulfur amino acid levels.
AB  - In liver, cysteine dioxygenase (CDO), cysteinesulfinate decarboxylase (CSD), and
      gamma-glutamylcysteine synthetase (GCS) play important regulatory roles in the
      metabolism of cysteine to sulfate, taurine and glutathione. Because glutathione
      is released by the liver and degraded by peripheral tissues that express gamma
      glutamyl transpeptidase, some peripheral tissues may be exposed to relatively
      high concentrations of cysteine. Rats were fed diets that contained low, moderate
      or high concentrations of protein or supplemental cysteine or methionine for 2
      wk, and CDO, CSD and GCS activities, concentrations and mRNA levels and the
      concentrations of cysteine, taurine and glutathione were measured in liver,
      kidney, lung and brain. All three enzymes in liver responded to the differences
      in dietary protein or sulfur amino acid levels, but only CSD in kidney and none
      of the three enzymes in lung and brain responded. Renal CSD activity was twice as
      much in rats fed the low protein diet as in rats fed the other diets. Changes in
      renal CSD activity were correlated with changes in CSD concentration. Some
      significant differences in cysteine concentration in kidney and lung and
      glutathione and taurine concentrations in kidney were observed, with higher
      concentrations in rats fed higher levels of protein or sulfur amino acids. In
      liver, the changes in cysteine level were consistent with cysteine-mediated
      regulation of hepatic CDO activity, and changes in taurine level were consistent
      with predicted changes in cysteine catabolism due to the changes in cysteine
      concentration and CDO activity. Changes in renal and lung cysteine, taurine or
      glutathione concentrations were not associated with a similar pattern of change
      in CDO, CSD or GCS activity. Overall, the results confirm the importance of the
      liver in the maintenance of cysteine homeostasis.

PMID- 12421855
TI  - Net portal absorption of enterally fed alpha-ketoglutarate is limited in young
      pigs.
AB  - Our aim was to quantify the intestinal metabolic fate of dietary alpha
      ketoglutarate (AKG). Female pigs (n = 6; 21 d old) were implanted with arterial,
      venous, portal and gastric catheters and an ultrasonic portal flow probe and fed
      a corn and soybean meal-based diet. On the day of the experiment, the pigs
      received a 4-h intragastric infusion of sodium AKG at a rate equivalent to 0,
      2.5, 5 or 10% of dietary intake. The net portal AKG balance of the control and
      2.5% treatments did not differ and were not different from zero. However, the net
      portal AKG balance of both the 5 [163 micro mol/(kg. h)] and 10% [159 micro
      mol/(kg. h)] treatments were greater (P < 0.05) than the control. Despite
      significant net AKG absorption at the 5 and 10% levels, the net portal appearance
      represented only 10.8 and 6.7%, respectively, of the enteral input. The net
      portal appearances of glutamate, glutamine, ammonia and the branched-chain amino
      acids were not affected by dietary AKG level. We conclude that the absorption of
      dietary AKG is limited in young pigs and does not change the net portal balance
      of amino acids or ammonia.

PMID- 12421854
TI  - Substituting honey for refined carbohydrates protects rats from
      hypertriglyceridemic and prooxidative effects of fructose.
AB  - Recent findings indicate that a high fructose diet has a prooxidant effect in
      rats compared with a starch diet. Because honey is rich in fructose, the aim of
      this study was to assess the effect of substituting honey for refined
      carbohydrates on lipid metabolism and oxidative stress. Rats were fed for 2 wk
      purified diets containing 65 g/100 g carbohydrates as wheat starch or a
      combination of fructose and glucose or a honey-based diet prepared by
      substituting honey for refined carbohydrates (n = 9/group). The same amount of
      fructose was provided by the honey and fructose diets. The hypertriglyceridemic
      effect of fructose was not observed when fructose was provided by honey. Compared
      with those fed starch, fructose-fed rats had a lower plasma alpha-tocopherol
      level, higher plasma nitrite and nitrate (NOx) levels and were less protected
      from lipid peroxidation as indicated by heart homogenate TBARS concentration.
      Compared with those fed fructose, honey-fed rats had a higher plasma alpha
      tocopherol level, a higher alpha-tocopherol/triacylglycerol ratio, lower plasma
      NOx concentrations and a lower susceptibility of heart to lipid peroxidation.
      Further studies are required to identify the mechanism underlying the antioxidant
      effect of honey but the data suggest a potential nutritional benefit of
      substituting honey for fructose in the diet.

PMID- 12421856
TI  - Supplemental feeding of difructose anhydride III restores calcium absorption
      impaired by ovariectomy in rats.
AB  - In three separate experiments, we examined the effects of feeding difructose
      anhydride III (DFAIII) on intestinal calcium (Ca) absorption using female Sprague
      Dawley rats (6 wk old) with or without ovariectomy (OVX). In Experiment 1, we
      showed that Ca absorption was lower in OVX rats fed the 2.0 and 3.0 g Ca/kg
      diets, but not the 1.0 g Ca/kg diet, than in sham-operated rats during a 3-wk
      test period. In Experiment 2, we demonstrated that Ca absorption rate in sham and
      OVX rats fed a diet containing 3% DFAIII was higher than that in rats fed a
      DFAIII-free diet 4 wk after consuming the test diets. Absorptive activities of
      everted sacs of the colon, but not of the duodenum, in rats fed DFAIII diet for 4
      wk were higher than those in rats fed the control diet. In Experiment 3, we
      determined which of the small and large intestines is responsible for the effects
      of DFAIII on Ca absorption using OVX rats with cecocolonectomy or transsection
      and reanastomosis (sham). Both the sham and cecocolonectomized rats were divided
      into four subgroups and fed a control, polyethylene glycol (PEG), 1.5% DFAIII or
      3% DFAIII diet. We set up the PEG group as another control group to observe the
      effects of shortening transit time of the small intestine in the DFAIII groups.
      Promotive effects of DFAIII on Ca absorption were abolished by cecocolonectomy.
      However, in the cecocolonectomized rats, the Ca absorption rate was still higher
      in the 1.5 and 3% DFAIII groups than in the PEG group. In conclusion, ovarian
      hormone deficiency impaired Ca absorption, but the reduction of Ca absorption was
      restored by feeding DFAIII.

PMID- 12421857
TI  - Melibiose, difructose anhydride III and difructose anhydride IV enhance net
      calcium absorption in rat small and large intestinal epithelium by increasing the
      passage of tight junctions in vitro.
AB  - An Ussing chamber technique was used to determine the effects of three
      indigestible disaccharides on net Ca transport from the luminal side to the
      basolateral side of isolated preparations of jejunal, ileal, cecal and colonic
      epithelium in rats. Permeability of Lucifer Yellow (LY) and transepithelial
      electrical resistance (TEER), which are indicators of intercellular passage of
      the intestinal mucosa, were also determined. The concentrations of Ca in the
      serosal and mucosal media were 1.25 mmol/L and 10 mmol/L, respectively. After a
      30-min incubation, the net Ca transport, LY passage and TEER were determined. In
      the control experiment, LY permeability was lowest, and TEER value was highest in
      the colon. The addition of 1-100 mmol/L melibiose, difructose anhydride (DFA)III,
      or DFAIV to the mucosal medium increased the net Ca absorption and LY
      permeability dose-dependently in the jejunum, ileum, cecum and colon
      preparations. Melibiose decreased TEER dose-dependently in the jejunum and cecum,
      but not in the ileum and colon. DFAIII decreased TEER dose-dependently in the
      jejunum, cecum and colon, but not in the ileum. DFAIV decreased TEER dose
      dependently in all four intestinal portions. Positive linear relationships were
      found between net Ca transport and LY passage in all portions of the intestine,
      whereas negative linear relationships were found between net Ca absorption and
      TEER. We concluded that the three indigestible saccharides directly affect the
      epithelial tissue and activate the passage of tight junctions, thereby promoting
      Ca absorption in the small and large intestine in vitro.

PMID- 12421858
TI  - Excess dietary vitamin E lowers the activities of antioxidative enzymes in
      erythrocytes of rats fed salmon oil.
AB  - In vitro studies suggest that high vitamin E supplementation has prooxidative
      activity, but very few studies have investigated this effect in vivo. We
      investigated the effect of excess vitamin E on the antioxidative status of rat
      erythrocytes and indicators of hemolysis. Six groups of growing male Sprague
      Dawley rats were fed purified diets with three different vitamin E doses [100,
      1000 and 10,000 mg all-rac-alpha-tocopheryl acetate (TA)/kg diet] and two
      different dietary fats (salmon oil and lard) for 8 wk. The rats whose diet
      contained salmon oil and 10,000 mg TA/kg had lower activities of superoxide
      dismutase (P < 0.05), glutathione peroxidase (P < 0.05), catalase (P < 0.05) and
      glucose-6-phosphate dehydrogenase (P < 0.05) and a lower concentration of
      glutathione (P < 0.05) in the erythrocyte cytosol than rats whose diet contained
      100 mg TA/kg. The concentration of free hemoglobin and the binding capacity of
      haptoglobin in plasma, both indicators of in vivo hemolysis, did not differ
      between rats fed the salmon oil diet with 100 or 10,000 mg TA/kg. In the rats
      whose diet contained lard, the activities of antioxidant enzymes in erythrocytes
      and indicators of in vivo hemolysis were independent of the dietary vitamin E
      concentration. The results of the study suggest that an excessive vitamin E
      intake, when combined with salmon oil in the diet, lowers the activities of
      antioxidant enzymes in erythrocytes without affecting in vivo hemolysis.

PMID- 12421860
TI  - Choice feeding of selenium-deficient laying hens affects diet selection, selenium
      intake and body weight.
AB  - Inadequate selenium (Se) supply often in combination with low vitamin E status
      causes deficiency symptoms in many species. It is likely that a vague discomfort
      or sickness is perceived before clear deficiency signs become apparent. We
      investigated whether Se-deficient hens reduce their Se deficit by selecting a
      diet containing more selenium when offered two diets with different Se
      concentrations. A Low-Se diet (0.07 mg Se/kg) was supplemented with Se-enriched
      yeast (Sel-Plex 50) to produce Medium-Se (0.20 mg Se/kg) and High-Se (1.50 mg
      Se/kg) diets. Each of two consecutive study parts (I and II) with the same hens
      and treatments began with a 6-wk baseline period (Medium-Se diet), subsequently
      followed a 9-wk depletion period (Low-Se diet or Medium-Se diet), then a 6-wk
      choice feeding period in which two diets with different Se concentrations (Low-Se
      and Medium-Se, Medium-Se and High-Se, or Low-Se and High-Se) were offered. A
      control group received the Medium-Se diet throughout the study. Daily Se intake,
      calculated from daily feed intake, followed similar patterns in both parts of the
      study, but Se-deficient hens preferred (P < 0.05) the High-Se diet to the Low-Se
      diet during the first 3 wk of choice feeding only in part I. We conclude that
      young Se-deficient laying hens reduce their Se deficit if they have a choice
      between a Low-Se and a High-Se diet by preferentially selecting the High-Se diet,
      possibly based on learned place preference and/or learned taste aversion to the
      Low-Se diet, presumably in response to discomfort due to Se-deficiency.

PMID- 12421859
TI  - The abundance and function of biotin-dependent enzymes are reduced in rats
      chronically administered carbamazepine.
AB  - The effect of dietary antiepileptic drug administration on the metabolism and
      function of the water-soluble vitamin biotin was analyzed in a physiologically
      relevant rat model of biotin nutriture. Administration of carbamazepine (CBZ) in
      semipurified rat diet at 1.5 and 2.9 g/kg for 19 d did not reduce growth rate or
      food intake. After this dietary treatment, brain lactic acid and ammonia
      concentrations were significantly elevated, but no changes in these metabolites
      occurred in the liver. Urinary biotin excretion was altered and the
      concentrations of biotin sulfoxides and biocytin in the serum were elevated.
      Brain biotin was unaffected, but concentrations of bisnorbiotin and biocytin were
      significantly reduced by dietary administration of CBZ. The relative abundance of
      hepatic acetyl CoA carboxylase 1 and 2, pyruvate carboxylase (PC), methylcrotonyl
      CoA carboxylase and propionyl CoA carboxylase was significantly reduced by CBZ,
      whereas the relative abundance of biotinylated PC was significantly reduced in
      the brain. In agreement with the carboxylase abundance data, the activity of
      hepatic PC was significantly reduced in rats consuming CBZ-containing diets.
      These data demonstrate that administration of the antiepileptic medication CBZ,
      even with food, reduces the abundance and function of biotin-dependent enzymes in
      the liver and brain, partially accounting for the metabolic alterations,
      including organic acidemia, that are observed clinically.

PMID- 12421861
TI  - Hyperhomocysteinemia due to short-term folate deprivation is related to electron
      microscopic changes in the rat brain.
AB  - We investigated the effects of folate deprivation on plasma folate and
      homocysteine and its effects on cerebral microvasculature using electron
      microscopy. Two levels of folic acid (0 mg and 4 mg/kg diet) were fed to 6-mo-old
      male rats for 8 wk. Dietary folate deprivation decreased plasma folate from 353.0
      +/- 29.7 nmol/L to 44.2 +/- 7.2 nmol/L with a concomitant increase in plasma
      homocysteine from 6.15 +/- 0.9 micro mol/L to 19.5 +/- 2.7 micro mol/L. Plasma
      folate was negatively correlated with plasma homocysteine at wk 8 (r = -0.876, P
      = 0.004). Electron microscopic studies of the brains of folate-deprived rats
      revealed cytoplasmic swelling and mitochondrial degeneration in the endothelium,
      perivascular amorphous fibrosis and pericytic degenerative appearance in the
      cerebrocortical microvascular wall. These morphologic changes might be helpful
      for elucidating the mechanisms underlying the cerebrovascular and neuropathology
      with folate deficiency.

PMID- 12421862
TI  - Mineral intakes of elderly adult supplement and non-supplement users in the third
      national health and nutrition examination survey.
AB  - Calcium, iron and zinc are important in many of the body's functions. We report
      dietary and combined (diet + supplements) intakes for these minerals for elderly
      supplement and non-supplement users in the United States and the prevalence of
      inadequate intakes. We calculated usual dietary intakes for adults 60 y and older
      from third National Health and Nutrition Examination Survey, 1988-94; mineral
      intakes from supplements and calcium-containing antacids were added to usual
      dietary intakes. We evaluated iron and zinc intakes using the dietary reference
      intakes, recommended dietary allowances and estimated average requirements for
      elderly adults, as well as calcium intakes using the Adequate Intake and the
      Healthy People 2010 objective. The highest prevalences of inadequate dietary
      intakes was for calcium (males, 70-75%; females, 87%) and zinc (males, 35-41%;
      females, 36-45%). Dietary supplements improved intakes, but nearly two-thirds of
      elderly adults had combined intakes below the calcium objective. Non-Hispanic
      blacks usually had lower intakes than non-Hispanic whites and higher prevalences
      of intakes below the standards. Supplement users had significantly higher mean
      dietary intakes than non-supplement users for all three minerals for total
      females and non-Hispanic white females (P < 0.05 for each mineral). Many elderly
      adults had inadequate dietary zinc intakes, and calcium intakes fell below the
      Healthy People 2010 objective; dietary supplements improved intakes. Even with
      supplements most older adults still had intakes below the calcium objective,
      partly because the supplements they took usually contained low doses of calcium.
      Total female and non-Hispanic white female supplement users were the only groups
      that had higher dietary intakes than non-supplement users for all three minerals.

PMID- 12421863
TI  - Passive diffusion does not play a major role in the absorption of dietary calcium
      in normal adults.
AB  - Several authors have indicated recently that passive diffusion is the dominant
      process by which dietary calcium is absorbed by normal adults. These conclusions
      have important implications in the maintenance of normal calcium status in
      humans. They imply that increasing luminal calcium concentration by increasing
      intake is the most important strategy in promoting calcium absorption. I present
      several studies that dispute this contention and two studies that suggest that
      passive diffusion is of little practical significance, even in young children.
      The contribution of passive diffusion is estimated to be between 8 and 23% of the
      total calcium absorbed by normal adults. Thus, it clearly does not represent the
      major path by which they absorb calcium. Children lacking the vitamin D receptor
      system do not absorb enough calcium by passive diffusion to prevent signs of
      rickets even when diets contain very large amounts of dietary calcium (>2 g/d).
      The conclusion drawn from this analysis is that passive diffusion (dictated by
      calcium intake) is not the major mechanism by which dietary calcium is absorbed
      by normal adult humans. The vitamin D-dependent processes are more important
      quantitatively and thus constitute a major determinant of calcium status.
      Individuals who are not exposed to sunlight may be especially at risk.

PMID- 12421864
TI  - Feeding the world in the coming decades requires improvements in investment,
      technology and institutions.
AB  - The world is food secure at the global level, yet nearly 800 million are food
      insecure. "Business as usual" is not going to bring us close to meeting the
      Millennium Development Goal of halving the proportion of the population consuming
      less than the minimum energy requirement. So what has to change? The three papers
      in this session offer clues in three broad areas: (a) increased investment-by
      developing and developed countries-in public goods such as agricultural research,
      education, and clean water, (b) technologies to boost agricultural productivity
      for the poor and institutions that guide the diffusion and application of
      technology that need to be developed and (c) national-level institutions and
      governance structures to be strengthened and held accountable for protecting and
      respecting human rights, for providing the right types of national-level public
      goods to those that most need them and for preserving peace and stability.

PMID- 12421865
TI  - Appropriate food policies and investments could reduce child malnutrition by 43%
      in 2020.
AB  - This report describes past trends in global child malnutrition and assesses
      future prospects for reducing child malnutrition. Most developing countries have
      significantly reduced the proportion of malnourished children during the past
      three decades. However, because of population growth, the absolute number of
      malnourished children has fallen much less sharply. Moreover, the number of
      malnourished children has increased in Sub-Saharan Africa. A global food supply
      and-demand model is used to project child malnutrition to 2020 under alternative
      assumptions on policies and investments that influence food security outcomes in
      education, clean water, agricultural research, irrigation and rural
      infrastructure. The baseline "best-estimate" projection shows that the number of
      malnourished children will continue to decline slowly but that child malnutrition
      will continue to increase in Sub-Saharan Africa. The optimistic scenario shows
      that better policy and more rapid economic and agricultural growth can lead to
      substantial food security improvements, but the pessimistic scenario shows that
      significantly worse outcomes are also possible with relatively small declines in
      policy and investment efforts relative to the baseline. A concerted effort to
      eliminate childhood malnutrition would require policy reform and significant
      increases in public investment to produce long-term gains in income growth,
      agricultural productivity and social indicators.

PMID- 12421866
TI  - Research needs to improve agricultural productivity and food quality, with
      emphasis on biotechnology.
AB  - Research into agricultural productivity, especially for crops in the developing
      world, should include resistance to plant viruses, fungi and the parasitic weed
      Striga. It must also include research into the development of resistance to
      Bacillus thuringiensis (Bt) toxin-expressing crops. Drought- and heat-tolerant
      crops, and those that can combat the problems of soil deficiencies, are required,
      and vaccine production in plants should be a high priority. Research into food
      quality should include the equivalent of "golden rice" in maize, the enhancement
      of the production of phytosterols and improved qualities of vegetable oils.

PMID- 12421867
TI  - Africa: addressing growing threats to food security.
AB  - Africa remains the only region in the world where the number of hungry people
      will still be on the increase in 2020, and the number of malnourished children
      will have increased correspondingly. In this report I have acknowledged the
      general public policy trends across Africa in terms of macroeconomic policy
      reforms and political transitions. These welcome trends have to still produce
      stable nations and economies. Although economic development is the long-term
      solution to Africa's challenge on hunger and poverty, this will take time. And it
      follows therefore that African nations have to pursue policies and strategies
      that promote long-term growth while at the same time offering short-term safety
      nets for the poorest of the poor. The growth and development strategy will have
      at its core the need to increase significantly the levels of public-sector
      investment in agriculture and rural development and to give top priority to the
      commercialization of smallholder agriculture so as to increase productivity and
      competitiveness. But food security at the household level is ultimately a balance
      between availability and access, and in this regard governments need
      complementary food security policies that increase the probability of food access
      by the vulnerable groups.

PMID- 12421868
TI  - Proceedings of the International Research Conference on Food, Nutrition, &
      Cancer. July 11-12, 2002. Washington, D.C., USA.

PMID- 12421869
TI  - The underlying basis for obesity: relationship to cancer.
AB  - An increase in the risk of cancer is one of the consequences of obesity. The
      predominant cancers associated with obesity have a hormonal base and include
      breast, prostate, endometrium, colon and gallbladder cancers. As the basis for
      understanding the problem of obesity has advanced, a number of new ideas have
      emerged about the relationship of obesity to cancer. The conversion of
      androstenedione secreted by the adrenal gland into estrone by aromatase in
      adipose tissue stroma provides an important source of estrogen for the
      postmenopausal woman. This estrogen may play an important role in the development
      of endometrial and breast cancer. Of interest is that experimental animals
      lacking aromatase or the estrogen receptor alpha are obese. Leptin is one of the
      many products produced by fat cells and has given rise to the ideas that the fat
      cell is an endocrine cell and that adipose tissue is an endocrine organ. The
      increased release of cytokines from this tissue may play a role in the
      inflammatory state that is associated with obesity. The gut also plays an
      important role in signaling satiety in response to food intake. Colon cancer is
      an important human disease, and experimental mice lacking gastrin are obese and
      have an increased risk of developing colon cancer in response to carcinogenic
      drugs. Efforts to control obesity through preventive strategies and treatment can
      be expected to have a benefit in reducing the risk of cancer.

PMID- 12421870
TI  - Physical activity and cancer prevention: etiologic evidence and biological
      mechanisms.
AB  - Scientific evidence is accumulating on physical activity as a means for the
      primary prevention of cancer. Nearly 170 observational epidemiologic studies of
      physical activity and cancer risk at a number of specific cancer sites have been
      conducted. The evidence for decreased risk with increased physical activity is
      classified as convincing for breast and colon cancers, probable for prostate
      cancer, possible for lung and endometrial cancers and insufficient for cancers at
      all other sites. Despite the large number of studies conducted on physical
      activity and cancer, most have been hampered by incomplete assessment of physical
      activity and a lack of full examination of effect modification and confounding.
      Several plausible hypothesized biological mechanisms exist for the association
      between physical activity and cancer, including changes in endogenous sexual and
      metabolic hormone levels and growth factors, decreased obesity and central
      adiposity and possibly changes in immune function. Weight control may play a
      particularly important role because links between excess weight and increased
      cancer risk have been established for several sites, and central adiposity has
      been particularly implicated in promoting metabolic conditions amenable to
      carcinogenesis. Based on existing evidence, some public health organizations have
      issued physical activity guidelines for cancer prevention, generally recommending
      at least 30 min of moderate-to-vigorous intensity physical activity on > or =5
      d/wk. Although most research has focused on the efficacy of physical activity in
      cancer prevention, evidence is increasing that exercise also influences other
      aspects of the cancer experience, including cancer detection, coping,
      rehabilitation and survival after diagnosis.

PMID- 12421871
TI  - Dietary intake, resting energy expenditure, weight loss and survival in cancer
      patients.
AB  - Anorexia, hypermetabolism and weight loss are common in advanced cancer. The
      progressive wasting may be due to diminished dietary intake as well as to
      increased energy expenditure mediated by metabolic alterations caused by the
      tumor. We studied dietary intake, resting energy expenditure and weight loss in
      297 patients with generalized malignant disease and their relation to survival.
      Patients were examined cross-sectionally at entry into an outpatient palliative
      care program that included anti-inflammatory treatment and nutritional
      counseling. Survivors were studied longitudinally after 4 mo during palliative
      care. We found at entry that the patients' mean dietary intake was low. Weight
      loss of >10% was present in 43% of the patients, and hypermetabolism was present
      in 48%. Dietary intake did not differ between normometabolic and hypermetabolic
      patients, nor was tumor type or gender related to energy and protein intake.
      Weight loss could not be accounted for by diminished dietary intake alone.
      Increased resting energy expenditure was not compensated for by an increase in
      spontaneous food intake. These findings indicate that feedback regulation of
      dietary intake in relation to energy expenditure is frequently lost in patients
      with cancer. Hypermetabolism and weight loss were significant predictors of
      decreased survival. Mean survival time was about 8 mo; 189 patients survived 4 mo
      or more, and 153 could be reexamined. At the 4-mo follow-up during palliative
      care, group mean weight was nearly maintained, with large individual variations.
      Weight loss during follow-up predicted decreased survival. Energy intake
      increased slightly, also with great variation, and an increased energy intake
      predicted longer survival.

PMID- 12421872
TI  - Diet, obesity and reflux in the etiology of adenocarcinomas of the esophagus and
      gastric cardia in humans.
AB  - Incidence rates for esophageal adenocarcinoma have increased >350% since the mid
      1970s. Rates for gastric cardia adenocarcinoma have also increased, although less
      steeply. This led to the initiation of large population-based case-control
      studies, particularly in the United States and Sweden, aimed at identifying risk
      factors for these cancers. Results have been emerging from these studies, with
      the consistent finding that obesity and gastroesophageal reflux disease are
      important risk factors for these cancers. Analyses of dietary factors are also
      available and indicate that diets high in total fat, saturated fat and
      cholesterol are associated with an increased risk of these cancers, whereas
      several nutrients, particularly those found in plant foods (fiber, vitamin C,
      beta-carotene, folate), are associated with a reduced risk. Considering the
      incidence trends of these cancers and the trends in the prevalence of risk
      factors, the increasing prevalence of obesity in the United States likely
      accounts for some of the increased incidence. However, other contributors to the
      increasing trends have been suggested and will be discussed. Because diet,
      obesity and gastroesophageal reflux disease may not act independently in
      contributing to these cancers, current research is attempting to identify
      associations between the three risk factors and potential mechanisms of action to
      better understand the etiology of these cancers.

PMID- 12421873
TI  - Energy imbalance and prostate cancer.
AB  - In this review, the emerging evidence that excessive energy intake relative to
      energy expenditure increases the risk of prostate cancer is discussed. The
      adverse effects of energy imbalance can be inferred from an experimental study
      demonstrating reduced prostate tumor growth, lower circulating concentrations of
      insulin-like growth factor-I and decreased expression of vascular endothelial
      growth factor with energy restriction in transplantable tumor models. The effects
      of energy restriction on factors mediating greater proliferation relative to
      apoptosis and angiogenesis suggest that energy imbalance may act late in the
      carcinogenic pathway. Energy intake also has been evaluated in relation to
      prostate cancer risk in 23 analytic epidemiologic studies. Among studies
      reporting effect estimates, 8 of 14 case-control studies support a direct
      association [top versus bottom quantile, OR(summary) = 1.3; 95% confidence
      interval (CI), 1.1-1.4], but none of four cohort studies do (RR(summary) = 1.0;
      95% CI, 0.8-1.2). The four case-control studies that evaluated advanced disease
      suggest a higher risk with higher energy intake (OR(summary) = 1.6; 95% CI, 1.2
      2.0). However, none of these studies considered the balance of energy intake with
      body size and physical activity, the major determinants of variability in energy
      demand. Numerous research questions remain to be addressed, including, Which
      biological pathways are adversely affected by energy imbalance? Does energy
      imbalance act early or late in prostate carcinogenesis? What is the optimal
      energy balance for minimizing risk of clinically important prostate cancer?
      Evidence is beginning to show that energy intake in excess of expenditure may
      affect prostate carcinogenesis and, in particular, risk of advanced disease.

PMID- 12421874
TI  - Flavonoid effects relevant to cancer.
AB  - Flavonoids, such as daidzein and genistein, present in dietary plants like
      soybean, have unique chemical properties with biological activity relevant to
      cancer. Many flavonoids and polyphenols, including resveratrol in red wine and
      epigallocatechin gallate in green tea, are known antioxidants. Some of these
      compounds have estrogenic (and antiestrogenic) activity and are commonly referred
      to as phytoestrogens. A yeast-based estrogen receptor (ER) reporter assay has
      been used to measure the ability of flavonoids to bind to ER and activate
      estrogen responsive genes. Recently, estrogenic compounds were also shown to
      trigger rapid, nongenomic effects. The molecular mechanisms, however, have not
      been completely detailed and little information exists regarding their relevance
      to cancer progression. As a preliminary step toward elucidating rapid
      phytoestrogen action on breast cancer cells, we investigated the effect of 17
      beta estradiol (E2), genistein, daidzein and resveratrol on the activation status
      of signaling proteins that regulate cell survival and invasion, the cell
      properties underlying breast cancer progression. The effect of these estrogenic
      compounds on the activation, via phosphorylation, of Akt/protein kinase B (Akt)
      and focal adhesion kinase (FAK) were analyzed in ER-positive and -negative human
      breast cancer cell lines. E2, genistein and daidzein increased whereas
      resveratrol decreased both Akt and FAK phosphorylation in nonmetastatic ER
      positive T47D cells. In metastatic ER-negative MDA-MB-231 cells, all estrogenic
      compounds tested increased Akt and FAK phosphorylation. The inhibitory action of
      resveratrol on cell survival and proliferation is ER dependent. Therefore, all
      estrogenic compounds tested, including resveratrol, may exert supplementary ER
      independent nongenomic effects on cell survival and migration in breast cancer
      cells.

PMID- 12421875
TI  - Phytoestrogens regulate vitamin D metabolism in the mouse colon: relevance for
      colon tumor prevention and therapy.
AB  - Soybean products are highly represented in the traditional Asian diet. Major
      components of soy proteins are phytoestrogens, such as isoflavones. They may be
      responsible for the extremely low incidence of prostate and mammary tumors and
      possibly also of colon cancer in countries such as China and Japan. Serum 1,25
      dihydroxyvitamin D3 level is inversely related to incidence of some cancers.
      Levels are determined by skin exposure to ultraviolet light or, to a minor
      extent, nutritional uptake and by subsequent conversion of the precursor vitamin
      D to the active hormone by the cytochrome P450 hydroxylases CYP27A1, CYP27B1
      (responsible for synthesis) and CYP24 (responsible for catabolism) in liver and
      kidney. However, vitamin D synthesis is also found in colonocytes and is enhanced
      during incipient malignancy. This may indicate an autocrine/paracrine role for
      this differentiation-inducing hormone in defense against progression. We were
      able to demonstrate that either a single large oral dose of genistein or feeding
      soy protein for 4 mo elevated CYP27B1 and decreased CYP24 expression in the mouse
      colon. Our data therefore suggest that an inverse correlation of soy product
      consumption with colon tumor incidence may be consequent to enhanced colonic
      synthesis of the antimitotic hormone 1,25-dihydroxyvitamin D3.

PMID- 12421876
TI  - Cancer survivorship research: challenge and opportunity.
AB  - With continued advances in strategies to detect cancer early and treat it
      effectively along with the aging of the population, the number of individuals
      living years beyond a cancer diagnosis can be expected to continue to increase.
      This paper reviews current prevalence data for cancer survivors; discusses
      definitional issues; examines cancer survivorship as a scientific research area;
      provides an overview of medical and psychosocial sequelae of cancer diagnosis and
      treatment experienced by survivors, gaps in knowledge and emerging research
      priorities; explores the role of weight, nutrition and physical activity as key
      variables carrying the potential to affect physiologic or psychosocial sequelae
      of cancer and its treatment; and discusses the evolving paradigm of cancer
      survivorship research. A large and growing community of cancer survivors is one
      of the major achievements of cancer research over the past three decades. Both
      length and quality of survival are important end points. Many cancer survivors
      are at risk for and develop physiologic and psychosocial late and long-term
      effects of cancer treatment that may lead to premature mortality and morbidity.
      Interventions--therapeutic and lifestyle--carry the potential to treat or
      ameliorate these late effects and must be developed, examined and disseminated if
      found effective. Diet, weight and physical activity interventions hold
      considerable promise for ameliorating multiple adverse sequelae of cancer and its
      treatment and should be investigated in larger populations of cancer survivors,
      those who are long-term survivors, those with understudied cancer sites and
      ethnocultural minority or medically underserved groups.

PMID- 12421877
TI  - Can lifestyle modification increase survival in women diagnosed with breast
      cancer?
AB  - Epidemiologic studies have linked diets high in vegetables and fruit with an
      increased likelihood of survival after the diagnosis of breast cancer, and
      clinical and epidemiologic studies have identified obesity as an important
      negative prognostic factor. Of the 26 studies published since 1990 that examined
      the relationship with obesity and survival, 17 reported a significant inverse
      relationship. Five of the eight cohort studies of breast cancer survivors that
      examined intakes of vegetables, fruit and related micronutrients published since
      1985 reported a positive relationship between these factors and survival. The
      hypothesis that lifestyle factors such as diet and physical activity may improve
      the prognosis in women who have been diagnosed with breast cancer is currently
      under study. The Women's Healthy Eating and Living Study is a randomized
      controlled study that tests the effects of a diet high in vegetables, fruit and
      fiber and low in fat on disease-free survival after treatment for early stage
      breast cancer (n = 3109). In the Healthy Weight Management for Breast Cancer
      Survivors Study, a multifaceted approach to promoting weight loss and long-term
      weight maintenance is being tested in 85 women at risk for breast cancer
      recurrence. The intervention emphasizes increased physical activity, strategies
      to improve body image and self-acceptance, and cognitive-behavioral therapy to
      promote healthy eating attitudes and behaviors. The results of these studies will
      contribute to understanding the roles of diet and physical activity in the
      progression of breast cancer.

PMID- 12421878
TI  - Omega-3 fatty acids to augment cancer therapy.
AB  - The results of animal studies have demonstrated that the consumption of omega-3
      fatty acids can slow the growth of cancer xenografts, increase the efficacy of
      chemotherapy and reduce the side effects of the chemotherapy or of the cancer.
      Molecular mechanisms postulated to contribute to the multiple benefits of omega-3
      fatty acids include 1) suppressing the expression of cyclooxygenase-2 in tumors,
      thus decreasing proliferation of cancer cells and reducing angiogenesis in the
      tumor; 2) decreasing the expression of AP-1 and ras, two oncogenes implicated in
      tumor promotion; 3) inducing differentiation of cancer cells; 4) suppressing
      nuclear factor-kappaB activation and bcl-2 expression, thus allowing apoptosis of
      cancer cells; and 5) reducing cancer-induced cachexia. It seems reasonable to
      assume that after appropriate cancer therapy, consumption of omega-3 fatty acids
      might slow or stop the growth of metastatic cancer cells, increase longevity of
      cancer patients and improve their quality of life.

PMID- 12421879
TI  - Prevention and management of prostate cancer using PC-SPES: a scientific
      perspective.
AB  - Complementary and alternative therapies are increasingly used in the United
      States by individuals diagnosed with cancer. PC-SPES is a multiherb dietary
      supplement used by many patients with prostate cancer (CaP). The wide acceptance
      of PC-SPES for hormone-naive and end-stage CaP relates to clinical trials
      demonstrating significant efficacy and low toxicity. Although the clinical
      efficacy of PC-SPES is highly encouraging, its scientific basis has progressed
      more slowly. This article describes our understanding of the in vitro mechanisms
      of action of PC-SPES in androgen-dependent LNCaP cells. We first demonstrated
      significant suppression of cancer cell growth by restriction of cell cycle
      progression at G(1)/S and drastic reductions in the expression of androgen
      receptor and prostate-specific antigen (PSA) by PC-SPES, providing a mechanistic
      rationale for its observed clinical effects. Further investigation of the anti
      CaP properties of PC-SPES revealed that two of its multicomponent herbs,
      Glycyrrhiza uralensis and Scutellaria baicalensis, inhibited cell growth and down
      regulated PSA in a manner comparable with PC-SPES. Exhaustive characterization of
      S. baicalensis resulted in the isolation of baicalein. Here we report that
      baicalein effectively suppressed growth and PSA expression and induced G(1)/S
      arrest in LNCaP cells. Although baicalein cannot account for the entire activity
      of PC-SPES, it does display similar anti-CaP activities. These data suggest that
      a single herb or bioactive compound could suffice for CaP chemoprevention by
      effecting multiple changes in target cells to intervene in CaP progression. These
      studies provide the impetus for further evaluation of the composition herbs
      within PC-SPES and the precise characterization of their bioactive ingredients.

PMID- 12421880
TI  - DNA alkylation and repair in the large bowel: animal and human studies.
AB  - O6-methylguanine (O6-MeG), a procarcinogenic DNA adduct that arises from exposure
      to methylating agents, has been detected in human colorectal DNA at levels
      comparable to those that cause adverse effects in model systems. O6-MeG levels
      vary within the colon, being higher in the cancer-prone regions of the large
      bowel. In rats and mice, O6-MeG persistence in colon DNA is associated with the
      induction of colon tumors after treatment with methylating agents. These tumors
      frequently contain K-ras GC-->AT transition mutations, which is consistent with
      the mutagenic properties of O6-MeG: such mutations are also commonly found in
      human colorectal cancers. O6-Alkylguanine adducts are removed by the DNA repair
      protein, O6-alkylguanine DNA-alkyltransferase (MGMT). MGMT overexpression in
      transgenic mice reduces the formation of K-ras GC-->AT mutations and tumors
      induced by methylating agents. Interindividual variations in human colon MGMT
      activity are large and large bowel tumors can occur in regions of low activity.
      Low MGMT activity in normal mucosa has been associated with the occurrence of K
      ras GC-->AT mutations, whereas reduced MGMT expression and an increased frequency
      of K-ras GC-->AT mutations in colorectal cancers have been linked to MGMT
      promoter methylation. MGMT activity is also lower in adenomas than in adjacent
      normal tissue but only in those adenomas with this specific mutation. These
      results are entirely consistent with the hypothesis that GC-->AT mutations in the
      K-ras oncogene result from the formation and persistence of O6-alkylguanine
      lesions in colorectal DNA. Human exposure to endogenous or exogenous alkylating
      agents may thus be an environmental determinant of colorectal cancer risk.

PMID- 12421881
TI  - Effect of white versus red meat on endogenous N-nitrosation in the human colon
      and further evidence of a dose response.
AB  - N-nitroso compounds are found in the colon and are formed endogenously because
      amines and amides are produced by bacterial decarboxylation of amino acids in the
      large gut. They can be N-nitrosated in the presence of a nitrosating agent. To
      test the hypothesis that increased nitrogenous residues from red meat would
      increase endogenous N-nitrosation, thus accounting for the epidemiologic
      association between red meat consumption and colorectal cancer, we fed increased
      levels of red meat and measured apparent total N-nitroso compounds (ATNCs) in
      fecal samples in a series of studies of volunteers maintained under controlled
      conditions. A result of these studies is that we have shown a consistent dose
      response to red meat consumption. Fiber, in the form of vegetables, bran or
      resistant starch, does not reduce the level of ATNCs formed, although transit
      time is reduced and fecal weight are increased. Here we show that the equivalent
      amount (420-600 g) of meat as white meat has no effect on fecal ATNCs in 12
      volunteers (P = 0.338). At dosages of 0, 60, 120, 240 and 420 g of red meat/d,
      mean levels of ATNC output are highly correlated with dose of meat: for
      concentration ATNC versus dose of meat in g/d, r = 0.972, beta = 0.252 ng/g (SE
      0.035); for total ATNC output versus dose of meat in g/d, r = 0.963, beta = 2.605
      microg/d (SE 0.419). The effects of nonmeat protein and of heme on increased N
      nitrosation and the genotoxic effects of the ATNCs produced are presently being
      investigated.

PMID- 12421882
TI  - Total N-nitroso compounds and their precursors in hot dogs and in the
      gastrointestinal tract and feces of rats and mice: possible etiologic agents for
      colon cancer.
AB  - We review evidence that red and processed meat are causes of colon cancer and
      that processed meat is a risk factor for childhood cancer and type 2 diabetes.
      Associations could be due to N-nitroso compounds (NOCs) derived from nitrosation
      of NOC precursors (NOCPs). We review our survey of total NOC and NOCP content of
      foods. Only rapidly nitrosated amines, including a glycosyl amino acid, were
      efficiently determined as NOCPs. NOCPs in hot dogs and rat feces were partly
      purified by adsorption-desorption and HPLC. After nitrosation, purified hot dog
      fractions were directly mutagenic in Ames test. The main NOCPs in these materials
      may be N-glycosyl amino acids and peptides. NOC levels in rat gastrointestinal
      tract rose steadily from stomach to feces. NOCP levels showed similar trend but
      with sharp increases from stomach to duodenum. One day after Min and C57BL/6J
      mice were fed 4% dextran sulfate sodium to induce acute colitis, fecal NOC levels
      increased 1.9-fold compared with untreated mice (P < 0.05). For 7 d Swiss mice
      received semipurified diet, 180 g beef-pork hot dogs mixed with 820 g diet or 180
      g sauteed beef mixed with 820 g diet. Fecal NOC outputs on day 7 were 3.7-5.0
      (hot dog) and 2.0-2.9 (beef) times those for control groups (P < 0.002 for
      combined groups), perhaps reflecting higher dietary NOC intakes. Feeding a
      similar hot dog mixture to mice did not affect normal 7-methyldeoxyguanosine
      level in colonic mucosal DNA. Overall, results support the hypothesis that
      colonic NOCs are a cause of colon cancer.

PMID- 12421883
TI  - Behavioral changes in observational and intervention studies.
AB  - Changes of diet and other lifestyle factors are often highly recommended, but
      evidence for the effectiveness of behavioral changes in adult lives is limited.
      In the European Prospective Investigation into Cancer and Nutrition (EPIC)
      Potsdam study, we investigated the reasons for and the direction of dietary
      changes as well as factors that are associated with the self-report of a change
      in diet. About 47% of the 27,548 cohort members reported a dietary change within
      the first 2 y of the follow-up. Detailed analysis of the type of change showed
      that public health recommendations are clearly understood. More vegetables and
      fruit and less fat are the most reported changes. Investigations into the reasons
      for dietary changes showed that in most instances and in ever shorter intervals,
      dietary recommendations resulting from progress in science are reinforced or
      partly modified. The health-conscious individuals in a population try to put
      these health messages into practice by modifying their behavior; these are the
      individuals who are particularly attracted to participate in scientifically
      oriented prospective studies and therefore are likely to be recruited by and
      retained in these studies. Behavioral changes over time may indicate dietary
      changes that are related to health and weight problems. The consideration of
      dietary changes during prospective data collection, therefore, is an important
      issue in the design and analysis of longitudinal studies-both cohort and
      intervention studies. Cohort studies in which dietary changes are adequately
      measured can contribute substantially to the evidence for health benefits
      resulting from changes in diet.

PMID- 12421888
TI  - Suspicions about the safety of vaccines.

PMID- 12421889
TI  - A population-based study of measles, mumps, and rubella vaccination and autism.
AB  - BACKGROUND: It has been suggested that vaccination against measles, mumps, and
      rubella (MMR) is a cause of autism. METHODS: We conducted a retrospective cohort
      study of all children born in Denmark from January 1991 through December 1998.
      The cohort was selected on the basis of data from the Danish Civil Registration
      System, which assigns a unique identification number to every live-born infant
      and new resident in Denmark. MMR-vaccination status was obtained from the Danish
      National Board of Health. Information on the children's autism status was
      obtained from the Danish Psychiatric Central Register, which contains information
      on all diagnoses received by patients in psychiatric hospitals and outpatient
      clinics in Denmark. We obtained information on potential confounders from the
      Danish Medical Birth Registry, the National Hospital Registry, and Statistics
      Denmark. RESULTS: Of the 537,303 children in the cohort (representing 2,129,864
      person-years), 440,655 (82.0 percent) had received the MMR vaccine. We identified
      316 children with a diagnosis of autistic disorder and 422 with a diagnosis of
      other autistic-spectrum disorders. After adjustment for potential confounders,
      the relative risk of autistic disorder in the group of vaccinated children, as
      compared with the unvaccinated group, was 0.92 (95 percent confidence interval,
      0.68 to 1.24), and the relative risk of another autistic-spectrum disorder was
      0.83 (95 percent confidence interval, 0.65 to 1.07). There was no association
      between the age at the time of vaccination, the time since vaccination, or the
      date of vaccination and the development of autistic disorder. CONCLUSIONS: This
      study provides strong evidence against the hypothesis that MMR vaccination causes
      autism.

PMID- 12421890
TI  - Effects of the amount and intensity of exercise on plasma lipoproteins.
AB  - BACKGROUND: Increased physical activity is related to reduced risk of
      cardiovascular disease, possibly because it leads to improvement in the
      lipoprotein profile. However, the amount of exercise training required for
      optimal benefit is unknown. In a prospective, randomized study, we investigated
      the effects of the amount and intensity of exercise on lipoproteins. METHODS: A
      total of 111 sedentary, overweight men and women with mild-to-moderate
      dyslipidemia were randomly assigned to participate for six months in a control
      group or for approximately eight months in one of three exercise groups: high
      amount-high-intensity exercise, the caloric equivalent of jogging 20 mi (32.0 km)
      per week at 65 to 80 percent of peak oxygen consumption; low-amount-high
      intensity exercise, the equivalent of jogging 12 mi (19.2 km) per week at 65 to
      80 percent of peak oxygen consumption; or low-amount-moderate-intensity exercise,
      the equivalent of walking 12 mi per week at 40 to 55 percent of peak oxygen
      consumption. Subjects were encouraged to maintain their base-line body weight.
      The 84 subjects who complied with these guidelines served as the basis for the
      main analysis. Detailed lipoprotein profiling was performed by nuclear magnetic
      resonance spectroscopy with verification by measurement of cholesterol in
      lipoprotein subfractions. RESULTS: There was a beneficial effect of exercise on a
      variety of lipid and lipoprotein variables, seen most clearly with the high
      amount of high-intensity exercise. The high amount of exercise resulted in
      greater improvements than did the lower amounts of exercise (in 10 of 11
      lipoprotein variables) and was always superior to the control condition (11 of 11
      variables). Both lower-amount exercise groups always had better responses than
      the control group (22 of 22 comparisons). CONCLUSIONS: The highest amount of
      weekly exercise, with minimal weight change, had widespread beneficial effects on
      the lipoprotein profile. The improvements were related to the amount of activity
      and not to the intensity of exercise or improvement in fitness.

PMID- 12421891
TI  - Leukotriene-receptor expression on nasal mucosal inflammatory cells in aspirin
      sensitive rhinosinusitis.
AB  - BACKGROUND: Patients with asthma who have aspirin sensitivity have greater
      cysteinyl leukotriene production and greater airway hyperresponsiveness to the
      effects of inhaled cysteinyl leukotrienes than their aspirin-tolerant
      counterparts. We hypothesized that the latter effect reflects elevated expression
      of the cysteinyl leukotriene receptor CysLT1 on inflammatory cells in the target
      organ and that its expression is down-regulated by aspirin desensitization.
      METHODS: We obtained nasal-biopsy specimens from 22 aspirin-sensitive and 12 non
      aspirin-sensitive patients with chronic rhinosinusitis and nasal polyps.
      Additional specimens were then obtained from subgroups of the aspirin-sensitive
      patients after intranasal application of lysine aspirin or placebo for two weeks
      (five and four patients, respectively) or for six months (five and four patients,
      respectively). The numbers of leukocytes expressing the CysLT1 and leukotriene B4
      (LTB4) receptors per unit area of sections of the nasal submucosa were determined
      by immunohistochemistry. RESULTS: The absolute number of cells expressing the
      CysLT1 receptor was significantly higher in the aspirin-sensitive patients than
      in the non-aspirin-sensitive patients (median, 542 cells per square millimeter
      [range, 148 to 1390] vs. 116 cells per square millimeter [range, 40 to 259];
      P<0.001). The percentage of CD45+ leukocytes expressing the CysLT1 receptor was
      also higher in the aspirin-sensitive subjects (25 percent of CD45+ leukocytes
      [range, 4 to 50] vs. 5 percent of CD45+ leukocytes [range, 2 to 11]; P<0.001);
      the percentage of CD45+ leukocytes expressing the LTB4 receptor did not differ
      significantly between these two groups. Desensitization was associated with a
      decrease in the numbers of inflammatory cells expressing CysLT1. CONCLUSIONS: The
      elevated numbers of nasal inflammatory leukocytes expressing the CysLT1 receptor
      in aspirin-sensitive patients with chronic rhinosinusitis as compared with their
      non-aspirin-sensitive counterparts and the down-regulation of receptor expression
      after desensitization to aspirin are probably fundamental in the pathogenesis of
      aspirin sensitivity and in the mechanism of aspirin desensitization.

PMID- 12421892
TI  - Two patients with unusual forms of varicella-zoster virus vasculopathy.

PMID- 12421893
TI  - Images in clinical medicine. End-stage autosomal dominant polycystic kidney
      disease.

PMID- 12421894
TI  - Clinical practice. Nondiabetic kidney disease.

PMID- 12421895
TI  - Genomic medicine--a primer.

PMID- 12421896
TI  - Exercise to reduce cardiovascular risk--how much is enough?

PMID- 12421897
TI  - Leukotriene receptors and aspirin sensitivity.

PMID- 12421898
TI  - Getting ready for gene-based medicine.

PMID- 12421899
TI  - Renovascular hypertension, endothelial function, and oxidative stress.

PMID- 12421900
TI  - Thrombophilia polymorphisms and intrauterine growth restriction.

PMID- 12421901
TI  - Recurrent glomerulonephritis and risk of renal allograft loss.

PMID- 12421902
TI  - Aberrant right subclavian artery and dysphagia lusoria.

PMID- 12421903
TI  - Acute exacerbations of chronic obstructive pulmonary disease.

PMID- 12421904
TI  - Hypocapnia.

PMID- 12421905
TI  - Peanut allergy.

PMID- 12421906
TI  - Recurrent peanut allergy.

PMID- 12421907
TI  - Images in clinical medicine. Floating left atrial thrombus.

PMID- 12421908
TI  - Cutting edge: tumor rejection mediated by NKG2D receptor-ligand interaction is
      dependent upon perforin.
AB  - We have investigated the primary immunity generated in vivo by MHC class I
      deficient and -competent tumor cell lines that expressed the NKG2D ligand
      retinoic acid early inducible-1 (Rae-1) beta. Rae-1beta expression on class I
      deficient RMA-S lymphoma cells enhanced primary NK cell-mediated tumor rejection
      in vivo, whereas RMA-Rae-1beta tumor cells were rejected by a combination of NK
      cells and CD8(+) T cells. Rae-1beta expression stimulated NK cell cytotoxicity
      and IFN-gamma secretion in vitro, but not proliferation. Surprisingly, only NK
      cell perforin-mediated cytotoxicity, but not production of IFN-gamma, was
      critical for the rejection of Rae-1beta-expressing tumor cells in vivo. This
      distinct requirement for perforin activity contrasts with the NK cell-mediated
      rejection of MHC class I-deficient RMA-S tumor cells expressing other activating
      ligands such as CD70 and CD80. Thus, these results indicated that NKG2D acted as
      a natural cytotoxicity receptor to stimulate perforin-mediated elimination of
      ligand-expressing tumor cells.

PMID- 12421909
TI  - Cutting edge: CD94/NKG2 is expressed on Th1 but not Th2 cells and costimulates
      Th1 effector functions.
AB  - Th1 and Th2 cells can be phenotypically distinguished by very few cell surface
      markers. To identify cell surface molecules that are specifically expressed on
      Th1 cells, we have generated a panel of mAbs that specifically bind the surfaces
      of murine Th1 but not Th2 cells. One of these Abs identified the NK cell receptor
      CD94 as a molecule also specifically expressed on the surface of Th1 cells. As in
      NK cells, CD94 is expressed on Th1 cells together with members of the NKG2 family
      of molecules, including NKG2A, C, and E. Cross-linking these receptors on
      differentiated Th1 cells in vitro costimulates proliferation and cytokine
      production with a potency similar to that obtained by cross-linking CD28. We
      propose that CD94/NKG2 heterodimers may costimulate effector functions of
      differentiated Th1 cells.

PMID- 12421910
TI  - Cutting edge: persistent viral infection prevents tolerance induction and escapes
      immune control following CD28/CD40 blockade-based regimen.
AB  - A continuing concern with CD28 and/or CD40 blockade-based strategies to induce
      tolerance and mixed chimerism is their potential to disrupt protective immunity
      to preexisting infections. In this report, we find that preexisting persistent
      infection with lymphocytic choriomeningitis virus (LCMV) clone 13 prevents the
      induction of tolerance, mixed chimerism, and donor-reactive T cell deletion. Mice
      continue to be refractory to tolerance induction even after viremia has been
      resolved and virus is present only at very low levels in peripheral tissues.
      Conversely, we find that the full tolerance regimen, or costimulation blockade
      alone, specifically inhibits already ongoing antiviral immune responses, leading
      to an inability to control viremia. These findings suggest that ongoing T cell
      responses continue to depend on costimulatory interactions in the setting of a
      chronic infection and provide insight into potential risks following
      costimulation blockade posed by chronic or latent viral infections such as
      hepatitis C, EBV, and CMV.

PMID- 12421911
TI  - Cutting edge: molecular analysis of the negative regulatory function of
      lymphocyte activation gene-3.
AB  - Lymphocyte activation gene (LAG)-3 (CD223) is a CD4-related activation-induced
      cell surface molecule that binds to MHC class II molecules with high affinity and
      negatively regulates T cell expansion and homeostasis. In this study, we show
      that LAG-3 inhibits CD4-dependent, but not CD4-independent, T cell function via
      its cytoplasmic domain. Although high affinity interaction with MHC class II
      molecules is essential for LAG-3 function, tailless LAG-3 does not compete with
      CD4 for ligand binding. A single lysine residue (K468) within a conserved
      "KIEELE" motif is essential for interaction with downstream signaling molecules.
      These data provide insight into the mechanism of action of this important T cell
      regulatory molecule.

PMID- 12421912
TI  - Cutting edge: fever-associated temperatures enhance neutrophil responses to
      lipopolysaccharide: a potential mechanism involving cell metabolism.
AB  - Although much progress has been made in elucidating the mechanisms underlying the
      physiological regulation of fever, there is little understanding of the
      biological utility of fever's thermal component. Considering the evolutionary co
      conservation of fever and innate immunity, we hypothesize that fever's thermal
      component might in general augment innate immune function and, in particular,
      neutrophil activation. Accordingly, we have evaluated the effect of febrile
      temperatures on neutrophil function at the single-cell level. We find that
      reactive oxygen intermediates and NO release are greatly enhanced at febrile
      temperatures for unstimulated as well as LPS-stimulated adherent human
      neutrophils. Furthermore, our studies suggest that these changes in oxidant
      release are linked to upstream changes in NADPH dynamics. Inasmuch as reactive
      oxygen intermediates and NO production are important elements in innate immune
      responses to bacterial pathogens, we suggest that the febrile rise in core
      temperature is a broad-based systemic signaling mechanism to enhance innate
      immunity.

PMID- 12421913
TI  - Cutting edge: CD4+CD25+ alloantigen-specific immunoregulatory cells that can
      prevent CD8+ T cell-mediated graft rejection: implications for anti-CD154
      immunotherapy.
AB  - Blockade of CD40-CD154 interactions can facilitate long-term allograft acceptance
      in selected rodent and in primate models, but, due to the ability of CD154
      independent CD8(+) T cells to initiate graft rejection, this strategy is not
      always effective. In this work we demonstrate that blockade of the CD40-CD154
      pathway at the time of transplantation enables the generation of donor
      alloantigen-specific CD4(+)CD25(+) regulatory T cells, and that if the regulatory
      cells are present in sufficient numbers they can suppress allograft rejection
      mediated by CD154-independent CD8(+) T cells.

PMID- 12421914
TI  - Cutting edge: inhibiting measles virus infection but promoting reproduction: an
      explanation for splicing and tissue-specific expression of CD46.
AB  - Membrane cofactor protein (MCP; CD46) regulates the complement cascade by
      inhibiting C3b and C4b deposited on self tissue. This function resides in the
      complement control protein repeats (CCPs), with CCPs 2-4 essential for
      regulation. MCP is expressed on the inner acrosomal membrane of human sperm, and
      Abs to CCP1 inhibit sperm-egg interactions. In somatic tissues, New World monkeys
      express an alternatively spliced form of MCP lacking CCP1. Although retaining
      complement-regulatory activity, this form is postulated to render these species
      less susceptible to strains of the measles virus whose hemagglutinin requires
      CCP1 and CCP2 for attachment. Using PCR, sequencing, Western blotting, and
      immunohistochemistry, we characterized MCP expression in the testes and sperm of
      two New World monkeys. In these species, sperm express MCP bearing CCP1. The germ
      cell-specific expression pattern of this domain strongly suggests an
      evolutionarily conserved role for MCP in fertilization.

PMID- 12421915
TI  - Cutting edge: association of the motor protein nonmuscle myosin heavy chain-IIA
      with the C terminus of the chemokine receptor CXCR4 in T lymphocytes.
AB  - The binding of chemokines to their receptors guides lymphocyte migration.
      However, the precise mechanism that links the chemotactic signals with the energy
      and traction force generated by the actomyosin complex of the cell has not been
      elucidated. Using biochemical approaches and mass spectrometry analysis, we found
      an association between the C-termini of CXCR4 and CCR5 and the motor protein
      nonmuscle myosin H chain-IIA. Immunoprecipitation experiments revealed that this
      association also occurs between the endogenous molecules in T lymphocytes. As
      expected, myosin L chain was also associated with CXCR4. Confocal microscopy
      analysis showed that CXCR4 and motor protein nonmuscle myosin H chain-IIA
      colocalize at the leading edge of migrating T lymphocytes, together with
      filamentous actin and myosin L chain. These results provide the first evidence of
      a biochemical association between chemokine receptors and motor proteins, a
      mechanosignaling mechanism that may have a key role in lymphocyte migration.

PMID- 12421916
TI  - Transfer of central nervous system autoantigens and presentation in secondary
      lymphoid organs.
AB  - Dendritic cells are thought to regulate tolerance induction vs immunization by
      transferring Ags and peripheral signals to draining lymph nodes (LN). However,
      whether myelin Ag transfer and presentation in LN occurs during demyelinating
      brain disease is unknown. In this study, we demonstrate redistribution of
      autoantigens from brain lesions to cervical LN in monkey experimental autoimmune
      encephalomyelitis (EAE) and in multiple sclerosis (MS). Immunohistochemical
      analysis revealed significantly more cells containing myelin Ags in cervical LN
      of monkeys with EAE compared with those of healthy control monkeys. Myelin Ags
      were observed in cells expressing dendritic cell/macrophage-specific markers, MHC
      class II, and costimulatory molecules. Moreover, these cells were directly
      juxtaposed to T cells, suggesting that cognate interactions between myelin
      containing APC and T cells are taking place in brain-draining LN. Indeed, myelin
      Ag-reactive T cells were observed in cervical LN from marmosets and rhesus
      monkeys. Importantly, these findings were paralleled by our findings in human
      tissue. We observed significantly more myelin Ag-containing cells in LN of
      individuals with MS compared with those of control individuals. These cells
      expressed APC markers, as observed in marmosets and rhesus monkeys. These
      findings suggest that during MS and EAE, modulation of T cell reactivity against
      brain-derived Ags also takes place in cervical LN and not necessarily inside the
      brain. A major implication is that novel therapeutic strategies may be targeted
      to peripheral events, thereby circumventing the blood-brain barrier.

PMID- 12421917
TI  - Tumor-derived heat shock protein 70 peptide complexes are cross-presented by
      human dendritic cells.
AB  - Our study demonstrates that tumor-derived heat shock protein (HSP)70 chaperones a
      tyrosinase peptide and mediates its transfer to human immature dendritic cells
      (DCs) by receptor-dependent uptake. Human tumor-derived HSP70 peptide complexes
      (HSP70-PC) thus have the immunogenic potential to instruct DCs to cross-present
      endogenously expressed, nonmutated, and tumor antigenic peptides that are shared
      among tumors of the melanocytic lineage for T cell recognition. T cell
      stimulation by HSP70-instructed DCs is dependent on the Ag bound to HSP70 in that
      only DCs incubated with HSP70-PC purified from tyrosinase-positive (HSP70
      PC/tyr(+)) but not from tyrosinase-negative (HSP70-PC/tyr(-)) melanoma cells
      resulted in the specific activation of the HLA-A*0201-restricted tyrosinase
      peptide-specific cytotoxic T cell clone. HSP70-PC-mediated T cell stimulation is
      very efficient, delivering the tyrosinase peptide at concentrations as low as 30
      ng/ml of HSP70-PC for T cell recognition. Receptor-dependent binding of HSP70-PC
      and active cell metabolism are prerequisites for MHC class I-restricted cross
      presentation and T cell stimulation. T cell stimulation does not require external
      DC maturation signals (e.g., exogenously added TNF-alpha), suggesting that
      signaling DC maturation is an intrinsic property of the HSP70-PC itself and
      related to receptor-mediated binding. The cross-presentation of a shared human
      tumor Ag together with the exquisite efficacy are important new aspects for HSP70
      based immunotherapy in clinical anti-cancer vaccination strategies, and suggest a
      potential extension of HSP70-based vaccination protocols from a patient
      individual treatment modality to its use in an allogeneic setting.

PMID- 12421918
TI  - Functional activity of natural antibody is altered in Cr2-deficient mice.
AB  - The major source of natural IgM Abs are B-1 cells, which differ from conventional
      B cells in their anatomic location, cell surface phenotype, restricted usage of
      particular V(H) genes and limited use of N-region addition during V-D-J
      rearrangement. The origin of B-1 cells is unclear. However, they are capable of
      self-renewal and their development is sensitive to signaling via the B cell
      receptor, as genetic defects that impair the strength of the signal often result
      in limited development. These findings suggest that B-1 cells require either an
      intrinsic signal, or contact with Ag, for positive selection and expansion and/or
      maintenance in the periphery. In support of interaction with cognate Ag,
      deficiency in the complement receptors CD21/CD35 results in a 30-40% decrease in
      the CD5(+) B-1 population. To determine whether this reduction reflects a loss of
      certain specificities or simply a proportional decline in the repertoire, we
      examined peritoneal B cells isolated from Cr2(+) and Cr2(def) mice for
      recognition of a B-1 cell Ag, i.e., phosphatidylcholine, and assayed for injury
      in an IgM natural Ab-dependent model of reperfusion injury. We found a similar
      frequency of phosphatidylcholine-specific CD5(+) B-1 cells in the two strains of
      mice. By contrast, the Cr2(def) mice have reduced injury in the IgM-dependent
      model of reperfusion injury. Reconstitution of the deficient mice with pooled IgM
      or adoptive transfer of Cr2(+) peritoneal B cells restored injury. These results
      suggest that complement receptors CD21/CD35 are important in maintenance of the B
      1 cell repertoire to some, but not all, specificities.

PMID- 12421919
TI  - Evidence that SHIP-1 contributes to phosphatidylinositol 3,4,5-trisphosphate
      metabolism in T lymphocytes and can regulate novel phosphoinositide 3-kinase
      effectors.
AB  - The leukemic T cell line Jurkat is deficient in protein expression of the lipid
      phosphatases Src homology 2 domain containing inositol polyphosphate phosphatase
      (SHIP) and phosphatase and tensin homolog deleted on chromosome ten (PTEN). We
      examined whether the lack of expression of SHIP-1 and PTEN is shared by other
      leukemic T cell lines and PBLs. Analysis of a range of cell lines and PBLs
      revealed that unlike Jurkat cells, two other well-characterized T cell lines,
      namely CEM and MOLT-4 cells, expressed the 5'-phosphatase SHIP at the protein
      level. However, the 3-phosphatase PTEN was not expressed by CEM or MOLT-4 cells
      or Jurkat cells. The HUT78 cell line and PBLs expressed both SHIP and PTEN.
      Jurkat cells exhibited high basal levels of phosphatidylinositol 3,4,5
      trisphosphate (PI(3,4,5)P(3); the lipid substrate for both SHIP and PTEN) as well
      as saturated protein kinase B (PKB) phosphorylation. Lower levels of
      PI(3,4,5)P(3) and higher levels of phosphatidylinositol 3,4-bisphosphate
      (PI(3,4)P(2)) as well as unsaturated constitutive phosphorylation of PKB were
      observed in CEM and MOLT-4 cells compared with Jurkat cells. In PBLs and HUT78
      cells which express both PTEN and SHIP-1, there was no constitutive PI(3,4,5)P(3)
      or PKB phosphorylation, and receptor stimuli were able to elicit robust
      phosphorylation of PKB. Expression of a constitutively active SHIP-1 protein in
      Jurkat cells was sufficient to reduce both constitutive PKB membrane localization
      and PKB phosphorylation. Together, these data indicate important differences
      between T leukemic cells as well as PBLs, regarding expression of key lipid
      phosphatases. This study provides the first evidence that SHIP-1 can influence
      the constitutive levels of PI(3,4,5)P(3) and the activity of downstream
      phosphoinositide 3-kinase effectors in T lymphocytes.

PMID- 12421920
TI  - Sonic hedgehog signaling modulates activation of and cytokine production by human
      peripheral CD4+ T cells.
AB  - Sonic hedgehog (Shh) is important in the growth and differentiation of a variety
      of cell types, including the development of T cells in the thymus. This prompted
      us to investigate whether Shh signaling is a functional component of the
      physiological response of human mature CD4(+) T cells following Ag recognition.
      In this study, we demonstrate that Shh and its receptor Patched (Ptc) are
      expressed on resting and activated human peripheral CD4(+) T cells. In
      approximately one-half of the randomly selected, anonymous blood donors tested,
      exposure of anti-CD3/28 Ab-activated CD4(+) T cells to the biologically active N
      terminal Shh peptide increased the transcription of ptc, thereby demonstrating
      that Shh signaling had occurred. Furthermore, the addition of exogenous Shh
      amplified the production of IL-2, IFN-gamma, and IL-10 by activated CD4(+) T
      cells. The synthesis of IL-2 and IFN-gamma, but not IL-10, by CD4(+) T cells was
      down-regulated by the addition of neutralizing anti-Shh Ab. Cell surface
      expression of CD25 and CD69 on activated T cells was up-regulated by exogenous
      Shh, whereas in the presence of the neutralizing anti-Shh Ab expression it was
      reduced. Collectively, our findings demonstrate that Shh-mediated signaling is a
      physiological component of T cell responses, which acts to modulate CD4(+) T cell
      effector function.

PMID- 12421921
TI  - Antigen-nonspecific recruitment of Th2 cells to the lung as a mechanism for viral
      infection-induced allergic asthma.
AB  - Respiratory viral infections have been shown to trigger exacerbations of asthma;
      however, the mechanism by which viral Th1-type inflammation exacerbates an
      allergic Th2-type disease remains unclear. We have previously shown that although
      adoptively transferred Th2 cells are inefficiently recruited to the lung in
      response to Ag, cotransfer of Th1 cells can increase accumulation of Th2 cells.
      In this study, we show that respiratory viral infection increases recruitment of
      resting Th2 cells specific for OVA even in the absence of OVA challenge. These
      findings suggest that the mechanism by which Th1-type inflammation enhances
      allergy is via an effect on recruitment. To study the role of the antigenic
      specificity of Th1 cells in the enhancement of Th2 cell recruitment and to
      determine whether virus-induced recruitment of OVA-specific Th2 cells may involve
      Th1 cells specific to a different Ag, we tested whether hen egg lysozyme-specific
      Th1 cells could synergize with OVA-specific Th2 cells. Challenge of mice that had
      received adoptively transferred Th1 cells plus Th2 cells induced the expression
      of inflammatory chemokines in the lung and increased both recruitment and
      activation of Th2 cells, leading to eosinophil recruitment, even in the absence
      of challenge with the Th2 Ag. Interestingly, as IL-5 supports eosinophilia,
      culture of resting Th2 cells with fresh APC induced production of IL-5 in the
      absence of specific Ag. Thus, Ag-specific activation of Th1 cells enhances the
      recruitment potential of the lung leading to recruitment and activation of Th2
      cells. This implies that circulating Th2 cells in allergic individuals could
      enter the lungs in response to infection or inflammation and become activated to
      trigger allergy.

PMID- 12421922
TI  - IgE cross-linking or lipopolysaccharide treatment induces recruitment of Th2
      cells to the lung in the absence of specific antigen.
AB  - We previously showed that Th1 cells can increase recruitment of Th2 cells to the
      lungs even in the absence of the Th2-specific Ag. The fact that Th2 recruitment
      is independent from the Th2 cell Ag suggested that Th1 cells may support Th2 cell
      recruitment using their Ag-nonspecific proinflammatory functions. To investigate
      the potential for inflammatory stimuli that are distinct from Ag-specific signals
      to affect the recruitment of T cells, we tested whether cross-linking of IgE or
      treatment with LPS modulated influx of Th2 cells into the airways in the presence
      or absence of inhaled Ag. When naive mice that had been treated with OVA-specific
      Th2 cells and passively sensitized with anti-DNP IgE were challenged by
      intranasal administration of either DNP-haptenated OVA or DNP-BSA, increased
      numbers of Th2 cells were recruited to the lung compared with mice challenged
      intranasally with OVA alone. Intranasal administration of LPS also increased
      recruitment of Th2 cells to the airways. These two distinct inflammatory stimuli
      increased the numbers of recruited Th2 cells equally with or without concurrent
      challenge using the cognate Th2 Ag. This Ag-independent recruitment of Th2 cells
      to the lung was not associated with localization of these cells to the regional
      lymph nodes and was independent of Th2 cell activation. Interestingly, P- or E
      selectin contributed to Th2 cell recruitment to the lung. These data suggest that
      Th2 cells of the adaptive immune response are similar to cells of the innate
      immune response in their lack of requirement for protein Ag to initiate cell
      recruitment. They demonstrate further that recruitment can occur independently of
      Ag-dependent activation.

PMID- 12421923
TI  - The osmoprotective function of the NFAT5 transcription factor in T cell
      development and activation.
AB  - The NFAT5/TonEBP transcription factor, a recently identified rel/NF-kappaB family
      member, activates transcription of osmocompensatory genes in response to
      extracellular hyperosmotic stress. However, the function of NFAT5 under isosmotic
      conditions present in vivo remains unknown. Here we demonstrate that NFAT5 is
      necessary for optimal T cell development in vivo and allows for optimal cell
      growth ex vivo under conditions associated with osmotic stress. Transgenic mice
      expressing an inhibitory form of NFAT5 in developing and mature T cells exhibited
      a 30% reduction in thymic cellularity evenly distributed among thymic subsets,
      consistent with the uniform expression and nuclear localization of NFAT5 in each
      subset. This was associated with a 25% reduction in peripheral CD4(+) T cells and
      a 50% reduction in CD8(+) T cells. While transgenic T cells exhibited no
      impairment in cell growth or cytokine production under normal culture conditions,
      impaired cell growth was observed under both hyperosmotic conditions and
      isosmotic conditions associated with osmotic stress. Transgenic thymocytes also
      demonstrated increased sensitivity to osmotic stress. Consistent with this, the
      system A amino acid transporter gene ATA2 exhibited NFAT5 dependence under
      hypertonic conditions but not in response to amino acid deprivation. Expression
      of the TNF-alpha gene, a putative NFAT5 target, was not altered in transgenic T
      cells. These results not only demonstrate an osmoprotective function for NFAT5 in
      primary cells but also show that NFAT5 is necessary for optimal thymic
      development in vivo, suggesting that developing thymocytes within the thymic
      microenvironment are subject to an osmotic stress that is effectively countered
      by NFAT5-dependent responses.

PMID- 12421924
TI  - Macrophage-derived complement component C4 can restore humoral immunity in C4
      deficient mice.
AB  - Mice with a disrupted C4 locus (C4(-/-)) have an impaired immune response to
      thymus-dependent Ags. To test the role of bone marrow-derived C4 in humoral
      immunity, we reconstituted deficient animals with wild-type bone marrow or an
      enriched fraction of bone marrow-derived macrophages. C4 chimeras were immunized
      with 4-hydroxy-3-nitrophenyl(5) conjugated to keyhole limpet hemocyanin (NP(5)-
      KLH) or infected with HSV-1, and the Ab response was evaluated. Wild-type bone
      marrow rescued the humoral immune response to both Ags, i.e., the soluble Ag and
      HSV-1, demonstrating that local C4 production is sufficient for humoral
      responses. Although the C4 chimeric animals lacked detectable C4 in their sera,
      C4 mRNA was identified in splenic sections by in situ hybridization, and C4
      protein deposits were identified in the germinal center areas of splenic
      follicles by immunofluorescence staining. Macrophages derived from bone marrow
      produced sufficient C4 protein to restore the humoral response to NP(5)-KLH in C4
      deficient animals when administered along with Ag. Cell-sorting experiments,
      followed by C4-specific RT-PCR, identified splenic macrophages (CD11b(+), CD11c(
      )) as a cellular source for C4 synthesis within the spleen.

PMID- 12421925
TI  - Bone morphogenetic protein 2/4 signaling regulates early thymocyte
      differentiation.
AB  - Bone morphogenetic protein (BMP)2 and BMP4 are involved in the development of
      many tissues. In this study, we show that BMP2/4 signaling is involved in
      thymocyte development. Our data suggest that termination of BMP2/4 signaling is
      necessary for differentiation of CD44(+)CD25(-)CD4(-)CD8(-) double negative (DN)
      cells along the T cell lineage. BMP2 and BMP4 are produced by the thymic stroma
      and the requisite BMP receptor molecules (BMPR-1A, BMPR-1B, BMPR-II), and signal
      transduction molecules (Smad-1, -5, -8, and -4) are expressed by DN thymocytes.
      BMP4 inhibits thymocyte proliferation, enhances thymocyte survival, and arrests
      thymocyte differentiation at the CD44(+)CD25(-) DN stage, before T cell lineage
      commitment. Neutralization of endogenous BMP2 and BMP4 by treatment with the
      antagonist Noggin promotes and accelerates thymocyte differentiation, increasing
      the expression of CD2 and the proportion of CD44(-)CD25(-) DN cells and
      CD4(+)CD8(+) double-positive cells. Our study suggests that the BMP2/4 pathway
      may function in thymic homeostasis by regulating T cell lineage commitment and
      differentiation.

PMID- 12421926
TI  - TRAIL/Apo-2 ligand induces primary plasma cell apoptosis.
AB  - Apoptosis constitutes the primary mechanism by which noncycling plasma cells are
      eliminated after the secretion of Ag-specific Abs in a humoral immune response.
      The underlying mechanism is not known. Here, we demonstrate that the expression
      of both TRAIL/Apo-2 ligand and the death receptors (DR) DR5 and DR4, but not Fas,
      are sustained in IL-6-differentiated Ig-secreting human plasma cells as well as
      primary mouse plasma cells generated in a T-dependent immune response. Plasma
      cell apoptosis is induced by both endogenous and exogenous TRAIL ex vivo,
      suggesting that TRAIL-mediated killing may, in part, be plasma cell autonomous.
      By contrast, resting and activated B cells are resistant to TRAIL killing despite
      comparable expression of TRAIL and DRs. The preferential killing of plasma cells
      by TRAIL correlates with decreased expression of CD40 and inactivation of NF
      kappaB. These results provide the first evidence that primary plasma cells
      synthesize TRAIL and are direct targets of TRAIL-mediated apoptosis, which may
      relate to the inactivation of the NF-kappaB survival pathway.

PMID- 12421927
TI  - Organ-specific cytokine polarization induced by adoptive transfer of transgenic T
      cells.
AB  - There are two distinct phenotypes of T cell cytokine responses that lead to
      different effector functions and different outcomes in disease processes.
      Although evidence suggests a possible role of the local microenvironment in the
      differentiation or localization of T cells with these phenotypes, there are no
      examples of divergent T cell cytokine phenotypes with the same Ag specificity
      concurrently existing in different tissue compartments. Using a CD8(+) T cell
      adoptive transfer model for graft-vs-host disease, we demonstrate that a potent
      type 2 cytokine response develops in the spleen while a potent type 1 cytokine
      response simultaneously develops in the testis. These experiments demonstrate for
      the first time that cytokine production can be oppositely polarized in different
      organs of the same individual. This may have important implications for organ
      specific pathology in infection or autoimmunity: infections or autoimmune
      diseases that affect multiple organs may have heterogeneity in tissue cytokine
      responses that is not revealed in systemic lymphocyte cytokine responses.
      Therefore, attempts to modulate the immune response phenotype may ameliorate
      pathology in one organ while exacerbating pathology in another.

PMID- 12421928
TI  - Lack of effector cell function and altered tetramer binding of tumor-infiltrating
      lymphocytes.
AB  - Tumor-specific CD8 T cell responses to MCA102 fibrosarcoma cells expressing the
      cytotoxic T cell epitope gp33 from lymphocytic choriomeningitis virus were
      studied. MCA102(gp33) tumors grew progressively in C57BL/6 mice, despite
      induction of peripheral gp33-tetramer(+) T cells that were capable of mediating
      antiviral protection, specific cell rejection, and concomitant tumor immunity.
      MCA102(gp33) tumors were infiltrated with a high number ( approximately 20%) of
      CD11b(+)CD11c(-) macrophage-phenotype cells that were able to cross-present the
      gp33 epitope to T cells. Tumor-infiltrating CD8 T cells exhibited a highly
      activated phenotype but lacked effector cell function. Strikingly, a significant
      portion of tumor-infiltrating lymphocytes expressed TCRs specific for gp33 but
      bound MHC tetramers only after cell purification and a 24-h resting period in
      vitro. The phenomenon of "tetramer-negative T cells" was not restricted to tumor
      infiltrating lymphocytes from MCA102(gp33) tumors, but was also observed when Ag
      specific T cells derived from an environment with high Ag load were analyzed ex
      vivo. Thus, using a novel tumor model, allowing us to trace tumor-specific T
      cells at the single cell level in vivo, we demonstrate that the tumor
      microenvironment is able to alter the functional activity of T cells infiltrating
      the tumor mass.

PMID- 12421929
TI  - Release and intercellular transfer of cell surface CD81 via microparticles.
AB  - The human tetraspan molecule CD81 is a coreceptor in B and T cell activation and
      a candidate receptor for hepatitis C virus infection. We examined the surface
      expression of CD81 on B and T lymphocytes by quantitative flow cytometry. Upon
      cellular activation, CD81 surface levels were rapidly reduced. This reduction
      occurred as early as 1 h after activation and was linked to the release of CD81
      positive microparticles into the cell culture medium. CD81 mRNA levels were not
      affected early after activation, but the release of CD81-positive microparticles
      was rapidly enhanced. In addition, intercellular transfer of CD81 was observed
      upon coculture of CD81-positive donor cells (Jurkat T cell line) with CD81
      negative acceptor cells (U937 promonocytic cell line). This transfer was rapidly
      increased upon T cell activation, coinciding with enhanced CD81 release from
      activated Jurkat cells. We propose that the release and intercellular trafficking
      of CD81-positive microparticles regulate the expression of CD81 surface receptors
      in lymphocytes and play a role in the immune response during infections.

PMID- 12421930
TI  - Expression of programmed death 1 ligands by murine T cells and APC.
AB  - Programmed death 1 (PD-1) is a new member of the CD28/CTLA-4 family, which has
      been implicated in the maintenance of peripheral tolerance. Two ligands for PD-1,
      namely, B7-H1 (PD-L1) and B7-DC (PD-L2), have recently been identified as new
      members of the B7 family but their expression at the protein level remains
      largely unknown. To characterize the expression of B7-H1 and B7-DC, we newly
      generated an anti-mouse B7-H1 mAb (MIH6) and an anti-mouse B7-DC mAb (TY25). MIH6
      and TY25 immunoprecipitated a single molecule of 43 and 42 kDa from the lysate of
      B7-H1 and B7-DC transfectants, respectively. Flow cytometric analysis revealed
      that B7-H1 was broadly expressed on the surface of mouse tumor cell lines while
      the expression of B7-DC was rather restricted. PD-1 was expressed on anti-CD3
      stimulated T cells and anti-IgM plus anti-CD40-stimulated B cells at high levels
      but was undetectable on activated macrophages or DCs. B7-H1 was constitutively
      expressed on freshly isolated splenic T cells, B cells, macrophages, and
      dendritic cells (DCs), and up-regulated on T cells by anti-CD3 stimulation on
      macrophages by LPS, IFN-gamma, GM-CSF, or IL-4, and on DCs by IFN-gamma, GM-CSF,
      or IL-4. In contrast, B7-DC expression was only inducible on macrophages and DCs
      upon stimulation with IFN-gamma, GM-CSF, or IL-4. The inducible expression of PD
      1 ligands on both T cells and APCs may suggest new paradigms of PD-1-mediated
      immune regulation.

PMID- 12421931
TI  - G protein-coupled chemokine receptors induce both survival and apoptotic
      signaling pathways.
AB  - Chemokine receptors are essential for triggering chemotaxis to immune cells;
      however, a number of them can also mediate death when engaged by nonchemokine
      ligands. When the chemokine receptor CXCR4 is engaged by stromal cell-derived
      factor (SDF1)alpha, it triggers cells to chemotax, and in some cell types such as
      neurons, causes cell death. To elucidate this dual and opposing receptor
      function, we have investigated whether CXCR4 activation by its chemokine
      SDF1alpha could lead to the simultaneous activation of both anti- and
      proapoptotic signaling pathways; the balance ultimately influencing cell
      survival. CXCR4 activation in CD4 T cells by SDF1alpha led to the activation of
      the prosurvival second messengers, Akt and extracellular signal-regulated protein
      kinase. Selective inhibition of each signal demonstrated that extracellular
      signal-regulated protein kinase is essential for mediating SDF1alpha-triggered
      chemotaxis but does not confer an antiapoptotic state. In contrast, Akt
      activation through CXCR4 by SDF1alpha interactions is necessary to confer
      resistance to apoptosis. The proapoptotic signaling pathway triggered by
      SDF1alpha-CXCR4 interaction involves the G(ialpha) protein-independent activation
      of the proapoptotic MAPK (p38). Furthermore, other chemokines and chemokine
      receptors also signal chemotaxis and proapoptotic effects via similar pathways.
      Thus, G(ialpha) protein-coupled chemokine receptors can function as death prone
      receptors and the balance between the above signaling pathways will ultimately
      mandate the fate of the activated cell.

PMID- 12421932
TI  - Retinoic acid stimulates the cell cycle machinery in normal T cells: involvement
      of retinoic acid receptor-mediated IL-2 secretion.
AB  - The mechanisms whereby vitamin A stimulates the immune system are poorly
      understood. In the current study, we attempted to elucidate the potential
      mechanisms of action of all-trans retinoic acid (atRA) on proliferation of human
      T lymphocytes. We found that physiological levels of atRA potently augmented T
      cell proliferation when added in combination with common T cell-stimulating
      agents. This was reflected in a time- and concentration-dependent stimulation of
      the cell cycle machinery. The presence of atRA led to elevated levels of cyclin
      D3, -E, and -A, decreased levels of p27(Kip1), increased activity of cyclin
      dependent kinase 2, and enhanced phosphorylation of the retinoblastoma protein
      (pRB). The atRA-mediated changes in the cell cycle machinery were late events,
      appearing after 20 h of stimulation, indicating that the effects of atRA were
      indirect. atRA did not alter the expression of the high-affinity IL-2R. However,
      the level of IL-2 secreted by T cells was strongly enhanced by atRA. rIL-2 was
      able to substitute for the effects of atRA on the cell cycle machinery and on DNA
      synthesis, and blocking the IL-2R markedly inhibited atRA-induced cell
      proliferation and pRB phosphorylation. A retinoic acid receptor (RAR)-selective
      agonist and 9-cis-RA had the same potency as atRA on T cell proliferation and IL
      2 secretion, whereas a retinoid X receptor-selective agonist had only marginal
      effects. Furthermore, a RAR-selective antagonist completely suppressed T cell
      proliferation and pRB phosphorylation induced by atRA. Taken together, these
      results suggest that atRA stimulates the cell cycle machinery and proliferation
      of normal human T cells by increasing IL-2 secretion through mechanisms involving
      RARs.

PMID- 12421933
TI  - Immune tolerance to combined organ and bone marrow transplants after fractionated
      lymphoid irradiation involves regulatory NK T cells and clonal deletion.
AB  - Immune tolerance to organ transplants has been reported in laboratory animals and
      in humans after nonmyeloablative conditioning of the host and infusion of donor
      bone marrow cells. We examined the mechanisms of immune tolerance to mouse
      cardiac allografts in MHC-mismatched hosts that developed mixed chimerism after
      posttransplant conditioning with a 2-wk course of multiple doses of lymphoid
      tissue irradiation, depletive anti-T cell Abs, and an infusion of donor bone
      marrow cells. When CD1(-/-) or J(alpha)281(-/-) hosts with markedly reduced NK T
      cells were used instead of wild-type hosts, then the conditioning regimen failed
      to induce tolerance to the heart allografts despite the development of mixed
      chimerism. Tolerance could be restored to the CD1(-/-) hosts by infusing enriched
      T cells from the bone marrow of wild-type mice containing CD1-reactive T cells
      but not from CD1(-/-) host-type mice. Tolerance could not be induced in either IL
      4(-/-) or IL-10(-/-) hosts given the regimen despite the development of chimerism
      and clonal deletion of host T cells to donor MHC-Ags in the IL-10(-/-) hosts. We
      conclude that immune tolerance to bone marrow transplants involves clonal
      deletion, and tolerance to heart allografts in this model also involves
      regulatory CD1-reactive NK T cells.

PMID- 12421934
TI  - Human MHC class I transgenic mice deficient for H2 class I expression facilitate
      identification and characterization of new HLA class I-restricted viral T cell
      epitopes.
AB  - Although mice transgenic (Tg) for human MHC (HLA) class I alleles could provide
      an important model for characterizing HLA-restricted viral and tumor Ag CTL
      epitopes, the extent to which Tg mouse T cells become HLA restricted in the
      presence of endogenous H2 class I and recognize the same peptides as in HLA
      allele-matched humans is not clear. We previously described Tg mice carrying the
      HLA-B27, HLA-B7, or HLA-A2 alleles expressed as fully native (HLA(nat)) (with
      human beta(2)-microglobulin) and as hybrid human/mouse (HLA(hyb)) molecules on
      the H2(b) background. To eliminate the influence of H2(b) class I, each HLA Tg
      strain was bred with a H2-K(b)/H2-D(b)-double knockout (DKO) strain to generate
      mice in which the only classical class I expression was the human molecule.
      Expression of each HLA(hyb) molecule and HLA-B27(nat)/human beta(2)-microglobulin
      led to peripheral CD8(+) T cell levels comparable with that for mice expressing a
      single H2-K(b) or H2-D(b) gene. Influenza A infection of Tg HLA-B27(hyb)/DKO
      generated a strong CD8(+) T cell response directed at the same peptide (flu
      nucleoprotein NP383-391) recognized by CTLs from flu-infected B27(+) humans. As
      HLA-B7/flu epitopes were not known from human studies, we used flu-infected Tg
      HLA-B7(hyb)/DKO mice to examine the CTL response to candidate peptides identified
      based on the B7 binding motif. We have identified flu NP418-426 as a major HLA-B7
      restricted flu CTL epitope. In summary, the HLA class I Tg/H2-K/H2-D DKO mouse
      model described in this study provides a sensitive and specific approach for
      identifying and characterizing HLA-restricted CTL epitopes for a variety of human
      disease-associated Ags.

PMID- 12421936
TI  - Effect of suppressive DNA on CpG-induced immune activation.
AB  - Bacterial DNA and synthetic oligodeoxynucleotides (ODN) containing unmethylated
      CpG motifs stimulate a strong innate immune response. This stimulation can be
      abrogated by either removing the CpG DNA or adding inhibitory/suppressive motifs.
      Suppression is dominant over stimulation and is specific for CpG-induced immune
      responses (having no effect on LPS- or Con A-induced activation). Individual
      cells noncompetitively internalize both stimulatory and suppressive ODN. Studies
      using ODN composed of both stimulatory and suppressive motifs indicate that
      sequence recognition proceeds in a 5'-->3' direction, and that a 5' motif can
      block recognition of immediately 3' sequences. These findings contribute to our
      understanding of the immunomodulatory activity of DNA-based products and the
      rules that govern immune recognition of stimulatory and suppressive motifs.

PMID- 12421935
TI  - The balance between donor T cell anergy and suppression versus lethal graft
      versus-host disease is determined by host conditioning.
AB  - Graft-vs-host disease (GVHD) remains the most life-threatening complication
      following the transfer of allogeneic bone marrow into immunocompromised hosts.
      Transferred alloreactive T cells respond in a complex manner. While massive T
      cell expansion is observed upon entry into an allogeneic environment, anergy,
      apoptosis, and repertoire selection are also observed. The study presented here
      shows that alloreactive T cell expansion and differentiation vs anergy and
      suppression are dramatically influenced by host conditioning. Using alloreactive
      CD4(+) and CD8(+) TCR transgenic (Tg) T cells, a novel GVHD model is presented
      that allows for the visualization of how alloreactive T cells behave when host
      conditioning is manipulated. Following the transfer of alloreactive CD4(+) and
      CD8(+) TCR Tg T cells into sublethally irradiated hosts, both Tg T cells
      populations expand, develop effector function, and cause GVHD. In contrast, when
      Tg T cells are transferred in non-irradiated hosts, expansion is observed, but
      there is no development of effector function or disease. Assessment of CD4(+) Tg
      T cell function following transfer into non-irradiated hosts reveals that these
      CD4(+) Tg cells are profoundly anergic and have acquired a regulatory function,
      as manifested in their ability to suppress the expansion of naive TCR Tg T cells
      in vitro and in vivo as well as the development of GVHD. These findings
      underscore the decisive effect of the inflammatory environment created by
      irradiation in determining the ultimate fate and function of alloreactive T cells
      in vivo

PMID- 12421937
TI  - HLA-DQ determines the response to exogenous wheat proteins: a model of gluten
      sensitivity in transgenic knockout mice.
AB  - We have investigated the genetic basis of the immune response to dietary gluten
      in HCD4/DQ8 and HCD4/DQ6 double transgenic mice. Mice were immunized with gluten
      i.p. or individual peptides s.c. and spleen or draining lymph node T cells were
      challenged in vitro. Strong proliferative responses to gluten were seen in the
      HCD4/DQ8 mice, whereas the HCD4/DQ6 mice responded to gluten poorly. A series of
      overlapping peptides spanning gliadin were synthesized. The HCD4/DQ8 mice reacted
      to many of the individual peptides of gliadin, while the HCD4/DQ6 mice were
      relatively unresponsive. T cells isolated from HCD4/DQ8 mice also responded well
      to modified (deamidated) versions of the gliadin peptides, whereas HCD4DQ6 mice
      did not. The T cell response to gluten was CD4 dependent and DQ restricted and
      led to the production of cytokines IL-6, TGF-beta, and IL-10. Finally, intestinal
      lymphocytes isolated from gluten-fed HCD4/DQ8 mice displayed an activated
      phenotype. These data suggest that this HLA class II transgenic murine model of
      gluten sensitivity may provide insight into the initiation of the MHC class II
      restricted gluten sensitivity in celiac disease.

PMID- 12421938
TI  - Allogeneic neonatal neuronal retina grafts display partial immune privilege in
      the subcapsular space of the kidney.
AB  - Transplantation of immature retinal tissues may offer a solution for restoring
      sight to individuals afflicted with degenerative retinal diseases. Promising
      results have recently demonstrated that neonatal retinal grafts placed in the eye
      can survive, differentiate into photoreceptor cells, and respond to evoked
      electrical stimuli. These transplants, however, were performed in immunologically
      immature recipients. Since it is important to know whether neonatal neuronal
      retina (NNR) tissue is immunogenic in immune-competent recipients, and whether
      this tissue displays inherent immune privilege, we have examined the fate of such
      grafts placed in a non-immune-privileged site of adult recipient mice. We found
      that typical, photoreceptor-dominated rosettes formed in differentiating NNR
      grafts, and that these allografts survived beyond 12 days, whereas genetically
      identical skin grafts were rejected earlier. Class II MHC-bearing cells of
      recipient origin were observed along the edge of NNR allografts as early as day
      5. Donor-specific delayed hypersensitivity was not detected at 12 days, but did
      emerge on day 20, coincident with rejection of NNR allografts. Lymph nodes, but
      not spleens, of mice bearing NNR grafts at 12 days contained regulatory lymphoid
      cells that suppressed delayed hypersensitivity in naive recipients. We conclude
      that NNR grafts accommodate and even differentiate in the non-immune-privileged
      space beneath the kidney capsule. Survival beneath the kidney capsule of NNR
      allografts, but not skin allografts, at 12 days and beyond implies that NNR
      tissue possesses inherent immune privilege. The vulnerability of these grafts to
      rejection by 20 days reveals this privilege to be partial and temporary.

PMID- 12421939
TI  - CD19 signaling pathways play a major role for murine AIDS induction and
      progression.
AB  - Infection of genetically susceptible mice with the LP-BM5 mixture of murine
      leukemia viruses including an etiologic defective virus (BM5def) causes an
      immunodeficiency syndrome called murine AIDS (MAIDS). The disease is
      characterized by interactions between B cells and CD4(+) T cells resulting in
      polyclonal activation of both cell types. It is known that BM5def is expressed at
      highest levels in B cells and that B cells serve as viral APC. The CD19-CD21
      complex and CD22 on the surface of B cells play critical roles as regulators of B
      cell responses to a variety of stimuli, influencing cell activation,
      differentiation, and survival. CD19 integrates positive signals induced by B cell
      receptor ligation by interacting with the protooncogene Vav, which leads to
      subsequent tyrosine phosphorylation of this molecule. In contrast, CD22
      negatively regulates Vav phosphorylation. To analyze the role of CD19, CD21, Vav,
      and CD22 in MAIDS, we infected mice deficient in CD19, CD21 (CR2), Vav-1, or CD22
      with LP-BM5 murine leukemia viruses. Infected CR2(-/-) mice developed MAIDS with
      a time course and severity indistinguishable from that of wild-type mice. In
      contrast, CD19 as well as Vav-1 deficiency restricted viral replication and
      suppressed the development of typical signs of MAIDS including splenomegaly,
      lymphadenopathy, and hypergammaglobulinemia. Finally, CD22 deficiency was found
      to accelerate MAIDS development. These results provide novel insights into the B
      cell signaling pathways required for normal induction and progression of MAIDS.

PMID- 12421940
TI  - Competition between MHC class I alleles for cell surface expression alters CTL
      responses to influenza A virus.
AB  - Mammalian cells express up to six different MHC class I alleles, many of which
      differ in terms of their interaction with components of the Ag presentation
      pathway and level of cell surface expression. However, it is often assumed in Ag
      presentation studies that class I alleles function independently of each other.
      We have compared cell surface expression levels and function of MHC class I
      molecules in F(1) hybrid mice with those in the homozygous parental strains. The
      level of cell surface expression of certain alleles in F(1) mice differed
      significantly from 50% of that found on the same cell type in the corresponding
      parental strain, suggesting allele-specific competition for cell surface
      expression, and not expression solely according to gene dosage. The strongest
      effect was observed in H-2(b) x H-2(k) F(1) mice, in which the H-2(b) class I
      molecules dominated over the H-2(k) class I molecules. The magnitude of H-2(k)
      restricted CTL responses to influenza A virus infection was similar in the F(1)
      hybrid and parental H-2(k) mice. However, in H-2(k) mice expressing a K(b)
      transgene, cell surface levels of the endogenous class I molecules were down
      regulated to a greater degree than in F(1) hybrid mice, and H-2(k)-restricted CTL
      responses against influenza A virus were greatly reduced, although the CTL
      repertoire was apparently present. Therefore, certain MHC class I molecules
      compete with each other for cell surface expression, and the resulting low cell
      surface expression of specific alleles can lead to a severe reduction in the
      ability to generate a CTL response.

PMID- 12421942
TI  - Injection of soluble antigen into the anterior chamber of the eye induces
      expansion and functional unresponsiveness of antigen-specific CD8+ T cells.
AB  - The injection of soluble Ag into the anterior chamber (a.c.) of the eye induces
      systemic tolerance, termed a.c.-associated immune deviation (ACAID),
      characterized by Ag-specific inhibition of delayed-type hypersensitivity
      responses and a reduction in complement-fixing Abs. Recently, we have shown that
      CD8(+) CTL responses are also inhibited in ACAID. In this study, we have used an
      adoptive transfer approach to follow the fate of Ag-specific CD8(+) TCR
      transgenic (OT-I) T cells in vivo during the induction and expression of ACAID.
      C57BL/6 (B6) recipients of OT-I splenocytes that were injected with chicken OVA
      in the a.c. displayed reduced OVA-specific delayed-type hypersensitivity and CTL
      responses, compared with those of mice given OVA in the subconjunctiva or an
      irrelevant Ag human IgG in the a.c. OT-I T cells increased 9-fold in the
      submandibular lymph nodes and 3-fold in the spleen following an a.c. injection
      with OVA, indicating that expansion rather than deletion of Ag-specific CD8(+) T
      cells was induced by this treatment. OT-I T cells expanded equivalently upon
      administration of OVA in CFA to mice previously given OVA in the a.c. or
      subconjunctiva. However, the lytic activity attributed to OT-I T cells was
      reduced on a per-cell basis in mice previously given OVA in the a.c. We conclude
      that tolerance of CTL responses in mice given Ag via the a.c. results from
      unresponsiveness of Ag-specific CD8(+) T cells.

PMID- 12421941
TI  - The adjuvant effects of Mycobacterium tuberculosis heat shock protein 70 result
      from the rapid and prolonged activation of antigen-specific CD8+ T cells in vivo.
AB  - Heat shock protein 70 (hsp70) is a potent adjuvant that links innate and adaptive
      immune responses. To study how hsp70 activates naive CD8(+) T cells in vivo, we
      tracked Ag-specific CD8(+) T cells in mice immunized with a fusion protein
      containing chicken OVA linked to hsp70 derived from Mycobacterium tuberculosis
      (OVA.TBhsp70). On a molar basis, OVA.TBhsp70 was several hundred times more
      effective than OVA peptide plus CFA in eliciting specific CD8(+) T cell
      responses. Immunization with OVA.TBhsp70 activated >90% of detectable OVA
      specific CD8(+) T cells within 3 days and led to the persistence of cytotoxic
      effectors for at least 17 days. These studies demonstrate that the potent
      adjuvant effect of M. tuberculosis hsp70 results from the relatively complete,
      rapid, and durable activation of Ag-specific CD8(+) T cells.

PMID- 12421943
TI  - Dendritic cell-associated lectin-1: a novel dendritic cell-associated, C-type
      lectin-like molecule enhances T cell secretion of IL-4.
AB  - We have characterized dendritic cell (DC)-associated lectin-1 (DCAL-1), a novel,
      type II, transmembrane, C-type lectin-like protein. DCAL-1 has restricted
      expression in hemopoietic cells, in particular, DCs and B cells, but T cells and
      monocytes do not express it. The DCAL-1 locus is within a cluster of C-type
      lectin-like loci on human chromosome 12p12-13 just 3' to the CD69 locus. The
      consensus sequence of the DCAL-1 gene was confirmed by RACE-PCR; however, based
      on sequence alignment with genomic DNA and with various human expressed sequence
      tags, we predict that DCAL-1 has two splice variants. C-type lectins share a
      common sequence motif of 14 invariable and 18 highly conserved aa residues known
      as the carbohydrate recognition domain. DCAL-1, however, is missing three of the
      cysteine residues required to form the standard carbohydrate recognition domain.
      DCAL-1 mRNA and protein expression are increased upon the differentiation of
      monocytes to CD1a(+) DCs. B cells also express high levels of DCAL-1 on their
      cell surface. Using a DCAL-1 fusion protein we identified a population of CD4(+)
      CD45RA(+) T cells that express DCAL-1 ligand. Coincubation with soluble DCAL-1
      enhanced the proliferation of CD4(+) T cells in response to CD3 ligation and
      significantly increased IL-4 secretion. In contrast, coincubation with soluble DC
      specific ICAM-3-grabbing nonintegrin (CD209) fusion protein as a control had no
      effect on CD4(+) T cell proliferation or IL-4 and IFN-gamma secretion. Therefore,
      the function of DCAL-1 on DCs and B cells may act as a T cell costimulatory
      molecule, which skews CD4(+) T cells toward a Th2 response by enhancing their
      secretion of IL-4.

PMID- 12421944
TI  - Absence of L-selectin delays mucosal B cell responses in nonintestinal effector
      tissues.
AB  - Previous studies suggest that lymphocyte trafficking to head and neck lymph
      nodes, also referred to as cranial-, oral-, nasal-associated lymphoid tissue
      (CONALT), is L-selectin (L-Sel) dependent, despite coexpression of
      alpha(4)beta(7), resulting in their marked reduction in L-Sel-deficient (L-Sel(-/
      )) mice. Consequently, early phase (16 days) Ab responses to cholera toxin (CT)
      are diminished. The following studies reveal that lack of mucosal effector
      responses is not caused by loss of inductive immune responses in the L-Sel(-/-)
      CONALT. Indeed, there was an increased accumulation of total IgA, but not Ag
      specific IgA Ab-forming cells (AFC) in L-Sel(-/-) CONALT. This increased
      accumulation was not evident in L-Sel(+/+) CONALT. Identification of lymphocyte
      homing receptors on L-Sel(-/-) and L-Sel(+/+) CONALT lymphocytes revealed no
      significant differences in expression of alpha(4)beta(7), which might contribute
      to lymphocyte homing in the absence of L-Sel. Studies of CONALT responses during
      the late phase (6 wk post-intranasal immunization) revealed the number of
      lymphocytes recovered from L-Sel(-/-) CONALT was less than L-Sel(+/+) CONALT;
      however, L-Sel(-/-) CT-specific and total AFC did not vary from 16-day responses,
      suggesting a defect in CT-specific B cell export. No significant differences in
      alpha(4)beta(7) expression between L-Sel(-/-) and L-Sel(+/+) CONALT were noted.
      Yet, these increases in CONALT AFC correlated with restoration of immunity in L
      Sel(-/-) nasal passages and reproductive tracts.

PMID- 12421945
TI  - Differential regulation of CD44 expression by lipopolysaccharide (LPS) and TNF
      alpha in human monocytic cells: distinct involvement of c-Jun N-terminal kinase
      in LPS-induced CD44 expression.
AB  - Alterations in the regulation of CD44 expression play a critical role in
      modulating cell adhesion, migration, and inflammation. LPS, a bacterial cell wall
      component, regulates CD44 expression and may modulate CD44-mediated biological
      effects in monocytic cells during inflammation and immune responses. In this
      study, we show that in normal human monocytes, LPS and LPS-induced cytokines IL
      10 and TNF-alpha enhance CD44 expression. To delineate the mechanism underlying
      LPS-induced CD44 expression, we investigated the role of the mitogen-activated
      protein kinases (MAPKs), p38, p42/44 extracellular signal-regulated kinase, and c
      Jun N-terminal kinase (JNK) by using their specific inhibitors. We demonstrate
      the involvement, at least in part, of p38 MAPK in TNF-alpha-induced CD44
      expression in both monocytes and promonocytic THP-1 cells. However, neither p38
      nor p42/44 MAPKs were involved in IL-10-induced CD44 expression in monocytes. To
      further dissect the TNF-alpha and LPS-induced signaling pathways regulating CD44
      expression independent of IL-10-mediated effects, we used IL-10 refractory THP-1
      cells as a model system. Herein, we show that CD44 expression induced by the LPS
      mediated pathway predominantly involved JNK activation. This conclusion was based
      on results derived by transfection of THP-1 cells with a dominant-negative mutant
      of stress-activated protein/extracellular signal-regulated kinase kinase 1, and
      by exposure of cells to JNK inhibitors dexamethasone and SP600125. All these
      treatments prevented CD44 induction in LPS-stimulated, but not in TNF-alpha
      stimulated, THP-1 cells. Furthermore, we show that CD44 induction may involve JNK
      dependent early growth response gene activation in LPS-stimulated monocytic
      cells. Taken together, these results suggest a predominant role of JNK in LPS
      induced CD44 expression in monocytic cells.

PMID- 12421946
TI  - Regulation of virus-induced IL-12 and IL-23 expression in human macrophages.
AB  - IL-23 is a novel cytokine that promotes the proliferation of naive and memory T
      cells and stimulates their IFN-gamma production. Besides functional similarities,
      IL-23 bears structural resemblance to IL-12. Biologically active IL-23 is a
      heterodimer whose p40 subunit is identical to IL-12p40 while its p19 subunit is
      distantly related to IL-12p35. In the present study we demonstrate that human
      monocyte-derived macrophages are able to produce IL-23 in response to virus
      infection. Sendai virus stimulates the expression of p19 and p40 mRNAs in
      macrophages. Furthermore, it enhances p35 mRNA expression and the production of
      IL-12. Influenza A virus, in contrast, fails to stimulate IL-12 or IL-23
      expression in macrophages. IL-12 and IL-23 contribute to the IFN-gamma-inducing
      activity that cell culture supernatant from Sendai virus-infected macrophages
      show in NK-92 cells. The induction of IFN-gamma production occurs in concert with
      IFN-alphabeta and IL-18, which are also secreted from the virus-infected cells.
      The IFN-gamma-inducing activity is inhibited by IL-4, which down-regulates the
      transcription of p19 and p40 genes and the secretion of IFN-alphabeta, IL-12, and
      IL-18. IFN-gamma, in contrast, up-regulates the p19 and p40 mRNA expression in
      Sendai virus infection. Thus, IL-4 and IFN-gamma serve as opposing factors in the
      regulation of IFN-gamma-inducing cytokines, including IL-23, in macrophages.

PMID- 12421947
TI  - Granulocyte-macrophage colony-stimulating factor (GM-CSF) and inflammatory
      stimuli up-regulate secretion of the soluble GM-CSF receptor in human monocytes:
      evidence for ectodomain shedding of the cell surface GM-CSF receptor alpha
      subunit.
AB  - Soluble GM-CSF receptor alpha subunit (sGMRalpha) is a soluble isoform of the
      GMRalpha that is believed to arise exclusively through alternative splicing of
      the GMRalpha gene product. The sGMRalpha mRNA is expressed in a variety of
      tissues, but it is not clear which cells are capable of secreting the protein. We
      show here that normal human monocytes, but not lymphocytes, constitutively
      secrete sGMRalpha. Stimulation of monocytes with GM-CSF, LPS, PMA, or A23187
      rapidly up-regulates the secretion of sGMRalpha in a dose-dependent manner,
      demonstrating that secretion is also regulated. To determine whether sGMRalpha
      arose exclusively through alternative splicing of the GMRalpha gene product, or
      whether it could also be generated through ectodomain shedding of GMRalpha, we
      engineered a murine pro-B cell line (Ba/F3) to express exclusively the cDNA for
      cell surface GMRalpha (Ba/F3.GMRalpha). The Ba/F3.GMRalpha cell line, but not the
      parental Ba/F3 cell line, constitutively shed a sGMRalpha-like protein that bound
      specifically to GM-CSF, was equivalent in size to recombinant alternatively
      spliced sGMRalpha (60 kDa), and was recognized specifically by a mAb raised
      against the ectodomain of GMRalpha. Furthermore, a broad-spectrum metalloprotease
      inhibitor (BB94) reduced constitutive and PMA-, A23187-, and LPS-induced
      secretion of sGMRalpha by monocytes, suggesting that shedding of GMRalpha by
      monocytes may be mediated in part through the activity of metalloproteases. Taken
      together, these observations demonstrate that sGMRalpha is constitutively
      secreted by monocytes, that GM-CSF and inflammatory mediators up-regulate
      sGMRalpha secretion, and that sGMRalpha arises not only through alternative
      splicing but also through ectodomain shedding of cell surface GMRalpha.

PMID- 12421948
TI  - TGF-beta 1 regulates adhesion of mucosal mast cell homologues to laminin-1
      through expression of integrin alpha 7.
AB  - Mucosal mast cells (MMC) or their precursors migrate through the intestinal
      lamina propria to reside intraepithelially, where expression of mouse mast cell
      protease-1 indicates the mature phenotype. Alterations in expression of integrins
      that govern cell adhesion to the extracellular matrix may regulate this process.
      As the key cytokine mediating differentiation of mouse mast cell protease-1
      expressing MMC homologues in vitro, TGF-beta1 was considered a likely candidate
      for regulation of the integrins that facilitate intraepithelial migration of MMC.
      Therefore, we examined adhesion of bone marrow-derived mast cells cultured with
      and without TGF-beta1 to laminin-1, fibronectin, and vitronectin along with
      expression of integrins likely to regulate this adhesion. Adhesion of PMA
      stimulated cultured mast cells to laminin-1 increased from 5.3 +/- 3.6% (mean +/-
      SEM) in the absence of TGF-beta1 to 58.7 +/- 4.0% (p < 0.05) when cultured mast
      cells had differentiated into MMC homologues in the presence of TGF-beta1.
      Increased adhesion of MMC homologues to laminin-1 was also stimulated by
      FcepsilonRI cross-linking and the calcium ionophore A23187. Expression of the
      laminin-binding integrin alpha(7) by MMC homologues grown in the presence of TGF
      beta1 was demonstrated by RT-PCR and flow cytometry, and preincubation of MMC
      homologues with the alpha(7)-neutralizing Ab 6A11 inhibited adhesion to laminin-1
      by 98% (p < 0.05), demonstrating a novel role for this molecule in adhesion of a
      hemopoietic cell to laminin-1.

PMID- 12421949
TI  - Positional scanning-synthetic peptide library-based analysis of self- and
      pathogen-derived peptide cross-reactivity with tumor-reactive Melan-A-specific
      CTL.
AB  - Synthetic combinatorial peptide libraries in positional scanning format (PS-SCL)
      have recently emerged as a useful tool for the analysis of T cell recognition.
      This includes identification of potentially cross-reactive sequences of self or
      pathogen origin that could be relevant for the understanding of TCR repertoire
      selection and maintenance, as well as of the cross-reactive potential of Ag
      specific immune responses. In this study, we have analyzed the recognition of
      sequences retrieved by using a biometric analysis of the data generated by
      screening a PS-SCL with a tumor-reactive CTL clone specific for an immunodominant
      peptide from the melanocyte differentiation and tumor-associated Ag Melan-A. We
      found that 39% of the retrieved peptides were recognized by the CTL clone used
      for PS-SCL screening. The proportion of peptides recognized was higher among
      those with both high predicted affinity for the HLA-A2 molecule and high
      predicted stimulatory score. Interestingly, up to 94% of the retrieved peptides
      were cross-recognized by other Melan-A-specific CTL. Cross-recognition was at
      least partially focused, as some peptides were cross-recognized by the majority
      of CTL. Importantly, stimulation of PBMC from melanoma patients with the most
      frequently recognized peptides elicited the expansion of heterogeneous CD8(+) T
      cell populations, one fraction of which cross-recognized Melan-A. Together, these
      results underline the high predictive value of PS-SCL for the identification of
      sequences cross-recognized by Ag-specific T cells.

PMID- 12421950
TI  - Peptide-independent folding and CD8 alpha alpha binding by the nonclassical class
      I molecule, thymic leukemia antigen.
AB  - The nonclassical class I molecule, thymic leukemia (TL), has been shown to be
      expressed on intestinal epithelial cells and to interact with CD8(+)
      intraepithelial T lymphocytes. We generated recombinant soluble TL (T18(d)) H
      chains in bacteria as inclusion bodies and refolded them with beta(2)
      microglobulin in the presence or absence of a random peptide library. Using a
      mAb, HD168, that recognizes a conformational epitope on native TL molecules, we
      observed that protein folds efficiently in the absence of peptide. Circular
      dichroism analysis demonstrated that TL molecules have structural features
      similar to classical class I molecules. Moreover, thermal denaturation
      experiments indicated that the melting temperature for peptide-free TL is similar
      to values reported previously for conventional class I-peptide complexes. Our
      results also show that CD8alphaalpha binding is not dependent on either TL
      associated peptide or TL glycosylation.

PMID- 12421952
TI  - CL-46, a novel collectin highly expressed in bovine thymus and liver.
AB  - Collectins are oligomeric molecules with C-type lectin domains attached to
      collagen-like regions via alpha-helical neck regions. They bind nonself
      glycoconjugates on the surface of microorganisms and inhibit infection by direct
      neutralization, agglutination, or opsonization. During the characterization of
      the gene encoding bovine CL-43 (43-kDa collectin), we identified a novel
      collectin-gene. We report the cloning and partial characterization of the novel
      collectin CL-46. The mRNA comprises 1188 nucleotides encoding a protein of 371 aa
      with an included leader peptide of 20 residues. CL-46 has two cysteine residues
      in the N-terminal segment, a potential N-glycosylation site in the collagen
      region, and an extended hydrophilic loop close to the binding site of the
      carbohydrate recognition domain. It is expressed in the thymus, liver, mammary
      gland, and tissues of the digestive system. Recombinant CL-46 corresponding to
      the alpha-helical neck region and the C-type lectin domain binds preferential N
      acetyl-D-glucoseamine and N-acetyl-D-mannoseamine. The gene encoding CL-46 spans
      approximately 10 kb and consists of eight exons, with high structural resemblance
      to the gene encoding human surfactant protein D. It is located on the bovine
      chromosome 28 at position q1.8 together with the gene encoding conglutinin and CL
      43. Several potential thymus-related cis-regulatory elements were identified in
      the 5'-upstream sequence, indicating that the expression in thymus may be
      modulated by signals involved in T cell development.

PMID- 12421951
TI  - Differential regulation of IL-12 and IL-10 gene expression in macrophages by the
      basic leucine zipper transcription factor c-Maf fibrosarcoma.
AB  - IL-12 is a principal activator of both innate and adaptive immunity against
      infectious agents and malignancies. Regulation of proinflammatory IL-12 gene
      expression in phagocytes by the anti-inflammatory cytokine IL-10 represents a
      major homeostatic process underlying host-pathogen and host-self interactions.
      Delineation of the signaling pathway of IL-10 is crucial to the understanding of
      immunological regulatory networks. In this study, we report that IL-10 and c
      musculoaponeurotic fibrosarcoma (Maf) induce their mutual expression in
      inflammatory macrophages. We demonstrate that c-Maf is one of the physiological
      mediators of IL-10's immunosuppressive activities. When overexpressed, c-Maf
      selectively inhibits transcriptional activation of IL-12 p40 and p35 genes while
      potently activating IL-10 and IL-4 expression, potentially contributing to the
      development of a state of anti-inflammation and dichotomy of immunologic
      polarization. c-Maf induces changes in nuclear DNA-binding activities at multiple
      sites including the ets, GA-12, NF-kappaB, C/EBP, and AP-1 elements. Nonetheless,
      the essential c-Maf-responsive element appears to be located elsewhere.
      Inhibition of IL-12 p40 gene expression by c-Maf requires the N-terminal
      transactivation domain, suggesting an indirect mechanism of transcriptional
      inhibition involving the induction of an unidentified repressor. In c-Maf
      deficient murine macrophages, IL-10 production is impaired. However, IL-10
      mediated inhibition of IL-12 production remains intact, indicating the existence
      of alternative mediators in the absence of c-Maf, consistent with the observation
      that a functional AP-1 is required for this pathway.

PMID- 12421953
TI  - Characterization of the interaction between L-ficolin/p35 and mannan-binding
      lectin-associated serine proteases-1 and -2.
AB  - Ficolins are oligomeric lectins comprising a collagen-like and a fibrinogen-like
      domain, with a binding specificity for N-acetylglucosamine. It has been reported
      recently that L-ficolin/P35 associates with mannan-binding lectin (MBL)
      associated serine proteases (MASP-1 and -2) and MBL-associated protein 19 (MAp19)
      in serum and forms complexes able to activate complement. Using surface plasmon
      resonance spectroscopy we have shown that recombinant MASP-1 and -2, their N
      terminal CUB1 (module originally found in complement proteins C1r/C1s, Uegf, and
      bone morphogenetic protein-1)-epidermal growth factor (EGF)-CUB2 and CUB1-EGF
      segments, and MAp19 bind to immobilized L-ficolin/P35 in the presence of Ca(2+)
      ions. Comparable K(d) values were obtained for the full-length proteases and
      their CUB1-EGF-CUB2 segments (9.2 and 10 nM for MASP-1 and 4.6 and 5.4 nM for
      MASP-2, respectively), whereas higher values were obtained for the CUB1-EGF
      segments (26.7, 15.6, and 14.3 nM for MASP-1, MASP-2, and MAp19). These values
      are in the same range as those determined for the interaction of these proteins
      with MBL. Binding was Ca(2+) dependent and was only partly sensitive to EDTA for
      MASP-1, MASP-2, and MASP-2 CUB1-EGF-CUB2. Half-maximal binding was obtained at
      comparable Ca(2+) concentrations for MASP-1 and MASP-2 (0.45 and 0.47 micro M,
      respectively), their CUB1-EGF-CUB2 segments (0.37 and 0.72 micro M), and their
      CUB1-EGF segments (0.31 and 0.79 micro M). These values are lower than those
      determined in the case of MBL, indicating a difference between MBL and L
      ficolin/P35 with respect to the Ca(2+) dependence of their interaction with the
      MASPs. Preincubation of the MASPs with soluble MBL inhibited subsequent binding
      to immobilized L-ficolin/P35 and, conversely, suggesting that these lectins
      compete with each other for binding to the MASPs in vivo.

PMID- 12421954
TI  - Empirical evaluation of a dynamic experiment design method for prediction of MHC
      class I-binding peptides.
AB  - The ability to predict MHC-binding peptides remains limited despite ever
      expanding demands for specific immunotherapy against cancers, infectious
      diseases, and autoimmune disorders. Previous analyses revealed position-specific
      preference of amino acids but failed to detect sequence patterns. Efforts to use
      computational analysis to identify sequence patterns have been hampered by the
      insufficiency of the number/quality of the peptide binding data. We propose here
      a dynamic experiment design to search for sequence patterns that are common to
      the MHC class I-binding peptides. The method is based on a committee-based
      framework of query learning using hidden Markov models as its component
      algorithm. It enables a comprehensive search of a large variety (20(9)) of
      peptides with a small number of experiments. The learning was conducted in seven
      rounds of feedback loops, in which our computational method was used to determine
      the next set of peptides to be analyzed based on the results of the earlier
      iterations. After these training cycles, the algorithm enabled a real number
      prediction of MHC binding peptides with an accuracy surpassing that of the
      hitherto best performing positional scanning method.

PMID- 12421955
TI  - Small interfering RNA-mediated gene silencing in T lymphocytes.
AB  - Introduction of small interfering RNAs (siRNAs) into a cell can cause a specific
      interference of gene expression known as RNA interference (RNAi). However, RNAi
      activity in lymphocytes and in normal primary mammalian cells has not been
      thoroughly demonstrated. In this report, we show that siRNAs complementary to CD4
      and CD8alpha specifically reduce surface expression of these coreceptors and
      their respective mRNA in a thymoma cell line model. We show that RNAi activity is
      only caused by a subset of siRNAs complementary to the mRNA target and that
      ineffective siRNAs can compete with effective siRNAs. Using primary
      differentiated T lymphocytes, we provide the first evidence of siRNA-mediated
      RNAi gene silencing in normal nontransformed somatic mammalian lymphocytes.

PMID- 12421956
TI  - Involvement of classical and novel protein kinase C isoforms in the response of
      human V gamma 9V delta 2 T cells to phosphate antigens.
AB  - Human gammadelta T cells expressing the Vgamma9Vdelta2 gene segments are
      activated polyclonally by phosphoantigens found on a wide variety of pathogenic
      organisms. After ligand exposure, Vgamma9Vdelta2 T cells proliferate and rapidly
      secrete large amounts of cytokines and chemokines that contribute to the innate
      immune response to these pathogens. Neither APCs nor costimulatory molecules are
      required. In this study we examined whether these phosphoantigens activate
      protein kinase Ctheta (PKCtheta). This novel PKC isoform is essential for Ag
      signaling through the alphabeta TCR in a costimulation-dependent fashion. The
      results showed that isopentenyl pyrophosphate (IPP), a soluble phospholigand
      released by mycobacteria, led to the rapid and persistent activation of PKCtheta
      in gammadelta T cells, as determined by evidence of translocation and
      phosphorylation. In contrast, no ligand-dependent response was detected for
      PKCalpha/beta or PKCdelta. Using the inhibitors Go6976 and rottlerin, a role for
      both conventional and novel PKC isoforms in IPP-induced proliferation, CD25
      expression, and cytokine and chemokine production was demonstrated. Gel-shift
      assays indicated that the transcription factors NF-kappaB and AP-1 were
      downstream targets of PKC activation. IPP also induced the rapid and persistent
      phosphorylation of extracellular signal-regulated kinases 1 and 2, p38 mitogen
      activated kinase, and stress-activated kinase/c-Jun N-terminal kinase, but only
      an inhibitor of conventional PKCs blocked these responses. We conclude that the
      gammadelta T cell response to phosphoantigens is regulated by both novel and
      conventional PKC isoforms, with PKCtheta being more responsive to ligand
      stimulation and PKCalpha/beta to growth-factor availability.

PMID- 12421957
TI  - Induction of HIV-1-specific immunity after vaccination with apoptotic HIV
      1/murine leukemia virus-infected cells.
AB  - Ag-presenting dendritic cells present viral Ags to T cells after uptake of
      apoptotic bodies derived from virus-infected cells in vitro. However, it is
      unclear whether apoptotic virus-infected cells are capable of generating immunity
      in vivo. In this study, we show that inoculation of mice with apoptotic HIV
      1/murine leukemia virus (MuLV)-infected cells induces HIV-1-specific immunity.
      Immunization with apoptotic HIV-1/MuLV-infected syngeneic splenocytes resulted in
      strong Nef-specific CD8(+) T cell proliferation and p24-induced CD4(+) and CD8(+)
      T cell proliferation as well as IFN-gamma production. In addition, systemic IgG
      and IgA as well as mucosa-associated IgA responses were generated. Moreover, mice
      vaccinated with apoptotic HIV-1/MuLV cells were protected against challenge with
      live HIV-1/MuLV-infected cells, whereas mice vaccinated with apoptotic
      noninfected or MuLV-infected splenocytes remained susceptible to HIV-1/MuLV.
      These data show that i.p. immunization with apoptotic HIV-1-infected cells
      induces high levels of HIV-1-specific systemic immunity, primes for mucosal
      immunity, and induces protection against challenge with live HIV-1-infected cells
      in mice. These findings may have implications for the development of therapeutic
      and prophylactic HIV-1 vaccines.

PMID- 12421959
TI  - CD8 T cell-mediated killing of Cryptococcus neoformans requires granulysin and is
      dependent on CD4 T cells and IL-15.
AB  - Granulysin is located in the acidic granules of cytotoxic T cells. Although the
      purified protein has antimicrobial activity against a broad spectrum of microbial
      pathogens, direct evidence for granulysin-mediated cytotoxicity has heretofore
      been lacking. Studies were performed to examine the regulation and activity of
      granulysin expressed by CD8 T cells using Cryptococcus neoformans, which is one
      of the most common opportunistic pathogens of AIDS patients. IL-15-activated CD8
      T cells acquired anticryptococcal activity, which correlated with the up
      regulation of granulysin. When granules containing granulysin were depleted using
      SrCl(2,) or when the gene was silenced using 21-nt small interfering RNA
      duplexes, the antifungal effect of CD8 T cells was abrogated. Concanamycin A and
      EGTA did not affect the antifungal effect, suggesting that the activity of
      granulysin was perforin independent. Following stimulation by the C. neoformans
      mitogen, CD8 T cells expressed granulysin and acquired antifungal activity. This
      activity required CD4 T cells and was dependent upon accessory cells.
      Furthermore, IL-15 was both necessary and sufficient for granulysin up-regulation
      in CD8 T cells. These observations are most consistent with a mechanism whereby
      C. neoformans mitogen is presented to CD4 T cells, which in turn activate
      accessory cells. The resultant IL-15 activates CD8 T cells to express granulysin,
      which is responsible for antifungal activity.

PMID- 12421958
TI  - Rejection of syngeneic colon carcinoma by CTLs expressing single-chain antibody
      receptors codelivering CD28 costimulation.
AB  - A new strategy to improve the therapeutic utility of redirected T cells for
      cancer involves the development of novel Ag-specific chimeric receptors capable
      of stimulating optimal and sustained T cell antitumor activity in vivo. Given
      that T cells require both primary and costimulatory signals for optimal
      activation and that many tumors do not express critical costimulatory ligands,
      modified single-chain Ab receptors have been engineered to codeliver CD28
      costimulation. In this study, we have compared the antitumor potency of primary T
      lymphocytes expressing carcinoembryonic Ag (CEA)-reactive chimeric receptors that
      incorporate either TCR-zeta or CD28/TCR-zeta signaling. Although both receptor
      transduced T cell effector populations demonstrated cytolysis of CEA(+) tumors in
      vitro, T cells expressing the single-chain variable fragment of Ig (scFv)-CD28
      zeta chimera had a far greater capacity to control the growth of CEA(+)
      xenogeneic and syngeneic colon carcinomas in vivo. The observed enhanced
      antitumor activity of T cells expressing the scFv-CD28-zeta receptor was
      critically dependent on perforin and the production of IFN-gamma. Overall, this
      study has illustrated the ability of a chimeric scFv receptor capable of
      harnessing the signaling machinery of both TCR-zeta and CD28 to augment T cell
      immunity against tumors that have lost expression of both MHC/peptide and
      costimulatory ligands in vivo.

PMID- 12421960
TI  - Resistance to metastatic disease in STAT6-deficient mice requires hemopoietic and
      nonhemopoietic cells and is IFN-gamma dependent.
AB  - Mice deficient for the STAT6 gene (STAT6(-/-) mice) have enhanced
      immunosurveillance against primary and metastatic tumors. Because STAT6 is a
      downstream effector of the IL-4R, and IL-13 binds to the type 2 IL-4R, IL-13 has
      been proposed as an inhibitor that blocks differentiation of tumor-specific
      CD8(+) T cells. Immunity in STAT6(-/-) mice is unusually effective in that 45-80%
      of STAT6(-/-) mice with established, spontaneous metastatic 4T1 mammary
      carcinoma, whose primary tumors are surgically excised, survive indefinitely, as
      compared with <10% of STAT(+/+) (BALB/c) mice. Surprisingly, STAT6(-/-) and
      BALB/c reciprocal bone marrow chimeras do not have increased immunosurveillance,
      demonstrating that immunity requires STAT6(-/-) hemopoietic and nonhemopoietic
      components. Likewise, CD1(-/-) mice that are NKT deficient and therefore IL-13
      deficient also have heightened tumor immunity. However, STAT6(-/-) and CD1(-/-)
      reciprocal bone marrow chimeras do not have increased survival, suggesting that
      immunity in STAT6(-/-) and CD1(-/-) mice is via noncomplementing mechanisms.
      Metastatic disease is not reduced in BALB/c mice treated with an IL-13 inhibitor,
      indicating that IL-13 alone is insufficient for negative regulation of 4T1
      immunity. Likewise, in vivo depletion of CD4(+)CD25(+) T cells in BALB/c mice
      does not increase survival, demonstrating that CD4(+)CD25(+) cells do not
      regulate immunity. Cytokine production and tumor challenges into STAT6(-/-)IFN
      gamma(-/-) mice indicate that IFN-gamma is essential for immunity. Therefore,
      immunosurveillance in STAT6(-/-) mice facilitates survival against metastatic
      cancer via an IFN-gamma-dependent mechanism involving hemopoietic and
      nonhemopoietic derived cells, and is not exclusively dependent on counteracting
      IL-13 or CD4(+)CD25(+) T cells.

PMID- 12421961
TI  - Nonsecreted bacterial proteins induce recall CD8 T cell responses but do not
      serve as protective antigens.
AB  - Secreted or nonsecreted Ag expressed by recombinant Listeria monocytogenes can
      prime CD8 T cells. However, Ag-specific memory CD8 T cells confer protection
      against bacteria secreting Ag, but not against bacteria expressing the
      nonsecreted form of the same Ag. This dichotomy may be explained by a long
      standing hypothesis that nonsecreted Ags are less effective than secreted Ags at
      inducing a protective immune response at the onset of infection. We tested this
      hypothesis by examining whether these two different forms of Ag induce different
      primary and secondary CD8 T cell responses. The primary responses to secreted and
      nonsecreted Ags expanded and contracted almost synchronously, although the
      responses to nonsecreted Ags were of lower magnitude. These results demonstrate
      that the kinetics of the CD8 T cell response are similar regardless of whether Ag
      is accessible to the endogenous MHC class I pathway or can only be presented
      through cross-presentation. No differences were detected in the CD8 T cell recall
      response to L. monocytogenes expressing secreted or nonsecreted Ags. Nonsecreted
      Ags are as effective as secreted Ags at the induction of a rapid recall response
      by memory CD8 T cells. Thus, the inability of nonsecreted bacterial proteins to
      serve as protective Ags cannot be attributed to a defective CD8 T cell response.

PMID- 12421962
TI  - Inducible costimulator protein controls the protective T cell response against
      Listeria monocytogenes.
AB  - The inducible costimulator protein (ICOS) was recently identified as a
      costimulatory molecule for T cells. Here we analyze the role of ICOS for the
      acquired immune response of mice against the intracellular bacterium Listeria
      monocytogenes. During oral L. monocytogenes infection, low levels of ICOS
      expression were detected by extracellular and intracellular Ab staining of
      Listeria-specific CD4(+) and CD8(+) T cells. Blocking of ICOS signaling with a
      soluble ICOS-Ig fusion protein markedly impaired the Listeria-specific T cell
      responses. Compared with control mice, the ICOS-Ig treated mice generated
      significantly reduced numbers of Listeria-specific CD8(+) T cells in spleen and
      liver, as determined by tetramer and intracellular cytokine staining. In
      contrast, the specific CD8(+) T cell response in the intestinal mucosa did not
      appear to be impaired by the ICOS-Ig treatment. Analysis of the CD4(+) T cell
      response revealed that ICOS-Ig treatment also affected the specific CD4(+) T cell
      response. When restimulated with listerial Ag in vitro, reduced numbers of CD4(+)
      T cells from infected and ICOS-Ig-treated mice responded with IFN-gamma
      production. The impaired acquired immune response in ICOS-Ig treated mice was
      accompanied by their increased susceptibility to L. monocytogenes infection. ICOS
      Ig treatment drastically enhanced bacterial titers, and a large fraction of mice
      succumbed to the otherwise sublethal dose of infection. Thus, ICOS costimulation
      is crucial for protective immunity against the intracellular bacterium L.
      monocytogenes.

PMID- 12421963
TI  - The protective immune response to heat shock protein 60 of Histoplasma capsulatum
      is mediated by a subset of V beta 8.1/8.2+ T cells.
AB  - Immunization with recombinant heat shock protein 60 (rHsp60) from Histoplasma
      capsulatum or a region of the protein designated fragment 3 (F3) confers
      protection from a subsequent challenge in mice. To determine the T cell
      repertoire involved in the response to Hsp60, T cell clones from C57BL/6 mice
      immunized with rHsp60 were generated and examined for Vbeta usage by flow
      cytometry and RT-PCR. Vbeta8.1/8.2(+) T cells were preferentially expanded; other
      clones bore Vbeta4, -6, or -11. When Vbeta8.1/8.2(+) cells were depleted in mice,
      Vbeta4(+) T cell clones were almost exclusively isolated. Measurement of cytokine
      production demonstrated that nine of 16 Vbeta8.1/8.2(+) clones were Th1, while
      only three of 13 non-Vbeta8.1/8.2(+) clones were Th1. In mice immunized with
      rHsp60, depletion of Vbeta8.1/8.2(+), but not Vbeta6(+) plus Vbeta7(+), T cells
      completely abolished the protective efficacy of Hsp60 to lethal and sublethal
      challenges. Examination of the TCR revealed that a subset of Vbeta8.1/2(+) clones
      that produced IFN-gamma and were reactive to F3 shared a common CDR3 sequence,
      DGGQG. Transfer of these T cell clones into TCR alpha/beta(-/-) or IFN-gamma(-/-)
      mice significantly improved survival, while transfer of other Vbeta8.1/8.2(+)
      clones that were F3 reactive but were Th2 or clones that were not reactive to F3
      but were Th1 did not confer protection. These data indicate that a distinct
      subset of Vbeta8.1/8.2(+) T cells is crucial for the generation of a protective
      response to rHsp60.

PMID- 12421964
TI  - A unique mechanism for innate cytokine promotion of T cell responses to viral
      infections.
AB  - The kinetics of CD8 T cell IFN-gamma responses as they occur in situ are defined
      here during lymphocytic choriomeningitis virus (LCMV) infections, and a unique
      mechanism for the innate cytokines IFN-alphabeta and IL-18 in promoting these
      responses is defined. Infections of mice with Armstrong or WE strains of LCMV
      induced an unexpectedly early day 4 IFN-gamma response detectable in serum
      samples and spleen and liver homogenates. Production of IFN-gamma was MHC class
      I/CD8 dependent, but did not require IL-12, NK cells, TCR-gammadelta T cells, MHC
      class II, or CD4 T cells. Peak response required specific Ag recognition, as
      administration of antagonist peptide partially impaired day 4 IFN-gamma
      induction, and viral peptide stimulation enhanced CD8 T cell IFN-gamma expression
      in culture. The IFN-gamma response was associated with IL-18 and IFN-alphabeta
      expression. Furthermore, both factors augmented peptide-driven IFN-gamma
      production in culture, and mice lacking IL-18 or IFN-alphabeta functions had
      reduced day 4 IFN-gamma. Collectively, these results demonstrate that during
      viral infections, there is a dramatic in vivo CD8 T cell response preceding
      maximal expansion of these cells, and that the mechanism supporting this response
      is dependent on endogenous innate cytokines. Because stimulation by microbial
      products is linked to innate cytokine expression, the studies also suggest a
      pathway for precisely limiting T cell functions to times of need.

PMID- 12421965
TI  - Proliferation requirements of cytomegalovirus-specific, effector-type human CD8+
      T cells.
AB  - Two prototypic types of virus-specific CD8(+) T cells can be found in latently
      infected individuals: CD45R0(+)CD27(+)CCR7(-) effector-memory, and CD45RA(+)CD27(
      )CCR7(-) effector-type cells. It has recently been implied that CD45RA(+)CD27(
      )CCR7(-) T cells are terminally differentiated effector cells and as such have
      lost all proliferative capacity. We show in this study, however, that stimulation
      of CMV-specific CD45RA(+)CD27(-)CCR7(-) T cells with their cognate peptide in
      concert with either CD4(+) help or IL-2, IL-15, or IL-21 in fact induces massive
      clonal expansion. Concurrently, these stimulated effector T cells change cell
      surface phenotype from CD45RA to CD45R0 and regain CCR7, while effector functions
      are maintained. Our data imply that CD45RA(+)CD27(-)CCR7(-) effector-type T cells
      contribute to immunity not only by direct execution of effector functions, but
      also by yielding progeny in situations of viral reinfection or reactivation.

PMID- 12421966
TI  - Pulmonary surfactant proteins A and D directly suppress CD3+/CD4+ cell function:
      evidence for two shared mechanisms.
AB  - Pulmonary surfactant is a lipoprotein complex that lowers surface tension at the
      air-liquid interface of the lung and participates in pulmonary host defense.
      Surfactant proteins (SP), SP-A and SP-D, modulate a variety of immune cell
      functions, including the production of cytokines and free radicals. Previous
      studies showed that SP-A and SP-D inhibit lymphocyte proliferation in the
      presence of accessory cells. The goal of this study was to determine whether SP-A
      and SP-D directly suppress Th cell function. Both proteins inhibited
      CD3(+)/CD4(+) lymphocyte proliferation induced by PMA and ionomycin in an IL-2
      independent manner. Both proteins decreased the number of cells entering the S
      and mitotic phases of the cell cycle. Neither SP-A nor SP-D altered cell
      viability, apoptosis, or secretion of IL-2, IL-4, or IFN-gamma when Th cells were
      treated with PMA and ionomycin. However, both proteins attenuated ionomycin
      induced cytosolic free calcium ([Ca(2+) ](i)), but not thapsigargin-induced
      changes in [Ca(2+)](i). In summary, inhibition of T cell proliferation by SP-A
      and SP-D occurs via two mechanisms, an IL-2-dependent mechanism observed with
      accessory cell-dependent T cell mitogens and specific Ag, as well as an IL-2
      independent mechanism of suppression that potentially involves attenuation of
      [Ca(2+)](i).

PMID- 12421967
TI  - Development of inflammation in proteoglycan-induced arthritis is dependent on Fc
      gamma R regulation of the cytokine/chemokine environment.
AB  - FcgammaRs are specialized cell surface receptors that coordinately regulate
      immune responses. Although FcgammaR expression is a prerequisite for the
      development of several immune complex-mediated diseases, the mechanism
      responsible for FcgammaR-dependent regulation in autoimmunity remains unclear.
      Therefore, we assessed FcgammaR-dependent regulation of inflammation in
      proteoglycan-induced arthritis (PGIA) using FcgammaR(-/-) mice. FcgammaRIIb(-/-)
      mice developed arthritis at an earlier time point and with a greater severity
      than wild-type (WT) mice. In gamma-chain(-/-) (FcgammaRI(-/-) and FcgammaRIII(-/
      )) mice, no clinical or histological evidence of inflammation was observed.
      Exacerbation of arthritis in FcgammaRIIb(-/-) mice correlated with enhanced PG
      specific Ab production, but did not significantly affect PG-specific T cell
      priming. In gamma-chain(-/-) mice, the absence of arthritis did not correlate
      with serum Ab responses, as PG-specific Ab production was normal. Although PG
      specific T cell proliferation was diminished, spleen cells from gamma-chain(-/-)
      mice successfully adoptively transferred arthritis into SCID mice. Our studies
      indicated that the mechanism responsible for FcgammaR regulation of PGIA
      development was at the level of inflammatory cytokine and beta-chemokine
      expression within the joint. FcgammaRIIb regulated the development of PGIA by
      controlling the initiation of cytokine and chemokine expression within the joint
      before the onset of arthritis, whereas the expression of FcgammaRI and or
      FcgammaRIII controlled cytokine and chemokine expression late in the development
      of PGIA during the onset of disease. These results suggest that FcgammaRs are
      critical for the development of inflammation during PGIA, possibly by maintaining
      or enhancing inflammatory cytokine and beta-chemokine production.

PMID- 12421968
TI  - Enhanced recruitment of Th2 and CLA-negative lymphocytes by the S128R
      polymorphism of E-selectin.
AB  - E-selectin is a cytokine-inducible endothelial cell adhesion molecule that binds
      a restricted population of T lymphocytes consisting of Th1 memory cells bearing
      the cutaneous lymphocyte Ag (CLA). A serine to arginine (S128R) polymorphism in E
      selectin has been reported at increased frequency in patients with systemic lupus
      erythematosus and atherosclerosis. Here we tested the hypothesis that the S128R
      substitution may contribute to increased vascular disease by altering the number
      and/or phenotype of lymphocytes interacting with E-selectin under shear flow. We
      observed that CHO cell monolayers transfected with S128R recruited significantly
      greater numbers of unfractionated lymphocytes than monolayers expressing an
      equivalent density of wild-type (WT) E-selectin. Depletion of the CLA(+)
      subpopulation or generation of CLA(-) lymphoblasts abolished rolling and arrest
      on WT E-selectin, but left a residual population that interacted with S128R.
      Generation of Th subsets revealed preferential interaction of Th0 and Th2, but
      not Th1, cells with S128R compared with WT. However, only T cells of a memory
      phenotype interacted with S128R, since neither monolayer supported rolling of
      CD45RA(+) cells. Our results demonstrate that the S128R polymorphism extends the
      range of lymphocytes recruited by E-selectin, which may provide a mechanistic
      link between this polymorphism and vascular inflammatory disease.

PMID- 12421969
TI  - A comparison of reactive oxygen species generation by rat peritoneal macrophages
      and mast cells using the highly sensitive real-time chemiluminescent probe
      pholasin: inhibition of antigen-induced mast cell degranulation by macrophage
      derived hydrogen peroxide.
AB  - Mast cells and macrophages live in close proximity in vivo and reciprocally
      regulate one another's function in various ways. Although activated macrophages
      possess a powerful reactive oxygen species (ROS) generating system, there is
      conflicting evidence regarding whether mast cells can produce ROS. We used the
      highly sensitive real-time chemiluminescent probe Pholasin to examine ROS release
      by peritoneal macrophages and mast cells isolated from OVA-sensitized rats.
      Macrophages stimulated with PMA (0.8 microM) or ionomycin (1 microM), but not OVA
      (1 microg/ml), released high-level ROS, levels of which peaked after 3-7 min and
      declined to baseline levels within 1 h. Superoxide was identified as the major
      ROS species induced by PMA but not by ionomycin. In contrast, purified mast cells
      stimulated with PMA released low-level ROS, which was entirely due to the
      contaminating (2%) macrophages, and did not release any detectable ROS in
      response to ionomycin or OVA at concentrations that induced degranulation.
      Stimulation of mixed cell populations with PMA to induce macrophage ROS release
      led to 50% inhibition of serotonin release from mast cells stimulated 5 min later
      with OVA. The PMA-induced inhibitory factor was identified as hydrogen peroxide.
      In conclusion, activated rat peritoneal macrophages but not mast cells produce
      ROS, and macrophage-derived hydrogen peroxide inhibits mast cell degranulation.
      The latter could be an important mechanism whereby phagocytic cells regulate mast
      cell activation and promote resolution of IgE-mediated inflammation.

PMID- 12421971
TI  - Adhesion of B cell lines to endothelial cells from human lymphoid tissue
      modulates tyrosine phosphorylation and endothelial cell activation.
AB  - Through the production of cytokines and growth factors the endothelium of
      secondary lymphoid organs plays a crucial role in controlling lymphocyte
      migration to the lymphoid microenvironment, an essential step in the initiation
      of the immune response. Here we demonstrate that direct contact of B cell lines
      with tonsil-derived human endothelial cells resulted in changes in the
      phosphorylation state of endothelial cells, causing their functional activation.
      We found a rapid (<15-s) and transient dephosphorylation, followed by a rapid
      rephosphorylation of tyrosine residues of the focal adhesion kinase, paxillin,
      and ERK2. Maximal rephosphorylation occurred after 15-30 min of B cell contact.
      Preincubation of lymphoid B cells with an adhesion-blocking Ab directed against
      alpha(4)beta(1) integrin abrogated adhesion-mediated changes of endothelial cell
      tyrosine phosphorylation, suggesting that cell contact was essential. Similar
      patterns of tyrosine phosphorylation, but with slightly different kinetics were
      induced after cross-linking of beta(1) integrin or CD40 on endothelial cells.
      Functional activation of endothelial cells by B cell adhesion was confirmed by
      the production of IL-6, IL-8, monocyte chemoattractant protein-1, M-CSF, and
      macrophage inflammatory protein-1beta mRNA. However, direct cross-linking of
      beta(1) integrin and CD40 failed to accomplish the same functional activation.
      These data indicate that direct contact of lymphoid B cells with the endothelium
      from lymphoid tissue induce endothelial cell signaling, resulting in chemokine
      and cytokine production. This phenomenon may provide a mechanism for the
      remodeling of the endothelium from lymphoid tissues, thus contributing to the
      free migration of lymphocytes and other cells into the lymphoid organs.

PMID- 12421970
TI  - Toll-like receptor 4 and Toll-IL-1 receptor domain-containing adapter protein
      (TIRAP)/myeloid differentiation protein 88 adapter-like (Mal) contribute to
      maximal IL-6 expression in macrophages.
AB  - Previous studies have shown that engagement of Toll-like receptors (TLR) 2 and 4
      can induce macrophages to express a variety of proinflammatory cytokines. We have
      recently demonstrated that TLR2 agonists poorly induce a subset of TLR4-inducible
      proinflammatory genes (e.g., inducible protein (IP)-10, inducible NO synthase
      (iNOS), monocyte chemoattractant protein-5, IL-12p40), due in part to
      differential activation of IFN-beta production and phosphorylation of the
      transcription factor STAT1. TLR4, but not TLR2, agonists can induce IFN-beta
      expression via a mechanism that requires the adapter protein Toll-IL-1R domain
      containing adapter protein (TIRAP)/myeloid differentiation protein 88 (MyD88)
      adapter-like (Mal), but not the adapter protein MyD88. Thus, the failure of TLR2
      agonists to induce STAT1-dependent genes results, in part, from their failure to
      induce the expression of IFN-beta. In this study, we show that IL-6 expression is
      also preferentially induced by activation of TLR4. TLR4-dependent induction of IL
      6 expression did require Toll-IL-1R domain-containing adapter protein
      (TIRAP)/MyD88 adapter-like (Mal), but unlike iNOS and IP-10, it did not require
      the expression of IFN-beta. Although exogenous IFN-beta and IFN-gamma could
      synergize with TLR2 agonists to restore high levels of iNOS expression and NO
      production, these IFNs could not synergize with TLR2 agonists to induce high
      levels of IL-6. Similarly, neutralizing anti-IFN Abs could block iNOS gene
      expression in LPS-stimulated murine macrophages, whereas these Abs had little
      effect on IL-6 gene expression in these cells. Together, these studies
      demonstrate that IL-6, like iNOS and IP-10, is differentially expressed in
      macrophages stimulated via TLR2 vs TLR4, although these differences appear to
      arise from distinct signaling mechanisms.

PMID- 12421972
TI  - Characterization of nitric oxide consumption pathways by normal, chronic
      granulomatous disease and myeloperoxidase-deficient human neutrophils.
AB  - The detailed mechanisms by which acutely activated leukocytes metabolize NO and
      regulate its bioactivity are unknown. Therefore, healthy, chronic granulomatous
      disease (CGD) or myeloperoxidase (MPO)-deficient human neutrophils were examined
      for their ability to consume NO and attenuate its signaling. fMLP or PMA
      activation of healthy neutrophils caused NO consumption that was fully blocked by
      NADPH oxidase inhibition, and was absent in CGD neutrophils. Studies using MPO
      deficient neutrophils, enzyme inhibitors, and reconstituted NADPH oxidase ruled
      out additional potential NO-consuming pathways, including Fenton chemistry, PGH
      synthase, lipoxygenase, or MPO. In particular, the inability of MPO to consume NO
      resulted from lack of H(2)O(2) substrate since all superoxide (O(2)(-.) reacted
      to form peroxynitrite. For healthy or MPO-deficient cells, NO consumption rates
      were 2- to 4-fold greater than O(2)(-.) generation, significantly faster than
      expected from 1:1 termination of NO with O(2)(-.). Finally, fMLP or PMA
      stimulated NO consumption fully blocked NO-dependent neutrophil cGMP synthesis.
      These data reveal NADPH oxidase as the central regulator of NO signaling in human
      leukocytes. In addition, they demonstrate an important functional difference
      between CGD and either normal or MPO-deficient human neutrophils, namely their
      inability to metabolize NO which will alter their ability to adhere and migrate
      in vivo.

PMID- 12421973
TI  - IL-17 expression in human herpetic stromal keratitis: modulatory effects on
      chemokine production by corneal fibroblasts.
AB  - Herpetic stromal keratitis (HSK) is an immunopathologic disease triggered by
      infection of the cornea with HSV. Key events in HSK involve the interaction
      between cornea-infiltrating inflammatory cells and resident cells. This
      interaction, in which macrophages, producing IL-1 and TNF-alpha, and IFN-gamma
      producing Th1 cells play a crucial role, results in the local secretion of immune
      modulatory factors and a major influx of neutrophils causing corneal lesions and
      blindness. The Th1-derived cytokine IL-17 has been shown to play an important
      role in several inflammatory diseases characterized by a massive infiltration of
      neutrophils into inflamed tissue. Here we show that IL-17 is expressed in corneas
      from patients with HSK and that the IL-17R is constitutively expressed by human
      corneal fibroblasts (HCF). IL-17 exhibited a strong synergistic effect with TNF
      alpha on the induction of IL-6 and IL-8 secretion by cultured HCF. Secreted IL-8
      in these cultures had a strong chemotactic effect on neutrophils. IL-17 also
      enhanced TNF-alpha- and IFN-gamma-induced secretion of macrophage-inflammatory
      proteins 1alpha and 3alpha, while inhibiting the induced secretion of RANTES.
      Furthermore, considerable levels of IFN-gamma-inducible protein 10 and matrix
      metalloproteinase 1 were measured in stimulated HCF cultures, while the
      constitutive secretion of monocyte chemotactic protein 1 remained unaffected. The
      data presented suggest that IL-17 may play an important role in the induction
      and/or perpetuation of the immunopathologic processes in human HSK by modulating
      the secretion of proinflammatory and neutrophil chemotactic factors by corneal
      resident fibroblasts.

PMID- 12421974
TI  - A protease-activated pathway underlying Th cell type 2 activation and allergic
      lung disease.
AB  - The respiratory allergens that induce experimental Th cell type 2-dependent
      allergic lung inflammation may be grouped into two functional classes. One class
      of allergens, in this study termed type I, requires priming with adjuvants remote
      from the lung to overcome airway tolerogenic mechanisms that ordinarily preclude
      allergic responses to inhaled Ags. In contrast, the other, or type II, allergen
      class requires neither remote priming nor additional adjuvants to overcome airway
      tolerance and elicit robust allergic lung disease. In this study, we show in an
      experimental model that diverse type II allergens share in common proteolytic
      activity that is both necessary and sufficient for overcoming airway tolerance
      and induction of pulmonary allergic disease. Inactivated protease and protease
      free Ag fragments showed no allergenic potency, demonstrating that only active
      protease acting on endogenous substrates was essential. Furthermore, induction of
      airway tolerance could be aborted and allergic lung disease established by simply
      adding purified protease to a type I allergen. Thus, exogenous proteases are
      common to type II allergens and may be generally required to overcome the innate
      resistance of the airway to Th cell type 2 activation and allergic inflammation,
      raising concern for their potential contribution to diseases such as asthma.

PMID- 12421975
TI  - Selective eosinophil adhesion to fibroblast via IFN-gamma-induced galectin-9.
AB  - Among galectin family members, galectin-9 was first described as a potent
      eosinophil chemoattractant derived from Ag-stimulated T cells. In the present
      study a role of galectin-9 in the interaction between eosinophils and fibroblasts
      was investigated using a human lung fibroblast cell line, HFL-1. RT-PCR, real
      time PCR, and Western blot analyses revealed that both galectin-9 mRNA and
      protein in HFL-1 cells were up-regulated by IFN-gamma stimulation. On the one
      hand, IL-4, known as a Th2 cytokine, did not affect the galectin-9 expression in
      HFL-1 cells. We further confirmed that IFN-gamma up-regulated the expression of
      galectin-9 in primary human dermal fibroblasts. Flow cytometric analysis revealed
      that IFN-gamma up-regulated surface galectin-9 expression on HFL-1 cells.
      Stimulation of HFL-1 cells with IFN-gamma up-regulated adhesion of eosinophils,
      but not neutrophils, to HFL-1 cells. This adherence of eosinophils to HFL-1 cells
      was inhibited by both lactose and anti-galectin-9 Ab. These findings demonstrate
      that IFN-gamma-induced galectin-9 expression in fibroblasts mediates eosinophil
      adhesion to the cells, suggesting a crucial role of galectin-9 in IFN-gamma
      stimulated fibroblasts as a physiological modulator at the inflammatory sites.

PMID- 12421976
TI  - Bax is crucial for IFN-gamma-induced resolution of allergen-induced mucus cell
      metaplasia.
AB  - Allergic airway responses cause proliferation of epithelial cells and mucus cell
      metaplasia (MCM), and the resolution of MCM involves reduction of cell numbers.
      The role of inflammation and apoptosis on this process was investigated in P
      selectin +/+ and -/- mice sensitized and challenged with OVA by analyzing the
      expression and the role of regulators of apoptosis in metaplastic mucus cells. No
      differences were observed in MCM at 5 days of allergen exposure between +/+ and 
      /- mice, despite reduced IL-13 levels in -/- mice. Although IL-4 levels were
      similar in both -/- and +/+ mice, IL-13 and IL-5 levels had decreased and IFN
      gamma levels were increased earlier in -/- compared with +/+ mice. MCM levels
      were decreased 4-fold at 7 days of allergen exposure in -/- mice and at 15 days
      in +/+ mice. The percentage of Bax-expressing mucus cells increased significantly
      at 7 days in -/- mice and at 10 days in +/+ mice. The Bax-positive mucus cells
      exhibited caspase-specific cleavage of cytokeratin 18. IFN-gamma caused Bax
      expression in IL-13-induced MCM in microdissected airway cultures. MCM remained
      significantly elevated in Bax -/- mice following 15 days of allergen exposure
      compared with +/+ mice, while the number of eosinophils was reduced in both Bax
      +/+ and -/- mice at 15 days. Together, these data demonstrate that reduced IL-13
      levels were sufficient to elicit maximum MCM, that IFN-gamma induces Bax in
      metaplastic mucus cells, and that Bax plays a critical role in the resolution of
      MCM, but not in the resolution of eosinophils.

PMID- 12421977
TI  - Absence of the complement anaphylatoxin C3a receptor suppresses Th2 effector
      functions in a murine model of pulmonary allergy.
AB  - Asthma is a chronic inflammatory disease of the lung resulting in airway
      obstruction. The airway inflammation of asthma is strongly linked to Th2
      lymphocytes and their cytokines, particularly IL-4, IL-5, and IL-13, which
      regulate airway hyperresponsiveness, eosinophil activation, mucus production, and
      IgE secretion. Historically, complement was not thought to contribute to the
      pathogenesis of asthma. However, our previous reports have demonstrated that
      complement contributes to bronchial hyperreactivity, recruitment of airway
      eosinophils, IL-4 production, and IgE responses in a mouse model of pulmonary
      allergy. To define the complement activation fragments that mediate these
      effects, we assessed the role of the complement anaphylatoxin C3a in a mouse
      model of pulmonary allergy by challenging C3aR-deficient mice intranasally with a
      mixed Ag preparation of Aspergillus fumigatus cell culture filtrate and OVA.
      Analysis by plethysmography after challenge revealed an attenuation in airway
      hyperresponsiveness in C3aR-deficient mice relative to wild-type mice. C3aR
      deficient mice also had an 88% decrease in airway eosinophils and a 59% reduction
      in lung IL-4-producing cells. Consistent with the reduced numbers of IL-4
      producing cells, C3aR-deficient mice had diminished bronchoalveolar lavage levels
      of the Th2 cytokines, IL-5 and IL-13. C3aR knockout mice also exhibited decreases
      in IgE titers as well as reduced mucus production. Collectively, these data
      highlight the importance of complement activation, the C3a anaphylatoxin, and its
      receptor during Th2 development in this experimental model and implicate these
      molecules as possible therapeutic targets in diseases such as asthma.

PMID- 12421978
TI  - A role for STAT5 in the pathogenesis of IL-2-induced glucocorticoid resistance.
AB  - Glucocorticoids (GC) are highly effective in the control of diseases associated
      with T cell activation. However, a subset of individuals is GC insensitive.
      Previous studies have demonstrated that IL-2 can induce steroid resistance in
      mouse T cells. However, the mechanism for this phenomenon is unknown. In the
      current study we found that the murine cell line (HT-2) is steroid resistant when
      incubated with IL-2, but steroid sensitive when grown in IL-4. Furthermore, when
      HT-2 cells are treated with IL-2, the glucocorticoid receptor (GCR) does not
      translocate to the cell nucleus after dexamethasone treatment. In contrast, the
      GCR in IL-4-stimulated HT-2 cells does translocate into the cell nucleus after
      dexamethasone treatment. IL-2-induced steroid insensitivity in HT-2 cells appears
      to be a signaling event as the effects of IL-2 on nuclear translocation of the
      GCR occurred within 30 min even in the presence of cycloheximide. Indeed,
      preincubation of HT-2 cells with a Janus-associated kinase 3 inhibitor restored
      nuclear translocation of the GCR even in the presence of IL-2.
      Immunoprecipitation experiments revealed that phosphorylated STAT5 and GCR formed
      immune complexes. This association may lead to retardation of GCR nuclear
      translocation because IL-2 was not able to induce steroid insensitivity in
      splenocytes from STAT5 knockout mice. This study demonstrates a novel role for
      STAT5 in IL-2-induced steroid insensitivity.

PMID- 12421980
TI  - In vivo biosynthesis of endogenous and of human C1 inhibitor in transgenic mice:
      tissue distribution and colocalization of their expression.
AB  - We have produced transgenic mice expressing human C1 inhibitor mRNA and protein
      under the control of the human promoter and regulatory elements. The transgene
      was generated using a minigene construct in which most of the human C1 inhibitor
      gene (C1NH) was replaced by C1 inhibitor cDNA. The construct retained the
      promoter region extending 1.18 kb upstream of the transcription start site,
      introns 1 and 2 as well as a stretch of 2.5 kb downstream of the polyadenylation
      site, and therefore carried all known elements involved in transcriptional
      regulation of the C1NH gene. Mice with high serum levels of human C1 inhibitor,
      resulting from multiple tandem integrations of the C1 inhibitor transgene, were
      selected. Immunohistochemistry in combination with in situ hybridization was
      applied to localize the sites of C1 inhibitor biosynthesis and to demonstrate its
      local production in brain, spleen, liver, heart, kidney, and lung. The
      distribution of human C1 inhibitor-expressing cells was qualitatively
      indistinguishable from that of its mouse counterpart, but expression levels of
      the transgene were significantly higher. In the spleen, production of C1
      inhibitor was colocalized with that of a specific marker for white pulp
      follicular dendritic cells. This study demonstrates a stringently regulated
      expression of both the endogenous and the transgenic human C1 inhibitor gene and
      reveals local biosynthesis of C1 inhibitor at multiple sites in which the
      components of the macromolecular C1 complex are also produced.

PMID- 12421979
TI  - Dysregulation of IFN-gamma signaling pathways in the absence of TGF-beta 1.
AB  - Deficiency of TGF-beta1 is associated with immune dysregulation and autoimmunity
      as exemplified by the multifocal inflammatory lesions and early demise of the TGF
      beta1 null mice. Elevated NO metabolites (nitrite and nitrate) in the plasma of
      these mice suggest a participatory role of NO in the pathogenic inflammatory
      response. To determine the mechanism for this dysregulation, we examined upstream
      elements that could contribute to the overexpression of NO, including inducible
      NO synthase (iNOS) and transcription factors Stat1alpha and IFN-regulatory factor
      1 (IRF-1). The coincident up-regulation of IFN-gamma, an iNOS inducer, and iNOS,
      before the appearance of inflammatory lesions, suggests that failed regulation of
      the IFN-gamma signaling pathway may underlie the immunological disorder in TGF
      beta1 null mice. In fact, IFN-gamma-driven transcription factors IRF-1 and
      Stat1alpha, both of which act as transcriptional activators of iNOS, were
      elevated in the null mice. Treatment of mice with a polyclonal anti-IFN-gamma Ab
      reduced expression and activity not only of transcription factors Stat1alpha and
      IRF-1 but also of iNOS. Furthermore, anti-IFN-gamma treatment delayed the
      cachexia normally seen in TGF-beta1 null mice and increased their longevity. The
      global nature of immune dysregulation in TGF-beta1 null mice documents TGF-beta1
      as an essential immunoregulatory molecule.

PMID- 12421981
TI  - In vivo role of p38 mitogen-activated protein kinase in mediating the anti
      inflammatory effects of CpG oligodeoxynucleotide in murine asthma.
AB  - DNA containing unmethylated CpG motifs is intrinsically immunostimulatory,
      inducing the production of a variety of cytokines and chemokines by immune cells.
      The strong Th1 response triggered by CpG oligodeoxynucleotide (ODN) inhibits the
      development of Th2-mediated allergic asthma in mice. This work documents that CpG
      ODN-induced IL-12 production plays a critical role in this process, because
      intrapulmonary CpG ODN inhibits allergic inflammation in wild-type but not IL-12(
      /-) mice. CpG ODN rapidly localized to alveolar macrophages (AM), thereby
      triggering the phosphorylation of p38 mitogen-activated protein kinase (MAP
      kinase). AM cultured with CpG but not control ODN up-regulated IL-12 p40
      expression and release, and these effects were blocked by the highly specific p38
      MAP kinase inhibitor SB202190. Intrapulmonary administration of this inhibitor
      blocked the ability of CpG ODN to produce IL-12 in the lungs and reversed the
      anti-inflammatory effects of CpG ODN on allergic lung inflammation. These
      findings indicate that IL-12 production by AM is stimulated by intrapulmonary CpG
      ODN administration through a p38 MAP kinase-dependent process, and IL-12 is a key
      cytokine that mediates CpG ODN-induced protection against allergic lung
      inflammation.

PMID- 12421982
TI  - Expression and function of C5a receptor in mouse microvascular endothelial cells.
AB  - The complement-derived anaphylatoxin, C5a, is a potent phlogistic molecule that
      mediates its effects by binding to C5a receptor (C5aR; CD88). We now demonstrate
      specific binding of radiolabeled recombinant mouse C5a to mouse dermal
      microvascular endothelial cells (MDMEC) with a K(d50) of 3.6 nM and to
      approximately 15,000-20,000 receptors/cell. Recombinant mC5a competed effectively
      with binding of [(125)I]rmC5a to MDMEC. Enhanced binding of C5a occurred, as well
      as increased mRNA for C5aR, after in vitro exposure of MDMEC to LPS, IFN-gamma,
      or IL-6 in a time- and dose-dependent manner. By confocal microscopy, C5aR could
      be detected on surfaces of MDMEC using anti-C5aR Ab. In vitro expression of
      macrophage inflammatory protein-2 (MIP-2) and monocyte chemoattractant protein-1
      (MCP-1) by MDMEC was also measured. Exposure of MDMEC to C5a or IL-6 did not
      result in changes in MIP-2 or MCP-1 production, but initial exposure of MDMEC to
      IL-6, followed by exposure to C5a, resulted in significantly enhanced production
      of MIP-2 and MCP-1 (but not TNF-alpha and MIP-1alpha). Although LPS or IFN-gamma
      alone induced some release of MCP-1 and MIP-2, pre-exposure of these monolayers
      to LPS or IFN-gamma, followed by addition of C5a, resulted in synergistic
      production of MIP-2 and MCP-1. Following i.v. infusion of LPS into mice, up
      regulation of C5aR occurred in the capillary endothelium of mouse lung, as
      determined by immunostaining. These results support the hypothesis that C5aR
      expression on MDMEC and on the microvascular endothelium of lung can be up
      regulated, suggesting that C5a in the co-presence of additional agonists may
      mediate pro-inflammatory effects of endothelial cells.

PMID- 12421983
TI  - The tissue-specific self-pathogen is the protective self-antigen: the case of
      uveitis.
AB  - Vaccination with peptides derived from interphotoreceptor retinoid-binding
      protein (a self-Ag that can cause experimental autoimmune uveoretinitis) resulted
      in protection of retinal ganglion cells from glutamate-induced death or death as
      a consequence of optic nerve injury. In the case of glutamate insult, no such
      protection was obtained by vaccination with myelin Ags (self-Ags associated with
      an autoimmune disease in the brain and spinal cord that evokes a protective
      immune response against consequences of injury to myelinated axons). We suggest
      that protective autoimmunity is the body's defense mechanism against destructive
      self-compounds, and an autoimmune disease is the outcome of a failure to properly
      control such a response. Accordingly, the specific self-Ag (although not
      necessarily its particular epitopes) used by the body for protection against
      potentially harmful self-compounds (e.g., glutamate) can be inferred from the
      specificity of the autoimmune disease associated with the site at which the
      stress occurs (irrespectively of the type of stress) and is in need of help.

PMID- 12421985
TI  - Differential expression of TRAIL and TRAIL receptors in allergic asthmatics
      following segmental antigen challenge: evidence for a role of TRAIL in eosinophil
      survival.
AB  - Asthma is a chronic lung disease exhibiting airway obstruction,
      hyperresponsiveness, and inflammation, characterized by the infiltration of
      eosinophils into the airways and the underlying tissue. Prolonged eosinophilic
      inflammation depends on the balance between the cell's inherent tendency to
      undergo apoptosis and the local eosinophil-viability enhancing activity. TRAIL, a
      member of the TNF family, induces apoptosis in most transformed cells; however,
      its role in health and disease remains unknown. To test the hypothesis that Ag
      induced inflammation is associated with TRAIL/TRAIL-R interactions, we used a
      segmental Ag challenge (SAC) model in ragweed-allergic asthmatics and
      nonasthmatic patients and analyzed bronchoalveolar lavage (BAL) material for 2
      wk. In asthmatic patients, the level of TRAIL in BAL fluid dramatically increased
      24 h after SAC, which significantly correlated with BAL eosinophil counts.
      Immunohistochemical analysis of bronchial biopsies from asthmatic patients
      demonstrated that TRAIL staining was increased in epithelial, airway smooth
      muscle, and vascular smooth muscle cells and throughout the interstitial tissue
      after SAC. This was confirmed by quantitative immunocytochemical image analysis
      of BAL eosinophils and alveolar macrophages, which demonstrated that expression
      levels of TRAIL and DcR2 increased, whereas expression levels of the TRAIL-Rs DR4
      and DR5 decreased in asthmatic subjects after SAC. We also determined that TRAIL
      prolongs eosinophil survival ex vivo. These data provide the first in vivo
      evidence that TRAIL expression is increased in asthmatics following Ag
      provocation and suggest that modulation of TRAIL and TRAIL-R interactions may
      play a crucial role in promoting eosinophil survival in asthma.

PMID- 12421984
TI  - Anticancer activity of sodium stibogluconate in synergy with IFNs.
AB  - Cancer cell resistance limits the efficacy of IFNs. In this study, we show that
      sodium stibogluconate (SSG) and IFN-alpha synergized to overcome IFN-alpha
      resistance in various human cancer cell lines in culture and eradicated IFN-alpha
      refractory WM9 human melanoma tumors in nude mice with no obvious toxicity. SSG
      enhanced IFN-alpha-induced Stat1 tyrosine phosphorylation, inactivated
      intracellular SHP-1 and SHP-2 that negatively regulate IFN signaling, and induced
      cellular protein tyrosine phosphorylation in cancer cell lines. These effects are
      consistent with inactivation of phosphatases as the basis of SSG anticancer
      activity. Characterization of SSG by chromatography revealed that only selective
      compounds in SSG were effective protein tyrosine phosphatase inhibitors. These
      observations suggest the potential of SSG as a clinically usable protein tyrosine
      phosphatase inhibitor in cancer treatment and provide insights for developing
      phosphatase-targeted therapeutics.

PMID- 12421987
TI  - The T cell response to Art v 1, the major mugwort pollen allergen, is dominated
      by one epitope.
AB  - Mugwort (Artemisia vulgaris) pollen allergens represent the main cause of
      pollinosis in late summer in Europe. At least 95% of sera from mugwort pollen
      allergic patients contain IgE against a highly glycosylated 24- to 28-kDa
      glycoprotein. Recently, this major allergen, termed Art v 1, was characterized,
      cloned in Escherichia coli, and produced in recombinant form. In the present
      study we characterized and compared the T cell responses to natural (nArt v 1)
      and recombinant Art v 1 (rArt v 1). In vitro T cell responses to nArt v 1 and
      rArt v 1 were studied in PBMC, T cell lines (TCL), and T cell clones (TCC)
      established from PBMC of mugwort-allergic patients. Stimulation of PBMC or
      allergen-specific TCL with either nArt v 1 or rArt v 1 resulted in comparable
      proliferative T cell responses. Eighty-five percent of the TCC reactive with rArt
      v 1 cross-reacted with the natural protein. The majority of the CD4(+)CD8(-)TCR
      alphabeta(+) Art v 1-specific TCC, obtained from 10 different donors, belonged to
      the Th2 phenotype. Epitope mapping of TCL and TCC using overlapping peptides
      revealed a single immunodominant T cell epitope recognized by 81% of the
      patients. Inhibition experiments demonstrated that the presentation of this
      peptide is restricted by HLA-DR molecules. In conclusion, the T cell response to
      Art v 1 is characterized by one strong immunodominant epitope and evidently
      differs from the T cell responses to other common pollen allergens known to
      contain multiple T cell epitopes. Therefore, mugwort allergy may be an ideal
      candidate for a peptide-based immunotherapy approach.

PMID- 12421986
TI  - A key role for prostaglandin I2 in limiting lung mucosal Th2, but not Th1,
      responses to inhaled allergen.
AB  - The cellular events that serve to regulate lung mucosal Th2 responses and limit
      allergic inflammatory reactions are unclear. Using the DO11.10 TCR transgenic
      mouse, we developed a model of T cell-mediated pulmonary inflammation and
      demonstrated that high levels of PGI(2) are produced in the airways following OVA
      inhalation. Selective inhibition of cyclooxygenase-2 in vivo specifically reduced
      PGI(2) synthesis and resulted in a marked increase in Th2-mediated, but not Th1
      mediated, lung inflammation. The elevated Th2-mediated inflammatory response
      elicited by the cyclooxygenase-2 inhibitor was associated with enhanced airway
      hyperreactivity and was coincident with a marked increase in the levels of IL-4,
      IL-5, and IL-13 in the airways, but a reduction in IL-10 production. In keeping
      with these observations, we found that the mRNA for the PGI(2) receptor was
      expressed by Th2, but not Th1, cells, and transcripts for the PGI(2) receptor
      were induced by IL-4 and OVA peptide stimulation. Interestingly, treatment with
      PGI(2) or its stable analog, carbaprostacyclin, augmented IL-10 production by Th2
      cells. Collectively, our findings reveal a key role for PGI(2) in differentially
      limiting Th2 responses, possibly by promoting production of the immunosuppressive
      cytokine IL-10 at the site of allergic lung inflammation. These results indicate
      an important role for prostanoids generated during inflammation in regulating
      mucosal T cell responses and highlight a potential risk in the use of
      cyclooxygenase-2-specific inhibitors by allergic asthmatics.

PMID- 12421988
TI  - Tobacco reduces membrane HLA class I that is restored by transfection with
      transporter associated with antigen processing 1 cDNA.
AB  - HLA class I molecules are recognized by CTL that eliminate virally infected and
      malignantly transformed cells presenting foreign peptide-a process termed
      immunosurveillance. Many tumors have reduced levels of membrane HLA class I.
      Tumor cells with mutations that reduce HLA class I avoid immunosurveillance and
      continue to proliferate. As tobacco use can induce tumors, we examined the effect
      of tobacco extracts on membrane HLA class I. These studies show that culture of
      cells in media containing tobacco extracts reduces membrane HLA class I, but not
      other proteins, on primary keratinocytes and other cell types. Culture in tobacco
      extracts, but not extracts of other substances, reduces TAP1 protein, but does
      not reduce expression of HLA class I H chain, L chain, or the housekeeping
      protein beta-actin. The reduction of TAP1 protein occurs within 4 h and is dose
      dependent. Culture in tobacco extracts reduces TAP1 protein abundance, but not
      steady-state mRNA abundance. Tobacco-treated cells show defects in HLA class I
      biosynthesis similar to those found in TAP1-deficient cell lines. Transfection
      with TAP1 cDNA restores TAP1 protein abundance, HLA class I biosynthesis, and
      cell surface expression. Combined, these data show that culture in tobacco
      extracts reduces TAP1 protein abundance and membrane HLA class I levels.
      Reduction in membrane HLA class I could permit subsequent malignant
      transformation of cells to be undetected by the immune system.

PMID- 12421989
TI  - The apoptotic ligands TRAIL, TWEAK, and Fas ligand mediate monocyte death induced
      by autologous lupus T cells.
AB  - Individuals with systemic lupus erythematosus show evidence of a significant
      increase in monocyte apoptosis. This process is mediated, at least in part, by an
      autoreactive T cell subset that kills autologous monocytes in the absence of
      nominal Ag. We have investigated the apoptotic pathways involved in this T cell
      mediated process. Expression of the apoptotic ligands TRAIL, TNF-like weak
      inducer of apoptosis (TWEAK), and Fas ligand on lupus T cells was determined, and
      the role of these molecules in the monocyte apoptotic response was examined. We
      report that these apoptotic ligands mediate the autologous monocyte death induced
      by lupus T cells and that this cytotoxicity is associated with increased
      expression of these molecules on activated T cells, rather than with an increased
      susceptibility of lupus monocytes to apoptosis induced by these ligands. These
      results define novel mechanisms that contribute to increased monocyte apoptosis
      characterizing patients with lupus. We propose that this mechanism could provide
      a source of potentially antigenic material for the autoimmune response and
      interfere with normal clearing mechanisms.

PMID- 12421990
TI  - DNA vaccination with heat shock protein 60 inhibits cyclophosphamide-accelerated
      diabetes.
AB  - Nonobese diabetic (NOD) mice spontaneously develop diabetes as a consequence of
      an autoimmune process that can be inhibited by immunotherapy with the 60-kDa heat
      shock protein (hsp60), with its mycobacterial counterpart 65-kDa (hsp65), or with
      other Ags such as insulin and glutamic acid decarboxylase (GAD). Microbial
      infection and innate signaling via LPS or CpG motifs can also inhibit the
      spontaneous diabetogenic process. In addition to the spontaneous disease,
      however, NOD mice can develop a more robust cyclophosphamide-accelerated diabetes
      (CAD). In this work, we studied the effect on CAD of DNA vaccination with
      constructs encoding the Ags human hsp60 (phsp60) or mycobacterial hsp65 (phsp65).
      Vaccination with phsp60 protected NOD mice from CAD. In contrast, vaccination
      with phsp65, with an empty vector, or with a CpG-positive oligonucleotide was not
      effective, suggesting that the efficacy of the phsp60 construct might be based on
      regulatory hsp60 epitopes not shared with its mycobacterial counterpart, hsp65.
      Vaccination with phsp60 modulated the T cell responses to hsp60 and also to the
      GAD and insulin autoantigens; T cell proliferative responses were significantly
      reduced, and the pattern of cytokine secretion to hsp60, GAD, and insulin showed
      an increase in IL-10 and IL-5 secretion and a decrease in IFN-gamma secretion,
      compatible with a shift from a Th1-like toward a Th2-like autoimmune response.
      Our results extend the role of specific hsp60 immunomodulation in the control of
      beta cell autoimmunity and demonstrate that immunoregulatory networks activated
      by specific phsp60 vaccination can spread to other Ags targeted during the
      progression of diabetes, like insulin and GAD.

PMID- 12421993
TI  - Musculoskeletal examination for medical students: the need to agree what we
      teach.

PMID- 12421991
TI  - Multiple HLA class II-restricted melanocyte differentiation antigens are
      recognized by tumor-infiltrating lymphocytes from a patient with melanoma.
AB  - Dramatic clinical responses were observed in patient 888 following the adoptive
      transfer of autologous tumor-infiltrating lymphocytes (TIL). Previously,
      extensive analysis of the specificity of class I-restricted T cells from patient
      888 TIL has revealed that these T cells recognize a mutated, as well as several
      nonmutated tumor Ags. Additional studies that were conducted on TIL from patient
      888 indicated that they contained CD4-positive T cells that recognized the
      autologous tumor that had been induced to express HLA class II molecules. Tumor
      reactive CD4-positive T cell clones were isolated from TIL and tested for their
      ability to react with Ags that are recognized by HLA class I-restricted, melanoma
      reactive T cells. Using this approach, T cell clones were identified that
      recognized an epitope expressed in both the tyrosinase-related protein 1 and
      tyrosinase-related protein 2 Ags in the context of the HLA-DRbeta1*1502 class II
      gene product. Additional clones were found to recognize an epitope of gp100 in
      the context of the same HLA-DR restriction element. These observations provide an
      impetus to develop strategies directed toward generating HLA class II-restricted
      tumor-reactive T cells.

PMID- 12421992
TI  - Defective production of functional 98-kDa form of Elf-1 is responsible for the
      decreased expression of TCR zeta-chain in patients with systemic lupus
      erythematosus.
AB  - Systemic lupus erythematosus (SLE), the prototypic autoimmune disease, is
      characterized by defective expression of TCR zeta-chain. Elf-1 (E-74-like factor)
      is a member of the Ets (E-26-specific) family and is crucial for the basal
      transcription of TCR zeta-chain in Jurkat cells. We previously demonstrated that
      Elf-1 exists in the cytoplasm mainly as 80-kDa form and after phosphorylation and
      O-glycosylation it moves to the nucleus as a 98-kDa which binds DNA. We now
      demonstrate that Elf-1 is crucial for the transactivation of TCR zeta-chain
      promoter in normal and SLE T cells. Defective expression of TCR zeta-chain in SLE
      T cells is associated with two distinct molecular defects in the generation of
      the 98-kDa DNA binding Elf-1 form. In the first, the levels of the 98-kDa form
      were either decreased or absent. In the second, the apparent levels of the
      nuclear Elf-1 form were normal but included only two of the three bands into
      which the nuclear Elf-1 form separated in isoelectric focusing gels. Because both
      the transcription and the translation processes of Elf-1 gene are normal in SLE T
      cells, our data demonstrate that abnormal posttranslational mechanisms of the Elf
      1 protein result in defective expression of functional Elf-1, and consequently,
      the transcriptional defect of TCR zeta-chain in patients of SLE.

PMID- 12421994
TI  - Reviews of acupuncture for chronic neck pain: pitfalls in conducting systematic
      reviews.
AB  - This paper examines some of the problems specifically associated with conducting
      research into acupuncture and how this can lead to further problems with
      subsequent systematic reviews. Studies for the treatment of chronic neck pain
      have been used as examples of how presented information can be misleading to an
      acupuncture-naive reader and how researchers must be sensitive to these problems
      when compiling their inclusion and exclusion criteria. The problems associated
      with scoring trials are discussed and further work to increase the scope of
      scoring mechanisms is recommended in order to produce meaningful systematic
      reviews in the future.

PMID- 12421995
TI  - Osteoclast formation and activity in the pathogenesis of osteoporosis in
      rheumatoid arthritis.
AB  - OBJECTIVE: Rheumatoid arthritis (RA) is often complicated by generalized
      osteopenia due to increased bone resorption by osteoclasts. We analysed a number
      of cellular and humoral factors that influence osteoclast formation from
      circulating precursors in RA patients. METHODS: Monocytes isolated from RA
      patients and normal controls were cultured with macrophage colony-stimulating
      factor (M-CSF) and nuclear factor-kappaB ligand (RANKL), or with RANKL-expressing
      UMR106 cells and 1,25 dihydroxyvitamin D(3) [1,25(OH)(2)D(3)]. Osteoclast
      differentiation was assessed by expression of tartrate-resistant acid phosphatase
      (TRAP) and vitronectin receptors (VNR) and lacunar resorption. RESULTS:
      Osteoclasts formed from RA patients exhibited increased resorptive activity but
      there was no difference in the relative proportion of circulating osteoclast
      precursors between RA patients and normal controls. Osteoclast precursors in RA
      patients were not more sensitive to the osteoclastogenic effects of
      1,25(OH)(2)D(3), M-CSF or RANKL. Dexamethasone, but not interleukin (IL) 1beta,
      tumour necrosis factor alpha and IL-6, increased osteoclast formation and lacunar
      resorption. CONCLUSION: There is an increase in the extent of lacunar resorption
      carried out by osteoclasts formed from circulating precursors in RA patients.
      This is not due to an increase in the number of circulating precursors or
      increased sensitivity to the osteoclastogenic effects of 1,25(OH)(2)D(3), M-CSF,
      RANKL or inflammatory cytokines. Our findings suggest that increased osteoclast
      functional activity rather than osteoclast formation is more likely to play a
      role in the generalized bone loss that occurs in RA, and that corticosteroids
      stimulate osteoclast formation and resorption.

PMID- 12421996
TI  - Comparison of two hyaluronan drugs and placebo in patients with knee
      osteoarthritis. A controlled, randomized, double-blind, parallel-design
      multicentre study.
AB  - OBJECTIVE: To compare the efficacy and safety of intra-articular injections of
      two different hyaluronan preparations and placebo in patients with knee
      osteoarthritis. METHODS: In a randomized, patient- and observer-blind, placebo
      controlled and multicentre trial with parallel groups, 210 patients, aged 60 yr
      or above, with knee osteoarthritis were included in a per protocol analysis. The
      patients were treated with three injections, once weekly, of either native high
      molecular-weight hyaluronan (Artzal((R))) or cross-linked hyaluronan
      (Synvisc((R))) or with placebo and were followed for 52 weeks. The primary
      efficacy measures were weight-bearing pain during study weeks 0-26 and the
      duration of clinical benefit measured with Kaplan-Meier survival analysis for
      weeks 0-52. The secondary outcome measures were resting and maximum pain,
      Lequesne index, WOMAC (Western Ontario and McMaster University Osteoarthritis
      Index) and SF-36 (Medical Outcomes Study Short Form Health Survey) scores.
      RESULTS: The intra-articular injections produced a significant reduction in
      weight-bearing pain, resting pain, maximum pain and Lequesne and WOMAC scores
      after 26 weeks. There were no significant differences in outcome between any of
      the three study groups during the first 26 weeks. In direct comparison against
      placebo for weeks 0-52, neither hyaluronan treatment (Artzal or Synvisc) showed a
      significantly longer duration of clinical benefit than placebo. However, when
      data for the two hyaluronan-treated groups were pooled, treatment with hyaluronan
      had a significantly longer duration of benefit compared with placebo (P = 0.047).
      CONCLUSION: Patients with knee osteoarthritis who were treated by injection into
      the knee of either of two hyaluronan preparations or placebo showed clinical
      improvement during the first 26 weeks of treatment, though neither hyaluronan
      preparation gave a longer duration of clinical benefit than placebo. However,
      when data for the two hyaluronan treatments were pooled, there was a
      significantly longer duration of clinical benefit for hyaluronan treatment than
      for placebo.

PMID- 12421997
TI  - Synovial fluid from patients with rheumatoid arthritis inhibits neutrophil
      apoptosis: role of adenosine and proinflammatory cytokines.
AB  - OBJECTIVE: In synovial fluid (SF) from patients with rheumatoid arthritis (RA),
      neutrophils are exposed to proinflammatory mediators endowed with either anti
      apoptotic or pro-apoptotic properties. We investigated neutrophil apoptosis in
      the presence of SF from 11 RA patients. METHODS: SF was obtained from affected
      knees of 11 patients with RA. Human neutrophil apoptosis was evaluated by light
      microscopic examination and flow-cytometric analysis of annexin V binding. Immune
      complex-induced neutrophil activation was evaluated as superoxide anion
      production. Adenosine levels in SF were detected by chromatographic analysis and
      cytokine levels were studied by enzyme-linked immunosorbent assay. RESULTS:
      Spontaneous and immune complex-triggered neutrophil apoptosis was reduced by SF
      from eight out of 11 patients. Immune complex-induced neutrophil activation was
      unaffected by SF. The cytokines tested had no role in promoting the anti
      apoptotic activity of SF. On the contrary, the anti-apoptotic activity of SF was
      found to depend on the presence of adenosine. Adenosine levels detected in the
      various samples of SF correlated significantly with the anti-apoptotic activity
      of the fluids and with the number of apoptotic neutrophils detected in the
      articular exudate. CONCLUSION: The microenvironment of rheumatoid SF is a
      proinflammatory milieu responsible for the in loco persistence of activated and
      long-surviving neutrophils. Adenosine plays a crucial role in this phenomenon,
      which is related to anti-apoptotic activity.

PMID- 12421998
TI  - Age and waiting time as predictors of outcome after total hip replacement for
      osteoarthritis.
AB  - OBJECTIVE: To investigate in a prospective study the relationship between age,
      pre-operative status, waiting time and post-operative outcome in patients
      assigned for unilateral total hip replacement (THR) due to osteoarthritis (OA).
      METHOD: One hundred and forty-eight patients (mean age 71 yr) with primary OA of
      the hip were investigated pre-operatively and 3, 6 and 12 months post-operatively
      with the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) and the
      Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). For 56 of
      the patients an additional evaluation was made when they were placed on the
      waiting list. RESULTS: One hundred and twenty-four patients fulfilled the study
      criteria (age 50 yr or over and unilateral THR for OA during the study period).
      Before surgery there were no differences in the WOMAC or SF-36 subscales (except
      mental health) between patients aged over and under 72 yr. Post-operatively, the
      younger patients reached a better score than the older patients. There were no
      differences in pre-operative status or post-operative outcome between the
      patients who had been on the waiting list more than and less than 3 months. Most
      pain relief after hip replacement was obtained by 3 months, while it took at
      least 1 yr to reach the full benefit in improved function. Ninety per cent of the
      patients had improved by at least 10 points on a 100-point scale for pain and
      function at 12 months. CONCLUSION: The age of the patients assigned for THR did
      not determine their pre-operative status. However, younger patients gained more
      function post-operatively than older patients and reached higher absolute mean SF
      36 values, except for pain. An average difference in time on the waiting list of
      3 months did not result in a difference in post-operative outcome. At least 1 yr
      is required for the average OA patient to gain the full benefit of the THR.

PMID- 12421999
TI  - Clinical significance of serum surfactant protein D (SP-D) in patients with
      polymyositis/dermatomyositis: correlation with interstitial lung disease.
AB  - OBJECTIVE: To determine the clinical significance of serum surfactant protein D
      (SP-D) levels in patients with polymyositis/dermatomyositis (PM/DM). METHODS:
      Serum SP-D levels were assayed using a sensitive enzyme-linked immunosorbent
      assay in 59 patients with PM/DM and in 29 healthy controls. RESULTS: The serum
      level of SP-D was significantly higher in patients with PM/DM than in healthy
      controls (mean+/-S.D. 61.7+/-122.6 vs 31.0+/-12.4 ng/ml, P < 0.01). The serum SP
      D level in patients with interstitial lung disease (ILD) was significantly higher
      than in those without ILD (118.7+/-220.2 vs 38.7+/-21.0 ng/ml, P < 0.001). Serum
      level of SP-D was correlated with the presence of ILD. The incidences of
      decreased vital capacity (%VC) and of decreased diffusing capacity of carbon
      monoxidase (%DLCO) were also significantly greater in patients with an elevated
      SP-D level than in those with a normal level (64 vs 7%, P < 0.02; 73 vs 27%, P <
      0.01). Moreover, the serum SP-D level was inversely correlated with %VC (r=
      0.452, P < 0.01) and %DLCO (r=-0.349, P < 0.05). CONCLUSION: The serum SP-D level
      may be a useful marker for ILD in patients with PM/DM.

PMID- 12422000
TI  - Pharmacogenetics in rheumatology: the prospects and limitations of an emerging
      field.
AB  - OBJECTIVES: To review the fundamental concepts of pharmacogenetics and analyse
      how the broad principles of this rapidly emerging field may influence the
      treatment of rheumatic disease in future. METHODS: The names of common rheumatic
      drugs and the terms 'pharmacogenetics', 'pharmacogenomics' and 'genetic
      polymorphism' were used as keywords to search the Medline and Current Contents
      databases. General review articles on pharmacogenetics were also examined.
      RESULTS: Pharmacogenetics is the study of how genetic differences influence the
      variability in drug toxicity and efficacy. Although the principles of
      pharmacogenetics have been known for several decades, recent technological
      advances have hastened the possibility of direct clinical applications. Most
      studies so far have been phenotypic analyses, but genotyping is now readily
      available for many polymorphisms. There are several examples pertinent to
      rheumatology that illustrate the important principles and foretell the usefulness
      of pharmacogenetics in individualizing therapy. However, further studies are
      needed. CONCLUSIONS: Because traditional pharmacotherapy in rheumatology has been
      empirical and because of the slow acting nature of many anti-rheumatic
      medications, the risk of significant side-effects and the increasing
      armamentarium of drugs available, pharmacogenetics is particularly relevant to
      rheumatology. There are many scientific and non-scientific concerns that should
      be addressed in future studies.

PMID- 12422001
TI  - Efficacy of infliximab in refractory ankylosing spondylitis: results of a six
      month open-label study.
AB  - OBJECTIVE: To evaluate the efficacy and safety of a loading regimen of the anti
      tumour necrosis factor alpha (TNF-alpha) antibody infliximab in predominantly
      axial severe ankylosing spondylitis (AS). METHODS: We enrolled in this study 50
      patients (76% males, 87% HLA-B27(+), median age 35 yr, median disease duration 13
      yr) with active AS [Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)
      >or=30/100 and serum C-reactive protein concentration >or=15 mg/l) despite
      treatment with a non-steroidal anti-inflammatory drug, and without peripheral
      arthritis, uveitis or active inflammatory bowel disease. Other disease-modifying
      anti-rheumatic drugs were discontinued >or=3 months before inclusion and were not
      allowed during the study. Patients received three infusions of infliximab (5
      mg/kg) at weeks 0, 2 and 6 and were monitored clinically and biologically until
      week 24. RESULTS: Forty-eight patients completed the treatment. In intention-to
      treat analysis, all parameters were significantly improved at week 2 and
      generally reached maximal improvement at week 8. The proportion of responders,
      defined by a reduction of >or=20% in the global assessment of pain (GAP) or by
      the AS Assessment Study Group (ASAS 20%) criteria, and the proportion of patients
      reaching partial remission were 98, 94 and 70% respectively. Relapse, defined as
      >or=50% loss of maximal GAP improvement, occurred in 73% of completers, with a
      median delay of 14 weeks after the third infusion. No serious adverse event
      related to the treatment was observed. CONCLUSIONS: This study confirms, in a
      large group of severely affected AS patients, the remarkable efficacy of
      infliximab. Relapse usually occurred after discontinuation of the drug, but
      almost one-third of completers were still free of relapse 4 months after the last
      infusion.

PMID- 12422002
TI  - Churg-Strauss syndrome: clinical and serological features of 19 patients from a
      single Italian centre.
AB  - OBJECTIVE: Churg-Strauss syndrome is a rare multisystem vasculitis of unknown
      aetiology. Due to the rarity of the disease, few single-centre case series have
      been described. The aim of this study was to evaluate a small series from a
      single Italian centre in order to describe the clinical features of the disease,
      the treatment and long-term follow-up. METHODS: Nineteen Churg-Strauss syndrome
      patients were selected from the medical records of all vasculitis patients
      attending the Immunology Unit at the Department of Internal Medicine of the
      University of Pisa in the decade between 1989 and 2000. Data were obtained
      retrospectively. RESULTS: All the patients had asthma and hypereosinophilia. As
      in other case series, the lungs, skin and peripheral nervous system were the most
      commonly involved organs. The majority of our patient received i.v. pulses of
      methylprednisolone followed by i.v. pulses of cyclophosphamide. The outcome and
      long-term follow-up were good. There were no fatalities observed in this series
      during the follow-up period. CONCLUSIONS: Churg-Strauss syndrome is a systemic
      vasculitis occurring in patients with a history of asthma and allergic rhinitis.
      The positive results of the treatment protocol used in this preliminary study
      deserve to be tested in controlled multicentre studies.

PMID- 12422003
TI  - Disease-specific, patient-assessed measures of health outcome in ankylosing
      spondylitis: reliability, validity and responsiveness.
AB  - OBJECTIVE: To assess the acceptability and measurement properties of four
      ankylosing spondylitis (AS)-specific, patient-assessed measures of health
      outcome: AS Quality of Life Questionnaire (ASQoL), Bath AS Disease Activity Index
      (BASDAI), the Body Chart and the Revised Leeds Disability Questionnaire (RLDQ).
      METHODS: Instruments were administered by means of a self-completed questionnaire
      to patients recruited from across the United Kingdom (UK). Instruments were
      assessed for data quality and scaling assumptions. Where appropriate,
      dimensionality was assessed using principle component analysis (PCA). Internal
      consistency reliability was tested using Cronbach's alpha. Test-retest
      reliability was assessed in those patients reporting no change in AS-specific
      health at 2 weeks. The convergent validity of the instruments was assessed and
      scores were correlated with responses to the health transition questions.
      Responsiveness was assessed for patients reporting change in health at 6 months.
      RESULTS: The BASDAI and Body Chart have low self-completion rates. Item responses
      for the RLDQ were skewed towards higher levels of functional ability. PCA
      supported instrument unidimensionality. Cronbach's alpha ranged from 0.87
      (BASDAI) to 0.93 (RLDQ). Test-retest reliability estimates support the use of the
      ASQoL and RLDQ in individual evaluation (>0.90). Correlations between instruments
      were in the hypothesized direction; the largest was between the ASQoL and BASDAI
      (0.79). The BASDAI had the strongest linear relationship, with responses to both
      specific and general health transition questions (P<0.01). With the exception of
      the Body Chart, instruments had a stronger relationship with general health
      transition. The BASDAI was the most responsive instrument. The Body Chart and
      RLDQ had low levels of responsiveness. CONCLUSION: The instruments have undergone
      a comprehensive comparative evaluation to assess the measurement properties
      required for patient-assessed measures of health outcome. Adequate levels of
      reliability and validity were found for all instruments. The BASDAI and the ASQoL
      were the most responsive to self-perceived change in health, but the BASDAI had
      low levels of self-completion.

PMID- 12422004
TI  - Effectiveness of TNF-alpha blockade with infliximab in refractory Wegener's
      granulomatosis.
AB  - OBJECTIVE: To study the effect of the chimeric monoclonal anti-tumour necrosis
      factor alpha (TNF-alpha) antibody infliximab in the induction of remission in six
      patients refractory to standard treatment with cyclophosphamide and
      corticosteroids. In four patients, other measures for treating refractory
      Wegener's granulomatosis (WG) that have been advocated previously, i.e.
      intensified cyclophosphamide therapy and additional intravenous immunoglobulin,
      were ineffective. METHODS: Patients received infliximab (3 mg/kg in two patients
      and 5 mg/kg in four patients) with a 2-week interval after the first
      administration and 4-week intervals between infusions until remission, in
      addition to cyclophosphamide and corticosteroids. Vasculitis activity was
      assessed with the Birmingham Vasculitis Activity Score (BVAS). A standardized
      interdisciplinary approach was used for the follow-up of specific organ
      involvement. RESULTS: Remission was induced in five patients and corticosteroid
      doses could be tapered. Acute-phase responses (e.g. C-reactive protein)
      normalized. Titres of c-ANCA (cytoplasmic pattern antineutrophil cytoplasmic
      antibodies) were no longer detectable. The BVAS was reduced to zero. The higher
      dose of infliximab (5 mg/kg) seemed more effective in inducing remission. One
      patient was withdrawn because of suspected systemic infection. Five patients
      remained in remission for 6-24 months of follow-up. CONCLUSION: The data suggest
      that infliximab may provide an effective and more specific therapeutic option in
      the treatment of active WG refractory to standard treatment.

PMID- 12422005
TI  - Outcome of neuropsychiatric systemic lupus erythematosus within a defined Swedish
      population: increased morbidity but low mortality.
AB  - OBJECTIVE: To investigate the outcome of neuropsychiatric involvement in systemic
      lupus erythematosus patients (NPSLE) recruited from a defined population.
      METHODS: All cases of adult SLE diagnosed during 1981-1995 within the Lund-Orup
      Health Care District were followed prospectively and neuropsychiatric
      manifestations were recorded. The SLICC/ACR (Systemic Lupus International
      Collaborating Clinics/American College of Rheumatology) Damage Index, mortality
      and working incapacity were recorded as measures of outcome. RESULTS: NPSLE
      manifestations developed in 38% (44/117) of the patients. A high rate of organ
      damage (SLICC/ACR Damage Index) was recorded in the NPSLE patients (P<0.001).
      Compared with patients without neuropsychiatric involvement, NPSLE patients were
      treated more intensively, with glucocorticoids (P<0.01) and cytostatic drugs
      (P<0.01). When compared with the normal population in the same area, the NPSLE
      patients had a higher rate of working incapacity (relative risk 4.0, 95%
      confidence interval 2.06-6.96), whereas mortality was not increased (standardized
      mortality rate 1.4, 95% confidence interval 0.5-3.0). CONCLUSIONS: SLE patients
      with neuropsychiatric involvement have an increased rate of organ damage and a
      high degree of working incapacity, which illustrates the severity of disease in
      this subgroup.

PMID- 12422007
TI  - Recurrent focal myositis of the peroneal muscles.
AB  - Recurrent focal myositis is a rare entity and can be difficult to diagnose and
      treat. A long-term follow-up and diagnostic evaluation was carried out in a
      patient who presented with ankle stiffness secondary to a painful mass within the
      calf. This process was diagnosed as focal myositis of the peroneal muscles, which
      recurred over a period of 7 yr. A review of the literature regarding focal
      myositis, treatment options and a successful conservative therapy regimen, as an
      alternative to a surgical protocol, are presented. After making the diagnosis
      with the help of a muscle biopsy, long-term therapy should be considered.
      Conservative treatment of focal myositis with anti-inflammatory drugs and
      physical therapy can be successful but recurrence may occur if the medical
      treatment is interrupted.

PMID- 12422006
TI  - A critical evaluation of commercial immunoassays for antineutrophil cytoplasmic
      antibodies directed against proteinase 3 and myeloperoxidase in Wegener's
      granulomatosis and microscopic polyangiitis.
AB  - OBJECTIVE: To evaluate the performance of 11 commercial enzyme-linked
      immunosorbent assay (ELISA) kits for the detection of antineutrophil cytoplasmic
      antibodies (ANCA) directed against proteinase 3 (PR3) and myeloperoxidase (MPO)
      in patients with Wegener's granulomatosis (WG) and microscopic polyangiitis
      (MPA). METHODS: Serum samples were taken from 92 patients with a histological and
      clinical diagnosis of WG (n=50) or MPA (n=42) and from 30 disease controls
      (systemic lupus erythematosus, n=15; rheumatoid arthritis, n=15) and 30 healthy
      controls. Each of the sera was tested for the presence of ANCA directed against
      PR3 and MPO using 11 commercially available direct ELISA kits, our in-house PR3-
      and MPO-ANCA capture ELISAs, and the indirect immunofluorescence technique (IFT).
      RESULTS: In tests for WG using PR3-ANCA, the commercial direct ELISA kits
      differed widely in their sensitivity (from 22 to 70%) and negative predictive
      value (NPV) (from 43 to 70%), but only moderately in their specificity (from 93
      to 100%) and positive predictive value (PPV) (from 93 to 100%). The highest
      sensitivity (74%) and specificity (100%) for PR3-ANCA were obtained with the in
      house capture ELISA. Similar differences and trends were noted for MPO-ANCA
      assays. Diagnostic sensitivity was more than 60% for four and at least 50% for
      six of the 11 ELISA kits. The PPV varied from 84 to 100% and the NPV from 58 to
      70%. In tests for MPA, the MPO-ANCA ELISA kit designated F and the in-house
      capture ELISA were best (both had sensitivity 62% and specificity 100%). For both
      WG and MPA, maximum sensitivity for ANCA was obtained with IFT (80 and 70%
      respectively). CONCLUSION: Determination of PR3-ANCA and MPO-ANCA with the
      commercial direct ELISA kits achieved poor sensitivity for both WG and MPA. The
      in-house PR3 and MPO-ANCA capture ELISAs performed better than the commercial
      ELISAs, combining higher specificity with similar sensitivity. IFT remains the
      best method for ANCA detection in both diseases.

PMID- 12422008
TI  - Assessment of specialist registrars in rheumatology: experience of an objective
      structured clinical examination (OSCE).
AB  - OBJECTIVES: Assessment of higher medical trainees (specialist registrars) in
      rheumatology is an important challenge facing the rheumatology community,
      particularly with the advent of the implemention of the changes recommended by
      the Calman Report in the UK. So far there has been remarkably little work in this
      area. Our aim was to implement and evaluate an objective structured clinical
      examination (OSCE) for rheumatology specialist registrars (SpRs). METHODS: Twelve
      SpRs completed a 12-station OSCE designed to assess core rheumatological clinical
      skills. The OSCE was designed and manned by consultant members of the West
      Midlands Rheumatology Services and Training Committee. The OSCE was evaluated by
      the SpRs, the participating consultant supervisors and the patients, by means of
      questionnaires. RESULTS: We present the details of the OSCE stations and the
      scores for each station. In terms of evaluation, 11 out of 12 SpRs felt that it
      was a very worthwhile exercise. Participating patients found it interesting, if
      tiring. All would be happy to participate in such an examination again. All
      participating consultants found it interesting and useful in terms of
      establishing the level of competence among trainees. CONCLUSION: The OSCE
      represents one practical approach to assessing clinical skills in rheumatology
      SpRs. It has potential in both formative and summative assessment. The broader
      issues around the assessment of rheumatology trainees are discussed.

PMID- 12422009
TI  - A rare cause of rash, eosinophilia and asthma in rheumatology.

PMID- 12422010
TI  - Is methotrexate effective in ankylosing spondylitis?

PMID- 12422011
TI  - Effectiveness of devil's claw for osteoarthritis.

PMID- 12422012
TI  - Remitting seronegative symmetrical synovitis with pitting oedema as the first
      manifestation of psoriatic arthropathy.

PMID- 12422014
TI  - Prevalence of diffuse idiopathic skeletal hyperostosis in Budapest, Hungary.

PMID- 12422015
TI  - The joys of online submission.

PMID- 12422017
TI  - Invisible liposomes: refractive index matching with sucrose enables flow
      dichroism assessment of peptide orientation in lipid vesicle membrane.
AB  - Valuable information on protein-membrane organization may in principle be
      obtained from polarized-light absorption (linear dichroism, LD) measurement on
      shear-aligned lipid vesicle bilayers as model membranes. However, attempts to
      probe LD in the UV wavelength region (<250 nm) have so far failed because of
      strong polarized light scattering from the vesicles. Using sucrose to match the
      refractive index and suppress the light scattering of phosphatidylcholine
      vesicles, we have been able to detect LD bands also in the peptide-absorbing
      region (200-230 nm). The potential of refractive index matching in vesicle LD as
      a general method for studying membrane protein structure was investigated for the
      membrane pore-forming oligopeptide gramicidin incorporated into the liposome
      membranes. In the presence of sucrose, the LD signals arising from oriented
      tryptophan side chains as well as from n-->pi* and pi-->pi* transitions of the
      amide chromophore of the polypeptide backbone could be studied. The observation
      of a strongly negative LD for the first exciton transition ( approximately 204
      nm) is consistent with a membrane-spanning orientation of two intertwined
      parallel gramicidin helices, as predicted by coupled-oscillator theory.

PMID- 12422018
TI  - Identification of phosphorylated residues that affect the activity of the mitotic
      kinase Aurora-A.
AB  - The activity of the kinase Aurora-A (Aur-A) peaks during mitosis and depends on
      phosphorylation by one or more unknown kinases. Mitotic phosphorylation sites
      were mapped by mass spec sequencing of recombinant Aur-A protein that had been
      activated by incubation in extracts of metaphase-arrested Xenopus eggs. Three
      sites were identified: serine 53 (Ser-53), threonine 295 (Thr-295), and serine
      349 (Ser-349), which are equivalent to Ser-51, Thr-288, and Ser-342,
      respectively, in human Aur-A. To ask how phosphorylation of these residues might
      affect kinase activity, each was mutated to either alanine or aspartic acid, and
      the recombinant proteins were then tested for their ability to be activated by M
      phase extract. Mutation of Thr-295, which resides in the activation loop of the
      kinase, to either alanine or aspartic acid abolished activity. The S349A mutant
      had slightly reduced activity, indicating that phosphorylation is not required
      for activity. The S349D mutation completely blocked activation, suggesting that
      Ser-349 is important for either the structure or regulation of Aur-A. Finally,
      like human Aur-A, overexpression of Xenopus Aur-A transformed NIH 3T3 cells and
      led to tumors in nude mice. These results provide further evidence that Xenopus
      Aur-A is a functional ortholog of human Aur-A and, along with the recently
      described crystal structure of human Aur-A, should help in future studies of the
      mechanisms that regulate Aur-A activity during mitotic progression.

PMID- 12422019
TI  - Linking climate change and biological invasions: Ocean warming facilitates
      nonindigenous species invasions.
AB  - The spread of exotic species and climate change are among the most serious global
      environmental threats. Each independently causes considerable ecological damage,
      yet few data are available to assess whether changing climate might facilitate
      invasions by favoring introduced over native species. Here, we compare our long
      term record of weekly sessile marine invertebrate recruitment with interannual
      variation in water temperature to assess the likely effect of climate change on
      the success and spread of introduced species. For the three most abundant
      introduced species of ascidian (sea squirt), the timing of the initiation of
      recruitment was strongly negatively correlated with winter water temperature,
      indicating that invaders arrived earlier in the season in years with warmer
      winters. Total recruitment of introduced species during the following summer also
      was positively correlated with winter water temperature. In contrast, the
      magnitude of native ascidian recruitment was negatively correlated with winter
      temperature (more recruitment in colder years) and the timing of native
      recruitment was unaffected. In manipulative laboratory experiments, two
      introduced compound ascidians grew faster than a native species, but only at
      temperatures near the maximum observed in summer. These data suggest that the
      greatest effects of climate change on biotic communities may be due to changing
      maximum and minimum temperatures rather than annual means. By giving introduced
      species an earlier start, and increasing the magnitude of their growth and
      recruitment relative to natives, global warming may facilitate a shift to
      dominance by nonnative species, accelerating the homogenization of the global
      biota.

PMID- 12422020
TI  - Two isoforms of the Notch antagonist Hairless are produced by differential
      translation initiation.
AB  - The Notch-signaling pathway controls cellular differentiation, including
      proliferation and cell death in all higher metazoans (including flies and men).
      Signal transduction through activated Notch involves the CSL group of
      transcriptional regulators. Notch signals need to be tightly regulated, and in
      Drosophila they are antagonized by the Hairless (H) protein. H silences the
      activity of Notch target genes by transforming the Drosophila CSL protein,
      Suppressor of Hairless [Su(H)], from a transcriptional activator into a repressor
      while recruiting one of the corepressors dCtBP or Groucho. The H protein has a
      calculated molecular mass of approximately 110 kDa and contains several
      functional domains apart from the two small corepressor-binding domains. However,
      although there is no indication for alternative splicing, two Hairless protein
      isoforms, H(p120) and H(p150), are observed throughout development. Here, we show
      that the smaller isoform derives from an internal ribosome entry site (IRES)
      within the ORF. The IRES is active in a heterologous assay and contains an
      essential, conserved structural element. The two Hairless isoforms have residual
      activity in vivo which is, however, reduced compared to a combination of both,
      which implies that both protein isoforms are necessary for WT function. In larval
      tissues, translation of the two isoforms is cell-cycle regulated: whereas the
      H(p150) isoform is translated during interphase, H(p120) is enriched during
      mitosis. Thus, the presence of either H isoform throughout the cell cycle allows
      efficient inhibition of Notch-regulated cell proliferation.

PMID- 12422022
TI  - Not CCUs but BCUs.

PMID- 12422023
TI  - The management of chronic back disorders.

PMID- 12422021
TI  - An exchanger-like protein underlies the large Mg2+ current in Paramecium.
AB  - There are very few molecules known to transport Mg(2+) in eukaryotes. The
      membrane of Paramecium tetraurelia passes a large Mg(2+)-selective current and
      exhibits a corresponding backward swimming behavior. Both are missing in a group
      of mutants called eccentric. By sorting an indexed WT genomic library through
      microinjection into the macronucleus, we have isolated a DNA fragment that
      complements the eccentric mutations. The Mg(2+) currents and behavior are
      restored fully in the transformed cells. Surprisingly, the conceptually
      translated protein is not homologous to any known ion channel but instead has
      some similarity to K(+)-dependent Na(+)Ca(2+) exchangers. Exchangers are either
      electrically silent or only pass very small and slow currents compared with ion
      channel currents. In light of recent ion-channel crystal structures and
      considering the need to have narrow ion-selective filters, we speculate on how an
      exchanger might evolve to show channel-like activities in special circumstances.
      The significance of finding the molecular basis of a Mg(2+)-specific pathway is
      also discussed.

PMID- 12422024
TI  - Assessing the provision of occupational health services in the construction
      industry in Hong Kong.
AB  - A survey was conducted to review the provision of occupational health services
      (OHS) in the construction industry, the most hazardous industry in Hong Kong. A
      questionnaire was used to collect information on various aspects of OHS from a
      sample of construction companies. OHS provision was estimated by an overall
      score, with the various components weighted for their importance regarding
      prevention. Factors affecting the provision of services were explored by multiple
      linear regressions. Only 58 of the 183 establishments (32%) performed
      environmental assessment; 37 (20%) offered medical examinations to their workers
      and 70 (38%) provided health and safety talks. Scores for the provision of OHS
      were generally low, especially for the component of surveillance concerning
      workers' health. In general, larger establishment size and having safety and/or
      health policies were the important factors leading to high scores.

PMID- 12422025
TI  - Improving subjective health at the worksite: a randomized controlled trial of
      stress management training, physical exercise and an integrated health programme.
AB  - Our objective was to evaluate the effect of 12 weeks of stress management
      training (SMT), physical exercise (PE) and an integrated health programme (IHP)
      in a worksite setting on subjective health complaints. To do this, we randomly
      split 860 employees into the following groups: control (n = 344), PE (n = 189),
      IHP (comprising physical exercise and health information) (n = 165) and SMT (n =
      162). There were no significant effects on subjective health complaints, sick
      leave or job stress. However, strong and specific positive effects were
      experienced for the particular goal areas defined for each intervention. The PE
      group showed improved general health, physical fitness and muscle pain, while the
      SMT group showed improved stress management. The IHP group showed the strongest
      effects, affecting most goals set for treatment.

PMID- 12422026
TI  - Inequity in occupational health services for government hospital workers in South
      Africa.
AB  - South Africa's inequitable public health system is mainly delivered by provincial
      health departments, and exemplifies the potential and problems of occupational
      health services in middle-income countries. The occupational health services for
      153 265 employees in all of South Africa's 370 provincial hospitals were
      described and compared. Information was obtained from 303 (82%) hospitals, using
      a self-completed questionnaire and telephone interviews. Thirty-two per cent of
      hospitals had an occupational health clinic, but 61% of employees worked in
      hospitals with a clinic. Occupational health clinics were more likely to be
      present in larger hospitals, and were strongly associated with provision of
      primary care and chronic disease services to workers. Thirty-nine per cent of
      hospitals had a safety officer, 41% had access to an industrial hygienist or
      environmental health officer, and 80% had health and safety committees, as
      required by law. While occupational health services were more likely in larger
      hospitals, workforce size did not explain the marked differences between
      provinces. The study shows that substantial occupational health services exist,
      but that important gaps persist, even in wealthier provinces and especially in
      provinces without coherent occupational health policies.

PMID- 12422027
TI  - The estimated workforce served by occupational physicians in the UK.
AB  - During the past decade, an occupational disease surveillance scheme has been
      created in the UK, based on systematic reporting of newly diagnosed cases by six
      groups of clinical consultants and by specialist occupational physicians. Labour
      Force Survey statistics have proved a reasonably satisfactory denominator for the
      former, but not for the occupational physicians, who provide services for only a
      selected subsection of the employed population. To remedy this deficiency,
      approximately 700 occupational physicians who were recorded as having been a
      reporter at some time were invited to provide their best estimate of the number
      of employees for whom they were responsible. After various exclusions--mainly
      physicians who were not, or were no longer, responsible for any defined
      workforce, and others who had not reported for at least 3 years--the number of
      active participants for whom data, by industry, occupation and sex, were obtained
      or estimated was 503. The resulting total number of employees served was
      estimated at 3.2 million, comprising 12% of the general working population. The
      proportion with access to an occupational physician varied enormously, from 43%
      in the health and social services to 1% in agriculture, forestry and fishing, and
      6% in the rest of industry. Numbers estimated for each industrial sector were
      fairly reliable, but by occupation less so, especially in the health and social
      services.

PMID- 12422028
TI  - The incidence of work-related disease reported by occupational physicians, 1996
      2001.
AB  - In the course of six calendar years, 1996-2001, 5491 new cases of work-related
      disease were reported by a 1-in-12 random sample of occupational physicians
      throughout the UK. This represented an estimated total of almost 66 000, or 11
      000 cases per annum. These cases have now been analysed by sex, occupation (nine
      categories) and industry (eight categories), and annual average incidence rates
      calculated in five main disease groups against a similarly classified denominator
      of 3.2 million employees served by the same physicians. The overall average
      annual estimated rate (342 per million) was eight times higher than that reported
      by clinical specialists, calculated in a similar manner against the entire
      employed population of the UK (28 million), but 17 times higher for
      musculoskeletal disease. For men employed in mines and quarries, and both men and
      women in metallic and automotive manufacture, rates for most types of disease
      were very high. Occupations with the highest rates were craftsmen and female
      associate professionals. In all these occupational and industrial groups with
      high rates, musculoskeletal complaints were the main cause, and skin, respiratory
      or stress diseases were next in importance. In each type of disease, there was a
      wide range in incidence rates, suggesting important differences in risk by
      occupation or industry.

PMID- 12422029
TI  - Neurological changes induced by a mobile phone.
AB  - Dysaesthesiae of the scalp after mobile phone use have been previously reported,
      but the basis for this has not been clear. We report a case of a 34-year-old
      journalist who complained of symptoms associated with use of a mobile phone. She
      agreed to a provocation study with her phone. Current perception threshold
      testing before and after exposure showed marked changes in the C-fibre nerves of
      the affected area compared with the opposite side. The case is supportive of a
      neurological basis for some cases of dysaesthesiae associated with mobile phone
      use.

PMID- 12422030
TI  - Tales of Kieran: The occupational physician's odyssey.

PMID- 12422041
TI  - Reversible holocord edema associated with intramedullary spinal abscess secondary
      to an infected dermoid cyst.
AB  - We report a case of a holocord high-intensity lesion extending from L1 up to the
      medulla oblongata on T2-weighted spinal magnetic resonance imaging (MRI)
      associated with an intramedullary spinal abscess secondary to an infected dermoid
      cyst. The intraoperative findings revealed that the high-intensity lesion on the
      T2-weighted image was edematous tissue. The MRI change in the spinal cord
      gradually improved in response to the use of postoperative antibiotics. The
      change was considered to represent reversible inflammatory changes, as there was
      no neurological deficit found at the cervical level and it resolved after surgery
      and medical treatment. The pathomechanism is discussed herein.

PMID- 12422042
TI  - Outcome analysis of initial neonatal shunts: does the valve make a difference?
AB  - OBJECTIVE: Ventriculoperitoneal shunts have one of the highest complication rates
      of all neurosurgical procedures. The purpose of this study was to identify
      factors associated with malfunction of shunts placed in infants with neonatal
      hydrocephalus, with the goal of maximizing long-term shunt survival. METHODS: We
      performed a retrospective chart review of 200 consecutive patients less than 1
      year old who underwent primary intracranial shunt placement for hydrocephalus by
      one of two experienced pediatric neurosurgeons at a single institution. A
      multivariate analysis was conducted to identify variables that were statistically
      independent predictors of a shunt malfunction or problem. RESULTS: Adequate data
      were available for 158 patients, with a mean follow-up of 39.8 months (range 6-99
      months). Variables tested for independent prediction of shunt revision included
      the etiology of the hydrocephalus, gestation period, age at shunt placement,
      surgeon, ventricular catheter entry site and valve opening pressure. Frontal
      versus occipital catheter entry site was not associated with a different revision
      rate. The only significant controllable factor associated with shunt malfunction
      was the valve opening pressure. The revision rate per year of follow-up was 4
      times higher for patients with no valve or a low-pressure valve than for patients
      with a medium- or high-pressure valve. CONCLUSIONS: This retrospective review
      demonstrated that the valve opening pressure is an important component of the
      shunt complication rate. A prospective multicenter randomized trial is warranted
      to further evaluate the conclusions of this study.

PMID- 12422043
TI  - Neuroendoscopic treatment of paediatric cerebrospinal fluid rhinorrhoea.
AB  - Endoscopic management of CSF rhinorrhoea in children is usually associated with a
      higher incidence of mucosal abrasion and post-operative synechiae formation due
      to surgical manoeuvres in narrower nasal passages. We have used the Gaab
      universal neuroendoscope for the treatment of CSF rhinorrhoea in children. Three
      patients were treated in the last 2 years with this technique. All patients
      became completely asymptomatic after the initial procedure without any
      significant complications. We conclude that the treatment of CSF rhinorrhoea in
      children by means of a neuroendoscope with a working sheath may be effective and
      less traumatic to the nasal passage.

PMID- 12422044
TI  - The postoperative course and management of 106 hemidecortications.
AB  - RATIONALE: The excellent long-term outcome for most children undergoing
      hemispherectomy is well documented. However, the condition of these children in
      the immediate postoperative period is poorly described. The purpose of this study
      was to evaluate the short-term issues surrounding hemispherectomy and their
      management in a series of patients from our institution. METHODS: 106
      hemispherectomies were performed at our institution from 1975 to 2001 (102
      hemidecortications). Medical records were retrospectively examined for
      information regarding immediate postoperative problems and care. RESULTS: Three
      children died in the immediate perioperative period, while 3 others had
      significant postoperative morbidity. 82% of these children had postoperative
      fevers (temperature >38.5 degrees C). Of these children, 62% had lumbar
      punctures. Ten cases had positive CSF growth, of which 6 cases were felt to have
      actual meningitis. Patients with CSF growth had a significantly longer prior
      duration of steroid therapy and higher maximum temperature peaks. CSF pleocytosis
      and an ill clinical appearance neared significance for prediction of CSF growth.
      Shunting was performed in 19% of all children and was associated with CSF growth.
      CONCLUSIONS: Postoperative fevers are common after hemidecortication, but
      meningitis is not. Children with CSF growth tended to appear more ill and have
      higher temperature spikes and CSF pleocytosis. Shunting was related to CSF
      growth.

PMID- 12422045
TI  - Failed endoscopic third ventriculostomy in children: management options.
AB  - Endoscopic third ventriculostomy (ETV) for obstructive hydrocephalus has a
      failure rate of 20-50% in various series. The present study analyzes ETV failures
      in 72 patients over a 2-year period and attempts to outline a management plan. Of
      the 72 patients who underwent ETV, it failed in 13. Seven of these failures
      occurred within 1 month, and in 5 others, ETV failed after 1-2 months. Another
      patient had a delayed failure 2 years after the initial surgery. Upon clinical
      failure, MRI scans were performed in all patients using either T2 fast spin echo
      or two-dimensional phase contrast MRI techniques. Of these, no flow could be
      demonstrated in 12 patients, whereas in 1 patient, good flow was observed.
      Endoscopic exploration was undertaken in the 12 patients in whom flow could not
      be demonstrated. Of the 12 who underwent endoscopic exploration, a patent stoma
      was observed in 7, necessitating insertion of a ventriculoperitoneal shunt (VPS).
      In the other 5, the stoma had closed by gliosis and a repeat ETV was performed.
      In 3 of these patients, in addition to the ETV, a VPS was also inserted in
      accordance with the family's wishes. VPS insertion was carried out in the patient
      with suggestion of good flow through the stoma. In failed ETV, MRI with flow
      studies is essential to identify the possible cause of failure. Endoscopic
      exploration is indicated for patients with no evidence of flow. A repeat ETV is
      indicated in patients with a closed stoma. Patients with a patent stoma could
      require insertion of a cerebrospinal fluid shunt.

PMID- 12422046
TI  - Assessment of continuous intracranial pressure recordings in childhood
      craniosynostosis.
AB  - In this study, we explored two strategies of assessing continuous intracranial
      pressure (ICP) recordings in children with craniosynostosis, namely either by
      computation of the mean ICP or by computation of the accurate numbers of ICP
      elevations of different durations. The ICP recordings of 121 consecutive patients
      with a tentative diagnosis of craniosynostosis who underwent continuous ICP
      monitoring were examined. The relationship between mean ICP and numbers of ICP
      elevations was defined. The distribution of numbers of ICP elevations between
      patients either undergoing surgery or conservative treatment was also compared,
      since the choice of treatment was heavily dependent on the results of ICP
      monitoring. At the time of ICP monitoring, calculation of mean ICP was the main
      parameter for assessment of ICP curves. After a median observation period of 16
      months, the ICP curves were reexamined by means of the software Sensometrics
      Pressure Analyser, which presents the ICP curve as a matrix of numbers of ICP
      elevations of different levels (20-40 mm Hg) and durations (0.5- 20 min). Since
      the recording period differed between the cases, the numbers were standardized to
      a given recording time of 10 h, to allow for comparisons between patients. Cases
      with a borderline mean ICP during sleep (mean ICP 10-15 mm Hg) constituted 40.5%
      of the 121 patients. In this group, a rather weak relationship between mean ICP
      and the number of ICP elevations above 20 mm Hg was found, as well as a
      relatively high number of ICP elevations above 20 mm Hg of various durations. As
      compared to the patients undergoing surgery, a rather high number of ICP
      elevations above 20 mm Hg of various durations was found in patients undergoing
      conservative treatment. The study confirmed our hypothesis that in children with
      craniosynostosis, calculation of mean ICP does not describe the ICP curve in a
      reliable way. Decision-making should also include the computation of the
      distribution of numbers of ICP elevations, since this procedure represents a more
      sensitive strategy of detecting intracranial hypertension.

PMID- 12422047
TI  - Unusual neuroenteric cysts: diagnosis and management.
AB  - Six cases of unusual neuroenteric (NE) cysts, occurring in children aged 15
      months to 18 years, are reported here. Three of the cysts were extramedullary,
      while the other three were intramedullary. Two of the extramedullary cysts were
      located at the lumbosacral region, an unusual site. Only one patient had the cyst
      located in a ventral relation to the cord in the cervicothoracic region. None of
      the patients had communication with the mediastinum or intraabdominal viscera.
      Stigmata of spinal dysraphism were seen in three patients. All the children had
      variable neurological involvement and it was difficult to differentiate NE cyst
      from other causes of spinal cord or cauda equina lesion, particularly in the
      absence of some dysraphic marker. One patient presented with minimal neurological
      deficits and painful torticollis; this patient was suspected to have an
      atlantoaxial dislocation. All patients were investigated with MRI, and the only
      diagnostic feature of an NE cyst was an intradural cyst with an anterior
      vertebral body anomaly in a single case. It was not possible to radiologically
      differentiate NE cyst from other intraspinal cysts in the rest of the patients.
      All patients were operated on by the posterior route; an attempt to excise the
      cyst nearly in toto was made. Evidence of neural tethering most probably due to
      cyst contents was seen in three patients. All patients improved after surgery.
      None showed recurrence of the cyst at follow-up of 3 months to 2 years.

PMID- 12422048
TI  - Dural ectasia in neurofibromatosis.

PMID- 12422049
TI  - Molecular targets in cancer therapy and their impact on cancer management.

PMID- 12422050
TI  - HER-targeted tyrosine-kinase inhibitors.
AB  - Improved understanding of tumor biology has led to the identification of numerous
      growth factors that are involved in malignant transformation and tumor
      progression. Many of these factors induce cellular responses through receptors
      with intrinsic tyrosine kinase (TK) activity. Therefore, inhibiting receptor TK
      activity is a way to effectively block the tumorigenic effects that arise from
      these pathways. The HER family of TK receptors is overexpressed or dysregulated
      in many types of human cancer. As a result these receptors were identified as
      targets for cancer therapy. Several agents have been developed that reversibly,
      or irreversibly, inhibit one, two or all of the HER receptors. Tarceva and Iressa
      are HER1-TK inhibitors that are advanced in development. Clinical data show that
      these agents as monotherapy have antitumor activity in patients with various
      types of solid tumor and are well tolerated; encouraging data are also produced
      when Tarceva or Iressa are combined with chemotherapeutic agents. Other dual or
      pan-HER, reversible or irreversible, TK inhibitors are being investigated in
      phase I trials. Early data show that they are generally well tolerated and have
      provided evidence of antitumor activity. HER-TK inhibitors are exciting agents
      that are likely to have a substantial impact on the way we treat patients with
      cancer.

PMID- 12422051
TI  - Perspectives on anti-HER monoclonal antibodies.
AB  - The ability of Herceptin to prolong survival in women with HER2-overexpressing
      breast tumors has proven the concept of using humanized or chimeric monoclonal
      antibodies (MAbs) for cancer therapy. MAbs have been developed that are specific
      for many tumorigenic molecules and receptors. They can potentially be used to
      treat a range of solid tumors. Among the most promising targets for therapy are
      members of the human epidermal growth factor receptor (HER/ErbB) family,
      particularly HER1 and HER2. Several MAbs have been produced that are directed
      against HER1. One of these agents, cetuximab (Erbitux), is now advanced in
      clinical development. HER2 is also a key target and methods are being
      investigated to maximize the effect of using MAbs to inhibit this receptor. One
      approach aims to augment the efficacy of trastuzumab (Herceptin) by coupling it
      to a chemotherapeutic agent, thus enabling the delivery of cytotoxic therapy at a
      cellular level. Another opportunity is based on research that shows that HER2
      acts as a dimerization partner for other HER receptors and consequently is
      important in HER-ligand-dependent tumor growth. Therefore, anti-HER2 MAbs that
      inhibit the association of HER2 with other HER family members have the potential
      to be highly effective. This article reviews some of these alternative approaches
      to MAb-based anti-HER therapy that will hopefully improve treatment outcome for
      patients with a range of solid tumors.

PMID- 12422052
TI  - Current status of HER2 testing.
AB  - HER2 gene amplification and receptor overexpression by tumors seems to be
      associated with poorer prognosis and may be predictive of response to certain
      anticancer therapies. Furthermore, and paramount to the clinician and patient, a
      positive HER2 status is a prerequisite eligibility requirement for Herceptin
      (trastuzumab) therapy in women with metastatic breast cancer. As a consequence,
      issues relating to accurate and reliable laboratory assessment of HER2 status are
      a matter of significant debate to pathologists and oncologists. Out of a wide
      range of techniques that have been used in research for the detection of HER2
      status, two technologies are now predominant in the routine clinical pathology
      laboratory: determination of HER2 protein overexpression by immunohistochemistry
      (IHC) and HER2 gene amplification by fluorescence in-situ hybridization (FISH).
      This article discusses some of the recent experiences, guidelines, and opinions
      of pathologists and clinicians concerning aspects of HER2 testing with respect to
      when to test (at initial diagnosis or pretreatment), the relative
      advantages/disadvantages of IHC and FISH, and where to test (local or centralized
      laboratories).

PMID- 12422053
TI  - Emerging technologies for HER2 testing.
AB  - HER2-positive status is the sole criterion for identifying patients with breast
      cancer for Herceptin therapy, which has known efficacy in women with metastatic
      breast cancer (MBC). Immunohistochemistry (IHC) and fluorescence in-situ
      hybridization (FISH), which measure the HER2 protein and gene, respectively, are
      currently the most widely used HER2 tests in the clinical setting. However,
      results from these assays are influenced by many variables including choice of
      antibody or probe, methodology, level of user experience and interlaboratory
      variability. Although there is no widespread standard testing algorithm, the
      importance of HER2 in clinical practice demands accurate and reproducible tests.
      Polymerase chain reaction (PCR) and chromogenic in-situ hybridization (CISH)
      represent upcoming methods for assessing HER2 gene amplification. Enzyme-linked
      immunosorption assay (ELISA), a semi-automated technique that can be used to
      measure the level of the HER2 extracellular domain (ECD) in serum, may also prove
      useful. While such technologies show great promise, they will at least have to be
      validated against IHC or FISH before being accepted into routine clinical
      practice.

PMID- 12422054
TI  - What can we learn from Herceptin trials in metastatic breast cancer?
AB  - Herceptin (trastuzumab), an anti-HER2 monoclonal antibody, is the first oncogene
      targeted therapy to be developed for the treatment of metastatic breast cancer.
      The Herceptin clinical trial program has demonstrated that treatment with
      Herceptin provides substantial clinical benefits when used either as monotherapy
      or in combination with a number of chemotherapeutic agents. Of note, accurate
      assessment of HER2 status is essential to ensure that the patients most likely to
      benefit from Herceptin are identified: patients with immunohistochemistry (IHC)
      3+ or fluorescence in-situ hybridization (FISH)-positive disease gain the
      greatest clinical benefits. In addition, clinical benefits appear to be greater
      the earlier Herceptin is used, although there is currently no direct clinical
      evidence to indicate whether an initial strategy of combination therapy is better
      than monotherapy or vice versa. Herceptin has been shown to be generally well
      tolerated. The most severe adverse events are rare serious infusion-related
      reactions and cardiotoxicity. These adverse events can be managed by standard
      care and patients at risk can often be identified prior to the initiation of
      Herceptin treatment. Currently, Herceptin should be given until disease
      progression, but there could be benefit in continuing treatment beyond disease
      progression.

PMID- 12422055
TI  - The future of targeted therapy: combining novel agents.
AB  - The anti-HER2 monoclonal antibody Herceptin demonstrates significant clinical
      benefits in patients with HER2-positive metastatic breast cancer (MBC). However,
      the combination of Herceptin plus anthracyclines, although efficacious,
      demonstrated a higher than expected incidence of cardiotoxicity. Therefore,
      studies are currently investigating Herceptin in combination with alternative
      anthracyclines, such as epirubicin and liposomal doxorubicin. Investigators are
      also beginning to examine the potential of Herceptin plus hormonal therapy, a
      combination that will delay the need to use cytotoxic chemotherapy. Furthermore,
      a plethora of novel agents have been developed that target the processes of
      tumorigenesis, including HER1 tyrosine-kinase inhibitors, farnesyl-transferase
      inhibitors, and cyclooxygenase 2 (COX2) inhibitors. Preclinical data demonstrate
      that the combination of Herceptin with these agents can produce at least additive
      effects and therefore a rationale exists to investigate these regimens in the
      clinical setting. As a result of the targeted nature of these agents, it is
      anticipated that such strategies will have favorable safety profiles. It is
      possible that through the development and use of biological anticancer agents,
      such as Herceptin, future anticancer regimens may be specifically tailored to
      each patient based on their molecular characteristics.

PMID- 12422056
TI  - Moving forward: Herceptin in the adjuvant setting.
AB  - HER2 overexpression/amplification, which is an early event in breast cancer
      development, is associated with a poor prognosis and may predict response to
      therapy. Herceptin, an anti-HER2 monoclonal antibody, has shown significant
      efficacy in the treatment of HER2-positive metastatic breast cancer and appears
      to provide greater benefit the earlier the drug is given. Moreover, Herceptin
      also demonstrates a favorable safety profile and is associated with quality-of
      life benefits. Taken together, these factors provide the rationale for moving
      this drug into the adjuvant setting, and four large-scale trials that will
      involve a total of more than 12,000 women with HER2-positive primary breast
      cancer have been undertaken to address this issue. In the United States, NSABP
      trial B31 and the Intergroup N9831 trial will investigate Herceptin in
      combination with the standard US regimen of anthracycline/cyclophosphamide
      followed by paclitaxel. Trial BCIRG 006, which is being conducted globally, will
      examine Herceptin in combination with platinum salts/docetaxel. The HERA Trial,
      involving countries outside the US, will examine q3-weekly Herceptin monotherapy
      given for 1 and 2 years after the completion of adjuvant chemo-/radiation
      therapy. The breadth of the ongoing Herceptin adjuvant trials will potentially
      allow the optimal treatment approach to be identified.

PMID- 12422057
TI  - Nonlinear measures of respiration: respiratory irregularity and increased chaos
      of respiration in patients with panic disorder.
AB  - BACKGROUND: Respiratory irregularity has been previously reported in patients
      with panic disorder using time domain measures. However, the respiratory signal
      is not entirely linear and a few previous studies used approximate entropy
      (APEN), a measure of regularity of time series. We have been studying APEN and
      other nonlinear measures including a measure of chaos, the largest Lyapunov
      exponent (LLE) of heart rate time series, in some detail. In this study, we used
      these measures of respiration to compare normal controls (n = 18) and patients
      with panic disorder (n = 22) in addition to the traditional time domain measures
      of respiratory rate and tidal volume. METHODS: Respiratory signal was obtained by
      the Respitrace system using a thoracic and an abdominal belt, which was digitized
      at 500 Hz. Later, the time series were constructed at 4 Hz, as the highest
      frequency in this signal is limited to 0.5 Hz. We used 256 s of data (1024
      points) during supine and standing postures under normal breathing and controlled
      breathing at 12 breaths/min. RESULTS: APEN was significantly higher in patients
      in standing posture during normal as well as controlled breathing (p = 0.002 and
      0.02, respectively). LLE was also significantly higher in standing posture during
      normal breathing (p = 0.009). Similarly, the time domain measures of standard
      deviations and the coefficient of variation (COV) of tidal volume (TV) were
      significantly higher in the patient group (p = 0.02 and 0.004, respectively). The
      frequency of sighs was also higher in the patient group in standing posture (p =
      0.02). In standing posture, LLE (p < 0.05) as well as APEN (p < 0.01) contributed
      significantly toward the separation of the two groups over and beyond the linear
      measure, i.e. the COV of TV. CONCLUSION: These findings support the previously
      described respiratory irregularity in patients with panic disorder and also
      illustrate the utility of nonlinear measures such as APEN and LLE as additional
      measures toward a better understanding of the abnormalities of respiratory
      physiology in similar patient populations as the correlation between LLE, APEN
      and some of the time domain measures only explained up to 50-60% of the
      variation.

PMID- 12422058
TI  - Effects of single and repeated restraint stresses on the expression of beta(1)
      adrenoceptor mRNA in the rat hypothalamus and midbrain.
AB  - We examined the effects of single and repeated restraint stresses on the
      expression of beta(1)-adrenoceptor mRNA in the rat midbrain and hypothalamus
      using reverse transcriptase-polymerase chain reaction (RT-PCR). After the rats
      had been restrained for 4 h (single stress), or for 4 h per day during 2 or 3
      consecutive days, the hypothalamus and midbrain were removed immediately and
      beta(1)-adrenoceptor mRNA levels in these regions were determined by RT-PCR.
      Single stress significantly decreased the mRNA level in the hypothalamus, but the
      mRNA level was near control levels after 2 and 3 days of stress. In the midbrain,
      single stress had no effect on the mRNA level, but 2 days of stress significantly
      increased it.

PMID- 12422059
TI  - Major depression with ischemic heart disease: effects of paroxetine and
      nortriptyline on measures of nonlinearity and chaos of heart rate.
AB  - Depression is associated with increased cardiovascular mortality in patients with
      preexisting cardiac illness. A decrease in cardiac vagal function as suggested by
      a decrease in heart rate variability (HRV) or heart period variability has been
      linked to sudden death in patients with cardiac disease as well as in normal
      controls. Recent studies have shown decreased vagal function in cardiac patients
      with depression as well as in depressed patients without cardiac illness. In this
      study, we compared 20 h awake and sleep heart period nonlinear measures using
      quantification of nonlinearity and chaos in two groups of patients with major
      depression and ischemic heart disease (mean age 59-60 years) before and after 6
      weeks of treatment with paroxetine or nortriptyline. Patients received
      paroxetine, 20-30 mg/day or nortriptyline targeted to 190-570 nmol/l for 6 weeks.
      For HRV analysis, 24 patients were included in the paroxetine treatment study and
      20 patients in the nortriptyline study who had at least 20000 s of awake data.
      The ages of these groups were 60.4 +/- 10.5 years for paroxetine and 60.8 +/-
      13.4 years for nortriptyline. There was a significant decrease in the largest
      Lyapunov exponent (LLE) after treatment with nortriptyline but not paroxetine.
      There were also significant decreases in nonlinearity scores on S(netPR) and
      S(netGS) after nortriptyline, which may be due to a decrease in cardiac vagal
      modulation of HRV. S(netGS) and awake LLE were the most significant variables
      that contributed to the discrimination of postparoxetine and postnortriptyline
      groups even with the inclusion of time and frequency domain measures. These
      findings suggest that nortriptyline decreases the measures of chaos probably
      through its stronger vagolytic effects on cardiac autonomic function compared
      with paroxetine, which is in agreement with previous clinical and preclinical
      reports. Nortriptyline was also associated with a significant decrease in
      nonlinearity scores, which may be due to anticholinergic and/or sympatholytic
      effects. As depression is associated with a strong risk factor for cardiovascular
      mortality, one should be careful about using any drug that adversely affects
      cardiac vagal function.

PMID- 12422060
TI  - Association between -1438G/A promoter polymorphism in the 5-HT(2A) receptor gene
      and fluvoxamine response in Japanese patients with major depressive disorder.
AB  - Genetic polymorphism of the serotonin 5-HT(2A) receptor seems to be associated
      with therapeutic response to selective serotonin reuptake inhibitors (SSRIs). The
      present study investigated whether a novel -1438G/A polymorphism in the promoter
      region of the 5-HT(2A )receptor gene is associated with therapeutic response to
      fluvoxamine (an SSRI) in 66 Japanese patients with major depressive disorder.
      Fluvoxamine (50 to 200 mg) was administered twice daily for 6 weeks. Fifty-four
      patients completed this study. The genotype distribution and the allele
      frequencies showed no significant difference between responders and non
      responders. The time-course of the Montgomery-Asberg Depression Rating Scale
      scores showed no significant difference among -1438G/G, -1438G/A, and -1438A/A
      genotype groups. The results demonstrated that the -1438G/A promoter polymorphism
      in the 5-HT(2A) receptor gene was unlikely to have a major role in therapeutic
      response to fluvoxamine in Japanese patients with major depressive disorder.

PMID- 12422061
TI  - Association analysis of two dopamine D2 receptor gene polymorphisms and p300
      event-related potential in depressive patients.
AB  - Previous Western studies have demonstrated an association between the dopamine D2
      receptor (DRD2) TaqI A polymorphism and components of P300 event-related
      potential. This finding was not replicated in our previous study of a sample of
      normal young Chinese females, however. In the current study of 105 patients
      diagnosed with major depression, we have further explored the association between
      the P300 components, and, the DRD2 TaqI A polymorphism and another functional
      DRD2 -141Cins/Del polymorphism. The results demonstrate that neither polymorphism
      is associated with P300 amplitude or latency, even after gender analysis. We
      suggest that these two DRD2 polymorphisms have no major effects on P300
      components for the Chinese population. The association between the DRD2
      polymorphism and P300 components may depend on ethnicity, the psychiatric state
      of the subjects, or the investigative paradigms used.

PMID- 12422062
TI  - Open-label evaluation of venlafaxine sustained release in outpatients with
      generalized anxiety disorder with comorbid major depression or dysthymia:
      effectiveness, tolerability and predictors of response.
AB  - In a setting of routine clinical practice, 32 outpatients with generalized
      anxiety disorder (GAD) and major depression (MD) (n = 21) or dysthymia (n = 11),
      according to DSM-IV criteria, were consecutively treated with flexible dosages of
      sustained-release venlafaxine (SR-VF) for at least 8 weeks. In a 16-week follow
      up, SR-VF daily dose could be modified on the basis of the therapeutic response
      and of the side effect profile. Symptomatological modifications were explored by
      means of the Clinical Global Impression (CGI) scale, Hamilton Rating Scale for
      Depression (HAM-D), and Hamilton Anxiety Scale (HAM-A). SR-VF was well tolerated
      and only 2 patients interrupted the treatment before 24 weeks; the mean final
      dose +/- SD was 135.5 +/- 71.8 mg (range 75-225); in 26 (81.2%) patients, a
      statistically significant response was observed in depressive symptomatology
      within the first 8 weeks. The mean total score of HAM-D showed a significant
      reduction during the first 8 weeks of treatment, while the mean total score of
      HAM-A did not present a significant reduction until week 24. In patients with MD,
      a statistically significant response was observed after the first 8 weeks, while
      the reduction of the anxiety scores required more time and, in some cases, did
      not appear at all. Conversely, in patients with GAD and dysthymia, anxious and
      depressive symptomatology improved simultaneously. Stepwise multiple regression
      indicated that the improvement of depression is negatively related to a high
      score of CGI anxiety severity, and the improvement of anxiety is related to the
      presence of dysthymia and, to a lesser extent, to a short duration of the
      illness. Our data confirm the effectiveness and tolerability of SR-VF in mixed
      anxiety-depressive states. The differential response suggests a pathophysiologic
      and clinical distinction between GAD with comorbid MD or dysthymia.

PMID- 12422063
TI  - Effects of irritability on craving before and after cue exposure in abstinent
      alcoholic inpatients: experimental data on subjective response and heart rate.
AB  - OBJECTIVE: Irritability is often linked with problem drinking. The aim of this
      study is to examine the possible influence of irritability on craving induced by
      a cue-exposure paradigm. METHODS: 30 male abstinent alcoholic inpatients of the
      Psychiatric Hospital of Munich University, Germany gave answers to a series of
      personality questionnaires. Results of this study concerning the impact of
      aggressivity on craving for alcohol has recently been published. In this study,
      the subjects were subdivided into a low- and a high-irritable group based on
      their scores on the irritability subscale of the Buss-Durkee Hostility Inventory
      and were exposed to alcohol cues. Craving was measured by means of the Alcohol
      Craving Questionnaire (ACQ) and Visual Analogue Scales (VAS). The heart rate was
      also assessed throughout the whole process. ANCOVA for repeated measurement was
      employed to evaluate the data - irritability disposition as the between-subject
      factor and the experimental manipulation (absence vs. presence of alcohol cues)
      as the within-subject factor. RESULTS: Major findings are: (1). main effects of
      irritability on 'emotionality', 'purposefulness', and 'expectancy' of the ACQ as
      well as on 'craving for alcohol' of the VAS were significant; (2). cue exposure
      also exerted a significant main effect on 'craving for alcohol' of the VAS and on
      the heart rate after the presentation of alcohol cues; (3). on 'compulsivity' of
      the ACQ and 'intention to alcohol intake' of the VAS; there was a significant
      interaction between irritability and cue exposure. The high-irritable alcoholics,
      compared with their statements in the baseline, tended to report a higher control
      over alcohol intake and a lower intention to alcohol use after cue exposure.
      However, after confrontation with alcohol stimuli, their low-irritable
      counterparts reported a much lower control and a slightly higher intention than
      they did in the baseline. CONCLUSIONS: The results of this study indicate that
      induced craving in hospitalized alcohol addicts probably varies with the
      magnitude of their irritability; it might make patients more aware of their
      vulnerability to alcohol, help them develop more differential coping strategies
      and improve medical therapy against alcohol craving.

PMID- 12422064
TI  - Effects of opipramol as an evening anaesthesiologic premedication.
AB  - To date, opipramol has not been examined within the context of evening
      premedication in anaesthesiology. A suitable drug for such an application should
      induce anxiolytic and sleep-favouring effects. Due to its pharmacological
      properties, one would expect opipramol to lead to these effects. In order to test
      this possibility, 72 female patients were randomly assigned to 50 mg opipramol,
      100 mg opipramol, or placebo (n = 24 patients per group) in the evening prior to
      surgery in a double-blind trial. Effects were recorded in the morning prior to
      the operation by means of self-rating questionnaires, regarding the patients'
      current subjective state and their judgement of the quality of sleep during the
      night before. The self-rating was done by the Multidimensional Mood Inventory
      BSKE (EWL), by use of the Multidimensional Somatic Symptom List (MSKL), and by
      use of the Wurzburg Sleep Questionnaire. Further dependent variables were heart
      rate and blood pressure. Opipramol significantly improved sleep quality.
      Especially the frequency of awakening at night was reduced. These effects could
      be observed predominantly after 100 mg opipramol. At this dosage, inner
      excitement was reduced as well. The autonomic variables remained uninfluenced.
      There were no adverse events and no hints for interactions with anaesthesiology.

PMID- 12422065
TI  - Fibrinogen and the amount of leukoaraiosis in patients with symptomatic small
      vessel disease.
AB  - We investigated whether there is a direct correlation between plasma fibrinogen
      levels and the amount of leukoaraiosis (LA) in patients with symptomatic small
      vessel disease. The study included 28 patients: 12 with a first-ever lacunar
      infarction (LI) and 16 with Binswanger's disease (BD). The mean age was 71 years
      (SD 8.6), and 21 were men. For each patient, we recorded demographic data,
      vascular risk factors and the results of blood chemistry analysis including
      fibrinogen (g/l), hematocrit (decimal fraction) and total serum proteins (g/l). A
      cerebral MR scan was performed in each patient and an LA score was obtained by an
      investigator blind to clinical data, using a semiquantified scale in six areas of
      each cerebral hemisphere (0-4 points in each area, total scoring range 0-48
      points). RESULTS: The mean (SD) for the LA score was 18.9 (10.7) and for plasma
      fibrinogen 3.97 (1.1). Pearson's and Spearman's correlation coefficients between
      fibrinogen and LA score were 0.43 (p = 0.02) and 0.49 (p = 0.007), respectively.
      Multiple-regression analysis between groups (LI or BD) and fibrinogen versus LA
      score showed the strongest association for the BD group (p = 0.014) and a direct
      relation with fibrinogen (p = 0.018). No statistically significant association
      was found between LA score and age, sex, any vascular risk factor, hematocrit or
      total serum protein. CONCLUSION: There is a significant correlation between
      plasma fibrinogen levels and the amount of LA in patients with symptomatic
      cerebral small-vessel disease. This result suggests that fibrinogen may be
      involved in the pathophysiology of LA in these patients.

PMID- 12422066
TI  - Transient topographical disorientation.
AB  - Transient topographical disorientation (TTD) is a short-lasting inability to find
      one's way in a familiar environment, while the patient remains conscious and is
      able to recall what happened. We report the study of 10 patients with episodes of
      TTD, studied on the days following the last episode. The episodes of TTD could be
      separated into two types: the patients either reported difficulties in spatial
      orientation with preserved abilities to recognize landmarks and objects, or the
      difficulties appeared with the recognition of landmarks. Tests exploring spatial
      orientation, as well as higher visuoperceptive capacities were altered in most of
      the patients and brain SPECT showed hypoperfusion of the right hemisphere in all
      patients, which could also be demonstrated 2 years later in some cases.
      Altogether, our findings suggest that TTD is frequently associated with a more
      persistent right hemisphere dysfunction of unknown cause. This chronic alteration
      could represent either a sequel of the acute episode or a preexisting right
      hemisphere deficit, which inclined the acute insult to be manifested as TTD.

PMID- 12422067
TI  - Therapeutic drug monitoring of lamotrigine in patients suffering from resistant
      partial seizures.
AB  - Sixty patients, all potential candidates for ongoing lamotrigine (LTG) treatment
      as add-on therapy for resistant partial seizures and receiving carbamazepine
      (CBZ) and/or valproate (VPA) treatment, were submitted to therapeutic drug
      monitoring (TDM). The aim was to evaluate the possible relation between serum
      levels and the clinical effect of LTG, to verify whether CNS toxicity has to be
      considered the result of a pharmacokinetic or a pharmacodynamic interaction with
      CBZ, and to investigate whether possible changes in the clinical response during
      long-term treatment are dependent on LTG serum level variations. Sixteen patients
      achieved complete control, 26 a >or=50% reduction in seizures, the remainder did
      not respond. Mean LTG serum concentrations were higher in responders than in
      nonresponders, the difference being statistically insignificant. The best results
      were observed in VPA-cotreated patients with the highest LTG blood levels. CNS
      toxicity occurred after giving LTG to subjects who subsequently developed the
      highest LTG concentrations, whereas CNS toxicity seemed unrelated to CBZ and CBZ
      epoxide serum concentrations. No decrease in LTG, CBZ and VPA serum levels was
      observed even in patients showing a reduction in the response during long-term
      treatment.

PMID- 12422068
TI  - The premenstrual period and exacerbations in multiple sclerosis.
AB  - The aim of this study was to assess whether an association exists between the
      premenstrual period and exacerbations of multiple sclerosis (MS). The subjects
      were 56 premenopausal patients with relapsing MS and a regular menstrual cycle.
      Data over the previous 2 years were gathered from a structured MS database and a
      comprehensive questionnaire. 42% had exacerbations starting in the premenstrual
      phase. Within this group the proportion of premenstrual exacerbations was
      significantly higher than in the remaining period of the menstrual cycle, and in
      45% all exacerbations had started during the premenstrual phase. There was no
      relationship with the premenstrual syndrome, and there was no protective effect
      of oral contraceptives. Our results suggest that the premenstrual period triggers
      exacerbations in a subgroup of females with MS.

PMID- 12422069
TI  - Association study for Parkinson's disease and a dopamine transporter gene
      polymorphism (1215A/G).
AB  - The dopamine transporter (DAT) may play a role in the pathogenesis of Parkinson's
      disease (PD) because dopamine-specific neurotoxins are taken into dopaminergic
      nerve terminals via the DAT. A recent study has demonstrated that a DAT
      polymorphism in exon 9 (1215A/G) is associated with susceptibility to PD. This
      finding was not replicated by another study, however. Therefore, the significance
      of this association was tested using a Chinese sample population consisting of
      102 PD patients and 174 controls, together with the association for onset age.
      Comparing the two groups, neither the genotypic (p = 0.272) nor allelic
      frequencies (p = 0.209) were statistically different. Further, the mean onset age
      was not significantly different for PD patients comparing the DAT genotypes (p =
      0.925). Our findings confirm those of the previous negative report and, taken
      together, suggest that the DAT polymorphism (1215A/G) does not play a major role
      in the susceptibility to PD. Other DAT genetic variants, and the association of
      these variants with PD symptomatology or treatment response, may merit further
      investigation.

PMID- 12422070
TI  - Peripheral neuropathy of Machado-Joseph disease in Taiwan: a morphometric and
      genetic study.
AB  - Machado-Joseph disease (MJD) is a dominantly inherited cerebellar ataxia
      associated with spasticity, ophthalmoplegia, dystonia and peripheral neuropathy.
      Presented here are 5 MJD cases. A morphometric analysis of the histopathology of
      their sural nerves was carried out to know the relationship between axon size and
      myelin thickness. MJD cases were identified by polymerase chain reaction. On the
      basis of the clinical symptoms, there was 1 type I, 2 type II and 2 type III
      patients. The sural nerves were biopsied for single-fiber, ultrastructural and
      morphometric analysis. Morphometric parameters such as fiber and axon sizes,
      myelin thickness and g ratio (axon diameter:fiber diameter) were estimated. The
      pathological features of the sural nerves in the 2 type III and 1 of the type II
      patients revealed a loss of myelinated and unmyelinated fibers, and the
      morphometry studies showed a decreased fiber density, the loss of large
      myelinated fibers, a smaller size of the axons with thinner myelin sheaths and an
      increased percentage of myelinated fibers with a g ratio (axon diameter:fiber
      diameter) above 0.7. However, only subtle pathological changes were noted in the
      type I patient and the remaining type II patient. Our findings suggested that
      there is a loss of large myelinated fibers and distal axonopathy with relative
      hypomyelination in the neuropathy of patients with MJD.

PMID- 12422071
TI  - Increased detection of 14-3-3 protein in cerebrospinal fluid in Sporadic
      Creutzfeldt-Jakob Disease during the disease course.
AB  - Diagnosis of Creutzfeldt-Jakob Disease (CJD) is based on neurological signs
      associated with characteristic electroencephalographic activity or detection of
      14-3-3 protein in cerebrospinal fluid. However, the time course of 14-3-3 protein
      release during sporadic CJD is unknown. We report two observations in which the
      level of the detected 14-3-3 protein increased significantly with time. These
      preliminary cases suggest that there may be an increased release of 14-3-3
      protein during the course of CJD as already proven for iatrogenic CJD.

PMID- 12422072
TI  - Single photon emission computed tomography of an acute focal demyelinating
      disease mimicking a brain tumor.

PMID- 12422073
TI  - Yellow glasses improve contrast sensitivity of a patient with a visual variant of
      Alzheimer's disease.

PMID- 12422074
TI  - Cavernous angioma in the brachium pontis presenting with trigeminal neuralgia: a
      case report.

PMID- 12422075
TI  - Four cases of cerebral venous sinus thrombosis.

PMID- 12422076
TI  - Blepharospasm in bardet-biedl syndrome: a case report.

PMID- 12422077
TI  - Familial focal dystonia.

PMID- 12422078
TI  - Encephalitis caused by human herpesvirus-6 in a liver transplant recipient.

PMID- 12422079
TI  - [The efficacy of combining antibiotic treatment with topical intranasal steroid
      administration in the treatment of chronic otitis media with effusion].
AB  - OBJECTIVES: We evaluated the efficacy of antibiotic treatment with or without
      topical administration of intranasal budesonide in chronic otitis media with
      effusion (OME). PATIENTS AND METHODS: The study included 62 patients (age range 2
      to 12 years) with chronic OME. The patients were randomly assigned to three
      groups, namely, antibiotic treatment (20 patients, ampicillin/sulbactam, 25
      mg/kg/daily), antibiotic treatment combined with intranasal budesonide (20
      patients, 200 mg/daily), and no treatment (22 patients). All patients and
      families were questioned regarding the presence of allergy, frequent upper
      respiratory tract infections, passive smoking, low birth weight, and pre-school
      nursery attendance. Otoscopic examination findings and the results of
      tympanograms obtained at the time of diagnosis, and at the end of four and eight
      weeks of treatment were evaluated. RESULTS: At the end of eight weeks,
      significant improvement in tympanograms and otoscopic findings was obtained in
      both groups when compared with the control group (p<0.05). Resolution rates were
      24% (9/37 ears), 39% (14/36), and 5% (2/40) with antibiotic, budesonide, and no
      treatment groups, respectively. Although budesonide treatment was associated with
      a higher rate of resolution of effusion compared to that of antibiotic alone,
      this did not reach significance (p>0.05). CONCLUSION: Further studies with larger
      patient series are required to better evaluate the efficacy of antibiotic
      treatment and topical intranasal steroid administration in chronic OME.

PMID- 12422080
TI  - [Clinical assessment of patients with chronic otitis media with cholesteatoma].
AB  - OBJECTIVES: We evaluated clinical features and treatment results of patients with
      chronic otitis media (COM) with cholesteatoma. PATIENTS AND METHODS: The study
      included 83 patients (53 males, 30 females; mean age 27.5 years; range 7 to 60
      years) who were treated for COM with cholesteatoma. All patients underwent
      otoscopic examination, audiometric investigation, temporal bone computed
      tomography, and when necessary, cranial tomography. Open or closed mastoidectomy
      was performed depending on the extent of cholesteatoma and perioperative
      appearance of the ear. RESULTS: Open- and closed-technique mastoidectomies were
      performed in 64 and 19 patients, respectively. Ossicular chain defects were
      observed in 90.3% of patients, and 9.7% had no detectable ossicular chain.
      Cranial complications were present in 28%. Of patients who had undergone open
      mastoidectomy, 75% had dry ears, 11% had recurrent ear discharge, and 14%
      required revision mastoidectomy because of recurrence. Of those who had been
      treated by closed-technique, 79% had dry ears, whereas 21% required revision
      mastoidectomy. Recurrent cholesteatoma was detected in 85% of patients during
      revision mastoidectomy. CONCLUSION: We prefer open-technique mastoidectomy in
      chronic otitis media patients with extensive cholesteatoma, bone destruction, and
      hearing impairment. This choice mainly relies on the socioeconomic status of
      patients and difficulty in having patient compliance with follow-up controls.

PMID- 12422081
TI  - [Adult onset otitis media with effusion: an etiologic study].
AB  - OBJECTIVES: We investigated the etiologic causes and the value of nasal endoscopy
      in adult onset otitis media with effusion (OME). PATIENTS AND METHODS: The study
      included 50 patients with adult-onset OME (28 males, 22 females; mean age 46
      years; range 18 to 41 years). Pneumatic otoscopy, otomicroscopy, pure-tone
      audiometry and tympanometry were performed in all patients. The nasal cavity and
      the nasopharynx were examined by nasal endoscopy. Skin prick tests were performed
      and serum specific IgE levels were determined in all patients. Computed
      tomography scans of the nasal cavity, paranasal sinuses, nasopharynx, and the
      skull base were obtained when indicated. RESULTS: Adult-onset OME was bilateral
      in 24 patients. Allergy was detected in three patients. Four patients had marked
      septal deviation. Mucopurulent discharge in the middle meatus was observed in 20
      patients and polypoid tissue in the lateral nasal wall in two patients. Mucoid
      and purulent discharge and edema were observed at the orifice of the eustachian
      tube in 13 patients and 10 patients, respectively. Biopsies obtained from
      nasopharyngeal masses revealed squamous cell carcinoma in one patient and
      lymphoid hyperplasia in four patients. CONCLUSION: We concluded that nasal
      endoscopy was a reliable method in the investigation of etiologic factors in
      adult-onset OME.

PMID- 12422082
TI  - [Comparison of hearing levels and tympanic membrane healing obtained by cartilage
      palisade and temporal fascia tympanoplasty techniques: preliminary results].
AB  - OBJECTIVES: We compared the levels of hearing and tympanic membrane healing
      obtained by cartilage palisade and temporal fascia tympanoplasty techniques.
      PATIENTS AND METHODS: Tympanoplasty procedures with the use of cartilage palisade
      (30 patients; 14 males, 16 females; mean age 28 years; range 10-62 years) and
      temporal fascia (30 patients; 17 males, 13 females; mean age 30 years; range 12
      58 years) were compared with respect to tympanic membrane healing and hearing
      levels. The size of perforations in the cartilage tympanoplasty group was greater
      than that of the temporal fascia group. Audiological assessments were performed
      in the postoperative third and sixth months. The follow-up period was at least
      six months. Tympanic membrane healing and hearing levels were statistically
      analyzed using the chi-square and Mann-Whitney U-tests. RESULTS: Tympanic
      membrane healing rates were 80% (24 patients) and 86% (26 patients) in the
      temporal fascia and cartilage tympanoplasties, respectively. Postoperatively,
      hearing levels improved in both groups. However, no significant differences were
      found between the two treatment groups with respect to tympanic membrane healing
      and hearing levels. CONCLUSION: Our findings suggest that cartilage palisade
      graft can be safely used in the treatment of tympanic membrane perforations, with
      no adverse effects on the hearing levels in the postoperative six months.

PMID- 12422083
TI  - [The relationship between ostial patency and medical treatment in acute maxillary
      sinusitis: an experimental study].
AB  - OBJECTIVES: We investigated the relationship between ostial patency and medical
      treatment in an experimental model of acute maxillary sinusitis. DESIGN AND
      METHODS: Forty healthy New Zealand white rabbits were assigned to two groups. The
      left maxillary sinus ostia were filled with absorbable gelatin sponge in one
      group (n=20). In the other group, half of the ostuim was blocked by bone
      particles and tissue adhesive (Histoacryl). Following induction of acute
      maxillary sinusitis, each group was divided into four subgroups, one of which was
      left untreated. The other subgroups received systemic antibiotic therapy plus
      topical administration of physiological saline solution, a decongestant, and a
      steroid, respectively, for 10 days. All rabbits were monitored for four weeks.
      Each week nasal smear samples were obtained for neutrophil and leucocyte counts.
      In the end, maxillary sinus biopsies were obtained to determine the extent of
      healing. RESULTS: There were no significant differences between subgroups having
      the same ostium patency. However, compared to the subgroups with patent ostia,
      corresponding subgroups with semi-patent ostia exhibited significantly increased
      nasal smear and nasal biopsy scores starting from the second week. CONCLUSION:
      The degree of ostial patency seems to have a significant role in the treatment of
      acute maxillary sinusitis.

PMID- 12422084
TI  - [Reconstruction of nasal cutaneous defects with the use of supratrochlear artery
      based paramedian forehead flap].
AB  - OBJECTIVES: We evaluated oncologic and functional results of paramedian forehead
      flap in the reconstruction of nasal cutaneous defects. PATIENTS AND METHODS:
      Supratrochlear artery-based paramedian forehead flap was employed in 14 patients
      (13 men, 1 woman; mean age 57 years; range 46 to 63 years) for the reconstruction
      of nasal cutaneous defects resulting from excision of squamous or basal cell
      carcinoma. No other treatment modalities were performed other than removal of the
      primary lesion. The mean follow-up was 42.4 months (range 8 to 83 months).
      RESULTS: None of the patients developed flap necrosis, local recurrences, or
      distant metastasis. Airway problems of varying extent were observed in 10
      patients (71.4%), the severity of which became attenuated in time as the flap
      gained proper contraction. CONCLUSION: Acceptable functional and successful
      oncologic results can be obtained in the reconstruction with the use of
      paramedian forehead flap.

PMID- 12422085
TI  - [Laser posterior cordectomy in bilateral vocal cord paralysis].
AB  - OBJECTIVES: We evaluated the functional results of laser posterior cordectomy
      with respect to respiration, phonation, and deglutition. PATIENTS AND METHODS:
      Unilateral laser posterior cordectomy was performed in nine patients (7 women, 2
      men; mean age 56 years; range 46 to 61 years) with bilateral vocal cord
      paralysis. Postoperatively, respiration, deglutition, and phonation were
      evaluated with the use of an exercise tolerance scale, the Pearson scale, and
      wavelet analysis, respectively. The mean follow-up period was 14.2 months.
      RESULTS: Respiration was satisfactory in eight patients. Of these, four patients
      had excellent, and four patients had good exercise tolerance. The procedure
      resulted in success without tracheotomy in four patients. No deglutition or
      aspiration problems developed. Of eight patients with satisfactory respiration,
      voice quality remained unchanged in six patients, whereas an improved voice
      quality was noted in two patients who received postoperative phoniatric
      rehabilitation. CONCLUSION: Laser posterior cordectomy for the treatment of
      bilateral vocal cord paralysis resolves respiration problems, it restores
      phonation and deglutition functions, as well.

PMID- 12422086
TI  - Tracheal reconstruction with free composite cartilage graft: a case report.
AB  - Tracheal resection followed by an end-to-end anastomosis has been the method of
      choice for the treatment of tracheal neoplasms. We hereby report a 40-year-old
      female patient in whom we performed reconstruction with composite nasal septal
      cartilage graft following one-staged tracheal resection. Histopathologic
      diagnosis was well-differentiated adenoid cystic carcinoma. Fiberoptic and biopsy
      examinations made within the first postoperative month showed no residual or
      recurrent tumor at the resection site. The patient received radiotherapy
      postoperatively. She has been free of disease for 18 months. To our knowledge,
      the use of composite nasal septal cartilage graft in the reconstruction of
      tracheal tumors has not been previously reported.

PMID- 12422087
TI  - Giant hemangiopericytoma of the neck: a case report.
AB  - Hemangiopericytomas are rare vascular tumors and one-thirds occurs in the head
      and neck. These tumors grow slowly and may easily be mistaken for a benign
      lesion. A twenty-nine-year-old man presented with a large mass on the left side
      of his neck. Palpation, ultrasonography, and magnetic resonance imaging findings
      were incorporated into a histopathologic diagnosis of malignant
      hemangiopericytoma. The tumor was subtotally excised following preoperative
      embolization of the branches of the subclavian artery and the left vertebral
      artery. The patient was submitted to radiotherapy. He has been under close follow
      up for 16 months without any recurrences.

PMID- 12422088
TI  - [Current trends and future prospects in biological markers in squamous cell
      carcinoma of the head and neck].

PMID- 12422089
TI  - Secondary procedures after endovascular aortic aneurysm repair.
AB  - PURPOSE: The purpose of this study was to evaluate the incidence, distribution,
      and indications of secondary procedures after endovascular aortic aneurysm repair
      (EAR). METHODS: At a single institution, 179 patients underwent EAR with four
      different endografts (AneuRx, n = 117; Zenith, n = 49; Ancure, n = 12; and
      Talent, n = 1). The vascular section database was queried for patients who needed
      secondary procedures after the original EAR. The mean time from EAR to the
      termination of the study was 27.0 +/- 16.7 months. Type I or III endoleaks were
      treated aggressively. Type II endoleaks were treated only in the presence of
      aneurysm expansion. RESULTS: Thirty-five (35/179; 19.6%) secondary procedures
      were performed in 32 patients. Indications for secondary procedures included 14
      limb occlusions or stenoses (40.0%), 13 endoleaks (37.1%), six endograft
      migrations (17.1%), one delayed aneurysm rupture (2.8%), and one device
      malfunction (2.8%). Seven of the 10 early (<90 days) limb failures (70%) occurred
      within the first 60 patients. At that time, a protocol with aggressive external
      iliac artery evaluation was adopted. In the next 125 patients, the rate of early
      limb occlusion or stenosis was 2.4% (P =.025, with Fisher exact test).
      Distribution of secondary procedures included 23 endoluminal interventions
      (65.7%; angioplasty +/- stent placement, thrombolysis, endocuff placement,
      embolization), eight traditional peripheral procedures (22.9%; femoral-femoral
      bypass, thrombectomy), two laparoscopic interventions (5.7%; inferior mesenteric
      artery ligation), and two laparotomies (5.7%; delayed conversions). Interventions
      for limb occlusion or stenosis occurred earliest (3.5 +/- 5.4 months; P <.05,
      with analysis of variance), followed by treatment of endoleaks (14.3 +/- 12.9
      months) and migration (27.5 +/- 10.4 months). The one delayed rupture occurred at
      15.3 months. CONCLUSION: Secondary procedures after EAR are common.
      Reinterventions can be grouped temporally on the basis of indication. Treatment
      for limb ischemia is predominately early (>/=3 months), whereas treatment for
      endoleaks occurs at approximately 1 year and interventions for migration
      predominate after 2 years.

PMID- 12422090
TI  - Temporin A as a prophylactic agent against methicillin sodium-susceptible and
      methicillin sodium-resistant Staphylococcus epidermidis vascular graft infection.
AB  - OBJECTIVE: The purpose of this study was to investigate the efficacy of temporin
      A as a prophylactic agent in a rat model of vascular graft infection from
      methicillin sodium-susceptible and methicillin sodium-resistant Staphylococcus
      epidermidis. METHODS: The prospective, randomized, controlled animal study set in
      a research laboratory in a university hospital used 280 adult male Wistar rats
      (weight range, 280 to 350 g). Graft infections were established in the back
      subcutaneous tissue of rats with implantation of 1-cm(2) sterile Dacron grafts
      followed by topical inoculation with 2 x 10(7) colony-forming units of S
      epidermidis. The study for each staphylococcal strain included: one control group
      (no graft contamination), one contaminated group that did not receive any
      antibiotic prophylaxis, one contaminated group that received temporin A-soaked
      graft, two contaminated groups that received perioperative intraperitoneal
      cefazolin (30 mg/kg) or vancomycin hydrochloride prophylaxis (10 mg/kg), and two
      contaminated groups that received temporin A-soaked graft and perioperative
      intraperitoneal cefazolin (30 mg/kg) or vancomycin hydrochloride (10 mg/kg)
      prophylaxis. All grafts were explanted at 7 days after implantation. The main
      outcome measure was quantification of bacterial contamination. RESULTS: Overall,
      the perioperative prophylaxis based on soaked grafts was not significantly
      different to that of parenteral vancomycin hydrochloride. Only the combination
      between temporin A and vancomycin hydrochloride produced a complete bacterial
      inhibition for both strains. CONCLUSION: Temporin A showed a similar
      antibacterial in vitro activity against the two different strains. The in vivo
      results suggest its potential use in providing prophylaxis to direct graft
      contamination when used in combination with parenteral vancomycin hydrochloride.

PMID- 12422092
TI  - Does thigh compression improve venous hemodynamics in chronic venous
      insufficiency?
AB  - OBJECTIVE: The aim of this study was to investigate the hemodynamic effects of
      thigh compression in patients with deep venous incompetence. PATIENTS AND
      METHODS: This diagnostic test study was set in a municipal general hospital.
      Twelve patients with venous leg ulcers (CEAP classification, C6 Es Ad Pr; four
      men and eight women), with a mean age of 56.5 +/- 16.8 years, with popliteal
      venous reflux of more than 1 second detected with duplex scan, underwent
      investigation with the following methods: 1, the pressure exerted under thigh
      length compression stockings class II and short-stretch adhesive compression
      bandages was measured with an MST tester (Salzmann, Switzerland) and a CCS 1000
      device (Juzo, Germany), respectively; 2, the great saphenous vein and the femoral
      vein on the thigh were compressed with a pneumatic cuff (0, 20, 40, and 60 mm Hg)
      containing a window through which the diameters of these veins could be measured
      with duplex ultrasonography; and 3, with the same thigh-cuff occlusion procedure,
      the venous filling index (VFI) for each experiment was measured with air
      plethysmography. These values reflected the presence and extent of venous reflux
      in each experiment depending on the degree of venous narrowing. RESULTS: The mean
      pressure of a class II compression stocking was about 15 mm Hg at the thigh
      level, and adhesive bandages achieved a pressure of more than 40 mm Hg in the
      same location. A statistically significant reduction of the diameters of the
      great saphenous vein and the femoral vein could be obtained only when the cuff
      pressure on the thigh was equal to or higher than 40 mm Hg (P <.001). A reduction
      of the venous reflux (VFI) was achieved only with a thigh pressure of 60 mm Hg (P
      <.001). No significant reduction was seen of VFI with a thigh pressure in the
      range of the class II stockings. Previous investigations have shown that, in
      patients with deep venous incompetence, a pressure cuff on the thigh with 60 to
      80 mm Hg is able to reduce ambulatory venous hypertension. CONCLUSION: Thigh
      compression as exerted with class II thigh-length compression stockings is not
      able to significantly reduce venous diameter or venous reflux. However, with a
      pressure of 40 to 60 mm Hg on the thigh that can be achieved with strongly
      applied short-stretch bandages, considerable hemodynamic improvement, including
      reduced venous reflux, can be obtained in patients with severe stages of chronic
      venous insufficiency from deep vein incompetence. The practical value of these
      preliminary findings should be investigated with further clinical trials.

PMID- 12422091
TI  - Postthrombotic syndrome after isolated calf deep venous thrombosis: the role of
      popliteal reflux.
AB  - OBJECTIVE: The purpose of this study was to evaluate the long-term clinical and
      hemodynamic outcomes after isolated first-time calf deep venous thrombosis
      (cDVT). METHODS: This retrospective clinical study was set in an academic
      referral center. From 1990 to 1994, 617 patients were seen with acute DVT. This
      number included 82 patients with phlebographically confirmed cDVT. Of those
      patients, 50 attended the clinical assessment 6 to 10 years (mean, 8.4 years)
      after the acute event. All patients with cDVT underwent treatment with
      anticoagulant therapy (96% heparin and warfarin, 4% only warfarin). The duration
      of the heparin treatment was 4.0 to 8.0 days (mean, 6.4 days), and warfarin was
      given for 2.0 to 7.5 months (mean, 3.4 months). Compression stockings were used
      regularly (mean, 9.2 months; range, 0.25 to 64 months) in 30% of the patients
      after acute cDVT. The initial ipsilateral phlebograms were reevaluated to confirm
      the diagnosis of cDVT without popliteal involvement. The clinical assessment
      included evaluation of both legs according to CEAP clinical classification C0-6.
      Bilateral color-flow duplex scan imaging was performed to assess reflux in deep
      popliteal segments. Photoplethysmographic measurement of venous refilling time
      was conducted in both legs to observe deep reflux. RESULTS: The mean age was 57
      years (range, 30 to 76 years) at the time of the clinical assessment. Cause of
      acute cDVT was idiopathy in 52%, coagulopathy in 2%, trauma in 10%,
      immobilization in 22%, and postoperative in 14% of the cases. During the follow
      up period, seven recurrent DVTs (14%) were seen. In the clinical assessment, 17
      legs (34%) with previous cDVT had skin changes (CEAP C4-6). No active ulcers were
      found. Contralaterally, the frequency of C4-6 was 10% (n = 5; P <.05). After
      exclusion of recurrent DVTs, the distribution of the clinical classification
      still remained the same. Deep popliteal reflux was detected in 20 legs (40%) with
      previous cDVT. Contralaterally, popliteal reflux was seen in nine cases (18%; P
      <.05). Plethysmography showed deep reflux in 16 legs (33%) with cDVT and in nine
      cases (18%) contralaterally (P >.05). A significant association was found between
      deep popliteal reflux and skin changes (P <.05). CONCLUSION: In the long-term
      follow-up, cDVT may lead to significant postthrombotic disease. Reflux in the
      primarily uninvolved popliteal vein is frequent and may be associated with more
      severe disease.

PMID- 12422094
TI  - Presidential address: There really is a pony in there.

PMID- 12422093
TI  - A metaanalysis comparing surgical thrombectomy, mechanical thrombectomy, and
      pharmacomechanical thrombolysis for thrombosed dialysis grafts.
AB  - BACKGROUND: The achievement and maintenance of access sites for hemodialysis is a
      persistent challenge for both the vascular surgeon and the clinical nephrologist.
      The advent of improved interventional, endovascular, and pharmacomechanical
      techniques for the treatment of thrombosis has raised questions as to whether
      surgical thrombectomy is the most effective treatment. OBJECTIVE: The purpose of
      this study was to determine the role of surgical thrombectomy as the standard of
      care for the patient with end-stage renal disease and a thrombosed/stenosed
      arteriovenous graft (AVG). DESIGN AND METHODS: The study was designed as a
      metaanalysis. All publications that directly or indirectly described randomized
      controlled trials for the treatment of thrombosed dialysis grafts in patients
      with end-stage renal disease and AVG were searched. Relative risk (RR) and risk
      difference were used as the measure of effect for each dichotomous outcome. All
      of the studies that met the inclusion criteria were limited to prosthetic AVGs.
      RESULTS: The overall results suggested a clear superiority of surgery over
      endovascular procedures at 30 days, 60 days, 90 days, and 1 year. The RRs (95%
      CI) at these time points were 1.32 (1.07, 1.60), 1.34 (1.13, 1.58), 1.22 (1.05,
      1.40), and 1.22 (1.07, 140), respectively, and favored surgery in all cases (30
      days, P =.010; 60 days, P =.0007; 90 days, P =.007; and 1 year P =.003). The
      number needed to treat to prevent one endovascular occlusion after thrombectomy
      was 8 at 30 days, 6 at 60 days, 8 at 90 days, and 7 at 1 year. The rates of
      technical failure were significantly greater in the endovascular group compared
      with the surgical group (RR, 1.90; 95% CI, 1.32, 2.73; P =.0005), which generated
      an absolute risk reduction of 16% (P =.0002). No significant difference was seen
      in the complication rates between the two groups. CONCLUSION: The analysis of all
      currently available randomized controlled trials clearly supports the use of
      surgical thrombectomy for the treatment of thrombosed prosthetic vascular access
      grafts. The use of endovascular techniques has been found to be inferior to
      surgery in terms of both primary patency and technical failure rates.

PMID- 12422095
TI  - D-dimer and calf circumference in the evaluation of outpatient deep venous
      thrombosis.
AB  - OBJECTIVE: Duplex ultrasonography (DU) is the primary method for diagnosis of
      deep venous thrombosis (DVT) but is relatively expensive and not always readily
      available. Attempts to exclude the diagnosis of DVT with D-dimer or clinical
      criteria independently have been unsuccessful. The goal of our study was to
      evaluate a second-generation rapid quantitative D-dimer and simple clinical
      parameters for screening of outpatients for DVT. PATIENTS AND METHODS: Patients
      undergoing DU of the lower extremities for suspected DVT were prospectively
      evaluated. Patients undergoing lower extremity venous ultrasound scan for
      suspected pulmonary embolism or already on anticoagulant therapy were excluded
      from the study. Data were analyzed to assess the optimal combination of
      characteristics to include and exclude proximal DVT. RESULTS: One hundred fifty
      six outpatients met inclusion criteria and were enrolled in the study. Elevated
      levels of D-dimer of 0.5 ng/mL or more were noted in 21 of 22 patients diagnosed
      with DVT, yielding a sensitivity of 95% and negative predictive value of 99%.
      Subjective symptoms of swelling or pain were present in 94% of all outpatients.
      Asymmetric calf swelling of more than 2.0 cm was noted in 14 of 22 patients (64%)
      with proximal DVT compared with 22 of 134 patients (16%) without DVT (P <.003).
      No single clinical history variable was significant on multivariate analysis. All
      outpatients with proximal DVT had either leg swelling of more than 2 cm or a
      positive D-dimer. CONCLUSION: A combination of a second-generation quantitative D
      dimer and calf measurement provides an easy and effective means of excluding
      proximal DVT when screening outpatients. Patients with calf circumference 2.0 cm
      or less and a negative D-dimer may undergo nonemergent DU. Patients with a
      positive D-dimer or asymmetrical calf swelling of more than 2.0 cm alone or in
      combination should undergo emergent DU.

PMID- 12422096
TI  - The pelvic venous syndromes: analysis of our experience with 57 patients.
AB  - BACKGROUND: The pelvic venous syndromes comprise a group of poorly understood
      disorders of the pelvic and gonadal venous circulation. The objective of this
      paper was to review our experience with the pelvic venous syndromes and, in the
      light of the current literature, make management recommendations. MATERIALS AND
      METHODS: Fifty-seven female patients (age range, 24 to 48 years; mean, 34 years)
      with symptoms of pelvic pain, dysuria, dysmenorrhea, dyspareunia, and the
      presence of vulval and pelvic varices were studied. Diagnosis included physical
      examination, Doppler scan, duplex ultrasound scan, computed tomography, magnetic
      resonance imaging, and retrograde cinevideoangiography. The symptoms were
      classified as: 1, mild (n = 15); 2, moderately severe (n = 19); and 3, severe (n
      = 23). Group 1 was treated with sclerotherapy/local excision of vulval varices.
      Group 2 had gonadal vein resection (GVR; n = 12) and sclerotherapy or gonadal
      vein coil embolization (GVE; n = 7) and sclerotherapy. Only the incompetent side
      was treated. Patients in group 3 with isolated hypogastric vein tributary reflux
      were treated either with hypogastric vein tributaries division (HVTD) or with
      embolization (HVTE) as the only procedure. Those with combined gonadal and
      hypogastric vein reflux were treated with HVTE followed by GVR. The follow-up
      period ranged from 2.5 to 24 years (mean GVR/HVTD, 12.4 years; mean GVE/HVTE, 2.3
      years). Pain improvement was assessed with a visual analog scale and through
      mailed questionnaires (response rate, 100%). Patient results were classified as
      excellent (asymptomatic), moderate (mild discomfort), or no improvement. RESULTS:
      In group 1, 12 patients had excellent results and three had moderate results. In
      group 2, 10 patients treated with GVR had excellent results, one had moderate
      results, and one had no improvement. Three patients treated with GVE were
      asymptomatic, and four had no improvement. In group 3, three patients treated
      with HVTD were asymptomatic and two had no improvement. Five patients treated
      with HVTE were asymptomatic, and one had no improvement. Of the 12 patients
      treated with HVTE and GVR, 10 were asymptomatic, one had moderate results, and
      one had no improvement. CONCLUSION: Local excision of vulval varices and
      sclerotherapy were sufficient in patients with mild symptoms. Gonadal vein
      excision produced better results than GVE. In patients with isolated hypogastric
      vein reflux, embolization was a better option than surgical treatment. GVR
      preceded by embolization of the incompetent tributaries of the internal iliac
      vein was indicated in patients with combined reflux and severe symptoms.
      Supplemental sclerotherapy of vulval varices is recommended after control of the
      intrapelvic reflux.

PMID- 12422097
TI  - Performance characteristics of the venous clinical severity score.
AB  - OBJECTIVE: To facilitate study of the natural history and management of venous
      disease, a 10-component venous clinical severity (VCS) score has been proposed as
      an objective measure of disease severity. The purpose of this study was to
      evaluate the validity and reliability of this instrument. METHODS: VCS component
      scores (0 to 3) for pain, varicose veins, edema, pigmentation, inflammation,
      induration, stocking use, and ulcer size, duration, and number were measured in
      consecutive patients with chronic venous disease. Differences between observers
      (n = 3) and on serial evaluation by the same observer were determined. RESULTS:
      One hundred twenty-eight limbs in 64 patients were evaluated. Mean VCS score
      increased from CEAP class 0 (1.7 +/- 1.8) to class 6 (14.7 +/- 3.0; R =.84; P
      <.0001). Scores in 68 limbs evaluated twice by the same observer differed by a
      mean of only 0.8 (P =.15), with a reliability coefficient of 0.6. Mean scores of
      8.0 (+/- 5.1), 7.2 (+/- 5.1), and 8.0 (+/- 5.4) were obtained in 63 limbs
      evaluated by all three investigators (P =.02). Only the component scores for
      pain, inflammation, and pigmentation showed significant (P <.05) interobserver
      variability. Interobserver agreement on the absence of disease or presence of
      severe disease as defined by scores of 3 or less or 8 or more was good (kappa =
      0.59 and 0.65, respectively). CONCLUSION: The VCS score is a critically needed
      tool for evaluating changes in venous disease over time. The score is reliable
      and shows good correlation with CEAP clinical classification.

PMID- 12422098
TI  - Patient, operative, and surgeon factors that influence the effect of superficial
      venous surgery on disease-specific quality of life.
AB  - BACKGROUND AND OBJECTIVE: Superficial venous surgery for CEAP 2 disease leads to
      an improvement in disease-specific quality of life (QoL) in the short term.
      However, which factors influence the magnitude of this improvement, how surgery
      affects QoL in patients with CEAP 4 to 6 disease, and whether this improvement is
      durable are not known. The objective of this study was to identify patient,
      operative, and surgeon factors that might influence the change in disease
      specific QoL in the 2 years after superficial venous surgery. METHODS: This
      prospective study was comprised of 203 unselected, consecutive patients with CEAP
      2 to 6 disease who underwent saphenous with or without subfascial endoscopic
      perforator surgery and who completed the Aberdeen Varicose Vein Symptoms Severity
      Score (AVVSSS) before surgery and at 4 weeks, 6 months, and 2 years after
      surgery. Univariate and multivariate analyses were performed. RESULTS: At
      baseline, recurrent and ulcer (CEAP 5 and 6) diseases were associated with a
      higher (worse) AVVSSS. Surgery was associated with a significant improvement in
      median (interquartile range [IQR]) AVVSSS: baseline, 17.8 (11.8 to 27.2); 4
      weeks, 13.8 (7.9 to 21.3); 6 months, 9.6 (4.2 to 15.8); and 2 years, 8.1 (4.0 to
      14.7). One hundred seventy-five patients (86%) at 6 months and 177 patients (87%)
      at 2 years reported an improvement in AVVSSS. Postoperative AVVSSS at both 6
      months and 2 years was most significantly influenced by preoperative score (P
      <.0001). After adjustment for baseline AVVSSS, the following factors were
      identified in multivariate analysis as having a significant and independent
      positive (+) or negative (-) impact on AVVSSS: at 6 months, (-) recurrent disease
      (P =.009), (-) CEAP 4 disease (P =.026); and at 2 years, (+) long saphenous
      surgery (P =.02), (-) CEAP 5 disease (P =.030). CONCLUSION: In this unselected
      series, saphenous surgery with or without subfascial endoscopic perforator
      surgery led to an improvement in disease-specific QoL in 87% of patients out to 2
      years. Although univariate analysis results suggested that many baseline factors
      might be associated with outcome, multivariate analysis results suggested that
      only surgery for recurrent disease and for CEAP 4/5 disease remained as
      significant negative, and only long saphenous surgery as significant positive,
      independent prognostic factors. These data provide evidence of the medium-term
      clinical effectiveness of venous surgery across the full spectrum of CEAP
      clinical grades, show the importance of multivariate analysis, and reemphasize
      the importance of minimization of recurrence.

PMID- 12422099
TI  - Recanalization of totally occluded iliac and adjacent venous segments.
AB  - PURPOSE: The purpose of this study was to report our experience with percutaneous
      recanalization of totally occluded iliac veins and inferior vena cava. MATERIAL
      AND METHODS: Recanalization of the iliac vein was performed in 38 limbs. In nine
      limbs, recanalization of the inferior vena cava was also necessary (two with
      filter). In 28 of 38 limbs, the stent was extended below the groin crease into
      the common femoral vein segment. Large-caliber (14 or 16 mm for iliac vein)
      flexible self-expanding stents were used. Stents were routinely extended for a
      short distance into the inferior vena cava to forestall development of iliocaval
      stenosis. Intravascular ultrasound scan was a valuable tool in the procedure. The
      median length of the recanalized segment was long (22 cm), and multiple stents
      (median, n = 3) were necessary in most patients. Forty-five percent of the
      patients had coagulation abnormalities. RESULTS: No morbidity or mortality was
      seen. Actuarial primary, primary assisted, and secondary patency rates of the
      stents at 24 months were 49%, 62%, and 76%, respectively. Median pain level
      decreased significantly (level 4 to level 0; P <.0001) after stent placement, and
      more than two thirds of the patients became totally pain free after the
      procedure. Swelling also improved significantly, and a third of the patients
      became totally free of any swelling after stent placement. Sixty-six percent of
      cases with stasis ulcers/dermatitis (n = 14) were resolved (actuarial, 1 year),
      although uncorrected reflux persisted in many of these limbs. CONCLUSION:
      Percutaneous recanalization of the occluded iliac vein with stent placement
      appears to be successful in the short term, with good patency, significant
      symptom resolution, and minimal morbidity.

PMID- 12422100
TI  - Endovascular treatment of abdominal aortic aneurysm is associated with a low
      incidence of deep venous thrombosis.
AB  - OBJECTIVE: This study was performed to define the incidence of acute deep venous
      thrombosis (DVT) after endovascular treatment of abdominal aortic aneurysms
      (AAAs). Because aortic endograft placement requires prolonged femoral vessel
      instrumentation, it may be hypothesized that these patients are at increased risk
      for development of an acute DVT. PATIENTS AND METHODS: Fifty consecutive patients
      (42 men, eight women) ranging in age from 48 to 85 years (mean, 72 years)
      underwent endovascular treatment of an AAA from January 2000 to August 2001.
      Clinical examination and bilateral lower extremity duplex ultrasonography for DVT
      were performed on the first postoperative day and at the 1-month follow-up visit.
      No patient had a prior DVT or identifiable hypercoagulable state. Seven patients
      (14%) had concurrent malignant disease. Preoperative antiplatelet agents were
      administered in 26 patients (52%), and nine (18%) were on warfarin sodium therapy
      before surgery. No new DVT prophylaxis was initiated perioperatively. Epidural
      anesthesia was used in 60% of the patients, with general endotracheal anesthesia
      used in the remainder. Risk factors for DVT were evaluated with univariate
      statistical analysis. RESULTS: Three patients (6%) had an acute postoperative DVT
      develop. Two occurred in the femoral veins, and one occurred in the popliteal
      vein. Of these patients, one had been continued on perioperative anticoagulation
      therapy, and the remaining two were started on low-molecular weight heparin and
      warfarin sodium therapy on recognition of the DVT. One patient had an
      intraoperative injury of the affected common femoral vein, and this individual
      was the only one to have clinical signs of a DVT. The mean follow-up period was 8
      +/- 0.8 months. In this experience, factors that may have placed patients at
      increased risk for an acute DVT were not identified. CONCLUSION: Six percent of
      patients undergoing endovascular repair of AAAs had postoperative DVT develop.
      These patients had a number of risk factors for the development of a DVT;
      however, no specific factor was identified that predisposed to DVT.

PMID- 12422101
TI  - External pneumatic compression does not increase urokinase plasminogen activator
      after abdominal surgery.
AB  - External pneumatic compression (EPC) devices prevent lower extremity deep venous
      thrombosis (DVT) by reducing stasis. There is a widely held belief that they also
      enhance endogenous fibrinolysis; however, recent studies of tissue plasminogen
      activator (the primary activator of fibrinolysis) and plasminogen activator
      inhibitor-1 (the primary inhibitor of fibrinolysis) failed to confirm this. The
      hypothesis of this study was that EPC devices increase the level of urokinase
      plasminogen activator (uPA), a second activator of fibrinolysis. This was a
      prospective trial in which 44 subjects who underwent major abdominal surgery were
      randomized to receive unfractionated heparin injections, thigh-length sequential
      EPC devices, or both for DVT prophylaxis. Prophylaxis was begun immediately
      before surgical incision and continued until postoperative day 5 or discharge.
      Venous blood samples were collected from an antecubital vein for measurement of
      systemic uPA levels and from the common femoral vein for measurement of regional
      uPA levels. Samples were collected the day before surgery, after induction of
      anesthesia but before surgical incision, and on postoperative days 1, 3, and 5.
      uPA levels (ng/mL) were measured with an enzyme-linked immunoassay. Baseline uPA
      levels (0.41 to 0.56 ng/mL; P >.05, analysis of variance with repeated measures)
      were similar among the three groups. uPA levels did not change after surgery in
      systemic or regional blood samples in any group. There were no significant
      differences in systemic or regional uPA levels in the groups treated with EPC
      devices relative to those treated with heparin at any time point (P >.05,
      analysis of variance with repeated measures). Enhancement of fibrinolysis with
      EPC devices remains unproven; the findings reported here suggest that effective
      DVT prophylaxis can only be assured when the devices are used in a manner that
      reduces venous stasis.

PMID- 12422102
TI  - Air plethysmographic assessment of external valvuloplasty in patients with
      valvular incompetence of the saphenous and deep veins.
AB  - PURPOSE: The indications for deep venous valvuloplasty remain controversial in
      patients with incompetent deep vein valves associated with primary varicose
      veins. The purpose of this study was to evaluate the usefulness of external
      femoral valvuloplasty performed simultaneously with varicose vein surgery from
      the standpoint of venous function determined with air plethysmography. PATIENTS
      AND METHODS: Thirty-one limbs of 25 patients (12 men, 13 women; mean age, 56.3
      years; range, 33 to 80 years) with chronic venous insufficiency caused by
      valvular incompetence of both deep veins and saphenous veins were studied in a
      prospective, nonrandomized fashion. Descending phlebography showed moderate to
      severe reflux of grade 3 or 4 with Herman and Kistner classifications. Clinical
      severity of disease was CEAP classification 2S (in six limbs), classification 3
      (in three limbs), classification 4 (in 16 limbs), classification 5 (in two
      limbs), and classification 6 (in four limbs). We performed superficial venous
      surgery alone in 14 limbs (control group), which consisted of stripping or
      ligation of incompetent saphenous veins and ligation of all incompetent
      perforators. In the remaining 17 limbs (study group), we performed superficial
      venous surgery simultaneously with external valvuloplasty of the femoral vein
      with intraoperative endoscopic observation. Venous reflux of the limbs was
      evaluated with air plethysmographic examination before surgery and at 1, 6, 12,
      and 24 months after surgery in both groups. RESULTS: Preoperative venous filling
      index (mean +/- standard deviation) in the control and study groups was 9.4 +/-
      3.8 mL/min and 8.8 +/- 3.5 mL/min, respectively (not significant), and it
      decreased to 7.0 +/- 3.6 mL/min (P <.01) and 2.8 +/- 1.0 mL/min (P <.01),
      respectively, 1 month after surgery. Postoperative index values in the study
      group were significantly lower than values in the control group (P <.01), and
      this difference continued for more than 2 years after surgery (P <.05). After a
      follow-up period of 12 to 37 months (average, 25 months), the venous clinical
      severity score was higher in the control group (3.4 +/- 1.7) than in the study
      group (2.1 +/- 0.3; P <.05), and the venous disability score was higher in the
      control group (1.4 +/- 0.6) than in the study group (0.8 +/- 0.8; P <.05).
      CONCLUSION: Although further follow-up study is necessary, these results point to
      the functional and clinical usefulness of femoral valvuloplasty performed
      simultaneously with varicose vein surgery in patients with moderate to severe
      deep venous reflux. The venous filling index obtained with air plethysmography is
      an excellent predictor of the clinical severity of the disease and of
      postoperative clinical results.

PMID- 12422103
TI  - P-selectin inhibition enhances thrombus resolution and decreases vein wall
      fibrosis in a rat model.
AB  - PURPOSE: The purpose of this study was to compare the efficacy of P-selectin
      inhibition with standard anticoagulant and thrombolytic therapy in a rodent model
      of established deep vein thrombosis (DVT). METHODS: Rats underwent temporary
      inferior vena cava (IVC) ligation for 2 days to create a stasis-induced
      thrombosis. On day 2, the animals had the IVC ligature removed and received
      either recombinant P-selectin glycoprotein ligand-Ig (rPSGL-Ig; 4 mg/kg)
      intravenously, low-molecular weight heparin (LMWH; 450 IU/kg) subcutaneously,
      tissue plasminogen activator (tPA; 0.5 mg/kg) intravenously, combination rPSGL-Ig
      plus tPA, or saline vehicle. IVC segments were harvested from rats at 4 (n = 8)
      and 7 (n = 3) days after treatment. All treatments were given as a single dose
      except for daily LMWH. Evaluation included contrast venography with computer
      image analysis, thrombus weight/length (mass), vein wall leukocyte counts,
      cytokine and tissue factor analysis with enzyme-linked immunosorbent assay, and
      (ED1) monocyte immunohistochemical staining. Collagen was estimated with a
      quantitative assay. RESULTS: Contrast venography revealed that rats with both
      rPSGL-Ig and tPA treatment had significantly smaller thrombi as compared with
      controls at day 7 (0.34 +/- 0.07 cm(2) and 0.34 +/- 0.05 cm(2) versus 0.68 +/-
      0.13 cm(2); P <.05). LMWH and tPA groups had significantly decreased thrombus
      mass at harvest compared with controls on day 4 (0.06 +/- 0.009 g/cm and 0.08 +/-
      0.01 g/cm versus 0.1 +/- 0.005 g/cm; P <.05), and rPSGL-Ig showed a similar trend
      (P =.072). Vein wall, but not thrombus, monocytes were more numerous in those
      rats receiving rPSGL-Ig versus controls at day 4 (30 +/- 4 cells/5 high power
      fields [HPFs] versus 19 +/- 2 cells/5 HPFs; P <.05) and at day 7 (32 +/- 2
      cells/5 HPFs versus 20 +/- 3 cells/5 HPFs; P <.05). rPSGL-Ig treatment was
      associated with significantly reduced vein wall collagen at day 7 versus controls
      (1.3 +/- 0.6 pg/mg versus 3.7 +/- 0.5 pg/mg; P <.05) and a trend toward lower
      tissue factor levels. CONCLUSION: rPSGL-Ig, LMWH, and tPA showed equal DVT
      resolution efficacy over 7 days. However, only rPSGL-Ig was associated with a
      decrease in vein wall fibrosis, suggesting that purely accelerating DVT
      resolution may not decrease long-term vein scarring.

PMID- 12422104
TI  - Arteriovenous graft featuring end-to-end anastomosis to a deep vein for
      hemodialysis.
AB  - We describe a new vascular access grafting technique featuring end-to-end
      anastomosis to a deep vein in the forearm, designed to create a functional
      arteriovenous fistula in the forearm of patients whose subcutaneous veins are not
      usable for this purpose because of occlusion or attenuation. This new technique
      offers a valuable option in this setting.

PMID- 12422105
TI  - The effect of external pneumatic compression on regional fibrinolysis in a
      prospective randomized trial.
AB  - INTRODUCTION: External pneumatic compression devices (EPC) prevent deep venous
      thrombosis (DVT) by reducing lower extremity venous stasis. Early studies
      suggested they also enhance fibrinolytic activity; however, in a recent study,
      EPC had no effect on systemic fibrinolysis in patients undergoing abdominal
      surgery. The hypothesis of this study was that EPCs enhance regional fibrinolysis
      in these subjects. METHODS: Forty-five patients (44 male, one female; mean age,
      67 years) undergoing major abdominal surgery (35 bowel procedures, 10 aortic
      reconstructions) were prospectively randomized to one of three groups for DVT
      prophylaxis: subcutaneous heparin injections (HEP), thigh-length sequential EPC
      devices (EPC), or both (HEP+EPC). Prophylaxis was begun immediately before
      surgical incision and continued until postoperative day 5 or patient discharge.
      Venous blood samples were collected from the common femoral vein for measurement
      of regional fibrinolysis after induction of anesthesia but before initiation of
      prophylaxis, and on postoperative days 1, 3, and 5. A baseline sample was
      collected the day before surgery. Fibrinolysis was quantified with measurement of
      the activities of tissue plasminogen activator (tPA; the activator of
      fibrinolysis) and its inhibitor plasminogen activator inhibitor-1 (PAI-1) with
      amidolytic technique. RESULTS: tPA activity in all groups was normal at baseline;
      baseline PAI-1 activity was elevated. Within each prophylaxis group, no
      significant changes occurred in either tPA or PAI-1 activities after induction of
      anesthesia or after surgery compared with before surgery (P >.05, analysis of
      variance with repeated measures). No changes occurred between postoperative
      samples and after anesthesia within each group. No significant enhancement of
      fibrinolysis, manifested as either increased tPA activity or decreased PAI-1
      activity, occurred in either EPC group compared with the HEP group at any time
      point (P >.05, analysis of variance with repeated measures). No differences were
      noted when surgery was performed for malignant disease versus nonmalignant
      disease. CONCLUSION: In this study, enhanced regional fibrinolysis in the lower
      extremities could not be detected with the use of EPCs, as measured with tPA and
      PAI-1 activity in common femoral venous blood samples. EPC devices do not appear
      to prevent DVT with fibrinolytic enhancement; effective and safe prophylaxis is
      provided only when the devices are used in a manner that reduces lower extremity
      venous stasis.

PMID- 12422106
TI  - Varicose veins of the lower limbs and venous capacitance in postmenopausal women:
      relationship with obesity.
AB  - OBJECTIVE: The purpose of this study was to examine the association between body
      mass index (BMI), venous capacitance, and clinical evidence of varicose veins
      after adjustment for sex hormones in postmenopausal women. METHODS: This study
      group of the DIANA (DIet and ANdrogens) project (a randomized controlled trial on
      the effect of some dietary changes on sex hormone pattern in women with elevated
      androgenic hormone levels in Italy) was comprised of 104 healthy volunteer
      postmenopausal women, aged 48 to 65 years. The main outcome measures were
      physical examination to determine the presence and severity of varicose veins and
      plethysmographic measurement of lower limb venous capacitance and outflow.
      RESULTS: Women in the upper quartile of BMI (>30 kg/m(2)) showed a positive
      association with clinical evidence of varicose veins (odds ration, 5.8; 95% CI,
      1.2 to 28.2) after adjustment for age, estradiol, testosterone, and sex hormone
      binding globulin. No association was found between BMI and plethysmographic
      measurements of venous parameters. CONCLUSION: Obesity is associated with
      clinical evidence of varicose veins independently from the influence of sex
      hormones in postmenopausal women and is not associated with venous capacitance.
      Increased body weight increases the risk of varicose veins.

PMID- 12422107
TI  - A decade experience with infrainguinal revascularization in a dialysis-dependent
      patient population.
AB  - OBJECTIVE: Although previous series have reported outcomes of lower extremity
      (LE) revascularization in patients with end-stage renal disease, the issue of LE
      bypass for limb salvage in this group has not been resolved. We herein present
      the largest series to date of a 10-year single-institution experience with LE
      bypass in patients with dialysis dependence. METHODS: With prospectively entered
      data from a university teaching hospital's vascular registry, we reviewed the
      records of all patients with dialysis dependence who underwent LE arterial bypass
      between January 1, 1990, and May 31, 1999. RESULTS: A total of 146 consecutive
      patients (177 limbs) underwent infrainguinal revascularization, of whom nearly
      all (92%) had diabetes and tissue loss (91%). The in-hospital mortality rate was
      3% (five patients). The rates for perioperative congestive heart failure,
      myocardial infarction, arrhythmia, and wound infection were 2%, 3%, 5%, and 10%,
      respectively. The actuarial graft primary and secondary patency rates at 1 and 3
      years were 84% and 85%, and 64% and 68%, respectively. The limb salvage rates
      were 80% and 80% at 1 and 3 years. The 1-year and 3-year cumulative survival
      rates were 60% and 18%, respectively. At 5 years, survival was poor with only 5%
      of the entire cohort of 146 patients still alive. Multivariate logistic
      regression analysis at 6 months identified age (odds ratio, 0.96, 0.91) and
      number of years on dialysis (odds ratio, 0.79, 0.74) as significant (P <.05)
      negative predictors of both limb salvage and survival, respectively. CONCLUSION:
      Infrainguinal arterial reconstruction can be performed on patients with dialysis
      dependence with acceptable rates of limb salvage given the high incidence rate of
      perioperative complications and poor longevity of this patient group. Advanced
      age and number of years on dialysis seem to correlate with poorer outcome.

PMID- 12422108
TI  - Prediction of early graft failure with intraoperative completion duplex
      ultrasound scan.
AB  - PURPOSE: The purpose of this study was to determine intraoperative hemodynamic
      parameters that predict early failure of infragenicular vein grafts with
      intraoperative completion duplex ultrasound scan. METHODS: We reviewed the
      results of intraoperative duplex scans that were selectively performed after
      completion of 45 tibial/pedal vein bypass grafts at high risk for failure. Bypass
      was performed for rest pain (39%) or tissue loss (61%), and 60% of the cases were
      disadvantaged because of compromised vein quality or poor arterial outflow. A 10
      MHz low-profile transducer was used to scan the entire graft at bypass
      completion. All grafts were determined to be technically adequate (absence of
      retained valves, arteriovenous fistulas, or localized velocity increases and the
      presence of bypass-dependent distal pulses). Peak systolic velocity (PSV) and end
      diastolic velocity (EDV) were also measured at each anastomosis, in the outflow
      artery and in the proximal and distal portions of each graft. Resistive indices
      (RI) were calculated at each measurement point (PSV-EDV/PSV). Statistical
      analysis was performed with unpaired t test, chi(2) test, and multivariate
      analyses. RESULTS: Twenty infragenicular vein bypass grafts (44%) thrombosed
      within 12 months. Intraoperative hemodynamic parameters were significantly
      different between grafts that remained patent or thrombosed. EDV was lower (5 +/-
      1 cm/s versus 13 +/- 3 cm/s; P =.02) and RI was higher (0.90 versus 0.81; P <.01)
      in the proximal portions of grafts that thrombosed within 12 months. Distal EDV
      was also lower (6 +/- 1 cm/s versus 15 +/- 2 cm/s; P <.01) and distal RI was
      higher (0.89 versus 0.78; P <.01) in grafts that thrombosed. With multivariate
      analysis, only low distal EDV was predictive of early graft failure (P <.05).
      Distal bypass EDV of less than 8 cm/s predicated early graft thrombosis with 76%
      sensitivity and 75% specificity (positive predictive value, 71%; negative
      predictive value, 78%). Absence of diastolic flow (EDV of 0 cm/s) predicted early
      graft failure with 100% specificity and 100% positive predictive value.
      CONCLUSION: In this initial experience, low EDV measured with intraoperative
      duplex scan was associated with early thrombosis of tibial level vein grafts.
      When such values are observed, measures should be taken to improve graft
      hemodynamic parameters. Prospective study of infragenicular vein bypass grafts
      may better define hemodynamic parameters predictive of early graft thrombosis.

PMID- 12422109
TI  - Outcome of common iliac arteries after aortoaortic graft placement during
      elective repair of infrarenal abdominal aortic aneurysms.
AB  - PURPOSE: The purpose of this study was determination of the expansion rates
      relative to the size of the common iliac artery (CIA) after elective placement of
      a straight aortic tube graft for an infrarenal abdominal aortic aneurysm (AAA).
      METHODS: Between January 1993 and December 1997, 74 men (mean age, 69 years) with
      AAA underwent surgical repair with a straight tube graft. All patients underwent
      preoperative and postoperative computed tomography (CT) scans. The mean follow-up
      period was 68.3 months. The preoperative CT scan revealed a dilatation of at
      least one of the two CIAs in 32 patients (43.2%; group A). Within this group, the
      CIA was ectatic (12 mm < diameter < 18 mm) in 13 patients (subgroup A1) and
      aneurysmal (diameter >/=18 mm) in 19 patients (subgroup A2). The diameters of
      both CIAs were normal (diameter </=12 mm) in the other 42 patients (56.8%; group
      B). RESULTS: Two patients (2.7%) in group A2 needed reoperation because of
      expansion of the diameter of the CIA; the preoperative diameter of the CIA in
      both patients was 30 mm. The diameters of the CIA aneurysms in the 17 other
      patients in subgroup A2 were smaller than 30 mm on the preoperative CT scan.
      After aortic surgery, the sizes of these aneurysms remained stable the first 5
      years and reached a diameter of 30 mm on the CT scans obtained 7 to 8 years after
      surgery. Overall, 10 of the 74 patients (13.5%) had a CIA aneurysm develop that
      was smaller than 30 mm in diameter (mean diameter, 19.2 mm) 7 to 8 years after
      aortic surgery. The presence of a celiac aorta dilatation greater than or equal
      to 25 mm was the only statistically significant factor predictive of
      postoperative expansion of a CIA dilatation (P =.03). CONCLUSION: Straight
      aortoaortic tube grafts are indicated for CIAs with diameters smaller than 18 mm.
      Aorta biiliac bifurcated grafts are justified when the CIA diameter is between 18
      and 30 mm, when the patient's life expectancy is longer than 8 years, or when the
      diameter of the celiac aorta is greater than or equal to 25 mm. A CIA aneurysm
      greater than or equal to 30 mm should be repaired during the same operative
      session as the AAA with placement of an aorta biiliac bifurcated graft.

PMID- 12422111
TI  - The Carotid Surgery for Ischemic Stroke trial: a prospective observational study
      on carotid endarterectomy in the early period after ischemic stroke.
AB  - OBJECTIVE: The purpose of this study was to examine the safety of carotid
      endarterectomy (CEA) within 6 weeks after a nondisabling carotid-related ischemic
      stroke. Endpoints were the perioperative stroke or mortality rate and the
      incidence rate of cerebral bleedings. METHODS: This prospective observational
      multicenter trial was performed in community and university centers. One hundred
      sixty-four hospitalized patients with nondisabling carotid-related ischemic
      stroke were included. The patients were identified clinically with the modified
      Rankin scale (initial neurologic deficit grade >/= 2, n = 160). Four patients
      with evidence of ischemic territorial infarction on cerebral computed tomographic
      (CT) scan but no persisting functional deficit were also included. CEA was
      performed within 6 weeks after stroke. Neurologic examinations were performed
      initially, before surgery, 3 days after surgery, and 6 weeks after CEA. Worsening
      of more than 1 grade on the Rankin scale was considered as a new stroke or stroke
      extension. Unenhanced CT scans of the brain were performed before and after
      surgery. CT scans were evaluated blind to clinical patient data. Statistical
      analysis included univariate and multivariate analysis. RESULTS: The combined
      stroke or mortality rate within 30 days after CEA was 6.7%. Ten patients had a
      new ipsilateral stroke or stroke extension, and one patient died after surgery of
      a myocardial infarction. One patient (0.6%) had parenchymatous cerebral bleeding,
      and in 10 patients, hemorrhagic transformation within the preexisting ischemic
      infarction was detected but no infarct extension was observed. In the
      multivariate analysis, American Society of Anesthesiology (ASA) grades III and IV
      and decreasing age were significant predictors for an increased perioperative
      risk. Patients with a higher risk profile (ASA classification grades III and IV)
      had a high perioperative risk when CEA was performed within the first 3 weeks
      (14.6% versus 4.8% beyond 3 weeks). Patients without severe concomitant diseases
      (ASA grades I/II) had a low perioperative risk of 3.4% if CEA was performed
      within the first 3 weeks. CONCLUSION: Early CEA within 6 weeks after a carotid
      related ischemic stroke can be performed with a perioperative stroke or mortality
      rate comparable with the results reported in the European Carotid Surgery Trial
      and the North American Symptomatic Carotid Endarterectomy Trial. The risk of
      parenchymatous bleeding is low. ASA grades III and IV and decreasing age were
      predictive of an increased perioperative risk, especially if CEA was performed
      within the first 3 weeks. Patients at low risk can undergo operation safely
      within the first 3 weeks. Individual patient selection in an interdisciplinary
      approach between neurologists, anesthesiologists, and vascular surgeons remains
      mandatory in these patients.

PMID- 12422110
TI  - Endovascular abdominal aortic aneurysm repair with general versus local
      anesthesia: a comparison of cardiopulmonary morbidity and mortality rates.
AB  - PURPOSE: The purpose of this study was to compare the cardiopulmonary morbidity
      and mortality rates after endovascular abdominal aortic aneurysm (EAAA) repair
      with local anesthesia (LA) with intravenous sedation versus general anesthesia
      (GA). METHODS: Data from patients who underwent elective infrarenal EAAA repair
      between June 1996 and October 2000 were retrospectively reviewed. Patients with
      two or more Eagle clinical cardiac risk factors were considered to be at
      increased risk for a major postoperative cardiac event. Univariate and
      multivariate analyses for major cardiac and pulmonary morbidity and mortality
      rates were analyzed with respect to anesthetic type (GA versus LA), age, size of
      aneurysm, mean number of Eagle risk factors, and presence of two or more cardiac
      risk factors. RESULTS: Two hundred twenty-nine patients underwent EAAA repair.
      The GA (158 patients) and LA (71 patients) groups were significantly different
      with respect to mean age (73 versus 76 years; P =.01) and mean number of cardiac
      risk factors per patient (1.2 versus 1.6; P =.002). No difference was seen in the
      overall cardiopulmonary complication rate (13% for GA and 19% for LA; P =.3),
      pulmonary complication rate (3.8% for GA and 7% for LA; P =.3), or
      cardiopulmonary mortality rate (3.2% for GA and 2.8% for LA; P =.9). The major
      cardiac event rate was higher in patients with two or more Eagle risk factors
      (22%) versus those patients with one or less Eagle risk factors (3.4%; P <.001),
      irrespective of anesthetic type. In analysis of patients with one or less Eagle
      risk factors, no difference was seen in the major cardiac event rate by
      anesthetic type (3% for GA and 5% for LA; P =.6). Also, no difference was seen in
      major cardiac events in patients with two or more Eagle risk factors by
      anesthetic type (24% for GA and 22% for LA). On multivariate analysis, the mean
      number of Eagle risk factors per patient (P <.0001) and the presence of two or
      more Eagle risk factors were associated with major cardiac and cardiopulmonary
      complications, whereas age, size of AAA, and anesthetic type were not.
      CONCLUSION: No difference exists in overall cardiac and pulmonary morbidity and
      mortality rates after EAAA repair in comparison of GA and LA. The presence of two
      or more preoperative cardiac risk factors significantly increases the risk of a
      major postoperative cardiac event.

PMID- 12422112
TI  - Serum lipids act as inverse acute phase reactants and are falsely low in patients
      with critical limb ischemia.
AB  - BACKGROUND: Lipid levels generally fall after an acute myocardial infarction.
      This study was conducted to see what trends lipid levels had in patients who
      underwent operation for critical limb ischemia. METHODS: The study was
      prospective and included 30 patients who underwent operation for critical limb
      ischemia. Serum lipid profiles and C-reactive protein were analyzed before
      surgery and 3 months after peripheral bypass surgery. In addition, comparison of
      lipid levels after surgery was made with 287 healthy and 283 ischemic heart
      disease controls from The Copenhagen City Heart Study. RESULTS: Total, low
      density lipoprotein, and high density lipoprotein cholesterol levels were found
      to be significantly lower before surgery than 3 months after surgery (P <.001).
      In contrast, C-reactive protein was higher before surgery and decreased after 3
      months (P <.0001). An inverse linear correlation was found between total
      cholesterol/low density lipoprotein cholesterol and C-reactive protein (P <.001
      and P <.04, respectively). Comparison with controls showed that cholesterol
      levels 3 months after surgery were significantly lower (P <.009). CONCLUSION:
      Serum cholesterol levels are not reliable in the preoperative period and should
      therefore be measured at least 3 months after surgery when they seem to approach
      a more representative level.

PMID- 12422113
TI  - Chlamydia pneumoniae antigens facilitate experimental aortic dilatation:
      prevention with azithromycin.
AB  - OBJECTIVE: The purpose of this study was to investigate whether Chlamydia
      pneumoniae (live, antigens, or polysaccharide) cause abdominal aortic aneurysm in
      a susceptible animal host with appropriate drug reversal. METHODS: At laparotomy,
      preparations of C pneumoniae (live, formalin-inactivated, and heat-inactivated)
      in calcium chloride were applied to the adventitial surface of the abdominal
      aorta of rabbits fed a cholesterol-enriched diet. Aortic diameter was measured
      with ultrasonography. After 3 weeks, immunohistochemistry was used to detect
      aortic C pneumoniae and macrophages. Presence of C pneumoniae DNA also was
      assessed. RESULTS: At high doses (5 x 10(7) organisms) periaortic application of
      both live and formalin-inactivated preparations resulted in doubling of aortic
      diameter after 3 weeks, from 2.0 +/- 0.5 mm to 4.3 +/- 1.3 mm (P <.02). C
      pneumoniae DNA and antigens, together with a heavy macrophage infiltrate, were
      detected in the dilated aorta. In contrast, periaortic application of heat
      inactivated preparations resulted in minimal macrophage influx and aortic
      dilatation. Treatment of rabbits with azithromycin or carprofen for 10 days after
      laparotomy abolished the effects of formalin-inactivated C pneumoniae on aortic
      dilatation. Azithromycin reduced the number of macrophages in the aortic wall
      more effectively than carprofen. CONCLUSION: Because membrane antigenicity is
      retained in formalin-inactivated but not heat-inactivated organisms, in this
      experimental model, chlamydial membrane antigens (rather than live organisms)
      appear to cause the aneurysmal dilatation and associated macrophage recruitment.
      Azithromycin is likely to reverse these effects with an antiinflammatory
      mechanism.

PMID- 12422114
TI  - Paracrine effect of vascular smooth muscle cells in the prevention of aortic
      aneurysm formation.
AB  - OBJECTIVE: Inflammation and elastinolysis are observed in the media of abdominal
      aortic aneurysms (AAAs) where vascular smooth muscle cell (VSMC) density is
      decreased. In contrast, elastin and VSMCs are preserved in the noninflammatory
      media of stenotic atherosclerotic lesions. We have tested the hypothesis that
      VSMCs exert a protective effect against inflammation and proteolysis in a model
      of AAA in rats, in which medial elastin degradation is driven by inflammation and
      matrix metalloproteinases. METHOD: Decellularized guinea pig aortas (xenografts)
      were implanted orthotopically into Fischer-344 rats and seeded with a suspension
      of rat VSMCs syngeneic to the rat recipient, or were infused with culture medium
      as a control. Diameter and elastin in the media were quantified 8 weeks after
      implantation. Inflammation, matrix metalloproteinase (MMP) and tissue inhibitor
      of matrix metalloproteinase (TIMP) expression were analyzed 1 and 2 weeks after
      implantation. RESULTS: VSMC addition prevented AAA formation (mean +/- standard
      deviation diameter increase: 198.2% +/- 106.6% vs 35.3% +/- 17.8%, P =.009),
      elastin degradation, and decreased infiltration by monocyte-macrophages. Reverse
      transcriptase polymerase chain reaction, zymography and reverse zymography for
      MMP-2, MMP-9, TIMP-1, TIMP-2, and TIMP-3 demonstrated a shift of the proteolytic
      antiproteolytic balance upon addition of VSMCs. Transcriptional changes were
      observed in the adventitia, although seeded VSMCs remained located in the intima.
      CONCLUSIONS: VSMCs exert a paracrine effect on the adventitia that participate in
      artery wall homeostasis against inflammation and proteolysis. Failure of this
      protective mechanism results in AAA formation. The understanding of the molecular
      mechanisms underlying VSMC protective effect may represent a new approach in the
      treatment of aneurysm and plaque rupture.

PMID- 12422115
TI  - Influence of stent design and material composition on procedure outcome.
AB  - Although intravascular stents have received widespread application, significant
      limitations remain. In stent restenosis, the most pervasive problem affecting
      stents, is related in part to technical aspects of the device. Design features of
      the stent that influence outcome have been identified and optimized for improved
      performance. The influence of stent materials on critical aspects of healing,
      such as thrombotic, inflammatory, and hyperplastic responses, are less well
      understood. For this reason, significant progress in this area is lacking.
      Current stents have significant contamination with industrial impurities on the
      surface and in the bulk. This fact adds to the difficulties in interpreting the
      biologic reaction of the host to the device. Better understanding of the basic
      biologic interactions is the path to significant improvement.

PMID- 12422116
TI  - Genetic interventions for vein bypass graft disease: a review.
AB  - The failure of vein bypass grafting in the coronary or lower extremity
      circulation is a common clinical occurrence that incurs significant morbidity,
      mortality, and cost. Vein grafts are uniquely amenable to intraoperative genetic
      modification because of the ability to manipulate the tissue ex vivo with
      controlled conditions. Although the pathophysiology of vein graft failure is
      incompletely understood, numerous relevant molecular targets have been
      elucidated. Interventions designed to influence cell proliferation, thrombosis,
      inflammation, and matrix remodeling at the genetic level have been described, and
      many have been tested in animal models. Both gene delivery and gene blockade
      strategies have been investigated, with the latter now reaching the stage of
      advanced clinical trials. This review describes the basic and translational
      science of genetic interventions for vein graft disease and the current state of
      application in the clinic.

PMID- 12422117
TI  - Spontaneous rupture of collateral venous aneurysm in a patient with agenesis of
      the inferior vena cava: a case report.
AB  - We present a case of rupture of collateral venous vessels in the presence of
      agenesis of the inferior vena cava in a young woman. The embryologic development,
      pitfalls in diagnosis, and options for treatment in cases with agenesis of the
      inferior vena cava are discussed.

PMID- 12422118
TI  - Percutaneous transhepatic treatment of symptomatic mesenteric venous thrombosis.
AB  - Three patients were seen with acute mesenteric venous thrombosis. With a
      transhepatic access, percutaneous pharmacologic thrombolysis was performed in one
      patient with extensive thrombosis of the portal and mesenteric veins, resulting
      in complete thrombolysis of the portal vein and partial thrombolysis of the
      superior mesenteric vein. In two patients with focal thrombosis, the use of
      mechanical devices achieved complete thrombolysis. Percutaneous thrombolysis of
      portal and mesenteric veins with a transhepatic approach, followed by coil
      embolization, is a promising endovascular technique for treatment of symptomatic
      acute mesenteric venous thrombosis.

PMID- 12422119
TI  - Atheroembolization: a harmful complication of therapeutic internal iliac artery
      occlusion.
AB  - Coil embolization of the internal iliac artery (IIA) for proper endovascular
      treatment of aortoiliac aneurysms is a procedure with an acceptable morbidity
      rate consisting of buttock claudication in 12% to 55% and erectile dysfunction in
      1% to 13%. Atheroembolic complications in this context are not yet reported. We
      present a case with gangrene of the prepuce and focal cutaneous necrosis of the
      ipsilateral buttock and foot after coil embolization of one IIA. Multiple
      atheroemboli were found with the histopathologic examination of the excised
      prepuce. Atheroembolization is a rare complication of therapeutic IIA occlusion,
      and the ischemic sequels can be severe because of the coincidence of
      atheroembolization and occlusion of the main supplying artery.

PMID- 12422120
TI  - The endovascular treatment of a renal arteriovenous fistula: Placement of a
      covered stent.
AB  - We describe the case of a 40-year-old man with an acquired renal arteriovenous
      fistula (AVF) treated with endovascular placement of a homemade
      polytetrafluoroethylene covered Palmaz stent (Johnson & Johnson, Warren, NJ). The
      patient was seen with a abdominal bruit 5 years after exploratory laparotomy for
      multiple knife stab wounds. An abdominal computed tomographic scan showed an
      atrophic right kidney and enlarged right renal vein and inferior vena cava.
      Arteriography confirmed a 5-mm to 7-mm AVF between the right renal artery and
      vein. In November 1999, the patient was taken to the operating room where a
      Palmaz 308 polytetrafluoroethylene covered stent was placed within the renal
      artery at the site of the fistula. Exclusion of the fistula was confirmed with
      arteriogram. To our knowledge, this is one of the earliest reports and the
      longest follow-up of the endovascular placement of a covered stent for treatment
      of an acquired renal AVF. Continued application of covered stent treatment for
      renal AVFs should prove less expensive with improved renal preservation and, with
      prefabricated stent grafts, prove less cumbersome and time consuming than coil
      embolization.

PMID- 12422121
TI  - Lower extremity compartment syndrome after coronary artery bypass.
AB  - Compartment syndrome is a rare and dangerous complication of coronary artery
      bypass. All reported cases involved the vein donor limb. Once recognized,
      immediate fasciotomy is necessary to prevent irreversible ischemia and limb loss.
      Diagnosis requires a high index of suspicion and close observation of the
      patient, particularly those remaining intubated during the early postoperative
      period.

PMID- 12422122
TI  - Azygous vein to right atrium bypass graft in a patient with idiopathic fibrosing
      mediastinitis and symptomatic superior and inferior vena cava obstructions.
AB  - We report an unusual case of a patient with diminished cardiac output caused by
      systemic venous occlusions of unclear etiology with a history of idiopathic
      fibrosing mediastinitis and retroperitoneal fibrosis. On thoracic, abdominal, and
      pelvic venograms, the patient was previously known to have superior vena caval
      and infrarenal inferior vena caval occlusions. Subsequent studies revealed
      retrograde flow through the azygous and hemiazygous veins and numerous caval
      portal anastomoses providing venous return from the upper and lower extremities.
      After an extensive hypercoagulable state work-up, no abnormalities were found. To
      relieve the symptoms, the patient underwent an elective right thoracotomy with
      azygous vein to right atrial bypass graft. The patient has had complete
      amelioration of the disabling symptoms and participates in many activities that
      he could not tolerate previously. Because this condition and procedure are
      unreported, we present a novel surgical treatment option to palliate symptoms
      caused by concurrent superior and inferior caval obstructions by improving venous
      return to the heart.

PMID- 12422123
TI  - Safety maneuvers to prevent embolism complicating endovascular aortic repair.
AB  - The endoluminal approach of the diffusely atheromatous aorta (DAA) is an emerging
      tool to prevent further embolization. We treated one symptomatic patient with
      DAA. We designed a catheter with a balloon at the tip for occlusion of both
      common iliac arteries through which the antegrade flow was allowed by an iliac to
      femoral arterio-arterial shunt connected to an in-line filter. Filter wires were
      also placed in the superior mesenteric and both renal arteries' take-off, keeping
      their antegrade flow. The endograft was then introduced through these tubes.
      Endoluminal treatment of the primary source of atheromatous embolization is
      feasible, representing a new approach to be considered.

PMID- 12422124
TI  - Robot-assisted laparoscopic aortobifemoral bypass for aortoiliac occlusive
      disease: a report of two cases.
AB  - This article describes the use of robotic technology in laparoscopic
      aortobifemoral bypass grafting. In two patients with disabling intermittent
      claudication on the basis of severe aortoiliac occlusive disease, laparoscopic
      aortobifemoral bypass grafting was performed with a proximal end-to-side
      anastomosis constructed with robotic arms that had been mounted on the operating
      table and were controlled from a separate console. No complications occurred.
      Operating times were 290 and 260 minutes, and aortic anastomosis times were 48
      and 37 minutes, respectively. Blood loss was less than 200 mL in both cases. A
      normal diet was resumed on the second postoperative day, and the patients were
      discharged home on postoperative days 4 and 6. To our knowledge, this is the
      first report on robot-assisted laparoscopic aortobifemoral bypass in the world
      literature.

PMID- 12422125
TI  - Relevance of basic laboratory and clinical research activities as part of the
      vascular surgery fellowship: an assessment by program directors and
      postfellowship surgeons.
AB  - INTRODUCTION: Decreased federal monies for graduate medical education, increased
      clinical training demands, and a decreased pool of general surgery trainees
      applying to vascular surgery fellowships have brought into question the relevance
      of the fellowship research experience. This study sought to describe the recent
      laboratory experience of the fellows, the value of this experience to program
      directors (PDs) and the trainees, and what factors related to this experience
      contributed to the trainee entering an academic career versus a private practice
      career. METHODS: A survey regarding the relevance of research experience during
      fellowship training was mailed in 2001 to all Accreditation Council for Graduate
      Medical Education-approved vascular surgery fellowship PDs and vascular surgery
      fellows (VSFs) from 1988 to 2000 applying for the American Board of Surgery
      Certificate of Added Qualification in General Vascular Surgery. RESULTS: Survey
      responses were received from 89% of the PDs (74/83) and 69% of the VSFs
      (259/378). Among the PDs, 70% had completed an approved fellowship, and current
      bench research was performed by 46%. The PDs afforded protected research time to
      69% of the VSFs (with a mean duration of 12 months). This research was in the
      basic science laboratory 34% of the time. Only 42% of the PDs considered basic
      laboratory research to be an important part of the fellowship, whereas 99%
      believed that clinical research was important. Among the PDs, 42% believed that
      more practice-oriented fellowships with no basic research were needed, whereas
      35% believed that basic research should remain an integral component of the
      fellowship. VSF basic science productivity was significantly greater from those
      programs that offered protected research time as compared with those that did not
      (mean basic science paper published, 1.7 +/- 0.1 versus 0.3 +/- 0.6 per VSF; P
      <.001). At the time of the survey, 99 VSFs had entered academic careers and 136
      were in private practice. Basic science research had been undertaken by 56% of
      the VSFs during medical school and by 53% during general surgery residency.
      Research during the fellowship was performed by 65% of the VSFs. This experience
      was considered helpful in choosing an academic or private practice career by 44%
      of the VSFs. A greater proportion of academic surgeons had research experience as
      VSFs when compared with VSFs who became private practitioners (71% versus 57%; P
      <.05). VSFs who entered academic careers had a more productive publication record
      in fellowship than did those who chose private practice (mean paper, 2.4 versus
      1.5; P <.05). Overall, 78% of the VSFs believed that their research experience
      was maturing beyond the technical skills learned. CONCLUSION: This report
      provides a benchmark of the vascular surgery fellowship research experience. Most
      VSFs considered the research experience as it now exists to be worthwhile, and
      less than half of the PDs believed that it should remain as it is. Research
      experience in fellowship seemed more influential than that in medical school or
      general surgical residency in promoting an academic career.

PMID- 12422127
TI  - Regarding "Carotid artery stenting in a vascular surgery practice".

PMID- 12422126
TI  - Professional self-regulation: eyewitness to incompetent surgery.

PMID- 12422133
TI  - New insights into the role of aldosterone in cardiorenal disease and the clinical
      implications. Introduction.

PMID- 12422134
TI  - Aldosterone: cardiovascular assault.
AB  - BACKGROUND: Blocking the renin-angiotensin-aldosterone system with angiotensin
      converting enzyme inhibitors has improved cardiovascular morbidity and mortality
      rates. However, because of aldosterone "escape," the effectiveness of this
      blockade decreases over time. METHODS: Various in vitro and in vivo studies were
      evaluated to determine the mechanisms by which aldosterone contributes to
      morbidity and mortality. RESULTS: Aldosterone has several deleterious properties.
      It causes a vasculopathy with both endothelial dysfunction and a reduction in
      fibrinolysis, leading to heart, brain, and kidney damage. Aldosterone causes
      myocardial hypertrophy and fibrosis, autonomic imbalance, and electrolyte
      abnormalities, contributing to myocardial dysfunction, arrhythmias, and sudden
      cardiac death. Studies have shown that all of these deleterious effects can, at
      least in part, be reversed by aldosterone receptor blockade. This may explain why
      adding an aldosterone blocker to standard heart failure therapy, including
      angiotensin-converting enzyme inhibitors, reduces morbidity and mortality rates
      by an additional 30% compared with standard therapy alone. CONCLUSIONS:
      Eplerenone is a selective aldosterone blocker whose role in reducing morbidity
      and mortality rates in patients with cardiovascular disease is being
      investigated.

PMID- 12422135
TI  - New biology of aldosterone, and experimental studies on the selective aldosterone
      blocker eplerenone.

PMID- 12422136
TI  - Clinical implications of aldosterone blockade.
AB  - BACKGROUND: Aldosterone contributes to hypertension, cardiac and vascular
      remodeling, and heart failure. The significant risk reduction provided by the
      addition of spironolactone to standard therapy in patients with severe heart
      failure has renewed interest in aldosterone blockade. METHODS: This review
      describes recent clinical studies of eplerenone, a selective aldosterone blocker,
      in patients with hypertension. RESULTS: In a 16-week study, eplerenone was more
      effective than placebo or losartan in lowering systolic blood pressure (BP) and
      diastolic BP in black patients with mild to moderate hypertension. The BP
      lowering efficacy of eplerenone was similar in blacks and whites. In a separate
      study in patients whose BP was controlled inadequately by angiotensin-converting
      enzyme inhibitors or angiotensin-receptor blockers, addition of eplerenone
      significantly reduced systolic BP, and to a lesser extent, diastolic BP. There
      were no significant changes in potassium levels in this study. Eplerenone
      increased active renin and aldosterone levels, indicating that it blocks the
      renin-angiotensin-aldosterone system. Gynecomastia, or breast tenderness, was
      uncommon and occurred at a rate comparable to placebo. CONCLUSIONS: Eplerenone is
      a selective aldosterone blocker that effectively lowers BP in both white and
      black patients with hypertension and provides meaningful further antihypertensive
      efficacy when added to patients whose hypertension is inadequately controlled by
      angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers.

PMID- 12422137
TI  - Increased myocardial ischemia after food is not explained by endothelial
      dysfunction.
AB  - BACKGROUND: Recent studies suggest that a high-fat meal can impair endothelial
      function. The aim of this study was to determine whether greater myocardial
      ischemia after either a low-fat or a high-fat meal is associated with an increase
      in brachial artery endothelial dysfunction. METHODS: Twenty subjects with
      coronary artery disease and > or =1-mm ST-segment depression during exercise were
      studied. In a randomized, double-blind, crossover design, ST-segment changes
      during treadmill exercise and brachial artery diameter and flow-mediated dilation
      were measured before and 3 hours after a low-fat milkshake meal or the same meal
      supplemented with 64 grams of cooked fat. RESULTS: After the low-fat but not the
      high-fat meal, resting brachial artery diameter decreased (before meal 4.72 +/
      0.50 mm, after low fat meal 4.62 +/-0.49 mm, P =.001; after high fat meal 4.70 +/
      0.51 mm, not significant). High-flow brachial artery diameter was similar before
      (4.81 +/- 0.48 mm) and after the low-fat (4.82 +/- 0.48 mm) and high-fat (4.84 +/
      0.48 mm) meals (P >.05 for all). Brachial artery flow-mediated dilation was not
      impaired after either meal. Exercise duration decreased more after the low-fat
      meal (mean change 39 seconds, 95% CI -14 to -63 seconds, P =.004) than after the
      high-fat meal (-7 seconds, 95% CI +19 to -34 seconds, not significant). ST
      segment depression during equivalent exercise was greater after compared with
      before both meals (before meals 1.03 +/- 0.69 mm, after low fat 1.27 +/- 0.80 mm,
      P =.03; after high fat 1.24 +/- 0.74 mm, P =.04). CONCLUSIONS: Increased
      myocardial ischemia after food is caused by mechanisms other than endothelial
      dysfunction and by meal components other than cooked fat.

PMID- 12422138
TI  - Esmolol in acute ischemic syndromes.
AB  - BACKGROUND: beta-Blockers have been shown to reduce both morbidity and mortality
      rates in patients with acute coronary syndromes. However, because of potential
      side effects, their use is limited in patients who might benefit the most from
      such therapy. It was thought that the use of an ultra-short-acting intravenous
      beta-blocker might produce similar results with fewer complications in those
      patients with relative contraindications to beta-blocker therapy. METHODS:
      Accordingly, we evaluated the use of esmolol in patients with acute coronary
      syndromes and relative contraindication to beta-blocker therapy in a prospective
      randomized trial. One hundred eight patients at 21 sites received an infusion of
      intravenous esmolol or standard therapy on admission and were followed for 6
      weeks from the day of admission. The primary efficacy outcome was a composite
      event consisting of any of the following that occurred during the index
      hospitalization: death, myocardial (re)infarction, recurrent ischemia, or
      arrhythmia as well as silent myocardial ischemia assessed by ambulatory
      electrocardiographic monitoring. Safety end points including hypotension,
      bradyarrhythmias, new or worsening congestive heart failure, and bronchospasm
      were also recorded. RESULTS: Event rates for primary end points were similar in
      the 2 groups: death (2% in the standard care group vs 4% in the group receiving
      esmolol), myocardial (re)infarction (4% standard vs 7% esmolol), ischemia (12% vs
      13%), arrhythmias (4% vs 2%), and silent ischemia (13% vs 15%). There was a
      higher incidence of transient hypotension in the group receiving esmolol (2% vs
      16%), but all such events were noted to resolve after discontinuation of the
      esmolol infusion. There were no additional differences in safety end points:
      bradycardia (2% for those receiving standard care vs 9% receiving esmolol), new
      congestive heart failure (10% vs 16%), bronchospasm (0% vs 7%), and heart block
      (2% vs 2%). CONCLUSIONS: The use of an ultra-short-acting beta-blocker such as
      esmolol might offer an alternative to patients with contraindications to standard
      beta-blocker therapy. Although this trial had limited power to detect safety and
      efficacy differences between the 2 therapies, it was observed that safety end
      points, which occurred during esmolol administration, resolved readily when the
      infusions were decreased or discontinued. Additional testing is needed to
      substantiate these findings.

PMID- 12422139
TI  - The search for myocardial viability: do Q waves help?

PMID- 12422140
TI  - Angiotensin-converting enzyme gene insertion/deletion polymorphism and
      cardiovascular disease: identifying the guideposts for navigating the genetics
      landscape.

PMID- 12422141
TI  - Risk stratification in acute coronary syndromes: the need for continued vigilance
      in "low-risk" patients.

PMID- 12422142
TI  - Carotid artery intimal-medial thickness: indicator of atherosclerotic burden and
      response to risk factor modification.
AB  - BACKGROUND: A number of studies have used B-mode ultrasound to measure carotid
      intimal-medial thickness as an indicator of the severity of carotid
      atherosclerosis. METHODS: We reviewed the available data on carotid intimal
      medial thickness in defining severity of atherosclerosis, with the use of high
      quality studies that addressed clinical end points. RESULTS: Data from multiple
      studies demonstrate a high degree of reproducibility in measurements of intimal
      medial thickness. A number of agents that include 3-hydroxy-3-methylglutaryl
      coenzyme A reductase inhibitors, angiotensin-converting enzyme inhibitors, and
      insulin sensitizers reduce carotid intimal-medial thickness and cardiovascular
      events, such as myocardial infarction and stroke. CONCLUSIONS: In this review
      article, various methods of measuring carotid intimal-medial thickness are
      examined and critiqued. In addition, the effects of various lifestyle
      modifications and therapeutic agents on intimal-medial thickness and
      cardiovascular end points are evaluated.

PMID- 12422143
TI  - A meta-analysis of the angiotensin-converting enzyme gene polymorphism and
      restenosis after percutaneous transluminal coronary revascularization: evidence
      for publication bias.
AB  - BACKGROUND: The insertion/deletion polymorphism of the gene encoding angiotensin
      converting enzyme is a controversial risk factor for restenosis after
      percutaneous transluminal coronary revascularization in patients. Genetic
      association studies addressing this issue are frequently hampered by insufficient
      power. Therefore, we conducted a meta-analysis of this association, taking into
      account the possibility of publication bias. METHODS: We used the MEDLINE
      database and reviewed citations in relevant articles to identify 12 studies.
      Information on the design of the studies, the detailed genotype distribution, the
      angiographic follow-up rate, and the restenosis rate were categorized by use of a
      standardized protocol. RESULTS: Overall, DD (deletion-deletion) homozygotes had a
      higher restenosis risk than II (insertion-insertion) carriers (odds ratio 1.22,
      95% CI 1.04-1.44, P <.05). However, the published studies were significantly
      heterogeneous, especially those addressing in-stent restenosis. Smaller studies
      tended to have positive results more frequently, which is characteristic of
      publication bias. Correcting for publication bias, we estimated the odds ratio to
      be 1.15 (95% CI 0.98-1.32, not significant). None of the published studies met
      all rules of genetic epidemiology. CONCLUSION: We conclude that a clinically
      significant association of the angiotensin-converting enzyme polymorphism with
      restenosis after percutaneous transluminal coronary revascularization in patients
      is unlikely. This meta-analysis provides evidence that the pooled estimate based
      on published literature, which favors an association, is distorted by publication
      bias. Hence, screening for this mutation in clinical practice is not justified.
      Future research should preferentially focus on gene-gene interaction and comply
      with the rules of genetic epidemiology.

PMID- 12422144
TI  - Cardiac repolarization: current knowledge, critical gaps, and new approaches to
      drug development and patient management.

PMID- 12422145
TI  - C-reactive protein levels on admission are associated with response to
      thrombolysis and prognosis after ST-segment elevation acute myocardial
      infarction.
AB  - BACKGROUND: Several studies have shown the independent association of high plasma
      C-reactive protein (CRP) levels with an adverse prognosis in patients with acute
      myocardial infarction. However, the possible association of plasma CRP levels
      with response to thrombolysis and short- and long-term cardiac mortality has not
      been investigated. The aim of this study was to evaluate these possible
      associations. METHODS: Three hundred nineteen consecutive patients who received
      intravenous thrombolysis because of ST-segment elevation acute myocardial
      infarction were prospectively studied. Patients were classified according to
      tertiles of plasma CRP levels on admission. RESULTS: Patients at the top tertile
      had a significantly lower incidence of complete ST-segment resolution (third vs
      first, P <.001, third vs second, P =.009) or Thrombolysis In Myocardial
      Infarction (TIMI) 3 flow in the infraction-related artery (third vs first, P
      <.001, third vs second, P =.02), more compromised left ventricular function
      (third vs first, P =.02, second vs third, P =.04), greater inhospital mortality
      (third vs first, P =.03, third vs second, P =.06), and greater 3-year cardiac
      mortality (third vs first, P =.01, third vs second, P =.07). CONCLUSIONS: Plasma
      levels of CRP on admission may be a predictor of reperfusion failure and of short
      and long-term prognosis in patients with ST-segment elevation acute myocardial
      infarction.

PMID- 12422146
TI  - Minimal ST-segment deviation: a simple, noninvasive method for identifying
      patients with a patent infarction-related artery after fibrinolytic
      administration.
AB  - BACKGROUND: Because rescue intervention may improve the outcome of patients who
      fail to achieve epicardial reperfusion after fibrinolytic administration for
      acute ST-elevation myocardial infarction (STEMI), simple noninvasive measures of
      infarction-related artery (IRA) patency are needed. The sum of ST-segment
      resolution (sum-STRES) has a high positive predictive value (PPV) for a patent
      IRA, but is quite time-consuming. METHODS: We retrospectively developed a very
      simple assessment that requires only the measurement of ST-segment deviation in a
      single electrocardiographic lead on a single electrocardiogram (ECG) 90 minutes
      after fibrinolytic administration. The ECG obtained immediately before
      fibrinolytic administration was reviewed as a means of selecting the single lead
      with the greatest ST-segment deviation. The absolute magnitude of ST deviation
      was measured in this lead on the 90-minute ECG. Minimal ST-segment deviation
      (MSTD) was defined as < or =1 mm ST deviation for inferior infarctions and < or
      =2 mm ST deviation for anterior infarctions. We compared the predictive value of
      this method with established but more complex ECG methods using data from the
      Thrombolysis In Myocardial Infarction (TIMI) 14 trial of low-dose fibrinolytic
      with full-dose glycoprotein IIb/IIIa inhibition. RESULTS: Of the 604 patients
      with an evaluable ECG and angiographic data, 383 (63%) had MSTD. The presence of
      MSTD had a positive predictive value (PPV) of 91% for a patent IRA (TIMI flow
      grade 2 or 3). Results were similar for inferior and anterior infarctions. MSTD
      was a means of identifying 90% of patients with complete sum-STRES. The PPV of
      MSTD compared favorably with that of standard measures of ST-segment resolution,
      but it required only a few seconds to perform. CONCLUSIONS: The presence of MSTD
      at 90 minutes after fibrinolytic administration indicates a very high likelihood
      of IRA patency. MSTD may be helpful in identifying patients with STEMI treated by
      means of fibrinolytics who could safely avoid emergent coronary angiography.

PMID- 12422147
TI  - Reduced microvascular and myocardial damage in patients with acute myocardial
      infarction and preinfarction angina.
AB  - BACKGROUND: After acute myocardial infarction, the presence of ischemic
      preconditioning as a result of preinfarction angina has a protective role,
      limiting necrosis extent and guaranteeing greater myocardial functional recovery.
      The relationship between preinfarction angina, microvascular reflow, and
      myocardial function is poorly known. We hypothesized that after acute myocardial
      infarction patients with preinfarction angina have both microvascular integrity
      and myocardial function preservation. METHODS AND RESULTS: In 51 patients with a
      first acute myocardial infarction, we noninvasively assessed microvascular
      perfusion and coronary flow reserve with intravenous myocardial contrast
      echocardiography and investigated myocardial contractile recovery with low-dose
      dobutamine and 90-day follow-up echocardiography. Typical angina was present in
      25 patients and absent in 26 patients during the 7 days preceding the myocardial
      infarction. Compared with those patients without preinfarction angina, patients
      with preinfarction angina showed a greater microvascular reflow extent and
      coronary flow reserve (respectively, 25.2% +/- 22.8% vs 48.3% +/- 23.3%, P <.05,
      and 3.44 +/- 0.75 vs 1.95 +/- 0.67, P <.0001), a better regional myocardial
      function, as expressed with wall motion score index in the risk area at
      dobutamine (1.67 +/- 0.61 vs 2.10 +/- 0.43, P <.005) and at follow-up (1.72 +/-
      0.56 vs 2.22 +/- 0.40, P <.0001) echocardiogram, despite being similar in the
      first echocardiogram (2.60 +/- 0.28 vs 2.63 +/- 0.28, P = not significant), and
      significantly less pronounced left ventricular dilation at follow-up. CONCLUSION:
      Presence of preinfarction angina, because of the preconditioning effect, reduces
      myocardial damage and favors myocardial viability, limiting left ventricular
      remodeling. This beneficial effect seems to be at least partly mediated by the
      more preserved microvascular integrity and functional vasodilation after acute
      myocardial infarction.

PMID- 12422148
TI  - A combination of troponin T and 12-lead electrocardiography: a valuable tool for
      early prediction of long-term mortality in patients with chest pain without ST
      segment elevation.
AB  - BACKGROUND: Electrocardiography (ECG) obtained on admission and a troponin T (tn
      T) level measured early after admission are simple and accessible methods for
      predicting outcome in patients with suspected unstable angina or myocardial
      infarction without persistent ST-elevations. However, there are few studies about
      the combination of these 2 methods as a means of predicting long-term outcome.
      METHODS: ECG was obtained on admission, and a tn-T level was analyzed on
      admission and after 6 hours in 710 consecutive patients admitted because of chest
      pain and no ST-elevations. Patients were observed for a median time of 40 months
      for death. RESULTS: ST-segment depressions > or =0.05 mV were present in 266
      patients (37%). These patients had a 9.7-fold increased risk of death, compared
      with patients with normal ECG results. Isolated T-Wave inversions or pathological
      signs other than ST-T changes were present in 196 patients (28%), who had a 4.5
      fold increased risk of death compared with patients who had normal ECG results.
      At 6 hours after admission, 169 patients (24%) had at least 1 sample of tn-T > or
      =0.10 microg/L, which resulted in an 3.7-fold increased risk of death. In a
      multivariate analysis, both ECG on admission and tn-T level came out as
      independent predictors of outcome. When these methods were combined, patients
      could be divided into low- (tn-T level <0.10 microg/L and no ST-segment
      depression), intermediate- (tn-T level > or =0.10 microg/L or ST-segment
      depression), and high-risk groups (tn-T level > or =0.10 microg/L and ST-segment
      depression). CONCLUSIONS: ECG and tn-T level are valuable tools to quickly risk
      stratify patients with chest pain. The combination of these methods is superior
      to either one alone.

PMID- 12422149
TI  - Elevation of serum levels of the anti-inflammatory cytokine interleukin-10 and
      decreased risk of coronary events in patients with unstable angina.
AB  - BACKGROUND: Inflammation is an important phenomenon in atherosclerotic plaque
      growth and in plaque instability. Cytokines are nuclear mediators in the
      inflammatory response; some have proinflammatory and others anti-inflammatory
      roles. Proinflammatory cytokines have been associated with worse outcomes in
      unstable angina. The aims of this study were to determine the role of the anti
      inflammatory cytokine interleukin (IL)-10 and the proinflammatory to anti
      inflammatory ratios in the short-term prognosis of patients with unstable angina.
      METHODS: Serum levels of proinflammatory cytokines IL-1beta, IL-6, and IL-8, and
      of the anti-inflammatory cytokine IL-10 were determined on admission in 127
      consecutive patients with severe unstable angina, and comparisons were made
      between patients who had cardiovascular events (death, nonfatal myocardial
      infarction, readmission for refractory angina) (n = 20) and patients without
      coronary events (n = 107) during a follow-up period of 3 months. RESULTS: IL-10
      levels were lower (0.67 +/- 1.13 vs 1.33 +/- 1.67 pg/mL, P =.04) and IL-8 levels
      were higher (3.6 +/- 2.41 vs 2.23 +/- 2.47 pg/mL, P =.029) in patients in whom
      cardiovascular events subsequently developed compared with those without events,
      with resulting higher proinflammatory to anti-inflammatory cytokine ratios in the
      former group, whereas no significant differences were seen in IL-1beta or IL-6
      levels between the groups, except for the subgroup of patients with prolonged
      rest angina and persistent electrocardiographic changes. A greater ratio of IL-8
      to IL-10 serum levels was observed in patients who had coronary events (28 +/- 25
      vs 12 +/- 21, P =.007). The risk of subsequent coronary events increased in
      patients in the highest quartile of proinflammatory to anti-inflammatory cytokine
      ratio (IL-8/IL-10). Patients in the highest quartile had a relative risk 3.8
      times higher than those in the lowest quartile (P =.01). CONCLUSIONS: Lower
      levels of IL-10, with higher proinflammatory to anti-inflammatory cytokine
      ratios, were observed on admission in patients with unstable angina who
      subsequently had cardiovascular events. Higher levels of the anti-inflammatory
      cytokine IL-10 may be needed to provide protection in unstable angina.

PMID- 12422150
TI  - Development and validation of a simple exercise test score for use in women with
      symptoms of suspected coronary artery disease.
AB  - BACKGROUND: Recently revised American College of Cardiology/American Heart
      Association guidelines for exercise electrocardiography (ExECG) have suggested
      that ExECG scores be used to assist in management decisions in patients with
      suspected coronary artery disease (CAD). METHODS: We used 442 women who underwent
      both ExECG and coronary angiography (CAD > or =1 lesion with > or =50% stenosis;
      CAD prevalence was 32%) to derive an ExECG score including clinical and ExECG
      variables. By use of logistic regression analysis, variables were selected and
      relative weights were determined. Variable codes multiplied by respective weights
      were summed to produce a final ExECG score. The score was validated in separate
      populations concerning angiographic as well as prognostic end points. RESULTS:
      Clinical variables selected and their weights included age (5), symptoms (2),
      diabetes (2), smoking (2), and estrogen status (1). ExECG variables selected and
      their weights included ST depression (2), exercise heart rate (4), and Duke
      Angina Index (3). For the validation group, score ranges are shown with the
      prevalence of CAD: <20 = 0/5 or 0%, 20-29 = 3/26 or 11%, 30-39 = 20/56 or 36%, 40
      49 = 33/81 or 41%, 50-59 = 24/49 or 49%, 60-69 = 22/32 or 69%, and >70 = 7/7 or
      100%. Frequency of death within 3 predetermined subgroups was as follows: low <40
      = 3/1237 (0.2%), intermediate 40-60 = 9/383 (2.3%), high >60 = 4/54(7%); P<.0001.
      CONCLUSION: A simple ExECG score was developed for use specifically in women.
      When evaluated in separate cohorts, the score stratified women with suspected
      coronary disease into groups with a gradually increasing frequency of coronary
      disease and death.

PMID- 12422151
TI  - Angina 1 year after percutaneous coronary intervention: a report from the NHLBI
      Dynamic Registry.
AB  - BACKGROUND: As percutaneous coronary intervention (PCI) is most commonly
      performed for relief of angina, it is important to identify factors associated
      with recurrence of anginal symptoms. METHODS: We examined symptoms at 1-year
      follow-up in 1755 consecutive NHLBI Dynamic Registry patients who underwent PCI
      in the setting of symptoms or acute infarction. RESULTS: At 1-year follow-up, 26%
      of patients reported angina in the previous 6 weeks. Younger patients and females
      reported more symptoms. History of coronary artery bypass graft (CABG) or PCI,
      prior myocardial infarction (MI), diabetes, graft disease, and extensive coronary
      artery disease (CAD) (>4 significant lesions) were also associated with follow-up
      angina. Patients receiving stents reported less angina (24% vs 29%, P <.05).
      Completely revascularized patients and those with residual single-vessel disease
      had comparable 1-year angina rates (23% both subgroups), while 32% of patients
      with residual multivessel CAD reported symptoms. Patients undergoing repeat PCI
      during follow-up reported more 1-year angina than others (34% vs 24%, P <.001),
      whereas those undergoing CABG after post-PCI hospitalization had less symptoms
      (15% vs 26%, P <.05). After adjustment for baseline symptom status and outcome of
      index PCI, residual CAD, and reintervention during follow-up, patient
      characteristics significantly predictive of angina included female sex, age <62
      years, and prior MI. CONCLUSIONS: While approximately three quarters of patients
      receiving PCI are angina-free at 1 year, females continue to have more symptoms,
      as do other subgroups including patients with history of MI or previous
      intervention. As these symptoms are associated with self-reported activity and
      quality of life limitation, evaluations of PCI should include angina as a key
      follow-up outcome.

PMID- 12422152
TI  - A rapid B-type natriuretic peptide assay accurately diagnoses left ventricular
      dysfunction and heart failure: a multicenter evaluation.
AB  - BACKGROUND: B-Type natriuretic peptide (BNP), a protein released from the left
      ventricle in response to volume expansion and pressure overload, has emerged as
      the first whole blood marker for the identification of individuals with
      congestive heart failure (CHF). OBJECTIVE: The purpose of this study was to
      assess the performance of a point-of-care assay to diagnose and evaluate the
      severity of CHF on the basis of the New York Heart Association (NYHA)
      classification system. METHODS: Through a prospective, multicenter trial, whole
      blood samples were collected from a total of 1050 inpatients, outpatients, and
      healthy control patients. Participants were divided into subgroups for BNP
      analysis: patients without cardiovascular CHF (n = 473), patients with
      hypertension and no cardiovascular disease (n = 168), NYHA class I CHF (n = 73),
      class II CHF (n = 135), class III CHF (n = 141), and class IV CHF (n = 60).
      RESULTS: Circulating BNP concentrations determined from the bedside assay
      increased with CHF severity, as determined by the NYHA classification system, but
      were only statistically significant (P <.001) between individuals with and
      without CHF. Individuals without CHF had a median BNP concentration of 9.29
      pg/mL. Median BNP values, with their corresponding interquartile ranges, for NYHA
      classification I through IV were 83.1 pg/mL (49.4-137 pg/mL), 235 pg/mL (137-391
      pg/mL), 459 pg/mL (200-871 pg/mL), and 1119 pg/mL (728->1300 pg/mL),
      respectively. With the use of a decision threshold of 100 pg/mL, the assay
      demonstrated 82% sensitivity and 99% specificity for distinguishing control
      patients and patients with CHF. CONCLUSIONS: BNP concentrations obtained from
      whole blood samples are useful in the diagnosis of CHF and staging the severity
      of the disease.

PMID- 12422153
TI  - Polymorphisms of the beta1-adrenergic receptor predict exercise capacity in heart
      failure.
AB  - BACKGROUND: Exercise performance in patients with congestive heart failure is
      partially dependent on cardiac beta1-adrenergic receptor (beta1AR) function.
      There are 2 common polymorphisms of the beta1AR gene that alter the encoded amino
      acids at positions 49 (Ser or Gly) and 389 (Gly or Arg) and alter receptor
      function in vitro. Their relevance to modification of cardiac function in heart
      failure is not known. METHODS: Exercise testing was performed in 263 patients
      with idiopathic or ischemic cardiomyopathy (left ventricular ejection fraction
      approximately 25%). Potential associations were sought between beta1AR genotypes
      and the primary outcome variables of peak oxygen consumption (VO2), heart rate
      response, and exercise time. RESULTS: The major determinants of exercise capacity
      were the polymorphisms at position 389, where patients homozygous for Gly389 had
      significantly lower peak VO2 compared with those with Arg389 (14.5 +/- 0.6 vs
      17.7 +/- 0.4 mL/kg/min, P =.006), despite similar clinical characteristics
      including left ventricular ejection fraction. Consistent with a gene dose
      response, heterozygosity was associated with an intermediate response (16.9 +/-
      0.6 mL/kg/min, P <.05). When position 49 genotypes were included, a graded
      relationship between the 5 2-locus haplotypes and VO2 was found. Two haplotypes
      displayed the most divergent peak VO2: homozygous Gly389/Ser49, and homozygous
      Arg389/Gly49 carriers (14.4 +/- 0.5 vs 18.2 +/- 0.8 mL/kg/min, P =.001). Genotype
      did not predict the heart rate response. The above results were independent of
      beta-blocker or other medication use, left ventricular ejection fraction, beta2AR
      genotype, or other demographic and clinical characteristics. CONCLUSION: beta1AR
      polymorphisms are a significant determinant of exercise capacity in patients with
      congestive heart failure. Early identification, by genetic testing for these
      polymorphisms, of heart failure patients at risk for development of depressed
      exercise capacity may be useful for initiation of specific therapy tailored to
      genotype.

PMID- 12422154
TI  - Effect of thalidomide in patients with chronic heart failure.
AB  - BACKGROUND: Congestive heart failure (CHF) is characterized by enhanced immune
      activation, which possibly plays a pathogenic role in this disorder. We therefore
      examined whether immunomodulation with thalidomide could improve cardiac
      performance in patients with CHF. METHODS: Nine patients with chronic symptomatic
      CHF and left ventricular ejection fraction (LVEF) <40%, who were receiving
      "optimal" conventional cardiovascular treatment, were given 200 mg thalidomide
      daily in an open design for a period of 6 weeks. Tumor necrosis factor (TNF)
      alpha and LVEF were measured at baseline and on completion of the study. RESULTS:
      Two patients withdrew because of side effects. Sedation was common and required
      dose reduction in 6 of 7 patients completing the study. Plasma levels of TNF
      alpha were elevated at baseline compared with levels in healthy control patients,
      but decreased significantly from 33.9 +/- 10.1 pg/mL to 19.3 +/- 6.1 pg/mL during
      therapy (P <.05). LVEF increased in all patients from 26% +/- 9% to 34% +/- 10%
      at the end of the observation period (P <.05). CONCLUSIONS: In this pilot study,
      therapy with thalidomide in patients with CHF resulted in decreased TNF-alpha
      levels and increased cardiac performance. Although few patients were included,
      our results suggest that thalidomide should be further investigated as an
      immunomodulating agent in CHF.

PMID- 12422155
TI  - Transvenous internal cardioversion for atrial fibrillation: a randomized
      comparison between catheters with different coil length.
AB  - OBJECTIVES: The aim of this study was to evaluate the effects of 2 different
      right atrial electrode coil lengths on energy and voltage requirements for
      transvenous atrial cardioversion. METHODS: Twenty-six patients (mean age 61 +/-
      11 years) with chronic persistent atrial fibrillation (AF) (mean duration 11 +/-
      10 months) underwent transvenous cardioversion. A 6F catheter with a 5.5-cm coil
      was positioned in the coronary sinus. Another catheter with either a 5.5-cm or an
      8-cm coil was positioned along the lateral wall of the right atrium, according to
      a randomized allocation. R wave-synchronized biphasic shocks were delivered
      according to a step-up protocol. After cardioversion of baseline AF, AF was
      reinduced, the right atrial catheter was substituted, and cardioversion was
      repeated with the alternative right atrial coil. RESULTS: Successful
      cardioversion was obtained in all of the patients. Leading edge voltage of
      effective shocks was significantly lower when catheters with an 8-cm coil in
      right atrium were used compared with the alternative 5-cm coil catheters (301 +/-
      80 volts vs 340 +/- 78 volts, P <.001), and delivered energy (6.75 +/- 4.25
      joules vs 7.86 +/- 4.29 joules, P =.043) and shock impedance (60 +/- 9 ohm vs 66
      +/- 10 ohm, P <.001) were lower. Moreover, shock-induced discomfort, evaluated by
      assessment of pain score, was reduced (3.69 +/- 1.09 vs 4.12 +/- 0.99, P =.035).
      CONCLUSIONS: The use of a longer right atrial coil results in lower shock
      impedance, lower energy and voltage requirements, and lower discomfort during
      transvenous atrial cardioversion. The results of the current study are of value
      either for transvenous internal cardioversion of chronic persistent AF or for
      implantable atrial defibrillators.

PMID- 12422156
TI  - Sex differences in QTc interval and QT dispersion: dynamics during exercise and
      recovery in healthy subjects.
AB  - BACKGROUND: Sex differences have been described in resting cardiac repolarization
      and susceptibility to torsade de pointes in humans. This study compares the QT
      interval and QT-dispersion dynamics during exercise and recovery between healthy
      men and women. METHODS: Twenty healthy subjects (10 males aged 30 +/- 4 years, 10
      females aged 31 +/- 11 years) underwent symptom-limited bicycle ergometry
      followed by a 10-minute recovery period. Digital 12-lead electrocardiograms (ECG)
      were recorded every 10 seconds during exercise and recovery. For each lead, the
      QTp interval (Q onset to T peak) was automatically measured by use of QT Guard
      (GE Marquette, Milwaukee, Wis). QTp dispersion was defined as the difference
      between the maximum and minimum QTp for each ECG. To quantify QT dynamics, we fit
      the QTp in lead V(3) (QTpV(3)) versus cycle length (CL) relationship to a
      quadratic function during exercise and recovery with nonlinear regression
      analysis. Similar regression analysis was performed for the QTp dispersion versus
      CL relationship. RESULTS: At baseline, QTpcV(3) was longer in women than in men
      (338 +/- 25 vs 278 +/- 15 ms, P <.0001), but QTp dispersion was similar (35 +/-
      18 vs 41 +/- 19 ms). At peak exercise, QT dispersion decreased compared with
      baseline in both men and women. During exercise and recovery, women had a steeper
      QTpV(3)-CL relationship. QTpV(3) hysteresis, a measure of the exercise and
      recovery QTpV(3)-CL curve separation, was greater in women than in men when
      measured 1 minute into recovery (33 +/- 20 vs 6 +/- 8 ms, P <.001). No sex
      difference in QTp-dispersion-rate adaptation was observed during exercise or
      recovery. CONCLUSIONS: Healthy women exhibit greater QT-interval-rate adaptation
      during both exercise and recovery than men, resulting in more QT-interval
      hysteresis. Greater QT prolongation during decelerating heart rates in recovery
      may play a role in increasing proarrhythmia risk in women.

PMID- 12422157
TI  - Assessment of residual myocardial viability in regions with chronic
      electrocardiographic Q-wave infarction.
AB  - BACKGROUND: Q waves on the electrocardiogram are often considered to be
      reflective of irreversibly scarred myocardium due to antecedent transmural
      myocardial infarction. However, there are some indications that residual viable
      tissue may be present in Q-wave-infarcted regions. It is clinically relevant to
      know how many Q-wave regions contain viable tissue because these patients may
      benefit from revascularization in terms of improvement of function and long-term
      survival. METHODS: Patients (n = 150) with chronic electrocardiographic Q-wave
      infarction, heart failure symptoms, and chronic coronary artery disease underwent
      dobutamine-atropine stress echocardiography to assess myocardial viability.
      Residual viability in regions with Q-wave infarction was considered present when
      the end-diastolic wall thickness (EDWT) was >6 mm and the response during
      dobutamine infusion indicated viable tissue. RESULTS: Baseline echocardiography
      revealed 517 dysfunctional myocardial regions; 202 of the dysfunctional regions
      were related to Q waves on the electrocardiogram and the other 315 dysfunctional
      regions were not. EDWT was < or =6 mm in 13 regions with a Q wave on the
      electrocardiogram, with only 1 region exhibiting viable tissue during dobutamine
      stress echocardiography. EDWT was >6 mm in 189 regions with a Q wave, with 118
      (62%) having viable tissue on dobutamine stress echocardiography. In 6
      dysfunctional regions without a Q wave, EDWT was < or =6 mm, with all being
      nonviable on dobutamine stress echocardiography; of the 309 regions without a Q
      wave and EDWT >6 mm, 204 (66%) exhibited viability on dobutamine stress
      echocardiography. CONCLUSIONS: Fifty-eight percent of dysfunctional regions
      related to chronic Q waves were viable according to the combined information of
      EDWT and dobutamine stress echocardiography. EDWT </=6 mm virtually excludes
      viability; regions with EDWT >6 mm need additional testing to detect or exclude
      viability.

PMID- 12422158
TI  - Characterization of the warm-up phenomenon in patients with coronary artery
      disease.
AB  - BACKGROUND: The warm-up phenomenon, that is, attenuation of myocardial ischemia
      during repeated physical exercise, has been demonstrated in numerous studies.
      However, its duration and underlying factors have not been properly studied in
      patients with coronary artery disease. METHODS: Fifty-two patients with stable
      angina pectoris and previous positive stress testing underwent cardiac
      catheterization and 2 successive exercise tests randomly separated by resting
      periods of 15, 30, 60, or 120 minutes (groups 1-4). RESULTS: The percentage of
      patients demonstrating the warm-up phenomenon was 85%, 31%, 31%, and 46% in
      groups 1 through 4, respectively (P =.018). The differences in the parameters
      (test 2 to test 1) registered during exercise tests were 28.1 +/- 7.1, 3.5 +/-
      5.8, -4.9 +/- 4.8, and 4.9 +/- 5.1 (P =.003) for the double product (beats/min x
      mm Hg. 100) at 0.1 mV ST depression; 1.1 +/- 0.2, 0.2 +/- 0.2, 0.2 +/- 0.2, and
      0.2 +/- 0.2 (P =.004) for the time (min) to 0.1 mV ST depression; -3.4 +/- 1.2,
      0.5 +/- 0.7, -0.3 +/- 0.8, and -0.3 +/- 0.3 (P =.032) for the ST/HR-slope
      (microV/beats/min); and -0.3 +/- 0.2, 0.1 +/- 0.1, -0.1 +/- 0.1, and -0.7 +/- 0.4
      (P =.047) for the ischemic burden (mV x min) in groups 1 through 4, respectively.
      The patients having angiographically less severe disease showed significantly
      better ischemia adaptation (P =.012), but there was no correlation between the
      extent of adaptation and other clinical or angiographic findings. CONCLUSIONS:
      The warm-up phenomenon is commonly encountered in patients with coronary artery
      disease, although the protection appears to wane relatively quickly. The
      adaptation appears to be markedly better in patients with less severe disease.

PMID- 12422159
TI  - Effectiveness of percutaneous device occlusion for atrial septal defect in adult
      patients with pulmonary hypertension.
AB  - BACKGROUND: Adult patients with atrial septal defect (ASD) and pulmonary
      hypertension have a more advanced degree of disease, frequently having functional
      class deterioration and atrial arrhythmias when they are aged >40 years. Surgery
      at this age prolongs life expectancy and limits functional deterioration.
      Although percutaneous ASD device occlusion is an accepted alternative to surgery,
      there is limited information on the immediate and long-term effects of device
      occlusion in middle-aged and elderly patients with ASD and pulmonary
      hypertension. METHODS: From a total of 101 patients with secundum ASD who were
      receiving treatment with percutaneous device occlusion, we selected for analysis
      29 adult patients (mean age 56 +/- 14 years) with a baseline peak pulmonary
      pressure of >40 mm Hg (mean 65 +/- 23 mm Hg). Three of the patients had
      suprasystemic pulmonary pressure and a bidirectional shunt. Six patients were
      asymptomatic at treatment. The remaining 23 had different degrees of dyspnea; 14
      of them had an advanced New York Heart Association functional class (III-IV).
      Twelve patients had chronic atrial fibrillation. At cardiac catheterization, the
      mean ratio of pulmonary to systemic flow was 1.8 +/- 0.5, and the pulmonary-to
      systemic pressure ratio was 0.66 +/- 0.22. The mean diameter of the defect, as
      evaluated by the stretching balloon method, was 26 +/- 7 mm. All patients
      received an Amplatzer septal occluder (Golden Valley, Minn). Seven patients had
      combined therapeutic procedures for associated anomalies before the implant:
      mitral balloon valvuloplasty (n = 1), stent coronary revascularization (n = 1),
      stent in pulmonary vein stenosis (n = 1), and internal catheter defibrillation (n
      = 4). After treatment, patients were followed up by clinical and
      echocardiographic Doppler studies every 6 months. RESULTS: Immediately after the
      implantation, the peak systolic pulmonary pressure significantly decreased to 54
      +/- 21 mm Hg (P <.001). A clear improvement in functional status was observed
      after the treatment in all symptomatic patients, especially in those with
      refractory heart failure. There were no major complications. Six patients who had
      atrial fibrillation at baseline study recovered to a stable sinus rhythm after
      treatment, and it was maintained at discharge. Complete ASD occlusion by
      echocardiographic Doppler at discharge was observed in 28 patients (97%). After a
      mean follow up of 21 +/- 14 months, clinical improvement persisted in all
      previously symptomatic patients, and the peak systolic pulmonary pressure,
      obtained by echocardiographic Doppler, further decreased to 31 +/- 11 mm Hg (P
      <.001) compared with baseline and immediately after hemodynamic measurements.
      CONCLUSIONS: Our findings suggest that percutaneous device occlusion of ASD in
      adult patients with pulmonary hypertension is safe and effective and provides
      significant and prolonged relief.

PMID- 12422161
TI  - Chelation therapy for coronary heart disease.

PMID- 12422163
TI  - Prevalence of Chlamydia pneumoniae in nonrheumatic stenotic aortic valves.

PMID- 12422165
TI  - Relationship between hematocrit, primary hemostasis, and cardiovascular disease
      in athletes.

PMID- 12422164
TI  - Effect of hydroxymethyl glutaryl coenzyme A reductase inhibitors on serum C
      reactive protein levels: possible implications.

PMID- 12422166
TI  - Private embryos, public policy.

PMID- 12422167
TI  - Reform by stealth.

PMID- 12422168
TI  - Gene centre chips in with better route to microarrays.

PMID- 12422170
TI  - US biologists wary of move to view embryos as human beings.

PMID- 12422171
TI  - Developing countries to gain from carbon-trading fund.

PMID- 12422172
TI  - Academies back Smithsonian's calls for direct funds.

PMID- 12422173
TI  - Theses spark twin dilemma for physicists.

PMID- 12422174
TI  - Health initiative gets warm welcome.

PMID- 12422175
TI  - Mussel model calls for cash to combat invading species.

PMID- 12422176
TI  - Japanese physicists beam as meson production soars.

PMID- 12422177
TI  - Hostage deaths put gas weapons in spotlight.

PMID- 12422178
TI  - Controversial HIV study puts whole-cat work on pause.

PMID- 12422179
TI  - Space science: out of this world.

PMID- 12422180
TI  - Science education: put your lab in a different class.

PMID- 12422181
TI  - Sharp eyes saw through early effort to fake prints.

PMID- 12422182
TI  - Slow-moving journals hinder conservation efforts.

PMID- 12422183
TI  - Science and government share anti-terrorist goals.

PMID- 12422184
TI  - Peer review to select academic job applicants.

PMID- 12422185
TI  - The future of electronic data.

PMID- 12422186
TI  - Access to scientific literature.

PMID- 12422197
TI  - Toxic oxygen: the radical life-giver.

PMID- 12422198
TI  - Carbon cycle: the wildfire factor.

PMID- 12422199
TI  - What is a naked retina good for?

PMID- 12422200
TI  - Twinkle, twinkle, neutron star.

PMID- 12422201
TI  - Protein folding: with a little help...

PMID- 12422203
TI  - Plant ecology: express delivery by bat.

PMID- 12422204
TI  - Condensed-matter physics: magnetic frustration squeezed out.

PMID- 12422205
TI  - Astronomy: close encounters of the tidal kind.

PMID- 12422206
TI  - Tackling multiple sclerosis.

PMID- 12422207
TI  - Suction feeding by a tiny predatory tadpole.

PMID- 12422208
TI  - An ATP-gated ion channel at the cell nucleus.

PMID- 12422209
TI  - Structure of a T7 RNA polymerase elongation complex at 2.9 A resolution.
AB  - The single-subunit bacteriophage T7 RNA polymerase carries out the transcription
      cycle in an identical manner to that of bacterial and eukaryotic multisubunit
      enzymes. Here we report the crystal structure of a T7 RNA polymerase elongation
      complex, which shows that incorporation of an 8-base-pair RNA-DNA hybrid into the
      active site of the enzyme induces a marked rearrangement of the amino-terminal
      domain. This rearrangement involves alternative folding of about 130 residues and
      a marked reorientation (about 130 degrees rotation) of a stable core subdomain,
      resulting in a structure that provides elements required for stable transcription
      elongation. A wide opening on the enzyme surface that is probably an RNA exit
      pathway is formed, and the RNA-DNA hybrid is completely buried in a newly formed,
      deep protein cavity. Binding of 10 base pairs of downstream DNA is stabilized
      mostly by long-distance electrostatic interactions. The structure implies
      plausible mechanisms for the various phases of the transcription cycle, and
      reveals important structural similarities with the multisubunit RNA polymerases.

PMID- 12422210
TI  - Gravitationally redshifted absorption lines in the X-ray burst spectra of a
      neutron star.
AB  - The fundamental properties of neutron stars provide a direct test of the equation
      of state of cold nuclear matter, a relationship between pressure and density that
      is determined by the physics of the strong interactions between the particles
      that constitute the star. The most straightforward method of determining these
      properties is by measuring the gravitational redshift of spectral lines produced
      in the neutron star photosphere. The equation of state implies a mass-radius
      relation, while a measurement of the gravitational redshift at the surface of a
      neutron star provides a direct constraint on the mass-to-radius ratio. Here we
      report the discovery of significant absorption lines in the spectra of 28 bursts
      of the low-mass X-ray binary EXO0748-676. We identify the most significant
      features with the Fe XXVI and XXV n = 2-3 and O VIII n = 1-2 transitions, all
      with a redshift of z = 0.35, identical within small uncertainties for the
      respective transitions. For an astrophysically plausible range of masses (M
      approximately 1.3-2.0 solar masses; refs 2-5), this value is completely
      consistent with models of neutron stars composed of normal nuclear matter, while
      it excludes some models in which the neutron stars are made of more exotic
      matter.

PMID- 12422211
TI  - Pressure-induced crystallization of a spin liquid.
AB  - Liquids are expected to crystallize at low temperature. The only exception is
      helium, which can remain liquid at 0 K, owing to quantum fluctuations. Similarly,
      the atomic magnetic moments (spins) in a magnet are expected to order at a
      temperature scale set by the Curie-Weiss temperature theta(CW) (ref. 3).
      Geometrically frustrated magnets represent an exception. In these systems, the
      pairwise spin interactions cannot be simultaneously minimized because of the
      lattice symmetry. This can stabilize a liquid-like state of short-range-ordered
      fluctuating moments well below theta(CW) (refs 5-7). Here we use neutron
      scattering to observe the spin liquid state in a geometrically frustrated system,
      Tb(2)Ti(2)O(7), under conditions of high pressure (approximately 9 GPa) and low
      temperature (approximately 1 K). This compound is a three-dimensional magnet with
      theta(CW) = -19 K, where the negative value indicates antiferromagnetic
      interactions. At ambient pressure Tb(2)Ti(2)O(7) remains in a spin liquid state
      down to at least 70 mK (ref. 8). But we find that, under high pressure, the spins
      start to order or 'crystallize' below 2.1 K, with antiferromagnetic order
      coexisting with liquid-like fluctuations. These results indicate that a spin
      liquid/solid mixture can be induced by pressure in geometrically frustrated
      systems.

PMID- 12422212
TI  - Epitaxial core-shell and core-multishell nanowire heterostructures.
AB  - Semiconductor heterostructures with modulated composition and/or doping enable
      passivation of interfaces and the generation of devices with diverse functions.
      In this regard, the control of interfaces in nanoscale building blocks with high
      surface area will be increasingly important in the assembly of electronic and
      photonic devices. Core-shell heterostructures formed by the growth of crystalline
      overlayers on nanocrystals offer enhanced emission efficiency, important for
      various applications. Axial heterostructures have also been formed by a one
      dimensional modulation of nanowire composition and doping. However, modulation of
      the radial composition and doping in nanowire structures has received much less
      attention than planar and nanocrystal systems. Here we synthesize silicon and
      germanium core-shell and multishell nanowire heterostructures using a chemical
      vapour deposition method applicable to a variety of nanoscale materials. Our
      investigations of the growth of boron-doped silicon shells on intrinsic silicon
      and silicon-silicon oxide core-shell nanowires indicate that homoepitaxy can be
      achieved at relatively low temperatures on clean silicon. We also demonstrate the
      possibility of heteroepitaxial growth of crystalline germanium-silicon and
      silicon-germanium core-shell structures, in which band-offsets drive hole
      injection into either germanium core or shell regions. Our synthesis of core
      multishell structures, including a high-performance coaxially gated field-effect
      transistor, indicates the general potential of radial heterostructure growth for
      the development of nanowire-based devices.

PMID- 12422213
TI  - The amount of carbon released from peat and forest fires in Indonesia during
      1997.
AB  - Tropical peatlands are one of the largest near-surface reserves of terrestrial
      organic carbon, and hence their stability has important implications for climate
      change. In their natural state, lowland tropical peatlands support a luxuriant
      growth of peat swamp forest overlying peat deposits up to 20 metres thick.
      Persistent environmental change-in particular, drainage and forest clearing
      threatens their stability, and makes them susceptible to fire. This was
      demonstrated by the occurrence of widespread fires throughout the forested
      peatlands of Indonesia during the 1997 El Nino event. Here, using satellite
      images of a 2.5 million hectare study area in Central Kalimantan, Borneo, from
      before and after the 1997 fires, we calculate that 32% (0.79 Mha) of the area had
      burned, of which peatland accounted for 91.5% (0.73 Mha). Using ground
      measurements of the burn depth of peat, we estimate that 0.19-0.23 gigatonnes
      (Gt) of carbon were released to the atmosphere through peat combustion, with a
      further 0.05 Gt released from burning of the overlying vegetation. Extrapolating
      these estimates to Indonesia as a whole, we estimate that between 0.81 and 2.57
      Gt of carbon were released to the atmosphere in 1997 as a result of burning peat
      and vegetation in Indonesia. This is equivalent to 13-40% of the mean annual
      global carbon emissions from fossil fuels, and contributed greatly to the largest
      annual increase in atmospheric CO(2) concentration detected since records began
      in 1957 (ref. 1).

PMID- 12422214
TI  - The origin of geomagnetic jerks.
AB  - Geomagnetic jerks, which in the second half of the twentieth century occurred in
      1969 (refs 1, 2), 1978 (refs 3, 4), 1991 (ref. 5) and 1999 (ref. 6), are abrupt
      changes in the second time-derivative (secular acceleration) of the Earth's
      magnetic field. Jerks separate periods of almost steady secular acceleration, so
      that the first time-derivative (secular variation) appears as a series of
      straight-line segments separated by geomagnetic jerks. The fact that they
      represent a reorganization of the secular variation implies that they are of
      internal origin (as has been established through spherical harmonic analysis),
      and their short timescale implies that they are due to a change in the fluid flow
      at the surface of the Earth's core (as has also been established through mapping
      the time-varying flow at the core surface). However, little is understood of
      their physical origin. Here we show that geomagnetic jerks can be explained by
      the combination of a steady flow and a simple time-varying, axisymmetric,
      equatorially symmetric, toroidal zonal flow. Such a flow is consistent with
      torsional oscillations in the Earth's core, which are simple oscillatory flows in
      the core that are expected on theoretical grounds, and observed in both core flow
      models and numerical dynamo models.

PMID- 12422215
TI  - Adaptive visual metamorphosis in a deep-sea hydrothermal vent crab.
AB  - Hydrothermal vents along the mid-ocean ridges host ephemeral ecosystems of
      diverse endemic fauna including several crustacean species, some of which undergo
      planktonic development as larvae up to 1,000 m above and 100 km away from the
      vents. Little is known about the role of vision in the life history of vent
      fauna. Here we report that planktonic zoea larvae of the vent crab Bythograea
      thermydron possess image-forming compound eyes with a visual pigment sensitive to
      the blue light of mesopelagic waters. As they metamorphose and begin to descend
      to and settle at the vents, they lose their image-forming optics and develop high
      sensitivity naked-retina eyes. The spectral absorbance of the visual pigment in
      these eyes shifts towards longer wavelengths from larva to postlarva to adult.
      This progressive visual metamorphosis trades imaging for increased sensitivity,
      and changes spectral sensitivity from the blue wavelengths of the larval
      environment towards the dim, longer wavelengths produced in the deeper
      bathypelagic vent environment of the adults. As hydrothermal vents produce light,
      vision may supplement thermal and chemical senses to orient postlarval settlement
      at vent sites.

PMID- 12422216
TI  - Neurons in medial prefrontal cortex signal memory for fear extinction.
AB  - Conditioned fear responses to a tone previously paired with a shock diminish if
      the tone is repeatedly presented without the shock, a process known as
      extinction. Since Pavlov it has been hypothesized that extinction does not erase
      conditioning, but forms a new memory. Destruction of the ventral medial
      prefrontal cortex, which consists of infralimbic and prelimbic cortices, blocks
      recall of fear extinction, indicating that medial prefrontal cortex might store
      long-term extinction memory. Here we show that infralimbic neurons recorded
      during fear conditioning and extinction fire to the tone only when rats are
      recalling extinction on the following day. Rats that froze the least showed the
      greatest increase in infralimbic tone responses. We also show that conditioned
      tones paired with brief electrical stimulation of infralimbic cortex elicit low
      freezing in rats that had not been extinguished. Thus, stimulation resembling
      extinction-induced infralimbic tone responses is able to simulate extinction
      memory. We suggest that consolidation of extinction learning potentiates
      infralimbic activity, which inhibits fear during subsequent encounters with fear
      stimuli.

PMID- 12422217
TI  - P75 interacts with the Nogo receptor as a co-receptor for Nogo, MAG and OMgp.
AB  - In inhibiting neurite outgrowth, several myelin components, including the
      extracellular domain of Nogo-A (Nogo-66), oligodendrocyte myelin glycoprotein
      (OMgp) and myelin-associated glycoprotein (MAG), exert their effects through the
      same Nogo receptor (NgR). The glycosyl phosphatidylinositol (GPI)-anchored nature
      of NgR indicates the requirement for additional transmembrane protein(s) to
      transduce the inhibitory signals into the interior of responding neurons. Here,
      we demonstrate that p75, a transmembrane protein known to be a receptor for the
      neurotrophin family of growth factors, specifically interacts with NgR. p75 is
      required for NgR-mediated signalling, as neurons from p75 knockout mice are no
      longer responsive to myelin and to each of the known NgR ligands. Blocking the
      p75-NgR interaction also reduces the activities of these inhibitors. Moreover, a
      truncated p75 protein lacking the intracellular domain, when overexpressed in
      primary neurons, attenuates the same set of inhibitory activities, suggesting
      that p75 is a signal transducer of the NgR-p75 receptor complex. Thus,
      interfering with p75 and its downstream signalling pathways may allow lesioned
      axons to overcome most of the inhibitory activities associated with central
      nervous system myelin.

PMID- 12422218
TI  - The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses
      paralysis in central nervous system autoimmune disease.
AB  - Statins, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors,
      which are approved for cholesterol reduction, may also be beneficial in the
      treatment of inflammatory diseases. Atorvastatin (Lipitor) was tested in chronic
      and relapsing experimental autoimmune encephalomyelitis, a CD4(+) Th1-mediated
      central nervous system (CNS) demyelinating disease model of multiple sclerosis.
      Here we show that oral atorvastatin prevented or reversed chronic and relapsing
      paralysis. Atorvastatin induced STAT6 phosphorylation and secretion of Th2
      cytokines (interleukin (IL)-4, IL-5 and IL-10) and transforming growth factor
      (TGF)-beta. Conversely, STAT4 phosphorylation was inhibited and secretion of Th1
      cytokines (IL-2, IL-12, interferon (IFN)-gamma and tumour necrosis factor (TNF)
      alpha) was suppressed. Atorvastatin promoted differentiation of Th0 cells into
      Th2 cells. In adoptive transfer, these Th2 cells protected recipient mice from
      EAE induction. Atorvastatin reduced CNS infiltration and major histocompatibility
      complex (MHC) class II expression. Treatment of microglia inhibited IFN-gamma
      inducible transcription at multiple MHC class II transactivator (CIITA) promoters
      and suppressed class II upregulation. Atorvastatin suppressed IFN-gamma-inducible
      expression of CD40, CD80 and CD86 co-stimulatory molecules. l-Mevalonate, the
      product of HMG-CoA reductase, reversed atorvastatin's effects on antigen
      presenting cells (APC) and T cells. Atorvastatin treatment of either APC or T
      cells suppressed antigen-specific T-cell activation. Thus, atorvastatin has
      pleiotropic immunomodulatory effects involving both APC and T-cell compartments.
      Statins may be beneficial for multiple sclerosis and other Th1-mediated
      autoimmune diseases.

PMID- 12422219
TI  - Recruitment and regulation of phosphatidylinositol phosphate kinase type 1 gamma
      by the FERM domain of talin.
AB  - Membrane phosphoinositides control a variety of cellular processes through the
      recruitment and/or regulation of cytosolic proteins. One mechanism ensuring
      spatial specificity in phosphoinositide signalling is the targeting of enzymes
      that mediate their metabolism to specific subcellular sites. Phosphatidylinositol
      phosphate kinase type 1 gamma (PtdInsPKI gamma) is a phosphatidylinositol-4
      phosphate 5-kinase that is expressed at high levels in brain, and is concentrated
      at synapses. Here we show that the predominant brain splice variant of PtdInsPKI
      gamma (PtdInsPKI gamma-90) binds, by means of a short carboxy-terminal peptide,
      to the FERM domain of talin, and is strongly activated by this interaction.
      Talin, a principal component of focal adhesion plaques, is also present at
      synapses. PtdInsPKI gamma-90 is expressed in non-neuronal cells, albeit at much
      lower levels than in neurons, and is concentrated at focal adhesion plaques,
      where phosphatidylinositol-4,5-bisphosphate has an important regulatory role.
      Overexpression of PtdInsPKI gamma-90, or expression of its C-terminal domain,
      disrupts focal adhesion plaques, probably by local disruption of normal
      phosphoinositide balance. These findings define an interaction that has a
      regulatory role in cell adhesion and suggest new similarities between molecular
      interactions underlying synaptic junctions and general mechanisms of cell
      adhesion.

PMID- 12422220
TI  - Type I gamma phosphatidylinositol phosphate kinase targets and regulates focal
      adhesions.
AB  - The ability of cells to form cell contacts, adhere to the extracellular matrix,
      change morphology, and migrate is essential for development, wound healing,
      metastasis, cell survival and the immune response. These events depend on the
      binding of integrin to the extracellular matrix, and assembly of focal adhesions,
      which are complexes comprising scaffolding and signalling proteins organized by
      adhesion to the extracellular matrix. Phosphatidylinositol-4,5-bisphosphate
      (PtdIns(4,5)P(2)) regulates interactions between these proteins, including the
      interaction of vinculin with actin and talin. The binding of talin to beta
      integrin is strengthened by PtdIns(4,5)P(2), suggesting that the basis of focal
      adhesion assembly is regulated by this lipid mediator. Here we show that the type
      I phosphatidylinositol phosphate kinase isoform-gamma 661 (PIPKI gamma 661), an
      enzyme that makes PtdIns(4,5)P(2), is targeted to focal adhesions by an
      association with talin. PIPKI gamma 661 is tyrosine phosphorylated by focal
      adhesion associated kinase signalling, increasing both the activity of
      phosphatidylinositol phosphate kinase and its association with talin. This
      defines a mechanism for spatial generation of PtdIns(4,5)P(2) at focal adhesions.

PMID- 12422221
TI  - Nbs1 is essential for DNA repair by homologous recombination in higher vertebrate
      cells.
AB  - Double-strand breaks occur during DNA replication and are also induced by
      ionizing radiation. There are at least two pathways which can repair such breaks:
      non-homologous end joining and homologous recombination (HR). Although these
      pathways are essentially independent of one another, it is possible that the
      proteins Mre11, Rad50 and Xrs2 are involved in both pathways in Saccharomyces
      cerevisiae. In vertebrate cells, little is known about the exact function of the
      Mre11-Rad50-Nbs1 complex in the repair of double-strand breaks because Mre11- and
      Rad50-null mutations are lethal. Here we show that Nbs1 is essential for HR
      mediated repair in higher vertebrate cells. The disruption of Nbs1 reduces gene
      conversion and sister chromatid exchanges, similar to other HR-deficient mutants.
      In fact, a site-specific double-strand break repair assay showed a notable
      reduction of HR events following generation of such breaks in Nbs1-disrupted
      cells. The rare recombinants observed in the Nbs1-disrupted cells were frequently
      found to have aberrant structures, which possibly arise from unusual crossover
      events, suggesting that the Nbs1 complex might be required to process
      recombination intermediates.

PMID- 12422222
TI  - Structure of a protein determined by solid-state magic-angle-spinning NMR
      spectroscopy.
AB  - The determination of a representative set of protein structures is a chief aim in
      structural genomics. Solid-state NMR may have a crucial role in structural
      investigations of those proteins that do not easily form crystals or are not
      accessible to solution NMR, such as amyloid systems or membrane proteins. Here we
      present a protein structure determined by solid-state magic-angle-spinning (MAS)
      NMR. Almost complete (13)C and (15)N resonance assignments for a micro
      crystalline preparation of the alpha-spectrin Src-homology 3 (SH3) domain formed
      the basis for the extraction of a set of distance restraints. These restraints
      were derived from proton-driven spin diffusion (PDSD) spectra of biosynthetically
      site-directed, labelled samples obtained from bacteria grown using [1,3
      (13)C]glycerol or [2-(13)C]glycerol as carbon sources. This allowed the
      observation of long-range distance correlations up to approximately 7 A. The
      calculated global fold of the alpha-spectrin SH3 domain is based on 286 inter
      residue (13)C-(13)C and six (15)N-(15)N restraints, all self-consistently
      obtained by solid-state MAS NMR. This MAS NMR procedure should be widely
      applicable to small membrane proteins that can be expressed in bacteria.

PMID- 12422224
TI  - Absolute comparison of simulated and experimental protein-folding dynamics.
AB  - Protein folding is difficult to simulate with classical molecular dynamics.
      Secondary structure motifs such as alpha-helices and beta-hairpins can form in
      0.1-10 micros (ref. 1), whereas small proteins have been shown to fold completely
      in tens of microseconds. The longest folding simulation to date is a single 1-
      micro s simulation of the villin headpiece; however, such single runs may miss
      many features of the folding process as it is a heterogeneous reaction involving
      an ensemble of transition states. Here, we have used a distributed computing
      implementation to produce tens of thousands of 5-20-ns trajectories (700 micros)
      to simulate mutants of the designed mini-protein BBA5. The fast relaxation
      dynamics these predict were compared with the results of laser temperature-jump
      experiments. Our computational predictions are in excellent agreement with the
      experimentally determined mean folding times and equilibrium constants. The rapid
      folding of BBA5 is due to the swift formation of secondary structure. The
      convergence of experimentally and computationally accessible timescales will
      allow the comparison of absolute quantities characterizing in vitro and in silico
      (computed) protein folding.

PMID- 12422227
TI  - Mice and humans: chromosome engineering and its application to functional
      genomics.
AB  - Functional modeling of human genes and diseases requires suitable mammalian model
      organisms. For its genetic malleability, the mouse is likely to continue to play
      a major role in defining basic genetic traits and complex pathological disorders.
      Recently, gene targeting techniques have been extended towards developing new
      engineering strategies for generating extensive lesions and rearrangements in
      mouse chromosomes. While these advances create new opportunities to address
      similar aberrations observed in human diseases, they also open new ways of
      scaling-up mutagenesis projects that try to catalogue and annotate cellular
      functions of mammalian genes.

PMID- 12422228
TI  - Molecular basis of inherited predispositions for tumors.
AB  - On the basis of literature data and own experience the authors review the current
      knowledge about the molecular basis of inherited predispositions for tumors. They
      hypothesize that in the near perspective 5-10 years studies using existing
      registry data/material and the latest novel technology will allow the
      identification of the molecular background for the majority of hereditary cancers
      which will have enormous practical consequences especially for the prevention of
      malignancies.

PMID- 12422229
TI  - Recognition and repair of DNA-cisplatin adducts.
AB  - Anticancer activity of cisplatin (cis-diamminedichloroplatinum) is believed to
      result from its interaction with DNA. The drug reacts with nucleophilic sites in
      DNA forming monoadducts as well as intra- and interstrand crosslinks. DNA
      cisplatin adducts are specifically recognized by several proteins. They can be
      divided into two classes. One constitutes proteins which recognize DNA damage as
      an initial step of the nucleotide excision and mismatch repair pathways. The
      other class contains proteins stabilizing cellular DNA-protein and protein
      protein complexes, including non-histone proteins from the HMG (high-mobility
      group) family. They specifically recognize 1,2-interstrand d(GpG) and d(ApG)
      crosslinks of DNA-cisplatin adducts and inhibit their repair. Many HMG-domain
      proteins can function as transcription factors, e.g. UBF, an RNA polymerase I
      transcription factor, the mammalian testis-determining factor SRY and the human
      mitochondrial transcription factor mtTFA. Moreover, it seems that some proteins,
      which probably recognize DNA-cisplatin adducts non-specifically, e.g. actin and
      other nuclear matrix proteins, can disturb the structural and functional
      organization of the nucleus and whole cell. The formation of complexes between
      DNA and proteins in the presence of cisplatin and the changes in the cell
      architecture may account for the drug cytotoxicity.

PMID- 12422230
TI  - NTPase/helicase of Flaviviridae: inhibitors and inhibition of the enzyme.
AB  - RNA nucleoside triphosphatases (NTPase)/helicases represent a large family of
      proteins that are ubiquitously distributed over a wide range of organisms. The
      enzymes play essential role in cell development and differentiation, and some of
      them are involved in transcription and replication of viral single-stranded RNA
      genomes. The enzymatic activities of a NTPase/helicase were also detected in the
      carboxyl-terminal non-structural protein 3 (NS3) of members of the Flaviviridae
      family. The crucial role of the enzyme for the virus life cycle was demonstrated
      in knock out experiments and by using NTPase/helicase specific inhibitors. This
      makes the enzyme an attractive target for development of Flaviviridae-specific
      antiviral therapies. This review will summarize our knowledge about the function
      and structure of the enzyme, update the spectrum of inhibitors of the enzymatic
      activities of the NTPase/helicase and describe the different mechanisms by which
      the compounds act. Some of the compounds reviewed herein could show potential
      utility as antiviral agents against Flaviviridae viruses.

PMID- 12422231
TI  - Increased expression of ribosomal protein S2 in liver tumors, posthepactomized
      livers, and proliferating hepatocytes in vitro.
AB  - The ribosomal protein S2 (RPS2) is encoded by a gene from the highly conserved
      mammalian repetitive gene family LLRep3. It participates in aminoacyl-transfer
      RNA binding to ribosome, potentially affecting the fidelity of mRNA translation.
      These studies were designed to measure the expression of RPS2 during increased
      cell proliferation. Using Western and Northern blot analyses, we found that the
      levels of RPS2 protein and its corresponding mRNA were higher in mouse
      hepatocellular carcinoma, in mouse livers after one-third partial hepatectomy,
      and in serum-starved cultured hepatocytes following serum treatment. Our study
      shows that the increased expression of RPS2 correlates with increased cell
      proliferation. However, whether the altered expression of this protein reflects
      its involvement in cellular proliferation or represents an associated phenomena
      is still a key question that needs to be explored.

PMID- 12422232
TI  - Optimisation of transfection conditions of CD34+ hematopoietic cells derived from
      human umbilical cord blood.
AB  - Human umbilical cord blood is frequently used as a source of transplantable
      hematopoietic cells and more recently as a target of gene therapy - a new
      approach for treatment of various disorders. The aim of our study was
      optimisation of the transfection conditions of cord blood-derived CD34(+)
      hematopoietic cells. Mononuclear cells fraction was isolated from cord blood
      samples by density gradient centrifugation. Subsequently, CD34(+) hematopoietic
      cells were separated on immunomagnetic MiniMACS columns. Pure population of
      CD34(+) cells was incubated in a serum free medium supplemented with
      thrombopoietin, stem cell factor and Flt-3 ligand for 48 h and then transfected
      with plasmid DNA carrying the enhanced version of green fluorescent protein
      (EGFP) as a reporter gene. We studied the influence of various pulse settings and
      DNA concentrations on the transfection efficiency, measured by flow cytometry as
      the fluorescence of target cells due to the expression of EGFP. The optimal
      settings were as follows: 4 mm cuvette, 1600 microF, 550 V/cm, and 10 microg of
      DNA per 500 microl. With these settings we obtained a high transfection frequency
      (41.2%) without a marked decrease of cell viability. An increase of the pulse
      capacitance and/or of DNA concentration resulted in a greater electroporation
      efficiency, but also in a decrease of cell viability. In conclusion, the results
      described here allow one to recommend electroporation as an efficient method of
      gene delivery into CD34(+) hematopoietic cells derived from human umbilical cord
      blood.

PMID- 12422233
TI  - Spectral properties of phthalocyanines incorporated into resting and stimulated
      human peripheral blood cells.
AB  - Human peripheral blood cells stimulated by phytohemagglutinin (which serve as a
      model of cancerous cells) and resting cells were incubated in dimethyl sulfoxide
      solutions of various phthalocyanines. In order to diminish the influence of
      atmospheric oxygen the cells were embedded in a polymer (polyvinyl alcohol) film.
      Fluorescence spectra of the samples were measured over two regions of excitation
      wavelengths: at 405 nm (predominant absorption of the cell material) and in the
      regions of strong absorption of phthalocyanines (at about 605 nm and 337 nm). The
      intrinsic emission of cell material became changed as a result both of cells'
      stimulation and of incubation of cells in dye solution. In most cases the
      stimulated cells when stained by dye exhibited higher long wavelength
      fluorescence intensity than resting cells. This suggests higher efficiency of dye
      incorporation into cancerous cells than into healthy cells. The absorption
      spectra of samples were also measured. The spectra of various phthalocyanines in
      incubation solvent, in polymer and in the cells embedded in polymer, were
      compared. The comparison of properties of the cells stimulated for different time
      periods enabled to establish the conditions of stimulation creating a population
      of cells incorporating a large number of sensitizing molecules.

PMID- 12422235
TI  - The effect of Arg209 to Lys mutation in mouse thymidylate synthase.
AB  - Mouse thymidylate synthase R209K (a mutation corresponding to R218K in
      Lactobacillus casei), overexpressed in thymidylate synthase-deficient Escherichia
      coli strain, was poorly soluble and with only feeble enzyme activity. The mutated
      protein, incubated with FdUMP and N(5,10)-methylenetetrahydrofolate, did not form
      a complex stable under conditions of SDS/polyacrylamide gel electrophoresis. The
      reaction catalyzed by the R209K enzyme (studied in a crude extract), compared to
      that catalyzed by purified wild-type recombinant mouse thymidylate synthase,
      showed the K(m) value for dUMP 571-fold higher and V(max) value over 50-fold
      (assuming that the mutated enzyme constituted 20% of total crude extract protein)
      lower. Thus the ratios k(cat, R209K)/k(cat, 'wild') and (k(cat, R209K)/K(m,
      R209K)(dUMP))/( k(cat, 'wild')/K(m, 'wild')(dUMP)) were 0.019 and 0.000032,
      respectively, documenting that mouse thymidylate synthase R209, similar to the
      corresponding L. casei R218, is essential for both dUMP binding and enzyme
      reaction.

PMID- 12422234
TI  - Adhesion properties of human bladder cell lines with extracellular matrix
      components: the role of integrins and glycosylation.
AB  - Integrin subunits present on human bladder cells displayed heterogeneous
      functional specificity in adhesion to extracellular matrix proteins (ECM). The
      non-malignant cell line (HCV29) showed significantly higher adhesion efficiency
      to collagen IV, laminin (LN) and fibronectin (FN) than cancer (T24, Hu456) and v
      raf transfected (BC3726) cell lines. Specific antibodies to the alpha(2),
      alpha(5) and beta(1) integrin subunits inhibited adhesion of the non-malignant
      cells, indicating these integrin participation in the adhesion to ECM proteins.
      In contrast, adhesion of cancer cells was not inhibited by specific antibodies to
      the beta(1) integrin subunit. Antibodies to alpha(3) integrin increased adhesion
      of cancer cells to collagen, LN and FN, but also of the HCV29 line with collagen.
      It seems that alpha(3) subunit plays a major role in modulation of other integrin
      receptors especially in cancer cells. Differences in adhesion to ECM proteins
      between the non-malignant and cancer cell lines in response to Gal and Fuc were
      not evident, except for the v-raf transfected cell line which showed a distinct
      about 6-fold increased adhesion to LN on addition of both saccharides. N
      Acetylneuraminic acid inhibited adhesion of all cell lines to LN and FN
      irrespective of their malignancy.

PMID- 12422236
TI  - Effect of A(n) tracts within the UP element proximal subsite of a model promoter
      on kinetics of open complex formation by Escherichia coli RNA polymerase.
AB  - In the open transcription complex (RPo), Escherichia coli RNA polymerase
      sigma(70) and alpha subunits are known to be in contact with each other and with
      the promoter region overlapping the -35 hexamer and the proximal part of the UP
      element. To probe the effect of A(n) DNA bending tracts in this region on
      initiation of transcription, kinetics of the formation of RPo by Escherichia coli
      RNA polymerase at two groups of synthetic consensus-like promoters bearing single
      DNA bending tracts (i). A(5 )within the proximal subsite region of the UP element
      (promoters Pk and Pl) and (ii). A(5)(Pg) or A(8)(Pm) in the region including the
      downstream end of the proximal UP subsite and the -35 consensus hexamer was
      studied in vitro using the fluorescence-detected abortive initiation assay. The
      kinetic data obtained demonstrate that the overall second-order rate constant
      k(a) of RPo formation is: (i.by almost one order of magnitude larger at Pk and
      Pl, relative to that at a control unbent promoter, and mainly due to a higher
      value of the equilibrium constant, K(1), of the initial closed complex; and (ii).
      several-fold smaller at Pg and Pm owing to a strongly decreased value of K(1).
      For Pm, the latter parameter was found to be dependent exponentially on four
      Mg(2+) ions, as compared with the seven ions remaining in equilibrium with the
      initial closed complex at the parent Pa promoter. This indicates that promoter
      region bearing a stiff A(8).T(8) fragment of B -DNA forms a smaller number of
      ionic contacts with the alpha subunit. These findings provide a new insight to
      and support the present model of interactions between RNA polymerase alpha and
      sigma(70) subunits with the proximal UP subsite and the -35 region of promoters.

PMID- 12422237
TI  - Interaction of three Caenorhabditis elegans isoforms of translation initiation
      factor eIF4E with mono- and trimethylated mRNA 5' cap analogues.
AB  - Translation initiation factor eIF4E binds the m(7)G cap of eukaryotic mRNAs and
      mediates recruitment of mRNA to the ribosome during cap-dependent translation
      initiation. This event is the rate-limiting step of translation and a major
      target for translational control. In the nematode Caenorhabditis elegans, about
      70% of genes express mRNAs with an unusual cap structure containing m(3)(2,2,7)G,
      which is poorly recognized by mammalian eIF4E. C. elegans expresses five isoforms
      of eIF4E (IFE-1, IFE-2, etc.). Three of these (IFE-3, IFE-4 and IFE-5) were
      investigated by means of spectroscopy and structural modelling based on mouse
      eIF4E bound to m(7)GDP. Intrinsic fluorescence quenching of Trp residues in the
      IFEs by iodide ions indicated structural differences between the apo and m(7)G
      cap bound proteins. Fluorescence quenching by selected cap analogues showed that
      only IFE-5 forms specific complexes with both m(7)G- and m(3)(2,2,7)G-containing
      caps (K(as) 2 x 10(6) M(-1) to 7 x 10(6) M(-1)) whereas IFE-3 and IFE-4
      discriminated strongly in favor of m(7)G-containing caps. These spectroscopic
      results quantitatively confirm earlier qualitative data derived from affinity
      chromatography. The dependence of K(as) on pH indicated optimal cap binding of
      IFE-3, IFE-4 and IFE-5 at pH 7.2, lower by 0.4 pH units than that of eIF4E from
      human erythrocytes. These results provide insight into the molecular mechanism of
      recognition of structurally different caps by the highly homologous IFEs.

PMID- 12422238
TI  - Computer simulations of protein folding with a small number of distance
      restraints.
AB  - A high coordination lattice model was used to represent the protein chain.
      Lattice points correspond to amino-acid side groups. A complicated force field
      was designed in order to reproduce a protein-like behavior of the chain. Long
      distance tertiary restraints were also introduced into the model. The Replica
      Exchange Monte Carlo method was applied to find the lowest energy states of the
      folded chain and to solve the problem of multiple minima. In this method, a set
      of replicas of the model chain was simulated independently in different
      temperatures with the exchanges of replicas allowed. The model chains, which
      consisted of up to 100 residues, were folded to structures whose root-mean-square
      deviation (RMSD) from their native state was between 2.5 and 5 A. Introduction of
      restrain based on the positions of the backbone hydrogen atoms led to an
      improvement in the number of successful simulation runs. A small improvement
      (about 0.5 A) was also achieved in the RMSD of the folds. The proposed method can
      be used for the refinement of structures determined experimentally from NMR data.

PMID- 12422239
TI  - Functional reconstitution of Ral-binding GTPase activating protein, RLIP76, in
      proteoliposomes catalyzing ATP-dependent transport of glutathione conjugate of 4
      hydroxynonenal.
AB  - Earlier studies from our laboratories have shown that RLIP76, a previously
      described Ral-binding GTPase activating protein (Jullien-Flores et al., 1995, J.
      Biol. Chem. 270: 22473), is identical with the xenobiotic transporter DNP-SG
      ATPase, and can catalyze ATP-dependent transport of glutathione-conjugates as
      well as doxorubin (Awasthi et al., 2000, Biochemistry, 39: 9327). We have now
      reconstituted purified bacterially expressed RLIP76 in proteoliposomes, and have
      studied ATP-dependent uptake of the glutathione conjugate of 4-hydroxynonenal (GS
      HNE) by these vesicles. Results of these studies show that RLIP76 reconstituted
      in proteoliposomes catalyzes ATP-dependent transport of GS-HNE against a
      concentration gradient. The transport of GS-HNE is saturable with respect to ATP
      as well as GS-HNE with K(m) values of 1.4mM and 2.5 microM, respectively. These
      studies demonstrate that RLIP76 mediates active transport of GS-HNE, and are
      consistent with our previous work showing that RLIP76-mediated efflux of GS-HNE
      regulates the intracellular concentration of 4-HNE and thereby affects 4-HNE
      mediated signaling.

PMID- 12422240
TI  - An approach based on diffusion to study ligand-macromolecule interaction.
AB  - A new approach has been developed to study binding of a ligand to a macromolecule
      based on the diffusion process. In terms of the Fick's first law, the
      concentration of free ligand in the presence of a protein can be determined by
      the measurement of those ligands which are diffused out. This method is applied
      to the study of binding of methyl-orange to lysozyme in phosphate buffer of pH
      6.2, at 30 degrees C. The binding isotherm was determined initially, followed by
      application of the Hill equation to the data obtained, then binding constant and
      binding capacity were estimated.

PMID- 12422241
TI  - The effects of the interaction of myosin essential light chain isoforms with
      actin in skeletal muscles.
AB  - In order to compare the ability of different isoforms of myosin essential light
      chain to interact with actin, the effect of the latter protein on the proteolytic
      susceptibility of myosin light chains (MLC-1S and MLC-1V - slow specific and same
      as ventricular isoform) from slow skeletal muscle was examined. Actin protects
      both slow muscle essential light chain isoforms from papain digestion, similarly
      as observed for fast skeletal muscle myosin (Nieznanska et al., 1998, Biochim.
      Biophys. Acta 1383: 71). The effect of actin decreases as ionic strength rises
      above physiological values for both fast and slow skeletal myosin, confirming the
      ionic character of the actin-essential light chain interaction. To better
      understand the role of this interaction, we examined the effect of synthetic
      peptides spanning the 10-amino-acid N-terminal sequences of myosin light chain 1
      from fast skeletal muscle (MLC-1F) (MLCFpep: KKDVKKPAAA), MLC-1S (MLCSpep:
      KKDVPVKKPA) and MLC-1V (MLCVpep: KPEPKKDDAK) on the myofibrillar ATPase of fast
      and slow skeletal muscle. In the presence of MLCFpep, we observed an about 19%
      increase, and in the presence of MLCSpep about 36% increase, in the myofibrillar
      ATPase activity of fast muscle. On the other hand, in myofibrillar preparations
      from slow skeletal muscle, MLCSpep as well as MLCVpep caused a lowering of the
      ATPase activity by about 36%. The above results suggest that MLCSpep induces
      opposite effects on ATPase activity, depending on the type of myofibrils, but not
      through its specific N-terminal sequence - which differs from other MLC N
      terminal peptides. Our observations lead to the conclusion that the action of
      different isoforms of long essential light chain is similar in slow and fast
      skeletal muscle. However the interaction of essential light chains with actin
      leads to different physiological effects probably depending on the isoforms of
      other myofibrillar proteins.

PMID- 12422242
TI  - Comparison of serological specificity of anti-endotoxin sera directed against
      whole bacterial cells and core oligosaccharide of Escherichia coli J5-tetanus
      toxoid conjugate.
AB  - The rough mutants of Gram-negative bacteria are widely used to induce protective
      antisera but the nature of the target epitope for such antibodies is not
      precisely defined. Endotoxin is one of several antigens present on the surface of
      bacterial cells, which are able to elicit specific antibodies. We studied the
      specificity of antibodies produced against a conjugate of E. coli J5 endotoxin
      core oligosaccharide with tetanus toxoid. The use of chemically defined antigen
      for immunisation excludes the possibility of production of antibodies against
      other cell surface antigens. A comparison of this monospecific anti-endotoxin
      serum with antiserum against E. coli J5 whole cells was performed in order to
      distinguish the role that endotoxin core oligosaccharide plays in the interaction
      with humoral host defences from that of other potentially important Gram-negative
      bacterial surface antigens. The reactivity of both sera with smooth and rough
      lipopolysaccharides was determined in ELISA, immunoblotting and by flow
      cytometry. Both antisera reacted with similar specificity with most
      lipopolysaccharides of identical or related core type. Less distinct reactions
      with endotoxins of the antibacterial serum in comparison with the anti-conjugate
      serum were found in all serological tests. LPS of E. coli O100 that showed the
      strongest reactions with both sera was used to stimulate IL-6, TNFalpha and
      nitric oxide production by the J-774A.1 cell line. Both sera were used to inhibit
      that stimulation and no inhibitory effects of the examined sera in comparison
      with non-immune serum were observed.

PMID- 12422243
TI  - Steroid signal transduction activated at the cell membrane: from plants to
      animals.
AB  - Steroid hormones in plants and in animals are very important for physiological
      and developmental regulation. In animals steroid hormones are recognized by
      nuclear receptors, which transcriptionally regulate specific target genes
      following binding of the ligand. In addition, numerous rapid effects generated by
      steroids appear to be mediated by a mechanism not depending on the activation of
      nuclear receptors. Although the existence of separate membrane receptors was
      postulated many years ago and hundreds of reports supporting this hypothesis have
      been published, no animal membrane steroid receptor has been cloned to date.
      Meanwhile, a plant steroid receptor from Arabidopsis thaliana has been identified
      and cloned. It is a transmembrane protein which specifically recognizes plant
      steroids (brassinosteroids) at the cell surface and has a serine/threonine
      protein kinase activity. It seems that plants have no intracellular steroid
      receptors, since there are no genes homologous to the family of animal nuclear
      steroid receptors in the genome of A. thaliana. Since the reason of the rapid
      responses to steroid hormones in animal cells still remains obscure we show in
      this article two possible explanations of this phenomenon. Using 1,25
      dihydroxyvitamin D(3) as an example of animal steroid hormone, we review results
      of our and of other groups concordant with the hypothesis of membrane steroid
      receptors. We also review the results of experiments performed with ovarian
      hormones, that led their authors to the hypothesis explaining rapid steroid
      actions without distinct membrane steroid receptors. Finally, examples of
      polypeptide growth factor that similarly to steroids exhibit a dual mode of
      action, activating not only cell surface receptors, but also intracellular
      targets, are discussed.

PMID- 12422244
TI  - Functionality versus strength -- has functional selection taken place in the case
      of the ecdysteroid receptor response element?.
AB  - Nuclear receptors are ligand-dependent transcription factors responsible for
      controlling differentiation, growth and development of higher eukaryotes. Three
      amino acids within the recognition alpha-helix of the DNA-binding domain of the
      nuclear receptors constitute the so-called "P-box" which determines response
      element specificity. In the ultraspiracle (Usp) protein, which together with EcR
      forms the heterodimeric ecdysone receptor, the P-box residues are E19, G20 and
      G23. Substitution of E19, the most characteristic amino acid for estrogen
      receptor-like P-boxes, with alanine showed that the mutation did not appreciably
      alter the affinity of the wild-type Usp DNA-binding domain (UspDBD(WT)) for a
      probe containing natural ecdysone response element (hsp27(wt)). Since in many
      cases E19 contacts a G/C base pair in position -4, which is absent in hsp27(wt),
      we analysed the interaction of UspDBD(WT), E19A and other P-box region mutants
      with the hsp27(wt) derivative which contains a G/C instead of an T/A base pair in
      position -4. UspDBD(WT) exhibited higher affinity for this element than for
      hsp27(wt). Moreover, a different interaction pattern of P-box region mutants was
      also observed. Thus we conclude that the E19 residue of UspDBD is not involved in
      any hsp27(wt) sequence-discerning contacts. However, substitution of the
      hsp27(wt) T/A base pair in position -4 with G/C generates target sequence with
      distinct functional characteristics and possibly with a new specificity. These
      results could serve as a basis for understanding the role of the presence of a
      T/A or G/C base-pair in the position -4 in the two types of ecdysone response
      elements found in nature.

PMID- 12422245
TI  - Structure, catalytic activity and evolutionary relationships of 1
      aminocyclopropane-1-carboxylate synthase, the key enzyme of ethylene synthesis in
      higher plants.
AB  - Both ethylene and the enzymes of ethylene synthesis are subjects of intensive
      scientific investigation. The present review discusses structure, catalytic
      activity and evolutionary relationships of 1-aminocyclopropane-1-carboxylate
      synthase, identified for the first time in ripening tomato in 1979. This enzyme
      is responsible for the conversion of S-adenosyl-L-methionine to 1
      aminocyclopropane-1-carboxylic acid, which is the key step of ethylene synthesis
      in higher plants. The role of this enzyme (especially in the fruit ripening) was
      demonstrated in 1991 in transgenic tomato plants, expressing 1-aminocyclopropane
      1-carboxylate synthase antisense RNA. On the basis of mutagenesis and
      crystallization of the enzyme, new data were provided on the three-dimensional
      structure and amino-acid residues which are critical for catalysis. The control
      of ethylene production is of great interest for plant biotechnology because it
      can delay senescence and overmaturation. These processes are responsible for
      large loss of vegetables and fruit on storage. Detailed structural and
      biochemical data are necessary to help design 1-aminocyclopropane-1-carboxylate
      synthase inhibitors, whose application is expected to have immense agricultural
      effects.

PMID- 12422246
TI  - Plastoquinone: possible involvement in plant disease resistance.
AB  - The plant Solanum nigrum treated with the pathogen Phytophthora infestans-derived
      elicitor responded by elevated reactive oxygen species (ROS) production, lipid
      peroxidation and lipoxygenase (EC 1.13.11.12) activity in comparison with control
      plants indicating that oxidative stress took place. We demonstrate that these
      events are accompanied by a significant increase in plastoquinone (PQ) level. It
      is postulated that PQ may be associated with mechanisms maintaining a tightly
      controlled balance between the accumulation of ROS and antioxidant activity that
      determines the full expression of effective defence.

PMID- 12422247
TI  - Induction of the synthesis of an additional family of long-chain dolichols in the
      yeast Saccharomyces cerevisiae. Effect of starvation and ageing.
AB  - The yeast Saccharomyces cerevisiae strain W303 synthesizes in the early
      logarithmic phase of growth dolichols of 14-18 isoprene residues. The analysis of
      the polyisoprenoids present in the stationary phase revealed an additional family
      which proved to be also dolichols but of 19-24 isoprene residues, constituting
      39% of the total dolichols. The transfer of early logarithmic phase cells to a
      starvation medium lacking glucose or nitrogen resulted in the synthesis of the
      longer chain dolichols. The additional family of dolichols represented 13.8% and
      10.3% of total dolichols in the glucose and nitrogen deficient media,
      respectively. The level of dolichols in yeast cells increased with the age of the
      cultures. Since both families of dolichols are present in stationary phase cells
      we postulate that the longer chain dolichols may be responsible for the physico
      chemical changes in cellular membranes allowing yeast cells to adapt to nutrient
      deficient conditions to maintain long-term viability.

PMID- 12422248
TI  - The chronicles of HIV therapeutics: where to begin, when to start and how will it
      end--a tale of two decades and beyond?

PMID- 12422249
TI  - Trends in oral antihyperglycemic and insulin use in the Nova Scotia senior
      population (1993-1999).
AB  - Trends in prescribing patterns of insulin and oral antihyperglycemic drugs for
      Nova Scotia seniors pharmacare beneficiaries were examined from April 1, 1993 to
      March 31, 2000 and evaluated relative to published guidelines. The number of
      patients, prescriptions, and drug costs for oral antihyperglycemic drugs and
      insulins were calculated. The source of insulin was examined subsequent to the
      marketing of human insulin in 1993. The percentage of patients using human
      insulin increased from 66% in 1993 to 96% in 1995, and beef and pork insulin use
      decreased from 38% in 1993 to 19% in 1995. First generation sulfonylureas
      decreased between 1993 and 1999; chlorpropamide decreased from 23% to 7% of
      antihyperglycemic users, and tolbutamide decreased from 4% to 1%. Among second
      generation sulfonyl-ureas, glyburide remained frequently used with 59% of
      antihyperglycemic users in 1999, while gliclazide increased in use from 2% to 22%
      between 1993 and 1999. Metformin, a biguanide, increased in use from 29% to 37%
      of antihyperglycemic users. Acarabose having been introduced to the market later,
      increased in use from 1% to 5% between 1996 and 1999. Once human insulin became
      available, patients were rapidly transferred from animal to human insulin.
      Chlorpropamide remained widely used despite safety concerns for use in the
      elderly. Glyburide was the most frequently prescribed oral antihyperglycemic
      agent. Recently raised concerns about its safety in patients with renal disease
      require follow-up. Further work is needed to determine the reasons for slow
      uptake of recommendations related to chlorpropamide and the effect of switches to
      human insulin and newer oral antihyperglycemics on patient outcomes and health
      care costs.

PMID- 12422250
TI  - Naltrexone in the treatment of alcohol dependence: a Canadian trial.
AB  - OBJECTIVES: Alcohol dependence is a prevalent psychiatric disorder affecting
      approximately 12% of the adult population at some point in their lifetime.
      Psychosocial treatments are associated with only modest success rates. The first
      Canadian clinical trial with naltrexone, an opiate antagonist, was conducted to
      evaluate its safety and usefulness as an adjunctive treatment in the management
      of alcohol dependence. METHODS: One hundred twenty alcohol-dependent individuals
      were assessed to receive treatment with 50 mg of naltrexone orally for 12 weeks
      in an open-label trial. Patients were seen biweekly and received a concurrent
      psychosocial intervention. Treatment was conducted at multiple sites in Canada.
      RESULTS: Fifty-four per cent of subjects completed the entire 12 weeks of
      treatment. During the study, 39% of patients abstained, while of the individuals
      reporting drinking at baseline, 86% were consuming less alcohol by their final
      visit. These reductions were accompanied by a significant decrease in craving for
      alcohol at week 12, as measured by the Obsessive Compulsive Drinking Scale
      (P<0.01). Naltrexone was well tolerated and no serious adverse events were
      experienced. CONCLUSIONS: The data lend support to the hypothesis that endogenous
      opioid activity is involved in the regulation of alcohol intake, and that
      antagonists of endogenous opioids decrease craving and drinking. Opiate
      antagonists such as naltrexone are a new strategy in the treatment of alcohol
      dependence. Naltrexone can be safely given to female and male alcoholics, is
      acceptable to patients, and plays a role in reducing alcohol consumption and
      preventing relapse to heavy drinking.

PMID- 12422251
TI  - Adverse drug reactions to protease inhibitors.
AB  - Protease inhibitors are drugs that are commonly used in the therapy of people
      living with HIV infection. These drugs are commonly used in combination and act
      by inhibiting viral protease, blocking viral replication. Adverse drug reactions
      to protease inhibitors include gastrointestinal problems, rash and metabolic
      disturbances. The metabolic derangements associated with protease inhibitor
      therapy are the most problematic adverse events associated with therapy, and vary
      in incidence from drug to drug. These derangements include hyperlipidemia,
      abnormal fat distribution (lipodystrophy) and impaired glucose tolerance, which
      is believed to be due to peripheral insulin resistance. Clinicians caring for
      patients being treated with protease inhibitors must be vigilant for adverse
      events, notably those involving altered lipid and glucose metabolism.

PMID- 12422252
TI  - Confirming false adverse reactions to drugs by performing individualized,
      randomized trials.
AB  - One-patient, randomized, double-blind, controlled trials (N-of-1 RCTs) have
      traditionally been used to assess the efficacy of treatment. At the Drug Safety
      Clinic, Toronto, this methodology is used to evaluate adverse effects related to
      medication use, specifically when the symptoms are vague and are in response to
      more than one medication. Two patients are described with histories of drug
      allergies to multiple medications; as well, guidelines for conducting N-of-1
      trials are summarized. The first patient had a history of prolonged periorbital
      and generalized weakness lasting up to one week after exposure to a variety of
      drugs. Because of the ambiguous results of local anesthetic skin testing, an N-of
      1 trial was performed using lidocaine without preservative. Two short-lived
      episodes of blepharospasm and lethargy were observed with placebo; no subjective
      or objective reaction occurred with active drug. The second patient had a history
      of prolonged weakness and drowsiness after exposure to many medications; she had
      been told that she was allergic to all drugs with a benzene ring. During the
      first N-of-1 trial, generalized weakness was observed with 10 mg of
      dimenhydrinate and all four placebo doses. During the second N-of-1 challenge
      using codeine, no unwarranted reactions occurred with either active or placebo
      drug. Traditional testing of these patients to disprove the clinical symptoms is
      often difficult because of the anxiety level associated with the patients' past
      experiences. N-of-1 trials provide a useful alternative for the management of
      patients with nonspecific symptomatology attributed to drug ingestion.

PMID- 12422253
TI  - Impact of migraine symptoms on health care use and work loss in Canada in
      patients randomly assigned in a phase III clinical trial.
AB  - BACKGROUND: Migraine is prevalent and associated with substantial direct and
      indirect costs that may vary across geographic and national boundaries. The
      effects of migraine, self-reported by Canadians, on health care resource use as
      well as paid and unpaid work loss were examined. PATIENTS AND METHODS: The
      Migraine Background Questionnaire (MBQ) was self-administered during the
      screening visit of a phase III clinical trial of rizatriptan (a potent, selective
      5-hydroxytryptamine(1B/1D)-receptor agonist or 'triptan'). Patients suffering
      from moderate to severe migraine in the previous six months were offered the
      opportunity to participate. Migraine frequency was determined and costs were
      estimated and assigned based on known direct costs of health care resource
      utilization, and indirect costs of paid and unpaid work and productivity loss.
      RESULTS: One hundred thirty-four patients completed the MBQ. In the previous
      year, 89% of those patients reported visiting a clinic, 23% reported visiting an
      emergency room and 5% reported being hospitalized for migraine. Patients reported
      an average of 6.5 days absent from work, 44 days working with migraine headache
      and 10.4 reduced workday equivalents due to ineffectiveness at work with
      migraine. Based on data obtained from the Ontario, the average overall annual
      cost due to migraine was estimated to be 3,025 dollars/patient; most of this
      (87%) due to indirect costs. CONCLUSION: In Canada, patients with moderate to
      severe migraine, as identified in a phase III clinical trial, reported lost work
      days and reduced effectiveness while at work, as well as increased health care
      resource utilization due to migraine. The associated cost was estimated to be
      substantial.

PMID- 12422267
TI  - A novel transporter, Pfcrt, confers antimalarial drug resistance.
AB  - The elucidation of the molecular details of drug resistance phenomena is a very
      active area of research that crosses many disciplinary boundaries. Drug
      resistance is due to altered drug-target interaction, and/or dysregulated
      signaling related to cell growth and death. Since many drugs need to rapidly
      diffuse into and within cells in order to find their targets, and since
      transmembrane ion transport is an important facet of cellular signaling, it is
      not surprising that membrane transport phenomena have been implicated in the
      evolution of drug resistance in tumor cells, bacteria, and intracellular
      parasites such as Plasmodium falciparum, the causative agent of the most lethal
      form of human malaria. The most infamous membrane transport protein involved in
      drug resistance is "MDR protein" or "P-glycoprotein" (Pgp),1 which was found to
      be overexpressed in drug-resistant tumor cells over 15 years ago, and which is
      representative of the ATP-binding cassette (ABC) superfamily that also includes
      the important cystic fibrosis transmembrane conductance regulator (CFTR) and
      sulfonyl urea receptor (SUR) ion channels. Availability of mouse and human Pgp
      cDNA rather quickly led to the identification of homologues in many species,
      including P. falciparum, and these were de facto assumed to be the ultimate
      determinants of drug resistance in these systems as well. However, research over
      the past 10 years has taught us that this assumption likely is wrong and that the
      situation is more complex. We now know that human Pgp plays a relatively minor
      role in clinically relevant tumor drug resistance, and that an integral membrane
      protein with no homology to the ABC superfamily, Pfcrt, ultimately confers
      chloroquine resistance in P. falciparum. Thus, the general hypothesis that
      membrane transport and membrane transport proteins are important in drug
      resistance phenomena remains correct, but at a genetic, biochemical, and
      physiological level we have recently witnessed a few very interesting surprises.

PMID- 12422268
TI  - Artificial cell based on lipid hollow polyelectrolyte microcapsules: channel
      reconstruction and membrane potential measurement.
AB  - A new model system as an artificial cell based on hollow polyelectrolyte
      microcapsules (HPM), fabricated by step-wise adsorption of polyelectrolytes and
      phospholipids, was proposed. To demonstrate the feasibility of the functioning of
      HPM coated with lipid layers as a model biosystem, the membrane permeability for
      ions and the channel reconstruction were examined by measuring the membrane
      potential as one of the most important cell parameters. The membrane potential
      was measured by confocal microscopy using the potentiometric fluorescent dye
      tetramethylrhodamine ethyl ester perchlorate (TMRE). The influence of the lipid
      composition (phosphatidylcholine--DPPC-HPM, phosphatidylcholine/phosphatidic acid
      9/1-(DPPC/DPPA)-HPM) and metal cations (Na+, K+, Ca2+) on the membrane potential
      was shown. Addition of DPPA was found to lead to an increase of the negative
      membrane potential value. To investigate the ion-transport activity of the lipid
      HPM, the ion channel-forming peptides valinomycin and gramicidin were used. The
      selectivity of the valinomycin and gramicidin channels for K+ and for K+, and Na+
      ions, respectively, and the tolerance for Ca2+ ions is evidence that lipid-HPM
      functions as an artificial cell.

PMID- 12422269
TI  - Anomalous effects of external TEA on permeation and gating of the A-type
      potassium current in H. aspersa neuronal somata.
AB  - The model proposed for external TEA block of Shaker K+ channels predicts a
      proportional relationship between TEA sensitivity and calculated electrical
      distance derived from measurements of voltage dependence of TEA block. In the
      present study, we examined this relationship for the A-type K+ current (IA) of
      Helix aspersa in neuronal somata using the whole-cell patch-clamp technique.
      External TEA inhibited IA with strong voltage dependence, such that the TEA
      dissociation constant was increased at depolarized test potentials. The half
      inhibition constant (V0.5) for TEA block was approximately 21 mM at 0 mV, and
      V0.5 increased to approximately 67 mM at 50 mV. The calculated electrical
      distance for TEA block suggested that TEA traversed 65% of the way into the
      membrane electrical field. TEA also caused significant shifts in the voltage
      dependence of A-type K+ channel gating. For example, at TEA concentrations below
      that required to fully suppress delayed outward currents, TEA caused depolarizing
      shifts in the voltage-dependence of A-type channel activation, steady-state
      inactivation, time for removal of inactivation, and slowed channel activation
      kinetics. Taken together, these observations suggest that TEA biased the local
      field potential near voltage-sensing domains of A-type K+ channels, causing the
      transmembrane electrical field to be relatively hyperpolarized in the presence of
      TEA. In summary, the calculated electrical distance of TEA block of A-type K+
      channels in H. aspersa neurons is unprecedented among other K+ channels. This
      raises concerns about the conventional interpretation of this value. Furthermore,
      the voltage-dependent properties of IA are modified by TEA at concentrations
      previously used to isolate delayed rectifier potassium channels (IKDR)
      selectively. This lack of specificity has important implications for recent, as
      well as future studies of IA in H. aspersa and possibly other snail neurons.

PMID- 12422270
TI  - Cultured gill epithelia from freshwater tilapia (Oreochromis niloticus): effect
      of cortisol and homologous serum supplements from stressed and unstressed fish.
AB  - Procedures for the preparation and culture of branchial epithelia from dispersed
      gill cells of freshwater tilapia (Oreochromis niloticus) are described. Epithelia
      were cultured on permeable supports (terephthalate membranes, "filters") and
      bathed on both the apical and basolateral side with isotonic media containing 6%
      fetal bovine serum (FBS). When the apical medium was replaced with freshwater
      (pseudo in vivo asymmetrical culture conditions), transepithelial resistance
      (TER) increased markedly, transepithelial potential became negative, and
      paracellular permeability decreased. The physiological effects of cortisol and
      10% homologous (tilapia) serum were investigated. Tilapia serum (TS) was prepared
      from unstressed and stressed fish and therefore allowed comparison between the
      effects of homologous serum derived from fish in differing physiological states.
      Under both symmetrical and asymmetrical culture conditions, cortisol
      significantly elevated TER across cultured tilapia gill epithelia, indicative of
      a significant increase in epithelial "tightness." Cortisol reduced
      transepithelial Na + and Cl? movement and paracellular permeability. The
      glucocorticoid agonist dexamethasone elicited a similar response, which was
      inhibited by the glucocorticoid antagonist (receptor blocker) RU486. Cortisol did
      not stimulate active ion transport across epithelia under either symmetrical or
      asymmetrical culture conditions. In epithelia supplemented with TS from stressed
      fish, physiological changes in cultured preparations were consistent with those
      observed in FBS + cortisol-supplemented epithelia. Differences between the
      physiological status of epithelia supplemented with TS from unstressed and
      stressed fish could be abolished with RU486. Using TS as a medium supplement did
      not stimulate active ion transport under asymmetrical culture conditions,
      although Na +-K +-ATPase activity increased in TS-supplemented epithelia relative
      to FBS-supplemented preparations.

PMID- 12422271
TI  - The transport systems of Ventricaria ventricosa: hypotonic and hypertonic turgor
      regulation.
AB  - The time course of hypertonic and hypotonic turgor regulation was studied in
      Ventricaria (Valonia) using pressure probe and I/V(current-voltage) analysis. Of
      11 cells, 9 exhibited hypertonic turgor regulation, ranging from 100% regulation
      in 150 min to 14% regulation (14% recovery of the decrease in turgor) in 314 min.
      Some cells began regulating immediately, others took up to 90 min to begin. The
      resting PD (potential difference) became more positive in most cells. The I/V
      characteristics became more nonlinear with high resistance between -150 and -20
      mV and negative conductance region near -70 mV. Prolonged (16 sec) voltage clamps
      to negative levels (-100 to -150 mV) showed progressively more rapid current turn
      off, but subsequent I/V characteristics were not affected. Clamping to +150 mV,
      however, abolished the high conductance between -50 and +100 mV to yield a
      uniform high resistance I/V characteristic, similar to that in high [K+]o.
      Decreasing illumination from 2.02 micromol sec(-1) m(-2) to 0.5 micromol sec(-1)1
      m(-2) had a similar effect. Two out of a total of three cells exhibited hypotonic
      turgor regulation. Both cells started regulating within minutes and achieved near
      50% regulation within 50 min. The PD became more negative. The I/V curves
      exhibited high resistance between +50 and +150 mV. The characteristics were
      similar to those in cells exposed to low [K+]o. Prolonged voltage clamps to both
      negative and positive levels showed slow current increase. Decreased illumination
      increased the membrane resistance.

PMID- 12422272
TI  - Presteady-state and steady-state kinetics and turnover rate of the mouse gamma
      aminobutyric acid transporter (mGAT3).
AB  - We expressed mouse gamma-aminobutyric acid (GABA) transporter (mGAT3) in Xenopus
      laevis oocytes and examined its steady-state and presteady-state kinetics and
      turnover rate by using tracer flux and electrophysiological methods. In oocytes
      expressing mGAT3, GABA evoked a Na+-dependent and Cl(-)-facilitated inward
      current. The dependence on Na+ was absolute, whereas that for Cl(-) was not. At a
      membrane potential of -50 mV, the half-maximal concentrations for Na+, Cl(-), and
      GABA were 14 mM, 5 mM, and 3 microM. The Hill coefficient for GABA activation and
      Cl(-) enhancement of the inward current was 1, and that for Na+ activation was >
      or =2. The GABA-evoked inward current was directly proportional to GABA influx
      (2.2 +/- 0.1 charges/GABA) into cells, indicating that under these conditions,
      there is tight ion/GABA coupling in the transport cycle. In response to step
      changes in the membrane voltage and in the absence of GABA, mGAT3 exhibited
      presteady-state current transients (charge movements). The charge-voltage (Q-V)
      relation was fitted with a single Boltzmann function. The voltage at half-maximal
      charge (V(0.5)) was +25 mV, and the effective valence of the moveable charge
      (zdelta) was 1.6. In contrast to the ON transients, which relaxed with a time
      constant of < or =30 msec, the OFF transients had a time constant of 1.1 sec.
      Reduction in external Na+ ([Na+]o) and Cl(-) ([Cl(-)]o) concentrations shifted
      the Q-V relationship to negative membrane potentials. At zero [Na+]o (106 mM Cl(
      )), no mGAT3-mediated transients were observed, and at zero [Cl(-)]o (100 mM
      Na+), the charge movements decreased to approximately 30% of the maximal charge
      (Q(max)). GABA led to the elimination of charge movements. The half-maximal
      concentrations for Na+ activation, Cl(-) enhancement, and GABA elimination of the
      charge movements were 48 mM, 19 mM, and 5 mM, respectively. Q(max) and I(max)
      obtained in the same cells yielded the mGAT3 turnover rate, 1.7 sec(-1) at -50
      mV. The low turnover rate of mGAT3 may be due to the slow return of the empty
      transporter from the internal to the external membrane surface.

PMID- 12422273
TI  - Fluorescent probes DPH, TMA-DPH and C17-HC induce erythrocyte exovesiculation.
AB  - An experimental approach has been developed to study human erythrocyte
      vesiculation, using the fluorescent probes diphenylhexatriene (DPH),
      trimethylamino-diphenylhexatriene (TMA-DPH) and heptadecyl-hydroxycoumarin (C17
      HC). Acetylcholinesterase (AChE) enzyme activity measurements confirmed the
      presence of exovesicles released from erythrocyte membranes labeled with DPH, TMA
      DPH or C17-HC. The fluorescence intensity and anisotropy values obtained showed
      that the amphiphilic probes TMA-DPH and C17-HC are preferentially incorporated in
      the exovesicles (when compared with DPH). There is a significant decrease of the
      cholesterol content of the exovesicle suspensions with time, independently of the
      fluorescence probe used, reaching undetectable cholesterol levels for the samples
      incubated for 48 hr. The ratios between the concentration of cholesterol released
      in the exovesicles after 1 hr incubation with DPH, TMA-DPH or C17-HC and the
      probe concentration used in the incubation were 84.7, 3.82 and 0.074,
      respectively. The size of the released vesicles was evaluated by dynamic light
      scattering spectroscopy. Some hypotheses are proposed that could explain the
      resemblance and differences between the results obtained for erythrocytes labeled
      with each probe, considering the present knowledge of membrane vesiculation
      mechanisms, lipid microdomains (rafts), erythrocyte membrane phospholipid
      asymmetry and AChE inhibition by TMA-DPH and C17-HC. This work demonstrates that
      the fluorescent probes DPH, TMA-DPH and C17-HC induce rapid erythrocyte
      exovesiculation; their use can lead to new methodologies for the study of this
      still poorly understood mechanism.

PMID- 12422274
TI  - EBMT Working Party on Pediatric Diseases. Frankfurt/Maine, Germany, 21-23 June
      2002. Abstracts.

PMID- 12422288
TI  - Complementary and alternative medicine in asthma--safety, effectiveness and
      costs.

PMID- 12422289
TI  - Climatic change: possible impacts on human health.
AB  - This paper addresses a number of problems relating to climatic change and human
      health. Following an introduction outlining the overarching issues, a short
      summary is given on climatic change and its anthropogenic causes. The rest of the
      paper then focuses on the direct and indirect impacts of global climatic change
      on health. Direct effects comprise changes in the hygrothermal stress response of
      humans, atmospheric pollution, water quality and availability; indirect effects
      include the potential for the spread of vector-borne diseases outside their
      current range. The paper concludes with some comments on possible response
      strategies aimed at alleviating the adverse effects of climatic change on human
      health.

PMID- 12422290
TI  - Complementary and alternative medicine in asthma: do they work?
AB  - OBJECTIVE: An increasing number of patients with asthma are attracted by
      complementary and alternative medicine (CAM). Therefore, it is of importance that
      scientific evidence about the efficacy of this type of therapy is regarded.
      METHOD: We searched the electronic databases Medline, Embase and the Cochrane
      Library for controlled trials and systematic reviews to evaluate the evidence of
      the most popular alternative therapies, i.e. acupuncture, homeopathy, breathing
      techniques, herbal and nutritional therapies. RESULTS: Claims that acupuncture is
      effective for the treatment of asthma are not based on well-performed clinical
      trials. The role of homeopathy in the treatment of asthma needs further
      evaluation. Breathing techniques, e.g. improved control of breathing by yoga, may
      contribute to the control of asthma symptoms, but due to the small number of
      controlled trials and due to the small number of patients it is not possible to
      make firm judgments. Herbal remedies cannot be recommended based on the available
      evidence. Recommendations for a diet high in vitamin C and marine fatty acids are
      not harmful, but evidence for clinically meaningful effects are scant.
      CONCLUSION: Up to now evidence is lacking that alternative forms of medicine are
      more effective than placebo in asthma. However, lack of evidence does not always
      mean that treatment is ineffective, but it could mean that effectiveness has not
      been adequately investigated. High quality research as in conventional therapy
      should be fostered in complementary medicine.

PMID- 12422291
TI  - Serum C-reactive protein in children with adenovirus infection.
AB  - OBJECTIVES: (1) To evaluate serum C-reactive protein (CRP) concentrations in
      children with adenovirus infection, and (2) to compare CRP concentrations in
      adenovirus and influenza virus infection. PATIENTS AND METHODS: Retrospective,
      comparative single-center study conducted in Emergency Department patients of a
      paediatric tertiary care center. Comparison of CRP in adenovirus infection and
      influenza was performed in patient groups stratified according to age and
      duration of fever. RESULTS: In 87 children with adenovirus infection (median age,
      1.5 years; interquartile range, 0.9-3.0), CRP levels of <2 mg/L, <10 mg/L, and
      <100 mg/L were found in 4 (4%), 12 (13%), and 66 (76%) patients, respectively.
      Median CRP in the children with adenovirus infection and in 130 children with
      influenza was 49 mg/L (21-96) and 9 mg/L (3-20), respectively (p = 0.001). A
      statistically significant difference remained when these 2 patient groups were
      stratified according to age (</=2 vs. >2 years) and duration of fever (</=3 vs.
      >3 days) (p <0.001). In adenovirus infection CRP concentrations were unrelated to
      age, duration of fever and severity of illness, as judged by the extent of
      mucosal involvement and by the frequency and duration of hospitalisation.
      CONCLUSION: Paediatric adenovirus infection is associated with substantially
      elevated CRP concentrations in the absence of secondary bacterial infection. CRP
      levels were independent of the duration of illness, indicating that adenoviruses
      trigger an immediate inflammatory host response resembling invasive bacterial
      infection.

PMID- 12422292
TI  - Cross-sectional investigation on the accuracy of alternate site glucose testing
      using the Soft-Sense glucose meter.
AB  - QUESTIONS UNDER STUDY: The aim of this study was to evaluate possible differences
      in the results of blood glucose testing with the Soft-Sense blood glucose
      monitoring system (Abbott MediSense, Wiesbaden, Germany; not yet available in
      Switzerland) using different sites for drawing whole blood samples. METHODS: In
      total, 66 patients participated in the study. Blood glucose measurements were
      performed with the Soft-Sense device taking capillary blood from the forearm and
      the fingertip. The results were compared with blood glucose measurements by means
      of a laboratory reference method using blood from the fingertips. RESULTS: 276
      blood glucose data sets could be obtained and were used for the examination of
      the accuracy of blood glucose measurements at both different sites. Blood glucose
      results obtained from the arm with Soft-Sense correlated well and were nearly
      parallel with the results achieved from the fingertip with a laboratory reference
      method (regression analysis: slope = 0.981; intercept = 0.045 mmol/l (0.819
      mg/dl); correlation coefficient r = 0.943). Error grid analysis showed 99.2% of
      the measurements within clinically acceptable zones A and B. In addition, finger
      stick measurements done with the Soft-Sense device and the reference method
      revealed a strong correlation (regression analysis: slope = 0.959; intercept = 
      0.042 mmol/l (0.748 mg/dl); correlation coefficient r = 0.972). Error grid
      analysis showed 98.9% of all blood glucose readings within clinically acceptable
      zones A and B. Mean absolute percent deviations were 9.3+/- 8.1% for the finger
      tests and 11.2+/- 8.7% for the arm tests. If blood glucose values exceeded 11.1
      mmol/l (200 mg/dl), measurements revealed from the forearm were slightly lower
      than the measurements obtained from the fingertips. CONCLUSIONS: The results
      indicate that the automated blood glucose monitoring device Soft-Sense provides
      accurate results independent of the measuring site. As with other alternate site
      testing devices, nearly painless blood collection at the forearm might help to
      increase patients readiness to perform more frequent measurements by self blood
      glucose monitoring, which is a known prerequisite of improved blood glucose
      control.

PMID- 12422293
TI  - [Effective therapy in hypertension].

PMID- 12422294
TI  - [Blood coagulation in normotensives and hypertensives in relation to their body
      mass index].
AB  - BACKGROUND AND PERSPECTIVE: Various parameters of the coagulation cascade and
      fibrinolysis are important predictors of myocardial infarction and stroke, for
      which hypertension is a risk factor. It is unclear whether an elevated blood
      pressure by itself can produce activated clotting. PATIENTS AND METHODS:
      Coagulation tests were done on overweight hypertensive (n=40); aged 49 +/- 8
      years; group 3), overweight normotensives (n=19; aged 51 +/- 8 years; group 2)
      and normal-weight normotensives (n=20; aged 51 +/- 8; group 1). RESULTS:
      Plasminogen-activator-inhibitor 1 (PAI-1), a measure of impaired fibrinolysis,
      was elevated in group 2 (20.5 +/- 11 U/ml; p < 0.001), compared with group 1
      (11.6 +/- 6 U/ml), and was even higher in group 3 (27.5 +/- 9 U/ml; p < 0.05).
      Fibrinogen and factor VIII, parameters that promote clotting, were elevated in
      group 2 (360 +/- 61 mg/dl and 143 +/- 15 %, respectively; p < 0.001), and in
      group 3 (368 +/- 63 mg/dl and 146 +/- 18%; p < 0.001) compared to group 1 (304 +/
      40 mg/dl and 127 +/- 17%). Correspondingly, fibrin monometers, a measure of
      intravascular coagulation, were elevated in group 3 (p < 0.05) and partial
      thromboplastin time (PTT) decreased (p < 0.001). Pearson correlation showed a
      significant (p < 0.001) positive relationship between PAI-1 and body mass index
      (BMI) (0.539), triglycerides (0.512), blood pressure (0.388 to 0.534), fibrinogen
      (0.404, and a negative one with HDL-cholesterol (0.625). BMI also correlated with
      fibrinogen (0.509; p < 0.001) and factor VIII (0.337; p < 0.01). CONCLUSIONS:
      Fibrinolysis and activated coagulation are reduced in hypertensive subjects: this
      favours the occurrence of myocardial infarction and stroke. In addition to the
      level of blood pressure, the extent of the changes are effected especially by BMI
      and metabolic risk factors.

PMID- 12422295
TI  - [Therapy resistant hypertension--significance of electronic compliance
      monitoring].
AB  - HISTORY AND CLINICAL FINDINGS: A 71-year-old woman was admitted with arterial
      hypertension resistant to drug therapy (office readings 197/82 mmHg) under
      medication with beta-blocker, AT 1 -antagonist and a diuretic. The only physical
      pathologic finding was an adipositas. DIAGNOSIS, TREATMENT AND COURSE: The
      patient was suffering from isolated systolic hypertension, grade 3 corresponding
      to WHO-guidelines. Despite antihypertensive triple therapy office as well as self
      measured blood pressure values (mean 170/82 mmHg) remained elevated. Thus, the
      patient fulfilled the criteria of a resistant hypertension. The degree of
      compliance was only 50 %, detected by using a Medication-Event-Monitoring-System
      (correct dosing interval 17.1 %). We discussed the results of compliance- and
      blood pressure self-measurement with the patient. In the following period of
      compliance- and blood pressure self-measurement (with unchanged antihypertensive
      therapy) the compliance increased dramatically with a degree of 90,9 % and self
      measured blood pressure values almost normalized (mean 137/71 mmHg). CONCLUSION:
      The control of compliance by using electronic compliance-monitoring may help to
      discover non-compliance as a frequent cause of resistant hypertension and to
      avoid unnecessary cost-extensive procedures.

PMID- 12422296
TI  - [Pitfalls in hypertension management--misjudgements in diagnosis and therapy].
AB  - HISTORY AND CLINICAL FINDINGS: A 71-year-old woman with arterial hypertension,
      diabetes type 2, peripheral vascular disease and Sjogren's syndrome presented
      with progressive weakness, dizziness, insomnia, palpitations and headache. These
      symptoms did not improve by changing her antihypertensive treatment. The
      patient's general condition was quite normal and there were no signs of acute or
      chronic cardiopulmonary decompensation. INVESTIGATIONS: Besides arterial
      hypertension, she also had an elevated body mass index, dyslipoproteinemia,
      microalbuminuria, diabetic metabolism, left ventricular hypertrophy with signs of
      an abnormal diastolic cardiac function as well as atherosclerotic lesions (in
      both carotid arteries) which were identified as the patient's cardiovascular risk
      factors. Ambulant blood pressure monitoring revealed decreasing BP values for a
      period of 5 hrs after drug intake but, subsequently, severe hypertensive values
      (up to 220 mmHg systolic) without adequate decrease at night. Moreover, a
      hyperkinetic regulation of her circulation was demonstrated by hemodynamic
      monitoring and assessment of the autonomic nervous system. TREATMENT: By changing
      drug treatment, i. e. administration of an anti-adrenergic calcium antagonist of
      the non-dihydropyridine type combined with an ACE inhibitor and a diuretic,
      respectively, (both given in fixed combinations) led to the normalization of the
      blood pressure and pulse rate as well as an improvement of the patient's
      condition. CONCLUSIONS: This case emphasizes the importance of ambulant blood
      pressure monitoring and an assessment of the heart rate in individually adapted
      antihypertensive drug therapy. The application of metabolically neutral fixed
      drug combinations with special regard to associated diseases, organ protection
      and the patient's compliance resulted in normotensive blood pressure values and
      an improvement of the quality of life.

PMID- 12422297
TI  - [Echocardiography in the assessment of hypertension].

PMID- 12422299
TI  - Risk evaluation and therapeutical implications of pulse pressure in primary
      arterial hypertension.
AB  - SUMMARY: Analysis of the results raised in the Framingham and the MRFIT study
      have clearly shown that increased pulse pressure is an independent cardiovascular
      risk factor. This is valid for all age groups and both sexes. The risk increases
      with pulse pressures over 60 - 65 mmHg for office blood pressure and 53 mmHg for
      24-h-mean of ambulatory blood pressure. Pulse pressure is strongly correlated
      with systolic blood pressure and will be highest in case of isolated systolic
      hypertension. Urinary albumin excretion and left ventricular hypertrophy are
      closely associated with pulse pressure. With elevated pulse pressure
      cardiovascular risk is increased 2- to 4-fold in relation to age and endpoint.
      The risk of myocardial infarction is raised more if pulse pressure is associated
      with low mean arterial blood pressure while risk of stroke is increased with wide
      pulse pressure and high mean arterial pressure. The risk of pulse pressure can be
      seen in normotensives and in early pregnancy. Therapeutic management of pulse
      pressure will be similar to that of systolic blood pressure, since normalization
      of systolic blood pressure will also lower or normalize pulse pressure. Results
      of preliminary studies suggest that diuretics are superior to other drugs in
      decreasing pulse pressure. An increase of pulse pressure during therapy should be
      avoided since each 10 mmHg increase in pulse pressure will raise the risk of
      stroke and myocardial infarction about 24 % and 32 %.

PMID- 12422298
TI  - [Hypertensive emergency].

PMID- 12422300
TI  - [Intracellular signal transduction of angiotensin II and possible interventions
      in the renin-angiotensin system].

PMID- 12422301
TI  - [New options in the drug treatment of hypertension: claim and reality].

PMID- 12422303
TI  - Oncosurgery: a new reality in metastatic colorectal carcinoma.
AB  - Surgery is the only curative option for the treatment of liver metastases from
      colorectal cancer. However, fewer than 25% of hepatic metastases are suitable for
      resection and as many as 70% of these will recur. A variety of factors have been
      identified as significant predictors of long-term survival following hepatic
      resection, and improved surgical techniques such as cryosurgery, radiofrequency
      ablation, portal vein embolization, and two-stage hepatectomy have been developed
      to overcome some of the negative factors that contribute to poor prognosis.
      Whereas adjunctive 5-fluorouracil-based chemotherapy has had little impact on
      outcome, the new platinum derivative oxaliplatin added to 5-fluorouracil plus
      leucovorin has improved time-dependent parameters of efficacy and successfully
      downstaged the disease in some patients with unresectable metastases. In a recent
      study in 389 such patients, 151 of which had liver-only metastases, 51% treated
      with oxaliplatin became resectable with some patients achieving a complete
      histologic response. In another series of 95 initially unresectable patients who
      became resectable after treatment with oxaliplatin-based therapy, 41% were still
      alive after 4.2 years, with 64% of these being recurrence-free. Postoperative
      chemotherapeutic regimes have also been developed to eliminate residual disease
      after surgery; however, the advantage of preoperative chemotherapy is the
      potential to achieve a conversion from unresectability to resectability of
      hepatic metastases from primary colorectal cancer.

PMID- 12422304
TI  - Oxaliplatin-related side effects: characteristics and management.
AB  - Oxaliplatin is the only third-generation platinum derivative to have found a
      place in routine cancer therapy. It is particularly useful therapy for advanced
      colorectal cancer and has shown scheduling flexibility in combination with 5
      fluorouracil/folinic acid. Oxaliplatin has a unique pattern of side effects
      unrelated to those observed with other therapeutic platinum derivatives. During
      the course of oxaliplatin clinical trials, the adverse events most often cited
      were hematologic toxicity, gastrointestinal tract toxicity, and a neurolopathy
      unlike that observed with other platinum derivatives. Grade 3/4 neutropenia
      occurred in 41.7% of patients in the phase III clinical trial that used the
      FOLFOX-4 regimen, and thrombocytopenia is a rare event sometimes observed after
      multiple cycles of therapy. Nausea and vomiting is usually mild to moderate and
      readily controlled with standard antiemetics. Grade 1/2 diarrhea may occur but
      studies have shown that 5-fluorouracil contributes significantly more to
      gastrointestinal toxicity than does single-agent oxaliplatin. Nephrotoxicity has
      not been reported in any of the oxaliplatin trials, allowing administration of
      oxaliplatin without hydration. Oxaliplatin-induced neurotoxicity consists of a
      rapid-onset acute sensory neuropathy and a late-onset cumulative sensory
      neuropathy that occurs after several cycles of therapy. In about three fourths of
      patients, neurotoxicity is reversible with a median time to recovery of 13 weeks
      after treatment discontinuation. To date, oxaliplatin has proven to be a safe and
      effective therapy for colorectal cancer and side effects have been easy to manage
      with appropriate awareness from patients and care providers.

PMID- 12422305
TI  - Clinical aspects and molecular basis of oxaliplatin neurotoxicity: current
      management and development of preventive measures.
AB  - Neurotoxicity is the most frequent dose-limiting toxicity of oxaliplatin. Acute
      neurotoxicity is characterized by the rapid onset of cold-induced distal
      dysesthesia and/or paresthesia. Sensory symptoms may also be accompanied by cold
      dependent muscular contractions of the extremities or the jaw. The symptoms,
      often occurring during or shortly after infusion, are usually transient and mild.
      A persistent sensory peripheral neuropathy may also develop with prolonged
      treatment, eventually causing superficial and deep sensory loss, sensory ataxia,
      and functional impairment. Studies have shown patients with acute sensory
      symptoms to display little or no axonal degeneration, suggesting a specific
      effect of oxaliplatin on sensory neurons and/or motor neurons or muscle cells
      that is not observed with other platinum agents. The similarity of the acute
      symptoms induced by oxaliplatin with those caused by several drugs or toxins
      acting on neuronal or muscular ion channels suggests that these symptoms may
      result from a specific interaction of oxaliplatin with ion channels located in
      the cellular membrane. Recent data indicate that oxaliplatin may act on specific
      isoforms of the voltage gated sodium (Na(+)) channel to increase the excitability
      of sensory neurons, an action inhibited by the Na(+) channel blocker
      carbamazepine. This contention is supported by recent clinical findings
      indicating that pharmacologic blockade of Na(+) channels may prevent and/or
      repress the acute neurotoxicity of oxaliplatin. Although there is no indication
      at the moment that a common cellular mechanism induces both the acute and the
      cumulative neurotoxicity of oxaliplatin, controlled clinical trials are currently
      underway to establish the value of Na(+) channel blockade against both acute and
      cumulative oxaliplatin neurotoxicities.

PMID- 12422306
TI  - The role of oxaliplatin in the treatment of advanced metastatic colorectal
      cancer: prospects and future directions.
AB  - In the last 50 years, 5-fluorouracil-based therapy has been the mainstay of
      adjuvant and palliative treatment for colorectal cancer but response rates and
      median survival have been dismal despite the introduction of thymidylate synthase
      modulators such as leucovorin. Recently, new therapeutic approaches have been
      introduced. These include oral 5-fluorouracil analogues, pure thymidylate
      synthase inhibitors, dihydropyrimidine dehydrogenase inhibitors, and agents with
      mechanism of action unrelated to thymidylate synthase such as irinotecan, a
      topoisomerase I inhibitor, and oxaliplatin, the only platinum derivative with
      significant activity in colorectal cancer. Current treatment strategies involve
      combination therapies because this approach is the most effective. For instance,
      responses observed with oxaliplatin and 5-fluorouracil indicate synergy between
      the two agents and the combination of capecitabine plus oxaliplatin or irinotecan
      has shown high activity both in chemotherapy-naive and in pretreated patients
      with advanced colorectal cancer. Additionally, it is likely that future
      therapeutic management of advanced colorectal cancer may include combination
      therapy of one of the new oral 5-fluorouracil analogues, because of the
      convenient oral regimens. The identification of colorectal cancer-specific
      prognostic factors will undoubtedly influence treatment decisions. For instance,
      patients overexpressing epidermal growth factor receptor and p53 with thymidylate
      synthase have a worse prognosis. To target these biomarkers, antibodies such as
      cetuximab, an anti-EGFR antibody, and angiogenesis inhibitors and tyrosine kinase
      inhibitors have been introduced and are undergoing clinical evaluation. Over the
      last 5 years the armamentarium to fight colorectal cancer has increased
      significantly, giving more hope for effective disease management.

PMID- 12422308
TI  - Overview of epidermal growth factor receptor biology and its role as a
      therapeutic target in human neoplasia.
AB  - The ability of the epidermal growth factor receptor (EGFR) to transform
      epithelial cells, the overexpression of EGFR and its ligands in several human
      carcinomas, and the causal association of the receptor network with accelerated
      tumor progression provided a rationale for targeting this signaling system with
      tumor-selective strategies. Two of these antireceptor approaches, both based on
      the known structure/function of the EGFR, will be discussed. The first strategy
      involved the development of humanized monoclonal antibodies against the
      nonconserved receptor's extracellular domain. These antibodies block ligand
      binding and can induce receptor downregulation. The second approach was the
      generation of adenosine triphosphate-mimetics that compete with adenosine
      triphosphate for binding to the receptor's kinase pocket and disable the ability
      of the EGFR to transduce intracellular signals. Early clinical studies already
      suggest that both of these approaches, either alone or in combination with
      standard anticancer therapies, alter the natural history of EGFR-expressing
      cancers with little toxicity to the tumor-bearing host.

PMID- 12422309
TI  - Epidermal growth factor receptor-targeted therapy in colorectal cancer.
AB  - Advanced colorectal carcinoma is a major cause of morbidity and mortality in the
      United States and other developed countries. Thus, new therapeutic strategies are
      urgently needed. The expression of various growth factors, growth inhibitors, and
      their receptors contributes to the development of colorectal cancer as well as to
      the proliferation and survival of malignant cells. Approximately 65% to 70% of
      human colon carcinomas have been shown to express the epidermal growth factor
      receptor (EGFR). Several investigators have reported that EGFR expression
      correlates with more aggressive disease and a poorer prognosis. Epidermal growth
      factor receptor plays a crucial role in initiating signal transduction; thus,
      strategies directed towards interruption of this signaling pathway have been
      shown to impair tumor cell proliferation. These include anti-EGFR monoclonal
      antibodies, immunotoxin conjugates, and EGFR tyrosine kinase inhibitors.
      Preclinical and clinical trials using these new therapeutic modalities appear
      promising in the treatment of colorectal cancer and are reviewed in this article.

PMID- 12422310
TI  - IMC-C225, an anti-epidermal growth factor receptor monoclonal antibody for
      treatment of head and neck cancer.
AB  - Squamous cell carcinoma of the head and neck remains a clinical challenge because
      of the high rate of locoregional disease recurrence. The importance of the
      epidermal growth factor receptor (EGFR) in the development and progression of
      many solid tumors, including squamous cell carcinoma of the head and neck, is
      well understood; increased expression is associated with enhanced tumor
      invasiveness, resistance to chemotherapy, and a lower patient survival rate.
      Several approaches have been developed to achieve EGFR blockade as an anticancer
      treatment strategy, including the anti-EGFR monoclonal antibody IMC-C225, which
      competitively binds to the extracellular receptor site and prevents binding by
      the natural EGFR ligands EGF and transforming growth factor-alpha. Preclinical
      studies to evaluate IMC-225 in human cancer cell lines in vitro and human tumor
      xenografts in vivo have shown its potent antitumor activity. Clinical efficacy of
      IMC-C225 appears to involve multiple mechanisms, including inhibition of cell
      cycle progression, induction of apoptosis, inhibition of angiogenesis, inhibition
      of metastasis, and enhancement of the response to chemotherapy and radiation
      therapy. Phase I studies of IMC-C225 combined with chemotherapy or radiation
      showed promising response rates in patients with recurrent or refractory squamous
      cell carcinoma of the head and neck. Phase II and III trials to examine the
      efficacy and safety of these combinations are currently underway. To date, IMC
      C225 has been well tolerated, with skin rashes and allergic reactions being the
      most clinically important adverse events reported. IMC-C225 displays dose
      dependent elimination characteristics and a half-life of approximately 7 days.
      Current recommendations for dosing include a 400 mg/m(2) loading dose, followed
      by weekly infusions at 250 mg/m(2).

PMID- 12422311
TI  - Epidermal growth factor receptor-targeted therapy for pancreatic cancer.
AB  - Epidermal growth factor receptor (EGFR) plays an important role in tumor
      development and maintenance. It is a cell surface molecule that mediates signal
      transduction from the cell surface to cytoplasm. Elevated expression of EGFR or
      its ligand correlates with worse prognosis in a variety of human cancers.
      Therefore, blockade of EGFR activity would provide a novel strategy for the
      treatment of cancer. Two classes of EGFR inhibitors, monoclonal antibodies and
      tyrosine kinase inhibitors, have been described. The preclinical activity of
      these EGFR inhibitors and phase I clinical data are summarized in this article. A
      phase II trial of the EGFR inhibitor IMC-C225 in combination with gemcitabine for
      patients with advanced pancreatic cancer is discussed.

PMID- 12422312
TI  - Epidermal growth factor receptor expression, signal pathway, and inhibitors in
      non-small cell lung cancer.
AB  - The majority of non-small cell lung cancers (NSCLCs) overexpress the epidermal
      growth factor receptor (EGFR). The EGFR is frequently overexpressed in
      preneoplastic bronchial lesions. Thus, EGFR is an excellent potential target for
      prevention and therapy. New agents developed to inhibit EGFR function include
      monoclonal antibodies to EGFR and small-molecule receptor tyrosine kinase
      inhibitors. Preclinical studies showed that both types of inhibitors blocked the
      in vitro growth of human NSCLC cell lines by inhibiting receptor phosphorylation
      and phosphorylation of downstream proteins including MAP kinases and AKT. Both
      types of inhibitors also slowed the growth of human NSCLC tumors in nude mice.
      Additive or synergistic growth inhibition resulted from the combination of either
      type of inhibitor with chemotherapy and/or radiotherapy. Clinical phase I and
      phase II trials showed that both types of inhibitors could be delivered safely,
      and serum concentrations equivalent to or higher than those required for in vitro
      activity were achieved. Skin rash was the dose-limiting toxicity with all
      inhibitors. The skin rash was dose related and reversible. Objective responses
      were observed in advanced-stage patients refractory to chemotherapy, though the
      responses were partial responses. Response rates appear higher when the
      inhibitors are combined with chemotherapy. The results of randomized trials
      comparing the use of chemotherapy alone with chemotherapy plus the inhibitors are
      eagerly awaited.

PMID- 12422313
TI  - Epidermal growth factor receptor expression and measurement in solid tumors.
AB  - The efficacies of targeted therapies for cancer treatment are dependent on the
      expression of the targeted molecule in the tumors of the treated patient
      population. Immunohistochemistry is an attractive assay format for determining
      protein expression in biopsies of solid tumors, and is widely used in pathology
      laboratories. An optimized immunohistochemistry assay for the epidermal growth
      factor receptor (EGFR) has been developed for the detection of EGFR in
      colorectal, head and neck, and other tumors that express EGFR, and the assay is
      being used in colorectal cancer trials of IMC-C225 to select patients for
      treatment. The specificity of the assay and the detection technology used will be
      described, along with other assay methodologies and applications for EGFR
      testing.

PMID- 12422314
TI  - Safety experience with IMC-C225, an anti-epidermal growth factor receptor
      antibody.
AB  - In phase II trials, the anti-epidermal growth factor receptor antibody IMC-C225
      did not appear to significantly exacerbate the common toxicities associated with
      cytotoxic chemotherapy when combined with standard anticancer treatments in
      patients with colorectal cancer, squamous cell carcinoma of the head and neck, or
      pancreatic cancer. The most common treatment-related adverse events reported
      during therapy with IMC-C225 were an acne-like rash and hypersensitivity
      reactions. The acne-like rash appeared as a sterile, suppurative form of
      folliculitis, commonly starting on the face, scalp, chest, and upper back. It
      resolved without scarring once treatment was stopped. Notably, the appearance of
      acne-like rash, particularly grade 3, was associated with higher treatment
      responses in patients with refractory colorectal cancer. The hypersensitivity
      reactions occurred less often than acne-like rash. They responded to standard
      treatments and were less common after the first dose. In summary, IMC-C225 is
      generally well tolerated as a single agent and when combined with chemotherapy or
      radiotherapy and possesses a manageable toxicity profile.

PMID- 12422316
TI  - Subcutaneous adipose tissue thickness alters cooling time during cryotherapy.
AB  - OBJECTIVE: To determine if differing subcutaneous adipose thickness alters the
      treatment duration required to produce a standard cooling effect during
      cryotherapy. DESIGN: A 4-group, between-groups comparison in which the
      independent variable was skinfold thickness (0-10mm, 11-20mm, 21-30mm, 31-40mm)
      and the dependent variable was cooling time, defined as the treatment duration
      required to decrease intramuscular (IM) temperature 7 degrees C from baseline.
      SETTING: A sports injury research laboratory. PARTICIPANTS: Forty-seven
      volunteers with anterior thigh skinfold measurement of less than 40mm.
      INTERVENTION: Topical cryotherapy (750g crushed-ice bag) to the anterior thigh to
      produce a typical cooling effect, defined as IM temperature at 1cm subadipose
      declining by 7 degrees C. MAIN OUTCOME MEASURE: Cryotherapy treatment duration
      required to produce a standardized cooling effect in subjects with differing
      subcutaneous adipose thickness. RESULTS: Analysis of variance revealed that mean
      time to cool IM tissues by 7 degrees C differed across all groups, with cooling
      time increasing as adipose thickness increased. The mean +/- standard deviation
      cooling times were as follows: 31-40mm (58.6+/-11.7min), 21-30mm (37.8+/-9.6min),
      11-20mm (23.3+/-6.7min), and 0-10mm (8.0+/-3.4min). CONCLUSIONS: During cold
      application, there is a clinically important direct relationship between adipose
      thickness and required cooling time. This relationship necessitates dramatic
      adjustments to cryotherapy duration to produce similar IM temperature changes. A
      25-minute treatment may be adequate for a patient with a skinfold of 20mm or
      less; however, a 40-minute application is required to produce similar results in
      a patients with skinfolds between 21 and 30mm, whereas a 60-minute application is
      required for patients with skinfolds of 30 to 40mm.

PMID- 12422317
TI  - Dynamic imaging in mild traumatic brain injury: support for the theory of medial
      temporal vulnerability.
AB  - OBJECTIVE: To determine whether patients with mild traumatic brain injury (TBI)
      and persistent postconcussive symptoms have evidence of temporal lobe injury on
      dynamic imaging. DESIGN: Case series. SETTING: An academic medical center.
      PARTICIPANTS: Twenty patients with a clinical diagnosis of mild TBI and
      persistent postconcussive symptoms were referred for neuropsychologic evaluation
      and dynamic imaging. Fifteen (75%) had normal magnetic resonance imaging (MRI)
      and/or computed tomography (CT) scans at the time of injury. INTERVENTIONS:
      Neuropsychologic testing, positron-emission tomography (PET), and single-photon
      emission-computed tomography (SPECT). MAIN OUTCOME MEASURES: Temporal lobe
      findings on static imaging (MRI, CT) and dynamic imaging (PET, SPECT);
      neuropsychologic test findings on measures of verbal and visual memory. RESULTS:
      Testing documented neurobehavioral deficits in 19 patients (95%). Dynamic imaging
      documented abnormal findings in 18 patients (90%). Fifteen patients (75%) had
      temporal lobe abnormalities on PET and SPECT (primarily in medial temporal
      regions); abnormal findings were bilateral in 10 patients (50%) and unilateral in
      5 (25%). Six patients (30%) had frontal abnormalities, and 8 (40%) had
      nonfrontotemporal abnormalities. Correlations between neuropsychologic testing
      and dynamic imaging could be established but not consistently across the whole
      group. CONCLUSIONS: Patients with mild TBI and persistent postconcussive symptoms
      have a high incidence of temporal lobe injury (presumably involving the
      hippocampus and related structures), which may explain the frequent finding of
      memory disorders in this population. The abnormal temporal lobe findings on PET
      and SPECT in humans may be analogous to the neuropathologic evidence of medial
      temporal injury provided by animal studies after mild TBI.

PMID- 12422318
TI  - Functional gains and therapy intensity during subacute rehabilitation: a study of
      20 facilities.
AB  - OBJECTIVES: To document patient, program characteristics, and therapy service
      provision in subacute rehabilitation across 3 types of facilities that provide
      subacute rehabilitation, to examine the determinants of therapy intensity, and to
      evaluate the contribution of rehabilitation services to functional gains. DESIGN:
      A retrospective study linking administrative billing data and patients'
      functional assessment records. SETTING: Twenty facilities part of the Uniform
      Data System for Medical Rehabilitation (UDSMR) subacute database PARTICIPANTS: A
      total of 1976 billing records of patients with stroke, orthopedic, and debility
      impairments, discharged in 1996 and 1997, were retrieved and linked with the FIM
      trade mark instrument ratings from UDSMR subacute database. INTERVENTIONS: Not
      applicable. MAIN OUTCOMES MEASURES: Total therapy intensity and Rasch-transformed
      FIM domain gains (ie, gains in self-care, mobility, cognition). RESULTS: Therapy
      intensity was mostly determined by impairment and facility type, although
      variances explained by the predictors were small. Patients in all 3 impairment
      groups made functional gains; gains were related weakly, although significantly,
      to therapy intensity and rehabilitation duration after controlling for other
      variables. CONCLUSIONS: The provision of rehabilitation therapies varied across
      facilities. Skilled nursing facilities with subacute rehabilitation units tended
      to provide more therapies than subacute units in acute or rehabilitation
      hospitals.

PMID- 12422319
TI  - Responsiveness of the Impact on Participation and Autonomy questionnaire.
AB  - OBJECTIVE: To evaluate the responsiveness of a newly developed generic
      questionnaire, the Impact on Participation and Autonomy (IPA), which focuses on 2
      aspects of participation: perceived participation and the experience of problems.
      DESIGN: Preliminary study of questionnaire responsiveness compared with
      transition indices. Participants completed 2 assessments, 3 months apart. To
      measure change, they completed 9 transition indices at the second assessment. One
      transition index assessed perceived change in general, the other 8 addressed 1 of
      the specific problem experience items in the IPA. SETTING: Outpatient clinic of
      the rehabilitation department of an academic hospital. PARTICIPANTS: Fifty-seven
      consecutive persons admitted for multidisciplinary rehabilitation treatment, with
      various diagnoses, were enrolled in the study; 49 persons completed both
      assessments. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Standardized
      response mean (SRM) and area under the receiver operating characteristic curve
      (AUC) for participation domain scores and problem scores. RESULTS: SRMs and AUCs
      for the participation domains ranged from 0.1 to 1.3 and from 50% to 92%,
      respectively. The SRMs of the items on the experience of problems ranged from 0.4
      to 1.5, whereas their AUCs ranged from 56% to 74%. CONCLUSIONS: The IPA detected
      within-person improvement over time, but its responsiveness must be confirmed in
      a larger study sample.

PMID- 12422320
TI  - Evaluation of healthy and diseased muscle with magnetic resonance elastography.
AB  - OBJECTIVE: To investigate whether a new tissue-imaging technique, magnetic
      resonance elastography (MRE), offers a viable, noninvasive way to study healthy
      and diseased muscle. DESIGN: Convenience sample. SETTING: A magnetic resonance
      imaging (MRI) laboratory. PARTICIPANTS: Eight control subjects (4 men, 4 women),
      between the ages of 24 and 41 years, with normal neuromuscular examinations and
      histories, and 6 subjects (3 men, 3 women), ages 17 to 63 years, with lower
      extremity neuromuscular dysfunction (1 with childhood poliomyelitis, 2 with
      flaccid, 3 with spastic paraplegia). INTERVENTIONS: Subjects lay supine with
      their legs within the coils of a 1.5T MRI machine, with their feet strapped to a
      footplate positioned so that the axes of rotation of their ankles coincided with
      the apparatus. All subjects were tested in a no-load (0 torque) condition.
      Control subjects were also evaluated as they isometrically resisted ankle dorsi-
      (20.2Nm, 40.5Nm) and plantar- (8.2Nm, 16.4Nm) flexion moments. Subjects with
      neuromuscular dysfunction were evaluated in the same manner, except 1 individual
      with residual lower-extremity strength who could only be tested in the resting
      and passive ankle dorsiflexion modes. Shear waves were induced with a 150-Hz
      electromechanic transducer located over the belly tibialis anterior. MRE images
      were collected with a gradient-echo technique gated to the transducer's motion.
      Wave-phase propagation was visualized with 8 equally offset images across 1
      vibration-cycle. MAIN OUTCOME MEASURES: Changes in shear-wave wavelength (lambda)
      and muscle stiffness (as expressed by the shear modulus [G]) in the tibialis
      anterior and gastrocnemius muscles. RESULTS: Wavelength and G differed between
      the groups in all the muscles studied, and increased as the load increased.
      Moreover, lambda and G in the neuromuscular disease group at rest (eg, 3.88+/
      0.48cm; range, 2.87-4.91cm; 38.40+/-00.77kPa; range, 22.35-59.67kPa) and in the
      lateral gastrocnemius were, respectively, more than 1.5 and 2.4 times larger than
      they were in the same muscle in the control group (2.56+/-0.28cm, 16.16+/
      00.19kPa; P=.0002) (1Pa=1N/m(2)). CONCLUSIONS: Shear-wave wavelength and muscle
      stiffness increased with load in healthy muscle. In addition, at least for our
      sample, these quantities differed significantly between muscles with and without
      neuromuscular disease. In summary, MRE appears to provide in vivo physiologic
      information about the mechanical properties of muscle at rest and during
      contraction that is not otherwise available. The potential of this technique for
      monitoring the effects of treatment and exercise on both healthy and diseased
      muscle merits further research.

PMID- 12422321
TI  - Medical students' attitudes toward persons with disability: a comparative study.
AB  - OBJECTIVES: To investigate first-year medical students' attitudes toward persons
      with disability and to examine whether gender and a background in disability
      determine attitudes toward persons with disability. DESIGN: A cross-sectional
      survey. SETTING: University settings in the United States and Canada.
      PARTICIPANTS: Ninety first-year medical students (US, n=46; Canada, n=44) were
      surveyed. INTERVENTION: Medical students given 3 surveys. MAIN OUTCOME MEASURES:
      Attitude Toward Disabled Persons (ATDP) Scale, Scale of Attitudes Toward Disabled
      Persons (SADP), and Rehabilitation Situations Inventory (RSI). RESULTS: There
      were no differences between the medical student groups from the United States and
      Canada. Compared with norms, medical students overall have more positive
      attitudes on the ATDP. Their attitudes were less positive on the SADP and on its
      optimism-human rights subscale. On the RSI, they were less comfortable with
      sexual situations and depression. Male medical students held poorer attitudes as
      scored than female medical students. Those with a background in disability were
      more comfortable dealing with challenging rehabilitation situations. Comfort with
      challenging rehabilitation situations showed significant differences across
      levels of experience but not gender. The more positive medical students'
      attitudes are toward persons with disability, the more likely they are to be
      comfortable with challenging rehabilitation situations. CONCLUSION: First-year
      medical students from the United States and Canada held similar attitudes and had
      less positive attitudes than SADP norms. Gender and background in disability
      influenced attitudes. Male medical students were more likely to hold negative
      attitudes. Specific educational experiences need to promote more positive
      attitudes.

PMID- 12422322
TI  - Electromyographic activity of the trunk extensor muscles: effect of varying hip
      position and lumbar posture during Roman chair exercise.
AB  - OBJECTIVE: To evaluate the effect of hip position and lumbar posture on the
      surface electromyographic activity of the trunk extensors during Roman chair
      exercise. DESIGN: Descriptive, repeated measures. SETTING: University-based
      musculoskeletal research laboratory. PARTICIPANTS: Twelve healthy volunteers (7
      men, 5 women; age range, 18-35y) without a history of low back pain were
      recruited from a university setting. INTERVENTIONS: Not applicable. MAIN OUTCOME
      MEASURES: Surface electromyographic activity was recorded from the lumbar
      extensor, gluteal, and hamstring musculature during dynamic Roman chair exercise.
      For each muscle group, electromyographic activity (mV/rep) was compared among
      exercises with internal hip rotation and external hip rotation and among
      exercises by using a typical lumbar posture (nonbiphasic) and a posture that
      accentuated lumbar lordosis (biphasic). RESULTS: For the lumbar extensors,
      electromyographic activity during exercise was 18% greater with internal hip
      rotation than external hip rotation (P< or =.05) and was 25% greater with a
      biphasic posture than with a nonbiphasic posture (P< or =.05). For the gluteals
      and hamstrings, there was no difference in electromyographic activity between
      internal and external hip rotation or between biphasic and nonbiphasic postures
      (P >.05). CONCLUSION: The level of recruitment of the lumbar extensors can be
      modified during Roman chair exercise by altering hip position and lumbar posture.
      Clinicians can use these data to develop progressive exercise protocols for the
      lumbar extensors with a variety of resistance levels without the need for complex
      equipment.

PMID- 12422323
TI  - Electromyographic activity of the lumbar and hip extensors during dynamic trunk
      extension exercise.
AB  - OBJECTIVE: To evaluate the effects of exercise intensity and multiple sets on
      muscle activation patterns during trunk extension exercise. DESIGN: Descriptive,
      repeated measures. SETTING: University-based musculoskeletal research laboratory.
      PARTICIPANTS: Twenty volunteers recruited from a university setting.
      INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: Electromyographic activity
      was recorded from the L3-4 paraspinal region, gluteus maximus, and biceps femoris
      muscles during multiple sets of trunk extension exercise at intensities
      representing 40%, 50%, and 70% of peak isometric force. RESULTS: As exercise
      intensity increased, the electromyographic activity of the gluteus maximus
      increased to a greater extent than the activity of the paraspinal region. At the
      50% intensity level, biceps femoris electromyographic activity was significantly
      greater than the paraspinal region electromyographic activity, whereas at the 70%
      intensity no differences were found between muscles. During multiple sets of
      exercise at the same intensity a muscle by set interaction was observed. This
      interaction revealed that with respect to other muscle groups, the
      electromyographic activity of the gluteus maximus increased between sets 1 and 2,
      whereas electromyographic decrements occurred in the paraspinal region. During
      exercise at the 40% intensity level, biceps femoris electromyographic activity
      increased to a greater extent between sets 1 and 2 when compared with the
      paraspinal region. CONCLUSION: Exercise intensity and multiple sets result in
      alterations in muscle recruitment patterns of the lumbar and hip extensor
      muscles. These findings raise questions as to the efficacy of added loading and
      multiple sets during trunk extension exercise.

PMID- 12422324
TI  - The clinical identification of peripheral neuropathy among older persons.
AB  - OBJECTIVE: To identify simple clinical rules for the detection of a diffuse
      peripheral neuropathy among older outpatients. DESIGN: Observational, blinded,
      controlled study. SETTING: A tertiary-care electrodiagnostic laboratory and
      biomechanics laboratory. PARTICIPANTS: One hundred research subjects, 68 with
      electrodiagnostic evidence of peripheral neuropathy, between the ages of 50 and
      80 years. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASUREMENTS: One examiner,
      unaware of the results of electrodiagnostic testing, evaluated Achilles' and
      patellar reflexes, Romberg testing, semiquantified vibration, and position sense
      at the toe and ankle in all subjects, and unipedal stance time and the Michigan
      Diabetes Neuropathy Score in a subset of subjects. RESULTS: Significant group
      differences were present in all clinical measures tested. Three signs, Achilles'
      reflex (absent despite facilitation), vibration (128Hz tuning fork perceived for
      <10s), and position sense (<8/10 1-cm trials) at the toe, were the best
      predictors of peripheral neuropathy on both univariate and logistic regression
      (pseudo R(2)=.744) analyses. The presence of 2 or 3 signs versus 0 or 1 sign
      identified peripheral neuropathy with sensitivity, specificity, and positive and
      negative predictive values of 94.1%, 84.4%, 92.8%, and 87.1%, respectively.
      Values were similar among subgroups of subjects with and without diabetes
      mellitus. When other clinicians applied the technique to 12 more subjects,
      excellent interrater reliability regarding the presence of peripheral neuropathy
      (kappa=.833) and good to excellent interrater reliability for each sign (kappa
      range,.667-1.00) were shown. CONCLUSION: Among older persons, the presence of 2
      or 3 of the 3 clinical signs strongly suggested electrodiagnostic evidence of a
      peripheral neuropathy, regardless of etiology. Age-related decline in peripheral
      nerve function need not be a barrier to the clinical recognition of a diffuse
      peripheral neuropathy among older persons.

PMID- 12422325
TI  - Body composition in ambulatory women with multiple sclerosis.
AB  - OBJECTIVE: To compare whole-body fat mass and fat-free mass (FFM) in ambulatory
      patients with multiple sclerosis (MS) and control subjects without MS. DESIGN:
      Nonrandomized controlled trial or cross-sectional study. SETTING: An exercise
      physiology laboratory at a medical school. PARTICIPANTS: Seventeen ambulatory
      patients with MS and 12 control subjects (all subjects were women). The median
      Expanded Disability Status Scale (EDSS) score was 4.0 for the individuals with
      MS. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Whole-body percentage
      of fat-free mass (%FFM), percentage of body fat (%BF), FFM, and fat mass.
      RESULTS: A significant difference in age was observed between the groups; thus,
      age was used as a covariate in the body composition analyses. No significant
      differences were observed between the groups in %BF: 32.5+/-13.9 and 27.8+/-5.6
      (P=.54) for MS and controls, respectively, or %FFM, 67.1+/-14.9 and 71.3+/-12.4
      (P=.42) for MS and controls, respectively. For individuals with MS, no
      significant relation was observed between EDSS score and %BF (P=.24) or between
      EDSS score and %FFM (P=.24). CONCLUSION: No significant differences were observed
      in body composition between ambulatory MS patients and controls. Furthermore, the
      EDSS score was not a significant predictor of %BF or %FFM for people with MS.

PMID- 12422326
TI  - Reliability of the two-minute walk test in individuals with transtibial
      amputation.
AB  - OBJECTIVE: To determine inter- and intrarater reliability of the two-minute walk
      test (2MWT) in individuals with transtibial amputation. DESIGN: Prospective; test
      retest method by a pair of trained physical therapists. SETTING: Two regional
      amputee rehabilitation centers in Canada. PARTICIPANTS: Thirty-three subjects (23
      men, 10 women; mean age +/- standard error, 63.6+/-2.0y) with transtibial
      amputation; 6 in outpatient rehabilitation, 27 in inpatient rehabilitation. The
      most common primary diagnoses were peripheral vascular disease (n=15) and
      diabetes (n=11). INTERVENTIONS: Each subject performed a total of four 2MWTs, 1
      test for each rater, on 2 consecutive days at approximately the same time of day.
      Subjects were given at least a 20-minute rest between tests. The order of raters
      was randomized on the first day and reversed for the next day. The walk tests
      were performed in the same enclosed corridors with the same starting point for
      all tests. The subjects were familiar with the test or were given 1 or more
      practice tests at least 1 day before testing. Subjects were allowed to walk with
      a mobility aid of their choice. Raters used a digital stopwatch to time the tests
      and a calibrated wheel with a counter to measure the distance walked in meters.
      The raters were blinded to each other's scores. MAIN OUTCOME MEASURE: Distance
      walked in 2 minutes (in meters). RESULTS: Within-rater reliability was high
      (intraclass correlation coefficient [ICC],.90-.96). Between rater reliability was
      also high (ICC.98-.99). Analysis of variance (ANOVA) showed a significant effect
      for day of test (P<.001) in the inpatient group but no effect for therapist
      (P=.098) or for interaction of day and therapist (P=.710). Similarly, in the
      outpatient group, ANOVA showed a significant effect for day (P=.013) but no
      effect for therapist (P=.259) or interaction of day and therapist (P=.923).
      CONCLUSION: Although the 2MWT showed evidence of inter- and intrarater
      reliability in individuals with unilateral below-knee amputation, the distance
      walked in 2 minutes continued to improve over time. This improvement was not
      solely the result of a training and learning effect.

PMID- 12422327
TI  - A clinical test of stepping and change of direction to identify multiple falling
      older adults.
AB  - OBJECTIVES: To establish the reliability and validity of a new clinical test of
      dynamic standing balance, the Four Square Step Test (FSST), to evaluate its
      sensitivity, specificity, and predictive value in identifying subjects who fall,
      and to compare it with 3 established balance and mobility tests. DESIGN: A 3
      group comparison performed by using 3 validated tests and 1 new test. SETTING: A
      rehabilitation center and university medical school in Australia. PARTICIPANTS:
      Eighty-one community-dwelling adults over the age of 65 years. Subjects were age-
      and gender-matched to form 3 groups: multiple fallers, nonmultiple fallers, and
      healthy comparisons. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Time
      to complete the FSST and Timed Up and Go test and the number of steps to complete
      the Step Test and Functional Reach Test distance. RESULTS: High reliability was
      found for interrater (n=30, intraclass correlation coefficient [ICC]=.99) and
      retest reliability (n=20, ICC=.98). Evidence for validity was found through
      correlation with other existing balance tests. Validity was supported, with the
      FSST showing significantly better performance scores (P<.01) for each of the
      healthier and less impaired groups. The FSST also revealed a sensitivity of 85%,
      a specificity of 88% to 100%, and a positive predictive value of 86%. CONCLUSION:
      As a clinical test, the FSST is reliable, valid, easy to score, quick to
      administer, requires little space, and needs no special equipment. It is unique
      in that it involves stepping over low objects (2.5cm) and movement in 4
      directions. The FSST had higher combined sensitivity and specificity for
      identifying differences between groups in the selected sample population of older
      adults than the 3 tests with which it was compared.

PMID- 12422328
TI  - Eccentric contraction injury in dystrophic canine muscle.
AB  - OBJECTIVE: To test the hypothesis that eccentric contractions induce greater
      injury in dystrophic compared with normal canine muscle. DESIGN: Blinded cohort
      study. SETTING: Animal laboratory. ANIMALS: Ten dogs with a homologue to Duchenne
      muscular dystrophy (Golden retriever muscular dystrophy [GRMD]) and 10 normal
      littermates. INTERVENTIONS: Contractions induced in tibiotarsal flexors and
      extensors by sciatic nerve stimulation. Because more powerful extensors overrode
      flexors, eccentric contractions occurred in flexors. Concentric contractions were
      induced in contralateral flexors by peroneal nerve stimulation. MAIN OUTCOME
      MEASURE: Tibiotarsal flexion force 3 days after contractions. Muscle was examined
      for injury (esterase activity, Evans blue dye penetration) and regeneration
      (embryonic myosin isoform expression). RESULTS: Mean force deficit after
      eccentric flexor contractions was 43.3%+/-25.7% in GRMD dogs compared with
      25.0%+/-18.4% in controls (P=.04, Wilcoxon rank-sum test). Concentric
      contractions induced force deficits in GRMD but not normal dogs; however, the
      difference between the 2 groups was not significant (P=.08, Wilcoxon rank-sum
      test). After concentric contractions in controls, force decrements correlated
      with esterase activity measured by area (r=.794, P=.006) and intensity (r=.697,
      P=.025, Spearman rank correlation). No other significant correlation was detected
      between force and biopsy data. CONCLUSIONS: Force data support the hypothesis
      that eccentric contractions induce greater injury in dystrophic compared with
      normal canine muscle. Phenotypic features of the dystrophic canine model used
      here are similar to those of humans with Duchenne's.

PMID- 12422329
TI  - Scaling of the revised Oswestry low back pain questionnaire.
AB  - OBJECTIVE: To evaluate the measurement properties of the Revised Oswestry
      Disability Questionnaire (RODQ) by using rating scale analyses. DESIGN:
      Calibration of item responses by using a data set. SETTING: Four outpatient
      therapy clinics in the northeastern United States. PATIENTS: Convenience sample
      of 95 community-dwelling adults exhibiting mild to severe low back pain-related
      disability (LBP-D). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: The
      RODQ. RESULTS: Several Rasch analyses were performed, with 1 item deleted and 2
      response categories collapsed, creating a better test without increased error. A
      schema for item administration and evaluation was also developed. CONCLUSIONS: By
      using the abbreviated scale, suggested item order, and predicted responses,
      abbreviated versions of the instrument can be applied to measure LBP-D more
      efficiently.

PMID- 12422330
TI  - Changes in sagittal lumbar configuration with a new method of extension traction:
      nonrandomized clinical controlled trial.
AB  - OBJECTIVE: To determine if a new method of lumbar extension traction can increase
      lordosis in chronic low back pain (LBP) subjects with decreased lordosis. DESIGN:
      Nonrandomized controlled trial with follow-up at 3 months and 1(1/2) years.
      SETTING: Primary care spine clinic in Nevada. PATIENTS: Beginning in mid-1998,
      the first 48 consecutive patients, who met the inclusion criteria of chronic LBP
      with decreased lordosis and who completed the treatment program were matched for
      sex, age, height, weight, and pain scores to 30 control subjects with chronic
      LBP, who received no treatment. INTERVENTIONS: A new form of 3-point bending
      lumbar extension traction was provided in-office 3 to 4 times a week for 12+/-4
      weeks. Per session, traction duration was started at 3 minutes and was increased
      to a maximum of 20 minutes. For short-term pain relief, torsion lumbar spinal
      manipulation was provided in the initial 3 weeks. MAIN OUTCOME MEASURES: Pain as
      measured on a visual analog scale (VAS) and standing lateral lumbar radiographic
      measurements. RESULTS: Pain scales and radiographic measurements did not change
      in the control subjects. In the traction group, VAS ratings decreased from mean
      +/- standard deviation of 4.4+/-1.9 pretreatment to 0.6+/-0.9 posttreatment
      (P<.001), and radiographic angles (except at T12-L1) showed statistically
      significant changes. Mean changes were 5.7 degrees at L4-5 (P<.001), 11.3 degrees
      between posterior tangents on L1 and L5 (P<.001), 9.1 degrees in Cobb angle at
      T12-S1 (P<.001), 4.6 degrees in pelvic tilt (P<.001), and 4.7 degrees in
      Ferguson's sacral base angle (P<.001). At long-term follow-up (17(1/2)mo), 34 of
      the 48 (71%) subjects returned. Improvements in lordosis were maintained in all
      34. CONCLUSIONS: This new method of lumbar extension traction is the first
      nonsurgical rehabilitative procedure to show increases in lumbar lordosis in
      chronic LBP subjects with hypolordosis. The fact that there was no change in
      control subjects' lumbar lordosis indicates the stability of the lumbar lordosis
      and the repeatability of x-ray procedures. Because, on average, chronic LBP
      patients have hypolordosis, additional randomized trials should be performed to
      evaluate the clinical significance of restoration of the lumbar lordosis in
      chronic LBP subjects.

PMID- 12422331
TI  - The effect of spasticity on cortical somatosensory-evoked potentials: changes of
      cortical somatosensory-evoked potentials after botulinum toxin type A injection.
AB  - OBJECTIVE: To evaluate the changes in cortical somatosensory-evoked potentials
      (SEPs) after botulinum toxin type A injection to determine what effect spasticity
      has on cortical SEPs. DESIGN: Intervention study and before-after trial. SETTING:
      University-affiliated hospital in Korea. PARTICIPANTS: Twelve children with
      spastic hemiplegic cerebral palsy (CP), 7 children with spastic diplegic CP, and
      8 patients with traumatic brain injury. INTERVENTION: All participants had
      botulinum toxin type A injected into the muscles of the spastic limb. MAIN
      OUTCOME MEASURES: SEPs were recorded before and 7 days after the botulinum toxin
      type A injection. Spasticity of the affected spastic limb was also measured. The
      short latency and amplitude of waves in SEPs were measured. The SEP results were
      divided into 3 groups: flat (no evoked potential), abnormal (evoked but delayed
      in latency), and normal (clear waveform with normal latency). RESULTS: The normal
      response of cortical SEP increased after injection. The SEPs exhibited more
      frequent improvement in the limbs, with greater improvement of spasticity in
      grade (>1.0 grade) and in patients of younger age (<3y) after injection (P<.05).
      CONCLUSION: The observed improvement of cortical SEPs with associated reduction
      of spasticity that occurred after the botulinum toxin type A injection indicates
      that spasticity itself can be considered a factor affecting cortical SEPs.

PMID- 12422332
TI  - Development of a noninvasive measure of pelvic and hip angles in seated posture.
AB  - OBJECTIVE: To develop a valid noninvasive means to measure pelvic tilt and hip
      angle in seated posture. DESIGN: Validation cohort study using radiographs as a
      criterion standard for pelvic posture. SETTING: Rehabilitation hospital.
      PARTICIPANTS: Volunteer sample of 10 adult men with no known physical disability.
      INTERVENTIONS: Radiographs were taken as subjects sat in erect, anterior, and
      posterior postures. An electromagnetic tracking device was as a pointer to
      digitize the anterior superior and posterior superior iliac spines and as a 6
      degrees of freedom (df) sensor mounted on the thigh and sacrum. MAIN OUTCOME
      MEASURES: Variables included pelvic tilt and hip flexion angle. Intra- and
      interrater reliability of radiographic measures was determined by using
      intraclass correlation coefficient comparison of the results from 2
      investigators. Validity was determined by comparing noninvasive measures of
      pelvic and hip angles to radiographic measures by using correlation, analysis of
      variance (ANOVA), and regression. RESULTS: Reliability of radiographic measures
      of pelvic tilt and hip angles were >/=.98. Pelvic tilt comparison: pointer:
      r=.89, R(2)=.80; 6-df sensor: r=.91, R(2)=.83; hip angle comparison using 6-df
      sensor: r=.78 with average difference of 4.25 degrees. ANOVA showed that
      differences between all invasive and noninvasive measures did not differ
      significantly (P>.05). CONCLUSION: Results indicated excellent reliability of
      radiographic analysis techniques and represented an improvement over previously
      published techniques. Noninvasive measures of pelvic tilt and hip angle were
      shown to be valid.

PMID- 12422333
TI  - Race: predictor versus proxy variable? Outcomes after spinal cord injury.
AB  - OBJECTIVE: To examine the impact of race on acute, rehabilitation, and long-term
      outcomes after spinal cord injury (SCI). DESIGN: Two case control studies (study
      1: acute and rehabilitation outcomes, study 2: long-term outcomes) in which white
      and nonwhite individuals were matched case for case on multiple demographic,
      medical, and geographic characteristics with the rationale being that a case
      control methodology would increase the internal validity of the design, thereby
      increasing confidence in the assertion that any between-group differences
      observed may be specifically attributed to race. SETTING: Data drawn from the
      Spinal Cord Injury Model Systems. Institutional practice and general community.
      PARTICIPANTS: Study 1: 187 pairs of individuals, study 2: 158 pairs of matched
      individuals. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Outcome
      measures assessed included economic (eg, cost of care), treatment-related (eg,
      length of hospital stay), functional (eg, FIM instrument), and medical (eg,
      number of medical complications) variables, as well as self-reported life
      satisfaction, level of handicap, and mental and physical health. RESULTS: In
      study 1, none of the outcome measures differed significantly across racial
      groups. Similarly, study 2 failed to indicate significant differences in any of
      the outcome variables across racial groups, with the exception that nonwhites
      were at increased risk of greater self-reported handicap in the area of mobility.
      Power analyses indicated these finding were not merely the result of inadequate
      power. CONCLUSION: For the outcomes assessed in studies 1 and 2, race appeared to
      act primarily as a proxy for other variables (eg, injury severity, age,
      educational achievement), which in turn may be associated with poor outcome after
      SCI. Theoretical implications and recommendations are discussed.

PMID- 12422334
TI  - Clinical and electrophysiologic correlates of quantitative sensory testing in
      patients with incomplete spinal cord injury.
AB  - OBJECTIVE: To determine the degree of association among indices of preserved
      sensation derived from quantitative sensory testing (QST), somatosensory evoked
      potentials (SEPs), and the clinical characteristics of patients with spinal cord
      injury (SCI). DESIGN: A controlled correlational study of diverse measures of
      preserved sensory function. SETTING: Regional SCI rehabilitation center in
      Ontario, Canada. PARTICIPANTS: Thirty-three patients with incomplete SCI and 14
      able-bodied controls. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: QST
      measures of perceptual threshold for temperature and vibration, American Spinal
      Injury Association sensory scores (light touch, pinprick), and tibial nerve SEPs.
      RESULTS: There was a low degree of association (kappa) between QST results and
      sensory scores (|kappa|=.05-.44). QST measures yielded greater numbers of
      patients with SCI being classified as impaired, suggesting a greater sensitivity
      of QST to detect more subtle sensory deficits. QST measures of vibration
      threshold generally corresponded to the patients' SEP recordings. QST measures of
      modalities conveyed within the same tract were significantly (P<.05) correlated
      (|r|=.46-.84) in patients with SCI, but not in controls, whereas those modalities
      mediated by different pathways had lower and generally nonsignificant
      correlations (|r|=.05-.44) in both patients and controls. CONCLUSIONS: The low
      degree of association between QST measures and sensory scores is likely
      attributable to measurement limitations of both assessments, as well as various
      neuroanatomic and neuropathologic factors. QST provides more sensitive detection
      of preserved sensory function than does standard clinical examination in patients
      with incomplete SCI.

PMID- 12422335
TI  - Prevalence of hepatitis C infection in a large urban hospital-based sample of
      individuals with spinal cord injury.
AB  - OBJECTIVE: To examine the prevalence and clinical characteristics of hepatitis C
      infection in individuals with chronic spinal cord injury (SCI). DESIGN:
      Retrospective case survey. SETTING: Outpatient clinic devoted to SCI follow-up
      care located in a county-government rehabilitation center. PARTICIPANTS: A total
      of 531 unselected individuals with chronic SCI. INTERVENTIONS: Patients underwent
      routine annual physical examinations at the outpatient clinic, and were tested
      for hepatitis C antibodies, antibodies to hepatitis core antigen, alanine
      aminotransferase (ALT), and bilirubin. MAIN OUTCOME MEASURES: Prevalence of
      hepatitis C antibodies and liver test abnormalities. RESULTS: Seventeen percent
      of the cohort was anti-hepatitis C virus (HCV) reactive (HCV positive). The
      prevalence of HCV infection in those who sustained SCI before 1990 was 21%
      compared with 7% (10/147) of those who were injured from 1990 onward (, P=.0002).
      Period of injury (Wald, P=.0042) and age (Wald, P=.048) were the only significant
      factors for anti-HCV reactivity. Thirty percent of the HCV-positive individuals
      had abnormal ALT levels compared with only 10% of the HCV-negative individuals (,
      P<.0001). Individuals who were HCV positive were more likely to be hepatitis B
      core antigen-reactive compared with those who were HCV negative (31% vs 9%;,
      P<.0001). CONCLUSIONS: The prevalence of HCV infection among individuals with
      chronic SCI is significantly higher than the general population. The majority of
      those with SCI and HCV infection have normal liver tests. Clinicians should
      maintain a high index of suspicion for HCV infection, even in the absence of
      elevated aminotransferase activities.

PMID- 12422336
TI  - Herpes zoster-associated voiding dysfunction: a retrospective study and
      literature review.
AB  - OBJECTIVES: (1) To describe the demographic features of patients with voiding
      dysfunction associated with herpes zoster; (2) to discuss the pathophysiology of
      voiding dysfunction associated with herpes zoster; and (3) to suggest the best
      management policy. DESIGN: A retrospective study. SETTING: A university
      affiliated medical center in Taiwan. PARTICIPANTS: Four hundred twenty-three
      patients (mean age, 55.5y) admitted with the diagnosis of herpes zoster from 1988
      to 2000. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Dermatomal
      distribution of skin eruptions, urologic symptoms, treatment (catheterization,
      urecholine), clinical course of voiding dysfunction, and outcome. RESULTS:
      Seventeen (mean age, 61.2+/-14.1y) of 423 patients (4.02%) with voiding
      dysfunction related to this virus infection were identified. Ten (58.8%) were
      men, and 7 (41.2%) were women. The incidence of dysfunction was as high as 28.6%
      if only lumbosacral dermatome-involved patients were considered. We classified
      urologic manifestations caused by herpes zoster into 3 groups: cystitis
      associated (n=12), neuritis-associated (n=4), and myelitis-associated (n=1).
      Urinalysis revealed pyuria in all patients with cystitis-associated voiding
      dysfunction and microscopic hematuria in all patients with neuritis-associated
      voiding dysfunction. All patients, although receiving different treatment
      regimens for voiding dysfunction, regained a normal or balanced bladder within 8
      weeks. No major urologic sequelae were noted. CONCLUSION: Voiding dysfunction,
      although a transient course, is not uncommon in patients with herpes zoster
      involving lumbosacral dermatomes. Treatment with intermittent catheterization
      (our preferred choice) or indwelling catheter placement is recommended if the
      patients have prolonged difficulty in urination. This disease entity usually has
      a benign clinical course, and almost every patient will either regain normal
      voiding or, at least, balanced bladder function.

PMID- 12422337
TI  - Motor recovery after stroke: a systematic review of the literature.
AB  - OBJECTIVE: To collect and integrate existing data concerning the occurrence,
      extent, time course, and prognostic determinants of motor recovery after stroke
      using a systematic methodologic approach. DATA SOURCES: A computer-aided search
      in bibliographic databases was done of longitudinal cohort studies, original
      prognostic studies, and randomized controlled trials published in the period 1966
      to November 2001, which was expanded by references from retrieved articles and
      narrative reviews. STUDY SELECTION: After a preliminary screening, internal,
      external, and statistical validity was assessed by a priori methodologic
      criteria, with special emphasis on the internal validity. DATA EXTRACTION: The
      studies finally selected were discussed, based on the quantitative analysis of
      the outcome measures and prognostic determinants. Meta-analysis was pursued, but
      was not possible because of substantial heterogeneity. DATA SYNTHESIS: The search
      resulted in 174 potentially relevant studies, of which 80 passed the preliminary
      screening and were subjected to further methodologic assessment; 14 studies were
      finally selected. Approximately 65% of the hospitalized stroke survivors with
      initial motor deficits of the lower extremity showed some degree of motor
      recovery. In the case of paralysis, complete motor recovery occurred in less than
      15% of the patients, both for the upper and lower extremities. Hospitalized
      patients with small lacunar strokes showed relatively good motor recovery. The
      recovery period in patients with severe stroke was twice as long as in patients
      with mild stroke. The initial grade of paresis was the most important predictor
      for motor recovery (odds ratios [OR], >4). Objective analysis of the motor
      pathways by motor-evoked potentials (MEPs) showed even higher ORs (ORs, >20).
      CONCLUSIONS: Our knowledge of motor recovery after stroke in more accurate,
      quantitative, and qualitive terms is still limited. Nevertheless, our data
      synthesis and quantitative analysis comprises data from many methodologically
      robust studies, which may support the clinician in the management of stroke
      patients. With respect to early prognosis of motor recovery, our review confirms
      clinical experience that the initial grade of paresis (as measured on admission
      in the hospital) is the most important predictor, although the accuracy of
      prediction rapidly improves during the first few days after stroke. Initial
      paralysis implies the worst prognosis for subsequent motor recovery. Remarkably,
      the prognostic accuracy of MEPs appears much higher than that of clinical
      examination for different subgroups of patients.

PMID- 12422338
TI  - Maximizing extraction of botulinum toxin type A from vials.
AB  - OBJECTIVES: To determine the residual botulinum toxin remaining in vials after
      using 3 different extraction methods and to analyze the different techniques for
      measuring extraction efficacy. DESIGN: Multicentered comparative study. SETTING:
      Three academic movement disorder clinics. PARTICIPANTS: Thirty physicians were
      randomly surveyed for their botulinum toxin extraction methods. Three physicians
      evaluated the most common methods. INTERVENTIONS: Not applicable. MAIN OUTCOME
      MEASURE: Amount of toxin left in vials after each extraction method. RESULTS:
      Toxin was least successfully extracted by using the vial inversion method. More
      toxin was extracted by using the 2-in needle method. The top removal method
      produced the least waste of toxin but is considered unsafe. CONCLUSIONS: The best
      and safest method for consistently extracting the most botulinum toxin from its
      vial was to use a long 21-gauge 2-in needle attached to a 3-mL syringe.

PMID- 12422339
TI  - Distribution in allele frequencies of predisposition-to-atopy genotypes in
      Chinese children.
AB  - Asthma is one of the most common chronic diseases in childhood; it is caused by a
      complex interaction between genetic factors and exposure to environmental
      allergens and irritants. Previous studies using the candidate gene approach
      showed that asthma was linked to a number of susceptibility genetic loci in
      Caucasian subjects. There are, however, only a few studies on asthma
      predisposition genes in the Chinese population. We studied the distribution of
      allele frequencies of I50V for the interleukin-4 receptor, two polymorphisms in
      intron 2 and exon 7 for the high-affinity IgE receptor (Fc epsilon RI-beta), R16G
      and E27Q for the beta(2)-adrenoceptor,and R275Q (824G/A) for CC chemokine
      receptor 3 in Chinese children.Seventy-six patients, with a mean age of 10.6
      years, and 70 age- and sex-matched controls, were studied. Significantly more
      subjects in the asthma group had specific IgE antibodies against environmental
      allergens (P < 0.0001; odds ratio, 9.82). Genotyping of the six genetic markers
      showed that none of the six polymorphisms was associated with asthma in this
      cohort. The allele frequencies of I50V, R16G, and E27Q in our population were
      similar to those published for Asian subjects but not Caucasians. The R275Q
      substitution was a rare finding in our study and in the published reports. Our
      results demonstrate ethnic differences in polymorphisms of atopy candidate genes.
      Additional studies involving larger samples are required to investigate the
      association between asthma or atopy and the genotypes studied to date in Chinese
      children.

PMID- 12422340
TI  - Perception of intrinsic and extrinsic respiratory loads in children with life
      threatening asthma.
AB  - There is a subpopulation of asthmatic patients with a history of life-threatening
      asthma (LTA) who have a reduced perception of respiratory loads. The aim of this
      study was to determine if these patients have a reduced perception of both
      intrinsic and extrinsic loads. Children with asthma were classified into life
      threatening asthma and control asthmatic groups. Perception of extrinsic loads
      was assessed by magnitude estimation of inspiratory resistive loads. Magnitude
      estimation was measured with handgrip estimation of resistive load magnitude.
      Perception of intrinsic loads was by methacholine bronchoprovocation in doses
      sufficient to a drop to 40% below baseline of forced expired volume in 1 sec
      (FEV(1)). Chest tightness, breathlessness, and air hunger, as estimated by a Borg
      scale were, used to rate methacholine perception. Life-threatening asthma
      subjects had a lower slope than nonlife-threatening asthma subjects for magnitude
      estimation of resistive loads. Life-threatening asthma patients also had a lower
      maximum Borg score for all three symptoms. There was no significant difference in
      magnitude estimation of symptom type.These results suggest that life-threatening
      asthma subjects have poor perception of extrinsic and intrinsic loads. This
      suggests that there is a similarity between the sensations elicited by intrinsic
      and extrinsic loads, allowing for the identification of poor-perceiving patients
      with either method of assessment and who suffer from life-threatening asthma.

PMID- 12422341
TI  - Ventilatory control in newborn mice prenatally exposed to cocaine.
AB  - Infants born to mothers who used cocaine during pregnancy are at increased risk
      for neonatal death and respiratory impairments. Confounding factors such as
      multiple substance abuse make it difficult to isolate the effects of cocaine. We
      used a murine model to test the hypothesis that prenatal cocaine exposure may
      impair ventilatory responses to chemical stimuli in newborns. Seventy-two
      pregnant mice were randomly assigned to three groups: cocaine (COC), saline
      (SAL), and untreated (UNT). COC and SAL mice received subcutaneous injections of
      either 20 mg/kg of cocaine or a saline solution twice a day from gestational days
      8-17. Ventilation (V'(E)) and tidal volume (V(T)), both divided by body weight,
      and breath duration (T(TOT)) were measured using whole-body plethysmography in
      freely moving COC (n = 47), SAL (n = 123), and UNT (n = 93) pups on postnatal day
      2.The comparison between SAL and UNT pups showed significant differences in
      baseline breathing and in V'(E) responses to hypoxia, suggesting that maternal
      stress caused by injections affected the development of ventilatory control in
      pups. Baseline T(TOT) was significantly longer in COC than in SAL pups. V'(E)
      responses to hypoxia were significantly smaller in COC than in SAL pups (+27 +/-
      35% vs. +38 +/- 25%), but V'(E) responses to hypercapnia were similar (29 +/- 15%
      vs. 25 +/- 23%).Thus, breathing control was impaired by prenatal cocaine
      exposure, possibly because of abnormal development of neurotransmitter systems,
      such as the dopamine and serotonin systems.

PMID- 12422342
TI  - Cost effectiveness of guideline advice for children with asthma: a literature
      review.
AB  - Asthma is an important chronic disease among children. This study reviews the
      cost effectiveness of interventions in the long-term care of asthmatic children
      and compares these results with treatment advice in four current guidelines. Cost
      effectiveness studies were searched for in Medline, Embase, Healthstar, Biosis,
      and the Office of Health Economics-Health Economic Evaluations Database (OHE
      HEED), and the Cochrane Library was searched for meta-analyses of clinical
      trials. In the four reviewed guidelines, cost effectiveness is not explicitly
      used as a criterion. The cost-effectiveness studies show sufficient evidence for
      the cost effectiveness of treatment with inhaled steroids and for self-management
      programs for severe asthmatic patients. Inclusion of these results in the
      guidelines would not lead to significant changes in current treatment advice. The
      effectiveness of various measures for trigger avoidance is not fully proven, and
      hence neither is their cost effectiveness. Available information on the cost
      effectiveness of cromolyn could be used to focus the guidelines. Finally,
      evidence exists that organizational interventions, e.g., the employment of asthma
      nurses, can result in cost savings, but it is unclear to what extent these
      results can be generalized. More cost-effectiveness studies are needed,
      especially on long-acting bronchodilators and self-management programs for mild
      and moderate asthma, in order to help make the guidelines more informative and
      reduce the differences between them.

PMID- 12422343
TI  - Detection and correction of endotracheal-tube position in premature neonates.
AB  - Due to the short airways in premature children, an accurate position of the
      endotracheal tube (ETT) is crucial for adequate mechanical ventilation.
      Verification of ETT-position is done in chest radiographs. However, ETT-position
      varies substantially with head movement. When the head is flexed, the tube might
      appear too deeply inserted, and inadvertent extubation may occur in cases of
      retraction of ETT after radiography. Extension of the cervical spine will suggest
      an inappropriately high ETT-position, so that intended corrections can lead to
      main-stem intubation. Radiographic visible skeletal structures could serve as
      reference points to allow the detection of head declination and imperfect
      positioning of ETT. Ratios of anatomical landmarks were used to estimate head
      position. In this study, 111 radiographs of 24 preterm neonates with a
      gestational age of 24-29 weeks and weights of 500-1,000 g were analyzed. A
      mathematical algorithm for the detection and correction of ETT-positions, based
      on common chest radiographs, was developed. In 108 cases (97.3%), ETT-distance
      from the midtracheal level was less than 2 mm after use of the proposed
      correction.Thus, the suggested correction equation for head position enables
      verification of the actual ETT-position without requiring a defined placement of
      the head during radiography. Moreover, it can be helpful for estimating the depth
      of ETT-insertion in conditions when radiography is not available.

PMID- 12422344
TI  - Techniques for measurement of thoracoabdominal asynchrony.
AB  - Respiratory motion measured by respiratory inductance plethysmography often
      deviates from the sinusoidal pattern assumed in the traditional Lissajous figure
      (loop) analysis used to determine thoraco-abdominal asynchrony, or phase angle
      phi. We investigated six different time-domain methods of measuring phi, using
      simulated data with sinusoidal and triangular waveforms, phase shifts of 0-135
      degrees, and 10% noise. The techniques were then used on data from 11 lightly
      anesthetized rhesus monkeys (Macaca mulatta; 7.6 +/- 0.8 kg; 5.7 +/- 0.5 years
      old), instrumented with a respiratory inductive plethysmograph, and subjected to
      increasing levels of inspiratory resistive loading ranging from 5-1,000 cmH(2)O.
      L(-1). sec(-1). The best results were obtained from cross-correlation and maximum
      linear correlation, with errors less than approximately 5 degrees from the actual
      phase angle in the simulated data. The worst performance was produced by the loop
      analysis, which in some cases was in error by more than 30 degrees. Compared to
      correlation, other analysis techniques performed at an intermediate level.
      Maximum linear correlation and cross-correlation produced similar results on the
      data collected from monkeys (SD of the difference, 4.1 degrees ) but all other
      techniques had a high SD of the difference compared to the correlation
      techniques. We conclude that phase angles are best measured using cross
      correlation or maximum linear correlation, techniques that are independent of
      waveform shape, and robust in the presence of noise.

PMID- 12422345
TI  - Measuring ease of breathing in young patients with cystic fibrosis.
AB  - Our objective was to compare two new objective measures of ease of breathing with
      the visual analog scale (VAS). Twenty-eight patients with CF, 7-34 years old
      (FEV(1) 25-114% of predicted), enrolled. Ease of breathing was evaluated by a
      standard 10-cm VAS, maximum phonation (time, in seconds, to sustain the syllable
      "Ahh") using a single breath, and counting in a single breath at one number per
      second (Count) at rest, following 3 min of stepping exercise at 15 steps per
      minute (STEP15), and 3 min at 30 steps per minute (STEP30). Heart rate (HR) and
      oxyhemoglobin saturation (SaO(2)) were measured.HR and VAS increased
      significantly, and SaO(2), phonation, and Count decreased significantly from rest
      to STEP15 and STEP30. Phonation time correlated significantly (and inversely)
      with HR after exercise. Phonation time was positively correlated with SaO(2) at
      rest and after STEP30. Counts at rest and after STEP30 were significantly related
      to SaO(2). VAS showed no relationship to heart rate at rest or after exercise,
      but was related to SaO(2) at the end of STEP30. Test-retest reliability for three
      trials of phonation was 0.92, and for the five trials of counting was 0.93.
      Correlation coefficients for maximum phonation at rest, STEP15, and STEP30 on 2
      separate days were 0.61, 0.94, and 0.91, respectively. Correlation coefficients
      for Count at rest, STEP15, and STEP30 on 2 separate days were 0.96, 0.94, and
      0.94, respectively. Correlation coefficients for VAS at rest, STEP15, and STEP30
      on 2 separate days were 0.25, 0.89, and 0.97, respectively. Thus both the maximum
      phonation and Count have good test-retest reliability within one session, and
      across 2 separate days, for both rest and exercise conditions. In conclusion,
      maximum phonation and Count are valid and reliable measures of ease of breathing;
      they reflect increasing work loads and show stronger correlations with heart rate
      and SaO(2) than does VAS. These measures could be an important tool for clinical
      research and patient care.

PMID- 12422346
TI  - Crouzon syndrome: association with absent pulmonary valve syndrome and severe
      tracheobronchomalacia.
AB  - Airway obstruction is common among patients with craniosynostosis. We describe an
      infant with a clinical and genetic diagnosis of Crouzon syndrome who presented
      with respiratory distress and heart murmur in early neonatal life. Cardiac
      evaluation revealed absent pulmonary valve syndrome. She needed intubation at age
      1 month, and repeated trials of extubation failed because of marked respiratory
      distress, stridor, and severe expiratory obstruction and wheezing. Correction of
      her cardiac anomaly did not relieve her respiratory distress; only after
      endobronchial stenting and tracheostomy was it possible to gradually wean her
      from mechanical ventilation. This case report demonstrates and discusses the
      different causes of airway obstruction in Crouzon syndrome and the morbidity and
      mortality that can result from pulmonary involvement in this craniosynostotic
      syndrome. It also demonstrates the difficult therapeutic challenge created by the
      combination of cardiopulmonary abnormalities in Crouzon patients.

PMID- 12422347
TI  - Plastic bronchitis in children: a case series and review of the medical
      literature.
AB  - Plastic bronchitis is characterized by marked obstruction of the large airways by
      bronchial casts. We reviewed our experience and the literature to determine
      whether mortality rates are determined by underlying disease or cast type. We
      present 3 children with obstructive bronchial casts. One 3-year-old patient with
      Noonan's syndrome developed respiratory failure following surgery for tetralogy
      of Fallot requiring support with extracorporeal membrane oxygenation (ECMO) the
      first such case. There were 42 cases in the literature of children with plastic
      bronchitis. Casts may be divided into two types. Type I casts are inflammatory,
      consisting mainly of fibrin with cellular infiltrates, and occur in inflammatory
      diseases of the lung. Type II, or acellular casts, consist mainly of mucin with a
      few cells, and usually occur following surgery for congenital cardiac defects.
      Patients categorized by underlying disease included 31% with asthma or allergic
      disease, 40% with underlying cardiac defects, and 29% with other diseases.
      Mortality was 16%, but increased to 29% in patients with cardiac defects. Deaths
      occurred as long as 1 year after surgical repair for underlying defects. There
      were no deaths in patients with asthma. Life-threatening events were
      statistically higher in patients with cardiac defects (41%) than in those with
      asthma (0%, P = 0.02). Higher mortality in patients with type II casts compared
      to type I casts did not reach statistical significance (28% vs. 6%; P = 0.06). In
      conclusion, patients presenting with plastic bronchitis are at high risk for
      serious complications, especially with underlying cardiac disease.

PMID- 12422348
TI  - Relapsed non-Hodgkin's lymphoma diagnosed by flexible bronchoscopy.
AB  - Pulmonary relapse of non-Hodgkin's lymphoma (NHL) occurred in a 10-year-old girl
      who presented with cough, blood-tinged sputum, and chest tightness. The diagnosis
      of Ki-1 (CD30) anaplastic large-cell lymphoma was established using
      bronchoalveolar lavage (BAL) and transbronchial biopsy (TBB). These procedures
      demonstrated malignant cells that stained positive for CD30 and had the t(2;5)
      translocation, thereby avoiding the need for an open lung biopsy.

PMID- 12422349
TI  - Cystic fibrosis presenting as acute pancreatitis and obstructive azoospermia in a
      young adult male with a novel mutation in the CFTR gene.
AB  - Cystic fibrosis is rare in the Asian population, and is often associated with
      consanguinity and rare genotypes. We report on a 23-year-old Asian man from a
      consanguineous pedigree referred to the regional cystic fibrosis unit after a
      diagnosis of congenital bilateral absence of the vas deferens during
      investigations for infertility. A detailed history revealed several previous
      episodes of acute pancreatitis. Full diagnostic appraisal showed homozygosity for
      a novel cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation,
      but normal sweat test and nasal potential difference studies. An endoscopic
      retrograde cholangiopancreatogram (ERCP) showed chronic pancreatitis with bulky
      side branches. The vas deferens and the pancreas appeared exquisitely sensitive
      to mild CFTR dysfunction. Patients with cystic fibrosis and unexplained upper
      abdominal pain should be screened for pancreatitis, and consideration should be
      given to screening patients with idiopathic pancreatitis for mutations in the
      CFTR gene.

PMID- 12422350
TI  - To the editor: adverse effects of ceftazidime treatment.

PMID- 12422353
TI  - The application of bioinformatics to mass spectrometry.

PMID- 12422354
TI  - Precalibration of matrix-assisted laser desorption/ionization-time of flight
      spectra for peptide mass fingerprinting.
AB  - Identification of proteins using matrix-assisted laser desorption/ionization-time
      of flight (MALDI-TOF) peptide mass fingerprinting (PMF) is a key technique in
      proteomics. The method is known to be sensitive as well as amenable to high
      throughput operation, but the resulting identifications suffer from a relatively
      low level of confidence. One way of increasing the confidence is by improving
      measurement accuracy using one of several calibration methods. This paper
      presents a new strategy for calibration of MALDI-TOF PMF spectra that makes use
      of the phenomenon of peptide mass clustering, and enables spectrum calibration
      prior to the step of database interrogation, before or after peak extraction.
      Typically, mass errors are reduced by 40-60%. Accuracy improvement at this early
      stage can help avoid losing protein candidates, reduce the number of external
      calibration spots, eliminate internal calibrants, and reduce the number of
      candidates being scored, thereby reducing analysis time. Different variants of
      the method are discussed and compared to known calibration methods, such as
      relying on known calibrants or comparison to putative database candidates. In
      order to allow precise description of the method and to place the results in
      perspective, theoretical considerations of peptide databases and scoring
      functions are also discussed.

PMID- 12422355
TI  - Peptide mass fingerprinting peak intensity prediction: extracting knowledge from
      spectra.
AB  - Matrix-assisted laser desorption/ionization-time of flight mass spectrometry has
      become a valuable tool in proteomics. With the increasing acquisition rate of
      mass spectrometers, one of the major issues is the development of accurate,
      efficient and automatic peptide mass fingerprinting (PMF) identification tools.
      Current tools are mostly based on counting the number of experimental peptide
      masses matching with theoretical masses. Almost all of them use additional
      criteria such as isoelectric point, molecular weight, PTMs, taxonomy or enzymatic
      cleavage rules to enhance prediction performance. However, these identification
      tools seldom use peak intensities as parameter as there is currently no model
      predicting the intensities based on the physicochemical properties of peptides.
      In this work, we used standard datamining methods such as classification and
      regression methods to find correlations between peak intensities and the
      properties of the peptides composing a PMF spectrum. These methods were applied
      on a dataset comprising a series of PMF experiments involving 157 proteins. We
      found that the C4.5 method gave the more informative results for the
      classification task (prediction of the presence or absence of a peptide in a
      spectra) and M5' for the regression methods (prediction of the normalized
      intensity of a peptide peak). The C4.5 result correctly classified 88% of the
      theoretical peaks; whereas the M5' peak intensities had a correlation coefficient
      of 0.6743 with the experimental peak intensities. These methods enabled us to
      obtain decision and model trees that can be directly used for prediction and
      identification of PMF results. The work performed permitted to lay the
      foundations of a method to analyze factors influencing the peak intensity of PMF
      spectra. A simple extension of this analysis could lead to improve the accuracy
      of the results by using a larger dataset. Additional peptide characteristics or
      even PMF experimental parameters can also be taken into account in the datamining
      process to analyze their influence on the peak intensity. Furthermore, this
      datamining approach can certainly be extended to the tandem mass spectrometry
      domain or other mass spectrometry derived methods.

PMID- 12422356
TI  - Comparative bioinformatic analysis of complete proteomes and protein parameters
      for cross-species identification in proteomics.
AB  - Peptide mass fingerprinting (PMF) remains the most amenable technique for protein
      identification in proteomics, using mass spectrometry as the primary analytical
      technique coupled with bioinformatics. This relies on the presence of the amino
      acid sequence of the protein in the current databanks. Despite this, it is
      desirable to be able to use the technique for organisms whose genomes are not yet
      fully sequenced and apply cross-species protein identification. In this study, we
      have re-examined the feasibility of such approaches by considering the extent of
      protein similarity between genome sequences using a data set of 29 complete
      bacterial and two eukaryotic genomes. A range of protein and peptide features are
      considered, including protein isoelectric focussing point, protein mass, and
      amino acid conservation. The effectiveness of PMF approaches has then been tested
      with a series of computer simulations with varying peptide number and mass
      accuracy for several cross-species tests. The results show that PMF alone is
      unsuitable in general for divergent species jumps, or when protein similarity is
      less than 70% identity. Despite this, there exists a considerable enrichment
      above random of tryptic peptide conservation and PMF promises to remain useful
      when combined with other data than just peptide masses for cross-species protein
      identification.

PMID- 12422357
TI  - ProbID: a probabilistic algorithm to identify peptides through sequence database
      searching using tandem mass spectral data.
AB  - With the recent quick expansion of DNA and protein sequence databases, intensive
      efforts are underway to interpret the linear genetic information of DNA in terms
      of function, structure, and control of biological processes. The systematic
      identification and quantification of expressed proteins has proven particularly
      powerful in this regard. Large-scale protein identification is usually achieved
      by automated liquid chromatography-tandem mass spectrometry of complex peptide
      mixtures and sequence database searching of the resulting spectra [Aebersold and
      Goodlett, Chem. Rev. 2001, 101, 269-295]. As generating large numbers of sequence
      specific mass spectra (collision-induced dissociation/CID) spectra has become a
      routine operation, research has shifted from the generation of sequence database
      search results to their validation. Here we describe in detail a novel
      probabilistic model and score function that ranks the quality of the match
      between tandem mass spectral data and a peptide sequence in a database. We
      document the performance of the algorithm on a reference data set and in
      comparison with another sequence database search tool. The software is publicly
      available for use and evaluation at
      http://www.systemsbiology.org/research/software/proteomics/ProbID.

PMID- 12422358
TI  - Molecular scanner experiment with human plasma: improving protein identification
      by using intensity distributions of matching peptide masses.
AB  - The development of high throughput utilities to identify proteins is a major
      challenge in present research in the field of proteomics. One such utility, the
      molecular scanner, uses proteins separated by two-dimensional polyacrylamide gel
      electrophoresis that are digested in the gel and during transfer onto a
      collecting membrane. After adding a matrix, the membrane is inserted into a
      matrix-assisted laser desorption/ionization-time of flight mass spectrometer and
      a peptide mass fingerprint (PMF) is measured for every scanned site. Since the
      spacing between scanned sites is much smaller than the size of the most abundant
      protein spots, there is a certain redundancy in the data that was used in an
      earlier experiment with Escherichia coli [1] to improve mass calibration and PMF
      identification results. It was observed that the signal intensity of a peptide
      mass as a function of the position on the membrane showed similar patterns if
      peptides stemmed from the same protein. Taking account of these similarities a
      clustering algorithm was used to find lists of experimental masses with similar
      intensity distributions, which provided clearer identification of the
      corresponding proteins. Here, these methods are applied to a human plasma scan,
      where proteins were highly modified and less separated. The presence of very
      abundant proteins like albumin and immunoglobulins added another difficulty. The
      calibration of the initial PMFs was not satisfactory and masses had to be
      recalibrated. After discarding chemical noise, the membrane was partitioned into
      regions and for each region protein identification was carried out separately. A
      new scoring method was used, where the PMF score was multiplied by a factor that
      measures the similarity of matching peptides. This method proved to be more
      robust than the method developed in [1] if the region where a protein was found
      had an extended, nonspherical shape and strong overlap with regions of other
      proteins. Many proteins annotated on the SWISS-2D PAGE human plasma master gel
      could be clearly identified and many interesting properties were observed.

PMID- 12422359
TI  - Error tolerant searching of uninterpreted tandem mass spectrometry data.
AB  - An error tolerant mode for database matching of uninterpreted tandem mass
      spectrometry data is described. Selected database entries are searched without
      enzyme specificity, using a comprehensive list of chemical and post-translational
      modifications, together with a residue substitution matrix. The modifications are
      tested serially, to avoid the catastrophic loss of discrimination that would
      occur if all the permutations of large numbers of modifications in combination
      were possible. The new mode has been coded as an extension to the Mascot search
      engine, and tested against a number of Liquid chromatography-tandem mass
      spectrometry datasets. The results show a number of additional peptide matches,
      but require careful interpretation. The most significant limitation of this
      approach is that it can only reveal new matches to proteins that already have at
      least one significant peptide match.

PMID- 12422360
TI  - FindPept, a tool to identify unmatched masses in peptide mass fingerprinting
      protein identification.
AB  - FindPept (http://www.expasy.org/tools/findpept.html) is a software tool designed
      to identify the origin of peptide masses obtained by peptide mass fingerprinting
      which are not matched by existing protein identification tools. It identifies
      masses resulting from unspecific proteolytic cleavage, missed cleavage, protease
      autolysis or keratin contaminants. It also takes into account post-translational
      modifications derived from the annotation of the SWISS-PROT database or supplied
      by the user, and chemical modifications of peptides. Based on a number of
      experimental examples, we show that the commonly held rules for the specificity
      of tryptic cleavage are an oversimplification, mainly because of effects of
      neighboring residues, experimental conditions, and contaminants present in the
      enzyme sample.

PMID- 12422361
TI  - Post-translational modification detection using metastable ions in reflector
      matrix-assisted laser desorption/ionization-time of flight mass spectrometry.
AB  - In addition to protein identification, characterization of post-translational
      modifications (PTMs) is an essential task in proteomics. PTMs represent the major
      reason for the variety of protein isoforms and they can influence protein
      structure and function. Upon matrix-assisted laser desorption/ionization (MALDI)
      most post-translationally modified peptides form a fraction of labile molecular
      ions, which lose PTM-specific residues only after acceleration. Compared to fully
      accelerated ions these fragment ions are defocused and show in reflector mass
      spectra reduced resolution. A short time Fourier transform using a Hanning window
      function now uses this difference in resolution to detect the metastable
      fragments. Its application over the whole mass range yields frequency
      distributions and amplitudes as a function of mass, where an increased low
      frequency proportion is highly indicative for metastable fragments. Applications
      on the detection of metastable losses originating from carboxamidomethylated
      cysteines, oxidized methionines, phosphorylated and glycosylated amino acid
      residues are presented. The metastable loss of mercaptoacetamide detected with
      this procedure represents a new feature and its integration in search algorithms
      will improve the specificity of MALDI peptide mass fingerprinting.

PMID- 12422362
TI  - An iterative calibration method with prediction of post-translational
      modifications for the construction of a two-dimensional electrophoresis database
      of mouse mammary gland proteins.
AB  - Protein databases serve as general reference resources providing an orientation
      on two-dimensional electrophoresis (2-DE) patterns of interest. The intention
      behind constructing a 2-DE database of the water soluble proteins from wild-type
      mouse mammary gland tissue was to create a reference before going on to
      investigate cancer-associated protein variations. This database shall be deemed
      to be a model system for mouse tissue, which is open for transgenic or knockout
      experiments. Proteins were separated and characterized in terms of their
      molecular weight (M(r)) and isoelectric point (pI) by high resolution 2-DE. The
      proteins were identified using prevalent proteomics methods. One method was
      peptide mass fingerprinting by matrix-assisted laser desorption/ionization-mass
      spectrometry. Another method was N-terminal sequencing by Edman degradation. By N
      terminal sequencing M(r) and pI values were specified more accurately and so the
      calibration of the master gel was obtained more systematically and exactly. This
      permits the prediction of possible post-translational modifications of some
      proteins. The mouse mammary gland 2-DE protein database created presently
      contains 66 identified protein spots, which are clickable on the gel pattern.
      This relational database is accessible on the WWW under the URL: http://www.mpiib
      berlin.mpg.de/2D-PAGE.

PMID- 12422363
TI  - Combinatorial use of mRNA and two-dimensional electrophoresis expression data to
      choose relevant features for mass spectrometric identification.
AB  - It is only recently that quantitative studies of differential proteome analysis
      (DPA) have become possible. In this paper the issues involved in quantitative DPA
      are discussed and novel tools to select features for identification by mass
      spectrometry (MS) are described. The problem of comparing two sets of gels on a
      global level is explored as well as how to find specific protein features that
      differentiate two sets of two-dimensional electrophoresis gels. The concept of a
      'virtual' gel, derived from gene expression data, is introduced. The virtual gel
      enables the co-analysis of data from gene and protein expression. We discuss the
      value of such an approach, and consider what new information can be gained by
      using gene and protein expression together. These tools are illustrated by
      analysis of data from tandem gene and protein expression experiments. Features
      that are highlighted by the above methods are putative candidates for MS
      identification. Tools are described that integrate the process of feature
      selection, cutting, and MS analysis.

PMID- 12422367
TI  - Opioid peptide receptor studies. 16. Chronic morphine alters G-protein function
      in cells expressing the cloned mu opioid receptor.
AB  - Chronic morphine treatment results in functional uncoupling of the mu opioid
      receptor and its G protein in both cell culture and animal models. In the present
      study, Chinese hamster ovary (CHO) cells stably expressing the cloned human mu
      opioid receptor (hMOR-CHO cells) were incubated with 1 microM of morphine (or no
      drug) for 20 h. Subsequently, we assessed DAMGO- and morphine-stimulated [(35)S]
      GTP-gamma-S binding and agonist-mediated inhibition of forskolin-stimulated cAMP
      accumulation. Using a single concentration of [(35)S]-GTP-gamma-S (0.05 nM),
      chronic morphine treatment did not significantly change basal [(35)S]-GTP-gamma-S
      binding, shifted the morphine EC(50) from 59 nM to 146 nM, and decreased the
      maximal stimulation (E(max)) from 201% to 177%. Similar results were observed
      with DAMGO. Binding surface analysis resolved two [(35)S]-GTP-gamma-S binding
      sites (high-affinity and low-affinity sites). In control cells, morphine
      stimulated [(35)S]-GTP-gamma-S binding by increasing the B(max) of the high
      affinity site. In morphine-treated cells, morphine stimulated [(35)S]-GTP-gamma-S
      binding by decreasing the high-affinity K(d) without changing the B(max).
      Morphine treatment increased the EC(50) (5-11-fold) for agonist-mediated
      inhibition of forskolin-stimulated cAMP accumulation. These changes were not
      observed in cells expressing a mutant mu opioid receptor which does not develop
      morphine tolerance, suggesting that the changes in [(35)S]-GTP-gamma-S binding
      observed in hMOR-CHO cells result from the development of morphine tolerance.

PMID- 12422368
TI  - Dehydroepiandrosterone (DHEA) such as 17beta-estradiol prevents MPTP-induced
      dopamine depletion in mice.
AB  - Previous work from our laboratory has shown prevention of 1-methyl-4-phenyl
      1,2,3,6-tetrahydropyridine (MPTP)-induced striatal dopamine (DA) depletion in
      mice by 17beta-estradiol, progesterone, and raloxifene. Dehydroepiandrosterone
      (DHEA), a neurosteroid, was shown to have neuroprotective activities in various
      paradigms of neuronal death but its effect in vivo in mice on MPTP toxicity has
      not been reported. We investigated the effects of 17beta-estradiol (2 microg/day)
      and DHEA (3 mg/day) for 5 days before and after an acute treatment of four MPTP
      (10 mg/kg) injections in male C57Bl/6 mice. Striatal DA concentrations and its
      metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were
      measured by HPLC. MPTP mice that received 17beta-estradiol or DHEA had striatal
      DA, DOPAC, and HVA concentrations comparable to intact animals and higher than
      striatal DA, DOPAC, and HVA levels in saline-MPTP-treated mice. MPTP treatment
      led to an increase of striatal DA turnover (assessed with the HVA/DA ratio); DHEA
      and 17beta-estradiol prevented this increase. 17beta-Estradiol did not affect
      striatal DA and metabolites concentrations in intact mice in this paradigm.
      Furthermore, in the substantia nigra DHEA and 17beta-estradiol prevented the MPTP
      induced dopamine transporter and tyrosine hydroxylase mRNA decreases measured by
      in situ hybridization. Therefore, DHEA such as 17beta-estradiol is active in
      preventing the catecholamine-depleting effect of MPTP and our results suggest
      that this involves neuroprotection of DA neurons.

PMID- 12422369
TI  - Estimating the number of release sites and probability of firing within the nerve
      terminal by statistical analysis of synaptic charge.
AB  - Investigating the function of individual synapses is essential to understanding
      the mechanisms that influence the efficacy of chemical synaptic transmission. The
      known simplicity of the synaptic structure at the crayfish neuromuscular junction
      (NMJ) and its quantal nature of release allows an assessment of discrete synapses
      within the motor nerve terminals. Our goal in this article is to investigate the
      effect of the stimulation frequency on the number of active release sites (n) and
      the probability of release (p) at those active sites. Because methods based on
      direct counts often provide unstable joint estimates of (n) and (p), we base our
      analysis on mixture modeling. In particular, the mixture modeling approach is
      used to estimate (n) and (p) for stimulation frequencies of 1 Hz, 2 Hz, and 3 Hz.
      Our results indicate that as the stimulation frequency increases, new sites are
      recruited (thus increasing n) and the probability of release (p) increases.

PMID- 12422370
TI  - Cocaine alters mu but not delta or kappa opioid receptor-stimulated in situ
      [35S]GTPgammaS binding in rat brain.
AB  - Chronic cocaine administration produces alterations in mu and kappa opioid
      receptor density as well as striatal and accumbens opioid-regulated adenylyl
      cyclase activity, suggesting a psychostimulant responsive interaction between
      opioidergic and dopaminergic systems. Stimulation of G-protein-coupled opioid
      receptors inhibits adenylyl cyclase production of cyclic AMP. The present study
      employed in situ [(35)S]GTPgammaS binding to measure opioid receptor-stimulated
      activation of G-proteins in response to acute and chronic cocaine exposure. Male
      Fischer rats received acute (1 or 3 days) or chronic (14 days) binge pattern
      cocaine administration. Three and 14 days of cocaine injections resulted in
      greater increases in the ability of the mu receptor agonist DAMGO to stimulate
      [(35)S]GTPgammaS binding in both the core and the shell of the nucleus accumbens,
      all regions of the caudate putamen and the cingulate cortex compared with saline
      matched controls. The greatest increases in DAMGO-stimulated [(35)S]GTPgammaS
      binding were observed in the dorsal areas of the caudate putamen in animals that
      received 14 days of cocaine. No significant changes in delta (DPDPE), or kappa
      (dynorphin A(1-17)) receptor-stimulated [(35)S]GTPgammaS binding were found in
      any brain region in response to cocaine administration. These results demonstrate
      that binge pattern cocaine administration induce changes in mu but not delta or
      kappa opioid receptor-mediated G-protein activity. This study provides support
      for the hypothesis that the addictive properties of both psychostimulants and
      opiates may share common neurochemical signaling substrates.

PMID- 12422371
TI  - Cocaine treatment increases expression of a 40 kDa catecholamine-regulated
      protein in discrete brain regions.
AB  - Previous reports from our laboratory have described brain-specific catecholamine
      regulated proteins, which bind dopamine and related catecholamines. Evidence from
      the molecular cloning of a 40 kDa catecholamine-regulated protein (CRP40)
      revealed that CRP40 is dopamine-inducible and has properties similar to those of
      the 70 kDa heat shock protein (HSP70) family. The present study investigates the
      effects of acute and chronic cocaine treatment on CRP40 expression in the
      striatum, nucleus accumbens, prefrontal cortex, and medulla. Acute treatment with
      cocaine increased CRP40 expression in the nucleus accumbens and striatum, whereas
      chronic treatment with cocaine increased CRP40 expression in the nucleus
      accumbens only. Neither of these treatments affected CRP40 levels in the
      prefrontal cortex or medulla. In addition, pretreatment with the spin-trapping
      agent alpha-phenyl-tert-butylnitrone did not attenuate cocaine-induced expression
      of CRP40, suggesting that the observed increases in CRP40 levels were not caused
      by free radicals. On the other hand, pretreatment with anisomycin, a protein
      synthesis inhibitor, blocked the cocaine-induced expression of CRP40. Thus,
      protein synthesis may be involved in the observed CRP40 level increases.
      Furthermore, neither acute nor chronic cocaine treatment affected levels of
      inducible or constitutively expressed HSP70, which indicates a specificity of
      cocaine's effects on CRP40. Since cocaine has been shown to increase
      extracellular dopamine levels, these findings suggest that increased expression
      of CRP40 is associated with high extracellular levels of dopamine (or its
      metabolites). Elevated levels of CRP40 could play a protective role for dopamine
      neurons in response to increased oxidative stress that has been shown to be
      induced by cocaine and that can lead to apoptosis and neurodegeneration.

PMID- 12422372
TI  - S-[18F]fluoromethyl-(+)-McN5652, a PET tracer for the serotonin transporter:
      evaluation in rats.
AB  - The [(18)F]fluoromethyl analog of (+)-McN5652 ([(18)F]FMe-McN) for imaging
      serotonin transporter (SERT) with positron emission tomography (PET) has recently
      been synthesized. We describe here the biological evaluation of [(18)F]FMe-McN in
      rats. Biodistribution studies of [(18)F]FMe-McN in rat brain ex vivo after an
      intravenous injection showed a high accumulation of radioactivity in the regions
      rich in SERT, such as raphe nuclei, hypothalamus, thalamus, substantia nigra,
      locus coeruleus, and amygdala. Region-to-cerebellum ratios reached a maximum
      value of 9 in raphe nuclei within 3.5 h after administration. The specificity and
      selectivity of [(18)F]FMe-McN binding to SERT was studied by preinjecting
      blocking doses of serotonin, norepinephrine, and dopamine transporter inhibitors.
      Fluoxetine, a specific inhibitor for SERT, decreased the specific binding of
      [(18)F]FMe-McN in raphe nuclei by 91 +/- 4%; in other regions rich in SERT,
      similar results were obtained. GBR12909 and nisoxetine, selective inhibitors for
      dopamine transporter (DAT) and norepinephrine transporter (NET), respectively,
      showed no significant effects on the uptake of [(18)F]FMe-McN. Our studies show
      that [(18)F]FMe-McN has a clear potential as a tracer for studies with PET of
      SERT function in humans.

PMID- 12422373
TI  - Interleukin-1beta abrogates long-term depression of hippocampal CA1 synaptic
      transmission.
AB  - Although interleukin-1beta (IL-1beta) is well known to modulate synaptic
      transmission and plasticity of the hippocampus, no study has yet evaluated how
      this cytokine affects long-term depression (LTD), one of the major forms of
      hippocampal synaptic plasticity. Here we report that at Schaffer collateral-CA1
      synapses, bath application of IL-1beta induces a long-lasting decrease in
      synaptic strength in intact slices, but not in disinhibited slices in the
      presence of bicuculline, a gamma-aminobutyric acid receptor antagonist. The IL
      1beta-induced synaptic depression efficiently foreclosed the subsequent induction
      of LTD in response to a 1-Hz tetanus and, conversely, it was also prevented by
      preexisting LTD. These results suggest that IL-1beta-induced, persistent
      depression of synaptic efficacy is required for GABAergic activation and shares,
      at least in part, a common cellular mechanism for LTD.

PMID- 12422374
TI  - Differences in regional and subcellular localization of G(q/11) and RGS4 protein
      levels in Alzheimer's disease: correlation with muscarinic M1 receptor binding
      parameters.
AB  - Deficits in M1 muscarinic receptor system signaling in Alzheimer's disease (AD)
      prompted an analysis of components of these systems, namely, the G(q/11) protein
      and the regulator of G-protein signaling (RGS) 4 protein. In AD parietal cortex,
      total levels of G(q/11) and RGS4 proteins were significantly lower than age
      matched control cases by 40% and 53%, respectively. However, the levels of
      membrane-bound G(q/11) and RGS4 protein in AD parietal cortex were maintained at
      levels comparable to controls. Furthermore, in the frontal cortex and cerebellum
      both the total and membrane levels of G(q/11) and RGS4 protein were not altered
      in AD cases compared to control cases. To our knowledge, this is the first report
      to examine RGS proteins in AD. Using receptor binding assays on the parietal
      cortex membrane fractions from AD cases, we found the muscarinic agonist
      carbachol still bound to high- and low-affinity sites (two-site fit) and the
      potency of 5-guanylylimidodiphosphate (GppNHp) to shift receptors from the high-
      to low-affinity state (based on the ternary complex model) was greater in AD
      cases compared to controls. In contrast, we previously reported a lack of high
      affinity agonist binding sites in the frontal cortex in AD cases even in the
      absence of GppNHp. The data suggest that the equilibrium dynamics between the
      cytosolic and membrane levels of G(q/11) and RGS4 may contribute to the regional
      differences in the coupling of muscarinic M1 receptors in AD and have
      implications for the variability in effects of cholingeric treatment strategies
      currently in place.

PMID- 12422375
TI  - Host brain regulation of dopaminergic grafts function: role of the serotonergic
      and noradrenergic systems in amphetamine-induced responses.
AB  - The indirect dopaminergic (DA) agonist amphetamine has frequently been used to
      study functional responses of DA grafted neurons. However, it is not known if
      striatal responses, primarily related to DA release by the grafted neurons, are
      modulated by the host striatal afferents. We investigated the changes in
      amphetamine-induced rotational behavior and striatal expression of Fos in DA
      denervated and grafted rats subjected to serotonergic denervation and/or
      treatment with the alpha(1)-adrenergic receptor antagonist Prazosin. Acute
      serotonergic lesions with p-chlorophenylalanine suppressed the expression of Fos
      induced by 1 mg/kg of amphetamine in both the grafted and the contralateral
      striatum. Chronic serotonergic denervation with 5,7-dihydroxytryptamine induced a
      significant reduction in Fos expression in both the grafted and nongrafted
      striata and a nonsignificant reduction in the contraversive rotation. In DA
      innervated striata, Prazosin significantly reduced the expression of Fos but only
      in the presence of serotonergic innervation. However, Prazosin did not decrease
      the expression of Fos induced by grafts located in striata not subjected to
      serotonergic denervation. The present results suggest functional integration of
      transplanted DA neurons and major host striatal afferent systems, particularly
      the serotonergic system, in modulating responses of the host striatal neurons.
      However, indirect effects exerted by the noradrenergic system on the normal
      striatum were not observed in the DA-denervated and grafted striata.

PMID- 12422376
TI  - Unique changes in synaptic morphology following tetanization under
      pharmacological blockade.
AB  - Long-term potentiation (LTP) in the hippocampus has been associated with changes
      in synaptic morphology. Whether these changes are LTP-dependent or simply a
      result of electrophysiological stimulation has not yet been fully determined.
      This study involved an examination of synaptic morphology in the rat dentate
      gyrus 24 h after electrophysiological stimulation sufficient to induce LTP. In
      one group, ketamine, a competitive NMDA antagonist, was injected prior to
      stimulation to block the formation of LTP. Synaptic morphological quantification
      included estimating the total number of synapses per neuron, determining synaptic
      curvature and the presence of synaptic perforations, and measuring the maximal
      PSD profile length of the synapses. The results indicated that most of the
      changes observed following the induction of LTP (increases in the proportion of
      concave-shaped synapses, increases in perforated concave synapses, and a decrease
      in the length of nonperforated concave synapses) are not observed under ketamine
      blockade, suggesting that they are LTP-specific and not simply the result of
      tetanic stimulation. Ketamine was associated, however, with several novel
      structural changes including a decrease in the length of the perforations in the
      concave perforated synapses, a reduction in the number of convex perforated
      synapses, and a nonlayer-specific increase in synaptic length compared to
      controls. Based on previous research, this combination of morphological
      characteristics is potentially less efficacious, which suggests that synapses
      that are tetanized but not potentiated, due to pharmacological blockade, appear
      to undergo opposing, compensatory, or homeostatic changes. These results support
      the suggestion that synaptic morphology changes are both stimulation- and area
      specific, are highly complex, and depend on the specific local physiology.

PMID- 12422377
TI  - Effects of birth insult and stress at adulthood on in vivo tyrosine hydroxylase
      and tryptophan hydroxylase activities in rat brain.

PMID- 12422378
TI  - How to talk to your patients about sex.

PMID- 12422379
TI  - Terrorism. Guarding against biological agents.

PMID- 12422380
TI  - Terrorism. Guarding against prejudice.

PMID- 12422381
TI  - Get your office software out of first gear.

PMID- 12422382
TI  - Botox? Smooth out the risks.

PMID- 12422383
TI  - Evidence based complementary intervention for insomnia.
AB  - Increasing scientific evidence point to a non-pharmacological complementary
      treatment for insomnia: white noise. Its presentation has been shown to induce
      sleep in human neonates and adults, probably by reducing the signal-to-noise
      ratio of ambient sound. White noise may be a simple, safe, cost-effective
      alternative to hypnotic medication in many psychiatric disorders, especially
      acute stress disorder and PTSD.

PMID- 12422385
TI  - Acute myocardial infarction and Friedreich's ataxia.
AB  - While cardiac disease is noted in 90% of patients with Friedreich's ataxia
      (FRDA), the finding of coronary artery disease is unusual. To the best of our
      knowledge only two cases of acute myocardial infarction (AMI) has been reported
      in patients with FRDA. Large vessel CAD has not been reported previously in
      patients with FRDA. We report a young patient with AMI and obstruction of large
      epicardial arteries.

PMID- 12422384
TI  - Report of the first annual Hawaii Asthma Research Consortium.
AB  - The first Hawaii Asthma Research Consortium was held on 7 May 2001 at Tripler
      Army Medical Center. Researchers investigating asthma-related problems and
      program directors of asthma projects were solicited statewide to present their
      projects. Ten lecturers focused on research and asthma projects in Hawaii in 20
      minute presentations. An informal ten-minute discussion followed each
      presentation to encourage audience questions about the project and to discuss
      possible collaboration efforts between institutions. The institutions that were
      represented include: American Lung Association-Hawaii, Kaiser Permanente Center
      for Health Research Hawaii, Kapiolani Medical Center, Tripler Army Medical
      Center, University of Hawaii at Manoa, and Waianae Coast Comprehensive Health
      Center.

PMID- 12422386
TI  - A 16-year-old female presenting with coma and hypertension.

PMID- 12422387
TI  - The Study of Tamoxifen and Raloxifene (STAR trial) for the prevention of breast
      cancer.

PMID- 12422388
TI  - [Emergency over-the-counter contraception].

PMID- 12422389
TI  - [Children's height and bulk].

PMID- 12422390
TI  - [Who are the users of emergency contraception?].
AB  - INTRODUCTION: A user profile is necessary in order to direct future campaigns for
      emergency contraception (EC). MATERIAL AND METHODS: Over a three-month period,
      423 women with prescriptions for EC were consecutively entered in the study,
      which was carried out in four inner-city pharmacies in Copenhagen, Denmark.
      RESULTS: The median age was 24 years (range 13-50 years). Most women (73%) were
      first-time users of EC. The reason for the current need for EC was most often
      condom failure (54%) or non-use of any contraceptive method (41%). Only six women
      (1.4%) reported non-use of contraception because of their knowledge of EC and
      only four women (0.9%) reported EC as the usual method of contraception.
      Knowledge about EC more often came from family or friends (51%) and advertising
      (47%), than from general practitioners (26%) or through sex education in schools
      (3%). Altogether 282 women (69%) received EC from a doctor in the medical
      emergency service or a casualty ward. DISCUSSION: Overall, EC is used as
      recommended. Its availability does not seem to reduce the use of safer
      contraceptive methods. The mandatory sex education in school should include
      information on EC.

PMID- 12422391
TI  - [BMI of Danish school children measured during the periods 1986/1987--1996/1997
      compared to Danish measurement in 1971/1972].
AB  - INTRODUCTION: A global epidemic in overweight and obesity in children has been
      postulated. There is a lack of consensus over definitions however, and national
      standards of BMI centiles have been published in various countries. This has made
      results on the prevalence of overweight difficult to interpret. Internationally
      based cut-off points have now been published, and a British study reports trends
      in overweight and obesity in children, as defined by these. The aim of this study
      was to compare the BMI of a sample of Danish children attending school in
      1986/1987-1996/1997 to that of Danish schoolchildren in 1971/1972. MATERIAL AND
      METHODS: The school health officers in 23 municipalities representing a "mini
      Denmark" collected from the school health records 3-4 routine measurements of
      height and weight in children attending school in 1986/1987-1996/1997. From these
      measurements, the children's BMIs were calculated and BMI centiles were
      constructed. The data covered a total of 11,167 measurements of 3371 children.
      RESULTS: The children in our study had higher BMI values than had children in
      1971/1972, both on average and for the highest centiles. The average BMI values
      were significantly higher from the age of 8 years in boys and 7 years in girls.
      The prevalence in overweight and obesity has increased. For 14-16-year-old boys,
      the average BMI was related to the educational level of the mother (negatively).
      DISCUSSION: The highest BMI centiles had especially increased. The proportion of
      overweight and obese 14-16-year-olds according to internationally based cut-off
      points had increased from 5.1% to 1.5% for boys and from 6.2% to 15.6% for girls
      since 1971/72. This trend calls for preventive efforts.

PMID- 12422392
TI  - [Body height of 6-15-year-old school children measured in the period 1986/1987 to
      1996/1997. Compared with Danish measurements in 1971/1972].
AB  - INTRODUCTION: Danish schoolchildren are said to have grown taller during the last
      25 years. Studies on this topic have not been nationwide, however. The aim of
      this study was to compare the heights of a nationwide sample of Danish
      schoolchildren in 1986/1987-1996/1997 to a sample in 1971/1972. MATERIAL AND
      METHODS: The school health officers in 23 municipalities representing a "mini
      Denmark" collected from the school health records 3-4 routinely measured heights
      in children attending school in 1986/1987-1996/1997. The data covered at total of
      11,351 height measurements of 3378 children. From these data, standards of height
      from the age of 6-16 years were calculated. RESULTS: The schoolchildren's average
      heights had increased about 1 cm at the start of school, 2-3 cm in girls and 5-6
      cm in boys aged 10-15 years and 0.6 cm in girls and 1.6 cm in boys aged 16 years,
      as compared to growth charts for 1971/1972. CONCLUSION: The children in our study
      were taller than schoolchildren in 1971/1972, and they seemed to have an earlier
      pubertal height spurt. A growth study of Danish children is needed.

PMID- 12422394
TI  - [Reflex dystrophy. Complex regional pain syndrome type I].
AB  - Reflex sympathetic dystrophy or complex regional pain syndrome type I is
      primarily a clinical diagnosis. The syndrome is most common after soft tissue
      damage or fractures and is more often seen in women than in men. The paramount
      symptom is pain, but oedema, a limited range of motion, changes in sensibility,
      and trophic changes are also seen. The pathogenesis is unknown, but most
      clinicians believe it to be caused by disturbances in the sympathetic or sensory
      nervous system and/or an excessive inflammatory response, most likely neurogenic
      inflammation. It seems that early treatment with physiotherapy and
      corticosteroids has a positive effect on the disease. Despite lack of
      documentation, the principles of treatment usually prescribed for the treatment
      of neurogenic pain must be taken into consideration. There is a lack of large
      double-blind studies on all aspects of the syndrome.

PMID- 12422393
TI  - [Prolonged chronic non-malignant pain conditions].

PMID- 12422395
TI  - [Elder abuse].

PMID- 12422396
TI  - [Do children of long-lived parents age more successfully?].
AB  - INTRODUCTION: Long-lived individuals are rare and may be selected in part for the
      genetic factors that promote successful ageing. The children of long-lived
      parents may therefore age more successfully than the children of short-lived
      parents. MATERIAL AND METHODS: We used three major cross-sectional, population
      based surveys to study the association of parental longevity with successful
      ageing in offspring. The measures of ageing were hand-grip strength, cognitive
      performance (mini mental state examination (MMSE) and a cognitive composite
      score), self-reported diseases, and self-rated health. RESULTS: For every
      additional ten years the parents lived, grip strength increased by 0.32 kg (95%
      CI = 0.00-0.63), the MMSE score by 0.20 points (95% CI = 0.03-0.37), and
      cognitive composite score by 0.24 points (95% CI = 0.07-0.40). A ten-year
      increment of parental life was associated with a reduction by approximately 0.20
      in the adjusted OR for having each of the following conditions: diabetes,
      hypertension, ischaemic heart disease, heart failure, stroke, or fair, poor or
      very poor self-rated health. Almost all the effects were seen solely in the
      cohort of 70+ year-olds, but not in the middle-aged or nonagenarians. DISCUSSION:
      Parental life span is positively associated with physical and cognitive
      functioning and avoidance of some of the common chronic diseases. However,
      overall the effects are small and are seen in the elderly, but not in the middle
      aged or the very old.

PMID- 12422397
TI  - [Assessment of the treatment of acute pancreatitis].
AB  - INTRODUCTION: The first international evidence-based guidelines for the
      management of acute pancreatitis were published in 1998. The aim of this study
      was to compare the care giving to patients with these guidelines. MATERIAL AND
      METHODS: During the period, June 1996 to May 1999, a survey was carried out of
      all patients with acute pancreatitis six months after discharge. RESULTS: One
      hundred and fifty-five patients with a first attack were identified within 48
      hours (goal: 100%). Fifty (32%) had gallstones identified. Fifty-one (32%) were
      severe cases with ten (20%) deaths (goal: < 30%). The overall mortality (6.4%)
      was within the goal of less than 10%. Objective severity stratification (Ranson
      scoring) was performed in 94% (goal: 100%), and in severe cases 82% (goal: 100%)
      had a CT. In severe gallstone pancreatitis, 90% (goal: 100%) underwent an early
      ERCP (< 72 hours after admission). One management goal was not met: in mild
      cases, only 20-25% (goal: 100%) with gallstone pancreatitis were given definitive
      treatment within four weeks. DISCUSSION: The treatment we offer our patients with
      acute pancreatitis is optimal--apart from one standard--when compared with
      international guidelines, but in spite of this exception the mortality rate is
      low.

PMID- 12422398
TI  - [Critical illness polyneuropathy--a neuromuscular complication in the intensive
      care patients].
AB  - Critical illness polyneuropathy is a serious, but potentially reversible,
      complication following the treatment of severe infection and respiratory failure
      in the intensive care unit. A case of prolonged tetraparesis after severe
      infection and ventilatory support in a middle-aged woman is described.

PMID- 12422399
TI  - [Biliary pain in genital Chlamydia infection].
AB  - We describe a case of clinical signs of acute cholecystitis as a complication to
      genital Chlamydia infection. Transabdominal ultrasound and magnetic resonance
      scanning were normal. Cholescintigraphy showed an obstruction of the ductus
      cysticus. The patient was treated with antibiotics and two weeks later was
      without symptoms.

PMID- 12422400
TI  - [Partial occlusion of the Bain circuit causes respiratory acidosis under general
      anesthesia].
AB  - The Bain circuit is a modification of the Mapleson D ventilation system used in
      general anaesthesia in children and adults. It has several advantages over other
      systems as it is light in weight, convenient, and has no valves. But it contains
      the risk of undetected leak or occlusion, because of its construction with a
      small inner tube, which provides the patient with fresh gas, inside a larger
      corrugated tube. We report a partial occlusion in the T-piece of the Bain
      circuit, leading to high peak pressure and respiratory acidosis under controlled
      ventilation in a 15-year-old boy.

PMID- 12422401
TI  - [Acute respiratory distress syndrome and steroid as anti-inflammatory therapy].

PMID- 12422402
TI  - [Time-limited contribution concerning anti-dementia agents].

PMID- 12422403
TI  - [Many Danes get too little of vitamin D].

PMID- 12422404
TI  - [Three criminal cases with Asperger's disorder: how their handicap was reflected
      in their antisocial behaviors].
AB  - Three patients with Asperger's disorder who were sent to Juvenile Court for
      sexual offenses are presented, and the relationship between this disorder and
      their crimes is discussed. All three adolescents showed unusual behaviors related
      to their crimes. The analysis of these cases suggested: 1) the idiosyncrasies
      seen in the crimes were closely related to their social deficits and obsessive
      traits, which are the two major problems in pervasive developmental disorder
      (PDD), 2) their offensive behaviors were not the direct results of their deficits
      due to PDD, and 3) their criminal behaviors should be understood in the unique
      context that is specific to PDD, not from conventional psychological viewpoints.
      Finally, current problems associated with PDD in Japan are discussed.

PMID- 12422405
TI  - [A case of intra-axial multiple cavernous angiomas, presented with dementia and
      cerebellar signs].
AB  - We reported a case of intra-axial multiple cavernous angiomas, presented with
      dementia and cerebellar signs. The patient, a right-handed 73-year-old woman,
      showed gait disturbances, tremor increased while writing and hypoactivity at the
      age of 71. Treatment with 1-dopa was not effective. At the age of 73, she was
      diagnosed as having intra-axial multiple cavernous angiomas on the gradient echo
      MRI study, which demonstrated large numbers of small low density areas (small
      dots) in the cerebellar cortex and moderate numbers of those in the cerebral
      cortices. Those small dots were not detected in the basal ganglia, the brain
      stem, and increased the thalamus. She clinically showed cerebellar signs, such as
      dysmetria, adiadochokinesia, and tremor worsening in the course of writings, in
      additions to the constructural apraxia, disturbances of writing, and severe
      perseverations. Those symptoms slightly fluctuated. However, she did not show any
      character changes. The results of Wisconsin card sorting test and Trial making
      test A were different from those usually seen in dementia with multiple
      infarctions in the cerebral white matters and basal ganglia. Although her
      cerebellar signs are considered to be due to numerous small dots in the
      cerebellar cortex, her parietal symptoms could not be understood by slight
      parietal changes such as hypoperfusions of SPECT, cerebral small dots, and
      infarctions in the white matters. We speculated that, by interactions between the
      cerebellar dysfunctions and slight parietal dysfunctions, she developed the
      parietal symptoms described above, which differed from dementia or Parkinsonism
      due to multiple cerebral infarctions, and which were characterized by slight
      fluctuations and alleviations with habituation.

PMID- 12422406
TI  - [A consideration of the relation between psychiatric knowledge and natural
      science].
AB  - Schools of psychiatric thought are as numerous as they are various, each
      developed from different sources and presuppositions and each claiming faithful
      adherents. One inherent difficulty in this profusion of choice lies in discerning
      whether or not a particular school's presuppositions are valid. To accept one
      theory is to choose one opinion towards philosophical aporiae--often at the
      expense of all others. In this paper, issues of scientific philosophy are
      examined in considering the presuppositions and progress of psychiatric schools.
      Popper convincingly argued that scientific statements should be "falsifiable."
      However, because propositions of psychoanalysis or phenomenological psychiatry
      are closely tied to individual clinical experiences, such statements tend to be
      exclusive and difficult to check or falsify by other reseachers. They are, in
      this respect and according to Popper's point of view, necessarily less
      scientific. Phenomena of the human mind, by its very nature, cannot be observed
      nor measured directly. Interpretation of the phenomena therefore depends almost
      entirely upon which theoretical school the researcher has adopted. Biological
      psychiatry, however, insists that any researcher can objectively measure such
      phenomenon, and that propositions of biological psychiatry can be connected with
      those of other branches of natural science. Natural science grandly attempts to
      comprehensively describe the whole world using one language. This means the
      researcher is supposedly measuring an object positioned in an ideal and definite
      position, reached only through infinite steps. Phenomenology is very conscious
      that the observed object consists at least partly of the observing subject, and
      so this ideal positioning seems untenable. Phenomenology therefore describes this
      world from another point of view, different from natural science, and the
      distinction between measurement of certain systems from inside or outside is
      important for purposes of explanation and clarification. Although natural science
      attempts to attain the ideal infinite view, on-going science is naturally
      limited. In psychiatric practice, we can never rely on one definitive theory; but
      must rather adopt an appropriate theory to solve an appropriate problem.

PMID- 12422408
TI  - Does the cardinal ligament of the uterus contain a nerve that should be preserved
      in radical hysterectomy?
AB  - The cardinal ligament (CL) of the uterus is present as a specific part of the
      parametrium when the pararectal and paravesical spaces are developed surgically.
      According to usual nerve-sparing radical hysterectomy (the Tokyo method), the CL
      is divided into two parts, the vascular part for dissection and the nerve part
      that contains the pelvic splanchnic nerve (PSN) as a major target for nerve
      sparing. In contrast, we hypothesized that the CL and another structure outside
      of the usual area for surgical dissection, that is, the lateral rectal ligament,
      are mutually continuous and that the PSN runs through the lateral ligament rather
      than the CL. In the present study, a combination of routine dissection, fresh
      cadaver dissection and in situ sectional anatomy revealed that: (i) the CL did
      not contain the PSN; (ii) a well-defined fascial structure existed in the bottom
      or dorsal margin of the CL area; and (iii) the pelvic plexus was separated from
      vascular components of the CL. The present results provide a new perspective for
      nerve-sparing radical hysterectomy with extensive lateral parametrial dissection
      of the CL.

PMID- 12422407
TI  - Melanin-concentrating hormone neuron system: the Wide Web that controls the
      feeding.
AB  - Recent evidence indicates that the hypothalamic control system of food intake
      involves many feeding-related neuropeptides. Melanin-concentrating hormone (MCH),
      one of a group of potent orexigenic peptides, is exclusively produced in neurons
      of the lateral hypothalamic area that give off fibers to the widespread brain
      regions. The receptor of MCH was recently identified to be localized in cell
      bodies and dendritic processes of particular neurons throughout the brain, in
      close spatial relation to MCH fibers. Leptin, an anorectic hormone secreted from
      the adipose tissue, acts on the specific receptor present on its target neurons
      in the brain, and suppresses the expression of both MCH and its receptor. Leptin
      receptor and STAT3, a transcription factor mediating the leptin signaling, are
      distributed in the widespread brain regions including the cerebral neocortex,
      hippocampal formation and lower brainstem as well as the hypothalamus where MCH
      fibers and the MCH receptor are abundantly present. These findings suggest that
      MCH exerts the effect through its specific receptor distributed throughout the
      brain and that the function of MCH is influenced by the condition of peripheral
      energy balance via leptin, the leptin receptor and STAT3, not only in the
      hypothalamus, but also in other brain regions. In the brain, MCH might be
      involved in various feeding-related functions, such as appetite, food-searching
      behavior, eating muscle movement, and control of energy balance, depending upon
      the physiological role of each region.

PMID- 12422409
TI  - Comparison of sarcomere alterations after muscle contraction and tension loading
      in the rat soleus muscle.
AB  - Muscle contraction induced by 30 min of continuous nerve stimulation at 50 Hz
      resulted in sarcomere changes of the soleus muscle in the rat in our previous
      study. To further investigate the cause of sarcomere alterations, the sciatic
      nerve was electrically stimulated intermittently for 30 min. Nerve stimulation
      was also conducted after cutting the tendons of the soleus, gastrocnemius and
      plantaris muscles in order to prevent imposing tension on these muscles as a
      result to their own contractions. In addition, the muscles were pulled by weights
      via their tendons to load high tension for 30 min without nerve stimulation.
      Sarcomere alterations immediately after treatments were quantified by electron
      microscopy. The percentages of aberrant sarcomere areas of the soleus muscle were
      25.7 +/- 16.4% (mean +/- SD) in the group of intermittent nerve stimulation with
      intact tendons and 21.1 +/- 35.4% in the group of tenotomy and continuous nerve
      stimulation, which were roughly equal to or more severe than the group of
      continuous nerve stimulation with intact tendons (18.8 +/- 15.8%) in our previous
      study. Sarcomere alterations consisted mainly of hypercontraction in these
      groups. Almost all sarcomere changes in the tension-loaded (pulled) soleus
      muscles were scarce myofilaments (1.7 +/- 1.0% by 600 g; 4.5 +/- 2.9% by 1200 g),
      and hypercontraction was not observed. These findings indicate that neither high
      tension nor a decrease of muscle blood flow during continuous contraction seems
      to be the primary cause of sarcomere alterations in the present study. There are
      probably other causes that produce aberrant sarcomeres.

PMID- 12422410
TI  - Colchicine-induced apoptosis and anti-Fas localization in rat-incisor
      ameloblasts.
AB  - Apoptosis of ameloblasts were examined by the TdT-mediated dUTP-biotin nick end
      labelling method and electron microscopy 8 h after injection of colchicine. The
      results showed that extensive apoptosis occurred in ameloblasts of secretion to
      maturation zones. To determine the possible involvement of stimulators in
      ameloblast apoptosis, Fas, Fas ligand, tumor-necrosis-factor alpha, and tumor
      necrosis-factor receptor 1 were examined utilizing immunohistochemistry and
      Western blotting analysis. Only Fas was consistently detected in the secretion,
      transition and maturation ameloblasts and overlying enamel organ epithelia. These
      results suggest that ameloblasts could undergo apoptosis by colchicine and that
      one of the ameloblast apoptosis mediators would be the Fas receptor.

PMID- 12422411
TI  - Developmental expression of beta-catenin in mouse retina.
AB  - Recent studies have shown that catenins play a pivotal role in neuronal
      signalling during vertebrate development. In order to study the significance of
      beta-catenin in the developing mouse retina, the localization of beta-catenin was
      examined by immunohistochemistry from embryonic day (E) 12 to adult mice.
      Immunoreactivity for beta-catenin was found in ganglion cells of the retina at
      E12, and extended to the inner and outer plexiform layer as well as the ganglion
      cell layer with the strongest immunolabelling from E16 through to postnatal day
      (P) 5. The immunoreactivity of ganglion cells was distributed on the cell
      surface. Thereafter, the immunoreactivity gradually decreased, being limited to
      the inner plexiform layer and ganglion-cell layer, including the nerve-fiber
      layer in P10. By P16, the weak immunoreactivity was detected in the inner
      plexiform layer and ganglion-cell layer, and almost disappeared in the adult
      retina. No distinct immunoreactivity was found in the retinal pigment epithelium.
      The reverse transcription polymerase chain reaction showed that beta-catenin
      messenger ribonuclic acid was detected at E12, E16, P1 and P16, and thereafter
      markedly decreased, being weakest in the adult. These findings show that beta
      catenin is expressed during development at the sites of synaptic connections of
      inner and outer plexiform layers, and on the ganglion cells and their fibers in
      the retina, suggesting that beta-catenin might play an important role in the
      synapse formation and ganglion-cell development during the morphogenesis of the
      retina.

PMID- 12422412
TI  - Immunohistochemical characterization of the intracellular pool of water channel
      aquaporin-2 in the rat kidney.
AB  - Aquaporin-2 (AQP2) is a member of water channel proteins expressed in the kidney
      collecting duct cells, where it is stored in the intracellular compartment. Upon
      stimulation of antidiuretic hormone (ADH), AQP2 is recruited to the plasma
      membrane, and plays a critical role in urine concentration. We
      immunohistochemically characterized the intracellular compartment harboring AQP2
      in the rat kidney using antibodies to the endoplasmic reticulum, Golgi apparatus,
      trans-Golgi network, lysosome, and endosome. Aquaporin-2 did not colocalize with
      calnexin, TGN38, Golgi 58K, cathepsin D or Igp-110. Small portions of AQP2
      bearing vesicles were positive for early endosome antigen 1. These localization
      patterns were basically the same in water-loaded and ADH-treated animals. These
      results indicate that AQP2-bearing vesicles constitute a unique intracellular
      compartment distinct from the endoplasmic reticulum, Golgi apparatus, trans-Golgi
      network and lysosome. Partial colocalization of AQP2 with early endosomes
      suggests that the endosomal system might be involved in the trafficking of AQP2.

PMID- 12422414
TI  - [Qualitative methodology].

PMID- 12422413
TI  - The effects of the total saponin of Dipsacus asperoides on the damage of cultured
      neurons induced by beta-amyloid protein 25-35.
AB  - According to the pathogenesis of Alzheimer's disease (AD), beta-amyloid protein
      (A beta) was directly toxic to neurons, leading to neurodegeneration. Total
      saponin of Dipsacus asperoides (tSDA) is one of the main ingredients of Dipsacus
      asperoide, a traditional Chinese medicine. To explore the effects of tSDA on
      neuronal damage induced by A beta in vitro, biochemical analysis combining
      primary cultured neurons were adopted. Neurons were treated with 35 mmol/L A beta
      for 24 h, and tSDA at concentrations of 1-300 mg/L were added to A beta-treated
      cultures 24 h in advance, A beta for 24 h, the survival rate of neurons decreased
      closely by 50%. Lactate dehydrogenase release and the Malondialdehyde (MDA) level
      increased substantially. However, if neurons were pretreated with tSDA, the
      survival rate of neurons was higher than A beta-treated alone. Lactate
      dehydrogenase release and the MDA level decreased distinctly. Results
      demonstrated that tSDA possessed a neuroprotective action and that tSDA protected
      neurons against the toxicity of A beta, most likely by relieving oxidative stress
      or inhibiting the process of A beta, inducing free radical generation.

PMID- 12422415
TI  - [Qualitative research in Spain: from political life to mistreatment of the
      sense].
AB  - A current of sociological thought came into being in Spain in the sixties
      consisting of what is known by the ill-defined term of qualitative methodology in
      our country. A blatant paradox, as the freedom with which this theoretical and
      methodological building would be erected was born precisely out of a lack of
      political freedom and freedom of thought of those dreadful years. Countering the
      official body of knowledge and also removed from all "protest" orthodoxy, a
      vivid, problematical reflection of the society's true situation conceived as
      critical theory took shape. It is in no way owing, as regards its assumptions,
      its findings or its formulations, to either English-U.S., sociology, which was
      predominant at the time, or to that which would later progressively makes it way
      to us. Taking exception to data and the imaginary all-powerful importance
      thereof, this methodology propounded a radical turnabout of the perspective of
      this research to focus on language, understood as the social discourse, in the
      powerful sense of the word, and not as a mere set of statements, also moving away
      from the more or less subjectivist conceptions of the meaning. Opposing the body
      of knowledge of this discipline, it construed research as a cross-roads,
      undertaking an endless task, as it is impossible to complete from a logical point
      of view. It then propounded listening to the sense, which is never the same as
      the meaning, and includes the analysis of the wording used for a full
      understanding thereof.... This is a totally autochthonous current perfectly well
      founded at its epistemological, methodological and technical levels, the
      continuing survival today of which is more than uncertain, as it dissolves into
      the body of university knowledge, into the ongoing flow of the quotes of authors,
      currents and disciplines. It is corrupted in its commercial use, where its
      discontinuance now seems assured in benefit of the marketing discourse, and it is
      running the risk of becoming completely useless in social areas of study (such as
      Health), where poorer English-U.S. perspectives are coming into play without
      apparently meeting with the least critical opposition.

PMID- 12422416
TI  - [Encounters and disencounters between qualitative and quantitative perspective in
      History of Medicine].
AB  - The presentation of qualitative research methods in the health care field
      underlines how these methods are irrelevant to and inconsistent with scientific
      traditions in the Health Sciences field. These methods are to of a quantitative
      nature--epidemiology usually being cited as an example--the connection between
      but qualitative methods and what are referred to as the Social Sciences seems
      predominant. This article is aimed, on the contrary, at pointing out that
      qualitative methodologies, which are richer and more highly complex that the
      quantitative approach, do comprise an intrinsic part of Health Science
      traditions. A run through the major milestones and events throughout the history
      of Medicine reveals the paradoxical protocol of Health Sciences, overlapping the
      Natural Sciences and Social Sciences, overlapping qualitative and the
      quantitative view. More specifically, this analysis revolves around a twofold
      approach to illness, by way of signs and symptoms, as a condensing these
      paradoxical protocol considered. A historical analysis reveals how the twofold,
      complex way of signs and symptoms is equivalent to the complex relationship which
      exists between the qualitative and the quantitative perspective. The signs
      correspond to quantitative approach and the symptoms to the more qualitative. The
      relationships between the two would be similar to that existing come to bear
      between the qualitative and quantitative perspectives in the field of the Social
      Sciences. These results show the qualitative perspective to be rooted in medical
      tradition itself and may therefore facilitate its use these by all health care
      professionals as a whole. The fact that the "semiology" so in vogue today in the
      social sciences stems from "clinical semiology" should not be overlooked.

PMID- 12422417
TI  - [Observation, interview and discussion group: the silence of 3 research
      practices].
AB  - Before entering into the opposition between quantitative perspective and
      qualitative perspective of social research, the need is discussed of considering
      the social research process as a social process and the empirical observation
      situations per se as social situations. Therefore, in social research, the object
      of observation and the ways of observation are made in the same stuff. As in any
      social situation, social norms come into play in the observation situation. Thus,
      the article develops the presentation of three qualitative social research
      practices from their design as producing different social situations which, in
      turn, take on the nature of immediate contexts which favor respective
      articulations between the practical norms of specific social groups and the
      dominant social norms in society at large. The practices presented are:
      participant observation, in-depth interview and discussion group. A different
      articulation among social norms which finds silence to be privileged way of
      observation. Hence, the conclusion is reached that the management and analysis of
      silence is fundamental both for distinguishing the qualitative from the
      quantitative perspective, the former opening up more to silence than the latter,
      and to distinguish one practice from another, especially for observing the
      effects proper of the observation during the observation processes.

PMID- 12422418
TI  - [Modes of analysis in qualitative research in health: critical perspective and
      spoken reflexions].
AB  - There is a consistent theoretical and methodological foundations on qualitative
      health research provided mainly by social sciences. However, this existent
      overlap between social and health aspects is a wide multidisciplinary field still
      underexplored. This article offers an overview of the main paradigms,
      methodologies and theoretical tendencies of qualitative research analyses within
      the health sciences context. Based on an initial classification, two opposite
      extremes for setting the bounds of the qualitative analysis continuum--from
      designs focusing on data description, which are purely exploratory, to those
      which go into theorizing processes so as to draw out interpretations and
      inferences--are discussed. Qualitative research is an important tool in the
      analysis of health problems from a social and cultural point of view. Adopting
      different procedures such as content and speech analysis, qualitative research
      approaches communication patterns and examines the diverse language ideologies.
      Sociological and anthropological traditions provide unique methodologies which
      allow to know the context where the phenomena appear and set out theoretical
      proposals in order to explain them, for example ethnomethodology or analytical
      induction. Lastly, some keys are suggested for developing a common area, out of
      which new epistemological perspectives may be set out based on different
      disciplines coming together.

PMID- 12422419
TI  - [Qualitative evaluation of the blood collection process in Catalonia].
AB  - Blood donation is indispensable for quality health service provision. The
      stagnation of the number of donations in Catalonia prompted up an external
      evaluation of the system of blood collection that could orient the future
      policies. An evaluation of blood-donor services in Catalonia was designed
      adopting a qualitative methodology. The evaluation design included the use of a
      variety of techniques namely participant observation, individual interviews,
      group interviews and documentary techniques. The field work was carried out in
      all blood-donation sectors of Catalonia from the 23th November to the 4th
      December, 1998. Using Atlas/ti, a computer science tool for the qualitative
      analysis of textual data, the information analysis partially followed the
      prescriptions of "grounded theory" and of some modalities of thematic content
      analysis. The results show the basic characteristics and deficiencies of the
      process and its organization, describing their strong and weak points. The
      findings also detail arguments on blood donation that the agents implied in the
      process, donors an professionals, use. We also report what reasons the blood
      donor service managers/providers gave for donating blood, and what perceptions
      they had of blood donors.

PMID- 12422420
TI  - [Qualitative research and health promotion in the Community of Madrid].
AB  - This article provides an account of the qualitative research experiment conducted
      by the Public Health Administration of the Autonomous Community of Madrid from
      1991 to date. This research was divided into two working areas, that is, the
      "Sociocultural Health Information System" and the "Research Program". The former
      analyses what health means for the inhabitants of the Autonomous Community of
      Madrid, the factors involved therein, the value they place thereon and its
      relative importance among all of their interests as a whole. The latter
      researches specific aspects of the health/illness processes identified by the
      experts in the development of Public Health programs. People envisage health in
      their own way and have their own health-related cultural models, not always the
      same as those put forward by the health care system, which have a determining
      bearing on their actions. The mere verification of social facts has revealed
      itself to be insufficient as regards understanding and helping to transform human
      behavior, questions of ideology and emotion take on major importance in this
      regard. Structural research, through the use of qualitative methods, affords us
      the possibility of gaining knowledge of these matters, setting the course of
      Health Education and Health Promotion measures. The aim is to feed back the
      information generated to the different sectors of the population involved, to
      institutions and professionals in the health care, social and educational fields,
      as well as to organizations related to Health Promotion, with the aim of
      generating changes in the institutions and developments in thinking of society at
      large.

PMID- 12422421
TI  - [Medical care for chronic disease: reflexions on methodologic procedures of a
      qualitative study].
AB  - Chronic diseases have been the focus of qualitative researchers. However, few
      studies have explained in depth the methodological options choOsed in the studies
      and their reasons. This paper presents some reflections on the methodological
      strategies and procedures used in a multisite, qualitative study whose focus are
      the individual's perspectives on chronic conditions and medical care. Such
      reflections are on the study's orientation, the selection of the area, the focus
      groups and the social relations among participants. We conclude stating that the
      methodological options and the strategies used, rather than being solely a
      technical issue, are deeply linked to the study's object, the social relations
      among participants and the context of research.

PMID- 12422422
TI  - [Quality criteria in Qualitative Research in Health: notes for a necessary
      debate].
AB  - The importance of gaining further knowledge as to the health-related needs and
      expectations of individuals, as well as of the factors involved in the
      effectiveness of health care activities, particularly of the professionals
      proper, make it possible to anticipate a boom in Qualitative Research in fields
      such as Public Health and Health Service Research. Such an increase should go
      hand in hand with a progressive improvement in the quality of the outcomes of
      research, to which end tools for assessing said quality are required. However,
      the epistemological implications of the qualitative focus contribute to the
      setting of the bounds of these tolls having been a source of controversy at both
      the conceptual level as well as with regard to the methods and techniques to be
      employed, although without hardly any involvement on the part of the health
      sciences in our country. This article provides a brief review of the main points
      of reference of said debate and, after stressing the importance of the
      theoretical development and of precision in practice, as well as the function of
      the guides with regard thereto, the epistemological adaptation, relevance,
      validity and reflexivity as possible basic criteria for the assessment of the
      quality of Qualitative Research are proposed.

PMID- 12422423
TI  - [Ten contributions to the use of qualitative methodology in an audit of internal
      communication in primary care].
AB  - Qualitative methodology, originally belonging to the Social Sciences domain, has
      progressively incorporated to Health Research to the scepticism of many and the
      admiration of others. Nowadays, validity and fiability of these qualitative
      techniques is still questioned by a great amount of health researchers and their
      use provokes doubt among reviewers and other members of the scientific community.
      This article presents as a fundamental measure for the validity of the
      qualitative methodology its precise use to approach determinate research
      objectives specific to them and, echoing the extra issue of the Health Services
      Research on December 1999 on this methodology, gathers the contribution of the
      use of these techniques from a complementary point of view, in a Internal
      Communication Audit conducted in the Primary Care Services of four Regional
      Health Systems: Area II of the INSALUD (National Health Institute), Basque Health
      System, Canary Health System and Andalusian Health System.

PMID- 12422425
TI  - [Qualitative evaluation of a promotion campaign for the use of condoms in an
      adolescent and youth population for the Community of Madrid].
AB  - BACKGROUND: The Program for Standardizing Condom Use has been carrying out
      different activities to promote condom use among the teenage and young adult
      population since November 1998. All of these measures have revolved around a
      specific measure aimed at making condoms more readily available, that is, the
      sale of condoms to the teenage and young adult population in pharmacies at low
      prices. The objective of this research was to assess the results from the
      standpoint of the persuasive effectiveness of these measures as related to
      modifying unsafe practices. METHODS: The qualitative methodology employed was the
      customary methodology within the context of market and opinion studies, that is
      qualitative after-test on the bases of open interviews with pharmacists and
      youths. A total of 7 interviews were held with pharmacists in addition to 14
      interviews with sexually active young people of both sexes within the 17-19 age
      range residing in unsafe areas from the standpoint of AIDS incidence. RESULTS:
      Two main risk factors were identified: a) The approaches taken on the part of
      certain sexually successful males, always within the context of casual sexual
      relations, of avoiding condom use for the purpose of greater sexual pleasure in
      view of a prior assessment of the degree of risk involved in the relations in
      question; the post-coital pill as an alternative means of contraception seems to
      be involved very often in such approaches. b) The inhibition of purchasing
      condoms in the pharmacy, which prevents taking due precautions and, therefore,
      directly gives rise to unsafe situations arising. CONCLUSIONS: The campaign in
      question has been assessed as being positive from the purely informative
      standpoint. No aspects have however been encountered which afford the poSsibility
      of effectively countering the main risk factor detected, the approaches taken of
      avoiding the use of a condom for the purpose of achieving greater sexual pleasure
      and the sanctioning of these practices on the part of the group. As regards this
      second risk factor, that of inhibition regarding purchase, no appreciable
      effectiveness has been noted as regards the sale of condoms at a low price in
      pharmacies.

PMID- 12422424
TI  - [Evolution of social representations about health among women from Madrid, 1993
      2000].
AB  - BACKGROUND: In 1993, initial research was conducted among the women in Madrid. In
      2000, a second research was conducted for the purpose of analyzing the possible
      evolution of the social representations related to health among women and, if
      necessary, to therefore reorient the health programs set forth in 1993 in terms
      of the results of the research. The aim was therefore to analyze the possible
      advancement of the opinions stated, of the health-related social representations
      which each one of the five types encountered in 1993 might express throughout the
      1993-2000 period. METHODS: The qualitative research conducted in 2000 was based
      on the holding of 10 discussion groups defined according to the women's
      "typologies" which had been set out in the 1993 research. The types in question
      were characterized in terms of different sociodemographic variables and of the
      role which they had stated as most important in 1993. The analysis of the stated
      opinions was put into graphic and topological form in order to display the
      aforementioned trend in the social representations. RESULT: This research
      revealed some major changes having taken place throughout the 1993-2000 period,
      the predominant stated opinion-related perspective had evolved out of the
      "housewife" role to the "working woman" role in 2000, the predominant social
      representations stressed a dimension more nearing a persona balance in 2000, in
      which the role of women themselves, outside the bounds of their families, is of
      major importance. The scope of their concerns also evolved to a concern related
      to the stress involved in being a working woman plus a housewife. CONCLUSIONS:
      This study made it possible to reach conclusions of a methodological type related
      to the ability of the qualitative methodology to make comparative, time-based
      studies and to conclusions of a more pragmatic type which afforded the
      possibility of changing the orientation of certain health programs aimed at women
      along a line more closely in keeping with their true concerns.

PMID- 12422426
TI  - [Practical nursing training in the University School of Nursing of the Community
      of Madrid. Opinion of students and health professionals. Qualitative study with
      discussion groups].
AB  - BACKGROUND: In the nursing schools, the contrast between what is taught in the
      classrooms and what is practiced at the health care centers usually creates a
      great deal of confusion on the part of the students. The objective of this
      research is to ascertain the opinion of the students and of the professionals at
      the health care centers where they are doing their training with regard thereto
      in order to detect their problems and see what differences exist between primary
      and specialized care. METHODS: This research was conducted throughout the first
      half of 2000 employing qualitative methodology, by means of four discussion
      groups comprised of students, former students, primary care training advisors and
      nursing professionals at the hospitals where the students of the school in
      question are doing their nursing training. The initial involvement employed was
      indirect. RESULTS: The comments of the nursing students and of their training
      advisors with regard to the practice nursing during the diploma studies reveal
      dissatisfaction on the part of both of these groups. In all of the groups point
      out anxiety as the leading factor involved in their teaching as well as learning
      activities and during professional training. The lack of identification as a
      group of professionals seems to be related to the lack of recognition on the part
      of the others, the demand for a degree being granted for their college studies
      and for the setting up of specialities would contribute to their social
      recognition and, as a result thereof, to their identification as a professional
      group. CONCLUSIONS: Until a solution is provided to the anxiety which the nursing
      professionals feel with regard to their professional practice, which they pass on
      to their students during nursing training, it will not be possible to achieve a
      higher degree of satisfaction with nursing training experiences either on the
      part of the training advisors or on the part of the students.

PMID- 12422427
TI  - [Situation analysis and proposals for improving primary care nursing in Mallorca:
      study with focal groups].
AB  - BACKGROUND: The primary care reform (PCR) has give rise to some major changes in
      the nursing profession. The objectives of this study are to analyze the
      achievements made by the nurses, to identify the problems they currently have in
      primary care and to suggest some lines along which work can be done for the
      future. METHOD: Qualitative research (focal group method). Eight groups were made
      segmented by occupational category and the position held. Scope of the analysis:
      the role of nurses, services supply and organization, participation and
      management, marketing and training. RESULTS: In the opinion of those surveyed,
      the PCR has entailed a broadening of the nurses' skills, although their role is
      still well-defined. The nurses are of the opinion that there is no listing of
      services inherent to nursing despite the leading role they obviously play in home
      care and health education. The need has been identified of assess the existing
      health programs in terms of results. Concerning to health services organization,
      main problems were related to the lack of adapting staffing in keeping with the
      rise in population and difficulties of internal communications within the health
      professional teams and the very small degree to which nursing services are
      disseminated. The need is felt of broadening pre-diploma training with regard to
      some subjects (health education) and skills (teamwork). CONCLUSIONS: Although the
      PCR has meant improvements for the nurses, solutions have as yet to have been
      provided to some aspects (including defining a listing of services, adapting
      staffing, internal communications, marketing, training) and given the opportunity
      the transferring of authorities over health care entail, further progress must be
      made toward innovative proposals to improve the health services.

PMID- 12422428
TI  - [Discourse of primary care professionals of the Community of Madrid on group
      work: sense, aims, and intervention scope].
AB  - BACKGROUND: Health Education with groups is an increasingly important activity in
      primary care. For the purpose of contributing to the furthering thereof, this
      research is aimed at ascertaining the opinions of the health care professionals
      with regard to the group practices and particularly with regard to their reason
      for being, purposes and fields of intervention. METHODS: From a qualitative
      structural perspective, four discussion groups and four open interviews were held
      with general practitioners, specialists in Pediatrics, in Family and Community
      Medicine, Nursing and Social Work in the Primary Care Areas in the Autonomous
      Community of Madrid. RESULTS: The opinions of the primary care professionals
      regarding the groups are confined to the activities of Health Education, this
      being an activity subject to individual inquiry. To form groups, the
      professionals include arguments on the order of hierarchy, efficiency,
      effectiveness and personal satisfaction. The main groups regarding which the
      group work was done are chronic patients (hypertension and diabetes), women (pre
      menopause, general malaise), school-age children and teachers, community
      associations and caregivers of the chronically ill. CONCLUSIONS: The majority of
      the primary care professionals consider the work with groups to be something on
      the side, the end purpose of which would be savings and, on a secondary scale,
      Health Education. These groups mainly regard chronic patients and women,
      community work being approached on a second plane.

PMID- 12422429
TI  - [Quality of the physician-patient relation and results of clinical encounters in
      primary care in Alicante: a study with focal groups].
AB  - BACKGROUND: The relationship between the quality of the physician-patient
      relationship and the outcomes of the clinical encounters in primary care are
      examined. METHOD: Focus groups of physicians and patients. A total of 24
      professionals and 22 patients took part. RESULTS: The physicians perceived a
      relationship to exist between the scarcity of healthcare resources (short length
      of time with each patient, care-providing overload, lack of specific resources,
      lack of training), conflicts with "difficult" patients and the influence of the
      psychosocial factors in the clinical encounter and error, burnout, defensive
      medicine and the low quality of the services. Communication/examination-related
      problems during the clinical interview and by negative feelings acted as
      intermediary factors in this relationship. The patients perceived a relationship
      to exist between an operating pattern characterized by short office visits
      scheduled at an overloaded pace and physician, patient communications problems
      and error and conflict in the clinical encounter. There is also a relationship
      between the physician's humanist attitude and a better outcome of the health
      problems. The objectives and priorities of the health care system, out of touch
      with the needs of the community, are seen as being key determining factors as
      regards the lacks considered to exist. CONCLUSIONS: The physician-patient
      relationship processes play a mediating role between the health care resources
      and the outcomes of the clinical encounters. Improving the care provided and the
      physician-patient relationship in primary care requires a multi-dimensional
      approach and view which goes beyond the measures taken regarding individual
      physician and patient-related factors.

PMID- 12422430
TI  - [Intervention with adolescents and youngsters in prevention and health
      promotion].
AB  - BACKGROUND: Over at least the past ten years, measures aimed at health promotion
      and prevention among young adults and teenagers have been being implemented from
      different public institutions and, in a certain sense, on a sectorial basis. The
      overall objective is to assess how the different measures carried out by
      different Public Institutions with regard to Health Promotion and Prevention have
      an impact on the actual conduct and practices of teenagers and young adults
      within the 14-25 age range in the Autonomous Community of Madrid. METHODS: A
      study based on a structural or qualitative methodology was conducted using the
      discussion group method, eight groups having been formed and their comments
      analyzed. RESULTS: The young adults do not feel any health-related prevention
      "system" as such exists on not considering themselves to be the object thereof.
      In the opinion of the young adults, disease, confined to the physical body, is
      conceived as being a short-lived, temporary and readily remedied based on the
      technological advances current medicine has to offer. On the contrary, the
      diseases related to the psychological perspective (mental disease dissociated
      with the area of the medical and connected to the individual/personal area)
      arouse interest in so much as young people are highly vulnerable to these
      diseases. CONCLUSIONS: Any measure aimed at generating identification and,
      therefore, the active response of young people must entail creating a connection
      between young people and health, which, not based exclusively in providing
      information, is capable of putting a space of control of the youths with regard
      to their harmful practices into play whilst at the same time highlighting their
      taking responsibility for their own actions. Considering we believe it best to
      "redefine" the term "prevention" in terms nearer to those of maintaining,
      improving or regaining (in short-lived cases) health, to thus connote the idea of
      physical and mental well-being.

PMID- 12422431
TI  - [View of the different social agents on the social participation in the health
      system in northeastern Brazil. A qualitative approximation].
AB  - BACKGROUND: Social participation in the health system constitutes one of the
      basic principles of Brazilian health sector reform. This paper analyses the
      concepts held by different groups of stakeholders with respect to social
      participation in health and identifies their opinions on hindering and enabling
      factors for this participation. METHODS: A qualitative study was conducted using
      individual interviews (II) and focus groups (FG) with different groups of
      stakeholders: 135 users (II, GF), 14 community leaders (II, GF), 12 Municipal
      Health Council (MHC) members (II), 8 policymakers and (II) 37 health personnel
      (II, GF) were interviewed. A narrative content analysis of the results was
      conducted. Two municipalities in North-eastern Brazil, Cabo de Santo Agostinho
      and Camaragibe, made up the area of study. RESULTS: In all groups, a distinction
      between individual and group participation emerged and reached different levels
      of elaboration. Many informants' ideas described also their own ways of action.
      Individual participation concepts and the utilization of health services were
      predominant among users. Population and institutional factors were identified as
      obstacles to participation: users and community leaders referred both type of
      factors, while the health personnel and MHC members put more emphasis on the
      former. Some informants among the health personnel did not identify any barriers.
      Policymakers emphasised the lack of political will. The enabling factors
      mentioned reflected the same logic. CONCLUSIONS: Concepts and perceived hindering
      factors to participation which were described appear to show different ways of
      interaction among the diverse stakeholders and the health services. The results
      point towards a limited effect of the health policy on social participation.
      Elements that could contribute to an improvement are identified.

PMID- 12422432
TI  - [Coping strategies in stress and sources of professional reward in specialized
      physicians of the Valencia Community. A study with semi-structured interviews].
AB  - BACKGROUND: The professionals in the medical field are particularly exposed to
      psychological risk factors which may affect their quality of life. Identification
      of stress coping strategies and the sources of professional rewards would afford
      the possibility of implementing preventive measures aimed a moderating the
      negative effect of these risk factors. The objectives of this study are to
      identify the stress coping strategies that are used by specialised doctors from
      six public hospitals of the Valencian Community, and to describe their sources of
      work reward and job satisfaction. METHODS: A qualitative study conducted by means
      of quasi-structured individual interviews of 47 specialists employed at six
      public hospitals in the province of Valencia. The interviews were taped and
      subsequently transcribed. An analysis was made of the substance of the opinions
      expressed. RESULTS: The coping strategies mentioned most often by the physicians
      interviewed, analyzed overall, are those focused on the emotions, specifically,
      disconnecting conduct and seeking social emotional support. However, when
      confronted with specific stressful factors in daily practice, the strategies most
      often employed as those focused on the problem. A major part of the physicians
      surveyed state not having any work reward. Among those who do state finding some
      aspects gratifying, top mention is made of their salary, personal satisfaction
      related to being in the medical field being ranked second. CONCLUSIONS: Including
      training related to active stress coping strategies in the professional
      curriculum of physicians could heighten their personal resources for dealing with
      stress. Organizational changes should additionally be made to increase their work
      rewards.

PMID- 12422433
TI  - [Qualitative analysis of the perception of people who participate in a clinical
      trial, Navarra].
AB  - BACKGROUND: The objective of this study is to explore the perception that
      participants in a clinical trial have about the information disclosured by the
      physician, during patient recruitment and along the study as a preliminary stage
      for drafting a questionnaire. METHODS: Qualitative study by means of quasi
      structure interviews to subjects of different features taken from a patients list
      obtained by randomized selection of participants in clinical trials approved
      within the 1998-1999 period. For conducting the interviews, a guide was prepared
      based on the recommendations of the Helsinki Declaration. RESULTS: Six (6)
      interviews were held with 7 individuals, as one married couple was interviewed.
      Most of the categories encountered belonged to the Helsinki Declaration. In
      addition, others being related to the fulfillment of expectations and to the
      balance of the risks/benefits done by the individuals for deciding to take part
      in the study. CONCLUSIONS: The patients were acceptably informed of the most
      points dealt with under the Helsinki Declaration. The existence of lacking areas
      having a major impact on the fulfillment of their expectations however having
      been revealed.

PMID- 12422434
TI  - [Perspective of informal caregivers on home care. Qualitative study with a
      computer program].
AB  - BACKGROUND: A hot debate exists in our country as to the models of home care
      which must be developed. This study is aimed at ascertaining how the family
      caregivers of terminal cancer patients, of the elderly suffering from dementia
      and of individuals having undergone major operations in outpatient surgery
      programs rate the quality of the home care provided. METHODS: A phenomenological
      type qualitative study based on discussion groups (9), triangular groups (5) and
      in-depth interviews (22). This study was conducted in Andalusia throughout the
      1999-2000 period. The subjects of the study were the main caregivers of patients
      provided with home care through the healthcare centers. The information must be
      analyzed by means of a Nudist-4 software-aided content analysis. The analysis
      variables were those of the Servqual model. RESULTS: For the caregivers of cancer
      patients, the most important aspects of the quality of the home care provided
      were the Response Capacity and Accessibility. This analysis revealed that the
      patients suffered pain but the pain was not controlled. Negative aspects
      hindering accessibility were the lack of home care coverage outside of regular
      working hours, the difficulty of getting in touch by phone, the length of time it
      takes for someone to come and the visits solely on request. The caregivers of
      patients having undergone major outpatient surgery want Security and Reliability.
      They complain of the short length of time within which the patients are released
      from the hospital and of the home care provided by the health care center. The
      caregivers of the elderly with dementia place top priority on being provided with
      the materials they need to take care of these patients. CONCLUSIONS: Caregivers'
      and patients' expectations differ, depending on health problems, therefore, the
      type of home care provided should vary, according to the health problems
      involved. It is necessary to develop a flexible model, capable of adapting to
      different patient needs and the diverse circumstances that affect family
      caregivers.

PMID- 12422435
TI  - [Sports in children and adolescents].
AB  - The current conditions in Belgium are paradoxical. Indeed, adequate measures are
      now in place to allow sports activities in a favorable environment: increase in
      leisure time, widespread availability of indoor and outdoor facilities. However,
      there has been a significant increase in obesity among young people as well as a
      gradual erosion in physical fitness of young Belgians. Therefore, physical
      activity is mandated, not only as a general personal health issue, but also as a
      public health issue. It should be encouraged, taking into account psychological
      and physiological growth parameters of teenagers.

PMID- 12422436
TI  - [Asthma and exercise].
AB  - Exercise-induced asthma (EIA) is defined as the clinical occurrence of shortness
      of breath, cough or wheeze that occurs typically 5-15 minutes after the cessation
      of the exercise. In most patients with EIA, bronchoconstriction is followed by a
      refractory period, during which repeated exertion causes less
      bronchoconstriction. The occurrence of this type of asthma is influenced by the
      intensity and the duration of exercise. It is now generally believed that EIA
      affects all patients with asthma if challenged with exercise of sufficient
      intensity. The estimate prevalence varies from 7 to 15% in the general
      population. EIA appears also to affect 3-14% of athletes. It is now clear that
      hyperventilation and hypertonicity of airway-lining fluid provide the stimulus
      for EIA with release of constrictor mediators. Recently, incidence of new
      diagnoses of asthma is associated with heavy exercise in communities with high
      concentrations of ozone, thus, air pollution and outdoor exercise could
      contribute to the development of asthma in children. Beta-agonists and/or
      disodium cromoglycate remain the preferred first-line therapy for EIA but now
      antileukotrienes provide an attractive therapeutic alternative. General
      recommendations can help reduce its severity: warm-up; breath through mask when
      exercising in cold, dry conditions; in recent years some reports have suggested
      that training and conditioning may help athletes and non-athletes with asthma
      have fewer symptoms after exercise, increase the threshold of exercise necessary
      to induce airway obstruction and finally improve their well-being. Scuba diving
      stays an absolute contra-indication if asthma.

PMID- 12422437
TI  - [Sports and type I diabetes: personal experience].
AB  - Energy for muscular exercise is derived initially from the breakdown of muscle
      glycogen, and later from circulating glucose released by the liver and from non
      esterified fatty acids. Muscle glucose uptake may increase 20-fold. In normal
      subjects, insulin secretion declines and release of counter-regulatory hormones
      increases. In type 1 diabetes, glycaemic changes during exercise depend largely
      on blood insulin levels. In the young diabetic, during insulin deficiency, and
      therefore in a poor degree of metabolic control, i.e. hyperglycaemic and ketotic,
      exercise accentuates hyperglycaemia and ketosis, leading to extreme fatigue. If
      the insulin dosage is too high, the increase in muscular assimilation, combined
      with the shutdown of liver glucose production, may result in a severe
      hypoglycaemia. During the recovery period, the repletion of muscular and hepatic
      glycogen stores may also provoke an hypoglycaemia during hours after the
      cessation of muscular work. The recommendations for physical activity in type 1
      diabetes include: 1) obtain good metabolic control; 2) in the few hours preceding
      the exercise, ingest complex carbohydrates; 3) in the case of unforeseen physical
      activity, increase glucose consumption immediately before, during, and after the
      activity; 4) in the case of foreseen activity, decrease the insulin dose (from 10
      to 50%) acting during and even after intense muscular work; 5) do not inject the
      insulin at a site that will be heavily involved in the muscular activity.

PMID- 12422438
TI  - [Scuba diving: practical aspects].
AB  - Keeping in mind some fundamental physic's laws permits to better understand the
      risks of scuba diving. Essentially, it concerns Boyle's-Mariotte's law
      (pressure/volume relationship), Dalton's and Henry's laws on the gases partial
      pressures. Contra-indications of scuba diving depend on the possibility of
      accidents due to preexisting diseases. The most frequent accidents occur in the
      O.R.L. and pulmonary systems with the risk of barotraumas, and also in the
      cardiovascular system with the risk of fainting, uncontrolled ascent to the
      surface and even drowning. The aptitude test is essential to evaluate and
      minimize these risks with judicious advices. Generally, complementary tests are
      performed. In some cases, diving must be limited to "recreational diving", and
      sporting deep diving, where the conditions are more tiring and hard, must be
      discouraged. A list is added to the paper, to assist those with any medical
      problem related with scuba diving, to find informations and advices.

PMID- 12422439
TI  - [Market economy, health economy?].
AB  - After the definition of the economy and its different types, we have to stress
      the political economy which integrates pure economy and society. The economical
      science will gradually introduce the health economy of which the definition urges
      to seek for a better distribution between public and private means to do more and
      better for the public health. The market economy is different from the state
      economy. She is principally conducted by the supply and demand law. The
      consumer's behaviour in a competitive market has some characteristics which
      favour the balance of this market. The healthcare market put also a health supply
      and demand forward but not with the same values. The needs, the supply, the
      consumption and the consumer's behaviour are different in this particular market
      which quickly evolves and progressively goes closer to the market economy. Is the
      healthcare an economical good or duty? The choices' criteria and the priorities
      are changeable. The role of the valuation studies in health economy is to try to
      clarify them and to favour a better use of the limited resources to the unlimited
      needs.

PMID- 12422440
TI  - [Conjugate vaccines].
AB  - Conjugate vaccines extend the vaccinal prevention for children to more diseases.
      Conjugating the capsular polysaccharide to a carrier protein transforms a T
      independent antigen in a T-dependent, allowing protection of the children (before
      2 years of age) against Haemophilus influenzae type b, meningococcal C and
      pneumococcal infections. This article reviews the 3 conjugate vaccines and their
      results with focus on some questions: antigens interference in the immunological
      response, serological subrogate for protection, herd immunity and replacement of
      circulating serotypes.

PMID- 12422441
TI  - [The safety of vaccination].
AB  - The high standard of safety that is expected from vaccines can only be obtained
      if these products undergo in depth evaluation of their side effects before
      marketing authorization is guaranted, as well as post-marketing surveillance and
      investigation of reported adverse events. The evaluation of the benefit/risk
      balance of vaccines is a dynamic process, influenced by the residual impact of
      the target disease and by the existence of alternative preventive or therapeutic
      approaches. The efforts made to ensure the safety of vaccination must be brought
      to the attention of the public and the health workers to maintain confidence in
      this important public health intervention.

PMID- 12422442
TI  - [Vaccinations for the traveller].
AB  - Long distance journeys are more and more frequent. Beside malaria prophylaxis,
      the general practitioner shall consider several points. Vaccinations against
      tetanus, diphtheria and (for a few years at least) polio should be done every ten
      years. Hepatitis A vaccine shall often be done (with > 20 years protection) but
      typhoid fever vaccine shall be limited to adventurous and/or long stays. Yellow
      fever vaccine (10 years validity) is only administrated in specialised centers;
      this is the only mandatory vaccine for certain african or south american
      countries. In certain instances, one shall consider vaccination against hepatitis
      B, meningococcal meningitis or, less often, against rabies, central european or
      japanese encephalitis. The vaccine against cholera (numerous side effects and
      poor efficacy) is no more available.

PMID- 12422443
TI  - [Euthanasia: the state of the question--introduction].
AB  - After a parliamentary debate which has lasted several years, the Parliament has
      just approved a law depenalizing euthanasia under certain conditions. The medical
      profession was barely involved in this debate. On the international stage, the
      WMA and the CPME have taken clear positions against euthanasia. In Belgium, the
      medical opinion is parted into two camps. The Rectors, medical Managers and
      ethical Committee Presidents of academic hospitals of "Universite libre de
      Bruxelles" (U.L.B.) and "Vrije Universiteit Brussel" (V.U.B.) have taken a clear
      position in favour of depenalization. However, many doctors, whatever their
      university, religion or political options have great fears about that law which
      raises more questions than answers: will it help the doctor?; will it help the
      dying patient?; will it give the doctors any legal protection which they do not
      already enjoy?; will it really allow patients to make use of their autonomy?;
      will it not, to the contrary, remove from the weakest in society the protection
      to which they are entitled? The future holds the answers to these disturbing
      questions.

PMID- 12422444
TI  - [Euthanasia: ethics and politics].
AB  - The ethical problems of euthanasia are evolving. After a long "silent" period,
      two conflicting moral codes have emerged. One, backed by most of the clergy, is
      based on the belief that a person's life does not belong to him/her. The other,
      adopted by a majority of free thinkers, maintains that each person has the right
      to appreciate the value of his/her own life. Underlying the controversy about
      rendering euthanasia legal or not, there is tension between the values of life
      and freedom. Surprisingly, the practices themselves do not seem to be questioned.
      However, the uncertain situation of the non-respect of a legal prohibition can
      undermine the doctor-patient relationship and also seems to have led to increase
      in the number of voluntary interruptions of life carried out without the
      patient's consent. The law cannot uphold one particular ethic over another. This
      is the reason why the text adopted in Belgium is based on the recognition of a
      person's autonomy. At the heart of the reform there is also the twofold will to
      bring practices into the open as much as possible and to protect practitioners
      who "rely" on a fundamental dialogue with their patients.

PMID- 12422445
TI  - [Euthanasia: practical implications].
AB  - Techniques used for euthanasia exist and have to be available for doctors. Their
      use ask for accurate information regarding schedules and pharmacology. Numerous
      medications may induce death at supratherapeutic doses but few are effective to
      ensure an end-of life without suffering, in the respect of human dignity. Some
      specific situation encountered in the terminal phase of life (delirium, dyspnea,
      bleeding) are described with their medical approaches. Terminal (or controlled)
      sedation and physician-assisted suicide are discussed. Two effective schedules
      based on the dutch experience and providing gentle and easy death are presented.

PMID- 12422446
TI  - [Implications of the new law relating to euthanasia for the general
      practitioner].
AB  - The new law relative to euthanasia does not explicitly foresee the implication of
      the general practitioner when an euthanasia procedure is carried out an hospital.
      At home, the law confers a central role on the general practitioner as far as
      information and coordination are concerned. There is a risk that the foreseen
      procedure will, in some cases, come up against the profoundly dual and intimate
      aspect of the patient-doctor relationship. The general practitioner is also given
      an administrative role. The doctor will, after having helped the patient die with
      dignity, have to fill in a registration document.

PMID- 12422447
TI  - [Chronic fatigue: introduction].
AB  - Chronic fatigue is frequent in primary care practice. After exclusion of medical
      causes, psychosocial factors and chronic fatigue syndrome (CFS) must be searched.
      The differential diagnosis is long and difficult, but it depends more of good
      clinical evaluation than of extensive laboratory investigation.

PMID- 12422448
TI  - [Neurologic and muscular mechanisms of fatigue].
AB  - Fatigue of voluntary muscular effort is a complex phenomenon, influenced by
      peripheral and central nervous system factors. Peripheral mechanisms of fatigue
      include impairment in neurotransmission and impulse propagation down the
      sarcolemna, dysfunction within the sarcoplasmic reticulum involving calcium
      release and uptake, impairment in the actin-myosin cross-bridge interactions and
      substrate depletion or accumulation of metabolites. The central fatigue is
      associated with reduction of motor cortical excitability, failure to drive the
      motoneurons adequately, changes in neurotransmitter activity, etc. Is fatigue an
      unexplained disabling symptom or a protective mechanism to prevent muscle fiber
      degeneration?

PMID- 12422449
TI  - [Fatigue and sleep: the point of view of the chronobiologist].
AB  - Chrono-fatigue is often present in patients engaged in shift or night work, as
      well as in passengers travelling across many time zones (jet lag syndrome). Some
      disturbances of the circadian system are responsible for clinical syndromes
      characterized by chrono-fatigue, one of them being the sleep delayed phase
      insomnia. Circadian sleep disorders, either functional or structural, are
      characterized not only by disturbances in sleep architecture and/or sleep
      quality, but also by the inability to fall asleep and stay awake at desired
      times. Similarly, sleep and fatigue present in those circadian disorders
      typically exhibit a daily cyclic pattern. Night workers and shift workers do have
      chronic sleep deprivation and desynchronisation of their circadian system with
      the entraining environment. Those phenomena are responsible for severe vigilance
      problems, a decrease in work productivity and deleterious health side effects.
      Fatigue and sleep problems in circadian disorders can now benefit from treatments
      based on the programed use of synchronizers of the circadian clock, like
      chronotherapy, bright light and melatonin, combined with adequate sleep hygiene
      recommendations.

PMID- 12422450
TI  - [Fatigue and quality of life in cancer patients].
AB  - Fatigue is the most frequent adverse event encountered in cancer patients and
      often underestimated by oncologists. This fatigue results in a deterioration of
      the quality of life physically, psychologically and socio-professionally. We have
      to distinguish various degrees of fatigue and identify "acute" fatigue from
      "chronic" fatigue. The acute fatigue appears normal after a physical or
      psychological effort and requires less than a week of rest to recover; the impact
      on quality of life is thus minimal. Chronic fatigue is more insidious; the causes
      are multiple. The patient feels that this fatigue is abnormal and
      disproportionate. It last several weeks and has a severe impact on the quality of
      life. Somatic mechanisms of fatigue related to the tumour and/or treatment are:
      vitaminic or proteic deficiencies due to malnutrition, accumulation of toxic
      metabolites, infections and septicemia, the abuse of sleeping tablets or
      antalgics, insomnias, immobilisation, organic insufficiencies or ionic
      disturbances. Anemia--observed in more than 50% of the cancerous patients-
      deserves a particular attention. The causes of this anemia are also multiple. It
      is obvious that anemia interferes with quality of life of the patient, decreases
      his physical performances and leads to a lack of motivation or energy. Patients
      with an hemoglobin level higher than 12 g/dl describe significantly less
      complaints and a higher physical and functional well being. To better assess the
      treatment of fatigue, it is important to first evaluate if the cause is organic,
      psychologic or mixed. Among the somatic causes, nutritious deficiencies, pain and
      anemia, ... all these complications can be treated with appropriate medications.
      This fatigue is often recognized by the patient as a progression of the tumour or
      as a treatment failure. Therefore, it is important to inform the patients of the
      possibility of that adverse event so that it does not generate additional stress
      and anxiety during the treatment.

PMID- 12422451
TI  - [Chronic fatigue syndrome: psychiatric perspectives].
AB  - Chronic fatigue syndrome (CFS) is a common illness of unknown etiology and
      pathogenesis characterized by severe disabling fatigue and a variety of
      musculoskeletal, neurocognitive, mood symptoms and sleep disorders lasting at
      least six months. A significant proportion of patients fulfilling operative
      criteria for a diagnosis of CFS will also meet criteria for a psychiatric
      disorder such as depression, somatization or anxiety disorders. Premorbid
      lifestyle may play a predisposing, and/or perpetuating role in CFS. Some patients
      improve with time but most remain functionally impaired for several years. A
      variety of interventions have been used in the treatment and management of CFS.
      Interventions which have shown promising results include cognitive behavioural
      therapy and graded exercise therapy. Antidepressants can be useful particularly
      in the case of comorbid affective disorders. Development of good therapeutic
      doctor-patient alliance with empathic care is central to the effective management
      of CFS. In this article we overview the nature and definition of CFS. The
      prevalence, the prognosis and the psychopathological issues are presented. The
      management of this controversial syndrome is discussed.

PMID- 12422452
TI  - [Management of hazardous alcohol use: context and difficulties].
AB  - A more active management in the hazardous alcohol use is recommended. The
      context: the health policy and promotion, the inter-sectoral partnership work,
      and their obstacles: the inefficiency of a neo-prohibition, the difficulties of
      aid under control, the risks on the medical secret, are described. Knowing these
      factors is essential to aim at lowering the alcohol abuse.

PMID- 12422453
TI  - [May the general practitioner not be concerned about the alcohol consumption of
      his patients?].
AB  - Based on a literature review, the author points out the importance, in adult
      general medicine practice, of the prevalences in different alcohol consumption
      levels, alcohol induced sicknesses and dependencies. The very large frequency of
      these problems in general practice, the somatic repercussions of an excessive
      consumption and the general practitioner's possibilities of action on preventive
      and curative levels lead the physician to make a research about the alcohol
      consumption level of all his patients, to write it down on the patients files, to
      give at least a pronounced advice and to carry out a follow-up. The actual
      commitment of general practitioners and their issues are tackled. French
      inquiries show that if intention of research on risk patients is very frequent
      (85% of the practitioners), this attitude is far from being systematic for a
      whole practice (research by less than 50% of the practitioners and inscription in
      a space for less than 30% of the patients files). This relative commitment seems
      to be induced (french and belgian inquiries) by an underestimation of the effect
      of the advice given to the patient, and by a discouragement feeling in front of
      the impression of low treatment efficiency as well as the relapses and the
      attitudes of that kind of patients.

PMID- 12422454
TI  - [Excessive alcohol consumption and the role of the general practitioner. When and
      how should he react?].
AB  - Patients who are excessive drinkers, at different degrees of severity, are
      frequent in a general practice consultation. These patients are at risk of
      developing several medical and psychosocial complications and to evolve towards a
      worsened situation. This condition is frequently under diagnosed and not
      considered during consultations, the patients seldom asking for help and
      frequently reluctant to talk about that issue. It is worthwhile to look for
      excessive alcohol consumption and dependence, and to discuss it with the patient.
      It is possible to increase motivation for change and to positively influence the
      consumption outcome. Moreover it is necessary to conduct early intervention,
      because the older the behaviour is the more difficult it is to change. We present
      here several attitudes and strategies that may be useful to increase motivation
      for change, and that can be used to complement those each general practitioner is
      already fruitfully using.

PMID- 12422456
TI  - [Gene therapy].
AB  - Gene therapy is a young scientific discipline, full of promises. Recently a major
      success was encountered through the correction of the SCID-X1 genetic defect in
      affected children. Gene therapy is also successfully developing in experimental
      oncology.

PMID- 12422455
TI  - [Clinical and therapeutic aspects in the treatment of alcohol addiction].
AB  - The alcohol-withdrawal syndrome is a well-known clinical situation, so does its
      treatment. However, new researches have shown that the risk of severe withdrawal
      manifestations increases proportionally with the number of previous
      detoxifications, according to a sensitisation stress model. As a consequence,
      special attention should be paid to patients with a clinical history of multiple
      alcohol detoxifications, even if they never previously had delirium tremens
      and/or comitiality. Even in the absence of characteristic neurologic lesions,
      long-lasting heavy drinking is associated with brain dysfunction, concerning
      mostly the frontal cortex. This is clinically associated to neuropsychological
      deficits, specifically disorders of working memory and the so-called "executive
      functions". These deficits have a dramatic importance, because they impair
      drastically the outcome of alcoholic patients after detoxification. In Belgium
      like in other countries, an increasing prevalence of hepatitis C is present in
      alcoholic patients. This is due probably to the increase of a former illegal
      drugs consumption in those patients. This association between alcoholism and
      hepatitis C is of major importance, because alcohol consumption increases the
      viral load and the risk of cirrhosis and hepatocarcinoma. Furthermore, alcohol
      reduces the response to interferon therapy.

PMID- 12422457
TI  - [The world tour of peripheral vertigo].
AB  - This world tour of the peripheral vertigo is described like a consultation and
      brings the reader to an approach of the diagnosis the most precise as it is
      possible. The primordial interest of a complete and concise anamnesis permits us
      to obtain a diagnostic in 80% of cases. Then, we detail the neurological tests
      and we choice the adequate and complementary tests. In the end, when we have
      established the final diagnosis, a judicious treatment can be applied.

PMID- 12422458
TI  - [Central vestibular syndromes].
AB  - The aim of this topic is on one hand to pick out the semiological features which
      can quickly show the way of central nervous system lesions related to the
      vestibular system and on the other hand to describe these main central vestibular
      syndromes. A particular attention is carried to central otolithics syndromes
      which often remain undiagnosed. They induce imbalance, non rotatory vertigo,
      intolerance to linear acceleration and most often there is no nystagmus on
      examination. Neurophysiological diagram are restricted to a minimum useful to the
      clinician.

PMID- 12422459
TI  - [Cardiovascular aspects of vertigo].
AB  - True vertigo described as a sensation of body or surrounding objects rotation is
      seldom of cardiovascular origin. The main causes are caused by ear pathology,
      neurologic pathology or are of toxic origin. Patients talk frequently of vertigo
      to describe symptoms in relation with a fall of the brain blood output. These
      dizziness feelings are frequently of cardiovascular origin and may be associated
      with syncope which represents a more important fall in the brain blood pressure.
      Medical history, physical examination, electrocardiogram represents the
      cornerstones of the cardiological workout allowing about 50% of likely diagnosis.
      The cardiologist will also have to distinguish between a disease of benign
      prognosis and a disease possibly associated with future sudden cardiac death. The
      main cardiological causes are: neurally mediated hypotension, orthostatic
      hypotension, cardiac arrhythmias, other cardiac or pulmonary diseases.
      Neurological, metabolic or psychiatric causes occur much less frequently. Most
      commonly used diagnostic tests include the resting electrocardiogram, the stress
      test, cardiac echography, holter techniques, tilt testing, cardiac and coronary
      angiography, electrophysiologic testing. However, despite an extensive workout
      some causes of dizziness or syncope remain unclear.

PMID- 12422460
TI  - [Ototoxicity-related vertigo].
AB  - Many substances may be the source of dizziness or transient equilibrium
      disturbances due to dysfunction of the CNS or to an impairment of visual or
      proprioceptive informations. Other agents are responsible for drop of arterial
      pressure by changing position, including antihypertensive drugs, alpha-blocking
      agents used in urology, antipsychotics, cyclic antidepressants, vasodilators and
      nitrates, dopaminergic antiparkinson drugs, sedatives, etc. Only drug with true
      ototoxic properties will be discussed here, namely substances that are able to
      damage the inner ear (cochlear or vestibular damage) or the VIIIth cranial nerve,
      causing impairment of equilibrium and/or (most often) hearing. No relevant data
      report the actual incidence of ototoxic problems, but more than 130 products have
      been classified as potentially dangerous. Individual susceptibility seems highly
      variable, but some predisposing factors have been identified: renal failure, age,
      combination of ototoxic drugs, familial sensitivity to ototoxic effects or
      previous neurosensorial deficit. We will first discuss the ototoxic medications
      that have certainly been extensively studied and among which we find several
      antibiotics (especially aminoglycosides and macrolides), the loop diuretics, and
      some antimalarial or chemotherapeutic agents. Environmental toxins and drug of
      abuse will then be discussed briefly because scientific data are much less
      significant. Early recognition of subjects who are at risk of developing
      ototoxicity, use of therapeutic monitoring and close observation of
      cochleovestibular functions in high risk situations (often not easy in critical
      patients) are the best way to prevent severe complications that have occasionally
      disastrous consequences on the quality of further life.

PMID- 12422461
TI  - [Diagnostic imaging of peripheral vertigo].
AB  - Clinical imaging investigation of vertigo is actually mainly performed using MRI,
      which offers a detailed analysis of cochieo-vestibular nerve and labyrinth.
      Computed tomography is reserved to the analysis of bony structures. Several
      causes of vertigo are described, e.g. tumours, labyrinthitis, malformations,
      Meniere's disease, otoscierosis, trauma, cholesteatomas and postoperative
      changes. The interest of imaging is discussed. The necessity to perform
      paraclinical tests prior to diagnostic imaging to optimise the choice of imaging
      is emphasized.

PMID- 12422462
TI  - [Rehabilitation of the vertigo patient].
AB  - Vestibular exercises are getting an increasing place in the different way to
      treat vertigo. Vestibular training can be an interesting alternative to drugs
      medication. We will limit this presentation to the principal peripheral
      vestibulopathy as benign paroxysmal positioning vertigo, vestibular neuritis and
      the dizziness of elderly.

PMID- 12422463
TI  - [Which anticoagulants?].
AB  - Anticoagulants used in daily practice include low molecular weight heparins
      (LMWHs) and vitamin K antagonists. LMWHs are easy to use by means of adjusted
      subcutaneous injection, weight-adjusted in case of therapeutic indications. LMWHs
      are cleared principally by the renal route and are contra-indicated in case of
      renal insufficiency. The LMWHs are indicated in the prevention and treatment of
      venous thromboembolism. They can be safely administered in pregnancy and during
      breast-feeding. Oral anticoagulant therapy is the treatment of choice for long
      term management. Vitamin K antagonists are contra-indicated in pregnancy,
      especially between the 6th and the 12th week of gestation (risk of embryopathy);
      they can be given during breast-feeding subject to some precaution. Main
      indications for vitamin K antagonists are long term treatment of venous
      thromboembolism, prevention of both arterial and venous thrombo-embolic events
      associated with the antiphospholipid--antibody syndrome, prevention of systemic
      embolism associated with heart valves and, rheumatic mitral valve disease and,
      atrial fibrillation and, acute myocardial infarction.

PMID- 12422464
TI  - [Follow-up of antiepileptic drugs].
AB  - All antiepileptic medications have potential side-effects. Some are rather
      specific like diplopia for carbamazepin or lamotrigin, whereas others are not,
      like fatigue or unsteadiness. Most are dose-related and can therefore be
      alleviated by dose reduction (e.g. somnolence or tremor) but a few are
      idiosyncratic (e.g. rash) and require cessation of the causative agent. Some can
      be detected and followed-up on a clinical basis but others necessitate specific
      examinations.

PMID- 12422465
TI  - [Estrogen replacement therapy: for whom, why and how?].
AB  - Symptoms may appear during the perimenopause, but it is often difficult to treat
      them at that time. Progestins are used to treat abnormal bleeding. Low dose
      hormone replacement therapy (HRT) or oral contraception are often used also. HRT
      can be used to maintain the bone density even in elderly women. Nevertheless, the
      treatment is often not taken for sufficient time. In order to improve compliance,
      a number of low dose HRT have been developed. For most patients these medications
      will preserve the bone mass, but data showing a fracture protection are missing.
      The exact role of HRT on cardiovascular pathologies is controversial.
      Observational data indicated a protective effect on atherosclerosis. But
      randomised studies contradicted these results: the latest randomised trial
      involving a continuous combined regimen of estrogen and progestin reported an
      increased risk in cardiovascular events as compared to placebo. It is still
      possible that estrogen decreases atheromatosis but that it increases the risk of
      thrombosis. SERM (Selective Estrogen Receptor Modulators) have agonistic and
      antagonistic proprieties to estrogens on selective tissues. They have a proven
      protective effect on bone and possibly also on cardiovascular system.
      Nevertheless, the risk of thrombosis seems to be similar to that of estrogens.
      The risk of breast cancer seems to be increased in long term HRT users but this
      subject is also controversial since discordant results have been reported.
      Furthermore, breast cancer mortality in HRT users seems to be lower than in non
      users.

PMID- 12422466
TI  - [Recent therapeutic strategies and new drugs].
AB  - Recent therapeutic strategies are presenting concerning the use of morphine,
      benzodiazepines, hypoglycemic agents, glucocorticoids and several specific
      treatments are indicated. Three new molecules deserve special attention:
      tiotropium, fondaparinux and omalizumab.

PMID- 12422467
TI  - [Chronic fatigue syndrome: the point of view of the internist].
AB  - Chronic fatigue is a very common symptom in primary care medicine. Psychiatric
      causes represent more than 80% of the cases. After excluding all known causes of
      fatigue, 30% of the patients remain without a specific diagnosis and suffered
      from idiopathic chronic fatigue. The chronic fatigue syndrome (CFS) which
      represents a very small subset of these patients is a heterogeneous disorder
      characterized by fatigue, neuropsychiatric symptoms, and various other somatic
      complaints. The cause remains underdetermined and most of the treatments are
      ineffective. Antidepressants drugs may be helpful. A supportive approach,
      cognitive behavioural therapy and graded exercise seem so far the only evidence
      based therapeutic approach.

PMID- 12422468
TI  - [Detection and prevention of colorectal cancer].

PMID- 12422469
TI  - [Colorectal cancer: curative treatment and surveillance].

PMID- 12422470
TI  - [Esophageal cancer].

PMID- 12422471
TI  - [Travellers' acute diarrhea].

PMID- 12422472
TI  - [Dyspepsia in 2002: which investigations, what treatment?].

PMID- 12422473
TI  - [Taking charge of adult's anal incontinence].

PMID- 12422474
TI  - [Ulcerative colitis].

PMID- 12422475
TI  - [Fabry disease: diagnostic due of substitutive enzyme-therapy].
AB  - Fabry disease is a X-linked sphingolipid storage disorder resulting from the
      defective activity of the lysosomal enzyme, alpha-galactosidase A. Hemizygotes
      develop severe multisystemic disease, dominated by renal failure and progressive
      neurological and cardiac involvement, causing premature death. Thirty percent of
      heterozygotes have severe involvement of one or several organs. With developments
      in molecular biology, it is now possible to produce the human recombinant enzyme
      alpha-galactosidase A. More than 20 patients are now treated in Switzerland.

PMID- 12422476
TI  - [Weil's disease: a case report of acquired leptospirosis in Switzerland].
AB  - Leptospirosis is a rare disease in Switzerland. However its incidence is probably
      underestimated, due to its broad spectrum of presentations, including subclinical
      benign forms and the ictero-hemorragic form of the Weil's syndrome, whose
      mortality is high. We describe here a case of Weil's syndrome acquired in
      Switzerland with a favourable outcome under antibiotherapy. Even in the absence
      of any travel, the association of an acute renal insufficiency and jaundice with
      only moderate hepatic cytolysis should lead to the suspicion of leptospirosis.
      Clinical and epidemiological aspects of the disease are discussed in the article.

PMID- 12422477
TI  - [The first proof of nicotine toxicity in the adult brain].

PMID- 12422478
TI  - [Humanitarian medicine between ethics and professionalism].

PMID- 12422479
TI  - [Correct and incorrect usage of antibiotics. Prevalence study in Franche-Comte].
AB  - OBJECTIVE: To report the results observed regarding the prescription of
      antibiotics according to various indications in the Franche-Comte area: curative
      for a community infection, curative for a nosocomial infection and prophylactic.
      METHOD: A total of 6,038 patients hospitalized in 32 hospital centers of the
      Franche-comte area were surveyed. RESULTS: Among the 1,016 (16.8% of the total)
      patients receiving anti-infection products, 47.7% received anti-infection agents
      for the treatment of a community infection, 25.9% for a nosocomial infection and
      26.4% for prophylaxis. Multiple antibiotherapy was more frequent for the
      treatment of community infections than for nosocomial infections [p = 0.067,
      Relative Risk = 1.11, (confidence interval: 95%: 1.00-1.24)]. Sixty percent of
      the prescriptions of 3rd generation cephalosporines were within the community
      framework. This class of antibiotics was widely prescribed for the treatment of
      E. coli infections, multi-sensitive to antibiotics, not only before but after
      bacteriological documentation. Among the 83 patients treated with fluoroquinolone
      for a nosocomial infection, 47 (56.6%) were treated with monotherapy. Regarding
      prophylaxis, 3rd generation cephalosporine and fluoroquinolone, which are not
      indicated for this, were widely used, in contradiction with the recommendations
      of the Societe Francaise d'Anesthesie et de Reanimation (French Society of
      Anesthesia and Reanimation). CONCLUSION: This survey, despite the limits related
      to the prevalence method, shows the high frequency of antibiotic prescriptions
      that do not conform to the recommendations of the ANDEM (French agency for the
      assessment of medical practice) and the scientific societies.

PMID- 12422480
TI  - [Psychosis revealing a silent celiac disease in a young women with trisomy 21].
AB  - INTRODUCTION: Down's syndrome is characterized by an abnormal frequency of
      coeliac disease and by the frequent occurrence of neurological disorders such as
      Alzheimer-type dementia of early onset. However, psychosis is rare in Down's
      syndrome. OBSERVATION: We report the case of a 41-year-old woman, who presented
      with Down's syndrome. She was living with her parents and had a normal social
      life. She suddenly experienced some esthesic hallucinations, depression,
      anorexia, affective flattening and autistic behavior. Biological evaluation
      revealed macrocytosis, polyclonal IgA and IgG hypergammaglobulinemia and strong
      positivity for anti-gliadin antibodies of IgG and IgA isotypes. Brain CTscan was
      normal. Since digestive specimen biopsies did not evidence villous atrophy, we
      concluded in a silent coeliac disease. After 12 months of gluten-free diet a
      spectacular and lasting improvement of both psychotic and depressive symptoms was
      obtained. DISCUSSION: The effects of abnormal interaction between the immune
      system and gluten can be expressed not only in the gut (coeliac disease) but also
      in the brain (psychosis) in genetically predisposed patients, such as those
      suffering from Down's syndrome. There was evidence for brain disorder related to
      coeliac disease in our patient. CONCLUSION: Our case report shows that, before
      concluding in Alzheimer-type dementia in Down's syndrome, a biological search for
      coeliac disease is useful since a gluten-free diet may improve the psychiatric
      symptoms.

PMID- 12422481
TI  - [Acute intoxication by redoul (Coriaria myrtifolia L.). Three observations].
AB  - INTRODUCTION: Coriaria myrtifolla L. (Redoul) is a shrub of the Mediterranean
      area. Poisoning with this plant is often accidental, following ingestion of the
      plant's fruit that are often mistaken for blackberries. OBSERVATIONS: Having
      eaten Coriaria myrtifolla L. berries, three sisters suffered from acute
      poisoning. One died. COMMENTS: Toxic effects are characterized by digestive
      (nausea, vomiting, abdominal pain), neurological (obnubilation, convulsions and
      their complications), and respiratory disorders (polypnea, respiratory problems,
      apnea, short and superficial respiration) together with myositis of the pupils.
      Treatment of this poisoning is purely symptomatic. In the case of convulsions,
      rapid resuscitation in an intensive care unit in necessary.

PMID- 12422482
TI  - [Intrathoracic myeloid metaplasia revealing a primitive myelofibrosis].

PMID- 12422483
TI  - [Lethal congenital toxoplasmosis resulting from reactivation of toxoplasmosis in
      a pregnant HIV-positive patient].

PMID- 12422484
TI  - [Edematous syndrome and alithiasic cholecystitis induced by gabapentin].

PMID- 12422485
TI  - [Value of [18F]-fluorodeoxyglucose (FDG) positron emission tomography in
      digestive cancerology].
AB  - COLORECTAL CANCERS: FDG-PET is a very effective tool in the follow-up of
      colorectal cancer for the early detection of recurrences, the search for other
      localisations in case of resectable lesions and for the evaluation of therapies.
      For the other digestive cancers, the data in the literature are less abundant and
      they do not yet have Marketing Authorization in France. OESOPHAGEAL CANCER: FDG
      PET appears very promising for staging and detection of recurrences of
      oesophageal carcinomas. Pancreatic cancer Although the indication is difficult,
      FDG-PET appears superior to morphological techniques for the characterization and
      the locoregional staging of pancreatic tumours. BILARY AND GASTRIC CARCINOMAS:
      FDG-PET is promising but its role has to be confirmed in larger series for the
      detection of biliary and gastric carcinomas. OTHER DIGESTIVE TUMOURS: In cases of
      hepatocarcinoma, FDG-PET appears efficient only in cases of undifferentiated
      tumours, and in cases of malignant neuroendocrine digestive tumours, is useful in
      combination with somatostatin receptor imaging.

PMID- 12422486
TI  - [Myocardial implantation of muscle cells].
AB  - THE DEVELOPMENT OF CELL THERAPY: The stakes in the management of heart failure
      have become such that new therapeutic strategies have to be developed. Among the
      cell, molecular and genetic approaches aimed at reinforcing the deficient heart
      muscle by restoring its functional potential, cell therapy is the favored option
      in clinical application perspectives. IN THE FIELD OF ISCHEMIC HEART FAILURE: All
      the experimental data have shown that implantation of contractile cells in the
      post-infarction areas led to improved cardiac function. INTERESTING PRELIMINARY
      RESULTS: For ethical and immuno-biological reasons, the successful
      transplantation of autologous skeletal myoblasts has led our team to conduct a
      phase I clinical trial. Although the results of this study are preliminary with
      regard to cardiac function, they suggest the validity of the cell transplantation
      concept and allow one to hope that this new treatment method will have its place
      among the therapeutic arms of heart failure.

PMID- 12422487
TI  - [New weapons for the treatment of psoriasis].

PMID- 12422488
TI  - The burden of depression.

PMID- 12422489
TI  - A training programme for refugee doctors.

PMID- 12422491
TI  - Physiotherapy in the management of cerebral palsy.
AB  - While most parents and professionals agree that physiotherapy treatment is
      beneficial for children with cerebral palsy, evidence as to its efficacy is
      controversial. Physiotherapy should be seen from the perspective of lifelong
      management of cerebral palsy and appropriate resources should be identified in
      adulthood.

PMID- 12422490
TI  - Management of cerebral palsy: the neurologist's view.
AB  - Cerebral palsy is a complex disorder which compromises motor abilities. Other
      systems are often involved and its effects on the child and their family may be
      profound. This article examines clinical aspects of cerebral palsy and discusses
      the approach to comprehensive management, with particular reference to the role
      of the neurologist.

PMID- 12422492
TI  - The value of ultrasound in sports medicine.
AB  - Musculoskeletal ultrasound is increasingly being used in the evaluation and
      treatment of sports-related injuries. This technique is widely available, rapid,
      and has a high patient acceptance. Its multiplanar capability and dynamic real
      time imaging can be correlated with clinical symptoms and compared to
      contralateral asymptomatic structures.

PMID- 12422493
TI  - Evidence-based lumbar puncture: best practice to prevent headache.
AB  - Lumbar puncture is routinely used to access cerebrospinal fluid. Headache is the
      most common complication, and can be debilitating. The risk of headache is
      related to age, sex, needle size and shape, and lumbar puncture procedure.
      Doctors continue to use 20 G bevelled needles followed by bed rest, although
      overwhelming evidence supports use of 22 G atraumatic needles with no bed rest.

PMID- 12422495
TI  - Neuroimaging violence in the mentally ill: what can it tell us?
AB  - Incidents of aggression and violence in severe mental disorders like psychosis,
      personality disorders and substance misuse disorders are higher than in the
      general population. Recent advances in neuroimaging techniques may help to
      predict violent behaviour in mentally ill individuals and to identify anomalies
      in brain functioning that may be amenable to treatment.

PMID- 12422494
TI  - Quetiapine: a well-tolerated and effective atypical antipsychotic.
AB  - Quetiapine is an atypical antipsychotic, licensed in the UK for the treatment of
      schizophrenia. This review of published literature identifies the evidence that
      quetiapine is both effective and well-tolerated and highlights the particular
      indications in which quetiapine will be of most value to clinicians and patients.

PMID- 12422496
TI  - Further reduction in mortality following myocardial infarction.
AB  - Omacor is a new omega-3 fatty acid product that is licensed for secondary
      prevention post-myocardial infarction. It confers an additional 20% reduction in
      all-cause mortality, based on the Gruppo Italiano per lo Studio della
      Sopravvivenza nell'Infarto miocardico prevenzione (GISSI-P) study data. The GISSI
      P results are compared with other trials of secondary prevention.

PMID- 12422497
TI  - Testicular cancer: current update and controversies.
AB  - Testicular cancer is an important disease affecting young men. The overall 5-year
      survival has improved to 95%. The goal now is to maintain the efficacy of
      treatment in advanced disease while reducing the associated side effects.

PMID- 12422498
TI  - Flexible training under threat.
AB  - As the number of women in medicine and the general demand for a better work-life
      balance rises, flexible training is an increasingly important mechanism for
      maintaining the medical workforce. The new pay deal, together with entrenched
      cultural attitudes, are potential threats. Ways forward include more substantive
      part-time posts, more part-time opportunities at consultant level, and using
      positive experiences as a way of tackling attitudes in the less accepting
      specialties.

PMID- 12422499
TI  - Common injuries of the foot and ankle.

PMID- 12422500
TI  - Necrotizing fasciitis: an unusual cause.

PMID- 12422501
TI  - Anterior abdominal wall ischaemia in association with multiple myeloma.

PMID- 12422502
TI  - What a performance!

PMID- 12422503
TI  - Surviving childhood cancer.

PMID- 12422504
TI  - Surviving childhood cancer.

PMID- 12422505
TI  - Surviving childhood cancer.

PMID- 12422506
TI  - Anaesthesia for caesarean section complicated by placenta praevia.

PMID- 12422507
TI  - Atypical location of double-strand origin of replication (nic site) on the
      plasmid pGA1 from Corynebacterium glutamicum.
AB  - The double-strand origin of replication (dso) of the rolling-circle-replicating
      (RC) plasmid pGA1 from Corynebacterium glutamicum was analyzed using the runoff
      DNA synthesis assay. The site- and strand-specific breakage of double-stranded
      plasmid DNA, representing the nic site of dso, was localized precisely within the
      sequence 5'-CTGG decreases AT-3' in the distal part of the pGA1 rep gene. This
      location of dso differs from the dso positions found on other RC plasmids and is
      in agreement with the classification of the plasmid pGA1 into a new group of RC
      plasmids.

PMID- 12422508
TI  - Some features of DNA-binding proteins involved in the regulation of the
      Streptomyces aureofaciens gap gene, encoding glyceraldehyde-3-phosphate
      dehydrogenase.
AB  - A gapR gene, encoding a protein similar to the AraC/XylS family of bacterial
      transcriptional regulators, was previously identified upstream of the gap gene,
      coding for glyceraldehyde-3-phosphate dehydrogenase in Streptomyces aureofaciens.
      The GapR protein overproduced in Escherichia coli was shown to bind to the gap-P
      promoter region. Using the gel mobility shift assay with cell-free protein
      extracts from different developmental stages of S. aureofaciens, we identified
      several other proteins, in addition to GapR, that specifically bound to the S.
      aureofaciens gap-P promoter region. When cell-free extracts from S. aureofaciens
      cultivated in liquid medium with glucose were analyzed, only one complex
      corresponding to GapR was detected. A new protein interacting with the gap-P
      promoter was detected in stationary culture of S. aureofaciens grown in the
      presence of mannitol as carbon sources. The GapR protein was partially purified
      from S. aureofaciens cultivated in liquid medium containing glucose and used for
      binding studies. DNA footprinting analysis revealed an identical protected region
      as previously identified for the GapR protein overproduced from Escherichia coli.
      The direct role of the GapR protein in the regulation of gap expression in S.
      aureofaciens in vivo was confirmed but regulation of gap expression seems to be
      more complex, possibly involving other regulatory protein(s), depending on the
      developmental stage of S. aureofaciens.

PMID- 12422509
TI  - Sequence similarities of protein kinase peptide substrates and inhibitors:
      comparison of their primary structures with immunoglobulin repeats.
AB  - Forty original sequences of peptide substrates and inhibitors of protein kinases
      and phosphatases were aligned in a chain matrix without artificial gaps. Fifteen
      protein kinase peptide substrates and inhibitors (PKSI peptides) contained a
      common dipeptide ArgArg and also additional important tetra-, tri- and dipeptide
      homologies. Three further peptide substrates were significantly similar to these
      peptides but lacked the ArgArg dipeptide. Sequence comparison of individual PKSI
      peptides revealed probabilistically restricted consensus sequence--PKSI motif-
      comprising 8 homologous and 13 non-randomly distributed amino acids without
      considering mutation analysis. This template motif was compared with the
      consensus sequences of 12 different immunoglobulin domains. In 11 of 12 these
      domains, the starts of homologous segments were found at nearly the same domain
      related sites, beginning with serine. A single-triplet mutation of any of the
      first two triplet bases that encode equally localized amino acids in each of the
      two sequence sets (PKSI and Ig) revealed additional homologies with the other
      set. A primary derived motif version composed of 9 homologous and seven non
      randomly distributed amino acids was consequently established by its feedback
      projection into the original sequence sets. This procedure yielded a second
      preliminary motif version (revised motif) formed by a sequence of 9 homologous
      amino acids and two non-randomly distributed amino acids. In addition, three
      shorter oligopeptide motifs called important stereotypes were derived, based on
      repeated homology between Ig chains and the revised motif. The most extensive
      similarities in terms of these stereotypes occurred in the CH2 and CH4 domains of
      Ig peptides, and inhibitors of cAMP dependent protein kinase and protein kinase
      A. Further comparisons based on a reference sequence set arranged with the aid of
      feedback projection revealed a lower similarity between variable Ig chains
      reflected in a decreased number of homologous amino acids. Two final motif
      versions, FMC and FMV, were found in two different subsets of constant and
      variable Ig chains, respectively. FMC was composed of seven homologous and one
      non-randomly distributed amino acids forming the dispersed structure STLR(C)LVSD,
      whereas 6 homologous and one questionable amino acid constituted FMV. Only CH4
      and CH1 domain segments contained all five high-incidence amino acids, which
      represented a higher level of similarity than homologous amino acids of all
      preliminary and final motifs. Four such amino acids were present also in three
      PKSI peptides. All similarities described here occur in domain segments
      positionally overlapping with the CDR1 region of variable chains. The results are
      discussed in terms of immunoglobulin evolution, the position of Fc receptor
      binding sites and degeneration or mutability of the triplets of motif
      constituting amino acids.

PMID- 12422510
TI  - Biological activity of secondary metabolites produced by a strain of Pseudomonas
      fluorescens.
AB  - Biological activity of secondary metabolites produced by a plant-growth-promoting
      Pseudomonas fluorescens was evaluated. The strain produced antibiotics phenazine
      (PHE), 2,4-diacetylphloroglucinol (PHL) and siderophore pyoverdin (PYO) in
      standard King's B and succinic acid media, respectively. After extraction, PYO
      was identified by comparing the UV-spectra and moss-green color development after
      'diazotized sulfanilic acid' (DSA) spray in TLC. PHE and PHL were identified by
      comparing standard compounds on TLC and orange-color development immediately
      after DSA spray. In vitro antibiosis study of the metabolites revealed their
      antibacterial and antifungal activity against bacterial test organisms
      Corynebacterium sp., Mycobacterium phlei and M. smegmatis and test fungi Fusarium
      moniliforme, F. oxysporum, F. semitectum, F. solani and Rhizoctonia solani. A
      statistically significantly higher plant growth was recorded in siderophore
      amended plantlets under gnotobiotic conditions whereas PHE and PHL did not show
      any plant-growth-promoting activity. These results support the importance of the
      secondary metabolites produced by the strain P. fluorescens in enhancing plant
      growth and in controlling fungal and bacterial pathogens.

PMID- 12422511
TI  - Electrorelease of Escherichia coli nucleoids.
AB  - Bacterial chromosome is assembled and folded into one or several nucleoids,
      depending on the metabolic status of the cell. Development of reliable nucleoid
      isolation protocols has always been an objective for researchers. A rapid and
      reproducible procedure for isolation of E. coli nucleoids is described here,
      while the cell envelope is maintained. Membrane dispersions and vesicles were
      prepared by lysozyme-EDTA treatment with subsequent rupture of the spheroplasts
      by electric field. Under these conditions the yield of electroreleased nucleoids
      was around 90%. The extent of DNA-envelope contacts was determined by light
      microscopy employing phase contrast and fluorescence modes.

PMID- 12422512
TI  - Effect of mutations in dnaK and dnaJ genes on cysteine operon expression in
      Escherichia coli.
AB  - The effect of mutations in dnaK and dnaJ genes on the expression of two operons
      that are part of cysteine regulon was determined using Escherichia coli strains
      harboring cysPTWA::lacZ and cysJIH::lacZ fusions. Null dnaJ and dnaKdnaJ mutants
      were impaired in beta-galactosidase expression from both fusions. Efficient
      complementation of this defect by wild-type alleles present on a low-copy number
      plasmid was achieved. The presence of the pMH224 plasmid coding for CysB* protein
      defective in DNA binding lowered beta-galactosidase expression from cysPTWA::lacZ
      fusion strain harboring wild-type dnaKdnaJ alleles but did not diminish enzyme
      expression in delta dnaJ and delta dnaKdnaJ strains.

PMID- 12422513
TI  - Antimicrobial activity of berberine--a constituent of Mahonia aquifolium.
AB  - The antimicrobial activity of the protoberberine alkaloid, berberine, isolated
      from Mahonia aquifolium, was evaluated against 17 microorganisms including two
      Gram-negative bacteria--Pseudomonas aeruginosa and Escherichia coli (both
      resistant and sensitive), two Gram-positive bacteria--Bacillus subtilis and
      Staphylococcus aureus, Zoogloea ramigera, six filamentous fungi--Penicilium
      chrysogenum, Aspergillus niger, Aureobasidium pullulans (black and white strain),
      Trichoderma viride (original green strain and brown mutant), Fusarium nivale,
      Mycrosporum gypseum and two yeasts--Candida albicans and Saccharomyces
      cerevisiae. The IC50, minimum inhibitory concentration (MIC), minimum
      microbicidal concentration (MMC) and minimum microbistatic concentration (MMS)
      varied considerably depending on the microorganism tested, the sensitivity
      decreasing as follows: S. aureus > P. aeruginosa S (sensitive) > E. coli S > P.
      aeruginosa R (resistant) > E. coli R > B. subtilis > Z. ramigera > C. albicans >
      S. cerevisiae > A. pullulans B (black) > A. pullulans W (white) > T. viride Br
      (brown) > M. gypseum > A. niger > F. nivale > P. chrysogenum > T. viride G
      (green).

PMID- 12422514
TI  - Effect of outer-membrane permeabilizers on the activity of antibiotics and plant
      extracts against Pseudomonas aeruginosa.
AB  - Several known outer membrane permeabilizers increased susceptibility of a highly
      resistant pathogenic strain Pseudomonas aeruginosa to different antibiotics and
      plant extracts. Of all the chemicals tested, EDTA, sodium citrate and sodium
      hexametaphosphate (HMP) were found to be potent permeabilizers as shown by
      enhanced lysis of the bacteria in the presence of lysozyme. In the presence of
      EDTA and sodium citrate susceptibility of the strain to gentamicin and rifampicin
      increased markedly. The strain was resistant to vancomycin but became susceptible
      when grown in the presence of increasing amounts of EDTA and sodium citrate.
      Similar results were obtained for erythromycin when treated with sodium citrate.
      EDTA was found to be most potent permeabilizer in enhancing the activity of the
      plant extracts. Though HMP was an effective permeabilizer it had a weak or no
      effect on the activity of the antibiotics and plant extracts.

PMID- 12422515
TI  - Variability of laccase activity in the white-rot basidiomycete Pleurotus
      ostreatus.
AB  - The production of laccase in liquid cultures of the white-rot fungus Pleurotus
      ostreatus was highly variable. During the first days of cultivation, the relative
      variability was as high as 80-100% and it decreased to 30% in the course of
      cultivation. The main source of variability was assumed to be the independent
      development of enzyme activity in individual cultures. Cultures with high laccase
      production showed also high production of the other ligninolytic enzyme--Mn
      dependent peroxidase. The variability was probably due to the source of inoculum,
      deactivation of the enzyme in culture liquid and genetic variations among the
      cultures. Variability of laccase activities was lower during solid-state
      fermentation on wheat straw and during the growth in nonsterile soil.

PMID- 12422516
TI  - Isolation and partial characterization of an antibacterial substance produced by
      Enterococcus faecium.
AB  - A strain of Enterococcus faecium isolated from Bulgarian yellow cheese
      "kashkaval" produced a bacteriocin-like substance named enterococcin A 2000. The
      antibacterial substance had a low molar mass (< 2 kDa), was relatively stable
      toward heat but was sensitive to selected proteolytic enzymes. It was active
      against Gram-positive bacteria including enterococci, such as Listeria, Bacillus
      and Streptococcus, and also against Gram-negative E. coli. Production of
      enterococcin A 2000 has a maximum near the end of the exponential phase of
      producer growth. The peptide was purified by ammonium sulfate precipitation,
      butanol extraction, followed by cation-exchange chromatography and reversed-phase
      chromatography. A partial sequence of purified enterococcin A 2000 indicated that
      this substance does not belong to the class IIa of bacteriocins presenting the
      consensus anti-Listeria motif YGNGV.

PMID- 12422518
TI  - Winemaking from Gaglioppo grapes with hybrid strains of Saccharomyces.
AB  - The fermentative behavior of two hybrid wine yeast strains (first-generation
      hybrid-strain 12,233 x 6167--obtained by hybridization of the cryotolerant strain
      S. bayanus 12,233 with the mesophilic strains S. cerevisiae 6167, and TT254 x
      6392 arising by hybridization of the thermotolerant strain S. cerevisiae TT254
      with the mesophilic strain S. cerevisiae 6392) was compared with that of a
      commercial wine yeast strain S. cerevisiae K1 in must from black grapes of the
      Calabrian variety Gaglioppo. The goal was to obtain wines with a high content of
      'polyphenols' from a grape must with a limited phenolic content such as the
      Gaglioppo must. The progress of the winemaking was estimated according to
      residual sugars; at the end of fermentation, the wines were decanted, bottled and
      principal physico-chemical characteristics determined. Our results point to the
      possibility to select wine yeasts (significantly differing in the above
      parameters) by their ability to interact with phenolic compounds.

PMID- 12422517
TI  - Fluctuations during growth of the plasma membrane H(+)-ATPase activity of
      Saccharomyces cerevisiae and Schizosaccharomyces pombe.
AB  - The plasma membrane H(+)-ATPase activity was determined under various growth
      conditions using the yeasts Saccharomyces cerevisiae and Schizosaccharomyces
      pombe. Under early batch-growth conditions in a rich medium, the budding yeast S.
      cerevisiae ATPase specific activity increased 2- to 3-fold during exponential
      growth. During late exponential growth, a peak of ATPase activity, followed by a
      sudden decrease, was observed and termed "growth-arrest control". The growth
      arrest phenomenon of S. cerevisiae could not be related to the acidification of
      the culture medium or to glucose exhaustion in the medium or to variation of
      glucose activation of the H(+)-ATPase. Addition of ammonium to a proline minimum
      medium also stimulated transiently the ATPase activity of S. cerevisiae. Specific
      activity of the fission yeast S. pombe ATPase did not show a similar profile and
      steadily increased to reach a plateau in stationary growth. Under synchronous
      mitotic growth conditions, the ATPase activity of S. cerevisiae increased during
      the cell division cycle according to the "peak" type cycle, while that of S.
      pombe was of the "step" type.

PMID- 12422519
TI  - Regulation of the production of polygalacturonase by Aspergillus niger.
AB  - Synthesis of ethylene in static cultures as well as the effect of endogenous and
      exogenous ethylene on the synthesis of polygalacturonase by Aspergillus niger
      were determined. This strain produced maximum ethylene amounts when cultured at
      30 degrees C for 3 d. The effect of adding ethylene precursors (citrate-cycle
      intermediates) on ethylene production was investigated. Best intracellular and
      extracellular polygalacturonase production was obtained with 2-oxoglutaric,
      pyruvic and fumaric acids, and with glutamic acid too. Addition of ethylene to
      the culture medium also increased the synthesis of polygalacturonase, although to
      a lower degree than when glutamic acid was added.

PMID- 12422521
TI  - Production of manganese-dependent peroxidase in a new solid-state bioreactor by
      Phanerochaete chrysosporium grown on wood shavings. Application to the
      decolorization of synthetic dyes.
AB  - The production of manganese-dependent peroxidase (MnP) by Phanerochaete
      chrysosporium in a new solid-state bioreactor, the immersion bioreactor,
      operating with lignocellulosic waste, such as wood shavings, was investigated.
      Maximum MnP and lignin peroxidase (LiP) activity of 13.4 and 8.48 mukat/L were
      obtained, respectively. The in vitro decolorization of several synthetic dyes by
      the extracellular liquid produced in the above-mentioned bioreactor (containing
      mainly MnP) was carried out and its degrading ability was assessed. The highest
      decolorization was reached with Indigo Carmine (98%) followed by Bromophenol Blue
      (56%) and Methyl Orange (36%), whereas Gentian Violet was hardly decolorized
      (6%).

PMID- 12422520
TI  - Effect of paraquat on cellular defense enzymes and glutathione level of Funalia
      trogii.
AB  - The effect of paraquat on the activities of antioxidant defense and detoxifying
      enzymes of the white-rot fungus Funalia trogii was determined. Paraquat increased
      the activities of glutathione reductase (GR), glutathione transferase (GT) and
      superoxide dismutase at 1 mmol/L, while at 0.1 mmol/L it did not affect the
      activity of GR and GT. It depressed the catalase activity and the amount of
      glutathione at all concentrations used. Paraquat treatment probably depresses
      antioxidant defense components such as catalase and glutathione.

PMID- 12422522
TI  - Extracellular laccases in ascomycetes Trichoderma atroviride and Trichoderma
      harzianum.
AB  - Laccase activity in Trichoderma harzianum and in our own isolate Trichoderma
      atroviride was correlated with the production of the green pigment in conidial
      spores. The laccases of the two fungal species exhibit comparable kinetic
      parameters, pH optima and thermal sensitivity but differed in physiological
      properties, such as their catalytic activity during growth.

PMID- 12422523
TI  - Composition of Casuarina leaf litter and its influence on Frankia-Casuarina
      symbiosis in soil.
AB  - Plant needles of Casuarina equisetifolia were collected and analyzed in parallel
      with soil analysis. In three strains of Frankia--symbionts of Casuarina--their
      infectivity and plant performance was determined in vitro after soil amendment
      with different leaf litter concentrations. Only one strain was able to nodulate
      the plant at all litter concentrations (0.5, 3 and 5%) although the nodules were
      very small. However, all treated plants grew poorly; their growth was reduced by
      approximately 90% (for 5% litter concentration) compared to plants grown on
      untreated soil, on the basis of total dry mass. Inhibition of nodulation can be
      attributed to high concentrations of some elements and compounds that were either
      found in C. equisetifolia litter or originally found in soil (i.e. chloride,
      cyanide, copper, manganese and phenols). In general, plant growth decreased as
      more litter was added. Plant total nitrogen content was also reduced after
      increasing the litter concentration. The inhibitory effect of high litter
      concentrations was mainly on plant growth and to a lesser extent on plant
      nodulation by Frankia strains.

PMID- 12422524
TI  - Soil microbial community of abandoned sand fields.
AB  - Microbiological evaluation of sandy grassland soils from two different stages of
      secondary succession on abandoned fields (4 and 8 years old fallow) was carried
      out as a part of research focused on restoration of semi-natural vegetation
      communities in Kiskunsag National Park in Hungary. There was an apparent total N
      and organic C enrichment, stimulation of microbial growth and microbial community
      structure change on fields abandoned by agricultural practice (small family farm)
      in comparison with native undisturbed grassland. A successional trend of the
      microbial community was found after 4 and 8 years of fallow-lying soil. It
      consisted in a shift of r-survival strategy to more efficient C economy, in a
      decrease of specific respiration and metabolic activity, forced accumulation of
      storage bacterial compounds and increased fungal distribution. The composition of
      microbial phospholipid fatty acids mixture of soils abandoned at various times
      was significantly different.

PMID- 12422525
TI  - Chlamydial infection of cats and human health.
AB  - Chlamydia psittaci var. felis is considered as a primary and important agent in
      the etiology of infectious diseases of the upper respiratory tract and eyes in
      cats, having zoonotic potential. We investigated 13 cats aged between 2 months
      and 7 years, in which conjunctivitis, rhinitis, laryngotracheitis,
      bronchopneumonia and lymph adenopathy was clinically diagnosed. To detect the
      antigen of C. psittaci the Clearview Chlamydia Direct Test was used for the first
      time. The presence of C psittaci in 10 of 13 investigated cats and in 8 nasal
      mucosa smears from 10 investigated cats were confirmed in conjunctiva. Using
      bacteriological examination different species of the genus Staphylococcus in
      conjunctiva from all 13 investigated animals were also confirmed. Serological
      investigation using complement fixation test was negative in all animals.

PMID- 12422526
TI  - Toxinogenicity and markers of pathogenicity of Pseudomonas aeruginosa strains
      isolated from patients with tumor diseases.
AB  - Potential virulence factors (elastase, proteinase, lipase, phospholipase C,
      alginate) as well as surface properties (hydrophobicity, motility) were
      determined in 103 Pseudomonas aeruginosa strains isolated from patients with
      cancer. Nontypable strains were the dominant group (60%), followed by serotypes
      O11 (17%), O12 (7%) and O4 (5%). Seventy-one strains (69%) produced high level of
      elastase (10-60 mg/L), 87% of the strains possessed high activity of proteinase
      (bacterial) (10-250 mg/L) and 69% of the strains demonstrated higher level of
      lipase (20-150 U/mL); these elevated levels of enzymes were associated mainly
      with nontypable strains. On the other hand, 79% of the strains did not produce or
      produced only a low level of phospholipase C and 60% of isolates did not manifest
      any or very low production of alginate. Hydrophobicity demonstrated by adherence
      of the bacteria to xylene was shown by 69% of strains; 94% of strains aggregated
      with ammonium sulfate. Motility in the range of 31-80 mm was found in 76 strains
      (74%). The considerable virulence of tested P. aeruginosa strains was confirmed.
      The nontypable strains manifested the most frequent group with high level of
      elastase, proteinase, lipase, hydrophobicity and motility.

PMID- 12422527
TI  - Comparison of genetic variability between Czech and foreign isolates of
      phytopathogenic bacteria Clavibacter michiganensis subsp. sepedonicus by Rep-PCR
      technique.
AB  - Repetitive-sequence-based polymerase chain reaction (Rep-PCR) method was used for
      analysis of genetic variability among bacterial populations from different world
      locations. Collection of 26 Czech and 13 foreign strains of Clavibacter
      michiganensis subsp. sepedonicus was amplified using BOX primer targeting to
      repetitive motif occurring in eubacterial genomes. Genetic fingerprints were
      visually compared and statistically evaluated by cluster analysis. Genetic
      similarity was estimated to be approximately 80% among all tested strains.
      Populations of these bacteria seem to be highly homogeneous; potential influence
      of geographic origin was not confirmed.

PMID- 12422528
TI  - Isolation of Carnobacterium piscicola from human pus--case report.
AB  - Carnobacterium piscicola was first described in 1984. These bacteria are often
      isolated from fish afflicted with bacterial infections. To date, there has been
      no reported isolation of this bacterium from human specimens. We report here the
      isolation of C. piscicola from the pus following traumatic amputation of the
      right hand in the wrist of a 35-year-old man. The traumatic amputation occurred
      with an industrial water sawmill. The identity of the human strain was determined
      biochemically, by 16S rDNA sequence similarity and by fatty-acid methyl-ester
      profile from bacterial cell.

PMID- 12422529
TI  - Influence of calcium hydroxide root-canal sealer on microbial growth in vitro.
AB  - The calcium hydroxide-based filling material Apexit, which is often used in
      endodontic practice, was evaluated for its antibacterial and antifungal effects
      against microorganisms isolated from oral cavity (Serratia marcescens,
      Pseudomonas putida, Staphylococcus aureus, Candida albicans). Two different
      quantitative techniques were employed--the direct-contact test was used to
      examine the efficacy of freshly mixed material while the broth-survival test was
      employed to check the antimicrobial properties of 5-d-old material. Apexit
      inhibited Gram-negative bacteria more effectively than Gram-positive ones but had
      none or a very weak inhibitory effect on C. albicans.

PMID- 12422530
TI  - Influence of a single gamma-irradiation on rat microflora.
AB  - Changes in leukocyte counts and in the gut microflora of laboratory rats
      irradiated with single whole-body dose of gamma rays (5.0 Gy) were determined.
      The number of leukocytes was lower especially 1 and 2 weeks after irradiation. A
      significant decrease in lymphocytes was observed 1 week and in monocytes 1 and 2
      weeks after irradiation. In parallel with these changes, an increase in common
      microflora was observed; some microorganisms, which normally are not present in
      duodenum, liver and mouth cavity, were detected in these organs.

PMID- 12422531
TI  - [Development of surgical antibioprophylaxis kits: evaluation of the impact on
      prescribing habits].
AB  - In our hospital, surgical antibioprophylaxis (ATBP) was too often administered
      too late, thus raising the infectious risk. Antibiotic stocks of the anaesthesia
      department were also systematically used, instead of nominal prescriptions of
      these drugs. The pharmacy could neither charge antibiotics to each surgical
      department nor quantify and differentiate ATBP from curative antibiotic therapy.
      The pharmacy and anaesthesia departments therefore set out to standardize
      surgical ATBP, in order to adapt this treatment to each surgical indication, and
      particularly in the case of allergy to beta-lactamase antibiotics (second line
      treatment kits). Consequently, prescription forms were developed and supplied to
      each surgery department, as well as ATBP kits. The kits were prepared and
      distributed by the pharmacy, and comprised boxes containing antibiotics in
      sufficient quantities to respect the protocols approved by the French Society of
      Anaesthesia and Resuscitation (SFAR). A protocol describing prescriptions,
      dispensation and administration has been presented to physicians and nurses.
      Fifteen surgical departments were included in our study and 30 different kits
      were prepared. From 1998 to 2001, 5586 surgical operations required
      administration of a kit (second line treatment kits in 5% of cases): 1848 (33%)
      in visceral surgery; 764 (13.8%) in urology; 802 (14%) in orthopaedics; 13 (0.2%)
      in vascular and thoracic surgery; 1236 (22%) in ear-nose-throat (ENT),
      periodontics and ophtalmology, and 923 (17%) in gynaecology and obstetrics. 93%
      of filled prescriptions forms were spontaneously returned to the pharmacy, the
      others were obtained during the renewal of kit stocks. The cost (over 4 years) of
      ATBP was quantified: 157,871 F for the 15 departments included, 26,123 F in
      visceral surgery, 13,520 F in urology, 73,741 F in orthopaedics, 569 F in
      vascular surgery, 39,720 F in ENT/ophthalmology/periodontics and 4,198 F in
      gynaecology and obstetrics. According to the Altemeier classification, 2226 class
      I, 3151 class II, and 209 class III surgical operations were performed. Since the
      kits have been brought into use, the committee for the protection against
      nosocomial infections (CLIN) has observed a reduction in the incidence of post
      operative infections, according to the Altemeier classification: from 1.6% to
      0.5% in class I, from 6.5% to 4.3% in class II, and from 11% to 8.5% in class
      III. The difference was statistically significant only for classes I (p < 0.01)
      and II (p < 0.001), and unchanged for class III (p = 0.3). No analysis was
      carried out for class IV (curative treatments). Both nurses and physicians have
      greatly appreciated the implementation of this organization. The advantage in
      terms of post-operative infections, administration exhaustiveness and stock
      management is obvious. The prescribed kits were systematically appropriate for
      the surgical interventions. In orthopaedics, cefamandole was used over 24 h (188
      kits) in ligament plasty and osteotomy, or for 48 h (499 kits) in prosthetic
      surgery; 24 amoxicillin/clavulanic acid (first line) and 9 clindamycin/gentamicin
      (second line) single dose kits have been prescribed in traumatic indications. In
      ophthalmology, kits were only prescribed in endophtalmitis (24
      ofloxacin/fosfomycin single amount kits), implant replacement or cornea graft
      (1076 ofloxacin 24 h kits) and cataract surgery in diabetic patients (12
      ofloxacin single amount kits). In ENT and periodontics, 124 surgical operations
      required cefazolin single dose kits. In vascular surgery, 5 pefloxacin/gentamicin
      48 h kits and 1 amoxicillin/clavulanic acid 48 h kit were used in contaminated
      limb amputation, 1 cefamandole 48 h kit in class I surgery and 1 vancomycin 24 h
      kit (betalactamase antibiotic allergy); in thoracic surgery, 1 cefamandole 24 h
      kit was used for a thoracic wound. In visceral surgery, 9 different kits have
      been used, depending on the opening (class II) or not (class I) of the digestive
      tract. 797 cefazolin (first line) and 68 clindamycin/gentamicin (second line)
      single dose kits were used in class I surgery, and 689 amoxicillin/clavulanic
      acid single dose (SD) kits in class II surgery. Specific protocols consisted of
      18 ceftriaxone/metronidazole and 48 metronidazole/gentamicin SD kits in
      oesophagus surgery, 11 ceftriaxone and 17 gentamicin SD kits in biliary
      endoscopy, 137 metronidazole SD kits in proctology and 34 amoxicillin/gentamicin
      6 h kits for prevention of endocarditis. In urology, 133 cefotaxime and 20
      pefloxacin/gentamicin SD kits were precribed in renal lithiasis, 102
      amoxicillin/clavulanic acid SD kits in cystectomy, 27 amoxicillin/gentamicin 6 h
      kits in endocarditis prevention and 58 cefamandole SD kits in all other
      indications. In gynaecology and obstetrics, 534 cefazoline and 19
      clindamycin/gentamicin (second line) SD kits were used, and 370 doxycyclin SD
      kits were prescribed in pregnancy termination. Some departments (orthopaedics and
      visceral surgery) adapted the protocols to their needs, specifically with regard
      to treatment duration. However, these situations were quickly corrected. A
      constant follow-up and update of this system, associated with routine audits,
      should allow the maintenance and possibly the improvement of these results, hence
      shortening treatment duration.

PMID- 12422532
TI  - [Circulation of pharmaceutical information among general practitioners in the
      region of Sousse (Tunisia)].
AB  - The general practitioner plays an essential role in the rational strategy of drug
      use by the quality of his prescription which translates the validity and the
      relevance of his pharmaceutical information. The objective of this work is to
      study the different means of pharmaceutical information used by general
      practitioners in the region of Sousse (Tunisia). We conducted a transversal,
      descriptive, exhaustive survey of 140 general practitioners in private (68) and
      public (72) practice during 1999. Data were collected through a questionnaire.
      This study, with a participation rate of 78%, showed that pharmaceutical
      dictionaries are the major source of information for 86% of general
      practitioners, that medical delegates have a positive image for 84% of them and
      that 36% of general practitioners do not subscribe to any medical journal. Thus,
      general practitioners are exposed to relatively unreliable pharmaceutical
      information coming generally from the pharmaceutical industry.

PMID- 12422533
TI  - Relaxant activity of methanolic extract from seeds of Peganum harmala on isolated
      rat aorta.
AB  - The activity of methanolic extract from the seeds of Peganum harmala L. (MEP) on
      vascular smooth muscle (rat aorta) was investigated. MEP induced relaxation in
      aorta precontracted with noradrenaline (10(-6) M) or KCl (80 mM) (IC50 = 14.49 +/
      1.15 and 5.93 +/- 1.26 micrograms/mL, respectively) in a dose-dependent manner
      and this relaxant effect was not endothelium-dependent. The vasodilatory effects
      were potentiated by isoprenaline (10(-9) M) (1.08 +/- 0.14 micrograms/mL) and
      negatively affected by a non-specific inhibitor of phosphodiesterase, IBMX (10(
      4) M) (20.81 +/- 1.06 micrograms/mL). Pretreatment with MEP (3, 6, 18
      micrograms/ml) shifted the phenylephrine-induced dose-response curves to the
      right and the maximum response was attenuated, indicating that the antagonist
      effect of MEP on alpha 1-adrenoceptors was non-competitive. These results suggest
      that MEP exerts a vasodilatory effect not related to the presence of endothelium
      and the main mechanism may be related to the inhibition of cyclic AMP
      phosphodiesterase.

PMID- 12422535
TI  - [The effect of argan oil on heart function during ischemia and reperfusion].
AB  - The aim of this study was to evaluate the effect of organ oil on isolated heart
      function before and after ischemia and on the activity of cardiac antioxidant
      enzymes. 16 Wistar rats were divided into 2 groups; control group and treated
      group receiving 5 mL/kg/day of organ oil. After 8 weeks of treatment, hearts were
      perfused and subjected to a global ischemia followed by reperfusion. Activity of
      cardiac antioxidant enzymes was assessed in freeze-clamped hearts at the end of
      reperfusion. Results showed that organ oil induces: 1--damage to heart function
      during the preischemic period, 2--decreased functional recovery during
      reperfusion and 3--significant increase in catalase activity. It seems that, in
      our experimental conditions, organ oil increases heart sensitivity to ischemia
      and reperfusion. However, the mechanism involved has yet to be understood.

PMID- 12422534
TI  - Antinociceptive action of extracts and fractions from Rubus imperialis
      (Rosaceae).
AB  - Rubus imperialis is a Brasilian medicinal plant which previously exhibited
      therapeutical perspectives. This work describes the antinociceptive action of
      methanolic extracts obtained from different parts of the plant (roots and
      branches) as well as hexane, chloroform and ethyl acetate fractions obtained from
      branches. Such extracts or fractions caused significative inhibition in the
      writhing test in mice at 10 mg/kg, given intraperitoneally. They were more active
      than two reference drugs, aspirin and paracetamol. The fractions also exhibited
      antinociceptive activity in the writhing test when administered orally at 200
      mg/kg. When analyzed in the formalin test, the chloroform fraction was the most
      active, causing considerable inhibition against both neurogenic and inflammatory
      phases of pain.

PMID- 12422536
TI  - [Clinical and histological features of cutaneous drug reactions].
AB  - Over the last 20 years, our understanding of cutaneous adverse drug reactions has
      improved, especially with regard to the management of affected patients. The
      pathophysiological mechanisms have been studied to improve our understanding. We
      report different clinical and histological features of cutaneous drug reactions
      to distinguish a non drug-induced rash from a cutaneous adverse drug reaction.

PMID- 12422537
TI  - [Current issues in photodermatitis].

PMID- 12422538
TI  - [The use of skin testing in the investigation of toxidermia: from pathophysiology
      to the results of skin testing].
AB  - Drug skin tests can be of value in investigating cutaneous adverse drug reactions
      (CADR). Guidelines have been recently published for drug skin tests to
      standardize the management of patients suffering from CADR in European
      dermatological departments. Three sorts of drug skin tests can be performed, each
      investigating specific immunological mechanisms: delayed cellular
      hypersensitivity with patch tests (PT), immediate hypersensitivity with prick
      tests and both immediate or delayed hypersensitivity with intradermal tests
      (IDT). The mechanisms involved in inducing CADR are not well elucidated. The
      results of the drug skin tests depend on the drug and the mechanisms i.e. the
      clinical features of the CADR. 164 patients developed a CADR that could be
      attributed to one drug. After a patch test and a negative prick and intradermal
      test, positive drug skin tests were nevertheless obtained in 72% of the cases.
      Some urticarias are due to an immediate IgE related hypersensitivity; in such
      cases prick tests and IDT performed with sequential dilutions can have immediate
      positive results. Vasculitis is related to circulating immune complexes and
      cannot be reproduced by skin tests. Delayed cellular hypersensitivity is involved
      in inducing maculopapular rashes, Baboon syndrome, localized or generalized
      eczema or acute generalized exanthematous pustulosis. In such CADR, drug PT or
      delayed positive reactions on IDT occur in more than 50% of the patients. Diluted
      drug patch tests can be positive in investigating drug rash with eosinophilia and
      systemic symptoms. As Stevens-Johnson and Lyell's syndromes are due to many both
      toxic and immunological mechanisms, drug skin tests are not of great value in
      investigating these severe CADR.

PMID- 12422539
TI  - [REVIDAL-GERDA: organization and collaboration with pharmacovigilance].

PMID- 12422540
TI  - [Cutaneous side-effects in drug assessment].
AB  - Drug-induced cutaneous side-effects are very frequent. All dermatitis may be
      induced by drugs. It is difficult to identify the drug responsible because
      patients take many drugs (prescriptions, self medication). For each pathology,
      physicians may use assessment methods based on specific chronological criteria
      (challenge, dechallenge, rechallenge) and specific semeiological criteria
      (promoting factors, alternate non-drug related explications, specific laboratory
      tests) to identify the drug responsible.

PMID- 12422541
TI  - [Retrospective of national pharmacovigilance surveys on drug-induced bullous,
      vesicular eruptions: methods and results ].
AB  - The academic interest for pharmacovigilance appears to be very low, because of
      the judged weakness of a "significant" relationship between drug utilisation and
      pathological events. We have tried to collect the relevant surveys of the French
      pharmacovigilance network on cutaneous toxic reactions to show the use of this
      work for current medical knowledge. This study was limited to the most relevant
      reports: 1--Cutaneous disorders induced by local reactions to ketoprofen,
      bufexamac, paracetamol (i.v.) 2--Cutaneous disorders observed in systemic
      hypersensitivity syndromes: allopurinol, chlormezanone, pristinamycine 3-
      Photosensitisation (toxicity), including: Individual characteristics of patients
      Nature of the observed syndromes Induction time and evolution of the disease
      Imputation and apparent incidence of the cases observed RESULTS: 1--Concerning
      "contact" dermitis, erythematous skin reactions are the most frequently observed.
      The causality link is proved in 272 patients of the cases. The mean age of the
      patients is 40-50 and the induction time from one to ten days. 2--In the
      hypersensitisation syndromes, severe skin reactions, combined with general
      reactions (fever), are the most frequently observed. The mean age is 50-60 and
      the number of serious cases is high (4.5%). 3--Severe burns with bullous skin
      reactions are observed in phototoxicity cases. The mean age of the patients is
      50. Time induction is short (ten days), the cases are frequently serious, but
      evolution appears good. In conclusion, the synthesis of pharmacovigilance surveys
      shows the value of this epidemiological approach to drug-induced skin reactions.
      It is regrettable that the results of this work are not more widely distributed.

PMID- 12422542
TI  - [Cosmetovigilance: a French pharmacovigilance system for cosmetics developed by
      the French health products safety agency. A proposal for the future].
AB  - Since 1999, the French health products safety agency (Afssaps) has been
      responsible for the safety of cosmetic products. Attempts are underway to set up
      a French post-marketing surveillance system for cosmetics and a working group
      specially in charge of setting this up has been created. The "cosmetovigilance"
      system has the three following objectives: public health concerns about "at risk"
      ingredients in cosmetic products: animal derivatives, glycol ethers, aluminium,
      camphor, etc; notification of adverse reactions: creation of standard reporting
      forms of adverse reactions; follow-up of laboratory quality controls: emergency
      and routine controls. The "cosmetovigilance" system is not only restricted to the
      study of adverse reactions occurring with cosmetic products. It will also address
      public health issues about ingredients and will rely on laboratory controls. The
      aim of the "cosmetovigilance" system is to investigate but also to prevent the
      risk of adverse reactions.

PMID- 12422543
TI  - [Misuse of drugs: conclusions of the pharmacovigilance workshops at La Baule,
      France].
AB  - Drug iatrogeny is a current Public Health issue; it is often related to misuse
      and is therefore preventable. The congress "Les Ateliers de Pharmacovigilance de
      La Baule" (May 2001) bringing together pharmacovigilance staff from both the
      industry and Health authorities, showed that misuse concerns every step of the
      drug process--prescription, dispensing and administration--and all health
      professionals as well as the patient. New concepts have been brought to light
      with regard to the definition of misuse: the medical point of view should be
      preferred, based on the risk taken by a given patient without the expected
      benefit. product characteristics alone are inadequate and should be enlarged by
      relevent scientific data. the main goal is to improve the quality of healthcare
      by preventing misuse. A working group including Pharmacovigilance staff from the
      industry, the CRPV and the Afssaps has: to reach a consensus on definition in
      France and then propose it to EMEA; to analyse and propose specific prevention
      actions; to write a vademecum of those involved in this prevention.

PMID- 12422544
TI  - [Characteristics of hypersensitivity syndrome to lamotrigine: review of one case
      reported in the Regional Center of Pharmacovigilance of Nantes].
AB  - Drug-induced hypersensitivity syndrome is an uncommon but potentially life
      threatening idiosyncratic drug reaction. In the literature, about five cases have
      been reported concerning hypersensitivity syndrome with lamotrigine. Most cases
      concern aromatic anticonvulsants but we report a case induced by lamotrigine
      which is a non aromatic anticonvulsant. A 73-year-old man was treated with
      lamotrigine for epilepsy due to a cerebrovascular stroke for 5 weeks. After 2
      weeks with a single oral dose of 50 mg lamotrigine, the patient received 100 mg.
      Quickly thereafter fever, erythema and edema involving the periorbital area
      appeared. He was then admitted to hospital and lamotrigine was immediately
      discontinued. He developed acute hepatic and renal failure. During his hospital
      stay, he was treated with systemic and topical corticosteroids. After slow
      improvement, he was discharged 4 weeks later. Concerning this typical case, we
      review the characteristics of hypersensitivity syndrome and the different
      etiopathogenesis. The hypersensitivity syndrome typically develops two to six
      weeks after a drug is first administered, later than most other serious skin
      reactions. This syndrome manifests as rash, fever, tender lymphadenopathy,
      hepatitis and eosinophilia. The mechanism of hypersensitivity syndrome is
      unknown. Several theories have been proposed. The reaction is secondary to
      circulating antibodies or concerns toxic metabolities. On the other hand,
      association of human herpes virus 6 infection may play a role in the development
      of hypersensitivity syndrome. Hypersensitivity reactions to the aromatic
      antiepileptic drugs appear to have an immune etiology much like lamotrigine:
      bioactivation, detoxification, covalent adduct formation, processing and
      presentation of antigen to the immune system, and consequent formation of
      antibody and T-cell immune effectors. Another theory involves toxic metabolites;
      the aromatic antiepileptic agents are metabolised by cytochrome P-450 to an arene
      oxide metabolite. This is normally detoxified by epoxide hydrolase. This enzyme
      may be lacking or mutated in persons that develop the syndrome, and this is
      genetically determined. Lamotrigine is mainly metabolised by hepatic
      glucuronidation, but hypersensitivity may involve similar processes such aromatic
      antiepileptic drugs, except that the toxic metabolite has not yet been found.
      Because of slow evolution and clinical similarity to many infectious illnesses,
      the diagnosis of hypersensitivity syndrome may be delayed. Prompt recognition and
      withdrawal of the suspected drug is essential. The goal of research is to
      describe a "susceptibility profile" identifying individuals at risk for these
      forms of drug toxicity.

PMID- 12422545
TI  - [Intracranial hemorrhages associated with oral anticoagulant therapy. Analysis of
      38 cases].
AB  - The major risk of oral anticoagulant therapy is haemorrhage potentially affecting
      all organs. Bleeding in the central nervous system is a rare but severe
      complication of anticoagulant therapy. This study aimed to analyse a series of
      intracranial haemorrhages. This series from the Regional Pharmacovigilance Center
      of Amiens included spontaneously reported and retrospectively collected cases
      from January 1999 to December 2000. During this period, 38 cases of intracranial
      bleeding possibly related to oral anticoagulant administration were reported; 19
      women and 19 men, median age 69.5 (29 to 87) years. In 34% of the cases, patients
      died and in 18% neurologic sequelae were still present at the time of the
      evaluation. In 21 cases (62%), the INR (International Normalized Ratio) was
      higher than the therapeutic range recommended for the indication. Among the most
      frequent risk factors, hypertension and recent minor trauma are highlighted in
      this series. In 17 cases, oral anticoagulants were associated with potentially
      potentiating drugs. Mental status changes or headache were prominent early
      symptoms which had often been present for days. Our data confirm that
      anticoagulant-associated intracranial haemorrhages are not rare, can be severe,
      potentially fatal and are probably underestimated by physicians. The fact that
      more than 50% of patients in this series were overanticoagulated at the time of
      bleeding suggests that many cases of intracranial haemorrhage could be prevented
      by improved anticoagulation control. Epidemiological studies are needed in order
      to prospectively evaluate the incidence of this type of complication and its
      avoidance. The value of anticoagulation clinics can be discussed.

PMID- 12422546
TI  - [Cardiotoxicity of 5-fluorouracil: report of 6 cases].
AB  - 5-fluorouracil (5-FU), a fluoropyrimidine antimetabolite, is widely used in the
      treatment of cancers of the digestive tract and breast. The clinical
      cardiotoxicity of 5-FU was first reported in 1975. Adverse cardiac effects
      include coronary disorders, heart failure and sudden death of suspected cardiac
      origin. Six new cases are reported, including 5 cases of angina and one of heart
      failure. The patients, 4 males and 2 females, were 26 to 71 years of age (mean:
      56.2). They had no medical history of heart failure, myocardial ischemia or
      electrocardiographic anomalies prior to 5-FU treatment. Three patients had
      hypertension of whom one had had type-II diabetes mellitus for the past 20 years.
      Clinical symptoms included chest pain in 4 patients and heart failure in one,
      whereas the last patient had ECG changes with no associated clinical symptoms.
      Clinical symptoms of angina totally disappeared after the cessation of 5-FU
      administration, but heart failure was alleviated only after the introduction of
      digitalis, a converting-enzyme inhibitor and a diuretic. It has been estimated
      that 1.6% of patients treated with 5-FU develop adverse cardiac effects. Patients
      at greater risk are those with a history of ischemic cardiac disease, thoracic
      radiotherapy or high-dose 5-FU therapy. The mechanism involved is not clearly
      elucidated. Spasms of the coronary arteries or toxic inflammation of the
      myocardium have been suspected. These 6 new cases confirm the potential for
      cardiotoxicity of 5-FU and the need for careful cardiac monitoring of treated
      patients.

PMID- 12422547
TI  - [Topic silver sulfadiazine bicytopenia: first case].

PMID- 12422548
TI  - [Possible serotonergic syndrome caused by combination of tramadol and sertraline
      in an elderly woman].

PMID- 12422549
TI  - [Myocardial infarct with protease inhibitors: a case report].

PMID- 12422550
TI  - [Anaphylactoid reactions to normal immunoglobulins].

PMID- 12422551
TI  - [Drug packaging and context of use as a cause of intoxication].

PMID- 12422552
TI  - [Methodology and long-term follow-up of drug induced side effects in children
      (cancer, leukemia, AIDS, growth hormone)].
AB  - Long-term follow up for medicines used in children is necessary in some
      therapeutic areas. Long-term effects (e.g. in cancer) may be detected many years
      after the treatment period. Growth, development and maturation specific to
      children can make these effects particularly harmful. The development plan of a
      paediatric drug should include, long term follow up on the basis of
      pharmacological-toxicological and safety data. These aspects should be taken into
      account when modifying the protocol (lower dosage, withdrawal of some
      associations etc). The follow up period may be very long, as in cancer (e.g.
      second tumour after treatment for cancer). A cohort is the best choice for this
      follow up, but other alternatives may be useful, including a specific follow-up
      Unit. Long-term follow-up is nevertheless difficult and expensive, manpower
      dependent and the risk of failure is great especially in the teenage years.

PMID- 12422553
TI  - [Identification, during development, of a methodology targeted at determining the
      positioning of new drugs for therapeutic strategies: examples of rheumatoid
      arthritis and cardiac insufficiency].
AB  - The Marketing Authorization (MA) granted to a new molecular entity does not allow
      for proper anticipation of its future positioning within the therapeutic
      strategy. A specific methodology should be devised as early as during the pre-MA
      development phase that could result in an initial positioning that should be
      subjected to further reappraisal with regard to scientific advances, the arrival
      of new treatments and further developments with this molecule. A methodology is
      thus proposed, based on early optimisation of the development plan, the granting
      of subsequent MAs, and reappraisal of the positioning within the strategy, based
      on analysis of all available data. It should be possible to take into account the
      economic context, within an agreed system with pre-defined medico-economic
      criteria. This may in turn raise the issue of the role of the various parties
      involved in this assessment, as well as how to understand the respective opinions
      of stakeholders: authorities, sponsors, prescribers and patients, each of whom
      has a specific view of the definition of the strategic objective that should
      apply to the disease concerned.

PMID- 12422554
TI  - [Good clinical practice in clinical trials: training clinicians,incentives to
      apply good clinical practice and assessment of compliance].
AB  - Fourteen years after the concept was created, it seemed important to assess how
      well investigators actually apply Good Clinical Practice. Various sources of
      information have revealed a general deficiency in their application:
      "investigation by the working group, Afssaps (French Agency for the Safety of
      Health-Care Products) inspections, industrial data". The deficiencies identified
      stem from different factors: lack of professionalization, lack of training, lack
      of motivation, the large numbers of poorly conducted studies. The working group
      drew up proposals intended to improve the training of investigators, to dissuade
      investigators from pursuing inadequate procedure and to verify the level of
      compliance. However in this respect, the investigator is not the only one at
      fault. Improved practice unavoidably requires better assistance on the part of
      the sponsors, more consistent supervision of monitoring, and greater vigilence by
      the authorities involved in the control and use of trials.

PMID- 12422555
TI  - [Role of pharmacokinetic-pharmacodynamic relationships in drug development].
AB  - An important part of drug development relies on the analysis of the relationships
      between drug doses and therapeutic and/or side effects. This analysis implies an
      in-depth understanding of the pharmacokinetics (PK) and pharmacodynamics (PD) of
      the drug and of the relationship which links them (PK-PD relationship). The aim
      of this round table was to define the place of the study of PK-PD relationships
      in drug development. After reviewing the definitions of PK models, PD models, and
      of integrated PK-PD models, the article highlights the importance of studying the
      PK-PD relationship during the successive phases of drug development (pre
      clinical, phase I/II, phase III) and in specific populations (children, elderly
      people). A number of examples taken from pharmaceutical development or
      international literature are given. They show the methodology used and the type
      of information which can be drawn at each step of drug development. The article
      also presents the difficulties which prevent a more systematic application of
      this kind of approach during drug development. Scientific limits, problems in
      relation with the misunderstanding of the approach both in academic institutions
      and in pharmaceutical companies, and difficulties related to the lack of specific
      guidelines are discussed. The conclusion emphasizes the importance of using PK-PD
      modeling all along drug development and presents a number of actions which could
      further broaden its use.

PMID- 12422556
TI  - [Clinical trials in oncology: specific methodology problems].
AB  - Clinical benefit in oncology patients can only be derived from coordinated and
      successive experimental trials. The following consensus thus emerged from the
      working party: The assessment of tolerance during clinical trials requires the
      actuarial rate of acute adverse events (AE) to be registered and the development
      of epidemiological structures involved in long-term assessment of AE.
      Experimental trials have to be assessed according to descriptive epidemiological
      data (generated in France and Europe) and completed with observational studies on
      post-marketing medical practice. The principle of an a priori authorization given
      by the Afssaps for gene and cell therapy trials was legalised in October 2001.
      The working group spoke strongly in favour of authorizing early trials only
      validating the process, and for reasonable objectives in terms of viral security
      assessment of annex therapeutic products. With regard to the development of new
      antiproliferative agents, the active dose (or optimal biological dose) replaces
      the maximal tolerable dose. Early efficacy criteria could be biological and
      specific. With cumulative subacute rather than acute toxicity, these agents can
      not be properly evaluated with a short term benefit/risk ratio as is done for
      cytotoxic drugs. Elderly people constitute a fragile, heterogeneous and
      increasing population, in whom adequate assessment of anticancer agents is
      mandatory. It is important to promote controlled clinical trials in children and
      to systematically monitor them over a very long period of time. Only rare tumours
      may be considered as orphan situations. Finally, a list of all clinical trials
      conducted in oncology should be made by the Afssaps, with the help of the FNLCC
      (Federation Nationale des Centres de Lutte Contre le Cancer) who have already
      begun this work.

PMID- 12422557
TI  - [Compliance, efficacy and quality of life].
AB  - Compliance is the appropriateness of patient behaviour to therapeutic
      prescriptions. Good compliance increases treatment efficacy although its
      constraints may harm quality of life. Factors affecting compliance are related to
      the patient, the disease, health-care workers, family and treatment itself.
      Psycho-sociologic theories have attempted to explain patient behaviour. In
      clinical trials, compliance has to be optimized, i.e. in the protocol, during the
      study and the statistical analysis. In real life, compliance concerns all those
      involved in health-care, particularly for education, training and motivation of
      the patients and their immediate environment. Observational surveys relating to
      compliance are needed to determine prioriites and to develop a "compliance
      approach" based on improving information and the use of tools for better
      therapeutic adherence. Evaluation of the quality of life and patient satisfaction
      aspects is necessary to validate this approach.

PMID- 12422558
TI  - [Drug distribution systems in hospitals].
AB  - Any drug generally made and marketed by drug companies must respect the quality
      standards conferred by New Drug Approval regarding both safety and efficacy. Once
      prescribed by a doctor, inside a hospital, the drug, or more precisely the
      decision of its prescription will follow a complex circuit, involving numerous
      intermediates (human and technical) leading to drug dispensation and follow-up.
      Regulatory guidelines and rules harmonise and standardise this drug pathway in
      hospitals. Any weakness in this distribution system will be the source of
      nosocomial drug iatrogeny. The present review aims at describing the different
      steps and stages from the prescription to an individual patient to drug
      administration and follow-up. The evaluation of this system will be mentioned in
      the perspective of optimisation. The computerised system is essential allowing
      tracking of a drug, and providing help for decision-making (by confrontation with
      data bases) and a research tool (i.e, pharmacoepidemiology). Different
      experiences of assessment of the performance of such a drug distribution system
      inside hospitals will be presented, trying to check the quality reference: the
      right drug, the right patient, the right moment, in good conditions. The
      challenge is to optimise and secure all steps of the process. This goal needs
      assessment and quality control of the different phases, opening the discussion
      between hospital policy and regulatory and technical considerations.

PMID- 12422559
TI  - [Mechanism of action of antidepressants and therapeutic perspectives].
AB  - Depression is an incapacitating disease which needs appropriate treatment. This
      article reviews the pharmacology of antidepressant drugs and the future
      perspectives of treating mood disorders such as depression. The foremost theory
      for explaining the biological basis of depression has been the monoamine
      hypothesis. Depression is due to a deficiency in one or other biogenic monoamines
      (serotonin, 5-HT; noradrenaline, NA; dopamine, DA). Antidepressant drugs are
      therefore classified according to their ability to improve monoaminergic
      transmission. Since this first theory, other explanations based on abnormal
      function of monoamine receptors or associated with impaired signalling pathways
      have been suggested. Notable progress has been accomplished in the treatment of
      major depressive disorders with new compounds recently discovered (selective
      serotonin reuptake inhibitors: SSRI; serotonin noradrenaline reuptake inhibitors:
      SNRI). Behavioural, electrophysiological and microdialysis studies have shown
      that serotonin (5-HT) receptors, mainly 5-HT1A, 5-HT1B and 5-HT2C sub-types,
      exert a key role in modulating antidepressant activity. Indirect activation of
      neurotransmitter receptors by antidepressants may also lead, via increases in
      endogenous levels of serotonin in synapses in specific brain regions, to
      activation of various G proteins coupled to a receptor, signal of transduction,
      transcription factors and neurotrophic factors such as brain-derived neurotrophic
      factor (BDNF). Thus, depression may be considered as a transduction mechanism
      anomaly. This hypothesis needs to be clarified by molecular biology. Although
      antidepressants have improved the therapeutic potential compared to tricyclics
      (TCA) in terms of reduced side effects, a number of problems still occur with
      these drugs. Clinical effects are not always observed until after this time has
      elapsed (4-6 weeks) and a substantial proportion of depressed patients show only
      partial or no response to antidepressants. Knowledge of the existence of links
      between neurotransmitter systems and the discovery of the most specific target, 5
      HT receptors, should lead to improvements in antidepressant therapy. Developing
      drugs using innovative mechanisms such as directly acting on 5-HT receptors (5
      HT1A agonists or 5-HT2 antagonists), would appear to be useful in the treatment
      of depression. The use of antidepressants in anxiety disorders such as
      obsessional compulsive disorders and even generalised anxiety, highlights the
      distinction between antidepressants and classic anxiolytics such as
      benzodiazepines, or even buspirone.

PMID- 12422560
TI  - [New antiepileptic drugs in pregnancy: outcome of 12 exposed pregnancies].
AB  - There is currently little evidence available concerning the risks of foetal
      exposure to new anti-epileptic drugs such as lamotrigine, vigabatrin,
      gabapentine, topiramate. A small number of malformations without organ
      specificity have been described and are not easy to interpret because of the
      existence of concomitant treatments. We have reported a series of 12 pregnancies
      with exposure to recent anti-epilepticdrugs and that were reported to the Post
      marketing Surveillance office in Tours, France. Five concerned Lamictal of which
      2 related to monotherapy, one concerned Epitomax used in monotherapy and there
      were 6 cases of polytherapy including Sabril. Associated drug therapies were
      Depakine, Tegretol, Rivotril and Urbanyl. Six of the patients were on folic acid
      supplements. The average age of the women was 26.5 years. In each case, treatment
      had been initiated before conception and was continued for at least 3 months. Of
      the 12 babies born, only one presented with a malformation (aplasia of the muscle
      of the left lower lip and asymmetrical abduction of the hips) following exposure
      to Lamictal and Depakine. Four infants, two of whom were premature, showed signs
      of neonatal stress: transient respiratory distress and difficulty in taking
      feeding-bottles following exposure throughout the pregnancy to Epitomax; suction
      disorders, hypotonia and vomiting were observed after exposure to Sabril,
      Tegretol and Rivotril throughout the pregnancy; respiratory distress and apnoea-
      bradycardia were observed after exposure throughout the pregnancy to Lamictal and
      Urbanyl; respiratory distress and thrombocytopaenia were observed after exposure
      throughout the pregnancy to Lamictal". This small series confirms that the
      current data concerning the teratogenicity of new anti-epileptic drugs are as yet
      insufficient to exclude any teratogenic risk. Consequently, strict adherence to
      current recommendations relating to drug use during pregnancy is essential. The
      treatment of all patients wishing to become pregnant should be discussed.

PMID- 12422561
TI  - [Assessment of drug-related risk using expected/observed methods (standardized
      rate method): definition and application to pharmacovigilance].
AB  - Indirect standardisation or the standardised rate method, consists of a
      comparison of the number of observed and expected cases. This method could be
      applied in the field of pharmacovigilance in order to investigate the potential
      relationship between drug exposure and the occurrence of an adverse event. It
      consists of the calculation of an expected number of events obtained by
      multiplying the exposed population by the event rate in the reference population.
      The comparison is made by means of a standardised mortality or incidence ratio
      (SMR or SIR). Three examples of this method are presented. The first example
      concerns central nervous system demyelinating disorders and hepatitis B vaccine,
      where the SIR calculated from spontaneous reports was equal to 1.05 (95% CI [0.82
      1.26]). In the second example, the SMR of cardiovascular deaths related to
      sildenafil was significantly different from 1 (0.69, [0.43-1.08]) using data from
      prescription-event monitoring. In the last example, a strong association between
      acute leukaemia and chemotherapy in breast cancer was found (SIR 28.5, [12.3
      56.2]) using exhaustive data from cancer registries. This method allows a quick
      and cheap risk assessment, although the quality of available data may limit
      validity of results. In this case, the hypothesis need to be examined by further
      ad-hoc clinical and pharmacoepidemiological studies.

PMID- 12422562
TI  - [Juvenile Still's disease: a case report of treatment with infliximab].

PMID- 12422563
TI  - Interaction between lansoprazole and bromocriptine in a patient with Parkinson's
      disease.

PMID- 12422564
TI  - [Reversible parkinsonism induced by prolonged treatment with valproate].

PMID- 12422565
TI  - [Tobacco and the global epidemic of lung cancer].

PMID- 12422566
TI  - [Pathophysiology and clinical aspects of brain edema].
AB  - Brain oedema is defined as an abnormal accumulation of fluid in the brain tissue
      accompanied by an increased volume of the brain. It results in the intracranial
      hypertension directly endangering the patient's life. No causal treatment of the
      brain oedema is known at present. The brain oedema is not a disease, but it is a
      symptom of various clinical states. That is why experimental studies of its
      pathophysiology become the centre of attention. Though the classification of
      brain oedema according to the pathogenesis is still used (the vasogenic type-
      resulting from the increased permeability of blood-brain barrier; the cytotoxic
      type--caused by the cell metabolism impairment), recent papers has shown a
      definite retraction from such categorisation. It has been shown that neither type
      of brain oedema comes alone, but both can occur simultaneously during the
      development of the pathological state of the brain. The most important appears to
      be the primary insult. It affects the state of blood-brain barrier and brings
      about the vasogenic extracellular oedema or it can influence the cell metabolism
      with subsequent cytotoxic, cellular oedema. Categorisation of oedema into
      extracellular and cellular reflects more precisely the impairment of the
      homeostasis of the internal environment of the brain. Contemporary view on the
      classification and pathophysiological mechanisms of the brain oedema is discussed
      in our review.

PMID- 12422567
TI  - [Helicobacter pylori and diabetes mellitus].
AB  - BACKGROUND: Helicobacter (H.) pylori participates significantly on the pathogeny
      of chronic gastritis, duodenal a gastric ulcer, carcinoma and lymphoma of the
      stomach. Attention was attracted also by some extragastric diseases, including
      diabetes mellitus, where the elevated antibodies levels against H. pylori was
      found. The aim of the work was to determine the seroprevalence in relation to the
      sex and type of disease in a cohort of diabetics and in a control group of blood
      donors. METHODS AND RESULTS: In 195 diabetic patients (type I and II) and 216
      blood donors levels of IgG antibodies were determined by ELISA method.
      Seroprevalence in the group of diabetic patients was 27%, in males 26% and in
      women 28% (n.s.). No differences related to sex or diabetes type were found.
      Significant differences in seroprevalence were found among the group of diabetic
      patients and blood donors (27% vs. 51%, p < 0.001), male diabetics of both types
      and blood donors (26% vs. 62%, p < 0.001). No differences were found between
      female diabetic patients and controls (28%, 27% vs. 40%, n.s.). CONCLUSIONS: Our
      study has shown a lower seroprevalence of H. pylori in diabetic patients of type
      I and II in comparison with the healthy population. Such finding differs from the
      generally accepted experience of the higher sensitivity of these patients to
      infection. The practical significance of the observation remains unsolved.

PMID- 12422568
TI  - [Adjuvant therapy of renal carcinoma].
AB  - A treatment approach in a group of 1498 patients with renal cell carcinoma (RCC)
      was studied. Out of these, 86 patients had the primarily generalised form. For
      the therapy of primary advanced metastasis, the treatment strategy was changed
      from conservative to an active approach. Such approach is based on the removal of
      75% of the tumor mass, the patient should be in good conditions with no
      metastases in CNS, bone and liver, and the primary tumor should not be a sarcoma.
      The new treatment strategy of patients with advanced RCC combines surgery and
      chemoimmunotherapy. 47 patients from the studied group were treated with combined
      INF alpha + IL-2 + 5FU + isotretinoin using the Atzpodien scheme. The toxicity
      was minimal and only in six patients the treatment was interrupted because of the
      disease progression. Results of this treatment strategy are encouraging, however,
      further randomised trials are recommended.

PMID- 12422569
TI  - [Hemophagocytic lymphohistiocytosis as a manifestation of visceral
      leishmaniasis].
AB  - A 7-year-old previously healthy Czech boy was admitted due to fever,
      hepatosplenomegaly and pancytopenia. Aspiration of bone marrow revealed no signs
      of hemoblastosis (nor hemophagocytosis). He was treated with antibiotics and
      virostatics without effect. Progression of hepatosplenomegaly and pancytopenia
      induced suspicion of hemophagocytic lymphohistiocytosis (HLH). Five weeks later,
      bone marrow hemophagocytosis of erythrocytes, nuclear elements and platelets was
      detected. He was given corticoids and intravenous immunoglobulins and transferred
      to our haematology department. Laboratory findings of mild pancytopenia,
      hypofibrinogenaemia, hyperlipidaemia and elevated levels of ferritin, LDH and
      immunoglobulins were compatible to the diagnosis of HLH. Immunologic evaluation
      revealed T-lymphocyte activation. Appropriate immunosuppressive treatment with
      Dexamethasone, etoposide and Cyclosporine A was launched, followed by transient
      subside of fever and improvement of peripheral blood count, but not regression of
      hepatosplenomegaly. Four weeks later, relapse of fever and deterioration of blood
      count led to intensification of immunosuppression. However, no effect was
      evident. Moreover, hypertrophic cardiomyopathy with ventricular arrhythmia
      occurred. Treatment with antilymphocytic globulin for resistant course of HLH was
      planned. Before that, a fifth bone marrow aspiration was performed. Surprisingly,
      many Leishmania amastigotes were observed within marrow macrophages. Leishmania
      infection was confirmed by positive serology. Immunosuppressive treatment was
      withdrawn and changed for causal treatment with liposomal Amphotericin B.
      Positive clinical effect with subside of fever was evident in ten days,
      splenomegaly gradually resolved during three weeks, restoration of normal blood
      count lasted six weeks. No relapses of HLH nor leishmaniasis occurred. In control
      bone marrow aspirate performed three months later, the parasites were not
      detected. Ten months after the event, the patient is in complete remission of HLH
      with normal immunologic parameters. Most probably, he contracted visceral
      leishmaniasis during a visit of a Neapol area in Italy 3 months before the onset
      of the disease.

PMID- 12422570
TI  - Stuck in the middle. The highly anticipated drug-eluting stents are good for
      heart patients, but are they bad for hospital balance sheets?
AB  - The Food and Drug Administration stands ready to OK a highly anticipated drug
      eluting stent as early as this week, but revenue at hospitals may fall as a
      result of declining volumes in cardiovascular surgeries, a lucrative service. The
      problem comes "because hospitals are stuck in the middle," says Jeffery Morneault
      (left), an executive at Health Alliance of Greater Cincinnati.

PMID- 12422571
TI  - With legal woes in past, HCA looks to grow.

PMID- 12422572
TI  - Self-sold. Tenn.-based system to be acquired by SunLink.

PMID- 12422573
TI  - Golden years, yellowed policies. Realities of aging societies worldwide should
      push U.S. toward insurance options.

PMID- 12422574
TI  - Strong at heart. High volumes and high technology aren't always key to the
      success stories of the facilities on Solucient's annual list of the nation's 100
      top cardiovascular hospitals.

PMID- 12422575
TI  - Off-pump cases take a beating.

PMID- 12422576
TI  - History of the discovery of cyclosporin and of its early pharmacological
      development.

PMID- 12422577
TI  - Survival of women with breast cancer in Austria by age, stage and period of
      diagnosis.
AB  - PURPOSE: To investigate survival of breast cancer patients by 1) age, 2) tumor
      stage and 3) period of diagnosis, also to determine the contribution of
      improvements in treatment and opportunistic mammography screening in Austria.
      METHODS: Survival was calculated overall and by 1) age groups (in years) < 50, 50
      64, > 65; 2) stage I, II, IV, unknown 3) for 17,025 patients diagnosed 1988-92,
      compared with 19,284 patients diagnosed 1993-97. Odds ratios for being diagnosed
      as stage I in the period 1993-97 compared to 1988-92 were calculated by age group
      and for all ages. RESULTS: In the later period (1993-97) age-adjusted mortality
      rate decreased overall by 3.3% (age: < 50; 8.2%, 50-64; 5.1%, > 65; 1.6%).
      Overall, stage I cases increased from 46.5% to 51%. Five year relative survival
      rates improved significantly overall, 6.7% (p < 0.001), and within age groups
      (age: < 50; 4.5% (p < 0.05), 50-64; 7.2% (p < 0.05) and > 65; 7.3% (p < 0.001).
      This improvement is confined to patients with stage I tumors in age groups 50-64
      (4.1%, p < 0.05) and > 65 (7.2%, p < 0.001) and to patients with stage II in age
      groups < 50 (7.7%, p < 0.01) and 50-64 (8.3%, p < 0.01). For patients younger
      than 50, in stage IV, diagnosed 1993-97, survival was significantly poorer (
      16.9%, p < 0.05) compared to 1988-92. The odds ratio of being diagnosed as stage
      I in the later period was 1.19 (95% CI: 1.14, 1.24) for all ages, 1.13 (95% CI:
      1.03, 1.24) and for women < 50, 1.3 (95% CI: 1.20, 1.40) 50-64 and 1.15 (95% CI:
      1.09, 1.22) > 65 years old. CONCLUSION: We conclude that treatment improvements,
      which are accessible to all patients countrywide due to the compulsory state
      insurance system, had a major impact on positive trends in mortality and
      survival. Opportunistic screening should have contributed to some extent
      beginning in the early nineties.

PMID- 12422578
TI  - Blood pressure and heart rate during an episode of unstable angina as predictors
      of in-hospital outcome.
AB  - PURPOSE: Risk stratification in patients with unstable angina remains a
      challenging task. Troponins, electrocardiographic changes and clinical
      characteristics are the most widely employed parameters. Blood pressure and heart
      rate are proven predictors of short-term outcome; no study, however, has
      investigated the dynamics of these variables. We postulated that measurements of
      these parameters performed at the beginning of an ischemic episode would reflect
      the extent of coronary disease and would predict short-term outcome. METHODS:
      Analysis of variance and multivariate logistic regression were used to analyze
      the relationship of systolic blood pressure and heart rate during ischemic
      episodes with the occurrence of adverse ischemic events (death, infarction, need
      for revascularization) prior to hospital discharge. RESULTS: In a group of 193
      patients mortality rate was 4.2%, infarction rate 8.4% and revascularization rate
      42.4%. Systolic blood pressure increased during ischemic episodes compared to
      baseline values in the group of survivors (p < 0.0001), while there were no
      significant changes in the group of non-survivors. The rise in heart rate during
      ischemic episodes was greater in non-survivors, even though significant changes
      were observed in both groups. Systolic pressure and heart rate were independent
      predictors of mortality (p = 0.01 and p = 0.003, respectively), but were not
      predictive of infarction or revascularization. CONCLUSION: Low systolic blood
      pressure and high heart rate at the beginning of an ischemic episode predict
      higher in-hospital mortality in patients with unstable angina. Clinical
      presentation during the ischemic episode should be considered in risk
      stratification.

PMID- 12422580
TI  - Basal glucose level as an independent predictor of fertilization rate in patients
      without polycystic ovary syndrome included in an in-vitro fertilization program.
AB  - Insulin resistance is a common characteristic of women with polycystic ovary
      syndrome (PCOS) who are known to differ in their in-vitro fertilization outcomes
      compared to non-PCOS patients. As insulin resistance can be found in a
      considerable proportion of normal individuals, we assessed its contribution to
      ovarian responsiveness and fertilization rate. 26 non-PCOS patients undergoing
      IVF for the first time were investigated. Insulin resistance was evaluated by
      using a euglycemic hyperinsulinemic clamp technique. According to multiple
      regression analysis insulin sensitivity, expressed as insulin stimulated glucose
      disposal rate, during euglycemic clamp (r = -0.81, p < 0.05 and r = -0.89; p <
      0.01) and basal estradiol level (r = -0.54; p < 0.05 and r = -0.56; p < 0.05)
      appeared significant negative predictors of the number of fertilized oocytes and
      embryos, respectively. Furthermore, basal glucose level appeared independently as
      a significant positive predictor of the number of fertilized oocytes and the
      number of embryos. (r = 0.90; p < 0.01 and r = 0.96; p < 0.01 respectively). We
      conclude that blood glucose concentration and insulin resistance respectively are
      independent predictors of IVF outcome.

PMID- 12422579
TI  - The impact of primary antibiotic resistance on the efficacy of ranitidine bismuth
      citrate- vs. omeprazole-based one-week triple therapies in H. pylori eradication-
      a randomised controlled trial.
AB  - AIMS: To compare ranitidine bismuth citrate with omeprazole as to their efficacy
      to eradicate H. pylori in two different treatment schedules both consisting of a
      combination of either of above with two antibiotics for 1 week, and to relate
      these treatment results to primary antibiotic resistance. METHODS: 256 H. pylori
      positive patients with non-ulcer dyspepsia were randomised to one of the
      following four treatment groups: omeprazole 20 mg + clarithromycin 500 mg +
      amoxycillin 1000 mg (OCA); ranitidine bismuth citrate 400 mg + clarithromycin 500
      mg + amoxycillin 1000 mg (RBCCA); omeprazole 20 mg + clarithromycin 500 mg +
      metronidazole 500 mg (OCM); ranitidine bismuth citrate 400 mg + clarithromycin
      500 mg + metronidazole 500 mg (RBCCM). All drugs were given twice daily for one
      week. The patients were assessed for prevalence of H. pylori by CLO test,
      histology and culture on gastric biopsy samples obtained during upper
      gastrointestinal endoscopy before randomisation and 4-6 weeks after completion of
      therapy. Bacterial sensitivity to clarithromycin, metronidazole and amoxycillin
      was determined by E-test. RESULTS: On per-protocol analysis, overall eradication
      rates were 96% for RBCCA vs. 85% for OCA (p = 0.03), and 95% for RBCCM vs. 79%
      for OCM (p = 0.01). Amongst the 196 patients (77% of the entire study group) in
      whom antibiotic sensitivity testing was technically feasible, primary resistance
      was found in 8% for clarithromycin, in 33% for metronidazole, and in 0% for
      amoxycillin. Eradication of clarithromycin sensitive/resistant strains was
      89%/40% for OCA (p = 0.0042) and 98%/80% for RBCCA (p = 0.0428). When strains
      were sensitive to both antibiotics, cure rates with OCM/RBCCM were 87%/96%
      respectively (p = 0.39), for strains resistant to clarithromycin only,
      eradication was achieved in 82% with OCM vs. 94% with RBCCM (p = 0.2), and in the
      case of metronidazole resistance in 85% with OCM vs. 94% with RBCCM (p = 0.09).
      CONCLUSIONS: Ranitidine bismuth citrate in combination with clarithromycin and
      either metronidazole or amoxycillin produced higher eradication rates than
      omeprazole co-administered with the same antibiotics. This appeared especially
      prominent in the subgroups with clarithromycin resistance without, however,
      reaching statistical significance. Efficacy of neither eradication regimen was
      influenced by metronidazole sensitivity to a significant degree.

PMID- 12422581
TI  - Concentrations of estrogens in patients with preeclampsia.
AB  - The role of estrogens in the pathophysiology of preeclampsia remains to be
      determined. The aim of our study was to compare serum concentrations of 17 beta
      estradiol and estriol in women with preeclampsia to normotensive pregnant
      controls. Serum concentrations of estrogens were measured in women with mild (n =
      24) and severe (n = 24) preeclampsia as well as is normotensive pregnant controls
      (n = 24). Patients were matched for gestational age. Pregnancies complicated by
      early onset severe preeclampsia are associated with increased rates of maternal
      and fetal morbidity. Subsequently, we created further subgroups before and after
      34 weeks of gestation (34 + 0). Serum estrogen concentrations were determined by
      standard ELISA technique. Compared to normotensive controls, the differences
      between the overall median serum concentrations of 17 beta-estradiol in women
      with mild (3811 v. 3730 pg/ml, P = 0.9) and severe (3811 v. 3630 pg/ml, P = 0.1)
      preeclampsia were statistically not significant. The differences between the
      overall median serum concentrations of estroil in controls and in patients with
      mild (121 v. 76 ng/ml, P = 0.6) and severe (121 v. 79 ng/ml, P = 0.4)
      preeclampsia were similar. The differences between the median concentrations of
      17 beta-estradiol in patient with early onset severe preeclampsia compared to
      patients with mild preeclampsia (3061 v. 3715 pg/ml, P = 0.004) and controls
      (3061 v. 3807 pg/ml, P = 0.006) were statistically significant. In addition, the
      differences between the median concentrations of estriol in women with early
      onset severe preeclampsia compared to controls were statistically significant (20
      v. 92 ng/ml, P = 0.02). The differences between the median concentrations of
      estrogens in those with late onset severe preeclampsia compared to women with
      mild preeclampsia were not significant. We found significantly lower
      concentrations of estrogens in women with early onset severe preeclampsia.

PMID- 12422582
TI  - Management of 46, XY partial gonadal dysgenesis--revisited.
AB  - 46, XY partial gonadal dysgenesis is a rare condition characterized by a varying
      degree of testicular dysgenesis, ambiguous genitalia, and usually absence of
      regression of Mullerian structures. The management of patients with these
      disorders warrants revisiting, owing to recent molecular biological findings and
      to reports on the long-term outcome of individuals with ambiguous genitalia. We
      report on a patient with 46, XY chromosomes, presence of the "sex-determining
      region of Y chromosome" (SRY) gene, scrotal gonads, fallopain tubes, uterus,
      vagina, and ambiguous genitalia with a penisoid, perineal hypospadia and sinus
      urogenitalis. Gonadal biopsy revealed virtually normal testicular tissue in both
      gonads. Removal of the gonads during surgery for a cystic adnex tumor revealed
      clear signs of partial gonadal dysgenesis. The decision to raise the child as a
      male was made by parents and physicians caring for the patient. Administration of
      testosterone, removal of the uterus and adnexes, in addition to repair of the
      hypospadia permitted an almost normal penis to be formed with normal male
      micturition. In the management of affected patients it has to be considered that
      establishing the diagnosis may be extremely tricky, even with the use of gonadal
      biopsies. The decision on sex assignment may be even more difficult, since future
      gender identity, limitations of genital reconstructive surgery and the potential
      for development of gonadal tumors have to be taken into consideration. While in
      the past, female sex assignment was commonly recommended for such patients,
      raising them in a male gender role is now considered. Parents should be involved
      in the decision that is ultimately based on extensive analysis of the individual
      case.

PMID- 12422583
TI  - "Evidence based medicine"--how it relates to knowledge, wisdom and serendipity.

PMID- 12422584
TI  - Tick-transmitted diseases in central Europe.

PMID- 12422585
TI  - Biology of Ixodes species ticks in relation to tick-borne zoonoses.
AB  - At least six tick-borne zoonoses are transmitted by members of the Ixodes ricinus
      species complex in northern hemisphere temperate regions, and include the
      relatively recently emerged diseases, Lyme borreliosis and ehrlichiosis. An
      understanding of the biology of these ticks is essential for the prevention and
      control of the zoonoses they transmit and this review summarises established
      knowledge in addition to addressing recent work on host specificity of ticks,
      inter- and intra-specific biological variation and factors affecting tick
      distribution and abundance.

PMID- 12422586
TI  - Theobald Smith--the discoverer of ticks as vectors of disease.
AB  - The cause of Texas fever in cattle, which is characterised by lysis of
      erythrocytes leading to anaemia, icterus, haemoglobinuria, and death, remained
      unsolved for many decades and assorted theories were proposed as an explanation
      for a disease being transmitted by apparently healthy animals. From 1889 to 1893,
      Theobald Smith and Frederick L. Kilbourne could demonstrate in elegantly
      conducted experiments how the disease was spread from cattle to cattle by ticks
      serving as the vector of transmission. Furthermore, they were able to identify
      the pathogen of Texas fever, an intra-erythrocytic protozoan which Smith named
      Pyrosoma bigeminum. Today it is recognised that either of two species of the now
      renamed genus Babesia, Babesia bigemina and Babesia bovis, may be involved in
      Texas fever and that babesiosis is generally transmitted by ticks. In animals,
      genera like Boophilus spp., Dermacentor spp. and Rhipicephalus spp. are possible
      vectors. The first case of tick-transmitted babesiosis in a human was reported by
      Skrabalo and Deanovic in 1957 and occurred near Ljubliana in the small town of
      Strmec, Croatia. In humans, the vectors of most reported cases are ticks of the
      genus Ixodes, which are among the most predominant ticks in Austria. However,
      cases of human babesiosis in Austria remain to be studied. Smith and Kilbourne's
      work was the first demonstration that ticks transmit disease of any kind.
      Furthermore, by proving that ticks carry Babesia microti--which causes babesiosis
      in animals and humans--this is the first account of a zoonotic disease and the
      foundation of all later work on the animal host and the arthropod vector.

PMID- 12422587
TI  - Prevalence of coinfection with Francisella tularensis in reservoir animals of
      Borrelia burgdorferi sensu lato.
AB  - INTRODUCTION AND PURPOSE: Studies on Lyme borreliosis and other tick-borne
      zoonoses in the Austrian and Slovakian borderland, a region endemic for
      tularemia, revealed a relatively high prevalence of infection with Borrelia
      burgdorferi s.l. and Francisella tularensis in small terrestrial mammals, as well
      as in the ticks, during a one-year survey. The occurrence of coinfection with the
      agents of Lyme borreliosis and tularemia was assessed in different species of
      rodents. METHODS: Organs of small mammals, live-trapped mostly in six-week
      intervals from May 1994 to April 1995, were cultured on appropriate media in
      order to grow borreliae and F. tularensis. RESULTS: Infection with B. burgdorferi
      s.l. and also with F. tularensis was found in all the most abundant rodent
      species. A significant difference was observed in the time period of isolation of
      these agents. Borrelia was cultured from May to January (PCR detected borrelia up
      to April), while F. tularensis was isolated from August to December. Coinfection
      was seen in two species of voles, Clethrionomys glareolus trapped in August and
      Microtus arvalis in October. The Borrelia strains isolated from these animals
      were identified as B. garinii. Isolates of F. tularensis belonged to the
      subspecies holarctica, biovar II. CONCLUSIONS: Results obtained indicate that in
      endemic regions for tularemia the prevalence of infection with borreliae could be
      modified in different animal species mainly during epizootic outbreaks of
      tularemia.

PMID- 12422588
TI  - Comparison of self-assessment and scutal index for the duration of Ixodes ricinus
      tick attachment.
AB  - Experimental studies have shown that the efficacy of transmission of B.
      burgdorferi sensu lato from an infected tick to an experimental animal is
      significantly associated with the duration of tick attachment. Scutal index is
      the ratio between body length and scutum width and was found to be an objective
      indicator of the duration of Ixodes scapularis tick attachment, but no data for
      I. ricinus have been published. In this preliminary report on 30 volunteers with
      an attached I. ricinus tick (21 had an adult female tick and 9 a nymph), none
      developed any sign of Lyme borreliosis but we were able to demonstrate two
      asymptomatic seroconversions in a six-week follow-up period. Twenty-six (87%)
      volunteers claimed that they were able to determine the approximate duration of
      tick attachment; participants with attached adult female ticks estimated the
      duration of attachment to be 30 (2-90) hours, while those with attached nymphs
      reported 48 (18-90) hours (p = 0.681). Scutal indices were 3.2 (2-5) for nymphs
      and 3.2 (1-5) for adult ticks, indicating 60- and 48-hour attachment,
      respectively. According to the volunteers' assessment and scutal index findings,
      approximately 80% and 45% of adult female ticks were removed within 48 hours
      after the tick bite (p = 0.032), respectively, while the corresponding values for
      nymphs were 85% and 17% (p = 0.053). Our findings were limited by low numbers of
      volunteers and by the lack of experimental data on the value of the scutal index
      for estimation of the duration of I. ricinus tick attachment.

PMID- 12422589
TI  - Clinical and epidemiological findings for patients with erythema migrans.
      Comparison of cohorts from the years 1993 and 2000.
AB  - OBJECTIVES: i) To present clinical and epidemiological findings on adult patients
      diagnosed with typical erythema migrans (EM) at our institution during the year
      2000 and ii) To compare the findings with data obtained by the same approach for
      an identical group of patients from 1993, with the aim of testing the hypothesis
      that, because of increased knowledge of Lyme borreliosis in 2000 compared with
      1993, patients will visit us earlier and consequently present with smaller skin
      lesions. PATIENTS AND METHODS: Patients who qualified for inclusion in the study
      were adults diagnosed with typical EM in 2000 and 1993 at the Lyme borreliosis
      Outpatients' Clinic, Ljubljana, Slovenia. Epidemiological and clinical data were
      obtained from a questionnaire. RESULTS: In 2000, 535 patients had typical EM: 309
      (57.8%) females and 226 (42.2%) males, aged 15-80 (median 47) years. Tick bite at
      the site of later EM was recalled by 311 (58.1%) patients a median of 14 days
      before the onset of the skin lesion, which was localised on the legs in 55.7% of
      patients. The median duration of EM prior to examination was 8.5 days, the
      largest diameter of EM was 12 (4-87) cm, and the average area of involved skin
      was 75 cm2. Thirty-six of 535 (6.7%) patients had more than one skin lesion
      (maximum number 21), 281/535 (52.5%) patients reported local symptoms (itching
      45.2%, burning 12.9%, and pain 7.1%), and 191/535 (35.7%) reported systemic
      symptoms (fatigue 17.4%, headache 17.2%, myalgia 12.6%, arthralgia 11.2%, vertigo
      3.6%, fever 2.5%, and chills 1.5%). In 1993, 892 patients with typical EM were
      diagnosed. They had similar characteristics to those in 2000 but were younger (44
      versus 47 years; p = 0.025), more often remembered a tick bite (654/892 versus
      311/535; p = 0.009), had a smaller diameter (10 versus 12 cm; p < 0.001) and
      surface area of EM (50.2 versus 75.0 cm2), presented more often with homogeneous
      skin lesions (378/892 versus 191/535; p = 0.010), and more frequently had some of
      the associated symptoms including nausea (43/892 versus 12/535; p = 0.021) and
      malaise (124/892 versus 51/535; p = 0.019). CONCLUSIONS: The majority of findings
      for the cohorts of EM patients seen in 1993 and 2000 were comparable but-
      contrary to expectations--in 2000 the duration of EM prior to attending our
      clinic was not shorter, and the skin lesions were larger and less often
      homogeneous. These findings indicate that knowledge of Lyme borreliosis did not
      increase during the period from 1993 to 2000.

PMID- 12422590
TI  - Solitary erythema migrans in children: comparison of treatment with azithromycin
      and phenoxymethylpenicillin.
AB  - OBJECTIVE: To compare clinical effectiveness and side effects of treatment with
      azithromycin or phenoxymethylpenicillin in children with solitary erythema
      migrans. METHODS: Consecutive patients younger than 15 years, referred to our
      institution in 1998 and 1999 with previously untreated typical solitary erythema
      migrans, were included in this prospective study. Basic demographic features and
      clinical data were collected by means of a questionnaire. The efficiency of
      treatment of acute disease, development of later major and/or minor
      manifestations of Lyme borreliosis and side effects of treatment were surveyed by
      follow-up visits during the first year. RESULTS: Forty-two patients received
      azithromycin 20 mg/kg/day for the first day followed by 10 mg/kg/day for a
      further four days and phenoxymethylpenicillin 100,000 IU/kg/day for 14 days. No
      differences in demographic and clinical pre-treatment characteristics were
      present in the two groups, with the exception of the duration of erythema migrans
      before treatment (3 days in the azithromycin group versus 4 days in the
      phenoxymethylpenicillin group; p = 0.0320). The clinical course during the post
      treatment period revealed no significant differences between the two groups in
      the duration of EM (3 days versus 4 days; p = 0.2471), the appearance of minor
      manifestations of Lyme borreliosis (17.5% in the azithromycin group versus 24.4%
      in the phenoxymethyl-penicillin group; p = 0.6252), or in the emergence of major
      manifestations of Lyme borreliosis (one patient in each treatment group). One
      year after antibiotic treatment all patients were asymptomatic. Side effects of
      treatment were observed in 5.3% of patients treated with azithromycin and in 6%
      treated with phenoxymethylpenicillin. The appearance of "Herxheimer's reaction"
      at the beginning of treatment was recorded in 7 out of 42 patients (6%) in each
      treatment group. CONCLUSIONS: Azithromycin and phenoxymethylpenicillin are
      equally effective in treatment of children with solitary erythema migrans and
      have comparable side effects.

PMID- 12422591
TI  - Cerebrospinal fluid findings in adult patients with multiple erythema migrans.
AB  - This prospective study was performed at the Department of Infectious Diseases,
      University Medical Centre Ljubljana, Slovenia, in the period from 1991 to 2000.
      We included all adult patients with multiple erythema migrans who gave consent to
      lumbar puncture, had routine blood and CSF tests performed, and borrelial
      antibody titres in CSF and blood determined. In the majority of these patients
      skin, blood, and CSF specimens were cultured in MKP medium for the presence of
      Borrelia. Of 332 patients with multiple erythema migrans, 200 (115 females, 85
      males, aged 15-80 years) fulfilled inclusion criteria. The median number of skin
      lesion was three (2-60). Sixty-three (31.5%) patients had no associated symptoms,
      whereas 137 (68.5%) patients (including two with arthritis, six with radicular
      pain, a patient with facial palsy, another patient with foot palsy and a patient
      with transitory diplopia) reported local and/or constitutional symptoms. Routine
      CSF examination revealed abnormal results in 62/200 (31%) patients: lymphocytic
      pleocytosis (6-1119 x 10(6)/L leukocytes) was found in 15 (7.5%) patients (six
      were clinically without systemic symptoms, six had mild systemic symptoms, three
      reported radicular pains) and elevated CSF protein concentration was present in
      52 (26%) patients (nine also had elevated CSF cell counts). Intrathecal borrelial
      antibody production was demonstrated in eight (4%) patients (only three of them
      had elevated CSF cell counts) and B. burgdorferi sensu lato was isolated from
      skin lesions, blood, and CSF in 77/191 (40.3%), 3/154' (1.95%), and 2/200 (1%)
      patients, respectively. B. afzelii predominated among the isolates. In patients
      with multiple erythema migrans abnormal CSF findings are not rare and may be
      present without any clinical sign of central nervous system involvement.

PMID- 12422592
TI  - Electrocardiographic findings in patients with erythema migrans.
AB  - OBJECTIVE: To identify asymptomatic heart involvement early in the course of Lyme
      borreliosis by analysis of electrocardiograms (ECGs) of patients with solitary
      erythema migrans (EM). METHODS: We enrolled in this prospective study 220
      consecutive previously healthy patients, receiving no medication, who were
      diagnosed with typical solitary EM at our Lyme borreliosis Outpatient Clinic in
      1998. Their ECG findings were compared with the ECG results in 165 age and sex
      matched healthy persons. RESULTS: Three patients with EM but none in the control
      group had first degree AV block (p = 0.319). Second and third degree AV blocks,
      electrocardiographic signs of pericarditis, myocarditis or rhythm disturbances
      were not found in any of the ECGs. Comparison of findings in patients with EM and
      the control group revealed statistically significant differences in frequency
      (66.2 +/- 1.47 beats/min in patients with EM versus 68.4 +/- 1.52 beats/min in
      controls; p = 0.043), duration of Q (0.013 +/- 0.001 s in patients with EM versus
      0.015 +/- 0.001 s in controls; p < 0.001), and in depth of S (0.135 +/- 0.016 mV
      in patients with EM versus 0.104 +/- 0.012 mV in controls; p < 0.05), but not for
      several other ECG parameters. These differences were found in females as well as
      in males. Comparison of ECG findings in subgroups of patients with EM (grouped
      according to EM characteristics such as length of incubation, duration of skin
      lesion and the presence of associated systemic symptoms) did not reveal any
      significant difference. CONCLUSIONS: AV blocks, the most typical heart
      manifestation of early disseminated Lyme borreliosis, are a rare finding in
      patients with solitary EM, and in our study their frequency did not differ from
      that in the control group. We do not have a reliable explanation for the shorter
      duration of Q and deeper S wave in patients with EM compared with age and sex
      matched controls.

PMID- 12422593
TI  - Solitary borrelial lymphocytoma in adult patients.
AB  - During the period from 1986 to 2000, 85 adult patients with solitary borrelial
      lymphocytoma were diagnosed at the Department of Infectious Diseases, University
      Medical Centre Ljubljana, Slovenia. There were 36 (42.4%) females and 49 (57.6%)
      males with a median age of 49 (15-74) years. Borrelial lymphocytoma was located
      on the breast (nipple--areola mammae region) in 68 (80%) patients, on the ear
      lobe in eight (9.4%), and in other locations in nine (10.6%). A concomitant
      erythema migrans enabling clinical diagnosis of Lyme borreliosis was registered
      or reported in 67 (78.8%) patients. Fifteen (17.6%) patients had no accompanying
      symptoms, 34 (40%) reported local and constitutional symptoms, 23 (27.1%)
      recounted only local symptoms, and 13 (15.3%) patients had solely constitutional
      symptoms. Clinical findings indicating early disseminated borrelial infection
      were observed at the first visit in 12 (14.1%) patients: six (7.1%) had multiple
      erythema migrans, one had meningitis, one meningoradiculitis and arthritis, one
      radiculoneuritis and arthritis, one peripheral facial palsy and concomitant
      meningitis, and two arthritis. In addition, one of the patients with borrelial
      lymphocytoma on the breast had acrodermatitis chronica atrophicans. A
      seropositive response to borrelial antigens was found in 30 (35.3%) patients at
      the initial examination. In 11/46 (23.9%) patients, infection with Borrelia
      burgdorferi sensu lato was confirmed by isolation of the agent from lymphocytoma
      tissue. Eight out of nine (88.9%) typed borrelial strains were found to be B.
      afzelii, and one (11.1%) B. bissettii. Patients were treated with doxycycline,
      azithromycin, amoxycillin, cefuroxime-axetil, phenoxymethylpenicillin, or
      ceftriaxone. Median time to complete disappearance of lymphocytoma was 28 days
      (range 7-270 days) after the institution of antibiotic treatment; disappearance
      took longer in patients with prolonged duration of the skin lesion prior to
      treatment. Treatment failure was registered in 11 (12.9%) patients who were later
      re-treated. The outcome of borrelial infection assessed at the end of a follow-up
      period of one year was favourable.

PMID- 12422594
TI  - Children with multiple erythema migrans: are there any pre-treatment symptoms
      and/or signs suggestive for central nervous system involvement?
AB  - OBJECTIVE: To establish eventual signs and symptoms suggestive for central
      nervous system involvement in children with multiple erythema migrans. METHODS:
      Patients younger than 15 years with multiple erythema migrans, diagnosed at our
      department from 1996 to 2000, were included in this prospective study.
      Demographic, clinical and laboratory findings were obtained and compared for a
      group of patients with pleocytosis (interpreted as a sign of central nervous
      system involvement) and a group of children with normal cerebrospinal fluid
      findings. RESULTS: Cerebrospinal fluid pleocytosis (cell counts > or = 5 x
      10(6)/l) was detected in 55/214 (25.7%) children; it was lymphocytic in 94.5% of
      patients and ranged from 5 to 320 (median, 10 x 10(6)/l). Compared with the group
      with normal cerebrospinal fluid findings, patients with pleocytosis more often
      reported having had Lyme borreliosis in the past (8/55 versus 3/159; p = 0.0011),
      had longer incubation periods (25.5 versus 14 days; p = 0.0269), larger diameter
      of the largest erythema migrans at the time of first examination (10 versus 5.5
      cm; p = 0.0055), higher frequency of associated systemic symptoms (45.5% versus
      21.4%; p = 0.0011), positive meningeal signs (10.9% versus 1.9%; p = 0.0100),
      borrelial IgG antibodies in cerebrospinal fluid (3/49 versus 0/150; p = 0.0142)
      and B. burgdorferi s.l. isolated from cerebrospinal fluid (7/52 versus 1/147; p =
      0.0004), but less often had mild initial disease (67.3% versus 88.7%; p =
      0.0006). CONCLUSIONS: Cerebrospinal fluid pleocytosis was detected in 25.7% of
      children with multiple erythema migrans. Although several clinical and laboratory
      abnormalities were present significantly more often in patients with elevated
      cell counts than with normal cerebrospinal fluid findings, discriminatory
      significance for the majority of these abnormalities was low, particularly
      because of low negative predictive values. In more than 2/3 of patients with
      pleocytosis the initial disease was mild, fewer than 1/2 reported systemic
      symptoms, and meningeal signs were expressed in only 11%.

PMID- 12422595
TI  - Procalcitonin levels in patients with Lyme borreliosis.
AB  - BACKGROUND: Serum and cerebrospinal fluid (CSF) procalcitonin levels were
      assessed and compared for different groups of patients with Lyme borreliosis.
      PATIENTS AND METHODS: 50 adult patients with Lyme borreliosis, referred to our
      department from March to June 2001, were included in this prospective study.
      Patients were divided into three groups. The first group consisted of 20
      consecutive patients with typical solitary erythema migrans, representing early
      localised Lyme borreliosis, the second group comprised 20 patients with early
      disseminated Lyme borreliosis (10 with multiple erythema migrans and 10 with
      neuroborreliosis), and 10 patients with acrodermatitis chronica athrophicans
      represented the group with chronic Lyme borreliosis. Blood specimens were taken
      from all patients included in the study, but CSF samples were restricted to those
      with disseminated and chronic Lyme borreliosis. The serum and CSF procalcitonin
      levels were determined utilizing the LUMI PCT (an immunoluminometric assay using
      two antigen-specific monoclonal antibodies). RESULTS: Serum and CSF procalcitonin
      levels were in normal range in the large majority of patients. The levels of
      serum procalcitonin did not differ in the three groups of patients with Lyme
      borreliosis (p = 0.5006). The corresponding values for patients with solitary
      erythema migrans (early localised Lyme borreliosis), early disseminated Lyme
      borreliosis, and chronic Lyme borreliosis were 0.26 (0.11-0.43), 0.22 (0.10
      0.67), and 0.28 (0.13-0.66) microgram/ml, respectively. Moreover, procalcitonin
      levels in CSF were also low and comparable for patients with multiple erythema
      migrans (median 0.38, range 0.24-0.54 microgram/ml), neuroborreliosis (median
      0.16, range 0.10-0.47 microgram/ml), and acrodermatitis chronica athrophicans
      (median 0.30, range 0.15-0.45 microgram/ml). The differences were not
      statistically significant (p = 0.7579). CONCLUSIONS: In the large majority of
      patients with Lyme borreliosis procalcitonin values are within normal range.
      Serum and CSF procalcitonin levels are of no value for differentiation between
      early localised, early disseminated and chronic Lyme borreliosis.

PMID- 12422596
TI  - Isolation of Borrelia burgdorferi sensu lato from a fibrous nodule in a patient
      with acrodermatitis chronica atrophicans.
AB  - A 66-year-old woman presented with a 2-year history of acrodermatitis chonica
      atrophicans of her left hand and associated fibrous nodules. In addition to skin
      changes she experienced profound fatigue, and pains and swelling of the left
      elbow and dorsum of the left hand. On clinical examination, typical livid-red
      discoloration of the skin distally from the left elbow was evident with atrophy
      on the dorsum of the hand. Nodules with diameters from 0.5 to 2 cm were present
      around the olecranon and along the ulnar region. The indirect immunofluorescent
      assay (IFA) without absorption in serum revealed negative borrelial IgM and
      positive IgG (1:512) antibody titres. Histological findings on tissue specimens
      were compatible with acrodermatitis chronica atrophicans and fibrous nodule
      tissue, respectively. Cultures in MKP medium of biopsy specimens from the
      involved skin and from one of the nodules were positive. Both isolates were
      identified as B. afzelii with concordant protein and plasmid profiles. The
      patient received a 3-week course of ceftriaxone (2 g daily, i.v.). Her condition
      progressively improved: pains and swelling vanished by the end of treatment,
      fibrous nodules diminished and skin lesions gradually began to fade. According to
      a MEDLINE literature search this is the first report of the isolation of B.
      burgdorferi sensu lato from a fibrous nodule in a patient with acrodermatitis
      chronica atrophicans.

PMID- 12422597
TI  - Cerebrospinal fluid findings in patients with symptoms suggesting chronic Lyme
      borreliosis.
AB  - BACKGROUND: Patients with non-specific long-lasting symptoms such as headache,
      concentration disturbances, and vertigo and who have positive serum borrelial
      antibody titres are often assumed to have chronic Lyme borreliosis. Because of
      the possibility that they may have central nervous system involvement they are
      frequently treated with courses of i.v. ceftriaxone. We assessed central nervous
      system involvement by examining cerebrospinal fluid samples in a group of such
      patients. PATIENTS AND METHODS: Adult patients who qualified for the study had
      non-specific symptoms suggesting central nervous system involvement for longer
      than six months (but without overt clinical signs of such involvement) and
      positive serum borrelial antibody titres and/or erythema migrans prior to the
      onset of symptoms. Cerebrospinal fluid was examined in all patients. RESULTS:
      None of the 77 patients included in the study (median duration of symptoms 18
      months) had pleocytosis and there was no isolation of Borrelia burgdorferi sensu
      lato from cerebrospinal fluid. Mildly elevated protein concentration and
      intrathecal borrelial IgG antibody synthesis were demonstrated in 16 (21%) and 7
      (9.1%) patients, respectively. CONCLUSIONS: In patients with non-specific long
      lasting symptoms attributed to Lyme borreliosis but with the absence of overt
      clinical signs suggesting central nervous system involvement, the findings of
      cerebrospinal fluid examination are usually in the normal range. Routine
      treatment of such patients with i.v. ceftriaxone is not to be encouraged.

PMID- 12422598
TI  - Multiple sclerosis and Lyme borreliosis.
AB  - In a deductive approach the two disease entities of multiple sclerosis and
      chronic progressive neuroborreliosis are discussed. Various clinical features,
      seroepidemiology, neuroimaging, CSF findings, CSF serology, specific proteins
      within the CSF and antibodies against neuronal structures as well as the most
      recent findings of different dendritic cells within the CSF are discussed as a
      means of differentiating these two disease entities.

PMID- 12422599
TI  - Characterization of Borrelia burgdorferi sensu lato strains isolated from human
      material in Slovenia.
AB  - The aim of the study was to assess genotypic and phenotypic diversity among a
      large number of clinical isolates of Borrelia burgdorferi sensu lato obtained
      from patients in Slovenia. Plasmid profiles and species identification were
      determined by PFGE, protein profiles by SDS-PAGE. Of 706 B. burgdorferi sensu
      lato human isolates 599 (85%) were found to be B. afzelii, 101 (14%) B. garinii
      and six (1%) B. burgdorferi sensu stricto. The vast majority of strains (605;
      86%) were isolated from skin, 58 (8%) from blood, and 43 (6%) from CSF. When
      analysed by RFLP, B. afzelii strains were unique, while heterogeneity was found
      within B. garinii and B. burgdorferi sensu stricto species. An unusual plasmid
      content was found in 52/706 (7%) isolated strains, more often in B. garinii than
      in B. afzelii strains. A plasmid dimer was found in B. afzelii and B. garinii
      strains, whereas multiple copies of the large plasmid were associated nearly
      exclusively with B. garinii strains. Analysis of protein profiles revealed that
      OspA and OspB are expressed more often by B. afzelii strains, and OspC by B.
      garinii strains. Heterogeneity of Borrelia strains may play a significant role in
      the virulence and pathogenesis of the infection. Differences in antigenic
      components have an important impact on serological testing and vaccine
      development.

PMID- 12422600
TI  - Comparison of pulsed-field gel electrophoresis (PFGE) and two different
      polymerase chain reactions (PCRs) for species identification of Borrelia
      burgdorferi sensu lato strains.
AB  - The purpose of the present study was to compare the findings of three different
      molecular-biological methods for Borrelia burgdorferi sensu lato species
      identification: (i) large DNA fragments pattern obtained with Mlul restriction
      endonuclease and separated with pulsed-field gel electrophoresis (PFGE); (ii)
      polymerase chain reaction (PCR), the region inside the 16S rRNA gene multiplied
      with species-specific primers; and (iii) PCR, the interspace region between the
      5S and 23S rRNA genes amplified, the PCR product restricted with Msel restriction
      endonuclease and fragments separated in polyacrylamide gel. Forty-eight Borrelia
      strains isolated from diverse clinical materials and two tick strains were
      analyzed. Each of the 50 isolates analyzed by PFGE was found to be a single
      species: 30 B. afzelii, 14 B. garinii, and 6 B. burgdorferi sensu stricto. PCR
      amplification of 16S rRNA with species-specific primers revealed a single species
      in 41/50 samples and in nine samples two species were detected. PCR of the 5S-23S
      interspace region restricted with MseI restriction endonuclease detected a single
      species in 48/50 samples and a mixture of two species was found in 2/50 samples.
      In all cases where a single species was identified using PCR the species was in
      accordance with the PFGE result, and in all cases where a mixture of two species
      was identified by PCR one of the species was the same as that detected by PFGE.
      Using a criterion of complete concordance of the results a significant difference
      in species identification was found when PFGE and the 16S rRNA PCR were compared
      (p = 0.0026), but not between 5S-23S interspace PCR and PFGE (p = 0.4949) or
      between 16S rRNA and 5S-23S interspace PCRs (p = 0.0552). PCR assays were faster
      and easier to perform than PFGE for Borrelia species identification, however PFGE
      remains a standard procedure for analyzing isolates and demonstrating
      heterogeneity within species.

PMID- 12422601
TI  - Population dynamics of a heterogeneous Borrelia burgdorferi B31 strain in an
      experimental mouse-tick infectious cycle.
AB  - We have recently shown that low-passage, infectious Borrelia burgdorferi strain
      B31 MI is a heterogeneous mixture of clones varying in colony morphology, growth
      rate, protein profiles, plasmid content and infectivity. In this study, we asked
      whether there is a selection for certain clonal populations during the infectious
      cycle when uncloned B31 MI is used as the starting strain. B31 MI derivatives
      were reisolated from various tissues of two mice after completion of a mouse-tick
      mouse infectious cycle and their protein and plasmid profiles were analyzed. Both
      mice developed ostensibly clonal infections despite the fact that the infectious
      cycle was started with a heterogeneous strain. Moreover, the mice became infected
      with two different clones varying in protein profile and growth phenotype.
      Comparison of the mouse reisolates to uncloned B31 MI and clonal variants derived
      from B31 MI before mouse-tick-mouse passage suggests that they were derived from
      clonal populations present in the uncloned B31 MI. Our results indicate the
      presence of at least two distinct populations within B31 MI that are competent to
      complete an experimental mouse-tick infectious cycle. The study provides insight
      into infectivity profiles and infection dynamics of different clonal populations
      present in a low-passage, infectious B. burgdorferi strain.

PMID- 12422602
TI  - Molecular diversity of the ospC gene in Borrelia. Impact on phylogeny,
      epidemiology and pathology.
AB  - Lyme borreliosis is a 2 steps disease: i) Localized erythema migrans ii)
      occasionally a disseminated disease. Three out of the 10 up to now described
      Borrelia species are pathogenic for man and each of them exhibits its own
      organotropism: joints for Borrelia burgdorferi sensu stricto (B.b. ss), nervous
      system for B. garinii, skin for B. afzelii, ospc gene is subject to lateral
      transfer leading to a huge diversity among corresponding encoded proteins. This
      allows the spirochete to develop a repertoire of epitopes to escape the host
      immune response. We noticed that the European endemic ospc repertoire is only a
      subset of the American one. This bottleneck situation transduces a "founder's
      event" suggesting B.b. ss has been imported from North America to Europe at
      historical times. Another valuable observation is the fact that isolates from
      disseminated forms (called "invasive") of the disease, all are distributed in
      only ten out of the 70 ospc genotypes. The conclusion is that in human, some OspC
      conformations are associated with the invasive potential of a given Borrelia
      isolate.

PMID- 12422603
TI  - Complement regulator-acquiring surface proteins of Borrelia burgdorferi: a new
      protein family involved in complement resistance.
AB  - The innate immune system, particularly the host complement system, plays an
      important role in the elimination of invading pathogens. Borrelia burgdorferi,
      like other human pathogens, has developed strategies to prevent complement
      mediated bacteriolysis. It is now well established that Borrelia differ in their
      complement resistance. In general terms, B. afzelii isolates are mainly resistant
      to complement-mediated bacteriolysis, whereas the majority of B. burgdorferi s.s.
      isolates display an intermediate complement-resistant phenotype. Most of the B.
      garinii isolates, in contrast, are efficiently killed by complement and,
      therefore, are classified as complement-sensitive. Complement resistance of B.
      afzelii and B. burgdorferi s.s. isolates correlates directly with the acquisition
      of the fluid-phase human complement regulators FHL-1/reconectin and factor H. To
      date, five distinct complement regulator-acquiring surface proteins (CRASPs) have
      been identified in B. afzelii and B. burgdorferi s.s. isolates. The individual
      CRASPs can be differentiated according to their size and their binding properties
      to FHL-1/reconectin and factor H. The domains that interact with CRASPs are
      localized at the C-terminal ends of these complement regulators. Thus, CRASPs
      represent a family of functional proteins involved in complement resistance of
      Borrelia. Furthermore, an alterable pattern of gene expression was observed for
      three CRASPs of B. afzelii: BaCRASP-1, BaCRASP-2, and BaCRASP-5 are up-regulated
      at 37 degrees C and down-regulated at 20 degrees C. The continued
      characterization of CRASPs at the molecular level is expected to identify new
      virulence factors and potential vaccine candidates.

PMID- 12422604
TI  - Cystic forms of Borrelia burgdorferi sensu lato: induction, development, and the
      role of RpoS.
AB  - It has been demonstrated recently that cells of Borrelia burgdorferi sensu lato,
      the etiological agent of Lyme disease, transform from mobile spirochetes into
      nonmotile cystic forms in the presence of certain unfavourable conditions, and
      that cystic forms are able to reconvert to vegetative spirochetes in vitro and in
      vivo. The purpose of this study was to investigate the kinetics of conversion of
      borreliae to cysts in different stress conditions such as starvation media or the
      presence of different antibiotics. Using the same experimental conditions we also
      investigated the possible role in cyst formation of RpoS, an alternative sigma
      factor that controls a regulon in response to starvation and transition to
      stationary phase. We observed that beta-lactams penicillin G and ceftriaxone, the
      antibiotics of choice in Lyme borreliosis treatment, favoured the production of
      cysts when used with serum-depleted BSK medium. In contrast, we observed a low
      level of cyst formation in the presence of macrolides and tetracyclines. In order
      to elucidate the role of the rpoS gene in cyst formation we analyzed the reaction
      of the rpoS mutant strain in comparison with its wild-type in different
      conditions. Under the same stimuli, both the wild-type borrelia and the rpoS
      knock-out isogenic strain produced cystic forms with similar kinetics, thus
      excluding the participation of the gene in this phenomenon. Our findings suggest
      that cyst formation is mainly due to a physical-chemical rearrangement of the
      outer membrane of Borrelia burgdorferi sensu lato leading to membrane fusion and
      controlled by different regulation mechanisms.

PMID- 12422605
TI  - Development and laboratory evaluation of a new recombinant ELISA for the
      serodiagnosis of Lyme disease.
AB  - OBJECTIVE: The use of recombinant proteins for serologic testing represents a
      modern approach for the improved laboratory diagnosis of Lyme disease (LD). The
      aim of the present study was to develop and evaluate a new recombinant ELISA (RE)
      for the detection of specific IgG and IgM antibodies against Borrelia
      burgdorferi. MATERIALS AND METHODS: The RE (Biotest AG, Dreieich, Germany) uses
      mixtures of recombinant p100, OspC, p18 of Borrelia afzelii and a fusion protein
      of recombinant internal fragments of the flagellum protein (p41) of Borrelia
      garinii strain PBi and Borrelia afzelii strain PKo. Serologic testing was
      performed on a commercially available ELISA processor without pre-absorption of
      sera. The sensitivity of the RE was determined by testing 226 sera obtained from
      patients suffering from Lyme disease (stage I: n = 148, stage II: n = 35, stage
      III: n = 43). Specificity of the RE was evaluated in 1107 sera from healthy blood
      donors and 275 sera from patients with other infectious diseases or autoimmune
      illnesses (leptospirosis: n = 53, syphilis: n = 70, toxoplasmosis: n = 60, herpes
      simplex virus: n = 30, HIV: n = 30; rheumatoid-factor positive: n = 32). In
      addition, 394 routine samples were prospectively tested in comparison with a well
      established whole-cell lysate extract ELISA (ENZYGNOST Borreliosis, DadeBehring,
      Germany) for relative sensitivity and specificity. RESULTS: Overall specificity,
      determined in 1107 healthy blood donors and 275 sera from patients with other
      diseases, was 94% for IgG and 91% for IgM. The overall sensitivities in 226 sera
      obtained from patients suffering from different stages of LD were 67-95%.
      Moreover, as revealed by prospective testing of 394 routine samples, the relative
      sensitivity of the RE in comparison with an established whole-cell lysate extract
      ELISA in the detection of seropositive samples was 81.1% for IgG and 86.5% for
      IgM with a relative specificity of 98.5% and 93% respectively. The ELISAs showed
      an overall agreement of 97% for IgG and 92.4% for IgM test results. CONCLUSION:
      The RE proved to be a reliable and specific screening test in the routine
      serodiagnosis of LD. In addition, the RE is easy to perform and requires no pre
      absorption.

PMID- 12422606
TI  - Evaluation of immunofluorescence test (IFT) and immuno (western) blot (WB) test
      in patients with erythema migrans.
AB  - The diagnosis of Lyme borreliosis is based on the recognition of typical clinical
      signs and is assisted by laboratory confirmation of borrelial infection. The aim
      of the present study was to assess the value of an immunofluorescence test (IFT)
      and an immuno (western) blot (WB) test for the detection of Borrelia burgdorferi
      sensu lato antibodies in patients with erythema migrans residing in Slovenia. We
      determined specific IgM and IgG antibodies in 117 patients with erythema migrans
      and 96 healthy persons using an IFT (in-house test) and a commercial WB test.
      Skin biopsies of erythema migrans lesions were cultured, and isolated strains
      were identified with PFGE. There were 66/117 (56.4%) culture-positive and 51/117
      (43.6%) culture-negative patients. B. afzelii was found in 52/62 (84%) and B.
      garinii in 10/62 (16%) biopsies. IFT-IgM antibodies were established in 2/117
      (1.7%) erythema migrans patients and in none of the control group, while WB-IgM
      antibodies were present in 56/117 (48%) patients with erythema migrans and 21/96
      (22%) members of the control group (p = 0.002). IFT-IgG antibodies were
      demonstrated in 3/117 (2.2%) erythema migrans patients and 2/96 (4%) persons of
      the control group, while corresponding values for WB-IgG were 36/117 (31%) and
      26/96 (27%), respectively (non-significant differences). IgM antibodies directed
      against p41 and OspC, and IgG antibodies directed against p41, p18 and OspC were
      frequently found in both erythema migrans patients and the control group. The
      only significant difference between erythema migrans patients and the control
      group in the WB test was in the reaction of IgM antibodies with OspC antigen,
      which was found in 54/117 (46%) erythema migrans patients and 18/96 (18.8%)
      healthy persons (p < 0.0001). The immune response in patients with erythema
      migrans was very similar to that of the control group determined with either the
      IFT or WB test.

PMID- 12422607
TI  - Quality of Lyme disease serology. Lessons from the German Proficiency Testing
      Program 1999-2001. A preliminary report.
AB  - OBJECTIVE: External quality control surveys are an important tool in regulating
      the quality of infection serology in general and of borreliosis serology in
      particular. We report on the results of a Lyme disease proficiency testing
      program which is regularly organised twice a year by our institutions in close
      cooperation with the Institute of Standardisation in the Medical Laboratory
      (INSTAND). METHODS: From 1999 to 2001, between 226 and 337 microbiological
      laboratories participated in each of the four surveys that have been held so far.
      In addition, between 23 and 30 laboratories from 13 other European countries also
      participated in each trial. In each survey two serum samples which had been
      unambiguously characterised by six reference laboratories to contain or not to
      contain antibodies against the Lyme disease spirochete were distributed in order
      to determine the accuracy of the diagnostic methods used in participating
      laboratories. The laboratories also reported interpretative statements of whether
      or not the test constellation suggested a possible borrelial infection and if an
      early or late phase of the specific antibody response was suspected. RESULTS:
      Test results were found to be in part highly variable and clearly correlated with
      the manufacturers and the applied test methodology. It was also clear that IgM
      tests were more difficult to handle than were IgG tests. ELISA-testing was more
      reproducible and proved to be more sensitive and specific than IFA and IHA
      testing. Quantification of test results and reporting of specific immunoblot
      bands also showed high variability. Moreover, for some assays a high number of
      false positive and false negative test results were reported by the participants.
      CONCLUSION: In view of our results further standardisation of Lyme disease
      serology is not just desirable but is urgently needed. Moreover, stronger
      criteria for the validation of available test kits must be applied.

PMID- 12422608
TI  - Limitation of serological testing for Lyme borreliosis: evaluation of ELISA and
      western blot in comparison with PCR and culture methods.
AB  - The aim of the study was to evaluate a one-step procedure using an ELISA test of
      high specificity and a two-step procedure using immunoblot as a confirmation
      test, and to compare the results of serological testing with detection of
      bacterial DNA and living spirochetes. Sera, synovial (SF) and cerebro-spinal
      fluids (CSF) were obtained from 90 patients with clinical symptoms of Lyme
      borreliosis. Serum samples were tested with recombinant ELISA and Western blot
      assay. Citrated blood, cerebrospinal and synovial fluids samples were cultured in
      cell line and tested by PCR to detect spirochetes. No correlation was found
      between levels of specific B. burgdorferi antibodies detected with a recombinant
      antigen ELISA and the number of protein fractions developed with these antibodies
      by immunoblot. Moreover, Lyme borreliosis patients who have live spirochetes in
      body fluids have low or negative levels of borrelial antibodies in their sera.
      This indicates that an efficient diagnosis of Lyme borreliosis has to be based on
      a combination of various techniques such as serology, PCR and culture, not solely
      on serology.

PMID- 12422609
TI  - Sensitivity of culture and polymerase chain reaction for the etiologic diagnosis
      of erythema migrans.
AB  - Skin biopsy samples from 150 patients with typical cutaneous manifestation of
      Lyme borreliosis, erythema migrans, were cultivated for the presence of Borrelia
      burgdorferi sensu lato in modified Kelly Pettenkofer (MKP) medium and analysed
      with two different polymerase chain reactions using either flagellin or nested
      OspA primers. Cultivation was successful in 75 of 150 (50%) skin samples. Out of
      70 strains that were typed using PFGE, B. afzelii was identified in 60 (86%), B.
      garinii in 10 (14%) specimens, while no B. burgdorferi sensu stricto strains were
      found. B. burgdorferi sensu lato DNA was detected with polymerase chain reaction
      in 28% and 61% of skin samples, using flagellin and nested OspA primers,
      respectively. Concordant results in all three procedures employed in the present
      study were found in 62 (41%) specimens: 25/150 (17%) were positive with all three
      methods and 37/150 (25%) samples were completely negative.

PMID- 12422610
TI  - Diagnostics of tick-borne diseases in the endemic region of Russia.
AB  - A clinical-laboratory survey of 1952 patients with acute feverish diseases
      developing after tick bite was carried out in the Pre-Ural region of Russia,
      which is endemic for tick-borne encephalitis and ixodid tick-borne borreliosis,
      in 1999-2001. Enzyme-linked immunosorbent assay and indirect immunofluorescence
      assay were used for the detection of tick-borne encephalitis, ixodid tick-borne
      borreliosis and ehrlichiosis specific antibodies. Tick-borne encephalitis was
      diagnosed in 22.8% of patients, ixodid tick-borne borreliosis in 50.5%,
      ehrlichiosis in 4.5% and mixed infections in 2.9%. For the first time in Russia,
      a new transmitted disease that appeared to be human monocytic ehrlichiosis was
      identified and its clinical manifestations were described. The common feature of
      these infections is the acute course and the marked general infectious syndrome
      at the early period of the disease. Disorders of the nervous system predominate
      in tick-borne encephalitis. In ixodid tick-borne borreliosis the development of
      erythema migrans and organic pathology (disorders of the cardio-vascular system
      and liver) associated with the involvement of the nervous and locomotor system
      are pathognomonically significant. The specific characteristics of human
      monocytic ehrlichiosis include nervous impairments, hepatic lesions, the frequent
      development of a two-wave course and hemogram changes.

PMID- 12422611
TI  - Duration of treatment for Lyme borreliosis: time for a critical reappraisal.
AB  - Over time the recommended duration of antibiotic therapy for patients with
      erythema migrans has increased. This change in prescribing practice is not
      evidence-based. The presumptions that post-treatment subjective complaints, which
      occur in a minority of patients, may be reduced by increasing the duration of
      initial therapy or ameliorated by a repeat course of parenteral or oral
      antimicrobials, have not been supported by recent clinical trials.
      Recommendations on duration of treatment of early Lyme borreliosis deserve
      critical reappraisal.

PMID- 12422612
TI  - Development of erythema migrans in spite of treatment with antibiotics after a
      tick bite.
AB  - OBJECTIVES: The recent information on the appearance of erythema migrans despite
      prophylaxis with 200 mg of doxycycline was the stimulus for a search among our
      patients for those who developed the skin lesion regardless of receiving
      antibiotics after a tick bite. METHODS: Data were reviewed for adult patients
      with erythema migrans diagnosed at our institution from 1994 to July 2001,
      targeting those who received antibiotics after a tick bite. RESULTS: Seven of
      5056 (0.14%) patients, diagnosed with typical erythema migrans, developed the
      skin lesion despite receiving antibiotics after a tick bite. Antibiotics were
      prescribed by general physicians: in four cases as prophylaxis of Lyme
      borreliosis within one day after tick detachment and in three cases because of
      development of acute respiratory tract infection two, five, and eight days after
      the bite, respectively. The dosages were as follows: azithromycin in a total dose
      of 3 g in three patients and 1.5 g in the fourth patient, amoxicillin-clavulanic
      acid 625 mg t.i.d. for ten days in the fifth patient, amoxycillin 500 mg t.i.d.
      for seven days followed by azithromycin 250 mg o.d. for eight days in the sixth,
      and amoxycillin 500 mg t.i.d. for eight days in the seventh. The patients (five
      females and two males, aged 18-61 years) were referred to our Department on
      average six (1-19) days after the appearance of skin lesions. They had typical
      solitary (five patients) or multiple (two patients) erythema migrans with the
      characteristics usually seen in European patients, except for a rather long
      incubation period (median value 28 days, range 10-40 days). All laboratory tests,
      including the examination of cerebrospinal fluid in three patients with the
      disseminated form of the illness, were within normal range. Borrelial antibodies
      were demonstrated in only one patient. A skin biopsy specimen obtained from the
      site of the erythema migrans was culture positive for Borrelia in 2/4 patients.
      CONCLUSIONS: Our study did not enable us to assess the frequency of antimicrobial
      prophylaxis failure or the efficacy of individual antibiotics for the prevention
      of Lyme borreliosis. However, the seven patients presented demonstrate that
      antibiotic prophylaxis for Lyme borreliosis after a tick bite, at least in
      Europe, is not entirely effective.

PMID- 12422613
TI  - Double infection with tick borne encephalitis virus and Borrelia burgdorferi
      sensu lato.
AB  - The limited information on co-infection with Borrelia burgdorferi sensu lato and
      tick-borne encephalitis (TBE) virus was a stimulus for presentation of two
      patients with well-defined double infection of the central nervous system. TBE
      virus and B. burgdorferi sensu lato infections are searched for in all patients
      with lymphocytic meningitis and/or meningoencephalitis admitted to our
      department. During the last ten years we identified two patients who had ELISA
      IgM and IgG antibodies to TBE virus in serum and a positive PCR result for TBE
      virus in cerebrospinal fluid as well as B. burgdorferi sensu lato isolated from
      cerebrospinal fluid. Intrathecal production of borrelial antibodies was not
      proven in either of the two patients. These findings show that in patients with
      acute lymphocytic meningitis originating in regions endemic for Lyme borreliosis
      and TBE, the possibility of concomitant infection should be considered.

PMID- 12422614
TI  - Severe tick-borne encephalitis in Slovenia: epidemiological, clinical and
      laboratory findings.
AB  - The aim of this retrospective study was to determine epidemiological, clinical
      and laboratory characteristics in adult patients with the severe form of tick
      borne encephalitis. Thirty-one patients with a severe course of disease admitted
      to the intensive care unit of the Department of Infectious Diseases at the
      University Medical Centre Ljubljana, Slovenia, between 1996 and 2000 were
      included in the study. Tick-borne encephalitis virus infection was confirmed by
      the demonstration of specific IgM and IgG antibodies in serum using routine
      serological screening tests. All the patients had specific IgM antibodies at
      admission and IgG antibodies were present in 90.3%. Nineteen patients suffered
      from severe meningoencephalitis, 11 from meningoencephalomyelitis, and
      dysfunction of the autonomic nervous system was found in one patient. The
      mortality rate was 3.3%. Tick bite was recorded in 58% and a characteristic
      biphasic course of the disease was found in 16 patients. The median cerebrospinal
      fluid leukocyte count was 112 x 10(6)/l, and in 93.5% of patients the
      cerebrospinal fluid protein concentration was greater than the cut-off value of
      0.45 g/l. The findings of the present study indicate some clinical,
      epidemiological and laboratory distinctions between published data on the mild or
      moderately severe form of tick-borne encephalitis and our patients with severe
      disease.

PMID- 12422615
TI  - An abortive form of tick-borne encephalitis (TBE)--a rare clinical manifestation
      of infection with TBE virus.
AB  - Tick-borne encephalitis (TBE) is one of the most important human infections of
      the central nervous system (CNS) and is endemic in several European countries,
      including a large part of Slovenia. In at least two-thirds of patients who
      develop CNS involvement, the disease has a characteristic biphasic course.
      Seroepidemiological studies on TBE virus infection in endemic areas of various
      European countries have demonstrated that asymptomatic infections are common. In
      some of these reports it was also suggested that there is an abortive form of TBE
      virus infection, which is manifested only by a febrile headache without meningeal
      involvement (i.e., the initial phase of illness without subsequent CNS
      involvement) and that it represents more than half of the cases of clinically
      manifested infection with TBE virus. The aim of this report was to evaluate
      patients who presented with the initial phase of TBE and monitor them for the
      appearance of the second, encephalitic phase of the disease. In 56/205 (27.3%)
      patients with febrile illness occurring after a tick bite, infection with TBE
      virus was demonstrated by the appearance of specific IgM and IgG antibodies
      against TBE virus during a follow-up period of 6 weeks. All 56 patients were
      diagnosed during the initial phase of TBE, however, only 1/56 (1.8%) had an
      isolated initial phase of TBE without subsequent CNS involvement, whereas 55/56
      (98.2%) patients developed a clinically biphasic course of illness with CSF
      abnormalities (pleocytosis) during the second phase of the disease. Detailed
      epidemiological, clinical and laboratory characteristics of this patient with an
      abortive form of TBE virus infection are presented. The results of our study
      support the view that the abortive form of central European TBE is a rare
      clinical manifestation of TBE virus infection.

PMID- 12422616
TI  - A study of systems for delivering antigens and plasmid DNA for intranasal
      immunization against tick-borne encephalitis virus.
AB  - Our previous studies indicated the possibility for some neurotropic viruses to
      spread into the brain of immune animals through the olfactory pathway. Thus,
      nasal mucosa in the olfactory region is likely to be a promising target for
      mucosal immunization to protect the CNS from neurotropic viral infections. THE
      MAIN IDEA OF THE RESEARCH: Intranasal immunization inducing mucosal and systemic
      immune responses blocks the propagation of neurotropic virus into the brain via
      the olfactory pathway and neutralizes the multiplication of virus in visceral
      organs, allowing more effective protection against neurotropic infections
      transmitted by bloodsucking arthropods to be achieved. Thus, study of the
      efficiency of delivery systems for intranasal immunization against tick-borne
      encephalitis (TBE) virus is an urgent task in the development of anti-TBE mucosal
      vaccine. To study intranasal immunization against TBE virus, we have chosen four
      delivery systems (DSs), namely, (i) biodegradable microparticles, (ii) cationic
      liposomes, and live attenuated (iii) bacterial and (iv) viral vectors. The gene
      of TBE virus protein E was inserted into the pcDNA3 plasmid (designated as
      pcDNA3/E-TBE). Three types of delivery system for plasmid DNA were developed and
      studied in vitro. The first system, artificial virus-like microparticles (VLP),
      consists of polyglycan-spermidine complexes that cover pcDNA3/E-TBE DNA. The
      second system is cationic liposomes with DNA of the plasmid pcDNA3/E-TBE. The
      third system is an attenuated Salmonella strain containing pcDNA3/E-TBE. The
      fourth system is a recombinant vaccinia strain with inserted genes of TBE virus
      proteins C, prM, E, NS1, NS2a, NS2b, and NS3. The DSs were tested in COS-7 and CV
      1 cell lines and macrophages by ELISA of cell lysate. The results obtained showed
      the expression of the E gene in transfected cells, thereby demonstrating that
      these DSs are suitable for mucosal immunization. High levels of immune response
      shifted to the Th1 type were detected in BALB/c mice following intranasal
      immunization with recombinant vaccinia-TBE strain and VLP-pcDNA3/E-TBE. The mice
      immunized intranasally with recombinant vaccinia-TBE strains were completely
      protected against intraperitoneal challenge with TBE virus strain Sofjin, whereas
      intranasal immunization with killed TBE vaccine failed to induce a significant
      level of protection.

PMID- 12422617
TI  - Epidemiological, clinical and laboratory distinction between human granulocytic
      ehrlichiosis and the initial phase of tick-borne encephalitis.
AB  - OBJECTIVE: To establish epidemiological, clinical and laboratory differences
      between adult patients with proven acute human granulocytic ehrlichiosis (HGE)
      and patients with the initial phase of tick-borne encephalitis (TBE). METHODS:
      Epidemiological, clinical and laboratory findings were compared in nine patients
      with acute HGE (established by the presence of specific DNA sequences of
      Ehrlichia phagocytophila in whole blood by polymerase chain reaction and/or by
      seroconversion or at least a four-fold change of serum antibody titres to E.
      phagocytophila by indirect immunofluorescence assay) and 29 patients with the
      initial phase of TBE (demonstrated in ELISA tests by the presence of serum IgM
      antibodies to TBE virus). RESULTS: Findings were similar for the majority of the
      general parameters examined, which included sex, age, incubation period, duration
      of fever, and frequency of additional tick bites. However, a statistically
      significant difference was found for the duration of fever before the first visit
      (median 7 days in patients with acute HGE and 4 days in patients with the initial
      phase of TBE; p = 0.0169), and for the frequency of hospitalisation, which was
      higher for patients with the initial phase of TBE (29/29) than for those with
      acute HGE (5/9; p = 0.0017). Comparison of clinical signs and symptoms and
      laboratory findings in the two groups revealed significant differences: in
      patients with acute HGE there was a higher frequency of chills (4/9 versus 3/29,
      respectively; p = 0.0407), myalgia (8/9 versus 13/29, respectively; p = 0.0263),
      and arthralgia (7/9 versus 3/29, respectively; p = 0.0003), and elevated values
      of lactate dehydrogenase (7/9 versus 3/29, respectively; p = 0.0003) and
      concentration of C-reactive protein (9/9 versus 6/29, respectively; p = 0.0000).
      CONCLUSIONS: In a patient with febrile illness occurring after a tick bite, a
      clinical report of chills, myalgia and arthralgia, and laboratory findings of
      elevated values for lactate dehydrogenase and concentration of C-reactive protein
      direct towards a diagnosis of acute HGE rather than the initial phase of TBE.

PMID- 12422618
TI  - Infection with Anaplasma phagocytophila in cervids from Slovenia: evidence of two
      genotypic lineages.
AB  - OBJECTIVE: Human granulocytic ehrlichiosis (HGE) was recently recognized as an
      emerging tick-borne infection in Europe. The disease is caused by Anaplasma
      (previously Ehrlichia) phagocytophila. The first confirmed acute human disease
      caused by A. phagocytophila was reported from Slovenia in 1998. The tick Ixodes
      ricinus was identified as the likely vector for this pathogen of humans and
      animals in Europe. In order to assess the possibility that roe and red deer in
      Slovenia serve as potential reservoir hosts for A. phagocytophila, materials from
      both species were examined. METHODS: Samples were obtained from 32 red deer
      (Cervus elaphus) and 56 roe deer (Capreolus capreolus). Polyvalent antibodies to
      the USG3 isolate of Anaplasma phagocytophila were detected by indirect
      immunofluorescence assay (IFA). DNA was extracted from spleen tissue. The 16S
      rRNA gene and a portion of the groESL heat shock operon were used for PCR
      detection and subsequent direct sequencing of amplified products. RESULTS:
      Serological and PCR results indicated that high proportions of roe and red deer
      were infected with A. phagocytophila. Infection was confirmed in 74% of the
      animals by IFA and in 86% of animals by PCR. While similar prevalences by PCR
      were seen in the two species (approximately 86%), the prevalence of antibodies
      was much higher in roe deer (94% vs. 35% in red deer). Sequence analysis of a
      1256-bp fragment of the groESL operon revealed genetic diversity among collected
      samples. Identity of sequences ranging from 98% to 100%. None of the A.
      phagocytophila groESL and 16S rRNA gene sequences from red or roe deer were
      identical to the sequences previously obtained from human patients with
      ehrlichiosis from Slovenia or elsewhere in the world. All red deer sequences
      clustered with those obtained from humans, whereas all but two sequences from roe
      deer clustered separately. CONCLUSIONS: The results of our study indicate that a
      high percentage of red deer and roe deer in Slovenia are infected with A.
      phagocytophila. Analysis of groESL and 16S rRNA gene sequences revealed two
      distinct genetic lineages. Among deer, one variant was primarily associated with
      roe deer. Although none of the sequences from red deer was identical to those
      found in humans, they were more closely related.

PMID- 12422619
TI  - Tick-borne lymphadenopathy (TIBOLA).
AB  - INTRODUCTION: From 1996 through 2000, we collected data on 86 patients with
      similar symptoms following a tick bite. The inclusion criteria were: enlarged
      regional lymph nodes and/or vesicular-ulcerative local reaction at the site of
      the tick bite. METHODS: Epidemiological and clinical data on these 86 patients
      were statistically analysed. All patients were tested for borrelia and 73 cases
      for Rickettsia slovaca antibodies by immunoblot. Fine-needle lymph node and/or
      skin biopsy was done in 13 patients. Gehomic PCR amplification was performed on
      these biopsy samples. RESULTS: Seventy-six patients described an "extremely big"
      tick, and/or recognised a Dermacentor spp. tick from a collection of several
      species indigenous to Hungary. The tick bite was usually (96%) located on the
      scalp region. The time from the recognition of the tick bite to the first symptom
      varied between 0 and 55 (mean nine) days. A characteristic local reaction
      (eschar) was seen in 70 (82%) patients. The eschar can be surrounded by a
      circular erythema (18 cases, 21%). The other main symptoms are the enlarged and
      sometimes painful lymph nodes in the region of the tick bite, characteristically
      in the occipital region and/or behind the sternocleidomastoideal muscle. The most
      frequent general symptoms were low-grade fever, fatigue, dizziness, headache,
      sweat, myalgia, arthralgia, and loss of appetite. Without treatment, the symptoms
      were seen to persist for as long as 18 months. One of the patients reported
      symptoms suggestive of encephalitis. The infection occurs most commonly in young
      children (age range: 2-57 years, mean: 12.6 years, 63% less than 10 years of
      age). A female predominance was registered (50/36). Doxycycline treatment can
      shorten the usually benign illness. R. slovaca PCR gave positive results from
      skin or lymph node biopsy samples in 10/13 (77%) patients. CONCLUSION: We have
      described a new and frequent tick-borne infection, most probably caused by R.
      slovaca.

PMID- 12422620
TI  - Bone lesions in malignant diseases--I. Current concepts of major pathogenetic
      mechanisms and forms.
AB  - Bones are among the major parts of the body that are targeted in neoplastic
      diseases. Bone lesions increasing in number and size and diffuse osteoporosis are
      found in 30-80% of cancer patients. All literature data about the pathogenetic
      factors of osteolytic and osteosclerotic bone lesions are classified into four
      groups: 1. Directly connected with the neoplastic tumour mass. 2. Humoral
      interaction between the tumour cells and bone cells. 3. Systemic effects and
      complications of the neoplastic process. 4. Extracancerous factors. We discuss
      here the basic pathogenetic forms of bone lesions in neoplasias: 1. Local
      osteolysis in the area of neoplastic infiltration. 2. Humorally activated
      demineralisation with hypercalcemia. 3. Light chain osteomalacia. 4.
      Hypophosphatemic osteomalacia. We consider the major current biochemical markers
      of bone remodelling and their use in diagnosing and monitoring bone disease in
      neoplastic conditions.

PMID- 12422621
TI  - Bone lesions in malignant diseases--II. Therapeutic management.
AB  - A pathogenetically based therapeutic strategy and modality for malignant bone
      diseases has been created only in the last two decades. The most frequent
      pathogenetic defect, osteoblast/osteoclast uncoupling in the osteolytic foci and
      the diffuse humoral osteoporosis afford little in terms of choice of treatment
      which makes the inhibitors of osteoclastic activity the major medicamentous
      agents for their management. We discuss the mechanisms of action,
      pharmacokinetics, preparations and regimens of administration of biphosphonates,
      calcitonine and galium nitrate. Results of large double blind, placebo-controlled
      studies of clondronate and pamidronate in oncohematologic diseases are
      summarised: statistically significantly lower frequency of the osteolytic foci,
      pathological fractures, hypercalcemic episodes, low levels of C-L bonds, increase
      of bone mineral density, management of pain, and better quality of life.

PMID- 12422622
TI  - Evaluation of the immunomodulatory activity of Aronia in combination with apple
      pectin in patients with breast cancer undergoing postoperative radiation therapy.
AB  - The aim of the present study was to evaluate the immunomodulatory activity of
      Aronia in combination with apple pectin in patients with breast cancer in the
      course of postoperative radiation therapy. Monoclonal antibodies were used to
      assay specific T cell subsets. Tests were performed prior to and after 26 and 50
      Gy of irradiation. The study comprised 42 women (19 to 65 years of age) receiving
      15 g of apple pectin in combination with 20 ml of Aronia concentrate (Bioactive
      Substance Laboratory--Plovdiv) twice daily during postoperative irradiation.
      Irradiation was performed by a 60Co-Rokus according to individualized treatment
      schedules. The following T lymphocyte populations were tested--CD3 total T
      lymphocytes, CD4 helper and inducer T cells, CD8 suppressor and cytotoxic T cells
      and NK cells. The levels of the polypeptide tissue antigen (TPA), an oncofetal
      protein, were tested in parallel. The TPA was used to assess treatment outcome in
      our patients. A group of 25 age-matched women with breast cancer served as
      controls. Immune status analysis of controls was performed prior to and following
      postoperative radiation. A total of 880 serum samples were tested. Assays of
      immunity parameters in the patients receiving Aronia in combination with apple
      pectin showed that CD4 and CD8 T cell counts increased significantly (P < 0.01
      and P < 0.05 respectively). In control patients CD3 T cell levels lowered, the
      other T cell levels remained unchanged. Initially the number of NK cells was
      increased in both groups of patients. It remained constant throughout the course
      of the study. The normal levels of TPA in both groups of patients indicated a
      good treatment outcome due to the adequacy of surgery and in combination with
      radiation therapy.

PMID- 12422623
TI  - Efficacy of the anesthetic protection in one-stage anterior and posterior spinal
      fusion in surgery of scoliosis.
AB  - Contemporary one-stage surgery of scoliosis including consecutive anterior and
      posterior spinal fusion is a highly traumatic procedure that requires effective
      anesthetic protection of the patient during operation and in the postoperative
      period. It has been established that anesthetic protection with alpha-1
      adrenoblockers and alpha-2-adrenoantagonists of clofelin allows minimization of
      the postaggressive catabolic reactions of the organism, preventing severe
      impairment of homeostasis, reducing considerably the rate of intra- and
      postoperative complications and thus ensuring the favorable outcome of the
      operation. The proposed method of anesthetic protection by using propofol could
      be a method of choice when intraoperative awakening of the patient is needed to
      control for possible neurological deficit.

PMID- 12422624
TI  - Comparative analysis of two regimens of antibiotic prophylaxis in elective
      colorectal surgery.
AB  - BACKGROUND: Antibiotic prophylaxis has greatly reduced the rate of postoperative
      infectious complications since its utilization in the elective colorectal surgery
      in the last several decades. Although the need of its application is
      indisputable, the optimal duration of antibiotic prophylaxis is still on debate.
      AIM: The aim of the present study was to compare two regimens of antibiotic
      prophylaxis with different duration. MATERIALS AND METHODS: A retrospective
      clinical study was conducted of 190 patients that underwent elective surgery for
      colorectal carcinoma in the Clinic between January 1997 and June 2000. The
      patients were divided into two groups according to the regimen of antibiotic
      prophylaxis. Group 1 (n = 92) patients received a 24-hour antibiotic prophylaxis
      and Group 2 (n = 98) had a prolonged antibiotic cover that lasted 5 days. The
      antibiotic prophylaxis was conducted with a third generation cefalosporin and
      metronidazole. RESULTS: Of all 190 patients 92 were in Group 1 and 98 in Group 2.
      Postoperative infectious wound complications were found in 14 (15.2%) patients
      from Group 1 and in 25 (25.5%) patients from Group 2. The difference did not
      reach statistical significance (P > 0.05). CONCLUSION: The results of the study
      show no advantage of the prolonged over short-term antibiotic prophylaxis. Based
      on the study findings the authors suggest that a 24-hour antibiotic prophylaxis
      should be recommended for the lower rate of side effects and lower cost.

PMID- 12422625
TI  - Traditional bowel preparation versus osmotic agent mannitol for preoperative
      colonic cleansing in elective colorectal surgery.
AB  - BACKGROUND: The need for mechanical cleansing of the bowel before elective
      colorectal surgery is generally accepted. There are various methods for
      preparation in use today, but it is still controversial which of them is superior
      to the others. AIM: To determine whether there is a significant difference in
      postoperative infectious wound complications rate between the traditional bowel
      preparation and oral lavage with the osmotic agent Mannitol. METHODS: A
      retrospective study from January 1997 to June 2000 was performed. Patients who
      underwent elective surgery for colorectal carcinomas were divided into two groups
      according to the method of colonic cleansing that was used. The traditional bowel
      preparation was performed with 30.0 cc Castor oil given per os in the day before
      the operation and three soap enemas (Group I). Patients from the other group
      (Group II) were given 500 cc 10% Mannitol in the day before the operation.
      RESULTS: There were 154 patients in Group I and 36 patients in Group II.
      Infectious wound complications developed in 26 patients from Group I versus 13
      patients from Group II. The difference was statistically significant (16.9% vs.
      36.1%, p < 0.01). The differences in the incidence of anastomotic leaks and
      mortality rate between the two groups were without statistical significance.
      CONCLUSION: The use of Mannitol is associated with increase in the postoperative
      infectious wound complications and therefore should be avoided as colonic
      cleansing method in elective colorectal surgery.

PMID- 12422626
TI  - Intensive rehabilitation of a knee joint in hemophilic patients--a preliminary
      study.
AB  - One of the most typical symptoms of hemophilia are the intra-articular
      hemorrhages, which cause chronic synovitis, damage of the joint and eventually
      hemophilic arthropathy. Adequate treatment of chronic synovitis with
      antihemophilic globulin combined with appropriate physiotherapy and
      rehabilitation is of primary importance for suspending development of hemophilic
      arthropathy. AIM: The present study aims to explore the changes in the range of
      movements in the knee joint, mass and strength of thigh musculature as well as
      gait stability in hemophilic patients after conduction of intensive
      rehabilitation programme. MATERIAL AND METHODS: Knee joints of 30 hemophilic
      patients were examined before and after conducting intensive rehabilitation. The
      assessments were done by angulometry of the knee joint, measurement of thigh
      circumference, and dynamometry. The rehabilitation course lasted 15 days.
      Kinesitherapy and modified physical factors were used in the treatment programme.
      Kinesitherapy included analytical exercises for the affected muscles and
      underwater gymnastics. The modified physical factors included electrotherapy with
      low-frequency impulse-magnetic field and interference currents. RESULTS: The
      applied intensive rehabilitation programme lead to variously expressed
      improvement of the examined parameters. CONCLUSION: The study results show that
      in most patients improvement of various degree is achieved which depends on the
      severity of damage of the locomotory apparatus. Prophylaxis with antihemophilic
      globulin combined with individually designed early rehabilitation is of crucial
      importance for maintenance of the musculoskeletal function in hemophilic
      patients.

PMID- 12422627
TI  - Anti-aggregation activity of crude water extract of Galega officinalis L.
      fractionated on Sephadex G-25 and Sepharose 4B.
AB  - The present study describes a method for preparation of biologically active
      fraction from crude water extract of Galega officinalis L. by gel filtration on
      Sephadex G-25 and Sepharose 4B. In an in vitro experiment (at a dose of 12.0 +/-
      0.45 micrograms/ml) fractionated extracts inhibited adenosine diphosphate (ADF)
      induced platelet aggregation by 50%. Inhibitory effects on collagen (0.18 mg/ml)
      and thrombin (0.7 U/ml) induced platelet aggregation were observed at doses of
      0.18 +/- 0.65 microgram/ml and 20 +/- 0.82 micrograms/ml, respectively. The
      optimum activity was observed at a temperature of 30-42 degrees C. It was found
      that the fraction contained 15.23% protein. As shown by amino acid analysis
      several amino acids (alanine, glycine, valine, lysine, asparagine, arginine and
      serine) accounted for 50% of its protein content. These amino acids formed tri-
      and tetrapeptides (RGD, RGDS, KRDS, RGDS), which inhibited platelet aggregation.
      The RGD and AGVD fibrinogen amino acid sequences responsible for the recognition
      and binding to the glycoprotein IIb/IIIa receptors consisted of the same amino
      acids.

PMID- 12422628
TI  - Treatment of incipient caries in children with fluoride gel.
AB  - AIM: The aim of this study was to determine the effect of the treatment of acute
      incipient caries in children with fluoride gel by following up the development of
      the white carious spots. METHODS: Clinical observation on 182 white spot carious
      lesions in 27 children aged 7 to 16 was carried out for 12 months in two groups-
      experimental and control. The experimental group received 4 applications of 0.42
      fluoride gel. Four stages of development of incipient caries were assessed: early
      stage, advanced stage, disappearance of the spot and formation of defect. The
      oral hygiene status was assessed with the indexes of Green-Vermillion and Silness
      and Lue. Evaluations were performed at the beginning of the study and at the end
      of the 1st, 2nd, 6th and 12th month. RESULTS: The results at the end of the study
      showed arrest of development of macula cariosa alba in the control group within
      the study period. In the experimental group reverse development and curing of
      macula cariosa alba was mainly observed. CONCLUSION: The fluoride gel we propose
      as well as the method of its application demonstrated very satisfactory results
      which gives us grounds to recommend it for the treatment of acutely developing
      initial caries on the vestibular surfaces of the permanent teeth in children from
      7 to 16 years of age.

PMID- 12422629
TI  - Comparative age study of the risk of demineralization during orthodontic
      treatment with brackets.
AB  - AIM: The aim of the study was to investigate the hypothesis of a higher risk of
      demineralization in regions adjacent to brackets at earlier age. METHODS: A
      prospective cohort study of 42 persons (22 persons aged 11-15 years and 20
      persons aged 19-24 years) in the process of orthodontic treatment with brackets
      was performed. The duration of the observation was 18 months. The object of
      evaluation were 508 vestibular surfaces of permanent teeth that had brackets
      fixed. The statistical analysis included non-parametric analysis and comparison
      of percentages. The attributive risk (AR) and the relative risk (RR) were also
      determined. RESULTS: After removal of brackets, 51.61% of the surfaces of the 11
      15 year olds showed demineralization. In the 19-24 year age group this result was
      6.92%. The difference was statistically significant (P < 0.001). The attributive
      risk was 86.59% and the relative risk was 7.45%. This indicates that age is a
      risk factor for demineralization adjacent to brackets. CONCLUSION: The results of
      the study support the hypothesis of a higher risk of demineralization in regions
      adjacent to brackets at earlier age. This is a direct consequence of the lower
      resistance of the dental tissues and the poorer cooperation from the younger
      patients in the orthodontic treatment process.

PMID- 12422630
TI  - Prevalence of early childhood caries and risk factors in children from 1 to 3
      years of age in Plovdiv, Bulgaria.
AB  - INTRODUCTION: Available data show that Early Childhood Caries (ECC) has a very
      wide range of prevalence (5% to 55%). Contemporary studies investigate the
      specific etiologic factors contributing to the appearance of ECC. As these
      questions are inadequately addressed in the stomatological literature in
      Bulgaria, we decided to investigate them in the present study. AIM: To determine
      the prevalence of ECC and the risk factors in children aged 12 to 47 months in
      Plovdiv. METHODS: The study is representative by design and is conducted in
      compliance with the requirements of World Health Organization. It includes 370
      children 1 to 3 years of age, selected randomly. The dental caries was diagnosed
      by the visual-tactile method with a dental explorer and mirror at the cavitation
      level. A survey for determining the risk factors for ECC is carried out among the
      mothers of all affected children. RESULTS: The results of the study demonstrate
      high prevalence of ECC in the studied populations--20.82% in 1-year-old children,
      40.0% in 2-year-old children and 56.15% in 3-year-old children. The analysis of
      the questionnaire data shows that the knowledge of mothers about the appropriate
      feeding of their children is insufficient. The use of baby's comforter with honey
      is not the only risk factor for developing caries. It is ascertained that
      frequent consumption of quickly soluble carbohydrates, as well as their prolonged
      contact with the tooth surface is highly significant risk factors too.
      CONCLUSIONS: The prevalence of ECC is high in the studied populations. The
      results of the questionnaire survey demonstrate the need for recommending
      adequate feeding practices of children till the age of 3 years to their mothers.

PMID- 12422631
TI  - Changes in the appearance and form of the spots of macula cariosa alba in
      treatment with fluoride gel.
AB  - AIM: The aim of this study was to establish the changes in the appearance of the
      surface and in the form of the carious spots in the treatment of acute initial
      caries with fluoride gel. MATERIAL AND METHODS: Clinical observation on 182 white
      carious spots in 27 children from 7 to 16 years of age was conducted for a period
      of 12 months. Two groups were formed--experimental (112 spots) and control (70
      spots). The treatment of the white spot lesions in the experimental group
      consists of 4 fluoride gel applications at an interval of 1 weeks. The evaluation
      of the spots is performed at the beginning of the study and at the end of the
      1st, 2nd, 6th and 12th month. RESULTS: The obtained results show that changes in
      the appearance of surface and form of the spots are observed in the period of the
      clinical study in both groups. The changes of the values of the percentages of
      spots with different form and appearance of the surface show that in the control
      group arrest of the progress of macula cariosa alba is achieved, while in the
      experimental group--regress and disappearance of the spots. CONCLUSION: The
      treatment of acute initial caries with 0.42% fluoride gel leads to changes in the
      appearance of the surface and form of the carious spot which manifests the
      regress and recovery of the spot.

PMID- 12422632
TI  - Eruption of first permanent molars in 4- to 8-year-old children in Plovdiv.
AB  - INTRODUCTION: The eruption age of the first permanent molars is one of the
      milestones by which the normal physical development of the child is evaluated.
      AIM: The need of current data about M1 eruption in 4- to 8-year-old children
      determines the aim of the present study. MATERIAL AND METHODS: The study includes
      928 children from 4 to 8 years of age, from randomly selected kindergartens and
      schools in Plovdiv. The initial, mean and the latest age of eruption were
      determined. RESULTS: The data show that there is no statistically significant
      difference in the eruption age of first permanent molars between the two genders,
      as well as between the upper and lower jaw. Statistically significantly higher
      percentage of 4-5 and 5-6 year-old children have had first permanent molars in
      1985 compared to their pairs in 2001. CONCLUSIONS: In 4- to 8-year-old children
      from Plovdiv the initial eruption age of first permanent molars is 5-6 years, the
      mean age--6-7 years, and the latest age--7-8 years.

PMID- 12422633
TI  - Comparison of caries epidemiology of the primary teeth in 3- to 6-year-old
      children from Plovdiv and Karlovo/Sopot.
AB  - INTRODUCTION: Dental caries is affected by multiple factors, including
      socioeconomic conditions and the presence or absence of anticaries prevention
      programs. AIM: The aim of the present study was to conduct comparative study of
      caries epidemiology of the primary teeth in 3- to 6-year-old children from
      Plovdiv and Karlovo/Sopot. MATERIAL AND METHODS: The study includes 1250 children
      from 3 to 6 years of age--830 from Plovdiv and 420 from Karlovo/Sopot, from
      randomly selected kindergartens. The following indicators were determined:
      prevalence of caries per persons (Ep); prevalence of caries per teeth (Et);
      incidence of caries (It); incidence of untreated and treated caries (Id, If).
      RESULTS: The results show that the caries indicators are higher in the children
      from Karlovo and Sopot than in their pairs in Plovdiv. Inadequacy of the children
      dental care system and stomatological treatment was found in both studied groups.

PMID- 12422634
TI  - Incidence of caries of the primary teeth (IT) in 3- to 8-year-old children in
      Plovdiv.
AB  - INTRODUCTION: There is a recognized trend of a decrease of the caries incidence
      of primary teeth (It) in Europe and worldwide. AIM: The need for updated data for
      the indicator It, as well as the need to study the trends of its development
      determine the aim of the present study. MATERIAL AND METHODS: The study includes
      1124 children from 3 to 8 years of age--536 girls and 588 boys, from randomly
      selected kindergartens and schools in Plovdiv. The carious and filled primary
      teeth were registered (df). The following indicators were determined: incidence
      of caries of primary teeth (It), total and by jaws; incidence of the untreated
      caries (Id); incidence of the treated caries (If). RESULTS: The obtained data
      suggest that It increases with age. No statistically significant difference was
      found between the values of the two genders, as well as in the comparison by
      jaws. A marked trend of decrease of the values of It in the last 5 years is
      outlined, as well as of distribution of the predominant percentage of carious and
      filled teeth into an increasingly smaller group of children.

PMID- 12422635
TI  - Caries epidemiology of the primary teeth in children from 3- to 8-years of age in
      Plovdiv.
AB  - INTRODUCTION: The need of current data on the epidemiology of caries of the
      primary teeth in 3- and 8-year-old children and establishing the trends in the
      prevalence of this disease in the last 18 years in Plovdiv determines the aim of
      the study. MATERIAL AND METHODS: The study includes 1124 children--536 girls and
      588 boys from randomly selected kindergartens and schools in Plovdiv. The carious
      and filled primary teeth were registered (df). The following indicators were
      determined: prevalence of caries per persons (Ep), prevalence of caries per teeth
      (Et) and incidence of caries per teeth (It). RESULTS: The results show that the
      values of caries indicators increase with age: Ep in 3-year-old children is
      23.13%, while in 8-year olds--83.22%. Et in 3-year-old children is 3.09%, while
      in 8-year olds--29.43%. The percentage of caries-free individuals in the target
      age group of WHO--5-year-old children is 47.32%. CONCLUSIONS: A trend of decrease
      of the prevalence and incidence of caries of the primary teeth is ascertained in
      children from 3 to 8 years of age in Plovdiv in the last 18 years. The disease is
      limited to an increasingly narrower children group.

PMID- 12422636
TI  - Surgical treatment of chronic mandibular dislocation--report of a case.
AB  - Chronic dislocation of the temporomandibular jaw (TMJ) can result from lax joint
      ligaments and parafunctioning joints; it can also be a consequence of a systemic
      connective tissue disorder. The authors report a case of hypermobile joint
      syndrome in combination with mitral valve prolapse. The case was managed by
      osteosynthesis using modified titanium plate.

PMID- 12422637
TI  - Meningioma of the lateral cerebral ventricle. A case report.
AB  - The authors present the case of a 58-year-old woman. At presentation the patient
      complained of vertigo and noise in the ears with six months history, and from
      headache, accompanied by nausea and vomiting from three months. The physical
      examination of the patient found no abnormalities. The neurological examination
      revealed discoordination syndrome and mild hemiparesis of the left limbs.
      Computed tomography of the brain without and with contrast medium showed oval
      tumor, localized in the region of trigonum collaterale and the posterior horn of
      the right lateral ventricle. Operative intervention was performed after a
      preoperative management of the patient: transcortical fenestration of the brain
      in the region of trigonum collaterale and the posterior horn of the right lateral
      ventricle. The tumor was totally removed. It is well isolated, oval in shape,
      with feeding blood vessel from plexus chorioideus and was attached to the wall of
      the ventricle with several thin bridges. Macroscopically the tumor was 3 cm in
      diameter, with smooth walls, well capsulated, grey-brownish in color and with
      firm elastic consistence. The histological findings revealed meningioma-
      meningotheliomatose variant.

PMID- 12422638
TI  - Recurrence of epidermoid cyst in the third ventricle. Case report.
AB  - The authors present the case of a 34-year-old man. The patients was admitted for
      the second time in the clinic. A year before an epidermoid cyst of the third
      ventricle, obstructing the two foramen Monroe and causing acute hydrocephaly, was
      surgically removed. In the operative intervention a cerebral fenestration of the
      lateral cerebral ventricle was performed and the epidermoid cyst was totally
      extirpated through the right foramen Monroe under operative microscope. The
      patient was discharged in excellent state, without complaints and neurological
      symptoms. The patient received attacks of severe headaches, staggering gate and
      double vision two months before his second admission. The neurological
      examination revealed paresis of left nervus abducens, staggering gait and
      pronounced psychic symptoms. The computed tomography of the brain revealed cystic
      formation, 3.4 cm in diameter, in the front part of the third cerebral ventricle.
      The intervention was performed after preoperative management of the patient and a
      cystic tumor with the histologic characteristics of an epidermoid cyst was
      totally extirpated under operative microscope, using the same approach as in the
      first operation. The patient was discharged in good state without complaints and
      no abnormalities detected in the neurological status.

PMID- 12422639
TI  - Thibierge--Weissenbach syndrome--a dynamic 17-year follow-up.
AB  - The case of a 55-year-old woman with Thieberge--Weissenbach syndrome is presented
      in this report. The disease was recognized as a separate diagnostic entity in
      1985. This study is focused on the clinical features and the course of the
      syndrome. Over a period of 17 years multiple X-ray examinations of the affected
      organs were performed. The role of radiography for the dynamic follow-up of the
      disease course is discussed.

PMID- 12422640
TI  - [Tuberculosis chemotherapy. Traditional and new approaches to the development of
      antimycobacterial drugs].

PMID- 12422641
TI  - [Effect of glucose on the antibiotic activity and antibiotic resistance of
      Streptomyces peucetius subsp. caesius ATCC 27952-2 and its mutants].
AB  - The growth of anthracycline producer Streptomices peucetius subsp. caesius ATCC
      27952-2 was inhibited by presence of glucose on complete media, containing
      alternative carbon sources. Amount of clones not producing antibiotic increased
      to 80.2 per cent along with elevation of glucose concentration in corn meal
      medium from 0.1 to 1.0 per cent. Mutants of S. peucetius subsp. caesius ATCC
      27952-2 able to grow on complete media with 2 per cent of glucose (glr-mutants)
      were obtained. Glr-mutants had decreased antibiotic production in comparison with
      27952-2 strain. 17 per cent of studied glr-mutants synthesized 1.6-3.1-fold
      quantities of anthracyclines in comparison with parental strain. Glr-mutants
      synthesized more biomass, although more slowly utilized glucose than strain 27952
      2.

PMID- 12422643
TI  - [Effect of glutoxim in the combination with antitubercular agents of the second
      choice on the growth of drug resistant Mycobacteria tuberculosis in the cultured
      murine lung tissue].
AB  - It was demonstrated that glutoxim combination with second line drugs for
      tuberculosis treatment (cycloserine + rifabutine, cycloserine + protionamide)
      provided statistically significant decrease of intracellular mycobacteria growth
      in the murine lung tissue culture. The decrease rate when compared to the control
      group was 3-5 times. The investigated Mycobacterium tuberculosis strain was
      isolated from the patient and was multi-drug resistant (MDR). Glutoxim addition
      to the second line drugs combinations provided also decrease of the MDR bacteria
      microcolonies growth in the lung tissue culture. Glutoxim combination with second
      line antituberculosis drugs allowed to keep vitality and functional activity of
      lung tissue cells.

PMID- 12422642
TI  - [Effect of levofloxacine on cell elements of the lung tissue and on the growth of
      drug resistant Mycobacteria tuberculosis].
AB  - Levofloxacin effect on morphokinetic parameters of the murine lung tissue culture
      was investigated. This model allowed also to evaluate the levofloxacin activity
      against drug-resistant intracellular and extracellular Mycobacterium
      tuberculosis: MBC was 0.5-1.0 mg/l. Bactericidal effect started on the 3d day of
      incubation and was maximal on 7th day. Tissue cells vitality was not changed.
      Combination of levofloxacin with antimycobacterial drugs of first choice was
      investigated: isoniazid demonstrated synergistic effect, pyrazinamide also
      demonstrated synergistic effect. Combination of levofloxacin with rifampicin was
      antagonistic.

PMID- 12422644
TI  - [Myrin P in the combined treatment of tuberculosis].
AB  - Experimental and clinical evaluation of the new antimycobacterial
      quadrocomposition Myrin P was performed. The composition consists of isoniazid,
      rifampicin, pyrazinamide and ethambutol in fixed doses. The results of the
      formulation application at 474 patients with primary pulmonary tuberculosis
      caused by drug-susceptible and drug-resistant mycobacteria are presented. High
      efficacy and good tolerability of the formulation was demonstrated.

PMID- 12422645
TI  - [Sensitivity of Mycobacterium tuberculosis to levofloxacin].
AB  - Susceptibility of 92 strains of mycobacteria to levofloxacin (5, 10 and 50
      mcg/mL) was investigated by indirect method of absolute concentrations on
      Levenstain-Jensen media. The investigation was performed on 85 strains of
      Mycobacterium tuberculosis isolated from 83 patients with different types of
      tuberculosis and also on drug-sensitive laboratory strains of M. tuberculosis
      H37Rv-M, H37Rv-GISK, Academia, M. bovis-bovinus 8, M. bovis BCG and on two
      strains of M. fortuitum with total resistance to antimycobacterial agents. 87.8
      per cent of clinical isolates were multi-drug resistant. From one patient treated
      with ciprofloxacin two strains of M. tuberculosis were isolated--one resistant to
      5 mcg/mL of levofloxacin and second strain-resistant to 10 mcg/mL of
      levofloxacin. All other clinical and laboratory strains of mycobacteria (97.8 per
      cent) were susceptible to all three concentrations of levofloxacin.

PMID- 12422646
TI  - [Sensitivity to levofloxacin of Mycobacterium tuberculosis strains with various
      phenotype isolated from patients with newly diagnosed and chronic tuberculosis].
AB  - Susceptibility to levofloxacin of 56 strains of Mycobacterium tuberculosis,
      isolated from 22 patients with first estimated and 84 patients with chronic
      tuberculosis was investigated. Ratio of multi-drug resistance achieved 54.5 per
      cent in first group and 94.1 per cent in the second group. 23 (41.1 per cent)
      isolated strains belonged to individual genotypes, 33 (58.9 per cent)--to Beijing
      group. All mycobacteria isolates were sensitive to critical concentration of
      levofloxacin--10 mcg/mL. The results of the investigation proves the ability to
      recommend levofloxacin application at the patients with first estimated
      tuberculosis and at the patients with most hazardous tuberculosis pathogen of
      Beijing group.

PMID- 12422647
TI  - [Sensitivity to levofloxacin of various types of non-tuberculosis Mycobacterium].
AB  - Activity of levofloxacin (Tavanic) against 10 species of nontuberculosis of
      mycobacteria was investigated by indirect method of absolute concentrations on
      Levenstain-Jensen media (levofloxacin concentration 5 and mcg/mL). The
      investigation was performed on 71 strains of nontubercolosis mycobacteria:
      Mycobacterium avium-intracellulare--24 strains, M. fortuitum--17 strains, M.
      chelonae--10 strains, M. malmoense--13 strains and 6 other species of
      mycobacteria. Susceptible to critical levofloxacin concentration were 8 species
      of 10. Resistance to levofloxacin (10 mcg/mL) was estimated for 16.7 per cent of
      M. avium-intracellulare and 30 per cent of M. chelonei strains. It is concluded
      that levofloxacin may be a drug of choice for management of mycobacteriosis
      caused by M. fortuitum, M. kansasii, M. xenopi, M. malmoense, and in the most of
      cases due to M. avium-intracellulare and M. chelonae.

PMID- 12422648
TI  - [Fibrin-collagen substance as a vehicle for local application of antibacterial
      agents].
AB  - Inhibitory activity of fibrin-collagen substance (FCS) impregnated by various
      antibacterial agents against various microorganisms was investigated. It was
      demonstrated that antibacterials bind well with FCS, providing its sufficient
      antibacterial activity. Determination of growth-inhibition zones showed that
      antibacterial agents diffuse into medium well and demonstrated the same activity
      as discs with antibiotics. For clinical practice it is recommended to use for
      impregnation the following drugs: gentamycin, meropenem, cefriaxone and
      ciprofloxacin.

PMID- 12422649
TI  - [Fluoroquinolones as antibacterial preparations and their use in the treatment of
      tuberculosis].

PMID- 12422650
TI  - [Antilipemic agents in combined therapy].
AB  - In the prevention of coronary heart disease the aim to achieve the target
      cholesterol and triglyceride levels and the maximal risk reduction leads to the
      combination of lipid lowering agents. The importance of the combination is
      supported by the fact that in monotherapy use of the high dose of the drugs, the
      lipid lowering effect is modest and the side effects are more frequent. The
      combined therapy is expected to be used more frequently despite the fact, that
      the improperly applied combination could have serious unfavourable effects. The
      authors review the advantages and drawbacks of the fibrate-statin combination,
      which could be used in the most frequent lipid abnormality, the high cholesterol
      and high triglyceride level, when the combination of micronized fenofibrate and
      fluvastatin is recommended. Beside the co-administration of other lipid lowering
      drugs (nicotine acid and resins), it is discussed the combination of statins and
      fibrates with a new, cholesterol absorption inhibitor, ezetimibe, a well
      tolerated drug with advantageous safety profile. Considering further metabolic
      risks the combination of lipid lowering drugs with glitazones, hormone
      replacement therapy, homocysteine reducing agents is as well highlighted.

PMID- 12422651
TI  - [Hypertension therapy and patient compliance].
AB  - In the treatment of chronic disease like hypertension it is very important to
      achieve good patient compliance. One third of the patients however takes his
      medicament irregularly. The failure of the treatment is usually caused by the
      patient, who is not aware of his illness, he feels healthy that's why he does not
      go to see the doctor or he stops taking the medicine. The cause of bad compliance
      can also be the doctor who does not spend enough time and energy on his patients.
      Rarely the therapy is broken off because of the side effects of the medication.
      In the last year 100 patients with hypertension were asked with help of a
      questionnaire about their drug-taking habits and their knowledge about
      hypertension. From the answers we found out that one third of the patients takes
      his drugs irregularly. Less than half of the patients reaches the normotension.
      Most of the patients who have been treated for many years do not know the goal
      blood pressure, the possible complications of hypertension, the goal of the
      treatment. Often they do not even know the name of their medicine. Compliance is
      a complicated problem. Improvement could be reached by regular teaching of the
      patients, by teaching the patients how to measure blood pressure at home, by
      increasing the number of educational publications, by regular training of the
      doctors, by keeping the rules of the treatment, by using modern and long-term
      effective drugs. It would be important to start with teaching the healthy way of
      living already at a young age.

PMID- 12422652
TI  - [Social background of small-for-gestational-age infants].
AB  - INTRODUCTION: The Small for Gestational Age birth rate is still unchanged during
      the last decades opposite to the premature birth frequency. This fact needs
      further examinations. AIM AND METHODS: The association of socio-economic status
      and the development of intrauterine growth retardation was analysed in a two year
      prospective study. The study group consisted of 34 patients having small-for
      gestational-age newborns. The control group consisted of those 68 women having
      normal term birth. RESULTS: Significant differences were found in the Body Mass
      Index, smoking habits during pregnancy, education, and poverty status. The
      difference in age was expressed, but not significant. There were no significant
      differences among alcohol and coffein consumption, family status, household
      crowding and employment. CONCLUSION: Beside the effective medical prenatal care
      the importance of education and social support is emphasised.

PMID- 12422653
TI  - [Ethics and law in intensive therapy].
AB  - INTRODUCTION: Intensive therapy is one of the newest areas of medicine. The
      patient who was thought to be hopeless yesterday is given a chance to survive. As
      in other fields of medicine parallel with their development, several ethical and
      legal problems arise and wait for solutions. AIMS: Two areas need urgent
      solutions especially at first ethical then at legal levels. These are the
      questions of life and death: where is the boundary of euthanasia and can the so
      called DNR ("Do Not Resuscitate") strategy be applied, which partial therapy
      withdrawal can be done compatibly with the basic ethical and legal requirement of
      protection of life. Important question as well, is that where lies the boundary
      of free self determination. How can be living wills be given when is it necessary
      to ask for the patient's consent, how much information is to be given to the
      patient. METHODS: Based on increasing experiences form Europe and the USA, some
      of the important fundamental principles of therapy withdrawal of intensive care
      therapy is outlined. Besides the above described questions, a short description
      of the Hungarian conditions will be given. RESULTS: Although the number of
      declarations given by professional corporations increase decisions of the jury
      help the medical practitioner in making his difficult decisions, but making the
      individual decision personal communication of the medical staff with the patient
      or his foster play an important role. Everything is the patient's right of free
      self determination based on the patient being properly informed. The ethical and
      even the legal attitude does not consider withdrawal of a widening circle of
      therapy to a form of euthanasia. CONCLUSIONS: In the mirror of international
      experiences concordance is reached in many aspects of therapy withdrawal in
      intensive care. In the mean time national regulations are not yet available, this
      is the reason, why based on the international declarations, keeping an eye on the
      Hungarian practice these regulations should be worked out in the near future.

PMID- 12422654
TI  - [Disease of the pharaoh Akhenaton].

PMID- 12422655
TI  - [In memory of Karoly Lechner].

PMID- 12422656
TI  - CT: considerations for safety, efficiency and cost containment.

PMID- 12422657
TI  - A new weapon in the treatment of non-Hodgkin's lymphoma.

PMID- 12422658
TI  - New technology enables high-speed, secure access for service.

PMID- 12422659
TI  - Staff retention and recruitment: "one great department".
AB  - The projected demand for healthcare workers during the next ten years has been
      the impetus for many organizations to develop more creative strategies to ensure
      adequate staffing levels in the future. In order to keep pace with service
      demands, the diagnostic imaging department at Valley Lutheran Medical Center
      (VLMC) in Mesa, Ariz., has been growing as well. Since November of 1999, the
      number of core FTEs increased from 54.5 to 96. As a result, efforts to retain the
      current employees became just as critical as efforts to recruit staff for the new
      positions that were created to support the expanded services. In February 2001,
      an AHRA seminar was held in Phoenix, which included a day-long session called
      "Workforce 2001: Recruitment, Selection, Retention of Quality Employees." The
      presenter, Clint Maun, C.S.P., emphasized the need to provide "passionate
      orientation" for new employees, encouraged team-based selection of new employees,
      and reminded the audience that new employees decide within the first three days
      whether or not they will stay with an organization, regardless of how long it
      actually takes to leave. Maun also described to the group a model for creating
      team effort called "One Great Unit" (OGU), which uses a "12-Week Plan" for
      engaging staff. For the diagnostic imaging department at VLMC, this concept was
      remodeled so that, instead of focusing on one modality (unit) in the department,
      the focus was on the whole department. The first step to creating "One Great
      Department" was to establish an Oversight Committee that would help define the
      focus of the 12-Week Teams. Five, front-line employees were recruited who
      represented a cross-section of the imaging department. To assist in the
      implementation, the director of learning and innovation at VLMC agreed to
      facilitate the first two meetings. The first 12-Week Team was called together in
      May 2001. The operational objective addressed was "improving communication inter-
      and intra-departmentally." Each member volunteered to take one issue to
      investigate. For instance, the team identified that unit secretaries used an
      outdated resource document for ordering radiology exams. The 2001 goal was to
      limit voluntary employee turnover to less than 15 percent, an aggressive goal
      considering that in 2000 the turnover rate was 40 percent. In January 2002, the
      2001 turnover rate was 14.5 percent (Bravo!). While we accomplished our goal,
      there are many challenges ahead. The Arizona market is so volatile that we cannot
      afford to rest on any previous success.

PMID- 12422660
TI  - Using Six Sigma to improve the film library.
AB  - The film library of a film-based radiology department is a mission-critical
      component of the department that is frequently underappreciated and under
      staffed. A poorly performing film library causes operational problems for not
      only the radiology department, but for the institution as a whole. Since Six
      Sigma techniques had proved successful in an earlier CT throughput improvement
      project, the University of Texas M.D. Anderson Cancer Center Division of
      Diagnostic Imaging decided to use Six Sigma techniques to dramatically improve
      the performance of its film library. Nine mini-project teams were formed to
      address the basic operating functions of the film library. The teams included
      film library employees, employees from other sections of radiology, employees
      from stakeholders outside of radiology, and radiologists and referring
      physicians, as appropriate to the team's mission. Each Six Sigma team developed a
      process map of the current process, reviewed or acquired baseline quantitative
      data to assess the current level of performance, and then modified the process
      map to incorporate their recommendations for improving the process. An overall
      project steering committee reviewed recommendations from each Six Sigma team to
      assure that all of the teams' efforts were coordinated and aligned with the
      overall project goals. The steering committee also provided advice on
      implementation strategies, particularly for changes that would have an immediate
      effect on stakeholders outside of the radiology department. After implementation
      of recommendations, quantitative data were collected again to determine if the
      changes were having the desired effect. Improvement in both quantitative metrics
      and in employee morale have been experienced. We continue to collect data as
      assurance that the improvements are being sustained over the long haul. Six Sigma
      techniques, which are as quantitatively-based as possible, are useful in a
      service-oriented organization, such as a film library. The primary problem we
      encountered was that most of the important film library customer services are not
      automatically captured in the RIS or in any other information system. We had to
      develop manual data collection methods for most of our performance metrics. These
      collection methods were burden-some to the frontline employees who were required
      to collect the data. Additionally, we had to invest many hours of effort into
      assuring that the data were valid since film library employees rarely have the
      educational background to readily grasp the importance of the statistical methods
      employed in Six Sigma. One of the most important lessons we learned was that film
      library employees, including supervisory personnel, must be held accountable for
      their performance in a manner that is objective, fair and constructive. The best
      methods involved feedback collected by the employees themselves in the ordinary
      course of their duties. Another important lesson we learned was that film library
      employees, as well as stakeholders outside of the film library, need to
      understand how important the film library is to the smooth functioning of the
      entire institution. Significant educational efforts must be expended to show film
      library employees how their duties affect their film library co-workers and the
      institution's patients. Physicians, nurses and employees outside of the film
      library must do their part too, which requires educational efforts that highlight
      the importance of compliance with film library policies.

PMID- 12422661
TI  - Temporary agency contracts: what should they include?
AB  - The AHRA Board committed to provide some tools to help our members with agency
      contracts. This article provides the sections for a contract and what they should
      include. Of course, the language will have to comply with your organization's
      requirements. To comply with HIPAA regulations for contracts, I've also included
      language for business associates. JCAHO requires that the following documentation
      be on file for all contracted personnel: 1. Hospital job description or formal
      contract outlining the job responsibilities. 2. All licenses, certifications and
      registrations are reviewed and a process is developed to ensure that they remain
      current. 3. Competency is evaluated and maintained. 4. Evidence that personnel
      received a general orientation. 5. Evidence that personnel received a
      departmental orientation. 6. Safety and infection control standards must be met.
      In order to aid with compliance when utilizing contracted personnel, my
      organization developed a Contractor Personnel Administrative Compliance
      Checklist, which identifies requirements for compliance, a reference for
      assistance, and places to record that the requirement has been met for each of
      the areas listed in the previous item. Our standard contract includes sections on
      general definition of engagement, credentials and work experience; health,
      including immunization and drug testing; corporation; JCAHO; terms of the
      contract; and, non-disclosure of information. A business associate agreement may
      be necessary to comply with HIPAA regulations. Using the template has made my job
      much easier than trying to read each contract that crosses my desk. If an agency
      refuses to sign our contract, then we do not conduct business with that company.
      If an agency requests changes to the contract, depending on the language, we may
      or may not agree to it. This information is not intended to be legal advice, but
      rather an educational overview. As with any contract, the reader should consult
      with legal counsel at his or her organization.

PMID- 12422662
TI  - Bottleneck or gateway to success.

PMID- 12422663
TI  - Fearless PACS.

PMID- 12422664
TI  - From Louisiana to la la land.

PMID- 12422665
TI  - [The storm around hormonal replacement therapy].

PMID- 12422666
TI  - [The clinical significance of findings in microscopic urinalysis].

PMID- 12422667
TI  - [Does inhibition of tyrosine phosphatase 1B protect from obesity and type 2
      diabetes?].

PMID- 12422668
TI  - [Regulation of serum HDL cholesterol and prevention of atherosclerosis].

PMID- 12422669
TI  - [Diagnostics and therapy of hypogammaglobulinemia].

PMID- 12422670
TI  - [Magnetic angiography and digital subtraction angiography in the diagnostic
      imaging of claudication patient].

PMID- 12422671
TI  - [Palliative radiotherapy for bone metastases--single-dose radiotherapy is
      effective].

PMID- 12422672
TI  - [Chronic low back pain].

PMID- 12422673
TI  - [On chronic prostatitis].

PMID- 12422674
TI  - [Glaucoma].

PMID- 12422675
TI  - [Deep venous thrombosis. Preventing embolism and recurrences].

PMID- 12422676
TI  - [Consulting Prof. Viola Hach-Wunderle, Frankfurt. Which patients are candidates
      for thrombosis? interview by Dr. Angelika Bischoff)].

PMID- 12422677
TI  - [Your patient with myocardial infarct. Admission to the nearest hospital or to a
      heart center?].

PMID- 12422679
TI  - [Operations with medical hypnosis. Through trance to distance from pain?
      (interview by Dr. med. Ulrich Scharmer)].

PMID- 12422678
TI  - [Tick removed. Sending on to examination?].

PMID- 12422680
TI  - [Hormonal "rejuvenation". Warning your patients from false claims!].
AB  - No intervention, including drugs and hormones, has been proven to slow or even
      reverse aging. Such promises, as well as the term "anti-aging medicine", are
      misleading. On the other hand, remarkable progress has been made in the
      prevention and treatment of age-related diseases. The use of hormones constitutes
      a potentially new option in the prevention and treatment of age-related diseases,
      but is not an established therapy. The status of scientific evidence for the
      treatment of seniors with growth hormone, melatonin, DHEA or testosterone is
      critically reviewed.

PMID- 12422681
TI  - [Anti-aging with healthy nutrition. This you can recommend!].
AB  - For a dietary anti-aging concept that "gives life to years and adds years to
      life" we recommend a low-fat, carbohydrate and fiber-rich diet containing plenty
      of fruits and vegetables and moderate amounts of protein (in particular of
      vegetable origin). Prolonging the fasting state by cancelling dinner is also of
      benefit. Five servings of fruits and vegetables (preferentially red, yellow and
      green) daily and whole-grain products provide sufficient amounts of vitamins C
      and E and the provitamin A beta-carotene, as well as secondary phytochemicals.
      Also to be recommended are low-fat dairy products, fish once or twice a week,
      little meat and eggs, and a maximum of 4-8 fl oz (1/8 to 1/4 liter) of red wine
      per day.

PMID- 12422682
TI  - [With scalpel and laser against traces of aging. Which patient wishes can be
      fulfilled?].
AB  - In our society, cosmetic surgery is on the increase. More and more men and women
      wish to improve their physical appearance. Underlying reasons are signs of aging,
      but also congenital changes. New methods of plastic surgery, e.g. liposuction,
      endoscopic procedures and low-scar techniques result in better outcomes and fewer
      complications. Nevertheless, the increasing popularity of cosmetic surgery with
      its constant media presence, is not without its dangers, since such interventions
      are not always performed by specialists. Cosmetic surgeon is not a protected
      professional title. Only plastic surgeons receive the necessary training to do
      such operations. All this means that quality assurance is of ever greater
      importance.

PMID- 12422683
TI  - [Preview of the German Lung Day. Which patients should attend lung screening?].

PMID- 12422684
TI  - ["Class 2000"--an initiative for primary education. Prevention begins in
      childhood].

PMID- 12422685
TI  - [Emergency in general practice. Acute vertigo--harmless or life threatening?].

PMID- 12422686
TI  - [Early summer meningoencephalitis and Lyme borreliosis. Relevant health risks in
      North Bavaria].

PMID- 12422687
TI  - [Abdominal cramps with fever, constipation and round liver lesion. How does this
      fit together?].

PMID- 12422688
TI  - [Bonus in reduced prescription costs. Would you comply?].

PMID- 12422689
TI  - [Professor Kossow attacks the Federal Physicians Group. Let general practitioners
      actively participate finally!].

PMID- 12422690
TI  - [Stable angina pectoris. PTCA improves symptoms, but not prognosis].

PMID- 12422691
TI  - [Selective aldosterone blocker for hypertension and heart failure. Better
      tolerance than previous drugs].

PMID- 12422692
TI  - [Bone loss stays mostly within physiological parameters. What helps in senile
      osteoporosis?].

PMID- 12422693
TI  - [Sports, diet, acarbose. Delaying the onset of diabetes].

PMID- 12422694
TI  - [User friendly inhalation system. Relief for asthmatic patients].

PMID- 12422695
TI  - [Primary sclerosing cholangitis. Early dilatation saves lives].

PMID- 12422696
TI  - [Proton pump inhibitor in reflux disease. Administer for maximum effect from the
      beginning].

PMID- 12422697
TI  - [Bisphosphonates in bone metastases. Fewer fractures, less pain].

PMID- 12422698
TI  - [Performing effective palliative medicine. General practitioner in terminal
      care].

PMID- 12422700
TI  - [Reduction in myocardial infarcts due to hormone replacement therapy? New studies
      come to a different conclusion].

PMID- 12422699
TI  - [Chronic inflammatory bowel diseases. Earlier transition to immunosuppressive
      drugs].

PMID- 12422701
TI  - [Help for suicidal colleagues. Heros also get tired].

PMID- 12422702
TI  - [Synthetic peptides and gene therapy. Is there hope for patients with dementia?].

PMID- 12422703
TI  - [Limits and possibilities of plastic surgery. Failed outcome of beak and tilted
      nose?].

PMID- 12422704
TI  - [When diet and oral antidiabetics are no longer enough. Optimal management of the
      diabetic patient with insulin].
AB  - In recent years, the approach to the insulin treatment of type 2 diabetics has
      undergone a change. Age and clinical status of the patient are decisive
      determinants for the selection of the appropriate form of treatment. The
      therapeutic strategy aims to achieve insulin substitution matched to the
      therapeutic objective, that is, continuous monitoring should be carried out to
      enable adaptation of the form and intensity of treatment to meet the target end
      point HbA1c < 6.5%. This necessity results in the earlier use of insulin in all,
      not only obese, type 2 diabetics. As a compromise solution, a certain percentage
      of these diabetics will have to be satisfied with simpler forms of insulin
      substitution and a higher HbA1c value. Attention is drawn to the other parameters
      of the metabolic syndrome, such as blood pressure, weight, and lipid metabolism.
      Particular importance attaches to non-pharmacological measures, in particular
      with the aim of avoiding a further increase in weight due to the treatment with
      insulin.

PMID- 12422706
TI  - [Strategies for control of diabetic foot syndrome. Amputation rate can be
      reduced!].
AB  - In two-thirds of the cases, wound healing can be achieved by good wound care,
      namely structured and stage-related management. Some 30% of the cases require
      extended and innovative therapeutic measures. In these complicated, poorly
      healing wounds, the supplementary use of special wound dressings or wound
      medication in the granulation phase can be considered. The application of such
      substances promoting wound healing (growth factors, cytokinin modulators, e.g.
      hyaluronic acid or protease inhibitors) may help to activate chronic lesions and
      thus initiate, and in particular abbreviate, healing. This aspect of reduced
      healing duration is of particular importance in the diabetic lesion, since it
      prevents or reduces secondary infection, the most common cause of major
      amputation.

PMID- 12422705
TI  - [Glinides and glitazones in diabetes treatment. Are they really effective?].
AB  - Good glucose control is a prerequisite for the prevention of long-term
      complications in type 2 diabetics. In recent years, two new groups of substances
      have been approved for the oral treatment of type 2 diabetes: glinides and
      glitazones. The former are short-acting agents that promote insulin secretion and
      offer an alternative to the sulfonylureas, in particular in patients with
      irregular eating habits and high postprandial glucose peaks. The glitazones
      improve one of the disorders underlying type 2 diabetes, insulin resistance. They
      are used in particular in patients who are inadequately controlled with a
      sulfonylurea or metformin and who show insulin resistance. Both groups of
      substances are a useful addition to the antidiabetic drug armamentarium. Endpoint
      studies involving these substances have, however, not yet been performed.

PMID- 12422707
TI  - [After cat bite antibiotics are obligatory. Acute management of bite injuries].

PMID- 12422708
TI  - [Smoking cessation in general practice. A new program is over 50% effective].

PMID- 12422709
TI  - [Smoking cessation as IGeL procedure. Cost effective for physician and patient].

PMID- 12422710
TI  - [Acute ischemia of the extremities. As critical as a myocardial infarct].
AB  - Acute limb ischemia is a vascular-surgical emergency requiring immediate referral
      to a hospital provided with all the necessary therapeutic facilities. Essential
      initial measures are protection of the limb against continued cooling, management
      of pain, and bolus administration of heparin. For the physician providing further
      care, not only an accurate history, but, ideally, also the results of earlier
      investigations such as ECG, abdominal US or Doppler studies, provide useful
      information. In patients who have not undergone prior surgery vascular-surgical
      management, that is, embolectomy with a balloon catheter, is the treatment of
      choice. Furthermore, the patient requires continuing care after discharge; here,
      wound management and the supervision of anticoagulation measures that might be
      needed are important tasks for the general practitioner.

PMID- 12422711
TI  - [Wishes of patients from health care reform. Voting rights in GKV and more
      information about the physician].

PMID- 12422712
TI  - [More frequent Doppler examinations in suspected peripheral arterial occlusive
      disease. Otherwise the outcome for sedentary patients can be an infarct].

PMID- 12422713
TI  - [Diabetes: LDL must be less than 100 mg/dl. Sweet vessels occlude more easily].

PMID- 12422714
TI  - [New indications. ACE inhibitor is now included in coronary heart disease
      therapy].

PMID- 12422715
TI  - [Bronchial asthma. Small bronchi are not spared].

PMID- 12422716
TI  - [Despite antihypertensive treatment with beta-blocker patients remain
      incapacitated].

PMID- 12422717
TI  - [Vascular damage decides prognosis of type 2 diabetic patients. Lowering blood
      glucose is not enough].

PMID- 12422718
TI  - [Fibromyalgia patient or simulating patient? You can tell from the tender
      points].

PMID- 12422719
TI  - [Electromagnetic fields. Telephoning until DNA is damaged?].

PMID- 12422720
TI  - [Infarct self test is approve. A new toy for the hypochondriac? (interview by Dr.
      med. Ulrich Scharmer)].

PMID- 12422721
TI  - [Should the primary care physician do fundoscopy? Patient referral to the
      specialist].

PMID- 12422722
TI  - [Do vascular stents solve the restenosis problem? You are too optimistic!].

PMID- 12422723
TI  - [Nutrition counseling for type 2 diabetic patients. Specialists are available for
      this!].

PMID- 12422724
TI  - [Increased triglycerides and/or low HDL cholesterol. A risk factor needing
      treatment?].
AB  - Elevated LDL (low density lipoprotein) cholesterol is considered an established
      risk factor for the development of atherosclerotic sequelae. In this context, low
      HDL cholesterol and/or raised triglyceride levels are now also receiving
      increasing attention as independent risk factors for atherosclerosis. The
      protective HDL cholesterol should be as high as possible (> 40 mg/dl or 1.0
      mmol/l). Low HDL cholesterol levels are associated with an increased coronary
      risk that cannot be eliminated by lowering LDL cholesterol concentrations.
      Measures to elevate HDL are primarily dietary adjustments, cessation of smoking,
      weight reduction and increased physical activity. Triglyceride levels above 1000
      mg/dL are also associated with an increased risk for the development of
      pancreatitis, and therefore also need to be treated.

PMID- 12422725
TI  - [Current therapy of hypercholesterolemia. How much statin does your patient
      need?].
AB  - Today, statins play an important role in the treatment of hypercholesterolemia.
      They have two effects on the metabolism of cholesterol: firstly, they reduce the
      synthesis of cholesterol and secondly they stimulate the expression of LDL
      receptors. LDL is reduced via both of the mechanisms. Various studies (the 4S,
      LIPID and CARE studies) have demonstrated the efficacy of statins in secondary
      prevention, that is, in patients with hypercholesterolemia and CAD. In the CARE
      study, for example, the statins reduced the incidence of fatal and non-fatal
      myocardial infarctions by 24%. A number of studies show that although primary
      prevention is effective, long-term tolerability is still a matter of controversy.
      A relatively frequent, dose-dependent side effect is myopathy, which has a
      reported incidence of 0.1-0.5%. In combination with fibrates, the incidence
      increases, and cases of rhabdomyolysis, some fatal, have been described. To
      minimize the side effects of statin treatment, therefore, target levels--which
      must be derived on the basis of the results of large studies--must be established
      for the individual patient.

PMID- 12422726
TI  - [Secondary prevention of cardiovascular diseases. What do you recommend to your
      patients after myocardial infarct?].

PMID- 12422727
TI  - [Acute venous thrombosis. When should it be operated?].

PMID- 12422728
TI  - [The essentials of thrombosis therapy. Anticoagulation and compression].

PMID- 12422729
TI  - [Autonomic neuropathies in diabetic patients. Heart involvement signals poor
      prognosis].

PMID- 12422730
TI  - [Principles of general ultrasound practice. Assessment of acute pelvic pain].

PMID- 12422731
TI  - [Compression therapy of venous varicose ulcer. New bandage saves time and money].

PMID- 12422732
TI  - [Focus on the HIV patient: from simple therapy regimen to long-term success].

PMID- 12422733
TI  - [New protease inhibitor atazanavir. Simple administration--less resistance].

PMID- 12422734
TI  - [43 million prescriptions analyzed. Are your women patients valued and costly?].

PMID- 12422735
TI  - [4 years sildenafil: new quality of life for many].

PMID- 12422736
TI  - [No taboo for heart patients].

PMID- 12422737
TI  - [Migraine has many faces. Success in differential diagnosis].

PMID- 12422738
TI  - [Already the drug of choices in the USA. Coxibe in joint pain].

PMID- 12422739
TI  - [Diabetes prevention. With the stomach shrinks the risk].

PMID- 12422740
TI  - [Theophylline in asthma and COPD. Saving on inhalational steroids].

PMID- 12422741
TI  - [MEDIAS 2 educational program. Turns the patient into a diabetes expert].

PMID- 12422742
TI  - [A better diuretic for patients with heart failure. Better control of potassium
      loss].

PMID- 12422743
TI  - [Case report. Dementia with apathy].

PMID- 12422744
TI  - [N. Lenau, the "lyricist of melancholia", described his soul's needs . As if I
      carried a dead person around inside of me].

PMID- 12422745
TI  - ["Sham" surgery. A study from the USA shows that placebo surgery is as good as
      arthroscopic debridement and lavage].

PMID- 12422746
TI  - [Financial interests characterize published reports on coxiber. Whom can we rely
      on?].

PMID- 12422747
TI  - [Alternative medicine is not always a worse alternative].

PMID- 12422748
TI  - [The CLASS study and its scientific statement. Ethical publishing rules
      neglected].

PMID- 12422749
TI  - [Transplantation and donation of tissues--six years with the new law. Experiences
      from the tissue bank in Lund].
AB  - Tissue transplantation is more common than organ transplantation. Legislative
      changes in 1996 transformed tissue banking and conditions for tissue
      transplantation in Sweden. After an initial decrease in donated tissue, heart
      valves are now available in sufficient numbers, but there is sometimes a shortage
      of valves the right size for pediatric cardiac surgery. Since the new
      transplantation legislation was implemented there has been an increase in the
      number of valves from neonatal donation and after sudden infant death. The number
      of donated corneas does not correspond to the number required for
      transplantation. A number of tissue coordinators have been established throughout
      the country and recently some new tissue banks were founded to increase the
      amount of tissue available for transplantation. The organization of the tissue
      bank in Lund is described. There is a lack of knowledge about tissue
      transplantation and donation among health professionals as well as the general
      public, and more education is warranted.

PMID- 12422750
TI  - [Survey of the use of antibiotics within geriatric care. Education is necessary
      for both physicians and nurses].

PMID- 12422751
TI  - [5-HTOL--a new biochemical alcohol marker with forensic applications].
AB  - The concentration of ethanol in blood and urine provides important evidence in
      criminal and civil litigation when alcohol-related crimes are investigated (e.g.,
      drunk driving). The determination of ethanol in body fluids is a routine
      procedure at forensic chemistry and toxicology laboratories and when gas
      chromatographic methods are used accurate and precise results are obtained.
      However, the risk for artifactual formation of ethanol, especially in postmortem
      specimens, always needs to be considered. The ratio of 5-HTOL/5-HIAA in urine
      provides a useful way to distinguish between ethanol produced after death, or
      generated in vitro after sampling, from the ethanol consumed. This article
      describes the application of the 5-HTOL/5-HIAA ratio as a biochemical marker for
      acute alcohol intake in various forensic situations. Examples include suspected
      drunk drivers, rape victims, and medico-legal autopsies where forensic ethanol
      analysis is requested.

PMID- 12422752
TI  - [MnDPDP--contrast medium with protective effect in acute myocardial infarction].

PMID- 12422753
TI  - [Increased use of complementary and alternative therapies within pediatrics. Has
      medicine failed?].

PMID- 12422755
TI  - [Complementary and alternative therapies and/or medicine. Well-reasoned
      therapeutic choices require educated patients].

PMID- 12422754
TI  - [A natural product from India that lowers blood cholesterol].

PMID- 12422756
TI  - [Alternative therapies are gaining ground in spite of the great progress of
      medicine].

PMID- 12422757
TI  - [Six perspectives on comorbidity and multiple treatments among the elderly: How
      do we know that the taken therapeutic measures are efficient?].

PMID- 12422758
TI  - [Writing sickness certificates is a pedagogical task--which sometimes can be
      performed via telephone].

PMID- 12422759
TI  - [Geriatrics in Kalmar are developing with the help of consultants in community
      health care].

PMID- 12422760
TI  - [Geriatrics are wanted!].

PMID- 12422761
TI  - [Placebo effect implies a good patient-physician relation].

PMID- 12422762
TI  - [SBU: Obesity costs 2 percent of health care budget].

PMID- 12422763
TI  - [What is the opinion of the Medical Society when it comes to manpower
      immigration?].

PMID- 12422764
TI  - [Low p-values are not all!].

PMID- 12422765
TI  - [Laparoscopic surgery of colorectal cancer. Apropos of 103 interventions].
AB  - PURPOSE: The aim of this study was to assess the feasibility and safety of
      laparoscopic surgery for the cure of colorectal cancer and to evaluate the
      oncologic follow-up. METHODS: Between March 1993 and December 2000 103 patients
      with colorectal cancer were treated by laparoscopy. Surgical, pathologic and
      follow-up data were recorded in a prospective registry database and analyzed by
      type of resection. RESULTS: A total of 42 women and 61 men with a mean age of
      66.7 years underwent 9 right hemicolectomies, 6 left hemicolectomies, 35
      sigmoidectomies, 41 low anterior resections and 12 abdominoperineal resections.
      Conversion was necessary in 14.5%. Postoperative complications occurred in 21
      patients (20.3%) and decreased with experience. Hospital mortality was 0.9%. All
      cancers (31% stage UICCI, 28% stage II, 37% stage III et 3% stage IV) were
      resected with tumor-free margins and the mean number of lymph nodes was 19.6.
      Patients resumed solid diet on the second postoperative day and mean
      hospitalization was 12.6 days. Three port site recurrences, 4 local recurrences
      and 10 distant metastases occurred after a mean follow-up of 34.5 months (8-92).
      CONCLUSION: Laparoscopic colorectal cancer surgery is technically feasible with
      acceptable morbidity and low mortality. An oncologic adequate resection can be
      performed. To determine whether the recurrence rates and the survival data are
      equivalent to open surgery, prospective randomized trials are necessary.

PMID- 12422766
TI  - Morbidity and outcome after sentinel lymph node dissection in patients with early
      stage malignant cutaneous melanoma.
AB  - OBJECTIVE: Prospective analysis of the morbidity and outcome of the sentinel
      lymph node (SLN) technique in a consecutive series of patients with early-stage
      melanoma. METHODS: Between 1997 and 1998, 60 patients with stage IB-II malignant
      melanoma underwent SLN dissection. Preoperative dynamic lymphoscintigraphy with
      mapping of the lymph vessels and lymph nodes and location of the sentinel node
      was performed the day before SLN dissection. SLN was identified by use of the
      blue dye technique. SLN was assessed for histopathological and
      immunohistochemical examination. Postoperative morbidity and mortality were
      recorded. Follow-up consisted of repetitive clinical examination with lymph nodes
      status, laboratory and radiologic findings. RESULTS: Tumor-positive SLN was
      observed in 18% of the patients and stage II disease was found in 91% of the
      patients with positive SLN. Breslow thickness was the only significant factor
      predicting involvement of a SLN (p = 0.02). In 36% of the positive SLN,
      metastases could be assessed only by immunohistochemical examination.
      Postoperative complications after SLN dissection were observed in 5% in
      comparison with 36% after elective lymph node dissection. After a mean follow-up
      of 32 months, recurrence was observed in 3% with a mean disease-free survival of
      8 months. Overall survival was 82% and 90% in patients with positive and negative
      SLN, respectively. Overall mortality was 15%, due to distant metastases in 78% of
      the cases. CONCLUSIONS: Staging of early-stage melanoma with the SLN dissection
      by use of the blue dye technique combined to lymphoscintigraphy and
      immunohistochemistry is reliable and safe, with less morbidity than elective
      lymphadenectomy. Long-term follow-up is mandatory to establish the exact
      reliability of SLN dissection.

PMID- 12422767
TI  - [Merkel cell carcinoma. Retrospective analysis of 4 cases with special reference
      to diagnosis, therapy and long-term outcome].
AB  - BACKGROUND: Merkel cell carcinoma is an aggressive neuro-endocrine skin tumor
      with early regional lymph node involvement and early distant metastases.
      Diagnostic work-up may be difficult because of the low incidence of the tumor.
      Treatment concepts are individual and long-term-outcome are varying markedly.
      METHODS: Retrospective analyse of four cases with special regard to the
      diagnostic, therapeutic approach and the long-term follow-up. RESULTS: In every
      case diagnosis has only been made histologically. In the first patient, suffering
      from a tumor on the upper arm, after the tumor removal, local and axillary
      radiotherapy has been performed. In a second case with an extended tumor on the
      shank, a palliative tumor-debulking was followed by a chemo- and radiotherapy.
      The third Patient had a tumor in the gluteal region with involvement of the
      regional lymph nodes. He was treated by a complete surgical excision and
      lymphadenectomy followed by a local radiotherapy with subsequent chemotherapy.
      The fourth patient with tumor on the elbow, without lymph node involvement,
      refused surgical intervention, therefore she has been treated by radio- and
      chemotherapy. All patients are respectively 1.2 and 3 years are alive without
      evidence of recurrence. One patient died after 1.5 year because of tumor relapse.
      CONCLUSION: Diagnosis of Merkel cell carcinoma is difficult and is established
      only by in- or excision biopsy of the tumor. If ever possible surgical excision
      combined with regional lymphadenectomy should be performed. Adjuvant radiotherapy
      is established, whereas the value of chemotherapy has not yet be defined and
      might be beneficial only in cases of expansive or disseminated growth. In our
      series we did encounter the often described metastatic involvement of other
      organs just in one case.

PMID- 12422768
TI  - [Blind loop syndrome].
AB  - Malabsorption can raise from several causes, including post surgical conditions.
      Noticeably, ileo-ileal anastomosis can lead to bacterial stagnation in the
      caecum, with recirculation of the intestinal content, and intestinal spreading of
      the colonic flora. We review here nine cases who were operated on in our
      department in the last 20 years. In five patients the syndrome appeared after an
      intestinal resection due to a postsurgical intestinal infarction due to
      adhesions. In four patients it appeared after an ileo-transverse derivation
      motivated by post-surgical occlusion. We conclude that any type of malabsorption
      appearing after abdominal surgery, even remotely from the surgical procedure
      should suggest this uncommon diagnosis. Surgical treatment, i.e. replacement of
      the intestinal anastomosis with a new termino-terminal anastomosis, is necessary
      and sufficient.

PMID- 12422769
TI  - [Bilateral popliteal artery entrapment syndrome. Is preventive operation on the
      asymptomatic side indicated?].
AB  - Popliteal artery entrapment is a rare cause of claudication symptoms, but should
      always be included in the differential diagnosis of lower limb ischaemia in young
      patients, especially men. On an embryological basis, PAES is the result of the
      abnormal development of the popliteal artery or the gastrocnemius muscle. The
      anomaly is manifested as one of four types. Untreated, the entrapment results in
      the deterioration of the artery, resulting in eventual occlusion. Presenting the
      case of a 37 year old female patient with bilateral PAES and a review of the
      literature we discuss the clinical findings, diagnosis, treatment options and the
      management of the often asymptomatic opposite side.

PMID- 12422771
TI  - Krukenberg's tumor, three years after a colic carcinoma.
AB  - We report a case of left ovarian Krukenberg's tumor in a 65 year-old patient,
      three years after resection of a colonic carcinoma (pT3, G2, pN1, Stage 3, Dukes
      C). The case is briefly discussed with reference to the literature. Krukenberg's
      tumor usually occurs in younger patients, with a peak frequency before 40 years.
      Both ovaries are involved in 90% of cases. Pathogenetically the ovarian
      involvement arises either from hematogenous, lymphatic spreading or from
      contiguous extension from the primary colonic tumor. There may be some anatomic
      predispositions such as utero-ovarian vessel anastomosis in the ligamentum latum
      or by peritoneal adhesions.

PMID- 12422770
TI  - [Combination of plate and external fixator for biological osteosynthesis of
      comminuted fractures].
AB  - In a comminuted fracture, a unilateral plate doesn't always give enough stability
      because the contralateral cortex cannot be used as a buttress. New plate systems
      as the Locking Compression Plate (LCP) may solve this problem. Another method to
      stabilize the contralateral cortex is by using an External Fixator (EF) in
      addition to a conventional platte either on the opposite side of the plate or on
      the ipsilateral side over the plate. By doing so, a half frame of an EF acts as a
      substitute for the damaged cortex. This method is easily available and may also
      be considered when a conventional plate osteosynthesis must be mechanically
      improved after the conventional plate is already put in place. With this
      combination of a plate with a EF we treated twelve patients with comminuted
      fractures of the tibia, the humerus and the femur. Eleven fractures healed
      without further operations or complications. In one case, there was a superficial
      wound infection with Staph. epidermidis that lead to an early metal removal, but
      healing of the fracture was not impaired. We also tested this set-up in a model
      and found, that the additional EF increased the stiffness of the plate by 73% for
      axial load. The combination of a plate and a contralateral EP is a useful way to
      treat comminuted fractures biologically achieving enough stability to allow early
      motion of the adjacent joints and fast healing of the fracture. Especially for
      fractures adjacent to a joint, this method is an alternative to an intramedullary
      nail.

PMID- 12422772
TI  - [Sprue].
AB  - Coeliac disease is an inflammatory disease of the small intestine. Coeliac
      disease occurs in individuals suffering from a genetically caused gluten
      intolerance. Mean clinical findings are malabsorption for several nutrients or
      steatorrhoe. Silent or latent courses are common. The diagnosis is based upon the
      histological finding of villous atrophy in duodenal or jejunal biopsies. Anti
      endomysium-antibodies are of high sensitivity and specificity. After gluten free
      diet the coeliac disease improves. Gluten free diet has to be taken lifelong
      preventing complications i.e. osteoporosis and malignancies.

PMID- 12422773
TI  - [Whipple disease--a rare systemic disease].
AB  - Whipple's disease is a rare, without antibiotic treatment deadly systemic
      infectious disease caused by the ubiquitary Gram positive bacterium Tropheryma
      whipplei. The agent can be demonstrated by light and electron microscopy and by
      PCR in tissues and body fluids affected. Men are affected more often than women.
      Most patients lose weight, have diarrhea, abdominal pain and arthralgias. In 10
      40% of cases involvement of the CNS, often asymptomatic, is observed. PAS
      positive macrophages in the lamina propria of duodenal biopsies are typical but
      not pathognomonic of Whipple's disease. Nowadays, the infectious agent should
      also be demonstrated by PCR. Treatment, mostly as a sequential therapy, is with
      antibiotics that cross the blood-brain barrier and should last for at least 1
      year in order to avoid relapses. Before ending therapy the absence of Tropheryma
      whipplei in duodenal tissue and cerebrospinal fluid must be confirmed.

PMID- 12422774
TI  - [Tumors of the small intestine].
AB  - Tumors of the small bowel are uncommon. Most of them are malignant neoplasmas
      with bad outcome. To ameliorate the doubtful prognosis tumors should be clarified
      carefully by means of histological, immunohistochemical and molecular methods.
      Patients suffering from familial adenomatous polyposis are at high risk to
      develop adenomas and adenocarcinomas of the duodenum. Therefore, the upper
      gastrointestinal tract should be monitored endoscopically in regular intervals.
      Surgically unresectable or metastatic malignant gastrointestinal stromal tumors
      should be included in an EORTC trial assessing the clinical activity of STI-571.
      This agent inhibits KIT-tyrosine kinase activity thus leading to a reduction of
      the tumor mass. Moreover, the WHO classification of lymphomas enables a more
      precise prognosis and individually tailored therapeutic strategies in primary
      lymphomas of the small bowel.

PMID- 12422775
TI  - [Eosinophilia and papular exanthema].

PMID- 12422776
TI  - [Sentinel lymph nodes: new localization technologies].

PMID- 12422777
TI  - [Correlation between chronic gastritis of the gastric stump, Helicobacter pylori
      infections and iron deficiency after gastrectomy for gastric cancer].
AB  - Atrophic chronic gastritis and Helicobacter pylori infection are considered
      possible causes of iron deficiency anemia, and sideropenic anemia is also
      frequent after subtotal gastrectomy. In this study, thirty-three patients who
      underwent subtotal gastrectomy for primary adenocarcinoma of stomach were follow
      up for at least 3 years, and included in this analysis. The presence of atrophic
      gastritis and H. pylori infection were detected by biopsy sampling and endoscopy
      every year after surgery. The iron status was evaluated by the assay of serum
      ferritin, serum iron and hemoglobin level. Statistical analysis revealed that
      atrophic gastritis was associated with lower iron serum levels, and gastric stump
      H. pylori infection was related to lower serum ferritin levels; on the contrary,
      no correlation of these factors with sex, age, malabsorption symptoms and stage
      of tumor was found. Atrophic chronic gastritis and Helicobacter pylori infection
      seem to play an important role as possible causes of post gastrectomy anaemia.

PMID- 12422778
TI  - [Sarcoma of the breast. Two clinical cases and review of the literature].
AB  - BACKGROUND: Sarcomas of the breast are rare neoplasm. Wide discordances exist
      about prognostic factors, therapy and life expectancy. METHODS: Two women
      affected by sarcoma of the breast; prognostic aspects and therapy are analyzed.
      RESULTS: After radical mastectomy one patient, with neoplasm of 4.5 cm in
      diameter, is still alive one year after the surgical procedure. CONCLUSIONS:
      Diagnosis of the sarcomas of the breast is very difficult with the common
      radiological imaging, specially in the early phases when the sarcomas often can
      simulate absolutely benign lesions. Prognostic factors are histological type and
      degree, mytosis number for field and, probably, dimensions of the neoplasm.
      Sarcomas less than 3 cm in diameter can be admitted to conservative surgical
      procedure, but radical mastectomy is unavoidable when dimensions exceed this
      limit.

PMID- 12422779
TI  - [Synchronous multiple gastric adenocarcinoma: a clinical case].
AB  - The Authors present a case of synchronous double gastric carcinoma in a 75-year
      old man. Synchronous multiple gastric carcinoma (SMGC) constitutes 4% to 10% of
      all gastric cancers. It exhibits several clinicopathological characteristics that
      differ from those of solitary cancers: SMGC occurs in older people (men more than
      women); early carcinoma is observed more frequently in SMGC than in solitary
      cancers; the rate of intestinal type lesions is higher in multiple than in single
      gastric carcinoma. With regard to the pathogenesis of multiple gastric cancer,
      the theory proposing a multicentric or independent origin rather than the local
      or distant spread of one cancer (multifocality) has been favored.

PMID- 12422780
TI  - [Clinical-therapeutic features of gynecomastia].
AB  - This study reports 36 cases of gynaecomastia surgically treated. The median age
      was 25-years old (range 14-65 years). In 27 patients (75%) gynaecomastia was
      bilateral, in the others only one breast was interested. According to Simon's
      classification; 12 patients with stage 1, 18 stage 2a, 3 stage 2b and 3 stage 3
      were observed. A specific cause was discovered in 12 cases: 2 Klinefelter
      syndrome and 10 adipomastia. Other 24 cases had an idiopathic origin.
      Subcutaneous mastectomy, through inferior periareolar approach was performed to
      all patients while submammary approach was reserved in selected patients (stage
      3).

PMID- 12422781
TI  - [Pica and intestinal occlusion: a clinical case].
AB  - Accidental or voluntary foreign bodies ingestion is a frequent reported event in
      emergency departments. Complication, foreign body shape related are not often
      observed and, once occurred, just few a cases need an open surgery approach,
      about 1%. The Authors report the case of a young woman with pica admitted to
      their Department in an emergency setting for acute intestinal obstruction due to
      the ingestion of not specified amount of elastics, which required an open surgery
      operation.

PMID- 12422782
TI  - [Non-Hodgkin's lymphoma of the testis. Report of a clinical case and review of
      the literature].
AB  - The Authors report a case of primary non-Hodgkin's lymphoma of the testis.
      Although lymphoma is a rare neoplasm, it is commonest tumor in the elderly age.
      Surgical therapy is essential but some times it can be associated to radio
      chemotherapy.

PMID- 12422783
TI  - [Difficult endoscopic extraction: pneumomediastinum and bilateral pneumothorax
      after attempted endoscopic extraction of needle incarcerated in hiatal hernia].
AB  - From June 1987 to April 2000, 167 (74%) of 223 patients suspected of swallowing
      foreign bodies were treated. Hundred-sixty-three were successfully treated
      endoscopically. The surgery rate was 2.4%. There was failure to remove a
      tablespoon, a tooth-brush, a dental prostheses with metallic hook, a knitting
      needle. The sharp and pointed foreign bodies were 35 (20.9%). Endoscopic removal
      of sharp and pointed foreign bodies in the upper gastrointestinal tract can be
      very difficult to manage. The Authors report iatrogenic perforation of esophagus
      gastric-fundus in a patient with hiatus hernia who ingested a big knitting-needle
      in order to suicide. They think that it is absolutely necessary to use special
      endoscopic equipment during the taking out of foreign-body procedure, especially
      when pointed and sharp-edge shaped bodies are involved and when there is high
      risk of iatrogenic lesions.

PMID- 12422784
TI  - [Intraoperative cholangiography in videolaparoscopic cholecystectomy:
      indications, advantages, and limitations].
AB  - Consensus doesn't exist about the intraoperative cholangiography specially if is
      need in every one laparoscopic cholecystectomy either exclusively in case of
      anatomical doubts or suspect of injures or stones of the common duct. We have
      considered 450 patient subjected to laparoscopic cholecystectomy during 1992
      2000. Patients suspicious to be affected by common duct lithiasis (28 cases) are
      subjected to ERCP with cleaning of the biliary tree. In 18 patients (4%) it has
      been necessary the laparotomic conversion; 176 patients (39%) have been subjected
      to intraoperative cholangiography, selected on anatomical regional disposition or
      anamnesis and biochemical and instrumental results (history of jaundice or
      gallstones pancreatitis, abnormal serum level of the biliary stasis biochemistry,
      common bile duct major of 8 mm, michrolitiasis of the gallbladder). In 7 cases
      (4%) we have discovered common bile duct stones. We don't attempt intraoperative
      cholangiography in every one laparoscopic cholecystectomy, but only in cases
      where we suspect presence of common bile duct stones either iatrogenic injuries
      or when we retain it necessary to clarify the regional anatomy. Unlikely just in
      patients where would be more useful, causes major risk of intra- and post
      operative complications, it is very difficult, often impossible, to attempt the
      intraoperative cholangiography. Routinary employing of the intraoperative
      cholangiography could be useful just for a little number of patients, while
      selective employing reduce 60% the X-ray. Collaboration with the radiologist is
      able to reduce the mistaken on the interpretation of the radiograms.

PMID- 12422785
TI  - [Surgical treatment of hemorrhoids in day-surgery].
AB  - The Authors report their own experience with day-surgery treatment of
      haemorrhoids and underline the advantages in terms of patients' compliance and
      reduction of the sanitary management in order to the cost that this way suggests.
      The serie here reported includes 72 patients treated, by two years, with day
      surgery haemorrhoidectomy. Here are indicated criteria of selection of the
      patients, related to the state of the illness, association of other pathologies
      and social factors. All the patients, moreover, have been treated according to a
      scheme that generally includes: a careful preoperatory valuation, local
      anaesthesia, standardized surgical method (Milligan-Morgan intervention),
      dimission few hours after the operation, control of the patients at their own
      home. The results obtained, careful examinted through an objective valuation
      (complications, relapses, time or reability) and subjective one (index of
      satisfaction of the patients), can be considered extremely positive.

PMID- 12422786
TI  - [Study of the facial nerve in parotid surgery].
AB  - The Authors, basing on cadaveric dissections and 40 parotidectomies performed,
      accurately describe relations between facial nerve and surrounding tissues in its
      extracranial tract, with particular reference to parotid surgery. They underline
      Schwalbe's apophysis as the sole safe and constant anatomic landmark in the
      dissection of the facial nerve trunk.

PMID- 12422788
TI  - Spotting patterns on the fly.
AB  - Recognizing and anticipating change in industry patterns is a core competence for
      companies today, allowing managers to capitalize on opportunities before they are
      apparent to others. Yet despite the growing realization that recognizing patterns
      is important, companies are far from mastering how to do it, especially at the
      strategic level, where information is usually less profuse and much less precise.
      Pattern recognition is not a new skill, though, at least not to people outside
      the business world. Since antiquity, naturalists have relied on their ability to
      spot patterns to make sense of their surroundings. And surprisingly, there is
      much businesspeople can learn from bird-watching--as removed as it may seem from
      the fast-paced, bruising world of business--in terms of the cognitive demands
      pattern recognition requires. To learn more, HBR spoke with David Sibley, perhaps
      the nation's foremost birdwatcher and illustrator, and Julia Yoshida, a birder
      since 1965 and a physician at the Lahey Clinic in Burlington, Massachusetts.
      Sibley explains how expert birders draw on a wealth of tacit knowledge built up
      over the years to make identifications in a matter of seconds: "Once you've
      mastered common patterns, the real trick is to educate yourself about where
      discrepancies are most likely to appear--and to concentrate your attention on
      those areas." Although so fast as to be almost unconscious, the process he
      describes seems to be as methodical as one of Yoshida's medical diagnoses.
      "Recognizing a pattern involves knowing what to look for, what the possibilities
      are, and then sorting out those patterns when you are actually confronted with
      the patient," Yoshida says. "I don't think it's a eureka moment at all. It's a
      methodical process."

PMID- 12422787
TI  - The moonlighter.
AB  - Jeremy Hicks, Zagante Systems' lead programmer, walks into the office at eight
      o'clock on a Sunday night and does a double take when he spots his boss, Melanie.
      She's equally surprised to find she isn't alone. Before leaving for the evening,
      Melanie pays Jeremy a visit, only to discover that he isn't hard at work on
      Zagante's new product--he's programming a game for another company. The next day
      over lunch, Melanie confronts Jeremy and lets him know that he needs to stay
      focused on Zagante's new software. Jeremy insists that he's fully engaged in it.
      So Melanie agrees to keep the moonlighting under wraps so long as it doesn't
      interfere with Jeremy's job. That night, Melanie sits down at her laptop and
      opens up a Google window. "Moonlighting," she types. Dismayed at the number of
      hits, she changes her search to "Fired for moonlighting." This search leads her
      to case after case, but none helps her with Jeremy. She tries one more time.
      "Promoted for moonlighting," she types. No surprise. Zero hits. Frustrated with
      Jeremy, yet anxious to keep such a talented employee, Melanie turns to Jill
      Darby, Zagante's HR director, for guidance. Jill has both good and bad news. The
      bad news is that the company has no moonlighting policy. The good news is that
      Jill can arrange for Jeremy to receive a low-interest loan. But when Melanie
      tells Jeremy about the loan, he doesn't go for it. He's not just freelancing for
      the money, it turns out; he's downright enjoying the work and doesn't appreciate
      his boss butting in to his private business. How should Melanie handle this
      moonlighting issue? Commentators Bill Jensen, author of Work 2.0: Rewriting the
      Contract; attorney Barry LePatner; economics professors Jean Kimmel and Karen
      Conway; and HR director Sandra Davis offer advice in this fictional case study.

PMID- 12422789
TI  - Arm yourself for the coming battle over Social Security.
AB  - The U.S. Social Security system is in deep trouble--and that's not just bad news
      for your friends and family. It's also bad news for your company. Unless the
      Social Security system is changed, by 2017 the cash flowing out of it will exceed
      the cash coming in, and by 2041 the system will be utterly insolvent. But the
      trouble will start sooner than that: In the next decade, the very prospect of the
      rising deficit will mean serious pressure on recent tax cuts, higher long-term
      interest rates, increased pension-funding costs, and other punishing conditions
      for U.S. businesses. Clearly, there's a lot at stake for companies, which is why
      executives need to participate in the growing debate about Social Security
      reform, says Robert Pozen, a visiting professor at Harvard Law School who served
      on the President's Commission to Strengthen Social Security. In this article, he
      urges business leaders to take a stance on how the system should be reformed,
      suggesting they work with interest groups to make their voices heard. After
      taking a comprehensive look at the debates surrounding Social Security reform,
      Pozen outlines the three main alternatives executives might choose to support:
      increasing contributions to Social Security, decreasing the growth of benefits
      for more-affluent workers, and increasing investment returns on Social Security
      assets. What's needed to fix the current system, he contends, is a careful
      balance of all three.

PMID- 12422790
TI  - The Empire strikes back. Counterrevolutionary strategies for industry leaders.
AB  - Industry leaders frequently worry that their companies will fall victim to some
      revolutionary business model or disruptive technology. But new research shows
      that it's strategically better for incumbents to counter a revolution than to
      ignore or fully embrace it. Successful incumbents rely on one or more of five
      approaches to restrain, modify, or, if necessary, neutralize a revolutionary
      threat. A company that perceives a revolution in its earliest stages can use
      containment strategies. By throwing up roadblocks--raising switching costs,
      perhaps, or launching discrediting PR efforts--an incumbent can often limit the
      degree to which customers and competitors accept a nascent insurgency. And,
      sometimes, revolutions die there. If not, early containment buys a company some
      time to shape the revolution so that it complements, rather than supersedes, the
      incumbent's strengths. And even if shaping efforts fail, they can give an
      industry leader more time to work out how to absorb the threat by bringing the
      new competencies or technologies inside the firm in such a way that they don't
      destroy its existing strengths and capabilities. When revolutions have progressed
      too far to slow them down, incumbents must take a more aggressive tack.
      Neutralizing strategies meet a revolution head-on and terminate it--by, say,
      temporarily giving away the benefits offered by the challenger for free.
      Annulment strategies allow the market leader to leapfrog over or sidestep the
      threat. These five strategic approaches need not be used in isolation, as a
      detailed case study of the way Anheuser-Busch countered the craft-beer revolution
      dramatically demonstrates. Sensible industry leaders do not lead revolutions;
      they know they may not survive the attempt. Instead, they prefer to lead
      counterrevolutions.

PMID- 12422791
TI  - Dear white boss. Do you remember that first management-team offsite.
AB  - It's easy for white managers to assume that their colleagues of color face the
      same basic challenges they do. On one level that's true--the work itself is the
      same. But on another level, African-American managers often contend with an
      atmosphere of tension, instability, and distrust that can be so frustrating they
      lose the desire to contribute fully. Their white bosses and coworkers are simply
      unaware of the "miasma" and are often puzzled when African-Americans quit
      apparently for no reason or seemingly overreact to a minor incident. This
      portrayal of what it's like to be different in the workplace takes the form of a
      fictional letter from a black manager to a white boss. The letter, based on
      interviews and surveys the authors conducted with hundreds of mid- to senior
      level African-American managers, is not about the lack of role models or mentors
      of color or any of the other barriers that limit opportunities for blacks in
      corporate America. Instead, the letter sheds light on the realities that lurk
      below the surface for black managers--the feeling that they leave some part of
      their identities at home and the sometimes subtle and often systemic racial
      biases that inhibit and alienate African-Americans. "Differences really do
      matter, although they may matter in ways you probably didn't expect. One of the
      big ways they matter is that race is always with us," the letter writer observes.
      "As a friend of mine said recently, 'I don't think a day goes by that I'm not
      reminded that I'm black.'" The letter may not apply to every leader, black or
      white, or to every organization, but the issues are more widespread than
      corporate America cares to acknowledge. It should be required reading for all
      white executives who don't want talent to slip through their fingers.

PMID- 12422792
TI  - Six IT decisions your IT people shouldn't make.
AB  - Senior managers often feel frustration--even exasperation--toward information
      technology and their IT departments. The managers complain that they don't see
      much business value from the high-priced systems they install, but they don't
      understand the technology well enough to manage it in detail. So they often leave
      IT people to make, by default, choices that affect the company's business
      strategy. The frequent result? Too many projects, a demoralized IT unit, and
      disappointing returns on IT investments. What distinguishes companies that
      generate substantial value from their IT investments from those that don't? The
      leadership of senior managers in making six key IT decisions. The first three
      relate to strategy: How much should we spend on IT? Which business processes
      should receive our IT dollars? Which IT capabilities need to be companywide? The
      second three relate to execution: How good do our IT services really need to be?
      Which security and privacy risks will we accept? Whom do we blame if an IT
      initiative fails? When senior managers aren't involved in these decisions, the
      results can be profound. For example, if they don't take the lead in deciding
      which IT initiatives to fund, they end up overloading the IT department with
      projects that may not further the company's strategy. And if they aren't
      assessing security and privacy risks, they are ignoring crucial business trade
      offs. Smart companies are establishing IT governance structures that identify who
      should be responsible for critical IT decisions and ensure that such decisions
      further IT's strategic role in the organization.

PMID- 12422794
TI  - The World Bank's innovation market.
AB  - Large, tradition-bound organizations can make space for radical, low-cost (and
      therefore low-risk) innovations. Just ask executives at the World Bank. The story
      of this best practice begins in 1998, when a young new-products group at the
      international funding agency proposed holding an Innovation Marketplace to
      capture novel ideas within the Bank for alleviating poverty. The forum, which
      eventually was opened to external participants, let people informally present
      their antipoverty ideas to potential funding sources. Funders could move among
      hundreds of booths and evaluate proposals for, say, a program that would provide
      postdisaster reconstruction insurance in developing countries or a vaccination
      development initiative. The marketplace truncated the Bank's standard project
      review processes, which often stretched to a year or more, and gave funders
      permission to make commitments in the tens of thousands of dollars, rather than
      in the tens of millions more typical of Bank-financed projects. The marketplace
      concept met with some skepticism at the beginning. Some senior executives at the
      Bank felt no group had the right to spend the agency's money without following
      its well-established resource allocations process. But the marketplace team
      believed an open process for allocating grants would produce more breakthrough
      ideas in the long run than a centralized one. In this article, the authors
      describe how the new-products team brainstormed to create a market for ideas, how
      it got senior management's support, and how it has expanded on the original
      concept for these innovation marketplaces. The program's success, they contend,
      offers hope both for the world's poor and for business leaders looking to find
      new ideas under the hard crust of corporate dogma, conformance, and bureaucracy.

PMID- 12422793
TI  - Why good accountants do bad audits.
AB  - On July 30, President Bush signed into law the Sarbanes-Oxley Act addressing
      corporate accountability. A response to recent financial scandals, the law
      tightened federal controls over the accounting industry and imposed tough new
      criminal penalties for fraud. The president proclaimed, "The era of low standards
      and false profits is over." If only it were that easy. The authors don't think
      corruption is the main cause of bad audits. Rather, they claim, the problem is
      unconscious bias. Without knowing it, we all tend to discount facts that
      contradict the conclusions we want to reach, and we uncritically embrace evidence
      that supports our positions. Accountants might seem immune to such distortions
      because they work with seemingly hard numbers and clear-cut standards. But the
      corporate-auditing arena is particularly fertile ground for self-serving biases.
      Because of the often subjective nature of accounting and the close relationships
      between accounting firms and their corporate clients, even the most honest and
      meticulous of auditors can unintentionally massage the numbers in ways that mask
      a company's true financial status, thereby misleading investors, regulators, and
      even management. Solving this problem will require far more aggressive action
      than the U.S. government has taken thus far. What's needed are practices and
      regulations that recognize the existence of bias and moderate its effects. True
      auditor independence will entail fundamental changes to the way the accounting
      industry operates, including full divestiture of consulting and tax services,
      rotation of auditing firms, and fixed-term contracts that prohibit client
      companies from firing their auditors. Less tangibly, auditors must come to
      appreciate the profound impact of self-serving biases on their judgment.

PMID- 12422795
TI  - How to identify your enemies before they destroy you.
AB  - We've all heard the stories about corporate giants who ignored disruptive
      innovations and paid a steep price: Think what the personal computer did to
      Digital or Japanese economy cars did to the Big Three automakers. Big companies
      now spend a lot of time and money trying to make sure they don't get blindsided
      by their smaller, leaner counterparts. But it's not easy to distinguish genuine
      threats from also-rans as they emerge. Most of the nascent technologies that
      typically bombard executives will not amount to competitive threats and deserve
      to be ignored. As a result, disruptions are usually not taken seriously until
      they become obvious--when it's often too late. A disruptive innovation is a
      technology, product, or process that creeps up from below an existing business
      and threatens to displace it. Usually, the disrupter offers lower performance and
      less functionality at a much lower price. The product or process is good enough
      to meet some customers' needs; others welcome the disruption's simplicity.
      Gradually, it improves to the point where it displaces the incumbent. But, the
      authors argue, disruption isn't inevitable. They have developed a tool that can
      help companies detect potential disruptive innovations while management still has
      time to respond effectively. The tool's decision-making methodology harnesses the
      organization's collective wisdom to determine how likely it is that a particular
      innovation will seriously damage an incumbent's business. The methodology has two
      components: an analytical instrument and an organizational process. There's
      nothing magical about it--but it gets managers to think systematically about
      identifying and addressing threats to the core business. And the tool's rigorous
      approach can spell the difference between flailing around and acting effectively
      in the face of a serious competitive threat.

PMID- 12422796
TI  - Hormone replacement therapy: the debate begins.

PMID- 12422797
TI  - Current concepts in multiple sclerosis: Part I.
AB  - Multiple sclerosis (MS) is a complex and challenging autoimmune disease of the
      central nervous system, affecting approximately 0.1% of the US population.
      Evidence to date suggests that viral infection triggers autoimmune attack against
      nerve cells in genetically-susceptible individuals. Neurologic deficits then
      appear, typically with a variable course and episodes of remission. Partial
      treatment success has been obtained with immunomodulating agents, such as
      interferon-beta and intravenous immunoglobulins. Current research is directed at
      elucidating potential viral causes of MS, as well as the interaction of host
      genes with the immunopathogenic mechanisms involved in MS. In the future, it may
      be possible to vaccinate susceptible individuals against MS, as well as refine
      immunomodulation therapy for the treatment of MS.

PMID- 12422798
TI  - SDFMC begins new nursing home quality initiative.

PMID- 12422799
TI  - The new politics of pot.

PMID- 12422800
TI  - Is pot good for you?

PMID- 12422801
TI  - Rethinking a heart-disease risk.

PMID- 12422802
TI  - Program succeeds tackling two diseases with one approach.

PMID- 12422803
TI  - New approach to high-risk pregnancy begins far earlier than traditional programs.
AB  - Why? Because traditional programs that focus on women as soon as they become
      pregnant are not making any headway against the incidence of low and very low
      birth weight (LBW) babies. As a result, while more of these babies are surviving,
      a significant number have disabilities that will impact them for life while
      costing the health care system dearly. Experts at Emory University in Atlanta
      believe there must be a better way to curb the incidence of poor birth outcomes,
      and they are putting their theories to work in a new program focused on
      "interpregnancy" care.

PMID- 12422804
TI  - Hand-held devices ease burden of behavioral health assessment.
AB  - Numerous studies show that people suffering from depression and other behavioral
      health disorders are among the highest utilizers of care, but primary care
      physicians often miss behavioral diagnoses because they don't have the time to
      administer and analyze effective screens for these conditions. To ease this
      burden, a Denver, CO-based company has developed an approach that takes advantage
      of a hand-held device and an array of quick evidence-based screens that can point
      providers in the right direction in a matter of minutes.

PMID- 12422805
TI  - CHF managers make the case for home-monitoring technology.
AB  - A growing number of disease managers are finding that remote home monitoring
      devices can make a big difference in their ability to cost-effectively manage CHF
      patients.

PMID- 12422806
TI  - [Evolution of the epidemiologic context of cardiovascular diseases: a critical
      historical approach].

PMID- 12422807
TI  - [Treatment of acute myocardial infarction: the best reperfusion strategy. Opinion
      of the clinical cardiologist].

PMID- 12422808
TI  - [Unstable angina: early prognostic stratification as guide for treatment. Opinion
      of the clinical cardiologist].

PMID- 12422809
TI  - [Unstable angina: early prognostic stratification as guide for treatment. Opinion
      of the interventionist cardiologist].

PMID- 12422810
TI  - [Aortic valve stenosis in the elderly: when to intervene? Opinion of the clinical
      cardiologist].

PMID- 12422811
TI  - [Aortic valve stenosis in the elderly: when to intervene? Opinion of the surgeon
      cardiologist].

PMID- 12422812
TI  - [Asymptomatic patient with volume overload: timing for surgery. Opinion of the
      surgeon cardiologist].

PMID- 12422813
TI  - [Atrial fibrillation: pharmacologic or electric therapy. Opinion of the clinical
      cardiologist].

PMID- 12422814
TI  - [Atrial fibrillation: pharmacologic or electric therapy. Opinion of the
      interventional cardiologist].

PMID- 12422815
TI  - [Heart failure: should treatment favor prognosis or quality of life? Opinion...
      in favor of prognosis].

PMID- 12422816
TI  - [Heart failure: should treatment favor prognosis or quality of life? Opinion...
      in favor of quality of life].

PMID- 12422817
TI  - [Advanced heart failure: therapeutic options. Opinion of the clinical
      cardiologist].

PMID- 12422818
TI  - [Advanced heart failure: therapeutic options. Opinion of the surgeon
      cardiologist].

PMID- 12422819
TI  - Under construction: 14 international conferences into the pandemic's history.

PMID- 12422820
TI  - Renewal of commitment. Barcelona 2002.

PMID- 12422821
TI  - On the trail of a vaccine. An interview with David M. Gold, J.D. Interview by
      David Pieribone.

PMID- 12422822
TI  - For your benefit. Working it all out.

PMID- 12422823
TI  - Stretching your budget with food stamps.

PMID- 12422824
TI  - Getting your $$$. Most applicants are interested in two Social Security benefit
      programs: Social Security Disability Insurance (SSDI) and Supplemental Security
      Income (SSI).

PMID- 12422825
TI  - When Medi-Cal says 'no' to Serostim.

PMID- 12422826
TI  - Should you enroll in a clinical trial?

PMID- 12422827
TI  - Building better bone.

PMID- 12422829
TI  - Global group launches U.S. human rights project.

PMID- 12422828
TI  - A tool to fight wasting. Bioelectric impedance analysis can yield important
      information.

PMID- 12422830
TI  - Preparations to fight smallpox might endanger HIV-positive individuals.

PMID- 12422831
TI  - Report: most nations still lack necessary will to fight AIDS.

PMID- 12422832
TI  - Court allows doctor to disclose dental worker's HIV status.

PMID- 12422833
TI  - HIV testing. Routine hospital tests could eliminate problem of undiagnosed HIV.

PMID- 12422834
TI  - AIDS/HIV issues to consider in event of smallpox outbreak.

PMID- 12422835
TI  - Medical marijuana. Congress must decide marijuana ballot initiative in D.C.

PMID- 12422836
TI  - Appeals court upholds order for HIV test in assault case.

PMID- 12422838
TI  - Court upholds conviction for reckless exposure to HIV.

PMID- 12422837
TI  - Ability to provide HIV care factors in psychiatric commitment.

PMID- 12422839
TI  - Needle exchange. Massachusetts high court to hear program challenge.

PMID- 12422840
TI  - [Academician Nikolai Grigor'evich Khrushchov].

PMID- 12422841
TI  - [Root system development ability of several alfalfa cultivars in the hilly and
      valley regions of Loess Plateau].
AB  - A field study was conducted in the hilly and valley regions of Loess Plateau in
      Gansu Province to analyze the root system development ability of several alfalfa
      (Medicago sativa) cultivars. Eight introduced cultivars and one local cultivar
      were arranged in the same site. The secondary roots of alfalfa cultivars grew
      mainly from the taproot underground 10-20 cm depth, and there were no secondary
      roots below 50 cm depth. The total amount of secondary roots of Sandili and
      Ameristand 201 was the biggest, and that of Longdong alfalfa was the lowest. The
      volume and biomass of different cultivars were decreased from 0-10 cm depth to
      below 50 cm depth, except those of Sandili and Ameristand 201 at 20-30 cm depth
      was bigger than at 10-20 cm depth. The biomass of Ameristand 201 was 170.54 g and
      bigger than that of others, and that of Longdong alfalfa, which was 22.4% of
      Ameristand 201, was the lowest. According to cluster analysis on 9 alfalfa
      cultivars, Sandili, Ameristand 201 and Amerigraze 401 were suitable for planting
      on the hills and valleys of Loess Plateau due to their root system development
      ability.

PMID- 12422842
TI  - The high-tech classroom. An analysis of NP education in cyberspace.

PMID- 12422843
TI  - Rheumatoid arthritis.
AB  - Rheumatoid arthritis (RA) is a systemic, debilitating disease characterized by
      chronic polyarticular inflammation that leads to erosion of joint and bones and
      to significant extra-articular, systemic, and cardiopulmonary manifestations. RA
      affects the patient's psychologic and social well-being as well as physical
      activity. The economical burden is high. Patients with RA may be admitted to the
      ICU for a variety of problems and present unique challenges to all physicians,
      including intensivists. This article discusses the basic pathophysiology and
      clinical manifestations of RA and the extra-articular disorders that bring these
      patients to an ICU. The management of these patients in ICU is discussed, with
      emphasis on airway management and outcome.

PMID- 12422844
TI  - [Belisario Penna: biographical photos].

PMID- 12422845
TI  - Rehabilitation and water quality monitoring in the Golden Horn.
AB  - In this work, the oceanographic aspects of the Golden Horn and some results of
      the Golden Horn Rehabilitation Project are presented. The hydrographic structure
      of the Golden Horn responds rapidly to the conditions in the southern Bosphorus,
      which is especially true for the outer parts of the estuary up to the Valide
      Sultan Bridge (VS). West of this bridge which was blocked by the pontoons of the
      bridge, carries the major pollution load and is dependent on the underlying water
      and surface mixing, for its renewal. The dissolved oxygen concentrations were
      measured below the detection limit in the region between the VS and Eyup-Sutluce
      (ES) section during the majority of the measurement periods where H2S has been
      determined simultaneously until February 2000. Although the microbial
      contamination of the estuary stations is very high, decreases in the
      contamination at stations are observed. The highest concentrations are recorded
      at the ES-VS section and supported by Fecal Coliform data during the rainy months
      in general despite the operational collector system surrounding the estuary. An
      obvious decrease of pollution in comparison with the data of the previous years
      is clearly observed as an encouraging result of the rehabilitation efforts
      achieved so far.

PMID- 12422846
TI  - Minimally invasive radiological diagnosis of pediatric hematological
      malignancies.

PMID- 12422847
TI  - TCD methodology in children with sickle-cell anemia.

PMID- 12422848
TI  - Prenatal cortical hyperostosis (Caffey disease).

PMID- 12422849
TI  - No indications of increased quiet sleep in infants who receive care based on the
      Newborn Individualized Care and Assessment Program (NIDCAP).

PMID- 12422852
TI  - Beating up bioethics.

PMID- 12422853
TI  - [Physicians and the development of professionalism in Brazil].

PMID- 12422854
TI  - [Effects of simulated microgravity on cardiovascular function and counter effect
      of lower body negative pressure].
AB  - Studies on effect of simulated microgravity on cardiovascular function and
      counter effect of lower body negative pressure (LBNP) in recent years were
      summarized. The mechanism of simulated microgravity induced orthostatic
      intolerance may involve the reduction of cardiovascular function and cerebral
      blood flow, and endocrine changes. The significance of mathematical model in the
      study of mechanism of microgravity induced orthostatic intolerance was also
      discussed. The counter effect of LBNP was emphasized.

PMID- 12422855
TI  - Beating up bioethics.

PMID- 12422856
TI  - Beating up bioethics.

PMID- 12422857
TI  - Walking a fine line.

PMID- 12422858
TI  - Design of a cardiac monitor in terms of parameters of QRS complex.
AB  - Objective. To design a portable cardiac monitor system based on the available
      ordinary ECG machine and works on the basis of QRS parameters. Method. The 80196
      single chip microcomputer was used as the central microprocessor and real time
      electrocardiac signal was collected and analyzed [correction of analysized] in
      the system. Result. Apart from the performance of an ordinary monitor, this
      machine possesses also the following functions: arrhythmia analysis, HRV
      analysis, alarm, freeze, and record of automatic papering. Convenient in
      carrying, the system is powered by AC or DC sources. Stability, low power and low
      cost are emphasized in the hardware design; and modularization method is applied
      in software design. Conclusion. Popular in usage and low cost made the portable
      monitor system suitable for use under simple conditions.

PMID- 12422859
TI  - Some clues about the President's Council on Bioethics.

PMID- 12422860
TI  - [Preliminary study on protecting effect of two kinds of Chinese medical herbs on
      changes of three physiology systems in suspended rats].
AB  - Objective. To observe the protecting effect of two kinds of Chinese medical herbs
      on changes of blood circulation, muscle and skeletal systems in tail suspended
      rats. Method. Changes of blood circulation, muscle and skeletal systems in tail
      suspended rats (n=15), Chinese medical herb group 1 (n=15) and Chinese medical
      herb group 2 (n=15) after 30 d tail suspension were compared with those in
      control group rats (n=15). Result. Two kinds of Chinese medical herbs have
      obvious effect on improving the condition of blood circulation, and have some
      effects on improving the muscle and skeletal systems in tail suspended rats.
      Conclusion. Chinese medical herbs have a good prospect of being used in space
      flight, and further studies are needed.

PMID- 12422861
TI  - Depo Provera and bone density.

PMID- 12422862
TI  - [Decrease in tetanic tension in 4-week tail-suspended rat soleus and analysis of
      its underlying mechanisms].
AB  - Objective. To observe the dynamic changes in tetanic tension in 4-week tail
      suspended rat soleus (SOL) and extensor digitorum longus muscle (EDL) and to
      elucidate its underlying mechanisms. Method. After 4 weeks of tail suspension SOL
      and EDL of the rats were isolated and perfused. Their isometric twitch and
      tetanic tensions were recorded. Result. Atrophy occurred in the SOL, but not in
      the EDL. The maximum twitch tension (Pt) decreased significantly and was more
      dependent on stimulation voltage in SOL of tail-suspended rat. Time to maximum
      twitch tension (TPT) and time from maximum twitch tension to half relaxation
      (TR50) were reduced in the SOL. Pt also decreased in the EDL, but TPT and TR50
      did not change in the EDL. The maximum tetanic tension reduced in SOL and EDL of
      tail-suspended rats. The decline rate of tetanic tension in SOL was faster than
      the control. The profile of tetanic contraction curve in atrophic SOL approached
      that in EDL. Conclusion. The above results suggested that the underlying
      mechanisms of reduced maximum twitch and tetanic tension in 4-week tail-suspended
      rat SOL may involve the reduction in number of cross-bridge per cross-section
      area or force produced per cross-bridge. The rapid decline rate in atrophic SOL
      may be related to the shift in myosin heavy chain and troponin I isoforms or to
      decrease in excitability.

PMID- 12422864
TI  - HHS advises IRBs on conflict issues.

PMID- 12422863
TI  - [Homeopathy: its history and epistemological foundations].

PMID- 12422865
TI  - [Expression of myosin heavy chain IIx mRNA as a molecular marker of disuse of
      soleus muscle in rats].
AB  - Objective. To make an Achilles tenotomy rat model to observe the change in soleus
      weight and expression of myosin heavy chain (MHC) isoform mRNA, and to find some
      clues for elucidating the mechanisms of soleus disuse. Method. Thirty male
      Sprague-Dawley [correction of Sprangue] rats were divided into 6 groups. On the
      lst, 3rd, 7th, 14th, 21st and 28th days after Achilles tenotomy, wet weight of
      soleus (SOL), plantaris (PL), gastrocnemius mediales (MG), and gastrocnemius
      lateral (LG) muscles were measured. Expression of MHC IIx mRNA was observed by
      means of reverse transcriptase-polymerase chain reaction (RT-PCR). Result. Wet
      weight of SOL, MG, LG, and PL decreased significantly on the 3rd day after the
      tenotomy. The wet weight of these muscles reduced to the minimum on the 7th or
      14th days after the tenotomy, and then recovered slightly on the 21st day after
      the tenotomy. There was only the expression of MHC I and MHC IIa mRNA in normal
      soleus muscle, but no MHC IIx or MHC IIb mRNA. The expression of MHC IIx mRNA
      occurred in SOL on the 3rd day after tenotomy and still expressed on the 28th day
      after tenotomy. There was no expression of MHC IIb mRNA in SOL after Achilles
      tenotomy. Conclusion. The appearance of atrophy of rat soleus induced by Achilles
      tenotomy is similar in time and extent with that induced by tail-suspension. The
      expression of MHC IIx mRNA is shown in rat soleus muscles in Achilles tenotomy
      and tail-suspension models. The study suggests that expression of MHC IIx mRNA
      may be used as a molecular marker of soleus muscle disuse in rats.

PMID- 12422866
TI  - New reporting rules for gene therapy and xeno trials.

PMID- 12422867
TI  - Public views genetic research cautiously.

PMID- 12422868
TI  - Kass to lead ES bioethics panel.

PMID- 12422869
TI  - RAC tries to regain foothold.

PMID- 12422870
TI  - [Estimated cosmic radiation doses for flight personnel].
AB  - Objective. To calculate individual annual cosmic radiation effective dose for
      monitored flight personnel. Method. With the help of aircraft flight information
      from flight performance manual, software CARI-6 developed by U.S. Federal
      Aviation Administration was used to calculate the effective dose of galactic
      cosmic radiation along the air lines, and to calculate the effective dose rate on
      the ground in Urumuqi, then individual annual cosmic radiation dose on flight
      personnel was estimated from the data calculated by CARI-6. Result. The annual
      cosmic radiation dose on the ground at Urumuqi was 0.420 mSv a-1. The average
      effective dose rate of all flights of Xinjiang Airlines from 1997 to 1999 was
      2.381 microSv h -1(0.33-3. 64 microSv h-1). Average annual cosmic radiation dose
      on flight personnel was 2.193 mSv a-1 (0.887-4.419 mSv a-1). Conclusion. Annual
      individual doses of all monitored flight personnel are well below the limit 20
      mSv a-1 recommended by International Commission on Radiological Protection
      (ICRP).

PMID- 12422871
TI  - Journals develop policy to liberate authors.

PMID- 12422872
TI  - Limited gene therapy trials to restart.

PMID- 12422873
TI  - [Lipid peroxidation in microalgae cells under simulated microgravity].
AB  - Objective. To provide direct evidences for effects of microgravity on structure
      and function of plasma membrane. Method. Malondialdehyde (MDA) content was
      examined on the basis of quantitative reaction of both MDA and thiobarbituric
      acid (TBA), and electrolyte leaking was determined with conductometer model DDS
      11A. Result. Experiments showed that under simulated microgravity, lipid
      peroxidation and the content of MDA increased. Meanwhile, the membrane
      permeability increased in cells of two microalgae: Anabaena sp PCC7120 and
      Synechococcus 7942. Conclusion. Our results suggest that there is some commonness
      between microgravity stress and certain other environmental stresses. And
      cellular membrane might be the site of perception of gravity in unicells without
      special gravity sensitive structure, such as alga cells.

PMID- 12422874
TI  - [A study of complexity and power spectrum of cortical EEG and hippocampal
      potential in rats under different behavioral states].
AB  - Objective. To study the complexity and the power spectrum of cortical EEG and
      hippocampal potential in rats under waking and sleep states. Method. Cortical EEG
      and hippocampal potential were collected by implanted electrodes in freely moving
      rats. Algorithmic complexity (Kc), approximate entropy (ApEn), power spectral
      density (PSD) and gravity frequency of PSD of the potential waves were
      calculated. Result. The complexity of hippocampal potential was higher than that
      of cortical EEG under every state. The complexity of cortical EEG was lowest
      under the state of non rapid eye movement (NREM) sleep. The complexity of
      hippocampal potential was highest under waking state. The total power of both
      potentials in 0.5- 30 Hz frequency band showed their highest values under NREM
      state. Conclusion. The values of Kc and ApEn are closely related to the
      distributions of PSD. When there are evident peaks in PSD, the complexities of
      signals will decrease. The complexities may be used to distinguish the difference
      between cortical EEG and hippocampal potential, or large differences between the
      same kind of potentials under different behavioral states.

PMID- 12422875
TI  - Jacques Cartier witnesses a treatment for scurvy.
AB  - In 1535, when Jacques Cartier landed in Canada for the second time, he sailed up
      the Saint-Lawrence, and spent the winter at Stadacone. His ships were frozen in
      the ice for five months. A strange disease attacked the indigenous population,
      and then the French sailors. In a two month period, almost all Cartier's men
      became sick. Facing such a tragic situation, the explorer carried out an
      examination on a dead sailor and described what would later be called scurvy. The
      Indians were able to extract a medicine from a tree called Anneda. This medicine
      worked quickly and allowed the sailors to leave Canada in May. However, 25 of the
      112 sailors had died during that icy winter.

PMID- 12422876
TI  - [Concern for children in family management texts].
AB  - Hausvaterliteratur designates works aimed at landlords and their wives in order
      to help them in the management of their estate. Among a wide-ranged list of
      topics tackled in these sizeable volumes, child welfare seldom fails to appear,
      though generally rather briefly. We consider in this paper a number of German
      works, most of them dating from the 17th century, though beginning with Johann
      Coler (1593) and winding up with Johann Joachim Becher (1714). These works
      include some advice on how to diagnose and manage the most common ailments, as
      well as some basic educational principles. A brief "pediatric" pharmacopoeia is
      often added. Although this review concerns only works in German, we have added
      references to a document taken from English literature, the diary of the
      clergyman and landlord Ralph Josselin. Dating from the same period (1643-1683),
      this document shows us how a landlord and his wife actually treated their sick
      children, thus shifting from theory to practice. "Hausvaterliteratur" can be
      considered as an early stage of what was later termed "Domestic Medicine".

PMID- 12422877
TI  - The doctrine of signatures in the medieval and Ottoman Levant.
AB  - This study traces the use of the Doctrine of Signatures among medieval and
      Ottoman physicians and its subsequent appearance in the pharmacological
      literature of the Levant. Close examination of the historical sources of the
      Levant seems to support the claim that although this theory did not originate in
      the region, it was certainly practised there. These sources have revealed 23
      substances with medicinal uses based on the Doctrine, bearing witness to the
      extent of its influence at the time. The main categories of the Doctrine
      uncovered were: similarity between the substance used and the human organ;
      resemblance in shape or behaviour to a specific animal; correlation between the
      colour of a substance and the colour of the symptoms; similarities between the
      substance and the patient's symptoms and the use of a substance that might
      produce symptoms of a particular disease in a healthy person to remedy those same
      symptoms in one who is sick.

PMID- 12422880
TI  - What to do when your lab is sold and how to hire MTs and MLTs when there is a
      tech shortage.

PMID- 12422881
TI  - Jean-Louis Baudelocque.

PMID- 12422879
TI  - Curbing the costs of tobacco use.

PMID- 12422878
TI  - Medicaid buy-in programs for workers with disabilities.

PMID- 12422882
TI  - Commentary: Judicial review of the pharmacy provision of emergency contraception
      in the UK.

PMID- 12422883
TI  - Giles of Rome.

PMID- 12422884
TI  - Medical devices; ear, nose, and throat devices; classification of the
      transcutaneous air conduction hearing aid system. Final rule.
AB  - The Food and Drug Administration (FDA) is classifying the transcutaneous air
      conduction hearing aid system (TACHAS) into class II (special controls).
      Elsewhere in this issue of the Federal Register, FDA is announcing the
      availability of a guidance document that will serve as the special control for
      the device. The agency is taking this action in response to a petition submitted
      under the Federal Food, Drug, and Cosmetic Act (the act) as amended by the
      Medical Device Amendments of 1976 (the amendments), the Safe Medical Devices Act
      of 1990, and the Food and Drug Administration Modernization Act of 1997 (FDAMA).
      The agency is classifying this device into class II (special controls) in order
      to provide a reasonable assurance of safety and effectiveness of the device.

PMID- 12422886
TI  - The idea of scientific progress in Antiquity and the Middle Ages.
AB  - The author reviews the development of the idea of scientific progress from Graeco
      Roman antiquity to the Middle Ages and shows that from Xenophanes (6th century
      BC) on, the notion of progress can be found in the works of many authors,
      including physicians, throughout the centuries. Even if at first the concept was
      often rather inchoate and limited to what we would call technology, in the Middle
      Ages the notion of scientific progress in general and in medicine in particular
      became closer to the modern one.

PMID- 12422885
TI  - [On Esquirol's historical and statistical study of the royal establishment at
      Charenton].
AB  - The authors present a critical interpretation of an historical and statistical
      work on the Maison Royal de Charenton by M. Esquirol, three years prior to the
      publication of his fundamental work: "Des maladies mentales". The three
      historical periods of life at the Maison Royal de Charenton are described,
      together with the work carried out under the leadership of Esquirol during the
      third period. Finally, particular attention is devoted to Esquirol's statistical
      studies, which are re-examined in the light of present-day statistical
      methodologies.

PMID- 12422887
TI  - [Relationships of molecular biology with paleoparasitology].
AB  - By demonstrating, in 1910, the presence of eggs of schistosomes in the kidneys of
      Egyptian mummies of the XXth Dynasty, Marc Armand Ruffer is considered as the
      founder of paleoparasitology. One century later, thanks to technologies derived
      from molecular biology, important advances have been made in the history of human
      parasitic diseases, especially in the fields of schistosomiasis, trypanosomiasis
      and leishmaniasis. For instance, it is probable that there was a common ancestor
      for the three main groups of schistosoma species which infect humans and animals
      today. Similarly, it is likely that South American and African trypanosomes arose
      from a common ancestral protozoa. This hypothesis is further sustained by the
      characterization of a protein (CCF-1 for Coelomic Cytolytic Factor-1), isolated
      from an annelid and which binds molecules expressed by two distinct species of
      trypanosoma. Lastly, recent data highlight the geographic distribution of various
      species of Leishmania in both the Old and the New World. Improvement in parasite
      phylogeny and systematics lead to a better understanding of the history of human
      parasitic diseases.

PMID- 12422888
TI  - HIV counselling and testing in rural Uganda: communities' attitudes and
      perceptions towards an HIV counselling and testing programme.
AB  - Study results on the assessment of a community-wide HIV counselling and testing
      programme are presented. The aim of this qualitative study was to elucidate
      whether HIV counselling and testing (HIV CT) was acceptable to a rural community
      and whether they expressed a need for it. From a total of 2,267 persons of
      Kigoyera Parish, western Uganda, who were HIV tested and counselled, 171 persons
      participated in 17 focus group discussions. Most participants expressed a strong
      need for HIV counselling and testing services. The counsellors were seen as
      competent and confidential. Community health workers were favoured as the
      preferred provider of HIV CT services. However, participants stressed that they
      should not come from the same community. Most participants felt that a HIV CT
      programme available only once is not enough and did not induce a change in sexual
      behaviour, e.g. increased condom use. They requested counselling services that
      are continuously offered. The study results also showed that there is a demand
      for HIV counselling services without being HIV tested.

PMID- 12422889
TI  - Baron Munchhausen and the syndrome which bears his name: history of an endearing
      personage and of a strange mental disorder.
AB  - Munchausen syndrome, a mental disorder, was named in 1951 by Richard Asher after
      Karl Friedrich Hieronymus, Baron Munchhausen (1720-1797), whose name had become
      proverbial as the narrator of false and ridiculously exaggerated exploits. The
      first edition of Munchhausen's tales appeared anonymously in 1785 (Baron
      Munchausen's narrative of his marvelous travels and campaigns in Russia), and was
      wrongly attributed to German poet Gottfried August Burger who actually edited the
      first German version the following year. The real author, Rudolph Erich Raspe,
      never claimed his rights over the successive editions of this book. This paper
      reviews the extraordinary personality of Baron Munchhausen, and the circumstances
      which led Rudolph Erich Raspe, Gottfried August Burger, and Richard Asher to pay
      homage to this very endearing personage.

PMID- 12422890
TI  - Renovascular hypertension, endothelial function, and oxidative stress.

PMID- 12422891
TI  - Renovascular hypertension, endothelial function, and oxidative stress.

PMID- 12422892
TI  - Renovascular hypertension, endothelial function, and oxidative stress.

PMID- 12422893
TI  - The impact factor: publish, be cited or perish...

PMID- 12422894
TI  - Thrombophilia polymorphisms and intrauterine growth restriction.

PMID- 12422895
TI  - Aberrant right subclavian artery and dysphagia lusoria.

PMID- 12422896
TI  - Hypocapnia.

PMID- 12422897
TI  - Effects of progestins on olfactory sensitivity and cognition.

PMID- 12422898
TI  - Early termination of WHI estrogen-progestin trial: effect on cognitive aging and
      dementia risk studies.

PMID- 12422899
TI  - Report on the 10th World Congress on the Menopause. 10-14 June 2002, Berlin,
      Germany.

PMID- 12422901
TI  - Cephalhaematoma in a child with acute promyelocytic leukaemia.

PMID- 12422902
TI  - [Expression of vascular endothelial growth factor in bone marrow cells of
      patients with acute myeloid leukemia].
AB  - OBJECTIVE: To investigate the role of vascular endothelial growth factor (VEGF)
      in the pathogenesis and progression of acute myeloid leukemia (AML). METHODS:
      Reverse transcription-polymerase chain reaction (RT-PCR) was employed for VEGF
      mRNA detection. VEGF levels in the bone marrow cell cultural supernatant and
      plasma from normal subjects and AML patients were determined by enzyme-linked
      immunosorbent assay (ELISA). RESULTS: VEGF mRNA expression was present in most of
      the AML cell lines HL-60, K562 and Raji, but not in Jurkat cells. The expression
      rate of VEGF mRNA in the bone marrow cells from AML patients (82%) was higher
      than the rates in normal subjects (30.76%) and AML patients with autologous bone
      marrow transplantation (41.67%). Refractory and non-refractory AML patients had
      higher mean plasma VEGF levels than the normal donors and AML patients with
      transplantation did, without significant differences observed in the latter 2
      groups. With also significant difference between them, refractory and non
      refractory AML groups had respectively 11.0 and 7.3-fold higher VEGF levels in
      the culture supernatant than the normal donor group did. CONCLUSION: The
      abnormality of VEGF expression may play an important role in the development of
      AML, and VEGF expression might be used as one of the indexes for prognostic
      assessment for AML patients.

PMID- 12422903
TI  - Can heparin prevent adverse pregnancy outcome?

PMID- 12422904
TI  - One-stop clinic for assessment of risk of chromosomal defects at 12 weeks of
      gestation.
AB  - Prenatal diagnosis of trisomy 21 requires an invasive test in women considered to
      be at high risk after screening. At present, there are four screening tests. For
      a 5% false-positive rate, the sensitivities are approximately 30% for maternal
      age alone, 60-70% for maternal age and second-trimester maternal serum
      biochemical testing, 75% for maternal age and first-trimester fetal nuchal
      translucency (NT) scanning, and 90% for maternal age with fetal NT and maternal
      serum free beta-human chorionic gonadotropin (beta-hCG) and pregnancy-associated
      plasma protein-A (PAPP-A) at 11-14 weeks. This article examines the methodology
      of first-trimester screening and summarizes the results from all studies
      reporting on the implementation of this method.

PMID- 12422905
TI  - Soluble adhesion molecule profile in normal pregnancy and pre-eclampsia.
AB  - OBJECTIVE: An exaggerated inflammatory response has been implicated as the cause
      of endothelial cell dysfunction and the maternal syndrome of pre-eclampsia.
      Adhesion molecules play a central role in the adherence of leukocytes to
      endothelial cells and the subsequent migration of white blood cells into
      perivascular tissue. Cellular forms of adhesion molecules mediate specific steps
      of leukocyte-endothelial cell interaction, and have been implicated in the
      pathophysiology of preeclampsia. Soluble forms of these molecules can be detected
      in plasma, and their concentrations are thought to reflect the degree of
      activation of a particular cell type. Elevations in soluble P-selectin (sP
      selectin) reflect platelet activation; changes in soluble L-selectin (sL
      selectin) suggest leukocyte activation; and an increase in soluble forms of E
      selectin (sE-selectin), vascular cell adhesion molecule 1 (sVCAM-1),
      intercellular adhesion molecule 1 (sICAM-1) and platelet endothelial cell
      adhesion molecule (sPECAM-1) indicate endothelial cell activation/dysfunction.
      The objective of this study was to determine whether normal pregnancy and pre
      eclampsia were associated with changes in the concentrations of soluble selectins
      and members of the immunoglobulin superfamily of adhesion molecules. STUDY
      DESIGN: A cross-sectional study was conducted to determine the plasma
      concentrations of sL-selectin, sE-selectin, sP-selectin, sVCAM-1, sICAM-1 and
      sPECAM-1 in peripheral blood obtained from non-pregnant women (n = 20), normal
      pregnant women (n = 100) and patients with pre-eclampsia (n = 55). Concentrations
      of soluble adhesion molecules were determined with enzyme-linked immunoassays.
      Parametric statistics were used for data analysis. RESULTS: Normal pregnancy was
      associated with a significant increase in the maternal plasma concentration of sP
      selectin, a decrease in sL-selectin, and no change in sE-selectin, sVCAM-1, sICAM
      1 and sPECAM-1. In contrast, pre-eclampsia was associated with a significant
      increase in sP-selectin, sE-selectin and sVCAM-1, a decrease in sL-selectin, but
      no change in sICAM-1 and sPECAM-1 concentrations. CONCLUSIONS: The increased
      concentration of sP-selectin and decreased sL-selectin, as well as the lack of
      change in endothelial cell-associated soluble adhesion molecules suggest that
      pregnancy is associated with platelet and leukocyte activation, but not
      endothelial cell activation. In contrast, pre-eclampsia appears to be
      characterized by activation of platelets, leukocytes and endothelial cells.

PMID- 12422906
TI  - Soluble adhesion molecules: marker of pre-eclampsia and intrauterine growth
      restriction.
AB  - OBJECTIVE: This study monitored circulating plasma levels of soluble vascular
      cellular adhesion molecule-1 (sVCAM-1), intracellular adhesion molecule-1 (sICAM
      1) and soluble E-selectin (sE-selectin) in women with healthy pregnancies, with
      pregnancy-induced hypertension (PIH), with pre-eclampsia and with pregnancies
      with isolated intrauterine growth restriction (IUGR) in order to determine
      whether elevated concentrations have a predictive value for the clinical signs of
      those pregnancy-induced disorders. METHODS: Plasma concentrations of sVCAM-1,
      sICAM-1 and sE-selectin were determined in healthy pregnant women at each
      trimester of pregnancy and in pregnant women with PIH, pre-eclampsia and IUGR
      using commercial kits. RESULTS: In the group of healthy pregnant women, plasma
      levels of sVCAM-1, sICAM-1 and sE-selectin did not change throughout pregnancy.
      No significant differences in the levels of these molecules were observed between
      healthy pregnant women at the third trimester of pregnancy and women with PIH. In
      addition, concentrations of soluble adhesion molecules were significantly higher
      in women with pre-eclampsia than in the group of women with healthy pregnancies.
      Only sVCAM-1 and sE-selectin levels were significantly higher in women with IUGR
      compared to healthy pregnant women. CONCLUSIONS: Abnormally circulating levels of
      sVCAM-1, sICAM-1 and sE-selectin may have a predictive value for pre-eclampsia
      and IUGR, as they may be linked with endothelial activation and/or damage.

PMID- 12422907
TI  - Antibiotic administration in patients with preterm premature rupture of membranes
      reduces the rate of histological chorioamnionitis: a prospective, randomized,
      controlled study.
AB  - OBJECTIVE: To determine whether antibiotic administration in patients with
      preterm premature rupture of membranes is associated with a reduction in the rate
      of histological chorioamnionitis and funisitis. METHODS: One hundred consecutive
      patients with preterm premature rupture of membranes and no labor between 24 and
      34 weeks were invited to participate in this study. Eligible patients randomly
      received either clindamycin-gentamicin for 7 days or placebo, and were managed
      expectantly until 35 weeks unless fetal or maternal indications developed.
      Microbial invasion of the amniotic cavity was defined as the presence of a
      positive amniotic fluid culture obtained by transabdominal amniocentesis.
      Cervicovaginal infection was diagnosed when bacterial vaginosis or a positive
      culture for cervicovaginal pathogens or facultative bacteria associated with a
      significant increase in the white blood cell count were found. Histological
      chorioamnionitis was based on the observation of polymorphonuclear leukocyte
      infiltration of the chorionic plate or the extraplacental fetal membranes.
      Funisitis was diagnosed in the presence of polymorphonuclear leukocyte
      infiltration into the umbilical vessel walls or Wharton jelly. Statistics were
      performed using contingency tables. RESULTS: Seventy-one patients with available
      histological study of the placenta were included. Thirty-five women received
      antibiotics and 36 were given placebo. Patients who received antibiotics had a
      significantly lower rate of histological chorioamnionitis than patients who
      received placebo (46% (16/35) vs. 69% (25/36), respectively; p < 0.05). This
      effect was more pronounced among women with microbial invasion of the amniotic
      cavity and/or cervicovaginal infection (58% vs. 89%, respectively; p < 0.01).
      Antibiotic therapy was associated with an increase in the frequency of placentas
      without histological abnormalities (29% vs. 6%; p < 0.01). The frequency of
      funisitis was not different between groups. CONCLUSION: Administration of
      antibiotics in patients with preterm premature rupture of membranes is associated
      with a significant reduction in the incidence of histological chorioamnionitis
      but it does not modify the frequency of funisitis.

PMID- 12422909
TI  - Predictive value of transvaginal cervical length in triplet pregnancies for
      spontaneous preterm delivery at < or = 32 weeks.
AB  - OBJECTIVE: To establish whether cervical length is a predictor of spontaneous
      preterm delivery at < or = 32 weeks in triplet pregnancies. METHODS: This was a
      case-control study of all triplet pregnancies followed with more than three
      sonographic assessments of cervical length at 4-week intervals from 1995 to 2000.
      Cervical length in women delivered spontaneously at < or = 32 weeks (cases) was
      compared with that of the remaining women (controls). Statistical analysis
      included Fisher's exact test, chi2 test, one-way analysis of variance, logistic
      regression and receiver operating characteristic (ROC) curve to determine optimal
      cervical length thresholds for spontaneous preterm delivery at < or = 32 weeks.
      RESULTS: Of the 58 women included in the study, 17 (29%) delivered spontaneously
      at < or = 32 weeks. The preterm delivery group had similar demographic and
      obstetric variables, but a higher rate of cerclage placement (65% vs 17%, p <
      0.001) than controls. Mean +/- standard deviation cervical length was
      significantly shorter among cases than controls at 16-20.0 weeks (3.0 +/- 1.2 vs.
      3.9 +/- 0.8 cm, p = 0.01), but not at 20.1-24.0 weeks (3.5 +/- 1.1 vs. 3.8 +/-
      1.0 cm, p = 0.76). Logistic regression analysis determined that cervical length
      at 16-20 weeks had an odds ratio of 0.43 (95% CI = 0.23, 0.80) for the prediction
      of spontaneous preterm delivery at < or = 32 weeks. ROC curve analysis identified
      a cervical length of < or = 2.6 cm as the optimal threshold for the prediction of
      spontaneous preterm delivery at < or = 32 weeks (sensitivity 41%, specificity
      92%). CONCLUSIONS: In a population of triplet gestations with a 29% rate of
      preterm delivery, cervical length at 16-20.0 weeks, but not at 20.1-24.0 weeks,
      was inversely correlated with the probability of preterm delivery at < or = 32
      weeks.

PMID- 12422908
TI  - Ripening of the uterine cervix in a post-cesarean parturient: prostaglandin E2
      versus Foley catheter.
AB  - OBJECTIVE: To compare the success and complication rates of prostaglandin E2
      tablets (PGE2) and a Foley catheter for the ripening of the uterine cervix in
      post-Cesarean section parturients. STUDY DESIGN: The study population in this
      retrospective cohort study consisted of parturients in their second pregnancy who
      had undergone Cesarean section in their previous delivery and who underwent
      ripening of the uterine cervix by using PGE2 (n = 55) or Foley catheter (n = 161)
      in the current pregnancy. The control group consisted of 1432 post-Cesarean
      section parturients without induction of labor. We compared the rates of
      placental abruption, non-reassuring fetal heart rate patterns, intrapartum fetal
      deaths (IPFD), uterine rupture, Apgar scores, labor dystocia, severe birth canal
      lacerations, vacuum deliveries and repeated Cesarean section rates in the three
      groups by using ANOVA, chi2 analysis and Fisher's exact test when appropriate.
      RESULTS: A significant increase in the rates of labor dystocia during the first
      stage (30.4% vs. 11.6%, p < 0.01) and repeated Cesarean deliveries (49.1% vs.
      35.2%, p < 0.01) were observed in women in whom the Foley catheter was used as
      compared to controls, respectively. No such changes were demonstrated in the PGE2
      group as compared to the controls. No significant differences were found between
      the PGE2 group and Foley catheter group as compared to the controls in rates of
      placental abruption, IPFD, uterine rupture, fetal distress, birth canal
      lacerations, vacuum deliveries and Apgar scores. CONCLUSIONS: PGE2 was found to
      be superior to the Foley catheter for ripening of the uterine cervix in a post
      Cesarean parturient, as demonstrated by a lower repeated Cesarean delivery rate.

PMID- 12422910
TI  - Predicting concordance of biochemical lung maturity in the preterm twin
      gestation.
AB  - OBJECTIVE: To propose a strategy for lung maturity amniocentesis in diamnionic
      twin gestations by exploiting indicators of concordance of lung maturity status.
      METHODS: Amniotic fluid from 92 diamnionic twin gestations was assayed for lung
      maturity by standard methodology. The rates of concordance of lung maturity
      status between twins were calculated after stratification by gestational age,
      chorionicity, gender and weight discordance. RESULTS: At the extremes of
      gestational age (28, 29, 36 and 37 weeks), twins are 100% concordant in lung
      status; for twins of 33-35.9 gestational weeks, lung concordance is significantly
      lower at 0.91 (p = 0.02); for 30-32.9 weeks, a rate of 0.52 is even lower (p =
      0.001). Same-gender twin pairs of 33-35.9 weeks and twin pairs with estimated
      fetal weight discordance exceeding 20% or less than 10% were uniformly concordant
      in their lung maturity. CONCLUSION: Non-selective single amniocentesis may be
      performed if the gestational age is greater than 35.9 weeks. Double amniocentesis
      should be performed in the following: twins of 30-32.9 gestational weeks and
      twins of 33-35.9 weeks unless the twin pair is gender-concordant, or calculated
      fetal weight discordance is less than 10% or greater than 20%.

PMID- 12422911
TI  - Diet during pregnancy and total antioxidant capacity in maternal and umbilical
      cord blood.
AB  - OBJECTIVE: To evaluate the longitudinal trend of total antioxidant capacity
      (ToAC) in a group of pregnant women and the relationship with their food habits
      and ToAC of their newborns. METHODS: ToAC of 12 pregnant women and of umbilical
      cord blood was determined by means of the oxygen radical absorbance capacity
      method; mothers' diet was assessed by the dietary history method. RESULTS:
      Mothers' oxygen radical absorbance capacity values decreased slightly from the
      first (5.41 +/- 0.28 mmol/l trolox eq.) to the third (5.23 +/- 0.26 mmol/l trolox
      eq.) trimester of pregnancy, but significantly at delivery (5.06 +/- 0.17 mmol/l
      trolox eq., p < 0.05 vs. the first, second and third trimesters). Oxygen radical
      absorbance capacity values of umbilical cord blood (4.87 +/- 0.24 mmol/l trolox
      eq.) correlated with mothers' values in the third trimester (r = 0.86; p = 0.004)
      of pregnancy and at delivery (r = 0.87; p = 0.0002). The mothers' diet was rather
      poor in fruit and vegetables and did not change throughout pregnancy.
      CONCLUSIONS: The lowering values of ToAC observed during pregnancy may be a
      physiological trend or a transient imbalance between higher antioxidant
      requirements and intake which reflects on newborns' ToAC. Nevertheless, efforts
      should be made to improve dietary habits in pregnancy in order to optimize the
      ToAC of mothers and newborns.

PMID- 12422912
TI  - Autosomal recessive hydrocephalus due to aqueduct stenosis: report of a further
      family and implications for genetic counselling.
AB  - We report on two abortuses with hydrocephalus due to congenital stenosis of the
      aqueduct of Silvius. The occurrence of this disorder in two siblings (a male and
      a female) with normal parents supports the autosomal recessive pattern of
      inheritance. Such a mechanism of inheritance should be taken into account when
      counselling families with congenital hydrocephaly due to aqueduct stenosis.

PMID- 12422913
TI  - Elective Cesarean section for breech presentation: a reminder about true lies.

PMID- 12422914
TI  - Screening for antimalarial toxicity: current concepts.

PMID- 12422915
TI  - Reversal of optic disc cupping after trabeculotomy in primary congenital
      glaucoma.
AB  - BACKGROUND: The phenomenon of reversal of glaucomatous cupping of the optic disc
      following lowering of the intraocular pressure (IOP) was originally recognized in
      infants. We evaluated the change in optic disc cupping with normalization of the
      IOP after trabeculotomy in primary congenital glaucoma and assessed the factors
      associated with reversal of cupping. METHODS: We reviewed the records of 17
      patients (24 eyes) who underwent trabeculotomy between July 1993 and June 1999
      and who had been followed for at least 1 year. Surgical success was defined as
      IOP less than 22 mm Hg without anti-glaucoma medication, stable or reduced optic
      disc cupping, and lack of further corneal enlargement disproportionate to normal
      growth. Patients who required more than one surgical procedure to control the IOP
      and those with cloudy media that precluded documentation of cupping were excluded
      from analysis. Optic disc cupping was assessed independently before and after
      surgery by two clinicians. The cup:disc ratio was estimated as the percentage of
      surface area of the optic disc occupied by cupping in the vertical axis. We
      accepted a difference of 0.1 or 0.2 in the cup:disc ratio between the two
      observers in each subjective assessment and used the mean value of the two
      results for data analysis. If the difference was more than 0.2, the eye was
      excluded from further study. RESULTS: Of the 17 patients 4 were excluded: 2
      because they received antiglaucoma medication to control the IOP postoperatively,
      1 because he underwent more than one surgical procedure to control the IOP during
      follow-up, and 1 owing to disagreement in the assessment of the cup:disc ratio
      between the two observers. Eighteen eyes of 13 patients were thus included in the
      analysis. Twelve eyes were from boys and six, from girls. The patients were
      followed for a mean of 43.2 (standard deviation [SD] 30.4) months (range 12 to 90
      months). The mean cup:disc ratios pre- and postoperatively were 0.74 (SD 0.20)
      and 0.60 (SD 0.21) respectively (p = 0.003). Of the 18 eyes 11 (61.1%) had
      documented reduction in optic disc cupping. The mean time to stabilization of
      cupping reversal was 4.8 (SD 2.8) months (range 2 to 12 months). In multivariable
      analysis the age of the patient at surgery was the only variable significantly
      associated with reversal of cupping (p = 0.027). The mean age at surgery for the
      11 eyes with reduction in cupping was 6.9 (range 3 to 15) months, compared with
      23.4 (range 12 to 42) months for the 7 eyes with unchanged cupping. The mean
      preoperative cup:disc ratio was 0.67 (SD 0.17) in the former group and 0.83 (SD
      0.17) in the latter group. Six of the seven eyes with unchanged cupping had
      advanced cupping. INTERPRETATION: Optic disc cupping can be reversed at an early
      stage of primary congenital glaucoma following successful reduction of IOP.
      Younger age at surgery was associated with reversal of cupping.

PMID- 12422916
TI  - Quantitative analysis of eyelash lengthening following topical latanoprost
      therapy.
AB  - BACKGROUND: There have been several reports, mostly qualitative, of ocular side
      effects of latanoprost, including lengthening of eyelashes. We investigated
      changes in eyelash length in patients receiving topically administered
      latanoprost. METHODS: Seventeen patients (11 men and 6 women aged 63 to 80 years)
      with glaucoma or ocular hypertension were treated with latanoprost (one drop to
      one eye daily at bedtime). All had dark brown irises. At the start of treatment
      and after 2, 6 and 10 weeks of treatment, a single eyelash was removed from the
      centre of the upper eyelid of the treated and fellow (control) eyes and measured.
      Adverse events (defined as any undesirable event occurring in a subject,
      regardless of whether it was considered related to the latanoprost treatment)
      were monitored carefully. At each examination patients were asked whether they
      had any ocular or systemic symptoms. RESULTS: For the eyes treated with
      latanoprost, the mean eyelash length (and standard deviation) was 5.8 mm (0.7 mm)
      at baseline, 6.5 mm (0.6 mm) at 2 weeks, 6.5 mm (0.9 mm) at 6 weeks and 6.6 mm
      (0.7 mm) at 10 weeks (p < 0.001 for all differences from baseline). The
      corresponding values for the untreated eyes were 5.7 mm (0.7 mm), 5.8 mm (0.7
      mm), 5.9 mm (0.7 mm) and 5.6 mm (0.7 mm); all differences were nonsignificant.
      INTERPRETATION: Latanoprost significantly increases eyelash length.

PMID- 12422917
TI  - Indocyanine green angiography in Bietti's crystalline retinopathy.
AB  - BACKGROUND: To our knowledge, the indocyanine green (ICG) angiographic features
      of Bietti's crystalline retinopathy have been described in a single case only. We
      report the ICG angiographic findings in four patients with Bietti's crystalline
      retinopathy and compare them with the fluorescein angiographic findings. METHODS:
      Review of the records of four patients with Bietti's crystalline retinopathy,
      three of whom were from a single consanguineous family. Fluorescein and ICG
      angiography were performed with the Heidelberg scanning laser ophthalmoscope.
      RESULTS: The ICG angiographic findings varied according to the stage of the
      disease. In the early stages no retinal pigment epithelium (RPE) alterations or
      choriocapillaris loss were noted. In advanced cases there was extensive
      chorioretinal atrophy. Most notably, intraretinal crystals did not exhibit
      fluorescence/cyanescence and had no masking effect on fluorescein or ICG
      angiography. In all cases angiography showed hypofluorescent/hypocyanescent dots,
      most likely corresponding to RPE alterations adjacent to atrophic areas.
      INTERPRETATION: ICG angiography does not give additional information in Bietti's
      crystalline retinopathy and probably is not superior to fluorescein angiography.
      However, it delineates the atrophic areas slightly better than does fluorescein
      angiography.

PMID- 12422918
TI  - Childhood Miller Fisher syndrome: case report and review of the literature.
AB  - Three years ago Ray Buncic and I were having a break from the lectures at an
      ophthalmology meeting. Ray told me of his earnest desire to provide Canadian
      ophthalmologists with a series of updates in pediatric ophthalmology. After a few
      days we were both back to the "busi-ness" of medicine, with little time to devote
      to such a project. Then, along came the COS Council on Continuing Professional
      Development (CPD) and the MaintCert program--a bold initiative to draw talent of
      Canadian ophthalmology into a program of continuing medical education (CME). One
      initiative was to use the Canadian Journal of Ophthalmology as a CME tool. This
      article by Eedy Mezer and Ray Buncic is highlighted as a Section 3 learning
      activity (self-assessment). I am delighted to have seen Ray bring forward his
      idea in this manner. The Canadian Journal of Ophthalmology has initiated this
      project in conjunction with the Council on CPD. There are a number of questions
      that relate to this article that can be answered on the COS Web site
      (http://www.eyesite.ca). Participants will be provided with an aggregate score
      and a certificate that can be printed to allow them to record this activity for
      Section 3 credits with the Royal College of Physicians and Surgeons of Canada.

PMID- 12422920
TI  - Melkersson-Rosenthal syndrome presenting with upper lid edema and facial palsy.

PMID- 12422919
TI  - Anterior uveitis and Sjogren's syndrome in a patient with primary biliary
      cirrhosis.

PMID- 12422921
TI  - Send in your cases, or the lost art of the concise case report.

PMID- 12422922
TI  - Does a homeopathic ultramolecular dilution of Thyroidinum 30cH affect the rate of
      body weight reduction in fasting patients? A randomised placebo-controlled double
      blind clinical trial.
AB  - OBJECTIVE: To test whether an ultramolecular dilution of homeopathic Thyroidinum
      has an effect over placebo on weight reduction of fasting patients in so-called
      'fasting crisis'. DESIGN: Randomised, placebo-controlled, double-blind, parallel
      group, monocentre study. SETTING/LOCATION: Hospital for internal and
      complementary medicine in Munich, Germany. SUBJECTS: Two hundred and eight
      fasting patients encountering a stagnation or increase of weight after a weight
      reduction of at least 100 g/day in the preceding 3 days. INTERVENTION: One oral
      dose of Thyroidinum 30cH (preparation of thyroid gland) or placebo. OUTCOME
      MEASURES: Main outcome measure was reduction of body weight 2 days after
      treatment. Secondary outcome measures were weight reduction on days 1 and 3, 15
      complaints on days 1-3, and 34 laboratory findings on days 1-2 after treatment.
      RESULTS: Weight reduction on the second day after medication in the Thyroidinum
      group was less than in the placebo group (mean difference 92 g, 95% confidence
      interval 7-176 g, P=0.034). Adjustment for baseline differences in body weight
      and rate of weight reduction before medication, however, weakened the result to a
      non-significant level (P=0.094). There were no differences between groups in the
      secondary outcome measures. CONCLUSIONS: Patients receiving Thyroidinum had less
      weight reduction on day 2 after treatment than those receiving placebo. Yet,
      since no significant differences were found in other outcomes and since
      adjustment for baseline differences rendered the difference for the main outcome
      measure non-significant, this result must be interpreted with caution. Post hoc
      evaluation of the data, however, suggests that by predefining the primary outcome
      measure in a different way, an augmented reduction of weight on day 1 after
      treatment with Thyroidinum may be demonstrated. Both results would be compatible
      with homeopathic doctrine (primary and secondary effect) as well as with findings
      from animal research.

PMID- 12422923
TI  - Is there scientific evidence that suppression of acute diseases in childhood
      induce chronic diseases in the future?
AB  - Seeking to understand the individual in his symptomatic totality has been an aim
      of homeopathy since its beginning. Throughout its history, homeopaths have been
      concerned that inadequate treatment of acute diseases in childhood may lead to
      future chronic diseases. Hahnemann cautioned that by treating acute diseases with
      allopathic medicine, with strong doses of drugs, or suppressing local symptoms of
      those diseases, would increase the risk of future chronic diseases. Burnett
      proposed the theory of vaccinosis and warned of chronic manifestations subsequent
      to smallpox vaccination. French homeopaths, seeking the physiopathological origin
      of chronic diseases, correlated it to the abnormal reaction of the
      reticuloendothelial system (RES). Through the study of experimental pathology,
      Maffei attributed symptomatic manifestations to the imbalance between the
      immunological phenomena of allergy and immunity. He termed the sensitizing and
      pathogenic effects of medications and vaccines, 'metallergy' and 'parallergy',
      respectively. The hygiene hypothesis is based on evidence that the imbalance of
      immunological response in childhood, specifically among the Th1 and Th2
      lymphocyte subpopulations, is responsible for the development of some allergic
      and chronic diseases in the future. The deranging factor for the predisposition
      to future allergic response (Th2) is the obstruction of natural manifestations of
      infectious diseases (Th1 response) in young children. Homeopathic treatment aims
      to equilibrate vital reaction, corresponding to an integrative physiological
      response, it may regulate Th1/Th2 imbalance. However, clinical trials to support
      this hypothesis are lacking.

PMID- 12422924
TI  - Potentized Mercuric chloride and Mercuric iodide enhance alpha-amylase activity
      in vitro.
AB  - Mercuric chloride 30c and Mercuric iodide 30c were prepared by successive
      dilution in 30 steps of 1:100 followed by sonication at 20KHz for 30s at each
      step. Both were prepared in two media: 90% ethanol and distilled water. Three
      preparations of Mercuric chloride 30 in water were used: 12-month old, 1-month
      old and 4-day old. The controls for the water and ethanol-water preparations were
      pure water 30c and 90% ethanol 30c, respectively. For the three water
      preparations there were three matched controls of water 30c of the same ages.
      Each potentized substance or its control was mixed with distilled water 1:100
      before testing. Hydrolysis of starch by alpha-amylase was measured by the
      standard procedure after incubation for 15 min at 27 degrees C. Mercuric chloride
      30c and Mercuric iodide 30c in both water and aqueous ethanol media, enhanced
      enzyme activity significantly, compared to their respective controls. Mercuric
      chloride 30c, prepared in water 12 months previously, produced no significant
      change in the enzyme activity compared to its control. We hypothesize that the
      structure of the active molecule imprinted on water polymers during the process
      of dynamization. The specifically structured water interacts with the active
      sites of alpha-amylase, modifying its activity. Ethanol molecules have large non
      polar part stabilizing the water structure and thus retaining activity for a
      longer time.

PMID- 12422925
TI  - On the physical basis of succussion.
AB  - It is argued that succussion drives the homeopathic tincture undergoing
      potentisation to a turbulent regime, where vortices continually form and
      disappear, ranging in size from the linear extent of the container to a minimum
      scale determined by viscosity and the rate of energy dissipation. Input
      mechanical energy cascades down this population of eddies and becomes available
      at the microscopic level to perform work (chemical, electrical, etc). A structure
      generated in the tincture would be rupted by vortices smaller than it, and this
      sets definite limits on the strength of succussion, so the power input leads to
      larger vortices than the structures one is trying to create and preserve through
      potentisation. An experimental procedure to test this proposal is suggested,
      based on Rayleigh scattering.

PMID- 12422926
TI  - A survey of the use of over-the-counter homeopathic medicines purchased in health
      stores in central Manchester.
AB  - BACKGROUND: There is little research on the use of over-the-counter (OTC)
      homeopathic medicines. OBJECTIVES: To obtain data on conditions treated by OTC
      homeopathy; perceived effectiveness; how long respondents had used OTC
      homeopathy; if respondents combined them with prescription drugs; reasons for
      using OTC homeopathy. METHODS: 75 users of OTC homeopathy completed
      questionnaires while purchasing OTC homeopathic remedies in three health food
      shops in central Manchester. RESULTS: The most frequently treated conditions were
      respiratory, mental/psychological and bruises/injuries. Respondents perceived OTC
      homeopathy to be effective for relieving these conditions. There was a trend for
      respondent's first using OTC homeopathy 4 or more years previously. Thirteen per
      cent combined it prescription drugs. The most strongly endorsed reasons for using
      OTC homeopathy were that was a natural treatment and was perceived as harmless.
      CONCLUSIONS: This study and possible future larger scale studies may show which
      conditions/ailments are being treated by OTC homeopathy and the reasons why
      people choose to use it. Such information may lead to further integration within
      the NHS.

PMID- 12422927
TI  - Improving homeopathic prescribing by applying epidemiological techniques: the
      role of likelihood ratio.
AB  - A committee of the Dutch Association of Homeopathic Physicians is trying to
      validate materia medica by evaluating successful cases. These cases are presented
      and assessed by a group of experienced homeopathic physicians to provide
      indications about the prevalence of symptoms related to particular homeopathic
      medicines. The next logical question is whether epidemiological techniques can be
      applied to them. We have some ideas concerning the information these data can
      provide, based on epidemiological theory and limited experimental data.
      Theoretical investigation suggests that the epidemiological concept of likelihood
      ratio is well adapted to homeopathy. Researching and applying likelihood ratio
      will lead to more accurate materia medica and repertory. These considerations
      already indicate some shortcomings in the representation of rare remedies and the
      use of grading in the current repertories.

PMID- 12422928
TI  - Patient-practitioner-remedy (PPR) entanglement. Part 1: a qualitative, non-local
      metaphor for homeopathy based on quantum theory.
AB  - A metaphor for homeopathy is developed in which the potentised medicine, the
      patient, and the practitioner are seen as forming a non-local therapeutically
      'entangled' triad, qualitatively described in terms of the transactional
      interpretation of quantum mechanics.

PMID- 12422929
TI  - The toxicology of Amanita phalloides.
AB  - This paper examines the biology and medical consequences of ingesting the
      potential lethal poisonous mushroom, Amanita phalloides, the Death Cap. The
      organism is a fungus, its structure, distribution and toxic components are
      described. Symptoms of human poisoning by Am. phalloides are described, following
      the order of Homeopathic Repertories.

PMID- 12422930
TI  - Molluscum contagiosum: a case series.
AB  - Molluscum contagiosum is a benign and contagious disease of the skin. In a series
      of 30 consecutive patients, 15 had full resolution, 12 were improved. Brief case
      histories of the 15 patients who fully resolved are presented. The homeopathic
      medicines most frequently associated with positive outcome were Natrum
      sulphuricum, Sulphur and Natrum muriaticum.

PMID- 12422931
TI  - 20 years ago British Homoeopathic Journal, October 1982.

PMID- 12422933
TI  - Homeopathy and quantum vacuum.

PMID- 12422932
TI  - International drug regulators discuss homeopathy.

PMID- 12422934
TI  - Hallucinogens and redemption.
AB  - This article examines drug substitution with regard to hallucinogens (ayahuasca,
      ibogaine, peyote and LSD) set within the concept of redemption. The model
      examines both religious and secular approaches to the contemporary use of
      hallucinogens in drug substitution, both by scientists and in religious settings
      worldwide. The redemptive model posits that the proper use of one psychoactive
      substance within a spiritual or clinical context helps to free an individual from
      the adverse effects of their addiction to another substance and thus restores
      them as functioning members of their community or group. Data is drawn from the
      U.S., Brazil, Peru, and West Africa. Two principle mechanisms for this are
      proposed: the psychological mechanism of suggestibility is examined in terms of
      the individual reaching abstinence goals from addictive substances such as
      alcohol and opiates. Neurophysiological and neurochemical mechanisms to
      understand the efficacy of such substitution are highlighted from ongoing
      research on hallucinogens. Research by two of the authors with the Unaio do
      Vegetal (UDV) Church in Brazil is examined in terms of the model.

PMID- 12422935
TI  - Jekyll and Hyde revisited: paradoxes in the appreciation of drug experiences and
      their effects on creativity.
AB  - Historically, states of intoxication--like dreams and madness--are seen in either
      one of two opposed ways. The intoxicated are either "possessed" or "under the
      influence" of an external agency, or revealing hidden feelings or truths (in vino
      veritas). Along the same lines, artists who worked during LSD, mescalin or
      psilocybin intoxication often refer to feelings of either being "possessed" or
      "liberated," a difference that can be explained partly by their expectations and
      partly by their evaluations, which both tend to conform to the cultural dichotomy
      in interpreting the irrational. Both interpretations, however, tend to obscure
      not only the other, but also-it is posited-the paradoxical nature of the drug
      experience itself. Analysis of a protocol shows that intoxication might comprise
      feelings of "possession" as well as "liberation" almost simultaneously, and
      mediumistic and some psychedelic art shows stylistic traits that can be seen as
      the visual expressions of both these feelings. It seems that the "demoniacal" and
      "psychedelic" mode come together in experiential reality, only to be divided in
      the cultural sphere.

PMID- 12422936
TI  - The serotonergic system and mysticism: could LSD and the nondrug-induced mystical
      experience share common neural mechanisms?
AB  - This article aims to explore, through established scientific research and
      documented accounts of personal experience, the similarities between religious
      mystical experiences and some effects of D-lysergic diethylamide or LSD. LSD
      predominantly works upon the serotonergic (serotonin-using neurons) diffuse
      neuromodulatory system, which projects its axons to virtually all areas of the
      brain including the neocortex. By its normal action it modulates awareness of the
      environmental surroundings and filters a high proportion of this information
      before it can be processed, thereby only allowing the amount of information that
      is necessary for survival. LSD works to open this filter, and so an increased
      amount of somatosensory data is processed with a corresponding increase in what
      is deemed important. This article describes the effects and actions of LSD, and
      due to the similarities with the nondrug-induced mystical experience the author
      proposes that the two could have common modes of action upon the brain. This
      could lead to avenues of research into mysticism and a wealth of knowledge on
      consciousness and how we perceive the universe.

PMID- 12422937
TI  - Snuff synergy: preparation, use and pharmacology of yopo and Banisteriopsis caapi
      among the Piaroa of southern Venezuela.
AB  - Current understanding of the preparation and use of yopo, a hallucinogenic snuff
      made from the ground seeds of the Anadenanthera peregrina tree, has departed
      little from the accounts of scientists and travelers made over a century ago.
      Schultes and others have made refinements to these early accounts. While several
      scholars have drawn attention to the fact that little ethnographic work has been
      conducted to assess the ethnobotanical diversity and cultural framework of the
      snuff hallucinogen complex, few subsequent studies deal with botanical variations
      in preparation and use. This article contrasts historical accounts of yopo
      preparation with ethnographic data I have recently collected among the Piaroa of
      southern Venezuela to demonstrate one way in which yopo preparation and use
      deviates from the basic model established by Humboldt, Spruce and Safford. Piaroa
      shamans include B. caapi cuttings in the preparation of yopo and consume doses of
      B. caapi prior to snuff inhalation concomitant with the strength of visions
      desired for particular tasks. I argue that the combined use of yopo and B. caapi
      by Piaroa shamans is pharmacologically and ethnobotanically significant, and
      substantiates claims of the use of admixtures in snuff; further ethnographic
      investigation of the snuff hallucinogen complex is necessary.

PMID- 12422938
TI  - The prevalence and correlates of depressive symptomatology among a community
      sample of crack-cocaine smokers.
AB  - Depression has been identified as a disorder of clinical significance among
      cocaine users. Even so, its prevalence in cocaine-abusing populations is
      uncertain. This research employed a cross-sectional design to determine the
      prevalence of current depressive symptomatology among a sample of 430 not-in
      treatment crack-cocaine users. Depression was assessed with the Beck Depression
      Inventory (BDI). The mean BDI score was 19.1. Overall, 80% of the sample had BDI
      scores that suggested more than minimal depression, and 55% had symptoms of
      moderate to severe depression. The results of a cumulative logistic regression
      analysis showed that men, African-Americans, and individuals with some college
      education were less likely to be depressed. Individuals with higher Addiction
      Severity Index composite scores for family/social, medical, legal, and alcohol
      problems had a greater likelihood of reporting symptoms of depression. Frequency
      of cocaine use and perceived need for treatment were also positively associated
      with higher BDI scores. The results suggest that the prevalence of depression
      among crack users is higher than has been previously reported. Treatment programs
      should routinely screen crack-cocaine users for depression. The BDI may be a
      suitable tool for such efforts since it has an acceptable level of internal
      consistency when employed with crack users (a = 0.89).

PMID- 12422939
TI  - Demystifying the injection drug user: willingness to participate in traditional
      drug treatment services among participants in a needle exchange program.
AB  - Injection drug users have been vilified in our culture as being wild-eyed and
      willing to do anything for the next hit. These individuals are typically seen as
      being unemployed, uneducated and completely disinterested in making any changes
      in their lives. Sixty-one participants in a syringe exchange program in
      Cleveland, Ohio were interviewed using the NIDA Risk Behavior Assessment. Fifty
      (81%) of the respondents were either in an abstinence-based program or reported a
      willingness to participate in such a program. Importantly, although the sample
      consisted of long-term daily users of injection drugs (m=19.95 years), the
      majority of the sample was employed (69%) and were high school graduates (51%).
      The results of this study suggest that injection drug users are willing to make
      changes in their use-related behaviors, involvement in a needle exchange program
      does not preclude involvement in abstinence-based programming, and needle
      exchange services may serve as an important component in a continuum of care when
      coupled with traditional abstinence-based services.

PMID- 12422940
TI  - Methamphetamine use and HIV risk among substance-abusing offenders in California.
AB  - Recent epidemiological surveys of illicit substance use show a particularly high
      prevalence of methamphetamine use in the western and southwestern United States
      most notably California. Moreover, in their analysis of 1995 Drug Use Forecasting
      data, Anglin and colleagues (1998) found that methamphetamine was a preferred
      substance among California arrestees. The present study uses data from 807 state
      prison inmates in California (32% of whom reported using methamphetamine prior to
      incarceration) to examine the associations between methamphetamine use and HIV
      risk behaviors. Methamphetamine users in this sample were significantly more
      likely than nonusers to have injected drugs during the six months prior to their
      current incarceration. Among injectors, however, injection-related risks (such as
      dirty needles and needle sharing, etc.) were not significantly associated with
      methamphetamine use. However, past six-month sex-related risks were dramatically
      higher for methamphetamine users. These patterns persisted even after controlling
      for background differences between the two groups. The results of this study
      underscore the importance of addressing the higher sex-related HIV/AIDS risk
      among methamphetamine users undergoing prison-based drug treatment.

PMID- 12422941
TI  - An exploratory study: the use of paroxetine for methamphetamine craving.
AB  - Methamphetamine abuse and dependence are growing problems nationally and
      worldwide. There are currently no effective pharmocologic treatments. Animal
      studies with SSRI's suggest that serotonergic modulation alters methamphetamine's
      behavioral effects. This exploratory study is a trial of the effects of the SSRI
      paroxetine versus placebo (in a double blind design) on craving and use in a
      population of methamphetamine users. Many subjects dropped out of the study, but
      those in active treatment who completed the eight week trial had a decrease in
      methamphetamine craving compared to the placebo treatment as measured by the OCDS
      modified for use in this population. Statistical analyses were not performed due
      to the low number of subjects. The preliminary data suggest that serotonergic
      agents may play a role in the effective treatment of methamphetamine abuse and
      dependence within the context of other effective behavioral interventions.

PMID- 12422942
TI  - Pathways to long-term recovery: a preliminary investigation.
AB  - Recovery from addiction is a lifelong process. While there is a large body of
      empirical data on the short-term effectiveness (one to two years) of various
      treatment modalities, very little is known about the processes of recovery over
      time. This is particularly unfortunate as treatment gains are often short-lived
      and even multiple treatment episodes do not always succeed in breaking the
      addiction cycle. Further, treatment represents only one of the paths to recovery.
      This article reports on a study of individuals in long-term recovery from
      substance abuse (median = 12 years) and examines the factors they cite as
      important in establishing and maintaining their recovery status. Key factors
      reported were social and community support, affiliation with 12-Step
      organizations and negative consequences of substance use. Implications for
      clinical practice and future research directions are discussed.

PMID- 12422944
TI  - "Mushroom madness" in the Papua New Guinea Highlands: a case of nicotine
      poisoning?
AB  - "Mushroom madness" is a condition that was first reported in the Western
      Highlands Province of Papua New Guinea. This condition was originally blamed on
      the ingestion of hallucinogenic mushrooms. This was later proven to be incorrect
      and this condition was explained instead as a form of collective hysteria. There
      is, however, ethnographic, phytochemical and pharmacological evidence to suggest
      that "mushroom madness" was actually a state of acute nicotine poisoning produced
      by the ingestion of toxic quantities of tobacco.

PMID- 12422943
TI  - Epidemiology and public health Consequences of methamphetamine use in
      California's Central Valley.
AB  - Methamphetamine use is an increasingly serious public health problem in
      California and other parts of the country. Despite sensationalistic media
      attention, however, very little is known about users of this clandestinely
      consumed drug. Employing methods known as Rapid Assessment and Response, the
      authors describe the epidemiology and public health implications of
      methamphetamine use in California's Central Valley, with a focus on Sacramento,
      which many social indicators suggest has been more severely affected by
      methamphetamine than any city in the nation. Data sources for this report include
      interviews with drug users, statistical reports, epidemiologic studies, and local
      informed expert opinion. In their social demography, methamphetamine users in the
      Central Valley are in marked contrast to those of coastal cities such as Seattle
      and San Francisco, being largely heterosexual, and of mixed racial/ethnic
      heritage. Three-quarters or more initiate their use of the drug while still in
      their teens, with more than a quarter beginning use before the age of 15. Many of
      these rapidly gravitate to regular use, and continue using well into their
      thirties. Methamphetamine users are at much higher risk of infection with HIV
      than opiate users, particularly if they inject. Partly because methamphetamine
      enhances libido, users of the drug typically also have many more sexual partners.
      Not surprisingly, data indicate that methamphetamine users are more likely than
      heroin users to be HIV-infected. Methamphetamine appears to be less of a street
      drug than heroin, complicating efforts at street outreach. However, because it is
      typically used in social settings, a social or diffusion approach to HIV
      prevention might be particularly promising.

PMID- 12422945
TI  - A comparison of the OnTrak Testcup-5 to laboratory urinalysis among arrestees.
AB  - Research studies that collect urine specimens to measure recent drug use have
      traditionally sent the specimens to laboratories for analysis. A new method of
      urinalysis-instant urine testing-may offer a quicker, equally accurate
      alternative to laboratory assays. To date, however, no studies have explored the
      efficacy of instant urine technology with individuals under criminal justice
      supervision. To address this limitation, the authors administered a single
      instant urine test-the OnTrak Testcup-5-to 136 adult male arrestees surveyed
      through Maryland's Substance Abuse Need for Treatment among Arrestees (SANTA)
      study. The specimens were subsequently shipped to an independent laboratory for
      reanalysis. Analyses indicate high agreement between the two techniques for
      marijuana, cocaine, and heroin. Potential uses for the OnTrak Testcup-5 are
      discussed.

PMID- 12422946
TI  - Defects of granulopoiesis in patients with severe congenital neutropenia.
AB  - To confirm the abnormalities of primitive myeloid progenitor cells in patients
      with severe congenital neutropenia (SCN), we studied their responsiveness to
      hematopoietic factors including granulocyte colony-stimulating factor (G-CSF). In
      all SCN patients studied no abnormalities of granulocyte colony-stimulating
      factor receptor (G-CSFR) gene were detected by polymerase chain reaction-single
      strand conformation polymorphism analysis and sequence analysis. A flow
      cytometric analysis of bone marrow cells based on the expression of CD34, Kit
      receptor, and G-CSFR demonstrated a reduced frequency of CD34+/Kit+/G-CSFR+ cells
      in patients with SCN. The granulocyte/macrophage (GM)-colony formation of
      CD34+/Kit+/G-CSFR+ cells in patients was markedly decreased at all concentrations
      of G-CSF in serum-deprived semisolid culture. The responsiveness of CD34+/Kit+/G
      CSFR+ cells in patients showed a reduced response to the combination of stem cell
      factor, the ligand for flk2/flt3, and interleukin-3 with or without G-CSF in
      serum-deprived semisolid and liquid suspension cultures. In contrast, no
      difference in the responsiveness of CD34+/Kit+/G-CSFR- cells was noted between
      SCN patients and normal subjects. The bone marrow cells from a patient who
      underwent bone marrow transplantation showed a restoration of both the reduced
      frequency and the decreased level of GM-colony formation of CD34+/Kit+/G-CSFR+
      cells. These results demonstrate that the presence of qualitative and
      quantitative abnormalities of primitive myeloid progenitor cells expressing G
      CSFR may play an important role in the impairment of granulopoiesis in patients
      with SCN.

PMID- 12422947
TI  - Effects of weaning by surrogate mothers (ACI) on tumor development in SD rats
      treated with methylnitrosourea (MNU) and/or N-methyl-N'-nitro-N-nitrosoguanidine
      (MNNG).
AB  - In this experiment, methylnitrosourea (MNU) was administered, followed by N
      methyl-N'-nitro-N-nitrosoguanidine (MNNG), to assess effects of surrogate
      mothering on tumor. One or two day old male SD pups were treated with or without
      30 mg/kg body weight of MNU and nursed by SD or ACI surrogate mothers for 5
      weeks. When 6-weeks-old they were then treated with 100 ppm MNNG or tap water for
      16 weeks. The tumor incidence in the MNNG alone group was significantly lower
      than with MNU alone or MNU+MNNG (p < 0.01). Kidney or nerve tumors mainly
      developed in the MNU group, gastric tumors in the MNNG group, and the two
      combined in the MNU+MNNG group. The incidence and mean number of tumors did not
      significantly differ between the two weaning groups. However, mean survival time
      with the ACI surrogate mothers after treatment with MNU was increased as compared
      with the SD mother group. Cumulative development of tumors in the ACI surrogate
      mother group was also delayed (p < 0.05). Similar results were obtained with
      MNU+MNNG and MNNG alone. The present experiment suggested that tumor induction
      might be effected by components of the mother's milk.

PMID- 12422948
TI  - A case of traumatic cyclodialysis followed by ultrasound biomicroscopy.
AB  - We report a case of persistent traumatic cyclodialysis treated by
      goniophotocoagulation and observed by ultrasound biomicroscopy (UBM) throughout
      the course. A 16 year-old male was struck in his right eye by a rocket firework.
      After the injury, hypotony continued for 4 months and he was referred to
      Hiroshima University Hospital. At that time, the best visual acuity in his right
      eye was 0.2 and the intraocular pressure was 6 mmHg. Three hundred and sixty
      degrees of cyclodialysis, partial peripheral anterior synechia, hypotony
      maculopathy and subretinal proliferative tissue were observed. Cyclodialysis was
      obvious by UBM. From 4 months after the injury goniophotocoagulation was
      performed six times in 2 months. Intraocular pressure recovered 6 months after
      the injury and reattachment of cyclodialysis and disappearance of the
      suprachoroidal space were confirmed by UBM. UBM was useful in observing
      cyclodialysis throughout the course.

PMID- 12422949
TI  - The effect of intentional expectancy on mental processing: a
      chronopsychophysiological investigation.
AB  - Expected events are processed faster than unexpected ones. Previously, we have
      reported evidence that passive expectancies determined by the preceding event
      sequence mainly affected the duration of motoric processes. Here we examined the
      effects of instructed, intentional expectancies in a two-choice reaction time
      (RT) task. As predicted, RTs were shorter for expected than unexpected events.
      Onset of the lateralized readiness potential as an index of selective response
      activation, and the latency of the P300 component of the event-related potential,
      reflecting the duration of perceptual processing, indicated that intentional
      expectancy affected the time demands for central processing but did not influence
      the duration of early perceptual or motoric processes. Together the present and
      our previous results provide evidence that different kinds of expectancy can be
      distinguished by their locus of action within the information processing system.

PMID- 12422950
TI  - Memory search instead of template matching? Representation-guided inference in
      same-different performance.
AB  - Data from two experiments using transformationally related patterns forming
      rotation/reflection equivalence sets of different size's are presented. In a same
      different experiment, two successively presented patterns were judged as same
      when they belonged to the same equivalence set, and different otherwise. Reaction
      times depended on the size of the equivalence set to which the patterns belong.
      This was the case, even when they were physically identical. Results are
      interpreted within a framework of memory-guided inference which assumes that
      participants perform a memory search within the equivalence sets activated by the
      compared patterns instead of comparing these directly. In Experiment 2, goodness
      ratings were required which are shown to reflect a second component of
      information processing.

PMID- 12422951
TI  - Impact of decision goal on escalation.
AB  - This research investigates the sunk-cost effect or escalation defined as the
      irrational tendency to choose to continue to invest money, time, or effort
      following unsuccessful investments. Building on previous research demonstrating a
      loss-sensitivity principle in sequential decision making, the hypothesis was
      proposed that a loss-minimization goal would lead to stronger effects of sunk
      outcomes (prior gains and losses) than would a gain-maximizing goal. The
      hypothesis was investigated in three experiments with undergraduates responding
      to investment decision scenarios. Although the tendency to continue investments
      was always larger for gain-maximizing than for loss-minimizing goal instructions,
      the sunk-outcome effect was stronger in the former case. However, when the
      decisions were personal and concerned lower stakes rather than business
      investments involving large amounts of money, the expected stronger effect of
      sunk outcomes was found for loss-minimizing goal instructions. Another finding
      was that the expected value was never ignored, thus suggesting that future
      research should focus on the joint effects of the expected value and sunk
      outcomes.

PMID- 12422952
TI  - Implicit learning of a recursive rule in an artificial grammar.
AB  - Participants performed an artificial grammar learning task, in which the standard
      finite state grammar (J. Verb. Learn. Verb. Behavior 6 (1967) 855) was extended
      with a recursive rule generating self-embedded sequences. We studied the
      learnability of such a rule in two experiments. The results verify the general
      hypothesis that recursivity can be learned in an artificial grammar learning
      task. However this learning seems to be rather based on recognising chunks than
      on abstract rule induction. First, performance was better for strings with more
      than one level of self-embedding in the sequence, uncovering more clearly the
      self-embedding pattern. Second, the infinite repeatability of the recursive rule
      application was not spontaneously induced from the training, but it was when an
      additional cue about this possibility was given. Finally, participants were able
      to verbalise their knowledge of the fragments making up the sequences-especially
      in the crucial front and back positions-, whereas knowledge of the underlying
      structure, to the extent it was acquired, was not articulatable. The results are
      discussed in relation to previous studies on the implicit learnability of complex
      and abstract rules.

PMID- 12422953
TI  - Additive factors analysis of reaction time with alphanumericals and line
      orientations as stimuli.
AB  - Most additive factors method (AFM) analyses of choice reaction time (CRT) have
      used alphanumerics whereas tests of single process models have often used line
      length or line orientation. The suggestion is raised that commonly observed
      additive effects of variables on CRT might not apply to stimuli of the latter
      category. This would mean a severe limitation of the AFM in that the stage
      structure of choice reactions would be stimulus specific. The issue is addressed
      in two experiments. The first showed additive effects of stimulus quality and
      stimulus-response compatiblility for both alphanumerics and line orientations as
      stimuli. The second showed that for both stimulus categories the effect of
      stimulus quality was fully reflected in visual fixation time. Together the
      results argue against a single central process and favour a stage model of CRT.

PMID- 12422954
TI  - Studies of muscarinic receptor subtypes in salivary gland function in
      anaesthetized rats.
AB  - The in vivo study aimed to examine whether muscarinic receptor subtypes other
      than muscarinic M3 receptors exert exocrine functional roles in the rat salivary
      glands. The effects of pirenzepine, methoctramine and 4-diphenylacetoxy-N
      methylpiperidine methiodide (4-DAMP) were examined on secretion from the major
      salivary glands evoked by acetylcholine (0.001-10 micromol kg(-1) i.v.) in
      pentobarbitone-anaesthetized rats. Observations were occasionally made on
      glandular blood flow. 4-DAMP (0.1-100 nmol kg(-1) i.v.) markedly and equipotently
      inhibited the acetylcholine-evoked fluid responses in all glands. Pirenzepine
      (0.1 micromol kg(-1) i.v.-10 mmol kg(-1) i.v.) showed significantly lower
      inhibitory potency than 4-DAMP, most conspicuously in the parotid, while
      methoctramine (0.1 micromol kg(-1) i.v.-10 mmol kg(-1) i.v.) exerted an even
      lesser inhibitory effect. Also against acetylcholine-evoked blood flow increases,
      4-DAMP showed a conspicuous potency. At 1 and 10 micromol kg(-1) i.v. of
      pirenzepine, the antagonist reduced the protein concentration in the
      submandibular saliva, but not in the parotid saliva. While 4-DAMP (1 and 10 nmol
      kg(-1) i.v.) significantly inhibited acetylcholine-evoked protein secretory
      responses in the submandibular glands, methoctramine (below 10 micromol kg(-1)
      i.v.) affected the responses in neither gland. The reduction of the protein
      concentration in submandibular saliva caused by 4-DAMP and pirenzepine was
      inhibited by N(omega)-nitro-L-arginine methyl ester (L-NAME; 30 mg kg(-1) i.p.),
      while L-NAME had no or only minute effects on the parotid protein secretion.
      Thus, in addition to muscarinic M3 receptors, other muscarinic receptors
      contribute to in vivo functional responses in rat submandibular and sublingual
      glands. While these other receptors are muscarinic M1 receptors in the sublingual
      gland, they may be a different subtype, possibly muscarinic M5 receptors, in the
      submandibular gland. However, muscarinic M1 receptors may induce indirect effects
      via nitric oxide in the submandibular gland.

PMID- 12422955
TI  - Fos expression in spinally projecting neurons after hypotension in the conscious
      rabbit.
AB  - Hypotension produces a reflex increase in the activity of sympathetic vasomotor
      nerves. Studies in anaesthetised animals have established that neurons in the
      rostral ventrolateral medulla (RVLM) that project directly to sympathetic
      vasomotor preganglionic neurons in the spinal cord are a critical component of
      the central pathways mediating this reflex response. There are also neurons in
      supramedullary regions (the A5 area in the pons and the paraventricular nucleus
      (PVN) in the hypothalamus), however, that project directly to the sympathetic
      vasomotor outflow. The aim of this study was to identify and map neurons within
      the A5 area and PVN, as well as in the RVLM, which may contribute to the reflex
      sympathoexcitatory response to a hypotensive challenge in conscious rabbits. In a
      preliminary operation, a retrogradely transported tracer was injected into a site
      centred on the intermediolateral cell column in the upper lumbar spinal cord.
      After a waiting period of at least 1 week, a moderate hypotension (decrease in
      arterial pressure of approximately 20 mm Hg) was induced in conscious rabbits for
      60 min by continuous infusion of sodium nitroprusside. In confirmation of
      previous studies, hypotension resulted in the expression of Fos in the RVLM, the
      A5 area and PVN. There were also retrogradely labelled neurons in all these
      regions. In both the RVLM and A5 area, approximately 40% of the retrogradely
      labelled neurons were also immunoreactive for Fos. In contrast, in the PVN the
      proportion of retrogradely labelled neurons that were also Fos-positive was much
      less (approximately 6%). This study has demonstrated that, in the conscious
      rabbit, a significant proportion of spinally projecting neurons within discrete
      regions in the RVLM and A5 area are activated by hypotension (as indicated by Fos
      expression). In the PVN, only a very small proportion of spinally projecting
      neurons are activated by hypotension, and thus these neurons appear to be
      regulated primarily by inputs other than baroreceptor inputs.

PMID- 12422956
TI  - Release of acetylcholine by Die-Huang-Wan to enhance insulin secretion for
      lowering plasma glucose in Wistar rats.
AB  - We have recently observed that Die-Huang-Wan has an ability to stimulate the
      secretion of insulin to decrease the plasma glucose levels in normal rats. In the
      present study, this effect of Die-Huang-Wan was reversed by the general
      muscarinic antagonists atropine and scopolamine, but not affected by the
      ganglionic nicotinic antagonist pentolinium or hexamethonium. Moreover,
      disruption of synaptically available acetylcholine using an inhibitor of choline
      uptake, hemicholinium-3, or vesicular acetylcholine transport, vesamicol,
      abolished the actions induced by Die-Huang-Wan. Mediation of acetylcholine
      released from nerve terminals by this product can thus be considered. Also,
      physostigmine at concentration sufficient to inhibit acetylcholinesterase
      enhanced the effect of Die-Huang-Wan. Blockade of the increase of plasma insulin
      and plasma glucose lowering action of Die-Huang-Wan by 4-diphenylacetoxy-N
      methylpiperdine methiodide (4-DAMP) indicated the mediation of muscarinic M3
      receptors. The results suggest that Die-Huang-Wan may enhance the release of
      acetylcholine from nerve terminals to stimulate the muscarinic M3 receptors for
      augmenting insulin release to produce plasma glucose lowering action.

PMID- 12422957
TI  - The sympathetic nervous system is involved in the inhibitory effect of morphine
      on the colon motility in rats.
AB  - The role of the sympathetic nervous system in the inhibitory effect of morphine
      on colonic motility was investigated in male adult Wistar rats. The responses of
      colonic motility and blood pressure to the intravenous administration of morphine
      under urethane anesthesia were recorded. Sympathectomy (6-hydroxydopamine) or
      pretreatment with phentolamine, an alpha-adrenoreceptor antagonist (3.15
      microM/kg, i.v.), or propranolol, a beta-adrenoreceptor antagonist (3.38
      microM/kg, i.v.), on the inhibitory effect of intravenously administered morphine
      on colonic motility were observed. The results of the investigation showed that a
      significant depression of colonic motility occurred in untreated rats following
      intravenous administration of morphine, while no significant effect was seen in
      the sympathectomized. Pretreatment with phentolamine or propranolol also
      significantly attenuated the depression of colonic motility induced by morphine.
      Morphine also produced a transient depression of the blood pressure. However,
      this inhibitory effect of morphine on blood pressure was intensified after
      sympathectomy or pretreatment with either phentolamine or propranolol. We
      conclude that sympathetic activity plays an important role in the inhibitory
      effects of morphine on colonic motility and that both alpha- and beta
      adrenoreceptors are involved.

PMID- 12422958
TI  - Role of the autonomic nervous system in emetic and cardiovascular responses in
      Suncus murinus.
AB  - To clarify the role of the autonomic nervous system in cardiovascular and emetic
      responses, we studied the influence of drugs that act on autonomic nervous
      function on emetic and cardiovascular responses induced by chemical or mechanical
      stimulation to the stomach in two strains of Suncus murinus, Jic:SUN-Her and
      Jic:SUN-Ler. Latency to the first retching in Jic:SUN-Her was significantly
      shorter than that in Jic:SUN-Ler to both mechanical and chemical stimulation.
      This result indicated that there are different sensitivities to mechanical and
      chemical stimulation to the stomach in these two strains of suncus. However, the
      numbers of emetic episodes were almost the same in these two strains. Mean blood
      pressure significantly increased from baseline prior to retching in both strains.
      Heart rate decreased in Jic:SUN-Her and increased in Jic:SUN-Ler prior to
      retching, suggesting that a different baroreflex responsiveness might exist in
      these two strains of suncus. Administration of acetylcholine and phenylephrine
      affected emetic response induced by mechanical and chemical stimulation. Although
      the baseline values of mean blood pressure and heart rate after administration of
      these drugs were different, changes in mean blood pressure and heart rate prior
      to retching were unaffected. This result suggested that the state of autonomic
      activity before the emetic response might be important in the development of the
      emetic response. Pretreatment with hexamethonium suppressed the cardiovascular
      response prior to retching and prolonged the latency to the first retching. This
      result indicated that there was an interaction between the mechanisms involved in
      cardiovascular and emetic responses. The change in autonomic function during the
      emetic response, especially enhancement of sympathetic activity prior to
      retching, may be relevant to emetic and cardiovascular responses. Moreover, these
      results suggest that different autonomic function or different baroreflex
      responsiveness in Jic:SUN-Her and Jic:SUN-Ler may be involved in emetic
      responses.

PMID- 12422959
TI  - Developmental changes in heart rate variability during exposure to prolonged
      hypercapnia in piglets.
AB  - The hypothesis that hypercapnia-induced differences in heart rate variability
      (HRV) would emerge during early maturation was tested using a developing porcine
      model. Piglets were randomly assigned to either exposed (10% CO2 for 1 h) or
      control (100% O2) conditions, and then to one of three study groups: (a) 5-8 days
      old, (b) 13-15 days old, (c) 26-34 days old. Experiments were performed on pairs
      of age-and litter-matched animals that were anesthetized, paralyzed, and
      artificially ventilated. HRV was evaluated using power spectral analysis, SD of
      differences between successive RR intervals, and cardiac interval analysis.
      Statistical comparisons of simultaneously studied animals were made at baseline,
      15 and 55 min after onset of hypercapnia, and 2 h after offset of hypercapnia.
      Our analyses revealed that only HRV of 26-34-day-old animals differed
      significantly from values of control animals. Cardiac intervals of those animals
      were distributed in such a manner that hypercapnia likely elicited coactivation
      of sympathetic and parasympathetic systems. Comparison of the distribution of
      cardiac intervals for other animals showed that 5-8-day-old animals had high
      frequency of balanced intervals at baseline that remained so during hypercapnia.
      Given that such coactivation may be neuroprotective, the paucity of balanced
      intervals in 13-15-day-old animals could mean that the end of the second
      postnatal week is associated with increased vulnerability.

PMID- 12422960
TI  - The effect of parasympathetic postganglionic denervation on parotid salivary
      protein secretion in anaesthetized sheep.
AB  - Effects of unilateral parasympathetic denervation of ovine parotid glands were
      examined in anaesthetized sheep 21-28 days after nerve section. Parasympathetic
      denervation reduced the mass of the ipsilateral gland while increasing that of
      the contralateral gland to the extent that total gland mass was greater than in
      sheep with normally innervated glands. The spontaneous secretion (8.8 +/- 1.1
      microl min(-1) g gland(-1)) was significantly less from denervated than from
      innervated glands of normal control animals (26.0 +/- 2.7 microl min(-1) g gland(
      1); P< 0.01) and contained more protein. Rates of flow, and the outputs of sodium
      and potassium, in response to sympathetic stimulation, were similar from normally
      innervated and chronically denervated glands, when allowance was made for the
      discrepancy in weights, whereas the output of protein was significantly enhanced
      following parasympathetic denervation (innervated--31.4 +/- 7.3 microg g gland(
      1), denervated--83.4 +/- 26.6 microg g gland(-1); P< 0.05). Intra-arterial
      infusions of acetylcholine (130 pmol min(-1) kg(-1)) elicited a flow of parotid
      saliva, the protein content of which was significantly enhanced by prior
      parasympathetic denervation. Intra-arterial infusions of vasoactive intestinal
      peptide (VIP; 2.5 pmol min(-1) kg(-1)) produced a small but statistically
      significant (P< 0.05) increase in the flow of parotid saliva from the
      contralateral, innervated but not from denervated glands. It also caused a small
      increase in protein output, which was significantly enhanced by prior
      denervation. VIP had no synergistic effect on the parotid responses to
      acetylcholine. The results show that the parasympathetic innervation to the
      parotid gland of the sheep exerts important trophic effects on the gland.
      Interaction of adrenergic and cholinergic receptors makes an important
      contribution to stimulation of the secretion of protein and prior denervation
      potentiates the protein responses to both acetylcholine and VIP.

PMID- 12422961
TI  - GABAergic systems in the nucleus tractus solitarius regulate noradrenaline
      release in the subfornical organ area in the rat.
AB  - Previous studies have shown that catecholaminergic neurons in the nucleus tractus
      solitarius (NTS) with ascending projections to the subfornical organ (SFO) are
      highly sensitive to gamma-aminobutyric acid (GABA). To clarify the role of the
      GABAergic system in the NTS in the regulation of the activity of noradrenergic
      NTS projections to the SFO, the present study was carried out to investigate the
      effects of local administration (50 nl) of GABA, the GABA(A) agonist muscimol,
      the GABA(B) agonist baclofen, the GABA(A) antagonist bicuculline or the GABA(B)
      antagonist phaclofen into the NTS on the release of noradrenaline (NA) in the
      region of the SFO using microdialysis techniques in rats under urethane
      anesthesia. Microinjections of GABA (10(-4) - 10(-2) M) into the region of the
      NTS significantly decreased the NA release in the SFO area. Injections of either
      muscimol (10(-4) - 10(-2) M) or baclofen (10(-5) - 10(-3) M) into the NTS region
      significantly attenuated the NA release in the SFO area. Injections of
      bicuculline (10(-5) and 10(-4) M), but not phaclophen (10(-6) - 10(-4) M), into
      the NTS region significantly enhanced the NA release in the SFO area, suggesting
      that the GABAergic system in the NTS may tonically inhibit the NA release in the
      SFO area through a GABA(A) receptor mechanism. Neither injection of these drugs
      in any of the doses used in this study into the NTS region caused any significant
      changes in the NA release in the sites away from the SFO. Injections of vehicle
      (50 nl) into the NTS region had no significant effect on the NA release in either
      the SFO area or the sites away from the SFO. These results suggest that the
      GABAergic system in the NTS may serve to decrease the release of NA in the SFO
      area and the two types of GABA receptors are involved in the modulation of the NA
      release.

PMID- 12422962
TI  - Orthostatic tolerance and spontaneous baroreflex sensitivity in men versus women
      after 7 days of head-down bed rest.
AB  - Many factors are involved in the development of orthostatic intolerance after
      real or simulated weightlessness. The aim of our study was to compare the effects
      of 7-day head-down bed rest (HDBR) in eight women and eight men on the
      spontaneous baroreflex sensitivity (standard spectral method and new time
      frequency algorithm) during lower body negative pressure (LBNP) tests. Results
      obtained before HDBR have shown in women, compared to men, higher heart rate,
      lower blood pressure, higher parasympathetic modulation at rest and greater
      decrease in baroreflex sensitivity with greater increase in sympathetic activity
      during LBNP. After HDBR, we observed in both men and women a dramatic decrease in
      orthostatic tolerance (7.0 min at R + 1 vs. 10.0 min, p<0.05, at BDC-1 in men;
      5.4 vs. 9.0 min, p<0.05, in women) together with a decrease in plasma volume (
      9.1 +/- 0.9% in men, -9.5 +/- 1.4% in women) and in spontaneous baroreflex
      sensitivity without gender effect. After HDBR, at the highest level of LBNP,
      diastolic blood pressure increased in men (+5.6 +/- 1.3 mm Hg) and decreased in
      women (-1.0 +/- 2.7 mm Hg) with a gender difference (p<0.05). This result
      suggests impaired vasoconstriction in women after HDBR. Neither endocrine
      response nor alterations to the cardiac baroreflex can explain gender differences
      in orthostatic tolerance after HDBR as reported by previous studies. Further
      studies need to be conducted in order to obtain a more precise analysis of gender
      difference in arteriolar vasoconstriction after HDBR. The time frequency method
      we developed to study changes in spontaneous baroreflex might be applied to the
      analysis of LBNP tests.

PMID- 12422963
TI  - Do vestibular otolith organs participate in human orthostatic blood pressure
      control?
AB  - We hypothesized that vestibular otolith organ stimulation contributes to human
      orthostatic responses. Twelve subjects underwent three 60 degrees upright tilts:
      (1) with the neck flexed from 0 degrees to 30 degrees relative to the body during
      60 degrees tilt, such that the head moved from horizontal to 90 degrees above
      horizontal (0 to 1 Gz otolith stimulation); (2) with the head and body aligned,
      such that they tilted together to 60 degrees (0 to 0.87 Gz otolith stimulation);
      and (3) with the neck flexed 30 degrees relative to the body during supine
      conditions, and the neck then extended to -30 degrees during 60 degrees body
      tilting, such that the head remained at 30 degrees above horizontal throughout
      body tilting (constant 0.5 Gz otolith stimulation). All three tilt procedures
      increased thoracic impedance, sympathetic nerve activity (N = 8 of 12), arterial
      pressure, and heart rate relative to supine conditions (all P < 0.04). Within the
      first 20 s of tilt, arterial pressure increased most obviously in the 0 to 1 Gz
      otolith condition. Thoracic impedance tended to increase more in otolith-constant
      conditions, but no dependent variable differed significantly between tilt
      conditions, and no significant time x tilt interactions emerged. Otolith inputs
      may contribute to early transient adjustments to orthostasis. However, lack of
      significant main effects of tilt condition and time x tilt interactions suggests
      that potential otolith effects on the variables we studied are relatively subtle
      and ephemeral, or that other mechanisms compensate for a lack of change in
      otolith input with orthostasis.

PMID- 12422964
TI  - Respiratory sinus arrhythmia and the heart rate response to carotid baroreceptor
      activation after hard dynamic exercise in humans.
AB  - The aim of this study was to examine the influence of 20 min of hard exercise
      (HR>160 beats min(-1)) on the efficacy of the cardiac parasympathetic nervous
      control of heart rate in humans (20-31 years; of either sex). This intensity of
      exercise was chosen to produce strong activation of the cardiac sympathetic
      nerves. Using well-controlled stimulus parameters, the efficacy of cardiac
      parasympathetic control of heart rate was assessed by recording the heart rate
      response to carotid baroreceptor activation (CBR) and the amplitude of
      respiratory sinus arrhythmia (RSA). Measurements were made while the subject
      performed light exercise (100-135 beats min (-1)) before (Control 1) and after
      very brief (Control 2) and prolonged (20 min; post) periods of hard exercise.
      There was no difference in the CBR in the three different measurement periods;
      0.33 +/- 0.17, 0.38 +/- 0.18 and 0.39 +/- 0.18 beats min(-1) mm Hg(-1) (mean +/-
      S.D., N=6) for Control 1, Control 2 and post, respectively. At a heart rate of
      120 beats min (-1), amplitude of the RSA was 6.1 +/- 2.4, 5.6 +/- 2.4 and 3.3 +/-
      2.1 beats min(-1) for Control 1, Control 2 and post, respectively (P<0.001 post
      vs. Control 1 and Control 2, N=8). The decrease in RSA amplitude following hard
      exercise may be attributable to an exercise-induced reduction in airway
      resistance and work of breathing. Overall, these results do not support the
      hypothesis that sustained hard exercise that produces strong activation of
      cardiac sympathetic nerves reduces cardiac parasympathetic efficacy.

PMID- 12422965
TI  - An alternative method to enhance vagal activities and suppress sympathetic
      activities in humans.
AB  - Vagal withdrawal and/or sympathetic overactivity is always accompanied by various
      kinds of stress and is dangerous to the body. We proposed that mild acupuncture
      on the Sishencong points may effectively enhance vagal activities but suppress
      sympathetic regulations of the heart in humans. Experiments were carried out on
      nine healthy male volunteers, while they were lying in a quiet room during 2-4
      P.M. Acupuncture was applied 2 mm deep into the skin using standard stainless
      acupuncture needles at the Sishencong points, which are located on the vertex of
      the head, each 1 cm away from Baihui (GV 20) in four directions. Four points
      around the temporal area were selected as control points. Forty minutes of
      precordial ECG signals before, during, and after acupuncture were recorded
      continuously. Frequency-domain analysis of the stationary RR intervals was
      performed to evaluate the total variance, high-frequency power (HF, 0.15-0.40 Hz)
      and low-frequency power (LF, 0.04-0.15 Hz) in normalized units (LF%). Acupuncture
      on the Sishencong points resulted in an increased HF but a decreased LF% compared
      with the before acupuncture stage. Such effects did not occur when manual
      acupuncture was applied to the control points. The differences in the heart rate
      dynamics between Sishencong and the control groups took place 10 min after
      initiation of acupuncture and persisted even after the removal of the needles.
      Based on these results, we concluded that manual acupuncture on the Sishencong
      points enhanced cardiac vagal and suppressed sympathetic activities in humans.
      The underlying mechanisms and potential applications warrant further
      investigations.

PMID- 12422966
TI  - Long-term follow-up of cellular proliferation as a predictive index for the
      relapse of nasal polyposis.
AB  - BACKGROUND: The objective of this study was to identify a reproducible clinical
      parameter for predicting relapses of nasal polyposis after surgery. METHODS:
      Ninety-three patients who had undergone ethmoidectomy of bilateral nasal polyps
      were followed for 3 years. Nasal polyps were obtained from all patients, and
      cellular suspensions were analyzed individually using flow cytometry. Based on
      the percentage of cells in the S phase, we identified three groups of patients
      (high, medium, and low percentages). RESULTS: A relapse of nasal polyposis was
      observed in 15.00, 70.00, and 100.00% of patients from the low-, medium-, and
      high-percentage groups, respectively. Patients suffering relapses had a high
      percentage of cells in the S phase. CONCLUSIONS: We identified two cutoff values
      for the percentage of cells in the S phase; above the first cutoff, some of the
      patients suffered relapses; above the second cut-off, all patients suffered
      relapses.

PMID- 12422967
TI  - Management of severe bilateral nasal wall collapse.
AB  - OBJECTIVE: The aim of this study was to examine and analyze the pathology
      contributing to severe bilateral nasal wall collapse seen in certain revision
      rhinoplasty patients and identify those surgical maneuvers in the previous nasal
      surgery, which may have contributed to this complication; suggest alternatives or
      modifying steps in nasal surgery to prevent lateral wall collapse; analyze
      consecutive revision rhinoplasties and identify those patients who have complete
      bilateral nasal collapse at the internal nasal valve; and analyze the results
      achieved after surgical reconstruction of complete bilateral nasal collapse.
      PATIENTS: We identified 49 patients, who presented from 1990 to 2000 for revision
      surgery, who had bilateral collapse of the upper lateral cartilage. All patients
      had at least one previous rhinoplasty and all but 14 patients had undergone two
      or more procedures. The patients were reconstructed with a conchal cartilage
      graft placed through an external rhinoplasty approach. RESULTS: All patients
      complained of nasal obstruction with forced nasal inspiration. The collapse was
      visualized on inspiration and when prevented with intranasal positioning of a
      bayonet, all patients experienced an immediate improvement in nasal breathing.
      Postoperatively, all patients experienced this same improvement in their nasal
      airway. Collapse was not identified in any of the patients after surgery. Two
      patients underwent revision because of cosmetic asymmetries. CONCLUSION: We
      strongly recommend a cartilage overlay to reconstitute the rigid midline
      continuity of the upper lateral cartilages. Unfortunately, with any significant
      hump removal, this structural interruption is, to varying degrees, inevitable in
      most rhinoplasty techniques. The upper lateral cartilages can be sutured to
      circumvent some of the inferior drift, but this will not reconstitute the rigid
      lateral cantilever effect of the intact cartilage.

PMID- 12422968
TI  - Bacteriology of chronic maxillary sinusitis in relation to sinoscopic appearance.
AB  - BACKGROUND: The bacteriology of chronic maxillary sinusitis in relation to
      different sinoscopic appearances is reported in this study. METHODS: When
      transantral sinoscopy via an anterior wall puncture was used to examine the
      maxillary antra in patients with chronic maxillary sinusitis, the sinoscopic
      appearances were divided into five types. Maxillary antra in which ostia were
      recognized under the endoscope and no secretion existed were classified as type
      1. Maxillary antra in which ostia were not recognized and no secretion existed
      belonged to type 2. Maxillary antra in which seromucoid secretion existed
      belonged to type 3. Maxillary antra in which mucopurulent discharge existed
      belonged to type 4. Maxillary antra in which fungal balls existed belonged to
      type 5. Swab specimens of these antra were sent for aerobic and anaerobic
      cultures. RESULTS: Between 1988 and 1998, 493 sinoscopic appearances of maxillary
      antra were classified. Among them, 72 were classified as type 1, 59 were type 2,
      75 as type3, 227 were type 4, and 60 were type 5. The culture rate of swab
      specimens from those antra with type 1 sinoscopic appearance was 56.9%. The
      culture rates were 59.3% for type 2, 48% for type 3, 64.8% for type 4, and 88.3%
      for type 5. Common cultured bacteria were similar among antra with different
      types of sinoscopic appearances, except type 5 antra, but less gram-negative
      aerobes grew from type 1 antra. CONCLUSIONS: This study shows that the
      bacteriology of noninvasive fungal sinusitis was different from that of ordinary
      chronic maxillary sinusitis. However, among ordinary chronic maxillary sinusitis,
      the bacteriology was similar between maxillary antra with different sinoscopic
      appearances except with mild disease.

PMID- 12422969
TI  - A comparison of endoscopic culture techniques for chronic rhinosinusitis.
AB  - BACKGROUND: Recent evidence suggests that endoscopically obtained cultures from
      the middle meatus give comparable results to antral puncture for acute sinusitis.
      The best method for obtaining middle meatal cultures remains somewhat
      controversial because it has been theorized that specimens obtained with a swab
      are contaminated easily. This study compares endoscopic culture results from two
      different methods: swab and aspiration. Specifically, this study sought to
      determine whether or not the culture contamination rate is higher using the swab
      versus an aspiration technique. METHODS: One hundred consecutive culture
      specimensfrom 81 chronic rhinosinusitis patients were compared. Fifty cultures
      were obtained using a swab technique (group I) and another 50 cultures were
      obtained by aspirating pathological material into a sterile suction trap (group
      II). The patient populations in each group were similar; there were no
      differences in terms of age, gender, comorbid medical conditions, or prior
      medical therapy. Cultures were considered contaminated if they yielded normal
      nasal flora or if rare or few Staphylococcus coagulase-negative colonies grew
      after no bacteria was identified in gram stain. Staphylococcus aureus,
      Staphylococcus coagulase-negative, and Pseudomonas aeruginosa were the three most
      common organisms in both groups. RESULTS: Gram-negative bacteria were noted in
      21/60 (35%) positive cultures. Although the contamination rate of the suction
      aspiration group (14%) was less than the endoscopic swab group (10%), this did
      not approach statistical significance (p = 0.75). CONCLUSIONS: Data from this
      study suggest that endoscopically guided aspiration of pathological material is
      no better than properly obtained swabs in directing antimicrobial therapy for
      chronic rhinosinusitis.

PMID- 12422970
TI  - The influence of the size of the maxillary sinus ostium on the nasal and sinus
      nitric oxide levels.
AB  - BACKGROUND: Nitric oxide (NO) is produced in significant quantities in the nasal
      sinuses and is thought to have a beneficial effect on the mucociliary transport
      of the sinuses and nose and to have significant antibacterial properties that
      contribute to the health of the sinuses. Recently, the concept of "mini
      functional endoscopic sinus surgery" has been introduced where the uncinate is
      removed without enlargement of the maxillary ostium. Although no scientific
      evidence has been published, enlargement of the ostium is thought to possibly
      disrupt the mucociliary pathway and decrease the concentration of NO in the nose
      and sinuses. The aim of this study was to establish the effect of enlargement of
      the maxillary ostium on sinus and nasal NO. METHODS: Twenty-nine patients who
      were post-endoscopic sinus surgery were included with 52 who were maxillary sinus
      ostia cannulated. There were 22 large maxillary sinus ostia and 30 small ostia.
      Smoking, allergy status, and topical steroid use were recorded. NO levels were
      measured in the nose and maxillary sinus after decongestion with patients mouth
      breathing and breath holding. RESULTS: This study shows that enlargement of the
      maxillary sinus ostium above its normal size (20 mm2) produces a significant
      decrease in both the maxillary sinus and the nasal cavity NO levels. In addition,
      the size of the ostium showed a significant correlation to the sinus NO level.
      Use of topical nasal steroid sprays and topical decongestants were shown to
      effect NO levels in the sinuses and nasal cavity. The lowered levels of NO were
      found irrespective of the technique of measurement of the NO. CONCLUSIONS: The
      effect of this lowered NO level on the susceptibility of the maxillary sinuses to
      recurrent infection is yet to be determined.

PMID- 12422971
TI  - Computed tomogram findings of mucous recirculation between the natural and
      accessory ostia of the maxillary sinus.
AB  - BACKGROUND: The phenomenon of recirculation involves the circulation of mucous
      secretion between the natural ostium and other openings and is observed mainly
      after surgery when the surgical opening is not connected. METHODS: Seven patients
      with a mucous stream transporting into an accessory ostium, as found during
      endoscopic examination, were entered into study. The coronal computed tomogram
      findings of the mucous recirculation were analyzed at three levels: anterior,
      middle, and posterior portion of it. RESULTS: The anterior portion was visualized
      at the level of the natural ostium in five patients. The middle portion inside
      the maxillary sinus was visible in six cases. The posterior portion was
      visualized at the level of the accessory ostium in five patients. Among the axial
      scans, mucous rings were visible in two patients. CONCLUSIONS: The primary mucous
      recirculation between the natural and accessory openings is shown as a ring
      structure in coronal computed tomogram scans.

PMID- 12422972
TI  - Outcomes of the modified endoscopic Lothrop procedure.
AB  - BACKGROUND: The aim of this study was to examine the long-term outcomes of the
      modified endoscopic Lothrop procedure for the management of the most severe forms
      of recalcitrant chronic frontal sinusitis. METHODS: This case series evaluated 13
      consecutive cases of the modified endoscopic Lothrop procedure for chronic
      frontal sinusitis from April 1996 to December 1999. Patent communication to the
      frontal sinus was evaluated by postoperative endoscopic exam. Postoperative
      patient symptomatology and medication requirements were assessed during clinic
      evaluation and by standardized telephone questionnaire. RESULTS: At a mean follow
      up period of 34.5 months, a 77% patency rate was obtained, with 2 of the 13
      patients requiring an osteoplastic flap with obliteration. Telephone
      questionnaire results indicate improved symptoms and decreased medication
      requirements in the majority of patients who maintained patency. CONCLUSIONS:
      These results show that the modified endoscopic Lothrop procedure provides a good
      alternative to the osteoplastic flap with obliteration for patients with the most
      severe forms of chronic frontal sinusitis. Initially, high patency rates decline
      with longer-term follow-up, and severe forms of chronic rhinosinusitis continue
      to significantly impact patient-perceived quality of life in some patients. The
      modified endoscopic Lothrop procedure should be reserved for patients who have
      failed more conservative endoscopic approaches to the frontal recess.

PMID- 12422973
TI  - Olfactory function in chronic renal failure.
AB  - BACKGROUND: Patients with chronic renal failure (CRF) show a high prevalence of
      poor nutritional state so that dietary treatment becomes a significant part of
      the therapeutic regimen. Because smell plays an important role in nutrition, this
      study aimed to investigate olfactory function in CRF patients. METHODS: A total
      of 64 CRF patients were investigated. Forty-nine of them were treated with
      hemodialysis, 15 CRF patients were not dialysis dependent. For comparison we
      examined 15 healthy subjects. Olfactory function was assessed for odor
      discrimination, odor identification, and butanol odor thresholds. RESULTS:
      Olfactory loss was found in 56% of the patients, with 3 functional anosmics and
      33 hyposmics. CRF had specific effects on individual tests of olfactory function.
      Elevated odor thresholds werefound in 11% of patients, 38% of patients had
      reduced odor discrimination, and 48% of patients exhibited deficits in odor
      identification. Results of psychological tests (Mini-Mental State Examination and
      Trail-Making Test) correlated with results from odor identification (p < 0.01)
      and discrimination (p < 0.01) but not with odor thresholds. CONCLUSIONS: The
      ability to discriminate and identify odors was found severely impaired whereas
      odor thresholds were similar to what is seen in the general population.
      Consequently, CRF patients should be counseled with regard to the possibility of
      reduced chemosensory functions.

PMID- 12422974
TI  - Factors predicting survival for cancer of the ethmoid sinus.
AB  - OBJECTIVE: The aim of this study was to determine survival and prognostic factors
      for ethmoid sinus cancer. METHODS: From the Surveillance, Epidemiology, and End
      Results database for the time period 1988-1998, all cases of ethmoid sinus
      malignancy were extracted. Demographic, staging, treatment, and survival data
      were computed. Survival analysis was conducted with the Kaplan-Meier method.
      Clinical factors influencing survival were determined with the Cox proportional
      hazards model. RESULTS: After excluding patients with metastatic disease on
      presentation (8.9%) and patients with missing data for T stage, a total of 180
      cases were identified. Average age was 60.2 years. Squamous cell carcinoma was
      the most common tumor (27.8%), followed by adenocarcinoma (12.8%). Overall mean
      survival was 57 months (median, 38 months) with a 5-year survival of 40.3%. The
      percentage of patients presenting with T4 lesions was 45.6%, which had a notably
      lower mean survival of 38 months (median, 18 months). Only 2.3% of patients had
      positive nodal disease. Increasing age, T stage, and absence of radiation therapy
      predicted poorer survival in the multivariate model Adenocarcinoma, adenoid
      cystic carcinoma, esthesioneuroblastoma, and melanoma showed more favorable
      survival than other tumor types. CONCLUSIONS: T stage and tumor histology are the
      most important prognostic factors in ethmoid sinus carcinoma. Survival for T4
      lesions is markedly worse than survivalfor T1-T3 lesions. Radiation therapy
      offers a survival benefit in ethmoid sinus malignancy.

PMID- 12422975
TI  - Safety of steroid injections.

PMID- 12422976
TI  - Diabetes in Papua New Guinea.

PMID- 12422977
TI  - Type 2 diabetes mellitus in Papua New Guinea--an historical perspective.
AB  - Type 2 diabetes mellitus is an increasing problem in Papua New Guinea (PNG). Five
      dominant themes emerge from the literature on diabetes in PNG: 1) The concept of
      the 'thrifty genotype' predisposing Papua New Guineans, like many other
      traditional populations, to type 2 diabetes, 2) Some coastal ethnic groups
      (particularly with Wanigelans and Tolais) appear to be more predisposed than
      others, 3) Prevalence of type 2 diabetes markedly rises with urbanization and
      adoption of a more western lifestyle, 4) Morbidity and mortality associated with
      the disease is high, and 5) Type 2 diabetes is overwhelmingly the most common
      type, with other types being rare. The literature is reviewed within the
      framework of these themes.

PMID- 12422979
TI  - Type 1 diabetes mellitus in children in Papua New Guinea.
AB  - Anecdotal and published information suggest a low incidence and prevalence of
      type 1 diabetes in Papua New Guinea (PNG). Incidence and prevalence were followed
      prospectively from July 1996, using the PNG Paediatric Surveillance Unit (PSU).
      No children were receiving insulin in Papua New Guinea at the start of the
      period. Over the next 4.5 years, 8 cases were reported--an annual incidence of
      0.08/100,000 children aged < 15 years and a prevalence of 0.28/100,000 aged < 15
      years. These figures are as low as any reported elsewhere. Three cases were from
      the small expatriate population. All cases in Melanesian children posed
      significant management problems, with two children dying during the study period.

PMID- 12422978
TI  - A survey of diabetes services in hospitals in Papua New Guinea.
AB  - AIM: To determine the number and distribution of diabetic persons in Papua New
      Guinea (PNG), and to document available services. METHODS: Survey of the 19
      hospitals thought to be the most significant centres for care of diabetes.
      RESULTS: 16 hospitals were successfully surveyed. Type 1 diabetes is very rare,
      with 18 known cases in the country (6 less than 15 years old). Known type 2 cases
      totalled around 4600 with almost all cases in coastal centres, particularly Port
      Moresby, East New Britain and Manus. There were very few cases in the highlands.
      Insulin is generally available, along with oral hypoglycaemic drugs. Testing for
      complications is very limited, and glycosylated haemoglobin (HbA1c) testing is
      available in only one centre. Only 3 trained diabetes educators are available in
      the country, with 1 dietitian and no specialist endocrinologists. CONCLUSIONS:
      The vast majority of persons with type 2 diabetes in PNG are undiagnosed and are
      not receiving treatment: based on the lower of two country prevalence estimates,
      less than 3% of the diabetic persons in the country are seen at health
      facilities. Services are limited, with only a handful of health professionals
      specially trained in diabetes. Expansion of services and awareness and prevention
      programs are urgently needed.

PMID- 12422980
TI  - Community screening for diabetes in the National Capital District, Papua New
      Guinea: is betelnut chewing a risk factor for diabetes?
AB  - This cross-sectional study was conducted intermittently in the National Capital
      District of Papua New Guinea from 1995 to 1999. Fasting capillary blood glucose
      (FCBG) was used as the screening test for diabetes. Blood glucose level was
      measured using the standard pocket-size reflectometer. A total of 769 individuals
      were screened. There were 385 males and 384 females ranging in age from 12 to 76
      years. High FCBG (hFCBG) (> or = 7.0 mmol/l) was found in 13% of those examined
      and was associated with older age (p = 0.001), high body mass index (p = 0.027),
      coastal region of origin (p = 0.012) and betelnut chewing (p < 0.001). The
      prevalence of hFCBG in those of highland origin was 9% compared to 16% among the
      coastal people. Among the Seventh Day Adventists, the prevalence of hFCBG was
      10%. The overall prevalence of hFCBG was the same in males and females but in
      those aged 35 years or more the prevalence was higher in females. Multivariate
      analysis (logistic regression) showed that hFCBG was significantly associated
      with betelnut chewing (p = 0.005) and age (p = 0.028); the body mass index (p =
      0.061) and region of origin (p = 0.056) associations approached statistical
      significance. Sex and smoking were not statistically significant factors. In
      conclusion, diabetes is common in the 'healthy' population of Port Moresby and
      rates in highlanders living there were surprisingly high. In this study, betelnut
      chewing was independently associated with diabetes, and may therefore be a risk
      factor for diabetes mellitus.

PMID- 12422981
TI  - Diabetes: the by-product of westernization in Papua New Guinea.
AB  - Before the 1960s diabetes was rare in Papua New Guinea. But by late 1970s there
      was evidence that diabetes type 2 was increasing among some urban dwellers. The
      problem is getting worse and in some urban communities the prevalence of diabetes
      has doubled within 14 years. Unfortunately no one knows the exact magnitude of
      the problem. Secondly there are simply not enough resources to handle the current
      known cases. This is compounded by the fact that many Papua New Guineans welcome
      western lifestyle with open arms. A change of eating habits and lifestyle is
      vital if any change is to be made to this by-product of westernization.

PMID- 12422982
TI  - The role of low birthweight in the aetiology of type 2 diabetes.
AB  - The aetiology of type 2 diabetes is still poorly understood. Although it is clear
      that obesity is a risk factor for the disease, obesity leads to diabetes only in
      susceptible individuals. Both genetic and environmental factors determine this
      susceptibility. This review describes the emerging evidence that low birthweight
      caused by malnutrition or a genetic predisposition increases the risk of type 2
      diabetes.

PMID- 12422983
TI  - Type 2 diabetes mellitus: an evolving therapeutic approach.
AB  - The ultimate or primary goal of therapy for type 2 diabetes is to prevent the
      mortality and morbidity related to the microvascular and macrovascular
      complications. It is increasingly obvious that to achieve this on a global
      perspective we will need to identify better and more effective strategies to
      prevent diabetes and its precursors, obesity and inactivity. Similarly, since a
      large percentage (at least 50%) of patients with type 2 diabetes are undiagnosed,
      we need to improve the implementation of strategies aimed at detecting this
      undiagnosed population. Without a diagnosis we will not prevent, detect or treat
      the complications of diabetes. Finally, therapy of type 2 diabetes is evolving as
      the evidence base for clinical decision-making grows and as new therapeutic
      options become available. The therapeutic approach has broadened considerably to
      include more intensive treatment of the diseases frequently associated with type
      2 diabetes and major contributors to morbidity and mortality, namely hypertension
      and dyslipidaemia.

PMID- 12422984
TI  - Diabetes education: a keystone in the management of diabetes.
AB  - Diabetes is reaching epidemic proportions in many countries of the world and the
      World Health Organization (WHO) predicts a tripling of the current prevalence
      rates by 2025. In reality there will not be sufficient physicians to cope with
      this epidemic. One solution is to utilize highly skilled allied health
      professionals to do much of the routine diabetes education and management.
      Convincing hospital administrators of this need, however, can be problematic
      especially when for many years the focus of the health service has been on
      communicable diseases. Selection of appropriate staff is very important as they
      will need to take on much of the burden of the work. Of course these staff
      require comprehensive clinical training beyond what is expected of most health
      professionals. In addition to this, it is generally recognized that a
      multidisciplinary team is an effective method of providing diabetes care.
      However, a multidisciplinary team is not simply the sum of different health
      professionals who work independently. Rather, the various members of the diabetes
      health care team, while working within their own scope of practice, need to
      integrate their roles to complement each other and blend together. Diabetes is
      one of the foremost health challenges facing the world in the new millennium. It
      has the potential to overwhelm health budgets. Health administrators and health
      service planners need to heed the warnings as the toll from this serious disease
      mounts.

PMID- 12422985
TI  - Superiority of traditional village diet and lifestyle in minimizing
      cardiovascular disease risk in Papua New Guineans.
AB  - In the traditional society of Papua New Guinea (PNG) atherosclerotic
      cardiovascular diseases (CVD) are rare. However, among the urban population
      reports of cases of atheroma-related CVD are increasing. The purpose of this
      study was therefore to compare the CVD risk factors in a homogeneous population
      of the Southern Highlands Province living in both rural and urban areas differing
      only in their diet and lifestyle. A total of 221 Samberigi people over the age of
      25 years were selected for the survey. These included 123 individuals from remote
      villages of Samberigi and 98 of their relatives who had lived in Port Moresby
      city continuously for a minimum of 5 years. The anthropometric measurements,
      blood lipid, blood glucose and glycosylated haemoglobin (HbA1c) levels were
      measured and compared. The rural diets were mainly of vegetarian type, limited in
      variety and low in fat and protein content. In the urban subjects, the typical
      meal comprised refined foods with high fat and protein content. The urban men and
      women had significantly (p < 0.05) greater body weight, body mass index (BMI),
      and waist and hip circumferences than their rural counterparts. In Port Moresby,
      57% of the men and 67% of the women were overweight or obese compared to 28% of
      their rural counterparts. Similarly, the mean plasma total cholesterol, low
      density lipoprotein cholesterol (LDLC), high-density lipoprotein cholesterol
      (HDLC), fasting blood glucose and HbA1c were significantly higher in the urban
      group. However, no significant differences were demonstrated for waist to hip
      ratio, LDLC/HDLC ratio and lipoprotein (a) levels between the two groups. The
      total cholesterol, LDLC and HbA1c were positively associated with age and BMI in
      both rural and urban locations. In conclusion, there were significant increases
      in CVD risk factors in the urban population compared to the rural residents. This
      was predominantly due to the adoption of a western lifestyle and diet as people
      moved from rural villages to the city of Port Moresby.

PMID- 12422986
TI  - The rocky road from roots to rice: a review of the changing food and nutrition
      situation in Papua New Guinea.
AB  - Although it is not happening uniformly within the country, the adoption of a
      modern lifestyle by Papua New Guineans is affecting their food habits and
      choices. More and more people consume rice, tinned fish and tinned meat. In towns
      and in villages with easy access to urban centres, these food items comprise an
      ever increasing part of the diet. These dietary changes are leading to increases
      in the prevalence of chronic lifestyle-related diseases such as obesity,
      hypertension and coronary heart disease. Although average calorie availability is
      similar in urban and rural sectors, at around 2600 kilocalories per person per
      day, the nutritional outcomes are different. This is mainly due to the higher
      energy density of the modern urban diet with a greater intake of fat and protein.
      The traditional diet is low in protein with rather high energy content from
      starchy root crops. Studies have shown that urban children tend to be taller and
      heavier than their rural counterparts and that the prevalence of overweight and
      obesity is higher among adults in urban than in rural areas. Finally, across all
      income groups and geographical regions, more women than men are chronically
      undernourished.

PMID- 12422987
TI  - Diabetes in Australian aboriginal and Torres Strait Islander peoples.
AB  - Type 2 diabetes arises from a complex and multifactorial set of factors,
      including genetic susceptibility, behaviour (including diet and exercise), early
      nutrition, obesity and psychosocial stress, leading to insulin resistance and
      pancreatic failure. These factors in turn are influenced by social and physical
      environmental factors. Each of these may be important determinants of the high
      prevalence and incidence of type 2 diabetes in Australian Aboriginal and Torres
      Strait Islander people. Public health interventions for primary and secondary
      prevention need to recognize this complexity. Although a reduction in the
      prevalence of obesity or diabetes in the short-medium term is rarely if ever
      achieved, there are documented examples of community-based programs which have
      been effective in reducing the risk of developing type 2 diabetes and its
      cardiovascular complications. Such interventions need to be community-directed
      and appropriate to local circumstances in order to be effective.

PMID- 12422988
TI  - Chronic diseases management in the Jamaican setting: HOPE worldwide Jamaica's
      experience.
AB  - The prevalence of hypertension and diabetes in Jamaica is very high. Hypertension
      is present in 3 out of 10 Jamaicans over the age of 30 years while the prevalence
      of diabetes mellitus varies between 13% and 18% for Jamaicans over 15 years. HOPE
      worldwide Jamaica is a 7-year-old private voluntary organization that
      collaborates with the government of Jamaica to provide a mobile medical service
      to poor rural communities. The records between January 1999 and December 1999 of
      1091 chronic disease patients aged > 30 years were reviewed. The average recorded
      age of the patients was 64 years and 82% among them were females. 60% had
      hypertension, 16% had diabetes and 24% had both diabetes and hypertension. There
      were 2390 visits for hypertension, with an average of 2 visits per patient. 34%
      of patients had a blood pressure of < or = 140/90 mmHg while 43% had a blood
      pressure < 160/95 mmHg. Compliance was defined as daily consistency in taking
      prescribed medication. 44% of the patients with hypertension were non-compliant
      at the time of their visit. Antihypertensive treatment included thiazide
      diuretics (65%), reserpine (50%), angiotensin converting enzyme (ACE) inhibitors
      (30%) and alpha-methyldopa (5%). There were 1122 visits for diabetes, with an
      average of 2 visits per patient. Among the diabetic patients 23% were controlled
      to a fasting blood glucose (FBG) level of less than 6.7 mmol/l and 38% to below 8
      mmol/l. 30% of the diabetic patients were non-compliant at the time of their
      visit. The most frequently used oral hypoglycaemic agents were metformin (78%),
      glyburide (43%) and chlorpropamide (30%). 14% of the diabetic patients were on
      treatment with insulin: insulin 70/30 (12%) and lente insulin (2%).
      Electrocardiograms (ECGs) were done in the previous two years on 267 patients
      (29%), among whom 38% had evidence of left ventricular hypertrophy and 16% of
      ischaemic heart disease. The level of blood pressure and blood glucose control
      was inadequate despite the provision of regular monitoring, surveillance and
      improved access to medication. It is perceived that poor socioeconomic
      conditions, lack of education, cultural beliefs and some other factors continue
      to militate against improved compliance and control. HOPE worldwide Jamaica is
      currently implementing programs to improve patient education, especially in
      compliance, to provide access to more effective medication with convenient once
      daily dosage regimens, and to develop support groups among chronic disease
      patients in order to improve compliance and control.

PMID- 12422989
TI  - List of medical research projects in Papua New Guinea. Approved or noted.

PMID- 12422990
TI  - Correlation between pharmacological effects and plasma cocaine concentrations
      after smoked administration.
AB  - The relationship between blood cocaine concentrations and pharmacological effects
      is of both theoretical and practical interest. This study utilized a computer
      assisted smoking device for the delivery of three active doses (10, 20, and 40
      mg) of cocaine base to seven human volunteers. Doses were administered in an
      ascending dose design with random placement of placebo. Physiological,
      subjective, and performance measures were collected concurrently with blood
      samples. Mean peak plasma cocaine concentrations were achieved at 2 min after the
      20-mg and 40-mg doses and at 5 min after the 10-mg dose. Maximal responses in
      systolic and diastolic blood pressure, "feel", "good" drug, and drug "liking"
      subjective effects were also achieved immediately after drug administration.
      Pupil diameter and heart rate increases demonstrated a modest counter-clockwise
      hysteresis in relation to plasma cocaine concentrations shortly after dosing.
      Systolic and diastolic blood pressure, heart rate, and some subjective and
      performance measures of drug effect demonstrated a biphasic response after smoked
      cocaine. Initial increases above baseline levels were followed by an apparent
      compensatory decrease below baseline levels at a later time after smoked cocaine.
      Despite evidence of hysteresis and biphasic responses for some measures, linear
      correlation was obtained between mean plasma cocaine concentrations and several
      pharmacological effects over a period of 4 h after dosing. Several subjective and
      cardiovascular measures returned to baseline levels in the presence of detectable
      concentrations of cocaine.

PMID- 12422991
TI  - Urinary elimination of cocaine metabolites in chronic cocaine users during
      cessation.
AB  - We previously showed that chronic cocaine use by active illicit users produced a
      longer plasma half-life than expected based on acute low-dose cocaine studies.
      Here we report urinary excretion patterns of cocaine metabolites as
      benzoylecgonine (BE) equivalents from 18 of the same individuals, housed for up
      to 14 days on a closed research unit. In addition, we evaluated whether
      creatinine normalization of BE equivalents increased mean detection time and
      reduced mean within-subject variability. All urine voids (N = 953) were
      individually assayed; BE equivalents were determined semi-quantitatively by FPIA.
      Compared to concentration in first void after admission, BE equivalents decreased
      to approximately 33%, 8%, and 4% at 24, 48, and 72 h, respectively. Mean +/- SD
      (range) time to first negative specimen (BE equivalents < 300 ng/mL) was 43.6 +/-
      17.1 (16-66) h. BE equivalents fluctuated considerably across successive
      specimens; 69% of participants tested positive at least once after testing
      negative, and the mean time to last positive specimen was 57.5 +/- 31.6 (11-147)
      h after the first specimen. Thus, mean cocaine metabolite detection times were
      consistent with prolonged elimination, with 63% of participants testing positive
      longer than the expected 48-h window of detection after admission to the unit.
      Mean time to last positive after last use of cocaine, known by self-report only,
      was approximately 81 +/- 34 (34-162) h. Creatinine normalization, with the cut
      off of 300 ng BE equivalents/mg creatinine, increased detection time: mean time
      to first negative specimen was 54.8 +/- 20.7 (20-100) h, and mean time to last
      positive specimen was 88.4 +/- 51.0 (35.6-235) h. Compared with the concentration
      in the first void after admission, BE equivalents/creatinine decreased to
      approximately 56%, 6%, and 5% at 24, 48, and 72 h. However, creatinine
      normalization did not reduce the fluctuation of BE equivalents across successive
      specimens. Thus, creatinine normalized values may be useful when the goal is to
      maximize the probability or duration of cocaine metabolite detection, but may be
      less useful in determining whether an individual has used cocaine since a
      previous specimen collection.

PMID- 12422992
TI  - Evaluation of a solid-phase extraction method for benzoylecgonine urine analysis
      in a high-throughput forensic urine drug-testing laboratory.
AB  - A novel extraction and derivatization procedure for the cocaine metabolite
      benzoylecgonine (BZE) was developed and evaluated for use in a high-volume
      forensic urine analysis laboratory. Extractions utilized a Speedisk 48 positive
      pressure extraction manifold and polymer-based cation-exchange extraction
      columns. Samples were derivatized by the addition of pentafluoropropionic
      anhydride and pentafluoropropanol. All analyses were performed in selected ion
      monitoring mode; ions included m/z 421, 300, 272, 429, and 303 with m/z 421 to
      429 ratio used for quantitation. The average extraction efficiency was 80%.
      Seventy-five common over-the-counter products, including prescription drugs, drug
      metabolites, and other drugs of abuse, demonstrated no significant interference
      with respect to chromatography or quantitation. The limit of detection and limit
      of quantitation were calculated at 12.5 ng/mL, and the assay was linear from 12.5
      to 20,000 ng/mL with an r2 of 0.99932. A series of 20 precision samples (100
      ng/mL) produced an average response of 97.8 ng/mL and a percent coefficient of
      variation of 4.1%. A set of 79 archived human urine samples that had previously
      been found to contain BZE were analyzed by 3 separate laboratories. The results
      did not differ significantly from prior quantitation or between laboratories. The
      Speedisk has proven viable for a high-volume production facility reducing overall
      cost of analysis by decreasing analysis time and minimizing waste production
      while meeting strict forensic requirements.

PMID- 12422993
TI  - Storage stability of simulator ethanol solutions for vapor-alcohol control tests
      in breath-alcohol analysis.
AB  - We conducted a one-year stability study on aqueous alcohol simulator solution,
      stored in sealed polyethylene bottles at 4 degrees C and at room temperature.
      Thirty-nine aliquots of simulator solution with a VAC target value of 0.079 +/-
      0.010 g/210 L were stored and analyzed independently monthly at two locations:
      The University of Oklahoma HSC Toxicology Laboratories (OUHSC) and Oklahoma
      Department of Public Safety Alcohol and Drugs Countermeasures Unit (DPS/ADCU).
      Paired Intoxilyzer 5000 Evidential Breath-Alcohol Analyzers + Guth Breath Test
      Simulators were used to measure 20 consecutive VACs generated at 34 degrees C
      with individual simulator solution aliquots, followed by VAC control tests in
      triplicate. Control tests at OUHSC were carried out with a NIST-traceable
      compressed ethanol/nitrogen gas mixture with a validated label ethanol
      concentration of 0.085 g/210 L +/- 2% at 760 torr. Control tests at DPS/ADCU were
      carried out with simulator-generated vapor-alcohol samples with a validated VAC
      of 0.10 +/- 0.01 g/210 L. The measurement results were analyzed by standard
      statistical methods with a STATGRAPHICS Plus for Windows Version 6.0
      microcomputer statistics program. No significant changes occurred during the one
      year study period in the concentration of the aqueous simulator alcohol solution,
      as reflected by close agreement of the mean results of each set of 20 consecutive
      VAC analyses. The summary descriptive statistics for the VAC measurements were
      OUHSC (4 degrees C) mean +/- SD = 0.077 +/- 0.0004 g/210 L, median = 0.077, mode
      = 0.077, span = 0.075-0.079; DPS/ADCU (4 degrees C) mean +/- SD = 0.079 +/-
      0.0013 g/210 L, median 0.079, mode = 0.078, span = 0.077-0.081; DPS/ADCU (Room
      Temp.) mean +/- SD = 0.078 +/- 0.0011 g/210 L, median = 0.078, mode = 0.078, span
      = 0.076-0.080. All OUHSC and DPS/ADCU VAC control tests were within acceptable
      target value ranges. The least squares linear regression model equations for y (=
      VAC, g/210) upon x (= time in months) were OUHSC (4 degrees C) y = 0.077 -
      0.000021x; DPS/ADCU (4 degrees C) y = 0.079 + 0.000032x; and DPS/ADCU (Room
      Temp.) y = 0.078 + 0.000038x. The essentially zero slopes for all 3 models
      signify that no significant change occurred in the alcohol concentrations of all
      39 simulator solutions aliquots measured over the 1-year study period, for either
      4 degrees C or room temperature storage. The Pearson correlation coefficients for
      the above three regression models were R = -0.20, 0.10, and 0.13, respectively;
      each value is close to zero, confirming the absence of significant statistical
      relationship between VACs and passage of time. The coefficients of determination
      for the above three regression models were 4.3%, 1.0%, and 1.7%, respectively.
      These statistics indicate that the fitted models explain only 1 to 4% of the
      small total variability in the VAC as a function of time. ANOVA statistics for
      each of the three sets of VAC test results yield a P-value greater than 0.10,
      indicating that there is not a statistically significant relationship between VAC
      and the passage of time, at a 90% or higher confidence level. We conclude that
      the ethanol concentration of simulator alcohol solutions stored in sealed
      polyethylene bottles, at either 4 degrees C or normal room temperature, does not
      change significantly for at least one year after preparation, and that a correct
      initial VAC target value will remain valid during that time period.

PMID- 12422994
TI  - Improved screen and confirmation test of 7-aminoflunitrazepam in urine specimens
      for monitoring flunitrazepam (Rohypnol) exposure.
AB  - Confirmed and alleged misuses of flunitrazepam (FM2, Rohypnol) have brought about
      serious interest in the development of an analytical methodology that can be
      effectively used for preliminary screen and confirmatory test of FM2 (or its
      metabolites) in urine specimens under high-volume settings. Reported methods do
      not serve this need well for the following reasons: (1) common benzodiazepine
      (BZ) immunoassays (IAs) have broad cross-reactivities toward widely prescribed
      BZs (and their metabolites) and are therefore likely to generate an unacceptable
      number of false positives and (2) because FM2 is typically used at low doses (1-4
      mg), IAs with low cross-reactivities toward FM2 (and its metabolites) are likely
      to generate false-negative results. In this current study, a familiar and
      effective two-step IA/gas chromatography-mass spectrometry (GC-MS) approach is
      successfully developed and applied to clinical specimens. Cross-reacting
      characteristics of the following BZ IAs toward various BZs (and their
      metabolites) are evaluated focusing on their effectiveness in serving as the
      preliminary test reagent in a two-step testing protocol: TDx, Beckman, CEDIA,
      Roche Cobas Integra, Emit II Plus, and Cozart ELISA. Although other IAs show
      broad cross-reactivities toward various BZs and their metabolites, diazepam is
      the only non-FM2 derived compound that exhibits noticeable cross-reactivity
      toward Cozart ELISA reagent. Cross-reactivity data and data derived from studies
      conducted on a limited number of clinical specimens demonstrate that, when used
      to monitor FM2 exposure in a large population group (including those exposed to
      other BZs), Cozart ELISA has the potential of being as effective as (or better
      than) those currently used in various workplace drug-testing programs for
      monitoring respectively targeted drugs. Data derived from this study further
      suggest that 50 ng/mL apparent 7-aminoflunitrazepam (Cozart ELISA) and 30 ng/mL
      free 7-aminoflunitrazepam (GC-MS) are potentially effective preliminary test and
      confirmation test cut-offs. To maximize efficiency, it is further suggested that
      urine specimens are first diluted by a factor of 5 for the preliminary test in
      which a 10-ng/mL 7-aminoflunitrazepam standard is used as the assay's cut-off
      standard.

PMID- 12422995
TI  - The defined HHS/DOT substituted urine criteria validated through a controlled
      hydration study.
AB  - This controlled hydration study was designed to validate the substitution
      criteria used by the Substance Abuse and Mental Health Services Administration
      (SAMHSA) to classify a workplace urine specimen as inconsistent with normal human
      urine. Study participants (n = 56) ingested at least 80 oz (2370 mL) of fluid
      over a 6-h period, 40 oz during the first 3 h (DOT hydration protocol) and 40 oz
      during the second 3-h period. Urine specimens (n = 498) were collected upon
      awakening, just prior to hydration, at the end of each hour of the 6-h test
      period, and upon awakening the next day. No urine specimen satisfied the paired
      substitution criteria of urine creatinine < or = 5.0 mg/dL and specific gravity <
      or = 1.001 or > or = 1.020. Seventy-three percent of the participants produced at
      least one specimen meeting the criteria for dilute urine: urine creatinine < 20.0
      mg/dL and specific gravity < 1.003. Fifty-five percent of the participants
      produced at least one dilute urine specimen during the first 3 h of hydration. In
      conclusion, this controlled hydration study supports the criteria set by SAMHSA
      for classifying a specimen as substituted (inconsistent with normal human urine).

PMID- 12422996
TI  - Evaluation of freezing point depression osmolality for classifying random urine
      specimens defined as substituted under HHS/DOT criteria.
AB  - This study evaluates the analytical performance characteristics of freezing point
      depression osmolality in urine and osmolality as a suitable analytical indicator
      for determining the concentration of urine specimens submitted for workplace drug
      testing. Specifically, this study attempted to determine the utility of urine
      osmolality to serve as an indicator of substitution as defined by HHS/SAMHSA
      criteria. Urine osmolality was validated by determining the accuracy, precision,
      analytical sensitivity, reportable range, and reference interval for the method.
      Osmolality was measured in workplace urine specimens (n = 66) with creatinine
      concentrations < or = 5.0 mg/dL. Comparing the results with the lower limit of
      the random urine reference intervals for specific gravity (1.002) and osmolality
      (50 mOsm/kg), 62% had specific gravities < or = 1.001, 52% had osmolalities < 50
      mOsm/kg, and 47% had both a creatinine < or = 5.0 mg/dL, specific gravity < or =
      1.001 and an osmolality < 50 mOsm/kg. Urine specimens (n = 311) were collected
      from 35 volunteers enrolled in a controlled water loading study in which at least
      80 oz (2370 mL) of fluid was ingested over a 6-h period. The lowest achieved
      osmolality was 28 mOsm/kg. Polyuria disorders have produced abnormally low urine
      osmolalities (lowest reported 18 mOsm/kg) but osmolalities < or = 23 mOsm/kg have
      resulted in death from water intoxication. An osmolality substitution cut-off to
      delineate a specimen as inconsistent with normal human urine can be set at some
      value < 50 mOsm/kg, when used in a population of individuals with urine
      creatinine concentrations < or = 5.0 mg/dL.

PMID- 12422997
TI  - Quantitative analysis of selegiline and three metabolites (N-desmethylselegiline,
      methamphetamine, and amphetamine) in human plasma by high-performance liquid
      chromatography-atmospheric pressure chemical ionization-tandem mass spectrometry.
AB  - This report describes a sensitive and specific high-performance liquid
      chromatography-atmospheric pressure chemical ionization-tandem mass spectrometry
      method for the detection of subnanogram concentrations of selegiline and its
      three principle metabolites, N-desmethylselegiline, methamphetamine, and
      amphetamine, in human plasma. The assay has a dynamic range of 0.1-20 ng/mL for
      selegiline and N-desmethylselegiline (norselegiline) and 0.2-20 ng/mL for
      methamphetamine and amphetamine. The inter- and intra-assay precision and
      accuracy varied by less than 11% for all analytes at 0.3, 2.5, and 15 ng/mL and
      less than 16% at the lower limit of quantitation (0.1 ng/mL for selegiline and
      norselegiline; and 0.2 ng/mL for methamphetamine and amphetamine). Selegiline and
      its metabolites showed no significant loss in quantitative accuracy after three
      freeze/thaw cycles or after up to 6 h at room temperature prior to extraction.
      Extracted plasma samples retained quantitative accuracy after storage for at
      least 7 days at -20 degrees C or up to 70 h at room temperature. Methanolic stock
      solutions were stable for at least 6 h when kept at room temperature or at least
      90 days when kept at -20 degrees C.

PMID- 12422998
TI  - Pharmacogenomics as molecular autopsy for postmortem forensic toxicology:
      genotyping cytochrome P450 2D6 for oxycodone cases.
AB  - Pharmacogenomics, the study of the impact of heritable traits on pharmacology and
      toxicology, may serve as an adjunct for certifying opioid fatalities. Oxycodone,
      frequently prescribed for the relief of moderate to severe pain, is metabolized
      by cytochrome P450 (CYP) 2D6, encoded by a polymorphic gene with three mutations
      (*3, *4, and *5) with a combined 95% allelic frequency and about 10% prevalence.
      Individuals with variant alleles are more susceptible to oxycodone toxicity. By
      assessing the prevalence of CYP2D6 polymorphisms and covariables, we hypothesized
      that oxycodone fatality may be partially due to poor drug metabolism caused by
      CYP2D6 variant alleles. From the Milwaukee County Medical Examiner's Office
      (MCMEO), a retrospective analysis of 15 oxycodone cases was followed by
      genotyping blood samples for the variant alleles by conventional and real-time
      PCRs. Institutional Review Board approval was obtained. Oxycodone, extracted from
      blood and/or urine, was quantitated by GC-MS. The results show two homozygous for
      2D6*4 and four heterozygous for 2D6*4. The MCMEO was not significantly different
      from those in the control group (n = 26) (p > 0.05, Fisher's Exact Test).
      However, genotyping CYP2D6 provided a more definitive interpretation of the
      oxycodone toxicity in four cases. Therefore, pharmacogenomics may serve as an
      adjunct in the determination of the cause and manner of death in forensic
      toxicology and a pharmacogenomic algorithm for genotyping has been proposed.

PMID- 12422999
TI  - Oxycontin: the concept of a "ghost pill" and the postmortem tissue distribution
      of oxycodone in 36 cases.
AB  - Oxycodone is a semi-synthetic opioid that is structurally similar to codeine and
      equipotent to morphine in producing analgesic effects. Oxycodone has been
      prescribed in many immediate-release formulations including Percodan, Percocet,
      Tylox, Roxicodone, and Toxicet. In 1995, the Food and Drug Administration
      approved Oxycontin, a controlled-release form of oxycodone. Although the
      immediate-release forms of oxycodone can be prescribed in doses of 10-30 mg every
      4 h, it is recommended that Oxycontin be prescribed in doses of 10-160 mg every
      12 h. In a six-year period, the Los Angeles County Department of Coroner's
      Toxicology Laboratory detected oxycodone in 67 cases, 36 of which were determined
      to be the controlled-release form. The objectives of this paper are to provide
      general information about Oxycontin, including postmortem tissue distributions of
      oxycodone in cases in which the controlled-release form was identified, and to
      introduce the concept of ghost pills. A ghost pill is a seemingly intact but drug
      free tablet that resembles an undigested pill. The isolation and identification
      of oxycodone from postmortem specimens was achieved using a basic, liquid-liquid
      extraction with screening and quantitation by gas chromatography-nitrogen
      phosphorus detection and gas chromatography-mass spectrometry, respectively.
      Oxycodone-d3 was used as an internal standard for quantitation. The assays were
      linear from 0.10 to 5.0 mg/L. The tissue distribution ranges of oxycodone in the
      36 case examples were heart blood 0.12-46 mg/L (36), femoral blood + < 0.10-13
      mg/L (35), liver 0.11-6.1 mg/kg (16), urine 2.5-122 mg/L (22), bile 0.19-49 mg/L
      (15), vitreous 0.24-0.82 mg/L (6), and gastric 0.06-119 mg total (21).

PMID- 12423000
TI  - Effects of oxidizing adulterants on detection of 11-nor-delta9-THC-9-carboxylic
      acid in urine.
AB  - Bleach, nitrite, chromate, and hydrogen peroxide-peroxidase are effective urine
      adulterants used by the illicit drug users to conceal marijuana-positive results.
      Methods for detecting nitrite and chromate are available. Effects of other
      oxidizing agents that could possibly be used as adulterants and are difficult to
      detect or measure are presented in this report. Urine samples containing 40 ng/mL
      of 11-nor-delta9-THC-9-carboxylic acid (THC-acid) were treated with 10 mmol/L of
      commonly available oxidizing agents. Effects of horseradish peroxidase of
      activity 10 unit/mL and extracts from 2.5 g of red radish (Raphanus sativus,
      Radicula group), horseradish (Armoracia rusticana), Japanese radish (Raphanus
      sativus, Daikon group), and black mustard seeds (Brassica nigra), all with 10
      mmol/L of hydrogen peroxide, were also examined. After 5 min, 16 h and 48 h of
      exposure at room temperature (23 degrees C) the specimens were tested by a gas
      chromatographic-mass spectrometric method for THC-acid. A control group treated
      with sodium hydrosulfite to reduce the oxidants, was also tested to investigate
      the effect of oxidizing agents on THC-acid in the extraction method. THC-acid was
      lost completely in the extraction method when treated with chromate, nitrite,
      oxone, and hydrogen peroxide/ferrous ammonium sulfate (Fenton's reagent). Some
      losses were also observed with persulfate and periodate (up to 25%). These
      oxidants, and other oxidizing agents like permanganate, periodate, peroxidase,
      and extracts from red radish, horseradish, Japanese radish and black mustard
      seeds destroyed most of the THC-acid (> 94%) within 48 h of exposure. Chlorate,
      perchlorate, iodate, and oxychloride under these conditions showed little or no
      effect. Complete loss was observed when THC-acid was exposed to 50 mmol/L of
      oxychloride for 48 h. Several oxidizing adulterants that are difficult to test by
      the present urine adulterant testing methods showed considerable effects on the
      destruction of THC-acid. The time and temperature for these effects were similar
      to those used by most laboratories to collect and test specimens. In several
      cases, the loss of THC-acid was > 94%.

PMID- 12423001
TI  - Performance evaluation of three on-site adulterant detection devices for urine
      specimens.
AB  - The performance of three on-site adulterant detection devices that assess the
      integrity of urine specimens collected for drug-of-abuse testing was evaluated:
      the Intect 7, MASK Ultra Screen, and Adultacheck 4. Intect 7 simultaneously tests
      creatinine, nitrite, glutaraldehyde, pH, specific gravity, and the presence of
      bleach and pyridinium chlorochromate (PCC). Mask Ultra Screen tests creatinine,
      nitrite, pH, specific gravity, and oxidants, and Adultacheck 4 tests creatinine,
      nitrite, glutaraldehyde, and pH. Urine specimens were prepared with the Substance
      Abuse and Mental Health Administration regulated analytes at 50% above the cut
      off concentrations. Stealth, Urine Luck, Instant Clean ADD-IT-ive, and KLEAR were
      added individually to the drug-added urine specimens so that their concentrations
      reflected the "optimum" usage reported in their package inserts and 25% above and
      below that optimum. Stealth is reported to be peroxidase; Urine Luck is believed
      to be PCC; Instant Clean ADD-it-ive reportedly contains glutaraldehyde, and Klear
      is a nitrite. The following diluents/adulterants were added at 25%, 33%, and 50%
      of the volume of drug-added urine: distilled water, bleach, ammonia, and vinegar.
      Of the devices tested, Intect 7 proved to be the most sensitive, and it correctly
      indicated the presence of adulterant or diluent in all samples tested. In order
      to do so, all indication pads had to be assessed in concert. Adultacheck 4
      specifically assesses four characteristics of urine integrity and is therefore
      very limited in detecting the use of several popular adulterants that are
      commercially available. Although it correctly assessed the four characteristics,
      it did not detect the use of Stealth, Urine Luck, or Instant Clean ADD-it-ive.
      Mask Ultra Screen can potentially detect a broader range of adulterants than
      Adultacheck 4. However, in practice, it only detected them at levels well above
      their optimum usage, making it less efficacious than Intect 7. Clearly, the
      specific identification of an adulterant is a trade-off for sensitive detection
      of several adulterants.

PMID- 12423002
TI  - Deposition of 7-aminoclonazepam and clonazepam in hair following a single dose of
      Klonopin.
AB  - The objective of this paper was to determine whether benzodiazepine clonazepam
      (CLO) and its major metabolite 7-aminoclonazepam (7-ACLO) could be detected in
      hair collected from healthy volunteers after receiving a single 3-mg dose of
      Klonopin (clonazepam). Such data would be of great importance to law enforcement
      agencies trying to determine the best time interval for hair collection from a
      victim of drug-facilitated sexual assault (DFSA) in order to reveal drug use. Ten
      healthy volunteers (6 women and 4 men, 23-49 years old) participated in the
      study. The following hair samples were collected from each volunteer: one before
      CLO administration, and 1, 3, 5, 14, 21, and 28 days after. All hair samples were
      pulverized and 50-mg aliquots were sonicated in methanol and digested with 0.1 N
      HCl at 55 degrees C for 18-24 h. Internal standard, diazepam-d5 (DIAZ-d5) was
      used. Both extracts were combined and extracted using HCX solid-phase extraction
      columns. After derivatization with HFBA all extracts were analyzed using highly
      sensitive negative chemical ionization gas chrometography-mass spectrometry.
      Standard curves for CLO (20-100 pg/mg) and 7-ACLO (1-20 pg/mg) were prepared by
      spiking aliquots (50 mg) of negative hair and had correlation coefficients of
      0.985 and 0.989, respectively. In addition, two levels of control hair were
      prepared for CLO and 7-ACLO. All method validation parameters were within
      acceptable limits. 7-ACLO was detected in hair of 6 out of 10 volunteers. In two
      cases 7-ACLO appeared in hair three days after CLO intake and remained detectable
      for the entire 28-day study period (3.6-8.4 pg/mg and 2.7-3.0 pg/mg), and in two
      subjects it was detectable 21 days later (4.9 and 2.7 pg/mg and 1.2 and 23
      pg/mg). In two volunteers 7-ACLO was detected only on day 28 (1.8 and 3.3 pg/mg).
      CLO was not detected in any of the samples.

PMID- 12423003
TI  - Segmental ion spray LC-MS-MS analysis of benzodiazepines in hair of psychiatric
      patients.
AB  - The aim of this study was to develop a liquid chromatography-tandem mass
      spectrometry (LC-MS-MS) method for the analysis of benzodiazepines in human hair.
      The method was tested by analyzing hair samples from forensic and clinical
      psychiatric patients where benzodiazepines had been prescribed during
      hospitalization and after care. Hair samples were obtained at discharge from the
      clinic and then after six months. Two-centimeter segments of the hair samples (10
      30 mg) were washed once with isopropanol, three times with phosphate buffer, and
      again with isopropanol, dried, weighed, and digested with proteinase K before
      solid-phase extraction with BondElut Certify columns. Diazepam, nordiazepam,
      oxazepam, alprazolam, OH-alprazolam, nitrazepam, 7-aminonitrazepam,
      flunitrazepam, 7-aminoflunitrazepam, clonazepam, and 7-aminoclonazepam were
      quantitated in MRM mode using one transition for each analyte and deuterated
      internal standard. The calibration range was 0.125-5 ng/mg for diazepam,
      nordiazepam, and oxazepam and 0.025-1.0 ng/mg for the other compounds. In the
      hair samples analyzed, diazepam, flunitrazepam, nitrazepam, and clonazepam was
      detected together with their metabolites. Alprazolam was not detected in any
      sample. Segmental hair analysis revealed differences in drug deposition in hair
      before and after release from psychiatric treatment. Both increases and decreases
      of hair drug concentrations were seen after release even though the prescribed
      dose was the same. This was taken as an indication of noncompliance during the
      after-care period. We conclude that the extraction and LC-MS-MS procedures were
      adequate to detect benzodiazepines in hair and that the results indicated that
      segmental hair analysis might provide retrospective information about medication
      intake.

PMID- 12423004
TI  - An evaluation of two wash procedures for the differentiation of external
      contamination versus ingestion in the analysis of human hair samples for cocaine.
AB  - In order to evaluate the effectiveness of a wash procedure using isopropanol
      followed by multiple extended phosphate buffer washes as compared with a methanol
      wash procedure previously reported, a contamination experiment was designed
      involving the soaking of human head hair in cocaine-contaminated aqueous
      solutions. Fourteen negative human head hair samples were soaked in a solution of
      cocaine HCl (1000 ng/mL) at room temperature for 1 h, then rinsed with distilled
      water and dried at room temperature. Using the extensive wash procedures (15-min
      isopropanol wash, followed by three 30-min phosphate buffer washes and then two
      60-min washes), in no case would any of the samples be reported out as positive
      at a cut-off of 5 ng cocaine/ 10 mg hair. With the methanol procedure, 8 of the
      14 methanol-washed samples exceeded a cut-off of 5 ng/10 mg hair. Extensive
      washing was shown to be far more effective for removal of external contamination
      than the methanol wash procedure reported. In all cases, the extensive aqueous
      wash protocol would allow the differentiation of ingestion versus external
      contamination, as defined by this soaking experiment. All samples underwent solid
      phase extraction and derivatization followed by liquid chromatographic-tandem
      mass spectrometric analysis. Analysis was performed on a triple quadrupole API
      2000 PerkinElmer Sciex mass spectrometer (MS) equipped with an atmospheric
      pressure ionization source via an ion spray interface. The MS operated in the
      positive Cl multiple reaction mode.

PMID- 12423005
TI  - Detection of cocaine analytes and opiates in nails from postmortem cases.
AB  - Postmortem fingernail and toenail specimens were utilized for the detection of
      cocaine analytes and opiates. Nail clippings were obtained from suspected
      overdoses and/or drug users. Nail clippings were washed with methanol and then
      solubilized in 0.1M potassium phosphate (pH 5.0). Analytes were isolated from the
      solubilized nails and methanolic washes by solid-phase or liquid-liquid
      extraction techniques. Quantitation was performed by gas chromatography-mass
      spectrometry. Clippings from each hand and foot were analyzed separately for
      comparison purposes. Concentrations of all the analytes were significantly higher
      in fingernails than in toenails. Cocaine analytes were detected in the nails of
      15 cases with the following concentration ranges (ng/mg): cocaine (n = 15) 1.2
      414.1; benzoylecgonine (n = 15) 1.4-170.3; ecgonine methyl ester (n = 14) 0.19
      27.0; norcocaine (n = 12) 0.11-32.7; cocaethylene (n = 2) 0.08-2.93. Opiates were
      detected in 17 cases with the following concentration ranges (ng/mg): morphine (n
      = 15) 0.05-407.9; 6-acetylmorphine (n = 15) 0.04-504.0; codeine (n = 9) 0.06
      8.84; hydromorphone (n = 4) 0.02-0.45. Oxycodone and hydrocodone were each
      detected in one case. The extent of drug incorporation due to external
      contamination was evaluated by comparing the differences in the amount of drugs
      detected in fingernails and toenails, along with the corresponding washes of
      those nails. These results demonstrate the usefulness of nails as postmortem
      specimens in detecting drugs of abuse.

PMID- 12423006
TI  - A field evaluation of five on-site drug-testing devices.
AB  - A field study was performed at two police agencies to evaluate the utility and
      accuracy of five on-site urine analysis drug-testing devices when used to test
      driving under the influence (DUI) arrestees. The devices evaluated were AccuSign,
      Rapid Drug Screen, TesTcup-5, TesTstik, and Triage. Standard workplace screening
      cut-off concentrations were used and samples were tested for marijuana, cocaine
      and metabolites, amphetamine(s), opiates, and PCP (except opiates 300 ng/mL).
      Four-hundred arrestees were recruited at each site, informed consent was
      obtained, and urine specimens were collected from each subject for analysis.
      Police officers conducted the testing with one device, and trained technicians
      performed testing with the other four devices. The device used by the officers
      was rotated. All positive and 5% of the negative samples were confirmed in a
      laboratory using mass spectrometry. Laboratory cut-off concentrations were 4
      ng/mL for carboxy-THC; 50 ng/mL for benzoylecgonine; 100 ng/mL for amphetamines;
      50 ng/mL for opiates; and 5 ng/mL for PCP. Approximately one-third (36%) of the
      subjects tested positive for at least one drug. No randomly selected sample, that
      tested negative on the devices, tested positive at the laboratory. Based on 800
      specimens, the false-negative rate for each device was < 1% for all drug classes.
      A false positive was defined as testing positive with the device, but the
      specimen did not contain detectable drug, given the study reporting criteria. For
      marijuana, benzoylecgonine, and opiates, all devices had < or = 0.25% false
      positive rates. For PCP, the false-positive rates were all < or = 1.5%. For
      amphetamine(s), the false-positive rates were all < or = 1.75%. These rates were
      adjusted because study confirmation batteries included methylenedioxyamphetamine,
      methylenedioxymethamphetamine (MDMA), additional over-the-counter sympathomimetic
      amines, hydromorphone, and hydrocodone. Without the expanded confirmation
      battery, false-positive rates approached 4% (Triage) for amphetamines and were >
      or = 2.25% for opiates. Fifty to 90% of the positive amphetamine(s) samples
      contained MDMA. A similar percentage of the opiate-positive samples contained
      hydromorphone or hydrocodone. When additional drugs were included in the
      confirmation testing, it was concluded that the on-site urine analysis drug
      testing results were useful in DUI investigations.

PMID- 12423007
TI  - An evaluation of the OnTrak Testcup-er on-site urine drug-testing device for
      drugs commonly encountered from emergency departments.
AB  - We evaluated the performance of the Roche OnTrak Testcup-er (TC-er), an on-site
      drug-testing device, for the detection of amphetamines (AMP), barbiturates (BRB),
      benzodiazepines (BNZ), benzoylecgonine (BE), and opiates (OPI) in urine specimens
      from hospital emergency departments. This device utilizes a competitive binding
      microparticle immunoassay to simultaneously determine the presence of the
      following drugs or drug classes in urine at and above the following cut-off
      concentrations: AMP, 1000 ng/mL; BRB, 200 ng/mL; BNZ 200 ng/mL; BE, 300 ng/mL;
      and OPI, 300 ng/mL. One hundred forty-nine urine specimens received from
      emergency departments were simultaneously tested by the EMIT II monoclonal
      immunoassay (Emit) and TC-er. Specimens yielding discordant results were analyzed
      by gas chromatography-mass spectrometry. There was a 98% (146/149) agreement of
      results between the methods for the presence or absence of drugs. TC-er yielded
      110 positive drug findings in 79 specimens, and Emit yielded 102 positive drug
      findings in 76 specimens. There was a 97% agreement between the methods for
      positive findings of at least one drug. The majority of discordant results were
      due to variations in selectivity of the assays for phenobarbital and BNZ
      metabolites. TC-er yielded a single false-positive result for amphetamines, and
      barbiturates, possibly three false-positive benzodiazepine results, and a single
      false-negative opiate finding. This represented four certain errors out of 745
      total results, or a 0.4% error rate. If the three false-positive BNZ results were
      also considered, the error rate would be 0.9%. TC-er demonstrated acceptable
      linearity around the cut-off concentration of each drug. The TC-er was determined
      to be a reliable device for rapid on-site testing of emergency department urine
      specimens.

PMID- 12423008
TI  - Validation of a microtiter plate ELISA for screening of postmortem blood for
      opiates and benzodiazepines.
AB  - The object of this study was to evaluate the suitability of the Neogen Corp.
      microtiter plate enzyme-linked immunoassays (ELISA) for opiates and
      benzodiazepines for screening of postmortem blood. Ninety postmortem whole blood
      specimens were obtained from drug-involved deaths which had been screened and
      confirmed positive for opiates and/or benzodiazepines. Forty negative specimens
      were obtained from non-opiate-involved deaths. Specimens were tested using the
      Neogen Opiates Group and Neogen Benzodiazepines Group microtiter plate ELISA
      assays. No matrix effects were found for whole blood in these assays and a
      dilution of 1:5 was chosen to facilitate pipetting and to bring the IC50 of the
      microtiter plate ELISA assay within the range of opiates and benzodiazepines
      encountered in medical examiner specimens. True positive, true negatives, false
      positives, and false negatives were determined and graphed for the ELISA results
      against gas chromatography-mass spectrometry (GC-MS), gas chromatography-nitrogen
      phosphorus detection and case histories. From these graphs and the ROC curves,
      the optimal cut-off for the Neogen Opiates Group ELISA was found to be between 20
      and 50 ng/mL morphine equivalents and the optimum cut-off for the Neogen
      Benzodiazepines Group ELISA was between 20 and 50 ng/mL temazepam equivalents.
      The Neogen Opiates Group ELISA had a sensitivity of 95.2% +/- 2.7% and a
      specificity of 92.2% +/- 3.4% versus GC-MS at a cut-off of 20-ng/mL cut-off and a
      sensitivity of 88.8% +/- 3.9% and specificity of 96.8% +/- 2.1% versus GC-MS at a
      50-ng/mL morphine equivalents cut-off. The Neogen Benzodizepines Group ELISA had
      a sensitivity of 100% +/- 1.3% and a specificity of 94.6% +/- 2.9% versus GC-MS
      (20-ng/mL temazepam equivalents cut-off) and a sensitivity of 95.8% +/- 2.5% and
      specificity of 98.2% +/- 1.8% versus GC-MS at a 50-ng/mL cut-off.

PMID- 12423009
TI  - Choice of an ELISA assay for screening postmortem blood for amphetamine and/or
      methamphetamine.
AB  - The object of this study was to evaluate the suitability of the Neogen Corp.
      microtiter plate enzyme-linked immunoassays (ELISA) for the screening of
      postmortem blood for amphetamine and methamphetamine and to choose the more
      appropriate assay for screening. Forty-seven postmortem whole blood specimens
      were obtained from drug-involved deaths, which had been screened and confirmed
      positive for methamphetamine and/or amphetamine. Eighty-five negative specimens
      were obtained from non-amphetamines-involved deaths, 17 of which involved
      decomposition. Specimens were tested using the Neogen Amphetamine Ultra and
      Neogen Methamphetamine/MDMA microtiter plate ELISA assays. No matrix effects were
      found for whole blood in these assays, and a dilution of 1:5 was chosen to
      facilitate pipetting and to bring the IC50 of the microtiter plate ELISA assay
      within the range of amphetamines concentrations encountered in medical examiner
      specimens. True positives, true negatives, false positives, and false negatives
      were determined relative to gas chromatography-mass spectrometry (GC-MS) and
      graphed for the ELISA. From these graphs and the receiver operating curves (ROC),
      the optimal cut-off for the Neogen Methamphetamine/MDMA ELISA was 50 ng/mL
      methamphetamine equivalents and the optimum cut-off for the Neogen Amphetamine
      Ultra ELISA was 100 ng/mL amphetamine equivalents. The Neogen Methamphetamine
      ELISA had a sensitivity of 93.6% +/- 3.5% and a specificity of 77.6% +/- 4.5%
      versus GC-MS at the cut-off of 50-ng/mL methamphetamine equivalents. The Neogen
      Amphetamine Ultra ELISA had a sensitivity of 95.7% +/- 3.0% and a specificity of
      72.9% +/- 5.2% versus GC-MS at the 100-ng/mL amphetamine equivalents cut-off. The
      areas under the ROCs were equivalent for the two ELISA assays.

PMID- 12423010
TI  - Comparison of EMIT II, CEDIA, and DPC RIA assays for the detection of lysergic
      acid diethylamide in forensic urine samples.
AB  - In an effort to determine a practical, efficient, and economical alternative for
      the use of a radioimmunoassay (RIA) for the detection of lysergic acid
      diethylamide (LSD) in human urine, the performance of two photometric
      immunoassays (Dade Behring EMIT II and Microgenics CEDIA) and the Diagnostics
      Products Corp. (DPC) RIA were compared. Precision, accuracy, and linearity of the
      3 assays were determined by testing 60 replicates (10 for RIA) at 5 different
      concentrations below and above the 500-pg/mL LSD cut-off. The CEDIA and RIA
      exhibited better accuracy and precision than the EMIT II immunoassay. In
      contrast, the EMIT II and CEDIA demonstrated superior linearity r2 = 0.9809 and
      0.9540, respectively, as compared with the RIA (r2 = 0.9062). The specificity of
      the three assays was assessed using compounds that have structural and chemical
      properties similar to LSD, common over-the-counter products, prescription drugs
      and some of their metabolites, and other drugs of abuse. Of the 144 compounds
      studied, the EMIT II cross-reacted with twice as many compounds as did the CEDIA
      and RIA. Specificity was also assessed in 221 forensic human urine specimens that
      previously screened positive for LSD by the EMIT II assay. Of these, only 11
      tested positive by CEDIA, and 3 were positive by RIA. This indicated a comparable
      specificity performance between CEDIA and RIA. This also was consistent with a
      previously reported high false-positive rate of EMIT II (low specificity). Each
      of the immunoassays correctly identified LSD in 23 out of 24 human urine
      specimens that had previously been found to contain LSD by gas chromatography
      mass spectrometry at a cut-off concentration of 200 pg/mL. The CEDIA exhibited
      superior precision, accuracy, and decreased cross-reactivity to compounds other
      than LSD as compared with the EMIT II assay and does not necessitate the handling
      of radioactive materials.

PMID- 12423011
TI  - Simultaneous quantitation of opioids in blood by GC-EI-MS analysis following
      deproteination, detautomerization of keto analytes, solid-phase extraction, and
      trimethylsilyl derivatization.
AB  - Seven opioid analytes including codeine, morphine, 6-acetylmorphine, hydrocodone,
      hydromorphone, oxycodone, and oxymorphone were detected in postmortem blood (n >
      1000). Two milliliters of specimen was deproteinated with approximately 2.5 mL of
      methanol and derivatized with hydroxylamine before solid-phase extraction and
      derivatization with BSTFA + 1% TMCS. Extracts were assayed by gas chromatography
      electron impact-mass spectrometry utilizing selected ion mode. One-microliter
      aliquots were injected onto an HP-1MS capillary column (30 m x 0.25-mm i.d., 0.25
      microm) with a helium linear velocity of 62 cm/s. Temperature programming began
      at 160 degrees C (hold 0 min), then increased at rates of 35 degrees C/min to 195
      degrees C, 5 degrees C/min to 240 degrees C, and 30 degrees C/min to 300 degrees
      C (hold 2 min) resulting in a total run time of 14-min. Quantitative
      determinations were based on the ratios of the analyte peak areas to the
      corresponding deuterated analogues. Calibration curves were linear for the
      following concentrations: 10-500 ng/mL (6-AM), 100-2000 ng/mL (oxycodone), and 50
      1000 ng/mL (all other opioids). LOQs ranged from 5 ng/mL (6-AM) to 20 ng/mL
      (oxycodone). Between-run precision yielded CVs ranging from 2.79% to 5.34% (n =
      12). These data suggest that methanolic deproteination and dual derivatization
      improve separation and simultaneous quantitation of seven opioid analytes in
      difficult matrices.

PMID- 12423012
TI  - Blood investigation in a fatality involving the veterinary drug T-61.
AB  - A case involving an acute fatality resulting from self-administration of about 30
      mL of T-61, a euthanasia solution, consisting of a mixture of embutramide,
      mebezonium, and tetracaine, in a 58-year-old veterinarian is presented. Forensic
      investigations consisted of an external body examination, during which 5 mL of
      fluorinated femoral blood was collected. Embutramide and tetracaine were
      quantitated using gas chromatography coupled to mass spectrometry after
      extraction with chloroform/isopropanol/n-heptane (50:17:33, v/v) at pH 9.5 and
      separation on an HP5-MS capillary column. Mebezonium was quantitated using liquid
      chromatography coupled to mass spectrometry after ion-pair extraction (saturated
      KI solution) with methylene chloride at pH 5.4 and separation on a 5-mm Nucleosil
      C18 column. Blood concentrations were 43.0, 6.5, and 0.21 mg/L for embutramide,
      mebezonium, and tetracaine, respectively. No other drugs, including ethanol, were
      detected.

PMID- 12423013
TI  - Death by paint thinner.
AB  - A 38-year-old Caucasian male, reportedly missing for four days, was found dead 40
      feet down a steep ravine, apparently after jumping down the cliff. Two
      rectangular cans of paint thinner, 1-qt and 1-gal sizes, were found in his
      vehicle at the top of the cliff. The autopsy report indicated that the decedent
      was normal except for the heart and myocardium, the lung parenchyma, and the
      gastric and esophageal mucosa. The stomach contents revealed a brownish liquid
      with a nearly clear, thick, oily film, and the small and large bowels showed oily
      liquid with a strong odor of a petroleum distillate. Toxicological analysis was
      negative for ethanol and common drugs of abuse. Valproic acid, diphenhydramine,
      and norsertraline where found in therapeutic concentrations, and sertraline,
      diazepam, and nordiazepam were found in subtherapeutic levels. Bupropion
      metabolites were also detected. Static adsorption-elution, commonly used in fire
      debris analysis, was used to examine the brain, liver, lung, blood, and urine. A
      liquid-liquid extraction was performed on the vitreous humor. The stomach
      contents and samples from the paint thinner cans were diluted with carbon
      disulfide. All but the blood and vitreous contained a medium petroleum
      distillate. The stomach content was consistent with the liquid from the one
      gallon can. Chromatograms suggest differential metabolism and/or distribution
      among the different organs.

PMID- 12423014
TI  - Differentiation of the 2,3-methylenedioxy regioisomer of 3,4-MDMA (ecstasy) by
      gas chromatography-mass spectrometry.

PMID- 12423015
TI  - Developmental control of promoter activity is not responsible for mature onset of
      Cf-9B-mediated resistance to leaf mold in tomato.
AB  - Cf-9 confers resistance to tomato seedlings and mature plants against
      Cladosporium fulvum races expressing the Avr9 elicitor. It is the central member
      of a cluster of five paralogous genes in an introgressed segment of chromosome 1
      derived from Lycopersicon pimpinellifolium. The other four genes have been named
      Hcr9-9A, Hcr9-9B, Hcr9-9D, and Hcr9-9E. Hcr9-9B, here designated Cf-9B, encodes
      weaker resistance than Cf-9, recognizes a different elicitor, and protects only
      mature plants from infection. The onset of Cf-9B-mediated resistance and the
      molecular basis for its developmental control were investigated in this study.
      Fungal inoculation of tomato plants containing reciprocal Cf-9/Cf-9B promoter
      coding region swaps, analysis of tomato plants containing promoter-gusA fusions,
      and a reverse transcriptase-polymerase chain reaction study of Cf-9 and Cf-9B
      transcripts in tomato plants suggested that transcriptional control of Cf-9B did
      not account for the late onset of Cf-9B-mediated resistance. Alternative
      explanations for the onset of Cf-9B-mediated resistance in mature plants are
      discussed.

PMID- 12423016
TI  - Genetic and cytogenetic mapping of DMI1, DMI2, and DMI3 genes of Medicago
      truncatula involved in Nod factor transduction, nodulation, and mycorrhization.
AB  - The DMI1, DMI2, and DMI3 genes of Medicago truncatula, which are required for
      both nodulation and mycorrhization, control early steps of Nod factor signal
      transduction. Here, we have used diverse approaches to pave the way for the map
      based cloning of these genes. Molecular amplification fragment length
      polymorphism markers linked to the three genes were identified by bulked
      segregant analysis. Integration of these markers into the general genetic map of
      M. truncatula revealed that DMI1, DMI2, and DMI3 are located on linkage groups 2,
      5, and 8, respectively. Cytogenetic studies using fluorescent in situ
      hybridization (FISH) on mitotic and pachytene chromosomes confirmed the location
      of DMI1, DMI2, and DMI3 on chromosomes 2, 5, and 8. FISH-pachytene studies
      revealed that the three genes are in euchromatic regions of the genome, with a
      ratio of genetic to cytogenetic distances between 0.8 and 1.6 cM per microm in
      the DMI1, DMI2, and DMI3 regions. Through grafting experiments, we showed that
      the genetic control of the dmi1, dmi2, and dmi3 nodulation phenotypes is
      determined at the root level. This means that mutants can be transformed by
      Agrobacterium rhizogenes to accelerate the complementation step of map-based
      cloning projects for DMI1, DMI2, and DMI3.

PMID- 12423018
TI  - Tissue specific localization of root infection by fungal pathogens: role of root
      border cells.
AB  - When roots of pea seedlings were inoculated uniformly with spores of Nectria
      haematocca or other pea pathogenic fungi, more than 90% developed lesions in the
      region of elongation within 3 days. More mature regions of most roots as well as
      the tip showed no visible signs of infection. Yet, microscopic observation
      revealed that 'mantles,' comprised of fungal hyphae intermeshed with populations
      of border cells, covered the tips of most roots. After physical detachment of the
      mantle, the underlying tip of most roots was found to be free of infection.
      Mantle-covered root tips did not respond to invasion of their border cells by
      activation of known defense genes unless there was invasion of the tip itself, as
      revealed by the presence of a lesion. Concomitant with the activation of defense
      genes was the induction of a cell-wall degrading enzyme whose expression is a
      marker for renewed production of border cells. Mantle formation did not occur in
      response to nonpathogens. The data are consistent with the hypothesis that border
      cells serve as a host-specific 'decoy' that protects root meristems by inhibiting
      fungal infection of the root tip.

PMID- 12423017
TI  - A mitogen-activated protein kinase gene (MGV1) in Fusarium graminearum is
      required for female fertility, heterokaryon formation, and plant infection.
AB  - Fusarium graminearum is an important pathogen of small grains and maize in many
      areas of the world. Infected grains are often contaminated with mycotoxins
      harmful to humans and animals. During the past decade, F. graminearum has caused
      several severe epidemics of head scab in wheat and barley. In order to understand
      molecular mechanisms regulating fungal development and pathogenicity in this
      pathogen, we isolated and characterized a MAP kinase gene, MGV1, which is highly
      homologous to the MPS1 gene in Magnaporthe grisea. The MGV1 gene was dispensable
      for conidiation in F. graminearum but essential for female fertility during
      sexual reproduction. Vegetative growth of mgv1 deletion mutants was normal in
      liquid media but reduced on solid media. Mycelia of the mgv1 mutants had weak
      cell walls and were hypersensitive to cell wall degrading enzymes. Interestingly,
      the mgv1 mutants were self-incompatible when tested for heterokaryon formation,
      and their virulence was substantially reduced. The ability of the mutants to
      accumulate trichothecene mycotoxins on inoculated wheat was also greatly reduced.
      Our data suggest that MGV1 in F. graminearum is involved in multiple
      developmental processes related to sexual reproduction, plant infection, and cell
      wall integrity.

PMID- 12423019
TI  - Generation of siRNAs by T-DNA sequences does not require active transcription or
      homology to sequences in the plant.
AB  - Delivery into plants of T-DNAs containing promoter, terminator, or coding
      sequences generated small interfering RNAs (siRNAs) specific to each type of
      sequence. When both promoter and transcribed sequences were simultaneously
      present in the T-DNA, accumulation of siRNAs to transcribed sequences was favored
      over accumulation of siRNAs to the nontranscribed upstream promoter sequences.
      The generation of specific siRNA sequences occurred even in the absence of T-DNA
      homology to sequences in the plant. Delivery of T-DNA, with homology to the
      transgene limited to the nontranscribed cauliflower mosaic virus 35S promoter
      (35SP) and the transcribed nopaline synthase transcription termination
      (NosT)signal sequences, into transgenic plants expressing the green fluorescent
      protein (GFP), generated siRNAs in infiltrated tissues to both 35SP (35SsiRNAs)
      and NosT (NosTsiRNAs), but not to the GFP sequence (GFPsiRNAs). In infiltrated
      tissues, the 35SsiRNAs failed to trigger the transcriptional silencing of the
      transgene, accumulation of 35SsiRNAs could be prevented by the potyviral HC-Pro,
      and the NosTsiRNAs required an initial amplification to trigger efficient
      transgene silencing, which is mediated by transcripts from the exogenous T-DNA,
      and not from the transgene. In upper leaves, silencing correlated with the
      presence of GFPsiRNAs and the absence of 35SsiRNAs, confirming that its spread
      was posttranscriptionally mediated by the transgene mRNA.

PMID- 12423021
TI  - FUM1--a gene required for fumonisin biosynthesis but not for maize ear rot and
      ear infection by Gibberella moniliformis in field tests.
AB  - We have analyzed the role of fumonisins in infection of maize (Zea mays) by
      Gibberella moniliformis (anamorph Fusarium verticillioides) in field tests in
      Illinois and Iowa, United States. Fumonisin-nonproducing mutants were obtained by
      disrupting FUM1 (previously FUM5), the gene encoding a polyketide synthase
      required for fumonisin biosynthesis. Maize ear rot, ear infection, and fumonisin
      contamination were assessed by silk-channel injection in 1999 and 2000 and also
      by spray application onto maize silks, injection into maize stalks, and
      application with maize seeds at planting in 1999. Ear rot was evaluated by visual
      assessment of whole ears and by calculating percentage of symptomatic kernels by
      weight. Fumonisin levels in kernels were determined by high-performance liquid
      chromatography. The presence of applied strains in kernels was determined by
      analysis of recovered isolates for genetic markers and fumonisin production. Two
      independent fumonisin-nonproducing (fum1-3 and fum1-4) mutants were similar to
      their respective fumonisin-producing (FUM1-1) progenitor strains in ability to
      cause ear rot following silk-channel injection and also were similar in ability
      to infect maize ears following application by all four methods tested. This
      evidence confirms that fumonisins are not required for G. moniliformis to cause
      maize ear rot and ear infection.

PMID- 12423020
TI  - Induction of systemic resistance to Botrytis cinerea in tomato by Pseudomonas
      aeruginosa 7NSK2: role of salicylic acid, pyochelin, and pyocyanin.
AB  - The rhizobacterium Pseudomonas aeruginosa 7NSK2 produces secondary metabolites
      such as pyochelin (Pch), its precursor salicylic acid (SA), and the phenazine
      compound pyocyanin. Both 7NSK2 and mutant KMPCH (Pch-negative, SA-positive)
      induced resistance to Botrytis cinerea in wild-type but not in transgenic NahG
      tomato. SA-negative mutants of both strains lost the capacity to induce
      resistance. On tomato roots, KMPCH produced SA and induced phenylalanine ammonia
      lyase activity, while this was not the case for 7NSK2. In 7NSK2, SA is probably
      very efficiently converted to Pch. However, Pch alone appeared not to be
      sufficient to induce resistance. In mammalian cells, Fe-Pch and pyocyanin can act
      synergistically to generate highly reactive hydroxyl radicals that cause cell
      damage. Reactive oxygen species are known to play an important role in plant
      defense. To study the role of pyocyanin in induced resistance, a pyocyanin
      negative mutant of 7NSK2, PHZ1, was generated. PHZ1 is mutated in the phzM gene
      encoding an O-methyltransferase. PHZ1 was unable to induce resistance to B.
      cinerea, whereas complementation for pyocyanin production or co-inoculation with
      mutant 7NSK2-562 (Pch-negative, SA-negative, pyocyanin-positive) restored induced
      resistance. These results suggest that pyocyanin and Pch, rather than SA, are the
      determinants for induced resistance in wild-type P. aeruginosa 7NSK2.

PMID- 12423022
TI  - Fungal ABC transporters and microbial interactions in natural environments.
AB  - In natural environments, microorganisms are exposed to a wide variety of
      antibiotic compounds produced by competing organisms. Target organisms have
      evolved various mechanisms of natural resistance to these metabolites. In this
      study, the role of ATP-binding cassette (ABC) transporters in interactions
      between the plant-pathogenic fungus Botrytis cinerea and antibiotic-producing
      Pseudomonas bacteria was investigated in detail. We discovered that 2,4
      diacetylphloroglucinol, phenazine-1-carboxylic acid and phenazine-1-carboxamide
      (PCN), broad-spectrum antibiotics produced by Pseudomonas spp., induced
      expression of several ABC transporter genes in B. cinerea. Phenazines strongly
      induced expression of BcatrB, and deltaBcatrB mutants were significantly more
      sensitive to these antibiotics than their parental strain. Treatment of B.
      cinerea germlings with PCN strongly affected the accumulation of
      [14C]fludioxonil, a phenylpyrrole fungicide known to be transported by BcatrB,
      indicating that phenazines also are transported by BcatrB. Pseudomonas strains
      producing phenazines displayed a stronger antagonistic activity in vitro toward
      ABcatrB mutants than to the parental B. cinerea strain. On tomato leaves,
      phenazine-producing Pseudomonas strains were significantly more effective in
      reducing gray mold symptoms incited by a ABcatrB mutant than by the parental
      strain. We conclude that the ABC transporter BcatrB provides protection to B.
      cinerea in phenazine-mediated interactions with Pseudomonas spp. Collectively,
      these results indicate that fungal ABC transporters can play an important role in
      antibiotic-mediated interactions between bacteria and fungi in plant-associated
      environments. The implications of these findings for the implementation and
      sustainability of crop protection by antagonistic microorganisms are discussed.

PMID- 12423023
TI  - Flagella-driven chemotaxis towards exudate components is an important trait for
      tomato root colonization by Pseudomonas fluorescens.
AB  - Motility is a major trait for competitive tomato root-tip colonization by
      Pseudomonas fluorescens. To test the hypothesis that this role of motility is
      based on chemotaxis toward exudate components, cheA mutants that were defective
      in flagella-driven chemotaxis but retained motility were constructed in four P.
      fluorescens strains. After inoculation of seedlings with a 1:1 mixture of wild
      type and nonmotile mutants all mutants had a strongly reduced competitive root
      colonizing ability after 7 days of plant growth, both in a gnotobiotic sand
      system as well as in nonsterile potting soil. The differences were significant on
      all root parts and increased from root base to root tip. Significant differences
      at the root tip could already be detected after 2 to 3 days. These experiments
      show that chemotaxis is an important competitive colonization trait. The best
      competitive root-tip colonizer, strain WCS365, was tested for chemotaxis toward
      tomato root exudate and its major identified components. A chemotactic response
      was detected toward root exudate, some organic acids, and some amino acids from
      this exudate but not toward its sugars. Comparison of the minimal concentrations
      required for a chemotactic response with concentrations estimated for exudates
      suggested that malic acid and citric acid are among major chemo-attractants for
      P. fluorescens WCS365 cells in the tomato rhizosphere.

PMID- 12423024
TI  - Coupling of iron assimilation and pectinolysis in Erwinia chrysanthemi 3937.
AB  - Two major virulence determinants of the plant-pathogenic enterobacterium Erwinia
      chrysanthemi strain 3937 are the production of pectate lyase enzymes that degrade
      plant cell walls and expression of two high-affinity iron uptake systems mediated
      by two structurally unrelated siderophores, chrysobactin and achromobactin. Low
      iron availability is a signal that triggers transcription of the genes encoding
      pectate lyases PelD and PelE as well as that of genes involved in iron transport.
      This metalloregulation is mediated by the transcriptional repressor Fur. In this
      study, we analyzed the molecular mechanisms of this control. We purified the
      Erwinia chrysanthemi Fur protein. Band shift assays showed that Fur specifically
      binds in vitro to the regulatory regions of the genes encoding the
      ferrichrysobactin outer membrane receptor Fct and the pectate lyases PelD and
      PelE. We identified the Fur-binding sites of these promoter regions by performing
      DNase I footprinting experiments. From these data, we propose that Fur could
      inhibit the activation of the pelD and pelE genes by the cAMP receptor protein
      CRP according to an anti-activation mechanism. To identify other possible
      effectors involved in this control, we screened a bank of insertion mutants for
      an increase in transcriptional activity of pelD and fct genes in response to iron
      limitation. We isolated a mutant affected in the kdgK gene encoding the 2-keto-3
      deoxygluconate (KDG) kinase, an enzyme involved in pectin catabolism. The growth
      of this mutant in the presence of pectic compounds led to a constitutive
      expression of iron transport genes as well as complete derepression of the
      pectinolysis genes. This effect was caused by intracellular accumulation of KDG.
      However, the derepression of iron transport genes by KDG does not involve the
      KdgR regulator of pectinolysis genes, which uses KDG as inducer. Thus, in Erwinia
      chrysanthemi, iron depletion or presence of KDG induces transcription of the
      genes involved in iron assimilation and pectinolysis. These important
      pathogenicity functions are coregulated by responding to common signals
      encountered in planta.

PMID- 12423025
TI  - Case-control study on the association of porcine circovirus type 2 and other
      swine viral pathogens with postweaning multisystemic wasting syndrome.
AB  - A field-based case-control study was conducted to assess the strength of
      association of porcine circovirus type 2 (PCV2) and some major swine viruses with
      postweaning multisystemic wasting syndrome (PMWS). Cases were defined as
      individual pigs with a clinical history of progressive weight loss and
      histopathological lesions characteristic of PMWS. Controls were pigs without
      clinical signs and histopathological lesions typical of PMWS. A total of 31 cases
      and 56 controls was identified from diagnostic submissions. Serum and various
      tissues were collected from all animals and assayed for PCV, porcine reproductive
      and respiratory syndrome virus (PRRSV), porcine parvovirus, porcine enterovirus
      types 1-3, swine influenza virus, porcine respiratory coronavirus, transmissible
      gastroenteritis virus, porcine endogenous retrovirus, porcine lymphotropic
      herpesvirus type 1, and bovine viral diarrhea virus. The proportion of case and
      control pigs positive for each virus was determined and statistically compared
      for determining the strength of the association that each virus had with PMWS
      individually or in combinations. Porcine circovirus type 2 had the strongest
      association (OR = 9.3, P = 0.006) with PMWS among the viruses tested for. Risk
      for PWMS was much higher (OR = 31.2, P = 0.0009) if the animal was concurrently
      infected with PCV2 and PRRSV, suggesting that development of PMWS may be enhanced
      by cofactor(s). Because PCV2 was also found in 62.5% of the controls, PCV2 from 5
      cases and 4 controls were selected and genetically compared. No significant
      genetic difference was observed between PCV2 from PMWS and control pigs.

PMID- 12423026
TI  - Seroprevalence and comparison of isolates of endometriotropic bovine herpesvirus
      4.
AB  - Sixty-eight cases of suppurative, ulcerative endometritis associated with Bovine
      Herpesvirus-4 (BHV-4) in postparturient dairy cows (62 Holsteins and 6 Jerseys,
      mean age 4.2 years) were confirmed by a combination of histopathology,
      fluorescent antibody assays, electron microscopic evaluation of uterus, and
      polymerase chain reaction (PCR). All cases occurred in the 3- to 28-day
      postpartum period, and histologic lesions among various cows were consistent when
      compared with postpartum interval. The endometrial lining epithelium was necrotic
      and ulcerated from 3 to 7 days postpartum, with only mild inflammation in the
      lamina propria and submucosa. From 1 to 4 weeks postpartum, the ulcers were
      confluent to diffuse. Epithelium was replaced by fibrinonecrotic, suppurative
      mats, resulting in severe bacterial pyometra by day 24. Seroprevalence to BHV-4
      in one dairy with a history of 18 mortality cases was 36% (107 of 296). In a
      random sample of 8 cows from this herd, none had serologic titers in blood
      sampled 2 weeks prepartum, but 3 of 8 seroconverted with significant titers of
      1:8 to 1:16 at 2 weeks postpartum. By 10 weeks postpartum, all 8 cows returned to
      negative serologic status. Two of 6 cats from the premises also had positive
      titers. Random serum samples taken from 480 dairy cattle at sale barns indicated
      76 (16%) were positive by serum neutralization. Clinical signs, postparturient
      timing, and histologic lesions were very similar to those previously reported in
      Belgium with BHV-4. But sequence analysis of PCR products of the glycoprotein B
      region of 4 separate field isolates of endometriotropic BHV-4 suggests these
      field isolates were more closely related to the North American nonvirulent strain
      DN-599 than to the endometriotropic European strain V.

PMID- 12423027
TI  - Use of a Mycoplasma hyopneumoniae nested polymerase chain reaction test to
      determine the optimal sampling sites in swine.
AB  - A number of polymerase chain reaction (PCR)-based diagnostic tests have been
      developed for Mycoplasma hyopneumoniae, including one from this research group.
      This report presents further development, optimization, and standardization of a
      nested PCR test. Detection sensitivity was 1 fg of M. hyopneumoniae chromosomal
      DNA (approximately 1 organism). This exceeded the sensitivity of or compared
      favorably with other published PCR tests. Polymerase chain reaction primers to
      porcine beta2-microglobulin were included as internal controls for amplifiable
      chromosomal DNA from porcine samples. To standardize the test, a number of
      samples from experimentally infected pigs, including nasal, tonsil,
      tracheobronchial swabs, lung tissue, bronchial alveolar lavage (BAL) fluid, and
      tracheobronchial brush samples, were examined by PCR. Samples obtained from BAL
      fluid and tracheobronchial sites were most predictive of infection, whereas nasal
      swabs and lung tissue were not reliable indicators of experimentally induced
      infection. In conclusion, the nested PCR developed for this study was found to be
      a highly sensitive and specific diagnostic tool for M. hyopneumoniae, but the
      enhanced sensitivity may be unnecessary if the proper sites are sampled.

PMID- 12423028
TI  - Mycobacterium bovis-infected white-tailed deer (Odocoileus virginianus):
      detection of immunoglobulin specific to crude mycobacterial antigens by ELISA.
AB  - White-tailed deer (Odocoileus virginianus) have recently emerged as a source of
      Mycobacterium bovis infection for cattle within North America. The objective of
      this study was to evaluate the antibody response of M. bovis-infected deer to
      crude mycobacterial antigens. Deer were experimentally inoculated with M. bovis
      strain 1315 either by intratonsilar instillation or by exposure to M. bovis
      infected (i.e., in contact) deer. To determine the time course of the response,
      including the effects of antigen administration for comparative cervical skin
      testing, serum was collected periodically and evaluated by enzyme-linked
      immunosorbent assay (ELISA) for immunoglobulin (i.e., IgG heavy and light chains)
      reactivity to mycobacterial antigens. The reactivity to M. bovis purified protein
      derivative (PPDb) exceeded (P < 0.05) the reactivity to M. avium PPD (PPDa) only
      after in vivo administration of PPDa and PPDb for comparative cervical testing of
      the infected deer. The mean immunoglobulin response, as measured by ELISA, of
      intratonsilar-inoculated deer to a proteinase K-digested whole-cell sonicate (WCS
      PK) of M. bovis strain 1315 exceeded (P < 0.05) the mean of the prechallenge
      responses to this antigen at approximately 1 month after inoculation and
      throughout the remainder of the study (i.e., approximately 11 months). This
      response also exceeded (P < 0.05) that of the uninfected deer. Although this is
      encouraging, further studies are necessary to validate the use of the proteinase
      K-digested M. bovis antigens in the antibody-based assays of tuberculosis.

PMID- 12423029
TI  - Detection of porcine teschovirus and enterovirus type II by reverse transcription
      polymerase chain reaction.
AB  - Porcine enteroviruses (PEVs) have been recognized as the causative agents of
      various clinical manifestations such as fertility disorders, neurological
      defects, and dermal lesions in pigs. Currently, the diagnosis of PEV infection is
      carried out by virus isolation, which although useful, is labor- and time
      intensive. The present investigation describes the development of a reverse
      transcription-polymerase chain reaction (RT-PCR) assay for the rapid and
      sensitive detection of PEVs of cytopathic effect groups I (now known as porcine
      teschoviruses [PTVs]) and II. The assay described not only detects the PTVs and
      CPE group II of PEVs but also allows them to be differentiated on the basis of
      the size of the amplification product, using the same set of oligonucleotide
      primers. The availability of specific and sensitive molecular diagnostic tools
      such as the RT-PCR assay described herein should facilitate efficient diagnosis
      of PTV and CPE group II infections in pigs.

PMID- 12423030
TI  - Managing lead exposure and toxicity in cow-calf herds to minimize the potential
      for food residues.
AB  - Lead poisoning is commonly diagnosed in cattle. In this study, 3 groups of cattle
      from different herds accidentally exposed to discarded lead batteries on pasture
      were intensively studied to determine the extent and severity of exposure. The
      losses from acute death due to lead toxicity were substantial in all the 3 study
      groups at 12%, 17%, and 4%. Blood samples were taken from all cattle around the
      time of the first diagnosis and then later in 2 of the 3 herds to monitor the
      change in lead concentrations over time. Asymptomatic lead toxicosis was observed
      in these herds. In these 3 groups, between 4% and 12% of asymptomatic cattle had
      blood lead concentrations consistent with acute lead poisoning (> 0.35 ppm), and
      between 7% and 40% of these asymptomatic animals were in the high-normal range
      (0.1-0.35 ppm). Because of the consistently high number of asymptomatic cattle
      with elevated lead levels, all cattle potentially exposed to a lead source should
      be tested before sale or slaughter to minimize the entry of lead into the food
      chain. The blood lead concentrations, which were monitored for months after the
      initial diagnosis, decreased slowly after the cattle were removed from the lead
      source. The prolonged retention of lead may be due to continued release and
      absorption of lead from metal particles in the reticulum or rumen. The mean
      reduction in the lead level was 0.046 ppm (95% CI, 0.017-0.075 ppm) every 30 days
      for these 2 herds. Using a single-component exponential model, the half-life of
      lead in the animals retested from Herds 1 and 2 was highly variable. The median
      half-life was 63 days (interquartile range, 34-107 days). One out of 8 pregnant
      heifers with high blood levels had a stillborn calf. There were no abortions or
      calf mortalities in this group. Blood samples were'collected from the calves
      around the time of birth. The concentrations of lead in the blood of the calves
      exposed in utero were low (0.010-0.095 ppm).

PMID- 12423031
TI  - Immunohistochemical staining of chlamydial antigen in emerald tree boas (Corallus
      caninus).
AB  - Of 120 privately owned captive-bred and wild-collected emerald tree boas (ETBs)
      (Corallus caninus), 97 died or were euthanatized. Eighteen snakes were
      necropsied, and tissues were collected from all major organs and processed for
      light microscopy. Histologic examination demonstrated histiocytic granulomas in
      the small intestine, heart, and esophageal tonsils of one ETB, small intestine of
      a second ETB, and in an esophageal tonsil of a third ETB. Within the center of
      these granulomas, small, basophilic, punctate organisms were demonstrated using
      hematoxylin and eosin staining. Transmission electron microscopic examination of
      an intestinal granuloma demonstrated developmental stages of organisms consistent
      with members of the family Chlamydiaceae. An immunoperoxidase staining technique
      and 2 different commercially available monoclonal antibodies against chlamydial
      lipopolysaccharide antigen was used to identify chlamydial antigen in these
      lesions. Liver of a puff adder (Bitis arietans) with previously reported systemic
      chlamydiosis served as the positive control. Both monoclonal antibodies stained
      antigen in these granulomas. Additionally, macrophages within aggregates of
      lymphoplasmacytic cells in the colon, small intestine, and esophageal tonsils of
      3 other ETBs contained antigen. Although both antibodies labeled antigen in
      serial sections of tissue, a difference in staining intensity was noted.

PMID- 12423032
TI  - Visceral nodular cartilaginous metaplasia in rockfishes (Sebastes spp.) in the
      eastern North Pacific Ocean.
AB  - Multiple, discrete, nodular foci of cartilaginous metaplasia were found in the
      spleens and kidneys of rockfishes taken from the northeastern Pacific Ocean
      during a survey to determine the incidence and the nature of diseases in these
      animals. These nodules sometimes occurred in association with granulomatous
      inflammation and distinct granulomas. Many of these fish were infected by
      Ichythophonus spp. or acid-fact bacteria (presumably Mycobacteria spp.). Some of
      the metaplastic foci contained encapsulated accumulations of eosinophilic
      vesicles and basophilic granular debris, described by other authors as "cysts of
      unknown etiology," which have been observed at different sites in a variety of
      temperate and tropical fish species.

PMID- 12423033
TI  - Retroperitoneal extraskeletal mesenchymal chondrosarcoma in a dog.
AB  - A young adult female Mastiff dog developed a large retroperitoneal mass, pleural
      effusion, and multiple pulmonary and pleural nodules. All masses were diagnosed
      as mesenchymal subtype chondrosarcomas, using histological and
      immunohistochemical criteria. Reports of canine extraskeletal mesenchymal
      chondrosarcomas (EMCs) are rare but involved animals less than 3 years of age in
      60% of the cases. This is the first description of this type of tumor developing
      distant metastases. Evidence from this case and previous reports suggests that
      EMCs are associated with a poor prognosis.

PMID- 12423034
TI  - Inclusion body myositis in spring peepers (Pseudacris crucifer).
AB  - In 2000, 2 adult captive spring peepers (Pseudacris crucifer) from the same
      zoological park were humanely euthanized. Histologically, both frogs had
      degeneration, atrophy, and necrosis of striated myofibers of the tongue admixed
      with chronic lymphohistiocytic inflammation. One frog had similar lesions in the
      skeletal muscles of the body wall. Several degenerate and necrotic myofibers
      contained single, eosinophilic, intranuclear inclusion bodies. Ultrastructural
      examination of the inclusions revealed nonenveloped, icosahedral, virus-like
      particles averaging 20-24 nm in diameter. This is the first reported case of
      inclusion body myositis in frogs and is believed to be due to parvoviral
      infection.

PMID- 12423035
TI  - Effect of formalin fixation on the immunohistochemical detection of PRRS virus
      antigen in experimentally and naturally infected pigs.
AB  - The purpose of this study was to determine the effect of formalin fixation on the
      immunohistochemical detection of porcine reproductive and respiratory syndrome
      (PRRS) viral antigen in lungs of experimentally and naturally infected pigs. In
      separate trials, five 24-day-old pigs and six 10-day-old pigs were housed as
      separate groups in isolation and inoculated intranasally with 10(5.5) TCID50 of
      an isolate of PRRS virus (PRRSV; P129). The older and younger pigs were
      euthanatized at 7 and 10 days post inoculation (dpi), respectively. At necropsy,
      all pigs had gross and microscopic lung lesions typical of PRRS, and PRRSV was
      isolated from all pigs. To insure uniform fixation, lungs from each pig were cut
      into 1-cm-thick slices and immersed into 10% neutral-buffered formalin. After
      fixation in formalin for 8 hours or 1, 2, 3, 5, 6, 8, 10, and 15 days, 3 lung
      sections from some or all pigs were processed for histological examination using
      routine methods. Immunohistochemical staining for PRRSV antigen was positive at
      the following times (days unless otherwise stated) after fixation (percentage of
      pigs staining positive for PRRSV in parentheses): 8 hours (100); 1 (100); 2
      (100); 3 (80); 5 (33); and 6, 8, 10, and 15 (0-all negative). To further evaluate
      the effects of formalin fixation on PRRSV immunodetection, 31 field cases of PRRS
      were selected for immunohistochemistry (IHC). Over a 3-month period, submitted
      cases were selected from the Purdue University Animal Disease Diagnostic
      Laboratory, W. Lafayette, Indiana, for IHC if 1) the clinical history included
      respiratory disease, 2) PRRSV was isolated from lung and/or serum from the
      submitted pigs or tissues, 3) at least 1 section of lung fixed in 10% neutral
      buffered formalin was submitted for IHC, and 4) the duration of fixation could be
      accurately determined from the case history. Of the 31 PRRSV-infected pig cases
      meeting the selection criteria, 23 were fixed in formalin for 4 days or less.
      Twenty-one of these 23 (91%) were positive by IHC. Two of 8 cases fixed for
      greater than 4 days (25%) were positive by IHC. In practical terms, 1-day
      shipping of fixed samples to a laboratory followed by routine tissue processing
      within a laboratory should not adversely affect immunohistochemical detection of
      PRRS viral antigen. But a delay in shipping or processing of more than 2 days
      could reduce or prevent the detection of PRRS viral antigen by IHC.

PMID- 12423036
TI  - Experimental in utero inoculation of late-term swine fetuses with porcine
      circovirus type 2.
AB  - All 37 fetuses of 3 laparotomized pregnant sows at 86, 92, and 93 days of
      gestation were inoculated intramuscularly through the uterine wall with porcine
      circovirus type 2 (PCV-2). The sows were allowed to farrow, and blood and tissue
      samples were collected from their piglets before and after suckling colostrum.
      Thirteen fetuses from 2 sows at 90 and 103 days of gestation were used as
      controls. Of the 37 PCV-2 inoculated fetuses, 24 were grossly normal and 13 were
      mummified, stillborn, or weak-born at farrowing. Infection with PCV-2 was
      demonstrated in various tissues of grossly normal and abnormal fetuses by virus
      isolation, polymerase chain reaction, and immunohistochemical methods. Antibodies
      specific to PCV-2 were also detected from the sera or thoracic fluids of abnormal
      fetuses and unsuckled normal pigs. No evidence of PCV-2 infection was found in
      any control fetuses. The present results confirm previous findings that PCV-2 can
      infect late-term swine fetuses and may cause reproductive abnormalities.

PMID- 12423037
TI  - Hepatic lipidosis in pregnant captive American bison (Bison bison).
AB  - Hepatic lipidosis, a hallmark lesion of lipid mobilization disorders in
      ruminants, was noted in four 3-year-old, pregnant bison (Bison bison) after
      periods of anorexia that progressed to recumbency and death. The affected bison
      were part of a herd at the National Animal Disease Center (NADC) that was used
      for brucellosis vaccine research. Microscopically, the liver contained swollen
      hepatocytes with numerous, variably sized, round, smoothly contoured vacuoles
      that displaced cytoplasmic structures. Hepatocytes in all zones of the lobule
      were affected equally. Hypoglycemia, decreased total carbon dioxide, elevated
      gamma-glutamyltransferase, elevated alkaline phosphatase, and increased
      nonesterified fatty acid levels were noted. As in the case of cattle, altered
      nutritional demands of late gestation combined with management factors such as
      obesity, nutrition, stress, and concomitant disease may be critical in the
      pathophysiology of lipid mobilization disorders in bison. Additionally, stressors
      unique to this research herd likely contributed to fatal hepatic lipidosis.

PMID- 12423038
TI  - Porcine circovirus type 2 (PCV-2) coinfections in US field cases of postweaning
      multisystemic wasting syndrome (PMWS).
AB  - The prevalence of different pathogens detected in combination with porcine
      circovirus type 2 (PCV-2) was studied retrospectively in field cases of
      postweaning multisystemic wasting syndrome (PMWS) diagnosed at the Iowa State
      University Veterinary Diagnostic Laboratory, Ames, Iowa, between January 2000,
      and September 2001. The presence of PCV-2 antigen in lymphoid tissues and/or
      lung, demonstrated by immunohistochemistry, together with moderate to severe
      lymphoid depletion and/or granulomatous lymphadenitis, was used as the criteria
      for the diagnosis of PMWS. A total of 484 cases fulfilled these criteria. Most of
      the cases (294/369) of PMWS occurred in pigs between the ages of 8 and 18 weeks,
      with a peak at 10 weeks of age. Porcine reproductive and respiratory syndrome
      virus was detected in 51.9% of the cases, Mycoplasma hyopneumoniae in 35.5%,
      bacterial septicemia in 14.0%, bacterial pneumonia in 7.6%, swine influenza virus
      in 5.4%, and PCV-2 alone in 1.9%. In cases with bacterial septicemia the most
      frequently isolated pathogen was Streptococcus suis. In cases with bacterial
      pneumonia, Pasteurella multocida was the most prevalent.

PMID- 12423039
TI  - Detection of feline coronavirus in captive Felidae in the USA.
AB  - Feline coronavirus (FCoV) is an important pathogen of domestic and nondomestic
      Felidae. Investigation into the prevalence of FCoV in exotic Felidae has relied
      primarily on serology. The usefulness of genetic detection of FCoV using reverse
      transcription and nested polymerase chain reaction (RT/nPCR) for viral screening
      was investigated. Seventy-five biologic samples, primarily feces, from captive
      felids from 11 institutions were tested using PCR. Serum samples collected from
      all but 12 of these animals were tested for antibodies to type I and type II FCoV
      by indirect immunofluorescence. Twenty-four animals were positive using RT/nPCR
      for virus. Twenty-nine animals were seropositive to type I and/or type II FCoV.
      From serologic data, infection with a virus antigenically related to FCoV type I
      occurred most commonly. Serology did not correlate with virus shedding because 13
      animals were seronegative to FCoV type I and II but positive using RT/nPCR for
      virus. Conversely, 20 animals were seropositive but negative using RT/nPCR for
      FCoV. Some of the populations in which virus was detected had experienced health
      problems, including feline infectious peritonitis (FIP), necrotizing colitis, and
      mild enteritis. In addition to its role in FIP, this virus may play a role in
      gastrointestinal diseases of infected animals. This study demonstrates that FCoV
      is a significant infectious agent of captive felids because over half of the
      animals tested were positive by viral genetic detection, serology, or both.
      Dependence upon one method for detection of infection is unreliable.

PMID- 12423040
TI  - Isolation of bovine viral diarrhea virus from an alpaca.
AB  - A frozen, stillborn alpaca (Lama pacos) was submitted to the Minnesota Veterinary
      Diagnostic Laboratory for diagnostic purposes. No gross or histopathologic
      changes of any significance were seen. A pool of lung, liver, and brain tissues
      was positive for bovine viral diarrhea virus (BVDV) by reverse transcription
      polymerase chain reaction. On inoculation in cell cultures, a noncytopathic BVDV
      (type 1b) was isolated. No evidence of BVDV was seen on immunohistochemical
      examination of tissues. This indicates the importance of using multiple tests for
      arriving at a diagnosis and appears to be the first report of BVDV isolation from
      alpaca.

PMID- 12423041
TI  - Neutralizing antibody decay and lack of contact transmission after inoculation of
      3- and 4-day-old piglets with porcine respiratory coronavirus.
AB  - Ten female neonatal piglets were infected with porcine respiratory coronavirus
      (PRCV) to measure the decay of a specific neutralizing antibody. By 42 weeks
      after exposure,1 of the gilts was serologically negative (< 5) for PRCV, and by
      48 weeks 2 more gilts were serologically negative. These data demonstrate that
      young mature gilts can be serologically negative, yet they could have been
      exposed to PRCV. Sentinel pigs were commingled with the PRCV-infected pigs at 8
      weeks after exposure, and no virus transmission occurred.

PMID- 12423042
TI  - Validation of an immunoperoxidase monolayer assay as a serologic test for porcine
      proliferative enteropathy.
AB  - The sensitivity and specificity of an immunoperoxidase monolayer assay (IPMA) was
      evaluated in a blind serologic study of a group of disease-free pigs and a group
      of pigs experimentally infected with intestinal homogenate containing Lawsonia
      intracellularis organisms. Sixty pigs from the control group were kept in the
      source farm, and another 60 animals were transferred to an isolation unit aid
      challenged intragastrically. All animals were bled before and 21 days after
      challenge. Fecal samples were collected on the same dates. The IPMA results were
      tested for sensitivity and specificity in a 2 x 2 table using the challenged and
      nonchallenged status as gold standard. Sensitivity and specificity were evaluated
      for different cutoff points (serum dilutions). Specificities of 100% were
      obtained for all the serum dilutions tested (1:15, 1:30, 1:60, and 1:120). The
      sensitivity levels were 90.7%, 88.9%, 81.5%, and 75.9% for the serum dilutions
      1:15, 1:30, 1:60, and 1:120, respectively. The sensitivity of the dilution 1:15
      was slightly, but not significantly, higher than the dilution currently used as
      the cutoff point (1:30). Cross-reactivity of the IPMA test was evaluated using
      sera from pigs experimentally inoculated with Brachyspira pilosicoli and various
      Campylobacter species. All these samples were negative. Sera samples from 3
      porcine proliferative enteropathy known negative populations, 40 growing pigs
      from 2 commercial farms and a group of 6 cesarean-derived and colostrum-deprived
      pigs, also tested negative by IPMA. The IPMA serologic test with the cutoff point
      of 1:30 showed specificity of 100% and sensitivity close to 90% and, therefore,
      is an appropriate diagnostic test for herd screening but not for diagnosing PPE
      on the individual level.

PMID- 12423043
TI  - Thermal valorisation of automobile shredder residue: injection in blast furnace.
AB  - Wastes with residual heating value, according to the trend of the world
      legislation, could be thermally reused. The present study is conducted to verify
      the possibility of thermal valorisation of a waste, denominated fluff, by
      injection in blast furnace. The fluff, arising from the automobile shredder
      operations, is a waste characterised by a high organic matrix and is potentially
      dangerous due to the heavy metals, oils filter and halogenated plastics content.
      The first step of the work is the chemical, physical and toxicological
      characterisation of this material. Then the fluff injection in a blast furnace
      tuyere is theoretically analysed with a mathematical model. Finally, experimental
      trials are conducted in a pilot plant, simulating the most important part of the
      blast furnace: the raceway, in order to analyse process and industrial aspects.
      In view of an industrial application a first economical evaluation is carried out
      on the basis of model and experimental results.

PMID- 12423044
TI  - Removal of cadmium ion by means of synthetic hydroxyapatite.
AB  - The reaction behaviour of synthetic hydroxyapatite [Ca10(PO4)6(OH)2] (HAP) toward
      cadmium ion was investigated for the Cd/Ca molar ratio in the range 1-0.005, by
      means of ions, pH measurements and XRD, SEM, IR techniques. The reaction
      behaviour between HAP and cadmium ion could be explained by a formation of an
      amorphous phase and/or a sorption mechanism.

PMID- 12423045
TI  - Use of municipal incinerator bottom ash as sintering promoter in industrial
      ceramics.
AB  - The use of glassy frits obtained from municipal incinerator bottom ash and glass
      cullet, as sintering promoters in the production process of porcelainized
      stoneware, was investigated. The emphasis was on studying the similarities and
      differences with respect to the standard body. The characterization involved the
      application of several techniques: chemical analysis, X-ray powder diffraction,
      linear shrinkage during firing, water absorption, bending strength and spot
      resistance test. The results show that, the addition of these glassy frits in the
      body improve the characteristics of water absorption and spot resistance which is
      related to the absence of surface porosity originated by the glassy phase.
      Moreover, addition of glassy frits to the porcelanized stoneware body does not
      change significantly its bending strength. In the firing conditions used there is
      a slight worsening in the tiles planarity, while there is a significant
      modification of the color, which becomes darker with respect to the base body.

PMID- 12423046
TI  - Inertization of hazardous dredging spoils.
AB  - Vitrification and production of ceramics materials starting from sediment
      excavated from Venice lagoon is described. This sediment is classified as toxic
      waste because contains several heavy metal ions and organic pollutants and was
      successfully vitrified at 1200-1350 degrees C. Twenty weight percentage of glass
      cullet, coming from a community glass recycling program, was added to the raw
      materials, previously calcined at 900 degrees C, as a way of adjusting the
      variations of composition of the individual sediment batches. Chemical durability
      (leaching) tests showed that the optimized glass compositions are inert, and thus
      not only volume reduction but also inertization of the waste was obtained by this
      process. Moreover, the economics of the entire process was analysed. The
      valorization of the waste was accomplished by the subsequent processing of the
      glass derived from the inertization. Glass ceramic materials were produced by
      viscous phase sintering of pressed glass powders which crystallized during the
      densification process. Sintered glass ceramic products had good mechanical
      characteristics (HV = 7.5 GPa, bending strength 150 +/- 8 MPa), making them
      suitable for applications in the building industry.

PMID- 12423047
TI  - Ni-MH spent batteries: a raw material to produce Ni-Co alloys.
AB  - Ni-MH spent batteries are heterogeneous and complex materials, so any kind of
      metallurgical recovery process needs a mechanical pre-treatment at least to
      separate irony materials and recyclable plastic materials (like ABS)
      respectively, in order to get additional profit from this saleable scrap, as well
      as minimize waste arising from the braking separation process. Pyrometallurgical
      processing is not suitable to treat Ni-MH batteries mainly because of Rare Earths
      losses in the slag. On the other hand, the hydrometallurgical method, that offers
      better opportunities in terms of recovery yield and higher purity of Ni, Co, and
      RE, requires several process steps as shown in technical literature. The main
      problems during leach liquor purification are the removal of elements such as Mn,
      Zn, Cd, dissolved during the leaching step, and the separation of Ni from Co. In
      the present work, the latter problem is overcome by co-deposition of a Ni-35/40%w
      Co alloy of good quality. The experiments carried out in a laboratory scale pilot
      plant show that a current efficiency higher than 91% can be reached in long
      duration electrowinning tests performed at 50 degrees C and 4.3 catholyte pH.

PMID- 12423048
TI  - The environmental fate of heavy metals arising from a MSW incineration plant.
AB  - Pollutant fluxes from municipal solid waste (MSW) incinerators are of a certain
      concern, especially gaseous emissions from the stack, which constitute the major
      effluent from the plant. In this work, heavy metals in soil and vegetation
      sampled in different sites around the plant are compared with those found in the
      gaseous emissions from an incinerator: the suspected source and environmental
      matrices are observed together, in order to detect a possible relationship of
      cause and effect, using statistical methods. The incinerator examined, regarding
      dimension and technology, can be considered a typical Italian one. Heavy metal
      concentrations in soil and vegetation show a clear dependence on sampling year;
      similar behaviour can be found in emission fluxes referring to the same years. A
      dependence on the distance from the incinerator is also apparent. This study
      supplies a methodological approach that can be easily extended and applied to
      other suspected contamination sources.

PMID- 12423049
TI  - Recovery of copper from contaminated soil by flushing.
AB  - In this work the development of a process for the recovery of copper from
      contaminated industrial soils is presented. Experimental tests on a standard soil
      contaminated with a solution of copper chloride were carried out. The metal was
      extracted from the contaminated soil by flushing with a 0.1 M aqueous solution of
      an ethylenediaminetetraacetic acid (EDTA) sodium salt. A maximum copper
      extraction efficiency of about 60% was observed. Copper was then separated from
      the extracted solution by precipitation with sodium hydroxide after addition of
      ferric sulfate.

PMID- 12423050
TI  - Utilisation of IGCC slag and clay steriles in soft mud bricks (by pressing) for
      use in building bricks manufacturing.
AB  - The subject of this study is the application to the construction of soft mud
      bricks (also known as pressed bricks), both green and heat-treated bodies, built
      from raw materials from Santa Cruz de Mudela, Ciudad Real, and IGCC slag from the
      power central of Puertollano (Ciudad Real, Spain). For this purpose, industrial
      level tests have been performed: the production of these kind of bricks from
      mixes of waste from ores of construction clays and to significant fraction of
      different ratios and clay granulometries mixed with IGCC slag. The results of
      this experimentation suggests that not only can IGCC slag be applied to a ceramic
      process, but also its use gives several advantages, as water and energy savings,
      as well as improvements on the final properties of products.

PMID- 12423051
TI  - Use of rubble from building demolition in mortars.
AB  - Because of increasing waste production and public concerns about the environment,
      it is desirable to recycle materials from building demolition. If suitably
      selected, ground, cleaned and sieved in appropriate industrial crushing plants,
      these materials can be profitably used in concrete. Nevertheless, the presence of
      masonry instead of concrete rubble is particularly detrimental to the mechanical
      performance and durability of recycled-aggregate concrete and the same negative
      effect is detectable when natural sand is replaced by fine recycled aggregate
      fraction. An alternative use of both masonry rubble and fine recycled material
      fraction could be in mortars. These could contain either recycled instead of
      natural sand or powder obtained by bricks crushing as partial cement
      substitution. In particular, attention is focused on the modification that takes
      place when either polypropylene or stainless steel fibers are added to these
      mortars. Polypropylene fibers are added in order to reduce shrinkage of mortars,
      stainless steel fibers for improving their flexural strength. The combined use of
      polypropylene fibers and fine recycled material from building demolition could
      allow the preparation of mortars showing good performance, in particular when
      coupled with bricks. Furthermore, the combined use of stainless steel fibers and
      mortars containing brick powder seems to be an effective way to guarantee a high
      flexural strength.

PMID- 12423052
TI  - Olive mill solid residues as heavy metal sorbent material: a preliminary study.
AB  - Biosorption of heavy metals is an innovative and alternative technology to remove
      these pollutants from aqueous solutions using inactive and dead biomasses such as
      agricultural and industrial wastes, algae and bacteria. In this study olive mill
      solid residue was used as heavy metal adsorbent material for its wide
      availability as agricultural waste and also for its cellulosic matrix, rich of
      potential metal binding active sites. Preliminary studies concerned with the
      removal of different heavy metals (Hg, Pb, Cu, Zn and Cd), the effect of pre
      treatments by water and n-hexane and the regeneration possibility. Olive mill
      solid residue resulted able to remove heavy metals from aqueous solutions with an
      affinity series reflecting the hydrolytic properties of the metallic ions, but
      also a particular affinity for copper. It can be supposed that biosorption
      phenomenon occur by a general ion exchange mechanism combined with a specific
      complexation reaction for copper ions. Water pre-treatment is sufficient to
      reduce COD release in the effluent according to the law limit, while n-hexane pre
      treatment strongly reduces also the adsorption properties of this material.
      Experimental isotherms obtained under different operating conditions were fitted
      using a non linear regression method for the estimation of the Langmuir
      parameters. Moreover a simple Scatchard plot analysis was performed for a
      preliminary investigation of the active sites, showing the presence of two
      different site affinities depending on the metal concentration, according to the
      previous hypothesis of two kinds of uptake mechanisms for copper biosorption.
      Regeneration tests gave good results in terms of yield of regeneration and also
      concentration ratios.

PMID- 12423053
TI  - Reuse of municipal solid wastes incineration fly ashes in concrete mixtures.
AB  - This study is aimed at assessing the feasibility of concrete production using
      stabilized m.s.w. (municipal solid waste) incineration fly ashes in addition to
      natural aggregates. The tested fly ashes were washed and milled, then stabilized
      by a cement-lime process and finally were reused as a "recycled aggregate" for
      cement mixture production, in substitution of a natural aggregate (with dosage of
      200-400 kg m(-3)). These mixtures, after curing, were characterized with
      conventional physical-mechanical tests (compression, traction, flexure, modulus
      of elasticity, shrinkage). In samples containing 200 kg(waste) m(-3)(concrete), a
      good compressive strength was achieved after 28 days of curing. Furthermore,
      concrete leaching behavior was evaluated by means of different leaching tests,
      both on milled and on monolithic samples. Experimental results showed a
      remarkable reduction of metal leaching in comparison with raw waste. In some
      cases, similar behavior was observed in "natural" concrete (produced with natural
      aggregates) and in "waste containing" concrete.

PMID- 12423054
TI  - Development of composite materials by mechanochemical treatment of post-consumer
      plastic waste.
AB  - Improvement of mechanical properties of recycled mixed plastic waste is one of
      the fundamental goals in any recycling process. However, polymer immiscibility
      makes the development of any effective reprocessing method difficult. In this
      work, a polymer milling process with liquid CO2 was applied to polymeric mixed
      waste, obtaining a powder material which was successfully utilized as a matrix
      for a new composite material. Developed materials have interesting mechanical
      properties and material performance can easily be improved. Investigations on
      selected mixtures of PP and PE clearly showed evidence of chemical
      compatibilization.

PMID- 12423055
TI  - Pyrolysis process for the treatment of scrap tyres: preliminary experimental
      results.
AB  - The aim of this work is the evaluation, on a pilot scale, of scrap tyre pyrolysis
      process performance and the characteristics of the products under different
      process parameters, such as temperature, residence time, pressure, etc. In this
      frame, a series of tests were carried out at varying process temperatures between
      550 and 680 degrees C, other parameters being equal. Pyrolysis plant process data
      are collected by an acquisition system; scrap tyre samples used for the
      treatment, solid and liquid by-products and produced syngas were analysed through
      both on-line monitoring (for gas) and laboratory analyses. Results show that
      process temperature, in the explored range, does not seem to seriously influence
      the volatilisation reaction yield, at least from a quantitative point of view,
      while it observably influences the distribution of the volatile fraction (liquid
      and gas) and by-products characteristics.

PMID- 12423056
TI  - Reuse of residues arising from lead batteries recycle: a feasibility study.
AB  - The performance of products arising from the stabilization/solidification of
      slags from lead batteries recycle into a Portland cement matrix has been
      evaluated not only in order to get a stabilized waste to be disposed of according
      to the current legislation, but also to obtain a recyclable material, with both
      economic and environmental benefits. Under this respect a detailed
      characterization of raw slags has been performed and different slag-cement
      samples have been prepared by varying the slag content. The parameters related to
      the cementation process have been evaluated and a series of tests on the final
      waste forms have been carried out, aimed at assessing both mechanical performance
      and leaching behaviour. In spite of the acceptable values for flexural,
      compressive and tensile strength, however, the high release of lead from the
      solidification products seems to be a limiting factor for a reusable material.
      While explanations of such phenomenon are given (high alkalinity of Portland
      cement; early "doping" of cementitious components by lead in the amorphous
      state), the main conclusion of the research work is that further efforts should
      be addressed to the adoption of a different or a modified incorporation matrix.

PMID- 12423057
TI  - Waste minimisation in a hard chromiun plating Small Medium Enterprise (SME).
AB  - The high potential of waste stream minimisation in the metal finishing sector
      justifies specific studies of Small and Medium Enterprises (SME). In this work,
      the minimisation options of the wastes generated in a hard chromium plating
      activity have been analysed. The study has been performed in a small job shop
      company, which works in batch mode with big pieces. A process flowsheet after
      connecting the unit operations and determining the process inputs (raw and
      secondary materials) and outputs (waste streams) has been carried out. The main
      properties, quantity and current management of the waste streams have been shown.
      The obvious lack of information has been identified and finally the waste
      minimisation options that could be adopted by the company have been recorded.

PMID- 12423058
TI  - Investigation of naphtalene sulfonate compounds sorption in a soil artificially
      contaminated using batch and column assays.
AB  - In the present work desorption tests of an artificially contaminated soil by
      naphatelene sulphonated compounds have been carried out by soil washing realised
      by water at different pH: Naphtalene-1,5-disulfonic acid (1-5 NDS), 2-naphthol
      6,8 disulphonic acid (G-acid) and sodium beta-naphtalene-sulphonate (beta-salt)
      have been selected as more representative organic compounds present in the ex
      industrial site of ACNA (Cengio, SV, Italy) in which very serious contamination
      levels of several pollutants are present both in the soils and surface waters.
      Equilibrium batch tests have been carried out in order to find the best operative
      condition in column washing tests. The obtained results can be considered very
      preliminary but useful to arrange a next experimental work that will be realised
      on real contaminated soils.

PMID- 12423059
TI  - Vitrification of electric arc furnace dusts.
AB  - Electric arc furnace baghouse dust (EAFD), a waste by-product of the steelmaking
      process, contains the elements that are volatilized from the charge during the
      melting (Cr, Pb, Zn, Cu and Cd). The results of leaching tests show that the
      concentration of these elements exceeds the regulatory limits. Consequently, EAFD
      cannot be disposed of in ordinary landfill sites without stabilization of the
      heavy metals. In this work, the vitrification of EAFD, from both carbon and
      stainless steel productions, were studied. The vitrification process was selected
      as the inertizing process because it permits the immobilization of the hazardous
      elements in the glass network and represents an environmentally acceptable method
      for the stabilization of this waste. Classes of various compositions were
      obtained by mixing EAFD with glass cullet and sand. The EAFD and the glass
      products were characterized by DTA, TG, X-ray analysis and by the TCLP test. The
      results show that the stability of the product is influenced by the glass
      structure, which mainly depends on the Si/O ratio. Secondary crystallization heat
      treatment were carried out on some samples. The results highlighted the formation
      of spinel phases, which reduced the chemical durability in acid media. The
      possibility to recover Zn from carbon steel production EAFD was investigated and
      about 60-70% of metal recovery was obtained. The resulting glass show higher
      chemical stability than glasses obtained without metal recovery.

PMID- 12423060
TI  - Treatment of industrial landfill leachate by means of evaporation and reverse
      osmosis.
AB  - In this paper a process for the treatment of landfill leachate involving
      evaporation and reverse osmosis was proposed. Experimental tests were performed
      on an industrial landfill leachate. The leachate was subjected to evaporation so
      as to obtain a distillate containing a small amount of organic material and a
      substantial amount of inorganic substances (consisting primarily of metals and
      ammonium salts). The distillate of the evaporation treatment was then subjected
      to reverse osmosis. The reverie osmosis tests were performed using two different
      membranes: the AD membrane (thin two-ply film of polyamide) and the SC membrane
      (thin three-ply film of polyamide). Tests carried out at different values of pH
      showed a reduction of organic content of about 88% when AD membranes were used
      and about 80% with SC membranes independently of pH. As regards ammonium,
      comparable reductions of over 97% were registered for both types of membrane in
      the optimal conditions of pH = 6.4 (97.1% for AD membranes and 97.7% for SC).

PMID- 12423061
TI  - Transfection efficiency and toxicity of polyethylenimine in differentiated Calu-3
      and nondifferentiated COS-1 cell cultures.
AB  - In the present study, we evaluated polyethylenimine (PEI) of different molecular
      weights (MWs) as a DNA complexing agent for its efficiency in transfecting
      nondifferentiated COS-1 (green monkey fibroblasts) and well-differentiated human
      submucosal airway epithelial cells (Calu-3). Studying the effect of particle
      size, zeta potential, presence of serum proteins or chloroquine, it appeared that
      transfection efficiency depends on the experimental conditions and not on the MW
      of the PEI used. Comparing transfection efficiencies in both cell lines, we found
      that PEI was 3 orders of magnitude more effective in COS-1 than in Calu-3 cells,
      because Calu-3 cells are differentiated and secrete mucins, which impose an
      additional barrier to gene delivery. Transfection efficiency was strongly
      correlated to PEI cytotoxicity. Also, some evidence for PEI-induced apoptosis in
      both cell lines was found. In conclusion, our results indicate that PEI is a
      useful vector for nonviral transfection in undifferentiated cell lines. However,
      results from studies in differentiated bronchial epithelial cells suggest that
      PEI has yet to be optimized for successful gene therapy of cystic fibrosis (CF).

PMID- 12423062
TI  - Aerosolization of lipoplexes using AERx Pulmonary Delivery System.
AB  - The lung represents an attractive target for delivering gene therapy to achieve
      local and potentially systemic delivery of gene products. The objective of this
      study was to evaluate the feasibility of the AERx Pulmonary Delivery System for
      delivering nonviral gene therapy formulations to the lung. We found that "naked"
      DNA undergoes degradation following aerosolization through the AERx nozzle
      system. However, DNA formulated with a molar excess of cationic lipids
      (lipoplexes) showed no loss of integrity. In addition, the lipoplexes showed no
      significant change in particle size, zeta (zeta) potential, or degree of
      complexation following extrusion. The data suggest that complexation with
      cationic lipids had a protective effect on the formulation following extrusion.
      In addition, there was no significant change in the potency of the formulation as
      determined by a transfection study in A-549 cells in culture. We also found that
      DNA formulations prepared in lactose were aerosolized poorly. Significant
      improvements in aerosolization efficiency were seen when electrolytes such as
      NaCl were added to the formulation. In conclusion, the data suggest that delivery
      of lipoplexes using the AERx Pulmonary Delivery System may be a viable approach
      for pulmonary gene therapy.

PMID- 12423064
TI  - Cloning and characterization of the rat multidrug resistance-associated protein
      1.
AB  - Multidrug resistance-associated protein 1 (MRP1) was originally shown to confer
      resistance of human tumor cells to a broad range of natural product anticancer
      drugs. MRP1 has also been shown to mediate efflux transport of glutathione and
      glucuronide conjugates of drugs and endogenous substrates. An ortholog of MRP1 in
      the mouse has been cloned and characterized. Significant functional differences
      between murine and human MRP1 have been noted. Since drug disposition and
      pharmacology studies often are conducted in rats, there is a need to clone and
      characterize the rat ortholog of MRP1. We isolated a rat MRP1 (rMRP1) cDNA from
      rat brain astrocytes, characterized its coding sequences, and verified the
      transport activity of the protein expressed in MRP1 cDNA-transfected Madin-Darby
      canine kidney (MDCK) cells. Our results showed that rMRP1 has a coding sequence
      of 4599 bp, which predicts a polypeptide of 1533 amino acids with an apparent
      molecular weight of 190 kd by Western immunoblot analysis. rMRP1-transfected MDCK
      cells are capable of efflux transport of a fluorescent MRP1 marker - calcein -
      that is inhibitable by known MRP1 inhibitors, indomethacin, and MK571. Sequence
      analysis indicates that rMRP1 is more closely related to mouse MRP1 than human
      MRP1.

PMID- 12423065
TI  - The effect of alkylpolyglycoside surfactants on the crystallization of spray
      dried salbutamol sulphate: a GravimetricNear-Infrared Spectroscopy Study.
AB  - This study monitored the effect of a series of structurally related surfactants
      on the crystallization of amorphous salbutamol sulphate. Amorphous salbutamol
      sulphate was prepared by spray drying from a solution in water and in the
      presence of various alkylpolyglycosides (APGs) at different concentrations. The
      particles were then analyzed using isothermal microcalorimetry and water vapor
      sorption (Dynamic Vapour Sorption, DVS) analysis combined with near-infrared
      spectroscopy (DVS-NIR). Both isothermal microcalorimetry and DVS-NIR were able to
      detect the transition from the amorphous to the crystalline state. The presence
      of APG surfactants modified the shape of the crystallization peak obtained using
      isothermal microcalorimetry. The gravimetric study combined with NIR revealed
      that while the crystallization was similar for the particles with or without
      surfactant, there was a great difference in the release of water from the newly
      formed crystal. In the presence of some of the surfactants tested, salbutamol
      sulphate released the water much faster than in the absence of surfactant. These
      results helped to explain the differences found in the isothermal
      microcalorimeter data. Differences were observed in the shapes of the NIR water
      peaks related to water due to the presence of the surfactant. In conclusion, the
      use of DVS combined with NIR has helped to analyze and understand the effect of
      APGs on the crystallization of amorphous salbutamol sulphate.

PMID- 12423063
TI  - Role of MRP4 and MRP5 in biology and chemotherapy.
AB  - Nucleotide efflux (especially cyclic nucleotides) from a variety of mammalian
      tissues, bacteria, and lower eukaryotes has been studied for several decades.
      However, the molecular identity of these nucleotide efflux transporters remained
      elusive, despite extensive knowledge of their kinetic properties and inhibitor
      profiles. Identification of the subfamily of adenosine triphosphate (ATP) binding
      cassette transporters, multidrug resistance protein (MRP) subfamily, permitted
      rapid advances because some recently identified MRP family members transport
      modified nucleotide analogs (ie, chemotherapeutic agents). We first identified,
      MRP4, based on its ability to efflux antiretroviral compounds, such as
      azidothymidine monophosphate (AZT-MP) and 9-(2-phosphonyl methoxyethyl) adenine
      (PMEA), in drug-resistant and also in transfected cell lines. MRP5, a close
      structural homologue of MRP4 also transported PMEA. MRP4 and MRP5 confer
      resistance to cytotoxic thiopurine nucleotides, and we demonstrate MRP4
      expression varies among acute lymphoblastic leukemias, suggesting this as a
      factor in response to chemotherapy with these agents. The ability of MRP4 and
      MRP5 to transport 3',5'-cyclic adenosine monophosphate (cAMP) and 3',5'-cyclic
      guanosine monophosphate (cGMP) suggests they may play a biological role in
      cellular signaling by these nucleotides. Finally, we propose that MRP4 may also
      play a role in hepatic bile acid homeostasis because loss of the main bile acid
      efflux transporter, sister of P-glycoprotein (SPGP) aka bile-salt export pump
      (BSEP), leads to a strong compensatory upregulation in MRP4 expression.
      Cumulatively, these studies reveal that the ATP-binding cassette (ABC)
      transporters MRP4 and MRP5 have a unique role in biology and in chemotherapeutic
      response.

PMID- 12423066
TI  - Comparison of the formulation requirements of dosator and dosing disc automatic
      capsule filling machines.
AB  - The overall objective of this study was to provide 'semi-quantitative' or
      'rigorous' definitions of the fluidity, lubricity and compactibility requirements
      of formulation for representative dosator and dosing disc capsule filling
      machines. To that end, model formulations were developed for those properties
      using Carr's compressibility index, ejection force, and plug breaking force at a
      specified compression force to gauge fluidity, lubricity, and compactibility,
      respectively. These formulations were each encapsulated on an Hofliger-Karg GKF
      400 dosing disc machine and a Zanasi LZ-64 dosator machine. Each machine was
      instrumented to measure plug compression and ejection forces. The encapsulation
      process was evaluated for %CV of fill-weight, ejection force, plug breaking force
      and the dissolution of marker drugs incorporated in the formulations. The f2
      metric was used to compare dissolution profiles. The results suggest: (1)
      formulations should meet different flow criteria for successful encapsulation on
      the two machines, (2) a relatively lower level of lubricant may be sufficient for
      the dosing disc machine, (3) a higher degree of formulation compactibility is
      needed for the dosator machine, and (4) transferring formulations between these
      machine types (same class, different subclass per FDA's SUPAC-IR/MR Manufacturing
      Equipment Addendum) could be challenging. In certain cases dissolution profiles
      for the same formulation filled on the two machines with equivalent compression
      force were different based on f2 < 50. Overall, the results of this study suggest
      a range of formulation characteristics appropriate for transferring formulations
      between these two types of machines.

PMID- 12423068
TI  - Thymidine 3',5'-diphosphoric acid derived cations and radicals: ab initio study.
AB  - The relative stabilities of thymidine-3',5'-diphosphoric acid (1) derived
      isomeric cations and radicals were calculated and key geometric parameters were
      thoroughly analyzed. The most probable sites of a hydride-ion (1', 2', 5-Me) and
      H-atom (4', 5', 5-Me) abstraction were identified, thus allowing prediction of
      the regioselectivity of potential damage to the deoxyribose ring and thymine
      moiety caused by carcinogenic agents of electrophilic and radical nature.
      [structure: see text]

PMID- 12423067
TI  - Model system to study classical nuclear export signals.
AB  - Signal-mediated protein transport through the nuclear pore complex is of
      considerable interest in the field of molecular pharmaceutics. Nuclear
      localization signals can be used to target genes/antisense delivery systems to
      the nucleus. Studying nuclear export is useful in enhancing the expression and
      the efficiency of action of these therapeutic agents. The mechanism of nuclear
      import has been well studied and most of the proteins participating in this
      mechanism have been identified. The subject of nuclear export is still in the
      initial stages, and there is a considerable amount of uncertainty in this area.
      Two main export receptors identified so far are Exportin 1 (Crm1) and
      Calreticulin. Crm1 recognizes certain leucine-rich amino acid sequences in the
      proteins it exports called classical nuclear export signals. This paper describes
      a model system to study, identify, and establish these classical nuclear export
      signals using green fluorescent protein (GFP). Two putative export signals in the
      human progesterone receptor (PR) and the strongest nuclear export signal known
      (from mitogen activated protein kinase kinase [MAPKK]) were studied using this
      model system.

PMID- 12423069
TI  - A chiral A2 B2 macrocyclic minireceptor with extreme enantioselectivity.
AB  - We describe a novel macrocyclic minireceptor that is assembled from a chiral 1,2
      diamine and 5-allyloxyisophthalic acid. After immobilization on HPLC silica, the
      chiral macrocycle preferentially binds the L-enantiomers of simple amino acid
      derivatives, with enantioselectivities values up to 3.0 kcal/mol. [structure: see
      text]

PMID- 12423070
TI  - The Synthesis of L-aminosugar and the studies of L-pyranoses on the ring III of
      pyranmycins.
AB  - The synthesis of a novel class of aminoglycoside, pyranmycin, and a convenient
      method for the preparation of 6-amino-L-idopyranosides were reported. One of the
      members in the reported pyranmycin families, TC010, has prominent activity
      against Escherichia coli, Staphylococcus aureus, and Bacillus megaterium. We also
      discovered that the (4)C(1) chair conformation on ring III of pyranmycin is
      essential for the antibacterial activity. [reaction: see text]

PMID- 12423071
TI  - Photoinduced electron transfer between non-native donor-acceptor moieties
      incorporated in synthetic polypeptide aggregates.
AB  - A series of analogous photoactive polypeptides that form helical homo and hetero
      aggregates in aqueous media were prepared. A pyrenyl ketone (the principal
      chromophore and an electron acceptor) was attached to the N-termini. An electron
      donor, amidoethylcarbazole, was introduced as a side chain of a non-native amino
      acid, NCb, 14 residues away. Photoinduced electron-transfer rate constants of the
      order of 10(8) s(-1) between remote pyrene and carbazole were measured.
      [structure: see text]

PMID- 12423072
TI  - Soluble alpha-amino acid salts in acetonitrile: practical technology for the
      production of some dipeptides.
AB  - Alpha-amino acids are soluble in acetonitrile when treated with phosphazene
      bases. As a result, the protection/deprotection events that are usually required
      for peptide coupling reactions can be minimized. This is illustrated in the
      synthesis of the important angiotensin-converting enzyme (ACE) inhibitor
      enalapril. [reaction: see text]

PMID- 12423073
TI  - Preparation of homoallylic alcohols by nickel-catalyzed cyclizations of allenyl
      aldehydes.
AB  - The direct cyclization of allenyl aldehydes with organozincs in the presence of
      Ni(COD)(2) provides synthetically versatile homoallylic alcohols. Both
      monosubstituted and 1,3-disubstituted allenes participate in the process, with
      the latter allowing preparation of stereochemically defined trisubstituted
      alkenes. [reaction: see text]

PMID- 12423074
TI  - Continuous solid-phase synthesis and disulfide cyclization of peptide-PNA-peptide
      chimeras.
AB  - Chelator peptides were extended from the N-terminus of peptide nucleic acid (PNA)
      dodecamers, which in turn were extended from the N-termini of disulfide-bridged
      peptide ligand analogues, using Fmoc coupling for all residues. The cysteine
      thiols were cyclized on a solid support, either before or after PNA extension.
      This simplified synthetic approach might allow preparation of a variety of
      multipeptide disulfide-bridged PNA chimeras. [structure: see text]

PMID- 12423075
TI  - Synthetic applications of azolium ylides to a traceless solid-phase synthesis of
      2-substituted azoles.
AB  - A new approach for the preparation of 2-substituted azole libraries using a
      polystyrene-carbamyl chloride resin in a traceless fashion is described. Azole
      substrates II are assembled in a one-pot condensation reaction of azoles and
      aldehydes with a resin-bound carbamyl chloride. Treatment of the azolyl-carbamate
      II with boron trifluoride etherate under thermal or microwave-assisted solvolysis
      conditions afforded 2-substituted azoles. [reaction: see text]

PMID- 12423076
TI  - Synthesis of chiral (alpha,alpha-difluoroalkyl)phosphonate analogues of
      (lyso)phosphatidic acid via hydrolytic kinetic resolution.
AB  - The hydrolytic kinetic resolution of 1,1-difluoro-3,4-epoxy-butylphosphonate
      using a chiral salen-Co complex was employed as a key step to obtain enantiomeric
      diols in 99% ee as key intermediates. The enantiomerically homogeneous
      (alpha,alpha-difluoroalkyl)phosphonates were obtained after selective
      esterification and deprotection of the corresponding phosphonates. These
      compounds are novel phosphatase-resistant analogues of lysophosphatidic acid and
      phosphatidic acid. [reaction: see text]

PMID- 12423077
TI  - First application of tunable alkyl or aryl sulfinamides to the stereoselective
      synthesis of a chiral amine: asymmetric synthesis of (R)-didesmethylsibutramine
      ((R)-DDMS) using (R)-triethylmethylsulfinamide ((R)-TESA).
AB  - A highly diastereoselective addition of i-BuLi to a triethylmethylsulfinamide
      derived aldimine was used as the key step in the first asymmetric synthesis of
      (R)-didesmethylsibutramine, a metabolite of sibutramine for the potential
      treatment of CNS disorders. [reaction: see text]

PMID- 12423078
TI  - Stereoselective bromination-suzuki cross-coupling of dehydroamino acids to form
      novel reverse-turn peptidomimetics: substituted unsaturated and saturated
      indolizidinone amino acids.
AB  - A general and efficient methodology has been developed to prepare the C4
      substituted dipeptide reverse-turn mimetics unsaturated (9a, 10a) and saturated
      (11a) azabicyclo[4.3.0] alkane amino acid derivatives. The side chain was
      introduced by bromination of dehydroamino acid intermediates followed by Suzuki
      coupling. Hydrogenation of the bicyclic dehydroamino acid 9a afforded saturated
      bicyclic lactam 11a. This approach can be further explored for the synthesis of a
      variety of such beta-turn mimetics with aryl and alkyl side chain
      functionalities. [reaction: see text]

PMID- 12423079
TI  - A versatile linkage strategy for solid-phase synthesis of N,N-dimethyltryptamines
      and beta-carbolines.
AB  - Various tryptamines are captured by a vinylsulfonylmethyl polystyrene resin,
      generating a safety-catch linkage. Beta-carbolines can be formed from 4 by a
      Pictet-Spengler reaction with the introduction of R(1). Tryptamine 4 can also be
      derivatized by acylation or copper-mediated coupling to introduce R(2). If X =
      Br, Suzuki coupling can be used to introduce R(3). After derivatization, the
      indole derivatives are activated with methyl iodide and released under mild basic
      condition. [reaction: see text]

PMID- 12423080
TI  - Asymmetric synthesis of chiral alpha-ferrocenylalkylamines and their use in the
      preparation of chiral redox-active receptors.
AB  - A new strategy for the asymmetric synthesis of chiral primary alpha
      ferrocenylalkylamines has been utilized to generate homochiral redox-active
      receptors that bind chiral carboxylate anions with moderate enantioselectivity
      and undergo a redox response to complexation. [structure: see text]

PMID- 12423081
TI  - Peptide-small molecule hybrids via orthogonal deprotection-chemoselective
      conjugation to cysteine-anchored scaffolds. A model study.
AB  - The feasibility of an orthogonal deprotection-conjugation protocol, holding the
      promise of libraries of functionally diverse chemical probes attached to cysteine
      anchored peptide scaffolds, has been explored with a model system. The necessary
      tools for assembly of the hybrid libraries have been prepared and the tandem
      procedure optimized. S-alkylation and S-sulfenylation are featured as the
      chemoselective ligation reactions. [reaction: see text]

PMID- 12423082
TI  - Copper(I) hydride-catalyzed asymmetric hydrosilylation of heteroaromatic ketones.
AB  - In situ generation of CuH ligated by Takasago's new nonracemic ligand, DTBM
      SEGPHOS, leads to an especially reactive reagent capable of effecting asymmetric
      hydrosilylation of heteroaromatic (H) ketones under very mild conditions. PMHS
      serves as an inexpensive source of hydride. Substrate-to-ligand ratios on the
      order of 2000:1 are employed. [reaction: see text]

PMID- 12423083
TI  - Isomerism of bis(7-azaindolyl)methane.
AB  - Three isomers of bis(7-azaindolyl)methane have been synthesized and fully
      characterized. Isomers 1 and 2 contain 7-azaindolyl groups that are bound to the
      CH(2) group through nitrogen atoms. However, 1 contains two "normal" 7-azaindolyl
      groups, whereas 2 contains both a normal 7-azaindolyl group and a tautomer form
      of 7-azaindolyl. The third isomer 4 contains two 7-azaindolyl groups that are
      bound to the CH(2) group through the carbon atom at the position-3. These three
      isomers show distinct absorption and emission spectra, attributable to the
      different forms of 7-azaindolyl groups in the isomers, as indicated by the
      results of ab initio calculations. [structure: see text]

PMID- 12423084
TI  - Well-defined, air-stable (NHC)Pd(Allyl)Cl (NHC = N-heterocyclic carbene)
      catalysts for the arylation of ketones.
AB  - A number of palladium-N-heterocyclic carbene (NHC) complexes were found to be
      active catalysts for the arylation of ketones. A large number of substrates, both
      aryl halides and ketones, are compatible with the reaction conditions. The ketone
      arylation reactions are achieved with low catalyst loading in short reaction
      times using aryl chlorides and triflates as reactive partners. [reaction: see
      text]

PMID- 12423085
TI  - Microwave-assisted solid-phase synthesis of peptoids.
AB  - Microwave irradiation reduces the reaction time for the solid-phase synthesis of
      peptoids. Under these conditions, coupling of each residue requires only 1 min.
      The purity and yields of peptoids synthesized in this way are as good as or
      better than those achieved using standard methods. [reaction: see text]

PMID- 12423086
TI  - Palladium-catalyzed reaction of acylzirconocene chloride and stereoselective
      formation of bicyclo[3.3.0] compounds.
AB  - The acylzirconocene chloride complex as an acyl group donor reacts with omega
      unsaturated alpha,beta-enones and -ynones under Pd-Me(2)Zn(Me(2)AlCl)-catalyzed
      conditions to give stereoselectively bicyclo[3.3.0] compounds through (i)
      formation of a Pd(II) intermediate by an oxidative addition of the Pd(0) catalyst
      to an enone function, (ii) cyclization of the Pd intermediate to an omega
      unsaturated group, (iii) an acyl group transfer from zirconium to Pd metal, (iv)
      reductive elimination of the Pd metal, and (v) intramolecular cis-selective aldol
      reaction. [reaction: see text]

PMID- 12423087
TI  - Regioselectivity of ring closure of 2-thia- and 2-sulfonyl-5-methyl-5-hexenyl
      radicals.
AB  - Ring closure of the alpha-substituted radicals 4 (X = S, SO(2)) is observed to be
      irreversible and to lead to significant amounts of the product of 6-endo
      cyclization. Indeed, reduction of the sulfonyl-based radical 4 (X = SO(2)), in
      which regioselectivity is believed to be controlled by a combination of both
      steric and FMO interactions, is found to provide an excellent route to the cyclic
      sulfone 7 (X = SO(2)) in high yield. [reaction: see text]

PMID- 12423088
TI  - A new paradigm for cationic cyclization of iron tricarbonyl diene complexes with
      pendant alkenes and arenes.
AB  - A new example of stereospecific cationic cyclization of iron tricarbonyl diene
      complexes with pendant alkenes and arenes is provided. Protonation of a double
      bond vicinal to the iron tricarbonyl diene moiety is employed to trigger the
      cyclization, rather than the previously reported Lewis/protic acid
      dehydroxylation of diastereomeric alcohols, eliminating one step of separation
      and avoiding some reactivity problems previously encountered for one of the
      alcohol diastereoisomers. [reaction: see text]

PMID- 12423089
TI  - Synthesis of amino- and guanidino-G-clamp PNA monomers.
AB  - Syntheses of the protected amino- and guanidino-G-clamp PNA monomers, 9a and 9b,
      respectively, have been accomplished in eight steps from 5-bromouracil. Enhanced
      stacking interactions and additional hydrogen bonds with guanine should increase
      the affinity of PNAs incorporating these cytosine analogues for their
      complementary strands. [reaction: see text]

PMID- 12423090
TI  - Catalytic diastereoselective Pauson-Khand reaction: an efficient route to
      enantiopure cyclopenta[c]proline derivatives.
AB  - Cyclopenta[c]proline derivatives were synthesized in a stereocontrolled manner
      and in good yields via catalytic Pauson-Khand reactions. The starting materials,
      optically pure enyne amino acid derivatives, can be easily prepared by an
      alkenylboronic acid-mediated Mannich-type reaction. [reaction: see text]

PMID- 12423091
TI  - On the introduction of a trifluoromethyl substituent in the epothilone setting:
      chemical issues related to ring forming olefin metathesis and earliest biological
      findings.
AB  - The disclosure herein describes the synthesis of 10,11-dehydro-13,14-desoxy-27
      trifluoro-[17]epothilone B via a stereoselective ring-closing metathesis and
      provides early biological evaluation data pertinent to this compound. [reaction:
      see text]

PMID- 12423092
TI  - Diterpenoids from cultured Erythropodium caribaeorum.
AB  - The known antimitotic agent eleutherobin and the briarane diterpenoids
      erythrolides A and B have been isolated from cultured specimens of Erythropodium
      caribaeorum in amounts comparable to those reported from wild-harvested reef
      animals. The novel diterpenoid aquariolide A, having an unprecedented highly
      rearranged carbon skeleton (named aquariane), has also been found. The aquariane
      skeleton can be formally derived from the briarane skeleton by sequential di-pi
      methane and vinyl-cyclopropane rearrangements. [structure: see text]

PMID- 12423093
TI  - Caminoside A, an antimicrobial glycolipid isolated from the marine sponge Caminus
      sphaeroconia.
AB  - Extracts of the marine sponge Caminus sphaeroconia showed potent activity in a
      screen for bacterial type III secretion inhibitors. Bioassay guided fractionation
      of the extract led to the isolation of the novel antimicrobial glycolipid
      caminoside A (1). The structure of caminoside A was elucidated by analysis of
      spectroscopic data and chemical degradation.[structure: see text]

PMID- 12423094
TI  - A new practical one-pot access to sulfonimidates.
AB  - Sulfonimidates were prepared from sulfinamides and iodosobenzene in a very mild
      one-pot procedure in good to excellent yields. This reaction allows quick and
      efficient access to a class of molecules of important synthetic as well as
      biological and industrial interest. [reaction: see text]

PMID- 12423095
TI  - Pinacol coupling reaction of beta-halo-alpha,beta-unsaturated aldehydes promoted
      by TiI4.
AB  - The pinacol reaction of beta-halogenated alpha,beta-unsaturated aldehydes was
      promoted by titanium tetraiodide to give coupling products in good yields with
      high dl-selectivity. Subsequent reduction with H(2)/Pd-C gave saturated vic-diols
      in good yields. Heck coupling reaction enabled the displacement of halogens with
      vinyl groups without the loss of stereochemical integrities. [reaction: see text]

PMID- 12423096
TI  - Molybdenum-mediated cleavage reactions of isoxazoline rings fused in bicyclic
      frameworks.
AB  - The molybdenum-mediated cleavage reactions of isoxazoline rings fused in bicyclic
      frameworks were investigated. A tandem N-O bond cleavage-retro aldol reaction of
      an isoxazoline ring fused in a bicyclic framework led to the cleavage of the
      bicyclic framework. These reactions provide a novel stereoselective synthesis of
      substituted cyclopentene rings, cyclopentane rings, and attached-ring systems.
      [reaction: see text]

PMID- 12423097
TI  - Silicon tether-aided coupling metathesis: application to the synthesis of attenol
      A.
AB  - A new synthesis of attenol A is described. Key features of this work include a
      crucial silicon tether-aided coupling metathesis step and the use of
      iodoetherification as an efficient protection method for 1,5-ene-ols. [reaction:
      see text]

PMID- 12423098
TI  - Borane-ammonia complexes stabilized by hydrogen bonding.
AB  - Novel boron-ammonia complexes, wherein an NH(3) molecule is tightly bound through
      all four of its atoms, have been prepared and studied. The solid-state structure
      of ortho MOM-phenyllithium is reported. [reaction: see text]

PMID- 12423099
TI  - Synthesis and spectroscopic properties of the elusive 3a,9a-diazaperylenium
      dication.
AB  - The 3a,9a-diazaperylenium dication (1) was synthesized for the first time in two
      steps from p-phenylene diamine. Ab initio calculations show a twisted ground
      state with a 6.4 degrees tilt between the two quinolizinium building blocks.
      Dication 1 is photoluminescent in fluid solutions of H(2)O, CH(3)CN, and
      CH(3)NO(2), but not in rigid matrices of the same solvents. This phenomenon has
      been attributed to a geometric relaxation of the tilted ground state into an
      emitting planar lowest singlet excited state. [structure: see text]

PMID- 12423100
TI  - Radical cation and dication of fluorene fully annelated with bicyclo[2.2.2]octene
      units: importance of the quinoidal resonance structure in the cationic fluorene.
AB  - Fluorene 1 fully annelated with bicyclo[2.2.2]octene units was newly synthesized
      and oxidized to stable cationic species. The structure of radical cation salt
      1(.+)SbCl(6)(-) was determined by X-ray crystallography, while the first fluorene
      dication 1(2+) was characterized by (1)H and (13)C NMR at -80 degrees C. Combined
      with the results of theoretical calculations, an important contribution of a
      quinoidal structure to the resonance hybrid was demonstrated in both 1(.+) and
      1(2+). [structure: see text]

PMID- 12423101
TI  - Carbanion stabilization by distal silyloxy groups. Origin of the high
      diastereoselectivity in the formation of quaternary centers with aryllead(IV)
      triacetate reagents.
AB  - Derivatives of methyl 5-hydroxy-2-oxo-1-cyclohexanecarboxylate react with
      aryllead(IV) reagents in high yield and with wide variation in
      diastereoselectivity. Ab initio calculations are consistent with a heretofore
      unrecognized attraction between the carbanionic center of the beta-ketoester
      intermediate and the distal OSiR(3) group. This attractive interaction stabilizes
      the silyl group in the axial conformation and leads to the excellent trans
      diastereoselection in the formation of quaternary centers. [reaction: see text]

PMID- 12423102
TI  - Basic and reductive sulfone-directed ring-opening reactions of difluorinated
      oxa[2.2.1]bicycloheptanes.
AB  - Phenylsulfenyl chloride reacts with racemic endo Diels-Alder adduct 4 (DEC =
      CONEt(2)) to afford lactone 8, which can be reduced and protected in a series of
      high-yielding steps. Key sulfone 10 can be ring opened under strong base
      conditions to afford vinyl sulfone 11. Attempted desulfonation resulted in the
      formation of a monofluoroalkene, but a direct desulfonation/eliminative ring
      opening with strain relief delivered highly functionalized monocyclic species 16.
      [reaction: see text]

PMID- 12423103
TI  - Amino acid-based dithiazines: synthesis and photofragmentation of their
      benzaldehyde adducts.
AB  - Alpha-amino acids and GABA are functionalized with dithiazine rings via reaction
      with sodium hydrosulfide in aqueous formaldehyde. The resulting dithiazines are
      lithiated at -78 degrees C and reacted with benzaldehyde furnishing amino acid
      based 2,5-bis-substituted dithiazines. These adducts undergo externally
      sensitized photofragmentation with quantum efficiency comparable to that of the
      parent dithiane adducts, thus offering a novel approach to amino acid-based
      photolabile tethers. [reaction: see text]

PMID- 12423104
TI  - A concise and regioselective synthesis of 1-alkyl-4-imidazolecarboxylates.
AB  - Reaction between ethyl 3-N,N-(dimethylamino)-2-isocyanoacrylate (1) and a primary
      amine (2) regioselectively affords 1-alkyl-4-imidazolecarboxylates (3) in good
      yields (52-89%). The method is applicable to unhindered and hindered amine
      substrates, as well as those containing reactive functionality such as alcohols
      and secondary and tertiary amines. [reaction: see text]

PMID- 12423106
TI  - Enantioselective reduction of trifluoromethyl ketones with chiral organomagnesium
      amides (COMAs).
AB  - Chiral organomagnesium amides (COMAs), readily prepared from dialkylmagnesiums
      and chiral secondary amines, can reduce trifluoromethyl ketones to form secondary
      alcohols with excellent enantioselectivities (up to 98:2 er) and chemical yields
      (typically >95% conversion, >85% isolated yields). These MPV-type reductions use
      an achiral hydride source, and the chiral amine is readily recovered. [reaction:
      see text]

PMID- 12423105
TI  - A novel sequential aminodiene Diels-Alder strategy for the rapid construction of
      substituted analogues of Kornfeld's ketone.
AB  - Through a novel sequence of aminodiene Diels-Alder reactions, amidofurans 18a-c
      were converted to tricyclic ketones 21a-c in moderate to good yields. Ketone 21a
      could be converted to Uhle's ketone (6) by cleaving the tert-butyl carbamate and
      oxidatively removing the methyl ester. Tricycle 21a readily underwent bromination
      to give 22. Formation of the corresponding enol triflate 25 followed by
      carbonylation gave ester 27, which was then coupled with N-methyl propriolamide
      to furnish 26. [reaction: see text]

PMID- 12423107
TI  - Highly enantioselective phenylacetylene additions to both aliphatic and aromatic
      aldehydes.
AB  - The readily available and inexpensive BINOL in combination with Ti(O(i)Pr)(4) is
      found to catalyze the reaction of an alkynylzinc reagent with various types of
      aldehydes including aliphatic aldehydes, aromatic aldehydes, and other alpha,beta
      unsaturated aldehydes to generate chiral propargyl alcohols with 91-99% ee at
      room temperature. No previous chiral catalysts have exhibited such a broad scope
      of enantioselectivity with respect to the type of aldehydes for this reaction.
      [reaction: see text]

PMID- 12423108
TI  - Tandem copper-catalyzed enantioselective allylation-metathesis.
AB  - Grignard reagents undergo enantioselective (up to 86% ee) copper-catalyzed S(N)2'
      substitution on achiral allylic chlorides. The reaction is wide in scope for both
      the Grignard reagent and the allylic substrate. The resulting terminal alkene
      could be submitted to intra- or intermolecular metathesis to afford new chiral
      synthons. The experimental conditions are compatible with a one-pot overall
      substitution-metathesis procedure without loss of enantioselectivity. [reaction:
      see text]

PMID- 12423109
TI  - A novel stereocontrolled synthesis of cis-fused bicyclic lactams via [3 + 2]
      cycloaddition of alkynyltungsten complexes with tethered aziridines.
AB  - Treatment of alkynyltungsten complexes with tethered aziridines in the presence
      of BF(3).Et(2)O led to [3 + 2]-cycloaddition reactions, affording bicyclic
      tungsten-enamine species stereoselectively. The stereochemistry of the resulting
      product reveals that ring opening of aziridine is initiated by S(N)2 attack of
      the tungsten fragment. Decomplexation of these organometallics with I(2) in
      CH(2)Cl(2), followed by hydrolysis, afforded only cis-fused bicyclic lactams
      efficiently. [reaction: see text]

PMID- 12423110
TI  - Protein-cleaving catalyst selective for protein substrate.
AB  - A protein-cleaving catalyst specific for a disease-related protein can be used as
      a catalytic drug. As the first protein-cleaving catalyst selective for a protein
      substrate, a catalyst for myoglobin was designed by attaching Cu(II) or Co(III)
      complex of cyclen to a binding site searched by a combinatorial method using
      peptide nucleic acid monomers as building units. [reaction: see text]

PMID- 12423111
TI  - Highly efficient synthesis of chiral beta-amino acid derivatives via asymmetric
      hydrogenation.
AB  - The Rh-TangPhos complex is an efficient hydrogenation catalyst for making chiral
      beta-amino acid derivatives. With the Rh-TangPhos system, high
      enantioselectivities (up to 99.6%) and turnover numbers have been obtained in the
      hydrogenation of E/Z isomeric mixtures of both beta-alkyl and beta-aryl beta
      (acylamino)acrylates. [reaction: see text]

PMID- 12423112
TI  - Intramolecular anti-hydrosilylation and silicon-assisted cross-coupling: highly
      regio- and stereoselective synthesis of trisubstituted homoallylic alcohols.
AB  - A highly regio- and stereoselective anti-intramolecular hydrosilylation of
      alkynyl silyl ethers catalyzed by a ruthenium arene complex has been developed.
      The resultant (Z)-alkylidenesilacyclopentanes are efficiently coupled with aryl
      or alkenyl halides in the presence of tetrabutylammonium fluoride and a
      palladium(0) catalyst. The yields are generally good, and the reaction is
      compatible with a wide range of functional groups. The overall transformation
      achieves the stereoselective conversion of homopropargyl alcohols to
      trisubstituted homoallylic alcohols. [reaction: see text]

PMID- 12423113
TI  - A facile ligation approach to prepare three-helix bundles of HIV fusion-state
      protein mimetics.
AB  - We have designed a facile ligation approach to prepare three-helix bundles
      mimicking the HIV membrane fusion-state proteins that may be useful as inhibitors
      and vaccine candidates for blocking HIV infection. [reaction: see text]

PMID- 12423115
TI  - Fluorous dimethyl sulfide: a convenient, odorless, recyclable borane carrier.
AB  - Borane gas and 2-(perfluorooctyl)ethyl methyl sulfide form a solid comprised of
      an approximately 1:1 mixture (fluorous BMS) of sulfide and the corresponding
      sulfide-borane. Fluorous BMS permits hydroboration of alkenes in a
      dichloromethane/perfluorinated hydrocarbon mixture with subsequent recycling of
      the fluorous sulfide by fluorous extraction. The use of fluorous BMS in the
      asymmetric reduction of ketones catalyzed by a chiral oxaborolidine catalyst, and
      in the reduction of other functional groups, is also reported. [reaction: see
      text]

PMID- 12423114
TI  - Solid-phase, Pd-catalyzed silicon-aryl carbon bond formation. Synthesis of
      sansalvamide A peptide.
AB  - A palladium-catalyzed silicon-aryl carbon bond formation on solid-phase is
      reported. A phenylalanine silane resin was prepared directly from protected iodo
      substituted phenylalanine with butyl diethylsilane polystyrene in one step. A
      rapid and high-yield solid-phase synthesis of sansalvamide A peptide was achieved
      from the phenylalanine silane resin. [reaction: see text]

PMID- 12423116
TI  - Ligand-modulated palladium oxidation catalysis: mechanistic insights into aerobic
      alcohol oxidation with the Pd(OAc)(2)/pyridine catalyst system.
AB  - Pd(OAc)(2):pyridine (1:4) is an efficient catalyst system for the oxidation of
      alcohols with molecular oxygen. A mechanistic study of this reaction reveals that
      pyridine promotes the aerobic oxidation of palladium(0) but inhibits the
      oxidation of alcohol by palladium(II). Kinetic results reveal that turnover
      limiting substrate oxidation consists of (i) formation of a palladium(II)
      alkoxide, (ii) pyridine dissociation, and (iii) beta-hydride elimination. These
      results provide a framework for the design and/or screening of more effective
      aerobic oxidation catalysts.

PMID- 12423119
TI  - Total syntheses of demethylasterriquinone B1, an orally active insulin mimetic,
      and demethylasterriquinone A1.
AB  - Two total syntheses of the unsymmetrical bis-indolylquinone natural product
      demethylasterriquinone B1 (also known as L-783,281) have been accomplished. The
      first exploits a known base-promoted condensation of indoles with bromanil, which
      stops at monoaddition using the sterically hindered 2-isoprenylindole. This
      permits addition of the second indole, 7-prenylindole, which gives both meta- and
      para-substituted bis-indolylquinone products. This regiochemical control problem
      was solved by extension of a method we recently developed for acid-promoted
      addition of indoles to 2,5-dichlorobenzoquinone. Under our original mineral acid
      conditions, reaction of 2-isoprenylindole with dichlorobenzoquinone fails, but it
      succeeds with 3-bromo-2,5-dichlorobenzoquinone using acetic acid as the promoter.
      The regiochemistry established in such selectively bromine-substituted quinones
      can be exploited in Stille couplings. As a model system, the synthesis of
      demethylasterriquinone A1 was accomplished using as the key step a Stille
      coupling of a 2,5-dibromobenzoquinone with an (N-isoprenylindol-3-yl)tin,
      producing the para-substituted bis-indolylquinone exclusively. Use of a (7
      prenylindole)tin in coupling with a bromo-2,5-dichloro-4-indolylbenzoquinone
      gives the demethylasterriquinone B1 precursor. The dihaloquinone products of
      these indole/quinone coupling processes can be hydrolyzed to the dihydroxyquinone
      natural products. Demethylasterriquinone B1 is of high recent interest as a small
      molecule insulin mimetic with oral anti-diabetic activity in mice.

PMID- 12423120
TI  - Structure and absolute stereochemistry of phormidolide, a new toxic metabolite
      from the marine cyanobacterium Phormidium sp.
AB  - The extract from a laboratory culture of an Indonesian isolate of the
      cyanobacterium Phormidium sp. displayed inhibitory activity in a Ras-Raf protein
      interaction assay. Assay-guided fractionation led to the isolation of both active
      and inactive materials of novel structure. The major inactive metabolite,
      phormidolide, was nevertheless highly toxic to brine shrimp (LC(50) = 1.5
      microM), and hence, its structure was elucidated using various spectroscopic
      methods, primarily NMR. A series of partial structures were developed from
      standard experiments and then assembled using GHMBC, 2D INADEQUATE, and ACCORD
      ADEQUATE data obtained on a (13)C-enriched sample. The relative stereochemistry
      at phormidolide's 11 chiral centers was established using the J-based
      configuration analysis method in concert with the G-BIRD(R)-HSQMBC NMR
      experiment. Absolute stereochemistry was determined on a bis-acetonide derivative
      using the variable temperature Mosher ester method. The robust number of NMR
      restraints provided from determination of most homonuclear and heteronuclear
      coupling constants in phormidolide, along with an abundance of NOE information,
      allowed construction of a refined lowest energy three-dimensional structure in
      Macromodel. Phormidolide is one of only a few macrolide-type natural products to
      be reported from marine cyanobacteria.

PMID- 12423121
TI  - Model compound studies of the beta-O-4 linkage in lignin: absolute rate
      expressions for beta-scission of phenoxyl radical from 1-phenyl-2-phenoxyethanol
      1-yl radical.
AB  - Arrhenius rate expressions were determined for beta-scission of phenoxyl radical
      from 1-phenyl-2-phenoxyethanol-1-yl, PhC*(OH)CH2OPh (V). Ketyl radical V was
      competitively trapped by thiophenol to yield PhCH(OH)CH2OPh in competition with
      beta-scission to yield phenoxyl radical and acetophenone. A basis rate expression
      for hydrogen atom abstraction by sec-phenethyl alcohol, PhC*(OH)CH3, from
      thiophenol, log(k(abs)/M(-1) s(-1)) = (8.88 +/- 0.24) - (6.07 +/- 0.34)/theta,
      theta = 2.303RT, was determined by competing hydrogen atom abstraction with
      radical self-termination. Self-termination rates for PhC*(OH)CH3 were calculated
      using the Smoluchowski equation employing experimental diffusion coefficients of
      the parent alcohol, PhCH(OH)CH3, as a model for the radical. The hydrogen
      abstraction basis reaction was employed to determine the activation barrier for
      the beta-scission of phenoxyl from 1-phenyl-2-phenoxyethanol-1-yl (V): log(k
      beta)/s(-1)) = (12.85 +/- 0.22) - (15.06 +/- 0.38)/theta, k beta (298 K) ca.
      (64.0 s(-1) in benzene), and log(k beta /s(-1)) = (12.50 +/- 0.18) - (14.46 +/-
      0.30)/theta, k beta (298 K) = 78.7 s(-1) in benzene containing 0.8 M 2-propanol.
      B3LYP/cc-PVTZ electronic structure calculations predict that intramolecular
      hydrogen bonding between the alpha-OH and the -OPh leaving group of ketyl radical
      (V) stabilizes both ground- and transition-state structures. The computed
      activation barrier, 14.9 kcal/mol, is in good agreement with the experimental
      activation barrier.

PMID- 12423122
TI  - Directed dihydroxylation of cyclic allylic alcohols and trichloroacetamides using
      OsO4/TMEDA.
AB  - The oxidation of a range of cyclic allylic alcohols and amides with OsO4/TMEDA is
      presented. Under these conditions, hydrogen bonding control leads to the
      (contrasteric) formation of the syn isomer in almost every example that was
      examined. Evidence for the bidentate binding of TMEDA to OsO4 is presented and a
      plausible mechanism described.

PMID- 12423123
TI  - Polyfunctional compounds containing the 4,6-dialkoxy-7-arylthioheptene moiety as
      synthetically useful intermediates. The course of lewis acid-induced
      transformations.
AB  - Data on the selectivity of the Lewis acids induced transformations of the title
      compounds are presented, and the routes leading to formation of products
      containing either cyclohexane or 1,3-diene units are described.

PMID- 12423124
TI  - Probing polyvalency in artificial systems exhibiting molecular recognition.
AB  - An approach to the study of polyvalency-the interaction of polyvalent receptors
      with polyvalent ligands-in unnatural systems is outlined. In this study, the
      complexation of dibenzylammonium cations by dibenzo[24]crown-8 or
      benzometaphenylene[25]crown-8 is utilized as the component receptor-ligand
      interaction. Two analogous multivalent receptors-each containing either seven
      dibenzo[24]crown-8 (DB24C8 CLUSTER) or seven benzometaphenylene[25]crown-8
      (BMP25C8 CLUSTER) moieties appended to a modified beta-cyclodextrin core-were
      prepared in moderate yields. For each of these multivalent receptors,
      complementary mono- and divalent ligands containing one or two dialkylammonium
      centers, respectively, were prepared in good yields. These ligands contained
      fluorine atom substituents to allow their interactions with crown ether compounds
      to be probed by (19)F NMR spectroscopy. The complexation of these monovalent
      ligands with the DB24C8 CLUSTER and the BMP25C8 CLUSTER was studied by
      determining the average binding constant (K(AVE)) between the receptors and
      ligands. The abilities of the crown ether clusters to complex with these
      monovalent ligands was compared with those of the monovalent crown ethers
      dibenzo[24]crown-8 and benzometaphenylene[25]crown-8. In both instances, it was
      found that clustering seven crown ethers together into one molecule is
      detrimental to the abilities of the crown ether moieties to complex with
      monovalent dialkylammonium ligands. The complexation of the divalent ligands by
      the DB24C8 CLUSTER and the BMP25C8 CLUSTER was then studied-again by determining
      K(AVE)-and their abilities to complex with these ligands was compared with those
      of their respective component interactions. By determining K(AVE) for the
      polyvalent interaction, it was possible to calculate an association constant,
      K(POLY), for the binding of the divalent ligands by the DB24C8 CLUSTER and the
      BMP25C8 CLUSTER compounds. In both instances K(POLY) for the polyvalent
      interaction was found to be approximately 2 orders of magnitude higher than the
      association constants, K(A), for the component interaction.

PMID- 12423125
TI  - Synthesis and application of arylmonophosphinoferrocene ligands: ultrafast
      asymmetric hydrosilylation of styrene.
AB  - A short and efficient synthetic route to a novel class of atropisomeric and
      planar chiral 2-aryl-1-diphenylphosphanylferrocene ligands is presented. The
      modular design of the ligands allows a synthetic approach in which both the
      aromatic moiety and the phosphino substituent can be varied easily. This permits
      fine-tuning of steric and electronic properties. The ligands have been tested in
      the asymmetric hydrosilylation of styrene where enantioselectivities up to 90%
      are obtained. Optimization of the palladium-to-ligand ratio resulted in hitherto
      unparalleled turnover frequencies (TOF) exceeding 180 000 h(-1). The absolute
      stereochemistry of the ligands was determined from an X-ray structure. 2D NMR
      experiments in combination with ab initio calculations were used to assign the
      conformation of the atropisomeric biarylic scaffold.

PMID- 12423126
TI  - An Orthogonally Protected alpha,alpha-bis(aminomethyl)-beta-alanine building
      block for the construction of glycoconjugates on a solid support.
AB  - Synthetic glycoclusters are extensively used as mimetics of naturally occurring,
      multivalent carbohydrate ligands in various glycobiological applications. Their
      preparation, however, is far from trivial, and it still is a limiting factor in
      the study of carbohydrate binding. We herein report the synthesis of an
      orthogonally protected building block, N-Alloc-N'-Boc-N' '-Fmoc-alpha,alpha
      bis(aminomethyl)-beta-alanine (1), and its use in the preparation of triantennary
      peptide glycoclusters (21-24) on a solid support. The assembly of the clusters
      involves removal of the amino protections of the solid-supported branching unit 1
      in the order Fmoc, Boc, and Alloc, and subsequent coupling of peracetylated O
      (glycopyranosyl)-N-Fmoc-L-serine pentafluorophenyl esters (galactose, glucose,
      mannose, and ribose) to each amino group exposed.

PMID- 12423127
TI  - Theoretical study and X-ray determination of bianthronyl [corrected] : long C-C
      bond length and preferred gauche conformation.
AB  - Five X-ray crystallographic structures of bianthronyl (1, 2b-5b) revealed the
      presence of long central C(sp3)-C(sp3) bonds (> or =1.60 A) and mostly gauche
      conformation. DFT calculations were carried out to study the structural features
      of bianthronyl and related model molecules [corrected]. Our B3LYP/6-31G gas-phase
      calculation results suggest that steric effect plays a role in causing the long C
      C sigma bond length (>1.60 A), nonplanarity of the anthracenone moiety (>20
      degrees ), and preferred gauche conformation. However, when the gauche preference
      is weak, environmental effects such as solvation and packing forces can reverse
      it. As the degree of nonplanarity of the anthracenone moiety is consistently
      larger in the anti conformation than in the gauche and the ease of achieving
      nonplanarity is determined by flexibility of the central six-membered rings
      directly connected to the C(sp3)-C(sp3) bond, one way to control the structure
      and anti-gauche energy difference of closely related compounds is by changing the
      clamping group (Z) in the central six-membered ring.

PMID- 12423128
TI  - The first kinetic evidence for acid catalysis in a monocyclic rearrangement of
      heterocycles: conversion of the Z-phenylhydrazone of 5-amino-3-benzoyl-1,2,4
      oxadiazole into N,5-diphenyl-2H-1,2,3-triazol-4-ylurea.
AB  - The title reaction has been studied in dioxane/water in a large (0.1-14.9) pS+
      range, evidencing, together with an uncatalyzed process at intermediate (3.5-8.0)
      pS+ values, the occurrence of a catalyzed pathway both in the acidic (pS+ 0.1
      3.5) and in the basic region (pS+ 8.0-14.9): specific-acid catalysis and general
      base catalysis, respectively, have been found to take place by means of kinetic
      investigations at different buffer concentrations. Mechanisms for the three
      pathways have been advanced on the grounds of structural features. In a
      comparison with previous data particular attention has been paid to the acid
      catalyzed pathway, herein observed for the first time in an azole-to-azole
      interconversion. The mechanistic hypotheses seem well supported by ab initio
      calculations.

PMID- 12423129
TI  - Tandem cyclization-cycloaddition behavior of rhodium carbenoids with carbonyl
      compounds: stereoselective studies on the construction of novel epoxy-bridged
      tetrahydropyranone frameworks.
AB  - Investigations and stereoselective studies on the tandem reactions of carbonyl
      ylides generated from alpha-diazo ketones in the presence of carbonyl compounds
      are presented in this paper. Intramolecular cyclization of rhodium carbenoids
      generated the transient five- or six-membered-ring carbonyl ylide dipoles, which
      efficiently underwent 1,3-dipolar cycloaddition reactions with various
      dipolarophiles such as aromatic aldehydes 15, alpha,beta-unsaturated aldehydes
      18/24, alpha,beta-unsaturated ketones 27/28/31, and dienone 34. The transient
      carbonyl ylides underwent cycloadditions with various aromatic aldehydes to
      furnish diverse epoxy-bridged tetrahydropyranone ring systems in a
      diastereoselective manner. The cycloaddition of carbonyl ylides with alpha,beta
      unsaturated aldehydes 18/24 or dienone 34 afforded C=O addition products in a
      chemoselective manner despite the presence of C=C bonds in the above
      dipolarophiles. Alternatively, the cycloaddition of carbonyl ylides with
      alpha,beta-unsaturated ketones 27/28 provided both the C=O and C=C cycloaddition
      products. The cycloaddition of carbonyl ylides with carbonyl compounds occurred
      in good yields and was found to be highly regio- and stereoselective. Single
      crystal X-ray analyses were performed to unambiguously establish the structure
      and stereochemistry of the novel epoxy-bridged tetrahydropyranone ring systems
      35a/38. Compound 35a exhibited both intermolecular C-H...O and intramolecular C
      H...pi interaction motifs in the solid-state architecture. The regio-, chemo-,
      and stereoselectivity observed in these reactions have been investigated by
      semiempirical AM1 MO calculations. FMO analyses and transition state calculations
      have been performed for the cycloaddition of carbonyl ylides with alpha,beta
      unsaturated carbonyl compounds such as tetracyclone (34) and cyclopentenone
      (27a). Both FMO and transition state calculations correctly predicted the regio-
      and stereochemistry of the cycloadducts. The calculations further revealed that a
      severe steric interaction caused by the phenyl rings present in dipolarophile 34
      with dipole 14a increases the activation barrier of the transition state during
      the cycloaddition process.

PMID- 12423130
TI  - Solid-phase synthesis of monocyclic beta-lactam derivatives.
AB  - Liquid-phase studies concerning the solid-phase synthesis of monocyclic beta
      lactams via the ester-enolate imine condensation route have been conducted
      utilizing triazene esters 1 and 2 as model compounds. Esters were attached to
      benzylamine resin 6 by a triazene linker employing the respective diazonium
      salts. Immobilized ester-enolates 8 and 10 were reacted with various imines and
      imine precursors to give polymer-bound beta-lactams 14 and 17 in different
      substitution patterns. Traceless cleavage from the triazene linker yields the
      desired beta-lactams 16 and 19.

PMID- 12423131
TI  - Remote electronic effects in the rhodium-catalyzed nucleophilic ring opening of
      oxabenzonorbornadienes.
AB  - We report the application of our rhodium-catalyzed nucleophilic ring-opening
      methodology to unsymmetrically arene-substituted oxabenzonorbornadienes. The
      regioselectivity of the ring opening was investigated using a variety of
      nucleophiles that led to a broad selection of dihydronaphthalene products. It was
      found that good to excellent regioselectivities are obtained using strongly pi
      donating substituents, whereas sigma-donating and electron-withdrawing
      functionalities have a minimal effect. Post ring-opening manipulations of
      functional groups in the dihydronaphthalene products were shown to give efficient
      access to mono- and diamine tetrahydronaphthalene building blocks.

PMID- 12423132
TI  - Thermal/hyperbaric heterocycloaddition of 1,4-dialkoxy-1,3-dienes: the de novo
      (E,Z) way to sugars.
AB  - 1-(Z)-Alkoxy-4-(E)-methoxybutadiene derivatives have been reacted with
      ethylgyoxylate and diethyl ketomalonate under thermal or hyperbaric conditions.
      They provide, with a total regioselectivity and fair to total endoselectivities,
      the expected dihydropyranic cycloadducts. Three of those pseudo-glycals have been
      converted in a few classical steps (deprotection, reduction, and dihydroxylation)
      into (racemic) allose, mannose, and gullose derivatives. The order of these three
      steps has a direct influence on the efficiency of the transformation and
      determines the stereochemistry of the final sugar.

PMID- 12423133
TI  - A general approach toward the synthesis of C-nucleoside pyrazolo[1,5-a]-1,3,5
      triazines and their 3',5'-bisphosphate C-nucleotide analogues as the first
      reported in vivo stable P2Y(1)-receptor antagonists.
AB  - In our effort to identify potent purinergic P2Y(1) receptor antagonists as potent
      platelet aggregation inhibitors with enhanced metabolic stability, we developed
      an efficient route for the large-scale preparation of 2'-deoxy-C-nucleosides of
      pyrazolo[1,5-a]-1,3,5-triazine. The key strategic elements of this novel
      synthetic approach involved the following: (i) the use of a novel activating
      group, the N-methyl-N-phenylamino group, which was easily generated in high yield
      by treatment of the pyrazolo[1,5-a]-1,3,5-triazin-4-one (5) with phosphorus
      oxychloride and dimethylaniline under high pressure, (ii) a regio- and
      stereospecific palladium-mediated coupling reaction of the readily available
      unprotected glycal 1,4-anhydro-2-deoxy-D-erythro-pent-1-enitol (4b) and the 8
      iodo derivative (16), and (iii) the stereoselective reduction of the ketone group
      of the furanosyl ring followed by the subsequent displacement of the N-methyl-N
      phenylamino group upon treatment with methylamine. The beta configuration at the
      anomeric C-1' position of the glycal moieties was perfectly retained throughout
      this conversion. This procedure afforded 8-(2'-deoxy-beta-D-ribofuranosyl)-2
      methyl-4-(N-methylamino)pyrazolo[1,5-a]-1,3,5-triazine (21) and 8-(2'-deoxy-beta
      D-xylofuranosyl)-2-methyl-4-(N-methylamino)pyrazolo[1,5-a]-1,3,5-triazine (24)
      with an overall yield of 50% and 39%, respectively. Finally, the conversion of
      nucleosides 21 and 24 to the pyrazolotriazine C-nucleotides 3',5'-bisphosphate 2
      and 3',5'-cyclophosphate 26 is also described herein and represents the first
      reported nucleotide derivatives within the pyrazolo[1,5-a]-1,3,5-triazine series.
      Preliminary biological testing has shown that compound 2 strongly inhibits ADP
      induced human platelet aggregation and shape change and possesses significant
      efficacies 30 min after injection in rat, highlighting a strong P2Y(1)-receptor
      antagonist activity in vitro combined with a prolonged duration of action in
      vivo.

PMID- 12423134
TI  - Synthesis of 1,3,5-cis,cis-triaminocyclohexane N-pyridyl derivatives as potential
      antitumor agents.
AB  - Iron deprivation has been previously proven to be a promising strategy in
      treating tumor cells. A series of cis,cis-1,3,5-triaminocyclohexane N-pyridyl
      derivatives as iron-depleting antitumor agents were prepared. Cytotoxic activity
      of these derivatives was evaluated in the HeLa cancer cell line. Among the tested
      derivatives, N-ethyl-N,N',N"-tris(2-pyridylmethyl)-cis,cis-1,3,5
      triaminocyclohexane (17) exhibited potent cytotoxicity against this cancer cell
      line. On the basis of the structure of 17, a bifunctional iron chelator 24 was
      designed and prepared. Bifunctional agent 24 possessing a maleimide linker that
      is functional for conjugation to thiolated monoclonal antibodies is a promising
      lead compound for development of antitumor conjugates for antibody-targeted
      therapies.

PMID- 12423135
TI  - Permanganate oxidation of 1,5,9-trienes: stereoselective synthesis of
      tetrahydrofuran-containing fragments.
AB  - Permanganate oxidation of farnesoate esters 12a-d afforded perhydro-2,2'
      bifuranyl compounds 16a-d, with control of relative stereochemistry at four new
      stereocenters. Subsequent oxidative cleavage of 16a-d then provided
      tetrahydrofuran-containing fragments 17a-d, one of them 17b possessing the same
      relative stereochemistry present in the C13-C21 portion of the polyether
      antibiotic semduramycin (1). Control of the absolute stereochemistry was achieved
      through the use of the Oppolzer sultam chiral auxiliary. The requisite starting
      trienes were prepared stereoselectively in just three steps from geranyl chloride
      or neryl chloride, providing a short and versatile route to polyether fragments.

PMID- 12423136
TI  - Oxazaborolidines as functional monomers: ketone reduction using polymer-supported
      Corey, Bakshi, and Shibata catalysts.
AB  - The first two polymer-supported versions of the Corey, Bakshi, and Shibata (CBS)
      catalyst have been prepared. Functional monomers based structurally upon the
      original B-methylated catalyst have been used to prepare catalytic polymers
      containing the CBS moiety bound both in a pendant fashion and in the form of a
      cross-link. Enantioselective reductions of two prochiral ketones have been
      carried out using the original catalyst in the solution phase as well as the two
      solid-state systems. While the pendant-bound system shows reduced
      stereoselectivity, the cross-linked version affords enantioselectivities almost
      identical to those of the solution-phase model.

PMID- 12423137
TI  - Configurational and conformational analysis of chiral molecules using IR and VCD
      spectroscopies: spiropentylcarboxylic acid methyl ester and spiropentyl acetate.
AB  - The chiral monosubstituted derivatives of spiropentane, spiropentylcarboxylic
      acid methyl ester, 1, and spiropentyl acetate, 2, have been synthesized in
      optically active form. Configurational and conformational analysis of 1 and 2 has
      been carried out using infrared (IR) and vibrational circular dichroism (VCD)
      spectroscopies. Analysis of the experimental IR and VCD spectra has been carried
      out using ab initio density functional theory (DFT). For both 1 and 2, DFT
      predicts two populated conformations. Comparison to experiment of the
      conformationally averaged IR and VCD spectra of 1 and 2, predicted using DFT,
      provides unequivocal evidence of the predicted conformations and yields the
      absolute configurations R(-)/S(+) for 1 and R(+)/S(-) for 2. These absolute
      configurations are consistent with the R(-)/S(+) absolute configuration of
      spiropentylcarboxylic acid, assigned previously via X-ray crystallography of its
      alpha-phenylethylammonium salt.

PMID- 12423138
TI  - Stereocontrolled aziridination of imines via a sulfonium ylide route and a
      mechanistic study.
AB  - The reaction of N-diphenylphosphinoyl imines 1 with [3
      (trimethylsilyl)allyl]dimethylsulfonium bromide (5) in the presence of NaH at
      room temperature predominantly gave trans-vinylaziridines 4. On the other hand,
      cis-vinylaziridines 4 were the main products when the preformed ylide prepared
      from the reaction of [3-(trimethylsilyl)allyl]diphenylsulfonium perchlorate (6)
      was reacted with the same imines 1 at low temperature. trans-Aziridines were also
      obtained when imines 1 and sulfinimines 9 were reacted with N,N-dimethylacetamide
      2-dimethylsulfonium bromide (7) in the presence of a base, respectively. A
      mechanistic study showed that the stereochemistry of these reactions was
      controlled by the reactivity of the imines and ylides. A higher reactivity of
      imines and ylides favors the formation of cis-aziridines, whereas a lower
      reactivity leads to trans-products.

PMID- 12423139
TI  - Regioregular head-to-tail oligothiophene-functionalized 9,9'-spirobifluorene
      derivatives. 2. NMR characterization, thermal behaviors, and electrochemical
      properties.
AB  - Oligothiophene-functionalized 9,9'-spirobifluorene derivatives exhibit good
      solubility in polar organic solvents, especially compounds 5a-d to 7a-d due to
      the introduction of the flexible n-hexyl chain. The structures of all compounds
      studied are characterized and verified by (1)H and (13)C NMR spectra. The results
      not only show that these organic conjugated materials with no substituents or n
      hexyl substituents are successfully synthesized through the corresponding
      synthetic methodologies, but also prove that chemical shifts of protons and
      carbons in the aromatic range change with the attachment and the increase of the
      thiophene ring at the 9,9'-spirobifluorene fragment. The thermal analysis results
      demonstrate that these compounds are quite stable, and evaporate from 300 to 700
      degrees C. Most of these compounds exhibit a stable amorphous state in the solid
      state. The electrochemical properties of all compounds studied are also
      investigated. The results indicate that radical cation behaviors of
      oligothiophene-modified 9,9'-spirobifluorene derivatives are more stable than
      those of normal oligothiophenes, that oxidative and reductive peak potentials
      shift cathodically or anodically, and that the HOMO and LUMO energy levels are
      also tuned with the increase of the thiophene ring owing to the enhanced pi
      electron delocalization and the increasing conjugation length. Oxidative
      potentials of nonsubstituted oligothiophene-functionalized 9,9'-spirobifluorene
      derivatives are more sensitive to the increase of thiophene rings than those of
      9,9'-spirobifluorene derivatives with n-hexyl groups. The energy levels and band
      gaps of all compounds studied are also calculated from the onset potentials of n
      doping and p-doping and are adjusted by varying thiophene oligomers and their
      attachment patterns to the 9,9'-spirobifluorene ring to make them suitable for
      the work functions of the electrodes.

PMID- 12423140
TI  - Synthesis, stability, and spectroscopic and electronic properties of three
      benzocyclohepta[alpha]azulenylium ions.
AB  - Novel pi-systems, three benzocyclohepta[alpha]azulenylium ions, 7a-c, are
      synthesized, and their stability and properties have been characterized in terms
      of the position of the benzo-annulation and compared with those of the parent
      cyclohepta[alpha]azulenylium ion 4. Benzocyclohepta[6,7-alpha]azulenylium ion
      (7a) (p K R+ = 7.3, E red = -0.567 V vs Ag/Ag+) and benzocyclohepta[6,5
      alpha]azulenylium ion (7b) (p K R+ = 5.1, E red = -0.482 V vs Ag/Ag+), which are
      annulated with benzene on the position having a high bond order of 4, are not
      appreciably destabilized compared with cyclohepta[alpha]azulenylium ion (4) (p K
      R+ = 7.3, E red = -0.458 V vs Ag/Ag+). On the other hand, benzocyclohepta[7,6
      alpha]azulenylium ion (7c) (p K R+ = 1.6, Ered = -0.197 V vs Ag/Ag+) is
      considerably destabilized, probably due to enhanced contribution of the quinoid
      structure of the benzene ring, which is annulated on the position having a low
      bond order of the cyclohepta[alpha]azulenylium ion moiety. Furthermore, the
      cations 7a and 7b are more stable than 12,13-dihydrobenzocyclohepta[7,6
      alpha]azulenylium ion (25) (p K R+ = 4.8, E red = -0.513 V vs Ag/Ag+), which is a
      dihydrogenated compound of 7a, while 7c is less stable than 25. These features
      are reflected in the considerable red shift of the longest absorption maximum of
      the electronic spectrum of 7c, as compared with those of 4, 7a, and 7b, and in
      the chemical shifts of the protons and their coupling constants of the (1)H NMR
      spectra. Furthermore, the (1)H NMR spectra and electronic spectra of 5H
      benzocyclohepta[6,7-alpha]azulen-5-one (8a) and 7H-benzocyclohepta[6,5
      alpha]azulen-7-one (8b) in acidic media have also been studied to clarify the
      spectral characteristics similar to those of 7a and 7b.

PMID- 12423141
TI  - Conformationally constrained alpha-boc-aminophosphonates via transition metal
      catalyzed/curtius rearrangement strategies.
AB  - A transition metal-catalyzed/Curtius rearrangement sequence toward the
      development of conformationally constrained alpha-Boc-aminophosphonates 2-6 is
      described. An approach using the versatile tert-butylphosphonoacetate moieties 1a
      and 1b to derive an array of mono- and bicyclic alpha-Boc-aminophosphonate
      systems is presented. Conformational constraint is incorporated using either the
      ring-closing metathesis reaction catalyzed by the first generation Grubbs
      catalyst or intramolecular cyclopropanation mediated by Rh2(OAc)4. Using the tert
      butyl ester functionality in 1a or 1b as a potential amino group, the Curtius
      rearrangement provides an efficient route toward the target alpha-Boc
      aminophosphonates.

PMID- 12423142
TI  - Solvolysis of 4-methylcyclohexylidenemethyliodonium salt: chirality probe
      approach to a primary vinyl cation intermediate.
AB  - Optically active 4-methylcyclohexylidenemethyl(aryl)iodonium tetrafluoroborate
      (1.BF(4)(-)) was prepared and its solvolysis was carried out at 60 degrees C in
      various solvents. The main product is optically active 4-methylcycloheptanone (or
      its enol derivative) in unbuffered solvents, accompanied by the iodoarene. The
      rearranged product always maintains the optical purity of the starting 1. Its
      stereochemistry conforms to a mechanism involving the rearrangement via the sigma
      bond participation in departure of the nucleofuge, followed by trapping of the
      resulting chiral 5-methylcyclohept-1-enyl cation with a nucleophilic solvent.
      That is, the achiral, primary vinyl cation is not involved during the reaction.
      The unrearranged substitution product is also obtained in a minor fraction in
      unbuffered methanol, ethanol, and acetic acid, but not in trifluoroethanol or
      hexafluoro-2-propanol: the methoxy product from methanolysis is largely
      racemized, but the acetolysis product is obtained mainly via retention of
      configuration. Reactions of 1 with bromide, acetate, and trifluoroacetate in
      chloroform give unrearranged substitution products in different degrees of
      inversion. These unrearranged products are concluded to be formed via the direct
      nucleophilic substitutions. Added bases such as sodium acetate in methanol lead
      to the unrearranged methoxy products of complete racemization, which is ascribed
      to the alpha elimination (to give an alkylidenecarbene) followed by the solvent
      insertion.

PMID- 12423143
TI  - Cycloheptyne intermediate in the reaction of chiral cyclohexylidenemethyliodonium
      salt with sulfonates.
AB  - Reactions of (R)-4-methylcyclohexylidenemethyl(phenyl)iodonium salt and its 3
      trifluoromethylphenyl and 4-methoxyphenyl derivatives (1) with tetrabutylammonium
      mesylate and triflate were carried out in chloroform at 60 degrees C. The
      products include (S)-4-methylcyclohexylidenemethyl sulfonate (2) and (R)-5
      methylcyclohept-1-enyl sulfonate (3) as well as iodoarene. Reactions of (S)-1
      were confirmed to provide the counterpart results. The rearranged triflate (R)
      3Tf formed in the reaction with triflate maintains mostly the ee (enantiomeric
      excess) of (R)-1, while the ee of the mesylate product 3Ms is largely lost. The
      (13)C-labeling at the exocyclic position of 1 results in the isotopic scrambling
      of C-1 and C-2 of 3Ms in the mesylate reaction. The degree of the scrambling
      agrees well with that of the loss of ee of (R)-3Ms obtained from (R)-1, implying
      that the racemization is not due to the intermediate formation of achiral,
      primary 4-methylcyclohexylidenemethyl cation. Reaction of 1 with mesylate in the
      presence of CH(3)OD provided the 3Ms deuterated at the 2-position. When
      tetraphenylcyclopentadienone was added to the mesylate reaction system, the
      adduct of the 4-methylcycloheptyne intermediate was obtained in 24% yield, but
      the normal products 2Ms and 3Ms were still formed. The 3Ms obtained here in a low
      yield maintains the high ee of 1. These results indicate that the cycloheptyne is
      an intermediate responsible for the formation of racemic product 3Ms in the
      mesylate reaction. It is also concluded that the unrearranged products 2 are
      formed via the competitive pathways of in-plane and out-of-plane S(N)2 reactions.

PMID- 12423144
TI  - Flash vacuum pyrolysis over solid catalysts. 2. pyrazoles over hydrotalcites.
AB  - Flash vacuum pyrolysis (fvp) reactions of NH-pyrazole (1) and 3,5
      diphenylpyrazole (2) were investigated in the presence of anionic clays having
      hydrotalcite structure (HT). Solid catalysts with Mg:Al ratio equal to 2:1
      containing carbonate (HT-1), nitrate (HT-2), and silicate (HT-3) as interlayer
      anions were employed. Between 400 and 600 degrees C, compound 1 remained almost
      unchanged and only unidentified volatile products were detected in small amounts.
      In contrast, 2 afforded benzonitrile (3) and phenylacetonitrile (4) by a ring
      fragmentation reaction at 450 degrees C. At a higher temperature (660 degrees C),
      the same products obtained in homogeneous fvp reactions, i.e., 2-phenylindene (5)
      and 3-phenylindene (6), were obtained showing no catalysis by HT under these
      conditions. Results showed that the yield is strongly dependent on the nature of
      the interlayer anion in the hydrotalcite structure. In comparison with reactions
      of 2 over zeolites, HTs exhibit selectivity for ring fragmentation reaction.

PMID- 12423145
TI  - Modification of the upper rim of homooxacalix[3]arenes and complexation between a
      nitrohomooxacalix[3]arene derivative and n-hexylamine.
AB  - Several functional groups were introduced on the upper rim of (lower rim free)
      homooxacalix[3]arene for the first time. The swinging nitrohomooxacalix[3]arene
      host 1 was fixed in the cone conformation by complexation with n-hexylamine.

PMID- 12423146
TI  - Intramolecular Diels-Alder reactions of brominated masked o-benzoquinones. A
      detour method to synthesize highly functionalized oxatricyclic [m.3.1.0] ring
      systems from 2-methoxyphenols.
AB  - Intramolecular Diels-Alder (IMDA) reactions of masked o-benzoquinones (MOBs) 5a-d
      to 7a-d and 17a-d to 19a-d generated in situ from 2-methoxyphenols 2-4 and 14-16,
      respectively, in the presence of alkenols 1a-d, resulting in highly
      functionalized oxatricyclic [m.3.1.0] ring systems are described. The MOBs 5a-d
      to 7a-d underwent the IMDA reactions to furnish the adducts 8a-d, 10a-d, and 12a
      d (direct method) in poor yields with the concomitant formation of considerable
      amounts of unexpected byproducts 9a-d, 11a-d, and 13a-d, respectively. To avoid
      the formation of byproducts and to improve the yields of the desired
      cycloadducts, a detour method comprising sequential bromination of 2
      methoxyphenols 2-4, tandem oxidative acetalization-Diels-Alder reaction, and
      debromination has been developed. The oxidation of bromophenols 14-16 in the
      presence of alkenols 1a-d produced the corresponding MOBs 17a-d to 19a-d, which
      underwent cycloaddition to afford the cycloadducts 20a-d to 22a-d, respectively,
      as sole products in good to high yields in a highly regio- and stereoselective
      manner. Treatment of the bromoadducts 20a-d to 22a-d with tributylammonium
      formate-palladium reagent produced the corresponding debrominated products 8a-d,
      10a-d, and 12a-d in high to excellent yields. In general, the latter oxatricycles
      were obtained in higher overall yields via the detour method than those via the
      direct method.

PMID- 12423147
TI  - Nucleophilic epoxidation of alpha'-hydroxy vinyl sulfoxides.
AB  - The nucleophilic epoxidation of a variety of alpha'-(1-hydroxyalkyl) vinyl
      sulfones and sulfoxides has been studied. The sulfones give rise to anti oxiranes
      with modest (E) or excellent (Z) selectivities and in good yields. The (E)
      sulfoxides display low reactivity within a reinforcing/nonreinforcing scenario.
      The use of t-BuOOLi in Et(2)O allows for a highly syn-selective epoxidation
      oxidation. The (Z)-sulfoxides display a remarkably high reactivity under these
      conditions. The reinforcing (S,S(S)) diastereomers (3e-g) yield hydroxy sulfinyl
      oxiranes with high yields and selectivities. In contrast, the (R,S(S))
      diastereomers (4e-g) show diminished reactivities and a very substrate-dependent
      stereochemical outcome. The structure of these oxiranes has been secured by
      chemical correlations and an X-ray crystal structure.

PMID- 12423148
TI  - Straightforward entry into 5-hydroxy-1-aminopyrrolines and the corresponding
      pyrroles from 1,2-diaza-1,3-butadienes.
AB  - The synthesis of 5-hydroxy-1-aminopyrroline-3-carboxylic acid derivatives and 5
      unsubstituted-1-aminopyrrole-3-carboxylic acid derivatives from 1,2-diaza-1,3
      butadienes and aldehydes is presented. These domino reactions offer the advantage
      of executing multistep transformation without intermediate workup procedures. The
      stereoselectivity of ring closure to 5-hydroxy-1-aminopyrroline-3-carboxylic acid
      derivatives and phenyl transposition to 2,3-diphenyl-1-aminopyrrole-3-carboxylic
      acid derivatives are also studied.

PMID- 12423149
TI  - Chemical synthesis of cyclodextrins by using intramolecular glycosylation.
AB  - An efficient synthesis of cyclodextrins (CDs) by using the intramolecular
      glycosylation is demonstrated. alpha-CD, an alpha(1-->4)linked hexaglucoside, was
      prepared via a block condensation of three maltose units. A modified key maltose
      intermediate as a precursor to both glycosyl donor and acceptor components was
      prepared in 6 steps starting from maltose. All the glycosylation for chain
      elongation and cyclization of saccharides was carried out after tethering the
      donor to the acceptor by the phthaloyl bridge to give the desired saccharides in
      good yields with complete alpha-selectivity. delta-CD composed of 9 glucose units
      was synthesized by the same manner from three maltotriose units.

PMID- 12423150
TI  - Synthesis of a new water-soluble C(2)-symmetric chiral diamine: preliminary
      investigation of its catalytic properties for asymmetric hydrogenation under
      biphasic conditions.
AB  - A water-soluble version of N,N'-dimethyl-1,2-diphenylethane-1,2-diamine was
      prepared by introduction of phosphonic acid moieties on the para position of the
      aromatic rings. Preliminary investigation of the catalytic properties of the
      iridium complex of this ligand under biphasic conditions showed that this system
      compared well with the homogeneous counterpart for the asymmetric hydrogenation
      of ketones but with noticeably higher reaction rates for the biphasic system.

PMID- 12423151
TI  - Dendritic oxazoline ligands in enantioselective palladium-catalyzed allylic
      alkylations.
AB  - First to fourth generation dendritic substituents based on 2,2
      bis(hydroxymethyl)propionic acid and (1R,2S,5R)-menthoxyacetic acid were attached
      to 2-(hydroxymethyl)pyridinooxazoline and bis[4-(hydroxymethyl)oxazoline]
      compounds. The new ligands obtained were assessed in palladium-catalyzed allylic
      alkylations. The first type of ligands exhibited enantioselectivity similar to
      that of a benzoyl ester derivative, whereas the latter type of ligands afforded
      products with higher selectivity than the analogous benzoyl ester. The activity
      of the dendritic catalysts decreased with increasing generation.

PMID- 12423152
TI  - A theoretical study of the reaction of alkynylboranes with butadiene: competition
      between cycloaddition and alkynylboration.
AB  - The reactions of alkynyldihaloboranes and alkynyldialkylboranes with butadiene
      have been explored by using DFT methods at the B3LYP level with the 6-31G basis
      set. Transition structures for the concerted [4+2] cycloaddition have been found
      for the alkynylborane derivatives. Along with these, another reactive pathway has
      been found for the cycloaddition process with transition structures of high [4+3]
      character. The transition structures for the 1,4-alkynylboration processes have
      also been found. The geometries computed for the cycloaddition transition
      structure with high [4+3] character and the 1,4-alkynylboration transition
      structures are surprisingly similar though leading to different products. IRC
      calculations suggest that the [4+3] cycloaddition and alkynylboration pathways
      are associated by a zwitterionic structure.

PMID- 12423153
TI  - Lobocyclamides A-C, lipopeptides from a cryptic cyanobacterial mat containing
      Lyngbya confervoides.
AB  - The structures of lipopeptides lobocyclamides A (1), B (2), and C (3) were solved
      using a combination of mass spectrometry, 2D NMR spectroscopy, and degradative
      analysis. Lobocyclamides B and C are the first peptides reported with the unusual
      amino acid 4-hydroxythreonine and also incorporate the rare homologous long-chain
      beta-amino acids 3-aminooctanoic acid and 3-aminodecanoic acid, respectively. The
      absolute configurations of the amino acid residues in each compound were
      assigned, after acid hydrolysis, by either direct chiral HPLC comparison with
      authentic standards or by prior derivatization by Marfey's method and reversed
      phase HPLC. Both compounds exhibited moderate antifungal activity against a panel
      of Candida spp., including two fluconazole-resistant strains. When tested as a
      mixture, lobocyclamides A and B displayed synergistic in vitro antifungal
      activity, a phenomenon noted earlier for the related peptides laxaphycins A and
      B.

PMID- 12423154
TI  - Ab initio calculations and mass spectrometric determination of the gas-phase
      proton affinities of 4,4'-disubstituted 2,2'-bipyridines.
AB  - The gas-phase proton affinities of 4,4'-di(R)-2,2'-bipyridines (R: H, Br, Cl,
      NO(2), Me) were determined by mass spectrometric measurements and by ab initio
      calculations at the HF/6-31G and MP2/6-31G levels of theory. The energy barriers
      for rotation about the central C-C bond were also studied computationally. Two
      minima were found for both unprotonated and protonated species, the global minima
      being at the trans planar and cis planar conformations, respectively. Local
      minima for the unprotonated compounds were at the cis nonplanar conformation and
      for the protonated compounds at the trans nonplanar. Two different proton
      affinity values were calculated for each compound by employing different
      conformations for the protonated species. The computational values were in good
      agreement with the experimental proton affinities. Substituents affect the proton
      affinity according to their ability to withdraw or to donate electrons, halogen
      and nitro-substituted bipyridines having a lower proton affinity and methyl
      substituted bipyridine having a higher proton affinity than 2,2'-bipyridine
      itself.

PMID- 12423155
TI  - Novel routes to 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazines and 5,6,9,10,11,11a
      hexahydro-8H-pyrido[1,2-a]pyrrolo[2,1-c]pyrazines.
AB  - Condensation reactions of benzotriazole and 2-(pyrrol-1-yl)-1-ethylamine (1) with
      formaldehyde and glutaric dialdehyde, respectively, afforded intermediates 2 and
      6. Subsequent nucleophilic substitutions of the benzotriazole group in 2 and 6
      with Grignard reagents, sodium cyanide, and sodium borohydride gave 1,2,3,4
      tetrahydropyrrolo[1,2-a]pyrazines 3a-e, 4, 5 and 5,6,9,10,11,11a-hexahydro-8H
      pyrido[1,2-a]pyrrolo[2,1-c]pyrazines 7a-c, 8, 9, respectively, in good yields.

PMID- 12423156
TI  - Novel syntheses of enantiopure hexahydroimidazo[1,5-b]isoquinolines and
      tetrahydroimidazo[1,5-b]isoquinolin-1(5H)-ones via iminium cation cyclizations.
AB  - Condensations of chiral diamines 11a-c with benzotriazole and formaldehyde gave
      benzotriazolyl intermediates 12a-c; similar condensations of alpha-amino-amides
      10a-c with benzotriazole and paraformaldehyde gave 14a-c. Subsequent treatment of
      12a-c and 14a-c with AlCl(3) led to enantiopure tricyclic 1,2,3,5,10,10a
      hexahydroimidazo[1,5-b]isoquinolines 1a-c and 2,3,10,10a-tetrahydroimidazo[1,5
      b]isoquinolin-1(5H)-ones 15a-c, respectively, via Lewis acid promoted iminium
      cation cyclizations.

PMID- 12423157
TI  - Synthesis of N-cycloalkenylazoles.
AB  - N-(1-Cycloalkenyl)pyrroles 3a,b, -pyrazoles 6a,b, and -imidazoles 9a,b were
      synthesized via elimination of benzotriazole or 5-phenyltetrazole from the
      corresponding 1-[1-(heterocycyl)cycloalkyl]benzotriazoles 2, 5, and 8 or 1-[1
      (heterocycyl)cyclohexyl]-5-phenyltetrazole (12 and 14). Intermediates 2, 5, 8, 12
      and 14 were obtained by cyclizations of dihaloalkanes with N-(benzotriazol-1
      ylmethyl)heterocycles, 1-imidazol-1-ylmethyl-5-phenyltetrazole (11), or 1-pyrazol
      1-ylmethyl-5-phenyltetrazole (13) in the presence of n-BuLi.

PMID- 12423158
TI  - A novel dilithiation approach to 3,4-dihydro-2H-1,3-benzothiazines, 3,4-Dihydro
      2H-1,3-benzoxazines, and 2,3,4,5-tetrahydro-1,3-benzothiazepines.
AB  - 3,4-Dihydro-2H-1,3-benzothiazines 4, 3,4-dihydro-2H-1,3-benzoxazines 9, and
      2,3,4,5-tetrahydro-1,3-benzothiazepines 6 were synthesized by directed ortho
      lithiation of thiophenols and phenols and by side-chain lithiation of substituted
      thiophenols, respectively, in one-pot by reacting with N,N-bis[(benzotriazol-1
      yl)methyl]amines 3 as 1,3-biselectrophile synthons.

PMID- 12423159
TI  - One-pot synthesis of 2,4-benzodiazepin-1-ones using benzotriazole methodology.
AB  - 2, 4-Benzodiazepin-1-ones were prepared in moderate to good yields by reaction of
      bis(benzotriazolylmethyl)amines with ortho-metalated N-substituted benzamides.

PMID- 12423160
TI  - Novel syntheses of alpha-morpholinoamides from alpha,alpha-dichloroacetamides.
AB  - Dichloroacetamides, on heating with benzotriazole, morpholine, and triethylamine,
      produce, in a one-pot reaction, alpha-benzotriazolyl-alpha-morpholinoacetamides
      4a,b. Intermediates 4a and 4b react with nucleophiles such as allylsilanes, silyl
      ethers, and organozinc reagents to afford diverse alpha-morpholinoamides.

PMID- 12423161
TI  - Stereospecific synthesis of highly functionalized tricyclic beta-lactams by
      radical cyclizations using titanocene monochloride.
AB  - The reductive opening of epoxyimonobactams 1 with titanoncene (III) chloride
      gives rise to radicals that can be trapped by intramolecular pi systems (i.e.,
      conjugated alkenes and lactone and amide carbonyls) in a stereospecific way to
      give new carbocyclic compounds such as tribactam 2.

PMID- 12423162
TI  - Synthesis of small cyclic peptides via reverse turn induced ring closing
      metathesis of tripeptides.
AB  - A reverse turn induced (gamma/beta-turn) cyclization of tripeptides 1 can be
      performed in a ring closing metathesis reaction with Grubbs' catalyst to the
      corresponding cyclic peptides 2. These cyclic peptides may be useful probes as a
      conformationally constrained mimic of the bioactive conformation of structurally
      related HIV protease inhibitors.

PMID- 12423163
TI  - A practical high through-put continuous process for the synthesis of chiral
      cyanohydrins.
AB  - A practical high through-put continuous process for the synthesis of chiral
      cyanohydrins is reported. Pretreated almond meal (or other solid raw enzyme
      sources) was loaded in a column to form a reactor, to which were attached a
      supplying system to deliver a solution of substrate and HCN in solvent on one end
      and a collecting-separating system on the other end. By controlling the flowing
      rate, optimal conditions were achieved for the hydrocyanation of various aromatic
      carboxaldehydes in a "micro-aqueous" medium to produce chiral cyanohydrins in
      high yields and high enantiomeric excess (ee) with high substrate/catalyst ratio.

PMID- 12423164
TI  - The newborn surface of dull metals in organic synthesis. Bismuth-mediated solvent
      free one-step conversion of nitroarenes to azoxy- and azoarenes.
AB  - When milled together with bismuth shots, nitroarenes are readily converted to
      azoxy- and/or azoarenes depending on substrates and conditions employed. Simple
      extraction with organic solvent followed by evaporation of the resulting dark
      pasty solid gave the product in good yield.

PMID- 12423165
TI  - S-homoadenosyl-L-cysteine and S-homoadenosyl-L-homocysteine. Synthesis and
      binding studies of hon-hydrolyzed substrate analogues with S-adenosyl-L
      homocysteine hydrolase.
AB  - Treatment of homoadenosine [9-(5-deoxy-beta-D-ribo-hexofuranosyl)adenine] with
      thionyl chloride and pyridine in acetonitrile gave 6'-chloro-6'
      deoxyhomoadenosine, which underwent nucleophilic displacement with L-cysteine or
      L-homocysteine to give homologated analogues of S-adenosyl-L-homocysteine. Each
      amino acid in aqueous sodium hydroxide at 60 degrees C gave excellent conversion
      from the chloronucleoside, and adsorption on Amberlite XAD-4 resin provided more
      convenient isolation than prior methods. Weak binding of these non-hydrolyzed
      analogues to S-adenosyl-L-homocysteine hydrolase was observed.

PMID- 12423166
TI  - alpha-Hypervalent iodine functionalized phosphonium and arsonium ylides and their
      tandem reaction as umpolung reagents.
AB  - alpha-Hypervalent iodine functionalized phosphonium and arsonium ylides 2 can be
      used as umpolung ylides to react with nucleophiles to give alpha-heteroatom
      substituted ylides 4 in good yields. The nucleophilic substitution-Wittig tandem
      reaction of 2 can occur smoothly to provide an efficient method for the synthesis
      of (Z)-alpha-halo-alpha,beta-unsaturated enoates or enones 6, stereoselectively.

PMID- 12423167
TI  - Highly efficient allyl cross-coupling reactions of allylindiums with organic
      electrophiles.
AB  - This paper describes highly efficient allyl cross-coupling reactions of
      allylindiums with organic electrophiles such as aryl and vinyl triflates, vinyl
      halides, dibromoolefin, and alkynyl iodide. The reactions were carried out using
      4 mol % Pd(PPh3)4 in the presence of 3 equiv of LiCl in DMF at 100 degrees C
      under a nitrogen atmosphere. Allylindium, generated from the reaction of 1 equiv
      of indium with 1.5 equiv of allyl halide, gave the best result as a coupling
      partner. The present method is mild and simple to apply, and it produces a
      diverse range of allylic compounds in good to excellent yields.

PMID- 12423168
TI  - Functionalized 2,2'-bipyridines and 2,2':6',2' '-terpyridines via stille-type
      cross-coupling procedures.
AB  - Stille-type cross-coupling procedures are utilized in order to prepare a variety
      of functionalized 2,2'-bipyridines and 2,2':6',2' '-terpyridines. Such N
      heterocyclic compounds are of great interest as chelating ligands for transition
      metal ions in the field of supramolecular chemistry. Various mono- and
      disubstitued 2,2'-bipyridines were synthesized in high yields and multigram
      scales using a modular design principle. The terpyridines may be functionalized
      in one step with different substituents at the outer pyridine rings and at the 4'
      position of the centered ring, leading to multifunctionalized compounds. The
      initially obtained methyl ester and ethyl ester groups can be simply converted
      into bromomethyl and hydroxymethyl groups which allow further functionalization
      reactions.

PMID- 12423169
TI  - Linchpin construction of unsymmetrical 1,4-alkynediols.
AB  - A one-pot preparation of unsymmetrical 1,4-alkynediols such as 2a by the coupling
      of trimethylsilylacetylene and two different aldehydes or ketones is reported.
      The dilithiated species 5 is generated by the sequential addition of the first
      aldehyde or ketone 1b to a solution of lithium trimethylsilylacetylide, followed
      by the addition of methyllithium, which removes the trimethylsilyl protecting
      group. Addition of the second aldehyde or ketone then leads to the unsymmetrical
      1,4-alkynediol 2a.

PMID- 12423170
TI  - Asymmetric synthesis of alpha,alpha-difluoro-beta-amino acid derivatives from
      enantiomerically pure N-tert-butylsulfinimines.
AB  - Addition of the Reformatsky reagent derived from ethyl bromodifluoroacetate to
      alkyl- and aryl-substituted N-tert-butylsulfinimines furnishes beta-tert
      butylsulfinamyl-beta-substituted alpha,alpha-difluoroproponiates in
      diastereomeric ratios ranging from 80:20 to 95:5. The diastereomers are easily
      separated and the enantiomerically pure, protected beta-amino esters are readily
      transformed to the corresponding acid, amide, and amine derivatives as useful
      synthons for medicinal chemistry targets.

PMID- 12423171
TI  - Intramolecular triple heck reaction. An efficient entry to fused tetracycles with
      a benzene core.
AB  - Twelve examples of 1,3,5-tribromo-2,4,6-trienylbenzenes were easily synthesized
      by alkylation, etherification, and amination methods. Under conditions A and B, a
      series of tetracycles with a benzene core, i.e., fused 5,6,6-, 6,6,6-, and 6,6,7
      tetracyclic compounds, were prepared efficiently via this intramolecular triple
      Heck reaction protocol.

PMID- 12423172
TI  - A modified synthesis of iodoazidoaryl prazosin.
AB  - The antihypertension agent iodoazidoaryl prazosin (IAAP) has been made using a
      convergent route involving addition of an acylated piperazine 7 to 2
      chloroquinazoline 5. IAAP has been shown to function as a multidrug resistance
      (MDR) reversal agent and bind to P-glycoprotein, a transmembrane transport
      protein. A study is also reported involving palladium-catalyzed substitution with
      amine heterocycles. With N,N-bis(2,6-diisopropyl)dihydroimidazolium chloride (10)
      as the ligand (2 mol %) for palladium(II) acetate (2 mol %) in THF at room
      temperature, morpholine added to 5 in 81% yield.

PMID- 12423173
TI  - A safe and mild synthesis of organic carbonates from alkyl halides and
      tetrabutylammonium alkyl carbonates.
AB  - A safe and mild procedure for the synthesis of mixed organic carbonates is
      described. Reaction of commercially available tetrabutylammonium methoxide and
      ethoxide with carbon dioxide yields the corresponding methyl and ethyl
      tetrabutylammonium carbonates (TBAMC and TBAEC). The reactions of these new
      compounds with several different alkyl halides give methyl and ethyl carbonates
      in high yields. The use of classic toxic and harmful chemicals such as phosgene
      and carbon monoxide is avoided.

PMID- 12423175
TI  - Effects of 4 weeks of creatine supplementation in junior swimmers on freestyle
      sprint and swim bench performance.
AB  - To determine whether 4 weeks of oral creatine (Cr) supplementation could enhance
      single freestyle sprint and swim bench performance in experienced competitive
      junior swimmers, 10 young men and 10 young women (x age = 16.4 +/- 1.8 years)
      participated in a 27-day supplementation period and pre- and posttesting
      sessions. In session 1 (presupplementation testing), subjects swam one 50-m
      freestyle and then (after approximately 5 minutes of active recovery) one 100-m
      freestyle at maximum speed. Blood lactate was measured before and 1 minute after
      each swim trial. Forty-eight hours later, height, mass, and the sum of 6
      skinfolds were recorded, and a Biokinetic Swim Bench total work output test (2 x
      30-second trials, with a 10-minute passive recovery in between) was undertaken.
      After the pretests were completed, participants were divided into 2 groups (n =
      10, Cr; and n = 10, placebo) by means of matched pairs on the basis of gender and
      50-m swim times. A Cr loading phase of 20 g x d(-1) for 5 days was then
      instituted, followed by a maintenance phase of 5 g x d(-1) for 22 days.
      Postsupplementation testing replicated the presupplementation tests. Four weeks
      of Cr supplementation did not influence single sprint performance in the pool or
      body mass and composition. However, 30-second swim bench total work scores for
      trial 1 and trial 2 increased after Cr (p < 0.05) but not placebo ingestion.
      Postexercise blood lactate values were not different after supplementation for
      the 50- and 100-m sprint trials either within or between groups. It was concluded
      that 4 weeks of Cr supplementation did not significantly improve single sprint
      performance in competitive junior swimmers, but it did enhance swim bench test
      performance.

PMID- 12423176
TI  - Effect of induced alkalosis on perception of exertion during exercise recovery.
AB  - In this investigation we studied the effect of manipulating the acid-base balance
      through sodium bicarbonate (NaHCO(3)) ingestion on ratings of perceived exertion
      for the overall body (RPE-O) and on differentiated ratings for the leg and chest
      (RPE-L, RPE-C) during exercise recovery. Six women of college age underwent 3
      experimental conditions in which NaHCO(3) was ingested in either a single (bolus)
      or periodic (distributed throughout the exercise) dosage, with calcium carbonate
      serving as a placebo control. Each subject pedaled a cycle ergometer at 90%
      Vo(2)peak for three 5-minute exercise sessions, each separated by 10 minutes of
      recovery. Repeated-measures analysis of variance with Tukey post hoc analysis was
      performed for acid-base and perceptual variables. Results indicate that a
      gradient of acid-base balance was established such that pH and bicarbonate
      concentration were significantly greater (p < 0.05) for the single condition in
      comparison with periodic and placebo conditions, and the periodic condition was
      significantly greater (p < 0.05) than placebo. The average percentage of recovery
      for RPE-L and RPE-C was 8% greater (p < 0.05) for the single condition than for
      the periodic and placebo conditions, at the first and second minutes of recovery.
      During the first minute of recovery, the average percentage of recovery for RPE-O
      was 10% greater (p < 0.05) for the single condition than for the placebo
      condition. During the second minute of recovery, the percentage of recovery for
      RPE-O for the single condition was significantly greater than those for both the
      periodic and placebo conditions by an average of 9%. These results strengthen the
      relationship between the acid-base balance and the subjective perception of
      exertion. In addition, this study provides preliminary data in support of RPE as
      an adjunct measure to quantify the extent of recovery from exercise.

PMID- 12423177
TI  - The effect of creatine monohydrate supplementation on obstacle course and
      multiple bench press performance.
AB  - Dietary creatine (Cr) supplementation has been shown to enhance muscular strength
      and endurance. This study determined the effects of Cr supplementation on
      performance of military training tasks. Two groups (Cr and placebo [Pl]) of 13
      male soldiers each performed 3 consecutive military obstacle course runs (
      approximately 3 minutes over 7 obstacles with a 2-minute rest between runs)
      followed by a rifle marksmanship task on 3 occasions (T(1), T(2), and T(3)), each
      separated by 5 days. They also completed a bench press protocol (5 sets to
      failure at 70% of 1 repetition maximum) and answered the Profile of Mood States
      questionnaire during each test session. Testing was done 3 times. No
      supplementation was given before T(1). Supplementation was provided using sports
      bars, with both groups receiving Pl bars between T(1) and T(2), whereas from T(2)
      to T(3) the Cr group consumed 24 g per day of Cr monohydrate in sports bars and
      the Pl group consumed an equal amount (kilocalories) of Pl sports bars. Creatine
      usage resulted in a significant (14%) increase in total bench press repetitions
      (p </= 0.05), but no difference between groups in obstacle course run times for
      the 3 runs from T(2) to T(3). Marksmanship or mood was not affected by Cr
      supplementation. An increase of 1.4 kg in body mass (p </= 0.005) and a 0.5%
      decrease in percent body fat (p </= 0.05) were observed after Cr ingestion.
      Creatine supplementation over 5 days improved performance during a controlled
      strength test but did not significantly improve military obstacle course
      performance.

PMID- 12423178
TI  - Serum chemistry and hematological adaptations to 6 weeks of moderate to intense
      resistance training.
AB  - This study examined immune cell and blood chemistry changes occurring in trained
      weightlifters after 1 week of rest followed by 6 weeks of Olympic-style
      resistance exercise. Blood was drawn weekly after 1 day of rest at the same time
      and on the same day of the week for 7 weeks. Lymphocyte numbers increased in
      weeks 5 through 7. Sodium concentration rose above entry levels in week 2,
      remained elevated, and peaked in week 5. Direct bilirubin dropped below baseline
      values in the final week. Chloride and alkaline phosphatase concentrations
      increased as training progressed. Chloride, potassium, albumin, CO(2), and
      alkaline phosphatase concentrations peaked in weeks 4 through 6. Serum creatinine
      was elevated in weeks 2 through 5. Data indicate that resistance training induces
      changes in immune cell count and blood chemistry that remain within, or near,
      normal clinical values. It appears that resistance training does not induce
      immunosuppression or negatively affect hepatic or renal function.

PMID- 12423179
TI  - Biomechanical model and evaluation of a linear motion squat type exercise.
AB  - A biomechanical model of a squat exercise performed on a device using a bar that
      is restricted to a linear motion was developed. Hip and knee moments were
      evaluated at varying foot positions. The range of motion of the exercise was
      limited by the knee joint angle beginning at an 80 degrees angle (flexed) to a
      179 degrees joint angle (extended). Variations in foot placement were evaluated
      for differences in torque applied about the transverse axes of the user's knee
      and hip joints. Because the user's feet were positioned farther forward
      (anterior), the moment about the knee decreased whereas the moment about the hip
      increased. Positive moments were those that resulted in forces to flex the knee
      and hip joints. Positive knee moments were determined in all conditions when the
      knee was flexed and became negative when the knee was at or near full extension.
      The model always produced positive moments about the hip. Thus, foot position is
      a critical factor in hip and knee moments, and therefore in the muscle groups
      stressed, in a linear motion squat type exercise.

PMID- 12423180
TI  - Three sets of weight training superior to 1 set with equal intensity for
      eliciting strength.
AB  - The purpose of this study was to compare single and multiple sets of weight
      training for strength gains in recreationally trained individuals. Sixteen men
      (age = 21 +/- 2.0) were randomly assigned to 1 set (S-1; n = 8) or 3 set (S-3; n
      = 8) groups and trained 3 days per week for 12 weeks. One repetition maximum
      (1RM) was recorded for bench press and leg press at pre-, mid-, and posttest.
      Subjects trained according to daily undulating periodization (DUP), involving the
      bench press and leg press exercises between 4RM and 8RM. Training intensity was
      equated for both groups. Analysis of variance with repeated measures revealed
      statistically significant differences favoring S-3 in the leg press (p < 0.05,
      effect size [ES] = 6.5) and differences approaching significance in the bench
      press (p = 0.07, ES = 2.3). The results demonstrate that for recreationally
      trained individuals using DUP training, 3 sets of training are superior to 1 set
      for eliciting maximal strength gains.

PMID- 12423181
TI  - The acute effects of heavy loads on jump squat performance: an evaluation of the
      complex and contrast methods of power development.
AB  - The purpose of this investigation was to examine power performance in jump squats
      when using the complex and contrast training methods. Eleven (n = 11) women
      participated in a familiarization session and in three randomly ordered testing
      sessions. One session involved completing sets of power exercises (jump squats)
      before sets of half squats (traditional method). The second session involved sets
      of half squats before sets of jump squats (complex method). A third session
      involved the alternation of sets of half squats and jump squats (contrast
      method). No significant difference in jump squat performance between each of the
      training methods was found. There was a significant difference (p < 0.05) in the
      first set of each session, with the complex method having a significantly lower
      peak power. Further, there was a significant difference (p < 0.05) in performance
      changes between the higher and lower strength groups, with the higher strength
      group having a greater improvement in performance using the contrast training
      method compared with the traditional method. It was concluded that contrast
      training is advantageous for increasing power output but only for athletes with
      relatively high strength levels.

PMID- 12423182
TI  - A comparative electromyographical investigation of muscle utilization patterns
      using various hand positions during the lat pull-down.
AB  - This study aimed at investigating the effects of different hand positions on the
      electromyographic (EMG) activity of shoulder muscles during the performance of
      the lat pull-down exercise. Ten healthy men performed 3 repetitions of the lat
      pull-down exercise using their experimentally determined 10RM (repetition
      maximum) weight. Four different common variations of the lat pull-down were used:
      close grip (CG), supinated grip (SG), wide grip anterior (WGA), and wide grip
      posterior (WGP). Normalized root mean square of the EMG (NrmsEMG) activity for
      the right posterior deltoid (PD), latissimus dorsi (LD), pectoralis major (PM),
      teres major (TM), and long head of the triceps (TLH) were recorded using surface
      electrodes and normalized using maximum voluntary contractions. Repeated measures
      analysis of variance for each muscle detected statistical differences (p < 0.05)
      in myoelectric activity among hand positions during both the concentric and
      eccentric phases of the exercise. During the concentric phase, NrmsEMG results
      for the LD included WGA > WGP, SG, CG. For the TLH: WGA > WGP, SG, CG and WGP >
      CG, SG. For the PD: CG, WGA, SG > WGP. For the PM: CG, WGA, SG > WGP. During the
      eccentric phase, the LD produced the following patterns: WGA > WGP, SG, CG and
      WGP > CG. The TLH pattern showed WGA > SG and CG. For the PD: CG > WGA, WGP. The
      results indicate that changes in handgrip position affect the activities of
      specific muscles during the lat pull-down movement. Also, performance of the lat
      pull-down exercise using the WGA hand position produces greater muscle activity
      in the LD than any other hand position during both the concentric or eccentric
      phases of the movement.

PMID- 12423183
TI  - Electromyographic and kinetic analysis of traditional, chain, and elastic band
      squats.
AB  - This study examined mean integrated electromyography (I-EMG) for the quadriceps
      and hamstring muscle groups, as well as mean and peak vertical ground reaction
      forces (GRFs), for 3 conditions of the back squat. Conditions included (a) squat
      with barbell and weight plates, (b) squat with barbell and weight plates plus
      chains hung on each end of the barbell to replace approximately 10% of the squat
      load, and (c) squat with barbell and weight plates plus elastic bands offering
      resistance equivalent to approximately 10% of the squat load. Weight plates equal
      to the load added by either the chains or elastic bands were removed for the
      latter 2 squat conditions. Vertical GRFs were obtained during a single testing
      session for all 3 squat conditions. The tests were performed on a 2-cm thick
      aluminum platform (0.76 x 1.0 m) bolted directly to a force plate (OR6-5-2000,
      AMTI, Watertown, MA). Surface electrode I-EMG data from the quadriceps and
      hamstrings were recorded at 500 Hz. The exercise order was randomly determined
      for 11 NCAA Division I athletes who had experience using these types of squats. A
      repeated measures analysis of covariance revealed no differences in I-EMG and GRF
      during the eccentric or concentric phase for any of the 3 squat conditions.
      Analyses showed that mean GRF and I-EMG was significantly different between
      eccentric and concentric phases for all groups. The results question the
      usefulness of performing squats combining barbell and weight plates with chain
      and elastic resistance.

PMID- 12423184
TI  - Snatch technique of collegiate national level weightlifters.
AB  - Bar trajectory during weightlifting movements is related to the position of the
      body during the lift and the displacement of the feet during the drop-under
      phase. The purpose of this study was to examine anterior-posterior foot
      displacement and its relationship with performance in the snatch of collegiate
      weightlifters. Snatch attempts of men weightlifters from the 1998 U.S.A.
      Weightlifting Collegiate National Championships were analyzed for horizontal
      displacement of the feet by video analysis. Lifts were analyzed under 2
      conditions: all lifts combined and the heaviest successful attempt for each
      lifter. Lifts (n = 74) were placed into 4 groups: forward displacement (FD, >2.5
      cm); no displacement (ND, +/-2.5 cm); rearward displacement (RD, >2.5 cm); and
      those that showed asymmetric (AS, >7 cm difference in right and left foot)
      displacement of the feet. Chi-square revealed no significant difference in
      success rate between groups for all attempts. No statistically significant
      differences were noted between groups in body mass to bar mass ratio or Sinclair
      formula for heaviest successful attempts. Results indicate that foot displacement
      did not significantly affect snatch success or lifting ability in collegiate
      national level lifters.

PMID- 12423185
TI  - Influence of hip orientation on Wingate power output and cycling technique.
AB  - The effect of altered hip orientation angle ([HOA] angle of hip joint center to
      bottom bracket relative to horizontal) on Wingate anaerobic test results and
      cycling technique while maintaining a constant body configuration angle (included
      angle between torso, hip, and bottom bracket) and maximum hip-to-pedal distance
      was examined. Nineteen recreational cyclists, all men, with no recent recumbent
      cycling experience completed 30-second Wingate tests in 3 recumbent positions
      (HOA = -20 degrees, -10 degrees, and 0 degrees ) and the standard cycling
      position (SCP) (HOA = 75 degrees ). Peak, average, and minimum power output, as
      well as fatigue index, were not significantly different across all positions (p <
      0.01). Average hip and knee extension angles increased slightly, and ankle angle
      did not change as HOA increased. These findings indicate that although HOA does
      have a small effect on cycling kinematics, these effects are not large enough to
      alter short-term power output. Therefore, anaerobic power output may be evaluated
      and compared in the recumbent positions and the SCP.

PMID- 12423186
TI  - The effects of cold-water immersion on power output and heart rate in elite
      cyclists.
AB  - The purpose of this study was to examine the effects of cold-water immersion on
      power output, heart rate, and time to peak power in 10 well-trained cyclists. The
      Compu-trainer Professional Model 8001 computerized stationary trainer was used to
      evaluate maximum power, average power, and time to peak power during a simulated
      cycling sprint. The heart rate was measured using a Polar heart rate monitor.
      Subjects performed 2 maximum-effort sprints (for approximately 30 seconds)
      separated by either an experimental condition (15 minutes of cold-water immersion
      at 12 degrees C up to the level of the iliac crest) or a control condition (15
      minutes of quiet sitting). All subjects participated under both control and
      experimental conditions in a counterbalanced design in which 5 subjects performed
      the experimental condition first and the other 5 subjects performed the control
      condition first. Each condition was separated by at least 2 days. The time to
      peak power was not different between the 2 conditions. Maximum and average powers
      declined by 13.7 and 9.5% for the experimental condition but only by 4.7 and 2.3%
      for the control condition, respectively. The results also demonstrated a
      significantly greater decline in maximum heart rate after cold-water immersion
      (8.1%) than under the control condition (2.4%). Average heart rate showed a
      decrease of 4.2% under the experimental condition, as compared with an increase
      of 1.5% under the control condition. The major findings of this study suggest
      that a relatively brief period of cold-water immersion can manifest significant
      physiological effects that can impair cycling performance.

PMID- 12423187
TI  - Net caloric cost of a 3-set flywheel ergometer resistance exercise paradigm.
AB  - Subjects (n = 23) performed three 3 x 8 seated leg press workouts on a flywheel
      ergometer to note the net caloric cost. This study's purpose was to examine net
      caloric cost as a function of total work on an inertial resistance exercise
      device offering more eccentric loading than conventional isotonic weight training
      equipment. High intraclass correlations for net caloric cost (0.89) and total
      work (0.94) result from data collected from 3 workouts. Average total work and
      net caloric cost values reveal a significant (r = 0.62, p < 0.05) correlation
      yielding the following equation: predicted net caloric cost = 33.2 + 0.006014331
      (total work). Current study data also show favorable net caloric cost (1.24 kcal
      x kg(-1) x d(-1)), exercise efficiency (9.48 kcal x 10(-3) per joule), and
      estimated mechanical loading (65 W min x kg(-1) LBM x d(-1)) values. The results
      of the current study serve as baseline knowledge for exercise prescriptions
      pertaining to net caloric cost, exercise efficiency, and mechanical loading using
      this device.

PMID- 12423188
TI  - The relationship of the heart rate deflection point to the ventilatory threshold
      in trained cyclists.
AB  - The purpose of this study was to assess the relationship of the heart rate
      deflection point (HRDP) to the ventilatory threshold (VT) in trained cyclists.
      Twenty-one endurance-trained cyclists (mean +/- SD: Vo(2)max = 67.6 +/- 4.7 ml x
      kg x min(-1)) completed a maximal cycle ergometer test of volitional fatigue
      using a ramped protocol. Ventilatory variables (Ve, Vo(2), Vco(2)) and power were
      measured online with averages reported every 20 seconds. Heart rate (HR) was
      recorded every 20 seconds using a Polar monitor. VT was calculated using the
      excess CO(2) elimination curve. The first derivative of a logistic growth curve
      fit to the HR-power data produced the HRDP. No significant differences (p > 0.01)
      existed between HR values at HRDP (171.7 +/- 9.6 b x min(-1)) and VT (169.8 +/-
      9.9 b x min(-1)) or between Vo(2) values at HRDP (53.6 +/- 4.2 ml x kg x min(-1))
      and VT (52.2 +/- 4.8 ml x kg x min(-1)). But power values at HRDP (318.7 +/- 30.7
      W) were significantly different (p < 0.01) from those at VT (334.8 +/- 36.7 W).
      There were significant relationships between HRDP and VT for the physiological
      variables of HR (r = 0.92, p < 0.001), Vo(2) (r = 0.72, p < 0.001), and power (r
      = 0.77, p < 0.001). These findings indicate that HR and Vo(2) at HRDP are not
      significantly different from the values at VT in trained cyclists. HR values
      derived from HRDP may be used to set parameters for training intensity.
      Variability in the speed/power-HRDP relationship across detrained/trained states
      may be used to evaluate training programs.

PMID- 12423189
TI  - Differences in strength and power among junior-high, senior-high, college-aged,
      and elite professional rugby league players.
AB  - Ninety-five rugby league players ranging from junior high-school to elite
      professionals were compared for measures of strength and power. Strength was
      assessed by 1 repetition maximum bench press strength (1RM BP). Upper-body and
      lower-body power outputs were assessed during bench press throws and jump squats
      with a resistance of 20 kg (BT P20 and JS P20, respectively). The 1RM BP was a
      potent descriptor of playing achievement levels and was significantly different
      among all groups investigated. Both the BT P20 and JS P20 of the elite
      professional National Rugby League (NRL) group were significantly higher than
      those of the college-aged rugby league (CRL) group, which in turn were
      significantly higher than those of the 3 high-school groups. Senior high-school
      players were more powerful in the upper body compared with nonresistance-trained
      junior high-school players but not with resistance-trained junior high-school
      players. There was no difference in lower-body power output among any of the 3
      high-school groups. The correlation between players achievement level and 1RM BP,
      BT P20, and JS P20 was significant for all 3 tests, with relations of r = 0.80, r
      = 0.74, and r = 0.61, respectively. The results of this study suggest that young
      rugby league players should strive to increase strength and power to attain NRL
      professional status in the future.

PMID- 12423190
TI  - Side-to-side comparisons of bone mineral density in upper and lower limbs of
      collegiate athletes.
AB  - This cross-sectional study investigated the effects of participation in various
      sports on side-to-side (contralateral) differences in bone mineral density (BMD)
      of the upper and lower limbs. The BMD of the arms and legs was measured using
      dual energy X-ray absorptiometry. The subjects were 184 collegiate athletes, both
      men and women, who participated in NCAA Division I-A baseball, basketball,
      football, golf, soccer, tennis, cross-country, indoor/outdoor track, and
      volleyball. Results revealed greater BMD of the right arms compared with the left
      arms for all teams, with the most pronounced differences observed in men's and
      women's tennis and men's baseball. Differences in the lower limbs were less
      common. No significant differences in lower limb BMD were found in the women. In
      men, differences in lower limb BMD were found in the football and tennis teams,
      with the nondominant leg having greater bone mass. Recognition of contralateral
      differences in bone density may be of particular interest to strength and
      conditioning professionals as they consider the need to include bilateral and
      unilateral training programs in an effort to maximize performance and minimize
      stress-related injuries.

PMID- 12423191
TI  - Effect of exercise-induced changes in residual lung volume on the determination
      of body composition.
AB  - The transient increase in residual lung volume (RV) as a result of exercise has
      been well documented. An accurate assessment of exercise-induced RV would be
      important when hydrostatic weighing (HW) is performed after exercise. The purpose
      of this study was to determine whether accurate HW measures could be performed
      after exercise when changes in RV are measured. Subjects (n = 32) performed
      pulmonary function (vital capacity [VC]-estimated RV), oxygen dilution-determined
      RV, and HW measures before and after either a maximal treadmill test (n = 16) or
      seated rest (n = 16). Two-way analysis of variance (p </= 0.05) was performed on
      RV and HW body composition to identify significance between pre- and
      posttreatment. A post hoc paired t-test was performed to identify the source of
      any significant interactions. Results showed that for exercising subjects, oxygen
      dilution-determined RV was significantly increased between pre- and
      posttreatment. Estimated RV did not differ significantly for either group.
      Hydrostatic weighing body composition data were not significantly different for
      either group when oxygen dilution-determined RV was used. Conversely, when
      estimated RV was used in the calculation of body composition, a significant
      difference was noted between pre- and posttreatment in the exercise group
      (percentage of fat increased, whereas percentage of lean body mass decreased).
      The results of this study suggest that accurate body composition estimation can
      be performed after exercise. Body composition accuracy, however, is reliant on
      the concomitant employment of HW and RV estimation techniques that are sensitive
      to transient changes in RV. For this study, the oxygen dilution method of RV
      determination was used. Estimated RV (VC method) was not sensitive to changes in
      RV, subsequently resulting in erroneous HW body composition after maximal
      exercise.

PMID- 12423192
TI  - Evaluation of the BOD POD for estimating percent fat in female college athletes.
AB  - The purpose of this investigation was to examine the accuracy of percent body fat
      (%BF) estimates obtained by air displacement plethysmography (ADP) using the BOD
      POD Body Composition System compared with hydrostatic weighing (HW) in a group of
      female college athletes (n = 80). In addition, %BF estimates by skinfold measures
      (SF) were also obtained for comparison. A lean subset (n = 39) of the sample was
      also examined. Mean %BF estimated for the entire sample by ADP (21.2 +/- 5.9%)
      was significantly greater than that determined by HW (19.4 +/- 6.4%) and SF (18.8
      +/- 5.5%). Results from the lean subset also revealed that %BF determined by ADP
      (17.1 +/- 3.7%) was significantly higher than %BF estimates by HW (14.3 +/- 2.8%)
      and SF (15.2 +/- 3.2%). The regression equation for the entire sample (%BF HW =
      0.937%BF ADP - 0.452, r(2) = 0.73, standard error of estimates (SEE) = 3.34) did
      not differ from the line of identity. In contrast, the line of identity differed
      significantly from the regression equation for the lean subset of female athletes
      (%BF HW = 0.48%BF ADP + 6.115, r(2) = 0.41, SEE = 2.18). The results of this
      investigation indicate that ADP significantly overestimated %BF by 8% in female
      athletes and by 16% for a leaner subset of the sample compared with HW. It
      appears that %BF estimates by SF may be more accurate than those obtained by ADP
      for female college athletes, regardless of body composition. Coaches and trainers
      evaluating body composition should consider the use of SF before ADP when
      measuring %BF in female college athletes. Sports scientists should continue to
      examine the possible gender and body composition bias for ADP.

PMID- 12423193
TI  - The energy expenditure of snowshoeing in packed vs. unpacked snow at low-level
      walking speeds.
AB  - Snowshoeing is currently ranked as one of the top 20 participatory sports in the
      United States, and the number of participants almost tripled, from 440,000 to 1.2
      million in 1998. Despite this large increase in participation, no scientific
      evidence exists to quantify any physiologic response to the activity. Therefore,
      the purpose of this investigation was to assess the energy expenditure of
      snowshoeing at selected low-level speeds and evaluate its acceptability as a form
      of aerobic conditioning exercise. Ten habitually active subjects (7 men, 3 women,
      mean age = 24 +/- 3.9 years, mass = 76.6 +/- 14.5 kg, height = 173.7 +/- 9.6 cm)
      were recruited. Steady state heart rate data were determined from 2 treadmill
      tests at 4 and 6 mph. Steady state heart rates at 4 mph and 6 mph from treadmill
      speeds were then reproduced outdoors under 2 snow conditions, packed, and
      unpacked snow, while caloric expenditure and speed were determined. Expired gases
      were collected in Douglas bags for both snowshoe and treadmill trials and then
      analyzed and corrected indoors for the fractional concentrations of carbon
      dioxide and oxygen. Data analyses indicate that caloric expenditure during
      snowshoeing may be considerably higher than previously reported. Snowshoeing on
      packed snow at 2.95 mph elicited a similar heart rate and energy expenditure
      response as walking on a treadmill at 4 mph or snowshoeing in unpacked snow at
      2.04 mph (Vo(2) = 18.18 +/- 0.8 ml x kg(-1) x min(-1)). Snowshoeing on packed
      snow at 3.97 mph elicited the same heart rate and energy expenditure response as
      walking on a treadmill at 6 mph or snowshoeing on unpacked snow at 2.87 mph
      (Vo(2) = 36.72 +/- 0.8 ml x kg(-1) x min(-1)). Furthermore, increasing walking
      speed on snow by just 1 mph at slow speeds (2 and 3 mph) resulted in
      approximately twice the energy expenditure. Our data indicate that current
      estimates of energy expenditure while snowshoeing underestimate by greater than
      50%. Apparently the energy expenditure during snowshoeing is much higher than
      previously considered and varies considerably because of snow terrain.
      Furthermore, energy expenditure levels similar to walking can be achieved on
      snowshoes at much slower speeds. This study represents an original investigation
      into energy expenditure during snowshoeing.

PMID- 12423194
TI  - Relationship between football playing ability and selected performance measures.
AB  - The relationships between football playing ability (FPA) and selected
      anthropometric and performance measures were determined among NCAA Division I-A
      football players (N = 40). Football playing ability (determined by the average of
      coaches' rankings) was significantly correlated with vertical jump (VJ) in all
      groups (offense, defense, and position groups of wide receiver-defensive back,
      offensive linemen-defensive linemen, and running back-tight end-linebacker).
      Eleven of 50 correlations (groups by variables), or 22%, were important for FPA.
      Five of the 11 relationships were related to VJ. Forward stepwise regression
      equations for each group explained over half of the criterion variable, FPA, as
      indicated by the R(2) values for each model. Vertical jump was the prime
      predictor variable in the equations for all groups. The findings of this study
      are discussed in relation to the specificity hypothesis. Strength and
      conditioning programs that facilitate the capacity for football players to
      develop forceful and rapid concentric action through plantar flexion of the
      ankle, as well as extension of the knee and hip, may be highly profitable.

PMID- 12423195
TI  - Test-retest reliability of 4 single-leg horizontal hop tests.
AB  - The purpose of this study was to determine the test-retest reliability of 4
      single-leg horizontal hop tests (i.e., single hop for distance, triple hop for
      distance, crossover hop for distance, and 6-m hop for time), with a time interval
      of approximately 4 weeks separating the 2 testing sessions. Eighteen healthy,
      young, adult men, all cadets enrolled at the U.S. Air Force Academy, Colorado,
      performed the single hop for distance, the triple hop for distance, the crossover
      hop for distance, and the 6-m hop for time during 2 testing sessions separated by
      31.2 +/- 0.4 days. Reliability data for each of the single-leg hop tests were
      studied through a repeated measures analysis of variance, intraclass correlation
      coefficients (ICCs), and standard errors of measurement (SEMs). The ICCs ranged
      from 0.92 to 0.97 for the 4 single-leg hop tests. The SEMs for the single-leg hop
      tests that assessed the distance hopped ranged from 4.61 to 17.74 cm. The SEM for
      the 6-m hop for time test was 0.06 seconds. No significant differences were noted
      when the mean scores of the 2 test trials were compared by a repeated measures
      analysis of variance for any of the single-leg hop tests. These results indicate
      that the single-leg hop tests examined in this study offer strength and
      conditioning professionals a reliable method to assess the single-leg horizontal
      hopping capabilities of healthy, young, adult men, with intervals of
      approximately 4 weeks between testing sessions.

PMID- 12423196
TI  - The relationship between selected blood lactate thresholds and match performance
      in elite soccer referees.
AB  - The aim of this study was to examine the relationship between selected blood
      lactate thresholds and competitive match activities in elite soccer referees.
      Eight elite-level referees (mean age, 37.6 +/- 3.4 years) were each observed
      during 2 Serie A matches (n = 16), and the mean of each match activity was used
      for analysis. Match activities were monitored using a technology similar to that
      reported by Ohashi and others. Blood lactate thresholds were assessed under field
      conditions during a progressive multistage protocol. Running velocities attained
      at selected blood lactate concentrations (2 and 4 mmol x L(-1), V2 and V4,
      respectively) were chosen because these are commonly used to assess endurance
      performance. Analyses of correlations were performed considering V2 and V4 values
      as independent variables and total distance, maximal velocity distance (runs
      performed at velocities faster than 24 km x h(-1)) and high-intensity activity
      distance (runs performed at velocities faster than 18 km x h(-1)) as dependent
      variables. Significance was set at p </= 0.05 for all measurements. The V2 and V4
      values were 10.9 +/- 1.8 km x h(-1) and 13.6 +/- 1.4 km x h(-1) (10.5-15.0),
      respectively. Mean peak-lactate corresponded to 9.4 +/- 1.6 mmol x L(-1). The V4
      value correlated moderately with the total distance covered during the match (r =
      0.73, p < 0.05). The results demonstrate the positive relationship of the running
      velocity attained at a blood lactate concentration of 4 mmol x L(-1) to the total
      amount of distance covered by a referee during a match.

PMID- 12423197
TI  - Absolute vs. relative machine strength as predictors of function in older adults.
AB  - This study examined the relationship between absolute and relative (1 repetition
      maximum/LBM) strength vs. 13 different functional measurements in 143 older
      adults (mean = 70.28, standard deviation = 7.90 years). Strength for 11 machine
      lifts was determined using a predicted 1-repetition maximal strength measurement.
      Zero-order correlation results between absolute and relative strength vs.
      function measures demonstrated very weak to moderate correlations in the range of
      0.02-0.57 and 0.01-0.44, respectively, with the lowest correlations present
      between strength and balance measures and the highest correlations present
      between strength and the carrying task (p </= 0.05). Stepwise multiple regression
      results also confirmed the low predictability of functional tasks using strength
      measures, with absolute and relative strength measures accounting for only 3-38%
      and 3-33% of the various functional measures, respectively. This study identified
      specific strength measurements that contribute to the variance in a functional
      task but also clearly indicated that strength alone cannot serve as a predictor
      of function in older adults.

PMID- 12423198
TI  - Assessment of the accuracy of the Conconi test in determining gas analysis
      anaerobic threshold.
AB  - The primary objective of this study was to assess the validity of the Conconi
      method of assessing anaerobic threshold (AT). Twenty-two competitive cyclists (11
      men, 11 women) performed an incremental, maximal oxygen uptake (Vdot;o(2)max)
      test on an electrically braked cycle ergometer. AT was assessed by a nonlinear
      increase in the carbon dioxide to oxygen consumption ratio (V-slope method). AT
      was also measured by a computer-assessed break point in heart rate from linearity
      (Conconi method). Mean values for heart rate at AT were 157.3 and 163.3 b x min(
      1) for the Conconi and V-slope methods, respectively. Although there was no
      significant difference (t = 1.07, p = 0.30) in the 2 methods, a rather low
      correlation coefficient (r = 0.458), high standard error of estimate (SEE = 10.7
      b x min(-1)), and high total error (TE = 16.7 b x min(-1)) would preclude the use
      of the Conconi method as a practical tool for assessing AT.

PMID- 12423199
TI  - Relations of strength training to body image among a sample of female university
      students.
AB  - College women enrolled in a strength training class were evaluated before and
      after the class using a combination of physical fitness measures, including
      weight, percentage of body fat, body circumference, and strength measures. Forty
      nine subjects participated in strength training, twice a week for a total of 12
      weeks. At the end of the class, participants were asked to respond to 9 open
      ended questions dealing with perceptions of body image. Physical results of the
      study showed a mean weight gain of 1 lb, an average increase in body fat of 0.9%,
      and a 5-11 lb improvement in maximal lifting ability. In addition, most subjects
      reported that they felt healthier and more fit and had an improved body image and
      a better attitude about their physical selves after strength training. In this
      study, exercise using strength training improved strength and body image in
      women.

PMID- 12423200
TI  - Muscle dysmorphia in elite-level power lifters and bodybuilders: a test of
      differences within a conceptual model.
AB  - The purpose of this study was to determine if associated characteristics of
      muscle dysmorphia (MD) were different between elite-level competitive
      bodybuilders and power lifters. Elite-level competitive bodybuilders (n = 100)
      and power lifters (n = 68) completed the muscle dysmorphia inventory (MDI) at the
      time of or immediately before competition. A 2 x 6 (group x MDI subscales)
      multivariate analysis of variance indicated that bodybuilders were significantly
      more likely to report body size-symmetry concerns (F(1, 167) = 10.31, p < 0.001),
      physique protection (F(1, 167) = 10.27, p < 0.001), dietary behavior (F(1, 167) =
      28.38, p < 0.001), and pharmacological use (F(1, 167) = 19.64, p < 0.001) than
      were power lifters. These results suggest that elite-level bodybuilders are
      significantly more likely to engage in characteristics associated with MD than
      are elite-level power lifters.

PMID- 12423202
TI  - Leptin activates the promoter of the interleukin-1 receptor antagonist through
      p42/44 mitogen-activated protein kinase and a composite nuclear factor kappa
      B/PU.1 binding site.
AB  - We have recently shown that leptin strongly induces the expression and secretion
      of the interleukin-1 receptor antagonist (IL-1Ra) [Gabay, Dreyer, Pellegrinelli,
      Chicheportiche and Meier (2001) J. Clin. Endocrinol. Metab. 86, 783-791] in
      monocytes. However, the intracellular signalling mechanisms involved remained
      unknown. We now demonstrate that the activation of the IL-1Ra promoter by leptin
      is strictly dependent on the presence of the long form of the leptin receptor (OB
      Rb), and that it also requires the activation of the p42/44 mitogen-activated
      protein kinases (MAPKs) as well as the presence of a nuclear factor kappaB (NF
      kappa B)/PU.1 composite site at position -80 of the IL-1Ra promoter. Although
      leptin is capable of activating a NF-kappa B reporter element in transient
      transfection experiments, the protein complex binding to the NF-kappa B/PU.1 site
      of the IL-1Ra promoter is not composed of the p65/p50 subunits of NF-kappa B, as
      is evident in electrophoretic gel mobility-shift experiments. In contrast, a
      protein complex which does not contain PU.1 binds to this composite element in a
      leptin-dependent manner. In summary, we characterize the signalling pathway for
      leptin and OB-Rb involved in the induction of IL-1Ra, involving p42/44 MAPK, and
      a yet uncharacterized complex of transcription factor(s) binding to a NF-kappa
      B/PU.1 composite element of the IL-1Ra promoter.

PMID- 12423201
TI  - Effects of nitrogen monoxide and carbon monoxide on molecular and cellular iron
      metabolism: mirror-image effector molecules that target iron.
AB  - Many effector functions of nitrogen monoxide (NO) and carbon monoxide (CO) are
      mediated through their high-affinity for iron (Fe). In this review, the roles of
      NO and CO are examined in terms of their effects on the molecular and cellular
      mechanisms involved in Fe metabolism. Both NO and CO avidly form complexes with a
      plethora of Fe-containing molecules. The generation of NO and CO is mediated by
      the nitric oxide synthase and haem oxygenase (HO) families of enzymes
      respectively. The effects of NO on Fe metabolism have been well characterized,
      whereas knowledge of the effects of CO remains within its infancy. In terms of
      the role of NO in Fe metabolism, one of the best characterized interactions
      includes its effect on the iron regulatory proteins. These molecules are mRNA
      binding proteins that control the expression of the transferrin receptor 1 and
      ferritin, molecules that are involved in Fe uptake and storage respectively.
      Apart from this, activated macrophages impart their cytotoxic activity by
      generating NO, which results in marked Fe mobilization from tumour-cell targets.
      This deprives the cell of the Fe that is required for DNA synthesis and energy
      production. Considering that HO degrades haem, resulting in the release of CO,
      Fe(II) and biliverdin, it is suggested that a CO-Fe complex will form. This may
      account for the rapid Fe mobilization observed from macrophages after haemoglobin
      catabolism. Intriguingly, overexpression of HO results in cellular Fe
      mobilization, suggesting that CO has a similar effect to NO on Fe trafficking.
      Preliminary evidence suggests that, like NO, CO plays important roles in Fe
      metabolism.

PMID- 12423203
TI  - Interactions of the designed antimicrobial peptide MB21 and truncated dermaseptin
      S3 with lipid bilayers: molecular-dynamics simulations.
AB  - Molecular-dynamics simulations covering 30 ns of both a natural and a synthetic
      antimicrobial peptide in the presence of a zwitterionic lipid bilayer were
      performed. In both simulations, copies of the peptides were placed in an alpha
      helical conformation on either side of the bilayer about 10 A (1 A=0.1 nm) from
      the interface, with either the hydrophobic or the positively charged face of the
      helix directed toward the bilayer surface. The degree of peptide-lipid
      interaction was dependent on the starting configuration: surface binding and
      subsequent penetration of the bilayer was observed for the hydrophobically
      oriented peptides, while the charge-oriented peptides demonstrated at most
      partial surface binding. Aromatic residues near the N-termini of the peptides
      appear to play an important role in driving peptide-lipid interactions. A
      correlation between the extent of peptide-lipid interactions and helical
      stability was observed in the simulations. Insertion of the peptides into the
      bilayer caused a dramatic increase in the lateral area per lipid and decrease in
      the bilayer thickness, resulting in substantial disordering of the lipid chains.
      Results from the simulations are consistent with early stages of proposed
      mechanisms for the lytic activity of antimicrobial peptides. In addition to these
      'free' simulations, 25 ns simulations were carried out with the peptides
      constrained at three different distances relative to the bilayer interface. The
      constraint forces are in agreement with the extent of peptide-bilayer insertion
      observed in the free simulations.

PMID- 12423204
TI  - Selenite sensitizes mitochondrial permeability transition pore opening in vitro
      and in vivo: a possible mechanism for chemo-protection.
AB  - There is a known connection between selenium supplementation and chemo-protective
      anti-cancer activity. This biological phenomenon may be due to the ability of
      selenium to instigate cellular apoptosis. However, the mechanism by which
      selenium promotes cellular apoptosis is still obscure. The present study shows
      that sodium selenite, a common dietary form of selenium, promotes the
      mitochondrial permeability transition (MPT) in isolated rat liver mitochondria
      both in vitro and following in vivo supplementation. A low selenium concentration
      (0.1-10 microM) strongly induced cyclosporin A-sensitive mitochondrial swelling.
      Selenium also promoted both calcium release from the matrix of isolated
      mitochondria and uncoupled respiration. The MPT-inducing effect of selenium
      provoked the release of cytochrome c, a pro-apoptotic factor, into the incubation
      medium. Selenium did not increase intra-mitochondrial peroxide production, but
      did consume endogenous mitochondrial glutathione. Moreover, the effect of MPT
      induction was greatly potentiated in the presence of thiol-bearing antioxidants,
      e.g. N -acetylcysteine and lipoamide. During MPT progression, selenium induced
      NADH oxidation via electron acceptance from complex I. Supplementation for 20
      days with 16 p.p.m. selenium in the drinking water of rats increased the
      propensity of mitochondria to undergo the MPT. More marked mitochondrial swelling
      in response to calcium and lower calcium-uptake capacity were observed, in the
      absence of liver damage or the intensive oxidation of reduced glutathione.
      Therefore selenite facilitates MPT pore opening via its thiol- and NADH/complex I
      dependent reduction, and thereby may provide chemo-protection by potentiation of
      the capacity of the mitochondria to regulate programmed cell death. Data from the
      present study suggest that selenium can regulate important mitochondrial
      functions both in vivo and in vitro.

PMID- 12423205
TI  - Structure and function of the globin and globin gene from the Antarctic mollusc
      Yoldia eightsi.
AB  - The mechanism of adaptation of haemoglobin from the Antarctic mollusc Yoldia
      eightsi to its low-temperature environment is a decrease in the oxygen affinity
      via an increased ligand-dissociation rate. At 2 degrees C this haemoglobin has an
      oxygen affinity similar to other haemoglobins at 25 degrees C. At 25 degrees C,
      Yoldia haemoglobin shows a low oxygen affinity, resembling that of human
      deoxyhaemoglobin. The mechanism involves a lower binding energy to oxygen,
      suggesting a loss or weakening of the usual hydrogen bond, leading to a higher
      oxygen-dissociation rate. However, Yoldia haemoglobin has the usual distal and
      proximal histidines, so the primary structure alone does not provide an obvious
      explanation for the low affinity. The CO-binding kinetics are biphasic, with the
      fraction of slow phase increasing at higher protein concentrations, indicating
      the formation of dimers or a higher level of polymerization. The protein-protein
      interaction appears to be of hydrophobic nature, since it can be partially
      reversed by addition of ethylene glycol as co-solvent. While the CO-association
      rates differ by a factor of 10, the oxygen equilibrium data could be simulated
      with a single affinity. The Yoldia haemoglobin gene contains three introns,
      interrupting the coding region at position NA1.2, B12.2 and G7.0. The
      conservation of the B12.2 and G7.0 introns is in contrast with the unprecedented
      NA1.2 intron. Phylogenetic analyses reveal a gene tree where the Yoldia
      haemoglobin gene is separated from other mollusc globin genes, confirming the
      specific adaptation of the Yoldia haemoglobin.

PMID- 12423206
TI  - The TATA-binding protein is not an essential target of the transcriptional
      activators Gal4p and Gcn4p in Saccharomyces cerevisiae.
AB  - According to the recruitment model, transcriptional activators work by increasing
      the local concentration of one or several limiting factors for the transcription
      process at the target promoter. The TATA-binding protein Tbp1 has been considered
      as a likely candidate for such a limiting factor. We have used a series of Gal4p
      and Tbp1 mutants to correlate the in vivo interaction between the two proteins
      with the strength of activation. We find a clear correlation between activation
      strength and in vivo interaction for the series of Gal4p mutants. Consistently,
      the weaker activator Gcn4p does not interact with Tbp1. However, a corresponding
      analysis of the series of Tbp1 mutants revealed that Tbp1 is not an essential
      target of the acidic activators Gal4p and Gcn4p. Furthermore, detailed analysis
      of a Tbp1 mutant deficient for transcriptional activation by Gal4p revealed that
      the mutant is defective in interactions with five other proteins involved in the
      process of transcription.

PMID- 12423207
TI  - Evidence for secretion-like coupling involving pp60src in the activation and
      maintenance of store-mediated Ca2+ entry in mouse pancreatic acinar cells.
AB  - Store-mediated Ca2+ entry (SMCE) is one of the main pathways for Ca2+ influx in
      non-excitable cells. Recent studies favour a secretion-like coupling mechanism to
      explain SMCE, where Ca2+ entry is mediated by an interaction of the endoplasmic
      reticulum (ER) with the plasma membrane (PM) and is modulated by the actin
      cytoskeleton. To explore this possibility further we have now investigated the
      role of the actin cytoskeleton in the activation and maintenance of SMCE in
      pancreatic acinar cells, a more specialized secretory cell type which might be an
      ideal cellular model to investigate further the properties of the secretion-like
      coupling model. In these cells, the cytoskeletal disrupters cytochalasin D and
      latrunculin A inhibited both the activation and maintenance of SMCE. In addition,
      stabilization of a cortical actin barrier by jasplakinolide prevented the
      activation, but not the maintenance, of SMCE, suggesting that, as for secretion,
      the actin cytoskeleton plays a double role in SMCE as a negative modulator of the
      interaction between the ER and PM, but is also required for this mechanism, since
      the cytoskeleton disrupters impaired Ca2+ entry. Finally, depletion of the
      intracellular Ca2+ stores induces cytoskeletal association and activation of
      pp60(src), which is independent on Ca2+ entry. pp60(src) activation requires the
      integrity of the actin cytoskeleton and participates in the initial phase of the
      activation of SMCE in pancreatic acinar cells.

PMID- 12423221
TI  - Pharmacokinetics and bioavailability of trimethoprim-sulfamethoxazole in alpacas.
AB  - The pharmacokinetics and bioavailability of trimethoprim-sulfamethoxazole (TMP
      SMX) were studied in six healthy male-castrate alpacas (Lama pacos) after
      intravenous (i.v.) or oral (p.o.) drug administration of 15 mg/kg TMP-SMX using a
      crossover design with a 2-week washout period. After 90 days one group (n = 3)
      was given a p.o. dose of 30 mg/kg TMP-SMX and the other group (n = 3) was given a
      p.o. dose of 60 mg/kg TMP-SMX. After i.v. administration of 15 mg/kg of TMP-SMX
      the mean initial plasma concentration (C0) was 10.75 +/- 2.12 microg/mL for
      trimethoprim (TMP) and 158.3 +/- 189.3 microg/mL for sulfamethoxazole (SMX).
      Elimination half-lives were 0.74 +/- 0.1 h for TMP and 2.2 +/- 0.6 h for SMX. The
      mean residence times were 1.45 +/- 0.72 h for TMP and 2.8 +/- 0.6 h for SMX. The
      areas under the respective concentration vs. time curves (AUC) were 2.49 +/- 1.62
      microg h/mL for TMP and 124 +/- 60 microg h/mL for SMX. Total clearance (Clt) for
      TMP was 21.63 +/- 9.85 and 1.90 +/- 0.77 mL/min kg for SMX. The volume of
      distribution at steady state was 2.32 +/- 1.15 L/kg for TMP and 0.35 +/- 0.09
      L/kg for SMX. After intragastric administration of 15, 30 and 60 mg/kg the peak
      concentration (Cmax) of SMX were 1.9 +/- 0.8, 2.6 +/- 0.4 and 2.8 +/- 0.7
      microg/mL, respectively. The AUC was 9.1 +/- 5, 25.9 +/- 3.3 and 39.1 +/- 4.1
      microg h/mL, respectively. Based upon these AUC values and correcting for dose,
      the respective bioavailabilities were 7.7, 10.5 and 7.94%. Trimethoprim was not
      detected in plasma after intragastric administration. These data demonstrate that
      therapeutic concentrations of TMP-SMX are not achieved after p.o. administration
      to alpacas.

PMID- 12423222
TI  - Relative oral bioavailability of microgranulated amoxicillin in pigs.
AB  - A new microgranulated formulation of amoxicillin trihydrate for in-feed
      medication was developed using a lipogelled matrix. Its relative bioavailability
      was compared with powdered drug in pigs and an assessment was made to determine
      whether therapeutic concentrations were achieved. Microgranules containing 10%
      (MICR10) and 30% (MICR30) amoxicillin and free amoxicillin trihydrate powder
      (reference, AMX) were administered at dosages of 50 mg of amoxicillin/kg b.w.
      using a three-way-crossover design. Amoxicillin analysis in serum was performed
      by a sensitive high performance liquid chromatography (HPLC) method with
      fluorometric detection, using an extraction procedure already described for
      edible tissues of fish and adapted and validated for pig serum. The oral
      bioavailability of both microgranulated formulations was higher than that of the
      reference formulation [relative bioavailability (F): 153.9 +/- 58.2% for MICR10;
      126.2 +/- 70.5% for MICR30] and the area under the concentration-time curve (AUC)
      values of MICR10 and AMX formulations were significantly different (P < 0.05).
      Differences between the mean maximum concentration (Cmax), time of Cmax (tmax)
      and mean residence time (MRT) of the drug formulations were not significant.
      Microgranulated amoxicillin is suitable for in-feed administration to pigs and,
      because of its higher oral bioavailability compared with the powdered compound,
      it may be more effective for the treatment of susceptible infections.

PMID- 12423223
TI  - Distribution of enrofloxacin in intestinal tissue and contents of healthy pigs
      after oral and intramuscular administrations.
AB  - The concentration of enrofloxacin in plasma, intestinal tissue, lymph nodes and
      intestinal contents was investigated in healthy pigs after oral (p.o.) and
      intramuscular (i.m.) administration of a single dose of 2.5 mg/kg bw. Tissue and
      content samples were collected from jejunum, ileum, caecum and colon from pigs
      killed at 2, 3 and 6 h after dosing. Intramuscular administration resulted in
      significantly higher concentrations in plasma, intestinal tissue and lymph nodes
      at 2 h but not at 3 or 6 h compared with p.o. administration. The absorption and
      distribution phase was longer after oral administration, and maximum
      concentrations in tissue and plasma were determined later than after i.m.
      administration. No difference between route of administration was observed in the
      intestinal content. Enrofloxacin concentrations in faeces during a 5-day dosing
      regimen with i.m. and p.o. administration were determined by both HPLC and bio
      assay. Higher concentrations were found after i.m. administration during the
      first day, but the difference was not significant after 2 days. The biologically
      active concentrations determined by bio-assay constituted 48-75% of the total
      concentrations determined by HPLC. On the basis of these results it was concluded
      that in order to ensure an immediate high concentration of enrofloxacin, and
      thereby avoid an initial selection for resistant mutants, the intramuscular route
      seems to be preferable to the oral route.

PMID- 12423224
TI  - Pharmacokinetics and endometrial tissue concentrations of enrofloxacin and the
      metabolite ciprofloxacin after i.v. administration of enrofloxacin to mares.
AB  - Enrofloxacin was administered i.v. to five adult mares at a dose of 5 mg/kg.
      After administration, blood and endometrial biopsy samples were collected at
      regular intervals for 24 h. The plasma and tissue samples were analyzed for
      enrofloxacin and the metabolite ciprofloxacin by high-pressure liquid
      chromatography. In plasma, enrofloxacin had a terminal half-life (t(1/2)), volume
      of distribution (area method), and systemic clearance of 6.7 +/- 2.9 h, 1.9 +/-
      0.4 L/kg, and 3.7 +/- 1.4 mL/kg/min, respectively. Ciprofloxacin had a maximum
      plasma concentration (Cmax) of 0.28 +/- 0.09 microg/mL. In endometrial tissue,
      the enrofloxacin Cmax was 1.7 +/- 0.5 microg/g, and the t(1/2) was 7.8 +/- 3.7 h.
      Ciprofloxacin Cmax in tissues was 0.15 +/- 0.04 microg/g and the t(1/2) was 5.2
      +/- 2.0 h. The tissue:plasma enrofloxacin concentration ratios (w/w:w/v) were
      0.175 +/- 0.08 and 0.47 +/- 0.06 for Cmax and AUC, respectively. For
      ciprofloxacin, these values were 0.55 +/- 0.13 and 0.58 +/- 0.31, respectively.
      We concluded that plasma concentrations achieved after 5 mg/kg i.v. are high
      enough to meet surrogate markers for antibacterial activity (Cmax:MIC ratio, and
      AUC:MIC ratio) considered effective for most susceptible gram-negative bacteria.
      Endometrial tissue concentrations taken from the mares after dosing showed that
      enrofloxacin and ciprofloxacin both penetrate this tissue adequately after
      systemic administration and would attain concentrations high enough in the tissue
      fluids to treat infections of the endometrium caused by susceptible bacteria.

PMID- 12423225
TI  - Does the rate of fat deposition influence the pharmacokinetic disposition of
      subcutaneously administered moxidectin and ivermectin in pigs?
AB  - Body condition has been shown to affect the pharmacokinetics of subcutaneously
      administered macrocyclic lactone anthelmintics but the underlying mechanism is
      unknown. This study examined the effect of different rates of fat deposition on
      the pharmacokinetics of moxidectin (MXD) and ivermectin (IVM). All animals
      initially received a diet with a high linoleic acid content for 7 weeks. One
      group of animals then received a normal grower diet while the other half received
      a maintenance ration. Within each diet group, animals were treated with either
      IVM (n = 4) or MXD (n = 4) or remained as untreated controls (n = 2). There was
      no difference in the proportion of linoleic acid between the drug treated groups
      and the untreated controls at any time throughout the study. At 4 and 9 weeks
      after treatment there was a significantly lower proportion of linoleic acid in
      the pigs fed the normal ration indicating a greater fat deposition in these
      animals compared with those that received the maintenance diet. There was an
      increased persistence of MXD in the plasma of pigs fed the normal ration compared
      with those fed the maintenance ration. No differences were seen in the kinetic
      disposition of IVM between pigs fed the maintenance or normal ration. Reducing
      the rate of fat deposition influenced the pharmacokinetic disposition of the
      highly lipophilic MXD but did not influence the pharmacokinetic disposition of
      the less lipophilic IVM.

PMID- 12423226
TI  - Disposition of oral clarithromycin in foals.
AB  - Clarithromycin offers numerous advantages over erythromycin and thus, is an
      attractive alternative for the treatment of Rhodococcus equi infections in foals.
      The disposition of clarithromycin was investigated in 6 foals after intragastric
      administration at a dose of 10 mg/kg body weight. Detectable serum concentrations
      of clarithromycin were found in 3 of 6 foals at 10 minutes and in all foals by 20
      minutes post-administration. Time to peak serum concentration (Tmax) was 1.5
      hours and peak serum concentration (Cmax) was 0.92+/-0.17 microg/ml. Mean serum
      concentrations decreased to 0.03 microg/ml at 24 h. No adverse reactions were
      noted during or after IG administration in any of the foals. Based on the
      pharmacokinetic parameters, the MIC90 of R. equi isolates, and predicted steady
      state concentrations, an oral dose of 7.5 mg/kg given every 12 hours would appear
      appropriate for the treatment of R. equi infections in foals.

PMID- 12423227
TI  - Pharmacological characterization of alpha1-adrenoceptor subtypes in the bovine
      tail artery.
AB  - Ioudina, M. V., Dyer, D. C. Pharmacological characterization of alpha1
      adrenoceptor subtypes in the bovine tail artery. J. vet. Pharmacol. Therap. 25,
      363-369. The purpose of this study was to identify the alpha1-adrenoreceptor
      subtypes present in the bovine tail artery which mediate contractions to
      adrenergic agonists. A61603, an alpha1A-selective agonist, was more potent
      compared with norepinephrine and phenylephrine. The pKA value of A61603 was 6.93
      +/- 0.19 microM (n=6). Antagonists, BMY 7378, WB 4101 and 5-methylurapidil,
      caused a parallel shift to the right of the concentration-response curve to
      A61603 with pA2 values of 6.62, 9.27 and 8.86, respectively. Prazosin, BMY 7378
      and WB 4101 inhibited phenylephrine induced contraction with pA2 values of 9.47,
      7.17 and 9.73, respectively. The pA2 values obtained for 5-methylurapidil, WB
      4101, BMY 7378 and prazosin against alpha1-adrenoceptor agonists were
      significantly correlated with pKi values (Zhu, Zhang & Han, 1997, Eur. J.
      Pharmacol.329, 55-61) for the cloned alpha1a-adrenoceptor but not with the cloned
      alpha1b- or alpha1d-adrenoceptor. BMY 7378, a selective alpha1D-adrenoceptor
      antagonist, was significantly more potent against the nonsubtype selective
      agonist phenylephrine than to A61603. Chloroethylclonidine (50 microM for 10 min)
      did not affect contractile responses to A61603, but caused a significant
      inhibition of contractile responses to phenylephrine. In conclusion, it appears
      that alpha1A- and alpha1D-adrenoceptors play a role in adrenergic mediated
      contraction in the bovine tail artery.

PMID- 12423228
TI  - Effect of renal insufficiency on the pharmacokinetics and pharmacodynamics of
      benazepril in cats.
AB  - The effect of renal insufficiency was studied on the pharmacokinetics (PK) and
      pharmacodynamics (PD) of the angiotensin-converting enzyme (ACE) inhibitor
      benazepril in cats. The active metabolite of benazepril, benazeprilat, is
      eliminated principally ( approximately 85%) via biliary excretion in cats. A
      total of 20 control animals and 32 cats with moderate renal insufficiency induced
      by partial nephrectomy were used. Assessments were made at steady state after
      treatment with placebo or benazepril (0.25-2 mg/kg) once daily for a minimum of
      10 days. The PK endpoint was the AUC (0-->24 h) of total plasma benazeprilat. The
      PD endpoints were systolic, diastolic and mean blood pressures (respectively SBP,
      DBP and MBP) measured by telemetry, and plasma ACE activity, assessed by an ex
      vivo assay. Renal function was assessed by glomerular filtration rate (GFR),
      measured by inulin clearance, and plasma creatinine concentrations (1/PCr). As
      compared with control animals, the renal insufficient cats had a 78% reduction in
      GFR (0.57 +/- 0.41 mL/min kg), increased plasma creatinine (2.7 +/- 1.0 mg/dL),
      urea (44.0 +/- 11.9 mg/dL) and ACE activity, and moderately increased blood
      pressure (SBP 171.8 +/- 5.1 mmHg) (all parameters P < 0.05). Renal insufficient
      cats receiving benazepril had significantly (P < 0.05) lower SBP, DBP, MBP and
      ACE, and higher GFR values as compared with placebo-treated animals. There were
      no significant differences in SBP, DBP, MBP, benazeprilat or ACE values according
      to the degree of renal insufficiency in cats receiving benazepril. It is
      concluded that no dose adjustment of benazepril is necessary in cats with
      moderate renal insufficiency.

PMID- 12423229
TI  - Reduced resident time and pharmacodynamic effects of acepromazine after
      subclinical multiple dosage in exercised thoroughbreds.

PMID- 12423230
TI  - Plasma concentrations of trimethoprim and sulfamethoxazole in llamas after
      orogastric administration.

PMID- 12423231
TI  - Depletion of residues of furosemide, a loop diuretic, in lactating dairy cows.

PMID- 12423232
TI  - Simulation of concentration-time profiles of benzyl-penicillin, enrofloxacin and
      dihydrostreptomycin in tissue cages in calves.

PMID- 12423233
TI  - Tilmicosin administration to young lambs with respiratory infection: safety and
      efficacy considerations.

PMID- 12423235
TI  - Increased CNS uptake and enhanced antinociception of morphine-6-glucuronide in
      rats after inhibition of P-glycoprotein.
AB  - Morphine-6-glucuronide (M6G) is a substrate of P-glycoprotein (P-gp), which forms
      an outward transporter at the blood-brain barrier. Inhibition of P-gp may
      therefore be expected to cause increased CNS uptake of M6G. We directly assessed
      the spinal concentrations of M6G and its antinociceptive effects in rats
      following pharmacological inhibition of P-gp. Spinal cord tissue concentrations
      of M6G were assessed by microdialysis with probes transversally implanted through
      the dorsal horns of the spinal cord at level L4. Ten rats received M6G
      intravenously (0.018 mg/kg loading dose plus 0.00115 mg/kg/min for an 8-h
      infusion), five of them together with PSC833 to inhibit P-gp (32-h infusion,
      starting 24 h before the addition of M6G). Antinociceptive effects were explored
      by means of formalin tests. After having obtained evidence for enhanced CNS
      uptake and antinociception of M6G in the presence of PSC833, additional
      behavioural experiments were performed in another 32 rats to assess the dose
      dependency of the antinociceptive effects of M6G either with or without PSC833 in
      comparison with both PSC833 alone and placebo. Inhibition of P-gp increased the
      M6G concentrations in the spinal cord approximately three-fold whereas the plasma
      concentrations were increased only by a factor of 1.4, which resulted in a more
      than doubled spinal cord/plasma concentration ratio (from 0.08 +/- 0.03 for M6G
      alone to 0.17 +/- 0.08 for M6G plus PSC833). Antinociceptive effects of M6G were
      significantly enhanced by inhibition of P-gp. Inhibition of P-gp alters the
      transport of M6G across the blood-brain barrier, resulting in enhanced spinal
      cord uptake and enhanced antinociception.

PMID- 12423236
TI  - Functional characterization of alternatively spliced 5-HT2 receptor isoforms from
      the pharynx and muscle of the parasitic nematode, Ascaris suum.
AB  - Serotonin (5-HT) receptors play key regulatory roles in nematodes and
      alternatively spliced 5-HT2 receptor isoforms have been identified in the
      parasitic nematode, Ascaris suum. 5-HT2As1 and 5-HT2As2 contain different C
      termini, and 5-HT2As1Delta4 lacks 42 amino acids at the C-terminus of the third
      intracellular loop. 5-HT2As1 and 5-HT2As2 exhibited identical pharmacological
      profiles when stably expressed in human embryonic kidney (HEK) 293 cells. Both 5
      HT2As isoforms had higher affinity for 5-HT than their closely related
      Caenorhabditis elegans homolog (5-HT2Ce). This increased 5-HT affinity was not
      related to the substitution in 5-HT2As1 of F120 for Y in the highly conserved DRY
      motif found in the second intracellular loop of other 5-HT receptors, since a 5
      HT2As1F120Y mutant actually exhibited increased 5-HT affinity compared with that
      of 5-HT2As1. As predicted, cells expressing either 5-HT2As1 or 5-HT2As2 exhibited
      a 5-HT-dependent increase in phosphatidylinositol (PI) turnover. In contrast,
      although 5-HT2As1Delta4 displayed a 10-fold higher affinity for 5-HT and 5-HT
      agonists than either 5-HT2As1 or 5-HT2As2, 5-HT2As1Delta4 did not couple to
      either PI turnover or adenyl cyclase activity. Based on RT-PCR, 5-HT2As1 and 5
      HT2As2 were more highly expressed in pharynx and body wall muscle and 5
      HT2As1Delta4 in nerve cord/hypodermis. This is the first report of different
      alternatively spliced 5-HT2 receptor isoforms from any system.

PMID- 12423237
TI  - Role of PKC and MAPK in cytosolic PLA2 phosphorylation and arachadonic acid
      release in primary murine astrocytes.
AB  - Although Group IV cytosolic phospholipase A2 (cPLA2) in astrocytes has been
      implicated in a number of neurodegenerative diseases, mechanisms leading to its
      activation and release of arachidonic acid (AA) have not been clearly elucidated.
      In primary murine astrocytes, phorbol myristate acetate (PMA) and ATP stimulated
      phosphorylation of ERK1/2 and cPLA2 as well as evoked AA release. However,
      complete inhibition of phospho-ERK by U0126, an inhibitor of mitogen-activated
      protein kinase kinase (MEK), did not completely inhibit PMA-stimulated cPLA2 and
      AA release. Epidermal growth factor (EGF) also stimulated phosphorylation of
      ERK1/2 and cPLA2[largely through a protein kinase C (PKC)-independent pathway],
      but EGF did not evoke AA release. These results suggest that phosphorylation of
      cPLA2 due to phospho-ERK is not sufficient to evoke AA release. However, complete
      inhibition of ATP-induced cPLA2 phosphorylation and AA release was observed when
      astrocytes were treated with GF109203x, a general PKC inhibitor, together with
      U0126, indicating the important role for both PKC and ERK in mediating the ATP
      induced AA response. There is evidence that PMA and ATP stimulated AA release
      through different PKC isoforms in astrocytes. In agreement with the sensitivity
      of PMA-induced responses to PKC down-regulation, prolonged treatment with PMA
      resulted in down-regulation of PKCalpha and epsilon in these cells. Furthermore,
      PMA but not ATP stimulated rapid translocation of PKCalpha from cytosol to
      membranes. Together, our results provided evidence for an important role of PKC
      in mediating cPLA2 phosphorylation and AA release in astrocytes through both
      ERK1/2-dependent and ERK1/2-independent pathways.

PMID- 12423238
TI  - Mapping sites responsible for interactions of agrin with neurons.
AB  - The multidomain proteoglycan agrin is a critical organizer of postsynaptic
      differentiation at the skeletal neuromuscular junction. Agrin is also abundant in
      the brain, but its roles there are unknown. As a step toward understanding these
      roles, we mapped sites responsible for interactions of neurons with agrin. First,
      we used a series of recombinant agrin fragments to show that at least four sites
      on agrin interact with chick ciliary neurons. Use of blocking antibodies and
      peptides indicated that neurons adhere to a site in the second of three G domains
      by means of alphaVbeta1 integrin, and to a site in the last of four epidermal
      growth factor (EGF) repeats via a distinct beta1 integrin. A third, integrin
      independent adhesion site is near to but distinct from the site that induces
      postsynaptic differentiation in muscles. These domains are insufficient, however,
      to account for neurite outgrowth-inhibiting properties of full-length agrin,
      which are mediated by the N-terminal half of the molecule. We then used a second
      set of agrin mutants to demonstrate and map a transmembrane domain in the amino
      terminus of the SN-isoform of agrin. The extracellular matrix-bound form of
      agrin, called LN, bears an amino-terminus required for secretion and binding to
      laminin. The SN form, which is selectively expressed by neurons, bears a variant
      amino terminus that converts agrin from a secreted, matrix-associated protein to
      a type-II transmembrane protein, providing a mechanism for presenting agrin in
      central, as opposed to neuromuscular, synaptic clefts. The SN-amino terminus can
      mediate externalization and membrane anchoring of heterologous proteins, but is
      insufficient to target them to the synapse. Together, these studies define sites
      that contribute to the subcellular localization of and signaling by neuronal
      agrin.

PMID- 12423239
TI  - The human SH-SY5Y neuroblastoma cell-line expresses a functional P2X7
      purinoceptor that modulates voltage-dependent Ca2+ channel function.
AB  - Fura-2 imaging of purinergic stimulation of non-differentiated neuronal human SH
      SY5Y cells resulted in a rapid elevation in intracellular Ca2+ ([Ca2+]i) that was
      dependent on extracellular Ca2+. The rank order of agonists (200 micro m) was as
      follows: 2',3'-O-(4-benzoyl-benzoyl)-ATP (BzATP) > ATP4- > ATP; whereas 2
      (methylthio)-ATP, ADP, UTP and alpha,beta-methylene-ATP and beta,gamma-methylene
      ATP were ineffective. The response to BzATP was inhibited by pyridoxal-phosphate
      6-azophenyl-2',4'-disulfonic-acid (PPADS, 1 micro m), 1-(N,O-bis[5
      isoquinolinesulfonyl]-N-methyl-l-tyrosyl)-4-phenylpiperazine (KN-62, 100 nm) and
      8-(3-benzamido-4-4-methylbenzamido)-naphthalene-1,3,5-trisulfonic-acid (suramin,
      200 micro m). The presence of a P2X7 receptor was confirmed by western blot
      studies using anti-P2X7. EC50 for BzATP was 212 +/- 6 micro m. BzATP > 30 micro m
      induced an initial, transient increase in [Ca2+]i before a plateau level was
      reached. BzATP < 30 micro m only produced a monophasic increase to the plateau
      level. The transient phase was reduced by the introduction of nimodipine (3 micro
      m) and to a smaller degree by omega-conotoxin GVIA (1 micro m) despite an almost
      equal presence of L and N-type Ca2+-channels. In whole-cell voltage-clamp studies
      at - 90 mV, BzATP (300 micro m) produced a fast activating inward current with a
      similar pharmacology as observed with Fura-2 imaging. Current clamp studies
      showed a dose-dependent depolarization to BzATP and ATP4-. BzATP also triggered
      transmitter release. Thus, the human neuronal SH-SY5Y cell line expresses a
      functional P2X7 receptor coupled to activation of Ca2+-channels.

PMID- 12423240
TI  - Specific diadenosine pentaphosphate receptor coupled to extracellular regulated
      kinases in cerebellar astrocytes.
AB  - In this study, we show specific intracellular responses evoked by the stimulation
      of astrocytes with the P1,P5-di(adenosine-5')pentaphosphate, Ap5A. The
      stimulation of astrocytes with micromolar concentrations of the dinucleotide
      elicited rapid increases in intracellular calcium concentration ([Ca2+]i),
      showing an EC50 value of 15.27 +/- 0.61 micro m. Moreover, the stimulation of
      cells with nanomolar concentrations of Ap5A, unable to induce calcium responses,
      increased the phosphorylated forms of extracellular-signal regulated kinase 1/2
      (ERK) with an EC50 value of 9.8 +/- 2.4 nm. The maximal activation was observed
      at 100 nm Ap5A, which was similar to that produced by epidermal growth factor
      (EGF) under the same experimental conditions. The present data reported here
      indicate that Ap5A mediated these effects by interacting with a specific
      receptor, not yet identified, which was different from the P2Y1 and P2Y2/P2Y4
      receptors present in all individual astrocytes.

PMID- 12423241
TI  - Cytochrome c associated apoptosis during ATP recovery after hypoxia in neonatal
      rat cerebrocortical slices.
AB  - Cellular injury was evaluated in superfused cerebrocortical slices (350 micro m)
      from 7-day-old Sprague-Dawley rats exposed to 30 min hypoxia followed by 4 h of
      reoxygenation. At the end of hypoxia homogenous cytosolic immunoreactivity of
      cytochrome c increased approximately fourfold, cytochrome c intensity in western
      blot analyses increased more than fivefold, and whole cell and cytosolic cleaved
      caspase-9 underwent 50% and 100% increases, respectively. Immunostaining of
      sections taken 1.5 h after hypoxia showed: (i) more than a threefold increase in
      cleaved caspase-9; (ii) localization of cleaved caspase-9 to the interior and
      peripheral exterior of nuclei; and (iii) homogeneously distributed cytochrome c
      in the cytosol. Western blot analysis for 1.5 h after hypoxia showed that
      cytosolic caspase-9 returned to control values, while whole cell caspase-9 stayed
      approximately the same, suggesting translocation of caspase-9 to nuclei. By 4 h
      after hypoxia there was significant nuclear fragmentation and an increase in
      TUNEL positive staining. 31P/1H nuclear magnetic resonance (NMR) confirmed
      substantial decreases of ATP and phosphocreatine during hypoxia, with rapid but
      incomplete recovery being close to steady state 1 h after reoxygenation. At all
      time points after hypoxia the primary injury was cytochrome c associated
      apoptosis.

PMID- 12423242
TI  - Lack of up-regulation of ferritin is associated with sustained iron regulatory
      protein-1 binding activity in the substantia nigra of patients with Parkinson's
      disease.
AB  - Dopaminergic neurones degenerate during Parkinson's disease and cell loss is most
      extensive in the subpopulation of melanized neurones located in the substantia
      nigra pars compacta. Iron accumulation, together with a lack of up-regulation of
      the iron-storing protein, ferritin, has been reported and may contribute to
      increased oxidative stress in this region. We investigated the binding activity
      of iron regulatory protein-1 (IRP1) to the iron-responsive element that precludes
      ferritin mRNA translation, in the substantia nigra of a group of parkinsonian
      patients who presented a statistically significant reduction in the number of
      nigral melanized-neurones and an increased iron content, together with unchanged
      H-ferritin and L-ferritin subunit levels as compared to matched controls. The
      levels of ferritin mRNAs and the binding activity of IRP1 to the iron-responsive
      element of ferritin mRNA did not differ significantly between the two groups.
      Moreover, there was no detectable contribution of the iron regulatory protein-2
      (IRP2) binding activity. No change in IRP1 control of ferritin mRNA translation
      explains the lack of up-regulation of ferritin expression in cytoplasmic extracts
      of SNpc that would be normally expected with cytosolic iron accumulation. The
      data of this study do not favor changes in transcription and post-transcriptional
      regulation of ferritin expression in Parkinson's disease and suggest a
      'compartmentalized' iron accumulation.

PMID- 12423243
TI  - Proteomic analysis of CA1 and CA3 regions of rat hippocampus and differential
      susceptibility to intermittent hypoxia.
AB  - The CA1 and CA3 regions of the hippocampus markedly differ in their
      susceptibility to hypoxia in general, and more particularly to the intermittent
      hypoxia that characterizes sleep apnea. Proteomic approaches were used to
      identify proteins differentially expressed in the CA1 and CA3 regions of the rat
      hippocampus and to assess changes in protein expression following a 6-h exposure
      to intermittent hypoxia (IH). Ninety-nine proteins were identified, and 15 were
      differentially expressed in the CA1 and the CA3 regions. Following IH, 32
      proteins in the CA1 region and only 7 proteins in the more resistant CA3 area
      were up-regulated. Hypoxia-regulated proteins in the CA1 region included
      structural proteins, proteins related to apoptosis, primarily chaperone proteins,
      and proteins involved in cellular metabolic pathways. We conclude that IH
      mediated CA1 injury results from complex interactions between pathways involving
      increased metabolism, induction of stress-induced proteins and apoptosis, and,
      ultimately, disruption of structural proteins and cell integrity. These findings
      provide initial insights into mechanisms underlying differences in susceptibility
      to hypoxia in neural tissue, and may allow for future delineation of
      interventional strategies aiming to enhance neuronal adaptation to IH.

PMID- 12423244
TI  - Synphilin-1 degradation by the ubiquitin-proteasome pathway and effects on cell
      survival.
AB  - Parkinson's disease is characterized by loss of nigral dopaminergic neurons and
      the presence of cytoplasmic inclusions known as Lewy bodies. alpha-Synuclein and
      its interacting partner synphilin-1 are among constituent proteins in these
      aggregates. The presence of ubiquitin and proteasome subunits in these inclusions
      supports a role for this protein degradation pathway in the processing of
      proteins involved in this disease. To begin elucidating the kinetics of synphilin
      1 in cells, we studied its degradation pathway in HEK293 cells that had been
      engineered to stably express FLAG-tagged synphilin-1. Pulse-chase experiments
      revealed that this protein is relatively stable with a half-life of about 16 h.
      Treatment with proteasome inhibitors resulted in attenuation of degradation and
      the accumulation of high molecular weight ubiquitinated synphilin-1 in
      immunoprecipitation/immunoblot experiments. Additionally, proteasome inhibitors
      stimulated the formation of peri-nuclear inclusions which were immunoreactive for
      synphilin-1, ubiquitin and alpha-synuclein. Cell viability studies revealed
      increased susceptibility of synphilin-1 over-expressing cells to proteasomal
      dysfunction. These observations indicate that synphilin-1 is ubiquitinated and
      degraded by the proteasome. Accumulation of ubiquitinated synphilin-1 due to
      impaired clearance results in its aggregation as peri-nuclear inclusions and in
      poor cell survival.

PMID- 12423245
TI  - Selective reduction by isolation rearing of 5-HT1A receptor-mediated dopamine
      release in vivo in the frontal cortex of mice.
AB  - Serotonin (5-HT)1A receptors modulate in vivo release of brain monoaminergic
      neurotransmitters which may be involved in isolation-induced aggressive behavior.
      The present study examined the effect of isolation rearing on the 5-HT1A receptor
      mediated modulation of dopamine (DA), 5-HT and noradrenaline (NA) release in the
      frontal cortex of mice. The selective 5-HT1A receptor agonist (S)-5-[-[(1,4
      benzodioxan-2-ylmethyl)amino]propoxy]-1,3-benzodioxole HCl (MKC-242) increased
      the release of DA and NA and decreased the release of 5-HT in the frontal cortex
      of mice. The effect of MKC-242 on DA release was significantly less in isolation
      reared mice than in group-reared mice, while effects of the drug on NA and 5-HT
      release did not differ between both groups. The effect of the other 5-HT1A
      receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin on cortical DA release
      was also less in isolation-reared mice than in group-reared mice, and that of the
      drug on cortical 5-HT release did not differ between both groups. In contrast to
      MKC-242-induced DA release, amphetamine-induced increase in cortical DA release
      in vivo was greater in isolation-reared mice. The present findings suggest that
      isolation rearing enhances the activity of cortical dopaminergic neurons and
      reduces selectively the 5-HT1A receptor-mediated release of DA in the cortex.

PMID- 12423246
TI  - Proteasomal dysfunction induced by 4-hydroxy-2,3-trans-nonenal, an end-product of
      lipid peroxidation: a mechanism contributing to neurodegeneration?
AB  - 4-Hydroxy-2,3-trans-nonenal (HNE) is a neurotoxic unsaturated aldehyde end
      product of lipid peroxidation. The addition of HNE to NT-2 and SK-N-MC cell lines
      induces apoptosis and we now investigated the time-course of events occurring
      prior to apoptosis. Treatment of both NT-2 and SK-N-MC cell lines with HNE led to
      HNE association with the proteasome, increased levels of protein carbonyls and
      ubiquitinated proteins, and decreased proteasomal function. There was also
      decreased metabolic activity, cytochrome c release and activation of caspase 3,
      followed by apoptotic changes including chromatin condensation, cell shrinkage
      and DNA fragmentation and laddering. Overexpression of mutant superoxide
      dismutase 1 proteins associated with amyotrophic lateral sclerosis decreased
      proteasomal activities in the absence of HNE and accelerated the apoptosis
      induced by HNE. By contrast, overexpression of wild-type superoxide dismutase 1
      did not affect basal levels of proteasomal activity. The data suggest that
      accumulation of ubiquitinated proteins and impairment of proteasomal function are
      important events in HNE toxicity. We propose that the proteasomal system is a
      significant target of HNE neurotoxicity in a wide range of neurodegenerative
      diseases, especially if abnormal proteins are being expressed.

PMID- 12423247
TI  - Changes in activity and expression of phosphofructokinase in different rat brain
      regions after basal forebrain cholinergic lesion.
AB  - Selective lesion of rat basal forebrain by the cholinergic immunotoxin 192IgG
      saporin was used as an animal model to address the question of whether the
      changes in cortical glucose metabolism observed in patients with Alzheimer's
      disease may be related to impaired cholinergic transmission. At different times
      after creating the immunolesion, the isoenzyme pattern and steady-state mRNA
      levels of the key glycolytic enzyme phosphofructokinase were determined in
      cortex, hippocampus, basal forebrain and nucleus caudatus. The loss of
      cholinergic input was accompanied by a persistent decrease in choline
      acetytransferase and acetylcholine esterase activities in the cortical target
      areas similar to the cholinergic malfunction seen in Alzheimer's dementia. The
      basal forebrain lesion induced by the immunotoxin resulted in a transient
      increase in phosphofructokinase activity peaking on day 7 after inducing the
      lesion in cortical areas. In parallel, an increased steady-state level of
      phosphofructokinase mRNA was determined by RT/real-time PCR and in situ
      hybridization. In contrast, analysis by western blotting and quantitative PCR
      revealed no changes in the phosphofructokinase isoenzyme pattern after
      immunolesion. It is concluded that common metabolic mechanisms may underlie the
      degenerative and repair processes in denervated rat brain and in the diseased
      Alzheimer's brain.

PMID- 12423248
TI  - Internalization of basic fibroblast growth factor at the mouse blood-brain
      barrier involves perlecan, a heparan sulfate proteoglycan.
AB  - In this study, the internalization mechanism of basic fibroblast growth factor
      (bFGF) at the blood-brain barrier (BBB) was investigated using a conditionally
      immortalized mouse brain capillary endothelial cell line (TM-BBB4 cells) as an in
      vitro model of the BBB and the corresponding receptor was identified using
      immunohistochemical analysis. The heparin-resistant binding of [125I]bFGF to TM
      BBB4 cells was found to be time-, temperature-, osmolarity- and concentration
      dependent. Kinetic analysis of the cell-surface binding of [125I]bFGF to TM-BBB4
      cells revealed saturable binding with a half-saturation constant of 76 +/- 24 nm
      and a maximal binding capacity of 183 +/- 17 pmol/mg protein. The heparin
      resistant binding of [125I]bFGF to TM-BBB4 was significantly inhibited by a
      cationic polypeptide poly-L-lysine (300 micro m), and compounds which contain a
      sulfate moiety, e.g. heparin and chondroitin sulfate-B (each 10 micro g/mL).
      Moreover, the heparin-resistant binding of [125I]bFGF in TM-BBB4 cells was
      significantly reduced by 50% following treatment with sodium chlorate, suggesting
      the loss of perlecan (a core protein of heparan sulfate proteoglycan, HSPG) from
      the extracellular matrix of the cells. This type of binding is consistent with
      the involvement HSPG-mediated endocytosis. RT-PCR analysis revealed that HSPG
      mRNA and FGFR1 and FGFR2 (tyrosine-kinase receptors for bFGF) mRNA are expressed
      in TM-BBB4 cells. Moreover, immunohistochemical analysis demonstrated that
      perlecan is expressed on the abluminal membrane of the mouse brain capillary.
      These results suggest that bFGF is internalized via HSPG, which is expressed on
      the abluminal membrane of the BBB. HSPG at the BBB may play a role in maintaining
      the BBB function due to acceptance of the bFGF secreted from astrocytes.

PMID- 12423249
TI  - Failure of the interaction between presenilin 1 and the substrate of gamma
      secretase to produce Abeta in insect cells.
AB  - Aggregates of beta-amyloid peptide (Abeta) are the major component of the amyloid
      core of the senile plaques observed in Alzheimer's disease (AD). Abeta results
      from the amyloidogenic processing of its precursor, the amyloid precursor protein
      (APP), by beta- and gamma-secretase activities. If beta-secretase has recently
      been identified and termed BACE, the identity of gamma-secretase is still
      obscure. Studies with knock-out mice showed that presenilin 1 (PS1), of which
      mutations are known to be the first cause of inherited AD, is mandatory for the
      gamma-secretase activity. However, the proteolytic activity of PS1 remains a
      matter of debate. Here we used transfected Sf9 insect cells, a cellular model
      lacking endogenous beta- and/or gamma-secretase activities, to characterize the
      role of BACE and PS1 in the amyloidogenic processing of human APP. We show that,
      in Sf9 cells, BACE performs the expected beta-secretase cleavage of APP,
      generating C99. We also show that C99, which is a substrate of gamma-secretase,
      tightly binds to the human PS1. Despite this interaction, Sf9 cells still do not
      produce Abeta. This strongly argues against a direct proteolytic activity of PS1
      in APP processing, and points toward an implication of PS1 in
      trafficking/presenting its substrate to the gamma-secretase.

PMID- 12423250
TI  - Brief, repeated exposure to substrates down-regulates dopamine transporter
      function in Xenopus oocytes in vitro and rat dorsal striatum in vivo.
AB  - In heterologous expression systems, dopamine transporter (DAT) cell-surface
      localization is reduced after relatively prolonged exposure to d-amphetamine
      (AMPH) or dopamine (DA), suggesting a role for substrate-mediated regulation of
      transporter function. Here, we investigated whether brief, repeated periods of
      substrate exposure modulated transporter function, first, in an in vitro model
      system and, second, in intact rat brain. In human DAT-expressing Xenopus laevis
      oocytes, repeated exposure to low micromolar concentrations of DA, AMPH or
      tyramine markedly reduced transport-mediated currents. This functional down
      regulation was attenuated by inclusion of a protein kinase C (PKC) inhibitor and
      probably reflects DAT redistribution, as cell-surface [3H]WIN 35 428 binding was
      significantly lower following DA exposure. High-speed chronoamperometry was used
      to measure clearance of exogenously applied DA in dorsal striatum (STR) and
      nucleus accumbens (NAc) of anesthetized rats. In STR, frequent (every 2 min)
      applications of DA altered DA clearance parameters in a manner consistent with
      profound down-regulation of DAT function. Similar changes were not observed in
      NAc or after repeated vehicle (ascorbic acid) application. Together, our results
      suggest that brief, repeated periods of substrate exposure lead to rapid down
      regulation of DAT activity and that this type of regulation can occur in vivo in
      STR, but not NAc.

PMID- 12423251
TI  - Abnormal Tau phosphorylation of the Alzheimer-type also occurs during mitosis.
AB  - In Alzheimer's disease, neurofibrillary degeneration results from the aggregation
      of abnormally phosphorylated Tau proteins into filaments and it may be related to
      the reactivation of mitotic mechanisms. In order to investigate the link between
      Tau phosphorylation and mitosis, Xenopus laevis oocytes in which most of the M
      phase regulators have been discovered were used as a cell model. The human Tau
      isoform htau412 (2+3-10+) was microinjected into prophase I oocytes that were
      then stimulated by progesterone that activate cyclin-dependent kinase pathways.
      Hyperphosphorylation of the Tau isoform, which is characterized by a decrease of
      its electrophoretic mobility and its labelling by a number of phosphorylation
      dependent antibodies, was observed at the time of germinal vesicle breakdown.
      Surprisingly, Tau immunoreactivity, considered as typical of Alzheimer's
      pathology (AT100 and phospho-Ser422), was observed in meiosis II. Because meiosis
      II is considered as a mitosis-like phase, we investigated if our observation was
      also relevant to a neurone-like model. Abnormal Tau phosphorylation was detected
      in mitotic human neuroblastoma SY5Y cells overexpressing Tau. Regarding AT100
      immunoreactivity and phospho-Ser422, we suggest that phosphatase 2A inhibition
      and a phosphorylation combination of mitotic kinases may lead to this Alzheimer
      type phosphorylation. Our results not only demonstrate the involvement of mitotic
      kinases in Alzheimer-type Tau phosphorylation but also indicate that Xenopus
      oocyte could be a useful model to identify the kinases involved in this process.

PMID- 12423252
TI  - Nicotinic-acetylcholine receptors are functionally coupled to the nitric
      oxide/cGMP-pathway in insect neurons.
AB  - In addition to their ionotropic role, neuronal nicotinic acetylcholine receptors
      (nAChRs) can influence second messenger levels, transmitter release and gene
      transcription. In this study, we show that nAChRs in an insect CNS control cGMP
      levels by coupling to NO production. In conditions that inhibit spiking, nicotine
      induced cGMP synthesis. This increase in cGMP was blocked by nicotinic
      antagonists, and by inhibitors of both nitric oxide synthase and soluble guanylyl
      cyclase. The nicotinic-evoked increase in cGMP was localized to specific NO
      sensitive neurons in the CNS, several of which are identified motoneurons.
      Because NO production requires Ca2+, we investigated the effect of nicotinic
      stimulation on [Ca2+]i in cultured neurons. We found that activation of nAChRs
      increased [Ca2+]i, which was blocked by nAChR antagonists. Nicotinic stimulation
      of neurons in the isolated CNS in low-Na+, also evoked increases in [Ca2+]i
      independent of fast changes in voltage. In addition, approximately 10% of the
      nicotinic-evoked [Ca2+]i increase in cultured neurons persisted when voltage
      gated Ca2+ channels were blocked by Ni2+. Under the same conditions, nicotinic
      stimulation of cGMP in the CNS was unaffected. These combined results suggest
      that nicotinic stimulation is coupled to NOS potentially by directly gating Ca2+.

PMID- 12423253
TI  - Altered chemokine expression in the spinal cord and brain contributes to
      differential interleukin-1beta-induced neutrophil recruitment.
AB  - The pattern of neutrophil recruitment that accompanies inflammation in the CNS
      depends on the site of injury and the stage of development. The adult brain
      parenchyma is refractory to neutrophil recruitment and associated damage as
      compared to the spinal cord or juvenile brain. Using quantitative Taqman RT-PCR
      and enzyme-liked immunosorbent assay (ELISA), we compared mRNA and protein
      expression of the rat neutrophil chemoattractant chemokines (CINC) in spinal cord
      and brain of adult and juvenile rats to identify possible association with the
      observed differences in neutrophil recruitment. Interleukin-1beta (IL-1beta)
      injection resulted in up-regulated chemokine expression in both brain and spinal
      cord. CINC-3 mRNA was elevated above CINC-1 and CINC-2alpha, with expression
      levels for each higher in spinal cord than in brain. By ELISA, IL-1beta induced
      greater CINC-1 and CINC-2alpha expression compared to CINC-3, with higher protein
      levels in spinal cord than in brain. In the juvenile brain, significantly higher
      levels of CINC-2alpha protein were observed in response to IL-1beta injection
      than in the adult brain following an equivalent challenge. Correspondingly,
      neutrophil recruitment was observed in the juvenile brain and adult spinal cord,
      but not in the adult brain. No expression of CINC-2beta mRNA was detected. Thus
      differential chemokine induction may contribute to variations in neutrophil
      recruitment in during development and between the different CNS compartments.

PMID- 12423254
TI  - Galanin inhibits tyrosine hydroxylase expression in midbrain dopaminergic
      neurons.
AB  - Galanin (GAL) inhibits midbrain dopamine (DA) activity in several experimental
      paradigms, yet the mechanism underlying this inhibition is unclear. We examined
      the effects of GAL on the expression of tyrosine hydroxylase (TH) in primary
      cultures of rat embryonic (E14) ventral mesencephalon (VM). One micromolar GAL
      had no effect on the number of TH-immunoreactive (ir) neurons in VM cultures.
      However, 1 micro m GAL reduced an approximately 100% increase in TH-ir neurons in
      1 mm dibutyryl cAMP (dbcAMP)-treated cultures by approximately 50%. TH-ir neuron
      number in dbcAMP-treated VM cultures was dose-responsive to GAL and the GAL
      receptor antagonist M40 blocked GAL effects. Semi-quantitative RT-PCR and
      quantitative immunoblotting experiments revealed that GAL had no effect on TH
      mRNA levels in VM cultures but reduced TH protein. VM cultures expressed GALR1,
      GALR2, and GALR3 receptor mRNA. However, dbcAMP treatment resulted in a specific
      approximately 200% increase in GALR1 mRNA. GALR1 activity is linked to a
      pertussis toxin (PTX)-sensitive opening of G protein-gated K+ channels (GIRKs).
      GAL reduction of TH-ir neuron number in dbcAMP + GAL-treated cultures was
      sensitive to both PTX and tertiapin, a GIRK inhibitor. GAL inhibition of midbrain
      DA activity may involve a GALR1- mediated reduction of TH in midbrain
      dopaminergic neurons.

PMID- 12423255
TI  - Stress-mediated signaling in PC12 cells - the role of the small heat shock
      protein, Hsp27, and Akt in protecting cells from heat stress and nerve growth
      factor withdrawal.
AB  - We have investigated the role of stress-activated signaling pathways and the
      small heat shock protein, Hsp27, in protecting PC12 cells from heat shock and
      nerve growth factor (NGF) withdrawal-induced apoptosis. PC12 cells and a stable
      cell line overexpressing Hsp27 (HSPC cells) were subjected to heat shock. This
      resulted in the rapid activation of Akt followed by p38 mitogen-activated protein
      kinase (MAPK) signaling, with phosphorylation and intracellular translocation of
      Hsp27 also detectable. Hsp27 was found to form an immunoprecipitable complex with
      Akt and p38 MAPK in both non-stimulated and heat shocked cells, although after
      heat shock there was a gradual dissociation of Akt and p38 from the Hsp27. Cells
      were differentiated with NGF and then subjected to NGF withdrawal, a treatment
      which results in substantial cell death over 24-72 h. Hsp27 was shown to be
      protective against this treatment, since HSPC cells which overexpress Hsp27
      showed significantly less cell death than the parental PC12 cells. In addition,
      we observed that phosphorylation of Akt was maintained in HSPC cells subjected to
      heat shock and NGF withdrawal compared with the parental cells. Taken together,
      our results suggest that Hsp27 may protect Akt from dephosphorylation and may
      also act in stabilizing Akt.

PMID- 12423256
TI  - Neuronal oxidative damage from activated innate immunity is EP2 receptor
      dependent.
AB  - Increase in prostaglandin (PG) E2 levels and oxidative damage are associated with
      diseases of brain that involve activation of innate immunity. We tested the
      hypothesis that cerebral oxidative damage resulting from activation of innate
      immunity with intracerebroventricular (icv) lipopolysaccharide (LPS) is dependent
      on PGE2-mediated signaling. We measured two quantitative in vivo biomarkers of
      lipid peroxidation: F2-isoprostanes (IsoPs) that derive from arachidonic acid
      (AA) that is uniformly distributed in all cell types in brain, and F4
      neuroprostanes (NeuroPs) that derive from docosahexaenoic acid (DHA) that is
      highly concentrated in neuronal membranes. LPS stimulated delayed elevations in
      cerebral F2-IsoPs and F4-NeuroPs that were completely suppressed by indomethacin
      or ibuprofen pre-treatment. LPS-induced cerebral oxidative damage was abolished
      by disruption of subtype 2 receptor for PGE2 (EP2). In contrast, initial
      oxidative damage from icv kainic acid (KA) was more rapid than with LPS also was
      completely suppressed by indomethacin or ibuprofen pre-treatment but was
      independent of EP2 receptor activation. The protective effect of deleting the EP2
      receptor was not associated with changes in cerebral eicosaniod production, but
      was partially related to reduced induction of nitric oxide synthase (NOS)
      activity. These results suggest the EP2 receptor as a therapeutic target to limit
      oxidative damage from activation of innate immunity in cerebrum.

PMID- 12423257
TI  - Polyethylene glycol immediately repairs neuronal membranes and inhibits free
      radical production after acute spinal cord injury.
AB  - Membrane disruption and the production of reactive oxygen species (ROS) are
      important factors causing immediate functional loss, progressive degeneration,
      and death in neurons and their processes after traumatic spinal cord injury.
      Using an in vitro guinea pig spinal cord injury model, we have shown that
      polyethylene glycol (PEG), a hydrophilic polymer, can significantly accelerate
      and enhance the membrane resealing process to restore membrane integrity
      following controlled compression. As a result of PEG treatment, injury-induced
      ROS elevation and lipid peroxidation (LPO) levels were significantly suppressed.
      We further show that PEG is not an effective free radical scavenger nor does it
      have the ability to suppress xanthine oxidase, a key enzyme in generating
      superoxide. These observations suggest that it is the PEG-mediated membrane
      repair that leads to ROS and LPO inhibition. Furthermore, our data also imply an
      important causal effect of membrane disruption in generating ROS in spinal cord
      injury, suggesting membrane repair to be an effective target in reducing ROS
      genesis.

PMID- 12423258
TI  - Impairment of cytoskeleton-dependent vesicle and organelle translocation in green
      algae: combined use of a microfocused infrared laser as microbeam and optical
      tweezers.
AB  - A Nd-YAG laser at 1064 nm is used as optical tweezers to move intracellular
      objects and a laser microbeam to cause impairment of cytoskeleton tracks and
      influence intracellular motions in desmidiaceaen green algae. Naturally occurring
      migrations of large nuclei are inhibited in Micrasterias denticulata and
      Pleurenterium tumidum when the responsible microtubules are targeted with a laser
      microbeam generating 180 mW power in the focal plane. Impairment of the
      microtubule tracks appears to be irreversible, as the nucleus cannot pass the
      former irradiated area in Pleurenterium or remains abnormally dislocated in
      Micrasterias. The actin filament-dependent movement of secretory vesicles and
      smaller particles can be manipulated by the same IR-laser at 90 mW when
      functioning as optical tweezers. In Closterium lunula particles are displaced
      from their cytoplasmic tracks for up to 10 micro m but return to their tracks
      immediately after removing the light pressure gained by the optical tweezers. The
      cytoplasmic tracks consist of actin filament cables running parallel to the
      longitudinal axis of Closterium cells as depicted by Alexa phalloidin staining
      and confocal laser scanning microscopy. Dynamics and extensibility of the
      cytoplasmic strands connecting particles to the tracks are also demonstrated in
      the area of large vacuoles which are surrounded by actin filament bundles. In
      Micrasterias trapping of secretory vesicles by the optical tweezers causes
      irreversible malformations of the cell shape. The vesicle accumulation itself
      dissipates within 30 s after removing the optical tweezers, also indicating
      reversibility of the effects induced, in the case of actin filament-mediated
      processes.

PMID- 12423259
TI  - Structure of the (110) antiphase boundary in gallium phosphide.
AB  - The morphology of antiphase boundaries in GaP films grown by molecular beam
      epitaxy on Si (001) has been studied by transmission electron microscopy. The
      inversion of the crystal polarity between antiphase domains was confirmed by
      convergent-beam electron diffraction. The APBs were often found to facet parallel
      to [110] planes. Strong-beam alpha-fringe contrast observed along the (110)
      facets indicates that adjacent antiphase domains are related by an additional
      rigid-body lattice translation. Diffraction-contrast analysis shows that this R
      corresponds to a shear parallel to the [001] direction and a small expansion. The
      magnitude of the translation was inferred, quantitatively, through a comparison
      between energy-filtered zero-loss images of the alpha-fringe contrast with
      numerical calculations. The components of the rigid-body lattice translation were
      determined to be 0.023 +/- 0.0033 nm in the [001] direction and 0.005 +/- 0.002
      nm in the 0 direction. Based upon a geometric model of the [110] antiphase
      boundary, the lengths of the Ga and P antisite bonds were calculated to be 254 +/
      2 pm and 227 +/- 4 pm, respectively.

PMID- 12423260
TI  - Pre-screening for antigen detectability in cells: a TEM-based solid phase digital
      immunogold detection method utilizing ultra low volumes of reagents.
AB  - Rapid and sensitive pre-screening for the presence of antigens in cell samples
      and confirmation of reactivity of antibodies, before proceeding with electron
      microscopy, is highly desirable. Most of the methods developed for this purpose
      are generally not very efficient and suitable for dealing with very small volumes
      of sample and reagents. In this work we present a simple, sensitive and rapid
      solid phase transmission electron microscope (TEM) based method for the detection
      of picogram (pg) levels of soluble antigens using as little as 10 micro L of
      reagents. Protein was adsorbed onto grids coated with polystyrene films to form
      the solid phase. The presence of antigen was detected using immunogold labelling.
      Gold particles adhering to the film were visualized and counted in a TEM
      providing a digital signal. This method was 100-fold more sensitive than dot blot
      in detection of rabbit IgG. We have demonstrated the utility of this technique by
      screening for Vitreoscilla haemoglobin (VHb) antigen in cell lysates and
      confirming the results directly with immunogold labelling transmission electron
      microscopy of cell sections.

PMID- 12423262
TI  - Determination of the water droplet size distribution of fat spreads using
      confocal scanning laser microscopy.
AB  - Knowledge of the water droplet size distribution of fat spreads is necessary for
      the development and production of high quality microbiological safe products. Fat
      spreads are water-in-oil emulsions. The water droplet size distribution can be
      determined by confocal scanning laser microscopy (CSLM) after staining the fat
      with Nile Red. The profiles of the non-fluorescent water droplets in the 2D
      images are identified and measured using image analysis. The 'true' water droplet
      size distribution is calculated from the distribution of the measured profile
      diameters using a Wicksell transformation of log-normal distributions. The
      influence of the fluorescent staining and CSLM parameters on the information were
      studied. The CSLM method was tested on fat spreads with a fat content ranging
      from 40% to 80%. The results were compared with those obtained by nuclear
      magnetic resonance spectroscopy (NMR). The distribution parameters [volume
      weighed geometric mean diameter (D3,3) and the standard deviation (sigma) of the
      logarithm of the droplet diameter] calculated for 80% fat spreads are in good
      agreement with those obtained by NMR (within +/- 7% relative). Small differences
      were found for 65% fat spreads and large differences were identified for 40% fat
      spreads. The precision for the determination of the D3,3 value by CSLM is worse
      than that of NMR, even when three images were used to calculate this parameter [3
      11% and 1-6% relative standard deviation (RSD), respectively]. The precision for
      the determination of exp(sigma) by CSLM is comparable or better than that of NMR
      (1-5% and 3-6% RSD, respectively). CSLM proved to be a reliable method for the
      determination of the water droplet size distribution of margarines (80% fat). The
      advantage of CSLM compared to NMR is that visual information is given about the
      water droplet size distribution in the sample.

PMID- 12423261
TI  - Two-photon fluorescence absorption and emission spectra of dyes relevant for cell
      imaging.
AB  - Two-photon absorption and emission spectra for fluorophores relevant in cell
      imaging were measured using a 45 fs Ti:sapphire laser, a continuously tuneable
      optical parametric amplifier for the excitation range 580-1150 nm and an optical
      multichannel analyser. The measurements included DNA stains, fluorescent dyes
      coupled to antibodies as well as organelle trackers, e.g. Alexa and Bodipy dyes,
      Cy2, Cy3, DAPI, Hoechst 33342, propidium iodide, FITC and rhodamine. In
      accordance with the two-photon excitation theory, the majority of the
      investigated fluorochromes did not reveal significant discrepancies between the
      two-photon and the one-photon emission spectra. However, a blue-shift of the
      absorption maxima ranging from a few nanometres up to considerably differing
      courses of the spectrum was found for most fluorochromes. The potential of non
      linear laser scanning fluorescence microscopy is demonstrated here by visualizing
      multiple intracellular structures in living cells. Combined with 3D
      reconstruction techniques, this approach gives a deeper insight into the spatial
      relationships of subcellular organelles.

PMID- 12423263
TI  - Deconvolution improves colocalization analysis of multiple fluorochromes in 3D
      confocal data sets more than filtering techniques.
AB  - Background and noise impair image quality by affecting resolution and obscuring
      image detail in the low intensity range. Because background levels in unprocessed
      confocal images are frequently at about 30% maximum intensity, colocalization
      analysis, a typical segmentation process, is limited to high intensity signal and
      prone to noise-induced, false-positive events. This makes suppression or removal
      of background crucial for this kind of image analysis. This paper examines the
      effects of median filtering and deconvolution, two image-processing techniques
      enhancing the signal-to-noise ratio (SNR), on the results of colocalization
      analysis in confocal data sets of biological specimens. The data show that median
      filtering can improve the SNR by a factor of 2. The technique eliminates noise
      induced colocalization events successfully. However, because filtering recovers
      voxel values from the local neighbourhood false-negative ('dissipation' of signal
      intensity below threshold value) as well as false-positive ('fusion' of noise
      with low intensity signal resulting in above threshold intensities), results can
      be generated. In addition, filtering involves the convolution of an image with a
      kernel, a procedure that inherently impairs resolution. Image restoration by
      deconvolution avoids both of these disadvantages. Such routines calculate a model
      of the object considering various parameters that impair image formation and are
      able to suppress background down to very low levels (< 10% maximum intensity,
      resulting in a SNR improved by a factor 3 as compared to raw images). This makes
      additional objects in the low intensity but high frequency range available to
      analysis. In addition, removal of noise and distortions induced by the optical
      system results in improved resolution, which is of critical importance in cases
      involving objects of near resolution size. The technique is, however, sensitive
      to overestimation of the background level. In conclusion, colocalization analysis
      will be improved by deconvolution more than by filtering. This applies especially
      to specimens characterized by small object size and/or low intensities.

PMID- 12423264
TI  - Time-resolved, three-dimensional quantitative microscopy of a droplet spreading
      on solid substrates.
AB  - A polarized microscope was used to study the spreading of mercury droplets on
      thin silver films. Using the differential interference contrast (DIC) method and
      semi-quantitative measurements of the optical path difference (OPD), the three
      dimensional shape of the liquid droplet that wets the solid surface was
      constructed with an angle resolution of 1 degrees. The evolution of the droplet
      shape was determined with a time resolution of 0.04 s. The quantitative results
      are compared with other wetting-reaction systems. In particular, it is
      demonstrated that the droplet has a spherical-cup shape during the entire wetting
      reaction process.

PMID- 12423266
TI  - Natural history of reflux esophagitis: what is the risk of progression and does
      it matter clinically?

PMID- 12423267
TI  - Psychosocial factors and childhood recurrent abdominal pain.
AB  - Recurrent abdominal pain in children is not a single condition but a description
      of a wide spectrum of clinical manifestations, some of which fit into a definite
      pattern, such as the irritable bowel syndrome, while others do not. Organic
      disorders may be present, but in the majority of children they cannot be
      detected. Although children with recurrent abdominal pain do not generally have
      psychological or psychiatric illness, there is a growing body of evidence to
      suggest that psychosocial stress plays an important role in this condition. This
      review will look into some of this evidence. The precise pathophysiology that
      results in abdominal pain is still not clearly understood, but the current belief
      is that visceral hypersensitivity or hyperalgesia and changes in the brain-gut
      axis linking the central and enteric nervous systems are important mechanisms.

PMID- 12423268
TI  - Delayed gastrointestinal transit in patients with hepatocellular carcinoma.
AB  - BACKGROUND AND AIM: Disturbed gastrointestinal (GI) motility exists in cirrhotic
      patients; however, less is known about the character of GI transit in
      hepatocellular carcinoma (HCC) patients. It is interesting to study the GI
      transit in HCC patients and to explore the patient factors modulating GI transit.
      METHODS: A non-invasive hydrogen breath test, which measured the orocecal transit
      time (OCTT), was used to study GI transit in 40 HCC patients, 20 cirrhotics and
      40 age- and sex-matched healthy volunteers with normal bowel habits. Meanwhile,
      their clinical manifestations and various blood parameters, such as platelet
      count, prothrombin time, erythrocyte sedimentation rate etc. were collected. The
      plasma endothelin-1 and nitrate/nitrite levels were also measured. RESULTS: The
      OCTT were delayed in HCC and cirrhotic patients compared with controls (116.3 +/-
      7.8 and 104.5 +/- 10.6 vs 75.3 +/- 5.1 min, P < 0.05). Neither the severity of
      liver damage, presence of ascites, tumor size, portal hypertension, nor various
      blood parameters, such as nitrate/nitrite, endothelin-1, platelet count etc., had
      any influence on GI transit. Only serum alpha-fetoprotein levels exhibited a
      trend toward positive correlation with the OCTT (r = 0.271, P = 0.091).
      CONCLUSIONS: Hepatocellular carcinoma patients have delayed GI transit. The
      confounding factor responsible for the disturbance of GI transit in HCC patients
      needs further exploration.

PMID- 12423269
TI  - Preventive effects of parathyroid hormone-related peptide on stress-induced
      gastric hypercontraction in the rat.
AB  - BACKGROUND AND AIMS: Parathyroid hormone-related peptide (PTHrP) appears to be a
      potent smooth muscle relaxant, but there has been no study of its effects on
      gastric motility in vivo. The purposes of this study were to evaluate the effects
      of external PTHrP on stress-induced gastric motility in vivo and on the
      expression of PTHrP and PTH/PTHrP receptors in the rat stomach. METHODS: Stress
      induced hypercontraction was evoked by restraint water immersion (RWI). Gastric
      motility was evaluated with a strain gauge force transducer, and the effects of
      external PTHrP-(1-34) (10 micro i.p.) on gastric motility were examined.
      Expressions of PTHrP and PTH/PTHrP receptor mRNA were evaluated by RNase
      protection assay. RESULTS: External PTHrP significantly suppressed abnormal
      contraction and mucosal lesions upon RWI stress. Upon RWI stress, the expression
      of PTHrP mRNA decreased, but that of PTH/PTHrP receptor mRNA was enhanced
      reciprocally. The PTH/PTHrP receptor was localized in smooth muscle cells of the
      muscle layers immunohistochemically. CONCLUSIONS: These findings suggest that
      smooth muscle contractile activity is modified by the autocrine/paracrine
      mechanism of PTHrP in the rat stomach and that the external PTHrP prevents stress
      induced hypercontraction and mucosal lesions.

PMID- 12423270
TI  - Role of the longitudinal smooth muscle coat in the ileal motile activity:
      evidence of ileo-ileal inhibitory reflex.
AB  - BACKGROUND: All gut movements are claimed to be activated essentially by the
      concentric contraction of the circular muscle, moving the chyme aborally. The
      role of the longitudinal smooth muscle of the small intestine in gut motility is
      poorly understood; this point was investigated in the current study. METHODS: The
      abdomens of 14 crossbreed dogs (eight dogs, six bitches) were opened. A segment
      of the small intestine was distended by a balloon in increments of 2 mL of
      saline, and the pressure and electrical activity were recorded proximally and
      distally to the balloon. The gut wall around the balloon was anesthetized and the
      test was repeated. The longitudinal muscle coat of the small intestine segment
      was then excised, and the pressure response and electrical activity were recorded
      on ileal distension. RESULTS: Two milliliter ileal distension produced pressure
      decrease (P < 0.05) proximally and distally to the balloon and caused balloon
      movement. Four, 6 and 8 mL distension effected similar pressure response, while
      10 mL showed no response. Electrical waves were recorded from the three
      electrodes applied to the ileal segment. Upon ileal distension, electrical
      activity increased over the distended area, with no activity proximally and
      distally to it. Balloon distension of the anesthetized ileal segment produced no
      pressure response or electrical activity. After longitudinal myectomy, no
      electrical activity was recorded at rest or upon ileal distension, and the
      balloon did not move. CONCLUSION: Ileal distension initiated circular muscle
      contraction only in the presence of the overlying longitudinal muscle, which
      appears to transmit the electrical activity to the circular muscle upon ileal
      distension. Ileal contraction is suggested to initiate ileal hypotonia in the
      proximal and distal ileal segments mediated through an 'ileo-ileal inhibitory
      reflex' that leads to aboral progress of the proximally and distally located
      chyme.

PMID- 12423271
TI  - Accuracy of a new near patient test for the diagnosis of Helicobacter pylori
      infection in Chinese.
AB  - BACKGROUND AND AIM: The performance of existing near patient tests for the
      diagnosis of Helicobacter pylori remains unsatisfactory. The aim of this study is
      to evaluate the accuracy of a new near patient test (Signify H. pylori) for the
      diagnosis of H. pylori and the usefulness of the Signify H. pylori test for a
      test and treat strategy. METHODS: Consecutive dyspeptic patients referred for
      upper endoscopy were recruited. Rapid urease test and histology were used as the
      gold standard. After endoscopy, blood was collected for the Signify H. pylori
      test and compared with a gold standard. RESULTS: Two hundred and forty-four
      patients were eligible for analysis and 121 (49.5%) were positive for H. pylori.
      The Signify H. pylori test showed a sensitivity, specificity, and accuracy of
      84.3, 89.4%, and 86.9%, respectively, for whole blood and 79.3, 88.6, and 84.0%
      for serum, respectively. The sensitivity and specificity of the Signify H. pylori
      whole blood test was 87.5 and 92.6% for patients less than 45-years-old and the
      accuracy was similar between patients referred from primary care physicians or
      gastroenterologists. The test is easy to operate and results are available within
      5 min. CONCLUSION: The Signify H. pylori test is accurate for the near patient
      diagnosis of H. pylori infection.

PMID- 12423272
TI  - New method for the determination of fecal consistency and its optimal value in
      the general population.
AB  - BACKGROUND: Although fecal consistency is an important factor, there has been
      only one study measuring this parameter. We developed a new method to measure
      fecal consistency and studied the relationship between fecal consistency and
      other fecal factors, including water content and weight. METHODS: The new method
      is a modification of the method of Exton-Smith and used an even balance. Subjects
      in the initial trial were 26 healthy women. Subsequently, fecal consistency was
      measured in a representative sample of the general Japanese population, in order
      to evaluate the optimal value to maintain large bowel function. RESULTS:
      Correlations between fecal consistency and fecal water content and weight were
      statistically consistent, although not highly correlated with each other. The
      optimal mean value was around 300 cm2: 'normal' in 'subjective defecatory state',
      295.5 cm2 and 305.2 cm2; 'once/day' in 'defecation frequency', 296.1 cm2 and
      310.2 cm2; 'soft and plump' in 'fecal characteristics', 293.6 cm2 and 298.3 cm2,
      in males and females, respectively. The coefficient of variation of this method
      ranged from 5.2% to 6.3%. CONCLUSIONS: This method is thought to be applicable to
      large-scale epidemiological surveys. The optimal value of fecal consistency in
      the general population was evaluated at approximately 300 g/cm2.

PMID- 12423273
TI  - Interferon-gamma regulates apoptosis by releasing soluble tumor necrosis factor
      receptors in a gastric epithelial cell line.
AB  - BACKGROUND AND AIMS: Interferon (IFN)-gamma and tumor necrosis factor (TNF) are
      predominant cytokines produced in the gastric mucosa of patients with
      Helicobacter pylori-infected gastritis. Several studies reported that IFN-gamma
      and TNF induced the synergistic effect on many cell lines. We attempted to
      clarify the apoptotic activity and the synergistic effect of IFN-gamma and TNF on
      the gastric epithelial cell, and whether IFN-gamma relates to soluble TNF
      receptors (sTNF-R) release from the gastric epithelial cell. METHODS: On the
      gastric epithelial cell line MKN45, cytotoxic and apoptotic effects of IFN-gamma
      and TNF were examined. Next, sTNF-R released in response to IFN-gamma and the
      protective effect of sTNF-R against the cytotoxic activity of TNF and IFN-gamma
      were examined by blocking the release of sTNF-R with a serine protease inhibitor
      such as phenylmethylsulfonyl fluoride. RESULTS: Interferon-gamma significantly
      decreased cell viability, but TNF decreased it only slightly. Interferon-gamma
      and TNF did not make a synergistic effect on cell viability and apoptosis.
      Interferon-gamma and TNF induced sTNF-R release from gastric epithelial cells.
      Phenylmethylsulfonyl fluoride significantly inhibited shedding of sTNF-R and a
      synergistic effect of TNF and IFN-gamma on apoptosis was observed. CONCLUSION:
      These results suggest that sTNF-R released by IFN-gamma regulate the injury on
      the gastric epithelial cell line induced by TNF.

PMID- 12423274
TI  - Oral administration of lactoferrin reduces colitis in rats via modulation of the
      immune system and correction of cytokine imbalance.
AB  - BACKGROUND AND AIMS: The natural immunomodulator, lactoferrin, is widespread
      among various biological fluids and is known to exert an anti-inflammatory
      effect. However, there has been only one study that examined the mode of action
      of lactoferrin in reducing intestinal damage. We investigated the therapeutic
      role of lactoferrin and its effect on the levels of pro-inflammatory and anti
      inflammatory cytokines, by using a rat model of dextran sulfate sodium (DSS)
      induced-colitis. METHODS: Male Sprague-Dawley rats were given distilled drinking
      water containing 2.5% (wt/vol) synthetic DSS ad libitum. Bovine lactoferrin was
      given once daily through gavage, starting 3 days before beginning the DSS
      administration, until death. The whole colon was removed to be examined
      macroscopically and histologically. Myeloperoxidase activity, and pro
      inflammatory and anti-inflammatory cytokines in the colonic tissue were also
      measured. RESULTS: Dextran sulfate sodium-induced colitis was attenuated by oral
      administration of lactoferrin in a dose-dependent manner, as reflected by
      improvement in clinical disease activity index, white blood cell count and
      hemoglobin concentration, macroscopic and histological scores, and
      myeloperoxidase activity. Reduced inflammation in response to lactoferrin was
      correlated with the significant induction of the anti-inflammatory cytokines,
      interleukin-4 and interleukin-10, and with significant reductions in the pro
      inflammatory cytokines, tumor necrosis factor alpha, interleukin-1beta, and
      interleukin-6. CONCLUSIONS: We concluded that oral administration of lactoferrin
      exerts a protective effect against the development of colitis in rats via
      modulation of the immune system and correction of cytokine imbalance. Lactoferrin
      has potential as a new therapeutic agent for inflammatory bowel disease.

PMID- 12423275
TI  - Effects of oxymatrine on the serum levels of T helper cell 1 and 2 cytokines and
      the expression of the S gene in hepatitis B virus S gene transgenic mice: a study
      on the anti-hepatitis B virus mechanism of oxymatrine.
AB  - BACKGROUND: Oxymatrine has been shown to have a remarkable inhibitory activity to
      hepatitis B virus (HBV) infection with a hepatitis B virus e antigen (HBeAg)
      serum conversion rate of approximately 45%. In order to explore the anti-HBV
      mechanism of oxymatrine, the effects of oxymatrine on serum levels of T helper
      (h)1 cytokines (interferon (IFN)-gamma and interleukin (IL)-2) and Th2 cytokines
      (IL-4 and IL-10), and the expression of S gene in HBV S gene transgenic mice were
      studied. METHODS: Each transgenic mouse was either injected with oxymatrine or
      saline intraperitoneally once a day for 30 days. Serum levels of IFN-gamma, IL-2,
      IL-4 and IL-10 were quantitated and compared to the data before the treatment.
      The expression of HBV S gene in transgenic mice was analyzed at the DNA, mRNA and
      protein levels. RESULTS: The serum levels of IFN-gamma in transgenic mice before
      or after oxymatrine treatment were 3.108 +/- 3.172 and 11.059 +/- 6.971 pg/mL,
      respectively. In contrast, serum levels before and after oxymatrine treatment for
      IL-4 were 29.045 +/- 13.235 and 13.024 +/- 9.002 pg/mL, respectively (P < 0.001).
      The serum levels of IL-2 in the control (saline injection) and oxymatrine-treated
      mice were 1.070 +/- 0.447 and 5.537 +/- 2.887 pg/mL, respectively (P < 0.0001);
      and that of IL-10 were 97.226 +/- 73.306 and 33.607 +/- 23.154 pg/mL,
      respectively (P < 0.01). No significant differences were observed in the
      expression of HBV S gene in the transgenic mice at the DNA, mRNA and protein
      levels before or after oxymatrine treatment. CONCLUSIONS: The fact that Th1
      cytokines are increased while Th2 cytokines are decreased suggests that
      oxymatrine treatment triggers the change of immune response to hepatitis B
      infection in transgenic mice, which leads to improved HBV inhibitory activities.
      The study can help us better understand the mechanisms of the anti-HBV drug,
      oxymatrine, and how it has potential as an application in clinical chronic
      hepatitis B treatment.

PMID- 12423276
TI  - Is delayed normalization of alanine aminotransferase a poor prognostic predictor
      in chronic hepatitis C patients treated with a combined interferon and ribavirin
      therapy?
AB  - BACKGROUND AND AIMS: Decreased alanine aminotransferase (ALT) level is the
      accepted basic indicator of an interferon (IFN) therapeutic effect in chronic
      hepatitis C. This study assessed whether delayed normalization of ALT predicts a
      poor response to a combined therapy of IFN and ribavirin in patients with chronic
      hepatitis C virus (HCV) infection. METHODS: Patients were treated with IFN-alpha
      2b three times weekly and oral ribavirin for 24 weeks. The ALT values were
      assessed monthly and patterns of changes in ALT activity were analyzed. Serum HCV
      RNA was checked at weeks 0, 12, 24, and 48. RESULTS: A total of 103 patients
      completed therapy and 69 (67%) of them achieved a sustained viral response (SVR).
      There was no significant difference in the SVR between patients with or without
      early normalization (week 12) of ALT level (69 vs 56%). Of the sustained
      responders, nine patients (13%) with delayed ALT normalization had a SVR. Nine of
      the 12 patients (75%) with abnormal ALT and negative HCV-RNA at week 12 had a SVR
      compared with none of four patients who had positive HCV-RNA at week 12 (P =
      0.0192). CONCLUSIONS: Lack of normalization of the ALT level at week 12 does not
      preclude successful virological outcome in hepatitis C patients receiving a
      combined therapy of IFN and ribavirin. Hepatitis C virus RNA at week 12 may be a
      useful predictor of treatment outcome in patients without early biochemical
      response.

PMID- 12423277
TI  - Rabbit model of non-cirrhotic portal fibrosis with repeated immunosensitization
      by rabbit splenic extract.
AB  - BACKGROUND: Non-cirrhotic portal fibrosis (NCPF) or idiopathic portal
      hypertension, a disease of unknown etiology, is a common cause of portal
      hypertension in developing countries. Attempts to understand the etiopathogenesis
      of NCPF by developing animal models have been made. We describe a novel approach
      using repeated injections of rabbit splenic extract that were obtained from a
      previously primed rabbit, to develop a model of NCPF. METHODS: Twenty-eight
      rabbits (1.5-2.0 kg) were divided into the control (group I, n = 13) and the
      experimental (group II, n = 15) groups. The supernatant obtained after
      centrifugation of a 20% splenic homogenate, containing 6 mg protein/mL, was mixed
      with Freund's complete adjuvant (1:1 ratio) and injected intramuscularly to the
      recipient rabbits every 2 weeks for 3 months. Portal pressure was measured by
      inserting a cannula into the gastrosplenic vein. RESULTS: The mean portal
      pressure in group II was significantly (P < 0.05) higher than group I at 1 (19.4
      +/- 2.9 vs 10.4 +/- 2.2 mmHg), 3 (16.7 +/- 1.1 vs 7.2 +/- 3.6 mmHg), and 6 (20.3
      +/- 5.4 vs 10.3 +/- 4.8 mmHg) months. The mean splenic weight in group II was
      significantly (P < 0.05) greater than group I at 1, 3 and 6 months.
      Histopathology of spleen showed medullary congestion, hemosidrin laden
      macrophages and mild fibrosis. Liver showed normal hepatocytes with mild portal
      lymphocytic infiltrates and Kupffer cell hyperplasia. No significant anomalies
      were observed in the tests of liver function at 1 and 6 months. CONCLUSIONS: This
      animal model showed significant splenomegaly, with persistent rise in portal
      pressure without hepatic parenchymal injury, quite akin to NCPF seen in humans.
      This study also proposes that repeated immunostimulation may have an important
      role in the pathogenesis of NCPF.

PMID- 12423278
TI  - Late hemodynamic changes following controlled hemorrhage and volume restitution
      with blood or Haemaccel in anesthetized portal hypertensive rats.
AB  - BACKGROUND AND AIM: In portal hypertensive rats, hemorrhage and acute volume
      restitution with Haemaccel induced increased cardiac output and portal venous
      inflow. In the present study, the late hemodynamic effects of this procedure were
      explored. METHODS: Portal hypertension was induced by portal vein constriction.
      Blood was withdrawn 11.2 +/- 3.2 days later, at a rate of 0.3 mL/min, for 15 min,
      followed by 15 min of stabilization. Haemaccel or blood were infused at the same
      rate and volume used for withdrawal. Hemodynamic measurements were performed
      after 24 h, using radioactive microspheres. Viscosity was measured with an
      Ostwald viscometer. Vascular hindrance was calculated as resistance/viscosity
      ratio. RESULTS: Blood viscosity of the Haemaccel group (n = 11), was lower than
      in the blood group (n = 11): 2.7 +/- 0.2 versus 4.0 +/- 0.4 (P < 0.01). Arterial
      pressure, cardiac output, peripheral resistance, portal pressure, portal venous
      inflow and splanchnic arteriolar resistance were not significantly different.
      Splanchnic arteriolar and portocollateral hindrance were higher in the Haemaccel
      group (11.7 +/- 5.3 and 1.5 +/- 0.6 vs 7.7 +/- 3.0 and 0.9 +/- 0.4 mmHg x min x
      100 gram body weight/mL, respectively, P < 0.05). CONCLUSION: In portal
      hypertensive rats, vital organs perfusion, 24 h after hemorrhage and isovolemic
      volume restitution with Haemaccel and blood, was similar. However, in Haemaccel
      transfused animals, a reduction in vascular hindrance, indicating
      vasoconstriction, was observed in the splanchnic organs, which drain into the
      portal circulation. Vasoconstriction of the portocollateral vascular bed was
      observed as well. We suggest that slow-rate volume replacement during a portal
      hypertensive-related bleeding episode enables hemodynamic adaptation to occur.
      Thus, undesirable hyperdynamic changes, which may aggravate secondary bleeding,
      are attenuated.

PMID- 12423279
TI  - Virtual colonoscopy for the detection of colorectal polyps and cancers in a
      Chinese population.
AB  - AIM: The aim of this study is to assess the sensitivity of virtual colonoscopy in
      detecting colorectal polyps and cancers in a Chinese population. METHODS: Seventy
      one consecutive Chinese patients (38 men and 33 women) referred for diagnostic
      colonoscopy were recruited. Patients received a routine bowel preparation in the
      morning followed by a helical abdominal computed tomography (CT) scan with air
      insufflation of the colon. The CT images were then processed by using surface
      rendered software and interpreted by a single radiologist who was blinded to the
      clinical information. Colonoscopy was performed in the same afternoon without
      knowledge of the radiology results. All polyps and cancers were proven
      histologically. RESULTS: Five colorectal cancers were diagnosed and all were
      detected by virtual colonoscopy. The sensitivity and specificity of virtual
      colonoscopy for the detection of patients with polyps of all sizes, and patients
      with polyps >/=10 mm were 59, 92, 88 and 100%, respectively. The procedure was
      well tolerated by all patients. CONCLUSIONS: This study was carried out in a real
      clinical setting without a preselection of cases. Virtual colonoscopy was
      satisfactory for the detection of polyps greater than 10 mm, and for the
      diagnosis of cancer, and it is also a promising imaging modality for colorectal
      neoplasm detection in a Chinese population.

PMID- 12423280
TI  - Gastrointestinal: situs inversus viscerum.

PMID- 12423281
TI  - Hepatobiliary and pancreatic: a subcapsular region of the liver not receiving
      portal vein blood.

PMID- 12423282
TI  - Strongyloides stercoralis infestation associated with septicemia due to
      intestinal transmural migration of bacteria.
AB  - Strongyloides stercoralis infestation is common in the tropics and is usually
      asymptomatic. Patients with immunocompromised states may develop hyperinfection
      and fulminant disease. It has been suggested that bacteria accompany S.
      stercoralis during its passage across the bowel wall, resulting in systemic
      sepsis. Herein is a report on a 30-year-old man with S. stercoralis infestation
      and small bowel bacterial overgrowth presenting as malabsorption syndrome. He
      developed extensive duodenojejunal ulceration, septicemia and fatal hypokalemia.
      Blood and jejunal fluid grew Escherichia coli with the same antibiotic
      sensitivity patterns. This supports the hypothesis of migration of bacteria from
      the intestinal lumen as a cause of septicemia in patients with fulminant S.
      stercoralis infestation.

PMID- 12423283
TI  - Granulomatous phlebitis of small hepatic vein.
AB  - Several cases of granulomatous phlebitis of small hepatic veins are reported in
      the literature, though the etiology remains unclear. We experienced a similar
      case of granulomatous phlebitis involving terminal hepatic venules and this case
      will be reported in comparison with two previous cases presenting in our
      laboratory. A 39-year-old-female had a long course of medical treatment for
      epilepsy. She suffered from acute liver injury after prolonged fever for more
      than 1 week. Leukocytosis (11,100/ micro L) without eosinophilia, and
      inflammatory reactions such as C-reactive protein (21.0 mg/dL) were pointed out.
      She suffered from transient disseminated intravascular coagulation, but these
      abnormalities recovered with antibiotic and steroid therapy. Liver biopsy
      revealed granulomatous lesions mainly involving terminal hepatic venules. The
      possibility of tuberculosis was excluded by a negative Thiel-Nielsen stain and a
      negative molecular study for bacterial deoxyribonucleic acid of Mycobacteria
      species. Extrahepatic involvements were not clear clinically. This case and the
      previous two cases shared granulomatous phlebitis of the intrahepatic small
      hepatic veins, as well as clinical features suggestive of bacterial infection.
      Clinicians should be aware of such a rare clinicopathological entity.

PMID- 12423285
TI  - Acute hepatitis induced by traditional Chinese herbs used in the treatment of
      psoriasis.

PMID- 12423286
TI  - Prevalence of cholelithiasis in the general population at Chandigarh in northern
      India.

PMID- 12423287
TI  - Colorectal laterally spreading tumors: clinical evaluation and endoscopic
      strategies updated.

PMID- 12423290
TI  - Toothbrushing promotes gingival fibroblast proliferation more effectively than
      removal of dental plaque.
AB  - OBJECTIVES: Removal of dental plaque is an essential element of periodontal
      treatment. However, there have also been studies of the effects of the mechanical
      stimulation provided by toothbrushing on gingival host-defense mechanisms. The
      aim of the study was to evaluate the effects of toothbrushing on gingival
      fibroblast proliferation in dogs over time, compared to effects of plaque removal
      without brushing. METHODS: The mouths of six mongrel dogs were divided into four
      quadrants: two for daily toothbrushing, and two for daily plaque removal with a
      curette. After 1, 3 and 5 weeks of treatment, histometrical analyses were
      performed to assess inflammatory cell infiltration, proliferating cell nuclear
      antigen (PCNA)-positive fibroblasts, procollagen type I-positive fibroblasts in
      the subepithelial connective tissue of junctional epithelium. RESULTS:
      Toothbrushing increased the number of PCNA-positive fibroblasts in the first
      week, increased the number of type I procollagen-positive fibroblasts at the
      fifth week, and reduced inflammatory cell infiltration at the third week.
      CONCLUSION: These findings suggest that mechanically stimulated fibroblasts begin
      proliferating within a week, and this cell division results in an increased
      number of fibroblasts at the third week. It takes 5 weeks before differences in
      collagen synthesis between brushing and plaque removal areas are detectable.

PMID- 12423291
TI  - Assessment of periodontal conditions and systemic disease in older subjects. I.
      Focus on osteoporosis.
AB  - BACKGROUND: Osteoporosis (OPOR) is a common chronic disease, especially in older
      women. Patients are often unaware of the condition until they experience bone
      fractures. Studies have suggested that OPOR and periodontitis are associated
      diseases and exaggerated by cytokine activity. Panoramic radiography (PMX) allows
      studies of mandibular cortical index (MCI), which is potentially diagnostic for
      OPOR. AIMS: i). To study the prevalence of self-reported history of OPOR in an
      older, ethnically diverse population, ii). to assess the agreement between
      PMX/MCI findings and self-reported OPOR, and iii). to assess the likelihood of
      having both a self-reported history of OPOR and a diagnosis of periodontitis.
      MATERIALS AND METHODS: PMX and medical history were obtained from 1084 subjects
      aged 60-75 (mean age 67.6, SD +/- 4.7). Of the films, 90.3% were useful for
      analysis. PMXs were studied using MCI. The PMXs were used to grade subjects as
      not having periodontitis or with one of three grades of periodontitis severity.
      RESULTS: A positive MCI was found in 38.9% of the subjects, in contrast to 8.2%
      self-reported OPOR. The intraclass correlation between MCI and self-reported OPOR
      was 0.20 (P < 0.01). The likelihood of an association between OPOR and MCI was
      2.6 (95%CI: 1.6, 4.1, P < 0.001). Subjects with self-reported OPOR and a positive
      MCI had worse periodontal conditions (P < 0.01). The Mantel-Haentzel odds ratio
      for OPOR and periodontitis was 1.8 (95%CI: 1.2, 2.5, P < 0.001). CONCLUSIONS: The
      prevalence of positive MCI was high and consistent with epidemiological studies,
      but only partly consistent with a self-reported history of osteoporosis with a
      higher prevalence of positive MCI in Chinese women. Horizontal alveolar bone loss
      is associated with both positive self-reported OPOR and MCI.

PMID- 12423292
TI  - Assessment of periodontal conditions and systemic disease in older subjects. II.
      Focus on cardiovascular diseases.
AB  - BACKGROUND: Panoramic radiographs (PMX)s may provide information about systemic
      health conditions. AIMS: i). To study clinical periodontal conditions and collect
      self-reported health status in a cohort of 1084 older subjects; ii). to study
      signs of alveolar bone loss and carotid calcification from panoramic radiographs
      obtained from these subjects; and iii). to study associations between study
      parameters. MATERIAL AND METHODS: PMXs from 1064 adults aged 60-75 (mean age
      67.6, SD +/- 4.7) were studied. Signs of alveolar bone loss, vertical defects,
      and molar furcation radiolucencies defined periodontal status. Medical health
      histories were obtained via self-reports. Signs of carotid calcification were
      identified from panoramic radiographs. RESULTS: The PMX allowed assessment of 53%
      of the films (Seattle 64.5% and Vancouver 48.4%). A self-reported history of a
      stroke was reported by 8.1% of men in Seattle and 2.9% of men in Vancouver (P <
      0.01). Heart attacks were reported by 12% of men in Seattle and 7.2% in Vancouver
      (N.S.). PMX evidence of periodontitis was found in 48.5% of the subjects, with
      carotid calcification in 18.6%. The intraclass correlation score for PMX findings
      of carotid calcification and stroke was 0.24 (95% CI: 0.10-0.35, P < 0.001). The
      odds ratio for PMX carotid calcification and periodontitis was 2.1 (95% CI: 1.3
      3.2, P < 0.001), and for PMX carotid calcification and stroke 4.2 (95% CI: 1.9
      9.1, P < 0.001). The associations disappeared when smoking was accounted for. A
      history of a heart attack was associated with stroke, gender, age, and PMX scores
      of alveolar bone loss. CONCLUSIONS: PMXs may provide valuable information about
      both oral conditions and signs of carotid calcification, data that are consistent
      with self-reported health conditions. Alveolar bone loss as assessed from PMXs is
      associated with cardiovascular diseases.

PMID- 12423293
TI  - Sister chromatid exchange (SCE) analysis in periodontitis.
AB  - BACKGROUND: Emerging data indicate that genetic factors may be associated with
      the etiopathogenesis of aggressive periodontitis. Sister chromatid exchange (SCE)
      is a sensitive method that might reflect an instability of DNA or a deficiency of
      DNA repair. The aim of the present study was to investigate SCE frequency of
      patients with different forms of periodontal disease and to determine whether
      this cytogenetic marker in patients with aggressive periodontitis can be
      differential compared to patients with chronic periodontitis and control
      subjects. METHODS: SCE was analysed in peripheral blood lymphocyte chromosomes of
      13 patients with generalised aggressive periodontitis (G-AP), 10 patients with
      chronic periodontitis (CP) and 10 control subjects. The periodontal parameters of
      probing depth, clinical attachment level, the presence of bleeding on probing and
      plaque were recorded. Peripheral blood lymphocytes obtained from both patient
      groups and control subjects were cultured in the presence of 5-Bromo-2
      deoxyuridine in complete darkness for 72 h. For scoring SCE frequency, 20
      metaphases were studied from each donor. RESULTS: The frequency of SCE was found
      to be 6.7 +/- 0.9 per cell in patients with G-AP, 6.5 +/- 1.5 per cell in CP
      patients and 6.9 +/- 1.1 in control subjects. No statistically significant
      differences were found between groups (p > 0.05). CONCLUSIONS: The data indicate
      that there the cyotogenetic damage in the aggressive type of periodontal disease
      is not greater than in chronic periodontitis and control subjects. Although no
      aberrant cytogenetic damage was observed in different forms of periodontitis
      compared to control, this does not discount the importance of other genetic
      factors in the pathogenesis of periodontal disease.

PMID- 12423294
TI  - Analysis of genetic polymorphisms at the interleukin-10 loci in aggressive and
      chronic periodontitis.
AB  - BACKGROUND/AIMS: Different cytokine genotypes have been described in periodontal
      disease. The aim of the present study was to investigate the genetic association
      of two previously described interleukin-10 (IL-10) polymorphisms in patients with
      aggressive (AP) and chronic periodontitis (CP) and to investigate possible
      associations with clinical manifestations. METHODS: Based on clinical parameters
      and radiographs, 23 patients with CP and 18 patients with AP were included in the
      study. Additionally, 21 age-matched healthy subjects served as a control group.
      Genomic DNA was isolated from whole blood samples and the IL-10 promoter
      sequences from positions - 597 to - 824 were amplified by polymerase chain
      reaction (PCR). Polymorphisms were detected by restriction-enzyme cleavage. The A
      and C alleles at the - 597 position were associated with the T and C alleles at
      the - 824 position, respectively. Fisher's exact test was used for the
      statistical analysis. RESULTS: No significant differences were observed in the
      allele frequencies between controls and AP patients (p = 0.70) or CP patients (p
      = 0.43), although the previously reported association between allele A at
      position - 597 and allele T at position - 824 was observed in our population.
      CONCLUSION: We conclude that the investigated polymorphisms are not associated
      with periodontal disease.

PMID- 12423295
TI  - Prevalence of aggressive periodontitis in school attendees in Uganda.
AB  - AIM: The prevalence and severity of early onset periodontitis (EOP) among
      students attending secondary schools in two regions of Uganda was studied.
      MATERIAL AND METHODS: 690 students (393 males and 297 females) aged 12-25 years
      (mean 17 years), representing a range of tribal groups, were recruited from six
      schools in the peri-urban Central and rural Western regions of Uganda. The study
      subjects were clinically examined in field conditions by a single calibrated
      examiner to measure gingival recession and probing depth at six sites per tooth,
      with subsequent calculation of clinical periodontal attachment level for each
      site. Subjects exhibiting >or= 4 mm of clinical periodontal attachment loss at
      approximal surfaces of one or more teeth were classified with EOP. A structured
      written questionnaire obtained demographic characteristics of the study subjects.
      RESULTS: 199 (28.8%) study subjects showed clinical features of EOP, of which 16
      (2.3%) subjects exhibited generalized EOP, 29 (4.2%) localized EOP, and 154
      (22.3%) incidental EOP. The percentage of EOP-affected males was significantly
      higher than females (33.8% vs. 22.2%, P < 0.001). EOP prevalence tended to
      increase with increasing age, but no association was found between EOP prevalence
      and socioeconomic status or residency in urban vs. rural areas of Uganda. Molars
      and mandibular incisors generally demonstrated the highest occurrence of >or= 4
      mm attachment loss. Clinical periodontal attachment loss of >or= 5 mm was mainly
      seen at first molars and incisors, suggesting that these two tooth types are
      first affected with attachment loss. Approximal tooth surfaces showed greater
      probing depth and attachment loss than buccal and lingual surfaces. Gingival
      recession was most prevalent at mandibular anterior teeth, whereas gingival
      margin coronal to CEJ was most frequently observed at second molars and maxillary
      incisors. CONCLUSION: A relatively high prevalence of EOP (28.8%) was found in
      young Ugandan school attendees, with 6.5% of these showing severe disease. EOP in
      Uganda was significantly more prevalent in males than females, and most
      frequently characterized by approximal involvement of molars and mandibular
      incisors. Etiologic and predisposing factors associated with the high occurrence
      of EOP in Uganda, as well as therapeutic and preventive measures of the disease
      in this population, remain to be delineated.

PMID- 12423296
TI  - A new method of plaque scoring: a laboratory comparison with other plaque
      indices.
AB  - AIM: The aim of this study was to propose a simple, clear and as sensitive as
      possible numerical plaque index for the use in clinical oral hygiene trials known
      as the New Method of Plaque Scoring (NMPS), and to evaluate this index for
      simplicity, clarity and examiner agreement in comparison with the Distal Mesial
      Plaque Index, Proximal Marginal Index and a modification to the modified Navy
      plaque Index. MATERIAL AND METHODS: The scoring system proposed for the NMPS is
      based on a numerical range from 0 to 10 representing the total stained plaque on
      the facial or lingual tooth surfaces with the greatest weight of scores placed at
      the gingival and proximal regions of the surface. For scoring purposes, a
      horizontal boundary is imagined on the smooth facial or lingual tooth surfaces
      between the gingival third (A) and coronal two/thirds, the latter being
      subdivided vertically into thirds, mesial (B), middle (D) and distal (C).
      Depending on the extent of plaque coverage, whole number scores 0-3 are assigned
      to A, B, C and 0 or 1 for D. Ten examiners scored four selected tooth surfaces on
      an acrylic model according to the NMPS and the three comparative indices. The
      time required for each examiner to score according to each index was recorded.
      The scores obtained from this trial were analyzed for examiner agreement and
      correlation between the four indices. RESULTS: The time required for scoring
      according to the NMPS was found to be significantly less than the three
      comparative indices. The variability between examiners was found to be least for
      the NMPS compared to the three comparative indices. A strong correlation was
      found between all pairs of indices. CONCLUSION: The proposed new method of plaque
      scoring seems to be simpler, clearer and more reproducible than the three
      comparative indices. However, clinical testing is warranted.

PMID- 12423297
TI  - A clinical evaluation of a novel data logger to determine compliance with the use
      of powered toothbrushes.
AB  - OBJECTIVES: The primary objective of this study was to evaluate the viability of
      an electronic data logger to record the brushing episodes of patients receiving
      standardised oral hygiene instructions. The secondary objective was to estimate
      the compliance of a group of patients diagnosed with chronic periodontal disease
      with brushing time instructions for the daily use of a powered toothbrush over a
      2-month period. MATERIAL AND METHODS: 17 modified Philips Jordan Sensiflex 2000
      powered toothbrushes (PTBs) were provided to patients (32-67 years) attending for
      non-surgical management of chronic periodontal disease. The PTBs incorporated an
      electronic data logger which recorded, for each individual brushing event: the
      length of time the brush was used (identifying the brushing speed setting); the
      maximum, minimum and average current during operation; and the time spent
      charging in between two consecutive brushing events. The patients were given
      detailed instructions with the PTB and were told to use it for 2 min each morning
      and 2 min in the evening. The patients returned for non-surgical management over
      two visits prior to reinforcement of the oral hygiene instructions 1 month after
      PTB allocation. Subjects were asked to complete a simple brushing diary to record
      their use of the toothbrush on a daily basis. After 2 months of using the PTBs at
      home, the brushes and diaries were collected and the data downloaded from the
      data loggers. RESULTS: Of the 17 data loggers allocated, two recorded no
      information and two subjects did not return for the follow-up appointments. The
      data from the remaining 13 data loggers were evaluated for level of compliance.
      An event of brushing between 120 and 130 s was considered to be compliant, one of
      between 90 and 120 or 130-150 s was partially compliant and brushing for < 90 s
      or > 150 s was recorded as non-compliant. Percentage compliance for all the
      events (2087 recordings) was 34%, partial- and non-compliance were calculated as:
      18%; 48% of events, respectively. CONCLUSION: This data logger has provided
      previously unrecorded data on the brushing times for a group of patients using a
      powered toothbrush at home during non-surgical management of chronic periodontal
      disease. The data suggested that almost half (48%) of the brushing events
      recorded by the data loggers were greater than 30 s above or below the instructed
      brushing time.

PMID- 12423298
TI  - Effect of initial periodontal therapy on sulcular/tongue sulfide level. A pilot
      study.
AB  - BACKGROUND: : Volatile sulfur compounds (VSC), such as hydrogen sulfide, methyl
      mercaptan and dimethyl sulfide, are toxic metabolites produced by periodontal
      pathogens. These VSC are also released from the tongue dorsum. Currently, limited
      data are available on how periodontal treatments may affect sulcular/tongue
      sulfide level. The aim of this study was to determine effect of initial therapy
      including oral hygiene instruction and scaling and root planing (SRP) on
      sulcular/tongue sulfide level. METHODS: : Thirteen subjects diagnosed with
      chronic periodontitis and having three representative periodontal pocket depth
      (PD) strata in one quadrant (PD <or= 3.0 mm: healthy, 4.0 mm <or= PD <or= 6.0 mm:
      moderate, and PD >or= 7.0 mm: severe disease sites) were selected. Clinical
      periodontal parameters were recorded at baseline and 3 weeks after completion of
      the initial therapy. The sulfide levels in three representative periodontal
      pockets (pS) and on three parts (anterior, middle, and posterior) of the tongue
      dorsum (tS) were measured using a commercial sulfide-monitoring device. RESULTS:
      : The pS levels of the three representative sites were reduced significantly
      following the initial therapy (p < 0.05). However, there was no significant
      reduction of the tS level in all three parts of the tongue. CONCLUSIONS: : The
      initial periodontal therapy such as oral hygiene and SRP reduces the sulcular
      sulfide level but not the tongue sulfide level. This suggests that sulcular
      sulfide level may be a possible indicator for assessing the outcome of initial
      periodontal treatment.

PMID- 12423299
TI  - The connective tissue graft: a comparative clinical evaluation of wound healing
      at the palatal donor site. A preliminary study.
AB  - OBJECTIVES: The aim of this study is to evaluate early healing results of the
      palatal wound by comparing three different surgical procedures for harvesting a
      connective tissue graft: the single-incision (SI), the free gingival graft (FGG)
      and the trap-door (TD) techniques. MATERIAL AND METHODS: 36 patients requiring a
      root coverage procedure were selected for treatment using a bilaminar technique
      and randomly assigned (12 per group) to the FGG, TD or SI groups. The size of the
      graft was standardised to 12 x 8 mm and the thickness ranged from 1 to 1.5 mm.
      The following parameters were recorded at 1, 2, 3, 4, 6 and 8 weeks postsurgery:
      immediate and delayed bleeding (iB, dB), sensibility (S), complete
      epithelialisation (CE), discomfort (D), and variation of feeding habits (FH).
      RESULTS: The difference in CE between the SI and FGG groups was statistically
      significant at the third postoperative week (100% and 50%, respectively). The
      discomfort rate at the first week postsurgery was the same in the SI and TD
      groups (50% without discomfort), but results were statistically significant
      different in the FGG group (0% without discomfort). No significant differences
      were found between the three groups for the other parameters. CONCLUSIONS:
      Statistically significant differences were found between the SI and FGG
      techniques in terms of CE, which occurred faster in the SI group. The discomfort
      rate recorded for both SI and TD groups was significantly lower than for FGG
      group. No marked differences were noted between SI and TD procedures. The latter
      was confirmed by patient interviews. The results of this preliminary study have
      little statistical significance because of the limited number of patients but
      they represent an important basis for a comparative clinical study, with a larger
      sample of participants, which is currently in progress.

PMID- 12423300
TI  - The involvement of nervous and some inflammatory response mechanisms in the acute
      snuff-induced gingival hyperaemia in humans.
AB  - BACKGROUND AND AIM: Tobacco users and especially cigarette smokers are at higher
      risk than non-smokers for periodontal disease. The pathogenic mechanism has been
      proposed to be the vasoconstrictive properties of nicotine, with reduced gingival
      blood flow (GBF) as a contributing factor in the development of periodontal
      disease. However, in a previous study in humans, we found GBF to increase in
      response to acute exposure to snuff. The present study was designed to
      investigate whether the tobacco-induced acute GBF increase is dependent on intact
      nervous conduction. We further investigated the effect of piroxicam (NSAID) and
      dexchlorpheniramin (DCPA) (antihistamine) on the snuff-induced responses in the
      gingiva, to see if chemical mediators of inflammation also influenced the
      response. MATERIAL AND METHODS: Laser Doppler flowmetry (LDF) was used to measure
      gingival blood flow bilaterally in the buccal maxillary gingiva, in the forehead
      skin and in the thumb. Also arterial blood pressure (BP) and heart rate (HR) were
      monitored. Infraorbital nerve block anaesthesia (INB), superficial mucosal
      anaesthesia, 20 mg piroxicam or 2 mg DCPA were used in combination with snuff to
      study the vascular responses to 500 mg snuff (1% nicotine). RESULTS: Snuff
      induced a rapid increase in GBF that was higher than the increase in BP,
      indicating an active vasodilatation. The snuff-induced vasodilatation was partly
      blocked by INB and more so by superficial mucosal anaesthesia. Piroxicam and DCPA
      exerted diverse effects on vascular homeostasis but had no effect on the snuff
      induced vasodilatation in the gingiva. CONCLUSIONS: The results of this study
      confirm that snuff induces local gingival vasodilatation, and imply that this
      vasodilatation most likely is a summation of responses due to both autonomic and
      antidromic reflex mechanisms. We further discuss the possible involvement of the
      nervously mediated effects of tobacco and nicotine on vascular homeostasis and in
      tobacco-associated periodontitis.

PMID- 12423301
TI  - Healing patterns in calvarial bone defects following guided bone regeneration in
      rats. A micro-CT scan analysis.
AB  - OBJECTIVE: The objective of this study was to evaluate healing patterns of
      critical-size calvarial bone defects treated according to principles of guided
      bone regeneration using micro-CT scan analysis. Specifically, the contribution of
      bone, periosteum and dura mater to the amount and mineralization of newly formed
      bone was evaluated. MATERIAL AND METHODS: Surgically induced, critical-size
      calvarial bone defects in 48 adult male Wistar rats received the following: an
      occlusive expanded polytetrafluoroethylene (ePTFE) membrane at the exo- and
      endocranial aspect (OO; n = 12); an occlusive membrane at the exocranial and a
      perforated membrane at the endocranial aspect (OP; n = 12); a perforated membrane
      at the exocranial and an occlusive membrane at the endocranial aspect (PO; n =
      12); and a perforated membrane at the exo- and endocranial aspect (PP; n = 12).
      The animals were euthanized at 4 weeks for quantitative analysis of bone volume
      fraction and mineralization in the region of interest (ROI) as well as in the
      external, middle and central area of the defect using micro-CT. RESULTS: Bone
      volume fraction ranged from 31.4% (OP) to 24.5% (PP). No differences were found
      among the groups. Bone volume fraction and mineralization in the middle area were
      significantly greater in group OP than in group PP, and in the central area in
      group OO and PO than in group PP. CONCLUSIONS: The results of this study suggest
      that use of occlusive ePTFE membranes enhances bone formation and maturation in
      the calvarial skeleton. When occlusion of endo- and exocranial tissues was
      compromised by membrane perforation, impaired bone formation and mineralization
      were observed.

PMID- 12423302
TI  - Hereditary gingival fibromatosis: a case report.
AB  - BACKGROUND/AIMS: Hereditary gingival fibromatosis is characterized by various
      degrees of attached gingival overgrowth. It usually develops as an isolated
      disorder but can be one feature of a syndrome. A case of a 38-year-old female is
      reported who presented a generalized severe gingival overgrowth, involving the
      maxillary and mandibular arches and covering almost all teeth. The clinical
      differential diagnosis included drug-induced overgrowth as well as idiopathic
      gingival fibromatosis. TREATMENT: Excess gingival tissue was removed by
      conventional gingivectomy. As the gingival enlargement was generalized to all
      quadrants, on both sides, the surgery was carried out under general anaesthesia.
      The postoperative course was uneventful and the patient's appearance improved
      considerably. Post-surgical follow-up after 20 months demonstrated a slight
      recurrence CONCLUSIONS: Hereditary gingival fibromatosis is a rare disorder
      characterized by the proliferative fibrous overgrowth of the gingival tissue.
      Resective surgery of the excess tissue is the treatment available. However,
      recurrence is a common feature.

PMID- 12423303
TI  - Interplay between T helper type 1 and type 2 cytokines and soluble major
      histocompatibility complex molecules: a paradigm in pregnancy.

PMID- 12423304
TI  - Redistribution of the sheep neonatal Fc receptor in the mammary gland around the
      time of parturition in ewes and its localization in the small intestine of
      neonatal lambs.
AB  - Maternal immunity is mediated exclusively by colostral immunoglobulins in
      ruminants. As the neonatal Fc receptor (FcRn) is suggested to be involved in the
      transport of immunoglobulin G (IgG) in the mammary gland, we cloned this receptor
      from sheep and analysed its expression in the mammary gland around the time of
      parturition and also in the small intestine from the newborn lamb. FcRn heavy
      chain mRNA was detected (by using in situ hybridization) exclusively in the
      acinar and ductal epithelial cells in mammary gland biopsies both before and
      after parturition. Immunohistochemistry revealed that the cytoplasm of the
      epithelial cells of the acini and ducts in the mammary gland biopsies stained
      homogeneously before parturition. A remarkable difference was observed in the
      pattern after lambing, where the apical side of the cells was strongly stained.
      The presence of the FcRn in the acinar and ductal epithelial cells of the mammary
      gland, and the obvious change in distribution before and after parturition,
      indicate that the FcRn plays an important role in the transport of IgG during
      colostrum formation in ruminants. Immunohistochemical analysis detected a strong
      apical and a weak basal FcRn signal in the duodenal crypt cells of a neonatal
      lamb, which have been previously demonstrated to secrete IgG1 in newborn
      ruminants. The FcRn was not detected in the duodenal enterocytes, which absorb
      intact IgG from the colostrum in a non-specific manner. These data suggest that
      FcRn is involved in IgG1 secretion in ruminant epithelial cells.

PMID- 12423305
TI  - Influence of gender and interleukin-10 deficiency on the inflammatory response
      during lung infection with Pseudomonas aeruginosa in mice.
AB  - Cystic fibrosis females have a worse prognosis compared to male patients.
      Furthermore, cystic fibrosis patients infected with Pseudomonas aeruginosa have
      been shown to have dysregulated cytokine profiles, as higher levels of tumour
      necrosis factor alpha (TNF-alpha), interleukin (IL)-8, and lower levels of IL-10
      are found in the bronchoalveolar lavage fluid compared to healthy controls. The
      present study was aimed at investigating the importance of gender and IL-10 in
      the susceptibility of C57BL/6 mice to pulmonary infection with Pseudomonas
      aeruginosa. We found that wildtype females were more susceptible than males to
      infection, as we observed greater weight loss, higher bacterial load, and
      inflammatory mediators in their lungs. IL-10 knockout mice, both females and
      males, had higher levels of TNF-alpha in the lungs compared to wildtype mice and
      maintained higher levels of polymorphonuclear cells and lower levels of
      macrophages for a longer period of time. Our results demonstrate that the number
      of bacteria recovered from the lungs of IL-10 knockout male mice was
      significantly higher than that observed in their wildtype male counterparts and
      we show that neutralization of IL-10 in infected female mice for a prolonged
      period of time leads to increased susceptibility to infection. Results reported
      in this study clearly demonstrate that females, both wildtype and IL-10 knockout
      mice are more susceptible to Pseudomonas aeruginosa infection than males, and
      that they mount a stronger inflammatory response in the lungs.

PMID- 12423306
TI  - Interleukin-3, but not granulocyte-macrophage colony-stimulating factor and
      interleukin-5, inhibits apoptosis of human basophils through phosphatidylinositol
      3-kinase: requirement of NF-kappaB-dependent and -independent pathways.
AB  - Basophils are key effector cells of allergic reactions. Although proinflammatory
      cytokines, such as interleukin (IL)-3, granulocyte-macrophage colony-stimulating
      factor (GM-CSF) and IL-5, inhibit eosinophil apoptosis in vitro, little is known
      about basophil apoptosis, and the signalling mechanisms required for basophil
      survival remain undefined. To address this issue, we used a novel negative
      selection system to isolate human basophils to a purity of > 95%, and evaluated
      apoptosis by morphology using light and transmission electron microscopy, and by
      annexin-V binding and propidium iodide incorporation using flow cytometry. In
      this study, we demonstrated that the spontaneous rate of apoptotic basophils was
      higher than that of eosinophils as, at 24 hr, 57.6 +/- 4.7% of basophils
      underwent apoptosis compared with 39.5 +/- 3.8% of eosinophils. In addition,
      basophil cell death was significantly inhibited when cultured with IL-3 for 48 hr
      (84.6 +/- 4.9% vehicle-treated cells versus 40.9 +/- 3.9% IL-3-treated cells). IL
      3 also up-regulated basophil CD69 surface expression. The effects of IL-3 on
      apoptosis and CD69 surface expression of human basophils were completely blocked
      by LY294002 (LY), a potent inhibitor of phosphatidylinositol 3-kinase (PI3-K),
      but only partially inhibited by lactacystin, a proteasome inhibitor that prevents
      degradation of IkappaB and NF-kappaB translocation. These observations reveal the
      novel finding that IL-3 prevents basophil apoptosis through the activation of PI3
      K, which is only partially NF-kappaB dependent. As basophils are active
      participants in allergic reactions and IL-3 is one of the abundant
      proinflammatory cytokines in secretions from allergic tissue, we suggest that IL
      3-mediated inhibition of basophil apoptosis may exacerbate the inflammation
      associated with allergic disorders.

PMID- 12423307
TI  - Interleukin-6 promotes the production of interleukin-4 and interleukin-5 by
      interleukin-2-dependent and -independent mechanisms in freshly isolated human T
      cells.
AB  - T helper 2 (Th2) cytokines [interleukin (IL)-4 and IL-5] play a central role in
      the development of allergic immune responses. After allergen provocation, the
      expression of Th2 cytokines is rapidly up-regulated in atopy and asthma. IL-6 is
      a multifunctional cytokine that is able to direct Th2 immune responses and is
      secreted by multiple tissue cell types. This study shows that IL-6 induces up
      regulation of IL-4 and IL-5 after short (5 min) preincubation periods in freshly
      isolated, alpha-CD3/alpha-CD28-stimulated T cells. After longer preincubation
      periods with IL-6 (12 and 24 hr), the priming effect on IL-4 production gradually
      disappears, whereas the effect on IL-5 becomes more pronounced. In contrast, a
      small but significant inhibitory effect is found on the production of the Th1
      cytokine interferon-gamma. Additional experiments indicate that the long-term
      priming effect of IL-6 on IL-5 production is dependent on IL-2 signalling. This
      is not the case for the short-term IL-6 effect on IL-5 secretion, where the p38
      mitogen-activated protein kinase-dependent induction of activator protein-1 DNA
      binding activity is involved, independent of signal transducer and activator of
      transcription 3 phosphorylation. In summary, these data demonstrate that the
      short-term and long-term priming effects of IL-6 on Th2 cytokine production are
      regulated by different mechanisms.

PMID- 12423308
TI  - G1/S cell cycle arrest provoked in human T cells by antibody to CD26.
AB  - CD26 is T cell costimulatory molecule with dipeptidyl peptidase IV (DPPIV) enzyme
      activity located in its extracellular region. The expression of CD26 is enhanced
      after activation of T cells, while it is preferentially expressed on a subset of
      CD4+ memory T cells in the resting state. In this paper, we demonstrate that
      binding of the soluble anti-CD26 monoclonal antibody (mAb) 1F7 inhibits human T
      cell growth and proliferation in both CD26-transfected Jurkat T-cell lines and
      human T-cell clones by inducing G1/S arrest, which is associated with enhancement
      of p21Cip1 expression. This effect depends on the DPPIV enzyme activity of the
      CD26 molecule. Moreover, we show that expression of p21Cip1 after treatment with
      the anti-CD26 mAb 1F7 appears to be induced through activation of extracellular
      signal-regulated kinase (ERK) pathway. These data thus suggest that anti-CD26
      treatment may have potential use in the clinical setting involving activated T
      cell dysregulation, including autoimmune disorders and graft-vs.-host disease.

PMID- 12423309
TI  - Interaction between nitric oxide and subsets of human T lymphocytes with
      differences in glutathione metabolism.
AB  - Nitric oxide (NO) modulates human T-lymphocyte responses through several
      mechanisms. In the current study we show that interactions between NO and
      glutathione (GSH) metabolism are related to the selective persistent inhibition
      of interferon-gamma (IFN-gamma) production by NO, which we previously identified.
      T cells were exposed to NO using the NO-donor compound Spermine-nonoate (Sper)
      and activated using anti-CD3 plus anti-CD28 monoclonal antibodies. Persistent
      inhibition of IFN-gamma by Sper was prevented by addition of the GSH precursor l
      cysteine, which inhibits Sper induced GSH depletion. Subsets of cells were either
      susceptible (GSH(low)) or resistant (GSH(high)) to NO-induced GSH depletion. The
      GSH(low) subset was characterized by enhanced numbers of CD4+ cells, reduced
      numbers of activated cells as characterized by CD25 and CD69, and reduced numbers
      of memory (CD45RO+) cells relative to the GSH(high) population. Rather than
      directly affecting susceptibility to NO, these surface markers reflected
      different expression patterns. Particularly, the GSHlow subset was further
      characterized by decreased activity of the GSH synthesis related enzymes multi
      drug resistance related protein (MRP)-1 and gamma-glutamyltranspeptidase (gamma
      GT). Blocking gamma-GT, using acivicin was shown to exacerbate NO-induced GSH
      depletion and NO-induced apoptosis. Since NO induced apoptosis selectively
      affects IFN-gamma production these findings implicate GSH metabolism in the
      modulation and maintenance of the T helper (Th)1/Th2 balance.

PMID- 12423310
TI  - Kinetics of thrombomodulin release and endothelial cell injury by neutrophil
      derived proteases and oxygen radicals.
AB  - Thrombomodulin is a transmembranous glycoprotein of endothelial cells. In vitro
      it is a marker of endothelial cell injury. In vivo the levels of serum
      thrombomodulin are regarded as a parameter of activity in vasculitides. The
      latter are pathophysiologically determined by neutrophil-derived inflammation and
      endothelial cell injury caused by secretion of proteases and hydrogen peroxide.
      It was the objective of this study to determine whether thrombomodulin is only a
      late marker of advanced endothelial cell injury or whether it indicates also
      earlier stages of cell alterations. Over 24 hr endothelial cell cultures were
      incubated with hydrogen peroxide or the neutrophil proteases proteinase-3,
      elastase and cathepsin G. The time-dependent increase of thrombomodulin in the
      supernatant was determined by enzyme-linked immunosorbent assay and immunoblot.
      In addition the viability (eosin, tetrazolium dye assay), detachment (crystal
      violet assay), and apoptosis (4',6-diamine-2'-phenylindole-dihydrochloride assay)
      of the respective endothelial cells were determined for adherent and non-adherent
      cells. A rapid thrombomodulin increase was found under all experimental
      conditions. The additional immunoblotting analysis showed the pattern of
      proteolytic cleavage caused by the protease reactivity. In case of hydrogen
      peroxide the thrombomodulin increase was closely correlated with the loss of cell
      viability and lysis. The incubation of endothelial cells with the different
      proteases resulted in a time-dependent detachment of primarily viable cells. In
      addition to cell necrosis apoptotic cell death was found in the subgroup of
      detached endothelial cells after prolonged incubation over 24 hr with proteinase
      3 (23%), elastase (31%), and cathepsin G (19%). In contrast, still adhering cells
      did not show any signs of necrosis or apoptosis. In summary these studies confirm
      in vitro that soluble thrombomodulin is not only a parameter of advanced
      endothelial cell destruction itself but also in addition an early marker of
      initial endothelial cell membrane changes induced by neutrophil derived proteases
      and oxygen radicals.

PMID- 12423311
TI  - Reactivation of latent tuberculosis by an inhibitor of inducible nitric oxide
      synthase in an aerosol murine model.
AB  - Exposure to Mycobacterium tuberculosis results in clinical tuberculosis only in a
      small percentage of healthy individuals. In most instances the bacilli are
      controlled by the immune system and survive in a latent state within granuloma.
      Immunosuppression, however, may result in reactivation of infection, resulting in
      clinical disease. Using a low-dose aerosol infection (30 colony-forming units) in
      mice, we describe a short-duration model for studying spontaneous and drug
      induced reactivation of anti-tuberculous drug-treated, latent tuberculosis
      infection. Although a 4-week treatment with rifampicin and isoniazid reduced the
      number of bacilli to undetectable levels, the infection spontaneously reactivated
      following therapy. By contrast, an 8-week treatment period induced a state of
      latent infection, requiring immunosuppression to reactivate infection. Finally, a
      12-week treatment period eliminated the bacilli completely and aminoguanidine did
      not induce reactivation of infection. In view of the fact that therapy in the
      selected protocol reduces the mycobacterial load to undetectable levels, the data
      suggest that an 8-week treatment period is necessary and sufficient to mount
      protective immunity in mice.

PMID- 12423312
TI  - Human autologous mixed lymphocyte reaction as an in vitro model for
      autoreactivity to apoptotic antigens.
AB  - Recent studies have indicated that cells undergoing apoptosis are the source of
      autoantigens which drive autoimmune responses in systemic lupus erythematosus
      (SLE). It has been recognized for many years that in vitro stimulation of T cells
      with irradiated major histocompatibility complex (MHC) class II-bearing
      autologous cells results in T-cell proliferation with immunological specificity
      and memory, namely the autologous mixed lymphocyte reaction (AMLR). The nature of
      the major stimulants in the AMLR is still unclear. We investigated whether
      apoptotic fragments from irradiated cells act as antigenic stimulators for AMLR
      or nucleohistone-primed T cells. T-cell proliferation in the primary AMLR was
      significantly suppressed by the presence of a caspase inhibitor Z-Val-Ala-Asp
      CH2F (Z-VAD.fmk), indicating that apoptotic antigens released from irradiated
      autologous feeder cells act as stimulators of AMLR T cells. This inhibitory
      effect of Z-VAD was not caused by toxic effects, because the T-cell response to
      the mitogen phytohaemagglutinin (PHA) was not inhibited by Z-VAD. A nucleohistone
      preparation was shown to contain antigens that are important in the AMLR, as
      culture with nucleohistone (but not with thyroglobulin or hen-egg lysozyme)
      primed T cells to respond with secondary kinetics in a subsequent AMLR that was
      also suppressed by Z-VAD. Our data provide evidence that the AMLR constitutes a
      model for the evaluation of cellular and molecular mechanisms that may be
      relevant to the pathogenesis of SLE and similar autoimmune diseases.

PMID- 12423313
TI  - Generation and characterization of ovine dendritic cells derived from peripheral
      blood monocytes.
AB  - Dendritic cells (DCs) are professional antigen-presenting cells with a highly
      immunostimulatory function and the capacity to activate naive T cells. In recent
      years the rapid progress in mouse and human DC research can be mainly attributed
      to the generation of DCs from precursor cells in vitro, although a lack of
      reagents has hampered DC research in many large animal models. Here we describe
      the generation and characterization of ovine monocyte-derived DCs in vitro. In
      addition to the characteristic morphology and non-adherence of DCs, peripheral
      blood mononuclear cell monocytes cultured with ovine granulocyte-macrophage
      colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4) expressed CD11c and
      major histocompatibility complex (MHC) class II, but did not express CD14. High
      levels of endocytosis and an ability to stimulate antigen-specific proliferation
      of CD4 T lymphocytes were also demonstrated.

PMID- 12423317
TI  - A conceptual model for the corporeal body.

PMID- 12423314
TI  - Necessity of the stalk region for immunoglobulin E interaction with CD23.
AB  - Previously, a soluble mouse CD23 chimera, composed of an N-terminal trimeric
      isoleucine zipper motif (lz) followed by the entire extracellular region (amino
      acids 48-331) of CD23 (lz-CD2348-331), was prepared and exhibited strong binding
      to rodent immunoglobulin E (IgE). In the current study, we report the
      construction of a similar human chimeric protein (lz-huCD2345-321), as well as a
      series of murine chimeric lz-CD23 mutants with incremental portions of stalk
      deleted, to further investigate the role of the stalk region in mediating the
      CD23-IgE interaction. All chimeric proteins were designed such that the predicted
      heptad structure of the stalk was retained. IgE binding, as determined by the
      capacity to inhibit 125I-IgE from binding to FcepsilonRI-bearing RBL-2H3 cells,
      and by surface plasmon-resonance analysis using an IgE-coated sensor chip, was
      unchanged from the original lz chimera and the binding parameters were similar to
      those of cell-surface CD23. The minimal murine chimera that retained IgE-binding
      activity was lz-CD23139-331, which still contains 35 amino acids of the stalk
      region. When the lz motif was linked to CD23 amino acid 157 (or higher),
      significant IgE-binding capacity was lost. With human lz-CD23, as with mouse,
      deletion of the stalk greatly reduced IgE-binding ability. In summary, the data
      support the concept that at least a portion of the stalk region of CD23 plays a
      crucial role in maintaining high-affinity/avidity interaction with IgE. The lz
      CD23 constructs represent a possible alternative for both blocking the
      IgE/FcepsilonRI interaction and inhibiting IgE production by B lymphocytes.

PMID- 12423318
TI  - COX-2-independent antiproliferative action of acetylsalicylic acid in human colon
      cancer cells.

PMID- 12423319
TI  - High oxidized LDL and elevated plasma homocysteine contribute to the early
      reduction of myocardial flow reserve in healthy adults.
AB  - BACKGROUND: Impairment of coronary blood flow reserve has been shown to be an
      early manifestation of atherosclerosis and coronary artery disease (CAD). We
      studied more closely the contribution of various risk factors on early
      deterioration of coronary function. MATERIALS AND METHODS: Fifty-one young,
      apparently healthy adults, with normal or mildly elevated serum cholesterol
      levels but without other major risk factors for CAD, such as diabetes or
      hypertension, underwent positron emission tomography (PET) studies. Coronary flow
      reserve (CFR) was measured using O15-water. In addition to the classical risk
      factors, the role of several new risk indicators, such as low-density lipoprotein
      (LDL) oxidation, infection (Chlamydia pneumoniae antibodies), and inflammation
      parameters (adhesion molecules, ICAM, VCAM, selectin, and C-reactive protein),
      homocysteine and body iron stores were investigated. RESULTS: Elevated lipid and
      lipoprotein levels were not associated with reduced coronary reactivity. However,
      high autoantibody titers against oxidized LDL (oxLDL) were associated with 21%
      lower CFR than low oxLDL (P < 0.05). Furthermore, high homocysteine levels
      predicted low CFR (P < 0.05). The other measured parameters, Chlamydia pneumoniae
      antibody levels, C-reactive protein and adhesion molecule concentrations did not
      associate with myocardial blood flow. In a stepwise regression model, oxLDL (P =
      0.03), homocysteine (P = 0.04) and triglycerides (P = 0.018) were significant
      predictors of CFR. CONCLUSIONS: The present study suggests an important role for
      oxidized LDL and plasma homocysteine on early impairment of coronary reactivity
      in young adults.

PMID- 12423320
TI  - Inflammatory imbalance between IL-10 and TNFalpha in unstable angina potential
      plaque stabilizing effects of IL-10.
AB  - BACKGROUND: The pathogenesis of atherosclerosis and acute coronary syndromes
      involves inflammation and immunological mechanisms. We hypothesized that patients
      with unstable angina may have an imbalance between inflammatory and anti
      inflammatory cytokines. DESIGN: Plasma levels of tumour necrosis factor
      (TNF)alpha and interleukin (IL)-10 were analyzed in 44 patients with stable
      angina, 29 patients with unstable angina and 20 controls. mRNA levels of these
      cytokines were analyzed in peripheral blood mononuclear cells (PBMC). We also
      studied the in vitro effects of IL-10 in PBMC from unstable angina patients.
      RESULTS: Our main findings were: (1) the angina patients and particularly those
      with unstable disease had significantly raised TNFalpha in comparison with the
      controls, both at the protein and mRNA level; (2) in contrast, the levels of IL
      10 were not different in the angina patients in comparison with the healthy
      controls, resulting in a markedly enhanced TNFalpha:IL-10 ratio, particularly in
      the unstable angina patients; (3) while exogenously added IL-10 markedly
      inhibited the release of TNFalpha, IL-8 and tissue factor as well as impairing
      the gelatinolytic activity and mRNA production of matrix metalloproteinase-9, it
      enhanced the tissue inhibitor of this metalloproteinase (i.e. TIMP-1) in PBMC
      from the unstable angina patients. CONCLUSION: Patients with unstable angina
      appear to have an imbalance between TNFalpha and IL-10, possibly favouring
      inflammatory net effects. IL-10 may have beneficial effects on mechanisms that
      are important in plaque rupture and thrombus formation.

PMID- 12423321
TI  - Soluble leptin receptors and serum leptin in end-stage renal disease:
      relationship with inflammation and body composition.
AB  - BACKGROUND: Elevated serum leptin (S-leptin) levels have been reported in
      patients with end-stage renal disease (ESRD). Apart from the decreased glomerular
      filtration rate (GFR), body composition and inflammation may affect leptin levels
      in ESRD. Leptin circulates both free of and bound to soluble leptin receptors
      (sOB-R), which are the main determinants of leptin activity and have not been
      described in ESRD until now. DESIGN: To analyze the association between S-leptin,
      sOB-R, and inflammation and body composition, we studied 149 (62% males) normal
      weight (BMI 24.7 +/- 0.4 kg m(-2)) ESRD patients (51 +/- 1 years old) shortly
      before the start of dialysis (GFR 7.0 +/- 0.2 mL min(-1)). sOB-R and plasma
      interleukin-6 (IL-6; n= 113) levels were evaluated using ELISA, S-leptin using
      RIA, and body composition was assessed by X-ray absorptiometry (n = 139). Forty
      one healthy subjects age (51 +/- 1 years), BMI (23.6 +/- 0.5 kg m(-2)) and gender
      matched (59% males) were used as controls. RESULTS: Median S-leptin was higher in
      the ESRD patients (10.0 ng mL(-1)) compared with the controls (3.9 ng mL(-1)) (P
      < 0.001). The median sOB-R did not differ significantly between the ESRD patients
      (44 U mL-1) and the controls (37 U mL-1). Thus, the sOB-R/S-leptin ratio was
      lower in the ESRD patients (9.5 +/- 1.2 vs. 12.3 +/- 1.8; P < 0.01) than the
      controls. A negative correlation was observed between S-leptin and sOB-R (Rho = 
      0.42; P < 0.0001) in the ESRD patients, a positive correlation was observed
      between lean body mass and the sOB-R/S-leptin ratio (Rho = 0.33, P = 0.0001)
      whereas fat mass was negatively correlated to both sOB-R (Rho = -0.26, P =
      0.002), and the sOB-R/S-leptin ratio (Rho = -0.62, P < 0.0001). Positive
      correlations were observed between IL-6 and S-leptin (Rho = 0.19; P < 0.05) and
      weak but significant body fat mass (Rho = 0.20; P < 0.05), respectively.
      CONCLUSIONS: This study demonstrates that despite markedly elevated S-leptin
      levels in the ESRD patients, sOB-R did not differ from the controls. In view of
      the anorexigenic and pro-atherogenic effects of leptin, further elucidation of
      the consequences of free bioactive leptin in the development of complications
      such as malnutrition and cardiovascular disease in ESRD patients is required.

PMID- 12423322
TI  - Higher antioxidant defences in plasma and low density lipoproteins from rugby
      players.
AB  - BACKGROUND: Even if physical activity constitutes a well-known antiatherogenic
      factor, the precise mechanisms underlying this protective effect are not
      completely clear. MATERIALS AND METHODS: Lipid and antioxidant profiles were
      evaluated in 15 well-trained rugby players and 15 sedentary controls. Lipoprotein
      fractions were separated by sequential ultracentrifugation and alpha-tocopherol
      content was determined in each fraction by high-performance liquid
      chromatography. Susceptibility to in vitro oxidation was also measured in
      intermediate and low density lipoproteins isolated from both groups of subjects
      as the production of conjugated dienes. RESULTS: Although the sportsmen were not
      receiving any special diet or vitamin supplementation they showed a slightly
      improved lipoprotein profile, mainly represented by increased high density
      lipoprotein-cholesterol levels (P < 0.05), and an enhanced antioxidant status.
      The latter was evidenced by an increment in total radical antioxidant potential
      (P < 0.001), higher ascorbic acid (P < 0.005) and alpha-tocopherol (P < 0.05)
      plasma concentrations, and elevated activities of superoxide dismutase (P <
      0.001) and arylesterase (P < 0.01). Moreover, only the fraction of intermediate
      and low density lipoproteins from rugby players presented higher alpha-tocopherol
      content in comparison with sedentary controls (484 +/- 67 vs. 377 +/- 123 microg
      dL(-1), respectively; P < 0.01). Nevertheless, the susceptibility to in vitro
      oxidation of this lipoprotein fraction was not different between both groups.
      CONCLUSIONS: Given that intermediate density and low density lipoproteins
      represent the most atherogenic fraction, this finding, in combination with the
      improved lipid and antioxidant status, would add to the link between regular
      physical activity and protection against cardiovascular disease.

PMID- 12423323
TI  - Prediction of body weight changes caused by changes in energy balance.
AB  - BACKGROUND: Experimental difficulties have so far restricted knowledge of the
      effects of energy imbalance on change in body weight. Direct measurement requires
      that the subjects are kept under dietary supervision for several months while the
      activity is being measured. MATERIALS AND METHODS: The effects of energy balance
      can be calculated using a combination of fundamental principles and directly
      measurable data: the law of energy conservation (increase in combustible energy
      equals the difference between energy intake and energy expenditure); data on
      energy expenditure of fat and lean tissues; and data on the composition of
      added/removed tissue during weight change. RESULTS AND CONCLUSIONS: We obtained
      an explicit differential equation describing the development of body weight over
      time, with energy intake and energy expenditure as control variables. Using this
      model it is possible to isolate and analyse the measured effects of parameters
      not included in the model, such as age or 'adaptivity' of the body.

PMID- 12423324
TI  - Therapy of circadian rhythm disorders in chronic fatigue syndrome: no symptomatic
      improvement with melatonin or phototherapy.
AB  - BACKGROUND: Patients with chronic fatigue syndrome (CFS) show evidence of
      circadian rhythm disturbances. We aimed to determine whether CFS symptoms were
      alleviated by melatonin and bright-light phototherapy, which have been shown to
      improve circadian rhythm disorders and fatigue in jet-lag and shift workers.
      DESIGN: Thirty patients with unexplained fatigue for > 6 months were initially
      assessed using placebo and then received melatonin (5 mg in the evening) and
      phototherapy (2500 Lux for 1 h in the morning), each for 12 weeks in random order
      separated by a washout period. Principal symptoms of CFS were measured by visual
      analogue scales, the Shortform (SF-36) Health Survey, Mental Fatigue Inventory
      and Hospital Anxiety and Depression Scale. We also determined the circadian
      rhythm of body temperature, timing of the onset of melatonin secretion, and the
      relationship between these. RESULTS: Neither intervention showed any significant
      effect on any of the principal symptoms or on general measures of physical or
      mental health. Compared with placebo, neither body temperature rhythm nor onset
      of melatonin secretion was significantly altered by either treatment, except for
      a slight advance of temperature phase (0.8 h; P = 0.04) with phototherapy.
      CONCLUSION: Melatonin and bright-light phototherapy appear ineffective in CFS.
      Both treatments are being prescribed for CFS sufferers by medical and alternative
      practitioners. Their unregulated use should be prohibited unless, or until, clear
      benefits are convincingly demonstrated.

PMID- 12423325
TI  - The effects of acetylsalicylic acid on proliferation, apoptosis, and invasion of
      cyclooxygenase-2 negative colon cancer cells.
AB  - BACKGROUND: Acetylsalicylic acid (ASA, aspirin), the most common nonsteroidal
      anti-inflammatory drug (NSAID), has been shown to have a protective effect
      against the incidence and mortality of colorectal cancer. However, the mechanism
      of its anticancer function remains unclear. The aim of this study was to
      determine the effects of acetylsalicylic acid on proliferation, apoptosis, and
      invasion in human cyclooxygenase-2 (COX-2) negative colorectal cancer cell lines.
      MATERIALS AND METHODS: After treatment with various concentrations of ASA, cell
      proliferation was measured in the human colon cancer cell line SW480. Apoptotic
      cells were identified by transmission electron microscopy, acridine orange
      staining, and flow cytometry. The invasive potential of SW480 cells was detected
      using an in vitro invasion assay. The production of carcinoembryonic antigen was
      measured by microparticle enzyme immunoassay. Expression of Bcl2, Bax, CD44v6,
      and nm23 were evaluated by immunocytochemistry. RESULTS: ASA significantly
      inhibited the proliferation of SW480 cells and stimulated apoptosis. Production
      of carcinoembryonic antigen and the invasive potential of SW480 cells were also
      inhibited by ASA. After treatment with ASA, down-regulation of Bcl2 and CD44v6
      expression and up-regulation of nm23 expression were observed in SW480 cells. No
      obvious effect of ASA was found on Bax expression. CONCLUSION: Our findings
      reveal that ASA inhibits the proliferation and promotes apoptosis in the human
      colon cancer cell line SW480. Down-regulation of Bcl2 expression might represent
      a potential mechanism by which ASA induces apoptosis in this COX-2 negative colon
      cancer cell line. Our results also suggest that ASA decreases the invasive
      potential of these colon cancer cells. Decreased CEA content and CD44v6
      expression and elevated nm23 expression may contribute to the effect of ASA on
      invasive potential of SW480 colon cancer cells.

PMID- 12423326
TI  - Factor XIII a-positive dermal dendrocytes and shear wave propagation in human
      skin.
AB  - BACKGROUND: The in vivo interdependence between the phenotypic characteristics of
      dermal cells and the strain imposed on the tissue has not been studied thoroughly
      in humans. In particular the mechanical force modulation of Factor XIII a
      expression in dermal dendrocytes (DD) remains unknown. MATERIALS AND METHODS: The
      present study compares the numerical density of Factor XIII a-positive DD and the
      in vivo shear wave velocity in the skin. The investigation was performed in 20
      men of normal weight and 20 obese men before and after entering a slimming
      process. RESULTS: Excess cutaneous fat places the skin under increased intrinsic
      tension. The resonance running time measurement (RRTM) and the DD density were
      significantly reduced in overweight individuals. After a short-term but intense
      slimming process, the same individuals showed a trend to normalization of these
      two parameters without, however, reaching significance. Pooling all data yielded
      a significant logarithmic correlation between RRTM values and densities in Factor
      XIII a-positive DD. CONCLUSION: Factor XIII a expression in human DD may be
      partially regulated by the intrinsic resting tensions in the skin.

PMID- 12423327
TI  - Effect of nicotine replacement and quitting smoking on circulating adhesion
      molecule profiles (sICAM-1, sCD44v5, sCD44v6).
AB  - BACKGROUND: Soluble ICAM-1 (sICAM-1; sCD54), sCD44v5 and sCD44v6 are circulating
      adhesion molecules, with immunomodulatory potential, that have been frequently
      attributed diagnostic, prognostic and aetiological significance in a number of
      inflammatory and malignant diseases. We have previously shown that systemic
      concentrations of these molecules are increased significantly in tobacco smokers,
      but reduce to within normal levels at 12 months following successful quitting.
      MATERIALS AND METHODS: We have been able to extend these observations by
      measuring levels before and 4, 8, 22 and 52 weeks after smoking cessation in
      subjects receiving high-dose nicotine replacement therapy (25 mg of nicotine; n =
      34) or placebo patches (n = 34) for 26 weeks. Smoking cessation was confirmed by
      regular measurement of expired-air CO levels and by plasma cotinine analysis.
      RESULTS: Plasma sICAM-1, sCD44v5 and sCD44v6 concentrations all declined rapidly
      within 4 weeks of smoking cessation (P < 0.001 for all declines). Additionally,
      no differences were observed between those using nicotine replacement and those
      who were not for sICAM-1, sCD44v5, or sCD44v6. CONCLUSIONS: The recovery in
      smoking-associated adhesion molecule profiles represents an almost immediate
      beneficial effect of smoking cessation. Nicotine replacement therapy is an
      effective aid to quitting and does not affect these recoveries. The elevated
      levels of these important risk factors in smokers (sICAM-1, sCD44v5 and sCD44v6)
      are linked to noxious element(s) in tobacco smoke other than nicotine or nicotine
      metabolites.

PMID- 12423328
TI  - Nitric oxide attenuates platelet-activating factor induced nasal airway plasma
      extravasation in healthy subjects.
AB  - BACKGROUND: Paranasal sinuses and the nose are important sources of nitric oxide
      (NO) in humans but the relevance of NO production to the control of nasal airway
      plasma exudation and its response to inflammatory mediators such as platelet
      activating factor (PAF) in healthy subjects is not well known. DESIGN: In this
      study we aimed to evaluate the effect of the nitric oxide synthase (NOS)
      inhibitor NG L-arginine methyl ester (L-NAME) on nasal airway plasma
      extravasation at baseline and after an acute challenge with PAF that induces most
      symptoms of rhinitis. Eleven healthy subjects were enrolled in the study. Plasma
      extravasation in the nasal airway was assessed by measuring the albumin content
      of nasal lavage. RESULTS: PAF challenge caused a significant increase in
      concentrations of albumin in the nasal lavage fluid (from 0.59 +/- 0.13 mg dL(-1)
      to 2.46 +/- 0.45 mg dL(-1)) after placebo. Pretreatment with L-NAME significantly
      prevented the increase of albumin in the nasal lavage fluid induced by PAF as
      compared to placebo (from 0.53 +/- 0.11 mg dL(-1) to 1.70 +/- 0.28 mg dL(-1); P <
      0.005). CONCLUSION: Topical administration of a NO inhibitor is able to attenuate
      the nasal airway plasma extravasation induced by PAF, suggesting that NO release
      in vivo is involved in the nasal response to PAF.

PMID- 12423329
TI  - Association between increased levels of IL-2 and IL-15 and outcome in patients
      with early acute respiratory distress syndrome.
AB  - BACKGROUND: Acute respiratory distress syndrome remains a serious, often fatal,
      condition, despite progress in modern critical care treatment. Cytokines play an
      important role in the pathogenesis of the syndrome, although their role in the
      evolution and outcome has not been clearly elucidated. We explored whether the
      measurement of serum and bronchoalveolar lavage IL-2 and IL-15 at the time of
      hospital admission can predict the outcome of this syndrome. METHODS: Serum and
      bronchoalveolar lavage levels of IL-2 and IL-15 were measured in eight patients
      with ARDS (group A) and 26 patients on high risk for ARDS development who never
      developed ARDS (group B) from samples obtained at the time of admission. RESULTS:
      Serum IL-2 (P > 0.05) and IL-15 (P < 0.05) levels were higher in group A than in
      group B. Serum levels of both cytokines were higher in patients who did not
      survive in both of the groups A and B compared to those who survived (P < 0.05,
      and P < 0.0001, respectively). The only significant change in BALF was the higher
      level of IL-15 in surviving group A patients (P < 0.05) when compared with the
      non survivors of the same group. For a serum cut-off level of 173 pg mL(-1) for
      IL-2 and 250 pg mL(-1) for IL-15, they exhibited a very high positive predictive
      value (PPV), negative predictive value (NPV), sensitivity and specificity for
      survival (100% in all). A positive correlation was found between serum levels of
      both cytokines and APACHE II score (IL-2, r = 0.61, and IL-15, r = 0.62,
      respectively, and P < 0.0001 for both). CONCLUSION: Determination of serum IL-2
      and IL-15 levels may be a valuable and simple aid to improve identification of
      patients with ARDS or at risk for ARDS who are at high risk of subsequent
      mortality.

PMID- 12423331
TI  - Control of the translational machinery in mammalian cells.

PMID- 12423332
TI  - Regulation of mammalian translation factors by nutrients.
AB  - Protein synthesis requires both amino acids, as precursors, and a substantial
      amount of metabolic energy. It is well established that starvation or lack of
      nutrients impairs protein synthesis in mammalian cells and tissues. Branched
      chain amino acids are particularly effective in promoting protein synthesis.
      Recent work has revealed important new information about the mechanisms involved
      in these effects. A number of components of the translational machinery are
      regulated through signalling events that require the mammalian target of
      rapamycin, mTOR. These include translational repressor proteins (eukaryotic
      initiation factor 4E-binding proteins, 4E-BPs) and protein kinases that act upon
      the small ribosomal subunit (S6 kinases). Amino acids, especially leucine,
      positively regulate mTOR signalling thereby relieving inhibition of translation
      by 4E-BPs and activating the S6 kinases, which can also regulate translation
      elongation. However, the molecular mechanisms by which amino acids modulate mTOR
      signalling remain unclear. Protein synthesis requires a high proportion of the
      cell's metabolic energy, and recent work has revealed that metabolic energy, or
      fuels such as glucose, also regulate targets of the mTOR pathway. Amino acids and
      glucose modulate a further important regulatory step in translation initiation,
      the activity of the guanine nucleotide-exchange factor eIF2B. eIF2B controls the
      recruitment of the initiator methionyl-tRNA to the ribosome and is activated by
      insulin. However, in the absence of glucose or amino acids, insulin no longer
      activates eIF2B. Since control of eIF2B is independent of mTOR, these data
      indicate the operation of additional, and so far unknown, regulatory mechanisms
      that control eIF2B activity.

PMID- 12423333
TI  - Does phosphorylation of the cap-binding protein eIF4E play a role in translation
      initiation?
AB  - Eukaryotic initiation factor 4E (eIF4E) plays an important role in mRNA
      translation by binding the 5'-cap structure of the mRNA and facilitating the
      recruitment to the mRNA of other translation factors and the 40S ribosomal
      subunit. eIF4E can interact either with the scaffold protein eIF4G or with
      repressor proteins termed eIF4E-binding proteins (4E-BPs). High levels of
      expression can disrupt cellular growth control and are associated with human
      cancers. A fraction of the cellular eIF4E is found in the nucleus where it may
      play a role in the transport of certain mRNAs to the cytoplasm. eIF4E undergoes
      regulated phosphorylation (at Ser209) by members of the Mnk group of kinases,
      which are activated by multiple MAP kinases (hence Mnk = MAP-kinase signal
      integrating kinase). The functional significance of its phosphorylation has been
      the subject of considerable interest. Recent genetic studies in Drosophila point
      to a key role for phosphorylation of eIF4E in growth and viability. Initial
      structural data suggested that phosphorylation of Ser209 might allow formation of
      a salt bridge with a basic residue (Lys159) that would clamp eIF4E onto the mRNA
      and increase its affinity for ligand. However, more recent structural data place
      Ser209 too far away from Lys159 to form such an interaction, and biophysical
      studies indicate that phosphorylation actually decreases the affinity of eIF4E
      for cap or capped RNA. The implications of these studies are discussed in the
      light of other, in vitro and in vivo, investigations designed to address the role
      of eIF4E phosphorylation in mRNA translation or its control.

PMID- 12423334
TI  - Regulation of peptide-chain elongation in mammalian cells.
AB  - The elongation phase of mRNA translation is the stage at which the polypeptide is
      assembled and requires a substantial amount of metabolic energy. Translation
      elongation in mammals requires a set of nonribosomal proteins called eukaryotic
      elongation actors or eEFs. Several of these proteins are subject to
      phosphorylation in mammalian cells, including the factors eEF1A and eEF1B that
      are involved in recruitment of amino acyl-tRNAs to the ribosome. eEF2, which
      mediates ribosomal translocation, is also phosphorylated and this inhibits its
      activity. The kinase acting on eEF2 is an unusual and specific one, whose
      activity is dependent on calcium ions and calmodulin. Recent work has shown that
      the activity of eEF2 kinase is regulated by MAP kinase signalling and by the
      nutrient-sensitive mTOR signalling pathway, which serve to activate eEF2 in
      response to mitogenic or hormonal stimuli. Conversely, eEF2 is inactivated by
      phosphorylation in response to stimuli that increase energy demand or reduce its
      supply. This likely serves to slow down protein synthesis and thus conserve
      energy under such circumstances.

PMID- 12423335
TI  - A single charged surface residue modifies the activity of ikitoxin, a beta-type
      Na+ channel toxin from Parabuthus transvaalicus.
AB  - We previously purified and characterized a peptide toxin, birtoxin, from the
      South African scorpion Parabuthus transvaalicus. Birtoxin is a 58-residue, long
      chain neurotoxin that has a unique three disulfide-bridged structure. Here we
      report the isolation and characterization of ikitoxin, a peptide toxin with a
      single residue difference, and a markedly reduced biological activity, from
      birtoxin. Bioassays on mice showed that high doses of ikitoxin induce unprovoked
      jumps, whereas birtoxin induces jumps at a 1000-fold lower concentration. Both
      toxins are active against mice when administered intracerebroventricularly. Mass
      determination indicated an apparent mass of 6615 Da for ikitoxin vs. 6543 Da for
      birtoxin. Amino acid sequence determination revealed that the amino-acid sequence
      of ikitoxin differs from birtoxin by a single residue change from glycine to
      glutamic acid at position 23, consistent with the apparent mass difference of 72
      Da. This single-residue difference renders ikitoxin much less effective in
      producing the same behavioral effect as low concentrations of birtoxin.
      Electrophysiological measurements showed that birtoxin and ikitoxin can be
      classified as beta group toxins for voltage-gated Na+ channels of central
      neurons. It is our conclusion that the N-terminal loop preceding the alpha-helix
      in scorpion toxins is one of the determinative domains in the interaction of
      toxins with the target ion channel.

PMID- 12423336
TI  - Barley alpha-amylase Met53 situated at the high-affinity subsite -2 belongs to a
      substrate binding motif in the beta-->alpha loop 2 of the catalytic (beta/alpha)8
      barrel and is critical for activity and substrate specificity.
AB  - Met53 in barley alpha-amylase 1 (AMY1) is situated at the high-affinity subsite 
      2. While Met53 is unique to plant alpha-amylases, the adjacent Tyr52 stacks onto
      substrate at subsite -1 and is essentially invariant in glycoside hydrolase
      family 13. These residues belong to a short sequence motif in beta-->alpha loop 2
      of the catalytic (beta/alpha)8-barrel and site-directed mutagenesis was used to
      introduce a representative variety of structural changes,
      Met53Glu/Ala/Ser/Gly/Asp/Tyr/Trp, to investigate the role of Met53. Compared to
      wild-type, Met53Glu/Asp AMY1 displayed 117/90% activity towards insoluble Blue
      Starch, and Met53Ala/Ser/Gly 76/58/38%, but Met53Tyr/Trp only 0.9/0.1%, even
      though both Asp and Trp occur frequently at this position in family 13. Towards
      amylose DP17 (degree of polymerization = 17) and 2-chloro-4-nitrophenyl beta-d
      maltoheptaoside the activity (kcat/Km) of all mutants was reduced to 5.5-0.01 and
      1.7-0.02% of wild-type, respectively. Km increased up to 20-fold for these
      soluble substrates and the attack on glucosidic linkages in 4-nitrophenyl alpha-d
      maltohexaoside (PNPG6) and PNPG5 was determined by action pattern analysis to
      shift to be closer to the nonreducing end. This indicated that side chain
      replacement at subsite -2 weakened substrate glycon moiety contacts. Thus whereas
      all mutants produced mainly PNPG2 from PNPG6 and similar amounts of PNPG2 and
      PNPG3 accounting for 85% of the products from PNPG5, wild-type released 4
      nitrophenol from PNPG6 and PNPG and PNPG2 in equal amounts from PNPG5. Met53Trp
      affected the action pattern on PNPG7, which was highly unusual for AMY1 subsite
      mutants. It was also the sole mutant to catalyze substantial transglycosylation -
      promoted probably by slow substrate hydrolysis - to produce up to maltoundecaose
      from PNPG6.

PMID- 12423338
TI  - Prediction of temporal gene expression. Metabolic opimization by re-distribution
      of enzyme activities.
AB  - A computational approach is used to analyse temporal gene expression in the
      context of metabolic regulation. It is based on the assumption that cells
      developed optimal adaptation strategies to changing environmental conditions.
      Time-dependent enzyme profiles are calculated which optimize the function of a
      metabolic pathway under the constraint of limited total enzyme amount. For linear
      model pathways it is shown that wave-like enzyme profiles are optimal for a rapid
      substrate turnover. For the central metabolism of yeast cells enzyme profiles are
      calculated which ensure long-term homeostasis of key metabolites under conditions
      of a diauxic shift. These enzyme profiles are in close correlation with observed
      gene expression data. Our results demonstrate that optimality principles help to
      rationalize observed gene expression profiles.

PMID- 12423337
TI  - Galactosyl-mimodye ligands for Pseudomonas fluorescens beta-galactose
      dehydrogenase.
AB  - Protein molecular modelling and ligand docking were employed for the design of
      anthraquinone galactosyl-biomimetic dye ligands (galactosyl-mimodyes) for the
      target enzyme galactose dehydrogenase (GaDH). Using appropriate modelling
      methodology, a GaDH model was build based on a glucose-fructose oxidoreductase
      (GFO) protein template. Subsequent computational analysis predicted chimaeric
      mimodye-ligands comprising a NAD-pseudomimetic moiety (anthraquinone
      diaminobenzosulfonic acid) and a galactosyl-mimetic moiety (2-amino-2
      deoxygalactose or shikimic acid) bearing an aliphatic 'linker' molecule. In
      addition, the designed mimodye ligands had an appropriate in length and chemical
      nature 'spacer' molecule via which they can be attached onto a chromatographic
      support without steric clashes upon interaction with GaDH. Following their
      synthesis, purification and analysis, the ligands were immobilized to agarose.
      The respective affinity adsorbents, compared to other conventional adsorbents,
      were shown to be superior affinity chromatography materials for the target
      enzyme, Pseudomonas fluorescensbeta-galactose dehydrogenase. In addition, these
      mimodye affinity adsorbents displayed good selectivity, binding low amounts of
      enzymes other than GaDH. Further immobilized dye-ligands, comprising different
      linker and/or spacer molecules, or not having a biomimetic moiety, had inferior
      chromatographic behavior. Therefore, these new mimodyes suggested by
      computational analysis, are candidates for application in affinity labeling and
      structural studies as well as for purification of galactose dehydrogenase.

PMID- 12423339
TI  - Domain V of m-calpain shows the potential to form an oblique-orientated alpha
      helix, which may modulate the enzyme's activity via interactions with anionic
      lipid.
AB  - The activity of m-calpain, a heterodimeric, Ca2+-dependent cysteine protease
      appears to be modulated by membrane interactions involving oblique-orientated
      alpha-helix formation by a segment, GTAMRILGGVI, in the protein's smaller
      subunit. Here, graphical and hydrophobic moment-based analyses predicted that
      this segment may form an alpha-helix with strong structural resemblance to the
      influenza virus peptide, HA2, a known oblique-orientated alpha-helix former.
      Fourier transform infrared spectroscopy showed that a peptide homologue of the
      GTAMRILGGVI segment, VP1, adopted low levels of alpha-helical structure (
      approximately 20%) in the presence of zwitterionic lipid and induced a minor
      decrease (3 degrees C) in the gel to liquid-crystalline phase transition
      temperature, TC, of the hydrocarbon chains of zwitterionic membranes, suggesting
      interaction with the lipid headgroup region. In contrast, VP1 adopted high levels
      of alpha-helical structure (65%) in the presence of anionic lipid, induced a
      large increase (10 degrees C) in the TC of anionic membranes, and showed high
      levels of anionic lipid monolayer penetration (DeltaSP = 5.5 mN.m-1), suggesting
      deep levels of membrane penetration. VP1 showed strong haemolytic ability (LD50 =
      1.45 mm), but in the presence of ionic agents, this ability, and that of VP1 to
      penetrate anionic lipid monolayers, was greatly reduced. In combination, our
      results suggest that m-calpain domain V may penetrate membranes via the adoption
      of an oblique-orientated alpha-helix and electrostatic interactions. We speculate
      that these interactions may involve snorkelling by an arginine residue located in
      the polar face of this alpha-helix.

PMID- 12423340
TI  - Identification and characterization of thioredoxin and thioredoxin reductase from
      Aeropyrum pernix K1.
AB  - We have identified and characterized a thermostable thioredoxin system in the
      aerobic hyperthermophilic archaeon Aeropyrum pernix K1. The gene (Accession no.
      APE0641) of A. pernix encoding a 37 kDa protein contains a redox active site
      motif (CPHC) but its N-terminal extension region (about 200 residues) shows no
      homology within the genome database. A second gene (Accession no. APE1061) has
      high homology to thioredoxin reductase and encodes a 37 kDa protein with the
      active site motif (CSVC), and binding sites for FAD and NADPH. We cloned the two
      genes and expressed both proteins in E. coli. It was observed that the
      recombinant proteins could act as an NADPH-dependent protein disulfide reductase
      system in the insulin reduction. In addition, the APE0641 protein and thioredoxin
      reductase from E. coli could also catalyze the disulfide reduction. These
      indicated that APE1061 and APE0641 express thioredoxin (ApTrx) and thioredoxin
      reductase (ApTR) of A. pernix, respectively. ApTR is expressed as an active
      homodimeric flavoprotein in the E. coli system. The optimum temperature was above
      90 degrees C, and the half-life of heat inactivation was about 4 min at 110
      degrees C. The heat stability of ApTR was enhanced in the presence of excess FAD.
      ApTR could reduce both thioredoxins from A. pernix and E. coli and showed a
      similar molar specific activity for both proteins. The standard state redox
      potential of ApTrx was about -262 mV, which was slightly higher than that of Trx
      from E. coli (-270 mV). These results indicate that a lower redox potential of
      thioredoxin is not necessary for keeping catalytic disulfide bonds reduced and
      thereby coping with oxidative stress in an aerobic hyperthermophilic archaea.
      Furthermore, the thioredoxin system of aerobic hyperthermophilic archaea is
      biochemically close to that of the bacteria.

PMID- 12423341
TI  - The import of ferredoxin-NADP+ reductase precursor into chloroplasts is modulated
      by the region between the transit peptide and the mature core of the protein.
AB  - Protein transport across organelles' membranes requires that precursor proteins
      adopt an unfolded structure in order to be translocated by the import machinery.
      Ferredoxin-NADP+ reductase precursor, as well as many others, acquires a tightly
      folded structure that needs to be unfolded before or during its import. Several
      steps of chloroplast protein import are not fully understood. In particular, the
      role of different regions of the precursor protein has not been completely
      elucidated. In this work, we have studied the import into chloroplasts of
      precursor proteins with inclusions of amino acid spacers between the transit
      peptide and the mature protein, and with deletions in the N-terminal region of
      the mature enzyme. We measured the import rate constants for these precursors and
      the results indicate that the distance between the transit peptide and the core
      of the mature protein determines the import kinetics. The longer precursors were
      imported into the organelle faster than the wild type form. Precursors with
      deletions in the N-terminal region of the mature protein also showed increased
      import rates compared to the wild type. Homology studies amongst all family
      members reveal that only chloroplastic proteins possess this region. We suggest
      that even if the first amino acids of the mature protein do not contribute to its
      overall structural stability, they condition the kinetic parameters of the import
      reaction. Besides, the distance between the transit peptide and the mature
      protein core may be modulating the import rate at which the chloroplast
      incorporates this protein from the cytosol.

PMID- 12423342
TI  - Bax-induced cell death in yeast depends on mitochondrial lipid oxidation.
AB  - The oxidant function of pro-apoptotic protein Bax was investigated through
      heterologous expression in yeast. Direct measurements of fatty acid content show
      that Bax-expression induces oxidation of mitochondrial lipids. This effect is
      prevented by the coexpression of Bcl-xL. The oxidation actually could be followed
      on isolated mitochondria as respiration-induced peroxidation of polyunsaturated
      cis-parinaric acid and on whole cells as the increase in the amount of
      thiobarbituric acid-reactive products. Treatments that increase the unsaturation
      ratio of lipids, making them more sensitive to oxidation, increase kinetics of
      Bax-induced death. Conversely, inhibitors of lipid oxidation and treatments that
      decrease the unsaturation ratio of fatty acids decrease kinetics of Bax-induced
      death. Taken together, these results show that Bax-induced mitochondrial lipid
      oxidation is relevant to Bax-induced cell death. Conversely, lipid oxidation is
      poorly related to the massive Bax-induced superoxide and hydrogen peroxide
      accumulation, which occurs at the same time, as chemical or enzymatic scavenging
      of ROS does not prevent lipid oxidation nor has any effects on kinetics of Bax
      induced cell death. Whatever the origin of mitochondrial lipid oxidation, these
      data show that it represents a major step in the cascade of events leading to Bax
      induced cell death. These results are discussed in the light of the role of lipid
      oxidation both in mammalian apoptosis and in other forms of cell death in other
      organisms.

PMID- 12423343
TI  - Oxidative deamination of lysine residue in plasma protein of diabetic rats. Novel
      mechanism via the Maillard reaction.
AB  - The levels of alpha-aminoadipic-delta-semialdehyde residue, the oxidative
      deamination product of lysine residue, in plasma protein from streptozotocin
      induced diabetic rats were evaluated. alpha-Aminoadipic-delta-semialdehyde was
      converted to a bisphenol derivative by acid hydrolysis in the presence of phenol,
      and determined by high performance liquid chromatography. Analysis of plasma
      proteins revealed three times higher levels of alpha-aminoadipic-delta
      semialdehyde in diabetic subjects compared with normal controls. Furthermore, we
      explored the oxidative deamination via the Maillard reaction and demonstrated
      that the lysine residue of bovine serum albumin is oxidatively deaminated during
      the incubation with various carbohydrates in the presence of Cu2+ at a
      physiological pH and temperature. This experiment showed that 3-deoxyglucosone
      and methylglyoxal are the most efficient oxidants of the lysine residue. When the
      reaction was initiated from glucose, a significant amount of alpha-aminoadipic
      delta-semialdehyde was also formed in the presence of Cu2+. The reaction was
      significantly inhibited by deoxygenation, catalase, and a hydroxyl radical
      scavenger. The mechanism we propose for the oxidative deamination is the Strecker
      type reaction and the reactive oxygen species-mediated oxidation. Based on these
      findings, we propose a novel mechanism for the oxidative modification of proteins
      in diabetes, namely the oxidative deamination of the lysine residue via the
      Maillard reaction.

PMID- 12423344
TI  - Hemocyanin from the keyhole limpet Megathura crenulata (KLH) carries a novel type
      of N-glycans with Gal(beta1-6)Man-motifs.
AB  - Keyhole limpet (Megathura crenulata) hemocyanin (KLH), an extracellular
      respiratory protein, is widely used as hapten carrier and immune stimulant.
      Although it is generally accepted that the sugar constituents of this
      glycoprotein are likely to be implicated in the antigenicity and biomedical
      properties of KLH, knowledge of its carbohydrate structure is still limited.
      Therefore, we have investigated the N-linked oligosaccharides of KLH. Glycan
      chains were enzymatically liberated from tryptic glycopeptides, pyridylaminated
      and separated by two-dimensional HPLC. Only neutral oligosaccharides were
      obtained and characterized by carbohydrate constituent and methylation analyses,
      MALDI-TOF-MS, ESI-ion trap-MS and sequential exoglycosidase digestion. The
      results revealed that KLH is carrying high mannose-type glycans and truncated
      sugar chains derived thereof. As a characteristic feature, a number of the
      studied N-glycans contained a Gal(beta1-6)Man-unit which has not been found in
      glycoprotein-N-glycans so far. Hence, our studies demonstrate that this marine
      mollusk glycoprotein is characterized by a unique oligosaccharide pattern
      comprising, in part, novel structural elements.

PMID- 12423345
TI  - Anti- and pro-oxidant effects of urate in copper-induced low-density lipoprotein
      oxidation.
AB  - We reported earlier that urate may behave as a pro-oxidant in Cu2+-induced
      oxidation of diluted plasma. Thus, its effect on Cu2+-induced oxidation of
      isolated low-density lipoprotein (LDL) was investigated by monitoring the
      formation of malondialdehyde and conjugated dienes and the consumption of urate
      and carotenoids. We show that urate is antioxidant at high concentration but pro
      oxidant at low concentration. Depending on Cu2+ concentration, the switch between
      the pro- and antioxidant behavior of urate occurs at different urate
      concentrations. At high Cu2+ concentration, in the presence of urate, superoxide
      dismutase and ferricytochrome c protect LDL from oxidation but no protection is
      observed at low Cu2+ concentration. The use of Cu2+ or Cu+ chelators demonstrates
      that both copper redox states are required. We suggest that two mechanisms occur
      depending on the Cu2+ concentration. Urate may reduce Cu2+ to Cu+, which in turn
      contributes to formation. The Cu2+ reduction is likely to produce the urate
      radical (UH.-). It is proposed that at high Cu2+ concentration, the reaction of
      UH.- radical with generates products or intermediates, which trigger LDL
      oxidation. At low Cu2+ concentration, we suggest that the Cu+ ions formed reduce
      lipid hydroperoxides to alkoxyl radicals, thereby facilitating the peroxidizing
      chain reaction. It is anticipated that these two mechanisms are the consequence
      of complex LDL-urate-Cu2+ interactions. It is also shown that urate is pro
      oxidant towards slightly preoxidized LDL, whatever its concentration. We
      reiterate the conclusion that the use of antioxidants may be a two-edged sword.

PMID- 12423346
TI  - Equilibrium unfolding and conformational plasticity of troponin I and T.
AB  - The structures and stabilities of recombinant chicken muscle troponin I (TnI) and
      T (TnT) were investigated by a combination of bis-ANS binding and equilibrium
      unfolding studies. Unlike most folded proteins, isolated TnI and TnT bind the
      hydrophobic fluorescent probe bis-ANS, indicating the existence of solvent
      exposed hydrophobic domains in their structures. Bis-ANS binding to binary or
      ternary mixtures of TnI, TnT and troponin C (TnC) in solution is significantly
      lower than binding to the isolated subunits, which can be explained by burial of
      previously exposed hydrophobic domains upon association of the subunits to form
      the native troponin complex. Equilibrium unfolding studies of TnT and TnI by
      guanidine hydrochloride and urea monitored by changes in far-UV CD and bis-ANS
      fluorescence revealed noncooperative folding transitions for both proteins and
      the existence of partially folded intermediate states. Taken together, these
      results indicate that isolated TnI and TnT are partially unstructured proteins,
      and suggest that conformational plasticity of the isolated subunits may play an
      important role in macromolecular recognition for the assembly of the troponin
      complex.

PMID- 12423347
TI  - The RuvABC resolvasome.
AB  - The RuvABC resolvasome of Escherichia coli catalyses the resolution of Holliday
      junctions that arise during genetic recombination and DNA repair. This process
      involves two key steps: branch migration, catalysed by the RuvB protein that is
      targeted to the Holliday junction by the structure specific RuvA protein, and
      resolution, which is catalysed by the RuvC endonuclease. We have quantified the
      interaction of the RuvA protein with synthetic Holliday junctions and have shown
      that the binding of the protein is highly structure-specific, and leads to the
      formation of a complex containing two tetramers of RuvA per Holliday junction.
      Our data are consistent with two tetramers of RuvA binding to the DNA
      recombination intermediate in a co-operative manner. Once formed this complex
      prevents the binding of RuvC to the Holliday junction. However, the formation of
      a RuvAC complex can be observed following sequential addition of the RuvC and
      RuvA proteins. Moreover, by examining the DNA recognition properties of a mutant
      RuvA protein (E55R, D56K) we show that the charge on the central pin is critical
      for directing the structure-specific binding by RuvA.

PMID- 12423348
TI  - Regulated expression and intracellular localization of cystatin F in human U937
      cells.
AB  - Cystatin F is a cysteine peptidase inhibitor recently discovered in
      haematopoietic cells by cDNA cloning. To further investigate the expression,
      distribution and properties of the native human inhibitor the promyeloid cell
      line U937 has been studied. The cells expressed relatively large quantities of
      cystatin F, which was found both secreted and intracellularly. The intracellular
      levels were unusually high for a secreted cystatin ( approximately 25% of the
      cystatin F in 2- or 4-day culture medium). By contrast, U937 cells contained only
      3-4% of the related inhibitor, cystatin C. Cystatin F purified from lysates of
      U937 cells showed three major forms carrying two, one or no carbohydrate chains.
      Immunocytochemistry demonstrated a marked cytoplasmic cystatin F staining in a
      granular pattern. Double staining with a marker for endoplasmic reticulum
      revealed no colocalization for cystatin F. Analysis of the promoter region of the
      cystatin F gene (CST7) showed that it, like that of the cystatin C gene (CST3),
      is devoid of typical TATA- and CAAT-box elements. In contrast to the cystatin C
      promoter, it does not contain multiple Sp1 binding sites, but has a unique site
      for C/EBPalpha, possibly explaining the restricted expression of the cystatin F
      gene. Cells stimulated with all-trans retinoic acid to differentiate them towards
      a granulocytic pathway, showed a strong ( approximately 18-fold) down-regulation
      of intracellular cystatin F and almost abolished secreted levels of the
      inhibitor. Stimulation with tetradecanoyl phorbol acetate, causing monocytic
      differentiation, also resulted in down-regulation (two fold to threefold) of
      cystatin F expression, whereas the cystatin C expression was essentially
      unaltered in both experiments. The results suggest that cystatin F as an
      intracellular cysteine peptidase inhibitor with readily regulated expression, may
      be a candidate to control the cysteine peptidase activity known to be essential
      for antigen presentation in different blood cell lineages.

PMID- 12423349
TI  - Characterization of an omega-class glutathione S-transferase from Schistosoma
      mansoni with glutaredoxin-like dehydroascorbate reductase and thiol transferase
      activities.
AB  - Glutathione S-transferases (EC 2.5.1.18) (GSTs), are a family of multifunctional
      enzymes present in all living organisms whose main function is the detoxification
      of electrophilic compounds. GSTs are considered the most prominent detoxifying
      class II enzymes in helminths. We describe here the characterization of novel
      dehydroascorbate reductase and thiol transferase activities that reside in the
      human parasite Schistosoma mansoni GSTx. Protein sequence analysis of this
      parasite product showed lower identity to known GSTs. However, phylogenic
      analysis placed SmGSTx among the recently described omega class GSTs (GSTO1-1).
      We report here that SmGSTO protein is a 28-kDa polypeptide, detected in all life
      stages of the parasite, being highly expressed in adult worms. Like other omega
      class GSTs, SmGSTO showed very low activity toward classical GSTs substrates as 1
      chloro-2,4-dinitrobenzene, and no binding affinity to glutathione-agarose matrix
      but showed some biochemical characteristics related with
      thioredoxins/glutaredoxins. Interestingly, SmGSTO was able to bind S-hexyl
      glutathione matrix and displayed significant glutathione-dependent
      dehydroascorbate reductase and thiol transferase enzymatic activities.

PMID- 12423350
TI  - Insights into the reaction mechanism of Escherichia coli agmatinase by site
      directed mutagenesis and molecular modelling.
AB  - Upon mutation of Asp153 by asparagine, the catalytic activity of agmatinase
      (agmatine ureohydrolase, EC 3.5.3.11) from Escherichia coli was reduced to about
      5% of wild-type activity. Tryptophan emission fluorescence (lambdamax = 340 nm),
      and CD spectra were nearly identical for wild-type and D153N agmatinases. The Km
      value for agmatine (1.6 +/- 0.1 mm), as well as the Ki for putrescine inhibition
      (12 +/- 2 mm) and the interaction of the enzyme with the required metal ion, were
      also not altered by mutation. Three-dimensional models, generated by homology
      modelling techniques, indicated that the side chains of Asp153 and Asn153 can
      perfectly fit in essentially the same position in the active site of E. coli
      agmatinase. Asp153 is suggested to be involved, by hydrogen bond formation, in
      the stabilization and orientation of a metal-bound hydroxide for optimal attack
      on the guanidinium carbon of agmatine. Thus, the disruption of this hydrogen bond
      is the likely cause of the greately decreased catalytic efficiency of the D153N
      variant.

PMID- 12423351
TI  - Identification of a set of genes involved in the biosynthesis of the
      aminonucleoside moiety of antibiotic A201A from Streptomyces capreolus.
AB  - A novel cosmid (pABC6.5) whose DNA insert from Streptomyces capreolus, the A201A
      antibiotic producer, overlaps the inserts of the previously reported pCAR11 and
      pCAR13 cosmids, has been isolated. These two latter cosmids were known to contain
      the aminonucleoside antibiotic A201A resistance determinants ard2 and ard1,
      respectively. Together, these three cosmids have permitted the identification of
      a DNA stretch of 19 kb between ard1 and ard2, which should comprise a large
      region of a putative A201A biosynthetic (ata) gene cluster. The sequence of the 7
      kb upstream of ard1 towards ard2 reveals seven consecutive open reading frames:
      ataP3, ataP5, ataP4, ataP10, ataP7, ata12 and ataPKS1. Except for the last two,
      their deduced products present high similarities to an identical number of
      counterparts from the pur cluster of Streptomyces alboniger that were either
      known or proposed to be implicated in the biosynthesis of the N6,N6-dimethyl-3'
      amino-3'-deoxyadenosine moiety of puromycin. Because A201A contains this chemical
      moiety, these ataP genes are most likely implicated in its biosynthesis.
      Accordingly, the ataP4, ataP5 and ataP10 genes complemented specific puromycin
      nonproducing Deltapur4, Deltapur5 and Deltapur10 mutants of S. alboniger,
      respectively. Amino acid sequence comparisons suggest that ata12 and ataPKS1
      could be implicated in the biosynthesis of the d-rhamnose and alpha-p-coumaric
      acid moieties of A201A. Further sequencing of 2 kb of DNA downstream of ard1 has
      disclosed a region which might contain one end of the ata cluster.

PMID- 12423352
TI  - Characterization of a cloned subtilisin-like serine proteinase from a
      psychrotrophic Vibrio species.
AB  - The gene encoding a subtilisin-like serine proteinase in the psychrotrophic
      Vibrio sp. PA44 has been successfully cloned, sequenced and expressed in
      Escherichia coli. The gene is 1593 basepairs and encodes a precursor protein of
      530 amino acid residues with a calculated molecular mass of 55.7 kDa. The enzyme
      is isolated, however, as an active 40.6-kDa proteinase, without a 139 amino acid
      residue N-terminal prosequence. Under mild conditions the enzyme undergoes a
      further autocatalytic cleavage to give a 29.7-kDa proteinase that retains full
      enzymatic activity. The deduced amino acid sequence of the enzyme has high
      homology to proteinases of the proteinase K family of subtilisin-like
      proteinases. With respect to the enzyme characteristics compared in this study
      the properties of the wild-type and recombinant proteinases are the same.
      Sequence analysis revealed that especially with respect to the thermophilic
      homologues, aqualysin I from Thermus aquaticus and a proteinase from Thermus
      strain Rt41A, the cold-adapted Vibrio-proteinase has a higher content of
      polar/uncharged amino acids, as well as aspartate residues. The thermophilic
      enzymes had a higher content of arginines, and relatively higher number of
      hydrophobic amino acids and a higher aliphatic index. These factors may
      contribute to the adaptation of these proteinases to different temperature
      conditions.

PMID- 12423354
TI  - Role of three isoforms of phospholipase A2 in capacitative calcium influx in
      human T-cells.
AB  - The present study was conducted on human Jurkat T-cell lines in order to
      elucidate the role of phospholipase A2 in capacitative calcium entry. We have
      employed thapsigargin (TG) that induces increases in [Ca2+]i by emptying the
      calcium pool of endoplasmic reticulum, followed by capacitative calcium entry. We
      designed a Ca2+ free/Ca2+ reintroduction (CFCR) protocol for the experiments,
      conducted in Ca2+-free medium. By employing CFCR protocol, we observed that
      addition of exogenous arachidonic acid (AA) stimulated TG-induced capacitative
      calcium influx. The liberation of endogenous AA and its autocrine action seems to
      be implicated during TG-induced capacitative calcium influx: TG potentiates the
      induction of constitutively expressed mRNA of four PLA2 isoforms (type 1B, IV, V,
      VI), the inhibitors of the three PLA2 isotypes (type 1B, V, VI) inhibit TG
      induced release of [3H]AA into the extracellular medium, and finally, these PLA2
      inhibitors do curtail TG-stimulated capacitative calcium entry in these cells.
      These results suggest that stimulation of three isoforms of PLA2 by thapsigargin
      liberates free AA that, in turn, induces capacitative calcium influx in human T
      cells.

PMID- 12423353
TI  - DNA and RNA damage by Cu(II)-amikacin complex.
AB  - The oxidation-promoting reactivity of copper(II) complex of aminoglycosidic
      antibiotic amikacin [Cu(II)-Ami] in the presence of hydrogen peroxide, was
      studied at pH 7.4, using 2'-deoxyguanosine (dG), pBR322 plasmid DNA and yeast
      tRNAPhe as target molecules. The mixtures of complex with H2O2 were found to be
      efficient oxidants, converting dG to its 8-oxo derivative, generating strand
      breaks in plasmid DNA and multiple cleavages in tRNAPhe. The complex underwent
      autooxidation as well, with amikacin hydroperoxides as likely major products.
      This reactivity pattern was found to be due to a combination of metal-bound and
      free hydroxyl radicals.

PMID- 12423355
TI  - The presence of a helix breaker in the hydrophobic core of signal sequences of
      secretory proteins prevents recognition by the signal-recognition particle in
      Escherichia coli.
AB  - Signal sequences often contain alpha-helix-destabilizing amino acids within the
      hydrophobic core. In the precursor of the Escherichia coli outer-membrane protein
      PhoE, the glycine residue at position -10 (Gly-10) is thought to be responsible
      for the break in the alpha-helix. Previously, we showed that substitution of Gly
      10 by alpha-helix-promoting residues (Ala, Cys or Leu) reduced the proton-motive
      force dependency of the translocation of the precursor, but the actual role of
      the helix breaker remained obscure. Here, we considered the possibility that
      extension of the alpha-helical structure in the signal sequence resulting from
      the Gly-10 substitutions affects the targeting pathway of the precursor. Indeed,
      the mutations resulted in reduced dependency on SecB for targeting in vivo. In
      vitro cross-linking experiments revealed that the G-10L and G-10C mutant PhoE
      precursors had a dramatically increased affinity for P48, one of the constituents
      of the signal-recognition particle (SRP). Furthermore, in vitro cross-linking
      experiments revealed that the G-10L mutant protein is routed to the SecYEG
      translocon via the SRP pathway, the targeting pathway that is exploited by
      integral inner-membrane proteins. Together, these data indicate that the helix
      breaker in cleavable signal sequences prevents recognition by SRP and is thereby,
      together with the hydrophobicity of the signal sequence, a determinant of the
      targeting pathway.

PMID- 12423356
TI  - Defective translocation of a signal sequence mutant in a prlA4 suppressor strain
      of Escherichia coli.
AB  - In the accompanying paper [Adams, H., Scotti, P.A., de Cock, H., Luirink, J. &
      Tommassen, J. (2002) Eur. J. Biochem.269, 5564-5571], we showed that the
      precursor of outer-membrane protein PhoE of Escherichia coli with a Gly to Leu
      substitution at position -10 in the signal sequence (G-10L) is targeted to the
      SecYEG translocon via the signal-recognition particle (SRP) route, instead of via
      the SecB pathway. Here, we studied the fate of the mutant precursor in a prlA4
      mutant strain. prlA mutations, located in the secY gene, have been isolated as
      suppressors that restore the export of precursors with defective signal
      sequences. Remarkably, the G-10L mutant precursor, which is normally exported in
      a wild-type strain, accumulated strongly in a prlA4 mutant strain. In vitro cross
      linking experiments revealed that the precursor is correctly targeted to the
      prlA4 mutant translocon. However, translocation across the cytoplasmic membrane
      was defective, as appeared from proteinase K-accessibility experiments in pulse
      labeled cells. Furthermore, the mutant precursor was found to accumulate when
      expressed in a secY40 mutant, which is defective in the insertion of integral
      membrane proteins but not in protein translocation. Together, these data suggest
      that SecB and SRP substrates are differently processed at the SecYEG translocon.

PMID- 12423357
TI  - Membrane embedded location of Na+ or H+ binding sites on the rotor ring of F1F0
      ATP synthases.
AB  - Recent crosslinking studies indicated the localization of the coupling ion
      binding site in the Na+-translocating F1F0 ATP synthase of Ilyobacter tartaricus
      within the hydrophobic part of the bilayer. Similarly, a membrane embedded H+
      binding site is accepted for the H+-translocating F1F0 ATP synthase of
      Escherichia coli. For a more definite analysis, we performed parallax analysis of
      fluorescence quenching with ATP synthases from both I. tartaricus and E. coli.
      Both ATP synthases were specifically labelled at their c subunit sites with N
      cyclohexyl-N'-(1-pyrenyl)carbodiimide, a fluorescent analogue of
      dicyclohexylcarbodiimide and the enzymes were reconstituted into proteoliposomes.
      Using either soluble quenchers or spinlabelled phospholipids, we observed a
      deeply membrane embedded binding site, which was quantitatively determined for I.
      tartaricus and E. coli to be 1.3 +/- 2.4 A and 1.8 +/- 2.8 A from the bilayer
      center apart, respectively. These data show a conserved topology among enzymes of
      different species. We further demonstrated the direct accessibility for Na+ ions
      to the binding sites in the reconstituted I. tartaricus c11 oligomer in the
      absence of any other subunits, pointing to intrinsic rotor channels. The common
      membrane embedded location of the binding site of ATP synthases suggest a common
      mechanism for ion transfer across the membrane.

PMID- 12423358
TI  - Characterization of the exopolysaccharide produced by Streptococcus thermophilus
      8S containing an open chain nononic acid.
AB  - The exopolysaccharide produced by Streptococcus thermophilus 8S in reconstituted
      skimmed milk is a heteropolysaccharide containing d-galactose, d-glucose, d
      ribose, and N-acetyl-d-galactosamine in a molar ratio of 2 : 1 : 1 : 1.
      Furthermore, the polysaccharide contains one equivalent of a novel open chain
      nononic acid constituent, 3,9-dideoxy-d-threo-d-altro-nononic acid, ether-linked
      via C-2 to C-6 of an additional d-glucose per repeating unit. Methylation
      analysis and 1D/2D NMR studies (1H and 13C) performed on the native
      polysaccharide, and mass spectrometric and NMR analyses of the oligosaccharide
      obtained from the polysaccharide by de-N-acetylation followed by deamination and
      reduction demonstrated the 'hepta'saccharide repeating unit to be: -->4)-alpha-D
      Galp-(1-->2)-beta-D-Ribf-(1-->4)-beta-D-Galp-(1-->4)-beta-D-Glcp-(1--7')-Sub-(1-
      >4)-beta-D-GalpNAc-(1--> in which Sug is 6-O-(3',9'-dideoxy-d-threo-d-altro
      nononic acid-2'-yl)-alpha-d-glucopyranose.

PMID- 12423359
TI  - Concerted regulation of free arachidonic acid and hormone-induced steroid
      synthesis by acyl-CoA thioesterases and acyl-CoA synthetases in adrenal cells.
AB  - Although the role of arachidonic acid (AA) in the regulation of steroidogenesis
      is well documented, the mechanism for AA release is not clear. Therefore, the aim
      of this study was to characterize the role of an acyl-CoA thioesterase (ARTISt)
      and an acyl-CoA synthetase as members of an alternative pathway in the regulation
      of the intracellular levels of AA in steroidogenesis. Purified recombinant ARTISt
      releases AA from arachidonoyl-CoA (AA-CoA) with a Km of 2 micro m. Antibodies
      raised against recombinant acyl-CoA thioesterase recognize the endogenous protein
      in both adrenal tissue and Y1 adrenal tumor cells by immunohistochemistry and
      immunocytochemistry and Western blot. Stimulation of Y1 cells with ACTH
      significantly stimulated endogenous mitochondrial thioesterases activity (1.8
      fold). Nordihydroguaiaretic acid (NDGA), an inhibitor of AA release known to
      affect steroidogenesis, affects the in vitro activity of recombinant ARTISt and
      also the endogenous mitochondrial acyl-CoA thioesterases. ACTH-stimulated steroid
      synthesis in Y1 cells was significantly inhibited by a synergistic effect of NDGA
      and triacsin C an inhibitor of the AA-CoA synthetase. The apparent IC50 for NDGA
      was reduced from 50 micro m to 25, 7.5 and 4.5 micro m in the presence of 0.1,
      0.5 and 2 micro m triacsin C, respectively. Our results strongly support the
      existence of a new pathway of AA release that operates in the regulation of
      steroid synthesis in adrenal cells.

PMID- 12423360
TI  - Baboon cytochrome P450 17alpha-hydroxylase/17,20-lyase (CYP17).
AB  - Human cytochrome P450 17alpha-hydroxylase (CYP17) catalyses not only the 17alpha
      hydroxlation of pregnenolone and progesterone and the C17,20-side chain cleavage
      (lyase) of 17alpha-hydroxypregnenolone, necessary for the biosynthesis of C21
      glucocorticoids and C19-androgens, but also catalyses the 16alpha-hydroxylation
      of progesterone. In efforts to understand the complex enzymology of CYP17,
      structure/function relationships have been reported previously after expressing
      recombinant DNAs, encoding CYP17 from various species, in nonsteroidogenic
      mammalian or yeast cells. A major difference between species resides in the lyase
      activity towards the hydroxylated intermediates and in the fact that the
      secretion of C19-steroids take place, in some species, principally in the gonads.
      Because human and higher primate adrenals secrete steroids, CYP17 has been
      characterized in the Cape baboon, a species more closely related to humans, in an
      effort to gain a further understanding of the reactions catalysed by CYP17.
      Baboon and human CYP17 cDNA share 96% homology. Baboon CYP17 has apparent Km and
      V values for pregnenolone and progesterone of 0.9 micro m and 0.4 nmol.h-1.mg
      protein-1 and 6.5 micro m and 3.9 nmol.h-1.mg protein-1, respectively. Baboon
      CYP17 had a significantly higher activity for progesterone hydroxylation relative
      to pregnenolone. No 16alpha-hydroxylase and no lyase activity for 17alpha
      hydroxyprogesterone. Sequence analyses showed that there are 28 different amino
      acid residues between human and baboon CYP17, primarily in helices F and G and
      the F-G loop.

PMID- 12423361
TI  - Co-existence of two regulatory NADP-glyceraldehyde 3-P dehydrogenase complexes in
      higher plant chloroplasts.
AB  - Light/dark modulation of the higher plant Calvin-cycle enzymes
      phosphoribulokinase (PRK) and NADP-dependent glyceraldehyde 3-phosphate
      dehydrogenase (NADP- GAPDH-A2B2) involves changes of their aggregation state in
      addition to redox changes of regulatory cysteines. Here we demonstrate that
      plants possess two different complexes containing the inactive forms (a) of NADP
      GAPDH and PRK and (b) of only NADP-GAPDH, respectively, in darkened chloroplasts.
      While the 550-kDa PRK/GAPDH/CP12 complex is dissociated and activated upon
      reduction alone, activation and dissociation of the 600-kDa A8B8 complex of NADP
      GAPDH requires incubation with dithiothreitol and the effector 1,3
      bisphosphoglycerate. In the light, PRK is therefore completely in its activated
      state under all conditions, even in low light, while GAPDH activation in the
      light is characterized by a two-step mechanism with 60-70% activation under most
      conditions in the light, and the activation of the remaining 30-40% occurring
      only when 1,3-bisphosphoglycerate levels are strongly increasing. In vitro
      studies with the purified components and coprecipitation experiments from fresh
      stroma using polyclonal antisera confirm the existence of these two aggregates.
      Isolated oxidized PRK alone does not reaggregate after it has been purified in
      its reduced form; only in the presence of both CP12 and purified NADP-GAPDH, some
      of the PRK reaggregates. Recombinant GapA/GapB constructs form the A8B8 complex
      immediately upon expression in E. coli.

PMID- 12423362
TI  - Restoring enzyme activity in nonfunctional low erucic acid Brassica napus fatty
      acid elongase 1 by a single amino acid substitution.
AB  - Genomic fatty acid elongation 1 (FAE1) clones from high erucic acid (HEA)
      Brassica napus, Brassica rapa and Brassica oleracea, and low erucic acid (LEA) B.
      napus cv. Westar, were amplified by PCR and expressed in yeast cells under the
      control of the strong galactose-inducible promoter. As expected, yeast cells
      expressing the FAE1 genes from HEA Brassica spp. synthesized very long chain
      monounsaturated fatty acids that are not normally found in yeast, while fatty
      acid profiles of yeast cells expressing the FAE1 gene from LEA B. napus were
      identical to control yeast samples. In agreement with published findings
      regarding different HEA and LEA B. napus cultivars, comparison of FAE1 protein
      sequences from HEA and LEA Brassicaceae revealed one crucial amino acid
      difference: the serine residue at position 282 of the HEA FAE1 sequences is
      substituted by phenylalanine in LEA B. napus cv. Westar. Using site directed
      mutagenesis, the phenylalanine 282 residue was substituted with a serine residue
      in the FAE1 polypeptide from B. napus cv. Westar, the mutated gene was expressed
      in yeast and GC analysis revealed the presence of very long chain monounsaturated
      fatty acids (VLCMFAs), indicating that the elongase activity was restored in the
      LEA FAE1 enzyme by the single amino acid substitution. Thus, for the first time,
      the low erucic acid trait in canola B. napus can be attributed to a single amino
      acid substitution which prevents the biosynthesis of the eicosenoic and erucic
      acids.

PMID- 12423364
TI  - Solution structure of the Alzheimer amyloid beta-peptide (1-42) in an apolar
      microenvironment. Similarity with a virus fusion domain.
AB  - The major components of neuritic plaques found in Alzheimer disease (AD) are
      peptides known as amyloid beta-peptides (Abeta), which derive from the
      proteolitic cleavage of the amyloid precursor proteins. In vitro Abeta may
      undergo a conformational transition from a soluble form to aggregated, fibrillary
      beta-sheet structures, which seem to be neurotoxic. Alternatively, it has been
      suggested that an alpha-helical form can be involved in a process of membrane
      poration, which would then trigger cellular death. Conformational studies on
      these peptides in aqueous solution are complicated by their tendency to
      aggregate, and only recently NMR structures of Abeta-(1-40) and Abeta-(1-42) have
      been determined in aqueous trifluoroethanol or in SDS micelles. All these studies
      hint to the presence of two helical regions, connected through a flexible kink,
      but it proved difficult to determine the length and position of the helical
      stretches with accuracy and, most of all, to ascertain whether the kink region
      has a preferred conformation. In the search for a medium which could allow a more
      accurate structure determination, we performed an exhaustive solvent scan that
      showed a high propensity of Abeta-(1-42) to adopt helical conformations in
      aqueous solutions of fluorinated alcohols. The 3D NMR structure of Abeta-(1-42)
      shows two helical regions encompassing residues 8-25 and 28-38, connected by a
      regular type I beta-turn. The surprising similarity of this structure, as well as
      the sequence of the C-terminal moiety, with those of the fusion domain of
      influenza hemagglutinin suggests a direct mechanism of neurotoxicity.

PMID- 12423363
TI  - Characterization of the 105-kDa molecular chaperone. Identification, biochemical
      properties, and localization.
AB  - We have characterized the biochemical properties of the testis and brain-specific
      105-kDa protein which is cross-reacted with an anti-bovine HSP90 antibody. The
      protein was induced in germ cells by heat stress, resulting in a protein which is
      one of the heat shock proteins [Kumagai, J., Fukuda, J., Kodama, H., Murata, M.,
      Kawamura, K., Itoh, H. & Tanaka, T. (2000) Eur. J. Biochem.267, 3073-3078]. In
      the present study, we characterized the biochemical properties of the protein.
      The 105-kDa protein inhibited the aggregation of citrate synthase as a molecular
      chaperone in vitro. ATP/MgCl2 has a slight influence of the suppression of the
      citrate synthase aggregation by the 105-kDa protein. The protein possessed
      chaperone activity. The protein was able to bind to ATP-Sepharose like the other
      molecular chaperone HSP70. A partial amino-acid sequence (24 amino-acid residues)
      of the protein was determined and coincided with those of the mouse testis- and
      brain-specific APG-1 and osmotic stress protein 94 (OSP94). The 105-kDa protein
      was detected only in the medulla of the rat kidney sections similar to OSP94 upon
      immunoblotting. The purified 105-kDa protein was cross-reacted with an antibody
      against APG-1. These results suggested that APG-1 and OSP94 are both identical to
      the 105-kDa protein. There were highly homologous regions between the 105-kDa
      protein/APG-1/OSP94 and HSP90. The region of HSP90 was also an immunoreactive
      site. An anti-bovine HSP90 antibody may cross-react with the 105-kDa protein
      similar to HSP90 in the rat testis and brain. We have investigated the
      localization and developmental induction of the protein in the rat brain. In the
      immunohistochemical analysis, the protein was mainly detected in the cytoplasm of
      the nerve and glial cells of the rat brain. Although the 105-kDa protein was
      localized in all rat brain segments, the expression pattern was fast in the
      cerebral cortex and hippocampus and slow in the cerebellum.

PMID- 12423365
TI  - The role of the second binding loop of the cysteine protease inhibitor, cystatin
      A (stefin A), in stabilizing complexes with target proteases is exerted
      predominantly by Leu73.
AB  - The aim of this work was to elucidate the roles of individual residues within the
      flexible second binding loop of human cystatin A in the inhibition of cysteine
      proteases. Four recombinant variants of the inhibitor, each with a single
      mutation, L73G, P74G, Q76G or N77G, in the most exposed part of this loop were
      generated by PCR-based site-directed mutagenesis. The binding of these variants
      to papain, cathepsin L, and cathepsin B was characterized by equilibrium and
      kinetic methods. Mutation of Leu73 decreased the affinity for papain, cathepsin L
      and cathepsin B by approximately 300-fold, >10-fold and approximately 4000-fold,
      respectively. Mutation of Pro74 decreased the affinity for cathepsin B by
      approximately 10-fold but minimally affected the affinity for the other two
      enzymes. Mutation of Gln76 and Asn77 did not alter the affinity of cystatin A for
      any of the proteases studied. The decreased affinities were caused exclusively by
      increased dissociation rate constants. These results show that the second binding
      loop of cystatin A plays a major role in stabilizing the complexes with proteases
      by retarding their dissociation. In contrast with cystatin B, only one amino-acid
      residue of the loop, Leu73, is of principal importance for this effect, Pro74
      assisting to a minor extent only in the case of cathepsin B binding. The
      contribution of the second binding loop of cystatin A to protease binding varies
      with the protease, being largest, approximately 45% of the total binding energy,
      for inhibition of cathepsin B.

PMID- 12423366
TI  - Molecular cloning of columbamine O-methyltransferase from cultured Coptis
      japonica cells.
AB  - To identify all of the O-methyltransferase genes involved in isoquinoline
      alkaloid biosynthesis in Coptis japonica cells, we sequenced 1014 cDNA clones
      isolated from high-alkaloid-producing cultured cells of C. japonica. Among them,
      we found all three reported O-methyltransferases and an O-methyltransferase-like
      cDNA clone (CJEST64). This cDNA was quite similar to S-adenosyl-l
      methionine:coclaurine 6-O-methyltransferase and S-adenosyl-l
      methionine:isoflavone 7-O-methyltransferase. As S-adenosyl-l
      methionine:columbamine O-methyltransferase, which catalyzes the conversion of
      columbamine to palmatine, is one of the remaining unelucidated components in
      isoquinoline alkaloid biosynthesis in C. japonica, we heterologously expressed
      the protein in Escherichia coli and examined the activity of columbamine O
      methyltransferase. The recombinant protein clearly showed O-methylation activity
      using columbamine, as well as (S)-tetrahydrocolumbamine, (S)-, (R,S)-scoulerine
      and (R,S)-2,3,9,10-tetrahydroxyprotoberberine as substrates. This result clearly
      indicated that EST analysis was useful for isolating the candidate gene in a
      relatively well-characterized biosynthetic pathway. The relationship between the
      structure and substrate recognition of the O-methyltransferases involved in
      isoquinoline alkaloid biosynthesis, and a reconsideration of the biosynthetic
      pathway to palmatine are discussed.

PMID- 12423367
TI  - Enzymic properties of recombinant BACE2.
AB  - BACE2 (Memapsin 1) is a membrane-bound aspartic protease that is highly
      homologous with BACE1 (Memapsin 2). While BACE1 processes the amyloid precursor
      protein (APP) at a key step in generating the beta-amyloid peptide and presumably
      causes Alzheimer's disease (AD), BACE2 has not been demonstrated to be directly
      involved in APP processing, and its physiological functions remain to be
      determined. In vivo, BACE2 is expressed as a precursor protein containing pre-,
      pro-, protease, transmembrane, and cytosolic domains/peptides. To determine the
      enzymatic properties of BACE2, two variants of its pro-protease domain, pro-BACE2
      T1 (PB2-T1) and pro-BACE2-T2 (PB2-T2), were constructed. They have been expressed
      in Escherichia coli as inclusion bodies, refolded and purified. These two
      recombinant proteins have the same N terminus but differ at their C-terminal
      ends: PB2-T1 ends at Pro466, on the boundary of the postulated transmembrane
      domain, and PB2-T2 ends at Ser431, close to the homologous ends of other aspartic
      proteases such as pepsin. While PB2-T1 shares similar substrate specificities
      with BACE1 and other 'general' aspartic proteases, the specificity of PB2-T2 is
      more constrained, apparently preferring to cleave at the NH2-terminal side of
      paired basic residues. Unlike other 'typical' aspartic proteases, which are
      active only under acidic conditions, the recombinant BACE2, PB2-T1, was active at
      a broad pH range. In addition, pro-BACE2 can be processed at its in vivo
      maturation site by BACE1.

PMID- 12423368
TI  - Differential scanning calorimetric study of myosin subfragment 1 with tryptic
      cleavage at the N-terminal region of the heavy chain.
AB  - The thermal unfolding of myosin subfragment 1 (S1) cleaved by trypsin was studied
      by differential scanning calorimetry. In the absence of nucleotides, trypsin
      splits the S1 heavy chain into three fragments (25, 50, and 20 kDa). This
      cleavage has no appreciable influence on the thermal unfolding of S1 examined in
      the presence of ADP, in the ternary complexes of S1 with ADP and phosphate
      analogs, such as orthovanadate (Vi) or beryllium fluoride (BeFx), and in the
      presence of F-actin. In the presence of ATP and in the complexes S1.ADP.Vi or
      S1.ADP.BeFx, trypsin produces two additional cleavages in the S1 heavy chain: a
      faster cleavage in the N-terminal region between Arg23 and Ile24, and a slower
      cleavage at the 50 kDa fragment. It has been shown that the N-terminal cleavage
      strongly decreases the thermal stability of S1 by shifting the maximum of its
      thermal transition by about 7 degrees C to a lower temperature, from 50 degrees C
      to 42.4 degrees C, whereas the cleavage at both these sites causes dramatic
      destabilization of the S1 molecule leading to total loss of its thermal
      transition. Our results show that S1 with ATP-induced N-terminal cleavage is
      able, like uncleaved S1, to undergo global structural changes in forming the
      stable ternary complexes with ADP and Pi analogs (Vi, BeFx). These changes are
      reflected in a pronounced increase of S1 thermal stability. However, S1 cleaved
      by trypsin in the N-terminal region is unable, unlike S1, to undergo structural
      changes induced by interaction with F-actin that are expressed in a 4-5 degrees C
      shift of the S1 thermal transition to higher temperature. Thus, the cleavage
      between Arg23 and Ile24 does not significantly affect nucleotide-induced
      structural changes in the S1, but it prevents structural changes that occur when
      S1 is bound to F-actin. The results suggest that the N-terminal region of the S1
      heavy chain plays an important role in structural stabilization of the entire
      motor domain of the myosin head, and a long-distance communication pathway may
      exist between this region and the actin-binding sites.

PMID- 12423369
TI  - Expression and purification of the recombinant subunits of toluene/o-xylene
      monooxygenase and reconstitution of the active complex.
AB  - This paper describes the cloning of the genes coding for each component of the
      complex of toluene/o-xylene monooxygenase from Pseudomonas stutzeri OX1, their
      expression, purification and characterization. Moreover, the reconstitution of
      the active complex from the recombinant subunits has been obtained, and the
      functional role of each component in the electron transfer from the electron
      donor to molecular oxygen has been determined. The coexpression of subunits B, E
      and A leads to the formation of a subcomplex, named H, with a quaternary
      structure (BEA)2, endowed with hydroxylase activity. Tomo F component is an NADH
      oxidoreductase. The purified enzyme contains about 1 mol of FAD, 2 mol of iron,
      and 2 mol of acid labile sulfide per mol of protein, as expected for the presence
      of one [2Fe-2S] cluster, and exhibits a typical flavodoxin absorption spectrum.
      Interestingly, the sequence of the protein does not correspond to that previously
      predicted on the basis of DNA sequence. We have shown that this depends on minor
      errors in the gene sequence that we have corrected. C component is a Rieske-type
      ferredoxin, whose iron and acid labile sulfide content is in agreement with the
      presence of one [2Fe-2S] cluster. The cluster is very sensitive to oxygen damage.
      Mixtures of the subcomplex H and of the subunits F, C and D are able to oxidize p
      cresol into 4-methylcathecol, thus demonstrating the full functionality of the
      recombinant subunits as purified. Finally, experimental evidence is reported
      which strongly support a model for the electron transfer. Subunit F is the first
      member of an electron transport chain which transfers electrons from NADH to C,
      which tunnels them to H subcomplex, and eventually to molecular oxygen.

PMID- 12423370
TI  - A functionally conserved member of the FTZ-F1 nuclear receptor family from
      Schistosoma mansoni.
AB  - The fushi tarazu factor 1 (FTZ-F1) nuclear receptor subfamily comprises orphan
      receptors with crucial roles in development and sexual differentiation in
      vertebrates and invertebrates. We describe the structure and functional
      properties of an FTZ-F1 from the platyhelminth parasite of humans, Schistosoma
      mansoni, the first receptor from this family to be characterized in a
      Lophotrochozoan. It contains a well conserved DNA-binding domain (55-63% identity
      to other family members) and a poorly conserved ligand-binding domain (20%
      identity to that of zebrafish FF1a). However, both the ligand domain signature
      sequence and the activation function 2-activation domain (AF2-AD) are perfectly
      conserved. Phylogenetic analysis confirmed that SmFTZ-F1 is a member of nuclear
      receptor subfamily 5, but that it clustered with the Drosophila receptor DHR39
      and has consequently been named NR5B1. The gene showed a complex structure with
      10 exons and an overall size of 18.4 kb. Two major transcripts were detected,
      involving alternative promoter usage and splicing of the two 5' exons, but which
      encoded identical proteins. SmFTZ-F1 mRNA is expressed at all life-cycle stages
      with the highest amounts in the larval forms (miracidia, sporocysts and
      cercariae). However, expression of the protein showed a different pattern; low in
      miracidia and higher in adult male worms. The protein bound the same monomeric
      response element as mammalian SF-1 (SF-1 response element, SFRE) and competition
      experiments with mutant SFREs showed that its specificity was identical.
      Moreover, SmFTZ-F1 transactivated reporter gene transcription from SFRE similarly
      to SF-1. This functional conservation argues for a conserved biological role of
      the FTZ-F1 nuclear receptor family throughout the metazoa.

PMID- 12423371
TI  - Purification and catalytic properties of a CO-oxidizing:H2-evolving enzyme
      complex from Carboxydothermus hydrogenoformans.
AB  - From the membrane fraction of the Gram-positive bacterium Carboxydothermus
      hydrogenoformans, an enzyme complex catalyzing the conversion of CO to CO2 and H2
      was purified. The enzyme complex showed maximal CO-oxidizing:H2-evolving enzyme
      activity with 5% CO in the headspace (450 U per mg protein). Higher CO
      concentrations inhibited the hydrogenase present in the enzyme complex. For
      maximal activity, the enzyme complex had to be activated by either CO or strong
      reductants. The enzyme complex also catalyzed the CO- or H2-dependent reduction
      of methylviologen at 5900 and 180 U per mg protein, respectively. The complex was
      found to be composed of six hydrophilic and two hydrophobic polypeptides. The
      amino-terminal sequences of the six hydrophilic subunits were determined allowing
      the identification of the encoding genes in the preliminary genome sequence of C.
      hydrogenoformans. From the sequence analysis it was deduced that the enzyme
      complex is formed by a Ni-containing carbon monoxide dehydrogenase (CooS), an
      electron transfer protein containing four [4Fe-4S] clusters (CooF) and a membrane
      bound [NiFe] hydrogenase composed of four hydrophilic subunits and two membrane
      integral subunits. The hydrogenase part of the complex shows high sequence
      similarity to members of a small group of [NiFe] hydrogenases with sequence
      similarity to energy conserving NADH:quinone oxidoreductases. The data support a
      model in which the enzyme complex is composed of two catalytic sites, a CO
      oxidizing site and a H2-forming site, which are connected via a different iron
      sulfur cluster containing electron transfer subunits. The exergonic redox
      reaction catalyzed by the enzyme complex in vivo has to be coupled to energy
      conservation, most likely via the generation of a proton motive force.

PMID- 12423372
TI  - Thermodynamic and kinetic characterization of trihaem cytochrome c3 from
      Desulfuromonas acetoxidans.
AB  - Trihaem cytochrome c3 (also known as cytochrome c551.5 and cytochrome c7) is
      isolated from the periplasmic space of Desulfuromonas acetoxidans, a sulfur
      reducing bacterium. Thermodynamic and kinetic data for the trihaem cytochrome c3
      are presented and discussed in the context of the possible physiological
      implications of its functional properties with respect to the natural habitat of
      D. acetoxidans, namely as a symbiont with green sulfur bacteria working as a mini
      sulfuretum. The thermodynamic properties were determined through the fit of redox
      titration data, followed by NMR and visible spectroscopy, to a model of four
      functional centres that describes the network of cooperativities between the
      three haems and one protolytic centre. The kinetics of trihaem cytochrome c3
      reduction by sodium dithionite were studied using the stopped-flow technique and
      the data were fitted to a kinetic model that makes use of the thermodynamic
      properties to obtain the rate constants of the individual haems. This analysis
      indicates that the electrons enter the cytochrome mainly via haem I. The
      reduction potentials of the haems in this cytochrome show little variation with
      pH within the physiological range, and the kinetic studies show that the rates of
      reduction are also independent of pH in the range studied. Thus, although the
      trihaem cytochrome c3 is readily reduced by hydrogenases from Desulfovibrio sp.
      and its haem core is similar to that of the homologous tetrahaem cytochromes c3,
      its physico-chemical properties are quite different, which suggests that these
      multihaem cytochromes with similar structures perform different functions.

PMID- 12423373
TI  - Purification, characterization and subunits identification of the diol
      dehydratase of Lactobacillus collinoides.
AB  - The three genes pduCDE encoding the diol dehydratase of Lactobacillus
      collinoides, have been cloned for overexpression in the pQE30 vector. Although
      the three subunits of the protein were highly induced, no activity was detected
      in cell extracts. The enzyme was therefore purified to near homogeneity by
      ammonium sulfate precipitation and gel filtration chromatography. In fractions
      showing diol dehydratase activity, three main bands were present after SDS/PAGE
      with molecular masses of 63, 28 and 22 kDa, respectively. They were identified by
      mass spectrometry to correspond to the large, medium and small subunits of the
      dehydratase encoded by the pduC, pduD and pduE genes, respectively. The molecular
      mass of the native complex was estimated to 207 kDa in accordance with the
      calculated molecular masses deduced from the pduC, D, E genes (61, 24.7 and 19,1
      kDa, respectively) and a alpha2beta2gamma2 composition. The Km for the three main
      substrates were 1.6 mm for 1,2-propanediol, 5.5 mm for 1,2-ethanediol and 8.3 mm
      for glycerol. The enzyme required the adenosylcobalamin coenzyme for catalytic
      activity and the Km for the cofactor was 8 micro m. Inactivation of the enzyme
      was observed by both glycerol and cyanocobalamin. The optimal reaction conditions
      of the enzyme were pH 8.75 and 37 degrees C. Activity was inhibited by sodium and
      calcium ions and to a lesser extent by magnesium. A fourth band at 59 kDa
      copurified with the diol dehydratase and was identified as the propionaldehyde
      dehydrogenase enzyme, another protein involved in the 1,2-propanediol metabolism
      pathway.

PMID- 12423374
TI  - Characterization of a Saccharomyces cerevisiae NADP(H)-dependent alcohol
      dehydrogenase (ADHVII), a member of the cinnamyl alcohol dehydrogenase family.
AB  - A new NADP(H)-dependent alcohol dehydrogenase (the YCR105W gene product, ADHVII)
      has been identified in Saccharomyces cerevisiae. The enzyme has been purified to
      homogeneity and found to be a homodimer of 40 kDa subunits and a pI of 6.2-6.4.
      ADHVII shows a broad substrate specificity similar to the recently characterized
      ADHVI (64% identity), although they show some differences in kinetic properties.
      ADHVI and ADHVII are the only members of the cinnamyl alcohol dehydrogenase
      family in yeast. Simultaneous deletion of ADH6 and ADH7 was not lethal for the
      yeast. Both enzymes could participate in the synthesis of fusel alcohols,
      ligninolysis and NADP(H) homeostasis.

PMID- 12423375
TI  - Characterization of selenoprotein P as a selenium supply protein.
AB  - Selenium (Se) is well known to be essential for cell culture when using a serum
      free medium, but not when a medium containing serum is used. This finding
      suggests that serum contains some usable form of Se. To identify the Se-supplier,
      T-lymphoma (Jurkat) cells were cultured for 3 days in the presence of human serum
      immunodepleted of Se-containing serum protein, selenoprotein P or extracellular
      glutathione peroxidase. The Se-dependent enzyme activities (glutathione
      peroxidases and thioredoxin reductase) and Se content within the cells markedly
      decreased only when cultured with selenoprotein P-depleted serum. Compared with
      other Se-containing proteins, the addition of purified selenoprotein P to the
      selenoprotein P-depleted serum or a serum-free medium was the most effective for
      the recovery of cellular glutathione peroxidase activity (index of Se status).
      These results suggest that selenoprotein P functions as a Se-supply protein,
      delivering Se to the cells.

PMID- 12423376
TI  - The search for animal models of epileptogenesis and pharmacoresistance: are there
      biologic barriers to simple validation strategies?

PMID- 12423377
TI  - Voltage-gated sodium channels in epilepsy.
AB  - Animal experiments, and particularly functional investigations on human
      chronically epileptic tissue as well as genetic studies in epilepsy patients and
      their families strongly suggest that some forms of epilepsy may share a
      pathogenetic mechanism: an alteration of voltage-gated sodium channels. This
      review summarizes recent data on changes of sodium channel expression, molecular
      structure and function associated with epilepsy, as well as on the interaction of
      new and established antiepileptic drugs with sodium currents. Although it remains
      to be determined precisely how and to what extent altered sodium-channel
      functions play a role in different epilepsy syndromes, future promising therapy
      approaches may include drugs modulating sodium currents, and particularly
      substances changing their inactivation characteristics.

PMID- 12423378
TI  - Calcium-dependent epileptogenesis in an in vitro model of stroke-induced
      "epilepsy".
AB  - PURPOSE: Stroke is the most common cause of acquired epilepsy. The purpose of
      this investigation was to characterize the role of calcium in the in vitro,
      glutamate injury-induced epileptogenesis model of stoke-induced epilepsy.
      METHODS: Fura-2 calcium imaging and whole-cell current clamp electrophysiology
      techniques were used to measure short-term changes in neuronal free intracellular
      calcium concentration and long-term alterations in neuronal excitability in
      response to epileptogenic glutamate injury (20 microM, 10 min) under various
      extracellular calcium conditions and in the presence of different glutamate
      receptor antagonists. RESULTS: Glutamate injury-induced epileptogenesis was
      associated with prolonged, reversible elevations of free intracellular calcium
      concentration during and immediately after injury and chronic hyperexcitability
      manifested as spontaneous recurrent epileptiform discharges for the remaining
      life of the cultures. Epileptogenic glutamate exposure performed in solutions
      containing low extracellular calcium, barium substituted for calcium, or N-methyl
      d-aspartate (NMDA)-receptor antagonists reduced the duration of intracellular
      calcium elevation and inhibited epileptogenesis. Antagonism of non-NMDA-receptor
      subtypes had no effect on glutamate injury-induced calcium changes or the
      induction epileptogenesis. The duration of the calcium elevation and the total
      calcium load statistically correlated with the development of epileptogenesis.
      Comparable elevations in neuronal calcium induced by non-glutamate receptor
      mediated pathways did not cause epileptogenesis. CONCLUSIONS: This investigation
      indicates that the glutamate injury-induced epileptogenesis model of stroke
      induced epilepsy is calcium dependent and requires NMDA-receptor activation.
      Further, these experiments suggest that prolonged, reversible elevations in
      neuronal free intracellular calcium initiate the long-term plasticity changes
      that underlie the development of injury-induced epilepsy.

PMID- 12423379
TI  - AIDA, a class I metabotropic glutamate-receptor antagonist limits kainate-induced
      hippocampal dysfunction.
AB  - PURPOSE: In the developing animal, intraperitoneal injections of kainic acid (KA)
      lead to a prolonged initial seizure followed by chronic recurrent seizures and
      long-term hippocampal dysfunction. We investigated whether the class I
      metabotropic glutamate receptor (mGluR) antagonist 1-aminoindan-1,5-dicarboxylic
      acid (AIDA) is neuroprotective in the KA model of epilepsy. METHODS: Immature
      rats aged postnatal day 20 (P20) and P30 were injected with fixed volumes of KA,
      KA + AIDA, AIDA, or saline. We monitored recurrent seizures. Thirty days later,
      we tested hippocampal function with the Morris water-maze test or prepared
      hippocampal slices to record extracellularly evoked and spontaneous potentials
      from the CA1 area. In a third group, we performed neuronal counts. RESULTS: In
      both age groups, acute seizures were similar in KA and KA + AIDA groups. Rare
      spontaneous recurrent seizures occurred only in KA-injected rats. The KA P20
      group performed significantly worse than controls in the water-maze test. The KA
      + AIDA group showed impaired performance on day 1, but learning improved
      substantially, reaching control values in the remaining 3 days. The P30 KA rats
      performed worse than controls on all trial days, whereas the KA + AIDA rats
      improved by day 3, but did not reach control values. Electrophysiologic
      recordings showed small but consistent differences between KA and control
      animals, suggestive of an adaptive modification in the gamma-aminobutyric acid
      (GABA)ergic system, reversed by AIDA. On histology, we observed a loss of CA1
      interneurons in both ages. Cell loss was reversed by the use of AIDA.
      CONCLUSIONS: Blockade of the class I mGluR during KA-induced seizures in the
      developing brain limits seizure-induced hippocampal dysfunction.

PMID- 12423380
TI  - Regional expression of multidrug resistance genes in genetically epilepsy-prone
      rat brain after a single audiogenic seizure.
AB  - PURPOSE: The multidrug resistance (mdr) gene family encodes the drug transport
      macromolecule P-glycoprotein (P-gp), which contributes to the functionality of
      the blood-brain barrier. Recent evidence suggests that P-gp-mediated drug
      extrusion may play a facilitatory role in refractory epilepsy. We investigated
      the regional expression of mdr genes in genetically epilepsy-prone rat (GEPR)
      brain after a single audiogenic seizure. METHODS: Three groups of adult male
      GEPRs (n = 5/group) were exposed to a seizure-inducing audiogenic stimulus and
      killed at 4 h, 24 h, and 7 days thereafter. A further group (n = 5) served as a
      stimulus-naive control. Expression of mdr1a and mdr1b in distinct anatomic brain
      regions (cortex, midbrain, pons/medulla, hippocampus) was determined by
      quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) in the
      presence of competitive internal standards. RESULTS: When compared with control,
      mdr1a expression in cortex and midbrain was significantly (p < 0.05) increased at
      24 h after a single audiogenic seizure. Cortical mdr1a expression remained
      elevated at 7 days after stimulus. In contrast, mdr1a expression in pons/medulla
      and hippocampus was unchanged. The mdr1b isoform was quantifiable in hippocampus
      alone and not influenced by seizure activity. CONCLUSIONS: These findings suggest
      that acute seizures in the GEPR can induce the expression of mdr genes. The
      pattern of increased expression appears to follow the anatomic pathway of
      audiogenic seizures in these animals, with initiation in the midbrain and
      propagation to the cortex. Further studies are required to investigate the
      effects of recurrent seizure activity and to characterise mdr expression in other
      experimental seizure models.

PMID- 12423381
TI  - Systemic overexpression of the alpha 1B-adrenergic receptor in mice: an animal
      model of epilepsy.
AB  - PURPOSE: A lack of selective alpha1-adrenergic receptor (alpha1-ARs) agonists and
      antagonists has made it difficult to clarify the precise function of these
      receptors in the CNS. We recently generated transgenic mice that overexpress
      either wild-type or a constitutively active mutant alpha 1B-AR in tissues that
      normally express the receptor. Both wild-type and mutant mice showed an age
      progressive neurodegeneration with locomotor impairment and probable stress
      induced motor events, which can be partially reversed by alpha 1-AR antagonists.
      We hypothesized that the wild-type and mutant mice may exhibit spontaneous
      epileptogenicity as compared with normal (nontransgenic) mice. METHODS: Normal,
      wild-type, and mutant mice were studied. Twenty mice (1 year old) underwent
      prolonged video-EEG monitoring over a 4-week period. Raw EEG data were blindly
      analyzed by visual inspection for the presence of interictal and ictal epileptic
      activities. RESULTS: During the acute postoperative period (< or = 3 days), both
      wild-type (26.1 +/- 8.07 spikes/day) and mutant mice (116.87 +/- 55.13) exhibited
      more frequent interictal spikes than did normal mice (2.17 +/- 0.75; p value,
      <0.05), but all three groups showed EEG and clinical seizures. During the later
      monitoring periods (>3 days), wild-type and mutant mice showed more frequent
      interictal spikes (15.44 +/- 4.07; p < 0.01; and 6.05 +/- 2.46; p < 0.05,
      respectively) as compared with normal mice (0.41 +/- 0.41), but only mutant mice
      had spontaneous clinical seizures (means +/- SEM). CONCLUSIONS: The selective
      overexpression of the alpha 1B-AR is associated with increased in vivo
      spontaneous interictal epileptogenicity and EEG/behavioral seizures. These
      results suggest a possible role (direct or indirect) for the alpha 1B-ARs in the
      development and expression of epileptogenicity.

PMID- 12423382
TI  - Relation between responsiveness to neurotransmitters and complexity of
      epileptiform activity in rat hippocampal CA1 neurons.
AB  - PURPOSE: Our previous works suggested that sensitivity of neurons with chaotic
      firing patterns to stimuli is significantly greater than that in neurons with
      periodic firing patterns, which shows that responsiveness of neurons may depend
      on the complexity of the firing series. This study was performed to determine the
      relation between responsiveness of the hippocampal CA1 neurons with epileptiform
      activity (EA) to neurotransmitters and their complexity of firing series.
      METHODS: Firing series of CA1 neurons were recorded extracellularly in rat
      hippocampal slice. Approximate entropy was used to describe the complexity of the
      interspike interval (ISI) series. EA was induced by local application of
      penicillin (1,000 IU/ml). The change of firing rate induced by neurotransmitters
      (glutamate and gamma-aminobutyric acid) was compared with that of the degree of
      complexity of ISI series in the process of EA. RESULTS: The excitatory responses
      to glutamate and the inhibitory responses to gamma-aminobutyric acid in CA1
      neurons appeared to be decreased during the process of penicillin-induced EA.
      However, during this same process, the approximate entropy of the ISI series also
      was decreased significantly. CONCLUSIONS: The results suggest that the reduced
      responses to neurotransmitters of the CA1 neurons appear to be closely related to
      the onset of EA. Furthermore, these neurons show that the changes in
      responsiveness are closely parallel to the decrease of degree of complexity of
      firing series during penicillin epileptogenesis.

PMID- 12423383
TI  - Effects of fluoxetine and TFMPP on spontaneous seizures in rats with pilocarpine
      induced epilepsy.
AB  - PURPOSE: Fluoxetine is a selective serotonin [5-hydroxytryptamine (5-HT)]
      reuptake inhibitor (SSRI) commonly used to treat depression. Some uncontrolled
      clinical studies have reported that SSRIs increase seizures, but animal
      experiments with evoked-seizure models have suggested that SSRIs at therapeutic
      doses decrease seizure susceptibility. We tested the hypothesis that fluoxetine
      and trifluoromethylphenylpiperazine (TFMPP, a nonselective 5-HT-receptor agonist)
      reduce the frequency of spontaneous motor seizures in pilocarpine-treated rats.
      METHODS: Fluoxetine (20 mg/kg) and TFMPP (5 mg/kg) were administered to rats with
      pilocarpine-induced epilepsy. Phenobarbital (PB; 10 mg/kg) was a positive
      control, and saline (i.e., 0.5 ml) controlled for the injection protocol. Each
      rat received each treatment (intraperitoneally) once per day for 5 consecutive
      days with 1 week between treatments. Rats were continuously video-monitored for
      the last 72 h of each treatment. RESULTS: When compared with saline over the
      entire 72-h observation period, PB and fluoxetine treatment, but not TFMPP,
      reduced the spontaneous-seizure rate. Plots of magnitude of the drug effect as a
      function of seizure frequency after saline treatment revealed larger drug effects
      for fluoxetine and PB in the rats with the highest control seizure rate. When the
      data from the five rats with the highest seizure frequency in saline were
      analyzed for the first 6 h after treatment, TFMPP also significantly reduced
      seizure frequency. CONCLUSIONS: Animal models with spontaneous seizures can be
      used to screen potential antiepileptic drugs, and fluoxetine and TFMPP reduce
      spontaneous seizures in the pilocarpine model of temporal lobe epilepsy.

PMID- 12423384
TI  - Epilepsy patients treated with antiepileptic drug therapy exhibit compromised
      ocular perfusion characteristics.
AB  - PURPOSE: Reduced cerebral blood flow and decreased cerebral glucose metabolism
      have been identified in patients with epilepsy treated with antiepileptic drug
      (AED) therapy. The purpose of this study was to determine whether ocular
      haemodynamics are similarly reduced in patients with epilepsy treated with AEDs.
      METHODS: Scanning laser Doppler flowmetry was used to measure retinal capillary
      microvascular flow, volume, and velocity in the temporal neuroretinal rim of 14
      patients diagnosed with epilepsy (mean age, 42.0 +/- 0.9 years). These values
      were compared with those of an age- and gender-matched normal subject group (n =
      14; mean age, 41.7 +/- 0.3 years). Student's unpaired two-tailed t tests were
      used to compare ocular blood-flow parameters between the epilepsy and normal
      subject groups (p < 0.05; Bonferroni corrected). RESULTS: A significant reduction
      in retinal blood volume (p = 0.001), flow (p = 0.003), and velocity (p = 0.001)
      was observed in the epilepsy group (13.52 +/- 3.75 AU, 219.14 +/- 76.61 AU, and
      0.77 +/- 0.269 AU, respectively) compared with the normal subject group (19.02 +/
      5.11 AU, 344.03 +/- 93.03 AU, and 1.17 +/- 0.301 AU, respectively). Overall, the
      percentage mean difference between the epilepsy and normal groups was 36.31% for
      flow, 28.92% for volume, and 34.19% for velocity. CONCLUSIONS: Patients with
      epilepsy exhibit reduced neuroretinal capillary blood flow, volume, and velocity
      compared with normal subjects. A reduction in ocular perfusion may have
      implications for visual function in people with epilepsy.

PMID- 12423385
TI  - Patients treated with vigabatrin exhibit central visual function loss.
AB  - PURPOSE: To investigate visual function in the central 10 degrees in patients who
      have undergone vigabatrin (VGB) antiepileptic drug (AED) therapy with the aim of
      identifying a clinical regimen for assessing central visual function. METHODS:
      The sample comprised 12 epilepsy patients (mean age, 38.6 +/- 11.7 years) who had
      been treated with VGB (either as monotherapy or polytherapy). A number of central
      visual-function tests were carried out for each eye, including high-contrast
      LogMAR visual acuity, short-wavelength automated perimetry (SWAP 10-2), spatial
      contrast sensitivity (CSV-1000), and Farnsworth-Munsell (FM) 100-hue colour
      discrimination. RESULTS: The group mean cumulative VGB dose was 5,086 +/- 3,245
      g. The average SWAP 10-2 mean deviation (MD) for the group was -3.24 +/- 3.23 dB;
      14 eyes of eight patients showed defects (range, -1.62 to -9.46 dB). The square
      root of the group mean total error score for FM 100-hue was 7.42 +/- 3.84; nine
      eyes of five patients were classified as abnormal with an unsolved colour axis
      suggestive of complex drug interactions. For contrast sensitivity, 15 eyes of
      eight patients yielded abnormal results in one or more spatial frequencies.
      Defects were more prominent at higher spatial frequencies. Overall, four patients
      had defects in all three visual-function tests, six patients had mixed defects,
      and two patients were normal. CONCLUSIONS: Visual-function deficits in epilepsy
      patients treated with VGB are present in the central 10 degrees of the retina. We
      recommend a battery of investigations, including SWAP 10-2 and spatial contrast
      sensitivity testing, to assess central visual function.

PMID- 12423386
TI  - Regional analyses of CNS microdialysate glucose and lactate in seizure patients.
AB  - PURPOSE: To correlate glucose (and lactate) results obtained from microdialysate
      to recent studies suggesting that glucose transporter activity may be
      significantly altered in seizures. METHODS: We used a fluorometric technique to
      quantify glucose and lactate levels in microdialysates collected from two to four
      depth electrodes implanted per patient in the temporal and frontal lobes of a
      series of four patients. Hour-by-hour and day-to-day changes in brain glucose and
      lactate levels at the same site were recorded. Additionally we compared regional
      variations in lactate/glucose ratios around the predicted epileptogenic region.
      RESULTS: Lactate/glucose ratios in the range of 1-2:1 were the most commonly
      seen. When the lactate/glucose ratio was <1:1, we typically observed a relative
      increase in local glucose concentration (rather than decreased lactate),
      suggesting increased transport, perhaps without increased glycolysis. In some
      sites, lactate/glucose ratios of 3:1-15:1 were seen, suggesting that a
      circumscribed zone of inhibition of tricarboxylic acid cycle activity may have
      been locally induced. In these dialysates, collected from probes closer to the
      epileptogenic region, the large increase in lactate/glucose ratios was a result
      of both increased lactate and reduced glucose levels. CONCLUSIONS: We conclude
      that regional variations in brain extracellular glucose concentrations may be of
      greater magnitude than previously believed and become even more accentuated in
      partial seizure patients. Data from concomitant assays of microdialysate lactate
      and glucose may aid in understanding cerebral metabolism.

PMID- 12423387
TI  - Hyperventilation-induced high-amplitude rhythmic slowing with altered awareness:
      a video-EEG comparison with absence seizures.
AB  - PURPOSE: Hyperventilation-induced high-amplitude rhythmic slowing (HIHARS) in
      children may be associated with clinical episodes of altered awareness. The
      presence of automatisms has been proposed as a distinguishing feature that helps
      to differentiate absence seizures from nonepileptic causes of decreased
      responsiveness. This retrospective, controlled, video-EEG study compared the
      clinical characteristics of episodes of HIHARS with loss of awareness with those
      of absence seizures. METHODS: The database of a tertiary Children's Hospital was
      searched for patients studied between April 1993 and April 1997 who had at least
      one episode of HIHARS with loss of awareness. The absence control group was
      obtained by selecting the next patient, after an HIHARS study subject, who met
      the following criteria: (a) had at least one absence seizure occurred during
      hyperventilation in the EEG recording, and (b) had a diagnosis of idiopathic
      generalized epilepsy. The video-EEG and medical histories of all patients were
      reviewed and summarized. RESULTS: We reviewed video-EEG recordings of 77 episodes
      of HIHARS with loss of awareness from 22 children and 107 absence seizures during
      hyperventilation from 22 children. Eye opening and eyelid flutter were seen more
      frequently in absence seizures, whereas fidgeting, smiling, and yawning occurred
      more frequently during HIHARS episodes. Arrest of activity, staring, and oral and
      manual automatisms were observed in both groups. CONCLUSIONS: Automatisms are
      common in both HIHARS and absence seizures. Yawning, smiling, and particularly
      fidgeting occur more commonly and eye opening and eyelid flutter less commonly in
      HIHARS. However, episodes of HIHARS with loss of awareness clinically mimic
      absence seizures, and these conditions can be distinguished reliably only by EEG.

PMID- 12423388
TI  - Various findings in surgically treated epilepsy patients with dysembryoplastic
      neuroepithelial tumors in comparison with those of patients with other low-grade
      brain tumors and other neuronal migration disorders.
AB  - PURPOSE: To determine whether dysembryoplastic neuroepithelial tumors (DNTs) that
      belong to the neuronal migration disorders (NMDs) are to be classified with them
      or with "other low-grade brain tumors" regarding several etiologic, clinical,
      magnetic resonance imaging (MRI), and EEG findings. METHODS: These findings of 21
      DNT patients were compared with those of 13 consecutive patients with other low
      grade brain tumors and 41 NMD patients. RESULTS: The result is absolutely clear:
      nearly all findings in DNT patients (complications during pregnancy, birth, the
      newborn period and the postnatal period, age at first seizure, epileptic
      syndrome, seizure type, febrile seizures, retarded milestones, intellectual and
      neurologic deficits, MRI, interictal and ictal EEG findings) being similar or in
      agreement with those of other low-grade brain tumors, not with those of other
      NMDs. CONCLUSIONS: Regarding various clinical features including surgery outcome,
      MRI, and EEG findings, DNTs should be classified with the other low-grade brain
      tumors, rather than with NMDs.

PMID- 12423389
TI  - Interictal epileptiform discharges relate to 1H-MRS-detected metabolic
      abnormalities in mesial temporal lobe epilepsy.
AB  - PURPOSE: To examine whether the distribution of interictal epileptiform
      discharges (IEDs) recorded from foramen ovale electrodes (FOEs) correlates with
      metabolite levels in medial structures of the temporal lobes in patients with
      mesial temporal lobe epilepsy (MTLE). METHODS: We studied 34 patients with MTLE.
      The lateralization ratio of IEDs was calculated after counting IEDs recorded from
      FOEs during prolonged video-EEG monitoring. Metabolite ratio between N
      acetylaspartate (NAA) and creatine (Cr) was calculated in each medial temporal
      structure. The correlation between the lateralization ratio of IEDs and metabolic
      ratio was evaluated. RESULTS: The asymmetry indexes of IEDs correlated with the
      asymmetry index of NAA/Cr ratio in the medial temporal structure (rho = -0.380; p
      = 0.027). Analysis of IEDs and metabolite ratio revealed a significant inverse
      relation in the contralateral side to the major epileptogenic focus (rho = 
      0.360; p = 0.037); however, this significance was not present in the ipsilateral
      side (rho = -0.018; p = 0.921). CONCLUSIONS: There is a correlation between the
      neuronal dysfunction or damage detected by MRS and the epileptic activity in the
      contralateral medial temporal structure. Our results suggest that the
      pathomechanism underlying the contralateral reduction of NAA/Cr ratio, frequently
      observed in patients with MTLE, might be related to the process of
      epileptogenesis generating the independent contralateral IEDs.

PMID- 12423390
TI  - Epileptic spikes: magnetoencephalography versus simultaneous
      electrocorticography.
AB  - PURPOSE: To test the sensitivity of extracranial magnetoencephalography (MEG) for
      epileptic spikes in different cerebral sites. METHODS: We simultaneously recorded
      MEG and electrocorticography (ECoG) by using subdural electrodes with 1-cm
      interelectrode distances for one patient with lateral frontal epilepsy and one
      patient with basal temporal epilepsy. We analyzed MEG spikes associated with ECoG
      spikes and compared the maximal amplitude and number of electrodes involved. We
      estimated and evaluated the locations and moments of the equivalent current
      dipoles (ECDs) of MEG spikes. RESULTS: In patient 1, MEG detected 100 (53%) of
      188 ECoG lateral frontal spikes, including 31 (46%) of 67 spikes that activated
      three subdural electrodes. MEG spike amplitudes correlated with ECoG spike
      amplitudes and the number of electrodes activated (p < 0.01). ECDs were
      perpendicular to the superior frontal sulcus. In patient 2, MEG detected 31 (26%)
      of 121 ECoG basal temporal spikes, but none that activated only three subdural
      electrodes. ECDs were localized in the entorhinal and parahippocampal gyri,
      oriented perpendicular to those basal temporal cortical surfaces. The ECD
      strength was 136.6 +/- 71.5 nAm in the frontal region, but 274.5 +/- 150.6 nAm in
      the temporal region (p < 0.01). CONCLUSIONS: When lateral frontal ECoG spikes
      extend >3 cm2 across the fissure, MEG can detect >50%, correlating with spatial
      activation and voltage. In the basal temporal region, MEG requires higher
      amplitude discharges over a more extensive area. MEG shows a significantly higher
      sensitivity to lateral convexity epileptic discharges than to discharges in
      isolated deep basal temporal regions.

PMID- 12423391
TI  - Interrater reliability among epilepsy centers: multicenter study of epilepsy
      surgery.
AB  - PURPOSE: To measure the interrater reliability of presurgical testing and
      surgical decisions among epilepsy centers. METHODS: Seven centers participating
      in an ongoing, prospective multicenter study of resective epilepsy surgery agreed
      to conform to a detailed protocol regarding presurgical evaluation and surgery.
      To assess quality assurance, each center independently reviewed 21 randomly
      selected surgical cases for preoperative study lateralization and localization,
      and surgical decisions. Interrater reliability was assessed by using intraclass
      correlation coefficients (ICCs), validated for use with multiple raters, and
      calculated in a two-way random model based on absolute agreement. RESULTS:
      Agreement for ICC values: > or = 0.75, excellent; 0.60-0.74, good; 0.40-0.59,
      fair; < or = 0.39, poor. One center was excluded for missing data. Agreement was
      excellent for extracranial EEG lateralization (0.8039), magnetic resonance
      imaging (MRI) lateralization (0.9521) and localization (0.9130), Wada
      lateralization (0.9453), and intracranial EEG localization (0.7905). Agreement
      was good for extracranial EEG localization (0.7384) and neuropsychological
      testing lateralization (0.7178) and localization (0.6891). Consensus about the
      decision to perform intracranial monitoring was fair (0.5397), in part reflecting
      one center's tendency toward intracranial monitoring. Overall agreements on
      whether to perform surgery (0.8311) and specific surgery recommended (0.8164)
      were excellent. CONCLUSIONS: High interrater reliability among six epilepsy
      centers was present for interpretation of most components of presurgical testing.
      Although consensus for the decision to perform intracranial monitoring was only
      fair, agreements for the ultimate decision about resective surgery and specific
      choice of resection were excellent. We believe that this study demonstrates the
      feasibility of implementing multicenter protocols for neurologic management,
      especially those involving localization, as well as protocols combining study
      results with clinical decision making.

PMID- 12423392
TI  - Systematic review and meta-analysis of incidence studies of epilepsy and
      unprovoked seizures.
AB  - PURPOSE: To evaluate the methodology of incidence studies of epilepsy and
      unprovoked seizures and to assess the value of their findings by summarizing
      their results. METHODS: A Medline literature search from January 1966 to December
      1999 was conducted. In each selected study, key methodologic items such as case
      definition and study design were evaluated. Furthermore, a quantitative meta
      analysis of the incidence data was performed. RESULTS: Forty incidence studies
      met the inclusion criteria. There was considerable heterogeneity in study
      methodology, and the methodologic quality score was generally low. The median
      incidence rate of epilepsy and unprovoked seizures was 47.4 and 56 per 100,000,
      respectively. The age-specific incidence of epilepsy was high in those aged 60
      years or older, but was highest in childhood. Males had a slightly higher
      incidence of epilepsy (median, 50.7/100,000) than did females (median,
      46.2/100,000), and partial seizures seemed to occur more often than generalized
      seizures. Developing countries had a higher incidence rate of epilepsy (median,
      68.7/100,000) than did industrialized countries (median, 43.4/100,000). Similar
      results were found for unprovoked seizures. The incidence of epilepsy over time
      appears to decrease in children, whereas it increases in the elderly.
      CONCLUSIONS: The age-specific incidence of epilepsy showed a bimodal distribution
      with the highest peak in childhood. No definitive conclusions could be reached
      for the incidence of unprovoked seizures and other specific incidence rates of
      epilepsy. More incidence studies with an adequate study methodology are needed to
      explore geographic variations and time trends of the incidence of epilepsy and
      unprovoked seizures.

PMID- 12423393
TI  - Models for epilepsy and epileptogenesis: report from the NIH workshop, Bethesda,
      Maryland.
AB  - PURPOSE: The workshop explored the current problems, needs, and potential
      usefulness of existing methods of discovery of new therapies to treat epilepsy
      patients. Resistance to medical therapy (pharmacoresistance) and the development
      of epilepsy (epileptogenesis) are recognized as two of the major problems in
      epilepsy treatment today. At the same time, there is growing awareness that the
      development of new therapies has slowed, a trend that has economic and scientific
      roots. To move toward new and more effective therapies, novel approaches to
      therapy discovery are needed. METHODS: A workshop was held in March 2001 with the
      charge to develop a plan to move the exploration and discovery process forward.
      Participants from academia, government, and industry reviewed the current status
      of epilepsy therapy and explored the identification of potential new therapies.
      RESULTS: At the end of the 2-day meeting, the panel made a series of
      recommendations. The two major recommendations were (a) to establish a means for
      continuing the examination of new approaches to therapy discovery, and (b) to
      identify models and approaches to therapy discovery that may identify treatments
      that are more successful than those available. Further recommendations were made
      to support the development of technology (miniaturization, computerization, video
      monitoring, etc.) to facilitate the use of the new models and to identify the
      mechanisms of therapy success and failure. CONCLUSIONS: Understanding the
      epidemiology of therapy resistance and providing support for new approaches to
      therapy development were identified as key issues for introduction of new and
      more effective treatments.

PMID- 12423394
TI  - Acute pancreatitis coincident with valproate use: a critical review.
AB  - PURPOSE: Acute pancreatitis has been associated with a number of medications,
      including valproate (VPA). Valproate-coincident pancreatitis is uncommon and is
      usually associated with other risk factors; however, the United States Food and
      Drug Administration has issued a box warning for risk of acute pancreatitis with
      VPA products. We reviewed cases of pancreatitis in VPA-treated patients from the
      clinical database of VPA/divalproex trials and compared the incidence of elevated
      amylase levels between VPA- and placebo-treated patients. METHODS: Report rates
      of acute pancreatitis coincident with VPA use in 34 clinical trials were
      calculated. Incidence rates of amylase elevations above the normal range in three
      clinical placebo-controlled migraine trials were compared between VPA- and
      placebo-treated patients. RESULTS: Among 3,007 VPA-treated patients in 34
      clinical trials, two reports of pancreatitis were considered by investigators to
      be probably related to VPA. Both patients recovered. Similar rates of amylase
      elevations were observed in VPA- (5.9%) and placebo-treated (6.1%) patients in
      the three migraine headache trials. CONCLUSIONS: VPA-coincident acute
      pancreatitis is uncommon and idiosyncratic. Checking amylase levels in the
      absence of other clinical signs and symptoms provides little value for predicting
      pancreatitis. Physicians should be guided by clinical symptoms of pancreatitis to
      identify cases.

PMID- 12423395
TI  - Partial epilepsy manifesting atonic seizure: report of two cases.
AB  - PURPOSE: Atonic seizures are commonly seen in patients with generalized epilepsy
      but only infrequently in patients with partial epilepsy. Clinically generalized
      atonic seizures as a partial epilepsy have not been studied in detail with
      video/EEG monitoring. Here we describe the clinical and physiologic
      characteristics of atonic seizures due to partial epilepsy and discuss the
      underlying mechanism. METHODS: Two patients with partial epilepsy manifesting
      atonic seizures, one with frontal lobe epilepsy (FLE) and the other with parietal
      lobe epilepsy (PLE), were reported. The long-term video/EEG monitoring, magnetic
      resonance imaging (MRI), and interictal fluorodeoxyglucose-positron emission
      tomography (FDG-PET) were investigated in each patient. RESULTS: Paroxysmal
      diminution of muscle tone mainly involved the axial muscles in both patients. In
      contrast with the abrupt falls seen in patients with Lennox-Gastaut syndrome, the
      falls in these patients were slow, taking 2-5 s to fall down. Ictal EEG records
      showed low-voltage fast activity in the frontocentral area followed by repetitive
      spikes at the midline frontocentral area in the patient with FLE, and rhythmic
      spikes in the left central area in the patient with PLE. Interictal FDG-PET
      disclosed hypometabolic regions consistent with the clinical and EEG findings.
      CONCLUSIONS: Slow falls might be a feature of atonic seizures in partial
      epilepsy. Long-lasting atonia in partial epilepsy could be due to either one of
      the following two possible mechanisms: (a) epileptic activities arising from the
      negative motor area, of which 50-Hz electric stimulation causes motor inhibition,
      or (b) sustained atonia with successive electromyogram (EMG) silent periods
      caused by epileptic discharges arising from the inhibitory area of the primary
      sensorimotor area.

PMID- 12423396
TI  - Ictal vomiting in association with left temporal lobe seizures in a left
      hemisphere language-dominant patient.
AB  - Ictal vomiting is considered a localizing sign indicating nondominant
      lateralization in patients with partial seizures of temporal lobe origin. We
      report a case of ictal vomiting associated with left temporal seizure activity in
      a left hemisphere language-dominant patient with a left mesial temporal glioma.
      Bilateral mesial temporal depth electrodes helped verify seizure lateralization.
      Surgery consisting of tumor resection and a left anterior temporal lobectomy and
      amygdalohippocampectomy resulted in freedom from seizures and episodes of
      vomiting. This case indicates that ictal vomiting can occur as a manifestation of
      left temporal onset seizures in left hemisphere-dominant patients.

PMID- 12423397
TI  - Electrical status epilepticus of sleep in association with topiramate.

PMID- 12423398
TI  - Midline spikes in children and clinical correlations.

PMID- 12423401
TI  - Dental gold alloys and contact allergy.
AB  - Contact allergy to gold as demonstrated by patch testing is very common among
      patients with eczematous disease and seems to be even more frequent among
      patients with complaints from the oral cavity. There is a positive correlation
      between gold allergy and the presence of dental gold. Gold allergy is often found
      in patients with non-specific stomatitides as well as in those with lichenoid
      reactions or with only subjective symptoms from the oral cavity. The therapeutic
      effect of substituting other dental materials for gold alloys is conspicuous in
      casuistic reports but less impressive in larger patient materials. The amount of
      dental gold is correlated qualitatively and quantitatively to the blood level of
      gold and the effects if any of circulating blood gold are unknown. There is
      clearly a need for prospective studies in the field and gold sodium thiosulfate
      is considered an important item in the dental series for patch testing.

PMID- 12423402
TI  - An epidemic of allergic contact dermatitis due to epilating products.
AB  - Over a period of 19 months, 33 cases of acute allergic contact dermatitis from
      Veet epilating waxes and/or the accompanying tissue (Reckitt Benckiser, Massy,
      France) were observed in France and Belgium. The lesions started on the legs and
      spread to other parts of the body, especially the face, and were sometimes so
      severe that hospitalization and/or systemic corticosteroids were required.
      Primary sensitization occurred as early as after the first application in several
      patients. Patch tests were performed in 26 of the patients and produced strong
      positive reactions to the tissue (25 times) and/or the wax (13 times). The
      allergenic culprits in the wax were modified-colophonium derivatives (colophonium
      in the standard series testing negatively in all except 4 patients), while
      methoxy PEG-22/dodecyl glycol copolymer and to a lesser degree lauryl alcohol
      turned out to be the main causal allergens in the tissue.

PMID- 12423403
TI  - The association between contact allergy and hand eczema in 2 cross-sectional
      surveys 8 years apart.
AB  - Hand eczema is a recurrent chronic skin disease related to contact allergy and
      atopic dermatitis. When possible, efforts should be redoubled to eliminate
      provoking factors. Our objective was to assess changes in the prevalence of self
      reported hand eczema and to evaluate the association between contact allergy and
      hand eczema among adult Danes before and after nickel exposure regulation in
      Denmark. In 1990 and 1998, random samples of 15-41-year-old persons were examined
      in 2 cross-sectional studies of the general population in Copenhagen, Denmark.
      The studies included questionnaires, patch and prick testing. From 1990 to 1998
      the prevalence of a history of hand eczema increased significantly. This increase
      did not appear to be fully explained by changes in the prevalence of flexural
      eczema, prick test reactivity, patch test reactivity, and nickel allergy. In
      1990, nickel allergy and allergic nickel contact dermatitis were significantly
      associated with a history of hand eczema among women. In 1998, these associations
      were not found. It can be concluded that, from 1990 to 1998, the prevalence of a
      history of hand eczema rose significantly. It was indicated that it might be
      possible to prevent the hand eczema related to nickel allergy by exposure
      regulation, public education or both.

PMID- 12423404
TI  - Further important sensitizers in patients sensitive to fragrances.
AB  - The aim of this study was to determine the frequency of responses to selected
      fragrance materials in consecutive patients patch tested in 6 dermatological
      centres in Europe. 1855 patients were evaluated with the 8% fragrance mix (FM)
      and 14 other frequently used well-defined fragrance chemicals (series I). Each
      patient was classified regarding a history of adverse reactions to fragrances:
      certain, probable, questionable, none. Reactions to FM occurred in 11.3% of the
      subjects. The 6 substances with the highest reactivity following FM were Lyral
      (2.7%), citral (1.1%), farnesol P (0.5%), citronellol (0.4%), hexyl cinnamic
      aldehyde (0.3%), and coumarin (0.3%). 41 (2.2%) of the patients reacted only to
      materials of series I and not to FM. 6.6% of 1855 patients gave a history of
      adverse reactions to fragrances which was classified as certain. This group
      reacted to FM only in 41.1%, to series I and FM in 12.0% and to series I only in
      7.2%. 74.3% of the 39 patients reacting to both FM and 1 of the materials of
      series I had any type of positive fragrance history, which was significantly
      higher in comparison to those with isolated reactions to series I (53.6% of 41),
      p = 0.04. The study identified further sensitizers relevant for patch testing of
      patients with contact dermatitis, of which Lyral is the most important single
      chemical.

PMID- 12423405
TI  - Dosage considerations in patch testing with liquid allergens.
AB  - This study examines reproducibility of water and ethanol drop volumes from
      plastic squeeze dropper bottles, examines the difference in drop volumes between
      commonly used liquid patch test solutions, and evaluates the volumes of water and
      ethanol needed to saturate Finn and IQ Chamber filter papers. 2 plastic squeeze
      dropper bottles recommended for use in patch testing have poor reproducibility
      compared to other bottles tested. 3 aqueous allergens tested (formaldehyde 1%,
      methylchloroisothiazolinone/methylisothiazolinone 0.01%, and dimethylol
      dihydroxyethyleneurea 4.5%) have drop volumes equivalent to water. Smaller drop
      volumes are produced by ethanol, hydrocortisone butyrate 1% in ethanol,
      cocamidopropyl betaine 1% a.q., and propylene glycol 30% a.q. Filter paper
      saturation volumes using distilled water are 16-19 micro L in standard Finn
      Chambers and 29-35 micro L in IQ Chambers. Ethanol saturation volumes are
      slightly lower. Previously recommended volumes of application for aqueous
      allergens of 15 micro L for standard Finn Chambers and 25 micro L for IQ Chambers
      (slightly below the filter paper saturation points) are appropriate. Selection of
      dropper bottles should consider drop volume reproducibility, differing drop
      volumes for different allergens, and the patch test chamber system being used.

PMID- 12423406
TI  - Hand dermatitis as an unsuspected presentation of textile dye contact
      sensitivity.
AB  - The aim of this study was to evaluate disperse dye sensitization in patients with
      hand dermatitis. From January 1996 to December 2000, we identified 130 patients
      with hand dermatitis reacting to one of the 7 dyes included in our standard
      series. In 82 subjects the dermatitis was localized to the hands alone, whereas
      48 patients had lesions both on the hands and on other skin sites. Disperse Blue
      dyes, and Disperse Orange 3 were the most common sensitizers. Among the 13
      subjects allergic to disperse dyes alone, we found 3 cases of occupational
      allergic contact dermatitis, 1 child with atopic dermatitis worsening after the
      use of synthetic fibre garments, 4 subjects affected by clothing dermatitis, and
      5 individuals occupationally exposed to irritants with a dermatitis involving the
      hands alone. In the latter, the hands may represent a 'locus minoris
      resistentiae', and both induction and elicitation of contact sensitization could
      be caused by impaired barrier function at a skin site repeatedly exposed to
      sensitizing garments.

PMID- 12423407
TI  - Dose-time relationships for elicitation of contact allergy to para
      phenylenediamine.
AB  - Skin-sensitizing chemicals exhibit dose-response relationships for the
      elicitation of contact dermatitis. Previously, considerable work has been carried
      out in which the elicitation of allergic skin reaction has been examined as a
      function of the applied concentration. However, the relationship between exposure
      time, dose and response has not been explored in any depth. The present work has
      extended our initial assessment of the relationship between both exposure time
      and concentration for para-phenylenediamine (PPD) in a group of 19 PPD-allergic
      volunteers. The results clearly demonstrate that a relationship exists between
      both exposure time and concentration. Positive responses to PPD were directly
      proportional to exposure time: at 5 min 16% responded; at 15 min, 38%; at 30 min,
      50%; and at 120 min, 69%. A similar direct relationship was found between
      concentration of PPD and response: after 120 min, 22% of patients had responded
      to 0.01%, and 69% to 1% PPD. All exposures for 1 and 2 min were negative.
      Subsequent evaluation using repeated 5 min open application testing demonstrated
      a cumulative effect, as after 8 days 39% of the panel reacted, more than double
      the number that reacted to a single occluded 5-min treatment. It was noted that
      there was marked subject variability in exposure time and dose required to elicit
      an allergic response. These results are of relevance for the general
      interpretation of patch test data, especially with regard to risk assessment.

PMID- 12423408
TI  - Positive patch test reactions to celecoxib may be due to irritation and do not
      correlate with the results of oral provocation.
AB  - Nonsteroidal anti-inflammatory drugs (NSAIDs) are among those therapeutics most
      frequently causing pseudoallergic and sometimes allergic cutaneous adverse
      reactions. Coxibs preferentially inhibiting cyclooxygenase-2 are increasingly
      propagated as alternatives in NSAID-sensitive patients. We evaluated the
      tolerability of celecoxib in NSAID-sensitive patients. In 14 consecutive patients
      (6 males, 8 females, age 18-72 years), scratch and patch tests with homogenized
      Celebrex were performed, followed by single-blind, placebo-controlled oral
      provocation (maximal single dose: 200 mg; cumulative dose: 350 mg). 8 of the
      first 10 patients showed erythematous reactions to celecoxib on patch testing
      after 2 days with decrescendo kinetics between then and day 3. 9 patients with no
      history of NSAID intolerance showed similar reactions. When the patch tests were
      repeated with homogenized Celebrex at final concentrations of 5% and 10% in
      petrolatum, no reaction was observed in any patient. Subsequent oral provocation
      was tolerated without adverse effects by all individuals. We conclude that patch
      tests with high concentrations of celecoxib cause irritant reactions and do not
      correlate with the outcome of oral provocation tests. Therefore, these tests
      should be performed with lower concentrations of celecoxib (Celebrex). Celecoxib
      itself seems to be a valuable alternative drug in NSAID-sensitive patients.

PMID- 12423409
TI  - Latex sensitization in dental students using powder-free gloves low in latex
      protein:a cross-sectional study.
AB  - In Germany, employers must provide low-protein, powder-free gloves. This study
      was carried out to determine the current prevalence of latex sensitization in
      dental students using these gloves and to compare our results with a study of the
      same design dating from 1990/1991 at our university. A cross-sectional study was
      performed by questionnaire, prick testing and determination of specific IgE
      antibodies. 226 of 403 dental students underwent prick testing with a panel of 8
      aero-allergens, 1 commercially available latex extract and 5 high-ammonia
      accelerator-free latex fluids. 39 of 226 dental students (17.3%) had a positive
      prick test response to at least 1 of the 6 latex substances tested. The prick
      test positivity was similar in preclinical education (semester 1-6) and in
      clinical education (semester 7-10), at 17.1% and 17.4%, respectively. In 9 of 32
      persons with positive prick tests, specific IgE antibodies to latex could be
      detected. Within the past 10 years, prick test positivity increased from 8.7% to
      17.3%. 14 students (6.2%) reported a history of glove intolerance, 3 of them
      (1.3%) showing a positive prick test to latex. By the use of low-protein, powder
      free gloves less students with glove intolerance were observed. The observed
      reactions to between 1 and 3 of 6 latex substances tested may indicate a decrease
      in intensity and spectrum of sensitization. Additionally non-occupational
      sensitization may be of importance.

PMID- 12423410
TI  - Contact leukoderma secondary to occupational toluenediamine sulfate exposure.

PMID- 12423411
TI  - Allergic contact dermatitis from trideceth-2-carboxamide monoethanolamine (MEA)
      in a hair dye.

PMID- 12423412
TI  - Conjunctivitis and bronchial asthma: symptoms of contact allergy to 1,3,5-tris (2
      hydroxyethyl)-hexahydrotriazine (Grotan BK).

PMID- 12423413
TI  - Simultaneous contact sensitivity to hydroxystearic acid and C18-36 acid
      triglyceride in lip glosses.

PMID- 12423414
TI  - Occupational allergic contact dermatitis from falcarinol.

PMID- 12423415
TI  - Contact dermatitis from textile and dye allergens requires a high index of
      suspicion for diagnosis.

PMID- 12423416
TI  - Father and child with milk allergy and positive reactions to latex gloves on
      prick and use testing.

PMID- 12423417
TI  - Evaluation of cross-reactivity between budesonide and desonide.

PMID- 12423418
TI  - Paronychia in cashew nut industry workers.

PMID- 12423419
TI  - Active sensitization to para-tertiary-butylphenol-formaldehyde resin.

PMID- 12423420
TI  - Comparative testing with budesonide in petrolatum and ethanol in a standard
      series.

PMID- 12423422
TI  - Species differences in bradykinin receptor-mediated responses of the airways.
AB  - 1. Bradykinin (BK) is a nine amino acid peptide (Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe
      Arg) formed from the plasma precursor kininogen during inflammation and tissue
      injury. The actions of BK are mediated by G protein-coupled cell surface
      receptors, designated B1 and B2. 2. BK has a plethora of effects in the airways
      including bronchoconstriction, bronchodilation, stimulation of cholinergic and
      sensory nerves, mucus secretion, cough and oedema resulting from promotion of
      microvascular leakage. These airway effects are mediated in the main by the B2
      receptor subtype. 3. BK acts mainly indirectly, primarily through airway nerve
      activation, but also by the release of prostanoids, thromboxanes and nitric oxide
      (NO). 4. Airway responses to BK have been studied in detail in guinea-pigs, mice,
      sheep and rats. This review describes the effects of BK in these species and
      draws comparison with its effects in normal humans and patients with respiratory
      diseases. 5. Despite its many and varied effects in the airways of animals and
      man, the exact contribution of BK to airways disease remains unclear.

PMID- 12423423
TI  - Dual adrenergic control of in vivo choline levels in the mouse major salivary
      glands.
AB  - 1. The purpose of this study was to demonstrate that the adrenergic nervous
      system regulates the in vivo choline levels in the mouse major salivary glands.
      2. Methoxamine (alpha1-adrenoceptor agonist, 2.5-20 mg kg-1, s.c.) elevated
      choline levels dose-dependently and the effect of methoxamine (10 mg kg-1) was
      completely inhibited by the alpha-adrenoceptor antagonist phentolamine (5 mg kg
      1, i.p.) but not by the beta-adrenoceptor antagonist propranolol (3 mg kg-1,
      i.p.). 3. In contrast, isoprenaline (beta-adrenoceptor agonist 0.25-20 mg kg-1,
      s.c.) lowered choline levels and the effect of isoprenaline (2 mg kg-1) was
      inhibited by propranolol, but not by phentolamine. 4 Noradrenaline (1-4 mg kg-1,
      s.c.) manifested both the alpha- and beta-adrenergic actions depending on its
      dose. Noradrenaline at 1-2 mg kg-1, lowered choline levels and the effect of
      noradrenaline (1 mg kg-1) was inhibited by propranolol, but not by phentolamine.
      On the other hand, noradrenaline (4 mg kg-1) elevated choline levels and the
      effect was blocked by phentolamine, but not by propranolol. 5. Tyramine (5-80 mg
      kg-1, s.c.) elicited the release of noradrenaline from sympathetic nerve
      terminals and induced essentially the same effects on the choline levels as
      noradrenaline. Tyramine (10 mg kg-1) lowered choline levels and the effect was
      inhibited by propranolol, but not by phentolamine. However, tyramine (80 mg kg-1)
      elevated choline levels and the effect was inhibited by phentolamine, but not by
      propranolol. 6. These results suggest that choline levels in the salivary glands
      may be under separate alpha- and beta-adrenergic control and suggest a
      possibility that the neurotransmitter noradrenaline released for sympathetic
      nerve terminals can manage the dual control of choline levels in some autonomic
      organs in a characteristic dose-dependent manner.

PMID- 12423424
TI  - Partial agonistic activity of labetalol, the arylethanolamine, on beta 3
      adrenoceptors in the guinea-pig gastric fundus.
AB  - 1. The agonistic and antagonistic effects of labetalol, the alpha1- and beta
      adrenoceptor antagonist, were studied on beta3-adrenoceptors in the guinea-pig
      gastric fundus. 2. Labetalol caused a concentration-dependent relaxation with a
      pD2 value of 5.58 +/- 0.09 and an intrinsic activity of 0.64 +/- 0.06, which was
      not affected by pretreatment with both the selective beta1-adrenoceptor
      antagonist, (+/-)-atenolol (100 microM), and the selective beta2-adrenoceptor
      antagonist, (+/-)-butoxamine (100 microM). 3. However, the non-selective beta1-,
      beta2- and beta3-adrenoceptor antagonist, (+/-)-bupranolol (3-30 microM), shifted
      the concentration-response curve of labetalol to the right (pA2 value=5.97 +/-
      0.08). 4. In the presence of (+/-)-atenolol (100 microM) and (+/-)-butoxamine
      (100 microM), relaxations to catecholamines [(-)-isoprenaline, (-)-noradrenaline
      and (-)-adrenaline], to the selective beta3-adrenoceptor agonist, BRL37344, and
      to the non-conventional partial beta3-adrenoceptor agonist, (+/-)-CGP12177A, were
      weakly antagonized by labetalol (10 microM). 5. These results indicate that
      labetalol, the arylethanolamine, acts as a partial agonist on beta3-adrenoceptors
      in the guinea-pig gastric fundus.

PMID- 12423425
TI  - Effects of defibrotide, a novel oligodeoxyribonucleotide, on ischaemia and
      reperfusion injury of the rat liver.
AB  - 1. The purpose of this study was to investigate the protective effects of
      defibrotide, a single-stranded polydeoxyribonucleotide, on ischaemia-reperfusion
      injury to the liver using a rat model. 2. Ischaemia of the left and median lobes
      was created by total inflow occlusion for 30 min followed by 60 min of
      reperfusion. Hepatic injury was assessed by the release of liver enzymes (alanine
      transferase, ALT and lactic dehydrogenase, LDH). Hepatic oxidant stress was
      measured by superoxide production, lipid peroxidation and nitrite/nitrate
      formation. Leukocyte-endothelium interaction and Kupffer cell mobilization were
      quantified by measuring hepatic myeloperoxidase (MPO), polymorphonuclear
      leukocyte adherence to superior mesenteric artery (SMA) and immunostaining of
      Kupffer cell. 3. Defibrotide treatment resulted in a significant inhibition of
      postreperfusion superoxide generation, lipid peroxidation, serum ALT activity,
      serum LDH activity, MPO activity, serum nitrite/nitrate level, leukocyte
      adherence to SMA, and Kupffer cell mobilization, indicating a significant
      attenuation of hepatic dysfunction. 4. A significant correlation existed between
      liver ischaemia/reperfusion and hepatic injury, suggesting that liver
      ischaemia/reperfusion injury is mediated predominantly by generation of oxygen
      free radicals and mobilization of Kupffer cells. 5. We conclude that defibrotide
      significantly protects the liver against liver ischaemia/reperfusion injury by
      interfering with Kupffer cell mobilization and formation of oxygen free radicals.
      This study provides strong evidence that defibrotide has important beneficial
      effects on acute inflammatory tissue injury such as that occurring in the
      reperfusion of the ischaemic liver.

PMID- 12423426
TI  - Effects of rutin and harmaline on rat reflux oesophagitis.
AB  - 1. This study was aimed at evaluating the effect of rutin and harmaline (1-methyl
      7-methoxy-3,4-dihydro-beta-carboline) on the development of the surgically
      induced reflux oesophagitis, on gastric secretion, lipid peroxidation,
      polymorphonucleocytes (PMNs) accumulation, superoxide and hydroxyl radical
      production in PMNs, cytokine [interleukin-1beta (IL-1beta), tumour necrosis
      factor-alpha (TNF-alpha)] production in blood and [Ca2+]i mobilization in PMNs.
      2. Rutin and harmaline significantly prevented the development of reflux
      oesophagitis and gastric secretion. Treatments of oesophagitis rats with rutin
      and harmaline inhibited lipid peroxidation, and myeloperoxidase (MPO) in the
      oesophagus in comparison with untreated rats. 3. Superoxide anion and hydrogen
      peroxide production in 1 microm formylmethionylleucylphenylalanine (fMLP)- or 0.1
      microg ml-1N-phorbol 12-myristate 13-acetate (PMA)-activated PMNs was inhibited
      by rutin and harmaline in a dose-dependent fashion. Rutin and harmaline
      effectively scavenged the hydroxyl radical and hydrogen peroxide. Treatments of
      oesophagitis rats with rutin and harmaline inhibited IL-1beta production in the
      oesophagus in comparison with untreated rats, but TNF-alpha production was not
      affected by rutin and harmaline. The fMLP-induced elevation of [Ca2+]i was
      inhibited by rutin. 4. The results of this study suggest that rutin and harmaline
      may have beneficial protective effects against reflux oesophagitis by the
      inhibition of gastric acid secretion, oxidative stress, inflammatory cytokine
      production (i.e. IL-1beta), and intracellular calcium mobilization in PMNs in
      rats.

PMID- 12423428
TI  - Thalidomide in dermatology.
AB  - Thalidomide is an effective agent to treat over 25 seemingly unrelated
      dermatological conditions that have an inflammatory or autoimmune basis. The main
      side-effects of teratogenesis and peripheral neuropathy limit its use. Currently,
      in Australia no assurance is given as to the quality, safety and efficacy of
      thalidomide. The use of thalidomide for toxic epidermal necrolysis can lead to an
      increase in mortality, and its use as a prophylactic agent for the prevention of
      chronic graft-versus-host disease following bone marrow transplantation has
      raised more speculations as to the safety of this notorious drug. A review of the
      therapeutic indications for thalidomide in dermatology as well as the mechanisms
      of action and side-effects of this drug are presented. The current suggested
      guidelines for its use in clinical practice in Australia are discussed.

PMID- 12423427
TI  - Neurochemical regulation of cough response to capsaicin in guinea-pigs.
AB  - 1. Although monumental efforts have been made to define the action sites of
      cough, the importance of neurotransmitter systems in the cough reflex has
      received limited attention. We studied the roles for four major neurotransmitters
      [acetylcholine, histamine, serotonin (5-hydroxytryptamine, 5-HT) and dopamine] in
      the modulation of the cough reflex. 2. Atropine (muscarinic cholinergic blocking
      agent), pyrilamine maleate (PM, histamine H1 blocker), cimetidine (histamine H2
      blocker), 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT, specific 5-HT1A
      receptor agonist) and SCH-23390 (selective dopamine D1 receptor antagonist) were
      examined on the cough response to inhaled capsaicin in conscious guinea-pigs. 3.
      All the drugs significantly decreased the number of capsaicin-induced coughs in a
      dose-dependent manner. To compare the sensitivity of these drugs on cough
      response, we calculated the effective doses for 50% inhibition of cough (ED50)
      when the animals were exposed to 3 x 10-4 m capsaicin. The ED50 values were 0.03
      microm kg-1 for atropine, 0.2 microm kg-1 for 8-OH-DPAT, 6.2 microm kg-1 for SCH
      23390, 8.5 microm kg-1 for PM and 13.9 microm kg-1 for cimetidine. 4. These
      findings indicated that all these four neurotransmitters may be involved in the
      regulation of the cough reflex. Multiple changes of these neurotransmitters in
      disorders of the central nervous system might synergically affect the cough
      reflex.

PMID- 12423429
TI  - Molecular and cellular biology of basal cell carcinoma.
AB  - The finding of mutations in the PTCH gene in both Gorlin's syndrome and sporadic
      basal cell carcinomas has significantly advanced our understanding of the
      molecular defects that lead to the formation of these tumours. Knowledge of the
      specific molecular and functional changes that have taken place in these tumours
      will help us devise more defined therapies, as well as give us a better
      understanding of normal molecular pathways involved in skin development and
      function. The following is a summary of our current understanding of the
      molecular and cellular biology of basal cell carcinoma.

PMID- 12423430
TI  - Atopic dermatitis: review of immunopathogenesis and advances in immunosuppressive
      therapy.
AB  - This paper reviews the theories of the pathogenesis of atopic dermatitis (AD),
      with a particular emphasis on its immunopathogenesis. The contribution of
      predisposing factors, immunopathogenic factors and provoking factors in the
      pathogenesis of AD are considered. Predisposing factors explored in this article
      include genetics and the disturbance of skin function. Immunopathogenic factors
      reviewed include T cell dysfunction, biphasic cytokine expression and the role of
      immunoglobulin E. Provoking factors considered include microbial factors,
      psychosomatic interactions, contact allergens and irritants, inhalant allergens,
      food and climate. Immunosuppressive treatments reviewed include cyclosporin,
      azathioprine, methotrexate, tacrolimus, interferon-gamma, phosphodiesterase
      inhibitors and pimecrolimus (SDZ ASM 981).

PMID- 12423431
TI  - Cost of psoriasis: a study on the morbidity and financial effects of having
      psoriasis in Australia.
AB  - Eighty-three participants with psoriasis were followed over a 2-year period
      assessing the severity, morbidity and cost of their disease over time. At
      recruitment, they were examined by a dermatologist who classified them on a
      global basis as mild (47%), moderate (35%) or severe (18%). A Psoriasis Area and
      Severity Index (PASI) score was also recorded at the initial interview.
      Participants completed questionnaires on the morbidity related to having
      psoriasis using the Psoriasis Disability Index (PDI) and a self-administered PASI
      (SAPASI) score at the initial interview and at 3-monthly intervals over the 2
      year period. During the 3-monthly follow ups, patients also collected information
      on the cost of treatment. Using the PDI data, two-thirds of the respondents said
      that, as a result of their psoriasis, they altered the way they carried out their
      normal daily activities; more than 50% wore different types or colours of
      clothing; more than 50% said their home was made more messy or untidy; and over a
      third had problems at the hairdresser or difficulties playing sport. The annual
      out-of-pocket expense for medical products was around AUD$250 per person, with
      costs ranging from zero to more than AUD$2,000 per individual over the 2-year
      period. Costs were highest for over-the-counter products purchased without a
      medical prescription. There were similar variations in the out-of-pocket expenses
      of medical consultations depending on the level of medical care required. The
      study revealed that the standard methods used for classification of severity of
      psoriasis, such as the PASI or SAPASI scores, do not take into account the
      treatment being used at the time the score is recorded and therefore may not
      accurately reflect the true severity.

PMID- 12423432
TI  - Prospective study of depressive symptoms and quality of life in acne vulgaris
      patients treated with isotretinoin compared to antibiotic and topical therapy.
AB  - There have been recent concerns about the possible association between
      isotretinoin therapy and depressive symptoms. We conducted a prospective study to
      evaluate depressive symptoms and quality of life in acne patients having either
      isotretinoin or antibiotics/topical treatments. There were 215 patients (mean age
      20 years) included in the study. Depression, quality of life and acne severity
      ratings were administered at baseline, 1 month, 3 months and end of treatment or
      6 months, and compared between both treatment groups. The changes in the mean
      depression scores did not differ significantly between both groups (P = 0.62).
      The incidence of isotretinoin patients with moderate depressive symptoms remained
      relatively unchanged from baseline. The changes in the quality-of-life measures
      scores between treatment groups showed no significant difference. No correlation
      between isotretinoin dose and depression score was found. Although five
      isotretinoin patients were withdrawn during the study because of worsening of
      mood, no definite causal relationship was established. This pilot study does not
      appear to support any direct link between depression and isotretinoin, apart from
      being a rare unpredictable idiosyncratic side-effect. However, because of the
      study limitations, a larger study is needed to confirm the findings.

PMID- 12423433
TI  - Acitretin for chemoprevention of non-melanoma skin cancers in renal transplant
      recipients.
AB  - A prospective, open randomized crossover trial was conducted to evaluate the
      efficacy of acitretin for chemoprevention of squamous cell carcinomas and basal
      cell carcinomas in renal allograft recipients. Analysis was performed according
      to the intention-to treat principle. Twenty-three patients with previous history
      of non-melanoma skin cancer enrolled into the study and were randomly allocated
      into two groups. They crossed over at the end of 1 year. Eleven (47.8%) patients
      completed the 2-year trial. Twelve (52.2%) patients withdrew from the trial. Nine
      of these withdrew because of side-effects of acitretin. The majority of the
      patients who continued with the acitretin could tolerate 25 mg of acitretin daily
      or on alternate days. The number of squamous cell carcinomas (SCC) observed in
      patients while on acitretin was significantly lower than that in the drug-free
      period (P = 0.002). A similar trend was observed in patients with basal cell
      carcinomas, but this was not significant and the numbers were small. Side-effects
      were a major limiting factor. A severe rebound increase in SCC occurred in one
      patient after the acitretin was ceased.

PMID- 12423434
TI  - Factors supporting sustainability of a community-based scabies control program.
AB  - Scabies remains a major problem in Aboriginal communities within the Northern
      Territory of Australia. Secondary skin infection with Group A streptococcus (GAS)
      is very common and post-streptococcal disease rates remain high. Treating
      families in isolation will have only limited success, as reinfection frequently
      occurs as a result of the high levels of movement between households and
      communities. We describe the results of a successful community intervention to
      reduce scabies and GAS skin infection in one of the largest Aboriginal
      communities in the Northern Territory, 15 months post-intervention, and we
      discuss factors that have led to the success and sustainability of the program.

PMID- 12423435
TI  - Thalidomide experience of a major Australian teaching hospital.
AB  - St Vincent's Hospital Melbourne cautiously prescribes thalidomide as a treatment
      for recalcitrant dermatoses. The guidelines used for prescribing and monitoring
      thalidomide for dermatological conditions at this institution are presented.
      Fourteen patients were treated with thalidomide (11 women, three men) over a 5
      year period. The diagnoses of patients treated were actinic prurigo, prurigo
      nodularis, lupus erythematosus and Behcet's syndrome. A clinical improvement was
      noted in 10 patients (71.4%) prescribed thalidomide. Cessation of thalidomide
      treatment occurred in seven patients (50%) because of adverse effects. Of the
      patients with adverse effects, four developed abnormal nerve conduction studies
      and three developed intolerable adverse events (such as dizziness and vomiting).
      Adverse effects from thalidomide treatment are common but, through vigilant
      treatment planning, patient education and regular monitoring, the risk of
      permanent peripheral neuropathy and teratogenicity from thalidomide toxicity can
      be minimized.

PMID- 12423436
TI  - Porphyria cutanea tarda in south-east New South Wales.
AB  - Thirteen patients with porphyria cutanea tarda diagnosed between 1994 and 2000
      were reviewed to evaluate the precipitating factors and associations of porphyria
      cutanea tarda in a regional area of coastal and rural NSW. The majority had more
      than one precipitating factor, with excess alcohol intake, mutations in the
      haemochromatosis gene, chronic hepatitis C infection and oestrogen therapy being
      the most common. Antibodies to the hepatitis C virus were detected in 25% and
      these patients presented at a younger age. Of the patients tested for the two
      known haemochromatosis gene mutations, six (46%) had at least one copy of the
      C282Y mutation. Two (15%) patients were homozygous for the C282Y mutation and two
      (15%) were compound heterozygous for the C282Y and H63D mutations. All patients
      responded to venesection, which is the treatment of choice for the majority of
      patients with porphyria cutanea tarda.

PMID- 12423437
TI  - Photosensitivity: the 9-year experience at a Sydney contact dermatitis clinic.
AB  - In this retrospective study, 81 patients with photosensitivity were referred to
      the Contact and Occupational Dermatitis Clinic at The Skin and Cancer Foundation
      Australia, in Sydney, between 1991 and 1999. Photoallergic contact dermatitis
      (PACD) was diagnosed in 39.5% of patients, with 87.5% of these reactions being to
      sunscreen chemicals. Polymorphic light eruption (PMLE) accounted for 19.7% of
      cases, drug photosensitivity 14.8%, and photoaggravated atopic dermatitis and
      chronic actinic dermatitis (CAD) each constituted 7.4%. Compared with overseas
      studies, there was a high incidence of PACD, possibly reflecting the referral
      bias and widespread use of sunscreens. The incidence of PMLE and CAD was less
      than studies from cooler climates overseas. No cause could be determined for
      three photosensitive patients.

PMID- 12423438
TI  - Docetaxel-induced nail dystrophy.
AB  - A 73-year-old man with metastatic prostate cancer treated with weekly docetaxel
      chemotherapy for 5 months developed an acute nail dystrophy restricted to the
      fingernails. This was characterized by onycholysis, subungual haemorrhage and
      acute paronychia, progressing to a subungual abscess of the right index finger.
      Nail bed hyperaemia and haemosiderin-like nail bed discoloration were present.
      Nail plate avulsion was performed to decompress the acutely painful subungual
      abscess. The right thumb, middle finger and left index finger demonstrated early,
      proximal white subungual collections of pus obscuring the lunula (onychophosis).
      Central nail plate fenestrations with a surgical drill led to exudation of
      purulent material. Cultures of the subungual abscess material yielded mixed
      organisms, possibly related to administration of flucloxacillin for 1 week prior
      to presentation. The patient completed a further two courses of docetaxel without
      sequelae, and the nail dystrophy appears to be resolving. Docetaxel-induced nail
      changes are a common adverse effect, occurring in 30-40% of patients. Mild
      changes do not usually warrant the discontinuation of treatment.

PMID- 12423439
TI  - Disseminated lobular capillary haemangioma.
AB  - A 58-year-old woman presented with a 5-week history of multiple widespread
      vascular lesions. Histological examination confirmed the clinical diagnosis of
      disseminated lobular capillary haemangioma. No underlying cause for this eruption
      could be found. The lesions resolved over the following 2 months without
      intervention. Reports of disseminated lobular capillary haemangioma are scarce in
      the literature. In general, this condition does not appear to be related to an
      underlying disorder and in particular is not a marker for underlying malignancy.
      No unifying concept as to the aetiology of disseminated lobular capillary
      haemangioma has been identified. The condition appears to follow a benign course,
      with spontaneous resolution over 6-12 months.

PMID- 12423440
TI  - Birt-Hogg-Dube syndrome and multinodular goitre.
AB  - A 50-year-old woman presented with multiple skin-coloured facial papules. There
      was a family history of similar lesions. Histology of one of these papules was
      consistent with fibrofolliculoma. Multiple fibrofolliculomas together with
      flexural acrochordons suggested the diagnosis of Birt-Hogg-Dube syndrome.
      Investigations to exclude associated disease revealed changes consistent with
      multinodular goitre on thyroid ultrasound. The literature regarding the
      association of Birt-Hogg-Dube syndrome with internal disease is reviewed.

PMID- 12423441
TI  - Benign familial pemphigus: little benefit from superficial radiotherapy.
AB  - Benign familial pemphigus (Hailey-Hailey disease) is a rare relapsing-remitting
      epidermal blistering disease palliated by a multitude of medical and surgical
      treatments. There are limited reports of benefit from low-penetration X-rays. We
      describe two resistant cases that appeared to respond initially to superficial
      radiotherapy, a 66-year-old man who had multiple courses to the groins (4 x 2.00
      Gy/5 x 3.00 Gy) and to the axillae and low back (10 x 2.00 Gy) and a 53-year-old
      man treated twice to the groins and perineum (5 x 3.00 Gy/10 x 2.00 Gy). However,
      on longer follow up, benefit was found to be questionable. We conclude that while
      superficial radiotherapy may offer temporary relief, there is little evidence
      that it alters the natural history of this disease.

PMID- 12423442
TI  - Isolated lichen planus of the lip.
AB  - Lichen planus (LP) is an inflammatory disease that may involve multiple skin
      sites as well as mucous membranes, hair follicles and nails. It rarely occurs on
      the lips and usually then in association with oral lesions. We report a 43-year
      old man with a 7-month history of inflammation and erosive lesions of the lower
      lip. Histopathological and immunofluorescence studies showed features of LP.
      Local treatment with betamethasone dipropionate 0.5% ointment led to complete
      resolution within 1 month. Four months later, the patient developed typical
      cutaneous LP. Isolated LP of the lip is unusual, although this condition may be
      underestimated and therefore under-reported in the literature.

PMID- 12423443
TI  - Sensitization to saw palmetto and minoxidil in separate topical extemporaneous
      treatments for androgenetic alopecia.
AB  - We report a 24-year-old woman with androgenetic alopecia who became sensitized to
      topical minoxidil following use of an extemporaneous preparation of minoxidil 4%
      with retinoic acid in a propylene glycol base. She subsequently also became
      sensitized to saw palmetto (Serenoa repens), a topical herbal extract commonly
      promoted for the treatment of hair loss.

PMID- 12423447
TI  - Review article: albumin in the treatment of liver diseases--new features of a
      classical treatment.
AB  - Albumin was introduced initially in the treatment of patients with cirrhosis and
      ascites to increase serum albumin concentration due to its oncotic effect.
      Although its administration declined some years later, at present it constitutes
      an essential treatment in clinical hepatology. Several studies have clearly
      demonstrated its efficacy in the prevention and treatment of circulatory
      dysfunction and hepatorenal syndrome in patients with cirrhosis. These effects
      can be due not only to its properties as a plasma expander but also to its
      capacity to bind numerous substances such as bile acids, nitric oxide and
      cytokines. Based on this capacity an albumin dialysis system (MARS) has recently
      been developed. The usefulness of this system in the management of patients with
      acute and chronic liver failure is, at present, under evaluation.

PMID- 12423448
TI  - Review article: albumin as a drug--biological effects of albumin unrelated to
      oncotic pressure.
AB  - Albumin is the main determinant of plasma oncotic pressure and it plays a pivotal
      role in modulating the distribution of fluids between compartments. Moreover, it
      has many other biological properties which may be important not only for its
      physiological actions but also for its therapeutic effects. Among the non-oncotic
      properties are its capacity of molecule transportation and free radical
      scavenging, its ability to modulate capillar permeability, neutrophil adhesion
      and activation and its haemostatic effects. The following article reviews these
      biological effects as well as its structure, synthesis, catabolism and
      distribution.

PMID- 12423449
TI  - Review article: volume expansion in patients with cirrhosis.
AB  - Adequate size and distribution of the circulating medium are important for
      cardiovascular function, tissue oxygenation, and fluid homoeostasis. Patients
      with cirrhosis have cardiovascular dysfunction with a hyperkinetic systemic
      circulation, abnormal distribution of the blood volume, vasodilation with low
      systemic vascular resistance, increased whole-body vascular compliance, and
      increased arterial compliance. The effectiveness and temporal relations of
      plasma/blood volume expansion depend highly on the type of load (water, saline,
      oncotic material, red blood cells). Patients with cirrhosis respond in some
      aspects differently from healthy subjects, owing to their disturbed circulatory
      function and neurohormonal activation. Thus the increase in cardiac output and
      suppression of the renin-angiotensin-aldosterone system and sympathetic nervous
      system during volume expansion may be somewhat blunted, and in advanced
      cirrhosis, especially the non-central parts of the circulation, including the
      splanchnic blood volume, are expanded by a volume load. Infusion of oncotic
      material (preferably albumin) is important in the prevention of post-paracentesis
      circulatory dysfunction. In conclusion, volume expansion in advanced cirrhosis is
      qualitatively and quantitatively different from that of healthy subjects, and in
      those with early cirrhosis. Timely handling is essential, but difficult as it is
      a balance between the risks of excess extravascular volume loading and further
      circulatory dysfunction in these patients with a hyperdynamic, but hyporeactive,
      circulation.

PMID- 12423450
TI  - Review article: albumin for circulatory support in patients with cirrhosis.
AB  - Renal function abnormalities and ascites in cirrhosis are the final consequence
      of a circulatory dysfunction characterized by marked splanchnic arterial
      vasodilation. This causes a reduction in effective arterial blood volume and the
      homoeostatic activation of vasoconstrictor and sodium-retaining systems. Albumin
      is very effective in preventing renal failure associated with large-volume
      paracentesis and spontaneous bacterial peritonitis, conditions that are known to
      cause an impairment of circulatory function in patients with cirrhosis and
      ascites. Moreover, albumin administration improves survival in patients with
      spontaneous bacterial peritonitis. In patients with hepatorenal syndrome the
      administration of vasoconstrictor drugs in combination with albumin improves
      circulatory and renal function markedly and survival slightly. By contrast, the
      administration of albumin without vasoconstrictors has marginal or no effects on
      renal function in this setting.

PMID- 12423451
TI  - Review article: the molecular adsorbents recirculating system (MARS) in liver
      failure.
AB  - In recent years different artificial liver support systems are being developed
      for use in patients with acute decompensation of chronic liver disease or acute
      liver failure. The molecular adsorbents recirculating system (MARS), a device in
      which patient's blood is dialysed across an albumin-impregnated membrane against
      a recirculated albumin-containing solution, seems to be effective in removing
      albumin-bound toxins, such as fatty acids, bile acids and bilirubin. Although the
      clinical experience with MARS is scarce, some pilot studies have reported its
      effectiveness at improving liver function and hepatic encephalopathy in patients
      with acute decompensation of chronic liver disease, and renal function in
      patients with hepatorenal syndrome type I. Data regarding MARS experience in
      acute liver failure and in primary graft dysfunction are encouraging but limited.
      Its real usefulness in these settings is, at present, under evaluation in
      randomized controlled clinical trials.

PMID- 12423453
TI  - Restenosis after balloon angioplasty and/or stent insertion - origin and
      prevention.

PMID- 12423454
TI  - Echo-planar MR imaging of dissolved hyperpolarized 129Xe.
AB  - PURPOSE: The feasibility of hyperpolarized 129Xe for fast MR angiography (MRA)
      was evaluated using the echo-planar imaging (EPI) technique. MATERIAL AND
      METHODS: Hyperpolarized Xe gas was dissolved in ethanol, a carrier agent with
      high solubility for Xe (Ostwald solubility coefficient 2.5) and long relaxation
      times. The dissolved Xe was injected as a bolus into a flow phantom where the
      mean flow velocity was 15 cm/s. Ultrafast EPI images with 44 ms scan time were
      acquired of the flowing bolus and the signal-to-noise ratios (SNR) were measured.
      RESULTS: The relaxation times of hyperpolarized Xe in ethanol were measured to
      T1=160+/-11 s and T2 approximately 20 s. The resulting images of the flowing
      liquid were of reasonable quality and had an SNR of about 70. CONCLUSION: Based
      on the SNR of the obtained Xe EPI images, it was estimated that rapid in vivo MRA
      with 129Xe may be feasible, provided that an efficient, biologically acceptable
      carrier for Xe can be found and polarization levels of more than 25% can be
      achieved in isotopically enriched 129Xe.

PMID- 12423455
TI  - Acute myocardial infarction in a patient with unstable angina.
AB  - A 58-year-old-man with unstable angina developed a violent retrosternal and
      interscapular pain during coronary angiography with no associated ECG
      abnormalities. The patient was immediately submitted to transesophageal
      echocardiography, which revealed an echo-free space behind the ascending aorta
      thought to be consistent with an aortic dissection. To confirm this finding the
      patient underwent contrast-enhanced helical CT, which ruled out a dissection but
      revealed a small hypoattenuating, ill-defined area within the lateral wall of the
      left ventricle, consistent with an acute myocardial infarction. The finding was
      first confirmed by bedside echocardiography and later validated by laboratory
      tests. Review of the left coronary angiogram showed the culprit lesion at the
      origin of a major acute marginal branch of the circumflex artery.

PMID- 12423456
TI  - Experimental intracerebral and subarachnoid/intraventricular haemorrhages.
AB  - PURPOSE: To compare the detectability of small experimental intracranial
      haemorrhages on MR imaging at 0.5 T and 1.5 T, from hyperacute to subacute
      stages. MATERIAL AND METHODS: 1 ml of autologous blood was injected into the
      brain of 15 rabbits to create intraparenchymal haematomas. Since the blood
      partially escaped into the cerebrospinal fluid (CSF) spaces, detectability of
      subarachnoid and intraventricular blood was also evaluated. MR imaging at 0.5 T
      and at 1.5 T was repeated up to 14 days, including T1-, proton density- and T2
      weighted (w) spin-echo (SE), FLAIR and T2*-w gradient echo (GE) pulse sequences.
      The last MR investigation was compared to the formalin-fixed brain sections in 7
      animals. RESULTS: The intraparenchymal haematomas were best revealed with T2*-w
      GE sequences, with 100% of sensitivity at 1.5 T and 90-95% at 0.5 T. Blood in the
      CSF spaces was significantly (p < 0.05) better detected at 1.5 T with T2*-w GE
      sequences and detected best during the first 2 days. The next most sensitive
      sequence for intracranial blood was FLAIR. SE sequences were rather insensitive.
      CONCLUSION: 1.5 T equipment is superior to 0.5 T in the detection of intracranial
      haemorrhages from acute to subacute stages. T2*-w GE sequences account for this
      result but other sequences are also needed for a complete examination.

PMID- 12423457
TI  - Oligodendrogliomas.
AB  - PURPOSE: To study the pattern of contrast enhancement in MR and CT of
      oligodendrogliomas and to compare this with other imaging findings and with
      histopathological grading criteria. MATERIAL AND METHODS: 20 patients with
      oligodendrogliomas (12 low-grade WHO II and 8 anaplastic WHO III) were reviewed.
      20 complete MR investigations, 20 non-enhanced CT studies and 16 CTs after
      contrast enhancement were estimated blindly without knowledge of the tumour
      histological grades. RESULTS: All anaplastic oligodendrogliomas showed tumour
      contrast enhancement on MR and CT images. Also in 6/12 low-grade
      oligodendrogliomas the contrast was enhanced on MR imaging. In 5 of these, tumour
      calcifications were detected by CT. The remaining 6/12 WHO grade II cases showed
      no significant MR contrast enhancement. Of the oligodendrogliomas grade II, CT
      showed contrast uptake in 3 cases and no enhancement in 6, while in 3 cases
      postcontrast CT was not available. A comparison of contrast enhancement with
      tumour grade resulted in a p-value of 0.042 for MR and of 0.011 for CT. A
      combined statistical test of tumour grade and calcifications detected by CT
      compared with MR contrast enhancement showed a significant correlation (p=0.014).
      CONCLUSION: These data demonstrated that a clear grading of oligodendrogliomas
      based on the image criterion MR contrast enhancement was not possible. We suppose
      that, besides tumour neovascularisation, additional factors such as
      calcifications may disturb the blood-brain barrier.

PMID- 12423458
TI  - Vertex epidural hematoma - neuroradiological findings and management.
AB  - Epidural hematomas occurring at the vertex are uncommon, and they can be
      difficult to diagnose by axial CT. We report a case of acute traumatic vertex
      epidural hematoma, which resolved spontaneously with time. We stress the
      importance of MR investigations in this diagnostic challenge.

PMID- 12423459
TI  - Negative spiral CT in acute pulmonary embolism.
AB  - PURPOSE: To retrospectively evaluate the clinical outcome of non-anticoagulated
      patients with clinically suspected acute pulmonary embolism (PE) and no symptoms
      or signs of deep venous thrombosis (DVT) following a negative contrast medium
      enhanced spiral CT of the pulmonary arteries (s-CTPA). MATERIAL AND METHODS:
      During a 24-month period, 739 of 751 patients underwent s-CTPA with acceptable
      diagnostic quality for clinically suspected acute PE. All patients who had a CT
      study not positive for PE were followed up with a questionnaire, a telephone
      interview and review of all medical reports, including autopsies and death
      certificates for any episodes of venous thromboembolism (VTE) during a 3-month
      period. RESULTS: PE was diagnosed in 158 patients. Of the remaining 581 patients
      with a negative s-CTPA, 45 patients were lost to follow-up. 88 patients were
      excluded because of anticoagulation treatment (cardiac disorder n=32, chronic VTE
      or acute symptomatic DVT n=31, PE diagnosed at pulmonary angiography n=1,
      thrombus prophylaxis during diagnostic work-up or other reasons than VTE n=24)
      and 7 patients undergoing lower extremity venous studies because of symptoms of
      DVT (all negative). Thus, 441 patients with a negative s-CTPA and no DVT
      symptoms, venous studies or anticoagulant treatment constituted the follow-up
      cohort. Four of these patients had proven VTE (all PE) during the 3-month follow
      up period. Two of the PE episodes contributed to the patient's death. CONCLUSION:
      Patients with clinically suspected acute PE, no symptoms or signs of DVT and a
      negative single slice s-CTPA using 3-5 mm collimation, may safely be left without
      anticoagulation treatment unless they are critically ill, have a limited
      cardiopulmonary reserve and/or if a high clinical suspicion remains.

PMID- 12423460
TI  - Dynamics of contrast enhancement in MR imaging and power Doppler ultrasonography
      of solid breast lesions.
AB  - PURPOSE: To evaluate the dynamics of contrast enhancement in solid breast lesions
      at contrast-enhanced MR imaging and power Doppler ultrasonography (US) and to
      compare the methods to histology and to each other. MATERIAL AND METHODS: Forty
      breast lesions were prospectively examined with dynamic MR and power Doppler US.
      Time-signal intensity curves of enhancement were obtained for both methods. The
      shape of the curve was analyzed to be benign, indeterminate or malignant. The
      curves were also analyzed quantitatively by calculating the slope of the curve
      and the area under the curve (both methods), relative enhancement (MR), and time
      to peak (US). The lesions were divided into malignant lesions, fibroadenomas, and
      other benign lesions. The results were compared to histology. RESULTS: In the
      subjective analysis of the MR curve in differentiating between benign and
      malignant lesions the accuracy was 90%. The MR curve also enabled differentiation
      between fibroadenomas and malignancies. The accuracy of the US curve was 38%.
      Quantitatively, statistically significant differences were found using all the MR
      variables, except between malignancies and fibroadenomas. Using the US variables,
      no significant difference was found between the groups. CONCLUSION: The dynamics
      of contrast-enhanced MR were reliable in the differential diagnosis of solid
      breast lesions, but contrast-enhanced power Doppler US was of limited value.

PMID- 12423461
TI  - Perforations and fistulae in gastrointestinal tuberculosis.
AB  - BACKGROUND: Perforation and fistulae, though uncommon, are serious complications
      of gastrointestinal tuberculosis. Patients with acute tuberculous perforation are
      subjected to surgery, whereas localized perforation and fistulae with subtle
      clinical signs are detected by barium contrast examination. There has been no
      report on radiological series regarding the incidence of perforation and
      fistulae, detected by barium contrast studies. MATERIAL AND METHODS: A
      retrospective analysis of barium contrast studies of 684 proven cases of
      gastrointestinal tuberculosis seen over a period of 15 years was done to detect
      the incidence of perforation and fistulae. RESULTS: Fifty-two patients (7.6%)
      with localized perforation and fistulae were seen. Twenty-eight patients had
      evidence of perforation, and 24 patients showed fistulae formation. The most
      common site of perforation and fistulae was the small bowel followed by the
      colon. Associated abnormalities noted were ulcerations, strictures, nodular
      filling defects and extrinsic compression. CONCLUSION: Perforation and fistulae
      along with other associated abnormalities of the gastrointestinal tract are
      suggestive of tuberculosis, particularly in a population predisposed to
      tuberculous infection.

PMID- 12423462
TI  - Videofluoroscopy of deglutition in children after repair of esophageal atresia.
AB  - PURPOSE: To evaluate the functional disorders of the oral and pharyngeal phases
      of deglutition after repair of esophageal atresia in children. MATERIAL AND
      METHODS: 19 children (10 girls, 9 boys, mean age 22 months) underwent
      videofluoroscopy of deglutition after repair of esophageal atresia. The
      videofluoroscopic studies were assessed according to functional and morphological
      changes in the oral, pharyngeal and esophageal phases. The persistence of
      radiologic findings on videofluoroscopy was determined. RESULTS: The oral phase
      was normal in all patients. The main functional disorder of the pharyngeal phase
      was aspiration in 7 (37%) children. A completely normal deglutition in the
      pharyngeal and esophageal phases was not seen in any patient. CONCLUSION:
      Videofluoroscopy after repair of esophageal atresia is helpful in differentiation
      of functional and morphological disorders that can lead to prandial aspiration
      and have an influence on the decision about continued therapy.

PMID- 12423463
TI  - Partial and complete tear of the anterior cruciate ligament.
AB  - PURPOSE: To analyze MR direct and indirect signs for knees with anterior cruciate
      ligament (ACL) partial or complete tear. MATERIAL AND METHODS: According to
      documented MR direct and indirect signs for ACL tear, we retrospectively reviewed
      the incidence of those signs in 15 partial ACL tear and 17 complete ACL tear
      patients. The findings were also compared with duration of injury (less or more
      than 6 weeks, as acute or chronic stages). RESULTS: A residual straight and tight
      ACL fiber in at least one pulse sequence was more frequently detected in partial
      ACL tears. The empty notch sign, a wavy contour of ACL, bone contusion at lateral
      compartment and lateral meniscus posterior horn tear were significantly more
      frequently seen in complete tear cases. The posterior cruciate ligament angle in
      chronic complete ACL tear cases (109 degrees +/-20 degrees ) had a tendency to be
      less than in chronic partial ACL tear cases (119+/-18 degrees ). CONCLUSION: The
      empty notch sign, a wavy ACL, bone contusion, and posterior horn of lateral
      meniscus tears are suggestive of a complete ACL tear. A residual straight and
      tight ACL fiber seen in at least one image section is a helpful sign to diagnosis
      of partial ACL tear. In the acute ACL injury stage, a focal increase of the ACL
      signal intensity is more suggestive of a partial ACL tear.

PMID- 12423464
TI  - Acetabular component migration in total hip arthroplasty using CT and a
      semiautomated program for volume merging.
AB  - PURPOSE: To develop a non-invasive method for detection of acetabular cup
      migration after total hip arthroplasty (THA) with a higher degree of accuracy
      than routine plain radiography. MATERIAL AND METHODS: Two CT examinations, 10 min
      apart, were obtained from each of 10 patients that had undergone THA. Using an in
      house developed semiautomated program for volume merging, the pelves in the two
      examinations were fused and the acetabular cup was visually and numerically
      evaluated to test the method's accuracy in detecting migration. RESULTS: In the
      visual evaluation of the best match a 1-mm translation of the cup was detectable.
      The numerical evaluation, comparing landmarks placed in the images of the
      acetabular cup and the head of the femur component in the two examinations,
      showed the mean difference in orientation of acetabular axes to be 2.5 degrees,
      the mean distance between centre of cup face to be 2.5 mm and the mean distance
      between centre of the head of the prosthetic femoral component to be 1 mm.
      CONCLUSION: This method has a significantly higher accuracy than routine plain
      radiography in detecting acetabular cup migration and could be used in clinical
      practice. It gives both a visual and a numerical correlate to migration.

PMID- 12423465
TI  - Association between joint bleeds and Pettersson scores in severe haemophilia.
AB  - PURPOSE: To assess and quantify the association of haemophilic arthropathy,
      measured by the radiological Pettersson score, with the number of joint bleeds
      suffered by the patient. MATERIAL AND METHODS: In order to quantify the effect of
      the cumulative number of joint bleeds on the Pettersson score, a study was
      performed using 295 Pettersson scores obtained in 117 patients with severe
      haemophilia. The patients were born between 1965 and 1994, and had no history of
      inhibitors. The number of joint bleeds was determined annually from the entry in
      the clinic and onwards. The localization of bleeds was not assessed. The patients
      entered the clinic at a median age of 3.6 years, and received intermediate dose
      prophylaxis, starting at a median age of 5.3 years. Evaluation of 1643 treatment
      years showed a mean of 6.8 joint bleeds/year. Pettersson scores were obtained at
      a mean age of 15.9 years (range 1.7-32.9) and had a median value of 4 points
      (range 0-50). RESULTS AND CONCLUSION: The Pettersson scores began to rise after
      the age of 5 years and increased with one point for every 13 joint bleeds (95%
      confidence interval 11-15). No evidence was found of 'autonomous' progression of
      Pettersson scores, independent of bleeds.

PMID- 12423466
TI  - CT findings in skeletal cystic echinococcosis.
AB  - PURPOSE: To evaluate the CT findings of skeletal cystic echinococcosis. MATERIAL
      AND METHODS: CT findings of 7 patients with pathologically confirmed skeletal
      cystic echinococcosis were evaluated. RESULTS: There were 4 men and 3 women, aged
      36-75 years. Hydatid cysts were located in the spine (n=2), a rib (n=3), the
      pelvis and a vertebra (n=1), the pelvis and the left femur (n=1). The size of the
      lesions varied from 1 cm to 15 cm. CT showed well defined, single or multiple
      cystic lesions with no contrast enhancement, no calcification, no daughter cysts,
      and no germinal membrane detachment. The cystic lesion had a honeycomb appearance
      in 2 cases; there was pathologic fracture in 2 cases, bone expansion in 5 cases,
      cortical thinning in 6 cases, cortical destruction in 6 cases, bone sclerosis in
      1 case, and soft tissue extension in 6 cases. CONCLUSION: Preoperative
      differential diagnosis of skeletal cystic lesions should include cystic
      echinococcosis, especially in endemic areas, since this diagnosis may easily be
      missed unless kept in mind.

PMID- 12423467
TI  - The use of video glasses at ultrasound-guided interventions.
AB  - PURPOSE: Video glasses form a virtual image in front of the user. We investigated
      the utility of video glasses at US-guided interventions. MATERIAL AND METHODS:
      The video glasses were tested at 75 consecutive US-guided interventions. The
      operator sees the US image in front of him, and below the glasses, simply by
      moving his eyes, he can see the patient and the field of intervention. RESULTS:
      The video glasses could be used at all 75 US-guided interventions. The image
      quality was below that of the US monitor, but adequate. The working posture was
      improved, it was easy to get accustomed to using the system, there was no
      increased time consumption, and the patients felt comfortable with the set-up.
      CONCLUSION: Use of video glasses facilitates US-guided interventions.

PMID- 12423468
TI  - Abdominal arteries should be evaluated by 3D contrast-enhanced MRA as the first
      step.

PMID- 12423469
TI  - Lithiasic inguinoscrotal herniation of the bladder secondary to prostate
      enlargement.

PMID- 12423476
TI  - Disclosing the sex of the fetus: a view from the UK.

PMID- 12423477
TI  - Music during pregnancy.

PMID- 12423478
TI  - Fetal learning: a prospective randomized controlled study.
AB  - OBJECTIVES: To examine whether prenatal exposure to a music stimulus alters fetal
      behavior and whether this continues into the newborn period. SUBJECTS AND
      METHODS: A prospective randomized control trial was conducted using an exposure
      learning model in 20 normal term pregnancies. Music was played to ten fetuses via
      a headphone on the maternal abdomen. Ten controls had the headphone without
      sound. All fetal studies took place within 72 h prior to elective delivery. All
      20 newborns were exposed to the same music on days 3-5. Computerized assessment
      of fetal heart rate and activity was documented and neonatal behavioral states
      were recorded. Nonparametric statistical analysis was used. RESULTS: For the
      first hour of study, exposed fetuses had higher mean heart rates (FHR) and spent
      more time exhibiting high FHR variation compared to unexposed fetuses, but
      neither of these differences was statistically significant. However, by the
      fourth hour the exposed fetuses not only demonstrated these two features but also
      exhibited more state transitions (P = 0.01) and higher FHR variation (P = 0.04)
      compared to unexposed fetuses. These effects were carried over into the neonatal
      period with prenatally exposed newborns manifesting more state transitions (P =
      0.01) and spending a higher proportion of time in awake states (P = 0.05) when
      exposed to the same music stimulus. CONCLUSION: Prenatal music exposure alters
      the fetal behavioral state and is carried forward to the newborn period. This
      suggests that a simple form of fetal programming or learning has occurred.

PMID- 12423479
TI  - Fetal duodenal obstructions: increased risk of prenatal sudden death.
AB  - OBJECTIVES: The aim of this study was to describe the outcome of fetuses with
      duodenal obstruction diagnosed prenatally and to compare the outcome with the
      results of studies of newborns. METHODS: All fetuses with a prenatal diagnosis of
      duodenal obstruction were registered and evaluated prospectively from January
      1985 to December 2000. RESULTS: Duodenal obstruction was found in 29 fetuses at a
      mean gestational age of 29+2 weeks. Polyhydramnios was found in 24 cases (83%).
      Six fetuses (21%) had trisomy 21. Associated anomalies, including trisomy 21,
      were found in 18 cases (62%). Four fetuses with normal karyotype died in utero at
      31-35 gestational weeks. Two of them had associated anomalies, but the anomalies
      could not explain the prenatal deaths and the deaths occurred suddenly and
      unexpectedly. Three infants died postnatally; all three had associated anomalies.
      Four infants with normal karyotype had neurological impairment suggesting that
      they might have had intrauterine asphyxia. CONCLUSIONS: The present study
      indicates that duodenal obstruction is a more serious condition than previously
      believed, with an increased risk of prenatal asphyxia and death, even when the
      karyotype is normal and no associated anomalies are present. We consider the
      possibility that it could be caused by bradycardia/asystole following vagal
      overactivity due to distension of the upper gastrointestinal tract.

PMID- 12423480
TI  - Congenital periventricular pseudocysts: prenatal sonographic appearance and
      clinical implications.
AB  - OBJECTIVE: Periventricular pseudocysts (PVPC) are diagnosed in approximately 1%
      of premature newborns that undergo brain sonography during the first 24 h of
      life. These pseudocysts are thought to develop antenatally due to germinal matrix
      hemorrhage, but have not been described until now in prenatal ultrasound studies.
      The aim of this study was to report the identification, differential diagnosis,
      and prognosis of PVPC detected by prenatal ultrasound examination. DESIGN:
      Between 1997 and 2001 we made an ultrasound diagnosis of PVPC in 11 fetuses. In
      nine fetuses the findings were characteristic of PVPC and these patients
      represent our study group. Fetal magnetic resonance imaging was performed in five
      patients. Termination of pregnancy was carried out in three patients, in one case
      intrauterine fetal death occurred at 31 weeks, and one infant died in the
      neonatal period. The surviving four newborns are being followed in the pediatric
      neurology clinic. RESULTS: PVPC were diagnosed by ultrasound scan in fetuses
      between 16 and 37 weeks of gestation (mean, 29.7 weeks). Magnetic resonance
      imaging confirmed the presence of PVPC in two cases. In eight cases the
      pseudocysts were unilateral and in one case bilateral. They were an isolated
      finding in five patients. Four of these fetuses were delivered at term and have
      normal neurological development at ages ranging from 6 to 25 months. All fetuses
      with additional pathologies (coarctation of the aorta, hemimegalencephaly,
      cytomegalovirus infection, hypoplasia of the vermis with dysmorphism) did not
      survive. CONCLUSIONS: The prenatal diagnosis of PVPC warrants an extensive search
      for possible associated pathological findings. As an isolated finding, antenatal
      PVPC seem to carry a good prognosis.

PMID- 12423481
TI  - Abnormal maternal cardiac function and morphology in pregnancies complicated by
      intrauterine fetal growth restriction.
AB  - OBJECTIVE: To explore maternal cardiac function through an echocardiographic
      evaluation, in a group of nulliparous patients with intrauterine fetal growth
      restriction during the third trimester of pregnancy. METHODS: Twenty-one
      consecutive nulliparous pregnant women who had fetuses with intrauterine growth
      restriction (IUGR) and abnormal umbilical artery Doppler pulsatility index (PI)
      underwent maternal echocardiographic examination during the third trimester of
      gestation. The data were then compared with those obtained from 21 normal
      nulliparous women who had fetuses with an estimated fetal weight > 10th
      percentile and a normal umbilical artery Doppler PI who were considered as the
      control group. RESULTS: Heart rate was slightly lower in the IUGR group, whereas
      blood pressure and total vascular resistance were higher compared with the
      control subjects. End-diastolic volume, stroke volume and cardiac output were
      lower in the IUGR patients compared with normal patients. The IUGR group had
      smaller left atrial maximal dimensions and greater left atrial minimal areas
      compared with the control subjects. Left atrial function was depressed in the
      IUGR group. A smaller left ventricular mass was present in the IUGR patients
      compared with the control subjects. Isovolumetric relaxation time (IVRT) was
      prolonged in the IUGR patients compared with the controls. CONCLUSIONS: The
      absence of a 'correct' maternal cardiovascular compensatory response to abnormal
      trophoblastic invasion, might be one of the factors that slowly determine the
      conditions of reduced placental perfusion and eventually of the development of
      fetal growth restriction.

PMID- 12423482
TI  - Second-trimester ultrasonographic assessment of the umbilical coiling index.
AB  - OBJECTIVE: To determine the relationship between gestational age and the
      ultrasonic measurement of umbilical coiling index (UCI), and to assess the
      ability of second-trimester ultrasonic measurements of UCI to predict the true
      UCI, determined at birth. SUBJECTS/METHODS: Five hundred and thirty-one
      consecutive women with uncomplicated pregnancies, booking for delivery with a
      singleton pregnancy, were recruited during a routine second-trimester fetal
      morphology scan. Multiple ultrasonographic measurements of the intercoil distance
      were performed between two to three coils of the umbilical cord, along its entire
      visible length. Three hundred and seventy-four patients (70%) were followed until
      delivery when the true UCI was measured. RESULTS: An adequate portion of
      umbilical cord for assessment of coiling was visualized in 99% of cases. Adequate
      ultrasonographic visibility rates for the fetal, middle and placental regions of
      the cord were different. All three regions of the umbilical cord could only be
      visualized adequately in 10% of cases, and two regions were visible in 75%. The
      UCI progressively decreased along the cord from the fetal insertion to the
      placental insertion. The mean decrease in UCI with increasing gestational age was
      similar in all parts of the cord before the 23rd week (160 days) of pregnancy,
      and plateaued off after this point, except in measurements performed near the
      fetal insertion. The sensitivity of second-trimester ultrasound examination for
      predicting hypercoiling at birth was 17.3% and for predicting hypocoiling was
      9.1%. DISCUSSION: Whilst UCI can be measured easily and reliably in the second
      trimester these estimates do not accurately reflect the UCI at term. Our original
      assumption that umbilical coiling does not alter after the initial formation of
      coils in the first trimester is incorrect; mixed patterns occurred in about 25%
      of cases. These patterns develop during the second and third trimesters,
      presumably due to snarls in the cord, and influence the final coiling number and
      therefore the relationship between the two measurements of UCI.

PMID- 12423483
TI  - Ultrasound estimation of amniotic fluid volume using the largest vertical pocket
      containing umbilical cord: measure to or through the cord?
AB  - OBJECTIVES: The purpose of this investigation was to determine the preferable
      method, either measuring to the umbilical cord or through the umbilical cord to
      the base of the pocket, of ultrasonically estimating amniotic fluid volume.
      SUBJECT AND METHODS: This was a prospective study carried out in singleton
      pregnancies undergoing a third-trimester amniocentesis. The amniotic fluid index
      (AFI) and single deepest pocket (SDP) were measured prior to amniocentesis. If
      measured spaces contained umbilical cord, measurements were made to and through
      the cord. Actual amniotic fluid volume was determined by the dye-dilution
      technique. RESULTS: One-hundred pregnancies were evaluated. Low dye-determined
      volume was identified in a significantly greater number of pregnancies using the
      AFI to the cord (7/28, 25%) compared to through the cord (2/28, 7%) (P = 0.025).
      The SDP technique to the cord was superior in low volumes (2/28, 7%) vs. (0/28,
      0%) through the cord (although statistical significance could not be determined
      because there were no low through-the-cord measurements). CONCLUSIONS: For the
      detection of low amniotic fluid volumes, the AFI to the cord is better than
      through the cord. Measurement to the cord and through the cord had similar
      accuracy for both the AFI and SDP techniques in normal and high dye-determined
      amniotic fluid volumes.

PMID- 12423484
TI  - Bedside estimation of Down syndrome risk during first-trimester ultrasound
      screening.
AB  - OBJECTIVE: To construct tables for 'bedside' estimation of Down syndrome risk
      based on maternal age and nuchal translucency measurements. METHODS: Likelihood
      ratios were calculated using the log multiple of median Gaussian model. The
      parameters for the model (mean and standard deviation) were derived from 5560
      normal and 51 Down syndrome-affected pregnancies scanned during the first
      trimester in three different centers. Equations for calculating maternal
      background risk and median values were obtained from previous reports. The
      results were compared to two modalities using the log Gaussian model and software
      that uses the delta-value model. RESULTS: The distribution fitted the data well,
      and the parameters obtained in the study group for the log multiple of median
      model were a mean of 0 and a standard deviation of 0.12356 among normal
      pregnancies and a mean of 0.305312 and a standard deviation of 0.240337 among
      Down syndrome-affected ones. The likelihood ratios obtained for the various
      combinations of fetal crown-rump lengths and nuchal translucency measurements
      were comparable to other modalities reported earlier. CONCLUSIONS: The results of
      the current study provide useful tables for simple and accurate 'bedside'
      estimation of Down syndrome risk without the need for computerized software or
      complicated calculations.

PMID- 12423485
TI  - Second-trimester amniocentesis vs. chorionic villus sampling for prenatal
      diagnosis in multiple gestations.
AB  - OBJECTIVE: To study the impact of invasive procedures for prenatal diagnosis on
      multiple pregnancies and compare first-trimester chorionic villus sampling with
      second-trimester amniocentesis. DESIGN: Retrospective study of 347 second
      trimester amniocenteses and 69 chorionic villus sampling procedures. RESULTS:
      Miscarriage occurred in 4.18% of women after amniocentesis and 4.54% of women
      after chorionic villus sampling. In the amniocentesis group the risk of
      miscarriage was higher in the cases with transplacental entry (4.54%) than in
      those with transamniotic entry (2.08%). The rates of preterm delivery < or = 32
      weeks and preterm delivery < or = 35 weeks in the amniocentesis group were 11.8%
      and 32.4% and in the chorionic villus sampling group 16.66% and 23.8%,
      respectively. Total fetal loss rate was similar in the amniocentesis group (8.8%)
      and the chorionic villus sampling group (10.22%). In the 21 cases where selective
      feticide was carried out the total fetal loss rate was lower in the chorionic
      villus sampling group (8.3%) than in the amniocentesis group (11.1%), although
      the difference did not reach statistical significance. CONCLUSION: Chorionic
      villus sampling appears to be a safe alternative to amniocentesis and should be
      considered as the method of choice particularly when there is a high risk of an
      affected fetus necessitating selective feticide.

PMID- 12423487
TI  - Intraobserver and interobserver reproducibility of ultrasound measurements of
      endometrial thickness in postmenopausal women.
AB  - OBJECTIVES: To determine intraobserver and interobserver reproducibility of
      ultrasound measurements of endometrial thickness in postmenopausal women. DESIGN:
      Forty-eight postmenopausal women underwent transvaginal ultrasound examination by
      two examiners. Each observer took three replicate measurements of the endometrium
      in each woman. Intraobserver repeatability was expressed as the difference
      between the highest and lowest measurement values obtained by one observer, the
      repeatability coefficient, and the intraclass correlation coefficient.
      Interobserver reproducibility was expressed as the difference between the mean of
      the three measurements of each observer, limits of agreement, and interclass
      correlation coefficient. The repeatability coefficient and the limits of
      agreement define the range within which 95% of the differences between two
      measurements are likely to fall. Data were analyzed for all women, as well as
      separately for women with endometrium < or = 6 mm and > 6 mm. The agreement
      between observers in classifying women as having endometrium < or = 4.4 mm or >
      or= 4.5 mm was determined by calculating Cohen's kappa. RESULTS: In women with
      endometrium <or = 6 mm the intraclass correlation coefficient was 0.95 for
      Observer 1 and 0.88 for Observer 2, the median difference between the highest and
      lowest values being 0.4 mm (range, 0-1.4) for Observer 1 and 0.7 mm (range, 0.1
      2.2) for Observer 2, and the repeatability coefficient was 0.8 mm and 1.4 mm,
      respectively. The corresponding figures for women with endometrium > 6 mm were
      0.99 and 0.99, 0.7 mm (0-2.9) and 1.0 mm (0.2-3.4), and 1.7 mm and 1.9 mm. In
      women with endometrium < or = 6 mm the interclass correlation coefficient was
      0.77, and the mean interobserver difference was 0.2 mm +/- 1.8 mm (2 standard
      deviations), when calculations were based on the mean of three measurements per
      observer (+/- 1.9 mm when calculations were based on only one measurement per
      observer). The corresponding figures for women with endometrium > 6 mm were 0.98,
      0.2 mm +/- 3.1 mm (+/- 3.2 mm). The agreement between observers in classifying
      women as having an endometrium < or = 4.4 mm or > or = 4.5 mm was very good
      (kappa 0.81). CONCLUSIONS: The reproducibility of endometrial measurements seems
      to be clinically acceptable and to allow reliable discrimination between
      postmenopausal women with endometrium < or = 4.4 mm and > or = 4.5 mm. In
      clinical practice, it is enough to take one endometrial measurement when
      performing transvaginal ultrasound examination.

PMID- 12423486
TI  - Ultrasound detection and perinatal outcome of fetal trisomies 21, 18 and 13 in
      the absence of a routine fetal anomaly scan or biochemical screening.
AB  - OBJECTIVES: To determine the prenatal detection rate of abnormality (fetal
      anomaly or growth restriction) in pregnancies complicated by fetal trisomies 21,
      18 and 13 in an obstetric population managed without routine biochemical or
      sonographic screening tests and to assess the perinatal outcome of these
      pregnancies. SUBJECTS AND METHODS: This was a retrospective analysis of obstetric
      and neonatal data pertaining to infants born with trisomy 21, 18 or 13 (n = 82)
      diagnosed between 1989 and 1997 (23 762 deliveries). RESULTS: Antenatal suspicion
      of aneuploidy, based on the detection of growth restriction or fetal anomaly, was
      present in 18.3% (11 of 60) of fetuses with trisomy 21, in 81.2% (13 of 16) of
      fetuses with trisomy 18, and in 83.3% (five of six) of fetuses with trisomy 13.
      The antenatal detection rates for growth restriction were accurate whereas the
      antenatal detection rates for fetal anomalies were poor. Intrauterine fetal death
      occurred in 18.8% of fetuses with trisomy 18 (three of 16) and in 50% (three of
      six) of cases of trisomy 13. For babies born alive with trisomy 18 or 13 the
      neonatal mortality was 93.8% (15 of 16). All cases of trisomy 21 fetuses survived
      beyond the perinatal period and the antepartum and intrapartum details of these
      pregnancies were unremarkable. CONCLUSION: In obstetric practice without routine
      biochemical or sonographic screening tests the detection of findings suggestive
      of aneuploidy is low for trisomy 21, but is high for trisomies 18 and 13. These
      findings provide information for counseling about the antenatal, intrapartum, and
      neonatal course of these trisomies.

PMID- 12423488
TI  - Measurement precision and normal range of endometrial thickness in a
      postmenopausal population by transvaginal ultrasound.
AB  - OBJECTIVES: The aim of this study was to examine the endometrial thickness (ET)
      in an asymptomatic postmenopausal population, and to assess the long-term
      variability. DESIGN: A total of 1182 asymptomatic generally healthy
      postmenopausal women were enrolled into this cross-sectional evaluation of the
      ET. Measurements were performed by transvaginal ultrasound. A subset of the women
      (n = 178) was examined twice 3 months to 2 years apart to assess the long-term
      variability. RESULTS: Cross-sectionally, ET varied with length of menopause.
      During the first 5 years after menopause (YSM) the mean ET was 2.3 mm but it
      decreased by 0.03 mm/year (P < 0.01). From 5 to 13 YSM the ET remained stable at
      a mean of 1.8 mm with no significant changes (P = 0.13). Thereafter there was a
      minimal increase of 0.01 mm/year (P < 0.05). In order to minimize the influence
      of natural changes on ET, only women who had reached the menopause more than 5
      years earlier were entered into the subsequent long-term study. The mean ET was
      2.0 mm +/- 1.0 mm with no significant differences within or between the
      observers' measurements. The precision errors were less than 1 mm. CONCLUSIONS:
      The normal range of the thickness of the postmenopausal endometrium in
      asymptomatic women varies with YSM. There is a high long-term agreement within
      and between observers in measuring the ET.

PMID- 12423489
TI  - Transvaginal sonography in the diagnosis of acute appendicitis.
AB  - OBJECTIVES: To evaluate transvaginal sonography with power Doppler capacity in
      the diagnosis of acute appendicitis and in discriminating appendicitis from
      pelvic inflammatory disease. PATIENTS AND METHODS: We describe transvaginal
      sonographic findings of six women with acute appendicitis selected from 31 women
      seen in an emergency room setting for clinically suspected pelvic inflammatory
      disease. The study population underwent gray-scale transvaginal sonography, and
      specific sonographic landmark findings for acute appendicitis and pelvic
      inflammatory disease were used. Hyperemia of any infectious complex was
      identified by power Doppler. Laparoscopy was performed after transvaginal
      sonography and was used as the gold standard. RESULTS: Laparoscopy showed acute
      appendicitis in six (19%) of the 31 patients. A thick walled non-compressible gas
      containing tubular structure with a diameter exceeding 6 mm was seen by
      transvaginal sonography in four of the six cases, consistent with uncomplicated
      appendicitis. A heterogeneous complex with surrounding hyperechogenic soft tissue
      was seen in two cases with gangrenous appendicitis. Power Doppler detected
      hyperemia in all six cases. Normal adnexal structures were imaged next to the
      inflamed appendix. The sonographic criteria consistent with acute appendicitis
      were clearly different from those of acute pelvic inflammatory disease.
      CONCLUSIONS: Transvaginal sonography provides an opportunity to distinguish
      between appendicitis and acute pelvic inflammatory disease. Prospective trials
      are needed in order to evaluate the impact of transvaginal sonography in the
      diagnosis of acute appendicitis.

PMID- 12423490
TI  - Subependymal pseudocysts in the fetal brain: prenatal diagnosis of two cases and
      review of the literature.
AB  - Subependymal pseudocysts are cerebral cysts found in 5% of all neonates. When
      they are isolated and typical, they result from persistence of the germinal
      matrix, have a good prognosis and regress spontaneously within a few months.
      However, associated anomalies are frequent and in such cases the prognosis is
      poor. They can be of infectious, vascular, metabolic or chromosomal origin.
      Subependymal pseudocysts have rarely been described in the antenatal period. We
      report the prenatal diagnosis of two cases of isolated pseudocysts at 32 and 23
      weeks. Both ultrasonography and magnetic resonance imaging assisted in the
      diagnosis and there was normal postnatal outcome in both cases.

PMID- 12423491
TI  - Autosomal recessive type of Adams-Oliver syndrome: prenatal diagnosis.
AB  - We report on three pregnancies complicated by Adams-Oliver syndrome in a
      consanguineous Turkish couple. Two cases were correctly diagnosed prenatally at
      22+3 and 13+0 weeks gestation following the first case of Adams-Oliver syndrome
      in which severe anomalies of the extremities were observed at 26+5 weeks'
      gestation. In this first case, the diagnosis of Adams-Oliver syndrome was made
      following termination of pregnancy at 27+2 weeks' gestation. In all three cases,
      autopsy was performed. All fetuses showed anomalies of the extremities, aplasia
      cutis and symmetric defects of the skull, with bone being replaced by collagenous
      tissue. Although there have been numerous cases of the postnatal diagnosis of
      Adams-Oliver syndrome following termination of pregnancy, this is the first
      description of the prenatal diagnosis of this disorder.

PMID- 12423492
TI  - Split hand and foot malformation: ultrasound detection in the first trimester.
AB  - The split hand split foot malformation is a rare disorder inherited in an
      autosomal dominant pattern with variable expression. In our case it was detected
      early by ultrasound in the twelfth week of gestation. To our knowledge, this is
      the earliest finding by ultrasound of this malformation. The sonographic findings
      were bilateral split hands and split foot. No other associated malformation was
      observed. The pathological findings were consistent with the diagnosis of split
      hand split foot malformation. Prenatal diagnosis, the genetic background, and the
      differential diagnosis are discussed.

PMID- 12423493
TI  - Three-dimensional power Doppler in the diagnosis of ovarian torsion.
AB  - Recent advances in ultrasound technology have enabled the diagnosis of overall
      tissue vascularization by three-dimensional (3D) power Doppler. This case report
      describes 3D power Doppler characteristics of unilateral ovarian torsion 2 weeks
      after embryo transfer in a pregnant patient with bilateral hyperstimulated
      ovaries. Before laparoscopic treatment the twisted right ovary showed the
      following 3D power Doppler indices: mean grayness index, 15.66; vacularization
      index, 0.24; flow index, 21.99; vascularization flow index, 0.05. One hour after
      laparoscopic treatment 3D power Doppler indices of the untwisted ovary were as
      follows: mean grayness index, 25.61; vacularization index, 3.81; flow index,
      42.800; vascularization flow index, 1.63. The resistance index of the ovarian
      vessels before and after laparoscopy showed no significant difference (5.1 vs.
      5.2). The diagnosis of ovarian torsion can be better made with 3D power Doppler
      sonography than with two-dimensional Doppler sonography.

PMID- 12423494
TI  - False positive diagnosis of conjoined twins in the first trimester.

PMID- 12423495
TI  - A case of a fetus with gastric perforation associated with congenital
      diaphragmatic hernia.

PMID- 12423496
TI  - Transient anhydramnios after early amniocentesis complicated by membrane rupture.

PMID- 12423499
TI  - American Association of Blood Banks 55th Annual Meeting. Orlando, Florida, USA.
      26-29 October 2002. Abstracts.

PMID- 12423497
TI  - Antenatal sonographic diagnosis of testicular torsion.
AB  - Antenatal testicular torsion is a well-established condition diagnosed and
      treated after birth. This report describes the antenatal diagnosis of testicular
      torsion with surgical and pathological confirmation. Antenatal and postnatal
      sonographic findings included enlarged testis and epipdidymis surrounded by
      hemorrhagic fluid organized in two concentric compartments ('double ring
      hemorrhage' image). A contralateral hydrocele with bulging of the scrotal septum
      towards the unaffected side were also present. Pathological examination
      demonstrated a recent extravaginal torsion, which is the predominant mechanism
      for testicular torsion in the fetus and neonate. Recognition of this phenomenon
      and the ultrasonographic images associated with it may enable the diagnosis of
      antenatal testicular torsion to be made on prenatal sonography of the fetus.

PMID- 12423504
TI  - Erythromelalgia due to essential thrombocythemia.

PMID- 12423505
TI  - Cord blood banking 2002: 112,010 of 7,914,773 chances.

PMID- 12423506
TI  - Transfusion hazard reporting: powerful data, but do we know how best to use it?

PMID- 12423507
TI  - Blood collection and transfusion in the United States in 1997.
AB  - BACKGROUND: Collections, processing, and transfusions of blood and blood
      components in the US in 1997 were measured and compared with 1994 and prior
      years. STUDY DESIGN AND METHODS: Questionnaires were returned by 2391 blood
      centers, AABB member hospitals, nonmember hospitals, and other facilities.
      Statistical procedures were used to verify that the sample was representative and
      to estimate national collections and utilization. RESULTS: The gross domestic
      blood supply in the US in 1997 was 12,602,000 units, 5.5 percent less than in
      1994. It included 11,741,000 units of allogeneic community blood, 643,000 units
      of autologous blood, and 205,000 units of allogeneic-directed blood. Platelet
      transfusions amounted to 9,037,000 platelet concentrate equivalent units, of
      which 62.4 percent were apheresis packs. Compared with 1994, total platelet units
      transfused increased by 14.9 percent and single-donor platelet units transfused
      increased by 31.7 percent, whereas platelet concentrate transfusion declined by
      3.8 percent. Transfusions of FFP increased by 26.6 percent compared with 1994.
      CONCLUSIONS: The margin of US allogeneic blood supply in excess of allogeneic
      transfusions in 1997 was 630,000 units, 5.4 percent of total allogeneic supply as
      compared with margins in prior years ranging between 9.3 and 10.9 percent.
      Although overall allogeneic available supply in 1994 was adequate to meet
      transfusion demand, the decrease in the margin between 1994 and 1997 is cause for
      concern. The rate of whole-blood collections in 1997 per 1000 members of the
      population aged 18 to 65 years was 12.6 percent lower than 1994. The RBC
      transfusion rate per 1000 members of the population in 1997 remained nearly the
      same as in 1994. However, the rates of platelet and of plasma transfusions both
      increased.

PMID- 12423508
TI  - In utero or ex utero cord blood collection: which is better?
AB  - BACKGROUND: The relative nucleated cell count of umbilical cord blood (CB)
      correlates with improved engraftment and survival. This study compares two
      collection methods to assess CB content, including cell numbers. STUDY DESIGN AND
      METHODS: The Massachusetts CB bank used trained obstetricians and midwives to
      collect CB in utero before the delivery of the placenta. The banks in California,
      Ohio, Oregon, and Minnesota used trained American Red Cross (ARC) personnel who
      collected CB ex utero after the delivery of the placenta. All banks processed CB
      by RBC sedimentation and volume reduction. RESULTS: The volume and total
      nucleated cell count of collected CB before processing, as well as after
      processing CFU-GM and CD34+ cells, showed no advantage of either method. In utero
      collections resulted in more rejections of collected units (due to labeling
      problems, bacterial contamination, clotting, and delay between collection and
      processing) than ex utero collections. There were fewer medical exclusions after
      in utero collection. CONCLUSION: CB can be collected successfully using either
      the in utero or ex utero methods; both methods produce comparable nucleated cell,
      MNC, CD34+, and CFU-GM numbers. Bacterial contamination, low volume, clotting,
      and delay until processing are generally higher with in utero collection.

PMID- 12423509
TI  - A phased consent policy for cord blood donation.
AB  - This article focuses on ethical and policy questions concerning when consent may
      be sought for the collection and donation of cord blood. It reviews the
      advantages and disadvantages of alternative times for securing consent,
      challenges common objections to seeking consent during labor or after collection,
      and describes a phased consent process--a process that permits consent during
      early labor to the ex utero collection of cord blood followed by after-consent
      collection to donation. The phased consent policy attends to the unique
      characteristics of cord blood collection and donation, respects donors and their
      families, maximizes the number and diversity of cord blood units collected,
      preserves the relationship between providers and patients, and preserves public
      trust in cord blood and other types of tissue banking.

PMID- 12423510
TI  - The role of the paternal health history in cord blood banking.
AB  - BACKGROUND: Umbilical cord blood (UCB) transplantation is becoming more widely
      used, yet ethical and policy issues regarding consent and health history persist.
      Whereas most UCB banks do not require paternal consent or paternal health history
      (PHH), both are obtained at this institution whenever possible. This study
      assessed the value of PHH in making UCB safer. STUDY DESIGN AND METHODS: A
      retrospective review was performed of all cord blood units (CBUs) collected by
      this bank between November 1999 and October 2000. All discarded CBUs were studied
      to identify those deferred based exclusively on PHH provided by the father in the
      PHH questionnaire. RESULTS: PHH was obtained for 301 of 655 (46%) CBUs collected.
      Of the 339 CBUs banked, 269 (79%) had PHH available. Three of the 301 CBUs in
      which PHH was available were discarded based solely on PHH, since maternal
      medical history and infectious disease testing were negative. Paternal high-risk
      factors in those three cases were: gave money or drugs for sex; traveled to an
      HIV high-risk area; and did not answer high-risk questions. CONCLUSION:
      Considerable time and effort is expended in the process and follow-up of
      obtaining PHH with an overall indistinct and unconvincing role in minimizing
      infectious disease transmission risk in UCB banking.

PMID- 12423511
TI  - Racial and ethnic composition of volunteer cord blood donors: comparison with
      volunteer unrelated marrow donors.
AB  - BACKGROUND: Umbilical cord blood is an alternative peripheral blood progenitor
      cell source for patients who need transplantation. A presumed advantage of cord
      blood is the ability to increase minority recruitment. STUDY DESIGN AND METHODS:
      The racial composition of five member cord blood banks of the National Marrow
      Donor Program (NMDP) was compared, representing 9020 cord blood donors with NMDP
      marrow donors from comparable geographic areas, representing 417,676 donors. Cord
      blood and marrow donors self-reported racial designations on questionnaires.
      Donor statistics were compared with baseline racial data of deliveries from
      participating hospitals for cord blood donors and with geographic census data for
      marrow donors. RESULTS: The California, Florida, and Massachusetts cord blood
      banks recruited a lower percentage of minorities than the corresponding marrow
      donor centers. In New York and Colorado, minority recruitment was equivalent. In
      California, Florida, Massachusetts, and New York, the cord blood banks recruited
      a lower percentage of minorities than those delivering at the respective
      hospitals. The cord blood banks in California, Colorado, Florida, and
      Massachusetts recruited a lower percentage of minorities compared with delivery
      data than the corresponding marrow donor centers compared with census population
      (p < 0.001). In New York, the percentages were similar. CONCLUSION: The problem
      of insufficient minority recruitment of cord blood has not yet been solved.
      Better strategies are needed to recruit minority donors.

PMID- 12423512
TI  - Nonobese diabetic-severe combined immunodeficient mice transplantation of volume
      reduced and thawed umbilical cord blood transplants following closed-system
      immunomagnetic cell selection.
AB  - BACKGROUND: Protocols for the expansion of human umbilical cord blood (UCB)
      progenitors begin with the selection of CD34+ cells from stored frozen and thawed
      units. Use of an immunomagnetic selection procedure within a closed blood bag
      system for volume-reduced UCB transplants was evaluated, and the influence of
      CD34 cell selection on in vivo engraftment potential was studied. STUDY DESIGN
      AND METHODS: Eleven thawed buffy coat-processed UCB units were processed within a
      standard blood bag with a washing solution. In six independent experiments, the
      same dosage of 2 x 104 CD34+ cells from paired selected and nonselected samples
      was transplanted into NOD-SCID mice. In two experiments, cells from the negative
      fraction were also transplanted. RESULTS: The purity of CD34+ cells after
      selection was correlated with the removal of supernatant after the first washing
      step and therefore with adequate removal of damaged or dead cells (r=0.86, p <
      0.01). Mice transplanted with unselected UCB cells had more human cells within
      their marrow than animals transplanted with selected cells (8.6 +/- 5.9% selected
      group vs. 19.8 +/- 14.2% unselected group; p=0.04), whereas no engraftment could
      be observed transplanting cells from the two negative fractions. A higher
      percentage of human CD45+ cells in the unselected group were found to be positive
      for CD38, CD14, CD33, and CD19, indicating a higher potential for these
      unselected progenitors to differentiate into myeloid cells and B cells.
      CONCLUSIONS: Processing of volume-reduced and thawed UCB transplants within a
      closed-bag system before immunomagnetic CD34+ cell selection allows for the
      preparation of CD34+ cells of significant purity at technically useful cell
      recoveries. However, these experiments indicate a potential impairment of
      engraftment capacity for the CD34+ cell-enriched fraction.

PMID- 12423514
TI  - Pharmacokinetic study of FFP photochemically treated with amotosalen (S-59) and
      UV light compared to FFP in healthy volunteers anticoagulated with warfarin.
AB  - BACKGROUND: To date, no clinical trials have characterized FFP infusion efficacy,
      and infusion still carries infectious risk. This single-blinded crossover study
      compared postinfusion kinetics of FVII in photochemically treated FFP to standard
      FFP. STUDY DESIGN AND METHODS: Subjects donated plasma by apheresis. Half of the
      collected plasma was treated with the psoralen amotosalen hydrochloride (S-59)
      and UVA light, and half were prepared as standard plasma. Subjects received
      warfarin over 4 days to lower FVII levels. On Day 4, subjects received 1 L of
      either treated or standard FFP. After 2 weeks, subjects underwent a regimen
      identical to that with the other type of FFP. RESULTS: After warfarin ingestion,
      the mean FVII concentration was 0.33 IU per mL. Both types of FFP exhibited
      comparable FVII kinetics, with a mean peak increment of 0.10 to 0.12 IU per mL
      occurring at the end of infusion. The effect disappeared after 8 hours.
      DISCUSSION: Study data of warfarin-treated healthy volunteers demonstrate that
      psoralen plus UV-treated FFP provides an equivalent in vivo coagulation response
      to control plasma. A 1-L dose of FFP in adults may provide an initial increment
      of 0.10 IU per mL of FVII. In the absence of bleeding, FVII levels return to
      baseline after 8 hours.

PMID- 12423513
TI  - Severe immune hemolysis after minor ABO-mismatched allogeneic peripheral blood
      progenitor cell transplantation occurs more frequently after nonmyeloablative
      than myeloablative conditioning.
AB  - BACKGROUND: Hemolysis as a result of donor-recipient minor ABO mismatching is a
      complication of allogeneic peripheral blood progenitor cell (PBPC)
      transplantation (PBPCT). The increased B-lymphocyte content of PBPC grafts and
      immunosuppressive regimens without methotrexate (MTX) may increase incidence and
      severity of this event. STUDY DESIGN AND METHODS: A total of 93 patients were
      analyzed after allogeneic PBPCT. In 25 (27%) cases, minor (n=21) or bidirectional
      (n=4) ABO mismatching was present. Of these, 15 patients received myeloablative
      and 10 received nonmyeloablative conditioning regimens. For GVHD, prophylaxis
      cyclosporin A (CsA) alone (n=2) or CsA with MTX (n=13) was given after
      myeloablative conditioning and CsA with mycophenolate mofetil (MMF) after
      nonmyeloablative conditioning (n=10). RESULTS: Hemolysis occurred in 4 out of 25
      (16%) patients with minor or bidirectional ABO mismatching only. Three patients
      underwent nonmyeloablative conditioning and were given CsA with MMF, and one
      patient underwent myeloablative conditioning and was given CsA alone for GVHD
      prophylaxis. Hemolysis began 7 to 10 days after transplantation, and donor type
      alloantibodies were detectable concomitantly with recipients type RBCs.
      CONCLUSION: Patients receiving minor or bidirectional ABO-mismatched PBPC grafts
      and GVHD prophylaxis without MTX are at risk of hemolysis. Prophylactic
      interventions in patients before minor ABO-mismatched PBPCT not receiving MTX
      should be taken into consideration. Careful monitoring of hemolysis parameters
      during the first 15 days after PBPCT transplantation is mandatory.

PMID- 12423515
TI  - Inactivation of HIV in blood.
AB  - BACKGROUND: The residual risk of HIV infection after HIV screening tests in
      combination with the risk of new emerging pathogens entering the blood supply has
      sparked research on the development of a technology for reduction of pathogens in
      RBCs. STUDY DESIGN AND METHODS: HIV-1 was treated with PEN110 (INACTINE) and
      analyzed for the kinetics of virus reduction in RBC, the effect of PEN110 on
      nucleic acids, the integrity of the virus morphology and viral proteins, and the
      ability of the virus to bind HIV cell receptors and enter susceptible cells.
      RESULTS: PEN110 effectively reduced HIV-1 to the limit of detection for a
      reduction factor of at least 5.57 log 50 percent tissue culture infectious dose
      per bulk test. The PEN110-treated virions maintained their morphology, protein
      integrity, and functionality. However, the PEN110-treated HIV-1 RNA genome was
      neither functional to serve as a template for RT-PCR amplification of about 1 kb
      nor able to support viral DNA synthesis in cell culture. CONCLUSION: These
      results suggest that PEN110 inactivates HIV-1 by targeting the viral nucleic
      acid.

PMID- 12423516
TI  - PEN110 treatment functionally inactivates the PBMNCs present in RBC units:
      comparison to the effects of exposure to gamma irradiation.
AB  - BACKGROUND: The presence of WBCs in blood components is the major factor
      influencing the immunologic consequences of transfusion. Attempts to ameliorate
      these responses have used WBC reduction or inactivation by ionizing radiation.
      PEN110 (Inactine, V. I. Technologies) is a chemical that inhibits the replication
      of infectious pathogens by modifying their nucleic acids. These experiments
      compared effects of PEN110 treatment or gamma irradiation on WBC function. STUDY
      DESIGN AND METHODS: Aliquots of non-WBC-reduced RBC units were treated with
      PEN110 or gamma irradiation with appropriate controls, and PBMNCs from these
      units were tested with in vitro assays. The assays included immunophenotyping,
      activating T cells with phorbol ester, proliferation of cells in response to
      mitogens or allogeneic cells, and determining the ability of cells to stimulate
      proliferative responses and to produce IL-8. DNA fragmentation following PEN110
      treatment was examined by PCR and terminal deoxynucleotidyl transferase-mediated
      deoxyuridine triphosphate-biotin nick end labeling assays. RESULTS: Treatment of
      non-WBC-reduced RBC units with PEN110 functionally inactivated WBC in all in
      vitro assays used. In contrast, while gamma irradiation inhibited proliferation
      of the WBCs, it did not or only partially inhibited the ability of WBC to
      function in the other assays. PEN110, but not gamma irradiation, rapidly induced
      fragmentation of cellular DNA. CONCLUSION: Because PEN110 was as effective as
      gamma irradiation at inhibiting WBC proliferation, PEN110 treatment could
      potentially be used to prevent the development of GVHD following transfusion.

PMID- 12423517
TI  - Inhibition of murine GVHD by PEN110 treatment.
AB  - BACKGROUND: The presence of WBCs in blood components is the primary factor
      influencing the immunologic consequences of transfusion, such as GVHD and
      alloimmunization. Depletion or inactivation of WBCs can reduce the deleterious
      responses. Because treatment with PEN110 (Inactine, V. I. Technologies), an
      ethyleneimine derivative that disrupts nucleic acid replication, was shown to
      inactivate in vitro human PBMNC function, the ability of PEN110-treated cells to
      trigger GVHD or alloantibodies was studied with in vivo murine models. STUDY
      DESIGN AND METHODS: In vitro assays were employed to confirm that PEN110
      treatment inactivated murine splenocyte function as effectively as for human
      PBMNCs. In vivo experiments in mice examined the ability of PEN110-treated cells
      to induce GVHD responses in a parent into F1 hybrid GVHD model, to induce
      alloantibodies, to stimulate MHC-restricted cytolytic T lymphocyte responses, and
      to persist after injection. RESULTS: PEN110-treated murine splenocytes did not
      respond or induce responses in any in vitro or in vivo assay. The PEN110-treated
      cells were eliminated from blood and secondary lymphoid organs much more rapidly
      than were untreated cells. CONCLUSION: PEN110 treatment prevents the development
      of GVHD and alloantibody production following WBC transfusion in a murine model
      system, supporting the continued development of PEN110 treatment of cellular
      blood components as an alternative to gamma irradiation for the prevention of
      GVHD.

PMID- 12423518
TI  - Autologous transfusion recovery of WBC-reduced high-concentration platelet
      concentrates.
AB  - BACKGROUND: This study evaluates the recovery and survival of high-concentration
      platelets (HCPs) compared to standard apheresis platelets (APCs) in a double
      label autologous human system. METHODS: Nine HCP units paired with APC units were
      stored, labeled with either 51Cr and 111In, and returned, and recovery and
      survival were determined. Standard in vitro platelet biochemical and functional
      parameters were monitored over the storage period and evaluated in a secondary
      analysis. RESULTS: Three each HCP units containing more than 2.2 x 10(11), 1.5 x
      10(11) to 2.1 x 10(11), and 0.8 x 10(11) to 1.1 x 10(11) platelets in 59.4 +/-
      2.5 mL were stored for 1, 2, or 5 days, respectively, and simultaneously with
      matched APC units (3.8 x 10(11) platelets, 282 mL). Recoveries were 72.3 +/- 8.6,
      60.8 +/- 14.6, and 52.5 +/- 6.7 percent for HCPs, respectively; and 59.4 +/- 6.4
      percent for APCs (p=0.37). HCP survivals were 202.0 +/- 14.9, 204.9 +/- 10.2, and
      162.6 +/- 17.0 hours; APC survivals were 155.4 +/- 20.3 hours (p=0.001).
      Secondary analysis with P-selectin added as a predictor in the model resulted in
      significant difference in recoveries for Day 1 HCPs versus Day 5 APCs (p=0.024)
      with no difference shown for HCPs on Days 2 or 5 versus APCs. No significant
      difference was found in survival (p=0.16). CONCLUSION: HCPs may be stored 24
      hours for high yield, 48 hours for intermediate yield, and up to 5 days for
      yields less than 1.6 x 10(11) platelets per bag with equivalent to superior
      recovery and survival of platelets in the autologous transfusion model compared
      to APCs.

PMID- 12423519
TI  - Treatment for the decline of ionized calcium levels during peripheral blood
      progenitor cell harvesting.
AB  - BACKGROUND: ACD-A solution containing sodium citrate and citric acid is used as
      an anticoagulant agent during peripheral blood progenitor cell (PBPC) harvesting,
      and in rare cases can cause fatal citrate intoxication. The aim of this study was
      to establish effective methods for stabilizing ionized calcium (ICa) levels
      during PBPC harvesting. STUDY DESIGN AND METHODS: ICa was measured during 46
      apheresis procedures conducted in 26 patients. Four patients in four procedures
      were infused with calcium gluconate solution before PBPC harvesting; three
      patients in six procedures were infused with calcium gluconate when symptoms of
      citrate intoxication appeared; and four patients in five procedures received a
      continuous infusion. Five patients in five procedures took an isotonic sports
      drink containing calcium when hypocalcemic symptoms appeared. The ICa level,
      blood pressure, and pulse rate were measured. RESULTS: ICa declined rapidly from
      the preapheresis level of 1.081(+/-0.092) mM to 0.937(+/-0.081) mM (13.3%, p <
      0.0001) 10 minutes after the start of apheresis and continued to decline until
      the completion of the procedure. When patients received a continuous infusion of
      calcium during apheresis, ICa was relatively stabilized. ICa significantly rose
      (6.1 +/- 3.6%, p < 0.02) within 2 to 5 minutes after oral intake of an isotonic
      sports drink containing calcium and was maintained within normal range for 31 to
      55 minutes. CONCLUSION: An isotonic sports drink containing calcium has a quick
      stabilizing and a longer maintenance effect on ICa. Thus, we recommend the intake
      of an isotonic sports drink containing calcium as the easiest and best method for
      preventing hypocalcemia during apheresis.

PMID- 12423520
TI  - Reliability of bedside ABO testing before transfusion.
AB  - BACKGROUND: Previous studies of bedside transfusion compatibility tests have
      shown high rates of erroneous transfusion decision, due to defective techniques
      and poor user performance. An experimental study was conducted to evaluate the
      error rate obtained with a new ready-to-use device (Vu-Test, Medigis), in
      comparison with the most popular bedside card used in France (Safety-Test ABO,
      Diagast Laboratories). STUDY DESIGN AND METHODS: A stratified random sample of
      nurses performed, in the clinical departments where they worked, cross-matches on
      12 randomly and blindly selected paired donor-recipient blood samples with Safety
      Test ABO and Vu-Test. The nurses detected agglutination, interpreted
      compatibility, decided whether to transfuse, and gave their opinion of the two
      devices. Three independent experts reviewed photographs of each test result.
      RESULTS: Thirty-five trained nurses and 10 student nurses carried out 268 tests
      with each device. One-hundred ninety tests (70.9%) performed with Safety-Test ABO
      and 177 tests (66.0%) performed with Vu-Test were entirely error-free (p=0.23).
      The risk of erroneous detection of agglutination was not different between the
      devices (p=0.69), but was significantly lower when the nurse had experience in
      transfusion (p < 0.001). According to the experts, Vu-Test was significantly
      better than Safety-Test ABO. CONCLUSION: Although the experts considered Vu-Test
      to be better than Safety-Test ABO, error rates were high with both devices.

PMID- 12423521
TI  - Hemovigilance network in France: organization and analysis of immediate
      transfusion incident reports from 1994 to 1998.
AB  - BACKGROUND: Hemovigilance networks have been introduced in several countries to
      improve knowledge of blood transfusion-related morbidity and mortality. The
      general organization of the French network and its results from 1994 through
      March 1999 are presented here. STUDY DESIGN AND METHODS: The hemovigilance
      network relies on blood transfusion centers and hospital correspondents, who
      analyze unexpected and untoward blood transfusion-related effects and transmit a
      Transfusion Incident Report (TIR) to a national database (Transfusion Incident
      Reports Electronic Data Management [GIFIT]). RESULTS: As of March 1, 1999, the
      GIFIT database contained 24,234 TIRs related to incidents that occurred from the
      start of the hemovigilance network until December 31, 1998. The network was not
      fully implemented until 1996; but the reporting rate seems to have since
      stabilized at approximately 7000 per year (2.5 reports per 1000 blood
      components). The highest reporting rate is observed with platelet concentrates
      (4.02/1000), followed by RBCs (1.71/1000) and FFP (0.34/1000). Bacterial
      contamination quickly appeared as a major cause of morbidity and mortality (185
      cases and 18 fatalities). However, a general trend of reduction in this type of
      incident was observed over time, which can be attributed to adoption of several
      preventive measures. In contrast, major ABO mismatchings during RBC transfusion
      remained at a constant rate throughout this period and accounted for six
      fatalities. After the implementation of universal WBC reduction, some incidents
      known to be related to WBCs, such as nonhemolytic febrile transfusion reactions
      (NHFTR) and HLA immunization, were dramatically reduced. CONCLUSION:
      Hemovigilance is an important tool not only to analyze blood transfusion
      incidents, but also to measure the effects of new processes or corrective actions
      at a national level.

PMID- 12423522
TI  - Assessing the accuracy of three viral risk models in predicting the outcome of
      implementing HIV and HCV NAT donor screening in Australia and the implications
      for future HBV NAT.
AB  - BACKGROUND: Risk modeling is now the most practical method of estimating the
      residual risk of viral transmission in developed countries. One method of
      assessing the accuracy of a risk model is to measure the observed against the
      predicted outcome after implementing a new screening method. The primary
      objective of this paper is to assess the accuracy of three published models in
      predicting the impact of implementing HIV and HCV NAT in Australia. STUDY DESIGN
      AND METHODS: Viral screening data on Australian donors for 2000 and 2001 were
      retrospectively analyzed. The data were applied to the three models to estimate
      the risk of transmission and predicted NAT yield for HIV, HCV, and HBV. RESULTS:
      The median risk estimates for the three models were 1 in 3,415,000 for HIV NAT, 1
      in 911,000 for HCV NAT, and 1 in 483,000 for HBsAg. The predicted NAT yield for
      the three models ranged from 0.17 to 0.30 per million donations for HIV, 1.20 to
      5.55 for HCV, and 0.47 to 1.01 for HBV. The observed NAT yield was not
      significantly different from the expected yield with any of the three models for
      either HIV or HCV. CONCLUSIONS: First, the residual risk in Australian donors is
      small in comparison with other transfusion complications and comparable to or
      lower than the risk in US and European nonremunerated donors. Second,
      mathematical risk modeling has sufficient precision to be used as a predictive
      tool for risk-benefit assessments of novel screening procedures. Finally, in
      relation to the case for implementing HBV NAT and/or anti-HBc in Australia, we
      conclude that at present, there is inadequate information about our donor
      population to perform an evidence-based risk-benefit analysis.

PMID- 12423523
TI  - Binding of activated platelets to WBCs in vivo after transfusion.
AB  - BACKGROUND: During preparation and storage of apheresis concentrates, platelets
      are being activated. One of the alterations that occur during this process is an
      increased expression of P-selectin (CD62p) on the cytoplasmic surface of
      platelets. This neoepitope represents a ligand for the binding of platelets to
      WBCs. It has been suggested that the activation of platelets is associated with
      the sequestration of platelets after transfusion. In this in vivo study, the
      binding of platelets to WBCs was analyzed following transfusion of platelet
      concentrates (PCs). STUDY DESIGN AND METHODS: Double apheresis concentrates were
      prepared with two different cell separators. One of the split products was stored
      for 1 to 2 days and the other one for 3 to 5 days. Flow cytometry was applied to
      analyze the degree of platelet activation in vitro, and also to measure the
      extent of platelet binding to WBC subclasses in vivo after transfusion into
      patients. RESULTS: The results of this study show that platelet activation occurs
      during apheresis and storage of PCs. After transfusion of the PCs, no significant
      binding of platelets to T or B-cells could be detected. However, a significant
      binding of platelets to monocytes and neutrophil granulocytes occurs. While in
      Baxter PCs stored for 1-2 days the amount of platelet-leukocyte aggregates in
      vivo was higher compared to COBE PCs, no such difference could be detected
      anymore for the PCs stored for 3-5 days. CONCLUSION: This study demonstrates that
      binding of activated platelets occurs to monocytes and neutrophil granulocytes
      but not to T- and B-cells in the circulation after transfusion. In addition, the
      interaction of platelets and WBCs is dependent on the degree of P-selectin
      expression. Platelets showing a higher degree of activation adhere to WBCs to a
      higher degree than nonactivated platelets.

PMID- 12423524
TI  - Non-frozen preservation of umbilical cord blood.

PMID- 12423525
TI  - Platelet transfusion and thrombotic thrombocytopenic purpura.

PMID- 12423526
TI  - The September 11, 2001 disaster and the New York blood supply.

PMID- 12423527
TI  - Understanding immunological effects on patients by therapeutic apheresis.

PMID- 12423528
TI  - Blood purification procedures and their related short- and long-term effect on
      patients.
AB  - At present, approximately 1 million patients are on chronic hemodialysis in the
      world. Some patients have been dialyzed for more than 20 years. However, chronic
      hemodialysis produces a new type of disease known as chronic hemodialysis
      syndrome. Procedurally induced immunomodulation may be the cause of this
      syndrome. Hematological changes imposed by this extracorporeal circulation for
      hemodialysis are discussed in this article. A comparison with procedurally
      induced immunomodulation by apheresis procedures is also provided. This repeated
      exposure of the blood-to-blood purification device with a large foreign surface
      produces quite substantial immunological effects to the patient. Thus, further
      studies were necessary to analyze more clearly the adaptation mechanism of the
      human defense system. On the basis of these studies, the following conclusion
      could be derived. Typically, Stage 1, human adaptation to the implanted or
      applied man-made machine, would be 48 h and could be divided into 3 phases. They
      would be Phase I (15-30 min) leukocyte storage, Phase II (2-24 h) leukocyte
      release, and Phase III (24-48 h) completion of the proper leukocyte response. To
      adapt hematologically in 48 h, the patient may experience 3 phases of adaptation
      reactions. When patients are subjected to extracorporeal circulation, the
      immunosuppressive state of hemodialysis is hypothesized through these studies.

PMID- 12423530
TI  - Apheresis of immune diseases and apheresis using immunological specificity.
AB  - It has been clearly shown that autoimmune diseases can be treated by apheresis by
      eliminating immune complexes, however, the effects of therapeutic apheresis are
      not limited to immune disorders. Almost all diseases are associated with immune
      systems. Immune systems can be regulated by advanced techniques of apheresis,
      including immunoadsorption and immunocytapheresis, removing immune effector
      molecules and various immune-associated cells selectively. Therefore, apheresis
      can be used as a nondrug treatment for many diseases. In addition, disease
      associated proteins that cause disease or are produced in the course of diseases
      and accumulate in the body could be eliminated selectively by apheresis using the
      extremely powerful ability of the immune system to recognize polypeptide
      structures specifically and distinguish miniscale differences among molecules. In
      this article, we discuss the current status of treatment of immune diseases by
      apheresis and possible treatment approach of a variety of diseases by apheresis
      based on immune reactions.

PMID- 12423529
TI  - Immunomodulation by the autonomic nervous system: therapeutic approach for
      cancer, collagen diseases, and inflammatory bowel diseases.
AB  - The distribution of leukocytes is regulated by the autonomic nervous system in
      humans and animals. The number and function of granulocytes are stimulated by
      sympathetic nerves whereas those of lymphocytes are stimulated by parasympathetic
      nerves. This is because granulocytes bear adrenergic receptors, but lymphocytes
      bear cholinergic receptors on the surface. These regulations may be beneficial to
      protect the body of living beings. However, when the autonomic nervous system
      deviates too much to one direction, we fall victim to certain diseases. For
      example, severe physical or mental stress --> sympathetic nerve activation -->
      granulocytosis --> tissue damage, including collagen diseases, inflammatory bowel
      diseases, and cancer. If we introduce the concept of immunomodulation by the
      autonomic nervous system, a new approach for collagen diseases, inflammatory
      bowel diseases, and even cancer is raised. With this approach, we believe that
      these diseases are no longer incurable.

PMID- 12423531
TI  - In vitro evaluation of dextran sulfate cellulose beads for whole blood infusion
      low-density lipoprotein-hemoperfusion.
AB  - We describe results from a feasibility study of a newly developed low-density
      lipoprotein (LDL) adsorbent designed for use in whole-blood infusion LDL
      hemoperfusion. The adsorbent has almost the same chemical structure as the
      Liposorber adsorbent (dextran sulfate cellulose beads) but has a larger particle
      size. In whole-blood perfusion tests, the adsorbent adsorbed atherogenic LDL
      cholesterol directly from whole blood but left concentrations of high-density
      lipoprotein cholesterol largely unchanged. In whole-blood perfusion tests using
      fresh human donor blood or bovine blood anticoagulated with acid citrate dextrose
      solution or sodium citrate, the adsorbent showed minimal side effects in terms of
      blood cell activation, complement activation, and blood cell loss, suggesting
      that it has excellent blood compatibility. In addition, the adsorbent showed
      mechanical stability and absence of hemolysis. In conclusion, the new adsorbent
      showed the appropriate characteristics for an LDL adsorbent column for use in
      whole-blood infusion LDL-hemoperfusion.

PMID- 12423532
TI  - Meaning of low-density lipoprotein-apheresis for hypercholesterolemic patients at
      high risk for recurrence of coronary heart disease.
AB  - The goal of cholesterol-lowering therapy in hypercholesterolemic patients at high
      risk for recurrence of coronary heart disease (CHD) is the prevention of acute
      coronary syndrome by stabilization of coronary atheromatous plaque. We often
      encounter patients in whom it is difficult to maintain the serum cholesterol
      level at a desirable level with dietary therapy and drug treatment, despite the
      development and use of statins. For secondary prevention in patients who are at
      high risk for the recurrence of CHD and whose cholesterol level cannot be
      controlled by drugs alone, low-density lipoprotein (LDL)-apheresis therapy, which
      involves removal of LDL through extracorporeal circulation, is now available.
      Many reports concerning improvement of vascular endothelial function, improvement
      of myocardial ischemia, regression of coronary atherosclerotic lesions,
      stabilization of coronary plaque, and reduction in the incidence of cardiac
      events as a result of LDL-apheresis treatment have been published in various
      countries. We believe that LDL-apheresis should be performed on
      hypercholesterolemic patients with existing CHD for whom diet and maximum
      cholesterol-lowering drug therapies have been ineffective or not tolerated and
      whose LDL cholesterol level is 160 mg/dL or higher.

PMID- 12423533
TI  - First steps toward the establishment of a German low-density lipoprotein
      apheresis registry: recommendations for the indication and for quality
      management.
AB  - New recommendations for the indication of treatment with selective extracorporeal
      plasma therapy low-density lipoprotein apheresis (LDL-apheresis) in the
      prevention of coronary heart disease are urgently needed. The following points
      are the first results of the ongoing discussion process for indications for LDL
      apheresis in Germany: all patients with homozygous familial hypercholesterolemia
      with functional or genetically determined lack or dysfunction of LDL receptors
      and plasma LDL cholesterol levels >13.0 mmol/L (>500 mg/dL); patients with
      coronary heart disease (CHD) documented by clinical symptoms and imaging
      procedures in which over a period of at least 3 months the plasma LDL cholesterol
      levels cannot be lowered below 3.3 mmol/L (130 mg/dL) by a generally accepted,
      maximal drug-induced and documented therapy in combination with a cholesterol
      lowering diet; and patients with progression of their CHD documented by clinical
      symptoms and imaging procedures and repeated plasma Lp(a) levels >60 mg/dL, even
      if the plasma LDL cholesterol levels are lower than 3.3 mmol/L (130 mg/dL).
      Respective goals for LDL cholesterol concentrations for high-risk patients have
      been recently defined by various international societies. To safely put into
      practice the recommendations for LDL-apheresis previously mentioned, standardized
      treatment guidelines for LDL-apheresis need to be established in Germany that
      should be supervised by an appropriate registry.

PMID- 12423535
TI  - Oxygen saturation and hemoglobin A content in patients with sickle cell disease
      undergoing erythrocytapheresis.
AB  - Severe hypoxia occurs in patients with acute chest syndrome, and
      erythrocytapheresis has been shown to improve oxygenation. Patients with sickle
      cell anemia also have decreased baseline oxygen saturation values, but the effect
      of erythrocytapheresis on steady-state oxygenation has not been well studied. We
      investigated the changes in oxygen saturation versus hematocrit, fraction of
      hemoglobin A, and transfusion volume during 71 prophylactic erythrocytapheresis
      procedures performed in 5 stable patients with sickle cell anemia. Each patient
      had a history of either acute chest syndrome or stroke, but no serious events
      occurred while enrolled in the chronic exchange program. The oxygen saturation
      improved from 1% to 6% during erythrocytapheresis in each of our patients (p <
      0.001) regardless of preprocedure saturation level or total hematocrit. We have
      shown that decreased baseline oxygen saturation in sickle cell disease is related
      to abnormal hemoglobin S levels, and oxygen saturation can be improved with
      erythrocytapheresis, independent of any change in the total hematocrit.

PMID- 12423534
TI  - Monitoring of peripheral blood CD34+ cell counts on the first day of apheresis is
      highly predictive for efficient CD34+ cell yield.
AB  - The purpose of this study was to evaluate the correlation of preleukapheresis
      circulating CD 34+ cells/micro L, white blood cells (WBC), and platelet counts on
      the first day of apheresis with the yield of collected CD 34+ cell counts in 40
      patients with hematological malignancies (n = 29) and solid tumors (n = 11). The
      median numbers of apheresis cycles, numbers of CD 34+ cells, peripheral blood
      (PB) mononuclear cells, and total nucleated cells collected were 2 (range, 1-4),
      5.5 x 106/kg (range, 0.05-33.78), 2.59 x 108/kg (range, 0.04-20.68), and 7.36 x
      108/kg (range, 0.15-28.08), respectively. There was a strong correlation between
      the number of preleukapheresis circulating CD 34+ cells/micro L and the yield of
      collected CD 34+ cells per kilogram (r = 0.962, p < 0.001). The threshold levels
      of PB C 34+ cell/micro L to obtain > or =1 x 106/kg and > or =2.5 x 106/kg CD 34+
      cell in one collection were 12/micro L and 34/ micro L, respectively. Fifteen of
      17 (88%) patients who had > or =34 CD 34+ cells/ micro L in the PB before
      collection reached the level of > or =2.5 x 106/kg in a single apheresis. Despite
      a low r value, WBC and platelet counts on the first day of apheresis also
      correlated with the yield of collected daily CD 34+ cells per kilogram (r =
      0.482, p < 0.01 and r = 0.496 p < 0.01, respectively). These data suggest that
      preleukapheresis circulating CD 34+ cells/ micro L correlated significantly
      better with the yield of collected CD 34+ cells than WBC and platelet counts on
      the first day of apheresis. Using a value of 34/micro L preleukapheresis
      circulating CD 34+ cells as a guide for the timing of peripheral blood stem cells
      collections can be time saving and cost-effective.

PMID- 12423536
TI  - Case reports on emergency treatment of cardiovascular syndromes through heparin
      mediated low-density lipoprotein/fibrinogen precipitation: a new approach to
      augment cerebral and myocardial salvage.
AB  - We report the first experiences with HELP apheresis as an emergency treatment for
      acute cardiovascular syndromes; two patients who were not eligible for lysis
      therapy and catheter intervention were treated with HELP apheresis instead. Both
      patients had a most severe, generalized atherosclerosis and reached the hospital
      too late for conventional measures. In both cases, the use of the apheresis
      dramatically improved the clinical situation to such an extent that the
      possibilities of this apheresis system urge further investigation.

PMID- 12423537
TI  - Leukapheresis in patients with previously untreated acute myeloid leukemia.

PMID- 12423538
TI  - Three-dimensional analyses of individual corneocytes with atomic force
      microscope: morphological changes related to age, location and to the pathologic
      skin conditions.
AB  - BACKGROUND/AIMS: The past morphological studies on individual corneocytes have so
      far mainly focused on their two-dimensional characteristics, particularly on
      their projected area, which have been widely employed for the estimation of the
      turnover rate of the stratum corneum because of the practical use. However,
      sometimes a poor correlation has been reported between the projected area of
      corneocytes and actually measured turnover time of the stratum corneum. The
      objective of the present study is to perform detailed three-dimensional
      measurements of individual corneocytes with atomic force microscope. Through
      analyses of the obtained data, we tried to find morphological parameters that
      reflect more closely the differentiation process of the corneocytes in the
      stratum corneum than the frequently used two-dimensional projected area. METHODS:
      We measured such morphological parameters as the volume, average thickness and
      real surface area of individual corneocytes isolated from the covered skin (the
      flexor surface of the upper arm) and the exposed skin (the cheek) of 12 healthy
      individuals belonging to different age brackets, in addition to their projected
      area. We further introduced a new parameter, a flatness index calculated by
      dividing the projected area of corneocytes by their thickness. Similarly, we
      measured corneocytes obtained from eight patients with atopic dermatitis (AD) and
      psoriatic patients. RESULTS: Obtained results showed that most of these
      morphological parameters varied greatly depending upon the anatomical location
      and age of the subjects. Needless to say great differences were found between
      healthy skin and lesional skin of atopic dermatitis or psoriasis. However, the
      volume and thickness of corneocytes collected from the same location of normal
      skin of the covered area (upper arm) with tape-strippings were noted to decrease
      as they differentiated in the stratum corneum, showing an increase in their
      surface area and projected area with a resultant increase in the flatness index.
      Moreover, the corneocyte collected from the lesional skin of AD or psoriasis
      showed a great decrease in flatness index, reflecting their poor differentiation
      in the stratum corneum due to its enhanced turnover rate. Most of all, we found a
      poor correlation between the projected area and the various three-dimensional
      morphologic parameters of the corneocytes, indicating that the projected area
      does not reflect the volume or thickness of corneocytes that are also greatly
      influenced by the differentiation process of corneocytes in the stratum corneum.
      CONCLUSIONS: To estimate the differentiation speed of the corneocytes, we suggest
      using their flatness index rather than the two-dimensional cell surface area,
      because the former is a concept that takes into account the three-dimensional
      characteristics of corneocytes.

PMID- 12423539
TI  - Effect of exposure of human skin to a dry environment.
AB  - BACKGROUND/AIMS: Changes in the skin conditions after exposure to low humidity
      have been generally experienced in everyday life, but there have been few reports
      to approach it-especially in healthy skin. We have examined the effect of low
      humidity on healthy human skin by using noninvasive measurement devices. METHODS:
      Skin conditions on the ventral forearm and the cheek before and after 3 or 6 h
      exposure to low humidity were evaluated by measuring skin surface conductance,
      skin surface capacitance and transepidermal water loss. Skin surface replicas
      were also taken before and after exposure and analysed for roughness parameters-
      Ra (arithmetic mean roughness value), Rz (10-point height), Sm (mean value of the
      profile element) and VC1 (anisotropy of skin furrows). RESULTS: There was a
      significant decrease of water content of stratum corneum at both test sites from
      the time points 0 h to 3 h and 6 h (P < 0.01) and transepidermal water loss from
      the time point 0 h to 6 h (P < 0.05). Regarding the roughness parameters, a
      significant increase of Rz in the directions of 45 degrees/225 degrees and 90
      degrees/270 degrees to the body axis and Sm in the directions of 0 degrees/180
      degrees (P < 0.05) on the forearm and VC1 (P < 0.05) on the cheek. The parameter
      Rz also showed a tendency to increase in the directions of 45 degrees/225 degrees
      (P = 0.06) on the cheek. A specific pattern of the changes to be related to the
      Langer's lines in the surface morphology was observed. The changes of skin
      surface pattern in our experiment lead us to consider that exposure to low
      humidity even in such a short period would be related to inducing aggravation of
      skin texture and the formation of fine wrinkles. CONCLUSION: A short exposure of
      skin to a low-humidity environment induced changes in the moisture contents in
      the stratum corneum and skin surface pattern, which lead us to assume that a dry
      environment in our daily life would make fine wrinkles related to lack of water
      in the stratum corneum.

PMID- 12423541
TI  - Development of a digital imaging system for objective measurement of
      hyperpigmented spots on the face.
AB  - BACKGROUND/AIMS: There are few available methods that can be used to quantify
      hyperpigmented spots on a wide area of the face. The objective of this study was
      to develop such a method through the use of specialized image analysis
      technologies. METHODS: This imaging system was composed of a source of
      illumination whose light intensity was controlled with a dimmer, a 3-CCD video
      camera connected to a computer, and a positioning device used to correctly align
      the subject's face. This system was calibrated by adjusting the light intensity,
      the camera position, and white balance of the camera in order to acquire
      reproducible images. Using a specific algorithm for the image analysis, this
      system enabled us to measure both the total area of hyperpigmented spots (mm2)
      and the averaged skin colour tone (quasi L*a*b*) excluding the area of those
      hyperpigmented spots in a wide area of the face. The accuracy and reproducibility
      of the system was validated using a mannequin head with six standard colour chips
      obtained from the GretagMacbeth ColorChecker, and brown-coloured patches that
      simulated hyperpigmented spots whose colour and area were both known. The
      correlation between CIE L*a*b* and quasi L*a*b* values was examined by conducting
      simultaneous measurements of the facial skin colour of 187 subjects with a
      tristimulus colourimeter (Minolta Chromameter) and our imaging system. RESULTS:
      The measurement errors in quasi L*a*b* values of colour chips and the area of
      brown patches were less than 2 and 5%, respectively, unless these chips or
      patches were located in the peripheral zone of the mannequin head. The variation
      in quasi L*a*b* values and the area of hyperpigmented spots (mm2) in five
      repeated measurements performed once every hour was less than 2%. There was an
      excellent correlation between the CIE L*a*b* and quasi L*a*b* values, and the
      Pearson's correlation coefficient between CIE L* and quasi L* value, for
      instance, was 0.908. CONCLUSIONS: : As long as the region to be evaluated is
      limited to the cheek and periorbital areas, this system enables automatic
      detection of hyperpigmented spots in a wide area of the face, as well as the
      correct measurement of those areas and determination of skin colours.

PMID- 12423540
TI  - Epidermal calcium release (ECR) in vivo sampled with a simple washout chamber
      technique.
AB  - BACKGROUND/AIMS: Epidermis forms the protective barrier of the skin by its
      outermost layer, stratum corneum. The purpose of this study was to investigate
      the epidermal barrier in view of epidermal calcium release (ECR), phosphate
      release, transepidermal water loss (TEWL) and skin surface pH. Calcium is mainly
      an intracellular ion. Calcium was sampled introducing a new and simple washout
      chamber technique for the study of epidermal release in vivo. METHODS: Test sites
      on forearms of 13 healthy subjects were pre-treated with 24 h water occlusion, 24
      h 2% sodium lauryl sulphate (SLS) or tape stripped. Both untreated and pre
      treated test sites were exposed to a water washout chamber with 200 micro
      deionized water as a solvent. Water washout chambers were removed after two hours
      and calcium and phosphate in the water was analyzed. Transepidermal water loss
      and pH were measured before and after the trial. RESULTS: pH increased after tape
      stripping and after exposure to SLS. Transepidermal water loss increased
      significantly at all test sites. Calcium was significantly released from SLS
      treated sites but not from tape stripped sites. There was generally a correlation
      between ECR, phosphate release, TEWL and pH. In this study ECR is showed to be a
      barrier marker of high reproducibility. CONCLUSIONS: Epidermal calcium release or
      ECR is found useful as an indicator of skin barrier function. Calcium release and
      increase of pH appear mainly to illustrate direct and corrosive damage to
      epidermal cells and functions contrasting TEWL, in this experiment probably
      reflecting intercellular damage of fracturing as exemplified by mechanical damage
      resulting from surface stripping. This new distinction of skin barrier damage
      into cellular damage resulting from a corrosive chemical trauma and intercellular
      damage and fracturing resulting from a mechanical trauma is exemplified in SLS
      provocative testing and tape stripping, the former characterized by increased
      ECR. The washout chamber technique was deemed technically reliable and
      reproducible, and has a major potential in experimental dermatology and skin
      pharmacology for the study of in vivo epidermal release of a range of endogenous
      and exogenous substances.

PMID- 12423542
TI  - Effect of elastic compression stockings in patients with varicose veins and
      healthy controls measured by strain gauge plethysmography.
AB  - BACKGROUND/AIMS: Oedema is one of the most frequent signs of chronic venous
      insufficiency and may be present at all stages of this disorder. The aim of this
      study was to compare the effects of four different types of elastic compression
      stockings on oedema prevention in patients with varicose veins. METHODS: An
      increase in foot volume after elevation of the leg was evaluated by strain gauge
      plethysmography in 20 limbs with varicose veins and 14 normal limbs, and the
      effects of four different compression stockings--8, 14, 22 and 30-40 mmHg--were
      compared. RESULTS: All stockings significantly reduced the foot volume increase
      compared with the no stockings patient group and the normal group. There was no
      significant difference in the volume increase in the normal group for all four
      stockings, while there was a significantly smaller volume increase in the 22 mmHg
      stocking compared to the 14 mmHg stocking in the patient group. Between the 22
      mmHg and 30-40 mmHg stockings or between the 14 mmHg and 8 mmHg stockings, there
      was no significant difference in the volume increase. CONCLUSION: Elastic
      stockings, even with a pressure as low as 8 mmHg, can prevent oedema in patients
      with varicose veins, as well as in normal controls. However, the 22 mmHg and 30
      40 mmHg stockings were better at preventing foot oedema in patients with varicose
      veins than those exerting less compression.

PMID- 12423543
TI  - Validation of segmentation techniques for digital dermoscopy.
AB  - PURPOSE: This study aims at evaluating two automatic contour detection techniques
      especially developed for dermoscopic images. METHODS: Twenty-five images of
      lesions with a fuzzy boundary have been randomly selected. Five dermatologists
      experienced in dermoscopy have manually drawn the border of all the lesions and
      repeated the procedure after two and four weeks. The ability of a dermatologist
      to reproduce its own results was evaluated by measuring the non-overlapping area
      enclosed by its three successive contours. The interobserver variability
      evaluated the contour accuracy when using automatic or manual drawings. The mean
      probability that a pixel has been misclassified was computed for every observer
      and automatic technique. RESULTS: Experts in dermoscopy are not able to reproduce
      measurements precisely and the two automatic techniques had a lower
      misclassification probability than those obtained by each dermatologist.
      CONCLUSION: This study demonstrates that a single dermatologist should not be
      used as a reference, and subjective validation of lesion contour is inaccurate
      outside an experts's group. It is argued that image processing techniques for
      computer-aided diagnosis must show the best compromise within such a group.

PMID- 12423544
TI  - Quantitative measurement of desquamation and skin elasticity in diabetic
      patients.
AB  - BACKGROUND/AIMS: Diabetes mellitus is responsible for many cutaneous alterations.
      Xerosis and sclerotic change of the skin are the most common findings. Recently
      non-invasive computerized devices have been developed and used for determining
      the desquamation rate and measuring the mechanical properties of the skin. Using
      these devices, the necessity to characterize the conditions of the skin in the
      healthy as well as the diseased state is increasing. The aim of this study was to
      compare the elasticity and desquamation rate between the diabetic population and
      the normal population using non-invasive, objective methods. METHODS: Skin sites
      of 96 diabetics with normal appearance, were measured for skin elasticity and
      desquamation rate using the Cutometer and visual grading and D-Squame-image
      analysis method, respectively. The values of parameters were compared to values
      of 83 non-diabetics' results. RESULTS: There was a significant decrease in skin
      elasticity (expressed by Uv/Ue and Ur/Uf of the face) and in the value of fine
      flakes in the diabetics. Although insignificant, the SDI (Scale Density Index)
      calculated from objective automatic measurement was higher in the diabetics than
      the control group. CONCLUSIONS: The elasticity of facial skin was decreased in
      patients with diabetes. Decrease of the fine flakes of the diabetes patients
      reflect that irritation and xerotic changes are aggravated in skins of diabetic
      patients. The results indicate the presence of skin elasticity alteration and
      desquamation with diabetes mellitus. Such non-invasive evaluations of the skin
      may be useful for evaluating changes in the skin that are associated with
      diabetes mellitus.

PMID- 12423545
TI  - The gold standard for photographing pigmented skin lesions for diagnostic
      purposes: contact versus distant imaging.
AB  - BACKGROUND: It is mandatory that a new diagnostic method be validated by
      comparison with a well-established reference procedure before being introduced
      for use in clinical practice. In the field of pigmented skin lesions (PSL),
      clinical examination should be considered the reference procedure for new
      diagnostic methods, such as dermoscopy. However, it has not yet been established
      which is the best photographic procedure for obtaining the most informative
      clinical images to be used in a formal diagnostic setting. METHODS: In this study
      we investigated the diagnostic information provided by the two most popular
      methods currently used for clinical photographing of PSL: "contact" images
      obtained with a Dermaphot (Heine Ltd) at original x 10 magnification without oil
      application and "distant" images obtained with a macro objective from a distance
      of 10 cm. RESULTS: Two experienced dermatologists observed clinical images of a
      series of 57 PSL (11 melanomas, 31 melanocytic nevi, 10 pigmented basal cell
      carcinomas, and four other diagnoses). The degree of concordance between the
      diagnoses based on "contact" and "distant" images (melanoma/non-melanoma) was
      very good (k = 0.819). Regarding histology, the degree of concordance was better
      when the diagnosis was based on "contact" images (k = 0.54) than "distant" images
      (k = 0.47). In particular, "contact" images were superior to "distant" images for
      diagnosis of non-melanoma lesions (specificity of melanoma diagnosis 87.7% vs.
      83.6%), but we found no difference in melanoma detection (73% of sensitivity for
      both methods). CONCLUSIONS: Although the two photographic procedures appear to
      provide similar levels of diagnostic information, the "contact" method seems to
      provide a higher specificity for melanoma diagnosis.

PMID- 12423546
TI  - Scrotal temperatures do not differ among young boys wearing disposable or
      reusable diapers.
AB  - BACKGROUND/AIMS: This study investigated the effect of specific, commonly used
      diaper types on scrotal temperatures in normal healthy, young boys. These
      included both modern disposable and reusable diapers as well as various types of
      protective outer coverings that are in common use in both North America and
      Europe METHODS: Scrotal and skin surface temperatures were continuously monitored
      in healthy, young males using a computerized data-logging system based on
      temperature probes specifically designed for paediatric studies. These systems
      could be used either tethered to the PC or made completely portable depending
      upon the age and activity of the child being measured. Based on our results from
      several pilot studies, it became clear that the best way to determine if
      disposable and reusable diapers differ with regard to their impact on scrotal
      temperatures is to run these comparisons under controlled laboratory conditions
      where "diaper type" was the primary variable. A 2-h time period was chosen to
      ensure that sufficient time had elapsed for thermal equilibrium to be established
      under the diapers. We also felt it necessary to study the impact of urination and
      simulated this condition over the last 15 min using standardized methods. In
      addition to the skin surface temperatures, we also measured the temperature of
      the tympanic membrane using an infrared thermometer as an estimate of "core"
      temperature for each individual at various times during the session. RESULTS AND
      CONCLUSIONS: In this study, we have clearly shown that scrotal temperatures are
      the same whether the child is wearing disposable or reusable cloth diapers with a
      protective cover. The only situation in which scrotal temperatures were found to
      be lower is when the cloth diaper is used alone without a protective cover but
      this is not representative of how these products are actually used. We also found
      that on average scrotal temperatures are significantly lower than core for each
      diaper type. Occasionally, we did see individuals in which the maximal scrotal
      temperatures approached core temperatures but in every case the thermal sensors
      were soiled by a bowel movement. We also found that skin surface temperatures
      increased not only when covered by a diaper but also due to the thermal
      insulation provided by outer garments and blankets.

PMID- 12423547
TI  - Benign dermoscopic network patterns in dysplastic melanocytic nevi.
AB  - BACKGROUND/AIMS: Epiluminescence microscopy (ELM) is a non-invasive clinical
      technique, which by employing the optical phenomenon of oil immersion makes
      surface structures of the skin accessible for in vivo examination and provides
      additional criteria for the diagnosis of pigment skin lesions (PSLs). Many ELM
      criteria have been described. One of the most important ELM criteria is the
      pigment network (PN). OBJECTIVE: The aim of this study is to identify benign ELM
      (dermoscopic) network patterns of dysplastic melanocytic nevi (DMN). METHODS:
      This study included 907 dysplastic melanocytic nevi in 178 patients. Prior to
      biopsy, each lesion was photographed with oil immersion, and the images were
      viewed on a high-resolution compact slide projector. For each PSL, the ELM
      Network Features and ABCD-score were evaluated. RESULTS AND DISCUSSION: The
      benign dermoscopic network features in DMN are the presents of a regular PN with
      delicate lines and margins, which predominantly thins out at the border of the
      lesion. For DMN, with these features, the mean ABCD score is smaller than ABCD
      score for DMNs with irregular, prominent PN and network patches, ending abruptly
      at the periphery. In DMN with a network predominantly thinning out at the border
      of the lesion several uniform network patterns were found-diffuse network
      pattern, patchy network pattern, structureless center pattern, globular center
      pattern, and pigmented-blotch center pattern. CONCLUSIONS: Benign features of
      pigment network are regularity, delicacy and thinning out at the border of the
      lesion. Benign dermoscopic network patterns are diffuse network pattern, patchy
      network pattern, structureless center pattern, globular center pattern, and
      pigmented-blotch center pattern. They can be found in DMN with a network
      predominantly thinning out at the border of the lesion.

PMID- 12423548
TI  - Digital dermoscopy analysis of atypical pigmented skin lesions: a stepwise
      logistic discriminant analysis approach.
AB  - BACKGROUND: Digital microscopy is a non-invasive diagnostic technique enabling
      determination of characteristics that cannot be appreciated by direct
      observation. If correctly applied, this technique can be useful for the diagnosis
      of pigmented skin lesions. PURPOSE: To evaluate the utility of digital microscopy
      for analysing atypical benign and malignant pigmented skin lesions exploiting
      digital numerical filtering and automatic measurements. METHODS: Forty-eight
      parameters were identified as possible discriminating variables, and were grouped
      in four categories: geometries, colours, textures, and islands of colour.
      Statistical analysis was used to identify the variables with the highest
      discriminating power. RESULTS: The high quality of the digital image made it
      possible to observe diagnostic signs in pigmented skin lesion images, acquired by
      the present technique, in great detail. Specially designed filtering enhanced
      certain diagnostic patterns. Stepwise discriminant analysis selected only 10
      variables (the means of these variables were higher in melanomas than in nevi).
      CONCLUSIONS: The combined use of digital dermoscopy and stepwise logistic
      discriminant analysis made it possible to single out the best objective variables
      for distinguishing atypical nevi and early melanoma.

PMID- 12423549
TI  - Melanoma or pigmented basal cell carcinoma: a clinical-pathologic correlation
      with dermoscopy, in vivo confocal scanning laser microscopy, and routine
      histology.
AB  - BACKGROUND/PURPOSE: New techniques are being explored for improving diagnostic
      accuracy of pigmented skin lesions. Confocal scanning laser microscopy (CSLM) may
      represent such a novel technique. The purpose of this report was to demonstrate
      the potential application of CSLM as an aid in the diagnosis of a pigmented skin
      lesion that is clinically suspicious for melanoma. METHODS: An irregular
      pigmented lesion was examined clinically and dermoscopically. The lesion was
      imaged by CSLM and subsequently excised for histologic examination. Findings from
      CSLM were correlated with features observed on the dermoscopic and histologic
      examination. RESULTS: Confocal scanning laser microscopy (CSLM) allowed for the
      non-invasive visualization of the histologic features of superficial pigmented
      BCC, including buds and "islands" of tumor cells at the dermoepidermal junction
      and melanin-laden macrophages. Conventional histology confirmed the diagnosis of
      pigmented BCC. CONCLUSION: Confocal scanning laser microscopy (CSLM) may serve as
      an aid in the non-invasive diagnosis of pigmented skin lesions clinically
      suspicious for melanoma.

PMID- 12423550
TI  - Glycerol as a chemical chaperone enhances radiation-induced apoptosis in
      anaplastic thyroid carcinoma cells.
AB  - INTRODUCTION: Anaplastic thyroid carcinoma, which is one of the most aggressive,
      malignant tumors in humans, results in an extremely poor prognosis despite
      chemotherapy and radiotherapy. The present study was designed to evaluate
      therapeutic effects of radiation by glycerol on p53-mutant anaplastic thyroid
      carcinoma cells (8305c cells). To examine the effectiveness of glycerol in
      radiation induced lethality for anaplastic thyroid carcinoma 8305c cells, we
      performed colony formation assay and apoptosis analysis. RESULTS: Apoptosis was
      analyzed with Hoechst 33342 staining and DNA ladder formation assay. 8305c cells
      became radiosensitive when glycerol was added to culture medium before X-ray
      irradiation. Apoptosis was induced by X-rays in the presence of glycerol.
      However, there was little apoptosis induced by X-ray irradiation or glycerol
      alone. The binding activity of whole cell extracts to bax promoter region was
      induced by X-rays in the presence of glycerol but not by X-rays alone.
      CONCLUSION: These findings suggest that glycerol is effective against
      radiotherapy of p53-mutant thyroid carcinomas.

PMID- 12423551
TI  - Molecular characterisation of drug-resistant Plasmodium falciparum from Thailand.
AB  - BACKGROUND: The increasing levels of Plasmodium falciparum resistance to
      chloroquine (CQ) in Thailand have led to the use of alternative antimalarials,
      which are at present also becoming ineffective. In this context, any strategies
      that help improve the surveillance of drug resistance, become crucial in
      overcoming the problem. METHODS: In the present study, we have established the in
      vitro sensitivity to CQ, mefloquine (MF), quinine (QUIN) and amodiaquine (AMQ) of
      52 P. falciparum isolates collected in Thailand, and assessed the prevalence of
      four putative genetic polymorphisms of drug resistance, pfcrt K76T, pfmdr1 N86Y,
      pfmdr1 D1042N and pfmdr1 Y1246D, by PCR-RFLP. RESULTS: The percentage of isolates
      resistant to CQ, MF, and AMQ was 96% (50/52), 62% (32/52), and 58% (18/31),
      respectively, while all parasites were found to be sensitive to QUIN. In
      addition, 41 (79%) of the isolates assayed were resistant simultaneously to more
      than one drug; 25 to CQ and MF, 9 to CQ and AMQ, and 7 to all three drugs, CQ, MF
      and AMQ. There were two significant associations between drug sensitivity and
      presence of particular molecular markers, i) CQ resistance / pfcrt 76T (P =
      0.001), and ii) MF resistance / pfmdr1 86N (P < 0.001) CONCLUSIONS: i) In
      Thailand, the high levels of CQ pressure have led to strong selection of the
      pfcrt 76T polymorphism and ii) pfmdr1 86N appears to be a good predictor of in
      vitro MF resistance.

PMID- 12423553
TI  - Old bugs for new tasks; the microbial offer in the proteomics era.

PMID- 12423552
TI  - Molecular surveillance of drug resistance through imported isolates of Plasmodium
      falciparum in Europe.
AB  - BACKGROUND: Results from numerous studies point convincingly to correlations
      between mutations at selected genes and phenotypic resistance to antimalarials in
      Plasmodium falciparum isolates. In order to move molecular assays for point
      mutations on resistance-related genes into the realm of applied tools for
      surveillance, we investigated a selection of P. falciparum isolates that were
      imported during the year 2001 into Europe to study the prevalence of resistance
      associated point mutations at relevant codons. In particular, we tested for
      parasites which were developing resistance to antifolates and chloroquine. The
      screening results were used to map the prevalence of mutations and, thus, levels
      of potential drug resistance in endemic areas world-wide. RESULTS: 337 isolates
      have been tested so far. Prevalence of mutations that are associated with
      resistance to chloroquine on the pfcrt and pfmdr genes of P. falciparum was
      demonstrated at high levels. However, the prevalence of mutations associated with
      resistance to antifolates at the DHFR and DHPS genes was unexpectedly low, rarely
      exceeding 60% in endemic areas. CONCLUSIONS: Constant screening of imported
      isolates will enable TropNetEurop to establish a screening tool for emerging
      resistance in endemic areas.

PMID- 12423554
TI  - Gender differences in factors influencing insulin resistance in elderly
      hyperlipemic non-diabetic subjects.
AB  - BACKGROUND: The increase in the prevalence of insulin resistance-related
      metabolic syndrome, a disorder that greatly increases the risk of diabetes, heart
      attack and stroke, is alarming. One of the most frequent and early symptoms of
      metabolic syndrome is hypertriglyceridemia. We examined the gender differences
      between various metabolic factors related to insulin resistance in elderly non
      diabetic men and postmenopausal women of comparable age suffering from
      hypertriglyceridemia, and compared them with healthy subjects of equal age.
      RESULTS: The indexes of insulin resistance HOMA IR and QUICKI were significantly
      higher in both hyperlipemic men and women than in controls; 95% confidence limits
      of hyperlipemic subjects did not overlap with controls. In both normolipemic and
      hyperlipemic men and women serum leptin correlated significantly with insulin
      resistance, while HDL-cholesterol correlated inversely with HOMA-IR only in women
      (both normo- and hyperlipemic), and serum tumor necrosis factor alpha (TNFalpha)
      only in hyperlipemic women. According to results of multiple regression analysis
      with HOMA-IR as a dependent variable, leptin played a significant role in
      determining insulin resistance in both genders, but--aside from leptin-
      triglycerides, TNFalpha and decreased HDL-cholesterol were significant
      determinants in women, while body mass index and decreased HDL-cholesterol were
      significant determinants in men. The coefficient of determination (R2) of HOMA IR
      by above mentioned metabolic variables was in women above 60%, in men only about
      40%. CONCLUSION: The significant role of serum leptin in determination of insulin
      resistance in both elderly men and postmenopausal women of equal age was
      confirmed. However, the study also revealed significant gender differences : in
      women a strong influence of triglycerides, TNFalpha and decreased HDL
      cholesterol, in men only a mild role of BMI and decreased HDL-cholesterol.

PMID- 12423555
TI  - Telomerase activity in human leukemic cells with or without monosomy 7 or 7q-.
AB  - BACKGROUND: In bone marrow material from patients with various leukemias we noted
      that samples with either a deletion on the long arm of one chromosome 7 (7q-) or
      a monosomy 7 had a higher telomerase activity. Considering that introduction of a
      chromosome 7 into a cancer cell line had been reported to eliminate telomerase
      activity, that 7q- is a common negative prognostic finding in cancers, and that
      the deleted segment (band 7q31) contains an unidentified tumor suppressor gene,
      we wondered if this gene might be a telomerase inhibitor. RESULTS: We found no
      significant difference in telomerase activity between the three groups of patient
      samples. In contrast to reports on tumor cell lines we observed no amplification
      of the telomerase genes. METHODS: We analyzed telomerase activity and copy number
      of the telomerase genes hTERT and hTR in frozen archival bone marrow samples from
      leukemia patients with a referral diagnosis of AML, and either a monosomy for
      chromosome 7, a deletion on the long arm of chromosome 7 (7q-), or none of these
      aberrations. Telomerase activity was measured with a commercially available kit,
      and the copy number of the telomerase genes was tested by FISH. CONCLUSIONS: We
      found no evidence of a telomerase inhibitor in band 7q31. The lack of telomerase
      gene amplification found in cell lines from solid tumors could reflect that this
      amplification is a property of solid tumors, not of hematological cancers.

PMID- 12423556
TI  - Reducing hypothalamic AGRP by RNA interference increases metabolic rate and
      decreases body weight without influencing food intake.
AB  - BACKGROUND: Several lines of evidence strongly suggest that agouti-related
      peptide (AGRP) plays a key role in the regulation of metabolic function but
      ablation of the AGRP gene has no apparent effect on metabolic function. Since
      specific pharmacological antagonists of AGRP do not presently exist, we assessed
      if reduction of hypothalamic AGRP mRNA by RNA interference (RNAI) would influence
      metabolic function, an outcome suggesting that pharmacological antagonists might
      constitute useful reagents to treat obesity. RESULTS: The RNAI protocol
      specifically reduced hypothalamic expression of AGRP mRNA by 50% and resulted in
      reduction of AGRP peptide immunoreactivity. Physiologically, the reduction in
      AGRP levels was associated with increased metabolic rate and reduced body weight
      without changes in food intake. CONCLUSION: AGRP can function to increase body
      weight and reduce metabolic rate without influencing food intake. The present
      study demonstrates that RNAI protocols can be used to assess physiological
      function of neuronal genes in vivo.

PMID- 12423557
TI  - [The mechanisms and effects of panax notoginside and methylprednisolone in a rat
      model of pulmonary fibrosis].
AB  - OBJECTIVE: To study the effects of panax notoginside (PNS) and methylprednisolone
      (solu-medrol) on the development of pulmonary fibrosis and the possible
      underlining mechanisms. METHODS: Rats were divided into 3 groups: pulmonary
      fibrosis group, PNS treated group and solu-medrol treated group. On days 1, 3, 7,
      14, and 28 after bleomycin treatment, 5 rats in each group were killed and the
      lungs and plasma were harvested for histopathological studies,
      immunohistochemical determination of collagen I and III and ELISA detection of
      MIP-1alpha and MCP-1. RESULTS: The degrees of fibrosis, the levels of collagen I
      and III, and the levels of MIP-1alpha and MCP-1 decreased significantly in the
      PNS and solu-medrol treated groups as compared with the fibrosis group (P <
      0.05). CONCLUSION: Both PNS and solu-medrol are effective in modulating the
      process of pulmonary fibrosis induced by bleomycin in rats.

PMID- 12423558
TI  - [T(1) carcinoma of the lung: characteristics of lymph node metastasis and its
      clinical significance].
AB  - OBJECTIVE: To investigate the frequency, distribution and features of lymph node
      metastasis in T(1) carcinoma of the lung, and to provide evidence for lymph node
      dissection. METHODS: Two hundred and fifteen patients with T(1) carcinoma of the
      lung underwent R2 surgery plus extended dissection of hilar, interlobular and
      mediastinal lymph nodes according to the mapping system developed by Naruke.
      RESULTS: 1 674 groups of lymph nodes were dissected. The metastatic rates of N(1)
      and N(2) were 11% and 6% respectively. Lymph node metastatic rates in carcinoma
      of the lung with maximum diameters less than 1.5 cm and between 1.6 cm
      approximately 3.0 cm were 5% and 8% respectively. N(1) and N(2) metastasis was
      not found in squamous cell carcinoma of the lung with a maximum diameter less
      than 1.5 cm. N(2) metastatic rates were 5% in squamous cell carcinoma 23% in
      adenocarcinoma and 3/9 in small cell carcinoma, the difference being significant
      (P < 0.01). 3/4 squamous cell carcinoma invaded only one group of N(2) nodes, but
      over 3 groups of lymph nodes were positive in 40% of adenocarcinoma. Saltatory
      metastasis accounted for 41% of N(2) metastasis. Fourteen percent of N(2)
      positive tumors in upper lobes metastasized to the lower mediastinum, whereas 60%
      of N(2)-positive cancers in lower lobes invaded the upper mediastinum.
      CONCLUSIONS: The frequency of lymph node metastasis increases with the growth of
      tumors. Metastasis in adenocarcinoma occurs more frequently than in squamous cell
      carcinoma, but most common in small cell carcinoma. Tumors at any site can
      metastasize to the distant mediastinum. Except for squamous cell carcinoma with
      maximum diameter less than 1.5 cm which are likely to be cured without lymph node
      dissection, other types of T(1) carcinoma of the lung need extended lymph node
      dissection.

PMID- 12423559
TI  - [The effect of rhodiola and acetazolamide on the sleep architecture and blood
      oxygen saturation in men living at high altitude].
AB  - OBJECTIVE: To study the changes of sleep architecture and blood oxygen saturation
      (SaO(2)) during sleep in men living at high altitude, and to investigate the
      effect of rhodiola and acetazolamide on these sleep indexes. METHODS: Twenty-four
      men aged 18 to 21 years who had stayed at high altitude (5 380 m above sea level)
      for 1 year were randomly divided into groups A (treated with oral rhodiola), B
      (treated with oral acetazolamide) and C (treated with rhodiola + acetazolamide).
      Their sleep architecture and SaO(2) were recorded for 24 days before and after
      taking the medicines. RESULTS: Compared with baseline, the waking SaO(2)
      (WSaO(2)), the lowest SaO(2) (LSaO(2)) and the mean SaO(2) (MSaO(2)) were
      increased significantly after treatment for 24 days (P < 0.01), and the times of
      oxygen desaturation >/= 4% per hour (DI4) and the percentage of time spent at
      SaO(2) below 80% (SIT(80)) were decreased significantly (P < 0.01). After
      treatment, the NREM I and II was shortened, and III + IV and REM sleep were
      prolonged (P < 0.01): the total waking time (TWT) was shortened, and the sleep
      efficiency index (SEI) was markedly increased (P < 0.01). Compared with group
      A's, groups B's and C's SIT(80) were increased (P < 0.05). CONCLUSION: Both
      rhodiola and acetazolamide were effective in modulating the sleep architecture
      and improving the sleep quality in young men living at high altitude, but there
      was no synergistic effect between rhodiola and acetazolamide.

PMID- 12423560
TI  - [Significance of the changes of platelet activation and fibrinolytic activity in
      patients with obstructive sleep apnea-hypopnea syndrome].
AB  - OBJECTIVE: To investigate the changes of platelet activation, coagulability, and
      fibrinolytic activation in patients with obstructive sleep apnea-hypopnea
      syndrome (OSAHS) before and after the institution of nasal continuous positive
      airway pressure (nCPAP). METHODS: Fifty-eight cases of OSAHS confirmed by
      polysomnography (PSG) were selected as the trial group, 20 subjects without OSAHS
      were recruited as the control group. Eleven patients with severe OSAHS were
      treated by nCPAP. Plasma GMP-140, GPIIb/IIIa and D-dimer were measured by ELISA.
      RESULTS: Plasma levels of GMP-140, GPIIb/IIIa and D-dimer were significantly
      higher in patients with moderate to severe OSAHS than those in the control group,
      P < 0.05, and nCPAP therapy decreased their levels significantly, P < 0.001. GMP
      140, GPIIb/IIIa and D-dimer were correlated positively with AHI, and negatively
      with minimal oxygen saturation, P < 0.001. CONCLUSIONS: Our findings suggest that
      activation of platelet and coagulation system with fibrinolytic activation may be
      associated with the high prevalence of cerebrovascular and cardiovascular events
      in patients with OSAHS. nCPAP therapy is effective in correcting these
      coagulatory and fibrinolytic abnormalities.

PMID- 12423561
TI  - [Imbalance of Th1/Th2 cytokines in patients with pulmonary tuberculosis].
AB  - OBJECTIVE: To explore if there is an imbalance of Th1/Th2 cytokines in patients
      with pulmonary tuberculosis and its correlation with disease severity and
      treatment results. METHODS: The levels of serum IgE, IL-4 and IFN-gamma were
      measured in 100 healthy controls and 124 patients with pulmonary tuberculosis who
      were sputum positive for Mycobacterium tuberculosis before treatment. The
      cytokine levels were compared and their correlation with disease severity, sputum
      conversion after treatment, and treatment protocols were analyzed. RESULTS: The
      serum levels of IgE, IL-4 and IFN-gamma were 1.048 +/- 0.496, 0.439 +/- 0.160 and
      0.213 +/- 0.017 respectively in pulmonary tuberculosis, and 0.867 +/- 0.289,
      0.421 +/- 0.024 and 0.224 +/- 0.005 respectively in the controls. The serum level
      of IL-4 was higher in patients with severe disease than that in patients with
      milder disease. Both IL-4 and IFN-gamma were significantly higher in cases
      receiving a second course of therapy than in patients receiving initial therapy.
      In patients who were sputum positive for Mycobacterium tuberculosis after two
      months of therapy, the serum level of IL-4 was higher but that of IFN-gamma was
      lower compared to those who became sputum negative for Mycobacterium tuberculosis
      after two months' treatment. CONCLUSIONS: Patients with active pulmonary
      tuberculosis before antituberculous therapy showed lower expression of Th1 and
      higher expression of Th2 cytokines, and this cytokine profile was correlated with
      disease severity. Patients with lower serum IFN-gamma and higher IL-4 before
      treatment were less responsive to antituberculous therapy.

PMID- 12423562
TI  - [Effect of budesonide on Clara cell secretory protein and its mRNA expression in
      a rat model of asthma].
AB  - OBJECTIVE: To investigate the effect of inhaled glucocorticoids on the expression
      of Clara cell secretory protein (CCSP) and its mRNA in lung tissue of a rat model
      of asthma. METHODS: The rat asthmatic model was established by sensitizing and
      challenging SD rats with aerosolized ovalbumin (OVA). Rats were divided into a
      control, an asthmatic and a glucocorticoid groups. Budesonide aerosol was
      delivered by a jet nebulizer. The CCSP mRNA level in the lung tissue and the CCSP
      level in bronchoalveolar lavage fluid (BALF) were determined by RT-PCR and dot
      immuno-blotting, respectively. RESULTS: The level of CCSP mRNA in the lung tissue
      was 0.65 +/- 0.04 in the control, 0.56 +/- 0.05 in the asthmatic and 0.63 +/-
      0.04 in the glucocorticoid groups, respectively (asthma versus control, P < 0.01;
      glucocorticoid versus asthma, P < 0.05). The CCSP level in BALF was 60 +/- 5 in
      the control, 49 +/- 5 in the asthmatic and 57 +/- 5 in the glucocorticoid groups,
      respectively (asthma versus control, P < 0.01; glucocorticoid versus asthma, P <
      0.05). Budesonide reduced the percentage of eosinophils in BALF and inhibited
      airway inflammation. CONCLUSIONS: OVA challenge in the rat model decreased CCSP
      mRNA, resulting in a reduction in CCSP production, which may contribute to
      asthmatic airway inflammation. Inhaled glucocorticoids increased the expression
      of CCSP mRNA in lung tissue, which may be a mechanism for the suppression of
      airway inflammation by glucocorticoids.

PMID- 12423563
TI  - [Modulation of allergic airway inflammation by immunostimulatory DNA sequences in
      conjunction with an allergen in a murine model of asthma].
AB  - OBJECTIVE: To compare the suppressive effects of immunostimulatory sequences (ISS
      DNA) alone or ISS-DNA in conjunction with ovalbumin (OVA) on airway inflammation
      in a mouse model of asthma. METHODS: Thirty six female BALB/c mice were divided
      into 4 groups: group ISS (A), group ISS + OVA (B), group OVA (C) and group normal
      saline (D). Mice in groups A, B and C were sensitized and challenged with OVA.
      Group A and group B were subdivided into subgroup A(1) and B(1) (injected
      intraperitoneally with ISS DNA 100 micro g or ISS DNA 100 micro g and OVA 10
      micro g once) and subgroup A(2) and B(2) (injected intraperitoneally with ISS DNA
      or ISS DNA and OVA twice). Blood samples were obtained every week for six weeks.
      OVA-specific IgE was measured by ELISA. Bronchoalveolar lavage fluid (BALF), lung
      tissues and spleen cells were collected. BAL total cell numbers and differentials
      were counted. Interferon gamma (IFN-gamma) produced by OVA-stimulated spleen
      cells was determined by ELISA. RESULTS: Eosinophil count in group A(1) [(2.39 +/-
      0.81) x 10(4)/ml], group A(2) [(2.62 +/- 0.77) x 10(4)/ml], group B(1) [(1.80 +/-
      0.12) x 10(4)/ml], and group B(2) [(1.84 +/- 0.67) x 10(4)/ml] were significantly
      lower than those in group C [(12.43 +/- 2.13) x 10(4)/ml], P < 0.05. The levels
      of IFN-gamma in group A(1) [(510 +/- 102) pg/ml], group A(2) [(492 +/- 98)
      pg/ml], group B(1) [(532 +/- 120) pg/ml], and group B(2) [(469 +/- 132) pg/ml]
      were significantly higher than those in group C [(194 +/- 80) pg/ml], P < 0.05.
      The serum level of IgE in group B was significantly lower than that in group C in
      four weeks, but that in group A was not significantly different from that in
      group C. A second dose of ISS-DNA did not show additional effect as compared to
      the signal dose treatment. CONCLUSIONS: ISS-DNA inhibited allergic airway
      inflammation in a murine model of asthma. ISS-DNA and OVA combination was more
      effective than ISS-DNA alone.

PMID- 12423564
TI  - [A clinical study on the relationship between endogenous carbon monoxide and
      hypoxic pulmonary hypertension].
AB  - OBJECTIVE: To study the plasma level of endogenous carbon monoxide (CO) in
      patients with chronic cor pulmonale (CCP) and its relationship with endothelin-1
      (ET-1) and hypoxic pulmonary hypertension (HPH). METHODS: There were examinations
      on the plasma levels of endogenous CO and ET-1 in 33 patients with CCP, and their
      correlation with PaO(2) and the ratio of right ventricular pre-ejection period to
      the pulmonary flow acceleration time (RVPEP/AT), an indicator of pulmonary
      hypertension. Thirty healthy subjects served as normal controls. RESULTS: The
      levels of endogenous CO, ET-1 and the ET-1/CO ratio in acute exacerbation and
      remission in the CCP group [CO: (1.34 +/- 0.18) mg/L, (1.07 +/- 0.14) mg/L; ET-1:
      (82 +/- 15) ng/L, (57 +/- 10) ng/L; ET-1/CO: 61 +/- 6, 53 +/- 5] were higher than
      those in the normal control group [CO: (0.55 +/- 0.12) mg/L, P < 0.001; ET-1: (27
      +/- 9) ng/L, P < 0.001; ET-1/CO: 48 +/- 7, P < 0.05]. The levels of plasma
      endogenous CO, ET-1, and the ET-1/CO ratio in acute exacerbation were higher than
      those in the remission stage (P < 0.001, P < 0.001, P < 0.05). The level of
      endogenous CO was negatively correlated with PaO(2) (r = -0.733, P < 0.01; r = 
      0.672, P < 0.01) and positively correlated with RVPEP/AT (r = 0.620, P < 0.01; r
      = 0.557, P < 0.01). The ET-1/CO ratio was positively correlated with RVPEP/AT (r
      = 0.501, P < 0.01; r = 0.485, P < 0.05) in patients with acute exacerbation or in
      remission. CONCLUSION: The increased level of plasma endogenous CO in patients
      with CCP suggests the involvement of CO in the pathophysiologic process of HPH.
      An imbalance between ET-1 and CO may be involved in the development of HPH.

PMID- 12423565
TI  - [Has the prognosis of cardiogenic shock post myocardial infarction changed?].

PMID- 12423566
TI  - [Cardiac surgery in elderly patients].

PMID- 12423567
TI  - [Trends in the proportion of patients younger than 75 years with acute myocardial
      infarction and Killip class III and IV. variables associated with occurence and
      case-fatality: 1978-1997].
AB  - INTRODUCTION: Acute pulmonary edema (Killip III) or cardiogenic shock (Killip IV)
      is associated with a higher mortality in the acute phase of myocardial infarction
      (AMI). OBJECTIVES: To analyze trends in the proportion of patients who developed
      Killip III and IV in AMI over a 20-year period in order to identify the variables
      associated with occurrence and case-fatality. METHODS: Hospital registry of first
      AMI in patients under than 75 years, from 1978 to 1997. Sociodemographic
      variables, cardiovascular risk factors, clinical variables, treatments,
      procedures, and worst Killip class were recorded. RESULTS: The registry included
      2,590 patients. Mean age was 60 years and 17% were women. Thirteen percent
      (13.5%) of the patients developed Killip III and IV, and no changes in this
      proportion were observed over the time period studied. Age, diabetes, previous
      angina, and anterior location of AMI were associated with a higher risk of Killip
      III and IV. Case-fatality at 28 days in this subgroup was 51.7%, with a
      decreasing linear trend over the years. Variables associated with a higher case
      fatality were age and malignant ventricular arrhythmias, whereas the periods 1990
      93 and 1994-97 were associated with a lower case-fatality. This protective effect
      disappeared after adjusting for treatment variables (antiplatelet agents and
      thrombolysis). CONCLUSIONS: The proportion of patients with AMI in which Killip
      class III and IV develops has remained stable in the last two decades. Although
      the 28-day case-fatality in these patients is high, a decrease has been observed
      in recent years in relation to the availability of new treatments (antiplatelet
      agents and thrombolysis).

PMID- 12423568
TI  - [Acute myocardial infarction in patients under 45 years].
AB  - INTRODUCTION AND OBJECTIVE: To evaluate the differential features of acute
      myocardial infarction in patients younger than 45 years old compared to older
      patients. PATIENTS AND METHODS: From 1995 to 1999, delays in the assistance,
      evaluation, and therapeutic strategies as well as complications in patients
      hospitalized with a diagnosis of acute myocardial infarction, have been
      registered in the intensive care units of the 17 hospitals participating in the
      PRIMVAC Register. RESULTS: During the study, 10,213 patients were registered,
      6.8% younger than 45 years old (691 patients). Young patients show a greater
      prevalence of cigarette smoking (80.9 vs 34.1%; p < 0.0001) and
      hypercholesterolemia (39.9 vs 28.6%; p < 0.0001), whereas arterial hypertension,
      diabetes, and history of coronary disease were significantly more frequent in the
      older group. This subgroup reached the healthcare system at an earlier stage (120
      vs 160 min; p < 0.0001). Thrombolysis was performed in 59.9% of patients younger
      than 45 years and in 45.9% of patients older than 45 years. Young patients were
      more frequently given aspirin (94.5%), heparin (70.6%), and beta-blocker drugs
      (38.4%), whereas patients older than 45 years were given a higher percentage of
      ACEI, digoxin, and inotropic drugs. Younger patients had a better prognosis and a
      lower mortality rate (3.5 vs 14%; p < 0.00001). CONCLUSIONS: Acute myocardial
      infarction in patients younger than 45 years had different clinical features and
      responded to different therapeutic and diagnostic approaches than acute
      myocardial infarction in patients over 45 years, as well as a better short-term
      prognosis.

PMID- 12423569
TI  - [Safety and usefulness of transesophageal echocardiography in the acute phase of
      myocardial infarction].
AB  - INTRODUCTION AND OBJECTIVES: The usefulness and safety of transesophageal
      echocardiography have been assessed in other studies but there is no report in
      which these factors have been evaluated in the acute phase of myocardial
      infarction. Patients and method. Transesophageal echocardiography was performed
      56 times in 55 patients in the first week after a myocardial infarction. RESULTS:
      The study was completed in 54 of 56 patients. The indications were a
      transthoracic acoustic window that did not provide an accurate diagnosis in 13
      (23.2%), diagnosis of mechanical complications and severity assessment of mitral
      regurgitation in 35 (62.5%), exclusion of aortic dissection in 4 (7.1%),
      assessment of the severity of aortic stenosis in 1 (1.8%), exclusion of the
      presence of atrial thrombus in 1 (1.8%), evaluation of the left ventricular
      outflow tract gradient in 1 (1.8%), and evaluation of the presence of a left
      ventricular thrombus in 1 patient (1.8%). Two patients (3.6%) died while the
      study was being made, the first one 10 minutes after finishing the echocardiogram
      due to progression of a partial rupture of the papillary muscle and the second
      due to left ventricle free wall rupture. In both patients, the indication for
      transesophageal echography was the need for proper evaluation of a post-Acute
      Myocardial Infarction mechanical complication. CONCLUSIONS: Transesophageal
      echocardiography is a very useful technique for evaluating patients during the
      acute phase of myocardial infarction but further studies are needed to establish
      its safety in these patients.

PMID- 12423570
TI  - [Effect of angiotensin blockade on the orthostatic response in patients with
      systemic arterial hypertension].
AB  - INTRODUCTION AND OBJECTIVES: The effect of the treatment of arterial hypertension
      with angiotensin inhibitors on the autonomic response to orthostatism was
      studied. PATIENTS AND METHOD: In 20 hypertensive patients, enalapril (10 to 20
      mg) was administered daily for four weeks. Then, irbesartan (150 to 300 mg) was
      given for four weeks. Finally, 10 mg of enalapril combined with 150 mg of
      irbesartan was prescribed for another four weeks. Heart rate variability at rest
      and during the head-up tilt test with controlled respiration was assessed at the
      beginning and end of each period. RESULTS: Mean arterial pressure showed a
      similar reduction in the three treatment periods. There were no changes in heart
      rate. Heart rate variability at rest showed differences in the spectral high
      frequency component between the control and the treatment periods (p = 0.10).
      There was an increase in the high-frequency component between the control and the
      third (p = 0.047) and the fourth periods (p = 0.03). In the head-up tilt test
      there was a decrease in total spectral high-frequency power. CONCLUSIONS: There
      was no increase in orthostatic intolerance with these drugs in hypertensive
      patients. The absence of changes in heart rate in spite of a decrease in blood
      pressure suggests resetting of the baroreflex function. The long-term control of
      hypertension with these drugs may have a favorable effect on heart rate
      variability, with an increase in parasympathetic activity.

PMID- 12423571
TI  - [Effects of myocardial stretching on excitation frequencies determined by
      spectral analysis during ventricular fibrillation].
AB  - INTRODUCTION AND OBJECTIVES: The aim of this study was to analyze the effects of
      myocardial stretching on excitation frequencies, as determined by spectral
      analysis, during ventricular fibrillation. METHODS: In 12 isolated rabbit heart
      preparations, ventricular activation during ventricular fibrillation was recorded
      with multiple electrodes. Recordings were obtained before, during and after
      ventricular dilatation produced with an intraventricular balloon. The dominant
      frequency of the signals obtained with each of the electrodes was determined by
      spectral analysis. RESULTS: During the control phase, the mean, minimum and
      maximum dominant frequencies were, respectively, 14.3 1.7, 12.5 1.7, and 16.2 1.4
      Hz, and the average difference between the maximum and minimum frequencies was
      3.6 2.1 Hz. This difference was over 4 Hz in four cases, and in no case did it
      exceed 8 Hz. During ventricular stretching, the mean dominant frequency increased
      significantly (21.1 6.1 Hz; p < 0.0001), as did the minimum values (14 2.6 Hz; p
      < 0.05) and especially the maximum values (26.6 7.7 Hz; p < 0.0001). The
      difference between the maximum and minimum frequencies (12.6 6.4 Hz; p < 0.001)
      was over 4 Hz in all cases except one, and over 8 Hz in 9 cases. The maximum
      values were distributed heterogeneously during ventricular stretching. Upon
      suppressing ventricular stretching, the dominant frequency did not differ from
      controls. CONCLUSIONS: Myocardial frequency maps during ventricular fibrillation
      show limited variations in the dominant frequency of the signals recorded in the
      lateral wall of the left ventricle. During stretching, the patterns were
      heterogeneous, due mainly to the marked increase in the maximum dominant
      frequency. In the experimental model used, the effects of stretching remitted
      after suppressing ventricular dilatation.

PMID- 12423572
TI  - [Effect of HMG-CoA reductase inhibition on endothelial dysfunction-inducing
      protein in hypercholesterolemic rabbits].
AB  - INTRODUCTION AND OBJECTIVES: In our laboratory, we recently obtained evidence
      that cultured bovine endothelial cells contain cytosolic proteins that form
      complexes with the 3'-unstranslated region of endothelial nitric oxide synthase
      (eNOS) mRNA and are associated with its destabilization. The aim of this study
      was to determine the presence of such proteins and the level of eNOS expression
      in hypercholesterolemic rabbits as an in vivo model of endothelial dysfunction.
      METHODS AND RESULTS: Endothelium-dependent relaxation in response to
      acetylcholine was reduced in aortic segments from hypercholesterolemic rabbits
      compared with controls. Treatment of hypercholesterolemic rabbits with
      simvastatin (25 mg/kg body weight/day) restored endothelium-dependent relaxation.
      Aortic eNOS expression was reduced in hypercholesterolemic rabbits and was
      accompanied by enhanced binding activity of a 60-KDa cytosolic protein and
      reduced stability of eNOS mRNA. Simvastatin treatment upregulated eNOS expression
      and reduced the interaction of cytosolic protein with the 3'-untranslated region
      of eNOS mRNA. CONCLUSIONS: These results demonstrate the presence of a 60-KDa
      protein that binds to eNOS mRNA and reduces eNOS expression in the vascular wall.

PMID- 12423573
TI  - [Cardiac surgery in elderly patients].
AB  - OBJECTIVE: The morbimortality of elderly patients, (age 70 years or older), who
      underwent surgery for valvular and coronary artery disease in the last 17 years
      was analyzed. PATIENTS AND METHOD: A total of 1,305 patients (654 valvular, 531
      coronary and 120 combined) operated from January 1985 to December 2000 were
      retrospectively studied. Mean age was 73.7 years. We analyzed the progression of
      the pathology, comorbidity, and results. A second retrospective analysis was made
      of patients who underwent surgery in the last three years (436 patients) to
      determine the relation between preoperative comorbidity and postoperative
      evolution. RESULTS: The mean hospital mortality was 16% (18% valvular, 11%
      coronary artery, and 23% combined). In the last three years this mortality was
      reduced to 11% (15.17, 6.26, and 16.18%, respectively) despite an increase in
      comorbidity. Comorbidity and complications increased with age (p < 0.05). Mean
      hospital stay was 15.5 days and the stay in intensive/semi-intensive care was 5
      days. Independent risk factors of postoperative complications were creatinine
      levels > 2 mg/dl, combined surgery, and prior surgery. Predictors of death were
      prior surgery, valvular surgery, and combined surgery, with a clear tendency in
      the case of obesity. The presence of any complication in the postoperative period
      (renal or respiratory failure, infections, or myocardial infarction) was an
      independent predictor of mortality. Off-pump coronary surgery reduced mortality.
      In recent years, the mortality of patients operated without extracorporeal
      circulation has decreased from 5.71% to 4% for those who underwent extracorporeal
      circulation. CONCLUSIONS: Nowadays, cardiac surgery in older patients accounts
      for more than 30% of our surgical activity. Mortality is being controlled
      although comorbidity is increasing. The difference with respect to younger people
      is due to comorbidity (creatinine > 2 mg/dl, combined surgery, and previous
      surgery) and the higher probability of complications (infections, renal, and
      respiratory complications), which worsens prognosis. We believe that off-pump
      coronary surgery helps to improve results.

PMID- 12423574
TI  - [The heart as a bitter fruit or as a lonely hunter].

PMID- 12423575
TI  - [Spanish Registry on Cardiac Catheterization Interventions. 11th official report
      of the Working Group on Cardiac Catheterization and Interventional Cardiology of
      the Spanish Society of Cardiology (years 1990-2001)].
AB  - The results of the Spanish Registry of the Working Group on cardiac
      catheterization and Interventional Cardiology of the Spanish Society of
      Cardiology (years 1990-2001) are presented. One-hundred-and-three centers
      contributed data, all the cardiac catheterization laboratories in Spain; 97
      centers performed mainly adult catheterization and 6 carried out only pediatric
      procedures. In 2001, 95,430 diagnostic catheterization procedures were performed,
      with 79,607 coronary angiograms, representing a total increase of 8.4% over 2000.
      The population-adjusted incidence was 1947 coronary angiograms per 106
      inhabitants. Coronary interventions increased by 15.4% compared with 2000, with a
      total of 31,290 procedures and an incidence of coronary interventions of 761 per
      106 inhabitants. Coronary stents were the most frequently used devices with
      39,356 implanted in 2001, and increase of 33.4% over 2000. Stenting accounted for
      88.2% of procedures. Direct stenting was done in 11,280 procedures (40.9%). IIb
      IIIa glycoprotein inhibitors were given in 7,012 procedures (22.4%). Multivessel
      percutaneous coronary interventions were performed in 8,445 cases (27%) and
      interventions were performed ad hoc during diagnostic study in 23,144 cases (74
      %).A total of 3,845 percutaneous coronary interventions were carried out in
      patients with acute myocardial infarction, an increase of 22.9% over 2000 and
      12.3% of all interventional procedures. Among non-coronary interventions, atrial
      septal defect closure was performed more often (161 cases, a 60% increase over
      2000). Pediatric interventions increased by 15.4% (from 817 to 943 cases).Lastly,
      we would like to underline the high rate of reporting by laboratories, which
      allowed the Registry to compile data that are highly representative of
      hemodynamic interventions in Spain.

PMID- 12423576
TI  - [Coronary angioplasty in diabetic patients. Current and future perspectives].
AB  - It has been estimated that 15-25% of patients who undergo percutaneous or
      surgical coronary angioplasty are diabetics. The indications for coronary
      revascularization and initial results of the procedure do not differ
      substantially between patients with diabetes mellitus and non-diabetics. However,
      the long-term results of both percutaneous and surgical coronary angioplasty are
      less favorable in diabetics in terms of mortality and the need for new
      revascularization procedures. The development and widespread use of stents and
      glycoprotein IIb/IIIa receptor inhibiting drugs have improved the clinical
      evolution of diabetics treated with angioplasty. Currently available data show
      that the administration of glycoprotein IIb/IIIa inhibitors to patients
      undergoing coronary angioplasty is especially useful in diabetics and improves
      short-term and long-term results, decreasing one-year mortality by 45%. There
      seem to be indications for the routine use of glycoprotein IIb/IIIa inhibitors in
      diabetics treated with angioplasty. While the use of stents has improved long
      term and short-term results in diabetics, the success rates of angioplasty in
      diabetics are still lower than in non-diabetics. Diabetes is still an independent
      predictor of restenosis and long-term events after stenting interventions.
      Analysis of the studies comparing percutaneous and surgical revascularization in
      diabetic patients with multivessel disease shows that surgery is superior in
      terms of long-term mortality and need for new revascularization procedures.
      Stenting has improved, but not substantially, the results of multivessel
      angioplasty in diabetics. Therefore, the indications for angioplasty in
      multivessel diabetics should be evaluated individually. Factors that contribute
      to the less favorable post-angioplasty evolution of diabetic patients are more
      rapid progression of atherosclerosis and, especially, a higher rate of
      restenosis. New angioplasty techniques, such as brachytherapy and drug-eluting
      stents, are likely to significantly improve the results of percutaneous
      interventions in diabetics, thus allowing the indications for angioplasty in
      diabetics to be extended even further in the near future.

PMID- 12423577
TI  - [Helical CT in left ventricular pseudoaneurysm rupture].

PMID- 12423578
TI  - [Endothelial dysfunction in cardiologists after 24 hours on call].
AB  - The objective was to determine if the stress caused by 24 hours on call in a
      cardiology emergency room alters endothelial function assessed by high-resolution
      ultrasonography in the brachial artery. Fifteen young physicians were studied in
      a crossover design: a) after a normal night of sleep at home, and b) after 24
      hours on call without sleeping in an emergency room. Both studies were made at
      rest, 5 minutes after forearm occlusion and 3 minutes after administration of
      sublingual nitroglycerin. High-resolution ultrasonography and a 7.5-MHz linear
      array transducer were used to measure the brachial artery lumen. After 24 hours
      on call, physicians had significantly higher resting systolic and diastolic blood
      pressure. They also had a non-significant increase in heart rate and a lower
      brachial artery diameter. Brachial artery dilatation caused by hyperemia was only
      3.35%, while it increased to 11.34% after normal sleep (p < 0.001). Only 2
      physicians showed more than 4.4% dilatation, which was considered a normal
      response, while 13 had more than 4.4% after a normal night of sleep at home (p <
      0.01). The response to nitroglycerin was similar under control conditions and
      after 24 hours of duty oncall.In conclusion, stress caused by 24 hours on call in
      a cardiology emergency room depresses or abolishes endothelial function.

PMID- 12423579
TI  - [Immediate and long-term results of implantation of the new platinum coronary
      stent (atlas stent) in patients with coronary artery disease].
AB  - BACKGROUND AND OBJECTIVES: We evaluated the technical and clinical results of
      implantation of the Atlas stent, the hospital stay, and the short and long-term
      clinical and angiographic outcome. PATIENTS AND METHOD: The study included 169
      patients (60.1 10.8 year-old), 60.3% of which had acute coronary syndromes and
      complex lesions. Immediate success was achieved in 98% of cases. The clinical
      follow-up in 85.7% of the patients at 14.3 6.8 months, revealed that 89% remained
      free of adverse events and most (94.4%) were functional class I of the CCS.
      Angiographic follow-up at 8.4 4.1 months of 40.9% of the cases revealed
      restenosis in 27.9%. There were 2 cases of subacute thrombosis. CONCLUSIONS: The
      application of the Atlas stent in patients with a diverse clinical spectrum
      demonstrated good immediate and long term results, with a rate of restenosis
      similar to that of other stents available on the market.

PMID- 12423580
TI  - [Ectopia cordis and cardiac anomalies].
AB  - Ectopia cordis is a rare disease that occurs in 5.5 to 7.9 per million live
      births. Only 267 cases had been reported as of 2001, most (95%) associated with
      other cardiac anomalies. We studied the cardiac malformations associated in 6
      patients with ectopia cordis. Depending on where the defect was located, the
      cases of ectopia were classified into four groups: cervical, thoracic, thoraco
      abdominal, and abdominal. All 6 patients died before the third day of life, 4
      during delivery. Three of the patients were included in the thoracic group,
      whereas the other 3 belonged to the thoraco-abdominal group. All the patients had
      associated ventricular septal defects, 3 double-outlet right ventricle (50%) and
      the rest (50%) tetralogy of Fallot-pulmonary atresia. Two patients with double
      outlet right ventricle presented mitral-valve pathology, a parachute valve and an
      atresic mitral valve. None of these cardiac anomalies have been reported to date.

PMID- 12423581
TI  - [Comparative study of thoracic approaches in atrial septal defect closure].
AB  - Our early experience in approaching ASD by right thoracotomy as opposed to
      midline sternotomy is presented. Between July 2000 and December 2001, 15 patients
      (group A) were operated by right thoracotomy. Mean age of patients was 8.6 years
      and mean weight was 31.6 kg. In the same period, midline sternotomy was used in
      16 patients (group B). Mean age was 4.7 years and weight was 16.5 kg. The
      duration of the procedure, by-pass, and aortic cross-clamping were similar.
      Bleeding was 265 ml (8.4 ml/kg) in group A, and 152 ml (9.2 ml/kg) in group B.
      The duration of the ICU stay and time of discharge were 2.4 days and 6 days in
      group A, and 2.23 days and 6.87 days in group B, respectively. No significant
      differences were found in ASD closure by thoracotomy and sternotomy. The cosmetic
      appearance acceptance of right thoracotomy was excellent.

PMID- 12423582
TI  - [Indications of treatment with clopidogrel in the guidelines of the Spanish
      Society of Cardiology for unstable angina/non-ST-segment elevation acute
      myocardial infarction].

PMID- 12423584
TI  - Epidemiology of femoral neck fractures.

PMID- 12423585
TI  - The non-operative treatment of impacted femoral neck fractures.

PMID- 12423586
TI  - Evidence-based results depending on the implant used for stabilizing femoral neck
      fractures.

PMID- 12423587
TI  - Treatment of femoral neck fractures in Hungary with the Manninger screw.

PMID- 12423588
TI  - Analysis of fracture gap changes, dynamic and static stability of different
      osteosynthetic procedures in the femoral neck.

PMID- 12423589
TI  - The influence of haemarthrosis on the development of femoral head necrosis
      following intracapsular femoral neck fractures.

PMID- 12423590
TI  - Intracapsular femoral neck fractures: the importance of early reduction and
      stable osteosynthesis.

PMID- 12423591
TI  - Correlation of bone density and geometric parameters to the mechanical strength
      of the femoral neck.

PMID- 12423592
TI  - Structure and composition of silicon-stabilized tricalcium phosphate.
AB  - Silicon stabilized tricalcium phosphate [Si-TCP] is formed within the calcium
      hydroxyapatite (HA)-tricalcium phosphate (TCP) system when a stoichiometric
      precipitate of hydroxyapatite is fired at 1,000 degrees in the presence of
      SiO(2). This paper proposes a composition range and crystallographic structure
      for Si-TCP. Reitveld XRD powder diffraction, transmission electron microscopy,
      infrared and proton nuclear magnetic resonance measurements show that crystalline
      Si-TCP is associated with the displacement of OH from an initial hydroxyapatite
      structure. The resulting calcium phosphate is modified by the incorporation of
      silicon into its structure with excess silica contributing to an amorphous
      component. Si-TCP has a monoclinic structure with a space group P2(1)/a akin to
      alpha-TCP with estimated lattice constants of a=12.863+/-0.004 A, b=9.119 +/
      0.003 A, c=15.232+/-0.004 A, beta=126.3+/-0.1 degrees. It is proposed that Si(4+)
      substitutes for P(5+)in the TCP lattice with the average chemical composition of
      Si-TCP set primarily by the mechanisms available for charge compensation. While
      the formation of OH vacancies in HA initiates the transformation to Si-TCP, two
      mechanisms of charge compensation in the Si-TCP structure are plausible. If O(2-)
      vacancies provide charge compensation, the composition of Si-TCP is
      Ca(3)(P(0.9)Si(0.1)O(3.95))(2) derived for the addition of 0.33 mol SiO(2):mol
      HA. If excess Ca(2+) compensates, the composition is
      Ca(3.08)(P(0.92)Si(0.08)O(4))(2) derived for the addition of 0.25 mol SiO(2):mol
      HA. The reaction occurs most effectively when SiO(2) is added as a colloidal
      suspension rather than by the in-situ thermal decomposition of a silicon
      metallorganic compound. The material is a bioceramic of major biological interest
      because of its osteoconductivity and unique influence on skeletal tissue repair
      and remodeling.

PMID- 12423593
TI  - TNF-alpha secretion and macrophage mortality induced by cobalt and chromium ions
      in vitro-qualitative analysis of apoptosis.
AB  - Metal ion toxicity is a major cause for concern in metal-metal hip replacements.
      A previous study in our laboratory demonstrated that Co(2+) and Cr(3+) induce
      macrophage apoptosis in vitro at 24h, with the implication of a caspase-3
      pathway. The aim of the present study was to look at the effect of a prolonged
      incubation time on macrophage response with regards to TNF-alpha secretion and
      macrophage mortality, more specifically apoptosis. J774 macrophages were exposed
      for up to 48 h to 0-10 ppm Co(2+) and 0-500 ppm Cr(3+). ELISA results
      demonstrated that Co(2+ )and Cr(3+) induced a concentration- and time-dependent
      increase of TNF-alpha secretion, but a decrease at the highest concentrations of
      Cr(3+) (350-500 ppm). This decrease was most likely due to a high toxicity of
      Cr(3+) at such concentrations. Higher levels of TNF-alpha were observed with
      Co(2+) than Cr(3+), demonstrating a higher stimulatory effect of this ion. Trypan
      blue and flow cytometry results demonstrated that both Co(2+) and Cr(3+) ions
      induce macrophage mortality in a dose- and time-dependent manner. The number of
      cells decreased when ion concentrations increased, especially at 48 h. In
      parallel with the TNF-alpha results, Co(2+) was more toxic than Cr(3+) since the
      maximal effects were reached with lower concentrations (8-10 ppm vs. 350-500 ppm,
      respectively). DNA analysis demonstrated that both Co(2+) and Cr(3+) ions induce
      macrophage apoptosis, with a stronger signal at 24h than at 48 h, suggesting the
      presence of more necrosis after 48 h. PARP cleavage, another marker of apoptosis,
      was observed at both 24 and 48 h, with a maximum intensity at 48 h and with the
      highest concentrations of ions. In conclusion, this study demonstrates that both
      Co(2+) and Cr(3+) ions can induce the release of TNF-alpha and macrophage
      mortality in a dose- and time-dependent manner. More specifically, Co(2+) and
      Cr(3+) ions induced apoptosis after both 24 and 48 h incubation, although DNA
      analysis suggested the presence of necrosis at 48 h. The relative importance of
      apoptosis and necrosis in the induction of macrophage mortality by these metal
      ions remains to be investigated.

PMID- 12423594
TI  - Degradation of tungsten coils implanted into the subclavian artery of New Zealand
      white rabbits is not associated with local or systemic toxicity.
AB  - OBJECTIVE: To assess whether corrosion of tungsten coils is related to residual
      shunting and to evaluate whether elevated tungsten serum levels are associated
      with local or systemic toxicity. METHODS: Tungsten coils (SPI, Balt, France) were
      implanted into the subclavian artery of New Zealand white rabbits leading to a
      residual high-flow shunt in 5/10 rabbits. Serial serum tungsten levels, complete
      blood count and clinical chemistry were analysed prior to the implantation as
      well as 15 min, 2 and 4 months thereafter. After 4 months the rabbits underwent
      repeat angiography before they were sacrificed and the internal organs were
      evaluated histopathologically. RESULTS: Mean tungsten levels rose from 0.48
      microg/l prior to the implantation to 12.4 microg/l 4 months post-implantation.
      The rise in serum tungsten levels was neither associated with residual shunting
      present at the time of implantation nor with residual shunting at the time of
      explantation. One animal had to be sacrificed because of non-resolving palsy of
      the upper extremity. The remaining animals had an uneventful clinical course with
      no signs of toxicity of the elevated tungsten levels. Histological examination
      revealed no evidence of local or systemic toxicity of the tungsten coils.
      CONCLUSION: Tungsten coils corrode and lead to a steady increase in serum
      tungsten levels starting as early as 15 min after implantation. Residual shunting
      does not seem to influence the kinetics of corrosion of tungsten coils. Despite
      markedly elevated serum tungsten levels 4 months after implantation degradation
      of tungsten coils is not associated with local or systemic toxicity.

PMID- 12423595
TI  - Silk-based biomaterials.
AB  - Silk from the silkworm, Bombyx mori, has been used as biomedical suture material
      for centuries. The unique mechanical properties of these fibers provided
      important clinical repair options for many applications. During the past 20
      years, some biocompatibility problems have been reported for silkworm silk;
      however, contamination from residual sericin (glue-like proteins) was the likely
      cause. More recent studies with well-defined silkworm silk fibers and films
      suggest that the core silk fibroin fibers exhibit comparable biocompatibility in
      vitro and in vivo with other commonly used biomaterials such as polylactic acid
      and collagen. Furthermore, the unique mechanical properties of the silk fibers,
      the diversity of side chain chemistries for 'decoration' with growth and adhesion
      factors, and the ability to genetically tailor the protein provide additional
      rationale for the exploration of this family of fibrous proteins for biomaterial
      applications. For example, in designing scaffolds for tissue engineering these
      properties are particularly relevant and recent results with bone and ligament
      formation in vitro support the potential role for this biomaterial in future
      applications. To date, studies with silks to address biomaterial and matrix
      scaffold needs have focused on silkworm silk. With the diversity of silk-like
      fibrous proteins from spiders and insects, a range of native or bioengineered
      variants can be expected for application to a diverse set of clinical needs.

PMID- 12423596
TI  - Mechanical properties of oligomer-modified acrylic bone cement.
AB  - The aim of this study was to determine the mechanical properties of acrylic bone
      cement modified with an experimental oligomer filler, based on an amino acid of
      trans-4-hydroxy-L-proline synthesized in the laboratory. The test specimens were
      tested either dry, or after being stored in distilled water or in simulated body
      fluid (SBF) for 1 week and then tested in distilled water. The three-point
      bending test was used to measure the flexural strength and flexural modulus of
      the cement, and the compression tests were used to measure the compression
      strength and modulus. One test specimen from each group was examined under a
      scanning electron microscope (SEM) to determine the nature of the oligomer filler
      in the polymethylmethacrylate-polymethylacrylate copolymer-based (PMMA-PMA/PMMA)
      polymer blend. In dry conditions, the flexural strength of the test specimens
      tested in air was 66 MPa, and the compression strength was 93 GPa (p<0.001) for
      the plain bone cement. For the test specimens including 20 wt% of oligomer
      filler, the flexural strength was 37 MPa, and the compression strength was 102
      MPa(p<0.001) in dry conditions. The storage in wet conditions (in distilled water
      and the SBF) decreased the flexural strength of the test specimens with 20 wt% of
      oligomer filler (p<0.001) by 60% and the flexural modulus by 44% compared to the
      plain bone cement specimens stored in the same conditions. The reduction in
      compression strength in wet conditions was 32%, and that of the compression
      modulus was 30% (p<0.001). No significant differences were found between test
      specimens stored in distilled water or SBF (ANOVA, p<0.001). In the SEM
      examinations, random voids were observed in the oligomer-PMMA-PMA/PMMA polymer
      blend after water or SBF storage. The results suggest that both water and SBF
      storage decrease the mechanical properties of the PMMA-PMA/PMMA bone cement
      modified with oligomer, while at the same time, there was porous formation in the
      bone cement structure.

PMID- 12423597
TI  - Physical and chemical limitations to preparation of beta radioactive stents by
      direct neutron activation.
AB  - Pure beta emitters are the sources of choice for intracoronary irradiations in
      restenosis prevention. In this work we reconsidered preparation of low activity
      32P sources by ion-implantation of stable 31P into highly biocompatible pure
      titanium stents, followed by neutron activation. Gamma-spectrometrical analysis
      has shown that during activations with high thermal neutrons flux production of
      gamma-active long-lived contaminants is much beyond the dosimetrically acceptable
      limit, mainly due to the competing (n,p) reactions induced by the fast neutrons
      on isotopes of the bulk stent material, and to a lesser extent due to (n,gamma)
      reactions on chemical impurities. A potential applicability of this method for
      obtaining alternative beta radioactive stents is discussed.

PMID- 12423598
TI  - Reaction of poly(acrylamide-co-vinylamine) with tresyl-PEG in the presence of
      PC12 cells.
AB  - Tresylation of an amine containing polymer film in the presence of PC12 cells did
      not result in a significant loss of cell viability, at least as assessed by
      trypan blue exclusion or MTT assay. PC12 cells were cultured atop reactive
      poly(acrylamide-co-vinyl amine) films or tissue culture polystyrene and exposed
      for 2 h to tresylated polyethylene glycol (TPEG) or unreactive hydrolyzed TPEG in
      0.1M TES (N-tris hydroxymethyl-2-aminoethane sulfonic acid). The loss in trypan
      blue viability was limited ( approximately 80% retained), provided the TPEG
      concentration was 10 micromol/g or less. Similarly when microencapsulated PC12
      cells (in a non-reactive polyacrylate hydrogel) were exposed to TPEG (10
      micromol/g in 0.1M TES) the loss of MTT activity was small. The loss of vaibility
      was attributed to the toxicity of the tresyl leaving group and not the reaction
      itself. Thus, it may be possible to surface modify cell containing microcapsules,
      at least under limited conditions, in order to improve their biocompatibility
      without compromising the viability of the enclosed cells. This should lead to the
      development of new (reactive) polymers for microencapsulation since
      biocompatibility need not be a design consideration in the first instance.

PMID- 12423599
TI  - Vancomycin encapsulation in biodegradable poly(epsilon-caprolactone)
      microparticles for bone implantation. Influence of the formulation process on
      size, drug loading, in vitro release and cytocompatibility.
AB  - Vancomycin encapsulation in biodegradable poly(epsilon-caprolactone)
      microparticles (200 microm mean diameter) was most efficient with a simple
      emulsion technique that dispersed 122.5 mg/g of polymer. Scanning electron
      micrographs showed smooth or pitted particles. Dissolution studies were
      correlated with microparticle morphology, indicating higher release with pitted
      particles when vancomycin was encapsulated in a dissolved state. The
      cytocompatibility of these poly(epsilon-caprolactone) microparticles was
      demonstrated by a direct contact cytotoxic assay. This material can be considered
      as an efficient drug delivery system for bone implantation.

PMID- 12423600
TI  - Mineralisation of two phosphate ceramics in HBSS: role of albumin.
AB  - The role of albumin in the mineralisation process of commercial hydroxyapatite
      (HAp) and synthesised biphasic (HAp-tricalcium phosphate) ceramics in a
      bufferless simulated inorganic plasma (HBSS) was investigated by conventional in
      vitro tests and static and dynamic wettability measurements. Albumin was either
      pre-adsorbed or solubilised in HBSS. It was found that calcium complexation by
      albumin plays a key role in early mineralisation kinetics, so that mineralisation
      is favoured when albumin is pre-adsorbed and hindered when it is dissolved in
      HBSS. In the biphasic ceramic this picture is complicated by the fact that
      albumin, in solution, seems to promote the dissolution of tricalcium phosphate,
      and simultaneously compete for calcium with the ceramic. It also appears that
      albumin has a stabilising effect of octacalcium phosphate present in deposits on
      commercial HAp. The same effect may be present in the case of the biphasic
      ceramic, at earlier mineralisation times, when octacalcium phosphate appears as a
      precursor of HAp. Octacalcium phosphate formation on commercial apatite is
      accompanied by carbonate substitution in phosphate positions.

PMID- 12423601
TI  - IL-1alpha, IL-1beta and TNF-alpha secretion during in vivo/ex vivo cellular
      interactions with titanium and copper.
AB  - Titanium (Ti) and copper (Cu) were used to evaluate cytokine secretion around
      materials with different chemical properties. Ti disks were coated with Cu or
      left uncoated. The disks were inserted subcutaneously in rats for 1, 3, 12, 18,
      24 and 48 h. Interleukin-1alpha (IL-1alpha), IL-1beta and tumor necrosis factor
      alpha (TNF-alpha) concentrations were measured in vivo around the materials, in
      sham operated sites, and after ex vivo incubation of surface adherent cells. Ti
      and Cu revealed distinct cytokine expression patterns. Cu recruited cells showed
      higher and prolonged release of IL-1alpha than Ti at longer times (>24 h),
      whereas Ti exhibited a transient IL-1alpha response at earlier periods (<24 h).
      An early enhanced secretion of TNF-alpha characterized Ti. Low amounts of IL
      1beta were found around both materials. Sham site recruited cells produced lower
      levels of cytokines. The results after ex vivo incubations were similar to those
      in vivo. This study shows that material chemical properties influence early
      cytokine production. The Ti-associated transient rise of IL-1alpha and TNF-alpha
      may be of importance for the early tissue response around biocompatible
      materials, while a delayed high IL-1alpha expression could be a marker of
      inflammation induced by toxic materials.

PMID- 12423602
TI  - Comparison of the cytotoxicity of clinically relevant cobalt-chromium and alumina
      ceramic wear particles in vitro.
AB  - Concern over polyethylene wear particle induced aseptic loosening of metal-on
      polyethylene hip prostheses has led to renewed interest in alternative materials
      such as metal-on-metal and alumina ceramic-on-alumina ceramic for total hip
      replacement. This study compared the effects of clinically relevant cobalt
      chromium and alumina ceramic wear particles on the viability of U937 histiocytes
      and L929 fibroblasts in vitro. Clinically relevant cobalt-chromium wear particles
      were generated using a flat pin-on-plate tribometer. The mean size of the
      clinically relevant metal particles was 29.5+/-6.3 nm (range 5-200 nm).
      Clinically relevant alumina ceramic particles were generated in the Leeds MkII
      anatomical hip simulator from a Mittelmieier prosthesis using micro-separation
      motion. This produced particles with a bimodal size distribution. The majority
      (98%) of the clinically relevant alumina ceramic wear debris was 5-20 nm in size.
      The cytotoxicity of the clinically relevant wear particles was compared to
      commercially available cobalt-chromium (9.87 microm+/-5.67) and alumina ceramic
      (0.503+/-0.19 microm) particles. The effects of the particles on the cells over a
      5 day period at different particle volume (microm(3)) to cell number ratios were
      tested and viability determined using ATP-Lite(TM). Clinically relevant cobalt
      chromium particles 50 and 5 microm(3) per cell reduced the viability of U937
      cells by 97% and 42% and reduced the viability of L929 cells by 95% and 73%,
      respectively. At 50 microm(3) per cell, the clinically relevant ceramic particles
      reduced U937 cell viability by 18%. None of the other concentrations of the
      clinically relevant particles were toxic. The commercial cobalt-chromium and
      alumina particles did not affect the viability of either the U937 histiocytes or
      the L929 fibroblasts.Thus at equivalent particle volumes the clinically relevant
      cobalt-chromium particles were more toxic then the alumina ceramic particles.
      This study has emphasised the fact that the nature, size and volume of particles
      are important in assessing biological effects of wear debris on cells in vitro.

PMID- 12423603
TI  - Microarchitectural and mechanical characterization of oriented porous polymer
      scaffolds.
AB  - Biodegradable porous polymer scaffolds are widely used in tissue engineering to
      provide a structural template for cell seeding and extracellular matrix
      formation. Scaffolds must often possess sufficient structural integrity to
      temporarily withstand functional loading in vivo or cell traction forces in
      vitro. Both the mechanical and biological properties of porous scaffolds are
      determined in part by the local microarchitecture. Quantification of scaffold
      structure-function relationships is therefore critical for optimizing mechanical
      and biological performance. In this study, porous poly(L-lactide-co-DL-lactide)
      scaffolds with axially oriented macroporosity and random microporosity were
      produced using a solution coating and porogen decomposition method.
      Microarchitectural parameters were quantified as a function of porogen
      concentration using microcomputed tomography (micro-CT) analysis and related to
      compressive mechanical properties. With increasing porogen concentration, volume
      fraction decreased consistently due to microarchitectural changes in average
      strut thickness, spacing, and density. The three-dimensional interconnectivity of
      the scaffold porosity was greater than 99% for all porogen concentration levels
      tested. Over a porosity range of 58-80%, the average compressive modulus and
      ultimate strength of the scaffolds ranged from 43.5-168.3 MPa and 2.7-11.0 MPa,
      respectively. Thus, biodegradable porous polymer scaffolds have been produced
      with oriented microarchitectural features designed to facilitate vascular
      invasion and cellular attachment and with initial mechanical properties
      comparable to those of trabecular bone.

PMID- 12423604
TI  - Cold hibernated elastic memory foams for endovascular interventions.
AB  - Cold hibernated elastic memory (CHEM) polyurethane-based foam is a new shape
      memory polymeric self-deployable structure. Standard cytotoxicity and
      mutagenicity tests were conducted on CHEM in vitro, to ensure biocompatibility
      before studying potential medical applications. In vivo, lateral wall aneurysms
      were constructed on both carotid arteries of eight dogs. Aneurysms were occluded
      per-operatively with CHEM blocks. In two dogs, CHEM embolization was compared
      with gelatin sponge fragment embolization. Internal maxillary arteries (Imax)
      were also occluded with CHEM using a 6F transcatheter technique. Angiography and
      pathology were used to study the evolution of aneurysms and Imax at 3 and 12
      weeks. Imax embolized with CHEM foam remained occluded at 3 weeks. Most aneurysms
      embolized with CHEM showed a small residual crescent of opacification at initial
      angiography, but angiographic scores were significantly better at 3 weeks. Thick
      neointima formation over the CHEM at the neck of aneurysms was demonstrated at
      pathology. The foamy nature of CHEM favours the ingrowth of cells involved in
      neointima formation. New devices for endovascular interventions could be designed
      using CHEM's unique physical properties.

PMID- 12423605
TI  - Glass ionomer as an expander of allograft in revision arthroplasty of the hip.
AB  - The use of glass ionomer as a bone graft expander was investigated in an in vivo
      model of revision hip arthroplasty. Bone grafts of pure allograft and allograft +
      glass ionomer particles in a 50:50 by weight mixture were implanted in an ovine
      hemi-arthroplasty model. Post-operative assessments of locomotor function,
      radiographic appearance and quantitative changes in mineralisation around the
      graft were made at 2, 4 and 6 months. Post-mortem assessments of radiographic and
      histologic appearance of the grafts were made at 6 months. No significant
      differences were noted in any of the measured or assessed parameters between the
      two graft types. The glass ionomer particles seemed to be well tolerated within
      the matrix of new bone, smaller sized particles appearing to be better
      incorporated than larger ones. The use of particles of glass ionomer as a bone
      graft expander, in this in vivo model of revision hip arthroplasty, would
      therefore appear to offer no detriment in performance over pure allograft in the
      short to medium term.

PMID- 12423606
TI  - Synthesis and physicochemical analysis of gelatin-based hydrogels for drug
      carrier matrices.
AB  - This study examined the interrelated effect of environmental pH, gelatin backbone
      modification and crosslinking modality on hydrogel morphology, surface
      hydrophilicity, in vitro swelling/degradation kinetics, in vitro drug release
      kinetics and in vivo degradation, inflammatory response and drug release
      activity. The percent glutaraldehyde fixation had a greater impact on the
      morphology of the dehydrated hydrogels than gelatin modification. Any decrease in
      percent glutaraldehyde fixation and/or modification of gelatin with polyethylene
      glycol dialdehyde (PEG-dial) and/or ethylenediaminetetraacetic dianhydride
      (EDTAD) increased hydrogel surface hydrophilicity. Swelling/degradation studies
      showed that modification of gelatin with PEG-dial generally increased the time to
      reach the maximum swelling weight ratio (T(max)) and the time to failure by
      hydrolysis (T(fail)), but had little effect on the maximum swelling weight ratio
      (R(max)) and the weight ratio at failure (R(fail)). Modification of gelatin with
      EDTAD generally had no effect on T(max) and T(fail), but increased R(max) and
      R(fail). Modification of gelatin with PEG-dial and EDTAD increased R(max), but
      had no effect on T(max), R(fail), or T(fail). Decreasing percent glutaraldehyde
      fixation generally increased R(max) and R(fail) but decreased T(max) and T(fail).
      Decreasing environmental pH from 7.4 to 4.5 had no effect on any
      swelling/degradation properties. In vitro drug release studies showed that
      modification of gelatin with PEG-dial and/or EDTAD generally decreased the
      maximum mass ratio of drug released (D(max)) and the time to reach D(max)
      (T(dmax)). Percent glutaraldehyde fixation did not significantly affect D(max) or
      T(dmax) (except for EDTAD-modified gelatin hydrogels). In vivo studies showed
      that gelatin-based hydrogels elicited comparable levels of acute and chronic
      inflammatory response as that of the empty cage control by 21 d.

PMID- 12423607
TI  - Evidence based medicine: review of BTS guidelines for the management of community
      acquired pneumonia in adults.
AB  - Community acquired pneumonia is a common illness with significant morbidity and
      mortality and a high cost to society. Guidelines for management in the UK issued
      by the British Thoracic Society have been in existence since 1993 (Br J Hosp Med
      1993; 49: 346-350). These have been updated in 2001 (Thorax 2001; 56(Suppl IV)).
      This review summarises the guidelines with emphasis on aetiology, investigations
      and antibiotic treatment.

PMID- 12423608
TI  - The prevalence of hepatitis C in England and Wales.
AB  - OBJECTIVES: To estimate the background population prevalence of hepatitis C in
      England and Wales, observe the prevalence over time and assess the extent of
      infection outside of known risk groups. METHODS: Sera from residual specimens
      from adult patients submitted to laboratories in England and Wales were tested
      for anti-HCV. Testing was carried out using a cost-effective pooling strategy.
      RESULTS: Although the prevalence of anti-HCV was highest in 1986 (1.07%), in the
      multivariable analysis, prevalence did not vary significantly between the 3
      periods 1986, 1991 and 1996 (P=0.14). The prevalence of infection was higher in
      males than in females (P=0.0013). An age-period-cohort analysis revealed a cohort
      effect due to a lower HCV prevalence in the most recent birth cohorts, that is,
      those born between the calendar years 1971-1975 and 1976-1980. CONCLUSIONS: The
      majority of HCV infections in England and Wales were probably acquired before
      1986. Infections in younger males identified in 1996 may signify more recent
      acquisition by injecting drug use.

PMID- 12423609
TI  - Effects of rhinovirus-induced common colds on granulocyte activity in allergic
      rhinitis.
AB  - OBJECTIVE: To explore the activities of mast cells, eosinophils, and neutrophils
      in patients with allergic rhinitis developing common colds and increased
      responsiveness to allergen following nasal rhinovirus inoculation. METHODS: We
      have revisited a nasal lavage material obtained from 17 patients who were
      successfully inoculated with rhinovirus outside the pollen season and received
      nasal allergen challenges before and after inoculation. We have examined indices
      of mast cell activity (tryptase), eosinophil degranulation (eosinophil
      peroxidase; EPO), and neutrophil activation (myeloperoxidase; MPO). RESULTS:
      Allergen challenges performed before rhinovirus inoculation increased the nasal
      output of EPO. Notably, this response was significantly greater after rhinovirus
      inoculation (cf. before inoculation). The output of MPO was also increased
      following allergen challenge after, but not before, rhinovirus inoculation. Nasal
      lavage fluid levels of tryptase were increased following allergen challenge
      similarly before and after rhinovirus inoculation. Also, the viral infection did
      not affect the baseline levels of tryptase. CONCLUSIONS: The present data
      demonstrate that rhinovirus infections activate both eosinophils and neutrophils,
      but that they may not affect mast cell activity. We suggest that common colds in
      part through stimulation of granulocyte activity potentiate the airway
      inflammation in allergic diseases.

PMID- 12423610
TI  - The burden of uncomplicated cases of chickenpox in Israel.
AB  - OBJECTIVE: The aim of this study was to assess the direct medical burden and work
      loss associated with uncomplicated chickenpox in Israel. METHODS: A total of 155
      otherwise healthy children and adolescents with chickenpox were recruited from 10
      physician offices in central Israel. Direct and indirect medical burdens were
      determined by caregiver interview. RESULTS: Mean age was 3.3+/-2.3 years. 51% of
      the patients were under 3 years of age. Each patient made on average 1.15 visits
      to a general practitioner. Most patients were taken to the Doctor's office only
      once during the illness while 23 patients (15%) were seen twice. Three patients
      were referred to the emergency room. Antihistamines (39%) and Calamine lotion
      (28%) were the most frequently prescribed medications, followed by acyclovir
      (17%) and antibiotics (6%). Following the patient's illness there were 72 cases
      of secondary spread of varicella to household members. The individuals who cared
      for the child missed a combined total of 2.5 days from work (on average per
      varicella episode). CONCLUSIONS: Israeli children acquire chickenpox at a younger
      age than children in North America and England and consume more prescribed
      medications. While the work loss in the present study was comparable to previous
      reports, the direct medical costs inflicted by this infection in Israel are not
      negligible even for uncomplicated cases.

PMID- 12423611
TI  - A household study of chickenpox in Guinea-Bissau: intensity of exposure is a
      determinant of severity.
AB  - OBJECTIVE: To determinate the relative importance of state of nutrition and
      intensity of exposure for clinical severity of chickenpox in a developing
      country. METHODS: A prospective household study was performed in a semi-urban
      area in Bissau, the capital of Guinea-Bissau, between December 1994 and June
      1995. Antibodies were measured in the acute and the convalescence phase to assess
      validity of clinical diagnoses. The clinical severity of infection was assessed
      by number of pox, fever response and skin infections. Severity was compared for
      index cases, i.e. the first case in the house, and secondary and tertiary cases
      infected following exposure at home. RESULT: Chickenpox was diagnosed in 165
      persons. The clinician's and the mothers' diagnoses corresponded well with the
      serological results. Median age was 36 months (range 3 months to 30.3 years).
      There was no correlation between nutritional status measured by arm-circumference
      and severity of infection. The number of pox was higher for secondary cases than
      for index cases (median 106 vs. 89, P<0.01), the difference being more pronounced
      for girls (P=0.018) than for boys (P=0.575). The risk of skin infection as a
      complication was correlated with the number of pox (P<0.001). CONCLUSION:
      Chickenpox was recognised correctly by Guinean mothers. The age distribution in
      Guinea-Bissau resembled the pattern in developed countries. The intensity of
      exposure was a major determinant of severity, especially for girls.

PMID- 12423612
TI  - Antibiotic prophylaxis for dental or urological procedures following hip or knee
      replacement.
AB  - OBJECTIVES: Reports of prosthetic joint infection associated with urological or
      dental procedures have prompted suggestions that these patients require
      antibiotic prophylaxis, but no guidelines have been agreed. We have polled
      orthopaedic surgeons, urologists, and dentists on this issue. METHODS: The
      questions asked were: could infection of a joint prosthesis result from a dental
      or urological procedure; does the risk of infection warrant patients informing
      their dentist or urologist about their joint replacement; should these patients
      have prophylactic antibiotics for (a) routine procedures and (b) lengthy
      procedures. RESULTS: Urologists and orthopaedic surgeons agreed that infection
      could probably result from urological procedures and that patients should
      definitely inform their urologist about their prosthesis. Orthopaedic surgeons
      thought that antibiotics were definitely indicated for routine and lengthy
      urological procedures while urologists thought antibiotics were probably
      indicated. Orthopaedic surgeons thought that infection probably could result from
      dental procedures, while dentists answered "don't know". Both groups agreed that
      patients should definitely inform their dentist about their prosthesis.
      Orthopaedic surgeons thought that antibiotics probably were necessary for routine
      and lengthy dental procedures, whereas dentists answered "probably not" and
      "don't know", respectively. CONCLUSIONS: These results could provide the basis
      for a consensus regarding prophylactic antibiotic use in this growing patient
      population.

PMID- 12423613
TI  - The changing clinical aspects of infective endocarditis: descriptive review of 90
      episodes in a French teaching hospital and risk factors for death.
AB  - OBJECTIVE: We wanted to describe the epidemiological aspects of infective
      endocarditis (IE) in a French hospital and identify the prognostic factors.
      METHODS: We reviewed the clinical, echocardiographic and microbiological
      features, and the outcome of 89 patients (90 episodes, median age 60 years) with
      IE over 18 months. Logistic regression analysis was used to identify prognostic
      factors for death. RESULTS: A native valve was involved in 68 cases (75.5%); in 7
      of these the patient was an intravenous drug user. A prosthetic valve was
      involved in 22 cases (24.5%); 5 of these were of early onset. Diagnosis was
      definite in 87% of cases. Median time to diagnosis was 3 days. Twenty-five
      patients (28%) were immunocompromised. A portal of entry, usually cutaneous, was
      identified in 65% of cases. Sixty-two percent of patients had an underlying heart
      disorder, usually degenerative. The infection involved the left heart in more
      than 75% of cases. One or more vegetations were detected in 75% of cases. The
      median size of vegetation was 15 mm. Isolated agents were mainly staphylococci
      (n=40 (44%), including 12 coagulase-negative isolates), and streptococci (n=23
      (25%), including 7 enterococci). In 11 cases (12%), cultures remained negative.
      Nineteen episodes were nosocomial and Staphylococcus aureus was implicated in 11
      of them. Fifty percent of patients had at least one complication: heart failure
      (n=42), kidney failure (n=44), embolism (n=35), septic shock (n=19). Surgery was
      performed in 49 cases (54%) due to heart failure (n=19), cerebral embolism
      (n=12), and/or severe valve lesions (n=27). Eighteen patients died, 10 of whom
      were infected with S. aureus. Nosocomial IE (P=0.0008), heart failure (P=0.004)
      and prosthetic valve (P=0.01), but not S. aureus were independently associated
      with death. CONCLUSIONS: S. aureus was the main microorganism isolated in our
      patients. However, it was not independently predictive of fatal outcome.

PMID- 12423614
TI  - Distribution of enterococci in Hong Kong.
AB  - OBJECTIVES: To study the distribution of hospital isolates of enterococci from
      urines, bile, blood and body fluids and to evaluate different methods for the
      identification of enterococci. METHODS: Enterococci isolated from urine, bile,
      blood and body fluids collected during 1997 and 1998 were identified by
      polymerase chain reaction (PCR), API 20 Strep and conventional biochemical tests.
      RESULTS: A total of 498 non-duplicate enterococci were studied: 398 and 43
      isolates from urine and bile, respectively, 49 from blood, two from cerebrospinal
      fluid and six from body fluids. Both API 20 Strep and PCR gave the same
      identification results for 240 Enterococcus faecalis isolates, 45 E. faecium
      isolates and one isolate each of E. gallinarum and E. Casseliflavus. These
      isolates were re-defined by conventional biochemical tests. PCR could correctly
      identify 303 (98%) isolates while API 20 Strep could only correctly identify 287
      (93%) isolates (99% of E. faecalis and 57-87% of the other Enterococcus sp.).
      Thus, PCR was used in the identification of the remaining isolates and the
      identity of isolates other than E. faecalis was subsequently confirmed by
      biochemical tests. CONCLUSIONS: The majority of enterococci isolated was E.
      faecalis (81%) while only 15% were E. faecium and 4% the other enterococcal
      species. PCR could correctly identify E. faecalis while the identity of other
      enterococcal species had to be confirmed by biochemical tests.

PMID- 12423615
TI  - Postantifungal effect and effects of sub-MIC concentrations on previously treated
      Candida sp. influence of growth phase.
AB  - OBJECTIVES: This study evaluates the influence of growth phase on the
      postantifungal effect (PAFE) and on the effect of sub-MIC concentrations (1/4x
      MIC) on Candida sp. in PAFE stage (PAFSE). METHODS: This stage was induced by pre
      treatments of 1.5 h of C. albicans or C. glabrata in their exponential or
      stationary phase, with 1x, 4x or 8x MIC of four antifungal agents that are
      fundamental for modern candidiasis therapy. RESULTS: Ketoconazole and fluconazole
      induced longer PAFSEs on microorganisms in logarithmic growth phase. However,
      this influence did not exist in the case of PAFSEs induced by AmB and 5-Fc or
      with the postantifungal effect induced by the four antifungal agents. In any way,
      significant PAFEs were always observed for Amphotericin B and 5-fluorocytosine
      (0.8-4.8 and 0.5-3 h, respectively, depending on the treatment dose). These
      values were increased (2.3-3.6 and 1.4-3.2 h respectively, depending on the pre
      treatment dose) by posterior exposition to 1/4x MIC of the respective antifungal
      agent. In the case of ketoconazole and fluconazole, both antimycotics were not
      able to induce significant PAFEs, but posterior treatments to 1/4x MIC of each of
      the two azoles led in both yeast species to significant PAFSE of up to 2.6 h
      duration with ketoconazole, and 0.8 h with fluconazole, depending on the pre
      treatment concentration. CONCLUSION: The growth phase of microorganisms should be
      considered in the planning of dosage protocols with azoles, because if the
      concentration applied is not high enough, the sub-MIC effects could be no
      significant for fungi in stationary phase of large wounds. Amphotericin B and 5
      fluorocytosine induced significant postantifungal effect onCandida sp. This
      effect was increased by posterior exposition to sub-MIC concentration of the
      antifungal agents. Ketoconazole and fuconazole were not able to induce
      significant PAFEs at the concentrations tested, but posterior treatments to sub
      MIC concentrations led to significant PAFSE. The growth phase of the culture at
      the time of its pre-treatment did not influence the length of the PAFE induced in
      it. However, the effect of the sub-MIC concentrations of Kz or Flu in yeast in
      PAFE phase was greater on yeast in exponential phase than for cultures in
      stationary phase.

PMID- 12423616
TI  - Disseminated Penicillium marneffei infection among HIV-infected patients in
      Manipur state, India.
AB  - OBJECTIVE: To further describe the clinical and epidemiological characteristics
      of Penicillium marneffei infection in human immunodeficiency virus (HIV) infected
      patients in India. METHODS: In continuation of our earlier report of four
      autochthonous cases of P. marneffei infection in HIV infected patients from
      Manipur, a northeastern state of India, we studied additional 46 cases of
      penicilliosis marneffei from the same area over a period of 19 months (April 1998
      October 1999). Clinical, microbiological features, and therapeutic responses were
      analyzed in 36 of the 46 patients as ten patients were lost to follow-up.
      RESULTS: Of the 198 HIV positive patients attending the J. N. Medical Hospital,
      Imphal, Manipur state during the period mentioned, 46 (25%) had P. marneffei
      disseminated infection. Of the 36 patients analyzed 31 (86%) were intravenous
      drug abusers, 1 had multiple sex partners, and 3 females acquired HIV infection
      from their respective spouses. A 9-year-old child acquired HIV infection by
      vertical transmission. The common clinical symptoms included fever (97%), weight
      loss (100%), weakness (86%), anemia (86%), and characteristic skin lesions (81%).
      Presumptive diagnosis was made by microscopic examination of Wright's-stained
      smears of fine needle aspirated material from skin lesions and lymph nodes
      showing numerous intracellular and extracellular, oval, elongated, yeast-like
      cells dividing by fission. The etiologic agent P. marneffei was isolated in
      culture from clinical materials in 10 cases when isolation was attempted. All
      patients were treated with oral itraconazole. All, except one patient, responded
      favorably to treatment within 7 days. CONCLUSION: Thus, the present cases further
      confirm the endemicity of penicilliosis marneffei in Manipur and resemble the
      epidemiology and clinical course of patients from other parts of south-east Asia.

PMID- 12423617
TI  - Eikenella corrodens discitis after spinal surgery: case report and literature
      review.
AB  - Eikenella corrodens is part of the normal flora of the mouth and upper
      respiratory tract and is usually associated with dental and head and neck
      infections. We report a case of Eikenella discitis occurring soon after spinal
      surgery in an otherwise healthy patient, review the literature on bone and joint
      infections unrelated to human bites and fist-fight injuries, and stress the
      importance of definitive diagnosis in post-operative spinal infections.

PMID- 12423618
TI  - Shigella flexneri bacteraemia in an immunocompetent male treated with oral
      ciprofloxacin.

PMID- 12423619
TI  - Incidence of meningococcal infection in children with fever and non-blanching
      rash.

PMID- 12423620
TI  - Meningitis caused by Streptococcus pyogenes in an intravenous drug user.

PMID- 12423623
TI  - Contribution of circulating IGF-I to wound repair in GH-treated rats.
AB  - Systemic administration of growth hormone (GH) stimulates granulation tissue
      formation, increases collagen deposition, improves the breaking strength of
      incisional wounds, and decreases donor-site healing times in burn patients. The
      possible role for circulating IGF-I in mediating this effect of growth hormone
      has not been investigated. To assess the relative effects of systemic IGF-I and
      GH on dermal repair, incisional wounds were created on the backs of male Sprague
      Dawley rats treated with GH, or IGF-I or a combination of GH and IGF-I. After 7
      days of treatment, wound strips were taken for wound strength and
      immunohistochemical analysis. Uninjured skin and liver samples were collected for
      mRNA analysis and plasma samples were taken at the completion of the experiment
      to determine circulating IGF-I levels. Increased circulating IGF-I levels and
      increased weight gain were observed only in the IGF-I and IGF-I+GH treatment
      groups, although steady-state igf-I levels were not altered in liver and
      uninjured skin after 7 days in any treatment group. IGF-I treatment had no
      positive effects on wound repair. Wound strength was increased with GH treatment
      only and associated with an increase in the intensity of IGF-I immunostaining in
      the granulation tissue of GH-treated animals. In line with the wound strength
      data, co-administration of IGF-I resulted in the decreased intensity of IGF-I
      immunostaining. We conclude that the GH-stimulated increase in wound strength is
      not mediated via endocrine-derived IGF-I and that only locally produced IGF-I
      acting in an autocrine or paracrine fashion contributes to the regulation of the
      wound repair process.

PMID- 12423624
TI  - IL-6-overexpression brings about growth impairment potentially through a GH
      receptor defect.
AB  - This paper is concerned with growth retardation associated with overproduction of
      interleukin-6 (IL-6). As a model, we used MUP/hIL-6 transgenic mice in which
      human IL-6 cDNA is overexpressed under the control of a MUP gene
      enhancer/promoter. The growth-retardation of MUP/hIL-6 transgenic mice was
      paralleled by reduced serum levels of IGF-I. As shown, hepatic IGF-I mRNA levels
      were reduced in the transgenic mice. MUP/hIL-6 transgenic mice are in a state of
      growth hormone (GH)-resistance, since their serum GH levels are either normal or
      elevated. To identify possible steps in GH signaling which might be perturbed in
      the transgenic mice, we examined the synthesis of GH receptor (GHR) mRNA. We
      noted a twofold reduction of hepatic GHR mRNA in the transgenic mice. We
      therefore conclude that overexpression of IL-6 brings about growth impairment in
      part through a GH receptor defect.

PMID- 12423625
TI  - Expression of insulin-like growth factor system constituents in differentiating
      rat osteoblastic cell populations.
AB  - The synthetic glucocorticoid dexamethasone (Dex) and insulin-like growth factor-I
      and -II (IGF-I and -II) stimulate osteoprogenitor proliferation and
      differentiation in bone cell populations isolated from adult rat vertebrae. Since
      glucocorticoids have been shown to regulate gene expression of IGFs and IGF
      binding proteins (IGFBPs) in several experimental models, we investigated whether
      Dex-stimulated osteoprogenitor proliferation and differentiation was associated
      with changes in mRNA levels of the IGF system components (i.e., IGF-I and -II,
      the type 1 and 2 IGF receptor, the insulin receptor and six IGFBPs).
      Osteoprogenitor-containing bone cell populations were isolated from the outgrowth
      of vertebral explant cultures of 3-month-old female rats and cultured for 20
      days. Total RNA was extracted at day 8, 14, and 20, and mRNA levels of the IGF
      system constituents were compared between differentiating (Dex-treated) and non
      differentiating (control) cultures. Northern hybridization data from 8- and 20
      day cultures showed that mRNA levels of IGF-I were markedly lower in Dex-treated
      cultures than in control cultures at day 8 and 20. At day 20, mRNA levels of
      IGFBP-3 were also lower in Dex-treated cultures. Signals of IGFBP-5 mRNA were
      undetectable. To increase the sensitivity of our detection methods and therefore
      evaluate mRNA levels of all the components of the IGF system, we performed
      reverse transcription-polymerase chain reaction (RT-PCR) analysis of RNA
      extracted at day 8, 14, and 20 of culture. In agreement with the Northern data,
      IGF-I mRNA levels in Dex-treated cultures were lower than in control cultures at
      all three time points, and IGFBP-3 levels were lower in Dex-treated cultures at
      day 20 of culture. However, at day 8 and 14, IGFBP-3 mRNA levels were higher in
      Dex-treated cultures than in controls. Levels of the 2 IGF receptor mRNA and the
      insulin receptor mRNA were lower in Dex-treated cultures. Dex-treated cultures
      also had decreased levels of IGFBP-1 mRNA but increased levels of IGFBP-2 mRNA at
      all three time points. IGFBP-4 levels were lower at day 14 in Dex-treated
      cultures than in controls but higher at day 20. IGF-II and IGFBP-5 mRNA levels in
      control and Dex-treated cultures were similar. Signals for IGFBP-6 were
      undetectable. Our findings show that glucocorticoid-induced osteoprogenitor
      proliferation and differentiation in adult rat bone cell populations are
      associated with significant changes in the mRNA levels of virtually all
      components of the IGF system. Some of these changes are dependent on the stages
      of development (e.g., regulation of IGFBP-3 and -4) and some remain similar
      trends at all stages (e.g., regulation of IGF-I and the three receptors).

PMID- 12423626
TI  - A novel heterozygous T51I mutation of growth hormone receptor is not associated
      with short stature.
AB  - A novel missense mutation of the growth hormone receptor (GHR) gene was
      identified in a Japanese short boy with GH insensitivity. The analysis of the GHR
      gene revealed a novel heterozygous T51I mutation in exon 4. To clarify the effect
      of this mutation on GH signaling, the mutant GHR was expressed in CHO cells and
      its functional properties were investigated. The signal transducer and activator
      of transcription 5 (STAT5)-mediated transcriptional activation in mutant GHR (GHR
      T51I)-expressing cells was significantly reduced as compared with wild-type GHR
      (GHR-wt)-expressing cells. The CHO cells co-expressing the GHR-T51I and GHR-wt,
      however, revealed no functional differences as compared with cells expressing GHR
      wt alone, indicating that the T51I mutation does not exert the dominant negative
      effect. In addition, the mother and the elder brother of the proband, whose
      heights were normal, possessed the same heterozygous mutation. These results
      suggest that the heterozygous T51I mutation of GHR does not inhibit the signal
      transduction of GH and is not responsible for GH insensitivity.

PMID- 12423627
TI  - Growth hormone receptor antagonist improves insulin resistance in acromegaly.
AB  - Growth hormone hypersecretion is a known cause of insulin resistance. This change
      in insulin sensitivity is believed to be mediated directly by growth hormone
      binding to its receptor. Five subjects ages 28-55 years who were participating in
      a clinical study that had been designed to assess the effects of a growth hormone
      receptor antagonist (Pegvisomant) on disease activity in acromegaly were
      evaluated to determine the role of growth hormone hypersecretion in inducing
      changes in insulin sensitivity. These subjects were treated with the 15-30 mg/day
      of Pegvisomant for periods ranging from 14 to 23 months. These doses were
      adequate to normalize IGF-I in four of the five subjects. The subjects were
      monitored to ensure that there were no significant changes in diet, exercise, or
      weight. Mean pretreatment IGF-I was 1104+/-277 ng/ml and decreased to a nadir of
      355+/-157 ng/ml on treatment. After a 6-week withdrawal period, mean IGF-I had
      increased to 549+/-142 ng/ml. Fasting insulin was 35.2+/-16 uU/ml prior to
      treatment then decreased to a nadir of 19.9+/-14.6 uU/ml on treatment and then
      increased to 24.5+/-11.3 uU/ml. Fasting glucose decreased from 187+/-68 to 122+/
      38 mg/dl and then increased to 159+/-41 mg/dl. Hemoglobin A(1)C decreased from
      8.1+/-1.7 to 6.3+/-1.5%. Two subjects with overt type II diabetes had decreases
      in hemoglobin A(1)C from 8.3 to 5.9% and from 11.4 to 8.6%. These changes were
      associated with decreases in the amount of medication needed to control blood
      glucose. Weight remained stable throughout the study. The results show that the
      Pegvisomant is an effective agent for improving insulin resistance in subjects
      who have acromegaly and that this effect is independent of weight loss. The
      results suggest a potential role for Pevisomant in the treatment of insulin
      resistant states other than acromegaly.

PMID- 12423628
TI  - Effects of lowering circulating free fatty acid levels on protein metabolism in
      adult growth hormone deficient patients.
AB  - Our study was conducted to define the roles of lowering circulating free fatty
      acids (FFA) and of growth hormone (GH) replacement on protein metabolism in GH
      deficient patients. To isolate the specific effects of FFA and GH we studied
      seven adult subjects with GH deficiency four times: (A) with administration of GH
      and Acipimox (an inhibitor of lipolysis), (B) with GH, without Acipimox, (C)
      without GH, with Acipimox and (D) without either. Each study included a 3 h basal
      period and a 3 h euglycemic clamp. Amino acid metabolism was assessed by stable
      isotope dilution technique at the whole body level and across the forearm.
      Overall, we saw no intervention effect on protein metabolism, but when the two
      situations in which Acipimox was given were combined, Acipimox decreased basal
      plasma FFA concentrations by 75% and increased serum urea concentrations by 20%,
      whole body appearance rates (reflecting protein degradation) of phenylalanine (by
      7%) and tyrosine (by 11%) and protein synthesis rates for phenylalanine (by 7%),
      whereas phenylalanine-to-tyrosine conversion was unaffected. Acipimox more than
      doubled net forearm phenylalanine release during the clamp and increased basal
      forearm phenylalanine disappearance (reflecting muscle protein synthesis). During
      the clamp whole body amino acid fluxes and phenylalanine-to-tyrosine conversion
      decreased together with a decrease in forearm protein breakdown. GH replacement
      did not affect any of these metabolic parameters. Although we failed to show any
      role for GH, the results show that lowering of FFA concentrations with Acipimox
      has pronounced effects on protein metabolism, including increased whole body and
      forearm protein breakdown, together with increased protein synthesis systemically
      and locally in the forearm. The increase in serum urea and a doubling of net
      forearm phenylalanine release after lowering of FFA strongly indicate that the
      overall effect is catabolic and supports a pivotal protein conserving role of
      lipids.

PMID- 12423629
TI  - Divergent regulation of proteasomes by insulin-like growth factor I and growth
      hormone in skeletal muscle of rats made catabolic with dexamethasone.
AB  - Insulin-like growth factor I (IGF-I) and growth hormone (GH) exert their anabolic
      actions by increasing protein synthesis, but only IGF-I has been reported to
      impede protein breakdown. Using a model of myofibrillar catabolism produced by
      dexamethasone (Dex) we have reported that IGF-I down-regulates Dex-induced mRNAs
      for Ubiquitin (Ub) and Ub-conjugating enzymes (E2) in skeletal muscle, whereas GH
      had no significant effect. In the present study, we used the same model to
      determine whether IGF-I (0.35 mg/100 g BW) and/or GH (0.3 mg/100 g BW) have
      effects on proteasome subunit mRNAs in skeletal muscles of rats treated with Dex
      (0.5 mg/100 g BW) for 3 days. Dex caused significant increases in C-2, -3, and -8
      proteasome subunit mRNAs (6.0-, 4.0-, and 6.6-fold increases, respectively).
      Injections of IGF-I in Dex-treated animals caused significant suppression of
      transcripts for C-2, -3, and -8 (32%, 42%, and 40%, respectively). GH restored
      the serum IGF-I levels in Dex treated animals, but caused further increases in
      proteasome subunit mRNAs (C-2, 35%; C-3, 34.5%; C-8, 33%; C-6, 42%; C-5, 32%; C
      9, 37%). Administration of IGF-I in the Dex/GH-treated animals decreased the
      mRNAs of proteasome subunits in a manner and degree similar to those observed in
      the Dex/IGF-I group. Surprisingly, injection of GH alone in normal animals
      increased proteasome subunit mRNAs in skeletal muscle (C-2, 85%; C-3, 109%; C-8,
      91%). This effect of GH on proteasome subunit mRNAs was also observed in liver.
      These findings suggest, therefore, that suppression of Dex-induced expression of
      proteasome subunit mRNAs in skeletal muscle is one of the mechanisms by which IGF
      I exerts its antiproteolytic activity in catabolic states. On the other hand, the
      biological function of GH in regulating proteasome subunits needs further
      investigation.

PMID- 12423630
TI  - Enzymatic synthesis of chondroitin sulfate E by N-acetylgalactosamine 4-sulfate 6
      O-sulfotransferase purified from squid cartilage.
AB  - Chondroitin sulfate E (CS-E), a chondroitin sulfate isomer containing GlcAbeta1
      3GalNAc(4,6-SO(4)) repeating unit, was found in various mammalian cells in
      addition to squid cartilage and is predicted to have several physiological
      functions in various mammalian systems such as mast cell maturation, regulation
      of procoagulant activity of monocytes, and binding to midkine or chemokines. To
      clarify the physiological functions of GalNAc(4,6-SO(4)) repeating unit,
      preparation of CS-E with a defined content of GalNAc(4,6-SO(4)) residues is
      important. We report here the in vitro synthesis of CS-E from chondrotin sulfate
      A (CS-A) by the purified squid N-acetylgalactosamine 4-sulfate 6-O
      sulfotransferase (GalNAc4S-6ST) which catalyzed transfer of sulfate from 3(')
      phosphoadenosine-5(')-phosphosulfate to position 6 of GalNAc(4SO(4)) residues of
      CS-A and dermatan sulfate (DS). When CS-A was used as an acceptor, about half of
      GalNAc(4SO(4)) residues, on average, were converted to GalNAc(4,6-SO(4))
      residues. Anion exchange chromatography of the CS-E synthesized in vitro showed
      marked heterogeneity in negative charge; the proportion of GalNAc(4,6-SO(4)) in
      the most negative fraction exceeded 70% of the total sulfated repeating units.
      GalNAc4S-6ST also catalyzed the synthesis of oversulfated DS with GalNAc(4,6
      SO(4)) residues from DS. Squid GalNAc4S-6ST thus should provide a useful tool for
      preparing CS-E and oversulfated DS with a defined proportion of GalNAc(4,6-SO(4))
      residues.

PMID- 12423631
TI  - Sequencing of rat liver cytosolic proteins by matrix-assisted laser desorption
      ionization-quadrupole time-of-flight mass spectrometry following electrophoretic
      separation and extraction.
AB  - A new technique is described that enables the direct determination of the
      complete or partial amino acid sequence of cytosolic proteins separated by gel
      electrophoresis and allows for the further observation of disease- or drug
      induced posttranslational modifications. The procedure uses a two-phase
      extraction strategy (ethyl acetate/ammonium bicarbonate) for the efficient
      separation of proteins/peptides from an electrophoretic matrix and subsequent
      sequence analysis by matrix-assisted laser desorption ionization-quadrupole time
      of-flight mass spectrometry. The method was tested using hepatocyte cytosolic
      proteins and compared to a complementary approach using direct solvent extraction
      from in-gel digests. Although the latter procedure identified the proteins, it
      did not enable complete amino acid sequence determination. In contrast, high
      sequence coverage was obtained using the peptide extraction procedure, without
      any apparent dependence on protein size. The technique minimized the chemically
      inconsistent modifications generated from in-gel digestion, thus aiding mass
      spectrometric interpretation and valid protein sequence identification.

PMID- 12423633
TI  - Characterization of the interactions between the small GTPase RhoA and its
      guanine nucleotide exchange factors.
AB  - A novel spectrophotometric method to study the kinetics of the guanine nucleotide
      exchange factors-catalyzed reactions is presented. The method incorporates two
      coupling enzyme systems: (a). GTPase-activating protein which stimulates the
      intrinsic GTP hydrolysis reaction of small GTPases and (b). purine nucleotide
      phosphorylase and its chromophoric substrate, 7-methyl-6-thioguanosine, for
      quantitation of the resultant inorganic phosphate. The continuous coupled enzyme
      system was used for characterization of the interactions between the small GTPase
      RhoA and its guanine nucleotide exchange factors, Lbc and Dbl. Kinetic parameters
      obtained here show that there is no significant difference in kinetic mechanism
      of these GEFs in interaction with RhoA. The Michaelis-Menten constants were
      determined to be around 1micro M, and the rate constants k(cat) were around 0.1s(
      1).

PMID- 12423632
TI  - Renaturation of human proinsulin--a study on refolding and conversion to insulin.
AB  - The production of human proinsulin in Escherichia coli usually leads to the
      formation of inclusion bodies. As a consequence, the recombinant protein must be
      isolated, refolded under suitable redox conditions, and enzymatically converted
      to the biologically active insulin. In this study we describe a detailed in vitro
      renaturation protocol for human proinsulin that includes native structure
      formation and the enzymatic conversion to mature insulin. We used a His(8)-Arg
      proinsulin that was renatured from the completely reduced and denatured state in
      the presence of a cysteine/cystine redox couple. The refolding process was
      completed after 10-30 min and was shown to be strongly dependent on the redox
      potential and the pH value, but not on the temperature. Refolding yields of 60
      70% could be obtained even at high concentrations of denaturant (3M guanidinium
      HCl or 4M urea) and protein concentrations of 0.5mg/ml. By stepwise renaturation
      a concentration of about 6 mg/ml of native proinsulin was achieved. The refolded
      proinsulin was correctly disulfide-bonded and native and monomeric as shown by RP
      HPLC, ELISA, circular dichroism, and analytical gel filtration. Treatment of the
      renatured proinsulin with trypsin and carboxypeptidase B yielded mature insulin.

PMID- 12423634
TI  - Formation of a self-assembled phenylboronic acid monolayer and its application
      toward developing a surface plasmon resonance-based monosaccharide sensor.
AB  - For the surface-optoelectronic study of sugar sensing, we synthesized and
      characterized dithiobis(4-butyrylamino-m-phenylboronic acid) (DTBA-PBA) as a
      recognition molecule. DTBA-PBA has a boronic acid group that has been known to
      form covalently bonded complexes with the 1,2- or 1,3-diol of sugars. A self
      assembled monolayer (SAM) of DTBA-PBA was formed on a gold surface and
      characterized by atomic-force microscopy, Fourier transform infrared reflection
      absorption spectroscopy, and surface electrochemical measurements. An interaction
      study between monosaccharides and DTBA-PBA SAM was performed using surface
      plasmon resonance spectroscopy. The increase in molecular interactions between
      DTBA-PBA SAM and monosaccharides resulted in an optically induced electron
      excitation change on the Au surface through a refractive index change of the
      interfacial recognition layer. This correlation between electron excitation and
      molecular interaction was measurable at very low monosaccharide concentrations
      (1.0 x 10(-12)M). DTBA-PBA SAM shows a selective fructose sensing among four
      kinds of monosaccharides, even in a low concentration range.

PMID- 12423635
TI  - Sample preparation for amino acid determination by integrated pulsed amperometric
      detection in foods.
AB  - This report describes a new sample preparation method for food which allows a
      complete separation of carbohydrates and amino acids prior to their analysis by
      anion-exchange chromatography and integrated pulsed amperometric detection. Food
      samples with high carbohydrate concentrations are applied to solid-phase
      extraction columns containing a strong cation-exchange resin. Carbohydrates are
      recovered initially; retained amino acids are eluted with 0.2 M CaC l(2)
      subsequently. The carbohydrate and the amino acid fractions are analyzed. The
      recovery calculated for 21 amino acids was in the range from 84 to 126%. The
      sample preparation was tested for amino acid concentrations between 4.2 and 84.0
      nmol of each amino acid (between 2.1 and 42.0 nmol of cystine) and correlation
      coefficients between 0.84 and 0.99 were obtained. The capacity of the solid-phase
      extraction columns employed was up to 3.7 micro mol. Sample preparation was
      evaluated with four different food samples: sourdough, skim milk, lemon juice,
      and potato.

PMID- 12423636
TI  - High-efficiency DNA ligation for clamp attachment without polymerase chain
      reaction.
AB  - We coupled ligation with mass action to achieve high-efficiency clamp attachment
      without polymerase chain reaction (PCR). Using a 10-fold molar excess of a GC
      rich clamp of synthesized and hybridized oligonucleotides, we achieved the
      maximum clamp-ligation efficiency in which the clamp was ligated to >95% of
      10(10)-10(12) restriction ends of a PCR-amplified fragment. The maximum
      efficiency was confirmed by ligating the clamp to 10(11)-10(12) restriction ends
      of human genomic DNA. Our approach can be added to a constant denaturant
      capillary electrophoresis (CDCE)-based method of analyzing rare point mutants at
      fractions as low as 10(-6); such mutants appear as small copy numbers in the
      initial samples. This CDCE-based method alone is applicable to only those DNA
      sequences juxtaposed with an internally occurring clamp of a higher melting
      temperature in genomic DNA. Since such sequences represent 9% of the human
      genome, the addition of clamp ligation significantly increases the scanning range
      for the human genome without reducing the initial mutant copy numbers.
      Furthermore, clamp ligation/attachment without PCR prevents PCR-created mutants
      from interfering with rare mutational analysis. In addition to those applications
      seeking high-efficiency DNA ligation, our approach can be generally applied to
      ligation of restriction ends.

PMID- 12423637
TI  - Is reduction of the sulfonated tetrazolium 2,3-bis (2-methoxy-4-nitro-5
      sulfophenyl)-2-tetrazolium 5-carboxanilide a reliable measure of intracellular
      superoxide production?
AB  - The sulfonated tetrazolium 2,3-bis (2-methoxy-4-nitro-5-sulfophenyl)-2
      tetrazolium 5-carboxanilide (XTT) is advantageous in that it yields a water
      soluble formazan, unlike most other available tetrazoliums. XTT is reducible by
      superoxide, as are other tetrazoliums, but is not directly reduced by xanthine
      oxidase plus xanthine or by glucose oxidase plus glucose. This led to the
      suggestion that XTT reduction might serve as a reliable index of intracellular
      O(2)(-) production. We now show that soluble extracts of Escherichia coli contain
      two NADPH:XTT reductases that act aerobically or anaerobically. That being the
      case, XTT reduction is not a reliable measure of intracellular O(2)(-).

PMID- 12423638
TI  - Oxyphor R2 and G2: phosphors for measuring oxygen by oxygen-dependent quenching
      of phosphorescence.
AB  - Oxygen-dependent quenching of phosphorescence is a useful and essentially
      noninvasive optical method for measuring oxygen in vivo and in vitro. Calibration
      of the phosphors is absolute, and once phosphors have been calibrated in one
      laboratory the same constants can be used by anyone else as long as the
      measurement is done under the same conditions. Two new phosphors, one based on Pd
      meso-tetra-(4-carboxyphenyl)porphyrin and the other on Pd-meso-tetra-(4
      carboxyphenyl)tetrabenzoporphyrin, are very well suited to in vivo oxygen
      measurements. Both phosphors are Generation 2 polyglutamic Pd-porphyrin
      dendrimers, bearing 16 carboxylate groups on the outer layer. These phosphors are
      designated Oxyphor R2 and Oxyphor G2, respectively. Both are highly soluble in
      biological fluids such as blood plasma and their ability to penetrate biological
      membranes is very low. The maxima in the absorption spectra are at 415 and 524 nm
      for Oxyphor R2 and 440 and 632 nm for Oxyphor G2, while emissions are near 700
      and 800 nm, respectively. The calibration constants of the phosphors are
      essentially independent of pH in the physiological range (6.4 to 7.8). In vivo
      application is demonstrated by using Oxyphor G2 to noninvasively determine the
      oxygen distribution in a subcutaneous tumor growing in rats.

PMID- 12423639
TI  - Protein-heparin interactions measured by BIAcore 2000 are affected by the method
      of heparin immobilization.
AB  - Surface plasmon resonance (SPR) biosensors such as the BIAcore 2000 are a useful
      tool for the analysis of protein-heparin interactions. Generally, biotinylated
      heparin is captured on a streptavidin-coated surface to create heparinized
      surfaces for subsequent binding analyses. In this study we investigated three
      commonly used techniques for the biotinylation of heparin, namely coupling
      through either carboxylate groups or unsubstituted amines along the heparin
      chain, or through the reducing terminus of the heparin chain. Biotinylated
      heparin derivatives were immobilized on streptavidin sensor chips and several
      heparin-binding proteins were examined. Of the surfaces investigated, heparin
      attached through the reducing terminus had the highest binding capacity, and in
      some cases had a higher affinity for the proteins tested. Heparin immobilized via
      intrachain bare amines had intermediate binding capacity and affinity, and
      heparin immobilized through the carboxylate groups of uronic acids had the lowest
      capacity for the proteins tested. These results suggest that immobilizing heparin
      to a surface via intrachain modifications of the heparin molecule can affect the
      binding of particular heparin-binding proteins.

PMID- 12423640
TI  - Nonradioactive technique to measure protein phosphatase 2A-like activity and its
      inhibition by drugs in cell extracts.
AB  - A nonradioactive assay has been developed that can be used to measure
      serine/threonine protein phosphatase (PP) activity, especially PP2A, in crude
      extracts from different cell lines. For this technique commercially available
      casein is used as an already phosphorylated substrate. The prerequisite for
      reliable measurements is the removal of free phosphate from cell extracts and
      substrate preparations with desalting columns. The use of different nonspecific
      or specific inhibitors as well as inhibition characteristics observed after
      extract dilution suggests that in the absence of magnesium, PP2A-like activity in
      the extracts is measured by this technique. Inclusion of magnesium allowed the
      detection of a protein phosphatase activity that is activated by magnesium, which
      is presumably PP2C. The use of structurally different as well as structurally
      related inhibitors of PP2A gave results comparable to those of reports from the
      literature that were obtained with radioactive assays. Thus, our data supported
      our hypothesis that this nonradioactive assay can be used for the identification
      of newly synthesized PP inhibitors as well as for performing structure-activity
      analysis within groups of such new agents.

PMID- 12423642
TI  - Dual-tag prokaryotic vectors for enhanced expression of full-length recombinant
      proteins.

PMID- 12423641
TI  - Mapping of protein phosphorylation by dual enzyme digestion and matrix-assisted
      laser desorption ionization-quadrupole orthogonal time-of-flight mass
      spectrometry.

PMID- 12423643
TI  - Determination of lysozyme activities in a microplate format.

PMID- 12423644
TI  - Acetaminophen-glutathione conjugate formation in a coupled cytochrome P-450
      glutathione S-transferase assay system mediated by subcellular preparations from
      adult and weanling rat tissues.
AB  - Previous studies from this laboratory indicated that glutathione (GSH) conjugate
      formation with acetaminophen (APAP) is remarkably induced in liver of weanling
      rats in response to a single overdose of the drug administered intraperitoneally
      (ip). Increased APAP-GSH conjugation has been attributed to inducible glutathione
      S-transferases (GSTs) in dividing hepatocytes. In order to verify this finding,
      an in vitro reconstitution assay containing liver microsomes (source of
      cytochrome P-450) and cytosolic fractions (source of GST) from livers and kidneys
      of adult and weanling rats has been established. In vitro incubation of the
      reaction mixture was followed by solvent extraction, enzymatic digestion and HPLC
      analysis of the conjugate. Under controlled conditions, in vitro, the rate of
      APAP-GSH conjugation reflected the GST activity of cytosolic sample added to
      incubation system. The activity of cytosolic GST in catalyzing this reaction was
      measured using cytosols prepared from various tissue sources, particularly from
      animals pretreated with dietary butylated hydroxylanisole (BHA). The extent of
      APAP-GSH conjugate formation mediated by cytosols varied in this order: BHA
      treated adult liver>BHA-treated weanling liver>control adult liver>control
      weanling liver>BHA-adult kidney>control adult kidney>BHA weanling kidney>control
      weanling kidney. In contrast to findings obtained from in vivo experiments, the
      rate of GST-dependent APAP conjugate formation with GSH in vitro is not induced
      in the presence of exogenous drug.

PMID- 12423645
TI  - The influence of the mycotoxins deoxynivalenol and zearalenol on in vitro
      maturation of pig oocytes and in vitro culture of pig zygotes.
AB  - The aim of the present study was to investigate the influence of specific toxins
      on in vitro maturation and embryo culture. alpha- and beta-zearalenol were tested
      at increasing levels from 3.75 to 90 microM and deoxynivalenol from 0.94 to 7.5
      microM in order to evaluate the effect on in vitro maturation rate of porcine
      cumulus-oocyte complexes. Furthermore, the influence of alpha-zearalenol (3.75-30
      microM) was appraised on the developmental competence of in vivo-derived zygotes
      during 5 days of in vitro culture. All three substances affected maturation and
      degeneration rates in a dose-dependent manner, but to different extents.
      Significant differences were obtained at a concentration of 7.5 microM alpha
      zearalenol and higher. beta-zearalenol negatively affected the process of oocyte
      development beginning at a concentration of 30.0 microM (P<0.05). Deoxynivalenol
      had significant influence on oocyte maturation at a concentration of 1.88 microM
      (31.4 vs 79.3% for control). Differences in embryonic development in vitro were
      observed at a concentration of 15 microM alpha-zearalenol (P<0.05). These data
      demonstrate a negative effect of alpha-zearalenol on embryonic development of
      zygotes, and a compound-specific, dose-dependent negative effect of the three
      substances on meiotic progression of porcine oocytes.

PMID- 12423646
TI  - Lipid peroxidation stimulated by Solvesso, Bawanol and methanol, and its
      counteraction by antioxidants in human placental mitochondria.
AB  - The influence of some solvents used in the paint and lacquer industry, Solvesso
      100, 150 and Bawanol, on the process of lipid peroxidation was evaluated. The
      interactions of the solvents with methanol and the antioxidative effect of
      coenzyme Q(10) (CoQ(10)) and vitamin E were also examined. The mitochondria
      isolated from human placenta were used as a model for investigation. The level of
      peroxidation was evaluated by malonodialdehyde (MDA) measurement. It was observed
      that Solvesso 150, Bawanol and methanol caused a statistically significant
      increase of MDA concentration and that the examined solvents had an antagonistic
      interaction with methanol. Solvesso 100 does not influence on MDA concentration
      but gives the same type of interaction with methanol as Solvesso 150. CoQ(10) and
      vitamin E proved to be effective antioxidants to counteract oxidative stress
      caused by the studied solvents, lowering lipid peroxidation expressed by MDA
      concentration.

PMID- 12423647
TI  - In vitro effects of monophthalates on cytokine expression in the monocytic cell
      line THP-1 and in peripheral blood mononuclear cells from allergic and non
      allergic donors.
AB  - It has recently been shown that plasticizers are present in indoor air dust,
      which may lead to human exposure via the inhalation route. Moreover, studies have
      indicated that plasticizers may possess adjuvant effects increasing the health
      damaging potential of allergens. The aim of this study was to investigate the in
      vitro effect of metabolites of phthalate plastisizers, such as whether an
      adjuvant effect is paralleled by changes of the cytokine expression in the
      monocytic cell line THP-1 and in peripheral blood mononuclear cells (PBMCs) from
      allergics and non-allergics. The toxicity monitored by cell viability was
      determined by incubating THP-1 cells with a 10-fold dilution series of
      monophthalates for 24 h. At different points in time cytokine expression (IL
      1beta, IL-6, IL-12alpha (p35)) in THP-1 cells incubated with non-toxic
      concentrations of monophthalate (2-20 microg/ml)+/-LPS (1 microg/ml) were
      determined using Quantitative Competitive RT-PCR. PBMCs from allergics and non
      allergics were incubated with monophthalate 220 microg/ml) for up to 48 h and
      cytokine expression (IL-4, IL-5, IFN-gamma) was measured using real-time PCR. The
      cytotoxic level of monophthalates is 20-200 microg/ml, depending on the
      individual monophthalate. There seems to be a correlation between increasing side
      chain length and toxicity. Monophthalates did not induce changes in cytokine
      expression in THP-1 cells, though there is an increase when co-incubating with
      LPS. Cytokine expression in PBMC seems virtually unchanged when co-incubated with
      monophthalate, though mono-n-butyl phthalate (MBUP) tends to increase the level
      of IL-4 in PBMCs from allergic individuals. The two cellular models demonstrated
      the dynamics of regulated cytokine mRNA and are applicable for in vitro
      immunotoxicological investigations. The results regarding monophthalates suggest
      these to have a limited effect on cytokine expression in the monocytic cell line
      THP-1 and weak effect on cytokine expression in PBMCs from allergic and non
      allergic individuals.

PMID- 12423648
TI  - Influence of vitamin D3 metabolites on cell proliferation and cytotoxicity of
      adriamycin in human normal and neoplastic cells.
AB  - The common features of biological activity displayed by vitamin D family members
      and adriamycin suggest the possibility of synergistic effects of the combination
      of these compounds. Until now, the mechanisms responsible mainly for adriamycin
      cytotoxic action have not been indicated. Therefore, observation of the possible
      common cell targets for adriamycin and vitamin D metabolites could shed more
      light on the mechanisms of cytotoxic activity of adriamycin. In the present
      study, the influence of calcidiol (25-hydroxyvitamin D(3)) and calcitriol
      (1alpha,25-dihydroxyvitamin D(3)) on the proliferation and cytotoxicity of
      adriamycin was studied. The following cell lines were tested: normal human
      fibroblasts-CRL 1502, human melanoma cells-ME18 and its subline-ME18/R, resistant
      to adriamycin. As was shown, 72 h of incubation with calcidiol or calcitriol,
      both at 10 microM, inhibited growth (to approx. 60%) only of the ME18 cells. Dose
      and time dependence of this effect has been confirmed. Antiproliferative events
      did not correlate with an increase of adriamycin cytotoxicity. It was noted that
      calcidiol and calcitriol had no significant influence on the adriamycin IC(50)
      values in any cell lines tested. These results point to the divergent mechanisms
      of action of adriamycin and vitamin D(3) metabolites.

PMID- 12423649
TI  - Serotonin-Cu(II)-mediated DNA cleavage: mechanism of copper binding by serotonin.
AB  - It has been proposed that considerable DNA damage may be caused by endogenous
      metabolites produced during the body's normal metabolic processes. 5
      hydroxytryptamine (serotonin) is an important neurotransmitter in brain and
      spinal cord. We have previously shown that serotonin induces oxidative cleavage
      of DNA strands in the presence of copper ions. In the present paper we have
      examined the mechanism of copper binding by serotonin using absorption
      spectroscopy, Cu(II)-mediated lipid peroxidation and by determining the oxidation
      of the serotonin molecule. Addition of increasing concentrations of Cu(II) to
      serotonin leads to a progressive enhancement in the absorption band and is
      accompanied by a shift towards a lower wavelength indicative of the formation of
      an oxidised species of serotonin. Studies with the structurally related molecules
      tryptophan and melatonin showed that only serotonin is able to reduce Cu(II) to
      Cu(I). Similarly, only serotonin was found to be able to abolish the copper
      mediated peroxidation of mitochondria. These results suggested the involvement of
      the phenolic group in copper binding. Further, it was also shown that the binding
      of copper to serotonin leads to the formation of a quinone in the absence of
      molecular oxygen. Based on these results, a model has been proposed in which
      serotonin reduces two molar equivalents of Cu(II) to Cu(I) through a reaction
      involving two electron oxidation of the phenolic ring to a quinone methide.

PMID- 12423650
TI  - Oxidative stress response of rat testis to model prooxidants in vitro and its
      modulation.
AB  - Understanding the effects of prooxidants on mammalian testis either in vitro or
      in vivo is important, since recent evidence shows that oxidative stress can play
      a vital role in the etiology of male infertility. In this investigation, we have
      examined the oxidative stress response of adult rat testis in vitro as induced by
      model prooxidants (tert-butyl hydroperoxide (t-bHP) and cumene hydroperoxide
      (cHP) deploying two models-testicular cell suspensions (TCS) and testicular
      explants (TE). Significant induction of oxidative stress was observed in both
      models as evidenced by increased thiobarbituric acid reactive substances (TBARS)
      levels on incubation with hydroperoxides. The response was both concentration and
      time dependent. At the highest concentration (200 microM), both hydroperoxides
      induced a 100% increase in the TE model, compared with a dramatic (380-560%)
      increase in the TCS model during a 30-min incubation. Further evidence of
      oxidative stress such as reduction in the GSH levels and alterations in the
      activity of antioxidant enzymes (catalase and glutathione peroxidase) were also
      obtained in the TE model. In the TE model, radical scavengers, namely thiourea,
      urea and mannitol, as well as antioxidants such as glutathione and catalase
      inhibited the t-bHP-induced lipid peroxidation response to varying degree. A
      similar degree of protection was also evident with known antioxidants such as
      ascorbic acid, butylated hydroxyanisole and butylated hydroxytoluene in the TE
      model. Further co-incubation of TE either with mercaptosuccinate (a potent
      glutathione peroxidase inhibitor) or 3-aminotriazole (an irreversible catalase
      inhibitor) resulted in a marked increase in t-bHP-induced lipid peroxidation,
      clearly suggesting the importance of both of these enzymic antioxidants in rat
      testis in vitro. These data suggest that the TE model may be further utilized to
      screen antioxidants in vitro and also investigate the prooxidant potency of
      xenobiotics in testicular cells.

PMID- 12423651
TI  - In vitro phototoxic properties of new 6-desfluoro and 6-fluoro-8
      methylquinolones.
AB  - A representative set of potent antibacterial 6-desfluoro-8-methylquinolones, in
      which the C-6 fluorine atom is replaced by -NH(2) or -H, and their 6-fluoro
      counterparts, were investigated to evaluate their phototoxic potential and to
      explore the mechanism behind their phototoxicity. The capacity to photosensitize
      biological substrates (lipids, proteins, DNA) has been analyzed, as well as their
      photocytotoxicity on red blood cells and 3T3 murine fibroblasts. The results
      obtained show that the quinolones studied are able to photosensitize red blood
      cell lysis in an oxygen-dependent way and induce a high decrease in cell
      viability after UVA irradiation. A major correlation with phototoxicity lies in
      the structure of the individual antibacterials and their hydrophobicity; in
      particular, 6-amino derivatives are less phototoxic than corresponding
      unsubstituted and fluorinated compounds. Cellular phototoxicity was inhibited by
      the addition of free radical and hydroxyl radical scavengers (BHA, GSH and DMTU),
      suggesting the involvement of a radical mechanism in their cytotoxicity. A good
      correlation was observed between lipid peroxidation and phototoxicity, indicating
      that the test compounds exert their toxic effects mainly in the cellular
      membrane. Preliminary experiments on pBR322 DNA show that these derivatives do
      not photocleave DNA, differently from the two photogenotoxic fluoroquinolones,
      ciprofloxacin and lomefloxacin, used as reference compounds.

PMID- 12423652
TI  - Induction of cytochrome P450 1B1 in MDA-MB-231 human breast cancer cells by non
      ortho-substituted polychlorinated biphenyls.
AB  - The effects of 12 non-ortho-substituted polychlorinated biphenyl (PCB) congeners
      on the induction of human cytochrome P450 1B1 (CYP1B1), an estradiol 4
      hydroxylase, were investigated in MDA-MB-231 breast cancer cells. Three
      independent quantitative assays were used, in which the rates of estrogen
      metabolism, the levels of the CYP1B1 and CYP1A1 mRNAs, and luciferase activities
      under the control of the CYP1B1 promoter were measured. Of the congeners
      investigated, 3,4,4',5-tetrachlorobiphenyl (PCB 81), 3,3',4,4',5
      pentachlorobiphenyl (PCB 126), 3,4',5-trichlorobiphenyl (PCB 39) and 3,3',4,5
      tetrachlorobiphenyl (PCB 78) were the most potent in each assay, causing four to
      10-fold increases in response. Exposure to 3,3',4,4',5,5'-hexachlorobiphenyl (PCB
      169) resulted in elevated CYP1B1 mRNA and increased CYP1B1-promoter driven
      luciferase activity, but caused depressed rather than elevated rates of E(2)
      metabolism due to inhibition of CYP1B1. The relative magnitudes of CYP1B1
      induction by the PCB congeners, as determined by the three assays, were in close
      agreement, with the exception noted for PCB 169. These results indicate that PCB
      structure-activity relationships for the induction of human CYP1B1 are similar to
      those observed for human CYP1A1, but differ somewhat from what has been reported
      for induction of rat CYP1A1.

PMID- 12423653
TI  - Prooxidant action of gallic acid compounds: copper-dependent strand breaks and
      the formation of 8-hydroxy-2'-deoxyguanosine in DNA.
AB  - Gallic acid and its alkylesters, polyphenolic compounds with antioxidative
      activity, acted as a prooxidant causing a copper-dependent DNA damage. Treatment
      of DNA from plasmid pBR322 and calf thymus with gallic acid plus copper ion
      caused strand scission and the formation of 8-hydroxy-2'-deoxyguanosine in DNA.
      Addition of catalase protected DNA from the gallic acid/copper-dependent strand
      breaks and the formation of 8-hydroxy-2'-deoxyguanosine, indicating that hydroxyl
      radical may participate in the DNA damage. Ethyl-, propyl- and butylgallates
      showed only a little DNA damage. Octyl- and laurylgallates caused negligible
      damage of DNA. DNA strand breaks and formation of 8-hydroxy-2'-deoxyguanosine
      were closely related to the reduction of copper by gallate compounds. These
      results imply that cuprous ion reduced by gallate derivatives may play a key role
      in the oxidative cleavage of DNA and the formation of base adduct. The cytotoxic
      effect of gallate compounds can be explained by their prooxidant action dependent
      on the reducing activity.

PMID- 12423654
TI  - Evaluation of CD86 expression and MHC class II molecule internalization in THP-1
      human monocyte cells as predictive endpoints for contact sensitizers.
AB  - The aim of this study was to explore the usefulness of a human monocyte cell line
      in the development of in vitro models for predictive testing of contact
      sensitizers. Several studies have shown that contact sensitizers induce CD86
      expression and enhanced internalization of MHC class II molecules in dendritic
      cells (DCs). We used THP-1, a human monocyte cell line, as a replacement for DCs
      for evaluation of these phenotypical alterations as predictive endpoints for
      contact sensitizers. Known sensitizers and irritants were evaluated. After 24-h
      exposure to samples, the expression of CD86 on THP-1 cells was measured by flow
      cytometry. Sensitizers such as dinitrochlorobenzene (DNCB), 2
      mercaptobenzothiazole (MBT), eugenol, p-phenylenediamine (PPDA) and ammonium
      tetrachloroplatinate (Pt) enhanced CD86 expression on THP-1 cells, while nickel
      sulfate, cobalt sulfate and irritants such as methylsalicylate (MS), sodium
      dodecyl sulfate (SDS) and dimethyl sulfoxide (DMSO) did not augment CD86
      expression. A synergistic effect was observed when DNCB and IFN-alpha were added
      simultaneously to a culture of THP-1 cells. Furthermore, internalization of MHC
      class II molecules was observed when the cells were treated with some of
      sensitizers for 2 h. The inducing effects of chemicals on the two phenotypical
      alterations were the same. These results suggest that these test systems can be
      used to predict contact-sensitizing ability of chemicals as an in vitro
      sensitization assay.

PMID- 12423655
TI  - Short-term assay for the identification of neurotoxic compounds and their liver
      derived stable metabolites.
AB  - The release of stable neurotoxic metabolites from liver after metabolic
      activation of xenobiotics can be investigated in cultures of primary rat
      hepatocytes as metabolic activation system and embryonic chicken brain cell
      cultures as target. It was shown that adult rat hepatocyte cell cultures are a
      reliable bioactivating system for xenobiotics such as cyclophosphamide and
      isophenphos resulting in the release of stable metabolites into the supernatant.
      The cultured embryonic chicken brain cells were able to discriminate between the
      toxicity of parent drugs and its metabolite(s) and between metabolites with an
      unspecific cytotoxic activity (cyclophosphamide) and metabolites with a high
      potential to damage specific nerve cell population(s) (isophenphos). The observed
      neurotoxicity of the isophenphos metabolites is not an acute effect but induced
      only after a prolonged exposure period. The present study provides evidence that
      the subsequent use of hepatocytes and brain cell cultures has the potential to be
      used as an in vitro screening system for the identification of specific and non
      specific neurotoxic compounds. Solely stable metabolites are taken into account,
      since in the in vivo situation only stable metabolites have a change to reach the
      nervous system. Our data suggest that the present approach is able to
      discriminate (a) between cell-type and organ specific toxicity, (b) between
      neurotoxicity derived after long-term or acute exposure, and (c) between the
      neurotoxicity induced by the native test compound or stable metabolites.

PMID- 12423656
TI  - Formation of reactive oxygen species in rat hepatoma-derived Fa32 cells to
      predict human toxicity.
AB  - The cytotoxicity of the MEIC (Multicentre Evaluation of In vitro Cytotoxicity)
      reference chemicals was investigated by measuring the increased reactive oxygen
      species (ROS) formation in rat hepatoma-derived Fa32 cells. ROS formation was
      measured with 2',7'-dichlorodihydrofluorescein diacetate as a fluorescent probe.
      The results were quantified by determining the ROS50. This is the concentration
      of test compound required to increase the ROS formation with 50% compared with
      control cells. An extremely high ROS formation was observed with ferrous sulfate.
      Of a total of 44 chemicals, an increased ROS formation was observed for 24. This
      was not the case for the 20 other chemicals. When the ROS formation in Fa32 cells
      was compared with human toxicity, the correlation coefficient was clearly higher
      than for human hepatoma-derived Hep G2 cells, at least when the extremely
      sensitive ferrous sulfate was withdrawn from the comparison. The Hep G2 assay was
      the best acute in vitro assay for the prediction of human toxicity within the
      MEIC study. Consequently, the ROS formation assay in Fa32 cells has a high
      predictive value for human toxicity, with the drawback that only ROS increasing
      chemicals can be evaluated.

PMID- 12423657
TI  - Rapid integrity assessment of rat and human epidermal membranes for in vitro
      dermal regulatory testing: correlation of electrical resistance with tritiated
      water permeability.
AB  - An approach is presented that allows for rapid selection of robust rat and human
      epidermal membranes for use on in vitro dermal regulatory studies. Tritiated
      water (THO) permeability was correlated with electrical resistance (ER) and the
      results used to propose ER values to judge membrane integrity. Rat and human
      epidermal membranes were prepared and mounted onto in vitro glass static
      diffusion cells (0.64 cm(2)) maintained at 32 degrees C. THO permeability
      coefficients (Kp) were determined and compared with ER measurements. Electrical
      resistance was also determined for various in vitro cell exposure areas from 0.64
      cm(2) to 2.54 cm(2). Our results show that rat epidermal membrane THO Kp values
      exhibited a lognormal distribution with a median value of 2.76 x 10(-3) cm/h.
      Human epidermal membrane THO Kp values were best described by a Weibull
      distribution with a median value of 1.13 x 10(-3) cm/h. The corresponding median
      electrical resistance measurements were 5.59 kOmega for rat and 23 kOmega for
      human epidermal membranes. Based on the widely used and accepted single point THO
      Kp thresholds of </=2.5 x 10(-3) cm/h (rat) and </=1.5 x 10(-3) cm/h (human), the
      corresponding ER values of >/=5.87 kOmega and >/=17.1 kOmega were calculated and
      proposed as acceptable benchmarks for pre-qualifying membranes. In our research
      exploring the relationship between ER and exposure area we report that an inverse
      relationship exists between ER and in vitro cell exposure area; as cell area
      increased, ER decreased. The use of electrical resistance provides a rapid and
      reliable method for evaluating the integrity of rat and human epidermal membranes
      for in vitro dermal kinetic testing.

PMID- 12423658
TI  - Ranking the toxicity of fatty acids on Jurkat and Raji cells by flow cytometric
      analysis.
AB  - The fatty acids have an important role in the control of leukocyte metabolism and
      function. Higher concentrations of certain fatty acids, particularly
      polyunsaturated fatty acids (PUFAs) and volatile fatty acids, can cause cell
      death via apoptosis or, when concentrations are greater, necrosis. In this study,
      we determined the highest concentrations of various fatty acids that are non
      toxic to two human leukemic cell lines, Jurkat (T-lymphocyte) and Raji (B
      lymphocyte). Toxicity was evaluated by either loss of membrane integrity and/or
      DNA fragmentation using flow cytometric analysis. There were no remarkable
      differences for the toxicity of the fatty acids between B and T cell lines. The
      cytotoxicity of the fatty acids was related to the carbon chain length and number
      of double bonds: docosahexaenoic acid=eicosapentaenoic acid=arachidonic
      acid=gamma-linolenic acid=stearic acid=palmitic acid > linoleic acid=palmitoleic
      acid > vacenic acid=lauric acid > oleic acid > elaidic acid > capric acid >
      butyric acid > caprylic acid=caproic acid=propionic acid. The proportion of cells
      undergoing apoptosis or necrosis, induced by the fatty acids tested, remains to
      be investigated.

PMID- 12423659
TI  - Cryopreserved precision-cut rat liver slices: morphology and cytochrome P450
      isoforms expression after prolonged incubation.
AB  - Precision-cut liver slices are an accepted in vitro system for toxicological
      investigations. However, cryopreservation of slices would make a more efficient
      utilisation, particularly of human liver tissue possible. In the present study
      sections of cryopreserved male rat liver slices were examined
      immunohistochemically for cytochrome P450 (CYP) isoforms expression after
      prolonged incubation and after exposure to typical inducers. Morphologically,
      with just thawed slices no major alterations were seen, but remarkable cell
      damage was observed even after 2 h of incubation mainly in the middle of the
      slices and in the periportal and intermediate regions of the lobules. After 24 h
      of incubation, viable cells were only observed at the edges of the slices or
      around bigger vessels. In the viable cells of the cryopreserved liver slices
      after 2 h of incubation CYP expression pattern was similar to that in normal
      liver specimens: a low CYP1A1, but a strong CYP2B1 and 3A2 expression
      predominantly in the central and intermediate lobular zones. After 24 h, the
      immunostaining for CYP2B1 and 3A2 in the viable cells was reduced, but that for
      CYP1A1 was increased. Incubation with beta-naphthoflavone further elevated CYP1A1
      and 2B1 expression. Phenobarbital caused an enhanced CYP2B1 and 3A2 and
      dexamethasone and pregnenolone 16 alpha-carbonitrile an increased CYP3A2
      immunostaining. These results show that also in cryopreserved liver slices and
      after a prolonged incubation, a distinct expression pattern and an in vitro
      induction of phase I enzymes can be demonstrated immunohistochemically.

PMID- 12423660
TI  - Kinetic analysis on the in vitro cytotoxicity using Living Skin Equivalent for
      ranking the toxic potential of dermal irritants.
AB  - The extent of cytotoxicity injured by several skin irritants was kinetically
      measured and analyzed in a three-dimensional cultured human skin model, Living
      Skin Equivalent-002 (LSE). Colorimetric thiazoyl blue (MTT) conversion assay was
      selected as a cytotoxicity assay, and olive oil (OO), lactic acid (LA), Triton X
      100 (TX) and sodium lauryl sulfate (SLS) were evaluated as model irritants. OO
      had almost no effect on the viability of LSE. When the other irritants were
      applied on the full-thickness LSE, two first-ordered decreasing phases, initial
      slow and following rapid phases, were found in the viability of LSE. LA and TX
      showed a bigger difference between the slow and rapid rates than SLS to show an
      inflection. The inflection time point from the slow to rapid rate was dependent
      on the kind and concentration of irritants applied. The higher the concentration
      of irritants applied, the more rapid the inflection point was observed. When LA
      and SLS were applied on the stratum corneum-stripped LSE, on the other hand,
      viability was mono-exponentially decreased with time. LA, TX and SLS probably
      decrease the barrier function of the stratum corneum to increase the rate of
      cytotoxicity during the irritant application. Interestingly, the rate of
      cytotoxicity on the stripped skin was similar to the late rapid rate on the full
      thickness skin in LA not in SLS. These results suggest that cytotoxicity of skin
      irritants on the full-thickness LSE can be represented by two first-order
      kinetics, and that the skin irritation rate is closely related by the barrier
      function of skin as well as the application concentration and intrinsic toxicity
      of irritants.

PMID- 12423661
TI  - Refinement of the Episkin protocol for the assessment of acute skin irritation of
      chemicals: follow-up to the ECVAM prevalidation study.
AB  - The Episkin model took part in the prevalidation study on in vitro tests for
      acute skin irritation of chemicals, which was carried out during 1999 and 2000.
      This prevalidation study was co-ordinated and supported by the European Centre
      for the Validation of Alternative Methods (ECVAM). During Phase 1 and Phase 2 of
      this study, reproducibility and transferability of the method were verified.
      Unfortunately, the performance of the method in terms of predictive ability was
      considered insufficient, due to a low specificity. In order to improve the
      performance of the Episkin method, the existing protocol was refined. This
      refinement consisted in reducing the exposure time of epidermis with chemicals.
      Sensitivity, specificity and accuracy of the new method were 70, 80 and 75%,
      respectively, thus meeting the acceptance criteria as defined by the Management
      Team. The Episkin method is now ready to enter a validation study of in vitro
      tests for acute skin irritation.

PMID- 12423662
TI  - GABAA receptors and benzodiazepines: a role for dendritic resident subunit mRNAs.
AB  - This review is designed to describe the evolution of the seminal observation made
      simultaneously in 1975 by Dr. W. Haefely's laboratory (Hoffman La Roche, Basel,
      Switzerland) and in the Laboratory of Preclinical Pharmacology (NIH, St.
      Elizabeths Hospital, Washington DC), that benzodiazepine action was mediated by a
      modulation of GABA action at GABA(A) receptors. In fact, our suggestion was that
      the benzodiazepine receptor was "a receptor on a receptor" and that this receptor
      was GABA(A). Needless to say, this suggestion created opposition, but we did not
      abandon the original idea, in fact, as shown in this review, there is now
      universal agreement with our hypothesis on the mode of action of benzodiazepines.
      Hence, this review deals with the allosteric modulation of GABA(A) receptors by
      benzodiazepines, the role of GABA(A) receptors and benzodiazepine structure
      diversities in this modulation, and describes the results of our attempts to
      establish a benzodiazepine (imidazenil) devoid of tolerance, withdrawal symptoms,
      and changes in the expression of GABA(A) receptor subunits during tolerance. It
      also deals with the idea that the synthesis of GABA(A) receptor subunits
      triggered by tolerance resides in dendrites and spines where mRNAs and the
      apparatus for this translation is located. New analytic procedures may foster
      progress in the understanding of tolerance to and withdrawal from
      benzodiazepines.

PMID- 12423663
TI  - Redox modulation of GABAA receptors obscured by Zn2+ complexation.
AB  - Redox reagents are thought to modulate gamma-Aminobutyric acid type A (GABA(A))
      receptors by regulating the redox state of the N-terminal disulphide bridge.
      Examining the redox sensitivity of recombinant GABA(A) receptors in human
      embryonic kidney cells, using whole-cell patch clamp techniques, revealed that
      alpha1beta2(H267A) and alpha1beta2gamma2 receptors, which are both less sensitive
      to Zn(2+) and H(+) modulation, ablated the potentiating effect of the reducing
      agent, dithiothreitol (DTT) seen for alpha1beta2 receptors. This effect could
      result from disruption to the redox signal transduction pathway or be due to DTT
      chelating Zn(2+) from its H267 inhibitory binding site, consequently potentiating
      GABA-activated currents in alpha1beta2 but not alpha1beta2(H267A) or
      alpha1beta2gamma2 receptors. A Zn(2+) chelating agent, tricine, potentiated GABA
      currents for the alphabeta constructs and vertically displaced GABA dose-response
      curves, suggesting that these receptors are subject to some inhibition by basal
      Zn(2+). Tricine, did not affect the GABA currents of either alpha1beta2(H267A) or
      alpha1beta2gamma2 receptors but did prevent the potentiation by 2 mM DTT and
      reduced the potentiation caused by 10 mM DTT on alpha1beta2 receptors. Thus, at
      low concentrations of DTT, a substantial component of the potentiation probably
      occurs via Zn(2+) chelation from H267 in the ion channel. In contrast, at higher
      DTT concentrations, it is more likely to be acting as a redox agent, which
      modulates both alphabeta and alphabetagamma subunit receptors.

PMID- 12423664
TI  - Large-amplitude 5-HT1A receptor activation: a new mechanism of profound, central
      analgesia.
AB  - We report the discovery of F 13640 and evidence suggesting this agent to produce
      powerful, broad-spectrum analgesia by novel molecular and neuroadaptative
      mechanisms. F 13640 stimulates G(alphaomicron) protein coupling to 5-HT(1A)
      receptors to an extent unprecedented by selective, non-native 5-HT(1A) ligands.
      Fifteen minutes after its injection in normal rats, F 13640 (0.01-2.5 mg/kg)
      decreases the vocalization threshold to paw pressure; 15 min upon injection in
      rats that are exposed to formalin-induced tonic nociception, F 13640 inhibits
      pain behavior. The initial hyperalgesia induced by 0.63 mg/kg F 13640 was
      followed, 8 hrs later, by paradoxical hypo-algesia; 5 mg/kg of morphine produces
      the opposite effects (i.e., hypo-algesia followed by hyper-algesia). Repeated F
      13640 injections cause an increase in the basal vocalization threshold and a
      reduction of F 13640-produced hyperalgesia; in these conditions, morphine causes
      basal hyperalgesia and antinociceptive tolerance. Continuous two-week infusion of
      F 13640 (0.63 mg/day) exerts little effect on the threshold in normal rats, but
      markedly reduces analgesic self-administration in arthritic rats. F 13640
      infusion also decreases allodynic responses to tactile and thermal stimulations
      in rats sustaining spinal cord or sciatic nerve injury. In these models of
      chronic nociceptive and neuropathic pain, the analgesia afforded by F 13640
      consistently surpasses that of morphine (5 mg/day), imipramine (2.5 mg/day),
      ketamine (20 mg/day) and gabapentin (10 mg/day). Very-high-efficacy 5-HT(1A)
      receptor activation constitutes a novel mechanism of central analgesia that grows
      rather than decays with chronicity, that is amplified by nociceptive stimulation,
      and that may uniquely relieve persistent nociceptive and neuropathic pains.

PMID- 12423665
TI  - 5-HT1A receptor-mediated autoinhibition does not function at physiological firing
      rates: evidence from in vitro electrophysiological studies in the rat dorsal
      raphe nucleus.
AB  - 5-HT(1A)-mediated autoinhibition of neurones in the dorsal raphe nucleus (DRN) is
      considered to be the principal inhibitory regulator of 5-HT neuronal activity.
      The activation of this receptor by endogenous 5-HT was investigated using
      electrophysiological recordings from the rat DRN in vitro. At a concentration
      which blocked the inhibitory effect of exogenous 5-HT, the 5-HT(1A) antagonist
      WAY 100635 did not alter basal firing rate or modulate the excitatory response to
      the alpha(1)-agonist phenylephrine. Blockade of 5-HT reuptake by a concentration
      of fluoxetine, which enhanced the inhibitory effect of exogenous 5-HT, lowered
      phenylephrine-induced basal firing presumably due to potentiation of the effect
      of endogenous 5-HT. However, this effect was not firing rate dependent and
      neither the proportional increase nor the time-course of the response to a higher
      concentration of phenylephrine were altered in the presence of fluoxetine. These
      data suggest that the inhibitory 5-HT(1A) receptor on raphe neurones is neither
      tonically activated nor plays any role in modulating the response to excitatory
      transmitters. Thus, at physiological firing rates this receptor does not appear
      to function as an autoreceptor of serotonergic neurones of the DRN.

PMID- 12423666
TI  - Human Ntera-2/D1 neuronal progenitor cells endogenously express a functional P2Y1
      receptor.
AB  - We report here that human Ntera-2/D1 (NT-2) cells, an undifferentiated committed
      neuronal progenitor cell line, endogenously express a functional P2Y(1) receptor,
      while other P2Y subtypes, except perhaps P2Y(4), are not functionally expressed.
      Quantitative RT-PCR analysis showed that NT-2 cells abundantly express mRNA for
      P2Y(1) and P2Y(11) receptors, while P2Y(2) and P2Y(4) receptors were detected at
      considerably lower levels. Western blot analysis also demonstrated expression of
      P2Y(1) receptors and Galpha(q/11) subunits. Various nucleotides induced
      intracellular Ca(2+) mobilisation in NT-2 cells in a concentration-dependent
      manner with a rank order potency of 2-MeSADP > 2-MeSATP > ADP > ATP > UTP >
      ATPgammaS, a profile resembling that of human P2Y(1) receptors. Furthermore,
      P2Y(1) receptor-specific (A3P5P) and P2Y-selective (PPADS, suramin) antagonists
      inhibited adenine nucleotide-induced Ca(2+) responses in a concentration
      dependent manner, consistent with expression of a P2Y(1) receptor. Moreover, of
      seven adenine nucleotides tested, only Bz-ATP and ATPgammaS elicited small
      increases in cAMP formation suggesting that few, if any, functional P2Y(11)
      receptors were expressed. P2Y(1) receptor-selective adenine nucleotides,
      including 2-MeSADP and ADP, also induced concentration-dependent phosphorylation
      and hence, activation of the extracellular-signal regulated protein kinases
      (ERK1/2). NT-2 cells, therefore, provide a useful neuronal-like cellular model
      for studying the precise signalling pathways and physiological responses mediated
      by a native P2Y(1) receptor.

PMID- 12423667
TI  - Induction of G protein-coupled receptor kinases 2 and 3 contributes to the cross
      talk between mu and ORL1 receptors following prolonged agonist exposure.
AB  - The molecular mechanism(s) underlying cross-tolerance between mu and opioid
      receptor-like 1 (ORL1) receptor agonists were investigated using two human
      neuroblastoma cell lines endogenously expressing these receptors and G protein
      coupled receptor kinases (GRKs). Prolonged (24 h) activation of the mu receptor
      desensitized both mu and ORL1 receptor-mediated inhibition of forskolin
      stimulated cAMP accumulation and upregulated GRK2 levels in SH-SY5Y and BE(2)-C
      cells. Prolonged ORL1 activation increased GRK2 levels and desensitized both
      receptors in SH-SY5Y cells. Upregulation of GRK2 correlated with increases in
      levels of transcription factors Sp1 or AP-2. PD98059, an upstream inhibitor of
      extracellular signal-regulated kinases 1 and 2 (ERK1/2), reversed all these
      events. Pretreatment with orphanin FQ/nociceptin (OFQ/N) also upregulated GRK3
      levels in both cell lines, and desensitized both receptors in BE(2)-C cells.
      Protein kinase C (PKC), but not ERK1/2, inhibition blocked OFQ/N-mediated GRK3
      induction and mu and ORL1 receptor desensitization in BE(2)-C cells. Antisense
      DNA treatment confirmed the involvement of GRK2/3 in mu and ORL1 desensitization.
      Here, we demonstrate for the first time a role for ERK1/2-mediated GRK2 induction
      in the development of tolerance to mu agonists, as well as cross-tolerance to
      OFQ/N. We also demonstrate that chronic OFQ/N-mediated desensitization of ORL1
      and mu receptors occurs via cell-specific pathways, involving ERK1/2-dependent
      GRK2, or PKC-dependent and ERK1/2-independent GRK3 induction.

PMID- 12423668
TI  - The ORL-1 (NOP1) receptor ligand nociceptin/orphanin FQ (N/OFQ) inhibits
      neurogenic dural vasodilatation in the rat.
AB  - The effects of the ORL-1 (NOP(1)) receptor ligand nociceptin (N/OFQ) and the
      nociceptin antagonists [Nphe(1)]N/OFQ-(1-13)-NH(2) (Nphe) and nocistatin (NST) on
      neurogenic dural vasodilatation (NDV) in the rat dura mater evoked by electrical
      stimulation of a closed cranial window were studied. The middle meningeal artery
      was visualised using intravital microscopy, and the vessel diameter analysed
      using a video dimension analyser. N/OFQ (1, 10, 100 nmol kg(-1); i.v., n=10)
      significantly and dose-dependently suppressed NDV maximally by 65% (P<0.01).
      Neither Nphe (100 nmol kg(-1); n=5) nor NST (100 nmol kg(-1); n=4) alone had an
      effect on NDV (P>0.05). Baseline vessel diameter was not significantly affected
      by application of N/OFQ, NST or Nphe. Application of the selective N/OFQ
      antagonist Nphe (10, 100 nmol kg(-1) i.v., n=8) dose-dependently and
      significantly (P<0.01) reversed the inhibition of NDV induced by application of
      N/OFQ (10 nmol kg(-1)). NST (10, 100 nmol kg(-1); n=7) failed to reverse the
      effects elicited by N/OFQ. Application of N/OFQ elicited a dose-dependent
      transient decrease in arterial blood pressure (P<0.01). Nphe dose-dependently
      reversed the cardiovascular effects induced by application of N/OFQ (10 nmol kg(
      1)) (P<0.01),while NST did not alter the blood pressure reaction elicited by
      N/OFQ. The results show that N/OFQ inhibits NDV, an effect which is antagonised
      by Nphe, but not by NST. ORL-1 (NOP(1)) receptors located on trigeminal sensory
      fibres may be involved in the regulation of dural vessel diameter and hence may
      play a role in migraine pathophysiology.

PMID- 12423669
TI  - Limited potentiation of blood pressure response to oral tyramine by brain
      selective monoamine oxidase A-B inhibitor, TV-3326 in conscious rabbits.
AB  - TV-3326 is a novel cholinesterase inhibitor that produces irreversible brain
      selective inhibition of monoamine oxidase (MAO)-A and B and has antidepressant
      like activity in rats after chronic oral administration. This study determined
      whether TV-3326 would cause less potentiation than other irreversible MAO
      inhibitors of the blood pressure (BP) response to oral tyramine in conscious
      rabbits. Dose-response curves were established for the increase in BP induced by
      tyramine (5-200 mg/kg) administered orally via a naso-pharyngeal tube. From
      these, the dose that increased BP by 30 mmHg (ED(30)) was computed for each
      rabbit before and after oral administration of clorgyline, 1 mg/kg for one week,
      tranylcypromine 10 mg/kg, once, moclobemide, 20 mg/kg 3 times and TV-3326, 26
      mg/kg for 2 weeks. Clorgyline, tranylcypromine and TV-3326 inhibited brain MAO-A
      by 90%; the former two inhibited intestinal MAO-A by 85-97% but TV-3326 had no
      effect. Tranylcypromine and clorgyline produced 6 and 20-fold increases in the
      pressor response to tyramine while TV-3326, like moclobemide, only potentiated it
      2-fold. If TV-3326 is found to produce as little potentiation of the tyramine
      response in human subjects, it may be a potentially useful therapeutic agent for
      the treatment of Alzheimer's disease with depression.

PMID- 12423670
TI  - Nitronyl nitroxides, a novel group of protective agents against oxidative stress
      in endothelial cells forming the blood-brain barrier.
AB  - Nitronyl nitroxides (NN) effectively decompose free radicals (. As brain
      endothelium, forming the blood-brain barrier (BBB), is both the main source and
      the target of reactive species during cerebral oxidative stress, we studied the
      effect of NN on brain endothelial cells injured by the mediator of oxidative
      stress H(2)O(2) (. H(2)O(2) caused hydroxyl radical generation, lipid
      peroxidation, membrane dysfunction, membrane leak and cell death, concentration
      dependently. Due to 0.5 mM H(2)O(2), oxy-radical-induced membrane phospholipid
      peroxidation (malondialdehyde) increased to 0.61+/-0.04 nmol/mg protein vs
      control (0.32+/-0.03, p<0.05), cells lost cytosolic proteins into the medium and
      viability decreased to 28+/-2% of control (p<0.05). Permeability through the
      endothelial monolayer (measure for the tightness of the BBB) rose to 250+/-40%
      after 0.15 mM H(2)O(2) (p<0.001). Addition of 10 microM of the NN 5,5-dimethyl
      2,4-diphenyl-4-methoxy-2-imidazoline-3-oxide-1-oxyl (NN-2), 1 mM phenylbutyl
      nitrone (PBN), or 10 microM of the lazaroid U83836E improved cell viability
      during incubation with 0.5 mM H(2)O(2) to 57+/-1%, 49+/-2%, and 42+/-3% (p<0.05,
      vs drug-free H(2)O(2) group). The permeability enhancement by 0.15 mM H(2)O(2)
      was reduced to 171+/-21%, 170+/-25%, and 118+/-32% (p<0.05 vs drug-free H(2)O(2)
      group). Generally, the assumption is supported that during cerebral oxidative
      stress the protection should also be directed to the cells of the BBB, which can
      be provided by antioxidative approaches. NN represent a new group of
      antioxdatively acting cytoprotectiva improving the survival and function of the
      endothelium against oxidative stress.

PMID- 12423671
TI  - Alpha-lipoic acid protects the retina against ischemia-reperfusion.
AB  - The aim of this study was to examine whether the antioxidant alpha-lipoic acid
      protects retinal neurons from ischemia-reperfusion injury. Rats were injected
      intraperitoneally with either vehicle or alpha-lipoic acid (100 mg/kg) once daily
      for 11 days. On the third day, ischemia was delivered to the rat retina by
      raising the intraocular pressure above systolic blood pressure for 45 min. The
      electroretinogram was measured prior to ischemia and 5 days after reperfusion.
      Rats were killed 5 or 8 days after reperfusion and the retinas were processed for
      immunohistochemistry and for determination of mRNA levels by RT-PCR. Ischemia
      reperfusion caused a significant reduction of the a- and b-wave amplitudes of the
      electroretinogram, a decrease in nitric oxide synthase and Thy-1
      immunoreactivities, a decrease of retinal ganglion cell-specific mRNAs and an
      increase in bFGF and CNTF mRNA levels. All of these changes were clearly
      counteracted by alpha-lipoic acid. Moreover, in mixed rat retinal cultures, alpha
      lipoic acid partially counteracted the loss of GABA-immunoreactive neurons
      induced by anoxia. The results of the study demonstrate that alpha-lipoic acid
      provides protection to the retina as a whole, and to ganglion cells in
      particular, from ischemia-reperfusion injuries. alpha-Lipoic acid also displayed
      negligible affinity for voltage-dependent sodium and calcium channels.

PMID- 12423672
TI  - Effects of norepinephrine on rat cultured microglial cells that express alpha1,
      alpha2, beta1 and beta2 adrenergic receptors.
AB  - Microglial cells rapidly become activated in response to even minor damage of
      neurons, suggestive of the intimate interactions between neurons and microglial
      cells. Although mediators for microglia-neuron interactions have not been well
      identified, neurotransmitters are possible candidates transmitting signals from
      neurons to microglial cells. Among the neurotransmitters, we focused on the
      effects of norepinephrine and other adrenergic agonists on the functions of rat
      cultured microglial cells. Reverse transcriptase polymerase chain reaction
      studies revealed that microglial cells expressed mRNAs encoding alpha1A, alpha2A,
      beta1 and beta2 receptors. Norepinephrine and a beta2 adrenergic agonist
      terbutaline elevated intracellular cAMP level of microglial cells.
      Norepinephrine, an alpha1 agonist phenylephrine, a beta1 agonist dobutamine and
      terbutaline suppressed the expressions of mRNAs encoding pro-inflammatory
      cytokines, interleukin-6 and tumor necrosis factor alpha. Release of tumor
      necrosis factor alpha and nitric oxide was suppressed by norepinephrine,
      phenylephrine, dobutamine and terbutaline. An alpha2 agonist clonidine and
      dobutamine upregulated the expression of mRNA encoding catechol-O-methyl
      transferase, an important enzyme to degrade norepinephrine. Norepinephrine,
      dobutamine and terbutaline upregulated the expressions of mRNA encoding 3
      phospshoglycerate dehydrogenase, an essential enzyme for synthesis of L-serine
      and glycine, which are amino acids necessary for neuronal survival. Clonidine
      upregulated the expression of mRNA encoding an anti-apoptotic factor Bcl-xL.
      These results suggest that norepinephrine participates in the regulation of brain
      function at least partly by modulating the functions of microglia.

PMID- 12423673
TI  - Chlorpromazine inhibits the glucocorticoid receptor-mediated gene transcription
      in a calcium-dependent manner.
AB  - Antipsychotic drugs can modulate transcription factors and also nuclear
      receptors, but their action on glucocorticoid receptors (GR)-members of the
      steroid/thyroid hormone receptor family has not been studied so far. In the
      present study we investigated effects of various antipsychotics on the
      glucocorticoid-mediated gene transcription in fibroblast cells, stably
      transfected with a mouse mammary tumor virus promoter (LMCAT cells).
      Chlorpromazine (3-100 microM) inhibited the corticosterone-induced gene
      transcription in a concentration- and time-dependent manner. Clozapine showed a
      similar, but less potent effect, while haloperidol acted only in high
      concentrations, and other antipsychotic drugs (sulpiride, raclopride,
      remoxipride) were without any effect. It was also found that a phorbol ester (an
      activator of protein kinase C (PKC)) and A-23187 (Ca(2+)-ionophore) attenuated
      the inhibitory effect of chlorpromazine on the GR-induced gene transcription. An
      antagonist of the L-type Ca(2+) channel, as well as an inhibitor of phospholipase
      C (PLC) inhibited the corticosterone-induced gene transcription, but had no
      effect on the chlorpromazine-induced changes. The involvement of a PKC/PLC
      pathway in the chlorpromazine action was confirmed by Western blot analysis which
      showed that the drug in question decreased the PLC-beta(1) protein level, and to
      a lesser extent that of the PKC-alpha protein in LMCAT cells. The aforementioned
      data suggest that inhibition of the glucocorticosteroid-induced gene
      transcription by chlorpromazine and clozapine may be a mechanism by which these
      drugs block some effects induced by glucocorticoids. The inhibitory effect of
      chlorpromazine on the corticosterone-induced gene transcription seems to depend
      on the inhibition of Ca(2+) influx and/or the inhibition of some calcium
      dependent enzymes, e.g. phospholipase beta(1).

PMID- 12423675
TI  - Multiplexed microsphere-based flow cytometric assays.
AB  - Flow cytometry has become an indispensable tool for clinical diagnostics and
      basic research. Although primarily designed for cellular analysis, flow
      cytometers can detect any particles in the lower micron range, including inert
      microspheres of different sizes, dyed with various fluorochromes. Over the past
      20 years, microspheres have been used as calibrators for flow cytometers and also
      as a solid support for numerous molecular reactions quantitated by flow
      cytometry. Proteins, oligonucleotides, polysaccharides, lipids, or small peptides
      have been adsorbed or chemically coupled to the surface of microspheres to
      capture analytes that are subsequently measured by a fluorochrome-conjugated
      detection molecule. More recently, assays for similar analytes have been
      multiplexed, or analyzed in the same assay volume, by performing each reaction on
      a set of microspheres that are dyed to different fluorescent intensities and,
      therefore, are spectrally distinct. Some recent applications with fluorescent
      microspheres have included cytokine quantitation, single nucleotide polymorphism
      genotyping, phosphorylated protein detection, and characterization of the
      molecular interactions of nuclear receptors. The speed, sensitivity, and accuracy
      of flow cytometric detection of multiple binding events measured in the same
      small volume have the potential to replace many clinical diagnostic and research
      methods and deliver data on hundreds of analytes simultaneously.

PMID- 12423674
TI  - Nicotinic receptors regulate the release of glycine onto lamina X neurones of the
      rat spinal cord.
AB  - Whole-cell patch clamp recordings were performed on neurones in the lamina X of
      rat spinal cord slices in order to characterize glycinergic synaptic currents and
      their modulation by nicotinic acetylcholine receptors. In the presence of TTX,
      bicuculline and kynurenic acid, glycine-induced currents and miniature
      glycinergic postsynaptic currents (mIPSCs) were recorded. These currents reversed
      near the chloride ion equilibrium potential and were blocked by strychnine (1
      microM). A selective nicotinic acetylcholine receptor (nAChR) agonist 1,1
      dimethyl-4-phenyl-piperazinium (DMPP), increased the frequency of glycinergic
      mIPSCs without altering significantly their amplitude distributions or their
      kinetic properties. The effects of DMPP were mimicked by different nAChRs
      agonists with the following apparent order of potency: ACh > DMPP > nicotine >
      cytisine. The effect of DMPP on mIPSCs was blocked by both d-tubocurarine and
      hexamethonium, and was reduced by dihydro-beta-erythroidine and
      methyllycaconitine (MLA), antagonists of non alpha7- and alpha7-containing
      nAChRs, respectively. In the absence of TTX, strychnine-sensitive glycinergic
      electrically evoked postsynaptic currents (eIPSCs) could be recorded. DMPP
      blocked the appearance of electrically evoked IPSCs while still inducing the
      appearance of spontaneous glycine IPSCs. These data demonstrate that neurones
      surrounding the central canal of the spinal cord present a glycinergic synaptic
      transmission which is modulated by terminal nAChRs.

PMID- 12423676
TI  - Tumor necrosis factor-alpha inhibits generation of glycophorin A+ cells by CD34+
      cells.
AB  - OBJECTIVE: The inhibitory effects of tumor necrosis factor-alpha (TNF-alpha) on
      cytokine-induced proliferation and differentiation of normal human erythroid
      progenitors have been characterized extensively, yet little is known about the
      maturation level of erythroid progenitors that are sensitive to TNF-alpha or of
      the expression of TNF receptors (TNFRs) in erythroid lineage. The aim of this
      study was to determine the extent to which human erythroid progenitor cells are
      sensitive to TNF-alpha, and to relate this to the expression of TNFRs in the
      erythroid lineage. MATERIALS AND METHODS: Highly purified human CD34+ cells
      underwent erythroid differentiation, with or without TNF-alpha. We used colony
      assay as well as a method by which colony-forming unit-erythroid (CFU-E) and
      glycophorin A (GPA; a specific marker for erythroid lineage) positive cells can
      be generated in liquid phase from purified human CD34+ cells in the presence of
      multiple cytokines, including stem cell factor (SCF), interleukin-3 (IL-3), and
      erythropoietin (EPO). During erythroid differentiation of CD34+ cells, TNFRs
      expression were monitored. RESULTS: TNF-alpha inhibited the generation of GPA+
      cells by CD34+ cells as well as the proliferative capacity of GPA+ cells
      supported by EPO, IL-3, and SCF. Erythroid progenitors became resistant to the
      inhibitory effect of TNF-alpha as they matured. The detectable expression of TNFR
      I was transient in the early phase of erythroid differentiation, whereas TNFR-II
      was expressed through the entire course of erythroid differentiation of CD34+
      cells. CONCLUSIONS: TNF-alpha suppresses erythropoiesis by inhibiting the
      generation of GPA+ cells derived from CD34+ cells as well as by inhibiting the
      proliferative capacity of GPA+ cells. Although the presence of TNFRs does not
      directly indicate that the receptor(s) mediates death signaling, altered
      expression of TNFRs depending on the level of maturation may imply altered
      sensitivities to TNF-alpha in various stage of erythroid progenitors.

PMID- 12423677
TI  - Hematopoietic abnormalities in mice deficient in gp130-mediated STAT signaling.
AB  - OBJECTIVE: Studies on mice lacking the common receptor subunit gp130 reveal that
      activation of gp130-dependent signaling pathways is essential for normal fetal
      and adult hematopoiesis. However, the extent to which hematopoiesis is dependent
      upon activation of a particular gp130 signaling pathway, namely STAT1/3 or
      SHP2/MAPK, is unknown. This study examined the specific contribution of gp130
      mediated STAT1/3 signaling to the regulation of hematopoiesis. MATERIALS AND
      METHODS: Hematopoiesis was examined at various developmental stages in mice
      homozygous for a targeted carboxy-terminal truncation mutation in gp130
      (gp130(delta)/(delta)) that deletes all STAT1/3 binding sites, thereby abolishing
      gp130-mediated STAT1/3 activation. RESULTS: Adult gp130(delta)/(delta) mice have
      increased numbers of immature colony-forming unit spleen progenitor cells in the
      bone marrow and spleen, elevated numbers of committed myeloid progenitor cells in
      the spleen and peripheral blood, and leukocytosis. Increased progenitor cell
      production was observed in gp130(delta)/(delta) fetal livers from 14 days of
      gestation onward. In contrast, the circulating platelet count was reduced by 30%
      in gp130(delta)/(delta) mice, without any corresponding decrease in the number of
      bone marrow and splenic megakaryocytes. In liquid cultures, megakaryocytes from
      gp130(delta)/(delta) mice are smaller than those from wild-type mice and do not
      increase in size upon stimulation with interleukin-6 or interleukin-11.
      Administration of either interleukin-6 or interleukin-11 to gp130(delta)/(delta)
      mice failed to increase platelet numbers, despite an increase in the production
      of megakaryocytes. CONCLUSIONS: Collectively, these results reveal that gp130
      mediated STAT1/3 activation is required to maintain the normal balance of
      hematopoietic progenitors during fetal and adult hematopoiesis. Furthermore, they
      suggest two distinct roles for gp130-mediated STAT1/3 activation in
      hematopoiesis, one restricting the production of immature hematopoietic
      progenitor cells and the other promoting the functional maturation of
      megakaryocytes to produce platelets.

PMID- 12423678
TI  - In vivo administration of interferon gamma does not cause marrow aplasia in mice
      with a targeted disruption of FANCC.
AB  - OBJECTIVE: Hematopoietic cells from patients with Fanconi anemia (FA) and mice
      carrying a targeted disruption of the gene encoding complementation group C
      protein (FANCC(-/-)) demonstrate an apoptotic phenotype in response to alkylating
      agents and cytokines including interferon gamma (IFN-gamma) in vitro. The aim of
      this study was to explore these apoptosis-inducing effects of IFN-gamma on the
      bone marrow of FANCC(-/-) mice as a potential strategy to select gene-corrected
      cells in vivo. Following pharmacokinetic studies to determine if serum
      concentrations effective in vitro can be achieved in vivo, we injected FANCC(-/-)
      mice with recombinant murine IFN-gamma. Hematopoietic effects were investigated
      by serial determinations of blood counts, progenitor colony formation, and marrow
      cellularity. RESULTS: Serial weekly intraperitoneal administrations of escalating
      doses of rmIFN-gamma did not affect peripheral blood counts in FANCC(-/-) mice,
      even after subsequent antibody-mediated fas ligation. Additionally, prolonged
      exposure after sequential daily administration of recombinant IFN-gamma did not
      impair progenitor cell clonogenicity in vitro. Pharmacokinetic data confirmed
      that the failure of IFN-gamma to induce marrow aplasia occurred in spite of peak
      serum levels greater than 100-fold in excess of those effective in vitro.
      CONCLUSION: We conclude that in spite of the well-documented in vitro apoptotic
      tendency of FA-phenotype hematopoietic cells, the in vivo administration of IFN
      gamma with and without subsequent fas ligation does not induce bone marrow
      failure in FANCC(-/-) (129SvJ strain) mice. Additional selective pressure may be
      necessary to achieve targeted ablation of uncorrected, FA-phenotype, marrow
      cells.

PMID- 12423679
TI  - Forced expression of p21 in GPIIb-p21 transgenic mice induces abnormalities in
      the proliferation of erythroid and megakaryocyte progenitors and primitive
      hematopoietic cells.
AB  - OBJECTIVE: p21(WAF1/Cip/kip) and p27(Kip1) are cyclin-dependant kinase inhibitors
      controlling cell-cycle exit and differentiation of numerous cell types. Among
      hematopoietic cells, megakaryocytes express high levels of p21, while in
      erythroid cells, p27(Kip1) is predominant. As p21 and p27 could display
      overlapping functions and as megakaryocytes and erythroid cells derive from a
      bipotent progenitor, we developed an in vivo model to determine the specific role
      of p21 in controlling the proliferation/differentiation balance of erythroid and
      megakaryocytic progenitors. METHODS: Transgenic mice that overexpressed p21 under
      the control of the human GPIIb promoter in early progenitors and along
      megakaryocytic differentiation were generated. Different subsets of hematopoietic
      progenitors (BFU and CFU) and primitive cells (CAFC, LTC-IC) were analyzed by
      methylcellulose assay. Phenotypic evolution and clonogenic properties of the lin(
      ) population were analyzed along erythroid and megakaryocytic differentiation.
      RESULTS: We observed p21 ectopic expression in early hematopoietic progenitors
      (lin(-)Sca(+)), megakaryocytes, and, to a lesser extent, erythroid cells. This
      expression induced an important decrease in the number of CFU-MK, BFU-E, CFU-E,
      primitive progenitors (CAFC day 35), and LTC-IC, but did not affect the
      maturation process of these cells and the blood cell count. CONCLUSIONS: We show
      that variation of p21 expression level changes the fate of hematopoietic cells by
      favoring either proliferation or differentiation pathways. This effect of p21 is
      exerted not only at the level of primitive progenitors but also in more mature
      progenitors. However, in vivo, a systemic compensation mechanism is most likely
      activated in response to variations of the flow of progenitor production.

PMID- 12423680
TI  - The catalytic DNA topoisomerase II inhibitor ICRF-193 and all-trans retinoic acid
      cooperatively induce granulocytic differentiation of acute promyelocytic leukemia
      cells: candidate drugs for chemo-differentiation therapy against acute
      promyelocytic leukemia.
AB  - OBJECTIVE: Although all-trans retinoic acid (ATRA) can bring about complete
      remission of acute promyelocytic leukemia (APL), the incidence of early
      recurrence is considerably high. Thus, chemotherapeutic agents, such as
      anthracycline agents or cytosine arabinoside (AraC), are generally co
      administered with ATRA. The therapeutic outcome of APL patients has significantly
      improved by chemo-differentiation therapy. Late-phase toxicities, such as
      cardiotoxicity and secondary carcinogenesis, are becoming clinically important.
      Therefore, we must identify the most suitable chemotherapeutic agents for the
      treatment of APL. METHODS: We examined the effects of ICRF-193 and several other
      anticancer drugs on the growth and differentiation of APL cell lines (NB4 and HT
      93) and other myeloid leukemia cell lines (HL-60 and U937). RESULTS: If
      anticancer agents were available that not only inhibited the proliferation of APL
      cells but also induced their differentiation, they would be very useful for the
      treatment of APL. DNR slightly induced the differentiation of APL cells. On the
      other hand, other DNA topoisomerase II inhibitors, such as ICRF-154 and ICRF-193,
      significantly induced the differentiation of APL cell lines and leukemia cells
      freshly isolated from APL patients. These drugs effectively cooperated with ATRA
      in inhibiting the growth and inducing the differentiation of APL cells, whereas
      DNR did not. The incidence of cardiotoxicity and secondary carcinogenesis
      associated with ICRF-193 are much lower than that with DNR. CONCLUSION: These
      results suggest that ICRF-193 may be useful in the treatment of patients with
      APL.

PMID- 12423681
TI  - CD40L induces proliferation, self-renewal, rescue from apoptosis, and production
      of cytokines by CD40-expressing AML blasts.
AB  - OBJECTIVE: Conflicting experimental and clinical results have been reported
      regarding the role of CD40 in acute myeloid leukemia (AML). In the present study,
      we analyzed the capability of CD40L/CD154 to modulate several functional aspects
      of CD40-expressing AML blasts. METHODS: After defining the constitutive
      expression levels of CD40 in a wide panel (n = 67) of AMLs and evaluating the
      capability of cytokines to modulate its expression, we investigated the effects
      of CD40 engagement by soluble (s) CD40L on proliferation, self-renewal capacity,
      apoptosis, homotypic adhesion, and cytokine production of leukemia cells.
      RESULTS: CD40 was detected in blast cells from about 37% of AMLs, the highest
      frequency being documented in monocytic subtypes, and its expression was
      upregulated or de novo induced by treatment with interleukin (IL)-1alpha, IL-3,
      IL-4, granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon
      gamma, and tumor necrosis factor-alpha. Exposure of CD40(+) AML blasts to sCD40L
      resulted in a dose-dependent proliferative response, enhancement of clonogenic
      growth and self-renewal capacity, and a striking increase in colony size. CD40
      engagement was able to rescue AML blasts from apoptosis induced by serum
      deprivation, as demonstrated by reduced expression of APO2.7 and annexin-V
      binding, as well as upregulation of the anti-apoptotic protein bcl-x(L). CD40
      triggering upregulated cell surface expression of the adhesion molecules CD54,
      CD58, and CD15 and resulted in homotypic aggregation of leukemia cells at least
      in part CD54-dependent. An increased production of IL-6 and GM-CSF by CD40(+) AML
      blasts was also documented upon sCD40L exposure. CONCLUSIONS: This study
      indicates a possible involvement of CD40 in the interactions of AML blasts with
      other growth-sustaining microenvironmental accessory cells and immune effectors,
      in turn expressing CD40L. Caution in the use of CD40 triggering in immunotherapy
      of AMLs is also suggested.

PMID- 12423682
TI  - Ultrasonic low-energy treatment: a novel approach to induce apoptosis in human
      leukemic cells.
AB  - OBJECTIVE: We evaluated the cytotoxic effect of ultrasonic irradiation at low
      energy on the viability of normal and leukemic cells and the potential mechanisms
      of action inducing this cytotoxicity. MATERIALS AND METHODS: Human leukemia cell
      lines (K562, HL-60, KG1a, and Nalm-6), primary leukemic cells, and normal
      mononuclear cells are treated by ultrasound at a frequency of 1.8 MHz during
      various exposure times (acoustical power of 7 mW/mL) and immediately tested for
      cell viability by the trypan blue exclusion assay. Apoptosis is evaluated by cell
      morphology, phosphatidylserine exposure, and DNA fragmentation. The mitochondrial
      potential, glutathione content, caspase-3 activation, PARP cleavage, and bcl
      2/bax ratio are tested by flow cytometry. Cloning efficiency is evaluated by
      assays in methylcellulose. RESULTS: The technique we describe here, using minute
      amounts of energy and in the absence of any chemical synergy, specifically
      triggers apoptosis in leukemic cells while necrosis is significantly reduced.
      Ultrasonic treatment of 20 seconds' duration induces a series of successive
      phases showing the characteristic features of apoptosis: mitochondrial
      transmembrane potential disturbances, loss of phosphatidylserine asymmetry,
      morphological changes, and, finally, DNA fragmentation. In contrast to K562
      cells, for which a significant reduction of cloning efficiency is observed, the
      growth of hematopoietic progenitors is totally unaffected. Ultrasound treatment
      is also associated with depletion of cellular glutathione content, suggesting a
      link with the oxidative stress. Moreover, the fact that active oxygen scavengers
      reduce ultrasonic-induced apoptosis suggests a sonochemical mechanism.
      CONCLUSION: The cell damage observed after exposure of leukemic cells to
      ultrasound is associated with the apoptotic process and may be a promising tool
      for a smooth, specific, and effective ex vivo purging of leukemic cells.

PMID- 12423683
TI  - Impact of the expression of P glycoprotein, the multidrug resistance-related
      protein, bcl-2, mutant p53, and heat shock protein 27 on response to induction
      therapy and long-term survival in patients with de novo acute myeloid leukemia.
AB  - OBJECTIVE: Resistance to chemotherapy-induced apoptosis and a multidrug
      resistance phenotype is the major problem in the treatment of acute myeloid
      leukemia (AML). PATIENTS AND METHODS: We recently demonstrated that the
      coexpression of at least two proteins, including P glycoprotein, multidrug
      resistance-related protein, bcl-2 (flow cytometry), p53 (luminometric
      immunoassay), and heat shock protein 27 (Western blotting), was predictive for
      response to induction therapy in de novo AML comparing leukemic blasts of 20
      responders with 20 nonresponders. After long-term follow-up, we now present our
      evaluation on the prognostic significance of these proteins in leukemic blasts of
      124 untreated AML patients with regard to the probability of remission (PoR) and
      overall survival (OS). RESULTS: Analyzing leukemic blasts obtained from bone
      marrow samples, we found that no single protein significantly correlated with PoR
      or OS. In contrast, the coexpression of at least two of these proteins was
      predictive for reduced OS in univariate as well as multivariate analysis.
      Although we could not identify any particular protein combination predictive for
      reduced OS, those patients with no or only one protein expressed in their
      leukemic blasts had a survival probability of 48% in contrast to 24% in those
      patients with the coexpression of two or more proteins. Among the clinical
      markers, only response to chemotherapy had a significant effect on OS and age was
      of prognostic relevance for PoR. CONCLUSION: We conclude that overexpression of
      only one protein possibly involved in resistance, is not sufficient to influence
      the prognosis for long-term survival in AML, whereas the expression of more than
      one protein is predictive for reduced OS. Protein combination seems to be
      individually different, and targeting only one protein in further clinical trials
      may not help to overcome multifactorial resistance.

PMID- 12423684
TI  - Molecular and functional characterization of human Dectin-1.
AB  - OBJECTIVE: Dendritic cells (DC) have several unique features that differ from
      other antigen-presenting cells and that enable them to initiate primary immune
      responses. The aim of this study was to identify and characterize genes that are
      differentially expressed in DC generated from CD14+ peripheral blood monocytes in
      vitro. MATERIALS AND METHODS: Using a subtractive cDNA library, we identified the
      full-length cDNA sequence of human Dectin-1b by rapid amplification of cDNA ends.
      Expression profiles were performed by reverse transcriptase polymerase chain
      reaction and Western blotting. For functional analysis, HeLa cells were
      transfected with the Dectin-1b coding region and used as stimulators for purified
      peripheral blood T-cell populations. RESULTS: Our subtractive cloning strategy
      revealed the human Dectin-1b cDNA, which encodes for a transmembrane protein of
      the C-type lectin-like receptor family. It is selectively expressed in several
      purified DC subpopulations but not in monocytes and is up-regulated upon
      stimulation with lipopolysaccharide. The nucleotide sequence was submitted to
      GenBank (accession no. AY009090). Furthermore, we demonstrate that the Dectin-1b
      splice variant transfected in HeLa cells up-regulates the activation markers on
      human T lymphocytes, induces the production of interferon-gamma, and promotes
      proliferation of both CD4+ and CD8+ T lymphocytes. CONCLUSION: The Dectin-1 gene
      is expressed during the development of DC from peripheral blood monocytes and the
      transfection of the splice variant 1b into HeLa cells results in the stimulation
      of effector functions of human T lymphocytes.

PMID- 12423685
TI  - Malignant progenitors from patients with CD87+ acute myelogenous leukemia are
      sensitive to a diphtheria toxin-urokinase fusion protein.
AB  - In previous studies, we demonstrated that the diphtheria toxin-urokinase fusion
      protein DTAT was selectively toxic to acute myeloid leukemia (AML) cell lines
      overexpressing the CD87 urokinase receptor. In the present study, we analyzed the
      sensitivity of patient leukemic progenitors to DTAT and correlated the
      sensitivity with CD87 expression. We isolated leukemic blasts by density gradient
      centrifugation and performed immunophenotyping by flow cytometry and blast
      sensitivity measurements by inhibition of cell proliferation and colony formation
      in semisolid media. We found CD87 overexpression in 18 (25%) of 71 patient
      leukemic blast samples, including 18 (28%) of 64 myeloid malignancies and 0 (0%)
      of 7 lymphoid malignancies. DTAT was toxic to patient leukemic blasts by both
      proliferation inhibition (IC50 <or=1 nM DTAT in 18/69 evaluable samples) and
      colony formation inhibition (>85% inhibition by 10 nM DTAT in 11/41 evaluable
      samples). Only AML and chronic myeloid leukemia (CML) blast crisis blasts (18/61
      [30%]) were sensitive to DTAT by the proliferation inhibition assay. Lymphoid
      leukemia and chronic phase CML/chronic myelomonocytic leukemia (CMML) progenitors
      were insensitive to DTAT by the proliferation inhibition assay (n = 7 and n = 3,
      respectively). Similarly, normal marrow progenitors were insensitive to DTAT by
      both proliferation inhibition (n = 2) and colony inhibition (n = 5) assays. The
      DTAT toxicity measured by both proliferation inhibition assay and colony
      inhibition assay correlated with CD87 density (p < 0.0001 and p = 0.001,
      respectively). DTAT toxicity results were similar for leukemic blasts measured by
      either of the two assays (p = 0.0002). This study provides the first evidence
      that a urokinase receptor targeted diphtheria fusion protein is toxic to patient
      AML blasts. The work also suggests that blast proliferation assays yield similar
      responses to leukemia colony-forming cell colony assays.

PMID- 12423686
TI  - Donor chimerism and stem cell function in a murine congenic transplantation model
      after low-dose radiation conditioning: effects of a retroviral-mediated gene
      transfer protocol and implications for gene therapy.
AB  - OBJECTIVE: We investigated low-dose radiation conditioning for the
      transplantation of retrovirus-transduced cells in a C57Bl6/J murine model.
      MATERIALS AND METHODS: The effect of low-dose radiation on stem cell function was
      investigated using a competitive repopulation assay. Stem cell function of marrow
      cells that underwent a retroviral-mediated gene transfer (RMGT) protocol was
      examined by this assay, and donor chimerism of these cells when transplanted into
      160-cGy conditioned syngeneic hosts was compared to fresh marrow. RESULTS:
      Irradiation with 300 or 160 cGy substantially decreased stem cell function as
      measured by competitive repopulation. Animals conditioned with 160 cGy and
      transplanted with 20 x 10(6) fresh marrow cells permitted donor cell engraftment
      of 53.6% +/- 11.4% 6 months after transplant compared to 100% donor cell
      engraftment after 1100 cGy irradiation. Lymphoid and myeloid engraftment did not
      significantly differ from total engraftment in submyeloablated hosts. When
      transplanted into lethally irradiated hosts, the competitive repopulating
      activity of marrow treated with a single dose of 5-fluorouracil followed by ex
      vivo culture according to a standard RMGT protocol was equal to 5-fluorouracil
      only treated marrow. However, cells treated with 5-fluorouracil or 5-fluorouracil
      plus ex vivo culture for RMGT repopulated less well than fresh marrow cells in
      160 cGy conditioned hosts. CONCLUSIONS: Low-dose irradiation decreases host stem
      cell function, allowing engraftment of both fresh and RMGT protocol-treated
      marrow, although the engraftment of 5-fluorouracil-treated cells was reduced at
      least two-fold, and 5-fluorouracil plus RMGT protocol-treated cells at least
      three-fold, compared to fresh marrow. Modification of current RMGT protocols may
      be important for optimizing engraftment under these conditions.

PMID- 12423687
TI  - Radiation pneumonitis in mice: a severe injury model for pneumocyte engraftment
      from bone marrow.
AB  - OBJECTIVE: To better understand the process by which pneumocytes can be derived
      from bone marrow cells, we investigated the in vivo kinetics of such engraftment
      following lethal irradiation. METHODS: A cohort of lethally irradiated B6D2F1
      female mice received whole bone marrow transplants (BMT) from age-matched male
      donors and were sacrificed at days 1, 3, 5, and 7 and months 2, 4, and 6 post-BMT
      (n = 3 for each time point). Additionally, 2 female mice who had received 200
      male fluorescence-activated cell sorter (FACS)-sorted CD34(+)lin(-) cells were
      sacrificed 8 months post-BMT. RESULTS: Lethal irradiation caused histologic
      evidence of pneumonitis including alveolar breakdown and hemorrhage beginning at
      day 3. To identify male-derived pneumocytes, simultaneous fluorescence in situ
      hybridization (FISH) for Y-chromosome and surfactant B messenger RNA was
      performed on lung tissue. Y(+) type II pneumocytes were engrafted as early as day
      5 posttransplant, and eventually from 2 to 14% of the pneumocytes were donor
      derived in individual mice. Co-staining for epithelial-specific cytokeratins
      demonstrated that by 2 months, marrow-derived pneumocytes could comprise entire
      alveoli, suggesting that type I cells derived from type II pneumocytes.
      CONCLUSIONS: We conclude that alveolar lining cells derive from bone marrow cells
      immediately after acute injury. Also, the CD34(+)lin(-) subpopulation is capable
      of such pulmonary engraftment.

PMID- 12423688
TI  - Side population cells from diverse adult tissues are capable of in vitro
      hematopoietic differentiation.
AB  - OBJECTIVE: Pluripotent hematopoietic stem cells and muscle-derived hematopoietic
      potential cells isolated by Hoechst 33342 dye-mediated fluorescein-activated cell
      sorting (FACS) as side population (SP) cells, give rise to hematopoietic cells as
      well as skeletal muscle cells following intravenous transplantation. However,
      besides bone marrow and skeletal muscle, it has remained unclear whether other
      adult tissues also contain SP cells that are enriched for cells that exhibit
      hematopoietic potential. METHODS: To test whether adult tissues contain SP cells
      with hematopoietic potential, Hoechst-FACS analysis and hematopoietic colony
      formation assays were performed with cells isolated from a variety of adult
      tissues, skeletal muscle, heart, brain, spleen, liver, kidney, lung, and small
      intestine and compared with peripheral blood and bone marrow cells. RESULTS: In
      addition to hematopoietic tissues, cell preparations from nonhematopoietic
      tissues, such as skeletal muscle, kidney, lung, and small intestine, displayed
      markedly higher hematopoietic colony formation activity compared to peripheral
      blood cells. Moreover, the hematopoietic progenitors in these adult tissues
      expressed the hematopoietic cell marker CD45. Hoechst-FACS analysis demonstrated
      that all adult tissues examined contained SP cells. In addition, these SP
      fractions were enriched for cells that efficiently formed hematopoietic colonies
      in vitro. CONCLUSION: These results indicate that hematopoietic progenitors are
      present in significant numbers in all adult tissues examined.

PMID- 12423689
TI  - Reliable engraftment, low toxicity, and durable remissions following allogeneic
      blood stem cell transplantation with minimal conditioning.
AB  - OBJECTIVE: Allogeneic blood stem cell transplantation (BSCT) can cure patients
      with hematologic malignancies by high-dose chemotherapy and allogeneic graft-vs
      tumor (GvT) reactions. To avoid high-dose conditioning and evaluate engraftment,
      toxicity, and GvT reactions, we treated a group of high-risk patients with a
      minimal intensive conditioning regimen followed by allogeneic BSCT. MATERIALS AND
      METHODS: Thirty-four patients with lymphoma (11), myeloma (10), chronic myeloid
      leukemia (4), myelodysplastic syndrome (5), and acute myeloid leukemia (4) were
      treated with fludarabine (3 x 30 mg/m(2)) and 200 cGy total-body irradiation
      followed by the infusion of peripheral blood stem cells from related (28) or
      unrelated (6) donors. Cyclosporine or tacrolimus and mycophenolate mofetile were
      given posttransplant. Most patients had advanced disease, were intensively
      pretreated, and had contraindications against conventional myeloablative
      transplantation. RESULTS: Thirty-two patients (94%) had engraftment of donor
      cells. Patients with lymphatic malignancies developed complete donor chimerism
      significantly faster than patients with myeloid malignancies (p < 0.05). Clinical
      responses were observed in 16 of 27 patients (59%) who had active disease at
      transplantation. Of 7 patients who were treated in remission, 5 remain free of
      disease. After a median follow-up of 325 days (range 100-844) 22 patients are
      alive (65%, 14 CR, 4 PR, 4 PD). Two patients (6%) died of treatment-related
      complications and 10 patients (29%) died of progressive disease. Acute graft-vs
      host-disease (GvHD) of grade II or more developed in 17 patients (50%). Chronic
      GvHD is present in 10 of 22 patients (45%) who are alive beyond day 100.
      CONCLUSIONS: Toxicity and survival in this group of high-risk patients are
      superior to those expected with conventional allogeneic transplantation. GvT
      reactions frequently occur in conjunction with GvHD and can induce durable
      remissions in patients with advanced hematologic malignancies.

PMID- 12423690
TI  - Antiviral prophylaxis and treatment (excluding HIV therapy).

PMID- 12423691
TI  - Antiviral therapy for hepatitis B virus infections: new targets and technical
      challenges.
AB  - There are presently only two licensed therapies for treating liver disease caused
      by infection with the hepatitis B virus (HBV). These are interferon-alpha and
      lamivudine. Neither agent was specifically developed as an antiviral compound for
      treating patients infected with HBV. Both therapies are limited in the clinic by
      a low response rate and in the case of lamivudine, selection of drug-resistant
      mutants, whilst troublesome side effects limit the use of interferon-alpha.
      Several promising nucleoside/nucleotide analogues are undergoing clinical trials,
      including adefovir dipivoxil and entecavir, both of which appear to be active
      against lamivudine- resistant HBV. In addition to these nucleoside/nucleotide
      analogues, it will be important to develop new agents with different modes of
      action, which can be added to the antiviral cocktails that will be required to
      adequately suppress and hopefully eliminate HBV replication.

PMID- 12423692
TI  - Detection of Australian bat lyssavirus using a fluorogenic probe.
AB  - BACKGROUND: Australian bat lyssavirus (ABLV) has been transmitted to humans
      following a scratch or bite from an infected bat in two cases. Following a
      scratch or bite to a person, the bat is usually submitted for testing and
      diagnosis is made using a direct fluorescent antibody test on a brain smear. A
      nested RT-PCR assay has also been utilised to confirm diagnosis. If positive for
      lyssavirus, post-exposure prophylaxis is administered. OBJECTIVES: The TaqMan
      assay was developed to improve the diagnosis of ABLV infection, following
      problems encountered with the generation of spurious PCR products in the nested
      RT-PCR and also to reduce the high risk of contamination inherent with nested
      PCRs. STUDY DESIGN: RNA was extracted from 161 bat brains and the samples were
      compared using a conventional RT-PCR and the TaqMan based assay. Samples from a
      patient with an ABLV infection collected antemortem and postmortem were also
      tested. RESULTS: The sensitivity of the new TaqMan based PCR assay compared
      favourably with the nested PCR previously in use in our laboratory. This assay
      was able to detect RNA in samples collected antemortem and postmortem for the
      diagnosis of a human case of ABLV. CONCLUSIONS: The major advantage of the TaqMan
      based assay was the speed of diagnosis with a result within minutes of completing
      the PCR (a result within 4 h of receiving the specimen). This test greatly
      reduces the chance of false positives through the elimination of second-round PCR
      and the requirement for agarose gels. The assay is sensitive and specific and
      should be invaluable for future antemortem and postmortem diagnosis of ABLV
      infection in humans.

PMID- 12423693
TI  - Acute central nervous system complications in varicella zoster virus infections.
AB  - BACKGROUND: In a previous multicenter study on central nervous system (CNS) viral
      infections varicella zoster virus (VZV) appeared the most frequent etiologic
      agent and appeared often without rash. OBJECTIVE: To evaluate the appearance and
      diagnostics of VZV in CNS more thoroughly, we studied the cases systematically by
      using sensitive and specific methods to learn the best diagnostic approach in
      order to start specific therapy. STUDY DESIGN: We analyzed all serum and
      cerebrospinal fluid samples of 174 patients, 88 females and 86 males, with acute
      CNS symptoms associated with VZV infection diagnosed in the multicenter study on
      viral CNS infections. RESULTS: About 38 patients (22%) had chickenpox, 59 (34%)
      had shingles, and 77 (44%) had no cutaneous symptoms at all. The mean age of
      chickenpox patients was 8.6 years, of the others 46.6 and 41.4 years. VZV
      specific nucleic acid was detected in the CSF in one fourth of the patients in
      all groups, primarily during the first week of illness. In serum specimens,
      specific IgM was present in two thirds of the patients with chickenpox, whereas
      in the others in one third of the cases. In CSF, specific IgM was present in 15
      17% of patients with skin manifestations, compared with 6% of those without rash.
      CONCLUSIONS: The role of VZV infections in CNS complications seems remarkable,
      often presenting without rash. Even these cases should be promptly recognized in
      order to conduct proper antiviral therapy. In children, a combination of PCR and
      IgM tests is the best approach. In adults, PCR, together with the measurement of
      intrathecal antibody production yields best results.

PMID- 12423694
TI  - Confirmation of an outbreak of parvovirus B19 in a primary school using IgM ELISA
      and PCR on thumb prick blood samples.
AB  - BACKGROUND: Although parvovirus infections are usually benign and self-limiting,
      it is important to confirm the diagnosis in a public health setting which might
      involve pregnant women and in which an outbreak could lead to medical
      consequences. In these situations, microbiological confirmation by thumb prick is
      a relatively low-invasive method that is simple to carry out. OBJECTIVE AND STUDY
      DESIGN: Because relatively small blood volumes are obtained in thumb prick blood
      samples, we compared the results of two different techniques during an outbreak
      of erythema infectiosum: the usual serological detection of IgM antibodies
      (ELISA) versus PCR-based detection of viral DNA. RESULTS: In a school-based
      outbreak, 39 cases (33 schoolchildren, three parents, three pre-schoolers) were
      registered over a period of 11 weeks. Sera were obtained from 23 of the school
      cases and two of the three parent cases. Of all thumb prick serum samples, 65%
      (15/23) tested positive or borderline positive for parvovirus IgM with ELISA,
      while 70% (16/23) tested positive or borderline positive with PCR. Although the
      overlap between the two tests was large (11 samples tested positive or borderline
      positive in both), a substantial number of samples showed contradictory results
      (nine samples). CONCLUSION: The overall picture of 37 clinical cases of erythema
      infectiosum and two adult cases with arthritis, linked to a primary school, fits
      in well with positive diagnostic results by either technique for parvovirus B19,
      convincingly demonstrating an outbreak of fifth disease. The considerable number
      of discrepancies in sample results demonstrates that maximum sensitivity of
      parvovirus testing would require both tests to be performed.

PMID- 12423695
TI  - Apoptosis induction by the infection with Gilchrist strain of rubella virus.
AB  - Apoptosis is an active process of cellular self-destruction, which can be
      initiated in response to several stimuli such as toxic substances, hormones,
      cytokines, trophic or osmotic modifications and viral infections. In this study,
      we demonstrate that in vitro rubella-virus (RV) induced cell death exhibited
      properties of apoptosis, characterized by condensation and segmentation of nuclei
      and internucleosomal cleavage of nuclear DNA. Apoptosis was not seen in the cells
      absorbed with UV-inactivated virus, indicating that the viral replication is
      required for the induction of apoptosis. Our results suggest that most of the
      cells undergoing apoptosis are non-infected neighboring cells.

PMID- 12423696
TI  - Initial therapy of HIV infection.
AB  - BACKGROUND: The use of antiretroviral therapy has improved the quality of life
      and has increased the survival of HIV-infected individuals. However, the rapid
      rate of virus mutation and subsequent emergence of drug-resistant HIV variants
      threaten the longer-term efficacy of HIV treatment. The initial regimen provides
      the greatest chance for lasting suppression of viral load. AIMS: Appropriate
      selection of the initial antiretroviral regimen is critical. The growing number
      of drug classes allows healthcare providers to individualize treatment regimens.
      Factors influencing the selection of first-line therapy include baseline viral
      load and CD4 count, drug pharmacokinetics, potency, tolerability, safety,
      resistance and salvageability. Characteristics likely to affect adherence, such
      as regimen complexity and pill burden, must also be considered, as poor adherence
      is the most common cause of treatment failure. CONCLUSION: The selection of the
      initial regimen requires consideration of several factors. Drugs from new classes
      as well as new drugs from existing classes with favorable resistance and side
      effect profiles are in various stages of development. Many of these drugs will
      enhance available options for initial therapy.

PMID- 12423697
TI  - Clinical utility of nested multiplex RT-PCR for group F adenovirus, rotavirus and
      norwalk-like viruses in acute viral gastroenteritis in children and adults.
AB  - BACKGROUND: The diagnosis of viral gastroenteritis can be carried out by non
      molecular techniques such as electron microscopy (EM), enzyme-immunoassay and
      latex agglutination tests and various molecular techniques. Normally molecular
      detection requires the use of three separate protocols to detect the three main
      causes of viral gastroenteritis, adenoviruses, rotaviruses and norwalk-like
      viruses (NLV) which have different types of nucleic acid. The development of a
      sensitive and specific assay which could detect these targets would have major
      advantages for the clinical virology laboratory. OBJECTIVES: The aims of the
      present study were to develop a sensitive and specific multiplex molecular assay
      and to apply it to the detection of viral agents in clinical cases of acute
      gastroenteritis. STUDY DESIGN: The multiplex assay was designed using Access RT
      PCR (Promega). Primers were researched and selected for their specificity and
      broad range detection of the viral agents across the various genotypes of group A
      rotaviruses, NLV and group F adenoviruses. RESULTS: From September 2000 to August
      2001 we tested 1945 clinical specimens. Rotavirus infections were detected in 190
      with an age range from 12 days to 8 years old. Group F adenovirus was detected in
      96 patients ranging from 15 days to 10 years old. A further single case of group
      F adenovirus was detected in an adult of 75 years old. NLVs were detected in 132
      patients. There were 55 infections in children less than 7 years old. In 10
      different outbreaks involving 130 adult patients there were 57 NLV positives.
      Sporadic NLV infection was detected in 11 of 600 adult patients. There were 4
      patients with dual infections. CONCLUSIONS: The assay detailed here has proved an
      invaluable tool for the investigation of acute gastroenteritis in specimens from
      patients of all ages. We found it convenient to use a single mastermix with a
      single protocol to test all specimens from patients of all ages. NLV in children
      is often overlooked and/or under reported, particularly where less sensitive
      assays such as EM are being employed for diagnosis.

PMID- 12423698
TI  - A rapid, single-step multiplex reverse transcription-PCR assay for the detection
      of human H1N1, H3N2, and B influenza viruses.
AB  - BACKGROUND: Influenza is a viral respiratory pathogen responsible for frequent
      seasonal epidemics. There are currently three major human influenza viruses in
      global circulation, H1N1, H3N2 and B. OBJECTIVES: A one-step multiplex reverse
      transcription (RT)-polymerase chain reaction (PCR) assay targeting the HA1
      segment of the human hemagglutinin gene was developed as a rapid surveillance
      method. STUDY DESIGN: A researcher-blind study was performed using 112 randomly
      selected, culture-positive clinical samples collected through the Department of
      Defense (Global Emerging Infectious Surveillance (DOD-GEIS) influenza network
      during the 2000-2001 influenza season. Three subtype specific primer sets capable
      of producing PCR products with base-pair lengths of 585, 402 and 290
      corresponding to influenza H1, H3, and B subtypes, respectively, were utilized
      together in a one step, one tube, reaction. RESULTS: Multiplex primers were able
      to simultaneously type, and subtype 100% (112/112) of positive cultures.
      CONCLUSIONS: The results confirm that this assay is a highly sensitive and timely
      surveillance tool for rapid detection and simultaneous subtyping of clinical
      influenza specimens isolated worldwide.

PMID- 12423699
TI  - Investigation of a human case of rabies in the United Kingdom.
AB  - In May of 2001 a Nigerian woman visiting the United Kingdom presented with fever,
      headache and difficulty swallowing. Within 24 h she showed a marked deterioration
      and died shortly afterwards. Autopsy samples from a range of tissues were
      analysed to confirm a clinical diagnosis of rabies. Phylogenetic analysis of the
      viral nucleoprotein gene confirmed that this was an infection with a genotype 1
      virus (classical rabies) belonging to the Africa 2 group, which is endemic in
      Northern Africa. Comparison of both the nucleoprotein and glycoprotein coding
      sequences of this isolate with an imported case of human rabies from 1996, also
      from Nigeria, showed that the two viruses were 99% homologous.

PMID- 12423700
TI  - Fourth generation human immunodeficiency virus (HIV) screening assays with an
      improved sensitivity for p24 antigen close the second diagnostic window in
      primary HIV infection.

PMID- 12423701
TI  - Impact of ramipril versus other angiotensin-converting enzyme inhibitors on
      outcome of unselected patients with ST-elevation acute myocardial infarction.
AB  - We examined the impact of treatment with ramipril versus other angiotensin
      converting enzyme (ACE) inhibitors on clinical outcome in unselected patients of
      the prospective multicenter registry Maximal Individual Therapy of Acute
      Myocardial Infarction PLUS registry (MITRA PLUS). Of 14,608 consecutive patients
      with ST-elevation acute myocardial infarction, 4.7% received acute therapy with
      ramipril, 39.0% received other ACE inhibitor therapy, and 56.3% received no ACE
      inhibitor therapy. In a multivariate analysis, the treatment with ramipril
      compared with the treatment without ACE inhibitors was associated with a
      significantly lower hospital mortality and a lower rate of nonfatal major adverse
      coronary and cerebrovascular events. Compared with other generic ACE inhibitors,
      ramipril therapy was independently associated with a significantly lower hospital
      mortality (odds ratio [OR] 0.54, 95% confidence interval [CI] 0.32 to 0.90) and a
      lower rate of nonfatal major adverse coronary and cerebrovascular events (OR
      0.65, 95% CI 0.46 to 0.93), but not with a lower rate of heart failure at
      discharge (OR 0.79, 95% CI 0.50 to 1.27).

PMID- 12423702
TI  - Repolarization measures and their relation to sex hormones in postmenopausal
      women with cardiovascular disease receiving hormone replacement therapy.
AB  - Women are more susceptible to the development of Torsades de Pointes ventricular
      tachycardia and have a longer heart rate-corrected QT interval than men. A causal
      role for estrogen has been implicated. The purpose of this study was to
      investigate if hormone replacement therapy (HRT) resulted in any changes in
      noninvasive depolarization and repolarization measurements, and to study their
      relation to circulating concentrations of sex hormones. Sixty postmenopausal
      women with cardiovascular disease (mean age 59 +/- 7 years; range 44 to 75) were
      randomized to receive oral conjugated estrogens, transdermal estradiol-17-beta
      (both with addition of progestins), or placebo. QRS, QT, and JT intervals and
      their dispersion on 12-lead electrocardiograms were analyzed at baseline, and
      after 6 and 12 treatment cycles of HRT. Blood samples for analyses of serum
      concentration of estrogens and androgens were obtained on the same occasions.
      Neither mean RR, QT, QTc, JT, and JTc intervals, nor QT and JT dispersion changed
      during treatment. There was a significant inverse relation between the mean JTc
      interval and the serum concentration of estradiol-17-beta, independent of age,
      testosterone levels, and abdominal obesity. There was also a significant inverse
      relation between the change in androstenedione levels and the change in QT
      interval (Spearman -0.35, p = 0.028) or JT interval (Spearman -0.41, p = 0.009)
      at 6 treatment cycles compared with baseline. In conclusion, treatment with oral
      conjugated estrogens or transdermal estradiol-17-beta combined with progestins
      did not alter depolarization or repolarization measurements. However, the inverse
      relation between repolarization and androgens fits with an effect of androgens on
      repolarization in postmenopausal women.

PMID- 12423703
TI  - Impact of aspirin on presentation and hospital outcomes in patients with acute
      coronary syndromes (The Global Registry of Acute Coronary Events [GRACE]).
AB  - The long-term use of aspirin (ASA) reduces the risk of subsequent acute coronary
      syndromes in patients with coronary artery disease (CAD). It is less clear
      whether ASA therapy benefits patients who develop an acute coronary syndrome
      despite its use. Baseline characteristics, type of acute coronary syndrome, and
      in-hospital events were compared on the basis of previous use of ASA in 11,388
      patients with and without a history of CAD presenting to 94 multinational
      hospitals. A total of 73.0% of patients with a history of CAD (n = 4,974) were
      previously on long-term ASA therapy compared with 19.4% of patients without a
      history of CAD (n = 6,414). After multivariate regression analysis controlling
      for various potentially confounding factors, patients with a history of CAD who
      were previously taking ASA were significantly less likely to present with ST
      segment elevation myocardial infarction (MI) (adjusted odds ratio [OR] 0.52, 95%
      confidence intervals [CI] 0.44 to 0.61) or die during hospitalization (OR 0.69,
      95% CI 0.50 to 0.95) in comparison to patients who were not taking ASA. Patients
      without a history of CAD and who were previously taking ASA also had a lower risk
      of developing ST-segment elevation MI (OR 0.35, 95% CI 0.30 to 0.40) and a trend
      toward a decreased hospital death rate (OR 0.77, 95% CI 0.55 to 1.07). These
      results demonstrate that patients with a history of CAD who present with an acute
      coronary syndrome despite prior ASA use have less severe clinical presentation,
      fewer hospital complications, and lower in-hospital death rates than patients not
      previously taking ASA.

PMID- 12423704
TI  - Comparison of in-hospital and one-year outcomes in patients with and without
      diabetes mellitus undergoing percutaneous catheter intervention (from the
      National Heart, Lung, and Blood Institute Dynamic Registry).
AB  - Extrapolation of improvements in percutaneous coronary intervention (PCI) and
      outcomes to patients with diabetes has not been systematically examined in
      clinical practice. Two waves of consecutive patients (n = 4,629) who underwent
      PCI from July 1997 to June 1999 enrolled in the National Heart, Lung, and Blood
      Institute Dynamic Registry comprise the study population. There were 1,058
      patients with treated diabetes and 3,571 patients without clinically evident
      diabetes. As a group, patients with diabetes tended to have more clinical,
      angiographic, and procedural risk factors. Although crude in-hospital mortality
      rates were higher in patients with diabetes (diabetics 2.3%, nondiabetics 1.3%; p
      = 0.02), the adjusted risk of in-hospital death (odds ratio 1.46, 95% confidence
      interval [CI] 0.80 to 2.66) was not significantly different. At 1 year, patients
      with diabetes had a significantly higher adjusted risk of mortality (risk ratio
      [RR] 1.80, 95% CI 1.35 to 2.41) and need for repeat revascularization (RR 1.40,
      95% CI 1.13 to 1.74). There was a significant interaction between stent use and
      diabetic status with the need for repeat revascularization (adjusted RR in
      nondiabetics 0.73, 95% CI 0.61 to 0.88; adjusted RR in patients with diabetes
      1.20, 95% CI 0.88 to 1.65). Beta blockers at the time of hospital discharge were
      significantly associated with reduced mortality rates at 1 year in both groups.

PMID- 12423705
TI  - Nephropathy requiring dialysis after percutaneous coronary intervention and the
      critical role of an adjusted contrast dose.
AB  - This study was undertaken to determine the incidence, risk factors, and in
      hospital outcome of nephropathy requiring dialysis (NRD) after percutaneous
      coronary intervention (PCI), and to evaluate the role of a weight- and creatinine
      adjusted maximum radiographic contrast dose (MRCD) on NRD. Data were obtained
      from a registry of 16,592 PCIs. The data were divided into development and test
      sets. Univariate predictors were identified and a multivariate logistic
      regression model was developed. The MRCD was calculated for each patient as: MRCD
      = 5 ml x body weight (kilograms)/serum creatinine (milligrams per deciliter).
      Predictive accuracy was assessed by receiver-operating characteristic curve
      analysis. In the development set, 41 patients (0.44%) developed NRD with a
      subsequent in-hospital mortality rate of 39.0%. NRD increased with worsening
      baseline renal dysfunction. Other risk factors included peripheral vascular
      disease, diabetes mellitus, congestive heart failure, and cardiogenic shock.
      There was a direct relation between the number of risk factors and NRD. After
      adjustment for baseline risk factors, MRCD was the strongest independent
      predictor of NRD (adjusted odds ratio 6.2, 95% confidence interval 3.0 to 12.8).
      NRD and in-hospital mortality were both significantly higher in patients who
      exceeded the MRCD compared with patients who did not (p <0.001). In conclusion,
      NRD following PCI is a rare complication with a poor prognosis. Baseline clinical
      characteristics identify patients at greatest risk for NRD. Optimization of
      procedural variables such as timing of the intervention relative to the
      diagnostic catheterization, staging coronary procedures, or dosing within the
      MRCD may help reduce the risk of this complication in high-risk patients. A risk
      prediction tool for NRD with guidelines for prevention is presented.

PMID- 12423706
TI  - Effectiveness of adjunctive stent implantation following directional coronary
      atherectomy for treatment of left anterior descending ostial stenosis.
AB  - The aim of this study was to evaluate the acute and long-term angiographic and
      clinical results of optimal plaque debulking by means of directional coronary
      atherectomy (DCA) followed by stent implantation for treatment of left anterior
      descending (LAD) ostial stenosis. Eighty consecutive patients (66 men; aged 57 +/
      10 years) with angina pectoris, documented anterior myocardial ischemia, and de
      novo LAD ostial stenosis prospectively underwent DCA and stent deployment. They
      were evaluated angiographically after 6 months and clinically for up to 30 +/- 29
      months. The primary success rate was 98%. The in-hospital complications were 1
      death due to in-stent subacute thrombosis 7 days after the procedure, 1 non-Q
      wave myocardial infarction, and 1 retrograde left main artery dissection. The
      angiographic binary restenosis rate was 14.5%, and the loss index was 0.38 +/-
      0.35. The target lesion revascularization (TLR) rates at 6, 12, and 24 months
      were 6.0%, 14.5%, and 16.3%, respectively, and the combined event rates (death,
      nonfatal myocardial infarction, TLR) at the same times were 8.7%, 17.5%, and
      21.2%, respectively. These results indicate that the combined approach of DCA and
      stent implantation is feasible and safe in patients with LAD ostial lesions, has
      a high success rate, a low incidence of restenosis, and a good long-term outcome.

PMID- 12423707
TI  - Cutting balloon angioplasty for the prevention of restenosis: results of the
      Cutting Balloon Global Randomized Trial.
AB  - The cutting balloon (CB) is a specialized device designed to create discrete
      longitudinal incisions in the atherosclerotic target coronary segment during
      balloon inflation. Such controlled dilatation theoretically reduces the force
      needed to dilate an obstructive lesion compared with standard percutaneous
      transluminal coronary angioplasty (PTCA). We report a multicenter, randomized
      trial comparing the incidence of restenosis after CB angioplasty versus
      conventional balloon angioplasty in 1,238 patients. Six hundred seventeen
      patients were randomized to CB treatment, and 621 to PTCA. The mean reference
      vessel diameter was 2.86 +/- 0.49 mm, mean lesion length 8.9 +/- 4.3 mm, and
      prevalence of diabetes mellitus in patients was 13%. The primary end point, the 6
      month binary angiographic restenosis rate, was 31.4% for CB and 30.4% for PTCA (p
      = 0.75). Acute procedural success, defined as the attainment of <50% diameter
      stenosis without in-hospital major adverse cardiac events, was 92.9% for CB and
      94.7% for PTCA (p = 0.24). Freedom from target vessel revascularization was
      slightly higher in the CB arm (88.5% vs 84.6%, log-rank p = 0.04). Five coronary
      perforations occurred in the CB arm only (0.8% vs 0%, p = 0.03). At 270 days,
      rates of myocardial infarction, death, and total major adverse cardiac events for
      CB and PTCA were 4.7% versus 2.4% (p = 0.03), 1.3% versus 0.3% (p = 0.06), and
      13.6% versus 15.1% (p = 0.34), respectively. In summary, the proposed mechanism
      of controlled dilatation did not reduce the rate of angiographic restenosis for
      the CB compared with conventional balloon angioplasty. CB angioplasty should be
      reserved for difficult lesions in which controlled dilatation is believed to
      provide a better acute result compared with balloon angioplasty alone.

PMID- 12423708
TI  - Efficacy and safety of ezetimibe added to ongoing statin therapy for treatment of
      patients with primary hypercholesterolemia.
AB  - Ezetimibe is a lipid-lowering drug that inhibits the intestinal absorption of
      dietary and biliary cholesterol by blocking passage across the intestinal wall.
      The efficacy and safety of adding ezetimibe to ongoing statin therapy in patients
      with primary hypercholesterolemia was evaluated in a randomized, double-blind,
      placebo-controlled study. The study group included 769 adults (aged > or =18
      years) with primary hypercholesterolemia who had not achieved National
      Cholesterol Education Program (NCEP) Adult Treatment Panel II goals with dietary
      alteration and statin monotherapy. Patients receiving a stable dose of a statin
      for > or =6 weeks were randomized to receive concurrent treatment with placebo (n
      = 390) or ezetimibe (n = 379), 10 mg/day, in addition to continuing their open
      label statin for 8 weeks. The primary efficacy variable was the percent change in
      low-density lipoprotein (LDL) cholesterol from baseline with statin monotherapy
      to end point after intervention (secondary variables: high-density lipoprotein
      [HDL] cholesterol and triglycerides). Ongoing statin therapy plus ezetimibe led
      to changes of -25.1% for LDL cholesterol (HDL cholesterol +2.7%; triglycerides 
      14.0%) compared with LDL cholesterol -3.7% (p <0.001), HDL cholesterol +1.0% (p
      <0.05), and triglycerides -2.9% (p <0.001) for placebo added to ongoing statin
      therapy. Among patients not at LDL cholesterol goal at on-statin baseline, 71.5%
      receiving statin plus ezetimibe versus 18.9% receiving statin plus placebo
      reached goal at end point (odds ratio 23.7; p <0.001). The co-administration of
      statin and ezetimibe was generally well tolerated. Adding ezetimibe to ongoing
      statin therapy led to substantial additional reduction in LDL cholesterol levels,
      facilitating attainment of NCEP goals. Ezetimibe offers a new therapeutic option
      for patients receiving statins who require further reduction in LDL cholesterol.

PMID- 12423709
TI  - Efficacy and safety of a potent new selective cholesterol absorption inhibitor,
      ezetimibe, in patients with primary hypercholesterolemia.
AB  - The efficacy and safety of ezetimibe, a new cholesterol absorption inhibitor, was
      evaluated in this randomized, double-blind, placebo-controlled trial of 892
      patients with primary hypercholesterolemia. After > or =2 weeks on the National
      Cholesterol Education Program (NCEP) Step I or a stricter diet and a 4- to 8-week
      single-blind placebo lead-in, patients with low-density lipoprotein (LDL)
      cholesterol 130 to 250 mg/dl and triglycerides < or =350 mg/dl were randomized
      3:1 to receive ezetimibe 10 mg or placebo orally each morning for 12 weeks. The
      primary efficacy end point was the percent reduction in direct plasma LDL
      cholesterol from baseline to end point. A total of 434 men and 458 women (ages 18
      to 85 years) received randomized treatment (666 ezetimibe 10 mg, 226 placebo).
      Demographics and baseline characteristics were similar between treatment groups.
      Ezetimibe significantly reduced direct LDL cholesterol by a mean of 16.9%,
      compared with an increase of 0.4% with placebo (p <0.01). Subgroup analysis
      indicated that response to ezetimibe was generally consistent across all
      subgroups, regardless of risk-factor status, gender, age, race, or baseline lipid
      profile. Ezetimibe effects on LDL cholesterol occurred early (2 weeks) and
      persisted throughout the 12-week treatment period. Compared with placebo,
      ezetimibe 10 mg also significantly improved calculated LDL cholesterol,
      apolipoprotein B, total cholesterol, triglycerides, high-density lipoprotein
      (HDL) cholesterol, and HDL(3) cholesterol (p <0.01). Ezetimibe was well
      tolerated. There were no differences in laboratory or clinical safety parameters,
      or gastrointestinal, liver, or muscle side effects from that of placebo.
      Ezetimibe 10 mg/day is well tolerated, reduces LDL cholesterol approximately 17%,
      and improves other key lipid parameters.

PMID- 12423710
TI  - Induction of heart rate and blood pressure turbulence in the electrophysiologic
      laboratory.
AB  - Heart rate turbulence (HRT) is a transient tachycardia and/or bradycardia that
      follows ventricular premature complexes (VPCs). Absent or blunted HRT is
      associated with a poor prognosis in patients with heart disease, but its
      physiology is unknown. We hypothesized that HRT might be mediated by baroreflexes
      following early depolarizations. We sought to induce and characterize HRT in the
      electrophysiologic laboratory by introducing 1 ventricular extrastimulus every 60
      seconds in 23 patients who underwent invasive electrophysiologic studies. On
      average, HRT was characterized by an initial RR interval decrease of 38 ms
      occurring 3.4 seconds after early depolarization. This was followed by a
      transient RR interval increase of 88 ms occurring 5.4 seconds later. HRT was
      preceded by similar hypotensive and/or hypertensive blood pressure turbulence.
      Baroreflex sensitivity estimates from post-VPCs and sinus sequences were similar
      (12.3 +/- 10.3 vs 10.2 +/- 8.9 ms/mm Hg, p = 0.51). The failure to induce HRT was
      associated with a limited initial hypotensive phase of blood pressure turbulence
      (-7.9 vs -12.1 mm Hg, p = 0.037). Patients with structural heart disease had
      reduced turbulence onset and reduced turbulence slope relative to those with
      structurally normal hearts, although blood pressure response was similar in both
      groups. HRT is an inducible, transient tachycardia and/or bradycardia that likely
      arises from a baroreflex response to transient hypotension following VPCs.
      Patients with structural heart disease have blunted HRT.

PMID- 12423711
TI  - Differential effect of glyburide (glibenclamide) and metformin on QT dispersion:
      a potential adenosine triphosphate sensitive K+ channel effect.
AB  - Glyburide (glibenclamide) is a specific blocker of the adenosine triphosphate
      (ATP) sensitive potassium (K+) channel. It has been reported to result in
      prolongation of the QT interval. QT interval dispersion (QTd) is a potentially
      sensitive marker for increased risk of arrhythmia and sudden cardiac death. The
      aim of the present study was to evaluate the effect of glyburide on QTd and
      compare it with that of metformin, a hypoglycemic agent that does not block the
      adenosine triphosphate sensitive K+ channel. Thirty patients with type 2 diabetes
      were randomized to glyburide and metformin groups. A 12-lead electrocardiogram
      was obtained before and at 2 months after being on glyburide or metformin.
      Therapy with QT and QTd were measured and QT corrected for rate (QTc). There was
      no significant difference between the glyburide and metformin groups in age (62
      +/- 9 vs 59 +/- 10 years), baseline RR interval (819 +/- 86 vs 753 +/- 100 ms),
      QT (387 +/- 28 vs 383 +/- 27 ms), and QTc (433 +/- 25 vs 444 +/- 15 ms).
      Glyburide was associated with a significant increase in QTc (433 +/- 24 to 467 +/
      24 ms, p <0.001), QTd (24 +/- 16 to 60 +/- 22 ms, p <0.001), and QTc dispersion
      (QTcd) (35 +/- 18 to 68 +/- 21 ms, p <0.001). In contrast, metformin was
      associated with a decrease in QTc (444 +/- 15 to 432 +/- 15 ms, p <0.01) and did
      not affect QTd (14 +/- 5 to 12 +/- 6 ms, p = NS) and QTcd (23 +/- 9 to 22 +/- 10
      ms, p = NS). Glyburide, unlike metformin, causes an increase in QT dispersion.
      Increased dispersion may be a factor underlying an increased risk of arrhythmias
      and sudden cardiac death.

PMID- 12423712
TI  - Comparison of actions of irbesartan versus atenolol on cardiac repolarization in
      hypertensive left ventricular hypertrophy: results from the Swedish Irbesartan
      Left Ventricular Hypertrophy Investigation Versus Atenolol (SILVHIA).
AB  - Left ventricular (LV) hypertrophy is associated with a substantial risk for
      malignant arrhythmias and sudden death. The effects of antihypertensive therapy
      on QT dispersion, which reflects cardiac repolarization heterogeneity, in
      relation to changes in LV mass has not been well studied. Repeat echocardiography
      and QT measurements (standard 12-lead electrocardiograms) were performed in
      hypertensive patients with LV hypertrophy, who were randomized double-blind to
      receive the angiotensin II type 1-receptor blocker irbesartan (n = 44) or the
      beta(1)-receptor blocker atenolol (n = 48) for 48 weeks, and in 37 matched
      hypertensive control subjects without LV hypertrophy. LV mass index was related
      to QT dispersion (r = 0.34, p <0.001). The reduction in LV mass was greater using
      irbesartan than using atenolol (-27 +/- 28 vs -15 +/- 21 g/m(2) at 48 weeks, p =
      0.021), with similar reductions in blood pressure. Irbesartan decreased QT
      dispersion (from 56 +/- 24 ms to 45 +/- 20 ms at 48 weeks; p <0.001) and QTc
      dispersion (from 57 +/- 24 to 44 +/- 19 ms at 48 weeks; p <0.001). In contrast,
      atenolol had minor effects. The decreases in QT and QTc dispersions were greater
      using irbesartan than using atenolol (p = 0.001 and p = 0.011, respectively); the
      same results were found when changes in LV mass, blood pressure, and heart rate
      were also included in multivariate analyses. Thus, heterogeneity of ventricular
      repolarization is related to the degree of LV hypertrophy. Irbesartan, but not
      atenolol, reduces QT and QTc dispersions independent of changes in LV mass, blood
      pressure, or heart rate, and thus seems to induce structural and electrical
      remodeling in a direction that could decrease the risk of fatal events in
      hypertensive patients.

PMID- 12423713
TI  - Effects of long-term beta-blocker (metoprolol or carvedilol) therapy on QT
      variability in subjects with chronic heart failure secondary to ischemic
      cardiomyopathy.
AB  - Chronic heart failure (CHF) is a risk factor for sudden death. Temporal and
      spatial changes in repolarization are among the most studied mechanisms for
      inducing fatal ventricular arrhythmias. Beta blockers effectively reduce the risk
      of sudden death in CHF. Our aim in this study was to investigate changes induced
      by metoprolol and carvedilol on the QT variability index (QTVI), a new measure
      reflecting the temporal heterogeneity of cardiac repolarization. A total of 82
      subjects, who were in New York Heart Association functional class II or III,
      underwent short-term spectral analysis of RR and QT variability before and after
      a 1-year course of high-dose metoprolol (40 subjects) or carvedilol (42 subjects)
      at baseline (rest) and after sympathetic stress (head-up tilt). At rest, both
      drug-treated groups had lower QTVI (p <0.001) than after placebo, but during tilt
      patients treated with carvedilol had a lower QTVI than those treated with
      metoprolol (p <0.05). Although both beta-blocker treatments helped to normalize
      the QTVI measured in normal subjects at rest, they each differentially altered
      the index after tilt. Carvedilol seemed to improve the QTVI more than metoprolol.

PMID- 12423714
TI  - Effects of pentoxifylline on cytokine profiles and left ventricular performance
      in patients with decompensated congestive heart failure secondary to idiopathic
      dilated cardiomyopathy.
AB  - Patients with severe heart failure have plasma cytokine concentrations that are
      more than twofold greater than those in patients with moderate heart failure.
      Although pentoxifylline, an immunomodulatory agent that inhibits tumour necrosis
      factor-alpha (TNF-alpha) production, improves pump function in mild-to-moderate
      heart failure, its effects on advanced heart failure have not been determined. In
      a prospective, randomized, double-blind, placebo-controlled study we compared the
      effects of 1-month therapy with pentoxifylline (400 mg 3 times daily) (n = 9) and
      placebo (n = 9) on left ventricular systolic function and dimensions as well as
      on plasma TNF-alpha (picograms per milliliter), interleukin-10 (IL-10), and the
      apoptosis-signaling receptor Fas/Apo-1 in patients with idiopathic dilated
      cardiomyopathy and advanced heart failure. All patients had New York Heart
      Association functional class IV heart failure, required intravenous inotropic
      agents for >72 hours at the beginning of the study, and received diuretics,
      digoxin, and an angiotensin-converting enzyme inhibitor for the duration of the
      study. Marked increases in TNF-alpha and Fas/Apo-1 concentrations were noted in
      the 18 patients compared with patients with functional class II to III heart
      failure and controls (p <0.001). Baseline characteristics were the same between
      the pentoxifylline and placebo groups. Pentoxifylline administration resulted in
      reduced TNF-alpha and Fas/Apo-1 concentrations, and an increase in ejection
      fraction at 1 month (p <0.05 compared with baseline and with placebo), effects
      that were not observed in the placebo-treated group. These data suggest that
      pentoxifylline may be a useful adjunct to conventional therapy in patients with
      severe heart failure.

PMID- 12423715
TI  - A novel TPM1 mutation in a family with hypertrophic cardiomyopathy and sudden
      cardiac death in childhood.
AB  - We sought to define the pathogenic mutation in a family with hypertrophic
      cardiomyopathy (HC) and a markedly arrhythmogenic phenotype. The proband was an 8
      year-old female with a sentinel event of sudden death. Screening echocardiograms
      revealed HC in 2 of her 3 siblings and her father. Her youngest male sibling was
      diagnosed with HC at age 2 years and died suddenly at age 6 years from
      ventricular fibrillation despite an implanted cardioverter defibrillator. Using
      DNA extracted from peripheral lymphocytes, linkage exclusion was performed by
      haplotype analysis of polymorphic markers for the HC genes. Genes not excluded by
      linkage were analyzed for mutations using denaturing high-performance liquid
      chromatography (DHPLC) and direct DNA sequencing. Using this strategy, a 610 T>G
      nucleotide substitution in the alpha-tropomyosin gene (TPM1) was identified
      resulting in a novel L185R (Leucine [L] to Arginine [R]) missense mutation. This
      mutation was a spontaneous germ-line mutation originating in the proband's
      father. L185R-TPM1 cosegregated with family members having clinical evidence of
      HC, including the proband as confirmed by molecular autopsy. The mutation was not
      present in 400 reference alleles. Thus, a novel missense mutation in TPM1 was
      discovered in a family with HC and sudden death in childhood. Unlike previously
      defined mutations that may disrupt the interactions between alpha-tropomyosin
      monomers, the L185R mutation may affect troponin-T binding. Defining the
      pathogenic mutation enabled definitive molecular diagnosis of 2 surviving
      children.

PMID- 12423716
TI  - Usefulness of troponin I as a marker of myocardial injury after pediatric cardiac
      catheterization.
AB  - Cardiac troponin I (cTnI) is a sensitive and specific marker of myocardial
      injury. The degree of myocardial injury associated with pediatric cardiac
      catheterization is unknown. We sought to investigate cTnI after pediatric cardiac
      catheterization, and to evaluate the degree of elevation observed with specific
      types of interventions. Seventy-three pediatric catheterizations were evaluated.
      Diagnostic procedures and interventions not expected to cause myocardial injury
      were assigned to group I, whereas interventional procedures expected to be
      associated with cardiac injury were assigned to group II. Group II procedures
      were further subdivided based on type of intervention. Serum samples were
      obtained before and after all procedures and analyzed for cTnI. Postprocedure
      cTnI levels were compared across groups and correlated with age and weight.
      Procedures in group II were associated with significantly higher cTnI levels than
      group I (median 2.65 ng/ml; interquartile range 0.9 to 4.9 ng/ml for group II vs
      0.3; 0.3 to 1.6 ng/ml for group I, p <0.001). Within group II, cTnI was inversely
      correlated with age (p <0.05) and weight (p <0.05). Radiofrequency catheter
      ablation (RFA) caused higher cTnI levels than other types of interventions
      (median 3.7 ng/ml; 1.9 to 9.5 ng/ml for RFA vs 1.75; 0.7 to 4.9 ng/ml for non
      RFA, p <0.05). Most pediatric interventional catheterization procedures are
      associated with myocardial injury, as evidenced by elevation of cTnI, with RFA
      causing higher levels than other interventions. Conversely, most diagnostic
      procedures are associated with no detectable myocardial injury. When compared
      with adult studies, pediatric patients seem to be at higher risk for myocardial
      injury from interventional cardiac catheterization.

PMID- 12423717
TI  - Crumbling of left ventricular hypertrophy as a surrogate end point (the Losartan
      for Intervention for Endpoint Reduction in Hypertension [LIFE] Study).

PMID- 12423718
TI  - Alternative approaches to cholesterol-lowering therapy.

PMID- 12423719
TI  - Optimized stent implantation according to intracoronary Doppler-derived
      parameters.

PMID- 12423720
TI  - Effect of reperfusion therapy on long-term outcome in patients >70 years of age.

PMID- 12423721
TI  - Comparison of acute coronary syndromes in men versus women > or = 70 years of
      age.

PMID- 12423722
TI  - Comparison of atherosclerotic risk factors in Asian Indian and American Caucasian
      patients with angiographic coronary artery disease.

PMID- 12423723
TI  - Comparison of green tea intake in Japanese patients with and without angiographic
      coronary artery disease.

PMID- 12423724
TI  - Predictors of mortality, coronary angiography, and revascularization in unstable
      angina pectoris and acute non-ST elevation myocardial infarction (the TIMI III
      Registry).

PMID- 12423725
TI  - Usefulness of dynamic multislice computed tomography of left ventricular function
      in unstable angina pectoris and comparison with echocardiography.

PMID- 12423726
TI  - Long-term safety of therapy stratification in patients with intermediate coronary
      lesions based on intracoronary pressure measurements.

PMID- 12423727
TI  - Quantitative and spatial relation of baseline atherosclerotic plaque burden and
      subsequent in-stent neointimal proliferation as determined by intravascular
      ultrasound.

PMID- 12423728
TI  - Plasminogen levels and risk of coronary artery disease.

PMID- 12423729
TI  - Response of different grades of pulmonary artery hypertension to balloon mitral
      valvuloplasty.

PMID- 12423730
TI  - Color tissue Doppler-derived long-axis left ventricular function in heart failure
      with preserved global systolic function.

PMID- 12423731
TI  - Relation of insulin resistance and body composition to left ventricular mass in
      children.

PMID- 12423732
TI  - Criminal consequences of commotio cordis.

PMID- 12423735
TI  - Combined carotid and transcranial color-coded sonography in acute ischemic
      stroke.
AB  - The objective of this study is to clarify whether the combination of carotid
      duplex sonography (CD) and transcranial color-coded sonography (TCCS) can
      accurately detect occlusive lesions in extra and intracranial brain arteries in
      acute stroke patients, using angiography as the standard. Just before
      angiography, we performed CD and TCCS in 40 consecutive patients within 24 h
      after stroke onset. We assessed 320 vessels in total, bilateral internal carotid
      arteries, vertebral arteries, M1 segments of middle cerebral arteries (MCAs), and
      P2 segments of posterior cerebral arteries (PCAs). Out of all vessels, 250
      (78.1%) could be evaluated by neurosonography because 32 MCAs and 38 PCAs were
      excluded due to inadequate acoustic windows for TCCS. Significant occlusive
      lesions (>50%) were observed in 21 out of 250 vessels by neurosonography.
      Angiography confirmed 20 occlusive lesions as revealed by neurosonography. In the
      remaining 229 neurosonographically normal vessels, angiography showed no
      significant lesions except M2 occlusions. The accuracy, sensitivity, and
      specificity of neurosonography for the detection of occlusive vessels were 99.6,
      100 and 99.6%, respectively. Occlusive lesions were observed in 20 of all
      patients by neurosonography. Nineteen of them were confirmed by angiography. The
      combination of CD and TCCS can make an accurate diagnosis for significant
      occlusive lesions in brain arteries in acute stroke patients.

PMID- 12423736
TI  - Bronchioloalveolar carcinoma: sonographic pattern of 'pneumonia'.
AB  - BACKGROUND: the sonographic pattern of bacterial pneumonia is predominantly well
      known and characterized by an air bronchogram, a marked vascularity on color
      Doppler sonography, and a high-impedance arterial flow pattern on Doppler
      spectral analysis. METHODS: in a retrospective study the sonographic findings in
      seven patients with peripheral BAC on X-ray examination were evaluated in
      relation to number, size, margins, echomorphology and sonographic arterial flow
      patterns of the lesions. RESULTS: the following sonomorphologic characteristics
      were found: multiple foci (n=4), single foci (n=3), smooth margins (n=5),
      irregular margins (n=2) and maximal diameter of size (range 5-15 cm). The
      echomorphology of the lesions was homogenously hypoechoic (n=1) or showed
      airbronchograms (n=6). Color Doppler sonography revealed a vascular tree pattern
      (n=5) or a marked presence of blood vessels (n=2). Doppler flow spectral analysis
      of arteries in investigated patients (n=5) demonstrates a high impedance
      (triphasic) flow pattern in four patients and a low impedance (monophasic) flow
      pattern in one patient. CONCLUSIONS: these findings indicate that BAC frequently
      shows a sonographic pattern of 'pneumonia'.

PMID- 12423737
TI  - Improved detection of liver metastases with contrast-enhanced wideband harmonic
      imaging: comparison with CT findings.
AB  - OBJECTIVE: To evaluate the capability of contrast-enhanced wideband harmonic
      imaging (WHI) to detect liver metastases in comparison with fundamental B-mode US
      and postcontrast CT. METHODS: We studied 27 patients with hepatic metastases from
      different malignancies with conventional B-mode sonography, WHI 3 min after
      injection of contrast agent (Levovist(R) 2.5 g, 300 mg/ml) and postcontrast
      helical CT (HCT). The number and location of the lesions and the smallest lesion
      for each patient were noted by two different observers and compared. RESULTS:
      Both readers recorded an increase in the number of lesions in harmonic mode
      compared with conventional B-mode in all 27 patients with hepatic metastases with
      a mean increase in both observers from 9.3 lesions with B-mode to 18.8 lesions
      with WHI. The smallest lesions were detected with WHI when compared with
      conventional US and HCT (2 mm with WHI, 5 mm with B-mode and 5 mm with CT). WHI
      detected more lesions than conventional US or HCT. CONCLUSIONS: Contrast-enhanced
      WHI seems superior to conventional US and HCT for the detection of hepatic
      metastases, specially for those nodules under 1 cm of diameter.

PMID- 12423738
TI  - The efficacy of liver biopsy under ultrasonographic guidance on an outpatient
      basis.
AB  - OBJECTIVE: To evaluate the safety and compliance of outpatient echo-guided liver
      biopsy (ELB) when compared to those performed on inpatients (IP). METHODS: From
      June 1996 to November 2000, we carried out 418 ELB on patients with diffuse liver
      disease: 246 inpatients (IP ELB) and 172 in a Day Hospital setting (DH ELB). The
      same inclusion and exclusion criteria were followed for both groups of patients,
      performing the same echo-guided intercostal liver biopsy with free-hand technique
      and post biopsy assessment with colordoppler examination; post biopsy follow-up
      consisted of 6-h bed rest and blood pressure and heart rate monitoring up to
      discharge. DH patients were discharged 8 h after biopsy, if they did not live
      further than a 30-min trip from the hospital. In both groups, the following data
      was evaluated: death rate, sample adequacy, number of passages, major and minor
      complications, pain score. RESULTS: The data analysed in our series show that ELB
      DH presents no fundamental differences in morbidity and mortality when compared
      to ELB IP.

PMID- 12423739
TI  - General practitioner's skills to perform limited goal-oriented abdominal US
      examinations after one month of intensive training.
AB  - A training program of "limited goal-oriented abdominal sonography" for general
      practitioners (GPs) was planned, set up and tested. After 1 month of intensive
      training (about 100 examinations), four test subjects succeeded in technically
      performing examinations in four patients out of five patients, and were able to
      rule out or exclude fluid collections, aortic aneurysms and common gallbladder
      disease.

PMID- 12423740
TI  - Grading of pars planitis by ultrasound biomicroscopy--echographic and clinical
      study.
AB  - OBJECTIVE: To determine the value of high frequency ultrasound biomicroscopy
      (UBM) in the assessment of pars planitis, and in particular to correlate UBM
      findings and ophthalmoscopy findings. METHODS: All patients with pars planitis
      were identified from the uveitis database of the Department of Ophthalmology,
      University of Aberdeen. Fifteen consecutive patients (age 14-52 years) underwent
      complete ophthalmological examination. UBM was performed at a sound frequency of
      50 MHz on 17 eyes of 10 patients to determine the extent of disease. UBM findings
      were evaluated by two investigators in a blinded fashion and graded from 0 to 3
      according to the following grading criteria: 0=no cells, 1=mild cells, 2=marked
      cells, 3=organization of cells. Opthalmoscopy findings were also graded using the
      same criteria. UBM and ophthalmoscopy findings were independently graded and
      compared. RESULTS: We found a good inter-observer correlation for the UBM grading
      of pars planitis (rho=0.86). There was no significant difference in the grading
      of pars planitis by indirect ophthalmoscopy as compared to grading by UBM
      (P>0.05). CONCLUSION: UBM appears to be a valuable and reliable diagnostic
      technique for the evaluation of patients with pars planitis and may be useful
      especially in patients with media opacities to diagnose and/or monitor efficacy
      of treatment.

PMID- 12423741
TI  - Observer variation in the sonographic measurement of optic nerve sheath diameter
      in normal adults.
AB  - AIM: To quantify the observer variation in the sonographic measurement of optic
      nerve sheath diameter (ONSD) in normal adults. MATERIALS AND METHODS: Sixty-seven
      normal adult volunteers underwent ultrasound examination of each eye by three
      independent observers using a 7 MHz sector probe. Three measurements were made of
      each eye by each observer and a mean value calculated for each eye. Median and
      5th-95th centile values for both intra- and inter-observer variation were
      calculated for the three observers. RESULTS: The median intra-observer variation
      was +/-0.1 mm, with 5th-95th centile values of +/-0-0.4 mm. The median inter
      observer variation was +/-0.2-0.3 mm, with 5th-95th centile values of +/-0-0.7
      mm. Careful review of examination technique by the three observers after the
      first 17 examinations was shown to reduce both intra- and inter-observer
      variation. CONCLUSION: The sonographic measurement of ONSD is a readily learned,
      reproducible technique with low intra- and inter-observer variation. The average
      inter-observer variation (+/-0.2 mm) is comparable to the inherent variability of
      the ultrasound machine. The importance of standardisation of examination
      technique is stressed.

PMID- 12423742
TI  - Performance testing of medical echo/Doppler equipment.
AB  - This paper describes the methods applied in a software package developed by the
      authors for use in a performance testing protocol for medical ultrasound
      equipment. The history of performance testing of medical ultrasound equipment is
      briefly reviewed. This paper is confined to the testing of performance of usage
      aspects, i.e. imaging performance and Doppler velocity estimation performance.
      Simple test objects are used which have a long life expectancy. The tests
      performed both in fundamental and in (tissue) harmonic modes when applicable are
      spatial resolution, contrast sensitivity, and clutter. The concept of a
      computational observer is used to define the lesion signal-to-noise ratio and the
      tissue-to-clutter ratio. Further imaging performance features are penetration
      depth, slice thickness and geometric conformity of display. Pulsed Doppler
      velocity measurement features tested are: sensitivity, depth and 3D size of the
      sample volume, velocity measurement, channel separation. The whole performance
      measurement protocol as well as the quantitative measurements in the digitized
      images are implemented in software, together with the graphs and data obtained
      from the measurements.

PMID- 12423743
TI  - EFSUMB: safety tutorial: epidemiology of diagnostic ultrasound exposure during
      pregnancy-European committee for medical ultrasound safety (ECMUS).
AB  - The present paper summarizes some of the epidemiological studies of in utero
      ultrasound exposure and subsequent childhood development. Emphasis is placed on
      birth weight, childhood malignancies, neurological development, handedness and
      speech development. The epidemiological evidence does not indicate any
      association between diagnostic ultrasound exposure during pregnancy and reduced
      birth weight, childhood malignancies or neurological development. However, a
      statistically significant association between ultrasound and left-handedness
      among males has been found in three studies. Thus, there is still need for more
      research.

PMID- 12423744
TI  - Deprogrammed sporulation in Streptomyces.
AB  - The bacterial genus Streptomyces forms chains of spores by septation at intervals
      in aerial hyphae and subsequent maturation on solid medium. Substrate hyphae
      undergo extensive lysis, liberating nutrients on which aerial hyphae develop.
      Some mutant strains, however, ectopically form spores by septation in substrate
      hyphae on solid medium or in vegetative hyphae in liquid medium, which suggests
      that all hyphae have the potential to differentiate into spores. A Streptomyces
      griseus mutant strain NP4, which has a mutation in the regulatory system for an
      ATP-binding cassette (ABC) transporter gene, forms ectopic spores in substrate
      hyphae only on glucose-containing medium. In addition, overexpression of a
      substrate-binding protein of the ABC transporter in the wild-type strain causes
      ectopic septation in very young substrate hyphae and subsequent sporulation in
      response to glucose. These ectopic spores germinate normally. The ectopic
      sporulation is independent of A-factor, a microbial hormone that determines the
      timing of aerial mycelium formation during normal development. Thus, substrate
      hyphae of Streptomyces have a potential to develop into spores without formation
      of aerial hyphae. For programmed development, therefore, the strict repression of
      septum formation in substrate mycelium should be necessary, as well as the
      positive signal relay leading to aerial mycelium formation followed by septation
      and sporulation.

PMID- 12423745
TI  - Comparative study and molecular characterization of ectomycorrhizas in Tilia
      americana and Quercus pubescens with Tuber brumale.
AB  - Mycorrhizas of Tuber brumale on Quercus pubescens and Tilia americana were
      obtained in vitro using micropropagated plantlets. Mycelium pure cultures were
      used for inoculation. Both the mycelium used for the inoculations, as well as the
      mycorrhizas which were obtained, were identified using several molecular
      approaches: analysis of the ITS region, polymerase chain reaction (PCR) specific
      primers and sequencing. The mycorrhizas were described from a morphological
      standpoint. Some of their biometric characteristics were different in bass-wood
      than they were in oak, thus showing the influence of the host plant on several of
      the morphological features believed to be necessary for the identification of the
      species. Considering the variability of their morphological characteristics,
      molecular analysis proved to be a necessary tool for the recognition of the
      mycorrhizas of Tuber spp.

PMID- 12423746
TI  - Competitive hybridization on spotted microarrays as a tool to conduct comparative
      genomic analyses of Xylella fastidiosa strains.
AB  - Xylella fastidiosa strains are responsible for several plant diseases and since
      such isolates display a broad host range and complex biological behavior, genomic
      comparisons employing microarray hybridizations may provide an effective method
      to compare them. Thus, we performed a thorough validation of this type of
      approach using two recently sequenced strains of this phytopathogen. By matching
      microarray hybridization results to direct sequence comparisons, we were able to
      establish precise cutoff ratios for common and exclusive sequences, allowing the
      identification of exclusive genes involved in important biological traits. This
      validation will enable the use of microarray-based comparisons across a wide
      variety of microorganisms

PMID- 12423747
TI  - Topological characterization of the essential Escherichia coli cell division
      protein FtsW.
AB  - The membrane topology of Escherichia coli FtsW, a 46-kDa essential protein, was
      analyzed using a set of 28 ftsW-alkaline phosphatase (ftsW-phoA) and nine ftsW
      beta-lactamase (ftsW-bla) gene fusions obtained by in vivo and in vitro methods.
      The alkaline phosphatase activities or resistance pattern of cells expressing the
      FtsW-PhoA or FtsW-Bla fusions confirmed only eight out of 10 transmembrane
      segments predicted by computational methods. After comparison with the recent
      topology of Streptococcus pneumoniae FtsW, we could identify all the fusions in
      absolute agreement with the predicted model: N-terminal and C-terminal ends in
      the cytoplasm, 10 transmembrane segments and one large loop of 67 amino acids
      (E240-E306) located in the periplasm.

PMID- 12423748
TI  - KEM1 is involved in filamentous growth of Saccharomyces cerevisiae.
AB  - The KEM1/XRN1 gene was originally identified because of its functions in
      microtubule-mediated processes, and is also known to be a major cytoplasmic 5'-3'
      exoribonuclease gene, which is involved in RNA turnover. Here we present evidence
      that KEM1 plays a role in filamentous growth. In Saccharomyces cerevisiae, the
      filamentation signalling shares multiple components of the MAP kinase cascade
      (STE7, STE11, and KSS1) and the transcription factor STE12 with mating process.
      Both haploid invasive growth and diploid pseudohyphal growth were found to be
      greatly impaired in kem1 mutant strains. KEM1 affected the level of FLO11
      transcripts and the expression of the filamentation-associated reporter genes,
      Ty1-lacZ and FLO11-lacZ. Suppression analysis implies that KEM1 does not affect
      the RAS/PKA pathway, but that it possibly functions downstream of the MAP kinase
      pathway during filamentation.

PMID- 12423749
TI  - Identification of shiga toxin-producing bacteria by a new immuno-capture toxin
      gene PCR.
AB  - Infections with bacteria producing shiga toxin are responsible for widespread
      disease and for the death of a large number of people. In the present study, we
      have developed a rapid method of high specificity for the detection of Shigella
      dysenteriae by combining immuno-capture of the bacteria and polymerase chain
      reaction (PCR) amplification of their toxin gene. We compared the sensitivity of
      our new method, referred to as immuno-capture toxin gene PCR (iTGPCR), with a
      conventional TGPCR (cTGPCR) method in detecting S. dysenteriae. Approximately 100
      colony forming units (CFU) of bacteria in a volume of 400 microl were divided
      into 20 tubes with 5 CFU (20 microl). One group of 10 tubes was analyzed by
      iTGPCR and the other by cTGPCR amplification. All were positive in the 10 tubes
      using iTGPCR but, in contrast, only half were positive in the 10 tubes with the
      cTGPCR method. This method was used to detect S. dysenteriae type I in sewage
      samples without the normal tedious preparation methods. These findings suggest
      that iTGPCR gives enhanced test sensitivity, and allows determination of pathogen
      serotype, and differentiation of toxin-producing strains from non toxin-producing
      strains.

PMID- 12423750
TI  - Cloning vectors for Streptococcus thermophilus derived from a native plasmid.
AB  - A 3.5-kb native plasmid (pND103) was identified in Streptococcus thermophilus ST2
      1. Preliminary sequence analysis indicated that pND103 belongs to group I S.
      thermophilus plasmids. A region of approximately 2 kb appears to contain three
      components: a plus origin of replication (ori) typical of plasmids that replicate
      via rolling circle replication; a gene encoding a replication protein (rep); and
      a gene encoding a small heat shock protein (hsp). pND103 was then used to
      construct S. thermophilus/Escherichia coli hybrid cloning vectors by ligating
      different portions of pND103 to an origin-probe vector (pND330) composed of pUC19
      and a Gram-positive erythromycin resistance gene. The shuttle vectors (pND913,
      pND914 and pND915) were successfully introduced back into plasmid-free S.
      thermophilus ST3-1 as well as to Lactococcus lactis LM0230 and E. coli JM109.
      Segregational and structural stability study indicated that these vectors can be
      maintained in these hosts. The results indicated that pND913, pND914 and pND915
      are potential shuttle cloning vectors for S. thermophilus.

PMID- 12423751
TI  - Inhibition of acetate and propionate assimilation by itaconate via propionyl-CoA
      carboxylase in isocitrate lyase-negative purple bacterium Rhodospirillum rubrum.
AB  - Itaconate is known as a potent inhibitor of isocitrate lyase. Unexpectedly,
      itaconate was a strong inhibitor of acetate and propionate assimilation in
      isocitrate lyase-negative purple non-sulfur bacterium Rhodospirillum rubrum. It
      was shown that in cell extracts of R. rubrum itaconate inhibited propionyl-CoA
      carboxylase (PCC) activity. The participation of PCC in propionate assimilation
      in R. rubrum is well-documented, but the inhibition of acetate assimilation
      suggests that PCC is also involved in acetate metabolism. PCC is one of the
      enzymes of the citramalate cycle, the anaplerotic pathway proposed for R. rubrum
      as a substitute for the glyoxylate cycle. These results provide further support
      for the hypothesis of the occurrence of the citramalate cycle in R. rubrum. PCC
      from other isocitrate lyase-negative phototrophs, Rhodobacter sphaeroides and
      Phaeospirillum fulvum, was not inhibited by itaconate.

PMID- 12423752
TI  - A rapid and efficient method using chromoslots to assign any newly cloned DNA
      sequence to its cognate chromosome in the filamentous fungus Podospora anserina.
AB  - An efficient method was developed to assign cloned genes to individual
      chromosomes of the fungus Podospora anserina. The chromosomes were separated by
      pulsed-field gel electrophoresis and the DNA was isolated from the gel bands. The
      DNA from the isolated chromosomes was slotted onto membranes; the resulting
      chromoslots were used to confirm that genetically mapped genes could be detected
      in the expected position. Then, 20 genes, not yet assigned to a linkage group,
      were attributed to individual chromosomes while six were attributed to a band
      containing two chromosomes.

PMID- 12423753
TI  - Detection of known and novel genes encoding aromatic ring-hydroxylating
      dioxygenases in soils and in aromatic hydrocarbon-degrading bacteria.
AB  - Primers were designed and successfully used to screen aromatic hydrocarbon
      degrading bacteria for the presence of class II aromatic ring-hydroxylating
      dioxygenase (RHD) genes and to amplify novel RHD genes from DNA extracted from
      soil using the polymerase chain reaction. Two previously undiscovered groups of
      genes encoding putative class II RHDs, designated the S and T clusters, were
      found in RHD different soil samples. Only one of 70 RHD gene fragments amplified
      from these soil samples could be assigned to a cluster of previously reported RHD
      genes. These results suggest that distinct and potentially numerically dominant
      groups of as-yet unrecognized aromatic hydrocarbon-degrading bacteria exist in
      soils.

PMID- 12423754
TI  - Inhibition of Escherichia coli heat-labile enterotoxin by neoglycoprotein and
      anti-lectin antibodies which mimic GM1 receptor.
AB  - Escherichia coli producing heat-labile enterotoxin is responsible for numerous
      cases of diarrhea worldwide, leading to considerable morbidity and mortality. The
      B subunits of this toxin are responsible for the binding to the receptor, the
      complex ganglioside GM1 which has galactose as its terminal sugar. In this study
      we showed that analogs of galactose (gal) and N-acetylgalactosamine (GalNAc)
      interfere with the binding of heat-labile toxin to GM1. Antibodies to lectins
      which mimic sugar structures and neoglycoprotein were employed. These compounds
      were able to inhibit heat-labile toxin activity efficiently in Vero cells: 37
      microg of IgG-enriched fraction from an antiserum inhibited up to 70% of this
      activity, and 50% of the binding of heat-labile toxin to GM1. Neoglycoprotein was
      more efficient than antibodies, since 2.5 microg of this ligand completely
      abolished the activity of heat-labile toxin on Vero cells. These data suggest
      that these molecules could be developed for prophylaxis and diagnosis of diarrhea
      caused by heat-labile toxin.

PMID- 12423755
TI  - Characterization of a novel plasmid pXZ608 from Corynebacterium glutamicum.
AB  - The complete nucleotide sequence of a novel cryptic plasmid pXZ608 from
      Corynebacterium glutamicum 227 was determined. pXZ608 was 5949 bp with six open
      reading frames (ORF1-6). The predicted ORF1 gene product was homologous to
      replication proteins of rolling circle replication plasmids. The conserved single
      and double-stranded origins of rolling circle replication were found, and
      interestingly, the two origins were both located on ORF1, which indicated that
      the Rep protein encoded by ORF1 could bind to its own gene region. Deletion
      analysis revealed that the minimal replicon was located on the 2.14-kb SacI
      BstEII fragment.

PMID- 12423756
TI  - The Brevibacterium flavum sigma factor SigB has a role in the environmental
      stress response.
AB  - We have previously cloned a gene encoding a SigB, a principal-like sigma factor
      in Brevibacterium flavum, which was induced by several stress conditions. To
      clarify the in vivo function of this sigma factor, the sigB gene was disrupted by
      a homologous recombination, replacing the internal essential coding region in B.
      flavum chromosome by a kanamycin resistance marker gene. This mutation
      dramatically decreased vegetative growth rates of B. flavum. Studies of the
      effect of the sigB mutation on growth and viability of the cells under conditions
      of stress showed that the sigB mutant had increased susceptibility to acid, salt,
      alcohol, heat and cold stress. The plasmid-born wild-type sigB gene complemented
      the mutation. Based on the results, we propose that SigB has a role in vegetative
      growth and in response to various environmental stresses.

PMID- 12423757
TI  - Transduction of concatemeric plasmids containing the cos site of Lactococcus
      lactis bacteriophage sk1.
AB  - Lactococcus lactis bacteriophage sk1 can transduce plasmids containing the phage
      cos site and surrounding DNA sequences at frequencies as high as 2x10(-3)
      transductants per PFU. Deletion analysis demonstrated that the presence of phage
      DNA spanning cos and putative R sites were the most important for efficient
      plasmid transduction. Inserts of 440 bp containing cos and the R sites were
      sufficient to induce transduction frequencies of 10(-4) transductants per PFU.
      The role of the R1 site was investigated by altering 14 of the 19 bases in the
      site. This resulted in a two-fold decrease in transduction frequency compared to
      a 26-fold decrease in transduction following deletion of the entire site. It was
      demonstrated that transducing plasmids were packaged as linear trimeric
      concatemers commencing at the cos site.

PMID- 12423758
TI  - Endosomal/lysosomal targeting of a single helper T-cell epitope of an
      intracellular bacterium by DNA immunisation induces a specific T-cell subset and
      partial protective immunity in vivo.
AB  - We evaluated here the effect of the intracellular targeting of a helper T-cell
      (Th) epitope, literiolysin O 215-226 derived from Listeria monocytogenes, on
      induction of a specific Th by gene gun immunisation. Immunisation of C3H/He mice
      with pE215LAMP plasmid encoding the Th epitope fused with the endosomal/lysosomal
      targeting signal of lysosome-associated membrane protein (LAMP)-1 gave the
      epitope-specific proliferative responses of CD4(+) T lymphocytes. In addition,
      specific interferon-gamma production from the splenocytes was observed.
      Concomitantly, pE215LAMP-immunised mice showed moderate, but significant
      protective immunity against listerial challenge. These results suggest that the
      intracellular targeting of a Th epitope to endosomal/lysosomal compartments by
      DNA immunisation is useful for eliciting a specific Th subset in vivo.

PMID- 12423759
TI  - Change of cell wall chitin content in amphotericin B resistant Kluyveromyces
      strains.
AB  - The culture of two Kluyveromyces species, Kluyveromyces lactis (ATCC 96897) and
      Kluyveromyces bulgaricus (ATCC 96631), in the presence of subinhibitory doses of
      amphotericin B leads to the selection of mutants which are resistant to this
      polyene. The mutants show an alteration of their cell wall composition with the
      main change corresponding to an increase of chitin. The enzyme activities
      involved in the metabolism of this polymer, i.e. chitin synthases and chitinase,
      were measured. The results demonstrate that in both mutants the activity of
      chitinase was drastically decreased by 99% in comparison with the activity
      measured in the corresponding wild-type strain while no significant change of the
      chitin synthase I, II and III activities could be detected.

PMID- 12423760
TI  - Genetic evidence for a novel thymidylate synthase in the halophilic archaeon
      Halobacterium salinarum and in Campylobacter jejuni.
AB  - A search of the complete genome sequence of the halophilic archaeon Halobacterium
      salinarum failed to identify a gene homologous to the thymidylate synthase (thyA)
      gene present in the closely related Haloferax volcanii. To understand the source
      of thymidine synthesis in Hbt. salinarum, a genomic library of Hbt. salinarum was
      constructed and used to complement a Hfx. volcanii thyA deletion mutation. The
      Hbt. salinarum ORF that complemented the thyA mutation shares sequence homology
      with ORFs found in numerous microorganisms that lack a thyA gene, including the
      recently discovered thyX of Helicobacter pylori. We also show that a homolog of
      the Hbt. salinarum ORF is present in Campylobacter jejuni and is able to
      complement an Escherichia coli thyA mutant under oxygen-limiting conditions.

PMID- 12423761
TI  - Human tryptophanyl-tRNA synthetase can efficiently complement the Saccharoymces
      cerevisiae homologue, Wrs1P.
AB  - Aminoacyl-tRNA synthetases corresponding to each of the 20 amino acids are
      essential proteins for nearly all cells. The tryptophan-specific enzyme in the
      cytoplasm of Saccharomyces cerevisiae (ScWRS) is a 49-kDa protein encoded by the
      WRS1 gene and required for survival. The human enzyme (HsWRS) is a 54-kDa protein
      with 46% sequence identity to ScWRS. HsWRS has a kinase domain in the N-terminal
      region and a serine phosphorylation site near the C-terminus not present in the
      yeast enzyme. To determine if the gene encoding the human protein could
      functionally complement the WRS1 gene, HsWRS cDNA was cloned in the expression
      vectors pVT100U and pYES then transformed into a diploid yeast where one copy of
      WRS1 had been replaced with a G418(R) gene. Tetrads derived from these
      transformants were dissected and spores germinated on media selecting for the
      presence of the plasmids. Haploid colonies were then tested for resistance to
      G418. G418(R) cells were unable to grow in the presence of 5-fluoroorotic acid,
      indicating their dependence on the plasmids for viability. Polymerase chain
      reaction analysis of these cells confirmed the presence of the HsWRS gene and the
      absence of WRS1. Growth rates of cells expressing HsWRS are essentially identical
      to the parent. This demonstrates that the human enzyme can function in yeast and
      effectively replace the ScWRS protein in spite of the presence of two unique
      functions and a >50% overall difference in amino acid sequence.

PMID- 12423762
TI  - Survival of Escherichia coli O157:H7 in private drinking water wells: influences
      of protozoan grazing and elevated copper concentrations.
AB  - The survival characteristics of Escherichia coli O157:H7 in private drinking
      water wells were investigated to assess the potential for human exposure. A non
      toxigenic, chromosomally lux-marked strain of E. coli O157:H7 was inoculated into
      well water from four different sites in the North East of Scotland. These waters
      differed significantly in their heavy metal contents as well as nutrient and
      bacterial grazer concentrations. Grazing and other biological factors were
      studied using filtered (3 and 0.2 microm) and autoclaved water. The survival of
      E. coli O157:H7 was primarily decreased by elevated copper concentrations. This
      hypothesis was supported by acute toxicity assay data. In addition, significant
      protozoan predation effects were observed in untreated water when compared with
      survival rates in filtered water. The combination of these two factors in
      particular determines the survival time of the pathogen in a private water well.
      It therefore appears that wells with higher water quality as assessed using the
      European Union Drinking Water Directive standards will also allow survival of E.
      coli O157:H7 for much longer periods.

PMID- 12423763
TI  - The intralaminar and midline nuclei of the thalamus. Anatomical and functional
      evidence for participation in processes of arousal and awareness.
AB  - The thalamic midline and intralaminar nuclei, long thought to be a non-specific
      arousing system in the brain, have been shown to be involved in separate and
      specific brain functions, such as specific cognitive, sensory and motor
      functions. Fundamental to the participation of the midline and intralaminar
      nuclei in such diverse functions seems to be a role in awareness. It is unknown
      whether the midline and intralaminar nuclei, together often referred to as the
      'non-specific' nuclei of the thalamus, act together or whether each nucleus is
      involved idiosyncratically in separate circuits underlying cortical processes.
      Detailed knowledge of the connectivity of each of these nuclei is needed to judge
      the nature of their contribution to cortical functioning. The present account
      provides an overview of the results of neuroanatomical tracing studies on the
      connections of the individual intralaminar and midline thalamic nuclei in the
      rat, that have been performed over the past decade in our laboratory. The results
      are discussed together with those reported by other laboratories, and with those
      obtained in other species. On the basis of the patterns of the afferent and
      efferent projections, we conclude that the midline and intralaminar thalamic
      nuclei can be clustered into four groups. Each of the groups can be shown to have
      its own set of target and input structures, both cortically and subcortically.
      These anatomical relationships, in combination with functional studies in animals
      and in humans, lead us to propose that the midline and intralaminar nuclei as a
      whole play a role in awareness, with each of the groups subserving a role in a
      different aspect of awareness. The following groups can be discerned: (1) a
      dorsal group, consisting of the paraventricular, parataenial and intermediodorsal
      nuclei, involved in viscero-limbic functions; (2) a lateral group, comprising the
      central lateral and paracentral nuclei and the anterior part of the central
      medial nucleus, involved in cognitive functions; (3) a ventral group, made up of
      the reuniens and rhomboid nucleus and the posterior part of the central medial
      nucleus, involved in multimodal sensory processing; (4) a posterior group,
      consisting of the centre median and parafascicular nuclei, involved in limbic
      motor functions.

PMID- 12423764
TI  - Evolutionary divergence of the reptilian and the mammalian brains: considerations
      on connectivity and development.
AB  - The isocortex is a distinctive feature of the mammalian brain, with no clear
      counterpart in other amniotes. There have been long controversies regarding
      possible homologues of this structure in reptiles and birds. The brains of the
      latter are characterized by the presence of a structure termed dorsal ventricular
      ridge (DVR), which receives ascending auditory and visual projections, and has
      been postulated to be homologous to parts of the mammalian isocortex (i.e., the
      auditory and the extrastriate visual cortices). Dissenting views, now supported
      by molecular evidence, claim that the DVR originates from a region termed ventral
      pallium, while the isocortex may arise mostly from the dorsal pallium (in
      mammals, the ventral pallium relates to the claustroamygdaloid complex). Although
      it is possible that in mammals the embryonic ventral pallium contributes cells to
      the developing isocortex, there is no evidence yet supporting this alternative.
      The possibility is raised that the expansion of the cerebral cortex in the origin
      of mammals was product of a generalized dorsalizing influence in pallial
      development, at the expense of growth in ventral pallial regions. Importantly,
      the evidence suggests that organization of sensory projections is significantly
      different between mammals and sauropsids. In reptiles and birds, some sensory
      pathways project to the ventral pallium and others project to the dorsal pallium,
      while in mammals sensory projections end mainly in the dorsal pallium. We suggest
      a scenario for the origin of the mammalian isocortex which relies on the
      development of associative circuits between the olfactory, the dorsal and the
      hippocampal cortices in the earliest mammals.

PMID- 12423766
TI  - Human brain plasticity: an emerging view of the multiple substrates and
      mechanisms that cause cortical changes and related sensory dysfunctions after
      injuries of sensory inputs from the body.
AB  - Injuries of peripheral inputs from the body cause sensory dysfunctions that are
      thought to be attributable to functional changes in cerebral cortical maps of the
      body. Prevalent theories propose that these cortical changes are explained by
      mechanisms that preeminently operate within cortex. This paper reviews findings
      from humans and other primates that point to a very different explanation, i.e.
      that injury triggers an immediately initiated, and subsequently continuing,
      progression of mechanisms that alter substrates at multiple subcortical as well
      as cortical locations. As part of this progression, peripheral injuries cause
      surprisingly rapid neurochemical/molecular, functional, and structural changes in
      peripheral, spinal, and brainstem substrates. Moreover, recent comparisons of
      extents of subcortical and cortical map changes indicate that initial subcortical
      changes can be more extensive than cortical changes, and that over time cortical
      and subcortical extents of change reach new balances. Mechanisms for these
      changes are ubiquitous in subcortical and cortical substrates and include
      neurochemical/molecular changes that cause functional alterations of normal
      excitation and inhibition, atrophy and degeneration of normal substrates, and
      sprouting of new connections. The result is that injuries that begin in the body
      become rapidly further embodied in reorganizational make-overs of the entire core
      of the somatosensory brain, from peripheral sensory neurons to cortex. We suggest
      that sensory dysfunctions after nerve, root, dorsal column (spinal), and
      amputation injuries can be viewed as diseases of reorganization in this core.

PMID- 12423765
TI  - Origin and functional role of the extracellular serotonin in the midbrain raphe
      nuclei.
AB  - There is considerable interest in the regulation of the extracellular compartment
      of the transmitter serotonin (5-hydroxytryptamine, 5-HT) in the midbrain raphe
      nuclei because it can control the activity of ascending serotonergic systems and
      the release of 5-HT in terminal areas of the forebrain. Several intrinsic and
      extrinsic factors of 5-HT neurons that regulate 5-HT release in the dorsal (DR)
      and median (MnR) raphe nucleus are reviewed in this article. Despite its high
      concentration in the extracellular space of the raphe nuclei, the origin of this
      pool of the transmitter remains to be determined. Regardless of its origin, is
      has been shown that the release of 5-HT in the rostral raphe nuclei is partly
      dependent on impulse flow and Ca(2+) ions. The release in the DR and MnR is
      critically dependent on the activation of 5-HT autoreceptors in these nuclei.
      Yet, it appears that 5-HT autoreceptors do not tonically inhibit 5-HT release in
      the raphe nuclei but rather play a role as sensors that respond to an excess of
      the endogenous transmitter. Both DR and MnR are equally responsive to the
      reduction of 5-HT release elicited by the local perfusion of 5-HT(1A) receptor
      agonists. In contrast, the effects of selective 5-HT(1B) receptor agonists are
      more pronounced in the MnR than in the DR. However, the cellular localization of
      5-HT(1B) receptors in the raphe nuclei remains to be established. Furthermore,
      endogenous noradrenaline and GABA tonically regulate the extracellular
      concentration of 5-HT although the degree of tonicity appears to depend upon the
      sleep/wake cycle and the behavioral state of the animal. Glutamate exerts a
      phasic facilitatory control over the release of 5-HT in the raphe nuclei through
      ionotropic glutamate receptors. Overall, it appears that the extracellular
      concentration of 5-HT in the DR and the MnR is tightly controlled by intrinsic
      serotonergic mechanisms as well as afferent connections.

PMID- 12423767
TI  - Experimental colonization of mice by fresh clinical isolates of Helicobacter
      pylori is not influenced by the cagA status and the vacA genotype.
AB  - Developing murine models of infection by Helicobacter pylori is quite useful but
      not all the strains are able to colonize the mouse. In order to study the
      influence of the two main virulence factors, CagA and VacA, on the establishment
      of H. pylori in mice, we have inoculated C57BL/6 mice with 15 strains randomly
      chosen among clinical strains freshly isolated from biopsy specimens of infected
      patients and five reference strains. Only six of the clinical strains and two of
      the reference strains could infect the animals regardless of the cagA status and
      the vacA genotype. We concluded that 40% of the H. pylori strains are able to
      infect mice and that the capacity of colonization is not influenced by the cagA
      status and the vacA genotype. These factors cannot be used to predict the success
      of an experimental infection.

PMID- 12423768
TI  - The partially degraded lipopolysaccharide of Burkholderia cepacia and ornithine
      containing lipids derived from some Gram-negative bacteria are useful complex
      lipid adjuvants.
AB  - The partially degraded lipopolysaccharide of Burkholderia cepacia (LPSdegr) and
      the ornithine-containing lipids were purified from some bacteria. The substances
      were developed as complex lipid adjuvants, because they have weak toxicity and
      are able to activate the immune systems of the living body. After various toxoid
      antigens such as pertussis toxoid, diphtheria toxoid and tetanus toxoid were
      mixed with the complex lipid adjuvants, the mixtures were administered to mice
      subcutaneously. Antitoxoid IgG antibody titers in the serum were measured several
      times over 3 months. The efficacy of the LPSdegr as adjuvant was almost as high
      as that of the ornithine-containing lipids, and it was almost equal to that of
      the aluminum hydroxide adjuvant (Alum), which is generally used as a vaccine
      adjuvant.

PMID- 12423769
TI  - Mycoplasma gallisepticum: Influence of cell invasiveness on the outcome of
      experimental infection in chickens.
AB  - Recently we have shown that a low (R(low)) and a high laboratory passage
      (R(high)) of the poultry pathogen Mycoplasma gallisepticum prototype strain R
      differ markedly in their capability to invade non-phagocytic eukaryotic cells. In
      the present study the infection traits of these two mycoplasma passages were
      compared in an in vivo setting. After aerosol inoculation of chickens, M.
      gallisepticum was re-isolated from the inner organs of birds infected with
      R(low), whereas no mycoplasma was recovered from the inner organs of birds
      infected with R(high). These results indicate that the two mycoplasma populations
      derived from strain R differ in their capacity to cross the mucosal barrier and
      suggest that cell invasion may play a major role in the observed systemic
      spreading of M. gallisepticum in its chicken host.

PMID- 12423770
TI  - Cyclooxygenase 2 activity modulates the severity of murine Lyme arthritis.
AB  - Cyclooxygenase (Cox) is a key enzyme in the biosynthetic metabolism of
      prostaglandins. The inducible isoform of Cox-2 has been implicated in
      inflammation and its specific inhibition can be used to treat noninfectious
      inflammatory diseases, such as rheumatoid arthritis. Borrelia burgdorferi, the
      agent of Lyme disease, can induce joint inflammation. Here we show that B.
      burgdorferi induced the upregulation of cox-2 gene expression in murine joints at
      the onset of arthritis in infected mice. The level of mRNA expression correlated
      with the degree of inflammation. The specific inhibition of Cox-2 diminished the
      degree of joint inflammation, without affecting B. burgdorferi-specific antibody
      or cytokine responses. Cox-2 activity is therefore associated with the genesis of
      infectious arthritis caused by B. burgdorferi.

PMID- 12423771
TI  - Immunologic and genetic characterization of lipooligosaccharide variants in a
      Neisseria meningitidis serogroup C strain.
AB  - Neisseria meningitidis shows great variation in expression of structurally
      different lipooligosaccharides (LOS) on its cell surface. To better understand
      the LOS diversity that may occur within an individual strain, a group C wild-type
      strain, BB305-Tr4, and two stable isogenic LOS variants, Tr5 and Tr7, were
      selected for this study. SDS-PAGE analysis showed a size reduction of Tr5 and Tr7
      LOS compared to that of Tr4. Immunoblotting showed that parental Tr4 LOS reacted
      with L1, L2 and L3,7 antibodies, variant Tr5 LOS with L1 and L6 antibodies, while
      Tr7 LOS was non-typeable. Genetic analysis showed that the gene organization at
      the lgt-1 locus in the three strains was lgtZ,C,A,B,H4 in Tr4, lgtZ,C,A,H4 in Tr5
      and lgtZ,C,A,H9 in Tr7. The genetic differences in the three strains were
      consistent with their phenotypic changes. Sequence comparison revealed two
      independent recombination events. The first was the recombination of repeated DNA
      fragments in the flanking regions to delete lgtB in Tr5. The second was the
      recombination of a fragment of two genes, lgtB and lgtH4, to create an inactive
      lgtH9 allele with a mosaic structure in Tr7. These findings suggest that besides
      phase variation, homologous recombination can contribute to the genetic diversity
      of the lgt locus and to the generation of LOS variation in N. meningitidis.

PMID- 12423772
TI  - Studies towards the potential of poliovirus as a vector for the expression of HPV
      16 virus-like-particles.
AB  - Development of human cervical carcinomas is associated with infection by certain
      human papillomavirus (HPV) types. Thus, protection against HPV infection through
      vaccination may prevent development of cervical cancer. The purpose of this study
      was to investigate the possibility of using a poliovirus recombinant vector to
      induce immunity against HPV. A poliovirus recombinant was constructed which
      contained the complete coding sequence of the HPV 16 major capsid protein L1,
      between the P1 and P2 region of the poliovirus polyprotein. A replication
      competent virus was obtained after transfection of the recombinant RNA into
      tissue culture cells. Electron microscopically examination of cells infected with
      the poliovirus-HPV L1 recombinant indicated that HPV 16 L1 self-assembles into
      virus-like particles. To investigate the immunological response in vivo,
      susceptible transgenic mice carrying the poliovirus receptor were infected with
      the recombinant poliovirus. In all mice a modest but consistent immune response
      against HPV 16 was observed. Based on these results, the potential for
      picornavirus-derived vectors in vaccine development against HPV infection is
      discussed.

PMID- 12423773
TI  - High prevalence of Mycoplasma infections among European chronic fatigue syndrome
      patients. Examination of four Mycoplasma species in blood of chronic fatigue
      syndrome patients.
AB  - Prevalence of Mycoplasma species infections in chronic fatigue syndrome (CFS) has
      been extensively reported in the scientific literature. However, all previous
      reports highlighted the presence of Mycoplasmas in American patients. In this
      prospective study, the presence of Mycoplasma fermentans, M. penetrans, M.
      pneumoniae and M. hominis in the blood of 261 European CFS patients and 36
      healthy volunteers was examined using forensic polymerase chain reaction. One
      hundred and seventy-nine (68.6%) patients were infected by at least one species
      of Mycoplasma, compared to two out of 36 (5.6%) in the control sample (P<0.001).
      Among Mycoplasma-infected patients, M. hominis was the most frequently observed
      infection (n=96; 36.8% of the overall sample), followed by M. pneumoniae and M.
      fermentans infections (equal frequencies; n=67; 25.7%). M. penetrans infections
      were not found. Multiple mycoplasmal infections were detected in 45 patients
      (17.2%). Compared to American CFS patients (M. pneumoniae>M. hominis>M.
      penetrans), a slightly different pattern of mycoplasmal infections was found in
      European CFS patients (M. hominis>M. pneumoniae, M. fermentansz.Gt;M. penetrans).

PMID- 12423774
TI  - Interaction of vitronectin with Haemophilus influenzae.
AB  - Eight strains of Haemophilus influenzae were tested for binding to human
      vitronectin. All strains adhered to vitronectin-coated glass slides but no
      binding was detected using soluble vitronectin, suggesting that surface
      association of vitronectin is a prerequisite. Vitronectin binding was not likely
      to be mediated by fimbriae as non-fimbriated and fimbriated isogenic strains
      adhered equally. Adhesion could be blocked by heparin, which is also known to
      block vitronectin binding to Staphylococcus aureus. However, no blocking was
      achieved with sialic acid-rich glycoproteins such as fetuin and mucin contrasting
      with Helicobacter pylori for which sialic acid seems to play an important role.
      With Streptococcus pneumoniae binding was detected both with soluble and surface
      associated vitronectin and could not be blocked by heparin. Our results suggest
      that H. influenzae, Streptococcus pneumoniae and Helicobacter pylori all use
      distinct modes to interact with vitronectin.

PMID- 12423775
TI  - The role of licA phase variation in the pathogenesis of invasive disease by
      Haemophilus influenzae type b.
AB  - LicA encodes the enzyme phosphorylcholine kinase which catalyses the
      incorporation of phosphorylcholine (ChoP) into H. influenzae LPS. Expression of
      this gene is subject to phase variation, resulting in the spontaneous loss, or
      gain of phosphorylcholine (ChoP)-decorated LPS structures. To investigate the
      role of this phenomenon in the pathogenesis of invasive disease an H. influenzae
      mutant was constructed which lacked the ability to phase vary licA. This was
      achieved by introducing an in-frame deletion of the 5'-CAAT-3' repeats into licA
      using polymerase chain reaction. The resultant mutant, licADelta5'-CAAT-3', was
      unable to switch off expression of licA and constitutively expressed ChoP
      decorated LPS structures, as judged by colony immunoblotting with Mabs 12D9 and
      HAS. This resulted in increased synthesis of high molecular mass LPS structures
      and the absence of non-ChoP-decorated LPS species as determined by T-SDS-PAGE
      analysis. Inability to switch off the expression of licA reduced the virulence of
      H. influenzae in an infant rat model of invasive disease and resulted in
      increased sensitivity to the bactericidal activity of serum in the presence of
      CRP. The ability to switch off the expression of licA through phase variation is
      therefore concluded to enhance the systemic survival of H. influenzae.

PMID- 12423776
TI  - A possible pitfall in the identification of Burkholderia mallei using molecular
      identification systems based on the sequence of the flagellin fliC gene.
AB  - Amotile Burkholderia mallei and motile Burkholderia pseudomallei display a high
      similarity with regard to phenotype and clinical syndromes, glanders and
      melioidosis. The aim of this study was to establish a fast and reliable molecular
      method for identification and differentiation. Despite amotility, the gene of the
      filament forming flagellin (fliC) could be completely sequenced in two B. mallei
      strains. Only one mutation was identified discriminating between B. mallei and B.
      pseudomallei. A polymerase chain reaction-restriction fragment length
      polymorphism assay was designed making use of the absence of an AvaII recognition
      site in B. mallei. All seven B. mallei, 12 out of 15 B. pseudomallei and 36
      closely related apathogenic Burkholderia thailandensis strains were identified
      correctly. However, in three B. pseudomallei strains a point mutation at gene
      position 798 (G to C) disrupted the AvaII site. Therefore, molecular systems
      based on the fliC sequence can be used for a reliable proof of strains of the
      three species but not for the differentiation of B. mallei and B. pseudomallei
      isolates.

PMID- 12423777
TI  - Neutralising human recombinant antibodies to human cytomegalovirus glycoproteins
      gB and gH.
AB  - A phage antibody display library of single chain fragment variable (scFv) was
      applied to develop anti-HCMV glycoprotein B (gB) and glycoprotein H (gH)
      neutralising libraries. To enrich for specific scFvs, the phage antibody was
      panned against cytomegalovirus epitopes derived from the N-terminal part of gB,
      the C-terminal part of gB and the N-terminal part of gH (NETIYNTTLKYGDV, VTSGSTKD
      and AASEALDPHAFHLLLNTYGR). A number of clones were differentiated by Bst N1
      fingerprinting. After isolation of specific clones against each peptide, the
      neutralising effect of each clone was assessed by plaque reduction assay. This
      resulted in the isolation of eight neutralising scFv antibodies with 51-63%
      neutralising effects. Sequence analysis of three neutralising clones revealed the
      amino acids specificity changes in heavy and light chains of antibody molecules.

PMID- 12423779
TI  - Bacteriocin diversity: ecological and evolutionary perspectives.
AB  - The bacteriocin family is the most abundant and diverse group of bacterial
      defense systems. Bacteriocins range from the well-studied narrow spectrum, high
      molecular weight colicins produced by Escherichia coli and the short polypeptide
      lantibiotics of lactic acid bacteria to the relatively unknown halocins produced
      almost universally by the haolobacteria. The abundance and diversity of this
      potent arsenal of weapons is clear. Less clear is their evolutionary origins and
      the role they play in mediating microbial interactions. The goal of this review
      is to explore what we know about the evolution and ecology of the best
      characterized family of bacteriocins, the colicins. We summarize current
      knowledge of how such extraordinary protein diversity arose and is maintained in
      microbial populations and what role these toxins play in mediating microbial
      population-level and community-level dynamics.

PMID- 12423780
TI  - Ton-dependent colicins and microcins: modular design and evolution.
AB  - Ton-dependent colicins and microcins are actively taken up into sensitive cells
      at the expense of energy which is provided by the proton motive force of the
      cytoplasmic membrane. The Ton system consisting of the proteins TonB, ExbB and
      ExbD is required for colicin and microcin import. Colicins as well as the outer
      membrane transport proteins contain proximal to the N-terminus a short sequence,
      called TonB box, which interacts with TonB and in which point mutants impair
      uptake. No TonB box is found in microcins. Colicins are composed of functional
      modules which during evolution have been interchanged resulting in new colicins.
      The modules define sites of interaction with the outer membrane transport genes,
      TonB, the immunity proteins, and the activity regions. Six TonB-dependent
      microcins with different primary structures are processed and exported by highly
      homologous proteins. Three of these microcins are modified in an unknown way and
      they have in common specificity for catecholate siderophore receptors.

PMID- 12423781
TI  - Killing of E coli cells by E group nuclease colicins.
AB  - The process by which the endonuclease domain of colicin E9 is translocated across
      the outer membrane, the periplasmic space and the cytoplasmic membrane to reach
      the cytoplasm of E. coli cells, resulting in DNA degradation and cell death, is a
      unique event in prokaryotic biology. Although considerable information is known
      about the role of the BtuB outer membrane receptor, as well as the mostly
      periplasmic Tol proteins that are essential for the translocation process, the
      precise nature of the interactions between colicin E9 and these proteins remains
      to be elucidated. In this review, we consider our current understanding of the
      key events in this process, concentrating on recent findings concerning receptor
      binding, translocation and the mechanism of cytotoxicity.

PMID- 12423782
TI  - The Tol proteins of Escherichia coli and their involvement in the translocation
      of group A colicins.
AB  - The Tol proteins are involved in outer membrane stability of Gram-negative
      bacteria. The TolQRA proteins form a complex in the inner membrane while TolB and
      Pal interact near the outer membrane. These two complexes are transiently
      connected by an energy-dependent interaction between Pal and TolA. The Tol
      proteins have been parasitized by group A colicins for their translocation
      through the cell envelope. Recent advances in the structure and energetics of the
      Tol system, as well as the interactions between the N-terminal translocation
      domain of colicins and the Tol proteins are presented.

PMID- 12423783
TI  - Mechanisms of colicin binding and transport through outer membrane porins.
AB  - To kill Escherichia coli, toxic proteins, called colicins, pass through the
      permeability barrier created by the outer membrane (OM) of the bacterial cell
      envelope. We consider a variety of different colicins, including A, B, D, E1, E3,
      Ia, M and N, that penetrate through the porins OmpF, FepA, BtuB, Cir and FhuA, to
      subsequently interact with a few targets in the periplasm, including TolA, TolB,
      TolC and TonB. We review the mechanisms, demonstrated and postulated, by which
      such toxins enter bacterial cells, from the initial binding stage on the cell
      surface to the internalization reaction through the OM bilayer. Our discussions
      endeavor to answer two main questions: what is the origin of colicin-binding
      affinity and specificity, and after adsorption to OM porins, do colicin
      polypeptides translocate through porin channels, or enter by another, currently
      unknown pathway?

PMID- 12423785
TI  - Importation of nuclease colicins into E coli cells: endoproteolytic cleavage and
      its prevention by the immunity protein.
AB  - A major group of colicins comprises molecules that possess nuclease activity and
      kill sensitive cells by cleaving RNA or DNA. Recent data open the possibility
      that the tRNase colicin D, the rRNase colicin E3 and the DNase colicin E7 undergo
      proteolytic processing, such that only the C-terminal domain of the molecule,
      carrying the nuclease activity, enters the cytoplasm. The proteases responsible
      for the proteolytic processing remain unidentified. In the case of colicin D, the
      characterization of a colicin D-resistant mutant shows that the inner membrane
      protease LepB is involved in colicin D toxicity, but is not solely responsible
      for the cleavage of colicin D. The lepB mutant resistant to colicin D remains
      sensitive to other colicins tested (B, E1, E3 and E2), and the mutant protease
      retains activity towards its normal substrates. The cleavage of colicin D
      observed in vitro releases a C-terminal fragment retaining tRNase activity, and
      occurs in a region of the amino acid sequence that is conserved in other nuclease
      colicins, suggesting that they may also require a processing step for their
      cytotoxicity. The immunity proteins of both colicins D and E3 appear to have a
      dual role, protecting the colicin molecule against proteolytic cleavage and
      inhibiting the nuclease activity of the colicin. The possibility that processing
      is an essential step common to cell killing by all nuclease colicins, and that
      the immunity protein must be removed from the colicin prior to processing, is
      discussed.

PMID- 12423784
TI  - Analysis of the Escherichia coli Tol-Pal and TonB systems by periplasmic
      production of Tol, TonB, colicin, or phage capsid soluble domains.
AB  - The aim of this review is to describe an in vivo assay of the interactions taking
      place in the Tol-Pal or TonB-ExbB-ExbD envelope complexes in the periplasm of
      Escherichia coli and between them and colicins or g3p protein of filamentous
      bacteriophages. Domains of colicins or periplasmic soluble domains of Tol or TonB
      proteins can be artificially addressed to the periplasm of bacteria by fusing
      them to a signal sequence from an exported protein. These domains interact
      specifically in the periplasm with the Tol or TonB complexes and disturb their
      function, which can be directly detected by the appearance of specific tol or
      tonB phenotypes. This technique can be used to detect new interactions, to
      characterize them biochemically and to map them or to induce tol or tonB
      phenotypes to study the functions of these two complexes.

PMID- 12423786
TI  - The modes of action of colicins E5 and D, and related cytotoxic tRNases.
AB  - Colicins E5 and D cleave the anticodon loops of distinct tRNAs of Escherichia
      coli both in vivo and in vitro, which accounts for their bactericidal actions
      through depletion of tRNAs and prevention of protein synthesis. The targets of
      colicin E5 are five tRNA species for four amino acids, tyrosine, histidine,
      asparagine and aspartic acid, and those of colicin D are four isoaccepting tRNAs
      for arginine. These two colicins represent a new class, the "tRNase-type", of the
      nuclease-type colicins, which previously comprised the DNase-type and ribotoxin
      type (or rRNase-type). On the other hand, a certain clinical E. coli strain
      produces a potentially suicidal "anticodon-nuclease", PrrC, in response to phage
      T4 infection, which specifically cleaves its own lysine tRNA. For these three
      tRNases, i.e. colicins E5 and D, and PrrC, the substrates and reaction products,
      as well as their physiological consequences, are very similar to each other, but
      so many molecular features are different that these three proteins are assumed to
      have acquired similar functions through evolutionary convergence from different
      origins.

PMID- 12423787
TI  - Structural aspects of the inhibition of DNase and rRNase colicins by their
      immunity proteins.
AB  - Nuclease E colicins that exert their cytotoxic activity through either non
      specific DNase or specific rRNase action are inhibited by immunity proteins in a
      high affinity interaction that gives complete protection to the producing host
      cell from the deleterious effects of the toxin. Previous X-ray crystallographic
      analysis of these systems has revealed that in both cases, the immunity protein
      inhibitor forms its highly stable complex with the enzyme by binding as an
      exosite inhibitor-adjacent to, but not obscuring, the enzyme active site. The
      structures of the free E9 DNase domain and its complex with an ssDNA substrate
      now show that inhibition is achieved without deformation of the enzyme and by
      occlusion of a limited number of residues of the enzyme critical in recognition
      and binding of the substrate that are 3' to the cleaved scissile phosphodiester.
      No sequence or structural similarity is evident between the two classes of
      cytotoxic domain, and the heterodimer interfaces are also dissimilar. Thus,
      whilst these structures suggest the basis for specificity in each case, they give
      few indications as to the basis for the remarkably strong binding that is
      observed. Structural analyses of complexes bearing single site mutations in the
      immunity protein at the heterodimer interface reveal further differences. For the
      DNases, a largely plastic interface is suggested, where optimal binding may be
      achieved in part by rigid body adjustment in the relative positions of inhibitor
      and enzyme. For the rRNases, a large solvent-filled cavity is found at the
      immunity-enzyme interface, suggesting that other considerations, such as that
      arising from the entropy contribution from bound water molecules, may have
      greater significance in the determination of rRNase complex affinity than for the
      DNases.

PMID- 12423788
TI  - On the interaction of colicin E3 with the ribosome.
AB  - Colicin E3 is a protein that kills Escherichia coli cells by a process that
      involves binding to a surface receptor, entering the cell and inactivating its
      protein biosynthetic machinery. Colicin E3 kills cells by a catalytic mechanism
      of a specific ribonucleolytic cleavage in 16S rRNA at the ribosomal decoding A
      site between A1493 and G1494 (E. coli numbering system). The breaking of this
      single phosphodiester bond results in a complete cessation of protein
      biosynthesis and cell death. The inactive E517Q mutant of the catalytic domain of
      colicin E3 binds to 30S ribosomal subunits of Thermus thermophilus, as
      demonstrated by an immunoblotting assay. A model structure of the complex of the
      ribosomal subunit 30S and colicin E3, obtained via docking, explains the role of
      the catalytic residues, suggests a catalytic mechanism and provides insight into
      the specificity of the reaction. Furthermore, the model structure suggests that
      the inhibitory action of bound immunity is due to charge repulsion of this acidic
      protein by the negatively charged rRNA backbone

PMID- 12423789
TI  - The pore-forming domain of colicin A fused to a signal peptide: a tool for
      studying pore-formation and inhibition.
AB  - Pore-forming colicins are plasmid-encoded bacteriocins that kill Escherichia coli
      and closely related bacteria. They bind to receptors in the outer membrane and
      are translocated across the cell envelope to the inner membrane where they form
      voltage-dependent ion-channels. Colicins are composed of three domains, with the
      C-terminal domain responsible for pore-formation. Isolated C-terminal pore
      forming domains produced in the cytoplasm of E. coli are inactive due to the
      polarity of the transmembrane electrochemical potential, which is the opposite of
      that required. However, the pore-forming domain of colicin A (pfColA) fused to a
      prokaryotic signal peptide (sp-pfColA) is transported across and inserts into the
      inner membrane of E. coli from the periplasmic side, forming a functional
      channel. Sp-pfColA is specifically inhibited by the colicin A immunity protein
      (Cai). This construct has been used to investigate colicin A channel formation in
      vivo and to characterise the interaction of pfColA with Cai within the inner
      membrane. These points will be developed further in this review.

PMID- 12423790
TI  - Insertion intermediates of pore-forming colicins in membrane two-dimensional
      space.
AB  - The formation of integral membrane voltage-gated ion channels by the initially
      soluble C-terminal channel polypeptide (CP) of the pore-forming colicins is a
      fruitful area for studies on membrane protein import. The dependence of CP import
      on specific membrane parameters can be better understood using liposomes and
      planar membranes of defined lipid composition. The membrane surface and
      interfacial layer provide special conditions for the transition of a pore-forming
      colicin from the soluble to the integral membrane state. The colicin E1 CP is
      arranged in the membrane interfacial layer as a conformationally mobile helical
      array that is extended far more in the two dimensions parallel to the membrane
      surface than in the third dimension perpendicular to it. The alpha-helical
      content of CP(E1) increases by approximately 30% upon binding to the membrane.
      The sequence of kinetically distinguishable events in the CP(E1)-membrane
      interaction is binding, unfolding to a subtended area of 4200 A(2), helix
      extension, and insertion, the last three events overlapping in their time course
      ( approximately 10 s(-1)). The extension into two dimensions and the interaction
      with the membrane surface may explain the reversible denaturation and refolding
      of secondary structure that occurs after boiling of the CP-membrane complex.
      Although DSC showed the presence of helix-helix interactions in the membrane
      bound state, the change in secondary structure and the extended surface area
      argue against a molten-globule intermediate in the CP-membrane interaction.
      However, the surface-bound state is mobile, as surface conformational mobility is
      a necessary prerequisite for insertion of CP trans-membrane helices into the
      bilayer. The requirement for this surface protein mobility, described by "thermal
      melting" FRET experiments, may provide the explanation for the precipitous
      decrease in the voltage-gated CP channel formation at high values of surface
      potential of planar bilayer membranes. Thus, the membrane interfacial layer, with
      the CP backbone situated near the acyl chain carbonyls, provides a favorable
      environment for the structure changes necessary for the transition from the
      soluble to the membrane-inserted state.

PMID- 12423791
TI  - High level expression of His-tagged colicin pore-forming domains and reflections
      on the sites for pore formation in the inner membrane.
AB  - There exists ample evidence for the assumption that pore-forming colicins cannot
      exert their toxicity within the producing cell and that they must gain access to
      the outer face of the cytoplasmic membrane to achieve this. We wished to
      construct pET-vectors to produce pore-forming domains of colicin A and N with N
      terminal hexa-histidine tags under the control of a T7 promoter. This was only
      possible when the correct immunity protein was also present. Hence it appears
      that this system exhibits the peculiarity that there is a toxicity associated
      with the over produced pore-forming domain. However, when the ratio of colicin to
      immunity protein is compared it is still clear that direct insertion into the
      cytoplasmic membrane does not occur and that membrane translocation of the
      colicin at limited sites may be occurring. This article reviews previous
      literature on the subject in terms of a model for limited sites of colicin
      action.

PMID- 12423792
TI  - Colicin A multimerizes when unfolded.
AB  - A purified preparation of colicin A produced by Escherichia coli cells contained
      various forms of colicin A. Unfolding of the purified colicin A with urea
      provoked multimerization. Dimers, tetramers and hexamers of colicin A were
      identified.

PMID- 12423793
TI  - Use of colicin-based genetic tools for studying bacterial protein transport.
AB  - Transport of proteins across the envelope of Gram-negative bacteria is a very
      challenging domain of investigation, which involves membrane-embedded
      proteinaceous complexes at which specific targeting occurs. These transporters
      (translocon or secreton) have been studied both with genetics and biochemistry.
      In this review we report recent developments that should help to identify novel
      interactions that exist within these complexes, and to decipher the signals that
      specifically direct transported proteins to the cognate system. These
      developments are exclusively based on the re-routing of colicins to these
      molecular machineries. The re-routing induces a lethal situation in the case of
      efficient or inefficient transport, depending on the system, thus creating a
      genetic tool for selection of mutations that correct or generate a transport
      default.

PMID- 12423794
TI  - The pyocins of Pseudomonas aeruginosa.
AB  - Pyocins are produced by more than 90% of Pseudomonas aeruginosa strains and each
      strain may synthesise several pyocins. The pyocin genes are located on the P.
      aeruginosa chromosome and their activities are inducible by mutagenic agents such
      as mitomycin C. Three types of pyocins are described. (i). R-type pyocins
      resemble non-flexible and contractile tails of bacteriophages. They provoke a
      depolarisation of the cytoplasmic membrane in relation with pore formation. (ii).
      F-type pyocins also resemble phage tails, but with a flexible and non-contractile
      rod-like structure. (iii). S-type pyocins are colicin-like, protease-sensitive
      proteins. They are constituted of two components. The large component carries the
      killing activity (DNase activity for pyocins S1, S2, S3, AP41; tRNase for pyocin
      S4; channel-forming activity for pyocin S5). It interacts with the small
      component (immunity protein). The synthesis of pyocins starts when a mutagen
      increases the expression of the recA gene and activates the RecA protein, which
      cleaves the repressor PrtR, liberating the expression of the protein activator
      gene prtN. R and F-pyocins are derived from an ancestral gene, with similarities
      to the P2 phage family and the lambda phage family, respectively. The killing
      domains of S1, S2, AP41 pyocins show a close evolutionary relationship with E2
      group colicins, S4 pyocin with colicin E5, and S5 pyocin with colicins Ia, and
      Ib.

PMID- 12423795
TI  - Focus on modified microcins: structural features and mechanisms of action.
AB  - Microcins are gene-encoded antimicrobial (poly)peptides secreted by
      Enterobacteriaceae. Produced under conditions of nutrient depletion, they are
      active against phylogenetically related microbial strains. Therefore, they are
      considered to play an important role in the microbial competitions within the
      intestinal flora. Among the limited sample of nine microcins hitherto described,
      a wide variety of structures and modes of action could be identified. The
      knowledge on microcins is very uneven, some being extensively studied, and others
      remaining uncharacterized. In this article, we have focused on a subgroup of
      highly modified microcins that show very original structures. We present an
      updated overview on the structures and mechanisms of action of microcins B17, C7
      and J25, and on the associated effector proteins, also encoded by the microcin
      genetic system, which include specific modification enzymes, export proteins, and
      immunity factors.

PMID- 12423796
TI  - The regulation of microcin B, C and J operons.
AB  - Microcins are ribosomally encoded small peptide antibiotics produced by Gram(-)
      enterobacteria. Microcin production-biosynthesis, maturation and secretion to the
      medium-is encoded by gene clusters organized in operons. Production of the best
      known plasmid-encoded microcins (MccB, MccC and MccJ) switches on when cells
      reach the stationary growth phase. This production is doubly regulated at
      transcriptional level by (a). the growth phase: microcin operons silent/repressed
      during exponential growth are induced/derepressed when cells sense nutrient
      starvation and stop exponential growth, and (b). global bacterial regulators
      acting as inducers or repressors of operon expression. The role played by these
      regulators (CRP, EmrR, IHF, H-NS, LRP, OmpR, Sigma-38 and SpoT) in the expression
      of specific microcin operons is reviewed.

PMID- 12423797
TI  - New developments in non-post translationally modified microcins.
AB  - Microcins are a family of low molecular weight antibiotic peptides produced by
      Enterobacteriaceae strains and active against related bacteria. According to some
      features we propose to classify these antibiotic substances into two distinct
      groups. The class I microcins contain Mcc B17, C7, J25 and D93 that are small
      molecules (molecular mass inferior to 5 kDa), largely post-translationally
      modified and with specific intracellular targets. The class II microcins, MccV,
      E492, H47, L and 24, share several common properties with class IIa Gram-positive
      bacteriocins: molecular mass ranging from 7 to 10 kDa, absence of modified amino
      acids, double-glycine type leader peptides, secretion mediated by an ABC
      transporter and antibacterial activity due to interaction with bacterial
      membrane. This review discusses common features of the class II microcins and
      provides new insights into these peptides.

PMID- 12423798
TI  - The expression of genes involved in microcin maturation regulates the production
      of active microcin E492.
AB  - The production of active microcin E492, a channel-forming bacteriocin, was
      studied in exponential and stationary phase. The structural gene for this
      bacteriocin (mceA) is transcribed in exponential as well as in stationary phase,
      but the active form is produced only during the exponential phase of growth. An
      inactive form of microcin E492 was purified from the stationary phase. The
      production of the inactive form correlated with the lack of transcription in the
      stationary phase of two genes (mceIJ) involved in microcin E492 maturation,
      consequently behaving as the inactive form purified from mutants in these genes.
      The inactive form of microcin purified from the stationary phase as well as the
      inactive form purified from mutants in the maturation genes (mceC, I, J) were
      unable to compete with the active form when tested using a viability test on
      sensitive cells. This result strongly suggests that the inactive form of microcin
      caused by the lack of expression of the maturation genes is impaired at the level
      of receptor recognition.

PMID- 12423799
TI  - Mode of action of modified and unmodified bacteriocins from Gram-positive
      bacteria.
AB  - The antibiotic activity of bacteriocins from Gram-positive bacteria, whether they
      are modified (class I bacteriocins, lantibiotics) or unmodified (class II), is
      based on interaction with the bacterial membrane. However, recent work has
      demonstrated that for many bacteriocins, generalised membrane disruption models
      as elaborated for amphiphilic peptides (e.g. tyriodal pore or carpet model)
      cannot adequately describe the bactericidal action. Rather, specific targets seem
      to be involved in pore formation and other activities. For the nisin and
      epidermin family of lantibiotics, the membrane-bound cell wall precursor lipid II
      has recently been identified as target. The duramycin family of lantibiotics
      binds specifically to phosphoethanolamine which results in inhibition of
      phospholipase A2 and various other cellular functions. Most of the class II
      bacteriocins dissipate the proton motive force (PMF) of the target cell, via pore
      formation. The subclass IIa bacteriocin activity likely depends on a mannose
      permease of the phosphotransferase system (PTS) as specific target. The subclass
      IIb bacteriocins (two-component) also induce dissipation of the PMF by forming
      cation- or anion-specific pores; specific targets have not yet been identified.
      Finally, the subclass IIc comprises miscellaneous peptides with various modes of
      action such as membrane permeabilization, specific inhibition of septum formation
      and pheromone activity.

PMID- 12423800
TI  - LasX, a transcriptional regulator of the lactocin S biosynthetic genes in
      Lactobacillus sakei L45, acts both as an activator and a repressor.
AB  - The 11 kb las locus, present on the 50 kb plasmid pCIM1, specifies the production
      of the lantibiotic lactocin S in Lactobacillus sakei L45. The gene cluster is
      organized into two oppositely orientated operons, lasAMNTUVPJW (lasA-W) and
      lasXY, the former of which contains the biosynthetic, immunity and transport
      genes. We have previously shown that inactivation of lasX abolishes lactocin S
      production and causes a drastic reduction in lasA-specific transcripts (encoding
      pre-lactocin S). The aim of this study was to determine whether or not the
      product of lasX, which is significantly similar to Rgg-like regulators, was
      directly involved in transcriptional regulation of the lactocin S biosynthetic
      genes. The divergently orientated and overlapping promoters, P(lasA)(-W) and
      P(lasXY), were transcriptionally fused to the Escherichia coli gusA gene, and the
      activity of the fusions was assayed in the presence and absence of lasX, which
      was expressed on a separate plasmid. A significant stimulation of expression (5-6
      fold) of the P(lasA-W)-gusA fusion was observed in the presence of lasX, whereas
      expression of the P(lasXY)-gusA construct was reduced 1.5-2-fold. Our results
      strongly suggest that LasX is a bifunctional regulatory protein, acting both as
      an activator of lasA-W transcription and as a repressor of lasXY transcription.
      While a transcription stimulation activity has been described for several of the
      Rgg-like proteins, the present study is the first to report an autorepressor
      function for a member of this protein group.

PMID- 12423801
TI  - Heterologous expression of bacteriocins using the mesentericin Y105 dedicated
      transport system by Leuconostoc mesenteroides.
AB  - Mesentericin Y105 (MesY105) is a class IIa anti-Listeria bacteriocin, produced by
      Leuconostoc (Ln.) mesenteroides Y105 and with potential food grade application.
      This bacterium produces a second bacteriocin, mesentericin B105 (MesB105), that
      does not belong to the same class. To study secretion of bacteriocins by the use
      of the MesY105 dedicated transport system (DTS), plasmids were constructed for
      heterologous expression by Ln. mesenteroides. pFBYC04 (Microbiology 144 (1998)
      2845) harbours two divergent operons required for MesY105 secretion, i.e. the
      mesYI operon, encoding pre-MesY105 and immunity, respectively, and the mesCDE
      operon for secretion. A pFBYC04 derivative, pDMJF01 was constructed by divergent
      PCR to remove the mesY gene. Ln. mesenteroides DSM20484(pDMJF01) was unable to
      produce MesY105. The mesYI operon and mesB, mesH and mesF genes, encoding pre
      MesB105, MesB105 immunity and a putative protein with unknown function,
      respectively, were cloned independently into a compatible pDMJF01 plasmid to
      produce, respectively, pDMJF:YI and pDMJF:BHF. DSM20484 transformed independently
      with these plasmids was unable to secrete any bacteriocin. MesY105 and MesB105
      secretion was observed for DSM20484(pDMJF01) harbouring both pDMJF:YI and
      pDMJF:BHF. This indicates that the MesY105 DTS permits the transport of MesB105.
      MesY105 secretion machinery was used to secrete pediocin PA-1 (PedPA-1) by
      DSM20484 by an in-frame gene fusion strategy where the gene portions
      corresponding to the MesY105 leader peptide and the mature PedPA-1 were ligated.
      Thus, MesY105 secretion machinery appears to be a useful tool for secretion of
      class II bacteriocins by Leuconostoc.

PMID- 12423802
TI  - Two-peptide bacteriocins produced by lactic acid bacteria.
AB  - Bacteriocins from lactic acid bacteria are ribosomally produced peptides (usually
      30-60 amino acids) that display potent antimicrobial activity against certain
      other Gram-positive organisms. They function by disruption of the membrane of
      their targets, mediated in at least some cases by interaction of the peptide with
      a chiral receptor molecule (e.g., lipid II or sugar PTS proteins). Some
      bacteriocins are unmodified (except for disulfide bridges), whereas others (i.e.
      lantibiotics) possess extensive post-translational modifications which include
      multiple monosulfide (lanthionine) bridges and dehydro amino acids as well as
      possible keto amide residues at the N-terminus. Most known bacteriocins are
      biologically active as single peptides. However, there is a growing class of two
      peptide systems, both unmodified and lantibiotic, which are fully active only
      when both partners are present (usually 1:1). In some cases, neither peptide has
      activity by itself, whereas in others, the activity of one is enhanced by the
      other. This review discusses the classification, structure, production,
      regulation, biological activity, and potential applications of such two-peptide
      bacteriocins.

PMID- 12423803
TI  - Potential of bacteriocin-producing lactic acid bacteria for improvements in food
      safety and quality.
AB  - Lactic acid bacteria (LAB) have been used for centuries in the fermentation of a
      variety of dairy products. The preservative ability of LAB in foods is attributed
      to the production of anti-microbial metabolites including organic acids and
      bacteriocins. Bacteriocins generally exert their anti-microbial action by
      interfering with the cell wall or the membrane of target organisms, either by
      inhibiting cell wall biosynthesis or causing pore formation, subsequently
      resulting in death. The incorporation of bacteriocins as a biopreservative
      ingredient into model food systems has been studied extensively and has been
      shown to be effective in the control of pathogenic and spoilage microorganisms.
      However, a more practical and economic option of incorporating bacteriocins into
      foods can be the direct addition of bacteriocin-producing cultures into food.
      This paper presents an overview of the potential for using bacteriocin-producing
      LAB in foods for the improvement of the safety and quality of the final product.
      It describes the different genera of LAB with potential as biopreservatives, and
      presents an up-to-date classification system for the bacteriocins they produce.
      While the problems associated with the use of some bacteriocin-producing cultures
      in certain foods are elucidated, so also are the situations in which
      incorporation of the bacteriocin-producer into model food systems have been shown
      to be very effective.

PMID- 12423804
TI  - Pelvic umbrella pack for refractory obstetric hemorrhage secondary to posterior
      uterine rupture.
AB  - BACKGROUND: Pelvic hemorrhage continues to be a serious complication of pregnancy
      and can lead to significant maternal morbidity. The pelvic umbrella pack is a
      useful alternative to control pelvic bleeding when standard measures fail. CASE:
      A patient with a previous low transverse cesarean delivery presented in active
      labor at term. After an uneventful vaginal delivery, defects in the posterior
      vaginal wall and lower uterine segment were identified. A hysterectomy with
      repair of the vaginal laceration was performed, but diffuse bleeding persisted.
      After routine surgical techniques failed to achieve adequate hemostasis, a pelvic
      umbrella pack was successfully used to tamponade pelvic bleeding. CONCLUSION: In
      the event of continued hemorrhage after hysterectomy, bleeding that is
      uncontrolled by surgical intervention may be controlled with a pelvic umbrella
      pack.

PMID- 12423805
TI  - Shigellosis complicating preterm premature rupture of membranes resulting in
      congenital infection and preterm delivery.
AB  - BACKGROUND: The association of chorioamnionitis with preterm birth is well
      established. Intra-amniotic infection complicates 13-60% of preterm premature
      rupture of membranes (PROM) with enteric gram-negative pathogens accounting for
      20-40% of recoverable organisms. However, the source of enteric pathogens leading
      to premature birth has been poorly characterized. CASE: A 36-year-old multiparous
      woman presented at 2567 weeks with preterm PROM. She reported a 5-day history of
      bloody, mucous diarrhea. A fourth cesarean delivery was performed secondary to
      the onset of labor. Fetal blood, placental membrane, and vaginal pool cultures
      revealed the presence of Shigella sonnei. With appropriate antibiotic therapy,
      the patient was discharged home on postoperative day 5. Neonatal stool cultures
      revealed evidence of in utero fetal transmission. CONCLUSION: It is prudent to
      treat pregnant patients with clinical symptoms suggestive of shigellosis because
      this pathogen can result in preterm PROM and preterm delivery. Neonatal testing
      is indicated if maternal disease is suspected before delivery.

PMID- 12423806
TI  - Dysmenorrhea after bilateral tubal ligation: a case of retrograde menstruation.
AB  - BACKGROUND: Endometriosis, arising de novo, is believed to be uncommon in women
      who have undergone bilateral tubal ligation because the occluded tube prevents
      outflow of blood and menses. CASE: A woman 10-year status-post bilateral tubal
      ligation suffered from dysmenorrhea and menorrhagia that began within 1 year
      after sterilization. At the time of bilateral tubal ligation, no endometriosis
      was observed. A recent magnetic resonance imaging scan showed no pelvic
      abnormalities, and the patient underwent a diagnostic laparoscopy in anticipation
      of finding endometriosis, yet none was found. At laparoscopy performed on day 3
      of her menstrual cycle, the proximal segments of her occluded fallopian tubes
      were dilated with blood. As this was the only abnormality found, we postulated
      that her dysmenorrhea might be related to the dilated proximal tubal stumps. We
      evacuated the bloody fluid and occluded the proximal tube at the cornua with
      Filshie clips. One year after surgery, the patient remains asymptomatic.
      CONCLUSION: This case is unique because bilateral tubal ligation combined with
      retrograde menstrual flow appears to have caused dysmenorrhea. Women who have
      undergone tubal ligation and who have dysmenorrhea may benefit from a diagnostic
      laparoscopy during menstruation to evaluate the possibility of retrograde
      menstruation dilating the proximal tubal stumps.

PMID- 12423807
TI  - Pain in the foot: calcaneal metastasis as the presenting feature of endometrial
      cancer.
AB  - BACKGROUND: Ninety percent of endometrial cancer cases present with abnormal
      bleeding. Bone metastasis as the presenting feature is extremely rare. CASE: A 76
      year-old woman presented with right heel pain. She had no vaginal bleeding or
      other symptoms suggestive of endometrial cancer. After failure of conservative
      therapy, imaging studies demonstrated a calcaneal metastasis. A biopsy showed
      adenocarcinoma. She received local radiation to her foot, with complete
      resolution of symptoms. Subsequent computed tomography scans showed multiple
      pulmonary nodules, pelvic and inguinal lymphadenopathy, and an enlarged uterus.
      Endometrial biopsy confirmed endometrial adenocarcinoma. She received palliative
      therapy and died 11 months after the diagnosis was made on the endometrial
      biopsy. CONCLUSION: This case highlights the rare presentation of endometrial
      cancer with foot pain secondary to calcaneal metastasis. Aggressive treatment of
      bone metastases can provide effective palliation of symptoms.

PMID- 12423808
TI  - Placenta accreta postpartum.
AB  - BACKGROUND: Placenta accreta is the abnormal attachment of the placenta to the
      uterus. It occurs when the decidua basalis is either absent or incomplete. It is
      uncommon and most often presents with a retained placenta and hemorrhage. CASE: A
      29-year-old gravida 1 had an uncomplicated antenatal course and delivery. The
      third stage of labor was complicated by a retained placenta necessitating manual
      removal. Her postpartum course was complicated by a persistent endometritis. The
      diagnosis of placenta accreta was made with the help of sonohysterography.
      CONCLUSION: Sonohysterography is a useful tool in discriminating a solid
      intracavitary mass from a placenta accreta postpartum.

PMID- 12423809
TI  - Gastric rupture associated with pregnancy.
AB  - BACKGROUND: Spontaneous gastric rupture during pregnancy is rare. CASE: A young
      primigravida delivered a 34-week stillborn infant. Shortly after delivery, she
      developed signs of hypovolemic shock. Ultrasound examination showed a large
      amount of free intra-abdominal fluid. At laparotomy, gastric rupture was
      encountered and repaired. Congenital eventration of the left hemidiaphragm was
      also noted. After a complicated postoperative course, the patient recovered and
      has done well. CONCLUSION: Rapid surgical intervention for gastric rupture
      associated with pregnancy is necessary for maternal survival.

PMID- 12423810
TI  - Uterine necrosis after arterial embolization for postpartum hemorrhage.
AB  - BACKGROUND: Selective embolization is an effective and reputedly safe method of
      managing pregnancy-related bleeding. However, we report an ischemic uterine
      necrosis after arterial embolization. CASE: The patient had heavy postpartum
      bleeding treated by embolization of the uterine arteries using polyvinyl alcohol
      particles (diameter 150-250 and 300-600 microm) and gelatin sponge pledgets. Her
      postoperative recovery was complicated by menorrhagia and pelvic pain. Because of
      the persistent menorrhagia and risk of infection, a hysterectomy was performed.
      Histopathology of the hysterectomy specimen revealed massive ischemic myometrial
      necrosis. CONCLUSION: This complication is most likely related to the small size
      of the particles used. In the management of postpartum bleeding by arterial
      embolization, the material of choice is gelatin sponge pledgets, and the use of
      small particles should be avoided.

PMID- 12423811
TI  - Respiratory distress in a pregnant woman with congenital vocal cord paralysis.
AB  - BACKGROUND: Vocal cord paralysis is one of the most common congenital laryngeal
      lesions. Hoarseness and dysphonia are common in unilateral cases. Stridor and
      respiratory distress are seen in bilateral cases. CASE: A 33-year-old
      primigravida with bilateral congenital vocal cord paralysis presented in the
      third trimester with a 2-week history of bronchitis and progressive shortness of
      breath. She developed stridor, her respiratory status deteriorated, and she was
      intubated with difficulty. She went into cardiac arrest, was resuscitated and
      placed on a ventilator, and a tracheotomy was performed. Her condition improved,
      she remained stable until 38 weeks, and was delivered by cesarean. CONCLUSION:
      Congenital vocal cord paralysis may result in life-threatening respiratory
      distress during pregnancy. Tracheotomy placement may be useful in the management
      of these patients.

PMID- 12423812
TI  - Primary breast lymphoma, contralateral breast cancer, and bilateral Brenner
      tumors of the ovary.
AB  - BACKGROUND: Primary lymphoma of the breast is an unusual clinical entity. Its
      presence with invasive breast cancer and bilateral Brenner tumors of the ovary is
      very rare. CASE: We report a 62-year-old woman referred for further evaluation of
      a palpable mass in her breast. She was diagnosed and treated for simultaneous
      primary lymphoma of the right breast, contralateral invasive ductal carcinoma,
      and bilateral Brenner tumors of the ovary. One year after treatment, she is free
      of recurrence or progression. CONCLUSION: Compared with breast carcinoma, primary
      breast lymphoma is a rare disease but should be considered in the differential
      diagnosis of breast masses. The presence of both breast malignancies presents a
      challenge in treatment decisions.

PMID- 12423813
TI  - Pelvic Castleman disease presenting as vaginal occlusion.
AB  - BACKGROUND: Castleman disease is a lymphoreticular disorder, which may be
      clinically silent. However, systemic manifestations can occur, which include
      generalized adenopathy and life-threatening bronchiolitis obliterans. CASE: A
      woman presented with vaginal mucosal lesions recalcitrant to initial treatment
      efforts. Progression of the disease required hospitalization for pulmonary
      involvement. Castleman disease was diagnosed after extensive multidisciplinary
      evaluation and excision of a pelvic mass. The patient's symptoms dramatically
      improved postoperatively. CONCLUSION: Castleman disease should be included in the
      differential diagnosis in patients with paraneoplastic symptoms and a pelvic
      mass.

PMID- 12423814
TI  - Treatment for prolapse of the sigmoid neovagina in Mayer-Rokitansky-Kuster-Hauser
      syndrome.
AB  - BACKGROUND: Colpopoiesis using the sigmoid colon may be used in treatment of
      patients with Mayer-Rokitansky-Kuster-Hauser syndrome. Prolapse of a sigmoid
      neovagina is rare and its treatment is not yet standardized. CASES: Two patients
      developed severe prolapse of a neovagina derived from the sigmoid colon. One
      patient underwent resection of the redundant sigmoid and an abdominal suspension
      procedure; however, the prolapse has recurred. The other patient was treated by
      removal of the entire sigmoid artificial vagina. An alternative neovagina was
      reconstructed with a pudendal thigh flap. She has no signs of recurrent prolapse
      and is satisfied with sexual intercourse. CONCLUSION: Replacement therapy by a
      connected skin graft may be an excellent optional method as a radical treatment
      for prolapse of a sigmoid neovagina.

PMID- 12423815
TI  - Favorable outcome in a pregnancy with complete fetal heart block and severe
      bradycardia.
AB  - BACKGROUND: Pregnancies complicated by congenital heart block usually have a poor
      prognosis when there is severe fetal bradycardia. CASE: We present a pregnancy
      with fetal heart rate of 40 beats per minute. She previously delivered a child
      with third-degree heart block by cesarean at 28 weeks. This pregnancy was
      complicated by a high ribonucleoprotein antibody anti-Ro/SSA titer and fetal
      bradycardia. The patient was treated with steroids and beta-mimetics. The fetus
      continued to grow normally with reassuring biophysical profiles. After fetal lung
      maturity documentation at 34 weeks, she delivered by repeat cesarean a healthy
      2349-g infant who required a permanent pacemaker. CONCLUSION: Reassuring
      antepartum testing and normal growth in pregnant women with anti-Ro/SSA
      antibodies and congenital heart block may allow expectant management until fetal
      maturity.

PMID- 12423816
TI  - Clitoral priapism: a rare condition presenting as a cause of vulvar pain.
AB  - BACKGROUND: Priapism of the clitoris is a rare condition associated with
      prolonged erection of the clitoris causing engorgement, swelling, and pain to the
      clitoris and immediate adjacent area. CASE: A 47-year-old woman presented
      complaining of vulvar and clitoral pain. Self-reported findings of a swollen and
      tender clitoris had been confirmed by physical examination during an episode of
      priapism, otherwise there were no abnormal findings on routine evaluation. The
      history and findings of prolonged clitoral swelling, tenderness, and pain of the
      clitoris and adjacent area were considered consistent with clitoral priapism, and
      discovered to be attributed to the use of trazodone hydrochloride, a heterocyclic
      antidepressant. The patient was initially treated with imipramine hydrochloride;
      however, it was the withdrawal of the medication instigating the condition that
      was the focal point in its management. CONCLUSION: Priapism of the clitoris is a
      condition that may develop during therapy with certain medications, specifically
      those possessing a strong alpha-adrenergic blockade. Conditions altering blood
      flow to the clitoris may also predispose to developing this condition.
      Familiarity with this condition and a high index of suspicion are paramount in
      establishing a diagnosis.

PMID- 12423817
TI  - Thermal balloon endometrial ablation for management of acute uterine hemorrhage.
AB  - BACKGROUND: Life-threatening abnormal uterine bleeding can be managed by a
      variety of techniques, which include intravenous estrogen, dilation and
      curettage, endometrial ablation, uterine artery embolization, or hysterectomy.
      Thermal balloon endometrial ablation has been used in the management of chronic
      dysfunctional uterine bleeding but has not been described in a case of acute
      uterine hemorrhage. CASE: A 44-year-old woman with end-stage liver disease
      presented with vaginal bleeding and fever. She was found to have sepsis,
      coagulopathy, and anemia. No anatomic uterine pathology was identified.
      Antibiotics, intravenous estrogen, and blood products were administered, but
      heavy bleeding persisted. Thermal balloon ablation resulted in abrupt cessation
      of uterine bleeding. CONCLUSION: Thermal balloon ablation appears to be an
      effective method for management of acute uterine hemorrhage.

PMID- 12423818
TI  - Coarctation of the descending thoracic aorta diagnosed during pregnancy.
AB  - BACKGROUND: Coarctation of the aorta is an uncommon condition complicating
      pregnancy. It is often associated with hypertension and usually involves the
      aortic isthmus. CASE: Coarctation of the descending thoracic aorta was found at
      21 weeks' gestation after physical findings of hypertension, a holosystolic
      murmur over the entire left hemithorax, and diminished lower extremity pulses.
      The diagnosis led to thoracotomy and placement of a graft bypass after an
      otherwise uneventful pregnancy. CONCLUSION: Unusual sites of coarctation of the
      aorta complicating pregnancy include the descending thoracic aorta.

PMID- 12423819
TI  - Atrial fibrillation in pregnancy associated with oral terbutaline.
AB  - BACKGROUND: Terbutaline has direct effects on the cardiac conduction system, but
      when used to treat preterm labor it is rarely associated with clinically
      significant cardiac arrhythmias. Commonly used drug references did not list
      atrial fibrillation as a complication of terbutaline, and our literature search
      found only one case of atrial fibrillation that occurred with parenteral
      administration. CASE: A 30-year-old gravida 1 carrying a twin gestation at 35
      weeks was taking 2.5 mg oral terbutaline four times daily for premature labor.
      She developed atrial fibrillation and was ultimately treated by chemical
      cardioversion with procainamide to restore normal sinus rhythm. CONCLUSION: This
      is the first report of atrial fibrillation during pregnancy associated with oral
      terbutaline. Atrial fibrillation should be added as a complication of oral
      terbutaline therapy.

PMID- 12423820
TI  - Uterine rupture at term after uncomplicated hysteroscopic metroplasty.
AB  - BACKGROUND: In patients with a prior uterine septum resection, uterine rupture
      during pregnancy has been reported with the use of energy sources or when
      complicated by perforation. CASE: A woman was found to have a uterine abnormality
      during her first pregnancy. After delivery, a septum was diagnosed and
      hysteroscopically incised using cold scissors without complication. Follow-up
      hysterosalpingogram showed a small residual septum. In her subsequent pregnancy,
      emergency cesarean after fetal bradycardia in early labor showed the placenta and
      fetus totally exteriorized through a cornua to cornua rupture of the fundus.
      CONCLUSION: Uterine rupture during pregnancy after metroplasty is rare but may
      occur regardless of the method of metroplasty, absence of complications, or
      careful follow-up.

PMID- 12423821
TI  - Androgen-secreting adrenal adenomas.
AB  - BACKGROUND: The androgen source in women with hirsutism and signs of virilism may
      be the ovary or adrenal gland. CASES: Three patients with androgen excess are
      reported. Two had hyperandrogenemia and Cushing syndrome with an adrenal mass
      greater than 5.5 cm; the third had a small adrenal adenoma secreting only
      testosterone and responsive to human chorionic gonadotropin. In all cases, the
      pathologic report from surgery and the long-term resolution of symptoms confirmed
      the benign nature of the tumors. CONCLUSION: Basal and dynamic hormonal tests
      cannot precisely differentiate ovarian from adrenal tumors. Adrenal adenomas must
      be considered as a cause of hyperandrogenic syndrome.

PMID- 12423822
TI  - Successful treatment of extremely severe fetal anemia due to Kell
      alloimmunization.
AB  - BACKGROUND: Repeated plasmapheresis was used to prevent fetal death from severe
      anti-Kell alloimmunization until intrauterine transfusions were feasible. CASE:
      Repeated maternal plasma exchanges (N = 40) beginning at 7 weeks' gestation were
      used to treat severe anti-Kell alloimmunization. Ultrasound examination at 19
      weeks' gestation revealed diffuse hydrops in this fetus (umbilical venous
      hemoglobin, 1.2 g/dL), which then required nine intrauterine transfusions through
      34 weeks. A healthy 3840-g girl was delivered by cesarean delivery at 36 weeks.
      Despite aplastic anemia during the first 3 months of life, she is healthy and has
      no observable abnormalities at age 8. CONCLUSION: A highly aggressive course of
      plasmapheresis and intrauterine transfusions can successfully treat fetal anemia
      caused by anti-Kell alloimmunization even when fetal hemoglobin is extremely low.

PMID- 12423823
TI  - Invasive squamous cell carcinoma of the vagina during pregnancy.
AB  - BACKGROUND: Squamous cell carcinoma of the vagina in pregnancy is rare. CASE: A
      28-year-old primigravida with antepartum bleeding at 20 weeks' gestation was
      diagnosed with squamous cell carcinoma after biopsy of a vaginal mass. The
      histology revealed an invasive grade 3 squamous cell carcinoma of large-cell,
      nonkeratinizing type. The patient declined pregnancy termination and immediate
      radiation treatment. She continued to have episodes of vaginal bleeding and was
      admitted at 30 weeks' gestation. A decision was made in consultation with the
      neonatal unit to deliver her at 32 weeks' gestation. After corticosteroid
      treatment, she was delivered by cesarean delivery. Positive pelvic lymph nodes
      were noted at surgery. Postoperatively, she received external beam radiation and
      brachytherapy and concurrent cisplatin chemotherapy. She is disease free 3 years
      from her original diagnosis. CONCLUSION: This case emphasizes the importance of a
      thorough pelvic examination to assess the vaginal walls and cervix at the first
      prenatal visit and with any antepartum bleeding episode.

PMID- 12423824
TI  - Rupture of noncommunicating rudimentary uterine horn pregnancy.
AB  - BACKGROUND: We present a rare case of pregnancy in a noncommunicating rudimentary
      horn that ruptured at 20 weeks. CASE: A 30-year-old woman presented with a
      history of two spontaneous abortions. An ultrasound scan showed a bicornuate
      uterus, with one normal and one hypoplastic horn. Hysterosalpingography revealed
      a single uterine cavity with only one tube, suggesting a unicornuate uterus.
      Hysteroscopy and laparoscopy were recommended but declined. She presented again 2
      months later at 7 weeks' gestation. A single intrauterine pregnancy in the
      hypoplastic right horn was diagnosed. A transvaginal scan showed a single
      cervical canal in continuity with the left uterine horn, which led to the
      suspicion of a pregnancy in a rudimentary horn. The option of pregnancy
      termination was offered. A laparoscopy was repeatedly suggested but declined.
      Excision of a ruptured noncommunicating rudimentary horn and ipsilateral
      salpingectomy were performed after an emergency laparotomy at 20 weeks because of
      the sudden onset of abdominal pain and signs of shock. CONCLUSION: Although a
      rudimentary horn pregnancy had been suspected before the laparotomy, the patient
      presented as a clinical emergency. This report, like others, indicates that
      prompt diagnosis and immediate removal of the rudimentary horn is lifesaving.

PMID- 12423825
TI  - An unusual presentation of struma ovarii mimicking a malignant process.
AB  - BACKGROUND: Struma ovarii is a rare form of ovarian neoplasm, composed entirely
      or predominantly of thyroid tissue. This tumor is generally benign, although
      malignant transformation has been reported. CASE: We report an unusual
      presentation of a postmenopausal woman with benign struma ovarii associated with
      a large amount of ascites, a markedly elevated CA 125 serum level, and a large
      complex pelvic mass thereby mimicking an ovarian cancer. CONCLUSION: This case
      serves to remind clinicians that clinical features highly suspicious for ovarian
      cancer do not necessarily confirm a malignancy.

PMID- 12423826
TI  - Modified Zavanelli maneuver for the alleviation of shoulder dystocia.
AB  - BACKGROUND: The Zavanelli maneuver has typically been instituted when
      conventional maneuvers have failed to alleviate shoulder dystocia. Previously
      reported cases involving the Zavanelli maneuver have described cephalic
      replacement followed by immediate cesarean delivery. CASE: We encountered a case
      in which, despite the McRoberts maneuver, suprapubic pressure, Wood's corkscrew
      manuever, and attempted extraction of the posterior fetal arm, the baby could not
      be delivered. The fetal vertex was partially reinserted into the vagina, and this
      dislodged the impacted shoulders. With expulsive efforts the mother was then able
      to achieve vaginal delivery of a 3870 g female infant. CONCLUSION: The modified
      Zavanelli maneuver may be used to successfully alleviate shoulder dystocia.

PMID- 12423827
TI  - Rupture of the symphysis pubis during vaginal delivery followed by two subsequent
      uneventful pregnancies.
AB  - BACKGROUND: Rupture of the symphysis pubis during vaginal delivery is a rare but
      debilitating complication. Factors contributing to rupture are poorly defined.
      CASE: A healthy primigravida suffered a rupture of her symphysis pubis during an
      otherwise uncomplicated vaginal delivery. She experienced significant pain and
      difficulty walking for 6 months after the injury. Her 5-cm symphyseal separation
      was managed successfully with physical therapy and activity restriction. The
      patient's two subsequent deliveries (one vaginal and one via cesarean delivery)
      were uneventful. CONCLUSION: Severe symphyseal rupture during vaginal delivery
      can be managed without surgery. Risk factors for rupture are not well defined.
      Based on a literature review, there is a significant risk of repeat symphyseal
      rupture with subsequent vaginal delivery.

PMID- 12423828
TI  - Triplet cervical pregnancy treated with intraamniotic methotrexate.
AB  - BACKGROUND: Multifetal cervical pregnancy is very rare. We are reporting a case
      of a triplet cervical pregnancy that was treated with direct intraamniotic
      instillation of methotrexate. CASE: A young multiparous woman was diagnosed as
      having three gestational sacs in her uterine cervix with embryonic cardiac
      activity observed within one of the sacs. She became pregnant by natural
      ovulation and coitus. After initial failure with a single-dose intramuscular
      injection, the patient was successfully treated with an intra-amniotic
      methotrexate injection under the guidance of transvaginal ultrasonography. Her
      reproductive capability was preserved. CONCLUSION: Direct intraamniotic injection
      can be considered as treatment for multifetal cervical pregnancy.

PMID- 12423829
TI  - Acute renal failure in association with severe hyperemesis gravidarum.
AB  - BACKGROUND: Severe hyperemesis gravidarum is a rare but potentially devastating
      complication of pregnancy. Among its many potential complications are
      dehydration, electrolyte imbalance, malnutrition, Wernicke encephalopathy, and
      compromised renal function. CASE: We report the case of a 21-year-old woman at 15
      weeks' gestation presenting to the emergency department with severe hyperemesis
      gravidarum associated with acute renal failure. Her initial serum creatinine and
      blood urea nitrogen were 10.7 mg/dL and 171 mg/dL, respectively. The patient
      underwent daily hemodialysis for 5 days with subsequent return of renal function
      to normal. CONCLUSION: Women with severe hyperemesis gravidarum may be at risk
      for acute renal failure caused by severe intravascular volume depletion.

PMID- 12423830
TI  - Uterine leiomyosarcoma metastatic to the thyroid.
AB  - BACKGROUND: Uterine leiomyosarcoma is an aggressive tumor that has a propensity
      for distant metastasis. Distant sites of spread include the lung, liver, brain,
      and bone. CASE: A woman in her 5th decade was diagnosed with stage IV
      leiomyosarcoma of the uterus. Distant metastasis in the chest was confirmed by
      thoracotomy at the time of her original diagnosis. She subsequently experienced
      multiple episodes of metastasis including metastatic disease to her thyroid. She
      survived 71 months after diagnosis of stage IV disease. CONCLUSION: Our case
      represents the first reported experience with uterine leiomyosarcoma metastatic
      to the thyroid. Additionally the case is notable because the patient experienced
      multiple episodes of asymptomatic stable disease after repetitive
      chemotherapeutic regimens.

PMID- 12423831
TI  - Postmenopausal intravenous leiomyomatosis with high levels of estradiol and
      estrogen receptor.
AB  - BACKGROUND: Intravenous leiomyomatosis is a rare variant of leiomyoma. CASE: The
      patient was a 49-year-old gravida 3, para 3 woman with menopause at age 46. She
      presented with a history of syncope. Vaginal examination revealed an enlarged and
      elastic-soft mass of the uterus. A pelvic ultrasound, computed tomography scan,
      and magnetic resonance imaging showed a heterogeneous, irregularly shaped 8- to
      10-cm tumor. In addition, the inferior vena cava was almost completely occluded.
      Cardiac ultrasound demonstrated a mobile mass in the right atrium. The serum
      estradiol was 208 pg/mL (normal 0-59). Intravenous leiomyomatosis with cardiac
      extension was diagnosed preoperatively. A resection of the intracardiac and
      intracaval mass and a subtotal hysterectomy with bilateral salpingo-oophorectomy
      were performed. The uterine tumor weighed 600 g, and the cordlike intravascular
      tumor extending from the internal iliac vein into the right ventricle was 40 cm
      long and weighed 60 g. Pathologic examination confirmed intravenous
      leiomyomatosis with no evidence of atypia. The level of estrogen receptor in the
      tissue was 140 fmol/mg protein. The postoperative course was uneventful, and she
      has been in good health for 17 months after the operation. CONCLUSION: We report
      a case of intravenous leiomyomatosis extending into the right ventricle treated
      with a one-stage operation. It is possible that a high concentration of serum
      estradiol and high level of tissue estrogen receptor are related to the
      intravenous leiomyomatosis.

PMID- 12423832
TI  - Streptococcus bovis bacteremia and fetal death.
AB  - BACKGROUND: Preterm premature rupture of membranes leading to intraamniotic
      infection and fetal death may be due to unusual bacterial species. CASE: A young
      multipara presented at 24 weeks and 6 days' gestation with rupture of membranes
      of 2 days' duration. She was febrile and hypotensive. No fetal heart activity was
      noted. Antibiotics, fluid resuscitation, and oxytocin were begun with delivery of
      a 798-g stillborn fetus. Maternal and fetal cultures demonstrated Streptococcus
      bovis as the infectious agent. CONCLUSION: Unusual bacteria such as S bovis are
      sometimes responsible for severe maternal and fetal infections. Aggressive fluid
      resuscitation, uterine evacuation, and triple antibiotic therapy until culture
      results are available are indicated.

PMID- 12423834
TI  - Thrombotic thrombocytopenic purpura and human immunodeficiency virus complicating
      pregnancy.
AB  - BACKGROUND: Thrombotic thrombocytopenic purpura is a rare but serious medical
      complication, but is relatively common among patients with human immunodeficiency
      virus (HIV) infection. It is characterized by the pentad of thrombocytopenia,
      microangiopathic hemolytic anemia, neurological symptoms, fever, and renal
      abnormalities. However, the pentad is often incomplete, especially in HIV
      positive patients. CASE: An HIV-positive patient complained of easy bruising,
      hematuria, fever, myalgias, and headache during the second trimester of
      pregnancy. Laboratory testing revealed hemolytic anemia and severe
      thrombocytopenia. Bone marrow biopsy was consistent with thrombocytopenic
      purpura. The patient recovered after plasmapheresis. At 36 weeks' gestation, she
      was delivered for preeclampsia and fetal growth restriction. CONCLUSION: Absence
      of the classic pentad seen in thrombocytopenic purpura among pregnant HIV
      positive patients may make the diagnosis of thrombocytopenic purpura challenging.
      Frequent monitoring of patients with thrombotic thrombocytopenic purpura for
      signs and symptoms of preeclampsia and fetal growth assessment is suggested.

PMID- 12423833
TI  - Metastatic endocervical adenocarcinoma presenting as a virilizing ovarian mass
      during pregnancy.
AB  - BACKGROUND: We report a case of metastatic endocervical adenocarcinoma that
      presented as a virilizing ovarian mass in a young pregnant woman and simulated a
      primary ovarian endometrioid tumor. CASE: A 34-year-old woman underwent cesarean
      delivery and right salpingo-oophorectomy at 34 weeks' gestation for a 32-cm
      androgen-producing ovarian mass. The ovarian tumor, initially interpreted as a
      primary ovarian endometrioid carcinoma, was demonstrated to represent metastatic
      endocervical endometrioid adenocarcinoma based on detection of human
      papillomavirus 16 (HPV-16) deoxyribonucleic acid in the tumor by in situ
      hybridization. The hysterectomy specimen demonstrated an endocervical
      adenocarcinoma associated with adenocarcinoma in situ that also contained HPV-16.
      CONCLUSION: Human papillomavirus is considered an etiological agent in the
      development of endocervical adenocarcinomas, having been demonstrated in greater
      than 90% of tumors. In contrast, recent studies have concluded that HPV is
      unlikely to play an etiological role in ovarian neoplasia. The demonstration of
      HPV-16 in both the endocervical and ovarian carcinomas in this patient supports
      the interpretation that the ovarian tumor is a metastasis.

PMID- 12423835
TI  - Spontaneous disappearance of a normal adnexa associated with a contralateral
      polycystic-appearing ovary.
AB  - BACKGROUND: Absence of the adnexa may be congenital or acquired. However, the
      etiology is often uncertain. CASE: A 27-year-old woman presented with a 3-year
      history of subfertility. Her irregular menstruation was associated with acne
      vulgaris, alopecia, and elevated body mass index. Transvaginal ultrasonography of
      the pelvis showed a normal uterus, a normal right ovary, but a polycystic
      appearing left ovary. A hysterosalpingogram demonstrated a normal uterine cavity,
      prompt filling and spilling of contrast material from the left fallopian tube,
      but no filling on the right. Subsequent laparoscopy showed an unexpected absence
      of right adnexa and presence of a solitary rounded free-floating mass enshrouded
      in the omentum. She did not have a history of abdominal pain or surgery.
      CONCLUSION: The evidence suggests that the patient might have had an asymptomatic
      infarction of the right adnexa.

PMID- 12423836
TI  - Spontaneous twin gestation after vaginal dilation in a woman with uterus
      didelphys and bladder exstrophy.
AB  - BACKGROUND: Bladder exstrophy is an uncommon anomaly rarely associated with
      uterus didelphys. Fertility is limited by associated vaginal malformations, which
      have traditionally required surgical reconstruction. CASE: A woman with a history
      of bladder exstrophy and hypoplastic vagina presented complaining of painful
      intercourse. The patient underwent vaginal dilator treatment after corrective
      surgery for the bladder defect. Without any further fertility therapy she
      subsequently conceived twins, with one implantation in each horn of a didelphic
      uterus. CONCLUSION: Bladder exstrophy, uterus didelphys, and vaginal hypoplasia
      share a common embryological devel-opment, and the finding of one anomaly can
      alert to the presence of another. Vaginal dilators may be used in place of
      surgical reconstruction to allow conception.

PMID- 12423837
TI  - Placental site trophoblastic tumor presenting with a pneumothorax during
      pregnancy.
AB  - BACKGROUND: Placental site trophoblastic tumor is a rare form of gestational
      trophoblastic disease that commonly presents with vaginal bleeding and amenorrhea
      after pregnancy. CASE: A women with a normal gestation at 37 weeks presented with
      a pneumothorax. The patient underwent placement of a chest tube and a subsequent
      thoracoscopic pulmonary bullous resection for persistence of the pneumothorax.
      Histological examination of the specimen revealed a metastatic placental site
      trophoblastic tumor. CONCLUSION: Gestational trophoblastic disease must be
      considered in the differential diagnosis of pneumothorax during pregnancy.

PMID- 12423839
TI  - Hormone replacement therapy: developing a strategy.

PMID- 12423838
TI  - Uterine artery embolization: what more do we need to know?

PMID- 12423840
TI  - Are doctors next?

PMID- 12423841
TI  - Bleeding patterns of the hormone replacement therapies in the postmenopausal
      estrogen and progestin interventions trial.
AB  - OBJECTIVE: To explore whether significant differences exist between bleeding
      patterns with common regimens of hormone replacement therapy using two different
      progestogens. METHODS: A total of 875 women in the Postmenopausal Estrogen and
      Progestin Interventions Trial took either placebo, conjugated equine estrogen
      0.625 mg, conjugated equine estrogen 0.625 mg plus medroxyprogesterone acetate
      2.5 mg in a continuous fashion, or conjugated equine estrogen 0.625 mg daily plus
      either cyclical medroxyprogesterone acetate 10 mg or cyclical micronized
      progesterone 200 mg/day for 12 days per month. Bleeding days, amounts, and
      episodes were recorded in diaries and aggregated by 6-month intervals for 3 years
      for the 596 participants with a uterus. Any bleeding for women on continuous
      regimens, or more than 6 episodes of bleeding per 6-month period for cyclical
      regimens, was considered excess. RESULTS: Conjugated equine estrogen plus
      micronized progesterone cyclical was associated with fewer excess episodes of
      bleeding than conjugated equine estrogen plus medroxyprogesterone acetate
      continuous in the first 6 months. Quantities of bleeding for conjugated equine
      estrogen plus micronized progesterone cyclical were less than for conjugated
      equine estrogen plus medroxyprogesterone acetate cyclical through 30 months and
      for the number of bleeding days through study end. The 3-year cumulative
      quantities, days, and episodes of bleeding were significantly lower for
      conjugated equine estrogen plus micronized progesterone cyclical than for
      conjugated equine estrogen plus medroxyprogesterone acetate cyclical. Placebo
      treated women had scant bleeding and conjugated equine estrogen had modest
      amounts relative to the combination therapies. CONCLUSION: The bleeding measures
      for conjugated equine estrogen plus micronized progesterone cyclical showed
      consistent advantages over those for cyclical conjugated equine estrogen plus
      medroxyprogesterone acetate in terms of quantity, length, and episodes of
      bleeding. In the first 6 months, conjugated equine estrogen plus micronized
      progesterone cyclical had fewer excess bleeding episodes than continuous
      conjugated equine estrogen plus medroxyprogesterone acetate.

PMID- 12423842
TI  - Comparison of long-term outcomes of myomectomy and uterine artery embolization.
AB  - OBJECTIVE: To compare long-term outcomes of uterine artery embolization and
      abdominal myomectomy in patients with symptomatic uterine myomas. METHODS: At a
      single institution in an 18-month time, 59 patients had bilateral uterine artery
      embolization and 38 patients had abdominal myomectomy to treat symptomatic
      uterine myomas. We reviewed medical records and surveyed patients 3 or more years
      after their procedures to assess how many needed further surgical procedures in
      the intervening years, to what extent symptoms remained improved, and how
      satisfied the patients were with the long term results of the index procedure.
      RESULTS: Follow-up was available on 51 embolization and 30 myomectomy patients
      and ranged from 37 to 59 months. Patients who had embolization were older (44
      versus 38 years, P <.001) and more likely to have had previous surgical
      procedures (P <.001) than those who had myomectomy. Taking into account the
      variable follow-up period, embolization patients were more likely to have had
      further invasive treatment for myomas (29% versus 3%) (P =.004). Among women not
      needing further surgery, overall symptoms improved in 92% (33/36) of embolization
      and 90% (26/29) of myomectomy patients (P =.78). Ninety-four percent (34/36) of
      embolization patients and 79% (23/29) of myomectomy patients were at least
      somewhat satisfied with their choice of procedure (P =.06). CONCLUSION: Women who
      had embolization were more likely than those who had myomectomy to need further
      invasive treatment (surgery or repeat embolization) in the 3-5 years after the
      index procedure. Among women who did not need such treatment, satisfaction and
      relief of symptoms were similar. Large, randomized trials are needed to more
      accurately compare these two procedures.

PMID- 12423843
TI  - Pregnancy after uterine artery embolization.
AB  - BACKGROUND: Uterine artery embolization is an increasingly popular alternative to
      hysterectomy and myomectomy as a treatment for uterine leiomyoma. Whether this
      procedure is safe for women desiring future fertility is controversial. CASES: A
      primigravida who had previously undergone uterine artery embolization had
      premature rupture of membranes at 24 weeks. She had a cesarean delivery at 28
      weeks, which was followed by uterine atony requiring hysterectomy. A primigravida
      who had previously undergone uterine artery embolization delivered appropriately
      grown dichorionic twins at 36 weeks. An analysis of the 50 published cases of
      pregnancy after uterine artery embolization revealed the following complications:
      malpresentation (17%), small for gestational age (7%), premature delivery (28%),
      cesarean delivery (58%), and postpartum hemorrhage (13%). CONCLUSION: Women who
      become pregnant after uterine artery embolization are at risk for
      malpresentation, preterm birth, cesarean delivery, and postpartum hemorrhage.

PMID- 12423844
TI  - Complications after uterine artery embolization for leiomyomas.
AB  - OBJECTIVE: To determine the frequency and severity of complications that occur as
      a result of uterine artery embolization for leiomyomas. METHODS: As part of an
      ongoing study of outcome after uterine embolization, prospective data regarding
      complications that occurred in 400 consecutive patients were gathered. Each
      patient had a minimum of a 3-month interval from the procedure at the time of
      analysis. Each complication was categorized and graded as to severity and outcome
      using the complication classification developed by the Society of Cardiovascular
      and Interventional Radiology (SCVIR) and a modified set of The American College
      of Obstetricians and Gynecologists (ACOG) criteria for complications of
      hysterectomy and myomectomy. All adverse events that occurred during the follow
      up period were included, including those that occurred after the 3-month minimum
      interval. Confidence intervals (CIs) were calculated for each complication.
      RESULTS: There were no deaths and no major permanent injuries. One patient
      required hysterectomy as a result of a complication, and one patient had an
      undiagnosed leiomyosarcoma. There were ten in-hospital complications and an
      additional 27 complications within the first 30 days, with 34 patients
      experiencing a periprocedural complication for a rate of 8.5% (95% CI 6.0%,
      11.7%). There were five serious complications (SCVIR class D), comprising 1.25%
      (95% CI 0.3%, 2.5%) of the study group. Using ACOG definitions for perioperative
      complications, the overall morbidity was 5% (95% CI 3.1%, 7.7%). CONCLUSION: The
      short-term complication rate was low in women undergoing uterine embolization.

PMID- 12423845
TI  - Labial necrosis after uterine artery embolization for leiomyomata.
AB  - BACKGROUND: Uterine artery embolization is increasingly used as an alternative to
      myomectomy, hysterectomy, and medical treatment for the management of symptomatic
      leiomyomata. CASE: A woman with an 18-week-size fibroid uterus who underwent
      uterine artery embolization developed a 3-cm, exquisitely tender, hypopigmented,
      necrotic-appearing area on the right labium minus. Spontaneous resolution
      occurred over 4 weeks. CONCLUSION: Labial necrosis is a possible complication of
      uterine artery embolization and may be successfully managed with conservative
      therapy.

PMID- 12423846
TI  - Embolic microspheres within ovarian arterial vasculature after uterine artery
      embolization.
AB  - BACKGROUND: Adverse events after uterine artery embolization, including
      hysterectomy and premature ovarian failure, are concerning for women who desire
      future fertility. CASE: A 39-year-old woman underwent emergency hysterectomy
      after uterine artery embolization embolic microspheres found within the ovarian
      arterial vasculature. CONCLUSION: Uterine artery embolization for the treatment
      of uterine fibroids has been associated with loss of ovarian function in up to
      14% of patients. This case report demonstrates that embolic microspheres injected
      into the uterine artery can unintentionally migrate through anastomotic channels
      into the ovarian arterial vasculature and potentially compromise ovarian blood
      flow. Hypoxic tissue injury may be the mechanism of premature ovarian failure
      observed after uterine artery embolization. Understanding the etiology of
      premature ovarian failure after uterine artery embolization might allow better
      patient selection.

PMID- 12423847
TI  - Lubrication of the vaginal introitus and speculum does not affect Papanicolaou
      smears.
AB  - OBJECTIVE: To test the hypothesis that lubrication of the vaginal introitus and
      external speculum does not adversely affect Papanicolaou interpretation. METHOD:
      One hundred eighty-two patients presenting for Papanicolaou smears as part of
      their visit were randomly assigned to have either only warm water or a water
      soluble lubricant to assist speculum insertion. Cytotechnicians and pathologists
      were blind to the cohort from which smears were obtained. RESULTS: Two
      unsatisfactory smears were found among 93 patients with the lubricant and two
      were found among 89 using only warm water. No significant difference was found
      using the t test for continuous variables and chi(2) for categoric variables.
      CONCLUSION: Use of a water soluble lubricant on the vaginal introitus and
      external speculum facilitates examination with no adverse effect on Papanicolaou
      smear interpretation.

PMID- 12423848
TI  - The effect of vaginal speculum lubrication on the rate of unsatisfactory cervical
      cytology diagnosis.
AB  - OBJECTIVE: Nonlubricated plastic specula can adhere to the vaginal introitus and
      cause discomfort with pelvic examination. We wanted to see if application of
      water-soluble gel lubricant to the plastic vaginal speculum would change the
      unsatisfactory cervical cytology diagnosis rate. METHODS: Five public health
      family planning clinic sites were randomized to either water-soluble gel or water
      only as lubricant during speculum examination for cervical cytology collection.
      The pathologists were unaware of the assignment of lubricant use. The cumulative
      rates of cervical cytology diagnoses were calculated for 6 months before, 6
      months during, and 6 months after the intervention. RESULTS: From July 1998
      through December 1999, 8534 Papanicolaou smears were collected, with 1440 using
      gel lubrication from January 1999 through June 1999. Rates of unsatisfactory
      smears for lubricant use clinics were 1.4% during use of lubricant and 1.4%
      without use (odds ratio [OR] 1.0; 95% confidence interval [CI] 0.6, 1.8). Rates
      of unsatisfactory smears for lubricant use versus nonlubricant use clinics during
      the gel intervention period were 1.4% versus 1.3% (OR 1.1; 95% CI 0.6, 2.0).
      There were no significant differences for the rates of atypical squamous cells of
      undetermined significance, low-grade squamous intraepithelial lesion, high-grade
      squamous intraepithelial lesion, or atypical glandular cells of undetermined
      significance within or between lubricant and nonlubricant clinics for each 6
      month period. There were no cases of invasive cancer. CONCLUSION: The use of a
      small amount of water-soluble gel lubricant on the outer inferior blade of the
      plastic vaginal speculum does not change cervical cytology results in a young,
      reproductive-age population.

PMID- 12423849
TI  - Tension-free vaginal tape: outcomes among women with primary versus recurrent
      stress urinary incontinence.
AB  - OBJECTIVE: To evaluate the outcomes of tension-free vaginal tape in the treatment
      of primary versus recurrent genuine stress urinary incontinence. METHODS: A
      retrospective, multicenter study of 245 consecutive women who were treated with
      tension-free vaginal tape for genuine stress urinary incontinence (157 for
      primary and 88 for recurrent genuine stress urinary incontinence) over a 27-month
      period was performed. Concurrent surgical repairs were performed as required.
      Subjective and objective outcome data were assessed from routine postoperative
      visits. Office and hospital records were reviewed to determine patient
      characteristics, intraoperative findings, and surgical outcomes. RESULTS: Women
      with recurrent genuine stress urinary incontinence were older (mean age 64.6
      versus 59.4 years, P =.004) than those with primary incontinence; they were less
      likely to have an intact uterus (22.7% versus 66.9%, P <.001), and were more
      likely to have intrinsic sphincter deficiency (70.5% versus 47.1%, P <.001). The
      mean duration of follow-up was 38 (+/-16) weeks. Cure rates among patients with
      recurrent versus primary genuine stress urinary incontinence were similar (85%
      and 87%, respectively, P =.23). Complication rates were similarly low in both
      groups (4.5% versus 7.6% for recurrent and primary genuine stress urinary
      incontinence, respectively, P =.35). Postoperative voiding dysfunction occurred
      at low rates in both groups. CONCLUSION: Tension-free vaginal tape is a highly
      effective treatment among patients with recurrent stress incontinence, with
      outcomes comparable with those among patients with primary incontinence.

PMID- 12423850
TI  - Release of tension-free vaginal tape for the treatment of refractory
      postoperative voiding dysfunction.
AB  - OBJECTIVE: To report our experience with surgical release of tension-free vaginal
      tape (TVT) for the treatment of persistent post-TVT voiding dysfunction. METHODS:
      A total of 1175 women underwent TVT placement for treatment of genuine stress
      urinary incontinence and/or intrinsic sphincter deficiency over a 2-year period.
      Additional procedures and vaginal repairs were performed as indicated. Among
      these patients, 23 women (1.9%) had persistent voiding dysfunction (urinary
      retention, incomplete bladder emptying, or severe urgency or urge incontinence)
      refractory to conservative management. This cohort underwent a simple vaginal TVT
      release procedure, performed on an outpatient basis. Preoperative
      characteristics, intraoperative, and postoperative details were assessed by
      review of operative notes, medical records, and office notes. Continence status
      was assessed using subjective and objective information. RESULTS: Mean age was 67
      years (range 46-86 years), and the mean interval between TVT placement and
      release was 17.3 weeks (range 2-69 weeks; median 8.6 weeks). For the release
      procedure, there were no intraoperative complications, and all patients were
      discharged on the day of surgery. All cases of impaired emptying were completely
      resolved, and all cases of irritative symptoms were resolved (30%) or improved
      (70%) by 6 weeks. Fourteen (61%) patients remained continent 6 weeks after the
      release procedure, six (26%) were improved over baseline, and three patients
      (13%) had recurrence of stress incontinence. CONCLUSION: Refractory voiding
      dysfunction after TVT is a relatively uncommon situation and can be successfully
      managed with a simple midline release procedure. In most cases, the release
      procedure does not compromise overall improvement in symptoms of stress
      incontinence.

PMID- 12423851
TI  - Antenatal diagnosis of single umbilical artery: is fetal echocardiography
      warranted?.
AB  - OBJECTIVE: To estimate the utility of fetal echocardiography in the evaluation of
      the fetus with isolated single umbilical artery. METHODS: A retrospective
      analysis of fetuses diagnosed with single umbilical artery by sonography was
      conducted between January 1995 and June 2000 (n = 127). In the 103 patients who
      had fetal echocardiograms, we examined the frequency of abnormal
      echocardiographic findings when the initial sonogram demonstrated a normal four
      chamber view and cardiac outflow tracts. RESULTS: Approximately 1% of fetal
      anomaly screens had a diagnosis of single umbilical artery. Of these, 72% were
      isolated (no other anomalies identified). No fetus in this group had an abnormal
      echocardiogram. There was one postnatal diagnosis of cardiac disease in this
      group; it was not predicted by either the four-chamber and outflow tract views or
      the echocardiogram. Among the group with other anomalies, the four-chamber view
      predicted every abnormal echocardiogram but one. CONCLUSION: Fetal
      echocardiography does not appear to add further diagnostic information to the
      antenatal evaluation of the fetus with isolated single umbilical artery when
      normal four-chamber and outflow tract views of the heart have already been
      obtained.

PMID- 12423852
TI  - Maternal health in sudden intrauterine unexplained death: do urinary tract
      infections protect the fetus?
AB  - OBJECTIVE: To study the impact of maternal health and obstetric complications on
      the risk for sudden intrauterine unexplained death. METHODS: All 76 cases of
      sudden intrauterine unexplained death and 165 explained stillbirths among
      singletons in Oslo, Norway (1986-1995) were compared with 582 controls.
      Information on maternal health was registered from antenatal health cards and the
      Medical Birth Registry of Norway. The effect of pregnancy duration was studied
      before logistic regression analysis corrected for pregnancy duration was
      performed. RESULTS: Urinary tract colonization or infection in pregnancy was
      associated with a reduced risk for subsequent sudden intrauterine unexplained
      death (odds ratio [OR] 0.29 [0.12-0.74]), whereas insufficient physiologic
      hemodilution during pregnancy (lowest hemoglobin greater than 13 g/mL) increased
      the risk for sudden intrauterine unexplained death (OR 9.50 [1.30-69.3]).
      However, the risk for sudden intrauterine unexplained death remained unaffected
      by the total number of indicators of impaired maternal health during pregnancy,
      in contrast to significant impact on other stillbirths. CONCLUSION: Urinary tract
      colonization or infection may offer protection against sudden intrauterine
      unexplained death. We hypothesize that the subsequent maternal immune response
      offers transplacental protection against lethal fetal infections by common
      pathogens of urinary tract infections. Other health indicators have little impact
      on sudden intrauterine unexplained death.

PMID- 12423853
TI  - Gestational cocaine exposure and intrauterine growth: maternal lifestyle study.
AB  - OBJECTIVE: To estimate the effects of cocaine exposure on intrauterine growth and
      to investigate at what point in gestation growth deviation would be manifested.
      METHODS: This is a secondary analysis of data from a multicenter project, the
      Maternal Lifestyle Study, designed to determine infant outcomes of in utero
      cocaine or opiates exposure. Four centers of the National Institute of Child
      Health and Human Development Neonatal Research Network enrolled 11,811 maternal
      infant dyads. A total of 1072 infants were cocaine exposed, 7565 were cocaine
      negative by maternal history and meconium results, and 3174 were excluded from
      analysis because of unconfirmed negative exposure. Outcome measures included
      birth weight, length, and head circumference. RESULTS: Percentile estimates for
      birth weight, length, and head circumference revealed growth deceleration in
      cocaine-exposed infants evident after 32 weeks' gestation. There was significant
      interaction between cocaine and gestational age. After controlling for
      confounders, at 40 weeks' gestation, cocaine exposure was estimated to be
      associated with a decrease of 151 g, 0.71 cm, and 0.43 cm in birth weight,
      length, and head circumference, respectively. Smoking had a negative impact on
      all growth measurements, with some indication of a dose-effect relationship.
      Heavy alcohol use was associated with decrease in weight and length only. Opiates
      had significant effect only on birth weight. CONCLUSION: In utero cocaine
      exposure is associated with growth deceleration involving all measurements,
      becoming more pronounced with advancing gestation.

PMID- 12423854
TI  - Maternal diabetes mellitus and infant malformations.
AB  - OBJECTIVE: To investigate the effects of pregestational, as opposed to
      gestational, diabetes on infant malformations. METHODS: All women delivering
      infants at Parkland Hospital between January 1, 1991, and December 31, 2000, were
      ascertained. Screening for gestational diabetes was methodically employed
      throughout the study period using National Diabetes Data Group criteria for
      diagnosis of pregestational and gestational diabetes. Standardized definitions of
      major infant malformations were specified before data analysis and subdivided
      according to the organ systems involved. RESULTS: A total of 145,196 women were
      delivered during the study period, and 2687 (1.9%) were diagnosed to have
      diabetes mellitus. Gestational diabetes was diagnosed in 2277 (1.6%) of whom 230
      (10%) had fasting hyperglycemia diagnosed, and the remainder consistently
      demonstrated fasting serum levels less than 105 mg/dL. Pregestational diabetes
      was diagnosed in 410 (0.3%) women. Infant malformations occurred in 1.5% of
      nondiabetic women compared with 1.2% of women with normal fasting glucose
      gestational diabetes, 4.8% in women with gestational diabetes plus fasting
      hyperglycemia, and 6.1% in those with pregestational diabetes (P <.001, for
      comparison of the latter two groups with the nondiabetic population). CONCLUSION:
      Women with pregestational diabetes or gestational diabetes plus fasting
      hyperglycemia have a three- to four-fold increased risk of infant malformations,
      whereas women with mild gestational diabetes have malformation rates no different
      than the general nondiabetic obstetric population.

PMID- 12423855
TI  - Differential blood flow in uterine, ophthalmic, and brachial arteries of
      preeclamptic women.
AB  - OBJECTIVE: To develop a method that employs noninvasive, pulsed Doppler
      ultrasonography combined with measurement of flow-mediated vasodilation to
      evaluate characteristic endothelial dysfunction in various degrees of
      preeclampsia. METHODS: Uterine, ophthalmic, and brachial arterial blood flow of
      99 pregnant women (control group [n = 32], non-preeclamptic intrauterine growth
      restriction group (n = 15), mild preeclampsia group [n = 25], and severe
      preeclampsia group [n = 27]) were evaluated by pulsed Doppler ultrasound or flow
      mediated vasodilation. RESULTS: Uterine, orbital, and brachial circulation were
      altered in preeclampsia, whereas no significant differences were observed between
      the non-preeclamptic intrauterine growth restriction and control groups.
      Pulsatility index in the uterine arteries of preeclamptic women with intrauterine
      growth restriction was approximately three-fold higher than that of normotensive
      women with or without intrauterine growth restriction. The peak ratio (defined to
      quantify characteristic flow velocity waveform) of the ophthalmic artery of
      hypertensive women was significantly higher than that of normotensive women. Flow
      mediated vasodilation in the brachial artery of preeclamptic women with
      intrauterine growth restriction was significantly lower than that in preeclamptic
      women without intrauterine growth restriction. Among preeclamptic women,
      elevation of the resistance in the uterine artery and reduced flow-mediated
      vasodilation were closely correlated to intrauterine growth restriction, whereas
      the elevated peak ratio of the ophthalmic artery was dependent on hypertension,
      irrespective of the presence of intrauterine growth restriction. CONCLUSION:
      Ultrasound evaluation of uterine and orbital circulation and flow-mediated
      vasodilation of the brachial artery helps differentiate the degree and severity
      of preeclampsia.

PMID- 12423857
TI  - Permanent blindness as a complication of pregnancy induced hypertension.
AB  - BACKGROUND: Visual disturbances are common symptoms of preeclampsia, but
      blindness remains a rare phenomenon. CASE: A 21-year-old secundagravida was
      admitted at 3547 weeks' gestation with a diagnosis of preeclampsia. She labored
      on her second hospital day and underwent a cesarean delivery for nonreassuring
      fetal status. On postoperative day 1, she reported blurring of her vision that
      progressed rapidly to complete vision loss. Ophthalmological examination revealed
      ischemic retinal changes bilaterally; radiographic examination showed lesions in
      the lateral geniculate bodies, consistent with infarcts, as the possible
      etiologies of her blindness. Five months later, the patient has not regained her
      sight and remains legally blind. CONCLUSION: Complete amaurosis is a rare
      complication of pregnancy demanding immediate ophthalmological and neurological
      evaluation as well as radiographic studies of the brain.

PMID- 12423856
TI  - Bilateral retinal occlusion progressing to long-lasting blindness in severe
      preeclampsia.
AB  - BACKGROUND: Temporary blindness in pregnancy associated with preeclampsia has
      been reported. Most cases have been attributed to cortical cerebral edema with
      transient vision impairment. We present a patient with bilateral retinal
      arteriole occlusions causing permanent blindness. CASE: A teenage primigravida at
      term presented with uterine contractions and preeclampsia. Twenty-four hours
      after delivery she developed sudden visual loss that progressed to total
      bilateral blindness. Imaging studies ruled out cerebral edema and an
      ophthalmologic examination found retinal hemorrhages and infarcts consistent with
      bilateral central retinal arteriole occlusions. At 2- and 6-month follow-up there
      was marked persistent visual impairment. CONCLUSION: The combination of blindness
      and preeclampsia is rare. Evaluation for ophthalmologic findings should be part
      of the initial patient assessment with preeclampsia.

PMID- 12423858
TI  - Pregnancy after classic cesarean delivery.
AB  - OBJECTIVE: To describe maternal and perinatal outcomes after a prior classic
      cesarean delivery. METHODS: A retrospective review was performed including all
      patients from 1990-2000 whose most recent pregnancy was preceded by classic
      cesarean delivery. RESULTS: During the 11-year period, there were 37,863
      deliveries and 157 patients (0.4%) underwent classic cesarean operations. In the
      next pregnancy, one case of uterine rupture (0.6%, 95% confidence interval 0.1,
      3.5) occurred at 29 weeks without preterm labor and resulted in fetal death. The
      prevalence of asymptomatic dehiscence was 9% (95% confidence interval 5, 15).
      There was no significant difference between patients with uterine dehiscence (n =
      15) and patients with intact uteri (n = 141) with regard to maternal
      demographics, duration of labor, cervical dilatation at time of surgery,
      transfusion of packed red cells, bowel injury, postpartum endometritis, wound
      breakdown, thrombophlebitis, or umbilical arterial pH less than 7.00 (P >.05).
      Duration of labor, cervical dilatation, and gestational age at repeat cesarean
      delivery were poor predictors for uterine rupture or dehiscence. CONCLUSION:
      Among patients with prior classic cesarean delivery, uterine rupture and
      dehiscence are neither predictable nor preventable. One in four patients will
      experience some form of maternal morbidity. Uterine rupture, although infrequent,
      can be fatal to the fetus. Uterine dehiscence, however, does not increase
      neonatal or peripartum maternal morbidity.

PMID- 12423859
TI  - Fetal heart rate parameters predictive of neonatal outcome in the presence of a
      prolonged deceleration.
AB  - OBJECTIVE: To correlate the presence of baseline variability and the duration of
      a prolonged deceleration/bradycardia in intrapartum fetal heart rate (FHR)
      tracings with the development of neonatal acidemia. METHODS: We identified 186
      patients with term gestations who had continuous electronic fetal monitoring for
      at least 2 hours before delivery, with an identified bradycardia during that
      period. Each patient had umbilical artery cord analysis done and delivery within
      30 minutes of that bradycardia. One investigator blinded to the cord gas outcome
      reviewed the last 2 hours of the tracing using the National Institute of Child
      Health and Human Development guidelines for FHR monitoring. We assessed the
      presence or absence of variability before the bradycardia and recovery or no
      recovery of the bradycardia and placed the patients into four groups. Group 1
      (128 patients) with normal variability and recovery, group 2 (40 patients) with
      normal variability and no recovery, group 3 (nine patients) with decreased
      variability and recovery, and group 4 (nine patients) with decreased variability
      and no recovery. We compared the incidence of neonatal acidosis defined as a pH
      of less than 7.0 at birth among the four groups. The relationship between the
      various groups was assessed using analysis of variance and the chi(2) test. In
      addition, a multiple logistic regression model was developed with the parameters
      of amplitude and recovery used to predict pH at birth. RESULTS: The presence of
      decreased variability and no recovery of the FHR of a bradycardia was associated
      with the lowest pH 6.83 +/- 0.16 and a 78% incidence of significant acidosis.
      Decreased variability before FHR bradycardia was the FHR parameter significantly
      correlated with low pH. CONCLUSION: The most significant factor predicting the
      development of pathologic neonatal acidemia and indicating the need for urgent
      delivery in the presence of a bradycardia is decreased variability before the
      bradycardia.

PMID- 12423860
TI  - Medical licensure examination scores: relationship to obstetrics and gynecology
      examination scores.
AB  - OBJECTIVE: We studied the correlations between both Step 1 and Step 2 of the
      United States Medical Licensure Examination (USMLE) and the National Board of
      Medical Examiners Obstetrics and Gynecology Examination (NBME-OB/GYN). METHODS:
      From July 1994 until June 2001, all third-year medical students at Texas Tech
      University Health Center at Amarillo were studied. The scores from the first
      attempts for the three examinations were obtained. We investigated for
      correlations between the examination scores and the score extremes. RESULTS: A
      total of 258 students were evaluated. The mean USMLE Step 1 score was 203.7; mean
      score for Step 2 was 205.0. The NBME-OB/GYN final examination was 86.0. We found
      linear correlations between the NBME-OB/GYN and the USMLE Step 1 (r =.463, P
      <.001) and USMLE Step 2 (r =.595, P <.001), as well as between the USMLE Steps 1
      and 2 (r =.666 P <.001). Students failing the USMLE Step 1 were more likely to
      fail their USMLE Step 2 (relative risk [RR] 9.3 [95% confidence interval (CI)
      2.1, 41.0]) and/or the NBME-OB/GYN (RR 3.3 [95% CI 1.03, 10.8]). Students scoring
      in the lowest 25th percentile of the NBME-OB/GYN were more likely to fail the
      USMLE Step 2. CONCLUSION: Both USMLE Steps 1 and 2 correlated with the NBME
      OB/GYN scores, as well as with each other. Students failing either the USMLE Step
      1 or NBME-OB/GYN were more likely to fail the USMLE Step 2. The use of this
      information could predict students at risk for low scores on future examinations.

PMID- 12423861
TI  - Obesity as an independent risk factor for infectious morbidity in patients who
      undergo cesarean delivery.
AB  - OBJECTIVE: Our purpose was to evaluate obesity (body mass index greater than
      30.0) as an independent risk factor for infectious morbidity in women having
      elective or nonelective cesarean deliveries. METHODS: Charts of 611 patients
      undergoing cesarean were reviewed. After exclusion of those with pre-existing
      chorioamnionitis, 574 cases were separated into two groups (elective or
      nonelective cesarean) and then subdivided based on the presence or not of
      postdelivery infectious morbidity. Estimated blood loss, operative time, number
      of vaginal examinations, labor length, use of internal monitors, body mass index
      (BMI), and obesity (BMI greater than 30.0) were then recorded. Student t test,
      chi(2), multivariate analysis, and receiver operating characteristics curves were
      used where appropriate (significance: P <.05). RESULTS: The mean gestational age
      at delivery was 38.3 weeks. Three hundred sixty patients had nonelective
      cesareans, and 214 had elective cesareans. Prophylactic antibiotics were used for
      86.6% of the nonelective group and 75.2% of the elective group. In the
      nonelective group and after multivariate analysis, significant risk factors for
      postoperative infections were as follows: labor length (18.4 hours versus 10.9, P
      <.003), number of vaginal examinations (6.1 versus 4.5, P <.001), BMI (36.6
      versus 32.3, P <.001), and obesity (81.8% versus 57.3%, P <.001). For the
      elective group, a higher BMI (38.9 versus 32.2, P <.003), and black race (63.2%
      versus 11.5%, P <.001) were found to be significant. CONCLUSION: Our data suggest
      that obesity is a independent risk factor for postcesarean infectious morbidity
      and endomyometritis, even if the cesarean is elective and prophylactic
      antibiotics are given.

PMID- 12423862
TI  - Rate of human papillomavirus clearance after treatment of cervical
      intraepithelial neoplasia.
AB  - OBJECTIVE: To investigate the rate of clearance of human papillomavirus (HPV)
      infection after surgical treatment for cervical intraepithelial neoplasia (CIN).
      METHODS: One hundred nine women with CIN I-III, treated with cryosurgery or
      conization at a university hospital, were observed with cervical HPV
      deoxyribonucleic acid (DNA) testing by general primer polymerase chain reaction
      and HPV typing at 0, 3, 6, 9, 12, and 24 months after treatment. Penile HPV DNA
      was analyzed from current sexual partners. RESULTS: Eighty-one percent of
      evaluable women were HPV DNA positive at treatment or enrollment. One year later,
      seven women (9%) remained positive for the same HPV type. Most women had cleared
      the HPV infection diagnosed at treatment within 3 months. The cryotherapy group
      had lower CIN grades, was younger, and had a slower HPV clearance rate (P <.002).
      Only four couples had HPV DNA of the same type detected. CONCLUSION: Surgical
      treatment of CIN usually results in clearance of HPV infection within 3 months.
      Human papillomavirus DNA testing may be useful as a rapid intermediate end point
      for monitoring the efficacy of treatments.

PMID- 12423863
TI  - Optimizing the hybrid capture II human papillomavirus test to detect cervical
      intraepithelial neoplasia.
AB  - OBJECTIVE: To estimate the optimal relative light unit ratio, and correspondingly
      viral load, of the hybrid capture II oncogenic human papillomavirus
      deoxyribonucleic acid test for detecting cervical intraepithelial neoplasia
      (CIN). METHODS: Women with abnormal cytology were referred for colposcopy, and a
      cervical swab or brush specimen was obtained for human papillomavirus testing.
      Sensitivities, specificities, and likelihood ratios of different relative light
      unit ratio cutoffs were calculated using a reference standard of colposcopy or
      biopsy of either CIN II+ (CIN II, III, or carcinoma), or CIN I+ (CIN I, CIN II+).
      The receiver operating characteristic curve was used to estimate optimal test
      positive cutoff points for the hybrid capture II test. RESULTS: CIN II+ was found
      in 18.7% (98 of 524) and CIN I in 10.5% (55 of 524) of the women. The optimal
      relative light unit ratio was 15.56, giving a sensitivity and specificity of
      82.7% and 73.2% for CIN II+, and 74.2% and 77.8% for CIN I+. In a stratified
      analysis, a higher relative light unit cutoff (15.19) optimized sensitivity and
      specificity for CIN II+ (sensitivity 81.8%, specificity 51.5%) for women with low
      grade squamous intraepithelial lesions cytology, whereas the optimal cutoff was
      2.36 (sensitivity 100%, specificity 73.0%) for women with atypical squamous cells
      of undetermined significance, yielding referral rates of 53.3% and 28.7%,
      respectively. Use of a swab or brush was not associated with the level of human
      papillomavirus detected (P >.05). CONCLUSION: Use of a higher cutoff for the
      relative light unit ratio (higher viral load) of the hybrid capture II test may
      improve the management of women, especially those with low-grade squamous
      intraepithelial lesions cytology.

PMID- 12423864
TI  - Pregnancy, labor, delivery, and pelvic organ prolapse.
AB  - OBJECTIVE: To compare 1) the occurrence of pelvic organ prolapse after vaginal
      and cesarean delivery, and 2) the susceptibility of black and white women to
      developing prolapse during childbirth. METHODS: Ninety-four nulliparous women
      were evaluated for pelvic organ prolapse at their 36-week antepartum and 6-week
      postpartum visits using the International Continence Society staging system. A
      change in International Continence Society stage from 36 weeks antepartum to 6
      weeks postpartum was considered pelvic organ prolapse that developed during
      childbirth. RESULTS: Forty-three (46%) of 94 nulliparous women had pelvic organ
      prolapse at their 36-week antepartum visit. Twenty-four (26%) had a stage II
      prolapse. Six weeks postpartum, 13 of 41 (32%) who had spontaneous vaginal
      delivery and nine of 26 (35%) who had cesarean delivery during active labor
      developed a new prolapse (P =.805). Seven (17%) who had spontaneous vaginal
      delivery and two (8%) who had cesarean delivery during active labor revealed a
      more severe prolapse (P =.237). Eighteen (33%) of 54 black and 17 (43%) of 40
      white women developed a new prolapse during childbirth (P =.363). Eight (15%)
      black and six (15%) white women revealed a more severe prolapse (P =.980).
      CONCLUSION: Our data suggest that elective cesarean is only partially effective
      in preventing pelvic organ prolapse. Cesarean delivery during active labor and
      vaginal delivery had a similar effect on the maternal pelvic support. This
      indicates that prolapse developed during the first and not the second stage of
      labor. Black women are as susceptible to developing prolapse during childbirth as
      their white counterparts.

PMID- 12423865
TI  - The effect of a nitric oxide donor on fetal heart rate patterns in patients with
      hypertension.
AB  - OBJECTIVE: To estimate whether nitric oxide donors can be administered safely to
      patients with pregnancy-associated hypertension based on computer analysis of
      antepartum fetal heart rate (FHR) tracings. METHODS: Thirty-minute recordings of
      FHR and fetal movements, before (stage I) and after (stage II) sublingual
      administration of 5 mg of isosorbide dinitrate, a nitric oxide donor, were
      obtained in 20 women with pregnancy-associated hypertension. RESULTS: Baseline
      FHR in stage I did not differ significantly from that in stage II (140.9 +/- 2.0
      beats per minute and 137.5 +/- 2.1 beats per minute, respectively). There were no
      significant differences between stage I and II in the number (9.67 +/- 1.14
      versus 9.56 +/- 1.07), amplitude (26.14 +/- 1.03 versus 24.5 +/- 0.85 beats per
      minute), and duration (36.03 +/- 1.46 versus 34.04 +/- 1.57 seconds) of heart
      rate accelerations. During stage II, the number (1.39 +/- 0.43) and duration
      (26.9 +/- 1.38 seconds) of heart rate decelerations did not change significantly
      as compared with stage I (1.67 +/- 0.33 and 26.23 +/- 1.13 seconds,
      respectively). However, the amplitude of heart rate decelerations was
      significantly higher in stage I compared with stage II (-19.36 +/- 1.44 versus 
      14.38 +/- 1.55 beats per minute, respectively). There were more fetal body
      movements during stage II than stage I (12.39 +/- 2.8 versus 9.72 +/- 2.0), but
      the difference was not statistically significant. CONCLUSION: Based on numeric
      analysis of FHR records, our data suggest that short-acting donors of nitric
      oxide can be administered safely to patients with pregnancy-associated
      hypertension.

PMID- 12423866
TI  - Circulating erythroblasts in maternal blood are not elevated before onset of
      preterm labor.
AB  - OBJECTIVE: Preterm labor has recently been reported to be associated with an
      increased release of cell free fetal deoxyribonucleic acid (DNA) into the
      maternal circulation. We have previously observed increases in both fetal cell
      traffic and cell free fetal DNA in preeclamptic pregnancies. In this study, we
      investigated whether fetal cell traffic is also disturbed in pregnancies with
      preterm labor. METHODS: In a case-control study, we examined 47 pregnancies
      complicated by preterm contractions that occurred between 20 and 34 weeks'
      gestation and an equal number of matched controls. Erythroblasts were enriched
      for by magnetic cell sorting and enumerated. These values were then correlated
      with subsequent pregnancy outcome. RESULTS: In the study group 16 patients
      delivered prematurely (subgroup A). The other 31 (subgroup B) delivered at term,
      as did all those in the control group. No significant difference was noted in
      erythroblast numbers between either one of the subgroups and the controls.
      CONCLUSION: Contrary to the reported increased levels of free fetal DNA in
      maternal serum, erythroblasts in maternal blood are not elevated significantly in
      pregnancies with threatened premature labor or in those that deliver preterm.

PMID- 12423867
TI  - Expectant management versus labor induction for suspected fetal macrosomia: a
      systematic review.
AB  - OBJECTIVE: To systematically review and summarize the medical literature
      regarding the effects of expectant management and labor induction on mode of
      delivery and perinatal outcomes in patients with suspected fetal macrosomia. DATA
      SOURCES: We supplemented a search of entries in electronic databases with
      references cited in original studies and review articles to identify studies
      assessing management of patients with suspected fetal macrosomia. METHODS OF
      STUDY SELECTION: We evaluated, abstracted data, and performed quantitative
      analyses in studies assessing the outcome of patients with suspected fetal
      macrosomia. Observational studies and randomized trials were included in this
      systematic review. TABULATION, INTEGRATION, AND RESULTS: Twenty-nine studies were
      identified, 11 of which met our criteria for systematic review and meta-analysis.
      These 11 studies included 3751 subjects. Of these, 2700 were managed expectantly,
      and 1051 underwent labor induction. We calculated an estimate of the odds ratio
      (OR) with 95% confidence intervals (CIs) for dichotomous outcomes, using random-
      and fixed-effects models for outcomes. Summary statistics for the nine
      observational studies showed that, compared with those whose labor was induced,
      women who experienced spontaneous onset of labor had a lower incidence of
      cesarean delivery (OR 0.39, 95% CI 0.30, 0.50) and higher rates of spontaneous
      vaginal delivery (OR 2.07, 95% CI 1.34, 3,19); however, significant differences
      in these outcomes were not noted when the two randomized trials were assessed. No
      differences were noted in rates of operative vaginal deliveries, incidence of
      shoulder dystocia, or abnormal Apgar scores in the analyses of the observational
      or randomized studies. CONCLUSION: Based on data from observational studies,
      labor induction for suspected fetal macrosomia results in an increased cesarean
      delivery rate without improving perinatal outcomes. Although their statistical
      power is limited, randomized clinical trials have not confirmed these findings.

PMID- 12423868
TI  - Drug therapy of urinary urge incontinence: a systematic review.
AB  - OBJECTIVE: To review the efficacy of drug therapy for urinary urge incontinence
      by examining the published literature. METHODS OF STUDY SELECTION: In October
      1999, we searched the medical databases MEDLINE, EMBASE, and Cochrane Controlled
      Trials Register to identify prospective randomized, double-blind, placebo
      controlled clinical trials in the English literature evaluating drug therapy
      (except hormonal therapy) of urinary urge incontinence. Trials were categorized
      by type of drug and outcome variables. TABULATION, INTEGRATION, AND RESULTS:
      Forty-seven trials were identified. Twenty-four, 12, and 11 trials evaluated
      anticholinergic drugs, drugs with anticholinergic and calcium antagonistic
      properties, and alternative regimens, respectively. Data regarding treatment
      effects of anticholinergic drugs are consistent with a high therapeutic efficacy
      and characteristic side effects. Therapeutic efficacy and side effect patterns of
      terodiline, an agent with anticholinergic and calcium antagonistic properties,
      were comparable to those of anticholinergic agents. Terodiline, however, has been
      withdrawn from the market because of its association with cardiac arrhythmia. Of
      the investigated alternative drug regimens, the papaverine-like smooth muscle
      relaxant flavoxate was reported to be ineffective. Studies investigating the
      dopamine agonist bromocryptine, the alpha-adrenoceptor blocker prazosin, or the
      gamma-aminobutyric acid receptor agonist baclofen showed subjective and/or
      objective improvement of symptoms without reaching statistical significance,
      whereas the tricyclic antidepressant doxepin, the neurotoxin capsaicin, and the
      prostaglandin synthase inhibitor flurbiprofen led to statistically significant
      subjective and/or objective improvement of symptoms. No data for subjective
      and/or objective improvement of symptoms could be extracted from the studies
      using the anticholinergic and calcium antagonistic agent propiverine and the
      calcium antagonist thiphenamil. CONCLUSION: Published trials support
      anticholinergic drugs as efficacious therapy for urinary urge incontinence, with
      predictable side effects. At present, these agents represent the pharmacological
      treatment of choice for this condition. The potential value of selected
      alternative drugs is underscored by the available data.

PMID- 12423870
TI  - The management of preterm labor.
AB  - Preterm birth is the leading cause of neonatal mortality and a substantial
      portion of all birth-related short- and long-term morbidity. Spontaneous preterm
      labor is responsible for more than half of preterm births. Its management is the
      topic of this review. Although there are many maternal characteristics associated
      with preterm birth, the etiology in most cases is not clear, although, for the
      earliest cases, the role of intrauterine infection is assuming greater
      importance. Most efforts to prevent preterm labor have not proven to be
      effective, and equally frustrating, most efforts at arresting preterm labor once
      started have failed. The most important components of management, therefore, are
      aimed at preventing neonatal complications through the use of corticosteroids and
      antibiotics to prevent group B streptococcal neonatal sepsis, and avoiding
      traumatic deliveries. Delivery in a medical center with an experienced
      resuscitation team and the availability of a newborn intensive care unit will
      ensure the best possible neonatal outcomes. Obstetric practices for which there
      is little evidence of effectiveness in preventing or treating preterm labor
      include the following: bed rest, hydration, sedation, home uterine activity
      monitoring, oral terbutaline after successful intravenous tocolysis, and
      tocolysis without the concomitant use of corticosteroids.

PMID- 12423869
TI  - Successful assisted reproductive technology: the beauty of one.
AB  - In 1999, the approximately 90,000 in vitro fertilization procedures accounted for
      98% of all types of assisted reproductive technologies in the United States.
      Since 1992, when Congress recognized a public health interest in reporting
      accurate and timely information about pregnancy success rates for infertility
      treatments, success has been defined as a live birth after an assisted
      reproductive technology cycle, regardless of the number of live-born infants per
      delivery. Because of pressures to achieve success, often more than one pre-embryo
      is transferred per cycle, frequently resulting in multifetal pregnancy reduction
      or multiple births. Twin and higher order births associated with assisted
      reproductive technology have increased significantly since 1980. Although births
      resulting from assisted reproductive technology amount to less than 1% of all
      live births, they now account for about a third of all twin births and more than
      40% of triplets and higher number births in the United States. Although multiple
      births fit the current definition of success, they create much higher risks for
      maternal and infant morbidity and mortality, contributing to more than $640
      million in excess initial hospital costs during the year 2000 alone. With recent
      improvements in assisted reproductive technology procedures that increase the
      likelihood of delivery after the transfer of just one pre-embryo per cycle, it is
      time to re-examine how success is measured. Assisted reproductive technology
      success should be redefined to be the proportion of cycles resulting in a
      singleton, live birth.

PMID- 12423871
TI  - Vaginal breech delivery is no longer justified.

PMID- 12423872
TI  - Vaginal breech delivery is no longer justified.

PMID- 12423874
TI  - Who was caring for Mary?

PMID- 12423875
TI  - Risk of warfarin during pregnancy with mechanical valve prostheses.

PMID- 12423877
TI  - Postoperative neuropathies after major pelvic surgery.

PMID- 12423879
TI  - Activation of acyl condensation reaction of monomeric 6-hydroxymellein synthase,
      a multifunctional polyketide biosynthetic enzyme, by free coenzyme A.
AB  - 6-Hydroxymellein (6HM) synthase is a multifunctional polyketide enzyme induced in
      carrot cells, whose fully active homodimer catalyzes condensation of acyl-CoAs
      and the NADPH-dependent ketoreduction of the enzyme-bound intermediate. 6HM
      forming activity of the synthase was markedly decreased when the reaction mixture
      pH was adjusted from 7.5 to 6.0. However, under these slightly acidic conditions,
      the acyl condensation catalyzed by the dissociated monomer enzyme was appreciably
      stimulated by addition of free coenzyme A (CoA). In contrast, the condensation
      reaction at pH 6.0 was significantly inhibited in the presence of CoA when the
      reaction was carried out with the NADPH-omitted dimer synthase. Among the kinetic
      parameters of the acyl condensation, velocity of the monomer-catalyzing reaction
      at the acidic pH was appreciably increased upon addition of CoA while K(m)s did
      not show any significant change in the presence and absence of the compound.
      These results suggest that CoA associates with a specific site in the dissociated
      monomeric form of 6HM synthase, and the velocity of the acyl condensation
      reaction catalyzed by the CoA-synthase complex appreciably increases in acidic
      conditions.

PMID- 12423880
TI  - Invertase from a strain of Rhodotorula glutinis.
AB  - An invertase (beta-D-fructofuranoside fructohydrolase, EC 3.2.1.26) from
      Rhodotorula glutinis was purified by ammonium sulfate fractionation, gel
      filtration and anion exchange chromatography. Invertase molecular weight was
      estimated to be 100 kDa by analytical gel filtration and 47 kDa by sodium dodecyl
      sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Molecular mass
      determinations indicated that the native enzyme exists as a homodimer. It is a
      glycoprotein that contains 19% carbohydrate. The enzyme attacks beta-D
      fructofuranoside (raffinose, stachyose and sucrose) from the fructose end. It has
      a K(m) of 0.227 M and a V(max) of 0.096 micromol/min with sucrose as a substrate.
      Invertase activity is stable between pH 2.6 and 5.5 for 30 min, maximum activity
      being observed at pH 4.5. The activation energy was 6520 cal/mol. The enzyme is
      stable between 20 and 60 degrees C. Mg(2+) and Ca(2+) ions stimulated invertase
      activity 3-fold, while Fe(2+), K(+), Co(2+), Na(+) and Cu(2+) increased activity
      about 2-fold. The transfructosylation reaction could not be observed. This enzyme
      is of particular interest since it appears to have a high hydrolytic activity in
      1 M sucrose solution. This fact would make the enzymatic hydrolysis process
      economically efficient for syrup production using by-products with high salt and
      sugar contents such as sugar cane molasses.

PMID- 12423881
TI  - Unusual 4-hydroxybenzaldehyde synthase activity from tissue cultures of the
      vanilla orchid Vanilla planifolia.
AB  - Tissue cultures of the vanilla orchid, Vanilla planifolia, produce the flavor
      compound vanillin (4-hydroxy-3-methoxybenzaldehyde) and vanillin precursors such
      as 4-hydroxybenzaldehyde. A constitutively expressed enzyme activity catalyzing
      chain shortening of a hydroxycinnamic acid, believed to be the first reaction
      specific for formation of vanilla flavor compounds, was identified in these
      cultures. The enzyme converts 4-coumaric acid non-oxidatively to 4
      hydroxybenzaldehyde in the presence of a thiol reagent but with no co-factor
      requirement. Several forms of this 4-hydroxybenzaldehyde synthase (4HBS) were
      resolved and partially purified by a combination of hydrophobic interaction, ion
      exchange and gel filtration chromatography. These forms appear to be
      interconvertible. The unusual properties of the 4HBS, and its appearance in
      different protein fractions, raise questions as to its physiological role in
      vanillin biosynthesis in vivo.

PMID- 12423882
TI  - alpha-Galactosidase from cultured rice (Oryza sativa L. var. Nipponbare) cells.
AB  - The alpha-galactosidase from rice cell suspension cultures was purified to
      homogeneity by different techniques including affinity chromatography using N
      epsilon-aminocaproyl-alpha-D-galactopyranosylamine as the ligand. From 11 l of
      culture filtrate, 28.7 mg of purified enzyme was obtained with an overall yield
      of 51.9%. The cDNA coding for the alpha-galactosidase was cloned and sequenced.
      The enzyme was found to contain 417 amino acid residues composed of a 55 amino
      acid signal sequence and 362 amino acid mature alpha-galactosidase; the molecular
      weight of the mature enzyme was thus calculated to be 39,950. Seven cysteine
      residues were also found but no putative N-glycosylation sites were present. The
      observed homology between the deduced amino acid sequences of the mature enzyme
      and alpha-galactosidases from coffee (Coffea arabica), guar (Cyamopsis
      tetragonolooba), and Mortierella vinacea alpha-galactosidase II were over 73, 72,
      and 45%, respectively. The enzyme displayed maximum activity at 45 degrees C when
      p-nitrophenyl-alpha-D-galactopyranoside was used as substrate. The rice alpha
      galactosidase and Mortierella vinacea alpha-galactosidase II acted on both the
      terminal alpha-galactosyl residue and the side-chain alpha-galactosyl residue of
      the galactomanno-oligosaccharides.

PMID- 12423883
TI  - Gene expression of ascorbic acid-related enzymes in tobacco.
AB  - GDP-D-mannose pyrophosphorylase (GMPase) and L-galactono-1, 4-lactone
      dehydrogenase (GalLDH) are key enzymes in L-ascorbic acid (AsA) biosynthesis of
      plants, and a full-length cDNA for GMPase was isolated from tobacco using PCR.
      Additionally, expression of GMPase, GalLDH and other AsA-related enzymes was
      examined in tobacco tissues and cultured BY-2 cells, and the relationship between
      their expression patterns and AsA content is discussed. It was found that the
      expression of GalLDH and GMPase mRNAs was markedly suppressed by loading AsA,
      suggesting that AsA concentration in the cells may regulate AsA biosynthesis.
      Moreover, the expression of GMPase and GalLDH mRNAs in tobacco leaf also
      suggested that AsA biosynthesis may be induced by light.

PMID- 12423884
TI  - Formation of pyridine nucleotides under symbiotic and non-symbiotic conditions
      between soybean nodules and free-living rhizobia.
AB  - Enzymatic regulation of pyricline nucleotide formation, under symbiotic and non
      symbiotic conditions, was analyzed using soybeans (Glycine max L. cv.
      'Akisengoku') and rhizobia (Bradyrhizobia japonicum strain A1017), respectively.
      It was found that levels of pyridine nucleotides in bacteroids in root nodules
      were different from those in free-living cells of rhizobia. This difference was
      associated with differences in activities of enzymes involved in the pathway from
      L-tryptophan to NAD and NADP. That is, these activities were lower in bacteroids
      than in free-living bacteria and lower in the nodule cytosol than in root
      extracts. The optimum pH for NAD synthetase in bacteroids, was 9.0. Additionally,
      the optimum pH for ATP-nicotinamide mononucleotide (NMN) adenyltransferase, final
      step enzyme in NAD formation, was estimated to be 7.6. In the bacteroid fraction,
      the K(m) of NAD synthetase (22 microM) was approximately 1/22 of that of ATP-NMN
      adenyltransferase (482 microM). Vmax values were estimated to be almost in the
      same order for both NAD synthetase and ATP-NMN adenyltransferase. This is the
      first report on the formation of pyridine nucleotides originating from L
      tryptophan in bacteroids in soybean nodules and free-living bacteria.

PMID- 12423885
TI  - Processing of N-glycans of two yellow lupin phosphohydrolases during seed
      maturation and dormancy.
AB  - Acid phosphatase (AP) and diphosphonucleoside phosphatase/phosphodiesterase
      (PPD1) were purified from yellow lupin (Lupinus luteus L.) immature green seeds
      (40 days after blooming), dry seeds (40 days later) and dry seeds stored for 160
      days. Both enzymes are known to differ in the type of N-glycosylation: the first
      has an N-glycosylation pattern typical for a vacuolar protein, while the second
      enzyme has a pattern typical for an extracellular or membrane-bound protein. N
      Glycans were released from each of the enzyme preparations, fluorescence labeled,
      separated and identified by HPLC (GlycoSep N and GlycoSep H columns). Changes in
      the level of each N-glycan during seed maturation and dormancy were compared. The
      results show that N-glycan processing in the case of AP and PPD1-two proteins
      residing in the same plant organ, but possibly in different compartments-is not
      synchronized and performed not only in metabolically active maturing seeds, but
      also in metabolically inactive dormant seeds.

PMID- 12423886
TI  - Monolignol biosynthesis in microsomal preparations from lignifying stems of
      alfalfa (Medicago sativa L.).
AB  - Microsomal preparations from lignifying stems of alfalfa (Medicago sativa L.)
      contained coniferaldehyde 5-hydroxylase activity and immunodetectable caffeic
      acid 3-O-methyltransferase (COMT), and catalyzed the S-adenosyl L-methionine
      (SAM) dependent methylation of caffeic acid, caffeyl aldehyde and caffeyl
      alcohol. When supplied with NADPH and SAM, the microsomes converted caffeyl
      aldehyde to coniferaldehyde, 5-hydroxyconiferaldehyde, and traces of
      sinapaldehyde. Coniferaldehyde was a better precursor of sinapaldehyde than was 5
      hydroxyconiferaldehyde. The alfalfa microsomes could not metabolize 4-coumaric
      acid, 4-coumaraldehyde, 4-coumaroyl CoA, or ferulic acid. No metabolism of
      monolignol precursors was observed in microsomal preparations from transgenic
      alfalfa down-regulated in COMT expression. In most microsomal preparations, the
      level of the metabolic conversions was independent of added recombinant COMT.
      Taken together, the data provide only limited support for the concept of
      metabolic channeling in the biosynthesis of S monolignols via coniferaldehyde.

PMID- 12423887
TI  - Oxidative cleavage of the C-C bond of 3,6-dialkylcyclohexane-1,2-diones by cell
      suspension cultures of Marchantia polymorpha.
AB  - Biotransformation of 3,6-dialkylcyclohexane-1,2-diones by cell suspension
      cultures of Marchantia polymorpha involves regioselective oxidative cleavage of
      the C-C bond to give the corresponding oxocarboxylic acids shortened by one
      carbon unit. In the case of cyclohexane-1,2-dione, adipic acid was obtained.

PMID- 12423888
TI  - S-Substituted cysteine derivatives and thiosulfinate formation in Petiveria
      alliacea-part II.
AB  - Three cysteine derivatives, (R)-S-(2-hydroxyethyl)cysteine, together with
      (R(S)R(C))- and (S(S)R(C))-S-(2-hydroxyethyl)cysteine sulfoxides, have been
      isolated from the roots of Petiveria alliacea. Furthermore, three additional
      amino acids, S-methyl-, S-ethyl-, and S-propylcysteine derivatives, were
      detected. They were present only in trace amounts (<3 microg g(-1) fr. wt),
      precluding determination of their absolute configurations and oxidation states.
      In addition, four thiosulfinates, S-(2-hydroxyethyl) (2-hydroxyethane)-, S-(2
      hydroxyethyl) phenylmethane-, S-benzyl (2-hydroxyethane)- and S-benzyl
      phenylmethanethiosulfinates, have been found in a homogenate of the roots. The
      formation pathways of various benzyl/phenyl-containing compounds previously found
      in the plant were also discussed.

PMID- 12423889
TI  - Polysaccharides of lichenized fungi of three Cladina spp.: significance as
      chemotypes.
AB  - The chemical structures of nigerans, an alpha-glucan, laminarans, a beta-glucan,
      galactoglucomannans and galactomannoglucans of three species of Cladina, namely
      C. arbuscula, C. confusa and C. substenius, were determined and compared.
      According to chemical and spectroscopic analyses, the glucans investigated to
      date, which have been isolated in 15 Cladonia species, as well as the
      galactomannoglucans and galactoglucomannans, have similar principal structures.
      This suggests that, in terms of polysaccharide structure, Cladonia and Cladina
      genera do not show differences. DNA studies support this idea and it is proposed
      that Cladina be reduced to a synonym under Cladonia.

PMID- 12423890
TI  - Bioactive terpenoids from sunflower leaves cv. Peredovick.
AB  - The CH(2)Cl(2) extract of dried leaves of Helianthus annuus L. cv. Peredovick(R)
      has yielded, in addition to the known sesquiterpene lactones annuolide E and
      leptocarpin, and the sesquiterpenes heliannuols A, C, D, F, G, H, I, the new
      bisnorsesquiterpene, annuionone E, and the new sesquiterpenes heliannuol L,
      helibisabonol A and helibisabonol B. Structural elucidation was based on
      extensive spectral (one and two-dimensional NMR experiments) and theoretical
      studies. The sesquiterpenes heliannuol A and helibisabonol A and the
      sesquiterpene lactone leptocarpin inhibited the growth of etiolated wheat
      coleoptiles.

PMID- 12423891
TI  - Mulberry anthracnose antagonists (iturins) produced by Bacillus amyloliquefaciens
      RC-2.
AB  - Bacillus amyloliquefaciens strain RC-2 produced seven antifungal compounds (1-7)
      secreted into the culture filtrate. These compounds inhibited the development of
      mulberry anthracnose caused by the fungus, Colletotrichum dematium. Chemical
      structural analyses by NMR and FAB-MS revealed that all these compounds were
      iturins (cyclic peptides with the following sequence: L-Asn --> D-Tyr --> D-Asn -
      > L-Gln --> L-Pro --> D-Asn --> L-Ser --> D-beta-amino acid -->) and compounds 1
      6 are identical to iturins A-2-A-7, respectively. Compound 7 (iturin A-8) is a
      new iturin, which has a -(CH(2))(10)CH(CH(3))CH(2)CH(3) group as a side chain in
      the beta-amino acid in the molecule.

PMID- 12423892
TI  - Insecticidal sesquiterpene pyridine alkaloids from Euonymus species.
AB  - Three insecticidal sesquiterpene pyridine alkaloids with a beta-dihydroagarofuran
      sesquiterpene skeleton, euoverrine A (1), B (2), and euophelline (3), and a known
      compound, euojaponine C (4), were isolated from the root bark of Euonymus
      verrucosides, E. fortunei and E. phellomana by bioassay-guided fractionation.
      Their chemical structures were elucidated mainly by analyses NMR and MS spectral
      data.

PMID- 12423893
TI  - Anhydronium bases from Rauvolfia serpentina.
AB  - Five anhydronium bases were isolated by preparative HPLC from a methanolic
      extract of Rauvolfia serpentina roots. For the first time 3,4,5,6
      tetradehydroyohimbine, 3,4,5,6-tetradehydro-(Z)-geissoschizol, 3,4,5,6
      tetradehydrogeissoschizol and 3,4,5,6-tetradehydrogeissoschizine-17-O-beta-D
      glucopyranoside were isolated from a natural source. In addition, the well-known
      anhydronium base serpentine was isolated. The structures of the compounds were
      determined by 1H and 13C NMR, MS and UV.

PMID- 12423894
TI  - Three series of high molecular weight alkanoates found in Amazonian plants.
AB  - Electron impact mass spectra were measured by high temperature high resolution
      gas chromatography-mass spectrometry (HT-HRGC-MS) for three homologous series of
      high molecular weight compounds present in the Amazonian plants Marupa (Simaruba
      amara) and Brazil nut (Bertholettia excelsa). Based on their mass spectra, the
      compounds were identified as three wax ester series of alpha-tocopherol (vitamin
      E), beta-tocopherol and phytol (2,6,10,14-tetramethylhexadec-14-en-16-ol). The
      interpretations are supported by high resolution mass spectrometry and GC
      retention indices of authentic standards.

PMID- 12423895
TI  - Composition of sugarcane waxes in rum factory wastes.
AB  - Wastes produced during fermentation and distillation of crude sugarcane juice in
      rum factories were evaluated as a new source of waxes. The chemical composition
      of the crude wax extracted from adsorbat of the wastes on fuller's earth was
      studied by GC-mass spectrometry. Series of linear alkanes (C19-C33), and wax
      esters constitute the main components. In addition, phytosterols, triterpene
      methyl ethers, ethyl and methyl esters of fatty acids, and free fatty acids were
      found as minor components. Acid (predominance of C16 and C18) and alcohol
      portions (C26-C32) of the wax esters were analysed after saponification.

PMID- 12423897
TI  - Prehension in young children with Down syndrome.
AB  - Prehension was examined in 3-year old children with Down syndrome (DS, n = 3) and
      in typically-developing children matched in chronological age (3-year olds; n =
      3) or mental age and motor experience (2-year olds; n = 3). The task required
      reaching to grasp dowels. Video-based movement analysis yielded temporal and
      kinematic measures. Children with DS were hypothesized to have deficits in
      feedback-dependent components of prehension (anticipatory grip-closure and
      deceleration of reach), whereas feedforward components (reach's acceleration
      phase; grasp's preshaping) were assumed to be unimpaired [Latash, 1993, Control
      of human movement, pp. 283-292; Latash, 1994, What is clumsiness? In: Motor
      Control and Down Syndrome II Proceedings of the second international conference,
      pp. 68-71]. The findings supported these hypotheses. In comparison to control
      groups, children with DS had significantly: (a) less time in deceleration of
      reaching, (b) fewer anticipatory grip-closures, and (c) longer movement times for
      dowel-lift. Young children with DS appeared to use dowel-contact to decelerate
      the limb and initiate grip-closure. In contrast, reach-acceleration time and
      grasp-preshaping did not differ across groups. These findings suggest that
      children with DS display qualitative differences in motor capabilities rather
      than simply a delayed rate of typical developmental progression.

PMID- 12423898
TI  - Recognition thresholds for plane-rotated pictures of familiar objects.
AB  - We investigated picture plane rotation effects on the minimum stimulus duration
      required to recognise pictures of familiar objects in a picture-word verification
      task. Participants made unspeeded responses, selecting from 126 written
      alternatives. Longer stimulus durations were needed to identify plane-misoriented
      views. These orientation effects were non-linear, arguing against a simple mental
      rotation account of compensation for plane misorientation in identification
      tasks. Orientation effects were found for almost all items, in particular
      including those labelled at the basic level (cf. Hamm, McMullen, 1998, Journal of
      Experimental Psychology: Human Perception and Performance 24, 413-426). We
      suggest that plane misorientation increases the difficulty of basic level as well
      as subordinate level identification unless only a small, visually dissimilar set
      of stimuli are presented. Errors in the task were analysed to provide an
      alternative, objective measure of perceived visual similarity, by assessing the
      number and nature of mistaken identifications made to a given target object. We
      propose that misorientation effects are best understood in terms of the effects
      of the perceived visual similarity of a target to its set of response
      alternatives rather than in terms of the level (basic or subordinate) at which
      the target is to be identified.

PMID- 12423899
TI  - States of awareness across multiple memory tasks: obtaining a "pure" measure of
      conscious recollection.
AB  - Four experiments were conducted to examine the nature of recollective experience
      across different explicit memory tests. Experiments 1 and 2 showed that the
      proportion of retrieved items that were given Remember responses were equivalent
      across free recall, category cued recall, category plus letter cued recall, and
      recognition memory tests unlike the result reported by Tulving [Can. Psychol. 26
      (1985) 1]. Experiments 3 and 4 revealed that Remember judgments are influenced by
      both conceptual and perceptual variables not only in the recognition task but in
      other explicit memory tasks as well. Taken together, the empirical evidence from
      this study demonstrates that explicit memory performance is accompanied by
      different states of awareness not only in recognition but also across other
      memory tasks including free recall.

PMID- 12423900
TI  - Exocentric pointing to opposite targets.
AB  - We use an exocentric pointing task to study exocentric visual directions to
      targets that are opposite to a pointer relative to the observer. (The apparent
      distance between the target and the pointer always exceeded 90 degrees of visual
      angle.) All pointing takes place in the horizontal plane at eye height. Observers
      could not see both target and pointer at a single glance. They had to look back
      and forth between them, using combinations of eye movements, head turns, twists
      at the waist and turning on the feet. In the limit of diametrically opposite
      targets we find that the observers pick either one of two distinct orientations
      of the pointer as equally "visually correct". Which one results depends on the
      stance assumed by the observer. The difference between the two equally acceptable
      pointings is between 5 degrees and 10 degrees. Such a result is predicted from
      earlier measurements in the context of a model that describes the geometry of the
      horizon as a Riemannian space with varying intrinsic curvature. The present
      results thus fit--perhaps surprisingly--very well in such a picture.

PMID- 12423901
TI  - Sex differences in recollective experience for olfactory and verbal information.
AB  - We examined recollective experience as a function of sex for olfactory and verbal
      information. In the first study, men and women studied a set of highly familiar
      odors with incidental or intentional encoding instructions. In the second study,
      participants were presented with a number of sentences. At recognition,
      participants indicated whether their positive response was based on conscious
      recollection (remembering), a feeling of familiarity (knowing), or guessing. The
      results indicated that recollection was higher among women than men, and that
      familiarity-based recognition was equally large across sex for both types of
      information.The finding that the sex-related experiential difference disappeared
      when controlling for verbal proficiency suggests that sex-related differences in
      activating verbal information play an important role for sex differences in
      recollective experience.

PMID- 12423903
TI  - Biotechnological aspects of marine sponges.

PMID- 12423904
TI  - Cultivation of primmorphs from the marine sponge Suberites domuncula:
      morphogenetic potential of silicon and iron.
AB  - Marine demosponges (phylum Porifera) are rich sources for potent bioactive
      compounds. With the establishment of the primmorph system from sponges,
      especially from Suberites domuncula, the technology to cultivate sponge cells in
      vitro improved considerably. This progress was possible after the elucidation
      that sponges are provided with characteristic metazoan cell adhesion receptors
      and extracellular matrix molecules which allow their cells a positioning in a
      complex organization pattern. This review summarizes recent data on the
      cultivation of sponges in aquaria and--with main emphasis--of primmorphs in
      vitro. It is outlined that silicon and Fe(+++) contribute substantially to the
      formation of larger primmorphs (size of 10 mm) as well as of a canal system in
      primmorphs; canals are probably required for an improved oxygen and food supply.
      We conclude that the primmorph system will facilitate a sustainable use of
      sponges in the production of bioactive compounds; it may furthermore allow new
      and hitherto not feasible insights into basic questions on the origin of Metazoa.

PMID- 12423905
TI  - Growth and regeneration in cultivated fragments of the boreal deep water sponge
      Geodia barretti Bowerbank, 1858 (Geodiidae, Tetractinellida, Demospongiae).
AB  - A cultivation method has been developed for the boreal deep-water sponge Geodia
      barretti (Demospongiae, Geodiidae), a species which is common in the deep
      Norwegian fjords. The species is known to contain secondary metabolites which are
      biologically active. Choanosomal fragments of 2-4 cm(3) (approximately 3-7 g)
      were kept in half-open systems. Cicatrisation and regeneration processes were
      surveyed by histological examination during 8 months of cultivation. During the
      first weeks, the weight of the fragments decreased. However, after about 6 weeks
      the weight equalled the original weight, and after 1 year the weight had
      increased by about 40% compared to the original weight. The initial decrease was
      due to complex healing processes and the regeneration of the cortex, a
      sterrastral layer typical for the family of the Geodiidae. We document, for the
      first time, the complete cortex reconstruction in an adult G. barretti, as well
      as the development of egg cells during cultivation. Our study represents the
      first attempt at biotechnological production of boreal sponge tissue. For
      successful farming of G. barretti and other boreal and arctic sponges, however,
      further investigation is needed on factors stimulating growth and secondary
      metabolite production in the target species.

PMID- 12423906
TI  - Development in primary cell culture of demosponges.
AB  - We have established primary cell culture of the marine demosponge Dysidea avara
      and Suberites domuncula. Microbial contamination was controlled by the use of a
      pool of antibiotics confirming the goodness of this procedure. Effect of pH,
      temperature and light was studied to establish the better growth conditions. The
      comparison of lipid composition of sponge and cells suggested a series of
      experiments to optimise the medium. A glucose dose-dependent experiment showed
      that the ideal glucose concentration is 1 g l(-1). Supplementing the medium with
      unsaturated fatty acid and retinol, no promotion of growth was observed, but the
      compounds were totally metabolised by cells. Increments from 70 to 160% in the
      number of cells were observed, supplementing the medium with different
      concentration of cholesterol. These results suggest that the analysis of the
      chemical composition of sponge and cells give indication on the composition of
      the nutrient media.

PMID- 12423907
TI  - Primmorphs from seven marine sponges: formation and structure.
AB  - Primmorphs were obtained from seven different marine sponges: Stylissa massa,
      Suberites domuncula, Pseudosuberites aff. andrewsi, Geodia cydonium, Axinella
      polypoides, Halichondria panicea and Haliclona oculata. The formation process and
      the ultra structure of primmorphs were studied. A positive correlation was found
      between the initial sponge-cell concentration and the size of the primmorphs. By
      scanning electron microscopy (SEM) it was observed that the primmorphs are very
      densely packed sphere-shaped aggregates with a continuous pinacoderm (skin cell
      layer) covered by a smooth, cuticle-like structure. In the presence of
      amphotericin, or a cocktail of antibiotics (kanamycin, gentamycin, tylosin and
      tetracyclin), no primmorphs were formed, while gentamycin or a mixture of
      penicillin and streptomycin did not influence the formation of primmorphs. The
      addition of penicillin and streptomycin was, in most cases, sufficient to prevent
      bacterial contamination, while fungal growth was unaffected.

PMID- 12423908
TI  - Progress towards a controlled culture of the marine sponge Pseudosuberites
      andrewsi in a bioreactor.
AB  - Explants of the tropical sponge Pseudosuberites andrewsi were fed with the marine
      diatom Phaeodactylum tricornotum. The food was supplied either as intact algae or
      as a filtered crude extract. Growth (measured as an increase in underwater
      weight) was found in both experiments. The explants fed with intact algae
      increased to an average underwater weight of 255% of the initial weight in 45-60
      days. The explants fed with crude extract increased to an average of 200% of the
      initial weight in 30 days. These results show that it is possible to grow a
      sponge using a single microorganism species as a food source. In addition, it was
      demonstrated that sponges are also capable of growing on non-particulate food.
      Therefore, this study is an important step forward towards the development of
      controlled, in vivo sponge cultures.

PMID- 12423909
TI  - In vitro sponge fragment culture of Chondrosia reniformis (Nardo, 1847).
AB  - In vitro cultivation systems for sponges (Porifera) have to be developed to
      produce compounds of value in biotechnological processes. Organotypic culture
      attempts, which maintain or mimic the natural tissue structure, are promising
      ways towards a biotechnology of sponges. We used the Mediterranean species
      Chondrosia reniformis for sponge fragment in vitro cultivation. The species is
      common throughout the Mediterranean, easy to keep in aquariums and shows good
      recovery and regeneration after fragmentation. The regeneration process of the 50
      80 mm(3) fragments lasted for several days and resulted in a rounded or ovoid
      body shape. The aquiferous system was reduced. Cells performed proliferation
      during the first weeks as we could demonstrate by 5-bromo-2'-deoxy-uridine (BrdU)
      incorporation. No proliferation could be demonstrated after a culture period of 3
      months, but silicate uptake. Cellular density decreased with cultivation length,
      but collagen production increased. Fragments have been kept in culture up to 19
      months. C. reniformis can be used as a model system to develop feeding strategies
      and evaluate the biotechnological potential of sponge fragment in vitro
      cultivation.

PMID- 12423910
TI  - Optimizing the formation of in vitro sponge primmorphs from the Chinese sponge
      Stylotella agminata (Ridley).
AB  - The establishment and optimization of in vitro primmorph formation from a Chinese
      sponge, Stylotella agminata (Ridley), collected from the South China Sea, were
      investigated. Our aims were to identify the key factors affecting primmorph
      formation in this species and to optimize the technique for developing an in
      vitro primmorph culture system. The size of dissociated cells from S. agminata is
      relatively small, in the range between 5 and 10 microm. Round-shaped primmorphs
      of less than 100 microm were formed 3 days after transferring the dissociated
      cells into seawater containing Ca(2+) and Mg(2+). The effect of various cell
      dissociation conditions, inoculum cell density, concentration of antibiotics, pH,
      and temperature was further investigated upon the formation of primmorphs. The
      time required for primmorph formation, primmorph size distribution, and the
      proliferating capability were microscopically documented. Healthy sponge S.
      agminata, inoculum cell density and culture temperature play a critical role for
      the successful formation of primmorphs and that the microbial contamination will
      have to be controlled.

PMID- 12423911
TI  - Primary cultures from the marine sponge Xestospongia muta (Petrosiidae,
      Haplosclerida).
AB  - In the context of the investigations on the origin and in vitro production of
      bioactive compounds, primary cultures were developed from ectosomal and
      choanosomal cell suspensions from the sponge Xestospongia muta. Dissociated cells
      aggregated and reorganized into a striking reticulated network of cells, typical
      for X. muta. Moreover, in some cultures an isotropic reticulation of small
      spicules, very similar to that found in the ectosome of adult sponges, was
      observed. Phytohaemagglutinin promoted aggregation and the reorganization of the
      cells. HPLC analyses revealed that straight-chain acetylenic compounds were
      recovered from short-term cultures and that they were synthesized during culture.
      Heterotrophic bacteria were assumed to be involved in the process. Together our
      results established that X. muta would be an excellent experimental model to
      study, in laboratory conditions, the differentiation of the skeleton and the in
      vitro biosynthesis of straight-chain acetylenic compounds.

PMID- 12423912
TI  - Sponge (2',5')oligoadenylate synthetase activity in the whole sponge organism and
      in a primary cell culture.
AB  - A high (2',5')oligoadenylate (2-5A) synthetase activity was found in the marine
      sponge Geodia cydonium. Here we demonstrate that the 2-5A synthetase activity is
      present also in other sponge species although the level of the 2-5A synthetase
      activity varies in several magnitudes in different sponges. The 2-5A synthesizing
      activity was maintained in the primary culture produced from a sponge.

PMID- 12423913
TI  - Identification and antibiotic susceptibility of bacterial isolates from probiotic
      products.
AB  - In the present study, a total of 55 European probiotic products were evaluated
      with regard to the identity and the antibiotic resistance of the bacterial
      isolates recovered from these products. Bacterial isolation from 30 dried food
      supplements and 25 dairy products, yielded a total of 268 bacterial isolates
      selected from several selective media. Counts of food supplements showed
      bacterial recovery in 19 (63%) of the dried food supplements ranging from 10(3)
      to 10(6) CFU/g, whereas all dairy products yielded growth in the range of 10(5)
      10(9) CFU/ml. After identification of the isolates using whole-cell protein
      profiling, mislabeling was noted in 47% of the food supplements and 40% of the
      dairy products. In six food supplements, Enterococcus faecium was isolated
      whereas only two of those products claim this species on their label. Using the
      disc diffusion method, antibiotic resistance among 187 isolates was detected
      against kanamycin (79% of the isolates), vancomycin (65%), tetracycline (26%),
      penicillinG (23%), erythromycin (16%) and chloramphenicol (11%). Overall, 68.4%
      of the isolates showed resistance against multiple antibiotics including
      intrinsic resistances. Initially, 38% of the isolated enterococci was classified
      as vancomycin resistant using the disc diffusion method, whereas additional broth
      dilution and PCR assays clearly showed that all E. faecium isolates were in fact
      vancomycin susceptible.

PMID- 12423914
TI  - Influence of temperature, water activity and pH on growth of some xerophilic
      fungi.
AB  - The combined effects of water activity (aw), pH and temperature on the
      germination and growth of seven xerophilic fungi important in the spoilage of
      baked goods and confectionery were examined. Eurotium rubrum, E. repens, Wallemia
      sebi, Aspergillus penicillioides, Penicillium roqueforti, Chrysosporium
      xerophilum and Xeromyces bisporus were grown at 25, 30 and 37 degrees C on media
      with pH values of 4.5, 5.5, 6.5 and 7.5 and a range of water activities (aw) from
      0.92 to 0.70. The aw of the media was controlled with a mixture of equal parts of
      glucose and fructose. Temperature affected the minimum aw for germination for
      most species. For example, P. roqueforti germinated at 0.82 aw at 25 degrees C,
      0.86 aw at 30 degrees C and was unable to germinate at 37 degrees C. E. repens
      germinated at 0.70 aw at 30 degrees C, but at 25 and 37 degrees C, its minimum aw
      for germination was 0.74. C. xerophilum and X. bisporus germinated at 0.70 aw at
      all three temperatures. The optimum growth occurred at 25 degrees C for P.
      roqueforti and W. sebi, at 30 degrees C for Eurotium species, A. penicillioides
      and X. bisporus and at 37 degrees C for C. xerophilum. These fungi all grew
      faster under acidic than neutral pH conditions. The data presented here provide a
      matrix that will be used in the development of a mathematical model for the
      prediction of the shelf life of baked goods and confectionery.

PMID- 12423915
TI  - The prevalence of Arcobacter spp. on chicken carcasses sold in retail markets in
      Turkey, and identification of the isolates using SDS-PAGE.
AB  - In this study, the prevalence of Arcobacter spp. on chicken carcasses sold in
      various retail markets in Turkey was investigated. The isolates were
      characterized and identified using various phenotypic and molecular tests. The
      membrane filtration technique employing 0.45-microm pore size membrane filters
      laid onto a nonselective blood agar was used after enrichment in Oxoid Arcobacter
      Enrichment Broth (AEB) to examine a total of 75 chicken carcasses (44 fresh and
      31 frozen). Species level identification was performed using SDS-PAGE of whole
      cell proteins and a recently developed multiplex-PCR assay. All isolates were
      identified as Arcobacter butzleri. Of the 44 fresh chicken carcasses examined, 42
      (95%) were positive for A. butzleri. A. butzleri was also recovered from seven
      (23%) of the 31 frozen carcasses examined.

PMID- 12423916
TI  - Characterization and heterologous expression of a class IIa bacteriocin,
      plantaricin 423 from Lactobacillus plantarum 423, in Saccharomyces cerevisiae.
AB  - Lactobacillus plantarum 423 produces a small heat-stable antimicrobial protein
      designated plantaricin 423. This protein is bactericidal for many Gram-positive
      foodborne pathogens and spoilage bacteria, including Listeria spp.,
      Staphylococcus spp., Pediococcus spp., Lactobacillus spp., etc. The DNA sequence
      of the plantaricin 423-encoding region on plasmid pPLA4 revealed a four open
      reading frame (ORF) operon structure similar to pediocin PA-1/AcH from
      Pediococcus acidilactici and coagulin from Bacillus coagulans I(4). The first
      ORF, plaA, encodes a 56-amino acid prepeptide consisting of a 37-amino acid
      mature molecule, with a 19-amino acid N-terminal leader peptide. The second ORF,
      plaB, encodes a putative immunity protein with protein sequence similarities to
      several bacteriocin immunity proteins. The plaC and plaD genes are virtually
      identical to pedC and pedD of the pediocin PA-1 operon, as well as coaC and coaD
      of the coagulin operon. Plantaricin 423 was cloned on a shuttle vector under the
      control of a yeast promoter and heterologously produced in Saccharomyces
      cerevisiae.

PMID- 12423917
TI  - Modelling growth and bacteriocin production by Lactobacillus curvatus LTH 1174 in
      response to temperature and pH values used for European sausage fermentation
      processes.
AB  - Lactobacillus curvatus LTH 1174, a strain isolated from fermented sausage,
      produces the antilisterial bacteriocin curvacin A. Its biokinetics of cell growth
      and bacteriocin production as a function of temperature (20-38 degrees C) and pH
      (4.8-7.0) were investigated in vitro during laboratory fermentations using de
      Man, Rogosa and Sharpe (MRS) medium. A predictive, successfully validated model
      was set up to describe the influence of temperature and pH on the microbial
      behavior. Both cell growth and bacteriocin activity were influenced by changes in
      temperature and pH. The optimum temperature value for cell growth, 34.5 degrees
      C, did not correspond with the optimum temperature for curvacin A production (20
      27 degrees C). Interestingly, the pH range for growth and curvacin A production
      was broad. Thus, Lb. curvatus LTH 1174 seems to be a promising bacteriocin
      producing strain for use in European sausage fermentations that are performed at
      temperatures near 25 degrees C.

PMID- 12423918
TI  - Microbial quality of domestic and imported brands of bottled water in Trinidad.
AB  - A cross-sectional study was conducted to determine the microbial quality of
      domestic and imported brands of bottled water available in Trinidad, purchased
      from six geographical regions in Trinidad, and representing the whole island. A
      sample size of 344 bottles of water was determined by using a precision rate of
      2% and a Type 1 error of 5%. The membrane filter technique was used with cultures
      grown on m-Endo agar and m-FC agar for total coliforms and thermotolerant
      coliforms, respectively. Aerobic plate count (APC) was determined on nutrient
      agar; Pseudomonas aeruginosa was detected on MacConkey agar, Escherichia coli was
      isolated on eosin methylene blue (EMB) and Salmonella spp. was assayed by using
      standard methods. Of the 344 water samples tested, 262 (76.2%) and 82 (23.8%)
      were domestic and imported brands, respectively. Eighteen (5.2%) of the 344
      samples contained coliforms with a mean count of 0.88+/-6.38 coliforms per 100
      ml, while 5 (1.5%) samples contained E. coli. The prevalence of total coliforms
      in domestic brands of bottled water was 6.9% (18 of 262) as compared with 0.0% (0
      of 82) detected in imported brands. The difference was statistically significant
      (p=0.004). Similarly, the prevalence of aerobic bacteria in domestic brands of
      bottled water (33.6%) was significantly higher (p=0.001) than was found in
      imported brands (14.8%). Twenty-six (7.6%) of the total samples of water
      contained Pseudomonas species, but all were negative for thermotolerant coliforms
      and Salmonella spp. It was concluded that based on the recommended zero tolerance
      for coliforms in potable water, 5% of bottled water sold in Trinidad could be
      considered unfit for human consumption.

PMID- 12423919
TI  - A new PCR-based method for monitoring inoculated wine fermentations.
AB  - A new PCR-based method has been developed to monitor inoculated wine
      fermentations. The method is based on the variation in the number and position of
      introns in the mitochondrial gene COX1. Oligonucleotide primers homologous to the
      regions flanking the Saccharomyces cerevisiae COX1 introns have been designed and
      tested for S. cerevisiae wine yeast strain differentiation. Four primers were
      selected for their subsequent use in a multiplex PCR reaction and have proved to
      be very effective in uncovering polymorphism in natural and commercial yeast
      strains. An important point is that the speed and simplicity of the technique,
      which does not require the isolation of DNA, allows early detection of the
      starter yeast strain throughout the fermentation process. The main advantage for
      the wineries is that the must sample can be used directly for the PCR reaction
      obtaining very fast results (in approximately 8 h). This allows the wine
      industries to intervene quickly if necessary.

PMID- 12423920
TI  - Applicability of a bacteriocin-producing Enterococcus faecium as a co-culture in
      Cheddar cheese manufacture.
AB  - Two strains, Enterococcus faecium RZS C5 and E. faecium DPC 1146, produce
      listericidal bacteriocins, so-called enterocins. E. faecium RZS C5 was studied
      during batch fermentation in both a complex medium (MRS) and in milk to
      understand the influence of environmental factors, characteristic for milk and
      cheese, on both growth and bacteriocin production. Fermentation conditions were
      chosen in view of the applicability of in situ enterocin production during
      Cheddar cheese production. Enterocin production by E. faecium RZS C5 in MRS
      started in the early logarithmic growth phase, and enterocin activity decreased
      during the stationary phase. The effect of pH on enterocin production and
      decrease of activity was as intense as the effect on bacterial growth. Higher
      enterocin production took place at pH 5.5 compared with pH 6.5. The use of
      lactose instead of glucose increased the production of enterocin, and at higher
      lactose concentration, production increased more and loss of activity decreased.
      The production in skimmed milk compared to MRS was lower and was detected mainly
      in the stationary phase. When casein hydrolysate was added to the milk, enterocin
      production was higher and started earlier, indicating the importance of an
      additional nitrogen source for growth of E. faecium in milk. For co-cultures of
      E. faecium RZS C5 with the starters used during Cheddar cheese manufacture, no
      enterocin activity was detected during the milk fermentation. Furthermore, the
      applicability of E. faecium RZS C5 and E. faecium DPC 1146 strains was tested in
      Cheddar cheese manufacture on pilot scale. Enterocin production took place from
      the beginning of the cheese manufacturing and was stable during the whole
      ripening phase of the cheese. This indicates that both an early and late
      contamination of the milk or cheese can be combated with a stable, in situ
      enterocin production. The use of such a co-culture is an additional safety
      provision beyond good manufacturing practices.

PMID- 12423921
TI  - Microbiological and fermentation characteristics of togwa, a Tanzanian fermented
      food.
AB  - Selected microbiological and metabolic characteristics of sorghum, maize, millet
      and maize-sorghum togwa were investigated during natural fermentation for 24 h.
      The process was predominated by lactic acid bacteria (LAB) and yeasts. The
      mesophiles, lactic acid bacteria, and yeasts increased and the Enterobacteriaceae
      decreased to undetectable levels within 24 h. The isolated microorganisms were
      tentatively identified as Lactobacillus plantarum, Lactobacillus brevis,
      Lactobacillus fermentum, Lactobacillus cellobiosus, Pediococcus pentosaceus,
      Weissella confusa, Issatchenkia orientalis, Saccharomyces cerevisiae, Candida
      pelliculosa and Candida tropicalis. The pH decreased from 5.24-5.52 to 3.10-3.34.
      Maltose increased initially and then decreased, fructose decreased and glucose
      levels increased during the first 12 h of fermentation. The organic acids
      detected during fermentation included DL-lactic, succinic, formic, pyruvic,
      citric, pyroglutamic and uric acid. Lactate was the predominant acid and
      increased significantly with time. The volatile organic compounds (VOC) detected
      included acetaldehyde, 2-methyl-propanal, 2-methyl-butanal, 3-methyl-butanal,
      ethanol, 2-methyl-1-propanol, 2-methyl-1-butanol, 3-methyl-1-butanol, diacetyl
      and acetoin. Ethanol was the predominant VOC and it increased significantly with
      time.

PMID- 12423922
TI  - Interaction of an odorant lactone with model phospholipid bilayers and its strong
      fluidizing action in yeast membrane.
AB  - Some odorant lactones are naturally present in fruits or in fermented products;
      they can also be used as food additives and can be produced by microorganisms at
      the industrial scale by biotechnological processes. Gamma-decalactone was
      previously shown to have antimicrobial properties. We determined by infrared
      spectroscopy measurements that this compound rapidly diffused into model
      phospholipid bilayers (within 2 min), modifying the general physical state of a
      dimyristoyl-L-alpha-phosphatidylcholine (DMPC) film. In vivo, the lactone
      strongly increased membrane fluidity in the model yeast Yarrowia lipolytica, as
      evaluated by fluorescence anisotropy measurements. This effect was more important
      than that of benzyl alcohol, which is known as a fluidizing agent in living
      cells, and may explain the toxic action of gamma-decalactone in microorganisms.

PMID- 12423923
TI  - Synthesis and utilisation of folate by yoghurt starter cultures and probiotic
      bacteria.
AB  - Thirty-two bacterial isolates from species commonly used in yoghurts and
      fermented milks were examined for their ability to synthesise or utilise folate
      during fermentation of skim milk. The organisms examined included the traditional
      yoghurt starter cultures, Lactobacillus delbrueckii subsp. bulgaricus and
      Streptococcus thermophilus, and probiotic lactobacilli, bifidobacteria, and
      Enterococcus faecium. Folate was synthesised by S. thermophilus, bifidobacteria,
      and E. faecium. S. thermophilus was the dominant producer, elevating folate
      levels in skim milk from 11.5 ng g(-1) to between 40 and 50 ng g(-1). Generally,
      lactobacilli depleted the available folate in the skim milk. Fermentations with
      mixed cultures showed that folate production and utilisation by the cultures was
      additive. Fermentations using a combination of Bifidobacterium animalis and S.
      thermophilus resulted in a six-fold increase in folate concentration. Although
      increased folate levels in yoghurts and fermented milks are possible through
      judicious selection of inoculum species, the folate levels remain relatively low
      in terms of recommended daily allowance.

PMID- 12423924
TI  - Antibacterial activity of extracts from some edible plants commonly consumed in
      Asia.
AB  - Extracts of edible plants (26 species) from China, Japan, Thailand and Yemen were
      screened for their antibacterial activity against Bacillus cereus, Staphylococcus
      aureus, Listeria monocytogenes, Escherichia coli and Salmonella infantis.
      Buffered methanol (80% methanol and 20% PBS) and acetone extracted inhibitory
      substances against tested bacteria from 16 plants, as revealed by the disc assay.
      The minimum inhibitory concentrations (MICs) of extracts determined by the agar
      dilution method ranged from 165 to 2640 mg l(-1). The most sensitive
      microorganism to extracts from Azadirachta indica, Cinnamomum cassia, Rumex
      nervosus, Ruta graveolens, Thymus serpyllum and Zingiber officinale was B.
      cereus, with MIC of 165 to 660 mg l(-1). E. coli and S. infantis were only
      inhibited by Cinnamomum cassia extracts at the highest MIC (2640 mg l(-1)). L.
      monocytogenes (Tottori) was more resistant than the ATCC 7644 strain to extracts
      from Ruta chalepensis, Artemisia absinthium and Cissus spp. EDTA (0.85 mM)
      reduced the MICs of Cinnamomum cassia and Cissus rotundifolia by at least 50%
      when tested against E. coli, S. infantis, S. aureus and L. monocytogenes.

PMID- 12423925
TI  - Occurrence of Yersinia enterocolitica and Campylobacter spp. in slaughter pigs
      and consequences for meat inspection, slaughtering, and dressing procedures.
AB  - The purpose of the present investigation was to assess the occurrence of Yersinia
      enterocolitica and Campylobacter spp. in the lymphoid tissues and intestinal
      tract in pigs and the risk for contamination during the compulsory meat
      inspection procedures and the procedures during slaughtering and dressing.
      Another objective of the investigation was to compare traditional isolation
      methods, the use of a polymerase chain reaction (PCR) method (BUGS'n BEADS
      bacterial DNA isolation kit) and an ELISA method (VIDAS CAM) as tools in risk
      management in the slaughterhouse. The results indicate that the compulsory
      procedure for the incision of the submaxillary lymph nodes represents a cross
      contamination risk for virulent Yersinia. In the screening of 97 animals in 1999,
      5.2% of the samples were positive, and by the sampling of 24 samples in 2000
      2001, 12.5% of the samples were positive. In the last case, Y. enterocolitica O:3
      was found in the kidney region in one of the subsequent carcasses that was only
      touched by the meat inspection personnel before sampling. In addition, incision
      of the mesenteric lymph nodes might represent a cross-contamination risk since
      8.3% of the samples were positive. The association between antibody titres and
      the occurrence of virulent yersiniae in the tonsils (21-18) was striking, with
      virulent yersiniae found in the tonsils in most pigs with high titres. The
      contents of the stomach, ileum, caecum, and colon also represent contamination
      risks for Y. enterocolitica O:3 if the slaughterhouse personnel cuts into the
      viscera with their knives by accident; the frequency of virulent Yersinia varied
      from 4.2% to 16.7% within these sections. Campylobacter was detected in the
      gastrointestinal tract of all pigs, and the high contamination of tonsils (66.7%)
      and intestinal tract (100%) might represent an occupational health hazard. There
      was no statistical difference between the traditional method for isolation of Y.
      enterocolitica [International Organization for Standardization, 1994.
      Microbiology-General Guidance for the Detection of Presumptive Pathogenic
      Yersinia enterocolitica (ISO 10273). International Organization for
      Standardization, Geneve, Switzerland (16 pp.)] and the BUGS'n BEADS detection
      method for virulent Y. enterocolitica. Likewise, there was no statistical
      difference between the traditional method for isolation of Campylobacter spp.
      [Nordic Committee on Food Analysis, 1990. Campylobacter jejuni/coli. Detection in
      Food. Method No. 119, 2nd ed. Nordic Committee on Food Analysis, Esbo (7 pp.)]
      and the BUGS'n BEADS detection method or the VIDAS CAM method for detection of
      Campylobacter spp.

PMID- 12423926
TI  - Microbiological quality of 18 degrees C ready-to-eat food products sold in
      Taiwan.
AB  - A total of 164 samples of 18 degrees C ready-to-eat (RTE) food products,
      purchased in 1999-2000 from convenience stores and supermarkets in central
      Taiwan, were examined to determine the microbiological quality of these products.
      The 18 degrees C RTE food products, manufactured by 16 factories, were divided
      into groups based on the type of food and their major ingredients. Aerobic plate
      count, coliforms, Escherichia coli, Bacillus cereus, Staphylococcus aureus and
      psychrotrophic Pseudomonas spp. were evaluated. The incidence of E. coli and
      coliforms in these 18 degrees C RTE food products was 7.9% and 75.0%,
      respectively, while 49.8% and 17.9% of the samples were found to contain B.
      cereus and S. aureus, respectively. Among the samples tested, 1.3% of the food
      products contained more than 10(5) CFU g(-1) of B. cereus and 0.7% contained more
      than 10(5) CFU g(-1) of S. aureus. The pH values of the samples were all below
      7.0, except for cold noodles, which had pH values ranging from 5.18 to 8.20.
      Among the five types of 18 degrees C food products tested, the highest incidence
      of E. coli (16%) and Pseudomonas spp. (64.0%) were detected in hand-rolled sushi
      in a cone shape. On the other hand, the highest incidence rate of coliforms, B.
      cereus, and S. aureus were found in sandwiches (88%), cold noodles (66.7%) and
      rice balls rolled in seaweed (25.0%), respectively. Food products made of ham
      contained the highest incidence of coliforms (88.0%) and E. coli (16.0%), while
      food products containing meat and ham as the major ingredients had the highest
      incidence rates of B. cereus (62.5%) and S. aureus (26.1%), respectively. For
      coliforms, E. coli, B. cereus and S. aureus, the percentage of 18 degrees C RTE
      food products exceeding the microbiological standards for RTE food accepted by
      Republic of China was 75.0%, 7.9%, 49.8% and 17.9%, respectively.

PMID- 12423927
TI  - Interactive inhibition of meat spoilage and pathogenic bacteria by lysozyme,
      nisin and EDTA in the presence of nitrite and sodium chloride at 24 degrees C.
AB  - To develop a nisin- and lysozyme-based antimicrobial treatment for use with
      processed ham and bologna, in vitro experiments were conducted to determine
      whether inhibition enhancing interactions occur between the antimicrobials
      lysozyme, chrisin (a commercial nisin preparation), EDTA, NaCl and NaNO(2).
      Inhibitory interactions were observed between a number of agents when used
      against specific pathogenic and spoilage bacteria. The observed interactions
      included lysozyme with EDTA (Enterococcus faecalis and Weissella viridescens),
      chrisin with EDTA (all Gram-positive organisms), EDTA with NaCl (Escherichia
      coli, Salmonella enterica serovar Typhimurium, Serratia grimesii), EDTA with
      nitrite (E. coli, Lactobacillus curvatus, Leuconostoc mesenteroides, Listeria
      monocytogenes, S. Typhimurium), chrisin with nitrite (Lc. mesenteroides, L.
      monocytogenes), and NaCl with nitrite (S. Typhimurium, Shewanella putrefaciens).
      Previous reports have described interactions between nisin with EDTA that
      resulted in enhanced antimicrobial effect against Gram-negative bacteria, or
      lysozyme with nisin against Gram-positive bacteria. These interactions were not
      observed in these experiments. We observed that unlike previous studies, these
      experiments were conducted on growing cells in nutrient broth, rather than under
      conditions of nutrient limitation. We propose that screening of antimicrobials
      for use in food systems in nutrient-deficient systems is inappropriate and that
      new protocols should be developed.

PMID- 12423928
TI  - Barotolerance of Staphylococcus aureus is increased by incubation at below 0
      degrees C prior to hydrostatic pressure treatment.
AB  - The effect of preincubation under low temperatures on inactivation of
      Staphylococcus aureus IFO 13276 by hydrostatic pressure treatment (HPT) was
      investigated. Preincubation before HPT was carried out by submerging cell
      suspension in an ethylene glycol bath at temperatures from 30 to -20 degrees C
      for 15 min. After HPT at the same temperatures, survivors of incubated S. aureus
      was not significantly (P > 0.05) influenced when preincubation took place at
      temperatures above 0 degrees C. Survivors of incubated S. aureus, however, were
      approximately two log cycles higher when preincubation took place at temperatures
      below 0 degrees C. This increase in barotolerance of S. aureus was not observed
      in the presence of 40 microg/ml of chloramphenicol.

PMID- 12423929
TI  - Dog shedding oocysts of Neospora caninum: PCR diagnosis and molecular
      phylogenetic approach.
AB  - Results of molecular determination of a dog isolate of Neospora caninum in the
      Czech Republic are presented. Colorless bisporocystic oocysts measuring 10-13
      micro m x 10-11 micro m were recovered from feces and used for DNA isolation. A
      diagnostic PCR procedure using previously described molecular methods was
      performed to determine the species. The N. caninum species-specific primers based
      on the Nc 5 region produced a positive result, while primers specific for
      Hammondia heydorni rDNA internal transcribed spacer 1 (ITS1) was negative.
      Sequencing and phylogenetic comparison of ITS1 rDNA and the D2 domain of the
      large subunit rDNA (D2 LSU) determined our isolate to be N. caninum. Phylogenetic
      analysis of closely related genera Toxoplasma, Neospora and Hammondia based on
      ITS1 and D2 LSU robustly distinguished three clades: (i). Toxoplasma gondii +
      Hammondia hammondi, (ii). N. caninum + Neospora hughesi, and (iii). H. heydorni.
      Based on phylogenetic relationships we propose three acceptable suggestions to
      solve the problem of taxonomy of these genera.

PMID- 12423930
TI  - Heifers immunized with whole-cell and membrane vaccines against Tritrichomonas
      foetus and naturally challenged with an infected bull.
AB  - The performance of a whole-cell vaccine and the other vaccine with cellular
      membranes of Tritrichomonas foetus applied to heifers naturally challenged by
      mating with an infected bull was determined. Forty heifers were divided into
      three groups: a control group (n=16) without immunizing, another group (n=12)
      immunized with whole cells (10(8)/dose) and a third group (n=12) immunized with
      cellular membranes (300 micro g of membranes/dose protein). The females were
      subcutaneously vaccinated at 3-week on two occasions and received a third
      intravaginal booster dose. After 3 weeks of the last vaccinal doses, the heifers
      were served by a T. foetus infected bull over 90-day period. The mean duration of
      infection for membrane-vaccinated heifers was 60 days +/-25, compared with 63
      days +/-35.8 of infection for whole-cell-vaccinated heifers and 79 days +/-41.3
      for control heifers. Calving rates were 6/12 for membrane-vaccinated heifers,
      3/12 for whole-cell-vaccinated animals, and 2/16 for control animals. Fetal
      mortality rates were 3/12 for membrane-vaccinated animals, 4/12 for those
      vaccinated with whole cells and 10/16 for control animals. These reproductive
      parameters were significantly different (P<0.05) between heifers vaccinated with
      membranes and control heifers. The hemolytic test and enzyme-linked
      immunoabsorbent assay (ELISA) with T. foetus antigen showed that serum
      immunoglobulins peaked before and during the breeding period. The heifers
      vaccinated with membranes developed an important response during the critical
      period of fetal loss, second and third month of the breeding time, and another
      month after the same period. The ELISA method was more sensitive and more
      reliable than the hemolytic test for the evaluation of the systemic immune
      response in females infected and/or vaccinated with T. foetus.

PMID- 12423931
TI  - Differential serological testing by simultaneous indirect immunofluorescent
      antibody test in canine leishmaniosis and ehrlichiosis.
AB  - A mixed indirect fluorescence antibody test (IFAT), based on cultured
      promastigotes Leishmania infantum and formol-inactivated suspension of cells
      infected with the bacteria Ehrlichia canis, was applied to make a differential
      diagnosis between canine ehrlichiosis and leishmaniosis. A titre greater than 80
      was considered positive for antibodies to E. canis and suggestive of antibodies
      to L. infantum. Positive sera were titrated subsequently by serial dilutions to
      confirm antibodies positive to Leishmania and establishing the antibody titre of
      both pathogens. Fluorescence was absent with negative control sera and background
      staining was minimal. No serological cross-reactions between positive sera for L.
      infantum or E. canis were detected. Results obtained by mixed IFAT did not differ
      when the same serum IFAT standard was compared. The test showed equivalent
      sensitivity (100%). The specifities were 100% for L. infantum and 98.5% for E.
      canis. The equivalence in sensitivity was confirmed by calculating the
      correlation coefficient between IFAT standards and mixed IFAT (r>or=0.99 for both
      pathogens). The results of our investigations demonstrated that mixed IFAT is a
      specific means of establishing serological differential diagnosis of canine
      leishmaniosis and ehrlichiosis.

PMID- 12423932
TI  - Neospora caninum NcSRS2 is a transmembrane protein that contains a
      glycosylphosphatidylinositol anchor in insect cells.
AB  - We investigated the terminal location of NcSRS2, a surface antigen of Neospora
      caninum that has potential use for diagnosis, and demonstrated its importance as
      a vaccine component against neosporosis, in an insect-baculovirus expression
      system. To examine the role of the hydrophobic C-terminal tail in NcSRS2, four
      types of recombinant baculoviruses were constructed. Immunoblotting and N
      terminal amino acid analysis revealed cleavage of a 6 kDa of the N-terminal
      signal peptide in the mature NcSRS2 protein. The recombinant NcSRS2 (rNcSRS2)
      lacking 25, and 62 amino acids from the termination codon were detected in
      supernatants from recombinant virus-infected cells, but not in recombinants with
      truncated 147 amino acids from the termination codon, and intact NcSRS2 gene (401
      amino acids). By flow cytometric and confocal laser scanning microscopic
      analyses, the truncation of the hydrophobic C-terminal tail in NcSRS2 was shown
      to result in the reduction of protein expression on the cell surface relative to
      intact rNcSRS2. Except for the recombinant lacking the 147 C-terminal residues,
      three other rNcSRS2 were detected in the supernatants after treatment with
      phosphatidylinositol-specific phospholipase C. Our results demonstrate that the
      N. caninum NcSRS2 is a transmembrane protein that contains a
      glycosylphosphatidylinositol-anchor molecule in insect cells, and that the
      hydrophobic C-terminal domain is an essential component for GPI-membrane
      attachment. We have likewise shown the usefulness of the insect-recombinant
      baculovirus system in the expression of rNcSRS2.

PMID- 12423933
TI  - A high rate of seroconversion for Neospora caninum in a dairy herd without an
      obvious increased incidence of abortions.
AB  - The purpose of this paper is to investigate the high rate of seroconversion for
      Neospora caninum in a dairy herd. Forty-five of 95 (47%) of the seronegative
      animals seroconverted within a period of 6 months. Seropositive animals were not
      equally distributed among age-groups. A high seroprevalence age-group of 8-30
      months was housed together during a period of 4 months, indicating a point source
      infection within this period. A lack of association between the serological
      status of daughters and mothers also indicated horizontal transmission of the
      infection. Low avidity indices in the seroconverted animals confirmed a recent
      infection in this herd. However, there was no increased abortion rate in
      connection with the seroconversion, which indicates that mass seroconversions in
      dairy herds may remain unnoticed. There was circumstantial evidence that the farm
      dog played a role in the transmission of the infection to the cattle. However,
      also evidence was found for an unexplained ongoing horizontal transmission after
      the initial point source exposure.

PMID- 12423934
TI  - Applications of PCR-based tools for detection and identification of animal
      trypanosomes: a review and perspectives.
AB  - This paper aims to review the applications of the polymerase chain reaction (PCR)
      for the detection and identification of trypanosomes in animals. The diagnosis of
      trypanosomes, initially based on microscopic observations and the host range of
      the parasites, has been improved, since the 1980s, by DNA-based identification.
      These diagnostic techniques evolved successively through DNA probing, PCR
      associated to DNA probing, and currently to PCR alone. Several DNA sequences have
      been investigated as possible targets for diagnosis, especially multi-copy genes
      such as mini-exon, kinetoplastid mini-circles, etc., but the most favoured target
      is the nuclear satellite DNA of mini-chromosomes, which presents the advantages,
      and the drawbacks, of highly repetitive short sequences (120-600 bp). Several
      levels of specificity have been achieved from sub-genus to species, sub-species
      and even types. Random priming of trypanosome DNA has even allowed "isolate
      specific" identification. Other work based on microsatellite sequences has
      provided markers for population genetic studies. For regular diagnosis, the
      sensitivity of PCR has increased with the advancement of technologies for sample
      preparation, to reach a level of 1 trypanosome/ml of blood, which has brought to
      field samples a sensitivity two to three times higher than microscopic
      observation of the buffy coat. Similarly, PCR has allowed an increase in the
      specificity and sensitivity of diagnosis in vectors such as tsetse flies.
      However, because of the diversity of Trypanosoma species potentially present in a
      single host, PCR diagnosis carried out on host material requires several PCR
      reactions; for example, in cattle, up to five reactions per sample may be
      required. Research is now focusing on a diagnosis based on the amplification of
      the internal transcribed spacer-1 (ITS-1) of ribosomal DNA which presents the
      advantages of being a multi-copy locus (100-200), having a small size (300-800
      bp), which varies from one taxon to another but is conserved in size in a given
      taxon. This may lead to the development of a multi-species-specific diagnostic
      protocol using a single PCR. By reducing the cost of the PCR diagnosis, this
      technique would allow a greater number of field samples to be tested in
      epidemiological studies and/or would increase the variety of Trypanosoma species
      that could be detected. Further investigations are required to develop and
      optimise multi-species-specific diagnostic tools for trypanosomes, which could
      also serve as a model for such tools in other pathogens.

PMID- 12423935
TI  - 28 kDa Fasciola gigantica cysteine proteinase in the diagnosis of prepatent ovine
      fasciolosis.
AB  - Coprological confirmation of ovine fasciolosis in the field, prior to out breaks
      of the disease and/or strategic antifluke medication, seem to be of little
      consequence. Efforts are, therefore, being made to evolve a putative antigen
      specific to serodiagnostic test for early diagnosis during prepatency. In the
      present investigation, 28 kDa cysteine proteinase was used in ELI SA and Western
      blot to detect Fasciola gigantica antibodies and further Dipstick-ELISA was
      developed for field application, using known positive monospecific sera from
      experimentally infected sheep with 100 F. gigantica metacercariae. Isolation of
      28 kDa cysteine proteinase was achieved from bubalian origin flukes. The specific
      antigen, recognised homologous antifluke antibodies by Western blot as early as
      2nd week post-infection (wpi) with 100% sensitivity, in sera samples of sheep
      harbouring 38 flukes and by 10th wpi in sheep harbouring 3-8 flukes. All sheep
      were found positive for the infection when ELISA and/or Dipstick-ELISA was
      applied from 4th wpi. In pooled sera of infected sheep, these were positive
      during 4th wpi.

PMID- 12423936
TI  - The inflammatory cell infiltrates in porcine cysticercosis: immunohistochemical
      analysis during various stages of infection.
AB  - Taenia solium metacestodes cause cysticercosis in both humans and pigs. In the
      former host species, the central nervous system involvement (neurocysticercosis
      (NCC)) may range from asymptomatic to life-threatening, but little is known about
      the corresponding variation in tissue response due to the difficulty in obtaining
      parasite-infected brain biopsies. The use of pigs as animal models for
      cysticercosis is ideal because the histological description of the animal's
      response around the parasites resembles the one recorded in human specimens. In
      this study the histological features of the immune response in swine were
      complemented by immunohistochemical analysis to determine the phenotype of the
      inflammatory cells. The presence of mononuclear cells and eosinophils, and the co
      localization of MHC-II with B lymphocytes and monocytes/macrophages within the
      granulomas surrounding the parasites, were features that closely resembled the
      descriptions made in prior studies with human specimens. In addition, there were
      novel findings such as the upregulation of the adhesin CD44 in cells resembling
      monocytes/macrophages, eosinophils and in astrocytes from the central nervous
      system. The upregulation of CD44 may be important for the recruitment of
      inflammatory cells to the site of the lesion. Finally, the presence of null-gamma
      delta-T cells since stage I of the immune response was similar to the early
      detection of these cells in mouse models for cysticercosis.

PMID- 12423937
TI  - Prevalence of canine dirofilariosis in the City of Buenos Aires and its outskirts
      (Argentina).
AB  - During the past 10 years, the prevalence of canine dirofilariosis in the City of
      Buenos Aires and its outskirts, particularly in the northern and southern areas,
      has increased significantly. In the present work, studies were carried out in
      dogs living in the city and in its northern, western and southern outskirts from
      1997 to 2001. For this purpose, 782 blood samples were collected and analyzed to
      determine circulating antigen, processed with the Witness Merial antigen test.
      The samples resulted in negative tests for subjects who lived in the city;
      however, 17.7 and 23.5% of the tests were positive from the northern and southern
      outskirts, respectively. When analyzed by sex, positive results were distributed
      as follows: 62.5% males and 37.5% females (P<0.05). No significant statistical
      difference was found on comparing purebred and cross-breds (P<0.05). It is
      interesting to point out the geographical distribution of the disease, which
      confirms that ecological factors such as water currents, abundant vegetation and
      the existence of mosquitoes all year round, are important for the biological
      cycle of Dirofilaria immitis.

PMID- 12423938
TI  - Relative resistance of Dorper crossbred ewes to gastrointestinal nematode
      infection compared with St. Croix and Katahdin ewes in the southeastern United
      States.
AB  - A study was conducted to evaluate relative resistance of Dorper crossbred (DO),
      Katahdin (KA), St. Croix (SC), and Hampshire (HA) ewes to natural and
      experimental gastro-intestinal (GI) nematode infection over a 20-month period.
      The objective of Experiment 1 was to evaluate breeds for resistance to infection
      acquired naturally from mixed grass pastures. In Year 1 (May-December 2000) de
      worming of ewes occurred during wet, hot conditions in July and during late
      pregnancy in December. In Year 2 (January-December 2001), ewes were de-wormed
      after fecal egg count (FEC) for a breed group rose above 1000 eggs per gram (epg)
      or after blood packed cell volume (PCV) of an individual ewe fell below 20. FEC
      was determined every 28 days and PCV every 14-28 days. In both the years, ewes
      were pastured together, except during the 28-days breeding periods, on tall
      fescue, bermudagrass, or ryegrass, and rotated among pastures dependent on forage
      availability. Ewes were in good or excellent condition (body condition score of 3
      4 out of 5) throughout the study. The objective of Experiment 2 was to evaluate
      the breeds for relative resistance to an experimental infection with Haemonchus
      contortus infective larvae. Both PCV and FEC were determined every 7 days from 14
      to 42 days after inoculation with 30000 infective larvae per ewe. In Experiment
      1, Year 1, FEC was slightly greater and PCV was lower from July to September in
      DO ewes (breed x time, P<0.001). In Year 2, de-worming occurred 14 days later in
      DO ewes compared with other breed types. Otherwise PCV and FEC were similar among
      the hair breeds and higher and lower, respectively, compared with HA ewes (breed
      x time, P<0.001). In Experiment 2, FEC and PCV were similar among hair breeds;
      FEC was lower and PCV higher in hair breeds compared with that of HA ewes
      (P<0.01). Relative resistance of mature Dorper crossbred ewes was comparable to
      that of Katahdin and St. Croix ewes and superior to that of Hampshire ewes.

PMID- 12423939
TI  - Evolution of nematode community in grazing sheep selected for resistance and
      susceptibility to Teladorsagia circumcincta and Trichostrongylus colubriformis: a
      4-year experiment.
AB  - Field trials were undertaken to compare nematode population dynamics in two
      experimental flocks of rams selected for high and for low faecal egg counts
      (FECs) following two doses with 20000 infective larvae, 12000 Teladorsagia
      circumcincta (Tcirc) and 8000 Trichostrongylus colubriformis (Tcol) separated by
      a treatment. The selection was done by dosing 200 ram lambs (INRA 401 breed) and
      FECs proceeded with egg identification on days 28 and 35 post-each-infection. The
      30 lambs with the lowest FECs constituted the group of permanent resistant rams
      (R), the 30 with the highest values the group of susceptible ones (S). Each group
      grazed separated pastures from April to November, this during 4 consecutive
      years. The contamination (number of eggs deposited) was estimated every 3 weeks
      on each pasture. The larval populations was measured by successive groups of
      tracer lambs. The infection of the permanent rams was done by slaughtering eight
      R and S rams on mid and end of each grazing season. Each autumn, new R and S ram
      lambs were selected to complete the R and S groups before turning out in spring.
      On third year, a third species (Haemonchus contortus, Hcon) was added to compare
      its behaviour with the two others. The regulation of parasite populations were
      studied by comparing what happens in R rams and pasture to S ones. The selected R
      ram lambs had a FEC of Tcirc 50% lower than S ones. This induced a similar
      lowered pasture contamination, a 25% decrease of infective larval population in
      years 2 and 3, and the worm burdens in R rams were the half of that in S rams
      after 2 years. The FEC of Tcol was 75% lower at the selection and induced similar
      difference in pasture contamination, but 65 and 96% reduction in L3 population,
      respectively, after 1 and 2 years. The worm burden was reduced by 99%. Adding
      Hcon species during the third year, in year 4, the L3 population was half in R
      pasture compared with S one, and R rams had 60% less worms of this species than S
      ones. This selection without any drench prevent outbreaks observed in young
      tracer lambs on S pasture. The comparison of selected resistant rams to selected
      susceptible ones and not to unselected controls gave more rapid information about
      the tendency of the regulation of the communities of nematode parasites.

PMID- 12423940
TI  - Numerical simulation of turbulent gas flames in tubes.
AB  - Computational fluid dynamics (CFD) is an emerging technique to predict possible
      consequences of gas explosion and it is often considered a powerful and accurate
      tool to obtain detailed results. However, systematic analyses of the reliability
      of this approach to real-scale industrial configurations are still needed.
      Furthermore, few experimental data are available for comparison and validation.
      In this work, a set of well documented experimental data related to the flame
      acceleration obtained within obstacle-filled tubes filled with flammable gas-air
      mixtures, has been simulated. In these experiments, terminal steady flame speeds
      corresponding to different propagation regimes were observed, thus, allowing a
      clear and prompt characterisation of the numerical results with respect to
      numerical parameters, as grid definition, geometrical parameters, as blockage
      ratio and to mixture parameters, as mixture reactivity. The CFD code AutoReagas
      was used for the simulations. Numerical predictions were compared with available
      experimental data and some insights into the code accuracy were determined.
      Computational results are satisfactory for the relatively slower turbulent
      deflagration regimes and became fair when choking regime is observed, whereas
      transition to quasi-detonation or Chapman-Jogouet (CJ) were never predicted.

PMID- 12423941
TI  - Comparative study of adsorption properties of Turkish fly ashes. I. The case of
      nickel(II), copper(II) and zinc(II).
AB  - The objective of this study was to compare two different Turkish fly ashes (Afsin
      Elbistan and Seyitomer) for their ability to remove nickel [Ni(II)], copper
      [Cu(II)] and zinc [Zn(II)] from an aqueous solution. The effect of contact time,
      pH, initial metal concentration and fly ash origin on the adsorption process at
      20+/-2 degrees C were studied. Batch kinetic studies showed that an equilibrium
      time of 2h was required for the adsorption of Ni(II), Cu(II) and Zn(II) on both
      the fly ashes. The maximum metal removal was found to be dependent on solution pH
      (7.0-8.0 for Ni(II), 5.0-6.0 for Cu(II) and 6.0-7.0 for Zn(II)) for each type of
      fly ash. With an increase in the concentrations of these metals, the adsorption
      of Ni(II) and Zn(II) increased while the Cu(II) adsorption decreased on both the
      fly ashes. Adsorption densities for the metal ions were Zn(II)>Cu(II)>Ni(II) for
      both the fly ashes. The effectiveness of fly ash as an adsorbent improved with
      increasing calcium (CaO) content. Adsorption data in the range of pH values (3.0
      8.0) using Ni(II) and Cu(II) concentrations of 25+/-2mg/l and Zn(II)
      concentration of 30+/-2mg/l in solution were correlated using the linear forms of
      the Langmuir and Freundlich equations. The adsorption data were better fitted to
      the Langmuir isotherm since the correlation coefficients for the Langmuir
      isotherm were higher than that for the Freundlich isotherm. The fly ash with high
      calcium content (Afsin-Elbistan) was found to be a metal adsorbent as effective
      as activated carbon and, therefore, there are good prospects for the adsorptions
      of these metals on fly ash with high calcium content in practical applications in
      Turkey.

PMID- 12423942
TI  - Comparative study of adsorption properties of Turkish fly ashes. II. The case of
      chromium (VI) and cadmium (II).
AB  - The purpose of the study described in this paper was to compare the removal of
      Cr(VI) and Cd(II) from an aqueous solution using two different Turkish fly ashes;
      Afsin-Elbistan and Seyitomer as adsorbents. The influence of four parameters
      (contact time, solution pH, initial metal concentration in solution and ash
      quality) on the removal at 20+/-2 degrees C was studied. Fly ashes were found to
      have a higher adsorption capacity for the adsorption of Cd(II) as compared to
      Cr(VI) and both Cr(VI) and Cd(II) required an equilibrium time of 2h. The
      adsorption of Cr(VI) was higher at pH 4.0 for Afsin-Elbistan fly ash (25.46%) and
      pH 3.0 for Seyitomer fly ash (30.91%) while Cd(II) was adsorbed to a greater
      extent (98.43% for Afsin-Elbistan fly ash and 65.24% for Seyitomer fly ash) at pH
      7.0. The adsorption of Cd(II) increased with an increase in the concentrations of
      these metals in solution while Cr(VI) adsorption decreased by both fly ashes. The
      lime (crystalline CaO) content in fly ash seemed to be a significant factor in
      influencing Cr(VI) and Cd(II) ions removal. The linear forms of the Langmuir and
      Freundlich equations were utilised for experiments with metal concentrations of
      55+/-2mg/l for Cr(VI) and 6+/-0.2mg/l for Cd(II) as functions of solution pH (3.0
      8.0). The adsorption of Cr(VI) on both fly ashes was not described by both the
      Langmuir and Freundlich isotherms while Cd(II) adsorption on both fly ashes
      satisfied only the Langmuir isotherm model. The adsorption capacities of both fly
      ashes were nearly three times less than that of activated carbon for the removal
      of Cr(VI) while Afsin-Elbistan fly ash with high-calcium content was as effective
      as activated carbon for the removal of Cd(II). Therefore, there are possibilities
      for use the adsorption of Cd(II) ions onto fly ash with high-calcium content in
      practical applications in Turkey.

PMID- 12423943
TI  - Reaction characteristics of Ca(OH)2, HCl and SO2 at low temperature in a spray
      dryer integrated with a fabric filter.
AB  - The objective of this research was to evaluate the reaction characteristics of
      CaOH2, HCl and SO2 in the flue gas emitted by a laboratory incinerator. The
      amount of sulfur retained in the residues (including the spray dryer ash and
      baghouse ash) was also evaluated in this study. The experimental parameters
      included HCl concentration (500-2000 ppm), SO2 concentration (500-2000 ppm),
      relative humidity (40-80% RH), and the addition of CaCl2 (30 wt.%). The results
      indicated that an HCl concentration of 500-2000 ppm did not affect HCl removal
      efficiency in the spray dryer at 150 degrees C and 45+/-5% RH. On the other hand,
      increase in SO2 concentration from 500 to 2000 ppm enhanced SO2 removal at 150
      degrees C and 75+/-5% RH. Moreover, increase in removal efficiency of SO2 was
      more obvious when the relative humidity was greater than 80%. When the flue gas
      contained both HCl and SO2 simultaneously, the removal efficiency of SO2 could
      increase from 56.7 to 90.33% at HCl concentration of 236 ppm. However, when the
      concentration of HCl exceeded 535 ppm, the removal efficiency of SO2 decreased
      with increasing concentration of HCl. The removal efficiency of SO2 could be
      increase to 97.7% with the addition of CaCl2.

PMID- 12423944
TI  - Factors affecting air sparging remediation systems using field data and numerical
      simulations.
AB  - Field data from five air sparging sites were used to assess the effect of several
      soil, contaminant, and air sparging system factors on the removal time and
      associated costs required to reach specified clean-up criteria. Numerical
      simulations were also performed to better assess the field data and to expand the
      data sets beyond the five field sites. Ten factors were selected and evaluated
      individually over a range of values based on information from practitioners and
      the literature. Trends in removal time and removal cost to reach a specified
      clean-up criterion were analyzed to ascertain the conditions controlling
      contaminant removal with variations in each factors' value. A linear sensitivity
      equation was used to quantify system dynamics controlling the observed
      contaminant removal trends for each factor. Factors found most critical across
      all field sites in terms of removal time and/or cost were contaminant type,
      sparge pulsing schedule, number of wells, maximum biodecay rate, total soil
      porosity, and aquifer organic carbon content. Factors showing moderate to low
      effect included the depth of the sparge point below the water table, air
      injection rate/pressure, horizontal air conductivity, and anisotropy ratio. At
      each field site, subsurface coverage of sparged air, sparged air residence time,
      contaminant equilibrium in the system, contaminant phase distribution, oxygen
      availability to microbes, and contaminant volatility seem to control the system
      responses and were affected by one or more of the 10 factors evaluated.

PMID- 12423948
TI  - Structural determination of the complex exopolysaccharide from the virulent
      strain of Cryphonectria parasitica.
AB  - The structure of a new exopolysaccharide from the virulent strain of
      Cryphonectria parasitica was elucidated by means of 2D NMR spectroscopy and
      selective degradations (mild hydrolysis and acetolysis). The polysaccharide is
      built up of mannose, galactose and rhamnose and has a rather complex non
      repetitive structure that can be idealised as follows:

PMID- 12423949
TI  - Synthesis of oligosaccharides corresponding to Streptococcus pneumoniae type 9
      capsular polysaccharide structures.
AB  - Two trisaccharides, alpha-D-Galp-(1-->3)-beta-D-ManpNAc-(1-->4)-beta-D-Glcp and
      alpha-D-Glcp-(1-->3)-beta-D-ManpNAc-(1-->4)-beta-D-Glcp, corresponding to
      structures from Streptococcus pneumoniae capsular polysaccharides type 9A, L, V
      and type 9N, respectively, have been synthesised as 2-aminoethyl glycosides and
      as protected TMSE glycosides. Ethyl thioglycosides were used as glycosyl donors
      and NIS/TfOH (in CH(2)Cl(2) for beta-linkages) and DMTST (in Et(2)O for alpha
      linkages) as promoters in the glycosylations. The beta-ManNAc motif was
      introduced at the disaccharide level by azide displacement of a 2-O-triflate with
      beta-D-gluco configuration. The protecting group patterns allow continued
      syntheses of larger structures.

PMID- 12423950
TI  - Structures of the O-polysaccharide chains of the lipopolysaccharides of
      Xanthomonas campestris pv phaseoli var fuscans GSPB 271 and X campestris pv
      malvacearum GSPB 1386 and GSPB 2388.
AB  - O-polysaccharides of phytopathogenic bacteria Xanthomonas campestris were
      isolated by mild acid degradation of the lipopolysaccharides and studied by sugar
      and methylation analysis, along with 1H and 13C NMR spectroscopy. The following
      structures of the repeating units of the polysaccharides of X. campestris pv.
      phaseoli var. fuscans GSPB 271 (1). and X. campestris pv. malvacearum GSPB 1386
      and GSPB 2388 (2). were established:The O-polysaccharides of X. campestris are
      structurally similar to those of some Pseudomonas syringae strains.

PMID- 12423951
TI  - Supercritical CO(2) fluid extraction of crystal water from trehalose dihydrate.
      Efficient production of form II (T(alpha)) phase.
AB  - Form II is a kind of metastable crystalline form of trehalose anhydrate, and it
      is easily converted to the dihydrate crystal by absorbing water in moist
      atmosphere at room temperature (Akao et al., Carbohydr. Res. 2001, 334, 233-241).
      It can be utilized as an edible and nontoxic desiccant, and thus its efficient
      production from the dihydrate is significant from a viewpoint of industrial
      applications. In this study, we attempt to extract crystal water from the
      dihydrate using supercritical CO(2). We examine the dependence of extraction
      efficiency on the extraction time, the temperature and pressure of the fluid.
      Then, FTIR measurements are carried out to detect the extracted water and to
      identify the polymorphic phase of the sugar sample after the extraction
      treatment. In particular, the so-called first derivative euclidean distance
      analysis for IR spectra is shown to be quite useful for the structural
      identification. Consequently, we demonstrate that form II is produced from the
      dihydrate through supercritical CO(2) fluid extraction if appropriate temperature
      and pressure conditions (around 80 degrees C and 20 MPa) are maintained.

PMID- 12423952
TI  - Three-dimensional structure of the inclusion complex between phloridzin and beta
      cyclodextrin.
AB  - The inclusion of phloridzin into beta-cyclodextrin was studied as a model of
      molecular recognition in membranes. Effects on 1H NMR spectra and NOE
      correlational peaks between phloridzin and beta-cyclodextrin were observed in the
      complex. Strong NOEs were observed between hydrogens of a phenol group in
      phloridzin and beta-cyclodextrin. The three-dimensional structure of the
      inclusion complex between phloridzin and beta-cyclodextrin was simulated with
      distance constraints estimated by the intensity of NOE peaks using the DADAS90
      programs. Two inclusion possibilities were suggested-the large rim of beta
      cyclodextrin as an entrance of the inclusion and the small rim of beta
      cyclodextrin as the entrance. In both cases, the phenol group of phloridzin was
      included in the hydrophobic space of beta-cyclodextrin.

PMID- 12423953
TI  - NMR studies of molybdate complexes of D-erythro-L-manno-octose and D-erythro-L
      gluco-octose and their alditols.
AB  - Different amounts and various types of bis-dinuclear tetradentate molybdate
      complexes of D-erythro-L-manno-octose, D-erythro-L-gluco-octose, D-erythro-L
      manno-octitol and D-erythro-L-gluco-octitol were characterized by 1H and 13C NMR
      spectroscopy in aqueous solutions. Detailed analysis of 1H-(1)H coupling
      constants and NOEs, together with chemical shifts, allowed characterization of
      the different isomers of these complexes.

PMID- 12423954
TI  - Electrophoretically mediated microscale reaction of glycosidases: kinetic
      analysis of some glycosidases at the nanoliter scale.
AB  - Capillary electrophoresis (CE) is one of the extremely important analytical
      techniques known for its high sensitivity and resolution. We have investigated
      electrophoretically mediated microanalysis (EMMA) for the assay of some native
      glycosidases. Under optimized conditions, the enzymatic reactions of alpha
      glucosidase, beta-galactosidase and beta-N-acetylglucosaminidase were carried
      out, and the Michaelis constants were obtained. The current method may have
      advantages over traditional assay methods, especially in terms of the amount of
      enzyme and substrate required for a reaction.

PMID- 12423955
TI  - A mild and selective method for cleavage of O-acetyl groups with dibutyltin
      oxide.
AB  - A mild and efficient neutral method for the cleavage of O-acetyl groups with
      dibutyltin oxide has been developed. This method is especially useful in the
      synthesis of glycosides containing base- or acid-sensitive multifunctional
      groups.

PMID- 12423956
TI  - Synthesis of 3-C-(6-O-acetyl-2,3,4-tri-O-benzyl-alpha-D-mannopyranosyl)-1
      propene: a caveat.
AB  - During the preparation of 3-C-(6-O-acetyl-2,3,4-tri-O-benzyl-alpha-D
      mannopyranosyl)-1-propene, using a published Sakurai-type reaction on the parent
      methyl glycoside, some observations were made on the sensitivity to reaction
      conditions that were not previously reported. This Note presents the study of
      this allylation reaction followed by acetolysis, which ultimately led to the best
      conditions to obtain the C-glycoside, and on further transformations to yield the
      corresponding aldehydic and acidic derivatives.

PMID- 12423957
TI  - Conformational studies of a novel cationic glycolipid, glyceroplasmalopsychosine,
      from bovine brain by NMR spectroscopy.
AB  - A novel glycosphingolipid containing a long chain aldehyde conjugated to
      galactose and glycerol, Gro1(3)-O-CH((CH(2))(n)CH(3))-O-6Galbeta-sphingosine
      (glyceroplasmalopsychosine) has been studied by NMR spectroscopy (Hikita et al.
      J. Biol. Chem. 2001, 276, 23084-23091). We further report here on the
      conformation showing the galactose and the glycerol at the end of two parallel
      hydrophobic chains, i.e. the sphingosine and the fatty aldehyde. This is proposed
      based on the interproton distances derived from ROESY experiments and 3 J (H,H)
      coupling constants. The absence of any intraresidual NOEs between protons in the
      glycerol residue suggested that the C-C-2 and C-C-3 bonds in the glycerol may be
      rotating freely, supporting the proposed conformation in which the unique
      terminal glycerol is in an environment with a minimal steric hindrance. The
      present study proposes a conformation of glyceroplasmalopsychosine greatly
      different from the two conventional plasmalopsychosines possessing a fatty
      aldehyde chain oriented in an opposite direction to the sphingosine.

PMID- 12423958
TI  - On the chain flexibility of arabinoxylans and other beta-(1-->4) polysaccharides.
AB  - The recent paper by Dervilly-Pinel and co-workers (Carbohydr. Res. 2001, 330, 365
      372) presents a complete macromolecular characterisation of a series of de
      esterified arabinoxylans extracted and fractionated from wheat flour. From their
      measurements, they were able to extract parameters related to chain flexibility,
      such as the Mark-Houwink exponent a and the chain persistence length. However,
      the estimate they obtain for the latter parameter is rather larger than would be
      expected, since the arabinoxylan backbone is beta-(1-->4) like cellulose and the
      galactomannans. By treating their data in an alternative, but well accepted
      manner, we are able to obtain a lower value of persistence length, which agrees
      well with estimates for this parameter for cellulose, in the literature, and our
      own recent measurements for a series of differently substituted galactomannans.
      These results suggest that the parameters obtained may be applicable to other
      beta-(1-->4) polysaccharides.

PMID- 12423959
TI  - 13C NMR spectroscopic analysis on the chiral discrimination of N
      acetylphenylalanine, catechin and propranolol induced by cyclic-(1-->2)-beta-D
      glucans (cyclosophoraoses).
AB  - Cyclosophoraoses (cyclic-(1-->2)-beta-D-glucans) produced by Rhizobium meliloti
      were used as a novel chiral NMR solvating agent. 13C NMR spectroscopic analysis
      as an enantiodiscriminating tool was carried out where NMR signal splittings were
      observed on the interactions of cyclosophoraoses with the enantiomers of N
      acetylphenylalanine, catechin and propranolol. The 13C chemical shifts of
      cyclosophoraoses induced by the enantiomeric interactions predominantly occurred
      at the C-1 and C-2 carbons associated with the -glycosidic linkage.

PMID- 12423961
TI  - Synthesis of a multivalent display of a CD22-binding trisaccharide.
AB  - Multivalent interactions have been implicated in the binding of B-cell surface
      glycoprotein CD22 to its physiological ligands. Because CD22 can influence B-cell
      antigen receptor (BCR) signaling, multivalent ligands that cluster CD22 may
      influence B-cell responses. Here, we report an efficient synthesis of a
      fluorophore-labeled multivalent display of a CD22-binding trisaccharide,
      Neu5Acalpha2,6Galbeta1,4Glc, using the ring-opening metathesis polymerization
      (ROMP). Our synthetic strategy involves the modification of an N
      hydroxysuccinimide (NHS) ester-substituted polymer generated by ROMP with the
      aminopropyl glycoside of the trisaccharide. The conjugation efficiency for the
      coupling is high; when 0.3 equiv of the trisaccharide derivative were used
      relative to NHS ester groups, the mole fraction (chi) of trisaccharide ligand
      incorporated onto the backbone was 0.3. A fluorescein-labeled version of the
      multivalent ligand binds to cells expressing CD22.

PMID- 12423962
TI  - Regioselective enzymatic hydrolysis of acetylated pyranoses and pyranosides using
      immobilised lipases. An easy chemoenzymatic synthesis of alpha- and beta-D
      glucopyranose acetates bearing a free secondary C-4 hydroxyl group.
AB  - Protected sugars with only one free hydroxyl group are useful building blocks for
      the synthesis of a large number of glycoderivatives. In order to avoid the
      problems of the classical chemical synthesis, we studied the regioselective
      enzymatic hydrolysis of different fully acetylated glycopyranoses and
      glycopyranosides. The main challenge was to obtain the hydrolysis of the
      substrates in only one position, with high regioselectivity, while avoiding any
      further hydrolysis towards partially acetylated sugars. Candida rugosa (CRL) and
      Pseudomonas fluorescens (PFL) lipases (EC 3.1.1.3) immobilised on octyl agarose
      afforded regioselective hydrolysis only in the 6- and 1-positions, respectively.
      Furthermore, a new one-pot chemoenzymatic approach has been developed in order to
      obtain alpha- and beta-protected glucopyranoses bearing a free secondary C-4
      hydroxyl group. For instance, 1,2,3,6-tetra-O-acetyl-alpha-D-glucopyranose was
      easily synthesised in good overall yield (70%) starting from 1,2,3,4,6-penta-O
      acetyl-alpha-D-glucopyranose by regioselective enzymatic hydrolysis in the 6
      position, catalysed by CRL, followed by a temperature- and pH-controlled acyl
      migration.

PMID- 12423963
TI  - Towards alpha- or beta-D-C-glycosyl compounds by tin-catalyzed addition of
      glycosyl radicals to acrylonitrile and vinylphosphonate, and flexible reduction
      of tetra-O-acetyl-alpha-D-glucopyranosyl bromide with cyanoborohydride.
AB  - Photo-induced radical addition of acetylated alpha-D-glucopyranosyl bromide (1).
      to acrylonitrile or diethyl vinylphosphonate, in the presence of catalytic
      amounts of tri-n-butyltin chloride and sodium (or tetra-n-butylammonium)
      cyanoborohydride in excess, allowed efficient preparations of alpha-configurated
      nonononitrile and 2-(alpha-D-glucopyranosyl)-ethylphosphonate (79, 70% yields,
      respectively). These conditions led to 2-(alpha-D-manno-, and galactopyranosyl)
      ethylphosphonates in 68 and 76% yields. Similarly, radical addition of acetylated
      1-bromo-beta-D-glucopyranosyl chloride (2). to acrylonitrile or diethyl
      vinylphosphonate afforded mainly intermediate chlorides which, upon radical
      reduction with excess tri-n-butyltin hydride, afforded the corresponding beta
      anomers (40 and 38%, respectively) by sequential C-C and C-H bond formation.
      Stereocontrol relies on the alpha-stereoselective quenching of D-glycopyranos-1
      yl radicals. We found also that UV light irradiation of 1 with excess NaBH(3)CN
      in tert-butanol afforded either 1,3,4,6-tetra-O-acetyl-2-deoxy-alpha-D-arabino
      hexopyranose (65% after crystallization) or, when 10% mol thiophenol was added,
      2,3,4,6-tetra-O-acetyl-1,5-anhydro-D-glucitol (79%). These are simple, tin-free,
      and easily controlled conditions, which compare well with known preparations of
      these reduced sugars.

PMID- 12423964
TI  - Conformation of the branched O-specific polysaccharide of Shigella dysenteriae
      type 2: molecular mechanics calculations show a compact helical structure
      exposing an epitope which potentially mimics galabiose.
AB  - Conformational analyses of the branched repeating unit of the O-antigenic
      polysaccharide of Shigella dysenteriae type 2 have been performed with molecular
      mechanics MM3. A filtered systematic search on the trisaccharide alpha-D-GalNAc
      (1-->3)-[alpha-D-GlcNAc-(1-->4)]-alpha-D-GalNAc forming the branch, shows
      essentially a single favored conformation. Also, the downstream alpha-D-GalNAc-(1
      ->4)-alpha-D-Glc linkage is sterically constrained. The alpha-D-Glc-(1-->4)-beta
      D-Gal moiety, however, forms a more flexible link region between the branch
      points, and shows a 90 degrees bend similar to what is known for the galabiose
      moiety occurring in globo-glycolipids. The calculations indicate that consecutive
      repeating units in their minimum energy conformation arrange in a helical
      structure with three repeating units per turn. This helix is very compact and
      appears to be stabilized by hydrophobic interactions involving the N-acetyl
      groups at the branch points. Random conformational search suggests the existence
      of another helical structure with four repeating units per turn. It appears
      possible that the alpha-D-Glc-(1-->4)-beta-D-Gal moiety, which is exposed on the
      surface of the helical structures, can evade recognition by the immune system of
      the host by the mimicry of globo structures.

PMID- 12423965
TI  - An alternate carbon source for enhancing production of polysaccharides by Silene
      vulgaris callus.
AB  - Pectin termed silenan and acidic arabinogalactan were isolated as cell-wall
      polysaccharides of Silene vulgaris callus in the presence of various carbon
      sources as components of the media. The maximum yields, productivity per litre of
      medium and production per day of acidic arabinogalactan, were achieved using
      glucose or galactose as the carbon source. Sucrose was found to increase the
      production of the polysaccharides. Yields, productivity and rate of production of
      arabinogalactan per day were decreased in the presence of arabinose. Yields of
      silenan, productivity and rate of production per day were closely related
      irrespective of the sugar used as the carbon source in the media (sucrose,
      glucose or galactose) and yields of silenan from the callus growing on arabinose
      were comparable. A concentration of sucrose in the 20-50 g/L range enhanced the
      biosynthesis of silenan and at 50 g/L the silenan contained the linear backbone
      and the ramified regions of the macromolecule.

PMID- 12423966
TI  - Structure of the arabinogalactan from gum tragacanth (Astralagus gummifer).
AB  - The polysaccharide obtained by ethanol precipitation from an aqueous solution of
      gum tragacanth contained arabinogalactan and tragacanthic acid, as well as starch
      ( approximately 0.6%). GC-MS, NMR, and ESI-MS analyses showed the structure of
      the arabinogalactan to be even more complex than previously determined, with core
      structures containing Arap, beta-Araf, and alpha-Galp units, as well as known
      terminal, and 2-O- and 3-O-substituted alpha-Araf units. Analysis was aided by
      examination of free, reducing oligosaccharides present in the gum. In addition to
      maltose, maltotriose, maltotetraose, and maltopentaose, the following were
      characterized: mixed alpha-Araf (1-->2)-alpha-Araf-(1-->4)-Ara and alpha-Araf-(1-
      >2)-alpha-Araf-(1-->5)-Ara, which correspond to the side chains of the
      arabinogalactan, beta-Galp-(1-->4)-beta-Galp-(1-->4)-beta-Galp-(1-->4)-Gal; and a
      mixture of beta-Galp-(1-->4)-beta-Galp-(1-->4)-Gal and beta-Glcp-(1-->4)-beta
      Galp-(1-->4)-beta-Galp-(1-->4)-Gal, which did not resemble side-chain structures
      of the arabinogalactan. The latter are suggested to be related to tragacanthic
      acid, which has been previously found to contain beta-Galp nonreducing end-units.

PMID- 12423967
TI  - Interaction of lead(II) with beta-cyclodextrin in alkaline solutions.
AB  - Polarographic and UV-spectrophotometric investigations of Pb(II) complex
      formation with beta-cyclodextrin have showed that the complexation of Pb(II) ions
      begins at pH >10. The formation of lead(II) 1:1 complex with the beta
      cyclodextrin anion was observed at pH 10-11.5. The logarithm of the stability
      constant of this complex compound is 15.9+/-0.3 (20 degrees C, ionic strength
      1.0), and the molar extinction coefficient value is ca. 5500 (lambda(max)=260
      nm). With further increase in solution pH the Pb-beta-cyclodextrin complex
      decomposes and converts to Pb(OH)(2) or Pb(OH)(3)(-) hydroxy-complexes. This
      process occurs with a decrease in Pb(II) complexation degree. The latter result
      could be explained by a decrease in the beta-cyclodextrin anion activity. Neither
      Pb(OH)(2) nor Pb(OH)(3)(-) encapsulation into beta-CD cavity was observed.

PMID- 12423968
TI  - Carbohydrates from Detarium microcarpum bark extract.
AB  - The bark extract of the medicinal plant Detarium microcarpum was analysed for its
      carbohydrate content by GLC-CIMS. Preparative HPLC of the benzoylated
      carbohydrate fraction led to the isolation of L-quino-1,5-lactone, D-(-)
      bornesitol, D-pinitol, myo-inositol, sucrose, D-glucose, and D-fructose
      benzoates, which were characterised by NMR spectroscopy experiments.

PMID- 12423969
TI  - Structure of the O-specific polysaccharide of Providencia alcalifaciens O16
      containing N-acetylmuramic acid.
AB  - The O-specific polysaccharide of Providencia alcalifaciens O16 was obtained by
      mild-acid degradation of the lipopolysaccharide and studied by chemical methods
      and NMR spectroscopy, including 2D 1H,(1)H COSY, TOCSY, NOESY, and 1H,(13)C HSQC
      experiments. It was found that the polysaccharide contains N-acetylmuramic acid,
      which was isolated by solvolysis with trifluoromethanesulfonic acid and
      identified by the specific optical rotation and NMR spectroscopy. The following
      structure of the trisaccharide repeating-unit of the polysaccharide was
      established:

PMID- 12423970
TI  - Synthesis of natural beta-D-(1-->3)-glucopyranosyl oligosaccharides.
AB  - beta-D-(1-->3)-Glucan core structure derivatives corresponding to schizophyllan,
      epiglucan and lentinan were synthesized efficiently. 4,6-O-Benzylidenated
      glucopyranosyl acceptors were found to be helpful in the attempted beta-D-(1-->3)
      bond formation. The epiglucan pentasaccharide showed a weak anti-tumor activity
      in preliminary mice tests.

PMID- 12423971
TI  - A first total synthesis of a novel sulfated ganglioside, 3'-O-sulfo-GM1b.
AB  - A first total synthesis of a novel sulfated ganglioside, 3'-O-sulfo-GM1b, is
      described. The suitably protected gangliotriose (GgOSe3) derivative, 2
      (trimethylsilyl)ethyl (2-acetamido-4,6-O-benzylidene-2-deoxy-beta-D
      galactopyranosyl)-(1-->4)-(2,6-di-O-benzyl-3-O-p-methoxybenzyl-beta-D
      galactopyranosyl)-(1-->4)-2,3,6-tri-O-benzyl-beta-D-glucopyranoside was
      glycosylated with the alpha-NeuAc-(2-->3)-galactose donor to give the protected
      GM1b oligosaccharide (95%). After proper manipulation of the protecting groups,
      the oligosaccharide was converted into the target ganglioside by the successive
      introduction of the ceramide and sulfo groups, followed by complete deprotection.

PMID- 12423972
TI  - Characterisation of pectin subunits released by an optimised combination of
      enzymes.
AB  - Pectins from sugar beet, lime and apple were degraded by a rhamnogalacturonan
      hydrolase associated or not with pectin methylesterases and side chain degrading
      enzymes (galactanase and arabinanase). The composition of the enzymatic mixture
      was optimised by following the reaction by viscosimetric means. The reaction
      products were fractionated by ion exchange chromatography. Treatment with all the
      enzymes released four fractions: (1). 227-247 mg/g of initial pectins and
      corresponded to neutral sugars from the side chains; (2,3). represented together
      184-220 mg/g of pectins and corresponded to rhamnogalacturonan; (4). 533-588 mg/g
      of pectins and corresponded to homogalacturonan. Lime pectins have the shortest
      rhamnogalacturonan regions. The molar masses of homogalacturonans were in the
      range of 16000-43400 g/mol according to the origin of pectins, corresponding to
      degrees of polymerisation of 85-250. The mode of action of the enzymes used is
      also discussed.

PMID- 12423973
TI  - Structural investigation of the O-specific polysaccharides of Morganella morganii
      consisting of two higher sugars.
AB  - The lipopolysaccharide of the bacterium Morganella morganii (strain KF 1676, RK
      4222) yielded two polysaccharides, PS1 and PS2, when subjected to mild acid
      degradation followed by GPC. The polysaccharides were studied by 1H and 13C NMR
      spectroscopy, including two-dimensional COSY, TOCSY, NOESY, 1H,(13)C HMQC, and
      HMBC experiments. Each polysaccharide was found to contain a disaccharide
      repeating unit consisting of two higher sugars, 5-acetamidino-7-acetamido-3,5,7,9
      tetradeoxy-L-glycero-D-galacto-non-2-ulosonic acid (a derivative of 8
      epilegionaminic acid, 8eLeg5Am7Ac) and 2-acetamido-4-C-(3'-carboxamide-2',2'
      dihydroxypropyl)-2,6-dideoxy-D-galactose (shewanellose, She). The two
      polysaccharides differ only in the ring size of shewanellose and have the
      following structures:Shewanellose has been previously identified in a phenol
      soluble polysaccharide from Shewanella putrefaciens A6, which shows a close
      structural similarity to PS2.

PMID- 12423974
TI  - An innovative challenge to the pharmaceutical industry.

PMID- 12423975
TI  - Interpreting the global burden of disease.

PMID- 12423976
TI  - Unleashing the power of prevention to achieve global health-gains.

PMID- 12423977
TI  - Connecting Fanconi's anaemia to breast cancer predisposition.

PMID- 12423978
TI  - Clinical trial protocols: agreements between the FDA and industrial sponsors.

PMID- 12423979
TI  - Medicines, society, and industry.

PMID- 12423980
TI  - Selected major risk factors and global and regional burden of disease.
AB  - BACKGROUND: Reliable and comparable analysis of risks to health is key for
      preventing disease and injury. Causal attribution of morbidity and mortality to
      risk factors has traditionally been in the context of individual risk factors,
      often in a limited number of settings, restricting comparability. Our aim was to
      estimate the contributions of selected major risk factors to global and regional
      burden of disease in a unified framework. METHODS: For 26 selected risk factors,
      expert working groups undertook a comprehensive review of published work and
      other sources--eg, government reports and international databases--to obtain data
      on the prevalence of risk factor exposure and hazard size for 14 epidemiological
      regions of the world. Population attributable fractions were estimated by
      applying the potential impact fraction relation, and applied to the mortality and
      burden of disease estimates from the global burden of disease (GBD) database.
      FINDINGS: Childhood and maternal underweight (138 million disability adjusted
      life years [DALY], 9.5%), unsafe sex (92 million DALY, 6.3%), high blood pressure
      (64 million DALY, 4.4%), tobacco (59 million DALY, 4.1%), and alcohol (58 million
      DALY, 4.0%) were the leading causes of global burden of disease. In the poorest
      regions of the world, childhood and maternal underweight, unsafe sex, unsafe
      water, sanitation, and hygiene, indoor smoke from solid fuels, and various
      micronutrient deficiencies were major contributors to loss of healthy life. In
      both developing and developed regions, alcohol, tobacco, high blood pressure, and
      high cholesterol were major causes of disease burden. INTERPRETATION: Substantial
      proportions of global disease burden are attributable to these major risks, to an
      extent greater than previously estimated. Developing countries suffer most or all
      of the burden due to many of the leading risks. Strategies that target these
      known risks can provide substantial and underestimated public-health gains.

PMID- 12423981
TI  - Effect of radiotherapy and other treatment-related factors on mid-term to long
      term cognitive sequelae in low-grade gliomas: a comparative study.
AB  - BACKGROUND: Because survival benefits of treatment with radiotherapy are
      questionable and such treatment can cause substantial damage to the brain over
      time, the optimum management strategy for low-grade gliomas remains
      controversial. We aimed to identify the specific effects of radiotherapy on
      objective and self-reported cognitive function, and on cognitive deterioration
      over time, in patients with low-grade gliomas treated with early radiotherapy.
      METHODS: 195 patients with low-grade glioma (of whom 104 had received
      radiotherapy 1-22 years previously) were compared with 100 low-grade
      haematological patients and 195 healthy controls. Our analyses aimed to
      differentiate between the effects of the tumour (eg, disease duration,
      lateralisation) and treatment effects (neurosurgery, radiotherapy, antiepileptic
      drugs) on cognitive function and on relative risk of cognitive disability.
      FINDINGS: Low-grade glioma patients had lower ability in all cognitive domains
      than did low-grade haematological patients, and did even less well by comparison
      with healthy controls. Use of radiotherapy was associated with poorer cognitive
      function; however, cognitive disability in the memory domain was found only in
      radiotherapy patients who received fraction doses exceeding 2 Gy. Antiepileptic
      drug use was strongly associated with disability in attentional and executive
      function. INTERPRETATION: Our findings suggest that the tumour itself has the
      most deleterious effect on cognitive function and that radiotherapy mainly
      results in additional long-term cognitive disability when high fraction doses are
      used. Additionally, the effects of other medical factors, especially
      antiepileptic drug use, on cognitive function in glioma patients deserve
      attention.

PMID- 12423982
TI  - Occupational driving and lumbar disc degeneration: a case-control study.
AB  - BACKGROUND: Back problems are reported more by occupational drivers than by any
      other occupational group. One explanation is that whole-body vibration caused by
      the vehicle leads to accelerated disc degeneration, herniation, and associated
      symptoms. We aimed to investigate the effects of lifetime driving exposure on
      lumbar disc degeneration in monozygotic twins with very different histories of
      occupational driving during their life. METHODS: We assessed 45 male monozygotic
      twin pairs from the population-based Finnish Twin Cohort who had greatly
      different patterns of occupational driving during their life. Data were obtained
      for driving exposures and potential confounding factors through an extensive,
      structured interview. We assessed disc degeneration with lumbar MRI. FINDINGS:
      Disc degeneration did not differ between occupational drivers and their twin
      brothers. We also did not identify any overall tendency for greater degeneration
      or pathology in occupational drivers than their twin brothers. INTERPRETATIONS:
      Although driving may exacerbate symptoms of back problems, it does not damage the
      disc. Our inability to identify structural damage should be encouraging to those
      employed in occupations involving motorised vehicles and operation of heavy
      equipment.

PMID- 12423983
TI  - Obstructive nephropathy and iliac aneurysm.

PMID- 12423984
TI  - Effect of nitazoxanide on morbidity and mortality in Zambian children with
      cryptosporidiosis: a randomised controlled trial.
AB  - BACKGROUND: Cryptosporidiosis in children in developing countries causes
      persistent diarrhoea and malnutrition and is associated with increased mortality,
      but there is no effective treatment. We aimed to assess the effect of
      nitazoxanide-a new broad-spectrum antiparasitic drug-on morbidity and mortality
      in Zambian children with diarrhoea due to Cryptosporidium parvum. METHODS:
      Children with cryptosporidial diarrhoea who were admitted to the University
      Teaching Hospital, Lusaka, Zambia, between November, 2000, and July, 2001, and
      whose parents consented to their having an HIV test were randomly assigned
      nitazoxanide (100 mg twice daily orally for 3 days) or placebo. The primary
      endpoint was clinical response on day 7 after the start of treatment. Secondary
      endpoints included parasitological response by day 10 and mortality at day 8.
      Analysis was by intention to treat, with exclusion of patients subsequently found
      to be negative for C parvum or co-infected at baseline. The trial was stratified
      by HIV serology. FINDINGS: 50 HIV-seropositive and 50 HIV-seronegative children
      were recruited for the study, four of whom were subsequently excluded. In HIV
      seronegative children, diarrhoea resolved in 14 (56%) of 25 receiving
      nitazoxanide and 5 (23%) of 22 receiving placebo (difference 33%, 95% CI 7-59;
      p=0.037). C parvum was eradicated from stool in 13 (52%) of 25 receiving
      nitazoxanide and three (14%) of 22 receiving placebo (38%, 95% CI 14-63;
      p=0.007). Four children (18%) of 22 in the placebo group had died by day 8,
      compared with none of 25 in the nitazoxanide group (-18%, -34 to 2; p=0.041). HIV
      seropositive children did not benefit from nitazoxanide. Nitazoxanide was not
      significantly associated with adverse events in either stratum. INTERPRETATION: A
      3-day course of nitazoxanide significantly improved the resolution of diarrhoea,
      parasitological eradication, and mortality in HIV-seronegative, but not HIV
      seropositive, children.

PMID- 12423985
TI  - DNA markers predicting benefit from adjuvant fluorouracil in patients with colon
      cancer: a molecular study.
AB  - BACKGROUND: Present clinical algorithms assign adjuvant chemotherapy according to
      prognosis, but clinical decision-making would be greatly improved if reliable
      predictive markers were available to identify which subsets of patients benefit
      most from treatment. We examined molecular markers in preserved tissue from
      patients with Dukes' B or C colon cancer randomised to receive, or not, adjuvant
      fluorouracil, and assessed each marker's prognostic and predictive value.
      METHODS: Formalin-fixed paraffin-embedded paired normal and tumour samples were
      obtained from 393 patients with colon cancer from the UK AXIS trial of
      postoperative portal vein infusion fluorouracil versus control. We measured loss
      of heterozygosity (LOH) and microsatellite instability at four loci: P53 (17p13),
      D18S61 (18q22.3), D18S851 (18q21.1), and DP1 (5q21). The prognostic value of each
      marker was assessed with the log-rank test, and the predictive value by
      comparison of treatment hazard ratios with the chi(2) test for heterogeneity
      (CSH). FINDINGS: In 228 (58%) patients informative for LOH at D18S61, this marker
      was significantly predictive: benefit from fluorouracil was significantly greater
      in patients retaining heterozygosity than in those with LOH (CSH p=0.02).
      Conversely, LOH at D18S61 was a significant prognostic marker of improved outcome
      in untreated patients. 314 (80%) patients were informative for LOH at at least
      one of the three 17p and 18q sites, of whom half retained heterozygosity at one
      or more site. The effect of chemotherapy in these patients was striking (hazard
      ratio 0.45, 95% CI 0.28-0.73), whereas chemotherapy had no effect in patients
      with no retained heterozygosity (0.91; 0.56-1.48), CSH p=0.039. INTERPRETATION:
      Retention of heterozygosity at one or more 17p or 18q sites was associated with
      the ability to benefit from adjuvant fluorouracil. These results support the
      principle of developing molecular markers as predictive factors in treatment
      decisions.

PMID- 12423986
TI  - A woman who gained weight and became schizophrenic.

PMID- 12423987
TI  - Metapneumovirus and acute wheezing in children.
AB  - A new respiratory virus, human metapneumovirus, was recently identified. We
      detected this virus by PCR in ten (8%) of 132 consecutive children admitted to
      Turku Hospital, Finland, for acute expiratory wheezing (median age 7 months,
      range 4-25). The mean duration of hospital stay was 2.5 days (SD 1.6) and mean
      duration of respiratory symptoms was 19 days (8). The white blood cell count, C
      reactive protein, and regulated upon activation, normal T-cell-expressed and T
      cell-secreted (RANTES) concentrations in nasal secretion remained low, whereas
      interleukin 8 concentrations in nasal secretion were high. Human metapneumovirus
      is a clinically important causative agent of acute wheezing in young children.

PMID- 12423988
TI  - Management of profound hypothermia in children without the use of extracorporeal
      life support therapy.
AB  - Profound hypothermia is managed more and more with extracorporeal life support
      technology, especially when a patient's circulation is compromised. Many centres
      do not have rapid access to this service, however, and are still dependent on
      active internal rewarming techniques--eg, peritoneal and pleural lavage. Such
      interventions are invasive, and associated with inherent risk. Here, we report
      our successful experience with an active external rewarming technique in children
      with profound hypothermia (core temperature <20 degrees C).

PMID- 12423989
TI  - Nitroglycerin in septic shock after intravascular volume resuscitation.
AB  - In patients with septic shock, oxygen consumption is increased, but oxygen
      delivery and extraction is impaired, partly because of microcirculatory shutdown
      and shunting. Orthogonal polarisation spectral (OPS) imaging allows visualisation
      of the microcirculation. We used this technique to assess microcirculatory flow
      in septic-shock patients who had a mean arterial blood pressure of more than 60
      mm Hg and central venous pressure greater than 12 mm Hg. The infusion of 0.5 mg
      of nitroglycerin intravenously then resulted in a marked increase in
      microvascular flow on OPS imaging. Improved recruitment of the microcirculation
      could be a new resuscitation endpoint in septic shock.

PMID- 12423990
TI  - European Parliament approves pharma law overhaul.

PMID- 12423992
TI  - Women's "non-traditional" stroke symptoms may delay emergency treatment.

PMID- 12423997
TI  - Little agreement about how to slim down the USA.

PMID- 12423998
TI  - Bali bombing offers lessons for disaster relief.

PMID- 12424003
TI  - Ireland pushes for openness by nuclear industry in Hague hearing.

PMID- 12424004
TI  - Canada waits for "grandaddy" of health-reform studies.

PMID- 12424005
TI  - The pharmaceutical industry as an informant.
AB  - The pharmaceutical industry spends more time and resources on generation,
      collation, and dissemination of medical information than it does on production of
      medicines. This information is essential as a resource for development of
      medicines, but is also needed to satisfy licensing requirements, protect patents,
      promote sales, and advise patients, prescribers, and dispensers. Such information
      is of great commercial value, and most of it is confidential, protected by
      regulations about intellectual property rights. Through their generation and
      dissemination of information, transnational companies can greatly influence
      clinical practice. Sometimes, their commercially determined goals represent
      genuine advances in health-care provision, but most often they are implicated in
      excessive and costly production of information that is largely kept secret, often
      duplicated, and can risk undermining the best interests of patients and society.

PMID- 12424006
TI  - Role of peroxisome proliferator-activated receptor gamma and retinoid X receptor
      heterodimer in hepatogastroenterological diseases.
AB  - The peroxisome proliferator-activated receptor gamma (PPARgamma) and its partner
      the retinoid X receptor (RXR) are two nuclear receptors that are expressed mainly
      in adipose tissue and which have a role in lipid metabolism and insulin
      sensitisation. New sites of PPARgamma/RXR expression have been described,
      especially in the intestinal tract, pancreas, and liver. Concomitantly, new
      functions have been attributed to this heterodimer in regulation of inflammation,
      by its inhibition of nuclear factor (NF)-kappaB and via stress-kinase pathways.
      These new sites and functions of PPARgamma/RXR have led to novel ideas about
      pathophysiology of different inflammatory digestive diseases and to development
      of innovative treatment strategies with PPARgamma activators.

PMID- 12424007
TI  - Pattern recognition.

PMID- 12424009
TI  - UK Government and WHO.

PMID- 12424008
TI  - Defective glycosylation in muscular dystrophy.
AB  - CONTEXT: Over the past 15 years the causative genes of several inherited muscular
      dystrophies have been identified. These genes encode sarcolemmal, extracellular
      matrix, sarcomeric, and nuclear envelope proteins. Although the post
      translational processing of muscle proteins has a significant role in their
      correct assembly and function, these processes have not been shown to be
      primarily involved in the pathogenesis of muscular dystrophies until recently. In
      the past 18 months, four different forms of inherited muscular dystrophy in human
      beings have been associated with mutations in genes encoding for putative
      glycosyltransferases. Aberrant glycosylation of alpha-dystroglycan, an external
      membrane protein expressed in muscle, brain, and other tissues, is a common
      feature in these disorders. alpha-dystroglycan is highly glycosylated, its sugar
      components varying in different tissues and controlling its interaction with
      extracellular matrix partners. Disrupted glycosylation of alpha-dystroglycan
      results in a loss of these interactions, giving rise to both progressive muscle
      degeneration and abnormal neuronal migration in the brain. STARTING POINT: Kevin
      Campbell and colleagues have recently demonstrated that patients with muscle-eye
      brain disease (MEB) and Fukuyama congenital muscular dystrophy (FCMD), as well as
      the myodystrophy (myd) mouse, have an abnormally glycosyated form of alpha
      dystroglycan (Nature 2002; 418: 417-22 and 422-25). The abnormally glycosylated
      protein did not bind to three of its extracellular matrix ligands, laminin alpha2
      chain, agrin, and neurexin. The investigators also showed that a neuronal
      migration disorder occurs in both the myd mouse and in a brain-restricted alpha
      dystroglycan knock-out mouse that is similar to that seen in patients with MEB
      and FCMD. These results identify alpha-dystroglycan as having an essential role
      in both muscle and brain development and function. WHERE NEXT: Emphasis is moving
      away from identifying the protein components of the muscle fibre that are
      involved in muscular dystrophies towards the post-translational processing of
      proteins and the enzymes involved in these modifications. This opens up new
      avenues of research. Abnormal glycosylation of alpha-dystroglycan may underlie
      other as yet uncharacterised forms of muscular dystrophy and neuronal migration
      disorders.

PMID- 12424010
TI  - AIDS in Africa.

PMID- 12424012
TI  - AIDS in Africa.

PMID- 12424013
TI  - AIDS in Africa.

PMID- 12424014
TI  - AIDS in Africa.

PMID- 12424017
TI  - Sympathetic pain again?

PMID- 12424018
TI  - Perioperative transfusion in anaemic patients undergoing coronary artery bypass.

PMID- 12424020
TI  - Interferon beta-1a and beta-1b for treatment of multiple sclerosis.

PMID- 12424021
TI  - Interferon beta-1a and beta-1b for treatment of multiple sclerosis.

PMID- 12424023
TI  - Osteoporosis, risk of radiation-induced fracture, and quality of life.

PMID- 12424025
TI  - Second-line treatment for chronic tuberculosis.

PMID- 12424026
TI  - Targeting of children in filariasis mass drug administration.

PMID- 12424032
TI  - Rating systems for total knee replacement.
AB  - The objective assessment of outcome of surgical procedures is assuming increasing
      significance as the culture of audit and revalidation advances. There is a clear
      need for surgeons in all fields, but especially in Orthopaedics, to be familiar
      with the available scoring systems and their relative strengths and weaknesses.
      It is clear from a recent survey of BASK members' practice that there is little
      consensus about which system to use (addendum). This review presents a summary of
      the scoring systems available for the assessment of patients undergoing total
      knee replacement. These scores are described in detail and their relative merits
      discussed. None of the systems reviewed is perfect but those developed most
      recently do appear to offer advantages over older systems. Overall, the Western
      Ontario and McMaster University Osteoarthritis Index, Short Form 36 and Oxford
      Knee Score have undergone the most thorough assessment of reliability and
      validity and are therefore appropriate for the assessment of outcome after total
      knee replacement.

PMID- 12424033
TI  - Total knee arthroplasty following prior distal femoral fracture.
AB  - BACKGROUND: Femoral fracture may predispose the knee to the development of post
      traumatic arthritis by either a direct intra-articular injury or residual limb
      malalignment. Malunion, intra-articular osseous defects, limb malalignment,
      retained internal fixation devices, and compromised surrounding soft tissues may
      in turn affect the outcome of total knee arthroplasty (TKA) in these patients.
      The aim of our study was to evaluate the result of TKA in patients with previous
      distal femoral fracture. METHODS: The results of 48 cemented condylar total knee
      arthroplasties, performed between 1980 to 1998, in 47 patients with a previous
      distal femoral fracture were reviewed. There were 37 females and 10 males with an
      average age of 65 years (range, 19-84 years). Follow-up averaged 6.2 years
      (range, 2-16 years). No patients were lost to follow-up. RESULTS: At the time of
      arthroplasty a femoral fracture non-union was present in three knees, all of
      which were treated with a long stem cemented femoral component and bone grafting.
      Malunion, defined as angulation greater than 10 degrees in the coronal plain or
      greater than 15 degrees in the sagittal plain, was present in 21 knees. Of these,
      six underwent distal femoral osteotomy during TKA. In the remaining 15 patients,
      with a malunion, the deformity was addressed by alterations in the orientation
      and location of bone resection. Other procedures were commonly needed at the time
      of arthroplasty and included: lateral retinacular release (22 knees), extensor
      mechanism realignment (eight knees), and collateral ligament reconstruction (two
      knees). The mean pre-operative Knee Society Scores were 40 (range, 0-80) for pain
      and 48 (range, 0-100) for function and improved significantly to a mean of 84
      (range, 37-99) and 66 (range, 0-100) points, respectively, at the latest follow
      up (P<0.001). The knee arc of motion improved from a pre-operative mean of 83-99
      degrees at the latest follow-up (P<0.004). Post-operative manipulation under
      anesthesia for poor motion was carried out in four knees. Two knees had aseptic
      loosening that required subsequent revisions. Three knees developed deep
      infection which was treated with debridement and retention of components in one
      knee, arthrodesis in another, and eventual amputation in one knee. CONCLUSIONS:
      Significant improvement in function and relief of pain is seen in the vast
      majority of patients with previous distal femoral fractures undergoing subsequent
      TKA. However, these patients are at increased risk for restricted motion and
      perioperative complications following TKA. Special efforts to preserve the
      vascularity of the skin and subcutaneous tissues, restore limb alignment, ensure
      correct component positioning, and achieve soft tissue balance may help minimize
      the problems identified in this study.

PMID- 12424034
TI  - Underestimation of varus angulation in knees with flexion deformity.
AB  - In order to investigate the change in limb alignment in cases of knee flexion
      deformity, 17 male volunteers aged from 25 to 35 years with no complaints and no
      knee disorders were selected. The femorotibial angle (FTA), which is the lateral
      angle at the intersection between the femoral axis and the tibial axis in an
      anteroposterior radiograph, was employed as an index of limb alignment. FTA in
      standing on one leg with and without knee flexion was measured. The mean standing
      FTA was 179.4+/-19 degrees in full extension, which decreased to 176.9+/-2.5
      degrees in a mean flexion position of 18+/-3.3 degrees (range 15-25 degrees )
      (P<0.002), and in all cases, standing FTA in flexion was smaller (more valgus
      angulated) than that in full extension. There was a significant positive
      relationship with a straight regression line (D=0.101KFA + 0.296, R=0.8505)
      between the angle of knee flexion (KFA) and the difference (D) in standing FTA
      between full extension and knee flexion. We conclude that limb alignment became
      more valgus-angulated with an increase in flexion deformity.

PMID- 12424035
TI  - Resource implications of a knee referral.
AB  - INTRODUCTION: The latest government targets state that by the end of 2005 the
      maximum waiting time for an outpatient appointment will be 3 months. These
      recommendations will not only increase the size of the outpatient clinics, but
      also the resources required thereafter. The purpose of this study was to analyse
      the outcome of new patient referrals to one knee outpatient service in order to
      quantify the resources required to investigate and treat these patients. METHOD:
      All new patients attending one consultant's knee outpatient service in the time
      period January 1st 1997 to December 31st 1997 were prospectively entered into a
      database recording patient details, source of referral and diagnosis. Eighteen
      months after the time period a cohort of 200 patients was randomly selected and
      the case notes were analysed. The number of outpatient appointment episodes, MRI
      scans, physiotherapy referrals and surgical episodes generated were recorded for
      each patient. RESULTS: Analysis of the initial database records show that a total
      of 662 new knee referrals were seen in 1997. Fifty-two percent (341) were made up
      of the five most common diagnoses, these being osteoarthritis, anterior knee
      pain, anterior cruciate ligament injury, medial ligament injury and medial
      meniscus injury. Retrospective analysis of the 200 patient notes revealed that
      these patients required a total of 499 outpatient episodes, 43 MRI scans, 180
      courses of physiotherapy and 93 surgical episodes (53 elective and 40 emergency).
      These figures can be used to predict the resources that would be required by all
      new patients seen in an outpatient knee service in a year. DISCUSSION: Each new
      patient that enters the cycle of investigation followed by treatment must be met
      by extra resources. If this does not occur the net result will be that although
      government targets may be met, the time taken to complete each patient episode
      will become longer. It is imperative that before an agreement is made to see new
      patients the resources required to manage them are in place.

PMID- 12424036
TI  - A comparison of bilateral vs. unilateral total knee arthroplasty mobilised using
      a flexion regime.
AB  - Fifty six consecutive, primary simultaneous bilateral total knee arthroplasties
      were prospectively compared to 172 consecutive, primary unilateral total knee
      arthroplasties. Outcome measures included length of stay, analgesic and blood
      requirement as well as range of movement and functional scores. All procedures
      were performed by a single surgeon using a uniform technique, including a
      postoperative flexion regime. Range of movement, analgesic requirement and
      complication rates were similar in each group. The bilateral cases stayed in
      hospital on average 1.7 days longer and required considerably more blood.

PMID- 12424037
TI  - Comparison of two methods for reconstruction of the posterior cruciate ligament
      using a computer based method: quantitative evaluation of laxity, three
      dimensional kinematics and ligament deformation measurement in cadaver knees.
AB  - The aim of this paper is to present a biomechanical comparison of two different
      methods for reconstruction of the posterior cruciate ligament in cadaver knees.
      We used an original computer-based method allowing precise calculation of three
      dimensional (3D) knee kinematic parameters as well as the estimation of combined
      graft deformation (elongation-flexion-torsion). After isolated posterior cruciate
      ligament (PCL) dissection, double bundle and 'over-the-bottom' methods were
      performed successively on each knee using synthetic polyester ligaments. The
      effect of pre-tensioning was tested with the 'over-the-bottom' method. antero
      posterior (A-P) and rotational laxity as well as 3D kinematics were recorded and
      analysed. Our computer based method allowed us to show that both reconstruction
      methods were equivalent in restoring A-P and rotational laxity as well as
      kinematic curves. Combined deformation of the prostheses was equivalent for both
      ligaments.

PMID- 12424038
TI  - Computer-based method for the 3-D kinematic analysis of posterior cruciate
      ligament and postero-lateral corner lesions.
AB  - Posterior cruciate ligament (PCL) rupture, whether or not combined with postero
      lateral corner (PLC) tears, are more often diagnosed today thanks to improved
      imaging techniques. However, due to the lack of reliable instrumentation to
      quantitatively evaluate the knee, much is still unknown about the function of
      these ligamentous structures. The aim of this paper is to present results on the
      effect of progressive resection of the PCL and PLC on knee laxity and 3-D knee
      kinematics. The results show that 3-D movement analysis is important and
      complements laxity measurements by helping to interpret the complex alteration of
      knee function.

PMID- 12424039
TI  - Combined chronic posterior cruciate and posterolateral corner ligamentous
      injuries: a comparison of posterior cruciate ligament reconstruction with and
      without reconstruction of the posterolateral corner.
AB  - Many have advocated the importance of correcting posterolateral rotatory
      instability (PLRI) in injuries causing rupture of the posterior cruciate ligament
      (PCL) and posterolateral corner. However, there have been few studies directly
      comparing the results of reconstructing the PCL in isolation with PCL
      reconstruction combined with stabilisation of the posterolateral corner. We
      report on a retrospective study into 17 consecutive patients with chronic
      combined posterior cruciate and posterolateral corner ligamentous injuries. The
      mean follow-up was 35 months (range 14-74 months). All patients had unstable
      knees, with significant PLRI. In 12 cases the PCL alone was reconstructed, in 5
      cases a combined PCL and posterolateral corner reconstruction was performed. At a
      mean follow-up of 35 months, both groups had significantly improved compared to
      their pre-operative status, as measured by Lysholm and Tegner scores and clinical
      examination (P<0.01). The group in which only the PCL was reconstructed had
      significantly lower scores compared to those who had the additional
      posterolateral corner reconstruction (Tegner P<0.04, Lysholm P<0.02).

PMID- 12424040
TI  - Intercondylar notch width and the risk for anterior cruciate ligament rupture in
      the osteoarthritic knee: evaluation by plain radiography and CT scan.
AB  - We measured the intercondylar notch morphometrically from radiographs and CT
      scans of 30 osteoarthritic knees. Our purpose was to assess the accuracy of the
      standing posteroanterior 30 degrees flexion view in determining whether there is
      a critical notch width that might predict a higher risk for rupture of the
      anterior cruciate ligament due to osteophytes. A correlation was found between
      measurements made on radiographs and CT scans and the appearance of the anterior
      cruciate ligament at operation. A narrow notch (less than 12 mm wide) was
      associated with absence of the anterior cruciate ligament.

PMID- 12424041
TI  - Kneeling requirements and arthroplasty surgery.
AB  - We investigated the physical characteristics and symptoms related to kneeling in
      a normal population. One hundred people were recruited at random. Of these, 27
      subjects had knee pain and 73 were normal. Measurements were in kilograms with
      subjects on scales in three positions: standing, kneeling at 90 degrees and
      kneeling at full flexion. All 73 normal subjects could kneel at 90 degrees with
      an average of 94% of their body weight and at full flexion with an average of 51%
      of their body weight. The 27 subjects with knee pain were able to kneel at 90
      degrees with an average of 97% of their body weight and in full flexion with an
      average of 50% of their body weight. Weight transmitted through the knees at full
      flexion is significantly less than when at 90 degrees whether subjects had pain
      or not. Future development of knee arthroplasty, when catering for kneeling might
      need to concentrate on achieving a better range of movement.

PMID- 12424042
TI  - Correlating the efficacy of knee viscosupplementation with osteoarthritic changes
      on roentgenological examination.
AB  - This study was designed to identify the roentgenological changes of the knee that
      correlated with an unfavourable outcome when treated with an intra-articular knee
      viscoelastic supplementation. A prospective cohort of 60 patients receiving a
      standard course of intra-articular knee viscoelastic supplementation with a
      commercial uncross-linked hyaluronic acid derivative of an intermediate molecular
      weight were studied. Follow up was for 12 weeks post-treatment with clinical
      improvement measured using the Western Ontario and McMasters Universities
      Osteoarthritis Index. X-Rays of the relevant knee were viewed and graded for the
      severity of joint space, osteophyte, tibial spine, sclerosis, cyst formation,
      alignment and general severity by an observer blinded to the outcome of the
      treatment. There were no appreciable differences noted in the age, sex, length of
      follow up, pre-treatment, the severity of symptoms before treatment and number of
      intra-articular injections given per course in each X-ray category identified.
      There was a significant amount of improvement in patients with a minor loss of
      medial and lateral joint space in all outcome measures. Minimal changes in tibial
      spine and global appearance also indicated a positive outcome in stiffness, pain
      and overall improvement. Thus, patients with moderate to severe osteoarthritic
      changes in joint space on roentgenological examination would not significantly
      benefit from intra-articular knee viscoelastic supplementation. In addition, we
      feel that changes in the tibial spine and global appearance are not reviewed
      consistently enough to be included as part of our recommendation. As such, we
      conclude that only patients with a minimal to mild loss in joint space on
      roentgenological examination should form part of the target group who are likely
      to benefit from intra-articular knee viscoelastic supplementation.

PMID- 12424043
TI  - The incidence of revision of the metal component of total knee arthroplasties in
      different tibial-insert designs.
AB  - Seventy-one revisions of knee arthroplasty due to wear of modular tibial
      polyethylene inserts undertaken from May 1990 to May 1999 were reviewed. In 38
      cases (53.5%), severe damage was noted that necessitated replacement of the metal
      components. This proportion was less than in a previous study (88.7%). All the
      cases were further divided into two groups based on the design of the tibial
      component, one group having mobile bearings and the other fixed. In only 17.7% of
      the mobile group was there a need to replace metal parts at revision, whereas
      83.8% of the fixed group required such replacement, which is much more comparable
      to the previous study. Therefore, the incidence of revision of the metallic
      component of a total knee arthroplasty depends greatly on the design of the
      tibial components.

PMID- 12424045
TI  - No smoke without fire--simple recommendations to avoid arthroscopic burns.
AB  - Despite anecdotal stories, the potential of the arthroscope tip or the light
      cable end to cause thermal burns to the surgical drapes and to patients has not
      been investigated in orthopaedic surgery. This study shows that the arthroscopic
      tip registering a temperature of 41.9 degrees C, is unlikely to cause skin burns
      but causes singeing of drapes without combustion. The light cable end registers a
      temperature of 101 degrees C with the potential for causing skin burns. It has
      been demonstrated to cause combustion of disposable arthroscopic drapes within
      seconds at a distance of 0.5 cm. It is recommended that the light source should
      be switched on only after the light cable has been connected to the arthroscope.
      The light cable end must not rest on the drapes once the light source has been
      switched on, as thermal burns will occur within seconds. A retractable shield of
      2.5 cm fitted to the light cable end may virtually avoid the potential for
      combustion.

PMID- 12424044
TI  - Intra-articular morphine and postoperative analgesia after knee arthroscopy.
AB  - The aim of this study was to evaluate the postoperative analgesic effect of intra
      articular administration of a low- and a high-dose morphine solution after knee
      arthroscopy. Thirty patients who underwent diagnostic arthroscopy or arthroscopic
      meniscectomy were allocated in three groups. At the end of the arthroscopic
      procedure patients in Group A received intra-articularly 20 ml normal saline
      (N/S), Group B received 5 mg morphine in 20 ml N/S and Group C received 15 mg
      morphine in 20 ml N/S. The postoperative pain was assessed using a visual
      analogue scale for 24 h, while all the patients stayed at hospital. Side effects
      from the central action of opioids were not detected. Although the pain scores in
      the group of low-dose morphine were lower than in the control group, we failed to
      detect any significant differences in pain scores among the three groups. There
      was evidence that a high-dose can cause hyperalgesia.

PMID- 12424046
TI  - Free your hands: an aid to tissue retraction during total knee replacement.

PMID- 12424047
TI  - False aneurysm of the superior lateral geniculate artery following Total Knee
      Replacement.
AB  - Arterial complications following Total Knee Replacement are uncommon. We present
      a case of false aneurysm of the superior lateral geniculate artery presenting in
      the immediate postoperative period with continued bleeding from the surgical
      wound. This is the first case of false aneurysm of this vessel described
      following Total Knee Replacement. A method of treatment is outlined. Early
      consultation with vascular surgery colleagues is recommended to prevent delayed
      diagnosis of serious vascular complications.

PMID- 12424048
TI  - The first combined Orthopaedic Knee Societies meeting. Cape Town, South Africa
      17th-20th March 2002.

PMID- 12424049
TI  - Ligament balancing and femoral component rotation in total knee arthroplasty. A
      symposium organised by the 'Knee unit' of the St. Maartenskliniek Nijmegen,
      Netherlands, 16th November 2001.

PMID- 12424050
TI  - Is prevention really better than cure?

PMID- 12424052
TI  - Clues to regulation of tumour responses to DNA damage deciphered.

PMID- 12424053
TI  - Urgent reform needed for radiation oncology in Australia.

PMID- 12424054
TI  - Large screening trial launched by NCI.

PMID- 12424055
TI  - Sea squirt assaults sarcomas.

PMID- 12424057
TI  - HPV vaccine trial may take place in India.

PMID- 12424065
TI  - Genetic testing for melanoma.

PMID- 12424066
TI  - Tamoxifen non-compliance: does it matter?

PMID- 12424067
TI  - Management of malignant gastrointestinal stromal tumours.
AB  - Gastrointestinal stromal tumours (GISTs) are the most common form of mesenchymal
      tumour of the gastrointestinal tract. Clinically, they range from small indolent
      tumours curable with surgery alone to aggressive cancers. Making a distinction
      between an indolent and a malignant GIST is unreliable with conventional
      histopathological techniques. The presence of metastases at the time of diagnosis
      confirms malignancy, but all GISTs should be regarded as having malignant
      potential. GISTs characteristically express the KIT protein, a transmembrane
      tyrosine kinase receptor for stem-cell factor. Most GISTs have a mutation in the
      KIT proto-oncogene that translates into a gain-of-function constitutive
      activation of the KIT kinase. KIT activation seems to be an early tumour
      promoting event in pathogenesis. Commonly, malignant GISTs show high-level
      primary resistance to conventional chemotherapy. Imatinib mesylate is an orally
      administered selective inhibitor of certain tyrosine kinases including KIT. Most
      patients with advanced malignant GISTs achieve clinical benefit and significant
      antitumour responses with imatinib mesylate. Responses have been durable, and
      most patients tolerate the drug well at clinically effective doses. Imatinib
      mesylate is the first effective systemic therapy for advanced GIST.

PMID- 12424068
TI  - Radiation-induced tumour necrosis factor-alpha expression: clinical application
      of transcriptional and physical targeting of gene therapy.
AB  - Promising data are emerging on a new anticancer agent, Ad.EGR-TNF, an adenoviral
      vector, which contains radio-inducible DNA sequences from the early growth
      response (EGR1) gene promoter and cDNA for the gene encoding human tumour
      necrosis factor-alpha. Ad.EGR-TNF combines the well-documented broad-spectrum
      anticancer activity of TNFalpha with the proven clinical usefulness of
      radiotherapy. Systemic delivery of the TNFalpha protein has had limited success
      clinically because of severe dose-limiting toxic effects. This limitation has
      been overcome by the use of a gene delivery approach, combined with a radiation
      inducible promoter to express the TNFalpha protein in the irradiated tumour
      tissue. Preclinical and early phase I clinical testing indicates that effective
      concentrations of TNFalpha can be delivered to the tumour site without
      significant systemic exposure or toxic effects. The combination of radiation and
      TNFalpha gene delivery has produced striking antitumour effects in model systems
      in animals. In the clinical setting, potent anticancer activity has been observed
      with a high rate of complete and partial objective tumour responses. A novel
      mechanism of destruction of the tumour vasculature seems to be central to this
      distinct antitumour activity. This review summarises the rationale, mechanistic
      basis, preclinical data, and preliminary clinical findings for this new treatment
      model.

PMID- 12424069
TI  - Antisense therapy for cancer--the time of truth.
AB  - The recent acceleration in the identification and characterisation of new
      molecular targets for cancer and the limited effectiveness of conventional
      treatment strategies has focused considerable interest on the development of new
      types of anticancer agents. These new drugs are hoped to be highly specific for
      malignant cells with a favorable side-effect profile due to well-defined
      mechanisms of action. Antisense oligonucleotides are one such class of new agent-
      they are short, synthetic stretches of DNA which hybridise with specific mRNA
      strands that correspond to target genes. By binding to the mRNA, the antisense
      oligonucleotides prevent the sequence of the target gene being converted into a
      protein, thereby blocking the action of the gene. Several genes known to be
      important in the regulation of apoptosis, cell growth, metastasis, and
      angiogenesis, have been validated as molecular targets for antisense therapy.
      Furthermore, new targets are rapidly being uncovered through coordinated
      functional genomics and proteomics initiatives. Phosphorothioate oligonucleotides
      are the current gold standard for antisense therapy; they have acceptable
      physical and chemical properties and show reasonable resistance to nucleases.
      Recently, new generations of these phosphorothioate oligonucleotides that contain
      2'-modified nucleoside building blocks to enhance RNA binding affinity and
      decrease indirect toxic effects have been developed. Antisense therapeutics are,
      after decades of difficulties, finally close to fulfilling their promise in the
      clinic.

PMID- 12424070
TI  - Subcutaneous seeding of pancreatic carcinoma along a VP shunt catheter.

PMID- 12424071
TI  - Totally implantable venous-access ports: local problems and extravasation injury.
AB  - Totally implantable venous-access ports (TIVAPs) are valuable instruments for
      long-term intravenous treatment of patients with cancer, but implantation and use
      of these devices are each associated with complications. In addition to the
      perioperative problems, long-term complications can arise; these can be
      classified in five categories-catheter malfunction, catheter-related venous
      thrombosis, catheter-related infection, port-related complications, and
      extravasation injury. Such complications reduce the benefits of reliable access
      to the venous system in patients with malignant tumours. The vast majority of
      such disadvantages are attributable to inexpert handling of ports and, therefore,
      should be avoidable. TIVAP placement procedures and TIVAP complications are
      discussed in this review, with special emphasis on local problems and
      extravasation injuries. To obtain maximum benefit from TIVAPs, all health-care
      personnel must be familiar with the use and routine maintenance procedures of the
      devices and treatment options for catheter-related complications.

PMID- 12424072
TI  - Radiotherapy for cancer of the head and neck: altered fractionation regimens.
AB  - A greater understanding of radiobiology led to the development of two classes of
      radiation fractionation schedules for the treatment of head and neck cancers. The
      aim of accelerated fractionation is to reduce tumour proliferation, which is a
      major cause of relapse, by shortening the total duration of radiotherapy. By
      contrast, hyperfractionation exploits the differential sensitivity of tumour
      cells and normal tissues to radiation, to increase the therapeutic gain. The
      results of clinical trials of various types of altered fractionation schedules in
      head and neck carcinomas are examined in this review. Acceleration of radiation
      by 1 week without dose reduction and hyperfractionation are consistently better
      than standard fractionation for locoregional control of intermediate to advanced
      carcinomas without an increase in late toxic effects. However, improvement in
      survival of patients has not been consistent. Clinical investigations show that
      improvement in locoregional disease control and consistent gain in survival have
      been achieved with combinations of radiotherapy and concurrent chemotherapy in
      patients with mostly stage IV carcinomas. However, these benefits have been at
      the expense of increased late morbidity. Consequently, concurrent
      radiochemotherapy is now preferred for non-surgical treatment of patients with
      locally advanced carcinomas, whereas altered fractionation is generally selected
      for patients with intermediate-stage tumours or who are medically unfit to
      receive chemotherapy. Further data is needed before the combination of altered
      fractionation with chemotherapy can be recommended outside of a study setting.

PMID- 12424073
TI  - Squamous intraepithelial lesion of the coccygeal region: an unusual site of
      presentation.

PMID- 12424074
TI  - Endobronchial mucosal metastases in breast cancer: a rare metastatic pattern.

PMID- 12424078
TI  - See you there.

PMID- 12424080
TI  - Rationale for treating epilepsy in children.
AB  - Growing evidence indicates that the effects of antiepileptic drugs on childhood
      epilepsies are partly linked to the specific type of epilepsy or epilepsy
      syndrome. Most (but not all) types of epilepsy can be classified into categories
      that are conceptually meaningful. It is likewise logical to set treatment targets
      and to estimate the risks according to the main syndromic groups, as they share
      common, electroclinical presentations and long-term prognosis. Treatment should
      then be adjusted to each patient's clinical characteristics. Treatment should be
      started soon, whenever there is indication that delay would harm the child.
      However, if seizures are not disabling, treatment may be delayed, in order to
      acquire more knowledge about the spontaneous expression of the disorder and the
      plan thoughtfully explained to the parents. In children presenting with partial
      symptomatic or cryptogenic epilepsy, it is important to assess the patient's
      response to several different drugs. However, in patients regarded as having
      refractory epilepsy, possibilities for a surgical solution must be evaluated
      early in the course of the disease. In severe epileptic encephalopathies,
      complete seizure control is impossible and, ideally, treatment should provide as
      much integration and autonomy, with alleviation of frequent seizures. Again, this
      should be carefully explained to the parents. In children with severe
      epileptiform EEG abnormalities coexisting with brain dysfunction (diffuse or
      specific), the extent of EEG-related neurological dysfunction should be
      determined, and vigorous treatment should be started to abate its effects.
      Finally, seizures could be worsened by inappropriate drugs, paradoxical reaction
      or intoxication. Severe childhood epilepsies are particularly at risk and mild
      idiopathic epilepsies may be transformed into severe disorders, priming a vicious
      circle of heavy treatment, whereby the original disorder is no longer
      recognizable.

PMID- 12424081
TI  - Epilepsy and women's issues: an update.
AB  - Although the fundamentals of epilepsy are similar for both males and females, the
      clinical management of epilepsy in women should take into consideration a variety
      of factors including: social and cultural issues, age, relationships, diagnosis
      and characterization, female specific syndromes, the influence of female
      hormones, hormonal contraceptives and hormonal replacement therapy, the cosmetic
      side effects of epilepsy treatment, fertility, pregnancy and child care.
      Regarding the issue of reproduction, there are several misconceptions in relation
      to fertility in women with epilepsy. In general, women with epilepsy do not have
      a markedly reduced fertility compared with those without. Standard AEDs in common
      use have been associated with an increased risk of foetal malformations and with
      newer AEDs there is very little information regarding teratogenicity. The
      incidence of congenital malformations is also known to increase with the number
      of AEDs. Before planning a pregnancy it is imperative that the best possible
      seizure control is achieved at the lowest possible AED dose, preferably in
      monotherapy. With this in mind, the importance of effective pre-pregnancy
      counselling should be stressed and along with appropriate patient management and
      folic acid supplementation, effective patient education, most women with epilepsy
      can lead normal lives and deliver healthy children. This report will provide an
      update on these important considerations for women with epilepsy from both a
      social and medical perspective.

PMID- 12424082
TI  - Epilepsy in elderly people: management issues.
AB  - Epilepsy in elderly people is far more common than many doctors realise. The
      prevalence and incidence are frequently underestimated due to underdiagnosis or
      misdiagnosis of the condition. As the proportion of older people in the
      population grows, the management of epilepsy in this population will become
      increasingly important. Elderly people are especially susceptible to the
      consequences of seizures, particularly loss of self-confidence, decreased
      independence, and "falls" resulting in physical injury. Establishing the
      diagnosis of epilepsy in old age can be more difficult than in younger patients
      due to the extensive range of differential diagnoses and a far higher prevalence
      of concomitant disease. Treatment strategies are demanding; they must allow for
      the complexities of co-morbidity, co-medication, alterations in drug handling,
      and drug effects on an aging body. Together with a growing array of antiepileptic
      medication from which to choose, these factors make the management of epilepsy in
      elderly people particularly challenging.

PMID- 12424083
TI  - Recent developments in treatment of status epilepticus: a review.
AB  - Considering that status epilepticus (SE) is a medical emergency associated with
      significant morbidity and mortality, there are surprisingly few evidence-based
      data to guide management decisions. The purpose of this review is to give an
      overview of the incidence and classification of SE and to summarise the recent
      developments in the treatment of generalized tonic clonic status epilepticus
      (GTCSE). These consist in two prospective randomised studies indicating that SE
      should be treated as soon as possible, even out-of hospital, by intravenous (IV)
      benzodiazepine. Lorazepam is probably the best choice for the initial therapy.
      However, the differences in efficacy as compared to diazepam, diazepam associated
      to phenytoin or phenobarbital were not significant. There is no Class I evidence
      to help us choose which drug to give in SE that is not responsive to the initial
      lorazepam. Traditionally, based on a long clinical experience, IV phenytoin is
      given as the second drug. Recently, phenytoin is being increasingly substituted
      by fosphenytoin, even though no formal, comparative tolerability studies have
      been performed to study this compound in GTCSE. Starting in the 1980's, the use
      of injectable valproic acid (IV VPA) has been reported in an increasing number of
      uncontrolled case series initiated by doctors, indicating relative easy use,
      relative good tolerability and suggesting that it may be efficacious. Finally, we
      have very little data concerning the treatment of SE refractory to a
      benzodiazepine and phenytoin. Despite this lack of data many centres today use
      midazolam or propofol rather than phenobarbital or pentobarbital in this setting
      because these compounds have short half-lives and are, therefore, easier to
      handle.

PMID- 12424084
TI  - Temporal pole and mesiotemporal epilepsy: introductory remarks.

PMID- 12424085
TI  - Anatomy of the temporal pole region.
AB  - The temporopolar region is not clearly defined from an anatomical point of view.
      A line going through the rostral area of the inferior temporal, occipito temporal
      and superior temporal sulci is considered to represent its posterior limit on the
      lateral and inferior sides. On the internal side, this posterior limit
      corresponds to the rhinal sulcus, an anterior and internal extention of the
      collateral sulcus. From a cyto-architectonic point of view, the temporopolar
      region is caracterized by a dysgranular paralimbic cortex which ensures the
      transition between allo- and isocortical areas. The temporal pole is mainly
      connected with the amygadala, the hippocampus, the superior temporal gyrus, and
      the occipitobasal cortex, but also with the orbitary gyrus and the insula with
      which it forms the insulo-orbito-polar-temporo-complex. The temporal pole
      occupies the most rostral part of the temporal lobe and can only be accurately
      defined once the anatomy of the temporal lobe as a whole has been outlined. The
      architectonic configuration of this region as well as its connections with the
      limbic system, and the superior, orbital and insular temporal cortices make it a
      discrete temporal structure. Understanding the anatomical and functional
      organization of the temporal pole enables us to hypothesize about the role played
      by this structure in the pathogenesis of the forms of epilepsy originating in
      mesial temporal lobe structures.

PMID- 12424086
TI  - Investigating temporal pole function by functional imaging.
AB  - Although the role of the temporal lobe   especially its mesial part   is becoming
      clearer, that of the temporal pole remains more mysterious. Temporal pole
      function can be investigated in various ways: by comparing anatomical and
      clinical data; through experiments in animals; and by using functional imaging
      techniques. Anatomo-clinical studies have suggested that the temporal pole is
      important in autobiographical memory; and studies in monkeys (conditioning and
      lesional experiments) have revealed a role for the temporal pole in a variety of
      functions, including taste and olfaction, face recognition, visual discrimination
      of two-dimensional pictures, and the mnemonic functions of matching and learning.
      Functional imaging techniques, whether based on positron emission tomography
      (PET) or magnetic resonance imaging (MRI), make it possible to observe the
      functioning of the temporal pole in vivo in both healthy control subjects and
      patients. Initially, this type of approach was simply used to confirm
      observations made in animals. More recently it has shed light on other functions,
      especially with respect to processes associated with linguistic integration,
      which underlie the ability to make lexical and semantic links between different
      words and make it possible to understand a story in a general way without prior
      specific knowledge. Studies of epileptic, demented and schizophrenic patients
      have revealed that abnormal patterns of temporal pole function are typical in all
      these conditions.

PMID- 12424087
TI  - Direct electrical stimulations of the temporal pole in human.
AB  - We report the results of 105 intracortical electrical stimulations of the temporo
      polar cortex performed in 30 patients during stereo-electroencephalography (SEEG)
      investigation of drug-resistant temporal lobe epilepsy. Clinical responses were
      elicited in 50% of the patients during 26 of the 105 stimulations. Responses are
      coherent with data found in the literature with mostly psychic, viscero
      sensitive, autonomic and viscero-motor phenomena being elicited. Nearly all
      responses were evoked by stimulation of the antero-medial part of the temporo
      polar cortex whereas only once was a clinical response elicited during
      stimulation of the lateral part of the temporo-polar cortex. Induced auras were
      more frequently reported when there was an afterdischarge associated to the
      clinical response (60 and 75% of the stimulation followed by a localized or a
      diffusing after-discharge, respectively) then when there wasn't any after
      discharge following stimulation. The clinical responses evoked during stimulation
      of the temporo-polar cortex only have a limited topographic specificity since
      they closely resemble symptoms elicited by stimulation of other limbic or
      paralimbic areas. Nonetheless these results do suggest that the antero-medial
      part of the temporo-polar cortex is included in the symptomatogenic zone in so
      called "temporo-limbic" epilepsies.

PMID- 12424088
TI  - The role of the temporal pole in auditory processing.
AB  - Experiments in animals have shown that the temporal pole and the amygdala are
      involved in auditory processing. Comparable data are scarce in humans. It is only
      known that after temporal lobectomy, hearing may be impaired and dichotic
      listening scores reduced on the ear contralateral to the operated temporal lobe.
      Middle-latency auditory evoked potentials (MLAEPs) and late auditory evoked
      potentials (LAEPs) have been recorded in 14 patients before and after temporal
      lobectomy for the treatment of drug-resistant temporal lobe epilepsy. The Na and
      Pa components of MLAEPs were significantly delayed and the Pa component amplitude
      reduced before and after surgery as compared to a group of 21 healthy subjects.
      Data in pre- and postoperative period were not statistically different. N100 and
      P200 component of LAEPs were similarly altered. It is concluded that in humans
      the amygdala and probably the temporal pole may be involved in the process of
      auditory activation-inhibition. The possible role of auditory processing
      impairment in cognitive deficits in TLE patients can also be questioned.

PMID- 12424089
TI  - Temporal pole MRI abnormalities in temporal lobe epilepsy.
AB  - Magnetic resonance imaging (MRI) demonstrates an abnormal aspect of the temporo
      polar region in 1/3 to 2/3 of patients suffering from cryptogenic temporal lobe
      epilepsy. This abnormal aspect is described as a white matter increased T2
      signal, resulting in a loss of gray-white matter demarcation, often associated
      with atrophy, as recently confirmed by quantitative volumetric measurements.
      These temporo-polar MRI findings appear to correctly lateralize the epileptogenic
      temporal lobe with a very high specificity, and have never been reported in extra
      temporal lobe epilepsy nor in control subjects. They are usually associated with
      MRI signs of hippocampal sclerosis, but the two conditions seem to be partly
      distinct from a pathophysiological point of view. Pathological correlates of
      temporo-polar white matter increased T2 signal are controversial, but the role of
      an abnormal myelin seems more likely than that of ectopic neurons. A myelin
      dysfunction would also be consistent with the correlation observed between
      lateral temporal hypometabolism and temporo-polar MRI abnormalities. Whether or
      not these MRI findings are associated with a better seizure outcome following
      temporal lobectomy remains a debated issue.

PMID- 12424090
TI  - Temporoporal metabolic abnormalities in temporal lobe epilepsies.
AB  - Positron emission tomography (PET) may be used to map regional cerebral glucose
      metabolism using 18F-deoxyglucose-PET in patients with partial epilepsy. An area
      of reduced glucose metabolism, that is commonly more extensive than the
      underlying anatomical abnormality, is reported in most of the patients with
      medically refractory partial epilepsy. These functional changes are useful in the
      delineation of the epileptogenic focus prior to surgery. Nevertheless, in
      patients with mesial temporal lobe epilepsy (MTLE) without mass lesion, the
      hypometabolism involves a large area of the temporal lobe, including the mesial
      structures, the temporal pole and part of the lateral temporal cortex. In such
      patients with MTLE, subcortical structures and extratemporal lobe areas are also
      often hypometabolic. The reasons for this large hypometabolism remain debated. In
      MTLE patients, the most severe hypometabolism is found in the temporo-polar
      region. The clinical significance of this temporo-polar hypometabolism is
      unknown. The pathophysiology of interictal hypometabolism probably involves
      several mechanisms, such as neuronal loss, deafferentation, postictal depression,
      and others epilepsy-related phenomena. The relationship between interictal
      temporo-polar hypometabolism and seizure onset or seizure spread remain
      speculative.

PMID- 12424091
TI  - The role of the temporal pole in the genesis of temporal lobe seizures.
AB  - Failure of selective amygdalo-hippocampectomy strongly suggests that the so
      called mesio-temporal lobe seizures do not always arise from the sole amygado
      hippocampo-parahippocampal complex. Studies in temporal lobe epilepsies have
      shown that even in the presence of hippocampal sclerosis, the temporo-polar
      region (TP) is often altered, both histologically, anatomically and functionally.
      These findings are in accordance with our last ten years experience in
      stereotactic intracerebral EEG recordings (SEEG), during which we frequently
      observed the simultaneous involvement of both the amygdala (A), the hippocampus
      (Hc) and the TP at the onset of temporal lobe seizures. Recently, we have
      reviewed the SEEG findings of 25 patients with a final diagnosis of temporal lobe
      epilepsy, in whom both mesial, lateral and polar temporal lobe structures were
      investigated. The analysis of the most representative seizure in each patient
      showed that a low voltage fast activity was recorded in the TP either initially
      or within the first 5 seconds in 13/25 patients (TP group, 52%), while in the
      remaining 12 cases, ictal discharges started in the Hc and/or amygdala with a
      later involvement of the TP (AH group, 48%). Preliminary results of a further
      study conducted in 48 patients have confirmed the high frequency of early TP
      involvement (2/3 of the cases) in temporal lobe seizures, the clinical
      characteristics of which did not differ from ictal clinical findings usually
      described in the mesio-temporal lobe epilepsy syndrome. History of prolonged
      febrile convulsions and diagnosis of Hc sclerosis were more frequent in the AH
      group, while early consciousness impairment during seizures and anterior temporal
      white matter changes on MRI were more frequently observed in TP patients. However
      a clear-cut distinction between the two groups remains rather difficult in the
      absence of intracerebral recordings.

PMID- 12424092
TI  - Reduced Ca2+-calmodulin-dependent protein kinase activity and expression in LV
      myocardium of dogs with heart failure.
AB  - Studies on the status of multifunctional Ca(2+)-calmodulin (CaM)-dependent
      protein kinase-II (CaMKII) in failing hearts are limited and controversial. The
      study was performed in the left ventricular (LV) myocardium of six dogs with
      heart failure (HF) (LV ejection fraction, 23 +/- 2%) and six normal (NL) dogs. In
      the LV homogenate, CaMKII activity and its protein level were determined by using
      the CaMKII peptide and antibody, respectively. Furthermore, the protein level of
      CaM and phosphorylated phospholamban (PLB) at threonine-17 (PLB-Thr(17)) and
      serine-16 (PLB-Ser(16)) were also determined in the LV homogenate using a
      specific antibody. In addition, the level of zinc, which inhibits protein kinase
      A activity, was determined in the LV tissue by inductively coupled plasma mass
      spectrometry. CaMKII activity and phosphorylated PLB-Thr(17) and PLB-Ser(16)
      levels, but not CaM and Zn levels, were significantly reduced in the LV
      homogenate of dogs with HF compared with NL dogs. These results suggest that
      CaMKII activity is reduced in the failing LV myocardium, and this abnormality is
      associated with reduced protein expression level of the enzyme but not due to
      changes in CaM and zinc levels. In conclusion, reduced CaMKII activity and
      phosphorylated PLB level may be partly responsible for impaired sarcoplasmic
      reticulum function in HF.

PMID- 12424094
TI  - Amplification of sumatriptan-induced contraction in rabbit saphenous vein but not
      in basilar artery.
AB  - The modulation of serotonin (5-HT(1B/1D)) receptor-induced vascular contractility
      by histamine and U-46619 was compared in the rabbit basilar artery and saphenous
      vein. In the saphenous vein, histamine (5 x 10(-7) M) significantly increased the
      potency (from pEC(50) of 6.0 to 6.8) and efficacy (from 52.3% to 88.2%) of
      sumatriptan. Likewise, U-46619 (5 x 10(-9) M) also increased the potency (from
      pEC(50) of 5.9 to 6.6) and efficacy (from 51.8% to 92.1%) of sumatriptan in the
      saphenous vein. In contrast, equieffective concentrations of histamine (10(-7) M)
      and U-46619 (3 x 10(-9) M) failed to amplify contraction to sumatriptan in the
      basilar artery. Contraction to sumatriptan was inhibited by nitrendipine (10(-7)
      M) in the basilar artery but not in the saphenous vein, suggesting that different
      contractile signaling mechanisms are operating in these tissues. Furthermore, U
      46619- and thrombin-induced contractility in the basilar artery were also not
      amplified by histamine, suggesting that lack of amplification of contraction in
      the basilar artery was not restricted to sumatriptan but was rather a
      characteristic of this cerebral vessel. These data suggest that in the in vivo
      plasma milieu sumatriptan will more markedly contract the peripheral saphenous
      vein than the basilar artery, a cerebral blood vessel.

PMID- 12424093
TI  - ANG II AT2 receptor modulates AT1 receptor-mediated descending vasa recta
      endothelial Ca2+ signaling.
AB  - We tested whether the respective angiotensin type 1 (AT(1)) and 2 (AT(2))
      receptor subtype antagonists losartan and PD-123319 could block the descending
      vasa recta (DVR) endothelial intracellular calcium concentration ([Ca(2+)](i))
      suppression induced by ANG II. ANG II partially reversed the increase in
      [Ca(2+)](i) generated by cyclopiazonic acid (CPA; 10(-5) M), acetylcholine (ACh;
      10(-5) M), or bradykinin (BK; 10(-7) M). Losartan (10(-5) M) blocked that effect.
      When vessels were treated with ANG II before stimulation with BK and ACh,
      concomitant AT(2) receptor blockade with PD-123319 (10(-8) M) augmented the
      suppression of endothelial [Ca(2+)](i) responses. Similarly, preactivation with
      the AT(2) receptor agonist CGP-42112A (10(-8) M) prevented AT(1) receptor
      stimulation with ANG II + PD-123319 from suppressing endothelial [Ca(2+)](i). In
      contrast to endothelial [Ca(2+)](i) suppression by ANG II, pericyte [Ca(2+)](i)
      exhibited typical peak and plateau [Ca(2+)](i) responses that were blocked by
      losartan but not PD-123319. DVR vasoconstriction by ANG II was augmented when
      AT(2) receptors were blocked with PD-123319. Similarly, AT(2) receptor
      stimulation with CGP-42112A delayed the onset of ANG II-induced constriction. PD
      123319 alone (10(-5) M) showed no AT(1)-like action to constrict microperfused
      DVR or increase pericyte [Ca(2+)](i). We conclude that ANG II suppression of
      endothelial [Ca(2+)](i) and stimulation of pericyte [Ca(2+)](i) is mediated by
      AT(1) or AT(1)-like receptors. Furthermore, AT(2) receptor activation opposes ANG
      II-induced endothelial [Ca(2+)](i) suppression and abrogates ANG II-induced DVR
      vasoconstriction.

PMID- 12424095
TI  - Voltage-sensitive dye mapping in Langendorff-perfused rat hearts.
AB  - An imaging system suitable for recordings from Langendorff-perfused rat hearts
      using the voltage-sensitive dye 4-[beta-[2-(di-n-butylamino)-6
      naphthyl]vinyl]pyridinium (di-4-ANEPPS) has been developed. Conduction velocity
      was measured under hyper- and hypokalemic conditions, as well as at physiological
      and reduced temperature. Elevation of extracellular [K(+)] to 9 mM from 5.9 mM
      caused a slowing of conduction velocity from 0.66 +/- 0.08 to 0.43 +/- 0.07 mm/ms
      (35%), and reduction of the temperature to 32 degrees C from 37 degrees C caused
      a slowing from 0.64 +/- 0.07 to 0.46 +/- 0.05 mm/ms (28%). Ventricular activation
      patterns in sinus rhythm showed areas of early activation (breakthrough) in both
      the right and left ventricle, with breakthrough at a site near the apex of the
      right ventricle usually occurring first. The effects of mechanically immobilizing
      the preparation to reduce motion artifact were also characterized. Activation
      patterns in epicardially paced rhythm were insensitive to this procedure over the
      range of applied force tested. In sinus rhythm, however, a relatively large
      immobilizing force caused prolonged PQ intervals as well as altered ventricular
      activation patterns. The time-dependent effects of the dye on the rat heart were
      characterized and include 1) a transient vasodilation at the onset of dye
      perfusion and 2) a long-lasting prolongation of the PQ interval of the
      electrocardiogram, frequently resulting in brief episodes of atrioventricular
      block.

PMID- 12424096
TI  - Ceramide-induced activation of NADPH oxidase and endothelial dysfunction in small
      coronary arteries.
AB  - We tested the hypothesis that ceramide induces endothelial dysfunction in small
      coronary arteries via NADPH oxidase-mediated superoxide and resulting
      peroxynitrite formation. With the use of dihydroethidium as a superoxide
      indicator, C(2)-ceramide was found to increase superoxide production in the
      endothelial cells of small coronary arteries, which was inhibited by the NADPH
      oxidase inhibitors N-vanillylnonanamide, apocynin, and diphenylene iodonium.
      NADPH oxidase expression was confirmed in endothelial cells, as indicated by the
      immunoblotting of its subunits gp91(phox) and p47(phox). C(2)-ceramide increased
      NADPH oxidase activity by 52%, which was blocked by NADPH oxidase inhibitors but
      not by inhibitors of NO synthase, xanthine oxidase, and mitochondrial electron
      transport chain enzymes. By Western blot analysis, ceramide-induced NADPH oxidase
      activation was found to be associated with the translocation of p47(phox) to the
      membrane. In isolated and pressurized small coronary arteries, N
      vanillylnonanamide, apocynin, or uric acid, a peroxynitrite scavenger, largely
      restored the inhibitory effects of ceramide on bradykinin- and A-23187-induced
      vasorelaxation. With the use of nitrotyrosine as a marker, C(2)-ceramide was
      found to increase peroxynitrite in small coronary arteries, which could be
      blocked by uric acid. We conclude that NADPH oxidase-mediated superoxide
      production and subsequent peroxynitrite formation mediate ceramide-induced
      endothelial dysfunction in small coronary arteries.

PMID- 12424097
TI  - Microarray expression analysis of effects of exercise training: increase in
      atrial MLC-1 in rat ventricles.
AB  - Previous studies have shown that endurance exercise training increases myocardial
      contractility. We have previously described training-induced alterations in
      myocardial contractile function at the cellular level, including an increase in
      the Ca(2+) sensitivity of tension. To determine the molecular mechanism(s) of
      these changes, oligonucleotide microarrays were used to analyze the gene
      expression profile in ventricles from endurance-trained rats. We used an 11-wk
      treadmill training protocol that we have previously shown results in increased
      contractility in cardiac myocytes. After the training, the hearts were removed
      and RNA was isolated from the ventricles of nine trained and nine control rats.
      With the use of an Affymetrix Rat Genome U34A Array, we detected altered
      expression of 27 genes. Several genes previously found to have increased
      expression in hypertrophied myocardium, such as atrial natriuretic factor and
      skeletal alpha-actin, were decreased with training in this study. From the
      standpoint of altered contractile performance, the most significant finding was
      an increase in the expression of atrial myosin light chain 1 (aMLC-1) in the
      trained ventricular tissue. We confirmed microarray results for aMLC-1 using RT
      PCR and also confirmed a training-induced increase in aMLC-1 protein using two
      dimensional gel electrophoresis. aMLC-1 content has been previously shown to be
      increased in human cardiac hypertrophy and has been associated with increased
      Ca(2+) sensitivity of tension and increased power output. These results suggest
      that increased expression of aMLC-1 in response to training may be responsible,
      at least in part, for previously observed training-induced enhancement of
      contractile function.

PMID- 12424098
TI  - Proteasome inhibition ablates activation of NF-kappa B in myocardial reperfusion
      and reduces reperfusion injury.
AB  - Both acute coronary occlusion and reperfusion of an infarct-related artery lead
      to significant myocardial cell death. Recent evidence has been presented that
      activation of the transcription factor nuclear factor-kappaB (NF-kappaB) plays a
      critical role in reperfusion injury. NF-kappaB is usually bound to its inhibitor,
      IkappaB, and classic activation of NF-kappaB occurs when the 20S proteasome
      degrades IkappaB that has been phosphorylated and ubiquitinated. In this study,
      activation of NF-kappaB was inhibited by systemic administration of a 20S
      proteasome inhibitor (PS-519) in a porcine model of myocardial reperfusion
      injury. The experimental protocol induced myocardial ischemia in the distribution
      of the left anterior descending coronary artery for 1 h with subsequent
      reperfusion for 3 h. A single systemic treatment with PS-519 reduced 20S
      proteasome activity; blocked activation of NF-kappaB induced by reperfusion;
      reduced creatine kinase, creatine kinase-muscle-brain fraction, and troponin I
      release from the myocardium; preserved regional myocardial function measured by
      segmental shortening; significantly reduced the size of myocardial infarction;
      and exhibited no acute toxicity. These data show that myocardial reperfusion
      injury can be inhibited by using proteasome inhibitors, which likely function
      through the inhibition of NF-kappaB activation.

PMID- 12424099
TI  - Selective contractile dysfunction of left, not right, ventricular myocardium in
      the SHHF rat.
AB  - The progression of hypertension to cardiac failure involves systemic changes that
      may ultimately affect contractility throughout the heart. Spontaneous
      hypertensive heart failure (SHHF) rats have depressed left ventricular (LV)
      function, but right ventricular (RV) dysfunction is less well characterized.
      Ultrathin (87 +/- 5 mircom) trabeculae were isolated from end-stage failing SHHF
      rats and from age-matched controls. Under near-physiological conditions (1 mM
      Ca(2+), 37 degrees C, 4 Hz), developed force (in mN/mm(2)) was not significantly
      different in SHHF LV and RV trabeculae and those of controls. SHHF LV
      preparations displayed a negative force-frequency behavior (40 +/- 7 vs. 23 +/- 4
      mN/mm(2), 2 vs. 7 Hz); this relationship was positive in SHHF RV preparations (27
      +/- 5 vs. 40 +/- 6 mN/mm(2)) and controls (32 +/- 6 vs. 44 +/- 9 mN/mm(2)). The
      response to isoproterenol (10(-6) M, 4 Hz) was depressed in SHHF LV preparations.
      The inotropic response to hypothermia was lost in SHHF LV trabeculae but
      preserved in SHHF RV trabeculae. Intracellular calcium measurements revealed
      impaired calcium handling at higher frequencies in LV preparations. We conclude
      that in end-stage failing SHHF rats, RV function is only marginally affected,
      whereas a severe contractile dysfunction of LV myocardium is present.

PMID- 12424100
TI  - Human protein metabolism: its measurement and regulation.
AB  - The body's protein mass not only provides architectural support for cells but
      also serves vital roles in maintaining their function and survival. The whole
      body protein pool, as well as that of individual tissues, is determined by the
      balance between the processes of protein synthesis and degradation. These in turn
      are regulated by interactions among hormonal, nutritional, neural, inflammatory,
      and other influences. Prolonged changes in either the synthetic or degradative
      processes (or both) that cause protein wasting increase morbidity and mortality.
      The application of tracer kinetic methods, combined with measurements of the
      activity of components of the cellular signaling pathways involved in protein
      synthesis and degradation, affords new insights into the regulation of both
      protein synthesis and breakdown in vivo. These insights, including those from
      studies of insulin, insulin-like growth factor I, growth hormone, and amino acid
      mediated regulation of muscle and whole body protein turnover, provide
      opportunities to develop and test therapeutic approaches with promise to minimize
      or prevent these adverse health consequences.

PMID- 12424101
TI  - Phosphorylated inositol compounds in beta -cell stimulus-response coupling.
AB  - Pancreatic beta-cell function is essential for the regulation of glucose
      homeostasis in humans, and its impairment leads to the development of type 2
      diabetes. Inputs from glucose and cell surface receptors act together to initiate
      the beta-cell stimulus-response coupling that ultimately leads to the release of
      insulin. Phosphorylated inositol compounds have recently emerged as key players
      at all levels of the stimulus-secretion coupling process. In this current review,
      we seek to highlight recent advances in beta-cell phosphoinositide research by
      dividing our examination into two sections. The first involves the events that
      lead to insulin secretion. This includes both new roles for inositol
      polyphosphates, particularly inositol hexakisphosphate, and both conventional and
      3-phosphorylated inositol lipids. In the second section, we deal with the more
      novel concept of the autocrine role of insulin. Here, released insulin initiates
      signal transduction cascades, principally through the activity of
      phosphatidylinositol 3-kinase. This new round of signal transduction has been
      established to activate key beta-cell genes, particularly the insulin gene
      itself. More controversially, this insulin feedback has also been suggested to
      either terminate or enhance insulin secretion events.

PMID- 12424102
TI  - Abdominal fat distribution and peripheral and hepatic insulin resistance in type
      2 diabetes mellitus.
AB  - We examined the relationship between peripheral/hepatic insulin sensitivity and
      abdominal superficial/deep subcutaneous fat (SSF/DSF) and intra-abdominal
      visceral fat (VF) in patients with type 2 diabetes mellitus (T2DM). Sixty-two
      T2DM patients (36 males and 26 females, age = 55 +/- 3 yr, body mass index = 30
      +/- 1 kg/m2) underwent a two-step euglycemic insulin clamp (40 and 160 mU. m(-2).
      min(-1)) with [3-3H]glucose. SSF, DSF, and VF areas were quantitated with
      magnetic resonance imaging at the L(4-5) level. Basal endogenous glucose
      production (EGP), hepatic insulin resistance index (basal EGP x FPI), and total
      glucose disposal (TGD) during the first and second insulin clamp steps were
      similar in male and female subjects. VF (159 +/- 9 vs. 143 +/- 9 cm2) and DSF
      (199 +/- 14 vs. 200 +/- 15 cm(2)) were not different in male and female subjects.
      SSF (104 +/- 8 vs. 223 +/- 15 cm2) was greater (P < 0.0001) in female vs. male
      subjects despite similar body mass index (31 +/- 1 vs. 30 +/- 1 kg/m2) and total
      body fat mass (31 +/- 2 vs. 33 +/- 2 kg). In male T2DM, TGD during the first
      insulin clamp step (1st TGD) correlated inversely with VF (r = -0.45, P < 0.01),
      DSF (r = -0.46, P < 0.01), and SSF (r = -0.39, P < 0.05). In males, VF (r = 0.37,
      P < 0.05), DSF (r = 0.49, P < 0.01), and SSF (r = 0.33, P < 0.05) were correlated
      positively with hepatic insulin resistance. In females, the first TGD (r = -0.45,
      P < 0.05) and hepatic insulin resistance (r = 0.49, P < 0.05) correlated with VF
      but not with DSF, SSF, or total subcutaneous fat area. We conclude that visceral
      adiposity is associated with both peripheral and hepatic insulin resistance,
      independent of gender, in T2DM. In male but not female T2DM, deep subcutaneous
      adipose tissue also is associated with peripheral and hepatic insulin resistance.

PMID- 12424103
TI  - Impact of chronic fructose infusion on hepatic metabolism during TPN
      administration.
AB  - During chronic total parenteral nutrition (TPN), net hepatic glucose uptake
      (NHGU) is markedly elevated. However, NHGU is reduced by the presence of an
      infection. We recently demonstrated that a small, acute (3-h) intraportal
      fructose infusion can correct the infection-induced impairment in NHGU. The aim
      of this study was to determine whether the addition of fructose to the TPN
      persistently enhances NHGU in the presence of an infection. TPN was infused
      continuously into the inferior vena cava of chronically catheterized dogs for 5
      days. On day 3, a bacterial clot was implanted in the peritoneal cavity, and
      either saline (CON, n = 5) or fructose (+FRUC, 1.0 mg. kg(-1). min(-1), n = 6)
      infusion was included with the TPN. Forty-two hours after the infection was
      induced, hepatic glucose metabolism was assessed in conscious dogs with
      arteriovenous and tracer methods. Arterial plasma glucose concentration was lower
      with chronic fructose infusion (120 +/- 4 vs. 131 +/- 3 mg/dl, +FRUC vs. CON, P <
      0.05); however, NHGU was not enhanced (2.2 +/- 0.5 vs. 2.8 +/- 0.4 mg. kg(-1).
      min(-1)). Acute removal of the fructose infusion dramatically decreased NHGU (2.2
      +/- 0.5 to -0.2 +/- 0.5 mg. kg(-1). min(-1)), and net hepatic lactate release
      also fell (1.6 +/- 0.3 to 0.5 +/- 0.3 mg. kg(-1). min(-1)). This led to an
      increase in the arterial plasma glucose (Delta13 +/- 3 mg/dl, P < 0.05) and
      insulin (Delta5 +/- 2 micro U/ml) concentrations and to a decrease in glucagon
      (Delta-11 +/- 3 pg/ml) concentration. In conclusion, the addition of chronic
      fructose infusion to TPN during infection does not lead to a persistent
      augmentation of NHGU.

PMID- 12424104
TI  - Postprandial leg uptake of triglyceride is greater in women than in men.
AB  - The postprandial excursion of plasma triglyceride (TG) concentration is greater
      in men than in women. In this study, the disposition of dietary fat was examined
      in lean healthy men and women (n = 8/group) in either the overnight-fasted or fed
      (4.5 h after breakfast) states. A [14C]oleate tracer was incorporated into a test
      meal, providing 30% of total daily energy requirements. After ingestion of the
      test meal, measures of arteriovenous differences in TG and 14C across the leg
      were combined with needle biopsies of skeletal muscle and adipose tissue and
      respiratory gas collections to define the role of skeletal muscle in the
      clearance of dietary fat. The postprandial plasma TG and 14C tracer excursions
      were lower (P = 0.04) in women than in men in the overnight-fasted and fed
      states. Women, however, had significantly greater limb uptake of total TG
      compared with men on both the fasted (3,849 +/- 846 vs. 528 +/- 221 total micro
      mol over 6 h) and fed (4,847 +/- 979 vs. 1,571 +/- 334 total micromol over 6 h)
      days. This was also true for meal-derived 14C lipid uptake. 14C content of
      skeletal muscle tissue (micro Ci/g tissue) was significantly greater in women
      than in men 6 h after ingestion of the test meal. In contrast, 14C content of
      adipose tissue was not significantly different between men and women at 6 h. The
      main effect of nutritional state, fed vs. fasted, was to increase the postmeal
      glucose (P = 0.01) excursion (increase from baseline) and decrease the postmeal
      TG excursion (P = 0.02). These results support the notion that enhanced skeletal
      muscle clearance of lipoprotein TG in women contributes to their reduced
      postprandial TG excursion. Questions remain as to the mechanisms causing these
      sex-based differences in skeletal muscle TG uptake and metabolism. Furthermore,
      nutritional state can significantly impact postprandial metabolism in both men
      and women.

PMID- 12424105
TI  - Phenylalanine kinetics in healthy volunteers and liver cirrhotics: implications
      for the phenylalanine breath test.
AB  - Expired 13CO2 recovery from an oral l-[1-13C]phenylalanine ([13C]Phe) dose has
      been used to quantify liver function. This parameter, however, does not depend
      solely on liver function but also on total CO2 production, Phe turnover, and
      initial tracer distribution. Therefore, we evaluated the impact of these factors
      on breath test values. Nine ethyl-toxic cirrhotic patients and nine control
      subjects received intravenously 2 mg/kg of [13C]Phe, and breath and blood samples
      were collected over 4 h. CO2 production was measured by indirect calorimetry. The
      exhaled 13CO2 enrichments were analyzed by isotope ratio mass spectrometry and
      the [13C]Phe and l-[1-13C]tyrosine enrichments by gas chromatography-mass
      spectrometry. The cumulative 13CO2 recovery was significantly lower in cirrhotic
      patients (7 vs. 12%; P < 0.01), in part due to lower total CO2 production rates.
      Phe turnover in cirrhotic patients was significantly lower (33 vs. 44 micro mol.
      kg(-1). h(-1); P < 0.05). When these extrahepatic factors were considered in the
      calculation of the Phe oxidation rate, the intergroup differences were even more
      pronounced (3 vs. 7 micro mol. kg(-1). h(-1)) than those for 13CO2 recovery data.
      Also, the Phe-to-Tyr conversion rate, another indicator of Phe oxidation, was
      significantly reduced (0.7 vs. 3.0 micro mol. kg(-1). h(-1)).

PMID- 12424106
TI  - Phenylalanine requirement in children with classical PKU determined by indicator
      amino acid oxidation.
AB  - Dietary restriction of phenylalanine is the main treatment for phenylketonuria
      (PKU), and current estimates of requirements are based on plasma phenylalanine
      concentration and growth. The present study aimed to determine more precisely the
      phenylalanine requirements in patients with the disease by use of indicator amino
      acid oxidation, with L-[1-13C]lysine as the indicator. Breath 13CO2 production (F
      13 CO2) was used as the end point. Finger-prick blood samples were also collected
      for measurement of phenylalanine to relate phenylalanine intake to blood
      phenylalanine levels. The mean phenylalanine requirement, estimated using a two
      phase linear regression crossover analysis, was 14 mg. kg(-1). day(-1), and the
      safe population intake (upper 95% confidence interval of the mean) was found to
      be 19.5 mg. kg(-1). day(-1). A balance between phenylalanine intake and the
      difference between fed and fasted blood phenylalanine concentration was observed
      at an intake of 20 mg. kg(-1). day(-1). The similarity between these two values
      (19.5 and 20 mg. kg(-1). day(-1)) suggests that the maximal phenylalanine intake
      for children with PKU should be no higher than 20 mg. kg(-1). day(-1).

PMID- 12424107
TI  - Allopregnanolone enhancement of GABAergic transmission in rat medial preoptic
      area neurons.
AB  - Gamma-aminobutyric acid (GABA)-mediated transmission in the medial preoptic area
      (MPOA) of the hypothalamus plays an important role in functions such as sex
      steroid hormone dynamics and control of body temperature. The action of
      allopregnanolone, the primary metabolite of progesterone, on GABAergic
      transmission was investigated by employing patch clamp whole cell recording on
      acutely dissociated rat MPOA neurons with the functional connection of
      presynaptic terminals. Allopregnanolone enhanced spontaneous GABA release on the
      MPOA neurons and induced prolonged decay of miniature GABAergic-inhibitory
      postsynaptic currents (mIPSCs). The facilitation of GABA release from the
      presynaptic terminals by allopregnanolone disappeared in Ca2+-free extracellular
      solution. The presynaptic action of this neurosteroid was also blocked by
      bumetanide, a blocker of cation-Cl- cotransporters, and by removal of
      extracellular Na+. The results suggest that allopregnanolone enhances GABAergic
      transmission at the MPOA neurons by pre- and postsynaptic mechanisms. The
      enhancement of GABA release by allopregnanolone might require a high Cl-
      concentration in the presynaptic terminal maintained by Na+-dependent, bumetanide
      sensitive mechanisms (e.g., Na+-K+-Cl- cotransporter) and might be mediated by
      Ca2+ influx into presynaptic terminal.

PMID- 12424108
TI  - Adrenomedullin improves cardiac function and prevents renal damage in
      streptozotocin-induced diabetic rats.
AB  - Adrenomedullin (AM) is a potent vasodilating peptide and is involved in
      cardiovascular and renal disease. In the present study, we investigated the role
      of AM in cardiac and renal function in streptozotocin (STZ)-induced diabetic
      rats. A single tail-vein injection of adenoviral vectors harboring the human AM
      gene (Ad.CMV-AM) was administered to the rats 1-wk post-STZ treatment (65 mg/kg
      iv). Immunoreactive human AM was detected in the plasma and urine of STZ-diabetic
      rats treated with Ad.CMV-AM. Morphological and chemical examination showed that
      AM gene delivery significantly reduced glycogen accumulation within the hearts of
      STZ-diabetic rats. AM gene delivery improved cardiac function compared with STZ
      diabetic rats injected with control virus, as observed by decreased left
      ventricular end-diastolic pressure, increased cardiac output, cardiac index, and
      heart rate. AM gene transfer significantly increased left ventricular long axis
      (11.69 +/- 0.46 vs. 10.31 +/- 0.70 mm, n = 10, P < 0.05) and rate of pressure
      rise and fall (+6,090.1 +/- 597.3 vs. +4,648.5 +/- 807.1 mmHg/s), (-4,902.6 +/-
      644.2 vs. -3,915.5 +/- 805.8 mmHg/s, n = 11, P < 0.05). AM also significantly
      attenuated renal glycogen accumulation and tubular damage in STZ-diabetic rats as
      well as increased urinary cAMP and cGMP levels, along with increased cardiac cAMP
      and Akt phosphorylation. We also observed that delivery of the AM gene caused an
      increase in body weight along with phospho-Akt and membrane-bound GLUT4 levels in
      skeletal muscle. These results suggest that AM plays a protective role in
      hyperglycemia-induced glycogen accumulation and cardiac and renal dysfunction via
      Akt signal transduction pathways.

PMID- 12424109
TI  - The underlying principles of scientific publication.

PMID- 12424110
TI  - ARROGANT: an application to manipulate large gene collections.
AB  - ARROGANT (ARRay OrGANizing Tool) is a software tool developed to facilitate the
      identification, annotation and comparison of large collections of genes or
      clones. The objective is to enable users to compile gene/clone collections from
      different databases, allowing them to design experiments and analyze the
      collections as well as associated experimental data efficiently. ARROGANT can
      relate different sequence identifiers to their common reference sequence using
      the UniGene database, allowing for the comparison of data from two different
      microarray experiments. ARROGANT has been successfully used to analyze microarray
      expression data for colon cancer, to compile genes potentially related to cardiac
      diseases for subsequent resequencing (to identify single nucleotide
      polymorphisms, SNPs), to design a new comprehensive human cDNA microarray for
      cancer, to combine and compare expression data generated by different microarrays
      and to provide annotation for genes on custom and Affymetrix chips.

PMID- 12424111
TI  - Identification of mixups among DNA sequencing plates.
AB  - MOTIVATION: During the process of high-throughput genome sequencing there are
      opportunities for mixups of reagents and data associated with particular
      projects. The sequencing templates or sequence data generated for an assembly may
      become contaminated with reagents or sequences from another project, resulting in
      poorer quality and inaccurate assemblies. RESULTS: We have developed a system to
      assess sequence assemblies and monitor for laboratory mixups. We describe several
      methods for testing the consistency of assemblies and resolving mixed ones. We
      use statistical tests to evaluate the distribution of sequencing reads from
      different plates into contigs, and a graph-based approach to resolve situations
      where data has been inappropriately combined. While these methods have been
      designed for use in a high-throughput DNA sequencing environment processing
      thousands of clones, they can be applied in any situation where distinct
      sequencing projects are performed at redundant coverage.

PMID- 12424112
TI  - MethPrimer: designing primers for methylation PCRs.
AB  - MOTIVATION: DNA methylation is an epigenetic mechanism of gene regulation.
      Bisulfite- conversion-based PCR methods, such as bisulfite sequencing PCR (BSP)
      and methylation specific PCR (MSP), remain the most commonly used techniques for
      methylation mapping. Existing primer design programs developed for standard PCR
      cannot handle primer design for bisulfite-conversion-based PCRs due to changes in
      DNA sequence context caused by bisulfite treatment and many special constraints
      both on the primers and the region to be amplified for such experiments.
      Therefore, the present study was designed to develop a program for such
      applications. RESULTS: MethPrimer, based on Primer 3, is a program for designing
      PCR primers for methylation mapping. It first takes a DNA sequence as its input
      and searches the sequence for potential CpG islands. Primers are then picked
      around the predicted CpG islands or around regions specified by users. MethPrimer
      can design primers for BSP and MSP. Results of primer selection are delivered
      through a web browser in text and in graphic view.

PMID- 12424113
TI  - PRIMEGENS: robust and efficient design of gene-specific probes for microarray
      analysis.
AB  - MOTIVATION: DNA microarray is a powerful high-throughput tool for studying gene
      function and regulatory networks. Due to the problem of potential cross
      hybridization, using full-length genes for microarray construction is not
      appropriate in some situations. A bioinformatic tool, PRIMEGENS, has recently
      been developed for the automatic design of PCR primers using DNA fragments that
      are specific to individual open reading frames (ORFs). RESULTS: PRIMEGENS first
      carries out a BLAST search for each target ORF against all other ORFs of the
      genome to quickly identify possible homologous sequences. Then it performs
      optimal sequence alignment between the target ORF and each of its homologous ORFs
      using dynamic programming. PRIMEGENS uses the sequence alignments to select gene-
      specific fragments, and then feeds the fragments to the Primer3 program to design
      primer pairs for PCR amplification. PRIMEGENS can be run from the command line on
      Unix/Linux platforms as a stand-alone package or it can be used from a Web
      interface. The program runs efficiently, and it takes a few seconds per sequence
      on a typical workstation. PCR primers specific to individual ORFs from Shewanella
      oneidensis MR-1 and Deinococcus radiodurans R1 have been designed. The PCR
      amplification results indicate that this method is very efficient and reliable
      for designing specific probes for microarray analysis.

PMID- 12424114
TI  - Comparison of microarray designs for class comparison and class discovery.
AB  - MOTIVATION: Two-color microarray experiments in which an aliquot derived from a
      common RNA sample is placed on each array are called reference designs.
      Traditionally, microarray experiments have used reference designs, but designs
      without a reference have recently been proposed as alternatives. RESULTS: We
      develop a statistical model that distinguishes the different levels of variation
      typically present in cancer data, including biological variation among RNA
      samples, experimental error and variation attributable to phenotype. Within the
      context of this model, we examine the reference design and two designs which do
      not use a reference, the balanced block design and the loop design, focusing
      particularly on efficiency of estimates and the performance of cluster analysis.
      We calculate the relative efficiency of designs when there are a fixed number of
      arrays available, and when there are a fixed number of samples available. Monte
      Carlo simulation is used to compare the designs when the objective is class
      discovery based on cluster analysis of the samples. The number of discrepancies
      between the estimated clusters and the true clusters were significantly smaller
      for the reference design than for the loop design. The efficiency of the
      reference design relative to the loop and block designs depends on the relation
      between inter- and intra-sample variance. These results suggest that if cluster
      analysis is a major goal of the experiment, then a reference design is
      preferable. If identification of differentially expressed genes is the main
      concern, then design selection may involve a consideration of several factors.

PMID- 12424115
TI  - Gene expression data analysis with a dynamically extended self-organized map that
      exploits class information.
AB  - MOTIVATION: Currently the most popular approach to analyze genome-wide expression
      data is clustering. One of the major drawbacks of most of the existing clustering
      methods is that the number of clusters has to be specified a priori. Furthermore,
      by using pure unsupervised algorithms prior biological knowledge is totally
      ignored Moreover, most current tools lack an effective framework for tight
      integration of unsupervised and supervised learning for the analysis of high
      dimensional expression data and only very few multi-class supervised approaches
      are designed with the provision for effectively utilizing multiple functional
      class labeling. RESULTS: The paper adapts a novel Self-Organizing map called
      supervised Network Self-Organized Map (sNet-SOM) to the peculiarities of multi
      labeled gene expression data. The sNet-SOM determines adaptively the number of
      clusters with a dynamic extension process. This process is driven by an
      inhomogeneous measure that tries to balance unsupervised, supervised and model
      complexity criteria. Nodes within a rectangular grid are grown at the boundary
      nodes, weights rippled from the internal nodes towards the outer nodes of the
      grid, and whole columns inserted within the map The appropriate level of
      expansion is determined automatically. Multiple sNet-SOM models are constructed
      dynamically each for a different unsupervised/supervised balance and model
      selection criteria are used to select the one optimum one. The results indicate
      that sNet-SOM yields competitive performance to other recently proposed
      approaches for supervised classification at a significantly reduced computational
      cost and it provides extensive exploratory analysis potentiality within the
      analysis framework. Furthermore, it explores simple design decisions that are
      easier to comprehend and computationally efficient.

PMID- 12424116
TI  - Nonparametric methods for identifying differentially expressed genes in
      microarray data.
AB  - MOTIVATION: Gene expression experiments provide a fast and systematic way to
      identify disease markers relevant to clinical care. In this study, we address the
      problem of robust identification of differentially expressed genes from
      microarray data. Differentially expressed genes, or discriminator genes, are
      genes with significantly different expression in two user-defined groups of
      microarray experiments. We compare three model-free approaches: (1).
      nonparametric t-test, (2). Wilcoxon (or Mann-Whitney) rank sum test, and (3). a
      heuristic method based on high Pearson correlation to a perfectly differentiating
      gene ('ideal discriminator method'). We systematically assess the performance of
      each method based on simulated and biological data under varying noise levels and
      p-value cutoffs. RESULTS: All methods exhibit very low false positive rates and
      identify a large fraction of the differentially expressed genes in simulated data
      sets with noise level similar to that of actual data. Overall, the rank sum test
      appears most conservative, which may be advantageous when the computationally
      identified genes need to be tested biologically. However, if a more inclusive
      list of markers is desired, a higher p-value cutoff or the nonparametric t-test
      may be appropriate. When applied to data from lung tumor and lymphoma data sets,
      the methods identify biologically relevant differentially expressed genes that
      allow clear separation of groups in question. Thus the methods described and
      evaluated here provide a convenient and robust way to identify differentially
      expressed genes for further biological and clinical analysis.

PMID- 12424117
TI  - Methods for assessing reproducibility of clustering patterns observed in analyses
      of microarray data.
AB  - MOTIVATION: Recent technological advances such as cDNA microarray technology have
      made it possible to simultaneously interrogate thousands of genes in a biological
      specimen. A cDNA microarray experiment produces a gene expression 'profile'.
      Often interest lies in discovering novel subgroupings, or 'clusters', of
      specimens based on their profiles, for example identification of new tumor
      taxonomies. Cluster analysis techniques such as hierarchical clustering and self
      organizing maps have frequently been used for investigating structure in
      microarray data. However, clustering algorithms always detect clusters, even on
      random data, and it is easy to misinterpret the results without some objective
      measure of the reproducibility of the clusters. RESULTS: We present statistical
      methods for testing for overall clustering of gene expression profiles, and we
      define easily interpretable measures of cluster-specific reproducibility that
      facilitate understanding of the clustering structure. We apply these methods to
      elucidate structure in cDNA microarray gene expression profiles obtained on
      melanoma tumors and on prostate specimens.

PMID- 12424118
TI  - Theoretical and experimental comparisons of gene expression indexes for
      oligonucleotide arrays.
AB  - MOTIVATION: Oligonucleotide expression arrays exhibit systematic and reproducible
      variation produced by the multiple distinct probes used to represent a gene.
      Recently, a gene expression index has been proposed that explicitly models probe
      effects, and provides improved fits of hybridization intensity for arrays
      containing perfect match (PM) and mismatch (MM) probe pairs. RESULTS: Here we use
      a combination of analytical arguments and empirical data to show directly that
      the estimates provided by model-based expression indexes are superior to those
      provided by commercial software. The improvement is greatest for genes in which
      probe effects vary substantially, and modeling the PM and MM intensities
      separately is superior to using the PM-MM differences. To empirically compare
      expression indexes, we designed a mixing experiment involving three groups of
      human fibroblast cells (serum starved, serum stimulated, and a 50:50 mixture of
      starved/stimulated), with six replicate HuGeneFL arrays in each group. Careful
      spiking of control genes provides evidence that 88-98% of the genes on the array
      are detectably transcribed, and that the model-based estimates can accurately
      detect the presence versus absence of a gene. The use of extensive replication
      from single RNA sources enables exploration of the technical variability of the
      array.

PMID- 12424119
TI  - Statistical analysis of a small set of time-ordered gene expression data using
      linear splines.
AB  - MOTIVATION: Recently, the temporal response of genes to changes in their
      environment has been investigated using cDNA microarray technology by measuring
      the gene expression levels at a small number of time points. Conventional
      techniques for time series analysis are not suitable for such a short series of
      time-ordered data. The analysis of gene expression data has therefore usually
      been limited to a fold-change analysis, instead of a systematic statistical
      approach. METHODS: We use the maximum likelihood method together with Akaike's
      Information Criterion to fit linear splines to a small set of time-ordered gene
      expression data in order to infer statistically meaningful information from the
      measurements. The significance of measured gene expression data is assessed using
      Student's t-test. RESULTS: Previous gene expression measurements of the
      cyanobacterium Synechocystis sp. PCC6803 were reanalyzed using linear splines.
      The temporal response was identified of many genes that had been missed by a fold
      change analysis. Based on our statistical analysis, we found that about four gene
      expression measurements or more are needed at each time point.

PMID- 12424120
TI  - A duplication growth model of gene expression networks.
AB  - MOTIVATION: There has been considerable interest in developing computational
      techniques for inferring genetic regulatory networks from whole-genome expression
      profiles. When expression time series data sets are available, dynamic models
      can, in principle, be used to infer correlative relationships between gene
      expression levels, which may be causal. However, because of the range of
      detectable expression levels and the current quality of the data, the predictive
      nature of such inferred, quantitative models is questionable. Network models
      derived from simple rate laws offer an intermediate level analysis, going beyond
      simple statistical analysis, but falling short of a fully quantitative
      description. This work shows how such network models can be constructed and
      describes the global properties of the networks derived from such a model. These
      global properties are statistically robust and provide insights into the design
      of the underlying network. RESULTS: Several whole-genome expression time series
      data sets from yeast microarray experiments were analyzed using a Markov-modeling
      method (Dewey and Galas, FUNC: Integr. Genomics, 1, 269-278, 2001) to infer an
      approximation to the underlying genetic network. We found that the global
      statistical properties of all the resulting networks are similar. The overall
      structure of these biological networks is distinctly different from that of other
      recently studied networks such as the Internet or social networks. These
      biological networks show hierarchical, hub-like structures that have some
      properties similar to a class of graphs known as small world graphs. Small world
      networks exhibit local cliquishness while exhibiting strong global connectivity.
      In addition to the small world properties, the biological networks show a power
      law or scale free distribution of connectivities. An inverse power law, N(k)
      approximately k(-3/2), for the number of vertices (genes) with k connections was
      observed for three different data sets from yeast. We propose network growth
      models based on gene duplication events. Simulations of these models yield
      networks with the same combination of global graphical properties that we
      inferred from the expression data.

PMID- 12424121
TI  - A simulated annealing algorithm for finding consensus sequences.
AB  - MOTIVATION: A consensus sequence for a family of related sequences is, as the
      name suggests, a sequence that captures the features common to most members of
      the family. Consensus sequences are important in various DNA sequencing
      applications and are a convenient way to characterize a family of molecules.
      RESULTS: This paper describes a new algorithm for finding a consensus sequence,
      using the popular optimization method known as simulated annealing. Unlike the
      conventional approach of finding a consensus sequence by first forming a multiple
      sequence alignment, this algorithm searches for a sequence that minimises the sum
      of pairwise distances to each of the input sequences. The resulting consensus
      sequence can then be used to induce a multiple sequence alignment. The time
      required by the algorithm scales linearly with the number of input sequences and
      quadratically with the length of the consensus sequence. We present results
      demonstrating the high quality of the consensus sequences and alignments produced
      by the new algorithm. For comparison, we also present similar results obtained
      using ClustalW. The new algorithm outperforms ClustalW in many cases.

PMID- 12424122
TI  - Empirical determination of effective gap penalties for sequence comparison.
AB  - MOTIVATION: No general theory guides the selection of gap penalties for local
      sequence alignment. We empirically determined the most effective gap penalties
      for protein sequence similarity searches with substitution matrices over a range
      of target evolutionary distances from 20 to 200 Point Accepted Mutations (PAMs).
      RESULTS: We embedded real and simulated homologs of protein sequences into a
      database and searched the database to determine the gap penalties that produced
      the best statistical significance for the distant homologs. The most effective
      penalty for the first residue in a gap (q+r) changes as a function of
      evolutionary distance, while the gap extension penalty for additional residues
      (r) does not. For these data, the optimal gap penalties for a given matrix scaled
      in 1/3 bit units (e.g. BLOSUM50, PAM200) are q=25-0.1 * (target PAM distance),
      r=5. Our results provide an empirical basis for selection of gap penalties and
      demonstrate how optimal gap penalties behave as a function of the target
      evolutionary distance of the substitution matrix. These gap penalties can improve
      expectation values by at least one order of magnitude when searching with short
      sequences, and improve the alignment of proteins containing short sequences
      repeated in tandem.

PMID- 12424123
TI  - An evaluation of beta-turn prediction methods.
AB  - MOTIVATION: beta-turn is an important element of protein structure. In the past
      three decades, numerous beta-turn prediction methods have been developed based on
      various strategies. For a detailed discussion about the importance of beta-turns
      and a systematic introduction of the existing prediction algorithms for beta
      turns and their types, please see a recent review (Chou, Analytical Biochemistry,
      286, 1-16, 2000). However at present, it is still difficult to say which method
      is better than the other. This is because of the fact that these methods were
      developed on different sets of data. Thus, it is important to evaluate the
      performance of beta-turn prediction methods. RESULTS: We have evaluated the
      performance of six methods of beta-turn prediction. All the methods have been
      tested on a set of 426 non-homologous protein chains. It has been observed that
      the performance of the neural network based method, BTPRED, is significantly
      better than the statistical methods. One of the reasons for its better
      performance is that it utilizes the predicted secondary structure information. We
      have also trained, tested and evaluated the performance of all methods except
      BTPRED and GORBTURN, on new data set using a 7-fold cross-validation technique.
      There is a significant improvement in performance of all the methods when
      secondary structure information is incorporated. Moreover, after incorporating
      secondary structure information, the Sequence Coupled Model has yielded better
      results in predicting beta-turns as compared with other methods. In this study,
      both threshold dependent and independent (ROC) measures have been used for
      evaluation.

PMID- 12424124
TI  - Finding relevant references to genes and proteins in Medline using a Bayesian
      approach.
AB  - MOTIVATION: Mining the biomedical literature for references to genes and proteins
      always involves a tradeoff between high precision with false negatives, and high
      recall with false positives. Having a reliable method for assessing the relevance
      of literature mining results is crucial to finding ways to balance precision and
      recall, and for subsequently building automated systems to analyze these results.
      We hypothesize that abstracts and titles that discuss the same gene or protein
      use similar words. To validate this hypothesis, we built a dictionary- and rule
      based system to mine Medline for references to genes and proteins, and used a
      Bayesian metric for scoring the relevance of each reference assignment. RESULTS:
      We analyzed the entire set of Medline records from 1966 to late 2001, and scored
      each gene and protein reference using a Bayesian estimated probability (EP) based
      on word frequency in a training set of 137837 known assignments from 30594
      articles to 36197 gene and protein symbols. Two test sets of 148 and 150 randomly
      chosen assignments, respectively, were hand-validated and categorized as either
      good or bad. The distributions of EP values, when plotted on a log-scale
      histogram, are shown to markedly differ between good and bad assignments. Using
      EP values, recall was 100% at 61% precision (EP=2 x 10(-5)), 63% at 88% precision
      (EP=0.008), and 10% at 100% precision (EP=0.1). These results show that Medline
      entries discussing the same gene or protein have similar word usage, and that our
      method of assessing this similarity using EP values is valid, and enables an EP
      cutoff value to be determined that accurately and reproducibly balances precision
      and recall, allowing automated analysis of literature mining results. .

PMID- 12424125
TI  - Euclidian space and grouping of biological objects.
AB  - MOTIVATION: Biological objects tend to cluster into discrete groups. Objects
      within a group typically possess similar properties. It is important to have fast
      and efficient tools for grouping objects that result in biologically meaningful
      clusters. Protein sequences reflect biological diversity and offer an
      extraordinary variety of objects for polishing clustering strategies. Grouping of
      sequences should reflect their evolutionary history and their functional
      properties. Visualization of relationships between sequences is of no less
      importance. Tree-building methods are typically used for such visualization. An
      alternative concept to visualization is a multidimensional sequence space. In
      this space, proteins are defined as points and distances between the points
      reflect the relationships between the proteins. Such a space can also be a basis
      for model-based clustering strategies that typically produce results correlating
      better with biological properties of proteins. RESULTS: We developed an approach
      to classification of biological objects that combines evolutionary measures of
      their similarity with a model-based clustering procedure. We apply the
      methodology to amino acid sequences. On the first step, given a multiple sequence
      alignment, we estimate evolutionary distances between proteins measured in
      expected numbers of amino acid substitutions per site. These distances are
      additive and are suitable for evolutionary tree reconstruction. On the second
      step, we find the best fit approximation of the evolutionary distances by
      Euclidian distances and thus represent each protein by a point in a
      multidimensional space. The Euclidian space may be projected in two or three
      dimensions and the projections can be used to visualize relationships between
      proteins. On the third step, we find a non-parametric estimate of the probability
      density of the points and cluster the points that belong to the same local
      maximum of this density in a group. The number of groups is controlled by a sigma
      parameter that determines the shape of the density estimate and the number of
      maxima in it. The grouping procedure outperforms commonly used methods such as
      UPGMA and single linkage clustering.

PMID- 12424126
TI  - A motif of a microbial starch-binding domain found in human genethonin.
AB  - The sequence of the starch-binding domain present in 10% of amylolytic enzymes of
      microbial origin and classified as the carbohydrate-binding module family 20, was
      identified in the equivalent part of sequence of human genethonin, a skeletal
      muscle protein of unknown function. The sequence identity between the starch
      binding domain from Bacillus sp. strain 1011 cyclodextrin glucanotransferase and
      the corresponding segment of human genethonin was higher than 28%. The amino acid
      residues known to be involved in the raw starch binding were found to be
      conserved in the genethonin sequence. The three-dimensional structure of the
      genethonin 'starch-binding domain' was modelled and its eventual function briefly
      discussed.

PMID- 12424127
TI  - AcePrimer: automation of PCR primer design based on gene structure.
AB  - AcePrimer is an internet-accessed application based on CGI/Perl programming that
      designs PCR primers to search for deletion alleles in Caenorhabditis elegans gene
      knockout experiments and uses electronic PCR to search the entire genomic DNA
      sequence for potential false priming or multiple PCR amplification targets.
      Features such as the ability to target specific exons with the 'poison primer'
      approach and evaluation of primers with electronic PCR provide a flexible, web
      based approach to design effective primers whilst minimizing the need for
      empirical optimization of PCR experiments.

PMID- 12424128
TI  - SNOMAD (Standardization and NOrmalization of MicroArray Data): web-accessible
      gene expression data analysis.
AB  - SNOMAD is a collection of algorithms for the normalization and standardization of
      gene expression datasets derived from diverse biological and technological
      sources. In addition to conventional transformations and visualization tools,
      SNOMAD includes two non-linear transformations which correct for bias and
      variance which are non-uniformly distributed across the range of microarray
      element signal intensities: (1). Local mean normalization; and (2). Local
      variance correction (Z-score generation using a locally calculated standard
      deviation).

PMID- 12424129
TI  - GeneCards 2002: towards a complete, object-oriented, human gene compendium.
AB  - MOTIVATION: In the post-genomic era, functional analysis of genes requires a
      sophisticated interdisciplinary arsenal. Comprehensive resources are challenged
      to provide consistently improving, state-of-the-art tools. RESULTS: GeneCards
      (Rebhan et al., 1998) has made innovative strides: (a). regular updates and
      enhancements incorporating new genes enriched with sequences, genomic locations,
      cDNA assemblies, orthologies, medical information, 3D protein structures, gene
      expression, and focused SNP summaries; (b). restructured software using object
      oriented Perl, migration to schema-driven XML, and (c). pilot studies,
      introducing methods to produce cards for novel and predicted genes.

PMID- 12424130
TI  - Poxvirus Orthologous Clusters (POCs).
AB  - Poxvirus Orthologous Clusters (POCs) is a JAVA client-server application which
      accesses an updated database containing all complete poxvirus genomes; it
      automatically groups orthologous genes into families based on BLASTP scores for
      assessment by a human database curator. POCs has a user-friendly interface
      permitting complex SQL queries to retrieve interesting groups of DNA and protein
      sequences as well as gene families for subsequent interrogation by a variety of
      integrated tools: BLASTP, BLASTX, TBLASTN, Jalview (multiple alignment), Dotlet
      (Dotplot), Laj (local alignment), and NAP (nucleotide to amino acid alignment).

PMID- 12424131
TI  - QuickTree: building huge Neighbour-Joining trees of protein sequences.
AB  - We have written a fast implementation of the popular Neighbor-Joining tree
      building algorithm. QuickTree allows the reconstruction of phylogenies for very
      large protein families (including the largest Pfam alignment containing 27000 HIV
      GP120 glycoprotein sequences) that would be infeasible using other popular
      methods.

PMID- 12424132
TI  - Ramachandran plot on the web.
AB  - A graphics package has been developed to display the main chain torsion angles
      phi, psi (phi, Psi); (Ramachandran angles) in a protein of known structure. In
      addition, the package calculates the Ramachandran angles at the central residue
      in the stretch of three amino acids having specified the flanking residue types.
      The package displays the Ramachandran angles along with a detailed analysis
      output. This software is incorporated with all the protein structures available
      in the Protein Databank.

PMID- 12424143
TI  - Role and regulation of activator protein-1 in toxicant-induced responses of the
      lung.
AB  - Aberrant cell proliferation and differentiation after toxic injury to airway
      epithelium can lead to the development of various lung diseases including cancer.
      The activator protein-1 (AP-1) transcription factor, composed of mainly Jun-Jun
      and Jun-Fos protein dimers, acts as an environmental biosensor to various
      external toxic stimuli and regulates gene expression involved in various
      biological processes. Gene disruption studies indicate that the AP-1 family
      members c-jun, junB, and fra1 are essential for embryonic development, whereas
      junD, c-fos, and fosB are required for normal postnatal growth. However, broad or
      target-specific transgenic overexpression of the some of these proteins gives
      very distinct phenotype(s), including tumor formation. This implies that,
      although they are required for normal cellular processes, their abnormal
      activation after toxic injury can lead to the pathogenesis of the lung disease.
      Consistent with this view, various environmental toxicants and carcinogens
      differentially regulate Jun and Fos expression in cells of the lung both in vivo
      and in vitro. Moreover, Jun and Fos proteins distinctly bind to the promoter
      regions of a wide variety of genes to differentially regulate their expression in
      epithelial injury, repair, and differentiation. Importantly, lung tumors induced
      by various carcinogens display a sustained expression of certain AP-1 family
      members. Therefore a better understanding of the mechanisms of regulation and
      functional role(s), as well as identification of target genes of members of the
      AP-1 family in airway epithelial cells, will provide additional insight into
      toxicant-induced lung diseases. These studies might offer a unique opportunity to
      use AP-1 family members and transactivation as potential diagnostic markers or
      drug targets for early detection and/or prevention of various lung diseases.

PMID- 12424144
TI  - Airway narrowing in asthma: does speed kill?

PMID- 12424145
TI  - Nitric oxide and the developing airway.

PMID- 12424146
TI  - Vascular endothelial cells actively participate in high inflation pressure
      induced permeability and edema.

PMID- 12424147
TI  - Inhibition of apoptosis in pulmonary endothelial cells by altered pH,
      mitochondrial function, and ATP supply.
AB  - We investigated the effect of altered extracellular pH, mitochondrial function,
      and ATP content on development of apoptosis in human pulmonary artery endothelial
      cells after treatment with staurosporine (STS). STS produced a concentration- and
      time-dependent increase in caspase-3 activity in pH 7.4 medium that reached a
      peak at 6 h. The increase in caspase activity was associated with significant DNA
      fragmentation. Fluorescent imaging of treated monolayers in pH 7.4 medium with
      Hoechst-33342-propidium iodide demonstrated a large percentage of apoptotic cells
      ( approximately 40%) with no evidence of necrosis. Caspase activity, DNA
      fragmentation, and percentage of apoptotic cells were reduced after STS treatment
      in acidic media (pH 7.0 and 6.6). The Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane
      N,N,N',N'-tetraacetic acid-AM inhibited STS-induced apoptosis, whereas the rise
      in intracellular Ca2+concentration in STS-treated cells in pH 7.4 medium was
      reduced in pH 7.0 medium. These results suggest that one mechanism for inhibitory
      effects of acidosis may be a pH-induced alteration in Ca2+ signaling. Treatment
      with STS in the presence of oligomycin (10 microM), an inhibitor of the
      mitochondrial F(0)F(1)-ATPase, in glucose-free media abolished caspase activation
      and DNA fragmentation in association with severe ATP depletion ( approximately 2%
      of control cells). Imaging demonstrated a change in the mode of cell death from
      apoptosis to necrosis under these conditions. This change was linked to the level
      of ATP depletion, because STS treatment in the absence of glucose or the presence
      of oligomycin in media with glucose still leads to apoptosis in the presence of
      only moderate ATP depletion. These results demonstrate that pH, mitochondrial
      function, and ATP supply are important variables that regulate STS-induced
      apoptosis in human pulmonary artery endothelial cells.

PMID- 12424148
TI  - Take back your mink, take back your pearls.

PMID- 12424149
TI  - Treatments for sleep problems in elderly people.

PMID- 12424150
TI  - Primary prevention of sudden cardiac death using implantable cardioverter
      defibrillators.

PMID- 12424151
TI  - Bisphosphonates as adjuvant treatment for breast cancer.

PMID- 12424152
TI  - Milburn refuses to renegotiate consultants' contract.

PMID- 12424153
TI  - Doctors open talks with Scottish Executive after voting "yes".

PMID- 12424155
TI  - Police find no evidence of forgery by accused paediatricians.

PMID- 12424157
TI  - Inquiry into handling of CJD alert welcomed.

PMID- 12424158
TI  - White couple can keep mixed race twins after IVF blunder.

PMID- 12424160
TI  - EU clamps down on reimportation of cheap drugs meant for Africa.

PMID- 12424161
TI  - BMA steps up call for ban on smoking in public places.

PMID- 12424163
TI  - What does zinc do?

PMID- 12424162
TI  - Effect of zinc supplementation started during diarrhoea on morbidity and
      mortality in Bangladeshi children: community randomised trial.
AB  - OBJECTIVE: To evaluate the effect on morbidity and mortality of providing daily
      zinc for 14 days to children with diarrhoea. DESIGN: Cluster randomised
      comparison. SETTING: Matlab field site of International Center for Diarrhoeal
      Disease Research, Bangladesh. PARTICIPANTS: 8070 children aged 3-59 months
      contributed 11 881 child years of observation during a two year period.
      INTERVENTION: Children with diarrhoea in the intervention clusters were treated
      with zinc (20 mg per day for 14 days); all children with diarrhoea were treated
      with oral rehydration therapy. MAIN OUTCOME MEASURES: Duration of episode of
      diarrhoea, incidence of diarrhoea and acute lower respiratory infections,
      admission to hospital for diarrhoea or acute lower respiratory infections, and
      child mortality. RESULTS: About 40% (399/1007) of diarrhoeal episodes were
      treated with zinc in the first four months of the trial; the rate rose to 67%
      (350/526) in month 5 and to >80% (364/434) in month 7 and was sustained at that
      level. Children from the intervention cluster received zinc for about seven days
      on average during each episode of diarrhoea. They had a shorter duration (hazard
      ratio 0.76, 95% confidence interval 0.65 to 0.90) and lower incidence of
      diarrhoea (rate ratio 0.85, 0.76 to 0.96) than children in the comparison group.
      Incidence of acute lower respiratory infection was reduced in the intervention
      group but not in the comparison group. Admission to hospital of children with
      diarrhoea was lower in the intervention group than in the comparison group (0.76,
      0.59 to 0.98). Admission for acute lower respiratory infection was lower in the
      intervention group, but this was not statistically significant (0.81, 0.53 to
      1.23). The rate of non-injury deaths in the intervention clusters was
      considerably lower (0.49, 0.25 to 0.94). CONCLUSIONS: The lower rates of child
      morbidity and mortality with zinc treatment represent substantial benefits from a
      simple and inexpensive intervention that can be incorporated in existing efforts
      to control diarrhoeal disease.

PMID- 12424164
TI  - Cross sectional, community based study of care of newborn infants in Nepal.
AB  - OBJECTIVE: To determine home based newborn care practices in rural Nepal in order
      to inform strategies to improve neonatal outcome. DESIGN: Cross sectional,
      retrospective study using structured interviews. SETTING: Makwanpur district,
      Nepal. PARTICIPANTS: 5411 married women aged 15 to 49 years who had given birth
      to a live baby in the past year. MAIN OUTCOMES MEASURES: Attendance at delivery,
      hygiene, thermal care, and early feeding practices. RESULTS: 4893 (90%) women
      gave birth at home. Attendance at delivery by skilled government health workers
      was low (334, 6%), as was attendance by traditional birth attendants (267, 5%).
      Only 461 (8%) women had used a clean home delivery kit, and about half of
      attendants had washed their hands. Only 3482 (64%) newborn infants had been
      wrapped within half an hour of birth, and 4992 (92%) had been bathed within the
      first hour. 99% (5362) of babies were breast fed, 91% (4939) within six hours of
      birth. Practices with respect to colostrum and prelacteals were not a cause for
      anxiety. CONCLUSIONS: Health promotion interventions most likely to improve
      newborn health in this setting include increasing attendance at delivery by
      skilled service providers, improving information for families about basic
      perinatal care, promotion of clean delivery practices, early cord cutting and
      wrapping of the baby, and avoidance of early bathing.

PMID- 12424165
TI  - Influence of psychological coping on survival and recurrence in people with
      cancer: systematic review.
AB  - OBJECTIVE: To summarise the evidence on the effect of psychological coping styles
      (including fighting spirit, helplessness/hopelessness, denial, and avoidance) on
      survival and recurrence in patients with cancer. DESIGN: Systematic review of
      published and unpublished prospective observational studies. MAIN OUTCOMES
      MEASURES: Survival from or recurrence of cancer. RESULTS: 26 studies investigated
      the association between psychological coping styles and survival from cancer, and
      11 studies investigated recurrence. Most of the studies that investigated
      fighting spirit (10 studies) or helplessness/hopelessness (12 studies) found no
      significant associations with survival or recurrence. The evidence that other
      coping styles play an important part was also weak. Positive findings tended to
      be confined to small or methodologically flawed studies; lack of adjustment for
      potential confounding variables was common. Positive conclusions seemed to be
      more commonly reported by smaller studies, indicating potential publication bias.
      CONCLUSION: There is little consistent evidence that psychological coping styles
      play an important part in survival from or recurrence of cancer. People with
      cancer should not feel pressured into adopting particular coping styles to
      improve survival or reduce the risk of recurrence.

PMID- 12424166
TI  - Cardiac arrest and ventricular arrhythmia in patients taking antipsychotic drugs:
      cohort study using administrative data.
AB  - OBJECTIVE: To examine the rates of cardiac arrest and ventricular arrhythmia in
      patients with treated schizophrenia and in non-schizophrenic controls. DESIGN:
      Cohort study of outpatients using administrative data. SETTING: 3 US Medicaid
      programmes. PARTICIPANTS: Patients with schizophrenia treated with clozapine,
      haloperidol, risperidone, or thioridazine; a control group of patients with
      glaucoma; and a control group of patients with psoriasis. MAIN OUTCOME MEASURE:
      Diagnosis of cardiac arrest or ventricular arrhythmia. RESULTS: Patients with
      treated schizophrenia had higher rates of cardiac arrest and ventricular
      arrhythmia than controls, with rate ratios ranging from 1.7 to 3.2. Overall,
      thioridazine was not associated with an increased risk compared with haloperidol
      (rate ratio 0.9, 95% confidence interval 0.7 to 1.2). However, thioridazine
      showed an increased risk of events at doses > or =600 mg (2.6, 1.0 to 6.6;
      P=0.049) and a linear dose-response relation (P=0.038). CONCLUSIONS: The
      increased risk of cardiac arrest and ventricular arrhythmia in patients with
      treated schizophrenia could be due to the disease or its treatment. Overall, the
      risk with thioridazine was no worse than that with haloperidol. Thioridazine may,
      however, have a higher risk at high doses, although this finding could be due to
      chance. To reduce cardiac risk, thioridazine should be prescribed at the lowest
      dose needed to obtain an optimal therapeutic effect.

PMID- 12424167
TI  - Oral anticoagulation and risk of death: a medical record linkage study.
AB  - OBJECTIVE: To study how mortality varies with different degrees of
      anticoagulation reflected by the international normalised ratio (INR). DESIGN:
      Record linkage analysis with death hazard estimated as a continuous function of
      INR. DATA SOURCES: 46 anticoagulation clinics in Sweden with computerised medical
      records. SUBJECTS: Records for 42 451 patients, 3533 deaths, and 1.25 million INR
      measurements. MAIN OUTCOME MEASURES: Mortality from all causes and from
      intracranial haemorrhage. RESULTS: Mortality from all causes of death was
      strongly related to level of INR. Minimum risk of death was attained at 2.2 INR
      for all patients and 2.3 INR for patients with mechanical heart valve prostheses.
      A high INR was associated with an excess mortality: with an increase of 1 unit of
      INR above 2.5, the risks of death from cerebral bleeding (149 deaths) and from
      any cause were about doubled. Among patients with an INR of > or =3.0, 1069
      deaths occurred within 7 weeks; if the risk coincided with that with an INR of
      2.9, the expected number of deaths would have been 569. Thus at least 500 deaths
      were associated with a high INR value, but not necessarily caused by the
      treatment. CONCLUSIONS: The excess mortality associated with high INR values
      supports the use of less intensive treatment and a small therapeutic window, with
      INR close to 2.2-2.3 irrespective of the indication for anticoagulant treatment.
      More preventive actions should be taken to avoid episodes of high INR.

PMID- 12424169
TI  - Observational study of 353 applications to London multicentre research ethics
      committee 1997-2000.

PMID- 12424168
TI  - Mortality in adults aged 26-54 years related to socioeconomic conditions in
      childhood and adulthood: post war birth cohort study.
AB  - OBJECTIVE: To examine premature mortality in adults in relation to socioeconomic
      conditions in childhood and adulthood. DESIGN: Nationally representative birth
      cohort study with prospective information on socioeconomic conditions. SETTING:
      England, Scotland, and Wales. STUDY MEMBERS: 2132 women and 2322 men born in
      March 1946 and followed until age 55 years. MAIN OUTCOME MEASURES: Deaths between
      26 and 54 years of age notified by the NHS central register. RESULTS: Study
      members whose father's occupation was manual at age 4, or who lived in the worst
      housing, or who received the poorest care in childhood had double the death rate
      during adulthood of those living in the best socioeconomic conditions. All
      indicators of socioeconomic disadvantage at age 26 years, particularly lack of
      home ownership, were associated with a higher death rate. Manual origins and poor
      care in childhood remained associated with mortality even after adjusting for
      social class in adulthood or home ownership. The hazard ratio was 2.6 (95%
      confidence interval 1.5 to 4.4) for those living in manual households as children
      and as adults compared with those living in non-manual households at both life
      stages. The hazard ratio for those from manual origins who did not own their own
      home at age 26 years was 4.9 (2.3 to 10.5) compared with those from non-manual
      origins who were home owners. CONCLUSIONS: Socioeconomic conditions in childhood
      as well as early adulthood have strongly influenced the survival of British
      people born in the immediate post war era.

PMID- 12424171
TI  - Why general practitioners use computers and hospital doctors do not--Part 1:
      incentives.

PMID- 12424170
TI  - Systematic review of mental health interventions for patients with common somatic
      symptoms: can research evidence from secondary care be extrapolated to primary
      care?
AB  - OBJECTIVES: To determine the strength of evidence for the effectiveness of mental
      health interventions for patients with three common somatic conditions (chronic
      fatigue syndrome, irritable bowel syndrome, and chronic back pain). To assess
      whether results obtained in secondary care can be extrapolated to primary care
      and suggest how future trials should be designed to provide more rigorous
      evidence. DESIGN: Systematic review. DATA SOURCES: Five electronic databases, key
      texts, references in the articles identified, and citations from expert
      clinicians. STUDY SELECTION: Randomised controlled trials including participants
      with one of the three conditions for which no physical cause could be found. Two
      reviewers screened sources and independently extracted data and assessed quality.
      RESULTS: Sixty one studies were identified; 20 were classified as primary care
      and 41 as secondary care. For some interventions, such as brief psychodynamic
      interpersonal therapy, little research was identified. However, results of meta
      analyses and of randomised controlled trials suggest that cognitive behaviour
      therapy and behaviour therapy are effective for chronic back pain and chronic
      fatigue syndrome and that antidepressants are effective for irritable bowel
      syndrome. Cognitive behaviour therapy and behaviour therapy were effective in
      both primary and secondary care in patients with back pain, although the evidence
      is more consistent and the effect size larger for secondary care. Antidepressants
      seem effective in irritable bowel syndrome in both settings but ineffective in
      chronic fatigue syndrome. CONCLUSIONS: Treatment seems to be more effective in
      patients in secondary care than in primary care. This may be because secondary
      care patients have more severe disease, they receive a different treatment
      regimen, or the intervention is more closely supervised. However, conclusions of
      effectiveness should be considered in the light of the methodological weaknesses
      of the studies. Large pragmatic trials are needed of interventions delivered in
      primary care by appropriately trained primary care staff.

PMID- 12424172
TI  - Why general practitioners use computers and hospital doctors do not--Part 2:
      scalability.

PMID- 12424173
TI  - Hotspots in climate change and human health.

PMID- 12424174
TI  - Haemophilus influenzae type b epiglottitis as a cause of acute upper airways
      obstruction in children.

PMID- 12424175
TI  - Antithrombotic therapy in peripheral vascular disease.

PMID- 12424176
TI  - Effects of war: moral knowledge, revenge, reconciliation, and medicalised
      concepts of "recovery".

PMID- 12424177
TI  - Have the latest reforms reversed WHO's decline?

PMID- 12424178
TI  - Suturing v conservative management of hand lacerations. All lacerations need to
      be examined thoroughly.

PMID- 12424179
TI  - Risk factor thresholds. Threshold is 37 000 pounds sterling per QALY.

PMID- 12424180
TI  - Most patients depressed by cancer do not need drugs.

PMID- 12424181
TI  - Management of infertility: one stop clinic may offer solution.

PMID- 12424182
TI  - Collaboration is key to preventing syphilis.

PMID- 12424183
TI  - Are inactivation procedures for blood products good or bad?

PMID- 12424184
TI  - Weber's test demystified. Physics renders Weber's test not so mysterious . . .

PMID- 12424185
TI  - What do new consultants have to say?

PMID- 12424186
TI  - Moving consultant post.

PMID- 12424187
TI  - Going from specialist registrar to consultant.

PMID- 12424189
TI  - The molecular genetics of the human I locus and molecular background explain the
      partial association of the adult i phenotype with congenital cataracts.
AB  - The human i and I antigens are characterized as linear and branched repeats of N
      acetyllactosamine, respectively. Conversion of the i to the I structure requires
      I-branching beta-1,6-N-acetylglucosaminyltransferase activity. It has been noted
      that the null phenotype of I, the adult i phenotype, is associated with
      congenital cataracts in Asians. Previously, the identification of molecular
      changes in the IGnT gene, associated with the adult i phenotype, has been
      reported. In the present study, we demonstrate that the human I locus expresses 3
      IGnT forms, designated IGnTA, IGnTB, and IGnTC, which have different exon 1, but
      identical exons 2 and 3, coding regions. The molecular genetics proposed for the
      I locus offer a new perspective on the formation and expression of the I antigen
      in different cells and provide insight into the questions derived from
      investigation of the adult i phenotype. Molecular genetic analyses of the I loci
      of the 2 adult i groups, with and without congenital cataracts, were performed,
      and enzyme function assays and expression patterns for the 3 IGnT transcripts in
      reticulocytes and lens-epithelium cells were analyzed. The results suggest a
      molecular genetic mechanism that may explain the partial association of the adult
      i phenotype with congenital cataracts and indicate that a defect in the I locus
      may lead directly to the development of congenital cataracts. The results also
      suggest that the human blood group I gene should be reassigned to the IGnTC form,
      not the IGnTB form, as described previously.

PMID- 12424190
TI  - RANK ligand and osteoprotegerin in myeloma bone disease.
AB  - Myeloma bone disease is due to interactions of myeloma cells with the bone marrow
      microenvironment, and is associated with pathologic fractures, neurologic
      symptoms and hypercalcemia. Adjacent to myeloma cells, the formation and
      activation of osteoclasts is increased, which results in enhanced bone
      resorption. The recent characterization of the essential cytokine of osteoclast
      cell biology, receptor activator of NF-kappa B ligand (RANKL) and its antagonist
      osteoprotegerin (OPG), have led to a detailed molecular and cellular
      understanding of myeloma bone disease. Myeloma cells induce RANKL expression in
      bone marrow stromal cells, and direct RANKL expression by myeloma cells may
      contribute to enhanced osteoclastogenesis in the bone microenvironment in myeloma
      bone disease. Furthermore, myeloma cells inhibit production and induce
      degradation of OPG. These effects result in an increased RANKL-to-OPG ratio that
      favors the formation and activation of osteoclasts. Patients with myeloma bone
      disease have inappropriately low serum and bone marrow levels of OPG. Specific
      blockade of RANKL prevented the skeletal complications in various animal models
      of myeloma, and suppressed bone resorption in a preliminary study of patients
      with myeloma bone disease.

PMID- 12424191
TI  - Retroviral transduction efficiency of G-CSF+SCF-mobilized peripheral blood CD34+
      cells is superior to G-CSF or G-CSF+Flt3-L-mobilized cells in nonhuman primates.
AB  - Gene transfer experiments in nonhuman primates have been shown to be predictive
      of success in human clinical gene therapy trials. In most nonhuman primate
      studies, hematopoietic stem cells (HSCs) collected from the peripheral blood or
      bone marrow after administration of granulocyte colony-stimulating factor (G-CSF)
      + stem cell factor (SCF) have been used as targets, but this cytokine combination
      is not generally available for clinical use, and the optimum target cell
      population has not been systematically studied. In our current study we tested
      the retroviral transduction efficiency of rhesus macaque peripheral blood CD34(+)
      cells collected after administration of different cytokine mobilization regimens,
      directly comparing G-CSF+SCF versus G-CSF alone or G-CSF+Flt3-L in competitive
      repopulation assays. Vector supernatant was added daily for 96 hours in the
      presence of stimulatory cytokines. The transduction efficiency of HSCs as
      assessed by in vitro colony-forming assays was equivalent in all 5 animals
      tested, but the in vivo levels of mononuclear cell and granulocyte marking was
      higher at all time points derived from target CD34(+) cells collected after G
      CSF+SCF mobilization compared with target cells collected after G-CSF (n = 3) or
      G-CSF+Flt3-L (n = 2) mobilization. In 3 of the animals long-term marking levels
      of 5% to 25% were achieved, but originating only from the G-CSF+SCF-mobilized
      target cells. Transduction efficiency of HSCs collected by different mobilization
      regimens can vary significantly and is superior with G-CSF+SCF administration.
      The difference in transduction efficiency of HSCs collected from different
      sources should be considered whenever planning clinical gene therapy trials and
      should preferably be tested directly in comparative studies.

PMID- 12424192
TI  - Inhibition of microsomal glucose-6-phosphate transport in human neutrophils
      results in apoptosis: a potential explanation for neutrophil dysfunction in
      glycogen storage disease type 1b.
AB  - Mutations in the gene of the hepatic glucose-6-phosphate transporter cause
      glycogen storage disease type 1b. In this disease, the altered glucose
      homeostasis and liver functions are accompanied by an impairment of
      neutrophils/monocytes. However, neither the existence of a microsomal glucose-6
      phosphate transport, nor the connection between its defect and cell dysfunction
      has been demonstrated in neutrophils/monocytes. In this study we have
      characterized the microsomal glucose-6-phosphate transport of human neutrophils
      and differentiated HL-60 cells. The transport of glucose-6-phosphate was
      sensitive to the chlorogenic acid derivative S3483, N-ethylmaleimide, and 4,4'
      diisothiocyanostilbene-2,2'-disulfonic acid, known inhibitors of the hepatic
      microsomal glucose-6-phosphate transporter. A glucose-6-phosphate uptake was also
      present in microsomes from undifferentiated HL-60 and Jurkat cells, but it was
      insensitive to S3483. The treatment with S3484 of intact human neutrophils and
      differentiated HL-60 cells mimicked some leukocyte defects of glycogen storage
      disease type 1b patients (ie, the drug inhibited phorbol myristate acetate
      induced superoxide anion production and reduced the size of endoplasmic reticulum
      Ca(2+) stores). Importantly, the treatment with S3484 also resulted in apoptosis
      of human neutrophils and differentiated HL-60 cells, while undifferentiated HL-60
      and Jurkat cells were unaffected by the drug. The proapoptotic effect of S3483
      was prevented by the inhibition of nicotinamide adenine dinucleotide phosphate
      oxidase or by antioxidant treatment. These results suggest that microsomal
      glucose-6-phosphate transport has a role in the antioxidant protection of
      neutrophils, and that the genetic defect of the transporter leads to the
      impairment of cellular functions and apoptosis.

PMID- 12424193
TI  - A significant diffuse component predicts for inferior survival in grade 3
      follicular lymphoma, but cytologic subtypes do not predict survival.
AB  - Grade 3 follicular lymphoma (FL3) is thought to have an aggressive clinical
      course. On the basis of possible biologic differences, the new World Health
      Organization (WHO) classification of lymphoma suggests further subdivision of FL3
      into grades 3a and 3b and states that the percentage of involvement by diffuse
      large B-cell lymphoma (DLBCL) should also be reported. However, the clinical
      implications of these features are unclear. Therefore, we studied 190 newly
      diagnosed patients with lymph node-based FL3 who received anthracycline
      containing combination chemotherapy. The follicular component was subclassified
      as grade 3a (FL3a) or grade 3b (FL3b) according to the WHO criteria, or as
      follicular large cleaved cell type (FLC). The percentage of a diffuse component,
      if present, was also recorded. Of the 190 cases, there were 107 FL3a (56%), 53
      FL3b (28%), and 30 FLC (16%) cases. Diffuse areas were seen in 72 cases (31 FL3a,
      28 FL3b, and 13 FLC). There were no significant differences in the clinical
      characteristics, overall survival, or event-free survival between patients with
      grades FL3a, FL3b, or FLC. However, those cases with a predominant diffuse
      component (> 50% diffuse) had a significantly worse overall survival (P =.0037)
      and event-free survival (P =.012). Therefore, we conclude that the subdivision of
      FL3 into cytologic subtypes does not appear to be important clinically. However,
      patients with FL3 having a diffuse component of more than 50% have an inferior
      survival that is similar to the survival of those with DLBCL.

PMID- 12424194
TI  - Two novel mutations in the alpha IIb calcium-binding domains identify hydrophobic
      regions essential for alpha IIbbeta 3 biogenesis.
AB  - The recently published crystal structure of the external domains of alphaVbeta3
      confirms the prediction that the aminoterminal portion of alphaV, which shares
      40% homology with alphaIIb, folds into a beta-propeller structure and that the 4
      calcium-binding domains are positioned on the bottom of the propeller. To gain
      insight into the role of the calcium-binding domains in alphaIIb biogenesis, we
      characterized mutations in the second and third calcium-binding domains of
      alphaIIb in 2 patients with Glanzmann thrombasthenia. One patient inherited a
      Val298Phe mutation in the second domain, and the other patient inherited an
      Ile374Thr mutation in the third domain. Mammalian cell expression studies were
      performed with normal and mutant alphaIIb and beta3 cDNA constructs. By flow
      cytometry, expression of alphaIIb Val298Phe/beta3 in transfected cells was 28% of
      control, and expression of alphaIIbIle374Thr/beta3 was 11% of control. Pulse
      chase analyses showed that both mutant pro-alphaIIb subunits are retained in the
      endoplasmic reticulum and degraded. Mutagenesis studies of the Val298 and Ile374
      residues showed that these highly conserved, branch-chained hydrophobic residues
      are essential at these positions and that biogenesis and expression of
      alphaIIbbeta3 is dramatically affected by structural variations in these regions
      of the calcium-binding domains. Energy calculations derived from a new model of
      the alphaIIb beta-propeller indicate that these mutations interfere with calcium
      binding. These data suggest that the alphaIIb calcium-binding domains play a key
      structural role in the beta-propeller, and that the structural integrity of the
      calcium-binding domains is critical for integrin biogenesis.

PMID- 12424195
TI  - Donor T cell-derived TNF is required for graft-versus-host disease and graft
      versus-tumor activity after bone marrow transplantation.
AB  - Previous studies in murine bone marrow transplantation (BMT) models using
      neutralizing anti-tumor necrosis factor (TNF) antibodies or TNF receptor (TNFR)
      deficient recipients have demonstrated that TNF can be involved in both graft
      versus-host disease (GVHD) and graft-versus-leukemia (GVL). TNF in these GVHD and
      GVL models was thought to be primarily produced by activated monocytes and
      macrophages, and the role of T cell-derived TNF was not determined. We used TNF(
      /-) mice to study the specific role of TNF produced by donor T cells in a well
      established parent-into-F1 hybrid model (C57BL/6J-->C3FeB6F1/J). Recipients of
      TNF(-/-) T cells developed significantly less morbidity and mortality from GVHD
      than recipients of wild-type (wt) T cells. Histology of GVHD target organs
      revealed significantly less damage in thymus, small bowel, and large bowel, but
      not in liver or skin tissues from recipients of TNF(-/-) T cells. Recipients of
      TNF(-/-) T cells which were also inoculated with leukemia cells at the time of
      BMT showed increased mortality from leukemia when compared with recipients of wt
      cells. We found that TNF(-/-) T cells do not have intrinsic defects in vitro or
      in vivo in proliferation, IFN-gamma production, or alloactivation. We could not
      detect TNF in the serum of our transplant recipients, suggesting that T cells
      contribute to GVHD and GVL via membrane-bound or locally released TNF.

PMID- 12424196
TI  - The spectrum of PIG-A gene mutations in aplastic anemia/paroxysmal nocturnal
      hemoglobinuria (AA/PNH): a high incidence of multiple mutations and evidence of a
      mutational hot spot.
AB  - Paroxysmal nocturnal hemoglobinuria (PNH) may arise during long-term follow- up
      of aplastic anemia (AA), and many AA patients have minor
      glycosylphosphatidylinositol (GPI) anchor-deficient clones, even at presentation.
      PIG-A gene mutations in AA/PNH and hemolytic PNH are thought to be similar, but
      studies on AA/PNH have been limited to individual cases and a few small series.
      We have studied a large series of AA patients with a GPI anchor-deficient clone
      (AA/PNH), including patients with minor clones, to determine whether their
      pattern of PIG-A mutations was identical to the reported spectrum in hemolytic
      PNH. AA patients with GPI anchor-deficient clones were identified by flow
      cytometry and minor clones were enriched by immunomagnetic selection. A variety
      of methods was used to analyze PIG-A mutations, and 57 mutations were identified
      in 40 patients. The majority were similar to those commonly reported, but
      insertions in the range of 30 to 88 bp, due to tandem duplication of PIG-A
      sequences, and deletions of more than 10 bp were also seen. In 3 patients we
      identified identical 5-bp deletions by conventional methods. This prompted the
      design of mutation-specific polymerase chain reaction (PCR) primers, which were
      used to demonstrate the presence of the same mutation in an additional 12
      patients, identifying this as a mutational hot spot in the PIG-A gene. Multiple
      PIG-A mutations have been reported in 10% to 20% of PNH patients. Our results
      suggest that the large majority of AA/PNH patients have multiple mutations. These
      data may suggest a process of hypermutation in the PIG-A gene in AA stem cells.

PMID- 12424197
TI  - Related umbilical cord blood transplantation in patients with thalassemia and
      sickle cell disease.
AB  - Allogeneic bone marrow transplantation (BMT) from HLA-identical siblings is an
      accepted treatment for both thalassemia and sickle cell disease (SCD). However,
      it is associated with decided risk of both transplant-related mortality (TRM) and
      chronic graft-versus-host disease (GVHD). We analyzed 44 patients (median age, 5
      years; range, 1-20 years) given an allogeneic related cord blood transplant for
      either thalassemia (n = 33) or SCD (n = 11). Thirty children were given
      cyclosporin A (CsA) alone as GVHD prophylaxis, 10 received CsA and methotrexate
      (MTX), and 4 patients received other combinations of immunosuppressive drugs. The
      median number of nucleated cells infused was 4.0 x 10(7)/kg (range, 1.2-10 x
      10(7)/kg). No patient died and 36 of 44 children remain free of disease, with a
      median follow-up of 24 months (range, 4-76 months). Only one patient with SCD did
      not have sustained donor engraftment as compared with 7 of the 33 patients with
      thalassemia. Three of these 8 patients had sustained donor engraftment after BMT
      from the same donor. Four patients experienced grade 2 acute GVHD; only 2 of the
      36 patients at risk developed limited chronic GVHD. The 2-year probability of
      event-free survival is 79% and 90% for patients with thalassemia and SCD,
      respectively. Use of MTX for GVHD prophylaxis was associated with a greater risk
      of treatment failure. Related CBT for hemoglobinopathies offers a good
      probability of success and is associated with a low risk of GVHD. Optimization of
      transplantation strategies could further improve these results.

PMID- 12424198
TI  - The proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells
      to conventional chemotherapeutic agents: therapeutic applications.
AB  - The proteasome inhibitor PS-341 inhibits nuclear factor-kappaB (NF-kappaB)
      activation, induces apoptosis in cancer cells, including multiple myeloma (MM)
      cells, and has marked clinical activity as a monotherapy for MM. In this study,
      we found that subtoxic concentrations of PS-341 potently sensitized MM cell lines
      and patient cells to DNA-damaging chemotherapeutic agents such as doxorubicin and
      melphalan, including cells resistant to these drugs and those isolated from a
      patient who had relapsed after PS-341 monotherapy. Moreover, PS-341 abolished
      cell adhesion-mediated drug resistance. Using gene expression profiling and
      proteomic analysis, we demonstrate that PS-341, among its other proapoptotic
      effects, down-regulates the expression of several effectors involved in the
      cellular response to genotoxic stress. These data suggest that, in addition to
      down-regulating the expression of apoptosis inhibitors, PS-341 inhibits genotoxic
      stress response pathways and thereby restores sensitivity to DNA-damaging
      chemotherapeutic agents. These studies, therefore, provide the framework for
      clinical use of this agent in combination with conventional chemotherapy.

PMID- 12424199
TI  - Amount of spontaneous apoptosis detected by Bax/Bcl-2 ratio predicts outcome in
      acute myeloid leukemia (AML).
AB  - The inability to undergo apoptosis is a crucial mechanism of multidrug resistance
      in acute myeloid leukemia (AML), and the analysis of mitochondrial apoptotic
      proteins may represent a significant prognostic tool to predict outcome. Bcl-2
      and Bax oncoproteins were evaluated in 255 de novo AML patients (pts) by flow
      cytometry using an anti-bcl-2 monoclonal antibody (MoAb) and an anti-bax MoAb.
      The results were expressed as an index (bax/bcl-2) obtained by dividing bax mean
      fluorescence intensity (MFI) and bcl-2 MFI. Lower bax/bcl-2 ratio was associated
      with French-American-British (FAB) M0-M1 classes (P =.000 01) and CD34 more than
      20% (P <.000 01). There were striking inverse correlations between CD34 or CD117
      MFI and bax/bcl-2 values (r = -.40, P <.000 001 and r = -.29, P =.000 002),
      confirming that immaturity is consistent with this index. Moreover, lower bax/bcl
      2 levels were correlated with poor-risk cytogenetics (P =.0002). A significant
      higher complete remission (CR) rate was found in pts with higher bax/bcl-2 levels
      (79% versus 45%; P =.000 01). Also, both a longer overall survival (OS) and
      disease-free survival (DFS) were observed in pts with higher bax/bcl-2 levels (P
      =.000 01 and =.019). Noteworthy, bax/bcl-2 levels accurately predicted the
      clinical response and outcome of pts with normal or unknown cytogenetics. Indeed,
      within this subset of 147 pts, higher bax/bcl-2 ratio was significantly
      associated both with a higher CR rate (86% versus 42%; P <.000 01) and a longer
      OS (P =.0016). The independent prognostic value of bax/bcl-2 ratio was confirmed
      in multivariate analysis. Therefore, mitochondrial oncoproteins, such as bcl-2
      and bax, represent both sensitive indicators of clinical outcome and potential
      targets of novel proapoptotic molecules in order to circumvent chemoresistance.

PMID- 12424200
TI  - HbF reactivation in sibling BFU-E colonies: synergistic interaction of kit ligand
      with low-dose dexamethasone.
AB  - Mechanisms underlying fetal hemoglobin (HbF) reactivation in stress
      erythropoiesis have not been fully elucidated. We suggested that a key role is
      played by kit ligand (KL). Because glucocorticoids (GCs) mediate stress
      erythropoiesis, we explored their capacity to potentiate the stimulatory effect
      of KL on HbF reactivation, as evaluated in unilineage erythropoietic culture of
      purified adult progenitors (erythroid burst-forming units [BFU-Es]). The GC
      derivative dexamethasone (Dex) was tested in minibulk cultures at graded dosages
      within the therapeutical range (10(-6) to 10(-9) M). Dex did not exert
      significant effects alone, but synergistically it potentiated the action of KL in
      a dose-dependent fashion. Specifically, Dex induced delayed erythroid maturation
      coupled with a 2-log increased number of generated erythroblasts and enhanced HbF
      synthesis up to 85% F cells and 55% gamma-globin content at terminal maturation
      (ie, in more than 80%-90% mature erythroblasts). Equivalent results were obtained
      in unicellular erythroid cultures of sibling BFU-Es treated with KL alone or
      combined with graded amounts of Dex. These results indicate that the stimulatory
      effect of KL + Dex is related to the modulation of gamma-globin expression rather
      than to recruitment of BFU-Es with elevated HbF synthetic potential. At the
      molecular level, Id2 expression is totally suppressed in control erythroid
      culture but is sustained in KL + Dex culture. Hypothetically, Id2 may mediate the
      expansion of early erythroid cells, which correlates with HbF reactivation. These
      studies indicate that GCs play an important role in HbF reactivation. Because Dex
      acts at dosages used in immunologic disease therapy, KL + Dex administration may
      be considered to develop preclinical models for beta-hemoglobinopathy treatment.

PMID- 12424201
TI  - NPM-ALK transgenic mice spontaneously develop T-cell lymphomas and plasma cell
      tumors.
AB  - Anaplastic Large Cell Lymphomas (ALCLs) carry translocations in which the
      anaplastic lymphoma kinase (ALK) gene is juxtaposed to various genes, the most
      common of which is the NPM/B23 gene. ALK fusion proteins result in the
      constitutive activation of ALK tyrosine kinase, thereby enhancing proliferation
      and increasing cell survival. A direct role for NPM-ALK in cellular
      transformation has been shown in vitro with immortalized cell lines and in vivo
      using retroviral transfer experiments. Nonetheless, there is no direct evidence
      of its oncogenic potential in T lymphocytes, which represent the most common
      target of ALK chimeras. Here, we describe a new mouse model of lymphomagenesis in
      which human NPM-ALK transcription was targeted to T cells. NPM-ALK transgenic
      (Tg) mice were born with the expected mendelian distribution, normal lymphoid
      organs, and a normal number and proportion of helper and suppressor T cells.
      However, after a short period of latency, all NPM-ALK Tg mice developed malignant
      lymphoproliferative disorders (mean survival, 18 weeks). NPM-ALK Tg thymic
      lymphomas displayed a T-cell phenotype characteristic of immature thymocytes and
      frequently coexpressed surface CD30. A subset of the NPM-ALK Tg mice also
      developed clonal B-cell plasma cell neoplasms. These tumors arose in peripheral
      lymphoid organs (plasmacytomas) or within the bone marrow and often led to
      peripheral neuropathies and limb paralysis. Our NPM-ALK Tg mice are a suitable
      model to dissect the molecular mechanisms of ALK-mediated transformation and to
      investigate the efficacy of new therapeutic approaches for the treatment of human
      ALCL in vivo.

PMID- 12424202
TI  - Nuclear localization of cyclin B1 regulates DNA damage-induced apoptosis.
AB  - Some cells undergo apoptosis in response to DNA damage, whereas others do not. To
      understand the biochemical pathways controlling this differential response, we
      have studied the intracellular localization of cyclin B1 in cell types sensitive
      or resistant to apoptosis induced by DNA damage. We found that cyclin B1 protein
      accumulates in the nucleus of cells that are sensitive to gamma radiation-induced
      apoptosis (thymocytes, lymphoid cell lines), but remains cytoplasmic in apoptosis
      resistant cells (primary and transformed fibroblasts). Treatment of both cell
      types with leptomycin B, an inhibitor of CRM1-dependent cyclin B1 nuclear export,
      induces apoptosis. Furthermore, ectopic expression of cyclin B1-5xE, a protein
      that preferentially localizes to the nucleus, is sufficient to trigger apoptosis.
      Conversely, expression of cyclin B1-5xA, a predominantly cytoplasmic protein,
      fails to induce apoptosis. This suggests that nuclear accumulation is necessary
      for cyclin B1-dependent apoptosis. Our observations are consistent with the idea
      that localization of cyclin B1 is among the factors determining the cellular
      decision to undergo apoptosis in response to DNA damage.

PMID- 12424203
TI  - Retroviral vector integration occurs in preferred genomic targets of human bone
      marrow-repopulating cells.
AB  - Increasing use of hematopoietic stem cells for retroviral vector-mediated gene
      therapy and recent reports on insertional mutagenesis in mice and humans have
      created intense interest to characterize vector integrations on a genomic level.
      We studied retrovirally transduced human peripheral blood progenitor cells with
      bone marrow-repopulating ability in immune-deficient mice. By using a highly
      sensitive and specific ligation-mediated polymerase chain reaction (PCR) followed
      by sequencing of vector integration sites, we found a multitude of simultaneously
      active human stem cell clones 8 weeks after transplantation. Vector integrations
      occurred with significantly increased frequency into chromosomes 17 and 19 and
      into specific regions of chromosomes 6, 13, and 16, although most of the
      chromosomes were targeted. Preferred genomic target sites have previously only
      been reported for wild-type retroviruses. Our findings reveal for the first time
      that retroviral vector integration into human marrow-repopulating cells can be
      nonrandom (P =.000 37).

PMID- 12424204
TI  - Retrovirus-mediated IL-7 expression in leukemic dendritic cells generated from
      primary acute myelogenous leukemias enhances their functional properties.
AB  - Myeloid lineage-derived dendritic cells (DCs) are considered the professional
      antigen-presenting cell type responsible for eliciting T-cell-mediated immune
      responses. Acute myelogenous leukemia (AML) is a disease in which tumor antigens
      are expressed by the malignant clone that also has the potential to differentiate
      into DC-like cells (leukemic DCs) with antigen-presenting capacity. This study
      investigated whether the constitutive expression of the cytokine interleukin-7
      (IL-7) in primary AML cells during their differentiation toward leukemic DCs
      results in superior antigen-presenting cells. A bicistronic retroviral vector
      encoding the IL-7 cytokine and the surface immunoselectable low-affinity nerve
      growth factor receptor (LNGFr) gene was constructed and used for transduction
      experiments. A serum-free system was used to transduce and differentiate leukemic
      cells toward leukemic DCs. The study included 8 patients with AML. The
      transduction efficiency with the cytokine vector varied among patients, ranging
      from 5% to 30% as judged by LNGFr expression. The leukemic origin of the
      transduced cells was confirmed in a patient with a chromosomal translocation
      t(9:11) by fluorescence in situ hybridization analysis. Cytokine modified-cells
      consistently secreted IL-7 (mean, 415 pg +/- 190/10(6) cells/48 hours; n = 5). We
      demonstrate that IL-7-transduced cells are included in the differentiated
      leukemic DC subset, and, as shown in a particular case, that about half of the
      mature CD80(+) and CD83(+) populations coexpress the LNGFr transgene. In
      addition, IL-7-modified leukemic cells induce stronger allo-T-cell stimulation
      and higher amounts of IL-2 production in T cells compared with control groups.
      Finally, cytokine-transduced leukemic DCs can effectively prime and generate
      cytotoxic T lymphocytes against autologous leukemic blasts.

PMID- 12424205
TI  - Self-treatment for malaria: the evidence and methodological issues.
AB  - Malaria remains an important cause of death, especially in sub-Saharan Africa.
      Self-treatment with antimalarial drugs is a common practice that raises important
      issues for policy-makers. A number of important questions concerning factors
      related to self-treatment, adequacy of self-treatment and the role of self
      treatment in malaria mortality remain unanswered. Although there are some common
      patterns, there is considerable diversity in treatment practices, even within a
      single country. Social science research on malaria treatment needs to move beyond
      description to evaluation of interventions. This will require a greater degree of
      methodological rigour and more attention to the generation of data that can be
      compared across time periods and studies. Definitions of malaria cases and the
      role of local disease categories in identifying cases need to be made more
      explicit. Illnesses should be classified by severity, using measures of perceived
      severity as well as biomedical signs of severity. Each treatment step should be
      considered in terms of four levels of analysis: who provided the treatment or
      advice, what the treatment was, where it was obtained and when it was taken in
      relationship to onset of illness.

PMID- 12424206
TI  - An implementation framework for household and community integrated management of
      childhood illness.
AB  - This paper describes the development and recent history of the third component of
      the Integrated Management of Childhood Illness (IMCI) strategy, improving
      household and community practices (HH/C IMCI). An implementation framework for
      this third component, developed through review of experiences of non-governmental
      organizations (NGOs) working in community-based child health and nutrition
      programmes, is then presented. This Framework responds to demand from NGOs and
      their partners for a description of the different categories of community-level
      activities necessary for the implementation of a comprehensive child health and
      nutrition programme. These categories of activities facilitate the systematic
      cataloguing, synthesis and coordination of organizational activities and
      experience. It also serves as a reference tool for improving communication of
      related community child health activities, and a guide for designing appropriate
      behaviour change strategies. The Framework was endorsed by participants in an
      international workshop held in Baltimore, Maryland in January 2001, and specified
      three linked elements that are integral to HH/C IMCI, supported by a multi
      sectoral platform that addresses constraints communities face in adopting
      practices that promote health and nutrition. The three programmatic Elements
      critical to HH/C IMCI programmes are (1). improving partnerships between health
      facilities or services and the communities they serve; (2). increasing
      appropriate and accessible care and information from community-based providers;
      and (3). integrating promotion of key family practices critical for child health
      and nutrition. The Framework presented in this paper is an ideal tool for
      describing, sharing and coordinating efforts in the field, and is purposely
      descriptive rather than prescriptive.

PMID- 12424207
TI  - Rejection of an innovation: health information management training materials in
      east Africa.
AB  - A shift towards decentralization in many low-income countries has meant more
      skills are demanded of primary health care managers, including data and
      information handling at all levels of the health care system. Ministries of
      Health are changing their central reporting health information systems to health
      management information systems with emphasis on managers utilizing information at
      the point of collection. This paper reports on a research study to investigate
      the introduction of new information management strategies intended to promote an
      informational approach to management at the operational health service level in
      low-income countries. It aims to understand the process taking place when
      externally developed training materials (PHC MAP), which are intended to
      strengthen health management information systems, are introduced to potential
      users in an east African country. A case study has been undertaken and this
      research has demonstrated that the dynamic equilibrium approach to organizational
      change is applicable to the introduction of new information management strategies
      and management approaches in low-income countries. Although PHC MAP developers
      envisaged a technical innovation needing implementation, potential users saw the
      situation as one of organizational change. Contributions to theory have been made
      and many implications for introducing new information systems or the
      informational approach to management are identified. This theoretical framework
      could also facilitate the introduction of future information management
      innovations and would allow practitioners to perceive the introduction of
      information management innovations as one of organizational change that needs to
      be managed. Consequently, issues that may facilitate or inhibit adoption could be
      identified in advance.

PMID- 12424208
TI  - Ministry of Health user fees, equity and decentralization: lessons from Honduras.
AB  - Decentralization is commonly championed as a means for achieving equity. To date,
      however, there has been little discussion of the mechanisms underlying this
      relationship, and several of the few empirical investigations that have addressed
      the topic have found the converse; that decentralization has exacerbated
      inequalities. This article examines the performance and equity in financing of
      the Honduras Ministry of Health's (MOH) decentralized user fee system. The MOH of
      Honduras established a national user fee policy in 1989. It provided a framework
      of rules and regulations and decentralized administration of the system to the
      regional offices. A survey conducted under the auspices of this study provided
      detailed information about the structures and operations of MOH user fee systems.
      The survey revealed that the systems vary markedly by region, creating horizontal
      inequities, and that they have numerous other shortcomings. The average price of
      a consultation is low, US dollars 0.16, and revenues have consistently equalled
      just 2% of MOH expenditures. The systems' administrative costs are equal to 67%
      of their revenues. Eliminating the user fee systems in all but the national and
      regional hospitals would actually save money and/or enable the MOH to provide
      more care. Average consultation prices are highest in health posts, intermediate
      in centres and lowest in the national hospitals, thereby encouraging the
      inappropriate use of the MOH's pyramidal referral system and fostering MOH
      inefficiency. Fee levels and exemption practices are horizontally and vertically
      inequitable. The likelihood of paying for an ambulatory visit is highest at a
      health post, 89%, and lowest at a hospital, 49%. Individuals from the poorest one
      fifth of households are the most likely to have to pay for care. Honduras'
      experience demonstrates that a decentralized user fee system is not necessarily
      equitable, and that, more generally, the gains that can be realized from
      decentralizing user fee systems are not automatic. They must be anticipated,
      planned for and cultivated by a well-designed and well-implemented initiative
      that is not a single, one-time event, but rather a dynamic, on-going enterprise.

PMID- 12424209
TI  - Effect of the Bamako-Initiative drug revolving fund on availability and rational
      use of essential drugs in primary health care facilities in south-east Nigeria.
AB  - OBJECTIVES: To compare the level of availability and rational use of drugs in
      primary health care (PHC) facilities where the Bamako Initiative (BI) drug
      revolving fund programme has been operational, with PHC centres where the BI-type
      of drug revolving fund programme is not yet operational. METHODS: The study was
      undertaken in 21 PHC centres with BI drug revolving funds and 12 PHC centres
      without BI drug revolving funds, all in Enugu State of Nigeria. Data were
      collected on the essential and non-essential drugs stocked by the facilities.
      Drug use was determined through analyses of prescriptions in each health centre.
      Finally, the proportion of consumers that were able to remember their dosing
      schedules was determined. FINDINGS: An average of 35.4 essential drugs was
      available in the BI health centres compared with 15.3 in the non-BI health
      centres (p < 0.05). The average drug-stock was adequate for 6.3 weeks in the BI
      health centres, but for 1.1 weeks in non-BI health centres (p < 0.05). More
      injections (64.7 vs. 25.6%) and more antibiotics (72.8 vs. 38%) were prescribed
      in BI health centres than in the non-BI health centres (p < 0.05). The BI health
      centres had an average of 5.3 drugs per prescription against 2.1 in the non-BI
      health centres. However, the drugs prescribed by generic name and from the
      essential drug list were higher in the BI health centres (80 and 93%) than the
      non-BI health centres (15.5 and 21%, respectively) (p < 0.05). CONCLUSION: It was
      observed that the BI facilities had a better availability of essential drugs both
      in number and in average stock. However, the BI has given rise to more drug
      prescribing, which could be irrational. The findings call for strategies to
      ensure more availability of essential drugs especially in the non-BI PHC centres
      as a strategy to decrease medical costs and improve the quality of PHC services,
      while promoting rational drug use in all PHC centres. More detailed studies (for
      example, by focus group discussion or structured interviews) should be undertaken
      to find out reasons for the over-prescription and to develop future interventions
      to correct this.

PMID- 12424210
TI  - The impact of National Health Insurance on neonatal care use and childhood
      vaccination in Taiwan.
AB  - The objective of this study was to assess the impact of National Health Insurance
      (NHI) on the utilization of neonatal care and childhood vaccination in Taiwan.
      Data are selected from two nationwide maternal and infant surveys undertaken in
      1989 and 1996, which were funded by the Department of Health. The questionnaire
      was administered in all 23 administrative districts, including two metropolitan
      areas - the cities of Taipei and Kaohsiung. The first and second cohort consisted
      of 1641 and 3499 infants, respectively. This study used a bivariate probit
      estimation procedure to examine the factors that determine the probability of
      neonatal care use and vaccination by pooling the 2 years. Generally, the mothers
      who are older, more educated and more satisfied with birth delivery services were
      found to be more likely to use neonatal preventive care. The likelihood of
      receiving such care also tends to rise with advancing gestational age and higher
      probability of neonatal complication (icterus neonatorum) and being born in a
      hospital. The likelihood of care was also found to vary regionally with northern
      neonates having higher odds of receiving preventive care than non-northern
      neonates. In spite of having an insignificant impact on the use of care, NHI does
      lessen the inequality in use of these two services in various regions. However,
      regional variations in neonatal care use still exist. Residents of the southern
      area remain less likely to receive neonatal care than those of the northern area
      after NHI. This finding deserves serious consideration when attempting to design
      effective policies, such as expanding medical institutions in the aboriginal
      southern areas so as to increase the accessibility of such health care.

PMID- 12424211
TI  - Increasing awareness of arsenic in Bangladesh: lessons from a public education
      programme.
AB  - Experts are making a major effort to find technical solutions to the serious
      public health problems posed by arsenic in drinking water in Bangladesh, but
      public education strategies receive less systematic attention. This article
      presents the findings of a study evaluating the impact of a 1999 campaign by the
      18 District Towns Project to educate the public about the arsenic problem in six
      Bangladesh towns, where half of the population was estimated to be using arsenic
      contaminated domestic water: (1). Water users were advised not to consume arsenic
      affected tube-well water; (2). A simple, temporary water treatment method was
      recommended for those using such water, if they had no safe alternative source;
      (3). Caretakers of tube-wells having arsenic-free water were advised to share
      their water sources with others. This evaluation study, utilizing a combination
      of quantitative and qualitative social research methods, found those influenced
      by the programme to have higher awareness levels and significantly lower levels
      of risk behaviour than others. Yet more than half of the at-risk, programme
      influenced survey respondents were found still to be drinking (57%) or cooking
      with (54%) arsenic-affected water. Despite the fact that the campaign did not
      have a satisfactory public health impact, the experience can inform future
      efforts to educate the Bangladeshi public about arsenic. One finding is
      widespread confusion about trusted tube-well water being newly labelled as
      'unsafe'. Some think the problem is in the hand pumps themselves. Awareness of
      life threatening danger from arsenic contamination was found to be low. Learning
      points from this experience are: the value of explaining together with water
      testing; giving people opportunities to ask questions; repeating messages;
      continuing to educate children about the serious risks of consuming surface
      water; conducting community-wide education programmes for people of all ages; and
      evaluating the impact of specific public education strategies. Respecting such
      principles in public information campaigns will greatly help the public to
      benefit from future technical developments.

PMID- 12424212
TI  - Willingness to pay for treated mosquito nets in Surat, India: the design and
      descriptive analysis of a household survey.
AB  - For willingness to pay (WTP) studies to have an appropriate impact on policy
      making, it is essential that the design and analysis are undertaken carefully.
      This paper aims to describe and justify the design of the survey tool used to
      assess hypothetical WTP for treated mosquito nets (TMN) in rural Surat, India and
      report its findings. Results from qualitative work were used as an input for
      developing the WTP questionnaire. A total of 1200 households belonging to 80
      villages in rural Surat were selected for the study. A bidding format was used to
      elicit WTP values, using three different starting bids. The scenario was
      constructed in a way to reduce the possibility of respondents acting
      strategically. The response rate was 100%. About 79% of the respondents were
      willing to buy TMNs and the mean WTP was Rs57. Descriptive results of economic
      and other taste and preference variables are also presented, which include
      preventive measures used by households and treatment seeking behaviour for
      malaria. It is observed that WTP as well as demographic variables and prevention
      methods differ significantly across arms of the trial. This paper suggests that
      policy-makers could use the evidence following further analysis, along with
      information on costs of implementation, to ascertain the levels of subsidy that
      may be needed at different levels of coverage.

PMID- 12424213
TI  - The role of public health programmes in reducing socioeconomic inequities in
      childhood immunization coverage.
AB  - OBJECTIVES: This paper asks whether intensive outreach services can eliminate
      socioeconomic differentials in vaccine coverage. METHODS: In 1990, the Matlab
      Maternal and Child Health/Family Planning Project (MCH-FP) surveyed 4238
      respondents in an intervention area that received outreach and 3708 respondents
      in a comparison area in rural Bangladesh. Interacted multiple regression methods
      assessed the degree to which various socioeconomic indicators predicted the
      probability of vaccine receipt in each area. RESULTS: Low parental schooling,
      small dwelling size and female gender were significantly associated with
      incomplete vaccination in the comparison area, where only the limited government
      services existed. Residence in the MCH-FP outreach area greatly reduced, and in
      some cases eliminated, the effects of these socioeconomic barriers to vaccine
      receipt. CONCLUSIONS: Public health programmes utilizing outreach can reduce
      prevailing gender and socioeconomic differentials in vaccine receipt.

PMID- 12424214
TI  - Building for the future: influence of housing on intelligence quotients of
      children in an urban slum.
AB  - INTRODUCTION: Interventions on behalf of the marginalized in society can assume
      many formats. In an urban slum the Government of Delhi built one-room houses for
      some of the residents in what is termed a 'plot area'. Not all residents could be
      accommodated in the project and the remainder continued to live next door in
      shanty houses of the slum. Nineteen years later, young children who had migrated
      with their parents, have grown up and have children of their own. We looked at
      the development of the children living in the two types of accommodation.
      METHODS: A total of 373 children were studied. All children (n = 200) between the
      ages of 3.5 and 5.5 years in a cluster of five residential blocks in the plot
      area were studied. As a control, children in two large clusters of shanty houses
      (n = 173) were also studied. For development assessment the Central Institute of
      Education (CIE) Test was performed. This is an Indian adaptation of the Standford
      Binet Test. Multiple regression analysis was utilized to determine the factors
      that influenced IQ most. RESULTS: The mean IQ of the children in the plot area
      was 92.5 (s.d. 13.38) and in the shanty houses 89.5 (s.d. 12.9) (p = 0.05).
      Analysis showed that the most significant factors affecting IQ were malnutrition
      in the first 6 months of life and attendance of the child at pre-school. For
      nutrition in the first 6 months, there was no difference between the groups. For
      attendance at pre-school, 110 of 200 in the plot area and 47 of 173 in the shanty
      houses were attending pre-school (p < 0.01). CONCLUSION: We find that children
      living in the permanent houses had a significantly better IQ than those in shanty
      houses. A review of the literature did not reveal a comparable study.

PMID- 12424217
TI  - Role of S-adenosylmethionine in two experimental models of pancreatitis.
AB  - Severe necrotizing pancreatitis occurs in young female mice fed a choline
      deficient and ethionine-supplemented (CDE) diet. Although the mechanism of the
      pancreatitis is unknown, one consequence of this diet is depletion of hepatic S
      adenosylmethionine (SAM). SAM formation is catalyzed by methionine
      adenosyltransferases (MATs), which are encoded by liver-specific (MAT1A) and non
      liver-specific (MAT2A) genes. In this work, we examined changes in pancreatic SAM
      homeostasis in mice receiving the CDE diet and the effect of SAM treatment. We
      found that both MAT forms are expressed in normal pancreas and pancreatic acini.
      After 48 h of the CDE diet, SAM levels decreased 50% and MAT1A-encoded protein
      disappeared via post-translational mechanisms, whereas MAT2A-encoded protein
      increased via pretranslational mechanisms. CDE-fed mice exhibited extensive
      necrosis, edema, and acute pancreatic inflammatory infiltration, which were
      prevented by SAM treatment. However, old female mice consuming the CDE diet that
      do not develop pancreatitis showed a similar fall in pancreatic SAM level. SAM
      was also protective in cerulein-induced pancreatitis in the rat, but the
      protection was limited. Although the pancreatic SAM level fell by more than 80%
      in the MAT1A knockout mice, no pancreatitis developed. This study thus provides
      several novel findings. First, the so-called liver-specific MAT1A is highly
      expressed in the normal pancreas and pancreatic acini. Second, the CDE diet
      causes dramatic changes in the expression of MAT isozymes by different
      mechanisms. Third, in contrast to the situation in the liver, where absence of
      MAT1A and decreased hepatic SAM level can lead to spontaneous tissue injury, in
      the pancreas the roles of SAM and MAT1A appear more complex and remain to be
      defined.

PMID- 12424218
TI  - Selective neuronal degeneration induced by soluble oligomeric amyloid beta
      protein.
AB  - The prevailing amyloid hypothesis for Alzheimer's disease (AD) holds that amyloid
      beta-protein (Abeta) causes neuronal degeneration by forming neurotoxic fibrillar
      structures. Yet, many aspects of AD pathology and symptoms are not well explained
      by this hypothesis. Here, we present evidence that neurotoxicity of soluble
      oligomeric Abeta closely corresponds to the selective neurodegeneration so
      distinctly manifest in AD. Selectivity was first observed in vitro, where only
      the human central nervous system neuronal cells were susceptible to soluble
      oligomeric Abeta. Furthermore, in mouse cerebral slice treated with soluble
      oligomeric Abeta, selective regiospecific toxicity was evident in the hippocampal
      CA1, a division important for memory, but not in the CA3 subfield. The fibrillar
      Abeta, however, killed neurons in all regions of the cerebral slice cultures and
      also in cerebellar slices. Remarkably, even at the highest soluble oligomeric
      Abeta concentrations, cerebellar neurons were completely spared, consistent with
      one of the hallmark features of AD pathology. Our observation of the selective
      neurodegeneration of soluble oligomeric Abeta to neurons involved in cognitive
      function may provide a new opportunity for the development of an effective AD
      therapy as well as elucidating the pathological mechanism of AD.

PMID- 12424219
TI  - Platelet-derived growth factor activates production of reactive oxygen species by
      NAD(P)H oxidase in smooth muscle cells through Gi1,2.
AB  - Recent findings indicate that platelet-derived growth factor (PDGF) plays a role
      in the generation of reactive oxygen species (ROS) as second messengers in smooth
      muscle cells (SMC). To identify the source and signal transduction pathway of ROS
      formation in SMC, we investigated PDGF-induced ROS formation. Stimulation of SMC
      with PDGF resulted in a rapid increase of ROS production. Using an inactivating
      antibody, we identified the increase to be dependent on p22phox, a NAD(P)H
      oxidase subunit. ROS release was completely inhibited by the Gi protein inhibitor
      PTX as well as an antibody against Galphai1,2, however, not by antibodies against
      Galphai3/0, Gas, and Gbeta1beta2. The effect of PDGF on ROS production in SMC
      membranes could likewise be mimicked by the use of a recombinant Galphai2 subunit
      but not by Galphai3, Galphai0, Gas, and Gbetagamma subunits. Immunoaffinity
      chromatography demonstrated coupling of Galphai1,2 to the PDGF a-receptor, which,
      after preincubation of the SMC membranes with PDGF, was increased in the absence
      of GTPgammaS but decreased in the presence of GTPgammaS and prevented by PTX
      treatment. These data define a novel G protein-dependent mechanism by which PDGF
      signaling is transduced through direct coupling of the Gai1,2 subunit of the
      trimeric G proteins to the PDGF tyrosine kinase receptor.

PMID- 12424220
TI  - Selenium deficiency increases susceptibility to glutamate-induced excitotoxicity.
AB  - Excitotoxic brain lesions, such as stroke and epilepsy, lead to increasing
      destruction of neurons hours after the insult. The deadly cascade of events
      involves detrimental actions by free radicals and the activation of proapoptotic
      transcription factors, which finally result in neuronal destruction. Here, we
      provide direct evidence that the nutritionally essential trace element selenium
      has a pivotal role in neuronal susceptibility to excitotoxic lesions. First, we
      observed in neuronal cell cultures that addition of selenium in the form of
      selenite within the physiological range protects against excitotoxic insults and
      even attenuates primary damage. The neuroprotective effect of selenium is not
      directly mediated via antioxidative effects of selenite but requires de novo
      protein synthesis. Gel shift analysis demonstrates that this effect is connected
      to the inhibition of glutamate-induced NF-kappaB and AP-1 activation.
      Furthermore, we provide evidence that selenium deficiency in vivo results in a
      massive increase in susceptibility to kainate-induced seizures and cell loss.
      These findings indicate the importance of selenium for prevention and therapy of
      excitotoxic brain damage.

PMID- 12424221
TI  - Glutathione disulfide induces apoptosis in U937 cells by a redox-mediated p38 MAP
      kinase pathway.
AB  - Changes in the intracellular reduced/oxidized glutathione ratio (GSH/GSSG) are
      crucial reduction-oxidation (redox) events that trigger downstream proliferation
      or death responses. We investigated the molecular mechanisms underlying redox
      mediated cell signaling upon an oxidative insult by treating U937 cells with
      exogenous nonpermeable GSSG. This treatment results in a significant decrease of
      exofacial cell membrane thiol groups and intracellular decrement of GSH content,
      owing to its engagement in the formation of mixed disulfides. Changes in
      thioredoxin redox state were also observed, and they may be related to the
      activation of upstream ASK1 and selective induction of downstream p38 mitogen
      activated protein kinase (MAPK) pathway, detectable by phosphorylation of MKK3/6
      and p38 MAPK. Moreover, an increase in reactive oxygen species production was
      detected, and cells were committed to apoptosis along the mitochondrial pathway,
      evidenced by Bcl-2 down-regulation, cytochome c release from mitochondria,
      caspase-9 cleavage, and caspase-3 activation. GSH ethyl ester, a precursor of
      GSH, by counteracting intracellular mixed disulfide formation, canceled both p38
      MAPK activation and GSSG-mediated apoptosis via inhibition of thioredoxin
      oxidation and stabilization of thioredoxin/ASK1 complex, whereas, blockage of p38
      MAPK by specific inhibitor SB 203580 allowed apoptosis at a very reduced extent.
      Results suggest that kinase cascade may serve as a primary transducer of
      cytoplasmic oxidative signals to the nucleus before apoptosis-inducing signals
      are activated.

PMID- 12424222
TI  - Long-term divergent selection on fatness in mice indicates a regulation system
      independent of leptin production and reception.
AB  - Divergent selection in mice on fatness over 60 generations produced a fat (F) and
      a lean (L) line, having about 22% and 4% body fat, respectively. To elucidate the
      importance of the leptin regulatory feedback loop in the genetic changes produced
      by this selection, Lep(ob) and Lepr(db) mutations causing leptin production and
      leptin receptor deficiency, respectively, were introgressed individually into
      both lines by repeated backcrossing. The fat amount increased significantly in
      homozygotes for Lep(ob) or Lepr(db) in both lines, for example, in F and L males
      from 8.5 to 18.8 and 17.2 g (P<0.001) and from 1.25 to 18.0 and 12.7 g (P<0.001),
      respectively. Line differences were, however, mostly maintained after
      introgression. Concentrations of circulating leptin were relatively independent
      of the original lines but heavily dependent on the introgressed genotype.
      Introgression of leptin production and receptor deficiencies had separate effects
      from long-term selection, indicating that the genes responsible for the line
      divergence must act independently of the leptin regulatory system. Energy budget
      analysis indicated that the major line differences were in the level of energy
      expended on physical activity, and these differences were preserved following
      introgression, suggesting that multiple pathways regulate fatness, which may be
      independently responsive to intervention.

PMID- 12424223
TI  - Targeted expression of IGF-1 transgene to skeletal muscle accelerates muscle and
      motor neuron regeneration.
AB  - Currently, there is no known medical treatment that hastens the repair of damaged
      nerve and muscle. Using IGF-1 transgenic mice that specifically express human
      recombinant IGF-1 in skeletal muscle, we test the hypotheses that targeted gene
      expression of IGF-1 in skeletal muscle enhances motor nerve regeneration after a
      nerve crush injury. The IGF-1 transgene affects the initiation of the muscle
      repair process after nerve injury as shown by increased activation of SCA
      1positive myogenic stem cells. Increased satellite cell differentiation and
      proliferation are observed in IGF-1 transgenic mice, shown by increased
      expression of Cyclin D1, MyoD, and myogenin. Expression of myogenin and nicotinic
      acetylcholine receptor subunits, initially increased in both wild-type and IGF-1
      transgenic mice, are restored to normal levels at a faster rate in IGF-1
      transgenic mice, which indicates a rescue of nerve-evoked muscle activity.
      Expression of the IGF-1 transgene in skeletal muscle results in accelerated
      recovery of saltatory nerve conduction, increased innervation as detected by
      neurofilament expression, and faster recovery of muscle mass. These studies
      demonstrate that local expression of IGF-1 augments the repair of injured nerve
      and muscle.

PMID- 12424224
TI  - NEPH1 defines a novel family of podocin interacting proteins.
AB  - Mutations of NPHS1 or NPHS2, the genes encoding for the glomerular podocyte
      proteins nephrin and podocin, cause steroid-resistant proteinuria. In addition,
      mice lacking NEPH1 develop a nephrotic syndrome that resembles NPHS mutations,
      suggesting that all three proteins are essential for the integrity of glomerular
      podocytes. Podocin interacts with the C-terminal domain of nephrin and
      facilitates nephrin-dependent signaling. NEPH1, a member of the immunoglobulin
      superfamily, is structurally related to nephrin. We report now that NEPH1 belongs
      to a family of three closely related proteins that interact with the C-terminal
      domain of podocin. All three NEPH proteins share a conserved podocin-binding
      motif; mutation of a centrally located tyrosine residue dramatically lowers the
      affinity of NEPH1 for podocin. NEPH1 triggers AP-1 activation similarly to
      nephrin but requires the presence of Tec family kinases for efficient
      transactivation. We conclude that NEPH1 defines a new family of podocin-binding
      molecules that are potential candidates for hereditary nephrotic syndromes not
      linked to either NPHS1 or NPHS2.

PMID- 12424225
TI  - Gamma-secretase/presenilin inhibitors for Alzheimer's disease phenocopy Notch
      mutations in Drosophila.
AB  - Signaling from the Notch (N) receptor is essential for proper cell-fate
      determinations and tissue patterning in all metazoans. N signaling requires a
      presenilin (PS)-dependent transmembrane-cleaving activity that is closely related
      or identical to the gamma-secretase proteolysis of the amyloid-beta precursor
      protein (APP) involved in Alzheimer's disease pathogenesis. Here, we show that N
      [N-(3,5-difluorophenacetyl)-L-alanyl]-(S)-phenylglycine t-butyl ester, a potent
      gamma-secretase inhibitor reported to reduce amyloid-beta levels in transgenic
      mice, prevents N processing, translocation, and signaling in cell culture. This
      compound also induces developmental defects in Drosophila remarkably similar to
      those caused by genetic reduction of N. The appearance of this phenocopy depends
      on the timing and dose of compound exposure, and effects on N-dependent signaling
      molecules established its biochemical mechanism of action in vivo. Other gamma
      secretase inhibitors caused similar effects. Thus, the three-dimensional
      structure of the drug-binding site(s) in Drosophila gamma-secretase is remarkably
      conserved vis-a-vis the same site(s) in the mammalian enzyme. These results show
      that genetics and developmental biology can help elucidate the in vivo site of
      action of pharmacological agents and suggest that organisms such as Drosophila
      may be used as simple models for in vivo prescreening of drug candidates.

PMID- 12424226
TI  - Relaxin deficiency in mice is associated with an age-related progression of
      pulmonary fibrosis.
AB  - Relaxin (RLX) is a peptide hormone with known antifibrotic properties. However,
      its significance in the lung and its role as a therapeutic agent against diseases
      characterized by pulmonary fibrosis are yet to be established. In this study, we
      examined age-related structural and functional changes in the lung of relaxin
      deficient mice. Lung tissues of male and female RLX knockout (-/-) and RLX wild
      type (+/+) mice at various ages were analyzed for changes in collagen expression
      and content. We demonstrate an age-related progression of lung fibrosis in RLX -/
      mice with significantly increased tissue wet weight, collagen content and
      concentration, alveolar congestion, and bronchiole epithelium thickening. The
      increased fibrosis was associated with significantly altered peak expiratory flow
      and lung recoil (lung function) in RLX -/- mice. Treatment of RLX -/- mice with
      relaxin in early and developed stages of fibrosis resulted in the reversal of
      collagen deposition. Organ bath studies showed that precontracted lung strips
      relaxed in the presence of relaxin. Together, these data indicate that relaxin
      may provide a means to regulate excessive collagen deposition in diseased states
      characterized by pulmonary fibrosis.

PMID- 12424227
TI  - Cardiac-specific overexpression of a high Ca2+ affinity mutant of SERCA2a
      attenuates in vivo pressure overload cardiac hypertrophy.
AB  - In cardiomyocytes, calcium plays important roles as a signal in cardiac
      hypertrophy and contraction-relaxation cycling. Elevation of Ca2+ concentration
      in myoplasm is associated with the onset and progression of hypertrophy as well
      as the enhancement of contractility. The cardiac Ca2+ ATPase (SERCA2a) of the
      sarcoplasmic reticulum plays a dominant role in lowering cytoplasmic calcium
      levels during relaxation and is regulated by phospholamban (PLN). To examine
      whether the modulation of SERCA2a activity results in the attenuation of cardiac
      hypertrophy and enhancement of contractility, we generated transgenic mice (TG)
      overexpressing a high calcium affinity SERCA2a mutant (K397/400E), lacking a
      functional association with PLN. In the TG hearts, the apparent affinity of
      SERCA2a for Ca2+ significantly increased compared with their nontransgenic
      littermate controls. The TG showed increased contraction and relaxation, with
      increases in the amplitude of Ca2+ transient and rapid Ca2+ decay. Upon induction
      of pressure overload by transverse aortic constriction, the TG developed less
      cardiac hypertrophy than littermate controls did. The activation of Ca2+
      sensitive protein kinase C by pressure overload was significantly attenuated in
      the TG hearts. Our findings indicate an association of SERCA2a activity with
      cardiac hypertrophy and thus a new therapeutic target for the prevention and
      treatment of cardiac hypertrophy.

PMID- 12424228
TI  - Trypanosoma cruzi induces edematogenic responses in mice and invades
      cardiomyocytes and endothelial cells in vitro by activating distinct kinin
      receptor (B1/B2) subtypes.
AB  - Trypanosoma cruzi, the protozoan that causes Chagas' heart disease, invades
      endothelial cells in vitro by activating the B2 kinin receptor (B2R). Here, we
      demonstrate that mice infected with trypomastigotes develop potent edema after
      treatment with the angiotensin-converting enzyme (ACE) (or kininase II) inhibitor
      captopril. Experiments performed with specific kinin receptor (B2R/B1R)
      antagonists and knockout mice revealed that the early-phase (3-h) edema is
      mediated by the constitutive B2R, whereas the late-phase (24-h) response depends
      on stimulation of the up-regulated B1R. Given previous evidence that parasite
      invasion of cells expressing B2R is potentiated by captopril, we investigated the
      prerequisites for in vitro infection of Chinese hamster ovary cells
      overexpressing either B1R or B2R, human umbilical vein endothelial cells
      activated by lipopolysaccharide, and neonatal rat cardiomyocytes. Our results
      indicate that captopril potentiates parasite invasion regardless of the kinin
      (B2/B1) activation pathways, whereas DL-2-mercaptomethyl-3-guanidino
      ethylthiopropanoic acid (MGTA), an inhibitor of kininase I (carboxypeptidase
      M/N), selectively decreases parasite infectivity for B1R-expressing cells. These
      data suggest that formation of the B1R agonist, i.e., [des-Arg] kinins,
      critically depends on the processing action of kininase I, here proposed as a
      potential pathogenesis cofactor. Collectively, our data suggest that fluctuations
      in the levels of kininases may modulate parasite infectivity and pathological
      outcome in Chagas' disease.

PMID- 12424229
TI  - The role of individual Nedd4-2 (KIAA0439) WW domains in binding and regulating
      epithelial sodium channels.
AB  - The amiloride-sensitive epithelial sodium channel (ENaC) is essential for fluid
      and electrolyte homeostasis. ENaC consists of alpha, beta, and gamma subunits,
      each of which contains a PPxY motif that interacts with the WW domains of the
      ubiquitin-protein ligases Nedd4 and Nedd4-2. Disruption of this interaction, as
      in Liddle's syndrome in which mutations delete or alter the PPxY motif of either
      the beta or the gamma subunits, results in increased ENaC activity. We report
      here that Nedd4-2 has two major isoforms that show tissue-specific expression;
      however, both isoforms can inhibit ENaC in Xenopus oocytes. Because there are
      four WW domains in Nedd4-2, we analyzed binding kinetics and affinity between
      individual WW domains and ENaC subunits. Using whole cell patch-clamp techniques,
      we studied the role of individual WW domains in the regulation of ENaC in
      mammalian cells. We report here that unlike Nedd4, only two of the Nedd4-2 WW
      domains, WW3 and WW4, are required for both the binding to ENaC subunits and the
      regulation of Na+ feedback control of ENaC. Although both WW3 and WW4
      individually can interact with all three ENaC subunits in vitro, both domains
      together are essential for in vivo function of Nedd4-2 in ENaC regulation. These
      data suggest that Nedd4-2 WW3 and WW4 interact with distinct, noninterchangeable
      sites in ENaC and that to prevent Na+ feedback control of ENaC it is necessary to
      occlude both sites.

PMID- 12424231
TI  - Electrophilic prostaglandins and lipid aldehydes repress redox-sensitive
      transcription factors p53 and hypoxia-inducible factor by impairing the
      selenoprotein thioredoxin reductase.
AB  - Tumor suppressor p53 exhibits an enigmatic phenotype in cells exposed to
      electrophilic, cyclopentenone prostaglandins of the A and J series. Namely, cells
      harboring a wild-type p53 gene accumulate p53 protein that is conformationally
      and functionally impaired. This occurs via an unknown molecular mechanism. We
      report that electrophilic cyclopentenone prostaglandins covalently modify and
      inhibit thioredoxin reductase, a selenoprotein that governs p53 and other redox
      sensitive transcription factors. This mechanism accounts fully for the unusual
      p53 phenotype in cells exposed to electrophilic prostaglandins. Based on this
      mechanism we derived, tested, and affirmed several predictions regarding the
      kinetics of p53 inactivation; the protective effects of selenium; the structure
      activity relationships for inhibition of thioredoxin reductase and impairment of
      p53 by electrophilic lipids; the susceptibility of hypoxia-inducible factor to
      inactivation by electrophilic lipids; and the equivalence of chemical
      inactivation of p53 to deletion of a p53 allele. Chemical precepts dictate that
      other electrophilic agents should also inhibit thioredoxin reductase and impair
      its governance of redox-sensitive proteins. Our results provide a novel framework
      to understand how endogenous and exogenous electrophiles might participate in
      carcinogenesis; how selenoproteins and selenium might confer protection against
      cancer; how certain tumors might acquire their paradoxical p53 phenotype; and how
      chronic inflammation might heighten the risk for cancer.

PMID- 12424232
TI  - The kinetic mechanism of phosphomevalonate kinase.
AB  - Phosphomevalonate kinase catalyzes an essential step in the so-called mevalonate
      pathway, which appears to be the sole pathway for the biosynthesis of sterols and
      other isoprenoids in mammals and archea. Despite the well documented importance
      of this pathway in the cause and prevention of human disease and that it is the
      biosynthetic root of an enormous diverse class of metabolites, the mechanism of
      phosphomevalonate kinase from any organism is not yet well characterized. The
      first structure of a phosphomevalonate kinase from Streptococcus pneumoniae was
      solved recently. The enzyme exhibits an atypical P-loop that is a conserved
      defining feature of the GHMP kinase superfamily. In this study, the kinetic
      mechanism of the S. pneumoniae enzyme is characterized in the forward and reverse
      directions using a combination of classical initial-rate methods including
      alternate substrate inhibition using ADPbetaS. The inhibition patterns strongly
      support that in either direction the substrates bind randomly to the enzyme prior
      to chemistry, a random sequential bi-bi mechanism. The kinetic constants are as
      follows: k(cat(forward)) = 3.4 s(-1), K(i(ATP)) = 137 microm, K(m(ATP)) = 74
      microm, K(i(pmev)) = 7.7 microm, K(m(pmev)) = 4.2 microm; k(cat(reverse)) = 3.9
      s(-1), K(i(ADP)) = 410 microm, K(m(ADP)) = 350 microm, K(i(ppmev)) = 14 microm,
      K(m(ppmev)) = 12 microm, where pmev and ppmev represent phosphomevalonate and
      diphosphomevalonate, respectively.

PMID- 12424233
TI  - The Caenorhabditis elegans ERp60 homolog protein disulfide isomerase-3 has
      disulfide isomerase and transglutaminase-like cross-linking activity and is
      involved in the maintenance of body morphology.
AB  - A novel protein disulfide isomerase gene, pdi-3, was isolated from the nematode
      Caenorhabditis elegans. This gene encodes an enzyme related to the ERp60 class of
      thioredoxin proteins and was found to exhibit unusual enzymatic properties.
      Recombinant protein displayed both disulfide bond isomerase activity and calcium
      dependent transglutaminase-like cross-linking activity. The pdi-3 transcript was
      developmentally constitutively expressed, and the encoded protein is present in
      many tissues including the gut and the hypodermis. The nematode hypodermis
      synthesizes the essential collagenous extracellular matrix (ECM) called the
      cuticle. Transcript disruption via double-stranded RNA interference resulted in
      dramatic and specific synthetic phenotypes in several C. elegans mutant alleles
      with weakened cuticles: sqt-3(e2117), dpy-18(e364, ok162, and bx26). These
      nematodes displayed severe dumpy phenotypes and disrupted lateral alae, a
      destabilized cuticle and abnormal male and hermaphrodite tail morphologies. These
      defects were confirmed to be consistent with hypodermal seam cell abnormalities
      and corresponded with the severe disruption of a cuticle collagen. Wild type
      nematodes did not exhibit observable morphological defects; however, cuticle
      collagen localization was mildly disrupted following pdi-3 RNA interference. The
      unusual thioredoxin enzyme, protein disulfide isomerase-3, may therefore play a
      role in ECM assembly. This enzyme is required for the proper maintenance of post
      embryonic body shape in strains with a weakened cuticle, perhaps through ECM
      stabilization via cross-linking activity, disulfide isomerase protein folding
      activity, protein disulfide isomerase chaperone activity, or via multifunctional
      events.

PMID- 12424234
TI  - Role of conserved tyrosine 343 in intramolecular electron transfer in human
      sulfite oxidase.
AB  - Tyrosine 343 in human sulfite oxidase (SO) is conserved in all SOs sequenced to
      date. Intramolecular electron transfer (IET) rates between reduced heme (Fe(II))
      and oxidized molybdenum (Mo(VI)) in the recombinant wild-type and Y343F human SO
      were measured for the first time by flash photolysis. The IET rate in wild-type
      human SO at pH 7.4 is about 37% of that in chicken SO with a similar decrease in
      k(cat). Steady-state kinetic analysis of the Y343F mutant showed an increase in
      K(m)(sulfite) and a decrease in k(cat) resulting in a 23-fold attenuation in the
      specificity constant k(cat)/K(m)(sulfite) at the optimum pH value of 8.25. This
      indicates that Tyr-343 is involved in the binding of the substrate and catalysis
      within the molybdenum active site. Furthermore, the IET rate constant in the
      mutant at pH 6.0 is only about one-tenth that of the wild-type enzyme, suggesting
      that the OH group of Tyr-343 is vital for efficient IET in SO. The pH dependences
      of IET rate constants in the wild-type and mutant SO are consistent with the
      previously proposed coupled electron-proton transfer mechanism.

PMID- 12424235
TI  - Regulation of receptor tyrosine kinase signaling by protein tyrosine phosphatase
      1B.
AB  - Receptor tyrosine kinases (RTKs) are key regulators of cellular homeostasis.
      Based on in vitro and ex vivo studies, protein tyrosine phosphatase-1B (PTP1B)
      was implicated in the regulation of several RTKs, yet mice lacking PTP1B show
      defects mainly in insulin and leptin receptor signaling. To address this apparent
      paradox, we studied RTK signaling in primary and immortalized fibroblasts from
      PTP1B(-/-) mice. After growth factor treatment, cells lacking PTP1B exhibit
      increased and sustained phosphorylation of the epidermal growth factor receptor
      (EGFR) and the platelet-derived growth factor receptor (PDGFR). However, Erk
      activation is enhanced only slightly, and there is no increase in Akt activation
      in PTP1B-deficient cells. Our results show that PTP1B does play a role in
      regulating EGFR and PDGFR phosphorylation but that other signaling mechanisms can
      largely compensate for PTP1B deficiency. In-gel phosphatase experiments suggest
      that other PTPs may help to regulate the EGFR and PDGFR in PTP1B(-/-)
      fibroblasts. This and other compensatory mechanisms prevent widespread,
      uncontrolled activation of RTKs in the absence of PTP1B and probably explain the
      relatively mild effects of PTP1B deletion in mice.

PMID- 12424236
TI  - Subunit communications crucial for the functional integrity of the yeast RNA
      polymerase II elongator (gamma-toxin target (TOT)) complex.
AB  - In response to the Kluyveromyces lactis zymocin, the gamma-toxin target (TOT)
      function of the Saccharomyces cerevisiae RNA polymerase II (pol II) Elongator
      complex prevents sensitive strains from cell cycle progression. Studying
      Elongator subunit communications, Tot1p (Elp1p), the yeast homologue of human IKK
      associated protein, was found to be essentially involved in maintaining the
      structural integrity of Elongator. Thus, the ability of Tot2p (Elp2p) to interact
      with the HAT subunit Tot3p (Elp3p) of Elongator and with subunit Tot5p (Elp5p) is
      dependent on Tot1p (Elp1p). Also, the association of core-Elongator (Tot1-3p/Elp1
      3p) with HAP (Elp4-6p/Tot5-7p), the second three-subunit subcomplex of Elongator,
      was found to be sensitive to loss of TOT1 (ELP1) gene function. Structural
      integrity of the HAP complex itself requires the ELP4/TOT7, ELP5/TOT5, and
      ELP6/TOT6 genes, and elp6Delta/tot6Delta as well as elp4Delta/tot7Delta cells can
      no longer promote interaction between Tot5p (Elp5p) and Tot2p (Elp2p). The
      association between Elongator and Tot4p (Kti12p), a factor that may modulate the
      TOT activity of Elongator, requires Tot1-3p (Elp1-3p) and Tot5p (Elp5p),
      indicating that this contact requires a preassembled holo-Elongator complex.
      Tot4p also binds pol II hyperphosphorylated at its C-terminal domain Ser(5)
      raising the possibility that Tot4p bridges the contact between Elongator and pol
      II.

PMID- 12424237
TI  - Okazaki fragment maturation in yeast. II. Cooperation between the polymerase and
      3'-5'-exonuclease activities of Pol delta in the creation of a ligatable nick.
AB  - To address the different functions of Pol delta and FEN1 (Rad27) in Okazaki
      fragment maturation, exonuclease-deficient polymerase Pol delta-01 and Pol delta
      5DV (corresponding to alleles pol3-01-(D321A, E323A) and pol3-5DV-(D520V),
      respectively) were purified and characterized in this process. In the presence of
      the replication clamp PCNA, both wild-type and exo(-) Pol delta carried out
      strand displacement synthesis with similar rates; however, initiation of strand
      displacement synthesis was much more efficient with Pol delta-exo(-). When Pol
      delta-exo(-) encountered a downstream primer, it paused with 3-5 nucleotides of
      the primer displaced, whereas the wild type carried out precise gap filling.
      Consequently, in the absence of FEN1, Pol delta exonuclease activity was
      essential for closure of simple gaps by DNA ligase. Compared with wild type,
      Okazaki fragment maturation with Pol delta-exo(-) proceeded with an increased
      duration of nick translation prior to ligation. Maturation was efficient in the
      absence of Dna2 and required Dna2 only when FEN1 activity was compromised. In
      agreement with these results, the proposed generation of double strand breaks in
      pol3-exo(-) rad27 mutants was suppressed by the overexpression of DNA2. Further
      genetic studies showed that pol3-exo(-) rad27 double mutants were sensitive to
      alkylation damage consistent with an in vivo defect in gap filling by exonuclease
      deficient Pol delta.

PMID- 12424238
TI  - Okazaki fragment maturation in yeast. I. Distribution of functions between FEN1
      AND DNA2.
AB  - In the presence of proliferating cell nuclear antigen, yeast DNA polymerase delta
      (Pol delta) replicated DNA at a rate of 40-60 nt/s. When downstream double
      stranded DNA was encountered, Pol delta paused, but most replication complexes
      proceeded to carry out strand-displacement synthesis at a rate of 1.5 nt/s. In
      the presence of the flap endonuclease FEN1 (Rad27), the complex carried out nick
      translation (1.7 nt/s). The Dna2 nuclease/helicase alone did not efficiently
      promote nick translation, nor did it affect nick translation with FEN1.
      Maturation in the presence of DNA ligase was studied with various downstream
      primers. Downstream DNA primers, RNA primers, and small 5'-flaps were efficiently
      matured by Pol delta and FEN1, and Dna2 did not stimulate maturation. However,
      maturation of long 5'-flaps to which replication protein A can bind required both
      DNA2 and FEN1. The maturation kinetics were optimal with a slight molar excess
      over DNA of Pol delta, FEN1, and proliferating cell nuclear antigen. A large
      molar excess of DNA ligase substantially enhanced the rate of maturation and
      shortened the nick-translation patch (nucleotides excised past the RNA/DNA
      junction before ligation) to 4-6 nt from 8-12 nt with equimolar ligase. These
      results suggest that FEN1, but not DNA ligase, is a stable component of the
      maturation complex.

PMID- 12424239
TI  - Nuclear overexpression of NADH:cytochrome b5 reductase activity increases the
      cytotoxicity of mitomycin C (MC) and the total number of MC-DNA adducts in
      Chinese hamster ovary cells.
AB  - NADH:cytochrome b(5) reductase (FpD) is an enzyme capable of converting the
      prodrug mitomycin C (MC) into a DNA alkylating agent via reduction of its
      quininone moiety. In this study, Chinese hamster ovary (CHO) cells were
      transfected with a cDNA encoding rat FpD. Despite the demonstrated ability of
      this enzyme to reduce MC in vitro, a modest 5-fold level of overexpression of FpD
      activity in CHO cells did not increase the cytotoxicity of the drug over that
      seen with the parental cell line under either aerobic or hypoxic conditions. When
      the enzyme, which is predominantly localized in the mitochondria, was instead
      directed to the nucleus of cells by the fusion of the SV40 large T antigen
      nuclear localization signal sequence to the amino terminus of an FpD gene that
      lacked the membrane anchor domain, drug sensitivity was significantly enhanced at
      all concentrations of MC examined (2-10 microm) under both aerobic and hypoxic
      conditions, with greater cell kill occurring under hypoxia. The marked increase
      in drug sensitivity under hypoxia at 10 microm MC corresponded to a measurable
      increase in total MC-DNA adducts at the same concentration. The results indicate
      that the cytotoxicity of MC is modulated by the subcellular location of FpD, with
      greater cell kill occurring when bioactivation occurs in the proximity of its
      target, nuclear DNA.

PMID- 12424240
TI  - Minimally modified LDL binds to CD14, induces macrophage spreading via TLR4/MD-2,
      and inhibits phagocytosis of apoptotic cells.
AB  - Minimally modified low density lipoprotein (mmLDL) is a pro-inflammatory and pro
      atherogenic lipoprotein that, unlike profoundly oxidized LDL (OxLDL), is not
      recognized by scavenger receptors and thus does not have enhanced uptake by
      macrophages. However, here we demonstrate that mmLDL (as well as OxLDL) induces
      actin polymerization and spreading of macrophages, which results in such pro
      atherogenic consequences as inhibition of phagocytosis of apoptotic cells but
      enhancement of OxLDL uptake. We also demonstrate for the first time that the
      lipopolysaccharide receptor, CD14, and toll-like receptor-4/MD-2 are involved in
      these mmLDL effects. Macrophages of the J774 cell line exhibited higher mmLDL
      binding and F-actin response than its CD14-deficient mutant, LR-9 cells.
      Similarly, Chinese hamster ovary cells transfected with human CD14 specifically
      bound mmLDL and responded with higher F-actin compared with control cells.
      Macrophages from C3H/HeJ mice, which have a point mutation in the Tlr4 gene,
      responded with lower F-actin to mmLDL and did not spread as well as macrophages
      from control animals. A significantly higher F-actin response was also observed
      in Chinese hamster ovary cells transfected with human toll-like receptor-4/MD-2
      but not with TLR4 alone or TLR2. Thus, in addition to inhibition of phagocytosis,
      the recognition of mmLDL by macrophage lipopolysaccharide receptors results in
      convergence of cellular immune responses to products of microorganisms and to
      oxidation-specific self-antigens, which could both influence macrophage function
      and atherogenesis.

PMID- 12424241
TI  - Multiple roles of the RNA polymerase beta subunit flap domain in sigma 54
      dependent transcription.
AB  - Recent determinations of the structures of the bacterial RNA polymerase (RNAP)
      and promoter complex thereof establish that RNAP functions as a complex molecular
      machine that contains distinct structural modules that undergo major
      conformational changes during transcription. However, the contribution of the
      RNAP structural modules to transcription remains poorly understood. The bacterial
      core RNAP (alpha(2)beta beta'omega; E) associates with a sigma (sigma) subunit to
      form the holoenzyme (E sigma). A mutation removing the beta subunit flap domain
      renders the Escherichia coli sigma(70) RNAP holoenzyme unable to recognize
      promoters. sigma(54) is the major variant sigma subunit that utilizes enhancer
      dependent promoters. Here, we determined the effects of beta flap removal on
      sigma(54)-dependent transcription. Our analysis shows that the role of the beta
      flap in sigma(54)-dependent and sigma(70)-dependent transcription is different.
      Removal of the beta flap does not prevent the recognition of sigma(54)-dependent
      promoters, but causes multiple defects in sigma(54)-dependent transcription. Most
      importantly, the beta flap appears to orchestrate the proper formation of the E
      sigma(54) regulatory center at the start site proximal promoter element where
      activator binds and DNA melting originates.

PMID- 12424242
TI  - Trans-targeting of the phage Mu repressor is promoted by conformational changes
      that expose its ClpX recognition determinant.
AB  - Dominant negative forms of the phage Mu repressor, including the mutant Vir
      repressors, are not only rapidly degraded by the ClpXP protease but also promote
      degradation of the unmodified, wild-type repressor. This trans-targeting of the
      wild-type repressor depends upon a determinant within its C-terminal domain,
      which is needed for recognition by ClpX. An environmentally sensitive fluorescent
      probe (2-(4'-maleimidylanilino)naphthalene-6-sulfonic acid (MIANS)) attached to
      the C terminus of the full-length repressor indicated that Vir induces the
      movement of this domain into a more exposed configuration. Vir also promoted
      attachment of MIANS to the C terminus of the repressor at an accelerated rate,
      and it greatly increased the rate of phosphorylation of a cAMP-dependent protein
      kinase motif attached to the repressor C terminus. While an excess of Vir was
      needed to promote repressor phosphorylation at maximal rates, the presence of
      ClpX could increase phosphorylation rates at lower Vir levels. trans-Targeting of
      the Mu repressor is therefore promoted by exposing its ClpX recognition
      determinant, and the action of ClpX can assist Vir in exposing these
      determinants.

PMID- 12424243
TI  - Tn5 transposase active site mutations suggest position of donor backbone DNA in
      synaptic complex.
AB  - Tn5 transposase (Tnp), a 53.3-kDa protein, enables the movement of transposon Tn5
      by a conservative mechanism. Within the context of a protein and DNA synaptic
      complex, a single Tnp molecule catalyzes four sequential DNA breaking and joining
      reactions at the end of a single transposon. The three amino acids of the DDE
      motif (Asp-97, Asp-188, and Glu-326), which are conserved among transposases and
      retroviral integrases, have been shown previously to be absolutely required for
      all catalytic steps. To probe the effect of active site geometry on the ability
      to form synaptic complexes and perform catalysis, single mutations at each
      position of the DDE motif were constructed. The aspartates were changed to
      glutamates, and the glutamate was changed to an aspartate. These mutants were
      studied by performing in vitro binding assays using short oligonucleotide
      substrates simulating the natural substrates for the synaptic complex formation
      and subsequent transposition steps. The results indicate that the aspartate to
      glutamate mutations restrict synaptic complex formation with substrates
      resembling the natural transposon prior to transferred strand nicking. This
      suggests a structural model in which the donor backbone DNA, prior to nicking,
      occupies the same space that is invaded by the longer side chains present in the
      aspartate to glutamate mutants. Additionally, catalytic assays support the
      previous proposal that the active site coordinates two divalent metal ions.

PMID- 12424244
TI  - Telomeric DNA ends are essential for the localization of Ku at telomeres in
      fission yeast.
AB  - The Ku70-Ku80 heterodimer is a conserved protein complex essential for the non
      homologous end-joining pathway. Ku proteins are also involved in telomere
      maintenance, although their precise roles remain to be elucidated. In fission
      yeast, pku70(+), the gene encoding the Ku70 homologue, has been reported. Here we
      report the identification and characterization of pku80(+), the gene encoding
      Ku80. Both pku70(+) and pku80(+) are essential for efficient non-homologous end
      joining. We also found that the pku70 and pku80 mutants are sensitive to methyl
      methanesulfonate and hydroxyurea, suggesting their roles in the S phase. The
      pku80 mutant shows telomere shortening and tandem amplification of a subtelomeric
      sequence but no defects in the telomere position effect, as was previously
      reported for the pku70 mutant. By using the chromatin immunoprecipitation assay,
      we demonstrated that Pku70 and Pku80 physically interact with telomeric repeats
      and subtelomeric sequences. Interestingly, this telomere association of Pku
      proteins is independent of Taz1, a telomeric DNA-binding protein. We also showed
      that the Pku proteins do not associate with ectopically integrated telomeric
      repeats in the internal region of circular chromosomes. These results indicate
      that the physical end of DNA is necessary for the localization of Pku80 at
      telomeres.

PMID- 12424245
TI  - Cell sorting experiments link persistent mitochondrial DNA damage with loss of
      mitochondrial membrane potential and apoptotic cell death.
AB  - In order to understand the molecular events following oxidative stress, which
      lead to persistence of lesions in the mtDNA, experiments were performed on normal
      human fibroblast (NHF) expressing human telomerase reverse transcriptase (hTERT).
      The formation and repair of H(2)O(2)-induced DNA lesions were examined using
      quantitative PCR. It was found that NHF hTERTs show extensive mtDNA damage (
      approximately 4 lesions/10 kb) after exposure to 200 microm H(2)O(2), which is
      partially repaired during a recovery period of 6 h. At the same time, the nDNA
      seemed to be completely resistant to damage. Cell sorting experiments revealed
      persistent mtDNA damage at 24 h only in the fraction of cells with low
      mitochondrial membrane potential (Delta Psi m). Further analysis also showed
      increased production of H(2)O(2) by these cells, which subsequently undergo
      apoptosis. This work supports a hypothesis for a feed-forward cascade of reactive
      oxygen species generation and mtDNA damage and also suggested a possible
      mechanism for persistence of lesions in the mtDNA involving a drop in Delta Psi
      m, compromised protein import, secondary reactive oxygen species generation, and
      loss of repair capacity.

PMID- 12424246
TI  - Differential role of actin, clathrin, and dynamin in Fc gamma receptor-mediated
      endocytosis and phagocytosis.
AB  - Clustering of macrophage Fc gamma receptors by multimeric immunoglobulin
      complexes leads to their internalization. Formation of small aggregates leads to
      endocytosis, whereas large particulate complexes induce phagocytosis. In RAW
      264.7 macrophages, Fc gamma receptor endocytosis was found to be dependent on
      clathrin and dynamin and insensitive to cytochalasin. Clathrin also associates
      with nascent phagosomes, and earlier observations suggested that it plays an
      essential role in phagosome formation. However, we find that phagocytosis of IgG
      coated large (> or =3 microm) particles was unaffected by inhibition of dynamin
      or by reducing the expression of clathrin using antisense mRNA but was eliminated
      by cytochalasin, implying a distinct mechanism dependent on actin assembly. The
      uptake of smaller particles (< or =1 microm) was only partially blocked by
      cytochalasin. Remarkably, the cytochalasin-resistant component was also
      insensitive to dominant-negative dynamin I and to clathrin antisense mRNA,
      implying the existence of a third internalization mechanism, independent of
      actin, dynamin, and clathrin. The uptake of small particles occurred by a process
      distinct from fluid phase pinocytosis, because it was not inhibited by dominant
      negative Rab5. The insensitivity of phagocytosis to dominant-negative dynamin I
      enabled us to test the role of dynamin in phagosomal maturation. Although
      internalization of receptors from the plasma membrane was virtually eliminated by
      the K44A and S45N mutants of dynamin I, clearance of transferrin receptors and of
      CD18 from maturing phagosomes was unaffected by these mutants. This implies that
      removal of receptors from the phagosomal membrane occurs by a mechanism that is
      different from the one mediating internalization of the same receptors at the
      plasma membrane. These results imply that, contrary to prevailing notions, normal
      dynamin and clathrin function is not required for phagocytosis and reveal the
      existence of a component of phagocytosis that is independent of actin and Rab5.

PMID- 12424247
TI  - Intermediate structural states involved in MRP1-mediated drug transport. Role of
      glutathione.
AB  - Human multidrug resistance protein 1 (MRP1) is a member of the ATP-binding
      cassette transporter family and transports chemotherapeutic drugs as well as
      diverse organic anions such as leukotriene LTC(4). The transport of
      chemotherapeutic drugs requires the presence of reduced GSH. By using
      hydrogen/deuterium exchange kinetics and limited trypsin digestion, the
      structural changes associated with each step of the drug transport process are
      analyzed. Purified MRP1 is reconstituted into lipid vesicles with an inside-out
      orientation, exposing its cytoplasmic region to the external medium. The
      resulting proteoliposomes have been shown previously to exhibit both ATP
      dependent drug transport and drug-stimulated ATPase activity. Our results show
      that during GSH-dependent drug transport, MRP1 does not undergo secondary
      structure changes but only modifications in its accessibility toward the external
      environment. Drug binding induces a restructuring of MRP1 membrane-embedded
      domains that does not affect the cytosolic domains, including the nucleotide
      binding domains, responsible for ATP hydrolysis. This demonstrates that drug
      binding to MRP1 is not sufficient to propagate an allosteric signal between the
      membrane and the cytosolic domains. On the other hand, GSH binding induces a
      conformational change that affects the structural organization of the cytosolic
      domains and enhances ATP binding and/or hydrolysis suggesting that GSH-mediated
      conformational changes are required for the coupling between drug transport and
      ATP hydrolysis. Following ATP binding, the protein adopts a conformation
      characterized by a decreased stability and/or an increased accessibility toward
      the aqueous medium. No additional change in the accessibility toward the solvent
      and/or the stability of this specific conformational state and no change of the
      transmembrane helices orientation are observed upon ATP hydrolysis. Binding of a
      non-transported drug affects the dynamic changes occurring during ATP binding and
      hydrolysis and restricts the movement of the drug and its release.

PMID- 12424248
TI  - A novel germ line-specific gene of the phosducin-like protein (PhLP) family. A
      meiotic function conserved from yeast to mice.
AB  - We identified a new member of the phosducin-like (PhLP) protein family that is
      predominantly, if not exclusively, expressed in male and female germ cells. In
      situ analysis on testis sections and analysis of purified spermatogenic cell
      fractions evidenced a stage-specific expression with high levels of RNA and
      protein in pachytene spermatocytes and round spermatids. Three mRNA species were
      detected, which correspond to different polyadenylation sites and vary in
      abundance during germ cell maturation. Only low levels of RNA were detected in
      whole ovary extracts, but expression of the protein became detectable within
      hours after hormonal induction of superovulation. The gene (Mgcphlp) is located
      on mouse chromosome 5 in the immediate vicinity of the Clock locus. The predicted
      amino acid sequence shows extensive similarities not only with the known
      mammalian PhLP proteins but also with the yeast phosducin-like protein Plp2,
      required for the production and growth of haploid cells. Expression of the murine
      protein was found to complement the defect of a yeast plp2 Delta mutant. We
      propose that MgcPhLP/Plp2 proteins exert a function in germ cell maturation that
      is conserved from yeast to mammals.

PMID- 12424249
TI  - Interfacial domains in Sindbis virus 6K protein. Detection and functional
      characterization.
AB  - Alphavirus 6K is a short, constitutive membrane protein involved in virus
      glycoprotein processing, membrane permeabilization, and the budding of virus
      particles. The amino-terminal region that immediately precedes the transmembrane
      anchor contains a conserved sequence motif consisting of two interfacial domains
      separated by Asn and Gln residues. The presence of this motif confers on the 6K
      pretransmembrane region the tendency to partition into the membrane interface. To
      study the functional importance of the interfacial sequences, three different
      Sindbis virus 6K variants were obtained with the following modifications:
      9YLW11xAAA, 18FWV20xAAA, and 9YLW11xAAA/18FWV20xAAA. Reconstituted mutant viruses
      were infectious and showed no defects in glycoprotein processing, although virus
      budding was hampered. Single 6K expression in Escherichia coli cells showed
      interfacial mutants to have a diminished capacity to modify membrane permeability
      and to have lower toxicity. In particular, the 9YLW11xAAA/18FWV20xAAA variant was
      expressed at high levels and did not enhance membrane permeability significantly,
      although it retained its integral membrane protein condition. Parallel analyses
      of membrane permeabilization in baby hamster kidney cells were carried out using
      a Sindbis virus replicon that synthesized both capsid protein and 6K.
      Transfection of the construct with wild-type 6K strongly increased permeability
      to the antibiotic hygromycin B. Replicons encoding 6K interfacial mutants induced
      lower membrane permeabilization. Again, the greatest impairment was observed for
      the 9YLW11xAAA/18FWV20xAAA variant, permeabilization activity of which was
      approximately 10% that of wild-type 6K. These findings show the importance of the
      interfacial 6K sequence for virus budding and modification of membrane
      permeability.

PMID- 12424250
TI  - Signaling through P2X7 receptor in human T cells involves p56lck, MAP kinases,
      and transcription factors AP-1 and NF-kappa B.
AB  - ATP-gated ion channel P2X receptors are expressed on the surface of most immune
      cells and can trigger multiple cellular responses, such as membrane
      permeabilization, cytokine production, and cell proliferation or apoptosis.
      Despite broad distribution and pleiotropic activities, signaling pathways
      downstream of these ionotropic receptors are still poorly understood. Here, we
      describe intracellular signaling events in Jurkat cells treated with millimolar
      concentrations of extracellular ATP. Within minutes, ATP treatment resulted in
      the phosphorylation and activation of p56(lck) kinase, extracellular signal
      regulated kinase (ERK), and c-Jun N-terminal kinase but not p38 kinase. These
      effects were wholly dependent upon the presence of extracellular Ca(2+) ions in
      the culture medium. Nevertheless, calmodulin antagonist calmidazolium and CaM
      kinase inhibitor KN-93 both had no effect on the activation of p56(lck) and ERK,
      whereas a pretreatment of Jurkat cells with MAP kinase kinase inhibitor P098059
      was able to abrogate phosphorylation of ERK. Further, expression of c-Jun and c
      Fos proteins and activator protein (AP-1) DNA binding activity were enhanced in a
      time-dependent manner. In contrast, DNA binding activity of NF-kappa B was
      reduced. ATP failed to stimulate the phosphorylation of ERK and c-Jun N-terminal
      kinase and activation of AP-1 in the p56(lck)-deficient isogenic T cell line
      JCaM1, suggesting a critical role for p56(lck) kinase in downstream signaling.
      Regarding the biological significance of the ATP-induced signaling events we show
      that although extracellular ATP was able to stimulate proliferation of both
      Jurkat and JCaM1 cells, an increase in interleukin-2 transcription was observed
      only in Jurkat cells. The nucleotide selectivity and pharmacological profile data
      supported the evidence that the ATP-induced effects in Jurkat cells were mediated
      through the P2X7 receptor. Taken together, these results demonstrate the ability
      of extracellular ATP to activate multiple downstream signaling events in a human
      T-lymphoblastoid cell line.

PMID- 12424251
TI  - Enhanced phagocytosis through inhibition of de novo ceramide synthesis.
AB  - Fcgamma receptors are important mediators of the binding of IgG to and induction
      of phagocytosis in neutrophils. COS-1 cells provide a potentially useful model
      for studying these receptors because transfection with the FcgammaRIIA renders
      these cells phagocytic. During FcgammaRIIA-mediated phagocytosis in COS-1 cells,
      endogenous ceramide levels increased 52% by 20 min (p < 0.01). Phospholipase D
      activity increased by 62% (p < 0.01). Correspondingly, the phagocytic index
      increased by 3.7-fold by 20 min. Two inhibitors of ceramide formation were used
      to assess the consequences of reduced ceramide generation. l-Cycloserine, an
      inhibitor that blocks serine palmitoyltransferase activity, lowered both
      sphingosine and ceramide levels. Under these conditions, the phagocytic index
      increased 100% in the presence of 2 mm l-cycloserine. The formation of ceramide
      resulting from the N-acylation of dihydrosphingosine or sphingosine by ceramide
      synthase is inhibited by the fungal toxin fumonisin B(1). When cells were treated
      with 5-50 microm fumonisin B(1), the cellular level of ceramide decreased in a
      concentration-dependent manner, while simultaneously the phagocytic index
      increased by 52%. Concomitantly, three indirect measures of FcgammaRIIA activity
      were altered with the fall in ceramide levels. Syk phosphorylation, phospholipase
      D activity, and mitogen-activated protein (MAP) kinase phosphorylation were
      increased at 30 min. When Syk phosphorylation was blocked with piceatannol and
      cells were similarly challenged, phosphatidylinositol 3-kinase activation was
      blocked, but no changes in either ceramide accumulation or MAP kinase activation
      were observed. Ceramide formation and MAP kinase activation are therefore not
      dependent on Syk kinase activity in this system. These results indicate that COS
      1 cells provide a useful model for the recapitulation of sphingolipid signaling
      in the study of phagocytosis. Ceramide formed by de novo synthesis may represent
      an important mechanism in the regulation of phagocytosis.

PMID- 12424252
TI  - The regulation and activation of ciliary neurotrophic factor signaling proteins
      in adipocytes.
AB  - Ciliary neurotrophic factor (CNTF) is primarily known for its roles as a lesion
      factor released by the ruptured glial cells that prevent neuronal degeneration.
      However, CNTF has also been shown to cause weight loss in a variety of rodent
      models of obesity/type II diabetes, whereas a modified form also causes weight
      loss in humans. CNTF administration can correct or improve hyperinsulinemia,
      hyperphagia, and hyperlipidemia associated with these models of obesity. In order
      to investigate the effects of CNTF on fat cells, we examined the expression of
      CNTF receptor complex proteins (LIFR, gp130, and CNTFRalpha) during adipocyte
      differentiation and the effects of CNTF on STAT, Akt, and MAPK activation. We
      also examined the ability of CNTF to regulate the expression of adipocyte
      transcription factors and other adipogenic proteins. Our studies clearly
      demonstrate that the expression of two of the three CNTF receptor complex
      components, CNTFRalpha and LIFR, decreases during adipocyte differentiation. In
      contrast, gp130 expression is relatively unaffected by differentiation. In
      addition, preadipocytes are more sensitive to CNTF treatment than adipocytes, as
      judged by both STAT 3 and Akt activation. Despite decreased levels of CNTFRalpha
      expression in fully differentiated 3T3-L1 adipocytes, CNTF treatment of these
      cells resulted in a time-dependent activation of STAT 3. Chronic treatment of
      adipocytes resulted in a substantial decrease in fatty-acid synthase and a
      notable decline in SREBP-1 levels but had no effect on the expression of
      peroxisome proliferator-activated receptor gamma, acrp30, adipocyte-expressed
      STAT proteins, or C/EBPalpha. However, CNTF resulted in a significant increase in
      IRS-1 expression. CNTFRalpha receptor expression was substantially induced in the
      fat pads of four rodent models of obesity/type II diabetes as compared with lean
      littermates. Moreover, we demonstrated that CNTF can activate STAT 3 in adipose
      tissue and skeletal muscle in vivo. In summary, CNTF affects adipocyte gene
      expression, and the specific receptor for this cytokine is induced in rodent
      models of obesity/type II diabetes.

PMID- 12424253
TI  - The tailspike protein of Shigella phage Sf6. A structural homolog of Salmonella
      phage P22 tailspike protein without sequence similarity in the beta-helix domain.
AB  - Bacteriophage Sf6 tailspike protein is functionally equivalent to the well
      characterized tailspike of Salmonella phage P22, mediating attachment of the
      viral particle to host cell-surface polysaccharide. However, there is significant
      sequence similarity between the two 70-kDa polypeptides only in the N-terminal
      putative capsid-binding domains. The major, central part of P22 tailspike
      protein, which forms a parallel beta-helix and is responsible for saccharide
      binding and hydrolysis, lacks detectable sequence homology to the Sf6 protein.
      After recombinant expression in Escherichia coli as a soluble protein, the Sf6
      protein was purified to homogeneity. As shown by circular dichroism and Fourier
      transform infrared spectroscopy, the secondary structure contents of Sf6 and P22
      tailspike proteins are very similar. Both tailspikes are thermostable homotrimers
      and resist denaturation by SDS at room temperature. The specific endorhamnosidase
      activities of Sf6 tailspike protein toward fluorescence-labeled dodeca-, deca-,
      and octasaccharide fragments of Shigella O-antigen suggest a similar active site
      topology of both proteins. Upon deletion of the N-terminal putative capsid
      binding domain, the protein still forms a thermostable, SDS-resistant trimer that
      has been crystallized. The observations strongly suggest that the tailspike of
      phage Sf6 is a trimeric parallel beta-helix protein with high structural
      similarity to its functional homolog from phage P22.

PMID- 12424254
TI  - N-formyl peptide receptor phosphorylation domains differentially regulate
      arrestin and agonist affinity.
AB  - Arrestins regulate the signaling and endocytosis of many G protein-coupled
      receptors (GPCRs). It has been suggested that the functions of arrestins are
      dependent upon both the number and pattern of phosphorylation sites present in an
      activated GPCR. However, little is currently known about the relationships
      between the sites of receptor phosphorylation, the resulting affinities of
      arrestin binding, and the ensuing mechanisms of receptor regulation for any given
      GPCR. To investigate these interactions, we used an active truncated mutant of
      arrestin (amino acids 1-382) and phosphorylation-deficient mutants of the N
      formyl peptide receptor (FPR). In contrast to results with wild type arrestins,
      the truncated arrestin-2 protein bound to the unphosphorylated wild type FPR,
      although with lower affinity and a low affinity for the agonist as revealed by
      competition studies with heterotrimeric G proteins. Using FPR mutants, we further
      demonstrated that the phosphorylation status of serines and threonines between
      residues 328-332 is a key determinant that regulates the affinity of the FPR for
      arrestins. Furthermore, we found that the phosphorylation status of serine and
      threonine residues between amino acids 334 and 339 regulates the affinity of the
      receptor for agonist when arrestin is bound. These results suggest that the
      agonist affinity state of the receptor is principally regulated by
      phosphorylation at specific sites and is not simply a consequence of arrestin
      binding as has previously been proposed. Furthermore, this is the first
      demonstration that agonist affinity of a GPCR and the affinity of arrestin
      binding to the phosphorylated receptor are regulated by distinct receptor
      phosphodomains.

PMID- 12424255
TI  - Characterization of the c-Myb-responsive region and regulation of the human type
      I collagen alpha 2 chain gene by c-Myb.
AB  - We have characterized the role of c-Myb and B-Myb in the regulation of human type
      I collagen alpha2 chain gene expression in fibroblastic cells. We have identified
      four Myb-binding sites (MBSs) in the promoter. Transactivation assays on wild
      type and mutant promoter-reporter constructs demonstrated that c-Myb, but not B
      Myb, can transactivate the human type I collagen alpha 2 chain gene promoter via
      the MBS-containing region. Electrophoretic mobility shift assay experiments
      showed that c-Myb specifically binds to each of the four MBS; however, the
      mutagenesis of site MBS-4 completely inhibited transactivation by c-Myb, at least
      in the full-length promoter. In agreement with these results, c-myb(-/-) mouse
      embryo fibroblasts (MEFs) showed a selective lack of expression of type I
      collagen alpha 2 chain gene but maintained the expression of fibronectin and type
      III collagen. Furthermore, transforming growth factor-beta induced type I
      collagen alpha 2 chain gene expression in c-myb(-/-) MEFs, implying that the
      transforming growth factor-beta signaling pathway is maintained and that the
      absence of COL1A2 gene expression in c-myb(-/-) MEFs is a direct consequence of
      the lack of c-Myb. The demonstration of the importance of c-Myb in the regulation
      of the type I collagen alpha 2 chain gene suggests that uncontrolled expression
      of c-Myb could be an underlying mechanism in the pathogenesis of several fibrotic
      disorders.

PMID- 12424256
TI  - Regulation of cellular and SV40 virus origins of replication by Chk1-dependent
      intrinsic and UVC radiation-induced checkpoints.
AB  - DNA replication is inhibited by DNA damage through cis effects on replication
      fork progression and trans effects associated with checkpoints. In this study, we
      employed a combined pulse labeling and neutral-neutral two-dimensional gel-based
      approach to compare the effects of a DNA damaging agent frequently employed to
      invoke checkpoints, UVC radiation, on the replication of cellular and simian
      virus 40 (SV40) chromosomes in intact cells. UVC radiation induced similar
      inhibitory effects on the initiation and elongation phases of cellular and SV40
      DNA replication. The initiation-inhibitory effects occurred independently of p53
      and were abrogated by the ATM and ATR kinase inhibitor caffeine, or the Chk1
      kinase inhibitor UCN-01. Inhibition of cellular origins was also abrogated by the
      expression of a dominant-negative Chk1 mutant. These results indicate that UVC
      induces a Chk1- and ATR or ATM-dependent checkpoint that targets both cellular
      and SV40 viral replication origins. Loss of Chk1 and ATR or ATM function also
      stimulated initiation of cellular and viral DNA replication in the absence of UVC
      radiation, revealing the existence of a novel intrinsic checkpoint that targets
      both cellular and SV40 viral origins of replication in the absence of DNA damage
      or stalled DNA replication forks. This checkpoint inhibits the replication in
      early S phase cells of a region of the repetitive rDNA locus that replicates in
      late S phase. The ability to detect these checkpoints using the well
      characterized SV40 model system should facilitate analysis of the molecular basis
      for these effects.

PMID- 12424257
TI  - Structure-function relationships in the stereospecific and manganese-dependent
      3,4-dihydroxyphenylalanine/tyrosine-sulfating activity of human monoamine-form
      phenol sulfotransferase, SULT1A3.
AB  - The human monoamine-form phenol sulfotransferase (PST), SULT1A3, has a unique 3,4
      dihydroxyphenylalanine (Dopa)/tyrosine-sulfating activity that is stereospecific
      for their d-form enantiomers and can be stimulated dramatically by Mn(2+). This
      activity is not present in the simple phenol-form PST, SULT1A1, which is
      otherwise >93% identical to SULT1A3 in amino acid sequence. The majority of the
      differences between these two proteins reside in two variable regions of their
      sequences. Through the characterization of chimeric PSTs where these two regions
      were exchanged between them, it was demonstrated that variable Region II of
      SULT1A3 is required for the stereospecificity of its Dopa/tyrosine-sulfating
      activity, whereas variable Region I of SULT1A3 is required for the stimulation by
      Mn(2+) of this activity. Further studies using point-mutated SULT1A3s mutated at
      amino acid residues in these two regions and deletional mutants missing residues
      84-86 and 84-90 implicate residue Glu-146 (in variable Region II of SULT1A3), as
      well as the presence of residues 84-90 of variable Region I, in the
      stereospecificity in the absence of Mn(2+). Residue Asp-86 (in variable Region I
      of SULT1A3), on the other hand, is critical in the Mn(2+) stimulation of the
      Dopa/tyrosine-sulfating activity of SULT1A3. A model is proposed, with reference
      to the reported x-ray crystal structure of SULT1A3, to explain how the normal
      role of SULT1A3 in dopamine regulation may be subverted in the presence of
      Mn(2+). These studies could be relevant in understanding the stereoselective
      action of SULT1A3 on chiral drugs.

PMID- 12424259
TI  - Responses of primate visual cortical neurons to stimuli presented by flash,
      saccade, blink, and external darkening.
AB  - Our visual experience constitutes an unending chain of transient events,
      including those caused by saccadic eye movements, by blinks, and by localized or
      global changes in the external world. The categorical perception of objects is
      maintained across different classes of transient events, suggesting that the
      neural circuitry underlying visual perception responds to different transient
      events in a similar manner. However, different sorts of transients do have
      different perceptual impacts: for example, the sudden changes in a scene due to a
      saccade or a blink do not disturb our perceptual continuity of a visual scene as
      much as an external change does. We recorded the responses of 103 single visual
      cortical neurons in two rhesus monkeys (V1: n = 38, V2: n = 19, V3V/VP: n = 30,
      V4V: n = 16) to the onset and offset of a visual stimulus that was elicited by
      four different conditions: 1) stimulus flashed on and off while the eyes remain
      fixed; 2) stimulus turned on and off along with the entire scene (external
      darkening); 3) stimulus constant, onset and offset induced by rapid saccadic eye
      movements; and 4) offset induced by an eyeblink. For most neurons the onset and
      offset of a visual stimulus elicited qualitatively similar responses regardless
      of condition. We found no systematic effect of different conditions across the
      neuronal population. Previously we have shown that when the visual scene is
      occluded by a blink V1 neuronal firing declines in a similar manner as when the
      external scene is darkened and the eyes left open. Here we show that this is also
      the case in V2, V3V/VP, and V4V. However, for a substantial minority of neurons,
      the response varied strongly as a function of the transient event. This overall
      pattern was the same in all four cortical areas studied here. We hypothesize that
      most neurons in visual cortex constitute a passive "filter bank", analyzing the
      scene for specific details regardless of condition. However, there are neurons
      that respond in a qualitatively different manner depending on how a stimulus is
      presented, and we hypothesize that these signals may be important for determining
      the perceptual salience of a visual event.

PMID- 12424260
TI  - Voluntary exercise induces a BDNF-mediated mechanism that promotes
      neuroplasticity.
AB  - We have investigated potential mechanisms by which exercise can promote changes
      in neuronal plasticity via modulation of neurotrophins. Rodents were exposed to
      voluntary wheel running for 3 or 7 days, and their lumbar spinal cord and soleus
      muscle were assessed for changes in brain-derived neurotrophic factor (BDNF), its
      signal transduction receptor (trkB), and downstream effectors for the action of
      BDNF on synaptic plasticity. Exercise increased the expression of BDNF and its
      receptor, synapsin I (mRNA and phosphorylated protein), growth-associated protein
      (GAP-43) mRNA, and cyclic AMP response element-binding (CREB) mRNA in the lumbar
      spinal cord. Synapsin I, a synaptic mediator for the action of BDNF on
      neurotransmitter release, increased in proportion to GAP-43 and trkB mRNA levels.
      CREB mRNA levels increased in proportion to BDNF mRNA levels. In separate
      experiments, the soleus muscle was paralyzed unilaterally via intramuscular
      botulinum toxin type A (BTX-A) injection to determine the effects of reducing the
      neuromechanical output of a single muscle on the neurotrophin response to motor
      activity. In sedentary BTX-A-treated rats, BDNF and synapsin I mRNAs were reduced
      below control levels in the spinal cord and soleus muscle. Exercise did not
      change the BDNF mRNA levels in the spinal cord of BTX-A-treated rats but further
      reduced the BDNF mRNA levels in the paralyzed soleus relative to the levels in
      sedentary BTX-A-treated rats. Exercise also restored synapsin I to near control
      levels in the spinal cord. These results indicate that basal levels of
      neuromuscular activity are required to maintain normal levels of BDNF in the
      neuromuscular system and the potential for neuroplasticity.

PMID- 12424261
TI  - Spontaneous development of synchronous oscillatory activity during maturation of
      cortical networks in vitro.
AB  - Recent studies have focused attention on mechanisms of spontaneous large-scale
      wavelike activity during early development of the neocortex. In this study, we
      describe and characterize synchronous neuronal activity that occurs in cultured
      cortical networks naturally without pharmacological intervention. The synchronous
      activity that can be detected by means of Fluo-3 fluorescence imaging starts to
      develop at the beginning of the second week in culture and eventually includes
      the entire neuronal population about 1 wk later. A synchronous increase of
      [Ca(2+)](i) in the neuronal population is associated with a burst of action
      potentials riding on a long-lasting depolarization recorded in a single cell. It
      is suggested that this depolarization results directly from synaptic current,
      which was comprised of at least three different components mediated by AMPA, N
      methyl-D-aspartate (NMDA), and GABA(A) receptors. We never observed a gradually
      depolarizing pacemaker potential and found no evidence for a change of
      excitability during inter-burst periods. However, we found evidence for a period
      of synaptic depression after bursts. Network excitability recovers gradually over
      seconds from this depression that can explain the episodic nature of spontaneous
      network activity. Using pharmacological manipulation to investigate the
      propagation of activity in the network, we show that synchronous network activity
      depends on both glutamatergic and GABA(A)ergic neurotransmission during a brief
      period. Reversal potential of GABA(A) receptor-mediated current was found to be
      significantly more positive than resting membrane potential both at 1 and 2 wk in
      culture, suggesting depolarizing action of GABA. However, in cultures older than
      2 wk, inhibition of GABA(A) receptors does not result in block of synchronous
      network activity but in modulation of burst width and frequency.

PMID- 12424262
TI  - Positive proprioceptive feedback elicited by isometric contractions of ankle
      flexors on pretibial motoneurons in cats.
AB  - Pretibial flexor motoneurons were recorded intracellularly in anesthetized cats
      during unfused isometric contractions of a subpopulation of motor units from
      either tibialis anterior (TA) or extensor digitorum longus (EDL) muscles. The
      contractions elicited excitatory postsynaptic potentials in 23 of 28 pretibial
      flexor motoneurons. No effect was observed in the remaining motoneurons. In
      control experiments, the effects of electrical stimulation of afferents within
      the TA nerve were investigated to help identify afferents responsible for the
      contraction-induced positive feedback. This feedback was ascribed to actions of
      Ia fibers because the pattern of the contraction-induced excitatory potentials
      was consistent with the known pattern of Ia discharge; in control experiments,
      electrical stimulation of group I fibers elicited only monosynaptic excitatory
      potentials; and the distribution of both the contraction-induced positive
      feedback among motor nuclei as well as the electrically evoked Ia excitatory
      monosynaptic potentials were restricted to homonymous and synergic motoneurons.
      Observation of the Ia contraction-induced positive feedback was facilitated by
      the absence of Ib autogenic inhibition. This contraction-induced Ia excitatory
      feedback in ankle flexors might either reinforce Ia-induced reflexes when these
      muscles are lengthened or help to lift the leg over an obstacle.

PMID- 12424263
TI  - Upper thoracic respiratory interneurons integrate noxious somatic and visceral
      information in rats.
AB  - The aim of this study was to determine if thoracic respiratory interneurons
      (TRINs) might receive peripheral noxious somatic and visceral inputs.
      Extracellular potentials of 78 respiration-related T(3) neurons, whose activity
      was driven by central respiratory output, were recorded from the intermediate
      zone in pentobarbital anesthetized, paralyzed, and ventilated male rats. These
      neurons were identified as interneurons by their locations and by the absence of
      antidromic activation from the cervical sympathetic trunk and cerebellum.
      Thoracic esophageal distension (ED) was produced by water inflation of a latex
      balloon (0.1-0.5 ml, 20 s). A catheter was placed in the pericardial sac to
      administer 0.2 ml bradykinin (10(-5) M) for noxious cardiac stimulation. Of 78
      TRINs examined for ED, activity of 24 TRINs increased and activity of 8 TRINs
      decreased. Intrapericardial bradykinin increased activity in 26/65 TRINs tested
      and decreased activity in 5 TRINs. Seventy-four TRINs were tested for effects of
      brush, pressure, and pinch of the chest and upper back areas. No TRINs responded
      to brushing hair. Low-threshold responses to pressure were observed in 27 TRINs.
      Fourteen TRINs were wide dynamic range and 4 TRINs had high-threshold responses.
      Peripheral stimuli affected all types of TRINs, including inspiratory,
      expiratory, and biphasic neurons. Simultaneous phrenic recordings showed that
      effects of various somatic and visceral stimuli on TRINs were independent of
      central respiratory drive. Various somatovisceral and viscerovisceral patterns of
      input were observed in TRINs. The results suggested that TRINs participate in
      intraspinal processing and integration of nociceptive information from somatic
      fields and visceral organs.

PMID- 12424264
TI  - Direction-selective neurons in the optokinetic system with long-lasting after
      responses.
AB  - We describe the responses during and after motion of slow cells, which are a
      class of direction-selective neurons in the pretectal nucleus of the optic tract
      (NOT) of the wallaby. Neurons in the NOT respond to optic flow generated by head
      movements and drive compensatory optokinetic eye movements. Motion in the
      preferred direction produces increased firing rates in the cells, whereas motion
      in the opposite direction inhibits their high spontaneous activities. Neurons
      were stimulated with moving spatial sinusoidal gratings through a range of
      temporal and spatial frequencies. The slow cells were maximally stimulated at
      temporal frequencies <1 Hz and spatial frequencies of 0.13-1 cpd. During motion,
      the responses oscillate at the fundamental temporal frequency of the grating but
      not at higher-order harmonics. There is prolonged excitation after preferred
      direction motion and prolonged inhibition after anti-preferred direction motion,
      which are referred to as same-sign after-responses (SSARs). This is the first
      time that the response properties of neurons with SSARs have been reported and
      modeled in detail for neurons in the NOT. Slow cell responses during and after
      motion are modeled using an array of Reichardt-type motion detectors that include
      band-pass temporal prefilters. The oscillatory behavior during motion and the
      SSARs can be simulated accurately with the model by manipulating time constants
      associated with temporal filtering in the prefilters and motion detectors. The
      SSARs of slow cells are compared with those of previously described direction
      selective neurons, which usually show transient inhibition or excitation after
      preferred or anti-preferred direction motion, respectively. Possible functional
      roles for slow cells are discussed in the context of eye movement control.

PMID- 12424265
TI  - Neck muscle vibration and spatial orientation during stepping in place in humans.
AB  - Unilateral long-lasting vibration was applied to the sternomastoid muscle to
      assess the influence of asymmetric neck proprioceptive input on body orientation
      during stepping-in-place. Blindfolded subjects performed 3 sequences of 3 trials,
      each lasting 60 s: control, vibration applied during stepping (VDS), and
      vibration applied before stepping (VBS). VDS caused clear-cut whole body rotation
      toward the side opposite to vibration. The body rotated around a vertical axis
      placed at about arm's length from the body. The rotation did not begin
      immediately on switching on the vibrator. The delay varied from subject to
      subject from a few seconds to about 10 s. Once initiated, the angular velocity of
      rotation was remarkably constant (about 1 degrees /s). In VBS, at the beginning
      of stepping, subjects rotated for a while as if their neck were still vibrated.
      At a variable delay, the direction of rotation reversed, and the effects were
      opposite to those observed during VDS. Under no condition did head rotation, head
      roll, or lateral body tilt accompany rotation. The results confirm and extend the
      notion that the neck proprioceptive input plays a major role in body orientation
      during locomotion. The body rotation does not seem to depend on the same
      mechanisms that modify the erect posture; rather, the asymmetric neck input would
      seem to modify the egocentric body-centered coordinate system.

PMID- 12424266
TI  - Persistent sodium current, membrane properties and bursting behavior of pre
      botzinger complex inspiratory neurons in vitro.
AB  - We measured persistent Na(+) current and membrane properties of bursting
      pacemaker and nonbursting inspiratory neurons of the neonatal rat pre-Botzinger
      complex (pre-BotC) in brain stem slice preparations with a rhythmically active
      respiratory network in vitro. In whole-cell recordings, slow voltage ramps
      (</=100 mV/s) inactivated the fast, spike-generating Na(+) current and yielded N
      shaped current-voltage relationships with nonmonotonic, negative-slope regions
      between -60 and -35 mV when the voltage-sensitive component was isolated. The
      underlying current was a TTX-sensitive persistent Na(+) current (I(NaP)) since
      the inward current was present at slow voltage ramp speeds (3.3-100 mV/s) and the
      current was blocked by 1 microM TTX. We measured the biophysical properties of
      I(NaP) after subtracting the voltage-insensitive "leak" current (I(Leak)) in the
      presence of Cd(2+) and in some cases tetraethylammonium (TEA). Peak I(NaP) ranged
      from -50 to -200 pA at a membrane potential of -30 mV. Decreasing the speed of
      the voltage ramp caused time-dependent I(NaP) inactivation, but this current was
      present at ramp speeds as low as 3.3 mV/s. I(NaP) activated at -60 mV and
      obtained half-maximal activation near -40 mV. The subthreshold voltage dependence
      and slow inactivation kinetics of I(NaP), which closely resemble those of I(NaP)
      mathematically modeled as a burst-generation mechanism in pacemaker neurons of
      the pre-BotC, suggest that I(NaP) predominantly influences bursting dynamics of
      pre-BotC inspiratory pacemaker neurons in vitro. We also found that the ratio of
      persistent Na(+) conductance to leak conductance (g(NaP)/g(Leak)) can distinguish
      the phenotypic subpopulations of bursting pacemaker and nonbursting inspiratory
      neurons: pacemaker neurons showed g(NaP)/g(Leak) > g(NaP)/g(Leak) in nonpacemaker
      cells (P < 0.0002). We conclude that I(NaP) is ubiquitously expressed by pre-BotC
      inspiratory neurons and that bursting pacemaker behavior within the heterogeneous
      population of inspiratory neurons is achieved with specific ratios of these two
      conductances, g(NaP) and g(Leak).

PMID- 12424267
TI  - Functional segregation of ITD sensitivity in the inferior colliculus of
      decerebrate cats.
AB  - Decerebration allows single-unit responses in the central nucleus of the inferior
      colliculus (ICC) to be studied in the absence of anesthesia and descending
      efferent influences. When this procedure is applied to cats, three neural
      response types (V, I, and O) can be identified by distinct patterns of excitation
      and inhibition in pure-tone frequency-response maps. Similarities of the
      definitive response map features with those of projection neurons in the auditory
      brain stem have led to the proposal that the ICC response types are derived from
      different sources of ascending input that remain functionally segregated within
      the midbrain. Additional evidence for the existence of these hypothesized
      parallel processing pathways has been obtained in our previous investigations of
      the effects of interaural level differences, brain stem lesions, and
      pharmacological manipulations on physiologically classified units. This study
      extends our characterization of the functional segregation of single-unit
      activity in the ICC by investigating how sensitivity to interaural time
      differences (ITDs) is related to the response types that are observed in
      decerebrate cats. The results of these experiments support our parallel
      processing model of the ICC by linking the ITD sensitivity of type V and I units
      to putative inputs from the medial superior olive and lateral superior olive and
      by showing that most type O units lack a systematic sensitivity to binaural
      temporal information presumably because their dominant ascending inputs arise
      from weakly binaural neurons in the dorsal cochlear nucleus.

PMID- 12424268
TI  - Rhythmic properties of neurons in the rostral ventrolateral medulla of the rat in
      vitro: effects of clonidine.
AB  - The rostral ventrolateral medulla (RVLM) is thought to be the main central site
      for generation of tonic sympathetic activity. In the rat in vitro slice
      preparation, we used intracellular recordings to identify different populations
      of neurons in the RVLM: 43 spontaneously active neurons with regular (R) or
      irregular (I) patterns of spike firing and 10 silent neurons. The degree of
      regularity was quantified by the coefficient of variation (CV = SD/mean) of
      interspike interval durations, as well as by the rhythmic properties of the spike
      autospectrum and autocorrelation. The distribution of CVs was clustered: R and I
      neurons were defined as those with CVs </=12% (n = 21) or >12% (n = 22),
      respectively. The R-type and I-type neurons resemble the type II and type I
      neurons, respectively, which were previously characterized in the RVLM in vivo as
      barosensitive and bulbospinal. Both types may be important in generation of
      sympathetic tone. Clonidine (1-100 microM) was applied to 10 R-type neurons and
      16 I-type neurons. The firing of 21/26 was depressed to the point of silence.
      However, 18/26 neurons were excited earlier in the perfusion. The later
      depression of firing occurred in both I and R neurons and in different cases was
      associated with either hyperpolarization or depolarization.

PMID- 12424269
TI  - Interhemispheric sleep EEG asymmetry in the rat is enhanced by sleep deprivation.
AB  - Vigilance state-related topographic variations of electroencephalographic (EEG)
      activity have been reported in humans and animals. To investigate their possible
      functional significance, the cortical EEG of the rat was recorded from frontal
      and parietal derivations in both hemispheres. Records were obtained for a 24-h
      baseline day, 6-h sleep deprivation (SD), and subsequent 18-h recovery. During
      the baseline 12-h light period, the main sleep period of the rat, low-frequency
      (<7.0 Hz) power in the non-rapid eye-movement (NREM) sleep EEG declined
      progressively. Left-hemispheric predominance of low-frequency power at the
      parietal derivations was observed at the beginning of the light period when sleep
      pressure is high due to preceding spontaneous waking. The left-hemispheric
      dominance changed to a right-hemispheric dominance in the course of the 12-h rest
      phase when sleep pressure dissipated. During recovery from SD, both low-frequency
      power and parietal left-hemispheric predominance were enhanced. The increase in
      low-frequency power in NREM sleep observed after SD at the frontal site was
      larger than at the parietal site. However, frontally no interhemispheric
      differences were present. In REM sleep, power in the theta band (5.25-8.0 Hz)
      exhibited a right-hemispheric predominance. In contrast to NREM sleep, the
      hemispheric asymmetry showed no trend during baseline and was not affected by SD.
      Use-dependent local changes may underlie the regional differences in the low
      frequency NREM sleep EEG within and between hemispheres. The different
      interhemispheric asymmetries in NREM and REM sleep suggest that the two sleep
      states may subserve different functions in the brain.

PMID- 12424270
TI  - Patterns of canal and otolith afferent input convergence in frog second-order
      vestibular neurons.
AB  - Second-order vestibular neurons (2 degrees VN) were identified in the isolated
      frog brain by the presence of monosynaptic excitatory postsynaptic potentials
      (EPSPs) after separate electrical stimulation of individual vestibular nerve
      branches. Combinations of one macular and the three semicircular canal nerve
      branches or combinations of two macular nerve branches were stimulated separately
      in different sets of experiments. Monosynaptic EPSPs evoked from the utricle or
      from the lagena converged with monosynaptic EPSPs from one of the three
      semicircular canal organs in ~30% of 2 degrees VN. Utricular afferent signals
      converged predominantly with horizontal canal afferent signals (74%), and lagenar
      afferent signals converged with anterior vertical (63%) or posterior vertical
      (37%) but not with horizontal canal afferent signals. This convergence pattern
      correlates with the coactivation of particular combinations of canal and otolith
      organs during natural head movements. A convergence of afferent saccular and
      canal signals was restricted to very few 2 degrees VN (3%). In contrast to the
      considerable number of 2 degrees VN that received an afferent input from the
      utricle or the lagena as well as from one of the three canal nerves (~30%),
      smaller numbers of 2 degrees VN (14% of each type of 2 degrees otolith or 2
      degrees canal neuron) received an afferent input from only one particular otolith
      organ or from only one particular semicircular canal organ. Even fewer 2 degrees
      VN received an afferent input from more than one semicircular canal or from more
      than one otolith nerve (~7% each). Among 2 degrees VN with afferent inputs from
      more than one otolith nerve, an afferent saccular nerve input was particularly
      rare (4-5%). The restricted convergence of afferent saccular inputs with other
      afferent otolith or canal inputs as well as the termination pattern of saccular
      afferent fibers are compatible with a substrate vibration sensitivity of this
      otolith organ in frog. The ascending and/or descending projections of identified
      2 degrees VN were determined by the presence of antidromic spikes. 2 degrees VN
      mediating afferent utricular and/or semicircular canal nerve signals had
      ascending and/or descending axons. 2 degrees VN mediating afferent lagenar or
      saccular nerve signals had descending but no ascending axons. The latter result
      is consistent with the absence of short-latency macular signals on extraocular
      motoneurons during vertical linear acceleration. Comparison of data from frog and
      cat demonstrated the presence of a similar organization pattern of maculo- and
      canal-ocular reflexes in both species.

PMID- 12424271
TI  - Block of glutamate-glutamine cycle between astrocytes and neurons inhibits
      epileptiform activity in hippocampus.
AB  - Recurrent epileptiform activity occurs spontaneously in cultured CNS neurons and
      in brain slices in which GABA inhibition has been blocked. We demonstrate here
      that pharmacological treatments resulting in either the block of glutamine
      production by astrocytes or the inhibition of glutamine uptake by neurons
      suppress or markedly decrease the frequency of spontaneous epileptiform
      discharges both in primary hippocampal cultures and in disinhibited hippocampal
      slices. These data point to an important role for the neuron-astrocyte metabolic
      interaction in sustaining episodes of intense rhythmic activity in the CNS, and
      thereby reveal a new potential target for antiepileptic treatments.

PMID- 12424272
TI  - Segregation of ON and OFF retinogeniculate connectivity directed by patterned
      spontaneous activity.
AB  - In many parts of the developing nervous system, the early patterns of
      connectivity are refined by processes that require neuronal activity. These
      processes are thought to involve Hebbian mechanisms that lead to strengthening
      and maintenance of inputs that display correlated pre- and postsynaptic activity
      and elimination of inputs that fire asynchronously. Here we investigated the role
      of patterned spontaneous retinal activity and Hebbian synaptic mechanisms on
      segregation of ON and OFF retinal afferents in the dorsal lateral geniculate
      nucleus (dLGN) of the developing ferret visual system. We recorded
      extracellularly the spontaneous spike activity of neighboring pairs of ganglion
      cells and found that OFF cells have significantly higher mean firing rates than
      ON cells. Spiking is best correlated between cells of the same sign (ON, ON; OFF,
      OFF) compared with cells of opposite sign (ON, OFF). We then constructed a simple
      Hebbian model of retinogeniculate synaptic development based on a correlational
      framework. Using our recorded activity patterns, together with previous calcium
      imaging data, we show that endogenous retinal activity, coupled with Hebbian
      mechanisms of synaptic development, can drive the segregation of ON and OFF
      retinal inputs to the dLGN. Segregation occurs robustly when heterosynaptic
      competition is present within time windows of 50-500 ms. In addition, our results
      suggest that the initial patterns of connectivity (biases in convergence of
      inputs) and the strength of inhibition in the network each play a crucial role in
      determining whether ON or OFF inputs dominate at maturity.

PMID- 12424273
TI  - Encoding of sound localization cues by an identified auditory interneuron:
      effects of stimulus temporal pattern.
AB  - An important cue for sound localization is binaural comparison of stimulus
      intensity. Two features of neuronal responses, response strength, i.e., spike
      count and/or rate, and response latency, vary with stimulus intensity, and
      binaural comparison of either or both might underlie localization. Previous
      studies at the receptor-neuron level showed that these response features are
      affected by the stimulus temporal pattern. When sounds are repeated rapidly, as
      occurs in many natural sounds, response strength decreases and latency increases,
      resulting in altered coding of localization cues. In this study we analyze
      binaural cues for sound localization at the level of an identified pair of
      interneurons (the left and right AN2) in the cricket auditory system, with
      emphasis on the effects of stimulus temporal pattern on binaural response
      differences. AN2 spike count decreases with rapidly repeated stimulation and
      latency increases. Both effects depend on stimulus intensity. Because of the
      difference in intensity at the two ears, binaural differences in spike count and
      latency change as stimulation continues. The binaural difference in spike count
      decreases, whereas the difference in latency increases. The proportional changes
      in response strength and in latency are greater at the interneuron level than at
      the receptor level, suggesting that factors in addition to decrement of receptor
      responses are involved. Intracellular recordings reveal that a slowly building,
      long-lasting hyperpolarization is established in AN2. At the same time, the level
      of depolarization reached during the excitatory postsynaptic potential (EPSP)
      resulting from each sound stimulus decreases. Neither these effects on membrane
      potential nor the changes in spiking response are accounted for by contralateral
      inhibition. Based on comparison of our results with earlier behavioral
      experiments, it is unlikely that crickets use the binaural difference in latency
      of AN2 responses as the main cue for determining sound direction, leaving the
      difference in response strength, i.e., spike count and/or rate, as the most
      likely candidate.

PMID- 12424274
TI  - Relationship between jaw stiffness and kinematic variability in speech.
AB  - Humans produce speech by controlling a complex biomechanical apparatus to achieve
      desired speech sounds. We show here that kinematic variability in speech may be
      influenced by patterns of jaw stiffness. A robotic device was used to deliver
      mechanical perturbations to the jaw to quantify its stiffness in the mid-sagittal
      plane. Measured jaw stiffness was anisotropic. Stiffness was greatest along a
      protrusion-retraction axis and least in the direction of jaw raising and
      lowering. Consistent with the idea that speech movements reflect directional
      asymmetries in jaw stiffness, kinematic variability during speech production was
      found to be high in directions in which stiffness is low and vice versa. In
      addition, for higher jaw elevations, stiffness was greater and kinematic
      variability was less. The observed patterns of kinematic variability were not
      specific to speech-similar patterns appeared in speech and nonspeech movements.
      The empirical patterns of stiffness were replicated by using a physiologically
      based model of the jaw. The simulation studies support the idea that the pattern
      of jaw stiffness is affected by musculo-skeletal geometry and muscle-force
      generating abilities with jaw geometry being the primary determinant of the
      orientation of the stiffness ellipse.

PMID- 12424275
TI  - Loud sound-induced changes in cochlear mechanics.
AB  - To investigate the inner ear response to intense sound and the mechanisms behind
      temporary threshold shifts, anesthetized guinea pigs were exposed to tones at 100
      112 dB SPL. Basilar membrane vibration was measured using laser velocimetry, and
      the cochlear microphonic potential, compound action potential of the auditory
      nerve, and local electric AC potentials in the organ of Corti were used as
      additional indicators of cochlear function. After exposure to a 12-kHz intense
      tone, basilar membrane vibrations in response to probe tones at the
      characteristic frequency of the recording location (17 kHz) were transiently
      reduced. This reduction recovered over the course of 50 ms in most cases. Organ
      of Corti AC potentials were also reduced and recovered with a time course similar
      to the basilar membrane. When using a probe tone at either 1 or 4 kHz, organ of
      Corti AC potentials were unaffected by loud sound, indicating that transducer
      channels remained intact. In most experiments, both the basilar membrane and the
      cochlear microphonic response to the 12-kHz overstimulation was constant
      throughout the duration of the intense stimulus, despite a large loss of cochlear
      sensitivity. It is concluded that the reduction of basilar membrane velocity that
      followed loud sound was caused by changes in cochlear amplification and that the
      cochlear response to intense stimulation is determined by the passive mechanical
      properties of the inner ear structures.

PMID- 12424276
TI  - Hippocampus retains the periodicity of gamma stimulation in vivo.
AB  - Several behavioral state dependent oscillatory rhythms have been identified in
      the brain. Of these neuronal rhythms, gamma (20-70 Hz) oscillations are prominent
      in the activated brain and are associated with various behavioral functions
      ranging from sensory binding to memory. Hippocampal gamma oscillations represent
      a widely studied band of frequencies co-occurring with information acquisition.
      However, induction of specific gamma frequencies within the hippocampal neuronal
      network has not been satisfactorily established. Using both in vivo intracellular
      and extracellular recordings from anesthetized rats, we show that hippocampal CA1
      pyramidal cells can discharge at frequencies determined by the preceding gamma
      stimulation, provided that the gamma is introduced in theta cycles, as occurs in
      vivo. The dynamic short-term alterations in the oscillatory discharge described
      in this paper may serve as a coding mechanism in cortical neuronal networks.

PMID- 12424277
TI  - Reaching to grasp with a multi-jointed arm. I. Computational model.
AB  - The generation of goal-directed movements requires the solution of many difficult
      computational problems. Among these are transformations from extrinsic to
      intrinsic reference frames, specifying solution paths, removing under
      specification due to excess degrees of freedom and path multiplicity, constraint
      satisfaction, and error correction. There are no current motor-control
      computational models that address these issues in the context of realistic arm
      movement with redundant degrees of freedom. In this paper, we conjecture there is
      a geometric stage between sensory input and physical execution. The geometric
      stage determines movement trajectories independently of forces. It uses a
      gradient technique that relies on the metric of the space of postures to resolve
      endpoint path selection, posture-change specification, error correction, and
      multiple constraint satisfaction on-line without preplanning. The model is
      instantiated in an arm with seven degrees of freedom that moves in three
      dimensional space. Simulated orientation-matching movements are compared with
      actual human movement data to assess the validity of several of the model's
      behavioral predictions.

PMID- 12424278
TI  - Combined influence of vergence and eye position on three-dimensional vestibulo
      ocular reflex in the monkey.
AB  - This study examined two kinematical features of the rotational vestibulo-ocular
      reflex (VOR) of the monkey in near vision. First, is there an effect of eye
      position on the axes of eye rotation during yaw, pitch and roll head rotations
      when the eyes are converged to fixate near targets? Second, do the three
      dimensional positions of the left and right eye during yaw and roll head
      rotations obey the binocular extension of Listing's law (L2), showing eye
      position planes that rotate temporally by a quarter as far as the angle of
      horizontal vergence? Animals fixated near visual targets requiring 17 or 8.5
      degrees vergence and placed at straight ahead, 20 degrees up, down, left, or
      right during yaw, pitch, and roll head rotations at 1 Hz. The 17 degrees vergence
      experiments were performed both with and without a structured visual background,
      the 8.5 degrees vergence experiments with a visual background only. A 40 degrees
      horizontal change in eye position never influenced the axis of eye rotation
      produced by the VOR during pitch head rotation. Eye position did not affect the
      VOR eye rotation axes, which stayed aligned with the yaw and roll head rotation
      axes, when torsional gain was high. If torsional gain was low, eccentric eye
      positions produced yaw and roll VOR eye rotation axes that tilted somewhat in the
      directions predicted by Listing's law, i.e., with or opposite to gaze during yaw
      or roll. These findings were seen in both visual conditions and in both vergence
      experiments. During yaw and roll head rotations with a 40 degrees vertical change
      in gaze, torsional eye position followed on average the prediction of L2: the
      left eye showed counterclockwise (ex-) torsion in down gaze and clockwise (in-)
      torsion in up gaze and vice versa for the right eye. In other words, the left and
      right eye's position plane rotated temporally by about a quarter of the
      horizontal vergence angle. Our results indicate that torsional gain is the
      central mechanism by which the brain adjusts the retinal image stabilizing
      function of the VOR both in far and near vision and the three dimensional eye
      positions during yaw and roll head rotations in near vision follow on average the
      predictions of L2, a kinematic pattern that is maintained by the saccadic/quick
      phase system.

PMID- 12424279
TI  - OFF responses in the auditory thalamus of the guinea pig.
AB  - ON and OFF auditory responses were examined in the medial geniculate body (MGB)
      of the guinea pig. Single- and multiunit recordings were carried out on 12
      anesthetized animals, and noise-burst or pure-tone stimuli were applied to the
      ear contralateral to the recording hemisphere. One hundred and thirty-five OFF or
      ON-OFF neurons and 160 ON neurons were studied, and the tuning curves of 21 ON
      OFF or OFF neurons were examined from various nuclei of the MGB. The mean minimum
      threshold of the OFF responses (40.8 +/- 20.0 dB SPL, mean +/- SD; range: 0-80 dB
      SPL) was significantly higher than that of the ON responses (28.5 +/- 17.6 dB
      SPL, range: 0-60 dB SPL; n = 17, P < 0.001). Of 10 ON-OFF neurons that showed
      identifiable tuning frequencies for both ON and OFF responses, 7 showed a higher
      OFF than ON best frequency (BF), 2 showed the same BF for both ON and OFF, and
      only 1 showed a slightly lower OFF than ON BF. Most OFF responses sampled from
      the borders of the ventral (MGv) and the rostromedial (MGrm) nuclei of the MGB
      showed single-peaked tuning curves, similar to those of the ON responses in the
      MGv. The neurons located in the shell (MGs) and dorsal (MGd) nuclei of the MGB
      showed complicated-either multi-peaked or broad-tuning curves. All OFF responses
      showed long-duration-selectivity for acoustic stimuli: the mean half-maximum
      duration was 116.5 +/- 114.8 ms (n = 19, range: 27-411 ms). The latencies of 135
      OFF responses were studied in various divisions of the MGB. The ventral border
      region of MGv showed the shortest latency, followed by the dorsal border region
      of the MGv, the MGrm, and the caudomedial nucleus (MGcm) of the MGB. The
      posterior nucleus of the thalamus (Po), the MGd, and the MGs showed much longer
      mean latencies of >30 ms (P < 0.05 compared with the border regions of the MGv,
      ANOVA), with Po showing the greatest mean latency of 60.3 ms and the greatest
      deviation of 25.5 ms). The latency of the OFF response (29.0 +/- 14.0 ms, n =
      135) was significantly greater than that of the ON response (15.6 +/- 9.6 ms, n =
      160, P < 0.001). The present results provide valuable information about the
      threshold, frequency tuning characteristics, minimal response latency, and
      duration selectivity of OFF neurons in the auditory thalamus.

PMID- 12424280
TI  - Activity-dependent sensitivity of proprioceptive sensory neurons in the stick
      insect femoral chordotonal organ.
AB  - Mechanosensory neurons exhibit a wide range of dynamic changes in response,
      including rapid and slow adaptation. In addition to mechanical factors,
      electrical processes may also contribute to sensory adaptation. We have
      investigated adaptation of afferent neurons in the stick insect femoral
      chordotonal organ (fCO). The fCO contains sensory neurons that respond to
      position, velocity, and acceleration of the tibia. We describe the influence of
      random mechanical stimulation of the fCO on the response of fCO afferent neurons.
      The activity of individual sensory neurons was recorded intracellularly from
      their axons in the main leg nerve. Most fCO afferents (93%) exhibited a marked
      decrease in response to trapezoidal stimuli following sustained white noise
      stimulation (bandwidth = 60 Hz, amplitudes from +/-5 to +/-30 degrees ).
      Concurrent decreases in the synaptic drive to leg motoneurons and interneurons
      were also observed. Electrical stimulation of spike activity in individual fCO
      afferents in the absence of mechanical stimulation also led to a dramatic
      decrease in response in 15 of 19 afferents tested. This indicated that electrical
      processes are involved in the regulation of the generator potential or encoding
      of action potentials and partially responsible for the decreased response of the
      afferents. Replacing Ca(2+) with Ba(2+) in the saline surrounding the fCO greatly
      reduced or blocked the decrease in response elicited by electrically induced
      activity or mechanical stimulation when compared with control responses. Our
      results indicate that activity of fCO sensory neurons strongly affects their
      sensitivity, most likely via Ca(2+)-dependent processes.

PMID- 12424281
TI  - Circle-drawing movements at different speeds: role of inertial anisotropy.
AB  - This study investigated the role of inertial anisotropy at the hand in causing
      distortions in movement. Subjects drew circles in the horizontal plane at four
      locations in the workspace at three instructed paces using elbow and shoulder
      movements. Specifically, we tested two hypotheses, which we would expect if the
      anisotropy of inertia were not completely accounted for by the CNS when
      generating circle-drawing movements: 1) speed will affect the circularity of
      figures, with faster movements associated with greater elongation into an oval
      shape, irrespective of workspace location for configurations with a similar angle
      between the forearm and upper arm. 2) The elongation of the circle at fast speeds
      will be in the direction of least inertia. The results showed that despite
      individual differences in the speed dependence of the relative motions at the
      elbow and the shoulder, the circularity decreased (distortion increased) with
      increased speed, and workspace location had no effect on circularity. We also
      found that the elongation of the circles at fast speeds was in a direction close
      to but significantly different from the direction of least inertia for three
      workspace locations and was in the direction of least inertia for the fourth
      location. We suggest that the elongation results from lack of full accounting by
      the CNS of the anisotropy of viscosity and inertia.

PMID- 12424282
TI  - Handedness: dominant arm advantages in control of limb dynamics.
AB  - Recent findings from our laboratory suggest that a major factor distinguishing
      dominant from nondominant arm performance is the ability by which the effects of
      intersegmental dynamics are controlled by the CNS. These studies indicated that
      the dominant arm reliably used more torque-efficient patterns for movements made
      with similar speeds and accuracy than nondominant arm movements. Whereas,
      nondominant hand-path curvatures systematically varied with the amplitude of the
      interaction torques transferred between the segments of the moving limb, dominant
      hand-path curvatures did not. However, our previous studies did not distinguish
      whether dominant arm coordination advantages emerged from more effective control
      of dynamic factors or were simply a secondary effect of planning different
      kinematics. The purpose of this study was to further investigate interlimb
      differences in coordination through analysis of inverse dynamics and
      electromyography recorded during the performance of reaching movements. By
      controlling the amplitude of intersegmental dynamics in the current study, we
      were able to assess whether systematic differences in torque-efficiency exist,
      even when differences in hand-path shape were minimal. Subject's arms were
      supported in the horizontal plane by a frictionless air-jet system and were
      constrained to movements about the shoulder and elbow joints. Two targets were
      designed, such that the interaction torques elicited at the elbow were either
      large or small. Our results showed that the former produced large differences in
      hand-path curvature, whereas the latter did not. Additionally, the movements with
      small differences in hand-path kinematics showed substantial differences in
      torque patterns and corresponding EMG profiles which implied a more torque
      efficient strategy for the dominant arm. In view of these findings we propose
      that distinct neural control mechanisms are employed for dominant and nondominant
      arm movements.

PMID- 12424283
TI  - Frequency selectivity of layer II stellate cells in the medial entorhinal cortex.
AB  - Electrophysiologically, stellate cells (SCs) from layer II of the medial
      entorhinal cortex (MEC) are distinguished by intrinsic 4- to 12-Hz subthreshold
      oscillations. These oscillations are thought to impose a pattern of slow periodic
      firing that may contribute to the parahippocampal theta rhythm in vivo. Using
      stimuli with systematically differing frequency content, we examined supra- and
      subthreshold responses in SCs with the goal of understanding how their
      distinctive characteristics shape these responses. In reaction to repeated
      presentations of identical, pseudo-random stimuli, the reliability
      (repeatability) of the spiking response in SCs depends critically on the
      frequency content of the stimulus. Reliability is optimal for stimuli with a
      greater proportion of power in the 4- to 12-Hz range. The simplest mechanistic
      explanation of these results is that rhythmogenic subthreshold membrane
      mechanisms resonate with inputs containing significant power in the 4- to 12-Hz
      band, leading to larger subthreshold excursions and thus enhanced reliability.
      However, close examination of responses rules out this explanation: SCs do show
      clear subthreshold resonance (i.e., selective amplification of inputs with
      particular frequency content) in response to sinusoidal stimuli, while
      simultaneously showing a lack of subthreshold resonance in response to the pseudo
      random stimuli used in reliability experiments. Our results support a model with
      distinctive input-output relationships under subthreshold and suprathreshold
      conditions. For suprathreshold stimuli, SC spiking seems to best reflect the
      amount of input power in the theta (4-12 Hz) frequency band. For subthreshold
      stimuli, we hypothesize that the magnitude of subthreshold theta-range
      oscillations in SCs reflects the total power, across all frequencies, of the
      input.

PMID- 12424284
TI  - A biophysical model of nonlinear dynamics underlying plateau potentials and
      calcium spikes in purkinje cell dendrites.
AB  - Computational capabilities of Purkinje cells (PCs) are central to the cerebellum
      function. Information originating from the whole nervous system converges on
      their dendrites, and their axon is the sole output of the cerebellar cortex. PC
      dendrites respond to weak synaptic activation with long-lasting, low-amplitude
      plateau potentials, but stronger synaptic activation can generate fast, large
      amplitude calcium spikes. Pharmacological data have suggested the involvement of
      only the P-type of Ca channels in both of these electric responses. However, the
      mechanism allowing this Ca current to underlie responses with such different
      dynamics is still unclear. This mechanism was explored by constraining a
      biophysical model with electrophysiological, Ca-imaging, and single ion channel
      data. A model is presented here incorporating a simplified description of [Ca](i)
      regulation and three ionic currents: 1) the P-type Ca current, 2) a delayed
      rectifier K current, and 3) a generic class of K channels activating sharply in
      the sub-threshold voltage range. This model sustains fast spikes and long-lasting
      plateaus terminating spontaneously with recovery of the resting potential. Small
      depolarizing, tonic inputs turn plateaus into a stable membrane state and endow
      the dendrite with bistability properties. With larger tonic inputs, the plateau
      remains the unique equilibrium state, showing long traces of transient inhibitory
      inputs that are called "valley potentials" because their dynamics mirrors that of
      inverted, finite-duration plateaus. Analyzing the slow subsystem obtained by
      assuming instantaneous activation of the delayed-rectifier reveals that the time
      course of plateaus and valleys is controlled by the slow [Ca](i) dynamics, which
      arises from the high Ca-buffering capacity of PCs. A bifurcation analysis shows
      that tonic currents modulate sub-threshold dynamics by displacing the resting
      state along a hysteresis region edged by two saddle-node bifurcations; these
      bifurcations mark transitions from finite-duration plateaus to bistability and
      from bistability to valley potentials, respectively. This low-dimensionality
      model may be introduced into large-scale models to explore the role of PC
      dendrite computations in the functional capabilities of the cerebellum.

PMID- 12424285
TI  - Compensatory and orienting eye movements induced by off-vertical axis rotation
      (OVAR) in monkeys.
AB  - Nystagmus induced by off-vertical axis rotation (OVAR) about a head yaw axis is
      composed of a yaw bias velocity and modulations in eye position and velocity as
      the head changes orientation relative to gravity. The bias velocity is dependent
      on the tilt of the rotational axis relative to gravity and angular head velocity.
      For axis tilts <15 degrees, bias velocities increased monotonically with
      increases in the magnitude of the projected gravity vector onto the horizontal
      plane of the head. For tilts of 15-90 degrees, bias velocity was independent of
      tilt angle, increasing linearly as a function of head velocity with gains of 0.7
      0.8, up to the saturation level of velocity storage. Asymmetries in OVAR bias
      velocity and asymmetries in the dominant time constant of the angular
      vestibuloocular reflex (aVOR) covaried and both were reduced by administration of
      baclofen, a GABA(B) agonist. Modulations in pitch and roll eye positions were in
      phase with nose-down and side-down head positions, respectively. Changes in roll
      eye position were produced mainly by slow movements, whereas vertical eye
      position changes were characterized by slow eye movements and saccades.
      Oscillations in vertical and roll eye velocities led their respective position
      changes by approximately 90 degrees, close to an ideal differentiation,
      suggesting that these modulations were due to activation of the orienting
      component of the linear vestibuloocular reflex (lVOR). The beating field of the
      horizontal nystagmus shifted the eyes 6.3 degrees /g toward gravity in side down
      position, similar to the deviations observed during static roll tilt (7.0 degrees
      /g). This demonstrates that the eyes also orient to gravity in yaw. Phases of
      horizontal eye velocity clustered ~180 degrees relative to the modulation in
      beating field and were not simply differentiations of changes in eye position.
      Contributions of orientating and compensatory components of the lVOR to the
      modulation of eye position and velocity were modeled using three components: a
      novel direct otolith-oculomotor orientation, orientation-based velocity
      modulation, and changes in velocity storage time constants with head position re
      gravity. Time constants were obtained from optokinetic after-nystagmus, a direct
      representation of velocity storage. When the orienting lVOR was combined with
      models of the compensatory lVOR and velocity estimator from sequential otolith
      activation to generate the bias component, the model accurately predicted eye
      position and velocity in three dimensions. These data support the postulates that
      OVAR generates compensatory eye velocity through activation of velocity storage
      and that oscillatory components arise predominantly through lVOR orientation
      mechanisms.

PMID- 12424286
TI  - Changes in electrophysiological properties of lamprey spinal motoneurons during
      fictive swimming.
AB  - Electrophysiological properties of lamprey spinal motoneurons were measured to
      determine whether their cellular properties change as the spinal cord goes from a
      quiescent state to the active state of fictive swimming. Intracellular
      microelectrode recordings of membrane potential were made from motoneurons in the
      isolated spinal cord preparation. Electrophysiological properties were first
      characterized in the quiescent spinal cord, and then fictive swimming was induced
      by perfusion with D-glutamate and the measurements were repeated. During the
      depolarizing excitatory phase of fictive swimming, the motoneurons had
      significantly reduced rheobase and significantly increased input resistance
      compared with the quiescent state, with no significant changes in these
      parameters during the repolarizing inhibitory phase of swimming. Spike threshold
      did not change significantly during fictive swimming compared with the quiescent
      state. During fictive swimming, the slope of the spike frequency versus injected
      current (F-I) relationship decreased significantly as did spike-frequency
      adaptation and the amplitude of the slow after-spike hyperpolarization (sAHP).
      Serotonin is known to be released endogenously from the spinal cord during
      fictive swimming and is known to reduce the amplitude of the sAHP. Therefore the
      effects of serotonin on cellular properties were tested in the quiescent spinal
      cord. It was found that, in addition to reducing the sAHP amplitude, serotonin
      also reduced the slope of the F-I relationship and reduced spike-frequency
      adaptation, reproducing the changes observed in these parameters during fictive
      swimming. Application of spiperone, a serotonin antagonist, significantly
      increased the sAHP amplitude during fictive swimming but had no significant
      effect on F-I slope or adaptation. Because serotonin may act in part through
      reduction of calcium currents, the effect of calcium-free solution (cobalt
      substituted for calcium) was tested in the quiescent spinal cord. Similar to
      fictive swimming and serotonin application, the calcium-free solution
      significantly reduced the sAHP amplitude, the slope of the F-I relationship, and
      spike-frequency adaptation. These results suggest that there are significant
      changes in the firing properties of motoneurons during fictive swimming compared
      with the quiescent state, and it is possible that these changes may be attributed
      in part to the endogenous release of serotonin acting via reduction of calcium
      currents.

PMID- 12424287
TI  - Effects of electrical stimulation of the chorda tympani nerve on taste responses
      in the nucleus of the solitary tract.
AB  - Despite evidence for an abundance of inhibitory synaptic processes within the
      taste-responsive portion of the brain stem, little is known about how these
      processes are activated or modulated. In this context, this study tested the
      hypothesis that activation of the chorda tympani nerve (CT) invokes inhibition
      that influences gustatory neural information processing in the rostral nucleus of
      the solitary tract (NTS). Stimulating electrodes were implanted in the middle ear
      of urethane-anesthetized rats to enable the passage of current across the CT.
      Electrophysiological responses to sucrose, NaCl, HCl, and quinine were recorded
      from single NTS neurons both individually and immediately following tetanic
      electrical stimulation of the CT. Additionally, NTS field responses to paired
      pulse stimulation of the CT were recorded. Electrical pulses delivered to the CT
      were found to produce a compound action potential with four components. Taste
      responsive units in the NTS showed tetanus-evoked responses that varied in
      latency and strength. Those cells that showed strong, short latency responses to
      CT stimulation showed large magnitude responses to NaCl and were relatively
      narrowly tuned. Units with longer latencies generally responded more broadly to
      taste stimuli and with lower response magnitudes. Following tetanus, taste
      responses in 20 (43%) of the 46 units were reversibly altered in a stimulus
      selective manner. Taste responses in 18 units were both enhanced and attenuated
      following tetanic stimulation, although attenuation was much more common.
      Additionally, tetanus was found to affect the temporal organization of spikes
      within taste responses to one stimulus in seven units (15%), four of which also
      showed changes in response magnitude to a different stimulus following tetanus.
      The influence of tetanus on taste responses was shown to be reliable and
      repeatable in neurons from which stimulus trials were recorded more than once.
      Across all units, responses to quinine were most dramatically and frequently
      attenuated following tetanus, while those to NaCl were least susceptible to
      change. NTS field responses evoked by paired pulse stimulation of the CT
      suggested that the initial pulse evoked an inhibitory influence in the NTS that
      decayed and returned to baseline by 2 s. These data are consistent with the idea
      that afferent input to the NTS normally activates inhibitory synaptic activity.
      As with other sensory systems, such inhibition may serve to facilitate contrast
      in the neural representation of different stimulus qualities.

PMID- 12424288
TI  - Activity-dependent increase of the AHP amplitude in T sensory neurons of the
      leech.
AB  - We identified a new form of activity-dependent modulation of the
      afterhyperpolarization (AHP) in tactile (T) sensory neurons of the leech Hirudo
      medicinalis. Repetitive intracellular stimulation with 30 trains of depolarizing
      impulses at 15-s inter-stimulus interval (ISI) led to an increase of the AHP
      amplitude (~60% of the control). The enhancement of AHP lasted for >/=15 min. The
      AHP increase was also elicited when a T neuron was activated by repetitive
      stimulation of its receptive field. The ISI was a critical parameter for the
      induction and maintenance of AHP enhancement. ISI duration had to fit within a
      time window with the upper limit of 20 s to make the training effective to induce
      an enhancement of the AHP amplitude. After recovery from potentiation, AHP
      amplitude could be enhanced once again by delivering another training session.
      The increase of AHP amplitude persisted in high Mg(2+) saline, suggesting an
      intrinsic cellular mechanism for its induction. Previous investigations reported
      that AHP of leech T neurons was mainly due to the activity of the Na(+)/K(+)
      ATPase and to a Ca(2+)-dependent K(+) current (I(K/Ca)). In addition, it has been
      demonstrated that serotonin (5HT) reduces AHP amplitude through the inhibition of
      the Na(+)/K(+) ATPase. By blocking the I(K/Ca) with pharmacological agents, such
      as cadmium and apamin, we still observed an increase of the AHP amplitude after
      repetitive stimulation, whereas 5HT application completely inhibited the AHP
      increment. These data indicate that the Na(+)/K(+) ATPase is involved in the
      induction and maintenance of the AHP increase after repetitive stimulation.
      Moreover, the AHP increase was affected by the level of serotonin in the CNS.
      Finally, the increase of the AHP amplitude produced a lasting depression of the
      synaptic connection between two T neurons, suggesting that this activity
      dependent phenomenon might be involved in short-term plasticity associated with
      learning processes.

PMID- 12424289
TI  - Cholinergic modulation of purinergic and GABAergic co-transmission at in vitro
      hypothalamic synapses.
AB  - The lateral hypothalamus (LH) is an important center for the integration of
      autonomic and limbic information and is implicated in the modulation of visceral
      motor and sensory pathways, including those underlying feeding and arousal
      behaviors. LH neurons in vitro release both ATP and GABA. The control of ATP and
      GABA co-transmission in LH may underlie the participation of LH in basic aspects
      of arousal and reinforcement. LH neurons receive cholinergic input from the
      pedunculopontine and laterodorsal tegmental nuclei as well as from cholinergic
      interneurons within the LH per se. This study presents evidence for nicotinic
      acetylcholine receptor (nAChR)-mediated enhancement of GABAergic, but not of
      purinergic, transmission despite the co-transmission of ATP and GABA at LH
      synapses in vitro. Facilitation of GABAergic transmission by nicotine is
      inhibited by antagonists of (alphabeta)*-containing nAChRs, but is unaffected by
      an alpha7-selective antagonist, consistent with a nAChR-mediated enhancement of
      GABA release mediated by non-alpha7-containing nAChRs. Activation of muscarinic
      ACh receptors enhances the release of ATP while concomitantly depressing
      GABAergic transmission. The independent modulation of ATP/GABAergic transmission
      may provide a new level of synaptic flexibility in which individual neurons
      utilize more than one neurotransmitter but retain independent control over their
      synaptic activity.

PMID- 12424290
TI  - Multiple components of membrane retrieval in synaptic terminals revealed by
      changes in hydrostatic pressure.
AB  - Membrane retrieval following exocytosis in synaptic terminals is fast and
      compensatory, however, little is known about the factors that regulate or
      contribute to this special form of endocytosis. We used whole-terminal
      capacitance measurements to examine the effect of hydrostatic pressure on
      compensatory endocytosis in single synaptic terminals of retinal bipolar neurons.
      We report that a small increase in hydrostatic pressure reversibly inhibits
      compensatory endocytosis. Elevation in hydrostatic pressure does not block all
      membrane retrieval, however. A small, fast component of endocytosis persists,
      while a slower component is inhibited. When the hydrostatic pressure is then
      stepped back to a near-neutral setting, an even slower form of endocytosis is
      observed that restores the resting membrane capacitance to baseline. Thus even
      when endocytosis is temporally uncoupled from calcium entry and exocytosis, it
      can still be compensatory, indicating that presynaptic surface area is highly
      regulated. Our results suggest that at least two distinct mechanisms of membrane
      retrieval contribute to compensatory endocytosis. Given its dramatic inhibitory
      effect on membrane retrieval, we suggest that hydrostatic pressure be carefully
      controlled when studying endocytosis in the whole cell recording configuration.

PMID- 12424291
TI  - Changes in Na(+) channel currents of rat dorsal root ganglion neurons following
      axotomy and axotomy-induced autotomy.
AB  - Section of rat sciatic nerve (axotomy) increases the excitability of neurons in
      the L(4)-L(5) dorsal root ganglia (DRG). These changes are more pronounced in
      animals that exhibit a self-mutilatory behavior known as autotomy. We used whole
      cell recording to examine changes in the tetrodotoxin-sensitive (TTX-S) and the
      tetrodotoxin-resistant (TTX-R) components of sodium channel currents (I(Na)) that
      may contribute to axotomy-induced increases in excitability. Cells were initially
      divided on the basis of size into "large," "medium," and "small" groups. TTX-S
      I(Na) predominated in "large" cells, whereas TTX-R I(Na) predominated in some,
      but not all "small cells." "Small" cells were therefore subdivided into "small
      slow" cells, which predominantly exhibited TTX-R I(Na) and "small fast" cells
      that exhibited more TTX-S I(Na). In contrast to results obtained in other
      laboratories, where slightly different experimental procedures were used, we
      found that axotomy increased TTX-R and/or TTX-S I(Na) and slowed inactivation.
      The effects were greatest in "small-slow" cells and least in "large" cells. The
      changes promoted by axotomy were expressed more clearly in animals that exhibited
      autotomy. Also, the presence of autotomy correlated with a shift in the
      properties of I(Na) in "large" rather than "small-slow," putative nociceptive
      cells. These trends parallel previous observations on axotomy-induced increases
      in excitability, spike height, and spike width that are also greatest in "small"
      cells and least in "large" cells. In addition, the presence of autotomy
      correlates with an increase in excitability of "large" rather than "small" cells.
      Increases in TTX-R and TTX-S I(Na) thus coincide with axotomy-induced increases
      in excitability and alterations in spike shape across the whole population of
      sensory neurons. Injury-induced changes of this type are likely associated with
      the onset of chronic pain in humans.

PMID- 12424292
TI  - Nature and interaction of signals from the receptive field center and surround in
      macaque V1 neurons.
AB  - Information is integrated across the visual field to transform local features
      into a global percept. We now know that V1 neurons provide more spatial
      integration than originally thought due to the existence of their nonclassical
      inhibitory surrounds. To understand spatial integration in the visual cortex, we
      have studied the nature and extent of center and surround influences on neuronal
      response. We used drifting sinusoidal gratings in circular and annular apertures
      to estimate the sizes of the receptive field's excitatory center and suppressive
      surround. We used combinations of stimuli inside and outside the receptive field
      to explore the nature of the surround influence on the receptive field center as
      a function of the relative and absolute contrast of stimuli in the two regions.
      We conclude that the interaction is best explained as a divisive modulation of
      response gain by signals from the surround. We then develop a receptive field
      model based on the ratio of signals from Gaussian-shaped center and surround
      mechanisms. We show that this model can account well for the variations in
      receptive field size with contrast that we and others have observed and for
      variations in size with the state of contrast adaptation. The model achieves this
      success by simple variations in the relative gain of the two component mechanisms
      of the receptive field. This model thus offers a parsimonious explanation of a
      variety of phenomena involving changes in apparent receptive field size and
      accounts for these phenomena purely in terms of two receptive field mechanisms
      that do not themselves change in size. We used the extent of the center mechanism
      in our model as an indicator of the spatial extent of the central excitatory
      portion of the receptive field. We compared the extent of the center to
      measurements of horizontal connections within V1 and determined that horizontal
      intracortical connections are well matched in extent to the receptive field
      center mechanism. Input to the suppressive surround may come in part from
      feedback signals from higher areas.

PMID- 12424293
TI  - Selectivity and spatial distribution of signals from the receptive field surround
      in macaque V1 neurons.
AB  - The responsiveness of neurons in V1 is modulated by stimuli placed outside their
      classical receptive fields. This nonclassical surround provides input from a
      larger portion of the visual scene than originally thought, permitting
      integration of information at early levels in the visual processing stream.
      Signals from the surround have been reported variously to be suppressive and
      facilitatory, selective and unselective. We tested the specificity of influences
      from the surround by studying the interactions between drifting sinusoidal
      gratings carefully confined to conservatively defined center and surround
      regions. We found that the surround influence was always suppressive when the
      surround grating was at the neuron's preferred orientation. Suppression tended to
      be stronger when the surround grating also moved in the neuron's preferred
      direction, rather than its opposite. When the orientation in the surround was 90
      degrees from the preferred orientation (orthogonal), suppression was weaker, and
      facilitation was sometimes evident. The tuning of surround signals therefore
      tended to match the tuning of the center, though the tuning of the surround was
      somewhat broader. The tuning of suppression also depended on the contrast of the
      center grating-when the center grating was reduced in contrast, orthogonal
      surround stimuli became relatively more suppressive. We also found evidence for
      the tuning of the surround being dependent to some degree on the stimulus used in
      the center-suppression was often stronger for a given center stimulus when the
      parameters of the surround grating matched the parameters of the center grating
      even when the center grating was not itself of the optimal direction or
      orientation. We also explored the spatial distribution of surround influence and
      found an orderly relationship between the orientation of grating patches
      presented to regions of the surround and the position of greatest suppression.
      When surround gratings were oriented parallel to the preferred orientation of the
      receptive field, suppression was strongest at the receptive field ends. When
      surround gratings were orthogonal, suppression was strongest on the flanks. We
      conclude that the surround has complex effects on responses from the classical
      receptive field. We suggest that the underlying mechanism of this complexity may
      involve interactions between relatively simple center and surround mechanisms.

PMID- 12424294
TI  - Spatial organization of receptive fields of V1 neurons of alert monkeys:
      comparison with responses to gratings.
AB  - We studied the spatial organization of receptive fields and the responses to
      gratings of neurons in parafoveal V1 of alert monkeys. Activating regions (ARs)
      of 228 cells were mapped with increment and decrement bars while compensating for
      fixational eye movements. For cells with two or more ARs, the overlap between ARs
      responsive to increments (INC) and ARs responsive to decrements (DEC) was
      characterized by a quantitative overlap index (OI). The distribution of overlap
      indices was bimodal. The larger group (78% of cells) was composed of complex
      cells with strongly overlapping ARs (OI >/= 0.5). The smaller group (14%) was
      composed of simple cells with minimal spatial overlap of ARs (OI </= 0.3). Simple
      cells were preferentially located in layers dominated by the magnocellular
      pathway. A third group of neurons, the monocontrast cells (8%), responded only to
      one sign of contrast and had more sustained responses to flashed stimuli than
      other cells. One hundred fourteen neurons were also studied with drifting
      sinusoidal gratings of various spatial frequencies and window widths. For complex
      cells, the relative modulation (RM, the ratio of the 1st harmonic to the mean
      firing rate), ranged from 0.6 +/- 0.4 to 1.1 +/- 0.5 (mean +/- SD), depending on
      the stimulus conditions and the mode of correction for eye movements. RM was not
      correlated with the degree of overlap of ARs, indicating that the spatial
      organization of receptive fields cannot reliably be predicted from RM values. In
      fact, a subset of complex cells had RM > 1, the traditional criterion for
      identifying simple cells. However, unlike simple cells, even those complex cells
      with high RM could exhibit diverse nonlinear responses when the spatial frequency
      or window size was changed. Furthermore, the responses of complex cells to
      counterphase gratings were predominantly nonlinear even harmonics. These results
      show that RM is not a robust test of linearity. Our results indicate that complex
      cells are the most frequently encountered neurons in primate V1, and their
      behavior needs to receive more emphasis in models of visual function.

PMID- 12424295
TI  - Inhibitory component of the resistance reflex in the locomotor network of the
      crayfish.
AB  - The aim of this study was to investigate the inhibitory components of a
      resistance reflex in the walking system of the crayfish. This study was performed
      using an in vitro preparation of several thoracic ganglia including motor nerves
      and the proprioceptor that codes movements of the second joint (coxo-basipodite
      chordotonal organ-CBCO). Sinusoidal movements were imposed on the CBCO, and
      intracellular responses were recorded from levator (Lev) and depressor (Dep)
      motoneurons (MNs). We found that in MNs that oppose the imposed movements (e.g.,
      the Lev MNs during the imposed downward movement), the response consists in a
      depolarization resulting from the summation of excitatory postsynaptic potentials
      (EPSPs). A movement in the opposite direction resulted in hyperpolarization
      during which inhibitory postsynaptic potentials (IPSPs) summated. The inhibitory
      pathway to each MN is oligosynaptic (i.e., composed of a small number of neurons
      in series) and involves spiking interneurons because it was blocked in the
      presence of a high-divalent cation solution. The IPSPs were mediated by a
      chloride conductance because their amplitude was sensitive to the chloride
      concentration of the bathing solution and because they were blocked by the
      chloride channel blocker, picrotoxin. Resistance reflex IPSPs related to single
      CBCO neurons could be identified. These unitary IPSPs were blocked in the
      presence of 3-mercapto-propionic acid, an inhibitor of gamma-amino-butyric acid
      (GABA) synthesis, indicating that they are mediated by GABA. In addition to this
      GABAergic pathway, electrical stimulation of the CBCO sensory nerve induced
      compound IPSPs that were blocked by glutamate pyruvate transaminase (GPT),
      indicating the presence of glutamatergic inhibitory pathways. These glutamatergic
      interneurons do not appear to be involved in the resistance reflex, however, as
      GPT did not block the unitary IPSPs. Functionally, the resistance reflex is
      mainly supported by movement-coding CBCO sensory neurons. We demonstrate that
      such movement-coding CBCO neurons produce both monosynaptic EPSPs in the MNs
      opposing imposed movements and oligosynaptic IPSPs in the antagonistic
      motoneurons. These results highlight the similarities between the inhibitory
      pathways in resistance reflex of the crayfish and in the stretch reflex of
      vertebrates mediated by Ia inhibitory interneurons.

PMID- 12424296
TI  - A two-state stochastic model of REM sleep architecture in the rat.
AB  - Rapid eye movement (REM) sleep is a recurring state throughout the sleeping
      period. Based on the examination of 45 sleep records of 3-mo-old male rats during
      the middle of the light phase, a stochastic model is proposed for the sequence
      X(1),Y(2), X(2),Y(2),. of REM sleep durations X and inter-REM sleep waiting times
      Y experienced by a rat during a sleeping period. In our model the probability
      distribution of any variable in the sequence, given the past, is allowed to
      depend on only the immediately previous variable. The conditional distributions
      f(y(i) | x(i)) and g(x(i+1) | y(i)) do not depend on the index i. It is shown
      that the marginal distributions tend to stationarity. Aggregations of the data on
      a discrete time scale suggest that the conditional distributions be formulated as
      two-component mixtures. These component distributions are modeled as Poisson and
      their means are called the means of short and long waiting time and the means of
      short and long REM sleep duration. Associated with each mean is a probability
      weight. Parametric forms are given to the means and probability weights. The
      model estimated by maximum likelihood shows a good fit to data of the 3-mo-old
      rats. The model fit to a smaller data set obtained from rats aged 15-22 mo shows
      a significant shortening of the means for both short and long REM sleep bout
      durations compared with the means of the 3-mo-old rats. Neuronal correlates for
      the behavior of the model are discussed in the context of the reciprocal
      interaction model of REM sleep regulation.

PMID- 12424297
TI  - Noise and coupling affect signal detection and bursting in a simulated
      physiological neural network.
AB  - Signal detection in the CNS relies on a complex interaction between the numerous
      synaptic inputs to the detecting cells. Two effects, stochastic resonance (SR)
      and coherence resonance (CR) have been shown to affect signal detection in arrays
      of basic neuronal models. Here, an array of simulated hippocampal CA1 neurons was
      used to test the hypothesis that physiological noise and electrical coupling can
      interact to modulate signal detection in the CA1 region of the hippocampus. The
      array was tested using varying levels of coupling and noise with different input
      signals. Detection of a subthreshold signal in the network improved as the number
      of detecting cells increased and as coupling was increased as predicted by
      previous studies in SR; however, the response depended greatly on the noise
      characteristics present and varied from SR predictions at times. Careful
      evaluation of noise characteristics may be necessary to form conclusions about
      the role of SR in complex systems such as physiological neurons. The coupled
      array fired synchronous, periodic bursts when presented with noise alone. The
      synchrony of this firing changed as a function of noise and coupling as predicted
      by CR. The firing was very similar to certain models of epileptiform activity,
      leading to a discussion of CR as a possible simple model of epilepsy. A single
      neuron was unable to recruit its neighbors to a periodic signal unless the signal
      was very close to the synchronous bursting frequency. These findings, when viewed
      in comparison with physiological parameters in the hippocampus, suggest that both
      SR and CR can have significant effects on signal processing in vivo.

PMID- 12424298
TI  - Neural activity in monkey dorsal and ventral cingulate motor areas: comparison
      with the supplementary motor area.
AB  - The cingulate motor areas are a recently discovered group of discrete cortical
      regions located in the cingulate sulcus with direct connections to the primary
      motor cortex and spinal cord. Although much is known about their anatomical
      relationship with other motor areas, relatively little is known about their
      functional neurophysiology. We investigated neural mechanisms of motor processing
      in the dorsal and ventral cingulate motor areas (CMAd and CMAv) during two
      dimensional visually guided arm movements. Single-neuron activity in CMAd and
      CMAv was recorded during an instructed delay task requiring combined elbow and
      shoulder movements. Neural activity associated with the onset of a visual cue
      (signal activity), delay (set activity), and motor response (movement activity)
      were assessed, and their onset time, duration, magnitude, and parameters of
      directional specificity were calculated. To determine how CMAd and CMAv compared
      with other premotor areas, we also analyzed the activity of neurons in the
      supplementary motor area (SMA) during the same task in the same monkeys.
      Comparison of CMAd, CMAv, and SMA revealed remarkably similar response
      properties. All three areas contained signal, set, and movement activity in
      similar proportions and in all possible combinations within single neurons. The
      average onset time of signal and set activity and the duration of signal activity
      were not significantly different across areas. The directional tuning of
      activities in all three areas were uniformly distributed and highly correlated
      within the same neuron. There were, however, some notable differences in movement
      activity between motor areas. Neurons with only movement activity were more
      numerous in CMAd and CMAv, whereas neurons with both set and movement activity
      were more prevalent in SMA. Furthermore, movement activity in SMA began earlier
      and had a shorter duration than movement activity in CMAd and CMAv, although
      there was substantial overlap in their distributions. These results indicate that
      CMAd and CMAv participate in the visual guidance of limb movements using similar
      neurophysiological mechanisms as SMA. The earlier average onset and shorter
      duration of movement activity in SMA suggest a more prominent role for this area
      in movement initiation, whereas the later onset and longer duration of movement
      activity in CMAd and CMAv suggest a more influential role in movement execution.
      Notwithstanding these differences, however, the remarkable similarities in
      response types and their combinatorial organization within single neurons across
      all cortical areas attests to the parallel organization and distributed nature of
      information processing in these three motor areas.

PMID- 12424299
TI  - Pursuit speed compensation in cortical area MSTd.
AB  - When we move forward the visual images on our retinas expand. Humans rely on the
      focus, or center, of this expansion to estimate their direction of self-motion or
      heading and, as long as the eyes are still, the retinal focus corresponds to the
      heading. However, smooth pursuit eye movements add visual motion to the expanding
      retinal image and displace the focus of expansion. In spite of this, humans
      accurately judge their heading during pursuit eye movements even though the
      retinal focus no longer corresponds to the heading. Recent studies in macaque
      suggest that correction for pursuit may occur in the dorsal aspect of the medial
      superior temporal area (MSTd); neurons in this area are tuned to the retinal
      position of the focus and they modify their tuning to partially compensate for
      the focus shift caused by pursuit. However, the question remains whether these
      neurons shift focus tuning more at faster pursuit speeds, to compensate for the
      larger focus shifts created by faster pursuit. To investigate this question, we
      recorded from 40 MSTd neurons while monkeys made pursuit eye movements at a range
      of speeds across simulated self- or object motion displays. We found that most
      MSTd neurons modify their focus tuning more at faster pursuit speeds, consistent
      with the idea that they encode heading and other motion parameters regardless of
      pursuit speed. Across the population, the median rate of compensation increase
      with pursuit speed was 51% as great as required for perfect compensation. We
      recorded from the same neurons in a simulated pursuit condition, in which gaze
      was fixed but the entire display counter-rotated to produce the same retinal
      image as during real pursuit. This condition yielded the result that retinal cues
      contribute to pursuit compensation; the rate of compensation increase was 30% of
      that required for accurate encoding of heading. The difference between these two
      conditions was significant (P < 0.05), indicating that extraretinal cues also
      contribute significantly. We found a systematic antialignment between preferred
      pursuit and preferred visual motion directions. Neurons may use this
      antialignment to combine retinal and extraretinal compensatory cues. These
      results indicate that many MSTd neurons compensate for pursuit velocity, pursuit
      direction as previously reported and pursuit speed, and further implicate MSTd as
      a critical stage in the computation of egomotion.

PMID- 12424300
TI  - Scene segmentation and attention in primate cortical areas V1 and V2.
AB  - The responses of many neurons in primary visual cortex are modulated by stimuli
      outside the classical receptive field in ways that may contribute to integrative
      processes like scene segmentation. To explore this issue, single-unit neuronal
      responses were recorded in monkey cortical areas V1 and V2 to visual stimuli
      containing either a figure or a background pattern over the receptive field.
      Figures were defined either by orientation contrast or by illusory contours. In
      all conditions, the stimulation over the RF and its nearby surround was
      identical. Both figure types enhanced the average population response in V1 and
      V2. For orientation contrast figures, enhancement averaged 50% in V2 and 30% in
      V1; for illusory contour figures, the enhancement averaged 24% in V2 and 18% in
      V1. These differences were statistically significant for figure type but not for
      visual area. In V2, the latency of enhancement to illusory contour-defined
      figures was longer than that to orientation-defined figures. Neuronal responses
      were recorded while the monkey performed a directed-attention task. Enhancement
      to both figure types was observed even when attention was directed away from the
      figure. Attention slightly enhanced responses in V2, independent of figure type,
      but did not affect responses in V1. There was no discernible effect of attention
      on background firing rate in either V1 or V2. These results suggest that scene
      segmentation is a distributed process, in which neuronal signals at successive
      stages of the visual hierarchy and over time increasingly reflect the global
      structure of the image. This process occurs independent of directed visual
      attention.

PMID- 12424301
TI  - Fast calcium signals in Drosophila motor neuron terminals.
AB  - Drosophila is a powerful model for neuroscientists, but physiological techniques
      have not kept pace with advances in molecular genetics. We introduce a reliable
      assay for intracellular calcium dynamics in Drosophila larval motor neuron
      terminals, and a new physiological solution that improves the longevity of the
      larval preparation. By loading calcium indicators into motor neuron terminals
      through cut axons, we obtained a high signal-to-noise ratio with confocal
      microscopy, and good temporal resolution of calcium-dependent fluorescence
      changes. We provide an estimate for the resting intracellular calcium
      concentration, the first description of calcium kinetics for a single action
      potential (AP), and improved resolution of calcium kinetics during AP trains. The
      very rapid decay of the calcium signal following a single AP (tau ~60 ms)
      indicates a previously unreported fast calcium extrusion mechanism in Drosophila
      motor neuron terminals well suited for sustaining physiological processes during
      the high rates of impulse activity which drive locomotor activity.

PMID- 12424302
TI  - Nitric oxide inhibits spinally projecting paraventricular neurons through
      potentiation of presynaptic GABA release.
AB  - Nitric oxide (NO) in the paraventricular nucleus (PVN) is involved in the
      regulation of the excitability of PVN neurons. However, the effect of NO on the
      inhibitory GABAergic and excitatory glutamatergic inputs to spinally projecting
      PVN neurons has not been studied specifically. In the present study, we
      determined the role of the inhibitory GABAergic and excitatory glutamatergic
      inputs in the inhibitory action of NO on spinally projecting PVN neurons.
      Spinally projecting PVN neurons were retrogradely labeled by a fluorescent dye,
      1,1'-dioctadecyl-3,3,3',3'-tetramethylindocasbocyane (DiI), injected into the
      spinal cord of rats. Whole cell voltage- and current-clamp recordings were
      performed on DiI-labeled PVN neurons in the hypothalamic slice. The spontaneous
      miniature inhibitory postsynaptic currents (mIPSCs) recorded in DiI-labeled
      neurons were abolished by 20 microM bicuculline, whereas the miniature excitatory
      postsynaptic currents (mEPSCs) were eliminated by 20 microM 6-cyano-7
      nitroquinoxaline-2,3-dione. Bath application of an NO donor, 100 microM S-nitroso
      N-acetyl-penicillamine (SNAP), or the NO precursor, 100 microM L-arginine, both
      significantly increased the frequency of mIPSCs of DiI-labeled PVN neurons,
      without altering the amplitude and the decay time constant of mIPSCs. The effect
      of SNAP and L-arginine on the frequency of mIPSCs was eliminated by an NO
      scavenger, 2-(4-carboxypheny)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide, and
      an NO synthase inhibitor, 1-(2-trifluoromethylphenyl) imidazole, respectively.
      Neither SNAP nor L-arginine significantly altered the frequency and the amplitude
      of mEPSCs. Under current-clamp conditions, 100 microM SNAP or 100 microM L
      arginine significantly decreased the discharge rate of the DiI-labeled PVN
      neurons, without significantly affecting the resting membrane potential. On the
      other hand, 20 microM bicuculline significantly increased the impulse activity of
      PVN neurons. In the presence of bicuculline, SNAP or L-arginine both failed to
      inhibit the firing activity of PVN neurons. This electrophysiological study
      provides substantial new evidence that NO suppresses the activity of spinally
      projecting PVN neurons through potentiation of the GABAergic synaptic input.

PMID- 12424303
TI  - Activation of delta-opioid receptors excites spinally projecting locus coeruleus
      neurons through inhibition of GABAergic inputs.
AB  - Stimulation of the noradrenergic nucleus locus coeruleus (LC) releases
      norepinephrine in the spinal cord, which inhibits dorsal horn neurons and
      produces analgesia. Activation of this descending noradrenergic pathway also
      contributes to the analgesic action produced by systemic opioids. The delta
      opioid receptors are present presynaptically in the LC. However, their functional
      role in the control of the activity of spinally projecting LC neurons remains
      uncertain. In this study, we tested the hypothesis that activation of presynaptic
      delta-opioid receptors excites spinally projecting LC neurons through inhibition
      of GABA release. Spinally projecting LC neurons were retrogradely labeled by a
      fluorescent dye, DiI, injected into the spinal dorsal horn of rats. Whole cell
      voltage- and current-clamp recordings were performed on DiI-labeled LC neurons in
      brain slices in vitro. Retrogradely labeled LC noradrenergic neurons were
      demonstrated by dopamine-beta-hydroxylase immunofluorescence. [D-Pen(2), D
      Pen(5)]-enkephalin (DPDPE, 1 microM) significantly decreased the frequency of
      GABA-mediated miniature inhibitory postsynaptic currents (IPSCs) of nine DiI
      labeled LC neurons from 2.1 +/- 0.5 to 0.7 +/- 0.2 Hz without altering their
      amplitude and the kinetics. On the other hand, the miniature excitatory
      postsynaptic currents (EPSC) of nine DiI-labeled LC neurons were not
      significantly altered by DPDPE. Furthermore, DPDPE significantly inhibited the
      amplitude of evoked IPSC but not EPSC in eight DiI-labeled LC neurons. Under the
      current-clamp condition, the firing activity in 9 of 11 DiI-labeled LC neurons
      was significantly increased by 1 microM DPDPE from 4.6 +/- 0.7 to 6.2 +/- 1.0 Hz.
      Bicuculline (20 microM) also significantly increased the firing frequency in 13
      of 20 neurons from 1.8 +/- 0.5 to 2.8 +/- 0.6 Hz. Additionally, the excitatory
      effect of DPDPE on LC neurons was diminished in the presence of bicuculline.
      Collectively, these data strongly suggest that activation of presynaptic delta
      opioid receptors by DPDPE excites a population of spinally projecting LC neurons
      by preferential inhibition of GABA release. Thus presynaptic delta-opioid
      receptors likely play an important role in the regulation of the excitability of
      spinally projecting LC neurons and the descending noradrenergic inhibitory
      system.

PMID- 12424304
TI  - Temporal coherence sensitivity in auditory cortex.
AB  - Natural sounds often contain energy over a broad spectral range and consequently
      overlap in frequency when they occur simultaneously; however, such sounds under
      normal circumstances can be distinguished perceptually (e.g., the cocktail party
      effect). Sound components arising from different sources have distinct (i.e.,
      incoherent) modulations, and incoherence appears to be one important cue used by
      the auditory system to segregate sounds into separately perceived acoustic
      objects. Here we show that, in the primary auditory cortex of awake marmoset
      monkeys, many neurons responsive to amplitude- or frequency-modulated tones at a
      particular carrier frequency [the characteristic frequency (CF)] also demonstrate
      sensitivity to the relative modulation phase between two otherwise identically
      modulated tones: one at CF and one at a different carrier frequency. Changes in
      relative modulation phase reflect alterations in temporal coherence between the
      two tones, and the most common neuronal response was found to be a maximum of
      suppression for the coherent condition. Coherence sensitivity was generally found
      in a narrow frequency range in the inhibitory portions of the frequency response
      areas (FRA), indicating that only some off-CF neuronal inputs into these cortical
      neurons interact with on-CF inputs on the same time scales. Over the population
      of neurons studied, carrier frequencies showing coherence sensitivity were found
      to coincide with the carrier frequencies of inhibition, implying that inhibitory
      inputs create the effect. The lack of strong coherence-induced facilitation also
      supports this interpretation. Coherence sensitivity was found to be greatest for
      modulation frequencies of 16-128 Hz, which is higher than the phase-locking
      capability of most cortical neurons, implying that subcortical neurons could play
      a role in the phenomenon. Collectively, these results reveal that auditory
      cortical neurons receive some off-CF inputs temporally matched and some
      temporally unmatched to the on-CF input(s) and respond in a fashion that could be
      utilized by the auditory system to segregate natural sounds containing similar
      spectral components (such as vocalizations from multiple conspecifics) based on
      stimulus coherence.

PMID- 12424305
TI  - Conditions for the triggering of spreading depression studied with computer
      simulations.
AB  - In spite of five decades of study, the biophysics of spreading depression (SD) is
      incompletely understood. Earlier we have modeled seizures and SD, and we have
      shown that currents through ion channels normally present in neuron membranes can
      generate SD-like depolarization. In the present study, we define the conditions
      for triggering SD and the parameters that influence its course in a model of a
      hippocampal pyramidal cell with more complete representation of ions and channels
      than the previous version. "Leak" conductances for Na(+), K(+), and Cl(-) and an
      ion pump were present in the membrane of the entire cell; fast inactivating
      voltage dependent conductances for sodium and potassium in the soma; "persistent"
      conductances in soma and apical dendrite, and K(+)- and voltage-dependent N
      methyl-D-aspartate (NMDA)-controlled conductance in the apical dendrite. The
      neuron was surrounded by restricted interstitial space and by a "glia
      endothelium" system of extracellular ion regulation bounded by a membrane having
      leak conductances and an ion pump. Ion fluxes and concentration changes were
      continuously computed as well as osmotic cell volume changes. As long as reuptake
      into the neuron and "buffering" by glia kept pace with K(+) released from the
      neuron, stimulating current applied to the soma evoked repetitive firing that
      stopped when stimulation ceased. When glial uptake was reduced, K(+) released
      from neurons could accumulate in the interstitium and keep the neuron depolarized
      so that strong depolarizing pulses injected into the soma were followed either by
      afterdischarge or SD. SD-like depolarization was ignited when depolarization
      spreading into the apical dendrite, activated persistent Na(+) current and NMDA
      controlled current. With membrane parameters constant, varying the injected
      stimulating current influenced SD onset but neither the depolarization nor the
      increase in extracellular K(+). Glial "leak" conductance influenced SD duration
      and SD ignition point. Varying maximal conductances (representing channel
      density) also influenced SD onset time but not the amplitude of the
      depolarization. Hypoxia was simulated by turning off the Na-K exchange pump, and
      this resulted in SD-like depolarization. The results confirm that, once ignited,
      SD runs an all-or-none trajectory, the level of depolarization is governed by
      feedback involving ion shifts and glutamate acting on ion channels and not by the
      number of channels open, and SD is ignited if the net persistent membrane current
      in the apical dendrites turns inward.

PMID- 12424306
TI  - Spreading depression: imaging and blockade in the rat neocortical brain slice.
AB  - Spreading depression (SD) is a profound but transient depolarization of neurons
      and glia that migrates across the cortical and subcortical gray at 2-5 mm/min.
      Under normoxic conditions, SD occurs during migraine aura where it precedes
      migraine pain but does not damage tissue. During stroke and head trauma, however,
      SD can arise repeatedly near the site of injury and may promote neuronal damage.
      We developed a superfused brain slice preparation that can repeatedly support
      robust SD during imaging and electrophysiological recording to test drugs that
      may block SD. Submerged rat neocortical slices were briefly exposed to artificial
      cerebrospinal fluid (ACSF) with KCl elevated to 26 mM. SD was evoked within 2
      min, recorded in layers II/III both as a negative DC shift and as a propagating
      front of elevated light transmittance (LT) representing transient cell swelling
      in all cortical layers. An SD episode was initiated focally and could be
      repeatedly evoked and imaged with no damage to slices. As reported in vivo,
      pretreatment with one of several N-methyl-D-aspartate (NMDA) receptor antagonists
      blocked SD, but a non-NMDA glutamate receptor antagonist (CNQX) had no effect.
      NMDA receptor (NMDAR) activation does not initiate SD nor are NMDAR antagonists
      tolerated therapeutically so we searched for more efficacious drugs to block SD
      generation. Pretreatment with the sigma-one receptor (sigma(1)R) agonists
      dextromethorphan (10-100 microM), carbetapentane (100 microM), or 4-IBP (30
      microM) blocked SD, even when KCl exposure was extended beyond 5 min. The block
      was independent of NMDA receptor antagonism. Two sigma(1)R antagonists [(+)-3PPP
      and BD-1063] removed this block but had no effect upon SD alone. Remarkably, the
      sigma(1)R agonists also substantially reduced general cell swelling evoked by
      bath application of 26 mM KCl. More potent sigma(1)R ligands that are
      therapeutically tolerated could prove useful in reducing SD associated with
      migraine and be of potential use in stroke or head trauma.

PMID- 12424307
TI  - Multiwavelength optical intrinsic signal imaging of cortical spreading
      depression.
AB  - Cortical spreading depression (CSD) is an important disease model for migraine
      and cerebral ischemia. In this study, we exploit the high temporal and spatial
      resolution of optical imaging to characterize perfusion-dependent and 
      independent changes in response to CSD and to investigate the etiology of
      reflectance changes during CSD. In this experiment, we characterized the optical
      response to CSD at wavelengths that emphasize perfusion-related changes (610 and
      550 nm), and we compared these results with 850 nm and blood volume data. Blood
      volume changes during CSD were recorded using an intravascular fluorescent dye,
      Texas Red dextran. We observed triphasic optical signals at 850 and 550 nm
      characterized by spreading waves of increased, decreased, then increased
      reflectance (Fig. 1) which expanded at a rate of approximately 3-5 mm/min. The
      signal at 610 nm had a similar initial phase, but the phase 2 response was
      slightly more complex, with a parenchymal decrease in reflectance but a vascular
      increase in reflectance. Reflectance values decreased in phase three. Blood
      volume signals were delayed relative to the optical intrinsic signals and
      corresponded temporally to phases 2 and 3. This is the first study to
      characterize optical imaging of intrinsic signal responses to CSD, in vivo, at
      multiple wavelengths. The data presented here suggest that changes in light
      scattering precede perfusion responses, the blood volume increase (phase 2) is
      accompanied by a reduction in deoxyhemoglobin, and the blood volume decrease
      (phase 3) is accompanied by an increase in deoxyhemoglobin. Previous studies have
      suggested the oligemia of spreading depression was a result of decreased
      metabolic demand. This study suggests that during the oligemic period there is a
      greater reduction in oxygen delivery than in demand.

PMID- 12424308
TI  - Dopamine modulates synaptic transmission in the nucleus of the solitary tract.
AB  - 10.1152/jn.00224.2002. Dopamine (DA) modulates the cardiorespiratory reflex by
      peripheral and central mechanisms. The aim of this study was to examine the role
      of DA in synaptic transmission of the nucleus tractus solitarius (NTS), the major
      integration site for cardiopulmonary reflexes. To examine DA's role, we used
      whole cell, voltage-clamp recordings in a rat horizontal brain stem slice.
      Solitary tract stimulation evoked excitatory postsynaptic currents (EPSCs) that
      were reduced to 70 +/- 5% of control by DA (100 microM). The reduction in EPSCs
      by DA was accompanied by a decrease in the paired pulse depression ratio with
      little or no change in input resistance or EPSC decay, suggesting a presynaptic
      mechanism. The D1-like agonist SKF 38393 Br (30 microM) did not alter EPSC
      amplitude, whereas the D2-like agonist, quinpirole HCl (30 microM), depressed
      EPSCs to 73 +/- 4% of control. The D2-like receptor antagonist, sulpiride (20
      microM), abolished DA modulation of EPSCs. Most importantly, sulpiride alone
      increased EPSCs to 131 +/- 10% of control, suggesting a tonic D2-like modulation
      of synaptic transmission in the NTS. Examination of spontaneous EPSCs revealed DA
      reversibly decreased the frequency of events from 9.4 +/- 2.2 to 6.2 +/- 1.4 Hz.
      Sulpiride, however, did not alter spontaneous events. Immunohistochemistry of NTS
      slices demonstrated that D2 receptors colocalized with synaptophysin and
      substance P, confirming a presynaptic distribution. D2 receptors also localized
      to cultured petrosal neurons, the soma of presynaptic afferent fibers. In the
      petrosal neurons, D2 was found in cells that were TH-immunopositive, suggesting
      they were chemoreceptor afferent fibers. These results demonstrate that DA
      tonically modulates synaptic activity between afferent sensory fibers and
      secondary relay neurons in the NTS via a presynaptic D2-like mechanism.

PMID- 12424309
TI  - NPY sensitivity and postsynaptic properties of heterotopic neurons in the MAM
      model of malformation-associated epilepsy.
AB  - Neuronal migration disorders (NMDs) can be associated with neurological
      dysfunction such as mental retardation, and clusters of disorganized cells
      (heterotopias) often act as seizure foci in medically intractable partial
      epilepsies. Methylazoxymethanol (MAM) treatment of pregnant rats results in
      neuronal heterotopias in offspring, especially in hippocampal area CA1. Although
      the neurons in dysplastic areas in this model are frequently hyperexcitable, the
      precise mechanisms controlling excitability remain unclear. Here, we used IR-DIC
      videomicroscopy and whole cell voltage-clamp techniques to test whether the
      potent anti-excitatory actions of neuropeptide Y (NPY) affected synaptic
      excitation of heterotopic neurons. We also compared several synaptic and
      intrinsic properties of heterotopic, layer 2-3 cortical, and CA1 pyramidal
      neurons, to further characterize heterotopic cells. NPY powerfully inhibited
      synaptic excitation onto normal and normotopic CA1 cells but was nearly
      ineffective on responses evoked in heterotopic cells from stimulation sites
      within the heterotopia. Glutamatergic synaptic responses on heterotopic cells
      exhibited a comparatively small, D-2-amino-5-phosphopentanoic acid-sensitive, N
      methyl-D-aspartate component. Heterotopic neurons also differed from normal CA1
      cells in postsynaptic membrane currents, possessing a prominent inwardly
      rectifying K(+) current sensitive to Cs(+) and Ba(2+), similar to neocortical
      layer 2-3 pyramidal cells. CA1 cells instead had a prominent Cs(+)- and 4-(N
      ethyl-N-phenylamino)-1,2-dimethyl-6-(methylamino) pyrimidinium chloride-sensitive
      I(h) and negligible inward rectification, unlike heterotopic cells. Thus
      heterotopic CA1 cells appear to share numerous physiological similarities with
      neocortical neurons. The lack of NPY's effects on intra-heterotopic inputs, the
      small contribution of I(h), and abnormal glutamate receptor function, may all
      contribute to the lowered threshold for epileptiform activity observed in
      hippocampal heterotopias and could be important factors in epilepsies associated
      with NMDs.

PMID- 12424310
TI  - Multiple modes of action potential initiation and propagation in mitral cell
      primary dendrite.
AB  - The mitral cell primary dendrite plays an important role in transmitting distal
      olfactory nerve input from olfactory glomerulus to the soma-axon initial segment.
      To understand how dendritic active properties are involved in this transmission,
      we have combined dual soma and dendritic patch recordings with computational
      modeling to analyze action-potential initiation and propagation in the primary
      dendrite. In response to depolarizing current injection or distal olfactory nerve
      input, fast Na(+) action potentials were recorded along the entire length of the
      primary dendritic trunk. With weak-to-moderate olfactory nerve input, an action
      potential was initiated near the soma and then back-propagated into the primary
      dendrite. As olfactory nerve input increased, the initiation site suddenly
      shifted to the distal primary dendrite. Multi-compartmental modeling indicated
      that this abrupt shift of the spike-initiation site reflected an independent
      thresholding mechanism in the distal dendrite. When strong olfactory nerve
      excitation was paired with strong inhibition to the mitral cell basal secondary
      dendrites, a small fast prepotential was recorded at the soma, which indicated
      that an action potential was initiated in the distal primary dendrite but failed
      to propagate to the soma. As the inhibition became weaker, a "double-spike" was
      often observed at the dendritic recording site, corresponding to a single action
      potential at the soma. Simulation demonstrated that, in the course of forward
      propagation of the first dendritic spike, the action potential suddenly jumps
      from the middle of the dendrite to the axonal spike-initiation site, leaving the
      proximal part of primary dendrite unexcited by this initial dendritic spike. As
      Na(+) conductances in the proximal dendrite are not activated, they become
      available to support the back-propagation of the evoked somatic action potential
      to produce the second dendritic spike. In summary, the balance of spatially
      distributed excitatory and inhibitory inputs can dynamically switch the mitral
      cell firing among four different modes: axo-somatic initiation with back
      propagation, dendritic initiation either with no forward propagation, forward
      propagation alone, or forward propagation followed by back-propagation.

PMID- 12424311
TI  - Na(+)-Ca(2+) exchanger controls the gain of the Ca(2+) amplifier in the dendrites
      of amacrine cells.
AB  - We have previously shown that disabling forward-mode Na(+)-Ca(2+) exchange in
      amacrine cells greatly prolongs the depolarization-induced release of
      transmitter. To investigate the mechanism for this, we imaged [Ca(2+)](i) in
      segments of dendrites during depolarization. Removal of [Na(+)](o) produced no
      immediate effect on resting [Ca(2+)](i) but did prolong [Ca(2+)](i) transients
      induced by brief depolarization in both voltage-clamped and unclamped cells. In
      some cells, depolarization gave rise to stable patterns of higher and lower
      [Ca(2+)] over micrometer-length scales that collapsed once [Na(+)](o) was
      restored. Prolongation of [Ca(2+)](i) transients by removal of [Na(+)](o) is not
      due to reverse mode operation of Na(+)-Ca(2+) exchange but is instead a
      consequence of Ca(2+) release from endoplasmic reticulum (ER) stores over which
      Na(+)-Ca(2+) exchange normally exercises control. Even in normal [Na(+)](o),
      hotspots for [Ca(2+)] could be seen following depolarization, that are
      attributable to local Ca(2+)-induced Ca(2+) release. Hotspots were seen to be
      labile, probably reflecting the state of local stores or their Ca(2+) release
      channels. When ER stores were emptied of Ca(2+) by thapsigargin, [Ca(2+)]
      transients in dendrites were greatly reduced and unaffected by the removal of
      [Na(+)](o) implying that even when Na(+)-Ca(2+) exchange is working normally, the
      majority of the [Ca(2+)](i) increase by depolarization is due to internal release
      rather than influx across the plasma membrane. Na(+)-Ca(2+) exchange has an
      important role in controlling [Ca(2+)] dynamics in amacrine cell dendrites
      chiefly by moderating the positive feedback of the Ca(2+) amplifier.

PMID- 12424312
TI  - Cerebral CBM1 neuron contributes to synaptic modulation appearing during
      rejection of seaweed in Aplysia kurodai.
AB  - The Japanese species Aplysia kurodai feeds well on Ulva but rejects Gelidium with
      distinctive rhythmic patterned movements of the jaws and radula. We have
      previously shown that the patterned jaw movements during the rejection of
      Gelidium might be caused by long-lasting suppression of the monosynaptic
      transmission from the multiaction MA neurons to the jaw-closing (JC) motor
      neurons in the buccal ganglia and that the modulation might be directly produced
      by some cerebral neurons. In the present paper, we have identified a pair of
      catecholaminergic neurons (CBM1) in bilateral cerebral M clusters. The CBM1,
      probably equivalent to CBI-1 in A. californica, simultaneously produced
      monosynaptic excitatory postsynaptic potentials (EPSPs) in the MA and JC neurons.
      Firing of the CBM1 reduced the size of the inhibitory postsynaptic currents
      (IPSCs) in the JC neuron, evoked by the MA spikes, for >100 s. Moreover, the
      application of dopamine mimicked the CBM1 modulatory effects and pretreatment
      with a D1 antagonist, SCH23390, blocked the modulatory effects induced by
      dopamine. It could also largely block the modulatory effects induced by the CBM1
      firing. These results suggest that the CBM1 may directly modulate the synaptic
      transmission by releasing dopamine. Moreover, we explored the CBM1 spike activity
      induced by taste stimulation of the animal lips with seaweed extracts by the use
      of calcium imaging. The calcium-sensitive dye, Calcium Green-1, was
      iontophoretically loaded into a cell body of the CBM1 using a microelectrode.
      Application of either Ulva or Gelidium extract to the lips increased the
      fluorescence intensity, but the Gelidium extract always induced a larger change
      in fluorescence compared with the Ulva extract, although the solution used
      induced the maximum spike responses of the CBM1 for each of the seaweed extracts.
      When the firing frequency of the CBM1 activity after taste stimulation was
      estimated, the Gelidium extract induced a spike activity of ~30 spikes/s while
      the Ulva extract induced an activity of ~20 spikes/s, consistent with the
      effective firing frequency (>25 spikes/s) for the synaptic modulation. These
      results suggest that the CBM1 may be one of the cerebral neurons contributing to
      the modulation of the basic feeding circuits for rejection induced by the taste
      of seaweeds such as Gelidium.

PMID- 12424313
TI  - Spatial organization and magnitude of orientation contrast interactions in
      primate V1.
AB  - We have explored the spatial organization of orientation contrast effects in
      primate V1. Our stimuli were either concentric patches of drifting grating of
      varying orientation and diameter or grating patches displaced in x-y coordinates
      around a central patch overlying the classical receptive field (CRF). All cells
      in the sample exhibited response suppression to iso-oriented stimuli exceeding
      the CRF. Changing the outer stimulus orientation revealed five response patterns:
      1) orientation alignment suppression (17% of cells)-a suppressive component tuned
      to the same orientation as the cell's optimal, 2) orientation contrast
      facilitation (63%)-responses to orientation contrast stimuli exceeded those to
      the center stimulus alone, 3) nonorientation specific suppression (3%), 4) mixed
      general suppression and alignment suppression (14%), and 5) orientation contrast
      suppression (14%)-cross-oriented stimuli evoked stronger suppression than iso
      oriented stimuli. Thus most cells (94%) showed larger responses to orientation
      contrast stimuli than to iso-oriented stimuli, and over one-half showed
      orientation contrast facilitation. There appeared to be a spatially structured
      organization of the zones driving the different response patterns with respect to
      the CRF. Nonorientation-specific suppression and orientation contrast suppression
      were predominantly evoked by orientation contrast borders located within the CRF,
      and orientation contrast facilitation was mainly driven by surround stimuli lying
      outside the CRF. This led to different response patterns according to border
      location. Zones driving orientation contrast facilitation were not necessarily
      contiguous to, nor uniformly distributed around, the CRF. Our data support two
      processes underlying orientation contrast enhancement effects: a simple variation
      in the strength of surround suppression drawing on the fact that surround
      suppression is tuned to the same orientation as the CRF and a second process
      driven by orientation contrast that enhanced cells' responses to CRF stimulation
      by either dis-inhibition or orientation contrast facilitation. We suggest these
      processes may serve to enhance response levels to salient image features such as
      junctions and corners and may contribute to orientation pop-out.

PMID- 12424314
TI  - Structural inhomogeneities differentially modulate action currents and population
      spikes initiated in the axon or dendrites.
AB  - Action potentials (APs) in CA1 pyramidal cells propagate in different directions
      along the somatodendritic axis depending on the activation mode (synaptic or
      axonal). We studied how the geometrical inhomogeneities along the apical shaft,
      soma, and initial axon modulate the transmembrane current (I(m)) flow underlying
      APs, using model and experimental techniques. The computations obtained at the
      subcellular level during forward- and backpropagation were extrapolated to
      macroscopic level (field potentials) and compared with the basic in vivo features
      of the ortho- and antidromic population spike (PS) that reflects the sum total of
      all elementary currents from synchronously firing cells. The matching of
      theoretical and experimental results supports the following conclusions. Because
      the charge carried by axonal APs is almost entirely drained into dendrites, the
      soma invasion is preceded by little capacitive currents (I(cap)), the ionic
      currents (I(ion)) dominating I(m) and the depolarizing phase. The subsequent
      invasion of the tapering apical shaft is preceded, however, by significant
      I(cap), while I(ion) decayed gradually. A similar pattern occurred during
      backpropagation of spikes synaptically initiated in the axon. On the contrary,
      when the AP was apically initiated, the dendritic I(ion) was boosted by the
      apical flare, it was preceded by weak I(cap) and spread forwardly at a slower
      velocity. Soma invasion is reliable once the AP reached the main apical shaft but
      less so distal to the primary bifurcation, where it may be upheld by concurrent
      synaptic activity. The decreasing internal resistance of the apical shaft guided
      most axial current into the soma, causing its fast charging. There, I(ion) began
      later in the depolarizing phase of the AP and the reduced driving force made it
      smaller. This, in addition to a poor temporal overlapping of somatodendritic
      inward currents within individual cells, built a smaller extracellular sink,
      i.e., a smaller PS. In both experiment and model, the antidromic (axon-initiated)
      PS in the soma layer is approximately 30% larger than an orthodromic (apical
      shaft-initiated) PS contributed by the same number of firing cells. We conclude
      that the dominance of capacitive or ionic current components on I(m) is a
      distinguishing feature of forward and backward APs that is predictable from the
      geometric inhomogeneities between conducting subregions. Correspondingly,
      experimental and model APs have a faster rising slope during ortho than
      antidromic activation. The moderate flare of the apical shaft makes forward AP
      conduction quite safe. This alternative trigger zone enables two different
      processing modes for apical inputs.

PMID- 12424315
TI  - Disruption of coherent oscillations in inhibitory networks with anesthetics: role
      of GABA(A) receptor desensitization.
AB  - The effect of anesthetic drugs at central synapses can be described
      quantitatively by developing kinetic models of ligand-gated ion channels.
      Experiments have shown that the hypnotic propofol and the sedative benzodiazepine
      midazolam have similar effects on single inhibitory postsynaptic potentials
      (IPSPs) but very different effects on slow desensitization that are not revealed
      by examining single responses. Synchronous oscillatory activity in networks of
      interneurons connected by inhibitory synapses has been implicated in many
      hippocampal functions, and differences in the kinetics of the GABAergic response
      observed with anesthetics can affect this activity. Thus we have examined the
      effect of propofol and midazolam-enhanced IPSPs using mathematical models of self
      inhibited one- and two-cell inhibitory networks. A detailed kinetic model of the
      GABA(A) channel incorporating receptor desensitization is used at synapses in our
      models. The most dramatic effect of propofol is the modulation of slow
      desensitization. This is only revealed when the network is driven at frequencies
      that are thought to be relevant to cognitive tasks performed in the hippocampus.
      The level of desensitization at synapses with propofol is significantly reduced
      compared to control synapses. In contrast, midazolam increases macroscopic
      desensitization at network synapses by altering receptor affinity without
      concurrently modifying desensitization rates. These differences in gating between
      the two drugs are shown to alter network activity in stereotypically different
      ways. Specifically, propofol dramatically increases the amount of excitatory
      drive necessary for synchronized behavior relative to control, which is not the
      case for midazolam. Moreover, the range of parameters for which synchrony occurs
      is larger for propofol but smaller for midazolam, relative to control. This is an
      important first step in linking alterations in channel kinetics with behavioral
      changes.

PMID- 12424316
TI  - Role of dendritic spines in action potential backpropagation: a numerical
      simulation study.
AB  - Two remarkable aspects of pyramidal neurons are their complex dendritic
      morphologies and the abundant presence of spines, small structures that are the
      sites of excitatory input. Although the channel properties of the dendritic shaft
      membrane have been experimentally probed, the influence of spine properties in
      dendritic signaling and action potential propagation remains unclear. To explore
      this we have performed multi-compartmental numerical simulations investigating
      the degree of consistency between experimental data on dendritic channel
      densities and backpropagation behavior, as well as the necessity and degree of
      influence of excitable spines. Our results indicate that measured densities of
      Na(+) channels in dendritic shafts cannot support effective backpropagation
      observed in apical dendrites due to suprathreshold inactivation. We demonstrate
      as a potential solution that Na(+) channels in spines at higher densities than
      those measured in the dendritic shaft can support extensive backpropagation. In
      addition, clustering of Na(+) channels in spines appears to enhance their effect
      due to their unique morphology. Finally, we show that changes in spine morphology
      significantly influence backpropagation efficacy. These results suggest that, by
      clustering sodium channels, spines may serve to control backpropagation.

PMID- 12424317
TI  - Global contour saliency and local colinear interactions.
AB  - Our visual system can link components of contours and segregate contours from
      complex backgrounds based on geometric grouping rules. This is an important
      intermediate step in object recognition. The substrate for contour integration
      may be based on contextual interactions and intrinsic horizontal connections seen
      in primary visual cortex (V1). We examined the perceptual rules governing contour
      saliency to determine whether the spatial extents of contextual interactions and
      horizontal connections match those mediating saliency. To quantify these rules,
      we used stimuli composed of randomly oriented nonoverlapping line segments.
      Salient contours within this complex background were formed by colinear alignment
      of nearby segments. Contour detectability was measured using a 2-interval-forced
      choice design. Contour detectability deteriorated with increasing spacing between
      contour elements and improved as the number of colinear line elements was
      increased. At short contour spacing, the detectability reached a plateau with
      alignment of a few line segments that together formed a contour subtending
      several visual degrees. At intermediate spacing, saliency built up progressively
      with a greater number of colinear lines, extending up to 30 degrees. When contour
      spacing was beyond a critical range (about 2 degrees ), however, the
      detectability dropped to chance levels, regardless of the number of colinear
      lines. Contour detectability was found to be a function not only of the relative
      spacing of contour elements with respect to the noise elements but also of the
      average density of the overall pattern. Furthermore, training significantly
      improved contour detection, increasing the critical spacing of line elements
      beyond which contours were no longer detectable. Our data suggest that global
      contour integration is based on mechanisms of limited spatial extent, comparable
      to the interactions observed in V1. These interactions can cascade over larger
      distances provided the spacing of stimulus elements is kept within a limited
      range.

PMID- 12424318
TI  - Angiotensin AT(1)-receptors depolarize neonatal spinal motoneurons and other
      ventral horn neurons via two different conductances.
AB  - Angiotensin receptors are highly expressed in neonatal spinal cord. To identify
      their influence on neuronal excitability, we used patch-clamp recordings in
      spinal cord slices to assess responses of neonatal rat (5-12 days) ventral horn
      neurons to bath-applied angiotensin II (ANG II; 1 microM). In 14/34 identified
      motoneurons tested under current clamp, ANG II induced a slowly rising and
      prolonged membrane depolarization, blockable with Losartan (n = 5) and (Sar(1),
      Val(5), Ala(8))-ANG II (Saralasin, n = 4) but not PD123319 (1 microM each; n =
      4). Under voltage clamp (V(H) -65 mV), 7/22 motoneurons displayed an ANG-II
      induced tetrodotoxin-resistant inward current (-128 +/- 31 pA) with a similar
      time course, an associated reduction in membrane conductance and net current
      reversal at -98.8 +/- 3.9 mV. Losartan-sensitive ANG II responses were also
      evoked in 27/78 tested ventral horn "interneurons." By contrast with motoneurons,
      their ANG-II-induced inward current was smaller (-39.9 +/- 5.2 pA) and analysis
      of their I-V plots revealed three patterns. In eight cells, membrane conductance
      decreased with net inward current reversing at -103.8 +/- 4.1 mV. In seven cells,
      membrane conductance increased with net current reversing at -37.9 +/- 3.6 mV. In
      12 cells, I-V lines remained parallel with no reversal within the current range
      tested. Intracellular dialysis with GTP-gamma-S significantly prolonged the ANG
      II effect in seven responsive interneurons and GDP-beta-S significantly reduced
      the ANG II response in four other cells. Peak inward currents were significantly
      reduced in all 13 responding neurons recorded in slices incubated in pertussis
      toxin (5 microgram/ml) for 12-18 h or in 12 neurons perfused with N
      ethylmaleimide. Of 29 interneurons sensitive to pertussis toxin or N
      ethylmaleimide treatment, 9 cells displayed a decrease in membrane conductance
      that reversed at -101.3 +/- 3.8 mV. In eight cells, membrane conductance
      increased and reversed at -38.7 +/- 3.4 mV. In 12 cells, the I-V lines remained
      parallel with no reversal within the current range tested, suggesting that both
      conductances are modulated by pertussis toxin-sensitive G proteins. These
      observations reveal a direct, G-protein-mediated depolarizing action of ANG II on
      neonatal rat ventral horn neurons. They also imply involvement of two distinct
      conductances that are differentially distributed among different cell types.

PMID- 12424319
TI  - Category-sensitive excitatory and inhibitory processes in human extrastriate
      cortex.
AB  - Single-cell recordings from the temporal lobe of monkeys viewing stimuli show
      that cells may be highly selective, responding for example to particular objects
      such as faces. However, stimulus-selective cells may be inhibited by nonpreferred
      stimuli. Can such inhibitory mechanisms be detected in human visual cortex? In
      previous recordings from the surface of human ventral extrastriate cortex, we
      found that specific categories of stimuli such as faces and words generate
      category-specific negative event-related potentials (ERPs) with a peak latency of
      about 200 ms (N200). Laminar recordings in animal cortex suggest that the human
      N200 reflects excitatory depolarizing potentials in apical dendrites of pyramidal
      cells. In this study we found that, at about half of word-specific N200 sites,
      faces generated a positive ERP (P200); conversely, at about half of face-specific
      sites, words generated P200s. The electrogenesis of N200 implies that P200 ERPs
      reflect hyperpolarizing inhibition of apical dendrites. These recordings,
      together with the prior animal recordings, provide strong circumstantial evidence
      that in human cortex populations of cells responsive to one stimulus category
      (such as faces) inhibit cells responsive to another category (such as words),
      probably by a type of lateral inhibition. Of the stimulus categories studied
      quantitatively, face-specific cells are maximally inhibited by words and vice
      versa, but other categories of stimuli may generate smaller P200s, suggesting
      that inhibition of category-specific cells by nonpreferred stimuli is a general
      feature of human extrastriate cortex involved in object recognition.

PMID- 12424320
TI  - From following edges to pursuing objects.
AB  - Primates can generate accurate, smooth eye-movement responses to moving target
      objects of arbitrary shape and size, even in the presence of complex backgrounds
      and/or the extraneous motion of non-target objects. Most previous studies of
      pursuit have simply used a spot moving over a featureless background as the
      target and have thus neglected critical issues associated with the general
      problem of recovering object motion. Visual psychophysicists and theoreticians
      have shown that, for arbitrary objects with multiple features at multiple
      orientations, object-motion estimation for perception is a complex, multi-staged,
      time-consuming process. To examine the temporal evolution of the motion signal
      driving pursuit, we recorded the tracking eye movements of human observers to
      moving line-figure diamonds. We found that pursuit is initially biased in the
      direction of the vector average of the motions of the diamond's line segments and
      gradually converges to the true object-motion direction with a time constant of
      approximately 90 ms. Furthermore, transient blanking of the target during steady
      state pursuit induces a decrease in tracking speed, which, unlike pursuit
      initiation, is subsequently corrected without an initial direction bias. These
      results are inconsistent with current models in which pursuit is driven by
      retinal-slip error correction. They demonstrate that pursuit models must be
      revised to include a more complete visual afferent pathway, which computes, and
      to some extent latches on to, an accurate estimate of object direction over the
      first hundred milliseconds or so of motion.

PMID- 12424321
TI  - Neurons in parafoveal areas V1 and V2 encode vertical and horizontal disparities.
AB  - Stereoscopic vision mainly relies on binocular horizontal disparity (HD), and its
      cortical encoding is well established in the foveal representation of the visual
      field. The role of vertical disparity (VD) is more controversial. Thus far, in
      the monkey, very few studies have investigated the HD sensitivity beyond 5
      degrees of retinal eccentricity and no evidence of a real encoding of VD exists
      in the parafoveal representation of areas V1 and V2. Using dynamic random dot
      stereograms, we have tested both HD and VD selectivities in the parafoveal
      representation of V1 (calcarine V1) and V2 (eccentricities > 10 degrees ) in a
      behaving monkey. HD and VD selectivities have been characterized using fitting
      with Gabor function. A large proportion of the tested cells were both HD and VD
      selective (47%) and, to a lesser extent, HD selective only (8%) or VD selective
      only (23%). We found a real encoding of VD, with the same diversity in the tuning
      profiles as described for HD, that cannot be assimilated to a simple perturbation
      of the HD matching process. Moreover, the VD encoding had a finer scale than the
      HD one, which is coherent with the smaller range of naturally occurring VD. For
      the HD encoding, both the percentage of selective cells and the tuning parameters
      were close to those reported in foveal V1. These results show that, at parafoveal
      eccentricities in V1 and V2, disparity detectors are tuned to both horizontal and
      vertical dimensions of the positional disparity existing between matched features
      in both retinas.

PMID- 12424322
TI  - Motor scaling by viewing distance of early visual motion signals during smooth
      pursuit.
AB  - The geometry of gaze stabilization during head translation requires eye movements
      to scale proportionally to the inverse of target distance. Such a scaling has
      indeed been demonstrated to exist for the translational vestibuloocular reflex
      (TVOR), as well as optic flow-selective translational visuomotor reflexes (e.g.,
      ocular following, OFR). The similarities in this scaling by a neural estimate of
      target distance for both the TVOR and the OFR have been interpreted to suggest
      that the two reflexes share common premotor processing. Because the neural
      substrates of OFR are partly shared by those for the generation of pursuit eye
      movements, we wanted to know if the site of gain modulation for TVOR and OFR is
      also part of a major pathway for pursuit. Thus, in the present studies, we
      investigated in rhesus monkeys whether initial eye velocity and acceleration
      during the open-loop portion of step ramp pursuit scales with target distance.
      Specifically, with visual motion identical on the retina during tracking at
      different distances (12, 24, and 60 cm), we compared the first 80 ms of
      horizontal pursuit. We report that initial eye velocity and acceleration exhibits
      either no or a very small dependence on vergence angle that is at least an order
      of magnitude less than the corresponding dependence of the TVOR and OFR. The
      results suggest that the neural substrates for motor scaling by target distance
      remain largely distinct from the main pathway for pursuit.

PMID- 12424323
TI  - International symposium on the role of tomato products and carotenoids in disease
      prevention. April 10, 2001. Proceedings and abstracts.

PMID- 12424324
TI  - Chemistry, distribution, and metabolism of tomato carotenoids and their impact on
      human health.
AB  - Recent epidemiological studies have suggested that the consumption of tomatoes
      and tomato-based food products reduce the risk of prostate cancer in humans. This
      protective effect has been attributed to carotenoids, which are one of the major
      classes of phytochemicals in this fruit. The most abundant carotenoid in tomato
      is lycopene, followed by phytoene, phytofluene, zeta-carotene, gamma-carotene,
      beta-carotene, neurosporene, and lutein. The distribution of lycopene and related
      carotenoids in tomatoes and tomato-based food products has been determined by
      extraction and high-performance liquid chromatography-UV/Visible photodiode array
      detection. Detailed qualitative and quantitative analysis of human serum, milk,
      and organs, particularly prostate, have revealed the presence of all the
      aforementioned carotenoids in biologically significant concentrations. Two
      oxidative metabolites of lycopene, 2,6-cyclolycopene-1,5-diols A and B, which are
      only present in tomatoes in extremely low concentrations, have been isolated and
      identified in human serum, milk, organs (liver, lung, breast, liver, prostate,
      colon) and skin. Carotenoids may also play an important role in the prevention of
      age-related macular degeneration, cataracts, and other blinding disorders. Among
      25 dietary carotenoids and nine metabolites routinely found in human serum,
      mainly (3R,3'R,6'R)-lutein, (3R,3'R)-zeaxanthin, lycopene, and their metabolites
      were detected in ocular tissues. In this review we identified and quantified the
      complete spectrum of carotenoids from pooled human retinal pigment epithelium,
      ciliary body, iris, lens, and in the uveal tract and in other tissues of the
      human eye to gain a better insight into the metabolic pathways of ocular
      carotenoids. Although (3R,3'R,6'R)-lutein, (3R,3'R)-zeaxanthin, and their
      metabolites constitute the major carotenoids in human ocular tissues, lycopene
      and a wide range of dietary carotenoids have been detected in high concentrations
      in ciliary body and retinal pigment epithelium. The possible role of lycopene and
      other dietary carotenoids in the prevention of age-related macular degeneration
      and other eye diseases is discussed.

PMID- 12424325
TI  - A review of epidemiologic studies of tomatoes, lycopene, and prostate cancer.
AB  - Prostate cancer is the most common cancer in American men. Preventable measures
      for this malignancy are not well established. Among potentially beneficial
      natural compounds is the carotenoid lycopene, which is derived largely from
      tomato-based products. Recent epidemiologic studies have suggested a potential
      benefit of this carotenoid against the risk of prostate cancer, particularly the
      more lethal forms of this cancer. Five studies support a 30% to 40% reduction in
      risk associated with high tomato or lycopene consumption, three are consistent
      with a 30% reduction in risk, but the results were not statistically significant,
      and seven were not supportive of an association. The largest relevant dietary
      study, a prospective study in male health professionals found that consumption of
      two to four servings of tomato sauce per week was associated with about a 35%
      risk reduction of total prostate cancer and a 50% reduction of advanced
      (extraprostatic) prostate cancer. Tomato sauce was by far the strongest predictor
      of plasma lycopene levels in this study. In the largest plasma-based study, very
      similar risk reductions were observed for total and advanced prostate cancer for
      the highest versus lowest quintile of lycopene. Other studies, mostly dietary
      case-control studies, have not been as supportive of this hypothesis. The reasons
      for these inconsistencies are unclear, but in three of the seven null studies,
      tomato consumption or serum lycopene level may have been too low to observe an
      effect. Because the concentration and bioavailability of lycopene vary greatly
      across the various food items, dietary questionnaires vary markedly in their
      usefulness of estimating the true variation in tissue lycopene concentrations
      across individuals. To optimize the interpretation of future findings, the
      usefulness of the questionnaire to measure lycopene levels in a population should
      be directly assessed. Although not definitive, the available data suggest that
      increased consumption of tomatoes and tomato-based products may be prudent.

PMID- 12424326
TI  - Tomatoes, lycopene intake, and digestive tract and female hormone-related
      neoplasms.
AB  - Tomato consumption showed a consistent inverse relation with the risk of
      digestive tract neoplasms in Italy in an integrated series of studies conducted
      in the 1980s. Another series of case-control studies was conducted between 1992
      and 1999 in different areas of Italy. Cases were patients below age 80 with
      incident, histologically confirmed cancer of the oral cavity and pharynx (n =
      754), esophagus (n = 304), colorectum (n = 1953), breast (n = 2529), and ovary (n
      = 1031). The comparison group involved, overall, over 5000 patients below age 80
      with acute, non-neoplastic, nonhormone-related diseases, unrelated to long-term
      diet modifications and admitted to the same network of hospitals. Information was
      collected in hospital by trained interviewers using a validated food frequency
      questionnaire, including 78 foods or groups of foods, various alcoholic beverage,
      and fat-intake pattern. The multivariate relative risk (RR) of oral, pharyngeal,
      and esophageal cancer decreased across subsequent levels of lycopene intake to
      reach 0.7 (95% confidence interval [CI] 0.4-1.0) for oral and pharyngeal, and 0.7
      (95% CI 0.4-1.1) for esophageal cancer in the highest quintile of intake. Both
      trends in risk were of borderline statistical significance. With reference to
      colorectal, breast, and ovarian cancer, although no consistent association was
      observed for lycopene (RR = 1.0 for colorectal, 1.2 for breast, and 1.1 for ovary
      in the highest quintile), tomato intake was inversely and significantly related
      with colorectal cancer (RR = 0.8). The inverse relation between lycopene and
      upper digestive tract neoplasms was not explained by alcohol or tobacco,
      sociodemographic factors, or total energy intake. The interpretation of such an
      inverse relation, however, remains open to discussion because it may be related
      to an effect of lycopene due to its antioxidant effect and/or a potential role of
      lycopene in decreasing insulin growth factor I, which is a promoter in the
      process of carcinogenesis.

PMID- 12424327
TI  - A review of animal model studies of tomato carotenoids, lycopene, and cancer
      chemoprevention.
AB  - There are relatively few reports on the cancer chemopreventive effects of
      lycopene or tomato carotenoids in animal models. The majority, but not all, of
      these studies indicate a protective effect. Inhibitory effects were reported in
      two studies using aberrant crypt foci, an intermediate lesion leading to colon
      cancer, as an end point and in two mammary tumor studies, one using the
      dimethylbenz(a)anthracene model, and the other the spontaneous mouse model.
      Inhibitory effects were also reported in mouse lung and rat hepatocarcinoma and
      bladder cancer models. However, a report from the author's laboratory found no
      effect in the N-nitrosomethylurea-induced mammary tumor model when crystalline
      lycopene or a lycopene-rich tomato carotenoid oleoresin was administered in the
      diet. Unfortunately, because of differences in routes of administration (gavage,
      intraperitoneal injection, intra-rectal instillation, drinking water, and diet
      supplementation), species and strain differences, form of lycopene (pure
      crystalline, beadlet, mixed carotenoid suspension), varying diets (grain-based,
      casein based) and dose ranges (0.5-500 ppm), no two studies are comparable. It is
      clear that the majority of ingested lycopene is excreted in the feces and that
      1000-fold more lycopene is absorbed and stored in the liver than accumulates in
      other target organs. Nonetheless, physiologically significant (nanogram) levels
      of lycopene are assimilated by key organs such as breast, prostate, lung, and
      colon, and there is a rough dose-response relationship between lycopene intake
      and blood levels. Pure lycopene was absorbed less efficiently than the lycopene
      rich tomato carotenoid oleoresin and blood levels of lycopene in rats fed a grain
      based diet were consistently lower than those in rats fed lycopene in a casein
      based diet. The latter suggests that the matrix in which lycopene is incorporated
      is an important determinant of lycopene uptake. A number of issues remain to be
      resolved before any definitive conclusions can be drawn concerning the anticancer
      effects of lycopene. These include the following: the optimal dose and form of
      lycopene, interactions among lycopene and other carotenoids and fat soluble
      vitamins such as vitamin E and D, the role of dietary fat in regulating lycopene
      uptake and disposition, organ and tissue specificity, and the problem of
      extrapolation from rodent models to human populations.

PMID- 12424328
TI  - Tomatoes, lycopene, and prostate cancer: progress and promise.
AB  - Prostate cancer has emerged as a major public health problem in nations that have
      an affluent culture with an aging population. The search for etiologic risk
      factors and an emphasis on the development of chemopreventive agents has gained
      momentum over the last decade. Among the landmark epidemiologic findings during
      this period has been the association between the consumption of tomato products
      and a lower risk of prostate cancer. The traditional reductionist scientific
      approach has led many investigators to propose that lycopene, a carotenoid
      consumed largely from tomato products, may be the component responsible for
      lowering the risk of prostate cancer. Thus, many laboratory and clinical studies
      are now underway with the goal of assessing the ability of pure lycopene to serve
      as a chemopreventive agent for prostate and other malignancies. The focus on
      lycopene should continue, and an improved understanding of lycopene absorption,
      distribution, role in antioxidant reactions, and metabolism is critical in the
      quest to elucidate mechanisms whereby this compound could possibly reduce
      prostate cancer risk. In contrast to the pharmacologic approach with pure
      lycopene, many nutritional scientists direct their attention upon the diverse
      array of tomato products as a complex mixture of biologically active
      phytochemicals that together may have anti-prostate cancer benefits beyond those
      of any single constituent. These contrasting approaches will continue to be
      explored in clinical, laboratory and epidemiologic studies in the near future,
      providing hope that the next generation will benefit from this knowledge and
      experience a lower risk of prostate cancer.

PMID- 12424329
TI  - Effects of lycopene supplementation in patients with localized prostate cancer.
AB  - Epidemiological studies have shown an inverse association between dietary intake
      of lycopene and prostate cancer risk. We conducted a clinical trial to
      investigate the biological and clinical effects of lycopene supplementation in
      patients with localized prostate cancer. Twenty-six men with newly diagnosed
      prostate cancer were randomly assigned to receive a tomato oleoresin extract
      containing 30 mg of lycopene (n = 15) or no supplementation (n = 11) for 3 weeks
      before radical prostatectomy. Biomarkers of cell proliferation and apoptosis were
      assessed by Western blot analysis in benign and cancerous prostate tissues.
      Oxidative stress was assessed by measuring the peripheral blood lymphocyte DNA
      oxidation product 5-hydroxymethyl-deoxyuridine (5-OH-mdU). Usual dietary intake
      of nutrients was assessed by a food frequency questionnaire at baseline.
      Prostatectomy specimens were evaluated for pathologic stage, Gleason score,
      volume of cancer, and extent of high-grade prostatic intraepithelial neoplasia.
      Plasma levels of lycopene, insulin-like growth factor-1, insulin-like growth
      factor binding protein-3, and prostate-specific antigen were measured at baseline
      and after 3 weeks of supplementation or observation. After intervention, subjects
      in the intervention group had smaller tumors (80% vs 45%, less than 4 ml), less
      involvement of surgical margins and/or extra-prostatic tissues with cancer (73%
      vs 18%, organ-confined disease), and less diffuse involvement of the prostate by
      high-grade prostatic intraepithelial neoplasia (33% vs 0%, focal involvement)
      compared with subjects in the control group. Mean plasma prostate-specific
      antigen levels were lower in the intervention group compared with the control
      group. This pilot study suggests that lycopene may have beneficial effects in
      prostate cancer. Larger clinical trials are warranted to investigate the
      potential preventive and/or therapeutic role of lycopene in prostate cancer.

PMID- 12424330
TI  - Tomato sauce supplementation and prostate cancer: lycopene accumulation and
      modulation of biomarkers of carcinogenesis.
AB  - As part of a randomized placebo-controlled study to evaluate the effect of
      lycopene supplementation on DNA damage in men with prostate cancer, a
      nonrandomized 5th arm using tomato sauce was included and reported here. Thirty
      two patients with localized prostate adenocarcinoma consumed tomato sauce-based
      pasta dishes for 3 weeks (30 mg of lycopene/day) before their scheduled radical
      prostatectomy. Prostate tissue was obtained as biopsies at baseline and as
      resected tissue at the time of the prostatectomy. Serum and prostate lycopene,
      serum prostate specific antigen (PSA) concentrations, and leukocyte DNA 8-OH
      deoxyguanosine/deoxyguanosine (8OHdG) were measured at baseline and at the end of
      the intervention. Cancer cells in paraffin sections of prostate biopsies and
      postintervention resected tissue were compared for 8OHdG staining and for
      apoptosis. Adherence to the daily consumption of tomato-based entrees was 81.6%
      of the intended dose, and serum and prostate lycopene concentrations increased
      1.97- and 2.92-fold (P < 0.001), respectively. Mean serum PSA concentrations
      decreased by 17.5% (P < 0.002) and leukocyte 8OHdG decreased by 21.3% (P < 0.005)
      after tomato sauce consumption. Resected tissues from tomato sauce-supplemented
      patients had 28.3% lower prostate 8OHdG compared with the nonstudy control group
      (P < 0.03). Cancer cell 8OHdG staining of Gleason Score-matched resected prostate
      sections was reduced by 40.5% in mean nuclear density (P < 0.005) and by 36.4% in
      mean area (P < 0.018) compared with the presupplementation biopsy. Apoptotic
      index was higher in hyperplastic and neoplastic cells in the resected tissue
      after supplementation. These data taken as a whole indicate significant uptake of
      lycopene into prostate tissue and a reduction in DNA damage in both leukocyte and
      prostate tissue. Whether reduction in DNA damage to prostate cancer cells is
      beneficial awaits further research, although reduction in serum PSA
      concentrations is promising.

PMID- 12424331
TI  - Lycopene and the lung.
AB  - The human lung, due to the oxidative and ozone stress to which it is exposed, is
      particularly vulnerable to oxidative damage. Concentrations of dietary
      antioxidants in the lung epithelial lining and lining fluids may provide
      protection against oxidative damage. A randomized clinical trial was conducted to
      study the effects of supplemental, carotenoid-rich vegetable juice (V-8) on lung
      function macrophage levels of carotenoids and in moderating ozone-induced lung
      damage. Healthy young adults (n = 23) were exposed to 0.4 ppm ozone in a chamber
      for 2 hr after either 2 weeks of antioxidant supplementation (including one can
      of V-8 juice daily) or placebo. Mean lung concentrations of lycopene increased by
      12%, and lung epithelial cell DNA damage as measured by the Comet Assay decreased
      20% in supplemented subjects. No change in peripheral blood lymphocyte DNA damage
      was observed as evidenced by no change in mean comet area or length in
      supplemented or placebo subjects. We were not able to separate the effects of
      lycopene from other carotenoids or antioxidants administered in this study;
      however, lycopene is the predominant carotenoid in V-8 (it represents 88% of
      total carotenoids). A review of the epidemiologic literature providing evidence
      for the effect of lycopene (diet or serum) or tomatoes on the risk of lung cancer
      reveals 27 observational epidemiologic studies (18 case-control and nine cohort
      studies) reporting relative risk (RR) estimates. RR estimates for cohort studies
      ranged from 0.63 to 1.24 (mean RR = 0.93, SD = 0.16). Odds ratios (OR) for case
      control studies ranged from 0.27 to 0.93 (mean OR = 0.61, SD = 0.16). Both plasma
      levels (RR = 1.01, OR = 0.37) and estimated intakes of lycopene from dietary
      sources (mean RR = 0.93, RR range = 0.80-1.05; mean OR = 0.67, OR range = 0.27
      0.93) were examined. Seventeen studies, three of which were cohorts, reported
      their results at the level of tomato consumption rather than, or in addition to,
      lycopene consumption (mean RR = 0.89, RR range = 0.63-1.24; mean OR = 0.61, OR
      range = 0.37-0.80). The published epidemiologic literature shows an interaction
      between study design and the relationship between lycopene and/ or tomatoes and
      risk of lung cancer. Overall, cohort studies did not show an association, whereas
      case-control studies showed a decreased risk with greater consumption of lycopene
      and tomatoes. Although lycopene can be found in the human lung, and there is
      evidence, albeit weak, for a protective association with lung cancer, its
      biologic role remains to be elucidated.

PMID- 12424332
TI  - Lycopene, atherosclerosis, and coronary heart disease.
AB  - Diets rich in fruits and vegetables containing carotenoids have been of interest
      because of their potential health benefit against chronic diseases such as
      cardiovascular diseases (CVD) and cancer. Interest particularly in lycopene is
      growing rapidly following the recent publication of epidemiological studies that
      have associated high lycopene levels with reductions in CVD incidence. Two
      studies were conducted. In the first one, we examined the role of lycopene as a
      risk-lowering factor with regard to acute coronary events and stroke in the
      prospective Kuopio Ischemic Heart Disease Risk Factor (KIHD) Study. The subjects
      were 725 middle-aged men free of coronary heart disease and stroke at the study
      baseline. In a Cox's proportional hazards' model adjusting for covariates, men in
      the lowest quartile of serum levels of lycopene had a 3.3-fold (P < 0.001) risk
      of the acute coronary event or stroke as compared with others. In the second
      study, we assessed the association between plasma concentration of lycopene and
      intima-media thickness of the common carotid artery wall (CCA-IMT) in a cross
      sectional analysis of the Antioxidant Supplementation in the Atherosclerosis
      Prevention (ASAP) study data in 520 asymptomatic men and women. In a covariance
      analysis adjusting for common cardiovascular risk factors, low plasma levels of
      lycopene were associated with an 18% increase of IMT in men as compared with men
      in whom plasma levels were higher than median (P = 0.003 for difference). In
      women, the difference did not remain significant after the adjustments. On the
      basis of these works, it is evident that the circulating levels of lycopene play
      some role with regard to cardiovascular health in Finland, at least in men. We
      conclude that circulating levels of lycopene, a biomarker of tomato-rich food,
      may play a role in early stages of atherogenesis and may have clinical and public
      health relevance.

PMID- 12424333
TI  - Lycopene, tomatoes, and the prevention of coronary heart disease.
AB  - Coronary heart disease (CHD) is one of the primary causes of death in the Western
      world. The emphasis so far has been on the relationship between serum cholesterol
      levels and the risk of CHD. More recently, oxidative stress induced by reactive
      oxygen species (ROS) is also considered to play an important part in the etiology
      of this disease. Oxidation of the circulating low-density lipoprotein (LDL(ox))
      is thought to play a key role in the pathogenesis of atherosclerosis and CHD.
      According to this hypothesis, macrophages inside the arterial wall take up the
      LDL(ox) and initiate the process of plaque formation. Dietary antioxidants such
      as vitamin E and beta-carotene have been shown in in vitro studies to prevent the
      formation of LDL(ox) and their uptake by microphages. In a recent study, healthy
      human subjects ingesting lycopene, a carotenoid antioxidant, in the form of
      tomato juice, tomato sauce, and oleoresin soft gel capsules for 1 week had
      significantly lower levels of LDL(ox) compared with controls. The antioxidant
      effects of lycopene have also been shown in four other human trials, including
      one where lycopene consumption reduced the levels of breath pentane. However, in
      one recent study, dietary supplementation with beta-carotene but not with
      lycopene was shown to inhibit LDL oxidation. The sources of lycopene used in most
      of these studies were either tomato products or lycopene extracted from tomatoes
      containing other carotenoids in various proportions. Therefore, it is not
      possible to attribute the effects solely to lycopene. Mechanisms other than the
      antioxidant properties of lycopene have also been shown to reduce the risk of
      CHD. Lycopene was shown to inhibit the activity of an essential enzyme involved
      in cholesterol synthesis in an in vitro and a small clinical study suggesting a
      hypocholesterolemic effect. Other possible mechanisms include enhanced LDL
      degradation, LDL particle size and composition, plaque rupture, and altered
      endothelial functions. Recent epidemiological studies have also shown an inverse
      relationship between tissue and serum levels of lycopene and mortality from CHD,
      cerebrovascular disease, and myocardial infraction. However, the most impressive
      population-based evidence comes from a multicenter case-control study where
      subjects from 10 European countries were evaluated for relationship between
      antioxidant status and acute myocardial infarctions. After adjusting for a range
      of dietary variables, only lycopene levels but not beta-carotene were found to be
      protective. At present, the role of lycopene in the prevention of CHD is strongly
      suggestive. Although the antioxidant property of lycopene may be one of the
      principal mechanism for its effect, other mechanisms may also be responsible.
      Controlled clinical and dietary intervention studies using well-defined subject
      populations and disease end points must be undertaken in the future to provide
      definitive evidence for the role of lycopene in the prevention of CHD.
      Mechanistic studies must also be initiated to understand the mode of lycopene
      action.

PMID- 12424334
TI  - Bioavailability of all-trans and cis-isomers of lycopene.
AB  - Lycopene, the predominant carotenoid in tomatoes, is among the major carotenoids
      in serum and tissues of Americans. Although about 90% of the lycopene in dietary
      sources is found in the linear, all-trans conformation, human tissues contain
      mainly cis-isomers. Several research groups have suggested that cis-isomers of
      lycopene are better absorbed than the all-trans form because of the shorter
      length of the cis-isomer, the greater solubility of cis-isomers in mixed
      micelles, and/or as a result of the lower tendency of cis-isomers to aggregate.
      Work with ferrets, a species that absorbs carotenoids intact, has demonstrated
      that whereas a lycopene dose, stomach, and intestinal contents contained 6-18%
      cis-lycopene, the mesenteric lymph secretions contained 77%-cis isomers. The
      ferret studies support the hypotheses that cis-isomers are substantially more
      bioavailable then all-trans lycopene. In vitro studies suggest that cis-isomers
      are more soluble in bile acid micelles and may be preferentially incorporated
      into chylomicrons. The implications of these findings are not yet clear. Rats
      appear to accumulate lycopene in tissues within the ranges reported for humans,
      suggesting that they can be used to study effects of lycopene isomers on disease
      processes. Investigations are underway to determine whether there are biological
      differences between all-trans and various cis-isomers of lycopene regarding its
      antioxidant properties or other biological functions.

PMID- 12424335
TI  - Overview of mechanisms of action of lycopene.
AB  - Dietary intakes of tomatoes and tomato products containing lycopene have been
      shown to be associated with decreased risk of chronic diseases such as cancer and
      cardiovascular diseases in numerous studies. Serum and tissue lycopene levels
      have also been inversely related to the risk of lung and prostate cancers.
      Lycopene functions as a very potent antioxidant, and this is clearly a major
      important mechanism of lycopene action. In this regard, lycopene can trap singlet
      oxygen and reduce mutagenesis in the Ames test. However, evidence is accumulating
      for other mechanisms as well. Lycopene at physiological concentrations can
      inhibit human cancer cell growth by interfering with growth factor receptor
      signaling and cell cycle progression specifically in prostate cancer cells
      without evidence of toxic effects or apoptosis of cells. Studies using human and
      animal cells have identified a gene, connexin 43, whose expression is upregulated
      by lycopene and which allows direct intercellular gap junctional communication
      (GJC). GJC is deficient in many human tumors and its restoration or upregulation
      is associated with decreased proliferation. The combination of low concentrations
      of lycopene with 1,25-dihydroxyvitamin D3 exhibits a synergistic effect on cell
      proliferation and differentiation and an additive effect on cell cycle
      progression in the HL-60 promyelocytic leukemia cell line, suggesting some
      interaction at a nuclear or subcellular level. The combination of lycopene and
      lutein synergistically interact as antioxidants, and this may relate to specific
      positioning of different carotenoids in membranes. This review will focus on the
      growing body of evidence that carotenoids have unexpected biologic effects in
      experimental systems, some of which may contribute to their cancer preventive
      properties in models of carcinogenesis. Consideration of solubility in vitro,
      comparison with doses achieved in humans by dietary means, interactions with
      other phytochemicals, and other potential mechanisms such as stimulation of
      xenobiotic metabolism, inhibition of cholesterogenesis, modulation of
      cyclooxygenase pathways, and inhibition of inflammation will be considered. This
      review will point out areas for future research where more evidence is needed on
      the effects of lycopene on the etiology of chronic disease.

PMID- 12424336
TI  - Lycopene and tomato products in health promotion.
AB  - International research through epidemiological techniques has provided
      information on risk factors and preventive approaches in chronic disease.
      Causation complementing this base of knowledge with laboratory research on
      associated markers for each disease has outlined the possible mechanisms whereby
      risk factors and preventive conditions operate. Furthermore, laboratory research
      in animal models and cell cultures has expanded the appropriate elements
      associated with each condition. Individuals in the Mediterranean area present
      with a lower risk of several important chronic diseases, including coronary heart
      disease and a number of types of cancer associated with nutritional traditions,
      such as breast, colon, and prostate cancer. Vegetables and fruits in general and
      cooked tomatoes, together with olive oil, appear to be the nutritional traditions
      that account for this lower risk. These results lead to public health
      recommendations to consume more vegetables and, especially, cooked tomatoes with
      olive oil.

PMID- 12424338
TI  - A chloroplast FKBP interacts with and affects the accumulation of Rieske subunit
      of cytochrome bf complex.
AB  - Immunophilins are intracellular receptors of the immunosuppressants cyclosporin
      A, FK506, and rapamycin. Although all immunophilins possess peptidyl-prolyl
      isomerase activity and are identified from a wide range of organisms, little is
      known about their cellular functions. We report the characterization and
      functional analysis of an FK506 and rapamycin-binding protein (AtFKBP13) from
      Arabidopsis. The AtFKBP13 protein is synthesized as a precursor that is imported
      into chloroplasts and processed to the mature form located in the thylakoid
      lumen, as shown by chloroplast import assays and Western blot analysis.
      Experiments show that AtFKBP13 is translocated across the thylakoid membrane by
      the DeltapH-dependent pathway. Yeast two-hybrid screening identified Rieske FeS
      protein, a subunit of the cytochrome bf complex in the photosynthetic electron
      transport chain, as an interacting partner for AtFKBP13. Both yeast two-hybrid
      and in vitro protein-protein interaction assays showed that the precursor, but
      not the mature form, of AtFKBP13 interacted with Rieske protein, suggesting that
      interaction between the two proteins occurs along the import pathway. When
      AtFKBP13 expression was suppressed by RNA interference method, the level of
      Rieske protein was significantly increased in the transgenic plants.

PMID- 12424339
TI  - Measurement in vivo of proliferation rates of slow turnover cells by 2H2O
      labeling of the deoxyribose moiety of DNA.
AB  - We describe here a method for measuring DNA replication and, thus, cell
      proliferation in slow turnover cells that is suitable for use in humans. The
      technique is based on the incorporation of (2)H(2)O into the deoxyribose (dR)
      moiety of purine deoxyribonucleotides in dividing cells. For initial validation,
      rodents were administered 4% (2)H(2)O in drinking water. The proliferation rate
      of mammary epithelial cells in mice was 2.9% per day and increased 5-fold during
      pregnancy. Administration of estradiol pellets (0-200 microg) to ovariectomized
      rats increased mammary epithelial cell proliferation, according to a dose
      response relationship up to the 100 microg dose. Similarly, proliferation of
      colon epithelial cells was stimulated in a dose-response manner by dietary cholic
      acid in rats. Bromodeoxyuridine labeling correlated with the (2)H(2)O results.
      Proliferation of slow turnover cells was then measured. Vascular smooth muscle
      cells isolated from mouse aorta divided with a half-life in the range of 270-400
      days and die-away values after (2)H(2)O wash-out confirmed these slow turnover
      rates. The proliferation rate of an adipocyte-enriched fraction from mouse
      adipose tissue depots was 1-1.5% new cells per day, whereas obese ad libitum-fed
      obob mice exhibited markedly higher fractional and absolute proliferation rates.
      In humans, stable long-term (2)H(2)O enrichments in body water were achieved by
      daily (2)H(2)O intake, without toxicities. Labeled dR from fully turned-over
      blood cells (monocytes or granulocytes) exhibited a consistent amplification
      factor relative to body (2)H(2)O enrichment ( approximately 3.5-fold). The
      fraction of newly divided naive-phenotype T cells after 9 weeks of labeling with
      (2)H(2)O was 0.056 (CD4(+)) and 0.043 (CD8(+)) (replacement rate <0.1% per day).
      In summary, (2)H(2)O labeling of dR in DNA allows safe, convenient, reproducible,
      and inexpensive measurement of cell proliferation in humans and experimental
      animals and is well suited for slow turnover cells.

PMID- 12424340
TI  - Membrane localization of MinD is mediated by a C-terminal motif that is conserved
      across eubacteria, archaea, and chloroplasts.
AB  - MinD is a widely conserved ATPase that has been demonstrated to play a pivotal
      role in selection of the division site in eubacteria and chloroplasts. It is a
      member of the large ParA superfamily of ATPases that are characterized by a
      deviant Walker-type ATP-binding motif. MinD localizes to the cytoplasmic face of
      the inner membrane in Escherichia coli, and its association with the inner
      membrane is a prerequisite for membrane recruitment of the septation inhibitor
      MinC. However, the mechanism by which MinD associates with the membrane has
      proved enigmatic; it seems to lack a transmembrane domain and the amino acid
      sequence is devoid of hydrophobic tracts that might predispose the protein to
      interaction with lipids. In this study, we show that the extreme C-terminal
      region of MinD contains a highly conserved 8- to 12-residue sequence motif that
      is essential for membrane localization of the protein. We provide evidence that
      this motif forms an amphipathic helix that most likely mediates a direct
      interaction between MinD and membrane phospholipids. A model is proposed whereby
      the membrane-targeting motif mediates the rapid cycles of membrane attachment
      release-reattachment that are presumed to occur during pole-to-pole oscillation
      of MinD in E. coli.

PMID- 12424342
TI  - Scientist support for biological weapons controls.

PMID- 12424341
TI  - Activin A induces craniofacial cartilage from undifferentiated Xenopus ectoderm
      in vitro.
AB  - Activin A has potent mesoderm-inducing activity in amphibian embryos and induces
      various mesodermal tissues in vitro from the isolated presumptive ectoderm. By
      using a sandwich culture method established to examine activin A activity, we
      previously demonstrated that activin-treated ectoderm can function as both a head
      and trunk-tail organizer, depending on the concentration of activin A. By using
      activin A and undifferentiated presumptive ectoderm, it is theoretically possible
      to reproduce embryonic induction. Here, we test this hypothesis by studying the
      induction of cartilage tissue by using the sandwich-culture method. In the
      sandwiched explants, the mesenchymal cell condensation expressed type II collagen
      and cartilage homeoprotein-1 mRNA, and subsequently, cartilage were induced as
      they are in vivo. goosecoid (gsc) mRNA was prominently expressed in the cartilage
      in the explants. Xenopus distal-less 4 (X-dll4) mRNA was expressed throughout the
      explants. In Xenopus embryos, gsc expression is restricted to the cartilage of
      the lower jaw, and X-dll4 is widely expressed in the ventral head region,
      including craniofacial cartilage. These finding suggest that the craniofacial
      cartilage, especially lower jaw cartilage, was induced in the activin-treated
      sandwiched explants. In addition, a normal developmental pattern was
      recapitulated at the histological and genetic level. This work also suggests that
      the craniofacial cartilage-induction pathway is downstream of activin A. This
      study presents a model system suitable for the in vitro analysis of craniofacial
      cartilage induction in vertebrates.

PMID- 12424343
TI  - Toxicology. Questions swirl over knockout gas used in hostage crisis.

PMID- 12424344
TI  - Astronomy. California astronomers eye 30-meter scope.

PMID- 12424345
TI  - Food aid. Zambia rejects GM corn on scientists' advice.

PMID- 12424346
TI  - Fishery science. Poor to feel pinch of rising fish prices.

PMID- 12424348
TI  - U.S. budget. Smithsonian science: vote of confidence.

PMID- 12424347
TI  - Techniques. A new window on the cell's inner workings.

PMID- 12424349
TI  - Biobanks. Population databases boom, from Iceland to the U.S.

PMID- 12424351
TI  - Profile: Brian Tucker. Bracing for the shocks of the future.

PMID- 12424350
TI  - Biobanks. Private biobanks spark ethical concerns.

PMID- 12424352
TI  - European research. Framework 6 debut prompts calls for a better approach.

PMID- 12424353
TI  - Paleoceanography. Inconstant ancient seas and life's path.

PMID- 12424354
TI  - Theoretical physics. Constructing spacetime--no strings attached.

PMID- 12424355
TI  - Patent law. New rules for German professors.

PMID- 12424356
TI  - Oceanography. What is the thermohaline circulation?

PMID- 12424357
TI  - Conservation biology. Predictive ecology to the rescue?

PMID- 12424358
TI  - Materials science. Talking ceramics.

PMID- 12424359
TI  - Neurobiology. A glial spin on neurotrophins.

PMID- 12424360
TI  - Paleoclimate. A poisoned chalice?

PMID- 12424361
TI  - Neuroscience. Freeing the bain from the perineuronal net.

PMID- 12424362
TI  - Signal transduction. Decoding NF-kappaB signaling.

PMID- 12424363
TI  - Emotion, cognition, and behavior.
AB  - Emotion is central to the quality and range of everyday human experience. The
      neurobiological substrates of human emotion are now attracting increasing
      interest within the neurosciences motivated, to a considerable extent, by
      advances in functional neuroimaging techniques. An emerging theme is the question
      of how emotion interacts with and influences other domains of cognition, in
      particular attention, memory, and reasoning. The psychological consequences and
      mechanisms underlying the emotional modulation of cognition provide the focus of
      this article.

PMID- 12424365
TI  - Resuscitating Asia's damaged heart.

PMID- 12424367
TI  - Reclaiming Afghanistan's past. Fate of Tilya Tepe remains a mystery.

PMID- 12424366
TI  - Unanswered questions of Afghan archaeology.

PMID- 12424368
TI  - Reclaiming Afghanistan's past. To dig or not to dig?

PMID- 12424370
TI  - Reclaiming Afghanistan's past. 'Then they buried their history'.

PMID- 12424369
TI  - Reclaiming Afghanistan's past. Leaning tower poses a technical and political
      challenge.

PMID- 12424371
TI  - Reclaiming Afghanistan's past. Buddhas may stretch out, if not rise again.

PMID- 12424372
TI  - Cell-to-cell communication across the prokaryote-eukaryote boundary.

PMID- 12424373
TI  - Macromolecular architecture in eukaryotic cells visualized by cryoelectron
      tomography.
AB  - Electron tomography of vitrified cells is a noninvasive three-dimensional imaging
      technique that opens up new vistas for exploring the supramolecular organization
      of the cytoplasm. We applied this technique to Dictyostelium cells, focusing on
      the actin cytoskeleton. In actin networks reconstructed without prior removal of
      membranes or extraction of soluble proteins, the cross-linking of individual
      microfilaments, their branching angles, and membrane attachment sites can be
      analyzed. At a resolution of 5 to 6 nanometers, single macromolecules with
      distinct shapes, such as the 26S proteasome, can be identified in an unperturbed
      cellular environment.

PMID- 12424374
TI  - Seismic images of crust and upper mantle beneath Tibet: evidence for Eurasian
      plate subduction.
AB  - Seismic data from central Tibet have been combined to image the subsurface
      structure and understand the evolution of the collision of India and Eurasia. The
      410- and 660-kilometer mantle discontinuities are sharply defined, implying a
      lack of a subducting slab beneath the plateau. The discontinuities appear
      slightly deeper beneath northern Tibet, implying that the average temperature of
      the mantle above the transition zone is about 300 degrees C hotter in the north
      than in the south. There is a prominent south-dipping converter in the uppermost
      mantle beneath northern Tibet that might represent the top of the Eurasian mantle
      lithosphere underthrusting the northern margin of the plateau.

PMID- 12424375
TI  - Fossil echinoderms as monitor of the Mg/Ca ratio of Phanerozoic oceans.
AB  - Opinion has long been divided as to whether the Mg/Ca ratio of seawater remained
      constant during the Phanerozoic or underwent substantial secular change. Existing
      empirical evidence for the Mg/Ca of ancient seawater provides a poorly resolved
      and often controversial signal. Echinoderm fossils that have retained their bulk
      original chemistry, despite micrometer-scale changes, preserve a record of
      seawater Mg/Ca and confirm that major changes in Mg/Ca occurred during the
      Phanerozoic. Echinoderms from the Cambrian and from the Carboniferous to the
      Triassic indicate a seawater Mg/Ca of approximately 3.3, whereas echinoderms from
      the Jurassic to the Cretaceous indicate a Mg/Ca of approximately 1.4. The present
      seawater Mg/Ca is approximately 5.

PMID- 12424376
TI  - Vibrational transition moment angles in isolated biomolecules: a structural tool.
AB  - Infrared spectroscopy is used extensively in the study of isolated biomolecules,
      but it becomes less useful as it is applied to systems of increasing complexity.
      Even if the individual vibrational bands can be resolved spectroscopically, their
      assignment becomes problematic when they are more closely spaced than can be
      determined using ab initio methods. We describe a method that helps to alleviate
      this difficulty by measuring the direction of the vibrational transition moment
      for each vibrational band. The molecules of interest (adenine and cytosine) are
      cooled to 0.37 kelvin in liquid helium nanodroplets and oriented in a large dc
      electric field. A polarized infrared laser is then used to determine the
      directions of the infrared transition moments relative to the permanent dipole
      moment. Comparisons with ab initio calculations provide detailed structural
      information, including experimental evidence for nonplanarity of adenine and
      three tautomers of cytosine.

PMID- 12424377
TI  - Sperm-female coevolution in Drosophila.
AB  - Rapid evolution of reproductive traits has been attributed to sexual selection
      arising from interaction between the sexes. However, little is known about the
      nature of selection driving the evolution of interacting sex-specific phenotypes.
      Using populations of Drosophila melanogaster selected for divergent sperm length
      or female sperm-storage organ length, we experimentally show that male
      fertilization success is determined by an interaction between sperm and female
      morphology. In addition, sperm length evolution occurred as a correlated response
      to selection on the female reproductive tract. Giant sperm tails are the cellular
      equivalent of the peacock's tail, having evolved because females evolved
      reproductive tracts that selectively bias paternity in favor of males with longer
      sperm.

PMID- 12424378
TI  - Ecological predictions and risk assessment for alien fishes in North America.
AB  - Methods of risk assessment for alien species, especially for nonagricultural
      systems, are largely qualitative. Using a generalizable risk assessment approach
      and statistical models of fish introductions into the Great Lakes, North America,
      we developed a quantitative approach to target prevention efforts on species most
      likely to cause damage. Models correctly categorized established, quickly
      spreading, and nuisance fishes with 87 to 94% accuracy. We then identified fishes
      that pose a high risk to the Great Lakes if introduced from unintentional
      (ballast water) or intentional pathways (sport, pet, bait, and aquaculture
      industries).

PMID- 12424379
TI  - Avian persistence in fragmented rainforest.
AB  - What factors determine the persistence of species in fragmented habitats? To
      address this question, we studied the relative impacts of forest deterioration
      and fragmentation on bird species in 12 rainforest fragments in Kenya, combining
      6 years of individual capture-recapture data with measurements of current
      captures and museum specimens. Species mobility, as estimated from species
      specific dispersal rates, and tolerance to habitat deterioration, as estimated
      from change in fluctuating asymmetry with increasing habitat disturbance,
      explained 88% of the variation in patch occupancy among eight forest bird
      species. Occupancy increased with mobility and with tolerance to deterioration,
      where both variables contributed equally to this relationship. We conclude that
      individual-level study, such as of dispersal behavior and phenotypic development,
      can predict patterns of persistence at the species level. More generally, for
      conservation tactics to stand a high chance of success, they should include
      action both within sites, to minimize habitat deterioration, and across
      landscapes, to maximize dispersal.

PMID- 12424380
TI  - The control of spikelet meristem identity by the branched silkless1 gene in
      maize.
AB  - Most of the world's food supply is derived from cereal grains that are borne in a
      unique structure called the spikelet, the fundamental unit of inflorescence
      architecture in all grasses. branched silkless1 (bd1) is a maize mutation that
      alters the identity of the spikelet meristem, causing indeterminate branches to
      form in place of spikelets. We show that bd1 encodes a putative ERF transcription
      factor that is conserved in different grasses and is expressed in a distinct
      domain of the spikelet meristem. Its expression pattern suggests that signaling
      pathways regulate meristem identity from lateral domains of the spikelet
      meristem.

PMID- 12424381
TI  - The IkappaB-NF-kappaB signaling module: temporal control and selective gene
      activation.
AB  - Nuclear localization of the transcriptional activator NF-kappaB (nuclear factor
      kappaB) is controlled in mammalian cells by three isoforms of NF-kappaB inhibitor
      protein: IkappaBalpha, -beta, and - epsilon. Based on simplifying reductions of
      the IkappaB-NF-kappaB signaling module in knockout cell lines, we present a
      computational model that describes the temporal control of NF-kappaB activation
      by the coordinated degradation and synthesis of IkappaB proteins. The model
      demonstrates that IkappaBalpha is responsible for strong negative feedback that
      allows for a fast turn-off of the NF-kappaB response, whereas IkappaBbeta and -
      epsilon function to reduce the system's oscillatory potential and stabilize NF
      kappaB responses during longer stimulations. Bimodal signal-processing
      characteristics with respect to stimulus duration are revealed by the model and
      are shown to generate specificity in gene expression.

PMID- 12424382
TI  - The neurotrophin receptor p75NTR as a positive modulator of myelination.
AB  - Schwann cells in developing and regenerating peripheral nerves express elevated
      levels of the neurotrophin receptor p75NTR. Neurotrophins are key mediators of
      peripheral nervous system myelination. Our results show that myelin formation is
      inhibited in the absence of functional p75NTR and enhanced by blocking TrkC
      activity. Moreover, the enhancement of myelin formation by endogenous brain
      derived neurotrophic factor is mediated by the p75NTR receptor, whereas TrkC
      receptors are responsible for neurotrophin-3 inhibition. Thus p75NTR and TrkC
      receptors have opposite effects on myelination.

PMID- 12424383
TI  - Reactivation of ocular dominance plasticity in the adult visual cortex.
AB  - In young animals, monocular deprivation leads to an ocular dominance shift,
      whereas in adults after the critical period there is no such shift. Chondroitin
      sulphate proteoglycans (CSPGs) are components of the extracellular matrix (ECM)
      inhibitory for axonal sprouting. We tested whether the developmental maturation
      of the ECM is inhibitory for experience-dependent plasticity in the visual
      cortex. The organization of CSPGs into perineuronal nets coincided with the end
      of the critical period and was delayed by dark rearing. After CSPG degradation
      with chondroitinase-ABC in adult rats, monocular deprivation caused an ocular
      dominance shift toward the nondeprived eye. The mature ECM is thus inhibitory for
      experience-dependent plasticity, and degradation of CSPGs reactivates cortical
      plasticity.

PMID- 12424384
TI  - Alcohol consumption impairs detection of performance errors in mediofrontal
      cortex.
AB  - The anterior cingulate cortex (ACC) is a critical component of the human
      mediofrontal neural circuit that monitors ongoing processing in the cognitive
      system for signs of erroneous outcomes. Here, we show that the consumption of
      alcohol in moderate doses induces a significant deterioration of the ability to
      detect the activation of erroneous responses as reflected in the amplitude of
      brain electrical activity associated with the ACC. This impairment was
      accompanied by failures to instigate performance adjustments after these errors.
      These findings offer insights into how the effects of alcohol on mediofrontal
      brain function may result in compromised performance.

PMID- 12424385
TI  - Martian meteorite launch: high-speed ejecta from small craters.
AB  - We performed high-resolution computer simulations of impacts into homogeneous and
      layered martian terrain analogs to try to account for the ages and
      characteristics of the martian meteorite collection found on Earth. We found that
      craters as small as approximately 3 kilometers can eject approximately 10(7)
      decimeter-sized fragments from Mars, which is enough to expect those fragments to
      appear in the terrestrial collection. This minimum crater diameter is at least
      four times smaller than previous estimates and depends on the physical
      composition of the target material. Terrain covered by a weak layer such as an
      impact-generated regolith requires larger, therefore rarer, impacts to eject
      meteorites. Because older terrain is more likely to be mantled with such
      material, we estimate that the martian meteorites will be biased toward younger
      ages, which is consistent with the meteorite collection.

PMID- 12424386
TI  - Observation of a strongly interacting degenerate Fermi gas of atoms.
AB  - We report on the observation of a highly degenerate, strongly interacting Fermi
      gas of atoms. Fermionic lithium-6 atoms in an optical trap are evaporatively
      cooled to degeneracy using a magnetic field to induce strong, resonant
      interactions. Upon abruptly releasing the cloud from the trap, the gas is
      observed to expand rapidly in the transverse direction while remaining nearly
      stationary in the axial direction. We interpret the expansion dynamics in terms
      of collisionless superfluid and collisional hydrodynamics. For the data taken at
      the longest evaporation times, we find that collisional hydrodynamics does not
      provide a satisfactory explanation, whereas superfluidity is plausible.

PMID- 12424387
TI  - A Numerical Model for Compressed Breast of Japanese Women in Mammography.
AB  - The purpose of this study is to develop a numerical model for compressed breast
      of Japanese women which can evaluate the radiation dose in mammography. The model
      should take account of the average data for thickness of the compressed breast,
      and area, height and width of the mammograms. The compressed breast thickness is
      typically 4.4 to 6.4cm for European and American women, whereas it is under 3.8cm
      for Japanese women. Therefore, applying the European and American models without
      any modification for Japanese women would result in an overestimation of the
      absorbed dose. The data of 560 mammograms were analyzed focusing on the size and
      geometry of the projected images (cranio-caudal) to formulate a compressed breast
      phantom. An extremely good linear coefficient of correlation (0.98) between the
      area and the product of the width and height of the projected images was found. A
      numerical model describing a part of a simple elliptic column was constructed
      from this relationship and the averaged thickness (3.15cm) of the compressed
      breast. This model will lead to a realistic estimation of the total volumetric
      absorbed dose in mammography.

PMID- 12424388
TI  - [Algebraic 2D PET image reconstruction using depth-of-interaction information]
AB  - Recently a high-performance PET scanner, which measures depth-of-interaction
      (DOI) information, is being developed for molecular imaging. DOI measurement of
      multi-layered thin crystals can improve spatial resolution and scanner
      sensitivity simultaneously. In this paper, we apply an algebraic image
      reconstruction method to 2-dimensional (2D) DOI-PET scanners using accurate
      system modeling, in order to evaluate the effects of using DOI information on PET
      image quality. Algebraic image reconstruction methods have been successfully used
      to improve PET image quality, compared with the conventional filtered
      backprojection method. The proposed method is applied to simulated data for a
      small 2D DOI-PET scanner. The results show that accurate system modeling improves
      spatial resolution without noise emphasis, and that DOI information improves
      uniformity of spatial resolution.

PMID- 12424389
TI  - Dose evaluation and effective dose estimation from CT fluoroscopy-guided lung
      biopsy.
AB  - The development of computerized tomography (CT) has made CT fluoroscopy possible
      with real-time CT images. However examination are expected to have high medical
      and occupational exposures. Then, exposures to patients and operating and
      assisting physicians during the CT fluoroscopy-guided lung biopsy were estimated.
      And changes in the examination conditions to lower the dose were made. Patient
      exposure was measured using an anthropomorphic phantom by simulation of clinical
      examination conditions. The surface dose to the physician was measured during
      actual clinical examinations. The average effective dose for the patient was 34+/
      22mSv. The highest surface dose amounted to 1.9 Gy, although this was in a very
      narrow field. Patient doses could be reduced by a factor of 2.5-3 by changing
      examination methods while still retaining diagnostic quality. The highest dose to
      the operating physician was 10mGy which was recorded on the back of the hand and
      the average effective dose was estimated as 5.99&mgr;Sv per 1-minute examination.
      Doses were reduced by about a factor of 50 by lowering the tube voltage from
      120kV to 80 kV and using a supplementary tool. The doses for assisting physicians
      were not significant. The exposure for physicians and patients was much affected
      by lowering the tube voltage used for fluoroscopy. Using a supplementary tool was
      effective for reducing the dose for physicians.

PMID- 12424390
TI  - [Compensating Patient Displacement by Couch Movements in Patient Positioning
      System]
AB  - It is important to position patient accurately in radiation therapy which has a
      good dose concentration especially, in charged particle radiotherapy.
      Misalignment of patient to the center of the beam axis causes complication of
      normal tissue and low dose in the target volume due to the concentration. Hyogo
      Ion Medical Center has a patient positioning system which can position within
      lmm. The system consists of X-ray TV system to detect displacement of patient and
      treatment couch which have 6 axes (3 translations and 3 rotations) to move
      patient accurately. Since the couch has 3 rotation axes, it is very difficult to
      express the displacement with translations and rotations of patient by the couch
      movements. Therefore, expression of translation and rotation to compensate the
      patient displacement was derived. Test of the expression was done in the patient
      positioning system. X-ray images were taken before and after moving the couch,
      and the actual displacement and the calculated one for 6 axis were compared. The
      actual and the calculated agreed each other within lmm for translation and 0.1
      deg for rotation.

PMID- 12424392
TI  - [Activity in ISO/TC210]

PMID- 12424391
TI  - [Corresponding Japanese to the dose unit of Cema]

PMID- 12424393
TI  - [Dr. Akifumi Fukumura who is a member of JSMP had received "Cristoph Schmelzer
      prize]

PMID- 12424394
TI  - Corticosteroids in ophthalmology: past-present-future.

PMID- 12424395
TI  - Indocyanine green angiography in the diagnosis of small choroidal tumours.
AB  - OBJECTIVE: To evaluate indocyanine green (ICG) angiography in the diagnosis of
      small choroidal tumours. METHODS: We studied 40 patients with small choroidal
      tumours, 22 males and 18 females. The tumour thickness on ultrasonography ranged
      from 2.2 to 4.3 mm. RESULTS: Nineteen pigmented tumours showed early and late
      diffuse hypofluorescence, consistent with naevi. Eight non-pigmented tumours
      showed normal choroidal vessels in calibre, configuration, and branching, typical
      of non-pigmented naevi. The early frame of ICG angiography showed in 13 cases
      pathological, intrinsic vascularization, suggestive of melanomas. CONCLUSION:
      This preliminary study suggests that ICG angiography may be helpful in
      differentiating choroidal naevi from small melanomas.

PMID- 12424396
TI  - RPE in perfusion tissue culture and its response to laser application.
      Preliminary report.
AB  - PURPOSE: To study the effects of conventional laser application on the retinal
      pigment epithelium (RPE) in a perfusion tissue culture model of porcine retinal
      pigment epithelium without overlying neurosensory retina. METHODS: RPE with
      underlying choroid was prepared from enucleated porcine eyes and fixed in a
      holding ring (Minusheet). Specimens were then placed in two-compartment tissue
      culture containers (MinuCell & Minutissue, Bad Abbach, Germany) and were cultured
      during continuous perfusion with culture medium at both sides of the entire
      specimen, the upper RPE and the lower choroid (12 specimens out of 6 eyes).
      Cultures were kept for 1, 3, 7 and 14 days and were examined histologically.
      Laser treatment was performed on each tissue ring by application of 3 x 3 laser
      burns one day after culture began (argon ion laser, wavelength: 514 nm, pulse
      duration: 100 ms; spot size: 200 microm) using different energy levels (400-1,000
      mW); (16 specimens out of 8 eyes). RESULTS: During laser treatment a marked
      lightening of the RPE with centrifugal spreading was observed. Using higher
      levels of energy, a contraction of the RPE towards the center of the laser spot
      was noticed. One day after laser photocoagulation histology revealed destruction
      of RPE; within 3-7 days of culture, migration and proliferation of neighboring
      cells was observed in several lesions. After 7 days the initial defect of the
      irradiated area was covered with dome shaped RPE cells and after 14 days
      multilayered RPE cells were showing ongoing proliferation. However, there were
      also cases without proliferation after laser treatment. The non-treated,
      continuously perfused RPE showed regular appearance in histological sections:
      during the first 7 days of culture, light microscopy revealed a normal matrix
      with a well-differentiated RPE monolayer. Subsequently proliferation even without
      treatment was observed and after 14 days the RPE became multilayered. CONCLUSION:
      It was possible to study the early healing response to the effect of laser
      treatment using the permanently perfused tissue culture system. A marked
      proliferation and repair of the laser defect could be observed in several but not
      all lesions. After 14 days even without laser treatment a proliferative
      multilayered RPE was present. Although this limits the use of the system for
      longer than 7 days, it seems to be useful for investigation of RPE-related
      disorders.

PMID- 12424397
TI  - Evaluation of polymerase chain reaction for the detection of adenoviruses in
      conjunctival swab specimens using degenerate primers in comparison with direct
      immunofluorescence.
AB  - PURPOSE: To investigate a rapid and sensitive polymerase chain reaction (PCR)
      based assay for the detection of adenoviral infections in conjunctival swabs.
      METHODS: Degenerate primers derived from the adenoviral hexon gene were designed
      for amplification of a 302-bp product by PCR. In 15 ocular swab specimens, using
      a simple sample preparation method, PCR was compared with a commercially
      available direct immunofluorescence test. RESULTS: Fourteen samples of patients
      with clinically diagnosed adenoviral keratoconjunctivitis, when screened by
      direct immunofluorescence, were positive for adenoviral protein. In all samples
      positive by immunofluorescence, the 302-bp product was amplifiable. The sample
      negative by direct immunofluorescence was positive using PCR. CONCLUSION: PCR
      using degenerate primers proved to have several advantages over current
      diagnostic techniques. It offers considerable improvement in sensitivity over
      immunoassays and speed over tissue culture isolation and is a highly potential
      tool for the diagnosis of adenoviral ocular infections.

PMID- 12424398
TI  - Conjunctival rotation autograft for primary pterygium.
AB  - PURPOSE: To evaluate the safety and effectiveness of conjunctival rotation
      autograft technique in preventing the recurrence of primary pterygium. METHODS:
      In this prospective study, 24 eyes of 24 consecutive patients with primary
      pterygium were evaluated. Conjunctival rotation autograft technique, which
      involved the removal of the underlying fibrovascular pterygium tissue and
      replacement of the original epithelium over the bare sclera with a 180 degrees
      rotation was performed in all eyes. RESULTS: Patients were 34-70 years of age
      (mean, 52.8; SD = 10.5). During the mean follow-up of 15.9 months (range, 12-23
      months; SD: 4.0), 4 recurrences (16.6%) were observed. Neither intraoperative nor
      postoperative complications were encountered except for recurrences and 3 suture
      openings, which were re-sutured postoperatively without further complications.
      CONCLUSION: Conjunctival rotation autograft technique appears to be effective and
      safe in preventing the recurrence of primary pterygium. A prospective randomised
      trial comparing conjunctival rotation autografting with other adjunctive
      procedures in addition to simple pterygium excision is required to determine its
      effectiveness.

PMID- 12424399
TI  - Midterm visual outcome and progression of diabetic retinopathy following cataract
      surgery. Midterm outcome of cataract surgery in diabetes.
AB  - OBJECTIVE: To assess the influence of cataract surgery on progression of diabetic
      retinopathy and visual acuity. METHODS: 37 patient eyes with mild to moderate
      diabetic retinopathy at baseline underwent phacoemulsification and intraocular
      posterior chamber lens implantation. They were examined 3.3 +/- (SD) 0.7 years
      after surgery. RESULTS: 83.8% of the eyes showed a better final visual acuity,
      and 67.6% achieved a final visual acuity of 0.5 or better. The retinopathy
      remained unchanged in 83.8% and progressed in 16.2% of the eyes. No eye
      progressed to proliferative retinopathy. CONCLUSION: Phacoemulsification and
      implantation of a posterior chamber intraocular lens is a safe procedure for
      patients with mild to moderate diabetic retinopathy.

PMID- 12424400
TI  - Management and results of retinal detachment after silicone oil removal.
AB  - Of the 168 eyes undergoing silicone oil removal from 1993 to 2000, 34 developed
      retinal detachment after the removal of silicone oil. The management and the
      results of the 34 eyes were reviewed. Surgical procedures included pars plana
      vitrectomy, encircling band, cryocoagulation, endotamponade. Five of the 34 eyes
      had a second retinal detachment after these operations. One of these 5 eyes had a
      third retinal detachment. Final retinal reattachment was achieved in all eyes.
      Visual acuity decreased in 16 of the 34 eyes with retinal detachment, and 18 of
      the 34 eyes had a visual acuity of less than 0.02. These results show that
      surgery for retinal detachment after silicone oil removal yields a high rate of
      anatomic success, while the visual outcome is poor for a substantial number of
      patients.

PMID- 12424401
TI  - Significant variation of the elevated nitric oxide levels in aqueous humor from
      patients with different types of glaucoma.
AB  - Though several studies have shown that the biochemical function of nitric oxide
      (NO) in the eye might play an important role in the regulation of intraocular
      pressure (IOP), local control of ocular blood flow and loss of retinal ganglion
      cells by apoptosis, it is unclear whether the role of NO is similar in the
      pathogenesis of different kinds of glaucoma: primary open-angle glaucoma (POAG),
      chronic closed-angle glaucoma (CCAG) and neovascular glaucoma (NVG). To further
      explore this issue, we measured the concentrations of NO in aqueous humor and
      plasma samples from patients with POAG (n = 31), CCAG (n = 76), NVG (n = 8) and
      cataract (n = 30). All of the NVG patients suffered from severe proliferative
      diabetic retinopathy, while other patients were free of any other systemic
      disease. The NO levels in both aqueous humor and plasma samples were assessed by
      chemiluminescence assay. We found that the NO levels in aqueous humor samples
      were greatly varied in patients with POAG (36.2 +/- 3.3 microM), CCAG (47.7 +/-
      3.4 microM) and NVG (65.8 +/- 5.4 microM), and all of them were significantly
      higher than in cataract patients (27.0 +/- 2.9 microM p < 0.05). Except NVG
      patients whose NO levels in plasma samples were highest (24.1 +/- 3.5 microM)
      among all groups, the plasma NO levels were not significantly different between
      the other glaucoma patients and the cataract patients. We therefore concluded
      that significant variation of the elevated NO levels in aqueous humor samples
      from the patients with different types of glaucoma may reflect their differences
      in the pathogenesis.

PMID- 12424402
TI  - Influence of latanoprost on the corneal epithelial barrier function in glaucoma
      patients.
AB  - AIM: To evaluate the influence of topically administered latanoprost, a
      prostaglandin F(2alpha) analog, on the corneal epithelial barrier function.
      PATIENTS AND METHODS: Twenty-four patients suffering from a glaucoma were
      enrolled. Ten patients without prior topical antiglaucoma medication received
      topical latanoprost (0.005%, once daily) for 30 days (monotherapy group); 14
      patients receiving topical antiglaucoma medication also received latanoprost
      (0.005%, once daily) for 180 days (combination treatment group). Before and 30
      days after treatment (monotherapy group) and before and 30 and 180 days after
      treatment (combination group), the corneal epithelial barrier function was
      measured by a fluorophotometric technique. RESULTS: The fluorescein uptakes in
      the monotherapy group were 54.6 +/- (SE) 7.5 and 57.1 +/- 11.0 ng/ml before and
      30 days after treatment, respectively (p = 0.81). In the combination group, the
      uptakes were 101.0 +/- 18.3 and 118.9 +/- 25.9 ng/ml (p = 0.38) and 93.4 +/- 17.5
      ng/ml (p = 0.58) before and 30 and 180 days after treatment, respectively.
      CONCLUSION: The corneal epithelial barrier function remained intact following the
      instillation of latanoprost in both groups.

PMID- 12424403
TI  - Anesthesia with EMLA cream for botulinum A toxin injection into eyelids.
AB  - We investigated the efficacy of an eutectic mixture of local anesthetics (EMLA)
      in reducing the pain of a botulinum toxin injection into eyelids. 17 patients
      with facial dyskinesia (9 blepharospasm and 8 hemifacial spasm) who had been
      treated regularly with botulinum toxin injections received EMLA cream and
      placebo. The pain was assessed by the ophthalmologist and the patient. Injection
      with EMLA cream showed lower pain scores (mean 1.82 +/- 2.13, median 1) than
      injection with placebo (8.76 +/- 2.17; p = 0.0001). Percutaneous anesthesia
      induced by EMLA cream is an effective and safe method which improves the comfort
      in patients who need repeated botulinum toxin injections for their facial
      dyskinesia.

PMID- 12424404
TI  - Treatment of vomiting after paediatric strabismus surgery with granisetron,
      droperidol, and metoclopramide.
AB  - We have compared the efficacy and safety of granisetron, droperidol, and
      metoclopramide in the treatment of postoperative vomiting (POV) in children
      scheduled for strabismus surgery. After experiencing POV during the first 3 h
      after recovery from anaesthesia, 120 patients received intravenously, in a
      randomized, double-blind manner, granisetron 40 microg/kg, droperidol 50
      microg/kg, or metoclopramide 0.25 mg/kg (n = 40 in each group). The patients were
      then observed for 24 h after administering the study drugs. Emesis-free episodes
      were more often observed in patients who had received granisetron (88%) than in
      those who had received droperidol (63%) or metoclopramide (58%; p < 0.05). No
      clinically serious adverse events were observed in any group. In conclusion,
      granisetron is more effective than droperidol or metoclopramide in the treatment
      of POV after paediatric strabismus surgery.

PMID- 12424405
TI  - A novel relation of fatty acid with age-related macular degeneration.
AB  - To evaluate the relation between fatty acids and age-related macular degeneration
      (ARMD), the fatty acid fractions within the red blood cell (RBC) membrane and
      plasma of 11 ARMD patients and 10 healthy individuals (controls) were determined
      and compared. RBC arachidonic acid (AA) and docosahexaenoic acid (DHA) exhibited
      significantly higher values in the ARMD patients than in the controls. RBC levels
      of palmitic, palmitoleic, oleic and linoleic acids, however, showed significantly
      higher values in the controls than in the ARMD patients. No significant
      variations were observed between the two groups in terms of plasma levels of AA,
      DHA, palmitic, palmitoleic, oleic and linoleic acids. Our findings indicate that
      polyunsaturated fatty acids, vulnerable to free radicals and reactive oxygen
      species, and easily peroxidized, may be related to ARMD induction.

PMID- 12424406
TI  - Subclinically dry eyes in urban Delhi: an impact of air pollution?
AB  - PURPOSE: To study the effects of air pollution on the eyes of persons staying in
      the metropolis of New Delhi. MATERIALS AND METHODS: 400 healthy volunteers from
      within and outside the metropolis of Delhi were investigated for the presence of
      tear film abnormalities. All persons underwent slitlamp examination to rule out
      any ocular surface disorder. The tear break-up time (BUT) was assessed along with
      a Schirmer test and the tear lysozyme activity and the tear pH were determined.
      RESULTS: Of the 210 persons staying in the metropolis, 50 (24%) had an abnormal
      BUT, 14 (6.6%) had an abnormal Schirmer test, and the tear lysozyme activity was
      found to be low in 12 (5%). In contrast, of those 190 persons living outside the
      metropolis, only 10 (5.2%) had an abnormal BUT, 4 (2%) had an abnormal Schirmer
      test, and none had a low lysozyme activity (p < 0.05). None of the persons in
      either group had significant eye symptoms. CONCLUSIONS: Tear film abnormalities
      are present in a large number of people staying within the metropolis of New
      Delhi who have apparently normal eyes. Air pollution over a long period of time
      could possibly be associated with their causation.

PMID- 12424407
TI  - Simple dacryops: a case series and review of the literature.
AB  - In this prospective, small case series, 3 patients with simple dacryops were
      analyzed along with a review of literature. All 3 patients in this series had
      classical clinical features of simple dacryops. All of them underwent complete
      cyst removal with the aid of a cryoprobe. Histopathology was compatible with
      dacryops. In 2 of the 3 patients, the cyst revealed calcification, which to the
      best of our knowledge has not been reported. None of the patients developed a
      recurrence. In conclusion, simple dacryops is an easily recognized clinical
      entity. This entity has been infrequently reviewed in the older literature, and
      in the last decade only 6 cases have been reported. Most of the patients
      underwent complete excision of the cyst with no recurrences.

PMID- 12424408
TI  - Coats'-like response in blood-filled senile retinoschisis.

PMID- 12424409
TI  - Cardiac tests in asymptomatic type 2 diabetics.
AB  - OBJECTIVE: To evaluate the use of noninvasive procedures for the detection of
      myocardial ischemia and its relation with other coexistent clinical factors in
      patients with asymptomatic type 2 diabetes mellitus. SUBJECTS AND METHODS: A
      total of 42 patients with type 2 diabetes mellitus, aged 41-72 years with no
      clinical history suggestive of coronary heart disease, were evaluated for silent
      myocardial ischemia by stress cardiac exercise tolerance test (ETT), 12-lead
      electrocardiography (ECG), transthoracic echocardiography and stress myocardial
      perfusion scan using technetium-99m tetrofosmin. RESULTS: Eleven patients (26.2%)
      showed an ischemic pattern on ETT, the resting ECG was suggestive of ischemia in
      only 2 (4.8%), echocardiography showed diastolic dysfunction in 9 (21.4%), and
      the stress myocardial perfusion scan was ischemic in 3 (7.3%). For subjects over
      the age of 57, a significant difference was found between age and ischemic ETT (p
      = 0.026) and diastolic dysfunction by echocardiography (p = 0.044). Patients with
      microalbuminuria and/or diastolic dysfunction were more likely than others to
      have ischemic ETT (p = 0.036 and 0.024, respectively) and patients with diastolic
      dysfunction had a higher prevalence of ischemic ETT. There was no relation
      between ischemic ETT and other major cardiac risk factors (hypertension,
      dyslipidemia, smoking, sex, duration of diabetes, BMI, and glycated hemoglobin
      levels). CONCLUSION: The cardiac ETT was most helpful for detecting myocardial
      ischemia in asymptomic type 2 diabetics. For equivocal ETT findings,
      echocardiography is recommended. The prevalence of myocardial ischemia was high
      in patients with type 2 diabetes mellitus.

PMID- 12424410
TI  - Laparoscopic cholecystectomy in 2,750 cases in a teaching hospital in Kuwait.
AB  - OBJECTIVE: To retrospectively analyse all laparoscopic cholecystectomies
      performed between April 1992 and May 1999. METHODS: Medical records of 2,750
      patients, clinically diagnosed with gall bladder disease, were reviewed. We
      analysed the operative time, length of postoperative hospital stay, conversion
      rate, intra- and postoperative complications as well as management outcome.
      RESULTS: The mean operative time was 59.2 min, and the mean postoperative
      hospital stay was 1.46 days. However, the majority of our patients (66.8%) were
      discharged after 1 day. The conversion rate was 3.8%, which was mainly due to
      acute gall bladder pathology. The postoperative complication rate was 4.6%; all
      cases were managed successfully with no mortality or delayed morbidity.
      CONCLUSION: Our findings indicate that laparoscopic cholecystectomy appears to be
      a safe and effective procedure with low morbidity and no mortality. Therefore, it
      should be considered as the procedure of choice for patients with gall bladder
      disease.

PMID- 12424411
TI  - TORCH agents in pregnant Saudi women.
AB  - OBJECTIVE: To determine the seroprevalence rates of IgG to common TORCH agents in
      pregnant Saudi women using indirect enzyme-linked immunosorbent assay. SUBJECTS
      AND METHODS: A total of 926 samples of sera were tested for antibodies to TORCH
      agents known to cause serious congenital infections: Toxoplasma gondii, rubella,
      cytomegalovirus (CMV), herpes simplex viruses (HSV-1 and HSV-2), varicella zoster
      virus (VZV) and human immunodeficiency virus (HIV-1 and HIV-2). RESULTS:
      Toxoplasma IgG antibodies were detected in 35.6%, CMV total IgG antibodies were
      found in 92.1%, rubella IgG antibodies in 93.3%, HSV-1 IgG antibodies in 90.9%,
      HSV-2 IgG in 27.1%, and VZV IgG antibodies in 74.4%. A 0% seroprevalence rate for
      HIV-1 and -2 was found. CONCLUSION: Pregnant Saudi women commonly have IgG
      antibodies to rubella, CMV, HSV-1 and -2, VZV, and T. gondii. Serological
      evidence of HIV infection was not observed.

PMID- 12424412
TI  - Open eye injuries in the pediatric population in Kuwait.
AB  - OBJECTIVE: To report the epidemiological characteristics of pediatric open globe
      injuries and to discuss treatment, management and outcomes of such injuries.
      MATERIALS AND METHOD: The hospital records and operative notes of 95 patients 16
      years old and younger who were treated for open eye injury at Ibn Sina Hospital,
      Kuwait between September 1995 and January 1999 were reviewed. The average age of
      patients was 6.6 years. Patients were divided into three groups according to
      their final visual acuity (FVA): group 1, FVA of 20/40 or better; group 2, 20/40
      20/200, and group 3, 20/400 or worse. The FVA of each group was compared to
      initial visual acuity (IVA), wound entry site, injury-to-presentation interval,
      injury-to-surgery interval, time of surgery, duration of surgery, associated
      injuries and medical treatment. RESULTS: Injury was most common in children 3-6
      years old. Most injuries occurred during play at home (46%), between the months
      of July and November (58%), and evening time (42%). The most common causes were
      glass, pencil, stick, soft drink bottle, metal bar, and stone. The cornea was the
      most common entry site (59 cases). Seventy-three patients presented on the day of
      injury, and 38 of them had surgical repair that same day. The follow-up period
      ranged from 2 weeks to 58 months. Thirty-eight patients (40%) had an FVA of 20/40
      or better (group 1), 23 (24%) between 20/40 and 20/200 (group 2), 12 (13%) 20/400
      or worse (group 3), and 22 (23%) had no record of FVA. The difference between IVA
      and FVA of wound entry site was statistically significant (p < 0.005).
      Differences due to injury-to-presentation interval, injury-to-surgery interval,
      time of surgery, duration of surgery, associated injuries, and the use of
      systemic antibiotics were found not to be statistically significant (p > 0.2).
      CONCLUSION: The prevalence of open globe injury among the pediatric population in
      Kuwait was high. Most injuries were due to household objects and occurred at home
      in the evening during the summer and autumn. IVA and anatomical location of the
      wound impacted on final outcome.

PMID- 12424413
TI  - Diagnosis of abdominal hydatid cyst disease: the role of ultrasound and
      ultrasound-guided fine needle aspiration cytology.
AB  - OBJECTIVE: To retrospectively analyze the role of ultrasound (US) imaging and US
      guided fine needle aspiration cytology in the diagnosis and management of
      abdominal hydatid cyst disease (HCD). SUBJECTS AND METHODS: The medical records
      of 55 diagnosed cases of HCD seen between January 1986 and December 2000 at
      Mubarak Al-Kabeer Hospital and Al-Amiri Hospital in Kuwait were reviewed for
      demographic and clinical data, including radiology and serology. The US findings
      of the patients were classified into four types as follows: type I: single or
      multiple well-defined cysts, with or without detached or collapsed wall and with
      or without echogenic contents; type II: single or multiple cysts with peripheral
      cysts, with or without echogenic contents; type III: solid or semisolid lesions,
      and type IV: cysts with calcified walls. RESULTS: The overall accuracy of US in
      the diagnosis of HCD was 80% (44/55 cases). US examination was suggestive of HCD
      type I, 16/19 (84%), type II, 21/23 (91%), type III, 3/8 (38%), and type IV, 4/5
      (80%). For the 11 remaining undiagnosed cases, US was useful for localizing the
      lesions for US-guided fine needle aspiration cytology. It established the
      diagnosis in all the 11 cases, without precipitating complications. CONCLUSION:
      US alone was valuable for diagnosing and localizing HCD in the abdomen except for
      solid-type lesions. US-guided fine needle aspiration cytology was useful in
      localizing and establishing the diagnosis of HCD in the cases where US alone was
      ineffective.

PMID- 12424414
TI  - Patient characteristics and practice patterns in the treatment of acute
      myocardial infarction in Kuwait: a pilot study.
AB  - OBJECTIVES: To determine the characteristics, management and outcomes of patients
      with acute myocardial infarction (AMI) admitted to the general hospitals and to
      assess the feasibility of establishing a registry for AMI in Kuwait. SUBJECTS AND
      METHODS: We prospectively included 111 consecutive patients (94 males and 17
      females, mean age 55 years) admitted to the coronary care units of the five
      participating hospitals during May 2000. The subjects all had a final diagnosis
      of AMI. A structured data collection form that included biochemical measurements
      was filled out for each patient. RESULTS: The prevalence of hypercholesterolemia,
      diabetes, hypertension and current smoking was 46, 45, 30 and 49%, respectively.
      Fifty-four of 57 patients who were eligible for thrombolytic therapy received
      treatment. The median time from symptom onset to thrombolytic therapy was 180
      min. At discharge 93% were prescribed aspirin, 81% beta-blockers, 40% angiotensin
      converting enzyme inhibitors, and 32% lipid-lowering drugs. The in-hospital
      mortality was 10%. CONCLUSIONS: The incidence of smoking, diabetes and
      hypercholesterolemia is high among our patients. Thrombolytic therapy is used
      regularly but insufficiently early. Based on this pilot study, it is feasible to
      establish an AMI registry in Kuwait.

PMID- 12424415
TI  - Primary antituberculosis drug resistance at Turkish military chest diseases
      hospital in Istanbul.
AB  - OBJECTIVE: The aim of this study was to investigate the prevalence of primary
      drug resistance to tuberculosis. METHODS: We evaluated the clinical data,
      radiological features and sputum samples from 365 newly diagnosed patients with a
      positive culture of pulmonary tuberculosis at the Turkish Military Chest Diseases
      Hospital, Istanbul, Turkey. No patients had taken antituberculosis drugs
      previously. The Bactec method was used to perform drug susceptibility testing for
      isoniazid, rifampicin, ethambutol, and streptomycin. RESULTS: Primary resistance
      to one or more drugs was detected in 87 (23.8%) patients; resistance to isoniazid
      was most common (54 patients) followed by resistance to ethambutol (n = 39),
      rifampicin (n = 11), and streptomycin (n = 9). One-drug resistance was detected
      in 69 patients; two-drug resistance in 11, three-drug resistance in 6, and four
      drug resistance in 1. Multidrug resistance (resistance to at least isoniazid and
      rifampicin) was detected in 10 patients. In logistic-regression analysis, primary
      drug resistance was associated with radiological advanced tuberculosis (p <
      0.001). CONCLUSION: Primary resistance to one or more drugs used in treating
      tuberculosis is relatively high. It is necessary to regularly screen for and
      treat drug resistance among those who live in close quarters, such as army
      barracks, school dormitories and prisons. Regular surveillance of drug
      sensitivity patterns should be maintained to determine appropriate alternate drug
      regimens and detect the spread of resistant stains in the population.

PMID- 12424416
TI  - Thyroid function in Kuwaiti subjects with Down's syndrome.
AB  - OBJECTIVE: To investigate the thyroid function of individuals with Down's
      syndrome (DS). METHODS: Thyroid function and antithyroid antibodies were measured
      in 58 Kuwaitis with DS who resided at a residential facility or attended
      rehabilitation centers. RESULTS: Twenty-six subjects (45%) were euthyroid and 32
      (55%) had thyroid dysfunction. One patient had previously been diagnosed with
      thyroid failure whereas the other 31 patients had newly discovered disease: 9
      patients had primary hypothyroidism (T(4) 9.95 +/- 1.1 pmol/l and TSH 15.15 +/-
      11.93 mU/l), 19 subclinical hypothyroidism (TSH 6.47 +/- 2.57 mU/l), 1 secondary
      hypothyroidism, 1 hyperthyroidism, and the remaining 1 subclinical
      hyperthyroidism. Antithyroid antibodies were found in 52% of the total subjects
      and in 59% of those with thyroid dysfunction. CONCLUSIONS: Thyroid dysfunction is
      common in Kuwaiti subjects with DS and is presumably the consequence of
      autoimmune thyroid disease. Periodic thyroid function testing is recommended in
      individuals with DS, which is best done through a national program.

PMID- 12424417
TI  - Diagnostic yield of mediastinal exploration.
AB  - OBJECTIVE: To report our experiences of surgical diagnostic procedures in
      patients with unidentified mediastinal pathology. METHODS: From July 1995 to July
      1999, 72 patients with mediastinal pathology had 73 surgical procedures for the
      purpose of tissue diagnosis. Of the 72 patients, 39 were female and 33 male, with
      an average age of 54 years. Mediastinoscopy and anterior mediastinotomy were
      performed in 54 and 15 patients, respectively (13 left and 2 right). Thoracoscopy
      was used in 3 cases, and 2 patients were diagnosed via cervical incision.
      Superior vena cava (SVC) obstruction was noted in 4 patients and four procedures
      were repeat procedures. Frozen section analysis was performed in 52 cases.
      RESULTS: Tissue diagnosis was achieved in all cases, enabling a specific
      diagnosis in 70 cases (97%). In 2 patients, the final diagnosis was non-specific
      and in 1 patient repeat biopsy was needed. The diagnoses were lymphoma (n = 32),
      tuberculosis (n = 20), metastatic disease (n = 11) and other pathology (n = 9).
      There was no operation-related mortality although 1 patient developed mediastinal
      haematoma, which was treated conservatively. The 2 in-hospital deaths resulted
      from causes secondary to the primary disease (invasive aspergilloma or Hodgkin's
      lymphoma). CONCLUSION: Mediastinoscopy is a safe surgical procedure with high
      diagnostic yield. Its routine use with mediastinotomy and thoracoscopy ensures
      accurate diagnosis. Careful surgical technique is mandatory in repeat procedures
      and SVC obstruction cases.

PMID- 12424418
TI  - Iron deficiency anaemia: an unusual complication of Meckel's diverticulum.
AB  - OBJECTIVES: To describe a case of Meckel's diverticulum with an unusual
      complication of iron deficiency anaemia due to chronic intestinal bleeding.
      CLINICAL PRESENTATION AND INTERVENTION: A 12-year-old boy presented with bloody
      diarrhoea and abdominal pain in association with a long-standing history of black
      stools and progressive pallor. Biochemical tests revealed low serum iron (1.2
      mmol/l) indicating iron deficiency anaemia and low serum albumin (29 g/l). The
      other tests were normal. Colonoscopy performed on the 8th day of hospitalization
      was normal. A technetium-99m pertechnetate scan showed an ectopic gastric mucosa
      in the Meckel's diverticulum confirmed at surgery in the region of the
      antimesentric border and on histopathology. CONCLUSION: Findings indicated that
      the patient had a bleeding Meckel's diverticulum, complicated by iron deficiency
      anaemia.

PMID- 12424419
TI  - Primary mediastinal yolk sac tumor in a 66-year-old woman.
AB  - OBJECTIVE: To report a rare case of nonseminomatous extragonadal germ cell tumor
      in a 66-year-old female with primary yolk sac tumor of the mediastinum. CLINICAL
      PRESENTATION AND INTERVENTION: A 66-year-old female was admitted to our hospital
      with a history of chest pain for 1 month. Computerized tomography of the thorax
      showed a left paracardiac mass adjacent to the aortic arch, left main pulmonary
      artery and pericardium. Total surgical excision could not be performed, but
      several biopsies which were taken through a thoracotomy revealed yolk sac tumor
      of the mediastinum. Systemic chemotherapy was started, but no response was
      observed and the patient died after one course of chemotherapy. CONCLUSION:
      Nonteratomatous mediastinal germ cell tumors are virtually nonexistent in women.
      To our knowledge, this is the oldest female patient with a primary mediastinal
      germ cell tumor. Chemotherapy was not effective especially in an old patient. We
      suggest surgery should be considered as primary treatment modality if diagnosis
      is made at an early stage.

PMID- 12424420
TI  - Influence of uremia on cell viability and cytokine release of human peritoneal
      mesothelial cells.
AB  - INTRODUCTION: There is still no evidence whether human peritoneal mesothelial
      cells (HPMC) from patients with end-stage renal failure are altered in cell
      viability or show a different pattern of the release of proinflammatory
      cytokines. Also the serum of patients with uremia may contain substances
      stimulating the cytokine release of HPMC. STUDY DESIGN: The IL-1beta-induced IL
      6/IL-8 release of HPMC from healthy donors and from patients with end-stage renal
      disease (ESRD) were measured before the start of chronic peritoneal dialysis (PD)
      and during PD therapy. Additionally the influence of uremic and non-uremic serum
      on IL-6 and IL-8 release of normal HPMC was studied. Cell viability was assessed
      by MTT assay and by the measurement of intracellular ATP (chemoluminescence
      assay). HPMC were obtained from the following patient groups: (1) non-uremic
      control patients (n = 7); (2) patients with ESRD undergoing PD catheter
      implantation for the first time (n = 7), and (3) patients on PD undergoing
      catheter exchange for noninfectious reasons (n = 6). Pooled human serum from PD
      patients and normal controls were used for stimulation experiments. HPMC from
      different donors were grown to confluence (second passage) and then stimulated
      with IL-1beta (1,000 pg/ml in M199) for 24 h. IL-6 and IL-8 concentrations were
      measured in the supernatant by ELISA. Additionally uremic and non-uremic sera
      were incubated with HPMC from normal donors for 24 h with a subsequent 24-hour IL
      1beta stimulation. Mesothelial cell protein mass was determined by the Bradford
      reagent. RESULTS: Non-uremic patients and ESRD patients did not differ with
      regard to the global cell viability of HPMC according to MTT assay activity or
      the intracellular ATP concentration. However, HPMC from uremic patients produced
      more IL-8 on IL-1beta stimulation than the non-uremic controls (group 2, 53.5 +/-
      15.7 pg/microg; group 3, 70.5 +/- 27.3 pg/microg vs. group 1, 24.0 +/- 11.8
      pg/microg). HPMC from patients on chronic PD additionally released significantly
      more IL-6 (30.5 +/- 13.8 pg/microg) on IL-1beta stimulation than uremic patients
      before the onset of PD (6.2 +/- 2.6 pg/microg; p < 0.01). Incubation of normal
      HPMC with the serum from uremic donors produced an enhanced stimulated IL-8
      release compared to the exposition with normal control serum (50.6 +/- 6.1 vs.
      20.8 +/- 2.9 pg/microg; p < 0.01). CONCLUSION: HPMC from uremic patients more
      readily release IL-8 on stimulation with IL-1beta. On chronic PD treatment IL-6
      release was further enhanced. Not further classified serum components in uremia
      also enhance IL-6 and IL-8 release of HPMC.

PMID- 12424421
TI  - Intrarenal infusion of angiotensin-(1-7) modulates renal functional responses to
      exogenous angiotensin II in the rat.
AB  - In the present study we investigated the possible role of angiotensin-(1-7) [Ang
      (1-7)] in modulating renal functional responses to intrarenal (i.e.) infusion of
      angiotensin II (ANG II) in normotensive anesthetized rats. ANG II (6 ng/min, n =
      14) decreased glomerular filtration rate (GFR), renal plasma flow (RPF), absolute
      and fractional sodium excretion by -24 +/- 5, -25 +/- 6, -44 +/- 6 and -28 +/-
      7%, respectively (p < 0.05). i.r. infusion of Ang-(1-7) (50 ng/min, n = 13) did
      not significantly alter GFR (+6 +/- 4%) but reduced RPF by -19 +/- 7% (p < 0.05).
      Ang-(1-7) increased absolute and fractional sodium excretion by +36 +/- 6 and +37
      +/- 8%, respectively (p < 0.05). Infusion of Ang-(1-7) did not prevent the
      decreases in GFR and RPF but completely blunted the decreases in absolute (-2 +/-
      2%) and fractional sodium excretion (-4 +/- 4%) induced by ANG II (n = 11).
      Blockade of the Ang-(1-7) receptor by [7-D-Ala]-Ang-(1-7) (5 microg/min, n = 11)
      significantly decreased GFR, RPF, absolute and fractional sodium excretion by -28
      +/- 7, -20 +/- 5, -32 +/- 7 and -24 +/- 4%, respectively (p < 0.05), suggesting
      that the action of endogenous ANG II is unopposed by compensatory effect of
      endogenous Ang-(1-7). i.r. infusion of Ang-(1-7) (n = 10) did not alter the
      effect of Ang-(1-7) receptor blockade on RPF (-21 +/- 6%) but blunted its effects
      on GFR (+4 +/- 3%) and absolute (+7 +/- 5%) and fractional (+6 +/- 4%) urinary
      sodium excretion probably by displacing the receptor blocker. While exogenous ANG
      II during blockade of the Ang-(1-7) receptor and the AT(2) receptor (by PD
      123319; 1 microg/min i.r., n = 9) resulted in the same decreases in absolute and
      fractional sodium excretion (-39 +/- 8 and -38 +/- 6%, respectively, p < 0.05) as
      did ANG II in the absence of Ang-(1-7) receptor blockade. These results suggest
      that in normotensive rats high i.r. Ang-(1-7) concentration attenuates the
      tubular, i.e. sodium reabsorptive effect, but not the vascular effect of
      exogenous i.r. ANG II. Results obtained during blockade of Ang-(1-7) and of AT(2)
      receptors imply that AT(2) receptors play a role in tubular sodium reabsorption
      in the presence of high ANG II concentration.

PMID- 12424422
TI  - Renal antioxidant status in rats with hypertension induced by N sup omega nitro-L
      arginine methyl ester.
AB  - Nitric oxide (NO) has a role in the etiopathogenesis of hypertension. Relaxation
      of vascular smooth muscles is failed when NO production is reduced leading to
      increased vascular peripheral resistance. N sup omega nitro-L-arginine methyl
      ester (L-NAME) is one of the inhibitors of NO production. The aim of this study
      was to investigate oxidant-antioxidant systems of renal tissue in rats with
      hypertension induced by L-NAME. Rats were divided into three groups: control
      group and study groups treated with 100 or 500 mg/l L-NAME in drinking water for
      15 days. The activities of catalase (CAT), glutathione peroxidase (GSH-Px) and
      superoxide dismutase (SOD), and the levels of malondialdehyde (MDA) and NO were
      studied in the renal tissue after hypertension induction. Arterial blood pressure
      was increased in both L- NAME groups. CAT activity of 500-mg L-NAME group was
      higher than control. GSH-Px activity of 500-mg L-NAME group was decreased
      compared with 100-mg ones. NO level was lower in 500-mg L-NAME group than
      control. MDA levels in both L-NAME groups were decreased compared with control.
      In conclusion, hypertension was induced with oral L-NAME treatment. Increased CAT
      activity was compensated with decreased GSH-Px activity in 500-mg L-NAME group.
      Both study groups were protected from lipid peroxidation with NO inhibition.

PMID- 12424423
TI  - Renal and cardiovascular effects of renal denervation in conscious rats after
      adenosine administration and nitric oxide synthase inhibition.
AB  - The role of renal nerves on renal and cardiovascular responses to adenosine
      administration and/or acute NO synthase inhibition was investigated. Conscious
      male Wistar rats with implanted catheters in femoral artery for blood pressure
      registration, femoral vein for drug infusion and bladder for urine collection
      were used. Adenosine was applied i.v. (1.0 mg/kg BW bolus) followed by infusion
      of 0.1 mg/kg.min, and/or nitric oxide synthase inhibition (NOSI) was performed by
      i.v. administration of 10 mg/kg BW N-Omega-nitro-L-arginine methyl ester (L-NAME)
      before and 1 week after bilateral renal denervation (BRD). NOSI decreased HR and
      increased SAP, MAP and DAP both in intact and BRD rats. Baroreflex sensitivity
      increased in intact and BRD rats. Adenosine did not change HR, blood pressure or
      baroreflex sensitivity in intact as well as BRD rats. NOSI increased V, VU(Na)
      and VU(CI) in intact rats but decreased V and did not alter VU(Na) and VU(CI) in
      BRD rats. Adenosine increased V, VU(CI) and C(cr) in intact rats but did not
      change renal excretory function in BRD rats. Combined application of adenosine
      and L-NAME led to a dramatic increase of V, VU(Na), VU(Cl) and C(cr) in intact
      rats. However, VU(Na) and VU(CI) in BRD rats were lower as compared to intact
      rats. Therefore, changes in renal excretory function seen after NOSI are not
      exclusively the result of pressure diuresis and natriuresis but in some way are
      dependent on renal nerves. Renal denervation attenuates the renal excretory
      response to adenosine. Sympathetic nervous system is important in mediating the
      effects of adenosine and/or NO on renal excretory function. Renal denervation did
      not change the pattern of baroreflex sensitivity after adenosine and/or L-NAME
      administration.

PMID- 12424424
TI  - Lack of a role of neuronal nitric oxide synthase in the regulation of the renal
      function in rats fed a low-sodium diet.
AB  - BACKGROUND/AIMS: It has been shown that nitric oxide (NO) generated from neuronal
      NO synthase (nNOS) counteracts angiotensin II mediated vasoconstriction in the
      pre- and in the postglomerular microcirculation. Previous studies have
      demonstrated that the nNOS expression in the macula densa of the renal cortex is
      enhanced by dietary salt restriction. In view of the well-known fact that dietary
      salt restriction also leads to an activation of the renin-angiotensin system, the
      present study was performed to assess the role of nNOS-derived NO in the
      regulation of the renal function in rats maintained on control (C) and low-salt
      (LS) diets. METHODS: Groups of rats were fed either the C or the LS diet. On day
      13 after adaptation to the appropriate diet, renal clearance studies were
      performed to determine the effects of acute nNOS inhibition either by S-methyl-L
      thiocitrulline (L-SMTC) or by N(omega)-propyl-L-arginine (L-NPA) on renal
      hemodynamics and sodium excretory function. In separate groups of rats maintained
      on either the C or the LS diet, the mRNA levels of nNOS and of renin in the renal
      cortex were examined using the semiquantitative reverse-transcriptase polymerase
      chain reaction. RESULTS: Intrarenal infusion of vehicle (0.9% saline; 4
      microl/min) did not change glomerular filtration rate (GFR), renal plasma flow
      (RPF), or sodium excretion in either C diet or LS diet rats. Acute intrarenal
      infusion of L-SMTC (0.3 mg/h) and L-NPA (0.01 mg/h) decreased GFR (-14 +/- 5 vs. 
      13 +/- 3%), RPF (-19 +/- 6 vs. -17 +/- 5%), and sodium excretion (-17 +/- 5 vs. 
      16 +/- 4%) in C diet rats as compared with control values (p < 0.05). In
      contrast, in LS rats, intrarenal administration of either L-SMTC or L-NPA did not
      cause significant changes in GFR, RPF, and sodium excretion. Furthermore, the
      mRNA expression for nNOS in the renal cortex was moderately increased in LS rats
      as compared with C rats (densitometric ratios of nNOS mRNA/GAPDH mRNA 0.31 +/-
      0.01 vs. 0.22 +/- 0.04, p < 0.05), in parallel with the renin expression (renin
      mRNA/GAPDH mRNA ratios 1.4 +/- 0.2 vs. 1.0 +/- 0.1, p < 0.05). CONCLUSIONS: These
      results indicate that in normotensive rats kept on a normal salt intake nNOS
      derived NO modulates both afferent and efferent arteriolar tones. In contrast,
      rats on an LS diet exhibit an impaired renal vascular responsiveness to nNOS
      derived NO or an impaired ability to release NO by nNOS despite enhanced
      expression of nNOS mRNA in the renal cortex. In addition, the lack of effect of
      acute nNOS inhibition on renal function suggests that NO derived by nNOS does not
      participate in counteracting the vasoconstrictor influences of elevated
      circulating and/or intrarenal angiotensin II levels on pre- and postglomerular
      microcirculation in rats on an LS diet.

PMID- 12424425
TI  - Immunoadsorption and plasma exchange in pregnancy.
AB  - BACKGROUND: During pregnancy, familial hyperlipidemia or systemic lupus
      erythematosus (SLE) can exacerbate having devastating consequences for both
      mother and fetus. Immunoadsorption is established for removal of pathogenic
      proteins lipoproteins or autoantibodies, but this procedure has only rarely been
      used in pregnancy. METHODS: We evaluated retrospectively 126 extracorporeal
      treatments during six pregnancies. Forty low-density lipoprotein
      immunoadsorptions, 6 sole plasma exchanges and 36 combined procedures (plasma
      exchange followed by immunoadsorption) were performed for severe
      hypertriglyceridemia, complicated by acute pancreatitis. Forty-four IgG
      immunoadsorptions were executed in 2 pregnant women suffering from SLE with a
      disastrous course during prior pregnancies. RESULTS: In hyperlipidemic pregnant
      women, mean triglyceride levels prior to treatment were 3,841 +/- 2,076 mg/dl
      (mean +/- SD) and total cholesterol was 617 +/- 354 mg/dl. Until delivery, a 27%
      reduction of triglycerides could be achieved. Clinical and serological signs of
      pancreatitis disappeared after initiation of extracorporeal therapy. Four healthy
      babies were delivered (birthweights between 2,250 and 3,360 g). In 1 woman
      suffering from SLE, intrauterine fetal death occurred in the 22nd week of
      gestation despite a reduction of cardiolipin antibodies by 69%. The second case
      (a twin pregnancy) was complicated by steroid-resistant antibody-mediated anemia.
      Due to frequent immunoadsorptions, red blood cell count improved (reduction of
      antierythrocyte antibodies by 66.6%) and 2 healthy babies (birthweights 2,120 and
      2,350 g) were delivered by cesarean section. CONCLUSION: Long-term antibody-based
      immunoadsorption has been demonstrated to be safe and well tolerated in pregnant
      women and enables normal intrauterine/fetal development. Although rarely
      indicated during pregnancy, this treatment modality might be a promising new
      technique for removal of autoantibodies and lipoproteins in patients with serious
      gestational complications without sufficient response to conventional therapy.

PMID- 12424426
TI  - Some aspects of hemostasis in CAPD patients treated with erythropoietin.
AB  - BACKGROUND: Bleeding diathesis and simultaneous thrombotic complications may be
      seen in dialyzed patients. Erythropoietin may shift the precarious balance of the
      hemostatic system towards thrombosis. Thrombin activatable fibrinolysis inhibitor
      (TAFI) is a key protein linking coagulation and fibrinolysis. METHODS: The
      effects of 3-month erythropoietin treatment on some hemostatic parameters--TAFI,
      fibrinolytic activity index (FAI), markers of ongoing coagulation (thrombin
      antithrombin complexes and prothrombin fragments 1 + 2), marker of ongoing
      fibrinolysis (plasmin-antiplasmin complexes) and marker of endothelial cell
      injury (thrombomodulin)--were studied in 17 patients on continuous ambulatory
      peritoneal dialysis (CAPD). Patients on CAPD not treated with rHuEPO were also
      studied. Healthy volunteers served as a control group. 2,000 U erythropoietin was
      given subcutaneously three times a week. Commercially available kits were used to
      determine hemostatic parameters. RESULTS: All the hemostatic parameters studied
      were significantly higher in CAPD patients when compared to the control group.
      All these hemostatic parameters except the plasmin-antiplasmin complexes did not
      differ significantly between patients before rHuEPO therapy and patients without
      rHuEPO. Erythropoietin therapy resulted in a significant decrease in plasmin
      antiplasmin complexes, a significant rise in FAI after 3 months of drug
      administration, and a tendency to decrease the TAFI concentration and activity
      (after 1 month, p = 0.11 and p = 0.10, respectively; after 3 months p = 0.07 and
      p = 0.06, respectively). Treatment with erythropoietin did not affect platelet
      count, prothrombin time, activated partial thromboplastin time, cholesterol,
      triglycerides, fibrinogen, total protein, albumin, serum iron, ferritin,
      fibronectin, pH, bicarbonates, creatinine, and urea. Hemoglobin and hematocrit
      increased significantly after 1 month of the therapy. CONCLUSION: Short-term
      treatment with erythropoietin seems to minimally affect hemostasis in CAPD
      patients.

PMID- 12424427
TI  - G-protein beta-3-subunit and eNOS gene polymorphism in transplant recipients with
      long-term renal graft function.
AB  - BACKGROUND: Despite new immunosuppressive drugs, only a minority of graft survive
      over 15 years. The aim of our study was to determine the influence of gene
      polymorphisms in the G-protein-beta(3) subunit (Gbeta3) and endothelial nitric
      oxide synthase (eNOS) on the long-term outcome of kidney grafts. METHODS: Using
      PCR, corresponding genotypes in Gbeta3 (C825T) and eNOS (G894T) gene polymorphism
      were evaluated in patients with preserved graft function over 15 years and in a
      control group of transplant recipients. RESULTS: There were no differences in
      allele and genotype distributions of both polymorphisms between groups. In Gbeta3
      polymorphism, the 825T allele carriers had a significantly lower body mass index
      while in eNOS polymorphism there were no links between genotypes, renal function
      and atherosclerosis risk factors. CONCLUSIONS: Our data suggest that these gene
      polymorphisms have only a minor influence on long-term renal graft function.

PMID- 12424428
TI  - Nephrotic proteinuria as a result of essential hypertension.
AB  - BACKGROUND: The presence of nephrotic-range proteinuria in a nondiabetic
      hypertensive patient is generally indicative of an underlying glomerular disease.
      A few published reports have noted nephrotic proteinuria in some patients with
      hypertensive nephrosclerosis. The frequency of this association is unknown.
      METHODS: We retrospectively reviewed renal biopsy reports on all cases of
      nephrotic syndrome over an 8-year period (1993-2000). We excluded all cases of
      diabetes mellitus, lupus, hepatitis, human immunodeficiency virus, and chronic
      use of nonsteroidal anti-inflammatory drugs. Biopsy specimens showing glomerular
      eosinophilic hyalinosis lesions, positive immunofluorescence staining, or dense
      deposits on electron microscopy were also excluded. Thirteen of the remaining 237
      (5.5%) biopsy specimens satisfied the standard histological criteria for
      hypertensive nephrosclerosis. RESULTS: All patients were African-Americans with a
      mean age of 47.5 +/- 13 years and an average mean arterial blood pressure of 122
      +/- 19 mm Hg. The mean values for urinary protein excretion, serum creatinine,
      albumin, and cholesterol were 8.9 g/day, 3.3 mg/dl, 3.1 g/dl, and 245 mg/dl,
      respectively. Optimal blood pressure control required at least three
      antihypertensive agents. Progression to end-stage renal disease occurred over a
      mean duration of 8.3 +/- 6.5 months. Multivariate regression showed a strong but
      nonsignificant association between the level of proteinuria at the time of
      biopsy, duration of hypertension, and number of blood pressure medications (R(2)
      = 0.56, p = 0.38). CONCLUSIONS: Nephrotic syndrome may be more common in poorly
      controlled essential hypertension than previously realized. In African-American
      patients, the differential diagnosis of nephrotic syndrome should include
      hypertensive nephrosclerosis, but abrogation of renal biopsy is not implied.

PMID- 12424429
TI  - Relationship between carotid artery intima-media thickness and atherosclerotic
      renal artery stenosis in type 2 diabetes with hypertension.
AB  - AIM: To assess the relation between intima-media thickness (IMT) of the common
      carotid artery and atherosclerotic renal artery stenosis (ARAS) > or =50% (one or
      both renal arteries) in type 2 diabetic patients with hypertension. METHODS: We
      performed a retrospective study of type 2 diabetic patients with hypertension who
      underwent magnetic resonance angiography or digital subtraction angiography for
      renal artery stenosis at the National Cardiovascular Center or at the Nagasaki
      Municipal Medical Center between May 1999 and May 2001. Renal artery stenosis was
      defined as a narrowing of the artery to at least 50% of normal. Thirty type 2
      diabetic patients with hypertension (17 men and 13 women, mean age 65.4 +/- 7.6
      years) were identified and divided into two groups: those with ARAS in one or
      both renal arteries (n = 15) and those without ARAS (n = 15). We used high
      resolution B-mode ultrasonography to measure the IMT of the common carotid
      artery. RESULTS: With and without ARAS were 9 men and 6 women (mean age 65.0 +/-
      7.6 years) and 8 men and 7 women (mean age 65.7 +/- 6.8 years), respectively. The
      IMT of the carotid artery was significantly greater in patients with ARAS than in
      patients without ARAS (1.07 +/- 0.10 vs. 0.84 +/- 0.12 mm, p < 0.01). However,
      the only clinical findings that statistically significantly differed were
      systolic blood pressure and plasma renin activity. CONCLUSION: Our findings
      suggest that the measurement of the IMT of the carotid artery may be useful as a
      noninvasive screening method for the defection of ARAS even in asymptomatic type
      2 diabetic patients.

PMID- 12424430
TI  - Effect of spironolactone on impaired fibrinolysis of hypertensive patients.
AB  - BACKGROUND/AIMS: Angiotensin-converting enzyme inhibitors and angiotensin II
      receptor antagonists have beneficial effects on impaired fibrinolytic activity of
      hypertensive patients. The aim of the study was to evaluate the effect of
      antialdosterone treatment on impaired fibrinolysis of hypertensive patients.
      METHODS: Fourteen hypertensive outpatients and 14 normotensive healthy volunteers
      participated in this study. Blood samples for plasminogen activator inhibitor-1
      (PAI-1) antigen and tissue plasminogen activator (t-PA) antigen were obtained at
      baseline in all patients and control subjects. Then all hypertensive patients
      used spironolactone 50 mg/day for a week. Blood samples were again obtained after
      a week of spironolactone treatment. RESULTS: The mean basal plasma level of PAI-1
      of hypertensive patients was higher than those of the normotensive control group
      (60.98 +/- 4.2 vs. 24.09 +/- 1.61 ng/ml, p < 0.01) The mean basal t-PA level was
      similar in the hypertensive and control subjects (7.49 +/- 0.65 vs. 8.78 +/- 0.92
      ng/ml, p > 0.05). The mean PAI-1 level decreased after a week of spironolactone
      treatment (60.98 +/- 4.2 vs. 42.99 +/- 7.98 ng/ml, p < 0.05). The mean plasma t
      PA level of hypertensive patients increased after spironolactone treatment (7.49
      +/- 0.65 vs. 11.09 +/- 1.33 ng/ml, p < 0.05). CONCLUSION: This study shows that
      spironolactone improves impaired fibrinolysis in systemic hypertension. It
      provides evidence for a direct link between aldosterone and the fibrinolytic
      system in humans.

PMID- 12424431
TI  - HESX1 and Septo-Optic Dysplasia.

PMID- 12424432
TI  - Other transcription factors and hypopituitarism.

PMID- 12424433
TI  - Growth Hormone Releasing Hormone (GHRH) and the GHRH Receptor.

PMID- 12424434
TI  - Ghrelin: the link connecting growth with metabolism and energy homeostasis.

PMID- 12424435
TI  - GH Gene Deletions and IGHD type IA.

PMID- 12424436
TI  - Growth hormone insensitivity (Laron syndrome).

PMID- 12424437
TI  - Insulin-like growth factor (IGF)-I gene deletion.

PMID- 12424438
TI  - SHOX mutations.

PMID- 12424439
TI  - The genetics of the Silver-Russell syndrome.

PMID- 12424442
TI  - Three-dimensional imaging for craniofacial reconstruction.

PMID- 12424440
TI  - Fibroblast growth factor receptor 3 mutations in achondroplasia and related forms
      of dwarfism.

PMID- 12424443
TI  - Maternal age and oral clefts: a reappraisal.
AB  - OBJECTIVE: The aim of the study was to test the hypothesis that increased
      maternal age is associated with a higher risk of having a child with oral clefts.
      STUDY DESIGN: A meta-analysis of 8 population-based studies with information
      regarding live birth and oral clefts was performed. RESULTS: No association
      between increased maternal age and isolated oral clefts was found. CONCLUSION:
      Oral clefts occurrence is not correlated with increasing maternal age, and
      inclusion of data mixing isolated and syndromic cases can confound the analysis
      and must be avoided.

PMID- 12424444
TI  - Lateral neck mass.

PMID- 12424445
TI  - Surgical and orthodontic management of compound odontoma without removal of the
      impacted permanent tooth.

PMID- 12424447
TI  - Long-term evaluations of temporomandibular disorders in patients undergoing
      orthognathic surgery compared with a control group.
AB  - OBJECTIVE: The purpose of this study was to investigate alterations in signs and
      symptoms of temporomandibular disorders (TMDs) in patients undergoing
      orthognathic surgery compared with a healthy group. STUDY DESIGN: Signs and
      symptoms of TMD in orthognathic surgery patients were evaluated before surgery, 1
      week after removal of intermaxillary fixation, and 1 and 2 years after surgery by
      means of Helkimo's Anamnestic and Dysfunction Indexes. At initial and final
      examinations, signs and symptoms of TMD of orthognathic surgery patients were
      compared also with those of healthy patients. The lengths of condylar pathways
      during opening, medial, and protrusive movements in orthognathic surgery patients
      were evaluated with axiography. RESULTS: A statistically significant reduction
      was noted for the TMD symptoms and signs 2 years after surgery compared with
      before surgery. At initial examination, orthognathic surgery patients did not
      report TMD signs and symptoms significantly more often than healthy subjects. At
      final examination, improvements in TMD symptoms of orthognathic surgery patients
      were found when compared with healthy subjects. CONCLUSION: The results of this
      study suggested that functional status of temporomandibular joint can be improved
      with orthognathic surgery, but no association could be clearly shown between TMD
      symptoms and the type of dentofacial deformity.

PMID- 12424446
TI  - Marsupialization for odontogenic keratocysts: long-term follow-up analysis of the
      effects and changes in growth characteristics.
AB  - OBJECTIVE: This study evaluated the effects of marsupialization on odontogenic
      keratocysts (OKCs) and its role in conjunction with enucleation and curettage.
      STUDY DESIGN: Twenty-eight primary OKCs, treated by marsupialization before
      enucleation and curettage, were examined in this study. The effect of
      marsupialization and recurrence data after a follow-up period of at least 3 years
      were evaluated. The changes of growth characteristics during marsupialization
      were analyzed by means of histopathologic and immunohistochemical studies with
      monoclonal anti-Ki-67 antibody. RESULTS: The effect of marsupialization was
      evaluated as extremely effective (64.3%), moderately effective (32.1%), and
      poorly effective (3.6%). In 5 lesions, the cysts disappeared macroscopically and
      further surgery was not done. Recurrence was observed in 6 lesions (21.4%), and
      there was no significant difference in recurrence rates between the lesions
      treated with or without marsupialization. There appeared to be a predilection for
      recurrence in the lesions in the mandibular ramus region and also for
      radiographically multilocular lesions. Microscopic examination showed substantial
      changes from a parakeratinized or orthokeratinized epithelium into a
      hyperplastic, stratified, nonkeratinizing squamous epithelium after
      marsupialization in many cases. There was no significant difference in labeling
      index between premarsupialization (20.2% +/- 12.0%) and postmarsupialization
      (15.3% +/- 10.3%). CONCLUSION: Marsupialization was found to be effective as a
      preliminary treatment for large OKCs. This procedure does not appear to affect
      the recurrence tendency of OKCs, and the probable changes in growth
      characteristics become rather less aggressive.

PMID- 12424448
TI  - Alveolar distraction: analysis of 10 cases.
AB  - OBJECTIVE: The purpose of this study was to evaluate intraoperative and
      postoperative complications of alveolar distraction and outcome. STUDY DESIGN:
      Ten patients with alveolar ridge deficiencies were treated with alveolar
      distraction osteogenesis by means of intraosseous distractors (Lead system,
      Stryker Leibenger, Kalamazoo, Mich). The deficiencies were caused by atrophy
      after periodontal disease or atrophy after tooth extraction (n = 6), benign tumor
      resection (n = 2), trauma (n = l), or oligodontia in a case of ectodermal
      dysplasia (n = l). The location of the defects was the anterior mandible (7),
      posterior mandible (1), and anterior maxilla (2). The mean follow-up was 1.8
      years, with a range of 10 months to 3 years. RESULTS: The mean alveolar
      distraction achieved in 10 cases was 8.7 mm (5-15 mm). The intraoperative and
      postoperative problems encountered were lingual (n = 3) and palatal (n = 2)
      displacement of the distracted segment, fracture of the distracted segment in a
      very thin alveolar bone (n = 1), and intraoperative bleeding (n = 1). CONCLUSION:
      Overall complication rate was 70%. However, most of the complications were minor
      and eliminated easily. Implant success rate was 85%.

PMID- 12424449
TI  - Surgical management of macroglossia: discussion of 7 cases.
AB  - OBJECTIVE: We present an overview of international literature concerning
      macroglossia-related etiology, clinical and instrumental diagnoses, surgical
      treatments, complications, and recurrences. Moreover, we present a series of
      cases of patients affected by macroglossia who have been treated surgically at
      the Department of Maxillofacial Surgery of the University of Rome "La Sapienza".
      METHODS: Between 1990 and 1999, only after attempts to solve this pathologic
      condition with medical and orthodontic treatment, we treated surgically a total
      of 7 patients (4 male and 3 female). The surgical techniques used were Kole
      glossectomy and Dingman and Grabb glossectomy. We analyzed the clinical and
      instrumental study and the surgical treatment, including possible complications
      and recurrences. RESULTS: After follow-up of a period from 2 to 9 years,
      macroglossia recurrences were absent, showing that the Kole and the Dingman and
      Grabb glossectomies are viable surgical options for treatment of macroglossia.
      CONCLUSION: The best therapy for each case macroglossia must be carefully
      evaluated, with the right medical therapy and orthodontic therapy attempted first
      and surgical treatment performed only when the first and second therapy fail.
      Moreover, surgical techniques must be chosen in accordance with the functional
      results that one wants to achieve and must be the most conservative technique to
      preserve the vascular-nerve bundle.

PMID- 12424450
TI  - Ten-year outcome of nonsurgical treatment for the internal derangement of the
      temporomandibular joint with closed lock.
AB  - OBJECTIVE: The objective of this study was to assess long-term 10-year results in
      comparison with the short-term outcomes of nonsurgical treatment for the internal
      derangement of the temporomandibular joint (TMJ) with closed lock. PATIENTS AND
      METHODS: The survey was conducted on 56 patients, 50 of whom responded. The age
      at first examination ranged from 13 to 75 years (mean, 33.2 years), and the
      pretreatment jaw opening was 30.3 mm on average. The short-term clinical outcome
      of nonsurgical treatment for 56 patients consisted of 42 successful and 14
      unsuccessful cases. The mean follow-up period was 9 years and 10 months. All
      patients rated their pain level on a visual analog scale (VAS) and filled out a
      pain, jaw-dysfunction, and activities-of-daily-limiting (ADL) questionnaire
      before and at time of the survey. Jaw opening was also self-assessed.
      Pretreatment and post-treatment scores were compared and statistically tested,
      and the treatment outcome was judged according to our success criteria. The
      patients were also asked for a global rating of the subjective outcome at the
      survey. Last, long-term outcomes were compared with short-term clinical outcomes.
      RESULTS: VAS was significantly reduced from 4.91 to 0.17 (P <.01). Pain,
      dysfunction, and ADL scores also decreased from 5.89 to 1.07, from 5.34 to 2.0,
      and from 5.55 to 1.36, respectively (P <.01). Jaw opening also improved.
      Consequently, 40 patients were assessed as excellent, 10 patients as good, and
      none as poor. The overall success rate was 89.3% when the 6 nonrespondents were
      included. The patients' self-rated outcome showed that 31 patients rated good, 10
      patients rated neither, and 9 patients did not rate, but none replied not good.
      Finally, the short-term clinical outcomes did not relate to the long-term
      outcomes. CONCLUSIONS: The long-term (10-year) outcomes of nonsurgical treatment
      for TMJ internal derangement with closed lock were considered to be acceptable
      and stable when compared with those of other treatment modalities. Short-term
      results had little effect on the long-term outcomes.

PMID- 12424451
TI  - Bone SPECT imaging of patients with internal derangement of temporomandibular
      joint before and after splint therapy.
AB  - OBJECTIVE: Temporomandibular joint (TMJ) patients with disc displacement without
      reduction have a misaligned disc-condyle structural relation. As the condition
      becomes chronic, painful osteoarthritic changes may occur. For these patients,
      splint therapy may help to position the condyle to a more structurally compatible
      and functional position and to decrease the loading force of articular surfaces.
      The aim of this study was (1). to evaluate osseous reactions and pain relief in
      patients with disc displacement without reduction after splint therapy and (2).
      to use single photon emission tomography (SPECT) bone imaging to compare the
      results with the opposite joint of the patient. STUDY DESIGN: Twelve patients,
      who presented with pain involving the TMJ and limited mouth opening and were
      confirmed by soft tissue imaging as having disc displacement without reduction,
      were included in the study. Each patient underwent bone SPECT imaging, after
      which semiquantitative evaluation of transaxial images was conducted. The ratios
      of affected TMJ to nonaffected TMJ, affected TMJ to occipital bone, and
      nonaffected TMJ to occipital bone were calculated. After 6 months of splint
      therapy, bone SPECT examinations were repeated. RESULTS: Before splint therapy,
      the ratios of affected TMJ to nonaffected TMJ and of affected TMJ to occipital
      bone were found to be significantly higher than the ratios after splint therapy
      (P < 0.005). CONCLUSION: Six-month splint therapy has a positive effect on the
      osseous reaction and pain related to internal derangements of TMJs.

PMID- 12424452
TI  - A retrospective investigation of advanced periodontal disease as a risk factor
      for septicemia in hematopoietic stem cell and bone marrow transplant recipients.
AB  - OBJECTIVE: Septicemia is a cause of death in hematopoietic stem cell transplant
      (HSCT) recipients. Extraction of teeth with advanced periodontitis has been
      advocated before HSCT to prevent septicemia in myeloablated hosts. The primary
      aim of the present study was to determine impact of chronic periodontitis, as
      measured by radiographic alveolar bone loss, on septicemia and transplant
      mortality. STUDY DESIGN: A retrospective design was used to study 77 subjects who
      received pretransplant dental evaluation, panoramic radiography, and full
      myeloablative allogeneic HSCT to treat hematologic malignancies. Radiographic
      crestal alveolar bone loss was measured with a Schei ruler on all teeth.
      Microorganisms isolated from positive blood cultures within the first 100 days
      after transplant were categorized as of likely origin from periodontal, oral, or
      any body sites. Spearman correlation and logistic regression analysis assessed
      associations between positive blood cultures, mean subject whole-mouth percent
      radiographic crestal alveolar bone loss, and 100-day survival. RESULTS:
      Radiographic crestal alveolar bone loss per study subject averaged 13% +/- 7%,
      with 18.2% exhibiting bone loss of 20% or greater. During the initial 100 days
      after transplant, 63.6% subjects yielded septicemia-associated positive blood
      cultures, with Staphylococcus epidermidis, Streptococcus mitis, Enterococcus
      faecalis, Streptococcus sanguis, Staphylococcus aureus, and Escherichia coli as
      the most common isolates recovered. No statistically significant associations
      were found between mean subject radiographic alveolar bone loss and septicemia of
      likely periodontal or oral origin. CONCLUSION: In this preliminary study, no
      relationship was found between radiographic periodontal status and septicemia or
      mortality within the initial 100 days after transplant. A larger-sized,
      prospective study is warranted to further delineate the risk of septicemia from
      periodontal and other oral diseases in immunocompromised patients.

PMID- 12424453
TI  - Candida albicans adherence to resin-composite restorative dental material:
      influence of whole human saliva.
AB  - OBJECTIVE: Attachment of Candida albicans to oral surfaces is believed to be a
      critical event in the colonization of the oral cavity and in the development of
      oral diseases such as Candida-associated denture stomatitis. Although there is
      considerable information about the adhesion of C albicans to buccal epithelial
      cells and prosthetic materials, there is very little information about the
      adhesion of C albicans to composite restorative materials. The purpose of this
      study was to investigate the degree of adhesion of C albicans to a resin
      composite restorative material (Herculite). METHODS: The adhesion of 2 strains of
      C albicans, a germinative and a germ tube-deficient mutant, was studied by a
      visual method after incubating the fungus and the resin with and without human
      whole saliva. RESULTS: In absence of saliva, the adhesion of the C albicans
      germinative isolate to the resin showed an increase in parallel with the
      germination, reaching a maximum at the end of the experiment (120 minutes).
      However, no significant differences were observed in the adhesion of the
      agerminative mutant during the period of time studied. In the presence of saliva,
      the adhesion of both isolates to the resin was significantly lowered. CONCLUSION:
      Germination and the presence of human whole saliva are important factors in the
      adhesion of C albicans to the resin-composite restorative material Herculite.

PMID- 12424454
TI  - p53, mdm2, and p21 expression in oral squamous cell carcinomas: relationship with
      clinicopathologic factors.
AB  - OBJECTIVE: The purpose of this study was to clarify the correlation of expression
      of cell cycle-associated gene proteins with clinicopathologic factors in oral
      squamous cell carcinoma (SCC). STUDY DESIGN: Formalin-fixed paraffin-embedded
      tissues from 69 oral SCC cases and 10 normal mucosa cases were stained by
      immunohistochemistry (IHC) for p53, mdm 2, and p21 proteins. RESULTS: We found
      p53, mdm 2, and p21 expression in 44 of 69 (63.8%), 25 of 69 (36.2%), and 37 of
      69 (53.6%) oral SCCs, respectively. Ki-67-labeling index of combined p53(+)/mdm
      2(+) expression cases was significantly higher than those that lacked combined
      expression (P =.004). Combined p53(+)/p21(+) expression showed a significant
      association with lymph node metastasis (P =.019). In survival analysis, combined
      p53(+)/p21(+) and p53(+)/mdm 2(+)/p21(+) expression was associated with poor
      clinical outcome (P =.018 and.012, respectively). CONCLUSION: Combined p53/mdm 2
      expression was associated with tumor proliferation in oral SCC. Combined p53/p21
      and p53/mdm 2/p21 expression may be a predictive factor in lymph node metastasis.

PMID- 12424455
TI  - Carcinoma cuniculatum of the jaw: a rare variant of oral carcinoma.
AB  - Carcinoma cuniculatum is a rare variant of carcinoma usually involving the foot.
      Only 13 cases have been described in the oral cavity, none of which was in the
      English-language literature. We describe a 56-year-old man who presented with a
      soft exophytic mass in the maxillary gingiva, alveolar bone destruction, and
      loosening of the teeth. Histopathologic study revealed thin papillary projections
      covered by a thick keratin layer in the superficial areas and multiple, branching
      keratin-filled crypts surrounded by well-differentiated squamous epithelium with
      only mild cytologic atypia but frequent mitosis. Immunohistochemistry results of
      p53 and polymerase chain reaction analyses for human papillomavirus 6, 11, 16,
      and 18 DNA were negative. The diagnosis was carcinoma cuniculatum of the jaw. The
      literature on this unusual oral pathosis is reviewed and the diagnostic challenge
      described. We suggest that carcinoma cuniculatum may sometimes be misdiagnosed as
      squamous cell carcinoma or verrucous carcinoma and, therefore, might be more
      prevalent than the small number of published cases implies.

PMID- 12424456
TI  - Paracoccidioidomycosis: report of 2 cases mimicking squamous cell carcinoma.
AB  - Paracoccidioidomycosis is an endemic fungal infection in Latin America. This
      mucocutaneous disease often involves the oral mucosa and may clinically resemble
      other infectious and neoplastic processes. Paracoccidioidomycosis that clinically
      suggested squamous cell carcinoma was diagnosed in 2 patients with a history of
      heavy alcohol and tobacco use. Antifungal therapy with ketoconazole and
      itraconazole resulted in resolution of the oral lesions. Interestingly, 1 patient
      had a pulmonary lesion that persisted after antifungal therapy, and biopsy proved
      this to be a squamous cell carcinoma of the lung.

PMID- 12424457
TI  - The central granular cell odontogenic tumor: report of 5 new cases.
AB  - This article reports 5 previously unreported cases of central granular cell
      odontogenic tumor and compares them with 25 cases from the literature. This
      lesion appears to be an uncommon benign odontogenic neoplasm of uncertain
      histogenesis; it occurs over a wide age range with a predilection for the
      mandibular premolar-molar region. Radiographically, it typically manifests as a
      well-defined unicystic or multilocular radiolucency, although it can be a mixed
      density lesion as well. In our series, there was a narrow spectrum of histologic
      features consisting of fibrous tissue of altering density and cellularity with
      plentiful numbers of large eosinophilic granular cells, variable amounts of
      "inactive-appearing" odontogenic epithelium, and the variable presence of
      calcified tissue resembling cementum or dystrophic calcifications. The
      ultrastructural and immunohistochemical findings in this study support a
      mesenchymal origin for the granular cells. One recurrence was documented in the
      current series in contrast to no recurrences in the literature.

PMID- 12424458
TI  - Expression of adenosine triphosphate P2X3 receptors in rat molar pulp and
      trigeminal ganglia.
AB  - OBJECTIVE: The objective of this study was to investigate the expression of
      adenosine triphosphate P2X3 receptor subunits in rat molar pulp and trigeminal
      ganglia and their relationship to substance P. STUDY DESIGN: Rat molar pulp and
      trigeminal ganglia were fixed and sectioned. Double immunostaining with anti-P2X3
      and anti-substance P were used to localize P2X3 and substance P expression
      simultaneously with different stains. RESULTS: P2X3 immunoreactivity (IR) fibers
      were present in root and coronal pulp. P2X3-IR fibers formed subodontoblastic
      plexus and advanced into the predentin and dentin. P2X3-IR neurons were localized
      in small and medium-sized cells in trigeminal ganglia. Colocalization of P2X3 and
      substance P was not found in either molar pulp or trigeminal ganglia. CONCLUSION:
      The results of this study indicated that adenosine triphosphate in pulp tissues
      may stimulate a subpopulation of non-substance P trigeminal afferent fibers
      through activation of P2X3 receptors.

PMID- 12424459
TI  - Influence of a microbrush on bonding fiber post into root canals under clinical
      conditions.
AB  - OBJECTIVE: The objective of this clinical report was to evaluate the
      effectiveness of a microbrush as a carrier of priming-adhesive solution in
      formation of resin tags, adhesive lateral branches, and resin-dentin
      interdiffusion zone (RDIZ) when the brush was used to bond fiber posts under
      clinical conditions. STUDY DESIGN: Twenty endodontically treated teeth, already
      scheduled for extraction for endodontic or periodontal reasons, were selected for
      this study. The patients were informed, and their written consent was obtained.
      The samples were randomly divided into 2 groups of 10 samples each. In group 1,
      One-Step (Bisco, Schaumburg, Ill) was applied with a brush with Duo-Link resin
      cement (Bisco). In group 2, One-Step was applied with a microbrush with Duo-Link
      resin cement (Bisco). Use of the adhesive systems and resin cements was strictly
      according to manufacturers' instructions. The priming-adhesive solution was light
      cured before the dual resin cement and the post were placed. Twenty Aestheti-Plus
      posts (white quartz fiber posts; RTD, St. Egreve, France) were used. A week after
      application, the root samples were extracted and processed for SEM observations.
      RESULTS: Both adhesive systems showed RDIZ and resin tag and adhesive lateral
      branch formation. In Group 2 samples, RDIZ morphology was easily detectable and
      uniform along root canals. Also, resin tag formation was well represented in all
      thirds. In group 1 samples, resin tag formation at the apical third and RDIZ
      formation was less evident. Statistically significant differences were found
      among the two groups at the apical third. CONCLUSION: The microbrush permitted a
      more uniform RDIZ and resin tag formation along the entire length of the canal
      than did the standard brush. The microbrush can be routinely used for bonding
      fiber posts into root canal preparations.

PMID- 12424460
TI  - Treatment of parotid ductal stenosis and concomitant resolution of autonomic
      symptomatology.
AB  - Salivary retention and recurrent sialadenitis as a result of ductal stenosis is
      an uncommon condition that presents difficult management problems. Ductal
      dilation with small angioplasty balloons is recognized to be of low morbidity and
      can eliminate the possible need for surgical intervention. This case report is
      interesting in that the successful treatment of parotid duct stenosis was
      accompanied by the resolution of a spectrum of autonomic symptoms that had
      seriously compromised the patient's quality of life.

PMID- 12424461
TI  - Calcification of the branches of the external carotid artery detected by
      panoramic radiography: a case report.
AB  - Atherosclerosis, a progressive inflammatory disease, may lead to stroke, coronary
      artery disease, or peripheral artery disease. The prevalence of atherosclerosis
      associated with morbidity and mortality is very high in industrialized countries.
      This report describes the case of a 49-year-old male patient whose panoramic
      radiograph taken as part of a dental examination showed calcification in the
      branches of the external carotid artery. The right facial artery and left
      maxillary, facial, and lingual arteries were also calcified. The patient had a
      history of thrombosis in the right axillary and brachial veins with extension to
      half of the brachiocephalic trunk. In addition, selective lesions were found in
      the aorta and mitral valve. The patient's medical history also included
      hypertriglyceridemia, essential arterial hypertonia, terminal renal
      insufficiency, renal anemia, neurogen disturbance micturition, secondary
      hyperparathyroidism, hyperuricemia, lymphatic edema, polyneuropathy,
      tachyarrhythmia absoluta, and erysipelas. The case presented reports on the
      possibility of detecting signs of atherosclerosis in arteries of the
      maxillofacial region by use of panoramic radiography.

PMID- 12424462
TI  - Osteosarcoma of the temporomandibular joint: report of 2 cases.
AB  - The aim of this article is to report 2 cases of osteosarcoma of the mandibular
      condyle, a rare pathological condition, and to emphasize and discuss the
      usefulness of different imaging modalities in the diagnosis and evaluation of
      osteosarcoma of the temporomandibular joint. In our assessment of the different
      imaging modalities, we found that 2-dimensional computed tomograms provide
      excellent detection of tumor calcification, cortical involvement, and in most
      instances, soft tissue and intramedullary extension, whereas 3-dimensional
      computed tomography vascular protocol can help to define the extension of the
      lesion, improving the visualization of the lesion's relationship to the adjacent
      anatomical structures. Magnetic resonance imaging is more effective in
      demonstrating the intramedullary and extraosseous tumor components on T2 weighted
      images. Because metastasis from body tumors to the maxillofacial region occurs
      occasionally, it is useful to examine the oral cavity when symptoms first appear
      and devote special attention to the subtle changes that may indicate early
      metastatic involvement.

PMID- 12424481
TI  - A Portuguese version of the Christo Inventory for Substance-Misuse Services: a
      simple outcome evaluation tool.
AB  - The Christo Inventory for Substance-Misuse Services (CISS) is a single page
      outcome evaluation tool completed by drug alcohol service workers either on the
      basis of direct client interviews or of personal experience of their client
      supplemented by existing assessment notes. It was developed to assist substance
      misuse services to empirically demonstrate the effectiveness of their treatments
      to their respective funding bodies. Its 0 to 20 unidimensional scale consists of
      10 items reflecting clients' problems with social functioning, general health,
      sexual/injecting risk behavior, psychological functioning, occupation, criminal
      involvement, drug/alcohol use, ongoing support, compliance, and working
      relationships. Good reliability and validity has already been demonstrated for
      the CISS [Christo et al., Drug and Alcohol Dependence 2000; 59: 189-197] but the
      original was written in English and a Portuguese version is presented here. The
      present review explores its applicability to a Brazilian setting, summarizes its
      characteristics and uses, and describes the process of translation to Portuguese.
      A pilot study conducted in a substance misuse service for adolescents indicated
      it is likely to be suitable for use among a Brazilian population. The simplicity,
      flexibility and brevity of the CISS make it a useful tool allowing comparison of
      clients within and between many different service settings.

PMID- 12424482
TI  - Morphological changes of carotid bodies in acute respiratory distress syndrome: a
      morphometric study in humans.
AB  - Carotid bodies are chemoreceptors sensitive to a fall of partial oxygen pressure
      in blood (hypoxia). The morphological alterations of these organs in patients
      with chronic obstructive pulmonary disease (COPD) and in people living at high
      altitude are well known. However, it is not known whether the histological
      profile of human carotid bodies is changed in acute clinical conditions such as
      acute respiratory distress syndrome (ARDS). The objective of the present study
      was to perform a quantitative analysis of the histology of carotid bodies
      collected from patients who died of ARDS. A morphometric study of carotid bodies
      collected during routine autopsies was carried out on three groups: patients that
      died of non-respiratory diseases (controls, N = 8), patients that presented COPD
      and died of its complications or associated diseases (N = 7), and patients that
      died of ARDS (N = 7). Morphometric measurements of the volume fraction of
      clusters of chief cells were performed in five fields on each slide at 40X
      magnification. The numerical proportion of the four main histological cell types
      (light, dark, progenitor and sustentacular cells) was determined analyzing 10
      fields on each slide at 400X magnification. The proportion of dark cells was 0.22
      in ARDS patients, 0.12 in controls (P<0.001), and 0.08 in the COPD group. The
      proportion of light cells was 0.33 (ARDS), 0.44 (controls) (P<0.001), and 0.36
      (COPD). These findings suggest that chronic and acute hypoxia have different
      effects on the histology of glomic tissue.

PMID- 12424483
TI  - Rapid detection of multidrug-resistant Mycobacterium tuberculosis using the
      mycobacteria growth indicator tube (MGIT) system.
AB  - The emergence of multidrug-resistant strains of Mycobacterium tuberculosis has
      increased the need for rapid drug susceptibility tests, which are needed for
      adequate patient treatment. The objective of the present study was to evaluate
      the mycobacteria growth indicator tube (MGIT) system to detect multidrug
      resistant M. tuberculosis strains. The MGIT system was compared with two standard
      methods (proportion and resistance ratio methods). One hundred clinical M.
      tuberculosis isolates [25 susceptible to isoniazid (INH) and rifampicin (RIF), 20
      resistant to INH, 30 resistant to INH-RIF, and 25 resistant to INH-RIF and other
      drugs] obtained in the State of S o Paulo were tested for INH and RIF
      susceptibility. Full agreement among the tests was found for all sensitive and
      all INH-resistant strains. For RIF-resistant strains results among the tests
      agreed for 53 (96.4%) of 55 isolates. Results were obtained within 6 days (range,
      5 to 8 days), 28 days and 12 days when using MGIT, the proportion method and the
      resistance ratio methods, respectively. The MGIT system presented an overall
      agreement of 96% when compared with two standard methods. These data show that
      the MGIT system is rapid, sensitive and efficient for the early detection of
      multidrug-resistant M. tuberculosis.

PMID- 12424484
TI  - Exhaled nitric oxide collected with two different mouthpieces: a study in
      asthmatic patients.
AB  - Techniques for collecting exhaled nitric oxide (ENO) recommend the use of
      antibacterial filters of 0.3 m. The aim of the present study was to compare the
      measurements of ENO obtained with two different filtering devices. Air samples
      from 17 asthmatic and 17 non-asthmatic subjects were collected by a recommended
      off-line technique using two different mouthpieces: 1) the Sievers disposable
      tool (A) under a breathing pressure of 18 cmH2O, and 2) a mouthpiece containing a
      HEPA filter (B) under a breathing pressure of 12 cmH2O. The nitric oxide samples
      were collected into an impermeable reservoir bag. Values for ENO were compared
      using two-way repeated measures ANOVA followed by the Tukey test. Agreement was
      assessed by Bland-Altman analysis. ENO values obtained with mouthpieces A and B
      were comparable for asthmatic (mean +/- SEM, 42.9 +/- 6.9 vs 43.3 +/- 6.6 ppb)
      and non-asthmatic (13.3 +/- 1.3 vs 13.7 +/- 1.1 ppb) subjects. There was a
      significant difference in ENO between asthmatics and non-asthmatics using either
      mouthpiece A (P<0.001) or B (P<0.001). There was a positive correlation between
      mouthpiece A and mouthpiece B for both groups. The Bland-Altman limits of
      agreement were considered to be acceptable. Mouthpiece B was less expensive than
      A, and these data show that it can be used without compromising the result. Our
      data confirm reports of higher ENO values in the presence of airway inflammation.

PMID- 12424485
TI  - Intravenous dipyrone for the acute treatment of episodic tension-type headache: a
      randomized, placebo-controlled, double-blind study.
AB  - Acute headaches are responsible for a significant percentage of the case load at
      primary care units and emergency rooms in Brazil. Dipyrone (metamizol) is easily
      available in these settings, being the most frequently used drug. We conducted a
      randomized, placebo-controlled, double-blind study to assess the effect of
      dipyrone in the acute treatment of episodic tension-type headache. Sixty patients
      were randomized to receive placebo (intravenous injection of 10 ml saline) or 1 g
      dipyrone in 10 ml saline. We used seven parameters of analgesic evaluation. The
      patients receiving dipyrone showed a statistically significant improvement
      (P<0.05) of pain compared to placebo up to 30 min after drug administration. The
      therapeutic gain was 30% in 30 min and 40% in 60 min. The number of patients
      needed to be treated for at least one to have benefit was 3.3 in 30 min and 2.2
      in 60 min. There were statistically significant reductions in the recurrence
      (dipyrone = 25%, placebo = 50%) and use of rescue medication (dipyrone = 20%,
      placebo = 47.6%) for the dipyrone group. Intravenous dipyrone is an effective
      drug for the relief of pain in tension-type headache and its use is justified in
      the emergency room setting.

PMID- 12424486
TI  - Ultrasonographic determination of goiter prevalence in southern Brazilian
      schoolchildren.
AB  - The aim of the present study was to estimate the prevalence of goiter in
      schoolchildren in a formerly iodine-deficient region in southern Brazil by
      assessing the relationship between body surface area (m2 ) and thyroid volume
      (ml) measured by ultrasonography. A population-based sample of 1,094 randomly
      selected schoolchildren (6 to 14 years; 556 boys and 538 girls) underwent
      clinical evaluation. A total of 119 (10.9%) children were diagnosed with goiter
      upon clinical examination according to WHO criteria (grade Ia: 65, grade Ib: 24,
      grade II: 29, grade III: 1). Of these, 85 underwent ultrasonography. In order to
      ascertain the absence of goiter in the 975 schoolchildren with a negative result
      upon clinical examination, one of ten children was randomly selected for
      ultrasonography. Sixty-two children agreed to be submitted to the exam. Thus, 147
      schoolchildren were evaluated by ultrasonography (7.5-MHz transducer). Goiter was
      considered to be present when the thyroid volume:body surface area index was >6.2
      ml/m . The estimated prevalence of goiter if all schoolchildren had been
      submitted to thyroid volume measurement by ultrasound was 7.2%; it was higher in
      the lower socioeconomic class (8.2%) than in the upper (7.8%) and middle classes
      (6.5%). In conclusion, the prevalence of goiter in schoolchildren of this region
      was higher than in other iodine-sufficient areas, especially in lower
      socioeconomic classes. Goiter in this region may be associated with naturally
      occurring goitrogens that operate more intensively among less privileged
      individuals.

PMID- 12424487
TI  - Trachoma among the Yanomami Indians.
AB  - The Yanomami are one of the last primitive groups of Indians living in Brazil.
      They have almost no contact with other cultures. The epidemiology of eye disease
      among Yanomami is virtually unknown. For the first time, a trachoma survey was
      conducted among Yanomami Indians in the State of Amazonas near the Venezuelan
      border of the Brazilian rain forest. Ophthalmic examination was carried out on a
      total of 613 individuals (338 males and 275 females) from eight Yanomami villages
      along the Maraui  River located in the upper Rio Negro Basin. Age was classified
      into three categories (children, adults, and elderly) and trachoma was classified
      into five grades: follicular, inflammatory intense, cicatricial, trichiasis, and
      corneal opacity. Trachoma was endemic in all villages visited. Overall, 30.3% of
      the subjects had trachoma. Females were significantly more affected (37.4%) than
      males (23.9%). The inflammatory trachoma rate reached 24.9% in children and the
      cicatricial form increased with age, reaching 13.9% among adults and 35.21% among
      the elderly. Trichiasis or corneal opacities were not detected and treatment of
      the entire population was initiated with 1 g azithromycin. The detection of
      endemic trachoma among the Yanomami is relevant for the understanding of the
      epidemiology of this disease in the Brazilian rain forest and underscores the
      necessity for a program of trachoma control in this region.

PMID- 12424488
TI  - Bone mineral density in juvenile systemic lupus erythematosus.
AB  - We evaluated spine bone mineral density (BMD) in Brazilian children with juvenile
      systemic lupus erythematosus (JSLE) in order to detect potential predictors of
      reduction in bone mass. A cross-sectional study of BMD at the lumbar spine level
      (L2-L4) was conducted on 16 female JSLE patients aged 6-17 years. Thirty-two age
      matched healthy girls were used as control. BMD at the lumbar spine was measured
      by dual-energy X-ray absorptiometry. Weight, height and pubertal Tanner stage
      were determined in patients and controls. Disease duration, mean daily steroid
      doses, mean cumulative steroid doses and JSLE activity measured by the systemic
      lupus erythematosus disease activity index (SLEDAI) were determined for all JSLE
      patients based on their medical charts. All parameters were used as potential
      determinant factors for bone loss. Lumbar BMD tended to be lower in the JSLE
      patients, however, this difference was not statistically significant (P = 0.10).
      No significant correlation was observed in JSLE girls between BMD and age,
      height, Tanner stage, disease duration, corticosteroid use or disease activity.
      We found a weak correlation between BMD and weight (r = 0.672). In the JSLE group
      we found no significant parameters to correlate with reduced bone mass. Disease
      activity and mean cumulative steroid doses were not related to BMD values. We did
      not observe reduced bone mass in female JSLE.

PMID- 12424489
TI  - Role of Tamm-Horsfall protein and uromodulin in calcium oxalate crystallization.
AB  - One of the defenses against nephrolithiasis is provided by macromolecules that
      modulate the nucleation, growth, aggregation and retention of crystals in the
      kidneys. The aim of the present study was to determine the behavior of two of
      these proteins, Tamm-Horsfall and uromodulin, in calcium oxalate crystallization
      in vitro. We studied a group of 10 male stone formers who had formed at least one
      kidney stone composed of calcium oxalate. They were classified as having
      idiopathic nephrolithiasis and had no well-known metabolic risk factors involved
      in kidney stone pathogenesis. Ten normal men were used as controls, as was a
      group consisting of five normal women and another consisting of five pregnant
      women. Crystallization was induced by a fixed supersaturation of calcium oxalate
      and measured with a Coulter Counter. All findings were confirmed by light and
      scanning electron microscopy. The number of particulate material deposited from
      patients with Tamm-Horsfall protein was higher than that of the controls
      (P<0.001). However, Tamm-Horsfall protein decreased the particle diameter of the
      stone formers when analyzed by the mode of the volume distribution curve
      (P<0.002) (5.64 +/- 0.55 microm compared to 11.41 +/- 0.48 microm of uromodulin;
      15.94 +/- 3.93 microm and 12.45 +/- 0.97 microm of normal men Tamm-Horsfall
      protein and uromodulin, respectively; 8.17 +/- 1.57 microm and 9.82 +/- 0.95
      microm of normal women Tamm-Horsfall protein and uromodulin, respectively; 12.17
      +/- 1.41 m and 12.99 +/- 0.51 microm of pregnant Tamm-Horsfall protein and
      uromodulin, respectively). Uromodulin produced fewer particles than Tamm-Horsfall
      protein in all groups. Nonetheless, the total volume of the crystals produced by
      uromodulin was higher than that produced by Tamm-Horsfall protein. Our results
      indicate a different effect of Tamm-Horsfall protein and uromodulin. This dual
      behavior suggests different functions. Tamm-Horsfall protein may act on
      nucleation and inhibit crystal aggregation, while uromodulin may promote
      aggregation of calcium oxalate crystals.

PMID- 12424490
TI  - Factors associated with adherence to antiretroviral therapy in HIV/AIDS patients:
      a cross-sectional study in Southern Brazil.
AB  - A cross-sectional study was conducted on HIV-infected adults being treated with
      antiretroviral drugs at a reference service in Southern Brazil. Participants
      answered a sociodemographic questionnaire and were tested by scales assessing
      sociocognitive variables. Adherence to treatment was assessed by a self-report
      inventory developed for the study. Clinical information was obtained from the
      patients' records. Significance tests were conducted using univariate logistic
      regressions followed by multivariate logistic regression analysis. A total of 195
      patients participated in the study and 56.9% of them reported > or = 95%
      adherence on the previous two days. In univariate analysis, the odds of adherence
      increased with self-efficacy (a person's conviction that he/she can successfully
      execute the behavior required to produce a certain desired outcome) in taking
      medications as prescribed (OR = 3.50, 95% CI 1.90-6.55), and decreased with
      perception of negative affect and physical concerns (OR = 0.71, 95% CI 0.53
      0.95). The odds were lower for taking antiretroviral medications >4 times a day
      (OR = 0.44, 95% CI 0.20-0.94) and higher for patients with 8 years of schooling
      (OR = 2.28, 95% CI 1.12-4.66). In the multivariate analysis, self-efficacy (OR =
      3.33, 95% CI 1.69-6.56) and taking medication >4 times a day (OR = 0.34, 95% CI
      0.14-0.80) were independently associated with adherence. Self-efficacy was the
      most important predictor of adherence, followed by number of times antiretroviral
      medication was taken per day. Among sociodemographic and clinical variables, only
      the number of years of schooling was associated with adherence. Motivational
      interventions based on self-efficacy may be useful for increasing treatment
      adherence.

PMID- 12424491
TI  - Immune response to respiratory syncytial virus in young Brazilian children.
AB  - We have evaluated the cellular and humoral immune response to primary respiratory
      syncytial virus (RSV) infection in young infants. Serum specimens from 65
      patients <=12 months of age (39 males and 26 females, 28 cases <3 months and 37
      cases > or = 3 months; median 3 3.9 months) were tested for anti-RSV IgG and IgG
      subclass antibodies by EIA. Flow cytometry was used to characterize cell surface
      markers expressed on peripheral blood mononuclear cells (PBMC) from 29 RSV
      infected children. There was a low rate of seroconversion in children <3 months
      of age, whose acute-phase PBMC were mostly T lymphocytes (63.0 +/- 9.0%). In
      contrast, a higher rate of seroconversion was observed in children >3 months of
      age, with predominance of B lymphocytes (71.0 +/- 17.7%). Stimulation of PBMC
      with RSV (2 x 10(5) TCID50) for 48 h did not induce a detectable increase in
      intracellular cytokines and only a few showed a detectable increase in RSV
      specific secreted cytokines. These data suggest that age is an important factor
      affecting the infants' ability to develop an immune response to RSV.

PMID- 12424492
TI  - Indirect effects of oral tolerance to ovalbumin interfere with the immune
      responses triggered by Schistosoma mansoni eggs.
AB  - The objective of the present study was to investigate whether the injection of a
      tolerated protein (indirect effects) affects the formation of granulomas around
      Schistosoma mansoni eggs trapped in the lungs after intravenous (iv) injection
      into normal (noninfected) C57BL/6 mice (6 animals per group). To induce oral
      tolerance to chicken egg ovalbumin a 1/5 dilution of egg white in water was
      offered ad libitum in a drinking bottle for 3 days. Control mice received water.
      After 7 days, control and experimental animals were injected iv with 2,000 S.
      mansoni eggs through a tail vein. In some mice of both groups the iv injection of
      eggs was immediately followed by intraperitoneal (ip) immunization with 10 micro
      g of dinitrophenylated conjugates of ovalbumin (DNP-Ova) emulsified in complete
      Freund's adjuvant (CFA) or only CFA; 18 days later, mice were bled and killed by
      ether inhalation. The lungs were fixed in formalin and embedded in paraffin.
      Serial sections of 5 m were stained with Giemsa, Gomori's silver reticulin and
      Sirius red (pH 10.2). Granuloma diameters were measured in histological sections
      previously stained with Gomori's reticulin. Anti-DNP and anti-soluble egg antigen
      (SEA) antibodies were analyzed by ELISA. In mice orally tolerant to ovalbumin the
      concomitant ip injection of DNP-Ova resulted in significantly lower anti-SEA
      antibodies (ELISA*: 1395 +/- 352 in non-tolerant and 462 +/- 146 in tolerant
      mice) and affected granuloma formation around eggs, significantly decreasing
      granuloma size (area: 22,260 +/- 2478 to 12,993 +/- 3242 m ). Active mechanisms
      triggered by injection of tolerated antigen (ovalbumin) reduce granuloma
      formation.

PMID- 12424493
TI  - Effects of caffeine on learning and memory in rats tested in the Morris water
      maze.
AB  - We studied some of the characteristics of the improving effect of the non
      specific adenosine receptor antagonist, caffeine, using an animal model of
      learning and memory. Groups of 12 adult male Wistar rats receiving caffeine (0.3
      30 mg/kg, ip, in 0.1 ml/100 g body weight) administered 30 min before training,
      immediately after training, or 30 min before the test session were tested in the
      spatial version of the Morris water maze task. Post-training administration of
      caffeine improved memory retention at the doses of 0.3-10 mg/kg (the rats swam up
      to 600 cm less to find the platform in the test session, P<=0.05) but not at the
      dose of 30 mg/kg. Pre-test caffeine administration also caused a small increase
      in memory retrieval (the escape path of the rats was up to 500 cm shorter,
      P<=0.05). In contrast, pre-training caffeine administration did not alter the
      performance of the animals either in the training or in the test session. These
      data provide evidence that caffeine improves memory retention but not memory
      acquisition, explaining some discrepancies among reports in the literature.

PMID- 12424494
TI  - Factor structure of Bech's version of the Brief Psychiatric Rating Scale in
      Brazilian patients.
AB  - The objective of the present study was to evaluate the factor structure of Bech's
      version of the Brief Psychiatric Rating Scale (BPRS), translated into Portuguese.
      The BPRS was administered to a heterogeneous group of psychiatric inpatients (N =
      98) and outpatients (N = 62) in a University Hospital. Each patient was evaluated
      from one to eight times. The interval between consecutive interviews was one week
      for the inpatients and one month for the outpatients. The results were submitted
      to factorial analysis. The internal consistency of the total scale and of each
      factor was also estimated. Factorial analysis followed by normalized orthogonal
      rotation (Varimax) yielded four factors: Withdrawal-Retardation, Thinking
      Disorder, Anxious-Depression and Activation. Internal consistency measured by
      Cronbach's alpha coefficient ranged from 0.766 to 0.879. The data show that the
      factor structure of the present instrument is similar to that of the American
      version of the BPRS which contains 18 items, except for the absence of the fifth
      factor of the latter scale, Hostile-Suspiciousness.

PMID- 12424495
TI  - Antinociceptive effects of the essential oil of Croton nepetaefolius on mice.
AB  - Croton nepetaefolius Baill., is an aromatic plant native to the northeast of
      Brazil where it is extensively used in folk medicine as a sedative, orexigen and
      antispasmodic agent. In the present study the antinociceptive effects of the
      essential oil of C. nepetaefolius (EOCn), administered orally, were evaluated in
      male Swiss mice (20-25 g). In the acetic acid-induced writhing test, EOCn (100
      and 300 mg/kg; N = 14 and N = 12, respectively) was effective at the highest
      dose. In the hot-plate test, EOCn at 30 and 300 mg/kg, but not at 3 mg/kg,
      significantly increased the latency at all observation times up to the 180th min
      (N = 12 for each dose). In the formalin test, EOCn significantly reduced paw
      licking in the second phase of the test at 100 mg/kg (N = 12), but decreased it
      in both phases at 300 mg/kg (N = 12). At 30 mg/kg, the effect of EOCn did not
      differ from control values in either phase of the formalin test (N = 6).
      Pretreatment with naloxone (5 mg/kg, ip) significantly reversed the analgesic
      effect of morphine (5 mg/kg, sc) on both phases, but not that of EOCn at 300
      mg/kg (N = 6) on both phases of the formalin test. The data show that orally
      administered EOCn promotes a dose-dependent antinociceptive effect whose
      mechanisms remain to be elucidated.

PMID- 12424497
TI  - Evaluation of the antiedematogenic activity of artemetin isolated from Cordia
      curassavica DC.
AB  - The species Cordia curassavica (Boraginaceae), known popularly as "erva
      baleeira", is used in folk medicine for the treatment of several inflammatory
      processes and as a healing agent. The objective of the present study was to
      evaluate the antiedematogenic activity of crude dichloromethane extracts of
      Cordia curassavica and of the artemetin-enriched fraction. The crude extract and
      artemetin fraction were tested in the model of carrageenin-induced paw edema in
      male Swiss mice (25-30 g). The crude dichloromethane extract (300 and 1000 mg/kg,
      po, N = 6) showed significant antiedematogenic activity, reducing the edema by
      42, 57 and 45% and 46, 62 and 69%, 3, 4 and 5 h after carrageenin administration,
      respectively. Indomethacin (10 mg/kg, po, N = 6) reduced the edema by 45 and 48%,
      after 4 and 5 h, but the artemetin-enriched fraction (30, 100 and 300 mg/kg, po,
      N = 6) had no activity. The dichloromethane extract (300 and 1000 mg/kg, po, N =
      6) also showed antinociceptive activity by reducing acetic acid-induced writhing
      in mice from 37.1 +/- 2.28 (control) to 17.3 +/- 1.34 and 13.2 +/- 1.44,
      respectively, but had no activity in the hot-plate test.

PMID- 12424496
TI  - Evaluation of antivenoms in the neutralization of hyperalgesia and edema induced
      by Bothrops jararaca and Bothrops asper snake venoms.
AB  - Neutralization of hyperalgesia induced by Bothrops jararaca and B. asper venoms
      was studied in rats using bothropic antivenom produced at Instituto Butantan
      (AVIB, 1 ml neutralizes 5 mg B. jararaca venom) and polyvalent antivenom produced
      at Instituto Clodomiro Picado (AVCP, 1 ml neutralizes 2.5 mg B. aspar venom). The
      intraplantar injection of B. jararaca and B. asper venoms caused hyperalgesia,
      which peaked 1 and 2 h after injection, respectively. Both venoms also induced
      edema with a similar time course. When neutralization assays involving the
      independent injection of venom and antivenom were performed, the hyperalgesia
      induced by B. jararaca venom was neutralized only when bothropic antivenom was
      administered iv 15 min before venom injection, whereas edema was neutralized when
      antivenom was injected 15 min or immediately before venom injection. On the other
      hand, polyvalent antivenom did not interfere with hyperalgesia or edema induced
      by B. asper venom, even when administered prior to envenomation. The lack of
      neutralization of hyperalgesia and edema induced by B. asper venom is not
      attributable to the absence of neutralizing antibodies in the antivenom, since
      neutralization was achieved in assays involving preincubation of venom and
      antivenom. Cross-neutralization of AVCP or AVIB against B. jararaca and B. asper
      venoms, respectively, was also evaluated. Only bothropic antivenom partially
      neutralized hyperalgesia induced by B. asper venom in preincubation experiments.
      The present data suggest that hyperalgesia and edema induced by Bothrops venoms
      are poorly neutralized by commercial antivenoms even when antibodies are
      administered immediately after envenomation.

PMID- 12424498
TI  - Effect of perimuscular injection of Bothrops jararacussu venom on plasma creatine
      kinase levels in mice: influence of dose and volume.
AB  - The effect of dose and volume of a perimuscular injection of Bothrops jararacussu
      venom on myonecrosis of skeletal muscle was studied in mice. An increase of the
      venom dose (0.25 to 2.0 micro g/g) at a given volume (50 micro l) resulted in an
      increase in plasma creatine kinase (CK) levels 2 h after injection. Plasma CK
      activity increased from the basal level of 129.27 +/- 11.83 (N = 20) to 2392.80
      +/- 709.43 IU/l (N = 4) for the 1.0 micro g/g dose. Histological analysis of
      extensor digitorum longus muscle 4 h after injection showed lesion of peripheral
      muscle fibers, disorganization of the bundles or the complete degeneration of
      muscle fibers. These lesions were more extensive when higher doses were injected.
      Furthermore, an increase in volume (12.5 to 100 micro l) by dilution of a given
      dose (0.5 micro g/g) also increased plasma CK levels from 482.31 +/- 122.79 to
      919.07 +/- 133.33 IU/l (N = 4), respectively. These results indicate that care
      should be taken to standardize volumes and sites of venom injections.

PMID- 12424499
TI  - Excitatory amino acid receptor blockade within the caudal pressor area and
      rostral ventrolateral medulla alters cardiovascular responses to nucleus raphe
      obscurus stimulation in rats.
AB  - Pressor responses elicited by stimulation of the nucleus raphe obscurus (NRO)
      depend on the integrity of the rostral ventrolateral medulla (RVLM). Therefore,
      to test the participation of excitatory amino acid (EAA) receptors in the
      cardiovascular responses evoked by NRO stimulation (1 ms, 100 Hz, 40-70 microA,
      for 10 s), the EAA antagonist kynurenic acid (Kyn) was microinjected at different
      sites in the ventrolateral medullar surface (2.7 nmol/200 nl) of male Wistar rats
      (270-320 g, N = 39) and NRO stimulation was repeated. The effects of NRO
      stimulation were: hypertension (deltaMAP = +43 +/- 1 mmHg, P<0.01), bradycardia
      (deltaHR = -30 +/- 7 bpm, P<0.01) and apnea. Bilateral microinjection of Kyn into
      the RVLM, which did not change baseline parameters, almost abolished the
      bradycardia induced by NRO stimulation (deltaHR = -61 +/- 3 before vs -2 +/- 3
      bpm after Kyn, P<0.01, N = 7). Unilateral microinjection of Kyn into the CVLM did
      not change baseline parameters or reduce the pressor response to NRO stimulation
      (deltaMAP = +46 +/- 5 before vs +48 +/- 5 mmHg after Kyn, N = 6). Kyn bilaterally
      microinjected into the caudal pressor area reduced blood pressure and heart rate
      and almost abolished the pressor response to NRO stimulation (deltaMAP = +46 +/-
      4 mmHg before vs +4 +/- 2 mmHg after Kyn, P<0.01, N = 7). These results indicate
      that EAA receptors on the medullary ventrolateral surface play a role in the
      modulation of the cardiovascular responses induced by NRO stimulation, and also
      suggest that the RVLM participates in the modulation of heart rate responses and
      that the caudal pressor area modulates the pressor response following NRO
      stimulation.

PMID- 12424501
TI  - Biologic problems.

PMID- 12424502
TI  - Effectiveness of zinc gluconate glycine lozenges (Cold-Eeze) against the common
      cold in school-aged subjects: a retrospective chart review.
AB  - Of the 62 million common colds requiring medical attention in the United States
      each year, more than 80% affect school-aged children. Controlled clinical trials
      have demonstrated the effectiveness of zinc gluconate glycine lozenges (Cold
      Eeze) in reducing cold duration. The objective of this study was to determine the
      effectiveness of zinc gluconate glycine lozenges in reducing the duration and
      severity of colds in school-aged subjects and to identify the benefits of
      prophylactic administration of zinc gluconate glycine lozenges in reducing the
      occurrence of colds. The medical charts of subjects enrolled at Utah's Heritage
      Center before and after the introduction of zinc gluconate glycine lozenges
      (between January 1998 and August 2001) were reviewed to identify those who
      experienced cold signs or symptoms. Two or more prespecified signs or symptoms on
      the same day identified a cold and, along with patient or medical staff reports
      and use of cold medications, were used to determine cold start and resolution
      dates. Results from subjects who did or did not take study treatment were
      compared statistically to determine the prophylactic effects of lozenge use.
      Effects of zinc gluconate glycine lozenges on the need for antibiotic therapy
      were also analyzed. The review encompassed 496 records. Treatment with zinc
      gluconate glycine lozenges significantly decreased cold duration (7.5 versus 9.0
      days for nonuse; P < 0.0001). Prophylaxis also significantly reduced the median
      number of colds per year (0.0 versus 1.3; P < 0.001) and concomitant antibiotic
      use to manage colds (4.1% versus 36.2%; P < 0.0001). Therapy with zinc gluconate
      glycine lozenges significantly reduced cold duration and antibiotic use in school
      aged subjects. Prophylactic administration also significantly decreased cold
      frequency.

PMID- 12424503
TI  - Chrono: a community-based hypertension trial of a chronotherapeutic formulation
      of verapamil.
AB  - An open-label, multicenter, dose-titration study evaluated 2,556 patients with
      stage I or II essential hypertension (untreated or previously treated with one
      antihypertensive agent) to assess the effect of a chronotherapeutic formulation
      of verapamil (Verelan PM) designed to provide maximum plasma concentrations in
      the midmorning hours. After starting with 200 mg/d at bedtime, the dose of
      Verelan PM was titrated to a maximum of 400 mg/d at 4-week intervals to achieve a
      target blood pressure (BP) <140/90 mm Hg using morning BP measurements. In 85.3%
      of patients, a diastolic blood pressure (DBP) response to less than 90 mm Hg or a
      10-mm Hg decline from baseline DBP was achieved. The systolic BP response (<140
      mm Hg or 10% decline from baseline) was attained in 76.9% of patients. Blood
      pressure was controlled in 62.6% of patients with Verelan PM monotherapy. Upward
      titration of Verelan PM from 200 to 400 mg nearly doubled the DBP response rate
      (45.8% to 85.3%). This chronotherapeutic formulation of verapamil was well
      tolerated in this community trial.

PMID- 12424504
TI  - Prescribing conventional antipsychotics in the era of novel antipsychotics:
      informed consent issues.
AB  - The goal of this study was to ascertain why patients are maintained on
      conventional antipsychotics and whether the risks/benefits and alternative
      treatments with novel antipsychotics are discussed with these patients. We
      reviewed the charts of 117 outpatients maintained on conventional antipsychotics
      at three New York hospitals: Hutchings Psychiatric Center (HPC), Syracuse
      Veterans Affairs Medical Center (SVA), and the Continuing Day Treatment Program
      (CDT). The major reasons for maintaining patients on conventional antipsychotics
      were good response (50%), patient choice (45%), and physician choice (36%).
      Despite the high incidence of tardive dyskinesia at all three hospitals (range:
      12%-50%), physicians often did not discuss the risks/benefits of continuing
      conventional antipsychotics with the patients. The treating psychiatrist
      discussed alternative treatments with 37% of patients at SVA, 58% at HPC, and 68%
      at CDT (P = 0.066, df = 2, Pearson chi(2) test). For patients who are receiving
      any antipsychotic therapy, discussions about the risks/benefits of treatments are
      integral for optimal treatment and medicolegal purposes.

PMID- 12424505
TI  - Safety and efficacy of combined use of low molecular weight heparin (enoxaparin,
      lovenox) and glycoprotein IIb/IIIa receptor antagonist (eptifibatide, integrelin)
      during nonemergent coronary and peripheral vascular intervention.
AB  - Coronary and peripheral intervention requires intraprocedural anticoagulation to
      prevent intraluminal thrombosis. Traditionally, unfractionated heparin (UFH) is
      administered during the procedure to achieve activated clotting time (ACT) of 300
      to 400 seconds. When the intravenous IIb/IIIa antagonists are also used, the
      recommended ACT is 250 to 300 seconds because higher anticoagulation (ACT, 300
      400 seconds) is accompanied by an unacceptable bleeding complication rate without
      added benefits. Because low molecular weight heparin has a more predictable
      anticoagulant effect and a higher anti-factor Xa/anti-factor IIa ratio, allows
      better bioavailability, is resistant to inhibition by activated platelets, and
      does not require routine monitoring using ACT, its use for intraprocedural
      anticoagulation (instead of UFH) has been an area of increasing interest. The
      safety and efficacy of coadministration of low molecular weight heparin with
      IIb/IIIa antagonists have not been adequately evaluated. We report a study of
      prospective evaluation of the safety and efficacy of combined use of intravenous
      enoxaparin and intravenous eptifibatide during nonemergent coronary and
      peripheral vascular intervention in 93 consecutive procedures performed on 56
      patients. The procedural success rate was 99% (92/93 procedures), the acute
      clinical success rate was 98% (54/55 patients), the major bleeding complication
      rate was 2% (1/56 patients), and the vascular complication rate was 0.0%. In
      conclusion, the use of intravenous enoxaparin in conjunction with intravenous
      eptifibatide during nonemergent coronary and peripheral vascular intervention is
      safe and effective and eliminates the need for routine measurement of ACT during
      the procedure.

PMID- 12424506
TI  - Population pharmacokinetics of digoxin in Egyptian pediatric patients: impact of
      one data point utilization.
AB  - A population pharmacokinetic (PK) study was designed to estimate the PK
      parameters of digoxin among a selected group of Egyptian pediatric patients (n =
      30) with mean age +/- SD and body weight +/- SD of 8.88 +/- 3.01 years and 23.9
      +/- 5.8 kg, respectively. All patients had heart failure and were maintained on
      digoxin given orally. Nonlinear mixed effect modeling software version 5 (NONMEM
      Project Group, San Francisco, CA) and one-compartment modeling were used for
      fitting the data. A one-trough steady-state plasma concentration level of digoxin
      was used in the analysis. The population mean estimates for clearance (CL/f) and
      volume of distribution (V/f), in which f represents oral bioavailability, were
      8.61 L/h and 450 L, respectively. Because of the limited number of samples per
      patient, regression analysis could not detect a correlation between patient
      covariates and estimated PK parameters. The analysis did not converge to obtain
      good parameter estimates. At least two samples per patient should be used to
      improve the PK estimation and allow better analysis of the relation between the
      potential covariates and estimated PK parameters.

PMID- 12424507
TI  - Patterns of use of an emergency department-based observation unit.
AB  - Emergency department (ED)-based observation units are becoming increasingly used
      for the assessment and treatment of patients who may not require inpatient
      management or monitoring. This is a retrospective study of 5,714 patients seen in
      an ED observation unit from October 16, 1996 through July 12, 2000. Of the 5,714
      patients seen in the observation unit, 4,191 were discharged and 1,314 were
      admitted. The average length of stay was 14.92 hours. The largest group of
      patients seen in the observation unit was those with chest pain (almost 26%).
      Patients suffering abdominal pain/colic represented the second largest group
      (almost 16%). Pediatric patients had the shortest stay, averaging only 11.2
      hours, although adult and geriatric patients averaged 15.1 hours and 15.4 hours,
      respectfully. The ED-based observation unit can be of great value to patient
      care. Although not a substitute for an inpatient unit, it is meant to be a
      convenient location from which to observe patients who exhibit questionable
      admitting criteria.

PMID- 12424508
TI  - Role of estrogen in the treatment of depression.
AB  - The role of estrogen in the treatment of depression is reviewed. The relation is
      examined in studies of perimenopausal and postmenopausal women with depressed
      mood, in studies of depressive disorders, and in studies of estrogen as an
      adjunct to antidepressant medication. The literature has many methodologic
      shortcomings, including combining women of various ages, failure to confirm life
      stage, the use of different types of estrogens, the inclusion of women with a
      range of mood disturbances, and the enrollment of women with concurrent
      psychiatric illness. There are few controlled evaluations of the use of estrogen
      to supplement ongoing antidepressant treatment. Estrogen alone seems to be
      beneficial for improving mood in perimenopausal and postmenopausal women.
      Estrogen is superior to placebo for reproductive-related mood disorders,
      including postpartum depression and mild depressive disorders during
      perimenopause. Replication is necessary, especially in moderate to severe levels
      of major depression. Estrogen may augment antidepressant treatment. Assessment
      and treatment implications are discussed.

PMID- 12424509
TI  - Diabetes and cardiovascular diseases.
AB  - Diabetes is a chronic illness that requires continuing medical care and patient
      self-management education to prevent acute complications and to reduce the risk
      of long-term complications. Diabetic people have cardiovascular disease (CVD)
      risk factors comparable to those of nondiabetics who have had a myocardial
      infarction or stroke. Physiologic changes in diabetic hypertensive people include
      endothelial dysfunction, altered platelet activity, and microalbuminuria, all of
      which may increase coronary heart disease risk. Hyperglycemia and dyslipidemia
      have been shown to effect physiologic changes in the vasculature; therefore,
      establishing normoglycemia, reducing cholesterol levels, and controlling blood
      pressure are the primary and initial goals in the management of diabetic
      hypertensive patients. The atherosclerotic risk is greatest in poorly controlled
      patients, possibly because of associated hypercholesterolemia and
      hypertriglyceridemia. Aggressive management of risk factors such as hypertension,
      dyslipidemia, and platelet dysfunction in diabetics has been shown to reduce
      morbidity and mortality in prospective randomized controlled clinical trials. In
      this article we review the impact of diabetes mellitus on cardiovascular
      morbidity and mortality.

PMID- 12424510
TI  - Molecular links between obesity and cardiovascular disease.
AB  - Obesity is a recognized risk factor for cardiovascular disease. Because the
      prevalence of obesity is rising in industrialized as well as developing nations,
      it is important to understand the mechanisms by which obesity targets the
      vascular system. A metabolic syndrome of insulin resistance is provoked by
      obesity, and this results in the dysregulation of a number of adipocyte-derived
      factors, which favors atherosclerosis. This review focuses on how products of the
      adipocyte, including free fatty acids and "adipo"-cytokines, may mediate the
      effect of obesity on insulin resistance and atherosclerosis.

PMID- 12424511
TI  - Aplastic anemia associated with interferon beta-1a.
AB  - Subcutaneous interferon beta-1a is a recognized treatment of relapsing multiple
      sclerosis, and it may delay the onset of definite multiple sclerosis in patients
      with a first clinical demyelinating episode. Interferon beta-1a exerts beneficial
      effects on cognitive functioning via both short-term and long-term mechanisms.
      The beneficial effect is thought to be a result of immune modulation, with
      inhibition of leukocyte proliferation and antigen presentation and an increased
      amount of interleukins. The systemic side effects of interferon beta-1a are flu
      like syndrome and development of neutralizing antibodies, the clinical
      significance of which is not known. There have been concerns about the rare
      development of an acute demyelinating disease after interferon beta-1a therapy as
      a result of upregulation of inflammatory mediators. In the clinical trials, there
      is evidence of development of mild anemia with a hemoglobin level below 10 g/dL
      only in 3% of the patients. There has been no reported case of development of
      aplastic anemia in patients being treated with interferon beta-1a. Described here
      is a case of development of aplastic anemia with interferon beta-1a in a patient
      with multiple sclerosis. Our patient underwent a complete hematologic evaluation
      to rule out other causes of aplastic anemia. Association with interferon beta-1a
      was highly suspected.

PMID- 12424512
TI  - Melatonin for refractory idiopathic thrombocytopenic purpura: a report of 3
      cases.
AB  - In addition to its well-known influence on circadian rhythms, melatonin has been
      described as being able to increase the number of platelets in circulating blood.
      This provided the rationale to evaluate melatonin for toxicity and efficacy in
      three patients with idiopathic thrombocytopenic purpura (ITP) refractory to
      initial treatment with corticosteroids or splenectomy (refractory ITP). Patients
      received melatonin for 1 month. The therapy was continued for 2 additional months
      in patients with stable or responding disease. After 3 months, the stable or
      responding patients continued the therapy for 3 months and more. All patients had
      a partial response after 1 month. Continuing with the treatment, none of the
      three patients had disease progression (average follow-up time of 31 months;
      range: 23-46 months). Toxicity was lacking, with the only side effect being
      drowsiness. Our experience suggests that melatonin may be safe and effective in
      patients with refractory ITP.

PMID- 12424513
TI  - Ibutilide-induced long QT syndrome and torsade de pointes.
AB  - Ibutilide is a class III antiarrhythmic agent used for the termination of atrial
      fibrillation and atrial flutter. It mainly affects membrane potassium currents
      and prolongs the cardiac action potential. This effect is reflected as QT
      interval prolongation on the surface electrocardiogram. Like other drugs that
      affect potassium currents, ibutilide is prone to induce a malignant ventricular
      tachycardia, torsade de pointes. We report four cases of torsade de pointes after
      administration of ibutilide for pharmacologic cardioversion of atrial
      fibrillation and atrial flutter; three of these cases required direct current
      cardioversion for termination of torsade de pointes. All four patients were
      female. We discuss the risk factors for development of ibutilide-induced torsade
      de pointes.

PMID- 12424514
TI  - Diagnostic and interventional nephrology.
AB  - The fragmented care of nephrology patients that results from referral to a
      radiologist for renal ultrasound (US) and biopsy, a surgeon for dialysis access
      placement, and an interventional radiologist for dialysis catheter placement and
      vascular access procedures often leads to delays in the treatment of these
      patients. Many specialists perform and interpret sonograms particular to their
      specialty rather than relying on technicians for performance and radiologists for
      interpretation, and nephrologists recently have begun to embrace this technology
      as an aid in the diagnosis and treatment of their patients. By combining an
      understanding of the pathophysiology of renal disease with the ability to perform
      clinical correlation and apply the laboratory data, the nephrologist is ideally
      suited to perform and interpret renal US and US guidance for percutaneous renal
      biopsies. Additionally, patients requiring peritoneal dialysis (PD) access have
      traditionally been referred to a general surgeon for catheter placement, which
      incurs additional delay in therapy and loss of decision-making control by the
      referring nephrologist. Recent data has emphasized that the peritoneal dialysis
      access procedure can be performed safely and effectively by a nephrologist
      trained in PD access procedures. Nephrologists also successfully perform tunneled
      hemodialysis catheter placement and vascular access procedures on an outpatient
      basis. The medical needs of patients with renal disease can be safely and
      efficiently delivered by a nephrologist trained in interventional nephrology
      (IN). This growing area of expertise will minimize delays, reduce cost, and allow
      physicians with training in the management of end-stage renal disease (ESRD)
      patients to be involved in the procedural aspects of their patients' care. An
      aggressive approach to the development of IN training programs at academic
      centers is warranted.

PMID- 12424515
TI  - Arrhythmia therapy.

PMID- 12424516
TI  - Public and private sector contributions to the discovery and development of
      "impact" drugs.
AB  - Recently, well-publicized reports by Public Citizen and the Joint Economic
      Committee (JEC) of the US Congress questioned the role of the drug industry in
      the discovery and development of therapeutically important drugs. To gain a
      better understanding of the relative roles of the public and private sectors in
      pharmaceutic innovation, the Tufts Center for the Study of Drug Development
      evaluated the underlying National Institutes of Health (NIH) and academic
      research cited in the Public Citizen and JEC reports and performed its own
      assessment of the relationship between the private and public sectors in drug
      discovery and development of 21 "impact" drugs. We found that, ultimately, any
      attempt to measure the relative contribution of the public and private sectors to
      the research and development (R&D) of therapeutically important drugs by output
      alone, such as counting publications or even product approvals, is flawed.
      Several key factors (eg, degree of uncertainty, expected market value, potential
      social benefit) affect investment decisions and determine whether public or
      private sector funds, or both, are most appropriate. Because of the
      competitiveness and complexity of today's R&D environment, both sectors are
      increasingly challenged to show returns on their investment and the traditional
      boundaries separating the roles of the private and public research spheres have
      become increasingly blurred. What remains clear, however, is that the process
      still starts with good science and ends with good medicine.

PMID- 12424517
TI  - Notch signaling is involved in nervous system formation in ascidian embryos.
AB  - Notch signaling plays crucial roles during embryogenesis in various metazoans.
      HrNotch, a Notch homologue in the ascidian Halocynthia roretzi, has been
      previously cloned, and its expression pattern suggests that HrNotch signaling is
      involved in nervous system formation. To determine the function of HrNotch
      signaling, in the present study we examined the effects of the constitutively
      activated forms of HrNotch. Overexpression resulted in larvae with defects in
      neural tube closure and brain vesicle formation. In embryos expressing the
      activated HrNotch, the expression of a neural marker gene, HrETR-1, was enhanced
      and expanded in the central nervous system, although ectopic expression decreased
      during the tailbud stage. The activated HrNotch also suppressed the formation of
      the adhesive organ (palps) and the peripheral nervous system, which consists of
      ciliary mechanosensory neurons, whereas it promoted epidermal differentiation.
      The suppression and promotion of the formation of these respective cell types
      were confirmed by examination of the expression of relevant tissue-specific
      markers. We also cloned Hrdelta, an ascidian homologue of DSL family genes, which
      encode ligands for which Notch acts as a receptor. The expression of Hrdelta was
      observed in the precursors of palps and peripheral neurons in addition to the
      CNS. These results suggest that Notch signaling is important for ascidian nervous
      system formation and that it affects the fate choice between palps and epidermis
      and between peripheral neurons and epidermis within the neurogenic regions of the
      surface ectoderm by suppressing the formations of palps and peripheral neurons
      and promoting epidermal differentiation.

PMID- 12424518
TI  - The highly conserved cardiogenic bHLH factor Hand is specifically expressed in
      circular visceral muscle progenitor cells and in all cell types of the dorsal
      vessel during Drosophila embryogenesis.
AB  - The highly conserved basic helix-loop-helix transcription factor Hand plays a
      crucial role in cardiogenesis, limb formation and other developmental processes
      of vertebrates. Humans, mice and other higher vertebrates have two related genes,
      dHand (also known as Hand2, Hed, Thing2) and eHand (also known as Hand1, Hxt,
      Thing1), whereas fish and Drosophila have only a single hand gene. We cloned
      Drosophila hand and studied the embryonic expression in detail by using various
      tissue-specific markers that allowed us to analyze the identity of hand
      expressing cells. We found hand to be expressed in the entire heart, including
      all cardioblasts and pericardial cells, in the progenitors of the circular
      visceral muscles, the lymph gland and garland cells, and in a few cells in the
      CNS. The expression of Drosophila hand starts after the inductive activity of the
      early regulators in these tissues, e.g. Tinman and Bagpipe, suggesting a role of
      Hand in differentiation rather than in tissue determination. In many aspects the
      expression pattern of Drosophila hand resembles the patterns of its vertebrates
      orthologues, for instance in cardiac tissues. We assume that Hand proteins might
      play a highly conserved role throughout evolution.

PMID- 12424519
TI  - Identification of a second presenilin gene in zebrafish with similarity to the
      human Alzheimer's disease gene presenilin2.
AB  - Presenilins play prominent roles in the molecular pathogenesis of Alzheimer's
      disease and during embryo development. We have isolated a zebrafish presenilin
      orthologue (pre2), which shows a high degree of sequence identity to the human
      PS2 protein. Zebrafish pre2 is maternally and ubiquitously expressed during early
      embryo development, whereas Pre2 protein expression is initiated between 6 and 12
      hours post fertilisation (hpf), suggesting strict regulation of pre2 translation.
      pre2 expression is especially high in neural-crest-derived melanocytes.

PMID- 12424521
TI  - X-linked small GTPase and OXPHOS genes are candidates for the genetic basis of
      hybrid inviability in Drosophila.
AB  - Genetic studies on postmating reproductive isolation in Drosophila have suggested
      that the genetic basis of hybrid inviability is much less complex than the basis
      of hybrid sterility, and may be associated with defects affecting the cell cycle.
      Here I report the identification of a cluster of genes in the middle of the X
      chromosome of D. melanogaster, which may be responsible for the inviability of
      hybrids between Drosophila species. Genes from this cluster code for small Ras
      GTPases proteins, which are hypothesized here to interact with proteins involved
      in oxidative phosphorylation (OXPHOS), encoded by genes present within the same
      cluster. At least six genes influencing small Ras GTPases/OXPHOS activity are
      transcribed from the same strand across 35 kb genomic DNA. This interval is
      predicted to harbor genes which, when mutated, rescue otherwise inviable hybrids
      between D. melanogaster and its three most closely related species. Moreover, a
      total of 16 small GTPase/OXPHOS genes are found within 530 kb genomic DNA
      encompassing the above cluster. In D. melanogaster mutants which fully rescue
      lethal hybrids, major lesions have now been identified very near or within
      untranslated regions of two OXPHOS genes from the above cluster. These
      observations led to a hypothesis focusing on antagonistic co-evolution between
      biparentally inherited genes influencing putative GTPase/OXPHOS activity and
      mitochondrial genes encoding OXPHOS proteins. Alterations in some of these genes
      are postulated to override hybrid inviability, thus revealing a pathway which
      implicates mitotic genes as critical players in this barrier to reproduction.

PMID- 12424520
TI  - XHRT-1, a hairy and Enhancer of split related gene with expression in floor plate
      and hypochord during early Xenopus embryogenesis.
AB  - We have isolated a Xenopus homologue of the mammalian hairy and Enhancer of split
      related gene HRT1. XHRT1 expression in late gastrula and early neurula embryos is
      restricted to two stripes of cells in the medial neural plate and in dorsal
      endodermal cells. At later stages, XHRT1 is expressed in the floor plate, in
      hypochord cells and in the somitogenic and anterior presomitic mesoderm. By
      tailbud stage, XHRT1 is also highly expressed in the dorsal hindbrain,
      telencephalon and eye vesicles, olfactory placodes, pronephros, branchial arches
      and tail fin. We also show that XHRT1 expression in medial neural cells is
      induced by Notch signaling and that there are differences in the way XHRT1 and
      other H/E(spl) genes are regulated.

PMID- 12424522
TI  - Distribution of telomeric (TTAGGG)(n) sequences in avian chromosomes.
AB  - The physical ends of mammalian and other vertebrate chromosomes consist of
      tandemly repeated (TTAGGG)(n) hexamers, nucleating a specialized telomeric
      structure. However, (TTAGGG)(n) sequences can also occur at non-telomeric sites,
      providing important insights into karyotypic evolution. By fluorescence in situ
      hybridization (FISH) we studied the chromosomal distribution of (TTAGGG)(n)
      sequences in 16 bird species, representing seven different orders. Many species,
      in particular the ratites, display (TTAGGG)(n) hybridization signals in
      interstitial and centromeric regions of their macrochromosomes in addition to the
      typical telomeric signals. In some but not all species these non-telomeric sites
      coincide with C-band-positive heterochromatin. The retention and/or amplification
      of telomeric (TTAGGG)(n) repeats at interstitial and centromeric sites may
      indicate the fusion of ancestral chromosomes. Compared with the macrochromosomes,
      the microchromosomes of most species are enriched with (TTAGGG)(n) sequences,
      displaying heterogeneous hybridization patterns. We propose that this high
      density of (TTAGGG)(n) repeats contributes to the exceptionally high meiotic
      recombination rate of avian microchromosomes.

PMID- 12424523
TI  - Characterization of the constriction with neocentric activity of 5RL chromosome
      in wheat.
AB  - In wheat-5RL monotelosomic and ditelosomic addition lines, a proximal
      constriction located on the long arm of rye chromosome 5R shows neocentric
      activity at metaphase I of meiosis. In some pollen mother cells this region is
      unusually stretched, acquires kinetic activity and co-orients with the true
      centromeres. In the work described here we characterized the putative neocentric
      constriction of 5RL using various approaches. Fluorescence in situ hybridization
      (FISH) revealed that the rye subtelomeric repetitive DNA sequence pSc119.2 is a
      constituent of the 5RL constriction. This FISH site corresponds with a
      heterochromatic C-band in normal rye. Other subtelomeric (pSc34, pSc74, pSc200),
      centromeric (CCS1, Bilby) and Arabidopsis-type telomeric sequences produce no
      detectable hybridization signal on the constriction. Immunolocalization with anti
      alpha-tubulin antibodies showed that microtubules are bound to the constriction
      in a similar way to their binding to true centromeres. Silver staining
      demonstrated that proteins are accumulated at the constriction, the signal being
      more prominent than that observed at the centromere and telomeres of 5RL. The
      frequency of neocentric activity in different plants varied dramatically in
      different generations and in siblings grown in different years, suggesting that
      activation of the neocentric site is dependent on internal features and
      environmental conditions.

PMID- 12424524
TI  - The evolutionarily conserved single-copy gene for murine Tpr encodes one
      prevalent isoform in somatic cells and lacks paralogs in higher eukaryotes.
AB  - Vertebrate Tpr and its probable homologs in insects and yeast are heptad repeat
      dominated nuclear proteins of M(r) 195,000 to M(r) 267,000 the functions of which
      are still largely unknown. Whereas two homologs exist in Saccharomyces
      cerevisiae, it has remained uncertain whether metazoans possess different
      paralogs or isoforms of Tpr that might explain controversial reports on the
      subcellular localization of this protein. To address these possibilities, we
      first determined the sequence and structure of the murine tpr gene, revealing a
      TATA box-less gene of approximately 57 kb and 52 exons. Southern hybridization of
      genomic DNA and radiation hybrid mapping showed that murine tpr exists as a
      single-copy gene on chromosome 1; RNA blotting analyses and EST (expressed
      sequence tag) database mining revealed that its expression results in only one
      major mRNA in embryonic and most adult tissues. Accordingly, novel antibodies
      against the N- and C-terminus of Tpr identified the full-length protein as the
      major translation product in different somatic cell types; reinvestigation of Tpr
      localization by confocal microscopy corroborated a predominant localization at
      the nuclear pore complexes in these cells. Antibody specificity and reliability
      of Tpr localization was demonstrated by post-transcriptional tpr gene silencing
      using siRNAs that eliminated the Tpr signal at the nuclear periphery but did not
      affect intranuclear staining of Tpr-unrelated proteins. Finally, we defined
      several sequence and structural features that characterize Tpr polypeptides in
      different species and used these as a guideline to search whole-genome sequence
      databases for putative paralogs of Tpr in higher eukaryotes. This approach
      resulted in identification of the Tpr orthologs in Arabidopsis thaliana and
      Caenorhabditis elegans, but also in the realization that no further paralogs of
      Tpr exist in several metazoan model organisms or in humans. In summary, these
      results reveal Tpr to be a unique protein localized at the nuclear periphery of
      the somatic cell in mammals.

PMID- 12424525
TI  - The actin loci in the genus Drosophila: establishment of chromosomal homologies
      among five nearctic species of the Drosophila obscura group by in situ
      hybridization.
AB  - The actin genes of five nearctic species of the Drosophila obscura group were
      mapped by in situ hybridization, using the 5C actin gene of D. melanogaster as a
      probe. In all species but D. azteca eight actin loci were observed variously
      dispersed over all five (A- E) chromosomal elements. In D. azteca ten actin
      hybridization sites were found; four of which most probably originated by
      duplications or by transposition events. Although the five nearctic species
      differ from all other Drosophila species of the D. obscura group so far studied
      in the number of loci as well as in the chromosomal distribution and location of
      the actin loci, the uniformity of the main pattern with six actin loci throughout
      the genus Drosophila reinforces the hypothesis that the chromosomal elements have
      maintained their essential identities during the course of evolution. Our
      findings are in accordance with the conclusion that the nearctic D. obscura
      species have differentiated from a common ancestor of the palearctic species and
      that they belong to two distinct subgroups, the pseudoobscura and the affinis
      subgroups.

PMID- 12424526
TI  - Evolutionary history of chromosome 10 in primates.
AB  - We have tracked the evolutionary history of chromosomes homologous to HSA10 (PHYL
      10) in primates using appropriate panels of PCP, YAC, and BAC probes. This
      approach allowed us to delineate more precisely the PHYL-10 constitution in the
      ancestor of catarrhine, platyrrhine, and prosimians. The results suggest that (i)
      in the ancestor of prosimians PHYL-10 was organized in two separate PHYL-10p and
      PHYL-10q chromosomes; (ii) in the progenitor of New World monkeys PHYL-10p was a
      separate chromosome, while PHYL-10q was associated with a chromosome homologous
      to HSA16; (iii) in the ancestor of Old World monkeys PHYL-10 was a unique
      chromosome with a marker order corresponding to the orang form. We have also
      analyzed the cat, chosen as an outgroup for its very conserved karyotype. In
      agreement with published data our experiments show that the PHYL-10 in cat is
      structured in two blocks, PHYL-10p and PHYL-10q, both as part of larger
      chromosomes. The overall data indicate that, contrary to common opinion, PHYL-10p
      and PHYL-10q were distinct chromosomes in the primate ancestor. Analysis of the
      Saimiri sciureus (SSC) PHYL-10q marker order showed that it was isosequential
      with the Callithrix jacchus PHYL-10q, as well as with the PHYL-10q platyrrhine
      ancestral form. The SSC centromere, nevertheless, was located in a different
      chromosomal region, therefore suggesting that a centromeric repositioning event
      occurred in this species.

PMID- 12424527
TI  - The polytene dot chromosome of Drosophila: D. melanogaster and D. subobscura.
AB  - The chromosome arms are assumed to be homologous within the genus Drosophila.
      Homology at the level of the polytene chromosome banding pattern between non
      sibling species is, however, almost impossible to establish as different
      processes such as inversion, transposition and unequal crossing over, have
      disturbed it. Even though the band sequences cannot be followed, we may ask
      whether there is a correlation in the total number of bands between species. The
      polytene dot chromosome is an excellent starting point for such an approach. Here
      we present the detailed cytology of polytene chromosome 4 of D. melanogasterand
      the polytene dot chromosome of D. subobscura using electron microscopy. The
      results show that the number of bands is about the same, around 30, in both
      species. We predict that by using thin sections and electron microscopy for the
      longer polytene chromosome arms, both species will turn out to have approximately
      equal band numbers.

PMID- 12424528
TI  - Classification and molecular organization of satellites elucidated by
      phylogenetic network analysis - examples from Triturus salamanders and Palorus
      beetles.
AB  - A phylogenetic network of 244 satellite DNA sequences across five species of
      aquatic salamanders (genus Triturus) revealed four types of satellite DNAs in a
      'p'-shaped 1-2*-3-4-2* arrangement. Analysis of dimer and trimer DNA sequences
      revealed a prevalence of homosequential (e.g. 1-1, 2-2) and particular (1-4 and 2
      3) heterosequential repeat motifs. Genetic diversity across types and species
      phylogeny indicated that type 1 and type 4 are derived from types 2 and 3.
      Support was also found for alternating motifs in Palorus flour beetle tandem
      repeats. The results were statistically significant, whether or not the
      underlying satellite DNA phylogenies were robust under bootstrap analysis.

PMID- 12424529
TI  - A versatile ODE approximation to a network model for the spread of sexually
      transmitted diseases.
AB  - We develop a moment closure approximation (MCA) to a network model of sexually
      transmitted disease (STD) spread through a steady/casual partnership network. MCA
      has been used previously to approximate static, regular lattices, whereas
      application to dynamic, irregular networks is a new endeavour, and application to
      sociologically-motivated network models has not been attempted. Our goals are 1).
      to investigate issues relating to the application of moment closure
      approximations to dynamic and irregular networks, and 2). to understand the
      impact of concurrent casual partnerships on STD transmission through a population
      of predominantly steady monogamous partnerships. We are able to derive a moment
      closure approximation for a dynamic irregular network representing sexual
      partnership dynamics, however, we are forced to use a triple approximation due to
      the large error of the standard pair approximation. This example underscores the
      importance of doing error analysis for moment closure approximations. We also
      find that a small number of casual partnerships drastically increases the
      prevalence and rate of spread of the epidemic. Finally, although the
      approximation is derived for a specific network model, we can recover
      approximations to a broad range of network models simply by varying model
      parameters which control the structure of the dynamic network. Thus our moment
      closure approximation is very flexible in the kinds of network models it can
      approximate.

PMID- 12424530
TI  - On the dynamics of discrete food chains: low- and high-frequency behavior and
      optimality of chaos.
AB  - In this paper we derive and analyze a discrete version of Rosenzweig's (Am. Nat.
      1973) food-chain model. We provide substantial analytical and numerical evidence
      for the general dynamical patterns of food chains predicted by De Feo and Rinaldi
      (Am. Nat. 1997) remaining largely unaffected by this discretization. Our
      theoretical analysis gives rise to a classification of the parameter space into
      various regions describing distinct governing dynamical behaviors. Predator
      abundance has a local optimum at the edge of chaos.

PMID- 12424531
TI  - Limits of a multi-patch SIS epidemic model.
AB  - We start from a stochastic SIS model for the spread of epidemics among a
      population partitioned into M sites, each containing N individuals; epidemic
      spread occurs through within-site ('local') contacts and global contacts. We
      analyse the limit behaviour of the system as M and N increase to infinity. Two
      limit procedures are considered, according to the order in which M and N go to
      infinity; independently of the order, the limiting distribution of infected
      individuals across sites is a probability measure, whose evolution in time is
      governed by the weak form of a PDE. Existence and uniqueness of the solutions to
      this problem is shown. Finally, it is shown that the infected distribution
      converges, as time goes to infinity, to a Dirac measure at the value x(*), the
      equilibrium of a single-patch SIS model with contact rate equal to the sum of
      local and global contacts.

PMID- 12424532
TI  - A nonlinear dynamical mechanism for bruit generation by an intracranial saccular
      aneurysm.
AB  - Intracranial saccular aneurysms have been clinically observed to emit a transient
      sound, a bruit, on each heartbeat. The mechanism causing the bruits has been a
      matter of contention. A qualitative analysis of the nonlinear dynamical
      properties of the Shah-Humphrey model for periodic pressure forcing of a thin
      necked saccular aneurysm, using the Fung nonlinear constitutive model for the
      aneurysm material, shows that a small blood pressure jump on each beat, whether
      the pressure is weakly aperiodic or periodic, induces transients in the radial
      deformation response of the aneurysmal wall on each heartbeat. These transient
      vibrations, which have a component with frequency near the natural frequency of
      the system but are not resonant phenomena and which decay rapidly to a limit
      cycle during each distinct forcing pressure cycle, can generate the bruits.

PMID- 12424533
TI  - The distribution of particles in the plane dispersed by a simple 3-dimensional
      diffusion process.
AB  - Populations of particles dispersed in the 2-dimensional plane from a single point
      source may be grouped as focus expansion patterns, with an exponentially
      decreasing density, and more diffuse patterns with thicker tails. Exponentially
      decreasing distributions are often modelled as the result of 2-dimensional
      diffusion processes acting to disperse the particles, while thick-tailed
      distributions tend to be modelled by purely descriptive distributions. Models
      based on the Cauchy distribution have been suggested, but these have not been
      related to diffusion modelling. However, the distribution of particles dispersed
      from a point source by a 3-dimensional Brownian motion that incorporates a
      constant drift, under the condition that the particle starts at a given height
      and is stopped when it reaches the xy plane (zero height) may be shown to result
      in both slim-tailed exponentially decreasing densities, and thick-tailed
      polynomially decreasing densities with infinite mean travel distance from the
      source, depending on parameter values. The drift in the third coordinate
      represents gravitation, while the drift in the first and second represents a
      (constant) wind. Conditions for the density having exponentially decreasing tails
      is derived in terms of gravitation and wind, with a special emphasis on
      applications to light-weighted particles such as fungal spores.

PMID- 12424535
TI  - Chimeric anti-CD20 monoclonal antibody (Mabthera) in remission induction and
      maintenance treatment of relapsed follicular non-Hodgkin's lymphoma: a phase III
      randomized clinical trial--Intergroup Collaborative Study.

PMID- 12424536
TI  - Distribution of Lewis (FUT3)genotype and allele: frequencies in a biethnic United
      States population.
AB  - The objective of the study was to examine the prevalence and distribution of four
      major single nucleotide polymorphisms (SNPs) (T59G, T1067G, T202C, and C314T) of
      the Lewis ( FUT3)gene in a biethnic United States population. This population
      based cross-sectional study was based on data from the Atherosclerosis Risk in
      Communities (ARIC) Study, which included 761 males and females aged 45-64 years,
      who had no known/detected clinical atherosclerotic disease (577 Caucasians, 184
      African Americans). The main outcome measures were prevalence of the Lewis
      genotype and allele frequencies for four SNPs of the FUT3gene. The most common
      genotype was the "wild type" at all four nucleotide positions ( WWWW), which was
      found to be present in 46.9% of ARIC participants. At least one mutant allele was
      detected in 51.7% of Caucasians, and 56.7% of African Americans ( P=0.59). The
      frequencies of mutant alleles ranged from 6.3% to 18.4% at the four FUT3gene
      sites examined. The distribution of the Lewis genotype and allele frequencies
      differed significantly by ethnicity at sites 59, 202, and 314. The prevalence of
      the Lewis genotype suggesting a lack of alpha(1,3/1,4) fucosyltransferase
      activity was 11.6% in Caucasians and 9.9% in African Americans ( P=0.67). Four
      specific SNPs of the Lewis genotype are common in the population at large.
      However, these four SNPs seem to fail to explain the majority of Lewis-negative
      phenotype in African Americans, given that Lewis-negative genotype prevalence was
      about one-third of what was expected. Use of rapid DNA sequencing and
      simultaneous Lewis phenotype determination could avoid the problems associated
      with haplotype determination and Lewis genotype grouping. Further studies testing
      SNPs of the Lewisgene are warranted, in particular among African Americans.

PMID- 12424537
TI  - Clinical relevance of the TNF-alpha promoter/enhancer polymorphism in patients
      with aplastic anemia.
AB  - Immune-mediated inhibition of hematopoiesis has been suspected as a major cause
      of the suppressed growth of progenitor cells in aplastic anemia (AA).
      Overproduction of TNF-alpha by bone marrow and peripheral blood-derived cells was
      shown to be of pathogenetic importance. Genetic factors have been suggested by
      higher specific histocompatibility antigen frequencies among AA patients as a
      group and among those unresponsive to immunosuppressive therapy with
      cyclosporine. In the present work we expand on the evidence for the contribution
      of the TNF system to therapeutic responses in patients with AA. The response to
      immunosuppressive therapy at 3 months was found to be significantly more frequent
      among carriers of the TNF2 (TNF -308 A) gene (TNF2 homozygotes and heterozygotes
      of the TNF-alpha promoter/enhancer polymorphism) than among those patients not
      carrying the TNF2 gene. The allelic distribution of the LT-alpha (TNF-beta) NcoI
      and IL-1 receptor antagonist variable number tandem repeat (VNTR) polymorphisms
      did not differ among the subgroups of patients. The association of the TNF-alpha
      genotype with a response to immunosuppressive therapy points to an immunogenetic
      association that may contribute to the pathogenesis and therapeutic response of
      aplastic anemia.

PMID- 12424538
TI  - Prospective randomized trial to evaluate two delayed granulocyte colony
      stimulating factor administration schedules after high-dose cytarabine therapy in
      adult patients with acute lymphoblastic leukemia.
AB  - In acute lymphoblastic leukemia (ALL), treatment with granulocyte colony
      stimulating factor (G-CSF) during remission induction shortens granulocytopenia
      and may decrease morbidity due to infections. However, the optimal timing of G
      CSF administration after chemotherapy is not known. In a prospective randomized
      multi-center study, adult ALL patients were treated with high-dose ARA-C [HDAC, 3
      g/m(2) bid (1 g/m(2) bid for T-ALL) days 1-4] and mitoxantrone (MI 10 mg/m(2)
      days 3-5). They were randomized to receive recombinant human G-CSF (Lenograstim)
      263 micro g/day SC starting either from day 12 (Group 1) or day 17 (Group 2).
      Fifty-five patients (41 male, 14 female) with a median age of 34 years (range: 18
      55 years) were enrolled into the study; 50 patients were evaluable. The median
      duration of neutropenia <500/ micro l after HDAC/MI was 12 days (range: 7-22
      days) in the early G-CSF Group 1 and also 12 days (range: 4-22 days) in the late
      G-CSF Group 2; this was shorter than in the historical control group (15 days,
      range: 4-43 days, n=46) where the patients received identical cytotoxic treatment
      without G-CSF. Seventeen infections were observed in 14 patients in Group 1 (47%)
      and 13 infections in 10 patients in Group 2 (50%) compared to 27 infections in 49
      patients of the historical control (54%). In Group 1, the patients received a
      median of 11 injections with G-CSF (range: 7-22) compared to 7 injections (range:
      4-19) in Group 2. The total administered dose of G-CSF in Group 2 was
      significantly reduced by 40% ( P<0.0001). The delayed start of G-CSF after
      HDAC/MI in ALL achieves the same clinical benefit compared to the earlier
      initiation of G-CSF. The reduction of treatment costs by reducing the total G-CSF
      dose may be important in future treatment with this hematopoietic growth factor.

PMID- 12424539
TI  - Autologous bone marrow transplantation with negative immunomagnetic purging for
      aggressive B-cell non-Hodgkin's lymphoma in first complete remission.
AB  - To evaluate the effect on survival of negative immunomagnetic purging in
      aggressive B-cell non-Hodgkin's lymphoma (NHL), 20 patients retrospectively
      staged according to the age-adjusted International Prognostic Index as high
      intermediate (11 patients) or high-risk (9 patients) received autologous bone
      marrow transplantation (ABMT) in first complete remission (CR1). All patients
      received six to eight cycles of a F-MACHOP-like protocol as induction treatment
      and then underwent high-dose chemotherapy (HDC) with a CBV-like regimen. Negative
      purging included a panel of monoclonal antibodies against B-cell antigens and
      immunomagnetic beads. The data were compared to a historical control of 18
      patients with the same characteristics treated in our institution who received
      unpurged bone marrow support. The median yield of mononuclear cells (MNC), colony
      forming units-granulocyte/macrophage (CFU-GM), and CD34+ cells after purging were
      52%, 49%, and 57%, respectively. The median B-cell depletion after negative
      selection was 1.8 logs. All patients obtained a complete engraftment with no
      significant differences between the purged and unpurged group. Two toxic deaths
      (one for each group) were observed and the main extrahematological toxicities
      were mucositis, vomiting, and diarrhea. The event-free survival (EFS) and overall
      survival (OS) at 3 years for the whole group of 38 patients were 73% (95% CI: 59
      88%) and 81% (95% CI, 68-94%), respectively. The comparison between patients
      receiving purged marrow and patients receiving unmanipulated marrow indicated no
      significant survival differences between the two groups both for EFS 84% (95% CI:
      67-100%) vs 61% (95%CI: 39-84%) ( P=0.12) and OS 84% (95% CI: 69-100%) vs 71%
      (95% CI: 50-93%) ( P=0.58). Our report shows that HDC followed by reinfusion of
      autologous bone marrow can produce long EFS and OS in high-intermediate and high
      risk patients with B-cell NHL transplanted in CR1, but was not be able to
      demonstrate a significant clinical advantage using immunomagnetic purged marrow.
      However, the use of ex vivo negative purging combined with innovative treatment
      modalities (peripheral blood stem cell transplant, in vivo administration of
      monoclonal antibodies) needs to be explored.

PMID- 12424540
TI  - Long-term outcome after allogeneic bone marrow transplantation for hematological
      malignancies with non-remission status. Results of a single-center study of 24
      patients.
AB  - To investigate the problem of allogeneic bone marrow transplantation (allo-BMT)
      for advanced stage patients, we retrospectively analyzed 24 consecutive patients
      who underwent allo-BMT in the non-remission stage. Twenty-four patients (19 males
      and 5 females) with acute leukemia, chronic myelogenous leukemia, and malignant
      lymphoma underwent allo-BMT. The patients had a median age of 30 years. There
      were eight cases of acute myelogenous leukemia (AML), six cases acute lymphocytic
      leukemia (ALL), nine cases of chronic myelogenous leukemia (CML), and one case of
      Burkitt's lymphoma. The 3-year overall survival rate was 22.5%, with a median
      survival time of 206 days in AML, 345 days in ALL, and 363 days in CML. Overall
      survival was associated with a recovery of platelets of less than 30 days and an
      acute graft-versus-host disease (acute GVHD) presence of less than grade II (
      p=0.042). Fourteen patients died of transplantation-related diseases. Our
      important problem is to decrease transplantation-related deaths in allo-BMT
      during the non-remission stage, and longer survival can be expected with better
      pretreatment and prophylaxis for GVHD. In addition, the selection of the source
      of hematopoietic stem cell transplantation at an optimal time is considered to be
      another problem to be approached.

PMID- 12424541
TI  - High-dose chemotherapy and autologous peripheral blood stem cell transplantation
      for treatment of unspecified peripheral T-cell lymphoma presented with
      hepatosplenomegaly and hypercytokinemia syndrome: report of three cases.
AB  - We report here three cases of peripheral T-cell lymphoma unspecified (PTCL-US),
      which presented with bone marrow infiltration and hepatosplenomegaly and were
      successfully treated with high-dose chemotherapy (HDCT) and autologous peripheral
      blood stem cell transplantation (auto-PBSCT). The patients were all characterized
      by cytokine-induced symptoms such as fever, anasarca, cytopenia, poor general
      condition, and disseminated intravascular coagulation syndrome. Laboratory data
      showed extremely high levels of soluble interleukin-2 receptor, beta(2)
      microglobulin, and ferritin. All three patients were negative for anti-adult T
      cell leukemia antibody. In one patient, hemophagocytosis was revealed by a
      histological examination of the bone marrow. The International Prognostic Index
      was high for all three patients, and they all achieved complete remission after
      the intensive chemotherapy for remission induction. During complete remission,
      they were treated with HDCT [modified interleukin-converting enzyme regimen]
      followed by auto-PBSCT. The recovery of hematopoiesis after auto-PBSCT was prompt
      and sustained engraftment was obtained. No serious adverse effects other than
      myelosuppression were noted. One patient died due to cerebrovascular disease
      without relapse 18 months after auto-PBSCT. The other two patients are still
      alive and have not suffered from relapse. Our observations suggest that auto
      PBSCT following HDCT may be an effective and safe therapeutic modality for high
      risk PTCL-US patients characterized by hepatosplenomegaly and cytokine-induced
      syndrome.

PMID- 12424542
TI  - Primary cutaneous aspergillosis caused by Aspergillus ustus following reduced
      intensity stem cell transplantation.
AB  - A 19-year-old woman with myelodysplastic syndrome underwent reduced-intensity
      stem cell transplantation [RIST: (cladribine 0.11 mg/kg for 6 days, busulfan 4
      mg/kg for 2 days, and rabbit antithymocyte globulin)] from her one HLA-mismatched
      mother. Prophylaxis against graft-versus-host disease (GVHD) was performed with
      cyclosporine A (CSA) alone. Severe acute GVHD in the skin, gut, and liver
      developed concurrently with stable engraftment, and methylprednisolone was
      administered (1-2 mg/kg per day, then pulse therapy with 1 g/day for 3 days)
      until day 40 of transplant, when a necrotic lesion of 10 mm in diameter appeared
      on the right cheek. The initial skin biopsy of the affected area showed a
      nonspecific inflammatory change. Routine X-ray and computed tomography
      examinations of the sinuses, chest, and abdomen disclosed no particular
      abnormalities. Despite intensive antibiotic therapy, the lesion rapidly extended
      to form an ulcer. A second biopsy specimen obtained from the lesion showed
      massive septa hyphae, suggesting mold infection. Although we immediately started
      amphotericin B, she died of multiorgan failure on day 68. Postmortem DNA sequence
      analysis of the specimen using the polymerase chain reaction identified
      Aspergillus ustus. Although this is an extremely rare complication after
      transplantation, this case highlights that we should pay more attention to
      primary cutaneous aspergillosis in severely immunosuppressed patients.

PMID- 12424543
TI  - Autoantibodies against a 72-kDa ductal cell membrane glycoprotein in a patient
      affected by Sjogren's syndrome and gastric MALT lymphoma.
AB  - Sjogren's syndrome is a chronic autoimmune disease affecting exocrine glands,
      resulting in xerostomia and xerophthalmia. Lymphocytic infiltration and fibrosis
      of exocrine glands as well as the presence of autoantibodies against organ
      specific and non-organ-specific antigens are the hallmarks of the disease. We
      investigated whether some patients affected by Sjogren's syndrome might have
      autoantibodies directed against epithelial duct cell membrane proteins. We
      screened sera from patients affected by Sjogren's syndrome by indirect
      immunofluorescence on monkey salivary gland sections and FG-Met-2 cells (a
      pancreatic carcinoma cell line with ductal features) for the presence of
      antisalivary duct antibodies. Positive sera were employed in immunoprecipitation
      experiments on (35)S-methionine in vivo labeled and surface-biotinylated FG-Met-2
      cells. The serum of a patient affected by Sjogren's syndrome and gastric mucosa
      associated lymphoid tissue (MALT) lymphoma gave positive and distinct membrane
      immunostaining on FG-Met-2 cells. Immunoprecipitation with the patient's serum
      from (35)S-methionine-labeled cell extracts followed by sodium dodecyl sulfate
      (SDS) polyacrylamide gel electrophoresis (PAGE) and autoradiography showed the
      presence of autoantibodies against a 72-kDa protein. After biotin-surface
      labeling of FG-Met-2 cells, a band with identical electrophoretic mobility was
      immunoprecipitated by the serum, demonstrating that the 72-kDa band is a membrane
      glycoprotein. We demonstrated by three complementary approaches, i.e.,
      immunocytochemistry, (35)S-methionine in vivo labeling, and cell surface
      biotinylation, the presence of autoantibodies directed against a duct cell
      membrane protein of 72-kDa in a patient affected by Sjogren's syndrome and
      gastric MALT lymphoma. Autoantibodies directed against this novel membrane
      autoantigen may be an additional serological marker in some cases of Sjogren's
      syndrome.

PMID- 12424544
TI  - A case of biphenotypic blast crisis of unclassified myeloproliferative disorder.
AB  - We report a first case of biphenotypic blast crisis of unclassified
      myeloproliferative disorder (MPD). A 20-year-old patient presented with fever,
      splenomegaly, marked leukocytosis (603 x 10(3)/ micro l), and blasts in the
      peripheral blood. Since Ph chromosome and bcr-abl gene rearrangement were absent,
      the diagnosis of an unclassified MPD in the blast crisis phase was established.
      Immunophenotyping confirmed a biphenotypic crisis of myeloid and T-lymphoid
      antigens. The patient went into a complete remission after chemotherapy, but
      marked granulocytic hyperplasia (M:E ratio of 5.7) and 90% cellularity remained.
      Blast crisis recurred during subsequent intensification chemotherapy and the
      patient did not go into a complete remission regardless of the intense
      chemotherapy. The blast crisis transformed from unclassified MPD had a grave
      prognosis as it responded poorly to chemotherapy. This unique blast crisis is
      distinguishable from the blast crisis of chronic myelogenous leukemia.

PMID- 12424545
TI  - del11(p11-13) with overexpression of Wilms' tumor gene during leukemic
      transformation of myelodysplastic syndrome.
AB  - We report a case of leukemic transformation from myelodysplastic syndrome (MDS)
      with a sole chromosome abnormality of del11(p11-13). The patient had been
      diagnosed as having MDS (refractory anemia with excess of blast cells, RAEB) in
      May 1998. At that time, cytogenetic analysis of bone marrow cells showed a normal
      karyotype. The patient received sequential chemotherapy with low-dose cytosine
      arabinoside (AraC) and macrophage colony-stimulating factor (M-CSF). Complete
      remission was obtained with this treatment, but the disease gradually progressed
      after June 1999. Cytogenetical analysis showed del11(p11-13) in 6 of 40 cells
      analyzed at that time, and the disease had evoluted to overt leukemia in December
      1999 with a gradual increase in the abnormal clone. Furthermore, mRNA of the WT1
      gene located at chromosome 11p13 was overexpressed during leukemic
      transformation, whereas it was not detected at the time of the initial diagnosis
      of MDS (RAEB) in May 1998. It was thought that this chromosome deletion and
      overexpression of WT1 resulted in the leukemic transformation in this patient.
      This is the first case report of del11(p11-13) being considered to be the primary
      cause of leukemic transformation from MDS.

PMID- 12424546
TI  - Interleukin-11 administration normalizes the platelet count in a hypersplenic
      cirrhotic patient.
AB  - We report the successful administration of interleukin-11 (IL-11 or oprelvekin),
      a promoter of megakaryocyte maturation, to a 54-year-old male Jehovah's Witness
      with hepatic cirrhosis and hypersplenic thrombocytopenia requiring surgery for
      symptomatic interstitial cystitis. This observation suggests that oprelvekin
      might be crucial in the acute management of certain types of hypersplenic
      thrombocytopenias.

PMID- 12424547
TI  - Effects of caffeine on performance and mood depend on the level of caffeine
      abstinence.
AB  - RATIONALE: Most studies of the effects of caffeine on performance have used
      regular caffeine consumers who are deprived at test. Thus the reported effects of
      caffeine could be explained through reversal of caffeine withdrawal. OBJECTIVES:
      To test how preloading deprived caffeine consumers with 0, 1 or 2 mg/kg caffeine
      altered the subsequent ability of caffeine to modify mood and performance.
      METHODS: Thirty moderate caffeine consumers were given a drink containing 0, 1 or
      2 mg/kg caffeine at breakfast followed 60 min later by a second drink containing
      either 0 or 1 mg/kg caffeine. Performance on a measure of sustained attention and
      mood were measured before and after each drink. RESULTS: Administration of both 1
      and 2 mg/kg caffeine at breakfast decreased reaction time and 1 mg/kg caffeine
      also increased performance accuracy on the sustained attention (RVIP) task
      relative to placebo. Both breakfast doses of caffeine also improved rated mental
      alertness. Similarly, 1 mg/kg caffeine administered 60 min after breakfast
      decreased reaction time and increased rated mental alertness in the group who had
      not been given caffeine at breakfast. However, this second dose of caffeine had
      no effect on subsequent performance or mood in the two groups who had received
      caffeine at breakfast. CONCLUSIONS: Caffeine reliably improved performance on a
      sustained attention task, and increased rated mental alertness, in moderate
      caffeine consumers who were tested when caffeine-deprived. However, caffeine had
      no such effects when consumers were no longer caffeine deprived. These data are
      consistent with the view that reversal of caffeine withdrawal is a major
      component of the effects of caffeine on mood and performance.

PMID- 12424548
TI  - Effects of caffeine, sleep loss, and stress on cognitive performance and mood
      during U.S. Navy SEAL training. Sea-Air-Land.
AB  - RATIONALE: When humans are acutely exposed to multiple stressors, cognitive
      performance is substantially degraded. Few practical strategies are available to
      sustain performance under such conditions. OBJECTIVE: This study examined whether
      moderate doses of caffeine would reduce adverse effects of sleep deprivation and
      exposure to severe environmental and operational stress on cognitive performance.
      METHODS: Volunteers were 68 U.S. Navy Sea-Air-Land (SEAL) trainees, randomly
      assigned to receive either 100, 200, or 300 mg caffeine or placebo in capsule
      form after 72 h of sleep deprivation and continuous exposure to other stressors.
      Cognitive tests administered included scanning visual vigilance, four-choice
      visual reaction time, a matching-to-sample working memory task and a repeated
      acquisition test of motor learning and memory. Mood state, marksmanship, and
      saliva caffeine were also assessed. Testing was conducted 1 and 8 h after
      treatment. RESULTS: Sleep deprivation and environmental stress adversely affected
      performance and mood. Caffeine, in a dose-dependent manner, mitigated many
      adverse effects of exposure to multiple stressors. Caffeine (200 and 300 mg)
      significantly improved visual vigilance, choice reaction time, repeated
      acquisition, self-reported fatigue and sleepiness with the greatest effects on
      tests of vigilance, reaction time, and alertness. Marksmanship, a task that
      requires fine motor coordination and steadiness, was not affected by caffeine.
      The greatest effects of caffeine were present 1 h post-administration, but
      significant effects persisted for 8 h. CONCLUSIONS: Even in the most adverse
      circumstances, moderate doses of caffeine can improve cognitive function,
      including vigilance, learning, memory, and mood state. When cognitive performance
      is critical and must be maintained during exposure to severe stress,
      administration of caffeine may provide a significant advantage. A dose of 200 mg
      appears to be optimal under such conditions.

PMID- 12424549
TI  - Effects of lorazepam and oxazepam on perceptual and procedural memory functions.
AB  - RATIONALE: Lorazepam has been found to consistently impair performance on both
      episodic and perceptual priming tasks, whereas other benzodiazepines have shown
      perceptual priming to be preserved. However, it has recently been postulated that
      benzodiazepines may exert time-dependent effects on implicit memory processes
      after research findings indicated some benzodiazepines, other than lorazepam,
      impair performance on priming tasks when tested at the time of peak plasma
      concentration level after benzodiazepine administration. OBJECTIVES: To compare
      time-dependent effects of lorazepam and oxazepam on implicit memory tasks,
      specifically perceptual priming and procedural learning. METHODS: Thirty-three
      healthy female undergraduates were randomised to one of three time groups (pre
      peak, peak, post-peak) and administered placebo, 2.5 mg lorazepam, and 30 mg
      oxazepam, in counterbalanced order, at 1-week intervals. Assessments included
      word-stem completion (perceptual priming) and rotary pursuit (procedural
      learning) tasks. RESULTS: At all time intervals, lorazepam but not oxazepam
      significantly impaired perceptual priming but procedural learning was preserved
      under both drugs. CONCLUSIONS: These findings are consistent with previous
      research showing a differential effect of lorazepam in impairing perceptual
      memory but the notion that benzodiazepines exert time-dependent effects on
      implicit memory processes was not supported.

PMID- 12424550
TI  - Antalarmin, a putative CRH-RI antagonist, has transient reinforcing effects in
      rhesus monkeys.
AB  - RATIONALE: During the course of our investigation of antalarmin, a corticotropin
      releasing hormone (CRH) antagonist, in rhesus monkeys, we noticed that large,
      intravenous doses of antalarmin resulted in behavioral changes that resembled
      intoxication. OBJECTIVES: Antalarmin was evaluated in rhesus monkeys for its
      reinforcing effectiveness as well as for its effects on hypothalamic-pituitary
      adrenal (HPA) axis activity. METHODS: Twelve monkeys, each with a surgically
      implanted indwelling venous catheter, were trained to respond for and receive the
      short-acting barbiturate, methohexital. Monkeys responded on one of two
      schedules: a fixed ratio (FR) 10 (30 or 100), timeout (TO) 10 s schedule on which
      they received methohexital, antalarmin, vehicle or saline injections; or an FR30,
      TO 45 s during which saline, vehicle, or four different doses of methohexital or
      antalarmin were available. Each dose was available during a 25-min period
      separated by a 10-min TO. Blood samples were obtained from three monkeys before,
      during and after the self-administration sessions and assayed for ACTH and
      cortisol. RESULTS: Antalarmin initially served as a reinforcer in 11 of 12
      monkeys, although its reinforcing effects dissipated after three to four
      exposures under both operant schedules. Self-injection of antalarmin did not
      produce any change in cortisol levels, although methohexital did attenuate ACTH
      and cortisol release. CONCLUSIONS: This study provides the first evidence for
      transient reinforcing properties of a putative centrally acting CRH-R1 selective
      antagonist.

PMID- 12424551
TI  - Effects of stimulant medications on the EEG of children with attention
      deficit/hyperactivity disorder.
AB  - RATIONALE: Stimulant medications are the most commonly used treatments for
      attention deficit/hyperactivity disorder (ADHD) in North America and Australia,
      although it is still not entirely known how these medications work. OBJECTIVES:
      This study aimed to investigate the effects of stimulant medications on the EEG
      of children with the Combined subtype of ADHD. METHOD: An initial EEG was
      recorded during an eyes-closed resting condition and Fourier transformed to
      provide absolute and relative power estimates for the delta, theta, alpha and
      beta bands. Theta/alpha and theta/beta ratios were also calculated. Subjects were
      placed on a 6-month trial of a stimulant and a second EEG was recorded at the end
      of the trial. RESULTS: The ADHD group had significantly greater absolute delta
      and theta, less posterior absolute beta, more relative theta, and less relative
      alpha than the control group, which is typical of EEG studies of children with
      ADHD. The use of stimulant medications resulted in normalisation of the EEG,
      primarily evident in changes in the theta and beta bands. CONCLUSIONS: These
      results suggest that stimulants act to increase cortical arousal in children with
      ADHD, normalising their brain activity.

PMID- 12424552
TI  - SR146131, a cholecystokinin-A receptor agonist, antagonizes prepulse inhibition
      deficits produced by dizocilpine and DOI.
AB  - RATIONALE: Converging evidence has demonstrated that cholecystokinin (CCK)
      inhibits mesolimbic brain dopamine (DA) function via activation of CCK-A (CCK-1)
      receptors. These effects of CCK have stimulated interest in the potential use of
      CCK agonists as antipsychotic drugs. Most research on the antipsychotic-like drug
      effects of CCK has used CCK or CCK analogues that nonselectively activate both
      CCK-A and CCK-B (CCK-2) receptors, which may produce opposite effects. SR146131,
      a CCK-A selective nonpeptide agonist, has recently been developed (Sanofi
      Synthelabo). OBJECTIVE: To determine whether SR146131 exhibits antipsychotic-like
      qualities in the prepulse inhibition (PPI) paradigm. METHODS: We performed
      experiments to determine whether SR146131 (vehicle, 0.01, 0.1, 1.0 mg/kg) would
      attenuate PPI deficits induced by amphetamine (2.0 mg/kg), an indirect dopamine
      agonist, and dizocilpine (0.1 mg/kg), a noncompetitive N-methyl-D-aspartate
      (NMDA) antagonist. Since SR146131 demonstrated significant effects on PPI
      disrupted by the noncompetitive NMDA antagonist, an effect associated with drugs
      that inhibit serotonin (5HT)2A transmission, we also tested the effects of
      SR146131 on PPI disruption produced by 2,5-dimethoxy-4-iodoamphetamine (DOI, 0.5
      mg/kg), a direct 5HT2A agonist. RESULTS: SR146131 did not significantly affect
      startle magnitude, baseline PPI, or amphetamine-induced PPI deficits. However, it
      dose-dependently antagonized dizocilpine and DOI-induced PPI deficits.
      CONCLUSIONS: The lack of an effect of SR146131 on amphetamine-induced disruption
      of PPI suggests that a selective nonpeptide CCK-A agonist may not produce
      antipsychotic-like effects on dopamine transmission. However, the unexpected
      effects of SR146131 on dizocilpine and DOI-induced PPI deficits are consistent
      with the effects of drugs that inhibit transmission in the 5HT2A receptor system,
      including atypical antipsychotic drugs. Possible mechanisms underlying these
      findings are discussed.

PMID- 12424553
TI  - St John's wort extract (LI 160) in somatoform disorders: results of a placebo
      controlled trial.
AB  - RATIONALE AND OBJECTIVE: Preliminary data have shown that St John's wort might
      possess some specific efficacy in patients with somatoform complaints. Therefore,
      the efficacy of the Hypericum extract LI 160 in patients with somatoform
      disorders should be studied in a double-blind placebo-controlled fashion.
      METHODS: This was a multicentre, randomised, placebo controlled, 6-week trial
      comparing the efficacy of LI 160 (600 mg/day) and placebo in 151 out-patients
      suffering from somatization disorder (ICD-10: F45.0), undifferentiated somatoform
      disorder (F45.1), or somatoform autonomic dysfunctions (F45.3). The primary
      outcome measure was the decrease of the Hamilton Anxiety Scale, subfactor somatic
      anxiety (HAMA-SOM), during the trial period. RESULTS: LI 160 was superior
      effective concerning the primary outcome criterion HAMA-SOM [decrease from 15.39
      (SD 2.68) to 6.64 (4.32) in the Hypericum group and from 15.55 (2.94) to 11.97
      (5.58) in the placebo group (statistically significant difference, P=0.001)].
      This was corroborated by the result of a statistically significant superior
      efficacy in the outcome criteria additionally used such as Clinical Global
      Impression, HAMA-total score, HAMA, subscore psychic anxiety, Hamilton Depression
      Scale, Self-Report Symptom Inventory 90 items - revised (SCL-90-R), and SCL-90-R,
      subscore somatic anxiety. The efficacy of LI 160 was preserved after splitting
      the population in those with and those without mild depressive symptoms
      [corrected]. Tolerability of LI 160 was excellent. CONCLUSION: The data from this
      trial show excellent efficacy and tolerability for LI 160 in somatoform
      disorders. The efficacy is independent of an existing depressive mood. This is
      the first study showing the efficacy of a drug in patients with somatisation
      disorder independent of depressive symptomatology.

PMID- 12424554
TI  - Cluster analysis of symptoms during antidepressant treatment with Hypericum
      extract in mildly to moderately depressed out-patients. A meta-analysis of data
      from three randomized, placebo-controlled trials.
AB  - RATIONALE: Although extracts from Hypericum have long played a major role in the
      treatment of mild to moderate depression, information pertaining to the drug's
      therapeutic profile is sparse. OBJECTIVES: To investigate whether the
      administration of the Hypericum extract has a selective effect on particular
      signs and symptoms of depression as opposed to a more general acceleration of
      recovery. METHODS: A meta-analysis was performed on the original data of three
      double-blind, randomized multicenter trials, during which 544 out-patients
      suffering from mild to moderate depression according to DSM-IV criteria received
      3x300 mg/day Hypericum extract (WS 5570 or WS 5572) or placebo over a double
      blind treatment period of 6 weeks. The primary outcome measure for treatment
      efficacy in the original trials was the change in the total score of the Hamilton
      Rating Scale for Depression (HAMD, 17-item version) between baseline and
      treatment end. The relationship between the symptoms of depression represented by
      the items of the HAMD was assessed by means of cluster analysis and individual
      item analysis. RESULTS: Two clusters of items were identified which were stable
      in several independent subsets of the full data set. While cluster 1 (HAMD items
      1, 2, 3, 7, 8, 12, 13, 14, 16) was interpreted to represent the core symptoms of
      depression (including somatic aspects), cluster 2 (items 4, 5, 6, 9, 10, 11, 15,
      17) was primarily composed of items assessing depression-related anxiety and
      insomnia. In both clusters, Hypericum extract reduced the symptoms of depression
      more effectively than placebo. However, the herbal drug was particularly
      effective in the core symptoms of the disorder. CONCLUSIONS: The results indicate
      that Hypericum extract accelerated the recovery from depression in a rather
      general manner, by influencing all investigated signs and symptoms of the
      disease. The drug's therapeutic profile was thus found to be similar to the
      profile of selective serotonin reuptake inhibitors.

PMID- 12424555
TI  - Conditioned anxiety to nicotine.
AB  - RATIONALE: Despite its reinforcing properties nicotine has also been reported to
      produce anxiety in humans and anxiogenic effects in animal tests of anxiety.
      OBJECTIVE: The aims of this study were three-fold: (a) to investigate whether
      anxiety can be conditioned to cues associated with an acute anxiogenic dose of
      nicotine, (b) to investigate whether the conditioned anxiety is specific to a
      particular test of anxiety, and (c) to investigate whether nicotine pre-exposure
      influences the development of a conditioned anxiogenic effect. METHODS: An
      anxiogenic dose of nicotine was administered to rats either before or after
      experience with the social interaction (SI) test. The retention of a conditioned
      anxiogenic response was examined when the rats were re-tested undrugged in the SI
      test 24 h later. To test whether conditioned anxiety was test specific, rats that
      had been tested in the elevated plus-maze with an anxiogenic dose of nicotine
      were retested undrugged in the SI test 24 h later, and vice versa. We then
      examined the effects of 4 days or 4 weeks pre-exposure to nicotine on the
      development of a conditioned anxiogenic response in the SI test. RESULTS: Rats
      injected with nicotine (0.45 mg/kg s.c.) 5 min before the social interaction test
      spent significantly less time in SI, indicating an unconditioned anxiogenic
      effect than did vehicle-injected controls or rats injected with nicotine after
      the test. After 24 h when all groups were tested undrugged only those previously
      tested in SI after nicotine injection showed a significant conditioned anxiogenic
      effect. This conditioned anxiety was test specific. Rats injected with nicotine
      before the SI test did not show an anxiogenic response when tested 24 h later
      undrugged in the plus-maze, and vice versa. Furthermore, although 4 days exposure
      to nicotine (0.45 mg/kg s.c.) did not prevent the development of a conditioned
      anxiogenic response, 4 weeks self-administration of nicotine (total dose, 0.45
      mg/kg i.v) in an operant chamber did not affect the acute anxiogenic response to
      nicotine in the SI test, but it did prevent the development of conditioned
      anxiety. CONCLUSIONS: The present findings suggest that anxiety can be
      conditioned following exposure to an anxiogenic dose of nicotine, and that this
      anxiety is specific to the contextual cues associated with the SI test.

PMID- 12424556
TI  - Quantifying fear potentiated startle using absolute versus proportional increase
      scoring methods: implications for the neurocircuitry of fear and anxiety.
AB  - RATIONALE: The fear-potentiated startle paradigm [increased startle in the
      presence of a conditioned fear stimulus (CS)] has become increasingly popular as
      a tool for evaluating the potential efficacy of putative anxiolytic compounds.
      However, when the tested compounds also influence baseline startle, it is unclear
      how comparisons with control groups can best be made. OBJECTIVE: To evaluate the
      validity of absolute difference (startle amplitude on CS minus non-CS test
      trials) vs. proportional increase (the absolute difference score divided by
      startle amplitude on non-CS test trials) scoring methods. METHODS: The effect on
      proportional increase and absolute difference scores of baseline shifts that
      occur with or without concomitant increases in fear was evaluated in rats. A
      reliable measure should yield similar scores across shifting baselines, provided
      that fear levels remain constant. RESULTS: Preexisting baseline differences, and
      those brought about by different startle-eliciting noise burst intensities, by
      strychnine injections, or by CRH infusions, each increased absolute difference
      scores without markedly influencing proportional change scores. These baseline
      differences were not associated with different fear levels. Increases in baseline
      startle brought about by unsignaled footshocks or by a second CS - increases
      which are associated with increased fear - partially occluded additional CS
      induced increases using either measure. CONCLUSIONS: Across different baselines,
      CS-elicited fear is most accurately reflected in proportional change scores.
      Under certain conditions saturation effects may interfere with an accurate
      assessment using either measure. However, these same saturation effects may
      provide opportunities to explore the neural circuitry of fear and anxiety in
      novel ways.

PMID- 12424557
TI  - Specific abnormalities in serotonin release in the prefrontal cortex of isolation
      reared rats measured during behavioural performance of a task assessing
      visuospatial attention and impulsivity.
AB  - RATIONALE: Rats reared in social isolation exhibit hyperactivity and specific
      attentional disturbances in later adult life. These behavioural abnormalities may
      be relevant to impulsivity and other neuropsychiatric syndromes such as attention
      deficit hyperactivity disorder and schizophrenia where disturbances in circuitry
      involving the prefrontal cortex have been identified. OBJECTIVE: To establish
      whether isolation-reared rats show a differential susceptibility to cognitive
      processes that depend on the prefrontal cortex and its monoaminergic innervation.
      METHODS: Rats were reared in isolation from postnatal day 28 or in social groups
      of four and trained on the five-choice serial reaction time task, which assesses
      spatially divided visual attention. Following a range of manipulations designed
      to tax visual attention and response control, in vivo microdialysis was used in
      conjunction with behavioural testing to assess dopamine (DA) and serotonin (5-HT)
      release in the prefrontal cortex, either under baseline conditions prior to task
      initiation, or during task performance. Subjects were challenged with amphetamine
      (0.125 mg/kg intravenously) every 15 min, commencing 15 min after the start of
      the task. RESULTS: Apart from being consistently slower to collect food rewards
      and showing more perseverative responses to an auditory distractor, isolates were
      unimpaired on accuracy, impulsivity and correct latency measures on the five
      choice task. Basal levels of DA and 5-HT in the prefrontal cortex were also
      unaffected by isolation rearing. Amphetamine increased the speed of responding in
      control and isolation-reared animals and increased premature (impulsive)
      responding, but only in socially-reared animals. Cortical DA release increased to
      a similar extent in both groups following amphetamine challenge. By contrast, 5
      HT release was attenuated in isolates under these conditions. CONCLUSIONS: These
      findings highlight a rather specific deficit in 5-HT release in the prefrontal
      cortex of isolation-reared rats, although this appears not to affect visual
      attentional function. Rather, these data may be relevant to reduced impulsiveness
      of isolation-reared rats on the five-choice task. These findings are important in
      the context of animal models of attentional disturbances in schizophrenia.

PMID- 12424558
TI  - The evolution of the axillofemoral bypass over two decades.
AB  - To determine if the indications and numbers of the axillofemoral bypass have
      changed, a retrospective analysis was performed of all patients undergoing
      axillofemoral bypass over the past two decades. Group A (1980-89) and group B
      (1990-99) were compared using demographics, comorbid illness, perioperative
      outcomes, and indications for operation. There were 33 extraanatomic bypasses
      performed in group A and 24 extraanatomic bypasses in group B. The average age in
      both group A and group B was 69 years. Males comprised a higher percentage in
      group B (75%) than in group A (55%). The percentage of smokers was roughly
      equivalent (group A 76%, group B 71%). Coronary artery disease was more prevalent
      in group A (85%) than in group B (63%). Diabetes mellitus was also more common in
      group A (33%) than in group B (21%). All of the grafts in group B were composed
      of PTFE and there were 2 early (30 day) failures (6%). There were no
      perioperative deaths, strokes, or myocardial infarctions. At our institution, the
      axillofemoral bypass is now reserved almost exclusively for the treatment of
      graft infections and rarely for primary limb ischemia. This evolution is a
      reflection of the increase in interventional techniques used to improve inflow in
      high-risk patients who require revascularization.

PMID- 12424559
TI  - Treatment of hepatitis B.
AB  - Chronic hepatitis B virus (HBV) infection affects approximately 350 million
      people worldwide. Treatment of chronic hepatitis B is aimed at sustained
      suppression of HBV replication and remission of liver disease. Currently,
      antiviral treatment is indicated for hepatitis B e antigen (HBeAg)-positive
      patients in the immune clearance phase, and for HBeAg-negative patients with
      evidence of active liver disease and continued high levels of HBV replication.
      Treatment is not recommended for patients in the immune tolerance phase or the
      inactive carrier state, due to lack of efficacy of current treatment. This review
      updates safety and efficacy data of interferon alpha and lamivudine in the
      treatment of chronic hepatitis B. Management strategies in different clinical
      scenarios and future treatments are also discussed.

PMID- 12424560
TI  - Long-term effects of Helicobacter pylori eradication in Mongolian gerbils.
AB  - BACKGROUND: In this study, to clarify whether Helicobacter pylori eradication
      alters the course of the development of gastric mucosal changes in the stomach,
      we examined the long-term effects of H. pylori eradication on H. pylori
      inoculated gerbils. METHODS: A total of 40 H. pylori-inoculated gerbils were
      randomized and subjected, at 22 months after inoculation, to eradication
      treatment with dual therapy of omeprazole plus clarithromycin, or with therapy
      with a novel quinolone compound, Y-34867, alone. The animals were killed at the
      start of administration (control group) or at 8 months after the completion of
      therapy (vehicle or eradication-treatment groups). RESULTS: Severe
      histopathological changes in the gastric mucosa were observed in all H. pylori
      inoculated gerbils at the start of administration. At 8 months after completion
      of therapy, the frequency of gastritis, erosion, intestinal metaplasia, and
      gastric carcinoid in the eradication therapy groups was markedly reduced compared
      with that in the control and vehicle groups. Values for anti- H. pylori IgG
      titer, bacterial counts, and gastrin also decreased significantly. CONCLUSIONS:
      These results suggest that H. pylori eradication may have had a therapeutic
      effect not only on gastritis, erosion, and gastric ulcer but also on glandular
      atrophy, intestinal metaplasia, and gastric carcinoid.

PMID- 12424561
TI  - Gastric emptying of liquids is delayed by co-ingesting solids: a study using
      salivary paracetamol concentrations.
AB  - BACKGROUND: Paracetamol concentrations in plasma, a frequently used index of
      gastric emptying (GE) of liquids, are closely correlated with those in saliva. GE
      of liquids is delayed by co-ingesting solids. No researchers have used salivary
      paracetamol concentrations to show this phenomenon. The aim of this study was to
      elucidate whether salivary paracetamol concentrations can detect the food-induced
      delay in liquid GE. METHODS: Paracetamol absorption was measured twice in five
      healthy male volunteers. Following an overnight fast, they received 10 mg/kg
      paracetamol in 200 ml water alone on one occasion, and received this solution
      after consuming a 400 kcal-containing cookie on another occasion. After thorough
      rinsing of the month, 1 ml saliva was obtained, simultaneously with 2 ml blood,
      at 0, 0.25, 0.5, 0.75, 1.0, 2.0, 3.0, 4.0, and 6.0 h after paracetamol intake.
      The peak concentration (C(max)), the time to C(max) (t(max)), the area under the
      curve (AUC), and C(max)/AUC in plasma were calculated. Salivary C(max) and t(max)
      were also determined. RESULTS: Plasma C(max) and AUC were not significantly
      different between the two occasions. In contrast, significant differences in
      plasma t(max) and C(max)/AUC ( P < 0.05) established the food-induced delay in
      GE. Salivary t(max) could detect the delayed GE, whereas salivary C(max) could
      not. CONCLUSIONS: Salivary t(max) can document the solid meal-induced delay in
      liquid GE.

PMID- 12424562
TI  - Analysis of tumor morphology in metastatic colorectal cancer: does this
      classification have any clinical significance?
AB  - BACKGROUND: Macroscopic classification of metastatic liver tumors has been
      recommended to predict patient prognosis. METHODS: We examined the morphological
      analysis of metastatic colorectal cancer in 64 patients who underwent hepatic
      resection and the relationship with clinicopathologic factors. To identify the
      irregularity of the tumor, we calculated three formulas: (1) actual area of
      representative cut surface of tumor/circular length of tumor margin, (2) actual
      area of representative cut surface of tumor/elliptic area, defined by the major
      and minor axes, and (3) deviation of radius of marginal curvature. RESULTS:
      Following Yasui's macroscopic classification, the values of formulas (1) and (2)
      in confluent nodules were significantly lower than those in simple nodules ( P <
      0.05), while the value of formula (3) in confluent nodules was significantly
      greater than that in simple nodules ( P< 0.05). Only a lower value of formula (1)
      (less than 0.19) was significantly associated with postoperative recurrence ( P<
      0.05) and a lower value tended to be associated with a shorter disease-free
      survival after hepatectomy, but not significantly ( P= 0.09). However, most
      values were not associated with any clinicopathologic factors or postoperative
      survival. CONCLUSIONS: We conclude that differences in the morphological
      irregularity of liver tumors in metastatic colorectal cancer do not have clinical
      significance.

PMID- 12424563
TI  - Pit pattern and three-dimensional configuration of isolated crypts from the
      patients with colorectal neoplasm.
AB  - BACKGROUND: This study examined the usefulness of magnifying videoscopic pit
      pattern diagnosis in the differential diagnosis of colonic neoplasms. The
      relationship between pit patterns and the three-dimensional configuration of the
      neoplastic gland was evaluated for its contribution toward an understanding of
      pit patterns. METHODS: A total of 3005 colorectal lesions were examined
      endoscopically and histopathologically. Pit patterns were classified into six
      types. All materials used for crypt isolation were derived from segments of 21
      colorectal lesions and one normal colonic mucosa. For the crypt isolation, the
      HCl-digestion method was used. RESULTS: The magnifying videoscopic diagnosis was
      comparable with the histological diagnosis in the 3005 colorectal lesions.
      Isolated crypts with the type-I pit pattern resembled a test-tube; the type-II
      pit pattern was also tubular, but had observed fissures at the bottom; the type
      III l pit pattern was a reversed triangle or tongue-like in shape; and the type
      III s pit pattern was columnar and either tapered off or meandered. Isolated
      crypts with the type-IV b pit pattern appeared as long reversed triangles with
      protuberances, and the type-IV v pit pattern was flat with slender tubules or
      finger-like processes. The isolated crypts with the type-V pit pattern were
      complicated and indistinct in shape. CONCLUSIONS: Evaluation of the three
      dimensional configuration revealed that when the pit patterns, of each isolated
      crypt differed, their three-dimensional configurations also differed. Recognition
      of the differences in the three-dimensional configuration should contribute
      toward both an understanding of pit-pattern diagnosis and the further development
      of the endoscopic diagnosis of various colorectal lesions.

PMID- 12424564
TI  - Tiny staining spots in liver cirrhosis associated with HCV infection observed by
      computed tomographic hepatic arteriography: follow-up study.
AB  - BACKGROUND: It is important to distinguish small lesions with increased arterial
      perfusion observed by computed tomographic arteriography (CT-A) from
      hepatocellular carcinoma (HCC). However, the clinical characteristics and
      prognosis of such lesions have not been clarified. METHODS: We retrospectively
      examined 200 patients with cirrhosis related to hepatitis C virus (HCV) infection
      who had undergone both CT-A and CT arterioportography between 1995 and 1998, and
      found 80 tiny staining spots (TSS)s, with a diameter of 5-10 mm, by CT-A (35
      patients). The mean TSS observation period was 29.0 months. If the major axis was
      larger than 10 mm and showed a 1.5-fold or more increase, the lesion was regarded
      as tumor growth (TG). The TSS lesions were divided into two groups according to
      whether the patient had or did not have HCC. The prognosis of TSS was classified
      into three groups; HCC-suspected group, nontumor group, and unclassified group,
      in which TG was negative although transcatheter arterial embolization (TAE) had
      been performed. RESULTS: Of the 40 TSSs in 14 patients without HCC, 2 (5%) were
      suspected as HCC. Of the 40 TSSs in 21 patients with HCC, 13 (32.5%) were
      suspected as HCC. There were no significant differences in the size, position,
      and morphology of TSSs among the three prognostic groups. Of the 7 TSSs with a
      high signal intensity on T2-weighted magnetic resonance (MR) images, 5 were in
      the HCC-suspected group. CONCLUSIONS: We recommend early treatment of TSSs
      accompanying HCC or showing features of malignancy at the imaging workup.

PMID- 12424565
TI  - Promoter analysis of human cholecystokinin type-A receptor gene.
AB  - Background. We have previously shown that polymorphism in the promoter region of
      the human cholecystokinin type-A receptor ( CCKAR) gene is a genetic factor
      affecting obesity. However, there have not yet been any reports of analysis of
      the promoter activity of CCKAR genes, and thus almost nothing is known about
      CCKAR transcriptional regulation. Methods. Using STC-1 cells, an enteroendocrine
      tumor cell line, we measured the promoter activity of the human CCKAR gene by a
      transient transfection method. Results. We showed that STC-1 cells expressed
      CCKAR as well as its peptide-ligand, CCK. Analysis of a series of 5'-deleted
      promoter constructs showed that the proximal 622-base region upstream from the
      initiation site, which contained two GC-box motifs, was important as a regulatory
      region for the transcriptional activity. However, no significant differences were
      found for the promoter activities of polymorphic promoter constructs.
      Conclusions. These results suggest that the reported polymorphism may not play a
      role in transcriptional regulation.

PMID- 12424566
TI  - Cysteinyl leukotrienes in the bile of patients with obstructive jaundice.
AB  - BACKGROUND: Cysteinyl leukotrienes (LTs) are potent proinflammatory mediators.
      They are predominantly excreted from blood by hepatobiliary elimination. To
      explore the clinical significance of biliary cysteinyl LTs, we determined their
      concentration changes in bile during treatment in patients with obstructive
      jaundice. METHODS: Bile samples were obtained during endoscopic or transhepatic
      biliary drainage. Leukotrienes C(4), D(4), and E(4) were quantified by two-step
      reversed-phase high-performance liquid chromatography and subsequent
      radioimmunoassay. RESULTS: The increased excretion of cysteinyl LTs (LTC(4) +
      LTD(4) + LTE(4)) decreased between day 1 and 14 after drainage (means, 171 pmol/h
      to 79 pmol/h; P < 0.02). During drainage, the excretion was higher when there was
      additional cholangitis (mean, 225 and 86 pmol/h, with and without cholangitis,
      respectively; P < 0.001). The concentrations of LTD(4) and LTE(4) were also
      higher with additional cholangitis than without (LTD(4), mean 6.0 vs 2.0 nM; P <
      0.05; LTE(4), 6.8 vs 2.4 nM; P < 0.02, respectively). Biliary LTC(4) was detected
      only in patients with cholangitis. The biliary excretion of cysteinyl LTs was
      positively correlated with leukocyte concentration ( r = 0.68; P < 0.005) and C
      reactive protein ( r = 0.73; P < 0.005) in blood. Furthermore, only in the
      absence of cholangitis, the excretion was positively correlated with serum gamma
      glutamyl transferase ( r = 0.76; P < 0.02) and alanine aminotransferase ( r =
      0.72; P < 0.02). CONCLUSIONS: The excretion of biliary cysteinyl LTs increases
      with the severity of cholestasis and hepatic inflammation in patients with
      obstructive jaundice. An additional increase of cysteinyl LTs was observed during
      bacterial cholangitis. The increased biliary excretion of biologically active
      cysteinyl LTs may contribute to the aggravation of cholestasis and inflammatory
      reaction in obstructive jaundice.

PMID- 12424567
TI  - Usefulness of p53 gene mutations in the supernatant of bile for diagnosis of
      biliary tract carcinoma: comparison with K- ras mutation.
AB  - BACKGROUND: The sensitivity of bile cytology for the diagnosis of biliary tract
      carcinoma (BTCa) is still low. In addition, the incidence of detection of genetic
      mutations in the bile of BTCa is not satisfactory yet. To improve the molecular
      diagnosis of BTCa, we analyzed p53 and K- ras mutations in DNA extracted from not
      only the sediment but the supernatant of bile samples. METHODS: Polymerase chain
      reaction-single-strand conformation polymorphism and direct sequencing were used
      for analyses of p53 mutations in exons 5 through 8. K- ras mutations at codon 12
      were examined by mutant allele-specific amplification. RESULTS: In bile
      supernatant from patients with BTCa, p53 and K- ras mutations were detected in
      50.0% (15/30) and 56.7% (17/30) of cases, respectively. The incidence of p53and K
      ras mutations in the sediment was 33.3% and 43.3%, respectively. When a
      combination assay with both genes was used, molecular abnormalities were detected
      in 80.0% of cases, including 3 in which p53 alone was positive. In addition,
      either p53 or K- rasmutations were detected in 12 of 15 (80.0%) cases of BTCa in
      which the cytologic diagnoses were negative. p53 mutations were detected in
      neither supernatant nor sediment in 20 patients with cholelithiasis, although the
      incidence of K- ras mutations in the sediment was 20%. CONCLUSIONS: The incidence
      of p53 and K- ras mutations is higher in the supernatant than in the sediment,
      and simultaneous analyses of p53 and K- ras in the two bile fractions could
      enhance the genetic diagnosis of BTCa. Notably, the specificity of p53 mutations
      for cancer was very high in bile samples, and the sensitivity was also relatively
      high.

PMID- 12424568
TI  - Intestinal cryptosporidiosis as an initial manifestation in a previously healthy
      Japanese patient with AIDS.
AB  - BACKGROUND: Cryptosporidium parvum infection has been recognized as one of the
      pathogens causing severe and persistent diarrhea in immunodeficient patients,
      such as those with AIDS, worldwide. However, in Japan, the frequency of this
      infection has been rare, except for environmental contamination through the water
      supply. In this communication, we describe a Japanese patient with AIDS
      presenting with intestinal Cryptosporidiosis as an initial manifestation.
      METHODS: The oocysts of Cryptosporidium parvum in his stool were detected by the
      Ziehl-Neelsen method and electron microscopy. The antigen-specificity was proved
      by immunostaining, using a fluorescein isothiocyanate (FITC)-labeled monoclonal
      antibody and enzyme-linked immunosorbent assay (ELISA), using Cryptosporidium
      specific antibody. RESULTS: A 28-year-old Japanese homosexual man was admitted to
      our hospital because of severe watery diarrhea of 1-week duration. Numerous
      oocysts of Cryptosporidium parvum were observed in his stool. Cryptosporidium
      parvum antigen was detected in stool samples. Serological examinations revealed
      that anti-HIV-1 antibody was positive, and HIV RNA was positive at a high level.
      He was diagnosed as having AIDS associated with intestinal Cryptosporidiosis. The
      circulating CD4+ T-cell count was 152/microl. His diarrhea was not alleviated by
      administration of loperamide and an ordinary antibiotic agent, but ultimately
      resolved by the administration of the macrolide antibiotic agent, clarithromycin.
      CONCLUSIONS: We emphasize that the presence of Cryptosporidium parvum infection
      should be kept in mind in searching for pathogens causative of severe diarrhea in
      AIDS patients.

PMID- 12424569
TI  - Therapeutic effect of intraarterial prednisolone injection in severe intestinal
      Behcet's disease.
AB  - A 64-year-old woman with severe intestinal Behcet's disease who was unresponsive
      to conventional therapies, including intensive intravenous steroid injections,
      underwent intraarterial steroid injection therapy. After the infusion of
      prednisolone into the mesenteric arteries, her colon ulcers improved markedly,
      and the frequency of bloody stools decreased immediately. The present case
      suggests that intraarterial steroid injection therapy may be potentially useful
      in severe intestinal Behcet's disease.

PMID- 12424570
TI  - Spontaneous regression of focal nodular hyperplasia of the liver.
AB  - Focal nodular hyperplasia (FNH) of the liver is a rare benign lesion that
      probably reflects a local hyperplastic response of hepatocytes to a vascular
      abnormality. Currently, the natural history of the disease remains largely
      unknown. We present a patient with FNH of the liver who was followed up for 4
      years. A 22-year-old woman with a 3-year history of oral contraceptive use was
      referred to our hospital in September 1996 for further examination of a liver
      tumor. A diagnosis of FNH was made using various imaging methods, such as
      ultrasonography, enhanced computed tomography (CT) scanning, MR imaging, and
      hepatic angiography, as well as fine-needle biopsy. A decrease in the size of the
      lesion was observed by enhanced CT scanning during the 4-year observation period.
      In this patient, oral contraceptive use and its discontinuation may have
      influenced the natural history of FNH. The present case suggests that an accurate
      diagnosis is of the utmost importance, and a patient with FNH should be managed
      conservatively rather than by resection, because FNH has the potential for
      spontaneous regression with the discontinuation of oral contraceptives.

PMID- 12424571
TI  - Acute onset of nephrotic syndrome during interferon-alpha retreatment for chronic
      active hepatitis C.
AB  - A 57-year-old woman was scheduled to receive recombinant interferon-alpha
      retreatment for chronic active hepatitis C. During the course of therapy, the
      patient showed rapid onset of oliguria, dizziness, edema, and a pre-shock state.
      She was subsequently admitted to hospital and was diagnosed as having nephrotic
      syndrome. After admission, albumin-dominant proteinuria persisted despite the
      discontinuation of interferon therapy. Light microscopy of a renal needle biopsy
      specimen showed interstitial lymphoid cell infiltration, but no marked changes of
      the glomeruli and no staining for immunoglobulin or complement. Electron
      microscopy showed diffuse effacement of the glomerular epithelial foot processes,
      leading to a diagnosis of minimal change nephrotic syndrome with interstitial
      nephritis. Proteinuria resolved after the initiation of oral prednisolone therapy
      (1 mg/kg per day). The number of patients with chronic hepatitis C requiring
      interferon retreatment is increasing rapidly. We herein report this rare case of
      acute onset of nephrotic syndrome during interferon-alpha retreatment.

PMID- 12424572
TI  - Stage I mantle-cell lymphoma that was difficult to differentiate from abdominal
      tuberculous lymphadenitis and metastatic pancreatic cancer.
AB  - A 62-year-old Japanese man was referred to our hospital because of general
      fatigue. Abdominal ultrasonography and enhanced computed tomography scanning
      revealed many enlarged lymph nodes, mainly around the pancreas tail and the hilus
      of the spleen. Neither blood examination nor gallium scintigraphy revealed any
      abnormalities, whereas the diagnostic tuberculin test was strongly positive.
      Because we could not reach a final diagnosis, an exploratory laparotomy was
      performed. Histopathological examination revealed mantle-cell lymphoma. After
      chemotherapy combined with radiotherapy, the lymph-node swelling had disappeared.
      Herein, we report this case of stage-I mantle cell lymphoma that was difficult to
      differentiate from metastatic pancreatic cancer and abdominal tuberculous
      lymphadenitis.

PMID- 12424573
TI  - Pancreatic T-cell lymphoma with high level of soluble interleukin-2 receptor.
AB  - An 82-year-old man was admitted to hospital with symptoms of abdominal fullness
      and loss of appetite. Abdominal computed tomography (CT) scan and ultrasonography
      showed enlargement of the whole pancreas with para-aortic lymphadenopathy.
      Endoscopic retrograde pancreatography (ERP) showed diffuse narrowing of the main
      pancreatic duct (MPD), and brushing cytology from the MPD was non-neoplastic.
      Differential diagnosis between lymphoma and other exocrine and endocrine
      pancreatic malignancies was needed, and the level of serum soluble interleukin-2
      receptor (17 751 U/ml) was revealed to be significantly high, which was strongly
      suggestive of pancreatic lymphoma. Chemotherapy was refused by the patient's
      family and the patient succumbed after 2 months of conservative follow-up.
      Autopsy revealed diffuse, mixed cell-type, non-Hodgkin's lymphoma of T-cell
      subtype.

PMID- 12424574
TI  - Long-term follow-up of intraductal papillary adenoma of the pancreas.
AB  - Intraductal papillary mucinous tumors of the main pancreatic duct are often
      considered to be premalignant or malignant, and therefore surgical resection is
      recommended. We report two autopsy cases of intraductal papillary mucinous tumor
      of the pancreas following long-term observation. The first patient was an 84-year
      old man with early gastric cancer treated by endoscopic mucosectomy. The second
      patient was a 77-year-old man with hepatocellular carcinoma treated by
      percutaneous pure ethanol injection and transarterial embolization. In both
      patients, endoscopic retrograde pancreatography showed a diffusely dilated main
      pancreatic duct, with intraductal filling defects expressing mucus, as well as
      dilated side branches. Obvious intramural nodules were not detected. Due to their
      advanced age and personal requests, both patients were managed conservatively and
      followed nonoperatively. In the first patient, serial pancreatograms showed
      progression of the pancreatic duct dilatation. Both patients died of gastric
      cancer, the first patient 7(1)/(2) years and the second, 10 years after first
      presentation, respectively. Autopsies revealed extensive intraductal papillary
      adenoma throughout the dilated mucus-filled main pancreatic duct. However, there
      was no evidence of progression to adenocarcinoma. Based on these observations, we
      suggest that, in patients with intraductal papillary mucinous tumor of the
      pancreas without obvious intramural nodules, even if the tumor is in the main
      pancreatic duct, pancreatectomy may not be mandatory, particularly in the
      elderly.

PMID- 12424575
TI  - Contrast-enhanced CT is a good imaging modality for symptomatic inflammatory
      bowel disease.

PMID- 12424576
TI  - Nonocclusive mesenteric ischemia: reality.

PMID- 12424577
TI  - For whom do physicians examine gastric emptying? The actual situation and
      prospects for gastric emptying measurement.

PMID- 12424578
TI  - Microstructures of localized colorectal lesions: three-dimensional representation
      of the crypts.

PMID- 12424579
TI  - Clinical manifestations and diagnosis of invasive aspergillosis in
      immunocompromised children.
AB  - Invasive aspergillosis (IA) is a serious life-threatening complication in
      immunocompromised children. The commonest risk groups are children with acquired
      immunodeficiency syndrome, leukaemia, corticosteroid and other immunosuppressive
      therapy, chronic granulomatous disease and severe combined immunodeficiency as
      well as neonates. The clinical manifestations are heterogeneous and many organ
      systems can be involved. Diagnosis based on the clinical presentation alone is
      cumbersome. Innovative and sensitive laboratory test systems which detect fungal
      antigens or DNA in clinical specimens have been recently developed. Specific
      Aspergillus antibody detection using recombinant antigen technique has also been
      introduced. Although each individual technique has drawbacks, the combined use of
      culture with antigen and antibody ELISA as well as PCR should result in an
      earlier and more definitive diagnosis of IA in children presenting with clinical
      and/or radiological signs of aspergillosis. In high risk children these methods
      are valuable for serial screening and early detection of Aspergillus infection.
      The implementation of accurate diagnostic criteria and standardised diagnostic
      flow charts in children at risk will lead to a better outcome of IA in the
      future. CONCLUSION: definite, well-timed early diagnosis and sufficient therapy
      is elementary for a successful outcome of invasive aspergillosis in
      immunocompromised children. To date, the diagnosis of invasive aspergillosis
      remains a combination of clinical presentation, radiology and microbiological
      tests.

PMID- 12424580
TI  - Acute septicaemic acalculous cholecystitis complicated by empyema caused by
      Salmonella group D in a previously healthy child.
AB  - We describe a rare case of acute acalculous cholecystitis (AC) due to Salmonella
      group D infection in a previously healthy child who developed gall bladder
      empyema and bacteraemia. Salmonella group D was recovered from blood culture, as
      well as cultures of stool, bile and gall bladder wall samples. The patient was
      successfully treated using cholecystectomy in combination with ceftriaxone
      therapy. CONCLUSION: Rapid diagnosis of acute acalculous cholecysitis can reduce
      mortality in this disease.

PMID- 12424581
TI  - Evaluation of oesophageal atresia without fistula by three-dimensional computed
      tomography.
AB  - During the last decade, an increasing number of paediatric surgeons have chosen
      to perform a delayed oesophageal anastomosis for oesophageal atresia (OA) without
      tracheo-oesophageal fistula (TOF). The gap between the two oesophageal pouches is
      an important determinant in the surgical management of these patients. We
      describe a new method using spiral computed tomography (CT) to evaluate the gap
      between the proximal and distal oesophageal pouches. In our last four cases of OA
      without TOF, Stamm gastrostomy was performed soon after birth. At about 4 weeks
      of age, these patients underwent spiral CT with air inflation via the gastrostomy
      feeding tube with 3 mm slice thickness, pitch 1, and reconstruction interval
      every 1.5 mm. A three-dimensional reconstruction was done and measurements of the
      gap between the two segments were recorded. The procedure was repeated at monthly
      intervals until the optimal conditions for surgery were observed. All the babies
      thrived well on gastrostomy feeding. The gap distances were 2.4, 3.8, 4.2 and 5.9
      cm respectively. Delayed primary oesophageal anastomosis was accomplished in
      three cases and gastric transposition was performed in another case at 12, 13, 14
      and 16 weeks of age. The exact anatomical position the operation correlated well
      with the pre-operative three-dimensional CT results. CONCLUSION: this new
      technique is an easy and non-invasive method to assess the long gap in babies
      with oesophageal atresia without tracheo-oesophageal fistula. The radiological
      findings are also consistent with surgical anatomical situation during surgery
      suggesting that this investigation is useful in the pre-operative planning of
      oesophageal anastomosis or replacement.

PMID- 12424582
TI  - Immunogenicity and reactogenicity of a novel hexavalent DTPa-HBV-IPV/Hib vaccine
      compared to separate concomitant injections of DTPa-IPV/Hib and HBV vaccines,
      when administered according to a 3, 5 and 11 month vaccination schedule.
AB  - In an open randomised trial, 312 eligible infants were enrolled to receive either
      a single injection of the hexavalent diphtheria-tetanus-acellular pertussis
      hepatitis B virus-inactivated polio/ Haemophilus influenzae b (DTPa-HBV-IPV/Hib)
      vaccine, or concomitant injections of commercial DTPa-IPV/Hib and HBV vaccines
      (comparator). Vaccines were administered at 3, 5 and 11 months of age. The
      statistical approach for non-inferiority showed that the DTPa-HBV-IPV/Hib vaccine
      was at least as immunogenic as the comparator vaccines in terms of immunogenicity
      of all antigens 1 month after the 2nd dose. Non-inferiority criteria were also
      met immediately before and 1 month after the 3rd dose for all antigens except
      poliovirus type 3 prior to the 3rd dose. The majority of subjects were
      seroprotected against diphtheria, tetanus, polyribosyl-ribitol-phosphate,
      hepatitis B and poliovirus after the 2nd dose and maintained seroprotective
      antibody levels until the 3rd dose. A marked difference was observed in anti-HBs
      antibody geometric mean antibody concentrations (GMCs) at 1 month after the 2nd
      dose (higher GMCs in DTPa-HBV-IPV/Hib group). Reactogenicity (incidence of
      solicited local and general symptoms) was similar between the two study groups
      and no vaccine-related serious adverse events occurred. CONCLUSION: the new
      diphtheria-tetanus-acellular pertussis-hepatitis B virus-inactivated polio/
      Haemophilus influenzae b vaccine administered at 3, 5 and 11 months of age was
      safe and at least as immunogenic as the comparator vaccines thus providing an
      effective and more comfortable option for this infant vaccination schedule.

PMID- 12424583
TI  - The seroepidemiology of primary varicella-zoster virus infection in Flanders
      (Belgium).
AB  - The age-specific seroprevalence of varicella-zoster virus (VZV) antibodies was
      assessed in a sample of the Flemish (Belgian) population. ELISA tests were used
      to analyse 1673 sera from subjects aged 1 to 44 years (October 1999-April 2000).
      Chickenpox infections in Flanders appear to affect children at a younger age than
      in other European countries since 47.37% (95% CI: 37.33-57.41) is already immune
      at 2 years of age. For older age-groups, the prevalence is similar to that of
      most European countries: 80.19% (95% CI: 72.60-87.78) at 5 years, 92.52% (95% CI:
      87.54-97.51) at 9 years and 100%> or =40 years. The accuracy of non-positive
      recollections of varicella histories among Flemish 10 to 17-year olds was
      examined on the basis of a second (residual) serum bank. In this group, VZV
      seroprevalence was almost always 100% (or nearly 100%), irrespective of age,
      degree of reliability (negative or uncertain answers) or level of ascertainment
      (child personally or parents). The limited size of this second data set did not
      allow for an accurate assessment of the negative predictive value of such
      recollections. CONCLUSION: since varicella-zoster virus predominantly affects
      very small children and is generally perceived as benign, the required high
      coverage rate of a universal childhood varicella vaccination programme may be
      hard to attain. Adolescent strategies can minimise the population risks involved
      but the accuracy of non positive antecedents of chickenpox needs to be documented
      to assess the efficiency of such strategies.

PMID- 12424584
TI  - Does critical incident reporting contribute to medication error prevention?
AB  - Medication-related critical incidents (CIs) comprise harmful and potentially
      harmful events. The aim of CI monitoring is quality improvement through system
      changes. In a prospective survey, we analysed our drug-related CIs of the year
      2001 with an emphasis on how they contributed to system changes. A voluntary,
      anonymous, non-punitive CI reporting was used. The study was performed in a
      multidisciplinary, 23-bed, neonatal-paediatric intensive care unit (ICU). CI
      severity was graded: minor (no interventions required), moderate (requiring
      routine therapy, available outside the ICU), major (need for therapeutic
      interventions specific to the ICU). There were 284 drug-related CIs, 76% (95%
      confidence interval 71%-81%) of minor, 19% of moderate and 5% of major severity.
      A total of 24 CIs were potentially life threatening (if not detected). Some 27%
      of CIs were intercepted, 17% before preparation and 10% before administration of
      the drug to the patient. There was a negative correlation between median delay
      (from CI to detection) and mean severity of the different drug classes involved
      (P = 0.027). As to the impact on quality, 46 CIs were followed by system changes
      and 63% (95% confidence interval 49%-77%) of these CIs were of minor severity.
      Examples of system changes are: double checking for potentially harmful drugs,
      standardised prescription form and contact to the national drug control agency
      regarding misleading drug labels. CONCLUSION: most of the system changes were
      based on minor critical incidents which were often detected only after a longer
      period of time. This shows the value of our "low-threshold" critical incident
      monitoring. Repeated checks along the drug delivery process (prescription,
      preparation, administration) are an important means to reduce adverse drug
      events.

PMID- 12424585
TI  - Glucagon therapy as a possible cause of erythema necrolyticum migrans in two
      neonates with persistent hyperinsulinaemic hypoglycaemia.
AB  - Erythema necrolyticum migrans (ENM) usually presents as a cutaneous
      paraneoplastic phenomenon which is in most cases associated with a glucagon
      producing tumour. Here it is for the first time described as a side-effect of
      glucagon treatment in persistent hyperinsulinaemic hypoglycaemia of infancy
      (PHHI). In both patients, the skin lesions disappeared after discontinuation of
      glucagon administration. In the first child the erythema resolved without
      scarring within 10 days after glucagon was substituted with other medication
      while in the second patient healing followed subtotal pancreatectomy which
      rendered glucagon infusion unnecessary. Initially the clinical resemblance to
      atopic dermatitis is prone to cause diagnostic errors, especially in this age
      group. CONCLUSION: erythema necrolyticum migrans should be considered as a
      differential diagnosis in patients who develop erythematosquamous skin lesions
      under glucagon treatment.

PMID- 12424586
TI  - Polymorphisms of surfactant protein B encoding gene: modifiers of the course of
      neonatal respiratory distress syndrome?
AB  - Surfactant protein B (SP-B) is a lipophilic protein and plays a major role in
      lung mechanics. Polymorphisms of surfactant protein A, another component of the
      surfactant system, have been previously described to be a risk factor for
      respiratory distress syndrome (RDS) and bronchopulmonary dysplasia (BPD) in
      preterms. The aim of this prospective study was to determine whether
      polymorphisms within intron 4 of the SP-B gene are related to the incidence,
      severity and complications of RDS in Caucasian newborns. In order to identify SP
      B intron 4 polymorphisms, we analysed genomic DNA by means of polymerase chain
      reaction, fragment length and sequence analysis in 140 preterms and 58 healthy
      term neonates. The frequency of intron 4 variations did not differ between
      preterms and terms. A total of 111 preterms with the intron 4 wild type (group 1)
      and 29 preterms carrying the genetic variations (group 2) did not differ in
      gestational age, gender distribution and birth weight. Compared to group 1, the
      overall incidence of RDS (75.7% versus 93.1%, P < 0.05), the frequency of severe
      RDS (28.4% versus 55.2%, P < 0.01) and BPD (21.6% versus 48.3%, P < 0.01) were
      all higher in group 2. The median duration of oxygen dependency (4 days versus 17
      days, P < 0.05) and the need for surfactant administration were also higher in
      group 2 than in group 1 (43.2% versus 72.4%, P < 0.01). Duration of mechanical
      ventilation and rate of chronic lung disease at 36 weeks were comparable in both
      groups. CONCLUSION: we suggest that polymorphisms in intron 4 of the surfactant
      protein B gene independently modify the course of neonatal respiratory distress
      syndrome.

PMID- 12424587
TI  - Neonatal intrahepatic cholestasis caused by citrin deficiency: severe hepatic
      dysfunction in an infant requiring liver transplantation.
AB  - Adult-onset type 2 citrullinaemia (CTLN2) is caused by a deficiency of the citrin
      protein encoded by the SLC25A13 gene. Citrin, an aspartate glutamate carrier in
      mitochondria, is an essential component of the malate-aspartate NADH shuttle.
      Recently, citrin deficiency has been reported to manifest as neonatal
      intrahepatic cholestasis. We report here five cases with neonatal intrahepatic
      cholestasis caused by citrin deficiency. Genetic diagnosis revealed compound
      heterozygotes of 851del4/IVS11 + 1G-->A in two patients, IVS11 + 1G-->A/E601X,
      and IVS11 + 1G-->A/unknown in each one patient and homozygote for S225X in one
      patient. All cases revealed high levels of alpha-fetoprotein, which are not
      observed in CTLN2 patients. The condition was self-limiting and spontaneously
      disappeared after 5-7 months of age in four patients. However, one patient
      developed hepatic dysfunction from the age of 6 months and required a living
      related liver transplantation at the age of 10 months. The patient showed
      complete recovery after transplantation, and now at the age of 3 years, shows
      normal growth and mental development. CONCLUSION: we report the first case of
      neonatal intrahepatic cholestasis caused by citrin deficiency with severe hepatic
      dysfunction requiring a living-related liver transplantation. Patients with this
      disorder should be followed up carefully, even during infancy.

PMID- 12424588
TI  - Transient proteinuria in an infant born to a mother with HELLP syndrome.
AB  - The syndrome of haemolysis, elevated liver enzymes and low platelet count (HELLP
      syndrome) is a severe form of pre-eclampsia and eclampsia associated with poor
      maternal and neonatal outcome. We report here the case of an infant born to a
      mother with HELLP syndrome. The infant was initially diagnosed as having
      nephrotic syndrome but after a follow-up period of 25 days proteinuria and oedema
      had disappeared. CONCLUSION: to our knowledge, transient proteinuria with
      maternal HELLP syndrome has not been previously described in the literature.

PMID- 12424589
TI  - Severe Fusobacteria infections (Lemierre syndrome) in two boys.
AB  - Abscess formation is a rare cause of febrile illness in childhood but always has
      to be considered in such clinical presentations. Belonging to the resident flora
      of the oropharyngeal region, Fusobacteria are known to cause local infections;
      from here they may extend to other sites via the bloodstream or are aspirated
      into the lung (Lemierre disease). We report on two boys with Lemierre disease due
      to infection by Fusobacteria in monoculture causing two different clinical
      phenotypes. Case 1 presented with a large subphrenic abscess and pneumonic
      infiltration of the right middle lobe. Primary focus of infection was periodontal
      disease. Case 2 presented with a life-threatening septicaemia due to a
      retropharyngeal abscess and perforated otitis media followed by osteomyelitis of
      the atlas and thrombosis of the left sigmoid sinus and internal jugular vein.
      CONCLUSION: Fusobacteria should be considered in any abscess formation in
      children. A thorough examination of the oropharyngeal region as a possible site
      of primary manifestation is mandatory.

PMID- 12424590
TI  - Cleidocranial dysplasia with decreased bone density and biochemical findings of
      hypophosphatasia.
AB  - Cleidocranial dysplasia (CCD; MIM 119600) is an autosomal dominant skeletal
      dysplasia characterised by hypoplastic clavicles, patent fontanelles, short
      stature, tooth anomalies and other variable skeletal changes. Different mutations
      of the RUNX2/CBFA1 gene (MIM 600211) have been detected in patients with CCD. We
      investigated a mother and daughter with features of CCD presenting with reduced
      plasma alkaline phosphatase activity, increased urinary phosphoethanolamine
      excretion and decreased bone density. The latter findings were suggestive of
      hypophophatasia but mutation analysis showed no mutation in the tissue
      nonspecific alkaline phosphatase gene (TNSALP; MIM 171760). However, a
      heterozygous mutation (Arg169Pro caused by nucleotide change 506G > C) was
      detected in the RUNX2 gene. Metabolic alterations gradually improved in both
      mother and daughter but bone-specific alkaline phosphatase remained low (less
      than 30% of normal) and mild phosphoethanolaminuria persisted. Recent studies in
      the Cbfa1 knock-out mouse showed decreased expression of alkaline phosphatase in
      differentiating bone. CONCLUSION: we suggest that the observed metabolic
      alterations are secondary to the RUNX2 gene mutation affecting early bone
      maturation and turnover. This is the first description of biochemical findings of
      hypophosphatasia in patients with cleidocranial dysplasia.

PMID- 12424591
TI  - Severe cleidocranial dysplasia can mimic hypophosphatasia.
AB  - Cleidocranial dysplasia (OMIM 119600) is a skeletal dysplasia caused by mutations
      in the bone/cartilage specific osteoblast transcription factor RUNX2 gene. It is
      characterised by macrocephaly with persistently open sutures, absent or
      hypoplastic clavicles, dental anomalies, and delayed ossification of the pubic
      bones. A few patients have been reported with recurrent fractures or osteoporosis
      but these are not considered features of the disease. We report a patient with
      classical findings of cleidocranial dysplasia: markedly hypoplastic clavicles,
      delayed ossification of the pubic rami, multiple pseudoepiphyses of the
      metacarpals, and dental anomalies including delayed eruption of permanent
      dentition and multiple supernumerary teeth. The patient also had radiographic and
      biochemical features of hypophosphatasia (OMIM 241500, 146300) and was initially
      diagnosed with this condition. Serum alkaline phosphatase activity has been
      consistently reduced and specific enzyme substrates, phosphoethanolamine and
      pyridoxal-5'-phosphate, have been elevated. However, no mutations were found on
      direct sequencing of the tissue-nonspecific alkaline phosphatase ( TNSALP) gene
      using a protocol that detects up to 94% of all mutations causing
      hypophosphatasia. CONCLUSION: We propose that a subset of patients with
      cleidocranial dysplasia have features of secondary hypophosphatasia due to
      decreased expression of the tissue-nonspecific alkaline phosphatase gene.

PMID- 12424592
TI  - Temporary closure of the abdominal wall (laparostomy).
AB  - The definitive closure of the abdominal wall, i.e., a closure of the fascial
      layer and skin may not be favorable in the treatment of numerous surgical
      conditions, e.g., peritonitis, trauma, or mesenteric ischemia. In these cases,
      the abdominal wall is temporarily closed, and a laparostomy is created to
      facilitate re-exploration or to prevent abdominal compartment syndrome. Regarding
      the technique and material used for the temporary closure, no prospective
      randomized data exists, but mesh materials are commonly used. They provide
      drainage of infectious material, permit visual control of the underlying viscera,
      facilitate access to the abdominal wall, preserve the fascial margin, enable
      healing by secondary intention, and allow mobilization of the patient. In the
      case of decreasing intra-abdominal pressure, meshes can be trimmed to centralize
      the rectus muscle and to facilitate definitive closure. Non-absorbable meshes
      have been frequently reported to cause enteric fistulae and persistent infection
      necessitating mesh explantation. While these infectious complications appear to
      occur less frequently with the use of absorbable materials, these meshes will
      finally lead to an incisional hernia, requiring repair with non-absorbable mesh
      after a period of 6-12 months. Nevertheless, in the complex situation requiring a
      temporary abdominal wall closure, use of absorbable mesh material is common and
      represents the state of the art.

PMID- 12424593
TI  - The effect of diaphragmatic stressors on recurrent hiatal hernia.
AB  - Hiatal disruption is one of the common mechanisms of failure after Nissen
      fundoplication. We investigated the correlation between various diaphragm
      stressors and disruption of the diaphragmatic closure. Thirty-seven patients with
      a hiatal hernia recurrence of 2 cm or greater, as proven by esophagram,
      endoscopy, or operative findings, were included. A retrospective analysis was
      conducted utilizing a standardized diaphragm stressor questionnaire for the study
      group and a control group of 50 patients without hiatal hernia recurrence.
      Logistic regression was used to determine the significant predictors of hiatal
      hernia recurrence. Three predictors emerged in the final model: weight lifting (P
      < 0.0174), vomiting (P < 0.0313) and hiccoughing (P < 0.2472). Of these, only
      vomiting and weight lifting were significant. The odds ratio for weight lifting
      is OR = 3.662 (95% CI: 1.256-10.676), and for vomiting it is OR = 4.938 (95% CI:
      1.154-21.126). Vomiting or heavy weight lifting is a significant predictor of
      hiatal hernia recurrence.

PMID- 12424594
TI  - Spigelian hernia: bibliographical study and presentation of a series of 28
      patients.
AB  - Spigelian hernias are rare defects of the abdominal wall. Our aim is to analyse
      the bibliography and present a series of 28 patients. A Medline bibliographical
      study was performed between 1970 and 2000 with analysis of the number of cases,
      series, ratio of cases to year and type of journal. We also present a personal
      study and analyse epidemiological, diagnostic, and treatment factors. There are
      159 articles, 479 cases, and 19 series of more than five patients published in 85
      journals (42.3% medical). Our diagnosis was preoperative in 75%, and programmed
      surgery was 3.6 times more common than emergency surgery. We found a significant
      relationship between hospital stay and type of surgery (P < 0.02) and surgical
      technique used (P < 0.001). We found that spigelian hernias have a
      multidisciplinary interest; they are given almost equal treatment in medical and
      surgical journals; preoperative diagnosis can be established in 75% of cases; and
      the best results are offered by the extraperitoneal laparoscopic approach.

PMID- 12424595
TI  - Preliminary experience with new bioactive prosthetic material for repair of
      hernias in infected fields.
AB  - Surgisis (Cook Surgical, Bloomington, Ind., USA) is a new four-ply bioactive,
      prosthetic mesh for hernia repair derived from porcine small-intestinal
      submucosa. It is a naturally occurring extracellular matrix which is easily
      absorbed, supports early and abundant new vessel growth, and serves as a template
      for the constructive remodeling of many tissues. As such, we believe that
      Surgisis mesh is ideal for use in contaminated or potentially contaminated fields
      in which ventral, incisional, or inguinal hernia repairs are required. From
      November 2000 through May 2002, 25 patients (11 male, 14 female) underwent
      placement of Surgisis mesh for a variety of different hernia repairs. A total of
      25 hernia repairs were performed in our patient population. Fourteen procedures
      (56%) were performed in a potentially contaminated setting (i.e. with
      incarcerated/strangulated bowel within the hernia or coincident with a
      laparoscopic cholecystectomy/colectomy). Eleven repairs (44%) were performed in a
      grossly contaminated field, including one in which an infected polypropylene mesh
      from a previous inguinal hernia repair was replaced with Surgisis and one in
      which necrotic bowel was discovered within the hernial sac. Median follow-up was
      15 months with a range of 1-20 months. Of the 25 total repairs, there was one
      wound infection complicated by enterocutaneous fistula in a patient originally
      operated on for ischemic bowel. The fistula was in a location independent of the
      Surgisis mesh. There were no mesh-related complications or recurrent hernias in
      our early postoperative follow-up period. Surgisis mesh appears to be a promising
      new prosthetic material for hernia repair, especially in contaminated or
      potentially contaminated fields. Obviously, long-term follow-up is still
      required.

PMID- 12424596
TI  - Is prosthetic umbilical hernia repair bound to replace primary herniorrhaphy in
      the adult patient?
AB  - Given the outstanding outcome that prosthetic repair has recently achieved in the
      repair of inguinal hernia, we wonder whether it should be implemented as the gold
      standard technique for umbilical hernia repair. We report on 213 adult patients
      who underwent surgery for umbilical hernia at our Day Surgery Unit from June 1992
      to January 1998. Criteria for exclusion included problematic social and family
      environment and ASA IV status. A polypropylene plug was placed in small umbilical
      defects, whereas large defects (> 3 cm in diameter) were repaired with a
      polypropylene mesh. The mean follow-up was 64 months. The mean age was 57.1
      years, with females accounting for the majority (57.8%). Most patients (88.3%)
      were classified as ASA I-II. With regard to the hernia size, 143 patients (67.1%)
      presented with small defects (< 3 cm). The anaesthetic technique of choice was
      local plus sedation. Reported complications included seroma (5.6%), haematoma
      (2.3%), wound infection (1.4%), and intolerance to prosthesis (0.95%), the last
      causing recurrence. The overall recurrence rate at a mean follow-up of 64 months
      was 0.95%. Prosthetic umbilical hernia repair can safely be performed in adults,
      and the rate of recurrence in this study is low in comparison to primary tissue
      repair.

PMID- 12424597
TI  - Chronic postherniorrhaphy pain--a call for uniform assessment.
AB  - The reported incidence of chronic postherniorrhaphy pain is estimated to be 10
      15% and therefore has considerable socio-economic consequences. Interpretation of
      available data regarding pathogenesis, relation to surgical techniques, and
      postoperative pain treatment is hindered by differences in the description and
      definition of postherniorrhaphy pain. We propose a scheme for uniform assessment
      of chronic postherniorrhaphy pain in order to facilitate interpretation of future
      studies.

PMID- 12424598
TI  - Laparoscopic ventral hernia repair during the learning curve.
AB  - Large series of laparoscopic ventral hernia repair have shown excellent results.
      However, published comparative studies have had conflicting outcomes. We
      retrospectively reviewed the first 29 laparoscopic ventral hernia repairs
      performed at a VA Medical Center from January 2000 to June 2001. The outcome was
      compared to that of open repairs performed during the same time period. Outcomes
      between the groups were similar in all respects, except for the length of stay.
      The conversion rate for the laparoscopic approach was 13.8%. There was one death
      in the laparoscopic group due to an unrecognized enterotomy. There were three
      recurrences in the open group and one in the laparoscopic group with a mean
      follow up of 13 months. In our series, laparoscopic hernia repair resulted in a
      shorter hospital stay but no other significant benefits, along with a risk of
      missed enterotomy. The risk-benefit ratio for this procedure may be high during
      the learning curve.

PMID- 12424599
TI  - Postoperative perineal hernia.
AB  - Large perineal hernia is an uncommon complication following abdominoperineal
      resection of the rectum, but it does present a difficult surgical dilemma. Repair
      of this hernia is a challenging surgical problem. Various methods of repair have
      been proposed and include an abdominal, perineal, or combined abdominoperineal
      approach to the hernia. This report describes a patient with a large perineal
      hernia after an abdominoperineal resection. The spectrum of perineal hernias, the
      aetiology, and the different techniques of surgical repair are discussed.

PMID- 12424600
TI  - Spigelian hernia in a child: case report and review of the literature.
AB  - Spigelian hernias (SHs) are rarely observed among children. The diagnosis is not
      difficult to make once it has been considered. The condition requires a high
      index of suspicion because of its high potential for life-threatening
      complications. A 12-year-old boy underwent open appendectomy for presumed acute
      appendicitis. A normal appendix found at laparotomy suggested another etiology
      for the acute abdomen. Incarceration of the greater omentum in a spigelian hernia
      was found, and the hernia repaired. The repair of pediatric SH is straightforward
      and utilizes endogenous tissues. Patients should be followed up for as long as
      possible to develop data on the durability of the repair technique selected.

PMID- 12424601
TI  - Management of chronic postoperative pain following incisional hernia repair with
      Composix mesh: a report of two cases.
AB  - There are new prosthetic biomaterials that are used to repair various defects in
      the abdominal wall. These have been developed within the last several years. The
      results of many of these products are not yet available. We report on two
      patients who developed chronic-pain syndromes that could only be related to the
      use of Composix mesh. This entity may become more conspicuous in the future,
      thereby presenting the surgeon with difficulty in approaching this new and
      difficult problem. We believe that shrinkage of the prosthesis was responsible
      for the pain. Both of these patients responded favorably to resection of the mesh
      by the open or laparoscopic technique. This was followed by repair of the fascial
      defect with DualMesh by the open or laparoscopic method. We were successful in
      the achievement of the relief of the pain and the repair of the hernia in both
      cases. We believe that this entity can be treated successfully by this approach.
      The laparoscopic method is favored.

PMID- 12424602
TI  - William James Lytle: a historical review.

PMID- 12424605
TI  - Neonatal necrotizing enterocolitis: clinical considerations and pathogenetic
      concepts.
AB  - Necrotizing enterocolitis (NEC), a disease affecting predominantly premature
      infants, is a leading cause of morbidity and mortality in neonatal intensive care
      units. Although several predisposing factors have been identified, such as
      prematurity, enteral feeding, and infection, its pathogenesis remains elusive. In
      the past 20 years, we have established several animal models of NEC in rats and
      found several endogenous mediators, especially platelet-activating factor (PAF),
      which may play a pivotal role in NEC. Injection of PAF induces intestinal
      necrosis, and PAF antagonists prevent the bowel injury induced by bacterial
      endotoxin, hypoxia, or challenge with tumor necrosis factor-a (TNF) plus
      endotoxin in adult rats. The same is true for lesions induced by hypoxia and
      enteral feeding in neonatal animals. Human patients with NEC show high levels of
      PAF and decreased plasma PAF-acetylhydrolase, the enzyme degrading PAF. The
      initial event in our experimental models of NEC is probably polymorphonuclear
      leukocyte (PMN) activation and adhesion to venules in the intestine, which
      initiates a local inflammatory reaction involving proinflammatory mediators
      including TNF, complement, prostaglandins, and leukotriene C4. Subsequent
      norepinephrine release and mesenteric vasoconstriction result in splanchnic
      ischemia and reperfusion. Bacterial products (e.g., endotoxin) enter the
      intestinal tissue during local mucosal barrier breakdown, and endotoxin
      synergizes with PAF to amplify the inflammation. Reactive oxygen species produced
      by the activated leukocytes and by intestinal epithelial xanthine oxidase may be
      the final pathway for tissue injury. Protective mechanisms include nitric oxide
      produced by the constitutive (mainly neuronal) nitric oxide synthase, and
      indigenous probiotics such as Bifidobacteria infantis. The former maintains
      intestinal perfusion and the integrity of the mucosal barrier, and the latter
      keep virulent bacteria in check. The development of tissue injury depends on the
      balance between injurious and protective mechanisms.

PMID- 12424608
TI  - A story of mice and men.

PMID- 12424609
TI  - Cytosine deaminase and thymidine kinase gene therapy in a Dunning rat prostate
      tumour model: absence of bystander effects and characterisation of 5
      fluorocytosine metabolism with 19F-NMR spectroscopy.
AB  - The rat prostate tumour cell line R3327 AT-1 was transfected with a gene coding
      for a fusion protein comprised of cytosine deaminase (CD from E. coli) and
      thymidine kinase (TK from Herpes simplex virus, HSV-1). The resulting AT
      1/CDglyTK cell line was sensitive to the prodrug 5-fluorocytosine (IC(50) = 78
      microM, 96-h incubation) via CD and to ganciclovir (GCV, IC(50) = 1 microM, 96 h)
      via TK. Subcutaneous tumours generated from 100% CDglyTK(+) cells responded well
      to 5-FC therapy (500 mg/kg, i.p., 14 daily treatments, four out of seven animals
      in remission) and to GCV therapy (30 mg/kg, i.p., 14 daily treatments, five of
      six animals in remission). However, experiments with mixtures of CDglyTK(+) and
      CDglyTK(-) cells showed low levels of connexins (intercellular gap junctions) and
      no bystander effect for nontransfected cells using either 5-FC or GCV therapy.
      Furthermore, (19)F-NMR spectroscopy showed that incubation of cultured CDglyTK(+)
      cells with 774 microM 5-FC for 16 h resulted in the following intracellular
      concentrations: 5-FC = 314 microM, 5-FU = 52 microM, cytotoxic fluoronucleotides
      = 163 microM; extracellular 5-FU reached only 6.4 microM. Thus, in this model
      system intracellular trapping of 5-FU (slow export) contributes to the failure of
      the CD/5-FC bystander effect via an extracellular route.

PMID- 12424610
TI  - Adeno-associated virus vector-mediated gene transfer into dystrophin-deficient
      skeletal muscles evokes enhanced immune response against the transgene product.
AB  - Duchenne muscular dystrophy (DMD) is an X-linked, lethal muscular disorder caused
      by a defect in the DMD gene. AAV vector-mediated micro-dystrophin cDNA transfer
      is an attractive approach to treatment of DMD. To establish effective gene
      transfer into skeletal muscle, we examined the transduction efficiency of an AAV
      vector in skeletal muscles of dystrophin-deficient mdx mice. When an AAV vector
      encoding the LacZ gene driven by a CMV promoter (AAV-CMVLacZ) was introduced,
      beta-galactosidase expression markedly decreased in mdx muscle 4 weeks after
      injection due to immune responses against the transgene product. We also injected
      AAV-CMVLacZ into skeletal muscles of mini-dystrophin-transgenic mdx mice
      (CVBA3'), which show ameliorated phenotypes without overt signs of muscle
      degeneration. AAV vector administration, however, evoked substantial immune
      responses in CVBA3' muscle. Importantly, AAV vector using muscle-specific MCK
      promoter also elicited responses in mdx muscle, but at a considerably later
      period. These results suggested that neo-antigens introduced by AAV vectors could
      evoke immune reactions in mdx muscle, since increased permeability allowed a
      leakage of neo-antigens from the dystrophin-deficient sarcolemma of muscle
      fibers. However, resident antigen-presenting cells, such as myoblasts, myotubes
      and regenerating immature myofibers, might also play a role in the immune
      response.

PMID- 12424611
TI  - Prostate targeting: PSP94 gene promoter/enhancer region directed prostate tissue
      specific expression in a transgenic mouse prostate cancer model.
AB  - To date, only a few prostate-specific vector genes have been tested for prostate
      targeting in gene therapy of prostate cancer (CaP). Current clinical trials of
      gene therapy of CaP utilize the only two available vector genes with a
      combination of a rat probasin promoter and a human PSA promoter sequence in an
      adenovirus vector to target CaP. There is an urgent need to establish additional
      vector gene systems to sustain and propagate the current research. Since PSP94
      (prostate secretory protein of 94 amino acids) is one of the three most abundant
      proteins secreted from the human prostate and is generally considered to be
      prostate tissue-specific in both human and rodents, we performed a transgenic
      experiment to assess the promoter/enhancer region of PSP94 gene-directed prostate
      targeting. Firstly, a series of progressive deletion mutants of a 3.84 kb PSP94
      gene promoter/enhancer region (including parts of the intron 1 sequence) linked
      with a reporter LacZ gene was constructed and assessed in vitro in cell culture.
      Next, transgenic mice were generated with two transgene constructs using the SV40
      early region (Tag oncogene) as a selection marker. PSP94 gene promoter/enhancer
      region-directed SV40 Tag expression specifically in the mouse was demonstrated in
      three breeding lines (A, B, C, n = 374) by immunohistochemistry staining of Tag
      expression. Specific targeting to the prostate in the PSP94 gene-directed
      transgenic CaP model was characterized histologically by correlation of SV40 Tag
      induced tumorigenesis (tumor grading) with puberty and age (10-32 weeks).
      Prostatic hyperplasia was observed as early as 10 weeks of age, with subsequent
      emergence of prostatic intraepithelial neoplasia (PIN) and eventually high grade
      carcinoma in the prostate. The PSP94 transgenic mouse CaP model was further
      characterized by its tumor progression and metastatic tendency at 20 weeks of age
      and also by its responsiveness and refractoriness to androgen manipulation. This
      study indicates that the PSP94 gene promoter/enhancer has the potential for
      prostate specific targeting and may ultimately be of use in gene therapy of CaP.

PMID- 12424612
TI  - A novel strategy for the generation of angiostatic kringle regions from a
      precursor derived from plasminogen.
AB  - In this study we have explored the feasibility of generating angiostatin by
      incorporating an endoproteolytic furin cleavage site into plasminogen to allow
      conversion of the precursor molecule into an angiostatic active K1-3 fragment. We
      show that secretable angiostatin can be successfully generated from cells
      infected with adenovirus carrying the furin-mutated plasminogen (AdmuthPlgK3).
      Supernatant from cells transduced with AdmuthPlagK3 inhibits tube formation and
      proliferation and migration of human umbilical vein endothelial cells with an
      efficiency similar to that of supernatant from cells infected with adenovirus
      expressing kringle 1-3 of plasminogen (AdK1-3). Administration of AdmuthPlgK3 and
      AdK1-3 in mice results in significantly decreased endothelial cell infiltration
      in VEGF-embedded Matrigel plugs. Treatment with AdmuthPlgK3 and AdK1-3 exerts
      strong antitumoral effect in models of hepatocellular carcinoma and Lewis lung
      cancer. This antitumor effect was associated with decreased microvessel density
      in the tumors. Taken together, our data demonstrate that angiostatin endowed with
      strong antiangiogenic and antitumor effects can be released from a furin-mutated
      plasminogen acting as a precursor. This strategy may have potential to develop
      angiostatic anti-cancer therapies.

PMID- 12424613
TI  - Novel PDGFbetaR antisense encapsulated in polymeric nanospheres for the treatment
      of restenosis.
AB  - Nanospheres composed of the biocompatible and biodegradable polymer, poly-DL
      lactide/glycolide and containing platelet-derived growth factor beta-receptor
      antisense (PDGFbetaR-AS) have been formulated and examined in vitro and in vivo
      in balloon-injured rat restenosis model. The nanospheres (approximately 300 nm)
      of homogenous size distribution exhibited high encapsulation efficiency (81%),
      and a sustained release of PDGFbetaR-AS (phosphorothioated). Cell internalization
      was visualized, and the inhibitory effect on SMC was observed. Partially
      phosphorothioated antisense sequences were found to be more specific than the
      fully phosphorothioated analogs. A significant antirestenotic effect of the naked
      AS sequence and the AS-NP (nanoparticles) was observed in the rat carotid in vivo
      model. The extent of mean neointimal formation 14 days after injection of AS-NP,
      measured as a percentage of luminal stenosis, was 32.21 +/- 4.75% in comparison
      to 54.89 +/- 8.84 and 53.84 +/- 5.58% in the blank-NP and SC-NP groups,
      respectively. It is concluded that PLGA nanospheres containing phosphorothioated
      oligodeoxynucleotide antisense could serve as an effective gene delivery systems
      for the treatment of restenosis.

PMID- 12424614
TI  - Muscle-derived cell-mediated ex vivo gene therapy for urological dysfunction.
AB  - We have tested the feasibility of muscle-based gene therapy and tissue
      engineering for urological dysfunction using highly purified muscle-derived cells
      (MDC) that display stem cell characteristics. We then explored the potential use
      of these MDC as an alternative therapy for the treatment of impaired detrusor
      contractility. The MDC were genetically engineered to express the gene encoding
      beta-galactosidase and injected into the bladder walls of SCID mice. The injected
      bladders were harvested at various time-points after injection and assayed for
      beta-galactosidase activity; the presence of myofibers within the injected tissue
      was determined by detection of fast myosin heavy chain isoform (MyHCs). We have
      demonstrated that the injected MDC are capable of not only surviving in the lower
      urinary tract, but also improving the contractility of the bladder following an
      induced injury. Two potential mechanisms can be used to explain this finding.
      First, we have observed that some of the beta-galactosidase-expressing cells
      expressed alpha-smooth muscle actin, suggesting a differentiation into smooth
      muscle. Second, a stain for acetylcholine receptors (AChRs), which identifies the
      location of neuromuscular junctions, revealed that the myofibers derived from the
      doner cells became innervated into the bladder as early as 2 weeks after
      injection. These results suggest that gene therapy and tissue engineering based
      on MDC potentially can be used for urological dysfunction.

PMID- 12424615
TI  - Polyethylenimine-mediated cellular uptake, nucleus trafficking and expression of
      cytokine plasmid DNA.
AB  - Although polyethylenimine (PEI) has been widely used as a nonviral vector, there
      is little mechanistic understanding on PEI-mediated delivery. Here, we studied
      whether the expression of murine interleukin-2 (mIL-2) plasmids could be improved
      by complexation with PEI at various N/P ratios, and whether the cellular uptake,
      nuclear translocation, and retention of plasmids could be affected by the N/P
      ratios. Compared with the naked mIL-2, PEI/mIL-2 complexes showed at least two
      orders of magnitude higher expression at Raw264 cells in the N/P ratio-dependent
      manner. PEI-mediated cellular uptake and nuclear trafficking of plasmids,
      quantitated by competitive polymerase chain reaction, also depended on the N/P
      ratios showing the highest cell and nuclear levels of plasmids at 10/1. The
      higher cellular levels of plasmid DNA after PEI-mediated delivery were also
      observed in other cell lines. Unlike naked plasmids, PEI/mIL-2 complexes (N/P
      ratios >/=4/1) showed prolonged cellular and nuclear retention of mIL-2 plasmids.
      The nuclear translocation and higher cellular level of plasmids given in PEI
      complexes were similarly observed by fluorescence microscopy. Moreover, PEI/mIL-2
      complexes revealed high stability against DNase I, partly explaining the
      prolonged subcellular retention. These results indicate that the expression of
      plasmid mIL-2 might be highly enhanced by complexation with PEI and that such
      increased expression could be attributed by the higher cellular uptake, nuclear
      translocation and prolonged retention.

PMID- 12424616
TI  - A novel 'sort-suicide' fusion gene vector for T cell manipulation.
AB  - Retroviral suicide gene vectors have successfully been used in clinical studies
      to improve the safety of adoptive immunotherapy with allogeneic T lymphocytes in
      the treatment of malignant and viral diseases. At the same time these studies
      have revealed several problems that are yet to be resolved including impaired T
      cell function due to long ex vivo culture. Here we present new retroviral vectors
      co-expressing truncated CD34, a gene transfer marker which ensures rapid
      enrichment of transduced cells using commercially available GMP-approved devices,
      and a splice-corrected variant of Herpes simplex virus thymidine kinase (scHSVtk)
      which confers high sensitivity to the prodrug ganciclovir. We show that a
      retroviral hybrid vector, MP71, based on the myeloproliferative sarcoma virus
      (MPSV) and the murine embryonic stem cell virus (MESV), encoding a tCD34/scHSVtk
      fusion protein mediates high expression of the 'sort-suicide' selection marker,
      thereby allowing for highly efficient purification and selective elimination of
      transduced cells.

PMID- 12424617
TI  - Laser fluorescence bronchoscopy for detection of fluorescent reporter genes in
      airway epithelia.
AB  - Current methods for detecting successful gene transfer to airway epithelia
      involve obtaining a sample of the target tissue. This may affect the longevity of
      expression of the transgene under evaluation. We describe a laser fluorescence
      bronchoscopic system that can detect the expression of the fluorescent protein,
      green fluorescence protein (GFP), in the airway of monkeys that have been
      transfected with adenovirus, without the need for obtaining tissue. This
      technique will have applications in pre-clinical and clinical studies of gene
      transfer to airway epithelia and other surface epithelia accessible by endoscopy.

PMID- 12424619
TI  - Genetic regulation of host responses to Salmonella infection in mice.
AB  - Salmonella spp are Gram-negative bacteria capable of infecting a wide range of
      host species, including humans, domesticated and wild mammals, reptiles, birds
      and insects. The outcome of an encounter between Salmonella and its host is
      dependent upon multiple factors including the host genetic background. To
      facilitate the study of the genetic factors involved in resistance to this
      pathogen, mouse models of Salmonella infection have been developed and studied
      for years, allowing identification of several genes and pathways that may
      influence the disease outcome. In this review, we will cover some of the genes
      involved in mouse resistance to Salmonella that were identified through the study
      of congenic mouse strains, cloning of spontaneous mouse mutations, use of site
      directed mutagenesis or quantitative trait loci analysis. In parallel, the
      relevant information pertaining to genes involved in resistance to Salmonella in
      humans will be discussed.

PMID- 12424620
TI  - Association between adult-onset Still's disease and interleukin-18 gene
      polymorphisms.
AB  - Recently, we reported that serum concentration of IL-18 is strikingly high in
      patients with adult-onset Still's disease (AOSD). The aim of the present study
      was to screen for genetic polymorphisms in the human IL-18 (hIL-18) gene and to
      determine the association of polymorphisms with susceptibility to AOSD. We
      investigated the 6.7 kb region upstream of exon 2 of hIL-18 gene, in which a
      promoter activity had been reported. Sixteen AOSD patients, 144 rheumatoid
      arthritis (RA) patients and 92 healthy control individuals were studied. We found
      seven single nucleotide polymorphisms and a single 9 bp insertion which were
      frequently present in the AOSD patients. Three haplotypes including a unique
      combination of these polymorphisms were also determined. Of them, haplotype S01
      contained all eight of these polymorphisms. The frequency of individuals carrying
      a diplotype configuration, ie a combination of two haplotypes, of S01/S01 was
      significantly higher in the AOSD patients than in the healthy controls
      (P=0.00059, Fischer's exact probability test, odds ratio [OR]=7.81, 95%
      confidence interval [95% CI]=2.48-24.65) and the RA patients (P=0.015, Fischer's
      exact probability test, OR=4.0, 95% CI=1.39-11.54). We therefore conclude that
      possession of the diplotype configuration of S01/S01 is a major genetic risk
      factor for susceptibility to AOSD.

PMID- 12424621
TI  - Interleukin-1 receptor antagonist VNTR-polymorphism in inflammatory bowel
      disease.
AB  - Both genetic and environmental factors have been implicated in the etiology of
      inflammatory bowel diseases (IBD) i.e., Crohn's disease (CD) and ulcerative
      colitis (UC). Polymorphisms in cytokine genes are likely to influence an
      individual's predisposition to IBD. In intron 2 of the interleukin-1 receptor
      antagonist (IL-1ra) gene, a variable number of an 86-bp tandem repeat (VNTR)
      polymorphism leads to the existence of five different alleles. In order to
      analyze the association between certain IL-1ra VNTR-alleles and IBD, we
      investigated the IL-1ra genotype and allele frequencies in 342 unrelated IBD
      patients and in 401 healthy control individuals. CD patients were also genotyped
      for the three main associated variants in the NOD2/CARD15 gene. In the IBD group,
      a significant decrease in the frequency of IL-1ra allele 1 (P=0.048) compared to
      controls was observed. The frequency of IL-1ra genotype 1/1 was significantly
      lower in the IBD population vs the control group (P=0.018). Analysis of the CD
      population without NOD2 homozygotes and compound heterozygotes revealed a more
      significant decrease in IL-1ra genotype 1/1 compared to controls (P=0.038). These
      results support the hypothesis that the IL-1ra VNTR-polymorphism could be among
      the genetic factors that are of importance in IBD susceptibility.

PMID- 12424622
TI  - Differential regulation of interleukin-10 production by genetic and environmental
      factors--a twin study.
AB  - Interleukin-10 (IL-10) has a critical role in the regulation of immune responses.
      The relative contribution of genetic and environmental factors to IL-10
      production is under debate. We performed a twin study in 246 monozygotic and
      dizygotic twins to assess the heritability of IL-10 production after LPS
      stimulation in whole blood. In addition, the influence of promoter single
      nucleotide polymorphisms (-1082, -819 and -592) on transcriptional activity and
      their binding to nuclear factors was studied in luciferase reporter gene and
      electrophoretic mobility shift assays. IL-10 production showed a genetic
      determination with a heritability of 0.5. Decreasing body mass index (BMI),
      smoking and female gender lead to decreased IL-10 production. In monocytes, the 
      1082A allele showed higher binding affinity to the transcription factor PU.1
      resulting in decreased transcriptional activity of -1082A promoter haplotypes.
      Genetic determination of IL-10 secretion is probably lower than that previously
      reported. Fifty percent of the observed variability explained by genetic factors.
      Female individuals produce less IL-10 than male subjects. Environmental factors
      like smoking and decreasing BMI exert suppressing effects on IL-10 production.
      Although the -1082A allele shows higher binding affinity to the PU.1
      transcription factor and lower transcriptional activity, this polymorphism
      probably explains only a small fraction of the observed heritability.

PMID- 12424623
TI  - A promoter polymorphism in the gene encoding interleukin-12 p40 (IL12B) is
      associated with mortality from cerebral malaria and with reduced nitric oxide
      production.
AB  - Interleukin-12 (IL-12) is an important regulatory cytokine in infection and
      immunity. Administration of IL-12 may reduce complications of severe malaria in
      rodents. Polymorphisms in IL12B, the gene encoding the IL-12 p40 subunit,
      influence the secretion of IL-12 and susceptibility to Type 1 diabetes. We
      therefore investigated whether IL12B polymorphisms may affect the outcome of
      severe malaria. Homozygosity for a polymorphism in the IL12B promoter was
      associated with increased mortality in Tanzanian children having cerebral malaria
      but not in Kenyan children with severe malaria. Furthermore, homozygotes for the
      IL12B promotor polymorphism had decreased production of nitric oxide, which is in
      part regulated by IL-12 activity. These studies suggest that IL12B polymorphisms,
      via regulation of IL-12 production, may influence the outcome of malaria
      infection in at least one African population.

PMID- 12424624
TI  - A TaqI polymorphism in the 3'UTR of the IL-12 p40 gene correlates with increased
      IL-12 secretion.
AB  - Interleukin-12 (IL-12) is a key cytokine for the induction of Th1 immune
      responses. We evaluated whether a TaqI polymorphism in the 3'UTR of the IL-12 p40
      gene affects secretion of IL-12 in vitro, and whether this polymorphism is
      associated with susceptibility to Crohn's disease (CD). IL-12 p40 and p70
      secretion by monocytes in relation to genotype was determined in 63 healthy
      donors. Genotype and allele frequencies of the TaqI polymorphism in 150 CD
      patients were compared with 145 ethnically matched healthy controls (HC). No
      significant association was found between genotype and IL-12 p40 secretion after
      stimulation of monocytes with SAC+IFNgamma. In contrast, increasing IL-12 p70
      secretion was found across the categories of non-carriers, heterozygotes and
      homozygotes for the variant allele (median values+/-SEM: 147+/-27, 282+/-51 and
      482+/-34 pg/ml, respectively; P<0.005). The allele and genotype frequencies of
      this polymorphism in patients with CD did not differ statistically significantly
      from HC. The presence of a TaqI polymorphism in the IL12 p40 3'UTR correlates
      with increased in vitro IL-12 p70, but not p40 secretion. While this polymorphism
      does not appear to be correlated with susceptibility to CD in the limited
      population of patients tested here, it could influence the occurrence of the
      disease in certain subsets of patients.

PMID- 12424625
TI  - Analysis on the association of human BLYS (BAFF, TNFSF13B) polymorphisms with
      systemic lupus erythematosus and rheumatoid arthritis.
AB  - Recent studies indicated a substantial role of BLyS (BAFF, TNFSF13B) in the
      pathogenesis of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA)
      in humans and in animal models. This study was conducted to screen for
      polymorphisms of human BLYS, and to examine whether they are involved in the
      genetic susceptibility to human SLE and RA. A systematic polymorphism screening
      was performed in the coding region, 5' and 3' untranslated regions, and promoter
      region of human BLYS. Association of the detected polymorphisms with SLE and RA
      was analyzed in 221 Japanese patients with RA, 156 with SLE, and 227 healthy
      individuals, using the case-control approach. Four single nucleotide
      polymorphisms (SNPs) in the promoter, one SNP in intron 1, and one rare
      nonsynonymous substitution (Ala105Thr) in the coding region were detected. The
      BLYS SNPs were found to form three common haplotypes. Significant association
      with the susceptibility to SLE or RA was not observed. However, a tendency for
      the increase of -871T/T genotype was observed in SLE patients with anti-Sm
      antibody (P=0.082). BLYS mRNA level was significantly elevated in the monocytes
      from individuals carrying -871T (P=0.010). In addition, although statistically
      not significant, 105Thr allele was slightly increased in patients with RA
      compared with controls (P=0.058). Characterizing the functional and clinical
      significance of these new SNPs requires further study.

PMID- 12424626
TI  - Characterization of a nuclear-factor-kappa B (NFkappaB) genetic marker in type 1
      diabetes (T1DM) families.
AB  - Cytokine-induced beta-cell death is an important factor in the pathogenesis of
      type 1 diabetes mellitus (T1DM). The transcription factor NFkappaB plays an
      important role in cytokine-induced gene activation. Hence, NFKB1 is a possible
      candidate gene for T1DM disposition. A polymorphic (CA) dinucleotide repeat
      microsatellite has been identified near the NFKB1 gene. In a recent case-control
      study certain alleles of this NFKB1 microsatellite marker showed strong
      association to T1DM. The aim of our study was to investigate whether the
      association between the NFKB1 marker and T1DM could be confirmed in a Danish
      family collection. No T1DM association for any allele of the NFKB1 microsatellite
      marker could however be demonstrated in Danish T1DM families. In conclusion, we
      could not confirm the highly significant T1DM association of certain alleles of
      the NFKB1 marker previously reported.

PMID- 12424627
TI  - The IL12B 3' untranslated region DNA polymorphism is not associated with early
      onset type 1 diabetes.
AB  - A recent study employing Australian and UK type 1 diabetes families has
      demonstrated significant transmission bias to affected offspring of a
      polymorphism (1188A allele; termed allele 1) in the 3' untranslated region
      (3'UTR) of the interleukin 12B (IL12B) gene which encodes the IL-12p40 subunit of
      the pro-inflammatory cytokine IL-12. However, results from replication studies in
      other populations have been controversial. We performed both case-control (n=120
      cases; n=330 controls) and family-based (n=307 families) association studies,
      using the transmission disequilibrium test, to investigate if allele 1 is
      associated with early-onset type 1 diabetes in Northern Ireland. No association
      was observed between allele 1 and type 1 diabetes in either case-control (80.8%
      vs 80.8%; P=0.98) or family-based (49.7% transmissions; P=0.94) studies. Our
      results do not support earlier reports of an association between allele 1 in the
      3'UTR of the IL12B gene and type 1 diabetes.

PMID- 12424628
TI  - Chronic obstructive pulmonary disease is associated with the -1055 IL-13 promoter
      polymorphism.
AB  - IL-13 is strongly implicated in the development of asthma and chronic obstructive
      pulmonary disease (COPD). We previously identified an IL-13 promoter polymorphism
      (-1055 C to T) that is associated with allergic asthma. We now report an
      increased frequency of the -1055 T allele in COPD patients compared to healthy
      controls (P=0.002) and compared to a second control group consisting of smoking
      individuals with normal lung function (P=0.01). A closely linked IL-13 exon
      polymorphism is present at normal allelic frequencies (P=0.3 and 0.4,
      respectively). In addition, we observed a normal distribution of two IL-4
      polymorphisms at positions -590 and +33 (P=0.2 and 0.9, respectively). These
      results could implicate a functional role for the IL-13 promoter polymorphism in
      the enhanced risk to develop COPD.

PMID- 12424629
TI  - The glandular odontogenic cyst: clinical and radiological features; review of the
      literature and report of nine cases.
AB  - Nine cases with glandular odontogenic cysts (GOC's) are presented bringing the
      total number reported in the literature to 54. Our study confirmed that most
      GOC's occur in the mandible, whereas maxillary lesions present only in the
      globulo-maxillary region. The radiological features were found to be non
      distinctive and presented as well-defined radiolucencies with uni- and
      multilocular appearances. Most of the mandibular GOC's were unilocular, involved
      the symphysis region and only one extended into the ramus. All GOC's larger than
      6 cm in diameter showed perforated margins radiologically. Our two multilocular
      GOC's demonstrated microscopic features supporting their infiltrative
      radiological appearance. The invasive clinical and radiological features of GOC
      support the notion of a possible histo-pathologic overlap between GOC and low
      grade central mucoepidermoid carcinoma of the jaw.

PMID- 12424630
TI  - Mandibular bone invasion by gingival carcinoma on dental CT images as an
      indicator of cervical lymph node metastasis.
AB  - OBJECTIVES: To evaluate the significance of mandibular bone invasion by gingival
      carcinoma revealed by reformatted dental CT images as a prognostic indicator of
      cervical metastasis. METHODS: Thirty-two patients with squamous cell carcinoma of
      the lower gingiva were examined by dental CT. Cervical metastases and survival
      rates of these patients were analysed in relation to their clinical
      characteristics, histologic grading based on gingival biopsy, and mandibular bone
      invasion using reformatted dental CT imaging diagnoses prior to surgery. The
      dental CT images were classified into four types: Class I, no bone invasion;
      Class II, invasion confined to the alveolus; Class III, invasion extending
      between the alveolus and the mandibular canal; and Class IV, invasion beyond the
      mandibular canal. RESULTS: Logistic multivariate regression analysis showed that
      bony invasion identified on dental CT images was a significant prognostic factor
      in cervical metastases (P=0.028). The 5-year overall survival rates of Classes I,
      II, III, and IV were 100% (n=9), 76.2% (n=9), 71.4% (n=7), and 28.6% (n=7),
      respectively. CONCLUSIONS: The evaluation of mandibular bone invasion using
      dental CT images is useful as a prognostic indicator of cervical metastasis for
      patients with gingival carcinoma.

PMID- 12424631
TI  - MR imaging of benign and malignant lesions in the buccal space.
AB  - OBJECTIVES: To evaluate MRI characteristics of buccal space lesions and to
      discuss the sensitivity of MRI in predicting malignancy of those lesions.
      METHODS: Thirty patients with malignant (n=7) or benign (n=23) lesions
      originating in the buccal space were reviewed retrospectively. MR images were
      assessed for the margins, internal architecture, signal intensity of lesions and
      their relation to the surrounding structures. RESULTS: Two cases of soft tissue
      sarcoma were shown as ill-defined masses with infiltration into adjacent muscles
      and bone. On the other hand, all tumors of minor salivary gland origin, whether
      malignant (n=4) or benign (n=2), were well-defined and confined within the buccal
      fat pad without infiltration into surrounding structures. All haemangiomas (n=9)
      had very high T2-weighted signal intensity. Three out of them contained signal
      voids on all sequences thought to represent phleboliths, a finding strongly
      suggestive of the diagnosis. Inflammatory lesions were characterized by the
      presence of edema in the surrounding fat. When ill-defined margins, infiltration
      into muscles and bone destruction were used as the criteria for the malignancy,
      only two out of seven malignant tumors were correctly diagnosed (sensitivity
      29%). CONCLUSIONS: Although MR imaging was useful in demonstrating the extent of
      buccal space lesions, its diagnostic value in predicting malignancy was very
      limited. It was especially true for malignant tumors of minor salivary gland
      origin, which were typically seen as well-defined masses without infiltration
      into surrounding structures on MRI.

PMID- 12424632
TI  - Signal intensity changes in T2-weighted MR image of the human trapezius muscle
      upon cold pressor stimulation.
AB  - OBJECTIVE: The ability to measure hemodynamics of skeletal muscle proper is one
      of the major goals for muscle pain researchers. The aim of the present study was
      to evaluate the ability of signal intensity (SI) in T2-weighted trapezius muscle
      magnetic resonance imaging (MRI) to detect intramuscular hemodynamic changes
      during cold pressor stimulation (CPS). MATERIALS AND METHODS: Fifteen healthy
      volunteers (mean age, 25.9+/-2.1 years) participated in this study. T2-weighted
      MRI was acquired using a 1.5 tesla MR unit with a body array coil. The slice
      level was set perpendicular to the muscle long axis at the mid-point of the
      horizontal portion of the right trapezius muscle. Cold pressor stimulation (4
      degrees C) was applied to each subject's right foot and ankle for 2 min. The SI
      changes were recorded continuously for 7 min before, 2 min during, and 6 min
      after withdrawal of cold pressor stimulation. Six of these subjects also
      underwent a mock-CPS trial. RESULTS: The mean SI level in T2-weighted trapezius
      muscle MRI significantly increased during CPS (P<0.0001, one way repeated measure
      ANOVA) and returned to the baseline level after cold pressor withdrawal. No
      statistically significant signal changes were observed across the mock-CPS trial
      subjects. These findings are identical to the cold pressor-induced hemodynamic
      changes documented in the trapezius muscle by near-infrared spectroscopy
      evaluation. CONCLUSIONS: SI measurement in T2-weighted trapezius muscle MRI is
      sufficiently sensitive to detect intramuscular hemodynamic changes during CPS.

PMID- 12424633
TI  - Patterns of intra-osseous transmigration and ectopic eruption of mandibular
      canines: review of literature and report of nine additional cases.
AB  - OBJECTIVES: The purpose of this study is to (1). investigate the patterns of
      transmigration and eruption of permanent mandibular canines, plus the mechanisms
      affecting the eruption path, (2). classify the transmigration paths. MATERIAL AND
      METHODS: :A retrospective radiographic study using full mouth (FMX) and panoramic
      radiographs of dental radiology patients between July 1996 and July 2000.
      Transmigrated canines were identified from the radiographic records of 2150 new
      patients. The literature was reviewed regarding the individual patterns of canine
      transmigration and their final position within the mandible. A pattern
      classification was developed using literature data and the additional nine cases
      reported here. RESULTS: In the present study, mandibular canines were found
      transmigrated on nine occasions and, in a further six cases, found impacted
      without transmigration. Out of the nine cases, seven were female (ages 17-38) and
      two were male (ages 20 and 69). One female patient had a bilateral transmigration
      of the mandibular canines. A total of 127 transmigrated canines were reported in
      50 published studies from the literature. Transmigrated canines appear to fall
      into five patterns (Type 1-5) depending on their path of deviation. Type 1 was
      most common (45.6%) followed by Type 2 (20%), Type 4(17%), Type 3(14%) and Type 5
      (1.5%). CONCLUSIONS: Patterns of mandibular canine transmigration can be
      classified into five distinct patterns. The majority of cases demonstrated Type 1
      transmigratory pattern. No clear aetiology of this disorder could be found.

PMID- 12424634
TI  - Panoramic-based mandibular indices in relation to mandibular bone mineral density
      and skeletal status assessed by dual energy X-ray absorptiometry and quantitative
      ultrasound.
AB  - OBJECTIVES: The panoramic-based indices (Mandibular Cortical Index-MCI, the
      height of mandibular inferior cortex-IC (mm), Panoramic Mandibular Index-PMI,
      Mandibular Ratio-MR) were used to evaluate their diagnostic efficacy and to
      determine whether they correlate with bone mineral density (BMD (g/cm(2))) of the
      mandible and hip, and with ultrasound parameters of the calcaneus and hand
      phalanges in postmenopausal, edentulous women. METHODS: Basing on MCI women were
      divided into three subgroups differed in the appearance of the mandibular cortex
      (C1 n=6, C2 n=16, C3 n=8). BMD of the hip (neck-BMD, Ward's-BMD, trochanteric
      BMD) and mandible (m-BMD) were measured by dual-energy X-ray absorptiometry
      (DXA). Calcaneus using Achilles (Speed of Sound-SOS (m/s), Broadband Ultrasound
      Attenuation-BUA [dB/MHz], Stiffness Index-SI [%]) and hand phalanges (amplitude
      dependent speed of sound-Ad-SoS (m/s)) using DBM Sonic 1200 were assessed by
      Quantitative Ultrasound (QUS). RESULTS: There were no significant differences
      between subgroups in parameters measured except for significant differences in m
      BMD (P<0.01). Only m-BMD correlated significantly with DXA (r=0.43-0.45, P<0.05)
      and QUS (r=0.36-0.55, P<0.05) measurements excluding correlations with calcaneal
      SOS and trochanteric BMD. The ability of the mandibular variables to discriminate
      between normal and osteopenic/osteoporotic cases was assessed by calculating:
      specificity (ranging from 31 to 81%), sensitivity (ranging from 21 to 93%),
      negative and positive predictive values (ranging from 47 to 83% and 40 to 79%,
      respectively). CONCLUSION: MCI is a simple three-graded classification of changes
      in the cortex but is not able to distinguish normal and osteopenic/osteoporotic
      postmenopausal edentulous women. The efficacy of the panoramic-based mandibular
      indices in diagnosing osteopenia/osteoporosis is low to moderate.

PMID- 12424635
TI  - Radiographic evaluation of the relationship between the projection of genial
      tubercles and the lingual foramen.
AB  - OBJECTIVE: Reports in specialized literature present divergent opinions about
      what corresponds to the radiopaque areas surrounding the lingual foramen. The
      purpose of this study is to radiographically evaluate whether these areas
      correspond to the genial tubercles. METHODS: We selected 15 dry mandibles and
      obtained images of the lower incisors region by computed tomography (CT) and
      periapical radiography at vertical angles of -10 degrees, -20 degrees and -30
      degrees. For periapical radiography, the genial tubercles and the lingual foramen
      were marked with stainless steel wire to demonstrate the relationship between
      them. RESULTS: The images on periapical radiographs, as well as on CT scans of
      the region, showed that there is no relationship between radiopaque areas around
      the lingual foramen and the genial tubercles. CONCLUSION: The radiopaque area
      surrounding the lingual foramen corresponds to the walls of a nutrient canal and
      not to the genial tubercles. Therefore, we recommend that the information about
      this anatomical landmark be reviewed in specialized literature.

PMID- 12424636
TI  - Alteration of the horizontal mandibular condyle size associated with
      temporomandibular joint internal derangement in adult females.
AB  - OBJECTIVES: The purpose of this retrospective study was to analyse the
      relationship between horizontal size of the mandibular condyle and internal
      derangement (ID) of the temporomandibular joint (TMJ). METHODS: One hundred and
      thirty-nine joints in 88 women aged over 18 years were included in this study.
      The horizontal condylar size was measured in the antero-posterior and medio
      lateral (ML) dimensions using axial magnetic resonance (MR) images. Radiological
      findings of ID were also assessed from MR imaging. RESULTS: The condyles in the
      joints with permanent disk displacement were smaller than those in joints without
      displacement in both dimensions (Fisher's protected least significant difference,
      P<0.05). There were statistically significant correlations between horizontal
      condylar size in the ML dimension and both disk morphology and radiological stage
      of ID (Spearman's correlation coefficient by rank, P<0.05). CONCLUSIONS: The
      results of this study suggest a possible relationship between horizontal condylar
      size and disk displacement. It is also suggested that the condyle becomes smaller
      in the ML dimension with advancement of ID.

PMID- 12424637
TI  - Comparative evaluation of JPEG and JPEG2000 compression in quantitative digital
      subtraction radiography.
AB  - OBJECTIVES: The aim of this in vitro study was to compare the impact of JPEG and
      the novel JPEG2000 compression standard on quantitative digital subtraction
      radiography (DSR) and to determine the acceptable JPEG2000 compression ratios for
      DSR. METHODS: Nine dry pig mandible sections were radiographed three times
      ('Baseline', 'No change', and 'Gain') with standardized projection geometry. Bone
      gain was simulated by adding artificial bone chips (1, 4 and 15 mg). Images were
      registered, compressed by JPEG and JPEG2000 using compression ratios (CR) of 1 :
      7, 1 : 16, 1 : 22, and 1 : 31, and then subtracted. Image distortion was assessed
      objectively by calculating average pixel error and peak signal to noise ratio. No
      change areas in compressed and subtracted 'No change-Baseline' images and bone
      gain volumes in compressed and subtracted 'Gain-Baseline' images were calculated
      for both compression standards and compared. RESULTS: JPEG introduced less
      distortion at low CRs, while JPEG2000 was superior at higher CRs. At CR of 1 : 7,
      no significant difference between JPEG and JPEG2000 was found. JPEG2000 yielded
      better results for no change measurements at higher CRs. Volumes of simulated
      bone gain were overestimated when JPEG and underestimated when JPEG2000
      compression was used. CONCLUSIONS: At CR of 1 : 7 JPEG and JPEG2000 performed
      similarly, which indicates that CR of 1:7 in JPEG2000 can be used for DSR if
      images are registered before compression. At higher CRs, JPEG2000 is superior to
      JPEG but image distortions are too high for reliable quantitative DSR.

PMID- 12424638
TI  - Osteoid osteoma in the mandible.
AB  - A case of osteoid osteoma (OO) in the mandible of 26-year-old female is
      presented. Her main complaint was intermittent pain during a 3 year period. The
      panoramic radiograph of the mandible showed diffuse sclerosis including an ill
      defined circular radiopacity in the molar region. Computed tomography (CT)
      revealed an osseous lesion of 10 mm diameter that was located in the cortical
      bone of the mandible. Bone scintigraphy showed a localized region of high uptake
      of 99mTc HMDP. The lesion was diagnosed as an OO by histopathological examination
      of the surgical specimen and CT findings. Since radiological appearance has very
      significant meaning in the differentiation of an OO from other bone forming
      tumors, CT is the method of choice when the main symptom is pain and the
      conventional radiography was not informative.

PMID- 12424639
TI  - Bilateral calcifications secondary to synthetic soft tissue augmentation of the
      cheeks: report of a case.
AB  - Although esthetic soft tissue augmentation of the cheeks has been in practice for
      over a century, calcifications associated with the soft tissue substitutes were
      rarely reported. A case demonstrating bilateral concentric opacities in the soft
      tissues of the cheek secondary to cheek augmentation is presented. The opacities
      were detected accidentally during routine intraoral radiographic examination.
      This condition initially posed a challenge in radiographic diagnosis in the
      absence of adequate history and clinical information. In this report we have
      briefly reviewed different types of implant materials used for soft tissue
      augmentation. We believe that inflammation of the tissues adjacent to the implant
      material is possibly responsible for the development of calcifications associated
      with esthetic soft tissue augmentations.

PMID- 12424641
TI  - Lower third molar displaced in the sublingual space.

PMID- 12424646
TI  - Time course of cognitive recovery after propofol anaesthesia: a level of
      processing approach.
AB  - The aim of this study was to investigate the time course of recovery of verbal
      memory after general anaesthesia, as a function of the level (shallow or deep) of
      processing induced at the time of encoding. Thirty-one patients anaesthetized
      with propofol and alfentanil were compared with 28 control patients receiving
      only alfentanil. Memory functions were assessed the day before and 1, 6 and 24 hr
      after operation. Results show that for the anaesthetized group, shallow
      processing was impaired for 6 hr after surgery whereas the deeper processing was
      not recovered even at 24 hr. In addition, no specific effect of age was found.

PMID- 12424647
TI  - Behavioral characterization of mild cognitive impairment.
AB  - Results from recent investigations of behavioral and genetic outcomes in older
      people with mild cognitive impairment (MCI) have been inconsistent. These
      conflicting results may be attributed to between-study differences in the
      diagnostic systems employed, as well as the use of unreliable neuropsychological
      measures. We investigated behavioral and genetic outcomes in older people
      classified as having MCI according to novel criterion that required evidence of
      cognitive impairment on three consecutive neurological/neuropsychological
      assessments. One hundred and seventy four healthy older people were evaluated
      semi-annually for 12 months. Of these, 23 subjects were rated as having MCI on
      three consecutive assessments and were compared to 23 matched control subjects.
      Subjects rated as impaired on one or two of the three semi-annual assessments
      were also identified. MCI and matched control groups were compared on a range of
      behavioral measures. The prevalence of the Apolipoprotein E4 (ApoE4) allele was
      determined in all groups, and estimates of anxiety and depressive symptomatology
      were obtained. Subjective cognitive complaints were also assessed. Many subjects
      were classified as impaired on one or two assessments, however relatively few (n
      = 23) recorded consistent cognitive deficits. The most severe impairment observed
      in MCI subjects was on a test of pattern-location associative learning, however
      MCI subjects did not have insight into this impairment. The prevalence of the
      ApoE4 allele was not different between matched control and MCI groups. These
      results indicate that individuals with MCI can be differentiated from healthy
      older people and older people with transient cognitive impairments, but that such
      differentiation requires serial assessment of cognitive function.

PMID- 12424648
TI  - Cognitive functioning in Alzheimer's disease and vascular dementia: further
      evidence for similar patterns of deficits.
AB  - The purpose of the present study was to examine possible differences in patterns
      of cognitive performance between population-based samples of Alzheimer's disease
      (AD; n = 51) and vascular dementia (AD; n = 14) patients between 75 and 96 years
      of age. The two demented groups were comparable in age, years of education,
      gender distribution, and severity of dementia. The selection of cognitive tasks
      (letter and category fluency, Block design, Clock reading and setting, and
      episodic face recognition) was thought to address some of the inconsistencies in
      previous research. The main finding was that AD and AD patients were comparable
      on most tasks, although robust dementia-related deficiencies were found when
      comparing the results of the demented participants with those of the control
      participants. These findings suggest that AD and AD may affect several basic
      cognitive functions in an equal manner.

PMID- 12424649
TI  - Differences in executive functioning between Alzheimer's disease and subcortical
      ischemic vascular dementia.
AB  - The present study examined the performance of 114 individuals (62 males, 52
      females) on a variety of tests purported to measure executive abilities.
      Participants were diagnosed with possible or probable Alzheimer's disease (AD),
      subcortical ischemic vascular dementia (SVaD), or were normal controls (NoDx).
      Groups were matched for age and education, and clinical groups were matched for
      severity of dementia. Multivariate and univariate analyses of variance were
      performed which indicated that the AD and SVaD patients differed from the NoDx on
      all measures of executive functioning. Further, the AD group made significantly
      more episodic memory errors than the SVaD group. On the other hand, consistent
      with previous research, the SVaD group performed significantly better than the AD
      group on recognition memory, but not on free recall measures. Present findings
      suggest that AD patients have more executive self-monitoring problems than SVaD
      patients do, but SVaD patients have more retrieval problems (executive memory
      search), suggesting a fractionation of executive abilities. Thus, differences
      between dementia groups depend on the nature of the executive function assessed.

PMID- 12424650
TI  - Naming in patients with Alzheimer's disease: influence of age of acquisition and
      categorical effects.
AB  - The role of age of acquisition (AoA) and other variables classically supposed to
      influence lexical semantic tasks is explored in Alzheimer's disease (AD)
      patients. A naming test that included living and nonliving items was given to
      patients and controls. Measures of AoA of the test items were obtained from
      normal subjects. Living items were acquired earlier than nonliving items.
      Semipartial correlation analyses were performed to determine the independent
      contribution of each variable to naming. The "category" (living vs. nonliving
      items) was included as an independent factor. It emerged that AoA, name agreement
      and category (with living category predicting lower scores) were the main
      predictors of naming in AD patients. Only factor agreement reached significance
      in control groups. The hypothesis is discussed that the category dissociation may
      be produced by the different nature of the semantic correlation network that
      makes the categories differentially demanding of processing resources.

PMID- 12424652
TI  - Training of working memory in children with ADHD.
AB  - Working memory (WM) capacity is the ability to retain and manipulate information
      during a short period of time. This ability underlies complex reasoning and has
      generally been regarded as a fixed trait of the individual. Children with
      attention deficit hyperactivity disorder (ADHD) represent one group of subjects
      with a WM deficit, attributed to an impairment of the frontal lobe. In the
      present study, we used a new training paradigm with intensive and adaptive
      training of WM tasks and evaluated the effect of training with a double blind,
      placebo controlled design. Training significantly enhanced performance on the
      trained WM tasks. More importantly, the training significantly improved
      performance on a nontrained visuo-spatial WM task and on Raven's Progressive
      Matrices, which is a nonverbal complex reasoning task. In addition, motor
      activity--as measured by the number of head movements during a computerized test-
      was significantly reduced in the treatment group. A second experiment showed that
      similar training-induced improvements on cognitive tasks are also possible in
      young adults without ADHD. These results demonstrate that performance on WM tasks
      can be significantly improved by training, and that the training effect also
      generalizes to nontrained tasks requiring WM. Training improved performance on
      tasks related to prefrontal functioning and had also a significant effect on
      motor activity in children with ADHD. The results thus suggest that WM training
      potentially could be of clinical use for ameliorating the symptoms in ADHD.

PMID- 12424651
TI  - Neuropsychological profiles delineate distinct profiles of schizophrenia, an
      interaction between memory and executive function, and uneven distribution of
      clinical subtypes.
AB  - Neuropsychological performance in 151 patients with schizophrenia was examined
      using cluster analysis to identify neurocognitive subtypes. Hierarchical and
      iterative partitioning methods identified four clusters using an extended
      neuropsychological battery. Consistent with previous findings two extreme
      clusters were characterized by near normative performance and profound global
      dysfunction, respectively. The two remaining neurocognitive clusters displayed
      moderate-severe dysfunction and were differentiated by unique patterns of
      abstraction and flexibility, attention, spatial memory, and sensory-perception.
      Analysis of variance revealed an interaction between global memory and executive
      function for clusters III and IV. Although limited cluster differences were found
      relative to clinical and historical data, the distribution of previously defined
      clinical subtypes was uneven among neurocognitive clusters. Paranoid patients
      were significantly more likely to be classified into cluster II and
      disproportionately absent from clusters I and IV. Patients with negative and
      disorganized clinical subtypes comprised a disproportionate component of clusters
      I and IV but were less likely to be classified in cluster II. This suggests
      greater correspondence than previously postulated between systems responsible for
      clinical symptomatology and those moderating neurocognitive dysfunction.

PMID- 12424653
TI  - Specificity of conditional associative-learning deficits in obsessive-compulsive
      disorder (OCD) and non-OCD anxiety disorders.
AB  - The acquisition of conditional associations using neutral and disease-related
      nouns was studied in 15 inpatients with obsessive-compulsive disorder (OCD), 15
      inpatients with non-OCD anxiety disorders and 15 chronic pain inpatients.
      Patients were comparable with respect to age, sex, depression, intelligence,
      executive functions, verbal and spatial memory, visuoconstructive functions, and
      handedness. The investigation took place in the diagnostic phase prior to the
      patient's beginning a standardized behavioral treatment program. It was
      hypothesized that anxiety patients acquired disease-related material faster than
      pain patients but that only OCD patients show inferior performance with respect
      to neutral stimuli. Results show that the three patient groups were widely
      comparable concerning neuropsychological background measures and showed
      equivalent results with respect to disease-related stimuli. But OCD patients
      yielded an inferior degree of performance when neutral stimuli were used whereas
      non-OCD anxiety disorder and pain patients displayed an equivalent degree of
      performance both for neutral and disease-related material, respectively. Results
      are discussed within the framework of obsessive-compulsive spectrum disorders.

PMID- 12424654
TI  - Source monitoring in alcoholism.
AB  - Recent research on the neural bases of source memory suggests that this type of
      memory is relevant to the neuropsychological assessment of neurobehavioral
      disorders. Source memory refers to the ability to discriminate the origin or
      source of information (e.g., did I think of the idea or did I read about it). We
      examined source monitoring in abstinent alcoholic patients (N = 53) and
      nonalcoholic controls (N = 34) and report significant impairments in the
      alcoholic patients' ability to remember the source of recently presented
      information. Decrements in source memory were uncorrelated with alcoholic
      patients' neuropsychological deficits on the Wisconsin Card Sorting Test or the
      Benton Facial Recognition Test. Using qualitative measures of brain CT scans in a
      subsample of 39 alcoholic patients, we found that source memory was correlated
      with Sylvian fissure ratings in the left hemisphere. We propose that source
      memory decrements are another area of neuropsychological functioning affected in
      chronic alcoholism. Tasks of source memory may offer the neuropsychologist a
      valuable new tool for evaluating cognitive functions in neurobehavioral
      disorders.

PMID- 12424655
TI  - Differential profiles of verbal learning in traumatic brain injury.
AB  - Several recent investigations have utilized cluster analytic procedures to
      elucidate profiles of verbal learning on the California Verbal Learning Test
      following traumatic brain injury (TBI). Although the results of these studies
      have contributed to our understanding of verbal learning following TBI,
      limitations in sample composition and methodology render the results difficult to
      evaluate. The current study provides an analysis of verbal learning clusters in
      the most comprehensive sample (n = 160) of TBI patients reported thus far.
      Results obtained from multiple hierarchical agglomerative clustering procedures
      suggested the presence of two distinct clusters, the first consisting of
      performance patterns falling within normal limits and the second consisting of
      moderate-to-severe impairment. Two iterative partitioning analyses further
      suggested a reliable solution with better-than-chance agreement (kappa
      coefficients >.85, p <.001). Thus, it is concluded that a two-cluster
      classification solution provides a parsimonious understanding of verbal learning
      profiles after TBI.

PMID- 12424656
TI  - Measures of variations in performance during a sustained attention task.
AB  - In this study the authors developed and explored measures of short-term
      variations in accuracy on a test of sustained attention, a departure from
      traditional measures of average performance over long periods. The study
      participants were normal young adults, actively engaged in a continuous
      performance test (CPT). Both correct (hits) and incorrect (misses) responses to
      CPT targets appeared to aggregate in runs (2 or more consecutive hits or misses).
      Results of a Monte-Carlo procedure indicated that these runs were longer and
      fewer than would occur if hits and misses were randomly distributed. Average
      accuracy decreased between the first and second 5-min quarter of the test, then
      remained level. The length of hit runs followed the same pattern. However, other
      aspects of performance continued to change. The amount of time participants spent
      in miss runs began to increase significantly in the third quarter, and the
      frequency of miss runs did not increase until the fourth quarter. Explanations of
      these findings based upon changes in perceptual sensitivity or upon phasic
      increases in arousal caused by hits were rejected by further analysis. There was
      evidence that the length of miss runs was limited by a target-expectancy effect
      created by the specific parameters of our CPT. The authors conclude that measures
      of variations in performance reveal aspects of vigilance that are not tapped by
      traditional measures, and that factors that initiate, sustain and terminate both
      hit and miss runs are important targets of future research. Additional research
      is needed to determine whether or not the particular measures developed in this
      study may contribute to the understanding of attention problems in clinical
      populations.

PMID- 12424657
TI  - Identifying retrieval problems using the California Verbal Learning Test.
AB  - Wilde, Boake, and Sherer (1995) examined the discrepancy between Long Delayed
      Free Recall (LDFR) and Recognition Discriminability (RD)--the California Verbal
      Learning Test (CVLT) index thought to indicate the presence of memory retrieval
      problems--and found little evidence to recommend its use in traumatic brain
      injury (TBI). The present investigation re-examined this index from the
      perspective of a continuum of retrieval deficit severity. CVLT performance was
      examined in 122 TBI patients, and 2 retrieval deficit indicators of varying
      severity were evaluated. Memory-impaired control groups were matched with
      retrieval deficit groups on initial acquisition and demographic characteristics.
      Individuals with a LDFR/RD discrepancy did not show predicted differences on
      other CVLT indices of retrieval problems, similar to the findings of Wilde et al.
      (1995). In contrast, individuals with a consistent discrepancy between free
      recall and semantic cued recall (Short and Long Delay) had greater improvement
      with recognition cueing and made fewer intrusive errors than controls.
      Individuals who benefited from semantic cues (where retrieval of the target word
      is still required) also benefited from recognition cues (where retrieval demands
      are minimal). Evidence supported the existence of a continuum of retrieval
      deficit severity. An LDFR/RD discrepancy without performance improvement from
      semantic cueing appears to indicate a more severe retrieval deficit, whereas
      performance improvement from both recognition and semantic cueing indicates less
      severe retrieval deficits.

PMID- 12424658
TI  - Wishing doesn't make it so: a reply to Greiffenstein, Baker, and Gola.

PMID- 12424660
TI  - [Radiological error: what we cannot change and what we should do].

PMID- 12424661
TI  - [Hepatocellular carcinoma: Role of imaging diagnostics in detection, intervention
      and follow-up].
AB  - PURPOSE: Demonstration of techniques and clinical value of imaging diagnostics
      for screening, detection, interventional follow-up and therapy control of
      hepatocellular carcinoma (HCC). Diagnostic techniques for screening, detection
      and differential diagnosis of HCC are presented using color-coded duplex
      sonography (US), computer tomography (CT) and contrast-enhanced magnetic
      resonance techniques like MRI, MR angiography and MR cholangiopancreaticography
      (MRCP). Therapy control with imaging was performed for surgical methods like
      resection and liver transplantation as for well as transarterial
      chemoembolization (TACE), radiofrequency ablation (RF) and laser-induced
      thermotherapy (LITT). In screening, HCC color-coded duplex sonography reveals a
      sensitivity from 45 to 92 % and a specificity from 78 to 90 % when liver
      cirrhosis is present. The diagnostic results of CT were further improved with the
      newly developed techniques of multislice CT. The highest diagnostic accuracy can
      currently be achieved using contrast-enhanced MRI with a sensitivity from 82 to
      96 %. TACE presents a palliative therapy concept; MR-guided LITT and
      radiofrequency ablation are used as thermoablative methods for local therapy and
      the therapy control is based on the above imaging techniques. Contrast-enhanced
      MRI proves to be the superior imaging technique for the early diagnosis,
      differential diagnosis and follow-up of hepatocellular carcinoma.

PMID- 12424662
TI  - [Radiofrequency-thermoablation in malignant liver disease].
AB  - The clinical application of radiofrequency tumor ablation in primary liver tumors
      and metastatic liver disease is rapidly growing because this technique has proven
      to be simple, safe, and effective in first clinical studies. Most of the patients
      with malignant liver disease are not candidates for surgical resection due to
      localisation or comorbidity, so radiofrequency therapy offers a good alternative
      for inoperable patients. With this method, high frequency alternating current is
      delivered to tissue via a needle electrode, the produced heat leads to
      coagulation necrosis. The largest focus of necrosis that can be induced with the
      currently available systems is approximately 4 - 5 cm with a single application.
      The radiofrequency needle is usually placed with US or CT guidance. For follow up
      examinations CT and MRI can be used, they proved to be equally accurate in the
      assessment of treatment response.

PMID- 12424663
TI  - Rotational digital cholangiography (RDC) and 3D-cholangiography (3DC) for
      guidance of percutaneous biliary drainage procedures.
AB  - PURPOSE: To evaluate whether RDC and 3DC help clarifying anatomic details in
      biliary duct disease and is useful for guidance of drainage procedures. MATERIALS
      AND METHODS: RDC was conducted in 11 consecutive patients (8 male, 3 female, mean
      age 63 years). Nine patients underwent PTBD for malignant biliary duct stenosis,
      one patient because of ischemic stenosis after hepaticojejunostomy and one
      patient presented with an infected biloma. Images were obtained after initial
      bile duct puncture during single breath hold from 120 projection angles using a
      rotating C-arm. These images were immediately available and evaluated in order to
      facilitate the definitive drainage procedure. For additional 3D reconstruction,
      data were sent to a dedicated workstation and judged by a blinded observer.
      RESULTS: The availability of a rotating data set of images was judged to be
      helpful in three patients with complex anatomical situations. Additionally, RDC
      holds the potential to reduce fluoroscopy time. 3DC allowed analysis of the
      hepatic bifurcation from different viewing angles in 10 cases with high spatial
      resolution (mean voxel size 480 micro micro m 3). This may allow a better
      classification of hilar obstructions according to our preliminary observations.
      CONCLUSION: Images from RDC and 3DC are helpful in guiding PTBD procedures and
      for better diagnosis in selected patients with hilar biliary duct stenoses.

PMID- 12424664
TI  - [Comparison between biventricular cine MRI and MR flow quantification in
      ascending aorta and pulmonary outflow tract for the assessment of intracardial
      shunt volumes].
AB  - PURPOSE: Comparison between biventricular volumetric measurements and flow
      measurements in ascending aorta (Ao) and pulmonary outflow tract (Pu) for
      quantification of intracardial shunts, and evaluation of the combination of
      biventricular cine MRI with flow measurements for the assessment of RV and LV
      heart failure and valvular regurgitation (VR). MATERIAL AND METHODS: In 24
      patients, right (RV) and left (LV) ventricular volumetric and flow measurements
      were performed in the Ao and Pu to assess the ratio of RV stroke volume (SV) or,
      respectively, pulmonary SV to LV SV or, respectively, systemic aortic SV (Qp/Qs).
      34 patients without echocardiographically proven shunt or VR served as control
      group for measurement accuracy. Left-to-right shunt ratios were calculated from
      RV and LV SV, Pu and Ao SV, Pu and LV SV, and RV and Ao SV. Left ventricular VR
      was calculated by the difference of LV SV and Ao SV, and right ventricular VR by
      the difference of RV SV and Pu SV. Global systolic function was evaluated by
      biventricular cine MRI. RESULTS: Intracardial shunts with Qp/Qs > 1.16 can be
      quantified by flow measurements in Ao and Pu. Using biventricular volumetric
      measurements in cases without VR, requires a Qp/Qs > 1.21. 17 of 18 intracardiac
      shunts were identified on MRI, and all 8 hemodynamically significant shunts were
      quantitatively confirmed. The diagnosis of complete shunt closure or absent shunt
      was correctly made in all 6 cases. RV EF reduction was found in 6 of 24 patients.
      LV EF reduction was also found in 6 of 24 patients. CONCLUSION: Flow measurements
      in Ao and Pu are more accurate than biventricular cine MRI for the assessment of
      Qp/Qs ratios. Flow measurements in Ao and Pu combined with biventricular cine MRI
      enables the quantification of hemodynamic significant shunts, higher grade VR and
      biventricular global systolic function with a single examination.

PMID- 12424665
TI  - [The role of MRI for the evaluation of atrial septal defects before and after
      percutaneous occlusion with the amplatzer septal occluder(R)].
AB  - PURPOSE: Evaluation of morphologic and functional MRI of atrial septal defects
      (ASD) before and after percutaneous occlusion with the Amplatzer Septal Occluder
      (AOC). Comparison of MRI with transesophageal echocardiography (TEE), balloon
      measurement (IVBM) and cardiac catheterization with shunt quantification (CCSQ).
      MATERIALS AND METHODS: Twenty patients with ASD were examined before and three
      months after AOC implantation. ECG-triggered, breath-hold T1-weighted Turbo Spin
      Echo Segmented FLASH 2D and dynamic turbo-FLASH-GRE sequences after application
      of 0.2 mmol gadolinium DTPA per kg body weight were obtained in a 1.5 T MRI
      system. Defect size, and distance to coronal sinus (CS) and right upper pulmonary
      vein (RUPV) were determined for pre-interventional planning, and the AOC size was
      measured quantitatively for post-interventional follow-up. The shunts were
      evaluated qualitatively (occurrence of jets), semiquantitatively (jet length,
      turbulence square product) and quantitatively (flow measurement in the thoracic
      aorta and in the left and right pulmonary arteries). RESULTS: The average size of
      the ASD measured by MRI was 17.6 mm (11 - 24.8 mm) in the axial view, 15.9 mm
      (10.8 - 28.9 mm) in the sagittal view and 16.4 mm (12.1 - 24.8 mm) in the short
      axis view. In comparison, the average defect size was 15 mm (8 - 24 mm) by TEE
      and 20 mm (13 - 27 mm) by IVBM. The average distance to the RUPV was 17 mm (9.6 -
      21.9 mm) and to the CS 11.2 mm (5 - 17 mm). The AOC was visualized with only
      minimal artifacts. Qualitative analysis of the MRI findings revealed an
      occurrence of jets in 17/20 patients. Semiquantitative analysis documented a high
      correlation for jet length and square product of the turbulence to defect size r
      = 0.81 resp. r = 0.82. Mean QP/QS-ratio measured by MR-volumetry was 1.6 +/- 0.29
      and by MR-flow 1.6 +/- 0.26. The corresponding measurements were 1.7 +/- 0.3 for
      TEE and 1.5 +/- 0.5 for CCSQ. In comparison to TEE, the correlation coefficient
      was r = 0.96 for MR-volumetry and r = 0.85 for MR-flow measurement. CONCLUSION:
      MRI is found to be a valuable diagnostic method for pre-interventional planning
      and post-interventional follow-up of atrial septal defects occluded by the
      Amplatzer septal occluder.

PMID- 12424666
TI  - [Scar or recurrence--comparison of MRI and color-coded ultrasound with echo
      signal amplifiers].
AB  - PURPOSE: MRI is the most reliable method to differentiate scar and recurrent
      carcinoma of the breast after surgical treatment. This study compares MRI and
      color-coded ultrasound with and without echo signal amplifier (ESA). MATERIALS
      AND METHODS: Forty-two patients with suspected recurrent tumors were enrolled in
      this prospective study, with 38 patients after breast conserving therapy and 4
      after mastectomy. All patients had a clinical examination, mammography (n = 38),
      real time ultrasound (US), color-coded ultrasound without and with ESA
      (Levovist(R), Schering, Berlin), and dynamic MRI. The criteria used for duplex
      ultrasound were tumor vascularisation and flow pattern. The results were compared
      with histologic findings or the results of follow-up examinations for at least 12
      months. RESULTS: The detection of penetrating or central vessels proved to be an
      accurate sign of malignancy in duplex ultrasound. With the application of ESA,
      additional vessels were detected within the lesions, increasing the diagnostic
      accuracy (83 % with ESA versus 79 % without ESA). The sensitivity of color-coded
      ultrasound improved from 64 % to 86 % with echo signal amplifier. The specificity
      was 86 % without and 82 % with echo signal amplifier. MRI was found to have a
      sensitivity of 100 % and a specificity of 82 %. The same 5 lesions were false
      positive on MRI and color-coded US after Levovist(R). No lesion without signs of
      vascularity within or in its vicinity was malignant. CONCLUSION: Color-coded
      ultrasound seems to be a promising method in the differentiation between scar and
      recurrence. Lesions with penetrating or central vessels have a high probability
      of being malignant, whereas lesions without any signs of vascularity inside or
      nearby have a high probability of being benign. Advantage of contrast-enhanced US
      is its ubiquitous availability.

PMID- 12424667
TI  - [Focal secondary malignant liver lesions: MnDPDP-enhanced MRT at 0.2 tesla vs.
      helical CT-arterioportography].
AB  - PURPOSE: Prospective evaluation of the efficacy of MnDPDP- enhanced MRI using an
      open low-field scanner for the detection of focal malignant liver lesions in
      comparison with helical CT- arterioportography (CT AP). MATERIAL AND METHODS: As
      part of a phase III study, 27 consecutive patients we enrolled for comparison,
      with seven patients later eliminated for failing the inclusion criteria. Native
      and MnDPDP-enhanced MRI of the liver at a field-strength of 0.2 Tesla (Siemens
      Magnetom Open) and DSA with helical CT AP (Siemens Somatom Plus 4) were performed
      within one week. The lesions were compared collectively and after categorization
      by size: (a) < 1 cm, (b) 1 - 2 cm, and (c) > 2 cm. For statistical evaluation,
      the sign test with a significance level of p < 0.05 was used. RESULTS: CT AP
      depicted 114 lesions, whereas native MRI detected 62 and MnDPDP-enhanced MRI
      revealed 69 lesions. Significant differences were shown for collective comparison
      and for selective comparison of category (b), and of categories (a) and (b)
      combined. No significant differences were found between native and contrast
      enhanced MRI. CONCLUSION: MnDPDP should be reserved for high-field strengths
      since low field strengths cannot be expected to confirm or exclude malignant
      liver lesions reliably.

PMID- 12424668
TI  - [MRI in cavernous transformation of the portal vein: secondary biliary
      abnormalities and portoportal collaterals].
AB  - PURPOSE: Evaluation of portoportal collateral vessels and associated biliary
      abnormalities in patients with cavernous transformation of the portal vein by
      MRI. MATERIAL AND METHODS: Review of 34 MRI examinations performed on patients
      with angiographically or MR-angiographically proven cavernous transformation. The
      analysis included the pattern of the portoportal collateral circulation and the
      abnormalities of the biliary system, such as wall thickening, stenosis, dilations
      and irregularities of the extra-and intrahepatic bile ducts. RESULTS: 23 (67.6%)
      of 34 patients with cavernous transformation had paracholedochal portoportal
      collateral vessels, with 22 (64.7%) showing visible luminal channels.
      Epicholedochal venous collaterals could be observed in 8 (23.5%) patients. 24
      (70.5%) of 34 patients demonstrated biliary abnormalities due to portoportal
      collaterals, leading to stenosis with dilatation of the proximal bile ducts in 8
      (23.5%) patients. The ductal walls were irregular in 7 (20.5%) patients, and
      thickened in 11 (32.3%). The gallbladder wall was thickened in 4 (12.9%)
      patients. CONCLUSION: Portoportal collaterals in patients with cavernous
      transformation of the portal vein can be identified by MRI. These collaterals
      frequently alter the biliary system, which must be considered in differential
      diagnosis of biliary abnormalities observed in the presence of portoportal
      collaterals.

PMID- 12424669
TI  - [Magnetic Resonance Imaging (MRI) of the TMJ: Influence on therapy and inter
      observer agreement of two radiologists].
AB  - AIM: To evaluate the influence of MRI of the temporomandibular joint on the
      therapeutic strategy in patients with craniomandibular disorders (internal
      derangement) and, furthermore, to analyze interobserver agreement for defined MRI
      criteria. MATERIALS AND METHODS: Fifty-one unilateral and bilateral MRI
      examinations of 32 patients were enrolled. Therapeutic strategies before and
      after performance of the MRI were compared. Retrospectively, two radiologists
      independently analyzed the MR images for position of the disk, position of the
      condyle, signal intensity of the disk and bilaminar zone, osseous changes and
      several additional findings, using a check list. Agreement was tested by kappa
      statistics. RESULTS: In 56% of the cases, changes of the therapeutic regimen were
      registered after MRI. Statistically significant agreement of the two observers
      was found for anterior position of the disk (kappa = 0.44), transverse position
      of the disk (kappa = 0.46) and position of the condyle (kappa = 0.45). No
      significant agreement was found for signal intensity of the disk (kappa = 0.14)
      or bilaminar zone (kappa = 0.24), osseous changes (kappa = 0.13) and the
      additional findings (kappa = 0.29). DISCUSSION: MRI has a measurable impact on
      the therapeutic approach to the internal derangement of the TMJ. The position of
      the disk and condyle can be reproducibly judged, while the signal intensity of
      the disk and bilaminar zone and the osseous changes are subject to wide observer
      variations.

PMID- 12424670
TI  - [MRI of intraosseous fistulous systems and sequesters in chronic osteomyelitis
      with standard spin echo sequences, highly selective chemical-shift imaging,
      diffusion weighted imaging, and magnetization-transfer].
AB  - PURPOSE: To study and test the impact of modern MRI techniques in diagnostic
      imaging in the evaluation of intra-osseous fistulous systems and sequesters.
      MATERIALS AND METHODS: In a prospective study, nine patients with chronic
      osteomyelitis of the legs were examined by MRI. Patients with clinical signs of
      osteomyelitis requiring surgery were included in the study. T1-weighted spin echo
      (SE) sequences, proton density (PD) and T2-weighted fast spin echo (FSE)
      sequences, water- and fat-selective FSE sequences, and diffusion weighted (DW)
      PSIF sequences were used preoperatively. Furthermore, magnetizing transfer (MT)
      with gradient echo (GRE) sequences was evaluated. RESULTS: Water selective
      sequences revealed the highest sensitivity for the detection of fistulas (100%),
      providing the best delineation of the extent of the entire fistulous systems. Fat
      selective sequences (sensitivity 55.6%) and T1-weighted sequences (sensitivity
      77.8%) displayed fistulas as hypointense bands, which, however, cannot be well
      differentiated from cortical bone in the transcortical areas. PD and T2-weighted
      images were found to have a poor sensitivity (55.6% and 66.7%) for fistulas in
      any location. The sensitivity of water-selective sequences to demonstrate
      intraosseous sequesters was 100%. The sensitivity was low for the other
      sequences. In 4 of 5 patients with surgically proven infection, DW and MT
      revealed an abnormal spatial distribution, with high diffusion in the central
      parts of the fistulas and high MT effect peripherally surrounding a weak MT
      effect centrally. CONCLUSION: Water-selective sequences are superior when
      demonstrating fistulous systems and intraosseous sequesters. The combined use of
      MT and DW sequences seems to allow a differentiation between solid granulation
      tissue and liquid pus.

PMID- 12424671
TI  - [Characteristic mechanical properties of balloon-expandable peripheral stent
      systems].
AB  - PURPOSE: To measure in vitro geometric-mechanical characteristics of balloon
      expandable peripheral stent systems for determining suitability for specific
      vascular regions. MATERIALS AND METHODS: Balloon-expandable stents including
      their delivery systems manufactured by Guidant (OTW Megalink trade mark ), Inflow
      Dynamics (Antares), Medtronic (AVE Bridge trade mark ), Biotronik (Peiron trade
      mark ) and Cordis (Corinthian IQ trade mark ) were selected for this study. When
      expanded, all stents had a nominal diameter of 8 mm. The length was 38 - 40 mm.
      Stent profile, trackability, length change on expansion, stiffness, elastic
      recoil, and radio-opacity in the crimped and expanded state of these stent
      systems were determined with specially developed test methods. RESULTS: The
      Corinthian IQ trade mark, Megalink trade mark and Peiron trade mark required the
      smallest force to pass through the vascular model. While the Bridge trade mark
      system had the largest profile with a diameter of 2.430 mm, all other stent
      systems had a significantly smaller diameter ranging from 1.970 mm for the Peiron
      trade mark to 2.078 mm for the Corinthian IQ trade mark. In the distal region of
      the stent delivery system, the Megalink trade mark was the most flexible and the
      Bridge trade mark system the stiffest. Elastic recoil for all stents was in the
      range of 2.5 % to 3.5 %, with the exception of the Bridge trade mark stent, which
      had an elastic recoil of 4.79 %. The Corinthian IQ trade mark stent had
      noticeably the highest radial stiffness. In the expanded condition, the Peiron
      trade mark was the most flexible while the Corinthian IQ trade mark and the
      Antares trade mark were found to be the stiffest. Length change (shrinkage on
      expansion) ranged from 0.54 to 6.57%, with the exception of the Corinthian IQ,
      which shrunk > 7mm (18.5%) on expansion. All stent systems in the crimped and
      expanded state were readily visible radiographically. CONCLUSION: Specific data
      of significant parameters are available to aid in the selection of balloon
      expandable stents systems to be deployed in complex vascular regions. All
      examined stent systems showed adequate mechanical properties, but clinically
      relevant differences were found in stent trackability, bending stiffness and
      shrinkage on expansion.

PMID- 12424672
TI  - [Sample size determination in reference-controlled diagnostic trials].
AB  - PURPOSE: A tutorial illustration of a flexible approach to determine the sample
      size in reference-controlled diagnostic trials. MATERIALS AND METHODS: Assuming
      the usual setting of a new diagnostic method to be compared with a reference
      method, the emphasis is on the sensitivity of the new method in comparison with
      the reference method, using a binary outcome (positive versus negative) for both
      methods. Based on the confidence interval of the sensitivity, a simple but
      flexible procedure for determining the sample size is described, which
      incorporates clinically interpretable information. The procedure is illustrated
      by the fictitious planning of a trial to assess the diagnostic value of MRI
      versus arthroscopy as a reference, in the detection of meniscal ruptures.
      RESULTS: The principal investigator merely has to propose the range for the
      sensitivity in which the new method is considered equal to the reference method.
      Furthermore, it must be decided in advance how accurate the study outcome should
      determine the sensitivity of the new method, i.e., how wide its maximum
      confidence interval may become. The minimum sample size necessary for the trial
      can be directly derived from this outlined strategy, which can easily be extended
      by simultaneous consideration of sensitivity and specificity of the new method
      being tested. CONCLUSION: The flexible approach to planning by means of the
      confidence interval of the sensitivity controls the desired confidence of the
      outcome of the diagnostic trial. It allows a priori evaluation of study budget,
      study duration, number of study centers and, above all, any ethical limitations.
      It provides arguments for the investigator to proceed with the comparison and a
      rationale for the decision to conduct the comparison as mono- or multicentric
      trial

PMID- 12424673
TI  - [Combination of low and high resolution T1-weighted sequences for improved
      evaluation of morphologic criteria in dynamic contrast enhanced MRI of the
      breast].
AB  - PURPOSE: Presentation of a new protocol for simultaneous acquisition of both low
      and high resolution T 1 -weighted images of breast lesions for dynamic contrast
      enhanced MR mammography. Demonstration of possible diagnostic improvement with
      representative measurements in patients with suspected breast cancer by adding
      morphologic parameters from high resolution sequences to the analysis of the
      signal-time curve. MATERIALS AND METHODS: Dynamic MR imaging was performed with a
      1.5 T system (Magnetom SONATA, Siemens Medical Systems, Germany) and the
      manufacturer's double-breast coil. Coronal T 1 -weighted 3D FLASH sequences
      (spatial resolution 1.25 x 1.25 mm 2; slice thickness 1.7 mm) were acquired once
      before and five times after administration of contrast medium (Gd-DTPA, 0.15
      mmol/kg) injection. In addition, a high resolution T 1 -weighted 3D-FLASH
      sequence (spatial resolution, 0.63 x 0.63 mm 2) was obtained before
      administration of contrast medium and after the third post-contrast low
      resolution sequence. Except for the acquisition matrix, all imaging parameters
      were identical for both 3D pulse sequences. To assure comparison of the measured
      signal intensities for both T 1 -weighted sequences, calibrating phantom
      measurements were performed using a dilution series of Gd-DTPA. RESULTS: Phantom
      measurements demonstrated similar signal intensities and enhancement pattern for
      both sequences. A combined protocol consisting of both pulse sequences can be
      employed and does not interfere with the signal-time curve analysis. By measuring
      one high resolution sequence 3:18 minutes after administration of contrast
      medium, morphologic features can be evaluated without interference from barely
      enhancing surrounding tissue. The overall study time is not increased. The
      improved spatial resolution slightly increases the severity of motion artifacts.
      CONCLUSION: The new protocol is a clever way to improve the measurement of
      morphologic features without relevant loss of dynamic information. It is superior
      to converting the entire investigation to high resolution sequences and does not
      add any costs by not extending or duplicating the investigation. How much the new
      protocol can improve the specificity or sensitivity of MR-mammography is
      currently investigated on a larger patient group.

PMID- 12424674
TI  - [Ultrasound-guided puncture of the subclavian vein to implant central venous
      ports].
AB  - PURPOSE: To assess the safety and efficacy of ultrasound guided puncture of the
      subclavian vein instead of blind puncture or surgical procedure. The advantages
      compared with implantation of brachial ports are demonstrated. PATIENTS AND
      METHODS: In 41 oncologic patients the subclavian vein was punctured by ultrasound
      guidance in order to implant a port (34 left side, 7 right side). The study
      included 21 women and 20 men (range 34 - 79, mean 61 years). Imaging of the
      subclavian vein was performed with a 7,5 MHz linear ultrasound probe in B-mode
      and in colour doppler mode. Puncture was performed under ultrasound control (18
      G, 45 mm needle when skin-vessel distance was < 3 cm, 19 G, 75 mm needle when
      skin-vessel distance was > 3 cm). In 27 patients a Bardport was implanted, in 14
      patients a Vitalport (Cook). In three patients surgical port implantation failed.
      One of these patients had a partial thrombosis of the subclavian vein. RESULTS:
      Technical success was 100 %. In one patient we first punctured the subclavian
      artery at the beginning of our series without any complication. All port systems
      could be implanted. There was one haematoma in the port pocket without any effect
      to the port function. In the three surgical patients subclavian vein puncture and
      portimplantation was successful. CONCLUSION: Ultrasound guided puncture of the
      subclavian vein and port implantation by radiologists is a save procedure. A low
      risk approach to the subclavian vein is possible at any location. The long
      approach through the cubital vein with brachial port implantation is not
      necessary.

PMID- 12424675
TI  - [Examination of the constancy of the medium optical density of conventional chest
      radiographs].
AB  - PURPOSE: To determine whether the medium optical density of conventional chest
      radiographs is constant. MATERIALS AND METHODS: 47 PA chest radiographs were
      digitized to measure the optical density and its dynamic range of normal and
      pathologically altered lungs. RESULTS: For constant exposure factors and a
      correctly positioned region of interest, the medium optical density deviates only
      minimal despite differences in AP chest diameter, entry dose and dynamic range,
      and is largely independent of the pathologic pulmonary findings. CONCLUSION:
      Digitization of the radiograph enables the determination of the physical
      parameters used to operate the imaging system, such as medium optical density,
      image contrast, image latitude and density distribution, in accordance to the
      guidelines of the German Medical Association. If the region of interest
      encompasses the clinically relevant region of the lung, the measured value of the
      optical density corresponds with only minor variation to the average value of the
      entire lung region.

PMID- 12424676
TI  - [Cavernous hemangioma of the breast].

PMID- 12424677
TI  - [Delineated aneurysms of the large pulmonary arteries. A rare sequela of
      pulmonary hypertension].

PMID- 12424678
TI  - [Acute abdominal pain: CT diagnosis of omental volvulus].

PMID- 12424679
TI  - [Diagnosis and outcome of neurotropic enterovirus infections in childhood].
AB  - BACKGROUND: Enterovirus infections are among the most common causes of aseptic
      meningitis. Worldwide there are reports about recurring outbreaks, especially
      during the summer. They are favoured by conditions of bad hygiene and
      contaminated water, transmission is predominantly through the faeco-oral route or
      by droplet infection. The most common species are Coxsackie B and ECHO (Enteric
      Cytopathogenic Human Orphan) virus. ECHO viruses have a worldwide distribution
      and usually occur as "summer flu" or aseptic meningitis and meningoencephalitis
      in toddlers and infants. Type 30 caused an outbreak of aseptic meningitis in the
      Rhein-Main region in summer 1997. During five months 63 children younger than 16
      years were reported. PATIENTS AND METHODS: During this outbreak 18 children with
      prooved enterovirus infections were treated at the Frankfurt/Main University
      Children's Hospital. Standardized infectiological diagnostic procedures were
      performed and risc factors, clinical symptoms, inflammatory marker,
      neurophysiological findings (electroencephalography, evoked potentials) and
      outcome were assessed. RESULTS: The affected children were between 3 and 11 years
      old. Clinical symptoms were cephalgia, nausea, vomiting, meningism and seizures
      with fever. Virus isolation from faecal and cerebrospinal fluid (CSF) samples and
      the use of polymerase chain reaction (PCR) was superior to serological methods.
      Erythrocyte sedimentation rates showed more significant increase than C-reactive
      protein (CRP) and blood leukocytes. CSF pleocytosis showed high variation.
      Clinical course as well as prognosis and outcome were favourable. CONCLUSION:
      Virusisolation in stool and CSF is most promising in the diagnostic of cerebral
      enterovirus infections. Usually the outcome is favourable, encephalitis can occur
      as serious complication.

PMID- 12424680
TI  - [Congenital, solitary hepatic cyst: Observation of the development from birth
      upon the intervention in the 5th year of life].
AB  - BACKGROUND: Sonographic screening helps to discover pathological findings in
      asymptomatic patients. In these cases the decision about diagnostic and
      therapeutic consequences is difficult. CASE REPORT: We describe a girl with a
      congenital small solitary hepatic cyst with rapidly increasing size after the
      second year, which was interventionally sclerosed at the age of five years.
      CONCLUSION: Even in cases of small cysts long term follow up investigations are
      necessary, because the growth rate of the cyst can change.

PMID- 12424681
TI  - Burden of disease in hospitalized RSV-positive children in Germany.
AB  - BACKGROUND: In spite of a large amount of data from other countries, those on the
      burden of disease attributed to respiratory syncytial virus (RSV) in Germany are
      lacking and are urgently needed. METHOD: In a population-based cross-sectional
      study from July 1996 to June 1999 150 children from birth to 16 years of age
      hospitalized in Kiel and tested positive for RSV by polymerase chain reaction
      were investigated. Stepwise linear and logistic regression models were applied to
      predict a bacterial co-infection as well as the duration of hospitalization.
      RESULTS: Pneumonia (54 %) and wheezing bronchitis (including bronchiolitis, 27 %)
      were the predominating diagnoses; 25 % had an underlying condition. Four patients
      needed nasal continuous airway pressure and one intermittent mandatory
      ventilation; none died. According to the surrogate markers CRP and immature
      neutrophil fraction, 20 % to 30 % were suspected to have a bacterial co-infection
      on admission; antibiotics were prescribed in 65 % of the patients. The average
      duration of hospitalization was 9 days and was best predicted by young age, the
      presence of an underlying condition, intercostal retractions and high CRP on
      admission. CONCLUSIONS: Bacterial co-infection is the major confounder in burden
      of disease analyses in RSV. The decision not to administer antibiotics to
      children hospitalized with RSV can be risky, particularly when there is
      considerable diagnostic uncertainty. Within the realm of current clinical
      practice, complications and deaths related to RSV are rare in Germany.

PMID- 12424682
TI  - [Case report: neonatal hypertension].
AB  - BACKGROUND: Neonatal arterial hypertension is rare with an incidence between 0.2 
      3 %. Clinical presentation varies widely and is in some cases dramatic. PATIENT:
      A 4-day old full-term neonate was admitted to the intensive care unit with severe
      congestive heart failure and metabolic acidosis. Mechanical ventilation was
      initiated and dobutamine administered because of poor systolic function.
      Continuous monitoring of blood pressure revealed severe arterial hypertension (30
      to 40 mm Hg above the 95th percentile). Ultrasonography showed an echogenic left
      kidney with normal perfusion. Laboratory examinations revealed a raised
      peripheral renin activity, thrombocytopenia, slightly raised d-dimers, a
      microhematuria and mild proteinuria. After resolution of hypertension under
      therapy with an ACE-inhibitor, a MAG3 renal scan showed complete absence of renal
      function on the left side. Renal artery stenosis was excluded by venous
      transcardial angiography. Under therapy with Captopril, the patient was
      discharged and followed up for 8 months. He is developing normally with normal
      serum creatinine (0.4 mg/dl), but low renal function (17 %) of the left side as
      assessed by DMSA-scan and compensatory right kidney hypertrophy are observed.
      DISCUSSION: Diagnosis and treatment of neonatal hypertension are discussed with
      respect to the proposed case. After exclusion of other causes we conclude that a
      perinatal microangiopathic event may have lead to the renal lesions with
      malignant renovascular hypertension.

PMID- 12424683
TI  - [Inhibition of meconium induced activation of granulocytes from neonates and
      adults by pentoxyphylline].
AB  - BACKGROUND: Neutrophil activation plays a crucial role in the pathogenesis of the
      meconium aspiration syndrome. Therefore antiinflammatory strategies may offer
      therapeutic options. The methylxanthinderivative pentoxyphylline (PTX) is known
      to inhibit the tumor necrosis factor alpha-synthesis and neutrophil degranulation
      and thus may have beneficial effects on meconium-induced pulmonary inflammation.
      Effects of PTX on PMN-degranulation in neonatal whole blood have not yet been
      studied. PATIENTS AND METHODS: Heparin-anticoagulated (3 IE/ml) whole blood of
      healthy neonates (n = 6) and adult volunteers (n = 6) was incubated for 45 min.
      Spontaneous PMN-degranulation was compared with meconium-induced (3 mg/ml) and
      PTX-inhibited (0,025 - 0,4 mg/ml) degranulation by means of elastase (EL) and
      lactoferrin (LF) release from azurophilic and specific granules. EL- and LF
      plasma concentration was measured by immunoluminometric methods. RESULTS:
      Spontaneous degranulation of neonatal PMN was found to be significantly increased
      after 15 minutes compared with cells from adults (EL and LF concentration: 674
      and 660 ng/10 6 PMN vs. 284 and 261 ng/10 6 PMN). At 45 minutes adult PMN showed
      an acceleration of degranulation in contrast to neonatal cells (EL and LF: 1827
      and 1232 ng/10 6 PMN vs. 1400 and 860 ng/10 6 PMN). In presence of PTX (0,4
      mg/ml) spontaneous release of EL and LF from neonatal PMN was inhibited by nearly
      70 % at 45 min. while degranulation from adult PMN was found to be completely
      inhibited at 15 min. and reduced by 82 % and 78 % at 45 min. In presence of
      meconium (3 mg/ml) an increased degranulation of EL from PMN of both neonates and
      adults (317 % and 170 %) could be observed while LF release was found to be
      increased from neonatal cells only (267 % and 113 % respectively). PTX inhibited
      meconium-induced EL release in blood of bath neonates and adults by 63 % and 66
      %, while LF release was inhibited by 72 % and 57 % respectively. CONCLUSION:
      Neonatal PMN exhibit an increased degranulation from azurophilic and specific
      granules compared with cells from adults. PTX was found to be an effective
      inhibitor of spontaneous and meconium induced PMN degranulation and may offer new
      therapeutic options.

PMID- 12424684
TI  - [Prophylaxis of recurrent urinary tract infections in children. Results of an
      open, controlled and randomized study about the efficacy and tolerance of
      cefixime compared to nitrofurantoin].
AB  - Urinary tract infections are quite frequent in children. Urinary tract
      obstruction combined with recurrent urinary tract infections increase the risk
      for renal impairment. Therefore prophylaxis of reinfection is an important
      nephroprotective procedure. The aim of this open, controlled, randomised pilot
      study was to compare the efficacy and tolerance of a low dose prophylaxis with
      Cefixime versus Nitrofurantoin. 60 girls aged 1 to 11 years with at least 2
      urinary tract infections within the preceding year were included in the study.
      The minimum duration of therapy was 6 months and was extended to 12 months for
      most of the children. The number of recurrent infections was the main criteria
      for efficacy evaluation, whereas adverse events were analysed to evaluate
      tolerance. Statistical significant differences between the two treatment groups,
      regarding recurrence rates could not be demonstrated. Tolerance was comparable in
      both groups. The influence on gut flora of cefixime given as a low dose regimen
      over a long period of time corresponds with already published results and was not
      correlated with a higher number of gastrointestinal side effects. CONCLUSION: Low
      dose Cefixime (2 mg/kg bodyweight) is effective and well tolerated in the
      prophylaxis of recurrent urinary tract infections. Efficacy and tolerance of
      cefixime were comparable to the results obtained with nitrofurantoin. Due to the
      small number of patients this study was only a pilot study. Low-dose cefixime,
      however, could become an alternative to standard regimens in the prophylaxis of
      recurrent urinary tract infections. This should be investigated in further
      studies.

PMID- 12424685
TI  - Maternal smoking during pregnancy and behavioural characteristics in 2 - 4-month
      old infants.
AB  - The study aimed to assess potential relationship between maternal smoking during
      pregnancy and behavioural characteristics in 2 - 4-month-old infants. It covered
      period from 1999 to 2000 and comprised 250 randomly selected, apparently healthy
      singleton born infants from community setting (129 boys, 121 girls). The mothers
      were asked to complete the questionnaires addressing infant, maternal,
      demographic major characteristics with particular emphasis on maternal smoking
      during pregnancy. To objectively assess behavioural peculiarities of the infants,
      the mothers were requested to complete the Early Infancy Temperament
      Questionnaire. Of 250 mothers, 64. women (25.6 %) smoked during pregnancy. The
      infants of smoking mothers were more often born low birth weight and were also
      lighter at study; more frequently they were born at earlier gestational age, had
      lower Apgar score at 5 th minute, were less frequently breast fed at birth and at
      the time of study. Mothers who smoked during pregnancy were younger, had lower
      educational level, and less frequently were married. The infants born to smoking
      mothers had more frequent fussy periods occurring at about the same time of the
      day, protesting behaviour at face washing and washing in bath, indifferent
      attitude to the mother when held by new person, extreme reactions (either
      indifference or much feeling) during diapering and bowel movement, less attention
      to the parents during parent-infant play activity, and more sensitivity to the
      wet diaper. They were also characterised by more intensive reactions (displayed
      more amount of energy regardless of positive or negative behaviour) compared with
      the babies from the non-smoking group. This association remained after adjustment
      has been made for major potential confounders, and had a significant "dose
      response" effect. Maternal smoking during pregnancy may serve as a risk factor
      for infant's behavioural deviations.

PMID- 12424686
TI  - Early rather than recent exposure to tobacco increases bronchial reactivity.
AB  - BACKGROUND: Tobacco is well known to impair respiratory function of infants and
      children. This study was done to identify periods of increased vulnerability of
      the airways to tobacco products. PATIENTS AND METHODS: In 162 unselected
      schoolchildren maximum expiratory flow at 25 % of vital capacity (MEF25) was
      measured before and after cold air hyperventilation. Parental smoking habits were
      assessed by measurement of cotinine concentrations in children's urine and by
      interview. RESULTS: Children, whose mothers had smoked during pregnancy, showed
      increased bronchial reactivity at school age compared to children whose mothers
      had not smoked during pregnancy (median MEF25 [25th, 75th percentile] after cold
      air challenge as percent of baseline: 83 % [76, 95] vs. 95 % [79, 100]; p =
      0.03). Similar differences were found, when the study population was divided
      according to the maternal smoking status during the first six months of life. On
      the contrary, if the cotinine excretion exceeded the group median as a measure of
      recent exposure to tobacco smoke, bronchial reactivity was not increased (median
      MEF25 [25th, 75th percentile] as percent of baseline: 88 % [76, 100] vs. 93 %
      [79, 100]; p = 0.25). CONCLUSIONS: Pregnancy and early infancy were found to be
      periods of increased vulnerability of the airways to tobacco products.

PMID- 12424687
TI  - [Vanishing bile duct syndrome following allogeneic bone marrow transplantation].
AB  - BACKGROUND: Cholestasis following bone marrow transplantation is not rare, but
      should always be a warning signal. The main causes of cholestasis following bone
      marrow transplantation are hepatotoxic effects of drugs, venoocclusive disease
      (VOD), early graft-versus-host disease (GvHD), total parenteral nutrition, viral
      hepatitis, sepsis and opportunistic infections. Vanishing bile duct syndrome
      represents a very rare cause for cholestatic symptoms. CASE REPORT: We report on
      a 8-year-old boy suffering from myelodysplastic syndrome, who underwent
      allogeneic bone marrow transplantation and developed biliary ductopenia in terms
      of a vanishing bile duct syndrome. CONCLUSION: Differential diagnosis for
      cholestasis following bone marrow transplantation should include the vanishing
      bile duct syndrome.

PMID- 12424689
TI  - Immune protection of the brain--efficient and delicate.

PMID- 12424690
TI  - T cells in the central nervous system: the delicate balance between viral
      clearance and disease.
AB  - The central nervous system (CNS) is considered an "immunoprivileged" site with
      restricted access and a unique microenvironment that profoundly affects the
      capacity of T cells to exert their functions. The lymphocytic choriomeningitis
      virus model offers a unique system in which to evaluate the contrasting roles of
      specific T cells in causing lethal CNS disease or curing pervasive and life-long
      CNS infection. Specific T cell kinetics in the periphery is briefly discussed.
      The T cell-mediated mechanisms leading to fatal choriomeningitis are reviewed as
      are recent methodologic advances that will facilitate the study of antigen
      specific T cells in disease pathogenesis. Understanding the specific constraints
      imposed by the CNS on local T cell activity has important consequences for the
      design of therapeutic strategies aimed at preventing or curing CNS infection.

PMID- 12424691
TI  - The chemokine system in neuroinflammation: an update.
AB  - Chemokines and their receptors govern physiologic and pathologic leukocyte
      trafficking. The function of the chemokine system may be of particular interest
      for hematogenous leukocyte infiltration of the central nervous system (CNS)
      because of the distinct character of CNS inflammation and the exquisite
      specificity with which the chemokine system regulates cellular migration events.
      This review summarizes recent information about the expression and function of
      elements of the chemokine system in CNS inflammatory processes. Animal models of
      CNS demyelinating disease and the corresponding human disorder, multiple
      sclerosis are both considered.

PMID- 12424692
TI  - Transmission of prions.
AB  - The "protein only" hypothesis holds that the infectious agent causing
      transmissible spongiform encephalopathies is a conformational isomer of PrP, a
      host protein that is predominantly expressed in the brain. This hypothesis is
      strongly supported by many lines of evidence. To date, prion diseases are unique
      among conformational diseases in that they are transmissible-experimentally and
      by natural routes (mainly by ingestion). The pathway of prions to the brain has
      been elucidated in outline. A striking feature of prions is their extraordinary
      resistance to conventional sterilization procedures and their capacity to bind to
      surfaces of metal and plastic without losing infectivity. This property, first
      observed in a clinical setting, is now being investigated in experimental
      settings, both in animals and in cell culture.

PMID- 12424693
TI  - Subclinical scrapie infection in a resistant species: persistence, replication,
      and adaptation of infectivity during four passages.
AB  - Cross-species infection with transmissible spongiform encephalopathy agents may
      lead to subclinical infection and to adaptation of the infection to new species.
      This is of particular concern for the millions of people possibly exposed to
      bovine spongiform encephalopathy (BSE) by consumption of BSE-infected beef.
      Subclinical infection was studied by making 4 serial passages of hamster scrapie
      agent (263K) in mice. At each step, infectivity was followed by inoculation of
      hamsters and mice. Subclinical infection was demonstrated either by detection of
      abnormal protease-resistant prion protein (PrP-res) or in the absence of PrP-res
      by detection of infectivity. Replication and adaptation of hamster infectivity in
      mice was shown in year 2 after initial mouse passage. In third and fourth
      passages, dual-tropic, mouse-tropic, and hamster-tropic infectivity was found in
      different animals. In some cases infectivity similar to the original 263K hamster
      scrapie strain was found after 2 or 3 serial mouse passages totaling 1200-1550
      days.

PMID- 12424694
TI  - Glial cell responses to herpesvirus infections: role in defense and
      immunopathogenesis.
AB  - Glial cells can respond to herpesvirus infections through the production of
      cytokines and chemokines. Although specific interactions between resident glia
      and lymphocytes that infiltrate the infected brain remain to be defined, the
      presence of T cell chemotactic signals in microglial cell supernatants following
      infection with cytomegalovirus or herpes simplex virus has led to the concept
      that chemokines initiate a cascade of neuroimmune responses that result in
      defense of the brain against herpesviruses. While chemokines may play a defensive
      role by attracting T cells into the brain, aberrant accumulation of lymphocytes
      may also induce brain damage. Host defense mechanisms must balance control of
      herpesvirus spread with associated undesirable immunopathologic effects. A
      growing body of evidence suggests that through complex networks of chemokines and
      cytokines produced in response to herpesvirus infection, glial cells orchestrate
      a cascade of events that result in successful defense of or damage to the brain.

PMID- 12424695
TI  - Traffic of JC virus from sites of initial infection to the brain: the path to
      progressive multifocal leukoencephalopathy.
AB  - Progressive multifocal leukoencephalopathy (PML) is a demyelinating disorder of
      the human brain caused by infection with the human polyomavirus, JC. Up to 80% of
      humans express serum antibodies to JC virus (JCV), yet considerably fewer people
      develop PML-predominantly those under immunosuppressive conditions. Recent
      research showed JCV infection in multiple tissues throughout the body, suggesting
      sites for viral latency. These observations allow the proposal of pathways that
      JCV may use from sites of initial infection to the brain. Results from
      investigations into cell-surface receptors, intracellular DNA-binding proteins,
      and variant viral regulatory regions also suggest mechanisms that may regulate
      cellular susceptibility to JCV infection. Together, these data elucidate how JCV
      may establish infection in various cell types, persist latently or become
      reactivated, and ultimately reach the brain to cause PML.

PMID- 12424696
TI  - Immunopathogenesis of human T cell lymphotropic virus type I-associated
      neurologic disease.
AB  - This review focuses on current approaches to understanding the immunopathogenesis
      of human T cell lymphotropic virus (HTLV) type I-associated myelopathy/tropical
      spastic paraparesis (HAM/TSP) based on newly developed molecular and immunologic
      techniques that have been adapted to studies of HTLV-I proviral load, HTLV-I
      mRNA, and HTLV-I tax-specific CD8 T cells. These methods enable researchers to
      study previously inaccessible aspects of this disease and allow a more detailed
      analysis of virus/host immune responses as they relate to disease specificity in
      this disorder. The role of HTLV-I-specific CD8 T cell immune responses is
      highlighted. The elucidation of the immunopathology of HAM/TSP will enhance our
      understanding of other HTLV-I-associated disorders plus other neurologic,
      hematologic, and inflammatory diseases for which viral etiologies have been
      suggested.

PMID- 12424697
TI  - Human immunodeficiency virus (HIV) proteins in neuropathogenesis of HIV dementia.
AB  - Human immunodeficiency virus (HIV) infection of the nervous system is unique when
      compared with other viral encephalitides. Neuronal cell loss occurs in the
      absence of neuronal infection. Viral proteins, termed "virotoxins," are released
      from the infected glial cells that initiate a cascade of positive feedback loops
      by activating uninfected microglial cells and astrocytes. These activated cells
      release a variety of toxic substances that result in neuronal dysfunction and
      cell loss. The virotoxins act by a hit and run phenomenon. Thus, a transient
      exposure to the proteins initiates the neurotoxic cascade. High concentrations of
      these proteins likely occur in tight extracellular spaces where they may cause
      direct neurotoxicity as well. The emerging concepts in viral protein-induced
      neurotoxicity are reviewed as are the neurotoxic potential of each protein.
      Future therapeutic strategies must target common mechanisms such as oxidative
      stress and dysregulation of intracellular calcium involved in virotoxin-mediated
      neurotoxicity.

PMID- 12424698
TI  - Searching for clues: tracking the pathogenesis of human immunodeficiency virus
      central nervous system disease by use of an accelerated, consistent simian
      immunodeficiency virus macaque model.
AB  - An accelerated model of human immunodeficiency virus central nervous system
      disease was developed in which more than 90% of infected macaques develop typical
      simian immunodeficiency virus (SIV) encephalitis with neuronal dysfunction by
      postinoculation (pi) day 84. Infected macaques had replicating virus and
      microglial activation in the brain 10 days after inoculation; viral replication
      and microglial activation were suppressed at pi day 21. By pi day 56, viral
      recrudescence in the brain was detected in 2 of 6 infected macaques. CD4 cells
      were the predominant lymphocytes in the brain during acute and asymptomatic
      infection; cytotoxic T lymphocytes and NK cells predominated in macaques with
      encephalitis. Low levels of peripheral blood NK lytic activity at pi day 10,
      elevated cerebrospinal fluid (CSF) monocyte chemoattractant protein-1 after 28
      days, and high CSF viral RNA after 42 days predicted SIV encephalitis. This model
      is ideal to track the viral, cellular, and immunologic changes in the brain
      during acute and asymptomatic infection and during viral recrudescence and SIV
      encephalitis.

PMID- 12424700
TI  - Neuronal survival strategies in the face of RNA viral infection.
AB  - Neurons of the mammalian central nervous system (CNS) are an essential and
      largely nonrenewable cell population. Thus, viral infections that result in
      neuronal depletion, either by viral lysis or by induction of the cytolytic immune
      response, would likely lead to profound neurologic impairment. However, many
      viral infections that result in tissue destruction elsewhere in the host produce
      few overt symptoms in the CNS, despite readily detectable virus expression. This
      observation has lead to the speculation that neurons possess strategies to limit
      the replication and spread of otherwise cytopathic viruses. These strategies
      either favor the clearance of virus in the absence of appreciable neuronal loss
      or promote the establishment of noncytolytic persistent infections. This review
      discusses some of these strategies, with an emphasis on how such survival
      techniques lessen the potential for CNS neuropathology.

PMID- 12424699
TI  - Exploiting circuit-specific spread of pseudorabies virus in the central nervous
      system: insights to pathogenesis and circuit tracers.
AB  - The neurotropic alpha-herpesviruses are common mammalian pathogens that invade
      the peripheral and central nervous system of their hosts. Their ability to invade
      and spread in the nervous system in a directional manner has been exploited to
      develop them as neuronal circuit tracers. Tracing viruses spread among
      synaptically connected neurons and, by assaying brain sections for viral antigen
      or reporter genes expressed from the viruses, chains of synaptically connected
      neurons can be visualized. Virulent field strains generally are not good tracers,
      but some attenuated strains perform well. Live attenuated vaccine strains of
      pseudorabies virus (PRV), such as PRV Bartha, are among the most popular virus
      circuit tracers. It may be counterintuitive that attenuation results in improved
      neural tracing that requires extensive replication and spread in the brain. This
      report summarizes two lines of experiments directed to resolving this apparent
      paradox and introduces a new paradigm for tracing viruses.

PMID- 12424701
TI  - Strategy of Escherichia coli for crossing the blood-brain barrier.
AB  - A major contributing factor to high mortality and morbidity associated with
      bacterial meningitis is the incomplete understanding of the pathogenesis of this
      disease: It is unclear how circulating bacteria cross the blood-brain barrier
      (BBB). Recent studies with Escherichia coli K1 show that successful traversal of
      the BBB requires a high degree of bacteremia, invasion of brain microvascular
      endothelial cells (BMEC), host cell actin cytoskeleton rearrangements and related
      signaling pathways, and traversal of the BBB as live bacteria. Several microbial
      determinants such as the K1 capsule, OmpA, Ibe proteins, AslA, TraJ, and CNF1
      contribute to BMEC invasion. Of interest, E. coli K1 trafficking mechanisms
      differ from those of other meningitis-causing bacteria such as Listeria
      monocytogenes and group B streptococcus. Complete understanding of bacteria-BMEC
      interactions contributing to translocation of the BBB should assist in developing
      novel strategies to prevent bacterial meningitis.

PMID- 12424702
TI  - Pathophysiology of bacterial meningitis: mechanism(s) of neuronal injury.
AB  - No bacterial disease has undergone a more dramatic change in epidemiology during
      the past decade than acute bacterial meningitis. This review describes the
      changing epidemiology and considers some important recent observations that
      contribute to our understanding of the pathogenesis and pathophysiology of
      meningitis. The major focus is on the mechanisms of neuronal injury and the
      pathophysiologic concepts responsible for death and neurologic sequelae. In
      recent years, experimental studies have amplified our understanding of the
      substantial body of evidence that now implicates cytokines and chemokines,
      proteolytic enzymes, and oxidants in the inflammatory cascade leading to tissue
      destruction in bacterial meningitis. The molecular mechanisms responsible for
      oxidant-induced neuronal injury in meningitis are explored in some depth. Genetic
      targeting and/or pharmacologic blockade of the implicated pathways may be a
      future strategy for therapeutic adjunctive measures to improve outcome and may
      hold substantial promise, in concert with antimicrobial agents, in humans with
      acute bacterial meningitis.

PMID- 12424703
TI  - Immunopathogenesis of cerebral toxoplasmosis.
AB  - Interferon (IFN)-gamma is an absolute requirement for resistance against acute
      acquired infection with Toxoplasma gondii and development of toxoplasmic
      encephalitis (TE) during the late stage of infection. Multiple populations of
      both T and non-T cells are important sources of IFN-gamma in resistance. In the
      absence of IFN-gamma-producing non-T cells, T cells cannot prevent TE.
      Interleukin-12, Bcl-3, NF-kappaB(2), and CD40-CD40L ligand interaction are
      important for up-regulation of IFN-gamma production. T. gondii infects a variety
      of host cells, and IFN-gamma-mediated immune responses control the parasite in
      both phagocytic and nonphagocytic cells through at least five different
      mechanisms, most likely depending on the types of cells responding to IFN-gamma.
      Such effector functions involve production of NO by iNOS, tryptophan degradation
      by the enzyme IDO (indolamine 2,3-dioxygenase), unidentified mechanism(s)
      mediated by 47- to 48-kDa proteins encoded by an IFN-gamma responsive gene
      family, limiting the availability of intracellular iron to the parasite, and
      production of reactive oxygen intermediates.

PMID- 12424704
TI  - Bornavirus and the brain.
AB  - Borna disease virus (BDV) causes central nervous system (CNS) disease that is
      frequently manifested by behavioral abnormalities. BDV is a nonsegmented,
      negative, single-stranded RNA virus. On the basis of its unique genetic and
      biologic features, BDV is the prototypic member of a new virus family,
      Bornaviridae, within the order Mononegavirales. Therefore, the investigation of
      the molecular and cell biology of BDV may provide new insights about virus-cell
      interactions in the CNS. BDV is an important model system for the investigation
      of viral persistence in the CNS. Serologic and molecular epidemiologic studies
      suggest that BDV can infect humans. Despite controversy about potential
      association with human neuropsychiatric illnesses, BDV affords an intriguing
      model for the study of these illnesses. Neonatal BDV-infected rats display
      neurodevelopmental, physiologic, and neurobehavioral abnormalities that closely
      parallel some of the main features associated with several human mental
      disorders.

PMID- 12424705
TI  - Heterogeneity of pathogenesis in multiple sclerosis: implications for promotion
      of remyelination.
AB  - Enhancing myelin repair remains an important therapeutic goal in primary
      demyelinating diseases of the central nervous system (CNS) such as multiple
      sclerosis (MS). The emerging heterogeneity of pathology within MS lesions, and
      differential oligodendrocyte survival in particular, suggests that therapeutic
      strategies may need to be tailored to an individual patient's requirements. A
      number of therapeutic strategies have been proposed to enhance myelin repair in
      the CNS: cell transplantation, growth factor therapy, and antibody therapy, but
      each proposed therapy has different implications with respect to pathogenetic
      mechanisms of demyelination. Of these, antibody therapy is the most amenable to
      immediate application in patients-but a combination of therapeutic approaches may
      be required in practice.

PMID- 12424706
TI  - New technologies, human-microbe interactions, and the search for previously
      unrecognized pathogens.
AB  - Evidence suggests that a significant number of clinically important microbial
      pathogens remain unrecognized. Observations from the natural world, from patterns
      of disease in human populations, from the bedside, and from the clinical
      laboratory all contribute to this body of evidence. A variety of acute and
      chronic neurologic syndromes illustrate this point; despite features of
      infection, most cases of aseptic meningitis, encephalitis, and cerebral
      vasculitis cannot be assigned a microbiologic diagnosis. The development and
      clinical application of molecular methods have led to the discovery of novel
      members of the endogenous normal flora as well as putative disease agents.
      Current challenges include the establishment of criteria for disease causation
      and further characterization of the human microbiome during states of health.
      These challenges and the goal of understanding microbial contributions to
      inflammatory disease may be addressed effectively through the thoughtful
      integration of modern technologies and clinical insight.

PMID- 12424707
TI  - Parental origin and timing of de novo Robertsonian translocation formation.
AB  - Robertsonian translocations (ROBs) are the most common chromosomal rearrangements
      in humans. ROBs are whole-arm rearrangements between the acrocentric chromosomes
      13-15, 21, and 22. ROBs can be classified into two groups depending on their
      frequency of occurrence, common (rob(13q14q) and rob(14q21q)), and rare (all
      remaining possible nonhomologous combinations). Herein, we have studied 29 case
      subjects of common and rare de novo ROBs to determine their parental origins and
      timing of formation. We compared these case subjects to 35 published case
      subjects of common ROBs and found that most common ROBs apparently have the same
      breakpoints and arise mainly during oogenesis (50/54). These probably form
      through a common mechanism and have been termed "class 1." Collectively, rare
      ROBs also occur mostly during oogenesis (7/10) but probably arise through a more
      "random" mechanism or a variety of mechanisms and have been termed "class 2."
      Thus, we demonstrate that although both classes of ROBs occur predominantly
      during meiosis, the common, class 1 ROBs occur primarily during oogenesis and
      likely form through a mechanism distinct from that forming class 2 ROBs.

PMID- 12424708
TI  - Structural and functional characterization of factor H mutations associated with
      atypical hemolytic uremic syndrome.
AB  - Genetic studies have demonstrated the involvement of the complement regulator
      factor H in nondiarrheal, nonverocytotoxin (i.e., atypical) cases of hemolytic
      uremic syndrome. Different factor H mutations have been identified in 10%-30% of
      patients with atypical hemolytic uremic syndrome (aHUS), and most of these
      mutations alter single amino acids in the C-terminal region of factor H. Although
      these mutations are considered to be responsible for the disease, the precise
      role that factor H plays in the pathogenesis of aHUS is unknown. We report here
      the structural and functional characterization of three different factor H
      proteins purified from the plasma of patients with aHUS who carry the factor H
      mutations W1183L, V1197A, or R1210C. Structural anomalies in factor H were found
      only in R1210C carriers; these individuals show, in their plasma, a
      characteristic high-molecular-weight factor H protein that results from the
      covalent interaction between factor H and human serum albumin. Most important,
      all three aHUS-associated factor H proteins have a normal cofactor activity in
      the proteolysis of fluid-phase C3b by factor I but show very low binding to
      surface-bound C3b. This functional impairment was also demonstrated in
      recombinant mutant factor H proteins expressed in COS7 cells. These data support
      the hypothesis that patients with aHUS carry a specific dysfunction in the
      protection of cellular surfaces from complement activation, offering new
      possibilities to improve diagnosis and develop appropriate therapies.

PMID- 12424710
TI  - Brain edema in liver failure: basic physiologic principles and management.
AB  - In patients with severe liver failure, brain edema is a frequent and serious
      complication that may result in high intracranial pressure and brain damage. This
      short article focuses on basic physiologic principles that determine water flux
      across the blood-brain barrier. Using the Starling equation, it is evident that
      both the osmotic and hydrostatic pressure gradients are imbalanced across the
      blood-brain barrier in patients with acute liver failure. This combination will
      tend to favor cerebral capillary water influx to the brain. In contrast, the
      disequilibration of the Starling forces seems to be less pronounced in patients
      with cirrhosis because the regulation of cerebral blood flow is preserved and the
      arterial ammonia concentration is lower compared with that of patients with acute
      liver failure. Treatments that are known to reverse high intracranial pressure
      tend to decrease the osmotic pressure gradients across the blood-brain barrier.
      Recent studies indicate that interventions that restrict cerebral blood flow,
      such as hyperventilation, hypothermia, and indomethacin, are also efficient in
      preventing edema and high intracranial pressure, probably by decreasing the
      transcapillary hydrostatic pressure gradient. In our opinion, it is important to
      recall that rational fluid therapy, adequate ventilation, and temperature control
      are of direct importance to controlling cerebral capillary water flux in patients
      with acute liver failure. These simple interventions should be secured before
      more advanced experimental technologies are instituted to treat these patients.

PMID- 12424709
TI  - Molecular analysis of the cyclic AMP-dependent protein kinase A (PKA) regulatory
      subunit 1A (PRKAR1A) gene in patients with Carney complex and primary pigmented
      nodular adrenocortical disease (PPNAD) reveals novel mutations and clues for
      pathophysiology: augmented PKA signaling is associated with adrenal tumorigenesis
      in PPNAD.
AB  - We studied 11 new kindreds with primary pigmented nodular adrenocortical disease
      (PPNAD) or Carney complex (CNC) and found that 82% of the kindreds had PRKAR1A
      gene defects (including seven novel inactivating mutations), most of which led to
      nonsense mRNA and, thus, were not expressed in patients' cells. However, a
      previously undescribed base substitution in intron 6 (exon 6 IVS +1G-->T) led to
      exon 6 skipping and an expressed shorter PRKAR1A protein. The mutant protein was
      present in patients' leukocytes and tumors, and in vitro studies indicated that
      the mutant PRKAR1A activated cAMP-dependent protein kinase A (PKA) signaling at
      the nuclear level. This is the first demonstration of an inactivating PRKAR1A
      mutation being expressed at the protein level and leading to stimulation of the
      PKA pathway in CNC patients. Along with the lack of allelic loss at the PRKAR1A
      locus in most of the tumors from this kindred, these data suggest that alteration
      of PRKAR1A function (not only its complete loss) is sufficient for augmenting PKA
      activity leading to tumorigenesis in tissues affected by CNC.

PMID- 12424711
TI  - Ischemic preconditioning attenuates the oxidant-dependent mechanisms of
      reperfusion cell damage and death in rat liver.
AB  - In an in vivo rat model of liver ischemia followed by reperfusion a consistent
      appearance of necrosis and activation of biochemical pathways of apoptosis was
      reproduced and monitored after 30 minutes reperfusion. Preconditioning by
      application of a short cycle of ischemia-reperfusion (10 minutes + 10 minutes)
      positively conditioned recovery of the organ at reperfusion, attenuating both
      necrotic and apoptotic events. Preconditioning at least halved cell oxidative
      damage occurring early at reperfusion, and as a major consequence, the increase
      of cytolysis and apoptosis occurring at reperfusion was about 50% less. The
      attenuation of both pathways of cell death by preconditioning appeared at least
      partly related to its modulate action on H(2)O(2) and 4-hydroxy-2,3-trans-nonenal
      production. The overall data point to a marked diminished oxidant generation and
      oxidative reactions as one major possible mechanism through which ischemic
      preconditioning exerts protection against necrotic and apoptotic insult to the
      postischemic liver.

PMID- 12424712
TI  - Combination of interferon alfa-2b and ribavirin in liver transplant recipients
      with histological recurrent hepatitis C.
AB  - Recurrent hepatitis C virus (HCV) infection is an important cause of fibrosis and
      cirrhosis after liver transplantation (LT), with histological recurrence
      developing in at least 50% of patients within the first year. The aim of this
      study is to assess the safety and efficacy of interferon alfa-2b plus ribavirin
      in treating histological recurrent HCV after LT. Since 1998, patients with HCV
      with significant histological recurrence (fibrosis >/= 3 and/or histological
      activity index >/= 5) or progressive cholestatic disease after LT were treated
      with interferon alfa-2b (3 million units subcutaneously three times weekly) plus
      ribavirin (800 to 1,000 mg/d) for 12 months. Immunosuppression was tapered to
      cyclosporine/FK506 monotherapy. HCV RNA was assessed at entry, week 24, end of
      treatment, and 6 months after therapy. The primary end point was loss of HCV RNA
      6 months after therapy, whereas the secondary end point was histological
      response. Fifty-four patients met criteria for treatment and have completed
      follow-up. Patients were mainly men (71% men; mean age, 51 +/- 5 years) with
      genotype 1 infection (88%) and high viral load (mean HCV RNA, 38 +/- 9 mEq/mL).
      Dose modification was required in 72% of patients because of cytopenia or side
      effects. Intent-to-treat analysis showed that serum HCV RNA was undetectable in
      19 patients (35%) week 24, 21 patients (38%) week 48, and 16 patients (30%) at
      the 6-month follow-up. Paired liver biopsy results (before and within 6 months
      after treatment) were available for 35 patients. Patients who achieved viral
      eradication had no significant progression of fibrosis after 1 year of therapy.
      In summary, combination therapy is a reasonable antiviral option for recurrent
      HCV infection for established post-LT hepatitis and appears to prevent
      histological progression of disease if viral eradication is successful.

PMID- 12424713
TI  - Ribavirin dose modification based on renal function is necessary to reduce
      hemolysis in liver transplant patients with hepatitis C virus infection.
AB  - Hepatitis C virus (HCV) is currently the most common etiology for liver
      transplantation (LTx) in the United States. A significant number of patients
      develop recurrent HCV after LTx. Although there is no completely satisfactory
      treatment for recurrent HCV, a combination of interferon-alpha (INF) and
      ribavirin remains the most widely used. Ribavirin is eliminated through the
      kidneys and tends to accumulate in the presence of renal dysfunction. The primary
      side effect of ribavirin is hemolysis. The goal of the present study was to
      correlate the incidence of hemolysis with renal function in LTx patients with
      recurrent HCV who were being treated with ribavirin. The incidence of hemolysis
      and the renal function were examined in 72 liver transplant patients (58 male and
      14 female patients) with recurrent HCV receiving INF (3 million units, three
      times per week) and ribavirin (initial dose of 400 mg twice daily). Patients were
      grouped according to the decrease in the percentage of hematocrit after the
      introduction of ribavirin, with their baseline serum creatinine and creatinine
      clearance calculated using the Cockcroft-Gault formula. The decrease in the
      percentage of hematocrit after ribavirin treatment was also examined with respect
      to creatinine clearance as a continuous variable. In addition, for purposes of
      presentation, patients were analyzed in three groups: creatinine clearance of >/=
      70 mL/min (group A), creatinine clearance < 70 mL/min and >/= 40 mL/min (group
      B), and creatinine clearance < 40 mL/min (group C). Forty-five (62.5%) patients
      experienced a decrease in hematocrit (Hct) >/=15% after starting INF and
      ribavirin. The mean serum creatinine was 1.3 +/- 0.5 mg/dL (median, 1.3) in this
      group, and the mean calculated creatinine clearance was 71 +/- 29 mL/min (median,
      66.47). In the 27 patients who did not show a significant decrease (< 15%) in
      hematocrit, the mean serum creatinine was 1.1 +/- 0.3 mg/dL (median, 1.0) and the
      mean creatinine clearance was 95 +/- 39 (median, 96) mL/min (P =.018). On
      continuous variable of calculated creatinine clearance, there was a trend in the
      decrease in hematocrit after ribavirin treatment compared with pretreatment (P
      =.09). However, the rate of hemolysis was significantly different in group A
      (53.7%), group B (70.8%), and group C (100%) (P =.042). Patients on INF and
      ribavirin therapy who experienced hemolysis had significantly higher serum
      creatinine levels and lower creatinine clearances compared with those who did not
      have hemolysis. The incidence of hemolysis was significantly associated with
      higher serum creatinine and decreased creatinine clearance. Because ribavirin is
      eliminated by the kidneys, this observation points to the need for adjustments in
      the dose of this agent in LTx patients, who tend to have some degree of renal
      dysfunction, to reduce the incidence of hemolysis. Further pharmacokinetic
      studies of ribavirin in LTx patients with varying degrees of renal function may
      allow the development of an algorithm for the safer use of ribavirin in HCV
      positive LTx patients.

PMID- 12424714
TI  - Detection of hepatitis C virus sequences in brain tissue obtained in recurrent
      hepatitis C after liver transplantation.
AB  - Patients with chronic hepatitis C frequently report tiredness, easy fatigability,
      and depression. The aim of this study is to determine whether hepatitis C virus
      (HCV) replication could be found in brain tissue in patients with hepatitis C and
      depression. We report two patients with recurrent hepatitis C after liver
      transplantation who also developed severe depression. One patient died of
      multiorgan failure and the other, septicemia caused by Staphylococcus aureussis.
      Both patients had evidence of severe hepatitis C recurrence with features of
      cholestatic fibrosing hepatitis. We were able to study samples of their central
      nervous system obtained at autopsy for evidence of HCV replication. The presence
      of HCV RNA-negative strand, which is the viral replicative form, was determined
      by strand-specific Tth-based reverse-transcriptase polymerase chain reaction.
      Viral sequences were compared by means of single-strand conformation polymorphism
      and direct sequencing. HCV RNA-negative strands were found in subcortical white
      matter from one patient and cerebral cortex from the other patient. HCV RNA
      negative strands amplified from brain tissue differed by several nucleotide
      substitutions from serum consensus sequences in the 5' untranslated region. These
      findings support the concept of HCV neuroinvasion, and we speculate that it may
      provide a biological substrate to neuropsychiatric disorders observed in patients
      with chronic hepatitis C. The exact lineage of cells permissive for HCV
      replication and the possible interaction between viral replication and cerebral
      function that may lead to depression remain to be elucidated.

PMID- 12424715
TI  - Hepatocellular carcinoma: Can it be considered a controversial indication for
      liver transplantation in centers with high rates of hepatitis C?
AB  - Hepatocellular carcinoma (HCC) is still considered a controversial indication for
      liver transplantation (LT), mainly because of long waiting times and underlying
      viral cirrhosis. The goal was to evaluate the outcome of LT in 104 patients with
      HCC and cirrhosis, mainly hepatitis C virus (HCV)-related, in a center with a
      short waiting time (median, 105 days). Four groups were formed according to the
      HCC and HCV status: HCV positive with HCC (group 1, n = 81), HCV negative with
      HCC (group 2, n = 23), HCV positive without HCC (group 3, n = 200), and HCV
      negative without HCC (group 4, n = 207). Predictive factors of tumor recurrence
      were demographics, tumor related (size or number of nodules, capsule, bilobar
      involvement, vascular or lymphatic invasion, clinical and pathologic TNM staging,
      pre-LT percutaneous ultrasound-guided ethanol injection or transarterial
      chemoembolization, alpha-fetoprotein levels), donor and surgery related, and year
      of transplantation. The same variables and "tumor recurrence (yes/no)" were
      applied to evaluate the effect on survival. The median follow up was 29 months
      (range, 0 to 104 months). Patient survival was 70% at 1 year and 59% at 5 years
      for group 1, 87% at 1 year and 77% at 5 years for group 2, 81% at 1 year and 64%
      at 5 years for group 3, and 88% at 1 year and 77% at 5 years for group 4 (P
      =.013). Survival was significantly lower in patients with HCC than in those
      without (74% and 63% versus 85% and 70%, at 1 and 5 years, respectively; P =.05).
      The causes of death in those with and without HCC were tumor recurrence (24%) and
      recurrent HCV (8%) versus sepsis (34%) and recurrent HCV (14%). HCC recurrence
      occurred in 12 patients (11.5%) at a median of 14 months (range, 3 to 60 months)
      with a probability increasing from 8% at 1 year to 16% at 5 years. In patients
      with HCC, tumor recurrence was associated with vascular invasion (P =.0004) by
      multivariate analysis; variables predictive of survival were donor old age (P
      =.01), viral-related etiology (P =.02), and tumor recurrence (P =.001). Although
      LT still remains an adequate indication for HCC in centers with high prevalence
      of HCV infection and short waiting times, both tumor and HCV-related recurrent
      diseases hamper significantly the outcomes of these patients.

PMID- 12424716
TI  - Improvement of rat liver graft function after storage in University of Wisconsin
      solution containing testicular hyaluronidase.
AB  - Hyaluronan accumulates at sites of inflammation, which affects the organization
      of matrix and thereby the proliferation, migration, and adherence of cells. In
      this study we investigated possible beneficial effects of the hyaluronan
      degrading enzyme hyaluronidase on rat liver graft viability. Orthotopic rat liver
      transplantation was performed using a cuff technique in Wistar AL Bacharach Glaxo
      (WAG) rats grafted with WAG livers, which had been stored in the University of
      Wisconsin (UW) solution or in UW solution enriched with testicular hyaluronidase.
      Liver tissue architecture, as well as tissue and serum hyaluronan levels, were
      determined using immunohistochemistry and biochemical assays. Addition of
      testicular hyaluronidase (0.4 mg/mL) to livers preserved for 24 hours in cold UW
      solution followed by brief exposure to Ringer's lactate both prolonged the
      function of the grafted livers and improved their viability (4 of 10 grafts
      survived, compared with 0 of 10 in the control group). Hyaluronidase treatment
      did not damage the liver tissue architecture, and a reduced edema was observed in
      the survivors. Furthermore, 10 minutes after restoration of circulation, higher
      serum hyaluronan levels were observed in nonsuccessful compared with successful
      transplantations, whereas no differences in the levels of other serum viability
      markers were detected. We conclude that addition of testicular hyaluronidase to
      storage UW solution limits liver cell damage and considerably improves graft
      function. Furthermore, our data suggest that serum hyaluronan level is a better
      marker than other serum markers for early evaluation of postoperative graft
      function.

PMID- 12424717
TI  - Management and outcome of major bile duct injuries after laparoscopic
      cholecystectomy: from therapeutic endoscopy to liver transplantation.
AB  - Laparoscopic cholecystectomy is associated with a higher rate of bile duct
      injuries than an open cholecystectomy. The annual incidence of bile duct injuries
      has remained almost constant and these injuries tend to be more serious, making
      demands on the method of repair. We wanted to report the management and outcome
      of major bile duct injuries after laparoscopic cholecystectomy in patients
      referred to a hepatobiliary and liver transplantation unit. Eighteen patients (14
      women), with a median age of 53.5 years were referred to the liver surgery unit
      with a major bile duct injury after laparoscopic cholecystectomy. The injury was
      identified after a median of 3 days (range, 0 to 25 days) after operation and the
      median time interval to referral was 79 days (0 to 2270 days). Fourteen patients
      had undergone surgery before referral. By the time of referral, four patients had
      developed end-stage cirrhosis, necessitating liver transplantation. Three of them
      had undergone bilioenteric drainage operations at the referring institute. Of the
      remaining 14 patients, three were managed by therapeutic endoscopic procedures.
      Ten patients were managed with Roux-en-Y hepaticojejunostomy. One died of septic
      complications before the repair. A median time for hospitalization in our unit
      was 33 days (range, 10 to 164 days). At present, 16 patients are alive. One
      patient died of Kaposi's sarcoma 7 months after liver transplantation. A long
      interval between bile duct injury and referral was associated with the
      development of end-stage liver disease. Surgery of biliary lesions is demanding,
      and surgical experience with multidisciplinary approach, including therapeutic
      endoscopy and liver transplantation, is necessary for successful outcome.

PMID- 12424718
TI  - The optimal number of donor biopsy sites to evaluate liver histology for
      transplantation.
AB  - Macrovesicular steatosis (MaS), fibrosis, and inflammation have been associated
      with poor graft function after liver transplantation. We evaluated histological
      variation in livers to determine the optimal number of biopsies to estimate
      pathological characteristics in livers for transplantation. Specimens from
      autopsies performed during 3 months in 16- to 70-years-olds without known liver
      disease or drug and/or alcohol abuse were examined. Eight needle biopsies were
      performed, and hematoxylin and eosin-stained slides were evaluated. Percentages
      of MaS and microvesicular steatosis (MiS) were determined, and inflammation and
      fibrosis were scored as 0 to 4. MaS correlated positively with MiS, and
      inflammation correlated positively with fibrosis, whereas patient weight showed a
      significant correlation with liver weight and body mass index. No patient
      characteristic showed a significant correlation with histological findings.
      Subjects 55 years and older showed no increase in pathological findings compared
      with those younger than 55 years. When any site was compared with the average of
      the other sites, Spearman's rho correlation ranged from 0.89 to 0.95 for MaS,
      0.89 to 0.94 for MiS, 0.54 to 0.80 for inflammation, and 0.66 to 0.80 for
      fibrosis. Two biopsies explained 95% of variations for MaS and MiS and 85% for
      inflammation and fibrosis. There was no significant difference between findings
      in the right and left lobes of livers. These findings suggest that no single site
      best predicts pathological findings, and there is little variation among sites.
      In borderline cases of MaS, significant pathological characteristics may be found
      in additional biopsies. Therefore, we recommend two biopsy sites to evaluate
      donor livers with suspicious clinical histories.

PMID- 12424719
TI  - Role of echocardiography in detecting portopulmonary hypertension in liver
      transplant candidates.
AB  - Portopulmonary hypertension (PPHTN) is a recognized complication of end-stage
      liver disease that adversely affects the outcome of orthotopic liver
      transplantation (OLT). There are limited data on the role of Doppler
      echocardiography in assessing pulmonary artery systolic pressure (PASP) in this
      population. The purpose of our study was to examine the accuracy of Doppler
      echocardiography in evaluating pulmonary artery pressures in liver transplant
      candidates. Clinical and demographic data were gathered retrospectively for 78
      liver transplant candidates (48 men and 30 women, mean age 51 +/- 9.6 yr) who had
      PASP determined both by right heart catheterization (RHC) and echocardiography.
      Paired sample t-test was used to compare mean PASP by echocardiography and RHC.
      Correlation of PASP between echocardiography and RHC was determined using
      Pearson's linear correlation. Positive and negative predictive values for
      echocardiography for PASP > 50 mmHg are reported as compared with RHC. The mean
      PASP by echocardiography (43.2 +/- 12.3 mm Hg) was significantly higher than mean
      PASP by RHC (33.7 +/- 15.5 mm Hg; P <.001). Regarding PASP, there was a
      significant but weak correlation between echocardiography and RHC (r = 0.46, P
      =.01). The positive and negative predictive values of echocardiography for
      identifying clinically significant pulmonary hypertension (PASP > 50 mm Hg) were
      37.5% and 91.9%, respectively. Echocardiography is a useful tool in estimating
      PASP in liver transplant candidates. Patients with apparently elevated PASP by
      echocardiography should undergo invasive assessment by RHC before being excluded
      from liver transplant.

PMID- 12424720
TI  - Fulminant hepatic failure: outcome after listing for highly urgent liver
      transplantation-12 years experience in the nordic countries.
AB  - Fulminant hepatic failure is a common indication for liver transplantation.
      Outcomes of patients listed for a highly urgent liver transplantation have been
      studied, with special emphasis on etiology of the liver disease, clinical
      condition, and ABO blood type. Data have been collected from the Nordic Liver
      Transplantation Registry. All Nordic patients listed for a highly urgent primary
      liver transplantation during a 12-year period have been included. Of the 315
      patients listed for a highly urgent liver transplantation, 229 (73%) received a
      first liver allograft, 50 patients (16%) died without transplantation, and 36
      patients (11%) were permanently withdrawn and survived. In 43% of the patients,
      no definite etiology of the liver failure could be established. Paracetamol
      intoxication was the most frequent specific indication for listing. Patients with
      blood type A had no significant shorter waiting time (3.8 v 6.6 days; P =.1) but
      a higher rate of transplantation (82% v 66%, P =.006) as compared with blood type
      O patients. In a multivariate analysis, paracetamol intoxication remained the
      single independent predictor of an outcome without transplantation. In
      conclusion, a high transplantation rate was observed among patients listed for a
      highly urgent liver transplantation because of fulminant hepatic failure. Blood
      type O patients had a lower chance of receiving a liver allograft. Patients with
      paracetamol intoxication had both a higher mortality without transplantation and
      a higher withdrawal rate attributable to improved condition.

PMID- 12424721
TI  - Liver transplantation for acute liver failure--better safe than sorry.

PMID- 12424722
TI  - Risk factors for invasive aspergillosis in liver transplant recipients.
AB  - Aspergillosis is a potential, severe, and usually early complication of liver
      transplantation. New promising strategies, such as detecting Aspergillus
      antigenemia, have been used for the diagnosis of aspergillosis in
      immunosuppressed patients, but the impact in solid organ transplantation is not
      well known. A case-control study in 260 adults who underwent liver
      transplantation from January 1994 to June 2000 was performed. A case was defined
      as any liver transplant recipient with a proven or probable diagnosis of invasive
      aspergillosis. Controls were defined as a liver transplant recipient without
      aspergillosis infection with a survival longer than two months after
      transplantation. Clinical and analytical variables, including Aspergillus
      antigenemia, were compared. A special analysis was performed in patients in whom
      late aspergillosis developed (after day 100 posttransplantation). Among 260
      patients, invasive aspergillosis developed in 15 (5.6%). Median time from
      transplantation to aspergillosis in 13 patients with sufficient data for analysis
      was 126 days (range, 22 to 1117). Seven (54%) developed the infection after day
      100 posttransplantation. Thirty-eight patients were used as controls. Antigenemia
      was available in nine of 13 cases and in 33 of 38 controls. By multivariate
      analysis, retransplantation (OR, 29.9 [95% CI, 2.1 to 425.1]), dialysis
      requirements after transplantation (OR, 24.5 [95% CI, 1.25 to 354]), and the
      presence of Aspergillus antigenemia in serum at any time point after
      transplantation (OR, 50.0 [95% CI, 3.56 to 650]) were independently associated to
      aspergillosis. In the subgroup of patients that developed late aspergillosis,
      cytomegalovirus infection (OR, 6.7 [95% CI, 1.0 to 42.5]) was the only
      independent factor associated. Hepatic and renal dysfunction predispose to
      Aspergillus infection in liver transplant recipients. Cytomegalovirus infection
      and increased immunosuppression favor invasive aspergillosis during the late
      posttransplantation period. Aspergillus antigenemia seems to be a good predictor
      of invasive aspergillosis.

PMID- 12424723
TI  - The changing face of invasive aspergillosis in liver transplant recipients.

PMID- 12424724
TI  - Aspergillus osteomyelitis after liver transplantation.
AB  - A 57-year-old woman underwent liver transplantation and developed osteomyelitis
      in the femur attributable to Aspergillus fumigatus. The patient was treated
      successfully with amphotericin B and 5-fluorocytosine for 30 days, and then
      switched to itraconazole for 12 months. Plasma (1->3)-beta-D-glucan levels
      decreased significantly after the chemotherapy. Early diagnosis by (1->3)-beta-D
      glucan measurement and extended treatment with itraconazole can improve the
      prognosis of invasive Aspergillus infection.

PMID- 12424725
TI  - Usefulness of three-dimensional computed tomography in a living-donor extended
      right lobe liver transplantation.
AB  - Although living-donor liver transplantation (LDLT) of right lobe graft is
      becoming a popular option for adult patients, management of venous outflow
      remains controversial. We report a successful extended-right lobe liver
      transplantation using a recipient's left portal vein as a graft from the middle
      hepatic vein. Preoperative three-dimensional computed tomography (3D-CT) of the
      donor revealed a small right hepatic vein (RHV) without inferior RHV and a large
      middle hepatic vein (MHV) draining segments 5 and 8. During the donor operation,
      right lobe graft was harvested with the MHV, preserving the drainage vein from
      segment 4. The donor recovered uneventfully except for mild transient
      hyperbilirubinemia. The recipient's condition rapidly improved, and was
      discharged from hospital 49 days postoperation. A 3D-CT after LDLT also clearly
      revealed successful vascular anastomosis. Preoperative and postoperative 3D-CT
      was useful for determination of the vascular anatomy and the decision about the
      line of transection in the donor hepatectomy, as well as for evaluation of the
      vascular anastomoses after transplantation.

PMID- 12424726
TI  - Unsuspected primary hepatic angiosarcoma associated with portal vein thrombosis
      complicating cirrhosis.

PMID- 12424727
TI  - Combination of HBIG and lamivudine-resistant mutations: a formula for trouble?

PMID- 12424728
TI  - Liver transplant and familial amyloidotic polyneuropathy.

PMID- 12424729
TI  - Fragile X mental retardation protein in plasticity and disease.
AB  - Fragile X syndrome is the most common cause of mental retardation known to be
      inherited. The syndrome results from the suppressed expression of a single
      protein, the fragile X mental retardation protein (FMRP). Understanding the
      function and regulation of FMRP can, therefore, offer insights into both the
      pathophysiology of fragile X syndrome and the molecular mechanisms of learning
      and memory. We provide an overview of current concepts of how FMRP functions in
      the nervous system, with special emphasis on recent evidence that FMRP has a role
      in metabotropic glutamate receptor-activated protein translation and synaptic
      plasticity.

PMID- 12424730
TI  - Association and colocalization of G protein alpha subunits and Purkinje cell
      protein 2 (Pcp2) in mammalian cerebellum.
AB  - Previously, we have demonstrated a novel interaction between Galpha(o) protein
      and Purkinje cell protein-2 (Pcp2, also known as L7) in vitro and in transfected
      cells (Luo and Denker [1999] J. Biol. Chem. 274:10685-10688). Pcp2 is uniquely
      expressed in cerebellar Purkinje cells and in retinal bipolar neurons, and it may
      function as a cell-type specific modulator for G protein-mediated cell signaling.
      This interaction has been further evaluated in the present studies.
      Coimmunoprecipitation experiments reveal that Pcp2 associates with Galpha(o) in
      vivo in mouse cerebellum and eye extract. Pcp2 also associate with Galpha(i2) in
      the cerebellum. No detectable associations of Pcp2 with Galpha(z) and Galpha(q)
      subunits are observed. The association of Galpha(o) and Pcp2 is detected at
      postnatal day 1 (P1), and the association remains stable from day 3 (P3) until
      adulthood. Further, immunofluorescent double labeling and confocal microscopy
      suggest that Pcp2 and Galpha(o) are colocalized in the distal processes of
      cerebellar Purkinje cells including axonal endings and dendritic spines. Taken
      together, these findings indicate colocalization and association of Galpha(o) and
      Pcp2 in cerebellum and suggest a functional role in regions of synaptic activity.

PMID- 12424731
TI  - Bone morphogenetic protein-6 is a neurotrophic factor for calbindin-positive
      striatal neurons.
AB  - Bone morphogenetic proteins (BMPs) are a set of members of the transforming
      growth factor-beta superfamily recently described as promoting the
      differentiation of several neuronal populations within the basal ganglia. This
      study examined whether a member of this family, BMP-6, could exert neurotrophic
      effects on the neurons of the striatum, in which BMP-6 mRNA had been previously
      detected during development. Here we show that BMP-6 increases the number and
      differentiation of calbindin-positive neurons in vitro. Indeed, BMP-6 increased
      the total area, the perimeter, and the degree of arborization of this neuronal
      population. This trophic factor promoted dendritic growth without modifying
      axonal length or soma area. Furthermore, BMP-6 increased the number of glial
      fibrillary acidic protein-positive cells while decreasing the number of nestin
      positive cells. The suppression of cell proliferation or glial development by the
      antimitotic fluorodeoxyuridine removed the effects on striatal neurons,
      suggesting the involvement of astroglial cells in the differentiation induced by
      BMP-6. The current results confirm the relevance of BMPs in the development of
      the striatum and emphasize the crucial importance of the trophic interaction
      between glial and neuronal cells.

PMID- 12424732
TI  - Oligodendrogenesis is differentially regulated in gray and white matter of jimpy
      mice.
AB  - The factors that regulate oligodendrogenesis have been studied extensively in
      optic nerve, where oligodendrocyte production and myelination quickly follow
      colonization of the nerve by progenitor cells. In contrast, oligodendrocyte
      production in the cerebral cortex begins approximately 1 week after progenitor
      cell colonization and continues for 3-4 weeks. This and other observations raise
      the possibility that oligodendrogenesis is regulated by different mechanisms in
      white and gray matter. The present study examined oligodendrocyte production in
      the developing cerebral cortex of jimpy (jp) and jimpy(msd) (msd) mice, which
      exhibit hypomyelination and oligodendrocyte death due to mutations in and toxic
      accumulations of proteolipid protein, the major structural protein of CNS myelin.
      Proliferation of oligodendrocyte progenitors and production of myelinating
      oligodendrocytes was reduced in jp cerebral cortex when compared to wild-type
      (wt) and msd mice. The incidence of oligodendrocyte cell death was similar in jp
      and msd cortex, but total dying oligodendrocytes were greater in msd. We confirm
      previous reports of increased oligodendrocyte production in white matter of both
      jp and msd mice. The jp mutation, therefore, reduces oligodendrocyte production
      in cerebral cortex but not in white matter. These data provide additional
      evidence that oligodendrogenesis is differentially regulated in white matter and
      gray matter and implicate PLP/DM20 as a modulator of these differences.

PMID- 12424733
TI  - Role of c-Jun concentration in neuronal cell death.
AB  - A dimer of the basic region leucine zipper proteins c-Jun and c-Fos constitutes
      the classical activator protein-1 (AP-1) transcription factor. c-Jun is thought
      to play essential roles in many important cellular pathways, including the
      control of proliferation and cell death. To investigate the roles of c-Jun and c
      Fos concentrations in the regulation of neuronal cell death, we generated
      conditional alleles by fusing c-Jun and c-Fos to the ligand binding domain of the
      murine estrogen receptor (ER), with the aim of controlling the biological
      activities of c-Jun and c-Fos by the synthetic ligand 4-hydroxytamoxifen (4OHT).
      Transient transfection experiments revealed an increase in AP-1 activity
      following transfection of an expression vector encoding a c-Jun/estrogen receptor
      fusion protein (c-JunER) and stimulation with 4OHT. In contrast, a c-Fos/estrogen
      receptor fusion protein (c-FosER) was only weakly active in HT22 immortalized
      hippocampal cells and in PC12 pheochromocytoma cells. Highest levels of AP-1
      activity were obtained by cotransfection of c-FosER and c-JunER and stimulation
      with 4OHT. Using retroviral gene transfer, we generated HT22 and PC12 cells
      expressing either c-JunER or c-FosER. The AP-1 activity was moderately increased
      in 4OHT-treated HT22 and PC12 cells expressing c-JunER, whereas no biological
      activity was observed in cells expressing c-FosER. We tested the influence of
      4OHT-activated c-JunER or c-FosER upon cell survival and cell death by
      quantification of mitochondrial reduction capacity of 3-(4,5-dimethylthiazol-2
      yl)-2,5-diphenyltetrazolium bromide to formazan dye crystals. We did not observe
      any 4OHT-dependent decrease in cell survival in cells expressing c-JunER or c
      FosER. Likewise, the number of pycnic nuclei did not increase in HT22 or PC12
      cells expressing c-JunER or c-FosER. We conclude that an increase in the c-Jun
      concentration is not sufficient to trigger neuronal cell death. We propose that
      it is not the concentration of c-Jun that is critical for cell survival but
      rather the concentration of active, i.e., phosphorylated c-Jun.

PMID- 12424734
TI  - JNK3 contributes to c-jun induction and apoptosis in 4-hydroxynonenal-treated
      sympathetic neurons.
AB  - 4-hydroxynoneal (HNE), an end product of lipid peroxidation, induces apoptosis in
      many cell types, including neural cells. HNE toxicity is often accompanied by
      activation of the c-Jun N-terminal kinase/stress-activated protein kinase
      (JNK/SAPK) pathway. Here we have evaluated the hypothesis that the primary JNK
      associated with neurons, JNK3, contributes to HNE-induced neuronal apoptosis.
      First, we demonstrate that HNE induces caspase-dependent apoptosis in sympathetic
      neurons. Second, we show that HNE-induced c-Jun phosphorylation and c-jun
      induction are attenuated in JNK3-deficient neurons. Third, we show that HNE
      neurotoxicity is significantly inhibited by JNK3 deficiency. In summary, these
      results indicate that JNK3 plays a critical role in HNE-induced c-Jun activation
      and apoptosis in sympathetic neurons.

PMID- 12424735
TI  - The DNA damaging agent etoposide activates a cell survival pathway involving
      alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate receptors and mitogen
      activated protein kinases in hippocampal neurons.
AB  - Etoposide, an inhibitor of topoisomerase II that induces DNA damage and can
      trigger cell death, is used as a chemotherapeutic agent. Because chemotherapies
      can result in neurological complications and because DNA damage in neurons is
      implicated in the pathogenesis of several neurodegenerative disorders, we studied
      the effects of etoposide on cultured hippocampal neurons. We found that etoposide
      induces neuronal apoptosis and that, prior to the cell death commitment point,
      there is an increase in whole-cell alpha-amino-3-hydroxy-5-methylisoxazole-4
      propionate (AMPA)-induced current but no change in N-methyl-D-aspartate (NMDA)
      induced current. Associated with the increase in AMPA-induced current was an
      increase in the amounts of AMPA receptor subunits GluR1 and GluR4, whereas levels
      of the NMDA receptor subunit NR1 were unaffected by etoposide. AMPA receptor
      activation can result in excitotoxic cell death but can also activate signaling
      pathways that promote synaptic plasticity and cell survival. We found that
      etoposide increases the activation of p42 and p44 mitogen-activated protein (MAP)
      kinases, and that activation of the MAP kinases by etoposide requires AMPA
      receptor activation. Pharmacological blockade of AMPA receptors and p42/p44 MAP
      kinases, but not of NMDA receptors, exacerbated etoposide-induced cell death.
      These findings suggest that, although etoposide is neurotoxic, it also activates
      a cell survival pathway involving AMPA receptor-mediated activation of p42/p44
      MAP kinases. Agents that selectively inhibit the cell life or death pathways
      triggered by DNA damage may prove useful in the settings of cancer and
      neurodegenerative disorders, respectively.

PMID- 12424736
TI  - Diffusion parameters in the striatum of rats with 6-hydroxydopamine-induced
      lesions and with fetal mesencephalic grafts.
AB  - Functional recovery after transplantation of dopaminergic cells into the lesioned
      striatum is dependent on widespread diffusion of the transmitter released by the
      graft. In the present study, we investigated the diffusion parameters of the
      extracellular space in the striatum of control, 6-hydroxydopamine-lesioned,
      intrastriatally grafted, and sham-grafted rats in vivo. We used two types of
      grafts-single macrografts or multiple micrografts. The real-time iontophoretic
      tetramethylammonium method enabled us to extract three extracellular space
      diffusion parameters: volume fraction, alpha, tortuosity, lambda, and nonspecific
      uptake of tetramethylammonium, k'. Compared with controls (alpha = 0.19, lambda =
      1.59), in lesioned animals both alpha and lambda were lower (alpha = 0.14, lambda
      = 1.50). alpha and lambda were increased inside macro-and micrografts, where
      alpha = 0.24 and lambda = 1.80, and in sham-grafted areas, where alpha = 0.24 and
      lambda = 1.72. In regions outside the grafts (alpha = 0.15, lambda = 1.51) or in
      sham grafts (alpha = 0.14, lambda = 1.49), the values of alpha and lambda were
      similar to the values observed in lesioned striatum. Nonspecific uptake (k') did
      not differ among the groups. Our results show that, compared with control, alpha
      and lambda were decreased in dopamine-depleted areas and increased in areas with
      grafts. Multiple but smaller graft deposits, in contrast to their enlarged
      capability for dopaminergic reinnervation, impair the conditions for diffusion
      and extrasynaptic transmission in a larger area of the striatum than do single
      macrografts, presumably because of more extensive tissue damage, cell loss, and
      astrogliosis.

PMID- 12424737
TI  - Multiple aspects of homocysteine neurotoxicity: glutamate excitotoxicity, kinase
      hyperactivation and DNA damage.
AB  - Homocysteine (HC) is a neurotoxic amino acid that accumulates in several
      neurological disorders including Alzheimer's disease (AD). We examined the
      consequences of treatment of cultured murine cortical neurons with HC.
      Homocysteine-induced increases in cytosolic calcium, reactive oxygen species,
      phospho-tau immunoreactivity and externalized phosphatidyl serine (indicative of
      apoptosis). Homocysteine-induced calcium influx through NMDA channel activation,
      which stimulated glutamate excitotoxicity, as evidenced by treatment with
      antagonists of the NMDA channel and metabotropic glutamate receptors,
      respectively. The NMDA channel antagonist MK-801 reduced tau phosphorylation but
      not apoptosis after HC treatment, suggesting that HC-mediated apoptosis was not
      due to calcium influx. Apoptosis after HC treatment was reduced by co-treatment
      with 3-aminobenazmidine (3ab), an inhibitor of poly-ADP-ribosome polymerase
      (PARP), consistent with previous reports that ATP depletion by PARP-mediated
      repair of DNA strand breakage mediated HC-induced apoptosis. Treatment with 3ab
      did not reduce tau phosphorylation, however, therefore hyperphosphorylation of
      tau may not contribute to HC-induced apoptosis under these conditions. Inhibition
      of mitogen-activated protein kinase by co-treatment with the kinase inhibitor
      PD98059 inhibited tau phosphorylation but not apoptosis after HC treatment. HC
      accumulation reduces cellular levels of S-adenosyl methionine (SAM); co-treatment
      with SAM reduced apoptosis, suggesting that inhibition of critical methylation
      reactions may mediate HC-induced apoptosis. These findings indicate that HC
      compromises neuronal homeostasis by multiple, divergent routes.

PMID- 12424738
TI  - Time course assessment of methylmercury effects on C6 glioma cells: submicromolar
      concentrations induce oxidative DNA damage and apoptosis.
AB  - Organic mercury is a well-known neurotoxicant although its mechanism of action
      has not been fully clarified. In addition to a direct effect on neurons, much
      experimental evidence supports an involvement of the glial component. We assessed
      methylmercury hydroxide (MeHgOH) toxicity in a glial model, C6 glioma cells,
      exposed in the 10(-5)-10(-8) M range. The time course of the effects was studied
      by time-lapse confocal microscopy and supplemented with biochemical data. We have
      monitored cell viability and proliferation rate, reactive oxygen species (ROS),
      mitochondrial transmembrane potential, DNA oxidation, energetic metabolism and
      modalities of cell death. The earliest effect was a measurable ROS generation
      followed by oxidative DNA damage paralleled by a partial mitochondrial
      depolarization. The effect on cell viability was dose dependent. TUNEL, caspase
      activity and real-time morphological observation of calcein-loaded cells showed
      that apoptosis was the only detectable mode of cell death within this
      concentration range. N-acetyl-cysteine (NAC) or reduced glutathione (GSH)
      completely prevent the apoptotic effect of MeHgOH. The lowest effective MeHgOH
      concentration was 10(-7) M for ROS and DNA OH-adducts generation. The effect of
      submicromolar concentrations of MeHgOH on C6 cells could be relevant in the
      developmental neurotoxicity caused by low dose, long-term exposures, such as
      those of food origin. In addition, we have shown that the same concentrations are
      effective in the induction of DNA oxidative damage, with further potential
      pathogenetic implications.

PMID- 12424739
TI  - In vitro toxicity of several dithiocarbamates and structure-activity
      relationships.
AB  - Dithiocarbamates (DTCs) are chemicals featuring a great chelating capacity. The
      toxicological study of DTCs is very important in view of their relatively simple
      synthesis and wide array of sanitary and industrial applications. In this study,
      the toxicity of some of the more recently synthesized DTCs is determined using an
      extremely simple bioassay, described in previous studies, based on the inhibition
      of growth of Escherichia coli (IGEC). The lowest-observed-effect concentration
      (LOEC), the median effective concentration (EC(50)) and no-observed-effect
      concentration (NOEC) of the following sodium dithiocarbamates was determined: N
      benzyl-N-methyldithiocarbamate x 2H(2)O, N-benzyl-N-isopropyldithiocarbamate x
      3H(2)O, N-benzyl-N-ethyldithiocarbamate x 2H(2)O, N-butyl-N-methyldithiocarbamate
      x 2H(2)O, N,N-dibenzyldithiocarbamate x 2H(2)O and N-benzyl-2
      phenethyldithiocarbamate x 4H(2)O. Our results showed N,N-dibenzyl-DTC to be the
      least toxic of the tested substances, with an EC(50) value of 1,269.9 micro g ml(
      1), whereas N-butyl-N-methyl-DTC and N-benzyl-N-methyl-DTC, with respective
      EC(50) values of 14.9 micro g ml(-1) and 23.5 micro g ml(-1), were the most
      toxic. Regression analysis showed, through exponential models, that the degree of
      toxicity of this group of substances correlated with the molecular weight of the
      compound, the molecular weight of the smallest chemical radical linked to the
      dithiocarbamate group and the number of benzene rings present in the molecule.
      The consideration of these models allows us to establish that in general terms
      the toxicity of DTCs decreases exponentially with a greater molecular weight and
      the number of benzene rings.

PMID- 12424740
TI  - Haematological, hepatic and renal alterations after repeated oral or
      intraperitoneal administration of monoisoamyl DMSA. I. Changes in male rats.
AB  - Monoisoamyl 2,3-dimercaptosuccinic acid (MiADMSA), a vicinal thiol chelator, is
      gaining recognition recently as a better chelator than meso 2,3
      dimercaptosuccinic acid (DMSA) in decreasing heavy metal burden in tissues
      because of its lipophilic character. There is, however, little information
      available on the toxicological properties of this chelator after repeated
      administration in animals. In the present study, we investigated the dose
      dependent effect of MiADMSA on various biochemical parameters suggestive of
      alterations in haem biosynthesis and hepatic, renal and brain oxidative stress
      after 21 days of repeated intraperitoneal (i.p.) or oral (p.o.) administration to
      rats. The concentration of essential metals in blood and soft tissues was
      determined along with histopathological observations of hepatic and renal
      tissues. The results suggest that MiADMSA administration had no effect on blood
      delta-aminolevulinic acid dehydratase activity. However, an increase in zinc
      protoporphyrin and a decrease in haemoglobin levels were noted in animals given
      MiADMSA i.p. A moderate increase in serum alkaline phosphatase suggested mild
      hepatotoxicity at the highest dose (100 mg kg(-1), i.p.). This was confirmed by
      histopathological examinations, which identified basophilic stippling,
      granulation of the cytoplasm, haemorrhage and congestion. At the highest dose,
      levels of hepatic thiobarbituric acid reactive substance and oxidized glutathione
      were increased above those of control values. Levels of hepatic reduced
      glutathione were decreased. Taken together, these observations point to oxidative
      stress. In animals administered MiADMSA i.p. there was an increase in the brain
      malondialdehyde levels at the two higher doses (50 and 100 mg kg(-1)). Essential
      metal status revealed a significant effect of MiADMSA (p.o.) in increasing blood
      zinc while significantly decreasing the kidney zinc level. The most significant
      adverse effect of MiADMSA was on copper concentration, which showed significant
      depletion from almost all major organs. Magnesium levels in blood decreased but
      increased in liver of MiADMSA-administered rats. Histopathological observations
      of liver and kidneys suggest few moderate lesions. It can be concluded that
      repeated administration of MiADMSA is compromised with some mild toxic effect,
      particularly the loss of copper. The effects during oral administration are
      comparatively less pronounced than by the i.p. route.

PMID- 12424741
TI  - Pulmonary responses and recovery following single and repeated inhalation
      exposure of rats to polymeric methylene diphenyl diisocyanate aerosols.
AB  - Acute and repeated inhalation exposures (for 28 days) to polymeric methylene
      diphenyl diisocyanate (PMDI) were performed in rats. Investigations were made at
      the end of exposures and after 3, 10 and 30 days of recovery following single
      acute exposures and after 30 days of recovery following 28 days of exposure.
      Acute exposures to 10, 30 or 100 mg m(-3) PMDI produced clinical signs in all
      animals that were consistent with exposure to irritant aerosols. An exposure
      concentration-related body weight loss and increase in lung weight were seen post
      exposure, with complete recovery by day 8. The time course of changes in the lung
      over the initial days following exposure consisted of a pattern of initial
      toxicity, rapid and heavy influx of inflammatory cells and soluble markers of
      inflammation and cell damage, increased lung surfactant, a subsequent recovery
      and epithelial proliferative phase and, finally, a return to the normal status
      quo of the lung. During these stages there was evidence for perturbation of lung
      surfactant homeostasis, demonstrated by increased amounts of crystalline
      surfactant and increased number and size of lamellar bodies within type II
      alveolar cells. Repeated exposure over 28 days to the less toxic concentrations
      of 1, 4 or 10 mg m(-3) PMDI produced no clinical signs or body weight changes,
      but an increase in lung weight was seen in animals exposed to 10 mg m(-3), which
      resolved following the 30-day recovery period. Other effects seen were again
      consistent with exposure to irritant aerosols, but were less severe than those
      seen in the acute study. Analysis of bronchoalveolar lavage fluid revealed
      similar changes to those seen in the acute study. At both 10 and 4 mg m(-3) PMDI
      increased numbers of 'foamy' macrophages in lung lavage cell pellet correlated
      with the increased phospholipid content of the pellet. Changes in lung lavage
      parameters and electron microscopic evidence again suggested perturbations in
      surfactant homeostasis. Histologically, bronchiolitis and thickening of the
      central acinar regions was seen at 10 and 4 mg m(-3), reflecting changes in cell
      proliferation in the terminal bronchioles and centro-acinar regions. Almost all
      effects seen had recovered by day 30 post-exposure. Both acute and subacute
      studies demonstrate rapid recovery of effects in the lung following exposure to
      PMDI, with no progression of these effects even at concentrations higher than
      those shown to produce tumours in a chronic study. These findings add weight to
      the hypothesis that pulmonary tumours seen following chronic exposure to PMDI are
      most likely due to a combination of the chronic irritant effects of repeated
      exposure, coupled with the presence of insoluble polyureas formed by
      polymerization of PMDI (found in studies reported here and previous chronic
      studies), and therefore acute or short-term exposures to PMDI are likely to be of
      little concern for long-term pulmonary health.

PMID- 12424742
TI  - Responses in the respiratory tract of rats following exposure to sulphuric acid
      aerosols for 5 or 28 days.
AB  - Sulphuric acid mists have been classified by the International Agency for
      Research on Cancer as being carcinogenic to humans based on epidemiological
      findings of respiratory tract tumours. To determine if early changes in the
      respiratory tract following exposure to sulphuric acid (H(2)SO(4)) aerosols are
      consistent with the possible development of tumours after extended periods of
      exposure, groups of female rats were exposed to respirable aerosols of H(2)SO(4)
      at target concentrations of 0, 0.2, 1.0 or 5.0 mg m(-3) for 6 h per day for
      either 5 days or for 5 days a week over a 28-day period. Additional groups
      exposed to 0 or 5.0 mg m(-3) over the 28-day period were retained after exposure
      for 4 or 8 weeks to assess recovery. Histopathological examinations and
      quantitative cell proliferation measurements were conducted on the nasal
      passages, larynx and lung. Achieved concentrations were 0.3, 1.38 and 5.52 mg m(
      3) H(2)SO(4). Histological and cell proliferative changes were confined to the
      larynx and no effects were seen in the nasal passages or lungs. At the two
      highest concentrations, squamous metaplasia accompanied by significant cell
      proliferation was apparent after 5 and 28 days of exposure and there was a
      reduction in the severity of the pathological changes following the recovery
      periods. No effects were seen at 0.3 mg m(-3) after 5 days of exposure and only
      minimal metaplastic change was seen after 28 days in a few animals and was not
      accompanied by cell proliferation. The toxicological relevance of these findings
      is discussed.

PMID- 12424743
TI  - Differential stimulation of IgE production, STAT activation and cytokine and CD86
      expression by 2,4-dinitrochlorobenzene and trimellitic anhydride.
AB  - It has been reported that dermal exposure to trimellitic anhydride (TMA, 50%), a
      respiratory allergen, induced greater production of serum IgE and expression of
      Th2 cytokines than 2,4-dinitrochlorobenzene (DNCB, 1%), a potent contact
      sensitizer, in female BALB/C mice. To determine if there is any strain
      difference, four strains (B6C3F1, C57BL/6, BDF1 and BALB/C) of female mice were
      employed in this study to compare the differential effects of these chemicals on
      the hypersensitivity responses. Serum IgE levels were increased in TMA-treated
      B6C3F1, C57BL/6 and BDF1 mice when compared with the DNCB treatment and vehicle
      controls; in contrast, no difference was observed between TMA- and DNCB-treated
      BALB/C mice, although both chemicals induced greater IgE production than vehicle
      controls. In vitro expression of interleukin 4 (IL-4) and IL-13 mRNA by overnight
      concanavalin A (ConA)-stimulated draining lymph node cells was enhanced following
      in vivo treatment with TMA but not with DNCB in the B6C3F1, C57BL/6 and BDF1
      mice. In contrast, TMA and DNCB induced similar levels of IL-4 and IL-13 mRNA in
      the BALB/C mice. The IL-4 protein levels in the supernatants of overnight ConA
      treated draining lymph node cells were also increased in TMA-treated B6C3F1 and
      C57BL/6 mice when compared with the DNCB treatment and vehicle controls. Further
      mechanistic evaluation in the B6C3F1 mice indicated that the activation of STAT6
      but not STAT4 by ConA plus IL-2-treated draining lymph node cells was increased
      in TMA- but not DNCB-treated mice when compared with the vehicle controls.
      Furthermore, surface expression of B7.2 (CD86) by B cells was increased in both
      TMA- and DNCB-treated B6C3F1 mice when compared with the vehicles; however,
      greater B7.2 expression was observed in TMA-treated compared with DNCB-treated.
      Overall, these results demonstrate that a similar pattern of IgE and cytokine
      production was observed in these strains of mice except for BALB/C. Furthermore,
      differential activation of STAT6 and expression of CD86 following exposure to TMA
      and DNCB may contribute to the differential production of IgE and cytokines.

PMID- 12424744
TI  - Ultrastructural examination of rabbit aortic wall following high-fat diet feeding
      and selenium supplementation: a transmission electron microscopy study.
AB  - Experiments were carried out to examine the changes occurring in the wall of
      rabbit aortae following high-fat diet (HFD) feeding as well as HFD + selenium
      supplementation. Male New Zealand White rabbits were divided into three groups
      control, HFD-fed and HFD + Se supplementation-and were treated for three months.
      The study depicted that levels of serum total cholesterol and triglycerides were
      markedly increased in the HFD-fed group as compared with control animals.
      However, in the HFD + Se-fed group, these levels were markedly suppressed vis-a
      vis animals fed on HFD only. Development of atherogenic and atheromatic plaques
      has been shown at the light microscopy level in HFD-fed rabbits, whereas these
      developments were not visible in the HFD + Se-fed rabbits. Transmission electron
      microscopy findings indicated altered ultrastructure in the endothelial cells of
      the intimal layer as well as smooth-muscle cells of the medial layer in HFD-fed
      animals. However, these findings indicated normal ultrastructure in most of the
      cells, with little ultrastructural alterations from animals supplemented with Se
      along with HFD feeding. The study on the whole depicted the ability of Se to
      inhibit the onset of progression of aortic disease and hence has relevance to its
      therapeutic potential.

PMID- 12424745
TI  - Comparative effect of dietary administration of Lathyrus sativus pulse on
      behaviour, neurotransmitter receptors and membrane permeability in rats and
      guinea pigs.
AB  - Neurolathyrism, an upper motor neuron disease, has been thought to be caused by
      long-term dietary consumption of lathyrus pulse, which contains the toxin beta-N
      oxalyl-L-alpha,beta-diaminopropionic acid. Earlier behavioural studies employing
      oral feeding of lathyrus pulse to animals has been conducted without evaluating
      the biochemical toxicity potential. In the present investigation the effect of
      dietary feeding of 10%, 50% and 80% lathyrus pulse to rats and guinea pigs for 3
      months on neurobehavioural parameters, including locomotor activity, inclined
      plain test and neurotoxicological parameters such as neurotransmitter receptor
      binding, Ca(2+) influx and membrane fluidity, was investigated. Exposure of 50%
      low and high toxin lathyrus to rats did not cause any significant change in
      locomotor activity, whereas guinea pigs at the same dosage regimen of high toxin
      lathyrus showed significant lowering of inclined plain test scores. Furthermore,
      studies of neuroreceptor binding in rats fed 50% low and high toxin lathyrus
      showed significant changes in glutamate, dopamine and muscarinic receptors,
      whereas the benzodiazepine receptor elicited no change. Guinea pigs, on the other
      hand, fed 50% and 80% lathyrus in the diet showed significant changes in
      glutamate, dopamine, muscarinic and benzodiazepine receptors. Interestingly,
      significant elevation in intracellular calcium with a concomitant increase in
      membrane fluidity was observed in rats (50% low and high toxin) and guinea pigs
      (50% and 80%) fed a lathyrus diet. These results indicate that although both
      species (rats and guinea pigs) are susceptible to neurochemical changes on
      exposure to lathyrus, locomotor changes are only noticed in guinea pigs. Thus,
      guinea pigs may be more prone to lathyrus toxicity and may serve as a sensitive
      animal model compared with rats.

PMID- 12424746
TI  - Lack of changes in brain muscarinic receptor and motor activity of mice after
      neonatal inhalation exposure to d-allethrin.
AB  - Synthetic pyrethroids are among the most common pesticides and insecticides
      currently in worldwide use. Eriksson and co-workers postulated that oral exposure
      of mice to pyrethroids during a neonatal brain growth spurt induces permanent
      disturbance in the cerebral muscarinic cholinergic receptor (MAChR) and
      behaviour. However, the scientific basis for these phenomena is now under
      discussion. The present study was performed to determine whether the experimental
      findings of Eriksson's study could be reproduced in newborn mice by inhalation.
      Male and female NMRI mice were exposed to d-allethrin by whole-body inhalation
      for 6 h per day between postnatal days 10 and 16. Actual concentrations of d
      allethrin were 0.43, 1.35, 3.49 and 74.2 mg m(-3) (equivalent to 0.70, 2.2, 5.7
      and 120.2 mg kg(-1) day(-1), respectively), and the mass median aerodynamic
      diameter and geometric log-standard deviation of mist particles ranged from 2.58
      to 2.98 micro m and from 1.58 to 2.09 micro m for all groups, respectively. The
      highest exposure level in the present study (74.2 mg m(-3)) was ca. 13,000 times
      as high as the concentration used in practice. The MAChR in the three brain areas
      (cortex, hippocampus and striatum) and motor activity were examined at the ages
      of 17 days and 4 months. In addition, a water-maze test was performed at the age
      of 11 months. There was no systemic toxicity interfering with the interpretation
      of assay results. The neonatal exposure to d-allethrin by inhalation did not
      induce effects either on the brain MAChR density and motor activity at 17 days
      and 4 months or on performance in the learning/memory test at the age of 11
      months. The effects of allethrins on developmental neurotoxicity that Eriksson
      and co-workers reported previously were not reproduced in the present study.

PMID- 12424747
TI  - Dose-response relationship between total cadmium intake calculated from the
      cadmium concentration in rice collected from each household of farmers and renal
      dysfunction in inhabitants of the Jinzu River basin, Japan.
AB  - The association between total cadmium (Cd) intake and abnormal urinary findings
      was investigated in the Cd-polluted Jinzu River basin. In 1967 and 1968 the most
      systematic and large-scale health examinations were conducted among the entire
      population aged over 30 years of this region. We performed this study by
      targeting the subjects participating in the 1967 health survey conducted mainly
      in the heavily polluted area. From subjects who had eaten household rice of known
      Cd concentration, 1,075 inhabitants who had either resided in their current
      household since birth or who had moved there from a non-polluted area (group A),
      and 780 inhabitants who had resided in the current household since birth (group
      B), were selected as the target population. The total Cd intake for each person
      was calculated from the Cd dose ingested from rice and other foods. Logistic
      regression analysis was performed using the prevalence of abnormal urinary
      findings (proteinuria, glucosuria and proteinuria with glucosuria) as the
      criterion variable and the total Cd intake and age as explanatory variables. In
      subjects of groups A and B the odds ratios became higher as the dose of total Cd
      intake increased. Odds ratios in subjects of group A were statistically
      significant except for glucosuria of men and proteinuria of women. In subjects of
      group B the odds ratios were also significant for proteinuria + glucosuria of men
      and glucosuria of women. It was demonstrated that the greater the increase in
      total Cd intake, the greater the increase in abnormal urinary findings in the
      Jinzu River basin, and the association of the two factors was very close.

PMID- 12424748
TI  - Distinguishing animal subsets in toxicokinetic studies: comparison of non-linear
      mixed effects modelling with non-compartmental methods.
AB  - The purpose of this study was to compare the ability of non-compartmental
      analysis and compartmental mixed effects modelling (MEM) to determine the
      existence and magnitude of exposure differences (i.e. exposure ratio estimates)
      between subsets of animals during destructive toxicokinetic studies. Data from
      five toxicokinetic studies of an experimental compound were analysed using a
      linear trapezoidal calculation of the area under the curve (non-compartmental
      analysis) or modelled using MEM. With the non-compartmental method the Bailer
      Satterthwaite approximation was used to construct confidence intervals around the
      exposure estimates of each subset of animals and these were used to determine if
      exposure differed between the subsets. The MEM analyses were performed on the
      full datasets and on datasets with arbitrary reductions in the number of animal
      replicates. With MEM, additional model parameters were used to differentiate
      between subsets of animals, and were incorporated only if they were justified
      statistically. Estimates of the existence and magnitude of exposure differences
      between animal subsets were similar with the two techniques. The MEM analyses
      were influenced only marginally by substantial reductions in the number of
      animals studied and were less compromised by extremely limited or unbalanced
      data. These analyses show that MEM and non-compartmental methods are similarly
      effective at detecting exposure differences between animal subsets in
      toxicokinetic studies. Estimates provided by both methods were influenced by the
      degree of variance in the data. These results support the proposition that it may
      be possible to reduce the number of animals employed in toxicokinetic studies if
      MEM is used.

PMID- 12424749
TI  - Mode of acute action of cypermethrin on peripheral nerves.

PMID- 12424750
TI  - Practice and principles of pharmacodynamic determination of HISS-dependent and
      HISS-independent insulin action: methods to quantitate mechanisms of insulin
      resistance.
AB  - Injection of insulin causes release of HISS (hepatic insulin sensitizing
      substance) from the liver in the fed state. HISS action accounts for 50-60% of
      the glucose disposal produced by a wide range of insulin doses (5-100 mU/kg).
      Although the chemical nature of HISS is unknown, precluding pharmacokinetic
      studies, the pharmacodynamics of HISS has advanced because of the use of the
      rapid insulin sensitivity test (RIST) which is a transient euglycemic clamp used
      following a bolus of insulin. HISS action can be blocked by hepatic denervation
      and restored by intraportal but not intravenous infusion of acetylcholine or a
      nitric oxide donor. HISS release is prevented by blockade of hepatic muscarinic
      receptors, nitric oxide synthase blockers, indomethacin, and animal models of
      insulin resistance, including chronic liver disease, sucrose feeding,
      hypertension, aging, obesity, and fetal alcohol exposure. HISS acts on skeletal
      muscle but not liver, gut, or adipose tissue. HISS is released by insulin in the
      fed state but decreases to insignificance after 24-hr fasting in rats. Cats and
      dogs appear to require a longer period of fasting to prevent HISS action. Lack of
      HISS action is suggested to be the cause of post-meal hyperglycemia and
      hyperlipidemia in type 2 diabetes and other disease states with similar metabolic
      dysfunction. The RIST can be carried out up to six times in the same animal, is
      not affected by pentobarbital anesthesia, and can readily differentiate HISS
      dependent and HISS-independent insulin action.

PMID- 12424751
TI  - Mesangial cell proliferation inhibitors for the treatment of proliferative
      glomerular disease.
AB  - Mesangial cells (MC) serve a number of functions in the renal glomerular
      capillary including structural support of the capillary tuft, modulation of
      glomerular hemodynamics, and a phagocytic function allowing removal of
      macromolecules and immune complexes. The proliferation of MC is a prominent
      feature of glomerular disease including IgA nephropathy, membranoproliferative
      glomerulonephritis, lupus nephritis, and diabetic nephropathy. In experimental
      animal models of nephritis, MC proliferation frequently precedes and is linked to
      the increase of extracellular matrix in the mesangium and glomerulosclerosis.
      Reduction of MC proliferation in glomerular disease models by treatment with
      heparin, low-protein diet, or antibodies to platelet-derived growth factor
      (PDGF), have been shown to reduce extracellular matrix expansion and
      glomerulosclerotic changes. Therefore, MC proliferation inhibitors may offer
      therapeutic opportunities for the treatment of proliferative glomerular disease.
      It is also known that the MC proliferation is inhibited by many kinds of
      pharmacological drugs, for example, angiotensin converting enzyme (ACE)
      inhibitors, leukotriene D(4) (LTD(4)) antagonists, PDGF inhibitors, matrix
      metalloproteinases (MMP) inhibitors, 3-hydroxy-3 methyl glutaryl-coenzymeA (HMG
      CoA) inhibitors, cyclin-dependent kinases (CDK) inhibitors, and others. This
      review summarizes the recently reported MC proliferation inhibitors with their
      pharmacological properties on the basis of their chemical structures.

PMID- 12424752
TI  - Recent development in the design of sialyltransferase inhibitors.
AB  - Sialylation at the non-reducing end of glycoconjugates is an important biological
      process in cellular recognitions, tumor metastases, and immune responses, which
      are mediated by a family of enzymes known as sialyltransferases. Inhibition of
      sialyltransferases may prove useful in elucidating the biological functions of
      sialylation and may have therapeutic applications. This review summarizes the
      recent development in this field with particular focus on the strategies used for
      the design of carbohydrate mimetics and the structure-activity relationships of
      substrate-based sialyltransferase inhibitors.

PMID- 12424753
TI  - Medicinal chemistry approaches for the treatment and prevention of Alzheimer's
      disease.
AB  - Alzheimer's disease (AD) is the most common form of dementia, which is
      characterised by progressive deterioration of memory and higher cortical
      functions that ultimately result in total degradation of intellectual and mental
      activities. Modern strategies in the search of new therapeutic approaches are
      based on the morphological and biochemical characteristics of AD, and focused on
      following directions: agents that compensate the hypofunction of cholinergic
      system, agents that interfere with the metabolism of beta-amyloid peptide, agents
      that protect nerve cells from toxic metabolites formed in neurodegenerative
      processes, agents that activate other neurotransmitter systems that indirectly
      compensate for the deficit of cholinergic functions, agents that affect the
      process of the formation of neurofibrillary tangles, anti-inflammatory agents
      that prevent the negative response of nerve cells to the pathological process.
      The goal of the present review is the validation and an analysis from the point
      of view of medicinal chemistry of the principles of the directed search of drugs
      for the treatment and prevention of AD and related neurodegenerative disorders.
      It is based on systematization of the data on biochemical and structural
      similarities in the interaction between physiologically active compounds and
      their biological targets related to the development of such pathologies. The main
      emphasis is on cholinomimetic, anti-amyloid and anti-metabolic agents, using the
      data that were published during the last 3 to 4 years, as well as the results of
      clinical trials presented on corresponding websites.

PMID- 12424754
TI  - Structure-function relationships of vitamin D including ligand recognition by the
      vitamin D receptor.
AB  - First, the general structure and function of nuclear receptors (NRs) are
      described briefly to help our understanding of the mechanism of action of vitamin
      D mediated by the vitamin D receptor (VDR), a member of the NRs. Then we discuss
      the structure-function relationship (SFR) of vitamin D on the basis of ligand
      structures and the interaction of the ligand with the VDR. The SFR of vitamin D
      side chain analogs is discussed extensively in terms of our active space group
      concept, which was derived from conformational analyses of the side chains of
      vitamin D analogs and from studies with conformationally restricted 22-methyl
      1,25-(OH)(2)D(3) isomers. The mobile area of the side chain of vitamin D can be
      grouped into five regions (E, G, EA, EG, and F), and the SFR has been analyzed in
      terms of these spatial regions. The SFR of ligand/VDR interaction is discussed on
      the basis of the crystal structure of VDR-LBD(delta 165-215), docking of various
      vitamin D ligands into the ligand binding pocket (LBP) of the VDR, and functional
      analysis of amino acids lining the LBP. Finally, we discuss total SFR, combining
      the results of the two approaches, and future aspects of structure-based design
      of vitamin D analogs.

PMID- 12424755
TI  - Prenatal diagnosis of a fetus with pure partial trisomy 1q32-44 due to a familial
      balanced rearrangement.
AB  - We diagnosed a pure partial trisomy of the long arm of chromosome 1 in a fetus
      with multiple malformations detected prenatally. The father was a carrier of a
      balanced rearrangement involving 46,XY,inv(1)(qter-->p36::q32-->qter::p36-->q32).
      The fetus had preaxial polydactyly, low-set ears, macrocephaly, a prominent
      forehead, a broad and flat nasal bridge, a small mouth, an arched palate,
      micrognathia and unilateral renal agenesis. The couple had previously an infant
      with the same phenotypic abnormalities. The aberration was initially detected on
      amniocentesis with GTG banding and was confirmed by fluorescence in situ
      hybridization (FISH). Our case and other published pure trisomy 1q32-44 cases
      showed similarities, which allowed the further delineation of the trisomy 1q
      syndrome.

PMID- 12424756
TI  - The early development of the fetal kidney-an in utero sonographic evaluation
      between 13 and 22 weeks' gestation.
AB  - OBJECTIVES: To establish a nomogram for early fetal kidney development during
      early gestation. METHODS: The study is a prospective, cross-sectional evaluation
      of 275 male and female fetuses between 13 and 22 weeks in normal singleton
      pregnancies. Measurements of fetal kidney length were performed by high
      resolution transvaginal ultrasonography between 14 and 17 weeks' gestation, and
      by transabdominal ultrasonography beyond 18 weeks' gestation. RESULTS: Adequate
      kidney length measurements were obtained in all 275 normal fetuses as well as in
      six fetuses with urinary tract anomalies. Kidney length as a function of
      gestational age was expressed by the regression equation: (square root) kidney
      length (mm) = -11.66 + 1.52 x gestational age (weeks). The correlation
      coefficient, r = 0.983 was found to be highly statistically significant (p <
      0.0001). The normal mean and the 90% prediction limits were defined. Four cases
      with single kidney and two cases with posterior urethral valve had kidney length
      above the 95% upper limit. CONCLUSION: The present data offer a normal range of
      fetal kidney length from early stages of gestation that may allow intrauterine
      assessment of its development. It may also be helpful in the early prenatal
      diagnosis of renal abnormalities.

PMID- 12424757
TI  - The influence of prenatal screening and termination of pregnancy on perinatal
      mortality rates.
AB  - OBJECTIVES: This study concerns the possible effect of practice of prenatal
      screening of congenital anomalies followed by termination of pregnancy on the
      perinatal mortality between European countries. METHODS: Data of nine region
      specific EUROCAT registries from five European countries were used to compare the
      pregnancy termination rate and perinatal mortality due to congenital anomalies
      between the registries. The impact of pregnancy terminations on the perinatal
      mortality rate was estimated using a calculated lethality for each congenital
      anomaly in the hypothetical case that no pregnancy terminations had been
      performed and was expressed in the 'natural' perinatal mortality rate. RESULTS:
      There are large differences between the EUROCAT registries in the number of
      pregnancy terminations for congenital anomalies. The difference between the
      'natural' and regular perinatal mortality rate vary between 3.7 and 14.1 per 10
      000 live births and stillbirths. The difference is greater in regions where
      prenatal screening is more common than in regions where this is not common.
      CONCLUSION: Differences in practice of prenatal screening and termination of
      pregnancy of congenital anomalies contribute to the variations in the overall
      perinatal mortality rate between European regions and countries.

PMID- 12424758
TI  - Pregnancy outcome following prenatal diagnosis of an isodicentric X chromosome:
      first case report.
AB  - An isodicentric X chromosome, idic (X)(q27) was found in a female fetus during
      cytogenetic studies performed on amniotic cells due to advanced maternal age. No
      mosaicism was observed. Although segmental inversion duplications have been
      described for several other chromosomes, isodicentric chromosomes are reported
      only for gonosomes. Genetic counselling was based on ultrasound findings,
      cytogenetic replication studies and published cases of X chromosomes duplications
      ascertained pre- and postnatally. The pregnancy resulted in the birth of a
      healthy female infant.

PMID- 12424759
TI  - Fetal bradycardia in the first trimester: an unusual presentation of atrial
      extrasystoles.
AB  - We report a fetus with fetal bradycardia at 13 weeks of gestation secondary to
      atrial extrasystoles. The fetus subsequently developed paroxysmal
      supraventricular tachycardia and hydrops fetalis. The cardiac arrhythmia
      recovered spontaneously without any medical intervention. This case illustrates
      that atrial ectopic beats can present in the first trimester with fetal
      bradycardia. Rapidly evolving hydrops fetalis secondary to supraventricular
      tachycardia can develop, warranting close monitoring with weekly heart rate
      assessment. Fetal bradycardia secondary to atrial extrasystole should be
      differentiated from first trimester sinus bradycardia and those associated with
      major structural cardiac abnormality, which have a high fetal loss rate.

PMID- 12424760
TI  - Fetal capillary haemangioblastoma: an exceptional tumour. A review of the
      literature.
AB  - We report a case of a fetal haemangioblastoma located in the cerebellopontine
      angle. On prenatal ultrasonographic examination a hyperechogenic and
      heterogeneous mass with a major vascularization on colour Doppler imaging was
      observed. It increased progressively and laminated the cerebellum. A neoplastic
      tumour was suspected but its extent into the cerebral peduncle was unclear.
      Diagnosis was made at autopsy using histological, immunohistochemical and flow
      cytometric evaluation. Haemangioblastoma is an exceptional congenital tumour,
      which is either sporadic or integrated in von Hippel-Lindau disease (VHLD). We
      discuss the obstetrical management of prenatal brain tumours and the genetic
      counselling of haemangioblastoma.

PMID- 12424761
TI  - Rapid diagnosis of triploidy of maternal origin using fluorescent PCR and DNA
      fragment analysis in the third trimester of pregnancy.
AB  - OBJECTIVES: Triploidy is a common cause of spontaneous abortion in the very early
      stages of pregnancy. It is very rare for a prenatal diagnostic center to discover
      triploidy in the third trimester of pregnancy. A pregnant woman in the third
      trimester was referred to our genetic counselling clinic because of abnormal
      ultrasound findings. We planned to test for the most common chromosomal
      abnormalities. METHODS: We performed ultrasound examination, chorionic villus
      sampling, karyotyping and fluorescent-polymerase chain reaction (F-PCR) and
      fragment analysis. RESULTS: We diagnosed a 69,XXX karyotype fetus in the 31st
      week of gestation, based on a short tandem repeat (STR) pattern typical for
      triploidy, which was confirmed by karyotyping. The comparison of the fetal and
      parental STR patterns showed maternal origin of the extra haploid chromosome set.
      CONCLUSIONS: STR analysis of fluorescent-PCR and DNA fragment analysis is a rapid
      and reliable alternative to karyotyping for detection of certain aneuploidies.
      The method is also suitable for the determination of the origin of the extra
      chromosome set.

PMID- 12424763
TI  - Prenatal diagnosis of ductus venosus agenesis and its association with
      cytogenetic/congenital anomalies.
AB  - OBJECTIVES: We present an observational study of 12 cases of anomalies of the
      umbilical and portal vein systems associated with absence of the ductus venosus
      (DV) diagnosed over the past 5 years. The hemodynamic implications of each
      pattern of umbilico-portal system anomalies associated with absence of the DV
      have been investigated, as well as the frequency and types of associated
      anomalies and their embryological origin. METHODS: In all cases ultrasound, color
      Doppler, and cytogenetic investigations were performed. RESULTS: Four main
      patterns of abnormal venous circulation were documented: (1). the umbilical vein
      (UV) bypasses the liver and drains into the right atrium directly or through a
      dilated coronary sinus (three cases); (2). the UV bypasses the liver, with an
      infrahepatic or suprahepatic connection directly to the inferior vena cava (IVC)
      (two cases); (3). the UV bypasses the liver and drains directly into the iliac or
      renal veins (four cases); and (4). the UV drains directly into the portal veins
      (three cases). Among seven cases with other associated anomalies (58%), there
      were three cases of Turner's and Noonan's syndromes. Two fetuses and two neonates
      died and there were two terminations of pregnancy (TOP). CONCLUSIONS: In utero
      diagnosis of ultrasound patterns associated with DV anomalies is feasible. Fetal
      karyotyping should be considered, serial ultrasound examinations recommended and,
      in the presence of heart failure, delivery can be anticipated.

PMID- 12424762
TI  - Perinatal management and outcome of prenatally diagnosed congenital diaphragmatic
      hernia: a 1995-2000 series in Rennes University Hospital.
AB  - OBJECTIVES: To assess the prognosis of prenatally diagnosed congenital
      diaphragmatic hernia (CDH) during the years 1995-2000 in order to improve
      prenatal counselling. METHODS: Retrospective study of all 31 cases of women with
      prenatally diagnosed CDH. RESULTS: Nine pregnancies (29%) were terminated and two
      fetuses (6%) were stillborn. Ten fetuses (32%) had associated anomalies (four
      Fryns' syndrome) and four (13%) had underlying chromosomal anomalies. Twenty
      pregnancies were continued. Seven babies died before surgery either immediately
      in the delivery room (five between 1 and 45 min), or during the 'stabilisation
      period' (two babies, 7 and 21 h). Three babies presented with trisomy 18, Fryns'
      syndrome or transposition of the great arteries with microdeletion 22q11.
      Thirteen babies had the defect repaired (median 18 h, range 4-72 h) and 12
      survived. Mechanical ventilation was required for a median of 12 days. One
      survivor has cerebral palsy. CONCLUSION: Of 31 prenatally diagnosed CDH cases 38%
      are alive, of 20 ongoing pregnancies 60% are alive, and of 13 babies who
      underwent surgery 92% are alive. No baby with associated malformations survived.
      These numbers need to be known by each member of the counselling team in order to
      give parents adequate information to make their decision.

PMID- 12424764
TI  - Down syndrome maternal serum marker screening after 18 weeks' gestation.
AB  - Women having access to prenatal care late in pregnancy may still wish to benefit
      from maternal serum screening for Down syndrome. Therefore, we established
      reference values for alpha-feto protein (AFP) and free beta-human chorionic
      gonadotrophin (beta-hCG), and assessed the diagnostic value of maternal serum
      marker screening at 18-35 weeks' gestation based upon a series of 4072 sera from
      unaffected pregnancies and 118 sera from pregnant women with fetuses affected by
      Down syndrome. Using a 1/250 risk cut-off, a detection rate of 72.9% (95% CI =
      71.5-74.3%) was achieved with a false-positive rate of 7.51% (95% CI = 6.71
      8.3%). This was not significantly different from the percentages observed in our
      14-17 weeks routine screening (50 596 patients): 71.9% (95% CI = 71.5-72.3%) and
      6.48% (95% CI = 6.28-6.68%), respectively. Detection and screen-positive rates
      were, respectively, 51.3% (95% CI = 35.6-67.0%) and 5.95% (95% CI = 5.12-6.68%)
      in women aunder 35 years of age, and 84.8% (95% CI = 76.9-92.7%) and 24% (95% CI
      = 20.7-27.3%) in women aged 35 years and over. In conclusion, maternal serum
      marker screening is feasible at 18 weeks' gestation and later, which may be of
      interest in selected cases.

PMID- 12424765
TI  - Currarino triad: concurrent US and MRI diagnosis in the fetus and the mother.
AB  - We report an unusual case of the complete Currarino triad diagnosed in a fetus at
      21 weeks' gestation by means of prenatal ultrasonography (US). The highly
      suspicious findings in the fetus were accompanied by analogous US findings in the
      mother who suffered from mild symptoms of up to that time unrecognized Currarino
      triad. Consecutively, magnetic resonance imaging (MRI) confirmed the findings
      simultaneously in the fetus and in her mother. This is the first report
      describing the prenatal diagnosis of Currarino triad without the background of
      positive family history. To our knowledge, the prenatal MRI findings of Currarino
      triad have not yet been published.

PMID- 12424766
TI  - Ivemark syndrome with agenesis of the corpus callosum: a case report with a
      review of the literature.
AB  - Asplenia associated with situs ambiguus, symmetric liver, bilateral trilobulated
      lungs, and a complex heart defect was diagnosed on autopsy in a 14-day-old
      infant. Furthermore, examination of the brain displayed agenesis of the corpus
      callosum (ACC) with pachygyria and hydrocephalus. The characteristic association
      of asplenia with visceroatrial heterotaxia is traditionally named after the
      Swedish pediatrician, Ivemark. Although exceptional, association of Ivemark
      syndrome with callosal agenesis has been reported recently. The concept of
      'developmental fields' describes morphogenetically reactive units of the embryo
      determining and controlling the development of complex structures in a
      hierarchical manner. Lateralization defects such as situs inversus, asplenia or
      polysplenia due to defective left-right axis development, as well as decussation
      defects such as ACC, are considered as defects of the primary developmental
      field. Therefore, additional callosal agenesis in Ivemark syndrome may be a
      coherent and synchronic defect in the primary developmental field rather than a
      causally independent malformation.

PMID- 12424767
TI  - Prenatal diagnosis of the Hunter syndrome and the introduction of a new
      fluorimetric enzyme assay.
AB  - Prenatal diagnosis of the Hunter syndrome (mucopolysaccharidosis type II; MPS II)
      is preferably achieved by the assay of iduronate-2-sulphate sulphatase (IDS) in
      uncultured chorionic villi (CV) as this allows early (12th week), rapid (2-3
      days) and reliable results. We summarize the results of 174 prenatal analyses in
      the past 30 years, using various methods such as radiolabelled sulphate
      incorporation in amniotic fluid (AF) cells, glycosaminoglycan (GAG)
      electrophoresis in AF and IDS assay in CV, CV-cells, AF and AF-cells. Twenty
      seven fetuses with MPS II were diagnosed after finding clearly abnormal results
      in pregnancies with a male fetus; very low IDS activity has also been measured in
      some pregnancies with a (heterozygous) female fetus, emphasizing the need to
      combine enzyme assay with fetal sex determination. IDS activity has until
      recently been assessed by a cumbersome radioactive enzyme assay. Here we describe
      the use of a novel fluorigenic 4-methylumbelliferyl substrate, which allows a
      sensitive, rapid and convenient assay of IDS activity and reliable early prenatal
      diagnosis. This novel IDS assay was validated in retrospective analyses of 14 CV,
      CV-cell, AF and AF-cell samples from affected pregnancies in addition to
      prospective prenatal diagnosis in eight pregnancies at risk with one MPS II
      affected fetus.

PMID- 12424768
TI  - Degree of fetal umbilical venous constriction at the abdominal wall in a low-risk
      population at 20-40 weeks of gestation.
AB  - OBJECTIVES: To determine the degree of constriction of the umbilical vein at the
      abdominal wall in the second half of pregnancy. METHODS: A total of 283 low-risk
      singleton pregnancies were recruited for a cross-sectional study, and examined
      once at 20-40 weeks of gestation. Two sets of ultrasound measurements of the
      umbilical vein were taken: one at the fetal end of the umbilical cord and another
      at the inlet through the abdominal wall, the umbilical ring. The diameter was
      determined as an average of >or=5 repeat measurements. The blood velocity was
      recorded at the same site. RESULTS: The time-averaged maximum venous blood
      velocity in the cord was low (mean 13-19 cm/s during 20-40 weeks of gestation),
      and the corresponding mean diameter 3.6-8.2 mm. In contrast, the mean of the
      venous blood velocity at the umbilical ring was 34-41 cm/s and the diameter was
      2.8-5.9 mm during the same period. Of 191 pairs of observations, 41 (21%) had a
      velocity increment of >or=300 %, which corresponds to a diameter reduction to
      half or more at the umbilical ring. CONCLUSION: Constriction of the umbilical
      ring is a common phenomenon in the second half of pregnancy.

PMID- 12424769
TI  - Low or absent unconjugated estriol in pregnancy: an indicator for steroid
      sulfatase deficiency detectable by fluorescence in situ hybridization and
      biochemical analysis.
AB  - It has been previously reported that a low or absent maternal serum unconjugated
      estriol (uE3) level is associated with placental steroid sulfatase (STS)
      deficiency. Here we report a correlation between patients who present with a very
      low or absent maternal serum uE3 and a deletion of the STS gene as assessed by
      fluorescence in situ hybridization (FISH). We studied nine prenatal cases that
      presented to the clinical laboratory with an abnormal triple screen, specifically
      low or absent maternal serum uE3 and a 46,XY karyotype. FISH analysis showed
      complete deletion of a probe containing the STS gene in six cases and one case
      had a partial deletion (reduced but not absent signal). The remaining two cases
      were not deleted for the STS probe. All mothers tested whose fetus showed a
      deletion were shown to be STS deletion carriers using FISH. Biochemical analysis
      was performed on 7/9 prenatal specimens. All fetuses deleted for the STS probe
      were also found to be deficient for STS by biochemical analysis of cultured
      amniotic fluid (5/5). Of the two fetuses not deleted for the STS probe, one was
      deficient for STS activity, while the other had a normal result. The abnormal
      result of enzyme deficiency by biochemical analysis in a non-deletion case likely
      represents a mutation in the STS gene, not detectable by this FISH assay.
      Postnatal FISH confirmation of the STS deletion was performed in 1/7 cases.
      Clinical follow-up was available for 4/9 cases following birth.

PMID- 12424770
TI  - Prenatal diagnosis of Pelizaeus-Merzbacher disease.

PMID- 12424771
TI  - Risk of amniocentesis in women screened positive for Down syndrome with second
      trimester maternal serum markers.
AB  - In routine obstetrical practice, prior to offering invasive prenatal diagnosis,
      it is crucial to weigh the risks attendant on amniocentesis against the
      individual's risk of aneuploidy. We took advantage of a policy of follow-up of
      patients undergoing Down syndrome maternal serum screening to compare the rates
      of fetal loss before 24 weeks and of early premature delivery at 24-28 weeks
      between women who underwent amniocentesis and women who did not. A total of 54
      902 patients entered the study, of whom 4039 (7.35%) were lost to follow-up and
      387 were excluded because of a severe fetal abnormality. Of the 50 476 remaining
      patients, 3472 had an amniocentesis whereas 47 004 had not and served as
      controls. In the amniocentesis group, the fetal loss rate before 24 weeks was
      1.12% (95% CI=1.08-1.15) and the 24-28 weeks premature delivery rate was 0.40%
      (95% CI=0.39-0.41) which was significantly higher than in controls (0.42% with
      95% CI 0.41-0.43 and 0.24% with 95% CI 0.23-0.25, respectively). The 0.86%
      difference in adverse outcome rates between the amniocentesis and control groups
      may be attributable to amniocentesis and compares favourably with the positive
      predictive value of maternal serum markers (1.70%) observed in the present study.

PMID- 12424772
TI  - Type II single umbilical artery (persistent vitelline artery) in an otherwise
      normal fetus.
AB  - A single umbilical artery resulting from absence of the umbilical arteries and
      persistence of the vitelline artery that arises directly from the abdominal aorta
      has been described only in malformed fetuses with sirenomelia or caudal
      regression. Such an aberrant artery was suggested to be the etiology of
      sirenomelia caused by a 'steal' mechanism of blood flow from the caudal end of
      the embryo. We present a case in which prenatal ultrasound showed a similar
      aberrant single artery arising from the abdominal aorta in an otherwise normal
      fetus with a normal course of pregnancy. This vessel, a continuation of the
      superior mesenteric artery (SMA), corresponds to a persistent vitelline artery
      assuming the function of the umbilical arteries. The etiology of such a finding
      and its possible consequences are discussed.

PMID- 12424773
TI  - Evaluating the risk of tuberous sclerosis in cases with prenatal diagnosis of
      cardiac rhabdomyoma.
AB  - OBJECTIVE: To evaluate the prenatal parameters that increase the risk of tuberous
      sclerosis in prenatal management of fetal cardiac tumors suspected as
      rhabdomyoma. METHODS: The study was a retrospective survey of 18 documented cases
      in which cardiac rhabdomyoma was suspected during pregnancy. The following
      parameters were evaluated as possible risk factors associated with tuberous
      sclerosis: tumor size, isolated or multiple, and family history of tuberous
      sclerosis. RESULTS: Eighteen documented cases in which cardiac rhabdomyoma was
      found during pregnancy were evaluated. Of these cases, seven (39%) had proven
      tuberous sclerosis and 11 were found to be non-associated tuberous sclerosis
      tumors. When combining the present data with previous series, cases with
      diagnosis of tuberous sclerosis had equal mean tumor size to those with normal
      outcome. Family history of tuberous sclerosis in the presence of cardiac
      rhabdomyoma almost invariably ended with tuberous sclerosis (86%). All other
      cases with diagnosis of tuberous sclerosis and no family history had all multiple
      cardiac tumors. CONCLUSION: The present data suggest that 39% of in utero
      suspected cardiac rhabdomyoma would have tuberous sclerosis. Family history and
      multifocality remain the strongest predictors of tuberous sclerosis, whereas size
      of the cardiac tumor can not reliably be used to predict tuberous sclerosis in
      prenatal counseling.

PMID- 12424774
TI  - McKusik-Kaufman syndrome: prenatal diagnosis, genetics and follow up.
AB  - McKusick-Kaufman syndrome (MKKS) is a rare autosomal recessive genetic disease
      with classical hexadactyly and hydrocolpos in females and sometimes cardiac
      abnormality. We report such a case diagnosed just before birth with a favourable
      outcome. From this case we describe and discuss all the prenatal sonographic
      signs which are not always present. On the genetic side, the gene has recently
      been localized together with the mutation responsible for MKKS. The phenotypic
      relationship between MKKS which has a good prognosis and Bardet-Biedl syndrome
      (BBS) with a worse prognosis requires great caution before diagnosing MKKS and a
      long follow-up is necessary to recognize obesity, growth retardation and
      pigmentary retinitis.

PMID- 12424775
TI  - Estimation of risk in second trimester serum screening for Down syndrome among
      women who have already had first trimester screening.

PMID- 12424776
TI  - Right pulmonary agenesis with ipsilateral microtia: a new laterality association
      or part of the oculoauriculovertebral spectrum?

PMID- 12424779
TI  - It's time to revalue nursing education research.

PMID- 12424780
TI  - Patterns of mental distress following the violent death of a child and predictors
      of change over time.
AB  - We observed 173 parents bereaved by the violent death of an adolescent or young
      adult child. Data were collected 4, 12, 24, and 60 months postdeath. Using latent
      growth modeling, we examined how initial levels of mental distress and the rate
      of change over time are influenced by nine predictors: parents' gender, self
      esteem, three coping strategies, perceived social support, negative life
      stressors, posttraumatic stress disorder (PTSD) symptoms, and an intervention
      offered in the early bereavement period. The results support a multiple-risk and 
      protective factor model of loss accommodation. Parents' gender, self-esteem, and
      affective and repressive coping were predictive of changes in mental distress
      over time. Although parents' initial levels of PTSD were the best predictor of
      baseline mental distress, they did not predict reductions in distress 5 years
      later. Theoretical, empirical, and clinical implications are discussed.

PMID- 12424781
TI  - Testing equivalence of Spanish and English versions: the LaMonica-Oberst
      (revised) patient satisfaction with nursing care scale.
AB  - Despite recent emphasis on outcome measurement and an increasing proportion of
      Spanish speakers in the United States, most patient satisfaction studies exclude
      Spanish-speaking participants because Spanish versions of instruments are not
      available. A Spanish translation of the 15-item LaMonica-Oberst Patient
      Satisfaction Scale, completed by 64 Spanish-speaking patients living in the
      northeast and of predominantly Puerto Rican ancestry, produced two factors
      explaining 86.3% of score variation (alpha=.94 and.58). Evidence for equivalence
      to the English version and concurrent validity is presented. Generalizability and
      decision studies indicate that four additional items are needed on the
      dissatisfaction subscale to attain an acceptable dependability coefficient.

PMID- 12424782
TI  - Psychosocial outcomes of vaginal and cesarean births in Taiwanese primiparas.
AB  - The purpose of this study was to examine differences in psychosocial outcomes
      between primiparas experiencing vaginal deliveries and primiparas experiencing
      cesarean deliveries. One hundred and ninety-four vaginal delivery primiparas and
      81 cesarean delivery primiparas from the Kaohsiung city area in Taiwan were
      recruited at 6 weeks postpartum to participate in this study. Using two-sample t
      tests, we found no significant differences in perceived stress, self-esteem, or
      depression between vaginal and cesarean delivery primiparas. However, the
      cesarean delivery primiparas showed a significantly higher level of perceived
      social support than vaginal delivery primiparas. Types of cesarean (planned vs.
      unplanned) and types of anesthesia (general vs. epidural) were not significant
      factors influencing psychosocial outcomes for cesarean delivery primiparas. The
      lack of substantial differences between the groups may be a result of the
      normalizing effect of the high cesarean birthrate and greater social support
      given to this method of childbirth. Cultural concerns of offspring gender and
      choosing an auspicious time for delivery may also have ameliorative effects on
      the occurrence of psychosocial difficulties with a cesarean delivery in Taiwan.

PMID- 12424783
TI  - Effects of two types of social support and education on adaptation to early-stage
      breast cancer.
AB  - A Roy adaptation model-based support and education intervention for women with
      early-stage breast cancer was tested in a three-group, three-phase randomized
      clinical trial of a sample of 125 women. The experimental group received 13
      months of combined individual telephone and in-person group support and
      education, Control Group 1 received 13 months of telephone-only individual
      support and education, and Control Group 2 received one-time mailed educational
      information. The experimental group and Control Group 1 reported less mood
      disturbance at the end of all three phases, less loneliness at the end of Phases
      II and III, and a higher-quality relationship with a significant other at the end
      of Phase II than did Control Group 2. No group differences were found for cancer
      related worry or well-being. The findings suggest that individual telephone
      support may provide an effective alternative to in-person support groups. Further
      study of telephone interventions is recommended using ethnically and economically
      heterogeneous samples.

PMID- 12424784
TI  - Psychometric properties of the self-control schedule: Thai version.
AB  - The psychometric properties of the Thai version of the Self-Control Schedule
      (SCS), a measure of learned resourcefulness, were examined. Data were collected
      from 77 pregnant women who were HIV positive and 103 pregnant women who were HIV
      negative. Back-translation was completed, and agreement between the two content
      experts as determined by the Content Validity Index was 86%. To assure the
      equivalence of the translated SCS, English and Thai versions were completed by 16
      bilinguals, and the two versions were found to correlate highly (r=.95; p<.01).
      Internal consistency reliability for the Thai version of the SCS was.81.
      Confirmatory factor analysis was used to establish construct validity. The
      results suggest that the Thai version of the SCS has promise for use with
      pregnant Thai women; however, modification of some items would improve its
      understandability and cross-cultural applicability. Further psychometric testing
      in larger and more diverse samples is recommended.

PMID- 12424785
TI  - Theory building through mixed-method evaluation of a dementia special care unit.
AB  - The purpose of this article is to describe how the use of quantitative (quasi
      experimental) and qualitative (grounded-theory) methods in an evaluation of new
      dementia special care units led to a better understanding of how the nursing home
      environment affects residents with dementia, which in turn helped to advance
      theory development in person-environment interaction. The environmental
      intervention involved changes in social density (size of resident group), spatial
      density (space per person), and privacy. A second aim of the article is to
      illustrate that applied research cannot be perfectly preplanned; rather, it is a
      process that involves ongoing decisions and management of unexpected events. We
      describe the sequence of key methodological decisions made during the planning,
      implementation, and integration phases of the study, which was conducted over a
      21-month period. Results of this study highlight the benefits of mixed-method
      designs for evaluation research.

PMID- 12424787
TI  - Molecular inflammation hypothesis of aging based on the anti-aging mechanism of
      calorie restriction.
AB  - Accumulating evidence strongly suggests that oxidative stress underlies aging
      processes. Research provides consistent evidence that calorie restriction (CR)
      reduces age-related oxidative stress and has anti-inflammatory properties.
      However, information is lacking on the molecular mechanism that would better
      define the interrelation of reactive oxygen species and nitrogen species and the
      pro-inflammatory states of the aging process. In this review, the biochemical and
      molecular bases of the inflammatory process in the aging process are analyzed to
      delineate the molecular inflammation hypothesis of aging. The key players
      involved in the proposed hypothesis are the age-related upregulation of NF-kappa
      B, IL-1 beta, IL-6, TNFalpha, cyclooxygenase-2, and inducible NO synthase, all of
      which are attenuated by CR. Furthermore, age-related NF kappa B activation is
      associated with phosphorylation by I kappa B kinase/NIK and MAPKs, while CR
      blocked these activation processes. The modulation of these factors provides
      molecular insights of the anti-inflammatory action of CR in relation to the aging
      process. Based on available finding and our recent supporting evidence, we prefer
      to use "molecular inflammation" to emphasize the importance of the molecular
      reaction mechanisms and their aberrance, predisposing to fully expressed chronic
      inflammatory phenomena. It was further proposed that CR's major force of the
      regulation of redox-sensitive inflammation may well be its life-prolonging
      action.

PMID- 12424788
TI  - Effect of time of restriction on the decrease in mitochondrial H2O2 production
      and oxidative DNA damage in the heart of food-restricted rats.
AB  - In the present study, the question if medium-term (4 months) caloric restriction
      (40%) decreases mitochondrial H2O2 production and oxidative DNA damage was
      investigated. Caloric restriction (CR) is the only experimental manipulation that
      increases maximum life span. Previous long-term CR studies have showed that CR
      decreases the mitochondrial rate of free radical production in diverse tissues
      and species. Those studies agree with the idea that the superior longevity of the
      restricted animals can be partly due to their lower mitochondrial rate of free
      radical generation. However, caloric restriction effects strongly depend on
      implementation time. Previous studies have shown that the decrease induced by CR
      on oxygen radical generation and oxidative damage to mitochondrial DNA occurs
      after 1 year but not after 6 weeks of restriction. In the present investigation,
      mitochondrial H2O2 production did not change in medium-term (4 months) caloric
      restricted animals, and, in agreement with that, no differences were found in
      either mitochondrial or nuclear oxidative DNA damage between restricted and ad
      libitum-fed animals. These results confirm the importance of the time of CR
      implementation, and show that time longer than 4 months is needed to decrease the
      mitochondrial rate of free radical generation and the oxidative damage to mtDNA
      in the rat heart.

PMID- 12424789
TI  - Effect of dietary restriction beyond middle age: accumulation of altered proteins
      and protein degradation.
AB  - Dietary restriction (DR) from weaning or young adult stages in rodents throughout
      their usual life span has been shown to prolong longevity and lower or delay (or
      both) the occurrence of many late-onset diseases, but the effects of DR when
      performed at middle age or later have not been well investigated. We have studied
      the effect of DR initiated late in life on altered proteins and protein
      degradation. DR initiated in 23.5-month-old mice and continued for 2 months
      reduced the amount of altered proteins and shortened the half-life of proteins,
      including oxidatively modified ones. Furthermore, our more recent studies in rats
      demonstrated that DR initiated later in life (26.5 months old) restored the
      activities of proteasomes that have been implicated in removal of altered
      proteins. Thus, DR initiated even relatively late in life appears to have
      beneficial effects, restoring an animal's youthful condition in terms of the age
      related accumulation of altered proteins.

PMID- 12424790
TI  - Inhibition of H2O2-induced apoptosis of lymphocytes by calorie restriction during
      aging.
AB  - Calorie restriction (CR) is known to delay the aging process in rodents and is
      postulated to act by decreasing free radical generation and increasing
      antioxidant enzyme activity. The present study was designed to investigate the
      effect of CR and age on oxidative stress-induced apoptosis and associated changes
      in the levels of TNF-alpha, and Bcl-2 in splenic T lymphocytes. Ad libitum (AL)-
      or CR-fed C57BL/6J mice were sacrificed either at 6 (young) or 18 (old) months
      and splenic lymphocytes were incubated with or without 25 micro M H2O2 to induce
      apoptosis. Apoptosis increased with age in cells of AL-fed mice incubated with
      H2O2. CR prevented this rise in apoptosis in total splenic lymphocytes and in
      CD4(+) and CD8(+) T lymphocyte subsets either with or without H2O2. Free radicals
      increased and mitochondrial membrane potential decreased in aged mice. CR
      prevented these changes and also prevented the age-associated increase in TNF
      alpha and loss of Bcl-2 in total splenic lymphocytes and in CD4(+) and CD8(+)
      lymphocyte subsets. In summary, lymphocytes in aged AL-fed mice were much more
      susceptible to oxidative stress-induced apoptosis whereas CR normalized apoptosis
      by preventing the increase in TNF-alpha and the decrease in Bcl-2 associated with
      aging.

PMID- 12424791
TI  - Impact of aging and life-long calorie restriction on expression of apoptosis
      related genes in male F344 rat liver.
AB  - Aging enhances apoptosis of hepatocytes under normal physiological conditions and
      increases the susceptibility to apoptosis of hepatocytes, whereas chronic calorie
      restriction (CR) suppresses the age-enhanced susceptibility to apoptosis. To
      clarify the subcellular mechanisms of age-associated dysregulation of apoptosis
      and the effects of CR, we analyzed the expression of genes promoting apoptosis
      (p53, Fas receptor, Fas ligand, TNF receptor 1, TNFalpha, Bax, TGF beta 1) and
      genes preventing apoptosis (Bcl-2 and Bcl-XL) in the livers of 3-, 6-, 15-, and
      24-month-old male F344 rats that were either fed ad libitum or subjected to a 30%
      reduction in food intake (CR). After the age of 6 months, expression of p53, Fas
      receptor, Fas ligand, and TNFalpha mRNAs was up-regulated with aging. CR
      suppressed this age-enhanced p53 and Fas receptor mRNA expression, but expression
      of the other genes was not altered significantly by aging or CR. Expression of
      Fas receptor in hepatocytes, as detected immunohistochemically, increased with
      age, but CR suppressed age-accelerated Fas receptor expression. Our findings
      suggest that TNF ligand/TNF receptor family signaling, particularly Fas receptor
      expression, is important in age- and CR-modulated apoptosis of hepatocytes.
      Hepatocytes that were immunoreactive for p53 had slightly increased with aging,
      suggesting that p53 may mediate the age-enhanced up-regulation of Fas receptor in
      hepatocytes.

PMID- 12424792
TI  - Effects of food restriction on motoneuronal loss with advancing age in the rat.
AB  - The effects of life-long food restriction on motoneuronal cell death with
      advancing age was studied in male Fischer rats, which had access to food only 3
      days a week after weaning (FR rats). Motoneurons innervating the medial
      gastrocnemius muscle were labeled with retrogradely transported HRP. The number
      of labeled motoneurons in FR rats and rats fed ad libitum (AL rats) was similar
      at the age of 16 months (131.8 +/- 1.7 for FR rats vs. 133.8 +/- 4.5 for AL
      rats). However, at 28 months of age, AL rats had less labeled motoneurons
      compared to FR rats (117.0 +/- 2.4 for FR rats vs. 124.3 +/- 7.0 for FR rats).
      The number of type I muscle fibers in the medial gastrocnemius muscle increased
      significantly in AL rats during the period from 16 to 28 months of age, which
      might reflect motor unit reorganization following retraction of axons and/or
      death of innervating motoneurons. FR rats did not show statistically significant
      alteration. These findings were also true for the data compiled from several
      different experiments including those conducted for primarily different purposes
      in our laboratory. The results suggest that life-long food restriction retards
      motoneuronal cell death occurring with advancing age.

PMID- 12424793
TI  - Effects of caloric restriction on development of the proximal growth plate and
      metaphysis of the caput femoris in spontaneously hypertensive rats: microscopic
      and computer-assisted image analyses.
AB  - We previously demonstrated that caloric restriction (CR) reduced the prevalence
      of osteonecrosis in caput femoris of spontaneously hypertensive rats (SHR), a
      model of human Perthes' disease. The effects of CR on the development and
      pathology in the proximal femoral growth plate (GP) and adjacent structures in
      SHR were investigated by morphometric and computer-assisted image analyses. From
      6 weeks of age, the food intake of SHR was restricted to 65% of the mean intake
      of ad libitum fed control SHR (SHR-AL). Wistar Kyoto rats (WKY), from which the
      SHR strain was isolated, fed ad libitum were also included as controls. CR
      reduced prevalence of chondromucinous degeneration and dysarray of cartilage cell
      columns in the GP, becoming prevalent between 10 and 20 weeks in the SHR-AL
      group, attaining the same levels of the WKY group. Thicknesses of non-calcifying
      cell columns in the GP were greater in the SHR-AL than WKY group; CR slightly
      reduced the thickness, but incompletely. Thicknesses of calcifying cell columns
      did not significantly differ among the three groups. CR decreased volume density
      and mean thicknesses of the trabecular bone in areas adjacent to GPs, and was
      greater in the SHR-AL than the WKY group. The present morphologic analysis
      suggested that CR ameliorates dysplastic changes of trabecular bones in areas
      adjacent to the GP, rather than modulating the ossification process in the GP.
      The CR paradigm might give insight into the pathogenesis of, and a therapeutic
      strategy for, human Perthes' disease.

PMID- 12424794
TI  - Characterization of gene expression profile associated with energy restriction
      induced cold tolerance of heart.
AB  - Hypothermia is known to be a common feature of energy restriction (ER) and
      essential for a life-prolonging effect of ER. The heart is sensitive to
      hypothermia, but the heart in ER mice acquires some adaptation to hypothermia.
      The aim of the present study was to characterize the gene expression profile
      associated with ER-induced cold resistance of heart. We analyzed the expression
      of heart mRNA from ER (200 kJ/week) or control (400 kJ/week) B6 11-month-old male
      mice using cDNA array membranes including 588 genes. Eighty-eight out of 588
      genes were expressed in the heart. mRNAs increased by ER were glutathion S
      transferase Mu1, transcriptional factor 1 for heat shock gene (HSF1), and fetal
      myosin alkali light chain genes. mRNA decreased by ER were seven genes in four
      categories: (1). cell cycle or apoptosis-related proteins (cyclin G and
      nucleoside diphosphate kinase B); (2). stress response proteins (oxidative stress
      induced protein); (3). DNA repair proteins (protein involved in DNA double-strand
      break repair, Rad23 UV excision repair protein homologue and ubiquitin
      conjugating enzyme); and (4). cell-surface antigens (lamimin receptor 1). These
      data suggest that the heart of ER mice adapts to hypothermia involving heat shock
      proteins and their transcriptional factors and by changing structure and property
      of myofibrils. It is also suggested that ER induces protection against oxidative
      stress and inhibits cell proliferation of "nonmuscle cells" in the heart. Gene
      expression analysis using cDNA array was useful for screening genes associated
      with ER-induced cold adaptation.

PMID- 12424795
TI  - Anti-aging effects of caloric restriction: Involvement of neuroendocrine
      adaptation by peripheral signaling.
AB  - Many hormonal signals from peripheral tissues contribute to the regulation of
      energy homeostasis and food intake. These regulators including leptin, insulin,
      and ghrelin, modulate the orexigenic and anorexigenic neuropeptide expression in
      hypothalamic nuclei. The anti-aging effects of caloric restriction have been
      explained from an evolutional viewpoint of the adaptive response of the
      neuroendocrine and metabolic response systems to maximize survival during periods
      of food shortage. In organisms, excess energy is stored in adipose tissues as a
      triglyceride preparation for such survival situations. Adipose tissue has
      recently been recognized as an endocrine organ, and leptin, as secreted by
      adipocyte, seems to be an especially important factor for the adaptive response
      to fasting and neuroendocrine alterations under caloric restriction. In this
      review, we discuss the potential involvement of neuroendocrine modulators in
      longevity and the anti-aging effects of caloric restriction.

PMID- 12424796
TI  - Lifespan extension by caloric restriction: an aspect of energy metabolism.
AB  - Caloric restriction (CR) may retard aging processes and extend lifespan in
      organisms by altering energy-metabolic pathways. In CR rodents, glucose influx
      into tissues is not reduced, as compared with control animals fed ad libitum
      (AL), although plasma concentrations of glucose and insulin are lower. Gene
      expression profiles in rodents have suggested that CR promotes gluconeogenesis
      and fatty acid biosynthesis in skeletal muscle. In the liver, CR promotes
      gluconeogenesis but decreases fatty acid synthesis and glycolysis. In lower
      organisms such as yeasts and nematodes, incomplete blocks in steps of
      insulin/insulin-like growth factor-1 (IGF-1) signal pathway extend lifespan. The
      life-prolonging effect of CR in yeasts requires NPT1 and SIR2 genes, both of
      which relate to sensing energy status and silencing genes. These findings stress
      the substantial role of energy metabolism on CR. Future studies on metabolic
      adaptation and gene silencing with regard to lower caloric intake will be
      warranted to understand the mechanisms of the anti-aging and life-prolonging
      effects of CR.

PMID- 12424797
TI  - Effects of aging and caloric restriction on the gene expression of Foxo1, 3, and
      4 (FKHR, FKHRL1, and AFX) in the rat skeletal muscles.
AB  - In C. elegans, insulin-like hormone signal pathway plays a significant role in
      longevity. In particular, daf-16 gene product is indispensable factor for this
      lifespan-extension. This signal pathway is critical for dauer formation, which is
      a similar state to hibernation in mammals. We examined the expression level of
      mammalian daf-16 homologues, Foxo 1,3, and 4 (FKHR, FKHRL1, and AFX) mRNAs in the
      rat skeletal muscles during aging and in 30% caloric restricted of ad libitum
      fed. The expression level of AFX mRNA was significantly higher at 6 and 12 months
      than at 3 and 26 months, and FKHRL1 expression was significantly higher at 6
      months than at 3 and 26 months but FKHR expression showed no significant change
      with age. We observed a characteristic expression of AFX and FKHR mRNAs to be
      significantly higher in the second day in caloric restriction by every-other-day
      feeding than in ad libitum fed. This suggests that caloric restriction may
      increase the expression of FKHR-family genes and prevent the aging process in the
      skeletal muscles.

PMID- 12424798
TI  - Caloric restriction and aging in primates: Relevance to humans and possible CR
      mimetics.
AB  - For nearly 70 years it has been recognized that reduction in caloric intake by 30
      40% from ad libitum levels leads to a significant extension of mean and maximal
      lifespan in a variety of short-lived species. This effect of caloric restriction
      (CR) on lifespan has been reported in nearly all species tested and has been
      reproduced hundreds of times under a variety of different laboratory conditions.
      In addition to prolonging lifespan, CR also prevents or delays the onset of age
      related disease and maintains many physiological functions at more youthful
      levels. Studies in longer-lived species, specifically rhesus and squirrel
      monkeys, have been underway since the late 1980s. The studies in nonhuman
      primates are beginning to yield valuable information suggesting that the effect
      of CR on aging is universal across species and that this nutritional paradigm
      will have similar effects in humans. Even if CR can be shown to impact upon human
      aging, it is unlikely that most people will be able to maintain the strict
      dietary control required for this regimen. Thus, elucidation of the biological
      mechanisms of CR and development of alternative strategies to yield similar
      benefits is of primary importance. CR mimetics, or interventions that "mimic"
      certain protective effects of CR, may represent one such alternative strategy.

PMID- 12424799
TI  - Novel method for detection of ex vivo tumor necrosis factor alpha production by
      monocytes.
AB  - Tumor necrosis factor alpha (TNF-alpha) has come into recent focus as a
      proinflammatory cytokine derived from monocytes/macrophages. We developed a novel
      system (the SEK-5001 system) for measurement of ex vivo production of TNF-alpha
      stimulated by lipopolysaccharide (LPS) as a marker of immune function. In the
      present study, we evaluated the performance of this system as a diagnostic tool.
      Furthermore, we compared TNF-alpha levels with data from other immune function
      tests, including lymphocyte blast formation test and differential leukocyte
      counts. Incubation of whole blood with a stimulation of low-dose LPS (100 EU/mL
      blood) for 4 hr at 37 degrees C gave acceptable results. After incubation, plasma
      TNF-alpha levels were determined by enzyme-linked immunosorbent assay (ELISA).
      The specificity, reproducibility, and recovery of the SEK-5001 system were
      excellent. No correlation between TNF-alpha levels and total leukocyte counts was
      found. Lymphocyte blast formation test and monocyte counts, however, were
      correlated with TNF-alpha levels in blood from patients with hematological
      malignancy and aplastic anemia before treatment. This assay system may
      potentially be clinically applicable to assess in vivo immune function.

PMID- 12424800
TI  - Preparation and characterization of anti-anti-idiotypic monoclonal antibody ("Ab1
      like Ab3") in relation to carcinoembryonic antigen.
AB  - In order to analyze the epitope structure of carcinoembryonic antigen (CEA) and
      the idiotype network system, seven anti-idiotypic monoclonal antibodies (anti-Id
      MoAbs) were generated from a BALB/c mouse immunized with anti-CEA MoAb P1-356,
      which recognized a synthetic peptide P1 of CEA, domain I. These MoAbs were
      divided into four groups. The anti-Id MoAbs specifically reacted with MoAb P1
      356, but not with any MoAb, and inhibited the binding of MoAb P1-356 to CEA,
      indicating that all of these anti-Id MoAbs recognized private idiotopes at the
      combining sites of MoAb P1-356. Polyclonal anti-anti-idiotypic antiserum (Ab3)
      generated with anti-Id MoAbs M315 (Ab2), blocked the binding of MoAb P1-356 (Ab1)
      to CEA and reacted with CEA(Ag) and synthetic peptide P1. The analysis of
      serological assays suggested that it contains "Ab1-like Ab3." Therefore, we
      prepared anti-anti-Id MoAbs using anti-Id MoAb M315. Among 13 candidates, anti
      anti-Id MoAb 11B2 was selected, because it competed with MoAb P1-356 (Ab1)
      binding to CEA. A direct binding assay using MoAb11B2 showed that it reacted with
      purified CEA and with CEA synthetic peptide P1. In addition, MoAb 11B2 (Ab3)
      reacted with both CEA-producing cultured cells and colonic cancerous tissues in
      immunostaining. These results indicate that anti-anti-Id MoAb 11B2 is "Ab1-like
      Ab3." Therefore, it is suggested that anti-Id MoAb M315 bears an "internal image"
      of the MoAb P1-356-defined epitope on CEA.

PMID- 12424801
TI  - Drug-herb interactions: unexpected suppression of free Danshen concentrations by
      salicylate.
AB  - The general population of the U.S. uses over-the-counter herbal medicines.
      Danshen is a Chinese herbal product used for the treatment of cardiovascular
      disease. In a previous study we showed that Danshen has significant digoxin-like
      immunoreactivity, and we used this parameter to monitor total and free Danshen
      activities in sera (10). In this report we demonstrated strong protein binding of
      Danshen (50-70%), and we also identified albumin as the major serum protein that
      binds Danshen. Because salicylate, which is also strongly bound to albumin, is a
      widely used over-the-counter medicine in the U.S., we studied Danshen-salicylate
      interaction in vitro. We observed no significant change in free Danshen
      concentrations as measured by free-digoxin-like activity when salicylate
      concentrations were subtherapeutic (< or = 100 microg/mL). With therapeutic
      concentrations of salicylate (> or = 150 microg/mL), the free Danshen
      concentrations significantly decreased from the control. On the other hand,
      Danshen can displace salicylate from protein binding, thereby increasing the free
      salicylate concentration. We conclude that salicylate in therapeutic
      concentration can significantly decrease free Danshen concentrations, and Danshen
      can displace salicylate.

PMID- 12424802
TI  - Pre- and postsurgical detection of IgG, IgM, and IgA specific to hydatidosis by
      ELISA with purified antigen enriched with the 5/B antigen complex.
AB  - An enzyme-linked immunoassay (ELISA) using purified 5/B Echinococcus enriched
      antigen was used to follow IgG, IgM, and IgA antibody levels pre- and
      posttreatment or surgical removal of hydatid cysts. The sensitivity was 97%,
      37.5%, and 54.5%, respectively, and the specificity was 95.7%, 100%, and 98.9%,
      respectively. All isotypes could be detected 3 years after surgical removal of
      cysts in patients showing no remaining cyst evidence. This was especially true
      for IgG, which persisted in 85.2% of the patients. The data indicate that antigen
      purification improves specificity without affecting sensitivity, although this
      new antigen offers no advantages in the postsurgical monitoring of the patients.

PMID- 12424803
TI  - Clinical application of the serum 1,5-anhydroglucitol assay method using glucose
      3-dehydrogenase.
AB  - We attempted to develop a novel serum 1,5-anhydroglucitol (1,5-AG) assay kit
      using glucose 3-dehydrogenase (G3DH) from Halomonas sp. alpha-15 strain. The
      major advantages of this method are that the 1,5-AG detection requires a very
      small amount of G3DH, and the enzyme catalyzes a simple reaction. The analytical
      performances were acceptable for clinical use operated with a clinical automatic
      analyzer. The correlation with a commercial assay kit against sera of healthy
      volunteers was y=0.975x+0.008, r=0.993, Sylx=1.32 microg/mL. However, sham
      negative specimens were observed in the validation of this method using specimens
      from hospital patients.

PMID- 12424804
TI  - Changes in the mannan binding lectin (MBL) concentration in human milk during
      lactation.
AB  - The mannan binding lectin (MBL) activates the complement system by the lectin
      pathway after the recognition of some structural motifs (saccharides) present on
      the surface of microorganisms. MBL has been mostly identified and quantified in
      human serum by ELISA or microparticle immunonephelometry assays. This article
      reports the MBL levels as assessed by a microparticle immunonephelometric assay
      in 76 human milk samples. Immunonephelometry was performed using skim-milk
      samples diluted 20 times over a calibration range of 0.07-4.82 mg/L. MBL is
      indeed present in human milk and its concentration decreases significantly during
      development from colostrum (0.55+/-0.09 mg/L) to transitional (0.18+/-0.02 mg/L)
      and mature milk (0.17+/-0.02 mg/L). This innate molecule may be involved in the
      primary defenses of the mammary gland and the neonate, whose immune system is
      immature. The high levels observed during the first days of lactation support the
      hypothesis that this molecule plays a key role in limiting the colonization of
      the newborn gut by pathogens.

PMID- 12424805
TI  - A minor subspace algorithm based on neural Stiefel dynamics.
AB  - In the present paper we investigate iterative minor subspace analysis computation
      by describing a neural approach based on weight flow on Stiefel manifold and by
      discussing four neural algorithms and a purely algebraic algorithm known from the
      scientific literature. A comparison of numerical experimental results and
      computational complexity estimates confirms the effectiveness and efficiency of
      the proposed approach.

PMID- 12424806
TI  - Selecting neural networks for a committee decision.
AB  - To improve recognition results, decisions of multiple neural networks can be
      aggregated into a committee decision. In contrast to the ordinary approach of
      utilizing all neural networks available to make a committee decision, we propose
      creating adaptive committees, which are specific for each input data point. A
      prediction network is used to identify classification neural networks to be fused
      for making a committee decision about a given input data point. The jth output
      value of the prediction network expresses the expectation level that the jth
      classification neural network will make a correct decision about the class label
      of a given input data point. The proposed technique is tested in three
      aggregation schemes, namely majority vote, averaging, and aggregation by the
      median rule and compared with the ordinary neural networks fusion approach. The
      effectiveness of the approach is demonstrated on two artificial and three real
      data sets.

PMID- 12424807
TI  - An approach to improve Wang-Smith chaotic simulated annealing.
AB  - Previous research shows that Wang-Smith chaotic simulated annealing, which
      employs a gradually decreasing time-step, has only a scaling effect to
      computational energy of the Hopfield model without changing its shape. This makes
      the net has sensitive dependence on the value of damping factor. Considering Chen
      Aihara chaotic simulated annealing with decaying self-coupling has a shape effect
      to computational energy of the Hopfield model, a novel approach to improve Wang
      Smith chaotic simulated annealing, which reaps the benefits of Wang-Smith model
      and Chen-Aihara model, is proposed in this paper. With the aid of this method the
      improved model can affect on computational energy of the Hopfield model from
      scaling and shape. By adjusting the time-step, the improved neural network can
      also pass from a chaotic to a non-chaotic state. From numerical simulation
      experiments, we know that the improved model can escape from local minima more
      efficiently than original Wang-Smith model.

PMID- 12424808
TI  - An MLP training algorithm taking into account known errors on inputs and outputs.
AB  - A training algorithm is introduced that takes into account a priori known errors
      on both inputs and outputs in an MLP network. The new cost function introduced
      for this case is based on a linear approximation of the network function over the
      input distribution for a given input pattern. Update formulas, in the form of the
      gradient of the new cost function, is given for a MLP network, together with
      expressions for the Hessian matrix. This is later used to calculate error bars in
      a Bayesian framework. The error bars thus derived are discussed in relation to
      the more commonly used width of the target posterior predictive distribution. It
      will also be shown that the taking into account of known input uncertainties in
      the way suggested in this article will have a strong regularizing effect on the
      solution.

PMID- 12424809
TI  - A comparative study on kernel-based probabilistic neural networks for speaker
      verification.
AB  - This paper compares kernel-based probabilistic neural networks for speaker
      verification based on 138 speakers of the YOHO corpus. Experimental evaluations
      using probabilistic decision-based neural networks (PDBNNs), Gaussian mixture
      models (GMMs) and elliptical basis function networks (EBFNs) as speaker models
      were conducted. The original training algorithm of PDBNNs was also modified to
      make PDBNNs appropriate for speaker verification. Results show that the equal
      error rate obtained by PDBNNs and GMMs is less than that of EBFNs (0.33% vs.
      0.48%), suggesting that GMM- and PDBNN-based speaker models outperform the EBFN
      ones. This work also finds that the globally supervised learning of PDBNNs is
      able to find decision thresholds that not only maintain the false acceptance
      rates to a low level but also reduce their variation, whereas the ad-hoc
      threshold-determination approach used by the EBFNs and GMMs causes a large
      variation in the error rates. This property makes the performance of PDBNN-based
      systems more predictable.

PMID- 12424810
TI  - Genetic programming of polynomial harmonic networks using the discrete Fourier
      transform.
AB  - This paper presents a genetic programming system that evolves polynomial harmonic
      networks. These are multilayer feed-forward neural networks with polynomial
      activation functions. The novel hybrids assume that harmonics with non-multiple
      frequencies may enter as inputs the activation polynomials. The harmonics with
      non-multiple, irregular frequencies are derived analytically using the discrete
      Fourier transform. The polynomial harmonic networks have tree-structured topology
      which makes them especially suitable for evolutionary structural search.
      Empirical results show that this hybrid genetic programming system outperforms an
      evolutionary system manipulating polynomials, the traditional Koza-style genetic
      programming, and the harmonic GMDH network algorithm on processing time series.

PMID- 12424811
TI  - Neural adaptive control of nonlinear multivariable systems with application to a
      class of inverted pendulums.
AB  - In this paper multilayer neural networks (MNNs) are used to control the balancing
      of a class of inverted pendulums. Unlike normal inverted pendulums, the pendulum
      discussed here has two degrees of rotational freedom and the base-point moves
      randomly in three-dimensional space. The goal is to apply control torques to keep
      the pendulum in a prescribed position in spite of the random movement at the base
      point. Since the inclusion of the base-point motion leads to a non-autonomous
      dynamic system with time-varying parametric excitation, the design of the control
      system is a challenging task. A feedback control algorithm is proposed that
      utilizes a set of neural networks to compensate for the effect of the system's
      nonlinearities. The weight parameters of neural networks updated on-line,
      according to a learning algorithm that guarantees the Lyapunov stability of the
      control system. Furthermore, since the base-point movement is considered
      unmeasurable, a neural inverse model is employed to estimate it from only
      measured state variables. The estimate is then utilized within the main control
      algorithm to produce compensating control signals. The examination of the
      proposed control system, through simulations, demonstrates the promise of the
      methodology and exhibits positive aspects, which cannot be achieved by the
      previously developed techniques on the same problem. These aspects include fast,
      yet well-maintained damped responses with reasonable control torques and no
      requirement for knowledge of the model or the model parameters. The work
      presented here can benefit practical problems such as the study of stable
      locomotion of human upper body and bipedal robots.

PMID- 12424813
TI  - [The lived experience of family member caring for a person affected by
      Alzheimer's disease: preliminary results].
AB  - The aim of this article is to report the preliminary results from a
      phenomenological study on the lived experience of Alzheimer's caregivers. Eight
      caregivers involved in caring for two years at list were interviewed. The
      analysis of interviews by Giorgi's method showed a multidimensional reality
      synthesizable in eight spheres of themes: Illness, Patient, Caring, Caregiver's
      Life and Health, Coping, Spouse/Family, Others, Feelings. Illness has a great
      impact on the caregivers' life and causes the loss of the affected person even
      before his/her death. Caring is very hard and emotionally involving. Caregivers
      mainly complain the lack of support from the National Health System. The
      continuous involvement in caring produces also health problems, depression, and
      negative effects within the family. Others are considered as bad. The most common
      feelings are fear for possible accidents to the patients and remorses. Some
      caregivers have good coping style putting their faith in God, valuing the
      closeness of the family and living daily. The utility of the eight spheres of
      themes are discussed in order to guide the practice toward the caregivers.

PMID- 12424814
TI  - [Cost evaluation in psychiatry].
AB  - At scientific and technical level rigorously the concepts of psychiatry and
      economy do not seem to have contact points. The fields of specific competence are
      independent between they and peculiarly are addressed to different purposes. The
      mental disease is extremely versatile, it's composed in personal, affective,
      human, physical, psychological factors, to neurological times, social and
      cultural of the life of a patient little and leaves space considerations of
      economic type.

PMID- 12424815
TI  - [Nursing education at the university: what changes concerning nursing research?].
AB  - With regards to a modification in the nursing educational curriculum it is
      necessary to think about the role that the human resources duly trained in
      various educational levels will take within the nursing research process.
      Particular attention will be placed mainly on those resources who received a
      first level education not only to clarify the future role but also to emphasise
      the importance of including 'a nursing research methodology course' in their
      educational curriculum.

PMID- 12424816
TI  - [Nursing documentation in the Stroke Unit].
AB  - The organization of Stroke Unit improved prognosis of stroke patient. The
      randomized studies emphasized the importance of nursing in such a structure. In
      order to improve nursing process in our Stroke Unit, we designed a nurse record
      which includes a neurological scale, to define dependence classes and guidelines
      based on Virgina Henderson's theoretical model. In this paper, we present this
      nurse record and we describe the various steps of its design.

PMID- 12424817
TI  - [Quality of professional nursing activities: an integrated model].
AB  - The author introduces the Quality of services team as an essential cultural
      issue. Results parameters are shown.

PMID- 12424818
TI  - [Does the evaluation of the pressure ulcer risk increase better prevention?].
AB  - The aim of the study was to indagate if pressure sore risk group patients in a
      500 beds' hospital received more preventive care of a no risk control sample.
      Data have been collected on all patients (minimum stay of three days) from
      admission to discharge using an assessment dedicated tool. Results of a modified
      Norton Scale show that a 20% of pressure sores' risk patients receive more
      preventive care. A positive correlation was demonstrated particularly with:
      patient's position, bed side at 30 degrees inclination, pillows use, preventive
      local medications. However, in both groups, the general preventive intervention
      was definite as low. While an encrease of pressure sores (12%) has been
      demonstrated in the risk group, no alteration has been reported in the control
      group.

PMID- 12424819
TI  - [Biosciences between ethics and politics].
AB  - The increasing role of biosciences in the general organization of the culture and
      the consequences of this tendency in the society, involve the ridefinition of the
      concepts of disease and medicine. The need of rigorus informations locking of any
      false sensations is raising; in this context the role of bioethics, as a bridge
      between different knowledges to against the presumed idea of neutrality of
      science and to determinated social relationships based on equity.

PMID- 12424820
TI  - Effect of cadmium on sciatic nerve in diabetic rats: an ultrastructural study.
AB  - The present study demonstrated the ultrastructural effects of diabetes and
      cadmium on the peripheral nervous system. In this study we used 52 healthy Swiss
      male albino rats. They were divided into four groups: control (C), diabetic (D),
      cadmium (Cd), and diabetic and cadmium (D + Cd). The diabetic condition was
      induced by intravenous injection of 5 mg alloxan/100 g body weight, via the
      caudal vein. Cd and D + Cd groups were injected with CdCl2 intraperitoneally (2
      mg/Kg/week) for two months. At the end of the experimental period, animals were
      sacrificed and their sciatic nerves were dissected. The tissue samples were
      investigated by using light and electron microscopic techniques. Upon
      investigation, it was seen that myelinated axons in sciatic nerve of diabetic and
      Cd treatment groups had onion-bulb type myelin destruction, melting, and
      protrusion. Basal lamina of capillary endothelia of D, Cd, and D + Cd groups were
      thickened and the endothelial apical membrane was rough. In conclusion, Cd
      toxicity exacerbated the destructive effect of diabetes on the peripheral nervous
      system.

PMID- 12424821
TI  - Hypothalamic digoxin deficiency in obsessive compulsive disorder and la
      Tourette's syndrome.
AB  - The isoprenoid pathway related cascade was assessed in 15 patients with obsessive
      compulsive disorder (OCD) and la Tourette's syndrome (TS). The pathway was also
      assessed in right hemispheric dominant, left hemispheric dominant, and
      bihemispheric dominant individuals to assess whether hemispheric dominance has
      any correlation with these disease states. The levels of serum digoxin, HMG CoA
      reductase activity, and dolichol were found to be decreased in OCD and la
      Tourette's syndrome as well as in left hemispheric dominant individuals with a
      corresponding increase in RBC Na(+)-K+ ATPase activity, serum ubiquinone, and
      magnesium levels. There was an increase in tyrosine and its catabolites, and a
      reduction in tryptophan and its catabolites in the serum. The total and
      individual glycosaminoglycan (GAG) fractions, carbohydrate residues of
      glycoproteins, and the concentration of glycolipids decreased in the serum. The
      activity of GAG degrading enzymes and glycohydrolases were decreased. The RBC
      membrane glycoconjugates were increased while the membrane
      cholesterol:phospholipid ratio was decreased. The activity of free radical
      scavenging enzymes increased while the concentration of free radicals decreased
      significantly. On the other hand, there was hyperdigoxinemia and the reverse
      biochemical patterns in those with right hemispheric dominance. Membrane Na(+)-K+
      ATPase stimulation can result in decreased intracellular Ca2+ and increased
      magnesium levels. Increased levels of dopamine can lead to a tic syndrome, while
      reduced levels of serotonin and increased dopamine can both lead to obsessive
      compulsive disorder. Decrease in fucose and sialo-ligands, increased
      immunosuppressive morphine levels, decreased T-cell calcineurin signal
      transduction related to decreased intracellular calcium, reduced free radical
      production, and altered presentation of bacterial glycoconjugate antigens can
      lead to a hypoimmune response and recurrent respiratory infection in OCD
      patients. OCD and la Tourette's syndrome are associated with left hemispheric
      chemical dominance.

PMID- 12424822
TI  - Classical and atypical neuroleptics, and bone mineral density, in patients with
      schizophrenia.
AB  - There are some reports that classical neuroleptics may lead to osteoporosis or
      reduced bone mineral density (BMD). However, there is no adequate information
      about the effects of atypical neuroleptics on BMD. The aim of this study was to
      measure BMD in schizophrenic patients taking classical and atypical neuroleptics,
      compared to healthy controls. Seventy-five patients with schizophrenia (40 taking
      classical neuroleptics [CN], 35 taking atypical neuroleptics [AN]) and 20 healthy
      controls (HC) were included in the study. Spine (L1-L4) BMD was measured by dual
      energy X-ray absorptiometry. ANOVA showed that BMD was higher in HC than AN and
      CN. In addition, there was a negative correlation between the duration of
      neuroleptic treatment and BMD and the duration of the illness. These findings
      suggest that atypical neuroleptics may be safer than the classical neuroleptics
      in terms of reduced BMD.

PMID- 12424823
TI  - The effect of octreotide on kainate-induced wet dog shakes and seizure activity
      in male and female rats.
AB  - Systemic kainic acid (KA) administration to rats triggers wet dog shakes (WDS)
      followed by epileptic seizures. Although WDS are often associated with the
      occurrence of seizures, we have recently shown that following nitric oxide (NO)
      synthesis inhibition, the number of WDS decreased; subsequently the onset of
      seizure activity was shortened, and the number of convulsions was increased.
      Somatostatin (SS), whose release appears to be controlled by NO, inhibits seizure
      activity. There are sex differences in seizure susceptibility as well as in SS
      and NO activities in brain. The present study was undertaken to assess the effect
      of octreotide (OC), a stable SS analogue, on KA-induced WDS and seizures in rats,
      with emphasis on possible sex differences. WDS and seizures were induced by KA in
      male and female (proestrus) Sprague Dawley rats; OC or saline was injected 30 min
      before KA and the behavior was monitored for 120 min after KA. Octreotide
      increased the number of WDS and decreased the number of convulsions; this effect
      was more pronounced in males. Onset of KA-induced seizure activity was earlier in
      females than males; however, there was no effect of OC on seizure latency.
      Seizure activity started after the termination of WDS. These results show OC has
      opposite effects on WDS and convulsions, in that it stimulates the former and
      inhibits the latter. These results support our previous findings that WDS and
      seizure activity involve separate mechanisms and suggest that WDS may have an
      inhibitory effect on limbic seizures.

PMID- 12424824
TI  - Intersession reliability for H-reflex measurements arising from the soleus,
      peroneal, and tibialis anterior musculature.
AB  - The Hoffman reflex (H-reflex) has been widely used throughout neuroscience
      research, as it allows for the assessment of alpha motoneuron excitability
      arising from a specific motoneuron pool. Recently, a protocol has been developed
      allowing for the simultaneous examination of the soleus, peroneal, and tibialis
      anterior motoneuron pools elicited from a single peripheral stimulus. In order
      for this protocol to be useful, the reliability of the measures must be
      established. The purpose of the current study was to determine the intersession
      reliability of the soleus, peroneal, and tibialis anterior H-reflexes and their
      corresponding M-waves elicited from a single stimulus to the sciatic nerve. Ten
      healthy neurologically sound individuals (age: 23 +/- 7 yrs; height: 175 +/- 12
      cm; mass: 76 +/- 22 kg) volunteered to participate in this investigation. To
      obtain the measurements, the sciatic nerve was stimulated just prior to its
      bifurcation into the tibial and common peroneal nerves in the popliteal fossa. A
      1-ms square wave pulse was delivered in 0.2 V increments until the maximum M wave
      was seen in each muscle. The maximum H-reflex and M-waves were collected from
      each muscle and their ratios calculated. Intersession reliability over 2
      consecutive days was estimated using intraclass correlation coefficients (ICC
      [2.1]). Intersession reliability for the soleus Max H, Max M, and H:M ratio were
      0.9953, 0.9514, and 0.9747, respectively. The peroneal reliability measurements
      were as follows: 0.9979 (Max H), 0.9924 (Max M), and 0.9664 (H:M ratio).
      Intersession reliability was 0.8591, 0.9968, and 0.7810 for the tibialis anterior
      Max H. Max M. and H:M ratio, respectively. These results indicate that the H
      reflex measured from the soleus, peroneal, and tibialis anterior musculature
      elicited with a single peripheral stimulus to the sciatic nerve is reliable
      between sessions. This protocol allows the clinician/researcher to reliably
      investigate the alpha motoneuron excitability of multiple motoneuron pools about
      the ankle at a single point in time.

PMID- 12424825
TI  - Smoking and Parkinson's disease: explanatory hypothesis.
AB  - A systematic review was conducted to estimate the pooled risk of smoking for
      Parkinson's disease in Chinese populations. The four identified case-control
      studies had odds ratios with 95% confidence intervals nearly or overlapping
      unity. Pooled odds ratio of these studies was 0.77 with 95% confidence interval
      0.60 to 0.97. It was suggested that smoking induces debrisoquine 4-hydroxylase,
      which is responsible for the metabolism of antipsychotic drugs and the
      detoxification of certain environmental toxins known to cause dopaminergic neural
      damage. This could be the explanation of these contradictory results as
      cytochrome P-450 CYP2D6 debrisoquine hydroxylase gene polymorphism is known to be
      much lower in Chinese than in Caucasian people. This systematic review raises
      concerns about generalization of the conclusion previously settled by many cohort
      and case-control studies.

PMID- 12424826
TI  - MUPRO: a multipurpose robot.
AB  - The aim of this article was to describe an apparatus, called multipurpose neck
      robot (MURPO), designed to record both the forces exerted at head level and the
      head rotations in the horizontal plane in the behaving monkey. It consists of a
      mechanical device, comprising a cardan joint, a potentiometer, an electromagnetic
      brake, and four flexion load cells, plus an oleodynamic system allowing head
      rotation in the horizontal plane between +/- 20o. These components are assembled
      on a column bolted to the primate's chair. An electrical device provides DC power
      for the potentiometer and the brake. The apparatus enables us to measure both the
      force fields and the head movements during training sessions and
      electrophysiological investigations.

PMID- 12424827
TI  - Narrow-band spectral measurements of EEG during emotional tasks.
AB  - The objective of this study was to discover how narrow-band spectral measurements
      express emotional behavior. Electroencephalographic narrowband absolute and
      relative spectral powers were calculated for every 1 Hz of frequency from the
      recordings of 40 healthy male university students during emotional tasks.
      Sentences evoking positive, negative, and neutral emotional states were used as
      stimuli. Repeated multivariate analyses of variance were computed with IQ as
      covariate. The results showed only a few significant relations between absolute
      power and emotion. Relative power reflected better the differences determined by
      emotional states. The frequencies between 7.6 and 9.5 Hz showed differences
      between emotional states over the entire scalp with increased power during
      neutral state. Interaction between emotional states and cerebral regions revealed
      that all cerebral areas had an important role, especially frontal, parietal, and
      temporal regions. Hemispheric differences showed less power in the left
      hemisphere during positive emotional state (joy of love) in the 8.6 to 9.5 Hz
      band and in the right hemisphere during negative emotional state (frustration) in
      the 17.6 to 18.5 Hz band. Significant interaction between states, hemispheres,
      and electrode positions was observed in the frequency range of 17.6 to 19.5 Hz.
      As none of our results covered the range of any broad band, we may conclude that
      narrow-band calculations are more adequate for the study of emotions, because
      their use reduces the danger that frequency-specific effects go undetected or
      cancel each other.

PMID- 12424828
TI  - Human scalp recorded sigma activity is modulated by slow EEG oscillations during
      deep sleep.
AB  - The EEG during deep sleep exhibits a distinct cortically generated slow
      oscillation of around and below 1 Hz which can be distinguished from other delta
      (0.5-3.5 Hz) activity. Intracranial studies showed that this slow oscillation
      triggers and groups cortical network firing. In the present study, we examined
      whether the phases of the slow oscillation during sleep stage 4 are correlated
      with the magnitude of sigma (12-16 Hz) and gamma (> 20 Hz) scalp activity. For
      this purpose, 10-min segments of uninterrupted stage 4 sleep EEG from 9 subjects
      were analyzed by applying wavelet techniques. We found that scalp recorded sigma,
      but not gamma, activity is modulated by the phases of the slow oscillation during
      deep sleep. Enhancement of sigma activity was observed to be triggered by the
      peak of the surface positive slow wave component, whereas reduction of sigma
      activity started around the peak of the negative component.

PMID- 12424829
TI  - Our history.

PMID- 12424837
TI  - Genetic control of susceptibility in clinical and experimental uveitis.

PMID- 12424838
TI  - Central tolerance mechanisms in control of susceptibility to autoimmune uveitic
      disease.

PMID- 12424840
TI  - Anterior chamber associated immune deviation (ACAID): regulation, biological
      relevance, and implications for therapy.
AB  - Immune privilege was first explored in the late 1800s by van Dooremaal, and was
      then extended by Medawar in the mid 1900s to fit in with emerging concepts of
      transplantation immunology. Modern concepts and understanding of immune privilege
      come from subsequent studies produced by Medawar, Billingham, and Streilein. The
      exploitation of the model of anterior chamber immune deviation (ACAID) in mice
      has allowed us to look at both cellular and molecular mechanisms involved in the
      prevention of potentially damaging immune responses in such privileged sites.
      This review gives a historical perspective of the immune privilege research and
      provides up-to-date information of molecules, cells, and concepts newly
      recognized as contributing to tolerance induction induced in such specialized
      areas of the body. Evidence is given to support the idea that application of such
      information may lead to potential for therapeutic applications of ACAID
      mechanisms in prevention of progression of immune-inflammatory diseases in
      humans.

PMID- 12424839
TI  - Peripheral expression of ocular antigens in regulation and therapy of ocular
      autoimmunity.
AB  - The retina is a well-known immune-privileged tissue in the eye. Gene therapy and
      transgenic strategies have been taken to explore the relationship between the
      immune system and retinal antigens. Retroviruses were used to express retina
      specific antigens or fragments systemically, leading to an antigen-specific loss
      of susceptibility to autoimmune disease. Transgenic strategies used a neo self
      antigen, beta-galactosidase, or a known retinal antigen, interphotoreceptor
      retinoid-binding protein, to show that immune recognition of antigen by mice,
      which express solely in the retina, is not detectably different than that of mice
      that don't express this antigen. Together, these studies show that antigens
      expressed solely in the retina do not appear to be seen by the immune system,
      demonstrating that sequestration contributes to the lack of antigen recognition
      and absence of tolerance. Provision of these antigens outside of the retina
      provides the opportunity for development of peripheral tolerance, protection from
      autoimmunity, and potential therapies.

PMID- 12424841
TI  - Cell death and immune privilege.
AB  - The host response to pathogens involves complex inflammatory responses and immune
      reactions. While these are central to host defense and vital to clearing
      infections, they are often accompanied by injury to surrounding tissue. Most
      organ systems can tolerate these responses without permanent consequences.
      However, there are sites that limit the spread of inflammation because it can
      threaten organ function. The most prominent examples of these are the eye, brain,
      and reproductive organs (testis, ovary), where even minor bouts of inflammation
      can have long-term consequences for the survival of the organism. In these organs
      immune responses either do not proceed, or proceed in a manner different from
      other areas; thus, they are called "immunologically privileged." Here a
      functioning immune response can be the culprit that leads to disease.

PMID- 12424842
TI  - Immunology and immunomodulation of corneal transplantation.
AB  - Corneal allografts are the oldest, most common, and most successful transplants
      performed on humans and animals. The cornea is endowed with a constellation of
      unique factors that contribute to its immune privilege and the low incidence of
      immune rejection. In spite of this immune privilege, 10 percent of first-time
      corneal grafts will undergo immune rejection. Several novel therapeutic
      strategies hold promise for modulating the alloimmune response by either
      promoting antigen-specific tolerance or redirecting the host's response from a
      Th1 pathway toward a Th2 pathway.

PMID- 12424843
TI  - Th1 and Th2 responses in pathogenesis and regulation of experimental autoimmune
      uveoretinitis.
AB  - Experimental autoimmune uveoretinitis (EAU) in animals can be induced by
      immunization with retinal antigens or their fragments and represents human
      uveitis of putative autoimmune origin. The pathogenesis of EAU, and likely also
      of human uveitis, involves cell-mediated destruction of retinal tissues that is
      dependent on retinal antigen-specific T cells. Because in most cases a Th1-type
      response has been implicated in pathogenesis, the prevailing consensus has been
      that immunoregulatory manipulations designed to enhance the Th2 response at the
      expense of the Th1 response will be beneficial in clinical treatment of uveitis.
      This assumption may not always be correct. The present review will summarize the
      evidence that, despite a central role for Th1 response in uveitis, an unopposed
      Th2-like response can be equally or more destructive to the retinal tissues.
      Furthermore, the Th1 response itself triggers regulatory circuits that feed back
      and dampen further recruitment of antigen-specific T cells into the Th1 effector
      pool. Thus, although the Th1 effector response can and does result in retinal
      pathology, immunoregulatory strategies must take into account that immune
      deviation therapies designed to replace the Th1 with a Th2 response might result
      in exchanging one type of pathology for another rather than in achieving the
      desired therapeutic effect.

PMID- 12424844
TI  - Experimental autoimmune uveitides: multiple antigens, diverse diseases.
AB  - Human autoimmune uveitides are diverse and complex. Animal models have been
      developed for studying the pathogenesis of uveitis because of the difficulties in
      obtaining tissues from a patient's inflamed eye for experiments. There are animal
      models for experimental uveitis that provoke inflammation of different tissues of
      the eye and represent different forms of uveitis. Since inflammatory cells can
      infiltrate any part of the uvea and spill over to nonuveal tissues, such as
      retina, various antigens have been used to induce uveitis. Most of those models
      that represent autoimmune forms of uveitis are induced with proteins specific for
      photoreceptor cells (S-antigen, IRBP, rhodopsin, recoverin, phosducin).
      Nonretinal antigens, including melanin-associated proteins and myelin basic
      protein, are also good inducers of uveitis in animals.

PMID- 12424845
TI  - Cytokines in immunotherapy of experimental uveitis.
AB  - A better understanding of the basic mechanisms of uveitis and of the role of
      cytokines in experimental ocular inflammation autoimmune diseases should allow us
      to define new approaches for therapy. Modulation of the cytokine network by
      either blocking cytokine activity or administration of regulatory Th2 cytokines
      has shown its efficacy in several experimental autoimmune diseases including
      uveitis. However, cytokines present pleiotropic activities and thus may exert
      different effects depending on the autoimmune diseases, making interventions on
      their production complex. Anti-cytokine therapy or a combination of anti-cytokine
      drugs, antibodies, and cytokine gene therapy to synergize the therapeutical
      effects of other treatments appear to be of interest. Improvements in drug
      delivery and in biotechnology will also allow us to elaborate new and safe
      immunomodulatory strategies.

PMID- 12424846
TI  - Imaging ocular immune responses by intravital microscopy.
AB  - The eye offers excellent opportunities to observe cellular interactions in vivo.
      This applies especially to the immune response in which discrete events can be
      studied, including cell trafficking, transendothelial migration, adhesion,
      antigen presentation, and T cell activation. Intravital microscopy has allowed
      study of immune cell interactions in tissues such as the conjunctiva, the
      inflamed cornea, and the iris. Thus the realtime observation of presentation of
      antigen injected into the anterior chamber of the eye can be imaged using
      fluorescently labelled antigen and cells. Application of the scanning laser
      ophthalmoscope to the rat and mouse eye allows analysis of leukocyte-endothelial
      interactions in the retinal and choroidal circulations. These studies have
      provided important information on rolling and adhesion of leukocytes in real time
      in different microvascular beds that have not been manipulated in any way and
      has, for instance, provided quantitation to the effects of shear stress on
      leukocyte-endothelial adhesion. In addition, the model permits an accurate
      analysis of the timing of trafficking of T cells into the eye and the possibility
      of determining which cells, if any, may be responsible for antigen presentation
      in the tissues as opposed to the secondary lymphoid organs. Finally, these
      experimental methods are now being applied to the human eye and should prove
      valuable in determining the nature of tissue damage events in the eye as well as
      evaluating the response to treatments.

PMID- 12424847
TI  - Bench to bedside: new approaches to the immunotherapy of uveitic disease.
AB  - Intraocular inflammatory disease, or uveitis, appears to be due in large part to
      non-infectious, cell-mediated mechanisms. Experimental autoimmune uveitis (EAU)
      has been a valuable tool to better understand underlying mechanisms of this
      disorder, and it provides the possibility to evaluate new approaches to
      immunotherapy as well. Two approaches described here are oral tolerance and anti
      IL2 receptor therapy. Both therapies were evaluated in the animal model and
      showed positive therapeutic effects. Based on these observations, both approaches
      were used in the treatment of patients with uveitis. Oral tolerance showed
      initial promising results. Anti-IL2 receptor therapy has been used for over 4
      years in uveitis patients with an additional study evaluating this therapy in
      Behcet's disease. Future plans are to expand this approach to a larger number of
      patients. The use of animal models has been very useful in better understanding
      mechanisms of ocular disease and bringing new therapeutic approaches to the
      clinic.

PMID- 12424848
TI  - Epidemiologic trends in esophageal and gastric cancer in the United States.
AB  - Use of tobacco, moderate to heavy alcohol ingestion, infrequent consumption of
      raw fruits and vegetables, and low income accounted for more [figure: see text]
      than 98% of the SCE rates among both African American and white men and for 99%
      of the excess incidence among African Americans compared to whites in a case
      control study in three areas of the United States [14]. Thus, it is likely that
      declines in the prevalence of smoking and drinking, especially among men, and
      increased intake of fresh fruits and vegetables may have contributed to the
      downward incidence and mortality rate trends reported for SCE. In addition, it
      seems plausible that obesity, GERD, and possibly reductions in H. pylori
      prevalence have contributed to the upward trends in ACE rates. Reductions in
      smoking, improved diet, and reductions in H. pylori prevalence probably have
      contributed to the consistent reductions observed for NGA. Contributing factors
      are less clear for the rising incidence rates of GCA during the 1970s and 1980s.
      These incidence rates have not continued to rise in recent years.

PMID- 12424849
TI  - Molecular and biologic basis of upper gastrointestinal malignancy--esophageal
      carcinoma.
AB  - Esophageal cancer is one of the most deadly forms of gastrointestinal cancer.
      Even though the incidence of esophageal adenocarcinoma has been rising in Western
      populations over the past two decades, esophageal squamous cell carcinoma remains
      the predominant type of esophageal malignancy in the remainder of the world. With
      the recent advances in molecular biology, high-output genome wide screening has
      provided comprehensive profiles of molecular alterations in human esophageal
      carcinomas. The elucidation of the basic mechanisms of esophageal carcinogenesis
      brings with it the promise of developing treatment and preventive strategies that
      are based on the molecular biology of these tumors. The genetic alterations
      discussed in this article are not unique to the formation of esophageal
      carcinomas and represent only a fraction of the molecular changes found in these
      tumors. The goal of this article is to provide the clinician with a useful
      conceptual basis for evaluating studies on the molecular mechanisms underlying
      the development of esophageal carcinomas.

PMID- 12424850
TI  - Molecular and biologic basis of upper gastrointestinal malignancy. Gastric
      carcinoma.
AB  - Gastric cancer is one of the world's most common cancers and is a leading cause
      of cancer death worldwide. Neoplasia of the stomach is mainly composed of
      adenocarcinomas, which for more than 95% of cases. Although mesenchymal tumors
      (i.e., stromal tumors, leiomyomas and leiomyosarcomas, and schwannomas), primary
      lymphomas, and carcinoid tumors can also arise in the stomach, malignant tumors
      of these types occur much less often.

PMID- 12424851
TI  - Intraoperative lymphatic mapping and sentinel lymph node sampling in esophageal
      and gastric cancer.
AB  - Recent studies for SN mapping of esophageal and gastric carcinoma show that the
      SN concept is valid even for upper GI cancers with multidirectional and
      complicated lymphatic flow. The relatively high incidence of anatomic skip
      metastasis can be attributed to aberrant distribution of SNs. An individualized
      and minimally invasive surgical approach can be applicable to management of
      esophageal and gastric carcinoma based on SN status. Although there are several
      issues to be resolved, this novel procedure has the potential for great benefit
      to improve quality control in the treatment of upper GI cancer. Well-designed
      clinical trials of lymphatic mapping for upper GI cancer will be essential to
      determine whether this technique is widely applicable in the management of these
      tumors.

PMID- 12424852
TI  - Interventional endoscopy in the diagnosis and staging of upper gastrointestinal
      malignancy.
AB  - Increased population longevity as well as an emphasis on earlier diagnosis and
      more effective treatment of cancer have created an environment for new
      technologies and techniques to flourish. Some of the endoscopic entities
      discussed in this article have not been fully validated in clinical practice.
      Innovative spectroscopic modalities hold a great deal of promise, but are years
      away from general applicability. In contrast, many interventional endoscopic
      techniques are currently available and confer heightened levels of diagnostic and
      staging accuracy for gastric and esophageal malignancies. Earlier diagnosis can
      identify patients who may be eligible for less-invasive treatment options such as
      EMR. Minimally invasive treatment options and maximum staging accuracy are more
      important for patients who are marginal surgical candidates and for accurate
      comparison of clinical trials studying treatment options. Our challenge for the
      future is to properly integrate these technologic advances with the science of
      good medical practice.

PMID- 12424853
TI  - Nonsurgical management of Barrett's esophagus with high-grade dysplasia.
AB  - Endoscopic management options for BE with high-grade dysplasia consist of either
      surveillance methods or endoscopic mucosal ablative therapies. Intensive
      surveillance once a person is diagnosed with high-grade dysplasia may avoid an
      unneeded esophagectomy because it appears that most patients with high-grade
      dysplasia may not progress to esophageal adenocarcinoma. Only a single study has
      been presented that demonstrates that this approach does not lead to missed
      opportunities for intervention before progression to advanced stage disease [20].
      This study excluded patients with cancer detected within 1 year of diagnosis of
      high-grade dysplasia; thus, patients who wish to proceed with an observation
      approach should be aware that the rate of missed esophageal adenocarcinomas
      ranges from 38% to 73%. The ability to observe a patient with high-grade
      dysplasia, however, does have appeal because a number of these patients appear to
      lose the high-grade dysplasia over time. The other endoscopic management option
      for Barrett's esophagus with high-grade dysplasia is endoscopic mucosal ablative
      therapies. These include the KTP:YAG laser, the Nd:YAG laser, photodynamic
      therapy, and endoscopic mucosal resection. All ablative therapies are used in
      combination with control of gastroesophageal reflux. This allows the esophageal
      tissue to heal in an environment that is conducive to squamous mucosa. Although
      most are relatively small series with short durations of observation, they all
      have shown some promise in treating BE with high-grade dysplasia. These
      approaches have the advantage of eliminating the problem. The patient who is
      being observed must live with the thought of developing cancer. Patients who
      undergo successful ablation are returned to a normal life. The combination of
      therapies such as EMR with PDT may be the most promising approach to BE with high
      grade dysplasia; however, the long-term effects of ablative therapy are not known
      and continued surveillance is still advised for this group of patients. The
      choice of a nonsurgical approach for the management of BE with high-grade
      dysplasia is ultimately up to the individual patient. All patients must be
      carefully informed of the treatment effects, possible outcomes, and the surgical
      alternative. Most patients who select nonsurgical approaches are either elderly
      or are not good surgical candidates. The choice is often affected by local
      expertise, as surgical procedures should be performed in centers with surgeons
      expert in esophagectomy. Nonsurgical approaches should also be performed by
      physicians who are familiar with their application. Future advances in
      nonsurgical techniques such as new photosensitizers in PDT and improvements in
      diagnostic techniques may allow patients a greater opportunity to preserve their
      esophagus.

PMID- 12424854
TI  - Technique and role of minimally invasive esophagectomy for premalignant and
      malignant diseases of the esophagus.
AB  - Esophagectomy remains the standard of care in most centers for patients with
      resectable esophageal cancer. The choice of incision and conduit has remained the
      subject of much discussion. Open surgical approaches include the Ivor Lewis,
      transhiatal, left thoracoabdominal, three-hole, and left thoracoabdominal with
      left neck anastomosis. These techniques will be covered in the article by.
      Regardless of the approach, esophagectomy has been associated with considerable
      morbidity and mortality. Although modern anesthetic and surgical care has reduced
      the risks of esophagectomy, the incidence of major or minor complications is
      still approximately 70% to 80%, and the hospital mortality rate is 4% to 7% at
      experienced centers. In the hopes of reducing perioperative morbidity, minimally
      invasive techniques have been increasingly applied to esophageal surgery.
      Experience with laparoscopic antireflux surgery has allowed us to perform more
      and more complex surgery on the stomach and esophagus and, in 1995, surgeons
      began to report their experiences with minimally invasive esophagectomy using
      various techniques.

PMID- 12424855
TI  - Standard surgical approaches in the management of esophageal cancer.
AB  - Much controversy remains regarding the optimal treatment for patients with
      carcinoma of the esophagus. Further studies are necessary to examine the utility
      and efficacy of each approach in treating esophageal cancer either alone or in
      combination with other modalities. Until data from prospective randomized trials
      showing a clear benefit using a particular approach are available, surgeons
      should use their better judgement in individualizing and selecting the most
      appropriate surgical approach to provide the best chance of cure or lasting
      palliation for this disease that challenges both patient and surgeon.

PMID- 12424856
TI  - Transthoracic or transhiatal esophagectomy for cancer of the esophagus--does it
      matter?
AB  - Despite the ongoing controversy between proponents of TTE and THE, in the hands
      of experienced surgeons, both approaches provide excellent results for patients
      with carcinoma of the esophagus and EG junction. Ideally, surgeons dealing with
      esophageal carcinoma should be expert in both approaches and should select the
      best approach for the individual patient. The transhiatal approach appears to
      have a slightly lower operative mortality, and this advantage may be significant
      for the older, higher-risk surgical patient. Nevertheless, the transhiatal
      approach has a slightly higher risk of anastomotic complications and recurrent
      laryngeal nerve injury. Recent studies suggest, however, that the volume of
      experience of the surgeon is probably a more important factor in predicting
      operative mortality and complication rates than is the choice between TTE and
      THE. Cancer-related survival appears to be similar after the two procedures.

PMID- 12424857
TI  - Combined modality therapy of esophageal cancer--standard of care?
AB  - Because of the controversies and conflicting data described above, it is very
      difficult to provide strict guidelines for the treatment of patients with
      locoregional esophageal carcinoma. It is necessary, however, to try to put
      current knowledge in perspective. Surgery remains a standard of care for
      potentially resectable disease. Definitive chemoradiation is a standard of care
      for locoregional disease, particularly if a patient is medically unfit for
      surgery, if a surgeon experienced in esophagectomies is unavailable, or if the
      patient has cervical disease, which would require very extensive surgery.
      Chemoradiation is superior to radiation alone for these patients. Some frail
      patients may only be able to tolerate palliative radiation. Preoperative
      chemotherapy is controversial, with two large randomized studies resulting in two
      different conclusions regarding survival benefit. NCCN guidelines do not suggest
      this modality as a standard of care. After assessment of the patient's tumor
      stage, performance status, and personal wishes for aggressive treatment, it is
      possible that some physicians may consider offering this option to patients. The
      patient should have advanced disease, an excellent performance status, and
      understand the controversies and lack of consensus about this option.
      Preoperative chemoradiation is controversial. Only one of three randomized trials
      showed a clear survival benefit; however, the patients treated with surgery alone
      in that trial had an unusually poor outcome. The second trial showed no benefit,
      and the third trial was negative but statistically powered only to reveal a large
      survival difference and in multivariate analysis showed a possible trend to
      improved outcome. The NCCN guidelines do not advocate preoperative chemoradiation
      as a standard of care. As stated above, however, some physicians may consider
      offering this option to patients with advanced disease, excellent performance
      status, and who understand the controversies and lack of consensus about this
      option. Patients with adenocarcinoma of the GE junction treated with surgery
      alone should have postoperative chemoradiation, particularly if there is tumor
      involvement in the lymph nodes. No definitive trial has been performed to
      determine whether chemoradiation plus surgery is superior to chemoradiation
      alone.

PMID- 12424858
TI  - Is there a role for nontraditional resection of early gastric cancer?
AB  - Current trends in the treatment of gastric cancer indicate the emergence of a
      more sophisticated approach, with tailored therapy applied to individual cases.
      Treatment includes a broader spectrum of therapeutic options (Fig. 3), including
      EMR, laparoscopic or laparoscopy-assisted surgery, modified radical surgery, and
      typical radical surgery with lymph node dissections. Precise characterization of
      the lesions, especially the depth of invasion in the gastric wall, its size,
      histology and whether there is ulceration, is the key to successful treatment of
      N0 mucosal cancer. Micrometastasis and metastasis at the molecular level are
      issues that require further investigation. Laparoscopic surgery may be more
      widely accepted. The limitations of nodal dissection based on the concept of a
      sentinel node should be carefully evaluated in future studies. [figure: see text]
      Many treatment options, ranging from minimally invasive surgery to D2 node
      dissection, are available to the surgical oncologist who is treating EGC. As more
      information is gathered, surgeons will be better able to select patients who are
      good candidates for minimal surgical procedures.

PMID- 12424859
TI  - Site-dependent resection techniques for gastric cancer.
AB  - In addition to tumor stage and growth pattern, the tumor site is a major factor
      in determining the extent of resection and lymphadenectomy necessary in patients
      with gastric carcinoma. Total gastrectomy with D2-lymphadenectomy is the
      procedure of choice for tumors of the gastric corpus. Extended total gastrectomy
      with trans-hiatal resection of the distal esophagus is required for tumors of the
      proximal region; in these patients lymphadenectomy may also include splenic hilum
      and left retroperitoneal nodes. In patients with distal gastric carcinoma, a
      subtotal gastrectomy often achieves a complete tumor resection. Extended
      lymphadenectomy in these patients includes the retroduodenal and right para
      aortic nodes in addition to a D2-dissection. In patients with early tumor stages,
      anatomically oriented limited resection techniques are increasingly important.
      The concept of the sentinel lymph node may result in more selective
      lymphadenectomy strategies in the near future [15]. For patients with a locally
      advanced disease, these surgical concepts must be evaluated within multimodal
      treatment protocols [16].

PMID- 12424860
TI  - Is D2 lymphadenectomy for gastric cancer a staging tool or a therapeutic
      intervention?
AB  - The extent of lymphadenectomy for gastric cancer is a controversial topic widely
      debated by those treating the disease. Regional differences in outcome have been
      noted between patients treated in Japan centers and those treated in Western
      centers. Technical differences have been investigated within the context of two
      large, prospective randomized trials, which found no benefit to more extensive
      lymphadenectomy procedures with increased morbidity. Subsets of patients being
      treated for cure may benefit from extended resections. The impact of tumor
      features, such as depth of invasion and number of metastatic lymph nodes, has
      been described and incorporated into current staging systems. The role of
      enhanced pathologic evaluation of surgical specimens and impact on staging and
      treatment strategies is evolving.

PMID- 12424861
TI  - Adjuvant therapy for resected gastric carcinoma.
AB  - Despite its continued decline over the past 40 years, gastric carcinoma is a
      common gastrointestinal cancer and a major health problem around the world. In
      Asian countries, such as Korea, Japan, Taiwan, and China, it remains one of the
      leading causes of cancer-related death. Similarly, it is a common malignancy in
      many South American countries, Eastern European countries, and many countries of
      the former Soviet Union. In North America, the incidence of gastric carcinoma is
      low; however, the incidence of proximal gastric carcinoma has risen over the past
      15 years. In 2001, approximately 21,700 new cases and 12,800 deaths were
      estimated in the United States as a result of gastric carcinoma. In the United
      States, gastric cancer ranks 14th among all cancers in incidence rate and 10th in
      overall mortality rate. An early detection program has been established in Japan,
      where nearly 6,000,000 adults are screened annually. This type of mass screening
      for gastric cancer is not practiced elsewhere, however. Because the risk of
      relapse remains high for patients after a curative resection, there is a great
      need for effective adjuvant therapy for patients with gastric carcinoma.

PMID- 12424862
TI  - Surgical quality control in gastric cancer trials.
AB  - Quality control in prospective randomized surgical trials of gastric cancer
      treatment is reviewed. Progress and innovations in this area are described.
      Methodologic suggestions for future trials are made.

PMID- 12424863
TI  - Methods of palliation of esophageal and gastric cancer.
AB  - Esophageal and gastric malignancies are common worldwide. Less than half are
      amenable to curative treatment at the time of diagnosis because of advanced or
      metastatic disease. Palliation is often required for symptoms, such as dysphagia,
      gastrointestinal bleeding, aspiration caused by tracheoesophageal fistula, nausea
      and emesis secondary to gastric outlet obstruction, and malnutrition. This
      article reviews the gastric outlet obstruction, and malnutrition. This article
      reviews the medical, endoscopic, and surgical options for palliative treatment.

PMID- 12424864
TI  - Successful aging--an emerging paradigm of gerontology.
AB  - In the largely successful preventive approach to reduction in cardiovascular
      disease prevalence, three classic stages of investigation were used. First, an
      hypothesis was raised that diet and cholesterol levels were a cause of heart
      disease. Second, multiple longitudinal observational studies, led by the
      Framingham group, documented a strong association between these health risks and
      heart disease mortality. Finally, randomized controlled trials of cholesterol
      lowering drugs established proof of causality. Our understanding of the
      Successful Aging phenomenon has followed the same sequence. The Compression of
      Morbidity hypothesis sets forth a new and promising paradigm. Multiple
      longitudinal and cross-sectional observational studies show strong associations
      consistent with the hypothesis. Finally, randomized controlled trials of healthy
      aging interventions prove our ability to successfully intervene in this most
      important of all contemporary health problems: the health of seniors [28].

PMID- 12424865
TI  - The biology of senescence: potential for prevention of disease.
AB  - A recent series of advances in the understanding of mechanisms responsible for
      senescence have opened up potential avenues for delaying its onset and that of
      associated chronic diseases. Because the onset of senescence, like other
      biological processes, appears to be subject to regulation, advantage is being
      taken of pathways involved in this regulation to develop therapeutic
      interventions. These pathways include: (1) development of nutritional
      interventions based on the finding that caloric restriction extends maximum life
      span; (2) drugs to influence the metabolic pathways that link effects of caloric
      restriction to the changes in gene regulation that occur with aging; (3) drugs to
      prevent formation of advanced glycation end products resulting from reaction of
      reducing sugars with macromolecules; (4) agents to slow damaging effects of
      reactive oxygen species; and (5) methods to overcome effects of telomere
      shortening. Interventions to correct age-related, tissue specific changes in
      expression of transcription factors that enable cells to acquire specialized
      function are already in use (e.g., thiazolidinediones). In addition, because the
      aging process can be reset by factors present in oocytes, as shown by the cloning
      of healthy animals from senescent cells, methods to rejuvenate cells for
      transplantation or even intact tissues in individuals are within the realm of
      possibility. The hope in developing these interventions is to push back the onset
      of the chronic diseases associated with senescence and to prolong the period of
      adult vigor.

PMID- 12424866
TI  - Primary prevention of disease of old age.
AB  - Although increasing disability is a common concomitant of old age, several
      interventions may prevent or delay disabling diseases. The "young-old" differ
      little from middle-aged people in their potential to benefit from many
      interventions. As age increases, clinicians need to become increasingly
      circumspect about interventions with a potential for harm and for benefit. By
      carefully weighing existing disease burden, the state of our knowledge about
      prevention, and patient values, however, clinicians may develop a reasonable
      preventive program in consultation with the patient and, where there is
      diminished competence, relevant family members. As we gain new knowledge about
      genetic and other risk factors, we may be able to more accurately and effectively
      target preventive services to maximize benefits and minimize harms in the
      population as a whole.

PMID- 12424867
TI  - Exercise to prevent and treat functional disability.
AB  - There are myriad ways in which optimal levels of physical activity over the
      course of the life span could potentially contribute to the prevention of
      functional disability in old age. These include direct effects of exercise to
      maximize physiologic capacity and prevent or delay the onset of disability
      related conditions and more indirect effects, such as the modulation of
      psychosocial factors important in the expression of disability. Epidemiologic
      studies strongly suggest that functional disability is inversely related to
      physical activity level or physical fitness in various domains. Experimental
      studies confirm the benefits of exercise on correlates of disability, such as
      impairments of muscle strength or performance-based tests of functional
      limitations. However, the evidence that exercise can actually prevent disability
      in the long-term is not yet established by data from randomized clinical trials
      in the general population. Secondary prevention of disability in frail elders has
      been shown in a few trials. The available evidence, however, suggests that a
      rational exercise prescription for the prevention and treatment of disability at
      this time should include promotion of a physically active lifestyle and specific
      exercises targeting aerobic capacity, strength, and balance. Differential
      emphasis on specific elements of this prescription may be necessary and
      appropriate, depending on the etiology of the disability in specific cohorts,
      severity of physical impairments and functional limitations, and other individual
      characteristics relevant to exercise feasibility, safety, and efficacy.

PMID- 12424868
TI  - Prevention of cardiovascular diseases. Coronary artery disease, congestive heart
      failure, and stroke.
AB  - Cardiovascular disease leads to significant morbidity and mortality in the older
      population. Results of risk reduction can be dramatic in terms of patient
      survival and quality of life. This article reviews evidence for cardiovascular
      risk factors and disease prevention in older adults. Interventions which reduce
      morbidity and mortality from coronary artery disease, heart failure, and
      cerebrovascular disease in the elderly population are examined. Attention is
      given to the role of cardiovascular disease in older women and in minorities,
      subsets not well-represented in many studies.

PMID- 12424869
TI  - Prevention of brain aging and dementia.
AB  - The brain is subjected to multiple factors that result in damage to its cellular
      constituents, the neuron and supporting cells, and the neural networks that form
      the bases of cognitive ability. Like other systems, the brain has remarkable
      capacity to repair that damage and to adapt or compensate for the loss of neurons
      and the disruption of the neural architecture. Brain aging and dementia can be
      conceptualized as a balance between neuronal injury and repair. This balance can
      be affected not only by genetic and age-related factors but also by multiple
      environmental factors. The latter includes many factors, including education,
      nutrition, exercise, socialization, and stress. As individuals, we have the
      potential to modify these factors through lifestyle choices. Advances in
      neuroscience have led to the development of pharmacologic agents that can
      ameliorate the effects of even genetic (e.g., statins and antihypertensive
      agents) and age-related (e.g., antioxidants and estrogen replacement) factors. By
      altering the balance between neuronal injury and repair, we can delay the
      expression and progression of the neurodegenerative processes of brain aging, AD,
      and related dementias.

PMID- 12424870
TI  - Prevention of cancer in the older person.
AB  - Both primary and secondary cancer prevention may improve cancer control among
      older persons. Although chemoprevention of cancer is feasible, the agents
      currently used for chemoprevention have several complications. As a result, the
      use of these substances should be individualized based on risk-benefit ratio. It
      is reasonable to implement screening for cancer of the breast and of the large
      bowel in persons with a life expectancy of 5 years and longer. No definite
      recommendation may be issued at present related to screening for prostate, lung,
      and cervical cancer. Ongoing clinical trials may answer some of these questions.

PMID- 12424871
TI  - Osteoporosis in elderly: prevention and treatment.
AB  - Osteoporosis is a major clinical problem in older women and men. Almost any bone
      can fracture as a result of the increased bone fragility of osteoporosis. These
      fractures are associated with higher health care costs, physical disability,
      impaired quality of life, and increased mortality. Because the incidence of
      osteoporotic fracture increases with advancing age, measures to diagnose and
      prevent osteoporosis and its complications assume a major public health concern.
      BMD is a valuable tool to identify patients at risk for fracture, to make
      therapeutic decisions, and to monitor therapy. Several other modifiable and
      nonmodifiable risk factors for osteoporosis have also been identified. Treatment
      of potentially modifiable risk factors along with exercise and calcium and
      vitamin D supplementation forms an important adjunct to pharmacologic management
      of osteoporosis. Improved household safety can reduce the risk of falls. Hip
      protectors have been found to be effective in nursing home population. The
      pharmacologic options include bisphosphonates, HRT, SERMs and calcitonin. PTH had
      received FDA advisory committee approval. Alendronate has been approved for
      treatment of osteoporosis in men, and other treatments for men are under
      evaluation.

PMID- 12424872
TI  - Nutritional requirements with aging. Prevention of disease.
AB  - Early recognition of and intervention for nutritional disorders may help prevent
      functional disability and mortality in elderly patients. Prevention of
      nutritional disorders in older adults is often multidimensional and may require
      multidisciplinary collaboration. Proactive education of the older adult, early
      recognition of nutritional deficiencies, and rectification of the nutritional
      disorders are the keys to achieving ideal nutritional status in elders and
      enabling them to achieve successful aging.

PMID- 12424873
TI  - Principles of drug therapy in older patients: rational drug prescribing.
AB  - Health care providers must be aware of the issues involved in using drugs
      therapies in older patients because older patients are very vulnerable to the
      adverse effects of drugs. Although more data are needed to guide clinical
      decision making in prescribing drugs to older patients, some simple
      considerations can make drug use safer and more effective (Table 10). Careful,
      compassionate attention to these factors can have a profound effect on improving
      the quality of life, medication use, and the overall cost of health care in this
      vulnerable population.

PMID- 12424874
TI  - Social engagement and its relationship to health.
AB  - Older age is a time of life when major life tasks such as work and raising
      children have typically been completed. As a consequence, the daily demands for
      involvement in their social environment have lessened for older adults. It is
      believed that, because of their many possible benefits, social activities
      ultimately promote physical and mental health in older age. These propositions
      have captured the imagination of gerontologists and geriatricians for decades.
      Surprisingly, the body of relevant research is not plentiful. In this article we
      selectively review the theory and empirical support surrounding social engagement
      and its health consequences in older age.

PMID- 12424875
TI  - Community resources to promote successful aging.
AB  - Community resources are necessary for the health and well-being of older people.
      They can be organized with respect to the primary characteristic of successful
      aging they promote. Resources for avoiding disease and related disability include
      wellness programs, home health care, and mental health services. Resources that
      help older people sustain high functioning include senior centers, adult day
      care, and senior housing. Finally, active engagement with life is facilitated
      through employment services, learning experiences, and volunteer programs.
      Community resources for baby boomers in late life may differ from those available
      for today's elders. They will be no less important for successful aging, however.

PMID- 12424876
TI  - Policy initiatives to promote healthy aging.
AB  - An overwhelming array of policies and programs can be used to help older people
      (and future older people) maintain healthy lifestyles. How can clinicians help
      ensure that their patients take advantage of these opportunities? How can these
      broad-scope policies, educational and information initiatives, and direct service
      programs be turned into tools to help older people maximize health and
      independence? First, physicians do not need to do it all themselves. They need to
      know where to send their patients. For example, case managers in local aging
      service organizations and social workers, nurses, and discharge planners in
      hospitals can help connect elderly patients to appropriate benefits and services.
      Physicians play a critical role in creating a bridge between patients and the
      array of programs and information that can help them change their individual
      patterns of behavior. A serious lack of integration exists between what is known
      about healthy behaviors and lifestyles and what is really happening and available
      to older people today. From the earlier articles in this issue we know that much
      can be done to prevent many types of age-related disease and disability. This
      article provides examples of mechanisms that can be used to broadly disseminate
      knowledge about effective behavior and treatment changes and create mechanisms to
      turn this knowledge into real and widespread client-level, practice-level, health
      system, and community-wide interventions. Second, physicians need to understand
      that they are not merely subject to these policies and initiatives. They can help
      formulate and shape them. This political involvement includes active
      participation in policy initiatives of professional associations, involvement in
      research and demonstration activities, keeping informed about policy proposals at
      the federal and state levels, and helping advance ideas for improving health
      behaviors by speaking up and working toward change. These changes go beyond
      health initiatives to involve improving housing, nutrition, transportation, and
      other arenas that play a role in the health of communities and cities. According
      to the IOM, the most successful interventions are aimed at families,
      neighborhoods and communities. Interventions are also most likely to be
      successful when legislative, media, and marketing efforts support them [50].
      These broader policies may actually have the most potential impact in terms of
      developing sustainable lifestyle changes that reach all Americans, especially
      those with the greatest health needs. Within the aging population, those with
      greatest health needs include members of minority groups, recent immigrants, and
      the old-old. These groups are often overlooked when designing and implementing
      health promotion programs. It is important, however, to remember, for patients
      and for ourselves, you are never too old to benefit from prevention.

PMID- 12424877
TI  - Strategies for successful aging.
AB  - As a nation we are getting older and not all individuals will be fortunate enough
      to age as successfully as Jean Calment. Improving governmental policies and
      improving dissemination of information regarding aging to the lay public and
      health care professionals can make a difference though in how many older
      individuals can achieve old age with less disability. Teamwork among the patient,
      health care professionals, and society as a whole can help burnish the "golden
      years."

PMID- 12424879
TI  - Setting the stage for success.

PMID- 12424880
TI  - Medicaid HMOs worth the time?

PMID- 12424882
TI  - Patient information. Infant feeding: points to consider.

PMID- 12424881
TI  - Human papillomavirus and cervical cancer screening. Recent advances improve the
      clinical picture.

PMID- 12424883
TI  - Urogenital atrophy. A new approach to vaginitis diagnosis.

PMID- 12424884
TI  - Breast cancer today. New diagnostic and treatment methods improve outlook.

PMID- 12424885
TI  - Evaluation of the infertile couple. Nurse practitioners play essential role.

PMID- 12424886
TI  - Snaring a silent threat. Chlamydia declining thanks to screening and prevention.

PMID- 12424887
TI  - Breastfeeding by adolescent mothers. A strategy that works.

PMID- 12424888
TI  - Unclear and present danger. More vigilant hypertension treatment needed.

PMID- 12424889
TI  - Grief after miscarriage. Practical interventions can assist with far-reaching
      loss.

PMID- 12424890
TI  - Kienbock's disease. Differentiation from simple wrist sprains.

PMID- 12424891
TI  - Patient education trends. The main tool is cyberspace.

PMID- 12424892
TI  - Mining databases for cytochrome P450 genes.

PMID- 12424893
TI  - Sequence alignments, variabilities, and vagaries.
AB  - It seems as if the algorithms and weighting matrices for multiple sequence
      alignments of the highly divergent members of the P450 gene superfamily have
      advanced to the point that unknown proteins can be aligned to structurally known
      members with reasonable accuracy. As stated earlier, the alignment tends to break
      down at gaps in the sequence alignments, but these regions can be improved
      manually. This type of alignment and analysis is especially useful for extracting
      and analyzing the various genome databases. Variations of the conservation
      analysis can be used to identify charged and uncharged residues that may be
      important in domain/domain interactions with redox partners or effector molecules
      (e.g., cytochrome b5). From these alignments and with comparative analysis within
      families and across P450 families, one can readily obtain an estimation of those
      residues that might be involved in substrate binding, in redox partner
      interaction, and in the catalytic mechanism.

PMID- 12424894
TI  - Human CYP allele database: submission criteria procedures and objectives.

PMID- 12424895
TI  - Fine-scale mapping of CYP gene clusters: an example from human CYP4 family.

PMID- 12424896
TI  - Detection of single nucleotide polymorphisms in CYP2B6 gene.

PMID- 12424897
TI  - Genotyping human cytochrome: P450 1B1 variants.

PMID- 12424898
TI  - Genotyping human CYP2A6 variants.

PMID- 12424900
TI  - Molecular replacement in P450 crystal structure determinations.

PMID- 12424899
TI  - Purification and crystallization of N-terminally truncated forms of microsomal
      cytochrome P450 2C5.
AB  - Engineering more soluble forms of P450 2C5 has contributed to the crystallization
      of the enzyme. When detergents are used in both crystallization and purification
      of the protein, the ability to control the content and identity of the detergent
      is dependent on the protein exhibiting a sufficient degree of solubility to
      permit its concentration in the absence of detergents. The production of
      concentrated solutions of the protein containing little or no detergent provides
      a means for screening crystallization conditions and the selection of detergents
      that facilitate crystallization. These detergents can then be used not only to
      improve the purification of the protein, but also to solublize substrates for the
      cocrystallization of enzyme-substrate complexes.

PMID- 12424901
TI  - Optical biosensor and scanning probe microscopy studies of cytochrome P450
      interactions with redox partners and phospholipid layers.

PMID- 12424902
TI  - Cryoradiolysis for the study of P450 reaction intermediates.

PMID- 12424903
TI  - Analyzing binding of N-terminal truncated, microsomal cytochrome P450s to
      membranes.

PMID- 12424904
TI  - Sensitizer-linked substrates and ligands: ruthenium probes of cytochrome P450
      structure and mechanism.

PMID- 12424905
TI  - Combining pharmacophore and protein modeling to predict CYP450 inhibitors and
      substrates.

PMID- 12424906
TI  - High pressure: a new tool to study P450 structure and function.

PMID- 12424907
TI  - Use of in vitro pregnane X receptor assays to assess CYP3A4 induction potential
      of drug candidates.

PMID- 12424908
TI  - Analysis of CYP mRNA expression by branched DNA technology.

PMID- 12424909
TI  - Ligand-induced coactivator recruitment to peroxisome proliferator-activated
      receptor alpha characterized by fluorescence resonance energy transfer.

PMID- 12424910
TI  - Fluorescence-based ligand-binding assays for peroxisome proliferator-activated
      receptors.

PMID- 12424911
TI  - Developing toxicologically predictive gene sets using cDNA microarrays and
      Bayesian classification.

PMID- 12424912
TI  - Direct expression of fluorescent protein-tagged nuclear receptor CAR in mouse
      liver.

PMID- 12424913
TI  - Application of fluorescent differential display and peroxisome proliferator
      activated receptor (PPAR) alpha-null mice to analyze PPAR target genes.
AB  - In conclusion, we have applied the fluorescent differential method and the PPAR
      alpha-null mouse model for the rapid isolation of expression tags of PPAR alpha
      target genes that are involved in the action of peroxisome proliferators and in
      the regulation of lipid homeostasis under energy deprivation. Identification of a
      wide spectrum of PPAR alpha target genes will provide new insights into the
      diverse cellular pathways regulated by these receptor, and this information will
      be critical for understanding the complicated biological interactions among
      members of the PPAR alpha target genes. With the recent technological
      advancement, a newer method, such as DNA microarray, has emerged in the
      identification of differential gene expressions. This new DNA microarray method,
      in conjunction with the differential display method, is the first important step
      toward understanding the molecular mechanisms of gene interactions in any
      biological systems and can speed up the search for differential gene expressions.

PMID- 12424914
TI  - Histological and metabolism analysis of P450 expression in the brain.

PMID- 12424915
TI  - Proteomic analysis of rodent hepatic responses to peroxisome proliferators.

PMID- 12424916
TI  - Kinetic analysis for multiple substrate interaction at the active site of
      cytochrome P450.

PMID- 12424917
TI  - Design and application of fluorometric assays for human cytochrome P450
      inhibition.

PMID- 12424918
TI  - Automated quantitative and qualitative analysis of metabolic stability: a process
      for compound selection during drug discovery.

PMID- 12424919
TI  - Characterization of covalent adducts to intact cytochrome P450s by mass
      spectrometry.

PMID- 12424920
TI  - Mutagenesis testing based on bacterial expression of human P450s.

PMID- 12424921
TI  - Use of long-term cultures of human hepatocytes to study cytochrome P450 gene
      expression.

PMID- 12424922
TI  - Polarized cell cultures for integrated studies of drug metabolism and transport.

PMID- 12424923
TI  - Use of methylotropic yeast Pichia pastoris for expression of cytochromes P450.

PMID- 12424924
TI  - Partial recoding of P450 and P450 reductase cDNAs for improved expression in
      yeast and plants.

PMID- 12424925
TI  - Selective covalent labeling with radiolabeled suicide substrates for isolating
      P450s.

PMID- 12424926
TI  - Cloning of cDNAs encoding P450s in flavonoid/isoflavonoid pathway from elicited
      leguminous cell cultures.

PMID- 12424927
TI  - Selected cell cultures and induction methods for cloning and assaying cytochromes
      P450 in alkaloid pathways.

PMID- 12424928
TI  - Isolation and functional characterization of cytochrome P450s in gibberellin
      biosynthesis pathway.

PMID- 12424929
TI  - Serological study of hepatitis A virus infection amongst the students of a
      medical college in Delhi & evaluation of the need of vaccination.
AB  - BACKGROUND & OBJECTIVES: Recent seroepidemiological studies have demonstrated a
      decrease in the seroprevalence of hepatitis A virus (HAV) infection, thereby
      increasing the pool of susceptible adult population. Health care workers,
      especially those working in paediatric wards and nurseries, are at an increased
      risk of developing HAV infection. The present study was undertaken to determine
      the prevalence of antibody against HAV (IgG anti-HAV) among a batch of medical
      students of the Maulana Azad Medical College, New Delhi, so as to identify the
      proportion of students who would be susceptible to HAV infection and hence would
      benefit from a vaccination programme against HAV. METHODS: A total of 91 medical
      students were enrolled and divided into groups on the basis of sex. The serum
      samples were evaluated for the presence of immunoglobulin (IgG) against HAV (IgG
      anti-HAV) using a commercially available enzyme linked immunosorbent assay
      (ELISA) kit. RESULTS: The mean age of all the subjects was 19.9 +/- 1.5 yr and
      the male: female ratio was 1.2: 1. Fifty seven (62.6 +/- 5.1%) students were
      positive for IgG anti-HAV while 34 (37.4%) were seronegative and hence
      susceptible to HAV infection. No statistically significant difference was
      observed in the seroprevalence of HAV between males and females [64 +/- 6.7%
      (32/50) versus 60.9 +/- 7.6% (25/41)]. INTERPRETATION & CONCLUSION: our results
      indicate that more than one-third of the medical students were seronegative for
      IgG anti-HAV and hence at an increased risk of developing HAV infection as a
      result of occupational exposure. Therefore, we suggest that students in a health
      care set up should undergo vaccination against HAV after pre-vaccination immunity
      screening.

PMID- 12424930
TI  - Use of nested polymerase chain reaction for the detection of cytomegalovirus in
      clinical specimens.
AB  - BACKGROUND & OBJECTIVES: Since fluorescent antibody test (FAT) has low
      sensitivity in the rapid detection of cytomegalovirus (CMV) in clinical
      specimens, a nested polymerase chain reaction (nPCR) to detect the CMV-DNA was
      evaluated. METHODS: nPCR and FAT were carried out to detect CMV in single
      specimens from 104 patients and dual specimens from 32 patients with suspected
      active CMV infection. Of the 136 patients, 3 were HIV positive. RESULTS: CMV was
      detected by FAT alone in 3 (1.8%) and FAT and nPCR in 16 (9.5%) specimens and by
      nPCR alone in 84 (50.0%) specimens from 74 (54.4%) patients. nPCR increased the
      clinical sensitivity by 50.0 per cent in the specimens and 54.4 per cent in the
      patients (McNemar test, P < 0.001). Urine was found to be the ideal specimen for
      the detection of CMV as the detection rate in the urine was statistically higher
      (McNemar test, P < 0.05) than in the blood. Buffy coat and plasma samples from 35
      normal blood donors were subjected to nPCR and ELISA respectively. CMV-DNA was
      not detected in any of the samples while anti-CMV antibodies were detected in all
      of them. INTERPRETATION & CONCLUSION: The results showed that presence of CMV-DNA
      in the specimen indicates active infection and nPCR is a rapid, sensitive,
      specific and a more reliable diagnostic tool than FAT.

PMID- 12424931
TI  - Shigella isolation in Vellore, south India (1997-2001).
AB  - Shigellosis has been a major cause of dysentery for many years at Vellore, south
      India. In the last two years the number of Shigella being isolated from samples
      of faeces from patients with diarrhoea has decreased (5% isolation rate in 1997
      to 3.9% in 2001), although the microbiological methods and media used have not
      changed. Also, the nalidixic acid (NA) resistance has increased for S. sonnei
      (now 94%). This is noteworthy, since NA has been recommended for the empirical
      treatment of patients suspected to have shigellosis and this concept needs to be
      reconsidered based on available data.

PMID- 12424932
TI  - Common infecting leptospiral serovars in and around Pune, Maharashtra.
AB  - Leptospirosis is a disease with protean manifestations. The present study was
      conducted in Pune to examine the possibility of leptospiral infection among a
      group of patients with fever of undetermined origin and to identify the common
      infecting serovars. Serological evidence of leptospirosis was found in 22 of the
      118 (18.6%) patients with the help of microagglutination test (MAT) using a
      battery of 9 antigens. The serovars responsible for infection included autumnalis
      in eight cases, copenhageni in six, pomona in three, grippotyphosa in two and
      australis, batavia and canicola in one case each. Thus, there appears to be a
      focus of leptospirosis in and around Pune with autumnalis and copenhagni as the
      common infecting serovars.

PMID- 12424934
TI  - Evaluation of the effectiveness of salt iodization status in Tripura, north east
      India.
AB  - BACKGROUND & OBJECTIVES: Universal salt iodization programme was initiated during
      1988-89 in the goitre endemic state of Tripura. However, no decline in goitre
      prevalence was found about a decade after the initiation of programme. The
      present work evaluates the quality of implementation of the salt iodization
      programme and the possible involvement of dietary goitrogens in the process.
      METHODS: The study areas were selected at random and in the selected areas only,
      school children were chosen purposively instead of the entire population. Iodine
      nutritional status was evaluated by measuring the urinary iodine excretion. The
      iodine content of salt collected from households was tested by iodometric
      titration, urinary iodine was measured by dry ashing method and thiocyanate by
      oxidising bromine and then developing colour by benzedine hydrochloride. RESULTS:
      Urinary iodine level was measured in 1,123 samples from 22 study areas. In 17
      areas, the median urinary iodine values were > 100 micrograms/l indicating no
      biochemical iodine deficiency. However, the iodine intake of about 40 per cent of
      the studied population was below the cut-off level i.e., iodine level were < 100
      micrograms/l. About two-thirds of salt samples were found to contain iodine less
      than the adequacy level of 15 ppm. Thiocyanate was present in the 1,032 urine
      samples studied, in different concentrations. INTERPRETATION & CONCLUSION: The
      people of region are exposed to inadequately iodized salt in spite of the salt
      iodization programme. Further, they are exposed to a thiocyanate load. This study
      suggests that monitoring of salt iodization programme is essential to ensure the
      recommended level of iodine (15 ppm) in at least 90 per cent salt samples. The
      goitrogenic/antithyroid potential of cyanogenic foods used in the region need to
      be ascertained to understand the nature of action on thyroid function.

PMID- 12424933
TI  - Deferiprone (L1) as an adjuvant therapy for Plasmodium falciparum malaria.
AB  - BACKGROUND & OBJECTIVES: Mortality due to Plasmodium falciparum infection remains
      high in India, hence any modality of treatment which can improve the outcome of
      this disease is worth exploring. The present study was undertaken to see whether
      addition of an oral iron chelator, deferiprone (L1) to the conventional treatment
      regime for P. falciparum infection improves the clinical course and final
      outcome. METHODS: In this prospective, randomised double blind trial, 45
      consecutive patients with P. falciparum infection were randomised into two
      groups. Patients in Group I (control group, 21 patients) received standard
      quinine and doxycycline therapy along with supportive therapy and placebo
      capsules for 10 days. Patients in Group II (24 patients) received the same
      treatment as Group I but in place of placebo capsule received deferiprone
      capsules 75 mg/kg/day in 12 hourly divided doses. The parameters evaluated
      included the time taken in resolution of parasitaemia, fever and coma,
      differences in final outcome i.e., death or other severe complications, and side
      effects and deferiprone tolerance. RESULTS: Four patients in Group I and two in
      Group II died (P > 0.05). The resolution of fever and coma was significantly
      faster in Group II (P < 0.05) and parasitaemia cleared 24 h earlier in this
      Group. The drug was well tolerated and had no side effects. INTERPRETATION &
      CONCLUSION: Deferiprone (L1) seems to be a promising agent as an adjuvant in the
      treatment for severe P. falciparum malaria infection.

PMID- 12424935
TI  - [Diagnosis and therapy of Graves' ophthalmopathy--consensus guidelines].
AB  - On 22-09-2001 the VIth Grazer Hormonsymposion took place. Diagnosis and therapy
      of Graves' Ophthalmopathy was discussed in an interdisciplinary way by
      endocrinologists, surgeons and ophthalmologists. The results of the round-table
      discussion and the consensus talk are presented.

PMID- 12424936
TI  - Examination, prevention and treatment of osteoporosis in patients with
      inflammatory bowel disease: recommendations and reality.
AB  - BACKGROUND: Patients with inflammatory bowel disease (IBD) are at increased risk
      of developing osteopenia and osteoporosis. Our aim was to evaluate the current
      practices of examination, prevention and treatment of osteoporosis in IBD
      patients in a routine clinical setting. METHODS: A total of 154 consecutive
      patients with IBD (63 female, 91 male; 36 ulcerative colitis, 115 Crohn's
      disease, 3 indeterminate colitis), referred to two gastroenterological units for
      scheduled follow-up examinations, were included. Patient charts were evaluated
      regarding bone densitometry already performed and any prophylactic or therapeutic
      interventions in cases of low bone mineral density. RESULTS: Bone mineral density
      (BMD) measurements had been performed only in 38 patients (25%). BMD was
      abnormally low in 27 of the examined patients (71%), 20 of whom had osteopenia
      and seven had osteoporosis. Among the subgroup of patients on long-term steroid
      therapy (77 patients), 30 had been referred to bone densitometry during the
      course of disease, and 21 of them were found to have low bone mineral density.
      Preventive measures were prescribed in 12 patients (9% of the whole study
      population). In the majority of the patients with low bone mineral density,
      calcium and vitamin D were used as treatment. CONCLUSIONS: Despite the high
      prevalence of osteopenia and osteoporosis in patients with IBD, only a minority
      of these patients were included in a structured program in accordance with modern
      guidelines for diagnosing and preventing this extraintestinal complication in a
      routine clinical setting.

PMID- 12424938
TI  - [Recanalization of chronic coronary occlusions].
AB  - Recanalization of occluded coronary arteries is the aim of percutaneous
      interventions with acute myocardial infarction. Moreover, chronic coronary
      occlusion is a common finding during diagnostic coronary angiography and is often
      a contributing factor in the choice of revascularisation by surgery rather than
      by percutaneous coronary interventions (PCI). An occluded coronary artery with
      some degree of collateral supply is functionally comparable to a severe coronary
      stenosis. Therefore, recanalization of chronic occluded coronary arteries results
      in less angina and often in improvement of left ventricular function. Success is
      limited in particular in longer lasting occlusions. Characterization of lesions,
      where recanalization can performed successfully is warranted. We correlated
      primary success rates of attempted coronary recanalizations with localisation of
      lesions and procedural characteristics. We analyzed records of 124 consecutive
      patients, who underwent attempted coronary recanalization of chronically occluded
      coronary arteries at our institution in 1998. Revascularisation was successful in
      84 (64 male, 20 female) of 124 (92 male, 32 female) patients. Therefore, success
      rate was 67.7% (69.9% in men, 62.5% in women, p = 0.42). Target vessel was the
      left anterior descending artery (LAD) in 49 cases. Success rate in the LAD did
      not differ significantly from that in "non-LAD"-vessels (65.3% versus 69.3%; p =
      0.35). Successful recanalizations were performed using only one guide-wire in
      77.3%. More than one guide-wires were used during procedures without success in
      44.5% and exceeded use in successful interventions (p < 0.05). Procedures,
      failing to be successful after an attempt with a first guide-wire, could be
      performed successfully using at least a second wire in 50%. Coronary stenting
      after recanalization has been performed in 84.4% in the LAD and in 59.7% in non
      LAD vessels (p < 0.01). Success rate of attempted recanalizations of chronic
      occluded coronary arteries in unselected patients is high. Most procedures can be
      performed successfully using only one guidewire. Additional use of other wires
      can increase success rates in procedures with primary failure to pass the
      occlusion. Stenting has been performed in three out of four patients with
      successful recanalization of chronically occluded coronary arteries.

PMID- 12424937
TI  - [Raltitrexed and oxaliplatin in colorectal cancer: in vitro and in vivo study of
      a synergistic cytostatic combination].
AB  - AIM: To evaluate the efficacy of combined raltitrexed and oxaliplatin in vitro
      using 4 colorectal cell-lines and subsequently in vivo in 36 patients with
      advanced colorectal cancer failing palliative 5-fluorouracil/leucovorin-based
      chemotherapy. In the preclinical phase of this study, the efficacy of oxaliplatin
      and of raltitrexed as well as of 5-FU alone and in combination was evaluated in 4
      different human colorectalcarcinoma cell-lines with the MTT-test (Microculture
      Tetrazolium Assay). In the clinical phase 36 patients with metastatic colorectal
      cancer, who progressed while receiving or within 6 months after withholding
      palliative chemotherapy with 5-FU/leucovorin +/- irinotecan were enrolled in this
      study. Treatment consisted of oxaliplatin 130 mg/m2 and raltitrexed 3.0 mg/m2
      both given on day 1 every 3 weeks for a total of 8 courses unless prior evidence
      of progressive disease. A supraadditive effect was found for the experimental
      combination of oxalipatin and raltitrexed in 3/4 of cell lines. In the clinical
      phase the overall response rate was 33.3% for all 36 evaluable patients.
      Seventeen additional patients (47.2%) had stable disease, and only 7 (19.5%)
      progressed. The median progression-free survival was 6.5 months (range, 1.2 to
      14.0). After a median follow-up time of 12 months, 23 patients (63.8%) are still
      alive. The tolerance of treatment was acceptable with only 8/36 (22%)
      experiencing grade 3 or 4 neutropenia. Grade 3 nonhematologic adverse reactions
      included peripheral sensory neuropathy in 3, asthenia in 1, diarrhea in 2, and
      clinically insignificant increase in serum transaminases in 2 patients,
      respectively. Our data suggest that the combination of oxaliplatin and
      raltitrexed has not only in vitro, but also in vivo in patients with progressive
      fluoropyrimidine/leucovorine +/- irinotecan pretreated colorectal cancer
      antitumor activity. Because of its favorable toxicity profile and its convenient
      3-weekly outpatient administration schedule, further evaluation of this regimen
      seems warranted.

PMID- 12424939
TI  - [Subacute thyroiditis with cell destruction and temporary hyperthyroidism in
      Graves'disease--case report].
AB  - We present the case of a 60-year old woman with painful swelling of the thyroid
      gland and temporary thyrotoxicosis. 30 years ago she had experienced a period of
      hyperthyroidism because of Graves' disease. This time thyrotropin-receptor
      antibodies were negative, Tc-99 m scan revealed decreased uptake in both lobes
      (this pattern normalised later on) and fine needle aspiration presented leucocyte
      infiltration of the thyroid. Three months later hypothyroidism was observed
      requiring treatment with levothyroxine. The development of subacute thyroiditis
      and Graves' disease in the same person is rare, autoimmune factors and a possible
      relationship are discussed.

PMID- 12424940
TI  - [Renal cell carcinoma metastasis in a microfollicular adenoma of the thyroid
      gland].
AB  - A 60-year-old woman had a nephrectomy of her left kidney because of a renal cell
      carcinoma. She came to us for an oncologic F-18-fluordeoxyglucose-positron
      emission tomography (F-18-FDG-PET). In the positron emission tomography there was
      a pathologic fluordeoxyglucose-uptake in the left thyroid gland lobe. Thyroid
      investigation and Tc-99 m pertechnetate scintigraphy of the thyroid gland was
      done. It showed a hyperfunctioning nodule in the left thyroid gland lobe. Surgery
      was suggested. Histology showed a metastasis of a clear cell renal carcinoma in a
      microfollicular adenoma of the thyroid gland--a very rare combination.

PMID- 12424941
TI  - Lethal fulminate S. aureus sepsis in M. Behcet overnight cold exposure.
AB  - Whether patients with Behcet's disease (BD) and immunosuppressive therapy are
      generally prone to acquire severe infectious diseases is unknown. A 48-year-old
      man under corticosteroids and azathioprine for BD since 1995 was admitted because
      of a transitory ischemic attack. Between the third and fourth hospital day he was
      accidentally locked up, insufficiently dressed, in the hospital's chapel over
      night. On the following day, he developed fever and deteriorating consciousness
      until he became comatose. CT scans of the brain were normal and there was only a
      slight pleocytosis. Despite adequate therapy, the patient's condition further
      deteriorated such that he died. Responsible for his decline was a fulminate
      sepsis, diagnosed upon fever, increased C-reactive protein, thrombocyte decline,
      multi-organ failure, rhabdomyolysis, growth of S. aureus on blood culture, and
      autopsy. Patients with BD and immunosuppressive therapy, may be more vulnerable
      to infections and may develop lethal overwhelming sepsis already after overnight
      cold exposure.

PMID- 12424942
TI  - Long-term citrate anticoagulation for high-flux haemodialysis in a patient with
      heparin-induced thrombocytopenia type II.
AB  - For the first time, long-term use of regional citrate anticoagulation for high
      flux haemodialysis is reported in a patient with heparin-induced thrombocytopenia
      type II. A simple, flow-independent, citrate infusion protocol allowed efficient
      anticoagulation. Excellent solute removal, indicated by KT/V values of 1.52 to
      1.98, was achieved. Electrolyte and acid-base balance as well as calcium
      homeostasis were well controlled over a period of 9 months.

PMID- 12424943
TI  - Pediatric magnetic resonance imaging techniques.
AB  - Optimization of the MR image requires an understanding of technical parameters,
      pulse sequences, artifacts, and the use of contrast agents. More technical
      information and in-depth details about the practical concepts for performing MRI
      in children can be found in the references accompanying this article.

PMID- 12424944
TI  - Magnetic resonance imaging of cyanotic and noncyanotic congenital heart disease.
AB  - MRI has become an important imaging tool that complements echocardiography in the
      noninvasive evaluation of congenital heart defects. It can play a crucial role in
      diagnosis by assessing anatomic and functional features in CHD and identifying
      complications and postoperative sequelae. The performance and application of
      cardiac MRI require not only knowledge of the clinical question that needs to be
      addressed but knowledge of the anatomic characteristics of a variety of
      congenital heart lesions. A knowledge of the advantages and disadvantages of the
      different imaging sequences also is important so as to optimize and expedite the
      examination.

PMID- 12424945
TI  - Magnetic resonance imaging of mediastinal vessels.
AB  - Advances in technology have led to a changing role for MRI in the evaluation of
      the thoracic vasculature in children. MRI, especially with 3D gadolinium-enhanced
      MR angiography, can clearly demonstrate the morphology of the aortic and
      pulmonary vascular supply. In patients with nonvalvar obstructive lesions of the
      aorta (i.e., coarctation, interruption of the aortic arch, and supravalvar
      stenosis), MRI can reliably assess the site and extent of the obstruction.
      Similarly, MRI can depict the morphology of the central pulmonary arteries and
      aortopulmonary collateral vessels in patients with obstructive lesions of the
      pulmonary artery. MRI is also useful in assessing the course of the aorta and
      pulmonary arteries in patients with suspected vascular rings. The result is that
      MRI can supplement information obtained from echocardiography and angiography and
      reduce the need for angiography.

PMID- 12424946
TI  - Pediatric liver magnetic resonance imaging.
AB  - Imaging is a standard part of the evaluation of pediatric liver disease. Advances
      in MR imaging have improved the detection, characterization, and staging of
      hepatic lesions. Clinical information, however, is still important in selecting
      the best imaging study and in correctly interpreting the examination. This
      article addresses the clinical and imaging features of the common hepatic and
      biliary lesions in children. In addition, the techniques for performing hepatic
      MR imaging are reviewed.

PMID- 12424947
TI  - Imaging of neuroblastoma and Wilms' tumor.
AB  - Neuroblastoma and Wilms' tumor are the most common noncentral nervous system
      solid tumors in children. Imaging plays a crucial role in the evaluation of the
      primary tumor and regional and metastatic disease. There is a growing body of
      literature supporting the use of MRI as the technique of choice for the
      evaluation of local and regional disease in children with suspected
      neuroblastoma; however, in children with suspected Wilms' tumor, MRI will likely
      continue to play a role as a problem-solver when the results of CT are equivocal
      or indeterminant.

PMID- 12424948
TI  - Magnetic resonance imaging of the adolescent female pelvis.
AB  - MR imaging is well suited to evaluation of the pelvis. Ultrasonography remains
      the study of choice for the initial evaluation of a suspected gynecologic mass.
      MR imaging and computed tomography remain problem-solving tools that can help to
      characterize masses and stage gynecologic malignancies. MR imaging has the
      advantage of higher soft tissue contrast compared with computed tomography. This
      article reviews the MR findings of congenital anomalies and masses of the adnexa
      and uterus in adolescent girls.

PMID- 12424949
TI  - Magnetic resonance imaging of nongynecologic pelvic masses in children.
AB  - Pelvic neoplasms can arise from the genitourinary tract, gonads, soft tissues, or
      bone. The role of imaging is to confirm the presence of tumor, determine the site
      of origin, delineate the extent for staging and treatment planning, and serve as
      a baseline for monitoring response to therapy. MR imaging is well suited for the
      characterization and staging of pediatric pelvic tumors. This article reviews the
      imaging findings and staging evaluation of the common nongynecologic neoplasms in
      children. Prostatic, bladder, gonadal, and sacrococcygeal tumors are discussed.
      Gynecologic tumors are discussed elsewhere in this issue.

PMID- 12424950
TI  - Magnetic resonance angiography of the pediatric abdomen and pelvis.
AB  - Although abdominal and pelvic vascular disease is much less common in children
      than in adults, MR angiographic techniques widely used in adults can also be
      readily applied in the pediatric population with suspected vascular disease. MR
      techniques, equipment, and image analysis software are in a continual state of
      development and refinement. Given the advantages of MR angiography (i.e., its
      absence of ionizing radiation, capability to obtain images without iodinated
      contrast material, and limited invasiveness), the applications of MR angiography
      in the pediatric abdomen and pelvis are likely to continue to increase.

PMID- 12424951
TI  - Magnetic resonance of vascular anomalies.
AB  - More than half of the patients with vascular anomalies referred to the Vascular
      Anomalies Clinic at Children's Hospital, Boston, have been misdiagnosed. A major
      consequence of misdiagnosis is inappropriate treatment, including deferral of
      necessary treatment and inappropriate use of pharmacotherapy, radiation, surgery,
      and embolotherapy. Hemangiomas and vascular malformations are distinct categories
      with completely different biologic and clinical behavior, therapeutic
      requirements, and imaging features. This article reviews the biologic
      classification of vascular anomalies and corresponding MR imaging features, and
      presents a simplified guide to diagnosis.

PMID- 12424952
TI  - Fetal imaging.
AB  - Presently, MRI is an adjunct to prenatal sonography. It provides information that
      can aid in the diagnosis of fetal anomalies, affect prenatal counseling and
      management of the pregnancy, and guide prenatal intervention and delivery
      planning. With further advances in technology, particularly shorter scan times
      and better image resolution, the applications for fetal imaging are likely to
      increase.

PMID- 12424953
TI  - [Dream and reality: an experience].

PMID- 12424954
TI  - [What do nurses do to promote population's health?].
AB  - It is interest of the profession to theorize on this matter to direct and to
      reorganize the education. This article describes the phase of study developed up
      to today.

PMID- 12424955
TI  - [The caregivers of persons with Alzheimer's disease: the profile of hidden
      sacrifice].
AB  - In the article the general profile of AD's (Alzheimer Disease). Caregiver is
      identified by a quantitative method research work conducted in a large
      metropolitan Hospital. Many studies on the topic are taken into consideration
      pointing out the influence that the presence of AD patient at home has on the
      family and particularly on the primary caregiver. A significant importance has
      been given to identify the profile of caregivers in order to offer programmes and
      services that can sustain and be helpful for them to cope with the difficult
      situation of their hidden sacrifice.

PMID- 12424956
TI  - [National Health Plan (NSP) objective "Continuity of Care". The general framework
      and utilization of the scenario as instrument of reading of diverse vision of
      protagonists].

PMID- 12424957
TI  - [Phenomenology and phenomenological method: their usefulness for nursing
      knowledge and practice].
AB  - Phenomenology is a thought movement the main aim of which is to study human
      fenomena as they are experienced and lived. Key concepts of phenomenology are:
      the study of lived experience and subjectivity of human beings, the
      intentionality of consciousness, perception and interpretation. Phenomenological
      research method has nine steps: definition of the research topic; superficial
      literature searching; sample selection; gathering of lived experiences; analysis
      of lived experiences; written synthesis of lived experiences; validation of
      written synthesis; deep literature searching; writing of the scientific document.
      Phenomenology and phenomenological method are useful for nursing either to
      develop knowledge or to guide practice. Qualitative-phenomenological and
      quantitative-positivistic research are complementary: the first one guides
      clinicians towards a person-centered approach, the second one allows the
      manipulation of phenomena which can damage health, worsen illness or decrease the
      quality of life of people who rely on nursing care.

PMID- 12424958
TI  - [International Council of Nurses (ICN) concerning Health and Human Rights].

PMID- 12424959
TI  - [Analysis of 14 individuals who requested predictive genetic testing for
      hereditary neuromuscular diseases].
AB  - Predictive genetic testing for hereditary neuromuscular diseases is a delicate
      issue for individuals at risk and their families, as well as for medical staff
      because these diseases are often late-onset and intractable. Therefore careful
      pre- and post-test genetic counseling and psychosocial support should be provided
      along with such genetic testing. The Division of Clinical and Molecular Genetics
      was established at our hospital in May 1996 to provide skilled professional
      genetic counseling. Since its establishment, 14 individuals have visited our
      clinic to request predictive genetic testing for hereditary neuromuscular
      diseases (4 for myotonic dystrophy, 6 for spinocerebellar ataxia, 3 for
      Huntington's disease, and 1 for Alzheimer's disease). The main reasons for
      considering testing were to remove uncertainty about the genetic status and to
      plan for the future. Nine of 14 individuals requested testing for making
      decisions about a forthcoming marriage or pregnancy (family planning). Other
      reasons raised by the individuals included career or financial planning, planning
      for their own health care, and knowing the risk for their children. At the first
      genetic counseling session, all of the individuals expressed hopes of not being a
      gene carrier and of escaping from fear of disease, and seemed not to be mentally
      well prepared for an increased-risk result. To date, 7 of the 14 individuals have
      received genetic testing and only one, who underwent predictive genetic testing
      for spinocerebellar ataxia, was given an increased-risk result. The seven
      individuals including the one with an increased-risk result, have coped well with
      their new knowledge about their genetic status after the testing results were
      disclosed. None of them has expressed regret. In pre-test genetic counseling
      sessions, we consider it quite important not only to determine the psychological
      status of the individual, but also to make the individual try to anticipate the
      changes in his/her life upon receiving an increased-risk or a decreased-risk
      result. Sufficient time should be taken to build a good relationship between the
      individual and his/her family and the medical staff during pre-test counseling
      sessions. This will help the individuals feel satisfied with their own decisions
      for the future, whether they receive genetic testing or not.

PMID- 12424960
TI  - [Quantitative MRI study of progressive cerebral atrophy in multiple system
      atrophy].
AB  - We investigated cerebral atrophy in multiple system atrophy (MSA) by quantitative
      analysis of MRI. The subjects were 28 patients with MSA (14 striato-nigral
      degeneration; SND, 14 olivo-ponto-cerebellar atrophy; OPCA. 106 MRI examinations
      were performed totally) and 85 normal persons for control. The ratios of the
      ventral pons to the infratentorial space in the sagittal section, the putamen,
      cerebrum, frontal lobe and parietal & occipital lobes to the intracranial space
      in the horizontal section, and the temporal lobe to the intracranial space in the
      coronal section were measured. In the early stage of the disease, OPCA showed
      significant atrophy of the ventral pons compared with SND, and conversely, SND
      demonstrated significantly smaller putamen than that in OPCA. According to the
      progression of the disease, the atrophy of these neural tissues progressed, which
      resulted in no significant differences between SND and OPCA. The cerebral atrophy
      was observed in 17 MSA patients. The atrophy of the frontal lobe was much
      frequent and prominent to that in the temporal lobe and parietal & occipital
      lobes. SND showed higher incidence of the cerebral atrophy than OPCA in the early
      stage of the disease. In long period follow-up cases, one case showed cerebral
      atrophy in earlier stage, and another case in late stage. We indicated the
      involvement of the cerebral hemispheres in MSA, especially the frontal lobe.

PMID- 12424961
TI  - [A study of parasympathetic functions in Guillain-Barre syndrome].
AB  - Sympathetic hyperactivity in Guillain-Barre syndrome (GBS) may be due to the
      involvement of afferent fibers in the vagus and glossopharyngeal nerves within
      the baroreceptor pathway. Patients with GBS who have increased sympathetic
      nervous activity, do not, however, always show baroreceptor dysfunction such as
      orthosatic hypotension. We evaluated parasympathetic nervous activity in patients
      with GBS to clarity the mechanism of autonomic deficits. An atropine test (20
      micrograms/kg intravenous bolus infusion) and hemodynamic functional tests were
      conducted on 6 patients with GBS (49.5 +/- 13.6 years old) and age-matched
      healthy controls; 11 controls (50.5 +/- 17.6 YO) for atropine test and 81
      controls (48.5 +/- 8.8 years old) for hemodynamic functional tests. I.
      Parasympathetic nervous activity: (a) Atropine test: (1) Increase in pulse rate
      after the administration of atropine; the degree was significantly higher in the
      patients with GBS than that in the healthy controls (p = 0.027). (2) Atropine
      ratio (= increase in pulse rate following intravenous administration of
      atropine)/(mean pulse rate before the administration); the ratio was
      significantly higher in the patients with GBS than that in the healthy controls
      (p = 0.026). (b) Aschner eyeball pressure test: The degree of reflex bradycardia
      in the patients with GBS was significantly higher that the in the healthy
      controls (p = 0.039) II. Sympathetic nervous activity: (a) Cold pressor test: The
      degree of reflex hypertension was significantly higher in the patients with GBS
      than in the healthy controls (p = 0.008). (b) 70 degrees passive head-up test:
      Falls in systolic and diastolic blood pressure in the patients with GBS tended to
      be lower than in the healthy controls (p = 0.092, p = 0.091). These results
      suggest that both parasympathetic and sympathetic nervous activities increased,
      and the baroreceptor function is well preserved in GBS. We thus surmise that
      increased sympathetic nervous activity in GBS is not explained by reduced
      inhibition of the parasympathetic nervous activity.

PMID- 12424962
TI  - [A case of parkinsonian syndrome caused by normal pressure hydrocephalus
      accompanied by the cauda equina neurinoma].
AB  - A case of parkinsonian syndrome caused by normal pressure hydrocephalus (NPH)
      accompanied by cauda equina neurinoma is reported. A 69-year-old woman presented
      with typical symptoms of parkinsonism, including akinesia, resting and postual
      tremor, and cog-wheel rigidity. CT scan of the brain revealed dilatation of
      ventricles, but she did not present dementia and urinary incontinence that are
      common symptoms in NPH. Her cerebrospinal fluid (CSF) pressure was normal, and
      her protein level was high at 2,970 mg/dl. An electroencephalogram (EEG) showed
      diffuse slow waves. An IMP-SPECT images of the brain showed diffuse reduction of
      radioisotope uptake. Levodopa was not effective in treating her parkinsonism.
      Removal of the tumor caused dramatic improvement in her parkinsonism. Her CSF
      protein level was normalized and EEG and SPECT images were improved after the
      operation. However, ventricular size on brain CT showed no change. It was
      considered that the causal mechanism of NPH was due to high protein levels in the
      CSF. The parkinsonism in this case was caused by dysfunction of the circuits
      linking the cortex, basal ganglia, and thalamus associated with metabolic
      disorder due to periventricular ischemia. Typical parkinsonism caused by NPH
      associated with spinal cord tumor has not been reported. When we examine a
      patient with parkinsonian syndrome caused by NPH, we should check the CSF protein
      level. And if that level is high, the possibility of spinal cord tumor should be
      considered.

PMID- 12424963
TI  - [A patient with Parkinson's disease complicated by hypothyroidism who developed
      malignant syndrome after discontinuation of etizolam].
AB  - A 59-year-old man, who was diagnosed as having Parkinson's disease and depression
      seven years ago and was on oral antiparkinsonian agents, antianxiety agents, and
      antidepressants, developed a high fever, disturbed consciousness, and marked
      muscle rigidity after discontinuation of etizolam and amitriptyline. He was
      admitted to a nearby hospital. Hypothyroidism had been noted two months before
      admission. Marked muscle rigidity and increased serum CK were observed. Since
      discontinuation of benzodiazepine has been known to rarely trigger a neuroleptic
      malignant syndrome (NMS), he was diagnosed as having NMS. After receiving
      dantrolene and bromocriptine, these symptoms temporarily improved but he again
      developed consciousness disturbance, and convulsive seizures associated with an
      elevated serum CK. He was transferred to our hospital. On admission, the CK level
      was normal at 168 IU/l, while free T4 was 0.6 ng/dl (normal range, 0.9-2.3) and
      TSH was 108.7 mU/ml (normal range, 0.2-4.2) in serum, indicating the presence of
      primary hypothyroidism. As an increase in thyroid hormone dosage improved the
      thyroid function to normal level, his disturbed consciousness and muscle rigidity
      gradually improved. Convulsive seizure and recurrence of NMS in a short interval
      are unusual in neuroleptic malignant syndrome. In this patient, hypothyroidism
      may have contributed to the development of malignant syndrome through metabolic
      changes of the central dopaminergic system, and discontinuation of etizolam, a
      kind of benzodiazepine, may have triggered NMS, since there has not been reported
      that discontinuation of antidepressants including amitriptyline triggers NMS.

PMID- 12424964
TI  - [The first Japanese case of autosomal dominant Emery-Dreifuss muscular dystrophy
      with a novel mutation in the lamin A/C gene].
AB  - Emery-Dreifuss muscular dystrophy (EDMD) is a muscular disorder characterized by
      1) early contracture of the elbows. Achilles tendons and post-cervical muscles,
      2) slowly progressive muscle wasting and weakness with a humeroperoneal
      distribution, and 3) life-threatening cardiomyopathy with conduction block. Most
      of families with EDMD show X-linked recessive inheritance with mutations in the
      STA gene on chromosome Xq28, which encodes a protein named emerin. A rare
      autosomal dominant form of EDMD (AD-EDMD) is caused by mutations in lamin A/C
      gene (LMNA) on chromosome 1q21. Both emerin and lamin A/C are located in the
      inner surface membrane of the nucleus. A 49-year-old woman was skinny and slow
      runner from childhood and suspected as having a certain muscular disorder. At 35
      years, she was found to have the second degree atrioventricular block. At 45
      years, she was admitted to a hospital for right-side hemiplegia after cerebral
      infarction. Cardiac involvement was also observed including high degree
      atrioventricular block with chronic atrial fibrillation and frequent paroxysmal
      ventricular contraction on the electrocardiogram. At 49 years, she was referred
      to our hospital for further evaluation. She had possible dilated cardiomyopathy
      with conduction block. She also had muscular atrophy and weakness in all
      extremities, predominantly in the right-side, and contracture of bilateral
      Achilles tendon, knee and elbow joints, and postcervical muscles. Biopsied
      skeletal muscle and electromyogram showed myopathic changes. Since a novel point
      mutation of Ser303Pro was found in exon 5 of LMNA gene, she was diagnosed as
      having AD-EDMD and had a permanent pacemaker implantation. Her daughter also had
      some abnormalities on electrocardiogram. This is the first Japanese case of AD
      EDMD. Amiodaron was effective for non-sustained ventricular tachycardia. Early
      diagnosis and following cardiological examinations and treatments are important
      and necessary to improve the prognosis of the patients with EDMD.

PMID- 12424965
TI  - [A case of Turner syndrome complicated with brain infarction].
AB  - A 21 year-old female college student with a history of Turner syndrome at age 9,
      and 6-year growth hormone replacement therapy noticed weakness of right
      extremities when she got up on March 26, 2001. On admission, she showed right
      hemiparesis (4+/5) and hypesthesia on the right of body. The hemiparesis
      progressed (3-/5) in spite of antithrombotic therapy. Brain MRI revealed a high
      intensity lesion with a diameter of 1.5 cm in the posterior limb of the left
      internal capsule and putamen on DWI and T2WI. MR angiography and TC-CFI revealed
      no stenosis in her left middle cerebral artery, but > 50% stenosis in the
      horizontal portion (M1) of her right middle cerebral artery. Branch lesions were
      presumed to exist in the left M1. Non-atherosclerotic angiopathy, coagulopathy,
      and other conventional risk factors of brain infarction were not found.
      Pathogenesis of Turner syndrome might have played a role in the development of
      brain infarction in this patient.

PMID- 12424966
TI  - [A case of spinocerebellar ataxia type 3 (SCA3) associated with isolated ACTH
      deficiency].
AB  - 41-year-old woman who was admitted to our hospital because of an acute onset of
      unconsciousness on October 22, 1999. The level of blood sugar (BS) was 20 mg/dl.
      A pituitary hormone secretion test detected an isolated deficiency of ACTH.
      Neurological examinations showed gaze-evoked horizontal nystagmus in the lateral
      gaze of both eyes, ataxic speech, a slightly wide-based gait and a slight lack of
      coordination in the four extremities. A cranial MRI revealed moderate atrophy of
      the pons and the anterior lobe of the cerebellum. The analysis of SCD gene using
      white blood cells from the patient found that CAG repeat was abnormally prolonged
      to 74 CAG repeats in the Machado-Joseph disease 1 (MJD1) gene. We compared our
      patient with 11 reported cases of cerebellar ataxia associated with pituitary
      gland hormone deficiencies. Compared with 7 patients of the 11, who were reported
      as having spinocerebellar ataxia or cerebellar ataxia, none of the 7 received
      gene analysis of SCD and their deficient hormones differed from ours. Three out
      of the 7 had chorioretinopathy or chorioretinal atrophy, but the retinas of our
      patient were normal. One of the remaining 4 patients was diagnosed as having ACTH
      deficiency as was ours, but the diagnosis of the patient was myoclonus epilepsy
      associated with ragged red fibers (MERRF). The last 3 patients, who were
      diagnosed as having Boucher-Neuhauser syndrome, were similar to ours in terms of
      cerebellar ataxia but they were different in the presence of different hormone
      deficiencies and chorionretinopathy. Such an association of SCA3 and isolated
      ACTH deficiency as found in our patient has not been reported previously. The
      pathogenic mechanism of this association remains to be solved.

PMID- 12424967
TI  - [A patient of recurrent orbital myositis with good response to high-dose
      intravenous immunoglobulin (i.v.-i.g.) therapy].
AB  - We report a 62-year old woman with orbital myositis who had a favorable response
      to intravenous immunoglobulin (i.v.-IG) administration in preventing disease
      recurrence. She had been suffering from frequent relapses of swelling and redness
      of the left eye with increasing pain and diplopia caused by restricted eye
      movement of the left eyeball. T2-weighted magnetic resonance image of the orbit
      showed enlargement of the left medial rectus muscle. She was treated with 1 g of
      methylprednisolone per day for 3 days. One mg/kg per day of oral prednisolone was
      subsequently started with non-steroid anti-inflammatory drugs, which resulted in
      improvement. However, her symptoms were aggravated while the drug was tapered off
      even though she used a high dose of oral prednisolone. High dose of i.v.-IG (400
      mg/kg per day) was then administered for five days. Since the treatment, she has
      been free from recurrences of the disease for over one year, suggesting that i.v.
      IG can prevent the recurrence of orbital myositis. Some reports have suggested
      that i.v.-IG treatment is useful to prevent recurrence of other forms of
      inflammatory myositis, such as dermatomyositis or polymositis. Overproduction of
      the pro-inflammatory cytokines (IL-1, IL-1 beta, INF-alpha) and Th1 cytokines
      (INF-gamma, IL-2) are related to the deterioration of these diseases. I.v.-IG
      treatment suppresses the production of the pro-inflammatory cytokines. In our
      case, serum levels of the pro-inflammatory cytokines were all normal, but the IL
      4 level was elevated after the i.v.-IG treatment, suggesting that orbital
      myositis was probably related to the Th1 dominant disease that was suppressed by
      IL-4.

PMID- 12424968
TI  - [A case of recurrent bacterial meningitis by delayed cerebrospinal fluid (CSF)
      leakage due to a head trauma].
AB  - A 42-year-old man was admitted due to recurrent bacterial meningitis, as he had
      been treated here for bacterial meningitis three years prior to the current
      event. He had a remote history of head injury that he had almost forgotten, and
      his laboratory data showed no immunodeficiency state. 111In-DTPA cisternography
      showed an abnormal radioactive accumulation in the frontal lobe adjacent to the
      left frontal sinus at 23 hours after intrathecal injection, and MPR CT images
      revealed the left frontal sinus bone fracture. These findings indicated that he
      had a head injury by which a delayed CSF fistula has been formed. He was
      surgically treated for a CSF leakage. Although a combination therapy of ABPC and
      CTRX was efficacious for this patient, this regimen may not be ideal, as
      meningitis by PRSP has been increasing in incidence. Pneumococcal meningitis,
      once not a difficult infection to treat, could be a difficult one, as resistant
      strains to ABPC and CTRX have been more common.

PMID- 12424969
TI  - [Hashimoto's encephalopathy--case report and diagnostic issues in Japan].
AB  - We report a patient with Hashimoto's encephalopathy who showed remission and
      exacerbation 2 times, with a review of previously reported patients in Japan. A
      54-year-old woman was admitted to our hospital for various symptoms, such as
      tremors of the bilateral upper limbs, psychiatric symptoms, consciousness
      disorder, and convulsion. Steroid pulse therapy and the subsequent oral
      maintenance therapy resulted in remission. There was no relapse. The patient was
      positive for anti-thyroid antibody. Electroencephalography showed diffuse slow
      waves. The responsiveness to steroids suggested Hashimoto's encephalopathy.
      According to previous studies, clinical symptoms, magnetic resonance imaging
      (MRI) findings, and the responsiveness to steroids are similar among steroid
      reactive encephalopathy, non-herpetic limbic encephalitis, and Hashimoto's
      encephalopathy. Anti-thyroid antibody levels characteristically increased in
      patients with Hashimoto's encephalopathy. However, measurement of this parameter
      in patients with these diseases is rare. In patients with idiopathic
      encephalopathy/encephalitis, anti-thyroid antibody levels should be measured to
      facilitate accurate diagnosis.

PMID- 12424970
TI  - [A case of acute measles encephalitis with periodic synchronous discharge on
      electroencephalography].
AB  - A 18-year-old man was diagnosed as having measles on the basis of cutaneous and
      mucosal eruption and high grade fever on May 10, 2001. Six days after the skin
      eruption, the patient developed general convulsion (day1). He was admitted to our
      hospital because of status epilepticus. We made a diagnosis of acute measles
      encephalitis, based on the clinical features and pleocytosis with an increase in
      protein in the cerebrospinal fluid. Under artificial ventilation and sedation, he
      received intravenous immunoglobulin and dexamethasone. Electroencephalography
      (EEG) on day 4 revealed periodic synchronous discharge (PSD). Significant
      elevation of antibody titer for measles virus was found in the serum, but not in
      the cerebrospinal fluid. Polymerase chain reaction method did not show viral
      genes of measles virus, herpes simplex virus and herpes zoster virus. Serial EEG
      studies demonstrated a decrease in PSD, followed by irregular spike-wave
      complexes within 20 days. He recovered completely one month after the onset. It
      should be kept in mind that PSD can emerge on EEG in the early stage of acute
      measles encephalitis.

PMID- 12424971
TI  - [A case of Sjogren's syndrome with heat intolerance induced by generalized
      anhidrosis as its principal feature].
AB  - A 60-year-old man was admitted to our hospital because of heat intolerance
      induced by generalized anhidrosis. There were no abnormal findings on physical
      and neurological examinations except for anhidrosis. Reflex sweating to
      pilocarpine and acetylcholine was absent. Skin biopsy revealed no abnormalities
      of the sweat glands and ducts. Laboratory tests showed elevated levels of serum
      IgG and rheumatoid factor. Anti-nuclear antibodies, and antibodies to Sjogren's
      syndrome A and B were positive. Ocular examination revealed the presence of
      keratoconjunctivitis sicca. The pathological findings of minor salivary gland
      specimen confirmed a diagnosis of Sjogren's syndrome. This case suggests that
      generalized anhidrosis could be caused by the antigen-antibody reaction for the
      cholinergic receptor of sweat gland.

PMID- 12424972
TI  - [Different clinical phenotypes of siblings with familial amyotrophic lateral
      sclerosis showing Cys146Arg point mutation of superoxide dismutase 1 gene].
AB  - We reported different clinical phenotypes of siblings with familial amyotrophic
      lateral sclerosis (FALS) showing Cys146Arg point mutation of superoxide dismutase
      1 (SOD1) gene. They showed differences in disease onset of age, progression and
      severity. The propositus, a 50-year old woman, had muscle wasting and weakness in
      right lower leg with dysesthesia at the onset, which showed slow progression
      without other neurological symptoms until 2 years after the onset when bulbar
      palsy appeared. She has been alive for 3.5 years after the onset. In contrast, a
      61-year old man, elder brother of the propositus, had bulbar palsy at the onset,
      which showed rapid progression along with muscle weakness and wasting of upper
      extremities. Two years after the onset, he died due to respiratory failure.
      Detailed clinical features of FALS with Cys146Arg mutation of SOD1 have not been
      reported. Our cases suggest that FALS with the same SOD1 mutation could show
      variable clinical feature and course, and that some factors other than SOD1
      mutation should be considered for the pathogenesis of FALS.

PMID- 12424973
TI  - [Acquired stuttering as an early symptom in a patient with progressive
      supranuclear palsy].
AB  - We report a 57-year-old man with progressive supranuclear palsy (PSP) showing
      acquired stuttering (AS) as an early symptom. He had noticed micrographia at age
      48, and thereafter he began to suffer from progressive speech disturbance at age
      49. Neurological examination at age 57 revealed prominent acquired stuttering,
      supranuclear vertical gaze palsy, axial rigidity, disturbance of postural reflex,
      motor perseveration, and catalepsy, but no aphasia. A brain MRI study
      demonstrated atrophy of the midbrain tegmentum and dilatation of the third
      ventricle with a few lacunar infarcts in the basal ganglia. Anti-parkinsonian
      drugs were ineffective. We diagnosed his illness as PSP. His speech was
      characterized by repetition of sounds and syllables. It was more dominant at
      repetition of sentences than at that of words, and was improved with rhythmic
      stimulation. Although pathophysiology underlying AS remains unknown, the AS in
      this patient seems to be closely related to his motor perseveration and
      catalepsy. These symptoms may be caused by the disturbance of dopaminergic system
      from midbrain to limbic system and frontal cortex as reported in PSP. In
      conclusion, As can be an early and prominent symptom which may be related to
      characteristic impairment of the dopaminergic system.

PMID- 12424974
TI  - [A case of non-paralytic pontine exotropia with vertical dissociated nystagmus in
      the contralateral eye].
AB  - We report a 74-year-old woman presenting non-paralytic pontine exotropia (NPPE)
      with vertical monocular nystagmus in her contralateral eye, due to a small
      infarction in the upper pons. On forward gaze, the ocular position of the right
      eye was fixed at the midline, while the left eye was abducted. On the leftward
      gaze, the left eye was abducted and monocular nystagmus was noted, but the right
      eye was not able to pass midline, which indicated NPPE. Neither a skew deviation
      nor an alternating exotropia was observed. In the acute phase of this case,
      disturbances in the vertical eye movement of her right eye and the monocular
      upper gaze-evoked nystagmus of her left eye were observed. On the 7th hospital
      day, the monocular nystagmus disappeared simultaneously with an improvement of
      vertical eye movement. This finding suggests that the patient's vertical
      monocular nystagmus occurred due to an adaptive increase in the innervation to
      the left eye according to Hering's law of equal innervation, which indicates
      either horizontal dissociated nystagmus in MLF syndrome or NPPE.

PMID- 12424975
TI  - The adoption of bill 90. A historic event and a reason for collective pride.

PMID- 12424976
TI  - [Growing accustomed to death every day].

PMID- 12424977
TI  - [Significance of postnatal care for Algerian immigrants].

PMID- 12424978
TI  - [The PACT model].

PMID- 12424979
TI  - [Health education. How to facilitate the problems of new behaviors].

PMID- 12424980
TI  - [Haitian patients and arterial hypertension].

PMID- 12424981
TI  - When the child's illness is life threatening: impact on the parents.
AB  - An investigation of the impact on parents of children with life threatening (LT)
      and parents of children with non-life threatening (NLT) chronic illnesses
      measured satisfaction with social support received, perception of the impact of
      the child's illness, and coping behaviors. Eighty fathers and 80 mothers of
      children completed four questionnaires: (a) The Sociodemographic and Illness
      related Questionnaire (Krulik, Hirschfield, & Sharon, 1984); (b) Social Support
      Questionnaire (London, 1988); (c) Perception of the Impact of the Child's Chronic
      Illness on the Parent Questionnaire (Katz, 1994); and (d) Coping Health Inventory
      for Parents (CHIP) (McCubbin, McCubbin, Patterson, et al., 1983). The results of
      parents together and fathers and mothers separately, and parents of LT and
      parents of NLT chronic illnesses were compared using ANOVA, MANOVA, and Doubly
      multivariate analysis. Parents of children with LT and NLT illnesses reported
      significant differences in social support, perception of the impact of the
      illness, and coping behaviors. Although fathers and mothers reported significant
      differences in the use of the medical team as a coping behavior, no significant
      differences were found between fathers and mothers related to social support and
      perception of the impact of the illness.

PMID- 12424982
TI  - Empowering parents through asthma education.
AB  - Asthma is the most common chronic illness in children and has a significant
      impact on children and their families. Asthma management requires a multi-faceted
      approach, including an effective educational component. The purpose of this pilot
      study was to compare outcomes for parents who participated in empowering and
      traditional approaches to asthma education. Specific outcomes that were examined
      included (a) knowledge, (b) sense of control, (c) ability to make decisions, and
      (d) ability to provide care. The sample consisted of 57 families who participated
      in a multi-session educational intervention. Twenty-nine families participated in
      the empowering approach; the remaining 28 families received the traditional
      approach. Data were collected before, immediately after, and 6 months following
      the educational intervention. Significant differences were found regarding sense
      of control, ability to make decisions, and ability to provide care for parents
      who participated in the empowering approach. Both approaches resulted in
      increased knowledge. These findings have implications for asthma education and
      for the education of health professionals.

PMID- 12424983
TI  - Psychometric instrument evaluation: the pediatric family satisfaction
      questionnaire.
AB  - PURPOSE: The purpose of this study was to evaluate parental satisfaction with
      hospital care in general pediatric units. A search for a valid parental
      satisfaction instrument resulted in the selection of the Pediatric Family
      Satisfaction Questionnaire (PFSQ) (Budreau & Chase, 1994). This paper will report
      on the psychometric testing of the PFSQ. METHODS: The data were retrieved from
      several years of patient satisfaction surveys collected at a large Midwest
      hospital and clinics. The SPSS statistical software was used to test the
      reliability and construct validity of the PFSQ. RESULTS: Alpha for the total
      instrument was .83, based on 327 cases and 35 items. Factor analysis indicated
      two main factors, nursing care and medical care, with a total of 30 items.
      CONCLUSION: The PFSQ is considered a promising instrument for evaluating parental
      satisfaction in general, inpatient pediatric units. urther development of the
      instrument is suggested.

PMID- 12424984
TI  - Mindfulness meditation in pediatric clinical practice.
AB  - Complementary therapies are used in addition to conventional treatments;
      alternative therapies are generally used instead of conventional treatments. In
      the Five Domains of complementary and alternative therapies, patient education
      and cognitive-behavioral approaches are listed as mainstream interventions.
      Meditation is listed within the mind-body domain as a complementary intervention
      used to facilitate the mind's ability to affect bodily functions and symptoms.

PMID- 12424985
TI  - Peanut allergy: an increasing health risk for children.
AB  - Matthew, age 24 months, is brought into the clinic by his frantic mother. She
      reports Matthew started wheezing and broke out in a blotchy skin rash within 5
      minutes of eating a cracker with peanut butter. Matthew has a history of mild,
      intermittent asthma treated with nebulized albuterol, which the mother
      administered without improvement in the child's breathing pattern. He also has a
      history of moderate atopic dermatitis and a prior milk intolerance that he has
      since outgrown. No other food allergies are noted in his history, and the mother
      believes this is the first time Matthew has eaten peanut butter. It has been
      approximately fi hour since he ingested the peanut butter. Matthew's vital signs
      are temperature 98.6 degrees F, pulse 90, and respirations 60 with audible
      wheezing and repetitive cough. His blood pressure is 80/60. His face and chest
      are flushed with urticaria, and some swelling is noted around his mouth.

PMID- 12424986
TI  - Waiting for lung transplantation: family experiences of relocation.
AB  - The waiting period for pediatric lung transplantation begins when it is
      determined that a child's only choice, other than transplantation, is death
      within 1 year. Children who are on the waiting list must always be within beeper
      range of the transplant center. Six parents who temporarily relocated with their
      children to be closer to the transplant center shared their perceptions of the
      experience. Data analysis led to the formulation of a descriptive category,
      experiencing relocation, and six related themes--putting life on hold,
      experiencing diminished emotional support, establishing new sources of support,
      undergoing role change, worrying about money, and making the best of the
      situation. Recognizing the unique needs of parents who must relocate for a
      child's transplant supports the delivery of individualized nursing care and the
      effective allocation of program resources.

PMID- 12424987
TI  - Pediatric management problems.

PMID- 12424988
TI  - When the story doesn't match.

PMID- 12424989
TI  - Effectiveness of informational/behavioral interventions with parents of low birth
      weight (LBW) premature infants: an evidence base to guide clinical practice.

PMID- 12424990
TI  - Refining clinical terminology for expert system development: an application in
      the neonatal intensive care unit.
AB  - PURPOSE: To clarify terms surrounding the clinical problem of initiating oral
      feeding in premature infants cared for in the neonatal intensive care unit
      (NICU). Understanding terminology at the outset of expert system (ES) development
      forms the crucial foundation needed to build a system that is accurate, relevant,
      and useful for assisting clinicians. METHOD: Ethnographic methods were used. In
      phase 1 participant observation with an interdisciplinary neonatology team was
      used to study oral feeding for premature infants. In phase 2 in-depth interviews
      were conducted with a neonatal nurse practitioner (NNP) to explore feeding terms
      and the description and understanding of these terms. FINDINGS: Results showed
      that oral feeding was a complex term that encompassed several feeding options;
      specifically nipple, breast, gavage, and transpyloric feeding. CONCLUSIONS: Each
      of the terms had a specific meaning within the context of the NICU.

PMID- 12424991
TI  - Conjoined twins: whose best interest should prevail? An argument for separation.

PMID- 12424992
TI  - Comment on "Whose best interest?" Judging and balancing the interests of
      conjoined twins.

PMID- 12424993
TI  - Child rape in South Africa.

PMID- 12424994
TI  - Creating your own leadership brand.
AB  - Building equity in a brand happens through many encounters. The initial
      attraction must be followed by the meeting of expectations. This creates a
      loyalty that is part of an emotional connection to that brand. This is the same
      process people go through when they first meet a leader and decide if this is a
      person they want to buy into. People will examine your style, your competence,
      and your standards. If you fail on any of these fronts, your ability to lead will
      be severely compromised. People expect more of leaders now, because they know and
      recognize good leaders. And, predictably, people are now more cynical of leaders
      because of the well-publicized excess of a few leaders who advanced their own
      causes at the expense of their people and their financial future. This will turn
      out to be a good thing, because it will create a higher standard of leadership
      that all must aspire to achieve. When the bar is raised for us, our standards of
      performance are also raised.

PMID- 12424995
TI  - Knowledge about postpartum depression is family's responsibility.

PMID- 12424996
TI  - Betwixt and between: searching for nursing's moral foundations.

PMID- 12424997
TI  - Ethical challenges of the 21st century: attending to relations.

PMID- 12424998
TI  - Employed to go against one's values: nurse managers' accounts of ethical conflict
      with their organizations.
AB  - This qualitative descriptive study examined ethical conflict in the workplace as
      experienced by nurse managers. Using semi-structured interviews, 15 nurse
      managers employed by 7 hospitals in 1 province in eastern Canada were
      interviewed. Four themes of ethical conflict were identified in the data:
      voicelessness, "where to spend the money," the rights of the individual versus
      the needs of the organization, and unjust practices on the part of senior
      administration and/or the organization. The authors identify factors that
      mitigated or worsened the ethical conflict, as well as the outcomes for the nurse
      managers. They also discuss the implications for nurses, hospitals, and future
      research.

PMID- 12424999
TI  - Ethical orientation, functional linguistics, and the codes of ethics of the
      Canadian Nurses Association and the Canadian Medical Association.
AB  - The literature on codes of ethics suggests that grammatical and linguistic
      structures as well as the theoretical ethical orientation conveyed in codes of
      ethics have implications for the manner in which such codes are received by those
      bound by them. Certain grammatical and linguistic structures, for example, tend
      to have an authoritarian and disempowering impact while others can be empowering.
      The authors analyze and compare the codes of ethics of the Canadian Nurses
      Association (CNA) and the Canadian Medical Association (CMA) in terms of their
      ethical orientation and grammatical/linguistic structures. The results suggest
      that the two codes differ substantially along these two dimensions. The CNA code
      contains proportionally more statements that provide a rationale for ethical
      behaviour; the statements of the CMA code tend to be more dogmatic. Functional
      grammar analysis suggests that both codes convey a strong deontological tone that
      does not enhance the addressee's ability to engage in discretionary decision
      making. The nurses' code nonetheless implies a collaborative relationship with
      the client, whereas the medical code implies that the patient is the recipient of
      medical wisdom. The implications of these findings are discussed.

PMID- 12425000
TI  - Nursing as science: a critical question.
AB  - Nursing is a profound human activity generally influenced by two dynamics--the
      relationship between patient and nurse and the scientific paradigm. Often
      overlooked, however, are the incongruities that arise between these two dynamics.
      The patient-nurse relationship encompasses sameness, closeness, and connection,
      whereas science requires distance, detachment, and differentiation to fulfil the
      demands of objectivity. The patient-nurse relationship is both profound and
      intangible, whereas science attends only to that which can be observed and
      measured. The authors explore these dynamics and the incongruities between them.
      They consider the demands made by science on the patient-nurse relationship and,
      conversely, the place of the patient-nurse relationship in the development of
      nursing as science. These issues are critical to the advancement and practice of
      nursing.

PMID- 12425001
TI  - Unrelieved pain: an ethical and epistemological analysis of distrust in patients.
AB  - Unrelieved pain is a serious clinical problem that has received little attention
      in bioethics. This paper contends that unrelieved pain is the result of distrust
      in patients that reveals both an ethical and epistemological failure on behalf of
      nurses and physicians. The analysis is conceptually framed in previous work on
      the articulation of trust in nursing. Specifically, an argument is made that
      clinicians do not trust patients' subjective experiences, distrust patients from
      marginalized and relatively less powerful groups, and resist entrusting
      themselves or becoming vulnerable to patients' pain and suffering. The authors
      discuss the need for awareness and critical examination of deeply entrenched
      societal beliefs and values that influence everyday decision-making in pain
      management.

PMID- 12425002
TI  - Hope and feminist care ethics: what is the connection?
AB  - Health-care providers--including nurses--are considered to have an obligation to
      foster hope in their patients. Various interventions for fulfilling this
      obligation have been suggested. Comparatively little time, however, has been
      devoted to examining the moral aspects of this duty and to situating this
      investigation within an appropriate ethical framework. Given the significance of
      hope in patients' lives, and the significance of their relationships with health
      care providers, the author contends that a feminist care ethics approach is best
      suited for this investigation. In particular, the author draws upon Joan Tronto's
      ethic of care and discusses the 4 aspects of care she describes as they relate to
      the role of hope in health care. Ultimately, this paper shows that it is possible
      for health-care providers to care about and for hope. Based on this framework,
      future directions for nursing research are discussed.

PMID- 12425004
TI  - Authentic qualitative research and the quest for methodological rigour.

PMID- 12425003
TI  - Economism, efficiency, and the moral ecology of good nursing practice.
AB  - The free-market rhetoric dominating health-policy discussions today frames health
      care goods and services as commodities that consumers will or will not buy at a
      given price. Health-care systems are being redesigned and hospitals restructured
      with a view to increased efficiency and productivity. Drawing on the experiences
      of clinical nurses in the United States, this paper shows how the application of
      economism to nursing may severely disrupt the ecology of good practice, leading
      to difficulties in meeting minimal standards of nursing care and severely
      constraining the acts of compassion called for by the human experiences of
      illness, loss, and death. Concerns about moral responsibility and conflicts
      between institutional and nursing goals are described. Increasing mistrust of
      health-care systems on the part of practitioners, patients, and families suggests
      that it is time to attend closely to the moral ecology of caring practices.

PMID- 12425005
TI  - The human genome impact on health-care services: are nurses prepared?

PMID- 12425006
TI  - Decisions that matter: recognizing the contextuality of decision-making.

PMID- 12425007
TI  - Ethics and decision-making: lessons from the "cancer wars".

PMID- 12425008
TI  - The family as window onto the world of the patient: involving patients and
      families in the decision-making process.
AB  - The need to involve family members as patient advocates and as surrogates when
      patients are unable to speak for themselves is not an issue. What continues to be
      debated are the methods for involving family members in the decision-making
      process. Such decisions can be complex and the environment in which they are made
      can be chaotic, while clinicians' approach to decision-making is often seen as
      insensitive. Families struggle with the emotional burden of their role and
      clinicians struggle to translate complex information into comprehensible,
      meaningful, and practical language. There is a need to examine clinical practice
      to determine which approaches to involving family members are preferable from a
      philosophical as well as a practical point of view. The paper explores the many
      facets of the surrogate decision-making role and suggests a reorientation of
      current models of the professional-surrogate relationship.

PMID- 12425009
TI  - Management of pain during weaning from mechanical ventilation: the nature of
      nurse decision-making.
AB  - Despite extensive knowledge of pain and pain management, critical-care nurses
      commonly withhold analgesia from patients for extended periods prior to and
      during weaning from mechanical ventilation. Nurses working in critical care were
      interviewed (n = 10) to gain insight into the importance of pain management
      during weaning and the nature of decision-making in pain management. Using the
      research method of grounded theory, the author found decision-making to be a
      dynamic and continuous process of knowledge gathering, knowledge interpretation,
      and action, influenced by nurses' beliefs concerning (1) the existence of and
      importance of managing pain, and (2) the role of the nurse. The emergent theory
      has the potential to guide the development of interventions in which nurses make
      effective, holistic, competent decisions about pain management during weaning
      from mechanical ventilation.

PMID- 12425010
TI  - Equipoise in clinical nursing research.
AB  - Equipoise, a state of uncertainty about the relative merits of 2 or more
      treatments or therapeutic approaches, is fundamental to the ethical conduct of
      clinical research. The degree of uncertainty necessary for ethical conduct of a
      clinical trial is the subject of ongoing debate. The concept of equipoise has not
      received sufficient attention from nurse authors. This paper examines the concept
      of equipoise by drawing on the author's experience with 3 trials of psychosocial
      interventions in mental health. Arguments for and against using equipoise in the
      evaluation of ethics of clinical research are summarized. Equipoise may be
      impossible to achieve in trials of psychosocial treatments with multiple outcomes
      for patients and relatives. In addition, the need to achieve equipoise may put
      nurses who provide psychosocial treatments in clinical trials in conflict. In
      order to provide the best treatment possible, they must believe that what they
      are doing is in the best interests of their client. Yet, in order to accept
      randomization, they must, to some extent, relinquish that belief. Case examples
      are used to examine how discrepancies with respect to the "equipoise status" of
      researchers, clinicians, and research participants may be problematic in
      achieving methodologically sound, ethical clinical nursing research.

PMID- 12425011
TI  - Disease-specific influences on meaning and significance in self-care decision
      making in chronic illness.
AB  - The purpose of this study was to investigate the everyday self-care decision
      making of individuals with chronic illness for the purpose of developing a
      comparison of decision-making processes between chronic diseases and to identify
      criteria by which persons with various chronic conditions evaluate the quality of
      self-care decisions. A sample of 21 individuals with either Type II diabetes,
      HIV/AIDS, or multiple sclerosis, who were nominated as expert self-care managers
      by their clinicians, recorded the decisions they made in their daily self-care
      over a 1-week period and were interviewed in depth to elaborate on the decisions,
      the processes by which they made them, and the factors that influenced them. This
      process was repeated to obtain depth and detail in relation to decisions and
      decision-making processes. The findings revealed that although participants
      shared similar elements in their self-care decision-making, they differed in the
      perceived meaning and significance of their decisions, depending on disease
      specific attributes relating to timeliness, biomarkers, interaction within a
      social context, the construction of healthy practices, and available relevant
      information. Findings were analyzed and compared to suggest future directions for
      research and educational interventions to enhance the quality of self-care
      decision-making in chronic illness by considering the influence of disease
      specific attributes in self-care management.

PMID- 12425012
TI  - Navigating towards a moral horizon: a multisite qualitative study of ethical
      practice in nursing.
AB  - This paper reports the results of a qualitative study of nurses' ethical decision
      making. Focus groups of nurses in diverse practice contexts were used as a means
      to explore the meaning of ethics and the enactment of ethical practice. The
      findings centre on the metaphor of a moral horizon--the horizon representing "the
      good" towards which the nurses were navigating. The findings suggest that
      currents within the moral climate of nurses' work significantly influence nurses'
      progress towards their moral horizon. All too often, the nurses found themselves
      navigating against a current characterized by the privileging of biomedicine and
      a corporate ethos. Conversely, a current of supportive colleagues as well as
      professional guidelines and standards and ethics education helped them to move
      towards their horizon. The implications for nursing practice and for our
      understanding of ethical decision-making are discussed.

PMID- 12425013
TI  - Evaluation of an integrated model of discharge planning: achieving quality
      discharges in an efficient and ethical way.
AB  - Discharge planning has become increasingly important in an era of shortened
      lengths of stay in hospital. Prior research demonstrated that discharge practices
      presented resource and ethical problems. This evaluation of an integrated model
      of discharge planning (IMDP) included an assessment of resource utilization,
      respect for persons during decision-making, and the impact of the model in
      meeting the needs of elderly patients, families, and professionals. Two case
      studies involving a university and a community hospital were used to illustrate
      the context in which discharge planning occurs. Within and cross-case analyses of
      the discharge-planning process for 48 patients indicated that it is possible to
      implement the IMDP and that participants were satisfied. Further, hospital
      resources were used efficiently and patients were involved in decision-making.
      The study represents a successful implementation of a promising approach to
      discharge planning.

PMID- 12425014
TI  - A critical review and synthesis of literature on reminiscing with older adults.
AB  - Reminiscing is an intervention that has been used independently in nursing with
      different populations for many years. A critical analysis of the literature on
      reminiscing was carried out in 3 stages: identification of the studies to be
      included, review of the studies to ensure that they were research-based, and
      critical appraisal of the studies. The analysis resulted in clarity regarding the
      operational definitions of reminiscing and life review. Of the many studies
      reviewed, only a handful were research-based. The others were valuable in other
      respects, such as providing guidance for the design of imaginative and age
      related reminiscing and life-review programs.

PMID- 12425015
TI  - Twentieth-century social and health-care influences on location of death in
      Canada.
AB  - Providing the right care, in the right place, to dying persons is hampered by a
      lack of understanding of where death and dying normally take place and ignorance
      about what influences location of death. This paper reports the findings of a
      multidisciplinary historical investigation of 20th-century influences on location
      of death in Canada. It builds on a study that found a hospitalization-of-death
      trend in Canada over much of the 20th century but a reduction in hospital deaths
      beginning in 1994. This study found 2 key influences on location of death: (1)
      health-care and health-system developments that consolidated care in hospitals
      while also raising and sustaining public expectations of beneficial if not
      curative hospital care--the rising hospital-death rate throughout the 20th
      century can thus be considered an outcome of the shift of illness care from the
      home to the hospital; and (2) reduced availability of home-based caregivers. A
      number of developments limited the availability of home care for chronically ill
      and terminally ill persons, including the increased participation of women in the
      workforce and the shift in nursing from private home duty to hospitals. Although
      some health and social support for home care has developed recently, this support
      clearly does not match that for hospital care. These findings indicate that
      location of death is an important focal point for studying and planning
      improvements in end-of-life care.

PMID- 12425016
TI  - Molecular-genetic dissection of the late blight pathogen Phytophthora infestans.

PMID- 12425017
TI  - Crop protection in field vegetables. Could we cope without synthetic
      insecticides?

PMID- 12425018
TI  - Developments in detection of plant pathogens and other plant-related organisms:
      detection in the past towards detection in the future.

PMID- 12425019
TI  - The Beet soilborne pomovirus in Belgium and relationship with rhizomania.
AB  - The objective of this study was to determine the extend of the Beet soilborne
      pomovirus (BSBV) and the Beet virus Q in sugar beet fields in Belgium. During the
      2000 sugar beet growing season, more than 80 fields located in Belgium were
      investigated for the presence of the Beet necrotic yellow vein benyvirus (BNYVV),
      the BSBV and Polymyxa betae, the plasmodiophorid vector of both viruses. Fields
      investigated were identified either using previous recorded data or by visual
      identification of yellow leaves on sugar beets or root symptoms. Sampling
      position (longitude-latitude) was recorded using the global positioning system
      (G.P.S.) with the view to follow-up infested fields in the following years. Three
      different techniques were used to evidence the aforementioned biological agents:
      enzyme-linked immunosorbent assay (ELISA), a RT-PCR assay to detect the viruses
      and direct coloration of Polymyxa betae in plant root tissues, using lactophenol
      aniline blue. ELISA allowed the detection of 43 BSBV-infested soils, largely
      distributed in all Belgian sugar beet growing areas. These results were largely
      confirmed by RT-PCR using two different primers pairs targeting respectively a
      400 bp fragment of the 145K ORF located on virus RNA-1 and a 970 bp fragment of
      the conserved 3' end of the viral genome. Five other primer's pairs have also
      been evaluated for BSBV identification. The detection of BSBV-infested soils
      without BNYVV, as well as BNYVV-infested soils without BSBV allowed the design of
      a competition assay between both viruses. Among the samples, 21 were selected
      randomly and tested for the presence of Beet virus Q by RT-PCR. Here also, six
      fields were detected positive for this virus. Sequence data reveal a clonal
      population of BSBV isolates in Belgium though a high level of diversity is
      observed for the coat protein region. Compared to BSBV, BVQ isolates show less
      diversity at sequence level.

PMID- 12425020
TI  - Population dynamics of Pythium aphanidermatum in cucumber grown in closed
      systems.
AB  - Foot and root rot in cucumber, caused by Pythium aphanidermatum (Edson) Fitzp.,
      is an economically important disease in soilless culture systems. Nevertheless,
      very few data are available on the populations of this pathogen. Therefore, two
      detection methods, nested PCR (polymerase chain reaction) and plating on a
      selective medium after concentration of samples, were optimised and evaluated.
      With both methods very low concentrations of P. aphanidermatum could be detected;
      i.e. the detection limits were around 0.05 CFU/ml nutrient solution. In addition,
      real-time quantitative PCR using a Molecular Beacon probe was designed and
      tested. The potential and limitations of the different detection methods are
      discussed. With these different detection techniques, the population dynamics of
      P. aphanidermatum in a cucumber crop was followed. The impact of different
      disinfection treatments was studied in a greenhouse experiment with a cucumber
      crop growing on rockwool slabs in 12 independent closed systems. The nutrient
      solution was recirculated without disinfection (control), after UV-irradiation
      (250 mJ/cm2), or after slow sand filtration treatment. Part of the crop was
      inoculated with an isolate of P. aphanidermatum. The non-inoculated part could
      only become infected through the recirculated nutrient solution. Disease symptoms
      (stem rot, wilt, and root rot) and the yield loss were recorded in addition to
      the population dynamics of the pathogen. Very clear differences in the spread of
      the pathogen and in disease symptoms were measured between the systems with and
      without disinfection. UV-irradiation and slow sand filtration were both effective
      in removing the pathogen and protected the crop from disease symptoms.
      Correlation indices between the final yield and the different measurements during
      the experiment were calculated.

PMID- 12425021
TI  - An efficient in vitro test to determine carrot genotypes resistance to cavity
      spot.
AB  - As part of a carrot breeding programme, our objective was to develop a test for
      determining genotypes resistance against two Pythium species responsible for
      cavity spot. Ten different media were tested for carrot callus culture, Pythium
      culture and dual cultures. Carrot callus growth was greater on Murashige and
      Skoog medium plus 1.25 microM 2.4D plus 2.5 microM BA plus 2.5 microM NAA.
      Pythium violae was more sensitive to medium composition than Pythium sulcatum.
      When carrot callus were inoculated by Pythium violae or sulcatum on Murashige and
      Skoog mineral medium, callus growth of Bolero, an resistant cultivar in the
      field, was highly inhibited whereas Nanco, a susceptible cultivar was not. Such a
      medium should be used for screening genotypes resistance to Pythium. A Murashige
      and Skoog medium supplemented with 1.25 microM 2.4D, 2.5 microM BA and 2.5 microM
      NAA, where callus growth was highly reduced whatever the genotype used, should be
      useful for selection of cell lines tolerant to Pythium.

PMID- 12425022
TI  - Disinfection of Pythium-infested recirculation water by UV-oxidation technology.
AB  - Selective disinfection against Pythium aphanidermatum in recirculation water was
      tested with UV-irradiation and with UV-oxidation technology with the objective to
      reduce the electrical energy consumption per cubic meter treated water. UV
      oxidation technology is based on injection of hydrogen peroxide in recirculation
      water, just before passage along a UV-lamp, thus creating hydroxyl radicals.
      Pythium aphanidermatum was applied artificially to recirculation water from
      tomatoes, grown, in rockwool and coconut fibre. Other parameters in this study
      were pH and transmission value (T10) of the infested recirculation water. Results
      indicated that the recommended UV-C dose of 100 mJ/cm2 for elimination of fungal
      pathogens in general can be lowered in case recirculation water is infected with
      Pythium aphanidermatum only. When UV-oxidation technology was applied with 1 mmol
      hydrogen peroxide per litre recirculation water, the UV-C dose could be reduced
      even more in comparison with merely UV irradiation.

PMID- 12425023
TI  - Plant extracts in the control of Phytophthora cryptogea.
AB  - Grapefruit extract at dose 40 micrograms/cm3 inhibited Phytophtora cryptogea
      linear growth about 50% and almost completely suppressed zoosporangia formation.
      Drenching of gerbera plants with the extract at dose 165 micrograms/cm3 reduced
      population density of the pathogen about 70% and this high efficacy was noted at
      least one month after application. Treatment of gerberas with grapefruit extract
      resulted in protection of about 50% of plants against the pathogen. Biological
      activity of purple coneflower extract was lower than extract from grapefruit.
      Significant decrease of population density of the pathogen during the first 5
      days and increase of gerbera healthy stand was observed, however, in peat treated
      with that extract.

PMID- 12425024
TI  - Damping-off in conifer seedling nurseries in Noshahr and Kelardasht.
AB  - To study the damping-off of conifer seedlings, we have collected samples from the
      roots of conifer seedlings (Pinus nigra, Picea excelsa, Abieces spp, Cupressus
      arizonica, Cupressus sempervirens) from nurseries in the south of Iran (Noshahr
      and Kelardasht). After disinfecting the samples, we have used standard media like
      PDA, MA and CLA. The following fungi were identified: Fusarium solani, Fusarium
      oxysporum, Fusarium sambucinum, Clamydosporium, Rhizoctonia solani,
      Cylindrocarpon spp., Alternaria spp, Macrophomina phaseoli. Amongst the above
      mentioned fungi, Fusarium spp. were the commonest ones. Pathogenecity tests of
      Fusarium spp. and Rhizoctonia solani on seedlings were done. Isolated fungal
      colonies were purified using single mycelium and single spore methods. Fungal
      isolates were identified after subculturing on PDA and CLA media by Nelson
      method. These isolates were Fusarium solani, F. oxysporium, F. sambucinum and F.
      clamydosporum. Other fungal isolates were Rhizoctonia spp. In order to determine
      the infectivity of Fusarium on their hosts, seeds of Pinus nigra, Cupressus
      arizonica and Cupressus sempervirens var. horizontalis were cultured in four
      repetitions each containing 2 seedlings. After a seasonal growth, seedlings were
      inoculated with a suspension of Fusarium spores (4.5 +/- 0.3 x 1016 spore/ml).
      Infection of P. nigra, Cupressus arizonica and Cupressus sempervirens var.
      horizontalis with F. solani and Pinus nigra and Cupressus semperivirens var.
      horizontalis with F. oxysporum was high whereas that of Cupressus arizonica with
      F. sambucinum, F. mondiforme and F. clamydosporum was moderate.

PMID- 12425025
TI  - Antagonistic effects of several bacteria on Verticillium dahliae the causal agent
      of cotton wilt.
AB  - Experiments were carried out with 89 bacterial isolates that were collected from
      cotton rhizosphere in Gorgan province. The antagonistic effects of bacterial
      isolates on Verticillium dahliae Klebahn were studied using dual culture test.
      Five highly effective isolates were selected from these antagonists for
      subsequent studies. According to the biochemical, physiological and morphological
      tests, isolates 2020 and 3 were identified as Pseudomonas fluorescens and isolate
      204, 202 and 309 as Bacillus spp. These isolates were used to investigate their
      antagonistic mechanisms in vitro and their effects on cotton growth in vivo.
      Inhibition of V. dahliae by volatile metabolites and antibiotics was studied as
      described by Fiddamen (1994) and Kraus (1990). Production of hydrogen cyanide was
      studied qualitatively, using HCN-indicator paper of Castric and Castric (1983).
      Isolates 204, 202 and 309 inhibited the mycelial growth of the fungus through
      production of volatile metabolites. Isolates 2020 and 3 produced antibiotic as
      well as volatile metabolities that inhibited mycelial growth of V. dahliae. They
      both produced hydrogen cyanide. After four months of greenhouse study, the
      application of antagonistic bacteria had different effects on growth of cotton
      plants. Bacterial treatment in soil had better effects on plant growth than that
      of bacterial seed treatment. In soil treatments containing infested and non
      infested soil with V. dahliae, isolates 2020 and 3 caused an increase in plant
      height in comparison with those in infested and non-infested controls. In non
      infested soil, application of isolates 2020, 3 and 202 increased root length and
      dry weight of cotton plant, but in soil infested with the fungus, only isolate
      202 increased root length. Isolate 2020 increased plant dry weight. In
      conclusion, isolates 2020 and 3 belonging to P. fluorescens and isolate 202
      pertaining to genus Bacillus had the greatest effect on increasing the cotton
      growth.

PMID- 12425026
TI  - Remarkable, overlooked and new microfungi in North Rhine-Westphalia, Germany.
AB  - During our investigations of the micro flora in NRW in the years of 1999 and 2000
      we were able to collect and identify some new and rare species of micro fungi as
      parasites and saprophytes on wild and ornamental plants. Some of them are new for
      Germany: Podosphaera xanthii on Coreopsis verticillata; Cercospora traversiana on
      Trigonella foenum-graecum; Passalora dubia on Atriplex hortensis; Ophiobolus
      cirsii on Carduus spec.; Periconia britannica on Polemonium coeruleum; Ascochyta
      leptospora on Agropyron repens; Apomelasmia urticae on Urtica dioica;
      Cryptodiaporthe salicina on Salix caprea; Dasyscyphus nidulus on Anemone
      hupehensis; Rhopographus filicinus on Pteridium aquilinum; Sillia ferruginea on
      Corylus avellana; Sirococcus spiraeae on Spiraea spec. and Forsythia x
      intermedia. Examples of these findings are in the Herbarium ESS (Mycotheca Parva,
      Slg. Feige/Ale-Agha).

PMID- 12425027
TI  - Microfungi on Rosaceae in eastern Westphalia (Sauerland, North Rhine-Westphalia,
      Germany).
AB  - Microfungi occuring on Rosaceae in the Sauerland were examined. 38 microfungi
      from 27 different genera were found, including Ascomycetes of the orders
      Erysiphales, Helotiales, Hypocreales and Taphrinales and Basidiomycetes of the
      order Uredinales as well as mitosporic fungi. The examined samples have been
      collected in the period of march to september 2000. New hosts could be found for
      the following species: Discosia potentillae Lib., Phragmidium acuminatum (Fr.)
      Cooke, Stigmina carpophila (Lev.) M.B. Ellis, Seimatosporium pestalozzioides
      (Sacc.) B. Sutton, Septocyta ruborum (Lib.) Petr. and Zythiostroma mougeotii
      (Fr.) Hohn. Discosia potentillae Lib. is recorded for the first time for Germany
      and Cercospora potentillae Chupp & Greene for the first time for Europe.

PMID- 12425028
TI  - Virus-infections of wild hops in Hamburg.
AB  - More than 200 samples from wild hops were collected in the city of Hamburg and
      tested for the presence of PNRV/ApMV, ArMV, HLV and HMV. All viruses were
      detected, but in case of the ilarviruses (ApMV/PNRV) no reaction was found in DAS
      ELISA using ApMV antiserum, indicating, that, different to earlier results mainly
      from wild hops of southern areas of Germany, neither A nor I-types were present,
      but only C-type corresponding to the cherry strains of PNRV. Compared to results
      from escaped and cultivated hops, infestation was rather low but differing to
      some extent from data obtained for wild hops in other, mainly non-urban regions.

PMID- 12425029
TI  - Little cherry disease in a fruit farm at the Niederelbe ("Altes Land").
AB  - Little cherry disease (LCD) was detected as such at the Niederelbe in the early
      80s and is observed spreading since. Until now two clostero-viruses were detected
      and investigated on the molecular level (LChV1 and LChV2), but the use of that
      knowledge in performing PCR-detection did not lead to a coincidence of the
      presence of these two viruses with the presence of LCD. So symptomatological
      screening is still required. In a particular farm all cherry orchards were
      screened for the presence of LCD. They are all grouped around the farm buildings
      and so in a close juxtaposition. Despite that, every orchard shows a distinct
      pattern when the data are arranged according to symptom severity indicating a
      multifactorial incidence in the disease spread.

PMID- 12425030
TI  - The distribution of little cherry disease in Germany: LChV1 and LChV2 in
      cultivars of sweet cherry and in some other species.

PMID- 12425031
TI  - Control of mechanical viroid transmission by the disinfection of tables and
      tools.
AB  - Viroids are of practical importance as the cause of several economically
      significant infectious diseases. Potato spindle tuber viroid (PSTVd) causes
      severe yield losses in several crops, because the pathogen spreads fast within
      the culture. Viroids are small molecules, a few hundred nucleotides long, with a
      high degree of secondary structure. They do not code for any polypeptides and
      replicate independently of any associated plant virus. Viroids are readily
      transmitted by contaminated tools and tables. Furthermore PSTVd is transmitted
      through the pollen and true seed and can remain its infectious activity in seed
      for long periods. Vector transmission of PSTVd was reported to occur at low
      frequency. However, the mechanical transmission is the predominant factor and in
      this case we discuss the efficient disinfection of tools and tables as a main
      prophylactic trail to avoid viroid transmission. In previous studies we have
      tested the efficiency of several disinfectants to eliminate virus contamination.
      This paper demonstrates the efficient disinfection of MENNO-Florades (Menno
      Chemie-GmbH, Norderstedt, Germany. A selection of different concentrations of the
      disinfectant and various times of incubation were applied in regard to practical
      use. The tests were confirmed by biological assays using suitable indicator
      plants, tissue print hybridization, gel electrophoresis and by nucleic acid
      hybridization. It was shown that PSTVd was eliminated when using the determined
      combination: 2% of the disinfectant while incubating for one minute or
      alternative 3%, 30 seconds. The possibility of viroid inactivation by a chemical
      method of disinfection--while plants are not affected--opens a new perspective to
      control viroid transmission via tools and tables.

PMID- 12425032
TI  - Modes of action of biocontrol agents of Fusarium wheat foot rot.

PMID- 12425033
TI  - Biological activity of Pythium oligandrum against Phytophthora species.
AB  - Influence of Pythium oligandrum as an a.i. of Polyversum on population dynamic of
      Phytophthora cryptogea in peat and development of Phytophtora rot on gerbera,
      Lawson cypress and yew-tree were evaluated. Drenching of peat, artificially
      infested with P. cryptogea, with Polyversum immediatelly after gerbera planting
      resulted in significant decrease of colony forming units number within 4 weeks.
      Concentrations of the biopreparate used had no significant influence on its
      greater, biological activity. Drenching of plants with Polyversum at conc. 0.05
      or 0.1%, after planting into peat infested with P. cryptogea or P. cinnamomi,
      resulted in the strong suppression of Phytophthora foot or root and stem rot of
      gerbera, cypress and yew-tree.

PMID- 12425034
TI  - Grapefruit extract activity in the control of rose powdery mildew and black spot.
AB  - Efficacy of grapefruit extract (a.i. of Biosept 33 SL) in the control of
      Sphaerotheca pannosa var. rosae and Diplocarpon rosae on roses was investigated
      during 1998-1999. The extract was applied as plant spray in concentrations from
      0.017 to 0.099%. First treatment of rose shrubs was done when visible disease
      symptoms occurred on leaves and spraying was repeated 3 (in plastic tunnel) or 10
      times (in the field) at weekly intervals. In the second experiment roses with
      visible powdery mildew symptoms were sprayed once with grapefruit extract. Leaves
      were sampled one or 7 days after the extract application and germination of
      spores of S. pannosa var. rosae on potato dextrose agar was evaluated. In the
      next experiment roses grown under plastic tunnel were sprayed once with the
      tested preparation. After 24 hours leaves were collected and appearance of fungal
      hyphae and spores of S. pannosa var. rosae was studied in scanning electron
      microscope. In the control of S. pannosa var. rosae grapefruit extract at conc.
      0.066% was as effective as triforine (standard) applied at 0.027%. Reduction of
      concentration resulted in the decreased efficacy of the tested preparation.
      Spores of S. pannosa var. rosae collected one day after grapefruit extract
      application germinated in about 5%. Analyses of spore vitality 6 days letter
      showed that only about 15% of conidia could germinated on PDA agar. In contrary,
      spores from untreated leaves germinated in about 95%. Scanning electrone
      microscope analysis of leaves taken from plants protected with grapefruit extract
      showed that most of hyphae were separated from leaf surface. Almost all hyphae
      and spores were degenerated. In the control of D. rosae the preparation in all
      tested concentrations gave satisfactory results but was less effective than
      triforine.

PMID- 12425035
TI  - Pythium oligandrum in the control of Fusarium rot on some bulbous plants.
AB  - Pythium oligandrum was applied as tulip bulbs or gladiolus corms soak prior or
      after inoculation with formae speciales Fusarium oxysporum. The mycoparasite used
      before inoculation with pathogen suppressed the development of Fusarium rot. This
      effect was not observed, however, when P. oligandrum was used 24 hr after bulb
      inoculation. Soaking of forced tulip bulbs in oospore suspension of P. oligandrum
      may reduce Fusarium rot spread and increase number of flowers, but at conc. 2.5 x
      10(3)-10(4)/cm3 caused inhibition of tulip root growth.

PMID- 12425036
TI  - New host-virus relations between different Solanum species and viruses.
AB  - We have studied the susceptibility or resistance of Solanum capsicastrum Link. et
      Schauer, S. comatum Sendt., S. dulcamara L., S. luteum Mill., S. malacoxylon
      Sendt. and S. nigrum L. to three aphid transmissible viruses [alfalfa mosaic
      alfamovirus (AMV), potato M. carlavirus (PVM) and potato S carlavirus (PVS)]. Out
      of the species, S. capsicastrum, S. comatum, S. dulcamara, S. malacoxylon and S.
      nigrum to AMV, S. capsicastrum and S. malacoxylon to PVM and S. capsicastrum, S.
      luteum and S. nigrum to PVS showed the highest resistance (immunity). Symptoms
      could not be seen on inoculated plants and the virus could be detected by them
      neither by serological nor biological tests. Solanum luteum plants were
      susceptible to AMV. Solanum comatum, S. dulcamara, S. luteum and S. nigrum showed
      susceptibility to PVM. Solanum comatum and S. dulcamara were susceptible to PVS.
      Symptoms (necrotic lesions, mosaic and chlorosis) could be seen after inoculation
      and the absorbance values (DAS-ELISA) exceeded twice that of the healthy control
      samples during the serological tests.

PMID- 12425038
TI  - Potential of induced resistance to control Oidium lycopersici on tomato and
      tobacco.
AB  - Powdery mildew is widespread on greenhouse-cultivated tomato especially in
      Europe. Rhizobacteria, particularly Pseudomonas strains are well known for
      inducing resistance to many diseases on field crops. Plant disease resistance can
      also be induced by treatment with benzothiadiazole (BTH) which specifically
      induces the salicylic acid-dependent defence pathway. We investigated the
      possibility of inducing resistance to Oidium lycopersici on tomato and tobacco by
      treatment with BTH or with resistance-inducing rhizobacteria. Tomato
      (Lycopersicon esculentum) cv. Moneymaker and NahG tomato (a transgenic tomato
      which cannot accumulate salicylic acid (SA)) were planted in soil treated with P.
      aeruginosa KMPCH, a SA-producing mutant of P. aeruginosa 7NSK2, at 10(8) CFU/g.
      Four weeks-old plants were inoculated by exposure to an atmosphere heavily
      infested with O. lycopersici. P. aeruginosa 7NSK2 and KMPCH; and P. fluorescens
      WCS 417 were similarly tested on tobacco cv. Xanthi and Samsun NN. The results
      showed that the rhizobacteria had no effect on the levels of infection of the
      plants by O. lycopersici. There were also no differences between NahG and wild
      type plants. We conclude that the induced resistance pathways activated by
      rhizobacteria do not lead to enhanced resistance of tomato and tobacco to O.
      lycopersici. BTH was tested on tomato by soil application at 0.1 ppm or foliar
      spray with 100 microM solution 4 or 7 days before inoculation (dbi) and tobacco
      was treated by foliar spray with 1, 10 or 100 microM BTH, 4 dbi. While a dose
      dependent suppression of O. lycopersici by BTH was registered on tobacco, tomato
      infection by the powdery mildew was not affected by BTH. This difference
      indicates that BTH probably affects the tobacco-Oidium and the tomato-Oidium
      systems differently. We are currently investigating whether or not this
      difference can be associated with the production of different PR proteins.

PMID- 12425037
TI  - The effectiveness of ecologically acceptable ways of protection of field-grown
      tomato (Lycopersicon lycopersicum (L.) Karsten) from tomato late blight
      (Phytophthora infestans (Mont.) de Bary) in extreme weather conditions.
AB  - During the extremely wet vegetation season in 1999 the efficiency of protection
      of two cultivars of field grown tomato (Lycopersicon lycopersicum (L.) Karsten),
      'Pick Rite' and 'GO 101', against tomato late blight (Phytophthora infestans
      (Mont.) de Bary) using three ecologically acceptable growing techniques and
      agrochemical measures (growing on black plastic mulch with no fungicides used,
      spraying with Dithane M-45 (mancozeb), spraying with Cuprablau-Z (Cu-hydroxide)
      and control) have been studied. It was found out that under such extreme weather
      conditions none of these measures can ensure an adequate protection of tomato.
      The highest yield of healthy fruits (0.30 kg per plant) was obtained after a
      threefold spraying with Dithane M-45 (mancozeb), the highest percentage of non
      infected fruits (38.1%) after a twofold spraying with Cuprablau-Z (Cu-hydroxide).
      The black plastic mulch, used with the intention to reduce the plant contact with
      the potential inoculum in the soil proved to be ineffective.

PMID- 12425039
TI  - Colonisation of soilless growing media for tomato by Trichoderma harzianum.
AB  - An experiment was conducted to evaluate the distribution of T. harzianum in
      soilless media used in greenhouse growing systems for tomatoes. Growing media
      based on rockwool and based on coconut fibre were included. The fungus was
      applied to the roots of the plant by means of a conidial suspension. The upper
      plant parts were removed from the coconut fibre an the rockwool slab after 10 and
      15 weeks respectively. Both the coconut fibre and the rockwool slab were divided
      into fragments with a width of 10 cm. The coconut fibre medium fragments were
      again divided in an upper and a lower part. For every fragment the CFU/g was
      determined by two different methods. In the first method a known volume of
      growing medium was brought into suspension using a blender and diluted.
      Appropriate dilutions were plated on a selective medium. In the second method a
      known volume of growing medium was spread directly upon a selective medium in
      petri dishes. All dishes were incubated at room temperature and colonies were
      counted. Results showed that in the case of the coconut fibre growing medium T.
      harzianum was isolated in every fragment of the substrate. Highest densities were
      measured at the site of inoculation. In the lower part of the fragments less
      CFU/g were counted than in the upper part. In the case of the rockwool growing
      medium, there were several fragments in which no T. harzianum was isolated. The
      dilution technique demonstrated to be most useful in cases of high density. The
      direct spreading-method is best applied when low densities are expected. These
      observations demonstrate that the growing medium based upon coconut fibre is more
      appropriate for colonisation by T. harzianum. However, densities are higher at
      the site of inoculation in both tested growing media.

PMID- 12425041
TI  - Isozyme analysis and soluble mycelial protein pattern in Irania isolates of
      Fusarium oxysporum.

PMID- 12425040
TI  - Effect of seed treatment with organic acids on the control of common bunt
      (Tilletia tritici and T. laevis) in wheat.
AB  - Common bunt caused by Tilletia tritici and T. laevis is an important disease,
      causes considerable losses in wheat yield on a world wild. The disease reduces
      yields, complicates harvesting and lowers the quality of the grain. It occurs
      more frequently and causes greater damage on winter wheat than on spring wheat.
      Grain standards designate wheat that has an unmistakable odor of smut or that
      contains smut balls, portions of balls, or spores of smut in excess of a quantity
      equal to 14 balls of average size in 250 g of wheat as "light smutty". Samples
      containing an excess of 30 balls, or their equivalent, in 250 g of wheat are
      graded as "smutty". Grain in these grades brings lower prices. Using commercial
      acetic acid and lactic acid, the pathogen was successfully controlled, but the
      treatment negatively affected seed germination and seedling vitality. Using
      dilutions of acetic acid and lactic acid, significant control of the pathogen
      also was achieved with acetic acid without causing phytotoxicity. Dilutions of
      lactic acid also gave good control, but showed some phytotoxicity. Using 30-50
      ml/kg of vinegar, which is a natural source of acetic acid, proved to be one of
      the most effective alternatives for control of common bunt on wheat. The
      treatment had no negative effects on seed germination nor on seedling vitality.

PMID- 12425042
TI  - Effect of some compounds on the decay of strawberry fruits caused by Botrytis
      cinerea Pers.
AB  - Field experiments were conducted in the years 1997-2000 to determine the effect
      of various sprayings strawberry plants on the percentage of infected fruits
      caused by Botrytis cinerea Pers. The effect of garlic's extract at concentration
      1%, water solution of microcrystalline chitosan (3% polymer content) at
      concentration 0.2% and iprodione (255 g active form in 1000 cm3 of water) was
      estimated. The experiment was conducted on cultivar Senga-Sengana. During the
      growing season strawberry plants were sprayed three times--at the beginning of
      blooming, during full blooming and at the end of blooming. Ripped fruits were
      stored for 24 hours in a cooling chamber. Then the strawberry fruits were
      weighted and the percentage of infected fruits was estimated. In the first year
      of cultivation there was found no effect of used plant protection on the decay of
      strawberry fruits. Intensification of the disease was very low because of the
      lack of rainfalls and good weather. These conditions did not propitious the
      infection. In the second and in the third year of cultivation the best efficacy
      in control grey mould had iprodione which limited decay of strawberry fruits to
      9% (in the second year) and 11.1% (in the third year). In the second year the
      chitosan water solution had protective effect and the decay of strawberry fruits
      was diminished to 15%. The highest development of infection was in combination
      where garlic extract was used for spraying both in the second 23% and in the
      third year 32.5% as well.

PMID- 12425043
TI  - Dominance relationships of bean pathogens at Lake Balaton.
AB  - Dominance relationships of different bean pathogens were examined during 1999
      2000 in small plot trials at Lake Balaton in Hungary. In 1999 the dominant
      pathogen species were Xanthomonas campestris pv. phaseoli. The main cause of the
      stock decay was due to the infection of Fusarium spp. Bean plants were infected
      also by Alternaria, Colletotrichum, Macrophomina and Sclerotinia, species part
      from viruses. Among of thirty-eight examined bean cultivars and genotypes the
      variety "Diszbab" and the genotype 513 were the most resistant. In 2000
      Macrophomina phaseolina and Fusarium spp. caused epidemics. Most of the observed
      plants died early. The most healthy species and branches were the SC-34-1 and cv.
      Diszbab.

PMID- 12425044
TI  - Effects of nutritional factors on production of tabtoxin, a phytotoxin, by
      Pseudomonas syringae pv. tabaci.
AB  - Pseudomonas syringae pv. tabaci, the causal agent of the wildfire of tobacco,
      produces the phytotoxin tabtoxin. The effects of carbon, nitrogen sources and
      amino acids on growth and tabtoxin production by pv. tabaci, were examined by
      varying the components of a defined basal medium, which contained the following
      nutrients per liter: sucrose (10 g), KNO3 (5 g), MgSO(4).7H2O (0.2 g),
      CaCl(2).2H2O (0.11 g), FeSO(4).7H2O (20 mg), NaH2PO(4).2H2O (0.9 g) and
      H2PO(4).3HO (1 g). Bacterial growth was determined by cell density, and tabtoxin
      production was measured by the E. coli bioassay technique. Both growth and
      quantity of tabtoxin synthesized were significantly affected by carbon source,
      nitrogen source and amino acid supplements. Sorbitol, xylose and sucrose proved
      to be the best carbon sources for tabtoxin production. Specific toxin production
      was very low using glucose as a single carbohydrate source, although bacterial
      growth was well supported by glucose. Amount and type of nitrogen sources (NH4Cl
      or KNO3) affected the growth of pv. tabaci and quantities of tabtoxin produced.
      Nitrate was the best of these two forms of nitrogen for production of tabtoxin.
      Adding threonine to pv. tabaci grown in batch culture decreased the amount of
      tabtoxin production. Similar results were obtained with lysine, whereas, serine
      had no effects on quantities of tabtoxin production. The results of the present
      study were to formulate a medium which allowed for enhanced tabtoxin production
      by Pseudomonas syringae pv. tabaci.

PMID- 12425045
TI  - The physiological development of the chlorotic lesion induced by coronatine.
AB  - Toxins are secondary metabolites produced by several plant pathogenic
      microorganisms. These toxins play a major role in the development of disease
      symptoms. Coronatine, the non specific toxin, was extracted and purified from the
      culture medium of Pseudomonas syringae pv. glycinea. In this study, the effect of
      coronatine on the development of the chlorotic lesion on the Phaseolus vulgaris
      L. leaves, indicates that coronatine induced chlorosis on treated leaves as well
      as or untreated leaves on the same plant. An other effect of this toxin is the
      reduction of amount of both chlorophyll a and b. These results, provide that the
      development of chlorotic lesion is a primarily mode of action of coronatine.

PMID- 12425046
TI  - Pest insect control in organically-produced crops of field vegetables.
AB  - In the UK, the demand for organic vegetable and salad crops is increasing, mainly
      as a result of the requirements of the multiple retailers. However, approximately
      85% of the organic fruit and vegetable produce sold in the UK is imported. A
      major constraint to growing field vegetable crops, and particularly organically
      produced crops, is the reduction in crop yield and quality caused by pest
      insects. This paper will consider the control techniques currently available to
      organic growers and other techniques that may become available in the future.
      Growing plant varieties with complete or even partial resistance to pest insects
      can be an effective way of reducing crop damage. There are already varieties of
      carrot, with resistance to carrot fly, and lettuce, with resistance to certain
      pest aphid species, which are available commercially. Cultural techniques to
      exclude, deter or avoid pest insects are also being used by some organic growers.
      Although isolating new crops from sources of infestation can be a highly
      effective control strategy, many organic growers cannot use it, as the land
      converted for organic production is still limited. Various crop covers can be
      used to prevent pest insects from damaging field crops, but to be effective such
      covers have to be in place before the pests enter the crop. Several researchers
      have tried to develop techniques to prevent pest insects from finding their host
      plants. No technique involving semiochemicals has been sufficiently successful to
      be used in field vegetable production in the UK. Other studies have shown that
      the numbers of pest insects found on crop plants are reduced considerably when
      the crop is allowed to become weedy, is intercropped with another plant species,
      or is undersown with a living mulch. Hence, work is now needed to select
      background plant species that will both reduce pest insect numbers and cause the
      least reduction in yield to the harvested crop plants. There is also a need to
      obtain a better understanding of "companion planting", a practice used frequently
      by organic growers. To date, microbial control is the only biological technique
      that has been used successfully in field vegetable crops in the UK. However, only
      the toxicant produced by one microbial agent, the bacterium Bacillus
      thuringiensis, has so far been registered for use. The use of bacteria, fungi and
      viruses to control pests of field vegetable crops certainly has possibilities.
      However, in many cases there are still problems to be overcome to select
      pathogens that are compatible with, or can still be effective in, the wide
      fluctuations in temperature, humidity and soil moisture that occur under field
      conditions. Attempts are now being made to use entomopathogenic nematodes and
      predatory arthropods to control one major pest insect, the cabbage root fly.
      Techniques developed to improve the timing of application of various crop
      protection procedures in systems of conventional vegetable production apply
      equally well to organic production, despite the choice of control options being
      more limited. In particular, models to forecast the timing of pest insect attacks
      could be used to great effect, to indicate the best times to plant, protect and
      harvest a specific crop to minimise pest insect damage.

PMID- 12425047
TI  - Oviposition preferences of Episyrphus balteatus.
AB  - A crucial aspect of predator oviposition behaviour is host plant choice,
      especially in hoverflies where the newly hatched offspring are unable to move a
      great distance to search for the appropriate prey. Such offspring must generally
      feed on the host plant aphids previously selected by the mother. Some factors
      involved in the selection of the oviposition site of Episyrphus balteatus De Geer
      include aphids associated to chemical stimuli, aphid colony size and host plant
      characteristics. Here we tested the hypothesis that there will not only be a rank
      order hierarchy of preference for aphid prey species reared on the same host
      plant but that a similar hierarchy of different host plant of one aphid species
      could be established. Therefore we compared the number of eggs laid on different
      combinations of host plant and aphid species. Vicia faba L., secondary
      metabolites free, Brassica napus L. and Sinapis alba L., containing low and high
      levels of glucosinolates respectively were used. The latter compounds are well
      known allelochemicals from Brassicaceae having a strong influence on specialist
      and generalist insects from both phytophagous and entomophagous levels. These
      experiments enhance the importance of tritrophic interactions in biological
      control of pests by underlining the host plant influence on aphidophagous
      predators, either directly or through the odours emitted by the phytophagous
      prey.

PMID- 12425048
TI  - Data on the host plant selection of the horseradish flea beetle, Phyllotreta
      armoraciae (Koch, 1803) (Coleoptera, Chrysomelidae, Alticinae).
AB  - Crucifer feeding specialists within the Chrysomelidae family can be found mainly
      in the subfamilies of Chrysomelinae and Alticinae. Nearly all the species of
      Phyllotreta within Alticinae feed on crucifers or related genera of Resedaceae
      and Capparaceae. Oligophagy is a characteristic feature of Phyllotreta species
      but some species are monophagous. Under natural conditions Phyllotreta armoraciae
      (Koch, 1803) is considered as a monophagous species feeding only on horseradish
      (Armoracia lapathifolia Usteri). Ph. armoraciae is in fact not monophagous under
      laboratory conditions. It feeds on several cruciferous plants to the same extent
      as on horseradish. In our investigation we tried to clarify the host plant
      selection of Hungarian populations of Ph. armoraciae. Under laboratory conditions
      no consumption of Capsella bursa-pastoris (L.) Medic., Arabis sp. and Alyssum
      saxatile L. was observed even under stress conditions. Small amount of Brassica
      napus L. and Sinapis alba L. while appreciable amount of Barbarea vulgaris R.
      Br., Brassia nigra (L.) Koch and Alliaria petiolata (M. B.) Cavara et Grande were
      consumed. There was no significant difference in preference for Brassica nigra
      and Armoracia lapathifolia.

PMID- 12425049
TI  - Foliar application of Steinernema feltiae for the control of flower thrips.
AB  - Results of a programme, continued from 2000, of weekly commercial foliar
      applications of entomopathogenic nematodes for the control of western flower
      thrips, are presented. The programme was extended to include two, year-round
      crops of pot chrysanthemums and one crop of year-round Saintpaulias. From January
      to May 2001, the nematodes continued to give good control, particularly by
      reducing numbers of female thrips. In one case, attempts were made to reduce
      rates of nematodes to make the technique more competitive with the costs of
      chemical insecticide programmes, and the technique was also adapted to counter
      the effects on thrips of artificial lighting. Programmes successfully allowed the
      integration of dichlorvos low-volume applications to regulate thrips numbers in
      open flowers, which were never treated with the nematode sprays in order to
      prevent water deposits on the petals.

PMID- 12425050
TI  - Aphid pests of strawberry crops and their parasitoids in France.
AB  - The pest status of aphids on strawberry crops has changed with time. They were
      mainly considered with respect to virus transmission. Now, they are rather
      considered as sap-feeders and honeydew producers. As such, low populations
      regulated by natural enemies can be tolerated and systematic use of insecticides
      avoided. A survey of the species present in the different areas of production has
      been undertaken during 1999 and 2000 in France. During this survey, well known
      species of the strawberry crops have been found, like Chaetosiphon fragaefolii,
      Aphis forbesi or Acyrthosiphon rogersii. Widely polyphagous species like Aphis
      gossypii, Aulacorthum solani, Myzus ascalonicus or Macrosiphum euphorbiae were
      also present quite often. Eventually, aphids of the Rosaceae, not considered
      before as important pests of the strawberries, like Rhodobium porosum, have also
      been found in many different areas. The biology of the different species and
      their natural enemies have to be taken into account with respect to integrated
      control of strawberry pests.

PMID- 12425051
TI  - [Research methods to biologically control Thrips tabaci on leeks: results of a 5
      year study in the north of Calais].

PMID- 12425052
TI  - On-farm development and testing of IPM packages for control of sorghum head-bugs
      in Mali.
AB  - Improved caudatum sorghum cultivars have spread since their introduction in the
      late nineteen-eighties in the Kolokani area, Mali, being cultivated at the turn
      of the millennium by many farmers over hundred villages, under the name
      "Gadiabani". Being compact-panicled, these varieties are prone to damage by the
      panicle-feeding bug Eurystylus oldi. On-farm trials were conducted in 1998 and
      1999 in respectively five and 16 villages of this area, to establish the status
      of castor bean (Ricinus communis) as a source of sorghum infestation by E. oldi,
      and evaluate the management of this alternate host plant, in combination with
      sowing date manipulation and use of host plant resistance, as potential control
      options for this pest. Experimental designs were split-plots with three factors.
      Both years, eight sorghum cultivars were planted in two dates (DOS). The third
      factor studied was vicinity with castor in 1998, and castor management in 1999.
      There were five replicates in 1998, and three in 1999. Head-bug numbers were
      recorded on maturing grains, and head-bug damage was visually rated at grain
      maturity. In 1998, infestation and damage by head-bugs on sorghum panicles in
      trials located close to castor plants were significantly higher than on those
      with no castor in their vicinity. In 1999, castor management either by
      insecticidal treatment or physical removal of flowering castor spikes on plants
      neighboring test plots, immediately before sorghum flowering, significantly
      reduced E. oldi populations on sorghum panicles. In both years, the effect of
      sowing date was not significant on head-bug population, while in 1998, head-bug
      damage scores were significantly higher on DOS1 than on DOS2. In 1998, the
      genotypic effect was significant for both parameters, the hybrid ICSH 89002 being
      the most infested and damaged genotype, while Malisor 84-7 and 94-EPRS-GII-1122
      were respectively the less infested and the less damaged. In 1999, the genotypic
      effect was also significant, local guinea and head-bug resistant controls
      Bibalawili and Malisor 84-7 being the less infested cultivars, compared to ICSH
      89002, ICSV 1063, Gadiabani and ICSV 1079, which suffered severe infestation,
      while 87W810 and 94-EPRS-GII-1122 had an intermediate ranking. These results
      definitely demonstrate the role played by castor as a significant source of
      sorghum infestation by head-bugs, and the prospect for reducing both infestation
      and damage, by management of this alternate host, in conjunction with use of host
      plant resistance and to a lesser extent planting date manipulation, in IPM
      programs.

PMID- 12425053
TI  - Sex-ratio daily evolution in a population of Mononychellus tanajoa Bondar (Acari:
      Tetranychidae) in the laboratory.
AB  - The sex-ratio (number of females/number of males) of offsprings laid by
      fertilized female parents of Mononychellus tanajoa Bondar and its daily evolution
      was studied in the laboratory. The lowest sex-ratio value 0.1 (10.0% female
      offsprings) was obtained on the first day of the oviposition and the highest
      value 13.9 (93.3% female offsprings) on the 16th day of the oviposition period
      which lasted 38.1 +/- 4.9 days (mean +/- standard deviation). From a total number
      of 118.0 +/- 10.9 offsprings, 94.0 +/- 10.5 (on the average 79.7%) were "laid"
      during the first half of the oviposition period. The results also show that from
      a total number of 88.0 +/- 8.3 female offsprings, 74.0 +/- 8.0 (84.1%) were
      "laid" during the first half of the oviposition period whereas from a total
      number of 30.0 +/- 2.7 male offsprings, 20.0 +/- 2.5 (66.7%) were "laid" within
      the same period. The sex-ratio of each fertilized female parent was 3.1 +/- 0.2
      (75.8% +/- 1.0 female offsprings) and the sex-ratio within the mites population
      was 2.9 +/- 0.0 (74.6% +/- 0.1 female offsprings).

PMID- 12425054
TI  - Evolution of aphidophagous ladybird populations in a vegetable crop and
      implications as biological agents.
AB  - Aphidophagous predators such as hoverfly and ladybird beetles are effective
      biological agents to control aphid pests in perennial and annual cultivated
      species. Introduction and conservation of beneficial insects are two ways to
      increase natural control of pests. Whether massive releases of entomophagous
      insects are expensive and time consuming, the preservation of predator natural
      populations can be expected by reducing and by adapting chemical treatments in
      crop fields. Vegetable cultivated areas increased in Belgium for several years,
      mainly Fabaceae species such as peas and beans. In this work, the evolution of
      ladybird species population was assessed from May to June in broad bean fields
      (Vicia faba L.) between Waremme and Hannut, in Hesbaye. Weekly, the aphid and
      aphidophagous beetle populations were collected from yellow traps and determined
      on plants by visual observations. Even if five ladybird species were identified,
      three of them represented more than 95% of the collected insects (Coccinella
      septempunctata L., Propylea quatuor-decimpunctata L. and Psyllobora
      vingintiduopunctata L.). Evolution of coccinellid populations during the
      cultivation season was discussed in relation to the presence of potential aphid
      preys and the agrochemical treatments which were applied. Integrated pest
      management in vegetable fields constitute a reliable way to increase the quality
      level of fresh vegetables in terms of pesticide residue limitations.

PMID- 12425055
TI  - Distribution patterns of MCA-coated corn grit formulation after aerial
      application to maize fields.
AB  - Field studies in corn (Zea mays L.) were conducted during the summer of 2000 to
      evaluate distribution patterns of corn grits treated with MCA (4-methoxy
      cinnamaldehyde). Aerial application was used in a 8 ha corn field situated in
      south-east Hungary. Corn granules ('grits') of 10-12 mesh size were applied on
      July 18th, August 1st and August 28th at rates of 18.3, 21.9 and 20.2 kg grits/ha
      and were covered with 80, 119 and 120 g MCA/ha. Experiments were evaluated by
      collecting grits in 30-cm plastic saucers and by counting grits accumulated on
      leaves and in leaf axils on corn plants. Analysis revealed a statistical
      difference between MCA treated and untreated grit application rates only at the
      first application date. Variation in grit number per unit area and frequency of
      corn granule number per plant showed some transient technical application
      problems. However, altogether, grit distribution patterns indicate that aerial
      application is a viable tool for disseminating MCA in corn fields. With it,
      orientation disruption of the introduced maize pest Diabrotica virgifera
      virgifera LeConte (Coleoptera: Chrysomelidae) recently introduced into SE Europe
      will come within reach.

PMID- 12425056
TI  - Diseases and pests structure and dynamics in no-tillage system conditions,
      compared to the conventional technology.
AB  - The investigations that make up the subject of this paper have proposed to study
      the structure and the dynamics of the diseases and the pests of the wheat and
      corn cultures in the conditions of the "no tillage" culture system comparatively
      with the classical system. The quantification of the results of the "no tillage"
      culture system of the incidence of the diseases and pests requires a long
      standing investigation with the following objectives: the evidence and the
      establishing of the complex of the pest and disease which form the structure of
      the agrobiocenoses, the estimation of the numerical density, specifying the key
      species in the agro ecosystem in order to combat it integrally; the elaboration
      of the orientative systems of protection integrated on cultures, based on the
      technological elements specific to the "no tillage" culture system; the gradual
      promotion of the "no tillage" culture system in the areas and in the cultures
      that correspond to this system.

PMID- 12425057
TI  - Biorational agents--mechanism and importance in IPM and IRM programs for
      controlling agricultural pests.
AB  - Among the new approaches for controlling agricultural pests is the development of
      novel compounds affecting specific processes in insects such as chitin synthesis
      inhibitors, juvenile hormone mimics and ecdysone agonists. In addition, efforts
      have been made to develop compounds acting selectively on groups of insects by
      inhibiting or enhancing biochemical sites such as respiration (diafenthiuron),
      the nicotinyl acetylcholine receptors (imidacloprid and acetamiprid), the GABA
      receptors (avermectins), the salivary glands of sucking pests (pymetrozine) and
      others. Among the most recent novel insecticides with selective properties are
      novaluron, thiamethoxam, emamectin and spinosad. Novaluron (Rimon) is a novel
      chitin synthesis inhibitor that acts by both ingestion and contact. It is a
      powerful suppressor of lepidopteran larvae such as Spodoptera littoralis and
      Helicoverpa armigera (by ingestion) and of whiteflies such as Bemisia tabaci and
      Trialeurodes vaporariorum (by contact). Thiamethoxam (Actarn), a novel
      neonicotinoid acts specifically on aphids and whiteflies. Emamectin (Proclaim),
      an avermectin derivative acts on GABA receptor affecting diversity of insects
      such as mites, lepidopterans and thrips. Spinosad (Tracer) seems to act on both
      acetylcholine and GABA receptors affecting diversity of insect species and is
      considered an important agent for controlling the western flower thrips.

PMID- 12425058
TI  - Spinosad, a new tool for insect control in vegetables cultivated in greenhouses.
AB  - Spinosad is a biological insecticide derived as a fermentation product from the
      soil actinomycete Saccharopolyspora spinosa. The compound was tested for its
      possible use in northwestern Europe in vegetables cultivated in greenhouses.
      Spinosad is an insect control agent that has activity against a wide range of
      insect pests including caterpillars, leafminers and thrips. Because of its
      selectivity on a large number of beneficials used in greenhouses, spinosad is an
      interesting tool for insect control. A SC formulated product, containing 480 g
      a.i. litre-1, was tested in 1998, 1999 and 2000 in a range of trials at the
      research stations of Naaldwijk/Netherlands, and Gembloux/Belgium. This paper
      reviews and discusses the efficacy results on Trialeurodes vaporarium,
      Frankliniella occidentalis, Chrysodeixis Chalcites, Liriomyza Bryoniae. According
      the target insect rates from 4.8 till 36 g a.i./hl were tested. Consistent
      performance was recorded on F. occidentalis at rates of 9.6 g a.i./hl or above.
      Interesting efficacy results were recorded on the other above-mentioned insects.

PMID- 12425059
TI  - The development of spinosad for the control of Frankliniella occidentalis in
      protected ornamentals.
AB  - Fifteen trials were undertaken to determine the effectiveness of spinosad for the
      control of Frankliniella occidentalis on a range of glasshouse ornamentals. A
      range of dose rates were tested from 6-15 g as hl-1. A high level of control (>
      90%) was achieved at most assessments of both nymphs and adults with a
      comparatively flat dose response recorded. Rates of 9 g as hl-1 and above
      provided improved consistency of control compared with the lower rate of 6 g as
      hl-1 across trials. No adverse effect was recorded from eight selectivity trials
      completed on a range of pot plants and cut flowers at rates up to 72 g as hl-1
      with the exception of Saintpaulia ionantha. On this highly sensitive species some
      spotting of the flowers occurred following application rates of spinosad applied
      at 24 g as hl-1 and above. It is considered that the high level of activity of
      spinosad combined with its excellent plant safety profile will be of significant
      benefit to growers for the control of a major insect pest of glasshouse
      ornamentals.

PMID- 12425060
TI  - Cabbage root fly control using non-organophosphorus insecticides.
AB  - The need to find non-organophosphorus insecticides to control the cabbage root
      fly has never been so urgent. Of the six non-OP insecticides tested, fipronil was
      the most effective but spinosad, diflubenzuron and cyromazine also showed
      considerable promise. As expected, the transplant drenches (34 mg active
      ingredient (a.i./plant) were more effective than the module drenches (5 mg
      a.i./plant), which in turn were more effective than the film-coated seed
      treatments (0.001 mg a.i./plant), simply because of the different amounts of
      insecticide applied per plant. One remaining major problem is that, even if
      effective non-OP insecticides can be found, the manufacturers may still not
      support their insecticides being applied to minor crops such as field vegetables.

PMID- 12425061
TI  - Effects of insecticide treatments on insect density and diversity in vegetable
      open fields.
AB  - Vegetable open field areas increased for 15 years in Wallonia, mainly in Hesbaye.
      To be in accordance with quality standards, especially in terms of agro-chimical
      residues (R.M.L.), biological pest control was developed and allowed to reduce
      the insecticide use, leading to have safer fresh products. Among cultivated
      species in Wallonia, leguminous crops represent more than 85% of the vegetable
      production. To assess the impact of insecticide treatment on both pests (mainly
      aphids) and beneficial insects (predators and parasitoids), broad bean (Vicia
      faba L.) fields were investigated during all the production duration. Twelve
      fields between Waremme and Hannut were visited weakly from May to July. In each
      field, control untreated and treated plots were investigated. Insects were caught
      using yellow traps and determined until the family level. Approximately 90.000
      insects belonging to 59 major families (99% of captures) and 64 minor families
      were identified. These results showed that biodiversity in terms of family
      numbers was significantly higher in unsprayed plots. In addition, biodiversity
      and biomass (insect density) increased gradually during the season. Evaluation of
      pest and beneficial diversity and density was discussed in relation to aphicid
      (lambda-cyhalothrin, pirimicarb) treatments and the development of I.P.M. program
      in vegetable crops.

PMID- 12425062
TI  - Effectiveness of IGRS (CGA-184699) and (CGA-259205) on the respiratory metabolism
      of the red palm weevil, Rhynchophorus ferrugineus (Coleoptera: Curculionidae).
AB  - Prepupae of Rhynchophorus ferrugineus were topically applied with one of three
      dose-levels (1.00, 0.10 or 0.01 microgram/insect) of lufenuron (CGA-184699) or
      diofenolan (CGA-259205). The daily O2 consumption and CO2-output were determined
      and the respiratory quotient (RQ) was calculated. Lufenuron prohibited the pupae
      to consume O2, regardless of their age. Considering the CO2 release, this IGR
      exerted an inhibitory action on pupae increasingly correlated with the increasing
      dose-level. Volumes of consumed O2 reversely correlated with the dose value of
      diofenolan. Also, CO2 output was suffered an inhibitory effect of diofenolan
      which was consecutively related to the dose value. An U-shaped pattern of daily
      respiration was not, unfortunately, attained, irrespective of the IGR or its
      dose. In addition, RQ mean values were less than unity but exceeded 0.7.

PMID- 12425063
TI  - First steps to improve cotton crop management in Thailand.
AB  - Thai cotton growers yearly face serious pest problems consisting of heavy
      infestation associated with resistance to pesticides leading to expensive and
      harmful pest control practices. Thanks to a multi discipline research work
      carried out from 1991 to 1996, a decision-oriented model for cotton crop
      management was developed and compared to farmers' practices during the 1988
      cotton growing season 1998 in Klang Hat district, Thailand. This model, based on
      plant monitoring, involved a new cotton cultivar (DORA 11 as a replacement for
      Sri Samrong 60), seed treatment with imidacloprid (at 3.5 g of a.i./kg of seeds),
      a threshold-based spray of mepiquat chloride, a cotton growth regulator (Pix at
      1.5 l/ha) and a set of rules to selectively control with chemical and biological
      insecticides the major pests the American bollworm (Helicoverpa armigera Hubner)
      and the cotton leafhopper (Amrasca biguttula biguttula Ishida). This package was
      more friendly towards environment than farmers' practices since seed treatment
      does not harm beneficials at the beginning of cotton growing season while 1 and 5
      sprays were saved against respectively the American bollworm and sucking pests
      and more than 50% of the sprays directed against American bollworms involved
      biological insecticides (Bacillus thuringiensis toxins potentialized by a low
      dosage of endosulfan). Threshold-based sprays against the main pests, the use of
      a cotton growth regulator, earliness of cotton cultivar and seed treatment were
      accountable for savings in pesticide sprays. Involving a biological insecticide
      and endosulfan at the beginning of cotton growing season and using the same
      quantity of active ingredient at each spray during the cotton growing season also
      improved the management of pyrethroid resistance in American bollworm populations
      was also. There was no significant difference between yields inside farmers'
      fields and innovation plots. However, thanks to cheaper pest control practices
      economic results were better. Lastly few improvements of this package are
      proposed.

PMID- 12425064
TI  - RH-0345 restored partly the effects induced by KK-42 on reproductive events in
      mealworms.
AB  - In the mealworm, Tenebrio molitor L., KK-42, an imidazole derivative, was found
      to reduce ovarian ecdysteroid production, while RH-0345, a benzoylhydrazine
      analogue, has been reported to affect growth and development of mealworm ovaries
      in a manner similar to 20-hydroxyecdysone. In order to determine whether the
      reduction of reproduction events is dependent on inhibition of ecdysteroid
      production by ovaries, RH-0345 (10 micrograms/insect) was applied before or after
      topical application of KK-42 (10 micrograms/insect) on newly emerged adult
      females. KK-42 applied alone increased significantly the pre-oviposition period
      compared to controls. It also significantly delayed egg-laying compared to
      combined treatments using KK-42 before or after RH-0345. KK-42 applied alone or
      with and before RH-0345, was found to reduce significantly the duration of
      oviposition period. Moreover, there was a significant difference in the duration
      of oviposition period between the two combined treatments. The fecundity was
      significantly reduced in all treated series compared to controls. In addition,
      the fecundity recorded in treated series by RH-0345 alone or before KK-42 was
      significantly higher than in KK-42 treated series. Lastly, the viability of eggs
      laid was significantly reduced in all treated series compared to controls.
      Moreover, the combined treatment pronounced the reduction in egg viability. Free
      ecdysteroids (ecdysone and 20-hydroxyecdysone) in eggs of control and RH-0345
      treated females were analyzed by an enzymo-immunoassay using two specific
      antibodies.

PMID- 12425065
TI  - Comparative action of RH-0345 and pyriproxyfen on molting hormone production and
      protein analysis in mealworm pupae.
AB  - RH-0345 (halofenozide) was found to mimic the action of 20-hydroxyecdysone while
      pyriproxyfen was presented as a juvenile hormone analogue. In this study, RH-0345
      (5, 10 micrograms/pupa) and pyriproxyfen (0.10 and 0.20 microgram/pupa), applied
      topically on newly ecdysed pupae of Tenebrio molitor, were investigated on
      ecdysteroid titers and hemolymph protein concentrations. During normal pupal
      development, the ecdysteroid titer measured using an enzyme immunoassay showed a
      single peak at day 3. The two compounds did not shifted the moment of the pupal
      ecdysteroid peak. However, RH-0345 at the highest dose (10 micrograms/pupa)
      increased the ecdysteroid titres recorded from the second day after topical
      application while pyriproxyfen decreased this hormonal production. In a second
      series of experiments, the compounds were evaluated on the protein concentrations
      in the hemolymph. In control pupae, change in protein concentrations showed two
      peaks. At a 5 micrograms dose, RH-0345 was found to reduce significantly the
      value of the first peak and at the highest dose, the first peak was not observed
      and the values recorded following treatment were significantly lower than in
      controls. Changes in protein concentrations showed that pyriproxyfen suppressed
      the second peak and the values recorded were either significantly increased at
      day 2 and 3, either reduced from day 4.

PMID- 12425066
TI  - Evaluation of vegetal extracts as biological herbi- and pesticides for their use
      in Cuban agriculture.
AB  - The idea of an interuniversity project between the Universidad Central de Las
      Villas, Cuba and the University of Ghent, Belgium was conceived in order to
      improve the quality of the Cuban agriculture and to stimulate its independence
      from foreign chemical farm inputs, starting with an applied ethnobotanical
      investigation as basis for the development of sustainable agricultural practices.
      The project consists of three parts. The first, ethnobotanical part, subtends the
      two subsequent stages, i.e. the phytochemical and pharmacological stages. After
      ethnobotanical inventarization of plants with a possible phytotoxic or pesticide
      effect, these will be collected and taxonomically defined. Fresh vegetal material
      will be dried and ground, and this first crude extract (polar or apolar) will be
      tested for its activity in in vitro biological tests. When results are positive
      (presence of activity), this crude extract will be tested in vivo, which could
      lead to immediate application in agriculture (short-term strategy). The long-term
      strategy will lead to the identification of chemical substances, responsible for
      the activity of the crude extract. As highly sophisticated apparatus is needed
      for this last step (i.e. identification of chemical compounds), this will be
      performed by the Department of Organic Chemistry, Faculty of Agricultural and
      Applied Biological Sciences of the University of Ghent. The project has started
      in September 2000. Apart from all the (complicated) administrative steps to be
      undertaken for its successful execution, the ethnobotanical and phytochemical
      parts have already started. Ethnobotanical data were gathered in view of
      recollection of "traditional botanical knowledge", considering three main
      approaches: the use of plants in medicine, in Cuban religion (the famous
      "santeria") and the use of allelopathic plants in agriculture. Use of medicinal
      and religious plants is ubiquitous in Cuba. The concept of allelopathy, however,
      is much less known and applied. At this moment, and after preliminary screening
      and gathering of field data, in vitro germination tests are running, trying out
      extracts of tobacco (Nicotiana tabacum), banana (Musa spp.), sunflower
      (Helianthus annuus), Simarouba glauca and S. laevis (syn. Quassia, fam.
      Simaroubaceae).

PMID- 12425067
TI  - Effectiveness of different emulsifiers for neem oil against the western flower
      thrips (Thysanoptera, Thripidae) and the warehouse moth (Lepidoptera, Pyralidae).
AB  - The neem tree produces highly specified acting insecticides mainly in its seeds.
      By pressurizing or extracting the seeds an insecticide oil can be manufactured.
      For successful application emulsifiers are needed to render the oil soluble in
      water. The heavy oil has to be stable in emulsion, but on the other hand the
      surfactant should not reduce the ecological property of the neem oil. The
      emulsifiers Lutensol TO10, Emulan ELP, Rimulgan and Tween 80 and for comparison
      the formulation NeemAzal-T/S were tested in their emulsion stability, as well as
      in their insecticidal effects towards two different insect pests: The western
      flower thrips Frankliniella occidentalis and the ware house moth Ephestia
      elutella. The emulsifiers were applied purely, and in different contents mixed in
      neem oil. Data showed significant differences of mortality and development on the
      tested pests. Lutensol TO10 and Emulan ELP caused spontaneous mortality on the
      western flower thrips and an additive efficacy when mixed with neem oil. Rimulgan
      led to mortality of the larvae of the warehouse moth. NeemAzal showed in both
      bioassays the highest efficacy of 95% mortality.

PMID- 12425068
TI  - Protection of stored maize against Sitophilus zeamais (Motsch.) by use of
      essential oils of spices from Cameroon.
AB  - In storage, maize as other cereals is currently attacked by insects. The main
      specie present in Cameroon is Sitophilus zeamais (Coleop. Curculionidae). The
      popular way to prevent its damages is the use of synthetic insecticides. These
      chemicals extend their activities to non target animals. They are potentially
      dangerous for consumers and are implicated in the pollution of the environment.
      The development of products killing pests which are consumer-friendly is to be
      improved. In this respect, the use of essential oils from spices and aromatic
      plants could help. Six essential oils were tested, 3 are causes of high insect
      mortality. Xylopia aethiopica Dunal (Anonaceae) killed 97% of adults weevils and
      Ocimum gratissimum, (L.) (Lamiaceae) 74% after 4 days after ingestion. Piper
      nigrum (L.) (Piperaceae) killing more than 96% of weevil 48 hours after the
      contact. The potential of these non toxic products to protect stored maize
      against attacks of S. zeamais is hereby appraised.

PMID- 12425069
TI  - [The effect of food containing Cestrum paquii (Solanaceae) extract on various
      damaging Lepidoptera].
AB  - The repulsive activity of Cestrum parquii on the feeding behaviour of Pieris
      brassicae L. and Spodoptera littoralis Boisduval was studied. Antifeedant effect
      was observed at regular intervals during a week. Meal uptake was stopped after
      the first day, showing a strongly antifeedant effect of C. parquii extract on
      these two species. The impact of C. parquii with different concentrations of dry
      extract (2, 4, 8, 16, 32%) delayed the larval growth of Spodoptera littoralis
      Boisduval compared to untreated insects. Abnormal metamorphosis was observed with
      concentrations of 8 and 16% leading to death and abnormal morphogenesis. The
      antifeedant activity of C. parquii was also observed in S. littoralis and
      measured by the evolution of food uptake and the weight of larva. Effect seemed
      to be proportional to extract concentration in the diet. High concentration (32%)
      stopped growth in the earlier instar.

PMID- 12425070
TI  - Respiratory metabolic responsiveness during the pupal stage of the red palm
      weevil, Rhynchophorus ferrugineus (Coleoptera: Curculionidae) to certain plant
      extracts.
AB  - The prepupae of Rhynchophorus ferrugineous were topically applied with one of
      three dose-levels (0.1, 0.005 or 0.001 microgram/insect) of Jojoba oil (Joj) or
      azadirachtin (Azt). The daily O2 consumption and CO2 respiratory output were
      determined and the respiratory quotient (RQ) was calculated. After Joj
      treatments, O2 consumption of early- and late pupae increased as the dose-level
      was decreased. The respiration curve did not assume an U-shaped pattern as common
      in the pupal stage of many insect species. Also, an inhibitory action of Azt on
      the pupal respiration has been clearly exhibited. A similar result of the
      respiration curve was observed by Azt. All dose levels of Joj, but only the
      higher two ones of Azt, suppressed the CO2 release. Both botanicals inhibited the
      RQ during the pupal stage. However, all RQ mean values of treated or control
      pupae were < 1.0 and > 0.7.

PMID- 12425071
TI  - Insecticidal activity of selected actinomycete strains against the Egyptian
      cotton leaf worm Spodoptera littoralis (Lepidoptera: Noctuidae).
AB  - Actinomycete strains isolated from soil samples of Saudi Arabia and Egypt were
      used in the present study to investigate the biological activity of their
      secondary metabolites on the cotton leaf worm Spodoptera littoralis. Secondary
      metabolites of 41 strains were given to the newly molted last instar larvae
      through the food plant (Castor leaves). Many actinomycete strains (58% of all)
      caused larval mortality ranging from 10-60%. Treatments with strains no. 7, 36,
      41 resulted in significant prolongation of larval life (10.0 +/- 1.26, 11.5 +/-
      0.7 and 10.6 +/- 1.5 days Vs 9.2 +/- 0.4 of controls). Pupation was affected by
      the actinomycete treatments (60.1% of all). Success of pupation ranged only from
      20 to 80%, depending on the efficiency of the tested secondary metabolites. In
      contrast, the pupal duration had not been significantly affected but 19.5% of
      actinomycete strains halted the pupation, because different percentages of pupal
      deformities were counted (100% pupal deformation after treatment with secondary
      metabolites of actinomycete strains no. 36). In addition, considerable lethal
      effect of some actinomycetes were observed on pupae (60, 42.9, 40, 50 and 66.6%
      pupal mortalities caused by secondary metabolites of strains: 2, 9, 16, 18 and
      26, respectively). Secondary metabolites of 34.1% of all actinomycete strains
      blocked the adult emergence. Depending on the available data, Streptomyces and
      Streptoverticillum were found the most potent actinomycetes affecting the
      biological and physiological criteria of the present insect species.

PMID- 12425072
TI  - A comparison of recommended and reduced insecticide regimes in alfalfa.
AB  - The objective of this study was to evaluate the effects of the recommended rates
      of insecticides applied at two different population levels of the alfalfa weevil,
      Hypera variabilis Hbst. (Coleoptera: Curculionidae) and the reduced levels of
      insecticides on alfalfa weevil, predators and yield in 1998 and 1999. More
      specific objective was to search for options to reduce insecticide usage while
      implementing an effective pest control, thereby developing more economically and
      environmentally sound alfalfa production systems. The treatments used included:
      i) recommended rate insecticide (malathion) at population level of 5
      weevils/sweep, ii) recommended rate at population level of 10 weevils/sweep, iii)
      50% of recommended rate at population level of 10 weevils/sweep, iv) stripe spray
      of 50% rate at population level of 10 weevils/sweep, where insecticides were
      applied only on 0.5 m stripes in plots while the next 0.5 m stripes were not
      treated and v) control. The results indicated that the recommended rate
      insecticide application at 5 weevils/sweep level provided the highest reduction
      in the weevil densities in both years. No significant differences occurred among
      the weevil densities in the plots received the recommended rate, the 50% rate and
      the stripe spray insecticide treatments at 10 weevils/sweep level. Predators were
      in general more abundant in the insecticide treated plots compared to the
      control. The insecticide applications, except the stripe spray in 1999, led to
      increases in yields.

PMID- 12425073
TI  - Effects of neem-based and chemical insecticides on some arthropods in alfalfa.
AB  - In this study, we tested the effects of two different doses of neem
      (azadirachtin) on the alfalfa weevil, Hypera variabilis Hbst. (Coleoptera:
      Curculionidae), aphids and predators (Coccinellids, anthocorids, chrysopids and
      spiders) and compared the effects with those of a broad spectrum insecticide
      (malathion) in a controlled experiment in 1998 and 1999. Malathion treatments
      reduced alfalfa weevil densities significantly (p < 0.01) by 77.9 and 87.4% in
      1998 and 1999, respectively. Alfalfa weevil numbers in the low dose neem-treated
      plots were lower by 45.2% in 1998 and 50.2% in 1999. There were 45.3% fewer
      alfalfa weevils in the high dose neem-treated plots in 1999. In 1998, aphid
      numbers were reduced by 11.1, 25.3 and 41% in the low dose neem-treated plots,
      the malathion-treated plots and the high dose neem-treated plots, respectively.
      Aphids were more abundant in the malathion-treated plots, whereas they were fewer
      in the neem-treated plots compared to the control in 1999. The treatments did not
      have any significant effects on the total numbers of predators.

PMID- 12425074
TI  - Toxicity of boric acid to Blattella germanica (Dictyoptera: Blattellidae) and
      analysis of residues in several organs.
AB  - Pestiferous cockroach species are associated closely with humans and are
      important from medical and public health points of view. Conventional
      insecticides have been used widely to control cockroaches which have developed
      resistance to these compounds. Thus, interest has again centered on lesser-used
      compounds such as boric acid. Boric acid has been used as an insecticide for many
      years, especially against cockroach. Its mode of action on insects has not been
      satisfactorily established. In Algeria, Blattella germanica (Dictyoptera:
      Blattellidae) is a serious pest in the urban environment and their infestation
      were controlled for many years by organophosphate, carbamate or pyrethroid
      insecticides. In order to obtain more information on the mode of action of boric
      acid, we first evaluated the oral toxicity of boric acid on B. germanica adults.
      Then, the compound was determined in several organs by an colorimetric method.
      This insecticide was incorporated into the diet and orally administered at
      different concentrations ranging from 1 to 40% (w/w) to newly emerged adults.
      Mortality was recorded at different times during treatment (24, 48, 72 and 144
      h). Treatment resulted in a dose-dependent mortality since the LD50 (%) recorded
      are 85 at 24 h, 67 at 48 h, 39 at 72 h and 8 at 144 h, respectively. Then the
      quantity of boric acid accumulated in several organs (hemolymph, gut, ovaries,
      testicles and fat body) was determined as function the duration of treatment (1
      to 5 days) for two doses (LD50 and LD90). Results revealed that bioaccumulation
      of residues in these organs increased as function the duration of treatment. In
      addition, relatively important amounts of residues, are detected in fat body.

PMID- 12425075
TI  - The population dynamics of Fiorinia fioriniae (Targioni) (Homoptera: Diaspididae)
      and factors affecting its seasonal abundance in Egypt.
AB  - Fiorinia fioriniae (Targioni) was observed attacking Callistemon lanceolatus at
      the Experimental Farm of the Agricultural Research Station and Ruscus hypoglossum
      at Antoniades park in Alexandria Governorate; Egypt. The infestation rate on
      Ruscus hypoglossum, reached its maximum (98.0%) during autumn months, while the
      minimum rate 68.3%, was recorded during summer months. The fluctuating population
      density of F. fioriniae showed three distinct peaks. The first peak of 731.0
      individuals/10 branches was recorded in October 1998, the second (734.1) in
      December 1998, and the third, (506.9) in April 1999. The highest number of
      counted insects (1991.1/plant) was observed during the autumn season, followed by
      winter (1467.9), spring (978.2) seasons and the least number (271.6/plant) was
      recorded in summer. On the contrary, the highest rate of infestation by the
      immature stages was recorded during the winter season, followed by spring, summer
      and autumn seasons (42.8, 29, 24.6 and 21.9%) of the total counted insects,
      respectively. The scale insect has been parasitized with the aphelinid species
      Encarsia citrina (Aphelinidae) with a maximum rate of 28.1 of the total count
      during August. The statistical analysis was performed for determining the
      relationship between the prevailing weather factors of daily mean temperature,
      daily relative humidity, wind speed and day-light in one hand and the population
      activity of F. fioriniae on R. hypoglossum plants on the other hand.

PMID- 12425076
TI  - Identification and analysis of the main factors governing Liriomyza leafminers
      (Diptera: Agromyzidae) on protected crops, in the region of Kebily (Tunisia).

PMID- 12425077
TI  - The bionomics of the scale insect Eriococcus araucariae (Muskell) (Homoptera:
      Eriococcidae) on Araucaria excelsa in Egypt.
AB  - The eriococcid species, Eriococcus araucariae (Muskell) is considered as an
      economic pest of Araucaria excelsa at Montazah garden, in Alexandria Governorate,
      Egypt. This study was carried out from June, 1998 till May, 1999. The obtained
      data revealed that the numbers of this insect were relatively low in autumn and
      winter months, then increased from the beginning of May to a total number/tree
      72.0 +/- 1.60; continued its increase to reach 200.3 +/- 36.9/tree from the 2nd
      half of May and during June, July and August, with the highest number of
      inspected individuals (641.3 +/- 76.8/tree) in the 1st half of July. Thereafter,
      population began to decrease again from the beginning of September up to the end
      of April, decreased numbers 51.3 +/- 2.5/tree in the 1st half of September and
      (1.3 +/- 0.1/tree) in the 2nd half of October. Similarly, the occurrence of both
      immature stages and adults was also month-dependant all the year round. Adult
      males appeared three times in June, January and late March. There was a positive
      and significant relationship between the total population of E. araucariae and
      the daily mean temperature, wind speed and day light. This relation was
      negatively significant with the relative humidity.

PMID- 12425078
TI  - Ecological studies on the snow scale insect, Lineaspis striata (Newstead)
      (Homoptera: Diaspididae) on Thuja orientalis in Egypt.
AB  - The snow scale insect, Lineaspis striata (Newstead) was recorded as an important
      insect pest of Thuja orientalis in Alexandria Governorate, Egypt. The present
      study revealed that the total individuals were in high numbers, (143.7 +/- 43;
      141.8 +/- 20.7 and 149.0 +/- 48.5) during May, June and January, respectively.
      The fluctuating numbers of the immature stages have two peaks during June and
      November (6.9 +/- 0.7) and (20.5 +/- 5.0), respectively. The numbers of adult
      males reached the maximum (73.9 +/- 7.5) in October, while the females reached
      the maximum (88.7 +/- 2.2) in January. The insect has two annual generations. It
      is usually parasitized with Encarsia citrina (Aphelinidae), with maximum
      parasitization rate of 17.8 +/- 2.8 during August.

PMID- 12425079
TI  - Preliminary studies on insecticidal activities of actinomycete strains propagated
      on solid and broth media using Musca domestica (Diptera: Muscidae).
AB  - Forty-one actinomycete soil isolates were propagated on solid media and subjected
      to a screening program for their insecticidal activities. These strains were
      studied to evaluate their efficiency as biocontrol agents against third larval
      instar of the house fly Musca domestica. Two groups of larvae were fed on either
      artificial media with the organisms studied (group I), or on artificial media
      inoculated with the secondary metabolites (group II). Among the strains selected
      for biological activity screening 15 strains of group I affected significantly
      the larval duration of the examined insects, compared to 18 strains of group II.
      This increase ranged from 7.2 +/- 0.5 to 11.1 +/- 4.2 for group I and from 7.1 +/
      0.3 to 17.5 +/- 4.81 for group II compared to 7.0 +/- 0.5 of controls. The
      lethal effects of some strains were recorded when the strain no 27 caused the
      highest mortality percentage (80%) in group I, while 55% mortality was recorded
      for group II using the secondary metabolites (broth media) of strain 20. In
      addition, many strains affected the pupal and adult stages expressing latent
      effects of their strains. A slight reduction in larval duration was recorded for
      strain 22. Streptomyces and Streptoverticillium were recorded as the most
      effective genera.

PMID- 12425080
TI  - Survey of scale insects of ornamental plants in Alexandria Governorate, Egypt.
AB  - This investigation covers a survey of the scale insects associating with some
      ornamental plants at three chosen public gardens as well as at the experimental
      farm of the Agricultural Research Station in Alexandria Governorate, Egypt. A
      total of nineteen scale insect species belonging to sixteen genera related to
      four families of the super-family Coccoidea were found infesting eighteen
      ornamental plants during the period from April, 1998 up to March, 1999. These
      species are: Family: Asterolecaniidae--Represented by one species only The fig
      scale Russelaspis pustulans; (Cockerell) = (Asterolecanium pustulans Cock).
      Family: Coccidae--Represented by the seven species Florida wax scale. Ceroplastes
      floridensis Comstock, Green shield scale. Chloropulvinaria psidii (Maskell), Long
      brown scale. Caccus elongatus (Douglas), Brown soft scale Coccus hesperidum
      (Linn.), Tessellated scale. Eucalymnatus tessellatus (Signoret), Hemispherical
      scale. Saissetia coffeae (Walker), and Olive soft scale. Saissetia oleae
      (Olivier) Family: Diaspididae--Represented by the ten species: Oleander scale.
      Aspidiotus hederae (Vallot), Minute cypress scale. Carulaspis minima (Targioni
      Tozzetti), Dictyosprmum scale Chrysomphalus dictyospermi (Morgan), Palm fiorinia
      scale. Fiorinia fioriniae (Targioni), Latania scale Hemiberlisia lataniae
      (Signoret), Fig scale. Lepidosaphes ficus (Signoret), Snow scale. Lineaspis
      striata (Newstead), Masked scale. Mycetaspis personata (Comstock), Olive scale.
      Parlatoria oleae (Colvee), and White peach scale Pseudaulacaspis pentagona
      (Targioni-Tozzetti), Family: Eriococcidae--Represented by one species only
      Eriococcus araucariae (Maskell). During the same study, many species of natural
      enemies (nine parasitoids and eight predators), were also noticed to be
      associated with the aforementioned scale insects.

PMID- 12425081
TI  - Survey of insect and non-insect fauna associated with Acacia species in different
      localities in Egypt.
AB  - This study was conducted throughout the period from May, 1997 up to March 1999 to
      survey the associated insect and non-insect fauna with Acacia species at some
      localities in Alexandria and Matrouh Governorates, Egypt. The list of identified
      species associated with Acacia at different localities revealed that there were
      many species representing 34 families and relating to 11 insect orders. These
      collected insects could be grouped into five categories according to their
      feeding habits as destructive insects, true insect pollinators, saprophytic
      insects, parasitoids and predators and visitors. Regarding the non-insect fauna,
      three land snails, pseudoscorpion species and earthworms were recorded associated
      with Acacia trees and litters under the trees.

PMID- 12425082
TI  - Analysis of nematode-responsive promoters in sugar beet hairy roots.
AB  - One of the strategies to make crops resistant to the beet cyst nematode
      Heterodera schachtii is the destruction of the feeding site or syncytium. This
      can be achieved by local expression of the cytotoxic barnase gene under control
      of a nematode-inducible plant promoter that is active in the syncytium.
      Expression of barnase outside the feeding site has to be neutralized by its
      inhibitor barstar driven from a constitutive promoter that is downregulated in
      the syncytium. Several promoters that are upregulated in feeding structures were
      identified using the promoter tagging strategy in Arabidopsis thaliana (Barthels
      et al., 1997) or by differential cDNA screening in tomato (Van der Eycken et al.,
      1996). Nematode downregulated promoters in Arabidopsis were described by Goddijn
      et al. (1993). Five nematode-induced promoters (ARM1, 1164, 728, 25 and Lemmi9)
      and four downregulated promoters (CaMV35S, the nopaline synthase promoter (nos)
      and the rooting loci promoters RolC and RolD) fused to the beta-glucuronidase
      (gus) reporter gene were introduced into sugar beet hairy roots by transformation
      with Agrobacterium rhizogenes to evaluate their expression pattern. All
      upregulated promoters were found to be active at the base of lateral roots. The
      728 and 25 promoter were as well active in root tips. In the 25-gus lines GUS
      could also be detected in the vascular tissue, while the ARM1 promoter was also
      active in sugar beet callus. The Lemmi9 promoter and the 4 constitutive promoters
      were active in the entire root. The transgenic hairy roots were inoculated with
      Heterodera schachtii and at different time-points (4, 8, 15, 22 days after
      inoculation; dpi) GUS analysis was performed on the infected roots. For the ARM1,
      1164 and 728 promoter the highest gus expression level in syncytia was observed
      at 8 dpi. In 4 days old syncytia of the 25-gus lines the intensity of the GUS
      signal was of the same extent as the non-specific vascular signal. In later
      stages it even disappeared from the feeding sites. The gus expression level in
      syncytia of Lemmi9-gus hairy roots was equal to that in control roots. The RolC
      and 35S promoter were found to be downregulated at 8 dpi, the RolD promoter at 15
      dpi and the nos promoter already at 4 dpi.

PMID- 12425083
TI  - Observations on the feeding behaviour of Paratrichodorus anemones in relation to
      tobravirus transmission.
AB  - Feeding by P. anemones, an efficient vector of tobacco rattle virus (TRV), was
      investigated by video-enhanced interference light microscopy. Four stages were
      observed after transfer of individual nematodes, extracted from soil, to
      Nicotiana tabacum seedling roots in agar: i) acclimatisation; ii) approach and
      scrutiny; iii) preparation; and iv) feeding. Prior to commencement of stage 'iv'
      about 4 cells perforated by rapid onchiostyle thrusting remained alive, each
      having been almost immediately abandoned by the nematode. During the stage iv)
      approximately 5% of perforated cells remained alive. Feeding on individual cells
      was similar to that previously reported for Trichodorus similis: cells from which
      cytoplasm was ingested after a prolonged period of salivation were invariably
      killed, with adjacent cells being unaffected. During feeding a number of cells
      perforated but soon afterwards abandoned by P. anemones remained alive, providing
      an effective pathway for successful transmission of TRV to plants by the
      nematode.

PMID- 12425084
TI  - Effects of natural products on soil organisms and plant health enhancement.
AB  - TerraPy, Magic Wet and Chitosan are soil and plant revitalizers based on natural
      renewable raw materials. These products stimulate microbial activity in the soil
      and promote plant growth. Their importance to practical agriculture can be seen
      in their ability to improve soil health, especially where intensive cultivation
      has shifted the biological balance in the soil ecosystem to high numbers of plant
      pathogens. The objective of this study was to investigate the plant beneficial
      capacities of TerraPy, Magic Wet and Chitosan and to evaluate their effect on
      bacterial and nematode communities in soils. Tomato seedlings (Lycopersicum
      esculentum cv. Hellfrucht Fruhstamm) were planted into pots containing a
      sand/soil mixture (1:1, v/v) and were treated with TerraPy, Magic Wet and
      Chitosan at 200 kg/ha. At 0, 1, 3, 7 and 14 days after inoculation the following
      soil parameters were evaluated: soil pH, bacterial and fungal population density
      (cfu/g soil), total number of saprophytic and plant-parasitic nematodes. At the
      final sampling date tomato shoot and root fresh weight as well as Meloidogyne
      infestation was recorded. Plant growth was lowest and nematode infestation was
      highest in the control. Soil bacterial population densities increased within 24
      hours after treatment between 4-fold (Magic Wet) and 19-fold (Chitosan).
      Bacterial richness and diversity were not significantly altered. Dominant
      bacterial genera were Acinetobacter (41%) and Pseudomonas (22%) for TerraPy,
      Pseudomonas (30%) and Acinetobacter (13%) for Magic Wet, Acinetobacter (8.9%) and
      Pseuodomonas (81%) for Chitosan and Bacillus (42%) and Pseudomonas (32%) for the
      control. Increased microbial activity also was associated with higher numbers of
      saprophytic nematodes. The results demonstrated the positive effects of natural
      products in stimulating soil microbial activity and thereby the antagonistic
      potential in soils leading to a reduction in nematode infestation and improved
      plant growth.

PMID- 12425085
TI  - Evaluation of isolates of Verticillium chlamydosporium as biocontrol agents of
      Meloidogyne spp.

PMID- 12425086
TI  - Host suitability of arable and vegetable crops for Pratylenchus penetrans.
AB  - A method was developed to test host suitability for the rootlesion nematode, P.
      penetrans in pot-experiments. Quarts-sand with transplanted seedlings was
      inoculated with a suspension of P. penetrans in varying stages. It was
      demonstrated that in a greenhouse at 20 degrees C, a period of six weeks is
      enough for one generation to develop. After this period root material is
      separated from the soil and put in a mystifier where nematodes leave the roots.
      The root material should be held in the mystifier for four weeks. After
      elutriation of the soil fraction in the Oostenbrink elutriator it appeared that
      only few nematodes are in the soil fraction. Therefore it is not necessary to
      process the soil within potexperiments.

PMID- 12425087
TI  - Control of Pratylenchus vulnus in stone fruit nurseries.
AB  - Almond, peach and olive nurseries were prepared in sandy soil infested by
      Pratylenchus vulnus in southern Italy. Soil treatments before or at sowing
      included methyl bromide at the rate of 40 g/m2; 1.3 D at the rate of 15 ml/m2;
      dazomet at the rate of 100 g/m2 without plastic tarping, or at the rate of either
      100 or 50 g/m2 with tarping, and fenamiphos Gr 5 at the rate of 100 g/m2 or 240
      CS at the rate of 40 g/m2 as single application; fenamiphos Gr 10 and 240 CS were
      also applied at planting and two, four and six months after sowing, each time at
      the rate of 10 g/m2. The experiment was discontinued ten and thirteen months
      after sowing, respectively for olive and peach and almond. Methyl bromide, 1.3 D
      or fenamiphos, or dazomet, under certain circumstances, produced agronomically
      suitable plants, but none of the treatments eradicated the nematode.

PMID- 12425088
TI  - Tylenchida associated with different crops in Sennar State (Sudan).
AB  - A study was done on the taxonomy and morphology of plant parasitic nematodes
      (Tylenchida) found in Sennar State (Sudan). Sixty samples of different crops were
      collected in the sugarcane area. Thirty samples originated from soil around the
      roots of Saccharum officinarum (sugarcane) from different ratoons and thirty
      samples were collected from other crops (Mangifera indica; Citrus limon; Citrus
      aurantifolia; Citrus paradisi; Citrus sinensis, Phoenix dactylifera, Musa
      sapentium; Cassia italica, Capsicum annuum, Sorghum bicolor, Sorghum sudanensis,
      Gossypium barbadense, Ficus nitida, Khaya senegalensis, Eucalyptus microtheca,
      Acacia nilotica, Acacia seyal, Azardichta indica, Cajanus cajana, Caltropsis spp.
      and Liguster ovalifolium). Seven species belonging to seven different genera of
      Tylenchida were identified: Paratrophurus lobatus, Scutellonema clathricaudatum,
      Hoplolaimus aegypti and Filenchus cylindricus. Helicotylenchus plumariae,
      Pratylenchus thornei and Malenchus andrassyi are new records for Sudan. These
      seven species were compared with the descriptions given in the literature and
      differences and variations were discussed. Additional morphological data were
      described by means of SEM microscopy.

PMID- 12425089
TI  - Occurrence and diversity of egg pathogenic fungi of the Mediterranean cereal cyst
      nematode Heterodera latipons.
AB  - Eighteen fungal strains in nine genera present in German and Syrian soils were
      isolated from eggs of the barley cyst nematode H. latipons. The fungi were
      selected out of the soil microflora using the slide-frame baiting technique from
      a semiarid soil originating from Syria heavily infested with H. latipons and from
      a temperate soil from German heavily infested with H. schachtii. Fusarium and
      Acremonium were the most common fungi isolated from the both soils. The natural
      suppressiveness or antagonistic potential of egg pathogenic fungi in the Syrian
      and German soils toward H. latipons also was measured. The results demonstrated
      that a higher level of antagonistic potential and a greater level of fungal egg
      pathogen biodiversity is present in the semiarid Syrian soils. This is important
      for the natural control of the Mediterranean cereal cyst nematode H. latipons
      which is widely spread throughout the region. The high level of biodiversity in
      the soil may allow subsequent buffering of the pest even when unsuitable soil
      conditions for growth of the antagonistic fungi occur e.g. low organic matter, as
      is common in the semiarid soils of the Middle East. These isolates may also lend
      themselves to management in the field or to inundative approaches to biocontrol
      of cereal cyst nematodes in the semiarid production zone.

PMID- 12425090
TI  - Influence of plant species on the biological control activity of the antagonistic
      rhizobacterium Rhizobium etli strain G12 toward the root-knot nematode,
      Meloidogyne incognita.
AB  - The influence of plant species on the antagonistic activity of the rhizosphere
      bacterium Rhizobium etli G12 towards the root-knot nematode Meloidogyne incognita
      was studied. The crops tested were tomato, cucumber, cotton, soybean and pepper.
      The plants were evaluated for the following parameters: root gall-index, total
      number of galls and egg masses of M. incognita, as well as shoot and root fresh
      weight and root length. Results indicated a clear influence of plant species on
      the ability of R. etli G12 to reduce nematode infection. Based on the root gall
      index, nematode control by R. etli G12 was higher on vegetables (tomato,
      cucumber, pepper) than on field crops (soybean, cotton). Reduction in galling
      ranged from 17% for cotton to 50% for tomato. R. etli G12 also reduced the actual
      number of galls produced. The reduction in the number of galls produced between
      crops was not affected significantly as was seen when a galling index was used to
      measure activity. The reduction in the number of galls was similar in level for
      all the crops studied and ranged from 34% for cucumber to 47% for tomato. There
      was a significant reduction in the number of egg masses produced by the females
      ranging from 37% for soybean to 70% for pepper. This indicated a direct effect on
      female development in the root after penetration or delayed penetration on
      certain crops. The bacteria caused significant increases in shoot fresh weight
      from 11% for soybean to 31% for pepper and in root fresh weight from 3% for
      soybean to 39% for tomato and in root length from 11% for cucumber to 24% for
      pepper. R. etli G12 gave significant control of M. incognita on a broad range of
      host plants, but the level of control varied. The suitability of each plant
      species, therefore, must be examined before R. etli G12 can be recommend for
      control of this nematode.

PMID- 12425091
TI  - Induced systemic resistance of selected endophytic bacteria against Meloidogyne
      incognita on tomato.
AB  - In previous work, the four endophytic bacteria Pantoea agglomerans MK-29, Cedeca
      davisae MK-30, Enterobacter spp. MK-42 and Pseudomonas putida MT-19 were shown to
      reduce Meloidogyne incognita on tomato when applied as a seed treatment and/or
      soil drench. The objective of this work was to study these bacteria for their
      potential to induce systemic resistance against root knot nematodes on tomato. To
      guarantee spatial separation between inducing agent and pathogen a split-root
      system was chosen and inoculated with the bacteria as a drench application on one
      side of the root system and 6 days later with 2000 juveniles of Meloidogyne
      incognita on the other side of the split-root system. The experiment was
      maintained in the greenhouse and repeated once. The penetration rate of juveniles
      as well as the total number of root-knot galls and egg masses was recorded.
      Treatment with all four bacteria significantly reduced juvenile penetration and
      the number of root-knot galls when compared with the non-treated control. Induced
      systemic resistance is considered a possible control mechanism of endophytic
      bacteria against root-knot nematodes.

PMID- 12425092
TI  - [Competitiveness of hard wheat (Triticum durum Desf.) varieties against ripgut
      brome (Bromus rigidus Roth)].
AB  - Varieties with an excellent competitiveness against ripgut brome (Bromus rigidus
      Roth.) would be very important to reinforce others methods to control ripgut
      brome weed. This study was carried out in 1999-2000 season in a greenhouse
      experiment to test the aggressiveness degree of six varieties of hard wheat (Oum
      Rabia, Isly, Marzak, Karim, Sebou, and Massa) combined with ripgut brome. Plant
      density was fixed at 16 plants of wheat or Bromus for pure crop and 8 plants for
      wheat and 8 for Bromus mixture. The results showed that the numbers of
      kernels/spikes were higher in the mixture for on pure composition. For the kernel
      weight, the result was opposite except for Isly and Marzak varieties. Karim and
      Isly varieties obtained the highest grain yield and were more competitive in
      mixture composition but Sebou and Massa varieties were less competitive against
      ripgut brome. Results of ripgut brome productivity and water use efficiency were
      similar and were used to determine the aggressiveness coefficient of hard wheat
      varieties against ripgut brome. The reduction of the shoot dry matter of brome
      was 22 to 56% at flowering. The grain yield of brome was reduced from 57 to 81%.

PMID- 12425093
TI  - Primus (florasulam 50 G/L), a new triazolopyrimidine sulfonanilide herbicide to
      control broad-leaved weeds in maize when applied in early postemergence (1 to 6
      leaf stage of maize). Preliminary results.
AB  - OBJECTIVE: PRIMUS was developed in maize in Belgium in 1999 and 2000 in the
      course of research into limiting or replacing the use of triazines in maize. One
      of the imperatives of this research was to find the lowest possible residue
      content (MRL). SELECTIVITY TEST: An application of florasulam, at the dose of 5 g
      of active substance (a.s.) at the 2 to 3 leaf stage of the maize was found to be
      selective on 132 (in 1999) and 126 (in 2000) varieties of maize. EFFICACY TEST:
      Florasulam was tested at doses of between 1 and 5 g a.s./hectare. The treatments
      were applied in early postemergence at the 3-5 leaf stage of the maize or in 2
      separate applications: at the 1 leaf stage with a dose of 2 g a.s. florasulam at
      the 4 leaf stage with a dose of 2 g a.s. florasulam The herbicide was fully
      effective on the sensitive flora. A summary of the results is presented. A
      detailed weed spectrum is defined. PROGRAMMES: Herbicide programmes were
      developed on the basis of these findings. The results showed that the best
      partners for florasulam were triketones (sulcotrione and mesotrione) in very low
      doses. Sulcotrione was applied at doses of 75 to 150 g a.s./ha and mesotrione at
      25 to 50 g a.s./ha. Triple mixes of florasulam + triketone + nicosulfuron in very
      low doses and 1 or 2 applications were also tested. The results were highly
      encouraging and this work should lead to practical recommendations.
      PHYTOTOXICITY: Phytotoxicity was observed on some occasions. The phytotoxicity
      results for the different figures seem, however, to depend more on the climate
      (difference between daytime and night-time temperatures just before and after the
      treatment) than on the products tested in the mixes. However, the florasulam +
      nicosulfuron (sulfonyl-urea antigrasses) may sometimes cause serious problems
      with selectivity. The phytotoxicity noted in the tests was usually short-lived
      (30 days). CONCLUSION: The results of the tests show that it is possible to
      consider replacing atrazine-based programmes with very low doses of modern
      herbicides applied at early stages of the maize. A mixture of active substances
      is vital. Repeated very low doses at the 1/2 and 4/5 leaf stages of the maize
      were found to be the most effective.

PMID- 12425094
TI  - Adjuvant influence on glyphosate efficacy in the presence of CA2+.
AB  - Calcium ion in the spray water diminishes the efficacy of glyphosate. Ammonium
      sulphate (AS) is long shown to be the most efficacious remedy to this antagonism.
      However, it is sometimes claimed that acidified lecithins or terpenic alcohols
      can also be used to this aim, and even ethoxylated amines (EA) provided that
      calcium concentrations are not higher than 5 mM. We investigated these claims by
      examining dose-response curves of barley plants treated with glyphosate at
      various calcium concentrations in the presence of these adjuvants. Calcium ion
      increased the slope of the curves and ED50 values, indicating a decrease in
      efficacy. Acidified lecithins and terpenic alcohols did not modify the response
      of barley to glyphosate observed in the presence of calcium ion. AS restored the
      ED50 and slope values observed in the absence of calcium ion. It was concluded
      that the inhibition of glyphosate efficacy by calcium ion was not relieved by
      terpenic alcohols and acidified lecithins but was completely reverted by AS. EA
      decreased ED50 and ED90 values of the response curves established in the presence
      of calcium ion without influencing the slopes (which remained high). As a
      consequence, at calcium concentrations up to 5 mM the response curves obtained
      with AS and EA intersected. It followed that in the presence of EA, ED50 values
      were higher than AS, whereas ED90 values were lower. By contrast, at 10 mM
      calcium the response curves did not intersect and consequently, in the presence
      of EA, ED50 and ED90 values were both higher than AS. Since ED90 relates to
      efficacies sought in the field, our experiments explain why at low calcium
      concentrations EA may appear as a better remedy than AS. Glyphosate formulations
      containing ammonium sulphate or a higher concentration in surfactants than usual
      glyphosate formulations were also studied. In the presence of calcium ion they
      behaved in a way which was in agreement with the above observations.

PMID- 12425095
TI  - Dissipation and mobility of the sulfonylaminocarbonyl-triazolinone herbicide
      propoxycarbazone in the soil of winter wheat crops.
AB  - The new sulfonylaminocarbonyltriazolinone herbicide propoxycarbazone has been
      applied at the rate of 70 g ha-1 post-emergence in the spring on winter wheat
      fields located at three sites different as to their soil texture and composition.
      A method has been developed for the analysis of propoxycarbazone in soil by GC
      and GC-MS, after isolation and transformation of propoxycarbazone. The limit of
      sensitivity was 1 microgram propoxycarbazone kg-1 dry soil. In the sandy-loam
      soil at Melle, and in the clay-loam soil at Zevekote, the propoxycarbazone soil
      half-lives in the 0-10 cm surface soil layer were similar, i.e. about 54 days. In
      the loam soil at Cortil-Noirmont, the propoxycarbazone soil half-life was 31
      days. The difference as to the soil half-lives was related to the organic
      fertilization practized in the past on the three fields. At Cortil-Noirmont,
      after the winter wheat harvest at the end of August, the residues of
      propoxycarbazone in the 0-10 cm surface soil layer were very low, and at the end
      of September, propoxycarbazone was no more detected. At Melle and Zevekote, at
      the end of September, the concentrations of propoxycarbazone in the 0-10 cm
      surface soil layer were very low; at the end of October, propoxycarbazone was no
      more detected. After its application and until the end of October,
      propoxycarbazone was not detected in the 10-15 and 15-20 cm surface soil layers.

PMID- 12425096
TI  - Fate of the herbicide isoxaflutole in the soil of corn fields.
AB  - The herbicide isoxaflutole 1 (5-cyclopropyl-4-isoxazolyl)[2- (methylsulfonyl)-4
      (trifluoro-methyl)phenyl]-methanone) was applied pre-emergence at the rate of 125
      g ha-1 on corn fields located in three sites different as to their soil texture
      and composition. In the 0-10 cm surface soil layer, the isoxaflutole soil half
      life (soil dissipation kinetics of second order) was 9 days in sandy loam
      (Melle), 15 days in clay loam (Zevekote) and 18 days in loamy sand (Zingem) soil.
      The sum of the concentrations of isoxaflutole 1 and of its herbicide active
      metabolite diketonitrile 2 (2-cyano-3-cyclopropyl-1-(2-methylsulfonyl-4-
      trifluoromethylphenyl)propane-1,3-dione) had a soil half-life (dissipation
      kinetics of first order) of 45 days in sandy loam, and 63 days in the clay loam
      and loam sand soils. The soil metabolism of isoxaflutole thus generated, in the
      soil of field corn crops, a metabolite, the diketonitrile 2, which had an
      herbicide activity as high as the one of the parent isoxaflutole, and which much
      extended the herbicide protection given by isoxaflutole. At the crop harvest,
      isoxaflutole, the diketonitrile 2 and the acid 3 (2-methylsulfonyl-4
      trifluoromethylbenzoic acid) were no more detected in soil. During the corn
      crops, isoxaflutole, and its metabolites diketonitrile 2 and acid 3 were never
      detected in the 10-15 et 15-20 cm surface soil layers, indicating the very low
      mobility of these compounds in soil.

PMID- 12425097
TI  - Effects of glufosinate-ammonium on off crop vegetation--interim results.
AB  - In 2000 a field study was conducted at four different locations concerning the
      effects of low dosages of glufosinate-ammonium, a leaf acting herbicide, on off
      crop vegetation. Therefore species rich road verges and ditch banks not adapted
      to a history of herbicide use were sprayed twice with different dosages of
      glufosinate-ammonium, simulating drift (0, 2, 4, 16, 32 and 64% of the maximum
      field dose: 800 g a.i./ha). The parameters studied were short term phytotoxic
      effects and the effects on biomass, species cover and number of species in autumn
      (Braun-Blanquet releves). The results show significant phytotoxic effects at all
      dosages of glufosinate-ammonium on the non-target vegetation. The low
      concentrations (2 and 4%) had most impact when applied early in the season (9%
      average at the 2% dosage and 22% at 4% dosage, after the first spraying. At high
      dosages (32 and 64%) a decrease of the biomass of the vegetation was found in
      August. A comparison between treatments in August shows a small decrease in
      species number and cover in the 64% compared to the control. In the comparison
      between the spring and August releves, the decrease in the mean number of species
      was significantly stronger in the treated plots than in the untreated ones of 4%
      and higher. For monocotyledons in all treatments except 16%, a significantly
      stronger decrease in species number was found compared to the untreated. For
      dicotyledons only the 64% dosage differed from the untreated. Only at the 64%
      treatment the total cover of species decreased more than in the untreated plots.
      Since drift percentages of 2-4% can be expected at 1-2 m from a treated plot it
      can be concluded that the use of glufosinate-ammonium could result in visible
      short term phytotoxic effects (max 22%) on off-crop vegetation such as ditch
      banks and verges. There are also indications that effects on the number and cover
      of species in autumn can occur. Because in future glufosinate-ammonium could be
      used on a large scale in herbicide resistant crops like maize, which will be
      cultivated on the same field for many years, this study will be continued in 2001
      in order to investigate if there are--whether or not--sustainable effects on the
      off crop vegetation.

PMID- 12425098
TI  - Chemical control of perennial and annual weeds in herbicide resistant soybean
      crops.
AB  - In Romania, the first tests with Roundup Ready on soybean crops were performed in
      1998, on 2 soil types: a) at Teleorman Station on chernozem containing 3.5%
      humus, 4.5% clay b) at Braila Station placed in Danube Meadow on alluvial soil
      containing 3.90% humus and 46% clay. In every locality cultivated soybean
      cultivar S.2254 was resistant to glyphosate. During the three years of
      experiments (1998-2000) the crop of soybean was infested with various species of
      weeds (both annual and perennial) of which the most important are: Sorghum
      halepense (60-80%), Echinochloa crus-galli, Setaria glauca, Amaranthus
      retroflexus, Solarium nigrum, Yanthium italicum, Abutilon theoprasthi, Sinapis
      arvensis, Datum stramonium, Polygonum persicaria, Calystegia sepium, Cirsium
      arvense. In 3 years of experience the best weed control and the highest soybean
      production were obtained in the variants treated 2 times postemergent with
      Roundup Ready at a dose of 3 + 3 l/ha. Similar results were also obtained in the
      farms of the Academy of Agricultural Forestry Sciences, where GMO soybean was
      cultivated on 1500 hectares.

PMID- 12425099
TI  - Selectivity of florasulam in 4 grass species during the seed harvest year.
AB  - Results from one year indicated that florasulam (Primus) and its combination with
      fluorxypyr applied in spring of the seed harvest year, were completely selective
      in seed crops of 4 grass species; namely Agrostis stolonifera, Festuca rubra
      rubra, Koeleria macrantha and Lolium multiflorum. Experimental treatments also
      included a reference product i.e. bentazone + dichlorprop-P and an untreated
      control; in total 7 treatments were involved. The prime objective of this study
      was to investigate not only the effect on vegetative crop growth, but also the
      impact on generative growth. The main topics were: visual phytotoxicity, lodging,
      seed yield, straw yield, thousand seed weight, germination capacity, cleaning
      efficiency, harvest index, seed number per unit area and ear density. The
      reference treatments (bentazone + dichlorprop-P) were insufficiently selective in
      Koeleria spp. for vegetative parameters and seed yield, and less selective in
      Festuca spp. during establishment year but without any effect on seed yield. The
      so-called "non-sitting" seed crops following above treatments in creeping fescue
      and Italian ryegrass could be attributed to an inhibition effect.

PMID- 12425100
TI  - [Evaluation of the seed stock and dynamics of ripgut brome (Bromus rigidus Roth)
      in the cultivation of wheat in the Sais area of Morocco].
AB  - The study was conducted on experimental plots differing in cultivation treatment
      (deep or shallow) at the National School of Agricultural station for three years.
      The objective was to study the influence of the tillage practices on vertical
      distribution of the seeds of ripgut brome (Bromus rigidus Roth) in the soil
      profile. Four tillage methods were tested: Zero tillage (SD), disc plough (PDL)
      and a disc harrow at two depths, 20 cm (CDM) and 30 cm (CDP). The results show
      that the type of cultivation affected the distribution of the seeds of ripgut
      brome. Shallow plots were highly infested by Bromus rigidus (876 plant/m2). The
      total number of seeds of ripgut brome was 96 and 45% in 0-4 cm of the soil, 3 and
      29% in 4-15 cm and 1 and 26% in 15-30 cm, respectively of the deep (CDP) and
      shallow soil (SD). Deep tillage reduced the seed bank of ripgut brome by 96.6%
      and 66.7% for shallow. Seeds of ripgut brome survive more than three years at the
      deep soil. Processes of germination of this weed became functional after 98 days
      in the soil. The disc plough reduced significantly the brome population and seed
      bank compared to other tillage methods.

PMID- 12425101
TI  - [Cartography and geographical spread of the adventitious species of brome (Bromus
      spp.) among cereals in the Sais area of Morocco].
AB  - Bromus spp is causing serious problems in wheat in the Sais area. However, the
      damage of this weed varies from one region to another according to the agro
      climatic conditions and crop systems. The characterization of the infestation
      level in each situation is a prerequisite to develop a control strategy adapted
      to each environment. This study was undertaken in order to determine the
      infestation level and geographical spread of the weedy brome (Bromus spp) on
      wheat in Sais following crop systems and pedo-climatic conditions. The results
      obtained during two consecutive years (1998-99 and 1999-2000) revealed that
      ripgut brome (Bromus rigidus Roth.) was the most dominant species in wheat fields
      in the surveyed regions, followed by B. rubens L., B. sterilis L., B. madritensis
      L. and B. mollus L. Among, 18 regions and 100 infested wheat fields, 16.67% of
      fields were slightly infested (Plant density of Bromus (Dbr < 90 plants/m2,
      61.11% were moderately infested (90 < Dbr < 290 plants/m2) and 22.22% were highly
      infested (Dbr > 400 plants/m2). The maximum relative frequency was obtained with
      Bromus rigidus (47.15%) and the coverage was 40.43%. But, for B.rubens, B.
      madritensis and B. sterilis, the relative frequencies were respectively 31.42; 26
      and 15% and their coverages were respectively 28.9, 20.4 and 12.5%.

PMID- 12425102
TI  - Determination of resistant biotypes of Amaranthus retroflexus L. on triazines.
AB  - Considering the fact that since 1966 in our country the mostly produced have been
      triazine herbicides on the bases of ametryn, simazine, atrazine and prometryn, we
      have studied resistance of Amaranthus retroflexus from different sites in regard
      to the above mentioned herbicides. Seed of weed species for which exist
      possibility of resistance have been collected from different localities in
      Vojvodina, such as Backa Palanka, Backi Maglic and Becej. Studies were performed
      during 1999 and 2000 by whole plant studies (Thurnwachter, 1998) and by petri
      dish assays (Clay, Underwood, 1989). Plants were treated by range of atrazine
      rates (Atrazin S-50) including also susceptible, referent population. Results
      indicate atrazine resistance of Amaranthus retroflexus at Backa Palanka and Backi
      Maglic sites, which have been treated by triazine herbicides in many years
      lasting period.

PMID- 12425103
TI  - Efficacy of Phomopsis convolvulus as a mycoherbicide for Convolvulus arvensis.
AB  - The purpose of the investigations was to determine the efficacy of different
      conidia concentrations of Phomopsis convolvulus Ormeno on different leaf stages
      of Convolvulus arvensis seedlings and regrowth potential of C. arvensis 25 days
      after inoculation. Furthermore, the potential of P. convolvulus on the growth of
      C. arvensis derived from different root lengths was studied. The results showed a
      great reduction in dry weight of above-ground biomass with more than 80%
      irrespective of the conidia concentration (1 x 10(6), 10(7) and 10(8) conidia/ml)
      on plants of the leaf stage 1-3 and 5-7 and gave more than 80% reduction of root
      biomass with an exception in case of 1 x 10(6) conidia/ml on plants of the leaf
      stage 9-11. Mortality was reached complete only with 1 x 10(8) conidia/ml on
      plants of the leaf stage 1-3. Regrowth potential of C. arvensis at more developed
      leaf stages was higher than at early leaf stages. Within the 3 categories of root
      lengths tested (5, 10 and 15 cm), the 1-3 leaf stage shoots showed the highest
      susceptibility to P. convolvulus. Obtained results illustrate that the
      application of P. convolvulus with 1 x 10(8) conidia/ml at the young leaf stage
      (1-3 leaf stage) on all treatments give a great reduction of biomass and
      adversely affects regeneration of the plants.

PMID- 12425104
TI  - Comparative efficacy of five herbicides on winter cereal weeds in semi-arid
      region of Algeria.
AB  - Field chemical control trials on cereal weeds were conducted in the Setif region
      (north-east of Algeria), using five herbicides. The most abundant weeds were
      Fumaria densiflora DC., Veronica cymbalaria Bodard, Vaccaria pyramidata Medik,
      and Papaver rhoeas L.. The herbicides applied at the end-tillering stage of wheat
      were bromoxynil + diclofop-methyl, flamprop-isopropyl + MCPA, 2,4-D ester,
      diclofop-methyl and tribenuron-methyl. Compared to the untreated control, they
      increased grain yield by 359, 294, 216, 174 and 417 kg ha-1, respectively. These
      results showed the importance of the chemical control, which is applied in the
      Setif region on less than 5% of the total surface of cereals.

PMID- 12425105
TI  - Floristic and agronomic aspects of cereal weeds in the Constantine high plains.
AB  - Three hundred fifty nine fields of cereals were surveyed by stratified sampling
      in the Constantine high plains (north-east, Algeria). In total 254 species
      belonging to 34 plant families were recorded. The results indicated that five
      families the Asteraceae, Fabaceae, Poaceae, Brassicaceae and Apiaceae were
      prevalent and accounted for 55% of the species. Annuals (70%), broad leaved (87%)
      and the mediterranean floristic element (63%) were predominant and characterized
      the weed flora. The agronomic study permitted to distinguish 34 important
      species. This harmful flora was characterized by the prevalence of annual and
      broad leaved weeds. Although number of grasses was low were some abundant and
      frequent e.g. Avena sterilis L. and Bromus rigidus Roth.. Perennial species were
      represented by several weeds, the most frequent and abundant were Bunium
      incrassatum (Boiss.) B.T., Carduncellus pinnatus (Desf.) DC. and Convolvulus
      arvensis L..

PMID- 12425106
TI  - Consumer motivation towards purchasing fruit from integrated production in
      Belgium.
AB  - Consumer concerns about food safety have been steadily growing during the last
      decade. Along with the recognition of the increasing power from the consumer side
      of food chains, this has forced agricultural producers to innovate and adapt
      their production methods. One of those developments is integrated production of
      pip fruit (IFP). This research analyses and presents motivational structures of
      consumers towards purchasing IP fruit in Belgium. The research methodology builds
      on means-end-chain (MEC) theory, with data collected through personal laddering
      interviews with consumers. A hierarchical value map, indicating motivational
      structures for farm shop purchase of IP-labelled apples, is presented. IP-apple
      buyers pursue typical values, with health being paramount. The findings reveal
      interactions between market channel characteristics and product attributes,
      including characteristics that refer to production methods. Also, the study shows
      how outlet choice influences the perception and the motivation structure of the
      respondents for the specific product, fresh fruit in this case. From the
      findings, two sets of implications are set forth. First, marketing implications
      pertaining to advertising through the application of the "Means-End
      Conceptualization of the Components of Advertising Strategy" or MECCAS model.
      Second, implications to producers with respect to adapting their production
      methods to the needs and wants of the present end consumers.

PMID- 12425107
TI  - Pesticide residues in human food and wildlife in The Netherlands.
AB  - Several monitoring programmes for pesticide residues in food are currently
      operative in the Netherlands, some of which are related to EU directives. These
      programmes cover a range of products. This paper reviews the 1997 and 1998 data
      for fruit and vegetables, meat, milk, livestock and fish, as well as presenting
      data on pesticide residues in wildlife. The aim of the paper is to provide an
      overview of what is known about pesticide residues in the Netherlands, including
      indications of the origins of the compounds found. A total of 281 different
      compounds were monitored on fruit and vegetables. Of these compounds, 45% were
      actually found on products and 28% exceeded the standard. Expressed as
      percentages of the number of measurements, the data show that 0.3% of the
      measurements detected a compound, and standards were exceeded in 0.02% of the
      measurements. Some of the cases in which standards were exceeded concerned the
      use of compounds in minor crops, for which their use is not permitted. Other
      cases involved excessive dosages or application within the safety interval before
      harvest. In meat, milk and livestock, 10 persistent organochlorine compounds were
      measured. Most of these compounds, with the exception of lindane, are no longer
      in use, but are still being found as residues. The concentrations found were very
      low and have not exceeded standards for human consumption since 1993. No
      assessment was made, however, of products currently in use. Organochlorine
      compounds have also frequently been found in fish (eel), in higher concentrations
      than in meat, but in nearly all cases in quantities below the standards for human
      consumption. Ecological standards for accumulation in the food chain were
      exceeded on a larger scale and indications of exposure effects on piscivorous
      birds (cormorants) were found. No data on pesticide residues in wildlife are
      known for terrestrial organisms.

PMID- 12425108
TI  - Trends of pesticide use in The Netherlands.
AB  - In 1991, a policy plan was adopted in the Netherlands, one of whose aims was a
      50% reduction in pesticide use by 2000. The present paper surveys pesticide sales
      since 1974 and the use of such compounds in different crops per hectare as well
      as for the country as a whole. The results show that by the mid-1990s, pesticide
      consumption in kilogram terms had been reduced by about 50% compared to the mid
      1980s. This reduction, however, was almost totally caused by the reduction in the
      use of soil disinfectants, while reduction targets for herbicides and fungicides
      were not met at all. Arable crops, especially potatoes and maize, which cover
      large areas in the Netherlands, contributed most to total consumption, while
      apples, tulips and lilies also made considerable contributions. On a per hectare
      per year basis, pesticide consumption was highest in ornamental plants like
      roses, chrysanthemums, lilies and hyacinths, followed by vegetables grown in
      greenhouses, apples and pears and mushroom cultivation. A remarkable feature is
      that the majority of the 20 most commonly used compounds (in terms of total
      consumption in kilograms of active ingredient or area sprayed) had already been
      introduced before 1980. On a kilogram basis, fungicides and soil disinfectants
      were used in the largest quantities, together with mineral oil and followed by
      herbicides. On a per hectare basis, herbicides played a more important role,
      while one insecticide also featured.

PMID- 12425109
TI  - POCER, a new pesticide risk indicator.
AB  - POCER, the pesticide occupational and environmental risk indicator, has been
      developed in order to be able to quantify the health and environmental risk from
      the use of pesticides in agriculture. The POCER indicator is used as a decision
      tool to rank and choose between alternative pesticides, to evaluate the effect of
      certain pesticide reduction measures and to evaluate the effectiveness of policy
      measures. The practical use of the indicator is explained using examples.

PMID- 12425110
TI  - Database "SIGMA Pro" information system and bibliographical management of active
      substances of plant protection products and biocides.
AB  - In order to satisfy its obligations as stipulated in European legislative, in
      1998, the Management of Surface Waters in the Walloon Region modified its
      monitoring of plant protection products in surface waters in co-operation with
      the Regional Phyto Committee (LLN). Notably, this monitoring network takes into
      account the agricultural specifics of the main watersheds in Wallonia. It has led
      to the publication of a specific decree (A.G.W. of June 29th, 2000), which, among
      others, specifies the list of dangerous relevant substances in Walloon Region as
      well as their investigation methods (quality, monitoring network, action
      programmes). Together with the implementation of Directive 76/464/EEC concerning
      the pollution caused by some dangerous substances in aquatic environment, the
      Management of Surface Waters is also finalizing a database connected with plant
      production products. It contains technical data on active ingredients and
      relevant metabolites (nomenclature, toxicology, physico-chemical properties,
      ...), bibliographical information referring to these (synthesis of documents,
      table with results, ...) and some Internet connections. It has been elaborated so
      as to help Walloon public authorities make their decision.

PMID- 12425111
TI  - Assessment of the distribution of an insecticide applied to wheat tillers under
      field conditions.
AB  - In order to carry out a relevant assessment of pesticide toxicity towards
      beneficial arthropods under field conditions, it is important to have an accurate
      and reliable knowledge of the distribution of pesticide residues over the entire
      plant. As the compound is not homogeneously distributed over the plant, insects
      can encounter very different residue concentrations. The work presented aims to
      determine the quantities of deltamethrin residue on seven specific parts of the
      wheat tillers after spraying in the field. The results obtained indicate that the
      total quantity of pesticide applied per unit area represents only 40% of the
      maximum theoretical amount that would be expected on a horizontal surface area.
      Logically enough, a third of the spray deposit can be found on the flag leaf and
      over 70% is found on the entity formed by the ear and the two last leaves. On the
      other hand, the amounts recovered on the stalk are limited and do not exceed 10%
      of the total residue. Thus, beneficial arthropods are not exposed to pesticide
      amounts per unit area as high as those envisaged during standard toxicity tests
      carried out under laboratory conditions.

PMID- 12425112
TI  - Effects of diflubenzuron on growth and glutathione in mosquito fish (Gambusia
      affinis).
AB  - Although some biological control agents and related biorational approaches are
      available for mosquito control, insecticides remain the principal control method.
      In addition, the secondary affects of conventional insecticides in environment
      has led to the discovery of more target-specific chemical such as insect growth
      regulators. Dimilin (25% WP), the common name of diflubenzuron, prevent molting
      by interfering with chitin synthesis in several insect orders. This study
      evaluate toxicity of this insecticide on a larvivorous non-target species,
      Gambusia affinis (Cyprinodontiformes: Poeciliidae). Dimilin, applied for 24 h at
      a concentration of 78 ng/l, corresponding to the LD90 against the fourth instar
      larvae of Culex pipiens (Diptera: Culicidae) was first tested on growth and
      development of 7-day old juvenile mosquitofish during 45 days following
      treatment. Results showed that dimilin caused significant (p < 0.01) reduction in
      both length and weight of juveniles from days 30 following treatment, compared to
      controls. In a second series of experiments, designated for measurements of
      glutathione (GSH), adults of G. affinis were exposed continuously to a
      concentration of 78 ng/l for 30 days. Treatment resulted in a significant
      reduction in the amount of glutathione in mosquitofish bodies starting day 15
      during treatment, compared to controls.

PMID- 12425113
TI  - Pesticide assessment of the banana sector in an Ecuadorian watershed.
AB  - A survey was conducted in several Ecuadorian banana plantations to determine the
      actual pesticide management and their environmental impacts. It was detected that
      glyphosate, propiconazole, imazalil, tridemorph and imazalil are the pesticides
      most used in the Ecuadorian banana sector. As a first step, two screening models
      (EQC and EXAMS) were used to determine the overall distribution of these
      pesticides in a unitary environment. Whereas EQC evaluates soil, water, sediment
      and air compartments, EXAMS only takes into account water and sediment
      compartments. Although both models show different results due to their different
      approaches, a comparison can still be done considering only the aquatic portion
      of the unitary environment. For the case study presented here, all 5 pesticides
      tend to affect more the soil and water compartment.

PMID- 12425114
TI  - One-generation reproduction toxicity study of mancozeb and lead acetate.
AB  - The reproduction toxicity of lead acetate and 80% mancozeb containing fungicide
      formulation (Dithane M-45) were studied on rats. The lead acetate was applied in
      diet at the following dose groups: Control-1,000-5,000-10,000 mg/kg. Three
      treatment and a control groups were applied, 4,500 mg/kg Dithane M-45 was
      administered in all the dose levels simultaneously in diet. The basis of the
      method was the OECD Guideline for Testing of Chemicals No. 415. Clinical symptoms
      and mortality were not found in the parent generation. The body weight of female
      animals diminished significantly before the pregnancy period. This tendency was
      also seen on males after the combination treatment. Remarkable body weight growth
      of female animals was observed during lactation period at the two high dose
      levels. Diminished body weight data of offsprings were measured after treatment
      at the end of the lactation period. The histological examination showed a general
      tubulonephrosis in the trial. Summing up, it can be established the
      administration of fungicide Dithane M-45 did not increase the toxicity of lead
      acetate.

PMID- 12425115
TI  - Teratogenicity testing of dimethoate containing insecticide formulation (BI 58
      EC) in chicken embryos.
AB  - BI 58 EC insecticide formulation was tested for teratogenicity in chicken embryos
      after the treatment of embryonated eggs. The pesticide was diluted in water to
      0.8% concentration level, and the emulsion was injected into air space in a
      volume of 0.1 ml/egg or hen eggs were treated by the immersion technique. The
      morphological examinations were done on the days 13, 15 and 19 of incubation of
      chicken embryos. BI 58 EC produced an increased embryo mortality after the
      treatment which was the most expressive on day 15 of incubation. The trend of
      embryo weight showed similarity in the control and treated groups after both
      treatments. The developmental anomalies were sporadic and dose-effect dependency
      was not seen. Light microscopic findings exhibited a degenerative change in the
      liver tissue of both treated groups. In summary, the 38% dimethoate containing
      pesticide formulation (BI 58 EC) was toxic to the developing embryo at 0.8%
      concentration in our study.

PMID- 12425116
TI  - Teratogenicity test of dimethoate containing insecticide formulation and heavy
      elements (Cu, Cd) in chicken embryos after administration as single compounds or
      in combination.
AB  - The teratogenic effects of heavy elements (Cu-sulphate, Cd-sulphate) and a 38%
      dimethoate containing insecticide formulation (Bi 58 EC) were studied on chicken
      after administration as a single compounds or in combination. The test materials
      were injected directly into the airchamber with an injector on day 12 of
      incubation. Applied concentrations of heavy elements (Cu-sulphate, Cd-sulphate)
      were: 0.01-0.001% and the concentration of pesticide was 0.1%. Final volume was
      0.1 ml/egg. Evaluation was done on day 19 of incubation. After the administration
      of heavy elements (Cu-sulphate, Cd-sulphate) on day 12 of incubation, the average
      body mass of embryos significantly decreased at all the treated dose groups as
      compared to the control. Embryonic mortality did not increase at all the two dose
      levels of Cu-sulphate and at 0.001% conc. of Cd-sulphate, while the highest
      concentration of Cd-sulphate killed 20% of embryos treated. The number of embryos
      with developmental anomalies did not differ markedly from the control. The
      simultaneous administration of heavy elements (Cu-sulphate, Cd-sulphate) and
      dimethoate containing insecticide a statistically significant reduction in
      embryonic body mass occurred at all the treated dose groups. The incidence of
      developmental anomalies was markedly higher after the simultaneous use of heavy
      elements (Cu-sulphate, Cd-sulphate) and dimethoate containing formulation than in
      tests based on the separate use of heavy elements. Embryonic mortality increased
      at all the treated dose groups and reached almost 20% rate. In summary, it can be
      established that the simultaneous administration of heavy elements (Cu-sulphate,
      Cd-sulphate) and the dimethoate containing insecticide caused higher toxicity
      with respect to test of individual toxicity of heavy elements.

PMID- 12425117
TI  - The toxicological effects of the herbicide 2,4-DCPA on progesterone levels and
      mortality in Wistar female rats.
AB  - The effect of the ester butylglucol of 2,4-Dichlorophenoxyacetic acid (herbicide)
      on the rate of fertilization and on progesterone levels during gestation in rats,
      has been studied. The experiments consisted of four groups; one receiving the
      drug in the drinking water at a concentration of 125 mg/kg/day (the agriculture
      dose), the second and the third group received per os doses of 50 and 100
      mg/kg/day of the herbicide, while the fourth group served as controls. The
      obtained results show that all treatments lead to a decrease in both indexes of
      females' fertility and in that of newborn mortality. On the other hand, the index
      of fertilization has been highly affected by the drug application, with a clear
      delay in fertilization in animals treated with 100 mg/kg/day and 125 mg/kg/day.
      Progesterone levels have also been suppressed in individuals receiving the
      herbicide at 50 and 125 mg/kg/day.

PMID- 12425118
TI  - Influenza in the world.

PMID- 12425119
TI  - Decoding of malaria genomes opens new era in public health.

PMID- 12425120
TI  - Continuous spinal anesthesia for cesarean section for a morbidly obese patient.

PMID- 12425121
TI  - Prevention of postoperative nausea and vomiting.

PMID- 12425122
TI  - Fairness in credentialing and the certified registered nurse anesthetist.

PMID- 12425123
TI  - A proposal for an international accreditation process.

PMID- 12425124
TI  - The perceived influence of financial risk factors on the viability of nurse
      anesthesia educational programs.
AB  - Monetary cutbacks have occurred in the healthcare industry with increasing
      incidence since the mid-1980s. Attempts at self-preservation through cost
      constraint have been instituted by hospitals, Medicare and Medicaid, and private
      insurance companies. Curtailment of expenditures, as well as reestablishing
      profit, has taken many forms. These include managed care, mergers, changing
      profit status, and aggressive competition. The purpose of this study was to
      evaluate whether directors of nurse anesthesia programs (NAPs) perceived these
      items as being detrimental to their NAPs. Data were gathered by descriptive
      survey design by completing a survey tool. Findings identified directors
      perceived NAPs at moderate to high risk for closure because of the financial
      constraints hospitals are experiencing as a result of healthcare reimbursement
      cutbacks. We found it interesting that many directors were either unaware or
      considered the hospitals' financial burdens as not impacting their NAP. However,
      directors who had taken courses or seminars with a focus on issues affecting the
      financing and reimbursement of healthcare institutions perceived significantly
      greater risk than those who did not. Potential learning opportunities and
      strategies to ameliorate risk were identified. Additional education may provide
      the knowledge and insight to find alternatives to risk, develop strategies, and
      promote more successful and stable nurse anesthesia educational programs.

PMID- 12425125
TI  - A comparison of rocuronium and lidocaine for the prevention of postoperative
      myalgia after succinylcholine administration.
AB  - The incidence of postoperative myalgia (POM) after succinylcholine administration
      has been reported to range from 5% to 83%. The administration of small doses of
      nondepolarizing muscle relaxants or lidocaine before the administration of
      succinylcholine has been shown to decrease the incidence and severity of POM
      experienced by patients. The purpose of this investigation was to compare the
      severity of POM in subjects receiving pretreatment with rocuronium or lidocaine.
      Seventy-four subjects were enrolled in this randomized, double-blind
      investigation to measure the effect of pretreatment modalities on the incidence
      and severity of myalgia following succinylcholine administration. Pretreatment
      consisted of either lidocaine, 1.5 mg/kg, or rocuronium, 0.03 mg/kg. Myalgia was
      measured using a 4-point ordinal scale. Ordinal and nominal data were analyzed
      using a chi 2 test and the Fisher exact test. A P value of less than .05 was
      considered significant. Data for 53 subjects were included in the analysis. Of
      the lidocaine group, 21 (72%) of 29 reported no myalgia at 48 hours compared with
      only 9 (38%) of 24 in the rocuronium group (P = 0.023). Satisfaction was similar
      between the groups. Based on the results of this study, pretreatment with
      lidocaine may provide better relief from myalgia than rocuronium at 48 hours
      after surgery.

PMID- 12425126
TI  - Chronic gastroesophageal reflux disease and its effect on laryngeal visualization
      and intubation: a case report.
AB  - Gastroesophageal reflux disease (GERD) can have a profound effect upon
      visualization of the larynx. Changes at the cellular level can produce edema and
      subglottic stenosis thus causing airway difficulties of dire consequence if not
      recognized. Preoperative anesthesia evaluation of any patient presenting with a
      history of GERD should alert the anesthesia provider to the possibility of airway
      management problems. Subsequent steps should be taken to prepare the patient for
      potential difficult airway management. Preventative measures are desirable and
      support a better outcome, but in many instances such measures are deferred and
      anesthesia proceeds anyway; should this occur, immediate access to fiberoptic
      visualization and a difficult airway cart is imperative. Due to the increasing
      incidence of GERD in the general population, it is of utmost importance that it
      be considered during any airway assessment. This will enhance patient care and
      eliminate the element of surprise during this critical time.

PMID- 12425127
TI  - Costs and risks of weekend anesthesia staffing at 6 independently managed
      surgical suites.
AB  - We previously developed a statistical method that managers can use to assure that
      nurse anesthetists are on call on weekends for as few hours as possible while
      providing a specified level of care for operating room (OR) patients. The
      statistically derived staffing solutions are optimal, meaning that the total
      number of staffed hours is guaranteed to be as low as possible to achieve the
      specified risk of being unable to care for patients as promptly as they had in
      the recent past. We used the statistical method to review nurse anesthetist
      weekend staffing at 6 surgical suites that were part of a healthcare system with
      a cost-conscious management team. Four of the suites had already made staffing
      changes resulting in a greater than 6% risk of being understaffed. One suite had
      adequate current staffing but slightly exceeded the minimum total staffing hours.
      One suite had more anesthetist coverage than was needed, resulting in excess
      staffing costs greater than $200,000 per year. We conclude that the principal
      value of the statistical method may be in helping healthcare system
      administrators and anesthetists quantify the impact of contemplated reductions in
      staffing on their risk of understaffing and prologing patients' wait for OR care.

PMID- 12425128
TI  - The process of evaluating and regulating a new drug: phases of a drug study.
AB  - Nearly every aspect of anesthesia care involves a strong working knowledge of the
      pharmacodynamics and pharmacokinetics of a vast number of drugs. Several times
      each year, anesthesia providers are challenged with the introduction of a drug
      new to the market. Most healthcare providers understand that before a new drug
      can be used to treat patients, it must be put through meticulous clinical trials
      that are stringently regulated. These clinical trials are the most expensive and
      most vital part in the process of new drug development, as the establishment of
      safety and efficacy is paramount. The purpose of this article is to review the
      process every new drug must go through before it can be marketed in the United
      States, from the chemist's bench to the pharmacist's shelf (or anesthetist's
      cart!), and the primary institution and laws that govern this process.

PMID- 12425129
TI  - A study of clinical decision making by certified registered nurse anesthetists.
AB  - Anesthesia outcomes and related risk factors have been studied for more than 100
      years. Varying sample sizes and research methods have been used, with research
      findings that were open to multiple interpretations. Research with closed
      malpractice claims demonstrates that American Society of Anesthesiologists
      physical status II patients undergoing elective procedures are most likely to
      experience damaging events intraoperatively with resultant postoperative adverse
      outcomes. The process of care, including clinical decision making, contributes to
      adverse outcomes. Clinical decision making can be difficult to assess and
      measure. In this study, the cognitive psychology framework of information
      processing theory and literature pertaining to the use of heuristics, or rules of
      thumb, and clinical biases, were used to analyze cases from the AANA Foundation
      closed malpractice claims database. This database contains more than 300 files
      involving St Paul Fire and Marine Insurance Company-covered CRNAs from across the
      United States. These files were analyzed by 10 CRNA investigators on the AANA
      Closed Claims research team. Variables such as inadequate preinduction
      activities, e.g., incomplete preanesthetic assessments, and use of cognitive
      biases and inaccurate probability estimation were associated with adverse
      outcomes in this research sample. Teaching of decision science in basic and
      continuing nurse anesthesia education is advocated.

PMID- 12425130
TI  - Functional residual capacity: the human windbag.
AB  - Like the windbag of a bagpipe, the functional residual capacity (FRC) is the lung
      volume that acts as a reservoir of air for physiologic use. This reserve volume
      is particularly important during the period of apnea that occurs during induction
      of general anesthesia. The balance of the inward elastic recoil of the lung and
      the outward chest wall forces determines the FRC. Inward recoil forces are
      dependent on the interaction between the fibrous skeleton of the lung tissue and
      the alveolar surface tension regulated by pulmonary surfactant. Positioning and
      the use of inhaled and intravenous anesthetics influence outward chest wall
      forces. Factors that affect the FRC may be altered by volume recruitment
      maneuvers such as administration of vital capacity breaths, the application of
      positive end-expiratory pressure, and/or maintenance of anesthesia with a
      fraction of inspired oxygen of less than 1.0. This course reviews the basic
      anatomy and physiology of the FRC during the perioperative period. Understanding
      the processes that contribute to intraoperative loss of lung volume and knowledge
      of interventions that can allay them are paramount to providing a reliable and
      safe general anesthetic.

PMID- 12425131
TI  - [Molecular genetic aspects in otorhinolaryngology].

PMID- 12425132
TI  - [Cochlear implant management today].

PMID- 12425133
TI  - [Robotics and navigation].

PMID- 12425134
TI  - [Osteosynthesis systems in mouth, jaw and facial surgery].
AB  - The introduction of stable osteosynthesis of mandibular fractures in the late
      1960s for trauma patients meant an increase in quality of life. Intermaxillary
      immobilization and time in hospital could be reduced significantly. Later on,
      miniplates became popular in most trauma centers to treat mandibular fractures.
      Compared to the technique of stable osteosynthesis, miniplating is less demanding
      and the complication rates are similar. In midfacial fractures, too, miniplate
      osteosynthesis could guarantee three-dimensional stability. With the help of
      microplates even the smallest bony structures can be fixed following reduction.
      Degradable plates, which are available today, are used for craniofacial and
      midfacial indications; however, up to now degradable plates are not suitable for
      load-bearing areas.

PMID- 12425135
TI  - [Telemedicine: interaction between clinic and general practice].
AB  - BACKGROUND: The rapid development of information and communication technologies
      has led to a change of many practical aspects of professional and private life.
      These technologies also influence interactions between hospitals and outpatient
      units. METHODS: This paper provides an overview over current telemedical
      developments with effects on interactions between in- and outpatient units.
      RESULTS AND CONCLUSIONS: Probably the most important application of telemedicine
      in Germany is not distant patient care but an improved communication structure
      between different health care providers. Candidates for first routine
      applications are electronic medical reports and teleconsultations. The widespread
      use of telemedicine will be accompanied by an increased standardisation in
      medicine.

PMID- 12425136
TI  - [Reducing late toxicity with amifostine in fractionated irradiation of the rat
      salivary glands].
AB  - Clinical studies show that amifostine can reduce xerostomia and mucositis during
      radiotherapy of head and neck cancers. The aim of this study was to evaluate the
      radioprotective potency of amifostine with respect to late toxicity of salivary
      glands of rats. The head-neck-area of 8 male WAG/RijH rats (295 +/- 7 g) were
      irradiated with 60Co-gamma-rays (60 Gy/30 f/6 weeks). Amifostine (250 mg/m2 body
      surface) was applied via a venous port 15 min before each irradiation. Rats of a
      control group were irradiated with the same schedule with equal volumes of
      physiological saline. The morphological and sialoscintigraphical findings clearly
      demonstrate that amifostine has a remarkable cytoprotective effect on the late
      toxicity of irradiated salivary glands.

PMID- 12425137
TI  - [Reconstruction after extended partial laryngeal and hypopharyngeal resections. A
      new method with rib cartilage, chondrosynthesis and free radial transplants].
AB  - Partial pharyngectomy combined with subtotal laryngectomy results in permanent
      tracheostomy and long lasting swallowing difficulties in many cases. Based on our
      prior experimental and clinical studies on laryngeal chondrosynthesis the
      objectives of this project were to develop a method for reconstruction of up to
      two thirds of the larynx and one pyriform sinus. METHOD: The resected laryngeal
      framework is reconstructed with autogenous rib cartilage and stabilized with
      plates and screws. In addition a piece of cartilage is used as a buttress for
      apposition by the remaining mobile vocal cord. A free radial forearm flap covers
      the reconstructed framework and forms the sulcus of the pyriform sinus. RESULTS:
      Up to now 7 patients have been operated with this technique. The follow up was 35
      months on average. None of the patients has a clinically relevant aspiration. All
      patients have a well understandable voice and one of them--a teacher--could even
      resume his speech profession. CONCLUSION: In selected patients these techniques
      enable functional rehabilitation of swallowing, breathing and speech even after
      extended partial pharyngolaryngectomy.

PMID- 12425139
TI  - [Digital vs. analog hearing aids for children. Is there a method for making an
      objective comparison possible?].
AB  - Until now, the assumed benefits of digital hearing aids are reflected only in
      subjective descriptions by patients with hearing aids, but cannot be documented
      adequately by routine diagnostic methods. Seventeen schoolchildren with moderate
      severe bilateral symmetrical sensorineural hearing loss were examined in a double
      blinded crossover study. Differences in performance between a fully digital
      hearing aid (DigiFocus compact/Oticon) and an analogous digitally programmable
      two-channel hearing aid were evaluated. Of the 17 children, 13 choose the digital
      and 4 the analogous hearing aid. In contrast to the clear subjective preferences
      for the fully digital hearing aid, we could not obtain any significant results
      with routine diagnostic methods. Using the "virtual hearing aid," a subjective
      comparison and speech recognition performance task yielded significant
      differences. The virtual hearing aid proved to be suitable for a direct
      comparison of different hearing aids and can be used for double-blind testing in
      a pediatric population.

PMID- 12425138
TI  - ["Ultrasound tonsillectomy" in comparison with conventional tonsillectomy].
AB  - BACKGROUND AND OBJECTIVE: The postoperative convalescence after tonsillectomy is
      difficult because of a high rate of secondary hemorrhages and severe pain. The
      Ultracision Harmonic Scalpel cuts in the longitudinal direction and coagulates
      simultaneously by means of a 55.500 Hz vibrating blade. A randomized prospective
      simple blind study was conceived to compare the advantages and disadvantages of
      the "Ultrasound Tonsillectomy" with the conventional method. PATIENTS: Between
      8/1999 and 3/2000 25 tonsillectomies were performed with the Ultracision (TEuc
      group) and 25 with conventional methods (TEkonv-group). The age of the patients
      was between 18 and 65 years. RESULTS: The median intraoperative blood loss in the
      TEuc-group was significantly lower than the TEkonv-group (19.0 g/176.0 g), the
      pain symptoms were comparatively less. On the other hand postoperative blood
      losses of the TEuc-group were clearly higher (7/25 vs. 3/25), wounds healed more
      slowly, the development of the wound covering and the swelling of the uvula were
      significantly larger. CONCLUSIONS: Based on the results of the study the
      ultrasound technique is not superior to the conventional tonsillectomy.

PMID- 12425140
TI  - [Laryngoscopy in the awake infant].

PMID- 12425141
TI  - [Metastatic esthesioneuroblastoma. Challenge in interdisciplinary combined
      modality therapy].
AB  - Esthesioneuroblastoma is a rare tumor, which in many cases is diagnosed at an
      advanced stage with an high recurrence rate and incidence of metastases.
      Regionary metastases predict a poor prognosis. There is no standard therapy
      approach for these tumors. The most widly accepted primary therapy is radical
      craniofacial enbloc resection followed by radiation therapy. Today chemotherapy
      is getting more important and is administered with curative intention.
      Multidisciplinary management results in significantly longer survival in advanced
      tumor stages and recurrence. A clinical staging system as well as
      histopathological grading according of Hyams could be from importance for
      selection and timing of the different therapeutic modalities. We present a case
      of a 34-year-old female patient who was diagnosed with an advanced olfactory
      neuroblastoma of the upper nasal cavity with bilateral cervical lymph node
      metastasis (modified Kadish-stage D). Craniofacial resection and bilateral neck
      dissection was performed, followed by postoperative radiotherapy. Reviewing the
      recent literature the different therapeutic approaches are compared and
      discussed.

PMID- 12425142
TI  - [The Bonn declaration regarding the future of hearing aid management].

PMID- 12425143
TI  - [Pressure equalization during airline travel].

PMID- 12425144
TI  - [Vascular structure in the middle ear. Aberrant course of the internal carotid
      artery in the left tympanic membrane].

PMID- 12425145
TI  - [Dysplasia of the inner ear and inner ear canal].

PMID- 12425146
TI  - [Cerebral ischemia and histamine].
AB  - Cerebral ischemia induces excess release of glutamate and an increase in the
      intracellular Ca2+ concentration, which provoke catastrophic enzymatic processes
      leading to irreversible neuronal injury. Histamine plays the role of
      neurotransmitter in the central nervous system, and histaminergic fibers are
      widely distributed in the brain. In cerebral ischemia, release of histamine from
      nerve endings has been shown to be enhanced by facilitation of its activity. An
      inhibition of the histaminergic activity in ischemia aggravates the histologic
      outcome. In contrast, intracerebroventricular administration of histamine
      improves the aggravation, whereas blockade of histamine H2 receptors aggravates
      ischemic injury. Furthermore, H2 blockade enhances ischemic release of glutamate
      and dopamine. These findings suggest that central histamine provides beneficial
      effects against ischemic neuronal damage by suppressing release of excitatory
      neurotransmitters. However, histaminergic H2 action facilitates the permeability
      of the blood-brain barrier and shows deleterious effects on cerebral edema.

PMID- 12425147
TI  - [Gene therapy in cardiovascular medicine as new pharmacological therapy].
AB  - Gene therapy is emerging as a potential strategy for the treatment of
      cardiovascular disease, for which no known effective therapy exists. The first
      human trial in cardiovascular disease was started in 1994 to treat peripheral
      vascular disease using VEGF. Since then, at least 5 different potent angiogenic
      growth factors has been tested in clinical trials to treat peripheral arterial
      disease. In addition, therapeutic angiogenesis using VEGF gene was applied to
      treat ischemic heart disease. Results from these clinical trials seems to be more
      than expected. Improvement of clinical symptoms in peripheral arterial disease or
      ischemic heart disease has been reported. In this review, we have focused on the
      future potential of gene therapy for the treatment of cardiovascular disease as a
      new pharmacological therapy.

PMID- 12425148
TI  - [Free radicals and oxidative stress: targeted ESR measurement of free radicals].
AB  - The detection of free radicals generated within the body may contribute to
      clarifying the pathophysiological role of free radicals in disease processes. As
      an appropriate procedure to examine the generation of free radicals in a
      biological system, electron spin resonance (ESR) has emerged as a powerful tool
      for detection and identification. A method for determination of oxygen radical
      scavenging activity using ESR and the spin trapping technique was developed.
      Oxygen radicals were trapped by 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) or alpha
      phenyl-N-t-butylnitrone (PBN), and the DMPO or PBN spin adduct signal was
      measured quantitatively by an ESR spectrometer. The spin trapping method using
      ESR has also been reported for not only in vitro and ex vivo measurements but
      also in vivo measurements. In in vivo ESR, nitroxyl radical is being used as a
      spin trap well. ESR signal intensities of nitroxyl radical are measured after
      administration to animals and the signal decay rates of nitroxyl radical have
      reported to be influenced by various types of oxidative stress. With this method,
      it is possible to specify the type of radical or the location at which the free
      radicals are produced. The spin trapping method by in vivo ESR is an effective
      procedure for giving non-invasive measurements in animals. ESR imaging in the
      organs of live animals can also be obtained after injection of nitroxyl radicals
      as an imaging agent using ESR-computed tomography. In vivo ESR imaging has been
      established as a powerful technique for determining the spatial distribution of
      free radicals in living organs and tissues.

PMID- 12425149
TI  - [Coughing model by microinjection of citric acid into the larynx in guinea pig].
AB  - Many studies of cough were performed under the restrained or anesthetized
      condition, and coughs were evoked by inhalation of capsaicin or citric acid.
      Inhalation of irritants induced by "diving response" with apnea and coughs, and
      these responses induced a change of tidal volume. As a result, respiratory
      responses are dependent on the inhalation volume. Therefore we developed a new
      coughing model, and coughs were evoked by microinjection of citric acid into the
      larynx in the unanesthetized unrestrained guinea pig. Microinjection of 7.5%
      citric acid (2 microliters/30 s, 5 min) induced coughs (27.03 +/- 4.03 coughs/10
      min), and citric acid-induced responses were stable independent of the inhalation
      volume. In the inhalation studies, animals were exposed to citric acid only once
      because induced-responses were remarkably decreased by repeated administration at
      an interval of 24 h. However in our coughing model it was possible to repeatedly
      challenge the animals by microinjection of citric acid at intervals of 24 h.
      Microinjection of citric acid into the larynx induced coughs in Sprague-Dawley
      rats, but inhalation of citric acid did not induce cough. These results indicate
      that this coughing model is highly sensitive and correctly assessed cough
      responses.

PMID- 12425150
TI  - [Antimicrobial and clinical effect of linezolid (ZYVOX), new class of synthetic
      antibacterial drug].
AB  - Linezolid (ZYVOX), a novel synthesized antibacterial drug, was first approved in
      April 2001, as an antibacterial against vancomycin (VCM)--resistant enterococci
      in Japan. LZD has a wide spectrum of antibacterial activity against gram-positive
      bacteria with MIC90 of 0.5-4 mcg/mL. These antibacterial activities of LZD are
      similar to those of vancomycin (VCM). LZD also has similar antibacterial
      activities against drug-resistant bacteria including VRE and MRSA. Protein
      synthesis inhibitors, e.g., macrolides, tetracycline, aminoglycosides, and
      chloramphenicol, are known to bind the 30S and 50S subunits of ribosomes and
      inhibit the elongation cycle of protein synthesis. In contrast, LZD was found to
      inhibit the process of formation of the 50S, 30S-mRNA, and fMet-tRNA complex in
      the ribosome cycle, but not the elongation cycle. Due to this novel mechanism of
      action, LZD does not have a cross-resistance to drug-resistant bacteria and
      development of its resistance is quite slow. The antibacterial activity of LZD
      against VRE is bacteriostatic. In vivo antibacterial activity of orally
      administered LZD was demonstrated in a mouse model of systemic infection by VRE.
      When administered orally prior to the abscess formation in a mouse model of soft
      tissue infection by VRE, LZD showed similar antibacterial activity against VRE
      infection to that against VCM-susceptible enterococci. LZD is rapidly absorbed
      following oral administration and bioavailability when compared with intravenous
      administration is almost 100%. LZD administered orally twice-daily showed
      excellent efficacy in clinical trials with VRE-infected patients.

PMID- 12425151
TI  - [Cevimeline hydrochloride hydrate (Saligren capsule 30 mg): a review of its
      pharmacological profiles and clinical potential in xerostomia].
AB  - Cevimeline hydrochloride hydrate is a muscarinic receptor agonist with a chemical
      structure of a quinuclidine. Intraduodenal administration of cevimeline
      hydrochloride hydrate dose-dependently increased salivary secretion in normal
      mice and rats, two strains of autoimmune disease mice, and X-irradiated rats. The
      clinical efficacy of the cevimeline hydrochlide hydrate at 30 mg t.i.d. during 4
      weeks has been demonstrated in double blind comparative study with placebo. In
      addition, its treatments in 52 weeks have increased salivary flow and improved
      subjective and objective symptoms of patients with xerostomia in Sjogren's
      syndrome.

PMID- 12425152
TI  - [Status report on epidemiology of acute appendicitis].
AB  - The current incidence of appendicitis is about 100 per 100,000 person-years in
      Europe/America. Whereas the appendectomy rate is still decreasing, the incidence
      of appendicitis is now nearly stable. During the last 30 years the incidence of
      perforated appendicitis has not changed (approximately 20 per 100,000 person
      years). Established risk factors for acute appendicitis are age (peak: 10-19
      years), sex, and ethnic group/race. Classical theories (diet, hygiene) present
      illuminating models to explain the rise and fall of incidence in the last
      century; however, from a contemporary perspective the evidence is insufficient.
      The study of the epidemiology of appendicitis is complicated by the influence of
      referral, infrastructure, and surgical treatment strategy on the incidence of
      acute appendicitis. Therefore, there is a strong need for good prospective
      studies with high-quality data (e.g., studies directed by a central pathology
      department).

PMID- 12425153
TI  - [Pathology of appendicitis].
AB  - Acute appendicitis represents one of the most common inflammatory diseases of the
      gastrointestinal tract. Acute appendicitis is most frequently based on the
      coincidence of obstruction, reduced blood supply, ischemic damage of the mucosa,
      and bacterial infection. Inflammation at other abdominal sites may also involve
      the appendix in 7% of cases causing periappendicitis. In 15-20% there are no
      pathologic findings of acute inflammation but rather post-inflammatory residues
      and a neuroma-like proliferation of Schwann cells, typically found in neurogenic
      appendicopathy. This finding may in part explain the clinical symptoms.

PMID- 12425154
TI  - [Appendicitis. Present-day diagnosis].
AB  - At times, making the diagnosis of acute appendicitis may pose a considerable
      problem. However, prompt and accurate diagnosis is essential to obtain minimal
      morbidity. Diagnostic mistakes result either in delayed initiation of adequate
      therapy or unnecessary operations. During the past years, a number of new
      strategies and diagnostic procedures have been developed and refined, including
      structured patient interview pathways, scoring systems, ultrasound, computed
      tomography, and diagnostic laparoscopy. This review summarizes the diagnostic
      performance of these modalities and discusses their clinical impact. It is
      apparent that in everyday practice, none of the technical modalities can replace
      the skill and precision of surgical exploration.

PMID- 12425155
TI  - [Open vs. laparoscopic appendectomy].
AB  - This article discusses the question of whether open or laparoscopic appendectomy
      is preferable in today's clinical routine. The article is based on data from
      randomized studies, evaluation of meta-analyses, and data from nonrandomized,
      multicentric studies evaluating the treatment of appendicitis in routine clinical
      practice. According to the data analysis, open appendectomy (OA) offers
      advantages with regard to a significantly shorter operative time and lower
      hospital costs. Laparoscopic appendectomy (LA) is characterized by a
      significantly decreased rate of failed septic wound healing and faster recovery.
      Both procedures can be performed with the same degree of safety and comparable
      outcome for acute appendicitis. Laparoscopic appendectomy offers significant
      advantages for establishing a precise diagnosis in young fertile women and
      overweight patients suffering from lower abdominal pain. The currently available
      data do not provide precise guidelines for the treatment of perforating
      appendicitis. However, we found significant evidence indicating an increased rate
      of postoperative intra-abdominal abscess after laparoscopic appendectomy. Thus, a
      laparoscopic approach cannot be regarded as a standard technique in advanced
      appendicitis.

PMID- 12425156
TI  - [Current therapy of complicated appendicitis].
AB  - A significant number of complications in acute appendicitis develop due to
      delayed or even missed diagnosis. Potentially every patient can be affected due
      to a distinct feature of appendicitis--the rapidity with which the inflammation
      passes through the different stages. Even after a few hours, gangrenous
      appendicitis with impending overt perforation can have developed. In many cases,
      the term complicated appendicitis may be less significant than implied because,
      e.g., the rapidly developed perforation can be treated by appendectomy, which
      rarely presents a surgical challenge. However, every perforation of a hollow
      viscus in the abdomen leads to peritonitis of different degrees, which untreated
      can end lethally. The often cited statement of Dieu la Foy from the last but one
      century "no patient has to die from appendicitis" remains a surgical dream not
      quite fulfilled. Occasionally even today, patients with comorbidity die from the
      sequelae of appendicitis, i.e., high-risk groups including the very young and the
      very old and immunosuppressed patients. These patients should receive special
      attention when the diagnosis of appendicitis is considered. By definition,
      complicated appendicitis includes perforation of the appendix, empyema or abscess
      formation, and finally fecal peritonitis. The surgical procedure chosen and when
      to add supportive measures will depend on the specific complication present.
      Early or immediate appendectomy, i.e., the urgent indication to operate, is a
      generally accepted concept in the therapy of acute appendicitis. Even in
      complicated cases, the aim is just one operative procedure or if need be only the
      application of antibiotics.

PMID- 12425157
TI  - [Appendectomy reduces the risk of development of ulcerative colitis].
AB  - The etiology and pathogenesis of ulcerative colitis are still unclear. There is,
      however, a growing consensus that the disease is characterized by a complex
      interaction between genetic and environmental influences. Many studies in the
      last few years have suggested that appendectomy reduces the risk of development
      and improves the course of ulcerative colitis. The underlying mechanism of this
      effect is unknown. The appendix seems to play a more important role in the
      development and modulation of the mucosal immune system than believed so far.

PMID- 12425158
TI  - [Multimodal interdisciplinary therapy to improve function and long-term survival
      in patients with high-grade osteosarcoma of the extremities].
AB  - INTRODUCTION: The probability for survival of patients with highly malignant
      osteosarcoma of the extremities was essentially improved by (neo-)adjuvant
      chemotherapy. The goal was to further improve survival rates by introducing
      operative treatment of metastases. In the last 20 years, the percentage of limb
      preserving operations has increased. PATIENTS AND METHODS: A consecutive series
      of 23 patients with localized highly malignant osteosarcoma of the extremities
      received (neo-) adjuvant chemotherapy according to the Cooperative Osteosarcoma
      Study (COSS) protocol. Local treatment was performed by wide (22 patients) or
      radical (1 patient) resection (17 limb salvage procedures, 5 amputations, and 1
      rotationplasty). In four of seven patients who developed pulmonary metastases,
      the metastases (up to four) were resected. The patients did not receive salvage
      chemotherapy. RESULTS: The cumulative survival was 87% at 174 months. The four
      patients who underwent metastasectomy survived between 42 and 116 months without
      evidence of disease. One local recurrence developed outside the operative field
      and could be resected without influencing the functional or oncological outcome.
      After limb salvage procedures, the mean score according to the Musculoskeletal
      Tumor Society (MSTS) was 83%, and after rotationplasty 67%. CONCLUSIONS: In
      patients with osteosarcoma of the extremities, limb salvage is possible in a high
      percentage of cases with a low risk of local recurrence by an effective
      interdisciplinary cooperation between diagnostic radiologists, oncologists, and
      orthopedic surgeons. The midterm survival could be improved by the multimodal
      therapy from about 20% up to about 80%. Metastasectomy gives patients with a
      limited number of pulmonary metastases a realistic chance to survive.

PMID- 12425159
TI  - [Pain management in surgical wards. Quality and solutions for improvement in the
      early postoperative period].
AB  - INTRODUCTION: Following guidelines pain levels should not exceed a score of 3 on
      the visual analog scale (VAS 1-10). We were interested in the actual surgical
      pain management of the postoperative period and the potential influences of a
      nurse-controlled intravenous morphine administration (NCA) on its quality.
      METHODS: Interventional study: interview of patients and nursing staff and
      examination of records concerning pain treatment following surgery. RESULTS: The
      interviews were conducted with 110 patients before and 125 patients after the
      intervention program. Before the intervention, one-half of the patients noted
      that they were never asked about their pain intensity within the first 24 h after
      surgery. Only 42% of the records showed at least one VAS documentation. Every
      fourth individual experienced a pain intensity > 3 without having received a
      supplementary pain medication. Following the morphine intervention program,
      documentation of pain scores increased significantly (72%; p < 0.0001) and more
      patients were familiar with the VAS (64% vs 46%; p < 0.0004). Median maximum as
      well as actual pain at the time of the interview decreased by one point (VAS).
      The percentage of patients whose supplementary pain prescription was totally used
      showed a significant increase (p = 0.035). Following morphine administration, no
      single individual complained about an undue waiting time in comparison to 15% of
      patients previously. Even though the morphine intervention project caused more
      work for the nursing staff, 75% of the personnel were convinced that the
      procedure was worth this investment. CONCLUSION: This data revealed a relevant
      deficiency of surgical pain management. Already basic instructions on pain
      management can significantly improve this treatment. Assigning additional
      authority to the nursing staff, such as a nurse-based intravenous opioid
      administration, can significantly raise the motivation of the personnel as well
      as the satisfaction of the patients involved.

PMID- 12425160
TI  - [Current perspectives of orthogonal polarization spectral imaging in plastic
      surgery].
AB  - The technology of Orthogonal Polarization Spectral Imaging (OPSI), patented in
      the United States in 1999, has been heralded as an alternative to conventional
      intravital microscopy for several reasons, including ease of application and
      ability to perform continued observations. In the following examples, OPSI was
      applied to reconstructive plastic surgery. Two experimental and one clinical
      model are presented. Currently, the image quality does not allow a qualitative
      analysis of the microvasculature. The data analysis of images remains
      inconclusive. However, a technically modified version with improved image
      resolution and software could become a valuable experimental as well as clinical
      tool in the field of reconstructive plastic surgery in the future.

PMID- 12425161
TI  - [The carcinogenic potential of biomaterials in hernia surgery].
AB  - The implantation of meshes to correct inguinal as well as incisional hernias is
      widely used in the U.S.A. and Western Europe. The short and long term results of
      meshes are convincing concerning complications, recurrence rate and patient's
      comfort. On the other hand side some scientific groups discuss the possibility of
      malignant tumor development due to implanted meshes. In fact, experimental models
      exist which demonstrate that soft tissue sarcomas can be induced in mice and rats
      by implanting artificial materials such as synthetics or metal. Beside millions
      of hernia repairs using meshes worldwide no patient has been reported with a soft
      tissue tumor until today. The analyses of molecular markers of proliferation, of
      apoptosis as well as the modulation of heat shock proteins seem not to prove the
      carcinogenic potential of meshes. In conclusion, there are no data so far
      indicating a real risk for humans to develop malignant tumors due to implanted
      meshes. Therefore we further propagate the implantation of meshes in hernia
      repair in adult patients.

PMID- 12425162
TI  - [Comment by request of the editorial staff].

PMID- 12425163
TI  - [Aneurysm treatment with the "Talent stent graft". An update after 4 years of
      experience].
AB  - INTRODUCTION: The negative experience with stent grafts of the first generation
      shows the important role of the endograft in the treatment of abdominal aortic
      aneurysm. The midterm results of a stent graft (Talent) widely used in Germany
      were analyzed up to 4 years after the first implantation. PATIENTS AND METHODS:
      We report on 73 patients treated at our department using the Talent stent graft.
      The study analyzes patient data before, during, and after the operation as well
      as the results of clinical follow-up and CT scan examinations performed 3-47
      months after treatment. RESULTS: In 72 cases the implantation was successful.
      Endoleaks were found in three cases (type I n = 2, type III n = 1). Three
      patients had a complication at the vascular access site (3.9%). In one patient
      the short contralateral leg did not open. During the follow-up five patients died
      (7%). In two patients the graft limb occluded (3.3%). A migration of the graft
      components did not occur. In two cases a persistent type II endoleak was found
      (3.3%). CONCLUSIONS: The Talent stent graft showed good stability and easy
      adjustment. Even patients with a large aneurysm neck have been successfully
      treated. Problems while implanting the graft were only observed in cases of
      kinking of the iliac artery. A greater flexibility of the introducer system and a
      better rotational stability of the graft inside the introducer would be
      advisable.

PMID- 12425164
TI  - [Surgical decision making and behavior. Social psychology explanations and
      research perspectives].
AB  - Social psychology is the discipline that investigates thought processes,
      emotions, and behaviors in the interpersonal context. There are three broad topic
      domains: understanding oneself and other persons, interpersonal relations, and
      group influence. The most important method is the experiment. The value of the
      social psychological perspective is illustrated with regard to the following
      surgical research questions: How do surgeons arrive at their decisions? How do
      surgeons confirm their decisions? Why do decision aids (computer support,
      guidelines) receive so little acceptance? How should patients be informed? Which
      group processes play a role in the operating theatre? What are the determinants
      of patient outcomes? Social psychology can extend surgical research in three
      respects: better understanding of everyday phenomena in the clinical and surgical
      arena, methodologically refined and stronger patient-oriented study designs, and
      new perspectives for improved patient outcomes.

PMID- 12425165
TI  - [Rectal carcinoma in a patient with familial adenomatous polyposis coli after
      colectomy with ileorectal anastomosis and consecutive chemoprevention with
      sulindac suppositories].
AB  - Surgery is the definitive treatment in familial adenomatous polyposis coli (FAP).
      Proctocolectomy with ileal pouch anal anastomosis is recommended for the majority
      of FAP patients. Only in patients with attenuated FAP, is a colectomy with
      ileorectal anastomosis (IRA) accepted, although the risk for rectum carcinoma
      remains increased. Sulindac, a chemoprophylactic agent, regresses colorectal
      adenomas in patients with FAP. Under systemic Sulindac-therapy, three carcinomas
      in the rectum after colectomy with IRA have been described. We report the first
      known case of rectum carcinoma in a patient with FAP, 51 months after IRA and
      local Sulindac therapy.

PMID- 12425166
TI  - [Localization of primary small cell carcinoma with liver metastasis: a rare
      combination of colonic adenocarcinoma and undifferentiated small cell carcinoma].
AB  - Neuroendocrine or small cell cancer (SCC) is a rare tumor, accounting for less
      than 1% of all colorectal cancers. There is a high rate of metastasis in SCC.
      Overlying adenomas are commonly present in colorectal SCC. We present a case of a
      67-year-old female patient with liver metastasis of SCC. Initially, the primary
      tumor was not found and the patient underwent chemotherapy. Ten months later, an
      adenocarcinoma of the right hemicolon was endoscopically diagnosed due to anal
      hemorrhage and right hemicolectomy was performed. Microscopic examination
      revealed that the adenocarcinoma was combined with an undifferentiated
      carcinomatous component. Immunocytochemistry was positive for synaptophysin and
      chromogranin. In our case a very rare combination of colonic adenocarcinoma and
      SCC within an overlying adenoma was found.

PMID- 12425167
TI  - [Access-related complications in laparoscopic surgery. Tips and tricks to avoid
      trocar complications].

PMID- 12425168
TI  - Challenges and directions for environmental public health indicators and
      surveillance.

PMID- 12425169
TI  - Health-and-environment indicators in the context of sustainable development.
AB  - This paper gives a broad overview of issues relevant to the development and use
      of health-and-environment indicators in the broader context of sustainable
      development. Criteria for the construction of indicators are given, and their key
      characteristics are highlighted. Selected international indicator initiatives are
      discussed, as well as the concept and use of core indicators in policy and
      planning. Finally, an organizational framework for the consideration of health
      environment-development linkages is presented, which can be used in the
      development of health-and-environment indicators in various contexts. This
      framework is the Driving forces-Pressures-State-Exposures-Health Effects-Actions
      framework (DPSEEA) of the World Health Organization (WHO). It is a descriptive
      representation of the way in which various driving forces generate pressures
      which affect the state of the environment, and ultimately human health through
      the various exposure pathways by which people come into contact with the
      environment. Throughout the paper, emphasis is placed on work done within the UN
      system, in particular that of the WHO, and examples of suites of indicators
      developed and in use are provided.

PMID- 12425170
TI  - International monitoring for environmental health surveillance.
AB  - This paper offers an overview of existing international monitoring systems with
      relevance for environmental health surveillance. Representative monitoring
      systems are described that: address areas of chronic and acute exposure, and
      diseases and behavioural effects resulting from human-environment interactions;
      have an ecosystem focus with perhaps a secondary motivation of ascertaining human
      health impacts that may result from ecosystem conditions; and that incorporate
      socio-demographic and economic data that may reflect population health
      determinants. General conclusions on the state of environmental surveillance
      systems and suites of indicators reviewed are provided in relation to their
      utility for the development of a generic environmental health surveillance
      system. This review indicates, among other things, that no obvious short list of
      core indicators exists which spans "environmental health" to provide a sufficient
      set applicable in a global context. Through a summary of challenges and
      limitations in existing systems and indicator sets, recommendations are provided
      for the discussion of indicator selection and organization, and of developing
      general and widely applicable environmental health monitoring and surveillance
      systems.

PMID- 12425171
TI  - Cross-disciplinary communication needed to promote the effective use of
      indicators in making decisions.
AB  - This paper examines problems of assessment and decision-making that result from
      poor or inadequate communication of indicators among the disciplines of public
      health, the physical sciences, and economics. The specific examples used are
      drawn from climate impacts in the Americas although the issues are more general
      to environmental health. In terms of physical processes, problems arise in
      confusion about indicators at different steps along the DPSEEA framework of
      environmental health indicators and general scientific uncertainty about the
      underlying physical processes. Communication between public health and economics
      is hindered by a lack of understanding of economic costs used in making decisions
      and the presence of implicit value judgments in economic analysis. Organizational
      structures may further inhibit the effective use of indicators. Finally, the
      paper discusses the Pan American Health Organization proposal to enhance the
      communication of indicators by using information technology networking to support
      communication among program managers and decision-makers at the national and
      local levels. The aim of this initiative is to establish a better environment for
      making decisions. The problem of cholera in Peru is shown as an example of the
      need for better communication.

PMID- 12425172
TI  - Modern information technologies in environmental health surveillance. An overview
      and analysis.
AB  - In recent years we have witnessed the massive introduction of new information
      technologies that are drastically changing the face of our society. These
      technologies are being implemented en masse in developed countries, but also in
      some pockets of developing nations as well. They rely on the convergence of
      several technologies such as powerful and affordable computers, real-time
      electronic measurement and monitoring devices, massive production of digital
      information in different formats, and faster, wireless communication media. Such
      technologies are having significant impacts on every domain of application,
      including environmental health surveillance. The current paper provides an
      overview of those technologies that are having or will likely have the most
      significant impacts on environmental health. They include World Wide Web-based
      systems and applications, Database Management Systems and Universal Servers, and
      GIS and related technologies. The usefulness of these technologies as well as the
      desire to use them further in the future in the context of environmental health
      are discussed. Expanding the development and use of these technologies to obtain
      support for global environmental health will require major efforts in the areas
      of data access, training and support.

PMID- 12425173
TI  - Indicators of ocean and human health.
AB  - The interactions between humans and the ocean are significant, and necessitate
      more comprehensive study on an international scale. The world's oceans provide
      great health benefits to humans ranging from food and nutritional resources, to
      recreational opportunities and new treatments for human disease. However,
      recently, human health effects from exposure to substances present in the marine
      ecosystem such as synthetic organic chemicals (e.g., chlorobiphenyls, chlorinated
      dioxins and some industrial solvents), polycyclic aromatic hydrocarbons (PAHs),
      metals (both introduced and anthropogenic), marine toxins, and pathogens have
      been recorded and are of great concern. This paper reviews our state of knowledge
      of the interactions between oceans and human health and proposes indicators and a
      research strategy to investigate and monitor these relationships more closely.
      Four approaches to gathering information on indicators included here are:
      biomarkers; cellular pathology; physiological and behavioural responses; and
      changes in populations. All hold the potential to enhance our understanding of
      marine environmental quality and far-reaching effects on human health. Monitoring
      systems that include the rapid assessment of contaminants in the ecosystem and
      subsequent risk to human populations, with appropriate internationally
      distributed data bases, need to be developed and validated. Such tools would
      provide early detection of potential environmental threats, and enhance the
      ability to prevent human illness.

PMID- 12425174
TI  - Environmental health surveillance: indicators for freshwater ecosystems.
AB  - The relationship between the health of human populations and the state of the
      ecosystems in which they live is profoundly complex. As most environmental
      indicators relevant to human health depend on evidence of a direct cause and
      effect relationship, there are few indicators of the less direct consequences of
      environmental degradation on human health. Indicators of the direct consequence
      of contaminants in freshwater ecosystems on human health are highlighted in this
      paper and candidate indicators for environmental health are provided. Many of the
      indicators included here are from the State Of the Lakes Ecosystem Conference
      (SOLEC) program. SOLEC conferences in the past (1994 and 1996) examined the state
      of various components of the ecosystem through the use of ad hoc indicators, and
      provided subjective assessments of certain environmental conditions. At SOLEC 98,
      a comprehensive suite of 80 Great Lakes ecosystem health indicators was presented
      for review, refinement and acceptance. Candidate indicators for freshwater
      systems and environmental health presented here are organized following the
      "Pressure-State-Response" framework and cover the areas of drinking water,
      recreational water, freshwater food sources, and the availability of freshwater
      for economic activities.

PMID- 12425175
TI  - Indicators of environmental health in the urban setting.
AB  - The North American population is approximately 80% urbanized and spends almost
      90% of the time indoors. Accordingly, the built environment is the most important
      -one might almost say "natural"--human environment. Urban settlements incorporate
      within their boundaries natural ecosystems of plant and animal life (often highly
      adapted to the urban environment), and are in turn incorporated within wider
      bioregions and global ecosystems. But urban settlements are not just built and
      natural physical environments, they are social, economic, cultural and political
      environments; the whole constitutes an urban ecosystem. These ecosystems have
      profound implications for the physical, mental, social, emotional and spiritual
      well-being of their human inhabitants, as well as for human beings remote from
      these urban ecosystems. Therefore, this paper discusses urban ecosystems and
      human health and presents a framework for indicators of environmental health in
      the urban setting based on such an understanding. The concepts of environmental
      viability, ecological sustainability, urban livability, community conviviality,
      social equity, and economic adequacy are discussed in relation to human health
      and are used to organize proposed candidate indicators for urban ecosystems and
      public health.

PMID- 12425176
TI  - A strategy for developing environmental health indicators for rural Canada.
AB  - Our understanding of and ability to describe rural health conditions can be
      considerably enhanced by the use of rural health indicators which allow us to
      compare rural and nonrural areas or areas differentially located on the urban
      rural continuum in terms of various health conditions. However, while health
      indicators abound, there are very few that can be used to describe the health
      conditions of rural Canada. This paper discusses the concepts of health in a
      rural context and adopts a broad definition of health that goes beyond the mere
      absence of disease or impairment. We propose five broad categories of health
      indicators: health status indicators, health determinant indicators, health
      behaviour indicators, health resource indicators, and health service utilization
      indicators. The most commonly used health indicators in Canada and the datasets
      from which they are derived are examined in order to assess their applicability
      to "communities" or "regions". This review highlights the strengths and
      limitations of various datasets and indicators and their applicability to the
      "community" and "regional" scale for rural environments. Finally, challenges in
      data availability and use are discussed as they relate to rural health indicator
      development.

PMID- 12425177
TI  - Sentinel human health indicators: to evaluate the health status of vulnerable
      communities.
AB  - The presence of toxic substances in the Great Lakes (GL) basin continues to be a
      significant concern. In the United States, some 70,000 commercial and industrial
      compounds are now in use. More than 30,000 are produced or used in the Great
      Lakes ecosystem. These substances include organochlorines (e.g., polychlorinated
      biphenyls (PCBs), dioxins, furans, dieldrin, etc.), heavy metals such as
      methylmercury, and alkylated lead, and polycyclic aromatic hydrocarbons (e.g.,
      benzo[a]pyrene). The IJC has identified 42 locations in the GL basin of the
      United States and Canada as Areas of Concern (AOCs) because of high
      concentrations of these toxic substances. In 1990 the U.S. Congress amended the
      Great Lakes Critical Programs Act to create The Agency for Toxic Substances and
      Disease Registry (ATSDR) Great Lakes Human Health Effects Research Program
      (GLHHERP) to begin to address these issues. This program characterizes exposures
      to contaminants via consumption of GL fish and investigates the potential for
      short- and long-term adverse health effects. This paper reviews the GLHHERP
      program and indicators established to monitor and address the risks posed by
      these substances to vulnerable populations in the Great Lakes ecosystem.

PMID- 12425178
TI  - Indicators in environmental health: identifying and selecting common sets.
AB  - In association with the proposed goals of the conference, this paper is presented
      to support the conference discussions on environmental health indicators by
      providing background on indicators for environmental health and their
      identification, selection, organization and use. This paper discusses the purpose
      of indicator use, frameworks used to organize indicators and the common types of
      indicators in use in monitoring programs today. It proposes a process for the
      identification and selection of indicators within the different environments,
      stressing the importance of clear goal definition and scientific and use-based
      criteria selection to support decisions. Finally, the paper suggests methods by
      which to organize and limit the number of indicators retained within a program,
      and the development of a potential "core" of indicators common to many
      environments and geographical scales.

PMID- 12425179
TI  - Putting indicators to work. A summary of roundtable presentations on the Latin
      American and Caribbean experience with environmental health indicators.
AB  - A roundtable was held at the conclusion of the formal conference presentations to
      present and discuss experiences in Latin America and the Caribbean with indicator
      selection, implementation and use. Four presentations were given covering the
      following topics: the Pan American Health Organization's (PAHO) implementation of
      a core indicators program in the Americas; Latin America's use and application of
      the WHO developed Driving forces, Pressure, State, Exposure, Effect, Action
      framework (DPSEEA) for indicators; the Chilean experience in identifying,
      selecting and implementing indicators for use throughout the country; and
      finally, the use and application of the WHO DPSEEA framework to the issue of
      water quality monitoring in Brazil. Each paper presented a summary of knowledge
      gained to date from their experience and some of the strengths and challenges
      identified from the various approaches taken. The summary presented here provides
      a brief overview of the presentations given at the workshop.

PMID- 12425180
TI  - Epidemiology and pathophysiology of peripheral arterial disease.
AB  - Evidence that both asymptomatic and symptomatic peripheral arterial disease (PAD)
      represent an independent risk for cardiovascular morbidity and mortality has
      triggered a resurgence in epidemiologic and clinical interest in PAD. Between 8
      and 12 million people in the United States are presumed to have PAD, and as the
      US population ages the incidence of PAD is expected to increase. Epidemiologic
      studies have shown that the prevalence of PAD among men and women is similar, and
      autopsy studies of young adults have shown a high frequency of advanced
      atherosclerotic lesions in distal abdominal aorta by the second decade of life.
      The pathophysiology of PAD is complex and has not been studied thoroughly.
      Additional research to understand the pathophysiologic mechanisms in disease
      specific circulatory beds is crucial for the advancement of medical therapy for
      PAD.

PMID- 12425181
TI  - Diagnosis of peripheral arterial disease: utility of the vascular laboratory.
AB  - The risks of undiagnosed peripheral arterial disease (PAD) include progressive
      reduction in quality of life, potential limb loss, and unrecognized comorbid
      atherosclerotic (concomitant coronary and cerebrovascular) disease. Although a
      thorough historical review of symptoms and a comprehensive physical examination
      may lead the clinician to an appropriate index of suspicion, accurate diagnostic
      testing is crucial. Accredited vascular diagnostic laboratories provide a risk
      free description of the presence, severity, and location of PAD. This article
      describes the basic noninvasive diagnostic tests, criteria for diagnosis,
      advantages and disadvantages of each diagnostic modality, and a strategy for PAD
      therapy.

PMID- 12425182
TI  - Treatment of peripheral arterial disease.
AB  - Peripheral arterial disease (PAD) is a manifestation of systemic atherosclerosis
      strongly associated with cardiovascular (CV) morbidity and mortality.
      Approximately 12% of the US adult population is affected. Despite its prevalence,
      the disease has received little attention from clinicians. The primary causes of
      death in patients with PAD are myocardial infarction and stroke; thus, current
      treatment strategies for symptomatic PAD include aggressive modification of risk
      factors for CV disease such as cessation of smoking, treatment of hypertension
      and diabetes, and normalization of low-density lipoprotein cholesterol levels.
      All patients with PAD should be receiving antiplatelet therapy to prevent
      ischemic events. Medical treatment for patients with claudication includes
      exercise rehabilitation and drug therapy. Although many therapies for
      claudication have been thoroughly investigated, research continues on new
      treatments. In contrast, more prospective, randomized trials are needed to
      evaluate various therapies for treating patients with PAD.

PMID- 12425183
TI  - Vascular surgery for peripheral arterial disease.
AB  - The North American Symptomatic Carotid Endarterectomy Trial (NASCET) confirmed
      that carotid endarterectomy (CEA) can significantly cut the risk of stroke in
      patients with moderate and severe blockage. The standard today is that patients
      who have internal carotid artery stenosis > 70% with associated symptoms and who
      are appropriate surgical candidates should be offered CEA. Aneurysmal disease, a
      growing public health concern, poses the threat of death from rupture, and lower
      extremity arterial occlusive disease poses a significant risk of critical leg
      ischemia and limb loss. Both conditions involve surgical options. In treating
      their patients, primary care physicians should become familiar with the benefits
      and risks of vascular surgery to manage the various aspects of peripheral
      arterial disease.

PMID- 12425184
TI  - Understanding informed consent.

PMID- 12425185
TI  - The key to billing: documentation.

PMID- 12425186
TI  - Glucosamine for osteoarthritis.

PMID- 12425187
TI  - Acute bacterial rhinosinusitis. Care and treatment modalities.

PMID- 12425188
TI  - Evaluation of physical abuse in children. Solid suspicion should be your guide.

PMID- 12425189
TI  - Fruits and vegetables. Make their synergy work for your pediatric patients.

PMID- 12425190
TI  - Low-carbohydrate diets. What you and your patients need to know.

PMID- 12425191
TI  - The power of the perk. Understanding the health effects of caffeine.

PMID- 12425192
TI  - Just what we need, more caffeine.

PMID- 12425193
TI  - Patient information. Childhood immunization recommendations.

PMID- 12425194
TI  - Diabetes and depression. What is the link?

PMID- 12425195
TI  - Diagnosing acute abdominal pain. Your ears may tell you more than your hands.

PMID- 12425196
TI  - Practicing what I preach.

PMID- 12425197
TI  - [Acetylsalicylic acid and ACE inhibitors in heart disease--a phenomenon in dogs
      and cats?].

PMID- 12425198
TI  - [Acetylsalicylic acid--is everything clear? Probably not].

PMID- 12425199
TI  - [Treatment of hypertension in diabetics with trandolapril, an angiotensin
      converting enzyme inhibitor--a multicenter study].
AB  - Subjects with diabetes mellitus (DM) are high-risk patients because of the
      cardiovascular morbidity and mortality. A one-year open clinical prospective
      study took place in 7 centres in the Czech and Slovak Republic in 1996-1997. Aim
      of the study was treatment of hypertension in patients with DM of both types by
      the ACE inhibitor trandolapril in dose of 2-4 mg, possibly in combination with
      the calcium channel blocker verapamil--240 mg. The investigation was completed by
      79 patients (60 patients with DM type 2 and 19 with DM type 1). All patients
      achieved the target blood pressure which in 1997 was also for patients with DM
      less than 140/90 mm Hg. As good as 20% of the patients achieved these values when
      treated with 2 mg trandolapril, 52% on a dose of 4 mg and 23% after combined
      treatment. Only 25% of the patients achieved values lower than 130/85 mm Hg, as
      recommended in the contemporary recommendations "Prevention of ischaemic heart
      disease in adult age" published in 1998. On comparison of other risk factors in
      groups of patients with a BP below 130/85 mm Hg and higher than this borderlimit
      line it was revealed that one-year treatment of hypertension with trandolapril--4
      mg alone or combined with verapamil 240 mg led to a greater reduction of the
      pulse rate, fasting insulin level, hematicrit and triglycerides and to an
      increase of HDL-cholesterol. This study revealed that systematic treatment of
      hypertension by the above mentioned drugs in patients with DM is effective and
      well tolerated. In addition to reduction of the blood pressure the activity of
      the sympathetic nervous system was reduced and some metabolic parameters
      improved.

PMID- 12425200
TI  - [Therapeutic results and changes in prognosis in patients with multiple myeloma
      in central and northern Moravia over the past 40 years].
AB  - OBJECTIVE: The objective of the investigation is evaluation of therapeutic
      results and the development of the prognosis of patients with multiple myeloma
      (MM) as a result of consecutive changes of therapeutic procedures in patients of
      central and northern Moravia in the course of the last 40 years. METHODS AND
      RESULTS: The analyzed group of 562 patients with MM was concentrated at the Ist
      and IIIrd Medical Clinic of the Faculty Hospital Olomouc in 1959 - 2000, median
      age 63 (28-91) male/female ratio 1.1: 1.0. From analysis of Kaplan-Meier survival
      curves and the results of statistical analysis (log rank test p = 0.0000) ensued
      that during the evaulated period a very substantial change of prognosis occurred
      with improvement of theraupeutic  results and a significant prolongation of
      survival in general. The first " turning point" was the introduction of
      chemotheraphy with alkylating substances with Prednisone (1963-1975), leading as
      compared with the period of  symptomatic treatment alone (1959-1063) to a
      significant prolongation of the media value of general survival (M) from 8 to 19
      months (p = 0.0031) and 3-year survival from 4 to 23 % patients, whereby 10-year
      survival was only 0 %   and 1 %. The second "turning point" was the period from
      1976 - 1980 with introduction of systematic chemotherapy using conventional doses
      of  polychemotherapeutic (CP) regimes with better opportunities of supporting
      treatment (M = 40 months, p = 0.0000; 3-year and 10-year survival 55% and 5.5%
      patients). The therapeutic results acheived during the subsequent 15 years were
      however an unsatisfactory advance. During the interval between 1976-1995 in a
      group of 295 patients divided into 5-year sub-periods remission was acheived  (R
      = < 25 % of the baseline value of    M-protein) in 10-24 % patients, an
      inadequate response (NR) =  persistence in > 50 % M-protein) in 55-28 %,
      prolongation of the median of total survival in 232 of  the accessble patients
      for 44 months and long-term survival of 5 - 10 years after establisment of  the
      diagnosis increased from 25 to 36 % and from 5.5 to 16.5 % patients. The third
      "turning point" was 1996 characterized by the introduction of high-dosage
      chemotheraphy with transplantation of autologuos peripheral haematopoietic cells
      ("HD" therapy with ASCT) leading ina group of so far only 33, assessable patients
      under 65 years to acheived remission in 71 %, to decline of  NR in  10 % only and
      5 -year suvival so far in 91 % patients ( p = 0.0037). Improvement of therapeutic
      results and prognosis of  the disease as compared with  1976 - 1995 occurred in
      the whole group of patients also in 1996 - 2000 (CP and "HD"-therapy with ASCT)
      characterized by remission in 36 %, NR IN 33 % and 5 -year survival in 57 % (p =
      0.030). It  was reveled that the application of "HD" theraphy with ASCT led in
      1995-2000 to the acheivement of more favorable therapeutic results (R - 71 % NR -
      10 %. 5-year survival after the interval which elapsed so far 91 %), as compared 
      with 2 similar groups of subjects under 65 years meeting the criteria of "HD" 
      theraphy with ASCT, but treated only by conventional polychemotheraphy (1991 -
      1995 and 1996 - 2000: R - 24 and 32 %, NR - 42 and 23 %, 5-year survival 46 and
      68 % of the patients). In the group of 148 patients from the period of 1991-2000
      the patients had as regards remission (R) more favourable results as compared
      with patients with NR concerning the prognosis [M 63 vs.22 months, 5-year and 10
      year survival 53 vs. 17 % and 17 vs. 0 % of patients (p = 0.0000)]. CONCLUSION:
      From the submitted analysis ensured that during the period form 1959 - 2000 in
      patients with mutiple myeloma in central and northern Moravia as a result of the
      application of  modern methods of chemotheraphy and supporting treatment a
      significant improvements of   results  of conventional treatment occurred with a
      more than 5 fold prolongation of so far assessable median values of survival (8 -
      44 months) and long-term 10-year survival of almost one sixth of the patients.
      The real asset of   "HD" theraphy with transplantation of ASCT will be revealed
      by analyses made after a longer time interval.

PMID- 12425201
TI  - [Is mild essential hypertension without obvious organ complications and risk
      factors associated with increased levels of circulating markers of endothelial
      dysfunction? Effect of ACE inhibitor therapy].
AB  - The objective of the investigation was to assess whether circulating adhesion
      molecules, von Willebrand factor (vWf) and endothelin-1 are elevated in patients
      with mild uncomplicated essential hypertension without further risk factors of
      atherosclerosis and whether they could serve as indicators of endothelial
      dysfunction in this form of hypertension. Furthermore the authors investigated
      the effect of ACE inhibitor treatment (ACEI), quinapril, on the level of these
      markers of endothelial dysfunction. The level of adhesion molecules
      [intercellular cytoadhesion molecule-1 (ICAM-1), E-selectin, P-selectin], von
      Willebrand s factor (vWf) and endothelin-1 were assessed in patients with mild
      essential hypertension without further cardiovascular risk factors or clinical
      manifestations of atherosclerosis before and after quinapril treatment (n = 25)
      and compared with normotensive controls (n = 29). The results of the examinations
      provided evidence that contrary to controls the hypertensive subjects had
      significantly higher ICAM-1 levels (237.8 vs. 207.8 ng/ml, P = 0.02) vWf (118 vs.
      106 IU/dl, p < 0.05) and endothelin-1 (5.81 vs. 5.15 fmol/ml, p < 0.05). Three
      month treatment of hypertensive patients with ACEI led to a significant drop of
      endothelin-1 levels (5.81 vs. 5.26 fmol/ml, p = 0.01). The authors proved also an
      unequivocal declining trend of other cytoadhesion molecules and vWf after ACEI
      treatment, the changes however were not statistically significant. From the
      investigation it may be concluded that also patients with uncomplicated essential
      hypertension without other cardiovascular risk factors or clinical manifestations
      of atherosclerosis have significantly elevated plasma levels of ICAM-1, vWf and
      endothelin-1. Higher concentrations of these factors suggest endothelial
      dysfunction already in mild forms of essential hypertension without further risk
      factors or cardiovascular complications. A significant drop of endothelin-1 and
      declining trend of the other investigated indicators suggest that ACEI treatment
      can favourably influence endothelial dysfunction in hypertensive patients also
      independently on reduction of the BP.

PMID- 12425202
TI  - [Efficacy and tolerance of rilmenidine in patients with mild to moderate
      hypertension. Results of a Czech and Slovak 6-month multicenter study].
AB  - AIM OF THE STUDY: To evaluate the efficacy and tolerability of rilmenidine
      (Tenaxum) in the dose of 1-2 mg in patients with mild to moderate hypertension.
      GROUP OF PATIENTS AND METHODS: 243 patients (53% men, 47% women, mean age 52 +/-
      11 years with mild to moderate essential hypertension were included into the
      study. Several cardiovascular risk factors for CAD were reported in the
      investigated group of patients: dyslipidaemia in 54%, obesity in 29%, diabetes
      mellitus in 14% and smoking in 17% of subjects. 87% of patients were subjects
      with newly diagnosed untreated or shortly (< 3 months) treated hypertension. In
      remaining hypertensives the antihypertensive therapy was withdrawn two weeks
      before the beginning of rilmenidine treatment. The following parameters were
      studied: BMI, sitting and upright casual blood pressure, heart rate and basal
      laboratory tests. If necesary, additional therapy with indapamide or perindopril
      was allowed. RESULTS: Rilmenidine treatment resulted in normalisation of blood
      pressure (BP) or significant (decrease of SBP/DBP = 20/10 mm Hg) blood pressure
      decrease in 69%, 22% of subjects, respectively. At the end of 6-month period
      significant BP decrease was noted: 134 +/- 6/83 +/- 5 mm Hg vs. 161 +/- 12/99 +/-
      6 mm Hg (p < 0.001). Marked BP decrease was observed already during first visit
      after active treatment for 3 weeks. Six months of rilmenidine treatment led to
      significant heart rate decrease (71/min. +/- 8 vs. 74/min. +/- 9, p < 0.01). No
      significant laboratory (plasma Na, K, creatinine, urea, glycemia, triglycerides,
      haematocrit) changes were reported after rilmenidine treatment with the only
      exception of mild, but significant plasma cholesterol decrease. Rilmenidine had
      very good acceptability and mild side effects were noted in small percentage of
      patients. CONCLUSION: Rilmenidine is a centraly acting drug of IInd generation
      (imidazoline I1 receptors agonist) with potent antihypertensive and mild negative
      chronotropic effect. Rilmenidine has very good clinical tolerability without
      negative influence on metabolic parameters.

PMID- 12425203
TI  - [Implantation of coronary stents in reperfusion therapy in acute myocardial
      infarct].
AB  - BACKGROUND: Primary coronary angioplasty was accepted as a method of choice in
      the reperfusion treating strategy of the ST elevation acute myocardial
      infarction. Since 1995, when the very good results of the stent implantation in
      patients with acute myocardial infarction were published, there has been a
      general trend to more stenting also in the Czech Republic. AIM: The analysis of
      the effectivety and safety of the coronary stent implantation in acute myocardial
      infarction. METHODS: Prospective analysis of the patients with ST elevation acute
      myocardial infarction treated with primary coronary angioplasty with one coronary
      stent implantation at least in the period I/2000-XII/2000. RESULTS: In the above
      mentioned period the authors carried out the total of 116 primary coronary
      angioplasties in 116 patients with ST elevation acute myocardial infarction.
      Balloon angioplasty only was done in 27 patients (23.3%) only, at least one stent
      was implanted in 89 patients (76.7%). The average procedure time was 58 +/- 27.2
      mins, fluoroscopy 10.6 +/- 6.6 mins, sciagraphy 1.8 +/- 0.7 mins. Primary
      angiographical result was optimal in 82 cases (92.2%) with achieving TIMI flow 3,
      in 5 cases (5.6%) there was slower perfusion of the infarcted artery observed
      with TIMI flow 2 and in 2 cases (2.2%) the authors were unsuccessful with final
      TIMI flow 0-1. Coronary stents were implanted in 13 cases (13.8%) without
      predilatation as so called "direct stenting", in 19 cases (20.2%) the planned or
      "elective" stenting was done, in 47 cases (50%) the suboptimal result after
      balloon angioplasty only was the reason for stent implantation and in 15 cases
      (16%) it was rescue "bail-out" stenting in complications of the balloon
      angioplasty only or if the result after balloon angioplasty was unsuccessful.
      Primary angiographical success of the stented lesion was 100% and in 14 cases
      (15.7%) the abciximab as a representative of IIb/IIIa platelet blockers was
      given. Periprocedural complications (up-to 24 hours after the procedure) in the
      stented group of patients occurred in 2 cases (2.2%), further serious in-hospital
      cardiovascular complications occurred in another 4 cases (4.4%). The total of 5
      patients (5.5%) died in the hospital, out of which 4 patients (4.4%) died due to
      the primary cardiogennic shock and 1 patient (1.1%) admitted in pulmonary oedema
      died due to the heart failure progression. Excluding patients primary in
      cardiogennic shock the in-hospital mortality was 1.2% only. Hospital mortality in
      the group of patients treated with primary balloon angioplasty only was 3.7% (1
      patient). CONCLUSION: At present the coronary artery stenting is safe and highly
      effective method in acute myocardial infarction treatment.

PMID- 12425204
TI  - [Glycoprotein IIb/IIIa platelet blockers in acute myocardial infarct treated with
      primary coronary angioplasty].
AB  - BACKGROUND: Primary coronary angioplasty is at present accepted as the most
      effective reperfusion treatment strategy of the ST elevation acute myocardial
      infarction. The optimum approach appears to be combination of the interventional
      technique (mechanical reperfusion) with aggressive pharmacological treatment
      aimed at the platelets. Intravenous blockers of the glycoprotein receptors
      IIb/IIIa together with acetylsalicylic acid have the additive antiaggregant
      effect and are used more frequently as adjunctive therapy by coronary
      interventions in patients with acute coronary syndromes and the acute myocardial
      infarction. AIM: The assessment of safety and effectiveness of the IIb/IIIa
      platelet blockers in patients indicated to primary coronary angioplasty. METHODS:
      Since 1st January 2000 to 30th June 2001 the authors carried out the total of 912
      coronary angioplasties in their cathlab, from which in 195 cases (21.4%) the
      primary angioplasty in acute ST elevation myocardial infarction was conducted.
      IIb/IIIa blockers were administered in the total of 53 cases (5.1% from the whole
      amount of coronary angioplasties), in 30 cases (15.4% from the total of 195
      patients) of the primary coronary angioplasties, unlike the elective procedures,
      where these agents were given only in 9 patients (1.5% from the overall number of
      621 coronary angioplasties) (p < 0.001). The authors in their work analyse the
      group of patients treated with primary coronary angioplasty with adjuvant
      treatment of IIb/IIIa platelet blockers. RESULTS: In the stated period the
      IIb/IIIa platelet blockers were given to 30 patients at the age of 60.3 +/- 11.3
      on average (70% were men). The most frequent risk factors were smoking, in 18
      patients (60%), and hypertension, in 14 patients (40%). At least one coronary
      stent was implanted in 20 patients (66.7%). Abciximab was administered in 27
      cases (90%) and eptifibatid in 5 cases (10%). Solely in 5 cases (16.7%) the
      agents were administered at least 10 minutes before the intervention and
      therefore preventively, and in 25 cases (83.3%) the administration was rescue.
      The reason for preventive administration was in 3 cases determination of the
      angiographically high-risk coronary artery disease and in 2 cases the thrombosis
      of another non-infarction related artery. The most frequent reason for the rescue
      use was in 6 cases (22.2%) slow-flow or no-reflow fenomena even after the
      mechanical obstacles and in 5 cases (18.5%) that were successfully treated with
      further dilatation, the acute in-stent thrombosis was observed. The infarct
      related artery was most often the left anterior descending coronary artery,
      namely in 16 cases (54%). CONCLUSION: IIb/IIIa platelet blockers in primary
      coronary angioplasty administered either preventively or as rescue therapy are
      highly effective, relatively safe and improve the effectiveness of mechanical
      reperfusion. The total in-hospital mortality of this group of patients was 10%.

PMID- 12425205
TI  - [Use of a health insurance company database for study of theoretical exposure to
      hypolipidemic agents].
AB  - OBJECTIVE: The objective of the investigation was to analyze theoretical
      exposures to hypolipidaemics in patients treated chronically with these drugs,
      using the database of the health insurance company. INVESTIGATED GROUP: From the
      database (with information on age, sex of the insured person, the number of
      packages and the type of hypolipidemic and year of issue of the prescription) of
      subjects insured at the Employees Health Insurance Skoda Mlada Boleslav
      comprising some 100,000 insured subjects in 1994-2000. Patients with long-term
      (more than one year) hypolipidaemic treatment were selected in years from 1995 to
      1999. The group increased every year. In 1995 it comprised 668 cases in 1999,
      2396 subjects. METHOD: The consumption of hypolipidaemics was expressed in
      defined daily doses (DDD). The authors investigated the ratio of chronically
      treated patients and the proportion of the following groups of patients according
      to their annual consumption in 1995-1999: group of of drug "vacation" (0 DDD) and
      the group with a low (< 121.7 DDD), medium (< 243.3 & > 121.7 DDD) and optimal (>
      243.3 DDD) consumption of hypolipidaemics and their relationship to sex and age.
      For statistical ealuation software SPSS 10.1 was used. RESULTS: In the course of
      the investigation among the insured subjects the statin consumption increased 76
      times and the consumption of fibrates 5 times. The ratio of consumption of resin
      derivatives and of nicotinic acid was negligible. The size of the group of
      subjects treated with hypolipidaemics for longer than one year increased from
      0.8% in 1995 to 2.2% of the database. The average age increased from 55 to 59
      years. The ratio of seniors (> or = 65 years) increased in the course of the
      investigation and reached 33% in 1999 of all members of the investigated group.
      The mean annual consumption of hypolipidaemics increased significantly as
      compared with 1995 and the interannual increase as compared with the previous
      year was statistically significant in 1997 and 1999. In 1999 it was 237 DDD/per
      consumer. A lower consumption was recorded in women and in seniors. Drug
      "vacations" were recorded in 6% of the insured subjects of the group and the
      frequency did not change significantly in the course of the investigation and no
      relationship with age and sex was found. A low exposure according to DDD was
      found in 20%, medium exposure in about 40% and optimal exposure in only one third
      of the subjects of the investigated group. CONCLUSION: The authors developed a
      method which makes it possible, when individual data of the health insurance
      company are available, to investigate the theoretical exposure to hypolipidaemics
      in insured subjects treated on a long-term basis with these drugs. The authors
      provided evidence that analysis of the database of the health insurance company
      can provide certain signals for further pharmacoepidemiological research and for
      application in a defined medical discipline. Some of the insured subjects are
      exposed to smaller doses than theoretically assumed. It is necessary to extend
      the investigation so that the results will better reflect the population of
      patients and prescribing physicians. Complete evaluation of cases with a low
      exposure from the aspect of morbidity and drug compliance will be also essential.

PMID- 12425206
TI  - [Relation of polymorphism of genes controlling endothelial function and blood
      pressure and the occurrence of vascular complications in type 2 diabetes].
AB  - Genetic polymorphisms of factors regulating the function of endothelium and blood
      pressure are recently intensively studied also in type 2 diabetes because
      endothelial dysfunction and arterial hypertension are risk factors of
      atherosclerosis. The following review deals with relations of polymorphisms in
      the renin-angiotensin-aldosterone (RAAS) system, polymorphisms of NO-synthase
      (NOS) as well as the gene for atrial natriuretic peptide (hANP). So far most
      information was assembled on the influence of polymorphisms of RAAS genes, in
      particular the gene coding the angiotensin converting enzyme (ACE), on
      complications of type 2 diabetes. A relationship with the development of coronary
      disease was described in ACE genes, the receptor for angiotensin II--type 1
      (AT1R), angiotensinogen and in several NOS polymorphisms. Also the relationship
      of polymorphisms of genes ACE, AT1R, NOS and hANP was described in relation to
      the development of hypertension which is an important risk factor for
      macrovascular and microvascular complications of diabetes. In some investigations
      the relationship of polymorphisms of ACE and AT1R genes and the development of
      diabetic nephropathy was described where a significant acceleration of the
      process of atherogenesis occurs. As type 2 diabetes mellitus and atherosclerosis
      are polygenically determinal diseases, it will be in particular necessary to
      investigate in future the concurrent influence of several gene polymorphisms and
      their interactions with the diabetic milieu interieur on the development of
      macrovascular and microvascular complications of diabetes.

PMID- 12425207
TI  - [Role of cytokines in the development of local and systemic inflammation and
      septic shock].
AB  - A central position in the development of systemic inflammation is played by
      activation of the vascular endothelium and monocyte- macrophage system. Both are
      associated with the formation of inflammatory cytokines, the primary mission of
      which is mobilization of the organism to cope with the infection. The so-called
      acute stage response develops with typical clinical manifestations and laboratory
      values. When it is impossible to stop the inflammation the syndrome of systemic
      inflammatory response develops with excessive activity of inflammatory cytokines
      and immune mechanisms. This apparently favourable system can be highly toxic for
      the organism and can lead to the syndrome of multiorgan failure, to disseminated
      intravascular coagulation, to depression of the myocardium, refractory
      vasodilatation, hypertension and septic shock. The compensatory antagonistic
      mechanism which develops due to the formation of anti-inflammatory cytokines
      leads sometimes to the development of a balanced state of immunity which is most
      favourable from the prognostic aspect. In case of their excess however
      immunodepression develops which is equally dangerous for the patient as excessive
      cytokine activity. From what has been said ensues the need of regular monitoring
      of patients with sepsis and thus also detailed investigation of their immune
      system.

PMID- 12425208
TI  - [The SEN virus--will there be another letter in the alphabet of viral hepatitis?]
      ].
AB  - The SEN virus (SENV) is a small nonenveloped single-stranded DNA virus which is
      probably a circovirus. By phylogenetic analysis it is possible to differentiate
      genotypes SENV A-H. The pathway of transmission of infection is not known so far
      but the infection by this virus is frequent in recipients of blood transfusions
      and liver grafts and in intravenous drug addicts. This suggests possible
      parenteral transmission of infection. Other routes of transmission of the
      infection are also possible as the virus can be detected also in a significant
      proportion of young subjects without the risk of parenteral infection in the case
      history. Whether SENV causes hepatitis has not been proved unequivocally so far.
      The prevalence of this infection does not differ significantly in patients with
      different liver diseases, acute or chronic viral or non-viral. SENV infection
      very probably does not influence the course of chronic hepatitis C.

PMID- 12425209
TI  - [The significance of aldosterone in chronic heart failure: the RALES study].
AB  - Reduction of excessive neurohumoral activation in chronic heart failure (CHF)
      improves the prognoses. In addition to reduction of angiotensin production or
      angiotensin II action and the influence of the sympathoadrenal system also
      blocking of aldosterone effects becomes part of the therapeutic procedure in
      patients with CHF. Excessive systemic and probably also local aldosterone
      production promotes undesirable fluid retention, hypokalaemia and
      hypomagnesaemia, induction of hypertrophy and fibrosis of the heart muscle and
      blood vessels and the development of endothelial dysfunction, peripheral
      vasoconstriction and depression of the baroreflex. In addition to classical
      effects also the existence of a rapid, so-called non-genomic effect of
      aldosterone is assumed. Adding a blocker of aldosterone receptors to ACE
      inhibition was not recommended due to possibility development of hyperkalaemia.
      Later it was revealed that ACE inhibitors are unable to block sufficiently the
      action of aldosterone and that addition of spironolactone in small amounts to ACE
      inhibition and diuretics does not cause in patients with CHF a major increase of
      the potassium level. In the RALES study (Randomized Aldacton Evaluation Study)
      comprising 1663 patients with serious heart failure (NYHA III, IV) addition of 25
      mg spironolactone to standard treatment with ACE inhibitor, diuretic and as rule
      also digoxin reduced the mortality by another 30% as compared with the addition
      of placebo. Undesirable effects were minimal. As to potential protective
      mechanisms of spironolactone the greatest importance is ascribed to the reduction
      of excessive fibrosis of the heart muscle. Spironolactone reduces the level of
      the circulating N-terminal aminopeptide procollagen type III the high level of
      which is associated with deterioration of the prognosis.

PMID- 12425210
TI  - [Diagnosis and therapy of idiopathic thrombocytopenic purpura (ITP) in adults].
AB  - Idiopathic thrombocytopenic purpura (ITP) is an autoimmune disorder resulting
      from the binding of antibodies directed toward platelet surface glycoproteins GP
      IIb/IIIa and GP Ib/IX leading to their clearance by reticuloendothelial system.
      The diagnosis of ITP is made clinically by exclusion of other causes of
      thrombocytopenia. The treatment of chronic ITP is palliative, not curative and is
      directed toward inactivation and removal of a major site of platelet destruction
      and antibody production represented by the spleen. Spontaneous remission of ITP
      in adults are very rare. The goal of treatment for ITP is to prevent serious
      bleeding. About 30% of the affected patients show a long term response to steroid
      therapy. Splenectomy is the treatment of choice in the remaining patients. The
      treatment of patients refractory to corticosteroid therapy and splenectomy
      remains largely empirical and to date a generally accepted therapy has not been
      established. The newest approch to the treatment involves the use of monoclonal
      antibodies. In intracranial bleeding and in severe bleeding in refractory ITP use
      of rVIIa has been shown to might be useful. ITP in pregnancy represent a special
      situation. There is the trend toward treating these patients in a more
      conservative fashion.

PMID- 12425211
TI  - [Acetylsalicylic acid (ASA)--is everything clear?].
AB  - The authors summarize results of trials with acetysalicyl acid (ASA) in patients
      with ischaemic heart disease and in particular with chronic cardiac failure. They
      draw attention to the relatively frequent use this drug in common practice,
      although so far not a single trial was completed which would prove the effect of
      acetylsalicyl acid on long-term mortality. The authors discuss also possible
      interactions of acetylsalicyl acid and ACE inhibitors which in retrospective
      analyses indicate possible veakening of the ACE-I when administered concurrently
      with ASA in cardiac failure. The authors mention also other antiaggregation
      drugs, which similarly as ASA, significantly reduce the mortality in acute
      coronary syndrome. Their long-term administration is however not associated with
      further improvement of the diagnosis. Trials are mentioned which compare
      antiaggregation and anticolagulation treatment in patients with ischaemic heart
      disease. They analyze also the effect of dosage (benefit vs. risk). After ASA >
      300 mg there are more frequent complications, and without a proved effect on
      total mortality, while doses < or = 100 mg seem to be safer but there is evidence
      that they are effective in reducing the total mortality of patients with IHD
      and/or cardiac failure.

PMID- 12425212
TI  - [Repeat thrombolysis in acute myocardial infarction].
AB  - The author describes a case-history of streptokinase intolerance during treatment
      of acute myocardial infarction (IM) where it was impossible to ensure rescue
      percutaneous coronary angioplasty (PTCA) and to resolve this condition by
      subsequent alteplase treatment. The author discusses whether it is justified and
      indicated to use this procedure rarely mentioned in the literature.

PMID- 12425213
TI  - [Bioterrorism: the role of veterinarians in detection and prevention].
AB  - The fear of terrorist attacks has increased since the events of 11 September 2001
      in New York. In the weeks following the terrorist attack, letters containing
      anthrax spores were received at various locations in the USA. This shows that
      bioterrorism is possible and that is necessary to be prepared for the potential
      release of biological agents. Such agents can be distributed not only via the air
      and drinking water but also via household pets. The aim of terrorist attacks,
      namely, the disruption of society and daily life, can be achieved in three ways,
      ways which are of importance to practising veterinarians, namely, via pets, via
      contamination of pet foods of animal origin, and by the spread of infectious
      animal diseases that have far-reaching economic consequences. These ways are
      discussed in this article, together with possible ways in which veterinarians can
      act to diminish the consequences of such an event.

PMID- 12425214
TI  - [Standpoint of the Working Group for Veterinary Antibiotic Use requests good use
      of quinolones].

PMID- 12425215
TI  - [Explosive increase in Salmonella java in poultry. Consequences for public
      health].
AB  - In the Netherlands S. Paratyphi B variation Java increased in poultry from less
      than 2% of all isolates before 1996 up to 40% in 2001. This development in
      poultry runs in parallel with that in Germany and appears not to occur in other
      European countries. A German study shows that in the late nineties it concerns
      isolates of only one multi-resistant clone of Java (in Holland as well) whilst
      isolates before the middle nineties were genetically much more heterogeneous and
      sensitive to antibiotics. Although the exposition of humans to contaminated
      poultry meat is relatively high, human patients with a Java infection are rare.
      Treatment of poultry flocks with quinolones was about 13% in 2000-2001.
      Resistance to flumequin of Java increased from 3% between 1996-1999 to 20%
      between 2000-2002 whilst that of other serotypes in poultry remained about 7%.
      Java is also fast becoming less sensitive to ciprofloxacin which is the
      antibiotic of first choice in serious cases of salmonellosis. The ministries of
      public health, agriculture and the production boards, with their research
      institutes, together with the poultry meat production chain integrations have
      recently decided to work together in order to determine the public health
      importance of the Java epidemic in poultry and finding measures for effective
      control in the poultry industry.

PMID- 12425216
TI  - [InsemAn and UNIFORM-Agri together in STO and EDI-DAP].

PMID- 12425217
TI  - [Research ID-Lelystad brings improved RSV vaccine].

PMID- 12425218
TI  - [Misunderstandings in the group practice].

PMID- 12425219
TI  - [Traveling with pets to the United Kingdom].

PMID- 12425221
TI  - [MPA contamination cost more that 100 million euros].

PMID- 12425220
TI  - [Veterinary antibiotic legislation in jeopardy?].

PMID- 12425222
TI  - [Group Veterinarians in Business visits Veterinary Harbor Police ].

PMID- 12425223
TI  - Functional rehabilitation using orthognathic surgery, bone transplants and
      implants after irradiation of malignancy in early childhood.
AB  - Functional rehabilitation has been carried out in four young patients by use of
      orthognathic surgery, bone grafting and implants. All four patients had been
      successfully treated for malignant tumours in the midface during early childhood
      by use of full dose irradiation. Retarded growth of the maxilla together with
      missing root formation of permanent teeth prevented the alveolar process to
      develop. Bimaxillary osteotomies with inlay bone graft have been made in two
      cases and maxillary osteotomy le Fort I with interpositional and inlay grafting
      in two individuals. Implants surgery has been made in a second stage surgery. A
      total of eighteen implants has been inserted and during five years follow-up two
      implants have been lost (survival rate 90%). All patients have been successfully
      rehabilitated with fixed bridge prosthesis.

PMID- 12425224
TI  - Long-term cost of direct Class II molar restorations.
AB  - The aim was to evaluate the theoretical long-term treatment costs of direct class
      II molar restorations (amalgam, composite, glass ionomer) using the Median
      Survival Times (MSTs) derived from longevity studies conducted in the Nordic
      countries as time for replacement. Theoretical long-term cost calculations were
      based on fee schedules from all Public Dental Services (PDS) in Sweden, for
      patients, Social Insurance Offices (SI), and total cost. Costs over 10 years were
      calculated and sensitivity calculations were conducted in order to demonstrate
      the effect of different MSTs on the long-term cost development. Glass ionomer
      molar class II restorations had the lowest and composite restorations had the
      highest initial total cost. The highest total cost over 10 years was seen for
      composite restorations. Amalgam restorations had the lowest long-term total cost,
      except when the costs were based on the shortest MSTs for each material. As there
      were considerable differences in the long-term costs for class II molar
      restorations with different materials, the importance of cost-analyses over time
      cannot be enough emphasised when decisions about resource allocation in the
      dental health insurance system are considered.

PMID- 12425225
TI  - Treatment outcome of headache after occlusal appliance therapy in a randomised
      controlled trial among patients with temporomandibular disorders of mainly
      arthrogenous origin.
AB  - The aim of this study was to evaluate headaches before and after treatment with a
      stabilisation appliance and a control appliance in a randomised controlled trial
      in patients having temporomandibular disorders (TMD) of mainly arthrogenous
      origin. The effect of treatment was evaluated both in a short and in long-term
      perspective. 60 patients (mean age 30 years) with TMD of mainly arthrogenous
      origin were studied. The patients were selected from patients referred for
      treatment of TMD during a 3-year period to the Department of Stomathognathic
      Physiology, Faculty of Odontology, Malmo University. The 60 patients included in
      the study were randomly assigned to a treatment (T) or a control (C) group. The
      study was performed as a randomised controlled trial including evaluation of
      treatment effect on tension-type headache after 10 weeks, 6 and 12 months. At the
      10 weeks follow-up, the patients who reported a negative treatment outcome and/or
      discomfort associated with the use of the appliances had their appliances
      readjusted. Patients who demanded further treatment received a stabilisation
      appliance (21 patients from the C-group), creating a new mixed (M) group. All the
      60 patients reported frequency of headache from rarely up to daily at the start
      of the study. In the T-group 76% and in the C-group 83% of the patients reported
      headache at least once a week or more before treatment. At the 10 weeks follow
      up, a statistically significant difference was found regarding headache several
      times a week or more between the T- and C-groups and within the T-group. At the 6
      months follow-up, a statistically significant reduction was found in headache
      several times a week or more in the T- and M-groups. The number of patients with
      headache once a week or more decreased significantly in the T- and M-groups at
      the 12 months follow-up. We conclude that the stabilisation appliance seems to
      have an effect on the frequency of tension-type headache both in a short and in a
      long-term perspective in patients with TMD of mainly arthrogenous origin.

PMID- 12425226
TI  - Long-term follow-up by means of a questionnaire of 109 patients with long-lasting
      orofacial pain.
AB  - The aims were to follow-up, analyse and compare the pain status after 4-9 years
      with that at the baseline examination of 109 consecutive patients referred to the
      Pain Group at the Faculty of Odontology in Malmo, Sweden during the period 1988
      1993 due to long-lasting orofacial pain. A further aim was to identify predictive
      factors of significance for pain alteration. 85 (78%) women with a median age of
      51 years and 24 (22%) men with a median age of 60 years were included in the
      study. A survey of the pain status at the follow-up was conducted by means of a
      mailed questionnaire. The questionnaire covered the following aspects: pain
      alteration, pain intensity, pain location, medication and education. After one
      reminder, the non-responding patients were called for a telephone interview. A
      response level of 85% was obtained. Significant improvements were noted by the
      patients in the answers of the questionnaire in mainly three areas; the patients
      answered individually that pain relief had occurred, pain intensity rated on the
      VAS was lower at follow-up compared to the baseline examination and a decrease in
      drug use was reported. The responses indicated pain relief for 75% of the
      patients. However, only 27% of the patients experienced total disappearance of
      pain. Medication at baseline with opioids, muscle relaxants with central effect,
      antidepressants, neuroleptics, hypnotics or sedatives was found to be a
      predictive factor for persistent pain.

PMID- 12425227
TI  - Aspects of the quality of the information contained in radiological referrals.
AB  - A referral letter is an important carrier of information, and it is important
      that it contains what both the recipient and the referrers expect. Based on the
      concept of perceived quality of service, 126 consecutive referrals from the
      General Dental Service (GDS) and their associated replies from the Department of
      Oral Radiology (OR) were mutually evaluated. OR judged that necessary information
      about the patient was specified in over 80% of the cases, and that information
      pertinent to the issue and the proposed examination was included in over 90% of
      the cases. The referrers were very satisfied with the replies they received. Only
      1% reported that the information contained in the reply was not satisfactory for
      the continued care of the patient. Ninety-one per cent reported that they felt
      the reply to their referral was adequately long. A mutual questionnaire is a
      practicable tool to ensure quality in the referral process.

PMID- 12425228
TI  - [From taboo to self-actualization--acceptance problems and learning processes in
      working with mentally handicapped patients].
AB  - The article introduces the topic of "sexuality and people with developmental
      disabilities". It presents the historical stages of development and the
      institutional framework of the work with people with disabilities in Germany. Six
      criterions and standards respectively, are pointed out, that help to determine
      whether institutions support or hinder sexual self-determination. These standards
      are formulated as rights in the sense of the basic human rights.

PMID- 12425229
TI  - [Legal developments--from taboo to sexual self-determination for handicapped
      patients?].
AB  - The author describes the development in German law regarding the protection of
      sexual self-determination of disabled persons. Her analysis encompasses the last
      twenty years, starting from the "cripple-tribunal 1981", where disabled women
      first raised the subject in German public. As the main legal reforms for disabled
      persons in Germany, the author analysis the Thirty-First-Criminal-Law-Change-Act
      and the Sixth-Act-To-Reform-Criminal-Law of 1997/98 as well as the Ninth-Social
      Law-Code of 2001. The author welcomes these legislative reforms but points to the
      fact that the judiciary has yet failed to implement particularly the criminal law
      reform. In addition she shows that the new criminal law does not fill all former
      protection gaps. She demands further reforms in other areas of law. Finally she
      emphasizes that comprehensive information and education for all those who are
      concerned by the subject are necessary.

PMID- 12425230
TI  - [Sexual violence against people with handicaps in institutions].
AB  - Two research projects "Because Everything Concerning Violence Hurts--Sexual
      Exploitation of Girls and Women with Disabilities (Zemp and Pircher 1996) and
      "Sexualized Violence in the Daily Life of People with Disabilities" (Zemp et al.
      1997) will be introduced. The following study examined women and men with
      disabilities who live in a residential institution due to their physical, mental
      and/or psychological disability. Sexual exploitation starts where a person is
      used by another in order to satisfy certain needs without being informed or
      giving consent. Sexual exploitation is an expression of a power relationship.
      People with disabilities are underprivileged concerning resources, articulation
      and information, position in society and degree of organisation. We worked with
      questionnaires and semi-structured interviews. It was important to us not to
      exclude anybody from the study due to the severity of the disability. In cases
      where participants were incapable of verbal communication, we used "yes/no
      conversation" and "anatomical dolls". 130 men and 130 women between aged between
      18 and 78 participated in this study. All women received prophylactic
      contraception in order to avoid the product of rape. Both male and female
      participants showed diminished knowledge of sexual education. Approximately 64%
      of female and 50% of male participants indicate that they have been exploited
      sexually. Disabled room mates were the predominant group of perpetrators for the
      male and the third important for the female participants. Sexualized violence in
      residential institutions is directly linked to structural violence. This can only
      be fought effectively by a change in paradigms from controlled to self-determined
      life.

PMID- 12425231
TI  - [Change due to research--multiple responsibilities and goals of a general
      practice research model project on sexual self determination and sexual violence
      in institutions for mentally handicapped patients].
AB  - The present article gives inside in research work in progress. Habermas (1973)
      pointed out the interdependency of economical motivational and other personal
      interests and the scientific results in research. Starting research on (sexual)
      self determination in institutions for mentally retarded people we were
      confronted with quite a number of conflicts of interests. The present article
      tries to clarify these conflicts from different perspectives e.g. the perspective
      of the management of the institutions, the perspective of the concerned
      inhabitants and the perspective of the caregivers. Describing the areas and
      hindrances we try to find out what sort of fascilitators are needed to improve
      the participation of mentally handicapped persons in this research process. From
      a methodological point of view we chose a qualitative approach to generate
      prototypes and controlled this approach by an expert committee. One of the main
      results is that a policy against sexual abuse in these institutions has to be
      part of the general quality discussion.

PMID- 12425232
TI  - [Managing self determination and sexual violence in homes for young adults with
      mental handicap--report from an ongoing German model project].
AB  - This report is based upon a model project financially assisted by a grant from
      the German Federal Ministry for Families, Senior Citizens, Women and Youth,
      starting in 1999 and ending at the end of 2003. In cooperation with two
      disability care residential institutions, a conceptual approach and method to the
      questions of sexual self-determination and sexualized violence is being
      developed. Through qualitative methods of research e.g. focus groups,
      professional helpers of all hierarchies of the institution, including management,
      and the residents themselves, all had the chance to contribute their own opinions
      and experiences to the research topic. Specifically, to ensure their voice was
      heard, the people with mental retardation had an important impact on the
      questionnaire themselves. All aspects of sexuality were discussed--with notable
      difficulty arising in particular over the subject of sexual violence. It turned
      out that nonverbal communication and the interaction between the group members in
      the residents group were most indicative of their concerns. The staff at the
      nursing and living areas discussed the following topics: distance and closeness
      in the interaction between staff and residents, standards, reflections of their
      own professional attitudes, questions of legality as well as the tense topic of
      individual needs and tasks of the group. How those questioned described their
      solutions and ways of coping, and the impressions of the researchers forms the
      starting point for the compiled work. The initial ideas for the topics and the
      design of the concept are now laid out.

PMID- 12425234
TI  - Supporting open access to scientific information.

PMID- 12425233
TI  - [The Beverly Lewis House--report on development of a safe facility for mentally
      handicapped women with abuse histories].
AB  - This contribution introduces a battered women shelter in London, Great Britain
      which exclusively provides refuge to women with learning disabilities who
      experienced sexualized violence. In the case of sexual abuse in early childhood
      psychotherapy is provided. Beverly Lewis House is the only institution of its
      kind and is lead by the author of this article. The contribution gives an insight
      into the significance and the structures of such an institution. Six components
      will be described that are important for implementing a battered women shelter
      specified on serving women with a learning disability: the architecture and the
      structures of the institution, the funding, the team, the variety of offers, the
      establishment of a therapeutic climate and the further progress of the women
      after leaving the Beverly Lewis House. Furthermore, the staff are being
      instructed how to deal with behaviours resulting from abuse experiences such as
      eating disorders, self-harming behaviour and depressions. The contribution is
      predominantly written in "simple language" in order to make it accessible to
      people with learning disabilities.

PMID- 12425236
TI  - Standardization of health informatics--results and challenges.
AB  - OBJECTIVES: This review article aims to highlight the importance of standards for
      effective communication and provides an overview of international standardization
      activities. METHODS: This article is based on the experience of the author of
      European standardization in CEN, which he leads, and the global work of ISO,
      where he is leading the security working group, and an overview of the work of
      DICOM, IEEE and HL7, partly using their web presentations. RESULTS: Health
      communication is highly dependent of the general development of information
      technology with standards coming from ISO/IEC JTCI, ITU and several other
      organizations e.g. IETF, the World Wide Web consortium and Open group. A number
      of standardization initiatives have been in progress for more than ten years with
      the aim to facilitate different aspects of the exchange of health information.
      Electronic record architecture, Message structures, Concept representation,
      Device communication including imaging and Security are the main areas.
      CONCLUSIONS: Important results have been achieved, and in some fields and parts
      of the world, standards are widely used today. Unfortunately, we are still facing
      the fact that most healthcare information systems cannot exchange information
      with all systems for which this would be desired. Either the existing standards
      are not sufficiently implemented, or the required standards and necessary
      national implementation guidelines do not yet exist. This causes unacceptable
      risks to patients, inefficient use of healthcare resources, and sub-optimal
      development of medical knowledge. Fortunately, the different bodies are now
      largely co-operating to achieve global consensus.

PMID- 12425235
TI  - Imaging and the Human Brain Project: a review.
AB  - OBJECTIVES: Survey current work primarily funded by the US Human Brain Project
      (HBP) that involves substantial use of images. Organize this work around a
      framework based on the physical organization of the body. METHODS: Pointers to
      individual research efforts were obtained through the HBP home page as well as
      personal contracts from HBP annual meetings. References from these sources were
      followed to find closely related work. The individual research efforts were then
      studied and characterized. RESULTS: The subject of the review is the intersection
      of neuroinformatics (information about the brain), imaging informatics
      (information about images), and structural informatics (information about the
      physical structure of the body). Of the 30 funded projects currently listed on
      the HBP web site, at least 22 make heavy use of images. These projects are
      described in terms of broad categories of structural imaging, functional imaging,
      and image-based brain information systems. CONCLUSIONS: Understanding the most
      complex entity known (the brain) gives rise to many interesting and difficult
      problems in informatics and computer science. Although much progress has been
      made by HBP and other neuroinformatics researchers, a great many problems remain
      that will require substantial informatics research efforts. Thus, the HPB can and
      should be seen as an excellent driving application area for biomedical
      informatics research.

PMID- 12425237
TI  - Redefining and improving patient safety.
AB  - OBJECTIVES: The Institute of Medicine (IOM) has focused attention on patient
      safety in the United States. Other countries share these concerns. METHODS:
      Governmental agencies and professional organizations are redefining approaches to
      safety, calling upon the use of information and communication technology as an
      enabler and expanding the range of evidence admissible in documenting success.
      RESULTS: Efforts to understand medical errors have used retrospective chart
      review, incident reporting, and computerized surveillance; the result is an
      evolving picture of the number, nature, and cause of errors. Approaches used to
      prevent errors include computerized physician order entry, decision support
      tools, computerized monitoring, and evidence-based practice; varying levels of
      evidence document their success. CONCLUSIONS: Technology offers challenging
      capabilities, not simple solutions. New evidence and new tools demand new
      approaches and attention to human factors.

PMID- 12425238
TI  - Computer order entry system decreased use of sliding scale insulin regimens.
AB  - OBJECTIVES: Despite evidence documenting their ineffectiveness, sliding scale
      insulin is a commonly used regimen for glucose management for hospitalized
      patients with diabetes mellitus. At the Veterans Affairs Puget Sound Medical
      Center, where computer order entry has been mandated, we tested the hypothesis
      that an evidence-based minimal intervention order (supplemental insulin only when
      fasting serum glucoses exceeded 400 mg/dl) would decrease the use of sliding
      scale insulin orders. METHODS: Using a computerized order entry system, providers
      were initially offered a traditional sliding scale order or their own ad hoc
      orders for glycemic control of inpatients. After 34 weeks providers were offered
      a third option; a "minimal intervention order" with supplemental insulin only for
      glucose > 400 mg/dl. We extracted all regular insulin orders and performed a
      retrospective review of insulin sliding scale orders written between December 1,
      1998 and November 16, 1999. We compared the frequency of traditional insulin
      sliding scale orders before and after the introduction of the minimal
      intervention order. RESULTS: Nearly all orders in the first 34 weeks were
      traditional insulin sliding scales. We found a significant decrease in the number
      of traditional insulin sliding scale orders in the 16 weeks after the
      introduction of a computerized quick-order for minimal intervention, from
      978/1007 (97.1%) to 254/398 (63.8%) (P < 0.001). CONCLUSIONS: A simple, evidenced
      based quick-order in a computer order entry system rapidly and significantly
      reduced use of sliding scale insulin regimens for glycemic control of inpatients.

PMID- 12425239
TI  - A requirements index for information processing in hospitals.
AB  - OBJECTIVES: Reference models describing typical information processing
      requirements in hospitals do not currently exist. This leads to high hospital
      information system (HIS) management expenses, for example, during tender
      processes for the acquisition of software application programs. Our aim was,
      therefore, to develop a comprehensive, lasting, technology-independent, and
      sufficiently detailed index of requirements for information processing in
      hospitals in order to reduce respective expenses. METHODS: Two-dozen German
      experts established an index of requirements for information processing in
      university hospitals. This was done in a consensus-based, top-down, cyclic
      manner. Each functional requirement was derived from information processing
      functions and sub-functions of a hospital. RESULTS: The result is the first
      official German version of a requirements index, containing 233 functional
      requirements and 102 function-independent requirements, focusing on German needs.
      The functional requirements are structured according to the primary care process
      from admission to discharge and supplemented by requirements for handling patient
      records, work organization and resource planning, hospital management, research
      and education. Both the German version and its English translation are available
      in the Internet. CONCLUSIONS: The index of requirements contains general
      information processing requirements in hospitals which are formulated independent
      of information processing tools, or of HIS architectures. It aims at supporting
      HIS management, especially HIS strategic planning, HIS evaluation, and tender
      processes. The index can be regarded as a draft, which must, however, be refined
      according to the specific aims of a particular project. Although focused on
      German needs, we expect that it can also be useful in other countries. The high
      amount of interest shown for the index supports its usefulness.

PMID- 12425240
TI  - Characteristics of consumer terminology for health information retrieval.
AB  - OBJECTIVES: As millions of consumers perform health information retrieval online,
      the mismatch between their terminology and the terminologies of the information
      sources could become a major barrier to successful retrievals. To address this
      problem, we studied the characteristics of consumer terminology for health
      information retrieval. METHODS: Our study focused on consumer queries that were
      used on a consumer health service Web site and a consumer health information Web
      site. We analyzed data from the site-usage logs and conducted interviews with
      patients. RESULTS: Our findings show that consumers' information retrieval
      performance is very poor. There are significant mismatches at all levels
      (lexical, semantic and mental models) between the consumer terminology and both
      the information source terminology and standard medical vocabularies.
      CONCLUSIONS: Comprehensive terminology support on all levels is needed for
      consumer health information retrieval.

PMID- 12425241
TI  - Requirements Engineering for inter-organizational health information systems with
      functions for spatial analyses: modeling a WHO safe community applying Use Case
      Maps.
AB  - OBJECTIVES: To evaluate Use Case Maps (UCMs) as a technique for Requirements
      Engineering (RE) in the development of information systems with functions for
      spatial analyses in inter-organizational public health settings. METHODS: In this
      study, Participatory Action Research (PAR) is used to explore the UCM notation
      for requirements elicitation and to gather the opinions of the users. The Delphi
      technique is used to reach consensus in the construction of UCMs. RESULTS: The
      results show that UCMs can provide a visualization of the system's functionality
      and in combination with PAR provide a sound basis for gathering requirements in
      inter-organizational settings. UCMs were found to represent a suitable level for
      describing the organization and the dynamic flux of information including spatial
      resolution to all stakeholders. Moreover, by using PAR, the voices of the users
      and their tacit knowledge is intercepted. Further, UCMs are found useful in
      generating intuitive requirements by the creation of use cases. CONCLUSIONS: With
      UCMs and PAR it is possible to study the effects of design changes in the general
      information display and the spatial resolution in the same context. Both
      requirements on the information system in general and the functions for spatial
      analyses are possible to elicit when identifying the different responsibilities
      and the demands on spatial resolution associated to the actions of each
      administrative unit. However, the development process of UCM is not well
      documented and needs further investigation and formulation of guidelines.

PMID- 12425242
TI  - Representation of practice guidelines with XML--modeling with XML schema.
AB  - OBJECTIVES: Data and information in medicine are mainly represented in slightly
      structured or even unstructured, narrative text documents. It is nearly
      impossible to detect and handle relationships between data elements within
      narrative documents or to retrieve parts of documents that contain specific
      information. But information access and retrieval are essential to serve the
      delivery and application of evidence-based medicine. METHODS: The eXtensible
      Markup Language (XML) provides a standard means to explicitly describe a
      document's structure and to identify meaningful elements inside textual
      narrations. Information about the state-of-the-art medical care can be delivered
      to the physician by different means and media. Clinical practice guidelines are
      thought to be one possible solution to summarize and present current medical
      evidence. RESULTS: The structuring of resources containing medical information
      with XML can facilitate the provision of problem-specific medical information at
      the point of care by improving content retrieval and presentation. In our
      project, the XML Schema is used for the electronic representation in order to
      structure guidelines (and other text-based resources) in a standardized way.
      CONCLUSION: The transition from unstructured textual data towards structured and
      coded data will be a migration process. One of the premises of our approach is
      that the structure that is defined by the information model doesn't restrict the
      content of the documents. This approach may fill the gap between computerized,
      algorithmic guideline recommendations and text-based guideline distributions.

PMID- 12425243
TI  - The index as a new concept towards an integrated framework for the electronic
      patient record.
AB  - OBJECTIVE: To overcome some classical limitations of the POMR (Problem-Oriented
      Medical Record), including the management of divergent opinions between health
      professionals, in order to construct a common patient record across multiple
      disciplines in hospital settings and professional networks. METHODS: Using a
      complex clinical case, we improved a POMR model previously used by GPs in order
      to translate it into a hospital setting. The enhanced model has been assessed
      through use in various ongoing clinical cases and through extended discussion
      with professional end-users (physicians, nurses, general practitioners, and
      social workers). RESULTS: The Index concept (flexible structural link) is
      proposed as a major improvement in the construction of a POMR in a shared care
      environment. CONCLUSIONS: The Index introduces interesting new perspectives.
      Following its implementation in the Belgian pilot site in the CORINES project,
      further studies remain to be carried out in order to develop a cost/benefit
      assessment.

PMID- 12425244
TI  - Electronic signature for medical documents--integration and evaluation of a
      public key infrastructure in hospitals.
AB  - OBJECTIVES: Our objectives were to determine the user-oriented and legal
      requirements for a Public Key Infrastructure (PKI) for electronic signatures for
      medical documents, and to translate these requirements into a general model for a
      signature system. A prototype of this model was then implemented and evaluated in
      clinical routine use. METHODS: Analyses of documents, processes, interviews,
      observations, and of the available literature supplied the foundations for the
      development of the signature system model. Eight participants of the Department
      of Dermatology of the Heidelberg University Medical Center evaluated the
      implemented prototype from December 2000 to January 2001, during the course of an
      intervention study. By means of questionnaires, interviews, observations and
      database analyses, the usefulness and user acceptance of the electronic signature
      and its integration into electronic discharge letters were established. RESULTS:
      Since the major part of medical documents generated in a hospital are signature
      relevant, they will require electronic signatures in the future. A PKI must meet
      the multitude of responsibilities and security needs required in a hospital.
      Also, the signature functionality must be integrated directly into the workflow
      surrounding document creation. A developed signature model, fulfilling user
      oriented and legal requirements, was implemented using hard and software
      components that conform to the German Signature Law. It was integrated into the
      existing hospital information system of the Heidelberg University Medical Center.
      At the end of the intervention study, the average acceptance scores achieved were
      mean = 3.90; SD = 0.42 on a scale of 1 (very negative attitude) to 5 (very
      positive attitude) for the electronic signature procedure. Acceptance of the
      integration into computer-supported discharge letter writing reached mean = 3.91;
      SD = 0.47. On average, the discharge letters were completed 7.18 days earlier.
      CONCLUSION: The electronic signature is indispensable for the further development
      of electronic patient records. Application-independent hard and software
      components, in accordance with the signature law, must be integrated into
      electronic patient records, and provided to certification services using
      standardized interfaces. Signature-oriented workflow and document management
      components are essential for user acceptance in routine clinical use.

PMID- 12425245
TI  - Non-linear transform-based robust adaptive latency change estimation of evoked
      potentials.
AB  - OBJECTIVES: To improve the latency change estimation of evoked potentials (EP)
      under the lower order alpha-stable noise conditions by proposing and analyzing a
      new adaptive EP latency change detection algorithm (referred to as the NLST).
      METHODS: The NLST algorithm is based on the fractional lower order moment and the
      nonlinear transform for the error function. The computer simulation and data
      analysis verify the robustness of the new algorithm. RESULTS: The theoretical
      analysis shows that the iteration equation of the NLST transforms the lower order
      alpha-stable process en (k) into a second order moment process by a nonlinear
      transform. The simulations and the data analysis showed the robustness of the
      NLST under the lower order alpha-stable noise conditions. CONCLUSIONS: The new
      algorithm is robust under the lower order alpha-stable noise conditions, and it
      also provides a better performance than the DLMS, DLMP and SDA algorithms without
      the need to estimate the alpha value of the EP signals and noises.

PMID- 12425246
TI  - Classification of EEG mental patterns by using two scalp electrodes and
      Mahalanobis distance-based classifiers.
AB  - OBJECTIVES: In this paper, we explored the use of quadratic classifiers based on
      Mahalanobis distance to detect mental EEG patterns from a reduced set of scalp
      recording electrodes. METHODS: Electrodes are placed in scalp centro-parietal
      zones (C3, P3, C4 and P4 positions of the international 10-20 system). A
      Mahalanobis distance classifier based on the use of full covariance matrix was
      used. RESULTS: The quadratic classifier was able to detect EEG activity related
      to imagination of movement with an affordable accuracy (97% correct
      classification, on average) by using only C3 and C4 electrodes. CONCLUSIONS: Such
      a result is interesting for the use of Mahalanobis-based classifiers in the brain
      computer interface area.

PMID- 12425247
TI  - Implications of nondifferential misclassification on estimates of attributable
      risk.
AB  - OBJECTIVES: Only the effects of isolated nondifferential misclassification of
      exposure or disease on the estimates of attributable risk have been discussed in
      the literature. The aim of this paper is to broaden the spectrum of scenarios for
      which implications of misclassification are available. METHODS: For this purpose,
      a matrix-based approach allowing a comprehensive, unified analysis of various
      structures of misclassification is introduced. The relative bias or--in the
      situation of covariate misclassification--the relative adjustment are presented
      for the different misclassification scenarios. RESULTS: Under nondifferential
      misclassification of exposure or disease, the attributable risk is biased towards
      the null with the only exception of perfect sensitivity of exposure
      classification or perfect specificity of disease classification both leading to
      an unbiased attributable risk. From these two marginal effects, the consequences
      of simultaneous nondifferential independent misclassification of exposure and
      disease on the attributable risk are derived in the matrix-based approach.
      Misclassification of a dichotomous covariate leads to partial adjustment.
      CONCLUSIONS: To a large extent, the results for the attributable risk are in
      accordance with the well-known results for the relative risk. The algebraic
      differences between the two risk measures, however, make it necessary to repeat
      the methodological considerations for the attributable risk.

PMID- 12425248
TI  - Two-phase study to assess the number of cases based on claims databases:
      characteristics of the validation data set.
AB  - OBJECTIVE: In a two-phase study design, the characteristics of an external data
      set were studied for precision and bias of the number of incident or prevalent
      cases of a disease obtained from claims databases. METHODS: In the study
      population (first phase), incident or prevalent cases were counted whereas
      external data (second phase) provided sensitivity and specificity estimates to
      count cases in a claims database. Influence of potential differences in
      sensitivity and specificity between the two phases were evaluated. This was
      illustrated for 50-90% sensitivity and 99-99.99% specificity ranges. RESULTS AND
      CONCLUSIONS: The impact of differences in sensitivity and specificity depends on
      the odds of disease in the study population. We provide advice on the choice of
      adequate data sets to correct claims database estimates.

PMID- 12425249
TI  - Legal corner.

PMID- 12425250
TI  - Is your employer's coverage enough?

PMID- 12425251
TI  - American Nurses Association applauds JCAHO's focus on nursing shortage.

PMID- 12425252
TI  - ANA responds to outrageous Op-ed.

PMID- 12425253
TI  - Developing a comprehensive electronic adverse event reporting system in an
      academic health center.
AB  - BACKGROUND: In September 2000 University of Missouri Health Care (MUHC) conducted
      an assessment of patient safety activities. At least six separate data systems
      for reporting adverse events, with multiple conflicting paper reports, were found
      during this analysis. The disparate nature of these systems and their inability
      to be linked ensured that few systemic prevention activities were undertaken. In
      January 2001 an interdisciplinary team was convened with the goal of creating a
      comprehensive approach to patient safety reporting and resolution.
      IMPLEMENTATION: A secure, Web-based system, the MUHC Patient Safety Network
      System (PSN), was created that allows staff, physicians, patients, families, and
      visitors to report comments, adverse events, and near-miss events from any
      computer in the hospital and from home, using the Internet. Anonymous reporting
      is an option for near-miss events. Reports are immediately available to
      department managers responsible for resolution; managers are alerted to the
      presence of a report by e-mail. As a result, a pilot study performed in two MUHC
      intensive care units documented dramatic reductions in resolution time using the
      PSN. The pilot also demonstrated an increased willingness to report by physicians
      and respiratory therapists. Training was accomplished in the fall of 2001, and
      the PSN was successfully implemented throughout the hospital on January 1, 2002.
      NEXT STEPS: Implementation of the PSN has recently been extended to all
      ambulatory care settings. An additional component of the PSN that is being built
      will allow physicians to report complications.

PMID- 12425255
TI  - The Patient Visits Program: a strategy to highlight patient satisfaction and
      refocus organizational culture.
AB  - BACKGROUND: Seeking patient input may improve patients' perceptions of the
      quality of care and provide managers with helpful information for strategic
      decision making. In addition, the involvement of senior hospital leadership is
      critical to successful implementation of quality improvement initiatives and
      illustrates an organization's commitment to enhancing quality from the top down.
      IMPLEMENTING THE PVP: Senior management's Patient Visits Program (PVP) at Tufts
      New England Medical Center is a structured, ongoing initiative in which senior
      clinicians are paired with nonclinician administrators. During an initial
      evaluation period (Aug 1999-Feb 2001), PVP teams visited with patients and their
      families on a monthly basis to talk to them about their experiences. Patient
      suggestions were then evaluated and acted on. DISCUSSION: The PVP has been
      beneficial for patients and for the hospital team members--clinicians and
      nonclinicians alike--who participated in the patient interviews. The PVP may
      serve as a mechanism to enhance organizational awareness of the importance of
      patient satisfaction. The program provides opportunities for immediate service
      recovery, and faster, broader-reaching responses to quality complaints due to the
      multispecialty nature of the PVP teams. In addition, based on early available
      data, the PVP shows promise as an interventional strategy to improve patient
      satisfaction scores. CONCLUSIONS: A structured, ongoing program such as the PVP
      is an effective strategy to highlight the value of patient satisfaction, refocus
      organizational culture, and generate specific suggestions for improving the
      quality of patient care.

PMID- 12425254
TI  - Reducing failed extubations in the intensive care unit.
AB  - BACKGROUND: Failed extubation is associated with substantially increased
      morbidity, mortality, and costs for patients receiving mechanical ventilation. A
      study was designed in 1998 to identify risk factors for failed extubation and use
      a quality improvement model to reduce failed extubation rates in a surgical
      intensive care unit (SICU) in an academic hospital. METHODS: Study design
      involved a prospective cohort SICU with a concurrent control SICU. The primary
      outcome was rate of failed extubations per 1,000 ventilator days. Information on
      risk factors for failed extubations was also collected. Performance improvement
      staff identified failed extubation patients, and respiratory therapy provided
      information on ventilator days. The quality improvement model implemented three
      phases between October 1998 and June 2000: (1) identifying factors associated
      with failed extubation, (2) developing a guideline to reduce failed extubation,
      and (3) implementing the guideline. RESULTS: Significant factors associated with
      failed extubation included suctioning more frequently than every 4 hours versus
      the current model of "every 4 hours or greater" (odds ratio [OR] 11.3; 95%
      confidence interval [CI] 1.5-88.3), being agitated or sedated versus being alert
      (OR 4.5, CI: 1.2-14.7), and oxygen saturation < or = 95% versus > or = 95% (OR
      4.0; CI: 1.2-13). Failed extubation rate in the SICU decreased from 8/1,000 in
      October 1998 to 1.5/1,000 in June 2000, and control SICU rates remained unchanged
      (8/1,000). DISCUSSION: The intervention significantly reduced the rate of failed
      extubation in the SICU. By employing a quality improvement model and identifying
      risk factors for failed extubation, providers should be able to decrease risk of
      failed extubation for SICU patients.

PMID- 12425256
TI  - The combined effect of public profiling and quality improvement efforts on heart
      failure management.
AB  - BACKGROUND: A before-and-after study was conducted to examine the combined effect
      of public profiling and quality improvement activities on management of heart
      failure (HF) in the hospital setting. METHODS: Thirty-one hospitals in
      southeastern Michigan participated in this profiling and quality improvement
      study. One hospital closed after the baseline measurement. Two quality indicators
      were developed to evaluate the key processes of HF care, and one profiling
      indicator was designed for public profiling. The baseline results of the
      profiling indicator were publicly released. The individual hospitals were
      identified in the profiling report by name as "having statistically higher (or
      lower) rates than average." Remeasurement results were compared to the baseline
      results by using t-tests for the individual hospitals and all 30 hospitals as an
      aggregate. RESULTS: Two-thirds of the hospitals improved ejection fraction
      documentation; the aggregate result improved 5.4 percentage points (p < 0.05). No
      change was observed in the aggregate measure of prescribing angiotensin
      converting enzyme inhibitors (ACEIs) to eligible HF patients at discharge.
      Hospitals with low baseline rates made improvement in ACEI use at discharge, but
      those with good baseline performance tended to decline in performance. There was
      a 2.2 percentage point increase (p < 0.05) in the profiling indicator. SUMMARY
      AND CONCLUSIONS: There seemed to be differential impacts of interventions across
      indicators and hospitals. Public profiling may have the most positive impact on
      hospitals with low performance at baseline. Maintaining the baseline good
      practice was a struggle for hospitals with relatively high baseline rates.

PMID- 12425258
TI  - Skin cancer. Catch it early.

PMID- 12425257
TI  - Benefits of a mobile, point-of-care anticoagulation therapy management program.
AB  - BACKGROUND: Current guidelines recommend anticoagulation therapy for a number of
      medical conditions, but this therapy also has the potential for serious
      complications, particularly bleeding complications. Maintenance of
      anticoagulation within a narrow therapeutic window usually entails frequent
      monitoring with a blood test called the international normalized ratio (INR).
      Anticoagulation therapy management (ATM) clinics lead to improvements in quality
      of care, in terms of improved INR control and reduced complications. This study
      examined the impact of a mobile multisite, office-based ATM program that operated
      in seven cardiology offices in all three counties in Delaware. ATM PROGRAM: The
      ATM program was managed by a trained nurse who rotated among all seven offices.
      Patients made office visits to the nurse and received patient education, point-of
      care INR testing, and medication adjustment based on a physician-approved
      algorithm. METHODS: This retrospective cohort study compared INR levels in the
      year before (May 1998-Apr 1999) and the year after (Aug 1999-Jul 2000) the start
      of the ATM program. RESULTS: From the year before to the year after
      implementation of the ATM program, the percentage of in-range INRs increased from
      40.7% to 58.5% (p < 0.001). The percentage in the modified target range also
      increased (50.0% to 62.9%, p < 0.001). DISCUSSION: This study demonstrates the
      positive impact of a statewide office-based ATM program. If similar programs
      could be implemented in other networks of specialty offices or primary care
      offices, they could have a significant benefit to quality of care for patients
      who require anticoagulation therapy.

PMID- 12425259
TI  - Health tips. Choosing sunglasses.

PMID- 12425260
TI  - A clearer understanding of breast cancer risk and alcohol.

PMID- 12425261
TI  - Nasal sprays: an alternative to pills, needles.

PMID- 12425262
TI  - Post-traumatic stress disorder. Early help may be the key.

PMID- 12425263
TI  - Homocysteine. A factor in cardiovascular and memory health?

PMID- 12425264
TI  - High triglycerides. A red flag.

PMID- 12425265
TI  - I pay attention to how much calcium I get each day. But I recently heard that 
      without enough vitamin D, my body can't make use of the calcium. Please explain.

PMID- 12425266
TI  - My husband and I don't qualify for any government-sponsored programs to help with
      the cost of our drugs. Are there other options?

PMID- 12425267
TI  - Retinal detachment. Avoid vision loss with prompt treatment.

PMID- 12425268
TI  - Health tips. Put soy in your diet.

PMID- 12425269
TI  - An alternative to total knee replacement.

PMID- 12425270
TI  - HRT. Alternatives are available.

PMID- 12425271
TI  - COX-2 inhibitors. Understanding recent concerns.

PMID- 12425272
TI  - Schizophrenia. New drugs, renewed hope.

PMID- 12425273
TI  - My mother had numerous spinal fractures due to osteoporosis. I've just gone
      through menopause and tests show I don't have osteoporosis now. I have chosen not
      to take hormone replacement therapy. Under my doctor's directions, I'm getting
      adequate calcium and regular exercise. Are there any exercises I can do to reduce
      my risk of spinal fractures down the line?

PMID- 12425274
TI  - HRT: what to do now.

PMID- 12425275
TI  - Stamping out restless legs.

PMID- 12425276
TI  - Low-dose aspirin for everyone?

PMID- 12425277
TI  - An anti-nuclear shield for your thyroid.

PMID- 12425278
TI  - I'm blinking so much that it's beginning to interfere with my vision. What's
      wrong?

PMID- 12425279
TI  - What is an ESR and when is my doctor likely to order it?

PMID- 12425280
TI  - Antitrust.

PMID- 12425281
TI  - Appropriate interhospital patient transfer.

PMID- 12425282
TI  - Financial conflicts of interest in biomedical research.

PMID- 12425283
TI  - Guidelines on the role of physician assistants in the emergency department.

PMID- 12425284
TI  - Promotion of College policies on contracting and compensation.

PMID- 12425285
TI  - Verification of endotracheal tube placement.

PMID- 12425286
TI  - When will 3-dimensional (3D) imaging become practical in private practice? I
      enjoy using digital imaging now but wonder how quickly the current technology
      will become obsolete.

PMID- 12425287
TI  - Board certification.

PMID- 12425288
TI  - Orthodontist as CEO.

PMID- 12425289
TI  - Using rubber dam.

PMID- 12425290
TI  - Using rubber dam II.

PMID- 12425291
TI  - Unrestored carious teeth.

PMID- 12425292
TI  - Auditing treatments.

PMID- 12425293
TI  - Cochlear implants.

PMID- 12425294
TI  - Hygienists using lasers?

PMID- 12425295
TI  - Fee structure restrictions.

PMID- 12425296
TI  - Dental prescribing.

PMID- 12425297
TI  - Diswasher cure for ulcers.

PMID- 12425298
TI  - Biopsy procedures.

PMID- 12425299
TI  - Bone sequestration from lower 3rd molar region.

PMID- 12425301
TI  - Angular reconstitution: a posteriori assignment of projection directions for 3D
      reconstruction.
AB  - In computerized tomography as well as in most problems of three-dimensional
      reconstruction from projections, one knows from the experimental set-up the
      angular relationships between the projections from which the reconstruction is to
      be calculated. A serious difficulty is encountered when the angles are not known.
      In this paper, a method of "angular reconstitution" is described, which allows
      the a posteriori determination of the relative angular orientations of the
      projections and thus enables the three-dimensional reconstruction of the object
      to be calculated. For asymmetric objects, a minimum of three projections is
      required, which should not be related by a tilt around a single rotation axis.
      The method can be applied to determine the three-dimensional structure of
      biological macromolecules based on electron micrographs of randomly oriented
      individual molecules. Angular reconstitution, in combination with multivariate
      statistical techniques to classify and average the characteristic views of a
      molecule forms a complete, self-contained methodology for molecular structure
      analysis by electron microscopy.

PMID- 12425300
TI  - Recurrent dislocation of the temporomandibular joints: a diagnostic and treatment
      problem.

PMID- 12425302
TI  - Average out-of-pocket health care costs for Medicare+Choice enrollees increase
      substantially in 2002.

PMID- 12425303
TI  - Non-Hodgkin's lymphoma incidence in the world.

PMID- 12425304
TI  - Clinico-pathologic conference: 18-month old boy with fever and severe respiratory
      infection.
AB  - An 18-month-old boy with severe combined immunodeficiency (SCID) due to an IL2-y
      receptor defect had a successful engraftment following a related mismatched
      allogenic bone transplant. He subsequently developed post-transplantation
      lymphoproliferative disorder, with severe respiratory infection which resulted in
      death. The case presentation is followed by a discussion with differential
      diagnosis of the clinical findings, and then by a discussion of the pathology
      found and the implications of this diagnosis.

PMID- 12425305
TI  - Bridging the gap between ethics and clinical practice.

PMID- 12425306
TI  - Propofol as an antiarrhythmic.

PMID- 12425307
TI  - Propofol as an antiarrhythmic.

PMID- 12425308
TI  - The evolution of biotech.

PMID- 12425309
TI  - Easing the chemistry bottleneck: careers in high-throughput chemistry.

PMID- 12425310
TI  - From the Centers for Disease Control and Prevention. Iron deficiency--United
      States, 1999-2000.

PMID- 12425311
TI  - From the Centers for Disease Control and Prevention. Vancomycin resistant
      Staphylococcus aureus--Pennsylvania, 2002.

PMID- 12425312
TI  - [Opportunities in rheumatology].

PMID- 12425313
TI  - The position of the human embryo and foetus in international law and its
      relevance for the South African context.

PMID- 12425314
TI  - Decision-making at the end of life: the termination of life-prolonging treatment,
      euthanasia (mercy-killing) and assisted suicide in Canada in South Africa.

PMID- 12425315
TI  - Ban stand: cloning's big test.

PMID- 12425317
TI  - Physician-focused disease management program contributes to reductions in heart
      attacks.

PMID- 12425318
TI  - Extreme pathways and Kirchhoff's second law.

PMID- 12425319
TI  - Guidelines outline effectiveness of medical nutrition therapy in managing and
      preventing diabetes.

PMID- 12425320
TI  - Diabetics' high blood pressure is often undertreated, study says.

PMID- 12425321
TI  - Common drugs, used in combination, may pose risk.

PMID- 12425322
TI  - Retraction.

PMID- 12425324
TI  - HIV among drug users in China.

PMID- 12425323
TI  - Peroxisome proliferator-activated receptor alpha (PPARalpha) signaling in the
      gene regulatory control of energy metabolism in the normal and diseased heart.
AB  - The tremendous energy demands of the post-natal mammalian heart are fulfilled via
      dynamic flux through mitochondrial oxidative pathways. The capacity for energy
      production via fatty acid (FA) beta-oxidation pathway is determined, in part, by
      the regulated expression of genes encoding FA utilization enzymes and varies in
      accordance with diverse dietary and physiologic conditions. For example, fasting
      and diabetes activate the expression of cardiac FA oxidation (FAO). Peroxisome
      proliferator-activated receptor alpha (PPARalpha) is a ligand-activated
      transcription factor that is known to control the expression of many genes
      involved in cellular FA import and oxidation. Cardiac FA utilization rates are
      reduced in PPARalpha null mice due to diminished expression of genes encoding FAO
      enzymes. Recent work has shown that the PPARalpha regulatory pathway is
      deactivated in pathologic cardiac hypertrophy and hypoxia, two circumstances
      characterized by reduced FAO and increased dependence on glucose as a fuel
      source. Conversely, the activity of the PPARalpha gene regulatory pathway is
      increased in the diabetic heart, which relies primarily on FAO for energy
      production. In fact, evidence is emerging that excessive FA import and oxidation
      may be a cause of pathologic cardiac remodeling in the diabetic heart. This
      review summarizes the regulation of cardiac substrate utilization pathways via
      the PPARalpha complex in the normal and diseased heart.

PMID- 12425325
TI  - Trying to make sense of disorder.

PMID- 12425326
TI  - Euthanasia and assisted suicide.
AB  - Americans' moral acceptance of doctor-assisted suicide and euthanasia is on the
      rise, as is their belief that the practices should be legal.

PMID- 12425327
TI  - Trying to make sense of disorder.

PMID- 12425328
TI  - Older and wealthier.
AB  - The number of elder Americans with six-figure incomes will rise dramatically over
      the next five years--a boon to providers of health-care services, the travel
      industry and makers of luxury products.

PMID- 12425329
TI  - Calcium homeostasis and imbalance.
AB  - The human body is equipped with an efficient protection system against
      hypocalcemia. This system is composed of parathyroid glands, bone, kidney, and
      intestine. By appropriate actions of parathyroid hormone (PTH) and active vitamin
      D (1,25-dihydroxyvitamin D), a small fall of extracellular calcium ion
      concentration is instantly corrected. Thus, a defect of any step in this system
      results in the development of hypocalcemia. Overloaded calcium either from bone
      or intestine is efficiently excreted into the urine. Thus, hypercalcemia develops
      almost exclusively when a greater amount of calcium than the kidney can excrete
      is loaded. In chronic dialysis patients, either hypocalcemia or hypercalcemia may
      develop because of defects in these two defense systems against calcium
      imbalance.

PMID- 12425330
TI  - Fatigue failure in polysilicon not due to simple stress corrosion cracking.
AB  - In the absence of a corrosive environment, brittle materials such as silicon
      should be immune to cyclic fatigue. However, fatigue effects are well known in
      micrometer-sized polycrystalline silicon (polysilicon) samples tested in air. To
      investigate the origins of this phenomenon in polysilicon, we developed a fixed
      grip fracture mechanics microspecimen but could find no evidence of static stress
      corrosion cracking. The environmental sensitivity of the fatigue resistance was
      also investigated under cyclic loading. For low-cycle fatigue, the behavior is
      independent of the ambient conditions, whether air or vacuum, but is strongly
      influenced by the ratio of compressive to tensile stresses experienced during
      each cycle. The fatigue damage most likely originates from contact stresses at
      processing-related surface asperities; subcritical crack growth then ensues
      during further cyclic loading. The lower far-field stresses involved in high
      cycle fatigue induce reduced levels of fatigue damage. Under these conditions, a
      corrosive ambient such as laboratory air exacerbates the fatigue process. Without
      cyclic loading, polysilicon does not undergo stress corrosion cracking.

PMID- 12425331
TI  - Coverage decision-making in Medicaid managed care: key issues in developing
      managed care contracts.
AB  - Coverage provisions are the most complex part of any managed care contract. This
      is particularly true for Medicaid agencies, because of important differences
      between Medicaid and insurance. This Issue Brief identifies general issues that
      should be addressed by States as managed care contracts are developed and
      drafted, and it specifically explores the challenges faced by public purchasers
      when drafting managed care coverage provisions.

PMID- 12425332
TI  - An overview of Medicaid managed care litigation.
AB  - Since the enactment of Medicaid in 1965, states have had the option of offering
      beneficiaries enrollment in managed care arrangements. With the advent of
      mandatory managed care reaching millions of beneficiaries (including a growing
      proportion of disabled recipients), the amount and scope of litigation involving
      Medicaid managed care plans can be expected to grow. A review of the current
      litigation regarding Medicaid managed care reveals two basic types of lawsuits:
      (1) those that challenge the practices of managed care companies under various
      federal and state laws that safeguard consumer rights, protect health care
      quality, and prohibit discrimination; and (2) suits that assert claims arising
      directly under the Medicaid statute and implementing regulations, as well as
      claims related to Constitutional safeguards that undergird the program. Lawsuits
      asserting claims arising under Medicaid tend to raise two basic questions: (1)
      the extent to which enrollment in a Medicaid managed care plan alters existing
      Medicaid beneficiary rights and state agency duties under federal or state
      Medicaid law; and (2) the extent to which managed care companies, as agents of
      the state, act under "color of law" (i.e., undertaking to perform official duties
      or acting with the imprimatur of state authority). Additionally, states might see
      an increase in litigation brought by prospective and current contractors who
      assert that they have been wrongfully denied contracts or improperly penalized
      for poor performance. These assertions may involve claims that are grounded in
      federal and state law, the Medicaid statute, and the Constitution. Moreover, in
      light of the consumer protection elements of the managed care reforms contained
      in the Balanced Budget Act, future managed care litigation may focus on the
      manner in which companies carry out states' obligations toward managed care
      enrollees. Resolution of Medicaid managed care cases involves the application of
      general principles of administrative and regulatory law. Thus, Medicaid managed
      care cases have implications for other public purchasers of managed care
      arrangements, including state mental health and alcohol and substance abuse
      agencies.

PMID- 12425333
TI  - Attributions in explanations of risk estimates.
AB  - In the spring of 1993, nearly 40 percent of Milwaukee-area residents experienced
      a nationally publicized outbreak of cryptosporidium, a parasite that infested the
      metropolitan drinking water supply. Using open-ended survey data gathered from
      610 adult residents in the wake of that outbreak, this study looks at factors
      related to the ways in which people make sense of their quantitative personal
      risk estimates. The concepts of informal reasoning and attribution aided this
      endeavor. Analysis of open-ended comments about the risk of getting ill from a
      waterborne parasite indicated that explanations of personal risk were consistent
      with predictions made by attribution theory. Good outcomes, which included having
      remained healthy during the outbreak, were associated with a greater likelihood
      that respondents would attribute causation to themselves, while one specific bad
      outcome, having experienced the illness, was associated with a greater likelihood
      that respondents would attribute causation externally. This study also examined
      predictors of whether respondents employed probabilistic language in those
      attributions. Analysis indicated that income was positively related to the use of
      probability-oriented language, while age and race were negatively related to the
      use of such language (i.e., persons of color and older individuals were less
      likely to use such language).

PMID- 12425334
TI  - Findings of scientific misconduct.

PMID- 12425335
TI  - Findings of scientific misconduct.

PMID- 12425336
TI  - Cesar Milstein, scientist (1927-2002).

PMID- 12425337
TI  - [Fast automated finite element mesh generation of residual lower limb for
      clinical application].
AB  - Objective. To develop a model of fast automated mesh generation of residual lower
      limb for clinical application. Method. Actual geometry of the bone was
      represented as a standard pretreated model of bone, which was auto-located by
      employing an affine scaling transformation. Hexahedral or wedge elements were
      constructed by joining quadrilateral or triangular meshes generated by graph
      partitioning method and transport-mapping method from successive planar cross
      sections. Result. A model of fast automated mesh generation of residual lower
      limb was developed, which can be applied to different amputee and ensure the
      geometric integrality of bone. Auto-location of the bone was carried out. The
      mesh refinement can be controlled to adapt to different computational efficiency.
      The generated elements are hexahedral or wedge elements, both of which are more
      precise than tetrahedral element. Conclusion. The present method could be applied
      in finite element analysis method for prosthetic socket designing. Radioactive
      damage from those techniques such as CT or MRI to the amputee and the difficulty
      in image processing could be avoided.

PMID- 12425338
TI  - [Fast 3D surface rendering for CT or MR image on a personal computer].
AB  - Objective. To design a 3D surface reconstruction algorithm capable of
      reconstructing 3D shapes of the organs, bones and tissues rapidly from CT or MR
      image on a personal computer. Method. By transforming and decomposing the
      projection of the discrete 3D data field into shear transformation and warp
      transformation, a Shear-Warp algorithm realizing the 3D reconstruction was
      established. The algorithm reduce the amount of computation obviously. The 3D
      surface was reconstructed by using the principle of the parallel projection,
      basing on the Shear-Warp algorithm. Shear transformation was performed on the
      volume data at first. Then the warped 3D surface was obtained by making a
      threshold in the sheared space. The brightness of the 3D surface was calculated
      using Phong brightness model, and the final image was generated through the Warp
      transformation. Result. A direct 3D surface reconstruction algorithm was
      established basing on a principle of projection from the Shear-Warp algorithm,
      which was able to display 3D surface on a personal computer rapidly. Conclusion.
      Compared with other surface reconstruction algorithms, the proposed algorithm has
      the advantages of no preprocessing, no intermediate data are generated in the
      reconstruction. With this new algorithm, it is possible to realize fast 3D
      surface rendering for medical images on a personal computer without the support
      of any hardware accelerator.

PMID- 12425339
TI  - [Brain processing component during face cognition--N170 revealed by event-related
      potentials].
AB  - Objective. To observe features of early component N170 during face recognition.
      Method. Scalp distribution, amplitude, and latency of N170 was recorded during
      face recognition tasks in 16 normal subjects. Result. N170 was elicited by the
      face stimuli in only half of the subjects and the amplitude was modulated by
      cognitive tasks. Conclusion. N170 reflects not only face structure encoding unit
      but also direct visual processing unit. Whether N170 reflects the specialty in
      face recognition needs further study. The latency of N170 showed left hemisphere
      dominance and the amplitude showed right hemisphere dominance, indicating that it
      is not pure right hemisphere dominance in face recognition.

PMID- 12425340
TI  - [Two types of event-related brain slow potentials in auditory location
      discrimination (correction of dicrimination) task].
AB  - Objective. To study the difference between two types of event-related brain
      potentials (ERPs) in auditory location discrimination task. Method. Event-related
      potentials (ERPs) in auditory location discrimination task were recorded in 14
      normal subjects and were compared with head-down tilt (HDT) and head-up tilt
      (HUT) conditions. Result. 1) The subjects could be divided into group I (n=7) and
      group II (n =7) according to the feature of the target ERPs component (P3). The
      difference between the two groups was mainly that there was a negative slow wave
      after 150 ms in the ERPs of group II subjects, and that the reaction time and
      error rate in II group was higher than in I group. These data indicated that the
      psychological load on group II was larger than that on group I. 2) The reduction
      of mean slow potential amplitude during HDT was more significant in group II than
      in group I. Conclusion. The slow potential amplitude of ERPs may reflect the
      psychological load and the brain function state. Attention should be paid to the
      feature of auditory ERPs in space medical practice.

PMID- 12425341
TI  - [Changes in heart rate and blood pressure under push pull maneuver simulated on a
      tilt table].
AB  - Objective. Push-pull maneuver (PPM) was simulated using a tilt table to assess
      detailed cardiovascular responses and the simulation model. Method. Ten healthy
      fighter pilots were exposed to 3 times transition of body position of head-up
      tilt (HUT) for 1 min-->head-down tilt (HDT) for 10 s, 15 s and 20 s respectively-
      >HUT for 1 min in randomized sequences. The rate of tilt table rotation was 45
      degrees /s. Heart-level arterial blood pressure was monitored with 4 s intervals,
      and HR was continuously monitored by ECG. Result. HR and BP fell significantly
      during HDT compared with those during HUT; upon subsequent HUT, HR and BP were
      significantly less than those during previous HUT, except BP at 11-15 s.
      Conclusion. Cardiovascular responses to PPM can be simulated with a tilt table.
      It is suggested that the tilt table model is valid in simulating the PPM.

PMID- 12425342
TI  - [Roles of integrins and cytoskeleton in cellular mechanotransduction].
AB  - Integrins and cytoskeleton play important role in the conversion of mechanical
      signals into intracellular biochemical signals followed by physiological or
      pathological responses. At the same time, the system of extracellular matrix
      (ECM)-integrins-cytoskeleton (CSK) axis is in close connection with ion channels
      and signal transduction, and they interact with each other.

PMID- 12425343
TI  - Is hydrogeologic science on track?

PMID- 12425344
TI  - Perspectives on Mexican ground water resources.

PMID- 12425345
TI  - Comparison of formation and fluid-column logs in a heterogeneous basalt aquifer.
AB  - Deep observation boreholes in the vicinity of active production wells in
      Honolulu, Hawaii, exhibit the anomalous condition that fluid-column electrical
      conductivity logs and apparent profiles of pore-water electrical conductivity
      derived from induction conductivity logs are nearly identical if a formation
      factor of 12.5 is assumed. This condition is documented in three boreholes where
      fluid-column logs clearly indicate the presence of strong borehole flow induced
      by withdrawal from partially penetrating water-supply wells. This result appears
      to contradict the basic principles of conductivity-log interpretation. Flow
      conditions in one of these boreholes was investigated in detail by obtaining flow
      profiles under two water production conditions using the electromagnetic
      flowmeter. The flow-log interpretation demonstrates that the fluid-column log
      resembles the induction log because the amount of inflow to the borehole
      increases systematically upward through the transition zone between deeper salt
      water and shallower fresh water. This condition allows the properties of the
      fluid column to approximate the properties of water entering the borehole as soon
      as the upflow stream encounters that producing zone. Because this condition
      occurs in all three boreholes investigated, the similarity of induction and fluid
      column logs is probably not a coincidence, and may relate to aquifer response
      under the influence of pumping from production wells.

PMID- 12425346
TI  - Delineation of three-dimensional well capture zones for complex multi-aquifer
      systems.
AB  - The delineation of well capture zones is a basic component of ground water
      protection. The conventional methodology for capture zone delineation is backward
      advective particle tracking, often applied under the assumption of a two
      dimensional aquifer. The suitability of the conventional approach for complex
      heterogeneous multi-aquifer systems was investigated, using the Waterloo Moraine
      aquifer system as an example. It was found that the conventional approach
      produces irregular particle tracks that require judgment to interpret in a
      meaningful way, and it can raise questions that may affect the credibility of the
      capture zone delineation. As an alternative, the potentially powerful but little
      used backward-in-time advective-dispersive transport approach was investigated. A
      key advantage of this approach is its capability to represent local
      heterogeneities through the dispersion term. The dispersion process has a natural
      smoothing effect that results in unambiguous capture zones without the need for
      interpretation, thus enhancing credibility. The question of capture zone
      validation is also addressed. The meaning of a three-dimensional capture zone is
      considered, and it is shown that a fully three-dimensional representation of the
      system is crucial for valid results. The distinction between the maximum extent
      capture zone and the surface capture zone is also explained. In the case of
      complex heterogeneous systems, advective particle tracking can be used as an
      initial screening tool, whereas the more realistic backward-transport modeling
      approach can be used for final capture-zone delineation.

PMID- 12425347
TI  - Injection-extraction treatment well pairs: an alternative to permeable reactive
      barriers.
AB  - Two of the biggest drawbacks of using permeable reactive barriers (PRBs) to treat
      contaminated ground water are the high capital cost of installation, particularly
      when the contaminated ground water is deep below ground surface, and the
      uncertainty of whether or not PRBs remain effective for the long time scales
      (e.g., decades) needed for many contaminant plumes. The use of an injection
      extraction treatment well pair (IETWP) for capture and treatment of contaminated
      ground water can circumvent these difficulties, while still providing many of the
      same advantages offered by PRBs. In this paper, the hydraulics of IETWPs and PRBs
      are compared, focusing primarily on the width of the captured plume. It is
      demonstrated that IETWPs act as hydraulic barriers in a manner similar to PRBs,
      and that IETWPs provide excellent plume capture. A mathematical expression is
      presented for the plume capture width of an IETWP oriented perpendicular to the
      ground water flow direction in a homogeneous aquifer. Also discussed are other
      practical considerations that might determine whether an IETWP is better suited
      than a PRB for a particular contaminated site; these considerations include
      operating and maintenance costs, and the conditions under which an IETWP system
      can be used for in situ remediation.

PMID- 12425348
TI  - A global experimental system approach of karst springs' hydrographs and
      chemographs.
AB  - Investigation techniques for karst flow systems are based mainly on the study of
      different signals leaving the system caused by natural or induced external
      influences. Each signal represents one of the systems outputs (e.g., hydraulic,
      chemical, physical, or isotopic responses) that reflect the characteristics of
      the entire system. In this paper, we present a method to infer information about
      the structure of karst systems. It is based on a simultaneous analysis of
      chemical and hydraulic responses. Beside the classical piston flow at the
      beginning of a flood pulse, we define a chemically based recession flow phase.
      During this phase, field data show that the concentration of total dissolved
      solids can be considered as an exponential function of the logarithm of flow.
      This relationship allows two parameters to be defined, one of which is dependent
      on the structure and degree of development of the karst conduit network, the
      other is dependent mainly on bioclimatic factors. Data collected from seven karst
      springs are used to support ideas introduced in the paper.

PMID- 12425349
TI  - The capture efficiency map: the capture zone under time-varying flow.
AB  - The capture zone or contributing area of a ground water extraction well can be
      defined as that portion of the aquifer from which the well draws its water.
      Accurate delineation of capture zones is important in many ground water
      remediation applications and in the definition of wellhead protection areas.
      Their mathematical delineation is often simplified by using quasi-steady-state
      models based on time-weighted average pumping rates and background hydraulic
      gradients. We present a new semianalytic approach for the definition of capture
      zones under transient-flow conditions. We then use this approach to evaluate the
      effects of time variations in the direction of the background hydraulic gradient
      on capture. Results are presented in the form of capture efficiency maps (CEMs).
      Although the area contributing to a given well is found to generally expand
      relative to the steady-state average capture zone when the gradient direction
      varies, the zone of 100% capture may expand or contract depending on site
      specific conditions. We illustrate our CEM approach by applying it to the design
      of a plume containment system.

PMID- 12425350
TI  - Optimized system to improve pumping rate stability during aquifer tests.
AB  - Aquifer hydraulic properties are commonly estimated using aquifer tests, which
      are based on an assumption of a uniform and constant pumping rate. Substantial
      uncertainties in the flow rate across the borehole-formation interface can be
      induced by dynamic head losses, caused by rapid changes in borehole water levels
      early in an aquifer test. A system is presented that substantially reduces these
      sources of uncertainty by explicitly accounting for dynamic head losses. The
      system which employs commonly available components (including a datalogger,
      pressure transducers, a variable-speed pump motor, a flow controller, and
      flowmeters), is inexpensive, highly mobile, and easily set up. It optimizes the
      flow rate at the borehole-formation interface, making it suitable for any type of
      aquifer test, including constant, step, or ramped withdrawal and injection, as
      well as sinusoidal. The system was demonstrated for both withdrawal and injection
      tests in three aquifers at the Savannah River Site. No modifications to the
      control system were required, although a small number of characteristics of the
      pumping and monitoring system were added to the operating program. The pumping
      system provided a statistically significant, constant flow rate with time. The
      range in pumping variability (95% confidence interval) was from +/- 2.58 x 10(-4)
      L/sec to +/- 9.07 x 10(-4) L/sec, across a wide range in field and aquifer
      conditions.

PMID- 12425351
TI  - Recharge estimation for transient ground water modeling.
AB  - Reliable ground water models require both an accurate physical representation of
      the system and appropriate boundary conditions. While physical attributes are
      generally considered static, boundary conditions, such as ground water recharge
      rates, can be highly variable in both space and time. A practical methodology
      incorporating the hydrologic model HELP3 in conjunction with a geographic
      information system was developed to generate a physically based and highly
      detailed recharge boundary condition for ground water modeling. The approach uses
      daily precipitation and temperature records in addition to land use/land cover
      and soils data. The importance of the method in transient ground water modeling
      is demonstrated by applying it to a MODFLOW modeling study in New Jersey. In
      addition to improved model calibration, the results from the study clearly
      indicate the importance of using a physically based and highly detailed recharge
      boundary condition in ground water quality modeling, where the detailed knowledge
      of the evolution of the ground water flowpaths is imperative. The simulated water
      table is within 0.5 m of the observed values using the method, while the water
      levels can differ by as much as 2 m using uniform recharge conditions. The
      results also show that the combination of temperature and precipitation plays an
      important role in the amount and timing of recharge in cooler climates. A
      sensitivity analysis further reveals that increasing the leaf area index, the
      evaporative zone depth, or the curve number in the model will result in decreased
      recharge rates over time, with the curve number having the greatest impact.

PMID- 12425352
TI  - Errors with small volume elastic seepage meter bags.
AB  - The use of small volume elastic collection bags (condoms) has become popular in
      seepage meter studies in recent years, despite minimal field or laboratory
      validation of their use and, specifically, the impact of their elasticity on
      seepage measurements. A laboratory study was initiated after field results using
      small elastic collection bags produced seepage data that did not correlate with
      hydrometric data. The laboratory data demonstrate that condoms undergo
      significant mechanical relaxation during seepage measurement times typically
      observed in field settings. Unlike conventional nonelastic collection bags, which
      mechanically relax over several minutes, the condoms suffered from a slow
      mechanical relaxation or equilibration. Over nine hours, condoms gained 43 mL of
      water, approximately 50% of maximum workable volume (between mechanical
      relaxation effect and elastic limit), under stagnant flow conditions. This long
      term equilibration invalidates simple subtraction of equilibration volumes from
      collection volumes as a correction technique. Previously published studies using
      flexible small-volume elastic measurement bags (condoms) have not reported a
      mechanical relaxation effect. Overall, because the condom's small workable volume
      and inherent variability, we would not recommend any small-volume elastic
      measurement bags for quantitative seepage measurements.

PMID- 12425353
TI  - The Lisse effect revisited.
AB  - The Lisse effect is a rarely noted phenomenon occurring when infiltration caused
      by intense rain seals the surface soil layer to airflow, trapping air in the
      unsaturated zone. Compression of air by the advancing front results in a pressure
      increase that produces a water-level rise in an observation well screened below
      the water table that is several times as large as the distance penetrated by the
      wetting front. The effect is triggered by intense rains and results in a very
      rapid water-level rise, followed by a recession lasting a few days. The Lisse
      effect was first noted and explained by Thal Larsen in 1932 from water-level
      observations obtained in a shallow well in the village of Lisse, Holland. The
      original explanation does not account for the increased air pressure pushing up
      on the bottom of the wetting front. Analysis of the effect of this upward
      pressure indicates that a negative pressure head at the base of the wetting
      front, psi(f), analogous to that postulated by Green and Ampt (1911) to explain
      initially rapid infiltration rates into unsaturated soils, is involved in
      producing the Lisse effect. Analysis of recorded observations of the Lisse effect
      by Larsen and others indicates that the water-level rise, which typically ranges
      from 0.10 to 0.55 m, should be only slightly larger than psi(f) and that the
      depth of penetration of the wetting front is no more than several millimeters.

PMID- 12425354
TI  - Remediation of the Wells G & H Superfund Site, Woburn, Massachusetts.
AB  - Remediation of ground water and soil contamination at the Wells G & H Superfund
      Site, Woburn, Massachusetts, uses technologies that reflect differences in
      hydrogeologic settings, concentrations of volatile organic compounds (VOCs), and
      costs of treatment. The poorly permeable glacial materials that overlie fractured
      bedrock at the W.R. Grace property necessitate use of closely spaced recovery
      wells. Contaminated ground water is treated with hydrogen peroxide and
      ultraviolet (UV) oxidation. At UniFirst, a deep well completed in fractured
      bedrock removes contaminated ground water, which is treated by hydrogen peroxide,
      UV oxidation, and granular activated carbon (GAC). The remediation system at
      Wildwood integrates air sparging, soil-vapor extraction, and ground water
      pumping. Air stripping and GAC are used to treat contaminated water; GAC is used
      to treat contaminated air. New England Plastics (NEP) uses air sparging and soil
      vapor extraction to remove VOCs from the unsaturated zone and shallow ground
      water. Contaminated air and water are treated using separate GAC systems. After
      nine years of operation at W.R. Grace and UniFirst, 30 and 786 kg, respectively,
      of VOCs have been removed. In three years of operation, 866 kg of VOCs have been
      removed at Wildwood. In 15 months of operation, 36 kg of VOCs were removed at
      NEP. Characterization work continues at the Olympia Nominee Trust, Whitney
      Barrel, Murphy Waste Oil, and Aberjona Auto Parts properties. Risk assessments
      are being finalized that address heavy metals in the floodplain sediments along
      the Aberjona River that are mobilized from the Industri-Plex Superfund Site
      located a few miles upstream.

PMID- 12425355
TI  - A derivation of Darcy's law.

PMID- 12425356
TI  - About David Keith Todd.

PMID- 12425357
TI  - Trials and tribulations.

PMID- 12425358
TI  - The science behind statins and fibrates.

PMID- 12425359
TI  - Novel insights on high-density lipoprotein in coronary heart disease.

PMID- 12425360
TI  - Insulin resistance, heart disease and inflammation. Identifying the 'at-risk'
      patient: the earlier the better? The role of inflammatory markers.

PMID- 12425361
TI  - Metabolic syndrome, diabetes and coronary heart disease.

PMID- 12425362
TI  - At times like these..

PMID- 12425363
TI  - The role of botulinum toxin a in the management of lower limb spasticity in
      patients with cerebral palsy.
AB  - This study aimed to determine the effects of botulinum toxin-A (btA) on
      spasticity in children with cerebral palsy (CP). Thirty-five children with
      spastic CP were evaluated. The injection group consisted of 25 patients who were
      injected with btA and received conventional physical therapy. The control group
      consisted of 10 patients who were treated with conventional physical therapy
      only. In the injection group, btA was applied to the lower extremity spastic
      muscles at a total dose of 8-10 lU/kg. Spasticity was measured by the Ashworth
      scale. Gait function was evaluated by clinical gait assessment in all patients
      and temporal distance factors in 16 patients. All the parameters were recorded
      before treatment, after three days and after one month of therapy. Following
      injection of btA, significant improvement in all parameters was observed. No
      statistically significant progression was noted in the control group except
      clinical gait analysis scores. Comparing the three-day and one-month measurements
      of spasticity of the two groups, statistically significant results were obtained
      in favour of the injection group in all parameters except for clinical gait
      analysis scores. The findings of this study showed btA injection to be an
      effective treatment for reducing spasticity and improving gait function in
      patients with spastic CP

PMID- 12425364
TI  - Dermal objective pharmacodynamic profile of cetirizine and epinastine: two
      controlled, randomised, double-blind, crossover studies.
AB  - Two double-blind clinical pharmacology studies were performed in healthy
      volunteers to compare the dermal pharmacodynamic profile of epinastine with
      cetirizine, a well-documented anti-H1 antagonist, after oral administration at
      the usual recommended dosage, i.e. 10 mg cetirizine and 20 mg epinastine (versus
      placebo). Histamine skin challenges (prick test) were evaluated before and at 1,
      2, 4, 8 and 24 hr after drug intake by measuring the wheal and flare area
      (studies 1 and 2) along with laser Doppler monitoring of the microvascular
      responses (study 2). A decrease in wheal and flare areas was observed following
      intake of both drugs compared with placebo controls. With the notable exception
      of 1 hr post dose wheal values, which were consistently smaller after epinastine,
      cetirizine was superior to epinastine for both wheal and flare at all other
      times. At the prick test site, treatment with epinastine and cetirizine
      accentuated the increase in blood flow induced by histamine. This reflects the
      decrease of the whealing but there was no significant difference between the two
      active test compounds. At 1 cm from the prick test site, the administration of
      both active treatments inhibited the increase of blood flow, and cetirizine
      showed a more potent inhibitory effect from 8 hr post dose. This reflects the
      reduction of the flare induced after histamine-receptor activation of the axon
      reflex. In conclusion, epinastine shows a rapidly greater (within 1 hr post dose
      on the wheal only) but vanishing effect than cetirizine. At all other time
      points, cetirizine was generally more effective than epinastine.

PMID- 12425365
TI  - AGT and AT1R gene polymorphism in hypertensive heart disease.
AB  - Left ventricular hypertrophy in patients with hypertension is a main clinical
      prognostic entity The aim of this study was to evaluate the association between
      mutations at genes of the renin-angiotensin system (RAS) and the development of
      left ventricular hypertrophy. Genetic polymorphism in angiotensinogen (AGT) and
      angiotensin Il-type 1 receptor (AT1R) genes was examined in a group of well
      selected essential hypertensive caucasians with left ventricular involvement (n =
      40) and a group of healthy unrelated caucasians (n = 150). Cardiac morphology and
      function were assessed by M-mode echocardiography. Molecular variants were
      analysed by amplified fragment length polymorphism. We observed a statistically
      significant difference both for AGT and AT1R genotype distribution in patients
      with left ventricular hypertrophy compared with controls (p<0.05). A 0.49 and
      0.225 frequency was detected among cases for T and C mutant alleles at AGT and
      AT1R genes. Mutations in RAS genes are involved in the pathophysiology of target
      organ damage in essential hypertension. Evaluation of molecular factors
      conferring a risk of developing heart involvement may lead to better
      identification of patient subgroups and more effective control of the clinical
      course.

PMID- 12425366
TI  - Therapeutic approach in insulin resistance with acanthosis nigricans.
AB  - The aim of the present study was to evaluate the effect of metformin in very
      obese subjects with acanthosis nigricans. Five patients (two obese children, mean
      age 14.4 +/- 0.6 yr, mean BMI 35.2 +/- 1.9 kg/m2 and normal glucose tolerance,
      and three newly diagnosed obese type 2 diabetic patients, mean age 37.7 +/- 3.2
      yr, mean BMI 37.7 +/- 2.9 kg/m2) were enrolled in the study Insulin secretion was
      measured during oral glucose tolerance (OGT) and intravenous glucose tolerance
      (IVGT) tests. Insulin resistance was assessed by the homoeostasis model
      assessment (HOMA) index. All the patients were treated with metformin at a mean
      daily dose of 2.23 +/- 0.45 g. Six months after initiation of therapy we found a
      significant reduction in AUC for insulin secretion during OGTT (p < 0.05), due to
      reduction in both basal and stimulated insulin secretion (p<0.05). Body weight
      was reduced by mean 4.7 +/- 1.9% and body fat mass by 8.95 +/- 3.7%. We have
      demonstrated a significant decrease of 36.3% in insulin resistance (p < 0.01).
      Our results demonstrate that metformin reduces hyperinsulinaemia, body weight and
      fat mass and improves insulin sensitivity in patients with insulin resistance and
      acanthosis nigricans.

PMID- 12425367
TI  - 15. Image-guided breast biopsy.
AB  - The introduction of mammographic screening has led to an increased number of
      impalpable in situ and invasive breast cancers. Image-guided percutaneous biopsy
      in these patients has advantages over surgical biopsy, primarily cost savings and
      reducing the number of operations required for definitive treatment. Image-guided
      breast biopsy is also useful in palpable lesions. Image-guided biopsy should be
      used in conjunction with full clinical and imaging work-up as part of the triple
      assessment protocol. Techniques available include fine needle aspiration,
      automated needle-gun core and vacuum assisted large core biopsy. Lesions visible
      on ultrasound are preferentially biopsied using ultrasound guidance, while those
      seen only mammographically are biopsied using stereotactic guidance. Major
      complications are rare following image-guided biopsy. In most cases further
      management can be decided based on the biopsy result. If there is discordance
      between clinical and imaging features and the biopsy result, image-guided
      percutaneous biopsy should be repeated or surgical biopsy may be required.

PMID- 12425368
TI  - 16. Breast cancer in older women.
AB  - Elderly women are more likely to have less aggressive tumours, which are
      oestrogen receptor positive. They are less likely to be offered screening and
      often given inadequate treatment leading to a higher mortality rate. They should
      be assessed in the same way as their younger counterparts. Age should not be a
      consideration, rather life expectancy Patients' wishes are important but the
      mainstay of treatment is surgical, including axillary node clearance, with
      adjuvant tamoxifen as appropriate. Radiotherapy should not be withheld unless
      there are good reasons to contradict this. In unfit patients, tamoxifen alone is
      a suitable treatment but tumorectomy under local anaesthetic is preferable. If
      the tumour is oestrogen receptor negative, surgery and/or radiotherapy will be
      required.

PMID- 12425369
TI  - Assessment, diagnosis and management of lower urinary tract symptoms in men.
AB  - Lower urinary tract symptoms are very common and the approach to assessment and
      management has changed dramatically over the past few years. Previously referred
      to as prostatism, benign prostatic hyperplasia and bladder outflow obstruction,
      it is now recognised that in most men symptoms are due to a combination of benign
      prostatic enlargement and age-related bladder dysfunction. Most men require only
      simple tests for a diagnosis, with the more complex investigations reserved for
      when the diagnosis is not clear. Symptom bothersomeness and effect on quality of
      life are the critical factors when deciding how to treat a man. A cascade of
      treatments exists, including conservative management, medical therapy and
      surgery. A man moves up the cascade when the present management strategy fails to
      control symptoms. Traditional surgical techniques such as transurethral resection
      of the prostate are still appropriate for some men, although with improved
      medical treatments available the number of men undergoing surgery is declining.

PMID- 12425370
TI  - Ethnic differences in peripheral vascular disease.
AB  - The wide variation in the way coronary artery disease (CAD) affects different
      ethnic groups and the associated risk factor profiles of these groups have been
      extensively studied, but ethnic differences in the clinical manifestations of
      peripheral vascular disease (PVD) have been relatively neglected. The aim of the
      present review is to provide an overview of PVD in different ethnic groups and to
      explore possible pathophysiological factors accounting for these differences.
      Atherosclerotic PVD is generally less prevalent in Indo-Asians and Afro
      Caribbeans than in caucasians, despite the 'classical' risk factors being as
      prevalent, if not more so, suggesting the possibility of as yet unidentified risk
      factors in these groups. Angiographic and microscopic evidence suggests that
      patients of African or Afro-Caribbean origin suffer from a different pattern of
      PVD, which primarily affects the distal arteries. In contrast, Indo-Asians tend
      to suffer from thromboangiitis obliterans (Buerger's disease) far more frequently
      than other ethnic groups; thus, their arterial disease appears to present much
      earlier and with greater severity. However, if this sub-category of patient is
      excluded, they seem to suffer much less from 'simple' atherosclerotic disease
      than their caucasian counterparts. Despite a higher prevalence of diabetes among
      Indo-Asians, the prevalence of intermittent claudication is considerably less in
      this ethnic group.

PMID- 12425371
TI  - Genetic haemochromatosis.
AB  - Genetic haemochromatosis is an autosomal recessive inherited disorder of iron
      metabolism due to mutation of the HFE gene. In homozygotes (1 in 300 of the UK
      population), this results in excessive iron absorption from the gut and its
      deposition in major body organs. This may give rise to fatigue, arthritis,
      cardiac failure, diabetes mellitus, hepatic cirrhosis or skin pigmentation,
      occurring predominantly in males over 50 years of age. Identification uses
      measurement of serum iron, iron-binding capacity (or transferrin) and ferritin,
      together with initial or confirmatory genetic DNA studies.

PMID- 12425372
TI  - Ezetimibe in hypercholesterolaemia.
AB  - Ezetimibe is the first member of a new class of selective cholesterol absorption
      inhibitors, compounds that effectively block intestinal absorption of dietary and
      biliary cholesterol, without affecting absorption of fat soluble vitamins or
      triglycerides. Ezetimibe underwent glucuronidation to a single metabolite and
      localised at the intestinal wall, where it prevented luminal cholesterol
      absorption. Pre-clinical studies demonstrated the lipid-lowering and
      antiatherosclerotic properties of ezetimibe. The efficacy and safety of ezetimibe
      monotherapy have been determined in phase II/III studies: in phase II studies,
      the optimal efficacy was reached with ezetimibe 10 mg per day and the pooled
      efficacy data have shown that ezetimibe 10 mg has a positive effect on the
      lipoprotein profile with a significant reduction in LDL-cholesterol of 18.5%, an
      increase in HDL-cholesterol of 3.5% and a trend towards lowering in triglyceride
      concentrations (-4.9%). The monotherapy phase III studies have confirmed the
      efficacy with a decrease in LDL-C of 17.4% and have demonstrated an excellent
      safety and tolerability profile. The potential for a pharmacokinetic and/or
      pharmacodynamic interaction between ezetimibe and various statins and the
      efficacy and safety or the co-administration of ezetimibe and statins have been
      evaluated in different phase I/II studies: ezetimibe had no significant effect on
      the pharmacokinetics of simvastatin or atorvastatin. Ezetimibe 10 mg co
      administrated with the starting dose of any statin induced a mean 18% additive
      LDL-C lowering effect. This additive 18% reduction in LDL-C is achieved in one
      step compared with the three steps necessary with statin monotherapy.

PMID- 12425373
TI  - Fondaparinux (Arixtra): a new anticoagulant.
AB  - Fondaparinux is a promising new antithrombotic agent. This pentasaccharide
      selectively and specifically inhibits coagulation factor Xa, and requires
      antithrombin as co-factor It is entirely synthetic, in contrast to conventional
      heparin and low molecular heparins which are derived from animal tissues.
      Fondaparinux exhibits a high bioavailability and is convenient to use as it only
      needs to be given once daily by subcutaneous injection. Peak plasma levels are
      achieved within two hours of dosing and the plasma half-life of fondaparinux is
      approximately 17 hours. There is no specific antidote for fondaparinux: it is not
      neutralised by protamine sulphate. Fondaparinux shows no cross-reactivity with
      antibodies associated with heparin-induced thrombocytopenia. Several randomised,
      double-blind studies have demonstrated superiority with respect to a low
      molecular weight heparin (enoxaparin) in preventing venous thromboembolism in the
      setting of orthopaedic surgery. The results of clinical trials of fondaparinux in
      the treatment of deep vein thrombosis and acute coronary syndrome are also
      presented.

PMID- 12425374
TI  - Slow decompression of the bladder using an intravenous giving set.
AB  - Rapid decompression of the bladder has been associated with complications such as
      diuresis, hyperkalaemia, haematuria and hypotension. Although these complications
      are easily managed and rarely clinically significant, clinicians still practise
      slow decompression using a 'clamping' technique. Slow decompression using a
      giving set provides a more convenient and less time-consuming way of achieving
      this goal.

PMID- 12425375
TI  - Management of osteoporosis in an orthopaedic department: audit improves practice.
AB  - Patients presenting with an osteoporosis-related fracture are at increased risk
      of further fractures. We performed a retrospective survey to determine if elderly
      patients presenting to the orthopaedic unit at Manchester Royal Infirmary with
      low energy hip or distal radius fractures were being managed appropriately with
      regards to assessment, investigation and treatment for possible osteoporosis. The
      initial survey demonstrated that only 16% of elderly female patients with low
      energy hip fractures and none of those (0%) with distal radius fractures were
      started on treatment or referred for further investigations for possible
      osteoporosis. After changes in our practice, 76% (p < 0.00001) of patients with
      hip fractures and 81% (p < 0.00001) of those with distal radius fractures were
      investigated, started on treatment or referred to a consultant physician for the
      management of osteoporosis.

PMID- 12425376
TI  - Giant sigmoid diverticulum causing colonic and urinary obstruction.
AB  - Diverticulosis of the colon is a fairly common disease, but a solitary giant
      diverticulum is relatively rare. This case presented with symptoms of urinary and
      bowel obstruction.

PMID- 12425377
TI  - Invasive lobular carcinoma of the breast presenting successively with colonic and
      gastric metastases.
AB  - Involvement of the gastrointestinal tract by metastases from invasive lobular
      carcinoma of the breast is well recognised. We report a unique case where, four
      years after the initial management of the primary breast disease, the patient
      developed colonic metastases followed by a disease-free interval of two years and
      then presented with gastric metastases. The patient responded successfully to
      first- and second-line chemotherapeutic agents on both occasions and is currently
      being maintained on third-line hormonal therapy.

PMID- 12425378
TI  - Horner's syndrome following excision of a vagal paraganglionoma.
AB  - We report a case of excision of a vagal paraganglionoma resulting in Horner's
      syndrome. The case was initially misdiagnosed as a carotid body tumour and
      demonstrates the need for adequate preoperative imaging and patient counselling
      for likely complications of surgery.

PMID- 12425379
TI  - The lateral collateral ligament complex and related muscles act as a dynamic
      stabilizer as well as a static supporting structure at the elbow joint: an
      anatomical and experimental study.
AB  - Among 71 osteoligamentous elbow joint specimens from Japanese subjects, 66% of
      the lateral ulnar collateral ligaments (LUCLs) were in an incomplete form, such
      as a fibrous intermuscular septum lying between the anconeus, supinator and
      extensors, and terminated on the annular ligament. The 'typical' complete
      ligament, extending from the lateral epicondyle and over the radial collateral
      ligament (RCL) to the crista spinatoris, appeared in only 20% of the elbows
      examined. This observation suggests that, in Japanese subjects, the LUCL is not
      usually a simple ligamentous static stabilizer, but acts as a dynamic stabilizer,
      together with its related muscles. In addition, when the elbow was flexed by more
      than 90 degrees, the distance between the lateral epicondyle and the radial head
      became almost 1.5 mm larger than the distance from the epicondyle to the annular
      ligament. We therefore consider that, in the overflexed position, the radial head
      moves slightly distal while the length of the RCL remains almost constant. This
      morphometrical observation suggests that the annular ligament needs to be
      supported by the LUCL-muscle complex from the distal side, as well as by the RCL
      from the proximal side. This extended definition of the lateral collateral
      ligament complex and its associated muscular function is discussed.

PMID- 12425380
TI  - Formation of lymph follicles and germinal centers in the somatic and mesenteric
      lymph nodes of growing mice during ontogenesis.
AB  - We investigated the age-dependent changes that occur in the numbers of lymph
      follicles and germinal centers in various lymph nodes in BALB/C and ICR mice aged
      between four days and 16 to 18 weeks. Young adult BALB/C mice have a relatively
      small body size, compared to ICR mice at the same stage, where there is a
      relatively large body size. In BALB/C mice somatic (popliteal, brachial,
      axillary, inguinal, submandibular and deep cervical) and mesenteric lymph nodes
      were examined. In ICR mice only the somatic (popliteal, brachial and axillary)
      lymph nodes were examined. In both BALB/C and ICR mice, the primary follicles
      were apparent in most somatic nodes by the 6th postnatal day. Up to 28 days of
      age, the number of follicles per node increased, reaching different levels in
      nodes from different locations. Thereafter, in most of the somatic nodes in
      BALB/C mice the number of follicles increased only slightly, although there was a
      substantial increase in ICR mice, reaching a peak or a plateau at 8 or 12 weeks
      of age. In the mesenteric (ileocecal) nodes in BALB/C mice, the primary follicles
      first appeared at 10 to 12 days, then there was a linear increase until a plateau
      level was reached at 8 weeks of age. Germinal centers appeared in the mesenteric
      nodes at 28 days and increased rapidly in number thereafter. In most somatic
      nodes germinal centers were scarcely observable until 8 weeks of age. Based on
      our observations we have three suggestions. Firstly, in BALB/C mice there were
      two different patterns of age-dependent changes in the numbers of lymph follicles
      in the somatic and the mesenteric nodes during ontogenesis. These different
      patterns are probably due to variations in the magnitude of the exogenous antigen
      stimulatory effect. Secondly, it seems likely that the variations in the numbers
      of lymph follicles that are produced in somatic nodes at different locations
      during the first 28 days after birth relate to the dimensions of the body regions
      that are drained by that particular somatic node at that stage of development.
      Thirdly, in the relatively small BALB/C mice, the ontogenetic production of lymph
      follicles in a somatic node is mostly completed during the first four weeks of
      life, whereas in the relatively larger ICR mice, this process may continue until
      the young adult stage of 8 weeks.

PMID- 12425381
TI  - A case of an accessory palmaris longus muscle and a duplicate palmaris longus
      muscle with special reference to their nerve supply--morphologic significance of
      a common innervation trunk.
AB  - During a dissection of the forearm and hand, a duplicate palmaris longus muscle
      with an accessory palmaris longus muscle was observed on the right side of a 73
      year-old Japanese male cadaver. Duplications of the palmaris longus muscle have
      been reported by many authors. Humphry (1872) suggested the presence of radial,
      intermediate, and ulnar sectors in the superficial layers of the forearm flexor
      muscular angulus, based on a comparison of fore- and hind limbs and comparative
      anatomical theory. The palmaris longus muscle usually differentiates from the
      intermediate sector but differentiation from the other two sectors may also be
      possible. Some authors have asserted that a common innervation trunk is critical
      for determining an ontogenetic relation between the muscles (Fuchino, 1960;
      Honma, 1980; Yamada, 1986). We examined the nerve supply in addition to
      scrutinize these anomalous palmaris longus muscles. In our case, the ramification
      of the innervating nerves was specific. The branches to the second palmaris
      longus muscle and the flexor carpi radialis arose as a common trunk from the
      median nerve. The branches to the first palmaris longus muscle and the accessory
      palmaris longus muscle originated as another common trunk from the median nerve.
      From these observations, we speculated that the second palmaris longus muscle has
      differentiated from the flexor carpi radialis, while the accessory palmaris
      longus muscle has differentiated from the first palmaris longus muscle, based on
      Humphry's suggestion.

PMID- 12425382
TI  - Effects of probucol in hyperlipidemic rabbit liver: a preliminary ultrastructural
      study.
AB  - Probucol is a lipid-lowering agent with an antioxidant effect; however, its
      influence on the liver remains unclear. The effects of probucol on hyperlipidemic
      rabbit liver are investigated to add a structural data on its therapeutical
      profile. Local albino rabbits were divided into three groups. 1) Hyperlipidemic
      group: fed with 1% cholesterol (150 g/kg/day) enriched chow for 2 months. 2)
      Probucol treated group: group 1 + intraperitoneal probucol (10 mg/kg/day)
      administration for 15 days. 3) Control group fed with normal chow. The blood
      lipid profile was investigated biochemically. Liver samples were examined
      electronmicroscopically. Within the parenchymal cells of group 1, the amount of
      rough surfaced endoplasmic reticulum was increased, its cisterna was dilated
      displaying a moderately electron dense substance in it and showed close
      apposition with the condensed mitochondria. In group 2, smooth surfaced
      endoplasmic reticulum was in extensive amounts filling almost all of the
      cytoplasm, displayed a reticular, degenerated appearance and was in close
      relation with the condensed, degenerated mitochondria. Probucol may cause
      degenerative changes on the liver parenchyme at the subcellular level. It alters
      the structure of these cells mainly acting on the smooth surfaced endoplasmic
      reticulum and the mitochondria that are known to be involved in cellular
      detoxification.

PMID- 12425383
TI  - A blessed and charmed personal odyssey.
AB  - Sandwiched between hyperbolic concerns about our society and mankind's future, I
      have sought to depict the personal exploits of a not untypical psychologist
      through the mostly joyous times of America in the mid and late 20th century. I
      subscribe to the view that you, my reader, has shared a discipline that is and
      may become even more the noblest of all sciences. Having achieved the honored
      status of Professor Emeritus, I have no plans to curtail my efforts to advance
      our science and its worthy purposes. In almost 50 years of wandering in clinical
      academia, I have found only a small measure of ill will, mostly warmth, deep
      friendships, intellectual challenges, and a life of fulfillment, one in which I
      have had the satisfaction of seeing several of my scholarly missions achieve a
      measure of professional recognition before I become just a memory.

PMID- 12425384
TI  - Teaching cultural sensitivity in psychological assessment: a modular approach
      used in a distance education program.
AB  - In this article, I describe the teaching and evaluation of 8 multicultural
      assessment competencies in an American Psychological Association accredited,
      distance education, clinical psychology doctoral program. This modular approach
      consists of 15 hr of face-to-face, didactic and experiential multicultural
      assessment training designed to (a) augment personal awareness, (b) develop a
      conceptual base, (c) provide exposure to available assessment technologies, (d)
      ensure an understanding of an integrative model of culturally sensitive
      assessment, and (e) offer opportunities to apply this material to assessment
      cases. In addition to completing this training, students are evaluated on these
      competencies as part of their preinternship clinical comprehensive. I present
      preliminary evaluative outcome data as well as a critique of this approach.

PMID- 12425385
TI  - A teaching method for multicultural assessment: psychological report contents and
      cultural competence.
AB  - An earlier training model emphasized systematic feedback on accuracy of concepts
      contained in student assessment reports prepared with common data sets from
      standard tests. This feedback resulted in consistent increments in concept
      agreements between reports prepared by students and more experienced assessors.
      This model was applied in courses with multicultural students by contrasting
      standard and multicultural assessment and using data sets from multicultural
      assessees. These students experienced greater difficulty in demonstrating
      consistent increments of agreement in report concepts due to uneven knowledge of
      specific cultures, inapplicability of available norms, and interpretation issues.
      The effectiveness of combining standard and multicultural training should be
      compared with conventional standard training followed by culturally focused
      specialized assessment courses.

PMID- 12425386
TI  - Assessment training for practice in American Indian and Alaska Native settings.
AB  - The collaborative assessment model is extended as a training model. The
      experience of psychological assessment in American Indian and Alaska Native
      communities is often negative due to culturally inappropriate services and test
      interpretation. It is productive to address this negative experience, using it as
      a catalyst for learning. Training in measurement and construct validation
      provides initial basis for critique of negative experience. Training in
      collaborative assessment procedures then focuses on culturally appropriate
      assessment service practices, cultural orientation's affect on test
      interpretation, and multicultural assessment ethics. Writing skills are
      emphasized, including procedures in report writing for description of local
      adaptations, norms, and interpretative rules, and integration of the Diagnostic
      and Statistical Manual for Mental Disorders (4th ed., text revision; American
      Psychiatric Association, 2000) cultural formulation. Development of local norms
      and emic tests are emphasized.

PMID- 12425387
TI  - Teaching culturally informed psychological assessment: conceptual issues and
      demonstrations.
AB  - Multicultural assessment requires a strong conceptual foundation to address the
      complex and dynamic nature of culture. I present 3 conceptual issues as well as
      the demonstrations or exercises that I use to teach these concepts to students in
      a doctoral program of clinical psychology. The first conceptual issue is that
      multicultural assessment requires a solid foundation in traditional assessment
      theory and methods. Second, culturally informed assessors specify and test what
      about the social and cultural world matters to avoid making inferences based on
      group labels associated with ethnicity or race. Third, culturally responsive
      assessors must formulate and test both culture-specific and alternative
      (impairment or dysfunction) hypotheses, which refers to shifting cultural lenses
      (Kleinman & Kleinman, 1991). I then review exercises and demonstrations to
      illustrate these conceptual ideas. My aim is to help instructors guide students
      of assessment toward integrating a process-oriented way of thinking about
      culture, one that promotes a critical approach to our understanding of the role
      of culture in human behavior and its assessment.

PMID- 12425388
TI  - Differences on the projective hand test among chronic pain patients reporting
      three different pain experiences.
AB  - This study examined personality differences among individuals experiencing 3
      different types of pain. The projective Hand Test was administered to 90
      individuals who were seeking treatment at a pain clinic in an urban area of the
      southeast United States. These people were seeking treatment for either arthritis
      (n = 31), fibromyalgia (n = 29), or migraine headaches (n = 30). A 2 (gender) x 3
      (pain group) x Age Group multivariate analysis of variance was conducted using
      the quantitative Hand Test scoring variables as dependent measures. Results
      indicated that individuals who were seeking treatment for migraine headaches had
      a higher production rate of responses involving exhibitionistic displays (EXH)
      than individuals in the other 2 groups. Individuals who were seeking treatment
      for fibromyalgia had a higher production rate of responses indicating fear and
      phobic concerns (FEAR) than individuals in the other 2 groups. Individuals who
      were seeking treatment for arthritis had a higher production rate of Active (ACT)
      responses than individuals in the other 2 groups. Possible causes and
      consequences of these effects are discussed.

PMID- 12425389
TI  - A comparison of MMPI-2 high-point coding strategies.
AB  - High-point coding refers to the popular practice of classifying Minnesota
      Multiphasic Personality Inventory (Hathaway & McKinley, 1983) profiles based on
      which clinical scales are the most elevated. A previous review of high-point code
      studies (McGrath & Ingersoll, 1999a) noted marked discrepancies across studies in
      the rules used to define high-point codes. This study was conducted to evaluate
      the costs and benefits of different strategies for high-point coding. The impact
      of 4 rules for high-point coding on effect sizes and group sizes was evaluated.
      The 4 rules included requiring a minimum elevation, excluding potentially invalid
      protocols, restricting coding to well-defined codes, and replacing the lower
      scale in infrequently occurring codes with the next most elevated scale. The
      evidence supported the clinical utility of requiring a minimum elevation for code
      scales. The results were more equivocal concerning the value of well-defined
      coding and for not replacing the lower scale in infrequent codes. Results were
      surprisingly negative concerning the utility of excluding potentially invalid
      protocols, suggesting that guidelines developed in situations in which there is a
      clear motivation to distort results may not generalize to other settings.

PMID- 12425390
TI  - Emotions as wishes and beliefs.
AB  - Emotions can be assessed by means of different diagnostic methods, for example,
      by self-report instruments, ratings of facial expressions, or by projective
      techniques. This study presents an alternative approach: a computerized
      investigation of verbally expressed emotions by means of the Affective Dictionary
      Ulm (ADU; Dahl, Holzer, & Berry, 1992), which was applied to responses in the
      Holtzman Inkblot Technique (HIT; Holtzman, 1988; Holtzman, Thorpe, Swartz, &
      Herron, 1961). A normal group (n = 30), patients with neurotic disorders (n =
      30), borderline patients (n = 30), acute schizophrenics (n = 25), and chronic
      schizophrenics (n = 25) were compared in regard to verbally expressed emotions.
      According to the results, patients with neurotic disorders did not differ from
      the normal group in regard to verbally expressed emotions. Borderline patients
      expressed fear and emotions in general significantly more frequently than all
      other diagnostic groups. Furthermore, borderline patients differed in regard to
      specific emotions from patients with neurotic disorders, acute schizophrenics,
      and chronic schizophrenics. Acute schizophrenics did not differ from the normal
      group in regard to the expression of emotions, whereas chronic schizophrenics
      expressed anger, fear, anxiety, and emotions in general significantly less
      frequently than normals. By a discriminant analysis using verbally expressed
      emotions as predictors of the diagnosis, hit rates between 87% and 100% could be
      achieved. Furthermore, hypotheses about correlations between emotions on the one
      hand and internalized primitive object relations and bizarre-idiosyncratic
      thinking were tested empirically. Significant correlations could be demonstrated.
      These results support the validity of assessing emotions through a lexical
      content analysis of the HIT by use of the ADU.

PMID- 12425391
TI  - Differentiating overreporting and extreme distress: MMPI-2 use with compensation
      seeking veterans with PTSD.
AB  - This purpose of this study was to examine overreporting on the Minnesota
      Multiphasic Personality Inventory-2 (MMPI-2; Butcher, Dahlstrom, Graham,
      Tellegen, & Kaemmer, 1989) in compensation-seeking veterans with posttraumatic
      stress disorder (PTSD). A sample of veterans tested during a V.A. hospital
      compensation and pension exam were given the MMPI-2 and measures of PTSD,
      depression, and combat exposure. Veteran's MMPI-2s were only included in the
      analyses if their profile was extremely exaggerated, as measured by an F scale T
      score above 80, did not elevate the MMPI-2 VRIN and TRIN scales, and had a
      primary diagnosis of PTSD (n = 127). Using the Infrequency-Psychopathology, F(p),
      scale to distinguish overreporting from distress, it was found that 98 veterans
      elevated profiles due to distress, whereas 29 elevated due to overreporting, F(p)
      below and above 7, respectively. Differences between groups on MMPI-2 clinical
      scales and the other measures were assessed. Implications of these findings for
      assessing veteran response style and using the MMPI-2 with a PTSD population are
      discussed.

PMID- 12425392
TI  - The Marlowe-Crowne affair: short forms, psychometric structure, and social
      desirability.
AB  - The Marlowe-Crowne Social Desirability scale (Crowne & Marlowe, 1960) is widely
      used to assess and control for response bias in self-report research. Several
      abbreviated versions of the Marlowe-Crowne scale have been proposed and adopted
      in psychology and medicine. In this article I evaluate the adequacy of 9 short
      forms using confirmatory factor analysis across 2 samples (combined N = 867).
      There was some evidence for the adequacy of different short forms, but model
      adequacy was not consistent across samples. Supplementary analyses revealed a
      multidimensional structure to the full Marlowe-Crowne scale and indicated that
      the apparent adequacy of model fit for some short forms might be a statistical
      artifact. Using the Marlowe-Crowne scale or its various short forms as a control
      for response bias is discouraged on empirical and conceptual grounds.

PMID- 12425393
TI  - Relation of an ability measure of emotional intelligence to personality.
AB  - Is emotional intelligence simply a naive theory of personality, or is it a form
      of intelligence? If emotional intelligence is to be of value, it must measure
      something unique and distinct from standard personality traits. To explore this
      question, this study examined an ability test of emotional intelligence and its
      relationship to personality test variables to determine the extent to which these
      constructs overlap. A sample of 183 men and women took the Multifactor Emotional
      Intelligence Scale (Mayer, Caruso, & Salovey, 1999), an ability measure of
      emotional intelligence as well as measures of career interests, personality, and
      social behavior. Emotional intelligence was measured reliably and was relatively
      independent of traditionally defined personality traits, supporting the
      discriminant validity of the emotional intelligence construct.

PMID- 12425394
TI  - The MMPI-2 as a predictor of symptom change following treatment for posttraumatic
      stress disorder.
AB  - This study sought to examine the impact of personality factors on symptom change
      following treatment for 141 Vietnam veterans with chronic combat-related
      posttraumatic stress disorder (PTSD) using the Minnesota Multiphasic Personality
      Inventory-2 (Butcher, Dahlstrom, Graham, Tellegen, & Kaemmer, 1989). A series of
      partial correlation and linear multivariate regression analyses identified social
      alienation, associated with anger and substance use, as the most potent negative
      predictor of symptom change. Of the scales assessing personality disorder,
      Borderline Personality was identified as the strongest negative predictor of
      outcome. Regression analyses examining the most salient scales identified 5 items
      that contributed 14% of the variance in the prediction of change scores
      independently of the 21% accounted for by pretreatment PTSD severity.

PMID- 12425395
TI  - Using the PAI with an eating disordered population: scale characteristics, factor
      structure, and differences among diagnostic groups.
AB  - Psychometric properties of the Personality Assessment Inventory (PAI; Morey 1991)
      within an eating disordered sample seeking treatment (N = 238) and differences
      among eating disorder diagnostic groups on the PAI were examined. The PAI showed
      acceptable alpha coefficients, item-total correlations, and interitem
      correlations. The factor structure was similar to that reported by Morey (1991),
      with the addition of another factor related to interpersonal coolness and
      distance. Those with binge eating disorder (BED) reported fewer problems and less
      distress in general compared to other eating disordered groups. The BED and
      bulimia nervosa groups were different from the anorexia nervosa groups in
      frequency of matching on two PAI clusters. Use of the PAI with an eating
      disordered population and its utility in understanding eating disorder diagnostic
      groups is supported.

PMID- 12425396
TI  - Relationship between the rorschach and the MMPI-2 in a Swedish population: a
      replication study of the effects of first-factor related test-interaction styles.
AB  - A sizeable amount of research literature has failed to demonstrate a stable
      relationship between self-report and the Rorschach (Exner, 1993). However,
      principal component first-factor related test-interaction style has been shown to
      moderate convergence. In this study 78 psychiatric patients completed the
      Rorschach and the Minnesota Multiphasic Personality Inventory-2 (MMPI-2; Hathaway
      & McKinley, 1989). Practically no correlation was evident between the MMPI-2 and
      the Rorschach, measuring similar constructs, in all patients. Patients with
      similar test-interaction styles demonstrated positive intermethod correlations
      between both conceptually related and conceptually not directly related test
      indexes. The same scales were negatively correlated in patients with discordant
      test-interaction styles, and this difference between test-interaction style
      groups was significant. It is suggested that first-factor related test
      interaction style moderates convergence. It is further suggested that test
      interaction style moderates convergence between both conceptually related and
      conceptually not directly related measures of distress or psychopathology.

PMID- 12425397
TI  - Practicing what we preach.

PMID- 12425398
TI  - Suctioning techniques and airway management practices: pilot study and instrument
      evaluation (July 2002:363-368).

PMID- 12425399
TI  - Resource utilization related to atrial fibrillation after coronary artery bypass
      grafting (May 2002:228-238).

PMID- 12425400
TI  - Vasopressin in the cardiac surgery intensive care unit (July 2002:326-330).

PMID- 12425401
TI  - Cardiac outcomes after myocardial infarction in elderly patients with diabetes
      mellitus.
AB  - OBJECTIVES: To examine the association between (1) comorbid conditions related to
      diabetes mellitus, clinical findings on arrival at the hospital, and
      characteristics of the myocardial infarction and (2) risk of heart failure,
      recurrent myocardial infarction, and mortality in the year after myocardial
      infarction in elderly 30-day survivors of myocardial infarction who had non
      insulin- or insulin-treated diabetes. METHODS: Medical records for June 1, 1992,
      through February 28, 1993, of Medicare beneficiaries (n = 1698), 65 years or
      older, hospitalizedfor acute myocardial infarction in Connecticut were reviewed
      by trained abstractors. RESULTS: One year after myocardial infarction, elderly
      patients with non-insulin- and insulin-treated diabetes mellitus had
      significantly greater risk for readmission for heart failure and recurrent
      myocardial infarction than did patients without diabetes mellitus, and risk was
      greater in patients treated with insulin than in patients not treated with
      insulin. Diabetes mellitus, comorbid conditions related to diabetes mellitus,
      clinical findings on arrival, and characteristics of the myocardial infarction,
      specifically measures of ventricular function, were important predictors of these
      outcomes. Mortality was greater in patients not treated with insulin than in
      patients treated with insulin; the increased risk was mostly due to comorbid
      conditions related to diabetes mellitus and poorer ventricular function.
      CONCLUSIONS: Risk of heart failure, recurrent myocardial infarction, and
      mortality is elevated in elderly patients who have non-insulin- or insulin
      treated diabetes mellitus. Comorbid conditions related to diabetes mellitus and
      ventricular function at the time of the index myocardial infarction are important
      contributors to poorer outcomes in patients with diabetes mellitus.

PMID- 12425402
TI  - Cognitive impairment in heart failure: issues of measurement and etiology.
AB  - BACKGROUND: Clinicians need easy methods of screening for cognitive impairment in
      patients with heart failure. If correlates of cognitive impairment could be
      identified, more patients with early cognitive impairment could be treated before
      the problem interfered with adherence to treatment. OBJECTIVES: To describe
      cognitive impairment in patients with heart failure, to explore the usefulness of
      4 measures of cognitive impairment, and to assess correlates of cognitive
      impairment. METHODS: A descriptive, correlational design was used. Four screening
      measures of cognition were assessed in 42 patients with heart failure: Commands
      subtest and Complex Ideational Material subtest of the Boston Diagnostic Aphasia
      Examination, Mini-Mental State Examination, and Draw-a-Clock Test. Cognitive
      impairment was defined as performance less than the standardized (T-score) cutoff
      point on at least 1 of the 4 measures. Possible correlates of cognitive
      impairment included age, education, hypotension, fluid overload (serum osmolality
      < 269 mOsm/kg), and dehydration (serum osmolality > or = 295 mOsm/kg). RESULTS:
      Cognitive impairment was detected in 12 (28.6%) of 42 participants. The 4
      screening tests varied in effectiveness, but the Draw-a-Clock Test indicated
      impairment in 50% of the 12 impaired patients. A summed standardized score for
      the 4 measures was not significantly associated with age, education, hypotension,
      fluid overload, or dehydration in this sample. CONCLUSIONS: Cognitive impairment
      is relatively common in patients with heart failure. The Draw-a-Clock Test was
      most useful in detecting cognitive impairment, although it cannot be used to
      detect problems with verbal learning or delayed recall and should not be used as
      the sole screening method for patients with heart failure. Correlates of
      cognitive impairment require further study.

PMID- 12425403
TI  - An educational project to improve knowledge related to pulse oximetry.
AB  - BACKGROUND: Pulse oximetry is a frequently used, noninvasive monitoring tool for
      assessing arterial blood oxygenation. Physicians, registered nurses, and
      respiratory therapists are responsible for the accurate interpretation of pulse
      oximetry data as part of the evaluation and management of acutely and critically
      ill patients. OBJECTIVES: (1) To evaluate the extent of current knowledge about
      pulse oximetry and (2) to increase clinicians' knowledge of research-based
      practices related to the appropriate use of pulse oximetry and interpretation of
      its results. METHODS: A test/survey of 17 true-false questions based on the
      research-based practice protocol of the American Association of Critical-Care
      Nurses was developed to evaluate current knowledge of pulse oximetry. A
      convenience sample of medical, nursing, and respiratory therapy staff was invited
      to complete the test/survey before and several months after an educational
      program to improve staff members' knowledge of pulse oximetry. The program
      included educational forums, policy changes, competency checklists, and
      verification of inclusion of research-based principles in orientation programs.
      RESULTS: A total of 442 staff members completed the test/survey given before the
      educational program: 331 nurses, 82 physicians, and 29 respiratory therapists.
      The overall mean percentage of correct answers was 66%. Differences between
      disciplines were significant: respiratory therapists scored slightly higher (76%)
      than did nurses (64%) and physicians (66%) (P = .01). The scores on the
      test/survey given after the educational program increased significantly, from 66%
      to 82% (P < .01). CONCLUSIONS: This educational project improved staff members'
      knowledge of pulse oximetry monitoring.

PMID- 12425404
TI  - Cardiogenic shock in a patient with hypertrophic obstructive cardiomyopathy after
      insertion of a pacemaker.

PMID- 12425405
TI  - Oxidative stress in critically ill patients.
AB  - Oxygen-derived free radicals play an important role in the development of disease
      in critically ill patients. Normally, oxygen free radicals are neutralized by
      antioxidants such as vitamin E or enzymes such as superoxide dismutase. However,
      in patients who require intensive care, oxygen free radicals become a problem
      when either a decrease in the removal or an overproduction of the radicals
      occurs. This oxidative stress and the damage due to it have been implicated in
      many diseases in critically ill patients. Many drugs and treatments now being
      investigated are directed toward preventing the damage from oxidative stress. The
      formation of reactive oxygen species, the damage caused by them, and the body's
      defense system against them are reviewed. New interventions are described that
      may be used in critically ill patients to prevent or treat oxidative damage.

PMID- 12425406
TI  - Effects of an augmented postoperative fluid protocol on wound healing in cardiac
      surgery patients.
AB  - BACKGROUND: Cardiac surgery patients are vulnerable to hypoperfusion
      postoperatively and often have subcutaneous tissue oxygen tension less than 50 mm
      Hg. Hypovolemia most likely contributes to this hypoperfusion and may lead to
      impaired wound healing. OBJECTIVES: To determine if a modified postoperative
      fluid replacement protocol would result in improved tissue oxygen tension, blood
      flow, and healing in cardiothoracic surgery patients. METHODS: A total of 166
      cardiac surgery patients, 18 to 90 years old, participated in a randomized, 2
      group, repeated-measures study. The experimental group received fluid
      augmentation during the first 36 hours after surgery; the control group received
      standard postoperative replacement fluids. Subcutaneous tissue oxygen tension and
      temperature were measured 8, 18, and 36 hours after surgery. Tissue cellularity
      and accumulation of hydroxyproline were evaluated in tissue obtained from
      subcutaneous expanded polytetrafluoroethylene tubes. Wound complications were
      evaluated by using the ASEPSIS Wound Scoring System. RESULTS: Tissue oxygen
      levels, tissue cellularity, and accumulation of hydroxyproline were similar in
      the 2 groups. A negative correlation (P = .01) existed between higher tissue
      oxygen values and lower (better) ASEPSIS leg wound scores. More than 80% of the
      patients had tissue oxygen levels of 50 mm Hg or less at each time of measure.
      Many values were 30 to 40 mm Hg less than the ideal for control of bacteria and
      healing. CONCLUSIONS: The frequency of low oxygen levels is consistent with data
      from earlier studies. Determination of other interventions to improve
      subcutaneous tissue perfusion in cardiac surgery patients is needed.

PMID- 12425408
TI  - One year after September 11: revisiting our ethical visions of freedom and
      justice.

PMID- 12425409
TI  - Anger and acute coronary events.
AB  - A high level of anger has a powerful effect on the incidence of preventable
      cardiovascular death. Persuasive clinical evidence indicates that anger evokes
      physiological responses that are potentially life-threatening in the setting of
      CAD. Finally, emotional stress, anger, or worry have a dominant influence on the
      severity, frequency, and treatment of angina. The natural history of angina is
      characterized by episodic variations in the frequency and severity of symptoms
      coincident with periods of emotional stress. When angina is associated with
      periods of emotional stress or anger, the angina is not usually a result of
      progressive coronary disease, but rather is due to an increase in oxygen demand.
      Appreciation of this concept will help to rule out "true" unstable angina due to
      progressive coronary disease from recurrent angina that results from an increase
      in oxygen demand related to emotional stress. The former requires aggressive
      medical or surgical therapy; the latter, a demand-induced angina, responds to
      beta-adrenergic blockade and a tranquilizer.

PMID- 12425407
TI  - Effectiveness of 0.12% chlorhexidine gluconate oral rinse in reducing prevalence
      of nosocomial pneumonia in patients undergoing heart surgery.
AB  - BACKGROUND: Decreasing the levels of bacteria in the oropharynx should reduce the
      prevalence of nosocomial pneumonia. OBJECTIVES: To test the effectiveness of
      0.12% chlorhexidine gluconate oral rinse in decreasing microbial colonization of
      the respiratory tract and nosocomial pneumonia in patients undergoing open heart
      surgery. METHODS: A prospective, randomized, case-controlled clinical trial
      design was used. Peridex (0.12% chlorhexidine gluconate) was the experimental
      drug, and Listerine (phenolic mixture) was the control drug. A total of 561
      patients undergoing aortocoronary bypass or valve surgery requiring
      cardiopulmonary bypass were randomized to an experimental (n = 270) or a control
      (n = 291) group. Nosocomial pneumonia was diagnosed by using the criteria
      established by the Centers for Disease Control and Prevention. RESULTS: The
      overall rate of nosocomial pneumonia was reduced by 52% (4/270 vs 9/291; P = .21)
      in the Peridex-treated patients. Among patients intubated for more than 24 hours
      who had cultures that showed microbial growth (all pneumonias occurred in this
      group), the pneumonia rate was reduced by 58% (4/19 vs 9/18; P = .06) in patients
      treated with Peridex. In patients at highest risk for pneumonia (intubated > 24
      hours, with cultures showing the most growth), the rate was 71% lower in the
      Peridex group than in the Listerine group (2/10 vs 7/10; P = .02). CONCLUSIONS:
      Although rates of nosocomial pneumonia were lower in patients treated with
      Peridex than in patients treated with Listerine, the difference was significant
      only in those patients intubated more than 24 hours who had the highest degree of
      bacterial colonization.

PMID- 12425410
TI  - Bradycardic ECG monitoring alarms.

PMID- 12425411
TI  - Consolidate human research oversight under Regional Ethics Boards, NIH Clinical
      Bioethics Department proposes.

PMID- 12425412
TI  - HHS Human Subjects Advisory Committee charter to be expanded, membership to be
      reconstituted.

PMID- 12425413
TI  - AAMC Task Force releases recommendations on institutional conflicts of interest.

PMID- 12425414
TI  - Institute of Medicine urges colleges to improve research integrity.

PMID- 12425415
TI  - NHGRI plan for future of genomic research to be vetted at November meeting of
      scientists.

PMID- 12425416
TI  - Cow and dog moved up on post-human sequencing priority list at NHGRI.

PMID- 12425417
TI  - NIH Stem Cell Task Force examines barriers to embryonic stem cell research, and
      other stem cell research-related news.

PMID- 12425418
TI  - Cancer collaboration set to launch "universal portal" site for researchers and
      general public.

PMID- 12425419
TI  - Proactively shaping control arrangements can ensure data access, Duke's Reichman
      tells science community.

PMID- 12425420
TI  - Patient groups to help chart the course of $20 million NIEHS Parkinson's
      initiative.

PMID- 12425422
TI  - NIH health disparities elimination plan goes to NCMHD Advisory Council for
      review.

PMID- 12425421
TI  - Undergraduate biology education fails to keep pace, NAS National Research Council
      report finds.

PMID- 12425423
TI  - E-grants government-wide electronic application system scheduled to be up and
      running by October 1, 2003.

PMID- 12425424
TI  - Pasko Rakic, MD, PhD, selected to receive the 15th Annual Bristol-Myers Squibb
      Award for Distinguished Achievement in Neuroscience Research.

PMID- 12425425
TI  - Hackensack University Medical Center recognized as leader in improving health
      care quality: initiatives will after national quality improvement efforts.

PMID- 12425426
TI  - What inspires clinical research trainees and keeps them on the path?

PMID- 12425427
TI  - A gender gap in the next generation of physician-scientists: medical student
      interest and participation in research.
AB  - BACKGROUND: For 2 decades, the number of physician-scientists has not kept pace
      with the overall growth of the medical research community. Concomitantly, the
      number of women entering medical schools has increased markedly. We have explored
      the effect of the changing gender composition of medical schools on the present
      and future pipeline of young physician-scientists. METHODS: We analyzed data
      obtained from the Association of American Medical Colleges, the National
      Institutes of Health, and the Howard Hughes Medical Institute pertaining to the
      expressed research intentions or research participation of male and female
      medical students in the United States. RESULTS: A statistically significant
      decline in the percentage of matriculating and graduating medical students--both
      men and women-who expressed strong research career intentions occurred during the
      decade between 1987 and 1997. Moreover, matriculating and graduating women were
      significantly less likely than men to indicate strong research career intentions.
      Each of these trends has been observed for medical schools overall and for
      research-intensive ones. Cohort data obtained by tracking individuals from
      matriculation to graduation revealed that women who expressed strong research
      career intentions upon matriculation were more likely than men to decrease their
      research career intentions during medical school. Medical student participation
      in research supported the gender gap identified by assessing research intentions.
      Female medical student participation in the Medical Scientist Training Program
      and the Howard Hughes Medical Institute/National Institutes of Health-sponsored
      Cloisters Program has increased but lags far behind the growth in the female
      population in medical schools. CONCLUSION: Three worrisome trends in the research
      career intentions and participation of the nation's medical students (a decade
      long decline for both men and women, a large and persistent gender gap, and a
      negative effect of the medical school experience for women) presage a further
      decline in the physician-scientist pipeline unless they are reversed promptly and
      decisively.

PMID- 12425428
TI  - Suggestions for improving the effectiveness of oral presentations.

PMID- 12425429
TI  - Expression of the regenerating gene family in inflammatory bowel disease mucosa:
      Reg Ialpha upregulation, processing, and antiapoptotic activity.
AB  - BACKGROUND: The pathophysiology of inflammatory bowel disease (IBD) reflects a
      balance between mucosal injury related to an ongoing inflammatory process and
      mucosal reparative mechanisms. Proreparative mucosal factors may offer new
      therapeutic paradigms. Transcriptional profiling can be applied to identify
      candidate gene products involved in colonic mucosal regeneration. METHODS:
      Resection specimens from patients who underwent colonic resection for IBD or non
      IBD indications were analyzed by performing Affymetrix GeneChip hybridization
      (Affymetrix, Inc., Santa Clara, Calif) and histopathologic scoring. Expression
      and physiologic processing of Reg Ialpha, the most highly expressed member of the
      regenerating (Reg) gene family, was further studied by performing specific
      immunohistochemistry, protein sequencing, and mass spectroscopy. RESULTS: Foregut
      derived tissues normally express human Reg proteins with minimal expression in
      the colon. In the setting of tissue injury associated with IBD, Reg Ialpha Reg
      Ibeta, and Reg III mRNA were highly expressed in colonic mucosa. Paired
      histopathologic scoring demonstrated that Reg expression was not related to the
      presence or the degree of mucosal inflammation. Studies of the Reg Ialpha protein
      revealed evidence of proteolytic cleavage at the N-terminus. In IBD, intact Reg
      Ialpha protein was expressed by the metaplastic Paneth granular cell population.
      Whereas Reg Ialpha cleaved at the N-terminus, it was also deposited throughout
      the lamina propria. Reg Ialpha treatment was shown to reduce epithelial apoptosis
      that occurred in response to treatment with hydrogen peroxide. CONCLUSION:
      Ectopic expression, physiologic processing, and directed tissue deposition of Reg
      Ialpha are components of the colonic mucosal regenerative response in IBD. Reg
      Ialpha may serve to reduce epithelial apoptosis in inflammation.

PMID- 12425431
TI  - Taurine prevents apoptosis induced by high ambient glucose in human tubule renal
      cells.
AB  - BACKGROUND: Hyperglycemia selectively triggers apoptosis in tubule and
      endothelial cells. Taurine, a conditionally essential amino acid, is abundant in
      several tubule segments, but its role has not been defined fully. It can serve as
      an osmolyte or as an endogenous antioxidant. Taurine metabolism is altered in
      diabetes mellitus, with extracellular and intracellular pools reduced. It is
      still unknown whether taurine can play a role as a protective agent in apoptosis
      induced by high glucose in tubular cells. METHODS: Apoptosis (by annexin V
      binding and the terminal deoxynucleotidyl transferase-mediated deoxyuridine
      triphosphate nick end-labeling method), cellular reactive oxygen species (ROS)
      formation (by fluorescent probe 2'-7' dichlorofluorescin diacetate and FACScan
      flow cytometry), and Bcl-2 and Bax proteins (by immunostaining) were studied in a
      human proximal tubular cell line (HK-2) grown in a medium with physiologic (5.5
      mM) or high (30 mM) glucose concentrations for 48 hours. In separate experiments,
      taurine (3-24 mM) was added to the media. RESULTS: The exposure of human tubule
      cells to 30 mM glucose for 48 hours resulted in a significant increase in
      apoptosis compared with 5.5 mM glucose (35 +/- 8% vs. 6 +/- 3%, p < 0.001).
      Thirty mM mannitol failed to induce the effects of high glucose. High glucose
      mediated apoptosis was associated with a decrease in the expression of Bcl-2 (
      87%) and a twofold increase in the expression of Bax protein. Taurine had a dose
      dependent effect in preventing high-glucose-induced apoptosis (-78%, p < 0.001 at
      24 mM). Moreover, with taurine, intracellular ROS decreased by 34% (p < 0.05),
      and changes in intracellular ROS formation induced by taurine at 24 hours
      predicted the variations in the apoptotic index at 48 hours (r = 0.87, p < 0.02).
      Other antioxidants, such as glutathione and N-acetylcysteine, also attenuated the
      high glucose-induced apoptosis. CONCLUSION: These results demonstrate that
      taurine attenuates hyperglycemia-induced apoptosis in human tubular cells via an
      inhibition of oxidative stress. Taurine might act as an endogenous antioxidant in
      tubule cells and could exert a beneficial effect in preventing tubulointerstitial
      injury in diabetic nephropathy.

PMID- 12425430
TI  - Morphine enhances HIV infection of human blood mononuclear phagocytes through
      modulation of beta-chemokines and CCR5 receptor.
AB  - BACKGROUND: Injection drug use remains a significant risk for acquiring HIV
      infection. The mechanisms by which morphine enhances HIV infection of human
      immune cells are largely unknown. OBJECTIVE: In this study, we sought to
      determine the possible mechanisms by which morphine upregulates HIV infection of
      human blood monocyte-derived macrophages (MDM). METHODS: In this study, MDM were
      infected with the R5, X4, and R5X4 HIV strains. HIV replication was determined by
      performing reverse transcriptase activity assays. HIV receptors were determined
      by performing reverse transcriptase polymerase chain reactions and flow cytometry
      assays. beta-chemokines were analyzed by performing enzyme-linked immunosorbent
      assays. In addition, HIV R5 strain and murine leukemia virus envelope-pseudotyped
      HIV infection was performed to determine whether morphine affects HIV infection
      of macrophages at entry level. RESULTS: Morphine significantly enhanced HIV R5
      strain infection of MDM but had little effect on X4 strain infection. The
      macrophage-tropic R5 strain envelope-pseudotyped HIV infection was markedly
      increased by morphine, whereas murine leukemia virus envelope-pseudotyped HIV
      infection was not significantly affected. Furthermore, morphine significantly
      upregulated CCR5 receptor expression and inhibited the endogenous production of
      beta-chemokines in MDM. The opioid receptor antagonist naltrexone blocked the
      effects of morphine on the production of beta-chemokines. CONCLUSION: Opiates
      enhance HIV R5 strain infection of macrophages through the downregulation of beta
      chemokine production and upregulation of CCR5 receptor expression and may have an
      important role in HIV immunopathogenesis.

PMID- 12425432
TI  - Risk factors for osteoporosis in a subgroup of elderly men in a Veterans
      Administration nursing home.
AB  - BACKGROUND: General risk factors for osteoporosis in men include cigarette
      smoking, alcohol consumption, and diseases known to affect calcium or bone
      turnover. The aim of this study was to determine the specific incidence and major
      risk factors for osteoporosis in those at high risk for falling in a Veterans
      Administration nursing home that included a high proportion of psychiatric
      patients. METHODS: We performed a cross-sectional analysis of Veterans
      Administration Medical Center nursing home residents with high fall risk. Thirty
      nine men with a previous episode of falling or who were considered to be at high
      fall risk were enrolled. A review of the medical histories and pertinent hormonal
      and biochemical laboratory values was performed. Bone mineral density was
      measured by performing dual energy x-ray absorptiometry for all participants.
      RESULTS: We reviewed the medical records of 39 male nursing home residents with
      high fall risk. The patients' mean age was 74.7 +/- 6.8 years. A significant (p =
      0.00045) association was found between chronic obstructive pulmonary disease and
      osteoporosis independent of oral corticosteroid use. Additional risk factors
      found to be associated with osteoporosis included hypogonadism, lower body
      weight, antipsychotic medication use, and smoking. CONCLUSION: In a Veterans
      Administration nursing home population at high risk for falls, including
      psychiatric patients, chronic obstructive pulmonary disease independent of the
      use of corticosteroids, lower body weight, hypogonadism, use of antipsychotic
      medications, and smoking was found to be associated with osteoporosis.

PMID- 12425433
TI  - Prednisone induces cognitive dysfunction, neuronal degeneration, and reactive
      gliosis in rats.
AB  - BACKGROUND: High glucocorticoid serum levels and prednisone (PDN) therapy have
      been associated with depression, posttraumatic stress disorder, and some types of
      cognitive dysfunction in humans. OBJECTIVE: The aim of this study was to assess
      whether chronic (90 days) PDN administration produces disturbance in learning and
      memory retention associated with neuronal degeneration and cerebral glial
      changes. METHODS: Male Wistar rats were studied. Controls received 0.1 ml
      distilled water vehicle orally. The PDN group was treated orally with 5 mg/kg/d
      PDN, which is equivalent to moderate doses used in clinical settings. Learning
      and memory retention were assessed with the Morris water maze. The index of
      degenerated neurons as well as the number and cytoplasmic transformation of
      astrocytes and microglia cells were evaluated in the prefrontal cortex and the
      CA1 hippocampus. RESULTS: PDN-treated rats showed a significant delay of 20% in
      learning and memory retention as compared with controls. In addition, in the PDN
      group, the neuronal degeneration index was two times higher in the prefrontal
      cortex, and approximately 10 times higher in the CA1 hippocampus, than in control
      animals. The number and cytoplasmic transformation of astrocytes were also
      significantly higher in the PDN group than in control animals. In the PDN-treated
      group, isolectin-B4-labeled microglia cells were higher in the prefrontal cortex
      but not in the hippocampus. CONCLUSION: These results suggest that chronic
      exposure to PDN produces learning and memory impairment, reduces neural
      viability, and increases glial reactivity in cerebral regions with these
      cognitive functions.

PMID- 12425434
TI  - The V1 -V2-V3 complex: quasiconformal dipole maps in primate striate and extra
      striate cortex.
AB  - The mapping function w = k log(z + a) is a widely accepted approximation to the
      topographic structure of primate V1 foveal and parafoveal regions. A better
      model, at the cost of an additional parameter, captures the full field
      topographic map in terms of the dipole map function w = k log[(z + a)/(z + b)].
      However, neither model describes topographic shear since they are both explicitly
      complex-analytic or conformal. In this paper, we adopt a simple ansatz for
      topographic shear in V1, V2, and V3 that assumes that cortical topographic shear
      is rotational, i.e. a compression along iso-eccentricity contours. We model the
      constant rotational shear with a quasiconformal mapping, the wedge mapping.
      Composing this wedge mapping with the dipole mapping provides an approximation to
      V1, V2, and V3 topographic structure, effectively unifying all three areas into a
      single V1-V2-V3 complex using five independent parameters. This work represents
      the first full-field, multi-area, quasiconformal model of striate and extra
      striate topographic map structure.

PMID- 12425435
TI  - New classification scheme of cortical sites with the neuronal spiking
      characteristics.
AB  - Multiple cortical areas are mutually compared on the bases of neuronal spiking
      characteristics measured through three dimensionless interspike interval
      statistical coefficients. The spike sequences were recorded from the prefrontal
      cortical area (PF), the pre-supplementary motor area (Pre-SMA), the supplementary
      motor area (SMA) and the rostral cingulate motor area (CMAr) of a behaving monkey
      performing a waiting period task. The distribution of three statistical
      coefficients is found to be largely dependent on the recording site. By measuring
      the Hellinger distances among those distributions, Pre-SMA, SMA and CMAr are
      found to be mutually similar in comparison with PF.

PMID- 12425436
TI  - Stochastic resonance in the hippocampal CA3-CA1 model: a possible memory recall
      mechanism.
AB  - Stochastic resonance (SR) in a hippocampal network model was investigated. The
      hippocampal model consists of two layers, CA3 and CA1. Pyramidal cells in CA3 are
      connected to pyramidal cells in CA1 through Schaffer collateral synapses. The CA3
      network causes spontaneous irregular activity (broadband spectrum peaking at
      around 3 Hz), while the CA1 network does not. The activity of CA3 causes membrane
      potential fluctuations in CA1 pyramidal cells. The CA1 network also receives a
      subthreshold signal (2.5 or 50 Hz) through the perforant path (PP). The
      subthreshold PP signals can fire CA1 pyramidal cells in cooperation with the
      membrane potential fluctuations that work as noise. The firing of the CA1 network
      shows typical features of SR. When the frequency of the PP signal is in the gamma
      range (50 Hz), SR that takes place in the present model shows distinctive
      features. 50 Hz firing of CA1 pyramidal cells is modulated by the membrane
      potential fluctuations, resulting in bursts. Such burst firing in the CA1
      network, which resembles the firing patterns observed in the real hippocampal
      CA1, improves performance of subthreshold signal detection in CA1. Moreover,
      memory embedded at Schaffer collateral synapses can be recalled by means of SR.
      When Schaffer collateral synapses in subregions of CA1 are augmented three-fold
      as a memory pattern. pyramidal cells in the subregions respond to the
      subthreshold PP signal due to SR, while pyramidal cells in the rest of CA1 do not
      fire.

PMID- 12425437
TI  - Straight monotonic embedding of data sets in Euclidean spaces.
AB  - This paper presents a fast incremental algorithm for embedding data sets
      belonging to various topological spaces in Euclidean spaces. This is useful for
      networks whose input consists of non-Euclidean (possibly non-numerical) data, for
      the on-line computation of spatial maps in autonomous agent navigation problems,
      and for building internal representations from empirical similarity data.

PMID- 12425438
TI  - The connections between the frustrated chaos and the intermittency chaos in small
      Hopfield networks.
AB  - In a previous paper we introduced the notion of frustrated chaos occurring in
      Hopfield networks [Neural Networks 11 (1998) 1017]. It is a dynamical regime
      which appears in a network when the global structure is such that local
      connectivity patterns responsible for stable oscillatory behaviors are
      intertwined, leading to mutually competing attractors and unpredictable
      itinerancy among brief appearance of these attractors. Frustration destabilizes
      the network and provokes an erratic 'wavering' among the orbits that characterize
      the same network when it is connected in a non-frustrated way. In this paper,
      through a detailed study of the bifurcation diagram given for some connection
      weights, we will show that this frustrated chaos belongs to the family of
      intermittency type of chaos, first described by Berge et al. [Order within chaos
      (1984)] and Pomeau and Manneville [Commun. Math. Phys. 74 (1980) 189]. Indeed,
      the transition to chaos is a critical one, and all along the bifurcation diagram,
      in any chaotic window, the duration of the intermittent cycles, between two
      chaotic bursts, grows as an invert ratio of the connection weight. Specific to
      this regime are the intermittent cycles easily identifiable as the non-frustrated
      regimes obtained by altering the values of these same connection weights. We will
      more specifically show that anywhere in the bifurcation diagram, a chaotic window
      always lies between two oscillatory regimes, and that the resulting chaos is a
      merging of, among others, the cycles at both ends. The strength (i.e. the
      duration of its oscillatory phase before the chaotic burst) of the first cycle
      decreases while the regime tends to stabilize into the second cycle (with the
      strength of this second cycle increasing) that will finally get the control.
      Since in our study, the bifurcation diagram concerns the same connection weights
      responsible for the learning mechanism of the Hopfield network, we will discuss
      the relations existing between bifurcation, learning and control of chaos. We
      will show that, in some cases, the addition of a slower Hebbian learning
      mechanism onto the Hopfield networks makes the resulting global dynamics to drive
      the network into a stable oscillatory regime, through a succession of
      intermittent and quasiperiodic regimes. Finally, we will present a series of
      possible logical steps to manually construct a frustrated network.

PMID- 12425439
TI  - Category regions as new geometrical concepts in Fuzzy-ART and Fuzzy-ARTMAP.
AB  - In this paper we introduce novel geometric concepts, namely category regions, in
      the original framework of Fuzzy-ART (FA) and Fuzzy-ARTMAP (FAM). The definitions
      of these regions are based on geometric interpretations of the vigilance test and
      the F2 layer competition of committed nodes with uncommitted ones, that we call
      commitment test. It turns out that not only these regions have the same
      geometrical shape (polytope structure), but they also share a lot of common and
      interesting properties that are demonstrated in this paper. One of these
      properties is the shrinking of the volume that each one of these polytope
      structures occupies, as training progresses, which alludes to the stability of
      learning in FA and FAM, a well-known result. Furthermore, properties of learning
      of FA and FAM are also proven utilizing the geometrical structure and properties
      that these regions possess; some of these properties were proven before using
      counterintuitive, algebraic manipulations and are now demonstrated again via
      intuitive geometrical arguments. One of the results that is worth mentioning as
      having practical ramifications is the one which states that for certain areas of
      the vigilance-choice parameter space (rho,a), the training and performance
      (testing) phases of FA and FAM do not depend on the particular choices of the
      vigilance parameter. Finally, it is worth noting that, although the idea of the
      category regions has been developed under the premises of FA and FAM, category
      regions are also meaningful for later developed ART neural network structures,
      such as ARTEMAP, ARTMAP-IC, Boosted ARTMAP, Micro-ARTMAP, Ellipsoid-ART/ARTMAP,
      among others.

PMID- 12425440
TI  - Bayesian model search for mixture models based on optimizing variational bounds.
AB  - When learning a mixture model, we suffer from the local optima and model
      structure determination problems. In this paper, we present a method for
      simultaneously solving these problems based on the variational Bayesian (VB)
      framework. First, in the VB framework, we derive an objective function that can
      simultaneously optimize both model parameter distributions and model structure.
      Next, focusing on mixture models, we present a deterministic algorithm to
      approximately optimize the objective function by using the idea of the split and
      merge operations which we previously proposed within the maximum likelihood
      framework. Then, we apply the method to mixture of expers (MoE) models to
      experimentally show that the proposed method can find the optimal number of
      experts of a MoE while avoiding local maxima.

PMID- 12425441
TI  - Threshold disorder as a source of diverse and complex behavior in random nets.
AB  - We study the diversity of complex spatio-temporal patterns in the behavior of
      random synchronous asymmetric neural networks (RSANNs). Special attention is
      given to the impact of disordered threshold values on limit-cycle diversity and
      limit-cycle complexity in RSANNs which have 'normal' thresholds by default.
      Surprisingly, RSANNs exhibit only a small repertoire of rather complex limit
      cycle patterns when all parameters are fixed. This repertoire of complex patterns
      is also rather stable with respect to small parameter changes. These two
      unexpected results may generalize to the study of other complex systems. In order
      to reach beyond this seemingly disabling 'stable and small' aspect of the limit
      cycle repertoire of RSANNs, we have found that if an RSANN has threshold disorder
      above a critical level, then there is a rapid increase of the size of the
      repertoire of patterns. The repertoire size initially follows a power-law
      function of the magnitude of the threshold disorder. As the disorder increases
      further, the limit-cycle patterns themselves become simpler until at a second
      critical level most of the limit cycles become simple fixed points. Nonetheless,
      for moderate changes in the threshold parameters, RSANNs are found to display
      specific features of behavior desired for rapidly responding processing systems:
      accessibility to a large set of complex patterns.

PMID- 12425442
TI  - Multi-objective cooperative coevolution of artificial neural networks (multi
      objective cooperative networks).
AB  - In this paper we present a cooperative coevolutive model for the evolution of
      neural network topology and weights, called MOBNET. MOBNET evolves subcomponents
      that must be combined in order to form a network, instead of whole networks. The
      problem of assigning credit to the subcomponents is approached as a multi
      objective optimization task. The subcomponents in a cooperative coevolutive model
      must fulfill different criteria to be useful, these criteria usually conflict
      with each other. The problem of evaluating the fitness on an individual based on
      many criteria that must be optimized together can be approached as a multi
      criteria optimization problems, so the methods from multi-objective optimization
      offer the most natural way to solve the problem. In this work we show how using
      several objectives for every subcomponent and evaluating its fitness as a multi
      objective optimization problem, the performance of the model is highly
      competitive. MOBNET is compared with several standard methods of classification
      and with other neural network models in solving four real-world problems, and it
      shows the best overall performance of all classification methods applied. It also
      produces smaller networks when compared to other models. The basic idea
      underlying MOBNET is extensible to a more general model of coevolutionary
      computation, as none of its features are exclusive of neural networks design.
      There are many applications of cooperative coevolution that could benefit from
      the multi-objective optimization approach proposed in this paper.

PMID- 12425443
TI  - Extracting regression rules from neural networks.
AB  - This paper proposes a new framework and method for extracting regression rules
      from neural networks trained with multivariate data containing both nominal and
      numeric variables. Each regression rule is expressed as a pair of a logical
      formula on the conditional part over nominal variables and a polynomial equation
      on the action part over numeric variables. The proposed extraction method first
      generates one such regression rule for each training sample, then utilizes the
      kappa-means algorithm to generate a much smaller set of rules having more general
      conditions, where the number of distinct polynomial equations is determined
      through cross-validation. Finally, this method invokes decision-tree induction to
      form logical formulae of nominal conditions as conditional parts of final
      regression rules. Experiments using four data sets show that our method works
      well in extracting quite accurate and interesting regression rules.

PMID- 12425444
TI  - Neural network based optimal routing algorithm for communication networks.
AB  - This paper presents the capability of the neural networks as a computational tool
      for solving constrained optimization problem, arising in routing algorithms for
      the present day communication networks. The application of neural networks in the
      optimum routing problem, in case of packet switched computer networks, where the
      goal is to minimize the average delays in the communication have been addressed.
      The effectiveness of neural network is shown by the results of simulation of a
      neural design to solve the shortest path problem. Simulation model of neural
      network is shown to be utilized in an optimum routing algorithm known asflow
      deviation algorithm. It is also shown that the model will enable the routing
      algorithm to be implemented in real time and also to be adaptive to changes in
      link costs and network topology.

PMID- 12425445
TI  - A comment on "Global stability analysis in delayed Hopfield neural network
      models".

PMID- 12425446
TI  - A comment on "Global stability analysis in delayed Hopfield neural network
      models".

PMID- 12425447
TI  - Challenges and changing roles in HIV/AIDS social work: implications for training
      and education.
AB  - HIV/AIDS social work was changed fundamentally by the introduction of more
      effective medications to combat the disease, and by the spread of HIV/AIDS beyond
      the gay community to intravenous drug users and their sexual partners, women,
      children, adolescents, and people of color. This paper describes the professional
      challenges HIV/AIDS social workers now face at this stage in the history of the
      disease as a result of improved medications, and the spread of the disease to
      newer groups. We describe the roles HIV/AIDS social workers will play in the next
      wave of the epidemic, and discuss the implications of these changing roles for
      social work education and training.

PMID- 12425448
TI  - Needs and feelings of anxiety of relatives of patients hospitalized in intensive
      care units: implications for social work.
AB  - INTRODUCTION: This study explores the needs and anxiety levels of relatives faced
      with the stress of a family member's critical care hospitalization in relation to
      the relatives' age, gender, educational level and type of kinship with the
      patient and in relationship to the characteristics of the admission and the
      condition of the patient. METHODS: Participants were 200 relatives of 120
      different critical care patients. Family needs were measured by means of the
      Critical Care Family Needs Inventory. Anxiety was measured by means of the State
      version of the State-Trait Anxiety Inventory. RESULTS AND CONCLUSION: Relatives'
      needs and anxiety levels are found to be significantly related to demographic
      variables and type of kinship with the patient. The implications for clinical
      practice are discussed.

PMID- 12425449
TI  - Investigating factor structure of an instrument to measure social work students'
      preparedness for managed care environments.
AB  - This study investigated the factor structure of an instrument to measure social
      work students' perceptions of preparedness to enter managed care environments.
      Exploratory statistical procedures to reduce data through principle component
      analysis identified nine factors with eigenvalues greater than 1.0. These factors
      include: perceived understanding of agency financial agendas, managing personal
      risk and liability, perceived understanding of agency documentation requirements,
      awareness of ethical and value conflicts in documentation, classroom preparation
      for documentation, understanding the fit between client advocacy and managed care
      agendas, worrying about law suits in employment settings, perceived understanding
      of managed care gatekeeping and service authorization, and perceptions of field
      preparation for documentation. Recommendations are made for utilizing this brief
      self-report instrument in training students for managed care settings.

PMID- 12425450
TI  - Mind-body interventions: applications for social work practice.
AB  - In the past decade, we have seen an increase in the popularity of mind-body
      medicine as an alternative or complement to traditional health care
      interventions. This paper explores the history of mind-body medicine and how
      particular mind-body interventions focusing on stress reduction and relaxation
      can be useful complements to social work practice. Four types of mind-body
      interventions are described, research on their effectiveness is reviewed,
      conclusions are drawn, and the applicability to social work practice is
      discussed. Given existing empirical support for the effectiveness of these
      interventions, the authors suggest that efforts at both the systems and
      individual levels, including changes in social work education, can be made to
      enhance their use in traditional health settings, as well in other types of
      settings.

PMID- 12425451
TI  - How we do it: adrenal adenoma.

PMID- 12425452
TI  - Case of the month. Focal Nodular Hyperplasia.

PMID- 12425453
TI  - Multidetector row CT with dual-phase CT angiography in the preoperative
      evaluation of pancreatic cancer.

PMID- 12425454
TI  - Cystic pancreatic neoplasms: CT appearances.

PMID- 12425455
TI  - Camptothecin delivery methods.
AB  - Camptothecin has shown significant antitumor activity to lung, ovarian, breast,
      pancreas, and stomach cancers. Camptothecin, however, like a number of other
      potent anticancer agents such as paclitaxel, is extremely water insoluble.
      Furthermore, pharmacology studies have determined that prolonged schedules of
      administration given continuously are required. Thus, this insolubility has
      restricted its clinical application. For these reasons, a number of water-soluble
      analogs have been synthesized and a number of different formulation approaches
      have been investigated. In this review, we examine each of these approaches and
      discuss their advantages and limitations.

PMID- 12425456
TI  - Comparison of human duodenum and Caco-2 gene expression profiles for 12,000 gene
      sequences tags and correlation with permeability of 26 drugs.
AB  - PURPOSE: To compare gene expression profiles and drug permeability differences in
      Caco-2 cell culture and human duodenum. METHODS: Gene expression profiles in Caco
      2 cells and human duodenum were determined by GeneChip analysis. In vivo drug
      permeability measurements were obtained through single-pass intestinal perfusion
      in human subjects, and correlated with in vitro Caco-2 transport permeability.
      RESULTS: GeneChip analysis determined that 37, 47, and 44 percent of the 12,559
      gene sequences were expressed in 4-day andl6-day Caco-2 cells and human duodenum,
      respectively. Comparing human duodenum with Caco-2 cells, more than 1,000
      sequences were determined to have at least a 5-fold difference in expression.
      There were 26, 38, and 44 percent of the 443 transporters, channels, and
      metabolizing enzymes detected in 4-day, 16-day Caco-2 cells, and human duodenum,
      respectively. More than 70 transporters and metabolizing enzymes exhibited at
      least a 3-fold difference. The overall coefficient of variability of the 10 human
      duodenal samples for all expressed sequences was 31% (range 3% to 294%) while
      that of the expressed transporters and metabolizing enzymes was 33% (range 3% to
      87%). The in vivo / in vitro drug permeability measurements correlated well for
      passively absorbed drugs (R2 = 85%). The permeability correlation for carrier
      mediated drugs showed 3- 35-fold higher in human above the correlation of
      passively absorbed drugs. The 2- 595-fold differences in gene expression levels
      between the Caco-2 cells and human duodenum correlated with the observed 3- 35
      fold difference in permeability correlation between carrier-mediated drugs and
      passively absorbed drugs. CONCLUSIONS; Significant differences in gene expression
      levels in Caco-2 cells and human duodenum were observed. The observed differences
      of gene expression levels were consistent with observed differences in carrier
      mediated drug permeabilities. Gene expression profiling is a valuable new tool
      for investigating in vitro and in vivo permeability correlation.

PMID- 12425457
TI  - PepT1 mRNA expression is induced by starvation and its level correlates with
      absorptive transport of cefadroxil longitudinally in the rat intestine.
AB  - PURPOSE: To establish how closely intestinal transport activity for beta-lactam
      antibiotics is correlated with PepT1 expression, absolute expression level of
      PepT1 mRNA and transport activity were determined longitudinally in the small
      intestine of fed and starved rats. METHODS: For evaluation of absolute expression
      levels of PepTl mRNA, quantitative RT-PCR by LightCycler was used. The transport
      function was determined by quantifying the absorptive transport of cefadroxil
      across intestinal tissue sheets in a Ussing chamber. RESULTS: PepT1 mRNA
      expression was highest at the lower region and lowest at the upper region in the
      fed rats. The value of PepT1 was about 1/5-1/6 of that of GAPDH. The expression
      level in the starved rats was increased in all segments, but more profoundly in
      the upper region. Cefadroxil transport across intestinal tissue was higher in the
      lower region and lower in the upper region in fed rats, and increased in the
      upper region in starved rats. An excellent correlation was observed between
      expression levels and the permeability coefficients (r2 = 0.859, p < 0.05).
      CONCLUSIONS: The intestinal transport of cefadroxil is directly proportional to
      PepT1 expression, suggesting that the PepT1 expression level in the rat small
      intestine is the major determinant of the absorption of peptide-like compounds.

PMID- 12425458
TI  - Polyethylene glycol-diacyllipid micelles demonstrate increased acculumation in
      subcutaneous tumors in mice.
AB  - PURPOSE: The purpose of this work is to study the potential of micelles prepared
      from amphiphilic polyethelene glycol/phosphatidylethanolamine (PEG-PE) conjugates
      as a particulate drug delivery system capable of accumulation in tumors via the
      enhanced permeability and retention (EPR) effect. METHODS: Micelles were prepared
      from PEGs of different molecular lengths conjugated with PE. The micelles were
      characterized by fluorescence-based critical micellization concentration (CMC)
      measure ments, dynamic light scattering, and HPLC. Blood clearance an tumor
      accumulation of 111In-labeled micelles were studied in mic with subcutaneously
      established Lewis lung carcinoma (LLC) and EL4 T lymphoma (EL4) tumors. RESULTS:
      Various versions of PEG-PE conjugates with PEG blocks ranging from 750 to 5000 Da
      formed very stable low CMC micelles at all concentrations down to 10(-5) M. The
      size of the micelles varie between 7 and 35 nm depending on the length of the PEG
      block. Micelles remained intact after prolonged incubation with the blood serum.
      Upon intravenous administration into mice, the micelles demonstrated circulation
      longevity, and they efficiently and selectively accumulated in both subcutaneous
      Lewis lung carcinoma and EL4 T lymphoma tumors. CONCLUSIONS: PEG-PE conjugates
      form very stable, long-circulating micelles. These micelles efficiently
      accumulate in tumors in vivo an may potentially be used as a tumor-specific
      delivery system for poorly soluble anticancer drugs.

PMID- 12425459
TI  - Design and characterization of liposomes containing long-chain N-acylPEs for
      brain delivery: penetration of liposomes incorporating GM1 into the rat brain.
AB  - PURPOSE: To develop a suitable liposomal carrier to encapsulate neu roactive
      compounds that are stable enough to carry them to the brain across the blood
      brain barrier with the appropriate surface characteri tics for an effective
      targeting and for an active membrane transport. METHODS: Liposomes containing
      glycosides and a fusogenic lipid were prepared by extrusion. Photon correlation
      spectroscopy, fluorescent spectroscopy, and differential scanning calorimetry
      were used to characterize liposomal preparations. Tissue distribution was
      determined by using 3H-cholesterylhexadecylether as a marker. RESULTS: The
      incorporation of glycoside determinants and N-palmitoylphosphatidylethanolamine
      gives liposomes with similar in tial size, trapped volume, negative surface
      charge, bilayer fluidity, and melting temperature, except for
      monosialoganglioside-containing liposomes, which showed less negative surface
      charge and the highe size, trapped volume and melting temperature. All
      glycosilated formulations gave liposomes able to retain up to the 95% of
      encapsulated carboxyfluorescein after 90 min at physiologic temperature even in
      the presence of serum. Monosialoganglioside liposomes were recovered in the
      cortex, basal ganglia, and mesencephalon of both brain hemispheres. The liver
      uptake was higher for sulfatide- and glucose-liposomes, whereas the higher blood
      levels were observed for glucose- and mannose-liposomes. CONCLUSIONS: These
      results show the suitability of such liposomal formulations to hold encapsulated
      drugs. Moreover, the brain uptake of monosialoganglioside liposomes makes them
      good candidates as drug delivery systems to the brain.

PMID- 12425460
TI  - Improved inhalation behavior of steroid KSR-592 in vitro with Jethaler by
      polymorphic transformation to needle-like crystals (beta-form).
AB  - PURPOSE: The aim of the present study was to improve the dry powder inhalation
      behavior of steroid KSR-592 with lactose by altering the crystal shape and the
      particle size of the drug for use in a newly designed inhalation device,
      Jethaler. METHOD: The shape of the crystals was changed by polymorphic
      transformation of original crystal (alpha-form) to beta-form by agitating alpha
      form crystals in hexane containing 5% ethanol. The inhalation properties of the
      resultant crystals in vitro were evaluated with a twin impinger and cascade
      impactor. RESULTS: Needle-like crystals (beta-form) with dimensions of 1.8 microm
      in width x 41 microm in length were obtained by the polymorphic transformation,
      the kinetics of which was described by the Avrami equation. The beta-form
      crystals loaded on lactose particles were easily separated and crushed into fine
      particles in the airstream produced in the Jethaler, which increased dramatically
      the respirable fraction (RF) deposited in the twin impinger (43.8%) and the fine
      particle fraction (FPF) of the cascade impactor (FPF = 39.3%) compared with their
      values for the original crystals (RF = 5.8%, FPF = 4.7%). CONCLUSION: The dry
      powder inhalation properties of steroid KSR-592 (platelike crystal, alpha-form)
      were improved dramatically by changing the crystal shape to a needle-like shape
      by the polymorphic transformation to the beta-form.

PMID- 12425461
TI  - Rate-limited steps of human oral absorption and QSAR studies.
AB  - PURPOSE: To classify the dissolution and diffusion rate-limited drugs and
      establish quantitative relationships between absorption and molecular
      descriptors. METHODS: Absorption consists of kinetic transit processes in which
      dissolution, diffusion, or perfusion processes can become the rate-limited step.
      The absorption data of 238 drugs have been classified into either dissolution or
      diffusion rate-limited based on an equilibrium method developed from solubility,
      dose, and percentage of absorption. A nonlinear absorption model derived from
      first-order kinetics has been developed to identify the relationship between
      percentage of drug absorption and molecular descriptors. RESULTS: Regression
      analysis was performed between percentage of absorption and molecular
      descriptors. The descriptors used were ClogP, molecular polar surface area, the
      number of hydrogen-bonding acceptors and donors, and Abraham descriptors. Good
      relationships were found between absorption and Abraham descriptors or ClogP.
      CONCLUSIONS: The absorption models can predict the following three BCS
      (Biopharmaceutics Classification Scheme) classes of compounds: class I, high
      solubility and high permeability; class III, high solubility and low
      permeability; class IV, low solubility and low permeability. The absorption
      models overpredict the absorption of class II, low solubility and high
      permeability compounds because dissolution is the rate-limited step of
      absorption.

PMID- 12425462
TI  - How do fatty acids cause allosteric binding of drugs to human serum albumin?
AB  - PURPOSE: This study was undertaken to investigate how fatty acids cause the
      allosteric binding of drugs to human serum albumin (HSA). The influence of fatty
      acids on the binding of ketoprofen (KP), an NSAID, to HSA was examined by using a
      photoaffinity labeling technique. METHODS: Ultrafiltration was performed to
      quantitate the concentration of free KP. HSA, photolabeled with KP in the
      presence of myristate (MYR), octanoate, and diazepam, was cleaved with cyanogen
      bromide, separated by Tricine sodium dodecyl sulfate polyacrylamide gel
      electrophoresis and subsequently analyzed by autoradiography. RESULTS: The
      addition of MYR at molar ratios from 4 to 5, but not from 1 to 2, causes
      substantial increases in unbound KP for KP:HSA ratios of 0.5 and 1. The addition
      of two or more moles of MYR, octanoate, and diazepam per mole of HSA caused a
      pronounced decrease in the labeling of the 11.6- and 13.5-kDa peptides. However,
      only MYR showed an increase in labeling of the 20 kDa and, especially, the 9.4
      kDa peptides. At MYR:HSA ratios in excess of 3, a decrease in the extent of
      labeling of the 9.4-kDa peptide was observed. CONCLUSION: Long-chain fatty acids
      regulate the binding properties of HSA in a complex manner, in which a
      simultaneous competitive and allosteric mechanism operates and which mainly
      involves domain I.

PMID- 12425463
TI  - Transdermal use of phosphorodiamidate morpholino oligomer AVI-4472 inhibits
      cytochrome P450 3A2 activity in male rats.
AB  - PURPOSE: To determine if dermal absorption of an antisense phosphorodiamidate
      Morpholino oligomers (PMO) can inhibit target gene expression in the liver in
      vivo. METHOD: Antisense PMO targeted to cytochrome P450 (CYP) 3A2 was applied
      topically to adult male rats at doses of 0.03, 0.3, and 3.0 mg. CYP3A enzyme
      activity in the underlying skin and liver was evaluated 24 h following
      application. RESULTS: Systemic PMO bioavailability was determined by detection of
      full-length PMO in liver and fluorescence micrography in underlying skin. CYP3A
      enzyme activity were measured by hydroxylation of 7-benzyloxy-4-(trifluoromethyl)
      coumarin and data were expressed as nanomoles of product/ 100 microg S9
      protein/h. A topical dose of 0.03 mg inhibited enzyme levels from 576 +/- 17
      (vehicle) and 564 +/- 20 (control PMO) to 432 +/- 20 in the antisense-treated
      liver (p < 0.05). Increasing the dose to 0.3 mg further inhibited enzyme level to
      278 +/- 13 (p < 0.005). The inhibition did not increase further when the dose was
      increased to 3 mg. In the skin, starting enzyme levels were approximately one
      third of the liver (171 +/- 9) and maximum inhibition was reached at a lower
      dose. Topical delivery of 0.03 mg led reduced skin enzyme levels in half to 89 +/
      32 (p < 0.05). Increasing the dose to 0.3 mg and 3.0 mg did not produce any
      further inhibition, at 73 8 and 72 +/- 17 respectively. CONCLUSION: Topical
      application of antisense PMO in rats is a feasible delivery strategy for gene
      targets in liver and underlying skin.

PMID- 12425464
TI  - In vitro transfection of plasmid DNA by amine derivatives of gelatin accompanied
      with ultrasound irradiation.
AB  - PURPOSE: The purpose of this study is to examine the ultrasound (US)-enhanced
      gene expression by the complexes of a plasmid DNA with gelatin derivatives of
      aminization. METHODS: Gelatin derivatives with different introduced extents of
      ethylenediamine (Ed), spermidine (Sd), and spermine (Sm) were prepared with a
      water-soluble carbodiimide. The molecular size and zeta potential of the gelatin
      derivatives before and after complexation with the plasmid DNA were examined.
      After incubation with the complexes with or without US exposure, the DNA
      expression of rat gastric mucosal cells was measured to evaluate the effect of
      the type of gelatin derivatives on their gene expression. The cell uptake of the
      complexes, the cell viability, and the buffering effect of gelatin derivatives
      were examined. RESULTS: The apparent molecular size and zeta potential of gelatin
      derivatives became larger as their aminization extent increased although the Sm
      gelatin derivative of higher aminization showed a larger value than other
      corresponding derivatives. Irrespective of the type of gelatin derivatives, the
      apparent molecular size of plasmid DNA was reduced by increasing the gelatin-DNA
      mixing ratio to attain a saturated value of about 150 nm. The condensed gelatin
      DNA complexes showed the zeta potential of 10-15 mV. The cells incubated with the
      complex exhibited significantly stronger luciferase activities than free plasmid
      DNA, and the activity was further enhanced by US irradiation. The enhancement was
      significant for the Sm derivative compared with the corresponding Ed and Sd
      derivatives. The amount of plasmid DNA internalized into the cells was
      significantly increased by the complexation with every gelatin derivative,
      whereas US irradiation did not significantly increase the DNA internalization. US
      irradiation had no effect on the viability of cells incubated with every gelatin
      derivative-plasmid DNA complex, although the viability was decreased by the
      complex incubation. The buffering capacity of Sm derivative was higher than that
      of Ed and Sd derivatives and comparable with that of polyethylene amine.
      CONCLUSION: Among amine derivatives of gelatin, the Sm derivative enabled the
      plasmid DNA to induce the US-enhanced gene expression of cells in vitro most
      effectively because of the superior buffering effect.

PMID- 12425465
TI  - Analysis of poly(D,L-lactic-co-glycolic acid) nanosphere uptake by human
      dendritic cells and macrophages in vitro.
AB  - PURPOSE: The purpose of this study was to demonstrate and characterize
      phagocytosis of poly(D,L-lactic-co-glycolic acid) (PLGA) nanospheres by human
      dendritic cells (DCs). METHODS: Parallel cultures of DCs and macrophages (Mphi)
      were established from peripheral blood leukocytes using media supplemented with
      granulocyte-macrophage colony stimulator factor and interleukin-4 (for DC) or
      granulocyte-macrophage colony stimulator factor alone (for Mphi). PLGA
      nanospheres containing tetramethylrhodamine-labeled dextran with or without an
      adjuvant, monophosphoryl lipid A, were prepared using a water/oil/water solvent
      evaporation technique. Cells were incubated with the nanospheres for 24 h.
      Confocal laser scanning microscopy was used to determine the intracellular
      location of the nanospheres and flow cytometry to measure the fraction of
      phagocytic cells in the culture and the amount of uptake per cell. After
      phagocytosis, cells were stained for MHC class II molecules, CD14, CD80, and CD86
      to identify the phagocytic population. RESULTS: DCs phagocytosed PLGA nanospheres
      as efficiently as Mphi. Cell-surface marker expression conclusively established
      that the phagocytic cells were DC. CONCLUSIONS: DCs can take up PLGA nanospheres.
      Because DCs are the key professional antigen-presenting cells capable of
      stimulating naive T cells, our data suggest that PLGA nanospheres can be used as
      an efficient delivery system for vaccines designed to activate T cell-mediated
      immune responses.

PMID- 12425466
TI  - Uptake of FITC-chitosan nanoparticles by A549 cells.
AB  - PURPOSE: The objective of this study was to evaluate the extent and mechanism of
      uptake of fluorescent chitosan nanoparticles by the A549 cells, a human cell line
      derived from the respiratory epithelium. METHODS: Covalent conjugation with
      fluorescein-5-isothiocyanate yielded stably labeled chitosan molecules, which
      were successfully formulated into nanoparticles by ionotropic gelation. Uptake of
      fluorescein-5-isothiocyanate-chitosan nanoparticles and chitosan molecules by
      confluent A549 cells was quantified by fluorometry. RESULTS: Cellular uptake of
      chitosan nanoparticles was concentration and temperature dependent, having Km and
      Vmax of 3.84 microM and 58.14 microg/mg protein/h, respectively. Uptake of
      chitosan nanoparticles was up to 1.8-fold higher than that of chitosan molecules
      alone and was not inhibited by excess unlabeled chitosan molecules.
      Hyperosmolarity, chlorpromazine and K+ depletion inhibited by 65, 34, and 54%,
      respectively, the uptake of chitosan nanoparticles at 37 degrees C, but filipin
      had no influence on the uptake. Confocal imaging confirmed the internalization of
      the chitosan nanoparticles by the A549 cells at 37 degrees C. CONCLUSIONS:
      Formulation of chitosan into nanoparticles significantly improved its uptake by
      the A549 cells. Internalization of chitosan nanoparticles by the cells seems to
      occur predominantly by adsorptive endocytosis initiated by nonspecific
      interactions between nanoparticles and cell membranes, and was in part mediated
      by clathrin-mediated process.

PMID- 12425467
TI  - Characterization of the transport of uracil across Caco-2 and LLC-PK1 cell
      monolayers.
AB  - PURPOSE: The purpose of this study was to characterize the transport of uracil, a
      pyrimidine nucleobase, in Caco-2 and LLC-PK, cells. METHODS: Caco-2 and LLC-PK1
      cells were grown to confluency on a permeable polycarbonate membrane insert to
      permit transport and uptake experiments after the loading of uracil on either the
      apical or basolateral side. RESULTS: The vectorial transport of uracil in both
      directions was saturable with comparable Km and Vmax in Caco-2 cell monolayers,
      probably because of a Na+-independent transport system located on the basolateral
      membrane. In LLC-PK1 cell monolayers, two distinct transport systems, namely a
      Na+-dependent and a Na+-independent, were functional in the apical to basolateral
      (A-B) transport of uracil. The first system was saturable with a Km value of 3.67
      +/- 0.40 microM, a Vmax of 11.31 +/- 0.91 pmol/cm2/min, and a Na+:uracil coupling
      stoichiometry of 1.28 +/- 0.20. The second system was Na+ independent and
      satuable with a low affinity (Km, 50.37 +/- 9.61 microM) and Vmax (16.01 +/- 4.48
      pmol/cm2/min). The two transport systems appeared to be located on the apical
      membrane. CONCLUSION: The mechanism of uracil transport differs depending on cell
      lines; a Na+-independent system on the basolateral membrane in Caco-2 cells and
      both Na+-dependent and Na+-independent systems on the apical membrane in LLC-PK1
      cells seem to be responsible for the difference.

PMID- 12425468
TI  - Folate receptor-mediated liposomal delivery of a lipophilic boron agent to tumor
      cells in vitro for neutron capture therapy.
AB  - PURPOSE: This study was aimed at the in vitro evaluations of folate receptor (FR)
      targeted liposomes as carriers for a lipophilic boron agent, K[nido-7-CH3(CH2)15
      7,8-C2B9H11, in FR-overexpressing tumor cells for neutron capture therapy.
      METHODS: Large unilamellar vesicles (-200 nm in diameter) were prepared with the
      composition of egg PC/chol/K[nido-7-CH3(CH2)15-7,8-C2B9H11] (2:2:1, mol/mol),
      with an additional 0.5 mol % of folate-PEG-DSPE or PEG-DSPE added for the FR
      targeted or nontargeted liposomal formulations, respectively. RESULTS: Boron
      containing, FR-targeted liposomes readily bound to KB cells, an FR-overexpressing
      cell line, and were internalized via FR-mediated endocytosis. The boron uptake in
      cells treated with these liposomes was approximately 10 times greater compared
      with those treated with control liposomes. In contrast, FR-targeted and
      nontargeted liposomes showed no difference in boron delivery efficiency in F98
      cells, which do not express the FR. The subcellular distribution of the boron
      compound in KB cells treated with the FR-targeted liposomes was investigated by
      cellular fractionation experiments, which showed that most of the boron compound
      was found in either the cytosol/endosomal or cell membrane fractions, indicating
      efficient internalization of the liposomal boron. CONCLUSION: FR-targeted
      liposomes incorporating the lipophilic boron agent, K[nido-7-CH3(CH2)15-7,8
      C2B9H11], into its bilayer were capable of specific receptor binding and receptor
      mediated endocytosis in cultured KB cells. Such liposomes warrant further
      investigations for use in neutron capture therapy.

PMID- 12425469
TI  - Effect of organic isothiocyanates on the P-glycoprotein- and MRP1-mediated
      transport of daunomycin and vinblastine.
AB  - PURPOSE: Organic isothiocyanates (ITCs), or mustard oils, are non-nutrient
      components present in the diet, especially in cruciferous vegetables. The purpose
      of this investigation was to examine the effect of ITCs on P-glycoprotein (P-gp)-
      and multidrug resistance-associated Protein (MRP1)-mediated transport in
      multidrug resistant (MDR) human cancer cell lines. METHODS: The direct effect of
      ITCs on the 2-h cellular accumulation of daunomycin (DNM) and vinblastine (VBL),
      substrates for both P-gp and MRP1, were measured in sensitive and resistant MCF-7
      cells and in PANC-1 cells. Resistant MCF-7 cells (MCF-7/ADR) overexpress P-gp
      whereas PANC-1 cells overexpress MRP1. The following compounds were evaluated:
      allyl-, benzyl-(BITC), hexyl-, phenethyl-(PEITC), phenyl-, 1-naphthyl-(NITC),
      phenylhexyl-, phenylpropyl-, and phenylbutyl-ITC, sulforaphane, erucin, and
      erysolin. RESULTS: NITC significantly increased the accumulation of DNM and VBL
      in both resistant cell lines, but had no effect on DNM accumulation in sensitive
      MCF-7 cells. VBL accumulation in resistant MCF-7 cells was increased 40-fold by
      NITC whereas that in PANC-1 cells was increased 5.5-fold. Significant effects on
      the accumulation of DNM and VBL in resistant MCF-7 cells were also observed with
      benzyl-isothiocyanate whereas PEITC, erysolin, phenylhexyl-ITC, and phenylbutyl
      ITC increased the accumulation of DNM and/or VBL in PANC-1 cells. Overall, the
      inhibitory activities of these compounds in MCF-7 cells and PANC-1 cells were
      significantly correlated (r2 = 0.77 and 0.86 for DNM and VBL, respectively).
      Significant effects on accumulation were generally observed with the ITCs at 50
      microM concentrations, but not at 10 microM concentrations. CONCLUSIONS: One
      strategy to enhance the effectiveness of cancer chemotherapy is to reverse the
      MDR phenomena. Our results indicate that certain dietary ITCs inhibit the P-gp-
      and the MRP1-mediated efflux of DNM and VBL in MDR cancer cells and suggest the
      potential for diet-drug interactions.

PMID- 12425470
TI  - Novel gastroretentive dosage forms: evaluation of gastroretentivity and its
      effect on riboflavin absorption in dogs.
AB  - PURPOSE: [corrected] The purpose of this study was to design novel
      gastroretentive dosage forms (GRDFs) based on unfolding multilayer polymeric
      films, to investigate the mechanism of their gastroretentivity in dogs, and to
      assess the effect of compounding a narrow absorption window drug in a GRDF on the
      drug's absorption properties. METHODS: Dosage forms (DFs) with different
      dimensions and mechanical properties were administered to beagle dogs with acidic
      buffer (pH = 1.5), whose gastric retention time (GRT) was then determined by X
      ray pictures. Concurrent administration of radiopaque markers was used to assess
      the effect of the GRDF and/or acidic buffer on GRT. The absorption of riboflavin
      from a prototype GRDF was compared with a nongastroretentive controlled-release
      DF and to an oral solution of the drug. RESULTS: Large DFs (> or = 2.5 x 2.5 cm)
      containing rigid frame had prolonged GRT (>4 h). Administration of 400 mL of
      acidic buffer (or water) prolonged GRT whereas the GRDF did not cause additional
      prolongation. The extended absorption phase (>48 h) of riboflavin administered in
      a GRDF led to 4-fold increased bioavailability. CONCLUSION: The combination of
      large dimensions with rigidity produce gastroretentivity that can be used to
      improve absorption properties of a model of narrow absorption window drugs in the
      gastrointestinal tract.

PMID- 12425471
TI  - Particle interactions involved in aerosol dispersion of ternary interactive
      mixtures.
AB  - PURPOSE: To investigate the mechanism of action of ternary components within dry
      powder aerosols. METHODS: Ternary interactive mixtures were prepared containing
      salbutamol sulphate (SS), coarse lactose carriers and either micronized lactose
      (ML) or micronized glucose (MG). In vitro drug and excipient aerosol deposition
      was performed using a twin-stage impinger (TSI) at 60 L/min with a Rotahaler
      device. Adhesional properties of the lactose carrier were examined using an
      atomic force microscope (AFM) colloidal probe technique. RESULT: The fine
      particle fraction (FPF) from ternary mixtures were dependent upon carrier type (p
      < 0.001), ternary concentration (p < 0.001) and ternary component type (p <
      0.05). Ternary mixtures produced higher FPF than binary mixtures, except those
      containing Superfine (SF), which was attributed to the high proportion of
      intrinsic fine carrier particles. The higher FPF obtained from ternary mixtures
      was independent of the mixing order (p = 0.08). Increased adhesion force was
      observed on the carrier surface following the addition of ternary components (p <
      0.001). CONCLUSION: The results confirm that ternary components increase aerosol
      deposition of powder mixtures. Some results were not entirely consistent with the
      saturation of active site theory and a hypothesis involving competitive and
      multilayer adhesion was proposed and requires further testing.

PMID- 12425472
TI  - Peroral absorption of octreotide in pigs formulated in delivery systems on the
      basis of superporous hydrogel polymers.
AB  - PURPOSE: The aim of this study was to investigate the enhancement of peroral
      octreotide absorption using delivery systems based on superporous hydrogel (SPH)
      and SPH composite (SPHC) polymers. METHODS: Six female pigs (BW of 23.5 kg) were
      used in this study. SPH-based delivery systems were made of two components: 1) a
      conveyor system made of SPH and SPHC; 2) a core that contained octreotide. The
      core was inserted into the conveyor system (core inside, c.i.) or attached to the
      surface of the conveyor system (core outside, c.o.). Four different peroral
      formulations were investigated: c.i., c.o., core outside including trimethyl
      chitosan chloride (c.o.t.), and octreotide only in the absence of any polymer
      (o.o.). All formulations were placed in enteric-coated gelatin capsules (size
      000) and administered perorally. Intravenous administration was used to determine
      bioavailability (F) values. Blood samples taken from the cannulated jugular vein
      were analyzed by radioimmunoassay. RESULTS: Peroral administration of 15 mg o.o.
      resulted in low F values of 1.0 +/- 0.6% (mean +/- SEM) whereas c.i. and c.o.
      administrations resulted in remarkably higher F values of 12.7 +/- 3.6% and 8.7
      +/- 2.4%, respectively. By the addition of trimethyl chitosan chloride as an
      extra absorption enhancer to c.o.t., the highest bioavailability (16.1 +/- 3.3%)
      was achieved. CONCLUSIONS: These novel delivery systems based on SPH and SPHC
      polymers are able to increase the peroral bioavailability of octreotide by
      mechanical fixation and increasing the retention of the dosage form at the
      absorption site.

PMID- 12425474
TI  - A dispersion model for cellular signal transduction cascades.
AB  - PURPOSE: The purpose of this study was to evaluate the ability of the dispersion
      model to describe pharmacokinetic-pharmacodynamic data containing contributions
      from signal transduction cascades. METHODS: The partial differential equations
      and appropriate boundary conditions describing the dispersion model for signal
      transduction were obtained. Explicit analytical solutions to the dispersion
      equation were not available, and a numerical approach was necessary. Solutions
      were obtained by numerical inversion of the output Laplace transform. Generalized
      least square fitting was used to obtain parameter estimates for a variety of
      experimental data sets. RESULTS: The parameters of the dispersion model estimate
      the relative roles of diffusion, convection, and chemical reaction in signal
      transduction. The model is capable of describing messenger RNA and protein
      expression kinetics induced by drug action. CONCLUSIONS: The dispersion model may
      find potential applications in pharmacokinetic-pharmacodynamic models involving
      delayed drug effects mediated by transcriptional changes.

PMID- 12425473
TI  - Receptor-mediated pharmacokinetic/pharmacodynamic model of interferon-beta 1a in
      humans.
AB  - PURPOSE: An integrated receptor-based pharmacokinetic/pharmacodynamic (PK/PD)
      model of interferon-beta la (IFN-beta la) previously developed for monkeys was
      used to capture the time-course of drug and induced neopterin concentrations
      after intravenous (IV) and subcutaneous (SC) dosing in humans. METHODS: Data were
      extracted from the literature by digitalization. Single-dose (3 IV doses and I SC
      dose) PK/PD profiles were simultaneously fitted using the basic model and the
      ADAPT II computer program. Additional submodels incorporating neutralizing
      antibody formation and negative feedback inhibition were applied to account for
      drug accumulation and lower than expected neopterin concentrations encountered
      after multiple-dosing (1 SC dose every 48 hs). RESULTS: The basic model jointly
      captured the nonlinear PK behavior of the drug and induced neopterin
      concentrations after all single doses. Slow and incomplete absorption (F = 0.33)
      of the SC dose resulted in prolonged drug concentrations reflective of flip-flop
      kinetics. Despite lower drug concentrations, SC dosing produced a similar
      neopterin profile as compared with the IV doses; however, with a longer time to
      peak effect and slightly higher neopterin concentrations at later time points.
      The PD component of the model represents a modified precursor-dependent indirect
      response model driven by the amount of internalized drug-receptor complex. The
      latter stimulated a 6-fold increase in the production of the neopterin precursor
      (Smax = 5.89). Drug accumulation and lower than expected neopterin concentrations
      after multiple dosing were also captured after the inclusion of the submodels.
      CONCLUSIONS: The present integrated PK/PD model for IFN-beta 1a is mechanistic in
      nature with receptor-mediated disposition and dynamics and was successfully
      applied to human clinical data.

PMID- 12425475
TI  - Crystal structure of neotame anhydrate polymorph G.
AB  - PURPOSE: To determine the crystal structure of the neotame anhydrate polymorph G
      and to evaluate X-ray powder diffractometry (XRPD) with molecular modeling as an
      alternative method for determining the crystal structure of this conformationally
      flexible dipeptide. METHODS: The crystal structure of polymorph G was determined
      by single crystal X-ray crystallography (SCXRD) and also from the X-ray powder
      diffraction (XRPD) pattern using molecular modeling (Cerius2, Powder Solve
      module). RESULTS: From SCXRD, polymorph G crystals are orthorhombic with space
      group of P2(1)2(1)2(1) with Z = 4, unit cell constants: a = 5.5999(4), b =
      11.8921(8), c = 30.917(2) A, and one neotame molecule per asymmetric unit. The
      XRPD pattern of polymorph G, analyzed by Cerius2 software, led to the same
      P2(1)2(1)2(1) space group and almost identical unit cell dimensions. However,
      with 13 rigid bodies defined, Cerius2 gives a conformation of the neotame
      molecule, which is different from that determined by SCXRD. CONCLUSIONS: For
      neotame anhydrate polymorph G, the unit cell dimensions calculated from XRPD were
      almost identical to those determined by SCXRD. However, the crystal structure
      determined by XRPD closely resembled that determined by SCXRD, only when the
      correct conformation of the neotame molecule had been chosen before detailed
      analysis of the XRPD pattern.

PMID- 12425476
TI  - Measurement and mapping of pH in hydrating pharmaceutical pellets using confocal
      laser scanning microscopy.
AB  - PURPOSE: pH modifiers are often used to promote drug solubility/ stability in
      dosage forms, but predicting the extent and duration of internal pH modification
      is difficult. Here, a noninvasive technique is developed for the spatial and
      temporal mapping of pH in a hydrated pharmaceutical pellet, within a pH range
      appropriate for microenvironmental pH control by weak acids. METHODS: Confocal
      dual excitation imaging (Ex 488/Ex 568) of pellets containing a single, soluble,
      pH-sensitive fluorophore with cross-validation from a pH microelectrode. The
      technique was used to investigate the changing pH distribution in hydrating
      pellets containing two weak acids of differing solubility. RESULTS: The algorithm
      developed provided pH measurements over the range pH 3.5-5.5 with a typical
      accuracy of 0.1 pH units and with excellent correlation with pH microelectrode
      measurements. The method showed how pellets containing 25%w/w tartaric acid
      exhibited a rapid but transient fall in internal pH, in contrast to a slower more
      prolonged reduction with fumaric acid. CONCLUSIONS: Spatial and temporal
      monitoring of pH in pellets was achieved with good accuracy within a pH range
      appropriate to pH modification by weak acids. However, the method developed is
      also generic and with suitable fluorophores will be applicable to other pH ranges
      and other dosage forms.

PMID- 12425477
TI  - Supercritical fluids crystallization of budesonide and flunisolide.
AB  - PURPOSE: Budesonide and flunisolide anhydrate were crystallized using the
      solution enhanced dispersion by supercritical fluids (SEDS) technique. The aim
      was to investigate the possibility of preparing different pure polymorphs.
      METHODS: 0.25% w/v solutions of each drug were prepared from acetone and
      methanol. Operating conditions were 40-80 degrees C and 80-200 bars. The flow
      rate of drug solution was 0.3 mL/min and that of CO2 was 9-25 mL/min. Sample
      characterizations included differential scanning calorimetry, X-ray powder
      diffraction, variable temperature X-ray diffraction, scanning electron
      microscopy, and solubility studies. RESULTS: The particle morphology of
      budesonide was dependent on the nature of the solvent. SEDS processing of
      flunisolide with acetone at 100 bars resulted in the formation of polymorphic
      mixtures at 80 degrees C and a new polymorph III at 60 C and 40 degrees C. With
      methanol at 100 bars another new polymorph IV was formed with different particle
      morphology at 80 degrees C and a polymorphic mixture at 60 degrees C. CONCLUSION:
      Using the SEDS, microparticles of crystalline budesonide were prepared and new
      polymorphs of flunisolide were produced. Particle characteristics were controlled
      by the temperature, pressure and relative flow rates of drug solution and CO2.

PMID- 12425478
TI  - Dissolution and partitioning behavior of hydrophobic ion-paired compounds.
AB  - PURPOSE: This study was conducted to determine the effects of counterion
      hydrophobicity on organic/aqueous partition coefficients for hydrophobic ion
      paired (HIP) complexes. Furthermore, the coupled dissolution and reverse ion
      exchange kinetics for dissolution of HIP complexes into aqueous electrolyte
      solutions were measured and mathematically modeled. METHODS: HIP complexes of
      model drugs tacrine and l-phenylephrine were formed using linear sodium
      alkylsulfates and bis (2-ethylhexyl sodium sulfosuccinate). Equilibrium partition
      coefficients between chloroform and aqueous solutions for the complexes and the
      kinetics of dissolution of the complexes in buffered aqueous solutions were
      measured. RESULTS: The chloroform/aqueous partition coefficients for l
      phenylephrine/bis (2-ethylhexyl sodium sulfosuccinate) complexes decrease with
      increasing molar surface tension increment of salts added to the aqueous
      solution. The logarithm of the partition coefficient for a homologous series of
      alkyl sulfate complexes decreases as the hydrophilic-lipophilic balance number
      increases. Dissolution of HIP complexes in deionized water shows first order
      kinetics, whereas dissolution in aqueous electrolyte solutions shows biphasic
      kinetics. A kinetic model explains these dissolution rates. CONCLUSIONS:
      Solubility and dissolution rates for HIP complexes depend on the hydrophobic
      lipophilic balance number of the organic counter ion as well as on the
      electrolyte composition of aqueous solutions. Reverse ion-exchange kinetics are
      sufficiently slow to allow HIP complexes to be considered simple prodrugs.

PMID- 12425479
TI  - Monitoring the penetration enhancer dimethyl sulfoxide in human stratum corneum
      in vivo by confocal Raman spectroscopy.

PMID- 12425480
TI  - Significant genetic linkage of MDR1 polymorphisms at positions 3435 and 2677:
      functional relevance to pharmacokinetics of digoxin.

PMID- 12425481
TI  - Pericardial effusion in the nephrotic syndrome.
AB  - Hydropericardium is a known cause of pericardial effusion related to severely
      expanded extracellular fluid volume. Nephrotic patients have expanded
      extracellular fluid volume but obviously may have other causes for pericardial
      effusion. We tested the hypothesis that pericardial effusion is related to
      inflammation and not to hydropericardium in patients with nephrotic syndrome.
      Twenty nephrotic patients with systemic lupus erythematosus (SLE) were compared
      to 20 patients with nephrotic syndrome of other causes. No patient in either
      group had symptoms or signs of pericardial disease. Pleural effusion and ascites
      were equally common in SLE-nephrotic patients compared to non-SLE-nephrotic
      patients. However, 8 SLE patients had pericardial effusion, while none of the non
      SLE-nephrotic patients had pericardial effusion. We suggest that hydropericardium
      is rare in nephrotic patients and that an inflammatory or other secondary cause
      should be considered when pericardial effusion complicates nephrotic syndrome.

PMID- 12425482
TI  - Race and glomerulonephritis in patients with and without hepatosplenic
      Schistosomiasis mansoni.
AB  - BACKGROUND/AIMS: United States investigators have shown evidence of higher
      susceptibility to focal segmental glomerulosclerosis (FSGS) in blacks than in
      whites. This association between race and FSGS has not been assessed outside the
      US. The present study assesses the association between race and type of
      glomerulonephritis in a sample of Brazilian patients, taking into account the
      presence of the hepatosplenic form of Schistosomiasis mansoni (HSM). METHODS:
      Eighty patients with focal segmental glomerulosclerosis (FSGS) were compared to
      50 with membranoproliferative glomerulonephritis (MPGN). The association between
      race (i.e. black versus white) and type of glomerulonephritis was adjusted for
      age, gender and HSM by logistic regression. RESULTS: Blacks were more likely than
      whites to have FSGS (as compared to MPGN), both among patients with HSM (odds
      ratio (OR) = 2.67; 95% confidence interval (CI) = 0.81 - 8.81) and without HSM
      (OR = 2.19; 95% CI = 0.79 - 6.05). After adjustment for age, gender and HSM, the
      odds of FSGS remained significantly greater for blacks (OR = 2.49; 95% CI = 1.05 
      5.95). CONCLUSION: The increased likelihood of FSGS in Brazilian blacks is
      consistent with findings from US patients. The association between race and type
      of glomerulonephritis was similar between patients with and without HSM. Future
      investigations should focus on the mediators factors that might explain these
      findings.

PMID- 12425484
TI  - Correlative studies of urine fluorescence and free radical indicators.
AB  - AIMS: Inflammation results in the production of free radicals which damage
      proteins, lipids, and nucleic acids. The products of these reactions are cleared,
      in part, by the kidney and appear in the urine. In this study, urine fluorescence
      was measured in individuals with various nephropathies to determine the value of
      these assays for detecting the excretion of end products of radical-mediated
      chemical reactions. METHODS: Urine fluorescence was quantified at wavelengths
      which correspond to the presence of advanced glycosylation endproducts (AGE) and
      dityrosine (di-TYR). The samples were also tested for isoprostanes,
      nitrite/nitrate, hydrogen peroxide, and thiobarbituric acid reactive substances
      (TBARS). RESULTS: Fluorescence values, expressed per ml urine or per mg
      creatinine (crt), were not normally distributed and covered a wide range. There
      were significant differences in fluorescence among groups of patients classified
      by diagnosis, but the differences did not allow sharp distinction of diagnostic
      categories. Fluorescence assays correlated significantly with TBARS but not with
      isoprostanes, nitrite/nitrate, or hydrogen peroxide. Fluorescence tended to
      increase with age. Gender and race did not affect the results. CONCLUSIONS:
      Because of the many factors which can affect free radical production and tissue
      injury, the value of urine fluorescence assays to screen for radical-mediated
      toxicity appears to be limited. Serial studies of patients will be needed to
      determine whether urine fluorescence will be useful to monitor responses to
      treatment or be predictive of progression vs. remission of renal disease.

PMID- 12425483
TI  - Endothelin-1 in the kidney and urine of patients with glomerular disease and
      proteinuria.
AB  - BACKGROUND: Endothelin-1 (ET-1) is a strong vasoconstrictive peptide that is
      involved in the pathogenesis of arterial hypertension. There is increasing
      evidence, based on studies in experimental animals, that endothelin-1 is produced
      by tubular epithelial cells in response to activation by filtered protein and is
      involved in the development of renal scarring. The aim of this study is to
      examine the distribution of ET-1 in the renal tissue of patients with heavy
      proteinuria and to estimate the changes in its urinary excretion after
      immunosuppressive therapy. PATIENTS AND METHODS: Twenty-four patients with severe
      proteinuria (7.5 +/- 6.5 g/24 h) due to different types of glomerular disease and
      normal renal function (creatinine clearance 91 +/- 14 ml/ min) were investigated.
      All patients underwent a renal biopsy and commenced on immunosuppressive therapy
      with corticosteroids and cyclosporin A. The localization of ET-1 in the renal
      tissue was examined by immunohistochemistry and compared to control renal tissue
      from 9 patients who underwent nephrectomies because of hypernephroma. In patients
      with proteinuria, endothelin-1 excretion in the urine at diagnosis was determined
      by radioimmunoassay and compared to that of 14 healthy subjects. A second
      measurement of urinary ET-1 excretion was performed after remission of
      proteinuria or 6 months after the initiation of treatment in patients with
      persistent nephrotic syndrome. RESULTS: ET-1 in renal tissue of patients and
      controls was localized within the cytoplasm of endothelial cells. In nephrotic
      patients, it was also localized within the cytoplasm of tubular epithelial cells.
      Urinary ET-1 levels were higher in nephrotic patients compared to healthy
      subjects (746 +/- 180 ng/24 h vs 410 +/- 112 ng/ml, p < 0.001). In 17 of 24
      patients who showed remission of proteinuria with immunosuppressive therapy, the
      urinary ET-1 levels decreased (from 803 +/- 168 ng/24 h to 511 +/- 80 ng/24 h, p
      < 0.001) whereas in 7 patients with persistent proteinuria, urinary ET-1
      excretion remained elevated. CONCLUSIONS: The increased urinary excretion of ET-1
      in patients with severe proteinuria followed by a significant decrease after
      remission ofproteinuria with immunosuppressive treatment, along with its
      expression within tubular epithelial cells, suggests a possible relationship
      between proteinuria and renal ET-1 production.

PMID- 12425485
TI  - Total serum bile acids in renal transplanted patients receiving cyclosporine A.
AB  - BACKGROUND: A direct relationship between serum bile acids (SBA) and hepatic and
      hepatobiliary dysfunction has been demonstrated. However, there is little
      evidence that SBA are related to renal insufficiency. In a previous study, we
      showed that hemodialysis patients with advanced chronic renal failure (ACRF) have
      an increase of SBA in predialysis and a decrease in postdialysis. Consequently,
      it was assumed that the restoration of renal function in transplanted patients
      might decrease SBA levels. AIM OF THIS STUDY: Transplanted patients receiving
      cyclosporine A (CyA) were studied by monitoring CyA and SBA levels to determine
      if a probable relationship exists between renal function, CyA treatment and SBA
      levels. SUBJECTS. MATERIALS AND METHODS: SBA levels were determined in 15
      recently transplanted patients receiving CyA for 18 months and longer. In
      addition, 22 renal patients transplanted not less than 6 years ago were also
      included in the study and were characterized as the stable group. Five patients
      from this group received mycophenolate or azathioprine instead of CyA as
      immunosuppressant. In addition to SBA and CyA, creatinine, cholesterol, y-GT,
      viral markers and triglycerides were also determined in all patients. RESULTS: A
      significant and constant increase in SBA levels was observed in the recently
      transplanted group. However, after 18 months, SBA levels gradually decreased to
      those of patients considered stable under CyA treatment. In both recently
      transplanted and stable patients who received CyA, SBA values remained higher
      than normal, but stable patients under mycophenolate or azathioprine treatment
      showed no such increase. CONCLUSIONS: In recently transplanted patients, in
      patients studied for 18 months post transplant and in stable patients receiving
      CyA, the increase of SBA levels might be related to CyA treatment. This effect
      might be attributed to its cholestatic effect and also to a modification in
      uptake, metabolism, synthesis and excretion of SBA in the hepatocyte. These
      conclusions are supported by the results obtained in stable transplanted patients
      without CyA treatment showing normal SBA levels.

PMID- 12425486
TI  - Eleven years of experience with dialysis associated tuberculosis.
AB  - BACKGROUND: The aim of this retrospective study was to evaluate the incidence of
      tuberculosis (TB) in dialysis patients and to determine its clinical features and
      results of short-course (6 months) chemotherapy, mortality and risk factors of
      mortality. METHODS: The study included 48 TB patients among 330 patients on
      dialysis of whom 37 were on hemodialysis and 11 were on peritoneal dialysis at
      Security Forces Hospital in the period from October 1989 to October 2000. The
      diagnosis of TB was established by a combination of clinical, radiological,
      biochemical, microbiological and histological examinations. Treatment with anti
      TB drugs, the results of therapy and the outcome of patients were noted. RESULTS:
      There were 32 males and 16 females with age ranges of 18 -89 (mean = 53.4) and 40
      - 70 (mean 57.9) years, respectively. Their duration on dialysis ranged from 1
      month to 10 years (mean = 26 months). The presenting clinical features were fever
      (32), cough (16), weight loss (9), and anorexia (7). The organ systems involved
      were pulmonary (23), peritoneal (15), lymphadenopathy (11), pericardial (4), bone
      TB (3), bone marrow (2), epididimo-orchitis (1), right infraclavicular chest wall
      cold abscess (1), right infrascapular cold abscess (1) and right renal mass (1).
      Single organ system involvement was noted in 36 patients, 2 systems in 10
      patients and 3 systems in 2 patients. Two patients were treated empirically with
      good response. Evidence of tuberculosis was obtained from chest X-rays (23), bone
      X-rays (3), spinal MRIs (1), AFB (stain and culture) of sputum and fluid (15),
      ascitic fluid examination with exudate and raised adenine deaminase (ADA) levels
      (12), lymph node biopsy (8), pleural fluid examination with exudate and raised
      ADA levels (5), bone marrow aspiration (2), exudative pericardial fluid with
      raised ADA levels (2), nephrectomy and histopathology (1), dorsal spine biopsy
      (1) and laparotomy and biopsy ofperitoneum (1). Thirty-two patients received 4
      anti-TB drugs: isoniazid (INH), rifampicin (Rif), pyrazinamide (Pyra) and
      ethambutol (Eth), 10 received 3 drugs (INH, Rif and Pyra or Eth), 2 received 2
      drugs (INH + Rif) and a modified regimen was used in 3. The drug toxicities noted
      were hepatoxicity (5) and INH encephalopathy prior to the routine use of
      pyridoxine 100 mg daily (3), INH-induced SLE (1) and pyrazinamide-induced
      thrombocytopenia (1). The outcome of the patients was cured (35), expired (13),
      and 1 patient expired before starting therapy. Tuberculosis was not the direct
      cause of death in any of the patients. CONCLUSION: The incidence of TB in
      dialysis patients is 26 times more common than in the general Saudi population
      and a high index of suspicion is needed for early diagnosis and treatment.
      Extrapulmonary TB was noted in 52% of the patients. Short-course (6 months)
      chemotherapy is effective. INH-induced CNS toxicity is significant.

PMID- 12425487
TI  - Serum soluble transferrin receptor reflects erythropoiesis but not iron
      availability in erythropoietin-treated chronic hemodialysis patients.
AB  - BACKGROUND: The diagnosis of iron deficiency using the current commonly used
      tests is usually difficult in hemodialysis patients. Soluble transferrin receptor
      (sTfR) has caught the attention of physicians recently as regards its use as a
      parameter for the evaluation of iron status. This study was conducted in order to
      evaluate the correlation of serum soluble transferrin receptor (sTfR)
      concentration with hematological parameters and iron profiles, in the role of
      identifying iron deficiency among dialysis patients. METHODS: Seventy-three
      patients having received chronic hemodialysis and stable maintenance recombinant
      human erythropoietin (rHuEPO) therapy were included. Iron, total iron-binding
      capacity, ferritin and sTfR were measured in the first week. Following this,
      these patients began to receive intravenous iron dextran (2 mg/kg/week) for 4
      weeks. The hematocrit (Hct), hemoglobin (Hb) levels and reticulocyte counts were
      evaluated weekly. At the beginning of fifth week, the sTfR level was measured
      again. Patients were classified as belonging to one of the following groups:
      serum ferritin < 100 microg/L - absolute iron-deficient group; initial ferritin
      level > or = 100 microg/L with an increase in hemoglobin of greater than 1 g/dL
      at the end of the study occult iron deficiency group; others - non iron-deficient
      group. RESULTS: Seventy-one patients completed the study. The concentration of
      sTfR was positively correlated with Hct, Hb and reticulocyte index at the
      beginning (r = 0.236, p = 0.047; r = 0.257, p = 0.04; r = 0.401, p < 0.01,
      respectively) and at the end of the study (r = 0.384, p < 0.01; r = 0.338, p <
      0.01; r = 0.427, p < 0.001, respectively). After 4 weeks of iron and rHuEPO
      therapy, the sTfR concentration increased, rather than declined, from 21.85 +/-
      8.06 nM to 23.76 +/- 7.42 nM (p = 0.04) and the change was positively correlated
      with the changes in Hct, Hb and reticulocyte index. The administered rHuEPO doses
      did not differbetween the iron deficiency group (absolute deficiency, n = 3;
      occult deficiency, n = 10) and non-iron deficiency group (n = 58). The sTfR
      levels failed to identify the occult iron deficiency group because there was no
      difference between occult iron-deficient and non-iron-deficient patients (24.73
      +/- 9.09 nM versus 21.60 +/- 7.89 nM, p = 0.34). Instead, transferrin saturation
      (TS) could be a differential marker between the 2 groups (19.0 +/- 10.9% versus
      30.1 +/- 12.7%, p = 0.012). CONCLUSION: The serum sTfR concentration is indeed an
      appropriate marker for erythropoiesis. The erythropoitic effect of administered
      rHuEPO could mask the effect of iron status on the sTfR concentration. This might
      make the sTfR concentration no longer an appropriate index to identify the
      presence of occult iron deficiency. Thus, TS and ferritin currently remain better
      methods for the evaluation of iron status in rHuEPO-treated chronic hemodialysis
      patients.

PMID- 12425488
TI  - Angiotensin-converting enzyme (ACE) insertion/deletion polymorphism and survival
      in a cohort of chronic hemodialysis patients.
AB  - BACKGROUND: There are conflicting reports regarding the relationship between the
      angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism and the
      initiation and progression of cardiovascular disease. Moreover, there is no
      report regarding the relationship between the ACE I/D polymorphism and the
      prognosis of chronic dialysis patients. METHODS: We examined the frequency of the
      ACE I/D polymorphism in 727 chronic hemodialysis patients in Okinawa, Japan, and
      observed the prognosis over 2 years in 407 men and 320 women with mean age (SD)
      of 55.5 (13.9) years with a mean duration of dialysis of 84.3 (66.6) months.
      RESULTS: Genotype frequencies were 42.1% for II, 43.2% for ID, and 14.7% for DD.
      The relative risks of death were examined by Cox-proportional hazards analysis
      after adjusting for age, sex, age at the start of dialysis, presence of diabetes
      mellitus and hypertension and total cholesterol and serum albumin levels. The
      adjusted hazard ratio (95% confidence interval) was 1.03 (0.38 - 2.85) for DD
      genotype and 1.50 (0.83 - 2.70) for DD+ID genotype when compared to II genotype.
      CONCLUSION: ACE I/D polymorphism appears to have no relation to the short-term
      prognosis in chronic hemodialysis patients.

PMID- 12425489
TI  - Characterization of treatment dose delivered by albumin dialysis in the treatment
      of acute renal failure associated with severe hepatic dysfunction.
AB  - BACKGROUND: Acute liver cell failure (ALCF) commonly results in death and when
      complicated by acute renal failure (ARF), the mortality approaches 90%. Albumin
      dialysis allows partial replacement of some of the liver's excretory functions.
      The molecular absorbents recirculating system (MARS) has been recently introduced
      to provide this therapy. Thus allowing bridging to transplantation or hepatic
      regeneration. We have attempted to define the degree of "uremic" dialysis that
      this system can deliver as well as characterizing the dose of "hepatic"
      treatment, using a similar approach to solute remove as applied to assessing
      hemodialysis adequacy. As a secondary issue we also report on the clinical
      outcomes of this group of patients. METHOD: We treated 7 patients with ALCF and
      acute renal failure (6 of the patients having a formal diagnosis of hepatorenal
      syndrome), aiming to deliver a 5 treatment consecutive course consisting of 8
      hours of albumin dialysis using the MARS monitor, combined with hemodialysis.
      Clinical and biochemical outcomes were assessed, and dialysis adequacy measured
      using urea reduction ratios, calculated Kt/V and measured Kt/V (using ionic
      dialysance). Treatment dose, with respect to the highly protein bound and
      lipophilic toxins that accumulate in hepatic failure, was assessed by calculating
      the bilirubin reduction ratio and percentage reduction in plasma ammonia and
      total bile acids. RESULTS: All of the patients had a degree of biochemical
      improvement with albumin dialysis. Urine output increased and the degree of
      encephalopathy improved. Mean bilirubin fell from 612 +/- 105.5 micromol/l (range
      165.6 - 1,024 micromol/l) to 370.4 +/- 49.7 micromol/l (range 190.4 - 569.2
      micromol/l), ALT reduced from 3,280 +/- 2,266 IU/l (range 40 - 18,876) to 639 +/-
      230 IU/l (range 33 - 1677). Hepatic synthetic function improved with INR falling
      from 4.1 +/- 0.5 (range 2.1 - 6.4) to 2.8 +/- 0.6 (range 1.4 - 5.5). Plasma
      ammonia was reduced, falling from 162.4 +/- 15.4 (range 131.1 - 191.9 micromol/l)
      to 73.1 +/- 15 micromol/l (range 45.6 - 106.4 micromol/l). Bile acid levels fell
      from 132 +/- 10.2 micromol/l (range 110.7 - 155.8 micromol/l) to 36.9 +/- 6.1
      micromol/l (range 24.6 49.6 micromol/l). The mean urea reduction ratio (URR) was
      58.4 +/- 3.2% (range 39 - 76%). Mean Kt/V as assessed by ionic dialysance was 1.7
      +/- 0.01 (range 0.8-2.4). Mean bilirubin reduction ratio (BRR) was 28.6 +/- 1.4%
      (range 12.5 - 39%). BRR was proportional to both URR and Kt/V. BRR was also
      proportional to the percentage reduction of ammonia and bile acid levels. Three
      of the 7 patients survived to be discharged from hospital and 4 died. CONCLUSION:
      Albumin dialysis appears capable of improving the outcome in patients with ALCF
      and hepatorenal syndrome. Eight-hour intermittent treatments with the MARS system
      in combination with hemodialysis deliver an adequate dose of dialysis with
      respect to urea. BRR may be an appropriate tool to allow further quantitative and
      comparative study of this technique.

PMID- 12425490
TI  - Renal failure due to scleroderma with thrombotic microangiopathy developing in a
      woman treated with carboplatin for ovarian cancer.
AB  - Acute renal failure in association with microangiopathic hemolytic anemia and the
      pathological finding of thrombotic microangiopathy may occur in a number of
      conditions including hemolytic uremic syndrome, thrombotic thrombocytopenic
      purpura, and systemic sclerosis. Distinguishing between these conditions on
      clinical grounds may be difficult, and further investigations, including
      serological tests, are normally helpful. We present a patient who was treated
      with 5 doses of monthly carboplatin chemotherapy for stage IIb ovarian carcinoma
      and who subsequently developed acute renal failure and microangiopathic hemolysis
      together with some cutaneous features of systemic sclerosis. Initial serological
      tests, including anti-nuclear antibody titers measured using rat hepatocytes,
      were normal, and renal biopsy showed features of microangiopathic hemolysis,
      fibrinoid change, patchy tubular atrophy, and concentric intimal proliferation. A
      clinical diagnosis of diarrhea-negative hemolytic uremic syndrome was made and
      she was treated with plasma exchange and fresh frozen plasma infusion. However,
      she remained dialysis-dependent. Several weeks later she died following a cardiac
      arrest. Post-mortem examination revealed medial hypertrophy, concentric intimal
      proliferation, and thrombi within the small arteries of the kidneys and lungs.
      Subsequent results from tests taken at the time of her presentation with acute
      renal failure revealed a normal von Willebrand factor qualitative distribution,
      and a positive anti-nuclear antibody titer (using a human cell line) in
      association with positive autoantibodies to RNA polymerase types I, II, and III.
      Taken together, the clinical, laboratory, and post-mortem findings were
      suggestive of a diagnosis of systemic sclerosis. We discuss the differential
      diagnoses, and the associations between these and malignancy and chemotherapy.
      Finally, we consider the serological tests used for the diagnosis of systemic
      sclerosis that were, in this case, initially misleading.

PMID- 12425491
TI  - Episodic gross hematuria in association with allergy symptoms in a child.
AB  - BACKGROUND: A relationship between allergy and the development of various renal
      diseases has been postulated, but never proven. MATERIALS AND METHODS: We present
      the case of a child with idiopathic episodic gross hematuria. The child also has
      significant environmental allergies, and his episodes of hematuria coincide with
      flares of his allergic symptoms. The available literature on hematuria and
      allergy was reviewed in order to further explore the potential role that allergy
      may play in the pathogenesis of genitourinary tract disease. CONCLUSIONS: This
      case, as well as others reported in the literature, suggest that allergy should
      be considered as a possible diagnosis in children with otherwise unexplained
      hematuria.

PMID- 12425492
TI  - The Wake Forest era and the two-year school: 1902-1941.

PMID- 12425493
TI  - Medicine at the medical center then and now: one hundred years of progress.
AB  - The health and life expectancy of persons residing in the United States has
      improved dramatically during the 20th century. The average life span in the US
      has increased by more than 30 years since 1900. This significant gain is
      attributable to improvements in both public health and medical care. Tempering
      this notable achievement is the observation that the mortality rate per 1,000
      population, although showing a significant decline in the era from 1920 to 1940,
      has now plateaued, and may be showing a slight increase. Our scientists and
      physicians have appropriately exploited the scientific discoveries of the 20th
      century and are poised as a medical tour de force for the 21st century. The
      decline in deaths from coronary artery disease and stroke has resulted from risk
      factor modification and the innovations of surgeons and physicians who have
      dedicated themselves to early detection and better treatment of these cases.
      During the 1960s, patients admitted to our medical center with advanced Hodgkin's
      disease, hairy cell leukemia, and the acute leukemias had a life expectancy of <
      1 year. Today, even advanced Hodgkin's disease and hairy cell leukemia are
      curable, and many patients with other acute leukemias respond to therapy and have
      very durable remissions. The rate of maternal mortality has shown a dramatic
      decline, and many childhood diseases have been eradicated or reduced to
      infrequent occurrences. Our public health scientists and physicians are joining
      forces to further diminish the morbidity and mortality rates for many of our
      common diseases. The achievements of our past afford us the vision for what we
      can become.

PMID- 12425495
TI  - A history of firsts for Wake Forest University School of Medicine.

PMID- 12425494
TI  - The legacy of yesterday: the signature of the past at Wake Forest University
      School of Medicine.

PMID- 12425496
TI  - Physicians as detectives in detective fiction of the 20th century.
AB  - BACKGROUND: Surprisingly few detectives are physicians in 20th-century detective
      fiction. METHODS: Potential books with physician-detective characters were
      located by pursuing all mentions of characters referred to as 'Doctor" in any of
      several reference materials pertaining to mystery and detective fiction. RESULTS:
      As a result of the search, 53 authors whose detective characters are physicians
      were found. Examination of novels by these authors revealed that early in the
      20th century, physicians applied their own specialized scientific knowledge to
      detection. Mid-century physicians worked by intuition. In the 1990s, science
      returned to detective fiction in the form of standard forensic procedure, and the
      level of violence dramatically increased. CONCLUSION: The relation between
      science and violence at the end of the 20th century may not be accidental.

PMID- 12425497
TI  - Primary cardiac hydatid disease: cross-sectional imaging features.
AB  - BACKGROUND: Although hydatid disease is common, individual series are usually not
      large as far as primary cardiac hydatid disease is concerned. We believe this
      study is the largest series of primary cardiac hydatid disease for which cross
      sectional imaging is available. Methods. We reviewed the radiologic and medical
      records of 9 pathologically proven cases of primary cardiac hydatid disease.
      Echocardiography, computed tomography (CT), and magnetic resonance imaging (MRI)
      were used. In 5 patients, all three modalities were used, and in 4 only CT was
      available. RESULTS: Three types of cardiac involvement (pericardial, left
      ventricular, and right atrial wall) were detected. The cysts showed daughter cyst
      formation, detached parasitic membrane, rupture, segmental calcification, and end
      stage calcification. CONCLUSION: Echocardiography is useful in detecting the
      cystic nature. Computed tomography best shows the wall calcification. Magnetic
      resonance imaging depicts the exact anatomic location and nature of the internal
      and external structures and is the modality of posttreatment follow-up.

PMID- 12425498
TI  - Racial and age-related disparities in obtaining screening mammography: results of
      a statewide database.
AB  - BACKGROUND: This study compared mammography rates in Arkansas, based on race and
      age, to identify any disparities in obtaining mammography. METHODS: The Arkansas
      Mammography Data Collection Project contained data on 133,549 women, 87,680 of
      them aged 40 to 64 and 45,869 aged 65 years or older. Race data were available on
      64,526 women. Mammography rates were compared by patient age and race. RESULTS:
      Women aged 65 years and older were less likely to obtain mammograms than younger
      women: 21.67% versus 23.30%. Mammograms were more likely to be classified as
      diagnostic in older women and as screening in younger women. Older African
      American women were less likely to obtain mammograms than younger women of the
      same race (7.23% vs 8.02%), while older white women were more likely to obtain
      mammograms than younger white women (11.64% vs 11.31%). African Americans were
      less likely to obtain mammograms in both age groups. CONCLUSIONS: Older African
      American women are less likely to obtain mammograms than white and younger women.
      The reasons for this disparity warrant further evaluation.

PMID- 12425499
TI  - Characteristics and outcomes of patients with unresected early-stage non-small
      cell lung cancer.
AB  - BACKGROUND: This study describes the characteristics, management, and outcomes of
      patients with unresected early-stage non-small cell lung cancer (NSCLC). METHODS:
      A retrospective review was conducted to identify all patients with unresected
      stage I or stage II NSCLC diagnosed between 1990 and 1998. RESULTS: Ninety-seven
      patients were identified who met our criteria. The median age at diagnosis was 68
      years; 78% of patients were white, 81% were male, 81% had stage I disease, and
      67% had squamous cell carcinoma. Cancer-specific treatment, including
      chemotherapy, radiation therapy, and combined chemotherapy and radiation therapy,
      was administered to only 27 patients. The median survival time was 22 months for
      the treated group and 11 months for the untreated group. CONCLUSION: The majority
      of patients with unresected early-stage NSCLC do not receive cancer therapy. They
      should be thoroughly considered for treatment, however, especially in light of
      recent advances in surgery and radiation therapy, and the development of more
      active, less toxic chemotherapeutic agents.

PMID- 12425500
TI  - Appearance of previously injured posterior cruciate ligaments on magnetic
      resonance imaging.
AB  - BACKGROUND: The appearance of normal and injured cruciate ligaments on magnetic
      resonance imaging (MRI) has been well described in the literature. Few studies
      have reported on changes found on sequential imaging of injured posterior
      cruciate ligaments (PCLs) during the healing process, however. METHODS: Ten
      consecutive patients with isolated injuries to the PCL were evaluated with an
      initial clinical examination, x-rays, and MRI of the injured knee. Clinical
      examination and imaging studies were repeated at a minimum of 6 months after the
      initial injury. These studies were interpreted by radiologists blinded to the
      study design. RESULTS: Seven of the 10 patients were found to have PCL continuity
      on repeat MRI. One patient continued to demonstrate an abnormal appearance of the
      PCL on MRI, and 2 patients were lost to follow-up. CONCLUSIONS: Despite the
      healed appearance of their PCLs on imaging studies, 6 of 7 patients continued to
      demonstrate laxity on clinical examination. All returned to their preinjury
      occupations and to recreational sports, however. Our results are consistent with
      previously reported data.

PMID- 12425502
TI  - Are pediatricians adhering to principles of judicious antibiotic use for upper
      respiratory tract infections?
AB  - BACKGROUND: In 1997, the Centers for Disease Control and Prevention (CDC), in
      collaboration with other professional organizations, released principles for
      judicious use of antibiotics in pediatric upper respiratory illnesses (URI). This
      study compared use of antibiotics for URI in children before (1995) and after
      (1998) publication of the principles and compared survey responses with practice
      habits. METHODS: A questionnaire was mailed to a sample of pediatricians in
      northern Virginia. Office records of a randomly selected subset of pediatricians
      were reviewed. RESULTS: Seventy-five percent of pediatricians completed the
      questionnaire; 51/149 (34%) chose to prescribe antibiotics for purulent
      rhinorrhea of less than 10 days' duration. This was significantly lower than that
      reported in the 1995 survey. However, review of office records of a random sample
      of these pediatricians revealed no significant difference in antibiotic use in
      children with uncomplicated URI in the 2 years studied. CONCLUSIONS: Injudicious
      antibiotic use for URI is prevalent among pediatricians in northern Virginia.
      Actual practice habits are at variance with response to case vignettes.

PMID- 12425501
TI  - Complement and immunoglobulin levels in serum and ascitic fluid of patients with
      spontaneous bacterial peritonitis, malignant ascites, and tuberculous
      peritonitis.
AB  - BACKGROUND: We determined complement and immunoglobulin levels in ascitic fluid
      and serum of 47 patients with spontaneous bacterial peritonitis, malignant
      ascites, or tuberculous ascites. METHODS: Paracentesis was done to confirm the
      underlying cause of ascites. Biochemical, hematologic, and microbiologic
      investigations were also done. RESULTS: The highest serum and ascitic fluid C3
      and C4 levels and ascitic fluid IgM, IgA, and IgG levels were found in patients
      with tuberculosis. Ascitic fluid C3 level was found to be higher in the
      tuberculous group than in the patients with spontaneous bacterial peritonitis or
      malignant ascites. Ascitic fluid C4 levels were higher in patients with
      tuberculosis than in those with spontaneous bacterial peritonitis. CONCLUSION: We
      believe that further studies of the in vivo kinetics of immunoglobulins and
      complement in ascitic fluid of various causes are necessary for a better
      understanding of the host defense mechanisms of these fluids.

PMID- 12425503
TI  - Mediastinal staging of non-small cell lung carcinoma using computed and positron
      emission tomography.
AB  - BACKGROUND: We evaluated the accuracy of computed tomography (CT) and positron
      emission tomography (PET) in the mediastinal staging of non-small cell lung
      cancer. METHODS: Between May 14, 1999, and November 28, 2000, computerized
      tomography (CT) and positron-emission tomography (PET) were used to clinically
      stage 94 consecutive patients with non-small cell carcinoma of the lung (NSCCL).
      All patients underwent subsequent surgical staging with mediastinoscopy, anterior
      mediastinotomy, and/or thoracotomy with mediastinal lymphadenectomy. RESULTS:
      Overall accuracy was the same for both procedures. False-negative results
      occurred 3 times more often with CT; false-positive results occurred twice as
      often with PET. Sensitivity and specificity were 64% and 94%, respectively, for
      CT, versus 88% and 86%, respectively, for PET. Positive and negative predictive
      values were 80% and 88%, respectively, for CT, versus 71% and 95%, respectively,
      for PET. CONCLUSION: In addition to routine use of CT, PET seems to achieve high
      negative predictive value in the evaluation of mediastinal disease; PET seems
      particularly helpful in assessing absence of tumor in bulky nodes after
      neoadjuvant chemotherapy and/or radiotherapy.

PMID- 12425504
TI  - Sir William Osler's emphasis on physical diagnosis and listening to symptoms.

PMID- 12425505
TI  - The "bedsheet" Babinski.
AB  - BACKGROUND: Babinski's reflex (dorsiflexion of the hellus and fanning of the toes
      in response to plantar stimulation) is a classic sign in neurology. Although
      typically elicited by stroking the plantar surface of the foot with a firm
      object, other means of obtaining the response have been described. METHODS: We
      assessed the frequency of the Babinski response after plantar stimulation by
      exposing the feet by removal of the bedsheet or socks in 10 patients with
      neurologic disease and 10 control subjects. These results were compared with
      those obtained by traditional means of stimulation. RESULTS: We found a high
      correlation between the two responses (sensitivity of 80% and specificity of
      90%). CONCLUSION: Although this study is small and requires a larger study to
      verify its accuracy, it appears that simple observation of the toe response at
      the time that the feet are exposed frequently provides evidence of pyramidal
      tract dysfunction.

PMID- 12425506
TI  - Monofocal acute inflammatory Demyelination (MAID): a unique disorder simulating
      brain neoplasm.
AB  - BACKGROUND: Monofocal acute inflammatory demyelinating (MAID) lesions present as
      large masses that mimic brain tumors. The natural history and nosologic
      classification are not well defined. METHODS: Five patients with MAID from our
      files and 4 from the literature are presented. We defined MAID as a mass-like
      lesion, >4 cm in diameter. Demyelination was pathologically proven in all
      patients. RESULTS: Headaches and motor deficits were the most common presenting
      symptoms. Language problems and motor deficits were the most common findings on
      physical examination. After a median follow-up of 44 months, none of our 5
      patients had multiple sclerosis. In similar cases, additional lesions indicative
      of multiple sclerosis developed within an average of 8 months. CONCLUSIONS: It
      may be difficult to distinguish MAID from brain tumor. It may be that MAID
      represents a unique form of isolated demyelinating disease, or it may represent
      transition to multiple sclerosis.

PMID- 12425507
TI  - Thiazolidinediones: a review of their benefits and risks.
AB  - Several new drugs have become available for the treatment of type 2 diabetes
      mellitus in the past few years, and among them the thiazolidinediones are
      probably the most promising and interesting. Their mechanism of action involves a
      reduction in insulin resistance while simultaneously improving some of the
      independent risk factors for cardiovascular disease frequently found in patients
      with type 2 diabetes mellitus. On the other hand, while they might have many
      advantages over the other available antihyperglycemic agents, there are still
      some concerns about their long-term safety. Consequently, while awaiting the
      results of the planned long-term cardiovascular outcome studies, which will help
      establish their true benefits and risks, physicians must remain skeptical about
      these drugs and consider not only their claimed advantages, but also their not-so
      well-publicized risks. This article summarizes the known and/or presumed
      beneficial and toxic effects of these drugs.

PMID- 12425508
TI  - Low-grade endometrial stromal sarcoma recurring after 9 years.
AB  - A 61-year-old Japanese woman had recurrent low-grade endometrial stromal sarcoma
      (ESS) after primary treatment 9 years earlier. Initial and recurrent tumors
      showed the same configuration that the polycystic part showed in the solid tumor
      ultrasonographically. The central part of both the initial and recurrent tumors
      showed typical histologic findings, but bizarre cells were detected in the
      peripheral layer of the recurrent tumor. They resembled glandular cells, Comet
      cells of high-grade ESS, fibroblasts, decidual cells, and predecidual endometrial
      stromal cells at the middle to late secretory phases. The change and
      differentiation of low-grade ESS by therapy and environment seem to be the same
      as the differentiation in mesenchymal stem cells. We speculate that recurrence
      and prognosis of low-grade ESS are related by extrauterine development but not by
      mitotic activity or DNA content.

PMID- 12425509
TI  - Enterococcus faecalis causing empyema in a patient with liver disease.
AB  - A 57-year-old man with a history of liver disease had shortness of breath, fever,
      and pleuritic chest pain. Ascites was not present. Computed tomography (CT) of
      the chest revealed a large unilateral pleural effusion, compressive atelectasis,
      and no evidence of consolidation. Culture of the pleural fluid grew Enterococcus
      faecalis. Treatment with ampicillin in conjunction with tube thoracostomy
      resulted in clinical improvement. This case illustrates the development of
      spontaneous monomicrobial empyema due to E. faecalis in a patient with liver
      disease, in the absence of pneumonia and peritonitis.

PMID- 12425510
TI  - Listeria monocytogenes-induced monomicrobial non-neutrocytic bacterascites.
AB  - Spontaneous bacterial peritonitis (SBP) is a common complication in patients with
      cirrhosis of the liver. The organisms most commonly involved in this infection
      are gram-negative bacteria like Escherichia coli and Klebsiella pneumoniae, and
      gram-positive bacteria like Streptococcus pneumoniae and Staphylococcus aureus.
      Listeria monocytogenes is an uncommon gram-positive bacillus implicated in
      infections in neonates, pregnant females, the elderly, and immunocompromised
      patients. Listeria monocytogene-induced SBP is rare, with less than 40 cases
      reported in the medical literature. Monobacterial non-neutrocytic bacterascites
      (MNB) is a variant of SBP, where the ascitic fluid culture is positive but the
      ascitic neutrophil count is less than 250/mm3. Forty percent of these patients
      will subsequently have SBP. Only 2 cases of MNB from L monocytogenes have
      previously been reported. We report a case of MNB in a patient with cirrhosis
      whose ascitic neutrophil count was 164/mm', but Gram stain and microbiologic
      culture showed the growth of L monocytogenes.

PMID- 12425511
TI  - Giant intrathoracic extrapulmonary hydatid cyst manifested as unilateral pectus
      carinatum.
AB  - Liver and lung are the most common sites of hydatid disease, but it can also be
      seen elsewhere in the body. Extrapulmonary intrathoracic location of the disease
      is rare. This case of giant intrathoracic extrapulmonary hydatid cyst manifested
      as unilateral pectus carinatum serves to illustrate that hydatid disease can
      produce various symptoms and that it may also exist in locations apart from lung
      and liver.

PMID- 12425512
TI  - Rituximab: an anti-CD20 antibody for the treatment of chronic refractory immune
      thrombocytopenic purpura.
AB  - Immune thrombocytopenic purpura (ITP) is an autoimmune disease characterized by
      antibody-mediated platelet destruction. Despite initial response to
      corticosteroids, most adults relapse during steroid taper, and splenectomy is the
      treatment of choice for these patients. Those whom splenectomy fails to cure
      present a therapeutic challenge. Subsequent management usually involves some form
      of chronic immune suppression, which has serious side effects and long-term
      morbidity. Rituximab, a recently-approved anti-CD20 chimeric monoclonal antibody,
      has shown efficacy in preliminary studies. We report the cases of 3 patients with
      refractory ITP who achieved acceptable platelet counts after treatment with
      rituximab.

PMID- 12425513
TI  - Toxic epidermal necrolysis due to administration of celecoxib (Celebrex).
AB  - A 41-year-old woman was given celecoxib (Celebrex) for the treatment of carpal
      tunnel syndrome. An erythematous rash developed that progressed to exfoliative
      dermatitis, and the patient was diagnosed with toxic epidermal necrolysis. After
      transfer to the burn unit, she was treated with topical mupirocin calcium cream
      and bismuth tribromophenatein petrolatum gauze dressings. Her wounds healed well.
      This is the first case report of toxic epidermal necrolysis due to treatment with
      celecoxib of which we are aware.

PMID- 12425514
TI  - Ifosfamide-induced encephalopathy.
AB  - A 46-year-old man with a history of metastatic transitional cell carcinoma of the
      bladder received treatment with ifosfamide/mesna. He had reversible
      encephalopathy after the first cycle of chemotherapy. Adequate clinical response
      was achieved, with an obvious decrease in tumor size. Subsequently, an identical
      treatment was given without adverse central nervous system effects. Few data
      exist about retreatment with intravenous ifosfamide/mesna after induced
      encephalopathy, but this case suggests that this adverse effect may not recur in
      some patients.

PMID- 12425515
TI  - Combined false hyperkalemia and hypocalcemia due to specimen contamination during
      routine phlebotomy.
AB  - Combined pseudohyperkalemia and pseudohypocalcemia have not been previously
      reported in the clinical setting. We report 2 cases in which specimen
      contamination during routine phlebotomy with ethylenediaminetetraacetic acid
      (EDTA) caused alteration in serum levels of potassium and calcium. This
      alteration could be misleading when making clinical decisions and could produce
      adverse patient outcomes.

PMID- 12425516
TI  - Small cell carcinoma of the pleura.
AB  - We describe a patient with small cell carcinoma of the pleura who survived more
      than 4 years despite no response to chemotherapy. The natural history of pleural
      small cell carcinoma is unknown, and similar cases in the medical experience will
      shed light on possible treatment.

PMID- 12425517
TI  - Acute mediastinal widening.
AB  - Mediastinal abscess resulting from descending necrotizing mediastinitis is a rare
      infectious process. Odontogenic infections are the most commonly implicated
      underlying process. Descending necrotizing mediastinitis is a rapidly progressive
      infectious process that spreads through the fascial planes of the neck to gain
      access to the mediastinum. Early recognition of descending necrotizing
      mediastinitis is important because the reported mortality rate is 30% to 50% even
      in the antibiotic era. Clues to the diagnosis of descending necrotizing
      mediastinitis include evidence of severe oropharyngeal infection, neck swelling
      and crepitations, and complaints of dysphagia and odynophagia. Lateral
      radiographs of the neck sometimes show gas pockets, but chest films are often
      negative early in the disease process. A late chest x-ray finding is widening of
      the superior mediastinum. Therefore, computed tomography (CT) is the imaging
      procedure of choice. Optimal treatment includes adequate drainage of the neck and
      mediastinum and broad spectrum intravenous antibiotics. Commonly implicated
      organisms are alpha-hemolytic streptococci and Bacteroides fragilis.

PMID- 12425518
TI  - Rhabdomyolysis of infectious and noninfectious causes.

PMID- 12425519
TI  - Sectarian religious crises in Kaduna, Nigeria: 30 cases of abdominal gunshot
      injuries.

PMID- 12425520
TI  - Clay, Vicks, and Gold Medal flour.

PMID- 12425521
TI  - Immune-mediated inflammatory demyelinating dysfunction of the nervous system.

PMID- 12425522
TI  - Young woman with paraproteinemia.

PMID- 12425523
TI  - Is Pneumocystis a plant?
AB  - Pneumocystis, an AIDS-associated opportunistic pathogen of the lung has some
      unusual features. This article focuses on work done by my group to understand the
      organism's distinct sterols. Although Pneumocystis is closely related to fungi,
      it lacks the major fungal sterol, ergosterol. Several delta(7) 24-alkysterols
      synthesized by P. carinii are the same as those reported in some basidiomycete
      rust fungi. The 24-alkylsterols are synthesized by the action of S-adenosyl-L
      methionine:C-24 sterol methyl transferase (SAM:SMT). Fungal SAM:SMT enzymes
      normally transfer only one methyl group to the C-24 position of the sterol side
      chain and the cells accumulate C28 24-alkylsterols. In contrast, the P. carinii
      SAM:SMT and those of some plants catalyze one or two methyl transfer reactions
      producing both C28 and C29 24-alkylsterols. However, unlike most fungi, plants,
      and the kinetoplastid flagellates Leishmania and Trypanosoma cruzi, P. carinii
      does not appear to form double bonds at C-5 of the sterol nucleus and C-22 of the
      sterol side chain. Furthermore, the P. carinii SAM:SMT substrate preference for
      C30 lanosterol differs from that of homologous enzymes in any other organisms
      studied. C31 24-Methylenelanosterol and C32 pneumocysterol, products of SAM:SMT
      activity on lanosterol, can accumulate in high amounts in some, but not all,
      human-derived Pneumocystis jiroveci populations.

PMID- 12425524
TI  - Isolation and expression of two genes encoding eukaryotic release factor 1 from
      Paramecium tetraurelia.
AB  - Paramecium tetraurelia, like some other ciliate species, uses an alternative
      nuclear genetic code where UAA and UAG are translated as glutamine and UGA is the
      only stop codon. It has been postulated that the use of stop codons as sense
      codons is dependent on the presence of specific tRNAs and on modification of
      eukaryotic release factor one (eRF1), a factor involved in stop codon recognition
      during translation termination. We describe here the isolation and
      characterisation of two genes, eRF1-a and eRF1 b, coding for eRF1 in P.
      tetraurelia. The two genes are very similar, both in genomic organization and in
      sequence, and might result from a recent duplication event. The two coding
      sequences are 1,314 nucleotides long, and encode two putative proteins of 437
      amino acids with 98.5% identity. Interestingly, when compared with the eRF1
      sequences either of ciliates having the same variant genetic code, or of other
      eukaryotes, the eRF1 of P. tetraurelia exhibits significant differences in the N
      terminal region, which is thought to interact with stop codons. We discuss here
      the consequences of these changes in the light of recent models proposed to
      explain the mechanism of stop codon recognition in eukaryotes. Besides, analysis
      of the expression of the two genes by Northern blotting and primer extension
      reveals that these genes exhibit a differential expression during vegetative
      growth and autogamy.

PMID- 12425525
TI  - Epidermal growth factor binds to a receptor on Trypanosoma cruzi amastigotes
      inducing signal transduction events and cell proliferation.
AB  - Host growth factors induce proliferation of Trypanosoma cruzi amastigotes by
      mechanisms that remain poorly defined. Here we examined human epidermal growth
      factor (EGF) for its ability to bind to the mammalian multiplicative forms of T.
      cruzi and to induce growth of the parasites. EGF stimulated incorporation of [3H]
      thymidine into DNA and growth of amastigotes both in a concentration-dependent
      manner. Radiolabeled EGF was found to bind to amastigotes in a concentration
      dependent and saturable manner but it did not bind to trypomastigotes. Scatchard
      analysis showed a single class of receptors with a Kd of 0.8 nM and numbering 3.1
      x 10(3) per amastigote. Results from internalization experiments provided
      evidence of receptor-mediated endocytosis of EGF. Northern analysis showed a 3.0
      kb transcript for the putative EGF receptor (EGFR) homologue in amastigotes, but
      not trypomastigotes. Binding of EGF to amastigotes induced signal transduction
      events. EGF induced "in vitro" kinase activity as determined by gamma-[32P] ATP
      incorporation into amastigote proteins. EGF also increased protein kinase C
      activity in a concentration-dependent manner and Mitogen Activated Protein (MAP)
      kinase activity in a time- and concentration-dependent manner. A specific
      inhibitor (AG14782) of the EGFR and a MAP kinase inhibitor (PD98059) decreased
      EGF-dependent T. cruzi MAP kinase activity. These results describe a novel
      mechanism used by amastigotes to regulate their proliferation mediated by an EGF
      dependent signal transduction pathway.

PMID- 12425526
TI  - Laboratory susceptibility of Wyeomyia smithii (Diptera: Culicidae) to
      Ascogregarina taiwanensis (Apicomplexa: Lecudinidae).
AB  - Gregarines in the genus Ascogregarina are not known to develop in sabethine
      mosquitoes, but we successfully infected larvae of Wyeomyia smithii with
      Ascogregarina taiwanensis in the laboratory. Ascogregarina taiwanensis is a
      natural parasite of the exotic Asian tiger mosquito, Aedes albopictus. Only 18%
      to 70% of the W. smithii larvae had visible trophozoites, with a range of 1-92
      per larva. Trophozoites persisted in the midgut for more than 37 d, and one adult
      female W. smithii had gametocysts in its Malphigian tubules, which indicated that
      A. taiwanensis might fully develop in W. smithii. After 50 d, gregarines were not
      found in W. smithii larvae.

PMID- 12425527
TI  - Sequence survey of the genome of the opportunistic microsporidian pathogen,
      Vittaforma corneae.
AB  - The microsporidian Vittaforma corneae has been reported as a pathogen of the
      human stratum corneum, where it can cause keratitis, and is associated with
      systemic infections. In addition to this direct role as an infectious, etiologic
      agent of human disease, V. corneae has been used as a model organism for another
      microsporidian, Enterocytozoon bieneusi, a frequent and problematic pathogen of
      HIV-infected patients that, unlike V. corneae, is difficult to maintain and to
      study in vitro. Unfortunately, few molecular sequences are available for V.
      corneae. In this study, seventy-four genome survey sequences (GSS) were obtained
      from genomic DNA of spores of laboratory-cultured V. corneae. Approximately, 41
      discontinuous kilobases of V. corneae were cloned and sequenced to generate these
      GSS. Putative identities were assigned to 44 of the V. corneae GSS based on
      BLASTX searches, representing 21 discrete proteins. Of these 21 deduced V.
      corneae proteins, only two had been reported previously from other microsporidia
      (until the recent report of the Encephalitozoon cuniculi genome). Two of the V.
      corneae proteins were of particular interest, reverse transcriptase and
      topoisomerase IV (parC). Since the existence of transposable elements in
      microsporidia is controversial, the presence of reverse transcriptase in V.
      corneae will contribute to resolution of this debate. The presence of
      topoisomerase IV was remarkable because this enzyme previously had been
      identified only from prokaryotes. The 74 GSS included 26.7 kilobases of unique
      sequences from which two statistics were generated: GC content and codon usage.
      The GC content of the unique GSS was 42%, lower than that of another
      microsporidian, E. cuniculi (48% for protein-encoding regions), and substantially
      higher than that predicted for a third microsporidian, Spraguea lophii (28%). A
      comparison using the Pearson correlation coefficient showed that codon usage in
      V. corneae was similar to that in the yeasts, Saccharomyces cerevisiae (r = 0.79)
      and Shizosaccharomyces pombe (r = 0.70), but was markedly dissimilar to E.
      cuniculi (r = 0.19).

PMID- 12425528
TI  - Morphology and infraciliature of a new marine ciliate Euplotidium smalli n. sp.
      with description of a new genus, Paraeuplotidium n. g. (Ciliophora, Euplotida).
AB  - The morphology and infraciliature of a new hypotrichous ciliate, Euplotidium
      smalli n. sp., isolated from eutrophic coastal water in Korea, were observed in
      living cells and investigated using the protargol impregnation technique. This
      new ciliate bears 13-14 frontoventral cirri, 7 transverse cirri, and 5-6 dorsal
      kineties. Neither left marginal cirrus nor caudal cirrus is present. The new
      species differs from the related species, Euplotidium agitatum Noland, 1937 in
      the different number of frontoventral and transverse cirri and different body
      shape. With the exception of Euplotidium agitatum, the known species of the genus
      Euplotidium Noland, 1937 with the presence of left marginal cirrus are assigned
      to a new genus, Paraeuplotidium n. g. Diagnosis of Paraeuplotidium is:
      Gastrocirrhidae with funnel-shaped buccal cavity; with frontoventral and
      transverse cirri; left marginal cirrus present. Paraeuplotidium itoi (Ito, 1958)
      n. comb. is designated here the type species. Four additional species are
      included: Paraeuplotidium psammophilus (Vacelet, 1961) n. comb., Paraeuplotidium
      arenarium (Magagnini & Nobili, 1964) n. comb., Paraeuplotidium helgae (Hartwig,
      1980) n. comb., and Paraeuplotidium prosaltans (Tuffrau, 1985) n. comb. An
      improved generic diagnosis of Euplotidium is suggested based on morphology and
      infraciliature characters: marine hypotrichs with a funnel-shaped buccal cavity;
      with frontoventral and transverse cirri; neither left marginal cirrus nor caudal
      cirri present.

PMID- 12425529
TI  - Significant differences between procyclic and bloodstream forms of Trypanosoma
      brucei in the maintenance of their plasma membrane potential.
AB  - The plasma membrane potential (deltapsi) of procyclic and bloodstream
      trypomastigotes of Trypanosoma brucei was studied using the potentiometric
      fluorescent dye bisoxonol. Our results suggest that a proton pump plays a
      significant role in the regulation of deltapsi in procyclic and bloodstream
      forms, as evidenced by depolarization of the plasma membrane by H(+)-ATPase
      inhibitors (e.g. dicyclohexylcarbo-diimide, N-ethylmaleimide, diethylstilbestrol,
      and bafilomycin A1). In bloodstream stages the plasma membrane was significantly
      depolarized by ouabain only when the cells were incubated in sodium-rich buffers
      indicating that a sodium pump was being inhibited. In contrast, ouabain had no
      effect on the deltapsi of the procyclic stages in a sodium-rich buffer. However,
      it induced an additional significant depolarization in these stages when their
      plasma membrane was already partially depolarized by the H(+)-ATPase inhibitor
      dicyclohexylcarbo-diimide, indicating the presence of an ouabain-sensitive sodium
      pump whose activity is masked by the H(+)-ATPase. Unlike procyclic forms, the
      deltapsi of bloodstream-stage trypomastigotes was markedly sensitive to
      extracellular Na+ and K+ concentrations. Thus, there are significant differences
      between procyclic and bloodstream forms in the maintenance of the deltapsi and in
      their permeability to cations.

PMID- 12425530
TI  - Development of an in vitro clonal culture and characterization of the rRNA gene
      cluster of Perkinsus atlanticus, a protistan parasite of the clam Tapes
      decussatus.
AB  - Perkinsus atlanticus cultures were established either with trophozoites isolated
      from fresh gills, with hypnospores isolated from tissues incubated in fluid
      thioglycollate medium, or directly from infected hemocytes of carpet shell clams
      Tapes decussatus from Algarve (Southern Portugal), using a culture medium and
      conditions optimized for Perkinsus marinus. Perkinsus atlanticus isolates were
      cloned by limiting dilution, and their identity unequivocally established by PCR
      based species-specific diagnostic assays, and by sequencing the complete rRNA
      gene cluster. The rRNA gene cluster is 7.5-kb in length including 5S, IGS, SSU,
      ITS1, 5.8S, ITS2, LSU, and an inter-cluster spacer. rDNA sequences of the P.
      atlanticus clone were between 98.3-100% identical to P. atlanticus sequences
      previously obtained from clam tissue (non-clonal) isolates. Based on the IGS
      sequences available from Perkinsus species, a set of primers was designed to
      amplify P. atlanticus and the two clonally cultured Perkinsus species (P. marinus
      and P. andrewsi) currently available from a recognized repository. This Perkinsus
      "genus-specific" PCR-based assay complements the species-specific assays
      developed earlier and strengthen the detection of Perkinsus species for which
      specific detection assays are not yet available.

PMID- 12425531
TI  - Description of a new marine species of Askenasia Blochmann, 1895 (Ciliophora,
      Haptoria), with notes on its ecology.
AB  - A marine planktonic ciliate, belonging to the genus Askenasia Blochmann, 1895, is
      described with notes on its distribution and ecology. Specimens of this new
      species were collected from four coastal sites across the northern hemisphere.
      Samples were collected between March and December, from depths of 1-20 m.
      Relatively low (< 1 ml(-1)) densities were recorded from Atlantic and Pacific
      Oceans and North Sea coastal sites, whereas samples from the English Channel
      suggested that this species has the ability to form blooms. Specimens were
      protargol-stained, revealing the key features of the genus, including the
      diagnostic sub-equatorial kinety belt consisting of three unciliated
      monokinetids. However, the species is larger than other Askenasia with a single
      distinctive, rope-like, scalloped macronucleus. This species also appears to have
      an extra somatic kinety belt, which may be present but has not been observed in
      other Askenasia species. Based on size, kinety structure, kinety number, and
      macronuclear shape a new species has been established.

PMID- 12425532
TI  - Phytate as the sole phosphate source for growth of Tetrahymena.
AB  - Phytate, the storage form of phosphate in seeds and grains, is a major form of
      environmental phosphate loading from fertilizer inputs and agricultural runoff.
      We have investigated the ability of Tetrahymena populations to grow on phytate as
      their sole phosphate source. Populations grew equally well in chemically defined
      medium with phosphate and medium in which the phosphate was replaced with phytate
      in comparable concentrations between 0.5 mM and 6 mM. Intracellular phytate
      concentrations of cells grown in phytate showed a 4-6-fold increase over those
      grown in phosphate when measured during the late stage of exponential growth.
      These results demonstrate that phytate can provide a source of adequate phosphate
      for sustained growth in phytate-rich environments.

PMID- 12425533
TI  - The wax and wane of intestinal autointoxication and visceroptosis--historical
      trends of real versus apparent new digestive diseases.

PMID- 12425534
TI  - What are really the true late complications of endoscopic biliary sphincterotomy?

PMID- 12425535
TI  - Fine needle aspiration of pancreatic masses: the clinical impact.

PMID- 12425536
TI  - Anti-tissue transglutaminase antibody as the first line screening for celiac
      disease: good-bye antigliadin tests?

PMID- 12425537
TI  - Funding, disease area, and internal validity of hepatobiliary randomized clinical
      trials.
AB  - OBJECTIVE: The aim of this study was to assess whether funding and the disease
      area are related to the internal validity of hepatobiliary randomized clinical
      trials. METHODS: We gathered data on funding, disease area, methodological
      quality (randomization and double blinding), and sample size from 616
      hepatobiliary randomized clinical trials published from 1985 to 1996 in 12
      MEDLINE indexed journals. RESULTS: The internal validity (methodological quality
      and sample size) of trials funded by profit or nonprofit organizations was not
      significantly different. Compared with these trials, trials without funding were
      significantly less likely to report adequate generation of the allocation
      sequence (55% vs 41%, p = 0.001) and to be double blind (42% vs 25%, p < 0.001),
      but the proportion with adequate allocation concealment and the sample size were
      not significantly different. The trials covered 12 disease areas. The proportion
      of funded trials did not differ significantly in different disease areas. The
      disease area was significantly associated with the proportion of trials with
      adequate generation of the allocation sequence (p < 0.001), allocation
      concealment (p = 0.003), and double blinding (p < 0.001) as well as the sample
      size (p < 0.001). This association was not explained by the proportion of trials
      with funding. CONCLUSIONS: External funding was significantly associated with
      adequate methodological quality, but not with the sample size. Irrespective of
      funding, the disease area was significantly associated with the methodological
      quality and sample size. Accordingly, external funding and the disease area are
      significant predictors of the internal validity of hepatobiliary randomized
      clinical trials.

PMID- 12425538
TI  - Nonalcoholic steatohepatitis: what we know in the new millennium.
AB  - Nonalcoholic steatohepatitis (NASH) is a liver disease characterized by diffuse
      fatty infiltration and inflammation. The exact prevalence of NASH is unclear, but
      it is becoming more evident that the disease is much more common than previously
      thought. Although generally a benign, indolent process, it can progress to
      advanced liver disease in approximately 15-20% of patients. Clinical
      characteristics associated with NASH include obesity, hyperlipidemia, diabetes
      mellitus, and hypertension, all of which have been associated with underlying
      insulin resistance. Typically, this disease becomes evident in the fourth or
      fifth decade of life with an equal sex predilection. NASH is thought to be
      caused, in part, by impaired insulin signaling, leading to elevated circulating
      insulin levels and subsequent altered lipid homeostasis. This process is likely
      multifactorial and includes both genetic and environmental factors. Treatment
      options to date are limited and are based on very small clinical trials. Current
      investigations are focusing on improving the underlying insulin resistance that
      has been associated with NASH as well as other therapies that decrease oxidative
      stress or improve hepatocyte survival.

PMID- 12425539
TI  - Autosomal dominant infantile gastroesophageal reflux disease: exclusion of a
      13q14 locus in five well characterized families.
AB  - OBJECTIVES: A genetic locus for pediatric reflux was proposed on chromosome
      13q14, but is unconfirmed in independent kindreds. We sought to test this locus
      in families with multiple affected infants from our database of well
      characterized infants with reflux. METHODS: We screened the database for families
      with multiple affected infants. Affected proband phenotype required histological
      esophagitis; affected sibling/cousin phenotype required a threshold score on a
      diagnostic questionnaire. Screened families were reduced to five based on
      pedigree, consent, and phenotypic clarity. Linkage of the phenotype with the four
      previously reported markers (D13S218, D13S1288, D13S1253, and D13S263) was
      tested, using an autosomal dominant, 70% penetrance model. Linkage required
      logarithm-of-odds score > or = 3. RESULTS: Of 54 individuals in the five
      probands' generation, 21 (39%) were affected based on questionnaire, of whom
      nearly one half also had histological confirmation of esophagitis. Linkage to the
      defined region was excluded for the five families by two-point LOD scores (-1.47
      at D13S218, -1.32 at D13S1288, -3.43 at D13S1253, and -3.92 at D13S263) and by
      multipoint (multipoint LOD scores less than -2 between D13S218 and D13S263)
      linkage analysis. No family demonstrated even suggestive positive linkage (i.e.,
      LOD score >1). CONCLUSIONS: In five rigorously phenotyped families with autosomal
      dominant pattern infantile reflux, we excluded genetic linkage to the region of
      13ql4 previously identified responsible for an autosomal dominant form of
      pediatric reflux. These results suggest genetic heterogeneity, possibly related
      to phenotypic heterogeneity, in familial pediatric gastroesophageal reflux
      disease.

PMID- 12425540
TI  - Dysphagia: a cost analysis of the diagnostic approach.
AB  - OBJECTIVES: The initial diagnostic approach for dysphagia is controversial. The
      choices include barium swallow (BaS) versus esophagogastroduodenoscopy (EGD). The
      aim of this study was to determine the clinical cost of establishing a diagnosis
      and treating dysphagia based on initial diagnostic approach (BaS vs EGD).
      METHODS: Clinical outcome of patients with undiagnosed dysphagia evaluated by
      either internists in a primary care clinic (n = 100) or gastroenterologists (n =
      120) were determined based on the initial diagnostic test: BaS versus EGD. Final
      diagnoses in each group were determined based on any testing performed subsequent
      to the initial studies. Total cost in achieving the final diagnosis for each
      group were determined based on 2002 Medicare reimbursement cost. RESULTS: BaS
      (66% and 62%) and EGD (34% and 38%) were ordered in equal prevalence by
      gastroenterologists and internists, respectively. Final diagnoses included:
      benign obstruction (37% and 36%), gastroesophageal reflux disease (GERD) (18% and
      44%), achalasia (17% and 1%), nonspecific esophageal motility disorder (NSEMD)
      (17% and 11%), neoplasm (7% and 6%), and infectious esophagitis (4% and 2%) in
      subspecialty and primary care clinics, respectively. Motility disorders (NSEMD
      and achalasia) was diagnosed more often by gastroenterologists (40 of 120, 34%)
      than by internists (12 of 100, 12%) (p < 0.001). GERD was the predominant
      diagnosis made by internists (44 of 100, 44%) compared to gastroenterologists (22
      of 120, 18%) (p < 0.001). Although the cost of diagnosing benign obstruction was
      less for BaS ($73 +/- 13) than EGD ($370 +/- 5, p < 0.001), subsequent therapy
      with dilation increased the cost for barium testing first (BaS $602 +/- 22 vs EGD
      $515 +/- 5, p < 0.02). Cost of diagnosis or treatment of esophageal dysmotility
      (achalasia/NSEMD) was significantly (p < 0.001) less using BaS as the initial
      test. CONCLUSIONS: 1) BaS is less costly than EGD for diagnoses and treatment
      involving abnormal motility. 2) Initial EGD with therapeutic intent is less
      costly for patients with history suggesting benign obstruction. 3) Primary care
      physicians identified GERD and benign obstructions as the cause of dysphagia more
      often in their patient group than the gastroenterologists, making EGD a
      reasonable initial test in this setting instead of currently practiced BaS.

PMID- 12425541
TI  - Dyspeptic symptoms and gastric emptying in the irritable bowel syndrome.
AB  - OBJECTIVES: Irritable bowel syndrome (IBS) and dyspepsia often overlap. Delayed
      gastric emptying has been reported in IBS patients, although conflicting results
      exist. Whether overlapping dyspepsia correlates with gastric emptying
      abnormalities in IBS patients has not been clarified. This study aimed to
      evaluate gastric emptying of solids and its relationship with dyspeptic symptoms
      in IBS patients. METHODS: A total of 146 IBS outpatients seen in a referral
      center were evaluated for dyspeptic symptoms using a validated questionnaire.
      Gastric emptying of solids was evaluated scintigraphically in all patients and in
      50 healthy controls. RESULTS: Overlapping dyspepsia was diagnosed in 96 (66%) IBS
      patients. On average, gastric emptying rates were lower in IBS patients (mean +/-
      SEM, 33% +/- 1%/h) compared with controls (40% +/- 2%/h; p < 0.01). Specifically,
      gastric emptying was delayed in IBS patients with overlapping dyspepsia (31% +/-
      1%/h; p < 0.01), whereas IBS patients without dyspeptic complaints showed gastric
      emptying rates (37% +/- 2%/h) that were similar to those of healthy controls (40%
      +/- 2%/h). Relevant postprandial fullness (OR = 4.7, 95% CI = 1.8-12.5) and
      relevant nausea (OR = 3.3, 95% CI 1.2-9.3) were independently associated with
      delayed gastric emptying. CONCLUSIONS: IBS patients without overlapping dyspepsia
      have normal gastric emptying of solids. A significant association exists in IBS
      patients between delayed gastric emptying and overlapping relevant postprandial
      fullness and nausea.

PMID- 12425542
TI  - Effect of different probiotic preparations on anti-helicobacter pylori therapy
      related side effects: a parallel group, triple blind, placebo-controlled study.
AB  - OBJECTIVES: Several studies show that probiotics may prevent side effects during
      therapy against Helicobacter pylori (H. pylori). Other reports indicate
      competitive interaction between some probiotics and H. pylori. We compared
      efficacy of two different probiotics and one probiotic combination with placebo
      for preventing anti-H. pylori therapy-related side effects and for improving the
      eradication rate. METHODS: A total of 85 H. pylori positive, asymptomatic
      patients were randomized in four groups to receive probiotic or placebo both
      during and for 7 days after a 1-wk triple therapy scheme (rabeprazole 20 mg
      b.id., clarithromycin 500 mg b.i.d., and tinidazole 500 mg b.i.d.). Group I (n =
      21) received Lactobacillus GG; group II (n = 22), Saccharomyces boulardii; group
      III (n = 21), a combination of Lactobacillus spp. and biphidobacteria; and group
      IV (n = 21), placebo. Subjects filled in weekly symptom questionnaires for 4 wk.
      Blinded investigators collected and analyzed data. H. pylori status was rechecked
      after 5-7 wk. RESULTS: Side effects occurred mainly during the eradication week.
      None of them caused therapy discontinuation. In all probiotic-supplemented
      groups, there was a significantly lower incidence of diarrhea and taste
      disturbance during the eradication week with respect to the placebo group.
      Overall assessment of tolerability was significantly better in the actively
      treated patients than in the placebo group. No differences in the incidence of
      side effects between the probiotic groups were observed. The H. pylori
      eradication rate was almost identical between the probiotic and placebo groups.
      CONCLUSIONS: All the probiotics used were superior to placebo for side effect
      prevention, but were not associated with better compliance with antibiotic
      therapy. The effect of probiotic supplementation on side effects during anti-H.
      pylori regimens seemed to be independent of the probiotic species used.

PMID- 12425543
TI  - Inverse relationship between alcohol consumption and active Helicobacter pylori
      infection: the Bristol Helicobacter project.
AB  - OBJECTIVE: The aim of this study was to examine whether smoking or consumption of
      alcohol or coffee is associated with active Helicobacter pylori (H. pylori)
      infection. METHODS: This was a cross-sectional population study conducted as part
      of a randomized controlled trial of H. pylori infection eradication in southwest
      England. A total of 10,537 subjects, recruited from seven general practices,
      underwent 13C-urea breath testing for active infection with H. pylori and
      provided data on smoking, usual weekly consumption of alcohol, and daily intake
      of coffee. RESULTS: Smoking or coffee consumption were not related to active H.
      pylori infection. Total alcohol consumption was associated with a small, but not
      statistically significant, decrease in the odds of infection. After adjustment
      for age, sex, ethnic status, childhood and adult social class, smoking, coffee
      consumption, and intake of alcoholic beverages other than wine, subjects drinking
      3-6 units of wine/wk had an 11% lower risk of H. pylori infection compared with
      those who took no wine: OR = 0.89, 95% CI = 0.80-0.99. Higher wine consumption
      was associated with a further 6% reduction in the risk of infection: OR = 0.83,
      95% CI = 0.64-1.07. Intake of 3-6 units of beer (but no greater intake) was
      associated with a similar reduction in the risk of infection when compared to no
      beer intake (OR = 0.83, 95% CI = 0.75-0.91). CONCLUSIONS: This study indicates
      that modest consumption of wine and beer (approximately 7 units/wk) protects
      against H. pylori infection, presumably by facilitating eradication of the
      organism.

PMID- 12425544
TI  - Helicobacter pylori antigen stool test and 13C-urea breath test in patients after
      eradication treatments.
AB  - OBJECTIVES: Current guidelines recommend either the urea breath test (UBT) or the
      Helicobacter pylori antigen stool test (HpSA) for monitoring H. pylori infection.
      The aim of this study was to evaluate the agreement between the two tests in
      patients after treatment. METHODS: After eradication treatments, patients were
      tested with both UBT and HpSA. Cut-off values (delta value over baseline at 30')
      for UBT were positive (> or = 5 per thousand), indeterminate (3.01-4.99 per
      thousand), and negative (< or = 3 per thousand). Cut-off values (absorbance at
      450 nm) for HpSA test were positive (> or = 0.160), indeterminate (0.159-0.140),
      and negative (< 0.140). Patients with either discordant or indeterminate tests
      underwent repeat endoscopy with multiple gastric biopsies for rapid urease test
      (RUT), culture, histology, and immunohistochemistry to detect H. pylori and to
      assess the ratio between coccoid and bacillary forms. RESULTS: A total of 458
      patients were studied. Of these, 422 (92.2%) had concordant tests, three (0.6%)
      indeterminate tests (one on UBT and two on HpSA), and 33 (7.2%) discordant tests.
      A total of 28 patients (25 with discordant and three with indeterminate tests)
      underwent endoscopy. The HpSA was inaccurate in 24 cases (18 false negative, four
      false positive, and two indeterminate results), whereas the UBT was inaccurate in
      four cases (two false positive, one false negative, and one indeterminate
      results). Biopsy-based tests showed no bacillary or coccoid forms in all five
      endoscoped patients who were negative on UBT and positive on HpSA, but in one in
      whom the ratio between coccoid and bacillary forms was 3:1 in the antrum and
      corpus. CONCLUSIONS: UBT and HpSA test give discordant or indeterminate results
      in nearly 8% of patients after treatment. The HpSA test is less accurate than the
      UBT. Coccoid forms do not cause false positive HpSA results.

PMID- 12425545
TI  - Risk factors predictive of late complications after endoscopic sphincterotomy for
      bile duct stones: long-term (more than 10 years) follow-up study.
AB  - OBJECTIVE: Widespread use of laparoscopic cholecystectomy has extended the
      indications for endoscopic sphincterotomy (ES) to young patients with
      choledocholithiasis; however, long-term results of ES and risk factors for late
      complications are largely unknown. METHODS: Between 1977 and 1990, 145 patients
      aged 60 yr or younger underwent ES for choledocholithiasis. Long-term outcomes of
      ES were investigated in the year 2000, and prognostic factors for late
      complications were multivariately analyzed. RESULTS: Long-term information was
      available in 135 cases (93.1%), with a median overall follow-up duration of 14.5
      yr (range, 6.5-22.3 yr). There were neither biliary malignancies nor deaths
      attributable to biliary disease. Sixteen patients (11.9%) developed late
      complications, including choledochal complications (stone recurrence and/or
      cholangitis; 14 patients) and acute cholecystitis (two of 32 patients with the
      gallbladder in situ). Multivariate analysis identified two independent risk
      factors for choledochal complications: bile duct diameter > or = 15 mm and brown
      pigment stones at the initial ES. Choledochal complications were endoscopically
      manageable. All recurrent stones were brown pigment stones. CONCLUSIONS:
      Approximately 12% of patients develop late complications after ES, but
      retreatment with ERCP is effective. ES is a reasonable alternative even in young
      patients with choledocholithiasis. Careful follow-up is necessary, however,
      particularly for patients with a dilated bile duct or brown pigment stones.

PMID- 12425546
TI  - Comparison of endoscopic ultrasound-guided fine needle aspiration for focal
      pancreatic lesions in patients with normal parenchyma and chronic pancreatitis.
AB  - OBJECTIVES: The clinical value of endoscopic ultrasound-guided fine needle
      aspiration (EUS-FNA) of pancreatic lesions is uncertain in patients with normal
      parenchyma and chronic pancreatitis. The aim of this study was to analyze the
      diagnostic yield and influence of EUS-FNA on the clinical management of patients
      with pancreatic lesions, in the presence (CP) or absence (NP) of chronic
      pancreatitis. METHODS: A total of 207 consecutive patients with NP (n = 133) and
      CP (n = 74) were examined using linear array echo endoscopes for the procedure
      and 22-gauge needles. RESULTS: Adequate specimens were obtained from 200 lesions.
      A correct final diagnosis was established at histology (n = 108), bacteriology (n
      = 9), and clinical follow-up (n = 83). Cytology gave 17 false-negative EUS-FNA
      results (overall sensitivity: 85%). In patients with NP, 60 solid adenocarcinomas
      were detected, 32 other malignancies, and 38 benign lesions, with 11 false
      negative results (sensitivity: 89%). In patients with CP, only seven of 13
      malignancies (all solid adenocarcinomas) were identified using FNA (sensitivity:
      54%). Overall, malignancy was identified in 116 patients, 32 of whom (27%) had
      lesions other than primary solid adenocarcinomas. Management was altered in 25 of
      these patients, which changed the surgical approach in 21%. EUS-FNA influenced
      the therapeutic approach in 44% of the total patient group. CONCLUSIONS: EUS-FNA
      was especially useful in patients with a focal pancreatic lesion with normal
      parenchyma. Its sensitivity in patients with CP was unacceptably low, and
      resection of the tumor using standard surgical techniques was still usually
      required to confirm the correct diagnosis. Diagnostic EUS-FNA influenced clinical
      management in nearly half of patients.

PMID- 12425547
TI  - Initial experience of wireless-capsule endoscopy for evaluating occult
      gastrointestinal bleeding and suspected small bowel pathology.
AB  - OBJECTIVE: Small bowel pathology can be diagnosed using enteroscopy (which has
      limitations) and by x-ray (which is not sensitive for flat lesions). For the
      first time ever, we used a new technique, wireless-capsule video endoscopy, to
      diagnose small bowel pathology. Our aim was to prove the effectiveness and safety
      of this technology. METHODS: We used the Given (M2A) system in 35 patients, aged
      18-80 yr, who suffered from unexplained GI bleeding or in whom there was a
      clinical suspicion of small bowel disease. All patients had a small bowel x-ray.
      Patients with suspected narrowing of the bowel or a clinical suspicion of
      intestinal obstruction, or with a history of major abdominal surgery, were
      excluded from the study. No pregnant women or patients with diabetes mellitus
      were included. RESULTS: Abnormal findings were found in 29 of 35 (82.9%)
      patients. Twenty-two of 29 (75.9%) patients had significant pathological findings
      explaining their clinical situation. Diagnostic yield was therefore 62.9% (22 of
      35 patients). Among the various findings, the capsule detected ulcers, erosions,
      angiodysplasia, and submucosal lesions. The source of bleeding was found in 15 of
      20 patients with iron deficiency anemia. There were no immediate significant side
      effects and none reported up to 1 month after ingestion of the capsule. The
      capsule was evacuated by all patients. CONCLUSIONS: The wireless-capsule video
      endoscope, in our study of feasibility, was proven to be a safe, painless,
      ambulatory, and effective procedure, with a high diagnostic yield. Its major
      importance is in diagnosing small bowel pathology where all other imaging
      techniques have failed.

PMID- 12425548
TI  - Reflectance spectrophotometry in the gastrointestinal tract: limitations and new
      applications.
AB  - OBJECTIVES: Reflectance spectrophotometry (RS) assesses blood flow changes by
      measuring an index of Hb concentration (IHB) and index of Hb oxygen saturation
      (ISO2). We tested the following hypotheses: 1) endoscopic RS measurements
      obtained by two observers and with the aid of fiber optic and video endoscopes
      are similar, and 2) the method is suitable for documenting mesenteric
      venoconstriction associated with systemic hypoxia and blood flow autoregulation
      associated with hemorrhagic hypotension. METHODS: Study 1: two investigators
      obtained baseline gastric mucosal RS measurements in anesthetized rats (n = 3)
      before and after stepwise reduction of blood pressure induced by arterial
      hemorrhage. Study 2: subjects were examined by both fiber optic and video
      endoscopes. Endoscopic RS measurements were obtained at 20 cm from the anal
      verge. Study 3: video endoscope was used to obtain RS measurements in oxygen
      dependent patients on and off oxygen treatment. Study 4: the procedures in study
      1 were repeated in five additional rats by one of the investigators. RESULTS:
      Study 1: there was good agreement between the measurements of IHB and ISO2
      between the two investigators. Study 2: video endoscope-assisted measurements
      were consistently lower. Study 3: cessation of oxygen treatment produced a
      significant drop in oxygen saturation (pulse oximetry), decline in ISO2, and rise
      in IHB. Study 4: when blood pressure varied between 90% and 40% of baseline,
      gastric mucosal blood flow (IHB) was maintained at approximately 70% of baseline
      level. CONCLUSIONS: We confirmed that reproducible measurement can be obtained by
      different investigators using standardized techniques. Standardization of
      endoscopic equipment is also necessary to overcome the significant limitation of
      endoscopic equipment on RS measurements. RS measurements can document mesenteric
      venoconstriction associated with systemic hypoxia and blood flow autoregulation
      associated with hemorrhagic hypotension.

PMID- 12425549
TI  - Value of a screening algorithm for celiac disease using tissue transglutaminase
      antibodies as first level in a population-based study.
AB  - OBJECTIVE: Serological screening for celiac disease (CD) can detect a large
      number of otherwise undiagnosed patients based on the sequential evaluation of
      serological tests and intestinal biopsy. The aim of this study was to compare the
      screening value for CD of two different protocols for the same community-based
      population. METHODS: We screened 1,000 consecutive subjects (497 women, age range
      16-71 yr) attending a centralized laboratory for obligatory prenuptial blood
      tests. Serum samples obtained from all subjects were processed using two
      different protocols: I) a three-level classic screening consisting of the
      parallel use of IgG and IgA antigliadin antibodies as first level, followed by
      endomysial antibodies and total serum IgA for positive patients, and finally,
      intestinal biopsy of positive patients; and 2) a study screening protocol
      consisting of the parallel use of a commercial guinea pig antitissue
      transglutaminase antibody and total serum IgA as first line, endomysial
      antibodies (type IgA and/or IgG) for positive patients, and finally, intestinal
      biopsy. RESULTS: The classic screening protocol identified five subjects who were
      eligible for intestinal biopsy, which confirmed the presence of CD in all
      (prevalence 5.0 x 1,000, 95% CI = 1.6-11.6). Using the study algorithm, we
      detected seven new patients including the five patients detected by the first
      protocol (prevalence 7.0 x 1,000, 95% CI = 2.8-14.4). The two additional patients
      diagnosed using the proposed algorithm had positive IgG antigliadin antibodies
      and normal total serum IgA and were not detected by the classic protocol. Both
      patients were endomysial antibodies positive. The comparative analysis showed
      that the classic approach was more expensive (U.S. $4,687 per new patient
      detected) compared with the proposed study algorithm (U.S. $3,006). CONCLUSIONS:
      Our data showed that a new screening protocol using antitissue transglutaminase
      as first line followed by endomysial antibodies is a cost-effective screening and
      yielded more realistic figures of prevalence for CD in a community setting than
      the classic three-level sequential evaluation using antigliadin antibodies.

PMID- 12425550
TI  - Enhanced preattentive central nervous system reactivity in irritable bowel
      syndrome.
AB  - OBJECTIVE: Irritable bowel syndrome (IBS) is a common functional disorder
      characterized by enhanced perceptual sensitivity and hypervigilance toward
      afferent signals from the viscera. We hypothesize that the increased
      responsiveness of IBS patients is a generalized phenomenon applying to stimuli
      other than visceral and attempt to demonstrate increased responsiveness to sounds
      as measured by the P1 scalp potential. METHODS: Event-related potentials were
      recorded from IBS patients and control subjects in an auditory task requiring
      detection of rare pitch targets in a designated ear. Visual words served as
      targets in an additional block. RESULTS: Compared to control subjects, IBS
      patients displayed a robust increase in the amplitude of the P1 scalp potential
      elicited by both attended and unattended sounds. CONCLUSIONS: Enhanced P1
      indicates preattentive central nervous system dishabituation in response to
      repeated sounds. A generalized preattentive increase in central nervous system
      reactivity may be a feature that IBS shares with several anxiety disorders that
      frequently co-occur in these patients.

PMID- 12425551
TI  - Short duration exercise increases breath hydrogen excretion after lactulose
      ingestion: description of a new phenomenon.
AB  - OBJECTIVE: There is limited information on the effect of exercise on colonic
      function. Beneficial effects have been described, including prevention of colon
      cancer. In the present study, we demonstrate that short duration exercise results
      in enhancement of breath hydrogen excretion after consumption of lactulose.
      METHODS: Twelve normal volunteers who performed regular exercise were recruited.
      Each study subject underwent four study sessions (two resting and two exercise)
      after consumption of 10 g of crystalline lactulose. Colonic hydrogen production
      was measured in mid-expiratory breath samples obtained at baseline and frequent
      intervals to 420 min. Exercise sessions consisted of 5 min on a treadmill at a
      20% incline at 10 km/h. This was performed 180 min after lactulose ingestion in
      the two exercise sessions. RESULTS: A characteristic pattern in the hydrogen
      concentration versus time curves was seen after exercises, consisting of an
      initial decrease then an increase in concentration above baseline for up to 3 h.
      Mean area under the curve from 0 to 420 min for resting studies was 5,156 +/-
      2,621 ppm/min and was 7,051 +/- 2,447 ppm/min for exercise studies, p < 0.05 (37%
      increase). Mean area under the curve from 180 to 420 min was 2,808 +/- 1,592
      ppm/min for resting studies and 4,543 +/- 1,729 for exercise studies, p < 0.005
      (62% increase). CONCLUSION: This study demonstrates that exercise potentially
      enhances the metabolism of lactulose by colonic bacteria. The authors postulate
      that this effect is due to stirring of the colonic contents. The described
      phenomenon may explain, in part, the beneficial effects of exercise on colonic
      mucosa.

PMID- 12425552
TI  - Utility of the Rome I and Rome II criteria for irritable bowel syndrome in U.S.
      women.
AB  - OBJECTIVES: Using interview data from a large, community-based sample of American
      women, we assessed the lifetime prevalence of irritable bowel syndrome (IBS)
      using questions consistent with the Rome II criteria, determined the sensitivity
      of Rome I and II in women diagnosed with IBS by their community physician, and
      identified whether there are differences in the patients identified by Rome I
      versus II. METHODS: A geographically diverse national probability sample of women
      diagnosed with IBS was identified and interviewed by telephone screening of a
      national, random digit dialing sample of households. A parallel national survey
      of adult females was conducted to determine the lifetime prevalence of IBS in
      U.S. women. Screening and interviews were conducted by experienced, female
      interviewers. IBS was defined by variations on the Rome I/II criteria. RESULTS:
      In the national community sample, lifetime IBS prevalence was 5.4% using Rome II.
      Full interviews were completed in 1,014 IBS patients. In the IBS sample, Rome I
      was significantly more sensitive than Rome II (84% vs 49%, p < 0.001). There was
      47% agreement between Rome I and II. Of patients with IBS by Rome I, 58% met Rome
      II. Only 17.7% did not meet either Rome I or II. CONCLUSIONS: Rome I was more
      sensitive than Rome II in this community sample of female IBS patients. Rome I/II
      do not necessarily identify the same IBS patients. These findings have important
      implications for clinical research in IBS patients and raise questions about
      whether the Rome II criteria are sensitive enough to be useful in clinical
      practice.

PMID- 12425553
TI  - The utility of diagnostic tests in irritable bowel syndrome patients: a
      systematic review.
AB  - OBJECTIVE: The aim of this study was to determine the pretest probability of
      organic GI disease and the accuracy of diagnostic tests for organic GI disease in
      patients who meet symptom-based criteria for irritable bowel syndrome (IBS).
      METHODS: After a comprehensive literature search for studies examining the
      accuracy of diagnostic tests for organic GI disease among patients who meet
      symptom-based criteria for IBS, two independent observers qualitatively assessed
      the methodology of selected studies and extracted data. Data on the pretest
      probability of organic GI disease in this population and the accuracy of
      currently recommended diagnostic tests were converted to descriptive tables.
      RESULTS: Among patients meeting symptom-based criteria for IBS, the pretest
      probability of inflammatory bowel disease, colorectal cancer, or infectious
      diarrhea is less than 1%. Currently recommended diagnostic tests rarely identify
      organic GI disease in patients fulfilling symptom-based criteria for IBS.
      However, the pretest probability of celiac disease in patients meeting symptom
      based criteria for IBS was 10 times higher than the prevalence of celiac disease
      in the general population. CONCLUSIONS: There is insufficient evidence to
      recommend the routine performance of a standardized battery of diagnostic tests
      in patients who meet symptom-based criteria for IBS. Based upon the increased
      pretest probability of celiac disease, routine performance of serological tests
      for celiac disease may be useful in this patient population, though additional
      study is needed in this area.

PMID- 12425554
TI  - Cytokine profile in colonic mucosa of ulcerative colitis correlates with disease
      activity and response to granulocytapheresis.
AB  - OBJECTIVE: The aim of this study was to clarify the correlation between cytokine
      profile in colonic mucosa with disease activity and response to
      granulocytapheresis (GCAP) in patients with ulcerative colitis (UC), using a
      reliable, reproducible quantitative method. METHODS: Colonoscopic biopsies of
      inflamed colonic mucosa (16 patients, 21 cases) and uninflamed colonic mucosa (25
      patients, 33 cases) were obtained from UC patients. Messenger (m)RNA was
      extracted and subjected to realtime polymerase chain reaction for quantitative
      measurement of interleukin (IL)-12, interferon-gamma, tumor necrosis factor
      alpha, IL-4, IL-8, and IL-18 mRNAs. In seven patients with high disease activity
      despite prednisolone (PSL) treatment (> or = 20 mg/day), one course of GCAP was
      conducted, and pre- and post-GCAP cytokine profiles were determined. RESULTS: In
      inflamed colonic mucosa of UC patients, three cytokine profiles were observed: 1)
      high expression of interferon-gamma, tumor necrosis factor-alpha, and IL-4 mRNAs
      but low expression of IL-8 mRNA; 2) high expression of IL-8 mRNA and low
      expression of others; and 3) low expression of all cytokines examined. Inflamed
      colonic mucosa of patients with high disease activity showed the second pattern.
      Inflamed colonic mucosa of patients who were not treated with PSL and who had low
      disease activity showed the first pattern, whereas those on high-dose PSL
      exhibited the second pattern. IL-8 mRNA was significantly higher in inflamed UC
      samples than in uninflamed samples. GCAP was effective in five of seven PSL
      resistant patients (71.4%). IL-8 was the only cytokine that correlated with
      effectiveness of GCAP. Compared with GCAP nonresponders, responders had
      significantly higher IL-8 mRNA before GCAP and showed marked reduction of IL-8
      mRNA after GCAP. CONCLUSIONS: IL-8 mRNA was significantly increased in inflamed
      mucosa of UC. Patients with high IL-8 mRNA expression in colonic mucosa despite
      PSL treatment were responsive to GCAP. Therefore, quantitative measurement of
      mucosal IL-8 mRNA may be useful in predicting the response to GCAP.

PMID- 12425555
TI  - Lymphocytic colitis: clinical features, treatment, and outcomes.
AB  - OBJECTIVE: There are no reports of the clinical features or treatment outcomes in
      large series of patients with lymphocytic colitis, and it is not known whether
      treatments that appear to be beneficial in patients with collagenous colitis are
      also beneficial in lymphocytic colitis. We sought to analyze these issues in our
      patients with lymphocytic colitis. METHODS: All patients with biopsy-proven
      lymphocytic colitis evaluated at our institution between January 1, 1997, and
      December 31, 1999, were identified. Clinical features on presentation and
      treatment outcomes were abstracted from the medical records. RESULTS: A total of
      170 patients with lymphocytic colitis were identified (median age 67 yr, 61%
      female). Diarrhea, bloating, rectal urgency, fecal incontinence, weight loss,
      concomitant autoimmune disorders, and aspirin or nonsteroidal anti-inflammatory
      drug use were common. Loperamide, diphenoxylate/atropine, and bismuth
      subsalicylate were effective therapies and were well tolerated. However, no
      therapy produced a complete response in more than 40% of patients. CONCLUSIONS:
      Lymphocytic colitis typically presents in elderly patients as chronic diarrhea.
      Nocturnal stools, urgency, and abdominal pain occur frequently, as do weight
      loss, fecal incontinence, and concomitant autoimmune disorders. Many empiric
      treatment options are used, but overall response rates are disappointing.
      Randomized controlled trials are needed to determine the optimum therapeutic
      approach to these patients.

PMID- 12425556
TI  - Appendectomy protects against the development of ulcerative colitis but does not
      affect its course.
AB  - OBJECTIVES: Appendectomy has been shown to protect against the development of
      ulcerative colitis. The objective of this study was to examine the effect of
      appendectomy on the clinical features and natural history of colitis. METHODS: A
      total of 259 consecutive adults patients with ulcerative colitis were studied. Of
      the patients, 20 had undergone appendectomy (12 before onset of colitis and eight
      after diagnosis). RESULTS: The frequency of appendectomy was significantly less
      than in a group of 280 controls, which comprised partners of the patients and a
      group from the community (OR = 0.25; 95% CI = 0.14-0.44). This was even more
      significant if only the 12 patients who underwent surgery before the onset of
      colitis were considered (OR = 0.15; 95% CI = 0.07-0.28). Patients with prior
      appendectomy developed symptoms of ulcerative colitis for the first time at a
      significantly later age than those without appendectomy (42.5 +/- 6.5 vs 32.1 +/-
      0.8 yr; p < 0.01) or those who had appendectomy after the onset of colitis (24.6
      +/- 3.4 yr; p < 0.05). Appendectomy did not influence disease extent, need for
      immunosuppressive treatment with azathioprine or 6-mercaptopurine (as a marker of
      resistant disease), or the likelihood of colectomy. Five patients in the
      appendectomy group had clinical evidence of primary sclerosing cholangitis (25%).
      This was more common than in those without appendectomy (8%; OR = 4.09; 95% CI =
      1.04-13.60). CONCLUSIONS: These results indicate that although appendectomy may
      delay onset of colitis, it does not influence its course. However, it is
      associated with the development of primary sclerosing cholangitis. Appendectomy
      is unlikely to be of benefit in established ulcerative colitis.

PMID- 12425557
TI  - Virulence-associated genotypes of Helicobacter pylori: do they explain the
      African enigma?
AB  - OBJECTIVES: The aim of this study was to compare the distribution of virulence
      associated genotypes of Helicobacter pylori in two Colombian populations with
      contrasting gastric cancer risk but with similar H. pylori infection prevalence.
      METHODS: Gastric biopsies were taken from 241 subjects from the high gastric
      cancer risk area of Pasto and from 93 subjects from the low risk area of Tumaco.
      Four gastric biopsies from each patient were fixed in 10% buffered formalin for
      histopathologic analysis, and one was frozen immediately in liquid nitrogen and
      used for genotyping. CagA and vacA genotypes were determined by multiplex
      polymerase chain reaction and reverse hybridization on a line probe assay.
      RESULTS: In patients from the population with high risk for gastric cancer,
      statistically significant higher relative frequencies of cagA positive and vacA
      s1 and ml genotypes were found as compared to the population from the low risk
      area. CONCLUSIONS: Although H. pylori infection has been recognized as a cause of
      gastric cancer in humans, some large populations with high prevalence of
      infection have low gastric cancer rates. This so-called "African enigma" so far
      remains unexplained. Our findings suggest that virulence-associated genes of H.
      pylori may partially explain the African enigma. Other factors, including human
      genetic polymorphisms and diet, are also suspected to play a major role. Further
      investigations are needed to test this hypothesis.

PMID- 12425558
TI  - Effect of steroids on energy expenditure and substrate oxidation in women with
      Crohn's disease.
AB  - OBJECTIVE: Patients with Crohn's disease (CD) have increased energy expenditure
      and fat oxidation. Steroids, commonly used to treat flare-up of CD, induce weight
      gain. This study was designed to evaluate the effects of prednisone and
      budesonide on energy expenditure and substrate oxidation in patients with CD.
      METHODS: Twenty-nine women with CD and 10 healthy controls were studied. Ten
      patients received prednisone (0.75-1.0 mg/kg/day), nine received budesonide (9
      mg/ day), and 10 did not receive steroids. Resting energy expenditure and
      substrate oxidation were measured by indirect calorimetry in a fasting state and
      after a standard diet. RESULTS: In the fasting state, resting energy expenditure
      was higher in patients without steroids than in the controls. Lipid oxidation was
      lower (p < 0.01) in patients with prednisone (0.46 +/- 0.39 mg/kg/min) than in
      patients with budesonide (0.97 +/- 0.28 mg/kg/min) and without steroids (1.06 +/-
      0.32 mg/kg/min), but was similar with control subjects (0.47 +/- 0.20 mg/kg/min).
      Postprandially, lipid oxidation was lower (p < 0.01) in patients with prednisone
      (0.32 +/- 0.23 mg/kg/min) than in patients with budesonide (0.75 +/- 0.20
      mg/kg/min), without steroids (0.82 +/- 0.23 mg/kg/min), and controls (0.58 +/-
      0.15 mg/kg/min). Protein oxidation was significantly higher in patients with
      prednisone than in the other subjects. CONCLUSIONS: In women with CD, prednisone
      decreases lipid oxidation and increases protein oxidation. These effects are not
      observed with budesonide and may contribute to the weight gain and side effects
      commonly observed with prednisone. A low-fat/high-protein diet could be proposed
      during a course of prednisone.

PMID- 12425559
TI  - Tissue transglutaminase antibodies in patients with end-stage heart failure.
AB  - OBJECTIVE: For celiac disease (CD), screening a trend has recently emerged to
      measure tissue transglutaminase antibodies (tTGA) by immunoassays instead of the
      more laborious endomysial antibodies (EmA), as they recognize the same target,
      tissue transglutaminase (tTG). However, a high rate of false-positive results has
      been reported in some patient series with diseases known to be associated with
      CD. Moreover, tTG is a ubiquitous, multifunctional enzyme, overexpressed in
      experimental models of heart failure. Therefore, we assessed the specificity of
      tTGA assays in a large series of EmA-negative patients with end-stage heart
      failure. METHODS: We studied 288 patients with end-stage heart failure and 60
      blood donors. No subject had clinical evidence of CD or IgA deficiency, and all
      were EmA negative. Serum IgA and IgG tTGA were measured by means of commercial
      kits using as substrate, either guinea pig or recombinant human tTG. Blocking
      studies and Western blots were also performed using recombinant human tTG.
      RESULTS: All blood donor sera were IgA tTGA negative. IgA tTGA positivity was
      observed in 47.6% and 49.1% of patients with heart failure using, respectively,
      guinea pig tTG and recombinant human tTG as substrates. Preincubation of positive
      sera with recombinant human tTG resulted in 81% blocking of IgA tTGA in
      immunoassay. Western blot analysis confirmed the presence of antibodies against
      recombinant human tTG. IgA tTGA-positive sera were also IgG tTGA positive.
      CONCLUSIONS: IgA and IgG tTGA occur in a large number of EmA-negative patients
      with end-stage heart failure, and their presence is unlikely to be caused by
      concomitant CD.

PMID- 12425560
TI  - The 1-year and 3-month prognostic utility of the AST/ALT ratio and model for end
      stage liver disease score in patients with viral liver cirrhosis.
AB  - OBJECTIVES: The AST/ALT ratio has shown good diagnostic accuracy in patients with
      chronic viral liver disease. However, its prognostic utility has never been
      tested. Recently, the Model for End-Stage Liver Disease (MELD) has been proposed
      as a simple and effective tool to predict survival in patients with liver
      cirrhosis. The aims of this study were to assess the 3-month and 1-yr prognostic
      ability of the AST/ALT ratio in a series of patients with virus-related liver
      cirrhosis, and to evaluate the relationship between the AST/ALT ratio and the
      MELD score and to compare their prognostic ability. METHODS: The AST/ALT ratios
      and MELD scores of 99 patients with liver cirrhosis of viral etiology (73
      patients with hepatitis C virus and 26 with hepatitis B virus) who had been
      followed-up for at least 1 yr were retrospectively calculated and correlated with
      the patients' 3-month and 1-yr prognosis. Receiver operating characteristic
      curves were used to determine the AST/ALT ratio and the MELD score cut-offs with
      the best sensitivity (SS) and specificity (SP) in discriminating between patients
      who survived and those who died. Univariate survival curves were estimated by the
      Kaplan-Meier method using the cut-offs identified by means of receiver operating
      characteristic curves. RESULTS: AST/ALT ratios and MELD scores showed a
      significant correlation (r(s) = 0.503, p = 0.0001). In all, 8% and 30% of the
      patients had died after 3 months and 1 yr of follow-up, respectively. AST/ALT
      ratios and MELD scores were significantly higher among the patients who died
      during both 3-month and 1-yr follow-up. An AST/ALT ratio cut-off of 1.17 had 87%
      SS and 52% SP, whereas a MELD cut-off of 9 had 57% SS and 74% SP in
      discriminating between patients who survived and those who died after I yr. The
      combined assessment of the AST/ALT ratio and/or MELD score had 90% SS and 78% SP.
      Survival curves of the patients showed that both parameters clearly discriminated
      between patients who survived and those who died in the short term (AST/ALT
      ratio, p = 0.0094; MELD score, p = 0.0089) as well as in the long term (AST/ALT
      ratio, p < 0.0005; MELD score, p = 0.004). CONCLUSIONS: In patients with virus
      related cirrhosis, the AST/ALT ratio has prognostic capability that is not
      significantly different from that of an established prognostic score such as
      MELD. Combined assessment of the two parameters increases the medium-term
      prognostic accuracy.

PMID- 12425561
TI  - Increased expression of T cell chemokines and their receptors in chronic
      hepatitis C: relationship with the histological activity of liver disease.
AB  - OBJECTIVES: Although chemokines seem to be important in certain inflammatory
      disorders, little is known about the role of these proteins in chronic hepatitis
      C. METHODS: Expression of selected CXC and CC chemokines and their receptors was
      assessed by immunohistochemistry and flow cytometry in chronic hepatitis C.
      Tissue samples from normal liver and that of sustained responders were also
      evaluated. A comparative analysis between the histological grading and the
      intrahepatic expression level of chemokines was performed. RESULTS: The majority
      of liver-derived T lymphocytes expressed CXCR3 and CCR5 chemokine receptors,
      representing high enrichment over levels of CXCR3 + and CCR5 + T cells in blood
      from chronic hepatitis C. An intense intrahepatic expression of their respective
      ligands, the CXC chemokine Mig, and RANTES, was detected in the same patients
      studied, being restricted to the sinusoidal endothelium and to hepatocytes,
      respectively. A statistically significant association between the intrahepatic
      chemokine expression level and the inflammatory activity of chronic hepatitis C
      was found. Of note was the marked expression of both CXCR3 and its ligand Mig on
      endothelial cells from portal neovessels in chronic hepatitis C. CONCLUSIONS:
      Intrahepatic chemokine signaling could play a key role regulating significant
      pathological events during chronic hepatitis C, opening new avenues for
      therapeutic interventions based on chemokine activities.

PMID- 12425562
TI  - Functional status of patients with primary biliary cirrhosis.
AB  - OBJECTIVES: Although autoimmune diseases can have a significant impact on the
      quality of life, there has been a relative paucity of data with respect to the
      functional status of patients with primary biliary cirrhosis (PBC). METHODS: We
      conducted a case-control study of 182 patients ("cases") with PBC as well as 225
      age- and sex-matched friend control subjects using a standardized instrument
      obtained from the National Health and Nutrition Examination Survey. RESULTS: In
      all, 126 of 182 cases (69%) and 141 of 225 friend controls (62.6%) responded to
      this survey, a response rate comparable to or better than in similar previous
      studies of such instruments. Patients with PBC had a significantly reduced
      functional status score compared to their controls (p < 0.001). Interestingly, a
      lower level of education and the presence of arthritis and hypertension were
      significantly associated with these lower levels of functional capabilities.
      These data were subjected to multivariate analysis and confirmed. Age was not
      associated with impaired functional status in either the patients or controls.
      CONCLUSIONS: Studies of this nature have potential implications for the well
      being and management of patients with PBC, and focus on issues that can be
      addressed to help maintain functional status in this chronic disease.

PMID- 12425563
TI  - Hepatocellular fat accumulation and low serum cholesterol in patients infected
      with HCV-3a.
AB  - OBJECTIVES: The aim of this study was to prospectively investigate the prevalence
      of hepatic steatosis in chronic hepatitis C patients with respect to viral
      genotype, hepatic iron concentration, total body iron, body mass index, and serum
      lipid parameters. Furthermore, the effect of hepatitis C virus (HCV) eradication
      by antiviral therapy on serum cholesterol levels was studied. METHODS:
      Hepatocellular fat and hepatic iron were determined in liver biopsies obtained
      from 137 interferon-naive patients with chronic hepatitis C (100 men, 37 women,
      mean age 40.8 +/- 10.7 yr) enrolled in two prospective clinical trials of
      interferon/ribavirin therapy. Body mass index and fasting cholesterol levels were
      determined at baseline, during, and after therapy. RESULTS: Marked steatosis
      (>20% of fat-containing hepatocytes) was found in 74.5% of patients infected with
      HCV-3a compared with 17.9% in HCV-1 and 21.7% in HCV-4-infected patients (p <
      0.01). Steatosis in HCV-3a-infected patients did not correlate with the body mass
      index, hepatic iron content, ferritin, or transferrin saturation. At baseline,
      serum cholesterol was lower in patients infected with HCV-3a (147 +/- 42 mg/dl; p
      < 0.01) compared with HCV-1 (188 +/- 36) or HCV-4 (172 +/- 35). In contrast to
      HCV-1- or HCV-4-infected patients, serum cholesterol increased in HCV-3a
      virological responders at the end of treatment and 6 months after therapy
      (baseline 146 +/- 38, end of treatment 166 +/- 29, p < 0.05, sustained
      virological response 200 +/- 34, p < 0.01). However, serum cholesterol remained
      unchanged in HCV-3a nonresponders. CONCLUSIONS: Our data suggest that, in
      addition to inducing steatosis, HCV-3a lowers serum cholesterol. This metabolic
      effect is fully reversible after successful HCV-3a eradication. This unique
      property is not shared by other HCV genotypes.

PMID- 12425564
TI  - Effect of hepatitis B and C virus infections on the natural history of
      compensated cirrhosis: a cohort study of 297 patients.
AB  - OBJECTIVES: The aim of this study was to compare the prognosis of patients with
      hepatitis B surface antigen (HBsAg) positive and those with antibody to hepatitis
      C (anti-HCV) positive cirrhosis. METHODS: This was a retrospective cohort study
      of 297 untreated Western European patients with compensated viral cirrhosis
      (Child class A; 161 patients with hepatitis type B and 136 with type C) who were
      followed for a median period of 6.6 yr. RESULTS: At diagnosis, median age was
      lower (48 vs 58 yr, respectively) in HBsAg-positive cirrhotic patients. The
      Kaplan-Meier 5-yr probability of hepatocellular carcinoma (HCC) was 9% and 10% in
      HBsAg and anti-HCV-positive cirrhotic patients, respectively; the corresponding
      figures for decompensation unrelated to HCC were 16% and 28% and for survival
      were 86% and 84%, respectively. After adjustment for clinical and serological
      differences at baseline, the relative risk (95% CI) for HCC, decompensation and
      mortality was 1.53 (CI = 0.81-2.89), 0.59 (CI = 0.37-0.94), and 1.44 (CI = 0.85
      2.46) respectively, in HBsAg-positive patients compared with anti-HCV-positive
      cirrhotic patients. Among HBsAg-positive cirrhotic patients, the relative risk
      for HCC, decompensation, and mortality was 0.89 (CI = 0.30-2.63), 4.05 (CI = 1.09
      15.1), and 5.9 (CI = 1.64-21.3), respectively, in HBV-DNA positive (HBeAg
      positive or negative) compared with HBV-DNA negative (HBeAg negative) patients at
      entry. CONCLUSIONS: Patients with HBV infection may present with cirrhosis about
      10 yr earlier than those with HCV infection. HCV infection tends to be associated
      with a higher risk of decompensation, but these data should take into
      consideration the heterogeneity of HBV-related cirrhosis in terms of viremia
      levels and risk of hepatic failure. Survival shows no significant differences
      according to HBV or HCV etiology in Western European cirrhotic patients.

PMID- 12425565
TI  - Treatment patterns and costs associated with sessile colorectal polyps.
AB  - OBJECTIVES: Because of the paucity of existing literature on treatment and costs
      associated with sessile lesions, the objectives of this study were to perform a
      retrospective analysis on patients with sessile polyps to identify patient and
      polyp characteristics, to determine treatment patterns, and to estimate the cost
      of treating these patients. METHODS: We conducted a retrospective, observational
      cohort study of 280 patients who presented to a large teaching hospital between
      1997 and 2000 with at least one sessile or broad-based pedunculated colorectal
      polyp of any size or histology, not including adenocarcinoma greater than stage
      T1. RESULTS: Mean polyp size was 1.3 cm, and two thirds of polyps were removed in
      a single procedure. The number of repeat procedures increased with polyp size
      (Kendall T-b = 0.47; 95% CI = 0.39-0.55). Patients with polyps > or = 2 cm were
      5.88 times more likely than patients with smaller polyps to undergo a surgical
      procedure. Surgical procedures required 88.01 min longer than nonsurgical
      procedures (95% CI = 74.43-102.42). Mean total cost of treatment was $2,038
      (range $153 to $14,838). Open resection ($6,165) was the most costly surgical
      procedure, and piecemeal polypectomy ($892) was the most costly nonsurgical
      therapeutic procedure. CONCLUSIONS: One third of polyps required more than one
      procedure. Surgical procedures accounted for the majority of resource use in this
      sample. Finally, patients with polyps > or = 2 cm incurred almost half the total
      costs while accounting for only 22% of the sample. The greatest economic gains
      could be made by improving efficiency of polyp removal for these patients.

PMID- 12425566
TI  - Screening for colorectal cancer: the cost to find an advanced adenoma.
AB  - OBJECTIVE: Cancer Care Ontario has recommended a program to screen for colorectal
      cancer using fecal occult blood testing (FOBT). Patients who test positive on
      FOBT will require further investigation. We examined the cost of finding an
      advanced adenoma in these patients using four different strategies. METHODS:
      Using decision analysis software (DATA 3.5, TreeAge Software, Boston, MA), we
      considered four strategies for evaluating patients referred for a positive FOBT:
      1) flexible sigmoidoscopy to the splenic flexure, 2) flexible sigmoidoscopy with
      air contrast barium enema (ACBE), 3) virtual colonoscopy, and 4) colonoscopy. If
      an adenoma was found in any of the first three methods, colonoscopy and
      polypectomy were performed. An advanced adenoma was defined as a villous adenoma,
      tubular adenoma > or = 10 mm, high grade dysplasia, or cancer. Values for
      probabilities, test characteristics and costs ($CDN) were estimated from a
      MEDLINE literature review, local costs, and OHIP fee codes. Patients with
      adenomas identified as well as direct medical costs from a third party payer
      perspective were calculated. RESULTS: Assuming a probability of adenoma of 16.9%,
      the cost for each strategy (compared to no investigation) was as follows:
      flexible sigmoidoscopy to the splenic flexure, $226; flexible sigmoidoscopy with
      ACBE, $424; virtual colonoscopy, $597; and colonoscopy, $387. The cost to clear a
      patient of adenoma(s) was $1,930, $2,840, $3,681, and $2,290, respectively.
      Despite being most cost-effective, the sigmoidoscopy strategy was predicted to
      detect 69% of cases of advanced adenomas. The radiological strategies would be
      less expensive if ACBE cost less than $115 or virtual colonoscopy cost less than
      $291. The colonoscopy strategy was more cost-effective if the probability of an
      adenoma was > or = 33.5%. When the incremental costs were considered to
      investigate 1000 patients, virtual colonoscopy and sigmoidoscopy with ACBE were
      both more costly then colonoscopy, and neither detected as many cases of advanced
      adenomas. CONCLUSION: Improved access to colonoscopy seems to be the preferred
      approach to deal with increased referrals.

PMID- 12425567
TI  - Lansoprazole-associated microscopic colitis: a case series.
AB  - Lansoprazole is a potent proton pump inhibitor that has been well tolerated with
      minimal serious adverse events. One of the most commonly reported side effects is
      diarrhea in 3-8% of study patients. During 1997, approximately 850 veterans at
      our institution had their proton pump inhibitor converted from omeprazole to
      lansoprazole because of a formulary change. A number of patients subsequently
      developed chronic watery diarrhea. While evaluating six of these patients, we
      discovered microscopic colitis that resolved with discontinuation of
      lansoprazole. The diarrhea was described as three to 10 loose, nonbloody bowel
      movements per day with some abdominal cramping. Colonoscopy in five patients and
      flexible sigmoidoscopy in one patient revealed normal colonic mucosa, but random
      biopsies all supported microscopic colitis (five cases of lymphocytic colitis and
      one case of collagenous colitis). Complete symptom resolution occurred in all
      patients within 4 to 10 days of discontinuing lansoprazole. In all patients,
      follow-up biopsies demonstrated normalization of the colonic histology. This is
      the first published case series of patients with microscopic colitis that
      correlated clinically and histologically with the initiation and discontinuation
      of lansoprazole.

PMID- 12425568
TI  - Medicated prunes.

PMID- 12425569
TI  - Peroral pancreatoscopy and intraductal ultrasound for diagnosis of intraductal
      papillary mucinous tumors of the pancreas.

PMID- 12425571
TI  - Can EUS alone differentiate between malignant and benign cystic lesions of the
      pancreas?

PMID- 12425570
TI  - Maintenance infliximab infusions forever?

PMID- 12425572
TI  - Re: Herrlinger et al.--Pulmonary function abnormalities in inflammatory bowel
      disease.

PMID- 12425573
TI  - Re: Kawai et al.--Bacteria are not important in the formation of pure cholesterol
      stones.

PMID- 12425574
TI  - Re: Oxentenko et al.--Endoscopic markers in celiac disease.

PMID- 12425575
TI  - Re: Arguedas et al.--Hepatitis A prevention analysis.

PMID- 12425576
TI  - Intraspousal transmission of hepatitis C virus occurring after 42 years of
      marriage: no relation to HCV RNA titers.

PMID- 12425577
TI  - Helicobacter pylori infection does not affect the serum level of homocysteine.

PMID- 12425578
TI  - Improving screening and vaccination for hepatitis B in patients coinfected with
      HIV and hepatitis C.

PMID- 12425579
TI  - Fulminant Clostridium difficile colitis without diarrhea: lack of emphasis in
      diagnostic guidelines.

PMID- 12425580
TI  - Isolated gastric fundal varices: a challenging issue.

PMID- 12425582
TI  - Re: Gross et al.--Ablation therapy for Barrett's esophagus.

PMID- 12425581
TI  - A new technique for endoscopic resection of large lateral spreading tumors of the
      colon: duel intubation colonoscopy with endoclip-assisted "loop suturing" method.

PMID- 12425584
TI  - The usefulness of magnifying chromoendoscopy: pit pattern diagnosis can predict
      histopathological diagnosis precisely.

PMID- 12425583
TI  - Pantoprazole-induced recurrent anaphylactic shock.

PMID- 12425585
TI  - Evidence-based position statement on the management of irritable bowel syndrome
      in North America.

PMID- 12425586
TI  - Systematic review on the management of irritable bowel syndrome in North America.

PMID- 12425587
TI  - The separation of surface and bulk contributions in ELNES spectra.
AB  - We present a method to separate surface from volume contributions in the fine
      structure of ionization edges in electron energy loss spectrometry (ELNES). It is
      based on spectra taken at two positions with different surface-to-volume ratio.
      Contrary to the similar spatial difference method it uses well defined scaling
      factors, allowing an estimate of the errors propagated into the result.

PMID- 12425588
TI  - Mapping the mesoscale interface structure in polycrystalline materials.
AB  - A new experimental approach to the quantitative characterization of
      polycrystalline microstructure by scanning electron microscopy is described.
      Combining automated electron backscattering diffraction with conventional
      scanning contrast imaging and with calibrated serial sectioning, the new method
      (mesoscale interface mapping system) recovers precision estimates of the 3D
      idealized aggregate function G(x). This function embodies a description of
      lattice phase and orientation (limiting resolution approximately 1 degree) at
      each point x (limiting spatial resolution approximately 100 nm), and, therefore,
      contains a complete mesoscale description of the interfacial network. The
      principal challenges of the method, achieving precise spatial registry between
      adjacent images and adequate distortion correction, are described. A description
      algorithm for control of the various components of the system is also provided.

PMID- 12425589
TI  - A trajectory-based algorithm to determine and refine Euler angles of projections
      in three-dimensional microscopy. Improvements and tests.
AB  - An improvement of the trajectory matching algorithm is presented, which is based
      on the use of the derivative of trajectories and of the projection of
      experimental sinogram lines in the factor space determined by sinogram lines of
      projections of a model. The algorithm performance is illustrated by use of
      different phantom structures, to show the effect of symmetry on trajectory
      matching. A GroEL complex has also been reconstructed from both cryo-negatively
      stained and unstained frozen-hydrated samples. The refinement of this structure
      has been carried out by the trajectory matching algorithm as well as by
      conventional cross-correlation methods. Slight differences among the two results
      are discussed. The improved trajectory matching algorithm, based on chi2
      distances, runs much faster than correlation analysis and looks satisfactory as
      for the quality of the reconstructed structures.

PMID- 12425590
TI  - Direct compositional analysis of AlGaAs/GaAs heterostructures by the reciprocal
      space segmentation of high-resolution micrographs.
AB  - A detailed description of a combined reciprocal and real space technique for the
      mapping of layer compositions across interior interfaces from high-resolution
      electron micrographs is presented. The analysis is based on the reciprocal space
      extraction of chemically sensitive image information encoded in lattice images of
      AlGaAs/GaAs heterostructures taken under optimized imaging conditions. Analysis
      procedures include centering a set of apertures around chemically sensitive
      reflections in the Fourier transform of lattice images and performing an inverse
      transformation, thus extracting composition related information from experimental
      micrographs. It is demonstrated that this approach is characterized by the same
      spatial resolution as real space techniques but by improved capabilities with
      respect to analysing images characterized by a minor signal-to-noise ratio. For
      illustration purposes the stability of AlAs/GaAs multiple quantum wells grown
      under low-temperature conditions against thermal treatment as expressed by
      interfacial roughness parameters is investigated.

PMID- 12425591
TI  - Atomic configuration in core structure of Lomer dislocation in Si0.76Ge0.24/Si.
AB  - The core structure of a Lomer dislocation in SiGe/Si system has been revealed at
      atomic level. This is attained by applying the image deconvolution technique in
      combination with dynamical diffraction effect correction to the high-resolution
      image taken with a 200 kV field-emission gun high-resolution electron microscope.
      The Lomer dislocation has a Hornstra-like core. The contrast of the image
      simulated on the basis of derived atomic configuration is in agreement with that
      of the experimental image.

PMID- 12425592
TI  - Fluctuation microscopy in the STEM.
AB  - Fluctuation electron microscopy is a technique for studying medium-range order in
      disordered materials. We present an implementation of fluctuation microscopy
      using nanodiffraction in a scanning transmission electron microscope (STEM) at a
      spatial resolution varying from 0.8 to 5.0 nm. Compared to conventional TEM
      (CTEM), the STEM-based technique offers a denser scattering vector sampling at a
      reduced sample dose and easier access to variable resolution information. We have
      reproduced results on amorphous silicon previously obtained by CTEM-based
      fluctuation microscopy, and report initial variable-resolution measurements on
      amorphous germanium.

PMID- 12425593
TI  - Moire-like fringes in transmission electron microscopy images of coherently
      strained semiconductor islands.
AB  - Moire-like fringes are observed in transmission electron microscopy images of
      coherently strained semiconductor islands. They are due to the misfit between the
      island and the underlying substrate and they can be used to determine the
      chemical composition of these islands by measuring the fringe spacing of the
      Moire-like system. The results of a simple kinematical analysis are shown to be
      very similar to those of dynamical two-beam calculations. The interest of the
      kinematical analysis is that, contrary to the dynamical two-beam calculations, it
      makes it possible to understand how Moire-like fringes are related to parallel
      Moire fringes and how the fringe spacing is related to the strain field at the
      apex of the island, and then to the mean composition of the island.

PMID- 12425594
TI  - An assay for local quality in cryo-electron micrographs of single particles.
AB  - High quality of the cryo-electron micrographs is of crucial importance for the
      success of single particle three-dimensional reconstruction methods. In analyzing
      some micrographs from cryo-electron microscopy specimens, we found an
      extraordinary variability, within the same micrograph, in the appearance of
      particles. We developed a method for analyzing the variability of local image
      quality, using correspondence analysis of local power spectra. With this
      technique, we discovered a strong systematic variation of the envelope modulating
      an otherwise unchanged contrast transfer function. The underlying causes may be
      uncontrollable effects, such as variations in the thickness of ice, instability
      of the holey carbon, and charging. The method of assaying, resulting in "local
      quality maps", may be useful as a general tool for screening micrographs used as
      input for reconstructions.

PMID- 12425596
TI  - Parallel solid-phase synthesis of disubstituted 1,6-piperazine-2-ones.

PMID- 12425597
TI  - Solid-phase synthesis of tetrahydro-beta-carbolinehydantoins via the N
      acyliminium Pictet-Spengler reaction and cyclative cleavage.

PMID- 12425598
TI  - Solution-phase synthesis of a library of biaryl amides using Girard's reagent T
      as an acid chloride scavenger.

PMID- 12425599
TI  - Evaluation of a two-stage screening procedure in the combinatorial search for
      serine protease-like activity.
AB  - A series of peptidosteroid derivatives containing two independent peptide chains
      in which Ser and His are incorporated were synthesized by solid-phase peptide
      synthesis. The activity of the different compounds in the hydrolysis of the
      activated substrate NF31 was assessed in a stepwise fashion. First, the different
      resin-bound derivatives 6a-l and 6x-z were individually assayed for serine
      esterification in the absence of water. The use of a colored substrate allowed
      for a visual identification of the most active compounds. Through the inclusion
      of control substances, the involvement of histidine in the mechanism for serine
      acylation was shown. Second, the hydrolysis and methanolysis of the different
      acylated derivatives 8a-l and 8x were evaluated using UV spectroscopy, again
      indicating the involvement of histidine. The feasibility of applying the above
      procedures in a combinatorial context was proven via the screening of artificial
      libraries, created by mixing the different resin-bound peptidosteroid compounds.
      In this respect, the use of a photocleavable linker allowed for the unambiguous
      structural characterization of the selected members via application of single
      bead electrospray tandem mass spectrometry.

PMID- 12425600
TI  - Combinatorial electrochemical synthesis and characterization of tungsten-based
      mixed-metal oxides.
AB  - Automated systems for electrochemical synthesis and high-throughput screening of
      photoelectrochemical materials were developed and used to prepare tungsten-based
      mixed-metal oxides, W(n)O(m)M(x) [M = Ni, Co, Cu, Zn, Pt, Ru, Rh, Pd, and Ag],
      specifically for hydrogen production by photoelectrolysis of water. Two
      dimensional arrays (libraries) of diverse metal oxides were synthesized by
      automated cathodic electrodeposition of the oxides on Ti foil substrates.
      Electrolytes for the mixed oxides were prepared from various metal salts added to
      a solution containing tungsten stabilized as a peroxo complex. Electrodeposition
      of the peroxo-stabilized cations gave rise to three distinguishable oxide groups:
      (1) mixed-metal oxides [Ni], (2) metal-doped tungsten oxides [Pt, Ru, Rh, Pd,
      Ag], and (3) metal-metal oxide composites [Co, Cu, Zn]. The oxides typically
      showed n-type semiconducting behavior. Automated measurement of photocurrent
      using a scanning photoelectrochemical cell showed the W-Ni mixed oxide had the
      largest relative zero bias photocurrent, particularly at a low Ni concentration
      (5-10 atomic percent Ni). Pt and Ru were also found to increase the photoactivity
      of bulk tungsten oxide at relatively low concentrations; however, at
      concentrations above 5 atomic percent, crystallization of WO(3) was inhibited and
      photoactivity was diminished. Addition of Co, Cu, and Zn to WO(3) was not found
      to improve the photoelectrochemical activity.

PMID- 12425601
TI  - Split-pool method for synthesis of solid-state material combinatorial libraries.
AB  - The synthesis and analysis of inorganic material combinatorial libraries by the
      split-pool bead method were demonstrated at the proof-of-concept level.
      Millimeter-size spherical beads of porous gamma-alumina, a commonly used support
      material for heterogeneous catalysts, were modified with
      Al(13)O(4)(OH)(24)(H(2)O)(12)(7+) cations in order to promote irreversible
      adsorption of the anionic fluorescent dyes Cascade Blue, Lucifer Yellow, and
      Sulforhodamine 101. The compositions of individual beads were easily determined
      through three split-pool cycles using a conventional fluorescence plate reader.
      Small split-pool material libraries were made by adsorbing noble metal salts
      (H(2)PtCl(6), H(2)IrCl(6), and RhCl(3)) into the beads. Analysis of these beads
      by micro-X-ray fluorescence showed that quantitative adsorption of metal salts
      without cross-contamination of beads could be achieved at levels (0.3 wt % metal
      loading) relevant to heterogeneous catalysis. The method offers the potential for
      synthesis of rather large libraries of inorganic materials through relatively
      simple benchtop split-pool chemistry.

PMID- 12425602
TI  - Use of statistical design of experiments in the optimization of amide synthesis
      utilizing polystyrene-supported N-hydroxybenzotriazole resin.
AB  - Two fields that routinely perform reaction optimization studies are chemical
      development (prior to scale-up) and medicinal or combinatorial chemistry (prior
      to analogue synthesis or library production). To date, the use of statistical
      design of experiments (DoE) in conjunction with automated synthesizers has been
      applied in process research to a greater extent than in the medicinal or
      combinatorial laboratories. We have applied DoE in conjunction with an automated
      synthesizer to optimize the synthesis of amides employing resin-bound N
      hydroxybenzotriazole (PS-HOBt) active esters as intermediates. This methodology
      allowed the rapid development of an improved protocol for the parallel synthesis
      of amides by conversion of carboxylic acids to PS-HOBt esters followed by
      treatment with appropriate amines. Product isolation involved only simple
      filtration and evaporation.

PMID- 12425603
TI  - Solid-supported synthesis of putative peptide beta-turn mimetics via Ugi reaction
      for diketopiperazine formation.
AB  - The scope and limitations of the solid-supported synthesis of a bicyclic
      diketopiperazine, an internal, putative peptide beta-turn mimetic, are presented.
      The 4CC multicomponent Ugi reaction of alpha-N-Boc-diaminopropionic acid resin
      ester (an amine input), optically active alpha-bromoacid, aldehyde, and
      isocyanide is the key step in the proposed synthetic protocol. Application of
      cyclitive cleavage as the final step led to desired products in high purity.

PMID- 12425604
TI  - High-throughput bioassay-guided fractionation: a technique for rapidly assigning
      observed activity to individual components of combinatorial libraries, screened
      in HTS bioassays.
AB  - In this paper, we describe an automated, high-throughput analytical tool for the
      unambiguous characterization of the active component(s) of a combinatorially
      derived reaction mixture. We call this technique high-throughput bioassay-guided
      fractionation (BGF). The novel aspects of this communication are the
      systematization of the BGF concept, the application of BGF to combinatorial
      chemistry, and the high-throughput nature of the identification technique. The
      identification of the active component in a well mixture is an essential step for
      subsequent resynthesis or isolation of the active component(s) or for removal of
      intractable wells from further consideration. We believe the technique described
      is also applicable to any mixture library, provided the expected component (or
      components) of each well is (are) known. Example mixture libraries would include
      collections of synthetic chemicals and collections of purified natural products.
      The mixture need not come from libraries produced using parallel synthesis. The
      BGF tool described herein allows full utilization of highly diverse combinatorial
      libraries, thereby obviating costly up-front purification or extensive
      prescreening characterization efforts.

PMID- 12425605
TI  - Realities of high-throughput liquid chromatography/mass spectrometry purification
      of large combinatorial libraries: a report on overall sample throughput using
      parallel purification.
AB  - We report on the development of a validated, streamlined high-throughput process
      for the purification of parallel-synthesis-derived combinatorial libraries. The
      steps involved in this library purification process include dissolution of dry
      films of crude synthetic material, dual-column LC/MS purification, dual-column
      postpurification analysis, quantitation, reformatting, and submission of pure
      compounds for registration. Although the purification and postpurification
      analysis times decreased essentially linearly as a function of the number of HPLC
      columns employed, it was not possible to decrease the total purification process
      time linearly as a function of the number of columns employed in the system. This
      was due primarily to the fact that numerous steps in the total purification
      process are independent of sample analysis and purification (e.g., evaporation,
      reconstitution, and reformatting, etc.). Additionally, experiments were also
      performed to assess whether separate gradient pumps were necessary for each
      channel of this two-channel LC/MS or if acceptable results could be reliably
      obtained by splitting the flow from one set of gradient pumps between two HPLC
      columns. On the basis of the parallel, two-column LC/MS system employed in this
      work, throughput estimates were extrapolated to more massively parallel systems
      (e.g., four-channel LC/MS).

PMID- 12425606
TI  - Reaction monitoring in LPOS by 19F NMR. Study of soluble polymer supports with
      fluorine in spacer or linker components of supports.
AB  - Various soluble polystyrene supports with fluorinated spacer or linker were
      prepared and studied by (19)F NMR for their use in LPOS reaction monitoring.
      Among three types of systems studied, the perfluoro Wang linker was found to be
      most efficient for this purpose. Substrates could be easily anchored to and
      cleaved from this new support-bound linker. The anchoring of the linker and the
      substrates on the polymer led to significant changes in the fluorine resonances.
      Therefore, the progress of these reactions could be both monitored and
      quantified. On the other hand, the chemical transformations on the anchored
      substrates led only to moderate changes in the fluorine resonances. Nevertheless,
      the reaction progress could also be monitored in this case. After cleavage of
      products, the polymer supports were recovered without loss in loading. Membrane
      separation technology was used to purify some polymer-bound products as well as
      to obtain the polymer-free cleaved product.

PMID- 12425607
TI  - Automated analysis of proton NMR spectra from combinatorial rapid parallel
      synthesis using self-organizing maps.
AB  - It is now quite routine to acquire proton NMR spectra of compounds in 96-well
      plates prepared in a rapid parallel synthesis fashion using a flow-NMR automation
      setup. However, the analysis of 96 NMR spectra obtained in this manner is often
      laborious and painstakingly slow. We have developed a new, automated method for
      rapidly analyzing 96 NMR spectra of compounds synthesized in an 8 x 12 matrix
      using self-organizing maps (SOM). This unsupervised neural network is capable of
      clustering together NMR spectra containing a common pattern of -R groups and
      identifying outliers from within such clusters. Analysis of these outlier spectra
      can quickly help indicate the presence of undesired products, impurities,
      starting materials, and other unexpected errors in a 96-well plate synthesis by
      focusing the chemists' attention on the aberrant NMR spectra. Thus, SOM can be a
      valuable tool in performing efficient quality control on combinatorial libraries.

PMID- 12425608
TI  - Design and parallel solid-phase synthesis of ring-fused 2-pyridinones that target
      pilus biogenesis in pathogenic bacteria.
AB  - A new method for the solid-phase synthesis of enantiomerically enriched highly
      substituted ring-fused 2-pyridinones 13 has been developed. The synthesis
      mediates introduction of substituents at two positions in the 2-pyridinone ring
      in a diverse manner and is suitable for parallel synthesis. (19)F NMR
      spectroscopy was used as a tool to monitor each of the five steps in the reaction
      sequence. The optimized conditions thus obtained were then used to prepare a
      library of 20 2-pyridinones with high yields. The library members were chosen
      from a statistical multivariate design to ensure diversity and reliable data for
      structure-activity relationships. Screening of the library against the bacterial
      periplasmic chaperone PapD was performed using surface plasmon resonance. Three
      new 2-pyridinones with a higher affinity for the chaperone PapD than the previous
      best 13[10,1] were found, and important structural features could be deduced.

PMID- 12425609
TI  - Fast, easy, and efficient method for the purification of phenolic isomers using a
      selective solid-phase scavenging process.
AB  - The need for fast and efficient purification methods that can be easily handled
      and moreover automated is considerably increasing with the new techniques of high
      throughput chemical synthesis. Following our previous work on the use of simple
      polymeric scavengers in fast reactions and purifications of organic substances,
      this article presents the results found during the development of a new method
      for the purification of phenolic substances. The purification method was found to
      be regulated by the interaction of acidic phenol groups with a basic polystyrene
      resin. Furthermore, the scavenging of phenolic isomers proved to be very
      selective for a given isomer. But the most interesting aspect of this method is
      that it is based on a simple contact in situ with the resin and that the
      adsorption/desorption process of the phenol was found to be solvent-dependent.
      The phenols can thus be freed from impurities, or other isomers, by a simple and
      fast contact with the resin in the first solvent, filtration, and washings,
      followed by liberation of the purified phenol by a last soaking in another
      solvent for desorption. The method was successfully applied to the purification
      of a crude reaction mixture issued from the Fries rearrangement of phenyl
      acetate, as well as to small libraries of phenolic derivatives.

PMID- 12425610
TI  - Solid-phase synthesis of isoxazolines.
AB  - The polymer-supported synthesis of isoxazolines is described via nitrile oxide
      intermediates, starting from primary nitroalkanes in a one-pot process.

PMID- 12425612
TI  - Ab initio quantum calculation of the diabatic coupling matrix elements for the
      self-exchange redox couples M(Cp)20/+ (M = Fe, Co; Cp = C5H5).
AB  - The diabatic couplings between the metal centers in M(Cp)20/+ (M = Fe, Co; Cp =
      C5H5) were evaluated using ab initio methods at the Hartree-Fock level of theory.
      Excellent agreement with the experimental estimate is found for the Fe(Cp)20/+
      couple. For Co(Cp)20/+, the calculated numbers are substantially higher than the
      experimental estimates, suggesting that the latter may represent a considerable
      underestimate (a possibility mentioned in the experimental publication).

PMID- 12425611
TI  - Parallel synthesis of oxazolines and thiazolines by tandem condensation
      cyclodehydration of carboxylic acids with amino alcohols and aminothiols.
AB  - A combinatorial library of oxazolines and thiazolines was synthesized in moderate
      to excellent yields using a newly developed methodology. Free carboxylic acids
      were directly condensed with amino alcohols and aminothiols in the presence of 3
      nitrophenylboronic acid as a dehydration catalyst. The library synthesis
      illustrates the scope of this process: After traditional reaction optimization, a
      total of 17 oxazolines and 6 thiazolines were successfully prepared in a 24
      reaction setup in a Radleys GreenHouse parallel synthesizer. The yields of the
      parallel reactions ranged from moderate to excellent, depending largely on
      carboxylate reactivity and functionalization, and generally exceeded those of the
      traditional reaction setup. The target compounds were isolated in high purities
      (average purity is 96% according to GC analysis) after passing reaction mixtures
      through short PrepSep SPE Florisil cartridges.

PMID- 12425613
TI  - "ortho-Wurster's crowns": synthesis and properties of a novel phenylenediamine
      based redox-active macrocyclic ligand.
AB  - A hybrid, macrocyclic structure based on o-phenylenediamine and a crown ether
      promotes an intimate mutual interaction with a bound potassium ion in the form of
      chelation by the redox-active moiety. A general synthetic method and properties
      are described for the first member of a new class of redox-active, lariat-type
      macrocycles called the "o-Wurster's crowns".

PMID- 12425614
TI  - Unusual magnetic property associated with dimerization within a nickel tetramer.
AB  - A new ion-pair complex, 1-benzyl-4-aminopyridinium
      bis(maleonitriledithiolato)nickelate(III) (1), has been synthesized. The variable
      magnetic susceptibility results of 1 show a discontinuity around 184 K, which is
      phenomenologically similar to that observed for first-row transition metal
      complexes undergoing a spin crossover transition. The crystal structure analyses
      of 1 at high and low temperatures indicate that this unusual magnetic property is
      associated with a packing structure that changes from tetrameric spin clusters to
      dimers between neighboring spin carriers.

PMID- 12425615
TI  - Coupling of coordinated 2-iminophosphorano-1-phosphaallyl leading to bridged
      iminophosphoranato complexes of zirconium and hafnium.
AB  - Reaction of MCl4 (M = Zr, Hf) with 2 equiv of 2-iminophosphorano-1-phosphaallyl
      lithium [Li[P(Ph)C(=CHPh)P(Me)2=NSiMe3](THF)1.5] (1) affords ligand coupling
      complexes 3 and 4, respectively, while similar treatment of ZrCl4 with
      [Li[P(Ph)C(=C(SiMe2Bu(t))Ph)P(Me)2=NSiMe3](THF)2] (2) yields ligand transfer
      complex 5.

PMID- 12425616
TI  - Trans ruthenium(II) complexes with NH-bridged tetradentate symmetric and
      asymmetric polypyridyl ligands.
AB  - NH-Bridged tetradentate ligands were synthesized to achieve stable trans Ru(II)
      bis(polypyridyl) complexes. The polypyridyl part of the ligand was either
      symmetric, as in N,N-bis(1,10-phenanthroline-2-yl)amine (phen-NH-phen), or
      asymmetric, as in N-(1,10-phenanthroline-2-yl)-N-(6-yl-dipyridyl[2,3-a:2',3'
      c]phenazine)amine (dppz-NH-phen). Protonation of phen-NH-phen with
      trifluoroacetic acid and the subsequent reaction with RuCl3 yield trans-[Ru(phen
      NH-phen)Cl2]. The chloro ligands in this compound can easily be replaced by
      stronger ligands, such as CH3CN and DMSO. In this way, complexes trans-[Ru(phen
      NH-phen)(CH3CN)(DMSO)](PF6)2 (1), trans-[Ru(phen-NH-phen)(DMSO)2](PF6)2 (2), and
      trans-[Ru(phen-NH-phen)(CH3CN)2](PF6)2 (3) were obtained. X-ray structures were
      determined for 1 and 3. Following a procedure similar to that used with phen-NH
      phen, the complex trans-[Ru(dppz-NH-phen)(CH3CN)2](PF6)2 (4) was obtained. To our
      knowledge, this is the first reported trans ruthenium(II) bis(polypyridyl)
      complex with two different polypyridyl ligands in the equatorial plane.

PMID- 12425617
TI  - Self-assembly of nanoscale, porous T-symmetric molecular adamantanoids.
AB  - Treatments of lanthanide nitrate or perchlorate and C2-symmetric 2,2'-hydroxy
      1,1'-binaphthalene-6,6'-dicarboxylic acid (6,6'-H2BDA) led to diastereoselective
      self-assembly of nanoscale, porous molecular adamantanoids
      [Ln4(BDA)6(H2O)12]*12DMF (Ln = Gd, La, 1a,b). These adamantanoid clusters possess
      perfect T symmetry as a result of the C2-symmetric nature of BDA bridging ligands
      and C3-symmetric nature of lanthanide ions. Face-to-face intercluster hydrogen
      bonds formed between 2,2'-dihydroxyl groups of BDA ligands and carboxylate oxygen
      atoms direct the assembly of 3D polycages based on chiral molecular adamantanoid
      building blocks which possess two different types of open channels.

PMID- 12425618
TI  - Ferromagnetic coupling between low- and high-spin iron(III) ions in the
      tetranuclear complex fac-[[FeIII[HB(pz)3](CN)2(mu-CN)]3FeIII(H2O)3]* 6H2O
      ([HB(pz)3]- = hydrotris(1-pyrazolyl)borate).
AB  - The novel mononuclear PPh4-fac-[FeIII[HB(pz)3](CN)3]*H2O (1) [PPh4+=
      tetraphenylphosphonium cation; (HB(pz)3)- = hydrotris(1-pyrazolyl)borate] and
      tetranuclear fac-[[FeIII[HB(pz)3](CN)2(mu-CN)]3FeIII(H2O)3]*6H2O (2) have been
      prepared and characterized by X-ray diffraction analysis. Crystal data for
      compound 1: monoclinic, space group P21/c, a = 9.575(3) A, b = 21.984(4) A, c =
      16.863(3) A, beta = 100.34(2) degrees, U = 3486(1) A3, Z = 4. Crystal data for
      compound 2: orthorhombic, space group Pnam, a = 14.084(3) A, b = 14.799(4) A, c =
      25.725(5) A, U = 5362(2) A3, Z = 4. Compound 1 is a low-spin iron(III) compound
      with three cyanide ligands in fac arrangement and a tridentate pyrazolylborate
      ligand building a distorted octahedral environment around the iron atom. Compound
      2 is the first example of a molecular species containing three peripheral low
      spin iron(III) ions linked to a central high-spin iron(III) cation by single
      cyanide bridges, the anion of 1 acting as a monodentate ligand in 2. Variable
      temperature magnetic susceptibility measurements of 2 reveal the occurrence of a
      significant ferromagnetic coupling between the three peripheral low-spin
      iron(III) centers and the central high-spin iron(III) ion cations leading to a
      low-lying nonet spin state.

PMID- 12425619
TI  - Association patterns of platinated purine nucleobases in metal-modified pairs and
      triples.
AB  - Blocking of Watson-Crick or Hoogsteen edges in purine nucleobases by a metal
      entity precludes involvement of these sites in interbase hydrogen bonding,
      thereby leaving the respective other edge or the sugar edge as potential H
      bonding sites. In mixed guanine, adenine complexes of trans-a2PtII (a = NH3 or
      CH3NH2) of composition trans-[(NH3)2Pt(9-EtA-N1)(9-MeGH-N7)](NO3)2 (1a), trans
      [(NH3)2Pt(9-EtA-N1)(9-MeGH-N7)](ClO4)2 (1b), and trans,trans-[(CH3NH2)2(9-MeGH
      N7)Pt(N1-9-MeA-N7)Pt(9-MeGH-N7)(CH3NH2)2](ClO4)4*2H2O (2) (with 9-EtA = 9
      ethyladenine, 9-MeA= 9-methyladenine, 9-MeGH = 9-methylguanine), this aspect is
      studied. Thus, in 1b pairing of two adenine ligands via Hoogsteen edges and in 2
      pairing of two guanine bases via sugar edges is realized. These situations are
      compared with those found in a series of related complexes.

PMID- 12425621
TI  - Nonstoichiometric spinel ferrites obtained from alpha-NaFeO2 via molten media
      reactions.
AB  - Different solid/liquid "exchange" reactions involving divalent cations, protons,
      or ammonium ions have been performed at low/moderate temperatures (between 80 and
      500 degrees C) on alpha-NaFeO2 dipped in molten salts (or acid) media. Several
      ferrites have been obtained which are nonstoichiometric with partially inverse
      spinel structures. When sodium is replaced by divalent cations (Mg2+, Co2+, Ni2+,
      and Zn2+), the obtained ferrites are hyperstoichiometric (cation/oxygen ratio
      higher than 3/4) whereas proton or ammonium reactions result in
      hypostoichiometric materials (cation/oxygen lower than 3/4). All these ferrites
      present a platelet-like morphology and show ferrimagnetic, soft magnet behavior.

PMID- 12425620
TI  - The effect of substituents on the phenyl portion of the imido ligand on the
      structure and properties of molybdenum(VI) imido complexes.
AB  - Anilines with alkyl substituents on the phenyl ring (ArNH2 = 2,4,6
      trimethylaniline; 2,3-, 2,4-, 2,6-, and 3,4-dimethylaniline; and 2,6
      diisopropylaniline) react with MoO(X)2(dtc)2 (X = Cl or Br; dtc =
      diethyldithiocarbamate) in methanol in the presence of 2 equiv of triethylamine
      to form ionic imido complexes of the type [MoNAr(dtc)3]2[Mo6O19] or
      MoNAr(dtc)3]4[Mo8O26]. The same reaction in THF with butyllithium as base yields
      imido complexes of the type MoNAr(X)2(dtc)2. The structures of three ionic, five
      chloro, and two bromo complexes have been determined by X-ray crystallography. In
      all complexes, the molybenum center is a distorted pentagonal bipyramid. While
      the structures are similar, the angles of the imido linkages differ. The effect
      of the substituents on the phenyl ring of the imido ligand on the 95Mo NMR
      chemical shifts was determined. The Mo nucleus becomes more deshielded with the
      substituents in the following order: 3,4-Me2 < 2,3-Me2 < 2,4-Me2 < 2,6-Me2 <
      2,4,6-Me3 < 2,6 isopropyl. Complexes with more deshielded 95Mo centers tend to
      have angles of the imido linkage that are closer to 180 degrees.

PMID- 12425622
TI  - Crystal field effects on the optical absorption and luminescence properties of
      Ni2+-doped chlorides and bromides: crossover in the emitting higher excited
      state.
AB  - Single crystals of CsCdCl3, CsCdBr3, CsMgBr3, and MgBr2 doped with 0.1/5% Ni2+
      were grown by the Bridgman technique and studied by variable-temperature optical
      absorption and luminescence spectroscopies. At cryogenic temperatures all these
      systems are dual emitters; i.e., they emit light from two distinct, thermally
      nonequilibrated excited states. The emitting higher excited state is 1T2g in
      Ni2+:CsCdCl3 and Ni2+:CsCdBr3 and 1A1g in Ni2+:CsMgBr3 and Ni2+:MgBr2. This
      crossover manifests itself in a change from red broad-band to yellow sharp-line
      luminescence, and it is rationalized on the basis of crystal field theory.
      Temperature-dependent luminescence as well as two-color pump and probe
      experiments reveal that in Ni2+:CsMgBr3 and Ni2+:MgBr2 the 1T2g state lies only
      about 70 and 170 cm-1, respectively, above 1A1g. The effect of crystal field
      strength on thermally activated nonradiative multiphonon relaxation processes in
      the bromides is examined for both 1A1g/1T2g higher excited state and 3T2g first
      excited-state emission. Two-color excited-state excitation experiments are used
      to monitor Ni2+ excited-state absorption transitions originating from 3T2g.

PMID- 12425623
TI  - Design and crystal structures of triple helicates with crystallographic idealized
      D3 symmetry: the role of side chain effect on crystal packing.
AB  - Novel crystallographic D3-symmetric binuclear triple molecular helices
      [Co2L(1)3][BF4]4 (1), [Zn2L(1)3][BF4]4 (2), [Mn2L(1)3][BF4]4 (3),
      [Co2L(2)3][BF4]4 (4), [Zn2L(2)3][BF4]4 (5), and [Mn2L(2)3][BF4]4 (6) have been
      achieved to establish the side chain effect on molecular packing, where L1 is
      [(C5H4N)C(CH3)=N-(C6H4)-]2CH2 and L2 is [(C5H4N)C(CH3)=N-(C6H4)-]2O,
      respectively. Crystal structure analyses show that each helix crystallizes in a
      hexagonal crystal system with space group Pc1 and the general axis of the helix
      occupies the crystallographic 3-fold axial position with the other three
      crystallographic 2-fold symmetries perpendicular to it. Each metal center is
      bound to three pyridylimine units to attain C3 pseudooctahedral coordination
      geometry with respective equivalent metal-N (CH=N) and metal-N (pyridyl) bonds.
      It is speculated that the existence of the methyl group might minimize the
      potential intermolecular interactions, which would be the essential factor
      controlling the helices formed in idealized crystallographic D3 symmetry.
      Moreover, crystallographic idealized C3-symmetric helicates [Co2L(3)3][BF4]4 (7),
      [Zn2L(3)3][BF4]4 (8), [Ni2L(3)3][BF4]4 (9), and [Cu2L(3)3][BF4]4 (10) were also
      structurally characterized for comparison, where L3 is [(C5H4N)C(CH3)=N-]2. All
      the results indicate that the existence of the methyl group in the side chain of
      aromatic ligands could effectively reduce the potential - intermolecular
      interactions and the side chain effect of the methyl group in crystal packing is
      robust enough to be exchanged from one network structure to another, which
      ensures the generality and predictability of the crystallographic idealized
      symmetry formation to a certain extent.

PMID- 12425624
TI  - Synthesis and characterization of diametrically substituted tetra-O-n
      butylcalix[4]arene ligands and their chelated complexes of titanium, molybdenum,
      and palladium.
AB  - The ligation properties of three new upper-rim-substituted calix[4]arene ligands,
      5,17-bis(hydroxymethyl)-tetra-n-butoxycalix[4]arene ((HOCH2)2-nBu4Clx, 7), 5,17
      bis((diphenylphosphinito)methoxy)-tetra-n-butoxycalix[4]arene ((PPh2OCH2)2
      nBu4Clx, 8), and 5,17-bis((diphenylphosphino)methyl)-tetra-n-butoxycalix[4]arene
      ((PPh2CH2)2-nBu4Clx, 10) are reported herein. The newly prepared compounds differ
      from previously reported diametrically substituted calix[4]arene derivatives in
      that the lower-rim substituent was n-butyl. The presence of this lower-rim
      substituent did not reduce the inherent crystallinity of these complexes as
      purification of all materials occurred via simple crystallizations. The key
      precursor for the syntheses of 8 and 10 was 7, acquisition of which occurred in
      six steps starting from tetra-tert-butylcalix[4]arene, 1. Calix[4]arene
      derivatives include, tetra-n-butoxycalix[4]arene (nBu4Clx, 3), 5,11,17,23
      tetrabromo-tetra-n-butoxycalix[4]arene (Br4-nBu4Clx, 4), 5,17-dibromo-tetra-n
      butoxycalix[4]arene (Br2-nBu4Clx, 5), 5,17-bis(formyl)-tetra-n
      butoxycalix[4]arene ((CHO)2-nBu4Clx, 6), and 5,17-bis(chloromethyl)-tetra-n
      butoxycalix[4]arene ((ClCH2)2-nBu4Clx, 9), all of which were synthesized using
      modifications of existing procedures. Characterization of all compounds occurred,
      when possible, using 1H, 13C, and 31P NMR, elemental analyses, FAB-MS, ESI-MS, FT
      IR, and X-ray crystallography. The solid-state structures of all calix[4]arene
      intermediates and ligands showed that the annulus adopted the pinched-cone
      conformation in which the average C(5)...C(17) intraannular separation was 4.5 +/
      0.4 A. Reaction of 7 with CpTiMe3 yielded the cis-chelate, CpTi(Me)[(OCH2)2
      nBu4Clx] (11), quantitatively. Data obtained using ESI-MS (positive-ion mode)
      confirmed the monomer formulation showed above, and 1H NMR spectra provided
      sufficient information to deduce the nature of the Ti coordination sphere.
      Reaction of 8 with cis-Cl2Pd(NCPh)2 in refluxing benzene afforded cis
      Cl2Pd[(PPh2OCH2)2-nBu4Clx] (12) in good yields. The monomeric identity of this
      compound was verified by both X-ray crystallography and positive-ion ESI-MS. The
      cis-bidentate calix[4]arene ligand did not undergo any noticeable contortion upon
      chelation of the PdCl2 fragment. Acid-promoted decomposition of 12 occurred in
      the presence of adventitious HCl and gaseous HCl, and the products of this
      decomposition were 9 and [mu2-ClPd(PPh2OH)(PPh2O)]2. In addition, chelates of 8
      that contained Mo(CO)3L (L = NCMe (14a), NCEt (14b), and CO (14c)) showed that
      the mode of coordination was relatively insensitive to the identity of the metal.
      X-ray crystallography afforded views of the solid-state structures of 14b,c and,
      like 12, showed that the Mo(CO)3L fragment resided above the pinched-cone of the
      calix[4]arene. 1H NMR revealed that C-H/pi interactions existed between L (14a,b)
      and a phenyl ring of the coordinated phosphinite. Finally, the
      bis(diphenylphosphine)calix[4]arene ligand (10) readily coordinated the Mo(CO)3L
      species, but the reaction did not go to completion, as evidenced by 1H NMR, even
      after a 5 day reaction time. Data suggest that the product is similar to that
      observed for 12 and 14, but the incomplete reaction complicated attempts to
      obtain pure material and prohibited definitive assignment of the coordination
      array.

PMID- 12425625
TI  - Nanocrystalline tin as a preparative tool: synthesis of unprotected nanoparticles
      of SnTe and SnSe and a new route to (PhSe)4Sn.
AB  - The reactions of nanocrystalline tin metal (Sn*) with elemental selenium and
      tellurium and with the diaryldichalcogenides Ph2Se2 and Ph2Te2 have been
      investigated. Reaction of Sn* with the soluble tellurium source Ph2Te2 led to a
      clean formation of nanoparticles of cubic SnTe. Dependent on the concentration of
      Ph2Te2, the particles sizes could be varied between 15 and 60 nm in average,
      whereas the reaction of Sn* with Ph2Se2 formed molecular Sn(SePh)4 in high yield.
      The latter molecular compound was thermolyzed at 300 degrees C, yielding
      nanocrystalline SnSe with a broader distribution of size. The nanoparticles of
      SnTe were thoroughly investigated by transmission electron microscopy (TEM) and
      powder X-ray diffraction. The reactions of Sn* with elemental selenium and
      tellurium gave single- phase but microcrystalline SnSe and SnTe.

PMID- 12425626
TI  - Elimination of HX (X = Cl, Br) from haloalkenes on the Ru2Q2 (Q = S, Se) core
      complex.
AB  - Treatment of [[Ru(P(OCH3)3)2(CH3CN)3]2(mu-Q2)](CF3SO3)4 (1, Q = S; 2, Q = Se)
      with haloalkenes resulted in the formation of complexes carrying unsaturated C3Q2
      five-membered or C4Q2 six-membered rings via elimination of HX (X = Cl, Br). The
      reactions of 1 and 2 with allyl bromide gave the corresponding addition products,
      [[Ru(P(OCH3)3)2(CH3CN)3]2(mu-QCH=CHCH2Q)](CF3SO3)4 (3, Q = S; 4, Q = Se), via
      elimination of HBr. The elimination process seems to be thermodynamically
      controlled and takes place at the final stage of the reaction. The steric effect
      of the halogen atoms seems more operative than the electronic one.

PMID- 12425627
TI  - Pyrazolylborate-zinc-nucleobase-complexes, 2:(1) preparations and structures of
      Tp(Cum,Me)Zn and Tp(Ph,Me)Zn complexes.
AB  - The interactions of the nine most significant nucleobases (thymine, uracil,
      dihydrouracil, cytosine, adenine, guanine, diaminopurine, xanthine, hypoxanthine,
      in their deprotonated forms) with zinc and with themselves in pyrazolylborate
      zinc complexes Tp(Cum,Me)Zn-base and Tp(Ph,Me)Zn-base are described. Except for
      guanine, the complexes Tp*Zn-base could be isolated in all cases. Structure
      determinations could be performed for seven of the eight product types. Except
      for dihydrouracil and xanthine, the zinc ion is attached to that nitrogen of the
      base which in nucleosides bears the sugar moiety. In the solid state, all zinc
      bound nucleobases are involved in hydrogen bonding interactions. Except for
      xanthine, this includes homo base pairing across a crystallographic inversion
      center.

PMID- 12425628
TI  - Pyrazolylborate-zinc-nucleobase-complexes, 3:(1) base pairing studies.
AB  - In solution, the pyrazolylborate-zinc-nucleobase complexes show self-association
      and base pairing with external nucleobases. The self-association was studied
      quantitatively for Tp(Cum,Me)Zn-hypoxanthinate and Tp(Cum,Me)Zn-thyminate; the
      dimerization constants K(D) are 63 +/- 8 and 0.2 +/- 0.1 M(-1), respectively. Of
      the external nucleobases, 9-ethyladenine forms stable base pairs with the
      thyminate, uracilate, and xanthinate complexes, 9-isobutylguanine only with the
      cytosinate complex, 1-methylthymine with the adeninate and diaminopurinate
      complexes, and 1-methyluracil with the diaminopurinate complex. The association
      constant for the base pair Tp(Cum,Me)Zn-thyminate:9-ethyladenine was determined
      by NMR methods as K = 66 +/- 10 M(-1). Structure determinations of the
      crystalline adducts have confirmed the base pairing for Tp(Cum,Me)Zn-thyminate:9
      ethyladenine, Tp(Cum,Me)Zn-cytosinate:9-isobutylguanine, and Tp(Cum,Me)Zn
      xanthinate:9-ethyladenine. Both Watson-Crick and Hoogsteen base pairs have been
      observed. In the solid state, extended base pairing leads to quartet and polymer
      arrangements.

PMID- 12425629
TI  - Extraction of pertechnetate and perrhenate from water with deep-cavity
      [CpFe(arene)](+)-derivatized cyclotriveratrylenes.
AB  - Technetium-99 (beta-, t(1/2) = 2.15 x 10(5) years) is produced in a 6% fission
      yield from fission reactors. Technetium-99 continues to be of major concern at
      various nuclear sites because of its mobility in its most common chemical form
      during the reprocessing cycle and in the environment. Under these oxic aqueous
      environments the chemical form of Tc is typically Tc(VII)O4-, which is difficult
      to remove. Methods for pertechnetate removal to date have mixed results and pose
      further environmental concerns. Utilization of new cyclotriveratrylene host
      materials for the extraction of pertechnetate from 0.9% saline into nitromethane
      has shown high selectivity and efficiency. A deep-cavity host,
      tris[cyclopentadienyliron(II) arene]cyclotriguiasylene (2), has shown >95%
      extraction of pertechnetate and perrhenate into nitromethane from saline in the
      presence of competing anions, outperforming previously reported materials.

PMID- 12425630
TI  - Dianionic platinadiphospholene complexes.
AB  - 1,2,3,4-tetraphenyl-1,2-dihydrodiphosphetene 1 reacts with lithium or sodium
      naphthalenide to afford the corresponding dianionic salts 2 and 3. An X-ray
      crystal structure analysis shows that dianion 3 of general formula [(1)2
      2Na3(DME)2, Na(DME)3] is a polymeric structure consisting of [(1)2-2Na3(DME)2]
      units which are connected together through one sodium atom. Reaction of the
      dianionic lithium salt 2 with [Pt(COD)Cl2] affords the 4[Li(2.2.1)]2 complex,
      after the addition of 2 equiv of (2.2.1) cryptate. The overall geometry around
      platinum in 4[Li(2.2.1)]2 can be described as distorted square planar, and only
      the diastereomer (1-R, 2-S, 3-R, 4-S) is formed. X-ray data indicate that no
      delocalization takes place within each platinadiphospholene unit and that complex
      4[Li(2.2.1)]2 must be regarded as the coordination of two molecules of dianion 2
      onto a Pt2+ center. Reaction of the dianionic sodium salt 3 with 1 equiv of
      [Pt(COD)Cl2] produces the 4[Na(DME,Et2O)]2 complex which adopts a
      pseudotetrahedral geometry around platinum ( between interplane angles = 35), the
      two cationic units [Na(DME, Et2O)] being located along a C2 axis. Four weak
      interactions exist between the sodium cations and the phosphorus atoms. Only the
      (1-S, 2-S, 3-S, 4-S) diastereomer is formed. Bond distances in the diphospholene
      units of 4[Na(DME,Et2O)]2 are close to that of dianion 3 indicating that, like in
      4[Li(2.2.1)]2, the complex can be described as a platinum (+2) dianionic species.

PMID- 12425631
TI  - Mononuclear Ca(II)-bulky aryl-phosphate monoanion and dianion complexes with
      ortho-amide groups.
AB  - Two new mononuclear Ca(II) complexes with aryl dihydrogen phosphate ligands
      having two strategically oriented bulky amide groups, 2,6-(Ph3CCONH)2C6H3OPO3H2
      (1), including one with a phosphate monoanion, (NMe4)[CaII[O2P(OH)OC6H3-2,6
      (NHCOCPh3)2]3(NCMe)3] (3), and one with a phosphate dianion, [CaII[O3POC6H3-2,6
      (NHCOCPh3)2](H2O)3(MeOH)2] (4). Both are analogues for the NH...O hydrogen bonds
      in the active site of Ca(II)-containing phosphotransferase. Crystallographic
      studies of these Ca(II) complexes revealed that the amide NHs are directed to
      uncoordinated O atoms of the phosphates, and the IR and 1H NMR spectra indicate
      that strong NH...O hydrogen bonds are formed only in the phosphate dianion state.
      The ligand exchange reaction of 3 with a non-hydrogen-bonded phosphate ligand
      shows that the NH...O hydrogen bonds prevent the Ca-O bond from dissociation. A
      scatter plot analysis comparing the distance of a Ca-O bond with the Ca-O-P
      angle, the Fourier density analysis, and DFT calculations reveal that a partial
      degree of covalency in the Ca-O(phosphate) bonds is present.

PMID- 12425632
TI  - Holo- and hemidirected lead(II) in the polymeric [Pb(4)(mu-3,4-TDTA)2(H2O)2]*4H2O
      complex. N,N,N',N'-tetraacetate ligands derived from o-phenylenediamines as
      sequestering agents for lead(II).
AB  - The coordinating ability of the ligands 3,4-toluenediamine-N,N,N',N'-tetraacetate
      (3,4-TDTA), o-phenylenediamine-N,N,N',N'-tetraacetate (o-PhDTA), and 4-chloro-1,2
      phenylenediamine-N,N,N',N'-tetraacetate (4-Cl-o-PhDTA) (H4L acids) toward
      lead(II) is studied by potentiometry (25 degrees C, I = 0.5 mol x dm(-3) in
      NaClO4), UV-vis spectrophotometry, and 207Pb NMR spectrometry. The stability
      constants of the complex species formed were determined. X-ray diffraction
      structural analysis of the complex [Pb4(mu-3,4-TDTA)4(H2O)2]*4H2O (1) revealed
      that 1 has a 2-D structure. The layers are built up by the polymerization of
      centrosymmetric [Pb4L2(H2O)2] tetranuclear units. The neutral layers have the
      aromatic rings of the ligands pointing to the periphery, whereas the metallic
      ions are located in the central part of the layers. In compound 1, two types of
      six-coordinate lead(II) environments are produced. The Pb(1) is coordinated to
      two nitrogen atoms and four carboxylate oxygens from the ligand, whereas Pb(2)
      has an O6 trigonally distorted octahedral surrounding. The lead(II) ion is
      surrounded by five carboxylate oxygens and a water molecule. The carboxylate
      oxygens belong to four different ligands that are also joined to four other Pb(1)
      ions. The selective uptake of lead(II) was analyzed by means of chemical
      speciation diagrams as well as the so-called conditional or effective formation
      constants K(Pb)eff. The results indicate that, in competition with other ligands
      that are strong complexing agents for lead(II), our ligands are better
      sequestering agents in acidic media.

PMID- 12425633
TI  - Isolation of the new cubic phases RE4FeGa(12-x)Ge(x) (RE = Sm, Tb; x = 2.5) from
      molten gallium: single-crystal neutron diffraction study of the Ga/Ge
      distribution.
AB  - The compounds RE4FeGa(12-x)Ge(x) (RE = Sm, Tb) were discovered in reactions
      employing molten Ga as a solvent at 850 degrees C. However, the isostructural
      Y4FeGa(12-x)Ge(x) was prepared from a direct combination reaction. The crystal
      structure is cubic with space group Imm, Z = 2, and a = 8.657(4) A and 8.5620(9)
      A for the Sm and Tb analogues, respectively. Structure refinement based on full
      matrix least squares on F(o)2 resulted in R1 = 1.47% and wR2 = 4.13% [I > 2(I)]
      for RE = Sm and R1 = 2.29% and wR2 = 7.12% [I > 2(I)] for RE = Tb. The compounds
      crystallize in the U4Re7Si6 structure type, where the RE atoms are located on 8c
      (1/4, 1/4, 1/4) sites and the Fe atoms on 2a (0, 0, 0) sites. The distribution of
      Ga and Ge in the structure, investigated with single-crystal neutron diffraction
      on the Tb analogue, revealed that these atoms are disordered over the 12d (1/4,
      0, 1/2) and 12e (x, 0, 0) sites. The amount of Ga/Ge occupying the 12d and 12e
      sites refined to 89(4)/11 and 70(4)/30%, respectively. Transport property
      measurements indicate that these compounds are metallic conductors. Magnetic
      susceptibility measurements and Mossbauer spectroscopy performed on the Tb
      analogue show a nonmagnetic state for Fe, while the Tb atoms carry a magnetic
      moment corresponding to a mu(eff) of 9.25 mu(B).

PMID- 12425634
TI  - Peculiar antiaromatic inorganic molecules of tetrapnictogen in Na+Pn4- (Pn = P,
      As, Sb) and important consequences for hydrocarbons.
AB  - Although aromaticity has been observed in inorganic and all-metal species, the
      concept of antiaromaticity has not been extended beyond organic molecules. Here,
      we present theoretical and experimental evidence that the 6 -electron
      tetrapnictogen dianions in Na+Pn42- (Pn = P, As, Sb) undergo a transition from
      being aromatic to antiaromatic upon electron detachment, yielding the first
      inorganic antiaromatic Na+Pn4- molecules. Two types of antiaromatic structures
      were characterized, the conventional rectangular species and a new peculiar
      quasiplanar rhombus species. Aromaticity and antiaromaticity in the
      tetrapnictogen molecules were derived from molecular orbital analyses and
      verified by experimental photodetachment spectra of Na+Pn42-. On the basis of our
      findings for the tetrapnictogen clusters, we predicted computationally that the
      organic C4H4- anion also possesses two antiaromatic structures: rectangular and
      rhombus. Moreover, only the rhombus antiaromatic minimum was found for the
      radical NC3H4, thus extending the peculiar rhombus antiaromatic structure first
      uncovered in inorganic clusters into organic chemistry.

PMID- 12425635
TI  - Application of time-resolved infrared spectroscopy to electronic structure in
      metal-to-ligand charge-transfer excited states.
AB  - Infrared data in the nu(CO) region (1800-2150 cm(-1), in acetonitrile at 298 K)
      are reported for the ground (nu(gs)) and polypyridyl-based, metal-to-ligand
      charge-transfer (MLCT) excited (nu(es)) states of cis-[Os(pp)2(CO)(L)](n)(+) (pp
      = 1,10-phenanthroline (phen) or 2,2'-bipyridine (bpy); L = PPh3, CH(3)CN,
      pyridine, Cl, or H) and fac-[Re(pp)(CO)3(4-Etpy)](+) (pp = phen, bpy, 4,4'
      (CH3)2bpy, 4,4'-(CH3O)2bpy, or 4,4'-(CO2Et)2bpy; 4-Etpy = 4-ethylpyridine).
      Systematic variations in nu(gs), nu(es), and Delta(nu) (Delta(nu) = nu(es) -
      nu(gs)) are observed with the excited-to-ground-state energy gap (E(0)) derived
      by a Franck-Condon analysis of emission spectra. These variations can be
      explained qualitatively by invoking a series of electronic interactions.
      Variations in dpi(M)-pi(CO) back-bonding are important in the ground state. In
      the excited state, the important interactions are (1) loss of back-bonding and
      sigma(M-CO) bond polarization, (2) pi(pp*-)-pi(CO) mixing, which provides the
      orbital basis for mixing pi(CO)- and pi(4,4'-X(2)bpy)-based MLCT excited states,
      and (3) dpi(M)-pi(pp) mixing, which provides the orbital basis for mixing pipi-
      and pi(4,4'-X(2)bpy*-)-based MLCT states. The results of density functional
      theory (DFT) calculations on the ground and excited states of fac
      [Re(I)(bpy)(CO)3(4-Etpy)](+) provide assignments for the nu(CO) modes in the MLCT
      excited state. They also support the importance of pi(4,4'-X2bpy*-)-pi(CO)
      mixing, provide an explanation for the relative intensities of the A'(2) and A' '
      excited-state bands, and provide an explanation for the large excited-to-ground
      state nu(CO) shift for the A'(2) mode and its relative insensitivity to
      variations in X.

PMID- 12425636
TI  - One-dimensional polymers containing strictly collinear metal ions: synthesis and
      XRPD characterization of homoleptic binary metal pyrazolates.
AB  - The synthesis of a number of 3d transition metal binary pyrazolates in
      microcrystalline form, thus suitable for a full XRPD characterization, has been
      pursued. The crystal and molecular structures of the Fe(pz)3, Co(pz)2, Co(pz)3,
      and Ni(pz)2 polymers, together with the few congeners reported in the recent
      literature, show that these species tend to afford highly crystalline materials
      where strictly collinear chains of metal atoms are present. Depending on the
      synthetic strategy used, Ni(pz)2 has been found to crystallize as two different
      alpha (orthorhombic) and beta (monoclinic) phases, possessing nearly identical
      intramolecular features. Data for each compound follow. Fe(pz)3: C9H9FeN6,
      hexagonal, P63/m, a = 9.1745(3) A, c = 7.2191(4) A, Z = 2. Co(pz)2: C6H6CoN4,
      orthorhombic, Ibam, a = 7.5239(5) A, b = 14.3461(9) A, c = 7.4331(5) A, Z = 4.
      Co(pz)3: C9H9CoN6, hexagonal, P63/m, a = 9.1966(3) A, c = 7.1051(3) A, Z = 2.
      Alpha-Ni(pz)2: C6H6N4Ni, orthorhombic, Cmcm, a = 16.6758(11) A, b = 6.4872(4) A,
      c = 6.9423(6) A, Z = 4. Beta-Ni(pz)2: C6H6N4Ni, monoclinic, P21/m, a = 9.967(2)
      A, b = 6.975(1) A, c = 6.016(1), A, beta = 98.50(1)degrees, Z = 2. The thermal
      stability and the detailed structural properties of these model compounds have
      been evaluated, in the light of the technologically relevant crystal phases (the
      well-known metal-diazolates showing reversible spin-crossover or spin-transition
      behavior) obtainable upon doping, magnetic dilution, and ring substitution (in
      the 4-position).

PMID- 12425637
TI  - Synthesis and structures of niobium(V) complexes stabilized by linear-linked
      aryloxide trimers.
AB  - The preparation and characterization of a series of niobium(V) complexes that
      incorporate the linear-linked aryloxide trimers 2,6-bis(4,6-dimethylsalicyl)-4
      tert-butylphenol [H3(Me-L)] and 2,6-bis(4-methyl-6-tert-butylsalicyl)-4-tert
      butylphenol [H3(tBu-L)] are described. The chloride complex [Nb(Me-L)Cl2]2 (1)
      was prepared in high yield by reaction of NbCl5 with H3(Me-L) in toluene. In
      contrast, the analogous reaction with H3(tBu-L) gave a mixture of [Nb(tBu-L)Cl2]2
      (2) and [Nb(de-tBu-L)Cl2]2 (3a). During the formation of 3a, one of tert-butyl
      groups at the ortho position in the tBu-L ligand was lost. When the NbCl5/H3(tBu
      L) reaction was carried out in acetonitrile, Nb[H(tBu-L)]Cl3(NCMe) (4) was
      obtained. Heating a solution of 4 in toluene generated 2 and 3a. The isolated
      complex 4 underwent ligand redistribution in acetonitrile to produce Nb[H(tBu
      L)]2Cl(NCMe) (5). Treatment of NbCl5 with Li3(tBu-L) in toluene afforded 2. The
      chloride ligands in 1 and 2 smoothly reacted with 4 equiv of MeMgI and LiStBu,
      resulting in [Nb(R-L)Me2]2 [R = Me (6), tBu (7)] and Nb(Me-L)(StBu)2 (8),
      respectively. A number of the above complexes have been characterized by X-ray
      crystallography. In the structures of 1, 2, and 6, the R-L ligand is bound to the
      metal center with a U-coordination mode, while an alternative S-conformation is
      adopted for 3a and 8. Complexes 4 and 5 contain a bidentate H(tBu-L) diphenoxide
      monophenol ligand.

PMID- 12425638
TI  - Hypohalite ion catalysis of the disproportionation of chlorine dioxide.
AB  - The disproportionation of chlorine dioxide in basic solution to give ClO2- and
      ClO3- is catalyzed by OBr- and OCl-. The reactions have a first-order dependence
      in both [ClO2] and [OX-] (X = Br, Cl) when the ClO2- concentrations are low.
      However, the reactions become second-order in [ClO2] with the addition of excess
      ClO2-, and the observed rates become inversely proportional to [ClO2-]. In the
      proposed mechanisms, electron transfer from OX- to ClO2(k1OBr- = 2.05 +/- 0.03 M(
      1) x s(-1) for OBr(-)/ClO2 and k1OCl-= 0.91 +/- 0.04 M(-1) x s(-1) for OCl-/ClO2)
      occurs in the first step to give OX and ClO2-. This reversible step (k1OBr-/k(
      1)OBr = 1.3 x 10(-7) for OBr-/ClO2, / = 5.1 x 10(-10) for OCl-/ClO2) accounts for
      the observed suppression by ClO2-. The second step is the reaction between two
      free radicals (XO and ClO2) to form XOClO2. These rate constants are = 1.0 x
      10(8) M(-1) x s(-1) for OBr/ClO2 and = 7 x 10(9) M(-1) x s(-1) for OCl/ClO2. The
      XOClO2 adduct hydrolyzes rapidly in the basic solution to give ClO3- and to
      regenerate OX-. The activation parameters for the first step are DeltaH1(++) = 55
      +/- 1 kJ x mol(-1), DeltaS1(++) = - 49 +/- 2 J x mol(-1) x K(-1) for the OBr
      /ClO2 reaction and DeltaH1(++) = 61 +/- 3 kJ x mol(-1), DeltaS1(++) = - 43 +/- 2
      J x mol(-1) x K(-1) for the OCl-/ClO2 reaction.

PMID- 12425639
TI  - New lead inorganic-organic hybrid microporous and layered materials: synthesis,
      properties, and crystal structures.
AB  - Two new lead(II) phosphonates, namely, Pb2[PMIDA]*1.5H2O (1) (H4PMIDA =
      H2O3PCH2N(CH2CO2H)2) and Pb(H2L) (2) (H4L = CH3N(CH2PO3H2)2), have been
      synthesized by hydrothermal reactions at 150 degrees C. Complex 1 crystallized in
      tetragonal P42/n with cell dimensions of a = 17.317(7) and c = 7.507(5) A and Z =
      8. In complex 1, Pb(1) is 6-coordinated by chelation in a tetradentate fashion by
      a PMIDA ligand (3 O, 1 N) and two phosphonate oxygen atoms from neighboring
      Pb(PMIDA) units in a severely distorted octahedral geometry, whereas Pb(2) is 6
      coordinated by 4 carboxylate and 2 phosphonate oxygen atoms also with a severely
      distorted octahedral environment. These two different types of Pb(II) ions are
      interconnected through bridging carboxylate and phosphonate groups, resulting in
      a 3D network with micropores, whose cavity is filled by lattice water molecules
      interlinked via hydrogen bonds. Each PMIDA ligand bridges with 8 Pb(II) ions (3
      Pb(1) and 5 Pb(2)). Complex 2 is orthorhombic, P2(1)2(1)2(1), with a = 7.382(5),
      b = 7.440(6), and c = 30.75(2) A and Z = 8. The structure of 2 features a 2D
      double lead(II) phosphonate layer along the ab plane. Each lead(II) ion is 5
      coordinated by five phosphonate oxygen atoms from four ligands in a distorted
      trigonal bipyramid geometry. These double layers are further interconnected via
      hydrogen bonds between the protonated and uncoordinated phosphonate oxygens along
      the c-axis.

PMID- 12425640
TI  - Lanthanide complexes of [alpha-2-P2W17O61]10-: solid state and solution studies.
AB  - We have isolated the 1:1 Ln:[alpha-2-P2W17O61]10- complexes for a series of
      lanthanides. The single-crystal X-ray structure of the Eu3+ analogue reveals two
      identical [Eu(H2O)3(alpha-2-P2W17O61)]7- moieties connected through two Eu-O-W
      bonds, one from each polyoxometalate unit. An inversion center relates the two
      polyoxometalate units. The Eu(III) ion is substituted for a [WO]4+ unit in the
      "cap" region of the tungsten-oxygen framework of the parent Wells-Dawson ion. The
      point group of the dimeric molecule is Ci. The extended structure is composed of
      the [Eu(H2O)3(alpha-2-P2W17O61)]214- anions linked together by surface-bound
      potassium cations. The space group is P, a = 12.7214(5) A, b = 14.7402(7) A, c =
      22.6724(9) A, alpha = 71.550(3), beta = 84.019(3)degrees, gamma = 74.383(3), V =
      3883.2(3) A3, Z = 1. The solution studies, including 183W NMR spectroscopy and
      luminescence lifetime measurements, show that the molecules dissociate in
      solution to form monomeric [Ln(H2O)4(alpha-2-P2W17O61)]7- species.

PMID- 12425641
TI  - Hexaalkylguanidinium and 2-(dialkylamino)-1,3-dimethylimidazolinium
      trimethyldifluorosiliconates and perfluoroalkoxides. Accidental isolation and
      molecular structure of [C(NMe2)3]+F-*6CH2Cl2.
AB  - Hexaalkylguanidinium and 2-(dialkylamino)-1,3-dimethylimidazolinium
      trimethyldifluorosiliconates, precursors for two stable hexaalkylguanidinium
      perfluoroalkoxides, were synthesized by treating commercially available
      bis(dialkylamino)difluoromethane derivatives with (dialkylamino)trimethylsilanes
      in aprotic media. With hexamethylguanidinium pentafluoroethoxide the introduction
      of the lipophilic and electronegative C2F5O group was straightforwardly achieved
      in the case of primary and secondary alkyl triflates to furnish the respective
      fluorinated ethers. The molecular structures of [(CH2NMe)2C(NEt2)]+[Me3SiF2]- and
      [C(NMe2)3]+F-*6CH2Cl2 were determined, showing in the latter case a fluoride
      anion octahedrally coordinated by six methylene chloride molecules via hydrogen
      bridges with a F...H distance of 205 pm (C...F distance 270.0(3) pm).

PMID- 12425642
TI  - Structure of a fluorinated azoxy compound: fluoro(trifluoromethyl)-diazene-2
      oxide, CF3N(O)NF.
AB  - A gas-phase electron diffraction study of the azoxy compound which was
      synthesized by the reaction of CF3NO with N2F4 in a Pyrex glass vessel results in
      a trans CF3N(O)NF structure (F trans to CF3), although quantum chemical
      calculations (MP2 and B3LYP) predict a greater stability of the cis CF3NN(O)F
      isomer by about 12 kcal/mol. The CF3 group eclipses the N=N double bond. The
      following skeletal geometric parameters (r(a) values with 3sigma uncertainties)
      were obtained: N=N 1.287(15) A; N=O 1.231(6) A; N-F 1.380(6) A; N-C 1.498(6) A;
      N=N=O 131.2(13) degrees; N=N-F 103.5(13) degrees; N=N-C 114.0(12) degrees. The
      bond lengths in CF3N(O)NF are compared to those in azo, nitryl, and nitrosyl
      compounds with fluorine and/or CF3 substituents.

PMID- 12425643
TI  - Water soluble molecular switches of fluorescence based on the Ni(III)/Ni(II)
      redox change.
AB  - The water soluble Ni(II) complexes of the cyclam derivatives with 1,3
      benzodioxole and 1,2,3-trimethoxybenzene display the fluorescent emission typical
      of the covalently linked fluorophores, which results from a charge transfer
      excited state. On oxidation to Ni(III), the fluorescence is completely quenched
      due to the occurrence of an electron transfer (eT) process from the excited
      fluorogenic fragment Fl to the oxidized metal. Thus, fluorescence can be switched
      off/on at will, for several cycles, by consecutively oxidizing and reducing the
      metal center, in controlled potential electrolysis experiments both in
      acetonitrile and in aqueous 0.1 M HClO4. Occurrence of an eT process from Fl to
      Ni(III) ultimately depends upon the easy oxidation of Fl to Fl+, whereas failure
      of the occurrence of an eT process from Ni(II) to Fl has to be ascribed to the
      particular resistance of Fl fragments to the reduction.

PMID- 12425644
TI  - Reactivity of 3d transition metal cations in diethylene glycol solutions.
      Synthesis of transition metal ferrites with the structure of discrete
      nanoparticles complexed with long-chain carboxylate anions.
AB  - Study of the reactivity of 3d transition metal cations in diethylene glycol
      solutions revealed several key features that made it possible to develop a new
      method for synthesis of the nanocrystalline transition metal ferrites. The 3-7 nm
      particles of [MFe2O4]n[O2CR]m, where M = Mn, Fe, Co, Ni, and Zn, ligated on their
      surface with long-chain carboxylate anions, have been obtained in an isolated
      yield of 75-90%. The key features are the following. Complexation of the first
      row transition metal cations with diethylene glycol at a presence of alkaline
      hydroxide is sufficient to enable control over the rate of their hydrolysis. The
      reaction of hydrolysis leads to the formation of metal oxide nanocrystals in
      colloidal solution. The nanoparticles growth is terminated by an added long-chain
      carboxylic acid, which binds to their surface and acts as a capping ligand. The
      isolated nanocrystalline powders are stable against agglomeration and highly
      soluble in nonpolar organic solvents.

PMID- 12425645
TI  - Synthesis and characterization of the first azastibatranes and azabismatranes.
AB  - Syntheses of title compounds, viz. N(CH2CH2NR)3E (1, E = Sb, R = Me; 4, E = Bi, R
      = Me; 6, E = Sb, R = SiMe3; 8, E = Bi, R = SiMe3), by the reaction of E(NAlk2)3
      (3, E = Sb, Alk = Et; 5, E = Bi, Alk = Me) with N(CH2CH2NMeH)3 (2) or
      N(CH2CH2NSiMe3H)3 (7) are reported. The reactions of SbCl3 with N[CH2CH2N(Me)Li]3
      or N[CH2CH2N(SiMe3)Li]3 and BiCl3 with N[CH2CH2N(SiMe3)Li]3 resulted in compounds
      1, 6, and 8, respectively. Composition and structures of all novel compounds were
      established by 1H and 13C NMR spectroscopy and mass spectrometry. The X-ray
      structural study of 8 clearly indicated the presence of transannular interaction
      BiNdat in this compound, while 6 possesses a long Sb...Ndat distance. The
      structural data obtained from geometry optimizations on 6 and 8 reproduce
      experimental trends, i.e., a decrease in the E-Ndat distance from Sb to Bi. The
      values of electron density in E-Ndat critical point and the Laplacian of charge
      density for 8 indicate that a closed-shell interaction exists between the metal
      atom and Ndat atom.

PMID- 12425646
TI  - Structural, electronic, and magnetic consequences of O-carbonyl vs O-alkoxy ester
      coordination in new dicopper complexes containing the Cu2(mu-Cl)2 core.
AB  - The complexes [Cu2(mu-Cl)2(Cl)2(L)2] (L = dialkylpyridine-2,6-dicarboxylate; R =
      Et, L = depc, 1; R = i-Pr, L = dppc, 2) have been prepared and their magnetic
      properties studied. The crystal structures of complexes 1 and 2 have been solved.
      Compound 1 belongs to the P space group with Z = 2, a = 8.3020(10) A, b =
      9.2050(10) A, c = 10.065(2) A, alpha = 99.040(10), beta = 100.810(10), and gamma
      = 106.502(10) whereas 2 belongs to the C2/c space group with Z = 8, a =
      11.6360(10) A, b = 25.906(3) A, c = 11.76579(10) A, and beta = 107.900(10). The
      different alkyl ester substitutes produce substantial structural and electronic
      differences. The Cu2Cl2 core geometry is planar for 1 whereas it adopts a
      butterfly shape in the case of 2. Furthermore, in 2 the dppc ligand coordinates
      only by the carbonyl oxygen atoms whereas in 1 the depc ligand coordinates
      through carbonyl and alkoxy oxygen atoms. Magnetic susceptibility data show a
      ferromagnetic coupling between the two Cu(II) centers in both cases (J = 39.9(6)
      cm(-1) for 1, and J = 51.3(5) cm(-1) for 2) with very weak antiferromagnetic
      interactions (J ' = -0.59 cm(-1) and -0.57 cm(-1) for 1 and 2, respectively).
      Theoretical calculations at the extended Huckel level have also been carried out
      to further understand the electronic nature of complexes 1 and 2.

PMID- 12425647
TI  - Syntheses and characterizations of copper(II) polymeric complexes constructed
      from 1,2,4,5-benzenetetracarboxylic acid.
AB  - Four polymeric complexes with rectangular grids or channels,
      [Cu2(btec)(H2O)4*2H2O]n (2), [Cu2(btec)4/4[Cu(Hbtec)2/2(4,4'-Hbpy)(H2O)2]2*4H2O]n
      (3), [Cu2(btec)(hmt)(H2O)4*8H2O]n (4), and [Cu3(btec)(OH)2]n (5), were designed
      and constructed from Cu(II) ion and 1,2,4,5-benzenetetracarboxylic acid along
      with auxiliary ligands (where H4btec = 1,2,4,5-benzenetetracarboxylic acid, 4,4'
      Hbpy = monoprotonated 4,4'-bipyridine, and hmt = hexamethylenetetramine).
      Complexes 2, 3, and 4 have rectangular pores with the size of 6.5 A x 4.5 A, 6 A
      x 7 A, and 10.1 A x 11.8 A, respectively, while 5 has a channel of 7.4 A x 9.6 A.
      The complexes show interesting magnetic properties due to the different
      coordination modes of the carboxylate groups and the presence of auxiliary
      ligands. On lowering the temperature, the magnetic interactions in 2 are changed
      from antiferromagnetic to ferromagnetic. For 3, the antiferromagnetic
      interactions weaken sharply at low temperature. Complex 4 shows ferromagnetic
      interactions while 5 is antiferromagnetic.

PMID- 12425648
TI  - Evaluation of chain stiffness of partially oxidized polyguluronate.
AB  - The chain stiffness of macromolecules is considered critical in their design and
      applications. This study utilizes polyguluronate derived from alginate, a typical
      polysaccharide widely utilized in many biomedical applications, as a model
      macromolecule to investigate how the chain stiffness can be tightly regulated by
      partial oxidation. Alginate has a backbone of inherently rigid alpha-L-guluronate
      (i.e., polyguluronate) and more flexible beta-D-mannuronate. The chain stiffness
      of the polyguluronate was specifically studied in this paper, as this component
      plays a critical role in the formation of alginate hydrogels with divalent
      cations and is the dominant factor in determining the chain stiffness of
      alginate. We have utilized size-exclusion chromatography, equipped with
      refractive index, viscosity, and light-scattering detectors, to determine the
      intrinsic viscosity and the weight-average molecular weight of each fraction of
      samples. The chain stiffness of partially oxidized polyguluronate was then
      evaluated from the exponent of the Mark-Houwink equation and the persistence
      length. We have found that partial oxidation can be used to tightly regulate the
      steric hindrance and stiffness of the polyguluronate backbone. This approach to
      control the chain stiffness of inherently rigid polysaccharides by partial
      oxidation may find many applications in biomedical utilization of these
      materials.

PMID- 12425649
TI  - Secondary structure of proteins adsorbed onto or embedded in polyelectrolyte
      multilayers.
AB  - The structural changes of bovine serum albumin (BSA) and hen egg white lysozyme
      (HEL) upon their adsorption onto the surface or their embedding into the interior
      of poly(allylamine hydrochloride)-(poly(styrenesulfonate) (PAH-PSS) multilayer
      architectures were investigated by attenuated total reflection Fourier transform
      infrared (ATR-FTIR) spectroscopy. The presence of the polyelectrolytes seems, as
      previously observed for fibrinogen (J. Phys. Chem. B 2001, 105, 11906-11916), to
      prevent intermolecular interactions and, thus, protein aggregation at ambient
      temperature. The secondary structure of the proteins was somewhat altered upon
      adsorption onto the polyelectrolyte multilayers. The structural changes were
      larger when the charges of the multilayer outer layer and the protein were
      opposing. The adsorption of further polyelectrolyte layers onto protein
      terminated architectures (i.e., embedding the proteins into a polyelectrolyte
      multilayer) did not cause considerable further changes in their secondary
      structures. The capacity of the polyelectrolyte architectures to delay the
      formation of intermolecular beta-sheets upon increasing temperatures was not
      uniform for the studied proteins. PSS in contact with HEL could largely prevent
      the heat-induced aggregation of HEL. In contrast, PAH had hardly any effect on
      the aggregation of BSA. The differences are explained on the basis of protein
      polyelectrolyte interactions, affected mostly by the nature and the strength of
      the ionic interactions between the polyelectrolyte-protein contact surfaces.

PMID- 12425650
TI  - Microstructure and rheological behavior of pure and mixed pectin gels.
AB  - The microstructure and the rheological properties of pure HM (high methoxyl) and
      LM (low methoxyl) pectin gels and of mixed HM/LM pectin gels have been
      investigated. Gel formation of either the HM or LM pectin, or both, was initiated
      in the mixed gels by varying the sucrose and Ca(2+) content. The microstructure
      was characterized by transmission electron microscopy, light microscopy, and
      confocal laser scanning microscopy. HM and LM pectin gels showed aggregated
      networks with large pores around 500 nm and network strands of similar character.
      Small differences could be found, such as a more inhomogeneous LM pectin network
      with shorter and more branched strands of flexible appearance. LM pectin also
      formed a weak gel in 60% sucrose in the absence of calcium. A highly
      inhomogeneous mixed gel structure was formed in the presence of 60% sucrose and
      Ca(2+) ions, which showed large synergistic effects in rheological properties.
      Its formation was explained by the behavior of the corresponding pure gels. In
      the presence of 60% sucrose alone, a homogeneous, fine-stranded mixed network was
      formed, which showed weak synergistic effects. It is suggested that LM pectin
      interacts with HM pectin during gel formation, thereby hindering secondary
      aggregation leading to the aggregated networks observed for the pure gels.

PMID- 12425651
TI  - Stepwise self-assembled poly(amidoamine) dendrimer and poly(styrenesulfonate)
      microcapsules as sustained delivery vehicles.
AB  - Hollow microcapsules comprised of poly(styrenesulfonate) (PSS) and a fourth
      generation poly(amidoamine) dendrimer (4G PAMAM) were prepared by depositing
      PSS/4G PAMAM multilayers on melamine formaldehyde (MF) colloid particles by the
      layer-by-layer self-assembly technique and subsequently dissolving the templated
      cores. The PSS/4G PAMAM layers were unstable toward the core removal procedure
      (pH approximately 1), resulting in a low yield of intact hollow capsules (<10%
      for 3.5 microm diameter MF templates). Stretching of the multilayer film due to
      core swelling during MF core dissolution leads to partial or complete destruction
      of capsules, giving discrete PSS-4G PAMAM complexes. Yields were increased by
      increasing inter- and intramolecular attractive forces between the PSS chains in
      the capsules through electrostatic, hydrophobic, and a combination of these
      interactions. The yields, however, were practically unaffected by enhancing such
      effects between dendrimer molecules. Transmission electron microscopy and
      scanning force microscopy measurements show no deformation for 3.5 microm
      capsules stabilized through the various interactions stated above. Further,
      capsules were filled with low molecular weight dextran sulfate and subsequently
      loaded with a model, therapeutically active molecule, doxorubicin hydrochloride
      (DOX). Release of DOX from the capsules was also studied to highlight the drug
      delivery potential of the dendrimer-based microcapsules.

PMID- 12425652
TI  - Supramolecular formation of antibodies with viologen dimers: utilization for
      amplification of methyl viologen detection signals in surface plasmon resonance
      sensor.
AB  - Monoclonal antibodies for 1-(carboxypentyl)-1'-methyl-4,4'-bipyridinium
      dichloride have been prepared. The complex formation of one of the antibodies,
      10D5, with viologen dimer has been studied by a biosensor technique based on
      surface plasmon resonance. The dissociation constants of the complex between
      antibody 10D5 and methyl viologen or viologen dimer are found to be (2.0 +/- 0.2)
      x 10 (-7) and (1.5 +/- 0.5) x 10 (-7) M, respectively. Enhancement of response
      signal intensities in SPR is observed by the addition of the antibody solution to
      the viologen dimer-antibody complex indicating the formation of linear
      supramolecules between the antibody and viologen dimer. Amplification of methyl
      viologen sensing processes is realized by the inhibition of the complex formation
      between antibodies and viologen dimer-antibody complexes by methyl viologen and
      signal enhancement due to the supramolecular formation of the antibody and
      viologen dimer. The sensitivity in this system is found to be 2 orders larger
      than that obtained in the simple addition of methyl viologen to the antibody
      immobilized to the surface of the sensor chip.

PMID- 12425653
TI  - Cell interactions with polyelectrolyte multilayer films.
AB  - The short-term interactions of chondrosarcoma cells with polyelectrolyte
      multilayer films built up by the alternate adsorption of poly(L-lysine) (PLL) and
      poly(L-glutamic acid) (PGA) was studied in the presence and in the absence of
      serum. The films and their interaction with serum proteins were first
      characterized by means of optical waveguide lightmode spectroscopy, quartz
      crystal microbalance, and zeta potential measurements. In a serum-containing
      medium, the detachment forces measured by the micropipet technique were about
      eight times smaller on PGA-ending than on PLL-ending films. For these latter
      ones, the adhesion force decreased when the film thickness increased. In a serum
      free medium, the differences between the negative- and positive-ending films were
      enhanced: adhesion forces on PLL-ending films were 40-100% higher, whereas no
      cellular adherence was found on PGA-terminating films. PGA-ending films were
      found to prevent the adsorption of serum proteins, whereas important protein
      adsorption was always observed on PLL-ending films. These results show how cell
      interactions with polyelectrolyte films can be tuned by the type of the outermost
      layer, the presence of proteins, and the number of layers in the film.

PMID- 12425654
TI  - Compatibilization effect of poly(epsilon-caprolactone)-b-poly(ethylene glycol)
      block copolymers and phase morphology analysis in immiscible
      poly(lactide)/poly(epsilon-caprolactone) blends.
AB  - The miscibility and phase behavior of two stereoisomer forms of poly(lactide)
      (PLA: poly (L-lactide) (PLLA) and poly(DL-lactide) (PDLLA)) blends with
      poly(epsilon-caprolactone)-b-poly(ethylene glycol) (PCL-b-PEG) and PCL-b
      monomethoxy-PEG (PCL-b-MPEG) block copolymers have been investigated by
      differential scanning calorimetry (DSC). The DSC thermal behavior of both the
      blend systems revealed that PLA is miscible with the PEG segment phase of PCL-b
      (M)PEG but is still immiscible with its PCL segment phase although PCL was block
      copolymerized with PEG. On the basis of these results, PCL-b-PEG was added as a
      compatibilizer to PLA/PCL binary blends. The improvement in mechanical properties
      of PLA/PCL blends was achieved as anticipated upon the addition of PCL-b-PEG. In
      addition, atomic force microscopy (AFM) measurements have been performed in order
      to study the compositional synergism to be observed in mechanical tests. AFM
      observations of the morphological dependency on blend composition indicate that
      PLA/PCL blends are immiscible but compatible to some extent and that synergism of
      compatibilizing may be maximized in the compositional blend ratio before apparent
      phase separation and coarsening.

PMID- 12425655
TI  - Rheology and dynamic light scattering of silk fibroin solution extracted from the
      middle division of Bombyx mori silkworm.
AB  - Dynamic light scattering (DLS) and rheological measurements were performed on
      aqueous silk fibroin solutions extracted from the middle division of Bombyx mori
      silkworm over a wide range of polymer concentration C from 0.08 to 27.5 wt %. DLS
      results obtained in the dilute region of C less than 1 wt % are consistent with a
      model that an elementary unit is a large protein complex consisting of silk
      fibroin and P25 with a 6:1 molar ratio. Rheological measurements in the dilute C
      region reveal that those units (or clusters) with the hydrodynamic radius of
      about 100 nm form a network extending over the whole sample volume with small
      pseudoplateau modulus mainly by ionic bonding between COO(-) ions of the fibroin
      molecules and divalent metallic ions such as Ca(2+) or Mg(2+) ions present in the
      sample and also that, after a yield stress is reached, steady plastic flow is
      induced with viscosity much lower than the zero-shear viscosity estimated from
      creep and creep recovery measurements by 4-6 orders of magnitude. Angular
      frequency omega dependencies of the storage and the loss shear moduli, G'(omega)
      and G' '(omega), measured in the linear viscoelastic region, indicate that all
      solutions possess the pseudoplateau modulus in the low omega region and samples
      become highly viscoleastic for C greater, similar 4.2 wt %. Above C = 11.2 wt %
      another plateau appears at the high omega end accompanied by a distinct maximum
      of G' ' in the intermediate omega region. The relaxation motion with tau = 0.5 s
      corresponding to the maximum of G' ' is one of characteristic properties of the
      fibroin solutions in the high C region. Thermorheological behaviors of the
      solution with C = 27.5 wt % show that the network structure formed in the MM part
      of the silk gland is susceptible to temperature and a more stable homogeneous
      network is realized by raising the temperature up to T = 65 degrees C.

PMID- 12425656
TI  - Novel branched poly(ethylenimine)-cholesterol water-soluble lipopolymers for gene
      delivery.
AB  - A novel water-soluble lipopolymer was synthesized by linking cholesteryl
      chloroformate to the secondary amino groups of branched poly(ethylenimine) (PEI)
      of 1,800 and 10,000 Da. Conjugation through PEI secondary amines gives this newly
      synthesized lipopolymer (abbreviated as PEI-Chol) special advantage over our
      previously synthesized lipopolymers, which utilized the primary amino groups for
      conjugation, as the primary amino groups have a significant role in DNA
      condensation. Also, significantly, only one cholesterol molecule was grafted onto
      each PEI molecule (confirmed by (1)H NMR and MALDI-TOF mass spectrometry),
      leaving enough space for the steric interactions of the PEI's primary amines with
      the DNA. The PEI-Chol lipopolymer was characterized for the critical micellar
      concentration (cmc), buffer capacity, DNA condensation (by band retardation and
      circular dichroism), in vitro transfection efficiency, and cell viability. The
      cmcs of PEI-Chol 1,800 and PEI-Chol 10,000 were 496.6 and 1,330.5 microg/mL,
      respectively. The acid-base titration indicated high buffering capacity of the
      polymers around the pH range of 5-7, which indicated their potential for
      buffering in the acidic pH environment of the endosomes. The band retardation
      studies indicated that efficient condensation of the plasmid DNA could be
      achieved using these lipopolymers. The circular dichroism spectra indicated a
      change in DNA conformation and adoption of lower energy state upon condensation
      with these lipopolymers when an N/P ratio of 2.5/1 or above was formulated. The
      mean particle size of these complexes was in the range 110-205 nm, except for the
      complexes prepared using PEI of 1,800 Da, which had a mean particle size of 384
      +/- 300 nm. The zeta potential of DNA complexes prepared using PEI-Chol 1,800,
      PEI-Chol 10,000 and PEI of 1,800, 10,000, and 25,000 Da at an N/P ratio of 15/1
      was in the range 23-30 mV and was dependent on the N/P ratios. The in vitro
      transfection of PEI-Chol/pCMS-EGFP complexes in Jurkat cells showed high levels
      of expressed Green Fluorescent Protein (GFP) with little toxicity as determined
      by flow cytometry. These novel water-soluble lipopolymers provided good
      transfection efficiency with other desirable characteristics such as water
      solubility, free primary amino groups for efficient DNA condensation and high
      buffer capacity that indicated the possibility of efficient endosomal release.

PMID- 12425657
TI  - Phase separation in a sheared gelatin/maltodextrin mixture studied by small-angle
      light scattering.
AB  - The influence of shear on the structure of a gelatin/maltodextrin mixture was
      investigated using small-angle light scattering both during phase separation and
      after phase separation was allowed to occur quiescently. In all cases, phase
      separation occurred via spinodal decomposition to form a droplet morphology, and
      a characteristic length scale was formed in the structure that was prevalent
      during shear, as well as in quiescent conditions. Below the critical shear rate
      for droplet breakup, shear accelerated the coarsening rate of the droplets. A
      transient regime of rapid hydrodynamic coarsening was present when shear was
      initiated after phase separation and at late times in all cases once the droplets
      attained a certain size. At the critical shear rate for droplet breakup (1 s(
      1)), the rapid repetition of breakup and coarsening was postulated to occur,
      which enabled a microstructure consisting of elongated droplets with a narrow
      size distribution to form. When the shear rate enabled droplets to extend to such
      an extent that a percolated structure could form (10 s(-1)), then the structure
      was relatively stable and changed very slowly over time. At very high shear rates
      (100 s(-1)), droplet breakup was suppressed and a highly fibrillar morphology
      formed that was stable only while the system was under shear. Cessation of shear
      at high rates led to fiber breakup and the formation of many small droplets. For
      a given shear rate, the final microstructure appeared to be independent of the
      time that shear was started when the structure consisted of discrete droplets or
      fibers. When a percolated structure could form, however, the shear history
      appeared to be important.

PMID- 12425658
TI  - Water absorbency by wool fibers: Hofmeister effect.
AB  - Wool is a complex material, composed of cuticle and epicuticle cells, surrounded
      by a cell membrane complex. Wool fibers absorb moisture from air, and, once
      immersed in water, they take up considerable amounts of liquid. The water
      absorbency parameter can be determined from weight gain, according to a standard
      method, and used to quantify this phenomenon. In this paper we report a study on
      the water absorbency (or retention) of untreated wool fibers in the presence of
      aqueous 1 M salt solutions at 29 degrees C and a relative humidity of either 33%
      or 56%. The effect of anions was determined by selecting a wide range of
      different sodium salts, while the effect of cations was checked through some
      chlorides and nitrates. Our results show a significant specific ion and ion pair
      "Hofmeister" effects, that change the amount of water absorbed by the fibers. To
      understand this phenomenon, the water absorbency parameter (A(w)) is compared to
      different physicochemical parameters such as the lyotropic number, free energy of
      hydration of ions, molar surface tension increment, polarizability, refractive
      index increment, and molar refractivity. The data indicate that this Hofmeister
      phenomenon is controlled by dispersion forces that depend on the polarizability
      of ionic species, their adsorption frequencies, the solvent, and the substrate.
      These dispersion forces dominate the behavior in concentrated solutions. They are
      in accord with new developing theories of solutions and molecular interactions in
      colloidal systems that account for Hofmeister effects.

PMID- 12425659
TI  - Aqueous gel formation of a synthetic peptide derived from the beta-sheet domain
      of platelet factor-4.
AB  - We observed gelation of a 23-residue peptide derived from the beta-sheet domain
      of platelet factor-4 (PF4(24)(-)(46)). The gels were primarily heterogeneous
      mixtures of 50-200 microm spherical aggregates in a less-dense gel matrix.
      Infrared and circular dichroism spectroscopies showed gelation involving the
      conversion of PF4(24)(-)(46) from random coil to beta-sheet. We used aggregation
      induced NMR resonance broadening to show that temperature, pH, and ionic strength
      influenced PF4(24)(-)(46) gelation rates. Under identical solution conditions,
      gel formation took days at T </= 20 degrees C but only 30 min at T >/= 50 degrees
      C. Gelation was most rapid at pH values near the pK(a) of the central His35
      residue. Increases in solution ionic strength reduced the critical gelation
      concentration of PF4(24)(-)(46). Our results suggest that PF4(24)(-)(46) gels by
      a process combining aspects of both heat-set and beta-fibril gelation mechanisms.

PMID- 12425660
TI  - Electrospinning Bombyx mori silk with poly(ethylene oxide).
AB  - Electrospinning for the formation of nanoscale diameter fibers has been explored
      for high-performance filters and biomaterial scaffolds for vascular grafts or
      wound dressings. Fibers with nanoscale diameters provide benefits due to high
      surface area. In the present study we explore electrospinning for protein-based
      biomaterials to fabricate scaffolds and membranes from regenerated silkworm silk,
      Bombyx mori, solutions. To improve processability of the protein solution,
      poly(ethylene oxide) (PEO) with molecular weight of 900,000 was blended with the
      silk fibroin. A variety of compositions of the silk/PEO aqueous blends were
      successfully electrospun. The morphology of the fibers was characterized using
      high-resolution scanning electron microscopy. Fiber diameters were uniform and
      less than 800 nm. The composition was estimated by X-ray photoelectron
      spectroscopy to characterize silk/PEO surface content. Aqueous-based
      electrospining of silk and silk/PEO blends provides potentially useful options
      for the fabrication of biomaterial scaffolds based on this unique fibrous
      protein.

PMID- 12425662
TI  - NMR imaging of high-amylose starch tablets. 2. Effect of tablet size.
AB  - Carbohydrate polymers are widely used for pharmaceutical applications such as the
      controlled release of drugs. The swelling and water mobility in high-amylose
      starch tablets are important parameters to be determined for these applications.
      They have been studied at different time intervals by nuclear magnetic resonance
      imaging (NMRI) after the immersion of the samples in water. These tablets have a
      hydrophilic matrix, which swells anisotropically and forms a hydrogel in water.
      NMRI shows clearly the anisotropy of the water penetration and the swelling along
      the radial and axial dimensions of the tablets. Empirical relationships are
      established to describe the kinetics of water penetration and swelling of the
      tablets. Results show that water uptake and tablet swelling strongly depend on
      the size of the tablets. Gravimetric measurements of water uptake were also
      performed in comparison with the NMRI results.

PMID- 12425661
TI  - Collagen-binding matrix proteins from elastomeric extraorganismic byssal fibers.
AB  - The byssal threads of marine mussels represent a peculiar case of extraorganismic
      extracellular material. The threads consist of fibrous chimeric collagens such as
      preCol-P (with collagenous, elastin-like and histidine-rich domains) embedded in
      a microfibrillar matrix. We report here on the extraction, purification, and
      characterization of water-soluble proximal thread matrix protein 1 (PTMP1), which
      is preferentially located in the proximal portion of each byssal thread and
      decreases in a proximal to distal direction. PTMP1 has a mass of about 50 kDa as
      determined by matrix-assisted laser desorption-ionization with time-of-flight
      (MALDI-TOF) mass spectrometry. Glycine is the most common residue at 12.2 mol %,
      followed by asparagine/aspartic acid and glutamine/glutamic acid at 11.4 and 9.9
      mol %, respectively. Glycosylation has been detected by Western blotting with
      biotinylated concanavalin A and neutral sugar analysis. With degenerate primers
      designed from the N-terminal sequence and an additional internal peptide derived
      by Lys-C endopeptidase digestion, a complete cDNA sequence for this protein was
      obtained by polymerase chain reaction (PCR) amplification of a Mytilus edulis
      foot cDNA library. Two variants with minor sequence differences limited to the N
      terminus were found. The cDNA-deduced protein sequence reveals two symmetric
      internal repeats that together account for >85% of the protein. Sequence and
      epitope similarity of PTMP1 to the A domains of von Willebrand factor and
      integrin alpha(1)I suggest a capacity for collagen binding. Enzyme-linked
      immunosorbent assay (ELISA)-based measurement of PTMP1 binding to immobilized
      type I collagen shows high affinity (apparent K(D) = 0.25 microM), but the
      binding exhibits no dependence on metals. Using primers designed from M. edulis,
      we also found a PTMP1-like cDNA in a related species, M. galloprovincialis, with
      a deduced protein sequence having 97% identity with one M. edulis variant and 99%
      identity with the other. The corresponding cDNA sequences have 94% and 96%
      identity, respectively.

PMID- 12425663
TI  - Tailoring of physical and chemical properties of macro- and microhydrogels based
      on telechelic PVA.
AB  - Poly(vinyl alcohol), PVA, is amenable to several structural modifications because
      of the presence of the hydroxyl moiety in the backbone. The chemical versatility
      of this polymer can be used for the obtainment of new wall-to-wall pH-responsive
      PVA chemical hydrogels and for the preparation of air-filled microspheres, for
      example, microbubbles. Here, we report on the characterization of the physical
      and chemical properties of these novel networks that can be potentially used in
      different biomedical applications as controlled drug delivery and as ultrasonic
      contrast agent.

PMID- 12425664
TI  - Evaluation of the in vitro degradation of macroporous hydrogels using gravimetry,
      confined compression testing, and microcomputed tomography.
AB  - This study investigated the in vitro degradation characteristics of macroporous
      hydrogels based on poly(propylene fumarate-co-ethylene glycol) (P(PF-co-EG)).
      Four formulations were fabricated to test the effect of porosity and cross
      linking density on the degradation of the resulting macroporous hydrogels.
      Macroporosity was introduced by the addition of sodium bicarbonate and ascorbic
      acid, the precursors of the carbon dioxide porogen, in the initiation system for
      the hydrogel cross-linking. Macroporous hydrogels with porosities of 0.80 +/-
      0.03 and 0.89 +/- 0.03 were synthesized by the addition of sodium bicarbonate of
      concentrations 40 and 80 mg/mL and ascorbic acid of concentrations 0.05 and 0.1
      mol/L, respectively. Poly(ethylene glycol) diacrylate (PEG-DA) was utilized as a
      cross-linker. The molecular weight between cross-links had a significant effect
      on weight loss after 12 weeks, where samples with M(C) of 1,880 +/- 320
      synthesized with a P(PF-co-EG):PEG-DA ratio of 3:1 had a significantly greater
      mass loss due to degradation than those with M(C) of 1,000 +/- 100 synthesized
      with a P(PF-co-EG):PEG-DA ratio of 1:1. In contrast, porosity played a minimal
      role in determining the weight loss. Mechanical testing of the hydrogels under
      confined compression showed a decrease in compressive modulus over the
      degradation time for all formulations. In addition, an increase in hydrogel
      equilibrium water content and pore wall thickness was observed with degradation
      time, whereas the hydrogel porosity and surface area density remained invariant.
      The results from microcomputed tomography corroborated with the rest of the
      measurements and indicated a bulk degradation mechanism of the macroporous
      hydrogels.

PMID- 12425665
TI  - Constant-volume hydrogel osmometer: a new device concept for miniature
      biosensors.
AB  - A new type of biosensor is proposed that combines the recognition properties of
      "intelligent" hydrogels with the sensitivity and reliability of microfabricated
      pressure transducers. In the proposed device, analyte-induced changes in the
      osmotic swelling pressure of an environmentally responsive hydrogel are measured
      by confining it within a small implantable enclosure between a rigid
      semipermeable membrane and the diaphragm of a miniature pressure transducer.
      Proof-of-principle tests of this device were performed in vitro using pH
      sensitive hydrogels, with osmotic deswelling data for the same hydrogels used as
      a benchmark for comparison. The swelling pressure of the hydrogel was accurately
      determined from osmotic deswelling measurements against reservoirs of known
      osmotic stress. Values of swelling pressure vs salt concentration measured with a
      preliminary version of the sensor agree well with osmotic deswelling results.
      Through modification of the hydrogel with various enzymes or pendant binding
      moieties, the sensor has the potential to detect a wide range of biological
      analytes with good specificity.

PMID- 12425666
TI  - Reorganization of dynamic self-assemblies of cellulose diacetate in solution:
      dynamical critical-like fluctuations in the lower critical solution temperature
      system.
AB  - Dynamics of cellulose diacetate (CDA, the total degree of substitution (TDS) =
      2.44) in dimethylacetamide (DMAc) in dilute solution was investigated at 2, 10,
      20, 30, 40, 49.7, and 61.5 degrees C through dynamic light scattering in the
      quiescent state. The following three facts were made clear. First, CDA existed in
      three types of structures in the polar solvent, DMAc; one is a single CDA chain,
      and the others are dynamic structures, or self-assemblies, which were formed
      temporarily and locally by the solvent-mediated hydrogen bonding between the
      intermolecular C-6 position hydroxyls of the anhydroglucose units in the CDA
      backbone. Second, CDA showed a nature of low-temperature solubility in DMAc, that
      is, CDA is expected to dissolve molecularly below -12 degrees C but to take a
      phase separation above 65 degrees C, where two structures such as collapses of a
      single CDA chain and an aggregate appear. Third, a reorganization in the dynamic
      structures was detected at the temperature T = 33.8 degrees C. At this
      temperature, two dynamic structures showed the discontinuity in their correlation
      lengths, whereas the single CDA realized an uncorrelated chain state in the
      dynamical sense. In view of the low-temperature solubility of CDA in DMAc, this
      abnormal behavior around T was explained by dynamical critical-like fluctuations
      if T were treated as a kind of lower critical solution temperature (LCST) in the
      CDA/DMAc system. Here, the self-assemblies arise as the dynamical fluctuations
      under the spinodal decomposition situation and the competition between the
      hydrogen bonding (HB) and the hydrophobic interaction (HPhI) makes the
      conformation of CDA chains change drastically. In this scheme, the solvent
      mediated HB and HPhI play important roles in the structure reorganization of
      cellulose derivatives in strong electronegative solvents, though HB and HPhI
      cooperate with the inherent chain helicality.

PMID- 12425667
TI  - In situ immobilization of proteins and RGD peptide on polyurethane surfaces via
      poly(ethylene oxide) coupling polymers for human endothelial cell growth.
AB  - A "CBABC"-type pentablock coupling polymer, mesylMPEO, was designed and
      synthesized to promote human endothelial cell growth on the surfaces of
      polyurethane biomaterials. The polymer was composed of a central 4,4'
      methylenediphenyl diisocyanate (MDI) coupling unit and poly(ethylene oxide) (PEO)
      spacer arms with methanesulfonyl (mesyl) end groups pendent on both ends. As the
      presurface modifying additive (pre-SMA), the mesylMPEO was noncovalently
      introduced onto the poly(ether urethane) (PEU) surfaces by dip coating, upon
      which the protein/peptide factors (gelatin, albumin, and arginine-glycine
      aspartic acid tripeptide [RGD]) were covalently immobilized in situ by cleavage
      of the original mesyl end groups. The pre-SMA synthesis and PEU surface
      modification were characterized using nuclear magnetic resonance spectroscopy
      ((1)H NMR), attenuated total reflection infrared spectroscopy (ATR-FTIR), and X
      ray photoelectron spectroscopy (XPS). Human umbilical vein endothelial cells
      (HUVEC) were harvested manually by collagenase digestion and seeded on the
      modified PEU surfaces. Cell adhesion ratios (CAR) and cell proliferation ratios
      (CPR) were measured using flow cytometry, and the individual cell viability (ICV)
      was determined by MTT assay. The cell morphologies were investigated by optical
      inverted microscopy (OIM) and scanning electrical microscopy (SEM). The gelatin-
      and RGD-modified surfaces were HUVEC-compatible and promoted HUVEC growth. The
      albumin-modified surfaces were compatible but inhibited cell adhesion. The
      results also indicated that, for HUVEC in vitro cultivation, the cell adhesion
      stage was of particular importance and had a significant impact on the cell
      responses to the modified surfaces.

PMID- 12425668
TI  - Gelation behavior of native and acetylated konjac glucomannan.
AB  - Gelation kinetics of native and acetylated konjac glucomannan (KGM) samples in
      the presence of alkali (sodium carbonate) was studied by dynamic viscoelastic
      measurements. Molecular weight and other molecular parameters of KGM were
      determined by static light scattering and viscosity measurements. It was found
      that KGM molecules were degraded during acetylation treatment, but the molecular
      weights of acetylated samples were almost independent of the degree of
      acetylation (DA) and were about a half of that of a native sample. At a fixed
      alkaline concentration, increasing concentration of KGM or temperature shortened
      the gelation time, but increasing DA delayed it. The deacetylation reaction and
      subsequent aggregation process of acetylated samples needed longer time than that
      of native sample, and acetylated samples formed finally more elastic gels. It
      implied that the presence of acetyl groups exerts a strong influence on gelation
      behavior of KGM. It was suggested that the gelation rate of acetylated KGM and
      native KGM, which depends on the alkaline concentration and temperature, is an
      important factor that determines the elastic modulus of gels. This was supported
      by the experimental finding that the saturated elastic modulus tends to the same
      value when the ratio of alkali concentration to acetylated groups was kept
      constant. In slower gelation processes, junction zones are more homogeneously
      distributed and more numerous, leading to the more elastic gels.

PMID- 12425669
TI  - Disulfide cross-linked hyaluronan hydrogels.
AB  - A new disulfide cross-linking strategy was developed to prepare hyaluronic acid
      (HA) hydrogel from thiol-modified HA. First, dithiobis(propanoic dihydrazide)
      (DTP) and dithiobis(butyric dihydrazide) (DTB) were synthesized and then coupled
      to HA with carbodiimide chemistry. Next, disulfide bonds of the initially formed
      gel were reduced using dithiothreitol (DTT) to give, after exhaustive dialysis,
      the corresponding thiol-modified macromolecular derivatives HA-DTPH and HA-DTBH.
      The degree of substitution of HA-DTPH and HA-DTBH could be controlled from 20% to
      70% of available glucuronate carboxylic acid groups. The pK(a) values of the HA
      thiol derivatives were determined spectrophotometrically to be pK(a) = 8.87 (HA
      DTPH) and pK(a) = 9.01 (HA-DTBH). The thiol groups could be oxidized in air to
      reform disulfide linkages, which resulted in HA-DTPH and HA-DTBH hydrogel films.
      Further oxidation of these hydrogels with dilute H(2)O(2) created additional
      cross-links and afforded poorly swellable films. The disulfide cross-linking was
      reversible, and films could be again reduced to sols with DTT. Release of blue
      dextran from cross-linked films was used as a model for drug release. The rapid
      gelation of the HA-DTPH solution under physiological conditions was also
      achieved, which demonstrated the capacity for in situ cell encapsulation. Thus, L
      929 murine fibroblasts were encapsulated in HA-DTPH hydrogel; these cells
      remained viable and proliferated during 3 days of culture in vitro.

PMID- 12425670
TI  - Surface modification of polycaprolactone membrane via aminolysis and
      biomacromolecule immobilization for promoting cytocompatibility of human
      endothelial cells.
AB  - Amino groups were covalently introduced onto a polycaprolactone (PCL) surface by
      the reaction between 1,6-hexanediamine and the ester groups of PCL. The
      occurrence of the aminolysis and the introduction of free NH(2) groups were
      verified qualitatively by fluorescence spectroscopy, where rhodamine B
      isothiocyanate was employed to label NH(2) groups, and quantitatively by
      absorbance spectroscopy, where ninhydrin was used to react with NH(2) to generate
      a blue product. Due to the presence of deep pores on the PCL membrane, the
      aminolysis reaction could penetrate as deep as 50 microm to yield NH(2) density
      as high as 2 x 10(-7) mol/cm(2). By use of the NH(2) groups as active sites,
      biocompatible macromolecules such as gelatin, chitosan, or collagen were further
      immobilized on the aminolyzed PCL membrane via a cross-linking agent,
      glutaraldehyde. X-ray photoelectron spectroscopy (XPS) and surface wettability
      measurements confirmed the coupling of the biomacromolecules. The endothelial
      cell culture proved that the cytocompatibility of the aminolyzed PCL was improved
      slightly regardless of the NH(2) amount on the surface. After immobilization of
      the biomacromolecules, however, the cell attachment and proliferation ratios were
      obviously improved and the cells showed a similar morphology to those on tissue
      culture polystyrene. Measurement of the von Willebrand factor (vWF) secreted by
      these endothelial cells (ECs) verified the endothelial function. Hence, a better
      EC-compatible PCL was produced.

PMID- 12425672
TI  - Chemical modification of chlorinated microbial polyesters.
AB  - Chlorination of microbial polyesters poly(3-hydroxybutyrate) (PHB) and poly(3
      hydroxyoctanoate) (PHO) was carried out by passing chlorine gas through their
      solutions. The chlorine contents in chlorinated PHB (PHB-Cl) and chlorinated PHO
      (PHO-Cl) were between 5.45 and 23.81 wt % and 28.09 and 39.09 wt %, respectively.
      Molecular weights of the chlorinated samples were in the range of between one
      half to one-fourth of the original values because of hydrolysis during the
      chlorination process. Thermal properties of the PHO-Cl were dramatically changed
      with an increase in its glass transition (T(g) = 2 degrees C) and the melting
      transition (T(m)). The T(g) of PHB-Cl varied from -20 to 10 degrees C, and its
      T(m) decreased to 148 degrees C. The chlorinated poly(3-hydroxyalkanoate)s (PHA
      Cl) were converted to their corresponding quaternary ammonium salts (PHA
      N(+)R(3)), sodium sulfate salts (PHA-S), and phenyl derivatives (PHA-Ph). Cross
      linked polymers were also formed by a Friedel-Crafts reaction between benzene and
      PHA-Cl. The modified PHO derivatives were characterized by (1)H NMR and (13)C NMR
      spectrometry, Fourier transform infrared spectroscopy, gel permeation
      chromatography, and differential scanning calorimetry techniques.

PMID- 12425671
TI  - Change of surface structure of poly(3-hydroxybutyrate) film upon enzymatic
      hydrolysis by PHB depolymerase.
AB  - The change in the surface structure of poly[(R)-3-hydroxybutyrate] [PHB] films
      upon the enzymatic hydrolysis was analyzed by attenuated total reflection
      infrared [ATR/IR] spectrometry. As enzymes, PHB depolymerases isolated from
      Ralstonia pickettii T1 and Pseudomonas stutzeri were used. By curve decomposition
      of the carbonyl stretching band of ATR/IR spectra, the change in the surface
      crystallinity of PHB films by exposure to buffer containing 0, 1, and 4 microg of
      PHB depolymerases was estimated. It has been widely believed that the enzymatic
      hydrolysis first occurs in the amorphous phase, followed by the degradation in
      the crystalline phase, and extracellular PHB depolymerase can degrade only
      polymer chains in the surface layer of the film. Therefore, the surface
      crystallinity had been expected to increase upon the enzymatic degradation.
      However, the results were contrary to this expectation. The surface crystallinity
      was decreased by the enzymatic attack. Because ATR/IR spectrometry is sensitive
      to a small change in molecular structure of the sample surface, the decrease in
      the crystallinity shown by ATR/IR experiments probably does not indicate the
      complete loss of regularity of the crystalline phase. Because the chains at
      crystalline surface are more mobile than those inside the crystals, the C=O band
      for crystalline surface may appear at a position similar to those of the
      amorphous or interfacial phase in ATR/IR spectra of PHB. Only the chains inside
      the crystals may contribute to the C=O band of the crystalline phase. Thus, we
      rather suppose that the decrease in the crystalline peak of the ATR/IR spectra
      reflects the change in chain mobility or the increase of crystalline surface area
      by cracking of lamellas at the surface layers of PHB films or both.

PMID- 12425673
TI  - Relation between solution properties and degree of acetylation of chitosan: role
      of aging.
AB  - Aging of solutions of chitosan varying in degree of acetylation (DA) and degree
      of dissociation (alpha) was studied using two techniques. The first concerned
      potentiometric experiments performed during 3 days on solutions having the same
      concentration of amino groups (5.2% < DA < 70.6% and 0 < alpha < 1.1). The
      presence of aggregates at low alpha certainly depends on electrostatic
      interactions for low DA values and on hydrophobic interactions and H-bondings for
      high values. When alpha increases, the role of the cationicity of the amine
      groups, which depends on DA, seems to play a more important role on the behavior
      of the polymer chains. The second regarded capillary viscometric experiments
      performed during 5 days on solutions of the same polymer concentration (5.2% < DA
      < 70.6% and 0 < alpha < 0.30). The observations mentioned above and the results
      obtained in a previous paper (Biomacromolecules 2001, 2 (3), 765) are confirmed,
      and the influence of the electroviscous effects is discussed.

PMID- 12425674
TI  - A high field NMR study of the products ensuing from konjak glucomannan C(6)
      oxidation followed by enzymatic C(5)-epimerization.
AB  - Konjak glucomannan (KGM) is a water-soluble linear copolymer of (1-->4) linked
      beta-D-mannopyranosyl and beta-D-glucopyranosyl units. It has been selectively C6
      oxidized by a 2,2,6,6-tetramethylpiperidin-1-oxy mediated reaction to obtain the
      corresponding uronan. Oxidized KGM has been treated with three different C-5
      epimerases, AlgE4, AlgE6, and AlgE1, to obtain uronans with a various content of
      alpha-L-gulopyranuronate residues, namely, KGME4, KGME6, and KGME1. By use of 1D
      selective and 2D NMR techniques, a full assignment of the high field (600 MHz)
      NMR spectra of the purified native KGM and of the oxidized and epimerized
      derivatives has been obtained. Since in the anomeric region of the (1)H NMR
      spectrum of native KGM, diads sensitivity is present, the glucose-glucose,
      glucose-mannose, mannose-mannose, and mannose-glucose distribution has been
      obtained. In the (13)C spectrum of oxidized KGM, due to the presence of triad
      sensitivity on the C-4 resonance of glucuronic and mannuronic units, a better
      sequential investigation has been possible. As a result the average length of
      mannuronic blocks, N(M) is obtained. When AlgE4, AlgE6, and AlgE1 enzymes are
      used for the epimerization of oxidized KGM, the reaction products differ
      significantly both in the proportion and in the distribution of the mannuronic
      and guluronic residues. In epimerized KGM derivatives, a careful deconvolution of
      (1)H spectra allows the measurement of the degree of epimerization. In the case
      of KGME1 and KGME6, the average blocks length, N(G), of the guluronic blocks
      introduced in the polysaccharidic chain with the epimerization has also been
      calculated. Due to the shortness of mannuronic blocks in the oxidized KGM before
      the epimerization, N(G) in the epimerized compounds is also very low.

PMID- 12425675
TI  - Enzyme-based molecular imprinting with metals.
AB  - Aromatic monomers with various functional groups were utilized in horseradish
      peroxidase-catalyzed polymerization reactions with metal ions Cu(II), Ni(II), and
      Fe(III) as imprinting templates. The approach described combines molecular
      imprinting with enzymatic free radical coupling. Selectivity in metal ion
      affinity between the various polymer products was assessed and found to depend on
      the metal used in the imprinting process using aniline, tyramine, and phenol as
      monomers. Selectivity in binding metals was found when polymers imprinted with
      copper, nickel, or iron were screened against the three metals, with preference
      for the metal used in the imprinting step. A model for the structural features of
      the putative imprinted polymers is proposed based on electron paramagnetic
      resonance, NMR, and IR analysis. Specific potential benefits to this imprinting
      method include reactivity with a wide range of aromatic monomers to provide more
      diverse options for molecular recognition with the target analyte and thus
      polymer products with higher selectivity, mild reaction conditions for the enzyme
      polymerization step to enable imprinting against labile substrates, imprinted
      polymeric products that contain conjugated backbones that could be suitable for
      electronics-based biosensor applications, and a potential for combinatorial
      selection to further enhance specificity.

PMID- 12425676
TI  - Initial characterization of ethyl(hydroxyethyl) cellulose using enzymic
      degradation and chromatographic methods.
AB  - Two different ethyl(hydroxyethyl) cellulose (EHEC) samples were characterized by
      size-exclusion chromatography (SEC) with multiangle light scattering (MALS)
      detection and high-performance anion-exchange chromatography (HPAEC) with pulsed
      amperometric detection (PAD). The aim of the study was to investigate the molar
      mass distribution and the heterogeneity of the substituent distribution, factors
      that are thought to affect the functional properties of EHEC. The presence of
      blocks of unsubstituted glucose units was studied by enzymic degradation of EHEC
      by two different endoglucanases from Trichoderma reesei. The SEC-MALS analysis of
      the hydrolysis products showed that both enzymes were strongly inhibited by the
      large number of substituents along the cellulose chain. However, as the weight
      average molar mass was reduced from approximately 360,000 to 80,000 g/mol in one
      of the polymers and from 770,000 to 60,000 g/mol in the other polymer, it was
      suggested that both samples were composed of some unsubstituted regions where the
      enzymes got access to the glucosidic bonds. The amount of glucose released upon
      endoglucanase hydrolysis was determined by HPAEC-PAD, which gave information on
      the homogeneity of the substituent distribution. The production of unsubstituted
      glucose units indicated that one of the polymers had a more uneven distribution
      compared with the other. It was demonstrated that chemical characterization of
      EHEC is a complex task, which requires an analytical approach involving numerous
      different methods and techniques.

PMID- 12425677
TI  - Synthesis and self-association behavior of biodegradable amphiphilic
      poly[bis(ethyl glycinat-N-yl)phosphazene]- poly(ethylene oxide) block copolymers.
AB  - Amphiphilic diblock copolymers with varying compositions of hydrophilic
      poly(ethylene oxide) (PEO) and hydrophobic poly[bis(ethyl glycinat-N
      yl)phosphazene] (PNgly) were synthesized via the controlled cationic-induced
      polymerization of a phosphoranimine (Cl(3)P=NSiMe(3)) at ambient temperature
      using a PEO-phosphoranimine macroinitiator. The aqueous-phase transition behavior
      of PEO-PNgly-3 (M(n) = 10,000) and micelle formation of both PEO-PNgly-3 and PEO
      PNgly-4 (M(n) = 8,500) were investigated using fluorescence techniques and
      dynamic light scattering. The critical micelle concentrations (cmc's) of PEO
      PNgly-3 and PEO-PNgly-4 were determined to be 3 and 12 mg/L with the mean
      diameters of micelles being 120 and 130 nm, respectively. The hydrolytic
      degradation of these diblock copolymers was also studied in solution. These
      studies coupled with the biodegradability of the poly[bis(ethyl glycinat-N
      yl)phosphazene] block to give benign products make PEO-PNgly copolymers well
      suited for a wide variety of biomedical applications including novel
      biodegradable drug-delivery systems.

PMID- 12425678
TI  - Chitosan cross-linking with a water-soluble, blocked diisocyanate. 1. Solid
      state.
AB  - The present investigation focuses on the synthesis and application of a cross
      linking agent that is compatible with the solubility characteristics of chitosan.
      A water-soluble, blocked-diisocyanate was prepared as a bisulfite adduct to 1,6
      hexamethylene diisocyanate, which proved to be stable for several weeks in
      aqueous, acidic chitosan solutions at room temperature. Thermal cross-linking of
      chitosan as cast, dried films was investigated by varying the NCO/NH(2) ratio
      from 0.0 to 1.2. Spectroscopic (IR), thermal (TGA), swelling, and structural
      (WAXD) studies indicated that chitosan was cross-linked in a concentration
      dependent manner under mild thermal conditions: 60 degrees C for 24 h. Cross
      linking inefficiency was concluded to be due to lack of mobility of the reacting
      species in the solid state. In a preliminary study, the enzymatic degradation
      with Chitinase (E. C. 3.2.1.14) from Streptomyces griseus was found to be the
      greatest for non-crosslinked chitosan, followed by chitin, and then by cross
      linked samples.

PMID- 12425679
TI  - Cell adhesion and morphology in porous scaffold based on enantiomeric poly(lactic
      acid) graft-type phospholipid polymers.
AB  - Poly(D-lactic acid) (PDLA) and poly(L-lactic acid) (PLLA) macromonomers were
      synthesized for preparation of a novel cytocompatible polymer. The cytocompatible
      polymer was composed of 2-methacryloyloxyethyl phosphorylcholine (MPC), n-butyl
      methacrylate (BMA), and the enantiomeric PLLA (or PDLA) macromonomer. The degree
      of polymerization of the lactic acid in the PLLA and PDLA segments was designed
      to be ca. 20. The copolymer-coated surface was analyzed with static contact angle
      by water. From the result, the PLLA (or PDLA) segment and MPC unit were located
      on the coated surface, and the monomer unit in the copolymer was reconstructed by
      contacting water. Fibroblast cell culture was performed to evaluate cell adhesion
      on the coated surface, and the cell morphology was observed. The number of cell
      adhesion is correlated with the PL(D)LA content, and the cell morphology is
      correlated with the MPC unit content. The porous scaffold was prepared by the
      formation of a stereocomplex between the PLLA and PDLA, and the cell adhesion and
      following cell intrusion was then evaluated. The fibroblast cells adhered on the
      surface and intruded into the scaffold through the connecting pores after 24 h.
      The cell morphology became round shape from spreading with the decreasing PLLA
      (or PDLA) content in the copolymer. It is considered that the change in the cell
      morphology would be induced by the MPC unit as cytocompatible unit. These
      findings suggest that the porous scaffold makes it possible to have
      cytocompatibility and to produce three-dimensional tissue regeneration.

PMID- 12425680
TI  - New gelatin-based hydrogels via enzymatic networking.
AB  - New types of hydrogels have been obtained starting from high bloom purified
      gelatin A, alone or in mixtures with hyaluronan and with a hyaluronan derivative
      bearing primary amino groups, by transglutaminase-catalyzed cross-linking. The
      reticulation process, carried out adopting two different temperature protocols,
      and the ensuing materials have been characterized in terms of rheologically
      estimated gel times, equilibrium swelling in water and in phosphate buffer
      solution (PBS), and rigidity modulus. Main structural and conformational factors
      governing the physicochemical properties and the possible application of the new
      hydrogels are discussed.

PMID- 12425681
TI  - Methacrylate derivatives incorporating pyroglutamic acid.
AB  - Methacrylates containing pyroglutamic acid were synthesized in good yields.
      Methyl alpha-pyroglutamyl methylacrylate (PyMM) and methyl alpha
      pyroglutamidoundecanoyl methylacrylate (PyUM) give very fast photopolymerization
      rates both in homopolymerizations and with widely used commercial monomers N
      vinyl pyrrolidinone (NVP) and hydroxyethyl methacrylate (HEMA). Soluble or cross
      linked homopolymers can be obtained depending upon polymerization temperature.
      Pyroglutamic methacrylates polymerize without added initiator in the melt.
      Solution cast, photocured, and thermally cured coatings gave good to excellent
      adhesion to poly(ethylene terephthalate) and glass surfaces.

PMID- 12425682
TI  - Grace notes.

PMID- 12425683
TI  - Age-related macular degeneration.

PMID- 12425684
TI  - Biological secrets of exceptional old age: centenarian study seeks insight into
      aging well.

PMID- 12425685
TI  - Hitching a ride to health care: retired physicians volunteer to serve the
      uninsured.

PMID- 12425686
TI  - Elder abuse and neglect a new research topic.

PMID- 12425692
TI  - Risk of motor vehicle crashes in patients with cataract surgery.

PMID- 12425693
TI  - Thrombolytic therapy vs angioplasty in acute myocardial infarction.

PMID- 12425694
TI  - Thrombolytic therapy vs angioplasty in acute myocardial infarction.

PMID- 12425696
TI  - A woman attempting to discontinue hormone therapy.

PMID- 12425697
TI  - A woman attempting to discontinue hormone therapy.

PMID- 12425701
TI  - Antioxidants and risk of Alzheimer disease.

PMID- 12425702
TI  - Antioxidants and risk of Alzheimer disease.

PMID- 12425703
TI  - Vitamin E and C supplements and risk of dementia.

PMID- 12425705
TI  - Growth hormone and sex steroid administration in healthy aged women and men: a
      randomized controlled trial.
AB  - CONTEXT: Hormone administration to elderly individuals can increase lean body
      mass (LBM) and decrease fat, but interactive effects of growth hormone (GH) and
      sex steroids and their influence on strength and endurance are unknown.
      OBJECTIVE: To evaluate the effects of recombinant human GH and/or sex steroids on
      body composition, strength, endurance, and adverse outcomes in aged persons.
      DESIGN, SETTING, AND PARTICIPANTS: A 26-week randomized, double-blind, placebo
      controlled parallel-group trial in healthy, ambulatory, community-dwelling US
      women (n = 57) and men (n = 74) aged 65 to 88 years recruited between June 1992
      and July 1998. INTERVENTIONS: Participants were randomized to receive GH
      (starting dose, 30 micro g/kg, reduced to 20 micro g/kg, subcutaneously 3
      times/wk) + sex steroids (women: transdermal estradiol, 100 micro g/d, plus oral
      medroxyprogesterone acetate, 10 mg/d, during the last 10 days of each 28-day
      cycle [HRT]; men: testosterone enanthate, biweekly intramuscular injections of
      100 mg) (n = 35); GH + placebo sex steroid (n = 30); sex steroid + placebo GH (n
      = 35); or placebo GH + placebo sex steroid (n = 31) in a 2 x 2 factorial design.
      MAIN OUTCOME MEASURES: Lean body mass, fat mass, muscle strength, maximum oxygen
      uptake (VO(2)max) during treadmill test, and adverse effects. RESULTS: In women,
      LBM increased by 0.4 kg with placebo, 1.2 kg with HRT (P =.09), 1.0 kg with GH (P
      =.001), and 2.1 kg with GH + HRT (P<.001). Fat mass decreased significantly in
      the GH and GH + HRT groups. In men, LBM increased by 0.1 kg with placebo, 1.4 kg
      with testosterone (P =.06), 3.1 kg with GH (P<.001), and 4.3 kg with GH +
      testosterone (P<.001). Fat mass decreased significantly with GH and GH +
      testosterone. Women's strength decreased in the placebo group and increased
      nonsignificantly with HRT (P =.09), GH (P =.29), and GH + HRT (P =.14). Men's
      strength also did not increase significantly except for a marginally significant
      increase of 13.5 kg with GH + testosterone (P =.05). Women's VO(2)max declined by
      0.4 mL/min/kg in the placebo and HRT groups but increased with GH (P =.07) and GH
      + HRT (P =.06). Men's VO(2)max declined by 1.2 mL/min/kg with placebo and by 0.4
      mL/min/kg with testosterone (P =.49) but increased with GH (P =.11) and with GH +
      testosterone (P<.001). Changes in strength (r = 0.355; P<.001) and in VO(2)max (r
      = 0.320; P =.002) were directly related to changes in LBM. Edema was
      significantly more common in women taking GH (39% vs 0%) and GH + HRT (38% vs
      0%). Carpal tunnel symptoms were more common in men taking GH + testosterone (32%
      vs 0%) and arthralgias were more common in men taking GH (41% vs 0%). Diabetes or
      glucose intolerance occurred in 18 GH-treated men vs 7 not receiving GH (P
      =.006). CONCLUSIONS: In this study, GH with or without sex steroids in healthy,
      aged women and men increased LBM and decreased fat mass. Sex steroid + GH
      increased muscle strength marginally and VO( 2)max in men, but women had no
      significant change in strength or cardiovascular endurance. Because adverse
      effects were frequent (importantly, diabetes and glucose intolerance), GH
      interventions in the elderly should be confined to controlled studies.

PMID- 12425704
TI  - Effects of cognitive training interventions with older adults: a randomized
      controlled trial.
AB  - CONTEXT: Cognitive function in older adults is related to independent living and
      need for care. However, few studies have addressed whether improving cognitive
      functions might have short- or long-term effects on activities related to living
      independently. OBJECTIVE: To evaluate whether 3 cognitive training interventions
      improve mental abilities and daily functioning in older, independent-living
      adults. DESIGN: Randomized, controlled, single-blind trial with recruitment
      conducted from March 1998 to October 1999 and 2-year follow-up through December
      2001. SETTING AND PARTICIPANTS: Volunteer sample of 2832 persons aged 65 to 94
      years recruited from senior housing, community centers, and hospital/clinics in 6
      metropolitan areas in the United States. INTERVENTIONS: Participants were
      randomly assigned to 1 of 4 groups: 10-session group training for memory (verbal
      episodic memory; n = 711), or reasoning (ability to solve problems that follow a
      serial pattern; n = 705), or speed of processing (visual search and
      identification; n = 712); or a no-contact control group (n = 704). For the 3
      treatment groups, 4-session booster training was offered to a 60% random sample
      11 months later. MAIN OUTCOME MEASURES: Cognitive function and cognitively
      demanding everyday functioning. RESULTS: Thirty participants were incorrectly
      randomized and were excluded from the analysis. Each intervention improved the
      targeted cognitive ability compared with baseline, durable to 2 years (P<.001 for
      all). Eighty-seven percent of speed-, 74% of reasoning-, and 26% of memory
      trained participants demonstrated reliable cognitive improvement immediately
      after the intervention period. Booster training enhanced training gains in speed
      (P<.001) and reasoning (P<.001) interventions (speed booster, 92%; no booster,
      68%; reasoning booster, 72%; no booster, 49%), which were maintained at 2-year
      follow-up (P<.001 for both). No training effects on everyday functioning were
      detected at 2 years. CONCLUSIONS: Results support the effectiveness and
      durability of the cognitive training interventions in improving targeted
      cognitive abilities. Training effects were of a magnitude equivalent to the
      amount of decline expected in elderly persons without dementia over 7- to 14-year
      intervals. Because of minimal functional decline across all groups, longer follow
      up is likely required to observe training effects on everyday function.

PMID- 12425706
TI  - Behavioral training with and without biofeedback in the treatment of urge
      incontinence in older women: a randomized controlled trial.
AB  - CONTEXT: Previous research on urge urinary incontinence has demonstrated that
      multicomponent behavioral training with biofeedback is safe and effective, yet it
      has not been established whether biofeedback is an essential component that
      heightens therapeutic efficacy. OBJECTIVE: To examine the role of biofeedback in
      a multicomponent behavioral training program for urge incontinence in community
      dwelling older women. DESIGN: Prospective, randomized controlled trial conducted
      from April 1, 1995, to March 30, 2001. SETTING: University-based outpatient
      continence clinic in the United States. PATIENTS: A volunteer sample of 222
      ambulatory, nondemented, community-dwelling women aged 55 to 92 years with urge
      incontinence or mixed incontinence with urge as the predominant pattern. Patients
      were stratified by race, type of incontinence (urge only vs mixed), and severity
      (frequency of accidents). INTERVENTIONS: Patients were randomly assigned to
      receive 8 weeks (4 visits) of biofeedback-assisted behavioral training (n = 73),
      8 weeks (4 visits) of behavioral training without biofeedback (verbal feedback
      based on vaginal palpation; n = 74), or 8 weeks of self-administered behavioral
      treatment using a self-help booklet (control condition; n = 75). MAIN OUTCOME
      MEASURES: Reduction in the number of incontinence episodes as documented in
      bladder diaries, patients' perceptions and satisfaction, and changes in quality
      of life. RESULTS: Intention-to-treat analysis showed that behavioral training
      with biofeedback yielded a mean 63.1% reduction (SD, 42.7%) in incontinence,
      verbal feedback a mean 69.4% reduction (SD, 32.7%), and the self-help booklet a
      mean 58.6% reduction (SD, 38.8%). The 3 groups were not significantly different
      from each other (P =.23). The groups differed significantly regarding patient
      satisfaction: 75.0% of the biofeedback group, 85.5% of the verbal feedback group,
      and 55.7% of the self-help booklet group reported being completely satisfied with
      treatment (P =.001). Significant improvements were seen across all 3 groups on 3
      quality-of-life instruments, with no significant between-group differences.
      CONCLUSIONS: Biofeedback to teach pelvic floor muscle control, verbal feedback
      based on vaginal palpation, and a self-help booklet in a first-line behavioral
      training program all achieved comparable improvements in urge incontinence in
      community-dwelling older women. Patients' perceptions of treatment were
      significantly better for the 2 behavioral training interventions.

PMID- 12425707
TI  - Walking and leisure-time activity and risk of hip fracture in postmenopausal
      women.
AB  - CONTEXT: Physical activity can reduce the risk of hip fractures in older women,
      although the required type and duration of activity have not been determined.
      Walking is the most common activity among older adults, and evidence suggests
      that it can increase femoral bone density and reduce fracture risk. OBJECTIVE: To
      assess the relationship of walking, leisure-time activity, and risk of hip
      fracture among postmenopausal women. DESIGN, SETTING, AND PARTICIPANTS:
      Prospective analysis begun in 1986 with 12 years of follow-up in the Nurses'
      Health Study cohort of registered nurses within 11 US states. A total of 61,200
      postmenopausal women (aged 40-77 years and 98% white) without diagnosis of
      cancer, heart disease, stroke, or osteoporosis at baseline. MAIN OUTCOME
      MEASURES: Incident hip fracture resulting from low or moderate trauma, analyzed
      by intensity and duration of leisure-time activity and by time spent walking,
      sitting, and standing, measured at baseline and updated throughout follow-up.
      RESULTS: From 1986 to 1998, 415 incident hip fracture cases were identified.
      After controlling for age, body mass index, use of postmenopausal hormones,
      smoking, and dietary intakes in proportional hazards models, risk of hip fracture
      was lowered by 6% (95% confidence interval [CI], 4%-9%; P<.001) for each increase
      of 3 metabolic equivalent (MET)-hours per week of activity (equivalent to 1 h/wk
      of walking at an average pace). Active women with at least 24 MET-h/wk had a 55%
      lower risk of hip fracture (relative risk [RR], 0.45; 95% CI, 0.32-0.63) compared
      with sedentary women with less than 3 MET-h/wk. Even women with a lower risk of
      hip fracture due to higher body weight experienced a further reduction in risk
      with higher levels of activity. Risk of hip fracture decreased linearly with
      increasing level of activity among women not taking postmenopausal hormones
      (P<.001), but not among women taking hormones (P =.24). Among women who did no
      other exercise, walking for at least 4 h/wk was associated with a 41% lower risk
      of hip fracture (RR, 0.59; 95% CI, 0.37-0.94) compared with less than 1 h/wk.
      More time spent standing was also independently associated with lower risks.
      CONCLUSION: Moderate levels of activity, including walking, are associated with
      substantially lower risk of hip fracture in postmenopausal women.

PMID- 12425708
TI  - Prevalence of olfactory impairment in older adults.
AB  - CONTEXT: Older adults represent the fastest-growing segment of the US population,
      and prevalences of vision and hearing impairment have been extensively evaluated.
      However, despite the importance of sense of smell for nutrition and safety, the
      prevalence of olfactory impairment in older US adults has not been studied.
      OBJECTIVE: To determine the prevalence of olfactory impairment in older adults.
      DESIGN, SETTING, AND PARTICIPANTS: A total of 2491 Beaver Dam, Wis, residents
      aged 53 to 97 years participating in the 5-year follow-up examination (1998-2000)
      for the Epidemiology of Hearing Loss Study, a population-based, cross-sectional
      study. MAIN OUTCOME MEASURES: Olfactory impairment, assessed by the San Diego
      Odor Identification Test and self-report. RESULTS: The mean (SD) prevalence of
      impaired olfaction was 24.5% (1.7%). The prevalence increased with age; 62.5%
      (95% confidence interval [CI], 57.4%-67.7%) of 80- to 97-year-olds had olfactory
      impairment. Olfactory impairment was more prevalent among men (adjusted
      prevalence ratio, 1.92; 95% CI, 1.65-2.19). Current smoking, stroke, epilepsy,
      and nasal congestion or upper respiratory tract infection were also associated
      with increased prevalence of olfactory impairment. Self-reported olfactory
      impairment was low (9.5%) and this measure became less accurate with age. In the
      oldest group, aged 80 to 97 years, sensitivity of self-report was 12% for women
      and 18% for men. CONCLUSIONS: This study demonstrates that prevalence of
      olfactory impairment among older adults is high and increases with age. Self
      report significantly underestimated prevalence rates obtained by olfaction
      testing. Physicians and caregivers should be particularly alert to the potential
      for olfactory impairment in the elderly population.

PMID- 12425709
TI  - Academic geriatric programs in US allopathic and osteopathic medical schools.
AB  - CONTEXT: By 2030, 20% of the US population will be older than 65 years compared
      with 12.4% in 2000. The development of geriatric medicine research and training
      programs to prepare for this increasing number of older individuals is largely
      dependent on the successful establishment of academic geriatric medicine programs
      in medical schools. OBJECTIVE: To assess the structure, resources, and activities
      of academic geriatric medicine programs in US allopathic and osteopathic schools
      of medicine. DESIGN, SETTING, AND PARTICIPANTS: Survey distributed to the
      academic geriatric medicine leaders of the 144 US allopathic and osteopathic
      medical schools in March 2001. MAIN OUTCOME MEASURES: Organizational structure,
      program information, curriculum, budgetary issues, and characteristics of
      academic geriatric medicine leaders. RESULTS: A total of 121 program directors
      (84%) responded. Most schools (87%) had an identifiable academic geriatric
      program structure, with 67% established after 1984. The greatest proportion of
      faculty and staff time (40%) was spent in clinical practice, followed by research
      and scholarship (12%), residency and fellowship education (10% each), and medical
      student education (7.8%). Clinical practice accounted for the greatest portion
      (27%) of revenue, and 25.7% of the programs had total annual budgets of less than
      $250,000, while 11% had budgets of greater than $5 million. The largest obstacles
      to achieving the goals of an academic geriatric medicine program were a lack of
      research faculty and fellows and poor clinical reimbursement. CONCLUSIONS: Most
      US medical schools have an identifiable academic geriatric medicine program; most
      have been established within the last 15 years. Resources are needed to train
      faculty for roles as teachers and researchers and to develop medical school
      geriatric programs of the size and scope equivalent to other academic
      disciplines.

PMID- 12425710
TI  - Pregnancy in the sixth decade of life: obstetric outcomes in women of advanced
      reproductive age.
AB  - CONTEXT: As a result of oocyte donation, women in their sixth decade of life are
      now able to conceive and carry pregnancies to term. However, little is known
      about pregnancy outcomes in this population. OBJECTIVE: To describe pregnancy
      outcomes in women aged 50 years or older who conceived after in vitro
      fertilization with donor oocytes. DESIGN AND SETTING: Retrospective analysis of
      cycles conducted at a US university assisted reproduction program during calendar
      years 1991-2001. PATIENTS: Seventy-seven postmenopausal women with no chronic
      medical conditions (mean [SD] age, 52.8 [2.9] years; range, 50-63 years) who
      underwent 121 embryo transfer procedures (89 fresh and 32 frozen). Pregnancy
      outcomes were ascertained by chart review and telephone follow-up. MAIN OUTCOME
      MEASURES: Maternal and neonatal outcomes. RESULTS: There were 55 clinical
      pregnancies for a total pregnancy rate of 45.5%. The live birth rate was 37.2%.
      Of the 45 live births, 31 were singletons, 12 were twins, and 2 were triplets,
      for which the mean (SD) gestational ages at delivery were 38.4 (2.1) weeks, 35.8
      (2.8) weeks, and 32.2 weeks, respectively. Mean (SD) birth weights were 3039 g
      (703 g), 2254 g (581 g), and 1913 g, respectively. Apgar scores at 1 and 5
      minutes were 8.2 (0.9) and 9.1 (0.5), respectively. Of singletons, 68% were
      delivered by cesarean, and all multiples were delivered by cesarean. Mild
      preeclampsia was noted in 25% of patients and severe preeclampsia in 10%.
      Gestational diabetes required diet modification in 17.5%, and 2.5% required
      insulin. CONCLUSIONS: Appropriately screened women aged 50 years or older can
      successfully conceive via oocyte donation and experience similar pregnancy rates,
      multiple gestation rates, and spontaneous abortion rates as younger recipients.
      During pregnancy, they appear at increased risk of preeclampsia and gestational
      diabetes. A majority can expect to deliver via cesarean. However, there does not
      appear to be any definitive medical reason for excluding these women from
      attempting pregnancy on the basis of age alone.

PMID- 12425711
TI  - Alzheimer Disease: "It's okay, Mama, if you want to go, it's okay".
AB  - About 4 million people in the United States have Alzheimer disease (AD) and the
      number of incident cases is expected to more than double from 377,000 in 1995 to
      959,000 in 2050. Patients, their families, and health care professionals struggle
      with a relentless and irreversible neurological syndrome that can last from 2 to
      20 years. Alzheimer disease causes both cognitive and functional impairments that
      predispose the patient to behavioral symptoms, destroy intellectual capacity and
      personality, erase the ability to communicate one's wishes for care, and lead to
      life-threatening consequences. At the close of life, family members and
      clinicians face decisions regarding degrees of intensive medical care to be
      provided for treatment of the late-stage consequences of AD, including withdrawal
      of invasive interventions, initiation of hospice, and treatment of a range of
      progressive medical conditions. Physicians can assist patients with AD and their
      loved ones through the terminal phases of the illness by preparing them for the
      relentless progression of the disease and by supporting them through the
      intellectual and emotional conflicts accompanying the end of life.

PMID- 12425712
TI  - Responding to requests for physician-assisted suicide: "These are uncharted
      waters for both of us... ".

PMID- 12425713
TI  - Use it or lose it: activity may be the best treatment for aging.

PMID- 12425720
TI  - Pressure- and temperature-induced unfolding and aggregation of recombinant human
      interferon-gamma: a Fourier transform infrared spectroscopy study.
AB  - The effect of hydrostatic pressure on the secondary structure of recombinant
      human interferon-gamma (rhIFN-gamma) and its biologically inactive truncated form
      rhIFN-Delta C15 has been studied using Fourier-transform IR (FTIR) spectroscopy.
      In situ observation of the pressure-induced changes using the diamond anvil cell
      shows that the alpha-helical structure is mainly transformed into disordered
      structure at high pressure. Increasing pressure also induces the formation of a
      gel. Addition of 0.5 M MgCl(2) significantly reduces the pressure stability.
      Releasing the pressure below 300 MPa results in the formation of intermolecular
      antiparallel beta-sheets, which is seldom observed. This suggests that the
      intermolecular beta-sheet of rhIFN-gamma is stabilized by electrostatic
      interactions that are disrupted at high pressure. For comparison we also studied
      the effect of temperature. Temperature-induced changes reflect extensive
      transformation of alpha-helical structure into intermolecular antiparallel beta
      sheet, as is usually observed for most proteins.

PMID- 12425721
TI  - Nephropathic cystinosis associated with cardiomyopathy: a 27-year clinical follow
      up.
AB  - BACKGROUND: Nephropathic cystinosis is an autosomal recessive disease resulting
      from intracellular accumulation of cystine leading to multiple organ failure.
      CASE REPORT: We describe the clinical course of a patient managed from the age of
      six until his death at the age of 33 years. He underwent multiple surgery,
      including two renal transplants, developed transplant renal artery stenosis that
      was managed medically, and progressive heart failure at the age of 33 years. His
      death from a ruptured pseudoaneurysm associated with a restrictive cardiomyopathy
      is noteworthy. A limited cardiac autopsy revealed the presence of cystine
      crystals in interstitial cardiac histiocytes and one myocardial cell, along with
      1000-fold higher tissue cystine content of the left ventricular myocardium
      compared to patients without cystinosis, suggesting the possibility of direct
      cystine mediated metabolic injury.

PMID- 12425722
TI  - Threshold protocol for the exchange of confidential medical data.
AB  - BACKGROUND: Medical researchers often need to share clinical data without
      violating patient confidentiality. Threshold cryptographic protocols divide
      messages into multiple pieces, no single piece containing information that can
      reconstruct the original message. The author describes and implements a novel
      threshold protocol that can be used to search, annotate or transform confidential
      data without breaching patient confidentiality. METHODS: The basic threshold
      protocol is: 1) Text is divided into short phrases; 2) Each phrase is converted
      by a one-way hash algorithm into a seemingly-random set of characters; 3)
      Threshold Piece 1 is composed of the list of all phrases, with each phrase
      followed by its one-way hash; 4) Threshold Piece 2 is composed of the text with
      all phrases replaced by their one-way hash values, and with high-frequency words
      preserved. Neither Piece 1 nor Piece 2 contains information linking patients to
      their records. The original text can be re-constructed from Piece 1 and Piece 2.
      RESULTS: The threshold algorithm produces two files (threshold pieces). In
      typical usage, Piece 2 is held by the data owner, and Piece 1 is freely
      distributed. Piece 1 can be annotated and returned to the owner of the original
      data to enhance the complete data set. Collections of Piece 1 files can be merged
      and distributed without identifying patient records. Variations of the threshold
      protocol are described. The author's Perl implementation is freely available.
      CONCLUSIONS: Threshold files are safe in the sense that they are de-identified
      and can be used for research purposes. The threshold protocol is particularly
      useful when the receiver of the threshold file needs to obtain certain concepts
      or data-types found in the original data, but does not need to fully understand
      the original data set.

PMID- 12425724
TI  - Mechanistic explanations for the chemopreventive action of soyabean isoflavones:
      reducing the possibilities.

PMID- 12425723
TI  - Toxic cocaine- and convulsant-induced modification of forced swimming behaviors
      and their interaction with ethanol: comparison with immobilization stress.
AB  - BACKGROUND: Swimming behaviors in the forced swimming test have been reported to
      be depressed by stressors. Since toxic convulsion-inducing drugs related to
      dopamine [cocaine (COC)], benzodiazepine [methyl 6,7-dimethoxy-4-ethyl-beta
      carboline-carboxylate (DMCM)], gamma-aminobutyric acid (GABA) [bicuculline
      (BIC)], and glutamate [N-methyl-D-aspartate (NMDA)] receptors can function as
      stressors, the present study compared their effects on the forced swimming
      behaviors with the effects of immobilization stress (IM) in rats. Their
      interactions with ethanol (EtOH), the most frequently coabused drug with COC
      which also induces convulsions as withdrawal symptoms but interferes with the
      convulsions caused by other drugs, were also investigated. RESULTS: Similar to
      the IM (10 min) group, depressed swimming behaviors (attenuated time until
      immobility and activity counts) were observed in the BIC (5 mg/kg IP) and DMCM
      (10 mg/kg IP) groups at the 5 h time point, after which no toxic behavioral
      symptoms were observed. However, they were normalized to the control levels at
      the 12 h point, with or without EtOH (1.5 g/kg IP). In the COC (60 mg/kg IP) and
      NMDA (200 mg/kg IP) groups, the depression occurred late (12 h point), and was
      normalized by the EtOH cotreatment. At the 5 h point, the COC treatment enhanced
      the swimming behaviors above the control level. CONCLUSIONS: Although the
      physiological stress (IM), BIC, and DMCM also depressed the swimming behaviors, a
      delayed occurrence and EtOH-induced recovery of depressed swimming were observed
      only in the COC and NMDA groups. This might be correlated with the previously
      reported delayed responses of DA and NMDA neurons rather than direct effects of
      the drugs, which could be suppressed by EtOH. Furthermore, the characteristic
      psychostimulant effects of COC seemed to be correlated with an early enhancement
      of swimming behaviors.

PMID- 12425725
TI  - Selenium and breast-feeding.
AB  - The objective of the present review is to discuss Se nutrition during breast
      feeding, encompassing environmental and maternal constitutional factors affecting
      breast-milk-Se metabolism and secretion. A literature search of Medline and
      Webofscience was used to retrieve and select papers dealing with Se and breast
      milk. Although Se in natural foods occurs only in organic form, breast milk
      responds to organic and inorganic Se in supplements. Inorganic Se (selenite,
      selenate), which is largely used in maternal supplements, is not detectable in
      breast milk. The mammary-gland regulating mechanism controls the synthesis and
      secretion of seleno-compounds throughout lactation, with a high total Se level in
      colostrum that decreases as lactation progresses. Se appears in breast milk as a
      component of specific seleno-proteins and seleno-amino-acids in milk proteins
      that are well tolerated by breast-fed infants even in high amounts. Se in breast
      milk occurs as glutathione peroxidase (4-32 % total Se) > selenocystamine >
      selenocystine > selenomethionine. The wide range of breast-milk Se concentrations
      depends on Se consumed in natural foods, which reflects the Se content of the
      soils where they are grown. Se prophylaxis, either through soil Se fertilization
      or maternal supplements, is effective in raising breast-milk Se concentration. In
      spite of wide variation, the median Se concentration from studies worldwide are
      26, 18, 15, and 17 microg/l in colostrum (0-5 d), transitional milk (6-21 d),
      mature milk (1-3 months) and late lactation (>5 months) respectively. Se
      recommendations for infants are presently not achieved in 30 % of the reported
      breast-milk Se concentrations; nevertheless Se status is greater in breast-fed
      than in formula-fed infants.

PMID- 12425727
TI  - Serum concentrations of homocysteine are elevated during early pregnancy in
      rodent models of fetal programming.
AB  - Maternal malnutrition can lead to fetal abnormalities and increase susceptibility
      to disease in later life. Rat models have been developed to study the physiology
      and metabolism underlying this phenomenon. One particular model of 50 % protein
      restriction during pregnancy, the low-protein diet (LPD) supplemented with
      methionine, has been developed to investigate the underlying mechanisms. Recent
      studies have shown that rats fed a LPD during only the first 4 d of pregnancy
      produce offspring that develop hypertension. These results suggest that the very
      earliest stages of embryo development are susceptible to diet-induced heritable
      changes. We demonstrate a marked elevation of maternal serum homocysteine (hcy)
      concentrations during the initial phases of pregnancy in both rats and mice fed
      an LPD. Fetal growth and many of the circulating amino acids are similarly
      perturbed in both rats and mice fed the LPD during pregnancy, indicating that the
      response to the LPD diet is similar in rats and mice. These findings allow us to
      exploit the advantages of the mouse experimental system in future analyses aimed
      at understanding the molecular basis of fetal programming. Our present findings
      are discussed with particular reference to mechanisms which may initiate fetal
      programming, and to the feasibility of dietary interventions aimed at reducing
      early pregnancy loss and pre-eclampsia in man.

PMID- 12425726
TI  - Genistein-induced apoptosis in MCF-7 cells involves changes in Bak and Bcl-x
      without evidence of anti-oestrogenic effects.
AB  - South-east Asian women have a lower rate of breast cancer compared with their
      counterparts in western countries and the difference in soyabean consumption has
      been claimed to be a major contributing factor. Genistein is the most studied
      phytochemical in the soyabean. An anti-oestrogenic effect is believed to play a
      crucial part in its chemopreventive mechanism. In the present study, we expressed
      oestrogen receptor (OR) in an OR-negative cell line, HepG2, to investigate the
      pro- and anti-oestrogenic effect of genistein on the OR transcriptional activity.
      Genistein by itself had an estimated concentration that induced 50 % of the
      maximum response (EC50) of 2.5 microm for the binding to OR-alpha. In these
      experiments, genistein concentration as high as 50 microm could not reduce the
      oestrogen response element-driven luciferase activities initiated by oestradiol.
      Instead, genistein potentiated the OR transactivational activity while cell death
      was detected. On the other hand, an increased Bak and a reduced Bcl-x(L) was
      observed at 50 microm-genistein by Western analysis. The combined effect of these
      two proteins could be important in the apoptotic process. Since plasma genistein
      >50 microm has never been documented following consuming of soyabean or soyabean
      products, the present study does not support the notion that dietary soyabean
      exerts its chemopreventive effect through antagonizing OR.

PMID- 12425729
TI  - Large bowel fermentation of maize or sorghum-acorn diets fed as a different
      source of carbohydrates to Landrace and Iberian pigs.
AB  - Twenty-four finishing pigs (twelve Iberian and twelve Landrace) were used in a
      growing and slaughtering experiment. Animals were fed two diets differing in
      their ingredients, maize (diet C) or sorghum-acorn (diet A). At an average weight
      of 107.0 kg pigs were slaughtered and hindgut digesta sampled to study the effect
      of breed and diet on large bowel fermentation. Flows of digesta to the hindgut
      compartment were estimated based on an indigestible flow marker (Cr2O3) and were
      higher in Iberian than in Landrace pigs (P<0.001), and higher in animals fed diet
      A than diet C (P=0.07). The higher flows in Iberian pigs were mainly associated
      with a higher voluntary feed intake (3.50 v. 2.70 kg/d, P<0.01) and lower ileal
      digestibility of NSP (-12.8 v. 47.8, P<0.01). Differences between diets were
      mainly associated with a lower ileal digestibility of starch from diet A (89.2 v.
      96.9 %, P=0.06), although no differences in the resistant starch content were
      observed in vitro. Fermentation of different carbohydrates through the large
      bowel showed that NSP-glucose had lower digestibility in Iberian than in Landrace
      pigs (62.5 v. 94.2 %, P<0.001), but no differences were observed in starch, or
      other NSP-fibre fractions (arabinose, xylose and galactose). The type and amount
      of carbohydrates reaching the large bowel were related to the diet but also to
      breed, and promoted differences in the fermentative activity associated with
      different volatile fatty acid patterns and changes in microbial enzymic activity.

PMID- 12425728
TI  - Consumption of tall oil-derived phytosterols in a chocolate matrix significantly
      decreases plasma total and low-density lipoprotein-cholesterol levels.
AB  - In a randomized, double-blind, placebo-controlled trial we evaluated the effect
      of dietary chocolates enriched with a wood-based phytosterol-phytostanol mixture,
      containing 18 % (w/w) sitostanol, compared with placebo dietary chocolates in
      seventy subjects with primary hypercholesterolaemia (total cholesterol levels
      below 8 mmol/l). For 4 weeks, participants consumed three servings of the
      phytosterol-enriched chocolate/d that provided 1.8 g unesterified phytosterols/d
      or a placebo chocolate in conjunction with a low-fat, low-cholesterol diet.
      Plasma total and LDL-cholesterol levels were statistically significantly reduced
      by 6.4 % (-0.44 mmol/l) and 10.3 % (-0.49 mmol/l), respectively, after 4 weeks of
      phytosterol-enriched-chocolate treatment. Plasma HDL-cholesterol and
      triacylglycerol levels were not affected. Consumption of phytosterol-enriched
      chocolates significantly increased plasma lathosterol concentration (+20.7 %),
      reflecting an increased endogenous cholesterol synthesis in response to
      phytosterol-induced decreased intestinal cholesterol absorption. Furthermore, the
      chocolates enriched with phytosterols significantly increased both plasma
      sitosterol (+95.8 %) and campesterol (+64.1 %) levels, compared with the placebo
      chocolate group. However, the absolute values of plasma sitosterol and
      campesterol remained within the normal range, that is, below 10 mg/l. The
      chocolates with phytosterols were palatable and induced no clinical or
      biochemical side effects. These findings indicate that dietary chocolate enriched
      with tall oil-derived phytosterols (1.8 g/d) is effective in lowering blood total
      and LDL-cholesterol levels in subjects with mild hypercholesterolaemia and thus
      may be helpful in reducing the risk of CHD in these individuals.

PMID- 12425730
TI  - Age-related association of small intestinal mucosal enteropathy with nutritional
      status in rural Gambian children.
AB  - Small bowel enteropathy (assessed by the lactulose (L) : mannitol (M)
      permeability test) is a major factor in infant growth faltering and malnutrition
      in The Gambia. However, little is known about its persistence and nutritional
      effect beyond 2 years of age. This was addressed by two cross-sectional studies
      of intestinal permeability and nutritional status in 162 residents, aged 2-60
      years, living in three villages in rural Gambia. L:M ratio was found to be
      highest in the youngest children and although there was a significant improvement
      with age (P<0.0001), values were always greater than the range found in UK
      counterparts. M recovery (mean value 5.68 (se 0.12) %) was at all times between
      one-third and one-half of expected UK values and showed no improvement with age.
      Gut barrier function, assessed by L uptake, improved with age (P<0.001) and fell
      within the UK normal range beyond age 10 years. Both the L:M permeability ratio
      and L recovery were significantly associated with height-for-age z-scores and 
      0.22 respectively, P<0.001), a relationship that persisted throughout childhood
      and into adulthood. Change in height-for-age z-score between the two visits was
      also related to the L:M ratio P=0.018). The close within-subject correlation of
      permeability variabilities between the two visits suggests a long-term
      persistence of enteropathy within individuals. It appears that the small bowel
      enteropathy previously described in Gambian infants persists through to
      adulthood. Although the lesion improves with age, the relationship between
      attained height and L:M permeability raises the possibility that enteropathy may
      continue to limit growth throughout childhood and puberty.

PMID- 12425731
TI  - Nutritional status of drug addicts undergoing detoxification: prevalence of
      malnutrition and influence of illicit drugs and lifestyle.
AB  - The aim of the present study was to investigate the nutritional status of drug
      addicts, the prevalence of malnutrition among them and the influence of their
      drug habit and lifestyle factors on their nutritional indices. The study was
      conducted among 253 male drug addicts, who sought detoxification at the Central
      Drug Addiction Treatment Hospital, Dhaka, during the period of June 1998-July
      1999. One hundred age-, height- and socioeconomic-matched non-addicted healthy
      men were recruited by convenience as cohort controls. Results showed that the
      drug addicts had significantly (P<0.001) lowered BMI, haemoglobin, and serum
      total protein and albumin levels. Clinical signs of nutrient deficiency were
      diagnosed in about 74 % of drug addicts. The BMI, biochemical values and nutrient
      deficiency signs indicated that more than 60 % of drug addicts were suffering
      from multiple malnutrition. One-way ANOVA demonstrated a significant (P<0.05)
      negative correlation between drug habit, sexually transmitted diseases and
      selected nutritional indices, and a positive correlation between education,
      income and the nutritional indices. A series of multiple regression analyses
      revealed that education, income and age showed significantly predicted BMI and
      biochemical indices, and the group (non-drug addicts or drug addicts) had a
      significant negative effect on these parameters in favour of controls.

PMID- 12425732
TI  - Morphological and immune response alterations in the intestinal mucosa of the
      mouse after short periods on a low-magnesium diet.
AB  - The importance of Mg for the immune function is well recognized; however, there
      is no information available about the effect of Mg intake on the modulation of
      local immune response in the intestine. Thus, in the present study the hypothesis
      that short periods of Mg deprivation can affect intestinal mucosa and local
      immune response was tested. For this purpose, OF1 female mice were fed a
      semipurified diet (1000 mg Mg/kg diet). For 3 d before immunization and 1 d
      after, half of the animals were fed a Mg-deficient diet (30 mg Mg/kg diet), three
      immunizations per os were performed every 3 weeks with Escherichia coli producing
      the CS31A capsule-like protein (1010 or bacteria per animal). Mice were killed 10
      d after the last immunization. The level of specific anti CS31A immunoglobulin
      (Ig) G and IgA in the serum and secretory IgA in the intestinal secretions and
      faeces were measured by ELISA. The results indicated that administration of a
      high dose of immunogen with a low-Mg diet led to lower specific IgA levels in the
      intestinal mucus and serum. Administration of a low dose of immunogen with a low
      Mg diet led to lower IgA and IgG levels in the serum and secretory IgA
      coproantibodies. To assess alterations of intestinal mucosa caused by a low-Mg
      diet for a short period, histological and scanning electron microscopy analyses
      were performed on samples from mice (not submitted to the vaccination protocol)
      after 3 d on the Mg-deficient diet. These analyses showed several alterations,
      suggesting perturbations in the growth of the intestinal mucosa. These changes
      were accompanied by modifications in the expression of several genes involved in
      cell growth and stress response. From this present work, it may be concluded that
      short periods of Mg deprivation can affect the intestinal mucosa and local immune
      response of the intestine.

PMID- 12425733
TI  - Increasing the viscosity of the intestinal contents stimulates proliferation of
      enterotoxigenic Escherichia coli and Brachyspira pilosicoli in weaner pigs.
AB  - The present study was designed to evaluate the effect of increased viscosity of
      the intestinal digesta on proliferation of enterotoxigenic Escherichia coli and
      the intestinal spirochaete Brachyspira pilosicoli in weaned pigs. Pigs were fed
      an experimental diet based on cooked white rice (R), which was supplemented with
      carboxymethylcellulose (CMC; 40 g/kg diet) to increase digesta viscosity. Thirty
      six piglets weaned at 21 d of age were divided into six groups, three of which
      were fed R and three Addition of CMC increased digesta viscosity in the ileum
      (P=0.01), caecum (P=0.0007) and colon (P=0.0035), without increasing indices of
      large intestinal fermentation. Pigs fed developed a natural infection with
      enterotoxigenic E. coli after weaning and had more (P<0.0001) diarrhoea than pigs
      fed R. Subsequent experimental infection of two groups of pigs with B. pilosicoli
      resulted in more (P<0.0001) colonisation in pigs fed than R. At this time, all
      pigs fed had wetter (P<0.0001) faeces than those fed R, irrespective of whether
      they were infected with B. pilosicoli, but infected pigs also had an increased
      (P=0.025) number of days with diarrhoea post-infection irrespective of diet. In
      pigs fed it was not clear to what extent the increased viscosity associated with
      CMC, or the concurrent infection with enterotoxigenic E. coli, was responsible
      for the increased proliferation of B. pilosicoli. In a second experiment, five
      pigs that were weaned onto an R diet were transferred onto 3 weeks later. These
      pigs did not develop a natural infection with enterotoxigenic E. coli after the
      diet change, confirming the particular susceptibility of pigs to enterotoxigenic
      E. coli proliferation immediately post-weaning.

PMID- 12425734
TI  - Assessing sleeping energy expenditure in children using heart-rate monitoring
      calibrated against open-circuit indirect calorimetry: a pilot study.
AB  - Total energy expenditure (EE) can be assessed in children by the heart-rate (HR)
      monitoring technique calibrated against open-circuit indirect calorimetry (IC).
      In this technique, sleeping EE is usually estimated as the lowest value of a 30
      min resting EE measurement x 0 x 90 to give an average for the total sleeping
      period. However, sleeping is a dynamic process in which sleeping EE is modulated
      by the effect of factors such as body movement and different sleep stages. The
      aim of the present study was to determine a new method to improve the sleeping EE
      measurement by taking into account body movements during sleep. Twenty-four non
      obese children participated in the present study. All subjects passed through a
      calibration period. HR and EE measured by IC were simultaneously collected during
      resting, the postprandial period, and during different levels of activity.
      Different methods for computing sleeping EE (resting with different breakpoints
      ('flex point' HR with linear regression or 'inflection point' (IP) HR with the
      third order polynomial regression equation (P3)) were compared with EE measured
      for least 2.0 h in eight sleeping children. The best method of calculation was
      then tested in sixteen children undergoing HR monitoring and with a body movement
      detector. In a subset of eight children undergoing simultaneous sleeping EE
      measurement by IC and HR, the use of the equation resting when HR<IP and P3 when
      HR>IP during the sleeping period gave the lowest difference (1 (sd 5.4) %)
      compared with other methods (linear or polynomial regressions). The new formula
      was tested in an independent subset of sixteen other children. The difference
      between sleeping EE computed with the formula resting and sleeping EE computed
      with resting when HR<IP and the P3 equation when HR>IP during sleeping periods
      was significant (13 (sd 5.9) %) only for active sleeping subjects (n 6 of 16
      subjects). The correlation between the difference in the results from the two
      methods of calculation and body movements was close (r 0.63, P<0.005, Spearman
      test) as well as computed sleeping EE (Spearman test, r 0.679, P<0.001),
      indicating that this new method is reliable for computing sleeping EE with HR
      monitoring if children are moving during sleep and improves the total EE
      assessment.

PMID- 12425735
TI  - Determinants of fat mass in prepubertal children.
AB  - The aim of the present study was to compare variables of metabolism, physical
      activity and fitness to body composition in normal and overweight children in a
      cross-sectional study design. Body composition was assessed by anthropometric
      measurements and bioelectrical impedance analysis in forty-eight prepubertal
      children (age 5-11 years, thirteen normal-weight, thirty-five overweight). Total
      energy expenditure (EE) was measured by combination of indirect calorimetry (for
      measurement of resting EE) and individually calibrated 24 h heart-rate (HR)
      monitoring. Activity-related EE and physical activity level (PAL) were
      calculated. Time spent with min-by-min HR>FLEX HR was also used as a marker of
      moderate habitual and vigorous activities. Aerobic fitness (O2 pulse (O2
      consumption:HR at submaximal steady-state heart rate), submaximal O2 consumption
      (VO2submaximal), RER at a HR of 170 beats per min) was determined by bicycle
      ergometry. Muscle strength of the legs (maximal isometric strength of musculus
      quadriceps and of musculus ischiocruralis (Fa max and Fb max respectively)) was
      measured by computer tensiometry. When compared with normal children, overweight
      children had higher skinfold thicknesses (sum of skinfold thicknesses at four
      sites +160 %), fat mass (+142 %), waist (+24 %) and hip circumferences (+14 %),
      resting EE (+13 %) and RER (+5 %). No significant group differences were found
      for fat-free mass, muscle mass, total EE, activity-related EE, PAL, HR>FLEX HR,
      VO2submaximal, O2 pulse, Fa max and Fb max as well as the fat-free mass- or
      muscle mass-adjusted values for resting EE, aerobic fitness and muscle strength.
      When compared with normal children, overweight children had a lower measured v.
      estimated resting EE (Delta resting EE) and spent more time watching television.
      There were positive relationships between fat-free mass(x) and resting EE(x),
      total EE(y), aerobic fitness(y) and muscle strength(y), but only Delta resting
      EE(x) and HR>FLEX HR(x) correlated with fat mass(y). In a stepwise multivariate
      regression analysis resting EE adjusted for fat-free mass and Delta resting EE
      were significant determinants of % fat mass and explained 29.7 % of its variance.
      Thus, in the present cross-sectional study, resting EE was the most important
      determinant of fat mass.

PMID- 12425736
TI  - Predictors of micronutrient status in men and women over 75 years old living in
      the community.
AB  - Serum ferritin, serum vitamin B12, erythrocyte folate, plasma vitamin C and
      plasma 25-hydroxycholecalciferol levels were measured in 208 men and 197 women,
      >75 years old and living in the community, in order to assess micronutrient
      status. Anthropometric measurements (height, weight, demispan and mid-upper arm
      circumference) were made and a 114-item questionnaire covering a wide range of
      health and diet-related topics was administered by an interviewer. Only 4 % of
      subjects had a BMI <20, but the prevalence of marginal deficiency of the
      micronutrients ranged from 7 % for Fe to 47 % for vitamin D. There was no
      association between low micronutrient status (defined as being in the lowest
      third of the distribution of micronutrient status) and having BMI or mid-upper
      arm circumference in the lowest third of the distribution for any of the
      nutrients. Leaving food on the plate was strongly associated with both low Fe
      status and low vitamin D status. Having breakfast cereal less than once per week
      was strongly associated with low folate status, while having fresh fruit juice
      less than once per week, having had less than two portions of fruits and
      vegetables the previous day and believing that food is not important for health
      were strongly associated with low vitamin C status. Low vitamin D status was
      strongly associated with a wide range of general health and disability measures.
      Having a weekly household income of less than pound 150 was associated with low
      status of Fe, folate, vitamin C and vitamin D.

PMID- 12425737
TI  - Plasma amino acid concentrations in healthy and cognitively impaired oldest-old
      individuals: associations with anthropometric parameters of body composition and
      functional disability.
AB  - Only a few reports exist of plasma amino acid profiles in the oldest-old, and
      none exist of the oldest-old with cognitive problems. Therefore, we measured
      fasting plasma amino acid concentrations in twenty-three healthy community
      dwellers aged 90-103 years (group A); eighteen community-dwellers with mild
      cognitive impairment without dementia aged 91-104 years (group B); thirty-three
      patients with dementia aged 96-100 years (group C); and sixty healthy young
      controls aged 20-50 years. Biochemical and anthropometric parameters, and the
      basic activities of daily living (ADL) were also measured. Independent of
      cognitive status, in all oldest-old groups, essential:non essential amino acids
      (EAA:NEAA) was lower than in young controls and positively associated with body
      muscle mass. Patients with dementia were further characterized by a negative
      association between EAA:NEAA and the number of dependent ADL. All oldest-old
      groups had higher values of tyrosine:other large neutral amino acids (LNAA) than
      young controls. Groups B and C also had a higher phenylalanine:other LNAA. These
      data show that abnormalities in plasma amino acid profile are common in oldest
      old individuals independent of their cognitive status, but that, in oldest-old
      patients with dementia, they are associated with functional disability. The
      abnormalities in phenylalanine and tyrosine plasma availability could contribute
      to the cause or aggravation of concurrent cognitive problems because these amino
      acids are neurotransmitter precursors and compete with other LNAA for transport
      into the brain.

PMID- 12425738
TI  - UK Food Standards Agency alpha-linolenic acid workshop report.
AB  - The UK Food Standards Agency convened a group of expert scientists to review
      current research investigating whether n-3 polyunsaturated fatty acids (PUFA)
      from plant oils (alpha-linolenic acid; ALA) were as beneficial to cardiovascular
      health as the n-3 PUFA from the marine oils, eicosapentaenoic acid (EPA) and
      docosahexaenoic acid (DHA). The workshop also aimed to establish priorities for
      future research. Dietary intake of ALA has been associated with a beneficial
      effect on CHD; however, the results from studies investigating the effects of ALA
      supplementation on CHD risk factors have proved equivocal. The studies presented
      as part of the present workshop suggested little, if any, benefit of ALA,
      relative to linoleic acid, on risk factors for cardiovascular disease; the
      effects observed with fish-oil supplementation were not replicated by ALA
      supplementation. There is a need, therefore, to first prove the efficacy of ALA
      supplementation on cardiovascular disease, before further investigating effects
      on cardiovascular risk factors. The workshop considered that a beneficial effect
      of ALA on the secondary prevention of CHD still needed to be established, and
      there was no reason to look further at existing CHD risk factors in relation to
      ALA supplementation. The workshop also highlighted the possibility of feeding
      livestock ALA-rich oils to provide a means of increasing the dietary intake in
      human consumers of EPA and DHA.

PMID- 12425742
TI  - Design principles of liquid nebulization devices currently in use.
AB  - Liquid nebulization is a common method of medical aerosol generation. Nebulizers
      are of 2 types: jet (or pneumatic) small-volume nebulizer, and ultrasonic
      nebulizer. Jet nebulizers are based on the venturi principle, whereas ultrasonic
      nebulizers use the converse piezoelectric effect to convert alternating current
      to high-frequency acoustic energy. Important variables for both types of
      nebulizer are treatment time required, particle size produced, and aerosol drug
      output. There are several advantages to jet nebulization, including that
      effective use requires only simple, tidal breathing, and that dose modification
      and dose compounding are possible. Disadvantages include the length of treatment
      time and equipment size. Design modifications to the constant-output nebulizer
      have resulted in breath-enhanced, open-vent nebulizers such as the Pari LC Plus
      and the dosimetric AeroEclipse. Ultrasonic nebulizers generally have a higher
      output rate than jet nebulizers, but a larger average particle size. Ultrasonic
      nebulizers can also substantially increase reservoir solution temperature, the
      opposite of jet nebulizer cooling. Drug concentration in the reservoir does not
      increase with ultrasonic nebulization, as it does with jet nebulization.
      Ultrasonic nebulizers have the same advantages as jet nebulizers. Ultrasonic
      nebulizers are more expensive and fragile than jet nebulizers, may cause drug
      degradation, and do not nebulize suspensions well. Neither type of nebulizer
      meets the criteria for an ideal inhaler: efficient and quick dose delivery with
      reproducibility, cost-effectiveness, and no ambient contamination by lost
      aerosol.

PMID- 12425743
TI  - Aerosol delivery through an artificial airway.
AB  - For both lung and systemic diseases, aerosol delivery of drugs into the lungs can
      often offer substantial advantages over other routes of administration. In the
      intensive care unit, however, the artificial airway can be a substantial barrier
      to aerosol delivery, so clinicians must pay careful attention to the ventilator
      pattern, the delivery gas humidity/density, the device characteristics, and the
      circuit/tube properties. When those are optimized, aerosol delivery from a
      nebulizer or metered-dose inhaler and through an endotracheal tube can begin to
      approach that seen in a nonintubated patient. Novel approaches, such as
      generating the aerosol within the airway, offer the opportunity to greatly
      increase deposition efficiency and focal drug targeting in intubated patients.

PMID- 12425744
TI  - Assessing nebulizer performance.
AB  - The quality of the aerosol generated by a nebulizer system is a function of its
      design, operating parameters, and the drug formulation to be aerosolized. The
      aerosolized drug dose inhaled from a nebulizer is determined by the patient's
      breathing pattern. The site of deposition of the aerosol in the lung is primarily
      influenced by the inspiratory flow rate and additionally by the nature of the
      lung disease. Thus, tests of performance that incorporate these different
      variables will provide data that give a better understanding of overall nebulizer
      performance. As discussed in this paper, a number of in vitro and in vivo
      laboratory tests can be undertaken to measure the characteristics of the delivery
      system as well as the quality and quantity of the aerosolized drug provided. With
      this information one can estimate the dose of drug that will be inhaled and
      deposited below the larynx. The accuracy of these predictions can additionally be
      improved with the use of breath simulators and standard breath patterns. Breath
      monitors that capture and feed actual patient breathing patterns into the
      simulator to mimic nebulizer operation during actual patient use further increase
      the accuracy of dose estimation. With the vast number of nebulizers available and
      also in development, a comparison of information obtained from different
      nebulizers is key in making an informed decision when selecting an aerosol
      delivery system that can provide an efficacious dose of a particular drug to a
      specific patient population.

PMID- 12425745
TI  - Formulations and nebulizer performance.
AB  - To deliver a drug by nebulization, the drug must first be dispersed in a liquid
      (usually aqueous) medium. After application of a dispersing force (either a jet
      of gas or ultrasonic waves), the drug particles are contained within the aerosol
      droplets, which are then inhaled. Some drugs readily dissolve in water, whereas
      others need a cosolvent such as ethanol or propylene glycol. Some drugs are
      delivered as suspensions, and the efficiency of nebulizers can be different for
      solutions and suspensions. Solutions are delivered more efficiently with most
      devices. In general, conventional ultrasonic nebulizers should not be used to
      aerosolize suspensions, because of low efficiency. Newer strategies to improve
      the delivery of non-water-soluble drugs include the use of liposomes and the
      milling of the drug into very small "nanoparticles." In addition to the active
      therapeutic ingredient and solvents, drug formulations may include buffers (the
      solubility of some medications is influenced by pH), stabilizers, and, in the
      case of multi-dose preparations, antibacterial agents. Though formulations are
      designed to optimize drug solubility and stability, changes in formulation can
      also affect inhaled mass, particle size, and treatment time, though the
      differences between nebulizer brands probably have a greater impact than
      differences in formulation. Ultrasonic and jet nebulizers may damage protein and
      other complex agents through heat or shear stress. Additives to multi-dose
      formulations, especially antimicrobial and chelating agents, may cause adverse
      events, so there is a trend towards single-use, preservative-free vials.

PMID- 12425746
TI  - Nebulizer therapy for children: the device-patient interface.
AB  - A therapeutic aerosol benefits the patient only if the medication deposits in the
      airway. Advances in nebulizer design have made them more efficient and "user
      friendly," but the greatest problem with administering aerosolized medication
      continues to be educating patients and caregivers to use aerosol devices properly
      and consistently. Misuse and nonuse are the greatest impediments to effective
      aerosol delivery. The respiratory pattern and degree of patient cooperation also
      profoundly affect aerosol deposition, and those effects are greatly magnified in
      small children. There are many misconceptions about nebulizer use and nebulizer
      equipment, even in teaching hospitals, and these can have serious consequences
      when patients do not receive the medication they need. This review discusses how
      airway physiology, nebulizer technology, and patient education relate to
      appropriate nebulizer use. Education is critically important, but unfortunately
      it is often a misunderstood or neglected part of aerosol administration.

PMID- 12425747
TI  - Economic aspects of introducing new nebulizer technology.
AB  - The adoption of new medical technology has been a major factor in the development
      of today's highly sophisticated health care delivery system. Recently, important
      breakthroughs in biotechnology have introduced the possibility that certain
      terminal diseases may soon become a thing of the past. However, these advances
      have come at a steep price. Total health care spending in the United States is at
      an all-time high and the rate of increase in annual expenditures is once again in
      the double-digit neighborhood. It is clear that it will no longer be "business as
      usual" in health care, especially with regard to the introduction of new
      technology. New economic realities now require that those advocating the adoption
      of a new drug, device, or treatment balance their clinical enthusiasm with cost
      effectiveness considerations. This is especially important when the cost of a new
      drug or device is higher than that of existing drugs or devices. Unlike former
      times, when the decision to adopt new medical technology resided primarily with
      clinicians, the approval process is now exceedingly more complex and involves
      many more individuals, some of whom, clinicians and non-clinicians alike, tend to
      focus more on protecting their budgets than on approving expenditures for new
      technology. Pharmacoeconomics has emerged to formalize the decision-making
      process for the adoption of new drugs. Since many of the issues are similar, the
      basic principles of pharmacoeconomics hold promise for physicians and therapists
      championing the adoption of new nebulizers. Pharmacoeconomic data, when gathered,
      reviewed, and presented in a standardized and unbiased manner, can be a valuable
      tool to help justify the overall cost/benefit advantages of new nebulizer
      technology.

PMID- 12425748
TI  - Bringing new nebulizer technologies to market: regulatory issues.
AB  - This review outlines regulatory issues involved in bringing new nebulizer
      technologies to market and describes the regulatory roles of the Center for
      Devices and Radiologic Health and the Center for Drug Evaluation and Research.
      The responsible agency is determined by whether a new device involves a new drug
      formulation.

PMID- 12425749
TI  - Era of hope.

PMID- 12425752
TI  - Resistance to trastuzumab: a necessary evil or a temporary challenge?
AB  - The aim of this review article is to examine the potential mechanisms of
      resistance to trastuzumab. In the clinical setting, when trastuzumab is given as
      a single agent for first-line treatment of HER2-overexpressing metastatic breast
      cancer, it is associated with a 40% objective response rate. In the remaining
      cases, no tumor regression is observed, although HER2 protein is overexpressed
      and/or the corresponding gene is amplified. Hence, some other factors besides
      HER2 must play a role in determining the level of sensitivity to trastuzumab. The
      identification of the potential mechanisms of resistance to trastuzumab can be
      very helpful for the development of new compounds, which might overcome that
      resistance and/or have additive/synergistic antitumor effect when given in
      association with trastuzumab. Moreover, thorough understanding of the HER2
      pathway is essential to the identification of new predictive markers of response
      to trastuzumab that will help to better define the patients who are most likely
      to benefit from this drug.

PMID- 12425754
TI  - Management of premenopausal women with early-stage breast cancer: is there a role
      for ovarian suppression?
AB  - There is an overwhelming body of evidence that adjuvant ovarian
      ablation/suppression has a favorable impact on survival for premenopausal women
      with hormone-responsive early-stage breast cancer. This article reviews the
      randomized controlled trials that provide these data and the indirect evidence
      suggesting that much of the benefit seen for adjuvant chemotherapy in estrogen
      receptor-positive patients < 50 years of age is an indirect consequence of a
      chemical castration. Therefore, carefully selected women may have a choice of
      ovarian suppression with a gonadotropin-releasing hormone (GnRH) analogue, such
      as goserelin, as an alternative to chemotherapy, which would allow younger
      premenopausal women to retain fertility. In addition, if chemotherapy is selected
      and the patient does not develop permanent amenorrhoea, then additional treatment
      with a GnRH analogue is indicated.

PMID- 12425755
TI  - Phase III trial comparing granulocyte colony-stimulating factor to leridistim in
      the prevention of neutropenic complications in breast cancer patients treated
      with docetaxel/doxorubicin/cyclophosphamide: results of the BCIRG 004 trial.
AB  - This randomized, double-blind, phase III trial compared granulocyte colony
      stimulating factor (G-CSF; filgrastim) and leridistim (formerly myelopoietin), a
      chimeric dual agonist that binds both G-CSF and interleukin-3 receptors, for the
      prevention of neutropenic complications in patients with breast cancer receiving
      TAC (docetaxel/doxorubicin/cyclophosphamide) chemotherapy. Patients with
      metastatic (44%) or localized breast cancer (56%) were randomized to G-CSF 5
      microg/kg subcutaneously (s.c.) daily (n = 135), leridistim 5 microg/kg s.c.
      daily (n = 139), or leridistim 10 microg/kg s.c. every other day alternating with
      placebo (n = 139). Following administration of TAC (docetaxel 75 mg/m2,
      doxorubicin 50 mg/m2, cyclophosphamide 500 mg/m2) on day 1, patients received
      growth factor beginning on day 2 until the postnadir absolute neutrophil count
      exceeded 1500 cells/ microL. Chemotherapy cycles were repeated every 21 days. The
      incidence of febrile neutropenia was 7% in the G-CSF arm, 19% in the daily
      leridistim arm (P = 0.003 for comparison with G-CSF) and 22% in the alternate-day
      leridistim arm (P < 0.001 for comparison with G-CSF). There was no significant
      difference between treatment arms in the cumulative percentage of patients
      experiencing grade 4 neutropenia at some point during therapy (85%-88%). However,
      grade 4 neutropenia occurred in 53% of cycles in the G-CSF cohort, 61% of cycles
      in the daily leridistim group (P = 0.063 for comparison with G-CSF), and 63% of
      cycles in the alternate-day leridistim group (P = 0.015 for comparison with G
      CSF). We conclude that G-CSF is superior to leridistim in the prevention of
      febrile neutropenia in patients with advanced breast cancer receiving TAC
      chemotherapy. The up-front prophylactic use of G-CSF is a reasonable supportive
      therapy for patients treated with docetaxel/anthracycline-based combination
      chemotherapy.

PMID- 12425756
TI  - Dose-dense biweekly doxorubicin/docetaxel versus sequential neoadjuvant
      chemotherapy with doxorubicin/cyclophosphamide/docetaxel in operable breast
      cancer: second interim analysis.
AB  - Timing of systemic treatment in primary operable breast cancer is subject to
      extensive investigation, suggesting that pathologic complete remission (pCR)
      might improve survival in this setting. The German Adjuvant Breast Cancer Group
      previously demonstrated the feasibility of a dose-dense biweekly schedule of 4
      cycles doxorubicin 50 mg/m2 and docetaxel 75 mg/m2 (ddAT) +/- tamoxifen in the
      neoadjuvant setting to yield a pCR of 9.7% (Gepardo trial). Patients assigned to
      ddAT received prophylactic granulocyte colony-stimulating factor support (5 micro
      g/kg days 5-10). The current study (GeparDUO) was designed to assess whether the
      pCR rate, including no viable invasive and preinvasive tumor cells, achieved with
      ddAT was equivalent to sequential administration of doxorubicin/cyclophosphamide
      followed by docetaxel (AC-DOC) over 24 weeks in primary operable breast cancer.
      From June 1999 to September 2001, 913 patients were enrolled in this trial. In
      total, 395 patients randomized before August 1, 2000, were included in the second
      interim analysis. Safety data were available from 369 patients (ddAT, n = 191; AC
      DOC, n = 178) demonstrating that toxicity of both regimens was tolerable. Grade
      3/4 neutropenia occurred in 39.8% of patients receiving ddAT and in 69.3% of
      patients treated with AC-DOC. Efficacy data were available in 378 patients. A pCR
      occurred in 14.8% of the primary breast tumors. According to the recommendations
      of the data monitoring committee, recruitment to the study was halted as of
      September 2001 (n = 913/1000) due to the significant difference in pCR rates
      observed between the treatment arms. Surgery was documented in 380 patients.
      Breast conservation was possible in 288 cases (75.8%). The application of both
      schedules is safe and feasible in an outpatient setting. Although, results
      obtained from this interim analysis are encouraging, caution is recommended until
      the results obtained show statistical difference in pCR.

PMID- 12425757
TI  - Expression and regulation of tumor suppressor gene maspin in breast cancer.
AB  - Maspin (mammary serpin) is an inhibitor of serine proteases with tumor suppressor
      activity in breast cancer. Maspin was originally identified by subtractive
      hybridization in normal breast epithelial cells, but its expression decreased
      during tumor progression. The loss of maspin gene expression with increasing
      malignancy is by transcriptional regulation. Maspin is known to be involved in
      invasion and metastasis, interact with the p53 tumor suppressor pathway, and act
      as an inhibitor of angiogenesis. The immunohistochemical analysis and reverse
      transcription polymerase chain reaction of maspin in normal human breast tissue
      and breast carcinoma indicated a stepwise reduction of maspin expression during
      the progression from ductal carcinoma in situ to invasive carcinoma to lymph node
      metastasis. The lack of maspin expression in breast cancer seems to be associated
      with a short disease-free survival and supports maspin's function as an indicator
      for tumor aggressiveness and metastatic potential. New studies on the gene
      regulation of maspin provide evidence for promising potential of possible re
      expression of maspin in tumor cells. The function of maspin as a tumor suppressor
      gene involved in tumor invasion, metastasis, and angiogenesis may not be limited
      to breast cancer.

PMID- 12425758
TI  - Gonadal function in patients with testicular germ cell tumors.
AB  - The gonadal function of 18 patients with testicular germ cell tumors was
      evaluated. Seminal parameters after orchiectomy were examined in 15 patients. Six
      of them were available for follow-up observation after 2 or 3 courses of adjuvant
      chemotherapy. Serum gonadal hormones before and after orchiectomy were evaluated
      in 7 patients (testosterone and PRL were not examined in one patient). Five of 15
      (33.3%), 8 of 15 (53.3%), 13 of 15 (86.7%), 7 of 13 (53.8%), and 9 of 12 (75.0%)
      had abnormal values in seminal volume, sperm concentration, motility, morphology,
      and vitality, respectively. The sperm concentration gradually improved after
      chemotherapy following orchiectomy in 5 of 6 (83.3%) patients. In all the
      patients examined, serum levels of follicular stimulating hormone (FSH),
      luteinizing hormone (LH), and prolactin (PRL) increased after orchiectomy. Serum
      levels of testosterone increased in 4 patients, but decreased in 2 after
      orchiectomy. These findings suggest that several factors, including preexisting
      intrinsic defect and disturbance of the hypothalamus-pituitary-gonadal axis, are
      involved in the deterioration of gonadal function in patients with testicular
      germ cell tumors.

PMID- 12425759
TI  - Quality control, quality assurance, and proficiency testing in the andrology
      laboratory.
AB  - The primary goal of any andrology laboratory should be the performance of
      accurate, reproducible, high-quality, and clinically relevant laboratory testing.
      An underlining objective of such a goal is to better serve the ordering
      physician, and the patient, by continually improving laboratory performance.
      Quality control (QC) is the procedure that determines accurate and reproducible
      testing. Proficiency testing (PT) is the process allowing physicians to compare
      results from one laboratory to another. Quality assurance (QA) is the mechanism
      ensuring high-quality, clinically relevant testing. Together, QC, QA, and PT
      serve as the foundation responsible for a program that continually improves the
      overall quality of the testing, allowing the physician ordering the test to be
      more effective in treating the patient. Several examples are presented to assist
      the implementation of effective QC and QA programs aimed at continually improving
      performance in the andrology laboratory.

PMID- 12425760
TI  - Patient satisfaction with testosterone supplementation for the treatment of
      erectile dysfunction.
AB  - The long-term efficacy of testosterone supplementation for erectile dysfunction
      was evaluated using standardized questionnaires and differences between
      testosterone delivery systems analyzed. Forty-four patients receiving parenteral
      depo-testosterone, Testoderm scrotal patches, or Testoderm-TTS nonscrotal patches
      were evaluated with the Erectile Dysfunction Inventory of Treatment Satisfaction
      and International Index of Erectile Function questionnaires. Global questions
      regarding libido, energy, and improved erections demonstrated a significantly
      better response with depo-testosterone and Testoderm-TTS nonscrotal patches as
      compared to Testoderm scrotal patches. Testoderm-TTS nonscrotal patches and depo
      testosterone resulted in significantly higher overall treatment satisfaction (p
      <.001), confidence in ability to engage in sexual activity (p <.001), and total
      Erectile Dysfunction Inventory of Treatment Satisfaction and International Index
      of Erectile Function scores (p <.001). Testoderm-TTS nonscrotal patches were
      significantly better than depo-testosterone with regard to satisfaction with
      sexual intercourse (International Index of Erectile Function question 5, p <.05).
      Testosterone replacement improved the quality of erections and level of libido in
      patients with erectile dysfunction. Treatment delivery systems appear to impact
      the success of therapy.

PMID- 12425761
TI  - Male contraception, IV: hypotonic-like effect from Echeveria gibbiflora on human
      sperm.
AB  - At present there is no accepted method for the regulation of male fertility. The
      most appropriate form of contraception would undoubtedly be to develop from
      traditional plant-derived folk drugs a contraceptive male method. Hypoosmotic
      shock is used for validate plasma membrane function and its fertilizing capacity
      of human sperm. Such effect is induced in human sperm in the presence of a
      purified fraction from Echeveria gibbiflora (PFEG) aqueous crude extract. The
      hypotonic-like effect included a distension of the plasma membrane over the
      acrosome region and in some occasions around the sperm middle piece. An enhanced
      activity of the immobilizing and agglutination effects was induced
      instantaneously after the addition of PEFG versus aqueous crude extract activity
      (OBACE). Using electron microscopy it was possible to observe a deposit of a
      "sticky" dense material intercalated along the plasma membrane. The membrane was
      sealed making it impossible to measure the viability or metabolic activity of the
      treated sperm by the fluorescence (FDA-IP) technique. It was also possible to
      corroborate the dispersion of the acrosomal content and the disappearance of the
      acrosomal and nuclear membrane. Results that makes PFEG hypotonic-like effect a
      serious candidate to conduct a study to determine the predicting capacity of this
      compound in human infertility and suggest that the plant may yield a compound
      suitable for use as male contraceptive agent.

PMID- 12425762
TI  - Treatment of oligoasthenozoospermia with tranilast, a mast cell blocker, after
      long-term administration.
AB  - The authors retrospectively examined whether long-term administration of
      tranilast improves semen parameters in severe oligoasthenozoospermia. Fifty-two
      patients presenting with sperm concentration of less than 10 x 10(6) sperm/mL
      were enrolled. Subjects were partitioned into 3 groups as follows: patients
      displaying an atrophic testis with elevated (FSH) (group 1), patients exhibiting
      normal testicular volume with elevated FSH (group 2), and patients with normal
      testicular volume and normal FSH levels (group 3). Tranilast (300mg/day) was
      administered until pregnancy was achieved or for a period of up to 12 months.
      Sperm concentration was significantly increased at 3 months in 16 subjects (44%)
      in groups 1 and 3. In group 2, sperm concentration was increased at 12 months (5
      of 16 subjects; 31%). Total sperm count was obviously elevated at 3 months in
      groups 1 and 2, and at 6 months in group 3. Six pregnancies were achieved via
      natural intercourse. Tranilast, a mast cell blocker, demonstrates a certain
      clinical benefit in terms of improvement of semen parameters involving severe
      oligoasthenozoospermia, but it does not appear to afford clinical benefit in long
      term administration.

PMID- 12425763
TI  - Androgen receptor gene and male genital anomaly.
AB  - Male sexual differentiation, testicular descent, and spermatogenesis require
      androgens. Their action is mediated through the androgen receptor (AR), which
      binds to the androgen responsive element on DNA and regulates gene transcription.
      No mutations in any of the AR gene exons 1-8 are detected in males with isolated
      cryptorchidism, hypospadias, micropenis, or idiopathic male infertility. In
      addition, the CAG repeat length in exon 1 of the AR gene does not expand in males
      with isolated cryptorchidism, hypospadias, micropenis, or idiopathic male
      infertility. These facts indicate that an alteration of the AR gene is rare in
      these males. However, further studies will permit a better clarification on the
      relevance of the AR gene abnormalities to the development of isolated
      cryptorchidism, hypospadias, micropenis, or impaired spermatogenesis.

PMID- 12425764
TI  - Effect of renal transplantation on sexual function.
AB  - This investigation was conducted to determine whether renal transplantation can
      improve sexual function in male patients with chronic renal failure. The authors
      retrospectively studied 121 men undergoing renal transplantation who complained
      of any type or degree of sexual dysfunction pre-operatively. Sexual function was
      evaluated by questionnaire which included erectile, ejaculative, and orgasmic
      functions. Pre- and postoperative frequency of sexual intercourse was also
      recorded. Patient characteristics, laboratory data, and endocrinologic profiles
      were analyzed to identify factors that might influence sexual function. In
      patients with hormonal determinations, results essentially normalized after
      transplantation. However, only 43 patients (35.5%) reported improvement of
      overall sexual function after renal transplantation, while 34 (28.1%) reported
      worsening. Although frequency of sexual intercourse was unaffected by
      transplantation, 15 of 20 patients who had no intercourse before transplantation
      initiated intercourse afterward. These 15 patients all underwent transplantation
      before 40 years of age. Comparisons of variables by sexual function showed
      significant differences for type of immunosuppressive treatment, interval after
      renal transplantation, and serum concentration of hemoglobin A1c. It is concluded
      that renal transplantation cannot improve sexual function in all patients,
      although hormonal profiles were largely normalized, and that renal
      transplantation should be encouraged at a younger age.

PMID- 12425765
TI  - The expression of mannose-ligand receptor is correlated with sperm morphology.
AB  - The objective of the present study was to evaluate the association between the
      expression of sperm mannose-ligand receptors and sperm morphology. Sperm samples
      were obtained from 45 men, 30 fertile sperm donors and 15 infertile men. Sperm
      concentration, motility and morphology were evaluated and then incubated with
      control medium (Ham's F-10 + 1% HSA) for 4 h. Expression of mannose-ligand
      receptors was evaluated by mannosylated-BSA-FITC (subdivided into 3 patterns: I,
      for uncapacitated sperm; II, for capacitated; and III, for acrosome-reacted
      sperm). The mean (+/- SE) frequencies of sperm cells of the total sperm
      population that expressed patterns I, II, and III were 88 +/- 2.1%, 7 +/- 1.6%,
      and 5 +/- 0.8%, respectively, for fertile men, and 90 +/- 2.1%, 7 +/- 1.3%, and 3
      +/- 0.5%, respectively, for infertile men. The rate of pattern III expression of
      mannose-ligand receptors was significantly higher in the fertile group compared
      to the infertile patients (p <.01). A poor but significant correlation was
      observed between the rate of pattern III and the percentage of normal-forms sperm
      cell in the ejaculate (r =.35, p =.018). Fertile sperm samples express more
      advanced patterns of mannose-ligand receptors compared to infertile men. This
      phenomenon is related to the morphology of human sperm cell in the ejaculate more
      than to any other basic sperm characteristics.

PMID- 12425766
TI  - Self-efficacy and depression in late life: a primary prevention proposal.
AB  - Feelings of sadness and loneliness are ubiquitous in late life and a risk factor
      for depression and perhaps other mental illnesses in late life. Targeting sadness
      and loneliness for an intervention addresses both primary risk reduction for
      depressive disorders and promotion of overall mental health in the elderly.
      Nevertheless, few studies document the efficacy of primary prevention efforts in
      preventing depressive disorders in the elderly. The author argues that the
      attainment of positive mental health depends in considerable part upon an
      individual's self-efficacy--the belief that one can organize and execute the
      courses of action required to develop and enhance a person's belief that he or
      she can act in ways that lead to a desired goal. Self-efficacy is strengthened,
      not by some general or abstract instruction, but rather by the experience of
      successfully dealing with and thus overcoming specific problems. The extant
      literature suggests that many potential approaches may be available to develop
      and enhance self-efficacy in the elderly--approaches that potentially could be
      broadly applicable in community settings.

PMID- 12425767
TI  - Coping with family caregiving to persons with dementia: a critical review.
AB  - Seventeen empirical studies that relate the ways of coping employed by family
      caregivers of persons affected by dementia to their health and morale are
      critically reviewed for the purposes of determining whether there is any
      consensus regarding ways of coping that serve health-protective functions, and
      whether the studies' designs and measurement strategies are faithful to the
      transactional theory of coping upon which they are founded. Due to the use of
      cross-sectional designs, the adoption of different coping and outcome measures,
      the lack of specificity and the incomparability of the target stressors, the
      reliance on retrospective reports, and the use of inappropriate response formats,
      among other limitations, the interpretability of the cumulative body of empirical
      findings on caregiver coping is questionable. Ways of strengthening and
      broadening coping research to make it more fruitful and theoretically coherent
      are presented.

PMID- 12425768
TI  - Emotional reactions and life changes of caregivers of demented patients when home
      caregiving ends.
AB  - Many studies indicate that the cessation of caregiving of demented patients has
      positive effects on caregivers' lives but contradictory findings have also been
      reported. The aim of this study was to investigate how the caregivers of demented
      patients experienced the cessation of caregiving, how caregivers' lives changed
      after this event, and which factors predicted emotional reactions and life
      changes. Data were collected from 64 caregivers of demented patients, recruited
      from a previous controlled intervention study. The semi-structured telephone
      interviews sought (1) sociodemographic data, (2) emotional reactions the
      caregivers recalled from the point of cessation of caregiving, and (3) life
      changes experienced after that time point. At the point of cessation of
      caregiving, spouse caregivers had higher risk for loneliness, depressive feelings
      and sorrow than non-spouse caregivers. Feelings of relief were associated with
      non-spouses. Community care support obtained during the previous intervention
      study had protected the caregivers from loneliness, depressive feelings and
      sorrow. After the end of caregiving, spouse caregivers tended to experience more
      negative life changes. The increased number of leisure activities was associated
      with the support during community care.

PMID- 12425769
TI  - The effect of anticholinesterases on personality changes in Alzheimer's disease.
AB  - Anticholinesterases are known to be effective against cognitive and non-cognitive
      symptoms of Alzheimer's disease (AD) but their effect on the personality changes
      in the disease is not known. This study examines the effect of anticholinesterase
      treatment on personality changes in AD. It involved the carers of patients with
      mild to moderate AD who were currently receiving anticholinesterases in south
      Manchester. The personality change was measured using the Brooks and McKinlay
      Personality Inventory. The carers were asked to complete the inventory for each
      of three periods in the patients' lives: before the onset of AD, after the
      diagnosis of AD but before starting anticholinesterases, and currently on
      anticholinesterases. Fifty-eight carers participated in the study. Personality
      became more negative (total score on the personality inventory became less)
      following the onset of AD (p < 0.001). Following anticholinesterase treatment,
      the total score on the personality inventory remained the same or increased in 23
      (39%) patients. Scores on individual personality traits remained the same or
      increased in the majority of patients. In approximately one fifth of the
      patients, the traits 'does things himself', 'happy', 'calm' and 'cautious' showed
      improvement on anticholinesterases. The study confirms that personality changes
      are almost universal and negative in AD and suggests that anticholinesterases may
      have a positive effect. Further double blind prospective studies are needed to
      understand natural progression of personality changes in AD and to validate the
      findings of this study.

PMID- 12425770
TI  - A multidimensional model of the quality of life in older age.
AB  - The broad aim of the research presented here was to define the constituents and
      indicators of quality of life (QoL) in older age, in order to offer a more
      multidimensional and useful model of quality of life, based on the perspectives
      of older people themselves. This paper focuses on the extent to which self
      evaluations of global QoL are influenced by health, psychological and social
      variables, and social circumstances. It reports the results of a national survey
      of the quality of life in people aged 65 and over, living at home in Britain.
      Multiple regression analysis with the self-evaluation of quality of life rating
      as the dependent variable showed that the overall model (Model 9) of QoL
      indicators explained 26.7% of the variance in quality of life ratings. This is
      sizeable given the amorphous nature of this concept. The main independent
      predictors of self-rated global quality of life were: social comparisons and
      expectations, personality and psychological characteristics (optimism-pessimism),
      health and functional status and personal and neighbourhood social capital. These
      variables explained the highest proportion of the variance between groups in
      their quality of life ratings. Socio-economic indicators contributed relatively
      little to the model.

PMID- 12425771
TI  - Social networks and health of older people living in sheltered housing.
AB  - Eighty-seven residents from three sheltered accommodation schemes for people over
      60 years, were interviewed about: their physical and mental health, social
      networks, social support, decision to move in, and how they found living in
      sheltered housing. Twenty-four percent had a diagnosis of depression and 8%
      dementia, but few had ever seen a mental health professional. Over half (55%) had
      clinically significant levels of activity limitation and 37% had significant
      somatic symptoms. Despite provision of glasses or aids 31% could not see
      satisfactorily and 23% could not hear adequately. Locally integrated social
      networks were most common (41%). Residents with a private network (16%) were more
      likely than those with a locally integrated network to have significant activity
      limitation and to report often being lonely. There were no differences between
      network types in levels of depression or dementia. Poor health of a person or
      their spouse was the most commonly reported reason for moving to sheltered
      housing, followed by the possibly related reasons of problems with their old home
      no longer being suitable e.g. stairs, and because they wanted to have a warden or
      alarm system available should the need arise. Most residents were happy living in
      sheltered accommodation. Many made use of 'sheltered' features such as the common
      room, the communal laundry, the warden and the alarm. A minority of residents
      were lonely and a few were unhappy with sheltered accommodation.

PMID- 12425772
TI  - Televisits: sustaining long distance family relationships among institutionalized
      elders through technology.
AB  - The role of social support in the health of older persons is well documented.
      This support is particularly important for isolated nursing home residents. The
      purpose of this study was to test the feasibility of using low-cost videophones
      to enhance communication between nursing home residents and their families. Ten
      pairs of residents and family members received videophones and engaged in regular
      televisits for six months. All participants completed brief survey instruments
      prior to and after the study period to determine the effects of the televisits on
      the frequency and quality of contacts. A post-study survey assessed ease and
      satisfaction with using videophones. Findings include identification of technical
      and design problems, possible solutions, factors affecting actual use of
      equipment, and conditions under which benefits of use may be optimal. Categories
      for estimating potential actual users are suggested. Importantly, the study
      demonstrates that videophones can be used successfully by a wide range of frail
      nursing home residents and can enhance social interactions, regardless of
      distance. Affordable videophone technology offers the potential for reduced
      isolation among institutionalized elders and others with distance and mobility
      barriers.

PMID- 12425773
TI  - Examination of the association of age, disability, and mood among Jewish older
      adults in Israel.
AB  - The purpose of this study was to examine the association between chronological
      age, disability and mental health in later life. Secondary analysis of data from
      a national probability sample of Jewish persons age 60 and over in Israel (n =
      2,079) was employed. Mental health, measured on a 12-item mood scale, was
      successively regressed on age, sociodemographic characteristics, functional
      disability and physical health status, and on the interaction of age and
      disability. A significant negative association between age and mood emerged when
      confounding variables were not controlled (beta = -0.19). This association
      remained, to a lesser degree, after sociodemographic variables were entered (beta
      = -0.11). The addition of disability and health variables reversed the direction
      of the association (beta = 0.05). Finally, the entry of the interaction term (age
      x disability) bolstered the net association of age and mood (beta = 0.27). The
      analysis underscored the interaction of age and disability as a major threat to
      mental health in current aging cohorts.

PMID- 12425774
TI  - Psychosocial issues near the end of life.
AB  - End-of-life care has received increasing attention in the last decade; however,
      the focus continues to be on the physical aspects of suffering and care to the
      virtual exclusion of psychosocial areas. This paper provides an overview of the
      literature on the intra- and interpersonal aspects of dying, including the
      effects that psychosocial variables have on end-of-life decision-making; common
      diagnosable mental disorders (e.g., clinical depression, delirium); other types
      of personal considerations (e.g., autonomy/control, grief); and
      interpersonal/environmental issues (e.g., cultural factors, financial variables).
      Six roles that qualified mental health professionals can play (i.e., advocate,
      counselor, educator, evaluator, multidisciplinary team member, and researcher)
      are also outlined. Because psychosocial issues are ubiquitous and can have
      enormous impact near the end of life, properly trained mental health
      professionals can play vital roles in alleviating suffering and improving the
      quality of life of people who are dying.

PMID- 12425775
TI  - Decisional capacity in theory and practice: legal process versus 'bumbling
      through'.
AB  - The reform of guardianship law and practice remains an active topic of interest
      for service providers, policy makers, and advocates involved with older persons.
      Guardianship is a legal device designed to protect persons who lack the cognitive
      and emotional capacity to make their own life decisions. However, for most 'grey
      zone' individuals and even for many who are rather clearly and severely mentally
      disabled, the capacity issue never gets formally raised and the legal process of
      guardianship (or placement in a formal guardianship diversion program) never gets
      invoked. Instead, the various parties generally 'bumble through' extra-legally as
      best they can. When the capacity issue does get raised formally, it often is done
      so as a matter of legal self-protection for a health care provider or financial
      institution, rather than primarily for the ward's benefit. The central policy
      issue to be debated is whether we ought to be encouraging or discouraging
      extralegal, bumbling through-type handling of persons with questionable capacity
      rather than initiation of formal judicial involvement or a formalized
      guardianship diversion program. A closely related issue is what we ought to be
      teaching health care providers, financial officers, and other third parties who
      in reality are usually the ones who initially decide whether the formal
      guardianship system should be initiated for a particular person.

PMID- 12425776
TI  - Oral versus written administration of the Geriatric Depression Scale.
AB  - Forty-four female nursing home residents completed the Geriatric Depression Scale
      (GDS) twice, using both oral and written administration formats. Presentation was
      counterbalanced. The Mini-Mental State Exam and the Mattis Dementia Rating Scale
      were administered to each participant between the GDS administrations. All
      testing was completed within one session. Test-retest reliability analysis
      revealed a significant correlation between oral and written administrations for
      higher cognitive functioning participants, but no correlation for impaired
      participants. Therefore, the use of the GDS in a cognitively impaired elderly
      population is questioned. Additionally, oral versus written administration
      formats were found to be not equivalent in the higher functioning group.

PMID- 12425777
TI  - Developing individual leaders is not enough.

PMID- 12425778
TI  - Improved preventive care in family practices with outreach facilitation:
      understanding success and failure.
AB  - OBJECTIVES: To understand why some family practices with a facilitator improved
      preventive performance more than others. Sustainability of practice improvements
      one year after the intervention was also explored. METHODS: Interviews with
      physicians and nurses from seven practices and data gathered during the
      intervention were used to form case studies of three high performing and four low
      performing family practices. Case studies were developed using cross-case
      analysis with a combination of the constant-comparative method and memoing
      diagramming. Two researchers independently conducted in-depth coding of
      transcripts and documents, individual case construction for each study site, and
      then cross-case analysis of the identified themes between study sites. RESULTS:
      Staff involvement and a positive attitude toward implementation of changes were
      central to high improvement in performance. A lack of computers, low staff
      involvement or high staff turnover were associated with low improvement in
      performance. Personal characteristics of the facilitator are important. Six of
      the seven practices still had the prevention tools in place one year after the
      intervention and all noted that participation had improved their understanding of
      preventive medicine. CONCLUSIONS: When using facilitators, one should avoid
      practices in turmoil, strive for continuity over time, and recognise the
      importance of the relationship between the facilitator and the practice.

PMID- 12425779
TI  - How much variation in clinical activity is there between general practitioners? A
      multi-level analysis of decision-making in primary care.
AB  - OBJECTIVES: There is considerable policy interest in medical practice variation
      (MPV). Although the extent of MPV has been quantified for secondary care, this
      has not been investigated adequately in general practice. Technical obstacles to
      such analyses have been presented by the reliance on ecological small area
      variation (SAV) data, the binary nature of many clinical outcomes in primary care
      and by diagnostic variability. The study seeks to quantify the extent of
      variation in clinical activity between general practitioners by addressing these
      problems. METHODS: A survey of nearly 10 000 encounters drawn from a
      representative sample of general practitioners in the Waikato region of New
      Zealand was carried out in the period 1991-1992. Participating doctors recorded
      all details of clinical activity for a sample of encounters. Measures used in
      this analysis are the issuing of a prescription, the ordering of a laboratory
      test or radiology examination, and the recommendation of a future follow-up
      office visit at a specified date. An innovative statistical technique is adopted
      to assess the allocation of variance for binary outcomes within a multi-level
      analysis of decision-making. RESULTS: As expected, there was considerable
      variability between doctors in levels of prescribing, ordering of investigations
      and requests for follow up. These differences persisted after controlling for
      case-mix and patient and practitioner attributes. However, analysis of the
      components of variance suggested that less than 10% of remaining variability
      occurred at the practitioner level for any of the measures of clinical activity.
      Further analysis of a single diagnostic group--upper respiratory tract infection-
      marginally increased the practitioner contribution. CONCLUSIONS: The amount of
      variability in clinical activity that can definitively be linked to the
      practitioner in primary care is similar to that recorded in studies of the
      secondary sector. With primary care doctors increasingly being grouped into
      larger professional organisations, we can expect application of multi-level
      techniques to the analysis of clinical activity in primary care at different
      levels of organisational complexity.

PMID- 12425780
TI  - Using meta ethnography to synthesise qualitative research: a worked example.
AB  - OBJECTIVES: To demonstrate the benefits of applying meta ethnography to the
      synthesis of qualitative research, by means of a worked example. METHODS: Four
      papers about lay meanings of medicines were arbitrarily chosen. Noblit and Hare's
      seven-step process for conducting a meta ethnography was employed: getting
      started; deciding what is relevant to the initial interest; reading the studies;
      determining how the studies are related; translating the studies into one
      another; synthesising translations; and expressing the synthesis. RESULTS: Six
      key concepts were identified: adherence/compliance; self-regulation; aversion;
      alternative coping strategies; sanctions; and selective disclosure. Four second
      order interpretations (derived from the chosen papers) were identified, on the
      basis of which four third-order interpretations (based on the key concepts and
      second-order interpretations) were constructed. These were all linked together in
      a line of argument that accounts for patients' medicine-taking behaviour and
      communication with health professionals in different settings. Third-order
      interpretations were developed which were not only consistent with the original
      results but also extended beyond them. CONCLUSIONS: It is possible to use meta
      ethnography to synthesise the results of qualitative research. The worked example
      has produced middle-range theories in the form of hypotheses that could be tested
      by other researchers.

PMID- 12425781
TI  - Participation in health care priority-setting through the eyes of the
      participants.
AB  - OBJECTIVES: The literature on participation in priority-setting has three key
      gaps: it focuses on techniques for obtaining public input into priority-setting
      that are consultative mechanisms and do not involve the public directly in
      decision-making; it focuses primarily on the public's role in priority-setting,
      not on all potential participants; and the range of roles that various
      participants play in a group making priority decisions has not been described. To
      begin addressing these gaps, we interviewed individuals who participated on two
      priority-setting committees to identify key insights from participants about
      participation. METHODS: A qualitative study consisting of interviews with
      decision-makers, including patients and members of the public. RESULTS: Members
      of the public can contribute directly to important aspects of priority-setting.
      The participants described six specific priority-setting roles: committee chair,
      administrator, medical specialist, medical generalist, public representative and
      patient representative. They also described the contributions of each role to
      priority-setting. CONCLUSIONS: Using the insights from decision-makers, we have
      described lessons related to direct involvement of members of the public and
      patients in priority-setting, and have identified six roles and the contributions
      of each role.

PMID- 12425782
TI  - Evaluation of a complex intervention for changing professional behaviour: the
      Evidence Based Out Reach (EBOR) Trial.
AB  - OBJECTIVES: To identify the effect of a complex intervention (educational
      outreach visits by pharmacists) designed to change general practitioners' (GPs')
      prescribing on each step of a hypothesised pathway of change leading to the final
      primary trial outcome of change in prescribing. METHOD: The study was undertaken
      in six health authorities in the North of England and six in London. We described
      three steps leading to this outcome: the general practices agreeing to
      participate; GPs in each practice attending the outreach visit conducted by the
      pharmacists; and the GPs' prescribing practice being influenced by these visits.
      The outcomes of each step were assessed using a combination of quantitative and
      qualitative methods. RESULTS: Of the 102 practices randomly selected, 75 (73.5%)
      agreed to participate. The odds of all the doctors attending the outreach meeting
      in small practices (i.e. 1-2 partners) was 6.7 (95% CI: 4.4-23.5) compared with
      other practices (i.e. > 3 partners). Although the pharmacists reported that they
      had established a good rapport at 100 (72%) first visits and had agreed
      management plans for 110 (79%) of these visits, they were confident that the
      practice was likely to alter its prescribing in only 41% of these visits.
      Pharmacists' and GPs' satisfaction with the outreach visits did not necessarily
      lead to prescribing changes after the practice visit, and the GPs' knowledge of
      the guidelines promoted by the pharmacists did not necessarily translate into
      changes in clinical practice. The main barriers to the implementation of
      guidelines identified by the pharmacists at the follow-up visits were
      organisational difficulties, the GPs' scepticism of the evidence presented to
      them and the doctors' lack of interest in changing their prescribing behaviour.
      CONCLUSIONS: Although our study is limited by a post hoc rather than a pre hoc
      design, it provides a pragmatic approach to understanding the factors influencing
      the pathway of change in prescribing behaviour in response to academic outreach
      visits.

PMID- 12425784
TI  - Conceptualising the patient.

PMID- 12425783
TI  - Health policy-makers' perceptions of their use of evidence: a systematic review.
AB  - OBJECTIVES: The empirical basis for theories and common wisdom regarding how to
      improve appropriate use of research evidence in policy decisions is unclear. One
      source of empirical evidence is interview studies with policy-makers. The aim of
      this systematic review was to summarise the evidence from interview studies of
      facilitators of, and barriers to, the use of research evidence by health policy
      makers. METHODS: We searched multiple databases, including Medline, Embase,
      Sociofile, PsychLit, PAIS, IBSS, IPSA and HealthStar in June 2000, hand-searched
      key journals and personally contacted investigators. We included interview
      studies with health policy-makers that covered their perceptions of the use of
      research evidence in health policy decisions at a national, regional or
      organisational level. Two reviewers independently assessed the relevance of
      retrieved articles, described the methods of included studies and extracted data
      that were summarised in tables and analysed qualitatively. RESULTS: We identified
      24 studies that met our inclusion criteria. These studies included a total of
      2041 interviews with health policy-makers. Assessments of the use of evidence
      were largely descriptive and qualitative, focusing on hypothetical scenarios or
      retrospective perceptions of the use of evidence in relation to specific cases.
      Perceived facilitators of, and barriers to, the use of evidence varied. The most
      commonly reported facilitators were personal contact (13/24), timely relevance
      (13/24), and the inclusion of summaries with policy recommendations (11/24). The
      most commonly reported barriers were absence of personal contact (11/24), lack of
      timeliness or relevance of research (9/24), mutual mistrust (8/24) and power and
      budget struggles (7/24). CONCLUSIONS: Interview studies with health policy-makers
      provide only limited support for commonly held beliefs about facilitators of, and
      barriers to, their use of evidence, and raise questions about commonsense
      proposals for improving the use of research for policy decisions. Two-way
      personal communication, the most common suggestion, may improve the appropriate
      use of research evidence, but it might also promote selective (inappropriate) use
      of research evidence.

PMID- 12425785
TI  - Management or leadership?
AB  - This article considers the roots of the division between management and
      leadership, and suggests that the division encourages individuals and
      organizations to displace responsibility for problems in health services onto
      others. Given the significant limits to the power of leaders, the difficulty of
      establishing a science of leadership, and the increasing complexity facing health
      service management, the problems might appear insurmountable. However, drawing on
      lessons from the different approaches of the combatants in the infinitely greater
      complexity of the Second World War, it is suggested that trying to "manage" the
      chaos by controlling it, or relying on "leaders" to solve our problems, or buying
      in yet more consultants, are deeply problematic strategies; only mass leadership
      and collective responsibility are likely to solve the problems.

PMID- 12425789
TI  - Risk factors associated with the introduction of acute clinical infectious bursal
      disease among Danish broiler chickens in 1998.
AB  - The objective of the present study was to investigate risk factors associated
      with the introduction of acute clinical infectious bursal disease (IBD) among
      Danish broiler chickens in 1998. Data on 218 flocks were collected from
      hatcheries, abattoirs, farmers and veterinarians; 49 of the flocks had
      experienced acute clinical IBD (cases), 169 were unexposed (controls). The study
      was carried out using a case-control design. Cases were defined as the first
      flock on each premises to experience acute clinical IBD, and these were compared
      with non-diseased, non-IBD-vaccinated control flocks chosen randomly from each
      unaffected farm. The resulting numbers of cases and controls used for statistical
      analyses were 16 and 61, respectively. Statistically significant associations
      were seen between the initial 16 Danish cases of acute clinical IBD in 1998 and
      certain hatcheries, age of parent birds and a certain feed mill.

PMID- 12425788
TI  - A reovirus challenge model applicable in commercial broilers after live
      vaccination.
AB  - The efficacy of live reovirus vaccines may be determined by challenge via the
      foot pad route 3 to 4 weeks after vaccination. Swelling and discoloration in the
      foot pad and shank are scored for a period of 14 days. The major disadvantages of
      this challenge model are the subjective judgement of gross foot pad and/or shank
      lesions, that it is very difficult to induce lesions in broilers, and that it
      causes animal suffering. Other reovirus challenge models are based on reisolation
      of the virus from different tissues or on scoring microscopic lesions in the
      tendons. Some disadvantages of these models are that they either cannot be used
      after vaccination with live reovirus because they cannot discriminate between
      vaccine and challenge virus or that the microscopic lesions scored need not
      necessarily be related to the challenge virus but may have been induced by other
      factors. Therefore, we have attempted to develop a reovirus challenge model that
      was an improvement on the existing ones, using isolation of reovirus from
      different organs followed by specific detection of the challenge virus with a
      monoclonal antibody that can discriminate between challenge and vaccine virus.
      The reovirus challenge model was examined in specific pathogen free (SPF) White
      Leghorn chickens and commercial broilers. In vivo studies were conducted to
      examine the efficacy of an attenuated reovirus vaccine in SPF White Leghorn
      chickens and commercial broilers with maternal immunity against reovirus. No
      challenge virus could be detected in any of the organs of the vaccinated chickens
      3 and 10 days after challenge. In contrast, challenge virus could be isolated
      from the unvaccinated control group. At an increased challenge dose all
      unvaccinated challenge control birds were positive, while the vaccinated chickens
      were protected. It was shown that 1-day-old vaccination in the presence of
      maternal immunity was effective. It seemed that protection induced in broilers by
      the attenuated reovirus vaccine may not have been entirely humoral because in
      protected birds no antibodies against reovirus were detected by enzyme-linked
      immunosorbent at the time of challenge. Protection in these birds might therefore
      have been induced by cellular immunity.

PMID- 12425790
TI  - Molecular epidemiology of unilateral amyloid arthropathy in broiler breeders
      associated with Enterococcus faecalis.
AB  - Although symmetrical polyarticular amyloidosis has been described extensively in
      brown layers, spontaneous unilateral amyloid arthropathy has not been described
      previously in chickens. Birds from nine flocks of broiler parent stock (PS) had
      unilateral lameness associated with severe swelling of the left hock joint and
      the caudal aspect of the metatarsus. Gross pathology was restricted to the left
      hock joint and the left digital flexor tendons in almost all cases, suggesting an
      association with administration of Marek's disease vaccine. Amyloid deposits were
      found in 83% (25/30) of affected joints by histological examination of Congo red
      stained sections. Systemic amyloidosis, involving mainly the liver and spleen,
      was found in 59% (10/17) of birds. Enterococcus faecalis was isolated from joints
      in 77% (23/30) of cases and Staphylococcus aureus was isolated from the joint in
      one case (1/30). Thirty-five E. faecalis isolates from joints, tendons and blood
      samples from birds in five affected PS flocks were compared using pulsed-field
      gel electrophoresis (PFGE) to separate genomic fragments after digestion with
      SmaI. All but one isolate had identical or closely related restriction
      endonuclease digestion (RED) patterns that were very similar to a known
      arthropathic and amyloidogenic E. faecalis isolate. A further 30 E. faecalis
      isolates from seven grandparent stock (GPS) flocks and two isolates from two
      unaffected PS flocks of the same genetic background were analysed by PFGE. Among
      these isolates, 11 originating from four GPS flocks had RED patterns identical to
      or closely related to the reference amyloid-inducing strain. Moreover, one E.
      faecalis isolate from amyloidotic joints of brown layers housed in California,
      USA was included in the analysis and appeared to be identical to the reference
      strain. This study showed that the E. faecalis isolates involved in these
      outbreaks of unilateral amyloid arthropathy in broiler breeders belonged to the
      same clone as that responsible for outbreaks in brown layers.

PMID- 12425791
TI  - Quantitative comparison of intestinal invasion of zoonotic serotypes of
      Salmonella enterica in poultry.
AB  - The aim of the present study was to compare the invasion of selected zoonotic
      Salmonella serotypes of poultry in an in vivo chicken intestinal loop model and
      also in vitro in epithelial cell cultures. Invasion was measured relative to a
      reference strain, Salmonella Typhimurium 4/74 invH201::TnphoA. Two serotypes
      demonstrated intracellular log(10) counts that differed significantly from all
      other serotypes tested: Salmonella Enteritidis PT4 being 1.5 log(10) colony
      forming units (CFU) (31-fold) higher, and Salmonella Tennessee being 0.7 log(10)
      CFU (fivefold) lower than the reference strain (P < or = 0.0001). A group of
      serotypes, which can be vertically transmitted, showed significantly higher
      intracellular counts (fourfold to eightfold) than the reference strain. The group
      included S. Typhimurium 4/74, S. Typhimurium DT104 (poultry and porcine
      isolates), S. Enteritidis PT1, S. Enteritidis PT6, S. Enteritidis PT8, and
      Salmonella Berta. The serotypes Salmonella Hadar, Salmonella Virchow, S. 4,12:b:
      , S. Typhimurium DT41, and Salmonella Infantis, most of which are considered
      horizontally transmitted, did not show significantly different intracellular
      counts from the reference strain. Results from the cell culture invasion studies
      agreed with the in vivo data, with the exception of S. Berta and the poultry
      isolate of S. Typhimurium DT104.

PMID- 12425792
TI  - Dietary mannan-oligosaccharides and their effect on chicken caecal microflora in
      relation to Salmonella Enteritidis colonization.
AB  - This study first investigates the effects of mash diet, or mash supplemented with
      either 2.5% mannose-oligosaccharide (MOS) or palm kernel meal (PKM), on the
      microflora of the hen caecal contents. Second, it investigates the effect of
      caecal contents of hens (HCC) fed mash or mash supplemented with MOS or PKM on
      the major microflora groups of chicks, and their inhibitory effect on Salmonella
      enterica serovar Enteritidis (PT4) colonization. Finally, this study investigates
      the effect over time of diets supplemented with MOS or PKM on S. Enteritidis
      colonization and the microflora of chicks. In hens, supplemented diets increased
      Bifidobacterium spp., while decreasing members of Enterobacteriaceae and
      Enterococcus spp., compared with the mash diet. Chicks dosed with the HCC showed,
      on average, increased numbers of anaerobes, while the numbers of aerobes
      decreased including coliforms and S. Enteritidis compared with controls without
      HCC. In chicks fed the MOS-supplemented or PKM-supplemented diets, S. Enteritidis
      colonization decreased over time, compared with mash alone. Four-week-old PKM
      birds showed an increase in Bifidobacterium spp. and Lactobacillus spp., with a
      decrease in S. Enteritidis compared with week 2. Generally, the HCC and diets
      supplemented with MOS or PKM affected the birds intestinal microflora by
      increasing the Bifidobacterium spp. and Lactobacillus spp., while decreasing the
      Enterobacteriaceae groups. They also reduced susceptibility in young chickens to
      colonization by S. Enteritidis.

PMID- 12425793
TI  - Effect of an in ovo infection with a Dutch avian leukosis virus subgroup J
      isolate on the growth and immunological performance of SPF broiler chickens.
AB  - The effect of an in ovo infection with a Dutch isolate of avian leukosis virus
      subgroup J (ALV-J) on the growth of specific pathogen free (SPF) broiler chickens
      was analysed. During this study, possible immune suppressive effects of ALV-J
      were assessed by measuring delayed-type hypersensitivity with keyhole limpet
      haemocyanin (KLH), natural killer (NK) cell activity, the production of radicals
      of nitric oxide (NO) by macrophages, humoral immune response against Newcastle
      and infectious bursal disease vaccine viruses, and automated total and
      differential leukocyte counts. In an attempt to elucidate the underlying causal
      mechanisms of the induced growth retardation, 3,3',5-triiodothyronine (T3)
      concentrations in serum were measured. Four experiments were conducted. In
      experiment 1, ALV-J-injected birds were compared with ALV subgroup A (ALV-A)
      injected and negative control chickens. In experiment 2, ALV-J-injected birds
      were only compared with negative controls. Finally, in experiments 3a and 3b, ALV
      J-injected chickens were compared with negative controls and a group of chickens
      in which only 10% of birds had been injected with ALV-J. Birds were injected in
      ovo at day 7 of incubation with 10(4) median tissue culture infectious dose
      (TCID(50)) ALV-J or ALV-A, except in experiment 3a where 10(2) TCID(50) ALV-J was
      injected. Significant growth suppression was found in all 100% of ALV-J-infected
      groups. The average growth retardation of ALV-J-infected birds compared with
      negative controls at 6 weeks of age was approximately 8, 11, 2.5 and 6% for the
      four successive experiments performed. The delayed-type hypersensitivity test
      against KLH of ALV-J-infected birds showed a tendency towards lower wattle
      thickness; however, the difference with controls was not significant (P > 0.05).
      The same was true for NK cell activity and NO production by macrophages, although
      the difference was not significant. The total and differential leukocyte counts
      performed on blood samples from birds at 3, 4 and 6 weeks of age as well as the
      humoral immune response against Newcastle and infectious bursal disease vaccine
      viruses did not show significant differences between treatment groups either.
      Only the number of basophils were significantly higher (P = 0.02) in ALV-J
      infected birds at 3 weeks of age. No significant lower T(3) levels were found in
      ALV-J-infected birds in weeks 2 and 3 (experiment 2) and weeks 3 and 5
      (experiment 3b); however, at 4 weeks (experiment 2) and 6 weeks (experiment 3b)
      of age, T(3) levels were significantly lower suggesting mild hypothyroidism in
      these broilers. In conclusion, the present experiments show the occurrence of
      significant growth retardation in SPF broilers after an ALV-J in ovo infection.
      The various studies performed to assess the immune competence of ALV-J-infected
      chickens did not show significant differences in immune responsiveness. The
      assays on cellular immunity showed a tendency to a lower response in ALV-J
      infected birds, but these differences were not statistically significant.

PMID- 12425794
TI  - The effects of ochratoxin/aluminosilicate interaction on the tissues and humoral
      immune response of broilers.
AB  - This study aimed to evaluate the effect of dietary ochratoxin, in the presence or
      absence of aluminosilicate, on the histology of the bursa of Fabricius, liver and
      kidneys, and on the humoral immune response of broilers vaccinated against
      Newcastle disease virus. The exposure of birds to 2 p.p.m. ochratoxin, in the
      presence or absence of aluminosilicate, reduced their humoral immune response and
      the number of mitotic cells in the bursa. The relative weight of the livers of
      the birds exposed to this toxin was increased and, microscopically, there was
      hepatocyte vacuolation and megalocytosis with accompanying hyperplasia of the
      biliary epithelium. The kidneys showed hypertrophy of the renal proximal tubular
      epithelium, with thickening of the glomerular basement membrane. Aluminosilicate
      did not ameliorate the deleterious effects of the ochratoxin.

PMID- 12425795
TI  - Coronaviruses from pheasants (Phasianus colchicus) are genetically closely
      related to coronaviruses of domestic fowl (infectious bronchitis virus) and
      turkeys.
AB  - Reverse-transcriptase polymerase chain reactions (RT-PCRs) were used to examine
      RNA extracted from mouth/nasal swabs from pheasants exhibiting signs of
      respiratory disease. The oligonucleotides used were based on sequences of
      infectious bronchitis virus (IBV), the coronavirus of domestic fowl. A RT-PCR for
      the highly conserved region II of the 3' untranslated region of the IBV genome
      detected a coronavirus in swabs from 18/21 estates. Sequence identity with the
      corresponding region of IBVs and coronaviruses from turkeys was > 95%. A RT-PCR
      for part of the S1 region of the spike protein gene was positive with 13/21 of
      the samples. Sequence analysis of the RT-PCR products derived from nine of the
      pheasant viruses revealed that some of the viruses differed from each other by
      approximately 24%, similar to the degree of difference exhibited by different
      serotypes of IBV. Further analysis of the genome of one of the viruses revealed
      that it contained genes 3 and 5 that are typical of IBV but absent in both the
      transmissible gastroenteritis virus and murine hepatitis virus groups of
      mammalian coronaviruses. The nucleotide sequences of genes 3 and 5 of the
      pheasant virus had a similar degree of identity (approximately 90%) with those of
      coronaviruses from turkeys and chickens, as is observed when different serotypes
      of IBV are compared. This work: (a) confirms that coronaviruses are present in
      pheasants (indeed, commonly present in pheasants with respiratory disease); (b)
      demonstrates that their genomes are IBV-like in their organization; and (c) shows
      that there is sequence heterogeneity within the group of pheasant coronaviruses,
      especially within the spike protein gene. Furthermore, the gene sequences of the
      pheasant viruses differed from those of IBV to similar extents as the sequence of
      one serotype of IBV differs from another. On the genetic evidence to date, there
      is a remarkably high degree of genetic similarity between the coronaviruses of
      chickens, turkeys and pheasants.

PMID- 12425796
TI  - A fiber gene-based polymerase chain reaction for specific detection of pigeon
      adenovirus.
AB  - A polymerase chain reaction (PCR) was developed to detect a recently described
      pigeon adenovirus (PiAV). Primers located in the fiber gene of PiAV amplified a
      PCR fragment solely from PiAV DNA, whereas all 12 serotypes of fowl adenoviruses
      (FAV1 to FAV12), some of them able to infect pigeons, did not react. A PCR
      fragment of 967 base pairs was amplified from three different isolates
      serologically typed as PiAV and from some pigeon liver samples showing
      morphological and histological signs of an adenovirus infection. Those samples
      did not react with a published primer pair (H3/H4) able to detect FAV,
      demonstrating the specificity of both PCRs to react exclusively with the
      respective pathogen, PiAV or FAV. The presented PCR is a suitable diagnostic tool
      to gain further insight into the epidemiology of PiAV infections in pigeons.

PMID- 12425797
TI  - Metastatic subcutaneous sarcoma and abdominal carcinoma in a peach-faced lovebird
      (Agapornis roseicollis).
AB  - A 2-year-old male peach-faced lovebird (Agapornis roseicollis) with a
      subcutaneous sarcoma on the right carpus was treated by surgical amputation.
      Three months after surgery, lung metastases causing clinical signs of dyspnoea
      were diagnosed radiographically and subsequently the bird was euthanased. At
      necropsy, a tumour firmly attached to the right testis, kidney and lung was
      found, and several tumours were present in the lung parenchyma. Histopathology
      revealed a mesenchymal growth pattern in the carpal subcutis and lung neoplasms,
      and an infiltrating epithelial pattern in the abdominal one. Immunohistochemistry
      for muscle actin, keratin, neurone-specific enolase and chromogranin confirmed
      the different cell lineage of the neoplasms, thus leading to the diagnosis of a
      fibrosarcoma in the subcutis with pulmonary metastases, and a carcinoma of
      indeterminate origin in the cranial abdomen.

PMID- 12425798
TI  - [Breast cancer in multiple primary malignant neoplasms, epidemiological and
      clinical analysis].
AB  - OBJECTIVE: To investigate the epidemiological and clinical characteristics of
      breast cancer associated with multiple primary malignant neoplasmas (MPMNs).
      METHODS: The data of 519 patients of breast cancer associated with MPMNs admitted
      to the Cancer Hospital, CAMS and diagnosed by operation and pathology in the
      period of 1958 to 2001 were studied retrospectively to analyze the morbity, age
      of onset, sex ratio, predilection site of tumor, and the interval time between
      sequential tumors. The 519 patients, all female, were divided into four groups:
      bilateral primary breast cancer (1st group), synchronic Paget's disease (PD)
      associated with breast cancer in the same breast (2nd group), breast cancer as
      the first tumor associated with MPMNs (3rd group), and breast cancer as the
      second or third tumour associated with MPMNs (4th group). RESULTS: The
      constituent rate of bilateral primary breast cancer, synchronic Paget's disease
      (PD) associated with breast cancer in the same breast, breast cancer as the first
      tumor associated with MPMNs, and breast cancer as the second or third primary
      tumour associated with MPMNs was 3.0%, 0.8%, 3.2%, and 2.5% respectively. The
      median age of onset was 42.5, 47.3, 51.4, and 51.8 years respectively for the
      four groups. The mean interval time between the appearance of the first tumor and
      the appearance of the second tumor was 5.4, 0, 8.6, and 7.6 years in the four
      groups respectively. The predilection sites of second and third primary cancers
      in the third group were lung, breast, esophageal, ovary, and large intestine. The
      predilection sites of first primary cancer in the 4th group were uterus, ovary,
      large intestine, lung, lymphatic tissue, and esophagus successively. The
      involvement rate of breast in breast cancer associated with MPMNs was 72.4%.
      CONCLUSION: (1) Breast is one of the predilection organs of MPMNs. (2) The
      predilection organs of breast associated with MPMNs are the target organs of
      female hormone (eg, breast, ovary and uterus) and the organs involved by
      radiotherapy for breast cancer (eg, lung and esophagus). (3) Early diagnosis and
      timely and proper treatment have satisfactory effect.

PMID- 12425799
TI  - [Effect of mitogen-activated protein kinase signal transduction in non-estrogen
      antagonistic mechanism of tamoxifen].
AB  - OBJECTIVE: To investigate the effect of mitogen-activated protein kinase (MAPK)
      signal cascade in the non-estrogen antagonistic mechanism of tamoxifen (TAM).
      METHODS: Human breast cancer cells MCF-7 were cultured. TAM, PD98075, inhibitor
      of MAPK kinase (MEK), or TAM + PD98075 was added into the culture media, followed
      by methyl thiazolyl tetrazolium (MTT) and DMSO. Then the 542nm absorption value
      was measured and the growth curve was drawn. Western blot was used to measure the
      expression of p-extracellular signal-regulated kinase (ERK) in MCF-7 cells. Flow
      cytometry was applied to analyze the cell cycle and apoptosis. RESULTS: The
      optical density representing the relative expression of p-ERK was lower
      successively in the control, TAM, PD09875, and TAM + PD09875 groups. The
      apoptotic rate of MCF-7 cells was 6.44%, 8.3%, 36.5% and 53.5% in the control,
      PD98075, TAM, and TAM + PG98075 groups respectively The rate of cells in G(0)G(1)
      phase was 74.25%, 79.76%, 84.02%, and 95.82% in those groups respectively. Ther
      rate o cells in S phase was 21.03%, 15.22%, 11.43%, and 2.22% respectively in
      those groups. The rate of cells in G(2)M phase was 4.71%, 5.02%, 4.52%, and 1.96%
      respectively in those groups. CONCLUSION: MAPK signal transduction pathway plays
      a certain role in the non-estrogen antagonistic mechanism of tamoxifen.

PMID- 12425800
TI  - [Relationship among breast cancer and negative life event and cell immunity].
AB  - OBJECTIVE: To investigate the relationship among breast cancer and negative life
      event and cell immunity. METHODS: A questionnaire survey using the Life Event by
      YANG Desen to investigate the family life problems, work problems, and social and
      other problems was conducted among 115 patients with breast cancer diagnosed by
      pathology and cytology and 115 gender, age, profession, education, and life habit
      matched patients with benign breast diseases as controls. Fasting blood was drawn
      from all patients. Fluorescent-labeled bodies were added. Flow cytometry was made
      to count the immunocytes. RESULTS: The negative life event rate was 87% in the
      breast cancer group, higher than that in the control group (55%, P < 0.01). The
      rate of family problems in the breast cancer group was 63%, higher than that in
      the control group (40%). The total score of negative events was 31.5 +/- 9.7 in
      the breast cancer group, higher than that in the control group (17.3 +/- 5.6, P <
      0.01). The percentage of CD(3) (total T cell) in the breast cancer group was 58.8
      +/- 12.2%, significantly lower than that in the control group (63.9 +/- 9.9%, P <
      0.01). There was no difference in the percentages of CD(4), CD(8), CD(4)/CD(8),
      and the percentage of natural killer cells (NK) between the two groups.
      CONCLUSION: Breast cancer is closely correlated with negative life events,
      especially family problems concerning marriage and children. The negative life
      events are related to the decrease of total T cells, and unrelated to the
      percentages of other cells.

PMID- 12425801
TI  - [Genomic polymorphism within interleukin-1 family cytokines influences the
      outcome of septic patients].
AB  - OBJECTIVE: To determine the allele frequencies and genotype distribution of
      interleukin (IL)-1 alpha, IL-1 beta and IL-1 receptor antagonist (IL-1ra) gene
      polymorphism in septic patients. METHODS: A prospective, consecutive entry study
      was made among 60 patients with the diagnosis of sepsis who were admitted
      consecutively into the general intensive care unit (ICU), Peking Union Medical
      College Hospital between 1997 and 1999. APACHE II scoring and MODS scoring were
      made within 24 hours after admission. The genomic DNA of peripheral blood
      nucleated cells was extracted. The polymorphic regions within intron 6 of IL-1
      alpha gene containing variable numbers of a tandem repeat (VNTR) of 46 bp, and
      intron 2 of IL-1ra gene containing VNTR of 86 bp were amplified by means of
      polymerase chain reaction (PCR). Alleles A1-4 and RN1-4 were identified according
      to the size of amplified DNA product. The region containing the AvaI polymorphic
      site at position -511 of IL-1 beta gene was amplified by PCR, and subsequently
      digested with AvaI restriction enzyme. RESULTS: The frequencies of allele IL-1ra
      RN2 and genotype RN2/2 in the 60 septic patients were significantly higher than
      those in normal controls (0.34 vs 0.23, P < 0.01, and 0.12 vs 0.05, P < 0.05,
      respectively). The allele frequencies or genotype distribution of IL-1 alpha VNTR
      gene polymorphism and IL-1 beta AvaI polymorphism did not differ between the
      septic patients and normal controls. In addition, genotypes A2/2, B2/2 and RN2/2
      were associated with a significantly higher mortality (80%, 81% and 71%,
      respectively) in septic patients. Patients with any 2 of the three alleles, i.e.
      A2, B2 and RN2, suffered from a much more severe sepsis (as measured by APACHE II
      and MODS scores) and higher mortality rate ( 55-65%), while septic patients with
      genotypes A1/1, B1/1 or RN1/1 showed a much lower mortality (0-13%). CONCLUSION:
      Allele IL-1RN2 polymorphism, but not IL-1A or IL-1B gene polymorphism, is
      associated with susceptibility to sepsis. Alleles A2, B2 and RN2 might be
      important high-risk genetic markers for sepsis.

PMID- 12425802
TI  - [The human major histocompatibility complex region is not a major susceptibility
      locus for Graves disease among the Hans in north of China].
AB  - OBJECTIVE: To determine if the human major histocompatibility complex (MHC)
      region located on chromosome 6 p21 is a major susceptibility locus for Graves'
      disease (GD) among the Hans in North of China. METHODS: Four highly polymorphic
      microsatellite markers spanning the entire region of chromosome 6 p21 were
      employed to screen the DNA from blood samples of 54 Han multiplex families with
      GD (322 individuals) in Liaoning Province, northeast China. Tow-point and multi
      point Lod scores were calculated under different levels of penetrance, assuming
      both dominant and recessive models. Multipoint nonparametric linkage (NPL) scores
      were also calculated. RESULTS: The two-point Lod scores (theta = 0) and
      multipoint Lod scores for the 4 microsatellites were all less than -2 for all the
      markers tested, at all levels of penetrance, and in both the dominant and
      recessive modes of inheritance. No family showed a two-point Lod score or a
      multipoint Lod score of 1.0 or even larger under the assumed inheritance models.
      The maximum multipoint Lod score was 0.55 under the assumption of genetic
      heterogeneity, with the proportion of linked families of 29%. P values of greater
      than 0.05 were observed for all the multipoint NPL scores obtained. CONCLUSION:
      No locus linked with GD among the Hans in North of China exists on chromosome 6
      p21. Human MHC region is not a major susceptibility locus for northern Chinese
      Han Graves' disease.

PMID- 12425803
TI  - [Comparison of pantoprazole and omeprazole-based triple therapy regimens in the
      treatment of Helicobacter pylori infection].
AB  - OBJECTIVE: To compare the efficacies of pantoprazole and omeprazole-based triple
      regimens in the treatment of H. pylori infection for 1-week or 2-week. METHODS:
      147 patients with H. pylori associated gastritis were randomly divided into
      pantoprazole triple regimen group (pantoprazole 40 mg, amoxicillin 1 g, and
      metronidazole 400 mg, bid,for 1-week or 2-weeks) and omeprazole triple regimen
      (omeprazole 20 mg, amoxicillin 1 g, and metronidazole 400 mg, bid, for 1-week or
      2-weeks). The eradication was determined by (13)C-UBT at least 4 weeks after
      antibiotic therapy. RESULTS: The eradication rate of H. pylori for 1-week
      pantoprazole triple regimen and omeprazole triple regimen were 85.7% (42/49) and
      76.9% (20/26) respectively (P > 0.05). The eradication rates of H. pylori for 2
      weeks and pantoprazole triple regimen and omeprazole triple regimen were 93.9%
      (31/33) and 82.1% (32/39) for 2-week respectively (P > 0.05). CONCLUSION: The
      eradication rate of H. pylori in pantoprazole (or omerazole) triple therapy
      regimen for 2-weeks was higher than 1-week. However there were no significant
      difference between in these two groups (P > 0.05). There were no significant
      difference between pantoprazole and omeprazole triple therapy regimen in
      eradication rate of H. pylori for 1-week or 2-weeks (P > 0.05).

PMID- 12425804
TI  - [Genotyping of hepatitis C virus by hepatitis gene diagnosis microarray].
AB  - OBJECTIVE: To study the preparation of hepatitis C virus (HCV) diagnosis
      microarray and its accuracy in diagnosis of gene type of hepatitis C virus.
      METHODS: Probe and primer and primers were designed in 5'-untranslated region and
      C region of hepatitis C virus gene. The probes were synthesized by DNA
      synthesizer. Solutions of probe of the final concentration of 50 micromol/L were
      made by dissolving the probes into sodium carbonate buffer. Hepatitis C virus
      genotype array spotting was performed by pin-based spotting robot PixSys5500 with
      CMP3 pin. The gene chips were prepared by spotting the probes onto the specially
      treated glass sliders. Sixty HCV RNA positive serum samples were obtained from
      the in-patients of the Nanjing Second Hospital (experimental group), and 60 HCV
      RNA negative serum samples were obtained from the healthy people undergoing
      physical examination (control group). Quantitative examination of serum HCV RNA
      was made by fluorescent quantitation PCR. The HCV RNA in the serum specimens of
      the experimental group (with the HCV RNA concentration of more than 500
      copies/ml) and of the control group (with the HCV RNA concentration of less than
      500 copies/ml) was isolated and purified, underwent reversed transcription and
      nested PCR to be amplified, and then genotyped by gene microarray and HCV RNA
      sequencing. During the experiment, double blind method was used. RESULTS: Tested
      by the gene microarray, the serum specimens in the experimental group were all
      HCV RNA positive, out of which 46 cases were 1b type, 3 cases were 3a type, 3
      cases were 3b type, 2 cases were 2a type, 2 cases were 2b type, 2 cases were 1b +
      2a type, and 2 cases were 3a type. Tested by nucleotide sequencing assay, 50
      cases were 1b type, 3 cases were 3a type, 3 cases were 3b type, 2 cases were 2a
      type, and 2 cases were 2b type. The double-blind test results showed a
      coincidence rate of 93.3% in genotyping HCV by these two methods. CONCLUSION:
      Hepatitis gene microarray can be used in detection of serum HCV RNA and in
      diagnostic genotyping with great accuracy.

PMID- 12425806
TI  - [Industrial hand injuries by punch machines: a case-control study].
AB  - OBJECTIVE: To identify factors associated with industrial hand injuries by punch
      machines. METHODS: From September, 1999 to June, 2000, 108 patients of industrial
      hand injuries by punch machines were collected. For each patient, 2 controls were
      randomly selected. One was from the same industry; the other was from a big
      industry with thousands of punch machines. They matched on gender, job and age.
      In-person interviews were conducted to collect data on demographics, work
      history, work characteristics, work injuries, work organization, health
      behaviors, anthropometric and psychological factors. The Eysenck Personality
      Questionnaire (EPQ) was selected to evaluate the psychological performance. Risk
      factors were examined via multivariate logistic regression techniques. RESULTS:
      There were four important factors affecting hand injuries by punch machines: The
      first was the length of service index (odds ratio [OR] = 0.972, 95% confidence
      interval [CI] = 0.957, 0.988). The second index was neuroticism (OR = 1.649, 95%
      CI = 1.264, 2.151). A safety equipment index (OR = 0.260, 95% CI = 0.123, 0.547)
      and a safety operation criterion index (OR = 0.136, 95% CI = 0.064, 0.286) were
      also significant factors. CONCLUSIONS: Results suggest that the accident-prone
      population are those who have shorter service length and neurotic psychological
      performance. It may reduce the incidence of industrial hand injuries by punch
      machine to strengthen the appliance of safety equipment and enforcement of safety
      operation criterion, especially to the accident-prone population.

PMID- 12425805
TI  - [Alendronate in postmenopausal women with osteopenia and osteoporosis: effects on
      bone mineral density during treatment and after withdrawal].
AB  - OBJECTIVE: To determine the efficacy of alendronate (Fosamax) administration and
      withdrawal on the bone mineral density (BMD) in postmenopausal women with
      osteopenia and osteoporosis. METHODS: Alendronate (10 mg) and calcium carbonate
      (containing calcium 500 mg) were administered daily to 25 Chinese menopausal
      women with osteopenia and osteoporosis for 6 months and to 15 women for 12
      months. After the withdrawal of alendronate, calcium carbonate was administered
      continuously. Follow-up was made three times for the 6-month group: before
      treatment, 6 months after treatment, and 13 +/- 4 months (6 - 24 months) after
      aldoronate withdrawal, and was made four times for the 12-month group: before
      treatment, 6 months and 12 months after treatment, and 23 +/- 7 months (14 - 36
      months) after alendronate withdrawal to determine the BMD of lumbar spine 2
      approximately 4, neck of femur, Wards triangle, and greater trochanter and blood
      alkaline phosphatase (ALP). RESULTS: Compared to the baseline value, the BMD in
      lumbar spine and hip increased significantly 6 months after treatment in 6-month
      group, with the BMD in lumbar spine 2 - 4 increased by 5.3% (P < 0.001). In the 6
      month group, no significant decline was found in the BMD in lumbar spine and hip
      13 +/- 4 months after alendronate withdrawal, the BMD in greater trochanter even
      increased further compared with that 6 months after treatment. In the 12-month
      group, the BMD significantly increased except in the Wards triangle after 6
      months' treatment with an increase by 4.2% in lumbar spine 2 - 4 (P < 0.001).
      After 12 months' treatment the increment of BMD in lumbar spine 2 - 4 was 6.1% (P
      < 0.001) and the BMD of the hip remained unchanged. 23 +/- 7 months after the
      alendronte withdrawal the values of BMD in lumbar spine and hip were almost the
      same as that 12 months after treatment. CONCLUSION: Alendronate increases the BMD
      in spine and hip, especially in lumbar spine. The skeletal benefits are
      maintained for at least 13 - 23 months in spine and hip after withdrawal of
      alendrenate.

PMID- 12425807
TI  - Selection of surgical interference in mastoidectomy with tympanoplasty.
AB  - OBJECTIVE: To discuss the long-term results of different surgical patterns for
      chronic suppurative otitis media. METHODS: The data of 231 cases of chronic
      suppurative otitis media who underwent open-mastoidectomy with tympanoplasty
      (OMT), combined approach tympanoplasty (CAT), and intact bridge mastotymplasty
      (IBM) and were followed up for 2 - 5 years from 1990 to 2001 were collected to
      analyze the surgical technology, long-term recurrence rate, and level of hearing
      improvement. RESULTS: The improved hearing threshold level of air conduction in
      0.5, 1, 2 KHz was 21 dBHL after IBM, significantly higher than that after OMT (12
      dBHL) and that after CAT (9.5 dBHL). The long-term recurrence rate was 24.4%
      after CAT, higher than that after IBM (8.3%) and that after OMT (5.8%).
      CONCLUSION: IBM is a good choice for preserving or improving hearing based on
      eradication of the focus among patients with chronic suppurative otitis media.

PMID- 12425808
TI  - [Perioperative lung injury in ventricular septal defect with severe pulmonary
      hypertension, a clinical study of 31 cases].
AB  - OBJECTIVE: To investigate the mechanism of perioperative lung injury in patients
      of ventricular septal defect (VSD) with severe pulmonary hypertension. METHOD:
      The thromboxane B(2) (TXB(2)), 6-keto-prostagladin F(1 alpha) (6-keto-PGF(1
      alpha)), malonyldiadehyde (MDA), interleukin-6 (IL-6), and IL-8, and blood
      pressure, pulmonary arterial pressure (PAP) and total pulmonary pressure (TPR) in
      thirty-one patients of VSD, 16 cases without pulmonary hypertension and 15 cases
      with severe pulmonary hypertension, were examined after anesthesia (AA), over
      extracorporeal circulation (OEC), and 1 hour (PEC1), 6 hours (PEC6), 24 hours
      (PEC24), 48 hours (PEC48), and 72 hours (PEC72) post extracorporeal circulation.
      The respiratory index (RI) and ratio of 6-keto-PGF(1alpha) and TXB(2) (P/T) were
      calculated. Before and after extracorporeal circulation, pulmonary tissues were
      taken to be examined by light microscopy and electron microscopy. RESULT: In the
      cases with severe pulmonary hypertension the P/T was 0.81 +/- 0.26 after
      anesthesia, then decreased 0.65 +/- 0.28 over extracorporeal circulation, and
      reached its lowest value (0.51 +/- 0.32) 1 hour post extracorporeal circulation.
      MDA was 2.4 micromol/L +/- 0.6 micromol/L after anesthesia, then increased, was
      7.0 micromol/L +/- 1.7 micromol/L OEC, and reached its peak value (7.3 micromol/L
      +/- 0.9 micromol/L) PEC1. IL-6 was 0.27 ng/L +/- 0.12 ng/L after anesthesia, then
      increased, and reached its peak value (0.50 ng/L +/- 0.19 ng/L) PEC1. IL-8 was
      7.5 ng/L +/- 1.5 ng/L after anesthesia, then increased, was 152 ng/L +/- 50 ng/L
      PEC1, and reached its peak (183 ng/L +/- 63 ng/L) PEC6. TXB(2) was 251 ng/L +/-
      44 ng/L after anesthesia, then increased, and reached its peak (967 ng/L +/- 145
      ng/L) at PEC1. The PAP was 72.1 +/- 18.8 mm Hg after anesthesia, 55 mm Hg +/-
      15.3 mm Hg OPC, and 7.4 +/- 2.1 at PEC1, then decreased, and was 53 mm Hg +/- 15
      mm Hg at PEC72. The total pulmonary resistance (TPR) was 10.6 +/- 2.9 mm Hg x
      min(-1) x L(-1) after anesthesia, then increased, and reached its peak (15.0 +/-
      3.9 mm Hg x min(-1) x L(-1) at PEC6. Respiratory index (RI) was 0.88 +/- 0.23,
      then increased, and reached its peak (2.35 +/- 0.72) at PEC6. TXB(2) and RI were
      positively correlated with pulmonary vascular resistance (gamma = 0.283, P <
      0.05; gamma = 0.403, P < 0.05). RI was positively correlated with MDA (gamma =
      0.403, P < 0.05). Morphologic studies revealed discontinuities in the endothelial
      cell lining of pulmonary capillaries, infiltration of inflammatory cells,
      plugging of pulmonary capillaries with neutrophils, and intraalveolar hemorrhage.
      CONCLUSION: During the perioperative period, the pulmonary damage, which leads to
      pulmonary hypertensive crisis, is more severe among the cases of VSD with severe
      pulmonary hypertension than among the case without pulmonary hypertension.

PMID- 12425809
TI  - Effects of salvianolic acid-B on TGF-beta 1 stimulated hepatic stellate cell
      activation and its intracellular signaling.
AB  - OBJECTIVE: To investigate hepatic stellate cells (HSC) responses at different
      differentiation stages on transforming growth factor-beta 1, and to elucidate the
      mechanisms of salvianolic acid - B (SA-B), a water soluble compound from Salvia
      miltiorrhiza, against hepatic fibrosis, relating to interference with TGF-beta 1
      stimulated HSC activation and intracellular signal transduction via Smads.
      METHODS: HSC was isolated from rat by in situ perfusion of liver and 8.2%
      nycondenz gradient centrifugation, and primarily cultured on uncoated plastic for
      1 d, 4 d and 7 d respectively, which represented quiescent, intermediate and
      activated phenotypes. The cells were stimulated with 100 pmol/L TGF-beta 1, cell
      phenotypes were observed under inverted microscope, alpha-actin expression was
      checked by Western blot, and collagen secretion was measured with [(3)H] proline
      incorporation and collangenase digestion, then HSC at one definite
      differentiation stage that responded most sensitively to TGF-beta 1 was selected
      as the cell model for the following study. 0.1 micromol/L - 1 mmol/L SA-B was
      incubated with HSC and the cell proliferation was measured by intracellular
      [(3)H] thymidine pulse. SA-B was also incubated with TGF-beta 1 stimulated HSC,
      the collagen secretion was measured as above, alpha-actin and plasmin activator
      inhibitor-1 (PAI-1) were checked with Western blot, and alpha1 (I) procollagen
      mRNA levels were analyzed with Northern blot. The cytoplasmic and nuclear
      proteins were extracted, and cytoplasmic and nuclear Smad2, 3 expression and
      phosphorylation levels were measured with Western blot. RESULTS: As culture
      duration prolonged, HSC phenotypes underwent activation gradually, accompanied by
      the increase of alpha-actin expression and collagen secretion. TGF-beta 1
      increased the basal collagen levels at d1, d4 and d7 by 128.6%, 207.7% and 188.2%
      of the control respectively, while d4 HSC had the most sensitive response, and
      this intermediate HSC was used as cell model for the following study. Except 0.1
      mmol/L-1 mmol/L SA-B caused parts of HSC death, 0.1 micromol/L-10 micromol/L SA-B
      had no influence on cell shape, but decreased HSC proliferation in a dose depend
      manner, by 76%, 60.1% and 47.8% of the control respectively. 1 micromol/L-10
      micromol/L SA-B remarkably inhibited the collagen secretion of TGF-beta 1
      stimulated HSC by 68.6% and 56.1% of the control, PAI-1 and alpha-actin
      expression, and down-regulated alpha 1 (I) pro-collagen gene expression. 0.1
      micro mol/L approximately 10 micro mol/L SA-B decreased the cytoplasmic and
      nuclear Smad2, 3 protein expression, especially inhibited Smad2 phosphorylation
      and nuclear translocation. CONCLUSIONS: SA-B obviously inhibits intermediate HSC
      proliferation, decreases TGF-beta 1 stimulated HSC activation and matrix protein
      and gene expression, and inhibited stimulated HSC Smad2, 3 protein expression,
      phosphorylation and nuclear translocation. The inhibition of TGF-beta 1 signaling
      in HSC and its biological responses is the important mechanism of SA-B against
      hepatic fibrosis.

PMID- 12425810
TI  - The modulating effect of L-arginine on collagen metabolism of pulmonary artery in
      pulmonary hypertension induced by a left-to-right shunt.
AB  - OBJECTIVE: To explore the modulating effect of L-arginine on collagen metabolism
      of pulmonary artery in rats with high pulmonary blood flow-induced pulmonary
      hypertension and its molecular mechanism. METHOD: Eighteen rats were randomly
      divided into 3 groups of 6 rats: shunt group (pulmonary hypertension was
      established with an abdominal aorta and inferior vena cava shunting), shunt + L
      Arg group (L-arginine, 1 g x kg(-1) x d(-1) was given into the stomachs of rats
      for weeks after shunting), and control group. After 11 weeks of experiment, the
      pulmonary hemodynamics were studied, the contents of collagen I and collagen III
      expressions were detected by immunohistochemical assay. The expressions of
      procollagen I mRNA, procollagen III mRNA, TIMP-1 mRNA and MMP-1 mRNA were
      detected by in situ hybridization. RESULTS: After 11 weeks of experiment, the
      mean pulmonary artery pressure (MPAP) in shunt group was 23.0 mm Hg +/- 0.9 mm
      Hg, higher than that in shunt + L-Arg group (18.0 mm Hg +/- 1.8 mm Hg, P < 0.01)
      and that in control group (15.7 mm Hg +/- 1.1 mm Hg, P < 0.01). The expressing
      integral scores of collagen I and collagen III, the expression of procollagen I
      mRNA, Procollagen III mRNA, TIMP-1 mRNA, MMP-1 mRNA and the ratio of TIMP-1/MMP-1
      were significantly higher in the shunt group than in the other 2 groups (P < 0.01
      or P < 0.05). CONCLUSION: L-arginine reduces the synthesis of extracellular
      matrix-collagen and increases its degradation. Thus L-arginine has important
      modulating effects on pulmonary hypertension and pulmonary vascular remodeling
      induced by high pulmonary blood flow.

PMID- 12425811
TI  - Influence of anti-alginate serum combined with gatifloxacin on mucoid pseudomonas
      aeruginosa biofilm morphology.
AB  - OBJECTIVE: To investigate the influence of anti-alginate serum on morphology of
      biofilm (BF) of mucoid Pseudomonas aeruginosa. METHODS: The modified plate
      culture method was used to establish a biofilm model of mucoid Pseudomonas
      aeruginosa in vitro. The biofilm was treated by anti-alginate serum and/or
      different concentrations of gatifloxacin. The samples were then detected by
      scanning electron microscopy (SEM) and optical microscopy after being stained
      with AgNO(3). A group of samples treated by none agent was used as blank control.
      The optical density of bacterial biofilm was determined by using computer image
      analysis system. RESULTS: BF was achieved on the silicon slides in all groups 7
      days after the incubation of Pseudomonas aeruginosa. The silicon slides were
      covered by dense and black stained material in the blank group; the black stained
      material as mildly less in the group treated with anti-alginate serum, and much
      less in the group treated with gatifloxacin, and the BF was thin and only
      slightly stained black in the group treated with anti-alginate combined with
      gatifloxacin. SEM showed that the mucoid materials among bacteria was reduced and
      the number of bacteria was decreased and the shape of bacteria became irregular
      in the groups treated by anti-alginate serun and/or gatiflaxacin, especially the
      group treated by anti-alginate combined with gatifloxacin. Computer image
      analysis system showed that the mean optical density was 0.82 +/- 0.06 in the
      blank control group, 0.79 +/- 0.06 in anti-alginate serum group, 0.76 +/- 0.07 in
      of gatifloxacin group, and 0.70 +/- 0.04 in anti-alginate serum combined with
      gatifloxacin group. CONCLUSION: Anti-alginate serum affects the structure and
      morphology of the biofilm of mucoid Pseudomonas aeruginosa and destroys the
      biofilm structure when combined with gatifloxacin.

PMID- 12425812
TI  - Substitution of porcine small intestinal submucosa for rabbit Achilles tendon, an
      experimental study.
AB  - OBJECTIVE: To study the effect of substitution of porcine small intestinal
      submucosa (SIS) for rabbit Achilles tendon. METHODS: Porcine SIS was taken out
      and processed. Part of Achilles tendons of 20 rabbits' right legs were removed
      and substituted by porcine SIS and the Achilles tendon of the left legs were used
      as controls. One, four, eight, twelve, and sixteen weeks after the operation 4
      rabbits were killed and their right Achilles tendons were taken out to be
      examined histologically and their maximum load was tested. RESULTS: One week
      after the operation, the porcine SIS was already fused with the remaining part of
      rabbit Achilles tendon. Sixteen weeks after all the Achilles tendons looked like
      normal one. The maximum load of experimental Achilles tendon was 48 N +/- 9 N one
      week after the operation, and increased gradually. In the 16th week after the
      operation, the maximum load was 178 N +/- 6 N for the experimental Achilles
      tendon and 174 N +/- 10 N for the control tendon. The differences of maximum load
      between different weeks after operation, except that between one week and 4 weeks
      after, were statistically significant (P < 0.01). CONCLUSION: Substitution of
      porcine SIS for injured Achilles tendon is effective, thus proving the
      feasibility of in vivo tissue engineering technology.

PMID- 12425813
TI  - [Impact of high-normal blood pressure on risk of cardiocerebrovascular disease in
      11 provinces in China].
AB  - OBJECTIVE: To explore the impact of high-normal blood pressure on the risk of
      cardiovascular disease in different sexes in China. METHODS: A cohort baseline
      study was carried out among 27 739 subjects (age 35 approximately 64 years) to
      survey the general demographic data, smoking status, blood pressure, blood
      lipids, height, weight, was circumference, and hip circumference. By the end of
      each year, a follow-up was made until 31 December 1999 to all 27 739 persons to
      record the events of cardiocerebrovascular diseases and deaths. No intervention
      was made to the cohort population during follow-up. Cox regression model was used
      to carry out multifactoral analysis of the relationship between normal high blood
      pressure and risk of cardiocerebrovascular diseases. RESULTS: (1) The high-normal
      blood pressure rate was 13.4% (14.8% for males and 11.8% for females) in this
      cohort. (2) Those with high normal blood pressure had more risk factors of
      cardiocerebrovascular diseases than those with ideal blood pressure. (3) During
      follow-up, the yearly standardized incidence rates of coronary heart diseases,
      cerebral apoplexy, and cardiocerebrovascular diseases were significantly higher
      among those with high normal blood pressure than among those with ideal blood
      pressure. (P < 0.000 1). (4) The relative risk of cardiocerebrovascular disease
      was 2.8765 among those with high normal blood pressure (95% CI 2.050 6 - 4.035 1
      P < 0.000 1), 3.234 6 among males (95% CI 2.113 1 - 4.951 2, P < 0.000 1) and
      2.335 0 among females (95% CI 1.318 3 - 4.135 9, P < 0.000 1). CONCLUSION: The
      relative risk of cardiovascular disease was significant higher among those with
      high normal blood pressure than those with ideal blood pressure in 11 provinces
      in China. The necessity of lowering high-normal blood pressure to reduce CVD need
      to be evaluated.

PMID- 12425814
TI  - [Hypotensive effect of encapsulated genetically engineered fibroblasts expressing
      mutant atrial natriuretic peptide in hypertensive rats].
AB  - OBJECTIVE: To study the inhibitive effect of subcutaneous implantation of capsule
      filled with fibroblasts engineered to secrete the mutant human atrial natriuretic
      peptide (mhANP) on blood pressure in young spontaneously hypertensive rats (SHR)
      and to explore the feasibility of gene therapy for the treatment of hypertension.
      METHODS: A recombinant retroviral vector pLHY24 bearing mhANP cDNA was
      constructed. Primary fibroblasts derived from the skin of new born SHR were
      cultured and transfected with the vector pLHY24 to establish a genetically
      modified fibroblast line or transfected with the blank vector pLNCX. Then the two
      kinds of cell culture were put into specially made capsules with microholes. The
      capsules filled with the genetically modified allogenic fibroblasts and those
      with blank vector were implanted into the dorsal subcutaneous tissues of two
      groups of 10 young SHR respectively. The plasma ANP, blood pressure, urine
      volume, potassium and sodium concentrations in urine, and body weight were
      determined every week for 7 weeks. RESULTS: After delivery of retroviral vector
      bearing mhANP gene into the packaging cell PA317 and the primary fibroblasts,
      immunoreactive mhANP were detected in the cell culture medium at the
      concentration of (5.84 +/- 0.07) and (13.37 +/- 2.36) ng.10(-6) cells.24 h(-1)
      respectively. One week after implantation of the genetically modified allogenic
      fibroblasts the plasma level of mhANP was 131 pg/ml +/- 8 pg/ml, significantly
      higher than that in control group (104 pg/ml +/- 7 pg/ml, t = 8.62, P < 0.001).
      Although the blood pressure increased along with aging after the gene transfer,
      an obvious delay of blood pressure increase was seen significantly lower in test
      group [from (129 +/- 9) to (169 +/- 9) mm Hg] than that in the control group
      [from (145 +/- 10) to (181 +/- 9) mm Hg, P < 0.05 or 0.01]. A maximal blood
      pressure reduction of 28 mm Hg in young SHR was observed 7 days after
      transplantation as compared with controls. In addition, there was an obvious
      increase in urine volume of test group 2 weeks after transplantation and the
      effect lasted for more than 2 weeks. However, there were no statistical
      differences in body weight and the concentrations of K(+) and Na(+) in urine.
      CONCLUSION: Subcutaneous implantation of the encapsulated genetically modified
      fibroblasts engineered to secrete mutant ANP causes a lowering effect of blood
      pressure in young SHR.

PMID- 12425815
TI  - [Analysis of chromosomal aneuploidy in bronchoscopically gained cells].
AB  - OBJECTIVE: To study the feasibility of interphase fluorescence in situ
      hybridization (FISH) in detection of chromosomal aneuploidy in bronchoscopically
      gained cells from lung cancer patients and early diagnosis of lung cancer.
      METHOD: Cells gained from endobronchial brushings of 14 patients with lung cancer
      were examined by FISH with chromosomes 7, 8, 9 and 12 specific centromere probes.
      RESULT: Aneuploidy, mainly featured in gains of chromosomes 7, 8 and 12 and loss
      of chromosome 9 were observed in all of the 7 cases with cells from endobronchial
      brushings diagnosed as or suspicious of cancer cells by cytology. Aneuploidies of
      chromosomes 7, 8, and 9 were found in 3 of other 7 cases that appeared to be
      normal by cytologic criteria. CONCLUSION: Interphase FISH is feasible in
      detecting aneuploidy associated with malignancy in bronchoscopically gained cells
      that do not meet the criteria of malignancy by conventional cytologic study. This
      method may be applied to early diagnosis of lung cancer.

PMID- 12425816
TI  - [Construction and expression of red fluorescent protein reporter gene vector
      containing human eNOS promoter].
AB  - OBJECTIVE: To construct the red fluorescent protein reporter gene vector
      containing human eNOS promoter sequence to study the mechanism of regulating the
      expression of eNOS gene by vessel wall shear stress. METHODS: The genomic DNA of
      endothelial cells from fetal umbilical vein was drawn. The gene sequence of eNOS
      promoter gene therein was cloned by PCR technique and constructed into the red
      fluorescent protein vector, pDsRed-1. The recombinant vector, pDseNOSRed was then
      transfected into 293 cells, human fetal renal epithelial cells. Blank vector,
      pDsRed-1, was transfected into 293 cells as controls. The expression and
      distribution of the reporter gene were observed by fluorescent microscopy.
      RESULTS: PCR and double restriction enzyme digestion showed that the recombinant
      vector, pDseNOSRed, was constructed correctly. This vector was highly expressed
      in the 293 cells. Expression of red fluorescence, evenly distributed in whole
      cells, occurred since 12 hours after transfection, reached the peak concentration
      3648 h after transfection, and dissappeared almost completely 120 h after. No red
      fluorescence was observed in the control cells. CONCLUSION: A red fluorescent
      protein reporter gene vector containing human eNOS promoter sequence and
      expressed highly in mammalian cells has been constructed successfully, thus
      providing an important and convenient tool to study the mechanism mechanism of
      regulating the expression of eNOS gene by vessel wall shear stress.

PMID- 12425817
TI  - [Association of antipsychotic agent-induced weight gain with a polymorphism of
      the promotor region of the 5-HT2C receptor gene].
AB  - OBJECTIVE: To determine whether 5-hydroxytryptamine 2C (5-HT2C) receptor gene
      759C/T polymorphism influences the weight gain following antipsychotic agents
      (APS) treatment in patient with schizophrenia. METHODS: DNA was extracted from
      the peripheral blood of 117 Chinese first-episode patients of Han nationality
      with schizophrenia diagnosed according to CCMD-II-R criteria. PCR-RELP technique
      was used to analyse the frequencies of 5-HTR2C receptor gene 759C/T hemizygote
      (male) and genotype (female). Monotherapy with APS (chlorpromazine or
      rispperidone) was given for 10 weeks. The body weight was taken and body mass
      index (BMI) was calculated on admission and every week subsequently for each
      patient. The correlation of hemizygote or genotype and the BMI was analyzed.
      RESULTS: Ten weeks after treatment, there was an average increase in body weight
      of (3.2 +/- 3.5) kg or (5.7 +/- 6.2)% of the baseline weight with a range of -7
      kg approximately 12 kg or -7.8% approximately 32%. The frequency of mutant
      hemizygote was 58% among the 58 male subjects; the frequency of mutant homozygote
      was 0%, and the frequency of mutant heterozygote was 27.0% among the 59 female
      subjects. The body weight gain > 7% occurred in 53% of wild type hemizygote males
      and 47% of wild type homozygote females; and only 18% of mutant hemizygote males
      and 13% of mutant heterozygote females. The proportions of 759T hemizygote males
      or heterozygote females in those with body weight gain > 7% and those with body
      weight < 7% were significantly different (chi(2) = 22.35, v1, P = 0.000 1; chi(2)
      = 12.36, v1, P = 0.000 1). Patients without mutant allele were five to six times
      more likely to develop substantial weight gain (OR = 5.11, 6.68). CONCLUSION: The
      5-HT2C-receptor gene -759C/T polymorphism is associated with APS-induced weight
      gain. 759C-->T may be a protective factor for the development of weight gain in
      Chinese schizophrenic patients of Han nationality.

PMID- 12425818
TI  - [Recombinant heat shock protein 70 adenovirus transfection protects intestinal
      epithelial cells (IEC-6 cells) against hypoxia-reoxygenation in vitro].
AB  - OBJECTIVE: To study the feasibility of protection of intestinal epithelial cells
      (IEC-6 Cells) against hypoxia-reoxygenation through recombinant adenovirus
      mediated heat shock protein 70 (HSP70) gene transfection. METHODS: Recombinant
      adenovirus (AdCMVHSP70) was constructed with full length human HSP70 gene.
      Cultured intestinal epithelial cells (IEC-6 cells) were divided into four groups:
      three groups transfected with AdCMVHSP70 for 24 h, 48 h and 72 h respectively,
      and one group transfected with vacant recombinant adenovirus (control group). The
      over expression of transfected human HSP70 gene was detected by RT-PCR 48 h after
      transfection. After the cells in the four groups suffered 1 hour of hypoxia
      followed by 1 hour of reoxygenation, the effects of transfected human HSP70 gene
      overexpression during different transfection times (24 h, 48 h, and 72 h) were
      studied. The cell viability was analyzed by MTT method, and the apoptosis and
      dead cell ratio were evaluated with Annexin-V-FLOUS staining kit in vitro.
      RESULTS: The expression of human HSP70 gene was positive in the AdCMVHSP70
      transfected IEC-6 cells and negative in the control group. After hypoxia
      reoxygenation, the cell viability rates of HSP70 gene transfected groups were
      87.24 +/- 0.60, 90.27 +/- 0.64, and 78.52 +/- 0.61 respectively, all
      significantly higher than that of control group (all P < 0.01), while the
      apoptosis rates of HSP70 gene transfected 24 h and 48 h groups were 3.93 +/- 0.28
      and 3.95 +/- 0.54 respectively, significantly lower than that of control group
      (both P < 0.05), however, the apoptosis rate of HSP70 gene transfected 72h group
      was 11.49 +/- 1.45, not significantly different from that of control group (11.39
      +/- 1.62, P > 0.05). The dead cell ratios of HSP70 gene transfected groups were
      8.21 +/- 0.26, 5.83 +/- 0.32, and 5.83 +/- 0.32 respectively, significantly lower
      than that of control group (15.51 +/- 0.46, all P < 0.01). The peak of protection
      was at 48 h after the transfection. CONCLUSION: The over expression of human
      HSP70 mediated by recombinant adenovirus protects intestinal epithelial cells
      (IEC-6 cells) against hypoxia-reoxygenation in vitro. The probable mechanism may
      be concerned with the inhibition of cell apoptosis after hypoxia-reoxygenation.

PMID- 12425819
TI  - [Tissue engineered tendon with skin fibroblasts as seed cells, a preliminary
      study].
AB  - OBJECTIVE: To investigate the effect of tissue engineered tendon using autologous
      dermal fibroblasts in repairing tendon damage. METHODS: Skin tissues were
      resected from abdomen of 5 pigs. Fibroblasts were isolated from the skin pieces
      and cultured in vitro. Bundles of polyglycolic acid (PGA) were arranged in
      parallel and mixed with the suspension of fibroblasts to form a cell-scaffolded
      construct, which was further cultured in vitro for 1 week. The tendon of musculus
      flexor digitorum superficialis of pig's right leg was cut with a defect 3 cm long
      and then bridged with the cultured construct. Six weeks later, specimens of the
      regenerated tendon of right musculus flexor digitorum superficialis and specimens
      of corresponding left leg were taken for gross examination, microscopy and
      biomechanical analysis. RESULTS: After implantation of the fibroblast-biomaterial
      complex the wounds healed up and the pigs moved well. The histology of the
      implanted tendon was similar to that of natural tendon. The breaking strength and
      maximum tensile force were 173.0 +/- 18.2 N and 18.9 +/- 1.9 MPa, reaching 57.4%
      and 51.9% of those of normal tendon respectively. CONCLUSION: Skin fibroblasts
      can be used as seed cells to regenerate tendon with normal structure and
      function.

PMID- 12425820
TI  - [Induction of human cervical carcinoma by human papilloma virus and tumor
      promoters].
AB  - OBJECTIVE: To study the effect of human papillomavirus (HPV) and tumour promoters
      spermidine (SPD and N-butyrate) on malignant transformation of human embryo
      cervical cells. METHODS: Plasmid HPV16E6/E7 was constructed and transfected into
      human embryo cervical cells obtained by induced labor from pregnant women with
      severe heart diseases. Twenty-one scid mice were divided into 4 groups:
      experimental group (n = 7, incubated subcutaneously with the transfected cervical
      cells at the right shoulder, and then injected subcutaneously with spermidine and
      N-butyrate at the left shoulder three days after the incubation once a week for
      12 times), virus-infected group B (n = 5, incubated subcutaneously with
      transfected cervical cell only), tumor promoter group (n = 5, incubated with
      untransfected cervical cells and SPD and N-butyrate), and control group (n = 4,
      incubated subcutaneously with only untransfected cervical cells). Twelve weeks
      after incubation, the mice were killed. Pathological reexamination was conducted
      to detect the existence of tumor. PCR was used to detect HPV16E6/E7 gene in tumor
      tissues. RESULT: Tumor, diagnosed as fibrosarcoma by pathology, was found in 5
      out of the 7 mice in the experimental group. The tumor-forming rate was 0 in
      other groups. Expression of HPV16E6/E7 gene was detected in tumour tissues by
      PCR. CONCLUSION: HPV16E6/E7 gene containing retrovirus infection, synergized by
      spermidine and N-butyrate acid, causes malignant transformation in human cervical
      cells.

PMID- 12425821
TI  - [Serum procalcitonin and interleukin-6 help differentiate between severe sepsis
      and systemic inflammatory response syndrome of non-infectious origin].
AB  - OBJECTIVE: To evaluate the efficacy of serun procalcitonin (PCT) and interleukin
      (IL)-6 in differentiating between severe sepsis and systemic inflammatory
      response (SIRS) of non-infectious origin. METHOD: The serum PCT, IL-6, C-reactive
      protein (CRP), white blod cell count, percentage of neutrophils, and absolute
      neutrophil count were determined, and maximal body temperature was recorded among
      21 patients was 3.6 (1.8, 27.5) micro g/L, significantly higher than that in SIRS
      patients (1.3 micro g/L +/- 1.6 micro g/L, P < 0.05). The IL-6 in sepsis patients
      was 810 ng/L +/- 516 ng/L, significantly higher than that in SIRS patients (235
      ng/L +/- 177 ng/L, P < 0.01). However, the differences of CRP, WBC count,
      percentage of neutrophil, and absolute neutrophil count between the severe sepsis
      patients and SIRS patients were not statistically significant. PCT and IL-6
      showed sensitivity equal or over 80% and specificity equal to or over 70%. The
      infection score based on PCT and IL-6 showed the best discriminative power to
      differentiate between severe sepsis and SIRS with the artea under the receiver
      operating characteristic curve of 0.923. CONCLUSION: In comparison with the
      conventional inflammatory markers, PCT and IL-6 are more reliable indicators to
      differentiate between sepsis and SIRS.

PMID- 12425822
TI  - [Correlation between vascular endothelial growth factor and peritumoural edema in
      meningiomas].
AB  - OBJECTIVE: To study the relationship between the expression of vascular
      endothelial growth factor (VEGF) and peritumoural brain edema (PTBE) in
      meningiomas. METHODS: The expression of VEGF was investigated in 40 specimens of
      intracranial supratentorial meningioma resected during operation, using
      immunohistochemical techniques. The expression of factor VIII-related antigen
      (VIII-R Ag) was examined by immunohistochemistry so as to calculate the
      microvascular density (MVD). The formulae V = 4/3pi x abc and EI = V(edema) +
      V(tumor)/V(tumor) were used to determine the edema index (EI). The results of
      staining were compared with the data by MRI and neuroradiology in double blind
      fashion. RESULTS: Compared to VEGF-negative meningiomas, tumours with striking
      VEGF staining revealed a significantly higher mean EI (4.6 vs. 1.5, P = 0.003),
      higher edema incidence (88.2% vs. 41.7%, P = 0.023 68), and higher MVD (53.0 vs.
      26.5, P = 0.018). Equally, meningiomas with pial supply revealed a significantly
      higher mean EI than meningiomas with only dural supply (4.4 vs. 1.8, P = 0.044).
      Meningiomas severely adhered to brain revealed a higher edema incidence than
      those with milder adhesion (88.9% vs. 45.5%, P = 0.004 17). The tumour volume did
      not correlate with EI (P > 0.05). CONCLUSION: The VEGF expression and tumour
      angiogenesis are correlated with peritumoural brain edema. The rate of brain
      edema is higher in the tumors with pial supply and severe adhesion with brain.
      There is no a significant correlation between the tumour volume and edema degree.

PMID- 12425823
TI  - [Surgical treatment of spinal myeloma, report of 19 cases].
AB  - OBJECTIVES: To discuss the indications for surgical procedures of spinal myeloma.
      METHODS: A retrospective analysis was made of the data of operation results of
      Nineteen patients with spinal myeloma, 13 males and 6 females, with the mean age
      of 45.1 (range 31 approximately 52). Pain was present in all patients. Nine
      patients had neurological deficit. According to Frankel classification 5 cases
      were Frankel B, 3 cases were Frenkel C, and 1 case was Frenkel D. Fourteen cases
      were diagnosed before operation, and 5 cases were diagnosed by pathology after
      operation. Surgical procedures performed included anterior approach in 11 cases,
      posterior approach in 7 cases and combined approach in 1 case. RESULTS: Decrease
      of pain was observed in all cases after surgery. Neurological improvement was
      observed in 8 out of the 9 cases. Complication (alteration of intestinal flora)
      occurred in one case. Follow-up lasted more than 1 year except in one case with a
      follow-up of only 6 months. Four cases were lost of follow-up. One case was still
      alive during the follow-up 8 years after operation. Other cases survived for 26.5
      months on average (range 16 approximately 48 months). CONCLUSION: Surgery can
      ensure neurological improvement and spinal stability for patients with spinal
      myeloma, but should be associated with adjunctive medical treatment.

PMID- 12425824
TI  - [Transpedicular instrumentation and interbody fusion for spinal tuberculosis].
AB  - OBJECTIVE: To evaluate the surgical outcomes of spinal tuberculosis treated with
      transpedicular instrumentation and interbody auto-grafting. METHODS: Thirty-four
      patients of thoracolumbar tuberculosis were treated with transpedicular
      instrumentation, radical focus resection and interbody auto-grafting, combined
      with 6- or 9-month antituberculous medication from October 1996 to November 1998.
      All patients were followed-up prospectively for 3 to 5 years postoperatively.
      RESULTS: The back pain and tuberculous symptoms were relieved about one week
      postoperatively. The erythrocyte sedimentation rate came back to normal level
      from 4 to 6 weeks postoperatively. The solid interbody arthodesis was achieved
      from 4 to 6 months postoperatively. All patients were cured of tuberculous
      lesions in spinal column or in other region, and there were no tuberculous
      recurrence. In 12 patients, average preoperative kyphosis angle was 24 degrees
      (range 10 degrees approximately 32 degrees ), and that was 9 degrees (range 5
      degrees approximately 13 degrees ) immediately after surgery. The average
      correction of kyphotic deformity was 15 degrees and was maintained unchanged in
      follow-up period postoperatively. Nine patients who had type-C or type-D
      neurological lesions, according to Frankel gradation, had complete recovery one
      year postoperatively. CONCLUSION: In spinal tuberculous operation, transpedicular
      instrumentation and interbody fusion are essential in providing rigid
      stabilization of spinal column, correcting or preventing kyphotic deformity,
      accelerating focus healing up and shortening chemotherapy period. Transpedicular
      instrumentation is necessary in short segments fixation and preserving functional
      unit of spine.

PMID- 12425825
TI  - [Diagnosis and therapy of carotid body tumors].
AB  - OBJECTIVE: To summarize the experience in diagnosis and therapy of carotid body
      tumor. METHODS: A retrospective review was performed of 46 patients with carotid
      body tumors diagnosed and treated between February 1968 and March 2001. RESULTS:
      Fine-needle aspiration was performed in 2 cases with the the aspirate consisted
      of blood cells to undergo cytological examination. Blood pool imaging was
      performed in 12 cases, among which 10 cases (83%) were considered as carotid body
      tumor. Digital subtraction angiography was performed in 5 cases, all of which
      were correctly diagnosed. Fifteen cases underwent ultrasound examination, 14 of
      which (93%) were considered as carotid body tumor. Seven cases underwent computed
      tomography, among which 5 cases (71%) were considered as carotid body tumor. Four
      cases underwent magnetic resonance imaging, all of which were correctly diagnosed
      and 2 of which underwent magnetic resonance angiography. All 46 cases accepted
      surgical operation, five of them accepted radiotherapy too. The tumors didn't
      recur during the follow-up period. CONCLUSION: Ultrasonography is sufficient for
      the diagnosis of carotid body tumors. MRI/MRA help to draw out reasonable
      treatment fashion. Surgery is the first choice among treatments for carotid body
      tumors. Radiotherapy helps control effectively the aggression of tumors.
      Intraoperative meticulous dissection may decrease the incidence of postoperative
      complications.

PMID- 12425826
TI  - [Origin of N(18) median nerve somatosensory evoked potentials studied in patients
      with hemispherectomy].
AB  - OBJECTIVE: To probe into the neural generators of the median nerve (MN)
      somatosensory evoked potentials (SEP) in patients after hemispherectomy,
      especially with regard to N(18). METHODS: SEP induced by median nerve stimulation
      with both cephalic and noncephalic references were recorded in 20 patients with
      hemispherectomy entailing massive retrograde degeneration of thalamocortical,
      midbrain and pontine neurons documented by MRI evidence. Twelve dga and Aex
      matclod healty persons were used as controls. RESULTS: No additional focal
      response (cortical N(20)) was detected over the hemisphere-ectomized lateral
      scalp in all patients. The positive P(14) and negative N(18) scalp far-fields
      were preserved and the latencies of with the 12.5 +/- 0.8 ms and 17.6 +/- 1.6 ms
      respectively. The preserved N(18) response reflected the neural activity below
      the pons. CONCLUSION: The N(18) neural generators are located in the medulla.

PMID- 12425827
TI  - [Effect of dipfluzine on acute ischemic brain edema in gerbils].
AB  - OBJECTIVE: To examine the effect of dipfluzine (Dip), a novel calcium channel
      blocker first developed in China, on acute ischemic brain edema. METHODS: One
      hundred and thirty gerbils, 65 males and 65 females, weighing 68 +/- 10 g, were
      used. Eighty gerbils randomly divided into four groups of 20 animals: sham
      operation group, Dip 25 mg/kg group, and Dip 50 mg/kg group. All of the 120
      gerbils were injected with solution or Dip at different concentrations
      intraperitoneally. The skin of neck was incised one hour after injection. Except
      in the sham operation group, bilateral carotid artery ligation (BCAL) was
      performed in the other 70 gerbils to cause brain edema. Another 10 gerbils were
      used as normal controls without undergoing injection and operation. One hour
      after the operation, all of the animals were killed and the whole brain tissue
      was taken to detect the water and Na(+) and K(+) contents. The brain tissues of
      other 50 gerbils were used to produce homogenate to determine the Na(+), K(+)
      ATPase activity. RESULTS: The water and Na(+) contents in hippocampus of model
      control group were 77.4% and 279 +/- 22 micro mol/g dry tissue respectively,
      significantly higher than those in sham operation group (74.8% and 220 +/- 22
      micro mol/g dry tissue). The K(+) content in the hippocampus of the model control
      group was 381 +/- 28 micro mol/g dry tissue respectively, significantly lower
      than that in the sham operation group (430 +/- 30 micro mol/g dry tissue). The
      Na(+), K(+)-ATPase activity in the plasmalemma of brain cells in model control
      group was 179 +/- 62 micro mol pi/mg protein/min, significantly lower than that
      in sham operation group (1006 +/- 130 micro mol pi/mg protein/min, P < 0.01). The
      water contents of hippocampus in Dip 25 mg/kg group and Dip 50 mg/kg group were
      75.4 +/- 0.5% and 74.8 +/- 0.9% respectively, significantly lower than that in
      model control group (all P < 0.01). The Na(+) contents in hippocampus of Dip 25
      mg/kg group and Dip 50 mg/kg group were 235 +/- 39 micro mol/g dry tissue and 223
      +/- 36 micro mol/g dry tissue respectively, significantly lower than that in
      model control group (279 +/- 22 micro mol/g dry tissue, all P < 0.01). The K(+)
      content in hippocampus of Dip 25 mg/kg group and Dip 50 mg/kg group were 427 +/-
      32 micro mol/g dry tissue and 434 +/- 29 micro mol/g dry tissue respectively,
      significantly higher than that in model control group (P < 0.05 and P < 0.01).
      The Na(+), K(+)-ATPase activity in the plasmalemma of brain cells in Dip 25 mg/kg
      group and Dip 50 mg/kg group was 649 +/- 45 and 1 198 +/- 218 micro mol pi/mg
      protein/min respectively, significantly higher than that in model control group
      (r = 0.9981, P < 0.01). The correlation between brain water content and Na(+),
      K(+)-ATPase activity was significant (r = -0.999 7, P < 0.01). CONCLUSION: Dip
      attenuates dose-dependently the increased H(2)O and Na(+) contents, prevents the
      decrease in potassium level, and accelerates the restoration of lowered Na(+),
      K(+)-ATPase activity resulted from cerebral ischemia, thus preventing ischemic
      brain edema.

PMID- 12425828
TI  - [pcDNA3.1 parathyroid hormone gene therapy of hypoparathyroidism: an experimental
      study].
AB  - OBJECTIVE: To investigate the effect of pcDNA3.1 parathyroid hormone (PTH) gene
      therapy for hypoparathyroidism and the best dosage. METHODS: The parathyroid
      glands of 40 rabbits were resected so as to establish an animal model of
      hypoparathyroidism. The rabbits were randomly divided into 5 groups of 8 animals.
      Different doses of pcDNA3.1.PTH (50 micro g/kg, 150 micro g/kg, and 250 micro
      g/kg) containing human PTH gene, normal saline, and the vacant vector pcDNA3.1
      were injected into the muscle of different groups of rabbits: Before
      parathyroidectomy and 1, 2, 3, 5, 7, 10, 15, 30, and 60 days after the operation
      blood was drawn to detect the concentrations of calcium and PTH. RESULTS: The
      serum calcium and PTH began to increase one day after the injection of
      pcDNA3.1.PTH, and reached the peak concentrations at the seventh day. The levels
      lasted for two months. Seven days after the serum calcium and PTH were 2.83 +/-
      0.02 mmol/L and 11.303 +/- 0.025 pg/ml respectively in 150 micro g/kg group and
      were 2.81 +/- 0.07 mmol/L and 12.001 +/- 0.008 pg/ml respectively in 250 micro
      g/kg group. CONCLUSION: Human PTH gene therapy is effective in treating HPT with
      the most effective dose of 150 micro g/kg and 250 micro g/kg.

PMID- 12425829
TI  - [Pulmonary function in first generation children of chronic obstructive pulmonary
      disease (COPD) patients: assessment of related predicting factors].
AB  - OBJECTIVE: To study whether familial aggregation exists in pulmonary function
      impairment and COPD. METHODS: Pulmonary function, smoking habits, history of
      occupational dust exposure and clinical manifestation among 117 children of 59
      smokers with COPD and 55 children of 28 control smokers without COPD. A
      multivariate linear regression analysis was carried out to study FEV1 among the
      children. Logistic regression analysis was conducted to study the factors
      influencing the FEV1 < 70% pred. RESULTS: Height and male gender were positively
      correlated to children's FEV1 (ml); whereas age, clinical symptoms, history of
      occupational dust exposure and being children of diseased probands were
      negatively correlated to children's FEV1 (ml). With other relevant factors
      adjusted, the FEV1 (ml) was lower among those being children of COPD patients;
      the more severe the COPD conditions of the parents, the lower the FEV1 of the
      children. Cigarette consumption having clinical symptoms, and being children of
      COPD probands showed increased risk of FEV1 below 70% predicted (OR = 1.987).
      Height, age, and history of occupational dust exposure were not correlated to
      FEV1 < 70% pred among children. CONCLUSION: Being children of COPD parents is the
      independent risk factor for lower FEV1 (ml) and FEV1 below 70% pred, which
      demonstrates the presence of familial aggregation of COPD and pulmonary function
      impairment.

PMID- 12425830
TI  - [The effect and mechanism of felodipine on monocrotaline induced pulmonary
      hypertension in rats].
AB  - OBJECTIVE: To explore the effect and the mechanism of felodipine on pulmonary
      hypertension. METHODS: Adult male Wistar rats were given a single dose of
      subcutaneous monocrotaline (MCT, 60 mg/kg) to induce the mold of pulmonary
      hypertension. Felodipine (5 mg/kg) was administered intraperitoneally every day
      for 4 weeks after MCT injection. The parameters of right ventricular systolic
      pressure were monitored. The levels of endothelin-like immunoreactivity (ir-ET)
      and calcitonin gene related peptide (CGRP) in the plasma and the heart and
      pulmonary tissues were measured by radioimmunoassay and colorimetric analysis.
      Right ventricular myocardial tissue was studied under electron microscope.
      RESULTS: Continuous injection of felodipine significantly inhibited the
      progression of pulmonary artery pressure [(44.6 +/- 4.4) mm Hg versus (30.3 +/-
      2.1) mm Hg, (18.7 +/- 2.2) mm Hg]. Histological examination revealed that
      felodipine effectively prevented pulmonary arterial medial thickening. Felodipine
      significantly increased the level of CGRP in plasma [(84 +/- 19) pg/ml versus 149
      +/- 21) pg/ml], pulmonary homogenate [(22 +/- 4) pg/ml versus (29 +/- 3) pg/ml]
      and myocardial homogenate [(20.9 +/- 1.6) pg/ml versus 27.5 +/- 2.9) pg/ml].
      There was no change in the level of ir-ET in the heart and pulmonary tissues.
      Myocardial damage in the right ventricle was less severe in the felodipine
      treated group. CONCLUSIONS: Long-term use of felodipine was effective in
      preventing pulmonary hypertension induced by MCT. The underlying mechanism may be
      partly related to the increase of CGRP as well as the inhibition of Ca(2+)
      inflow. The results indicate that felodipine may be considered for clinical
      trials in the treatment of primary pulmonary hypertension.

PMID- 12425831
TI  - [Expression of adrenomedullin and its receptor in lungs of rats with hypoxia
      induced pulmonary hypertension].
AB  - OBJECTIVE: To investigate the effect and mechanism of the changes of
      adrenomedullin (ADM) and its receptor (ADMR) mRNA in the process of hypoxia
      pulmonary hypertension (HPH). METHODS: Thirty male Wistar rats were randomly
      divided into five groups: one control group and 4 hypoxia groups (3 d, 7 d, 14 d,
      21 d). Rats in the hypoxia groups were exposed to hypoxia for 3 d, 7 d, 14 d, and
      21 d respectively. The mean pulmonary arterial pressure (mPAP) and right
      ventricular hypertrophy index (RVHI) were measured, and hypoxic pulmonary
      vascular remodeling (HPSR) was observed with morphometric analysis.
      Semiquantitative in situ hybridization and reverse transcriptase-polymerase chain
      reaction (RT-PCR) were used to measure the expression of ADM and ADMR mRNAs in
      pulmonary artery walls and lung tissue. Inducible nitric oxide synthase (iNOS)
      was determined. RESULTS: (1) The level of mPAP (22.7 +/- 2.8) mm Hg, the ratio of
      vascular wall thickness to external diameter (MT%) (46 +/- 4)% and the ratio of
      vascular wall area to the total area (MT%) [(55 +/- 6)%] were significantly
      higher in the hypoxia 7 d group than those in the control group [(16.4 +/- 1.4)
      mm Hg, (35 +/- 3)% and (42 +/- 5)% respectively] (P < 0.01). These parameters
      reached a high-level stable phase on hypoxia 14 d; RVHI was significantly higher
      [(26.5 +/- 2.9)%] on hypoxia 14 d than in the control group [(22.9 +/- 2.2)%] (P
      < 0.01); (2) In situ hybridization showed that ADM and ADMR mRNAs were expressed
      dynamically in pulmonary arterial endothelial cells (PAEC) and ectoblast cells
      after hypoxia. In PAECs the expressions of ADM (6%) and ADMR (8%) were lower on
      hypoxia 3 d than in the control group (23%, 27%) (P < 0.01); but increased on
      hypoxia 7 d (33%, 52%). The expression level reached its peak on 14 d and
      remained at a high level on 21 d. In the ectoblast cells, ADM mRNA (42%) and ADMR
      mRNA (46%) were significantly higher in the hypoxia 7 d group than that in the
      control group (19% and 21%, respectively, P < 0.01), which further reached a high
      level on 14 d and 21 d; (3) RT-PCR showed that ADM mRNA (0.43 +/- 0.48) and ADMR
      mRNA (0.32 +/- 0.38) in the lung tissue were lower in the hypoxia 3 d group than
      those in the control group (0.69 +/- 0.10 and 0.48 +/- 0.05 respectively), but
      increased on 7 d (0.76 +/- 0.52) and (0.70 +/- 0.50). There was no difference in
      ADM mRNA between the hypoxia 7 d group and the control group, but the ADMR level
      in the hypoxia 7 d group was higher than the control (P < 0.01), with a maximum
      expression on 14 d and 21 d. iNOS mRNA increased significantly in the hypoxia 7 d
      group (1.21 +/- 0.44) as compared to the control group (1.05 +/- 0.17) (P <
      0.01). There was a positive correlation between ADM or ADMR and iNOS (r = 0.893,
      0.906, P < 0.01). CONCLUSION: ADM as an autocrine/paracrine factor may play an
      important protective role in the development of HPH.

PMID- 12425832
TI  - [Effects of respiratory syncytial virus infection on T-helper cytokines
      expression in Balb/c mice sensitized with ovalbumin].
AB  - OBJECTIVE: To determine the effects of RSV infection on the development of lung
      inflammation and the expressions of T-helper cell related cytokines in Balb/c
      mice pre-sensitized with ovalbumin. METHODS: Forty mice were randomly divided
      into four groups: (1) the control group: nonsensitized, noninfected; (2) the RSV
      group: nonsensitized, infected; (3) the OVA group: sensitized, noninfected; and
      (4) the OVA + RSV group: sensitized, infected (RSV 6.5 x 10(6) PFU nasal drip).
      Bronchoalveolar lavage (BAL) was performed in six mice from each group five days
      after RSV nasal inoculation. Cells in the BAL were counted and classified and the
      supernatants of the BALF were used for detection of IL-4 and IFN-gamma. Four mice
      in each group were sacrificed for lung RNA extraction, and IL-4, IL-5 and IFN
      gamma mRNA levels were determined by RT-PCR. RESULTS: (1) Total BAL cells from
      the RSV group [(14.5 +/- 5.4) x 10(6)/ml] and the OVA + RSV group [(16.8 +/- 4.9)
      x 10(6)/ml] were significantly higher than those in the control group [(7.7 +/-
      2.4) x 10(6)/ml] and the OVA group [(9.0 +/- 2.5) x 10(6)/ml] (all P < 0.05),
      with more lymphocytes in the RSV group (0.63 +/- 0.05) and the OVA + RSV group
      (0.77 +/- 0.09) than the control group (0.28 +/- 0.05) (P < 0.05) and the OVA
      group (0.36 +/- 0.03) (P < 0.05). More eosinophils were found in the OVA + RSV
      group (0.0690 +/- 0.0100) than in the RSV group (0.0090 +/- 0.0050), the OVA
      group (0.0100 +/- 0.0040) and the control (0.0030 +/- 0.0010) (all P < 0.05). (2)
      Pulmonary inflammation in the OVA + RSV group and the RSV group was more severe
      than that in the OVA group and the control group. More lymphocyte infiltration
      was found in the OVA + RSV and the RSV groups. More eosinophils were found in the
      OVA + RSV group, but not in the other groups. (3) Expression of IL-4, IL-5, and
      IFN-gamma mRNA: IFN-gamma mRNA expression (1.05 +/- 0.12) was higher in the RSV
      group, than in the control (0.00 +/- 0.00). There were only minimal expression of
      IL-5 mRNA and no expression of IL-4 mRNA, indicating a Th1-like cytokine
      response. Expressions of IL-4 mRNA and IL-5 mRNA were significantly higher in the
      OVA + RSV group than in the other groups, but the IFN-gamma mRNA expression was
      less than that in the RSV group, indicating a Th2-like cytokine response. (4) IFN
      gamma activation in BALF from the RSV group [(33.8 +/- 1.1) pg/ml] was
      significantly higher than that in the other groups (P < 0.05), while IL-4 showed
      no significant change as compared to the control group. The level of IL-4 in the
      OVA + RSV group [(24.0 +/- 1.5) pg/ml] was significantly higher than that in all
      the other groups (P < 0.05). CONCLUSION: RSV infection in OVA-sensitized Balb/c
      mice caused a different immune response from that caused by RSV infection in
      nonsensitized mice. RSV infection alone resulted in a Th1-like cytokine response,
      while infection after OVA sensitization resulted in a Th2-like response.

PMID- 12425833
TI  - [Clinical characteristics and diagnosis of Pneumocystis carinii pneumonia (PCP)
      in patients with the acquired immunodeficiency syndrome (AIDS)].
AB  - OBJECTIVE: To explore the clinical characteristics and the diagnostic methods for
      PCP in patients with AIDS. METHODS: Twelve cases of AIDS associated PCP confirmed
      by sputum polymerase chain reaction (PCR) were analyzed. RESULTS: Tuberculosis
      was found in 4 cases and pneumonia in 1 case of PCP. Sputum PCR was positive in
      all the 12 cases, of them blood PCR was positive in 9, Gomori methenamine silver
      stain (GMS) positive in 5 and Giemsa stain positive in 6 cases. The CD(4)(+)
      lymphocyte count was (5 approximately 155) x 10(6)/L, with a mean of (51 +/- 48)
      x 10(6)/L; the number of CD(4)(+) cells less than 100 x 10(6)/L in 10 cases (83%)
      with 9 cases (75%) less than 50 x 10(6)/L. The CD(4)(+)/CD(8)(+) ratio was 0.01
      approximately 0.29. CONCLUSIONS: PCP was common in patients with advanced AIDS
      and often co-infected with other opportunistic infections such as tuberculosis. A
      diagnosis of PCP should be considered if sputum PCR is positive and typical
      clinical manifestations are present in patients with AIDS.

PMID- 12425834
TI  - [Clinical analysis of 50 cases of pulmonary complications associated with
      Tsutsugamushi disease].
AB  - OBJECTIVE: To study the clinical features of pulmonary complications associated
      with tsutsugamushi disease. METHODS: Two hundred and thirty two patients with
      tsutsugamushi disease were retrospectively analyzed by chest X-ray,
      ultrasonography and lung function test. The differential diagnosis of
      tsutsugamushi disease associated lung complications from mycoplasma pneumonia,
      streptococcal pneumonia and tuberculosis was discussed. RESULTS: Pulmonary
      complications were present in 21.6% (50/232) of the patients with tsutsugamushi
      disease. Of them 42% were initially misdiagnosed as other pulmonary diseases. The
      characteristic radiographic manifestation was exudative lesions. The lesions were
      bilateral in 36 cases (72%), and unilateral in 14 cases (28%). Pleural effusion
      was present in 16 cases. Chloromycetin was effective in all the cases.
      CONCLUSIONS: Pulmonary complications were common in tsutsugamushi disease. The
      prognosis was good if diagnosed and treated properly at an early stage.

PMID- 12425835
TI  - [Results of bronchoplasty by fiberoptic bronchoscopic balloon dilatation in the
      management of proximal benign tracheobronchial stenosis].
AB  - OBJECTIVE: To assess the effect and safety of balloon dilatation through
      fiberoptic bronchoscopy in the management of benign tracheobronchial stenosis.
      METHODS: Thirty-seven patients with proximal benign tracheobronchial stenosis
      were treated by balloon dilatation through flexible fiberoptic bronchoscopy. A
      fiberoptic bronchoscope was inserted, a balloon catheter was sent to the stenotic
      segment from the working channel and positioned in the stenotic bronchus. Under
      direct visualization, the balloon was inflated for 1 min to 3 min. Repeat
      inflation-deflation cycles were done if airway narrowing remained after the
      initial operation. Before the procedure and immediately after the last operation,
      airway diameters, dyspnea index and complications were evaluated in all of the
      patients and FEV(1) was tested in 26 of the 37 patients. RESULTS: One to 6
      operations (2.4 +/- 1.1, approximately x +/- s) were required to achieve
      satisfactory dilatation. After high-pressure balloon dilatation, the average
      airway diameter increased from (2.6 +/- 1.2) mm to (6.9 +/- 1.8) mm (P < 0.01).
      Dyspnea index decreased from 2.0 +/- 0.8 to 0.7 +/- 0.6 (P < 0.01). FEV(1) was
      increased from (1.3 +/- 0.6) L to (1.8 +/- 1.0) L (P < 0.01). No severe
      complications were found in these patients CONCLUSION: Bronchoplasty by high
      pressure balloon dilatation through flexible fiberoptic bronchoscopy is a simple
      but effective and safe method to treat proximal benign tracheobronchial stenosis.

PMID- 12425836
TI  - [Primary pulmonary lymphoma: analysis of cases and review of the literature].
AB  - OBJECTIVE: To study the clinical characteristics, diagnosis and treatment of
      primary pulmonary lymphoma. METHODS: Six cases of primary pulmonary lymphoma
      diagnosed from 1989 to 2000 were retrospectively analyzed, and the literature was
      reviewed with regard to its clinical manifestations, X-ray features,
      bronchoscopic findings, diagnosis and treatment. RESULTS: Primary pulmonary
      lymphoma was a rare form of lymphoma. Its diagnosis was difficult because of the
      lack of specific characteristics. The most common symptoms were cough (4/6) and
      fever (2/6). X-ray features included solitary or multiple nodules and
      consolidation. Hilar or mediastinal lymphadenopathy might be absent in the early
      stage. Bronchoscopic examination revealed bronchial constriction, chronic mucosal
      inflammation or nearly normal bronchi. Definite diagnosis was made by pathologic
      and immunohistochemical examinations of the lung tissue obtained through surgical
      operation, pleuroscopy, or percutaneous needle lung biopsy. Treatment modalities
      included surgical resection, radiotherapy and chemotherapy. The prognosis was
      associated with the malignancy of lymphoma. CONCLUSIONS: The clinical
      manifestations of primary pulmonary lymphoma are nonspecific. Misdiagnosis is
      common. Appropriate invasive biopsy procedures are necessary for early diagnosis.

PMID- 12425837
TI  - [Effects of vaccae on airway inflammation and Th1/Th2 cytokines in sensitized
      mice].
AB  - OBJECTIVE: To study the inhibitory effect of Mycobacterium vaccae (M. vaccae) on
      the accumulation of airway inflammatory cells and its regulatory effect on IFN
      gamma/IL-4 balance in bronchoalveolar lavage fluids (BALF) from ovalbumin (OVA)
      challenged and sensitized mice, therefore to provide experimental evidence for
      the application of M. vaccae in the treatment of asthma. METHODS: Sensitized mice
      were given a single dose of M. vaccae 3 days before inhaled OVA-challenge by one
      of the three routes: intramuscularly (i.m.), by intratracheal (i.t) instillation
      or by cutaneous scarification (c.s). Accumulation of inflammatory cells, IFN
      gamma and IL-4 levels in BALF were determined. RESULTS: The total numbers of the
      inflammatory cells in BALF from the M. vaccae 2.25 micro g (per mouse) c.s group
      (6 +/- 6) x 10(8)/L, the 2.25 microgram i.t group (7 +/- 6) x 10(8)/L and the
      22.5 micro g i.m group (8 +/- 5) x 10(8)/L, were significantly lower than that of
      the model control (15 +/- 8) x 10(8)/L (P < 0.05). Eosinophils in the 2.25
      microgram c.s group 0.7 +/- 0.5, the 2.25 microgram i.t group 1.6 +/- 1.9, the
      7.5 micro g i.m group 2.6 +/- 1.3 and the 22.5 microgram i.m group 1.40 +/- 1.20,
      were significantly lower than those in the model group 4.90 +/- 4.60 (P < 0.05
      and P < 0.01). IFN-gamma levels in the 2.25 microgram c.s group (289 +/- 57)
      pg/ml, the 2.25 micro g i.t group (335 +/- 57) pg/ml and the 22.5 micro g i.m
      group (313 +/- 49) pg/ml, were significantly higher than that in the model group
      (216 +/- 42) pg/ml (P < 0.05 and P < 0.01). IL-4 levels in the 2.25 microgram c.s
      group (63 +/- 19) pg/ml, the 2.25 microgram i.t group (8 +/- 5) pg/ml and the
      22.5 micro g i.m group (13 +/- 6) pg/ml, were significantly lower than that in
      the model group (93 +/- 25) pg/ml (P < 0.05 and P < 0.01). The inhibitory effect
      on eosinophil accumulation by i.t or c.s M. vaccae was 10 times stronger than
      that by i.m M. vaccae. i.t M. vaccae was the most effective in regulating the IFN
      gamma/IL-4 ratio. CONCLUSION: M. vaccae inhibited airway inflammation via
      regulating Th1/Th2 balance, suggesting that it may be beneficial in the treatment
      of asthma.

PMID- 12425838
TI  - [Nuclear factor-kappa B and intercellular adhesion molecule-1 expression in
      airway epithelial cells from smoking rats].
AB  - OBJECTIVE: To investigate the changes and of nuclear factor-kappa B (NF-kappaB)
      and intercellular adhesion molecule (ICAM)-1 expression in airway epithelial
      cells from smoking rats. METHODS: Wistar rats (n = 39) were randomly divided into
      a nonsmoking control group and 2 smoking groups-smoking for 1 month and 3 months,
      with 13 rats in each group. Immunohistochemistry and in situ hybridization
      staining were used to semiquantitatively analyse the changes of NF-kappaB and
      ICAM-1 expression in airway epithelial cells. RESULTS: (1) The percentages of
      positive cells for NF-kappaB nuclear staining in bronchiolar epithelial cells in
      1 month smoking group (63 +/- 4)% and 3 month smoking group [(51 +/- 5)%] were
      significantly higher than that in the control group [(27 +/- 5)%] (P < 0.01
      respectively). (2) ICAM-1 mRNA expression in bronchial and bronchiolar epithelial
      cells in the 1 month smoking group (0.645 +/- 0.038, 0.747 +/- 0.041) and the 3
      month smoking group (0.688 +/- 0.062, 0.809 +/- 0.023) was significantly higher
      than those in the control group (0.526 +/- 0.023, 0.635 +/- 0.044), (P < 0.01
      respectively), and the expression of ICAM-1 mRNA in the 3 month smoking group was
      higher than that in the 1 month smoking group (P < 0.05 and P < 0.01
      respectively). (3) ICAM-1 protein expression in the main bronchial and
      bronchiolarepithelial cells in the 1 month smoking group (0.73 +/- 0.04, 0.94 +/-
      0.05) and the 3 month smoking group (0.77 +/- 0.04, 0.99 +/- 0.03) was
      significantly higher than those in the control group (0.57 +/- 0.04, 0.83 +/-
      0.04) (P < 0.01 respectively), and the expression of ICAM-1 protein in the 3
      month smoking group was higher than those in the 1 month smoking group (P < 0.05
      respectively). (4) ICAM-1 mRNA and protein expression in bronchioles were
      significantly higher than those in the bronchi (P < 0.01 respectively) in all
      groups. (5) The percentage of cells staining positive for nuclear NF-kappaB
      correlated with ICAM-1 protein expression in bronchioles from the 1 month smoking
      group (r = 0.462, P < 0.05). CONCLUSION: NF-kappaB and ICAM-1 may play an
      important role in smoking-induced airway inflammation.

PMID- 12425840
TI  - Study on the use of temporomandibular joint dysfunction index in
      temporomandibular disorders.
AB  - OBJECTIVE: To study the methodological techniques in measuring the severity of
      temporomandibulr disorders (TMD) and in evaluating the effectiveness of therapies
      in clinic. METHODS: Both Fricton's Craniomandibular Index (CMI) and Helkimo's
      Clinical Dysfunction Index were calculated from 60 TMD patients. Inter-rater
      reliability was tested to assess the consistency in use between different
      examiners. Fricton's CMI was used to assess the clinical improvement after
      accepting a treatment in 21 TMD patients diagnosed as acute disk displacement
      without reduction. RESULTS: Correlation Coefficient for inter-rater reliability
      in two groups was 0.879 and 0.939 respectively for Fricton's CMI and 0.744 and
      0.838 for Helkimo Clinical Dysfunction Index. Fricton's TMJ dysfunction index was
      decreased from 0.337 to 0.021 (P < 0.001) and Fricton's CMI was decreased from
      0.185 to 0.011 (P < 0.001) after the treatment in 21 TMD patients with disk
      displacement without reduction. CONCLUSIONS: To avoid using subjective and
      descriptive report in assessment of the severity of TMD and the effectiveness of
      therapies, Fricton's CMI is recommended as an objective criteria which is simple
      in clinical use, and ease in scoring.

PMID- 12425839
TI  - Effects of repeated + Gz forces on masticatory muscles.
AB  - OBJECTIVE: To study the effects of repeated + Gz forces on masticatory muscles.
      METHODS: 48 male Wistar rats were randomly divided into 4 groups. Group A was
      normally fed. Group B was only fixed with rat-kept devices for 5 minutes. Group C
      was borne + 1 Gz for 5 minutes. Group D was repeatedly exposed + 10 Gz (each for
      30 s, onset rate about 0.5 G/s, 5 times/d with + 1 Gz 1 minute intervals, 4 d/wk,
      3 weeks in total). The histological changes of the masseter, temporal and lateral
      pterygoid muscles were observed. RESULTS: No abnormal changes were observed in
      Group A, B and C. But pathological changes could be found in group D. The wrench
      and deformation of muscular fibers, the dissolution of partial myofibril, the
      swelling of mitochondria, the reduce of hepatin from the masseter and lateral
      pterygoid muscles could be found. CONCLUSIONS: Repeated + Gz stresses could
      induce the damage of masticatory muscles in different degrees.

PMID- 12425841
TI  - The shaping effects of three nickel-titanium rotary instruments on preparing
      curved canals in posterior teeth.
AB  - OBJECTIVE: To investigate the shaping effects of three nickel-titanium rotary
      instruments on preparing curved canals in posterior teeth. METHODS: 64 curved
      mesial canals of extracted lower molars, embedded in the Branmante models, were
      randomly assigned to four groups: (1) Flexofile; (2) LightSpeed; (3) ProFile; (4)
      Qantec SC. Apical preparation was carried out till size 30. The area of dentine
      removal, least remaining dentine thickness and transportation of canal center
      were measured. RESULTS: Flexofile resulted in more dentine removal and canal
      center transportation than LightSpeed and ProFile (P < 0.05) at the apical and
      mid-root levels. In the mid-root sections, Flexofile left the thinnest dental
      wall in the distal aspect; 87% of the canal centers in the Flexofile group were
      transported in a distal direction as compared with one third in other groups.
      CONCLUSIONS: LightSpeed and ProFile exhibited better shaping ability than
      Flexofile in preparing curved canals.

PMID- 12425842
TI  - Embolization of the AVM of jaws by direct percutaneous puncture combined with
      endovascular route.
AB  - OBJECTIVE: To report our experience to embolize the AVM of jaws by direct
      puncture in conjunction with endovascular treatment. METHODS: 5 cases of AVM of
      mandible and 2 cases of AVM of maxilla comprised this study group. The patients
      were embolized with coils with wool strands and PVA. The coils were placed
      directly into the center of the intraosseous lesion. The procedure was under the
      guidance of DSA machine (PHILIPS V3000). RESULTS: The acute arterial bleeding of
      4 patients was controllable. The chronic oozing bleeding in the other 3 cases
      disappeared in the 3 - 24 months follow-up and new bone formation was found in
      the follow-up radiography. CONCLUSIONS: The embolization of the AVM of jaws by
      direct puncture in conjunction with endovascular therapy is effective and safe,
      however the longer follow-up is expected.

PMID- 12425843
TI  - Assessment of efficacy of endovascular embolization for central arteriovenous
      malformations (AVM) in the jaw.
AB  - OBJECTIVE: To study the angiographic properties of central AVMs in the jaw, and
      to investigate the efficacy of embolization of them. METHODS: Eleven cases of
      central AVMs underwent angiography and embolization, nine cases experienced
      surgery after embolization, and the other two cases were embolized alone; all
      these cases were followed up after treatment. The angiographic features and
      embolization results were analyzed. RESULTS: Large venous pouches were
      angiographically opacified in 9 of 11 AVMs. Of the nine operated cases, curettage
      was safely performed. The intraoperative bleeding was evidently decreased, and
      the continuity of the jaw was preserved. Five of these operated cases were free
      of recurrence during 18 - 27 months in follow-up. The two cases embolized alone
      were free of recurrence during 24 months' follow-up. CONCLUSIONS: Via arterial
      and venous approaches, embolization could greatly decrease the intraoperative
      bleeding and thus help to preserve the continuity and potentiality of development
      of the jaw for intraosseous AVMs, moreover, it may be curative in some cases.

PMID- 12425844
TI  - Randomized controlled trial study for preventing dental fear during caries
      treatments.
AB  - OBJECTIVE: To determine the clinical effects of preventing dental fear (DF) by
      pre-operation-education or local anesthesia method during the process of tooth
      filling. METHODS: 150 school children, aged 7 to 12, participated present study.
      All of them suffered from occlusal caries on their mandibular first permanent
      molars. They were divided into 3 equal groups, and each had 50, 25 boys and 25
      girls. Group1 (pre-operation-education): taking about 1 hour to show them science
      and educational video tape on caries, then, clinic environment, including machine
      and instruments, and answering their questions; Group2 (local anesthesia): about
      15 minutes before treatment, injecting 1.8 ml of 2% lidocaine for local
      anesthesia; Group3 (blank): without any measurements for DF. After that, all
      subjects accepted same filling treatment as usual. DF of each case was evaluated
      by 3 evaluators blindly based on venham's clinical ratings of anxiety and
      cooperative. RESULTS: Significant difference was found between groups (0.57 +/-
      0.59, 0.83 +/- 0.66, 1.05 +/- 0.68, H = 18.646, P = 0.0001), also in DF rate
      (10%, 18% and 42%, chi(2) = 15.5031, P = 0.0004). But not between groups 1 and 2.
      CONCLUSION: During decayed tooth filling treatment, pre-operation-education is
      better than that of local anesthesia method, in DF prevention.

PMID- 12425845
TI  - The directionality of share adhesive strength between composite resin and dental
      hard tissue.
AB  - OBJECTIVE: To inspect the directionality of adhesive strength between composite
      resins and dental hard tissues. METHODS: Two kinds of composite resins were
      bonded with their luting kits to the enamel and dentin surfaces of bovine teeth
      separately. The dead load shear and impact shear testing were performed from both
      of root apex direction and cutting edge direction. RESULTS: The shear adhesive
      strength between the enamel and two kinds of composite resins was on the same
      behavior, that the shear adhesive strength of root apex direction was greater
      than that of cutting edge direction. In the dead load shear testing, the former
      was about two to three times of the latter (P < 0.05). In the impact shear
      testing, the former was about three to four times of the latter (P < 0.001). The
      effect of the direction of acting force was small on the shear adhesive strength
      between the dentin and two kinds of composite resins. In the both dead load shear
      testing and impact shear testing, there was no statistically significant
      difference between the datum of two directional loadings (P > 0.05, P > 0.5).
      CONCLUSION: The shear adhesive strength between the composite resins and enamel
      of bovine teeth is related to the acting direction of the shear force.

PMID- 12425846
TI  - Laboratory study on abutment movement of the combined clasp, the extension clasp
      and the telescopic crown.
AB  - OBJECTIVE: To study the influence of three kinds of retainers on the abutment
      movement of removable partial dentures (RPDs) for restoring the dentition with
      unilateral distal-extended tooth missing. METHODS: The combined clasp, the
      extension clasp and the telescopic crown were designed to retain RPDs. When food
      chip was masticated between dentitions, the displacement of abutments was
      measured by a high-sensitive-laser-transferring-detector, and then the data was
      statistically analyzed. RESULTS: All of abutments showed the inclination, torsion
      and vertical translocation. Of them, abutments with telescopic crowns had the
      lowest horizontal torsion (P < 0.01) and the highest vertical translocation (P <
      0.01). CONCLUSIONS: Compared with the combined clasp and the extension clasp, the
      telescopic crowns enable abutments to bear the load more axial and the stress to
      be distributed more even, so the design of the telescopic crown may be considered
      more favourable for the health of abutments.

PMID- 12425847
TI  - Microvascular submandibular gland transfer for severe keratoconjunctivitis sicca:
      operation key points, prevention and management of complications.
AB  - OBJECTIVE: To summarize operation key points, prevention and management of
      complications in vascularized autotransplantation of submandibular gland for
      treatment of severe keratoconjunctivitis sicca. METHODS: 23 patients with severe
      keratoconjunctivitis sicca were treated by this procedure. Postoperative (99m)Tc
      images, follow-up studies, and management of complications were performed.
      RESULTS: The transplantations were successful in 19 cases, whose symptoms of
      xerophthalmia disappeared. The patients could stop applying artificial tears. In
      4 patients the transplanted glands did not survive. Epiphora occurred in 5 cases.
      They were successfully treated by reducing the size of the graft. Obstruction of
      the Wharton's duct took place in one case and was treated by reconstructing the
      duct. When the superficial temporal vein was too small, venous bridging was
      applied. To select a relevant vein for anastomosis, blood oozing from the three
      veins was carefully inspected prior cutting off the gland when the external
      maxillary artery was preserved and was infused with heparin after the gland had
      been freed. CONCLUSIONS: If every point has been properly managed, the successful
      rate of operation could be warranted.

PMID- 12425848
TI  - Mucinous adenocarcinoma of salivary glands.
AB  - OBJECTIVE: To investigate the clinicopathological features of mucinous
      adenocarcinoma of salivary glands. METHODS: The clinical manifestations and
      histopathological characteristics of 6 cases of mucinous adenocarcinoma of
      salivary gland were studied by retrospective and routine histopathology and
      immunohistochemistry. RESULTS: Four mucinous adenocarcinoma occurred in palate
      and 2 in mouth floor. Average age of patients was 60 years (48 - 70) and males
      were affected more often than females (4:2). Pathologically, the tumor grew with
      infiltration of surrounding tissues. The tumor consisted of unitary mucinous
      cells and mucin pool was obvious. The cell pleomorphism and nuclear mitosis were
      often seen. Some tumors showed acinus-like structure. Tumor cells often formed
      incomplete duct-like structure and small clusters floating in mucinous pool.
      There were intracellular mucin and signet ring cells in the tumor. Tumor cells
      showed positive reaction to PAS, Alcin blue, and some cytokeratin staining.
      CONCLUSIONS: Mucinous adenocarcinoma of salivary gland is a rare malignant tumor
      which mainly affects palate and mouth floor of older patients. The tumor may
      originate from acinic cell of mucous acinus or multi-potential cell of salivary
      gland.

PMID- 12425849
TI  - Hemodynamic changes during inhalation 50% nitrous oxide in dental extraction on
      essential hypertensive patients.
AB  - OBJECTIVE: To study the effects of cardiovascular function in dental extraction
      on hypertensive patients by inhalation 50% nitrous oxide. METHODS: The 30
      hypertensive patients were randomly allocated into two groups: A group inhalation
      the 50% nitrous oxide and oxygen, B group inhalation the air and O(2). To
      measured the HR, BP, and SpO(2) in dental extraction. RESULTS: In a group the
      changes of blood pressure and heart rate are more smoother than B group. Two
      groups were significant in HR, BP and SpO(2) (P < 0.01). CONCLUSIONS: Inhalation
      with 50% nitrous oxide can keep the stability of cardiovascular system and it is
      a valid method in dental extraction on hypertensive patients.

PMID- 12425850
TI  - Effects of cyclosporin A on the levels of intercellular adhesion molecule-1
      expressed by oral fibroblasts.
AB  - OBJECTIVE: To investigate the effects of cyclosporin A (CSA) on the level of
      intercellular adhesion molecule-1 (ICAM-1) expressed by oral fibroblasts (FB).
      METHODS: The fibroblasts were obtained from normal buccal mucosa (NM-FB) and
      cultured in vitro. Then the levels of ICAM-1 expressed by fibroblasts incubated
      with or without CSA in the presence of 10% fetal calf serum for 48 hours at 37
      degrees C in 5% CO(2) and air were monitored by using cell-based ELISA for ICAM
      1. RESULTS: We demonstrated that NM-FB had ICAM-1 expression (A = 0.324 +/-
      0.030), and after 48 hours incubated with CSA the ICAM-1 levels expressed by oral
      buccal mucosa fibroblasts were dose-dependently decreased. CONCLUSIONS: CSA
      reduces the levels of ICAM-1 expressed by oral mucosal FB, and may be useful in
      the treatment of some oral mucosal disorders.

PMID- 12425851
TI  - Polymerase chain reaction analysis of the clonality of Porphyromonas gingivalis
      and collagenase gene.
AB  - OBJECTIVE: To investigate the genotypic characterization of Porphyromonas
      gingivalis (Pg) and the heterogeneity of a potential virulence factor-PrtC.
      METHODS: Arbitrarily primed polymerase chain reaction (AP-PCR) was applied to 80
      Pg strains isolated from 24 unrelated Chinese periodontitis patients. PCR
      reaction was used to detect a fragment of the collagenase gene (PrtC gene). To
      evaluate the sequence heterogeneity of the Pg PrtC genes, sequence analysis of
      four PrtC gene of clinical isolates was performed. RESULTS: Random primer OPA-05
      and OPA-17 distinguished 7 AP-PCR profiles (I through VII). The majority of the
      strains belonged to type VII which accounted for 25.8%. A 548bp fragment of PrtC
      gene was detected from 24 clinical strains. The PCR products were verified by the
      restriction endonucleases PstI and PvuI. Sequence analysis showed 4 PrtC genes
      were heterogeneous in their nucleotide composition and differed from reference
      strain Pg 53977. CONCLUSIONS: The results demonstrated genetic diversity existed
      among these clinical strains isolated from Chinese periodontitis patients and the
      PrtC genes are heterogeneous in their nucleotide sequence.

PMID- 12425852
TI  - The research and development of CAD-CAM system in restorative dentistry.
AB  - OBJECTIVE: To develop a dental CAD/CAM system with the autonomic intellectual
      property. METHOD: 28 standard teeth crowns were scanned using a newly 3-D laser
      scanner. As a development platform the Matlab 5.3 were used to process the
      acquired data, also be used to define the characterized areas on the surfaces of
      the crowns and to change the crowns form. The software of Surfacer 10.5 to
      develop a new CAD software for fixed prosthetics, and the 3.5 axis numerical
      controlled machine to manufacture the prosthetics were used. RESULT: It is the
      first time, the 3D graphic data bank of Chinese teeth crowns with a standard form
      was established. A software of the occlusal adjustment and the form modification
      were developed. It is also the first time, the authors realized the whole process
      to use the CAD-CAM for the manufacture of a crown. CONCLUSION: The successful
      result shows, that we have already mastered well the base theory, the mathematics
      method, the technology of a CAD-CAM system. It provides the basics for the future
      development.

PMID- 12425853
TI  - The prevalence of malocclusion in China--an investigation of 25,392 children.
AB  - OBJECTIVE: To investigate the prevalence of malocclusion in China. METHODS: Based
      on individual normal occlusion and Angle's classification of malocclusion,
      standard investigation form was made. 25,392 children of different dental ages
      were evaluated by orthodontic professionals. RESULTS: The prevalence of
      malocclusion among Chinese children was 67.82%. The prevalence of malocclusion
      among children with different dental age and the proportion of the different
      types of malocclusions were revealed. CONCLUSION: The prevalence of malocclusion
      among Chinese children had increased from 40% to 67% over the last 40 years.

PMID- 12425854
TI  - Study on the correlation between tongue size and openbite.
AB  - OBJECTIVE: To investigate the correlation between tongue size and openbite.
      METHODS: The tongue size of the openbite patients and the subjects with normal
      occlusion was measured by B-type ultrasonic imaging respectively. The tongue size
      of the openbite patients and the subjects with normal occlusion was compared.
      RESULTS: The tongue size in openbite group was larger than in normal occlusion
      group. The difference was statistically significant. CONCLUSIONS: Tongue size was
      related to the openbite.

PMID- 12425855
TI  - The characteristics of pseudo class III malocclusion in mixed dentition.
AB  - OBJECTIVE: To find the dentoskeletal characteristics of pseudo Class III
      malocclusion in mixed dentition. METHODS: Thirty-six patients (15 females, 21
      males with mean age: 10.7 +/- 2.0 years) were included in the pseudo Class III
      malocclusion group. Forty patients (21 females, 19 males with mean age: 9.7 +/-
      2.2 years) with Class III incisor relationship and Class III molar relationship
      were included in the skeletal Class III malocclusion group. All the subjects were
      followed up after growth spurt and were diagnosed either as pseudo Class III
      malocclusion or skeletal Class III malocclusion. Thirty-one patients with Class I
      malocclusion were included in the Class I malocclusion group. Selection criteria
      included: 1. skeletal Class I malocclusion with normal overjet and overbite. 2.
      mild to moderate crowding with Class I molar relationship. 3. straight facial
      profile. Cephalograms were taken in the mixed dentition for pseudo Class III
      malocclusion, skeletal Class III malocclusion and Class I malocclusion groups to
      compare the dentoskeletal characteristics. RESULTS: Females in the pseudo Class
      III malocclusion group showed more retrusion of "A" point with an average value
      of -1.63 mm compared with 0.52 mm in the Class I malocclusion group (P < 0.05).
      The upper incisors in the pseudo Class III malocclusion group were upright.
      CONCLUSIONS: Pseudo Class III malocclusion is characterized by decreased midface
      length, mandibular displacement, retroclined upper incisors and normal vertical
      development.

PMID- 12425856
TI  - The long-term stability of dentition in skeletal class III malocclusion following
      orthodontic-orthognathic surgery.
AB  - OBJECTIVE: To Investigate the changes in dentition at each treatment stage and to
      get some guidelines for clinical work. METHODS: Thirty-one cephalometric films of
      skeletal class III malocclusion patients were analyzed. All the patients were
      treated by orthodontic and orthognathic surgery. RESULTS: During presurgical
      orthodontic treatment, the lower Incisors were decompensated (labially Proclined
      by 7 degrees ). The upper incisors were uprighted during surgery following
      rotation of maxilla. After surgery, the upper anterior teeth kept tipping for
      ward. While the lower anterior teeth were In stable. The dentition was in good
      occlusion during observing stage. CONCLUSIONS: Lingually tipped lower Incisors
      were decompensated after presurgical orthodontic treatment in class III
      malocclusion patients, and lower Incisors kept in stable during observing stage,
      while the upper incisor had a little bit relapse.

PMID- 12425857
TI  - A study on the difference of craniofacial morphology between oral and nasal
      breathing children.
AB  - OBJECTIVE: The purpose of this study was to compare the difference of
      craniofacial morphology between oral and nasal breathing children, and discover
      the relationship between respiratory mode and craniofacial morphology. METHODS:
      Using the system for the simultaneous measurement of oral and nasal respiration,
      34 oral breathing children and 34 nasal breathing children aged from 11 to 14
      years were selected. RESULTS: Compared with the nasal-breathing children, the
      oral-breathing children showed apparently vertical growth pattern. The mandibuler
      plane Angle of oral breathing children is 39.3, which is significant greater than
      that of nasal breathing children (P < 0.01). The jans, the oral-breathing
      children had shorter mandibular body, larger gonion angle, retrusive chin and
      face (P < 0.05). On the other hand, in the sagittal direction, the oral breathing
      children may display all kinds of skeletal facial types. There is no significant
      difference between the two groups. CONCLUSIONS: Oral breathing is one of the
      factors related to the vertical over-development.

PMID- 12425858
TI  - Extract and identify ingredient from Ligustrum Lucidum Ait and study its effect
      to periodontal pathogen.
AB  - OBJECTIVE: To extract the effective ingredient (crystal I) from effective section
      (saponin) of Ligustrum Lucidum Ait, identify the chemical structure of crystal I,
      study the effect of crystal I on P. gingivalis, B. forsythus and P. intermedia.
      METHODS: Isolated crystal I from saponin using the silica gel column
      chromatograph. Identified crystal I with IR spectra, (1)H-NMR and (13)C-NMR.
      Measured the minimal inhibitory concentration (MIC) and the minimal bactericidal
      concentration (MBC) through micro-liquid dilution. Studied the killing curve of
      ursolic acid on B. forsythus and P. intermedia. RESULTS: The crystal I was
      identified as ursolic acid; its MIC and MBC to P. gingivalis, B. forsythus and P.
      intermedia were 0.740 and 0.295 microg/L respectively. The killing curve
      indicated that 0.800 microg/L ursolic acid could kill P. intermedia and B.
      forsythus in 3 and 6 hours respectively. CONCLUSION: Ursolic acid has obvious
      effect to inhibit periodontal pathogen.

PMID- 12425860
TI  - The intervention research on understanding of the AIDS prevention and
      occupational safety of the dentist in Kunming and west part of Yunnan.
AB  - OBJECTIVE: To investigate the knowledge, attitude of the AIDS prevention and
      occupational safety in dentist in Kunming and west part of Yunnan and evaluate
      the effect of education and intervention. METHOD: 165 dentists in Yunnan were
      tested by KABP questionnaire before education. All of the 165 dentists
      participated a course on AIDS prevention. After that course the same
      questionnaire was answered by participants. RESULT: The correct rates obviously
      increased. The understanding rates of the oral prevention measure were obviously
      improved. CONCLUSION: The knowledge of AIDS prevention is very low in dentist in
      Kunming and west part of Yunnan. The education intervention can effectively
      improve the understanding level of the AIDS prevention in dentist.

PMID- 12425859
TI  - In vitro study of the effects of Epimedium on osteoclastic bone resorption in
      various oral mineralized tissues.
AB  - OBJECTIVE: To investigated the bone resorption caused by osteoclasts and
      modulating functions of a Chinese herb, Epimedium on bone resorption. METHODS:
      Osteoclasts were separated from long-limb bones of new born rabbits, cultured
      with de-activated human tooth slices and glass slices, and treated with different
      concentrations of Epimedium. Osteoclasts on glass slices were stained by HE
      staining, TUNEL staining and absorption pits on tooth slices were observed by
      light microscope. RESULTS: HE staining shows that the Epimedium treated cells
      showed shrinkage of cytosol and condensation of nuclei. Some treated cells showed
      breakage of nuclei. TUNEL staining shows that treated cells showed shrinkage of
      cytosol, dark stained nuclei and light stained cytosol. These results indicate
      that Epimedium can induce osteoclast to commit apoptosis. Further study shows
      that the number and area of absorption pits formed on treated tissues are
      significantly different from those on control tissues. So the effect of Epimedium
      on bone resorption is dose-dependent. CONCLUSIONS: Epimedium can induce
      osteoclast apoptosis and inhibit bone resorption. The effect of Epimedium on bone
      resorption is dose-dependent.

PMID- 12425861
TI  - The time to certify pediatric urologists has arrived.

PMID- 12425862
TI  - Methodologic shortcomings inherent in a post-hoc analysis.

PMID- 12425863
TI  - Incidence and prevalence of overactive bladder.
AB  - Recent changes in terminology, diagnosis, and therapy have refocused attention on
      overactive bladder (OAB). This symptom syndrome is highly prevalent worldwide and
      significantly impairs the quality of life of those who suffer from it. Accurate
      epidemiologic incidence and prevalence studies of OAB have been hampered in the
      past by, among other issues, a generalized lack of agreement regarding definition
      of the disorder, and consequently, accurate case finding. This obstacle resulted
      in considerably wide estimates in the reported incidence and prevalence of OAB in
      the literature. A new symptom-based definition of OAB, formally adopted by the
      Standardization Committee at a recent International Continence Society meeting,
      should provide a framework for future epidemiologic studies. Current estimates of
      incidence, prevalence, effects on quality of life, and societal costs may need to
      be reassessed based on these new data.

PMID- 12425864
TI  - Advances in drug delivery: improved bioavailability and drug effect.
AB  - Alterations in drug delivery produce substantial changes in the bioavailability
      of anticholinergic agents. These bioavailability differences change the efficacy
      and tolerability of this drug class, which consistently enhances patient
      compliance and overall drug effect. In order for drug delivery to alter
      successfully the bioavailability of a specific agent, the metabolism of that
      agent and the effect of the degradatory pathway on drug-parent compound levels
      need to be established. This will enable researchers to design improved or
      altered delivery pathways to maximize the benefits of these agents. Intestinal
      metabolism is known to affect certain agents, specifically oxybutynin chloride.
      Therefore, delivery techniques have been designed that either substantially lower
      or totally bypass intestinal (presystemic) metabolism. These alternate paths
      include extended-release oral, cutaneous, intravesical, and intravaginal routes.
      In addition, improvements in drug delivery have also been found to influence
      positively efficacy and tolerability profiles associated with tolterodine
      tartrate, another anticholinergic agent. A long-acting oral formulation has been
      shown to increase drug efficacy while decreasing tolerability concerns and side
      effects such as xerostomia. These salubrious effects are, in part, due to the
      more stable serum-drug concentrations that are imparted by this long-acting
      formulation.

PMID- 12425865
TI  - Overactive bladder in the male patient: bladder, outlet, or both?
AB  - Generations of urologists have presumed that the cause of lower urinary tract
      symptoms (LUTS) in men is infravesical (prostatic) obstruction. When symptoms
      such as urinary urgency and frequency can't easily be explained directly by
      obstruction, secondary effects of obstruction on the bladder are identified as
      causative factors. Although to some extent this explanation may still be
      accurate, emerging concepts in the pathophysiology of LUTS in men may be at odds
      with these traditional explanations. The idea that primary bladder pathology may
      explain the symptom complex in at least one subset of men with LUTS has both
      experimental and clinical support. This review discusses the physiologic and
      clinical observations used to explain the mechanisms underlying LUTS.
      Specifically, this review focuses on two data sets: one supporting infravesical
      obstruction as the causative factor for LUTS, and another positing that a primary
      bladder abnormality is responsible.

PMID- 12425866
TI  - Overactive bladder in the female patient: the role of estrogens.
AB  - The prevalence of urinary incontinence is known to increase with age, affecting
      15% to 35% of community-dwelling women over 60 years of age. Other studies report
      a prevalence of 49% in women over 65 years of age. Epidemiologic studies have
      implicated estrogen deficiency in the etiology of lower urinary tract symptoms,
      although the role of estrogen replacement therapy remains controversial. This
      review presents recent evidence regarding the role of estrogen in lower urinary
      tract dysfunction, with a particular emphasis on the management of postmenopausal
      women with symptoms suggestive of overactive bladder.

PMID- 12425867
TI  - Conservative therapy for overactive bladder: pelvic floor exercises.
AB  - Overactive bladder affects the lives of millions of people. Anticholinergic
      medications are traditionally used to treat this condition, but some patients
      find these agents difficult to tolerate and ineffective. Conservative treatment
      with pelvic floor exercises, with or without biofeedback, electric stimulation,
      and behavioral modification, are excellent modalities that can be effective in
      the motivated patient. This review describes the available literature supporting
      the efficacy of pelvic floor exercises in the treatment of overactive bladder and
      guidelines for patient selection.

PMID- 12425868
TI  - PNU-83757: a new agent for the treatment of erectile dysfunction.

PMID- 12425869
TI  - Combination therapy for erectile dysfunction: where we are and what's in the
      future.
AB  - Penile erection occurs in response to visual, olfactory, imaginative, and tactile
      stimuli initiated within the brain and/or on the periphery. Responses to these
      stimuli are mediated by efferent autonomic outflow originating in the sacral
      spinal cord and transmitted by the cavernosal and penile nerves. A number of
      neurotransmitters can play an integral role in corpus cavernosum smooth muscle
      relaxation, in part regulating penile erection through increased smooth muscle
      synthesis of the secondary messengers cyclic adenosine monophosphate (cAMP) and
      cyclic guanosine monophosphate (cGMP). In addition to direct-acting agents, there
      are indirect-acting smooth muscle-relaxing agents. Phosphodiesterase (PDE)
      inhibitors such as sildenafil act indirectly and require sexual stimulation and
      endogenous nitric oxide production to activate the cGMP pathway effectively. In
      contrast, agents such as prostaglandin E(1) (PGE(1)) act directly on the
      trabecular smooth muscle, binding to specific e-prostanoid receptors and
      increasing cAMP synthesis. For this reason the direct-acting agents do not
      require sexual stimulation for efficacy. Combination pharmacotherapy has been
      used experimentally to treat erectile dysfunction for 25 years, using
      combinations of cAMP synthesis augmentors, smooth muscle relaxants and PDE
      inhibitors, and alpha-blockers administered via intracavernosal injection. The
      present era of oral pharmacotherapy treatment has resulted in significant
      awareness in the field of sexual dysfunction; however, a single agent may not be
      ideal to sustain penile rigidity, especially if comorbidities and severity of
      erectile dysfunction are accounted for. The rationale for and recent reports on
      combination therapy are presented in this review.

PMID- 12425870
TI  - Topical agents and erectile dysfunction: is there a place?
AB  - Despite the proven efficacy of oral therapy for erectile dysfunction (ED), some
      patients are unable to take these medications because of drug interactions (ie,
      sildenafil and nitroglycerin) or a lack of response. Topical agents represent
      another minimally invasive option for the treatment of ED. This review discusses
      the impediments to effective topical therapy and examines the developmental
      status of several candidate drugs. Although still in the investigative stage,
      topical medications can be another tool in the urologist's armamentarium against
      ED.

PMID- 12425871
TI  - Vasoconstriction and vasodilation in erectile physiology.
AB  - Recent studies have demonstrated that vasoconstriction in the erectile
      vasculature of the penis is mediated in part by RhoA/Rho-kinase signaling.
      However, this constrictor activity must be overcome to permit the vasodilation
      essential for erection. We hypothesize that the primary action of nitric oxide
      and other agents that cause penile erection is inhibition of the RhoA/Rho-kinase
      pathway, thereby allowing vasodilation and erection. This hypothesis, as well as
      experiments using hypogonadal and hypertensive animal models, are discussed in
      terms of the potential clinical value of Rho-kinase inhibitors for the treatment
      of erectile dysfunction.

PMID- 12425872
TI  - Female sexual dysfunction: state of the art.
AB  - Female sexual dysfunction, a common, multifactorial, and often undertreated
      medical condition, attracted the attention of the medical community with the
      successful introduction of medical therapy for male erectile dysfunction. This
      review discusses the updated classification systems and definitions,
      epidemiologic aspects, and new pathophysiologic and therapeutic implications of
      this sexual disorder.

PMID- 12425873
TI  - The etiology, diagnosis, and treatment of priapism: review of the American
      Foundation for Urologic Disease Consensus Panel Report.
AB  - Priapism is an important medical condition that requires immediate evaluation,
      and depending on etiology, may require emergency management. Based on the
      classification scheme offered by a recent consensus panel, priapism can be
      subdivided into ischemic and nonischemic types. The nonischemic type, usually the
      result of perineal trauma, can be treated with conservative therapy, whereas the
      nonischemic type, which arises from many varied causes, mandates immediate
      intervention. Corporal fibrosis and permanent erectile dysfunction can result
      from ischemic priapism that fails to resolve with therapy.

PMID- 12425874
TI  - [Infections in liver transplantations of the twenty-first century].

PMID- 12425875
TI  - [Early infection in liver transplant recipients: incidence, severity, risk
      factors and antibiotic sensitivity of bacterial isolates].
AB  - OBJECTIVES: To conduct a descriptive study with an analysis of risk factors for
      early infection in liver transplant patients, and to determine the resistance of
      the bacteria involved. PATIENTS AND METHODS: The study included 149 liver
      transplant recipients. All cases of infection occurring 0-90 days after
      transplantation were considered early infection. Pre-, intra- and postoperative
      variables were analyzed, and isolated microorganisms were studied. Selective
      bowel decontamination with quinolones, and perioperative and antifungal
      prophylaxis were carried out in all patients. RESULTS: The incidence of infection
      was 73.1%: bacterial (49.7%), viral (35.5%), fungal (10.1%) and mixed (4.5%). In
      the first postoperative month the most frequent infections were bacterial and in
      the second and third months, viral (p = 0.001). Multivariate analysis of risk
      factors identified the following: days of parenteral nutrition, duration of
      surgery > 5 hours, rejection and CMV seronegative status. Among 1278 cultures,
      the following microorganisms were isolated: 77.9% gram-positive cocci (GP) and
      19% aerobic gram-negative bacilli (GNB). Sensitivity of Staphylococcus to
      vancomycin was 99.6-100% and to teicoplanin 97.9-100%. VAN resistance was
      observed in 1.2% of E. faecalis and 4.5% of E. faecium. Among S. aureus strains,
      68.7% were MRSA. The resistance rate of GNB to quinolones was 38.8%. CONCLUSIONS:
      Incidence of infection was higher the first 30 days after transplantation, with
      bacterial infection predominating. Duration of surgery > 5 hours was the most
      important risk factor for acquiring bacterial infection. GP were the most
      frequently isolated bacteria. Empirical treatment of early bacterial infection
      should include vancomycin or teicoplanin. Selective bowel decontamination
      resulted in a low incidence of GNB infections, among which there was 38.8%
      resistance to quinolones.

PMID- 12425876
TI  - [Microbiological factors that influence the eradication of Helicobacter pylori in
      adults and children].
AB  - AIM: To study microbiological factors of Helicobacter pylori, such as
      antimicrobial susceptibility and virulence, which affect the eradication of the
      microorganism in gastric mucosa of adult and pediatric patients. METHODS: Fifty
      five H. Pylori strains were isolated from culture of biopsy specimens from 39
      adult and 16 pediatric patients. Antibiotic susceptibility was determined by agar
      dilution and study of virulence factors (cagA gene and alleles s1 and s2 of the
      vacA gene) by PCR. Outcome of treatment with amoxicillin (AMX), clarithromycin
      (CLR) and omeprazole was assessed by the urea breath test. We studied the
      relation of minimum inhibitory concentration (MIC) of AMX and CLR and presence of
      virulence factors with eradication of the microorganism.Results. The eradication
      rate was 69% (38/55), 71.7% in adults and 62.5% in children. Resistance to CLR
      and AMX was 14.5% and 0%, respectively. Overall eradication rates with respect to
      the variables studied were: 75% and 53% in strains with AMX MICs of < or = 0.01
      6mg/L and > or = 0.032 mg/L (range < or = 0.008-0.5) (p > 0.05), 79% and 12% in
      strains with clarithromicina MICs of < 1 mg/L and > or = 1mg/L (range # 0.008-64)
      (p < 0.05), 79% and 54% in cagA+ and cagA strains (p > 0.05) and 82% and 62% in
      s1 and s2 strains (p > 0.05), respectively. CONCLUSIONS: H. pylori strains with
      higher amoxicillin and clarithromycin MICs, and cagA and vacA s2 strains were
      related with lower rates of eradication in both adult and pediatric populations
      treated with amoxicillin, clarithromycin and omeprazole.

PMID- 12425877
TI  - [Comparative study of prognostic and risk factors for mortality in polymicrobial
      bacteremia-fungemia in a university hospital: development over 10 years].
AB  - OBJECTIVE: Eighty-two episodes of polymicrobial bacteremia in two time periods,
      1986-87 and 1996-97, were compared to assess differences in risk factors and
      outcome to mortality. METHODS: A prospective, concurrent, anterograde study with
      univariate analysis of all episodes of polymicrobial bacteremia was performed in
      Hospital de la Princesa. Logistic regression analysis was applied to all
      significant variables (p < 0.05) in the univariate analysis in either of the two
      time periods. RESULTS: Variables showing statistically significant differences in
      incidence between the two time periods included the following: hospital acquired
      bacteremia; previous use of antibiotics; genitourinary, respiratory and
      cardiovascular manipulations; septic metastases; and absence of leukocytosis.
      These factors were more frequently present during 1986-87 than during 1996-97.
      The overall RR of outcome to mortality was five-fold greater during the first
      period than the second: RR 5.6 (CI 1.76-17.56) p < 0.001. The clinical
      characteristics at the onset of bacteremia associated with mortality in the first
      period were: underlying disease - < RR 2.20 (CI 1.18-4.08), steroid treatment - <
      RR 4.24 (CI 0.68-26.59), hypotension - < RR 2.05 (CI 1.0-4.17), and disseminated
      intravascular coagulation - < RR 2.31 (CI 1.69-3.35). Clinical characteristics at
      the onset of bacteremia associated with mortality in the second period were:
      hypotension - < RR 1.44 (CI 1.01-2.08), underlying disease - < RR 1.16 (CI 1.02
      1.34), and disseminated intravascular coagulation - < RR 6.40 (CI 1.15-35.69).
      The variables independently associated with mortality in polymicrobial bacteremia
      were: period - < RR 2.05 (CI 1.50-2.10), underlying disease - < RR 7.05 (CI 2.68
      7.50), hypotension - < RR 7.06 (CI 3.80-7.29), and (probably) vascular
      manipulations - < RR 3.41 (CI 0.85-4.53). CONCLUSION: Polymicrobial bacteremia
      associated mortality was five-fold greater in 1986-87 than in 1996-97. The
      variables independently associated with mortality risk were underlying disease,
      hypotension, the period studied (which would include a number of variables not
      analyzed in this work) and, probably, vascular manipulations.

PMID- 12425878
TI  - [Neonatal meningitis due to Enterococcus spp.: presentation of four cases].
AB  - AIM: Enterococci are unusual etiologic agents of bacterial meningitis and account
      for only 0.3-4% of all cases. Neonatal enterococcal meningitis, which is rarely
      reported in the medical literature, presents characteristics that are
      significantly different from enterococcal meningitis affecting other age groups,
      particularly adults. PATIENTS AND METHODS: We retrospectively reviewed the
      clinical records of four newborns diagnosed with enterococcal meningitis in our
      center. Two were premature and two were term infants. Three were affected with
      early-onset meningococcal sepsis and one with late-onset sepsis. Risk factors for
      infection included intrapartum maternal fever in one case and prematurity in two
      cases, with prolonged stay in the neonatal intensive care unit and application of
      invasive procedures, and prior antibiotic treatment in one of infant. There were
      no apparent risk factors in the fourth case. Enterococcus faecalis was the causal
      agent in three cases and Enterococcus faecium in one. None of the enterococci
      were vancomycin-resistant. Antibiotic treatment included ampicillin and
      combinations of ampicillin and cefotaxime, ampicillin and amikacin, and
      vancomycin and gentamicin. None of the patients died. CONCLUSIONS: Enterococci
      rarely cause bacterial meningitis, though newborns seem more susceptible to this
      infection. With adequate bactericidal therapy, clinical outcome appears to be
      generally favorable.

PMID- 12425879
TI  - [Infectious disease assessment in solid organ transplant candidates].
AB  - BACKGROUND: Infections are one of the leading causes of morbidity and mortality
      in solid organ transplant recipients. Many of these infections can be prevented
      or their effects reduced by accurate preoperative evaluation of risk in the
      transplantation candidate. The elaboration of guidelines using a
      multidisciplinary approach can help to establish more rational diagnostic,
      therapeutic, and preventive measures in this setting. OBJECTIVE: To elaborate
      guidelines for the assessment of infectious diseases in transplant candidates,
      based on consensus among professionals in this field and under the auspices of
      Spanish scientific societies. MATERIAL AND METHODS: The Infections in Transplant
      Patients Group (GESITRA), within the Spanish Society of Infectious Diseases and
      Clinical Microbiology (SEIMC), appointed a panel of four microbiologists and
      infectious disease specialists to elaborate a draft of the guidelines, which was
      subsequently approved by all the members of this Group. With the support of the
      National Transplant Organization, the GESITRA document was then presented to
      various professionals in this field so they could provide their comments and
      suggestions. RESULTS: The final document, after incorporation of all appropriate
      modifications and suggestions, is presented herein. The guidelines focus on the
      following: a) diagnosis of active and latent infections, and identification of
      risk factors in the candidate; b) recommended approach for infections diagnosed
      during the evaluation process and their corresponding treatment; c) definition of
      infections contraindicating transplantation; and d) prevention of post
      transplantation infectious complications by systematic vaccination and
      instruction on preventive measures provided to patients, their relatives, and
      persons living with them. DISCUSSION: Using a multidisciplinary approach that
      included the efforts of experts in the field and the collaboration of scientific
      societies, a comprehensive document containing specific recommendations was
      elaborated. Systematic review of the guidelines in the future is considered
      worthwhile by both the authors and supporters of this document.

PMID- 12425880
TI  - Clinical relevance of mechanisms of antifungal drug resistance in yeasts.
AB  - A limited number of antifungal agents including azoles, polyenes, pyrimidine
      analogues are used today to combat infections caused by yeast pathogens. While
      clinical factors can contribute to failures to antifungal treatments, yeast
      pathogens exposed to these agents can still limit their action either because
      they are intrinsically resistant or because they acquire specific resistance
      mechanisms. Microbiological methods are available to measure the susceptibility
      of yeast pathogens against the existing antifungal agents and to distinguish
      between antifungal susceptible and antifungal resistant organisms. This
      distinction can ideally predict the success or failure of a treatment in clinical
      situations and is available only for a limited number of antifungal agents, i.e.
      the azole antifungals fluconazole and itraconazole and the pyrimidine analogue 5
      fluorocytosine. Cases of antifungal resistance have been reported for almost all
      classes of antifungal agents, but they have been mainly documented for the
      pyrimidine analogue 5-fluorocytosine and azole antifungals mainly in Candida
      species and less frequently in Cryptococcus species. This review summarizes the
      current knowledge on the different mechanisms of resistance to these agents in
      these yeast pathogens.

PMID- 12425881
TI  - [Furuncular skin lesion in a traveler coming from a South American country].

PMID- 12425882
TI  - [Diarrhea and weight loss in a male after a recent trip to Guatemala].

PMID- 12425883
TI  - [Reply to the article: "Clinical significance of Mycobacterium kansasii isolation
      and assessment of the need for identifying non-tuberculous mycobacteria"].

PMID- 12425885
TI  - [Endocarditis due to Stenotrophomonas maltophilia].

PMID- 12425886
TI  - [Streptococcus agalactiae pleural empyema in a healthy adult].

PMID- 12425887
TI  - [Diagnostic accuracy of semiquantitative analysis of positron emission tomography
      in radiologically indeterminate lung lesions].
AB  - OBJECTIVE: The objective of this work was to assess the Standardized Uptake Value
      (SUV) in the differential diagnosis of radiologically indeterminate lung lesions
      by means of ROC curves. MATERIAL AND METHOD: Forty seven patients were studied by
      Positron Emission Tomography with 18-fluorine-2-desoxy-D-glucose (FDG PET)
      analyzing the value of maximum SUV. The patients were classified into three
      groups. Group 1 = patients without previous neoplasia (WPN) + patients with
      previous neoplasia (PN). Group 2 = WPN. Group 3 = PN. RESULTS: The ROC curves
      showed a high diagnostic accuracy in the three groups, with area under the curve
      (AUC) values of 0.96, 0.98 and 0.91 respectively. The typical error was 0.03,
      0.02 and 0.08. The maximum SUV cutoffs with the best diagnostic accuracy for the
      three groups were: 2.6; 3 and 2.4, with an accuracy (A) of 93.6%, 97% and 92.3%,
      respectively. Analyzing all the patients globally (group 1), we obtained one
      false positive result in a patient with hamartoma (max SUV = 2.8) and two false
      negative results in one patient with lung metastases from malignant
      fibrohistiocytoma (max SUV = 0.7) and in another patient with lung metastases
      from unknown origin adenocarcinoma (max SUV = 1.9). CONCLUSIONS: FDG PET permits
      differentiation with a very high diagnostic accuracy of benign and malignant lung
      lesions using the maximum SUV. The differences observed between the different
      groups are due to the different disease prevalence, obtaining a lower negative
      predictive value of max SUV in patients with previous neoplasia.

PMID- 12425888
TI  - [Behavior of brain perfusion with SPECT tomography 99mTc ethylene dicysteine
      (ECD) in alcohol and cocaine dependents during abstinence].
AB  - Brain perfusion abnormalities after an abstinence period of 28 days in a group of
      patients with alcohol and / or cocaine dependence was investigated. They were
      related with gender, consumption period and number of drugs. Fifty men and 10
      women were included and SPECT perfusion was performed using 99mTc ethylene
      cysteine dimer (ECD) with qualitative and semiquantitative section analysis.
      Perfusion abnormalities were observed in 60% of the patients, principally in
      frontal, temporal and parietal lobes. The abnormalities were focal in 58.3%,
      diffuse in 41.7% and bilateral in 95% of all patients. Abnormalities were
      observed in 68% of the men and in only 20% of the women (p = 0.01). Patients with
      brain perfusion abnormalities had a longer period of consumption corresponding to
      a median of 17.5 years in patients with abnormalities versus nine years in those
      with no abnormalities (p = 0.036), however, their ages as well as the number of
      drugs consumed were not significantly different. In conclusion, after 28 days of
      alcohol and / or cocaine abstinence there is significant presence of brain
      perfusion abnormalities with 99mTc ECD. This could be explained by vasospasm and
      / or secondary endothelial lesions.

PMID- 12425889
TI  - [Effect of attenuation correction and scatter compensation on the 99mTc-MIBI
      myocardial perfusion spect in patients without coronary artery disease].
AB  - OBJECTIVE: Attenuation correction (AC) and scatter compensation (SC) techniques
      are recent developments of myocardial perfusion SPECT. Our aim was to evaluate
      the effect of AC + SC on the myocardial distribution of 99mTc-MIBI in a
      population without coronary artery disease. MATERIAL AND METHODS: A multiarray of
      Gd-153 linear sources was used for simultaneous transmission/emission 99mTc-MIBI
      myocardial perfusion SPECT in 27 patients without coronary artery disease. A
      visual analysis and polar map quantification was performed. Changes between non
      corrected (NC) and corrected (AC + SC) studies were compared. RESULTS: AC + SC
      produced an increase in liver activity and better visualization of the right
      ventricle. Intestinal activity increased in six patients. Myocardial homogeneity
      was increased by AC + SC. No differences by gender were observed after AC + SC.
      In females AC + SC led to a decrease of uptake in the anterior wall, apex and
      apical segments of the lateral wall and septum, and an increase in the inferior
      wall. In males AC + SC caused an increase of uptake in the inferior wall and in
      the basal segments of septum and a decrease of uptake in apex and apical segments
      of anterior and lateral walls. AC + SC generated false defects in the anterior
      wall of five patients. CONCLUSIONS: Our results show the usefulness of AC + SC
      for compensating the interferences produced by attenuation on the myocardial
      distribution of 99mTc-MIBI. Because AC + SC may introduce false defects, it must
      not be applied to normal perfused myocardium.

PMID- 12425890
TI  - [Quantification of bone scintigraphy as an objective method in the follow-up of
      radioisotopic synoviorthesis].
AB  - This work tries to provide the clinicians an objective tool that can contribute
      to the assessment of the results of radioisotopic synoviorthesis (RS). This study
      aims to assess the value of the quantification of bone scintigraphy in blood pool
      and late phase of the affected joints treated with 90Y silicate, in order to
      observe the clinical improvement experienced by most of these patients. A total
      of 69 bone scintigraphies (BS) in blood pool and late phase have been quantified.
      They belonged to 23 patients who were treated with RS with 90Y. The first
      scintigraphy study was performed before the treatment, the second and the third
      ones were performed 2 and 6 months after treatment. In each BS we quantified the
      index: counts per pixel of healthy / affected joint. We also have calculated the
      fraction in the late phase: counts per pixel of healthy bone / counts per pixel
      of affected and healthy joint. For the comparative statistical analysis of the
      results we used the Student's t test. We considered statistical significance when
      p < 0.05. All the patients presented clinical improvement. If we compare the
      index obtained in BS 2 months after treatment and pre-treatment we find
      statistical significance (p < 0.05) in the increase of index in the anterior view
      and late phase. If we compare the index obtained in BS 6 month after treatment
      and pre-treatment, we find a statistically significant increase in the anterior
      (p < 0.01) and posterior (p < 0.05) view of the blood pool phase and the anterior
      view of late phase (p < 0.01). The fraction counts per pixel of healthy bone /
      counts per pixel of affected and healthy joint did not present a significant
      increase in any BS control (2 and 6 months). We recommend quantification using
      the index (counts per pixel healthy / affected joint ) proposed in this work,
      because it is easy to perform, cheap and reliable in the follow-up of patients
      treated with RS.

PMID- 12425891
TI  - [Reflux in internal jugular vein and brain death].

PMID- 12425892
TI  - [Lung accumulation of 99mTc-pertechnetate in thyroid scintigraphy].

PMID- 12425894
TI  - [PET in neurology and psychiatry. II].

PMID- 12425893
TI  - [Hormone-dependent, diploid, infiltrating ductal breast carcinomas less than 2 cm
      in size: influence of an exclusive and moderate cellular proliferation on the
      clinicobiological features and recurrences of these malignant tumors].

PMID- 12425895
TI  - [LIV Annual Meeting of the Spanish Society of Neurology. Barcelona, Spain, 27-30
      November 2002. Abstracts].

PMID- 12425938
TI  - Effect of the ubiquitous transcription factors, SP1 and MAZ, on NMDA receptor
      subunit type 1 (NR1) expression during neuronal differentiation.
AB  - The silencer factor NRSF/REST has been reported to restrict expression to neurons
      of a variety of genes, including that encoding NMDA receptor subunit type 1
      (NR1), by suppressing transcription in nonneuronal cells. However, we recently
      reported that in addition to the absence of NRSF/REST-binding activity, another
      neuron-specific mechanism is necessary for high level expression of the NR1 gene
      in neurons. In this study, we explored the mechanism of induction of NR1 promoter
      activity during neuronal differentiation of the P19 cell line. We identified a 27
      base pair GC-rich region in the promoter as an important element responsible for
      induction of the NR1 gene after neuronal differentiation. We found that the
      ubiquitous transcription factors SP1 and MAZ bind to this GC-rich region.
      Surprisingly, the binding activities of SP1 and MAZ are not remarkably changed
      after neuronal differentiation. Mutations in the SP1 and MAZ sites impair binding
      of SP1 and MAZ proteins and also decrease NR1 promoter activity. These findings
      suggest that SP1 and MAZ mediate enhancement of NR1 promoter activity during
      neuronal differentiation despite the fact that their binding activity does not
      change.

PMID- 12425939
TI  - Analysis of sigma receptor (sigmaR1) expression in retinal ganglion cells
      cultured under hyperglycemic conditions and in diabetic mice.
AB  - The type 1 sigma receptor (sigmaR1) is a nonopiate and nonphencyclidine binding
      site that has numerous pharmacological and physiological functions. In some
      studies, agonists for sigmaR1 have been shown to afford neuroprotection against
      overstimulation of the NMDA receptor. sigmaR1 expression has been demonstrated
      recently in retinal ganglion cells (RGC). RGCs undergo apoptosis early in
      diabetic retinopathy via NMDA receptor overstimulation. In the present study we
      asked whether RGCs cultured under hyperglycemic conditions and RGCs of diabetic
      mice continue to express sigmaR1. RGCs were cultured 48 h in RPMI medium
      containing either 45 mM glucose or 11 mM glucose plus 34 mM mannitol (osmolar
      control). C57BL/6 mice were made diabetic using streptozotocin. The retina was
      dissected from normal and streptozotocin-induced diabetic mice 3, 6 and 12 weeks
      post-onset of diabetes. sigmaR1 was analyzed in cells using semiquantitative RT
      PCR and in tissues by semiquantitative RT-PCR, in situ hybridization, Western
      blot analysis and immunolocalization. The RT-PCR analysis of cultured RGCs showed
      that sigmaR1 mRNA is expressed under hyperglycemic conditions at levels similar
      to control cells. Similarly, analysis of retinas of diabetic mice showed no
      difference in levels of mRNA encoding sigmaR1 compared to retinas of control
      mice. In situ hybridization analysis showed that expression patterns of sigmaR1
      mRNA in the ganglion cell layer were similar between diabetic and control mice.
      Western blot analysis suggested that levels of sigmaR1 in retina were similar
      between diabetic and control retinas. Immunohistochemical analysis of sigmaR1
      showed a similar pattern of sigmaR1 protein expression between control and
      diabetic retina. These studies demonstrate that sigmaR1 is expressed under
      hyperglycemic conditions in vitro and in vivo.

PMID- 12425941
TI  - Regionally selective alterations in expression of the alpha(1D) subunit
      (Ca(v)1.3) of L-type calcium channels in the hippocampus of aged rats.
AB  - Calcium currents through the L-type voltage-sensitive calcium channel (L-VSCC)
      are increased in neurons of area CA1 of the hippocampus in aged rats and rabbits.
      Furthermore, increases in mRNA for the pore forming subunit alpha(1D) (Ca(v)1.3)
      have been observed in the hippocampus of aged rats. We have studied the protein
      expression of the two pore forming subunits, alpha(1C) (Ca(v)1.2) and alpha(1D),
      of L-VSCCs in the hippocampus of young and aged rats. Here we report selective
      age-related changes in expression of alpha(1D) in the hippocampus. Specifically,
      we find that alpha(1D) protein is increased in area CA1 of aged rats while it is
      decreased in area CA3. Our data suggest that the altered calcium currents seen in
      aged animals may be due, at least in part, to alterations in the expression of
      the alpha(1D) subunit of the L-type calcium channel. These findings contribute to
      our understanding of the mechanisms responsible for changes in calcium
      homeostasis during aging.

PMID- 12425940
TI  - Independent roles of SOCS-3 and SHP-2 in the regulation of neuronal gene
      expression by leukemia inhibitory factor.
AB  - The neurokine leukemia inhibitory factor (LIF) initiates signaling through
      heterodimerization of the low affinity LIF receptor (LIFR) and gp130. Tyrosine
      759 of gp130 is required for the negative regulation of LIF-mediated signaling by
      both the protein tyrosine phosphatase SHP-2 and the suppressor of cytokine
      signaling-3 (SOCS-3). We find that SOCS-3 is expressed in the neuronal cell lines
      SN56 and IMR32 and negatively regulates LIF-stimulated neuronal gene expression.
      Studies using antisense oligonucleotides targeted to SHP-2 or SOCS-3 indicate
      that either protein can negatively regulate LIF-stimulated neuronal gene
      expression independently of the other. Mutagenesis of the cytoplasmic domain of
      gp130 demonstrates that the four signal transducer and activators of
      transcription (STAT) binding sites within gp130 are necessary for the induction
      of vasoactive intestinal peptide (VIP) and choline acetyltransferase (ChAT)
      reporter genes, with the sites surrounding tyrosines 905 and 915 (Y905 and Y915)
      being most important in gp130-mediated reporter gene expression. While there are
      four STAT binding sites within gp130, only those surrounding Y905 and Y915 can
      mediate STAT1 activation; these results indicate that STAT1 may be essential for
      normal gp130-stimulated VIP and ChAT expression. Additionally, the negative
      regulation of signaling mediated by Y759 of gp130 is dependent upon intact STAT
      sites within the receptor. This indicates that STAT signaling is necessary for
      LIF- and CNTF-stimulated VIP and ChAT expression and Y759 of gp130 mediates the
      activities of SHP-2 and SOCS-3, which act to negatively regulate STAT activity.

PMID- 12425942
TI  - Delayed and differential induction of p38 MAPK isoforms in microglia and
      astrocytes in the brain after transient global ischemia.
AB  - The p38 MAPK signaling pathway has been implicated in various pathological
      conditions of neuronal and non-neuronal cells. Here we report the differential
      induction of p38 MAPK isoforms, p38alpha and p38beta, in the adult gerbil brain
      following transient global ischemia. The p38alpha and p38beta kinase activities
      were gradually enhanced with the peak activity occurring around 2-4 days after
      ischemic insult. Immunohistochemical analysis revealed that p38alpha expression
      was increased as early as 4 h after ischemic insult and enhanced further reaching
      maximum induction around 4 days after ischemia. The induced p38alpha was
      concentrated in microglia in hippocampus as well as in frontal and parietal
      cortices of the brain, where significant neuronal damage was occurred. By
      contrast, immunostaining with anti-p38beta antibody indicated that p38beta was
      markedly induced in astrocytes in hippocampus around 4 days after ischemic
      insult, which lasted for the next several days. The differential induction of p38
      MAPK isoforms following transient global ischemia, especially the induction of
      p38alpha and p38beta MAPKs in microglia and astrocytes, respectively, in
      different time points after ischemic insult suggest distinct roles of p38 MAPK
      isoforms in post-ischemic brain.

PMID- 12425943
TI  - Sodium/calcium exchanger subtypes NCX1, NCX2 and NCX3 show cell-specific
      expression in rat hippocampus cultures.
AB  - Na(+)/Ca(2+) exchange activity is known to be expressed throughout the brain in
      both glial and neuronal tissue. mRNA of all three major subtypes of the mammalian
      Na(+)/Ca(2+) exchanger protein (NCX1, NCX2, NCX3) has been detected in most brain
      areas, albeit at varying densities. [The term 'subtype' is used for exchangers
      that are products of different genes (NCX1, NCX2, NCX3); 'isoform' is used for
      splice variants of a single gene product]. However, for lack of subtype specific
      labels, the cellular expression pattern of this transport protein has remained
      largely unknown. We have now used three subtype-specific antibodies, two
      monoclonal and one polyclonal, to identify the cellular distribution of the
      exchanger subtypes in rat hippocampus cell cultures. Surprisingly, we found
      little overlap for the expression of this membrane protein in different cell
      types. NCX1 labeled mainly the membranes of neuronal cells and their associated
      dendritic network. It was found in nearly all neuronal cells of the population
      growing in culture. In cultures maintained for more than 3 weeks, NCX1 was
      increasingly detected in the membrane of glia cells. NCX2 immunoreactivity was
      predominantly localized in various types of glia cells. It was also detected in
      the membranes of a few neuronal cell bodies but never in the dendritic network.
      In addition to labeling membranes, the NCX2 antibody strongly cross-reacted with
      an unidentified glial fibrillar protein. NCX3 expression appeared very low in
      hippocampus cultures and was restricted to a small subpopulation of neuronal
      cells. It was never detected in glia cells. Our results provide novel information
      on the cell-specific expression of the three Na(+)/Ca(2+) exchanger subtypes
      (NCX1, NCX2 and NCX3) in mammalian brain. These data may reflect functional
      differences among the subtypes that are not obvious from studies in recombinant
      cell lines and hence, may help to understand the functional role of specific glia
      or neuron-associated Ca(2+) transport systems.

PMID- 12425944
TI  - Insulin-responsive glucose transporters-GLUT8 and GLUT4 are expressed in the
      developing mammalian brain.
AB  - We investigated the spatial and temporal distribution of insulin-responsive
      facilitative glucose transporter isoforms GLUT4 and GLUT8 in the developing mouse
      brain. Employing Western blot analysis and specific antibodies, GLUT4 and GLUT8
      peaked during the suckling phase. Immunohistochemical analysis revealed the
      presence of GLUT4 mainly in neurites in sensory and motor areas of cortical and
      subcortical structures of the brain from P7 until adulthood. In contrast, GLUT8
      was found in the same anatomical structures within neurites and cell bodies. Most
      striking was the presence of GLUT8 in the cell bodies of the substantia nigra. We
      conclude that both GLUT4 and GLUT8 are present in murine brain, with highest
      concentrations noted during the suckling phase. These insulin-responsive isoforms
      may have a unique role in augmenting substrate delivery under conditions of
      increased demand.

PMID- 12425945
TI  - Activation of calpain in cultured neurons overexpressing Alzheimer amyloid
      precursor protein.
AB  - We have previously reported that overexpression of wild-type amyloid precursor
      protein (APP) in postmitotic neurons induces cleavage-dependent activation of
      caspase-3 both in vivo and in vitro. In this study, we investigated the mechanism
      underlying APP-induced caspase-3 activation using adenovirus-mediated gene
      transfer into postmitotic neurons derived from human embryonal carcinoma NT2
      cells. Overexpression of wild-type APP significantly increased intracellular
      (45)Ca(2+) content prior to the activation of caspase-3 in NT2-derived neurons.
      Chelation of intracellular Ca(2+) markedly suppressed APP-induced activation of
      caspase-3. Furthermore, calpain, a Ca(2+)-dependent cysteine protease, was
      activated in neurons overexpressing APP as assessed by increased levels of
      calpain-cleaved alpha-fodrin and autolytic mu-calpain fragments. Neither calpain
      nor caspase-3 was activated in neurons expressing an APP mutant defective in the
      Abeta(1-20) domain. Calpain inhibitors almost completely suppressed APP-induced
      activation of neuronal caspase-3. E64d, a membrane permeable inhibitor of
      calpain, significantly suppressed APP-induced neuronal death. These results
      suggest that overexpression of wild-type APP activates calpain that mediates
      caspase-3 activation in postmitotic neurons.

PMID- 12425946
TI  - Schizophrenia and Nogo: elevated mRNA in cortex, and high prevalence of a
      homozygous CAA insert.
AB  - Schizophrenia is a major psychiatric disorder which is hypothesized to result
      from abnormal neurodevelopment or neural changes in adulthood and possibly
      associated with altered gene expression. To search for genes overexpressed in
      schizophrenia, cDNA library subtractive hybridization experiments between post
      mortem human frontal cerebral cortices from schizophrenia individuals and
      neurological controls were carried out. One of the genes over-expressed in
      schizophrenia was identified as Nogo (also known as reticulon 4, RTN4, NI 250, or
      RTN-X), a myelin-associated protein which inhibits the outgrowth of neurites and
      nerve terminals. The elevated expression of Nogo mRNA in schizophrenia was
      confirmed by quantitative reverse transcription-polymerase chain reaction
      studies: 16.5 pg Nogo cDNA/microg total RNA in schizophrenia, and 10.2 pg Nogo
      cDNA/microg total RNA in controls (n=7; P=0.01, t-test for n<30). To identify
      possible polymorphisms in this gene, the Nogo nucleotide sequence was determined
      in a series of schizophrenia and control samples. The Nogo mRNA was found to
      contain a CAA insert polymorphism in the 3'-untranslated region. The prevalence
      of individuals homozygous for this CAA insert was significantly higher in
      schizophrenia compared to controls in genomic DNA samples extracted from post
      mortem brain and blood samples: 17/81 or 21% in schizophrenia and 2/61 or 3% in
      controls (P=0.0022, chi(2)- and Fisher's exact-tests). Because the 3'
      untranslated regions of eukaryotic genes are known to regulate gene expression,
      the increased frequency of the Nogo CAA insert in schizophrenia may contribute to
      abnormal regulation of Nogo gene expression, and may indicate a role for Nogo in
      disturbed neurodevelopment in schizophrenia.

PMID- 12425947
TI  - Decreased hyperlocomotion induced by MK-801, but not amphetamine and caffeine in
      mice lacking cellular prion protein (PrP(C)).
AB  - The cellular prion protein (PrP(C)) has been involved in several
      neurodegenerative disorders however it has been proposed that it is also be
      implicated in psychotic disorders. We investigated the effect of three
      psychotropic drugs in locomotor activity of PrP(C) knockout (Prnp(O/O)) and wild
      type mice. The NMDA receptor channel blocker MK-801 (0.25 mg/kg), the indirect
      dopamine agonist amphetamine (1 mg/kg) and the adenosine receptor antagonist
      caffeine (10 mg/kg) were administered i.p. after 60 min of habituation and
      locomotion was monitored for 3 h. Prnp(O/O) mice presented a diminished
      hyperlocomotor response to MK-801 treatment but normal response to amphetamine
      and caffeine compared to wild type mice. These results suggest that lack of
      PrP(C) leads to a functional alteration in the glutamatergic system, whereas the
      regulation of both dopaminergic and adenosinergic systems are preserved. Finally,
      lack of PrP(C) seems not to exacerbate the response to these psychotropic drugs,
      which modulate neurotransmitter systems possibly involved in schizophrenia and
      psychotic disorders.

PMID- 12425948
TI  - Glucuronidation of odorant molecules in the rat olfactory system: activity,
      expression and age-linked modifications of UDP-glucuronosyltransferase isoforms,
      UGT1A6 and UGT2A1, and relation to mitral cell activity.
AB  - The aim of the present study was to examine the glucuronidation of a series of
      odorant molecules by homogenates prepared either with rat olfactory mucosa,
      olfactory bulb or brain. Most of the odorant molecules tested were efficiently
      conjugated by olfactory mucosa, whereas olfactory bulb and brain homogenates
      displayed lower activities and glucuronidated only a few molecules. Important age
      related changes in glucuronidation efficiency were observed in olfactory mucosa
      and bulb. Therefore, we studied changes in expression of two UDP
      glucuronosyltransferase isoforms, UGT1A6 and UGT2A1, in 1-day, 1- and 2-week-, 3
      , 12- and 24-month-old rats. UGT1A6 was expressed at the same transcriptional
      level in the olfactory mucosa, bulb and brain, throughout the life period
      studied. UGT2A1 mRNA was expressed in both olfactory mucosa and olfactory bulb,
      in accordance with previous results [Mol. Brain Res. 90 (2001) 83], but UGT2A1
      transcriptional level was 400-4000 times higher than that of UGT1A6. Moreover,
      age-dependent variations in UGT2A1 mRNA expression were observed. As it has been
      suggested that drug metabolizing enzymes could participate in olfactory function,
      mitral cell electrical activity was recorded during exposure to different odorant
      molecules in young, adult and old animals. Age-related changes in the amplitude
      of response after stimulation with several odorant molecules were observed, and
      the highest responses were obtained with molecules that were not efficiently
      glucuronidated by olfactory mucosa. In conclusion, the present work presents new
      evidence of the involvement of UGT activity in some steps of the olfactory
      process.

PMID- 12425949
TI  - The effect of aging on p38 signaling pathway activity in the mouse liver and in
      response to ROS generated by 3-nitropropionic acid.
AB  - Since mitochondrial dysfunction is a major source of oxidative stress in aged
      tissues, we asked whether the basal activities of stress response signaling
      pathway(s) are indicative of oxidative stress in aged tissues. To address this
      issue we asked whether: (a). aging affects the basal activity of the p38 MAPK
      stress signaling pathway; (b). the p38 MAPK pathway is activated by 3
      nitropropionic acid (3-NPA), an inhibitor of complex II (succinic dehydrogenase)
      and generator of reactive oxygen species (ROS); (c). aging affects the response
      of the p38 alpha signaling pathway to 3-NPA. Our studies have shown that the
      basal kinase activities of p38 alpha, its upstream activator, MKK3, and its
      downstream substrate, ATF-2, are elevated in livers of aged C57BL/6 male mice and
      that these kinase activities, which are induced by 3-NPA in young livers, do not
      occur in aged livers. Furthermore, although aging does not affect their protein
      pool levels there are specific increases in phosphorylation of threonine residues
      in the p38 alpha and ATF-2 catalytic sites that might account for the increased
      basal level kinase activities in the aged livers. Our studies suggest that
      failure to respond to 3-NPA may be a factor in the susceptibility of aged tissue
      to oxidative damage, and support our hypothesis that aged tissues (especially
      liver) develop a state of chronic stress even in the absence of a challenge.

PMID- 12425950
TI  - Oxidative, glycoxidative and lipoxidative damage to rat heart mitochondrial
      proteins is lower after 4 months of caloric restriction than in age-matched
      controls.
AB  - In this investigation the effect of 4 months of 40% restriction of calories on
      defined markers of oxidative, glycoxidative or lipoxidative damage to heart
      mitochondrial proteins was studied. The protein markers assessed were N(epsilon)
      (carboxyethyl)lysine (CEL), N(epsilon)-(carboxymethyl)lysine (CML), N(epsilon)
      (malondialdehyde)lysine (MDA-lys), and the recently described (PNAS 98:69-74,
      2001) main constituents of protein carbonyls glutamic and aminoadipic
      semialdehydes. All these markers were measured by gas chromatography/mass
      spectrometry. The results showed that glutamic semialdehyde was present in rat
      heart mitochondria at levels 20-fold higher than aminoadipic semialdehyde. After
      4 months of caloric restriction, the levels of CEL, CML, MDA-lys and glutamic
      semialdehyde were significantly lower in the mitochondria from caloric restricted
      animals than in the controls. These decreases were not due to a lower degree of
      oxidative attack to mitochondrial proteins, since the rate of mitochondrial
      oxygen radical generation was not modified by 4 months of caloric restriction.
      The decreases in MDA-lys and CML were not due either to changes in the
      sensitivity of mitochondrial lipids to peroxidation since measurements of the
      fatty acid composition showed that the total number of fatty acid double bonds
      and the peroxidizability index were not changed by caloric restriction. The
      results globally indicate that caloric restriction during 4 months decreases
      oxidative stress-derived damage to heart mitochondrial proteins. They also
      suggest that these decreases are due to an increase in the capacity of the
      restricted mitochondria to decompose oxidatively modified proteins.

PMID- 12425951
TI  - No reduction of energy metabolism in Clk mutants.
AB  - Mutation in any of the four clock genes (clk-1, clk-2, clk-3, gro-1) causes an
      average slowing down of many temporal processes, and an increase of mean life
      span. The latter effect has been linked to the slow phenotype, and it has been
      reasoned that any reduction of the rate of living would reduce the load of
      oxidative damage, which is thought to drive the ageing process. To test this
      model we measured several parameters describing metabolic output in wild type
      worms and all four Clk mutants. We found no gross changes in metabolic output, as
      assessed from oxygen consumption and heat production rates, lucigenin-mediated
      light production capacity, ATP content, and lipofuscin autofluorescence. Catalase
      and superoxide dismutase (SOD) were variably altered, but not cooperatively, as
      would be expected to enhance reactive oxygen species (ROS) scavenging activity.
      Thus we conclude that the prolonged life span of Clk mutants cannot be attributed
      to reduced metabolic rate or an increased activity of the major antioxidant
      enzymes catalase and SOD.

PMID- 12425952
TI  - The mortality rate as a function of accumulated deficits in a frailty index.
AB  - In a representative Canadian population survey (n=66589) the proportion of
      accumulated deficits in a frailty index showed a linear relationship with
      mortality in a log-log plot, such that the mortality rate was a power-law
      function of the frailty index. Represented in this way, the frailty index readily
      summarizes individual differences in health status. The exponent and amplitude
      parameters of the power function are gender specific, reflecting that while, on
      average, women accumulate more deficits than men of the same age, their risk of
      mortality is lower. The dependence of the mortality rate on the frailty index
      points to the merit of the index as a simple and accessible tool for estimating
      individual risks of mortality.

PMID- 12425953
TI  - Lifespan in captive baboons is heritable.
AB  - The effects of aging are evident in multiple organ systems, tissues, cell types,
      and molecules; all complex phenotypes affected by multiple shared and unique
      environmental factors and genes, which makes identifying the role of genetics in
      human aging difficult. Researchers have used yeast, nematodes, fruit flies, and
      mice to search for genes that influence the aging process. Given the phylogenetic
      distance and anatomic and physiologic dissimilarities of these organisms from
      humans, directly extrapolating these results to our species is problematic.
      However, nonhuman primates have a high degree of genetic, anatomic and
      physiologic similarity with humans and, thus, they may assist in the detection,
      characterization, and identification of genetic and environmental influences on
      human aging. Our goal is to demonstrate that effects of genes on variation in
      lifespan, a surrogate measure of aging, can be detected in a nonhuman primate
      species. Using variance component analysis, heritability of age at death was
      estimated to be 0.23+/-0.08 (P=0.0003) in 674 baboons from the Southwest
      Foundation for Biomedical Research (SFBR). This research demonstrates that
      lifespan is under partial genetic control. Given these findings, we believe that
      the baboon has potential as a model of human aging.

PMID- 12425954
TI  - Senescence-associated decline in hepatic peroxisomal enzyme activities
      corresponds with diminished levels of retinoid X receptor alpha, but not
      peroxisome proliferator-activated receptor alpha.
AB  - Aging is associated with alterations in hepatic peroxisomal metabolism and
      susceptibility to hepatocarcinogenicity produced by agonists of peroxisome
      proliferator-activated receptor alpha (PPAR alpha). Mechanisms involved in these
      effects are not well understood. However, as a heterodimer with retinoid X
      receptor alpha (RXR alpha), PPAR alpha regulates transcription of genes involved
      in oxidative stress, cell proliferation and apoptosis. Modulating these important
      cell functions as a result of aging may be responsible for altered hepatic
      peroxisomal responses in the senescent liver. Therefore, we investigated hepatic
      apoptosis, and peroxisomal beta-oxidation activity, a major source of H(2)O(2),
      as well as the activity of the peroxisomal anti-oxidant enzyme catalase, in male
      Fischer-344 rats of four age groups (4, 10, 50 and 100 week old). We further
      quantified protein levels of both PPAR alpha and RXR alpha in these animals. Data
      show that peroxisomal beta-oxidation and catalase activities were significantly
      lower in livers of the 100 week old animals compared with other age groups, while
      percentage of apoptotic hepatocytes were identical in all animal age groups.
      However, aging had no effect on hepatic PPAR alpha protein levels. In the
      senescent group, the level of decline in both peroxisomal enzyme activities of
      30% was surprisingly similar to the decline observed in the hepatic expression of
      the RXR alpha protein. Results from this study suggest that alterations in
      peroxisomal metabolism observed in the senescent liver may be a result of the
      decline in the availability of RXR alpha receptor, and not the primary PPAR alpha
      receptor. On the other hand, PPAR alpha-independent mechanisms appear to play a
      role in controlling apoptosis in the senescent liver.

PMID- 12425955
TI  - Changes in peripheral blood lymphocyte subsets in elderly subjects are associated
      with an impaired function of the hypothalamic-pituitary-adrenal axis.
AB  - A growing body of evidence indicates that ageing brings a progressive disruption
      in the immune and endocrine systems. However, very few reports have correlated
      the changes in the immune system with the endocrine function in the elderly. The
      aim of the present study was to investigate the changes occurring in the
      peripheral blood lymphocyte subpopulations with age and correlate them with the
      hypothalamic-pituitary-adrenal (HPA) function. We determined the peripheral blood
      lymphocyte phenotype and the T cell receptor usage by flow cytometry analysis.
      The HPA function was evaluated by the basal serum levels of adrenal steroids and
      the response to stimulation with a low-dose ACTH. In the elderly, we observed a
      decrease of major T subsets together with an increase of NK cells and activated T
      cells. With regard to the HPA function, the most significant decline was found in
      dehydroepiandrosterone (DHEA) and dehydroepiandrosterone-sulphate (DHEAS). A
      close correlation between immune changes with ageing and DHEA response to ACTH
      stimulation was found. The present study showed an inverse correlation of
      lymphocyte changes with the plasma levels of steroids, especially DHEA and its
      metabolite, DHEAS. This association was not found for other steroids and points
      for the possibility of using DHEA to correct the immunological decline associated
      with ageing.

PMID- 12425956
TI  - Infrequent occurrence of age-dependent changes in CpG island methylation as
      detected by restriction landmark genome scanning.
AB  - Hypermethylation of CpG islands, resulting in the inactivation of tumor
      suppressor genes, is an early event in the development of some malignancies.
      Recent studies suggest that this abnormal methylation may be a function of aging.
      The number of CpG islands that methylate with age is unknown. We used restriction
      landmark genome scanning (RLGS) to approximate the extent to which CpG islands
      change methylation status during aging. Comparison of more than 2000 loci in T
      lymphocytes isolated from newborn, middle age, and elderly people revealed that
      29 loci ( approximately 1%) changed methylation status during aging, with 23
      increasing methylation, and six decreasing. The same subset also changed
      methylation status with age in the esophagus, lung, and pancreas, but in variable
      directions. Virtual genome scanning identified one of these loci as a member of
      the forkhead family, recently implicated in aging, and another as an EST
      fragment. The methylation status of both correlated with level of expression.
      Confirming studies in multiple tissues from normal and DNMT1(+/-) mice
      demonstrated only one age dependent change in the methylation of more than 2000
      loci, occurring in liver and kidney. These results indicate that the methylation
      status of the majority of CpG islands in both mice and humans is tightly
      controlled during aging, and that changes are infrequent and in humans confined
      to a specific subset of genes.

PMID- 12425957
TI  - Mammary stem cell repertoire: new insights in aging epithelial populations.
AB  - The proliferative lifespan of mammary stem cells was examined in serially
      transplanted clonal-dominant epithelial populations. Five successive transplant
      generations were done. The epithelial cell number in each outgrowth expands
      approximately 500-fold in nulliparous hosts and approximately 10000-fold in
      impregnated hosts. Despite this, all resulting mammary outgrowths showed lineal
      identity with the original. Growth senescence was observed in some implants
      beginning at the third generation in impregnated recipients. The ability of an
      individual implant to support ductal morphogenesis and also secretory lobule
      development decayed at independent rates. Individual implants from a single
      clonal-dominant outgrowth occasionally gave rise to markedly different ductal
      development within the same host indicating an epithelial cell autonomous
      mechanism in ductal patterning. Both premalignant and malignant populations
      appeared focally within the aging transplants. These populations were also
      lineally related to the original outgrowth supporting the conclusion that the
      primary growth was derived clonally from one or a few lineally related
      antecedents. The premalignant and malignant descendant populations no longer
      exhibit growth senescence suggesting that they are supported by a perpetually
      self-renewing progenitor. Our evidence indicates that a single mammary cell may
      have the capacity to self-renew through five transplant generations. Even some
      sixth generation implants show vigorous growth.

PMID- 12425958
TI  - Age-related changes in the induction of DNA polymerases in rat liver by gamma-ray
      irradiation.
AB  - DNA polymerase activities related to DNA repair were examined in the livers of
      young (6-month-old) and aged (27-month-old) rats irradiated with gamma-rays. The
      activity of DNA polymerase alpha was little changed in the livers of gamma-ray
      irradiated rats, while DNA polymerases beta and gamma were induced in the livers
      of young and aged rats exposed by gamma-ray irradiation. These enzymes were
      induced from 2 to 6 h after irradiation of young and aged rats, respectively,
      although the induction in aged rats was weak. DNA polymerase beta activity in the
      livers of young rats irradiated with gamma-rays was 2-fold that in aged rats.
      Similarly, DNA polymerase gamma activity in the livers of young rats subjected to
      gamma-ray irradiation was 3-fold that in aged rats. The induction of
      proliferating cell nuclear antigen (PCNA) in the livers of aged rats irradiated
      with gamma-rays was also delayed compared with young rats. These results indicate
      that the decline in repair activity in aged rats leads to the accumulation of
      oxidative damage and DNA mutations in aged tissues.

PMID- 12425959
TI  - Assessment of the potential genotoxic risk of Phyllantus orbicularis HBK aqueous
      extract using in vitro and in vivo assays.
AB  - Phyllanthus orbicularis HBK is an endemic Cuban plant whose aqueous extract has
      been proposed as an effective drug for the treatment of viral diseases. In
      addition, antimutagenic properties of this extract have also been reported. In
      the present study, the genotoxicity of this plant extract was assessed using
      different in vitro and in vivo assays. Results from SOS gene induction, gene
      reversion and conversion, and SMART assays clearly show that P. orbicularis
      aqueous extract does not induce either primary DNA damage or mutation.
      Additionally, no statistically significant difference was found in the percentage
      of chromosomal aberrations in Chinese hamster ovarian (CHO) cells treated with
      the plant extract. On the contrary, micronuclei and abnormal anaphase were
      induced by this extract in CHO cells. This genotoxic effect was related to a high
      cytotoxicity. Single spots were detected in the SMART assay. These results point
      to a possible aneugenic effect of the P. orbicularis aqueous extract at cytotoxic
      doses which are much higher than those seen by their antiviral and antimutagenic
      activities.

PMID- 12425960
TI  - Glutathione S-transferase cytosolic isoforms as biomarkers of polychlorinated
      biphenyl (Arochlor-1254) experimental contamination in rainbow trout.
AB  - At the present work, different groups of rainbow trouts have been
      intraperitoneally treated with a polychlorinated biphenyls commercial mixture
      (Arochlor-1254) at three doses (5, 20 and 70 mg PCBs/ kg body weight) and they
      have been sampled at 0 (injection moment), 3, 6 and 9 weeks after xenobiotic
      exposure. Purification and characterization of the cytosolic isoforms of
      glutathione S-transferases from three different rainbow trout organs (liver,
      kidney and gills) have been developed in order to establish the existence of some
      enzymatic induction process. According to the enzymatic activity levels and
      protein content, liver samples showed the highest glutathione S-transferases
      induction process, and resulting dose and time dependent. Directly related, HPLC
      results from liver retained-affinity purified samples determined that this
      process was mainly associated to a pi-class related isoenzyme. Only some of the
      different GST isoenzymes from rainbow trout liver cytosol showed to be
      specifically induced by the polychlorinated biphenyls treatment, rendering these
      isoenzymes as valuable biomarkers for exposure to these environmental pollutants.

PMID- 12425961
TI  - Stable transfection of Chinese hamster ovary cells with glutamate-cysteine ligase
      catalytic subunit cDNA confers increased resistance to tert-butyl hydroperoxide
      toxicity.
AB  - Glutathione (GSH) plays vital roles in antioxidant defense mechanisms. To
      determine whether gene transfection strategies could be used to enhance GSH
      synthetic capacities and protect mammalian cells against oxidant stresses, we
      used liposome-mediated transfer of the cDNA for rat glutamate-cysteine ligase
      (GLCL) catalytic subunit (GLCLC) to transfect Chinese hamster ovary (CHO) cells.
      CHO cell lines (CHOhi) with stably enhanced GLCL activities (14.61+/-0.82 mU/mg
      protein) and greater GSH contents (45.7+/-1.37 nmol/mg protein) than observed in
      wild-type CHO K1 cells (0.26+/-0.01 mU/mg protein and 20.7+/-1.15 nmol/mg
      protein, respectively) were developed and were confirmed to have integrated the
      GLCLC cDNA into their genomic DNA and to exhibit increased GLCLC mRNA levels, by
      Southern and northern analyses, respectively. Similarly treated and selected CHO
      cell lines that showed no increases in GLCL activities (CHOun) were studied as
      controls for the effects of GLCLC transgene expression. CHOhi cells showed
      significantly greater resistance to oxidant stress caused by exposure to tert
      butyl hydroperoxide (tBuOOH) than did CHO or CHOun cells. Twenty-four hours after
      exposure to 400 or 800 microM tBuOOH, wild-type CHO cells had released more
      cellular lactate dehydrogenase (67.3+/-14.5% and 94.4+/-2%) than had CHOhi cells
      (5.11+/-0.5% and 46.0+/-5.4%, n=4, P<0.05). The present data demonstrate improved
      resistance to oxidant injury of CHO cells stably transfected with the GLCLC cDNA.
      Although additional enhancements in GLCL activities are possible by transfection
      with cDNAs for both catalytic and regulatory GLCL subunits, our results
      demonstrate that the increases in GLCL activities that can be attained by
      transfection of the GLCLC cDNA alone can enhance cellular antioxidant defense
      function.

PMID- 12425962
TI  - Temporal changes in cytokine gene expression profiles induced in mice by
      trimellitic anhydride.
AB  - Prolonged (13 day) topical exposure of BALB/c strain mice to the chemical
      respiratory allergen trimellitic anhydride (TMA) induces a selective T helper
      (Th) 2 profile of cytokine secretion in cells isolated from the draining lymph
      node. The ability of chemical respiratory allergens to elicit preferential type 2
      immune responses is a distinguishing characteristic and provides the theoretical
      basis for cytokine fingerprinting, a novel approach to hazard identification.
      This study aimed to further characterize the cytokine expression profile induced
      by TMA, and to investigate the kinetics of cytokine production at both the
      protein and mRNA level by comparison of acute (3 day) and chronic (13 day)
      exposure regimes. Acute exposure resulted in the expression of high levels of
      mRNA for both Th1- and Th2-type cytokines, including interleukins 4, 10, 15 (IL
      4, IL-10, IL-15) and interferon gamma (IFN-gamma), and the inflammatory cytokine
      IL-6, as determined by ribonuclease protection assay (RPA). However, following
      chronic exposure marked down-regulation of message for IL-6 and IFN-gamma was
      observed along with concomitant up-regulation of IL-4 and IL-10 expression. These
      cytokine mRNA profiles were broadly paralleled at the protein level. There was
      also a marked increase with time of mRNA for the Th2 cytokine IL-9, a cytokine
      not associated previously with chemical allergy. These data show that as the
      immune response to TMA develops, the cytokine gene expression profile of allergen
      activated lymph node cells evolves from a mixed Th1/Th2 phenotype to a more
      polarized Th2 profile.

PMID- 12425963
TI  - Hormonal and genotoxic activity of resveratrol.
AB  - Resveratrol (RES) is a natural polyphenol present in red wines and various human
      food items. The estrogenic activity of RES was demonstrated in two in vitro assay
      systems, i.e. binding to human estrogen receptor alpha and stimulation of MCF-7
      cell proliferation. To investigate the inhibition of cell proliferation observed
      at high concentrations of RES, we analyzed the compound for genotoxic potential.
      RES induced cellular toxicity, micronuclei, and metaphase chromosome displacement
      in L5178Y mouse lymphoma cells. Likewise, the induction of micronuclei was
      observed in Chinese hamster V79 cells. Determination of kinetochore signals in
      micronuclei and cell cycle analysis suggested that RES did not cause a direct
      disturbance of mitosis. In support of this notion, cell-free tubulin
      polymerization studies indicated no direct effect of RES on microtubule assembly.
      According to an estimation of daily intake and bioavailability, concentrations
      that were found genotoxic in vitro might be reached in human exposure. On the
      other side, the estrogenic acitivity might be beneficial. Therefore, further
      investigations of mechanisms, possibly including animal models, would be
      desirable to clarifiy a potential risk for humans.

PMID- 12425964
TI  - Organophosphate induced delayed neuropathy in genetically dissimilar chickens:
      studies with tri-ortho-cresyl phosphate (TOCP) and trichlorfon.
AB  - Measurements of plasma cholinesterase (pl.ChE), brain cholinesterase (Br.ChE) and
      brain Neuropathy Target Esterase (Br.NTE) were made in three different lineages
      of chickens. All birds received toxicants through gavage in a single oral dose
      between 08:00 and 09:00 h, after overnight fast. Babcock chickens were treated
      with 800 mg/kg tri-ortho-cresyl phosphate (TOCP) or 80 mg/kg trichlorfon. The
      TOCP group had 82% Br.NTE inhibition, when compared to the control group, and no
      birds displayed symptoms of clinical organophosphate-induced delayed neuropathy
      (OPIDN). Hy-line w36 lineage chickens were given 1600 mg/kg TOCP and despite this
      higher dose, Br.NTE inhibition was similar that presented by Babcock chickens.
      Isabrown chickens were given 1600 mg/kg TOCP or 80 mg/kg trichlorfon. At 36 h all
      trichlorfon treated birds had from 80 to 90% inhibition of Pl.ChE and Br.ChE,
      when compared to controls. However, Br.NTE was inhibited less than 20%, and there
      were no clinical signs of OPIDN. All TOCP treated isabrown chickens had more than
      80% Br.NTE inhibition while one of them exhibited just light signs of OPIDN, two
      chickens became totally paralyzed. This finding suggested that chicken strain was
      important in the appearance of OPIDN. In addition, 70-80% of NTE inhibition was
      necessary but was not sufficient to produce OPIDN in chickens, since babcock and
      hy-line w36 chickens exhibited NTE inhibition in the range of 70-80% without
      clinical signs of OPIDN.

PMID- 12425965
TI  - Activation of early signaling transcription factor, NF-kappaB following low-level
      manganese exposure.
AB  - Occupational and environmental exposure to manganese (Mn(2+)) is an increasing
      problem. It manifests neuronal degeneration characterized by dyskinesia
      resembling Parkinson's disease. The study was performed to test the hypotheses
      whether exposure to Mn(2+) alters cellular physiology and promotes intracellular
      signaling mechanism in dopaminergic neuronal cell line. Since transcription
      factors have been shown to play an essential role in the control of cellular
      proliferation and survival, catecholaminergic rich pheochromocytoma (PC12) cells
      were used to measure changes in the DNA binding activities of nuclear factor
      kappa B (NF-kappaB) by electrophoretic mobility shift assay (EMSA) following
      Mn(2+) (0.1-10 microM) exposure. Cells that were exposed to Mn(2+) produced five
      fold-activation of transcription factor NF-kappaB DNA binding activity. This
      remarkable increase was seen within 30-60 min period of Mn(2+) exposure.
      Activation of NF-kappaB DNA binding activity by Mn(2+) at 1.0 microM correlated
      with proteolytic degradation of the inhibitory subunit IkappaB(alpha) as
      evidenced in cytosol. Additional experiments on NF-kappaB reporter gene assay
      also showed increased NF-kappaB gene expression at 1.0 and 5.0 microM Mn(2+) and
      this was completely blocked in the presence of NF-kappaB translocation inhibitor,
      IkappaB(alpha)-DN supporting that NF-kappaB induction occurred during Mn(2+)
      exposure. In addition, Mn(2+) exposure to PC 12 cells led to activation of signal
      responsive mitogen activated protein kinase kinase (MAPKK). These results suggest
      that Mn(2+) at a low dose appears to induce the expression of immediate early
      gene, NF-kappaB through MAPKK by a mechanism in which IkappaB(alpha)
      phosphorylation may be involved.

PMID- 12425966
TI  - Acute ventilatory and circulatory reactions evoked by nicotine: are they
      excitatory or depressant?
AB  - Either excitatory or inhibitory cardio-respiratory responses induced by nicotine
      have been reported. We evaluated the joint and separate contributions of
      peripheral arterial chemoreceptors and pulmonary vagal afferences to nicotine
      induced cardio-respiratory responses in 11 pentobarbitone-anaesthetized cats.
      Nicotine, given i.v. in doses of from 1 to 200 microg/kg, evoked dose-dependent
      transient increases in tidal volume (VT) and arterial blood pressure (BP), but
      the highest doses evoked brief apnoea, immediately followed by intense
      hyperventilation, as well as discrete early hypotension followed by late
      hypertension. Bilateral section of the aortic and carotid nerves abolished all
      hyperventilatory responses to nicotine, giving way to apnoea followed by few
      cycles of reduced VT and profound hypotension followed by slight hypertension in
      response to intermediate doses (50-100 microg/kg). Subsequent bilateral vagotomy
      (BV) suppressed apnoeic and hypotensive responses. In other cats initially
      subjected to BV, only increases in VT and BP were observed in response to
      nicotine, effects which were no longer observed after additional carotid and
      aortic deafferentation. These data suggest that excitatory effects of nicotine on
      respiration and BP are reflexes evoked by stimulation of peripheral arterial
      chemoreceptors, while inhibitory effects are also reflex responses but evoked
      from stimulation of pulmonary vagal afferences.

PMID- 12425967
TI  - Effects of tryptophan depletion on central and peripheral chemoreflexes in man.
AB  - Klein (Arch. Gen. Psychiatry 50, 306-317, 1993) suggests that panic attacks are
      the result of a defective 'suffocation alarm' threshold that presents with carbon
      dioxide (CO(2)) hypersensitivity, exaggerated ventilatory response and panic in
      panic disorder (PD) patients. Serotonergic deficiencies enhance this ventilatory
      response in PD patients, as per 'suffocation alarm' theory predictions,
      suggesting that serotonin (5-HT) normalizes the ventilatory response. Other
      research supports a serotonin system-mediated stimulation of ventilation.
      Knowledge of 5-HT's role on ventilatory output and its neurophysiological sources
      impacts on the 'suffocation alarm' theory validity and predictive value. We used
      tryptophan depletion (TRP-) in concert with a modified Read rebreathing test to
      determine the effect of deficient serotonergic modulation on the central and
      peripheral chemoreflex threshold and sensitivity of response to CO(2) in 11
      healthy men. TRP- did not affect central or peripheral chemoreflex threshold or
      sensitivity of response to CO(2). However, basal ventilation was significantly
      elevated during TRP-. In contrast to 'suffocation alarm' theory predictions,
      decreased 5-HT neurotransmission does not significantly affect the respiratory
      chemoreflex response to CO(2), impacting on non-chemoreflex drives to breathe.
      Panic associated respiratory abnormalities may be related to defective 5-HT
      modulation of non-chemoreflex drives to breathe, unrelated to any respiratory
      chemoreflex abnormality.

PMID- 12425968
TI  - Muscimol inhibition of medullary raphe neurons decreases the CO2 response and
      alters sleep in newborn piglets.
AB  - Medullary raphe neurons are chemosensitive in vitro (Wang et al., J. Physiol.
      Lond. 511 (1998)), are involved in the ventilatory response to CO(2) in vivo
      (Dreshaj et al., Respir. Physiol. 111 (1998); Nattie and Li, J. Appl. Physiol. 90
      (2001)), and are abnormal in many Sudden Infant Death Syndrome (SIDS) victims
      (Panigrahy et al., J. Neuropathol. Exp. Neurol. 59 (2000)). In this study we
      determine whether the ventilatory response to CO(2) is altered when medullary
      raphe neuronal function is focally and reversibly inhibited in chronically
      instrumented newborn piglets. Ventilation was measured by whole body
      plethysmography in room air and in 5% CO(2) before and during microdialysis of
      muscimol, a gamma-amino butyric acid (GABA(A)) receptor agonist, into the
      medullary raphe. Muscimol (10 mM in the dialysate), had no effect on eupneic
      ventilation, but reduced significantly the CO(2) response by 17% during
      wakefulness. Sleep cycling was also disrupted, as characterized by a significant
      increase in the percentage of time spent awake and a significant decrease in the
      percentage of time spent in NREM sleep. Disturbances of medullary raphe function
      can alter central chemoreception and normal sleep architecture, which may
      contribute to the pathogenesis of SIDS.

PMID- 12425969
TI  - Thermal and respiratory control in young rats with altered caloric intake during
      postnatal development.
AB  - We asked to what extent differences in caloric intake during the first postnatal
      weeks may modify thermal and respiratory control of 1-month old rats. Large-size
      (Large) and small-size (Small) rats were obtained by raising rats in,
      respectively, small (6 pups) and large (16 pups) litters. In Small, the rate of
      oxygen consumption (V(O(2))/kg) was less than in Large during the first 2-3
      weeks, and higher thereafter, when the thermogenic needs to maintain body
      temperature (Tb) increased. At day 31, when body weight in Small was
      approximately 80% of Large, Small maintained Tb in the cold with higher
      V(O(2))/kg than Large. The total uncoupling protein of the brown adipose tissue
      was unchanged. Also pulmonary ventilation (VE/kg) was higher in Small,
      maintaining the proportionality with V(O(2)). Lung weight in Small was reduced in
      proportion to body weight, with higher protein-DNA ratio. The compliances of the
      respiratory system and lungs, normalized by body weight, and the hyperventilatory
      responses to hypoxia or hypercapnia, expressed as % increase in VE/V(O(2)), were
      similar in Small and Large. Differences between Small and Large were reduced or
      no longer present in a group of Small rats raised until their body weight was as
      in Large. We conclude that rather important developmental differences in caloric
      intake and metabolic level, in otherwise healthy rats, had no long-term carry
      over effects in the developmental processes of respiratory and thermal control,
      other than the effects strictly attributable to the alterations in body size.

PMID- 12425970
TI  - Dynamics of oxygen uptake following exercise onset in rat skeletal muscle.
AB  - Technical limitations have precluded measurement of the V(O(2)) profile within
      contracting muscle (mV(O(2))) and hence it is not known to what extent V(O(2))
      dynamics measured across limbs in humans or muscles in the dog are influenced by
      transit delays between the muscle microvasculature and venous effluent.
      Measurements of capillary red blood cell flux and microvascular P(O(2))
      (P(O(2)m)) were combined to resolve the time course of mV(O(2)) across the rest
      stimulation transient (1 Hz, twitch contractions). mV(O(2)) began to rise at the
      onset of contractions in a close to monoexponential fashion (time constant, J =
      23.2 +/- 1.0 sec) and reached it's steady-state value at 4.5-fold above baseline.
      Using computer simulation in healthy and disease conditions (diabetes and chronic
      heart failure), our findings suggest that: (1) mV(O(2)) increases essentially
      immediately (< 2 sec) following exercise onset; (2) within healthy muscle the J
      blood flow (thus O(2) delivery, J Q(O(2)m)) is faster than JmV(O(2)) such that
      oxygen delivery is not limiting, and 3) a faster P(O(2)m) fall to a P(O(2)m)
      value below steady-state values within muscle from diseased animals is consistent
      with a relatively sluggish Q(O(2)m) response compared to that of mV(O(2)).

PMID- 12425971
TI  - Oxygen uptake kinetics during high-intensity arm and leg exercise.
AB  - The purpose of the present study was to examine the oxygen uptake kinetics during
      heavy arm exercise using appropriate modelling techniques, and to compare the
      responses to those observed during heavy leg exercise at the same relative
      intensity. We hypothesised that any differences in the response might be related
      to differences in muscle fibre composition that are known to exist between the
      upper and lower body musculature. To test this, ten subjects completed several
      bouts of constant-load cycling and arm cranking exercise at 90% of the mode
      specific V(O(2)) peak. There was no difference in plasma [lactate] at the end of
      arm and leg exercise. The time constant of the fast component response was
      significantly longer in arm exercise compared to leg exercise (mean+/-S.D., 48+/
      12 vs. 21+/-5 sec; P < 0.01), while the fast component gain was significantly
      greater in arm exercise (12.1+/-1.0 vs. 9.2+/-0.5 ml min(-1) W(-1); P < 0.01).
      The V(O(2)) slow component emerged later in arm exercise (126+/-27 vs. 95+/-20
      sec; P < 0.01) and, in relative terms, increased more per unit time (5.5 vs. 4.4%
      min(-1); P < 0.01). These differences between arm crank and leg cycle exercise
      are consistent with a greater and/or earlier recruitment of type II muscle fibres
      during arm crank exercise.

PMID- 12425972
TI  - Reproducibility of the heart rate response to low-strain Valsalva manoeuvre in
      healthy subjects.
AB  - To elucidate whether the intrastrain cardio-acceleration and cardio-deceleration
      responses to low-strain Valsalva manoeuvre at expiratory pressures 10 and 20 mmHg
      (VM10,VM20) are reproducible, a beat-to-beat heart rate study was undertaken in
      46 subjects (40 male undergraduates aged 19-25 years and six laboratory workers
      (four females and two males aged 28-55 years). The intensity of the heart rate
      response (HRR) was assessed by a ratio of the mean value of the pre-strain heart
      rate (Valsalva means' ratio VMR). In each subject the HRR to VM10 and VM20 was
      measured by repeating each manoeuvre three times. Reproducibility was evaluated
      on a short-term (1 h), medium-term (1 and 6 months), and long-term (6 and 11
      years) basis. With the individual differences the initial short-term
      reproducibility study revealed either an cardio-acceleration or cardio
      deceleration response to VM10 and VM20, which persisted well in the repeated
      tests. On the ground of this result three individual modes of HRRs to VM10 and
      VM20 were distinguished: (i) Mode A, a deceleration response appeared both to
      VM10 and VM20; (ii) Mode B, a deceleration response appeared to VM10 and an
      acceleration response to VM20; (iii) Mode C, an acceleration response appeared
      both to VM10 and VM 20. All of these modes, as well as the separate acceleration
      and deceleration responses, were well reproducible at any cited time points. We
      suggest that the individual modes of HRR are induced by different states of
      autonomic cardiovascular reactivity: Mode A probably expresses a
      parasympathotonic (vagotonic), Mode C--a sympathotonic, and Mode B--an
      intermediate autonomic state. Thus, the individual modes of HRR to VM10 and to
      VM20 could be used as a method of non-invasive determination of cardiovascular
      autonomic reactivity.

PMID- 12425973
TI  - A simple breathing circuit to maintain isocapnia during measurements of the
      hypoxic ventilatory response.
AB  - We report the development and testing of a simple breathing circuit that
      maintains isocapnia in human subjects during hypoxic hyperpnea. In addition, the
      circuit permits rapid switching between two gas mixtures with different partial
      pressures of oxygen. Eleven volunteers breathed repeated cycles of exposure to
      air (2 min of 21% O(2), balance N(2)) and hypoxia (2 min of 8.3+/-0.1% O(2),
      balance N(2)). Hypoxia induced significant increases in minute ventilation,
      breathing frequency and tidal volume (P < 0.05) that were consistent over
      repeated cycles of hypoxia (P > 0.1, one-way ANOVA). The system successfully
      maintained isocapnia in all subjects, with an average change in end-tidal CO(2)
      of only -0.2 mmHg during hyperventilation in hypoxia (range 0.4 to -0.8 mmHg).
      This system may be suitable for repeated tests of the hypoxic ventilatory
      response (HVR) and may prove useful for exploring intra- and inter-individual
      variability of HVR in humans.

PMID- 12425974
TI  - Intravascular inhomogeneous oxygen distribution in microvessels: theory.
AB  - Cross-sectional oxygen distribution in microvessels in most previous studies has
      been assumed to be homogeneous. Recent studies using phosphorescence quenching
      microscopy or microspectrophotometry showed a decline in oxygen profile near the
      arterial wall. In this study we performed theoretical analysis of intravascular
      P(O(2)) and S(O(2)) profiles in arterioles by using a radial diffusion model with
      a constant oxygen efflux from the vascular lumen, taking intravascular flow
      distribution into account. Theoretical calculations indicated that radial oxygen
      diffusion and a laminar flow pattern would create inhomogeneous intravascular
      oxygen profile with a decline toward the arterial wall. As mean blood flow
      velocity became lower, the difference between the centerline oxygen level and the
      inner surface level became larger. In conclusion, it is suggested that oxygen
      efflux from the vascular lumen and less convective supply near the vascular wall
      create a decline in P(O(2)) as well as S(O(2)) toward the arterial wall.

PMID- 12425975
TI  - Role of 5-HT2A/C receptors in serotonergic modulation of respiratory motor output
      during tadpole development.
AB  - We tested the hypothesis that 5-HT(2A/C) receptors contribute to the modulation
      of respiratory motor output elicited by serotonin bath-application in the in
      vitro brainstem preparation from bullfrog tadpoles. Preparations were superfused
      with (1) a selective 5-HT(2A/C) receptor agonist (DOI, 0.5-25 microM) or (2) 5-HT
      in presence of a non-selective 5-HT(2A/C) receptor antagonist (methysergide
      maleate, 10 microM). Stage-related differences in 5-HT(2A/C) modulation were
      assessed by performing experiments on two groups: pre- and post-metamorphic
      tadpoles. 5-HT(2A/C) receptor activation with DOI did not alter either gill or
      lung burst frequency. Methysergide did not prevent the gill burst frequency
      attenuation elicited by 5-HT. Our results show no apparent contribution of the 5
      HT(2A/C) receptor subtypes to the serotonergic modulation of either gill- or lung
      related neural activity in either group. While 5-HT(2A/C) receptors are involved
      in the modulation of respiratory motor output in mammals, these receptor subtypes
      do not appear to play a significant role in this species.

PMID- 12425977
TI  - Modeling tree water flow as an unsaturated flow through a porous medium.
AB  - The electric circuit analogy has had a profound influence on how tree
      physiologists measure, model and think about tree water flow. For example,
      previous models that attempt to account for changes in saturation use the
      electric circuit analogy to define capacitance as the change in saturation per
      change in pressure. Given that capacitance is constant, this relationship implies
      that subjecting a block of wood to a pressure of -2.5 MPa for 2 min results in
      the same change in saturation as subjecting the same block to the same pressure
      for 2 days. Given the definition of capacitance, it is unclear how the electric
      circuit analogy could be used to predict changes in saturation separately from
      changes in pressure. The inadequacies in the electric circuit analogy discussed
      in this paper necessitate a new theory of tree water flow that recognizes the
      sapwood as being a porous medium and explicitly deals with the full implications
      of the unsaturated flow occurring in the sapwood. The theory proposed in this
      paper combines the Cohesion theory with a mathematical theory of multiphase flow
      through porous media. Based on this theory, both saturated and unsaturated tree
      water flow models are presented. Previous partial differential equation models of
      tree water flow based on the electric circuit analogy are shown to be
      mathematically equivalent to the model of saturated porous flow. The unsaturated
      model of tree water flow explicitly models the pressure profile and the rates of
      change in saturation and specific interfacial area (a measure of how the water in
      the unsaturated sapwood is partitioned between mobile and immobile components).
      The unsaturated model highlights the differences between saturated and
      unsaturated flow and the need to measure the variables governing tree water flow
      at higher spatial and temporal resolutions.

PMID- 12425978
TI  - Parameterizing a model of Douglas fir water flow using a tracheid-level model.
AB  - The theory of tree water flow proposed in Aumann & Ford (submitted) is assessed
      by numerically solving the model developed from this theory under a variety of
      functional parameterizations. The unknown functions in this nonlinear partial
      differential equation model are determined using a tracheid-level model of water
      flow in a block of Douglas fir tracheids. The processes of flow, cavitation, pit
      aspiration/deaspiration, flow through the cell wall and ray exudation in a block
      of approximately 79 000 tracheids are modeled. Output from the tracheid model
      facilitates determination of the hydraulic conductivities in the sapwood as a
      function of saturation and interfacial area between liquid and gaseous phases of
      water, the function governing the rate of change in saturation, and the function
      governing the rate of change in interfacial area. The models show complementary
      things. The tracheid model shows that capacitance, or the change in saturation
      per change in pressure, is not constant. When all refilling is stopped, it takes
      over 180 days for the hydraulic conductivity in the vertical direction to reach
      1/4 of its maximal value, showing the robustness of the transpiration stream for
      conducting water. The shape of the functions determined with the tracheid model
      change with different tracheid-level assumptions. When these functions are used
      in the differential equation model, it is shown that cell-wall conductivity plays
      an important part in the lag in flow observed in many conifers. The flow
      velocities and rates of change in saturation predicted by the differential
      equation model agree with those measured in Douglas fir. Both models support the
      theory of tree water flow presented in Aumann & Ford (submitted) and undermine
      the theory that water flow in trees is analogous to the flow of current in
      electric circuits.

PMID- 12425979
TI  - Non-equilibria in small metapopulations: comparing the deterministic Levins model
      with its stochastic counterpart.
AB  - In this paper, we examine, for small metapopulations, the stochastic analog of
      the classical Levins metapopulation model. We study its basic model output, the
      expected time to metapopulation extinction, for systems which are brought out of
      equilibrium by imposing sudden changes in patch number and the colonization and
      extinction parameters. We find that the expected metapopulation extinction time
      shows different behavior from the relaxation time of the original, deterministic,
      Levins model. This relaxation time is therefore limited in value for predicting
      the behavior of the stochastic model. However, predictions about the extinction
      time for deterministically unviable cases remain qualitatively the same. Our
      results further suggest that, if we want to counteract the effects of habitat
      loss or increased dispersal resistance, the optimal conservation strategy is not
      to restore the original situation, that is, to create habitat or decrease
      resistance against dispersal. As long as the costs for different management
      options are not too dissimilar, it is better to improve the quality of the
      remaining habitat in order to decrease the local extinction rate.

PMID- 12425980
TI  - Stopover strategies in passerine bird migration: a simulation study.
AB  - Long-distance bird migration consists of a series of stopovers (for refuelling)
      and flights, with flights taking little time compared to stopovers. Therefore, it
      has been hypothesized that birds minimize the total time taken for migration
      through efficient stopover behaviour. Current optimality models for stopover
      include (1) the fixed expectation rule and (2) the global update rule. These
      rules maximize the speed of migration by determining the optimal departure fuel
      load for a given fuel deposition rate. We were interested in simple behavioural
      rules approaching the stopover behaviour of real birds and how these rules
      compare to the time minimizing models above with respect to the total time taken
      for migration. The simple strategies were to stay at a site (1) until a fixed
      fuel load was reached or (2) for a constant number of days. We simulated
      migration of small nocturnal passerine birds across an environment of
      continuously distributed but variable fuel deposition rates, and investigated the
      influence of different stopover strategies on the duration of migration. Staying
      for a constant number of days at each stopover site, irrespective of the fuel
      deposition rate, resulted in only slightly longer than minimum values for
      migration duration. Additionally, the constant stopover duration, e.g. 10 days,
      may change by a day or two (per stopover) without having a large effect on total
      migration duration. There is therefore a possibility that real birds may be close
      to optimal migration speed without the need for very complex behaviour. When
      assessing the sensitivity of migration duration to factors other than stopover
      duration, we found that flight costs, search and settling time, mean fuel
      deposition rate and the accuracy in the choice of flight direction were the
      factors with the largest influence. Our results suggest that migrating birds can
      approximate optimal stopover duration relatively easy with a simple rule, and
      that other factors, e.g. those above, are more relevant for travel time.

PMID- 12425981
TI  - Cell lineage dynamics in stratified shoot apical meristems.
AB  - We devise a stochastic and spatially explicit model for the dynamics of the
      initials cells in a stratified shoot apical meristem (SAM). The meristem is
      composed of three layers with seven initials per layer. We investigate the
      probability and number of divisions for a mutant lineage to either reach fixation
      or becoming purged through selection or drift. In contrast to previous studies
      our results show that the functional organization of the initials in stratified
      SAMs acts as an efficient purging mechanism particularly of deleterious
      mutations. All mutants are rapidly purged when deleterious. The probability of
      fixation for mutants with a higher fitness than the wild type increases linearly
      up to 70%. The median number of divisions to fixation of both genotypes is
      insensitive to the mutant's fitness. The median number of divisions to wild-type
      fixation is less than 100, with the upper quartile below 200. The largest number
      of divisions to wild-type fixation are in the order of 100 000 divisions. Our
      results indicate that the spatial organization of SAM enables the efficient
      purging of mutant lineages, particularly if they are deleterious. On the other
      hand, long-lived chimeric stages are common when mutant lineages succeed to
      overcome the initial numerical disadvantage.

PMID- 12425982
TI  - Travelling waves of resistance in a bi-trophic pest adaptation model.
AB  - We consider a reaction-diffusion system for spatial spread of pest resistance to
      host plant resistance genes which is based on the Lotka-Volterra predator-prey
      equations, with logistic growth of the resource level and a diffusion term added
      to account for spatial spread of the pest. The model is phenotype specific, in
      which a pest subpopulation's fitness comes down to a balance between its resource
      assimilation rate and its respiration rate. We derive an expression for the rate
      of spatial spread of the resistant pest types from an initial point source, and
      discuss its relevance for adaptive pest resistance management strategies. Using
      results for an analogous single-species reaction-diffusion model in heterogeneous
      media, we consider the likely impact of pest-susceptible plant refugia on the
      speed of the travelling wave of resistant pests, and simultaneously the expected
      trade-off, in terms of crop yield decrease, when refugia are included. We also
      explore the possibility that resistance breaking by the pest population is not an
      inevitable phenomenon, particularly when refugia of the appropriate size are
      used.

PMID- 12425983
TI  - Amplification of the sequences displaying the pattern RNY in the RNA world: the
      translation --> translation/replication hypothesis.
AB  - Based on previous considerations published in J. theor. Biol., new analyses of
      the organization of the genetic system are reported in this paper. We show that
      theoretical considerations about the order observed in the genetic code table
      support the idea of a primitive self-aminoacylation process achieved by
      primordial tRNAs. The physico-chemical constraints connected with this process
      may explain why a primitive genetic system predominantly uses sequences with the
      codonic pattern RNN (R=purine; Y=pyrimidine; N=any of the four bases) to
      polymerize the amino acids into peptides through translation. These
      considerations lead us to propose the Translation --> Translation/Replication
      hypothesis, which may explain why only RNA sequences with the pattern RNY,
      instead of less restrictive RNN, are susceptible to amplification. Using these
      ideas, supported by properties of symmetry, features of the genetic code may be
      connected with the replication of specific RNA sequences in the RNA world.

PMID- 12425984
TI  - Zipf's law in importance of genes for cancer classification using microarray
      data.
AB  - Using a measure of how differentially expressed a gene is in two
      biochemically/phenotypically different conditions, we can rank all genes in a
      microarray dataset. We have shown that the falling-off of this measure
      (normalized maximum likelihood in a classification model such as logistic
      regression) as a function of the rank is typically a power-law function. This
      power-law function in other similar ranked plots are known as the Zipf's law,
      observed in many natural and social phenomena. The presence of this power-law
      function prevents an intrinsic cutoff point between the "important" genes and
      "irrelevant" genes. We have shown that similar power-law functions are also
      present in permuted dataset, and provide an explanation from the well-known
      chi(2) distribution of likelihood ratios. We discuss the implication of this
      Zipf's law on gene selection in a microarray data analysis, as well as other
      characterizations of the ranked likelihood plots such as the rate of fall-off of
      the likelihood.

PMID- 12425985
TI  - Are genes for fetal over-exploitation outlaws?

PMID- 12425986
TI  - Apoptotic epithelial cell death: a prerequisite for palatal fusion. An in vivo
      study in rabbits.
AB  - The aim of the present study was to investigate stage-specific changes in medial
      edge epithelium during in vivo fusion of embryonic palatal shelves in 25 Russian
      rabbits. MATERIAL AND METHODS: The embryos were dissected following Caesarian
      section at day 18. Palatal shelves of specific developmental steps
      (approximation, contact, fusion) were examined by light microscopy,
      immunohistochemistry and transmission electron microscopy. RESULTS: Light
      microscopy revealed that the superfical peridermal cells underwent apoptosis
      prior to contact of the basal epithelial cells. Following contact, an epithelial
      monolayer was left on each shelf with an intact basement membrane. Apoptosis of
      the epithelial cells was followed by discontinuity of the basement membrane.
      Islands of epithelial cells remained. CONCLUSION: This paper presents new data on
      palatal development in vivo. The results support our theory that apoptotic medial
      edge epithelial cell death is a precondition for palatal fusion. There were no
      indications of epithelial mesenchymal transformation or migration.

PMID- 12425987
TI  - Three-dimensional facial morphology, following primary cleft lip repair using the
      triangular flap with or without rotation advancement.
AB  - INTRODUCTION: There are numerous methods of repairing a cleft lip. In our
      institution, two methods have been used for primary lip repair, the triangular
      flap method, and the rotation-advancement plus small triangular flap method. The
      purpose of this study was to compare postsurgical anthropometric results
      following these two surgical methods. PATIENTS: Twenty children with a unilateral
      complete cleft lip, alveolus and palate (UCLAP) were selected for this study. Ten
      underwent primary lip repair by the triangular flap method (Triangular Group),
      and the other 10 underwent repair by the rotation-advancement plus small
      triangular flap method (Rotation Group). METHOD: They were documented with a
      three-dimensional optical scanner, and analysed with computer-aided
      anthropometric method reported previously (Comput. Methods Programs 58: 159-173,
      1999a; J. Cranio-Maxillofac Surg 27: 345-353, 1999b). RESULTS: The shapes of the
      nose and nostril were a little better in the Rotation Group. However, in the
      Rotation Group, differences between good and poor cases were more extreme than in
      the Triangular Group. The shape of Cupid's bow was good shortly after surgery in
      the Triangular Group. A good shape of Cupid's bow was also obtained in the
      Rotation Group, but the improvement was more delayed. On the non-cleft side, the
      length of Cupid's bow was more extended in the Triangular Group. Certain
      deformities were common to both groups, such as deviation of the columella and a
      flattened ala on the cleft side. CONCLUSION: Rotation-advancement plus the small
      triangular flap method was thought to produce somewhat better results, however,
      further improvements in the technique are needed.

PMID- 12425988
TI  - Preliminary results of standardized occipital advancement in the treatment of
      lambdoid synostosis.
AB  - INTRODUCTION: Lambdoid synostosis can be found unilaterally, bilaterally or in
      combination with other forms of craniosynostosis. Based on the concept of
      frontoorbital advancement, we used the occipital advancement in order to correct
      unilateral or bilateral lambdoid synostosis. METHODS: The standardized technique
      consists of transverse osteotomies, removal, remodelling and advancement of the
      occipital region. RESULTS: Standardized occipital advancement was performed in 21
      patients at a multidisciplinary craniofacial centre. The surgery was carried out
      for patients between 5 and 28 months of age. Aesthetically satisfactory skull
      shape and normalization of the intracranial pressure could be achieved. A major
      complication in the form of a life-threatening intraoperative haemorrhage
      occurred in one case. Other complications like infections have not been
      experienced. CONCLUSION: Standardized occipital advancement allows precise,
      reproducible and predictable positioning of the segments. Artificial 'sutures'
      are created as a result of the osteotomy. Remodelling leads to a well
      proportioned skull shape and posterior advancement leads to an increase in
      intracranial volume.

PMID- 12425990
TI  - Histology of surgically removed overgrown osteochondral rib grafts.
AB  - INTRODUCTION: Osteochondral rib grafts are most commonly used for mandibular
      condylar replacements. However, when used in growing patients, unpredictable
      growth of the constructed condyle/ramus is a common complication. Clinically two
      types of overgrowth, linear or exuberant, have been described. PURPOSE: In order
      to investigate growth disorders associated with osteochondral rib grafts in
      children, overgrown grafts were examined histologically. PATIENTS AND METHODS:
      The material consisted of seven samples (six patients) of osteochondral rib
      grafts, that had been removed due to overgrowth. RESULTS: Examination revealed
      that the clinical type of overgrowth was not related to any specific
      microarchitecture, which in itself, showed considerable variation. In three of
      the samples, a typical endochondral ossification zone was seen and in two others,
      signs of metaplasia, i.e. a gradual transformation of the cartilage cells into
      osteocytes, were noted. CONCLUSIONS: The study reveals that the clinical type of
      overgrowth, linear or exuberant, cannot be related to any typical histological
      finding. Furthermore, the findings suggest that local factors, such as mandibular
      movements and loading of the reconstructed condyle may have an effect on the
      structure of the osteochondral rib graft, and eventually on its growth.

PMID- 12425989
TI  - A pilot study of the effects of transpalatal maxillary advancement on
      velopharyngeal closure in cleft palate patients.
AB  - BACKGROUND AND AIMS: Impaired velopharyngeal closure function is sometimes a
      complication of a standard Le Fort I maxillary advancement in cleft palate
      patients. The transpalatal Le Fort I osteotomy has been suggested as an
      alternative technique that may avoid this problem. The aim of this pilot study
      was to examine the effects of the transpalatal approach on velopharyngeal
      function in a series of cleft palate patients. PATIENTS: Sixteen consecutive
      patients with a history of cleft palate exhibiting maxillary hypoplasia who
      underwent a transpalatal Le Fort I osteotomy. METHODS: All patients had a
      simultaneous audio/video speech recording and nasopharyngoscopy examination prior
      to maxillary advancement, followed by a repeat of the same examinations at least
      1 year post-operatively. Velopharyngeal function was measured in two ways: by
      direct observation using nasopharyngoscopy, and indirectly by means of perceptual
      assessment. Reliability studies of the two measures were performed with
      satisfactory results. RESULTS: No statistically significant difference was found
      between the pre- and post-operative data in either the perceptual speech
      assessment or nasopharyngoscopy examination. CONCLUSION: These results indicate
      that maxillary advancement by transpalatal Le Fort I osteotomy does not adversely
      affect velopharyngeal closure function.

PMID- 12425991
TI  - Tuberous sclerosis: clinicopathologic features and review of the literature.
AB  - INTRODUCTION: Tuberous sclerosis is a hamartoneoplastic syndrome, which may
      involve multiple organ systems. Oral hard tissue manifestations of the syndrome
      have been described in the literature only as recently as 1955. Patients who
      presented with clinical manifestations of tuberous sclerosis did not routinely
      undergo oral surveys to rule out 'lesions', and consequently data on 'lesions' in
      the maxillofacial complex is scant. Ten cases have been found in the English
      language literature, which describe maxillofacial 'lesions', which may be
      tumours, new growths, neoplasms or overgrowths occurring in patients diagnosed
      with tuberous sclerosis. PURPOSE: To review the literature for all maxillofacial
      lesions associated with tuberous sclerosis and to present an eleventh case of a
      patient with a maxillofacial lesion diagnosed as having tuberous sclerosis.
      RESULTS: Eleven cases were found with maxillofacial fibroblastic lesions
      associated with tuberous sclerosis. These lesions were all fibrous benign
      neoplasms found in the maxillofacial bony complex. CONCLUSIONS: Maxillofacial
      fibroblastic lesions in tuberous sclerosis have various histopathological
      presentations, some of which may be difficult to differentiate. Consequently,
      close microscopic examination of these lesions is necessary so that adequate
      surgical treatment is provided.

PMID- 12425992
TI  - Orbital emphysema during air travel: a case report.
AB  - Orbital emphysema is a well-recognized complication of fractures involving the
      orbit. Commonly, this follows nose blowing and occurs in the subcutaneous
      tissues. A case of emphysema within the orbital cavity caused by the pressure
      changes during air travel is presented. The clinical picture was similar to that
      seen in retrobulbar haemorrhage and required early surgical intervention.
      Circumstances where patients at risk may be exposed to abnormal atmospheric
      pressures are highlighted and the management of the condition is discussed.

PMID- 12425993
TI  - Functional rehabilitation following resection of the floor of the mouth: the
      nasolabial flap revisited.
AB  - INTRODUCTION: The aim of this study was to analyse the results of treatment
      following reconstruction of intraoral soft tissue using a nasolabial flap, with
      particular consideration of functional aspects. MATERIAL AND METHODS: In 26
      patients (over a period of 10 years), the intraoral repair of the defect was
      carried out in the anterior floor of the mouth, 19 have received a unilateral and
      seven a bilateral nasolabial flap. The defects were caused by resection of
      squamous cell carcinomas (T1-T2) of the intraoral mucosa in 24 cases and
      osteoradionecrosis with soft tissue loss in two cases. RESULTS: Complications of
      local wound healing were observed in three cases. In 23 patients the subsequent
      prosthetic rehabilitation was successful and allowed a return of masticatory
      function. In the other three cases, a secondary operation for flap remodelling
      would have been preferred, but the patients declined these operations.
      CONCLUSION: The nasolabial flap for replacement of soft tissue in the floor of
      the mouth represents a functional and aesthetically satisfactory alternative to
      reconstruction by microsurgically anastomosed flaps in cases with defects of up
      to 5 x 5 cm in size, especially in older, medically compromised patients who are
      therefore of poorer surgical risk.

PMID- 12425996
TI  - Carboxy-terminal truncated STAT5 is induced by interleukin-2 and GM-CSF in human
      neutrophils.
AB  - IL-2 and GM-CSF are potent activators of polymorphonuclear neutrophils (PMN)
      biologic activity. IL-2 and GM-CSF-mediated activation of STAT proteins was
      examined in nuclear extracts of human PMN. We found that both cytokines induced
      STAT5-like DNA-binding complexes that could not be supershifted using C-terminal
      specific anti-STAT5 antibodies. Therefore, we performed oligoprecipitation
      experiments with a STAT5-biotinylated DNA probe (biotin-MGFe) and the
      precipitated proteins were identified by Western immunoblotting. We found that GM
      CSF and IL-2 induced the DNA-binding activity of a C-terminal truncated isoform
      of STAT5. The truncated STAT5 form was present in the nucleus of PMN but the
      cytoplasmic extracts contained full-length STAT5, suggesting that PMN
      proteolytically process full-length STAT5 proteins. Proteolytic experiments
      demonstrated that PMN express a protease activity capable of producing C-terminal
      processed STAT5 proteins. In many settings, C-terminal truncation of the STAT5
      protein leads to inhibition of STAT5 biological activity. Two known STAT5
      regulated genes, encoding pim-1 and OSM proteins, failed to be induced by GM-CSF
      in PMN. These findings provide new insights to a mechanism by which PMN, a
      terminally differentiated cell, may regulate gene transcription by alternative
      proteolytic processing.

PMID- 12425997
TI  - Synergistic effect of adoptive T-cell therapy and intratumoral interferon gamma
      inducible protein-10 transgene expression in treatment of established tumors.
AB  - The lack of efficient T-cell infiltration of tumors is a major obstacle to
      successful adoptive T-cell therapy. We have previously shown that transplanted
      SP2/0 myeloma tumors engineered to express lymphotactin invariably induced tumor
      regress mediated by SP2/0 tumor-specific T cells. Herein, we further systemically
      characterize these activated T cells and investigate their therapeutic efficacy,
      either alone or with the chemokine interferon gamma (IFN-gamma)-inducible protein
      10 (IP-10) gene therapy. Following stimulation with SP2/0 cells, these activated
      T cells were CD25(+)FasL(+) L-selectin(low), expressed CXCR3 receptor and were
      chemoattracted by IP-10 in vitro. They comprised 64% CD4(+) Th1 and 36% CD8(+)
      Tc1 cells, both of which expressed IFN-gamma, perforin, and TNF-alpha, but not IL
      4. The activated T cells were strongly cytotoxic for SP2/0 tumor cells (79%
      specific killing; E:T ratio, 50), mainly via perforin-mediated pathway. Cell
      tracking using labeled T cells confirmed that these T cells infiltrated better
      into the IP-10-expressing tumors than non-IP-10-expressing ones. In vivo,
      combined intratumoral IP-10 gene transfer and adoptive T-cell immunotherapy for
      well-established SP2/0 tumors eradicated the tumors in 7 of the 8 mice. Control
      or IP-10 adenoviral treatments by themselves neither alter the lethal outcome for
      tumor-bearing mice nor did T-cell therapy by itself, although the latter two
      treatments did slow its time-frame. Taken together, our data provide solid
      evidence of a potent synergy between adoptive T-cell therapy and IP-10 gene
      transfer into tumor tissues, which culminated in the eradication of well
      established tumor masses.

PMID- 12425998
TI  - Regulation of T cell-dependent autoantibody production by a gammadelta T cell
      line derived from lupus-prone mice.
AB  - Lupus-prone (MRLxC57BL/6) F(1) mice lacking gammadelta T cells show more severe
      lupus than their T cell-intact counterparts, suggesting that gammadelta T cells
      down-modulate murine lupus. To determine the mechanisms for this effect, we
      assessed the capacity of gammadelta T cell lines derived from spleens of
      alphabeta T cell-deficient MRL/Mp-Fas(lpr) (MRL/Fas(lpr)) mice to down-regulate
      anti-dsDNA production generated by CD4(+)alphabeta T helper cell lines and
      activated B cells from wild-type MRL/Fas(lpr) mice. One line, GD12 (gd TCR(+),
      CD4(-)CD8(-)), had the capacity to reduce anti-dsDNA production in a contact
      dependent manner. GD12 also killed activated MRL/Fas(lpr) (H-2(k)) B cells, with
      less cytolysis of resting B cells than that generated by in comparison to
      cytokine-matched gammadelta T cell lines. In addition, GD12 also killed activated
      B cells derived from C57BL/6-Fas(lpr) (H-2(b)) or beta(2)-microglobulin (beta(2)
      M)-deficient MRL/Fas(lpr) mice, suggesting cytolysis was neither MHC- nor CD1
      restricted. Killing by GD12 was inhibited by anti-TNFalpha and anti-TNF-R1, and
      partially blocked by anti-gd TCR Fab fragments, but not by anti-FasL, anti-TNF-R2
      (p75) or concanamycin A. IL-10 produced by GD12 also partially inhibited
      alphabeta Th1-dependent but not alphabeta Th2-dependent autoantibody production.
      These findings prove that we have identtified a gammadelta T cell line that
      suppresses autoantibody synthesis by alphabeta T-B cell collaboration in vitro.

PMID- 12425999
TI  - Strength of prior stimuli determines the magnitude of secondary responsiveness in
      CD8+ T cells.
AB  - CD8+T cells can become anergic following activation, though the cellular
      mechanism, as compared to CD4+ T cells, remains poorly understood. Here, we
      examined the effects of different antigen-dose, peptide ligands, and engagement
      of costimulatory molecules on the induction of CD8+ T cell anergy. We observed
      that increasing strengths of signals delivered to CD8+ T cells by varying the
      antigen-dose and the nature of peptide ligands induced increasing degrees of non
      responsiveness to secondary stimulation. Furthermore, higher levels of LFA-3
      engagement of CD2 rendered CD8+ T cells unresponsive to secondary antigenic re
      challenge. This pattern of secondary responsiveness lasted up to 2 weeks
      following primary stimulation and was not correlated with prior cell division
      history. These results indicate that the strength of prior stimuli, which is
      determined by the sum of signals from both TCR and costimulatory molecules,
      determines the activation threshold and magnitude of CD8+ T cell responses.

PMID- 12426001
TI  - Activation of JAK2/STAT1-alpha-dependent signaling events during Mycobacterium
      tuberculosis-induced macrophage apoptosis.
AB  - Induction of apoptosis by Mycobacterium tuberculosis in murine macrophage
      involves TNF-alpha and nitric oxide (NO) production and caspase cascade
      activation; however, the intracellular signaling pathways implicated remain to be
      established. Our results indicate that infection of the B10R murine macrophage
      line with M. tuberculosis induces apoptosis independent of mycobacterial
      phagocytosis and that M. tuberculosis induces protein tyrosine kinase (PTK)
      activity, JAK2/STAT1-alpha phosphorylation, and STAT1-alpha nuclear
      translocation. Inhibitors of PTK (AG-126), or JAK2 (AG-490) inhibited TNF-alpha
      and NO production, caspase 1 activation and apoptosis, suggesting that M.
      tuberculosis-induction of these events depends on JAK2/STAT1-alpha activation. In
      addition, we have obtained evidence that ManLAM capacity to inhibit M.
      tuberculosis-induced apoptosis involves the activation of the PTP SHP-1. The
      finding that M. tuberculosis infection activate JAK2/STAT1-alpha pathway suggests
      that M. tuberculosis might mimic macrophage-activating stimuli.

PMID- 12426000
TI  - IL-6 rescues the hyporesponsiveness of c-Rel deficient B cells independent of Bcl
      xL, Mcl-1, and Bcl-2.
AB  - The hematopoietically restricted member of the NF-kappaB/Rel family, c-Rel, is
      essential for B cell survival and proliferation. Here we demonstrate that the
      production of the interleukins 6, 10, and 15 (IL-6, IL-10, and IL-15) are
      diminished in c-Rel(-/-) B lymphocytes. In a manner similar to that seen in IL-6(
      /-) B cells, resultant STAT activation is reduced in c-Rel(-/-) B cells following
      B cell receptor (BCR) ligation. Addition of either exogenous IL-6 or IL-10, but
      not IL-15, partially restores proliferation, and this occurs through enhanced
      cell survival rather than promoting cell cycle progression. This increase in
      viability occurs independently of Bcl-xL and Mcl-1 expression though, two
      survival genes reported to be downstream of IL-6 signaling. Nonetheless,
      transgenically expressed Bcl-xL, a direct c-Rel target gene in B cells, corrects
      not only the survival defect of c-Rel deficiency, but also partially ameliorates
      hypoproliferation. Together IL-6 and Bcl-xL are additive but incomplete in the
      restoration of proliferation. Known deficits in the induction of several key cell
      cycle components in c-Rel(-/-)B cells are not corrected upon treatment with
      exogenous cytokine. Together, these data demonstrate that IL-6 enhances B cell
      responses by employing multiple survival factors.

PMID- 12426002
TI  - Syngeneic mixed lymphocyte reaction (SMLR) with dendritic cells: direct
      visualization of dividing T cell subsets in SMLR.
AB  - Syngeneic mixed lymphocyte reaction (SMLR) has been considered to represent T
      cell response to self antigens. In this study using stimulator dendritic cells
      (DC), we analyzed cellular components responding to the syngeneic DC. It was
      shown that the predominant dividing cells were CD8(+) T cells although the
      response of CD4(+) T cells was essential for initiation of SMLR. In spite of the
      vigorous proliferation and expression of several activation markers, these SMLR
      activated CD8(+) T cells hardly killed syngeneic targets and most of the CD8(+) T
      cells produced no interferon-gamma upon restimulation with DC. Furthermore, in
      SMLR where CD8(+) T cells were absent or inhibited, a considerable proliferation
      of CD4(-) CD8(-) double negative-T cells that included TCRalpha/beta(+) natural
      killer-T cells (NKT cells), TCRgamma/delta(+) NKT cells and TCRgamma/delta(+) T
      cells was observed.

PMID- 12426003
TI  - T cell activation induces a noncoding RNA transcript sensitive to inhibition by
      immunosuppressant drugs and encoded by the proto-oncogene, BIC.
AB  - In a search for novel early T cell activation transcripts, we identified
      expressed sequence tags (ESTs) more abundantly expressed in normal human CD4(+) T
      lymphocytes fully activated by a 5 h exposure to CD3 plus CD28 mAbs, compared to
      the same cells stimulated with either CD3 mAb or CD28 mAb alone. An EST was
      identified that hybridized with a 1.7 kb transcript expressed in activated T
      cells but was undetectable by Northern blot analysis in resting T cells or other
      normal tissues. The T cell transcript was maximally induced within 6 h and
      remained elevated for at least 47 h. Induction of the transcript was blocked by
      cyclosporin A, FK506, and dexamethasone but not by rapamycin. The transcript was
      polyadenylated but lacked an open reading. A BLAST search of the NCBI database
      revealed that the transcript shared identity with the recently reported human BIC
      proto-oncogene that encodes a noncoding mRNA (W. Tam, Gene 274 (2001) 157). Our
      data demonstrate that transcriptional activation of the BIC proto-oncogene is an
      early and sustained T cell activation event and suggest an important role for
      noncoding mRNA in T cell function.

PMID- 12426004
TI  - Cryptic MBP epitope 1-20 is inducing autoimmune anterior uveitis without EAE in
      Lewis rats.
AB  - Lewis rats immunized with myelin basic protein (MBP) developed experimental
      autoimmune encephalomyelitis (EAE) and associated anterior uveitis (AU). Although
      several cryptic epitopes of MBP have strong encephalitogenic and uveitogenic
      properties, the peptide corresponding to the MBP residues 1-20 was uniquely
      capable of inducing AU without EAE. In this study, we showed that acetylation of
      the N-terminal amino acid did not produce encephalitogenicity, did not enhance
      uveitogenicity, and did not improve T cell proliferation in Lewis rats. The
      cytokine production profile induced by MBP(1-20) immunization was consistent with
      a Th1 response. In MBP-injected rats and in peptide-injected rats, the frequency
      of the IFN-gamma-secreting cells in MBP(69-89)-stimulated T cells was
      significantly higher than the frequency of IFN-gamma-secreting cells in MBP(1-20)
      stimulated T cells. However, similar numbers of IFN-gamma-producing specific
      cells were found in the eyes of MBP(69-89) and MBP(1-20) immunized rats. In these
      rats, the iris-infiltrating cells consisted of a much higher percentage of CD4(+)
      T cells expressing L-selectin (CD62L) than did those cells found in the spinal
      cord. The results demonstrate that MBP(1-20) is immunogenic and uveitogenic,
      although it induced only weak proliferation and weak Th1 reaction. The fact that
      T cells with the same specificity have different effects on target organs
      suggested that, in the eye and spinal cord, a distinct mechanism might mediate
      the recruitment of cells to these organs.

PMID- 12426006
TI  - Effects of intelligence level and place of residence on the ability of
      individuals with mental retardation to identify facial expressions.
AB  - This study was designed to investigate the abilities of individuals with mental
      retardation to recognize and match emotional facial expressions from a series of
      photographs depicting various facial expressions. There were four groups of
      participants according to their place of residence (community or institution) and
      their intelligence level (mild or moderate). Each individual participated in two
      tasks: (1) recognizing a facial expression from an array of three pictures
      presented, and (2) matching a facial expression from one picture with a picture
      depicting a similar emotion from an array of three pictures. All information was
      presented to the participants in the native language, Hebrew. The six facial
      expressions used for the study included happiness, sadness, fear, anger,
      surprise, and disgust. The ability to recognize and match facial expressions was
      significantly higher for individuals with mild than moderate mental retardation.
      There was no significant difference for place of residence. Happiness was the
      easiest feeling to recognize and match for all groups. Fear and anger were the
      most difficult to recognize, while sadness and anger were most difficult to
      match.

PMID- 12426005
TI  - In vitro and in vivo regulation by macrophage migration inhibitory factor (MIF)
      of expression of MHC-II, costimulatory, adhesion, receptor, and cytokine
      molecules.
AB  - The secretion of macrophage migration inhibitory factor (MIF) is enhanced by
      inflammatory and other stimuli. MIF regulates innate and adaptive immune
      responses, but the mechanisms of this regulation are poorly understood. Our
      hypothesis was that MIF generated by these stimuli regulates these responses by
      modulating key molecular expression. This hypothesis was tested by adding greater
      than constitutive concentrations of recombinant MIF to cultures of various cell
      types and flow cytometric assay. MIF modulated surface expression of MHC-II, B7
      2, CD40, CD40 ligand, ICAM-1 and Fcgamma, CR1/CR2, and IL-10 receptors and
      intracellular expression of IL-10, TNFalpha, and p40 (IL-12). MIF increased
      expression of B7-1 by B cells and CD40 L by T cells in spleens from Schistosoma
      mansoni-infected mice. Footpad injection of MIF reduced expression of MHC-II and
      CD40 by B cells in draining lymph nodes. Footpad injection of Mab to MIF reduced
      expression of B7-2 and CR1/CR2 by B cells and B7-2 by macrophages in these nodes.
      These data support our hypothesis.

PMID- 12426007
TI  - Mentoring treatment teams to integrate behavioral and psychopharmacological
      treatments in developmental disabilities.
AB  - Individuals with developmental disabilities often have a concomitant psychiatric
      disorder severe enough to require treatment. The behavioral endpoint of
      psychiatric disorders may require integrated behavioral and psychopharmacological
      treatments to stabilize their condition and enhance their quality of life. We
      used a mindfulness-based mentoring model to facilitate the integration of
      behavioral and psychopharmacological treatments at the treatment team level.
      Using a multiple baseline design across treatment teams, we assessed the degree
      of integration of these two treatment modalities using a 23-item rating scale,
      and then introduced mentoring successively across the three treatment teams.
      Following mentoring, six follow-up assessments at monthly intervals were
      undertaken to assess functioning of the treatment teams in the absence of
      mentoring. The low levels of integration of behavioral and psychopharmacological
      treatments occurring during baseline improved significantly within each team
      commensurate with the mentoring. Further, the enhanced treatment team functioning
      was maintained during a 6-month follow-up period. Mentoring of treatment teams
      may be an effective first step in integrating behavioral and
      psychopharmacological treatments that are deemed essential in the care and
      treatment of individuals with developmental disabilities and mental illness.

PMID- 12426008
TI  - Identification of early risk factors for language impairment.
AB  - The current study is a population-based investigation of birth risk factors for
      school-identified specific language impairment (SLI). The sample consisted of
      244,619 students (5,862 SLI) born in Florida between 1989 and 1990 who were in
      the Florida public school system at ages 6-7. Epidemiological measures of effect
      were used to investigate both individual- and population-level risk for SLI. Very
      low birth weight (VLBW), low 5-min Apgar score, late or no prenatal care, high
      birth order, and low maternal education were associated with highest individual
      level risk. Low maternal education and having an unmarried mother was associated
      with the highest population-level risk. The results not only suggest who needs to
      be screened for a future developmental disability, but identify a group of
      children who are at-risk for an SLI placement in school. Early intervention
      services for these children may be the most effective approach to reducing the
      incidence of school-identified SLI.

PMID- 12426009
TI  - Establishing reports of saying and doing and discriminations of say-do relations.
AB  - The purpose of the present study was to investigate a new procedure for
      establishing accurate discriminations of delayed acts of saying, of doing and
      discriminations of say-do correspondence and non-correspondence with three
      developmentally delayed subjects. A corrective feedback procedure for incorrect
      discrimination responses, that involved multiple-exemplars, was initially
      employed, but failed to establish most of the target discriminations for all
      three subjects. A near-errorless training intervention was subsequently employed
      that also involved multiple-exemplars. This training used two referents (one for
      acts of saying and another one for acts of doing) as prompts to produce accurate
      delayed reports of what they promise to do presently, and accurate delayed
      reports of what they did. Prompts were also used to indicate whether the say-do
      relations were the 'same' in terms of correspondence or not the same in terms of
      non-correspondence. Prompts were subsequently eliminated. All three subjects
      demonstrated highly accurate reports of delayed saying, doing and say-do
      correspondence or non-correspondence discriminations in the absence of prompts
      and with novel stimuli. The results are discussed in terms of generalized classes
      of behavior. The implications of these findings for the use of the errorless
      learning paradigm as a means of establishing complex behavior are also discussed.

PMID- 12426010
TI  - Health issues for adults with developmental disability.
AB  - The aim of this paper is to review recent literature on health issues for adults
      with developmental disability and reflect on how this research informs service
      provision, future research work, and social and health policy. Studies based on
      mortality data are most likely to aim at identifying individuals most at risk of
      premature death, and some researchers argue that health-oriented service systems
      appear ill-equipped to address the needs of the at risk groups. Morbidity studies
      highlight specific health concerns found in this population and commonly report
      high rates of untreated, yet treatable, conditions. The emerging literature on
      the behavioral determinants of health suggests risk of preventable morbidity and
      mortality because of the lack of health-promoting behaviors, particularly in
      relation to diet and physical activity. Of particular interest in this literature
      is the affect of living arrangements on health promoting activities. This paper
      concludes that future directions in health research for adults with developmental
      disability will be concerned with the complexity of the interactions between
      biology, pathology, and behavioral and environmental determinants. More use of
      self-reported health studies is suggested, as well as further exploration of
      effective strategies of health promotion and health promoting decision-making and
      self-determination among this population.

PMID- 12426011
TI  - Bupropion exposures: clinical manifestations and medical outcome.
AB  - Bupropion is an antidepressant and smoking cessation aid. Limited toxicological
      information exists for intentional and unintentional bupropion-only exposures. A
      retrospective review of all bupropion-only exposures reported to the Toxic
      Exposure Surveillance System from 1998 through 1999 was conducted. Data for the
      three bupropion products, Wellbutrin, Wellbutrin SR, and Zyban, included
      demographics, reason for exposure, clinical effects, therapy, and medical
      outcome. A total of 7,348 bupropion-only exposures were reported: 56% female and
      61% unintentional. The majority of exposures involved Wellbutrin SR; however,
      Wellbutrin exposures involved a higher percentage of intentional overdoses and
      serious clinical effects. Clinical effects related to bupropion were noted in
      2,247 (31%) exposures; 8% of all children <6-years-old compared to 46% of all
      teenagers. Seizures developed in 15% of all intentional exposures. Cardiovascular
      disturbances were extremely uncommon after overdose. The majority of
      unintentional bupropion-only exposures result in minimal or no clinical toxicity;
      however, a significant number of intentional overdoses result in seizures.

PMID- 12426012
TI  - Opioids prolong nuclear hepatobiliary imaging when given prior to scanning.
AB  - Opioid-mediated contraction of the distal common bile duct (CBD) may delay tracer
      passage during nuclear hepatobiliary imaging (NHI), mimicking pathologic
      obstruction. We sought to determine if opioid administration before NHI delays
      CBD visualization and prolongs imaging. The records of 198 Emergency Department
      patients who underwent NHI were reviewed (after excluding those with evidence for
      pathologic CBD obstruction). Opioids were administered before NHI in 56 cases.
      Delayed CBD visualization occurred in 28.6% of subjects who had received opioids
      and in 12.0% of those who had not (p < 0.01). Delayed imaging was performed in
      77.8% of those who had received opioids and in 53.5% of those who had not (p <
      0.01). The relative risk of delayed CBD visualization was 1.46 [95%CI 0.65-3.28]
      for meperidine, 4.18 [95%CI 2.00-8.82] for morphine, and 2.38 [95%CI 1.29-4.39]
      for any opioid. We conclude that opioids given before NHI are associated with
      delayed CBD visualization and more imaging sessions.

PMID- 12426013
TI  - Comparison of intravenous ketorolac and meperidine in the treatment of biliary
      colic.
AB  - To compare the analgesic efficacy and tolerability of intravenous (IV) ketorolac
      tromethamine with IV meperidine in the treatment of biliary colic, a prospective,
      randomized, double blind study was carried out upon a convenience sample of
      patients at a large inner city facility. Patients between the ages of 18 and 65
      years of age with a history and physical examination consistent with biliary
      colic were enrolled over a 2-year period. Patients were randomly assigned to
      receive ketorolac 30 mg IV or meperidine 50 mg IV. Pain was quantified using a 4
      point verbal rating system (VRS) as well as a visual analog scale (VAS). Patients
      were queried about their pain at times 0, 12 h, 1 h, and 2 h after administration
      of the study medication. Adverse effects were also recorded. A total of 324
      patients completed the study protocol with 175 patients receiving ketorolac and
      149 receiving meperidine. Patient demographics were similar for both groups with
      mean age for the ketorolac group of 36.1 years and for the meperidine group of
      34.6 years. Both groups were predominantly Latino and over 80% of patients in
      both groups were female. No significant difference in pain control was found
      between ketorolac and meperidine in either the VAS or VRS for any time interval
      studied. The mean change in the VAS at time 2 h was 6.2 cm +/- 3.6 cm for the
      ketorolac group, compared with 6.7 cm +/- 3.6 cm for the meperidine group (p =
      0.25). Although no significant difference was found in overall drug tolerability,
      patients receiving meperidine reported higher incidences of nausea and of
      dizziness than those receiving ketorolac (p = 0.009 and 0.003, respectively).
      Ketorolac tromethamine is a well-tolerated, effective medication in the treatment
      of acute biliary colic. It showed similar efficacy to meperidine with a decreased
      number of adverse effects.

PMID- 12426014
TI  - Delayed diagnosis of small bowel obstruction following laparoscopic lymph node
      dissection.
AB  - Laparoscopic surgical procedures are infrequently complicated by bowel herniation
      through unsutured trocar sites. Nevertheless, there is a risk of this
      complication in patients presenting with symptoms of small bowel obstruction
      after laparoscopy. We present a case of delayed small bowel obstruction due to a
      Richter's hernia, a rare type of hernia that involves incomplete protrusion of
      bowel wall through a surgical defect. Knowledge of this potential complication of
      laparoscopic procedures may prevent the significant morbidity that results from
      mechanical small bowel obstruction with necrosis.

PMID- 12426015
TI  - Spinal epidural hematoma complicating thrombolytic therapy with tissue
      plasminogen activator--a case report.
AB  - Patients who receive thrombolytic therapy are at risk of central nervous system
      (CNS) hemorrhage, and this diagnosis must be sought in any patient who develops
      neurologic complaints after thrombolysis and anticoagulation. Early imaging and
      neurosurgical consultation are essential to improve outcome after hemorrhage
      occurs. We describe a patient who developed spinal epidural hematoma (SEH) after
      thrombolysis and anticoagulation for acute myocardial infarction. Delay in
      diagnosis and management may have contributed to a poor outcome. The literature
      on SEH is reviewed, and approaches to improve the prognosis of patients suffering
      CNS hemorrhage after thrombolysis are discussed.

PMID- 12426017
TI  - The management of acute severe asthma.
AB  - Asthma is a common cause of morbidity and mortality in the United States, with
      over two million Emergency Department (ED) visits each year. Airway inflammation
      is recognized as a major component in the pathophysiology of asthma. The classic
      presentation of asthma is that of wheezing, cough, and dyspnea, however, the
      severity of airflow limitation correlates poorly with clinical signs. Forced
      exhaled volume in 1 s (FEV(1)) and the peak expiratory flow rate (PEFR) are
      direct reflections of the severity of airflow obstruction and are the standard
      measures used in the ED to assess the severity of airflow obstruction and the
      response to therapy. Beta2-adrenergic bronchodilators, ipratropium bromide, and
      corticosteroids form the cornerstone of therapy. Inhaled corticosteroids,
      leukotriene modifying drugs, and noninvasive positive pressure ventilation should
      be considered in patients with severe disease and in those who have responded
      poorly to standard therapy. Mechanical ventilation is usually well tolerated and
      may be lifesaving in patients with refractory asthma. Precautions are required to
      prevent dynamic hyperinflation during assisted ventilation.

PMID- 12426016
TI  - Chronic acetaminophen toxicity: a case report and review of the literature.
AB  - Acetaminophen is one of the most frequently used medications in the United
      States. While usual dosing of acetaminophen is considered harmless, both acute
      and chronic overdoses can be fatal. The majority of reported cases of chronic
      acetaminophen toxicity in adults occur in chronic alcohol abusers, patients
      taking P450-inducing medications, or following massive dosing. We describe a case
      of toxic hepatitis free of the aforementioned risk factors associated with
      chronic ingestion of moderately excessive doses of acetaminophen. Our patient
      ingested approximately 5.0 to 6.5 g of acetaminophen daily for 6 to 8 weeks via
      multiple medications. The inclusion of acetaminophen in numerous medications
      combined with the frequency of use of acetaminophen necessitates an increased
      concern for not only acute but also chronic acetaminophen toxicity.

PMID- 12426018
TI  - Skatepark injuries and the influence of skatepark design: a one year consecutive
      case series.
AB  - Skateboarding and in-line skating are popular activities that attract millions of
      participants yearly and have spawned the development of skateparks (SPs). This
      study examined the types and distribution of injuries within a local commercial
      SP. Subjects were prospectively enrolled in a university Emergency Department
      (ED) after an injury at a local SP. One hundred subjects were enrolled over 1
      year, representing 102 episodes and 106 injuries. Musculoskeletal injuries
      accounted for 80% of all injuries. Fractures and dislocations were the most
      frequent injuries (59%); six required operative management. One serious intra
      abdominal injury occurred. Head and facial injuries occurred in 17% of subjects;
      none required operative repair. Admission rate was 9%. Safety equipment use was
      greater than 91%. Significantly more injuries occurred in the ramp/bars areas
      compared to the half-pipe and gully areas, suggesting that SP design may
      significantly influence injury patterns. A substantial number of injuries
      occurred at the SP, despite controlled conditions and equipment requirements.

PMID- 12426019
TI  - Blurred vision, epistaxis, and fever in a young man.

PMID- 12426020
TI  - Abdominal pain and bruising.

PMID- 12426021
TI  - A national epidemic of unassigned patients: is the hospitalist the solution?

PMID- 12426022
TI  - BiPAP in severe acute congestive heart failure.

PMID- 12426023
TI  - Acute thoracic aortic dissection is a true emergency.

PMID- 12426024
TI  - Valproic acid is a structural analog of GABA that enters various metabolic
      pathways and has many clinical effects.

PMID- 12426025
TI  - Bochdalek hernia in adult.

PMID- 12426027
TI  - Problem gambling in the partner of the emergency department patient as a risk
      factor for intimate partner violence.
AB  - It has been suggested that the increase in gambling activity nationally has
      resulted in an increase in intimate partner violence (IPV). There are apparently
      no studies that have assessed problem gambling as a risk factor for IPV. To
      determine if problem gambling in the partner is a risk factor for IPV, a cross
      sectional study was conducted at a university-based Emergency Department (ED).
      All women aged 19 to 65 years who presented to the ED for treatment and were not
      decisionally incapacitated or acutely ill were eligible. Data were collected by a
      research assistant during 4 or 8-h blocks covering each day of the week over a 10
      week period during the months of June through August 1999. There were 300
      consecutive women approached, and 286 (95%) agreed to participate. Of the women
      who agreed to participate, 237 (83%) reported having an intimate partner in the
      last year, and 61 (25.7%) of these women were categorized as experiencing IPV.
      The odds ratio (OR) of experiencing IPV was the main outcome measure, estimated
      using standard logistic regression, given the presence of various personal and
      partner characteristics, including problem gambling in the partner. The results
      revealed that the relative odds were elevated for women whose partners were
      problem gamblers (adjusted OR: 10.5; 95% CI: 1.3-82) or problem drinkers
      (adjusted OR: 6.1; 95% CI: 2.5-14). The presence of both problem gambling and
      problem drinking in the partner was associated with an even higher OR (adjusted
      OR: 50; 95% CI: 9-280). Our study shows that problem gambling in the partner is
      associated with IPV. The causes of IPV are not fully known, but the association
      of problem gambling in the partner with IPV could lead to new intervention
      strategies and Emergency Medicine research in the future.

PMID- 12426026
TI  - Reports of osteopenia/rickets of prematurity are on the increase because of
      improved survival rates of low birthweight infants.

PMID- 12426028
TI  - A common carotid artery dissection.

PMID- 12426029
TI  - Acute aortic dissection shown on lateral chest X-ray film.

PMID- 12426030
TI  - Cognitive performance in schizophrenia: relationship to regional brain volumes
      and psychiatric symptoms.
AB  - In an all-male sample of schizophrenic patients stabilized by medication (n=62)
      and normal controls (n=27), we obtained neuropsychological test data and high
      resolution whole brain magnetic resonance scans, as well as detailed psychiatric
      rating scales on a subset of the patients (n=47). Schizophrenic patients had
      significantly worse overall age-adjusted cognitive performance than normal
      controls (average z-score=-0.90, range=-0.60 to -1.81), which included relatively
      more severe deficits with different types of memory, psychomotor speed, verbal
      fluency and verbal abstraction. Schizophrenic patients also had significantly
      smaller bilateral volumes in gray but not white matter in the prefrontal region,
      superior temporal gyrus and whole temporal lobe, but no group differences were
      observed in the hippocampus and parahippocampus. Correlations between the brain
      regions and cognitive performance revealed different sets of significant
      relationships for the two groups, particularly in the prefrontal and hippocampal
      regions. In addition, inverse correlations were observed between certain
      cognitive abilities (psychomotor speed, cognitive flexibility and verbal fluency)
      and patients' psychiatric ratings, especially with measures of negative symptoms.
      The convergence of findings for schizophrenic patients regarding the prefrontal
      region, negative symptoms, psychomotor speed and cognitive flexibility suggests
      that schizophrenic negative symptoms may involve disruption of frontal
      subcortical connections.

PMID- 12426031
TI  - Reversed hemispheric asymmetry during simple visual perception in schizophrenia.
AB  - Processing of sensory information in the human brain progresses from primary
      areas, dedicated to a single sensory feature, to multimodal areas, which
      integrate many features across sensory modalities. For some of these processes
      hemispheric dominance has developed. Here we report the results of a passive
      viewing task using positron emission tomography. Subjects were scanned twice
      while staring at a stationary visual noise pattern. Normal subjects showed a
      significant reduction of regional cerebral blood flow (rCBF) in a distributed
      right hemisphere network of brain regions during the second visual task.
      Schizophrenic subjects, however, showed significant increases of right hemisphere
      rCBF during the second visual task and showed significant decreases only in the
      left hemisphere. These results are consistent with the notion of reversed
      hemispheric asymmetry during the processing of sensory information in
      schizophrenia.

PMID- 12426032
TI  - Handedness and corpus callosum morphology.
AB  - Investigations of a relationship between callosal size and functional behavioral
      lateralization lead to the hypothesis that, as the size of the corpus callosum
      (CC) increases, interhemispheric information transfer is facilitated and
      behavioral laterality effects become smaller. The aim of our in vivo study was to
      investigate the relationship between functional asymmetry of handedness and CC
      size in healthy subjects. Magnetic resonance images of the CC and five CC
      subregions were obtained with a 1.5-T Magnetom using a three-dimensional T1
      sequence in 46 healthy men. Handedness was determined using the 'handedness
      dominance test' (HDT). According to the HDT values, 32 consistent and 14 non
      consistent right-handers were identified. No significant difference between
      handedness subgroups in CC regions and no significant correlations between HDT
      values and CC areas were detected.

PMID- 12426033
TI  - Low N-acetyl-aspartate and high choline in the anterior cingulum of recently
      abstinent methamphetamine-dependent subjects: a preliminary proton MRS study.
      Magnetic resonance spectroscopy.
AB  - Studies based on animal models report that methamphetamine (MA) abuse diminishes
      dopamine (DA) and serotonin innervation in frontal brain regions. In this in vivo
      human study, we used proton magnetic resonance spectroscopy (MRS), which yields
      measures of N-acetyl-aspartate (NAA), a marker of living neurons, to examine
      frontal brain regions possibly affected by methamphetamine dependence (MD). We
      tested the hypothesis that MD subjects would exhibit abnormally low levels of
      NAA, referenced to creatine (Cr), in anterior cingulate gray matter. We further
      hypothesized that the primary visual cortex, which receives relatively less DA
      innervation than the frontal brain regions, would show normal NAA/Cr ratios in MD
      subjects. Subjects included nine MD men (mean+/-standard deviation (S.D.)=32.5+/
      6.4 years) and nine age-matched control men (mean+/-S.D.=32.7+/-6.8 years). The
      MD subjects were MA-free for 4-13 weeks. Proton MRS metabolites were expressed as
      ratios of creatine; the absolute values of which did not distinguish controls and
      MD subjects. With regard to metabolite ratios, the MD men had significantly lower
      NAA/Cr in the cingulum (mean+/-standard error (S.E.): control=1.46+/-0.03;
      MD=1.30+/-0.03; Mann-Whitney P=0.01) but not in the visual cortex (mean+/-S.E.:
      control=1.64+/-0.06; MD=1.69+/-11; Mann-Whitney P=0.52) relative to controls.
      These results provide evidence for NAA/Cr deficit that is selective to the
      anterior cingulum, at least with respect to visual cortex, in MD subjects. The
      neuronal compromise that these changes reflect may contribute to the attentional
      deficits and dampened reward system in MD.

PMID- 12426034
TI  - Lack of self-control as assessed by a personality inventory is related to reduced
      volume of supplementary motor area.
AB  - The present study was performed to examine the relationship between schizophrenia
      related personality and brain morphometry. Magnetic resonance (MR) imaging and
      schizophrenia-related personality scales extracted from the Minnesota Multiphasic
      Personality Inventory (MMPI) were administered to 42 university students.
      Analysis of the relationships between the gray matter segmented from the MR
      images on a voxel-by-voxel basis through the use of the statistical parametric
      mapping technique and the schizophrenia-related personality subscale scores from
      the MMPI revealed that lack of self-control subscale scores were negatively
      related to the gray matter volume of the supplementary motor area (SMA).
      Furthermore, it was suggested that self-control including self-inhibition is
      associated with the density of the SMA, the precuneous and the cerebellar vermis,
      which govern voluntary movements and motor imagery. These results provide
      important clues to the neural basis for the disturbance of self commonly observed
      in schizophrenia spectrum disorders.

PMID- 12426035
TI  - MRI parcellation of the frontal lobe in boys with attention deficit hyperactivity
      disorder or Tourette syndrome.
AB  - Dysfunction of frontal-striatal-thalamic-frontal circuitry has been hypothesized
      to underlie both attention deficit hyperactivity disorder (ADHD) and Tourette
      syndrome (TS). Several research groups have therefore used anatomic magnetic
      resonance imaging (aMRI) to obtain volumetric measurements of subregions of the
      frontal lobe in these disorders. Most previous studies have relied on
      subparcellation methods that utilize callosal landmarks to derive subregions of
      the frontal lobe. In contrast, we present here an investigation of frontal lobe
      morphometry in ADHD and TS based on a reliable frontal subparcellation protocol
      that combines contiguous sulcal/gyral boundaries to derive frontal lobe modules
      based on prior functional studies. This highly reliable procedure subdivides the
      frontal lobe into five major modules: prefrontal, premotor, motor (precentral
      gyrus), anterior cingulate, and deep white matter. The first four modules are
      also segmented into gray and gyral white matter compartments. The protocol was
      applied to T1-weighted, SPGR coronal MRI images of 13 school-aged boys with ADHD,
      13 boys with TS, and 13 age- and gender-matched controls. In ADHD, we found
      volumetric reductions in both the gray and white matter of the prefrontal cortex.
      These findings, in conjunction with previous reports on basal ganglia
      abnormalities, suggest that prefrontal-striatal pathways may be anomalous in
      ADHD. In TS, we found volumetric decreases in the left deep frontal white matter.
      Decreases in deep white matter suggest the presence of abnormalities in long
      associational and projection fiber bundles in TS. The findings of this study both
      confirm and extend our knowledge of the neurobiology of ADHD and TS, indicating
      that the reliable parcellation method presented has the potential of increasing
      our understanding of the role of the frontal lobe in developmental and
      psychiatric disorders.

PMID- 12426036
TI  - Utility of simultaneous brain, CSF and hyperintensity quantification in dementia.
AB  - Improved methods of quantifying MRI are needed to study brain-behavior
      relationships in dementia. Rating scales are variable; lesion-tracing approaches
      can be subjective and ignore atrophy; segmentation of MRI hyperintensities is
      complicated by partial volume effects; and hyperintense lesions in different
      anatomical areas may have different effects. The goal of this study was to extend
      existing segmentation approaches to include hyperintensities and to demonstrate
      the utility of simultaneously assessing atrophy and lesion compartments in
      dementia. A semi-automated method was applied to quantify brain and cerebrospinal
      fluid (CSF) compartments and to subclassify hyperintensities into
      periventricular, deep white matter, thalamic and basal ganglia compartments.
      Twenty MR scans from participants in an ongoing dementia study were used to
      generate intra- and inter-rater reliability estimates. High intra- and inter
      class correlation coefficients (0.83-0.99) were obtained for all measures and the
      semi-automated measurements were highly correlated with traced volumes. Brain,
      CSF and specific lesion volumes were significantly correlated with
      neuropsychological functions. In models using only total hyperintensity volumes,
      the effects of lesion compartments (such as thalamic) were masked. Simultaneous
      quantification of atrophy and anatomically distinct hyperintensities is important
      for understanding cognitive impairments in dementia.

PMID- 12426037
TI  - Cortical hypoactivation during resting EEG in schizophrenics but not in
      depressives and schizotypal subjects as revealed by low resolution
      electromagnetic tomography (LORETA).
AB  - This study was performed in order to address the question whether the newly
      introduced technique of low-resolution electromagnetic tomography (LORETA) is
      able to detect hypofrontality in schizophrenic patients. We investigated resting
      EEGs of 19 unmedicated schizophrenics and 20 normal subjects. For comparison, we
      also investigated 19 subjects with schizotypal personality and 30 unmedicated
      depressive patients. A significant increase of delta activity was found in
      schizophrenic patients over the whole cortex, most strongly in the anterior
      cingulate gyrus and temporal lobe (fusiform gyrus). Both schizotypal subjects and
      depressive subjects showed significantly less delta, theta and beta activity in
      the anterior cingulum, a decrease of alpha1 activity in the right temporal lobe
      and a decrease of alpha2 activity in the left temporal lobe. The results suggest
      general cortical hypoactivation, most pronounced in the anterior cingulate and
      temporal lobe in schizophrenics, whereas there is evidence for a complex,
      frequency-dependent spatial pattern of hyperactivation in schizotypal subjects
      and depressive patients. The results are discussed within a neurophysiological
      and methodological framework.

PMID- 12426038
TI  - Right prefrontal rTMS treatment for refractory auditory command hallucinations -
      a neuroSPECT assisted case study.
AB  - Auditory command hallucinations probably arise from the patient's failure to
      monitor his/her own 'inner speech', which is connected to activation of speech
      perception areas of the left cerebral cortex and to various degrees of
      dysfunction of cortical circuits involved in schizophrenia as supported by
      functional brain imaging. We hypothesized that rapid transcranial magnetic
      stimulation (rTMS), by increasing cortical activation of the right prefrontal
      brain region, would bring about a reduction of the hallucinations. We report our
      first schizophrenic patient affected with refractory command hallucinations
      treated with 10 Hz rTMS. Treatment was performed over the right dorsolateral
      prefrontal cortex, with 1200 magnetic stimulations administered daily for 20 days
      at 90% motor threshold. Regional cerebral blood flow changes were monitored with
      neuroSPECT. Clinical evaluation and scores on the Positive and Negative Symptoms
      Scale and the Brief Psychiatric Rating Scale demonstrated a global improvement in
      the patient's condition, with no change in the intensity and frequency of the
      hallucinations. NeuroSPECT performed at intervals during and after treatment
      indicated a general improvement in cerebral perfusion. We conclude that right
      prefrontal rTMS may induce a general clinical improvement of schizophrenic brain
      function, without directly influencing the mechanism involved in auditory command
      hallucinations.

PMID- 12426039
TI  - Differences in regional cerebral blood flow during musical and verbal
      hallucinations.
AB  - A 51-year-old male patient suffered from both musical and verbal hallucinations
      with insight. We performed three single photon emission computed tomographic
      scans with the patient in different conditions: baseline without hallucinations,
      musical hallucinations, and verbal hallucinations. Clearly, different patterns of
      regional cerebral blood flow (rCBF) were observed during musical and verbal
      hallucinations. The findings suggest that musical and verbal hallucinations are
      associated with different patterns of rCBF, possibly reflecting the different
      causes of the two types of hallucinations.

PMID- 12426040
TI  - Theophylline-induced respiratory recovery following cervical spinal cord
      hemisection is augmented by serotonin 2 receptor stimulation.
AB  - Cervical spinal cord hemisection leads to a disruption of bulbospinal innervation
      of phrenic motoneurons resulting in paralysis of the ipsilateral hemidiaphragm.
      We have previously demonstrated separate therapeutic roles for theophylline, and
      more recently serotonin (5-HT) as modulators to phrenic nerve motor recovery;
      mechanisms that likely occur via adenosine A1 and 5-HT2 receptors, respectively.
      The present study was designed to specifically determine if concurrent
      stimulation of 5-HT2 receptors may enhance motor recovery induced by theophylline
      alone. Adult female rats (250-350 g; n=7 per group) received a left cervical (C2)
      hemisection that resulted in paralysis of the ipsilateral hemidiaphragm. Twenty
      four hours later rats were given systemic theophylline (15 mg/kg, i.v.),
      resulting in burst recovery in the ipsilateral phrenic nerve. Theophylline
      induced recovery was enhanced with the 5-HT2A/2C receptor agonist, (+/-)-2,5
      dimethoxy-4-iodoamphetamine hydrochloride (DOI; 1.0 mg/kg). DOI-evoked
      augmentation of theophylline-induced recovery was attenuated following subsequent
      injection of the 5-HT2 receptor antagonist, ketanserin (2.0 mg/kg). In a separate
      group, rats were pretreated with ketanserin, which did not prevent subsequent
      theophylline-induced respiratory recovery. However, pretreatment with ketanserin
      did prevent DOI-induced augmentation of the theophylline-evoked phrenic nerve
      burst recovery. Lastly, using immunocytochemistry and in situ hybridization, we
      showed for the first time a positive co-localization of adenosine A1 receptor
      mRNA and immunoreactivity with phrenic motoneurons of the cervical ventral horns.
      Taken together, the results of the present study suggest that theophylline may
      induce motor recovery likely at adenosine A1 receptors located at the level of
      the spinal cord, and the concurrent stimulation of converging 5-HT2 receptors may
      augment the response.

PMID- 12426041
TI  - Ischemic intensity influences the distribution of delayed infarction and
      apoptotic cell death following transient focal cerebral ischemia in rats.
AB  - The aim of this study was to investigate whether the apoptotic process
      contributes to the delayed infarction that follows a middle cerebral artery (MCA)
      occlusion of 20 min (mild ischemia group) and to compare this with the delayed
      component of infarct following 2 h of MCA occlusion (severe ischemia group).
      Adult male Sprague-Dawley rats underwent left MCA occlusion for either 20 min or
      2 h and were reperfused for 12, 24 and 72 h. On 2,3,5-triphenyltetrazolium
      chloride-stained coronal sections, delayed infarction was observed to develop in
      the whole MCA territory after mild ischemia, and also in the frontoparietal
      cortex after severe ischemia. At 24 h after 20 min of MCA occlusion,
      characteristic apoptotic features, including chromatin condensation and apoptotic
      bodies were frequently observed by electron microscopy. In both ischemic groups,
      Hoechst 33342 staining showed typically condensed and fragmented nuclei in the
      area showing delayed infarction, where TdT-dUTP nick end labeling (TUNEL)
      positive cells were also significantly increased. Caspase-3 activity was also
      found to be elevated 24 and 72 h after reperfusion and this peaked at 24 h in
      both groups. These findings suggest that ischemic severity may influence the
      distribution of delayed infarction, and that apoptosis is the underlying
      pathophysiologic mechanism.

PMID- 12426042
TI  - Mutant Taiep rats exhibit an increase in D1 binding in basal ganglia.
AB  - Previous reports have shown that the Taiep rat develop a progressive neurological
      syndrome characterized by tremor, ataxia, immobility episodes, audiogenic
      seizures and hind limb paralysis. Here we have investigated whether differences
      in levels of dopamine D1-like and D2-like receptors could be correlated with the
      progression of this neurological syndrome. Comparative autoradiographic study of
      Taiep and Sprague-Dawley (SD) rats at level of basal ganglia and limbic subregion
      were undertaken in 3- and 9-month-old rats. The Taiep rats exhibited a higher
      level of D1 receptors in the basal ganglia subregions compared to SD. However,
      there were no differences in the level of D1 receptors in the limbic subregions
      between these two strains. As compared to the SD rats, the Taiep rats did not
      appear to change levels of D2-like receptors. These data suggest that the
      differences in D1 receptors in these two strains rats may in part contribute to
      develop the dopamine related symptoms seen in the mutant rat, such as tremor,
      which is the earliest sign of the Taiep rat syndrome.

PMID- 12426043
TI  - Age and gender effects on microglia and astrocyte numbers in brains of mice.
AB  - The morphological changes that occur during normal brain aging are not well
      understood. This study used modern stereology to assess the effects of age and
      gender on total numbers of astrocytes and microglia in the hippocampal formation
      in C57Bl/6NNIA (B6) mice. Astrocytes and microglia were visualized using
      immunocytochemistry for glial fibrillary acidic protein (GFAP) and complement
      receptor 3 (Mac-1), respectively, and numbers of each cell type in dentate gyrus
      (DG) and CA1 regions were estimated using the optical fractionator method. The
      results reveal significantly greater ( approximately 20%) numbers of microglia
      and astrocytes in aged females compared to young female B6 mice. We also report
      that on average female B6 mice have 25-40% more astrocytes and microglia in DG
      and CA1 regions than age-matched male C57Bl/6J mice. Since astrocytes and
      microglia are thought to be targets of gonadal hormones, the effects of sex
      hormones and reproductive aging may be responsible for these findings.

PMID- 12426044
TI  - Spatial learning, exploration, anxiety, and motor coordination in female APP23
      transgenic mice with the Swedish mutation.
AB  - Transgenic mice overexpressing the betaAPP gene with the Swedish mutation under
      the control of the murine thy-1 promoter show Alzheimer-like characteristics
      including the accumulation of Abeta protein in the cerebral cortex. Female 16
      month-old APP23 transgenic mice were compared to age-matched non-transgenic mice
      in behavioral tests measuring spatial learning, exploration of environmental
      stimuli, anxiety, and motor coordination. APP23 transgenic mice had fewer fast
      ambulatory movements, either fast or slow stereotypy movements, and slow rears in
      a photocell activity chamber. The acquisition of spatial learning in the Morris
      water maze was impaired in APP23 transgenic mice, but not during the probe test
      or while swimming towards a visible platform. Neither were there intergroup
      differences in tests of anxiety or motor coordination. These results indicate
      that a learning deficit and hypoactivity, concordant with the early stages of
      Alzheimer's disease, characterize this mouse model with Abeta accumulation.

PMID- 12426045
TI  - MDMA alters the response of the circadian clock to a photic and non-photic
      stimulus.
AB  - 3,4-Methylenedioxymethamphetamine (MDMA or 'Ecstasy') is a widely used
      recreational drug that damages serotonin 5-HT neurons in animals and possibly
      humans. Published literature has shown that the serotonergic system is involved
      in photic and non-photic phase shifting of the circadian clock, which is located
      in the suprachiasmatic nuclei. Despite the dense innervation of the circadian
      system by 5-HT and the known selective neurotoxicity of MDMA, little is known
      about the effects of MDMA on the circadian oscillator. This study investigated
      whether repeated exposure to the serotonin neurotoxin MDMA alters the behavioural
      response of the Syrian hamster to phase shift to the serotonin 5-HT1A/7 receptor
      agonist 8-hydroxy-2-(di-n-propylamino) tetralin hydrobromide (8-OH-DPAT). This
      agonist was administered under an Aschoff Type I (CT8) and Aschoff Type II (ZT8)
      paradigm (5 mg/kg) and was given before and after treatment with MDMA (10, 15 and
      20 mg/kg administered on successive days). Pre-treatment with MDMA significantly
      attenuated phase shifts to 8-OH-DPAT. We also tested the ability of the clock to
      phase shift to a photic stimulus after treatment with MDMA. A 15-min light pulse
      (mean lux 125 at CT14 or ZT14) was administered before and after treatment with
      MDMA. Phase shifts to a photic stimulus were significantly attenuated by pre
      treatment with MDMA. Our study demonstrates that repeated exposure to MDMA may
      alter the ability of the circadian clock to phase shift to a photic and non
      photic stimulus in the hamster. Disruption of circadian function has been linked
      with a variety of clinical conditions such as sleep disorders, mood,
      concentration difficulties and depression, consequently outlining the potential
      dangers of long-term ecstasy use.

PMID- 12426046
TI  - IgG-immunostaining in the intact rabbit brain: variable but significant staining
      of hippocampal and cerebellar neurons with anti-IgG.
AB  - A significant number of brain neurons in the rabbit brain were immunostained with
      anti-rabbit gamma-immunoglobulin (IgG). IgG-positive neurons were often found in
      the cerebellum, lower brainstem and motor nuclei. Similar IgG-positive neurons
      were occasionally found in the hippocampus, cerebral cortex and midbrain, but not
      in the striatum and thalamus. These neurons showed very clear Golgi-like staining
      of soma and dendrites but IgG staining was absent from the cell nuclei and axons.
      In particular, groups of Purkinje neurons in the rabbit cerebellum showed strong
      IgG-positive staining. To confirm whether the staining reflected the existence of
      IgG molecules in these neurons, staining specificity was carefully evaluated.
      Staining was specifically eliminated by pre-absorption of the antibodies with the
      purified rabbit IgG. An antibody to the neural cell adhesion molecule (NCAM or
      CD56), a member of the immunoglobulin superfamily, exhibited a completely
      different pattern of staining as that for IgG. To determine whether IgG-like
      immunoreactivity was a general feature of mammalian brain, brain sections of
      rabbits, rats, and mice were immunostained with antibodies to IgGs of each of the
      three species. Similar IgG-positive neurons were observed in all three species,
      although the distribution and frequency was characteristic for each species. In
      rabbit brain, anti-rabbit IgG stained-neurons were more abundant compared to rat
      and mouse brain. IgG-positive microglia-like cells were evident in mouse brain,
      but less frequent in rabbit and were hardly observed in rat brain. To evaluate
      whether stained neurons could synthesize IgG, in situ hybridization was carried
      out using an antisense oligonucleotide probe to rabbit IgG DNA. No significant
      label was observed in cerebellum. These results suggest that a significant number
      of neurons in the intact rabbit brain take up IgGs and concentrate them in their
      cytoplasm, although the molecular uptake mechanism is retained for future
      studies. Our results also suggest that the rabbit may be a suitable animal to
      study the function(s) of IgG in brain neurons.

PMID- 12426047
TI  - Neuropilin-2 is overexpressed in the rat brain after limbic seizures.
AB  - Structural rearrangement and synaptic reorganization are known to occur in the
      brain after seizures. If neuronal rearrangement after seizures always results in
      abnormal hyperexcitability, it would provide an accurate pathway to the
      appropriate target and as a result, it may be the mechanism of epileptogenesis.
      This study examined the mechanism of axon guidance in the mature rat brain after
      seizures by evaluating the expression of the axonal guidance molecule, neuropilin
      2. We assessed the expression of neuropilin-2 by northern blotting and
      immunohistochemistry in rat with seizures created by kindling stimulation and
      kainate injection.The neuropilin-2 mRNA level was increased in the whole brain of
      the rats at 24 h after either type of seizure. Neuropilin-2 mRNA was not
      increased at 2 weeks after the last stimulation. Immunohistochemistry
      demonstrated that neuropilin-2 protein was increased in the dentate gyrus and the
      entorhinal cortex in the both seizure models. These findings suggested that there
      was overexpression of neuropilin-2 in the brains of mature rats with different
      types of seizure. Accordingly, neuropilin-2 might regulate remodeling after
      seizures as it does during the development of the hippocampal formation. Our
      findings suggest that axons may not project and outgrow 'aberrantly' after
      seizures, but may be regulated by the chemorepellent effect through neuropilin-2.

PMID- 12426048
TI  - Comparison of SLN-evoked swallows during rest and chewing in the freely behaving
      rabbit.
AB  - Interactions between the swallowing central neural pathway and the chewing
      central neural pathway were examined in freely behaving, unanesthetized rabbits.
      Pharyngeal swallows were elicited by electrical stimulation of the superior
      laryngeal nerve (SLN) and defined by thyrohyoid muscle (TH) activity in the
      electromyogram (EMG). Recordings were obtained from rabbits at rest and during
      chewing. The number of swallows elicited by the SLN stimulation was significantly
      increased (P<0.001) during quiet oral function (at rest) and during chewing. The
      increased number of swallows from each baseline was similar, signifying that the
      effect of the SLN stimulation was similar in generating swallowing in both
      groups. The swallows induced with SLN stimulation were very similar to natural
      swallows as defined by the temporal pattern of the EMG duration and the timing of
      EMG activities. Our results suggest that: (1). the peripheral inputs to the
      swallowing pathway may rarely be modulated by the chewing pathway in the
      generation of swallows; (2). the swallowing pathway and the chewing pathway may
      interact at the level of the rhythm generators; (3). each animal has its own
      threshold for eliciting pharyngeal swallowing, and the threshold may be
      independent of the number of chews.

PMID- 12426049
TI  - GABA(A) receptor antagonists enhance cortical acetylcholine release induced by 5
      HT(3) receptor blockade in freely moving rats.
AB  - ACh release from the rat frontal cortex was increased by both local, 0.1-1
      microM, and systemic, 0.1-10 microg/kg, administration of the 5-HT(3) receptor
      antagonist ondansetron, reaching a maximum peak of 143% over basal values.
      Bicuculline, 1-10 microM, and flumazenil, 5-10 mg/kg, antagonists at different
      sites of the GABA(A) receptor, also enhanced ACh release, with maximum effects of
      85 and 124% above baseline, respectively. GABA(A) receptor antagonists
      potentiated the effect induced by ondansetron on ACh release, reaching a peak
      increase of 238% (with bicuculline) and 259% (with flumazenil) over basal levels.
      These results suggest an interaction of ondansetron with GABAergic neurons
      modulating ACh release in the rat frontal cortex in vivo.

PMID- 12426050
TI  - Loss of benefit from estrogen replacement therapy in diabetic ovariectomized
      female rats subjected to transient forebrain ischemia.
AB  - In nondiabetic animals, estrogen has been shown to provide significant
      neuroprotection in focal and transient forebrain ischemia models. However, that
      neuroprotection may be diminished or lost in the diabetic. In this study, we
      compared the level of brain damage in intact, ovariectomized (OVX) and 17beta
      estradiol (E(2))-treated OVX female rats rendered diabetic and chronically (
      approximately 4 weeks) hyperglycemic via streptozotocin (STZ). Rats were
      subjected to 20 min of unilateral transient forebrain ischemia (reduction in
      cortical CBF to 20% of baseline). Neurologic function was analyzed daily and
      brain histopathology (in H&E-stained sections) was evaluated at 72 h of
      reperfusion. Supplemental histopathologic information was obtained from
      additional TUNEL-stained sections. When comparing neurologic outcome scores in
      the three groups, E(2)-treated OVX females displayed the highest degree of
      dysfunction and intact females the least (OVX rats not treated with E(2) were
      intermediate), with the difference between the intact and E(2)-treated groups
      being statistically significant. That same order was often observed with the
      regional histopathologic analyses of H&E-stained tissue. A significantly higher
      magnitude of neuronal loss in both OVX groups, when compared to intact females,
      was observed in the CA4 sector of the hippocampus and in the cortex. In addition,
      cell loss in the dorsal thalamus of the E(2)-treated group was significantly
      greater than in the intact females. Those results were generally corroborated by
      TUNEL-analysis, with 67% of the E(2)-treated, 33% of the control OVX, and only
      17% of the intact females displaying TUNEL-positive cells in multiple regions. In
      conclusion, the present findings strongly suggest that the neuroprotective
      benefits of estrogen replacement therapy may be lost in the diabetic female rat.

PMID- 12426051
TI  - The role of histamine in dural vessel dilation.
AB  - The pain of migraine is often throbbing suggesting an important role for the
      cranial blood vessels and their innervation by the trigeminal nerve. It is
      proposed that clinically effective anti-migraine compounds, such as 5-HT(1B/1D)
      agonists, have actions that include inhibiting calcitonin gene-related peptide
      (CGRP) release from trigeminal nerves. Human studies suggest that histamine can
      induce migraine possibly by activating nitric oxide (NO) synthase to promote
      endogenous NO production. The present studies investigated the effect of
      histamine and its antagonists on the cranial blood vessels using intravital
      microscopy to assess directly the diameter of dural arteries in sodium
      pentobarbitone anaesthetised rats. Electrical stimulation of a closed cranial
      window produces, by local depolarisation of nerves, dural vessel dilation that is
      monitored continuously on-line using video-microscopy and a video dimension
      analyser. Histamine infusion caused immediate and reproducible dilation of
      meningeal blood vessels (103.5+/-6%; n=40) that could be blocked by H(1)-
      (mepyramine) and H(2) (famotidine)-receptor antagonists (P<0.05), as well as a
      nitric oxide synthase inhibitor (N(G)-nitro-L-arginine methylester; P<0.05).
      Neurogenic dural vasodilation was not inhibited by H(2)-receptor antagonists, but
      was significantly inhibited by a H(1)-receptor antagonist at the high dose of 10
      mg/kg. The present studies demonstrate that histamine is likely to activate NO
      synthase to promote NO production. There is also evidence that H(1)-receptors may
      be present on trigeminal neurones as the H(1)-receptor antagonist inhibited
      neurogenic vasodilation, albeit at a large dose.

PMID- 12426052
TI  - Central serotonergic and adrenergic/imidazoline inhibitory mechanisms on sodium
      and water intake.
AB  - Recent studies have shown the existence of two important inhibitory mechanisms
      for the control of NACL and water intake: one mechanism involves serotonin in the
      lateral parabrachial nucleus (LPBN) and the other depends on alpha(2)
      adrenergic/imidazoline receptors probably in the forebrain areas. In the present
      study we investigated if alpha(2)-adrenergic/imidazoline and serotonergic
      inhibitory mechanisms interact to control NaCl and water intake. Male Holtzman
      rats with cannulas implanted simultaneously into the lateral ventricle (LV) and
      bilaterally into the LPBN were used. The ingestion of 0.3 M NaCl and water was
      induced by treatment with the diuretic furosemide (10 mg/kg of body weight)+the
      angiotensin converting enzyme inhibitor captopril (5 mg/kg) injected
      subcutaneously 1 h before the access of rats to water and 0.3 M NaCl.
      Intracerebroventricular (i.c.v.) injection of the alpha(2)-adrenergic/imidazoline
      agonist clonidine (20 nmol/1 microl) almost abolished water (1.6+/-1.2, vs.
      vehicle: 7.5+/-2.2 ml/2 h) and 0.3 M NaCl intake (0.5+/-0.3, vs. vehicle: 2.2+/
      0.8 ml/2 h). Similar effects were produced by bilateral injections of the
      5HT(2a/2c) serotonergic agonist 2,5-dimetoxy-4-iodoamphetamine (DOI, 5 microg/0.2
      microl each site) into the LPBN on water (3.6+/-0.9 ml/2 h) and 0.3 M NaCl intake
      (0.4+/-0.2 ml/2 h). Injection of the alpha(2)-adrenergic/imidazoline antagonist
      idazoxan (320 nmol) i.c.v. completely blocked the effects of clonidine on water
      (8.4+/-1.5 ml/2 h) and NaCl intake (4.0+/-1.2 ml/2 h), but did not change the
      effects of LPBN injections of DOI on water (4.2+/-1.0 ml/2 h) and NaCl intake
      (0.7+/-0.2 ml/2 h). Bilateral injections of methysergide (4 microg/0.2 microl
      each site) into the LPBN increased 0.3 M NaCl intake (6.4+/-1.9 ml/2 h), not
      water intake. The inhibitory effect of i.c.v. clonidine on water and 0.3 M NaCl
      was still present after injections of methysergide into the LPBN (1.5+/-0.8 and
      1.7+/-1.4 ml/2 h, respectively). The results show that the inhibitory effects of
      the activation of alpha(2)-adrenergic/imidazoline receptors in the forebrain are
      still present after blockade of the LPBN serotonergic mechanisms and vice versa
      for the activation of serotonergic mechanisms of the LPBN. Therefore, each system
      may act independently to inhibit NaCl and water intake.

PMID- 12426053
TI  - Kainic acid induces 14-3-3 zeta expression in distinct regions of rat brain.
AB  - Areas of the limbic system of adult male Wistar rats were screened for kainic
      acid-induced gene expression. Polymerase-chain-reaction-based differential
      display identified a 147-bp cDNA fragment, which represented an mRNA that was
      upregulated in the entorhinal cortex and hippocampus in the kainic-acid-treated
      animals. The sequence was 97.8% homologous to rat 14-3-3 zeta isoform mRNA.
      Detailed Northern analysis revealed increased mRNA levels in the entorhinal
      cortex 1 h after kainic acid exposure and continued elevation 24 h post-injection
      in both the entorhinal cortex and hippocampus. Western blot analyses confirmed
      that the protein product of this gene was also present in increased amounts over
      the same time period. Immunohistochemistry and terminal transferase-mediated dUTP
      nick end labelling (TUNEL) detected expression of 14-3-3 zeta protein exclusively
      in the entorhinal cortex and hippocampus, and only in TUNEL-positive neuronal
      cells. Expression of the tumor suppressor protein, p53 was also induced by
      kainate injection, and was co-localized with 14-3-3 zeta protein in selected
      cells only in the affected brain regions. The increase gene expression of 14-3-3
      zeta represents a transcription-mediated response associated with region
      selective neuronal damage induced by kainic acid.

PMID- 12426054
TI  - Estrogen blocks 3-nitropropionic acid-induced Ca2+i increase and cell damage in
      cultured rat cerebral endothelial cells.
AB  - Systemic administration of 3-nitropropionic acid (3-NPA, a mycotoxin) induces
      brain damage accompanied by disturbance in the blood-brain barrier (BBB). Since
      the endothelial cells are important components of the BBB and the first target of
      a systemic intoxication, in the present study, the effect of 3-NPA on primary
      cultured rat brain endothelial cells (rBECs) was examined by studying
      intracellular Ca(2+) ([Ca(2+)](i)) response using imaging techniques with fura-2.
      rBECs were prepared using a method of Kis et al. [Eur. J. Pharmacol. 368 (1999)
      35-42] and Szabo et al. [Neurobiology 5 (1997) 1-16]. Almost all cells were
      immunoreactive to antibody against the factor VIII-related antigen (von
      Willebrand factor). They showed a typical dose-dependent increase of [Ca(2+)](i)
      in response to ATP or bradykinin. Low concentrations of 3-NPA (1.7 mM, 3.4 mM)
      caused no changes, and a medium concentration (6.8 mM) increased the [Ca(2+)](i)
      gradually and progressively, and the increase was reversed incompletely back to
      the resting level after washing. A high concentration (13.6 mM) increased the
      [Ca(2+)](i) irreversibly. These elevations of [Ca(2+)](i) were absent in a Ca(2+)
      free medium. In endothelial cells treated with 17beta-estradiol (above 10(-5) M)
      or with a selective estrogen receptor modulator, tamoxifen (5 x 10(-7) M), no
      elevation of [Ca(2+)](i) was observed with 3-NPA treatment. The response to ATP
      was impaired after application of 3-NPA, but it was preserved by cotreatment with
      17beta-estradiol or tamoxifen. An estrogen receptor antagonist ICI 182,780
      inhibited these effects by 17beta-estradiol or tamoxifen. Lysosomal neutral red
      uptake and TUNEL experiments revealed the necrotic but not apoptotic cell death
      at least in this acute stage. Data indicate that a medium to high concentration
      of 3-NPA induces damage on rBECs as revealed by an accumulation of [Ca(2+)](i),
      but the damage was protected by cotreatment with 17beta-estradiol or tamoxifen,
      suggesting that estrogen may be protective for the brain vascular damage via
      estrogen receptor.

PMID- 12426055
TI  - Brain-derived neurotrophic factor (BDNF) mRNA in rats with neonatal ibotenic acid
      lesions of the ventral hippocampus.
AB  - Increasing evidence suggests that schizophrenia is a neurodevelopmental disorder
      with a progressive course characterized by worsening of symptoms and
      morphological alterations within the brain. This suggests that a
      neurodegenerative component may exist in schizophrenia. The role of brain-derived
      neurotrophic factor (BDNF) in neurodevelopment, cell viability and synaptic
      plasticity led to the investigation of BDNF as a potential candidate molecule in
      the pathophysiology of schizophrenia. BDNF mRNA was examined by in situ
      hybridization in the prefrontal cortex and hippocampus of animals with neonatal
      ibotenic acid lesions of the ventral hippocampus, a putative neurodevelopmental
      animal model of schizophrenia. Results demonstrate that animals with neonatal
      ibotenic acid lesions of the ventral hippocampus have reduced basal levels of
      BDNF mRNA. It is possible that alterations in this trophic factor render animals
      more susceptible to neurodegenerative insults.

PMID- 12426056
TI  - Sympathetic ingrowth to the trigeminal ganglion following intracerebroventricular
      infusion of nerve growth factor.
AB  - The objective of the present study was to examine the remodeling of uninjured
      sympathetic axons in the adult rat trigeminal ganglion following a 2-week in vivo
      intracerebroventricular infusion of NGF. The accumulation of infused NGF in the
      trigeminal was assessed using ELISA and sympathetic fibers were localized
      immunohistochemically with an antibody to tyrosine hydroxylase (TH). In addition,
      high performance liquid chromatography coupled with electrochemical detection
      (HPLC-ECD) allowed for biochemical measurements of the catecholamines
      norepinephrine (NE) and dopamine (DA). Increased NGF protein in the trigeminal
      ganglion was paralleled by a significant increase in sympathetic fibers and
      pericellular plexuses (i.e. baskets) in the cell body regions. Some ganglia
      showed elevated NE following NGF infusion, yet the 88% increase in mean NE did
      not reach significance. Following bilateral removal of the sympathetic superior
      cervical ganglia (SCG), a significant reduction was observed in overall NE levels
      and in TH-immunoreactive (-ir) fibers in the cell body regions and peripheral
      branches, suggesting the SCG as the origin of the sympathetic ingrowth. However,
      mean DA levels as well as TH-ir fibers within the trigeminal central branch were
      unaffected by NGF infusion or removal of the SCG and likely resulted from
      intrinsic dopaminergic cell bodies. In conclusion, our data provide evidence that
      the increased availability of NGF in the young adult rat trigeminal ganglion
      observed following in vivo NGF infusion enhanced sympathetic associations with
      the sensory neurons in the trigeminal, supporting a role for NGF in the
      regulation of sympathosensory interactions.

PMID- 12426057
TI  - Effects of the inferior alveolar nerve stimulation on tongue muscle activity
      during mastication in freely behaving rabbits.
AB  - Genioglossus (Gg) reflexes elicited by electrical stimulation of the inferior
      alveolar nerve were examined in naturally chewing rabbits. To eliminate possible
      contaminations of the digastric (Dig) activity in the Gg responses, the Dig nerve
      was denervated bilaterally. Masticatory and tongue muscles were well coordinated
      during chewing after the denervation; i.e., there were no significant differences
      in the phase durations between before and after denervation. The Gg reflex
      measured was divided into three categories depending on the chewing phase (i.e.,
      jaw-opening, OP; fast-closing, FC; and slow-closing, SC) in which the stimulus
      was delivered. The reflex amplitude was phasically modulated for the phases, in
      that the amplitude in the OP phase was larger than that in any other phase
      (P<0.05). On the other hand, the amplitude in the FC and SC phases was not
      significantly different to each other and from the control value obtained when
      the animal was awake and resting. The pattern of the modulation in the reflex
      amplitude was different from the previous report as to the Dig reflex in that
      OP<FC approximately SC<control was obtained. The results suggest that the
      modulatory mode in the Gg and Dig reflexes may be different in the pattern of the
      modulation under the natural chewing behavior and the Gg reflex is independent of
      the masticatory muscles in the nature. The reflex could be more sensitive to
      control the tongue movements collecting food bolus in the OP phase during chewing
      than in the jaw-closing phase.

PMID- 12426058
TI  - Lysosomal malfunction accompanies alpha-synuclein aggregation in a progressive
      mouse model of Parkinson's disease.
AB  - We have detected granular and filamentous inclusions that are alpha-synuclein-
      and ubiquitin-immunoreactive in the cytoplasm of dopaminergic and cortical
      neurons of C57/black mice treated chronically with 1-methyl-4-phenyl-1,2,3,6
      tetrahydropyridine (MPTP) and probenecid. The immunoreactive aggregates only
      become evident several weeks after large-scale dopaminergic cell death and a
      downregulation of alpha-synuclein gene expression. Numerous lipofuscin granules
      accumulate alpha-synuclein in the nigral and limbic cortical neurons of treated
      mice. These data provide evidence that insoluble proteins, such as alpha
      synuclein, build up as granular and filamentous inclusions in dopaminergic
      neurons that survive the initial toxic MPTP insult. They further suggest that
      defective protein degradation rather than altered gene expression underlies
      deposition of alpha-synuclein and that abundant lysosomal compartments are
      present to seal off the potentially toxic material.

PMID- 12426059
TI  - Zinc, magnesium and copper profiles in three experimental models of epilepsy.
AB  - Trace metals are involved in the mechanisms of CNS excitability, including
      epilepsy. In this study, atomic absorption spectrophotometry was used to
      determine concentrations of Mg(2+), Cu(2+) and Zn(2+) in plasma (microg/ml) and
      hair (microg/g) samples. Differential profiles of trace metals were detected in
      rats displaying three different kinds of seizures, i.e. acute audiogenic seizures
      (generalized tonic-clonic type GTC) and audiogenic kindling (limbic type; LS) in
      Wistar Audiogenic Rats (WARs) and electroshock-induced seizures (ES) in Wistar
      non-epileptic rats (resistant). Significantly lower Zn(2+) concentrations were
      observed in the plasma of WARs (0.80+/-0.02) compared with resistants (0.89+/
      0.03) in the basal (non-seizing) condition. After GTC, WARs showed lower Zn(2+)
      levels (0.64+/-0.12) while both Mg(2+) (12.56+/-1.51) and Cu(2+) (0.81+/-0.14)
      were higher than in non-seizing WARs. After ES-induced seizures only Mg(2+)
      changed, being higher than in the basal condition (11.78+/-2.25 and 8.90+/-0.95).
      In hair, basal levels of Mg(2+) and Cu(2+) (192.49+/-36.73 and 13.33+/-1.76) were
      higher whereas Zn(2+) (136.53+/-15.67) was lower in WARs than in resistants. WARs
      submitted to 0, 3 and 25 stimuli presented higher Mg(2+) concentrations as the
      number of stimuli increased. In animals receiving the same number of stimuli,
      Zn(2+) levels were higher for animals displaying GTC (151.09+/-5.53) than those
      displaying LS (128.07+/-8.51). In conclusion, seizure type (limbic or generalized
      tonic-clonic) and number of stimuli seem to be the determinant factors for
      changes in Zn(2+) and Mg(2+) levels, respectively.

PMID- 12426060
TI  - Far field effects of seizure like events induced by application of 4-AP in
      combined entorhinal cortex hippocampal slices.
AB  - Epileptiform activity induced by 4-AP in hippocampal area CA1 is characterised by
      short recurrent discharges. These are occasionally superimposed by slow field
      potential (fp) shifts. Simultaneous recordings of fps and [K(+)](o) in area CA1
      and temporal cortex showed a slow fp shift in both regions, but associated rises
      in [K(+)](o) occurred only in the cortex. Slow fps in area CA1 persisted after
      disruption of the perforant path, but were abolished after removal of the
      adjacent cortex from the hippocampus. These findings suggest that slow fps in CA1
      can represent far field effects of seizure like events generated in neighbouring
      cortex.

PMID- 12426061
TI  - Nefiracetam induces a long-lasting facilitation of hippocampal postsynaptic
      responses in mice lacking the NMDA receptor epsilon1 subunit.
AB  - The present study was designed to assess whether the facilitatory action of
      nefiracetam, a pyrrolidone derivative, on hippocampal postsynaptic responses is
      dependent upon N-methyl-D-aspartate (NMDA) receptors or not, by monitoring
      population spikes (PSs) in the dentate gyrus of hippocampal slices from mice
      lacking the NMDA receptor epsilon1 subunit. Nefiracetam (1 microM) induced a
      sustained facilitation of postsynaptic responses in the dentate gyrus of
      hippocampal slices from wild-type mice. The facilitation occluded the
      potentiation induced by high-frequency stimulation at the perforant path, and
      vice versa, suggesting a common mechanism between them. The perforant path long
      term potentiation (LTP) was not induced in epsilon1 subunit knock-out mice, but
      nefiracetam (1 microM) persistently potentiated PS amplitude, reaching 280% of
      basal levels 50 min after 10-min treatment, similar to the potentiation achieved
      with wild-type mice. The results of the present study, thus, suggest that
      nefiracetam exerts its facilitatory action on hippocampal postsynaptic responses
      in an NMDA receptor-independent manner.

PMID- 12426062
TI  - What is emotion?
AB  - There is no consensus in the literature on a definition of emotion. The term is
      taken for granted in itself and, most often, emotion is defined with reference to
      a list: anger, disgust, fear, joy, sadness, and surprise. This article expands on
      a thesis that motivational states can be compared to each other by means of a
      common currency (Philos. Trans. Roy. Soc. Lond. 270 (1975) 265-293). I have
      previously argued that this common currency is pleasure. Such a conclusion is
      based not on introspective intuition, as with early pre-scientific psychology (),
      but on experimental methods. As a follow-up to a definition of consciousness
      (Neurosci. Biobehav. Rev. 20 (1996) 33-40) as a four-dimensional experience
      (quality, intensity, hedonicity, and duration), I propose here that emotion is
      any mental experience with high intensity and high hedonic content
      (pleasure/displeasure).

PMID- 12426063
TI  - The science of emotion as a multidisciplinary research paradigm.
AB  - I discuss the emergence of a science of emotion and argue that research in this
      domain requires an appreciation of the organization of emotional processes at
      different levels as postulated by social neuroscience. Emotions cannot be
      understood without relying on a program of multidisciplinary research. Local
      multidisciplinarity cannot be achieved without a programmatic framework that
      takes three issues into account (1) the relationship of multiple levels of
      emotions and connected processes, (2) the mutually informative study of humans,
      animals, and artificial systems, and (3) the dynamic nature of emotions in a
      dynamic systems approach. Illustrations for my arguments are provided relating to
      facial expressions of humans.

PMID- 12426064
TI  - Application of a multilevel model of behavioural control to understanding
      emotion.
AB  - A model of the control of behaviour by a combination of direct stimulus-response
      (S-R) like and cognitive factors is extended to involve emotion. It is argued
      that emotion (a) interacts with such different levels of information processing
      and (b) is itself triggered at different levels of organization by processes that
      are similar to the S-R and cognitive. The model is applied to a range of
      phenomena that are related to emotion, such as modularity, impulsiveness,
      extinction, alcohol effects and attitudes.

PMID- 12426065
TI  - Emotional behaviour as the result of stochastic interactions. A process crucial
      for cognition.
AB  - This paper is aimed at exhibiting two striking features of the usual approach of
      emotional expression in science and philosophy, suggesting a different
      perspective. One is the generally shared belief that emotions are a state of
      utter disarray, which hampers objective knowledge; the other is the search for
      causal explanation, along a wide range of categorized approaches (psychology,
      neurosciences, developmental biology) each proposing its own theoretical
      framework. In both cases the result is to play down emotional expression.
      Alternatively, we propose to view emotions as something crucial in the choice of
      our conceptual tools, ideas and involvements, in the genesis of which various
      explanations interact in a complex stochastic way. Rather than being a harmful
      disruption of the mind calling for identification of a definite causality,
      emotional behaviour appears as a necessary process in cognition, which is
      irreducible to a unique origin.

PMID- 12426066
TI  - Emotional sounds and the brain: the neuro-affective foundations of musical
      appreciation.
AB  - This article summarizes the potential role of evolved brain emotional systems in
      the mediation of music appreciation. A variety of examples of how music may
      promote behavioral change are summarized, including effects on memory, mood,
      brain activity as well as autonomic responses such as the experience of 'chills'.
      Studies on animals (e.g. young chicks) indicate that musical stimulation have
      measurable effects on their behaviors and brain chemistries, especially increased
      brain norepinephrine (NE) turnover. The evolutionary sources of musical
      sensitivity are discussed, as well as the potential medical-therapeutic
      implications of this knowledge.

PMID- 12426067
TI  - Food and emotion.
AB  - The relationship between eating and emotion has always interested researchers of
      human behavior. This relationship varies according to the particular
      characteristics of the individual and according to the specific emotional state.
      We consider findings on the reciprocal interactions between, on the one hand,
      emotions and food intake, and, on the other, the psychological and emotional
      consequences of losing weight and dieting. Theories on the relationship between
      emotions and eating behaviors have their origin in the literature on obesity. The
      psychosomatic theory of obesity proposes that eating may reduce anxiety, and that
      the obese overeat in order to reduce discomfort. The internal/external theory of
      obesity hypothesizes that overweight people do not recognize physiological cues
      of hunger or satiety because of faulty learning. It thus predicts that normal
      weight people will alter (either increase or decrease) their eating when
      stressed, while obese people will eat regardless of their physiological state.
      The restraint hypothesis postulates that people who chronically restrict their
      food intake overeat in the presence of disinhibitors such as the perception of
      having overeaten, alcohol or stress. These theories are examined in the light of
      present research and their implications on eating disorders are presented.

PMID- 12426068
TI  - Emotions in farm animals: a new approach to animal welfare in applied ethology.
AB  - One of the major topics of applied ethology is the welfare of animals reared by
      humans. Welfare can be defined as a state of harmony between an individual and
      its environment. Any marked deviation from this state, if perceived by the
      individual, results in a welfare deficit due to negative emotional experiences.
      In humans, verbal language helps to assess emotional experiences. In animals,
      only behavioural and physiological measurements help to detect emotions. However,
      how to interpret these responses in terms of emotional experiences remains an
      open question. The information on the cognitive abilities of farm animals, which
      are available but scattered, could help the understanding of their emotions. We
      propose a behavioural approach based on cognitive psychology: emotions can be
      investigated in farm animals in terms of the individual's appraisal of the
      situation. This evaluative process depends on: (a) the intrinsic characteristics
      of the eliciting event (suddenness, novelty, pleasantness); (b) the degree of
      conflict of that event with the individual's needs or expectations; and (c) the
      individual's coping possibilities offered by the environment. The result of such
      an evaluation determines the negative versus positive emotions. We propose an
      analysis of the emotional repertoire of farm animals in terms of the relationship
      between the evaluative process of the event on the one hand and the behavioural
      and physiological responses on the other hand.

PMID- 12426070
TI  - Is it important to know about emotions in order to study emotions?

PMID- 12426069
TI  - Comparative analysis of the anxiety-related behaviors in four inbred mice.
AB  - An anxiety-related behavior is an emotional response of an organism, which is
      quantitatively measured by several behavioral paradigms. We employed two most
      frequently used behavioral tests, the open field and light-dark exploration, to
      comparatively analyze the anxiety-like behaviors in four inbred mice. For an
      accurate recording of movement, motion analysis software was developed that
      acquires a real-time video input to generate a behavioral path. Effects of the
      strains on the test results were evaluated by ANOVA with the Newman-Keuls post
      hoc comparison. Eight different behavioral indices, four from each tests, were
      grouped into two classes; the results of duration, center crossing, transition,
      rearing, and ambulation indicate strain differences of
      FVB/N>C57BL/6J>/=BALB/cA>/=CBA/N (I), while stretched-attend posture, peeping,
      and defecation show the tendency of FVB/N=C57BL/6J<CBA/N</=BALB/cA (II). The
      peeping is a novel type of behavior observed in this work. Although there is a
      variation among behavioral indices in their discrimination between inbred lines,
      the behaviors are highly correlated one another such that each class I or class
      II behaviors are clustered on two orthogonal factor planes as a result of the
      principal component analysis. The polarization of each inbred line toward these
      two behavioral biases may reflect genetic backgrounds of these strains.

PMID- 12426071
TI  - Synthesis and characterization of a dianionic carbohydrate-based phospholipid.
AB  - A novel carbohydrate-based phospholipid containing a phosphatidic acid head
      group, bis-(2,3-lauroyl)-1-methoxy-5-ribo-phosphatidic acid (DLRPA), was
      synthesized and characterized by 1H NMR, 13C NMR, and 31P NMR. This molecule is
      an analog of dilauroyl phosphatidic acid (DLPA). The T(m) of DLRPA decreases with
      increasing pH in a similar pattern to DLPA, as determined by MDSC. From this
      thermotropic behavior, the apparent pK(a)s of DLRPA are estimated to be 4 and 8.

PMID- 12426072
TI  - Chemical synthesis, iron redox interactions and charge transfer complex formation
      of alkylitaconic acids from Ceriporiopsis subvermispora.
AB  - In 1999, we first reported that a white rot fungus, Ceriporiopsis subvermispora
      produced a series of novel alkylitaconic acids (ceriporic acids). In the present
      paper we synthesized the metabolite, 1-nonadecene-2,3-dicarboxylic acid
      (ceriporic acid B) by Grignard reaction to analyze chemical properties of the
      alkylitaconates. Mass spectrometer (MS) and nuclear magnetic resonance (NMR)
      spectra of the synthetic compound was identical to those of the fungal metabolite
      isolated. The dicarboxylic acid inhibited autoxidation of Fe(2+) to Fe(3+) as
      well as reduction of Fe(3+) to Fe(2+) by the strong natural reductants, cysteine,
      glutathione, and ascorbic acid. The formation of charge transfer complexes (CTCs)
      between 1-heptadecene-2,3-dicarboxylic acid and oxidized intermediates from
      phenolic substrates were also observed. Thus, we herein report that the new class
      of lipid-related metabolites produced by C. subvermispora are potential
      metabolites participating in the control of iron redox reactions and CTCs
      formation from oxidized lignin fragments.

PMID- 12426073
TI  - Molecular modelling of membrane sterols with the use of the GROMOS 96 force
      field.
AB  - Membrane located sterols determine the structure and function of eucariotic cell
      membranes. Moreover, they are targets for important antifungal antibiotic
      amphotericin B. Knowledge about the geometry and dynamics of sterols in the
      environment of lipidic membranes is necessary to understand their functions.
      However, due to the dynamic character of the membrane, no experimental data about
      sterol behaviour on the molecular level is available. Hence molecular modelling
      simulations could be a source of useful information. The main goal of this paper
      is to prove the adequacy of the GROMOS 96 force field for molecular simulations
      of membrane sterols. We focused our attention on the reproduction of
      characteristic geometrical features observed in the crystal of cholesterol
      hemiethanolate by molecular dynamics simulations. The results presented clearly
      indicate that the GROMOS 96 force field can be a useful tool to simulate the
      highly lipophilic systems. Moreover, interactions responsible for the stability
      of such systems can also be recognised.

PMID- 12426074
TI  - Using simple 13C NMR linewidth and relaxation measurements to make detailed
      chemical shift assignments in triacylglycerols and related compounds.
AB  - Two simple experiments measuring the 13C linewidths nu(1/2) and spin-lattice
      relaxation times T(1) of each of the signals in the spectrum of trilinolein
      indicate that the nu(1/2) and T(1) values are consistent with the different
      degrees of motional freedom expected for the various 13C nuclei. However, for
      each chain, the nu(1/2) and T(1) measurements indicate a small reversal in
      mobility at C-10 relative to C-9 before motional freedom again steadily increases
      on each chain starting at C-11. The T(1) experiment allows unambiguous
      assignments of the C-8 signal and C-14 signal, which differ by only 0.010 ppm.
      Measurements of 13C nu(1/2) and T(1) values on tripalmitin provide secure
      assignments for the C-5 and C-6 signals, for which conflicting assignments have
      been reported. The T(1) measurements also show that among the tightly clustered C
      8 through C-12 signals, the C-11 signals are the most downfield, while the C-12
      signals are the most upfield, again contrary to a previous report. Similar
      measurements of 13C nu(1/2) and T(1) values on other triacylglycerols or related
      compounds may prove equally useful in making chemical shift assignments and
      detecting any discontinuities in motional freedom along a chain. The benefits and
      possible limitations of ultrahigh field NMR for studying triacylglycerols and
      related compounds are discussed.

PMID- 12426075
TI  - Effects of carbohydrate headgroups on the stability of induced cubic phases in
      binary mixtures of glycolipids.
AB  - This paper is part in a series of papers, investigating the influence of
      carbohydrate headgroups on the mesogenic properties of glycolipids. While
      previous papers focussed on the synthesis and mesogenic properties of the pure
      compounds, we will discuss here our results obtained with binary mixtures.
      Mixtures of compounds, one forming a lamellar phase and the other one a columnar
      phase in their pure state, displayed always an induced cubic phase. The stability
      of this induced cubic phase depends significantly on the structure of the
      carbohydrate headgroup of both components. Thus it was possible to derive
      structure-property relationships by comparison of the phase diagrams that have
      been obtained, if the carbohydrate headgroup of one component was changed
      systematically. We observed an interesting effect of galactose headgroups which
      might be of great biological importance. Furthermore, the observed kind of
      kinetic of the S(A)-->cub transition might also be of great biological relevance.

PMID- 12426076
TI  - Membrane destabilization induced by beta-amyloid peptide 29-42: importance of the
      amino-terminus.
AB  - Increasing evidence implicates interactions between Abeta-peptides and membrane
      lipids in Alzheimer's disease. To gain insight into the potential role of the
      free amino group of the N-terminus of Abeta29-42 fragment in these processes, we
      have investigated the ability of Abeta29-42 unprotected and Abeta29-42 N
      protected to interact with negatively-charged liposomes and have calculated the
      interaction with membrane lipids by conformational analysis. Using vesicles
      mimicking the composition of neuronal membranes, we show that both peptides have
      a similar capacity to induce membrane fusion and permeabilization. The fusogenic
      effect is related to the appearance of non-bilayer structures where isotropic
      motions occur as shown by 31P and 2H NMR studies. The molecular modeling
      calculations confirm the experimental observations and suggest that lipid
      destabilization could be due to the ability of both peptides to adopt metastable
      positions in the presence of lipids. In conclusion, the presence of a free or
      protected (acetylated) amino group in the N-terminus of Abeta29-42 is therefore
      probably not crucial for destabilizing properties of the C-terminal fragment of
      Abeta peptides.

PMID- 12426077
TI  - Biotinylated Stealth magnetoliposomes.
AB  - Dimyristoylphosphatidylethanolamine (DC(14:0)PE) and the dioleoyl analogue
      (DC(18:1cis)PE) were mixed with alpha-biotinylamido-omega-N-succinimidoxycarbonyl
      poly(ethylene glycol) (NHS-PEG-biotin) and quantitatively converted to alpha
      biotinylamido-omega-(dimyristoylphosphatidylethanolamino-carbonyl)polyethylene
      glycol (DC(14:0)PE-PEG-biotin) and the dioleoyl analogue DC(18:1cis)PE-PEG
      biotin, respectively. As shown by thin-layer chromatography and 1H NMR
      spectroscopy, PEGylation of both phosphatidylethanolamine types went to
      completion if the reaction was performed in organic solvent in the presence of
      triethylamine. The resulting derivatives were successfully incorporated into both
      classical phospholipid vesicles and a phospholipid bilayer surrounding nanometer
      sized magnetite cores. In the latter case, the so-called activated Stealth(1)
      magnetoliposomes were produced which very efficiently immobilized
      streptavidinylated alkaline phosphatase.

PMID- 12426078
TI  - Role of structure and pH in cyclization of allene oxide fatty acids: implications
      for the reaction mechanism.
AB  - Incubations of allene oxide synthases of flax or maize with the E,E-isomers of
      the 13- and 9-hydroperoxides of linoleic acid (E,E-13- and E,E-9-HPOD,
      respectively) at pH 7.5 afforded substantial yields of trans-disubstituted
      cyclopentenones. Under the conditions used, (Z,E)-HPODs were converted mainly
      into alpha-ketols and afforded only trace amount of cyclopentenones. These
      findings indicated that changing the double bond geometry from Z to E
      dramatically increased the rate of formation of the pericyclic pentadienyl cation
      intermediate necessary for electrocyclization of 18:2-allene oxides and thus the
      yield of cyclopentenones. The well-known cyclization of the homoallylic allene
      oxide (12,13-EOT) derived from alpha-linolenic acid 13-hydroperoxide (E,Z-13
      HPOT) into cis-12-oxo-10,15-phytodienoic acid was suppressed at pH below neutral
      and was not observable at pH 4.5. In contrast, cyclization of the allene oxide
      ((9E)-12,13-EOD) derived from (E,E)-13-HPOD was slightly favoured at low pH. The
      finding that the cyclizations of 12,13-EOT and (9E)-12,13-EOD were differently
      affected by changes in pH suggested that the mechanisms of cyclization of these
      allene oxides are distinct.

PMID- 12426079
TI  - A synthesis of the phenolic lipid, 3-[(Z)-pentadec-8-enyl] catechol, (15:1)
      urushiol.
AB  - A synthesis of (15:1)-urushiol, urushiol monoene, 3-[(Z)-pentadec-8-enyl]
      catechol, 1,2-dihydroxy-3-[(Z)-pentadec-8-enyl] benzene, one of the toxic
      principles of Rhus toxicodendron and of Rhus vernicifera is described. 6
      Chlorohexan-1-ol protected at the OH group with ethyl vinyl ether reacted with
      2,3-dimethoxybenzaldehyde in the presence of lithium to give, after removal of
      the protective group with methanolic 4-toluenesulphonic acid, 1-(2,3
      dimethoxyphenyl) heptane-1,7-diol. Catalytic hydrogenolysis in ethanol with
      palladium-carbon selectively afforded 7-(2,3-dimethoxyphenyl)heptane-1-ol
      accompanied by a small proportion of the 7-(3-methoxyphenyl)heptane-1-diol,
      formed by demethoxylation. Reaction of the dimethoxy compound with boron
      tribromide resulted in both bromination and demethylation to give 7-(2,3
      dihydroxyphenyl) heptylbromide. This bromide in tetrahydrofuran (THF) containing
      hexamethylphosphoric triamide reacted with excess lithium oct-1-yne to give 3
      (pentadec-8-enyl)catechol which, by catalytic hydrogenation in ethyl acetate
      containing quinoline, selectively formed the required cis product, 3-[(Z)
      pentadec-8-enyl]catechol which was identical chromatographically and
      spectroscopically with urushiol monoene separated from the natural product.

PMID- 12426080
TI  - Antioxidant effects of green tea polyphenols on free radical initiated
      peroxidation of rat liver microsomes.
AB  - Antioxidative effects of the principal polyphenolic components extracted from
      green tea leaves, i.e. (-)-epicatechin (EC), (-)-epicatechin gallate (ECG), (-)
      epigallocatechin gallate (EGCG), (-)-epigallocatechin (EGC), and gallic acid
      (GA), against free radical initiated peroxidation of rat liver microsomes were
      studied. The peroxidation was initiated by a water-soluble azo compound 2,2'
      azobis(2-amidinopropane hydrochloride (AAPH). The reaction kinetics was monitored
      by oxygen uptake and formation of malondialdehyde (MDA). Kinetic analysis of the
      antioxidation process demonstrates that these green tea polyphenols (GOHs),
      especially EC and ECG which bear ortho-dihydroxyl functionality, are good
      antioxidants for microsomal peroxidation. The antioxidant synergism of these GOHs
      with the endogenous alpha-tocopherol (TOH) (vitamin E) is also discussed.

PMID- 12426081
TI  - Conformation change of horseradish peroxidase in lipid membrane.
AB  - The electrochemical behavior of horseradish peroxidase (HRP) in the dimyristoyl
      phosphatidylcholine (DMPC) bilayer on the glassy carbon (GC) electrode was
      studied by cyclic voltammetry. The direct electron transfer of HRP was observed
      in the DMPC bilayer. Only a small cathodic peak was observed for HRP on the bare
      GC electrode. The electron transfer of HRP in the DMPC membrane is facilitated by
      DMPC membrane. UV-Vis and circular dichroism (CD) spectroscopy were used to study
      the interaction between HRP and DMPC membrane. On binding to the DMPC membrane
      the secondary structure of HRP remains unchanged while there is a substantial
      change in the conformation of the heme active site. Tapping mode atomic force
      microscopy (AFM) was first applied for the investigation on the structure of HRP
      adsorbed on supported phospholipid bilayer on the mica and on the bare mica. HRP
      molecules adsorb and aggregate on the mica without DMPC bilayer. The aggregation
      indicates an attractive interaction among the adsorbed molecules. The molecules
      are randomly distributed in the DMPC bilayer. The adsorption of HRP in the DMPC
      bilayer changes drastically the domains and defects in the DMPC bilayer due to a
      strong interaction between HRP and DMPC films.

PMID- 12426082
TI  - Thermal induced modification of the contact mechanics of adhering liposomes on
      cationic substrate.
AB  - The correlation between the mechanical property and the thermotropic transition
      of the phospholipid bilayer has been recently demonstrated (Chem. Phys. Lipids
      110 (2001) 27). However, the role of thermal induced mechanical responses of
      phospholipid bilayer on the contact mechanics of liposome adhering on a cationic
      substrate has not been determined. In this study, confocal-reflectance
      interference contrast microscopy, phase contrast microscopy and contact mechanics
      modeling are applied to probe the adhesion mechanisms of liposomes in the
      presence of electrostatic interactions during the thermotropic transition of the
      lipid bilayer. When temperature increases from 23 to 49 degrees C at pH 7.4, the
      degree of liposome deformation (a/R) and adhesion energy of dipalmitoyl-sn
      glycero-3-phosphocholine liposome increases by 10% and remains constant,
      respectively, on 3-amino-propyl-triethoxy-silane (APTES) modified substrate. The
      extents of increase in these two parameters are highly dependent on the
      physicochemical properties of the rigid substrate. At pH 4, the adhesion energies
      above and below the phase transition temperature (T(m)) are increased by one
      order of magnitude due to the formation of the free silanol groups on APTES
      substrate. In hypotonic condition, the degree of vesicle deformation remains
      constant and the adhesion energy reduces by 20% during sample heating. Under all
      conditions, the adhesion energy of the adhering liposome spans a few orders of
      magnitude against the increase of liposome size as the surface area to volume
      ratio is maximized in smallest vesicle.

PMID- 12426083
TI  - Ethanolamine plasmalogens protect cholesterol-rich liposomal membranes from
      oxidation caused by free radicals.
AB  - The aim of the present study is to investigate the effect of ethanolamine
      plasmalogens on the oxidative stability of cholesterol-rich membranes by
      comparing it with that of diacyl glycerophosphoethanolamine, using bovine brain
      ethanolamine plasmalogen (BBEP) or egg yolk phosphatidylethanolamine (EYPE)
      containing large unilamellar vesicles (LUVs) and the water-soluble radical
      initiator AAPH. Electron microscopic observation and particle size measurement
      visually demonstrated that ethanolamine plasmalogens protect cholesterol-rich
      phospholipid bilayers from oxidative collapse. Lipid analyses suggested that the
      effect of ethanolamine plasmalogens in stabilizing membranes against oxidation is
      partly due to the antioxidative action of plasmalogens involved in scavenging
      radicals at vinyl ether linkage.

PMID- 12426084
TI  - Anti-nociceptive and anti-inflammatory activity caused by Cistanche deserticola
      in rodents.
AB  - In the present study, the rhizomes of Cistanche deserticola (Orobanchaceae,
      abbreviated as CD) were extracted with 50% ethanol and isolated orderly by ethyl
      acetate, n-butanol and water. The analgesic and anti-inflammatory effects of CD
      extract and three layers were evaluated in several animal models. CD extracts
      effectively inhibited writhing response induced by 1% acetic acid and biphasic
      licking responses caused by 1% formalin, and also reduced the edema induced by 1%
      carrageenan but not zymosan. Furthermore, the butanolic and aqueous layers of CD
      extract not only reduced the pain induced by acetic acid and formalin, but also
      decreased the edema that induced by carrageenan. Effects of the butanolic layer
      of CD extract are better than that of the aqueous layer. In addition, the effect
      of the butanolic layer of CD extract was not abolished by naloxone. These results
      revealed that CD has analgesic and anti-inflammatory effects, and the butanolic
      and aqueous layers are mainly active constituents. Furthermore, the analgesic and
      anti-inflammatory effects of the butanolic layer of CD extract were not related
      to opioid receptors and immune system.

PMID- 12426085
TI  - Leaf methanol extract of Bidens pilosa prevents and attenuates the hypertension
      induced by high-fructose diet in Wistar rats.
AB  - Chronic fructose treatment in rats has repeatedly been shown to elevate blood
      pressure in association with insulin resistance and hyperinsulinemia. The purpose
      of the current study was to investigate the effect of the leaf methanol extract
      of Bidens pilosa on systolic blood pressure (SBP) and plasma glucose, insulin,
      cholesterol, triglycerides and creatinine levels in rats with fructose-induced
      hypertension. Wistar rats that drank a 10% fructose solution for 3-6 weeks showed
      significant increase not only in plasma insulin and cholesterol levels but also
      in SBP. B. pilosa extract was able to prevent the establishment of hypertension
      and lower elevated blood pressure levels. The extract also reduced the highly
      elevated plasma insulin levels provoked by the high fructose diet. These results
      suggest that the leaf methanol extract of B. pilosa exerts its antihypertensive
      effect in part by improving insulin sensitivity.

PMID- 12426086
TI  - Healing potential of Datura alba on burn wounds in albino rats.
AB  - Datura alba Nees (Solanaccae) is popular all over the world for its medicinal
      uses in asthma, muscle spasm, whooping cough, hemorrhoids, skin ulcers, etc. In
      India, it is widely used traditionally for the relief of rheumatism and other
      painful affections. Ayurveda and Siddha practitioners use oil based preparations
      of this plant from ancient days to till date for all types of wounds. Hence, the
      present study was chosen to evaluate its scientific validity. The alcohol extract
      of the D. alba leaves were investigated for the evaluation of its healing
      efficiency on burn wound models in rats. The crude alcohol extract and one of the
      fractions exhibited antimicrobial effect against all the pathogens studied. A 10%
      (w/w) formulation of alcoholic extract was topically applied on thermal wounds.
      Complete wound closure was observed within 12 days in treated rats. The effect
      produced by the ointment, in terms of wound contracting ability, wound closure
      time, tissue regeneration at the wound site and histopathological characteristics
      were significant in treated rats. Collagen, hexosamine and gelatinase expressions
      were also well correlative with the healing pattern observed. The present study
      thus provides a scientific rationale for the traditional use of this plant in the
      management of wounds.

PMID- 12426087
TI  - In vitro neuropharmacological evaluation of piperovatine, an isobutylamide from
      Piper piscatorum (Piperaceae).
AB  - Piperovatine, a sialogogic, piscicidal, and buccal local anesthesia producing
      isobutyl amide from the amazonian piscicidal and toothache-relieving plant, Piper
      piscatorum Trelease et Yuncker (Piperaceae), was evaluated for its ability to
      induce changes in neuronal intracellular calcium concentration. Ratiometric
      calcium imaging of Periplaneta americana neuronal cell cultures upon piperovatine
      application revealed that this compound induced dramatic increases in
      intracellular calcium concentration. Calcium flux was not affected by co
      application of the muscarinic acetylcholine receptor antagonist, atropine,
      indicating that the parasympathomimetic system was not involved in piperovatine's
      sialogogic actions. Calcium flux was, however, totally eliminated by co
      application of the voltage-gated sodium channel blocker, tetrodotoxin (TTX).
      This, in conjunction with the repetitive calcium spikes observed in the assay and
      previous radioligand binding studies on the chemical class, strongly suggest that
      activation of voltage-gated sodium channels characterizes piperovatine's mode of
      action

PMID- 12426088
TI  - Toxicological evaluation of Catha edulis leaves: a long term feeding experiment
      in animals.
AB  - In this study the long term (6 months) toxicological effect of varying levels of
      Catha edulis leaves were examined on the plasma concentration of liver enzymes as
      well as the histopathology of tissue sections of the liver. Both biochemical and
      histopathological data presented demonstrate signs of C. edulis toxicity. Our
      results show a significant increase in plasma levels of Alkaline phosphatase
      (ALP), Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) with
      all levels of C. edulis leaves tested and throughout the treatment period. The
      increase of ALP was more prominent than both ALT and AST at the higher level of
      30%. Plasma levels of AST though were only moderately increased at the higher
      level of 30% at the early stage of treatment (3 months) it significantly
      increased with all levels of C. edulis leaves in the long term (4-6 months). In
      addition, a time-dependent gradual increase in indirect bilirubin with a
      concomitant decrease in direct bilirubin levels were observed with the lower
      level of C. edulis (10%) with no signs of haemolysis. Histopathology of tissue
      sections of liver display evidences of increasing chronic inflammation with porto
      portal fibrosis in the tissue sections obtained from animals treated with both 20
      and 30% C. edulis.

PMID- 12426089
TI  - Evaluation of selected Sudanese medicinal plants for their in vitro activity
      against hemoflagellates, selected bacteria, HIV-1-RT and tyrosine kinase
      inhibitory, and for cytotoxicity.
AB  - Ethnobotanical investigations led to the selection of 19 plant species, used
      traditionally in Sudan against malaria and other similar tropical diseases, for
      further studies. Pamianthe peruviana (Amaryllidaceae) exhibited significant
      activity against a chloroquine-resistant Plasmodium falciparum strain (K1) and a
      chloroquine-sensitive strain (NF54) with IC(50) values of 0.6 and 1.1 microg/ml,
      respectively. Additionally, P. peruviana showed considerable activities against
      Trypanosoma brucei rhodesiense (IC(50) 1.5 microg/ml) and T. cruzi (IC(50) 11.8
      microg/ml). The antiplasmodial activity of the different extracts of Salvadora
      persica (Salvadoraceae) against P. falciparum NF54 strain were found to be 0.6
      microg/ml (stems) and 0.7 microg/ml (leaves). Extracts of different parts of
      Combretum hartmannianum (Combretaceae) possessed significant activity against the
      chloroquine-sensitive P. falciparum strain (NF54) with IC(50) values of 0.2
      microg/ml (bark), 0.4 microg/ml (stem) and 4.3 microg/ml (leaves). Most
      interestingly, the extracts of the leaves of C. hartmannianum totally inhibited
      the enzyme HIV-1 reverse transcriptase (HIV-1 RT) at a concentration of 66
      microg/ml. A comparably strong activity against p56(lck) tyrosine kinase was also
      seen for this extract.

PMID- 12426090
TI  - Study on the increment of the production of gastric mucus in rats treated with
      Opuntia ficus indica (L.) Mill. cladodes.
AB  - Opuntia ficus indica cladodes are used in traditional medicine of many countries
      for their cicatrisant activity. The major components of cladodes are carbohydrate
      containing polymers, which consist of a mixture of mucilage and pectin. In this
      paper we studied the cytoprotective effects of cladodes on experimental ethanol
      induced ulcer in rat. The O. ficus indica cladodes administration gives rise to
      cytoprotection phenomena by breaking up the epithelial cells and stimulating an
      increase in mucus production. When O. ficus indica cladodes are administered as a
      preventive therapy, keep the gastric mucosa under normal condition by preventing
      mucus dissolution caused by ethanol and favouring mucus production. An increase
      of mucus production is also observed during the course of the curative treatment.
      The treatment with O. ficus indica cladodes provokes an increase in the number of
      secretory cells. Probably, the gastric fibroblasts are involved in the antiulcer
      activity.

PMID- 12426091
TI  - Antimicrobial properties and phytochemical constituents of the leaves of African
      mistletoe (Tapinanthus dodoneifolius (DC) Danser) (Loranthaceae): an
      ethnomedicinal plant of Hausaland, Northern Nigeria.
AB  - African mistletoe (Tapinanthus dodoneifolius (DC) Danser) called 'Kauchi' in
      Hausa is a hemi-plant parasite used ethnomedicinally by the Hausa and the Fulani
      tribes of Northern Nigeria as a remedy for several human and animal ailments that
      include stomach ache, diarrhoea, dysentery, wound and cancer. Screening of the
      plant, obtained from 14 different hosts, revealed a wide spectrum of
      antimicrobial activities against certain multiple drug resistant bacterial and
      fungal isolates of farm animals. Interestingly, the inhibition of the growth of
      Agrobacterium tumefaciens, Bacillus sp., Escherichia coli, Salmonella sp.,
      Proteus sp. and Pseudomonas sp., bacterial sp. known to be associated with either
      crown gall or gastrointestinal tract and wound infections, by extracts of T.
      dodoneifolius gives credence to the ethnomedicinal usage of the plant.
      Phytochemical screening showed the common occurrence of anthraquinones, saponins,
      and tannins, a rare presence of alkaloids and the absence of phlobatannins in the
      hemi-parasite. Moreover, the antimicrobial activity and the presence or
      distribution of phytochemical substances in T. dodoneifolius appeared to be
      partly dependent on the host plant species.

PMID- 12426092
TI  - In vivo gastroprotective effects of five Turkish folk remedies against ethanol
      induced lesions.
AB  - Through evaluation of the data accumulated in Data Bank of Turkish Folk Remedies
      (TUHIB), five plant remedies, which are used to treat stomach ache were selected
      to test for their anti-ulcerogenic potency. In order to confirm the claimed
      activities, either decoction or methanol extracts were prepared from the roots of
      Asphodelus aestivus and Cichorium intybus, herbs of Equisetum palustre and Viscum
      album ssp. album and fruits of Laurus nobilis, according to their folkloric
      application way and tested for their effects on ethanol-induced gastric ulcer
      model in rats. Pharmacological experiments clearly demonstrated that the relevant
      extracts of all the plants given orally showed significant stomach protection
      against this model of ulcerogenesis. Results were further evaluated by using
      histopathological techniques.

PMID- 12426093
TI  - Effect of khat, its constituents and restraint stress on free radical metabolism
      of rats.
AB  - The leaves of khat (Catha edulis) are found to have stimulating and pleasurable
      effect and are chewed habitually by people of East Africa and Arabian Peninsula.
      Due to various toxic and psychostimulative effect of khat the present study was
      undertaken to evaluate the effect of intragastric khat alone or its major
      constituents flavonoids/alkaloids administration and before and after 4 h of
      immobilization stress in terms of alteration of free radical
      scavenging/metabolizing enzymes, uric acid and glucose in rats. Oral khat,
      alkaloid administration or 4 h restraint stress resulted in the decrease of the
      circulating levels of superoxide dismutase, catalase, glutathione-S-transferase
      and glucose with enhanced uric acid concentrations as compared with control rats.
      Oral treatment with flavonoid fraction of khat was found to enhance the
      activities of GST and catalase but showed no effect on SOD while the level of
      glucose was decreased and uric acid increased. The levels of these biochemical
      parameters were more altered in post stress khat/alkaloid treated rats than pre
      stress khat/alkaloid treated rats. The alteration in the levels of SOD, GST,
      catalase and uric acid in the pre stress khat treated rats were comparable with
      that of khat alone, except the level of glucose which was further decreased in
      pre stress khat treated rats. The flavonoid fraction of khat reduced the stress
      induced oxidative stress in terms of above mentioned biochemical parameters. The
      present study suggests that khat alone or khat/alkaloid consumption preceding
      stress may significantly decrease the levels of free radical
      metabolizing/scavenging enzymes and glucose leading to enhanced free radical
      concentration and toxicity of khat, which could be due to its alkaloid fraction
      as flavonoids were found to show antioxidant properties for oxidative stress
      generated during restraint stress.

PMID- 12426094
TI  - Ethnopharmacological survey of medicinal herbs in Israel, the Golan Heights and
      the West Bank region.
AB  - An extensive ethnopharmacological survey was conducted among the most well known
      Arabic indigenous herbal practitioners in Israel, the Golan Heights and the West
      Bank in order to evaluate the potential of local plants used in treating
      different diseases and illnesses. Thirty-one indigenous practitioners' of Arabic
      traditional medicine ranging in age from 40 to 116 years, were interviewed using
      a previously prepared questionnaire. The current survey revealed that 129 plant
      species are still in use in Arabic traditional medicine for the treatments of
      various diseases. Among these plants, there are 40 species used for treating skin
      diseases, 27 species for treating kidney and urinary system, 26 species for
      treating diabetes, 23 species for treating digestive system including stomach and
      intestinal pain and inflammation, 22 species for treating liver diseases, 16
      species for treating respiratory system and coughing, 13 species for treating
      forms of cancer and nine species for treating weight loss and cholesterol
      reduction. Additional findings and implications of this current survey including
      preparation methods and route of use are discussed in this report.

PMID- 12426099
TI  - The proteasome regulatory particle subunit Rpn6 is required for Drosophila
      development and interacts physically with signalosome subunit Alien/CSN2.
AB  - The eukaryotic 26S proteasome plays a central role in ubiquitin-dependent
      intracellular protein metabolism. The multimeric holoenzyme is composed of two
      major subcomplexes, known as the 20S proteolytic core particle and the 19S
      regulatory particle (RP). The RP can be further dissected into two multisubunit
      complexes, the lid and the base complex. The lid complex shares striking
      similarities with another multiprotein complex, the COP9 signalosome. Several
      subunits of both complexes contain the characteristic PCI domain, a structural
      motif important for complex assembly. The COP9 signalosome was shown to act as a
      versatile regulator in numerous pathways. To help define the molecular
      interactions of the signalosome during Drosophila development, we performed a
      yeast two-hybrid screen to identify proteins that physically interact with
      subunit 2 of the complex, namely Alien/CSN2. Here, we report that Drosophila
      Rpn6, a non-ATPase subunit of the RP lid complex, interacts with Alien/CSN2 via
      its PCI domain. The temporal and spatial expression patterns of Rpn6 and
      alien/CSN2 overlap on a large scale during development providing additional
      evidence for their interaction in vivo. Analyses of an Rpn6 P element insertion
      mutant and newly generated Rpn6 alleles reveal that Rpn6 is essential for
      Drosophila development.

PMID- 12426100
TI  - The human homolog of yeast SEP1 is a novel candidate tumor suppressor gene in
      osteogenic sarcoma.
AB  - The hSEP1 gene is the human homolog of yeast SEP1. Yeast SEP1 is a
      multifunctional gene that regulates a variety of nuclear and cytoplasmic
      functions including homologous recombination, meiosis, telomere maintenance, RNA
      metabolism and microtubule assembly. The function of hSEP1 is not known. We show
      loss or reduced expression of hSEP1 messenger RNA (mRNA) in three of four primary
      osteogenic sarcoma (OGS)-derived cell lines and in eight of nine OGS biopsy
      specimen. In addition, we find a heterozygous missense mutation
      (Valine(1484)>Alanine) at a conserved amino acid in the primary OGS-derived cell
      line U2OS. Importantly, we identified a homozygous missense mutation involving a
      CG-dinucleotide leading to a change in a conserved amino acid, aspartic
      acid(1137) >asparagine, in the primary OGS-derived cell line, TE85. hSEP1 mRNA
      expression was nearly undetectable in TE85 and low in U2OS cell lines. None of
      these mutations were identified in 20 normal samples consisting of bone,
      cartilage and fibroblast. The hSEP1 gene is located in chromosome 3 at 3q25-26.1
      between markers D3S1309 and D3S1569. An adjacent locus defined by the polymorphic
      markers D3S1212 and D3S1245 has previously been reported to undergo loss of
      heterozygosity (LOH) at a >70% frequency in OGS and claimed to harbor an
      important tumor suppressor gene in osteosarcoma. The homozygous mutation in the
      hSEP1 mRNA in TE85 cell line suggest that this gene itself is subject to LOH.
      Taken together, these results suggest that hSEP1 acts as a tumor suppressor gene
      in OGS.

PMID- 12426101
TI  - Molecular cloning of the fish interferon stimulated gene, 15 kDa (ISG15)
      orthologue: a ubiquitin-like gene induced by nephrotoxic damage.
AB  - In mammals, the response to nephrotoxicant-induced renal injury is limited to
      repair of the proximal tubule by surviving epithelial cells. In contrast, bony
      fish are capable of both repair, and de novo production of nephrons in response
      to renal damage. Importantly, toxicant-induced nephron neogenesis in goldfish
      (Carassius auratus) parallels nephron development in the mammalian embryo,
      providing a vertebrate model for kidney development. We utilized this model
      system to identify genes induced by the renal toxicant, gentamicin, that may
      function in nephron neogenesis. A novel ubiquitin-like (UBL) gene, 40.1, was
      identified by differential display analysis of control and gentamicin-treated
      goldfish kidney. 40.1 was induced dramatically 3-7 days following a sublethal
      dose of gentamicin, and returned to basal level by 14 days post-treatment. The
      induction of 40.1 coincided with early renal injury in the proximal tubules of
      gentamicin-injected fish; however, expression was not restricted to the kidney,
      suggesting that 40.1 induction may be a more general response to cell injury.
      Sequence analysis revealed that 40.1 contains tandem UBL domains, and shares
      homology with ISG15, a 15 kD interferon-(IFN) stimulated UBL found in mammals.
      Analysis of the genome database for the pufferfish, Fugu rubrides, identified a
      goldfish ISG15 (gfISG15) homologue with an IFN-stimulated response element in the
      promoter region, providing further evidence that gfISG15 is the true teleost
      ISG15 orthologue. Zebrafish and catfish ISG15 genes were subsequently identified
      by sequence analysis. Consistent with its predicted function as a UBL, gfISG15
      formed conjugates with cellular proteins in vitro and in transient transfections.
      Similar to the induction of mammalian ISG15 by microbial challenge, gfISG15 was
      induced in the spleen of mycobacteria-infected fish. These studies identified the
      first teleost ISG15 orthologue. The induction of gfISG15 as an early genetic
      event in response to a renal toxicant, and its conserved, stress-associated,
      expression in higher vertebrates suggests that ISG15 is an important component of
      the host response to diverse stress stimuli.

PMID- 12426102
TI  - Does the proposed DSE motif form the active center in the Hermes transposase?
AB  - Donor cleavage and strand transfer are two functions performed by transposases
      during transposition of class II transposable elements. Within transposable
      elements, the only active center described, to date, facilitating both functions,
      is the so-called DDE motif. A second motif, R-K-H/K-R-H/W-Y, is found in the site
      specific recombinases of the tyrosine recombinase family. While present in many
      bacterial insertion sequences as well as in the eukaryotic family of mariner/Tc1
      elements, the DDE motif was considered absent in other classes of eukaryotic
      class II elements such as P, and hAT and piggyBac. Based on sequence alignments
      of a hobo-like element from the nematode Caenorhabditis elegans, to a variety of
      other hAT transposases and several members of the mariner/Tc1 group, Bigot et al.
      [Gene 174 (1996) 265] proposed the presence of a DSE motif in hAT transposases.
      In the present study we tested if each of these three residues is required for
      transposition of the Hermes element, a member of the hAT family commonly used for
      insect transformation. While D402N and E572Q mutations lead to knock-out of
      Hermes function, mutations S535A and S535D did not affect transposition frequency
      or the choice of integration sites. These data give the first experimental
      support that D402 and E572 are indeed required for transposition of Hermes.
      Furthermore, this study indicates that the active center of the Hermes
      transposase differs from the proposed DSE motif. It remains to be shown if other
      residues also form the active site of this transposase.

PMID- 12426103
TI  - Genomic organization and expression profile of the small GTPases of the RhoBTB
      family in human and mouse.
AB  - Members of the RhoBTB subfamily of Rho GTPases are present in vertebrates,
      Drosophila and Dictyostelium. RhoBTB proteins are characterized by a modular
      organization, consisting of a GTPase (guanosine triphosphatase) domain, a proline
      rich region, a tandem of two BTB (Broad-Complex, Tramtrack, and Bric a brac)
      domains and a C-terminal region of unknown function and might act as docking
      points for multiple components participating in signal transduction cascades. We
      have determined the genomic organization and the expression pattern of the three
      RHOBTB genes of human and mouse. The exon-intron organization of each gene is
      conserved in three vertebrate species (human, mouse and Fugu). RHOBTB1 and
      RHOBTB2 have a similar exon-intron organization and are closely related to the
      single gene encoding the RhoBTB orthologs of two insect species. By contrast, the
      exon-intron organization of RHOBTB3 differed substantially from that of the two
      other genes, indicating that this gene arose by a duplication event independent
      of the one that gave rise to RHOBTB1 and RHOBTB2. RHOBTB1 (located on chromosome
      10) and RHOBTB3 (located on chromosome 5) appear ubiquitously expressed. However,
      they display a differential pattern of expression: RHOBTB1 showed high levels in
      stomach, skeletal muscle, placenta, kidney and testis, whereas RHOBTB3 was highly
      expressed in neural and cardiac tissues, pancreas, placenta and testis. RHOBTB2
      (located on chromosome 8) showed much lower levels of expression than the other
      two human RHOBTB genes and it was most abundant in neural tissues. The expression
      patterns of the human and mouse genes were roughly comparable. All three genes
      were also detected in fetal tissues, and in a number of cell lines RHOBTB3
      predominates. RHOBTB genes are upregulated in some cancer cell lines, suggesting
      that these proteins might participate in tumorigenesis.

PMID- 12426104
TI  - A predictable ligand regulated expression strategy for stably integrated
      transgenes in mammalian cells in culture.
AB  - Several strategies for regulated stable transgene expression in mammalian cells
      have been described. These strategies have different strengths and weaknesses,
      however they all share a common problem, namely predictability in application.
      Here we address this problem using the leading strategy for ligand inducible
      transgene expression, the tetracycline repressor system. Initially, we found the
      best stable clone out of 48 examined showed only 6-fold inducibility. Hence we
      looked for additions and modifications that improve the chances of a successful
      outcome. We document three important aspects; first, use of a mammalian codon
      optimized tetracycline repressor gene; second, addition of a steroid hormone
      receptor ligand binding domain to the tetracycline repressor-virion protein 16
      fusion protein activator; third, flanking the tet-operator/transgene cassette
      with insulator elements from the chicken beta-globin locus. By inclusion of these
      three design features, 18/18 clones showed low basal and highly inducible (>50 x)
      expression.

PMID- 12426105
TI  - Xenopus laevis red cone opsin and Prph2 promoters allow transgene expression in
      amphibian cones, or both rods and cones.
AB  - We have cloned the promoter regions of two Xenopus laevis genes, Prph2 (also
      called RDS) and red cone opsin (RCO) using a polymerase chain reaction-based gene
      walking method. The proteins coded by these genes are expressed exclusively in
      retinal photoreceptors. Although these promoter sequences are evolutionarily
      distant from previously described homologues, potentially informative
      similarities were noted that suggest conserved binding sites of the transcription
      factors Crx and Rx. The promoters were tested for function in transgenic X.
      laevis. RCO-driven expression was restricted to cones and pinealocytes, while the
      Prph2 promoter drove expression of a reporter green fluorescent protein transgene
      in both rod and cone photoreceptors, as well as low levels of expression in
      muscle tissue. This is the first description of transgene expression driven by a
      Prph2 promoter homologue from any species. In combination with the previously
      reported X. laevis opsin and arrestin promoters, these sequences will facilitate
      the development and analysis of X. laevis models of inherited retinal
      degeneration.

PMID- 12426106
TI  - Structure and promoter activity of the gene encoding ornithine decarboxylase
      antizyme expressed exclusively in haploid germ cells in testis (OAZt/Oaz3).
AB  - Ornithine decarboxylase antizyme 1 and 2 (OAZ1 and OAZ2) are expressed
      ubiquitously, and control the intracellular concentration of polyamines. Their
      testicular isoform, OAZt/Oaz3, is specifically expressed in differentiated
      haploid germ cells. We have identified and characterized the gene encoding OAZt
      in mice. The mouse OAZt gene contains, as does the human ortholog and paralogs,
      five exons and four introns. Comparison of the mouse OAZt with the human ortholog
      gene revealed that exon sizes are identical and nucleotide sequences in exons are
      highly homologous (83% identity). The major transcriptional start site was
      determined by primer extension assay. Promoter activity was confirmed by
      transgenic mouse assays, using the upstream region of the mouse OAZt gene fused
      to a EGFP reporter gene. The OAZt essential promoter located between -133 and
      +242, has two CREs and an Inr, and lacks a TATA box. These elements are conserved
      in the human ortholog but not in the paralogs, indicating that such a short
      upstream region including two CREs and Inr is sufficient to drive endogenous OAZt
      mRNA expression in the haploid testicular germ cells.

PMID- 12426107
TI  - A plasmid from a non-insect-transmissible line of a phytoplasma lacks two open
      reading frames that exist in the plasmid from the wild-type line.
AB  - Two novel rolling circle replication (RCR) plasmids, pOYM (3932 nt) and pOYNIM
      (3062 nt), were isolated from a mildly pathogenic variant line (OY-M) and a
      mildly pathogenic plus non-insect-transmissible line (OY-NIM), respectively, of
      onion yellows (OY) phytoplasma, a plant and insect endocellular mollicute. OY-M
      was isolated from an original wild-type line (OY-W) after regular maintenance
      using alternate plant/insect infections, while OY-NIM was further isolated from
      OY-M after maintenance by plant grafting without insect vectors. The RCR
      initiator proteins (Rep) of both plasmids, which have a characteristic structure
      with both plasmid- and virus-like domains, were highly homologous to that of a
      previously described OY-W plasmid, pOYW (3933 nt), and were expressed in OY-M-
      and OY-NIM-infected plants, indicating that this replicon is stably maintained in
      the phytoplasma. Interestingly, pOYNIM lacked two ORFs that exist in both pOYW
      and pOYM, which encode a single-stranded DNA binding protein (SSB) and an
      uncharacterized putative membrane protein, indicating that these two proteins are
      not necessary for the phytoplasma to live in plant cells. These are the first
      candidates as phytoplasma proteins possibly related to host specificity.

PMID- 12426108
TI  - Sequencing of a calcitonin receptor-like receptor in salmon Oncorhynchus
      gorbuscha. Functional studies using the human receptor activity-modifying
      proteins.
AB  - The calcitonin gene-related peptide (CGRP) receptor and adrenomedullin (ADM)
      receptor are generated by the concomitant expression of a calcitonin receptor
      like receptor (CL receptor) and a specific receptor activity-modifying protein
      (RAMP) in mammals. We have identified the sequence encoding the salmon CL
      receptor (sCL receptor) and studied its function after co-expression with the
      human RAMPs in Cos-7 cells. The potential open-reading frame encoded a 465-amino
      acid protein which is 72% identical to the human CL receptor and 85.8% identical
      to the flounder CL receptor. Function was assessed by measuring the cyclic
      adenosine monophosphate (cAMP) produced by Cos-7 cells transiently transfected
      with recombinant vectors for the sCL receptor and human RAMP. Co-expression of
      the CL receptor and RAMP1, formed a CGRP receptor, as in mammals. This CGRP
      receptor responded to selective analogs as a type 1 CGRP receptor. Cells co
      expressing the CL receptor and RAMP2 did not produce increased cAMP in response
      to human ADM. Cells co-expressing the CL receptor and RAMP3, produced such a
      response, as in mammals, indicating that the human ADM molecule is not the cause
      of the previous unresponsiveness. We suggest that the human RAMP2 molecule does
      not interact with the sCL receptor because of major differences in the sequences
      of the salmon CL receptor and the mammalian CL receptor. The availability of this
      receptor must allow to further study their structural basis. This identification
      of a non-mammalian CL receptor, and characterization of its function, give
      insight in the evolution of the CL receptor molecule.

PMID- 12426109
TI  - Serial registration of intraoperative MR images of the brain.
AB  - The increased use of image-guided surgery systems during neurosurgery has brought
      to prominence the inaccuracies of conventional intraoperative navigation systems
      caused by shape changes such as those due to brain shift. We propose a method to
      track the deformation of the brain and update preoperative images using
      intraoperative MR images acquired at different crucial time points during
      surgery. We use a deformable surface matching algorithm to capture the
      deformation of boundaries of key structures (cortical surface, ventricles and
      tumor) throughout the neurosurgical procedure, and a linear finite element
      elastic model to infer a volumetric deformation. The boundary data are extracted
      from intraoperative MR images using a real-time intraoperative segmentation
      algorithm. The algorithm has been applied to a sequence of intraoperative MR
      images of the brain exhibiting brain shift and tumor resection. Our results
      characterize the brain shift after opening of the dura and at the different
      stages of tumor resection, and brain swelling afterwards. Analysis of the average
      deformation capture was assessed by comparing landmarks identified manually and
      the results indicate an accuracy of 0.7+/-0.6 mm (mean+/-S.D.) for boundary
      surface landmarks, of 0.9+/-0.6 mm for landmarks inside the boundary surfaces,
      and 1.6+/-0.9 mm for landmarks in the vicinity of the tumor.

PMID- 12426110
TI  - Coupling of fluid and elastic models for biomechanical simulations of brain
      deformations using FEM.
AB  - In order to improve the accuracy of image-guided neurosurgery, different
      biomechanical models have been developed to correct preoperative images with
      respect to intraoperative changes like brain shift or tumor resection. All
      existing biomechanical models simulate different anatomical structures by using
      either appropriate boundary conditions or by spatially varying material parameter
      values, while assuming the same physical model for all anatomical structures. In
      general, this leads to physically implausible results, especially in the case of
      adjacent elastic and fluid structures. Therefore, we propose a new approach which
      allows to couple different physical models. In our case, we simulate rigid,
      elastic and fluid regions by using the appropriate physical description for each
      material, namely either the Navier equation or the Stokes equation. To solve the
      resulting differential equations, we derive a linear matrix system for each
      region by applying the finite element method (FEM). Thereafter, the linear matrix
      systems are linked together, ending up with one overall linear matrix system. Our
      new approach has been tested and compared to a purely linear elastic model using
      synthetic as well as tomographic images. It turns out from our experiments, that
      the integrated treatment of rigid, elastic and fluid regions improves the
      physical plausibility of the predicted deformation results as compared to a
      purely linear elastic model.

PMID- 12426111
TI  - Characterization of changes in blood vessel width and tortuosity in retinopathy
      of prematurity using image analysis.
AB  - Many retinal diseases are characterised by changes to retinal vessels. For
      example, a common condition associated with retinopathy of prematurity (ROP) is
      so-called plus disease, characterised by increased vascular dilation and
      tortuosity. This paper presents a general technique for segmenting out vascular
      structures in retinal images, and characterising the segmented blood vessels. The
      segmentation technique consists of several steps. Morphological preprocessing is
      used to emphasise linear structures such as vessels. A second derivative operator
      is used to further emphasise thin vascular structures, and is followed by a final
      morphological filtering stage. Thresholding of this image is used to provide a
      segmented vascular mask. Skeletonisation of this mask allows identification of
      points in the image where vessels cross (bifurcations and crossing points) and
      allows the width and tortuosity of vessel segments to be calculated. The accuracy
      of the segmentation stage is quite dependent on the parameters used, particularly
      at the thresholding stage. However, reliable measurements of vessel width and
      tortuosity were shown using test images. Using these tools, a set of images drawn
      from 23 subjects being screened for the presence of threshold ROP disease is
      considered. Of these subjects, 11 subsequently required treatment for ROP, 9 had
      no evidence of ROP, and 3 had spontaneously regressed ROP. The average vessel
      width and tortuosity for the treated subjects was 96.8 microm and 1.125. The
      corresponding figures for the non-treated cohort were 86.4 microm and 1.097.
      These differences were statistically significant at the 99% and 95% significance
      level, respectively. Subjects who progressed to threshold disease during the
      course of screening showed an average increase in vessel width of 9.6 microm and
      in tortuosity of +0.008. Only the change in width was statistically significant.
      Applying a simple retrospective screening paradigm based solely on vessel width
      and tortuosity yields a screening test with a sensitivity and specificity of 82%
      and 75%. Factors confounding a more accurate test include poor image quality,
      inaccuracies in vessel segmentation, inaccuracies in measurement of vessel width
      and tortuosity, and limitations inherent in screening based solely on examination
      of the posterior pole.

PMID- 12426113
TI  - Transport of toxic metals by molecular mimicry.
AB  - Intracellular concentrations of essential metals are normally maintained within a
      narrow range, whereas the nonessential metals generally lack homeostatic
      controls. Some of the factors that contribute to metal homeostasis have recently
      been identified at the molecular level and include proteins that mediate import
      of essential metals from the extracellular environment, those that regulate
      delivery to specific intracellular proteins or compartments, and those that
      mediate metal export from the cell. Some of these proteins appear highly
      selective for a given essential metal; however, others are less specific and
      interact with multiple metals, including toxic metals. For example, DCT1
      (divalent cation transporter-1; also known as NRAMP2 or DMT1) is considered to be
      a major cellular uptake mechanism for Fe(2+) and other essential divalent metals,
      but this protein also mediates uptake of Cd(2+), Pb(2+), and possibly of other
      toxic divalent metals. The ability of nonessential metals to interact with
      binding sites for essential metals is critical for their ability to gain access
      to specific cellular compartments and for their ability to disrupt normal
      biochemical or physiological functions. Another major mechanism by which metals
      traverse cell membranes and produce cell injury is by forming complexes whose
      overall structures mimic those of endogenous molecules. For example, it has long
      been known that arsenate and vanadate can compete with phosphate for transport
      and metabolism, thereby disrupting normal cellular functions. Similarly, cromate
      and molybdate can mimic sulfate in biological systems. Studies in our laboratory
      have focused on the transport and toxicity of methylmercury (MeHg) and inorganic
      mercury. Mercury has a high affinity for reduced sulfhydryl groups, including
      those of cysteine and glutathione (GSH). MeHg-l-cysteine is structurally similar
      to the amino acid methionine, and this complex is a substrate for transport
      systems that carry methionine across cell membranes. Once MeHg has entered the
      cell, some of it binds to GSH, and the resulting MeHg-glutathione complex appears
      to be a substrate for proteins that mediate cellular export of glutathione S
      conjugates, including the apically located MRP2 (multidrug resistance-associated
      protein 2) transporter, a member of the adenosine triphosphate-binding cassette
      protein superfamily. Because other toxic metals also form complexes with
      endogenous molecules, comparable mechanisms may be involved in their membrane
      transport and disposition.

PMID- 12426114
TI  - Molecular mechanism of copper transport in Wilson disease.
AB  - Wilson disease is an autosomal recessive disorder of copper metabolism. The
      Wilson disease protein is a putative copper-transporting P-type ATPase, ATP7B,
      whose malfunction results in the toxic accumulation of copper in the liver and
      brain, causing the hepatic and/or neurological symptoms accompanying this
      disease. The cytosolic N-terminal domain (approximately 70 kDa) of this ATPase
      comprises six heavy metal-associated domains, each of which contains the
      conserved metal-binding motif GMTCXXC. The N-terminal domain (Wilson disease
      copper-binding domain [WCBD]) has been expressed, purified, and characterized
      using various techniques. The WCBD binds six atoms of copper in the +1 oxidation
      state competitively, and with a greater affinity than all other metals. The
      copper atom is coordinated by two cysteines in a distorted linear geometry.
      Copper binds the WCBD in a cooperative manner and induces secondary and tertiary
      conformation changes. Zinc binding to the WCBD has also been characterized by
      circular dichroism spectroscopy and shown to produce conformational changes that
      are completely different from those induced by copper. The
      phosphorylation/nucleotide-binding domain of ATP7B has also been expressed and
      characterized and shown to be capable of binding ATP but lacking ATPase activity.
      A peptide corresponding to the sixth transmembrane domain of ATP7B has been
      constructed and shown to undergo secondary conformational changes upon binding a
      single atom of copper. Finally, a chimeric protein consisting of the WCBD and
      truncated ZntA, a zinc-transporting ATPase lacking the N-terminal domain, has
      been constructed and analyzed for metal ion selectivity. These results suggest
      that the core determines the metal ion specificity of P-type ATPases, and the N
      terminal metal-binding domain may play a regulatory role.

PMID- 12426115
TI  - Brain uptake, retention, and efflux of aluminum and manganese.
AB  - My colleagues and I investigated the sites and mechanisms of aluminum (Al) and
      manganese (Mn) distribution through the blood-brain barrier (BBB). Microdialysis
      was used to sample non-protein-bound Al in the extracellular fluid (ECF) of blood
      (plasma) and brain. Brain ECF Al appearance after intravenous Al citrate
      injection was too rapid to attribute to diffusion or to transferrin-receptor
      mediated endocytosis, suggesting another carrier-mediated process. The
      brain:blood ECF Al concentration ratio was 0.15 at constant blood and brain ECF
      Al concentrations, suggesting carrier-mediated brain Al efflux. Pharmacological
      manipulations suggested the efflux carrier might be a monocarboxylate transporter
      (MCT). However, the lack of Al (14)C-citrate uptake into rat erythrocytes
      suggested it is not a good substrate for isoform MCT1 or for the band 3 anion
      exchanger. Al (14)C-citrate uptake into murine-derived brain endothelial cells
      appeared to be carrier mediated, Na independent, pH independent, and energy
      dependent. Uptake was inhibited by substrate/inhibitors of the MCT and organic
      anion transporter families. Determination of (26)Al in rat brain at various times
      after intravenous (26)Al suggested a prolonged brain (26)Al half-life. It appears
      that Al transferrin and Al citrate cross the BBB by different mechanisms, that
      much of the Al entering brain ECF is rapidly effluxed, probably as Al citrate,
      but that some Al is retained for quite some time. Brain influx of the Mn(2+) ion
      and Mn citrate, determined with the in situ brain perfusion technique, was
      greater than that attributable to diffusion, suggesting carrier-mediated uptake.
      Mn citrate uptake was approximately 3-fold greater than the Mn(2+) ion,
      suggesting it is a primary Mn species entering the brain. After Mn(2+) ion, Mn
      citrate, or Mn transferrin injection into the brain, brain Mn efflux was not more
      rapid than that predicted from diffusion. The BBB permeation of Al and Mn is
      mediated by carriers that may help regulate their brain concentrations.

PMID- 12426116
TI  - Use of XAS for the elucidation of metal structure and function: applications to
      nickel biochemistry, molecular toxicology, and carcinogenesis.
AB  - Nickel has been shown to be an essential trace element involved in the metabolism
      of several species of bacteria, archea, and plants. In these organisms, nickel is
      involved in enzymes that catalyze both non-redox (e.g., urease, glyoxalase I) and
      redox (e.g., hydrogenase, carbon monoxide dehydrogenase, superoxide dismutase)
      reactions, and proteins involved in the transport, storage, metallocenter
      assembly, and regulation of nickel concentration have evolved. Studies of
      structure/function relationships in nickel biochemistry reveal that cysteine
      ligands are used to stabilize the Ni(III/II) redox couple. Certain nickel
      compounds have also been shown to be potent human carcinogens. A likely target
      for carcinogenic nickel is nuclear histone proteins. Here we present X-ray
      absorption spectroscopic studies of a model Ni peptide designed to help
      characterize the structure of the nickel complexes formed with histones and place
      them in the context of nickel structure/function relationships, to gain insights
      into the molecular mechanism of nickel carcinogenesis.

PMID- 12426117
TI  - Formation of reactive nitrogen species at biologic heme centers: a potential
      mechanism of nitric oxide-dependent toxicity.
AB  - The peroxidase-catalyzed nitration of tyrosine derivatives by nitrite and
      hydrogen peroxide has been studied in detail using the enzymes lactoperoxidase
      (LPO) from bovine milk and horseradish peroxidase (HRP). The results indicate the
      existence of two competing pathways, in which the nitrating species is either
      nitrogen dioxide or peroxynitrite. The first pathway involves one-electron
      oxidation of nitrite by the classical peroxidase intermediates compound I and
      compound II, whereas in the second pathway peroxynitrite is generated by reaction
      between enzyme-bound nitrite and hydrogen peroxide. The two mechanisms can be
      simultaneously operative, and their relative importance depends on the reagent
      concentrations. With HRP the peroxynitrite pathway contributes significantly only
      at relatively high nitrite concentrations, but for LPO this represents the main
      pathway even at relatively low (pathophysiological) nitrite concentrations and
      explains the high efficiency of the enzyme in the nitration. Myoglobin and
      hemoglobin are also active in the nitration of phenolic compounds, albeit with
      lower efficiency compared with peroxidases. In the case of myoglobin, endogenous
      nitration of the protein has been shown to occur in the absence of substrate. The
      main nitration site is the heme, but a small fraction of nitrated Tyr146 residue
      has been identified upon proteolytic digestion and high-performance liquid
      chromatography/mass spectrometry analysis of the peptide fragments. Preliminary
      investigation of the nitration of tryptophan derivatives by the
      peroxidase/nitrite/hydrogen peroxide systems shows that a complex pattern of
      isomeric nitration products is produced, and this pattern varies with nitrite
      concentration. Comparative experiments using chemical nitrating agents indicate
      that at low nitrite concentrations, the enzymatic nitration produces a
      regioisomeric mixture of nitrotryptophanyl derivatives resembling that obtained
      using nitrogen dioxide, whereas at high nitrite concentrations the product
      pattern resembles that obtained using peroxynitrite.

PMID- 12426119
TI  - Molecular mechanisms in nickel carcinogenesis: modeling Ni(II) binding site in
      histone H4.
AB  - Ni(II) compounds are well known as human carcinogens, though the molecular events
      which are responsible for this are not yet fully understood. It has been proposed
      that the binding of N(II) ions within the cell nucleus is a crucial element in
      the mechanism of carcinogenesis. The most abundant proteins in the cell nucleus
      are histones, and this makes them the prime candidates for this role. This
      article is a review of our recent studies of histone H4 models of Ni(II) binding.
      We analyzed the sequence of the N-terminal tail of the histone H4, Ac
      SGRGKGGKGLGKGGAKRH(18)RKVL-Am, for Ni(II) binding. This site has been proposed
      mainly because of the potent inhibitory effect of Ni(II) on the acetylation of
      lysine residues near the histidine H(18), and also because of the accessibility
      of the H4 tail in the histone octamer. Combined potentiometric and spectroscopic
      studies showed that the histidine 18 acted as an anchoring binding site for metal
      ions in the peptide investigated. Comparison with the results for Cu(II) binding
      are also reported. The results allowed us to propose that the binding of Ni(II)
      is able to promote a secondary structure with organized side-chain orientation on
      the N-terminal tail of histone H4.

PMID- 12426118
TI  - Structure and potential mutagenicity of new hydantoin products from guanosine and
      8-oxo-7,8-dihydroguanine oxidation by transition metals.
AB  - In vitro work in this laboratory has identified new DNA lesions resulting from
      further oxidation of a common biomarker of oxidative damage, 8-oxo-7,8
      dihydroguanine (OG). The major product of oxidation of OG in a nucleoside,
      nucleotide, or single-stranded oligodeoxynucleotide using metal ions that act as
      one-electron oxidants is the new nucleoside derivative spiroiminodihydantoin
      (Sp). In duplex DNA an equilibrating mixture of two isomeric products,
      guanidinohydantoin (Gh) and iminoallantoin (Ia), is produced. These products are
      also formed by the overall four-electron oxidation of guanosine by photochemical
      processes involving O(2). DNA template strands containing either Sp or Gh/Ia
      generally acted as a block to DNA synthesis with the Klenow exo(-) fragment of
      pol I. However, when nucleotide insertion did occur opposite the lesions, only 2'
      deoxyadenosine 5-triphosphate and 2'-deoxyguanine 5-triphosphate were used for
      primer extension. The Escherichia coli DNA repair enzyme Fpg was able to remove
      the Sp and Gh/Ia lesions from duplex DNA substrates, although the efficiency was
      depended on the base opposite the lesion.

PMID- 12426120
TI  - Guanine and 7,8-dihydro-8-oxo-guanine-specific oxidation in DNA by chromium(V).
AB  - The hexavalent oxidation state of chromium [Cr(VI)] is a well-established human
      carcinogen, although the mechanism of cancer induction is currently unknown.
      Intracellular reduction of Cr(VI) forms Cr(V), which is thought to play a
      fundamental role in the mechanism of DNA damage by this carcinogen. Two separate
      pathways of DNA damage, an oxidative pathway and a metal-binding pathway, have
      been proposed to account for the lesions observed in cell systems. We have used a
      model Cr(V) complex, N,N-ethylenebis(salicylidene-animato)oxochromium(V) [Cr(V)
      Salen], to investigate the oxidative pathway of DNA damage and to elucidate the
      lesions generated from this oxidation process. Reaction of Cr(V)-Salen with
      synthetic oligonucleotides produced guanine-specific lesions that were not 8-oxo
      2'-deoxyguanosine, based on the inability of iridium(IV) to further oxidize these
      sites. Oxidation products were identified using a 7,8-dihydro-8-oxo-2'
      deoxyguanosine (8-oxo-G) containing oligonucleotide to increase the yields of
      product for identification by electrospray ionization mass spectrometry. The
      guanine-based lesions observed by mass spectrometry corresponded to the lesions
      guanidinohydantoin and spiroiminodihydantoin. The effects of these Cr(V)-Salen
      induced lesions on DNA replication fidelity was assayed using a polymerase-based
      misincorporation assay. These lesions produced G --> T transversion mutations and
      polymerase stops at levels greater than those observed for 8-oxo-G. These data
      suggest a model by which chromate can cause DNA damage leading to mutations and
      cancer.

PMID- 12426121
TI  - Reductive activation with cysteine represents a chromium(III)-dependent pathway
      in the induction of genotoxicity by carcinogenic chromium(VI).
AB  - Induction of DNA damage by carcinogenic hexavalent chromium compounds [Cr(VI)]
      results from its reduction to lower oxidation states. Reductive metabolism of
      Cr(VI) generates intermediate Cr(V/IV)species, organic radicals, and finally
      Cr(III), which forms stable complexes with many biological ligands, including
      DNA. To determine the biological significance of different reaction products, we
      examined genotoxic responses and the formation of DNA damage during reduction of
      Cr(VI) by its biological reducer, cysteine. We have found that cysteine-dependent
      activation of Cr(VI) led to the formation of Cr-DNA and cysteine-Cr-DNA adducts
      as well as interstrand DNA cross-links. The yield of binary and ternary DNA
      adducts was relatively constant at different concentrations of Cr(VI) and
      averaged approximately 54 and 45%, respectively. Interstrand DNA cross-links
      accounted on average for 1% of adducts, and their yield was even less significant
      at low Cr(VI) concentrations. Reduction of Cr(VI) in several commonly used
      buffers did not induce detectable damage to the sugar-phosphate backbone of DNA.
      Replication of Cr(VI)-modified plasmids in intact human fibroblasts has shown
      that cysteine-dependent metabolism of Cr(VI) resulted in the formation of
      mutagenic and replication-blocking DNA lesions. Selective elimination of Cr-DNA
      adducts from Cr(VI)-treated plasmids abolished all genotoxic responses,
      indicating that nonoxidative, Cr(III)-dependent reactions were responsible for
      the induction of both mutagenicity and replication blockage by Cr(VI). The
      demonstration of the mutagenic potential of Cr-DNA adducts suggests that these
      lesions can be explored in the development of specific and mechanistically
      important biomarkers of exposure to toxic forms of Cr.

PMID- 12426122
TI  - Metabolic pathways of carcinogenic chromium.
AB  - The products of hexavalent chromium [Cr(VI)] reduction by glutathione (GSH) alone
      or in the presence of equimolar quantities of aspartate (Asp) and/or glutamate
      (Glu) and a chromium-containing material extracted from bovine liver were studied
      by ultraviolet-visible spectrum (UV-vis) studies, electrospray mass spectrometry
      (ES-MS), electron paramagnetic resonance (EPR), and nuclear magnetic resonance
      (NMR). Reduction of chromate by GSH was followed by UV-vis and NMR, revealing the
      formation of a paramagnetic complex in which GSH acts as a ligand. ES-MS and EPR
      measurements provided unequivocal evidence of a dimeric Cr(V)(2)GSH(2) species in
      which the two metal ions are bridged by the Gamma-Glu carboxylate. The analysis
      of the (1)H and (13)C shifts experienced by GSH protons and the values of
      paramagnetic contributions to proton spin-lattice relaxation rates provided a set
      of constraints for structural determination. The same experiments were repeated
      in the presence of an equimolar concentration of Asp, revealing the formation of
      a dimeric Cr(V) paramagnetic complex in which the two metals are now bridged by
      Asp. Nuclear magnetic resonance dispersion profiles show that water is not
      displaced by Asp and that the correlation time of this complex is slowed by the
      increased complexity. When Glu is also included in the solution in equimolar
      concentration to GSH and Asp, data are consistent with the formation of many mono
      and dinuclear species, with the three ligands competing with each other.
      Finally, the spectroscopic investigation of the chromium-containing material
      extracted from bovine liver revealed the presence of a complicate mixture of
      Cr(IV) or Cr(V) complexes, among which some Cr(V)-GSH species are present alone
      or with other ligands in the metal coordination sphere.

PMID- 12426123
TI  - Chromate-induced epimutations in mammalian cells.
AB  - Epigenetic gene silencing by aberrant DNA methylation of gene promoter regions is
      a nonmutagenic but heritable epigenetic mechanism that may mistakenly cause the
      silencing of important cancer-related tumor suppressor genes. Using a transgenic,
      V79-derived, mammalian cell line (G12) that contains a bacterial gpt reporter
      gene in its DNA, we can study carcinogen-induced gene inactivation by mutagenic
      as well as epigenetic DNA methylation mechanisms. Whereas numerous carcinogens
      have previously been shown to be mutagenic in these cells, a few carcinogens,
      including nickel, diethylstilbestrol, and X-rays, are also capable of silencing
      the G12 cell gpt transgene by aberrant DNA methylation. Here we report for the
      first time that carcinogenic potassium chromate salts can also induce aberrant
      DNA methylation in this system. In contrast insoluble barium chromate produced
      significant level of mutations in these cells but did not cause DNA methylation
      changes associated with transgene expression.

PMID- 12426124
TI  - Arsenate reductases in prokaryotes and eukaryotes.
AB  - The ubiquity of arsenic in the environment has led to the evolution of enzymes
      for arsenic detoxification. An initial step in arsenic metabolism is the
      enzymatic reduction of arsenate [As(V)] to arsenite [As(III)]. At least three
      families of arsenate reductase enzymes have arisen, apparently by convergent
      evolution. The properties of two of these are described here. The first is the
      prokaryotic ArsC arsenate reductase of Escherichia coli. The second, Acr2p of
      Saccharomyces cerevisiae, is the only identified eukaryotic arsenate reductase.
      Although unrelated to each other, both enzymes receive their reducing equivalents
      from glutaredoxin and reduced glutathione. The structure of the bacterial ArsC
      has been solved at 1.65 A. As predicted from its biochemical properties, ArsC
      structures with covalent enzyme-arsenic intermediates that include either As(V)
      or As(III) were observed. The yeast Acr2p has an active site motif HC(X)(5)R that
      is conserved in protein phosphotyrosine phosphatases and rhodanases, suggesting
      that these three groups of enzymes may have evolved from an ancestral oxyanion
      binding protein.

PMID- 12426125
TI  - Arsenite cocarcinogenesis: an animal model derived from genetic toxicology
      studies.
AB  - Although epidemiologic evidence shows an association between inorganic arsenic in
      drinking water and increased risk of skin, lung, and bladder cancers, no animal
      model for arsenic carcinogenesis has been successful. This lack has hindered
      mechanistic studies of arsenic carcinogenesis. Previously, we and others found
      that low concentrations (< or =5 microm) of arsenite (the likely environmental
      carcinogen), which are not mutagenic, can enhance the mutagenicity of other
      agents, including ultraviolet radiation (UVR) and alkylating agents. This
      enhancing effect appears to result from inhibition of DNA repair by arsenite, but
      not via inhibition of DNA repair enzymes. Rather, low concentrations of arsenite
      disrupt p53 function and upregulate cyclin D1. Failure to find an animal model
      for arsenic carcinogenesis might be because arsenite is not a carcinogen per se
      but acts as an enhancing agent (cocarcinogen) with a genotoxic partner. We tested
      this hypothesis with solar UVR in hairless but immunocompetent Skh1 mice. Mice
      were given 10 mg/L sodium arsenite in drinking water (or not) and irradiated with
      1.7 KJ/m(2) solar UVR 3 times weekly. As expected, no tumors appeared in any
      organs in control mice or in mice given arsenite alone. After 26 weeks irradiated
      mice given arsenite had a 2.4-fold increase in skin tumor yield compared with
      mice given UVR alone. The tumors were mostly squamous cell carcinomas, and those
      occurring in mice given UVR plus arsenite were much larger and more invasive.
      These results are consistent with the hypothesis that arsenic acts as a
      cocarcinogen with a second (genotoxic) agent by inhibiting DNA repair and/or
      enhancing positive growth signaling. Skin cancers in populations drinking water
      containing arsenic may be caused by the enhancement by arsenic compounds of
      carcinogenesis induced by UVR (or other environmental agents). It is possible
      that lung and bladder cancers associated with arsenic in drinking water may also
      require a carcinogenic partner.

PMID- 12426126
TI  - Oxidative DNA adducts and DNA-protein cross-links are the major DNA lesions
      induced by arsenite.
AB  - Arsenic is recognized to be a nonmutagenic carcinogen because it induces DNA
      damage only at very high concentrations. However, many more DNA strand breaks
      could be detected by digesting the DNA of arsenite-treated cells with
      endonuclease III, formamidopyrimidine-DNA glycosylase, and proteinase K. By doing
      so, arsenite could be shown to induce DNA damage in human cells within a
      pathologically meaningful concentration range. Oxidized guanine products were
      detected in all arsenite-treated human cells examined. DNA-protein cross-links
      were also detected in arsenite-treated NB4 and HL60 cells. In human umbilical
      vein endothelial cells, the induction of oxidized guanine products by arsenite
      was sensitive to inhibitors of nitric oxide (NO) synthase but not to oxidant
      modulators, whereas the opposite result was obtained in vascular smooth muscle
      cells. On the other hand, the arsenite-induced oxidized guanine products and DNA
      protein cross-links in NB4 and HL60 cells were sensitive to modulators of
      calcium, NO synthase, oxidant, and myeloperoxidase. Therefore, although oxidized
      guanine products were detected in all the human cells treated with arsenite, the
      pathways could be different in different cell types. Because the sensitivity and
      the mechanism of arsenic intoxication are cell specific, it is important that
      target tissues and target cells are used for investigations. It is also important
      that pathologically or pharmacologically meaningful concentrations of arsenic are
      used. This is because in most cases we are dealing with the chronic effect rather
      than acute toxicity.

PMID- 12426127
TI  - The molecular mechanisms of arsenic-induced cell transformation and apoptosis.
AB  - Arsenic is a well-documented human carcinogen associated with cancers of the
      skin, lung, liver, and bladder. Interestingly, arsenic has also been used as an
      effective chemotherapeutic agent in the treatment of certain human cancers.
      However, the mechanisms by which arsenic induces proliferation of cancer cells or
      cancer cell death are not well understood. We found that exposure of JB6 P+ cells
      to low concentrations of arsenic induces cell transformation, whereas higher
      concentrations of arsenic induce cell apoptosis. Arsenite induces phosphorylation
      of extracellular signal-regulated protein kinases (Erks) and c-Jun NH(2)-terminal
      kinases (JNKs). Arsenite-induced Erk activation was markedly inhibited by
      introduction of dominant-negative Erk2 into cells, whereas expression of dominant
      negative Erk2 did not inhibit JNKs or mitogen-activated protein kinase Erk kinase
      1/2. Furthermore, arsenite-induced cell transformation was blocked in cells
      expressing dominant-negative Erk2. In contrast, overexpression of dominant
      negative JNK1 increased cell transformation even though it inhibited arsenite
      induced JNK activation. Arsenic also induced AP-1 and nuclear factor kappa B (NF
      kappaB) activation. Blocking NF-kappaB activation by dominant-negative inhibitory
      kappa Balpha inhibited arsenic-induced apoptosis and enhanced arsenic-induced
      cell transformation. Arsenic induced activation of JNKs at a similar dose range
      that was effective for induction of apoptosis in JB6 cells. In addition, we found
      that arsenic did not induce p53-dependent transactivation. Similarly, apoptosis
      induction was not different between p53 wild-type (p53(+/+)) or p53-deficient
      (p53(-/-)) cells. In contrast, arsenic-induced apoptosis was almost totally
      blocked by expression of a dominant-negative mutant of JNK. Taken together with
      previous findings that p53 mutations are involved in approximately 50% of all
      human cancers and nearly all chemotherapeutic agents kill cancer cells mainly by
      apoptotic induction, we suggest that arsenic may be a useful agent for the
      treatment of cancers with p53 mutations. These results suggest that the
      activation of Erks is required for arsenic-induced cell transformation, whereas
      the activation of JNKs and NF-kappaB is involved in arsenic-induced apoptosis of
      JB6 cells.

PMID- 12426128
TI  - Sodium arsenite-induced stress-related gene expression in normal human epidermal,
      HaCaT, and HEL30 keratinocytes.
AB  - Arsenic is a carcinogen that poses a significant health risk in humans. Based on
      evidence that arsenic has differential effects on human, rodent, normal, and
      transformed cells, these studies addressed the relative merits of using normal
      human epidermal keratinocytes (NHEK) and immortalized human (HaCaT) and mouse
      (HEL30) keratinocytes when examining stress-induced gene expression that may
      contribute to carcinogenesis. We hypothesize that redox-related gene expression
      is differentially modulated by arsenic in normal versus immortalized
      keratinocytes. To test the hypothesis, we exposed keratinocytes to sodium
      arsenite for 4 or 24 hr, at which time serine threonine kinase-25 (stk25) and
      nicotine adenine dinucleotide phosphate [nad(p)h] quinone oxidoreductase gene
      expression were measured. The effect of glutathione reduction on arsenite-induced
      cytotoxicity and gene expression in NHEK also was evaluated by addition of l
      buthionine-[S,R]-sulfoximine (BSO) to culture media. Results indicate the term
      LC(50) for arsenite is approximately 10-15 microM in NHEK and HEL30 keratinocytes
      and 30 microM in HaCaT keratinocytes. Compared with HaCaT and HEL30
      keratinocytes, a nontoxic concentration of arsenite (2.5 microM) increases stk25
      and nad(p)h quinone oxidoreductase gene expression in NHEK, an effect partially
      attenuated by BSO. These data indicate that NHEK and HaCaT/HEL30 keratinocytes
      have similar sensitivities toward arsenite-induced cytotoxicity but unique gene
      expression responses. They also suggest that arsenite modulates gene expression
      in NHEK involved in cellular signaling and other aspects of intermediary
      metabolism that may contribute to the carcinogenic process.

PMID- 12426129
TI  - The role of biomethylation in toxicity and carcinogenicity of arsenic: a research
      update.
AB  - Recent research of the metabolism and biological effects of arsenic has
      profoundly changed our understanding of the role of metabolism in modulation of
      toxicity and carcinogenicity of this metalloid. Historically, the enzymatic
      conversion of inorganic arsenic to mono- and dimethylated species has been
      considered a major mechanism for detoxification of inorganic arsenic. However,
      compelling experimental evidence obtained from several laboratories suggests that
      biomethylation, particularly the production of methylated metabolites that
      contain trivalent arsenic, is a process that activates arsenic as a toxin and a
      carcinogen. This article summarizes this evidence and provides new data on a) the
      toxicity of methylated trivalent arsenicals in mammalian cells, b) the effects of
      methylated trivalent arsenicals on gene transcription, and c) the mechanisms
      involved in arsenic methylation in animal and human tissues.

PMID- 12426130
TI  - Fanconi anemia complementation group A cells are hypersensitive to chromium(VI)
      induced toxicity.
AB  - Fanconi anemia (FA) is an autosomal recessive disorder characterized by diverse
      developmental abnormalities, progressive bone marrow failure, and a markedly
      increased incidence of malignancy. FA cells are hypersensitive to DNA cross
      linking agents, suggesting a general defect in the repair of DNA cross-links.
      Some forms of hexavalent chromium [Cr(VI)] are implicated as respiratory
      carcinogens and induce several types of DNA lesions, including ternary DNA-Cr-DNA
      interstrand cross-links (Cr-DDC). We hypothesized that human FA complementation
      group A (FA-A) cells would be hypersensitive to Cr(VI) and Cr(VI)-induced
      apoptosis. Using phosphatidylserine translocation and caspase-3 activation, human
      FA-A fibroblasts were found to be markedly hypersensitive to chromium-induced
      apoptosis compared with CRL-1634 cells, which are normal human foreskin
      fibroblasts (CRL). The clonogenicity of FA-A cells was also significantly
      decreased compared with CRL cells after Cr(VI) treatment. There was no
      significant difference in either Cr(VI) uptake or Cr-DNA adduct formation between
      FA-A and CRL cells. These results show that FA-A cells are hypersensitive to
      Cr(VI) and Cr-induced apoptosis and that this hypersensitivity is not due to
      increased Cr(VI) uptake or increased Cr-DNA adduct formation. The results also
      suggest that Cr-DDC may be proapoptotic lesions. These results are the first to
      show that FA cells are hypersensitive to an environmentally relevant DNA cross
      linking agent.

PMID- 12426131
TI  - Chiral discrimination in platinum anticancer drugs.
AB  - In this article we review the biological activity of analogs of the antitumor
      drug cisplatin that contain chiral amine ligands. Interaction with DNA and
      formation of cross-links with adjacent purine bases are considered to be the
      crucial steps in the antitumor activity of this class of complexes. Because
      double-helical DNA has a chiral structure, interaction with enantiomeric
      complexes of platinum should lead to diastereomeric adducts. It has been
      demonstrated that DNA cross-links of platinum complexes with enantiomeric amine
      ligands not only can exhibit different conformational features but also can be
      processed differently by the cellular machinery as a consequence of these
      conformational differences. These results expand the general knowledge of how the
      stereochemistry of the platinum-DNA adduct can influence the cell response and
      contribute to understanding the processes that are crucial for antitumor
      activity. The steric requirements of the chiral ligands, in terms of
      configuration and flexibility, are also elucidated.

PMID- 12426132
TI  - Distinct mechanisms of oxidative DNA damage induced by carcinogenic nickel
      subsulfide and nickel oxides.
AB  - The U.S. National Toxicology Program has shown clear evidence of carcinogenicity
      of nickel subsulfide (Ni(3)S(2)) and some evidence of carcinogenicity of NiO
      (green) in rats. In the present study, DNA damage in cultured cells and in lungs
      of rats induced by nickel compounds was investigated to clarify the mechanism of
      nickel carcinogenesis. In cultured HeLa cells, Ni(3)S(2) induced a significant
      increase in 8-hydroxydeoxyguanosine (8-OH-dG) formation, whereas NiO (black), NiO
      (green), and NiSO(4) did not. On the other hand, in rats, intratracheal
      instillation of all these nickel compounds significantly increased 8-OH-dG
      content in the lungs. The disparities in DNA damage between cultured cells and
      animals could be accounted for by two different mechanisms for nickel-induced
      oxidative DNA damage in lungs of rats. One is direct oxidative DNA damage: Ni(II)
      enters the cells and then reacts with endogenous and/or nickel sulfide-produced
      hydrogen peroxide (H(2)O(2)) to give reactive oxygen species that cause DNA
      damage. This mechanism is supported by oxidative damage to isolated DNA treated
      with Ni(II) and H(2)O(2). The other mechanism is indirect oxidative DNA damage
      due to inflammation. This double mechanism for DNA damage may explain the
      relatively high carcinogenic risk associated with Ni(3)S(2).

PMID- 12426133
TI  - The prospective role of abnormal methyl metabolism in cadmium toxicity.
AB  - Several lines of evidence point to the probable role of abnormal methylation
      processes in the toxicology of metals and other xenobiotics. The spectrum of
      toxic effects exhibited by such metals as Ni, As, and Cd, as well as by Zn
      deficiency, often resemble those seen in animals chronically fed methyl-deficient
      diets. These metal-associated pathologies include cancer, atherosclerosis, birth
      defects, neurological disturbances, and pancreatic lesions. In addition, each of
      the above agents has been shown to alter normal methyl group metabolism in vivo
      or in vitro. In the present studies, we compared the effects on the enzyme DNA
      methyltransferase (MTase) of two metal ions: the essential metal Zn and the
      carcinogen Cd. MTase extracts were obtained from the hepatic nuclei of rats fed a
      methyl-deficient diet (lacking choline and folate) for 7 and 24 weeks. Control
      animals were fed the same diet supplemented with each of these vitamins. Zn and
      Cd both inhibited MTase in the nuclear extracts from both the control and the
      methyl-deficient rats. The inhibitory activity of Cd was greater than that of Zn
      regardless of whether the nuclear extracts were from the control or the deficient
      animals. In addition, the kinetics of Cd inhibition of MTase activity were
      different in the nuclear extracts from the control and methyl-deficient rats. The
      results provide evidence that the carcinogenic effects of Cd may be mediated in
      part through abnormal DNA methylation.

PMID- 12426134
TI  - Interference by toxic metal ions with DNA repair processes and cell cycle
      control: molecular mechanisms.
AB  - Nickel, cadmium, cobalt, and arsenic compounds are well-known carcinogens to
      humans and experimental animals. Even though their DNA-damaging potentials are
      rather weak, they interfere with the nucleotide and base excision repair at low,
      noncytotoxic concentrations. For example, both water-soluble Ni(II) and
      particulate black NiO greatly reduced the repair of DNA adducts induced by
      benzo[a]pyrene, an important environmental pollutant. Furthermore, Ni(II),
      As(III), and Co(II) interfered with cell cycle progression and cell cycle control
      in response to ultraviolet C radiation. As potential molecular targets,
      interactions with so-called zinc finger proteins involved in DNA repair and/or
      DNA damage signaling were investigated. We observed an inactivation of the
      bacterial formamidopyrimidine-DNA glycosylase (Fpg), the mammalian xeroderma
      pigmentosum group A protein (XPA), and the poly(adenosine diphosphate
      ribose)polymerase (PARP). Although all proteins were inhibited by Cd(II) and
      Cu(II), XPA and PARP but not Fpg were inhibited by Co(II) and Ni(II). As(III)
      deserves special attention, as it inactivated only PARP, but did so at very low
      concentrations starting from 10 nM. Because DNA is permanently damaged by
      endogenous and environmental factors, functioning processing of DNA lesions is an
      important prerequisite for maintaining genomic integrity; its inactivation by
      metal compounds may therefore constitute an important mechanism of metal-related
      carcinogenicity.

PMID- 12426135
TI  - Cysteine-modifying agents: a possible approach for effective anticancer and
      antiviral drugs.
AB  - Modification of cysteine residues in proteins, due to a) the participation of the
      thiol moiety of this amino acid in oxido-reduction reactions, b) its ability to
      strongly coordinate transition metal ions, or c) its nucleophilic nature and
      facile reaction with electrophiles, may be critically important for the design of
      novel types of pharmacological agents. Application of such procedures recently
      led to the design of novel antivirals, mainly based on the reaction of zinc
      finger proteins with disulfides and related derivatives. This approach was
      particularly successful for developing novel antiviral agents for human
      immunodeficiency virus and human papilloma virus. Several new anticancer
      therapeutic approaches, mainly targeting tubulin, have also been reported. Thus,
      this unique amino acid offers very interesting possibilities for developing
      particularly useful pharmacological agents, which generally possess a completely
      different mechanism of action compared with classic agents in clinical use, thus
      avoiding major problems such as multidrug resistance (for antiviral and
      anticancer agents) or high toxicity.

PMID- 12426137
TI  - Activation of gene expression by metal-responsive signal transduction pathways.
AB  - Metallothioneins are small, cysteine-rich, metal-binding proteins that play
      important roles in maintaining intracellular metal homeostasis and in transition
      metal detoxification. MTF-1 (metal transcription factor-1) plays a central role
      in regulating the metal-inducible, transcriptional activation of metallothionein.
      Here we report that the phosphorylation of MTF-1 plays a critical role in the
      activation of MTF-1/metal-responsive element-mediated transcription. Inhibitor
      studies indicate that signal transduction cascades, including those mediated by
      protein kinase C, tyrosine kinase, and casein kinase II, are essential for zinc-
      and cadmium-inducible transcription. In addition, calcium signaling is also
      involved in regulating transcription. In contrast, cAMP-dependent protein kinase
      may not be directly involved in the metal response. Contrary to what has been
      reported for other transcription factors, the inhibition of transcriptional
      activation does not impair the binding of MTF-1 to DNA, suggesting that
      phosphorylation is not regulating DNA binding. Elevated phosphorylation of MTF-1
      is observed under conditions of protein kinase C inhibition, suggesting that
      dephosphorylation of this transcription factor mediates its activation.

PMID- 12426136
TI  - Signaling from toxic metals to NF-kappaB and beyond: not just a matter of
      reactive oxygen species.
AB  - The nuclear factor kappa B (NF-kappaB) family of transcription factors controls
      expression of a number of early response genes associated with inflammatory
      responses, cell growth, cell cycle progression, and neoplastic transformation.
      These genes include a multitude of cytokines, chemokines, adhesion molecules,
      immune receptors, stress proteins, apoptotic or anti-apoptotic regulators, and
      several oncogenes. Accumulating evidence indicates that a variety of toxic metals
      are able to affect the activation or activity of NF-kappaB, but the molecular
      mechanisms involved in this process remain largely unknown. The signaling
      pathways mediating cytokine- or microorganism-induced NF-kappaB activation have
      been well established recently. Whether the same signaling systems are involved
      in metal-induced NF-kappaB activation, however, is unclear. In the present
      review, we have attempted to evaluate and update the possible mechanisms of metal
      signals on the activation and function of NF-kappaB.

PMID- 12426138
TI  - Attenuation of nuclear factor kappa B (NF-kappaB) promotes apoptosis of kidney
      epithelial cells: a potential mechanism of mercury-induced nephrotoxicity.
AB  - Nuclear factor kappa B (NF-kappaB), a pleiotropic transcriptional factor that
      promotes cell survival and protects cells from apoptosis, requires reduced thiols
      at critical steps in its activation pathway. Mercuric ion (Hg(2+)), one of the
      strongest thiol-binding agents known, impairs NF-kappaB activation and
      transcriptional activity in normal rat kidney epithelial (NRK52E) cells at
      concentrations as low as 0.5 microM by binding to specific reduced thiol moieties
      in the NF-kappaB activation pathway. We hypothesized that prevention of NF-kappaB
      activation by Hg(2+) will increase the sensitivity of kidney cells to the
      apoptosis-inducing effects of other toxicants to which these cells are otherwise
      resistant by virtue of their NF-kappaB-activating capacity. Fewer than 5% of
      untreated kidney cells in culture (70-90% confluent) were found to be apoptotic
      when evaluated by DNA fragmentation (terminal deoxynucleotide transferase
      mediated dUTP nick-end labeling) or flow cytometric DNA profile analyses. Hg(2+)
      (5 microM) treatment for 24 hr increased this proportion by 1.5- to 2-fold.
      Neither lipopolysaccharide (LPS) (1 microg/mL) nor tumor necrosis factor-alpha
      (TNF-alpha; 300 U/mL), both potent activators of NF-kappaB in kidney cells,
      significantly altered the proportion of apoptotic cells, compared with untreated
      controls, when applied without Hg(2+) pretreatment. However, when LPS or TNF
      alpha was administered after Hg(2+) pretreatment (5 microM for 30 min), the
      proportion of cells undergoing apoptosis 22 hr later increased by 4- to 6-fold
      compared with untreated controls. In contrast, Hg(2+) pretreatment did not
      increase the amount of apoptosis caused by apoptosis-inducing agents that do not
      activate NF-kappaB (staurosporine, Fas ligand). These findings suggest that
      Hg(2+) enhances the sensitivity of kidney cells to apoptotic stimuli as a
      consequence of inhibition of NF-kappaB activity. Because apoptosis is known to
      play a key role in the pathogenesis of renal failure resulting from toxicant
      injury to proximal tubular cells, promotion of apoptosis via inhibition of NF
      kappaB activity may define a novel molecular mechanism by which Hg(2+) toxicity
      is initiated in kidney cells.

PMID- 12426139
TI  - Cell signaling and cytotoxicity by peroxynitrite.
AB  - Reactive nitrogen species are now considered to play an important role in various
      pathologies. Although the pathological significance of these molecules,
      peroxynitrite in particular, has long been attributed to their abilities to react
      with any component of the cells, including lipids, proteins, and DNA, a paradigm
      shift has recently been occurring whereby reactive nitrogen species are
      appreciated as signaling molecules. The question therefore arises as to whether
      nitrosative stress is indeed the result of a random (stochastic) process of cell
      damage, as it has traditionally been viewed, or rather is a consequence of the
      specific activation of a cascade of signaling events. The above considerations
      have provided the bases for the research work performed in our laboratory, and
      the results obtained are illustrated in the present article. In particular, our
      results indicate that some effects of peroxynitrite are not directly mediated by
      the oxidant; rather, it appears that peroxynitrite triggers a signaling pathway
      that finally leads to cytotoxicity.

PMID- 12426140
TI  - Suppression of metallothionein-I/II expression and its probable molecular
      mechanisms.
AB  - Metallothionein (MT) promoter was methylated in rat hepatoma and in mouse
      lymphosarcoma cells by methylation of cytosine within the CpG dinucleotide
      region. After demethylation of MT-I promoter in mouse lymphosarcoma cells or in
      the transplanted rat hepatoma with 5-azacytidine, a potent inhibitor of DNA
      methyltransferase, the promoter was activated in response to heavy metal
      treatment. MT-I promoter was also suppressed in human prostate cancer lines PC3
      and DU145, probably by promoter methylation, whereas cadmium induced MT-I in the
      human prostate cancer line LNCaP. In the prostate cancer lines where MT-I was
      suppressed, glutathione-S-transferase-pi (GST-pi) was expressed. On the contrary,
      GST-pi gene was repressed in the cell line where MT-I was induced, which suggests
      an inverse relationship between MT-I induction and GST-pi expression in some
      prostate cancer lines. The expressions of GST-pi and gamma-glutamyl cysteine
      synthase were also significantly higher (5- to 12-fold) in the lymphosarcoma
      cells and the hepatoma relative to the parental tissues. The higher expressions
      of these two genes suggest a compensatory mechanism in the cells where the gene
      for the antioxidant MT-I/II is not induced. MT-I/II may function as a growth
      suppressor either alone or in concert with other factor(s), and consequently
      their lack of expression could facilitate the tumor growth. In addition to
      suppression of MT-I/II expression by promoter methylation, the lack of MT
      induction could also be brought about by nuclear factor I (NFI), probably by
      interaction with the metal transcription factor MTF-1. An inverse relationship
      was observed between the level of NFI and MT-I expression in some cells, which
      suggests a role for NFI in the relatively low constitutive levels of MT-I
      expression in these cells.

PMID- 12426141
TI  - The role of hypoxia-inducible signaling pathway in nickel carcinogenesis.
AB  - Using human and rodent cells in vitro, we characterized a hypoxia-inducible
      signaling pathway as one of the pathways affected by carcinogenic nickel
      compounds. Acute exposure to nickel activates hypoxia-inducible transcription
      factor-1 (HIF-1), which strongly induces hypoxia-inducible genes, including the
      recently discovered tumor marker Cap43. This gene has been cloned based on its
      nickel inducibility and was found to be highly inducible by hypoxia. To identify
      other HIF-1-dependent/independent nickel-inducible genes, we used cells obtained
      from HIF-1 alpha null mouse embryos and analyzed gene expression changes using
      the microarray technique. We found that genes coding for glycolytic enzymes,
      known to be regulated by HIF-1, were also induced in nickel-exposed cells. In
      addition, we identified a number of new genes highly induced by nickel in an HIF
      dependent manner. Elevated HIF-1 activity after acute nickel exposure might be
      selectively advantageous because nickel-transformed rodent and human cells
      possess increased HIF-1 transcriptional activity. Hypoxia plays an important role
      in tumor progression. It selects for cells with enhanced glycolytic activity,
      causing production of large amounts of lactic acid, one of the most common
      features of tumor cells (Warburg effect). Here, we hypothesize that exposure to
      nickel activates the hypoxia-inducible pathway and facilitates selection of cells
      with increased transcriptional activity of hypoxia-inducible genes, which may be
      important in the nickel-induced carcinogenic process.

PMID- 12426142
TI  - Activation of nuclear factor-kappaB and not activator protein-1 in cellular
      response to nickel compounds.
AB  - The predominant exposure route for nickel compounds is by inhalation, and several
      studies have indicated the correlation between nickel exposure and respiratory
      cancers. The tumor-promoting effects of nickel compounds are thought to be
      associated with their transactivation of transcription factors. We have
      investigated the possible activation of activator protein-1 (AP-1) and nuclear
      factor KB (NF-kappaB) in mouse C141 epidermal cells and fibroblasts 3T3 and B82,
      and human bronchoepithelial BEAS-2B cells in response to nickel compound
      exposure. Our results show that NF-kappaB activity is induced by nickel exposure
      in 3T3 and BEAS-2B cells. Conversely, similar nickel treatment of these cells did
      not induce AP-1 activity, suggesting that nickel tumorigenesis occurs through NF
      kappaB and not AP-1. We also investigated the role of NF-kappaB in the induction
      of Cap43 by nickel compounds using dominant negative mutant Ikappabeta kinase b
      KM BEAS-2B transfectants.

PMID- 12426143
TI  - Respiratory carcinogenicity assessment of soluble nickel compounds.
AB  - The many chemical forms of nickel differ in physicochemical properties and
      biological effects. Health assessments for each main category of nickel species
      are needed. The carcinogenicity assessment of water-soluble nickel compounds has
      proven particularly difficult. Epidemiologic evidence indicates an association
      between inhalation exposures to nickel refinery dust containing soluble nickel
      compounds and increased risk of respiratory cancers. However, the nature of this
      association is unclear because of limitations of the exposure data, inconsistent
      results across cohorts, and the presence of mixed exposures to water-insoluble
      nickel compounds and other confounders that are known or suspected carcinogens.
      Moreover, well-conducted animal inhalation studies, where exposures were solely
      to soluble nickel, failed to demonstrate a carcinogenic potential. Similar
      negative results were seen in animal oral studies. A model exists that relates
      respiratory carcinogenic potential to the bioavailability of nickel ion at
      nuclear sites within respiratory target cells. This model helps reconcile human,
      animal, and mechanistic data for soluble nickel compounds. For inhalation
      exposures, the predicted lack of bioavailability of nickel ion at target sites
      suggests that water-soluble nickel compounds, by themselves, will not be complete
      human carcinogens. However, if inhaled at concentrations high enough to induce
      chronic lung inflammation, these compounds may enhance carcinogenic risks
      associated with inhalation exposure to other substances. Overall, the weight of
      evidence indicates that inhalation exposure to soluble nickel alone will not
      cause cancer; moreover, if exposures are kept below levels that cause chronic
      respiratory toxicity, any possible tumor-enhancing effects (particularly in
      smokers) would be avoided.

PMID- 12426144
TI  - Molecular biology of deregulated gene expression in transformed C3H/10T1/2 mouse
      embryo cell lines induced by specific insoluble carcinogenic nickel compounds.
AB  - In the past, exposure of workers to mixtures of soluble and insoluble nickel
      compounds by inhalation during nickel refining correlated with increased
      incidences of lung and nasal cancers. Insoluble nickel subsulfide and nickel
      oxide (NiO) are carcinogenic in animals by inhalation; soluble nickel sulfate is
      not. Particles of insoluble nickel compounds were phagocytized by C3H/10T1/2
      mouse embryo cells and induced morphological transformation in these cells with
      the following order of potency: NiO (black) > NiO (green) > nickel subsulfide.
      Foci induced by black/green NiO and nickel monosulfide developed into anchorage
      independent transformed cell lines. Random arbitrarily primed-polymerase chain
      reaction mRNA differential display showed that nine c-DNA fragments are
      differentially expressed between nontransformed and nickel compound-transformed
      10T1/2 cell lines in 6% of total mRNA; 130 genes would be differentially
      expressed in 100% of the mRNA. Fragment R3-2 was a sequence in the mouse calnexin
      gene, fragment R3-1 a portion of the Wdr1 gene, and fragment R2-4 a portion of
      the ect-2 protooncogene. These three genes were overexpressed in transformed cell
      lines. Fragment R1-2 was 90% homologous to a fragment of the DRIP/TRAP-80
      (vitamin D receptor interacting protein/thyroid hormone receptor-activating
      protein 80) genes and was expressed in nontransformed but not in nickel
      transformed cell lines. Specific insoluble carcinogenic nickel compounds are
      phagocytized into 10T1/2 cells and likely generate oxygen radicals, which would
      cause mutations in protooncogenes, and chromosome breakage, and mutations in
      tumor suppressor genes, inactivating them. These compounds also induce
      methylation of promoters of tumor suppressor genes, inactivating them. This could
      lead to permanent overexpresssion of the ect-2, calnexin, and Wdr1 genes and
      suppression of expression of the DRIP/TRAP-80 gene that we observed, which likely
      contribute to induction and maintenance of transformed phenotypes.

PMID- 12426145
TI  - Silent latency periods in methylmercury poisoning and in neurodegenerative
      disease.
AB  - This article discusses three examples of delay (latency) in the appearance of
      signs and symptoms of poisoning after exposure to methylmercury. First, a case is
      presented of a 150-day delay period before the clinical manifestations of brain
      damage after a single brief (<1 day) exposure to dimethylmercury. The second
      example is taken from the Iraq outbreak of methylmercury poisoning in which the
      victims consumed contaminated bread for several weeks without any ill effects.
      Indeed, signs of poisoning did not appear until weeks or months after exposure
      stopped. The last example is drawn from observations on nonhuman primates and
      from the sequelae of the Minamata, Japan, outbreak in which low chronic doses of
      methylmercury may not have produced observable behavioral effects for periods of
      time measured in years. The mechanisms of these latency periods are discussed for
      both acute and chronic exposures. Parallels are drawn with other diseases that
      affect the central nervous system, such as Parkinson disease and post-polio
      syndrome, that also reflect the delayed appearance of central nervous system
      damage.

PMID- 12426146
TI  - Cognitive deficits and changes in gene expression of NMDA receptors after
      prenatal methylmercury exposure.
AB  - Previous studies showed learning and memory deficit in adult rats that were
      prenatally exposed to methylmercury chloride (MMC) in an advanced stage of
      pregnancy (15 days). Under these conditions, the cognitive deficits found at 60
      days of age paralleled particularly changes in the N-methyl-D-aspartate (NMDA)
      receptor characteristics. In the present study, we report the behavioral effects
      of a single oral dose of MMC (8 mg/kg) administered earlier at gestational day 8.
      The use of different learning and memory tests (passive avoidance, object
      recognition, water maze) showed a general cognitive impairment in the in utero
      exposed rats tested at 60 days of age compared with matched controls. Considering
      the importance of the glutamatergic receptor system and its endogenous ligands in
      learning and memory process regulation, we surmised that MMC could affect the
      gene expression of NMDA receptor subtypes. The use of a sensitive RNase
      protection assay allowed the evaluation of gene expression of two families of
      NMDA receptors (NR-1 and NR-2 subtypes). The result obtained in 60-day-old rats
      prenatally exposed to MMC, showed increased mRNA levels of the NR-2B subunit in
      the hippocampus but not in the frontal cortex. The data suggest that the
      behavioral abnormalities of MMC-exposed rats might be ascribed to a neurotoxic
      effect of the metal that alters the gene expression of a specific NMDA receptor
      subunit in the hippocampus.

PMID- 12426148
TI  - Induction of apoptosis in mammalian cells by cadmium and zinc.
AB  - In various mammalian cells, two group IIb metals, cadmium and zinc, induce
      several morphological and biochemical effects that are salient features of
      programmed cell death. In C6 rat glioma cells, cadmium caused externalization of
      phosphatidylserine, breakdown of the mitochondrial membrane potential, activation
      of caspase-9, internucleosomal DNA fragmentation, chromatin condensation, and
      nuclear fragmentation. In NIH3T3 murine fibroblasts, cadmium-induced apoptosis
      was inhibited by overexpression of the antiapoptotic protein Bcl-2. Cadmium
      induced DNA fragmentation in C6 cells was independent of inhibition of protein
      kinase A (PKA), protein kinase C (PKC), mitogen-activated protein kinase (MAPK),
      phosphatidylinositol-3-kinase, Ca-calmodulin-dependent protein kinase, and
      protein kinase G. Zinc at moderate concentrations (10-50 microM) protected
      against programmed cell death induced by cadmium, whereas deprivation of zinc by
      the membrane-permeable chelator N,N,N',N-terakis-(2-pyridylmethyl)ethylenediamine
      (TPEN) caused cell death with features characteristic of apoptosis. On the other
      hand, at elevated extracellular levels (150-200 microM), zinc alone caused
      programmed cell death in C6 cells. Zinc-induced apoptosis was independent of
      inhibition of PKA, PKC, guanylate cyclase and MAPK, but it was suppressed in the
      presence of 100 microM lanthanum chloride.

PMID- 12426147
TI  - Investigations of methylmercury-induced alterations in neurogenesis.
AB  - Methylmercury (MeHg) has been an environmental concern to public health and
      regulatory agencies for over 50 years because of its toxicity to the human
      nervous system. Its association with nervous system toxicity in adults and
      infants near Minamata Bay, Japan, in the 1950s initiated environmental health
      research inquiries that continue to this day. Observations of greater
      neurotoxicity with gestational compared with adult exposure suggest a unique
      susceptibility of the developing nervous system to MeHg. Despite extensive
      research conducted over the last half century, determination of definitive
      molecular mechanisms underlying the observed neurotoxic effects of MeHg have not
      been identified. This paper summarizes results of a series of experiments
      conducted to examine the effects of MeHg on neuroepithelial cell proliferation, a
      hypothesized mode of action for its selective effects on neurogenesis. Observed
      effects of MeHg on cell cycle entry and progression were associated with
      alterations in a variety of cell cycle regulatory molecules, including p21
      signaling pathways. We place these studies in the context of other cellular
      responses involved in signal transduction, including oxidative stress, altered
      protein phosphorylation, and altered intracellular calcium homeostasis. Although
      existing information suggests that no single mechanism underlies the diverse
      array of effects associated with MeHg-induced developmental neurotoxicity, we
      demonstrate characteristic effects of MeHg on cell signaling that contribute to
      observed effects on cell proliferation. Experimentally derived cell cycle kinetic
      and cytotoxicity data allowed development of a biologically based dose-response
      model of MeHg-induced alterations in neurodevelopment, which can form the basis
      for information synthesis and hypothesis testing and for use in assessing risks
      from environmental exposures.

PMID- 12426149
TI  - Possible involvement of copper(II) in Alzheimer disease.
AB  - The beta-amyloid (Abeta) peptide is a principal component of insoluble amyloid
      plaques that are characteristic neuropathological features of Alzheimer disease
      (AD). The amyloid peptide also exists as a normal soluble protein that undergoes
      a pathogenic transition to an aggregated, fibrous form. This transition can be
      affected by extraneous proteinaceous elements and nonproteinaceous elements such
      as copper ions, which may promote aggregation and/or stabilization of the
      fibrils. Copper has been found in abnormally high concentrations in amyloid
      plaques and AD-affected neuropil, and copper-selective chelators have been shown
      to dissolve Abeta peptide from postmortem brain specimens. Although Cu(2+) is an
      essential element for life and the function of numerous enzymes is basic to
      neurobiology, free or incorrectly bound Cu(2+) can also catalyze generation of
      the most damaging radicals, such as hydroxyl radical, giving a chemical
      modification of the protein, alternations in protein structure and solubility,
      and oxidative damage to surrounding tissue.

PMID- 12426150
TI  - A role for associated transition metals in the immunotoxicity of inhaled ambient
      particulate matter.
AB  - Epidemiologic studies demonstrate that infection, specifically pneumonia,
      contributes substantially to the increased morbidity and mortality among elderly
      individuals following exposure to ambient particulate matter (PM). This
      laboratory has previously demonstrated that a single inhalation exposure of
      Streptococcus pneumoniae-infected rats to concentrated ambient PM(2.5)
      (particulate matter with aerodynamic diameter < or =2.5 microm) from New York
      City (NYC) air exacerbates the infection process and alters pulmonary and
      systemic immunity. Although these results provide some basis for explaining the
      epidemiologic findings, the identity of specific PM constituents that might have
      been responsible for the worsening pneumonia in exposed hosts remains unclear.
      Thus, studies were performed to correlate the physicochemical attributes of
      ambient PM(2.5) with its in vivo immunotoxicity to identify and characterize the
      role of constitutive transition metals in exacerbating an ongoing streptococcal
      infection. Uninfected or previously infected rats were exposed in the laboratory
      to soluble divalent Fe, Mn, or Ni chloride salts. After exposure, uninfected rats
      were sacrificed and their lungs were lavaged. Lungs from infected hosts were used
      to evaluate changes in bacterial clearance and effects of exposure on the
      extent/severity of infection. Results demonstrated that inhalation of Fe altered
      innate and adaptive immunity in uninfected hosts, and both Fe and Ni reduced
      pulmonary bacterial clearance in previously infected rats. The effects on
      clearance produced in infected Fe-exposed rats were similar to those seen in
      infected rats exposed to ambient NYC PM. Taken together, these studies
      demonstrate that inhaled ambient PM can worsen the outcome of an ongoing
      pulmonary infection and that associated Fe may play some role in the
      immunotoxicity.

PMID- 12426151
TI  - Mercury-induced autoimmunity in mice.
AB  - We have studied the effect of gender, genetics, and toxicokinetics on immune
      parameters in mercury-induced autoimmunity in mice. Data strongly suggest that
      the mechanism for mercury-induced autoimmunity involves modification of the
      autoantigen fibrillarin by mercury followed by a T-cell-dependent immune response
      driven by the modified fibrillarin. Mice with different H-2 haplotypes were
      treated with (203)HgCl(2) in a dose of 0.5-16 mg Hg/L drinking water for 10
      weeks. Whole-body accumulation and renal accumulation of mercury were assessed.
      Serum antinuclear antibodies were used to evaluate the autoimmune response, and
      serum immunoglobulin E (IgE) to study effects on T-helper cells of type 2.
      Strains with a susceptible H-2 haplotype developed autoantibodies to the
      nucleolar protein fibrillarin (AFA) in a dose-dependent pattern within 2 weeks.
      The substantially lower whole-body and organ mercury level needed to induce AFA
      in the susceptible A.SW strain compared with the H-2 congenic B10.S strain
      demonstrates that genetic factors outside the H-2 region modify the autoimmune
      response. Mouse strains without the susceptible haplotype did not develop any
      autoimmune reaction irrespective of dose and organ deposition of mercury. In
      susceptible mouse strains, males and females had different thresholds for
      induction of autoimmune reactions. In susceptible strains, serum IgE increased
      dose dependently and reached a maximum after 1-2.5 weeks. A susceptible H-2
      haplotype is therefore a prerequisite for the autoimmune response. Mercury
      exposure will modulate the response, qualitatively through the existence of dose
      related thresholds for autoimmune response and quantitatively as increasing doses
      cause increasing autoimmune response. Further, gender and non-H-2 genes modulate
      both the induction and subsequent development of AFA. Induction of IgE seems not
      to be mechanistically linked to the AFA response.

PMID- 12426152
TI  - Pathology related to chronic arsenic exposure.
AB  - Millions now suffer the effects of chronic arseniasis related to environmental
      arsenic exposure. The biological mechanisms responsible for arsenic-induced
      toxicity and especially chronic effects, including cancer, are not well known.
      The U.S. Armed Forces Institute of Pathology (AFIP) is participating in an
      international research effort to improve this understanding by the development of
      the International Tissue and Tumor Repository for Chronic Arsenosis (ITTRCA). The
      ITTRCA obtains, archives, and makes available for research purposes, tissues from
      subjects exposed to arsenic. We provide here a short overview of arsenic-induced
      pathology, briefly describe arsenic-induced lesions in the skin and liver, and
      present five case reports from the ITTRCA. Arsenic-induced skin pathology
      includes hyperkeratosis, pigmentation changes, Bowen disease, squamous cell
      carcinoma, and basal cell carcinomas. A unique spectrum of skin lesions, known as
      arsenical keratosis, is rather characteristic of chronic arseniasis. Bowen
      disease, or squamous cell carcinoma in situ of the skin, has been well documented
      as a consequence of arsenical exposure. A spectrum of liver lesions has also been
      attributed to chronic arseniasis. Of these, hepatocellular carcinoma,
      angiosarcoma, cirrhosis, and hepatoportal sclerosis have been associated with
      arsenic exposure. We present case reports that relate to these health conditions,
      namely, squamous cell carcinoma, basal cell carcinoma, and Bowen disease of the
      skin and hepatocellular carcinoma and angiosarcoma of the liver. Four patients
      had been treated with arsenical medications for such conditions as asthma,
      psoriasis, and syphilis, and one case occurred in a boy chronically exposed to
      arsenic in drinking water.

PMID- 12426153
TI  - Molecular mechanisms of in vivo metal chelation: implications for clinical
      treatment of metal intoxications.
AB  - Successful in vivo chelation treatment of metal intoxication requires that a
      significant fraction of the administered chelator in fact chelate the toxic
      metal. This depends on metal, chelator, and organism-related factors (e.g., ionic
      diameter, ring size and deformability, hardness/softness of electron donors and
      acceptors, route of administration, bioavailability, metabolism, organ and
      intra/extracellular compartmentalization, and excretion). In vivo chelation is
      not necessarily an equilibrium reaction, determined by the standard stability
      constant, because rate effects and ligand exchange reactions considerably
      influence complex formation. Hydrophilic chelators most effectively promote renal
      metal excretion, but they complex intracellular metal deposits inefficiently.
      Lipophilic chelators can decrease intracellular stores but may redistribute toxic
      metals to, for example, the brain. In chronic metal-induced disease, where life
      long chelation may be necessary, possible toxicity or side effects of the
      administered chelator may be limiting. The metal selectivity of chelators is
      important because of the risk of depletion of the patient's stores of essential
      metals. Dimercaptosuccinic acid and dimercaptopropionic sulfonate have gained
      more general acceptance among clinicians, undoubtedly improving the management of
      many human metal intoxications, including lead, arsenic, and mercury compounds.
      Still, development of new safer chelators suited for long-term oral
      administration for chelation of metal deposits (mainly iron), is an important
      research challenge for the future.

PMID- 12426154
TI  - Cloning and sequence analysis of cDNA and genomic DNA of human thrombopoietin
      gene.
AB  - OBJECTIVE: To study the role of thrombopoietin (TPO) gene 5' untranslated region
      (UTR) and the intron in TPO expression regulation. METHODS: With the mRNA derived
      from Chinese human fetal liver as the template, full-length TPO cDNA
      (approximately 1.1 kb) and TPO genomic DNA(6.2 kb) along with all the introns of
      TPO gene were isolated by PCR and long-distance PCR techniques from Chinese fetal
      liver tissue. RESULT: Sequencing analysis indicated that all the coding sequences
      and the exon/intron splice sites were consistent with the results previously
      reported by Sohma et al except for only a DNA and all the introns in the intron
      of TPO gene. CONCLUSION: We have successfully cloned full-length TPO cDNA, TPO
      genomic DNA and all the introns of TPO gene from Chinese fetal liver tissue.

PMID- 12426155
TI  - Detection of the YMDD motif mutation of P gene of hepatitis B virus using
      polymerase chain reaction-restriction fragment length polymorphism.
AB  - OBJECTIVE: To establish a convenient approach to implement polymerase chain
      reaction-restriction fragment length polymorphism (PCR-RFLP) for detecting of
      gene mutation. METHODS: Serum samples were collected from l0 patients with
      chronic hepatitis B who had received oral lamivudine for at least l year, and 3
      methods including mismatched PCR-RFLP, direct sequence analysis of the PCR
      product and cloning prior to secondary sequence analysis were employed
      respectively to examine the YMDD motif mutation of P gene of hepatitis B virus
      (HBV). RESULTS: PCR-RFLP revealed wild-type HBV infection in 7 cases mixed
      infection in 1 case and HBV mutant infection in 2 cases. With direct sequence
      analysis of the PCR product, 9 cases were found with Wild-type HBV infection and
      1 with HBV mutant infection. However, 2 non-wild-type HBVV-infected cases as
      approved by PCR-RFLP, opposite to the results by direct sequence analysis, were
      both shown by sequence analysis after cloning to suffer mixed infection.
      CONCLUSION: Sequence analysis following cloning is the best way to detect YMDD
      motif mutation in HBV, but in terms of economy and practicability, mismatched PCR
      RFLP is of greater significance in mass screening of YMDD motif mutant HBV than
      the other 2 approaches.

PMID- 12426156
TI  - Expression of phospholipase-gamma1 in human fetal tissues.
AB  - OBJECTIVE: To investigate the expression of phospholipase C-gamma1(PLC-gamma1) in
      human fetal tissues. METHODS: Serial sections 5 &mgr;m in thickness were prepared
      from paraformadehyde-fixed and paraffin-embedded normal human fetal tissues
      including the cartilage, the cartilage membrane and the muscle tissues. The
      distribution of PLC-gamma1 expression was examined immunohistochemically in the
      sections. RESULTS: Immunoreactive PLC-gamma1 was readily detected in the cells of
      the cartilage, the cartilage membrane and the muscl tissues, which was largely
      confined within the cytoplasm. CONCLUSION: PLC-gamma1 is essential for the early
      development and cell proliferation of human embryos.

PMID- 12426157
TI  - Induction of erythroid differentiadon in K562 cells by different butyrate
      regimens.
AB  - OBJECTIVE: To investigate the hemoglobinization induced by butyrate and observe
      the effects of different butyrate regimens on erythroid differentiation of K562
      cells. METHODS: K562 cells, used as an in vitro model system, were stained with
      benzidine to assess hemoglobin (Hb) production in response to different treatment
      regimens of butyrate at varied concentrations. Comparison of the percentage of
      benzidine-positive cells (BZ%)in untreated and butyrate-treated K562 cells was
      performed. Protein absorption at 414 nm using a spectrophotometer and cellulose
      acetate gel electrophoresis were employed to determine the changes of Hb
      production in K562 cells. RESULT: The BZ% increased by 4 to 6 fold and Hb
      production by 9 to 14 fold 3 d after the cells were incubated with butyrate which
      selectively promoted fetal hemoglobin(HbF) production in K562 cells. The BZ%
      increased gradually and reached the peak of l9% to 28% on day 3 or 4 in cells
      receiving pulse treatment with butyrate for only once, followed by a subsequent
      rapid fall and on day 7 to 9, it decreased to the level of untreated K562 cells.
      The length of time for incubation with butyrate was not related to in the
      increment or the maintenance of the increased level of BZ%. Continuous treatment
      with butyrate yielded a similar result to that of a single administration of
      pulse treatment. In contrast, in cells with intermittent pulse treatment the BZ%
      reached a peak after 72 h and was maintained between 20% and 30% till 3 cycles of
      treatment was completed. CONCLUSION: Butyrate can induce the expression of globin
      genes and augment Hb producfion especially that of HbF. A sustained erythroid
      differentiation of K562 cells can be achieved by intermittent pulse treatment
      with butyrate which can be an ideal regimen for children with beta globin
      diseases.

PMID- 12426158
TI  - Immunocytochemical study of the marginal division in human striatum.
AB  - OBJECTIVE: To demonstrate the existence of the marginal division in human
      stritum. METHODS: The cytoar-chitecture and distribution of the neurotransmitters
      in human fetal striatum were studied using Nissl staining and immuno
      cytochemistry. RESULTS: In the sections with Nissl staining, a distinct fusiform
      cell zone was observed between the putamen and the globus pallidus of the human
      striatum. The long axes of these neurons in this region stretched dorsoventrally
      in parallel with the border between the putamen and the globus pallidus. Numerous
      L-ENK-, NT-, SOM-and SP-positive fibers and a few L-ENK-and NT-positive cells
      were found in the marginal division. CONCLUSION: For the first time we
      demonstrate that human also have the marginal division in the striatum which is
      similar to that of the mammals as the rats, cats and monkeys

PMID- 12426159
TI  - Relation of renin-angiotensin system gene polymorphisms and expressions with the
      efficacy of antihypertensive drugs.
AB  - OBJECTIVE: To investigate the relation of renin-angiotensin system (RA3) gene
      polymorphisms and expressions with the clinical efficacy of antihypertensive
      drugs. METHODS: This randomized, single-blind study consisted of 90 patients with
      essential hypertension, who were divided into losartan, lisinopril and nisodipine
      groups with corresponding medications as indicated. The genotypes of angiotensin
      converting enzyme (ACE) insertion/deletion, angiotensinogen (AGT) M235T
      polymorphism and expressions of ACE and AT1 receptor genes were examined
      individually. RESULTS: The basal level of mRNA expression of AT1 receptor was
      lower in patients with MM genotype of AGT gene than those in patients with MT 1
      and TT genotypes, but between the latter two, no significant differences were
      found. The three antihypertensive drugs, when significantly lowering the blood
      pressure, reduced AT1 receptor mRNA expression concurrently. Losartan and
      lisinopril both decreased ACE mRNA expression levels that were positively
      correlated with the difference of the diastolic blood pressure whereas nisodipine
      elevated ACE mRNA expression, showing inverse correlation to the difference of
      thediastolic blood pressure. CONCLUSION: For patients with hypertension who have
      elevated basal levels of AT1 mRNA expression and AGT T allele or who retain high
      basal expression levels of ACE mRNA AT1 antagonists and ACE inhibitors that
      execute their action through RAS are preferentially selected, and in cases of low
      basal levels of ACE mRNA calcium antagonists are preferred.

PMID- 12426160
TI  - Preparation of anfi-CD3 and anti-IgM&mgr; chain bispecific antibody by cell
      fusion.
AB  - OBJECTIVE: To prepare anti-CD3 and anti-Igm&mgr; chain bispecific antibody (BsAb)
      by means of cell fusion and assess the stability and activity of the hybrid
      hybridoma. METHODS: Mouse hybridoma cell line secreting anti-human CD3 monoclonal
      antibody (mAb) was trans formed into HAT-sensitive cells by 8-azaguanine, which
      was subsequently transfected by plasmid pCDaA3 containing neoR marker gene via
      FuGENETM6. The resulted mutant phenotype, named alphaCD3 HATs G418R, was fused
      with the hybridoma producing anti-IgM&mgr; chain mAb, and enzyme-linked
      immunosorbent assay and flow cytometry were employed to identify the fusion cells
      producing the target BsAb. RESULTS: Six rounds of cell fusion was performed and a
      total of l 080 wells inoculated, yielding 5 hybrid hybridoma cell lines. Two of
      the 5 cell lines were subcloned and continuously cultured in vitro for 2 months
      without losing their capability to secrete BsAb. CONCLUSION: Cell fusion
      technique can be utilized to prepare BsAb-producing hybrid hybridoma that has
      similar stability and activity to its parent hybridoma.

PMID- 12426161
TI  - Effects of gentiopicrooside injections on experimental hepatic injury.
AB  - OBJECTIVE: To investigate the protective and jaundice-relieving effects of
      gentiopicrooside (GPS) injections in mouse and rat models of chemical-induced and
      immune-mediated hepatic injury. METHODS: Mouse models of chemical-induced liver
      injury were established by CCl4 injections into the abdominal cavity, mouse
      models of immune-mediated liver damage by bacillus Calmette-Guerin (BCG) and
      lipopolysaccharide (LPS) and rat models of jaundice by oral alpha-naphthyliso
      thiocyanate (ANIT). Treatment with GPS injections was administered and both of
      enzyme activities of alanine aminotransferase (ALT) and aspartate
      aminotransferase (AST) in the Serum were measured in the models. The serum level
      of total bilirubin was determined in the jaundice models. RESULTS: Compared with
      those of the untreated models, the enzyme activities of ALT and AST were
      significantly reduced in groups with a 10 day GPS treatment (P<0.001, P<0.05).
      Higher dosage of GPS showed more conspicuous effects in relieving the jaundice.
      CONCLUSION: GPS can be administered as the antagonist against CC14-induced liver
      injury and offers protection against immune-mediated liver damage.

PMID- 12426162
TI  - Purification of murine CD34+ hematopoietic stem cells using immunomagnetic beads.
AB  - OBJECTIVE: To assess the efficiency of immunomagnetic beads in the purification
      of CD34+ cells from murine bone marrow. METHODS: CD34+ cells were isolated from
      murine bone marrow using immunomagnetic beads on MiniMACS device. Fluorescence
      activated cell sorter (FACS) was employed to determine the percentages of CD34+
      cells before and after the purification procedures followed by calculation of the
      viable cells surviving the purification by means of trypan blue staining.
      RESULTS: The purity of CD34+ cells amounted to 81.5% (ranging from 76.80% to
      85.38%) after the purification with a median recovery rate of 47.54% (ranging
      from 40.50% to 54.31%). The cell viability was not notably impaired (P=0.169).
      CONCLUSION: Highly purified CD34+ cells can be obtained from murine bone marrow
      using MiniMACS which does not impair the viability of the derived cells.

PMID- 12426163
TI  - Construction of single-chain Fv library against hepatocellular carcinoma.
AB  - OBJECTIVE: To construct a phage display single-chain Fv (ScFv) library against
      hepatocellular carcinoma (HCC). METHODS: The mRNA extracted from the spleen cells
      of immunized BALB/C mice was purified and reverse transcriptase-polymerase chain
      reaction (RT-PCR) was employed for the seperate amplification of the gene
      fragments encoding the heavy- and light-chain variable regions respectively,
      which were subsequently assembled into ScFv gene. Amplification of the resultant
      ScFv gene was performed before it was introduced in to E.coli TG1 via a phagemid
      vector pCANTAB5E. A proportion of the transformed cells was loaded onto SOBAG
      plates and incubated and the number of bacterial colonies counted. PCR,
      nucleotides sequence analysis and enzyme-linked immunosorbent assay (ELISA) were
      performed to evaluate the constructed ScFV library. RESULT: The phage display
      ScFv library had a capacity of approximately 2.14x106, with 90% of the phagemids
      containing ScFv gene insertion as demonstrated by PCR. The nucleotides sequence
      of ScFv gene was approved, and ELISA showed that the ScFv library could
      specifically conjugate with HCC antigen. CONCLUSION: The phage display ScFv
      library against HCC is successfully constructed, which may facilitate the
      acquisition of special antibodies and may be instrumental in the research and
      clinical management of HCC.

PMID- 12426164
TI  - Dynamic changes of TNF-alpha content in dogs after gunshot wound in the limbs in
      hot and humid environment.
AB  - OBJECTIVE: To investigate the dynamic changes of TNF-alpha content in the plasma
      and body tissues of dogs after gunshot wound in the limbs in hot and humid
      environment. METHODS: Eighteen dogs with gunshot wound were divided into 3 groups
      (6 in each), one observed in normal environment (Ne group) and the other two in
      hot and humid environment including a heat-acclimatized group (HA group) and a
      non-acclimatied group (NHA group). The contents of tumor necrosis factor-alpha
      (TNF-alpha) in the plasma and muscle tissues from the gunshot wound tract were
      measured at 0, 1, 3, 4, 6, 8, 10, 14, 18, 24 h respectively after the injury.
      RESULTS: TNF-alpha content in the muscular tissue from gunshot wound tract was
      significantly higher than that in the plasma (P<0.05). At 4 h after injury, TNF
      alpha content started to rise in NE group, reaching the peak level at 14 h, the
      rise and peaking of which occurred at 3 and 10 h respectively in NHE group with
      higher peak level than that in NE group (P<0.05). The changes of TNF-alpha
      participates in the pathophysiological process after gunshot wound in hot and
      humid environment and may play the role of and indicator for the pathological
      changes that take place after the injury.

PMID- 12426165
TI  - Inhibition of lung adenocarcinoma LA795 in mice by recombinant human endostatin.
AB  - OBJECTIVE: To evaluate the inhibitory effect of recombinant human endostatin on
      tumor growth and metastasis of adenocarcinoma LA795 in mice. METHODS: Recombinant
      human endostatin was purified rom endostadin-expressing pCX clones. LA795 cells
      were inoculated subcutaneously on the back of T739 mice, which were randomized
      into 2 groups. From the tenth day on, treatment group was given 20 mg/kg
      recombinant human endostatin subcutaneously daily for 14 consecutive days, and
      the control group received PBS in the same manner. The sizes of the subcutaneous
      tumors, lung weights, the number of metastases over the lung surface and the
      survival time of the mice were observed. RESULTS: The tumor sizes of the
      treatment group in creased slowly from (650+/-201) mm3 to (1 642+/-21) mm3 when
      compared with those of the control group which showed and increase from (623+/
      248) mm3 to (9 194+/-952) mm3. The lung weight of the 2 groups was (190+/-25) mg
      and (324+/-43) mg respectively, and the number of lung sung surface metastases
      was 8+/-2 and 22+/-8 for each. The average survival time of the rats in the 2
      groups was 48 d and 27 d, respectively. All parameters measured between the 2
      groups showed significant differences (P<0.01). CONCLUSION: Recom binent human
      endostatin has strong inhibitory effect on both the growth of primary tumor and
      metastasis of lung adenocarcinoma LA795 cells, and prolongs the survival time of
      the tumor-bearing mice.

PMID- 12426167
TI  - Development of a low-frequency physiotherapeutic device for diabetes manipulated
      by microcontroller.
AB  - OBJECTIVE: To develop a physiotherapeutic device for diabetes that generates
      special low-frequency waveform manipulated by a microcontroller. METHODS: A
      microcontoller and a digital-to-analog converter were utilized along with a
      keyboard and LED display circuit, to generate desired low-frequecy waveform with
      the assistance of a software. RESULTS: The complex waveform generated by this
      device met the demands for diabetes physiotherapy, and the frequency and
      amplitude could be freely adjusted. CONCLUSIONS: The utilization of a digital-to
      analog converter controlled by a microcontroller can very well serve the purpose
      of a low-frequency physiotherapy for diabetes.

PMID- 12426166
TI  - Effect of simvastatin on the proliferation of rat cardiac fibroblasts.
AB  - OBJECTIVE: To investigate the effects of simvastatin on the proliferation of rat
      cardiac fibroblasts (CFs) induced by arginine vasopressin (AVP). METHODS: CFs of
      neonatal Sprague-Dawley (SD) rats were isolated by trypsin digestion method and
      growth-arrested CFs were stimulated with 1x10-7 mol/L AVP in the presence of
      simvastatin (Sim) with varied concentrations. MTT assay was employed to measure
      CFs proliferation and determine the cell number, and the cell cycle distribution
      was determined with flow cytometer (FCM). RESULTS: With the increase of Sim
      concentration, D490 of CFs as shown by MTT assay gradually decreased, and for the
      cells treated with 1x10-6 mol/L Sim or 1x10-5 mol/L Sim, D490 (0.215+/-0.041and
      0.163+/-0.018, respectively) was significantly lower than that of the control
      (0.939+/-0.048, P<0.01). In a dose-dependent manner, Sim decreased the cell
      percentage at S stage and the proliferation index (PI) as its concentration
      increased, but acted to the contrary effect with the percentage of cells at G0/G1
      stage, and in CFs treated with 1x10-5 mol/L or 1x10-6 mol/l Sim, the 3 parameters
      were significantly different from those measured in the CFs with 1x10-7 mol/L AVP
      treatment (P<0.01). CONCLUSION: The results indicate that Sim can inhibit the
      proliferation of CFs induced by AVP, possibly through the mechanism of regulating
      the cell cycle distribution.

PMID- 12426168
TI  - Role of nitric oxide in omeprazole protection of the gastric mucosa in rats.
AB  - OBJECTIVE: To understand the role of nitric oxide in the protection mechanism for
      the gastric mucosa in rats provided by omeprazole. METHODS: Intravenous
      injections with omeprazole, N -nitro-L-arginine methyl ester (L-NAME), L
      arginine, or D-arginine were administered in rats with gastric mucosal lesion
      induced by pure ethanol. Gastric mucosal blood flow (GMBF), pH of the gastric
      juice and gastric mucosal NO 2 /NO 3 ratio were determined and the changes of
      ulcer index and the severity of tissue necrosis and neutrophil infiltration
      observed. RESULTS: The ulcer index of rats with omeprazole treatment was much
      lower than that of the control group (P<0.01) with lesser degree of tissue
      necrosis and neutrophil infiltration (P<0.01). The protective effect of
      omeprazole was significantly inhibited by prior administration of L-NAME that,
      however, was antagonized by prior administration of L-arginine, but not D
      arginine. Intravenous omeprazole administration obviously increased GMBF and
      gastric mucosal NO-2 /NO 3 ratio, and such effect, apart from its action against
      secretion, could be counteracted by pretreatment with L-NAME. CONCLUSION:
      Omeprazole can exert important protection against gastric mucosal lesion in rats
      mediated by nitric oxide, and the action of omeprazole against gastric acid
      secretion contributes little to the protective effect.

PMID- 12426169
TI  - Effects of 17beta-estradiol and progesterone on the expression of matrix
      metalloproteinases and tissue inhibitors of metalloproteinases in rat
      osteoblasts.
AB  - OBJECTIVE: To study the expression of matrix metalloproteinases (MMP) and tissue
      inhibitors of metalloproteinases (TIMP) in the osteoblasts of SD rats and to
      assess the change of MMP-2 and TIMP-1 induced by 17beta-estradiol (E2) and
      progesterone (P), for the purpose of understanding the role of MMP-2 and TIMP-1
      in bone resorption. METHODS: The expression and localization of the MMP-2 in
      cultured rat osteoblasts were observed immunohistochemically, and MMP-2 and TIMP
      1 mRNA expression assayed by reverse transcriptase-polymerase chain reaction (RT
      PCR) after the cells were treated with E2 and P at varied concentrations.
      RESULTS: MMP-2 protein expression was observed in cultured rat osteoblats, which
      was inhibited by E2 treatment. The expression of MMP-2 mRNA decreased as doses of
      E2 and P increased but TIMP-1 underwent no obvious changes. CONCLUSION: E2 and P
      can promote the bone formation and slow down the processes of bone matrix
      degradation and bone resorption by inhibiting the action of MMP-2 in the
      osteoblasts, and P has the same important effect as estrogen has in the treatment
      of postmenopausal osteoporosis.

PMID- 12426170
TI  - Expression of cyclin D1 in small cell lymphoma and its clinical implications.
AB  - OBJECTIVE: To observe the expression of cyclin D1 and explore its clinical
      significance in small cell lymphoma. METHODS: Immunohistochemical method was used
      to detect the expression of CD20, CD45RO and cyclin D1 in 31 formalin- fixed and
      paraffin-embedded tissue samples of human small cell lymphomas. RESULTS: Twenty
      eight cases were categorized into B cell lymphoma and 3 into T cell lymphoma.
      Only 5 cases of B cell lymphoma had cyclin D1 expression (17.86%) that did not
      significantly differ between nodal and extranodal lymphomas (P>0.05), indicating
      the presence of mantle cell lymphoma. CONCLUSION: The overexpression of cyclin D1
      is a highly characteristic and specific indicator that discriminates mantle cell
      lymphoma from other small cell lymphomas, and this protein may offer critial
      guidance for therapeutic protocol and prognostic estimation.

PMID- 12426171
TI  - gyrA gene mutations in quinolone-resistant Shigellae flexneri.
AB  - OBJECTIVE: To study the resistance mechanism of quinolone against Shigellae
      flexneri. METHODS: The N-terminal coding region of gyrA gene of 38 quinolone
      resistant Shigellae flexneri were amplified by PCR and mutations detected by
      single- strand conformation polymorphism (SSCP), followed by sequence analysis.
      RESULTS: Eight isolates were found to be positive for gyrA mutations, and DNA
      sequence analysis of gyrA gene revealed 2 mutations that resulted in changes of
      the amino acids (Ser-83--Leu, Asp-87--Gly). CONCLUSION: gryA gene mutations is
      closely related to high resistance of Shigellae flexneri to quinolone.

PMID- 12426172
TI  - Effects of sera from burn patients after escharectomy during the early stage of
      burn injury on endothelial monolayer permeability: an in vitro study.
AB  - OBJECTIVE: To understand the prophylactic and therapeutic effect of early eschar
      excision after burn injury on endothelial cell damage. METHODS: Fourteen patients
      with severe burns were randomized into 2 groups to receive escharectomy within 48
      h postburn (group A) or after 48 h postburn (group B). Serum samples were
      obtained from these patients on 1, 3 and 7 d respectively after burn injury.
      After the sera were incubated for 24 h with human umbilical vein endothelial
      cells (HUVEC) cultured in vitro, changes in the permeability of the vascular
      endothelial cell (EC) monolayer were determined with 99mTc-labelled albumin, and
      changes of the cell viability also observed. RESULTS: In response to treatment
      with the sera isolated form the burn patients, the permeability of the
      endothelial monolayer was lowered in group A as compared with that of group B,
      but the viability of the ECs improved. CONCLUSION: Escharectomy performed at
      early stage postburn is effective to counteract endothelial cell damage and
      thereby may be carried out as a preventive measure against multiple organ
      dysfunction after burn in jury.

PMID- 12426173
TI  - Evaluation of myocardial viability with myocardial contrast echocardiography: a
      preliminary clinical study.
AB  - OBJECTIVE: To evaluate the efficacy of myocardial contrast echocardiography (MCE)
      in the assessment of myocardial viability, with positron emission tomography
      (PET) as the golden standard. METHODS: Eleven patients with anterior wall Q wave
      myocardial infarction were enrolled in this study, who received successful
      percutaneous transluminal coronary angioplasty (PTCA) 3 to 19 months prior to the
      examinations by PET and MCE that were completed within 2 d. RESULTS: MCE score
      for the segments of necrotic myocardium, viable myocardium and normal myocardium
      was mostly 0, 0.5 and 1 respectively, and there was a significant difference
      between the grades of MCE score in identifying myocardial viability. In terms of
      diagnosing myocardium survival, MCE result was closely correlated with that of
      PET (with the correlation index rp of 0.78). CONCLUSION: Myocardial perfusion
      evaluation can be effectively accomplished by MCE, which might serve as a new
      approach to assess myocardial viability in clinical practice.

PMID- 12426174
TI  - Thallium-201 myocardial scintigraphy in hypertensive patients with and without
      left ventricular hypertrophy: a clinical study.
AB  - OBJECTIVE: To evaluate the myocardial perfusion in hypertensive patients with and
      without left ventricular hypertrophy using thallium-201 (201TI) myocardial
      scintigraphy and explore the mechanism that causes the perfusion abnormalities.
      METHODS: Thallium-201 myocardial scintigraphy was performed in 85 patients with
      clinically suspected coronary artery disease to assess the myocardial perfusion
      status. For patients with myocardial perfusion abnormalities as indicated by the
      scintigraphy, coronary angiography was ordered within 1 month. RESULTS: The
      incidence of 201TI myocardial perfusion abnormalities in hypertensive patients
      with ventricular hypertrophy (85.7%) was significantly higher than that in the
      normotensive (39.3%, P<0.01) and hypertensive patients not complicated with
      hypertrophy (61.2%, P<0.05). The semiquantitative score was higher in the
      hypertensive patients with hypertrophy than in the normotensive (P<0.01) and
      hypertensive patients without hypertrophy (P<0.05). More hypertensive patients
      with hypertrophy (9/18) had normal results of coronary angiography than the
      normotensive (0/13, P=0.044) and hypertensive patients without hypertrophy did
      (3/19, P<0.05). CONCLUSIONS: A higher rate of 201TI perfusion abnormalities
      occurs in the hypertensive patients with ventricular hypertrophy, which may be
      attributed to the pathological changes in the major coronary vessels and to the
      coronary microvascular diseases as well.

PMID- 12426175
TI  - Differentiation and telomerase activity of human mesenchymal stem cells.
AB  - OBJECTIVE: To study the differentiation of human mesenchymal stem cells (MSCs)
      derived from human fetal bone marrow and observe its telomerase activity.
      METHODS: MSCs were isolated from fetal bone marrow of the femur followed by cell
      culture and amplification. In situ hybridization was employed to detect
      telomerase activity in the MSCs. Subcutaneous implantation of MSCs into nude mice
      was performed to observe their differentiation potentials 4 weeks after the
      implantation. RESULTS: Human MSCs were found positive for telomerase activity and
      they showed the potential to differentiate into such tissue cells as of the bone,
      cartilage, adipose, skeletal muscle, tendon-like tissue and unmyelinated nerve
      fiber-like bundles. CONCLUSION: Human MSCs are multipotent stem cells that may
      differentiate into many types of tissue cells with high levels of telomerase
      activity.

PMID- 12426176
TI  - Construction of recombinant eukaryotic expression plasmid containing hepatitis B
      virus genome with partial deletion of the core promoter.
AB  - OBJECTIVE: To construct an eukaryotic expression vector containing the full
      length genome with partially deleted core promoter of hepatitis B virus (HBV).
      METHODS: A linearized genome containing the entire HBV 3.5 kb mRNA
      transcriptional units (P3.8 I plasmid) was used, which initiated from the
      upstream sequences of the basic core promoter. The objective eukaryotic
      expression vector was constructed by molecular cloning and PCR-based site
      directed mutagensis in vitro, and identifcation was performed using polymerase
      chain reaction-restriction fragment length polymorphism (PCR-RFLP) followed by
      cloning and sequencing analysis. RESULTS: The eukaryotic expression vectors
      containing HBV genomes with 20/21 bp deletion (position 1 748/1 747 to 1 767) in
      the core promoter or with precore stop mutation at nucleotide 1896 as well were
      constructed successfully as confirmed by sequence analysis with RFLP. CONCLUSION:
      The recombinant expression vector may lay the foundation for further studies into
      the biological significance of the above mentioned mutations in vitro.

PMID- 12426177
TI  - Acquisition of expressed sequence tags from Schistosoma japonicum cercariae
      (mainland China strain) and its homology analysis.
AB  - OBJECTIVE: To understand the general profiles of the genes included in
      Schistosoma japonicum (Sj) cercarriae cDNA library that we have constructed for
      the purpose of identifying novel genes. METHODS: The phages in Sj cercariae cDNA
      library were transformed into plasmids after they had invaded into E.coli BM25.8,
      and the E.coli clones containing the plasmids were cultured in LB medium
      supplemented with aminobenzylpenicillin. The isolated colonies were selected for
      plasmid extraction and the DNAs subsequently extracted from the plasmids
      underwent sequence analysis with a sequencing primer to obtain the expressed
      sequence tags (ESTs). After sequence editing of the resulted ESTs, comparison of
      these sequences with those listed in the GenBank database was performed for
      homology analysis. The new sequences generated from the analysis were submitted
      to GenBank and the accession numbers acquired. RESULTS and CONCLUSION :Altogether
      58 ESTs were identified among which 3 possed highly homologous nucleotide
      sequences with the known genes of Sj, 2 showed the homology with Schistosoma
      mansori genes, 7 had the homologous protein sequences, but not the nucleotide
      sequences, with other species, and another 27 were poorly homologous in terms of
      both the nucleotide and protein sequences.

PMID- 12426178
TI  - Expression of stem cell factor mRNA in primary leukemia cells.
AB  - OBJECTIVE: To observe the expression of stem cell factor (SCF) mRNA in primary
      human leukemia cells and investigate its significance in deciding the prognosis
      of leukemia patients. METHODS: Primary leukemia cells were isolated form the bone
      marrow of 49 patients with leukemia, and the expression of SCF mRNA determined by
      nested reverse transcriptase polymerase chain reaction (RT-PCR). RESULTS: Among
      the 19 patients with acute lymphatic leukemia (ALL), 5 were positive and 14
      negative for SCF mRNA. In cases of acute myeloid leukemia (AML, n=30), 24 of M1
      to M4 subtypes were found positive for SCF mRNA but 4 of M5 subtype and 2 of M6
      subtype were negative. There was a significant difference between ALL and AML
      groups (P<0.05). Eight (27.6%) cases were refractory leukemia in the total of 29
      patients who were positive for SCF, while 12 (60.0%) were refractory among the 20
      patients negative for SCF (P<0.05). CONCLUSIONS: The expression rate of SCF was
      significantly higher in AML than in ALL cases, and the negative expression of SCF
      mRNA might be indicative of unfavorable prognosis, but the exact mechanism needs
      futher investigation.

PMID- 12426179
TI  - Cloning and sequence analysis of HIV-1 gene fragments isolated by restriction
      digest polymerase chain reaction method.
AB  - OBJECTIVE: To clone and analyze the HIV-1gene fragments isolated by restriction
      digest polymerase chain reaction (RD-PCR). METHOD: All the HIV-1 gene fragments
      were divided into 10 subgroups and amplified by RD-PCR. The PCR products of each
      subgroup were purified and cloned into the T-vectors, then identified rapidly.
      The plasmids were extracted from positive clones and the target gene fragments
      were amplified and sequenced. RESULTS: Sequences analysis showed that all the
      fragments amplified were HIV gene. CONCLUSION: A method for cloning and
      identifying multiple fragments has been improved and used for restriction
      fragments.

PMID- 12426180
TI  - Effect of E1B mutant adenovirus on p53-deficient leukemic cells.
AB  - OBJECTIVE: To study the effect of E1B mutant adenovirus (dl1520) on 3 p53
      deficient leukemic cell lines K562, Jurkat and HL-60. METHODS: The replication
      efficiency of dl1520 in the 3 leukemic cell lines was assessed by plaque assay,
      and the number of cells killed by the adenovirus determined by using trypan-blue
      in a course of 10 d following the infection. RESULTS: The replication efficiency
      of dl1520 in the 3 leukemic cell lines was significantly lower than that in the
      positive control, and no significant cytocidal effect against the 3 cell lines
      was observed. CONCLUSION: dl1520 can not inhibit the malignant blood cells as
      K562, Jurkat and HL-60 cell lines.

PMID- 12426181
TI  - Automatic segmentation of cardiac magnetic resonance images using knowledge base.
AB  - OBJECTIVE: To study the automated implementation of cardiac magnetic resonance
      image (MRI) segmentation. METHODS: By training the feature parameters of the
      images and establishing a knowledge base, an efficient method for extracting and
      using prior knowledge was proposed. RESULTS and CONCLUSION: Through extracting
      and using prior knowledge of cardiac MRI, automation of cardiac MRI segmentation
      can be well accomplished.

PMID- 12426182
TI  - Registration of serial tissue section images.
AB  - OBJECTIVE: This study aims to tackle the problem of image registration during
      computer-assisted three-dimensional (3D) reconstruction of serial tissue
      sections. METHODS: We proposed segmentation-counting algorithm for computerized
      image registration on the basis of joint histogram. This approach utilizes
      thresholding of the 2 images to be registered, and the criterion function is
      defined as the counting in a specific region of the joint histogram. The
      registration parameters can be obtained by optimizing the criterion function.
      RESULTS: In the trial application of this approach in image registration for the
      serial tissue sections of mouse wse embryos, a more efficient result was
      achieved. CONCLUSION: The method can rapidly accomplish the image registration
      task for serial tissue sections with simpler calculation processes.

PMID- 12426183
TI  - Effect of recombinant human interleukin-10 on the in vitro proliferation of rat
      vascular smooth muscle cells.
AB  - OBJECTIVE: To observe the effects of recombinant human interleukin-10 (rhIL-10)
      on the proliferation of rat vascular smooth muscle cells (VSMCs) cultured in
      vitro. METHOD: Aortic VSMCs cultured in vitro were treated with varied doses of
      rhIL-10 alone or in combination with tumor necrosis factor-alpha (TGF-alpha) or
      platelet-derived growth factor-BB(PDGF- BB) respectively. The VSMC proliferation
      was quantified by colormetric assay. RESULTS: Compared with control, both TNF
      alpha and PDGF-BB stimulated conspicuous proliferation of VSMCs, but the effect
      of which was not observed by rhIL-10 treatment alone. In the presence of rhIL-10,
      the proliferation effects of both TGF-alpha and PDGF-BB on VSMCs were
      significantly inhibited (P<0.05). CONCLUSION: rhIL-10 can inhibit VSMC
      proliferation induced by TNF-alpha and PDGF-BB, thus may provide a new
      therapeutic approach for regulating vascular wall remodeling after vascular
      injury.

PMID- 12426184
TI  - Association of epileptiform activity with neuronal death in the CA3 subfield of
      the hippocampus following focally evoked limbic seizures.
AB  - OBJECTIVE: To investigate the relationnship between epileptiform activity and
      cell death in the CA3 subfield of hippocampus following focally evoked limbic
      seizures through a quantitative study. METHODS: Wistar rats used in this study
      received intra-amygdaloid injection of kainic acid to induce type epileptiform
      activity of different duration with continuous electroencephalographic (EEG)
      monitoring. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling
      (TUNEL) was used to detect apoptotic cells. The number of CA3 neurons survived
      and TUNEL-positive cells were counted to estimate the number of necrotic cells.
      RESULTS: Epileptiform activity induced necrosis in the major form of apoptosis of
      the cells in CA3 subfield of the hippocampus following focally evoked limbic
      seizures. The longer the type epileptiform activity lasted, the less neurons
      survived, with consequent increase in the number of both necrotic and apoptotic
      cells. CONCLUSION: Prolongation of type IV seizures dose-dependently causes
      increase in apoptotic and necrotic cells in CA3 subfield of the hippocampus.

PMID- 12426185
TI  - Isolation and purification of pulmonary surfactant-associated protein A from
      human amniotic fluid and its bioactivity assessment.
AB  - OBJECTIVE: To isolate and purify pulmonary surfactant-associated protein A(SP-A)
      from human amniotic fluid. METHODS: Human amniotic fluid was collected from 11
      parturients and SP-A was isolated by extraction and dialysis followed by
      purification procedures. The specificity of SP-A was detected by Western blotting
      and the bioactivity assessed by MTP-1 film balance. RESULTS: An amount of 12 mg
      (20 ml) purified SP-A was obtained, and the protein presented a single band upon
      SDS-PAGE with relative molecular mass of 31 000. Western blotting also displayed
      one specific band. Film balance demonstrated that the minimum surface tension
      alphamin of Exosurf, an synthetic pulmonary surfactant, was 7.7+/-0.3,
      significantly higher than alphamin of Exosurf and SP-A mixture(1.5+/-0.22,
      P<0.05), indicating enhanced bioactivity of the mixture. CONCLUSION: Dialysis can
      effectively purify SP-A from human amniotic fluid with little damage of its
      biological activity.

PMID- 12426186
TI  - Changes in adenine nucleotide, SOD and MDA contents and mitochondria
      ulteractructure during diaphragm fatigue in dogs induced by diaphragm pacing.
AB  - OBJECTIVE: To explore the possible mechanisms for the occurrence of diaphragm
      fatigue induced by diaphragm pacing. METHODS: The phrenic nerve of 8 dogs were
      exposed and subjected to stimulation with electric pulses emitted by a diaphragm
      pacemaker to induce diaphragm fatigue models, and the contents of ATP, ADP, AMP
      and AXP in the diaphragm muscles before and after diaphragm pacing were
      determined by high-performance liquid chromatography (HPLC). The contents of SOD
      and MDA were also measured and the morphological alteration of the mitochondria
      observed with transmission electron microscope. RESULTS: The contents of ATP,
      ADP, AXP and SOD were found significantly lower but MDA was higher during fatigue
      than those in normal conditions, while AMP content manifested no obvious change.
      Some mitochondria in the diaphragm muscles swelled and in a few cases, vacuolar
      degeneration was observed. CONCLUSIONS: The exhaustion and synthesis disturbance
      of ATP may explain the generation of diaphragm fatigue, and the reduction of
      dynamophore and ultrastructural injuries of the cells induced by oxygen free
      radicals may also contribute to this result.

PMID- 12426187
TI  - Radiosensitivity of hepatocarcinoma cell line BEL-7402.
AB  - OBJECTIVE: To assess the radiosensitivity of human hepatocarcinoma cell line BEL
      7402. METHODS: Human hepatocarcinoma cell line BEL-7402 was cultured in vitro and
      then subjected to exposure to 6 MV X-ray at the doses ranging from 0 to 10 Gy.
      The survival rate of the cells following the exposure was assessed by determining
      the colony-forming units during further cell culture 12 to 14 d after the
      exposure, and the parameters for the radiosensitivity calculated. RESULTS and
      CONCLUSION: The parameters of BEL-7402 cells (D0=1.6, Dq=1.3, n=2, 4, SF2=0.63+/
      0.05 Gy) demonstrates a high sensitivity of the cells to radiation.

PMID- 12426188
TI  - The detection of phytohemagglutinin-lymphokine activated killer cells' in vitro
      antitumor action with MTT colorimetry.
AB  - OBJECTIVE: To detect the in vitro antitumor action of phytohemagglutinin and
      lymphokine activated killer (PHA- LAK) cells. METHOD: MTT colorimetric assay was
      used to detect the in vitro cytotoxicity of PHA-LAK cells on K562 MGc80-3 143TK
      Hela and LoVo. RESULTS: The significant cytotoxicity of PHA-LAK cells on these
      five tumor cells from different organs could be found in vitro. The PHA-LAK cell
      activity on 143TK could reach 57.3% when the ratio of effective cell (EC) to
      target cell (TC) was 7.5:1. The antitumor effect did not increased or even
      decreased when the ratio of EC to TC was 15:1. CONCLUSIONS: (1)PHA-LAK cell has
      non-specific cytotoxicity against tumor cells and can overcome the problems of
      the quantity and activity of immunocyte of traditional adoptive cellular
      immunotherapy. (2)Under some conditions does MTT colorimetric assay be a
      susceptible, simple and convenient method for detecting the cytotoxicity of
      immunocytes.

PMID- 12426189
TI  - Effect of estradiol and progesterone on calcitonin expression in in vitro
      cultured human endometrial epithelial cells in the implantation window.
AB  - OBJECTIVE: To explore the effect of estradiol and progesterone on the expression
      of calcitonin in human endometrial epithelial cells cultured in vitro. METHODS:
      Human endometrial epithelial cells were cultured in vitro in DMEM medium. After
      the cells were treated respectively with estradiol and progesterone at different
      concentrations for 24 and 48 h, the fluorescence density of the cells was
      measured by flow cytometer. RESULTS: Progesterone treatment of the epithelial
      cells for 24 h produced in a dose-dependent manner significantly higher
      fluorescence level than that of the control (P<0.01). Small dose of estradiol
      took little effect on calcitonin expression, but high-concentration estradiol
      resulted in lowered fluorescence level than the control. CONCLUSION: Progesterone
      promotes calcitonin expression in cultured human endometrial epithelial cells in
      a dose-dependent manner, while estradiol tends to inhibit its expression.

PMID- 12426190
TI  - Determination and analysis of complete nucleotide sequence of Chinese genotype D
      hepatitis B virus: the first report.
AB  - OBJECTIVE: To determine the complete nucleotide sequence of a Chinese hepatitis B
      virus (HBV) strain of genotype D. METHOD: The complete nucleotide sequence of HBV
      derived from a Chinese chronic asymptomatic carrier was amplified by PCR and
      cloned to conduct sequence analysis. Homology of the resulted nucleotide sequence
      with those of published HBV strains was assessed by using DNASIS, and complete
      sequence analysis of the phylogenetic tree of 30 genotype D HBV strains conducted
      by the assistance of Clustalw. RESULTS: With the complete nucleotide sequnce of 3
      182 bp, this HBV strain belongs to ayw3 subtype and D genotype, with the Genebank
      accession number AF280817. Its complete nucleotide homology is 98.3% to 94.5%
      with the published sequences of genotype D HBV strains and less than 89.5% with
      the other HBV strains of genotype A, B, C, E, F and G published in GenBank.
      CONCLUSION: The evolutionary relations of the complete nucleotide sequence of
      this HBV strain is the closest to those of the 4 Swedish strains out of the 30
      genotype D strains published in GenBank.

PMID- 12426191
TI  - Hot-spot mutations in HBV pre-C region in HBeAg-negative patients with severe
      hepatitis B.
AB  - OBJECTIVE: To investigate the association of hot-spot mutations in hepatitis B
      virus (HBV) pre-C region with the occurrence and outcome of severe hepatitis B.
      METHODS: A total of 68 patients with severe hepatitis B negative for hepatits B e
      antigen (HBeAg) were enrolled in this study, including 6 cases of acute, 38 cases
      of subacute and 24 chronic severe hepatitis B, with another 44 HBeAg-positive
      patients with chronic hepatitis B serving as control. Mismatch PCR and
      restriction fragment length polymorphism analysis were employed to examine the
      mutations of T1862 and A1896 in this 2 groups of patients. RESULTS: The mutation
      rates at A1896 and T1862 were 66.7% (4/6) and 0 (0/6) respectively in acute
      severe hepatitis B cases, 42.1% (16/38) and 15.8% (6/38) in subacute severe
      hepatitis, 25.0% (6/24) and 16.7% (4/24) in chronic severe hepatitis, and 45.5%
      (20/24) and 2.3% (1/44) in chronic hepatitis cases. There were significant
      differences in terms of T1862 mutation between patients with severe hepatitis and
      chronic hepatitis (P<0.01). CONCLUSION: T1862 mutation is closely related to the
      exacerbation of chronic hepatitis, while the role of A1896 mutation in this
      process requires further investigation.

PMID- 12426192
TI  - Changes in cardiac function reserve after percutaneous balloon mitral
      valvuloplasty: a longterm follow-up study.
AB  - OBJECTIVE: To evaluate the long-term effect of percutaneous balloon mitral
      valvuloplasty (PBMV) by observing the changes in mitral valve reserve after PBMV
      and during the long-term follow-up and by exploring the relations of these
      changes with stress echocardiographic scores. METHODS: Stress echocardiogaphy was
      performed in patients receiving PBMV for mitral stenosis both after surgery and
      during the long-term follow-up study, and Wilkins scores of the patients were
      obtained pre-operatively. Intravenous isoproterenol was administered before test
      to increase the heart rate to simulate mild, moderate and heavy exercises, and
      the indices for cardiac function were recorded. RESULTS: After PBMV, mitral valve
      reserve and cardiac function reserve were partly restored, and stress
      echocardiographic score was closely related to long-term cardiac function ( =
      0.82). CONCLUSIONS: PBMV can increase mitral valve area and partly resotreit
      funtional reserve, and stress echocardiographic score is more predictive of the
      long-term cardiac function than Wilkins score.

PMID- 12426193
TI  - Detection of interleukin-6 and -12 in of hepatitis B patients and its clinical
      significance.
AB  - OBJECTIVE: To investigate the clinical significance of detecting interleukin-6
      (IL-6) and interleukin-12 (IL-12) in the immunological mechanism of hepatitis B
      virus infection (HBV). METHODS: Serum IL-6 and IL-12 levels were determined using
      enzyme-linked immunosorbent assay in patients with chronic, acute or advanced
      hepatitis B as well as in healthy subjects. RESULTS: In chronic, acute, severe
      hepatitis B patients, serum IL-6 levels were significantly elevated as hepatitis
      worsened (199.7+/-26.9, 129.5+/-22.8, 286.1+/-56.7 pg/ml respectively), in that
      order compared with the normal control levels (56.41+/-12.9 pg/ml). IL-12 levels,
      in contrast, tended to be lowered with the deterioration of hepatitis (24.6+/
      13.4, 135.3+/-60.8, 19.7+/-9.0 pg/ml respectively), in that order, with the
      control level of 34.7+/-11.8 pg/ml. CONCLUSION: Serum IL-6 level is closely
      correlated to the degree of hepatocyte damage in hepatitis B, while IL-12 may be
      instrumental in the defense mechanism against HBV infection, and IL-12 level
      elevation can be indicative of hepatitis recovery.

PMID- 12426194
TI  - Effects of patient-controlled upper and lower epidural analgesias on
      postoperative respiratory and circulatory function.
AB  - OBJECTIVE: To compare the effects of patient-controlled high thoracic epidural
      analgesia (PCHEA) and low thoracic epidural analgesia (PCLEA) on respiratory and
      circulatory functions after operation. METHODS: Thirty-six patients were divided
      into 2 groups with 18 in each, and one group (Group H) received PCHEA during
      thoracic operations and the other (Group L) received PCLEA during abdominal
      operations. Postoperative patient-controlled analgesia (PCA) was performed in all
      the patients with 0.125% bupivacaine and 0.01% morphine delivered through the
      same epidural space for PCHEA or PCLEA. RESULTS: Postoperative analgesia did not
      produce significant differences in the respiration rate (Rr), tidal volume (Vt),
      vital capacity (VC) and oxygen saturation (SpO2) between the groups, but in both
      groups, Vt and VC were significantly improved compared with those before starting
      patient-controlled epidural analgesia (PECA) (P<0.01). In group H, its effects on
      systolic and diastolic blood pressure and heart rate were more obvious than in
      group L (P<0.05), and both groups showed these improvements after PCA
      started(P<0.01). CONCLUSION: PCHEA shows more marked effects on the respiratory
      and circulatory functions of the patients, which may mainly result from its
      blocking the cardiac sympathetic nerves. PCEA is able to improve postoperative
      respiratory function but both PCHEA and PCLEA necessitate individual-based
      adjustment of the PCA pump for the safety of the patient.

PMID- 12426195
TI  - Study on embryo morphology and clinical result of intracytoplasmic sperm
      injection for infertility.
AB  - OBJECTIVE: To explore the relevance of the embryo morphology with the clinical
      result of intracytoplasmic sperm injection (ISCI) for infertility treatment.
      METHODS: A retrospective analysis was conducted of 291 ISCI and 352 in vitro
      fertility (IVF) cycles collected during the period from Juanary, 1999 to March,
      2001. RESULTS: Significant difference was not found in the fertility rates
      between the 2 groups (75.7% vs 73.2%, P=0.5738), nor in the oocyte lysis rates
      (10.6% vs 7.9%, P=0.238). The rates of the embryos with more than 20% fragments
      were similar between the 2 groups (41.2% vs 55.8%, P=0.137), but ICSI group had a
      significantly lower rate of blastocyst formation (43.1% vs 55.8%, P<0.001). The
      clinical pregnancy rates and miscarriage rates did not vary significantly between
      the 2 groups (34.7% vs 39.9%, P=0.189; 8.9% vs 13.4%, P=0.079). CONCLUSIONS: ISCI
      is an effective treatment for male infertility to achieve uneventful clinical
      pregnancy.

PMID- 12426196
TI  - Role of soy protein in cholesterol-lowering: how good is it?

PMID- 12426197
TI  - Unraveling pleiotropic effects of statins on plaque rupture.

PMID- 12426198
TI  - Oxidative stress and coronary plaque stability.

PMID- 12426199
TI  - Can we image the "active" thrombus?

PMID- 12426200
TI  - Multiple signaling pathways in flow-mediated endothelial mechanotransduction: PYK
      ing the right location.

PMID- 12426201
TI  - HIV therapies and atherosclerosis: answers or questions?

PMID- 12426202
TI  - Detection of superoxide in vascular tissue.
AB  - During the past decade, it has become apparent that reactive oxygen species play
      a critical role in the genesis of many vascular diseases. The superoxide anion is
      among the most important of these, not only because of its rapid reaction with NO
      but also because it serves as a progenitor for many other reactive oxygen
      species. Although there are many approaches to detecting and quantifying
      superoxide in chemical systems, its detection in intact tissues is more
      difficult. The validity of the most popular and frequently used assay for this
      purpose, lucigenin-enhanced chemiluminescence, has been recently questioned. It
      has been suggested that lucigenin itself, especially at high concentrations (>50
      micromol/L), may act as a source for superoxide via redox cycling. Lower
      lucigenin concentrations (5 micromol/L) do not participate in redox cycling to an
      important extent in intact tissues and, therefore, provide an accurate assessment
      of the rate of superoxide production in such samples. Other useful assays for
      superoxide include those using the fluorescent dye dihydroethidine, 2-methyl-6
      phenyl-3,7-dihydroimidazo(1,2-alpha)pyrazin-3-one (CLA), and 2-(p-hydroxybenzyl)
      6-(p-hydroxyphenyl) 8-benzylimidazo[1,2-alpha]pyrazin-3-one (coelenterazine). The
      chemiluminescent compound 5-amino-2,3-dihydroxy-1,4-phthalayineidone (luminol)
      may also be used to detect various reactive oxygen species and may be made
      specific for various oxidants, such as hydrogen peroxide, superoxide, and
      peroxynitrite, by altering the experimental conditions. Although each of these
      methods may be associated with potential artifacts, the use of > or =2 different
      techniques that yield similar results provides a reliable approach for the study
      of reactive oxygen species in intact vascular tissues.

PMID- 12426203
TI  - Inflammation and restenosis in the stent era.
AB  - The pathophysiology of restenosis involves early elements of direct injury to
      smooth muscle cells, deendothelialization, and thrombus deposition. Over time,
      this leads to smooth muscle cell proliferation/migration and extracellular matrix
      deposition. There is an increasing body of evidence to suggest that inflammation
      plays a pivotal role linking early vascular injury to the eventual consequence of
      neointimal growth and lumen compromise. The widespread use of coronary stents has
      fundamentally altered the vascular response to injury by causing a more intense
      and prolonged inflammatory state. Many of the cellular and molecular elements
      responsible for leukocyte recruitment have been elucidated, providing potential
      therapeutic targets for restenosis. This review seeks to provide an integrated
      view of the pathophysiology of restenosis that explains the central role of
      inflammation.

PMID- 12426204
TI  - Increased monocyte adhesion to aortic endothelium in rats with
      hyperhomocysteinemia: role of chemokine and adhesion molecules.
AB  - OBJECTIVE: The stimulatory effect of homocysteine (Hcy) on monocyte
      chemoattractant protein (MCP)-1 expression in vitro has been suggested to play an
      important role in Hcy-mediated atherosclerosis. We investigated whether such a
      stimulatory effect occurs in vivo, leading to monocyte adhesion to the
      endothelium. METHODS AND RESULTS: Sprague-Dawley rats were divided into 4 groups.
      Hyperhomocysteinemia was induced in 1 group of rats after 4 weeks of a high
      methionine diet (serum Hcy levels were 4- to 5-fold higher than levels in control
      rats). The number of ED-1-positive cells present on the surface of aortic
      endothelium was significantly elevated in hyperhomocysteinemic rats. There was a
      significant increase in the expression of MCP-1, vascular cell adhesion molecule
      1 (VCAM-1), and E-selectin in the endothelium. Antibodies recognizing MCP-1, VCAM
      1, or E-selectin could abolish the enhanced monocyte binding to the aortic
      endothelium of hyperhomocysteinemic rats. Endothelium-dependent aortic relaxation
      was impaired in hyperhomocysteinemic rats. CONCLUSIONS: These results suggest
      that in the absence of other known risk factors, hyperhomocysteinemia stimulates
      the expression of MCP-1, VCAM-1, and E-selectin in vivo, leading to increased
      monocyte adhesion to the aortic endothelium. Such an effect may contribute
      significantly to the development of atherosclerosis by facilitating
      monocyte/macrophage infiltration into the arterial wall.

PMID- 12426205
TI  - 3-hydroxy-3-methylglutaryl coenzyme A reductase-independent inhibition of CD40
      expression by atorvastatin in human endothelial cells.
AB  - OBJECTIVE: 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors
      (statins) exert potent anti-inflammatory effects that are independent of their
      cholesterol-lowering action. We have investigated the effects of these drugs on
      cytokine-stimulated CD40 expression in human cultured endothelial cells and
      monocytes. METHODS AND RESULTS: Reverse transcription-polymerase chain reaction
      and Western blot analysis revealed that treatment of either cell type with
      atorvastatin, cerivastatin, or pravastatin (1 to 10 micromol/L) inhibited
      interferon-gamma plus tumor necrosis factor-alpha-stimulated CD40 expression by
      approximately 50%, an effect that was not reversed by the HMG-CoA reductase
      product mevalonic acid (400 micromol/L). In contrast, mevalonic acid prevented
      the inhibitory effect of atorvastatin on cytokine-stimulated vascular cell
      adhesion molecule-1 expression and subsequent adhesion of THP-1 monocytes to the
      cultured endothelial cells. Transcription factor analysis revealed an inhibition
      by atorvastatin of nuclear factor-kappaB plus signal transducer and activator of
      transcription-1-dependent de novo synthesis of interferon regulatory factor-1,
      governing cytokine-stimulated CD40 expression in these cells. One consequence of
      this statin-dependent downregulation of CD40 expression was a decrease in CD40
      ligand-induced endothelial interleukin-12 expression. CONCLUSIONS: By interfering
      with cytokine-stimulated CD40 expression in vascular cells, statins thus seem
      capable of attenuating CD40 ligand-induced proinflammatory responses, including
      atherosclerosis. In addition, they point to the coexistence of HMG-CoA reductase
      dependent and -independent effects of statins in the same cell type.

PMID- 12426206
TI  - Fluid shear stress activates proline-rich tyrosine kinase via reactive oxygen
      species-dependent pathway.
AB  - OBJECTIVE: Fluid shear stress (flow) modulates endothelial cell (EC) function via
      specific signal transduction events. Previously, we showed that flow-mediated
      tyrosine phosphorylation of p130 Crk-associated substrate (Cas) required calcium
      dependent c-Src activation. Because flow increases reactive oxygen species (ROS)
      production in ECs and because H(2)O(2) increases tyrosine phosphorylation of
      proline-rich tyrosine kinase (PYK2), we hypothesized that flow may activate PYK2
      via ROS. METHODS AND RESULTS: Exposure of bovine aortic ECs to flow stimulated
      PYK2 phosphorylation rapidly, with a peak at 2 minutes. The activation of PYK2
      and phosphorylation of Cas induced by flow were inhibited by pretreatment with
      the antioxidant N-acetylcysteine. Flow-induced PYK2 phosphorylation was inhibited
      by BAPTA-AM, an intracellular calcium chelator. Bovine aortic ECs transfected
      with kinase-inactive PYK2 showed attenuated flow-stimulated Cas tyrosine
      phosphorylation. Although flow-induced Cas phosphorylation was inhibited by
      kinase-inactive Src, PYK2 activation induced by flow was not inhibited by
      overexpression of kinase-inactive Src. CONCLUSIONS: These results show a redox
      sensitive pathway for flow-mediated activation of nonreceptor tyrosine kinase
      activity that requires ROS and intracellular calcium, but not Src kinase.

PMID- 12426207
TI  - Vascular endothelial growth factor-induced genes in human umbilical vein
      endothelial cells: relative roles of KDR and Flt-1 receptors.
AB  - OBJECTIVE: This study evaluated the relative roles of the vascular endothelial
      growth factor (VEGF) receptors KDR and Flt-1 in the mediation of altered gene
      expression elicited by VEGF. METHODS AND RESULTS: We used mutants of VEGF
      selective for the KDR and Flt-1 receptors to differentiate gene expression
      patterns mediated by wild-type VEGF (VEGFwt) in human umbilical vein endothelial
      cells. RNA was extracted from cells treated for 24 hours with 1 nmol/L of each
      ligand, and gene expression was monitored by using oligonucleotide arrays
      (Affymetrix U95A). We report that activation of KDR was sufficient to upregulate
      all the genes induced by VEGFwt. In contrast, there were no genes selectively
      upregulated by the Flt-selective mutant. However, high concentrations of the Flt
      selective mutant could augment the expression of some genes induced by submaximal
      concentrations of VEGFwt but not the KDR-selective mutant. CONCLUSIONS: The
      binding of VEGF to its receptor, KDR, is necessary and sufficient to induce the
      gene expression profile induced by this growth factor. Furthermore, in human
      umbilical vein endothelial cells, the Flt-1 receptor appears to act as a decoy
      receptor, tempering the response to lower concentrations of VEGF.

PMID- 12426209
TI  - Growth factors enhance interleukin-1 beta-induced persistent activation of
      nuclear factor-kappa B in rat vascular smooth muscle cells.
AB  - OBJECTIVE: Activation of extracellular signal-regulated kinases (ERKs) is
      required for interleukin-1beta to persistently activate nuclear factor (NF)
      kappaB and concomitantly express inducible NO synthase (iNOS) in rat vascular
      smooth muscle cells (VSMCs). The present study examined whether platelet-derived
      growth factor (PDGF) or epidermal growth factor (EGF) could influence the VSMC
      response to interleukin-1beta via an ERK-related signaling pathway. METHODS AND
      RESULTS: Treatment of VSMCs with PDGF or EGF alone potently induced ERK
      phosphorylation and DNA synthesis but did not induce NF-kappaB activation or iNOS
      expression. However, either PDGF or EGF markedly enhanced interleukin-1beta
      induced persistent NF-kappaB activation and iNOS expression but did not affect
      the early and transient NF-kappaB activation. Growth factor-induced DNA synthesis
      was attenuated in the presence of interleukin-1beta. Inhibition of ERK
      phosphorylation with selective inhibitors (PD98059 or U0126) attenuated
      interleukin-1beta-induced persistent NF-kappaB activation and iNOS expression in
      either the absence or presence of the growth factors. CONCLUSIONS: These results
      indicate that interleukin-1beta-induced expression of NF-kappaB-dependent genes,
      such as iNOS, is potentiated in the presence of growth factors through a
      mechanism requiring ERK-dependent enhanced NF-kappaB activation, and the results
      also suggest that NF-kappaB activation is not required for PDGF or EGF to trigger
      DNA synthesis in VSMCs.

PMID- 12426208
TI  - Improvement of collateral perfusion and regional function by implantation of
      peripheral blood mononuclear cells into ischemic hibernating myocardium.
AB  - OBJECTIVE: This study was performed to evaluate the angiogenic effect of
      implantation of peripheral blood mononuclear cells (PB-MNCs) compared with bone
      marrow mononuclear cells (BM-MNCs) into ischemic hibernating myocardium. METHODS
      AND RESULTS: A NOGA electromechanical system was used to map the hibernating
      region and to inject cells. PB-MNCs and BM-MNCs contained similar levels of
      vascular endothelial growth factor and basic fibroblast growth factor, whereas
      contents of angiogenic cytokines (interleukin-1beta and tumor necrosis factor
      alpha) were larger in PB-MNCs. Numbers of endothelial progenitors were
      approximately 500-fold higher in BM-MNCs. In BM-MNC-implanted myocardia of pigs,
      an increase in systolic function (ejection fraction from 33% to 52%) and regional
      blood flow (2.1-fold) and a reduction of the ischemic area (from 29% to 8%) were
      observed. PB-MNC implantation reduced the ischemic area (from 31% to 17%), the
      extent of which was less than that seen with BM-MNCs. In saline-implanted
      myocardium, the ischemic area expanded (from 28% to 38%), and systolic function
      deteriorated. Angiography revealed an increase in collateral vessel formation by
      PB-MNC or BM-MNC implantation. Capillary numbers were increased 2.6- and 1.7-fold
      by BM-MNC and PB-MNC implantation, respectively. BM-MNCs but not PB-MNCs were
      incorporated into neocapillaries. CONCLUSIONS: Catheter-based implantation of PB
      MNCs can effectively improve collateral perfusion and regional function in
      hibernating ischemic myocardium by its ability to mainly supply angiogenic
      factors and cytokines.

PMID- 12426210
TI  - Endothelial determinants of dendritic cell adhesion and migration: new
      implications for vascular diseases.
AB  - OBJECTIVE: Atherosclerosis is a chronic disease triggered by endothelial injury
      and sustained by inflammation. Dendritic cells (DCs) are critical for the cell
      mediated arm of an immune response and are known to influence inflammatory
      immunity. A fundamental aspect of DC function is their capacity to adhere and
      migrate through vascular endothelial cells (ECs). We investigated the role of
      endothelial activation and dysregulation of the NO pathway on DC adhesion and
      migration. METHODS AND RESULTS: We discovered that DC adhesion and migration are
      modulated by changes in endothelial function. DC adhesion and transmigration were
      markedly increased after exposing ECs to hypoxia, oxidized low density
      lipoprotein, or tumor necrosis factor-alpha. Specifically, inhibition of
      endothelial NO synthase increased DC binding and transmigration. L-Arginine or 3
      hydroxy-3-methylglutaryl coenzyme A reductase inhibition partially decreased DC
      EC interaction. CONCLUSIONS: The results of this study suggest that the adhesion
      and migration of DCs are increased by stimuli known to accelerate atherogenesis.
      Vice versa, augmentation of endothelial NO synthase activity prevents DC
      adhesion. These findings may provide insight into the inflammatory processes
      occurring in atherosclerosis. Because DCs control immunity, regulating DC-EC
      interaction may be relevant to inflammation and atherogenesis.

PMID- 12426211
TI  - Pharmacological potentiation of natriuretic peptide limits polymorphonuclear
      neutrophil-vascular cell interactions.
AB  - OBJECTIVE: Activated polymorphonuclear neutrophils (PMNs) are the main source of
      circulating neutral endopeptidase (NEP). We tested the hypothesis that NEP
      inhibition could potentiate the effect of atrial natriuretic peptide (ANP) on PMN
      vascular cell interactions in vitro. METHODS AND RESULTS: ANP alone and its
      potentiation by retrothiorphan, the NEP inhibitor, significantly inhibited
      superoxide, lysozyme, and matrix metalloproteinase (MMP)-9 release by N-formyl
      Met-Leu-Phe-stimulated PMNs. Activated PMNs degraded exogenous ANP, which was
      prevented by NEP inhibition. Hypoxia significantly increased the adhesion of PMNs
      to endothelial cells and their subsequent MMP-9 release by 60% and 150%,
      respectively (P<0.01). ANP and its potentiation by retrothiorphan limited PMN
      adhesion to hypoxic endothelial cells and thus decreased their MMP-9 release
      (P<0.01). Smooth muscle cells (SMCs) incubated with conditioned medium of N
      formyl-Met-Leu-Phe-stimulated PMNs exhibited morphological and biochemical
      changes characteristic of apoptosis (terminal deoxynucleotidyl transferase
      mediated dUTP nick end-labeling positivity, nuclear condensation/fragmentation,
      poly ADP-ribose polymerase cleavage, and DNA laddering). SMC detachment and
      subsequent apoptosis could be related to leukocyte elastase-induced pericellular
      proteolysis, inasmuch as both events are inhibited by elastase inhibitors. ANP
      and its potentiation by retrothiorphan were able to limit elastase release,
      fibronectin degradation, and SMC apoptosis. CONCLUSIONS: ANP potentiation by NEP
      inhibition could limit PMN activation and its consequences on vascular cells.

PMID- 12426212
TI  - Simvastatin promotes atherosclerotic plaque stability in apoE-deficient mice
      independently of lipid lowering.
AB  - OBJECTIVE: This study sought to determine whether simvastatin, a 3-hydroxy-3
      methylglutaryl coenzyme A reductase inhibitor, has stabilizing effects on
      vulnerable atherosclerotic plaques that are independent of their lipid-lowering
      capabilities. METHODS AND RESULTS: Simvastatin (50 mg/kg per day) was
      administered to 30-week-old apolipoprotein E-deficient mice exhibiting advanced
      unstable atherosclerotic lesions within the innominate/brachiocephalic artery.
      Simvastatin was administered in the chow to separate groups of mice for 6, 12,
      18, or 24 weeks. Simvastatin significantly increased serum cholesterol after 12,
      18, and 24 weeks of treatment. The average cross-sectional area of
      atherosclerotic lesion increased in the innominate artery after 12 and 24 weeks
      of treatment, concomitant with the increase in serum cholesterol. However,
      histological analysis of sections of the innominate artery stained with Movat and
      von Kossa stains demonstrated a 49% reduction in the frequency of intraplaque
      hemorrhage and a 56% reduction in the frequency of calcification, both markers of
      advanced and unstable atherosclerotic plaques. CONCLUSIONS: These data suggest
      that despite an increase in serum cholesterol and lesion size, simvastatin has
      stabilizing effects on advanced atherosclerotic lesions.

PMID- 12426213
TI  - Superoxide generation in directional coronary atherectomy specimens of patients
      with angina pectoris: important role of NAD(P)H oxidase.
AB  - OBJECTIVE: NADH/NADPH oxidase is an important source of reactive oxygen species
      (ROS) in the vasculature. Recently, we demonstrated that p22(phox), an essential
      component of this oxidase, was expressed in human coronary arteries and that its
      expression was enhanced with the progression of atherosclerosis. The present
      study was undertaken to investigate its functional importance in the pathogenesis
      of coronary artery disease. For this aim, the expression of p22(phox), the
      distribution of oxidized low density lipoprotein (LDL), and the generation of ROS
      in directional coronary atherectomy (DCA) specimens were examined. METHODS AND
      RESULTS: DCA specimens were obtained from patients with stable or unstable angina
      pectoris. The distribution of p22(phox) and of oxidized LDL was examined by
      immunohistochemistry. The generation of superoxide in DCA specimens was assessed
      by the dihydroethidium method and lucigenin-enhanced chemiluminescence. ROS were
      closely associated with the distribution of p22(phox) and oxidized LDL. Not only
      inflammatory cells but also smooth muscle cells and fibroblasts generated ROS.
      There was a correlation between ROS and the expression of p22(phox) or oxidized
      LDL. The generation of ROS was significantly higher in unstable angina pectoris
      compared with stable angina pectoris. CONCLUSIONS: ROS generated by p22(phox)
      based NADH/NADPH oxidase likely mediate the oxidative modification of LDL and
      might play a major role in pathogenesis of atherosclerotic coronary artery
      disease.

PMID- 12426214
TI  - Dose-dependent regulation of NAD(P)H oxidase expression by angiotensin II in
      human endothelial cells: protective effect of angiotensin II type 1 receptor
      blockade in patients with coronary artery disease.
AB  - OBJECTIVE: Angiotensin II (Ang II)-mediated induction of vascular superoxide
      anion formation could contribute to the development of endothelial dysfunction,
      hypertension, and atherosclerosis. An NAD(P)H oxidase has been identified as a
      major endothelial source of superoxide anions. However, the molecular mechanism
      underlying the regulation of NAD(P)H oxidase activity in response to Ang II is
      not well understood. METHODS AND RESULTS: We investigated the dose-dependent
      regulation of superoxide anion formation and of NAD(P)H oxidase subunit
      expression in response to Ang II in human endothelial cells. Ang II regulates
      superoxide anion formation and the limiting subunit of endothelial NAD(P)H
      oxidase, gp91-phox, in a dose-dependent manner via Ang II type 1 (AT1) receptor
      mediated induction and Ang II type 2 receptor-mediated partial inhibition at
      higher Ang II concentrations. Furthermore, AT1 receptor blocker therapy before
      coronary bypass surgery downregulates the gp91-phox expression in internal
      mammary artery biopsies of patients with coronary artery disease. CONCLUSIONS:
      Our data support a dose-dependent induction of proatherosclerotic oxidative
      stress in human endothelial cells in response to Ang II. The expression of
      NAD(P)H oxidase subunit gp91-phox is critical for endothelial superoxide anion
      formation. AT1 receptor blockade has an antiatherosclerotic and antioxidative
      potential by the reduction of oxidative stress in the vessel wall.

PMID- 12426215
TI  - Lipoprotein response to diets high in soy or animal protein with and without
      isoflavones in moderately hypercholesterolemic subjects.
AB  - OBJECTIVE: The objective of this study was to assess the independent effect of
      soy relative to common sources of animal protein and soy-derived isoflavones on
      blood lipids. METHODS AND RESULTS: Forty-two subjects with LDL cholesterol levels
      > or =3.36 mmol/L were fed each of four diets in randomized order for 6 weeks per
      phase. Diets contained a minimum of 25 g animal protein or isolated soy
      protein/4.2 MJ, with each containing trace amounts or 50 mg of isoflavones/4.2
      MJ. Soy protein had a modest effect on total, LDL and HDL cholesterol, and
      triglyceride concentrations (-2%, P=0.017; -2%, P=0.042; +3%; P=0.034, -11%,
      P<0.001, respectively). Soy protein had no significant effect on plasma lipids in
      individuals with LDL cholesterol <4.14 mmol/L and significantly reduced total and
      LDL cholesterol and triglyceride concentrations in individuals with LDL
      cholesterol > or =4.14 mmol/L (-4%, P=0.001; -5%, P=0.003; -15%, P<0.001,
      respectively). No significant effect of isoflavones on plasma lipid levels was
      observed either constituent to the soy protein or supplemental to the animal
      protein. CONCLUSIONS: Although potentially helpful when used to displace products
      containing animal fat from the diet, the regular intake of relatively high levels
      of soy protein (>50 g/day) had only a modest effect on blood cholesterol levels
      and only in subjects with elevated LDL cholesterol levels (> or =4.14 mmol/L).
      Soy-derived isoflavones had no significant effect.

PMID- 12426216
TI  - The atheroprotective effect of dietary soy isoflavones in apolipoprotein E-/-
      mice requires the presence of estrogen receptor-alpha.
AB  - OBJECTIVE: Although the mechanisms by which dietary soy inhibits atherosclerosis
      are unclear, one line of evidence implicates an important role for its
      phytoestrogenic isoflavones. We sought to determine whether soy isoflavones exert
      atheroprotective effects through estrogen receptor-dependent processes and, if
      so, which estrogen receptor subtype (ie, alpha or beta) is involved. METHODS AND
      RESULTS: We compared the effects of diets rich in soy protein that were either
      isoflavone depleted (0.04 mg/g protein isolate) or isoflavone-replete, or
      Soy(+IF) (1.72 mg/g protein isolate) in apolipoprotein E-deficient (ee) mice that
      had been crossed with estrogen receptor-alpha- and -beta-deficient mice to
      produce double-knockout alphaalphaee and betabetaee mice and (estrogen receptor)
      wild-type controls (AAee and BBee). Both male and ovariectomized female mice were
      studied (n=10 to 17 per treatment group; total n=201). After 16 weeks,
      atherosclerosis was assessed by quantifying the aortic content of esterified
      cholesterol. Atherosclerosis was reduced 20% to 27% (P<0.05) by Soy(+IF) in
      betabetaee, BBee, and AAee mice but was unaffected in alphaalphaee mice. The
      inhibitory effect of Soy(+IF) was unrelated to sex, total plasma cholesterol,
      VLDL, LDL, and HDL cholesterol. CONCLUSIONS: The results indicate a necessary
      role for estrogen receptor-alpha-dependent processes in mediating the
      atheroprotective effects of dietary soy isoflavones.

PMID- 12426217
TI  - C-reactive protein relaxes human vessels in vitro.
AB  - OBJECTIVE: C-reactive protein (CRP) is a sensitive marker of inflammation and a
      prognostic marker in cardiovascular disease. Evidence suggests direct biological
      activities of CRP within the vascular wall. The study was designed to examine the
      vasoreactive effects of CRP. METHODS AND RESULTS: Human internal mammary artery
      rings were obtained during cardiovascular bypass surgery and suspended in an
      organ bath chamber. The rings were precontracted with endothelin-1, and response
      to cumulative concentrations of CRP was obtained. Experiments were repeated after
      initial incubation with 20, 40, and 60 mmol/L KCl, the potassium channel blockers
      BaCl, tetraethylammonium chloride, and glibenclamide, and the NO synthase
      inhibitor N-monomethyl-L-arginine and also after removal of the endothelium. CRP
      caused dose-dependent relaxation of human internal mammary artery rings, which
      was not affected by preincubation with N-monomethyl-L-arginine or removal of the
      endothelium. Maximum relaxation response to CRP (79.5+/-10%) was attenuated by
      KCl (2.5+/-11.5%, P<0.001), BaCl (24.5+/-7.5%, P<0.001), and tetraethylammonium
      chloride (34.9+/-8.25%, P<0.01) but not by glibenclamide. Conclusions- The
      present study demonstrates that CRP exerts an endothelium-independent
      vasorelaxing effect via potassium channels. Thus, the study suggests a role of
      CRP in the regulation of vascular tone.

PMID- 12426218
TI  - Associations between cardiorespiratory fitness and C-reactive protein in men.
AB  - OBJECTIVE: This study examined the association between cardiorespiratory fitness
      and C-reactive protein (CRP), with adjustment for weight and within weight
      categories. METHODS AND RESULTS: We calculated median and adjusted geometric mean
      CRP levels, percentages of individuals with an elevated CRP (> or =2.00 mg/L),
      and odds ratios of elevated CRP across 5 levels of cardiorespiratory fitness for
      722 men. CRP values were adjusted for age, body mass index, vitamin use, statin
      medication use, aspirin use, the presence of inflammatory disease, cardiovascular
      disease, and diabetes, and smoking habit. We found an inverse association of CRP
      across fitness levels (P for trend<0.001), with the highest adjusted CRP value in
      the lowest fitness quintile (1.64 [1.27 to 2.11] mg/L) and the lowest adjusted
      CRP value in the highest fitness quintile (0.70 [0.60 to 0.80] mg/L). Similar
      results were found for the prevalence of elevated CRP across fitness quintiles.
      We used logistic regression to model the adjusted odds for elevated CRP and found
      that compared with the referent first quintile, the second (odds ratio [OR] 0.43,
      95% CI 0.22 to 0.85), third (OR 0.33, 95% CI 0.17 to 0.65), fourth (OR 0.23, 95%
      CI 0.12 to 0.47), and fifth (OR 0.17, 95% CI 0.08 to 0.37) quintiles of fitness
      had significantly lower odds of elevated CRP. Similar results were found when
      examining the CRP-fitness relation within categories of body fatness (normal
      weight, overweight, and obese) and waist girth (<102 or > or =102 cm).
      CONCLUSIONS: Cardiorespiratory fitness levels were inversely associated with CRP
      values and the prevalence of elevated CRP values in this sample of men from the
      Aerobics Center Longitudinal Study.

PMID- 12426219
TI  - ATP-binding cassette transporter 1 participates in LDL oxidation by artery wall
      cells.
AB  - OBJECTIVE: We have previously reported that products of the lipoxygenase pathway,
      hydroperoxyoctadecadienoic acid and hydroperoxyeicosatetraenoic acid, as well as
      cholesterol linoleate hydroperoxides, collectively termed seeding molecules, are
      removed by apolipoprotein A-I (apoA-I) from the artery wall cells and render low
      density lipoprotein (LDL) resistant to oxidation by human artery wall cells. The
      mechanisms by which oxidized lipids are transported and/or transferred to
      lipoproteins and the pathways by which apoA-I facilitates their removal remain
      unclear. ATP-binding cassette transporter 1 (ABCA1) is known to facilitate the
      release of cellular phospholipids and cholesterol from the plasma membrane to
      apoA-I and high density lipoprotein. Therefore, we evaluated whether ABCA1
      participates in LDL oxidation. METHODS AND RESULTS: In this report, we show that
      (1) chemical inhibitors of ABCA1 function, glyburide and DIDS, block artery wall
      cell-mediated oxidative modification of LDL, (2) inhibition of ABCA1 with the use
      of antisense (but not sense) oligonucleotides prevents LDL-induced lipid
      hydroperoxide formation and LDL-induced monocyte chemotactic activity by the
      artery wall cells, and (3) oxysterols that induce ABCA1 expression, such as
      22(R)hydroxycholesterol, enhance cell-mediated LDL oxidation. Furthermore, we
      also show that 22(R)hydroxycholesterol induces the production of reactive oxygen
      species in the artery wall cells, which can be removed by incubating the artery
      wall cells with apoA-I. CONCLUSIONS: Our data suggest that ABCA1 plays an
      important role in artery wall cell-mediated modification/oxidation of LDL by
      modulating the release of reactive oxygen species from artery wall cells that are
      necessary for LDL oxidation.

PMID- 12426220
TI  - Inhibition of the apical sodium-dependent bile acid transporter reduces LDL
      cholesterol and apoB by enhanced plasma clearance of LDL apoB.
AB  - OBJECTIVE: Cloning of the ileal apical sodium-dependent bile acid transporter
      (ASBT) has identified a new pharmacological target for the modulation of plasma
      lipoproteins. The objective of this study was to determine whether a novel,
      specific, minimally absorbed ASBT inhibitor (SC-435) decreases LDL cholesterol
      through the alteration of plasma apoB kinetics. METHODS AND RESULTS: Miniature
      pigs were treated for 21 days with 10 mg/kg/day of SC-435 or placebo. SC-435
      decreased plasma cholesterol by 9% and LDL cholesterol by 20% with no effect on
      other lipids. Autologous (131)I-VLDL, (125)I-LDL, and [(3)H]-leucine were
      injected simultaneously to determine apoB kinetics. LDL apoB concentrations
      decreased significantly by 10% resulting entirely from an increase in LDL-apoB
      fractional catabolic rate. SC-435 had no effect on either total LDL apoB
      production or VLDL apoB converted to LDL. SC-435 increased VLDL apoB production
      by 22%; however, the concentration was unchanged as a result of increased VLDL
      apoB direct removal. SC-435 increased hepatic mRNA and enzymatic activity for
      both cholesterol 7alpha-hydroxylase and HMG-CoA reductase. Hepatic LDL receptor
      mRNA increased significantly, whereas apoB expression was unaffected.
      CONCLUSIONS: A low dose of the ASBT inhibitor, SC-435, significantly reduces
      plasma LDL cholesterol through enhanced LDL receptor-mediated LDL apoB clearance,
      secondary to increased expression of cholesterol 7alpha-hydroxylase.

PMID- 12426221
TI  - B-lymphocyte deficiency increases atherosclerosis in LDL receptor-null mice.
AB  - OBJECTIVE: Atherosclerosis is an inflammatory disease characterized by innate and
      adaptive immune responses. We investigated the role of B cells and antibodies in
      the development of atherosclerosis in low density lipoprotein (LDL) receptor
      deficient (LDLR(-/-)) mice. METHODS AND RESULTS: Using wild-type and B cell
      deficient mice as bone marrow donors, we were able to generate LDLR(-/-) mice
      that possessed <1.0% of their normal B cell population. B cell-deficient LDLR(-/
      ) mice on a Western diet showed marked decreases in total serum antibody and anti
      oxidized LDL antibody. B cell deficiency was associated with a 30% to 40%
      increase in the lesion area in the proximal and distal aortas. Real-time reverse
      transcription-polymerase chain reaction and enzyme-linked immunospot analyses
      showed a decrease in proatherogenic (interferon-gamma) and antiatherogenic
      (interleukin-10 and transforming growth factor-beta) cytokine mRNA and a decrease
      in interleukin-4- and interferon-gamma-producing cells. Additionally, we observed
      a decrease in splenocyte proliferation to oxidized LDL in the B cell-deficient
      LDLR(-/-) mice, suggesting that B lymphocytes may play a role in the presentation
      of lipid antigen. CONCLUSIONS: Collectively, these data demonstrate that B cells
      and/or antibodies are protective against atherosclerosis and that this protection
      may be conferred by B cell-mediated immune regulation.

PMID- 12426222
TI  - Retarded intracellular lipid transport associated with reduced expression of
      Cdc42, a member of Rho-GTPases, in human aged skin fibroblasts: a possible
      function of Cdc42 in mediating intracellular lipid transport.
AB  - OBJECTIVE: Many cell types in atherosclerotic lesions are thought to have various
      biological abnormalities, such as impaired lipid homeostasis and slow cell
      proliferation, which may be related to senescence at cellular and individual
      levels. One of the common characteristics of senescent cells in vitro is the
      alteration of actin cytoskeletons, which have been reported to be involved in the
      intracellular transport of lipids. Recently, we raised the hypothesis that Cdc42,
      which is a member of the Rho-GTPase family and is known to play an important role
      in actin dynamics, might be important in cellular lipid transport. METHODS AND
      RESULTS: In the present study, we found that the protein expression levels and
      GTP-binding activities of Cdc42 were decreased in aged human skin fibroblasts.
      Moreover, we found the intracellular kinetics of Golgi-associated lipids to be
      retarded in these cells, which was demonstrated by the fluorescence recovery
      after photobleaching (FRAP) technique and the use of N-[7-(4-nitrobenzo-2-oxa-1,3
      diazole)]-6-aminohexanoyl-D-erythro-sphingosine as a tracer. To correlate the
      decreased expression of Cdc42 with the retarded FRAP, we complemented the amount
      of wild-type c-myc-tagged Cdc42Hs (myc-Cdc42Hs-WT) by adenovirus-mediated gene
      transfer. We further tested the effect of the dominant-active form (myc-Cdc42Hs
      DA, V12Cdc42Hs) or dominant-negative form (myc-Cdc42Hs-DN, N17Cdc42Hs) of Cdc42Hs
      on FRAP. Introduction of myc-Cdc42Hs-WT or myc-Cdc42Hs-DA recovered the retarded
      FRAP in the aged fibroblasts. Conversely, control fibroblasts infected with myc
      Cdc42Hs-DN exhibited significantly retarded FRAP. CONCLUSIONS: These data clearly
      indicate that the expression of Cdc42, a small G protein, is decreased in the
      aged cells in close association with the retarded intracellular lipid transport.
      The present study demonstrates a possible function of Cdc42 in the mediation of
      intracellular lipid transport.

PMID- 12426223
TI  - Differential role of heparan sulfate proteoglycans on aggregated LDL uptake in
      human vascular smooth muscle cells and mouse embryonic fibroblasts.
AB  - OBJECTIVE: Low density lipoprotein (LDL) receptor-related protein (LRP) binds and
      internalizes aggregated LDL (agLDL) in human vascular smooth muscle cells
      (VSMCs). To analyze the contribution of proteoglycans (PGs) to agLDL uptake in
      human VSMCs, in wild-type mouse embryonic fibroblasts (MEF line), and in LRP
      deficient mouse embryonic fibroblasts (PEA13 line). METHODS AND RESULTS: PGs in
      the medium and cellular and extracellular matrix have been isolated by metabolic
      radiolabeling with [35S]Na2SO4 and characterized by selective digestion with
      heparinase I and III (4 U/mL each) and chondroitinase ABC (2 U/mL). To examine
      the contribution of PGs and LRPs to agLDL internalization, nonexpressing and LRP
      expressing cells, treated or not with polysaccharidase, were incubated with agLDL
      (25, 50, and 100 micro g/mL) for 18 hours. In human VSMCs, agLDL was unable to
      induce cholesteryl ester (CE) accumulation in antisense LRP-oligodeoxynucleotide
      treated cells, and heparan sulfate (HS)-PG depletion leads to a reduction of the
      CE accumulation. In mouse fibroblasts, PEA13 compared with MEF showed lower, but
      still considerable, CE accumulation, and HS-PG depletion almost completely
      inhibited CE accumulation. CONCLUSIONS: In MEF, HS-PGs can function alone as
      receptors that bind and internalize agLDL in the absence of LRP, but in human
      VSMCs, although HS-PGs facilitate agLDL binding to the cells, LRP is essential
      for agLDL internalization.

PMID- 12426224
TI  - Metabolism of apoA-I as lipid-free protein or as component of discoidal and
      spherical reconstituted HDLs: studies in wild-type and hepatic lipase transgenic
      rabbits.
AB  - OBJECTIVE: Apolipoprotein (apo)A-I exists in 3 forms in plasma: as lipid-free
      apoA-I, as a component of pre-beta-migrating discoidal high density lipoproteins
      (HDLs), and as a component of alpha-migrating spherical HDLs. This study
      investigates (1) the in vivo metabolism of apoA-I in each of these forms and (2)
      the effects of hepatic lipase (HL) on apoA-I metabolism. METHODS AND RESULTS:
      Wild-type and HL transgenic rabbits were studied. When lipid-free (125)I-apoA-I
      and 125I-apoA-I in pre-beta-migrating discoidal reconstituted HDLs (rHDLs) were
      injected into wild-type rabbits, the label rapidly appeared in alpha-migrating
      particles and decayed with the same fractional catabolic rate (FCR) as when they
      were injected as a component of spherical rHDLs. Spherical rHDLs did not change
      in size when they were injected into wild-type rabbits but were reduced in size
      in HL transgenic rabbits. The FCR of apoA-I in HL transgenic rabbits was double
      that in wild-type rabbits. CONCLUSIONS: In vivo, (1) lipid-free apoA-I rapidly
      incorporates into preexisting alpha-migrating particles, (2) pre-beta-migrating
      discoidal HDLs are rapidly converted into alpha-migrating HDLs, (3) the FCR of
      apoA-I is independent of the form in which it is introduced into plasma, and (4)
      HL reduces the size of alpha-migrating HDLs and increases the rate of catabolism
      of apoA-I.

PMID- 12426225
TI  - Nonfasting apolipoprotein B and triglyceride levels as a useful predictor of
      coronary heart disease risk in middle-aged UK men.
AB  - OBJECTIVE: The Apolipoprotein-related Mortality Risk (AMORIS) study concluded
      that the apolipoprotein (apo)B/apoA-I ratio was the best predictor of coronary
      heart disease (CHD) risk. We have compared the pairwise combinations of total
      cholesterol, triglycerides (TGs), apoB, high density lipoprotein (HDL)
      cholesterol, low density lipoprotein cholesterol, and apoA-I on CHD risk
      prediction in middle-aged men. METHODS AND RESULTS: Healthy middle-aged men
      (n=2508), free of CHD at baseline, were examined prospectively. Over 6 years of
      follow-up, there were 163 CHD events (including acute myocardial infarction,
      coronary artery surgery, and ECG evidence of silent myocardial infarction). The
      relative risk (RR) of CHD associated with cholesterol, TGs, apoB, apoA-I,
      apoB/apoA-I, low density lipoprotein cholesterol, and HDL cholesterol were
      examined by survival analysis. The apoB/apoA-I ratio was associated with the
      strongest effect on the RR (3.58, 95% CI 2.08 to 6.19). In multivariate analysis,
      apoA-I had no significant effect on risk. Examining RR by quartiles, apoB and HDL
      in combination (RR 8.38, 95% CI 3.21 to 21.92) were better predictors of CHD risk
      than apoB and TGs (RR 4.05, 95% CI 1.57 to 6.23). However, apoB and TGs in
      combination added risk information over and above lifestyle factors, whereas apoB
      and HDL cholesterol did not. CONCLUSIONS: The combined evaluation of apoB with
      TGs provides useful diagnostic criteria for CHD risk.

PMID- 12426226
TI  - Val64Ile polymorphism in the C-C chemokine receptor 2 is associated with reduced
      coronary artery calcification.
AB  - OBJECTIVE: Studies in mice have shown that genetic disruption of monocyte
      chemotactic protein-1 or its receptor, the C-C chemokine receptor 2 (CCR2),
      inhibits atherosclerosis, but few data exist in humans to suggest that the
      monocyte chemotactic protein-1-CCR2 interaction is important in atherogenesis. A
      common polymorphism in the human CCR2 gene resulting in a substitution of
      isoleucine for valine (Val64Ile) has been associated with other disease
      phenotypes in humans. METHODS AND RESULTS: A cohort of first-degree relatives of
      persons with premature coronary artery disease was recruited and quantitatively
      phenotyped for the extent of CAC, a marker of coronary atherosclerosis, by using
      electron beam CT. The extent of CAC was significantly lower in subjects with the
      CCR2-Ile64 variant (Val/Ile and Ile/Ile genotypes) than in subjects carrying 2
      Val64 alleles, even after adjustment for traditional risk factors. CONCLUSIONS:
      This study provides genetic evidence linking CCR2 with coronary atherosclerosis
      in humans.

PMID- 12426227
TI  - In vivo imaging of thrombin activity in experimental thrombi with thrombin
      sensitive near-infrared molecular probe.
AB  - OBJECTIVE: Thrombin, a serine protease, plays an important role in thrombosis as
      well as other cellular and developmental processes. In this study, we
      investigated the ability of a novel thrombin-activatable molecular probe to
      provide in vivo images of thrombin activity in experimental thrombi. METHODS AND
      RESULTS: The thrombin probe consists of a near-infrared (NIR) fluorochrome
      attached to a delivery vehicle via a thrombin-specific oligopeptide substrate. In
      human blood, endogenous thrombin activated the thrombin probe and increased the
      fluorescence signal by 18-fold (P=0.008). Hirudin, a specific thrombin inhibitor,
      suppressed probe activation by 82% (P=0.007). Imaging of in vivo thrombin
      activity was then investigated in acute experimental murine thrombosis models up
      to 12 hours. After systemic thrombin probe injection, focal NIR fluorescence
      signal enhancement was rapidly detected within acute and subacute thrombi. In
      contrast, no thrombosis signal enhancement was seen in similar experiments with a
      control NIR fluorochrome. CONCLUSIONS: Thrombin activity can be imaged in vivo by
      using a novel thrombin-activatable and thrombin-specific NIR molecular probe. The
      thrombin probe could enhance the understanding of the role of thrombin in
      thrombogenesis and other homeostatic and pathological conditions.

PMID- 12426228
TI  - Increased serum homocysteine and sudden death resulting from coronary
      atherosclerosis with fibrous plaques.
AB  - INTRODUCTION: Modest elevations of total homocysteine have been associated with
      increased risk for coronary atherosclerosis but correlation between elevated
      homocysteine and plaque morphology has not been described in humans. METHODS: We
      determined serum homocysteine at postmortem from 87 men with coronary thrombus
      (62 of whom were diagnosed as acute), from 35 men with severe coronary disease
      without thrombus, and from 46 controls. In coronary deaths, atherosclerotic
      plaques at the sites of maximal luminal narrowing of the four epicardial coronary
      arteries were classified as fibrous plaques, fibrous cap atheromas, thin-cap
      atheromas, and healed ruptures, and macrophage infiltration was assessed
      semiquantitatively. RESULTS: Median serum homocysteine postmortem as a result of
      acute thrombus was 10.4 micro mol/L (P=0.4 versus controls), 12.1 micro mol/L in
      men with organized thrombi (P=0.1 versus controls), 15.6 micro mol/L in men
      without thrombus (P=0.007 versus controls), and 9.8 micro mol/L in controls. The
      median homocysteine was 12.1 micro mol/L in 65 men with healed infarcts (P=0.03
      versus controls). The number of fibrous plaques was associated with log
      normalized homocysteine (P=0.004), independent of age, albumin, smoking,
      hypertension, and serum cholesterol. Homocysteine levels in the upper tertile
      (>15 micromol/L) were associated with sudden death without acute or organized
      thrombus (odds ratio 3.8, P=0.03) independent of age and other risk factors; the
      coexistence of diabetes increased the association (odds ratio 25.1, P=0.009,
      versus lowest tertile < or =8.5 micromol/L). CONCLUSIONS: Increased serum
      homocysteine is associated with sudden death in the absence of acute coronary
      thrombosis, especially with concomitant diabetes, and with the presence of lipid
      poor, fibrous plaques.

PMID- 12426229
TI  - Differences in airway inflammation in patients with fixed airflow obstruction due
      to asthma or chronic obstructive pulmonary disease.
AB  - To determine whether patients with fixed airflow obstruction have distinct
      pathologic and functional characteristics depending on a history of either asthma
      or chronic obstructive pulmonary disease (COPD), we characterized 46 consecutive
      outpatients presenting with fixed airflow obstruction by clinical history,
      pulmonary function tests, exhaled nitric oxide, sputum analysis, bronchoalveolar
      lavage, bronchial biopsy, and high-resolution computed tomography chest scans.
      Subjects with a history of COPD (n = 27) and subjects with a history of asthma (n
      = 19) had a similar degree of fixed airflow obstruction (FEV1: 56 +/- 2 versus 56
      +/- 3% predicted) and airway hyperresponsiveness (PC20FEV1: 2.81 [3.1] versus
      1.17 [3.3]). Subjects with a history of asthma had significantly more eosinophils
      in peripheral blood, sputum, bronchoalveolar lavage, and airway mucosa; fewer
      neutrophils in sputum and bronchoalveolar lavage fluid; a higher CD4+/CD8+ ratio
      of T cells infiltrating the airway mucosa; and a thicker reticular layer of the
      epithelial basement membrane. They also had significantly lower residual volume,
      higher diffusing capacity, higher exhaled nitric oxide, lower high-resolution
      computed tomography scan emphysema score, and greater reversibility to
      bronchodilator and steroids. In conclusion, despite similar fixed airflow
      obstruction, subjects with a history of asthma have distinct characteristics
      compared with subjects with a history of COPD and should be properly identified
      and treated.

PMID- 12426231
TI  - Hypersensitivity of laryngeal C-fibers induced by volatile anesthetics in young
      guinea pigs.
AB  - Inhalation induction of anesthesia with a single volatile anesthetic is commonly
      used in children but is sometimes associated with increased cough, secretion, and
      airway obstruction, which may result in part from stimulation of laryngeal C
      fibers. We examined the effects of two popular volatile anesthetics, halothane
      and sevoflurane, on laryngeal C-fiber responsiveness in urethane-anesthetized
      guinea pigs (from age 4-5 weeks). After administration of halothane or
      sevoflurane to the functionally isolated upper airway, laryngeal C-fiber
      afferents recorded from the internal branch of the superior laryngeal nerve and
      identified by a conduction velocity of less than 2.0 m/second were tested for
      responsiveness to chemical and mechanical stimuli. Halothane doubled C-fiber
      responsiveness to capsaicin injected into the left atrium or nebulized to the
      larynx and to laryngeal hyperinflation, compared with sevoflurane, but it had no
      effect on baseline activity. The data indicate that, compared with sevoflurane,
      halothane more markedly enhances laryngeal C-fiber sensitivity to chemical and
      mechanical stimuli in young guinea pigs, which would explain the greater number
      of respiratory-related complications in children during induction of anesthesia
      with this agent.

PMID- 12426230
TI  - Immunologic and hemodynamic effects of "low-dose" hydrocortisone in septic shock:
      a double-blind, randomized, placebo-controlled, crossover study.
AB  - Within the last few years, increasing evidence of relative adrenal insufficiency
      in septic shock evoked a reassessment of hydrocortisone therapy. To evaluate the
      effects of hydrocortisone on the balance between proinflammatory and
      antiinflammation, 40 patients with septic shock were randomized in a double-blind
      crossover study to receive either the first 100 mg of hydrocortisone as a loading
      dose and 10 mg per hour until Day 3 (n = 20) or placebo (n = 20), followed by the
      opposite medication until Day 6. Hydrocortisone infusion induced an increase of
      mean arterial pressure, systemic vascular resistance, and a decline of heart
      rate, cardiac index, and norepinephrine requirement. A reduction of plasma
      nitrite/nitrate indicated inhibition of nitric oxide formation and correlated
      with a reduction of vasopressor support. The inflammatory response (interleukin-6
      and interleukin-8), endothelial (soluble E-selectin) and neutrophil activation
      (expression of CD11b, CD64), and antiinflammatory response (soluble tumor
      necrosis factor receptors I and II and interleukin-10) were attenuated. In
      peripheral blood monocytes, human leukocyte antigen-DR expression was only
      slightly depressed, whereas in vitro phagocytosis and the monocyte-activating
      cytokine interleukin-12 increased. Hydrocortisone withdrawal induced hemodynamic
      and immunologic rebound effects. In conclusion, hydrocortisone therapy restored
      hemodynamic stability and differentially modulated the immunologic response to
      stress in a way of antiinflammation rather than immunosuppression.

PMID- 12426232
TI  - Atypical pathogen infection in adults with acute exacerbation of bronchial
      asthma.
AB  - In a serologically based prospective study, acute infections with four atypical
      pathogens were determined in 100 adults hospitalized for acute exacerbation of
      bronchial asthma, and compared with the corresponding rate in a matched control
      group. Paired sera were tested using immunofluorescence or enzyme immunoassay
      methods to establish the serologic diagnosis. In 18 patients (18%), there was
      evidence of acute infection with Mycoplasma pneumoniae, compared with 3% in the
      control group (p = 0.0006). In 10 of these patients there was evidence of
      infection with at least one additional pathogen, a respiratory virus in 7. There
      was no significant difference between the study groups in the rates of acute
      infection by Chlamydia pneumoniae (8% in the hospitalized patients versus 6% in
      the control subjects), Legionella spp. (5 versus 3%, respectively), or Coxiella
      burnettii (no patients in either group). We conclude that of these four atypical
      pathogens, only infection with M. pneumoniae is associated with hospitalization
      for acute exacerbation of bronchial asthma. In most of these M. pneumoniae
      patients there is evidence of infection with a respiratory virus as well. The
      pathophysiologic and therapeutic significance of these findings should be tested
      in further studies specifically designed to address these questions.

PMID- 12426233
TI  - Experimental and clinical rationale for use of MMF in nontransplant progressive
      nephropathies.
AB  - The incidence of progressive nephropathies and, consequently, the population
      suffering from end-stage renal disease have increased steadily in recent years,
      posing an ever-growing cost, in both human and financial terms, to society. There
      is mounting evidence that, in both immune-mediated and nonimmune-mediated chronic
      nephropathies, renal inflammatory events are key to the propagation and
      perpetuation of renal injury. Mycophenolate mofetil (MMF) is an antilymphocyte
      agent recently introduced in clinical practice for the prevention of allograft
      rejection. The present review discusses clinical and experimental evidence that
      the anti-inflammatory action of MMF can be advantageously used to arrest immune-
      and nonimmune-mediated progressive injury of native kidneys as well.

PMID- 12426235
TI  - Manganese superoxide dismutase gene therapy protects against irradiation-induced
      cystitis.
AB  - Urinary bladder cystitis occurs in patients receiving radiation therapy for
      pelvic tumors. Radiation-induced formation of superoxide radicals is believed to
      damage the urothelium, exposing the underlying bladder smooth muscle to urine,
      culminating in nerve irritation and muscle dysfunction. We tested whether
      overexpression of MnSOD could decrease superoxide levels and protect the bladder
      from radiation damage. Pelvic irradiation led to sloughing of urothelial umbrella
      cells, with decreased transepithelial resistance, increased water and urea
      permeabilities, and increased expression of inducible nitric oxide synthase. Six
      months after irradiation, cystometrograms showed elevated intravesical pressures
      and prolonged voiding patterns. However, urothelia transfected with the MnSOD
      transgene recovered from radiation injury more rapidly, and detrusor function was
      much closer to that of control bladders than irradiated bladders without the
      transgene. We conclude that MnSOD gene therapy is protective, which could lead to
      its use in mitigating radiation cystitis and preventing dysfunction of the
      urinary bladder.

PMID- 12426234
TI  - Chloride channels in the kidney: lessons learned from knockout animals.
AB  - Cl- channels are involved in a range of functions, including regulation of cell
      volume and/or intracellular pH, acidification of intracellular vesicles, and
      vectorial transport of NaCl across many epithelia. Numerous Cl- channels have
      been identified in the kidney, based on single-channel properties such as
      conductance, anion selectivity, gating, and response to inhibitors. The molecular
      counterpart of many of these Cl- channels is still not known. This review will
      focus on gene-targeted mouse models disrupting two structural classes of Cl-
      channels that are relevant for the kidney: the CLC family of voltage-gated Cl-
      channels and the CFTR. Disruption of several members of the CLC family in the
      mouse provided useful models for various inherited diseases of the kidney,
      including Dent's disease and diabetes insipidus. Mice with disrupted CFTR are
      valuable models for cystic fibrosis (CF), the most common autosomal recessive,
      lethal disease in Caucasians. Although CFTR is expressed in various nephron
      segments, there is no overt renal phenotype in CF. Analysis of CF mice has been
      useful to identify the role and potential interactions of CFTR in the kidney.
      Furthermore, observations made in CF mice are potentially relevant to all other
      models of Cl- channel knockouts because they emphasize the importance of
      alternative Cl- pathways in such models.

PMID- 12426236
TI  - Renal principal cell-specific expression of green fluorescent protein in
      transgenic mice.
AB  - The purpose of this study is to develop transgenic mice with principal cell
      specific expression of green fluorescent protein (GFP). After the cloning and
      sequencing of the mouse aquaporin-2 (AQP2) gene, 9.5 kb of the promoter were used
      to drive expression of GFP in transgenic mice. In transgenic mice, GFP was
      selectively expressed in principal cells of the renal collecting duct and not in
      intercalated cells. Expression was increased by dehydration of mice. AQP2 and GFP
      expression was maintained in primary cultures of renal medulla that were
      stimulated with cAMP or vasopressin analogs. GFP-expressing cells were then
      isolated by fluorescence-activated cell sorting. RT-PCR analysis showed
      expression of AQP2, AQP3, AQP4, vasopressin type 2 receptor, and cAMP response
      element binding protein but not H+-ATPase B1 subunit or anion exchanger 1. After
      expansion of these cells in culture, RT-PCR analysis showed continued expression
      of the same genes. This pattern of gene expression is that of principal cells
      rather than intercalated cells. This transgenic mouse model can be used in future
      studies of gene expression during the development, differentiation, and
      maturation of renal principal cells.

PMID- 12426237
TI  - Cd-MT causes endocytosis of brush-border transporters in rat renal proximal
      tubules.
AB  - Nephrotoxicity in humans and experimental animals due to chronic exposure to
      cadmium (Cd) is manifested by defects in the reabsorptive and secretory functions
      of proximal tubules (PT). The main symptoms of Cd nephrotoxicity, including
      polyuria, phosphaturia, aminoaciduria, glucosuria, and proteinuria, suggest that
      various brush-border membrane (BBM) transporters are the main targets of Cd.
      Specific transporters may be either directly inhibited by Cd or lost from the BBM
      after Cd treatment, or both. We have recently proposed that Cd may impair the
      vesicle-dependent recycling of BBM transporters by inhibiting vacuolar H+-ATPase
      (V-ATPase) activity and endocytosis in PT cells (Herak-Kramberger CM, Sabolic I,
      and Brown D. Kidney Int 53: 1713-1726, 1998). The mechanism underlying the Cd
      effect was further explored in an in vivo model of experimental Cd nephrotoxicity
      induced by Cd-metallothionein (Cd-MT; 0.4 mg Cd/kg body mass; a single dose sc)
      in rats. The time-dependent redistribution of various BBM transporters was
      examined in this model by fluorescence and gold-labeling immunocytochemistry on
      tissue sections and by immunoblotting of isolated renal cortical BBM. In PT cells
      of Cd-MT-treated rats, we observed 1) shortening and loss of microvilli; 2) time
      dependent loss of megalin, V-ATPase, aquaporin-1 (AQP1), and type 3 Na+/H+
      exchanger (NHE3) from the BBM; 3) redistribution of these transporters into
      vesicles that were randomly scattered throughout the cell cytoplasm; and 4)
      redistribution of NHE3, but not megalin, into the basolateral plasma membrane.
      The internalization of BBM transporters was accompanied by fragmentation and loss
      of microtubules and by an increased abundance of alpha-tubulin monomers in PT
      cells. Transporter redistribution was detectable as early as 1 h after Cd-MT
      treatment and increased in magnitude over the next 12 h. We conclude that the
      early mechanism of Cd toxicity in PT cells may include a colchicine-like
      depolymerization of microtubules and impaired vesicle-dependent recycling of
      various BBM proteins. These processes may lead to a time-dependent loss of cell
      membrane components, resulting in reabsorptive and secretory defects that occur
      in Cd-induced nephrotoxicity.

PMID- 12426238
TI  - Exhaled NO is reduced at an early stage of hypoxia-induced pulmonary hypertension
      in newborn piglets.
AB  - Altered nitric oxide (NO) production could contribute to the pathogenesis of
      hypoxia-induced pulmonary hypertension. To determine whether parameters of lung
      NO are altered at an early stage of hypoxia-induced pulmonary hypertension,
      newborn piglets were exposed to room air (control, n = 21) or 10% O(2) (hypoxia,
      n = 19) for 3-4 days. Some lungs were isolated and perfused for measurement of
      exhaled NO output and the perfusate accumulation of nitrite and nitrate (NOx-),
      the stable metabolites of NO. Pulmonary arteries (20-600-microm diameter) and
      their accompanying airways were dissected from other lungs and incubated for NOx-
      determination. Abundances of the nitric oxide synthase (NOS) isoforms endothelial
      NOS and neural NOS were assessed in homogenates of PAs and airways. The perfusate
      NOx- accumulation was similar, whereas exhaled NO output was lower for isolated
      lungs of hypoxic, compared with control, piglets. The incubation solution NOx-
      did not differ between pulmonary arteries (PAs) of the two groups but was lower
      for airways of hypoxic, compared with control, piglets. Abundances of both eNOS
      and nNOS proteins were similar for PA homogenates from the two groups of piglets
      but were increased in airway homogenates of hypoxic compared with controls. The
      NO pathway is altered in airways, but not in PAs, at an early stage of hypoxia
      induced pulmonary hypertension in newborn piglets.

PMID- 12426239
TI  - The trans-exudative pleural effusion.

PMID- 12426240
TI  - Pleural effusion prediction failures.

PMID- 12426241
TI  - Talc for pleurodesis?

PMID- 12426242
TI  - Environmental measures and asthma.

PMID- 12426243
TI  - Chlamydia pneumoniae and the "Dutch Hypothesis".

PMID- 12426244
TI  - FEES/FEESST and videotape recording: there's more to this than meets the eye.

PMID- 12426245
TI  - TGIF: tracheal gas insufflation: for whom?

PMID- 12426246
TI  - Exudative effusions in congestive heart failure.
AB  - OBJECTIVES: Pleural effusions due to congestive heart failure (CHF) typically are
      transudates, but an occasional patient with CHF is found to have an exudate in
      the absence of an apparent cause other than CHF. We sought to determine the
      incidence and clinical significance of such exudative effusions. DESIGN: Patients
      with CHF and effusions seen during the 7-year period from January 1994 through
      December 2000 were identified from their hospital discharge diagnoses and
      radiographs, while those who had undergone thoracentesis were identified from a
      review of the laboratory logs. The presenting symptoms and clinical course were
      determined from a review of the medical records. The effect of RBC contamination
      on pleural fluid lactate dehydrogenase (LDH) levels was determined by measuring
      the LDH activity of mock pleural fluid containing known amounts of RBC. RESULTS:
      Seven hundred seventy patients had CHF with an effusion, but only 175 patients
      underwent a thoracentesis. In this select group, 86 patients had transudates and
      89 had exudates. A noncardiac cause for the exudate was readily identified in 59
      patients by hospital discharge, and 7 more patients had an etiology found during
      follow-up. Eleven of the remaining 23 patients had undergone coronary artery
      bypass graft (CABG) surgery > or = 1 year prior to presentation, and 50% of the
      effusions in patients who had undergone CABG surgery were exudates. Thus, CHF
      related exudates were identified in only 12 patients, and in 4 of these patients
      the exudates could be explained by RBC contamination of the pleural fluid. The
      clinical presentation of patients with CHF-associated exudates was similar to
      that of CHF patients with transudates. CONCLUSION: In most patients who have CHF
      and an exudative effusion, there is a noncardiac cause for the pleural effusion.
      The high frequency of exudates in patients with a history of CABG indicates a
      persistent impairment in lymphatic clearance from the pleural cavity. Exudative
      effusions due solely to CHF are rare.

PMID- 12426248
TI  - Is it meaningful to use biochemical parameters to discriminate between
      transudative and exudative pleural effusions?
AB  - OBJECTIVES: The usefulness of biochemical criteria to separate pleural
      transudates from exudates is controversial, and the limitations of Light's
      criteria in patients receiving diuretic therapy is of general concern. We
      evaluated the added value of biochemical criteria to clinical judgment for
      separating transudates from exudates. SETTING: A community teaching hospital.
      DESIGN: A prospective, observational study for the evaluation of diagnostic
      tests. PATIENTS AND MEASUREMENTS: In 249 consecutive patients referred for
      diagnostic thoracentesis, two physicians classified the pleural effusion as
      transudate or exudate based on all available information just before performing
      the thoracentesis. The sensitivity, specificity, and accuracy of the clinical
      presumption were compared with those of Light's criteria, and serum-pleural fluid
      albumin and protein gradients. The combined accuracy of biochemical and clinical
      criteria was also assessed. RESULTS: The accuracy of Light's criteria (93%) was
      significantly higher than that showed by the initial clinical presumption (84%; p
      < 0.01) and that of the alternative biochemical criteria: serum-pleural fluid
      albumin gradient (87%; p < 0.03) and serum-pleural fluid protein gradient (86%; p
      < 0.01). In patients receiving diuretic therapy, the accuracy of Light's criteria
      was 83% (60 of 72 cases), neither different to that of the albumin gradient (88%;
      63 of 72 cases) nor to that of the protein gradient (86%; 62 of 72 cases). When
      these alternative biochemical criteria were applied exclusively to patients
      receiving diuretics who were thought to have a transudative effusion by clinical
      criteria, but having fluid identified as exudative by Light's criteria, the
      results did not improve significantly. Using a multiparametric model for the
      population receiving diuretics, the accuracy was greater (93%; 67 of 72 cases)
      than that of Light's criteria but without reaching statistical significance (p =
      0.12). CONCLUSIONS: Light's criteria are significantly superior to the clinical
      presumption to separate pleural transudates from exudates. In patients receiving
      diuretics, Light's criteria lose accuracy, which is similar to that showed by the
      use of alternative biochemical criteria alone or combined with clinical judgment.

PMID- 12426249
TI  - A novel instrument for the evaluation of the pleural space: an experience in 34
      patients.
AB  - STUDY OBJECTIVES: To test a novel semirigid pleuroscope to be used by
      pulmonologists for the diagnosis and treatment of pleural diseases. DESIGN:
      Prospective study. SETTING: Three tertiary referral centers for pulmonary
      diseases. PATIENTS: Thirty-four patients who were referred for medical
      thoracoscopy between September 2000 and April 2001. MEASUREMENTS AND RESULTS:
      Thirty-six procedures were performed. The most common indications were for
      pleurodesis of a malignant pleural effusion (53%) or for evaluation of an
      exudative effusion of unknown etiology (44%). All operators found the instrument
      easy to use. In all but one case, the images were thought to be adequate, despite
      the presence of adhesions in 12 patients and loculations in 8 patients. Pleural
      biopsies were performed in 13 patients, and talc pleurodesis procedures were
      performed in 25 patients. Mean (+/- SD) duration of chest tube drainage was 2.9
      +/- 1.8 days postprocedure. There were no complications. CONCLUSIONS: The
      prototype semirigid pleuroscope is a useful instrument in the diagnosis and
      management of pleural diseases. It is similar in design to a standard flexible
      bronchoscope, so the skills involved in operating the instrument should already
      be familiar to the practicing pulmonologist. It is compatible with existing video
      processors and light sources, so little additional equipment must be added to the
      endoscopy suite. The semirigid pleuroscope may allow for an increase in the
      performance of medical thoracoscopy by pulmonologists.

PMID- 12426250
TI  - Effect of air filtration systems on asthma: a systematic review of randomized
      trials.
AB  - STUDY OBJECTIVES: To systematically review the evidence of randomized trials
      evaluating the effects of residential air filtration systems on patients with
      asthma. DATA SOURCES: We searched for published and unpublished studies using
      MEDLINE, the Cumulative Index to Nursing and Allied Health Literature, and the
      Cochrane Collaboration. We reviewed all reference lists for additional articles
      of relevance, and contacted experts in the field and air filter manufacturers.
      STUDY SELECTION: We identified 10 relevant randomized controlled trials that
      examined the influence of a residential air filtration system on patients with
      asthma. DATA EXTRACTION: In duplicate and independently, we abstracted data on
      the methodologic quality, population, intervention, and outcomes. DATA SYNTHESIS:
      Five of 10 studies enrolled adults only. One study included children only. The
      sample size ranged from 9 to 45 participants in each study, for a total of 216
      patients across all studies. Two studies reported a statistically significant
      decrease in airway responsiveness associated with air filter utilization. Air
      filters were associated with significantly lower total symptom scores (weighted
      mean difference of 0.47; 95% confidence interval [CI], 0.69 to 0.25) on a 10
      point scale, and lower sleep disturbance score (weighted mean difference of 0.93;
      95% CI, 1.44 to 0.42); however, heterogeneity of results weakens the inferences
      from these trials. Air filtration systems were not associated with any
      differences in medication use or morning peak expiratory flow values. None of
      these trials employed validated scales to measure clinical symptoms or quality of
      life. CONCLUSIONS: Among patients with allergies and asthma, use of air filters
      is associated with fewer symptoms. Rigorous sufficiently powered randomized
      clinical trials are needed to more precisely define the influence of air
      filtration on health-related quality of life and symptom control for asthmatic
      patients.

PMID- 12426251
TI  - Matrix metalloproteinase-9 expression in asthma: effect of asthma severity,
      allergen challenge, and inhaled corticosteroids.
AB  - BACKGROUND: Asthma is associated with remodeling of the extracellular matrix
      (ECM) and increased airway obstruction, and the mechanisms of this process are
      unknown. Matrix metalloproteinases (MMPs) are a group of enzymes capable of
      degrading the ECM. They are released along with their inhibitors, tissue
      inhibitor of MMP (TIMP). STUDY OBJECTIVE: s: To determine whether severe,
      persistent asthma is associated with increased levels of MMP-9 in the airway
      compared with mild asthma, and to assess the effect of both allergen exposure and
      steroid treatment on MMP-9 and TIMP-1 levels. DESIGN: Prospective analysis of
      levels and activity of MMP-9 and TIMP-1 in BAL fluid (BALF) and induced sputum
      obtained from asthmatics of differing disease severity. In patients with mild
      asthma, MMP-9 and TIMP-1 levels were studied in induced sputum following allergen
      challenge and in BALF after inhaled steroid therapy. PATIENTS: Eighteen patients
      with mild asthma, 10 patients with severe asthma, and 10 nonsmoking, atopic
      subjects had their sputum studied. Fourteen of the patients with mild asthma
      underwent allergen challenge. BAL was collected from 16 patients with mild asthma
      before and after 4 weeks treatment with inhaled budesonide, 800 micro g bid, or
      placebo. RESULTS: Patients with severe asthma had increased levels and activity
      of sputum MMP-9 in their sputum compared with patients with mild asthma and
      normal subjects. Allergen challenge increased the MMP-9/TIMP-1 ratio and MMP-9
      activity. Inhaled budesonide had no effect on MMP-9 or TIMP-1 in patients with
      mild asthma. CONCLUSIONS: MMP-9 may play a role in chronic airway inflammation
      and remodeling in asthma, as concentrations are increased in severe, persistent
      asthma and following allergen challenge. Inhaled steroids may not affect MMP-9
      and TIMP in patients with mild asthma, and additional studies in patients with
      more severe asthma are needed.

PMID- 12426252
TI  - Matrix metalloproteinase-9, but not tissue inhibitor of matrix metalloproteinase
      1, increases in the sputum from allergic asthmatic patients after allergen
      challenge.
AB  - OBJECTIVE: The aim of the study was to determine whether allergen inhalation
      modulates the levels of matrix metalloproteinase (MMP)-9 and tissue inhibitor of
      matrix metalloproteinase (TIMP)-1 in the induced sputum recovered from patients
      during a late-phase reaction. METHOD: Eight allergic asthma patients and five
      healthy control subjects inhaled a dose of Dermatophagoides pteronyssinus extract
      corresponding to the provocative concentration of the allergen causing a 20% fall
      in FEV(1) and saline solution. Lung function was carefully monitored for 6 h, and
      an induced sputum test was performed at 6 h after sham challenge or allergen
      challenge. The total and differential cell counts were analyzed, and the levels
      of MMP-9 (by enzyme-linked immunosorbent assay [ELISA] and zymography), TIMP-1
      (by ELISA), and albumin (by rocket immunoelectrophoresis) were measured. RESULTS:
      The sputum eosinophil counts (p < 0.01) and MMP-9 levels (p < 0.05) increased
      significantly in atopic asthma patients after undergoing the allergen challenge
      but did not in the control subjects. By contrast, TIMP-1 and albumin levels were
      not significantly increased in any group. MMP-9 levels, measured after the
      allergen challenge in asthmatic patients, were significantly correlated with
      FEV(1) variations after allergen inhalation (r = 0.51; p < 0.05) and with the
      sputum neutrophil percentage (r = 0.71; p < 0.01). CONCLUSION: The levels of MMP
      9, but not TIMP-1, increase after inhaled allergen challenge in the sputum of
      allergic asthmatic patients. This protease increase may lead to a transient
      imbalance between MMP-9 and TIMP-1 favoring proteolytic extracellular matrix
      degradation.

PMID- 12426253
TI  - Sputum eosinophilia and maximal airway narrowing in Dermatophagoides
      pteronyssinus allergic rhinitis patients: only rhinitis or rhinitis plus mild
      asthma?
AB  - STUDY OBJECTIVE: To study the existence of bronchial disease among rhinitis
      patients. To evaluate the laboratory test or set of tests (ie, symptoms,
      exposure, and sensitization to the allergen, and the provocative dose of
      methacholine [Mth] causing a 20% fall in FEV(1) [PD(20)] and the maximal response
      plateau [MRP] to Mth) that best identifies a case of mild asthma. DESIGN: Cross
      sectional analysis in 52 Dermatophagoides pteronyssinus-monosensitized patients
      who were consulting a physician for perennial rhinitis. SETTING: Allergy
      Department, Hospital Doctor Negrin, Las Palmas, Grand Canary Island, Spain.
      INTERVENTIONS AND MEASUREMENTS: Patients filled out a standardized asthma symptom
      questionnaire, and underwent sputum induction and Mth challenge in which 40%
      falls in FEV(1) were attained. Dose-response curves were expressed in terms of
      both PD(20) values and the level of the MRP. D pteronyssinus allergen exposure
      was assessed in dust samples from patients' beds. RESULTS: No difference between
      patients who positively responded to the questionnaire and those who did not was
      observed. Mth-PD(20) values were not detected in 13% of the patients reporting
      bronchial symptoms, and an MRP was not identified in 59% of the subjects who did
      not respond positively. A higher degree of allergen sensitization (ascertained
      from skin test results, and total and specific serum IgE levels) and higher
      degree of sputum eosinophilia were detected in subjects in whom an MRP had not
      been identified. The presence of sputum eosinophilia provided the best
      differentiation between those patients who presented with an MRP and those who
      did not. CONCLUSION: The individual perception of bronchial symptoms is highly
      variable among perennial allergic rhinitis patients. The lack of a maximal airway
      narrowing plateau is related to the presence of sputum eosinophilia, which might
      be useful in the detection of patients susceptible to anti-inflammatory therapy.
      Prospective studies evaluating whether these patients are more likely to develop
      symptomatic asthma in the future and if the early anti-inflammatory treatment
      prevents its development are needed.

PMID- 12426254
TI  - Correlation between cysteinyl leukotriene release from leukocytes and clinical
      response to a leukotriene inhibitor.
AB  - STUDY OBJECTIVES: Antileukotriene drugs are widely used in patients with
      bronchial asthma, but not all patients show significant clinical improvements,
      and no factors have been identified that are correlated with the clinical
      response to these drugs. This study was designed to examine the factors
      correlated with a response to a leukotriene receptor antagonist, pranlukast, in
      patients with asthma. DESIGN: WBC counts, IgE, and ex vivo leukotriene release
      from leukocytes were measured, and 31 patients with asthma were treated with
      pranlukast, a leukotriene receptor antagonist, for 4 weeks. MEASUREMENTS: Outcome
      measurements included twice-daily peak expiratory flow rate (PEFR), daytime and
      nocturnal symptoms, and frequency of beta(2)-agonist use. Subjects with a
      reduction of > 20% in symptom scores or beta(2)-agonist use, or an improvement of
      PEFR of > 10% were designated as responders; others were designated as
      nonresponders. Logistic regression analysis assessed the efficacy of models using
      various allergic markers correlated with the response to pranlukast. RESULTS:
      There were 16 responders and 15 nonresponders. The release of cysteinyl
      leukotrienes from the leukocytes of the responders was higher than that of the
      nonresponders (p < 0.05). There was a significant correlation between the
      clinical response and the release of cysteinyl leukotrienes, but not demographic
      features, WBC counts, percentage of eosinophils, or serum IgE levels (p < 0.05).
      Subjects with a release of cysteinyl leukotrienes of > 3,500 pg/mL were 11.0
      times more likely to respond to pranlukast than those with < 3,500 pg/mL (95%
      confidence interval, 2.0 to 60.5). CONCLUSION: Cysteinyl leukotriene release from
      leukocytes is correlated with leukotriene receptor antagonist response.

PMID- 12426255
TI  - Childhood asthma in an urban community: prevalence, care system, and treatment.
AB  - OBJECTIVES: We describe the system of asthma care in Hartford, CT, an urban,
      minority community. METHODS: The health field concept was used to organize
      factors influencing asthma prevalence and severity. Data were obtained from
      national, state, and municipal reports, and from surveys of children in Hartford
      seeking medical care in an asthma program called Easy Breathing. RESULTS: Between
      June 1, 1998, and May 1, 2000, 21% of children receiving Medicaid in Hartford did
      not file a medical claim. Between 1998 and 2000, the number of providers in
      Hartford decreased by 37% while the number of outpatient visits increased by 8%.
      Using claims data, we found the following: 19.0% of Hartford children had asthma
      (data from the International Classification of Disease, ninth revision, and the
      National Drug Code); and 12% of children with asthma filled a prescription for
      inhaled corticosteroid therapy, 83% for a bronchodilator, and 36% for an oral
      corticosteroid. Children with asthma were more likely to be hospitalized (10% vs
      5%, respectively) and to visit an emergency department (45% vs 29%,
      respectively), and, on average, they had more hospital days (0.603 vs 0.415 days
      per child, respectively) and more outpatient visits per year (4.7 vs 2.5 visits,
      respectively) compared to children without asthma. Asthma prevalence in the 6,643
      children surveyed in the Easy Breathing program was 41%. Persistent asthma was
      diagnosed in 50% of the children with asthma. Asthma prevalence varied by ethnic
      origin, age, and gender, and was highest in Hispanic/Puerto Rican children, in
      children 5 to 10 years of age, in boys up to 10 years of age, and in girls after
      15 years of age. CONCLUSION: Improved personal behaviors and medical care will
      have a limited sustained impact on childhood asthma until basic environmental
      issues are modified. The health field concept provides a mechanism with which to
      address the issues surrounding asthma in urban communities.

PMID- 12426256
TI  - Asthma in the elderly: cockroach sensitization and severity of airway obstruction
      in elderly nonsmokers.
AB  - STUDY OBJECTIVES: To test the hypothesis that the presence of sensitization to
      indoor allergens is associated with increased severity of airway obstruction in
      elderly subjects with asthma. DESIGN: Cohort study of subjects enrolled in a
      public hospital asthma clinic. SETTING: Asthma clinic in a municipal public
      hospital serving an indigent population in New York City. PATIENTS: Subjects aged
      > or = 60 years with asthma who were enrolled in the Bellevue Hospital Asthma
      Clinic. Total serum IgE and allergen-specific IgE measurements were performed in
      a cohort of elderly never-smokers who had asthma (45 patients) who had undergone
      spirometry before and after bronchodilator (BD) therapy. MEASUREMENTS AND
      RESULTS: The results of radioallergosorbent tests demonstrated that most subjects
      (ie, 60%) were sensitized to at least one allergen, with many sensitized to at
      least one indoor allergen. Cockroach (CR) was the most common allergen to which
      subjects were sensitized, with 47% displaying an elevated serum-specific IgE
      level. Fewer subjects were sensitized to dust mite, cat, dog, or ragweed.
      Subjects sensitized to CR (CR+) had greater reductions in airflow compared to
      subjects not sensitized to CR (CR-) [64 +/- 4.4% predicted vs 77.1 +/- 4.1%
      predicted FEV(1), respectively; p < 0.05]. Following BD administration, only 29%
      of CR+ subjects achieved a normal post-BD FEV(1) compared to 58% of CR- subjects.
      Lung volume measurements differed between CR+ and CR- subjects, with a greater
      elevation of functional residual capacity in CR+ subjects. CONCLUSION: In a
      population of elderly urban patients with asthma, the presence of CR-specific
      serum IgE is associated with more severe asthma, as reflected by an increase in
      airway obstruction and hyperinflation.

PMID- 12426257
TI  - Comparison of individuals with and without specific IgA antibodies to Chlamydia
      pneumoniae: respiratory morbidity and the metabolic syndrome.
AB  - STUDY OBJECTIVES: To determine whether a correlation exists between markers for
      persistent Chlamydia pneumoniae infection, respiratory morbidity, and the
      metabolic syndrome. DESIGN: Case-control study. A group of individuals with
      serologic markers (specific IgA > or = 1/128) suggestive of persistent C
      pneumoniae infection were compared with a group of control subjects without IgA
      antibodies (< 1/32). SETTING: Apoteksgardens Health Care Center, Kopparberg,
      Sweden. PARTICIPANTS: One hundred case subjects (61 men and 39 women) and 100
      control subjects matched for age and gender (mean age, 55 years). MEASUREMENTS
      AND RESULTS: Individuals completed a questionnaire on respiratory symptoms and
      smoking habits. Body mass index (BMI) was calculated, BP, and peak expiratory
      flow (PEF) were determined. Blood specimens were drawn for determination of high
      sensitivity C-reactive protein (hsCRP), blood glucose level, serum lipids, and
      Chlamydia antibodies. No significant difference was found between case subjects
      and control subjects regarding myocardial infarctions, stroke, diabetes type II,
      BP, BMI, hsCRP, blood glucose levels, and serum lipids. Symptoms of both asthma
      and chronic bronchitis were more common in case subjects, as were symptoms of
      chronic upper respiratory tract infections (p < 0.005). Case subjects with asthma
      or chronic bronchitis had more chronic upper respiratory tract disorders (p <
      0.05). Symptoms of chronic respiratory tract diseases increased parallel to
      increasing specific C pneumoniae IgA antibody titers (p < 0.0005). PEF percentage
      of the predictive value was inversely correlated (p < 0.0005) to IgA antibody
      titers. CONCLUSION: The data show that persistent increased levels of C
      pneumoniae IgA antibodies were associated with pronounced respiratory
      dysfunction. These data provide additional evidence suggesting that IgA
      antibodies may be a marker for persistent C pneumoniae infection.

PMID- 12426258
TI  - Pulmonary interstitial disease in Ig deficiency.
AB  - STUDY OBJECTIVES: To determine the frequency and type of interstitial lung
      disease (ILD) in consecutive subjects with symptomatic Ig deficiency. PATIENTS:
      One hundred forty-eight consecutive subjects with repeated respiratory infections
      and Ig deficiency. MEASUREMENTS: Ig classes and IgG subclasses (IgGSCs), the
      response to vaccination, pulmonary function tests, chest radiography, CT scan, Ga
      scan and, when possible, BAL and lung biopsy. RESULTS: Twenty-nine of 148
      subjects (19 men and 10 women aged 18 to 72 years) had evidence of ILD. In 20
      subjects, no cause of ILD was apparent. The remaining nine cases were ostensibly
      due to identifiable causes. Twenty subjects had IgGSC deficiency, 8 subjects had
      common variable immunodeficiency, and 1 subject had combined IgM plus IgGSC
      deficiency. No isotype deficiency was consistently related to a specific ILD.
      After administration of IV Ig, eight subjects, all with IgGSC deficiency,
      improved clinically, physiologically, radiologically, and occasionally
      histologically, regardless of immunologic or radiologic features. In this
      selective sample, the prevalence of ILD in consecutive subjects with recurrent
      respiratory infections and Ig deficiency (29 of 148 subjects; 19.6%) was higher
      than in the general population (0.8%; p < 0.05). CONCLUSIONS: ILD in Ig
      deficiency is frequent and usually involves IgGSC deficiency.

PMID- 12426259
TI  - Should bronchoscopy be performed in the evaluation of suspected pediatric
      pulmonary tuberculosis?
AB  - BACKGROUND: Pulmonary tuberculosis (PTB) infection in children is difficult to
      diagnose. OBJECTIVE: To evaluate the effectiveness of fiberoptic bronchoscopy in
      the diagnosis of PTB. METHODS: Four hundred twenty-two children underwent
      bronchoscopic evaluation. The study population was composed of 80 children (study
      group) who were suspected of having PTB and 342 children with chronic cough or
      recurrent/persistent pneumonia (control group). Videotape reviews of each
      bronchoscopy were correlated with the results of smears and cultures. RESULTS:
      The majority of children in the study group (54 of 80 children) were new
      immigrants from Ethiopia, while most of the control group (323 of 342 children)
      were born in Israel. Among patients in the control group, physical anomalies such
      as laryngotracheomalacia were more common among children in the control group
      (105 of 342 children) compared with those in the study group (5 of 80 children; p
      < 0.03). In the study group, external compression of the right main bronchus,
      usually at the entrance, was more common (32 of 80 children) compared with the
      control group (6 of 342 children; p < 0.001). Cultures from BAL fluid revealed
      Mycobacterium tuberculosis in 3 of the 80 children from the study group compared
      with 2 children from the control group (p < 0.08). The children with positive
      cultures from the control group had external compression of the right main
      bronchus that had been documented by bronchoscopy. CONCLUSION: Bronchoscopy in
      children with suspected PTB has a low yield and does not significantly aid
      bacteriologic confirmation. External compression at the entrance to the right
      main bronchus is suggestive of PTB infection.

PMID- 12426260
TI  - Factors associated with the treatment of latent tuberculosis infection among
      health-care workers at a midwestern teaching hospital.
AB  - STUDY OBJECTIVE: To assess factors associated with initiating therapy and
      compliance with treatment for latent tuberculosis infection among health-care
      workers with positive tuberculin skin test results. DESIGN: Prospective cohort
      study. SETTING: An urban midwestern teaching hospital in St. Louis, MO. STUDY
      POPULATION: Health-care workers with positive tuberculin skin test results.
      MEASUREMENTS: (1) Rates of initiating therapy for latent tuberculosis infection
      among all health-care workers with positive tuberculin skin test results, and (2)
      compliance rates with therapy for latent tuberculosis infection among health-care
      workers with recent tuberculin skin test conversion. RESULTS: A total of 440
      tuberculin skin test-positive health-care workers were evaluated from January 1,
      1994, to May 1, 2000. Of those evaluated, 1 health-care worker had presumed
      active tuberculosis, 1 had no record of being evaluated, 1 had missing records,
      and 33 were not recommended isoniazid therapy, leaving 404 workers for analysis.
      Overall, 396 of 404 health-care workers (98%) with positive tuberculin skin test
      results initiated isoniazid therapy. In univariate analysis, bacille Calmette
      Guerin (BCG) vaccination (p = 0.02) and foreign birth (p = 0.03) were
      significantly associated with not initiating isoniazid therapy. Compliance data
      were available for 388 of 404 health-care workers (96%). Of these, 318 of 388
      health-care workers (82%) were compliant with 6 months of therapy. BCG
      vaccination (odds ratio [OR], 3.5; 95% confidence interval [CI], 1.8 to 7.1) and
      symptoms while receiving therapy (OR, 4.5; 95% CI, 2.0 to 10.1) were
      significantly associated with noncompliance in multivariate analysis. Among new
      converters, Asian race (p = 0.006), foreign birth (p = 0.01), BCG vaccination (p
      = 0.006), and symptoms while receiving therapy (p < 0.001) were significantly
      associated with noncompliance in univariate analysis. CONCLUSION: This hospital
      had a high rate of initiating isoniazid therapy for tuberculosis infection among
      their health-care workers, and a high rate of compliance with therapy. These
      rates of initiation and completion of isoniazid therapy were much higher than
      those previously reported in the literature. This may be largely due to a focused
      program, which includes active follow-up of health-care workers with positive
      tuberculin skin test results, consisting of physician counseling and monthly
      phone consultations by nurses, along with free services and medications provided
      on-site.

PMID- 12426261
TI  - Cellular composition of stent-penetrating tissue.
AB  - BACKGROUND: A surprisingly low number (< 20%) of relevant (> 75%) restenoses
      occur in exophytic lesions after treatment with uncovered metal stents. The goal
      of this study was to investigate whether radial stent forces can exert localized
      influence on tumor growth. PATIENTS AND METHODS: In 17 patients, intraluminal
      tumor tissue was histologically investigated before and 1 week after stent
      implantation. The amount of intact tumor cells (ITCs) was compared to necrotic
      and nontumor cells. The result in patency was proved by fiberoptic bronchoscopy.
      RESULTS: Initially, stenoses in all patients were > 75%. Before stent
      implantation, biopsy samples in seven patients showed > 67% ITCs, and five
      patients had 34 to 67% ITCs. Five patients had 1 to 33% ITCs, and no patients had
      0% ITCs. One week after stent implantation, the cellular aspect of the biopsy
      samples had changed significantly (p < 0.03): two patients had > 67% ITCs, one
      patient had 34 to 67% ITCs, and seven patients had 1 to 33% ITCs. Seven patients
      had no ITCs at all. Endoscopically, patency increased significantly (prestent, 10
      +/- 14.1%; poststent, 90.6 +/- 14.3% [mean +/- SD]; p < 0.0001). CONCLUSION:
      Pressure exerted by the stent on adjacent tumor tissue may cause a profound
      reduction in the amount of ITCs, most probably caused by radial and shear stress
      forces that compromise blood supply and nutrients of the tumor stroma.

PMID- 12426262
TI  - Structural changes of the airway wall impair respiratory function, even in mild
      asthma.
AB  - STUDY OBJECTIVES: To clarify whether structural changes of the airway wall impair
      respiratory function in patients with mild asthma, and to determine whether mild
      asthma should be treated with inhaled steroids. SETTING: Showa University
      Hospital in Tokyo. PATIENTS: Thirteen healthy nonatopic volunteers (control
      subjects), 26 patients with mild asthma treated with a bronchodilator alone
      without oral or inhaled corticosteroids or antiallergic agents, and 10 patients
      with mild-to-moderate asthma treated with inhaled corticosteroids. MEASUREMENTS:
      We measured the thickness of the epithelial reticular basement membrane (Rbm) of
      the airway wall in bronchial biopsy specimens from patients with asthma and from
      healthy control subjects. We also performed spirometry and histamine challenge
      tests to evaluate airflow obstruction and airway hyperresponsiveness. RESULTS:
      The thickness of the Rbm in patients with mild asthma was significantly greater
      than that in healthy control subjects and was negatively correlated with the
      FEV(1) as a percentage of FVC and the provocative concentration of histamine that
      caused a 20% decrease in FEV(1) from the post-saline solution baseline value.
      Moreover, the Rbm was thicker in patients with mild asthma not treated with
      inhaled steroids than in patients with mild-to-moderate asthma treated with
      inhaled steroids. CONCLUSIONS: The thickness of the Rbm is increased even in mild
      asthma and is correlated with airway obstruction and hyperresponsiveness. Our
      results suggests that anti-inflammatory treatment with inhaled steroids should be
      started in the early stage of bronchial asthma to prevent structural changes from
      occurring in the airway wall.

PMID- 12426263
TI  - Prediction of emergency department visits for respiratory symptoms using an
      artificial neural network.
AB  - STUDY OBJECTIVES: Accurate prediction of the effect of atmospheric changes,
      including pollutants, on emergency department (ED) visits for respiratory
      symptoms would be useful, but has proven difficult. The main difficulty is the
      limitation of the classical linear models and logistic regression with multiple
      variables to handle the multifactorial effect. DESIGN AND SETTING: To predict ED
      visits, we have created a computer-based model called an artificial neural
      network (ANN) using a back-propagation training algorithm and genetic algorithm
      optimization. This ANN was fed meteorologic and air pollution input variables and
      trained to predict the number of patients admitted to the ED with respiratory
      symptoms of asthma, COPD, and acute and chronic bronchitis on the corresponding
      day. One thousand twenty data sets were extracted from an ED admittance database
      at the Barzilai Medical Center (Ashkelon, Israel), and randomized to a network
      training set (n = 816) and a test set (n = 204). RESULTS: The neural network
      performed best when the predictor variables used were temperature, relative
      humidity, barometric pressure, SO(2), and oxidation products of nitric oxide, and
      the data presented as peak value 24 h prior to ED admission and the average
      during the 7 days before the ED visit. The neural network was able to predict the
      test set with an average error of 12%. CONCLUSION: Based on meteorologic and
      pollution data, the use of an ANN can assist in the prediction of ED visits
      related to respiratory conditions.

PMID- 12426264
TI  - Anxiety and depression are related to the outcome of emergency treatment in
      patients with obstructive pulmonary disease.
AB  - STUDY OBJECTIVES: To investigate whether psychological factors predict outcome
      after emergency treatment for obstructive pulmonary disease. SETTING: Emergency
      department at a university hospital. PATIENTS: Forty-three patients presenting
      with exacerbation of asthma or COPD. INTERVENTION: The patients received
      emergency treatment and were followed up for 4 weeks. MEASUREMENT: Spirometry,
      blood sampling, pulse oximetry, breathing rate, pulse rate, and dyspnea score was
      measured before and during emergency treatment. The psychological status was
      assessed using the hospital anxiety and depression (HAD) scale questionnaire at
      the end of the follow-up period. RESULTS: Anxiety and/or depression was found in
      17 patients (40%). Of these patients, nine patients (53%) were admitted to
      hospital or had a relapse within 1 month, compared with five patients (19%) in
      the group without anxiety and/or depression (p < 0.05). Among patients who
      relapsed within 1 month (n = 14), the HAD total score was 12.4 +/- 5.9 compared
      with 8.6 +/- 5.1 (mean +/- SD) among the patients without a relapse (p < 0.05).
      After making adjustments for age, gender, atopic status, treatment, and pack
      years, the significant association between treatment failure and anxiety and/or
      depression still remained. CONCLUSION: Our study indicates that anxiety and
      depression are related to the outcome of emergency treatment in patients with
      obstructive pulmonary disease. Further studies should be conducted evaluating the
      effect of treatment of anxiety and depression in patients with recurrent
      exacerbations of asthma and COPD.

PMID- 12426265
TI  - MRI of acute myocarditis: a comprehensive approach based on various imaging
      sequences.
AB  - STUDY OBJECTIVES: To explore the diagnostic performance of MRI for the diagnosis
      of acute myocarditis, using a comprehensive imaging approach. DESIGN AND
      SETTINGS: Twenty patients with myocarditis and 7 age-matched and gender-matched
      control subjects underwent comprehensive MRI. Magnetic resonance (MR)
      examinations included axial T2-weighted sequences, precontrast and postcontrast
      ECG-gated T1-weighted sequences in axial and short heart axis, cine-MRI, and
      serial dynamic turbo fast low-angle shot (turboFLASH) acquisitions in the short
      axis following Gd injection for a period of 2 min. Precontrast and postcontrast
      images were postprocessed using subtraction. Two observers read all images
      qualitatively and quantitatively. Myocardial enhancement was compared between
      patients and control subjects. PATIENTS: Myocardial involvement was focal in 6
      patients examined within 1 week from clinical onset, and diffuse in the remaining
      14 patients examined later. RESULTS: Qualitatively, contrast-enhanced T1-weighted
      subtracted images had 100% sensitivity and specificity for myocardial
      involvement. Postcontrast T1-weighted images were able to discriminate the early
      phase (nodular enhancement) from the later phase of myocarditis (diffuse
      enhancement). Quantitatively, myocardial enhancement was 56% +/- 3.2% in
      patients, vs 29% +/- 3.1% in control subjects using T1-weighted MRI (p < 0.0001).
      Serial turboFLASH images displayed greater myocardial enhancement between 25 s
      and 120 s in patients than in control subjects (p < 0.0001); however, there was
      marked enhancement of skeletal muscles in both early and late stages of
      myocarditis compared to control subjects (p < 0.0001). CONCLUSION: On the basis
      of subtracted cardiac-gated T1-weighted images and serial postinjection
      turboFLASH images, our study shows that myocarditis is largely, at least in the
      early stages, a focal process in the myocardium. It also provides evidence of
      transient skeletal muscle involvement, which may actually be useful for
      diagnosis.

PMID- 12426266
TI  - Cardiac Munchausen syndrome.
AB  - OBJECTIVE: To examine the reports on cardiac Munchausen syndrome for clinical
      characteristics. METHODS: Cases, case series, and related articles on the subject
      in all languages were identified through a comprehensive literature search.
      RESULTS: Fifty-eight cases of cardiac Munchausen syndrome were identified. Mean
      +/- SD patient age was 44 +/- 12 years (range, 23 to 71 years). Fifty-four
      patients (93%) were men. The most common presenting complaint was chest pain
      simulating acute coronary syndrome (86%). Syncope and dyspnea were also reported.
      Mostly, these patients were admitted directly from the emergency department to
      the coronary care unit. Acute myocardial infarction was the most common admitting
      diagnosis. The other admitting diagnoses were cardiac arrest and arrhythmia. The
      average number of hospital admissions for cardiac symptoms was 6 per patient
      (range, 1 to > 29 admissions). Numerous procedures including cardiac
      catheterization, coronary angiography, peripheral arteriography, permanent
      pacemaker placement, electrophysiological studies, intra-aortic balloon
      insertion, pulmonary artery catheter insertion, and electrical cardioversion have
      been performed in these patients. Twenty-four patients (41%) had history of
      undergoing prior multiple invasive procedures, but only 10 of these patients
      admitted having undergone these procedures. Ninety-five percent of patients
      altered their stories, with many leaving the hospital against medical advice when
      confronted with possibility of cardiac Munchausen syndrome as the correct
      unifying diagnosis. None of the patients reported for follow-up. CONCLUSION:
      Cardiac Munchausen syndrome results in unnecessary investigations and organ
      damage from unneeded aggressive procedures. There is scarce information available
      on the prognosis of these patients, especially in the long term.

PMID- 12426267
TI  - Oximeter performance: the influence of acquisition parameters.
AB  - STUDY OBJECTIVE: This study was designed to determine whether different
      desaturation indexes (DIs) would be obtained in patients with sleep-disordered
      breathing by systematically altering two acquisition parameters: the recording
      setting and the display mode. DESIGN: Prospective clinical study. SETTING:
      Community sleep-disorders center. PATIENTS: The study included 75 patients who
      were suspected of having sleep-disordered breathing. INTERVENTIONS: Each patient
      had simultaneous pulse oxyhemoglobin saturation (SpO2) traces at three recording
      settings (3 s, 6 s, and 12 s) during the diagnostic phase of split-night
      polysomnography. On-line and memory displays of those data at each recording
      setting were obtained. DIs for > or = 3% desaturation events per hour were
      calculated for each of the six traces. RESULTS: The mean on-line DIs
      significantly differed from each other, with slower (longer) recording settings
      resulting in lower values than faster (shorter) settings. The memory DIs all
      significantly underestimated the on-line DIs. Pearson correlations ranged from
      0.82 to 0.90 between the on-line/memory DI pairs, but Bland-Altman analysis
      detected disagreement at higher levels of disordered breathing. CONCLUSIONS:
      These findings confirm that significantly different SpO2 data are obtained at
      various acquisition options. The recording setting and display mode parameters
      should be disclosed in all reports employing oximetry with the fastest recording
      setting and on-line display mode preferable for case finding of sleep-disordered
      breathing.

PMID- 12426268
TI  - Implementation of an oxygen therapy clinic to manage users of long-term oxygen
      therapy.
AB  - STUDY OBJECTIVES: To evaluate the initial benefits of establishing an oxygen
      therapy clinic (OTC) to manage users of long-term oxygen therapy (LTOT). DESIGN:
      Cross-sectional observational study. SETTING: Military-affiliated, tertiary care
      hospital. PATIENTS OR PARTICIPANTS: Current users of LTOT at our institution and
      patients with new oxygen prescriptions between June 2000 and May 2001.
      INTERVENTION: The OTC evaluation consisted of a focused medical interview and
      physical examination by a respiratory therapist. Demographic data, indications
      for supplemental oxygen, oxygen-related diagnoses, cardiopulmonary review of
      systems, pertinent physical examination findings, pulmonary function testing, and
      oximetry data were recorded. Patients prescribed oxygen during hospitalization
      were followed up for recertification within 90 days based on the recommendations
      of the Fifth Oxygen Consensus Conference. Also, patients with existing oxygen
      prescriptions and new oxygen prescriptions during the study period were evaluated
      in the OTC. Data are provided for the initial evaluation in this clinic.
      MEASUREMENTS AND RESULTS: A total of 283 patients were evaluated in the OTC
      during the study period. Ninety-seven patients with a new oxygen prescription
      during hospitalization were evaluated, with a mean +/- SE time from discharge to
      evaluation of 2.6 +/- 0.4 months. At follow-up, 50.5% of these patients no longer
      met Medicare guidelines for LTOT. A significant change in oxygen prescription was
      required in 27.9% of these patients. A total of 95 outpatients with existing
      oxygen prescriptions were contacted for recertification in the OTC. Of these
      patients, 31.6% no longer met Medicare criteria for LTOT and 26% required a
      significant change to their oxygen prescription. Oxygen therapy was discontinued
      in 22% of the 91 patients who were referred from other outpatient clinics, and
      the oxygen prescription was changed in another 29.7%. CONCLUSIONS: Results of
      this initial evaluation suggest that the institution of a respiratory therapist
      managed OTC to manage home oxygen patients can significantly decrease
      inappropriate supplemental oxygen use, which can result in significant cost
      savings while providing improved health-care delivery. Further evaluation is
      necessary to identify the long-term benefits and cost savings in this population.

PMID- 12426269
TI  - High prevalence of autoimmune thyroid disease in pulmonary arterial hypertension.
AB  - STUDY OBJECTIVES: An association between thyroid disease and pulmonary arterial
      hypertension (PAH) has been reported, yet the pathogenetic relationship between
      these conditions remains unclear. Because immune system dysfunction may underlie
      this association, we sought to determine the prevalence of autoimmune thyroid
      disease (AITD) in patients with PAH. DESIGN AND SETTING: Prospective
      observational study at a single academic institution. PATIENTS: Sixty-three
      consecutive adults with PAH (ie, sustained pulmonary artery systolic pressure, >
      25 mm Hg) were evaluated for clinical, biochemical, and serologic features of
      AITD. MEASUREMENTS: Thyroid gland dysfunction was determined by clinical
      examination for goiter, and by biochemical measurements of thyrotropin and free
      thyroxine. Immune system dysfunction was determined by serologic measurements of
      antibodies to thyroglobulin and thyroid peroxidase. First-degree family history
      of AITD also was ascertained in order to investigate for genetic clustering of
      autoimmunity. RESULTS: Thirty-one patients (49%; 95% confidence interval [CI], 37
      to 62%) received diagnoses of AITD. Eighteen patients were newly diagnosed, and 9
      patients required the initiation of pharmacologic treatment. There was no
      chronologic relationship between the diagnosis or treatment of PAH and that of
      AITD. Sixteen patients (25%; 95% CI, 15 to 36%) had 24 first-degree family
      members with AITD. CONCLUSIONS: Approximately half of the patients with PAH have
      concomitant AITD. These two conditions may be linked by a common immunogenetic
      susceptibility, and the elucidation of this association may advance the
      understanding of the pathophysiology and treatment of PAH. Systematic
      surveillance for occult thyroid dysfunction in patients with PAH may prevent the
      hemodynamic exacerbation of right heart failure.

PMID- 12426270
TI  - Significance of a plasma D-dimer test in patients with primary pulmonary
      hypertension.
AB  - BACKGROUND: D-dimer, a degradation product of fibrin, has been increasingly used
      as a marker or prognostic factor in various thrombotic diseases. OBJECTIVE: To
      assess the significance of a d-dimer test in patients with primary pulmonary
      hypertension (PPH). PATIENTS AND METHODS: Fourteen patients with PPH (12 women
      and 2 men) aged 25 to 68 years (mean +/- SD age, 50 +/- 14 years) entered the
      study. Plasma d-dimer was determined by Miniquant assay (Biopool International;
      Venture, CA) 3 +/- 5 months after the disease onset, and patients were followed
      up for 1 year. We compared the d-dimer levels to the demographic, clinical, and
      hemodynamic data of the patients. RESULTS: D-dimer levels were positively
      correlated with New York Heart Association classification (r = 0.59, p = 0.01)
      and pulmonary artery pressure (r = 0.43, p = 0.03) and were negatively correlated
      with oxygen saturation (r = - 0.45, p = 0.03) and 6-min walk distance (r = -
      0.49, p = 0.04). One-year survival was also negatively correlated with d-dimer
      (point-biserial r = - 0.71, p = 0.004), with a higher d-dimer value associated
      with poorer survival. No significant correlations were found between d-dimer
      values and sex, age, diffusing capacity of the lung for carbon monoxide, or
      cardiac index. CONCLUSION: D-dimer levels may have a role in the evaluation of
      patients with PPH. This simple, noninvasive test may be helpful for identifying
      patients who are at a higher risk for severe disease.

PMID- 12426271
TI  - Can continuous positive airway pressure therapy improve the general health status
      of patients with obstructive sleep apnea?: a clinical effectiveness study.
AB  - STUDY OBJECTIVES: To determine the short-term and long-term impacts of continuous
      positive airway pressure (CPAP) therapy on health-related quality of life (HRQL)
      in patients with obstructive sleep apnea (OSA). DESIGN: Prospective longitudinal
      cohort study. SETTING: University sleep disorders center. PATIENTS: Three hundred
      sixty-five patients with an apnea-hypopnea index (AHI) > or = 20 per hour of
      sleep and 358 patients with an AHI of < 20. INTERVENTIONS: All patients with AHIs
      > or = 20 received CPAP therapy; those with AHIs < 20 did not. The HRQL of all
      study participants was measured using the 36-item medical outcomes study short
      form (SF-36) questionnaire at baseline and then at 3 and 12 months of follow-up.
      RESULTS: Although the SF-36 scores were similar at baseline, after 3 months of
      therapy, the CPAP group had higher adjusted emotional summary scores than did
      those who did not receive CPAP therapy (score increase, 1.72; 95% confidence
      interval [CI], 0.08 to 3.37). These improvements were maintained for 12 months.
      The gains in the SF-36 scores were most striking in the vitality domain (score
      increase, 10.52; 95% CI, 7.04 to 14.00 U increment). The severe OSA group (ie,
      AHIs > or = 40) experienced the largest benefit. Their adjusted vitality scores
      were 12.3 U higher (95% CI, 8.0 to 16.6) than those persons without OSA (ie, AHIs
      < 5). CONCLUSIONS: CPAP therapy was associated with marked short-term and long
      term improvements in the vitality of patients with moderate-to-severe OSA in the
      community. These findings suggest that CPAP therapy is effective in improving the
      long-term HRQL of patients with OSA.

PMID- 12426272
TI  - Tissue hypoxia in sleep apnea syndrome assessed by uric acid and adenosine.
AB  - STUDY OBJECTIVE: Although the overnight increase in urinary uric acid/creatinine
      ratio (DeltaUA/Cr) is considered by some to be a marker of tissue hypoxia in
      patients with obstructive sleep apnea-hypopnea syndrome (OSAS), this index is not
      universally accepted. The purpose of this study was to confirm the validity of
      DeltaUA/Cr as a marker of tissue hypoxia by measuring the plasma level of
      adenosine during sleep, and also to test the hypothesis that the heart rate (HR)
      response to apnea is a determinant of tissue hypoxia. DESIGN: Intergroup
      comparative study. SETTING: A university hospital, Sapporo, Japan. PATIENTS:
      Eighteen patients with OSAS who had apnea-associated, moderate-to-severe arterial
      desaturation. The patients were classified into two groups: the DeltaUA/Cr
      positive group, who were considered to have tissue hypoxia, and the DeltaUA/Cr
      normal group, who were not. MEASUREMENTS AND RESULTS: Although there were no
      significant differences between two groups of the patients in either arterial
      desaturation parameters or the apnea-hypopnea index, the plasma level of
      adenosine during sleep was significantly higher in the DeltaUA/Cr-positive group
      than in the DeltaUA/Cr-normal group. Successful treatment with nasal continuous
      positive airway pressure significantly decreased both DeltaUA/Cr and the plasma
      level of adenosine only in the DeltaUA/Cr-positive group. The magnitude of the HR
      increase after the termination of apnea was significantly smaller in the
      DeltaUA/Cr-positive group. CONCLUSIONS: DeltaUA/Cr is a marker of tissue hypoxia,
      which does not necessarily parallel arterial desaturation indexes in OSAS.
      Intersubject variability in the HR response to apnea may explain the discrepancy
      between tissue hypoxia and arterial desaturation indexes.

PMID- 12426273
TI  - Quality-of-life evaluation of patients with neuromuscular and skeletal diseases
      treated with noninvasive and invasive home mechanical ventilation.
AB  - BACKGROUND: Home mechanical ventilation (HMV) is known to be a successful therapy
      for chronic respiratory insufficiency, with regard to long-term survival.
      However, the quality of life (QoL) of patients receiving HMV has not previously
      been systematically investigated. The purpose of this study was to assess the QoL
      of patients with neuromuscular disorders and skeletal deformities (ie,
      restrictive lung disease) receiving HMV. METHODS: Patients receiving HMV treated
      by tracheostomy or noninvasive ventilation (NIV). Three different, standardized,
      and validated questionnaires were used: the Sickness Impact Profile (SIP), the
      Health Index (HI), and the Sense of Coherence (SOC) scale. Underlying diseases
      were postpolio dysfunction (37%), neuromuscular disorder (20%), scoliosis (15%),
      and other diseases (28%). RESULTS: The group treated with tracheostomy had higher
      HI scores than the group treated with NIV. For the three main diagnosis groups
      treated with tracheostomy or NIV, the patients with postpolio dysfunction treated
      with tracheostomy had lower SIP scores than the patients with postpolio
      dysfunction treated with NIV. This was in contrast to the patients with
      neuromuscular disorders treated with tracheostomy, who had higher scores in the
      SIP, compared with patients with postpolio dysfunction treated with tracheostomy
      and patients with neuromuscular disorders treated with NIV. A SIP score > 10%
      indicates a functional disability of clinical importance, and a high score on the
      HI and SOC scale indicates good perceived health. For the three main diagnosis
      groups treated with NIV, the patients with scoliosis had no dysfunction of
      clinical importance (4.6 +/- 3.7) on the SIP score compared with patients with
      postpolio dysfunction (15.5 +/- 7.6) and patients with neuromuscular disorders
      (13.2 +/- 5.2) [mean +/- SD]. The men showed more dysfunction in the SIP score
      than the women. CONCLUSION: Patients receiving HMV reported a good perceived
      health, despite severe physical limitations. The patients with postpolio
      dysfunction and the patients with scoliosis treated with tracheostomy perceived
      the best health, compared with NIV for this diagnosis.

PMID- 12426274
TI  - A randomized controlled trial to evaluate the effect of informing patients about
      their pretreatment responses to two respiratory questionnaires.
AB  - STUDY OBJECTIVES: Previous studies with short recall periods have suggested that
      informed administration (previous responses available) may improve the
      responsiveness and validity of health-related quality-of-life (HRQL)
      questionnaires in comparison to blind administration (previous responses
      unavailable). Informed administration may, however, have less impact in studies
      with longer recall periods. The objective of this randomized trial was to compare
      the validity and responsiveness of the blind and informed Chronic Respiratory
      Questionnaire (CRQ) and the St. George's Respiratory Questionnaire (SGRQ) with a
      3-month interval between questionnaire completion. STUDY DESIGN: We randomized 85
      patients to blind or informed administration of the CRQ and SGRQ before and after
      they underwent a standard respiratory rehabilitation program. Patients also
      completed other HRQL instruments. RESULTS: At the follow-up administration, we
      observed important and statistically significant improvement in all four CRQ
      domains and three SGRQ domains. The results of blind and informed administration
      differed little. This was true for both the CRQ and the SGRQ, and for both
      responsiveness and validity. CONCLUSIONS: In contrast to the improved measurement
      properties after shorter recall periods, the administration of the informed
      version after > or = 12 weeks may not result in improvements in responsiveness or
      validity.

PMID- 12426275
TI  - Correlates of prolonged hospitalization in inner-city ICU patients receiving
      noninvasive and invasive positive pressure ventilation for status asthmaticus.
AB  - STUDY OBJECTIVES: To describe the outcome of patients with status asthmaticus
      (SA) treated in a medical ICU with positive pressure ventilation (PPV), and to
      identify those factors associated with increased length of hospital stay. DESIGN:
      Retrospective chart review. SETTING: University-based hospital in Chicago, IL.
      PATIENTS: All patients admitted with SA and treated with PPV over a 5-year
      period. RESULTS: The first ICU admission for each of 78 patients was analyzed.
      Fifty-six patients underwent endotracheal intubation (ETI) during the
      hospitalization, while 22 patients were treated with noninvasive PPV alone. Three
      patients died. The median hospital length of stay was 5.5 days. Cox regression
      analysis revealed the following factors to be independently associated with
      increased length of hospital stay: female gender (p < 0.01), ETI (p < 0.01), the
      administration of neuromuscular blockers for > 24 h (p < 0.01), inhaled
      corticosteroid use prior to ICU admission (p = 0.01), and increasing APACHE
      (acute physiology and chronic health evaluation) II score (p < 0.01).
      CONCLUSIONS: This study suggests that while the mortality associated with SA
      treated with contemporary methods of PPV is low, certain factors, including
      female gender, ETI, and the prolonged use of neuromuscular blockade, are
      associated with an increased length of hospital stay. The development of
      respiratory failure despite preadmission use of inhaled corticosteroids is also
      associated with prolonged hospitalization.

PMID- 12426276
TI  - Prognostic value of the indocyanine green plasma disappearance rate in critically
      ill patients.
AB  - OBJECTIVE: Measurement of the indocyanine green plasma disappearance rate (ICG
      PDR) has been proposed as a clinical tool for the assessment of liver perfusion
      and function in transplant donors as well as a prognostic marker. In this study,
      we analyzed the prognostic value of the ICG-PDR in critically ill patients.
      DESIGN: Retrospective analysis. SETTING: Operative ICU of a university hospital.
      MEASUREMENTS AND RESULTS: We analyzed 336 critically ill patients (120 female and
      216 male; age range, 10 to 89 years; mean +/- SD age, 53 +/- 19 years) who were
      treated in our ICU between 1996 and 2000. All these patients were hemodynamically
      monitored by the transpulmonary double indicator (thermo-dye) dilution technique.
      Each patient received a femoral artery sheath through which a 4F flexible
      catheter with an integrated thermistor and fiberoptic was advanced into the
      abdominal aorta. The ICG-PDR was calculated using a computer system. For each
      measurement, 15 to 17 mL of 2% indocyanine green were injected in a central vein.
      Statistical analysis using the lowest value of the ICG-PDR in each individual
      showed that it was significantly lower in nonsurvivors (n = 168) than in
      survivors (n = 168) [median, 6.4%/min vs 16.5%/min; p < 0.001]. Sensitivity and
      specificity with respect to survival was analyzed by receiver operating
      characteristics. The area under the curve (AUC) as a measure of accuracy was
      0.815 when using lowest the ICG-PDR in each patient. For ICU admission (data from
      178 patients), AUCs were 0.680 for the APACHE (acute physiology and chronic
      health evaluation) II, 0.755 for the simplified acute physiology score (SAPS) II,
      and 0.745 for the ICG-PDR. CONCLUSION: The ICG-PDR as a marker of liver perfusion
      and function is a good predictor of survival in critically ill patients:
      mortality increased with lower ICG-PDR values, and nonsurvivors had significantly
      lower ICG-PDR values than survivors. Sensitivity and specificity of the ICG-PDR
      on ICU admission with respect to survival was comparable to that of APACHE II and
      SAPS II scores.

PMID- 12426277
TI  - Incidence and type of aspiration in acute care patients requiring mechanical
      ventilation via a new tracheotomy.
AB  - STUDY OBJECTIVES: To investigate the incidence of aspiration and type of
      aspiration (overt or silent) in patients requiring mechanical ventilation via a
      new tracheotomy, ie, within the previous 2 months. DESIGN: Prospective,
      consecutive. SETTING: Urban, tertiary, acute care hospital. PATIENTS: Fifty-two
      adult inpatients referred for a swallow evaluation between March 1999 and
      December 2001. MEASUREMENTS AND RESULTS: Fiberoptic endoscopic evaluation of
      swallowing was used to determine incidence and type of aspiration. Aspiration was
      defined as evidence of food material in the airway below the level of the true
      vocal folds, with silent aspiration defined as no overt symptoms of aspiration
      (eg, coughing or choking). Thirty-five of 52 patients (67%) did not aspirate, and
      17 of 52 patients aspirated (33%). Fourteen of the 17 patients (82%) who
      aspirated were silent aspirators. Patients who aspirated were significantly older
      (mean age, 73 years; range, 48 to 87 years) than those who did not aspirate (mean
      age, 59 years; range, 20 to 83 years; p < 0.05). Patients who aspirated were
      posttracheotomy for significantly less time (mean, 14 days; range, 3 to 48 days)
      than those who did not aspirate (mean, 23 days; range, 1 to 62 days) [p < 0.05].
      No significant difference was observed regarding the duration of translaryngeal
      intubation for aspirators (mean, 14 days; range, 0 to 31 days) vs nonaspirators
      (mean, 14 days; range, 0 to 29 days; p > 0.05). CONCLUSIONS: Two thirds of
      patients requiring short-term mechanical ventilation via a new tracheotomy
      swallowed successfully. When aspiration occurred, it was predominantly silent
      aspiration. It is important to consider age, number of days posttracheotomy,
      functional reserve, and clinical judgment of recovery rate before performing a
      swallow evaluation in this population. Specifically, swallowing success will
      occur most frequently in patients < 70 years old, with optimal timing for a
      successful swallow outcome at approximately 3 weeks posttracheotomy in patients >
      70 years old and 1 week in patients < 70 years old, and in conjunction with
      improving medical and respiratory status.

PMID- 12426278
TI  - Blood cultures in the critical care unit: improving utilization and yield.
AB  - Sepsis is a common cause of morbidity and death in critically ill patients, and
      blood culture samples are often drawn in an effort to identify a responsible
      pathogen. Blood culture results are usually negative, however, and even when
      positive are sometimes difficult to interpret. Distinguishing between true
      bacteremia and a false-positive blood culture result is important, but
      complicated by a variety of factors in the ICU. False-positive culture results
      are costly because they often prompt more diagnostic testing and more antibiotic
      prescriptions, and increase hospital length of stay. A number of factors
      influence the yield of blood cultures in critically ill patients, including the
      use of antibiotics, the volume of blood drawn, the frequency with which culture
      samples are drawn, and the site from which the culture samples are taken. Skin
      preparation techniques, handling of the cultures in the microbiology laboratory,
      and the type of blood culture system employed also influence blood culture yield.
      Attempts to identify predictors of true bacteremia in critically ill patients
      have been disappointing. In this review, we discuss factors that influence blood
      culture yield in critically ill patients, suggest ways to improve yield, and
      discuss true bacteremia vs false-positive blood culture results. We also discuss
      the costs and consequences of false-positive blood culture results, and list
      noninfectious causes of fever in the ICU.

PMID- 12426279
TI  - Distribution of calibrated talc after intrapleural administration: an
      experimental study in rats.
AB  - STUDY OBJECTIVE: Many reports have shown that talc is the most effective and
      least expensive agent for the creation of a pleural symphysis. However, its use
      still remains controversial due to severe acute respiratory side effects possibly
      related to the systemic dissemination of talc particles. The purpose of this
      study was to assess the distribution of calibrated talc after intrapleural
      administration in rats. MATERIAL AMD METHODS: Thirty-seven Wistar male rats were
      randomly assigned to undergo pleurodesis by talc slurry (33 rats) or by simple
      chest tube drainage (control group; 4 rats). Forty milligrams of calibrated talc
      suspended in 1 mL sterile saline solution was injected into rats in the treated
      group. The animals were randomly assigned for autopsy at 24 or 72 h after pleural
      injection. Lungs, parietal pleura, diaphragm, liver, kidneys, spleen,
      pericardium, brain, and blood were assessed by polarized light for birefringent
      talc particle detection and counting. RESULTS: No deaths were observed. The
      autopsies showed no pleurodesis at 24 and 72 h. Despite high doses of talc
      (extrapolated from the dose of 10 g in a 70-kg adult man), few talc particles
      were found in the liver of two rats, in the spleen of one rat, and only one
      particle of talc was observed at the brain surface of the rat studied by scanning
      electron microscopy. No particles were found in the other organs, in particular
      in the contralateral lung and blood, contrasting with previously published
      results using noncalibrated talc particles. CONCLUSIONS: The lack of systemic
      dispersion of talc particles, with the packaging talc we currently use in our
      clinical practice, is probably due to the size of the talc particles, which are
      larger than the other talc preparations. Calibrated talc is required in case of
      intrapleural administration for pleurodesis to avoid systemic dissemination and
      potential secondary acute respiratory failures.

PMID- 12426280
TI  - Ventilating with tracheal gas insufflation and periodic tracheal occlusion during
      sleep and wakefulness.
AB  - INTRODUCTION: The current invasive and noninvasive methods for delivering long
      term ventilatory support rely on cumbersome patient interfaces that may interfere
      with upper airway function. To overcome these limitations, a novel system was
      developed to ventilate conscious, spontaneously breathing dogs through a self
      contained cuffed cannula that was used for tracheal gas insufflation (TGI) and
      periodic tracheal occlusion (PTO). We hypothesized that TGI + PTO would provide
      greater ventilatory support than would TGI alone and that its effect would be
      more pronounced during sleep than wakefulness. METHODS: Chronically
      tracheostomized dogs were monitored for sleep (ie, EEG, electro- oculogram, and
      nuchal electromyogram) and breathing (ie, tracheal pressure [Ptr] and upper
      airway flow via snout mask). A thin transtracheal cannula housed within a cuffed
      tracheostomy tube was used for TGI and PTO monitoring. E, gas exchange, and
      breathing patterns were examined during sleep and wakefulness at baseline (ie, no
      TGI) and during the application of TGI alone (at 5, 10, and 15 L/min) and the
      application of TGI + PTO. RESULTS: Compared to baseline breathing without TGI,
      TGI at 5, 10, and 15 L/min decreased minute ventilation without influencing
      PaCO(2). In contrast, TGI + PTO led to progressive increases in ventilation,
      positive Ptr swings, and decreases in PaCO(2) as the flow rate was increased
      during sleep and wakefulness. Moreover, spontaneous breathing efforts ceased
      during TGI + PTO at flow rates of 10 and 15 L/min during wakefulness, and at all
      flow rates during sleep. CONCLUSIONS: The findings indicate that TGI + PTO can
      fully support ventilation in a spontaneously breathing canine model during sleep
      and wakefulness. Its streamlined interface could ultimately prove to be
      clinically significant, once technical concerns are addressed.

PMID- 12426281
TI  - Apoptosis and B-cell lymphoma-2 of peripheral blood T lymphocytes and soluble fas
      in patients with allergic asthma.
AB  - STUDY OBJECTIVE: s: The dysregulation of apoptosis and the expression of
      apoptosis-related molecules of allergen-reactive T lymphocytes have been
      suggested to play a key role in the development and maintenance of the
      inflammatory reactions in allergic asthma. Glucocorticoids are effective drugs
      for treating allergic inflammation. In this study, we investigated the effect of
      dexamethasone (DEX) on the apoptosis and B-cell lymphoma (Bcl)-2 expression of
      peripheral blood T lymphocytes as well as the soluble form of Fas (sFas) in
      allergic asthmatic patients. METHODS: Peripheral blood lymphocytes from 41
      allergic asthmatic patients and 30 age-matched and sex-matched control subjects
      were treated with 0.1 and 1 micro M DEX. The percentages of apoptosis and
      expression of the Bcl-2 molecule in T lymphocytes were assessed by flow
      cytometry. The plasma concentration of sFas was measured using the enzyme-linked
      immunosorbent assay. RESULTS: DEX (0.1 and 1 micro M) could induce the apoptosis
      of T lymphocytes from allergic asthmatic patients and control subjects in a dose
      dependent manner in vitro. The apoptotic susceptibility of T lymphocytes to DEX
      and the plasma sFas concentration were significantly higher in allergic
      asthmatics. The ex vivo expression of Bcl-2 was significantly lower in the T
      lymphocytes of asthmatic patients than in those of the control subjects. However,
      DEX did not have any significant effect on the expression of Bcl-2 in vitro.
      CONCLUSIONS: The T lymphocytes of asthmatic patients have higher apoptotic
      susceptibility to DEX treatment in vitro and a lower expression of the Bcl-2
      molecule.

PMID- 12426282
TI  - Real-time chest ultrasonography: a comprehensive review for the pulmonologist.
AB  - This review discusses real-time pulmonary ultrasonography (US) for the practicing
      pulmonologist. US supplements chest radiography and chest CT scanning. Major
      advantages include bedside availability, absence of radiation, and guided
      aspiration of fluid-filled areas and solid tumors. Pulmonary vessels and vascular
      supply of consolidations may be visualized without contrast. US may help to
      diagnose conditions such as pneumothorax, hemothorax, pleural or pericardial
      effusion, pneumonia, and pulmonary embolism in the critically ill patient who is
      in need of bedside diagnostic testing. The technique of US, which is cost
      effective compared to CT scanning and MRI, may be learned relatively easily by
      the pulmonologist.

PMID- 12426283
TI  - Recruitment of lung diffusing capacity: update of concept and application.
AB  - Lung diffusing capacity (DL) for carbon monoxide (DLCO), nitric oxide (DLNO) or
      oxygen (DLO2) increases from rest to peak exercise without reaching an upper
      limit; this recruitment results from interactions among alveolar volume (VA), and
      cardiac output (q), as well as changing physical properties and spatial
      distribution of capillary erythrocytes, and is critical for maintaining a normal
      arterial oxygen saturation. DLCO and DLNO can be used to interpret the
      effectiveness of diffusive oxygen transport and track structural alterations of
      the alveolar-capillary barrier, providing sensitive noninvasive indicators of
      microvascular integrity in health and disease. Clinical interpretation of DL
      should take into account Q in addition to VA and hemoglobin concentration.

PMID- 12426284
TI  - Adrenal insufficiency in the critically ill: a new look at an old problem.
AB  - Stress from many sources, including pain, fever, and hypotension, activates the
      hypothalamic-pituitary-adrenal (HPA) axis with the sustained secretion of
      corticotropin and cortisol. Increased glucocorticoid action is an essential
      component of the stress response, and even minor degrees of adrenal insufficiency
      can be fatal in the stressed host. HPA dysfunction is a common and underdiagnosed
      disorder in the critically ill. We review the risk factors, pathophysiology,
      diagnostic approach, and management of HPA dysfunction in the critically ill.

PMID- 12426285
TI  - Top ten list in mechanical ventilation.

PMID- 12426286
TI  - Pulmonary embolism: what have we learned since Virchow?: treatment and
      prevention.

PMID- 12426287
TI  - Worldwide racial and ethnic distribution of alpha1-antitrypsin deficiency:
      summary of an analysis of published genetic epidemiologic surveys.
AB  - STUDY OBJECTIVES: Alpha1-antitrypsin (AAT) deficiency is a genetic disease that
      is widely known in Europe as a disease of white individuals, who, along with
      their descendants in other parts of the world, are at the highest risk for liver
      and/or lung disease. There is a limited database of individuals affected by this
      disease worldwide. It has been estimated, for example, that there are 70,000 to
      100,00 individuals affected in the United States, with comparable numbers in
      Europe. STUDY DESIGN: Genetic epidemiologic studies in the peer-reviewed
      literature have been used in an exploratory study to estimate the number of
      carriers and the number of those individuals who are homozygous or heterozygous
      for the two most common defective alleles for AAT deficiency in 58 individual
      countries. The total country database of 373 control cohorts has been combined to
      estimate the numbers of carriers and deficiency allele combinations for PiS and
      PiZ in 11 geographic regions and worldwide. The study was designed to be
      illustrative rather than comprehensive, and more detailed publication of the
      enormous database developed in this exploratory study is planned. CONCLUSIONS:
      The database presented indicates that in a total population of 4.4 billion in the
      countries surveyed worldwide, there are at least 116 million carriers (PiMS and
      PiMZ) and 3.4 million deficiency allele combinations (PiSS, PiSZ, and PiZZ).
      Furthermore, this database demonstrates that AAT deficiency is found in various
      populations of African blacks, Arabs and Jews in the Middle East, whites in
      Australia/New Zealand, Europe, and North America, central Asians, far east
      Asians, and southeast Asians. These data demonstrate that AAT deficiency is not
      just a disease of whites in Europe, but that it affects individuals in all racial
      subgroups worldwide. In addition, AAT deficiency may be one of the most common
      serious hereditary disorders in the world.

PMID- 12426288
TI  - Enhancement of exercise performance in COPD patients by hyperoxia: a call for
      research.
AB  - This essay summarizes 16 reports, published since 1956, that describe the effects
      of hyperoxia on exercise endurance in persons with COPD who have severe airflow
      obstruction (ie, FEV(1) < 1.0 L or < 39% of predicted) and mild hypoxemia at rest
      (ie, PaO(2) > 62 mm Hg or arterial oxygen saturation [SaO(2)] measured by pulse
      oximetry of > 91%). The term hyperoxia is used because, in a proportion of study
      participants, oxygen administration increased exercise endurance in a dose
      dependent fashion, up to a fraction of inspired oxygen of 0.5 or a flow of 100%
      O(2) of 6 L/min. The process appears to be dependent on an increase in PaO(2)
      rather than on the restoration of SaO(2) to normal levels. The results of
      pulmonary function tests were not predictive of response. Increased exercise
      performance was associated with a decrease in dyspnea, respiratory frequency, and
      minute ventilation. The slowing of respiratory frequency and the decrease in
      pulmonary air trapping likely accounted for the decrease in dyspnea. Slowing of
      the respiratory rate, which occurred at the expense of the retention of CO(2), is
      most likely due to a hyperoxia-induced decrease in chemoreceptor ventilatory
      drive from the aortic and carotid bodies. Research is called for to determine the
      following: (1) the prevalence of COPD patients who have severe airflow limitation
      accompanied by mild hypoxemia; (2) the proportion of these patients who show
      improvements in exercise performance during a test of hyperoxic exercise; and (3)
      whether enhanced exercise performance during a brief test translates into a
      meaningful increase in the ability to perform the activities of daily living.

PMID- 12426289
TI  - Ex-smoker with productive cough, weight loss, and draining lesion.

PMID- 12426290
TI  - Multiple pulmonary nodules in an HIV-positive man on highly active antiretroviral
      therapy.

PMID- 12426292
TI  - Persistent lung infiltrates in an immunocompetent 25-year-old woman.

PMID- 12426291
TI  - Justifying video-assisted thoracic surgery for spontaneous hemopneumothorax.
AB  - STUDY OBJECTIVES: Video-assisted thoracic surgery (VATS) has gained a prominent
      role in routine thoracic surgery practice. This study discusses the clinical
      aspects and utility of VATS in spontaneous hemopneumothorax (SHP). PATIENTS: Of
      363 spontaneous pneumothorax (SP) cases, 24 patients presented with SHP (6.6%).
      The clinical features, surgical indications, emergency VATS technique, and
      patient outcomes are discussed. RESULTS: All 24 patients were male (mean age,
      25.3 years). Eleven patients were in hypovolemic shock, and their hemoglobin
      levels ranged from 6.7 to 12.7 g/dL; therefore, they received fluid resuscitation
      and blood transfusion. The amount of blood drained through the chest tube varied
      from 200 to 3,500 mL. Emergency VATS revealed that 5 cases were simple
      hemothoraces and 19 cases were associated with pneumothorax. The cause of
      bleeding was identified by thoracoscopy, as from an aberrant vessel (n = 11),
      torn parietal pleura (n = 4), ruptured vascularized bullae (n = 2), and lung
      parenchyma (n = 1). Six patients had no evidence of an obvious bleeding site.
      Bullous lesions were at the apex of the upper lobe in 14 patients, and multiple
      lobar involvement was seen in 2 patients. All the bullae were resected with
      endoscopic stapler in eight patients and ligated with a homemade endoloop in
      eight patients. The mean operation time was 42 min. The mean chest tube removal
      time was 3.5 days after insertion, and mean postoperative stay was 4.5 days.
      There is no recurrence of SHP or SP during the follow-up period. CONCLUSION: SHP
      complicated by severe bleeding presents a potentially grave emergency. VATS may
      be considered as feasible treatment for patients with SHP.

PMID- 12426293
TI  - Is brisk walking an adequate aerobic training stimulus for cardiac patients?
AB  - Walking is the most common aerobic training modality utilized in cardiac
      rehabilitation programs. However, it remains unclear whether or not brisk walking
      is of a sufficient intensity to improve aerobic fitness in this population. In
      this study, we investigated whether men and women with coronary artery disease
      can achieve an exercise intensity that is sufficient to induce a training effect,
      ie, a training heart rate (THR), defined as >/= 70% of measured maximal heart
      rate (HRmax), via brisk walking on a flat surface. One hundred forty-two
      outpatient volunteers from the William Beaumont Hospital Cardiac Rehabilitation
      Program (Royal Oak, MI) and the University of Wisconsin-La Crosse Exercise and
      Health Program (La Crosse, WI) were asked to walk one mile as briskly as possible
      on measured tracks. Heart rate was monitored throughout the walk via
      radiotelemetry. The percentage of patients within each gender and phase of
      rehabilitation who attained a THR were assessed using peak or symptom-limited
      exercise testing to determine the HRmax. All of the women and 90% of the men
      achieved a THR, averaging 85 +/- 8% and 79 +/- 10% of HRmax, respectively (mean
      +/- SD). There was no difference in the percentage of phase II or phase III
      cardiac rehabilitation program patients who achieved a THR. These findings
      suggest that brisk walking is of a sufficient intensity to elicit a THR in all
      but the most highly fit patients with coronary disease. Thus, physicians and
      allied health professionals can prescribe brisk walking on a flat surface to
      their cardiac patients with confidence that this intensity will achieve
      cardiorespiratory and health benefits.

PMID- 12426294
TI  - Esophageal perforation associated with noninvasive ventilation: a case report.
AB  - Noninvasive positive-pressure ventilation (NIPPV) is widely used to treat acute
      respiratory failure, the goal being to avoid exposing patients to the morbidity
      associated with tracheal intubation. NIPPV may reduce the rates of intubation,
      morbidity, and mortality in selected patient subgroups. Although time-consuming
      for physicians and nurses, NIPPV is fairly easy to use, and few severe
      complications have been reported. Esophageal perforation is a well-recognized
      complication of tracheal intubation but has not been described in association
      with NIPPV. We report a case of fatal esophageal perforation associated with
      NIPPV after a surgical procedure.

PMID- 12426295
TI  - Lung injury linked to etanercept therapy.
AB  - Etanercept is the first anticytokine drug approved to treat rheumatoid arthritis.
      Side effects are infrequent, the most common being local skin reactions,
      headaches, and upper respiratory tract symptoms. We report the first case of lung
      injury that occurred while receiving this agent. Biopsy specimens of lung and
      skin lesions demonstrated noncaseating granulomas associated with a microscopic
      particulate. Withdrawal of etanercept achieved clinical stabilization, and the
      addition of prednisone resulted in rapid improvement.

PMID- 12426296
TI  - Posterior myocardial infarction and complete right bundle- branch block.
AB  - We describe two patients with posterior myocardial infarction (PMI) with
      unusually atypical clinical presentations and cardiac enzymatic profiles, but
      with the abrupt development of complete AV block in patient 1, and Mobitz II
      second-degree AV block with paroxysmal phases of higher degrees of AV block in
      patient 2, and mitral regurgitation leading to symptomatic pulmonary congestion.
      Also, both patients had complete right bundle-branch block (RBBB) [old in patient
      1, new in patient 2], the pattern of which was altered due to the associated PMI.
      The alteration included tall R waves involving the early part of the QRS complex,
      and tall T waves, both noted in the right precordial leads. The mechanism of
      these ECG modulations of the RBBB pattern was believed to be a superimposition of
      the early depolarization and repolarization consequences of the PMI. The
      significance of this observation lies in the ECG detection of PMI, frequently
      underdiagnosed particularly in patients with an atypical presentation, and with
      the RBBB adding further to the complexity. Thus, it is gratifying to note the
      contribution of the ECG to diagnostics, the only modality that provided a
      pathophysiologic insight in these two patients who appeared to be abruptly
      deteriorating clinically without an apparent reason.

PMID- 12426297
TI  - Catamenial pneumothorax: an example of porous diaphragm syndromes?

PMID- 12426298
TI  - Work-related inhalation injuries.

PMID- 12426299
TI  - Intraoperative photodynamic therapy after pleuropneumonectomy for malignant
      pleural mesothelioma.

PMID- 12426300
TI  - End-of-life care: data supportive?

PMID- 12426301
TI  - How to blow your defense.

PMID- 12426302
TI  - What about the role of the US Food and Drug Administration?

PMID- 12426305
TI  - Epidermal growth factor receptor-dependent and -independent cell-signaling
      pathways originating from the urokinase receptor.
AB  - Urokinase-type plasminogen activator (uPA) and vitronectin activate cell
      signaling pathways by binding to the uPA receptor (uPAR). Because uPAR is
      glycosylphosphatidylinositol-anchored, the signaling receptor is most likely a
      uPAR-containing multiprotein complex. This complex may be heterogeneous within a
      single cell and among different cell types. The goal of this study was to
      elucidate the role of the EGF receptor (EGFR) as a component of the uPAR
      signaling machinery. uPA activated extracellular signal-regulated kinase (ERK) in
      COS-7 cells and in COS-7 cells that overexpress uPAR, and this response was
      blocked by the EGFR inhibitor, tyrphostin AG1478, implicating the EGFR in the
      pathway that links uPAR to ERK. By contrast, Rac1 activation, which occurred as a
      result of uPAR overexpression, was EGFR-independent. COS-7 cell migration was
      stimulated, in an additive manner, by uPAR-dependent pathways leading to ERK and
      Rac1. AG1478 inhibited only the ERK-dependent component of the response. CHO-K1
      cells do not express EGFR; however, these cells demonstrated ERK activation in
      response to uPA, indicating the presence of an EGFR-independent alternative
      pathway. As anticipated, this response was insensitive to AG1478. When CHO-K1
      cells were transfected to express EGFR or a kinase-inactive mutant of EGFR, ERK
      activation in response to uPA was unchanged; however, the EGFR-expressing cells
      acquired sensitivity to AG1478. We conclude that the EGFR may function as a
      transducer of the signal from uPAR to ERK, but not Rac1. In the absence of EGFR,
      an alternative pathway links uPAR to ERK; however, this pathway is apparently
      silenced by EGFR expression.

PMID- 12426307
TI  - TrmB, a sugar-specific transcriptional regulator of the trehalose/maltose ABC
      transporter from the hyperthermophilic archaeon Thermococcus litoralis.
AB  - We report the characterization of TrmB, a protein of 38,800 apparent molecular
      weight, that is involved in the maltose-specific regulation of a gene cluster in
      Thermococcus litoralis, malE malF malG orf trmB malK, encoding a binding protein
      dependent ABC transporter for trehalose and maltose. TrmB binds maltose and
      trehalose half-maximally at 20 microm and 0.5 mm sugar concentration,
      respectively. Binding of maltose but not of trehalose showed indications of
      sigmoidality and quenched the intrinsic tryptophan fluorescence by 15%,
      indicating a conformational change on maltose binding. TrmB causes a shift in
      electrophoretic mobility of DNA fragments harboring the promoter and upstream
      regulatory motif identified by footprinting. Band shifting by TrmB can be
      prevented by maltose. In vitro transcription assays with purified components from
      Pyrococcus furiosus have been established to show pmalE promoter-dependent
      transcription at 80 degrees C. TrmB specifically inhibits transcription, and this
      inhibition is counteracted by maltose and trehalose. These data characterize TrmB
      as a maltose-specific repressor for the trehalose/maltose transport operon of
      Thermococcus litoralis.

PMID- 12426306
TI  - The Kruppel-like factor KLF2 inhibits peroxisome proliferator-activated receptor
      gamma expression and adipogenesis.
AB  - Obesity is an important public health problem associated with a number of disease
      states such as diabetes and arteriosclerosis. As such, an understanding of the
      mechanisms governing adipose tissue differentiation and function is of
      considerable importance. We recently reported that the Kruppel-like zinc finger
      transcription factor KLF15 can induce adipocyte maturation and GLUT4 expression.
      In this study, we identify that a second family member, KLF2/Lung Kruppel-like
      factor (LKLF), as a negative regulator of adipocyte differentiation. KLF2 is
      highly expressed in adipose tissue, and studies in cell lines and primary cells
      demonstrate that KLF2 is expressed in preadipocytes but not mature adipocytes.
      Constitutive overexpression of KLF2 but not KLF15 potently inhibits peroxisome
      proliferator-activated receptor-gamma (PPARgamma) expression with no effect on
      the upstream regulators C/EBPbeta and C/EBPdelta. However, the expression of
      C/EBPalpha and SREBP1c/ADD1 (adipocyte determination and differentiation factor
      1/sterol regulatory element-binding protein-1), two factors that feedback in a
      positive manner to enhance PPARgamma function, was also markedly reduced. In
      addition, transient transfection studies show that KLF2 directly inhibits
      PPARgamma2 promoter activity (70% inhibition; p < 0.001). Using a combination of
      promoter mutational analysis and gel mobility shift assays, we have identified a
      binding site within the PPARgamma2 promoter, which mediates this inhibitory
      effect. These data identify a novel role for KLF2 as a negative regulator of
      adipogenesis.

PMID- 12426308
TI  - Protein phosphatase 2A (PP2A) regulates interleukin-4-mediated STAT6 signaling.
AB  - Interleukin-4 (IL-4) plays a pivotal role in the induction and maintenance of
      allergy by promoting Th2 differentiation and B cell isotype switching to IgE.
      Studies on STAT6-deficient mice have demonstrated the essential role of STAT6 in
      mediating the biological functions of IL-4. IL-4 induces tyrosine phosphorylation
      of STAT6, which in turn leads to transcription of IL-4-specific genes. In
      addition, serine phosphorylation of STAT6 has recently been reported. Here we
      study the functional role of STAT6 serine phosphorylation and the kinases and
      phosphatases involved. We show that inhibition of protein phosphatase 2A (PP2A)
      induces serine phosphorylation of STAT6 and severely inhibits DNA binding of
      STAT6. In contrast, IL-4-induced tyrosine phosphorylation of Janus kinase-1 and
      STAT6 is not affected, suggesting that PP2A acts downstream of Janus kinases in
      IL-4 signaling. In conclusion, we provide the first evidence that PP2A plays a
      crucial role in the regulation of STAT6 function.

PMID- 12426309
TI  - Altered interactions between the A1 and A2 subunits of factor VIIIa following
      cleavage of A1 subunit by factor Xa.
AB  - Factor VIIIa consists of subunits designated A1, A2, and A3-C1-C2. The limited
      cofactor activity observed with the isolated A2 subunit is markedly enhanced by
      the A1 subunit. A truncated A1 (A1(336)) was previously shown to possess similar
      affinity for A2 and retain approximately 60% of its A2 stimulatory activity. We
      now identify a second site in A1 at Lys(36) that is cleaved by factor Xa. A1
      truncated at both cleavage sites (A1(37-336)) showed little if any affinity for
      A2 (K(d)>2 microm), whereas factor VIIIa reconstituted with A2 plus A1(37-336)/A3
      C1-C2 dimer demonstrated significant cofactor activity ( approximately 30% that
      of factor VIIIa reconstituted with native A1) in a factor Xa generation assay.
      These affinity values were consistent with values obtained by fluorescence energy
      transfer using acrylodan-labeled A2 and fluorescein-labeled A1. In contrast,
      factor VIIIa reconstituted with A1(37-336) showed little activity in a one-stage
      clotting assay. This resulted in part from a 5-fold increase in K(m) for factor X
      when A1 was cleaved at Arg(336). These findings suggest that both A1 termini are
      necessary for functional interaction of A1 with A2. Furthermore, the C terminus
      of A1 contributes to the K(m) for factor X binding to factor Xase, and this
      parameter is critical for activity assessed in plasma-based assays.

PMID- 12426310
TI  - Characterization of the physical interaction of Gli proteins with SUFU proteins.
AB  - The Hedgehog signaling pathway is involved in both development and cancer
      induction in a wide range of organisms. The end point of the Hedgehog signal
      transduction cascade is the Gli/Ci, zinc-finger transcription factors. Proteins
      such as Fused, Suppressor of fused (SUFU), Costal-2, and protein kinase A are
      essential for regulation of Gli/Ci processing, activity, and localization.
      Coimmunoprecipitation and Far Western assays, coupled with truncation analysis
      and mutagenesis have been used to define the region of interaction between Gli
      proteins and SUFU. We identify a novel motif SYGH in Gli/Ci family proteins,
      which is required for the interaction with SUFU. Mutational studies revealed that
      Gly(122) and His(123) are crucial for binding to SUFU, suggesting the importance
      of hydrophobicity for the correct binding conformation. Functional analysis
      revealed that the activity of GLI transcription factors with mutations in this
      motif is no longer suppressed by co-expression of SUFU. Moreover, we have found
      that a C-terminal 19-amino acid deletion in SUFU (delta465) is sufficient to
      abrogate interaction with GLI1. Interestingly, this SUFU mutant localizes in the
      nucleus, most probably because it is not efficiently sequestered in the
      cytoplasm. Taken together, we identified a novel motif in the Gli/Ci family of
      proteins that is essential both for protein-protein interaction with SUFU and for
      functional repression of GLI1 by SUFU.

PMID- 12426311
TI  - A new phosphatidylinositol 4,5-bisphosphate-binding site located in the C2 domain
      of protein kinase Calpha.
AB  - In view of the interest shown in phosphatidylinositol 4,5-bisphosphate
      (PtdIns(4,5)P(2)) as a second messenger, we studied the activation of protein
      kinase Calpha by this phosphoinositide. By using two double mutants from two
      different sites located in the C2 domain of protein kinase Calpha, we have
      determined and characterized the PtdIns(4,5)P(2)-binding site in the protein,
      which was found to be important for its activation. Thus, there are two distinct
      sites in the C2 domain: the first, the lysine-rich cluster located in the beta3-
      and beta4-sheets and which activates the enzyme through direct binding of
      PtdIns(4,5)P(2); and the second, the already well described site formed by the
      Ca(2+)-binding region, which also binds phosphatidylserine and a result of which
      the enzyme is activated. The results obtained in this work point to a sequential
      activation model, in which protein kinase Calpha needs Ca(2+) before the
      PtdIns(4,5)P(2)-dependent activation of the enzyme can occur.

PMID- 12426312
TI  - Ligand binding promotes the entropy-driven oligomerization of integrin alpha IIb
      beta 3.
AB  - Integrin alpha(IIb)beta(3) clusters on the platelet surface after binding
      adhesive proteins in a process that regulates signal transduction. However, the
      intermolecular forces driving integrin self-association are poorly understood.
      This work provides new insights into integrin clustering mechanisms by
      demonstrating how temperature and ligand binding interact to affect the
      oligomeric state of alpha(IIb)beta(3). The ligand-free receptor, solubilized in
      thermostable octyl glucoside micelles, exhibited a cooperative transition at
      approximately 43 degrees C, monitored by changes in intrinsic fluorescence and
      circular dichroism. Both signals changed in a direction opposite to that for
      global unfolding, and both were diminished upon binding the fibrinogen gamma
      chain ligand-mimetic peptide cHArGD. Free and bound receptors also exhibited
      differential sensitivity to temperature-enhanced oligomerization, as measured by
      dynamic light scattering, sedimentation velocity, and sedimentation equilibrium.
      Van't Hoff analyses of dimerization constants for alpha(IIb)beta(3) complexed
      with cHArGD, cRGD, or eptifibatide yielded large, favorable entropy changes
      partly offset by unfavorable enthalpy changes. Transmission electron microscopy
      showed that ligand binding and 37 degrees C incubation enhanced assembly of
      integrin dimers and larger oligomers linked by tail-to-tail contacts.
      Interpretation of these images was aided by threading models for
      alpha(IIb)beta(3) protomers and dimers based on the ectodomain structure of
      alpha(v)beta(3). We propose that entropy-favorable nonpolar interactions drive
      ligand-induced integrin clustering and outside-in signaling.

PMID- 12426313
TI  - The yeast mitochondrial degradosome. Its composition, interplay between RNA
      helicase and RNase activities and the role in mitochondrial RNA metabolism.
AB  - The yeast mitochondrial degradosome (mtEXO) is an NTP-dependent exoribonuclease
      involved in mitochondrial RNA metabolism. Previous purifications suggested that
      it was composed of three subunits. Our results suggest that the degradosome is
      composed of only two large subunits: an RNase and a RNA helicase encoded by
      nuclear genes DSS1 and SUV3, respectively, and that it co-purifies with
      mitochondrial ribosomes. We have found that the purified degradosome has RNA
      helicase activity that precedes and is essential for exoribonuclease activity of
      this complex. The degradosome RNase activity is necessary for mitochondrial
      biogenesis but in vitro the degradosome without RNase activity is still able to
      unwind RNA. In yeast strains lacking degradosome components there is a strong
      accumulation of mitochondrial mRNA and rRNA precursors not processed at 3'- and
      5'-ends. The observed accumulation of precursors is probably the result of lack
      of degradation rather than direct inhibition of processing. We suggest that the
      degradosome is a central part of a mitochondrial RNA surveillance system
      responsible for degradation of aberrant and unprocessed RNAs.

PMID- 12426314
TI  - Mitogen-activated protein kinases play an essential role in oxidative burst
      independent expression of pathogenesis-related genes in parsley.
AB  - Plants are continuously exposed to attack by potential phytopathogens. Disease
      prevention requires pathogen recognition and the induction of a multifaceted
      defense response. We are studying the non-host disease resistance response of
      parsley to the oomycete, Phytophthora sojae using a cell culture-based system.
      Receptor-mediated recognition of P. sojae may be achieved through a thirteen
      amino acid peptide sequence (Pep-13) present within an abundant cell wall
      transglutaminase. Following recognition of this elicitor molecule, parsley cells
      mount a defense response, which includes the generation of reactive oxygen
      species (ROS) and transcriptional activation of genes encoding pathogenesis
      related (PR) proteins or enzymes involved in the synthesis of antimicrobial
      phytoalexins. Treatment of parsley cells with the NADPH oxidase inhibitor,
      diphenylene iodonium (DPI), blocked both Pep-13-induced phytoalexin production
      and the accumulation of transcripts encoding enzymes involved in their synthesis.
      In contrast, DPI treatment had no effect upon Pep-13-induced PR gene expression,
      suggesting the existence of an oxidative burst-independent mechanism for the
      transcriptional activation of PR genes. The use of specific antibodies enabled
      the identification of three parsley mitogen-activated protein kinases (MAPKs)
      that are activated within the signal transduction pathway(s) triggered following
      recognition of Pep-13. Other environmental challenges failed to activate these
      kinases in parsley cells, suggesting that their activation plays a key role in
      defense signal transduction. Moreover, by making use of a protoplast co
      transfection system overexpressing wild-type and loss-of-function MAPK mutants,
      we show an essential role for post-translational phosphorylation and activation
      of MAPKs for oxidative burst-independent PR promoter activation.

PMID- 12426315
TI  - Proteasomes modulate conjugation to the ubiquitin-like protein, ISG15.
AB  - ISG15 is a ubiquitin-like protein that is induced by interferon and microbial
      challenge. Ubiquitin-like proteins are covalently conjugated to cellular proteins
      and may intersect the ubiquitin-proteasome system via common substrates or
      reciprocal regulation. To investigate the relationship between ISG15 conjugation
      and proteasome function, we treated interferon-induced cells with proteasome
      inhibitors. Surprisingly, inhibition of proteasomal, but not lysosomal, proteases
      dramatically enhanced the level of ISG15 conjugates. The stimulation of ISG15
      conjugates occurred rapidly in the absence of protein synthesis and was most
      dramatic in the cytoskeletal protein fraction. Inhibition of ISG15 conjugation by
      ATP depletion abrogated the proteasome inhibitor-dependent increase in ISG15
      conjugates, suggesting that the effect was mediated by de novo conjugation,
      rather than protection from proteasomal degradation or inhibition of ISG15
      deconjugating activity. The increase in ISG15 conjugates did not occur through a
      stabilization of the ISG15 E1 enzyme, UBE1L. Furthermore, simultaneous
      modification of proteins by both ISG15 and ubiquitin did not account for the
      proteasome inhibitor-dependent increase in ISG15 conjugates. These findings
      provide the first evidence for a link between ISG15 conjugation and proteasome
      function and support a model in which proteins destined for ISG15 conjugation are
      proteasome-regulated.

PMID- 12426316
TI  - Involvement of Aurora A kinase during meiosis I-II transition in Xenopus oocytes.
AB  - The Aurora kinase family has been involved both in vivo and in vitro in the
      stability of the metaphase plate and chromosome segregation. However, to date
      only one member of this family, the protein kinase Aurora B, has been implicated
      in the regulation of meiotic division in Caenorhabditis elegans. In this species,
      disruption of Aurora B results in the failure of polar body extrusion. To
      investigate whether Aurora A is also required in meiosis, we microinjected highly
      specific alpha-Aurora A antibodies in Xenopus oocytes. We demonstrated that
      microinjected oocytes fail to extrude the first polar body and are arrested with
      condensed chromosomes on a typical metaphase I plate, which has not performed its
      normal 90 degrees rotation. We additionally found that, although the failure of
      first polar body extrusion observed in alpha-Aurora A-microinjected oocytes is
      likely mediated by Eg5, the impairment of the metaphase plate rotation does not
      involve this kinesin-like protein. Surprisingly, although chromosomes remain
      condensed at a metaphase I stage in alpha-Aurora A-microinjected oocytes, the
      cytoplasmic cell cycle events progress normally through meiosis until metaphase
      II arrest. Moreover, these oocytes are able to undergo parthenogenetic
      activation. We conclude that Aurora A and Eg5 are involved in meiosis I to
      meiosis II transition in Xenopus oocytes.

PMID- 12426317
TI  - 14-3-3 Interacts directly with and negatively regulates pro-apoptotic Bax.
AB  - The Bcl-2 family of proteins comprises well characterized regulators of
      apoptosis, consisting of anti-apoptotic members and pro-apoptotic members. Pro
      apoptotic members possessing BH1, BH2, and BH3 domains (such as Bax and Bak) act
      as a gateway for a variety of apoptotic signals. Bax is normally localized to the
      cytoplasm in an inactive form. In response to apoptotic stimuli, Bax translocates
      to the mitochondria and undergoes oligomerization to induce the release of
      apoptogenic factors such as cytochrome c, but it is still largely unknown how the
      mitochondrial translocation and pro-apoptotic activity of Bax is regulated. Here
      we report that cytoplasmic protein 14-3-3 theta binds to Bax and, upon apoptotic
      stimulation, releases Bax by a caspase-independent mechanism, as well as through
      direct cleavage of 14-3-3 theta by caspases. Unlike Bad, the interaction with 14
      3-3 theta is not dependent on the phosphorylation of Bax. In isolated
      mitochondria, we found that 14-3-3 theta inhibited the integration of Bax and Bax
      induced cytochrome c release. Bax-induced apoptosis was inhibited by
      overexpression of either 14-3-3 theta or its mutant (which lacked the ability to
      bind to various phosphorylated targets but still bound to Bax), whereas
      overexpression of 14-3-3 theta was unable to inhibit apoptosis induced by a Bax
      mutant that did not bind to 14-3-3 theta. These findings indicate that 14-3-3
      theta plays a crucial role in negatively regulating the activity of Bax.

PMID- 12426318
TI  - A central role for the JNK pathway in mediating the antagonistic activity of pro
      inflammatory cytokines against transforming growth factor-beta-driven SMAD3/4
      specific gene expression.
AB  - We have focused our attention on the molecular events underlying the antagonistic
      activities of pro-inflammatory cytokines against transforming growth factor-beta
      (TGF-beta)/SMAD signaling. Using jnk1/2-knockout (jnk(-/-)) and I kappa B kinase
      gamma/nemo(-/-) fibroblasts, we have determined the specific roles played by the
      JNK/AP-1 and NF-kappa B/Rel pathways in this phenomenon. We demonstrate that, in
      a cellular context devoid of JNK activity (i.e. jnk(-/-) fibroblasts),
      interleukin-1 and tumor necrosis factor-alpha (TNF-alpha) did not inhibit the
      formation of SMAD-DNA complexes and the resulting SMAD-driven transcription in
      response to TGF-beta. On the other hand, lack of NF-kappa B activity in nemo(-/-)
      fibroblasts did not affect the antagonistic effect of pro-inflammatory cytokines
      against TGF-beta. In the latter cell type, overexpression of antisense c-jun mRNA
      or of a dominant-negative form of MKK4 blocked the inhibitory activity of TNF
      alpha, similar to what was observed in normal human dermal fibroblasts. Among JNK
      substrates, c-Jun and JunB (but not activating transcription factor-2)
      antagonized TGF-beta/SMAD signaling in a JNK-dependent manner. Overexpression of
      JNK1 in jnk(-/-) fibroblasts restored the ability of cytokines and Jun proteins
      to interfere with SMAD signaling. In junAA mouse embryo fibroblasts, in which c
      Jun can no longer be phosphorylated by JNK, JunB substituted for c-Jun in
      mediating the cytokine effect against SMAD-driven transcription in a JNK
      dependent manner. These results suggest a critical role for JNK-mediated c-Jun
      and JunB phosphorylation in transmitting the inhibitory effect of pro
      inflammatory cytokines against TGF-beta-induced SMAD signaling. In addition, we
      demonstrate that such a JNK-dependent regulatory mechanism underlies the
      antagonistic activity of TNF-alpha against TGF-beta-induced up-regulation of type
      I and III collagens in fibroblasts.

PMID- 12426319
TI  - Transcription factor occupancy of the insulin gene in vivo. Evidence for direct
      regulation by Nkx2.2.
AB  - Consensus-binding sites for many transcription factors are relatively non
      selective and found at high frequency within the genome. This raises the
      possibility that factors that are capable of binding to a cis-acting element in
      vitro and regulating transcription from a transiently transfected plasmid, which
      would not have higher order chromatin structure, may not occupy this site within
      the endogenous gene. Closed chromatin structure and competition from another DNA
      binding protein with similar nucleotide specificity are two possible mechanisms
      by which a transcription factor may be excluded from a potential binding site in
      vivo. Multiple transcription factors, including Pdx-1, BETA-2, and Pax6, have
      been implicated in expression of the insulin gene in pancreatic beta cells. In
      this study, the chromatin immunoprecipitation assay has been used to show that
      these factors do, in fact, bind to insulin control region sequences in intact
      beta cells. In addition, another key islet-enriched transcription factor, Nkx2.2,
      was found to occupy this region using the chromatin immunoprecipitation assay. In
      vitro DNA-binding and transient transfection assays defined how Nkx2.2 affected
      insulin gene expression. Pdx-1 was also shown to bind within a region of the
      endogenous islet amyloid polypeptide, pax-4, and glucokinase genes that were
      associated with control in vitro. Because Pdx-1 does not regulate gene
      transcription in isolation, these sequences were examined for occupancy by the
      other insulin transcriptional regulators. BETA-2, Pax6, and Nkx2.2 were also
      found to bind to amyloid polypeptide, glucokinase, and pax-4 control sequences in
      vivo. These studies reveal the broad application of the Pdx-1, BETA-2, Pax6, and
      Nkx2.2 transcription factors in regulating expression of genes selectively
      expressed in islet beta cells.

PMID- 12426320
TI  - The Armadillo family protein p0071 is a VE-cadherin- and desmoplakin-binding
      protein.
AB  - p0071, a member of the armadillo protein family, localizes to both adherens
      junctions and desmosomes in epithelial cells and exhibits homology to the
      adherens junction protein p120 and the desmosomal protein plakophilin-1. p0071 is
      also present at dermal microvascular endothelial intercellular junctions and
      colocalizes with VE-cadherin, an endothelium-specific cadherin that associates
      with both actin and intermediate filament networks. To define the role of p0071
      in junction assembly, p0071 was tested for interactions with other components of
      the endothelial junctional complex. In transient expression assays, p0071
      colocalized with and formed complexes with both VE-cadherin and desmoplakin.
      Deletion analysis using the yeast two-hybrid system revealed that the armadillo
      repeat domain of p0071 bound directly to VE-cadherin. Site-directed mutagenesis
      experiments demonstrated that p0071 and p120 bound to the same region on the
      cytoplasmic tail of VE-cadherin and that overexpression of p0071 could displace
      p120 from intercellular junctions. In contrast to VE-cadherin, desmoplakin was
      found to associate with the non-armadillo head domain of p0071. Cotransfections
      and triple-label immunofluorescence analysis revealed that VE-cadherin
      colocalization with desmoplakin in transfected COS cells required p0071,
      suggesting that p0071 may couple VE-cadherin to desmoplakin. Based on previous
      findings that both VE-cadherin and desmoplakin play central roles in
      vasculogenesis, these new results suggest that p0071 may play an important role
      in endothelial junction assembly and in the morphogenic events associated with
      vascular remodeling.

PMID- 12426321
TI  - Translational repression of human matrix metalloproteinases-13 by an
      alternatively spliced form of T-cell-restricted intracellular antigen-related
      protein (TIAR).
AB  - Human matrix metalloproteinases-13 (HMMP13) shows a wide substrate specificity,
      and its expression is limited to pathological situations such as chronic
      inflammation and cancer. The coding sequence for HMMP13 is 86% identical to rat
      matrix metalloproteinases-13 (RMMP13); however, the regulation of HMMP13 and
      RMMP13 protein synthesis in renal mesangial cells is strikingly different. In
      human cells there is a discordance between HMMP13 mRNA levels and protein
      expression. Following IL-1 beta or TGF-beta(1) stimulation, HMMP13 mRNA levels
      increase significantly, whereas the protein expression is absent. This
      discordance is because of a species-dependent translational repression. In
      addition to the 3'-untranslated region of the matrix metalloproteinases-13
      (MMP13) gene, the differential expression of an alternatively spliced transcript
      of the RNA-binding protein TIAR in human cell cultures is also critical for this
      post-transcriptional regulation. Transient expression of the 17-amino acid insert
      of the alternatively spliced form of TIAR reverses the HMMP13 mRNA silencing
      observed in human and primate species. In addition, co-transfection of the
      alternatively spliced form of TIAR and HMMP13 into Rat2 cells suppresses HMMP13
      protein expression. Thus, we report for the first time that a species-dependent
      TIAR isoform plays a major role in the post-transcriptional silencing for HMMP13.

PMID- 12426322
TI  - Two short segments of Smad3 are important for specific interaction of Smad3 with
      c-Ski and SnoN.
AB  - c-Ski and SnoN are transcriptional co-repressors that inhibit transforming growth
      factor-beta signaling through interaction with Smad proteins. Among receptor
      regulated Smads, c-Ski and SnoN bind more strongly to Smad2 and Smad3 than to
      Smad1. Here, we show that c-Ski and SnoN bind to the "SE" sequence in the C
      terminal MH2 domain of Smad3, which is exposed on the N-terminal upper side of
      the toroidal structure of the MH2 oligomer. The "QPSMT" sequence, located in the
      vicinity of SE, supports the interaction with c-Ski and SnoN. Sequences similar
      to SE and QPSMT are found in Smad2, but not in Smad1. The N-terminal MH1 domain
      and linker region of Smad3 protrude from the N-terminal upper side of the MH2
      oligomer toroid. Smurf2 induces ubiquitin-dependent degradation of SnoN, since it
      appears to be located close to SnoN through binding to the linker region of
      Smad2. In contrast, transcription factors Mixer and FoxH3 (FAST1) bind to the
      bottom side of the Smad3 MH2 toroid; therefore, c-Ski does not affect the
      interaction of Smads with these transcription factors. Our findings thus
      demonstrate the stoichiometry of how multiple molecules can associate with the
      Smad oligomers and how the Smad-interacting proteins functionally interact with
      each other.

PMID- 12426323
TI  - Pertussis toxin-insensitive activation of the heterotrimeric G-proteins Gi/Go by
      the NG108-15 G-protein activator.
AB  - A ligand-independent activator of heterotrimeric brain G-protein was partially
      purified from detergent-solubilized extracts of the neuroblastoma-glioma cell
      hybrid NG108-15. The G-protein activator (NG108-15 G-protein activator (NG-GPA))
      increased [(35)S]guanosine 5'-O-(thiotriphosphate) ([(35)S]GTPgammaS) to purified
      brain G-protein in a magnesium-dependent manner and promoted GDP dissociation
      from Galpha(o). The NG-GPA also increased GTPgammaS binding to purified,
      recombinant Galpha(i2), Galpha(i3), and Galpha(o), but minimally altered
      nucleotide binding to purified transducin. The NG-GPA increased GTPgammaS binding
      to membrane-bound G-proteins and inhibited basal, forskolin- and hormone
      stimulated adenylyl cyclase activity in DDT(1)-MF-2 cell membranes. In contrast
      to G-protein coupled receptor-mediated activation of heterotrimeric G-proteins in
      DDT(1)-MF-2 cell membrane preparations, the action of the NG-GPA was not altered
      by treatment of the cells with pertussis toxin. ADP-ribosylation of purified
      brain G-protein also failed to alter the increase in GTPgammaS binding elicited
      by the NG-GPA. Thus, the NG-GPA acts in a manner distinct from that of a G
      protein coupled receptor and other recently described receptor-independent
      activators of G-protein signaling. These data indicate the presence of unexpected
      regulatory domains on G(i)/G(o) proteins and suggest the existence of pertussis
      toxin-insensitive modes of signal input to G(i)/G(o) signaling systems.

PMID- 12426324
TI  - The value of complete microbial genome sequencing (you get what you pay for).

PMID- 12426325
TI  - On the high value of low standards.

PMID- 12426326
TI  - Biochemical properties of Neisseria gonorrhoeae LgtE.
AB  - A fragment of chromosomal DNA encoding the lgtE gene of Neisseria gonorrhoeae
      strain F62 was amplified by PCR and cloned into the expression vector pET15b.
      Functional LgtE was purified and its biochemical properties were determined. The
      purified enzyme was maximally active in buffer containing manganese; minimal
      activity was obtained in buffer containing other divalent cations. LgtE was only
      able to mediate the addition of UDP-galactose into neisserial
      lipooligosaccharides (LOSs). We used a variety of genetically defined and
      chemically verified LOS structures to determine acceptor specificity. LgtE was
      able to mediate the addition of galactose into a variety of LOS structures,
      indicating the this enzyme possesses broad acceptor specificity. Furthermore, it
      was able to add multiple galactose residues onto LOS. We also determined that
      this enzyme was capable of adding galactose onto both the alpha and beta chains
      of neisserial LOS.

PMID- 12426327
TI  - The rpoZ gene, encoding the RNA polymerase omega subunit, is required for
      antibiotic production and morphological differentiation in Streptomyces
      kasugaensis.
AB  - The occurrence of pleiotropic mutants that are defective in both antibiotic
      production and aerial mycelium formation is peculiar to streptomycetes.
      Pleiotropic mutant KSB was isolated from wild-type Streptomyces kasugaensis A1R6,
      which produces kasugamycin, an antifungal aminoglycoside antibiotic. A 9.3-kb DNA
      fragment was cloned from the chromosomal DNA of strain A1R6 by complementary
      restoration of kasugamycin production and aerial hypha formation to mutant KSB.
      Complementation experiments with deletion plasmids and subsequent DNA analysis
      indicated that orf5, encoding 90 amino acids, was responsible for the
      restoration. A protein homology search revealed that orf5 was a homolog of rpoZ,
      the gene that is known to encode RNA polymerase subunit omega (omega), thus
      leading to the conclusion that orf5 was rpoZ in S. kasugaensis. The pleiotropy of
      mutant KSB was attributed to a 2-bp frameshift deletion in the rpoZ region of
      mutant KSB, which probably resulted in a truncated, incomplete omega of 47 amino
      acids. Furthermore, rpoZ-disrupted mutant R6D4 obtained from strain A1R6 by
      insertion of Tn5 aphII into the middle of the rpoZ-coding region produced neither
      kasugamycin nor aerial mycelia, similar to mutant KSB. When rpoZ of S.
      kasugaensis and Streptomyces coelicolor, whose deduced products differed in the
      sixth amino acid residue, were introduced into mutant R6D4 via a plasmid, both
      transformants produced kasugamycin and aerial hyphae without significant
      differences. This study established that rpoZ is required for kasugamycin
      production and aerial mycelium formation in S. kasugaensis and responsible for
      pleiotropy.

PMID- 12426328
TI  - Requirement of flhA for swarming differentiation, flagellin export, and secretion
      of virulence-associated proteins in Bacillus thuringiensis.
AB  - Bacillus thuringiensis is being used worldwide as a biopesticide, although
      increasing evidence suggests that it is emerging as an opportunistic human
      pathogen. While phospholipases, hemolysins, and enterotoxins are claimed to be
      responsible for B. thuringiensis virulence, there is no direct evidence to
      indicate that the flagellum-driven motility plays a role in parasite-host
      interactions. This report describes the characterization of a mini-Tn10 mutant of
      B. thuringiensis that is defective in flagellum filament assembly and in swimming
      and swarming motility as well as in the production of hemolysin BL and
      phosphatidylcholine-preferring phospholipase C. The mutant strain was determined
      to carry the transposon insertion in flhA, a flagellar class II gene encoding a
      protein of the flagellar type III export apparatus. Interestingly, the flhA
      mutant of B. thuringiensis synthesized flagellin but was impaired in flagellin
      export. Moreover, a protein similar to the anti-sigma factor FlgM that acts in
      regulating flagellar class III gene transcription was not detectable in B.
      thuringiensis, thus suggesting that the flagellar gene expression hierarchy of B.
      thuringiensis differs from that described for Bacillus subtilis. The flhA mutant
      of B. thuringiensis was also defective in the secretion of hemolysin BL and
      phosphatidylcholine-preferring phospholipase C, although both of these virulence
      factors were synthesized by the mutant. Since complementation of the mutant with
      a plasmid harboring the flhA gene restored swimming and swarming motility as well
      as secretion of toxins, the overall results indicate that motility and virulence
      in B. thuringiensis may be coordinately regulated by flhA, which appears to play
      a crucial role in the export of flagellar as well as nonflagellar proteins.

PMID- 12426329
TI  - Substrate specificity of the AmpG permease required for recycling of cell wall
      anhydro-muropeptides.
AB  - AmpG was originally identified as a gene required for induction of beta
      lactamase. Subsequently, we found AmpG to be a permease required for recycling of
      murein tripeptide and uptake of anhydro-muropeptides. We have now studied the
      specificity of the AmpG permease. The principal requirement is for the presence
      of the disaccharide, N-acetylglucosaminyl-beta-1,4-anhydro-N-acetylmuramic acid
      (GlcNAc-anhMurNAc). These unique substrates for AmpG, which contain murein
      peptides linked to GlcNAc-anhMurNAc, are produced by turnover of the cell wall
      during logarithmic growth. AmpG permease is sensitive to carbonylcyanide m
      chlorophenylhydrazone, demonstrating that AmpG permease is a single-component
      permease and that transport is dependent on the proton motive force.

PMID- 12426330
TI  - Impact of phosphorylation of specific residues in the tyrosine autokinase, Wzc,
      on its activity in assembly of group 1 capsules in Escherichia coli.
AB  - Wzc(CPS) is a tyrosine autokinase essential for the assembly of a high-molecular
      weight (HMW) group 1 capsular polysaccharide (CPS) in Escherichia coli.
      Homologues of Wzc participate in the formation of CPS and exopolysaccharides in a
      variety of gram-positive and gram-negative bacteria. Phosphorylation of tyrosine
      residues in the Wzc(CPS) C terminus is essential for HMW CPS assembly.
      Overexpression of Wzb(CPS) (phosphatase) in a wild-type background caused a 3.7
      fold decrease in the amount of cell-associated K30 CPS produced, confirming the
      importance of Wzc(CPS) phosphorylation for capsule assembly. In this study, the
      tyrosine-rich region was dissected in an attempt to identify residues critical
      for Wzc(CPS) phosphorylation and/or capsule expression. Site-directed mutagenesis
      demonstrated that no single tyrosine residue in this region is sufficient for
      detectable phosphorylation of Wzc(CPS) in vivo or for HMW CPS expression.
      Furthermore, no single tyrosine residue is essential for phosphorylation or
      capsule assembly, since removal of any one tyrosine residue has no detectable
      effect. Altering combinations of tyrosine residues (from two to five) led to
      Wzc(CPS) derivatives that were still competent for phosphorylation but that could
      not support assembly of HMW CPS, showing that phosphorylation of Wzc per se is
      not an accurate measure of its ability to function in capsule assembly. One
      interpretation of these data is that the overall level of phosphorylation in this
      region, rather than the precise combination of residues accessible to
      phosphorylation, is important for the activity of Wzc(CPS). Tyrosine 569, a
      residue shown to modulate the in vitro phosphorylation of Wzc(CA) from E. coli K
      12, was also mutated. The derivative with this mutation still functioned in
      capsule assembly. Quantitation of K30(CPS) from this mutant revealed no
      difference in the amount of polymer produced. Finally,
      dithiobis(succinimidylpropionate) cross-linking was used to confirm that Wzc(CPS)
      forms complexes in vivo, independent of the phosphorylation state of the protein.

PMID- 12426331
TI  - Structural analysis and evidence for dynamic emergence of Bacillus anthracis S
      layer networks.
AB  - Surface layers (S-layers), which form the outermost layers of many Bacteria and
      Archaea, consist of protein molecules arranged in two-dimensional crystalline
      arrays. Bacillus anthracis, a gram-positive, spore-forming bacterium, responsible
      for anthrax, synthesizes two abundant surface proteins: Sap and EA1. Regulatory
      studies showed that EA1 and Sap appear sequentially at the surface of the
      parental strain. Sap and EA1 can form arrays. The structural parameters of S
      layers from mutant strains (EA1(-) and Sap(-)) were determined by computer image
      processing of electron micrographs of negatively stained regular S-layer
      fragments or deflated whole bacteria. Sap and EA1 projection maps were calculated
      on a p1 symmetry basis. The unit cell parameters of EA1 were a = 69 A, b = 83 A,
      and gamma = 106 degrees, while those of Sap were a = 184 A, b = 81 A, and gamma =
      84 degrees. Freeze-etching experiments and the analysis of the peripheral regions
      of the cell suggested that the two S-layers have different settings. We
      characterized the settings of each network at different growth phases. Our data
      indicated that the scattered emergence of EA1 destabilizes the Sap S-layer.

PMID- 12426332
TI  - vanE gene cluster of vancomycin-resistant Enterococcus faecalis BM4405.
AB  - Acquired VanE-type resistance to low levels of vancomycin (MIC = 16 microg/ml) in
      Enterococcus faecalis BM4405 is due to the inducible synthesis of peptidoglyean
      precursors terminating in D-alanine-D-serine (Fines,M., B. Prichon, P. Reynolds,
      D. Sahm, and P. Courvalin, Antimicrob. Agents Chemother. 43:2161-2164, 1999). A
      chromosomal location was assigned to the vanE operon by pulsed-field gel
      electrophoresis and hybridization, and its sequence was determined. Three genes,
      encoding the VanE ligase, the VanXYE DD-peptidase, and the VanTE serine racemase,
      that displayed 43 to 53% identity with the corresponding genes in the vanC operon
      were found. In addition, two genes coding for a two-component regulatory system,
      VanRE-VanSE, exhibiting 60 and 44% identity with VanR,-VanS, were present
      downstream from vanTE. However, because of a stop codon at position 78, VanSE was
      probably not functional. The five genes, with the same orientation, were shown to
      be cotranscribed by Northern analysis and reverse transcription-PCR. The vanE,
      vanXYE, and vanTE genes conferred inducible low-level resistance to vancomycin
      after cloning in E. faecalis JH2-2, probably following cross talk with a two
      component regulatory system of the host.

PMID- 12426333
TI  - Aquifex aeolicus PilT, homologue of a surface motility protein, is a thermostable
      oligomeric NTPase.
AB  - Bacterial surface motility works by retraction of surface-attached type IV pili.
      This retraction requires the PilT protein, a member of a large family of putative
      NTPases from type II and IV secretion systems. In this study, the PilT homologue
      from the thermophilic eubacterium Aquifex aeolicus was cloned, overexpressed, and
      purified. A. aeolicus PilT was shown to be a thermostable ATPase with a specific
      activity of 15.7 nmol of ATP hydrolyzed/min/mg of protein. This activity was
      abolished when a conserved lysine in the nucleotide-binding motif was altered.
      The substrate specificity was low; UTP, CTP, ATP, GTP, dATP, and dGTP served as
      substrates, UTP having the highest activity of these in vitro. Based on
      sedimentation equilibrium and size exclusion chromatography, PilT was identified
      as a approximately equal 5- to 6-subunit oligomer. Potential implications of the
      NTPase activity of PilT in pilus retraction are discussed.

PMID- 12426334
TI  - Functions required for extracellular quinolone signaling by Pseudomonas
      aeruginosa.
AB  - A set of 30 mutants exhibiting reduced production of the phenazine poison
      pyocyanin were isolated following transposon mutagenesis of Pseudomonas
      aeruginosa PAO1. The mutants could be subdivided into those with defects in the
      primary phenazine biosynthetic pathway and those with more pleiotropic defects.
      The largest set of pleiotropic mutations blocked the production of the
      extracellular Pseudomonas quinolone signal (PQS), a molecule required for the
      synthesis of secondary metabolites and extracellular enzymes. Most of these pqs
      mutations affected genes which appear to encode PQS biosynthetic functions,
      although a transcriptional regulator and an apparent response effector were also
      represented. Two of the genes required for PQS synthesis (phnA and phnB) had
      previously been assumed to encode phenazine biosynthetic functions. The
      transcription of one of the genes required for PQS synthesis (PA2587/pqsH) was
      regulated by the LasI/R quorum-sensing system, thereby linking quorum sensing and
      PQS regulation. Others of the pleiotropic phenazine-minus mutations appear to
      inactivate novel components of the quorum-sensing regulatory network, including
      one regulator (np20) previously shown to be required for virulence in neutropenic
      mice.

PMID- 12426335
TI  - Autolysis and autoaggregation in Pseudomonas aeruginosa colony morphology
      mutants.
AB  - Two distinctive colony morphologies were noted in a collection of Pseudomonas
      aeruginosa transposon insertion mutants. One set of mutants formed wrinkled
      colonies of autoaggregating cells. Suppressor analysis of a subset of these
      mutants showed that this was due to the action of the regulator WspR and linked
      this regulator (and the chemosensory pathway to which it belongs) to genes that
      encode a putative fimbrial adhesin required for biofilm formation. WspR homologs,
      related in part by a shared GGDEF domain, regulate cell surface factors,
      including aggregative fimbriae and exopolysaccharides, in diverse bacteria. The
      second set of distinctive insertion mutants formed colonies that lysed at their
      center. Strains with the most pronounced lysis overproduced the Pseudomonas
      quinolone signal (PQS), an extracellular signal that interacts with quorum
      sensing. Autolysis was suppressed by mutation of genes required for PQS
      biosynthesis, and in one suppressed mutant, autolysis was restored by addition of
      synthetic PQS. The mechanism of autolysis may involve activation of the
      endogenous prophage and phage-related pyocins in the genome of strain PAO1. The
      fact that PQS levels correlated with autolysis suggests a fine balance in natural
      populations of P. aeruginosa between survival of the many and persistence of the
      few.

PMID- 12426336
TI  - Substrate specificity of the RND-type multidrug efflux pumps AcrB and AcrD of
      Escherichia coli is determined predominantly by two large periplasmic loops.
AB  - AcrAB-TolC is a constitutively expressed, tripartite efflux transporter complex
      that functions as the primary resistance mechanism to lipophilic drugs, dyes,
      detergents, and bile acids in Escherichia coli. TolC is an outer membrane
      channel, and AcrA is an elongated lipoprotein that is hypothesized to span the
      periplasm and coordinate efflux of such substrates by AcrB and TolC. AcrD is an
      efflux transporter of E. coli that provides resistance to aminoglycosides as well
      as to a limited range of amphiphilic agents, such as bile acids, novobiocin, and
      fusidic acid. AcrB and AcrD belong to the resistance nodulation division
      superfamily and share a similar topology, which includes a pair of large
      periplasmic loops containing more than 300 amino acid residues each. We used this
      knowledge to test several plasmid-encoded chimeric constructs of acrD and acrB
      for substrate specificity in a marR1 DeltaacrB DeltaacrD host. AcrD chimeras were
      constructed in which the large, periplasmic loops between transmembrane domains 1
      and 2 and 7 and 8 were replaced with the corresponding loops of AcrB. Such
      constructs provided resistance to AcrB substrates at levels similar to native
      AcrB. Conversely, AcrB chimeras containing both loops of AcrD conferred
      resistance only to the typical substrates of AcrD. These results cannot be
      explained by simply assuming that AcrD, not hitherto known to interact with AcrA,
      acquired this ability by the introduction of the loop regions of AcrB, because
      (i) both AcrD and AcrA were found, in this study, to be required for the efflux
      of amphiphilic substrates, and (ii) chemical cross-linking in intact cells
      efficiently produced complexes between AcrD and AcrA. Since AcrD can already
      interact with AcrA, the alterations in substrate range accompanying the exchange
      of loop regions can only mean that substrate recognition (and presumably binding)
      is determined largely by the two periplasmic loops.

PMID- 12426337
TI  - Chimeric analysis of the multicomponent multidrug efflux transporters from gram
      negative bacteria.
AB  - Many multidrug transporters from gram-negative bacteria belong to the resistance
      nodulation-cell division (RND) superfamily of transporters. RND-type multidrug
      transporters have an extremely broad substrate specificity and protect bacterial
      cells from the actions of antibiotics on both sides of the cytoplasmic membrane.
      They usually function as three-component assemblies spanning the outer and
      cytoplasmic membranes and the periplasmic space of gram-negative bacteria. The
      structural determinants of RND transporters responsible for multidrug recognition
      and complex assembly remain unknown. We constructed chimeric RND transporters
      composed of N-terminal residues of AcrB and C-terminal residues of MexB, the
      major RND-type transporters from Escherichia coli and Pseudomonas aeruginosa,
      respectively. The assembly of complexes and multidrug efflux activities of
      chimeric transporters were determined by coexpression of hybrid genes either with
      AcrA, the periplasmic component of the AcrAB transporter from E. coli, or with
      MexA and OprM, the accessory proteins of the MexAB-OprM pump from P. aeruginosa.
      We found that the specificity of interaction with the corresponding periplasmic
      component is encoded in the T60-V612 region of transporters. Our results also
      suggest that the large periplasmic loops of RND-type transporters are involved in
      multidrug recognition and efflux.

PMID- 12426338
TI  - Functional analysis of the Bacillus subtilis Zur regulon.
AB  - The Bacillus subtilis zinc uptake repressor (Zur) regulates genes involved in
      zinc uptake. We have used DNA microarrays to identify genes that are derepressed
      in a zur mutant. In addition to members of the two previously identified Zur
      regulated operons (yciC and ycdHI-yceA), we identified two other genes, yciA and
      yciB, as targets of Zur regulation. Electrophoretic mobility shift experiments
      demonstrated that all three operons are direct targets of Zur regulation. Zur
      binds to an approximately 28-bp operator upstream of the yciA gene, as judged by
      DNase I footprinting, and similar operator sites are found preceding each of the
      previously described target operons, yciC and ycdHI-yceA. Analysis of a yciA-lacZ
      fusion indicates that this operon is induced under zinc starvation conditions and
      derepressed in the zur mutant. Phenotypic analyses suggest that the YciA, YciB,
      and YciC proteins may function as part of the same Zn(II) transport pathway.
      Mutation of yciA or yciC, singly or in combination, had little effect on growth
      of the wild-type strain but significantly impaired the growth of the ycdH mutant
      under conditions of zinc limitation. Since the YciA, YciB, and YciC proteins are
      not obviously related to any known transporter family, they may define a new
      class of metal ion uptake system. Mutant strains lacking all three identified
      zinc uptake systems (yciABC, ycdHI-yceA, and zosA) are dependent on micromolar
      levels of added zinc for optimal growth.

PMID- 12426339
TI  - Long-chain acyl-homoserine lactone quorum-sensing regulation of Rhodobacter
      capsulatus gene transfer agent production.
AB  - Many proteobacteria use acyl-homoserine lactones as quorum-sensing signals.
      Traditionally, biological detection systems have been used to identify bacteria
      that produce acyl-homoserine lactones, although the specificities of these
      detection systems can limit discovery. We used a sensitive approach that did not
      require a bioassay to detect production of long-acyl-chain homoserine lactone
      production by Rhodobacter capsulatus and Paracoccus denitrificans. These long
      chain acyl-homoserine lactones are not readily detected by standard bioassays.
      The most abundant acyl-homoserine lactone was N-hexadecanoyl-homoserine lactone.
      The long-chain acyl-homoserine lactones were concentrated in cells but were also
      found in the culture fluid. An R. capsulatus gene responsible for long-chain acyl
      homoserine lactone synthesis was identified. A mutation in this gene, which we
      named gtaI, resulted in decreased production of the R. capsulatus gene transfer
      agent, and gene transfer agent production was restored by exogenous addition of N
      hexadecanoyl-homoserine lactone. Thus, long-chain acyl-homoserine lactones serve
      as quorum-sensing signals to enhance genetic exchange in R. capsulatus.

PMID- 12426340
TI  - Programmed translational frameshift in the bacteriophage P2 FETUD tail gene
      operon.
AB  - The major structural components of the P2 contractile tail are encoded in the
      FETUD tail gene operon. The sequences of genes F(I) and F(II), encoding the major
      tail sheath and tail tube proteins, have been reported previously (L. M. Temple,
      S. L. Forsburg, R. Calendar, and G. E. Christie, Virology 181:353-358, 1991).
      Sequence analysis of the remainder of this operon and the locations of amber
      mutations Eam30, Tam5, Tam64, Tam215, Uam25, Uam77, Uam92, and Dam6 and missense
      mutation Ets55 identified the coding regions for genes E, T, U, and D, completing
      the sequence determination of the P2 genome. Inspection of the DNA sequence
      revealed a new open reading frame overlapping the end of the essential tail gene
      E. Lack of an apparent translation initiation site and identification of a
      putative sequence for a programmed translational frameshift within the E gene
      suggested that this new reading frame (E') might be translated as an extension of
      gene E, following a -1 translational frameshift. Complementation analysis
      demonstrated that E' was essential for P2 lytic growth. Analysis of fusion
      polypeptides verified that this reading frame was translated as a -1 frameshift
      extension of gpE, with a frequency of approximately 10%. The arrangement of these
      two genes within the tail gene cluster of phage P2 and their coupling via a
      translational frameshift appears to be conserved among P2-related phages. This
      arrangement shows a striking parallel to the organization in the tail gene
      cluster of phage lambda, despite a lack of amino acid sequence similarity between
      the tail gene products of these phage families.

PMID- 12426341
TI  - Lactococcus lactis lytic bacteriophages of the P335 group are inhibited by
      overexpression of a truncated CI repressor.
AB  - Phages of the P335 group have recently emerged as important taxa among
      lactococcal phages that disrupt dairy fermentations. DNA sequencing has revealed
      extensive homologies between the lytic and temperate phages of this group. The
      P335 lytic phage phi31 encodes a genetic switch region of cI and cro homologs but
      lacks the phage attachment site and integrase necessary to establish lysogeny.
      When the putative cI repressor gene of phage phi31 was subcloned into the medium
      copy-number vector pAK80, no superinfection immunity was conferred to the host,
      Lactococcus lactis subsp. lactis NCK203, indicating that the wild-type CI
      repressor was dysfunctional. Attempts to clone the full-length cI gene in
      Lactococcus in the high-copy-number shuttle vector pTRKH2 were unsuccessful. The
      single clone that was recovered harbored an ochre mutation in the cI gene after
      the first 128 amino acids of the predicted 180-amino-acid protein. In the
      presence of the truncated CI construct, pTRKH2::CI-per1, phage phi31 was
      inhibited to an efficiency of plaquing (EOP) of 10(-6) in NCK203. A pTRKH2
      subclone which lacked the DNA downstream of the ochre mutation, pTRKH2::CI-per2,
      confirmed the phenotype and further reduced the phi31 EOP to <10(-7). Phage phi31
      mutants, partially resistant to CI-per, were isolated and showed changes in two
      of three putative operator sites for CI and Cro binding. Both the wild-type and
      truncated CI proteins bound the two wild-type operators in gel mobility shift
      experiments, but the mutated operators were not bound by the truncated CI. Twelve
      of 16 lytic P335 group phages failed to form plaques on L. lactis harboring
      pTRKH2::CI-per2, while 4 phages formed plaques at normal efficiencies.
      Comparisons of amino acid and DNA level homologies with other lactococcal
      temperate phage repressors suggest that evolutionary events may have led to
      inactivation of the phi31 CI repressor. This study demonstrated that a number of
      different P335 phages, lytic for L. lactis NCK203, have a common operator region
      which can be targeted by a truncated derivative of a dysfunctional CI repressor.

PMID- 12426342
TI  - Isolation of the gene for the B12-dependent ribonucleotide reductase from
      Anabaena sp. strain PCC 7120 and expression in Escherichia coli.
AB  - The gene for ribonucleotide reductase from Anabaena sp. strain PCC 7120 was
      identified and expressed in Escherichia coli. This gene codes for a 1,172-amino
      acid protein that contains a 407-amino-acid intein. The intein splices itself
      from the protein when it is expressed in E. coli, yielding an active
      ribonucleotide reductase of 765 residues. The mature enzyme was purified to
      homogeneity from E. coli extracts. Anabaena ribonucleotide reductase is a monomer
      with a molecular weight of approximately 88,000, as determined by sodium dodecyl
      sulfate-polyacrylamide gel electrophoresis and Superose 12 column chromatography.
      The enzyme reduces ribonucleotides at the triphosphate level and requires a
      divalent cation and a deoxyribonucleoside triphosphate effector. The enzyme is
      absolutely dependent on the addition of the cofactor, 5'-adenosylcobalamin. These
      properties are characteristic of the class II-type reductases. The cyanobacterial
      enzyme has limited sequence homology to other class II reductases; the greatest
      similarity (38%) is to the reductase from Lactobacillus leichmannii. In contrast,
      the Anabaena reductase shows over 90% sequence similarity to putative reductases
      found in genome sequences of other cyanobacteria, such as Nostoc punctiforme,
      Synechococcus sp. strain WH8102, and Prochlorococcus marinus MED4, suggesting
      that the cyanobacterial reductases form a closely related subset of the class II
      enzymes.

PMID- 12426343
TI  - Gene expression profiling of the pH response in Escherichia coli.
AB  - Escherichia coli MG1655 acid-inducible genes were identified by whole-genome
      expression profiling. Cultures were grown to the mid-logarithmic phase on
      acidified glucose minimal medium, conditions that induce glutamate-dependent acid
      resistance (AR), while the other AR systems are either repressed or not induced.
      A total of 28 genes were induced in at least two of three experiments in which
      the gene expression profiles of cells grown in acid (pH 5.5 or 4.5) were compared
      to those of cells grown at pH 7.4. As expected, the genes encoding glutamate
      decarboxylase, gadA and gadB, were significantly induced. Interestingly, two acid
      inducible genes code for small basic proteins with pIs of >10.5, and six code for
      small acidic proteins with pIs ranging from 5.7 to 4.0; the roles of these small
      basic and acidic proteins in acid resistance are unknown. The acid-induced genes
      represented only five functional grouping categories, including eight genes
      involved in metabolism, nine associated with cell envelope structures or
      modifications, two encoding chaperones, six regulatory genes, and six unknown
      genes. It is unlikely that all of these genes are involved in the glutamate
      dependent AR. However, nine acid-inducible genes are clustered in the gadA
      region, including hdeA, which encodes a putative periplasmic chaperone, and four
      putative regulatory genes. One of these putative regulators, yhiE, was shown to
      significantly increase acid resistance when overexpressed in cells that had not
      been preinduced by growth at pH 5.5, and mutation of yhiE decreased acid
      resistance; yhiE could therefore encode an activator of AR genes. Thus, the acid
      inducible genes clustered in the gadA region appear to be involved in glutatmate
      dependent acid resistance, although their specific roles remain to be elucidated.

PMID- 12426344
TI  - Mutants of Streptomyces clavuligerus with disruptions in different genes for
      clavulanic acid biosynthesis produce large amounts of holomycin: possible cross
      regulation of two unrelated secondary metabolic pathways.
AB  - A Streptomyces clavuligerus ccaR::aph strain, which has a disruption in the
      regulatory gene ccaR, does not produce cephamycin C or clavulanic acid, but does
      produce a bioactive compound that was identified as holomycin by high-performance
      liquid chromatography (HPLC) and infrared and mass spectrometry. S. clavuligerus
      strains with disruptions in different genes of the clavulanic acid pathway fall
      into three groups with respect to holomycin biosynthesis. (i) Mutants with
      mutations in the early steps of the pathway blocked in the gene ceaS (pyc)
      (encoding carboxyethylarginine synthase), bls (encoding a beta-lactam
      synthetase), or open reading frame 6 (ORF6; coding for an acetyltransferase of
      unknown function) are holomycin nonproducers. (ii) Mutants blocked in the
      regulatory gene ccaR or claR or blocked in the last gene of the pathway encoding
      clavulanic acid reductase (car) produce holomycin at higher levels than the wild
      type strain. (iii) Mutants with disruption in cyp (coding for cytochrome P450),
      ORF12, and ORF15, genes that appear to be involved in the conversion of
      clavaminic acid into clavaldehyde or in secretion steps, produce up to 250-fold
      as much holomycin as the wild-type strain. An assay for holomycin synthetase was
      developed. This enzyme forms holomycin from holothin by using acetyl coenzyme A
      as an acetyl group donor. The holomycin synthase activities in the different
      clavulanic acid mutants correlate well with their production of holomycin.

PMID- 12426345
TI  - Functional analysis of the heat shock regulator HrcA of Chlamydia trachomatis.
AB  - HrcA is a regulator of bacterial heat shock gene expression that binds to a cis
      acting DNA element called CIRCE. It has been proposed that HrcA and CIRCE
      function as a repressor-operator pair. We have purified recombinant HrcA from the
      pathogenic bacterium Chlamydia trachomatis and have shown that it is a DNA
      binding protein that functions as a negative regulator of transcription. HrcA
      bound specifically to the CIRCE element in a concentration-dependent manner. HrcA
      repressed the in vitro transcription of a chlamydial heat shock promoter, and
      this repression was promoter specific. HrcA-mediated repression appears to be
      dependent on the topological state of the promoter, as repression on a
      supercoiled promoter template was greater than that on a linearized template.
      These results provide direct support for the role of HrcA as a transcriptional
      repressor in bacteria. This is the first report of the in vitro reconstitution of
      transcriptional regulation in Chlamydia.

PMID- 12426346
TI  - A third transposable element, ISPpu12, from the toluene-xylene catabolic plasmid
      pWW0 of Pseudomonas putida mt-2.
AB  - A 3,372-bp insertion sequence, ISPpu12, has been identified on the archetypal
      toluene-xylene TOL catabolic plasmid pWW0 from Pseudomonas putida mt-2. The
      insertion sequence element is located on the plasmid between bases 84397 and
      87768 in a region which also contains the termini and transposase genes of the
      catabolic transposons Tn4651 and Tn4653 (A. Greated, L. Lambertson, P. A.
      Williams, and C. M. Thomas, Environ. Microbiol., in press). ISPpu12 has terminal
      inverted repeats of 24 bp with three mismatches and contains four open reading
      frames, a tnpA homologue and three open reading frames (lspA, orf1, and orf2) of
      undetermined function. After insertion in vitro of a Km(r) cassette into ISPpu12
      either in the intergenic region between orf1 and orf2 or directly into the orf1
      gene and ligation into a suicide vector, the modified ISPpu12-Km transposes at
      high frequency, often in multiple copies, into the chromosome of a P. putida
      recipient. Inactivation of lspA, orf1, and orf2 by introducing a 7-bp deletion
      into the 5' region of each gene had no major effect upon transposition, but a
      similar mutation of tnpA completely eliminated transposition. Analysis of the
      literature and of strains derived from the chlorobenzoate-degrading Pseudomonas
      sp. strain B13 suggests that the promiscuity of this element has played an
      important role in the history of plasmid pWW0. Database comparisons and the
      accompanying paper (A. J. Weightman, A. W. Topping, K. E. Hill, L. L. Lee, K.
      Sakai, J. H. Slater, and A. W. Thomas, J. Bacteriol. 184:6581-6591, 2002) show
      that ISPpu12 is a transposable element also found in other bacteria.

PMID- 12426347
TI  - Transposition of DEH, a broad-host-range transposon flanked by ISPpu12, in
      Pseudomonas putida is associated with genomic rearrangements and dehalogenase
      gene silencing.
AB  - Pseudomonas putida strain PP3 produces two hydrolytic dehalogenases encoded by
      dehI and dehII, which are members of different deh gene families. The 9.74-kb DEH
      transposon containing dehI and its cognate regulatory gene, dehR(I), was isolated
      from strain PP3 by using the TOL plasmid pWW0. DEH was fully sequenced and shown
      to have a composite transposon structure, within which dehI and dehR(I) were
      divergently transcribed and were flanked on either side by 3.73-kb identical
      direct repeats. The flanking repeat unit, designated ISPpu12, had the structure
      of an insertion sequence in that it was bordered by 24-bp near-perfect inverted
      repeats and contained four open reading frames (ORFs), one of which was
      identified as tnpA, putatively encoding an ISL3 family transposase. A putative
      lipoprotein signal peptidase was encoded by an adjacent ORF, lspA, and the
      others, ISPpu12 orf1 and orf2, were tentatively identified as a truncated cation
      efflux transporter gene and a PbrR family regulator gene, respectively. The orf1
      orf2 intergenic region contained an exact match with a previously described
      active, outward-orientated promoter, Pout. Transposition of DEH-ISPpu12 was
      investigated by cloning the whole transposon into a suicide plasmid donor,
      pAWT34, and transferring the construct to various recipients. In this way DEH
      ISPpu12 was shown to transpose in a broad range of Proteobacteria. Transposition
      of ISPpu12 independently from DEH, and inverse transposition, whereby the vector
      DNA and ISPpu12 inserted into the target genome without the deh genes, were also
      observed to occur at high frequencies in P. putida PaW340. Transposition of a
      second DEH-ISPpu12 derivative introduced exogenously into P. putida PP3 via the
      suicide donor pAWT50 resulted in silencing of resident dehI and dehII genes in
      about 10% of transposition transconjugants and provided a genetic link between
      transposition of ISPpu12 and dehalogenase gene silencing. Database searches
      identified ISPpu12-related sequences in several bacterial species, predominantly
      associated with plasmids and xenobiotic degradative genes. The potential role of
      ISPpu12 in gene silencing and activation, as well as the adaptation of bacteria
      to degrade xenobiotic compounds, is discussed.

PMID- 12426348
TI  - Vibrio cholerae phage K139: complete genome sequence and comparative genomics of
      related phages.
AB  - In this report, we characterize the complete genome sequence of the temperate
      phage K139, which morphologically belongs to the Myoviridae phage family (P2 and
      186). The prophage genome consists of 33,106 bp, and the overall GC content is
      48.9%. Forty-four open reading frames were identified. Homology analysis and
      motif search were used to assign possible functions for the genes, revealing a
      close relationship to P2-like phages. By Southern blot screening of a Vibrio
      cholerae strain collection, two highly K139-related phage sequences were detected
      in non-O1, non-O139 strains. Combinatorial PCR analysis revealed almost identical
      genome organizations. One region of variable gene content was identified and
      sequenced. Additionally, the tail fiber genes were analyzed, leading to the
      identification of putative host-specific sequence variations. Furthermore, a K139
      encoded Dam methyltransferase was characterized.

PMID- 12426349
TI  - Arginine operator binding by heterologous and chimeric ArgR repressors from
      Escherichia coli and Bacillus stearothermophilus.
AB  - Bacillus stearothermophilus ArgR binds efficiently to the Escherichia coli carAB
      operator, whereas the E. coli repressor binds very poorly to the argCo operator
      of B. stearothermophilus. In order to elucidate this contradictory behavior
      between ArgRs, we constructed chimeric proteins by swapping N-terminal DNA
      binding and C-terminal oligomerization domains or by exchanging the linker
      peptide. Chimeras carrying the E. coli DNA-binding domain and the B.
      stearothermophilus oligomerization domain showed sequence-nonspecific rather than
      sequence-specific interactions with arg operators. Chimeras carrying the B.
      stearothermophilus DNA-binding domain and E. coli oligomerization domain
      exhibited a high DNA-binding affinity for the B. stearothermophilus argCo and E.
      coli carAB operators and repressed the reporter-gene transcription from the B.
      stearothermophilus PargCo control region in vitro; arginine had no effect on, and
      indeed even decreased, their DNA-binding affinity. With the protein array method,
      we showed that the wild-type B. stearothermophilus ArgR and derivatives of it
      containing only the exchanged linker from E. coli ArgR or carrying the B.
      stearothermophilus DNA-binding domain along with the linker and the alpha4
      regions were able to bind argCo containing the single Arg box. This binding was
      weaker than binding to the two-box operator but was no longer arginine dependent.
      Several lines of observations indicate that the alpha4 helix in the
      oligomerization domain and the linker peptide can contribute to the recognition
      of single or double Arg boxes and therefore to the operator DNA-binding
      specificity in similar but not identical ArgR repressors from two distant
      bacteria.

PMID- 12426350
TI  - Transcriptional phase variation of a type III restriction-modification system in
      Helicobacter pylori.
AB  - Phase variation is important in bacterial pathogenesis, since it generates
      antigenic variation for the evasion of immune responses and provides a strategy
      for quick adaptation to environmental changes. In this study, a Helicobacter
      pylori clone, designated MOD525, was identified that displayed phase-variable
      lacZ expression. The clone contained a transcriptional lacZ fusion in a putative
      type III DNA methyltransferase gene (mod, a homolog of the gene JHP1296 of strain
      J99), organized in an operon-like structure with a putative type III restriction
      endonuclease gene (res, a homolog of the gene JHP1297), located directly upstream
      of it. This putative type III restriction-modification system was common in H.
      pylori, as it was present in 15 out of 16 clinical isolates. Phase variation of
      the mod gene occurred at the transcriptional level both in clone MOD525 and in
      the parental H. pylori strain 1061. Further analysis showed that the res gene
      also displayed transcriptional phase variation and that it was cotranscribed with
      the mod gene. A homopolymeric cytosine tract (C tract) was present in the 5'
      coding region of the res gene. Length variation of this C tract caused the res
      open reading frame (ORF) to shift in and out of frame, switching the res gene on
      and off at the translational level. Surprisingly, the presence of an intact res
      ORF was positively correlated with active transcription of the downstream mod
      gene. Moreover, the C tract was required for the occurrence of transcriptional
      phase variation. Our finding that translation and transcription are linked during
      phase variation through slipped-strand mispairing is new for H. pylori.

PMID- 12426351
TI  - The nitrate reductase and nitrite reductase operons and the narT gene of
      Staphylococcus carnosus are positively controlled by the novel two-component
      system NreBC.
AB  - In Staphylococcus carnosus, the nreABC (for nitrogen regulation) genes were
      identified and shown to link the nitrate reductase operon (narGHJI) and the
      putative nitrate transporter gene narT. An nreABC deletion mutant, m1, was
      dramatically affected in nitrate and nitrite reduction and growth. Transcription
      of narT, narGHJI, and the nitrite reductase (nir) operon was severely reduced
      even when cells were cultivated anaerobically without nitrate or nitrite. nreABC
      transcripts were detected when cells were grown aerobically or anaerobically with
      or without nitrate or nitrite. NreA is a GAF domain-containing protein of unknown
      function. In vivo and in vitro studies showed that NreC is phosphorylated by NreB
      and that phospho-NreC specifically binds to a GC-rich palindromic sequence to
      enhance transcription initiation. This binding motif was found at the narGHJI,
      nir, and narT promoters but not at the moeB promoter. NreB is a cytosolic protein
      with four N-terminal cysteine residues. The second cysteine residue was shown to
      be important for NreB function. In vitro autophosphorylation of NreB was not
      affected by nitrate, nitrite, or molybdate. The nir promoter activity was iron
      dependent. The data provide evidence for a global regulatory system important for
      aerobic and anaerobic metabolism, with NreB and NreC forming a classical two
      component system and NreB acting as a sensor protein with oxygen as the effector
      molecule.

PMID- 12426352
TI  - Degradation of a Caulobacter soluble cytoplasmic chemoreceptor is ClpX dependent.
AB  - In order to determine whether ClpXP-mediated proteolysis is a common mechanism
      used to regulate the chemotaxis machinery during the cell cycle of Caulobacter
      crescentus, we have characterized a soluble cytoplasmic chemoreceptor, McpB. The
      mcpB gene lies adjacent to the major chemotaxis operon, which encodes 12
      chemotaxis proteins, including the membrane chemoreceptor McpA. Like McpA, McpB
      possesses a C-terminal CheBR docking motif and three potential methylation sites,
      which we suggest are methylated. The McpB protein is degraded via a ClpX
      dependent pathway during the swarmer-to-stalked cell transition, and a motif,
      which is 3 amino acids N-terminal to the McpB CheBR docking site, is required for
      proteolysis. Analysis of the degradation signal in McpB and McpA reveals a common
      motif present in the other four chemoreceptors that possess CheBR docking sites.
      A green fluorescent protein (GFP) fusion bearing 58 amino acids from the C
      terminus of McpA, which contains this motif, is degraded, suggesting that the C
      terminal sequence is sufficient to confer ClpXP protease susceptibility.

PMID- 12426353
TI  - Regulation of the hydrogenase-4 operon of Escherichia coli by the sigma(54)
      dependent transcriptional activators FhlA and HyfR.
AB  - The hyf locus (hyfABCDEFGHIJ-hyfR-focB) of Escherichia coli encodes a putative 10
      subunit hydrogenase complex (hydrogenase-4 [Hyf]); a potential sigma(54)
      dependent transcriptional activator, HyfR (related to FhlA); and a putative
      formate transporter, FocB (related to FocA). In order to gain insight into the
      physiological role of the Hyf system, we investigated hyf expression by using a
      hyfA-lacZ transcriptional fusion. This work revealed that hyf is induced under
      fermentative conditions by formate at a low pH and in an FhlA-dependent fashion.
      Expression was sigma(54) dependent and was inhibited by HycA, the negative
      transcriptional regulator of the formate regulon. Thus, hyf expression resembles
      that of the hyc operon. Primer extension analysis identified a transcriptional
      start site 30 bp upstream of the hyfA structural gene, with appropriately located
      -24 and -12 boxes indicative of a sigma(54)-dependent promoter. No reverse
      transcriptase PCR product could be detected for hyfJ-hyfR, suggesting that hyfR
      focB may be independently transcribed from the rest of the hyf operon. Expression
      of hyf was strongly induced ( approximately 1,000-fold) in the presence of a
      multicopy plasmid expressing hyfR from a heterologous promoter. This induction
      was dependent on low pH, anaerobiosis, and postexponential growth and was weakly
      enhanced by formate. The hyfR-expressing plasmid increased fdhF-lacZ
      transcription just twofold but did not influence the expression of hycB-lacZ.
      Interestingly, inactivation of the chromosomal hyfR gene had no effect on hyfA
      lacZ expression. Purified HyfR was found to specifically interact with the hyf
      promoter/operator region. Inactivation of the hyf operon had no discernible
      effect on growth under the range of conditions tested. No Hyf-derived hydrogenase
      or formate dehydrogenase activity could be detected, and no Ni-containing protein
      corresponding to HyfG was observed.

PMID- 12426354
TI  - Differential expression of the CO2 fixation operons of Rhodobacter sphaeroides by
      the Prr/Reg two-component system during chemoautotrophic growth.
AB  - In Rhodobacter sphaeroides, the two cbb operons encoding duplicated Calvin-Benson
      Bassham (CBB) CO2 fixation reductive pentose phosphate cycle structural genes are
      differentially controlled. In attempts to define the molecular basis for the
      differential regulation, the effects of mutations in genes encoding a subunit of
      Cbb3 cytochrome oxidase, ccoP, and a global response regulator, prrA (regA), were
      characterized with respect to CO2 fixation (cbb) gene expression by using
      translational lac fusions to the R. sphaeroides cbb(I) and cbb(II) promoters.
      Inactivation of the ccoP gene resulted in derepression of both promoters during
      chemoheterotophic growth, where cbb expression is normally repressed; expression
      was also enhanced over normal levels during phototrophic growth. The prrA
      mutation effected reduced expression of cbb(I) and cbb(II) promoters during
      chemoheterotrophic growth, whereas intermediate levels of expression were
      observed in a double ccoP prrA mutant. PrrA and ccoP1 prrA strains cannot grow
      phototrophically, so it is impossible to examine cbb expression in these
      backgrounds under this growth mode. In this study, however, we found that PrrA
      mutants of R. sphaeroides were capable of chemoautotrophic growth, allowing, for
      the first time, an opportunity to directly examine the requirement of PrrA for
      cbb gene expression in vivo under growth conditions where the CBB cycle and CO2
      fixation are required. Expression from the cbb(II) promoter was severely reduced
      in the PrrA mutants during chemoautotrophic growth, whereas cbb(I) expression was
      either unaffected or enhanced. Mutations in ccoQ had no effect on expression from
      either promoter. These observations suggest that the Prr signal transduction
      pathway is not always directly linked to Cbb3 cytochrome oxidase activity, at
      least with respect to cbb gene expression. In addition, lac fusions containing
      various lengths of the cbb(I) promoter demonstrated distinct sequences involved
      in positive regulation during photoautotrophic versus chemoautotrophic growth,
      suggesting that different regulatory proteins may be involved. In Rhodobacter
      capsulatus, ribulose 1,5-bisphosphate carboxylase-oxygenase (RubisCO) expression
      was not affected by cco mutations during photoheterotrophic growth, suggesting
      that differences exist in signal transduction pathways regulating cbb genes in
      the related organisms.

PMID- 12426355
TI  - Gene islands integrated into tRNA(Gly) genes confer genome diversity on a
      Pseudomonas aeruginosa clone.
AB  - Intraclonal genome diversity of Pseudomonas aeruginosa was studied in one of the
      most diverse mosaic regions of the P. aeruginosa chromosome. The ca. 110-kb large
      hypervariable region located near the lipH gene in two members of the predominant
      P. aeruginosa clone C, strain C and strain SG17M, was sequenced. In both strains
      the region consists of an individual strain-specific gene island of 111 (strain
      C) or 106 (SG17M) open reading frames (ORFs) and of a 7-kb stretch of clone C
      specific sequence of 9 ORFs. The gene islands are integrated into conserved
      tRNA(Gly) genes and have a bipartite structure. The first part adjacent to the
      tRNA gene consists of strain-specific ORFs encoding metabolic functions and
      transporters, the majority of which have homologs of known function in other
      eubacteria, such as hemophores, cytochrome c biosynthesis, or mercury resistance.
      The second part is made up mostly of ORFs of yet-unknown function. Forty-seven of
      these ORFs are mutual homologs with a pairwise amino acid sequence identity of 35
      to 88% and are arranged in the same order in the two gene islands. We hypothesize
      that this novel type of gene island derives from mobile elements which, upon
      integration, endow the recipient with strain-specific metabolic properties, thus
      possibly conferring on it a selective advantage in its specific habitat.

PMID- 12426356
TI  - A Sinorhizobium meliloti lipopolysaccharide mutant altered in cell surface
      sulfation.
AB  - The Rhizobium-legume symbiosis involves the formation of a novel plant organ, the
      nodule, in which intracellular bacteria reduce molecular dinitrogen in exchange
      for plant photosynthates. Nodule development requires a bacterial signal referred
      to as Nod factor, which in Sinorhizobium meliloti is a beta-(1,4)-linked tetramer
      of N-acetylglucosamine containing N-acyl and O-acetyl modifications at the
      nonreducing end and a critical 6-O-sulfate at the reducing end. This sulfate
      modification requires the action of three gene products: nodH, which catalyzes
      the sulfonyl transfer, and nodPQ, which produce the activated form of sulfate, 3'
      phosphoadenosine-5'-phosphosulfate. It was previously reported that S. meliloti
      cell surface polysaccharides are also covalently modified by sulfate in a
      reaction dependent on NodPQ. We have further characterized this unique form of
      bacterial carbohydrate modification. Our studies have determined that one of the
      nodPQ mutant strains used in the initial study of sulfation of cell surface
      harbored a second unlinked mutation. We cloned the gene affected by this mutation
      (referred to as lps-212) and found it to be an allele of lpsL, a gene previously
      predicted to encode a UDP-glucuronic acid epimerase. We demonstrated that lpsL
      encoded a UDP-glucuronic acid epimerase activity that was reduced in the lps-212
      mutant. The lps-212 mutation resulted in an altered lipopolysaccharide structure
      that was reduced in sulfate modification in vitro and in vivo. Finally, we
      determined that the lps-212 mutation resulted in a reduced ability to elicit the
      formation of plant nodules and by altered infection thread structures that
      aborted prematurely.

PMID- 12426357
TI  - Evolution of the C30 carotenoid synthase CrtM for function in a C40 pathway.
AB  - The C30 carotene synthase CrtM from Staphylococcus aureus and the C40 carotene
      synthase CrtB from Erwinia uredovora were swapped into their respective foreign
      C40 and C30 biosynthetic pathways (heterologously expressed in Escherichia coli)
      and evaluated for function. Each displayed negligible ability to synthesize the
      natural carotenoid product of the other. After one round of mutagenesis and
      screening, we isolated 116 variants of CrtM able to synthesize C40 carotenoids.
      In contrast, we failed to find a single variant of CrtB with detectable C30
      activity. Subsequent analysis revealed that the best CrtM mutants performed
      comparably to CrtB in an in vivo C40 pathway. These mutants showed significant
      variation in performance in their original C30 pathway, indicating the emergence
      of enzymes with broadened substrate specificity as well as those with shifted
      specificity. We discovered that Phe 26 alone determines the specificity of CrtM.
      The plasticity of CrtM with respect to its substrate and product range highlights
      the potential for creating further new carotenoid backbone structures.

PMID- 12426358
TI  - Identification by RNA profiling and mutational analysis of the novel copper
      resistance determinants CrdA (HP1326), CrdB (HP1327), and CzcB (HP1328) in
      Helicobacter pylori.
AB  - Mechanisms involved in maintaining cytoplasmic metal ion homeostasis play a
      central role in the adaptation of Helicobacter pylori to the changing gastric
      environment. An investigation of the global regulatory responses to copper ions
      by using RNA profiling with a threshold factor of 4.0 revealed that copper
      induces transcription of 19 H. pylori genes and that only the ferritin gene pfr
      is repressed. The 57-fold copper induction identified the HP1326 gene encoding an
      H. pylori-specific protein as a candidate for a novel copper resistance
      determinant. The HP1326 gene is expressed as a monocistronic unit, and two small
      HP1326 mRNAs are copper induced. The HP1326 protein is secreted and is required
      for copper resistance maintained by cytoplasmic copper homeostasis, as H. pylori
      HP1326 mutants were copper sensitive and displayed increased copper induction of
      HP1326 transcription as well as elevated copper repression of ferritin synthesis.
      The clear copper-sensitive phenotype displayed by H. pylori HP1327 and HP1328
      mutants provides strong evidence that the HP1326 protein, together with the
      signal peptide site of the H. pylori-specific protein HP1327, whose gene is
      located downstream from that encoding HP1326, and the CzcB and CzcA metal efflux
      system component homologs HP1328 and HP1329, constitutes a novel type of copper
      efflux pump, as discussed below. The HP1329 gene could not be inactivated, but
      the 14-fold transcriptional copper induction determined by RNA profiling points
      towards a function of the encoded CzcA homolog in copper resistance. In summary,
      results from RNA profiling identified the novel H. pylori-specific copper
      resistance determinants CrdA (HP1326) and CrdB (HP1327), which are required for
      adaptation to copper-rich environmental conditions.

PMID- 12426359
TI  - Isolation of glucocardiolipins from Geobacillus stearothermophilus NRS 2004/3a.
AB  - Glucose-substituted cardiolipins account for about 4 mol% of total phospholipid
      extracted from exponentially grown cells of Geobacillus stearothermophilus NRS
      2004/3a. Individual glucocardiolipin species exhibited differences in fatty acid
      substitution, with iso-C(15:0) and anteiso-C(17:0) prevailing. The compounds were
      purified to homogeneity by a novel protocol and precharacterized by matrix
      assisted laser desorption ionization time-of-flight mass spectrometry.

PMID- 12426360
TI  - Transcriptional response of Pasteurella multocida to defined iron sources.
AB  - Pasteurella multocida was grown in iron-free chemically defined medium
      supplemented with hemoglobin, transferrin, ferritin, and ferric citrate as iron
      sources. Whole-genome DNA microarrays were used to monitor global gene expression
      over seven time points after the addition of the defined iron source to the
      medium. This resulted in a set of data containing over 338,000 gene expression
      observations. On average, 12% of P. multocida genes were differentially expressed
      under any single condition. A majority of these genes encoded P. multocida
      proteins that were involved in either transport and binding or were annotated as
      hypothetical proteins. Several trends are evident when the data from different
      iron sources are compared. In general, only two genes (ptsN and sapD) were
      expressed at elevated levels under all of the conditions tested. The results also
      show that genes with increased expression in the presence of hemoglobin did not
      respond to transferrin or ferritin as an iron source. Correspondingly, genes with
      increased expression in the transferrin and ferritin experiments were expressed
      at reduced levels when hemoglobin was supplied as the sole iron source. Finally,
      the data show that genes that were most responsive to the presence of ferric
      citrate did not follow a trend similar to that of the other iron sources,
      suggesting that different pathways respond to inorganic or organic sources of
      iron in P. multocida. Taken together, our results demonstrate that unique subsets
      of P. multocida genes are expressed in response to different iron sources and
      that many of these genes have yet to be functionally characterized.

PMID- 12426361
TI  - Up-regulated expression of the cbb(I) and cbb(II) operons during
      photoheterotrophic growth of a ribulose 1,5-bisphosphate carboxylase-oxygenase
      deletion mutant of Rhodobacter sphaeroides.
AB  - In a Rhodobacter sphaeroides ribulose 1,5-bisphosphate carboxylase-oxygenase
      deletion strain that requires an exogenous electron donor for photoheterotrophic
      growth, transcription of the genes of the Calvin-Benson-Bassham (CBB) cycle was
      increased. This finding pointed to a potential physiological effector that
      enhances the capability of the positive transcriptional activator CbbR to mediate
      cbb transcription. This effector is most likely ribulose 1,5-bisphosphate or a
      metabolite derived from this CBB pathway intermediate.

PMID- 12426362
TI  - DNA microarray analysis of the expression profile of Escherichia coli in response
      to treatment with 4,5-dihydroxy-2-cyclopenten-1-one.
AB  - We carried out DNA microarray-based global transcript profiling of Escherichia
      coli in response to 4,5-dihydroxy-2-cyclopenten-1-one to explore the
      manifestation of its antibacterial activity. We show that it has widespread
      effects in E. coli affecting genes encoding proteins involved in cell metabolism
      and membrane synthesis and functions. Genes belonging to the regulon involved in
      synthesis of Cys are upregulated. In addition, rpoS and RpoS-regulated genes
      responding to various stresses and a number of genes responding to oxidative
      stress are upregulated.

PMID- 12426363
TI  - Leaderless mRNAs bind 70S ribosomes more strongly than 30S ribosomal subunits in
      Escherichia coli.
AB  - By primer extension inhibition assays, 70S ribosomes bound with higher affinity,
      or stability, than did 30S subunits to leaderless mRNAs containing AUG or GUG
      start codons. Addition of translation initiation factors affected ribosome
      binding to leaderless mRNAs. Our results suggest that translation of leaderless
      mRNAs might initiate through a pathway involving 70S ribosomes or 30S subunits
      lacking IF3.

PMID- 12426364
TI  - cis-acting sequences of Bacillus subtilis pyrG mRNA essential for regulation by
      antitermination.
AB  - Expression of the Bacillus subtilis pyrG gene, which encodes CTP synthetase, is
      repressed by cytidine nucleotides. Regulation involves a termination
      antitermination mechanism acting at a transcription terminator located within the
      5' untranslated pyrG leader sequence. Deletion and substitution mutagenesis of a
      series of pyrG'-lacZ transcriptional fusions integrated into the B. subtilis
      chromosome demonstrated that only the terminator stem-loop and two specific 4- to
      6-nucleotide RNA sequences were required for derepression of pyrG by starvation
      for cytidine nucleotides. The first sequence, GGGC/U, comprises the first four
      nucleotides at the 5' end of the pyrG transcript, and the second, GCUCCC, forms
      the first six nucleotides of the 5' strand of the terminator stem. All of the
      nucleotides lying between the two required RNA sequences can be deleted without
      loss of regulation. We propose that an as-yet-unidentified regulatory protein
      binds to these two RNA segments and prevents termination of transcription in the
      pyrG leader region when intracellular CTP levels are low.

PMID- 12426365
TI  - The viable but nonculturable state and starvation are different stress responses
      of Enterococcus faecalis, as determined by proteome analysis.
AB  - The protein expression patterns of exponentially growing, starved, and viable but
      nonculturable (VBNC) Enterococcus faecalis cells were analyzed to establish
      whether differences exist between the VBNC state and other stress responses. The
      results indicate that the protein profile of VBNC cells differs from that of
      either starved or exponentially growing bacteria. This demonstrates that the VBNC
      state is a distinct physiological phase within the life cycle of E. faecalis,
      which is activated in response to multiple environmental stresses.

PMID- 12426366
TI  - Low-temperature-induced changes in composition and fluidity of
      lipopolysaccharides in the antarctic psychrotrophic bacterium Pseudomonas
      syringae.
AB  - The Antarctic psychrotrophic bacterium Pseudomonas syringae was more sensitive to
      polymyxin B at a lower (4 degrees C) temperature of growth than at a higher (22
      degrees C) temperature. The amount of hydroxy fatty acids in the
      lipopolysaccharides (LPS) also increased at the lower temperature. These changes
      correlated with the increase in fluidity of the hydrophobic phase of
      lipopolysaccharide aggregates in vitro.

PMID- 12426367
TI  - Variation in satellite DNA profiles--causes and effects.
AB  - Heterochromatic regions of the eukaryotic genome harbour DNA sequences that are
      repeated many times in tandem, collectively known as satellite DNAs. Different
      satellite sequences co-exist in the genome, thus forming a set called a satellite
      DNA library. Within a library, satellite DNAs represent independent evolutionary
      units. Their evolution can be explained as a result of change in two parameters:
      copy number and nucleotide sequence, both of them ruled by the same mechanisms of
      concerted evolution. Individual change in either of these two parameters as well
      as their simultaneous evolution can lead to the genesis of species-specific
      satellite profiles. In some cases, changes in satellite DNA profiles can be
      correlated with chromosomal evolution and could possibly influence the evolution
      of species.

PMID- 12426368
TI  - Storage function of cartilage oligomeric matrix protein: the crystal structure of
      the coiled-coil domain in complex with vitamin D(3).
AB  - The five-stranded coiled-coil domain of cartilage oligomeric matrix protein
      (COMPcc) forms a continuous axial pore with binding capacities for hydrophobic
      compounds, including prominent cell signalling molecules. Here, we report the X
      ray structure of the COMPcc domain in complex with vitamin D(3) at 1.7 A
      resolution. The COMPcc pentamer harbours two molecules of the steroid hormone
      precursor in a planar s-trans conformation of the conjugated triene, with the
      aliphatic tails lying along the molecule axis. A hydrophilic ring of five Gln54
      side chains divides the channel into two hydrophobic compartments in which the
      bound vitamin D(3) pair is fixed in a head-to-head orientation. Vitamin D(3)
      binding induces a volumetric increase of the cavities of approximately 30% while
      the main chain distances of the pentamer are retained. This adaptation to the
      bulky ring systems of the ligands is accomplished by a rotamer re-orientation of
      beta-branched side chains that form the knobs into holes of the coiled-coil
      structure. Compared with binding of vitamin D and retinoic acid by their
      classical receptors, COMP exerts a distinct mechanism of interaction mainly
      defined by the pattern of hydrophobic core residues.

PMID- 12426369
TI  - Microscopic evidence for a minus-end-directed power stroke in the kinesin motor
      ncd.
AB  - We used cryo-electron microscopy and image reconstruction to investigate the
      structure and microtubule-binding configurations of dimeric non-claret
      disjunctional (ncd) motor domains under various nucleotide conditions, and
      applied molecular docking using ncd's dimeric X-ray structure to generate a
      mechanistic model for force transduction. To visualize the alpha-helical coiled
      coil neck better, we engineered an SH3 domain to the N-terminal end of our ncd
      construct (296-700). Ncd exhibits strikingly different nucleotide-dependent three
      dimensional conformations and microtubule-binding patterns from those of
      conventional kinesin. In the absence of nucleotide, the neck adapts a
      configuration close to that found in the X-ray structure with stable interactions
      between the neck and motor core domain. Minus-end-directed movement is based
      mainly on two key events: (i) the stable neck-core interactions in ncd generate a
      binding geometry between motor and microtubule which places the motor ahead of
      its cargo in the minus-end direction; and (ii) after the uptake of ATP, the two
      heads rearrange their position relative to each other in a way that promotes a
      swing of the neck in the minus-end direction.

PMID- 12426370
TI  - A giant protease with a twist: the TPP II complex from Drosophila studied by
      electron microscopy.
AB  - Tripeptidyl peptidase II (TPP II) is an exopeptidase of the subtilisin type of
      serine proteases that is thought to act downstream of the proteasome in the
      ubiquitin-proteasome pathway. Recently, a key role in a pathway parallel to the
      ubiquitin-proteasome pathway has been ascribed to TPP II, which forms a giant
      protease complex in mammalian cells. Here, we report the 900-fold purification of
      TPP II from Drosophila eggs and demonstrate via cryo-electron microscopy that TPP
      II from Drosophila melanogaster also forms a giant protease complex. The
      presented three-dimensional reconstruction of the 57 x 27 nm TPP II complex at
      3.3 nm resolution reveals that the 150 kDa subunits form a superstructure
      composed of two segmented and twisted strands. Each strand is 12.5 nm in width
      and composed of 11 segments that enclose a central channel.

PMID- 12426371
TI  - Dynamic interaction of CD2 with the GYF and the SH3 domain of compartmentalized
      effector molecules.
AB  - Intracellular protein interaction domains are essential for eukaryotic signaling.
      In T cells, the CD2BP2 adaptor binds two membrane-proximal proline-rich motifs in
      the CD2 cytoplasmic tail via its GYF domain, thereby regulating interleukin-2
      production. Here we present the structure of the GYF domain in complex with a CD2
      tail peptide. Unlike SH3 domains, which use two surface pockets to accommodate
      proline residues of ligands, the GYF domain employs phylogenetically conserved
      hydrophobic residues to create a single interaction surface. NMR analysis shows
      that the Fyn but not the Lck tyrosine kinase SH3 domain competes with CD2BP2 GYF
      domain binding to the same CD2 proline-rich sequence in vitro. To test the in
      vivo significance of this competition, we used co-immunoprecipitation experiments
      and found that CD2BP2 is the ligand of the membrane-proximal proline-rich tandem
      repeat of CD2 in detergent-soluble membrane compartments, but is replaced by Fyn
      SH3 after CD2 is translocated into lipid rafts upon CD2 ectodomain clustering.
      This unveils the mechanism of a switch of CD2 function due to an extracellular
      mitogenic signal.

PMID- 12426372
TI  - A secreted soluble form of ApoE receptor 2 acts as a dominant-negative receptor
      and inhibits Reelin signaling.
AB  - Specialized neurons throughout the developing central nervous system secrete
      Reelin, which binds to ApoE receptor 2 (ApoER2) and very low density lipoprotein
      receptor (VLDLR), triggering a signal cascade that guides neurons to their
      correct position. Binding of Reelin to ApoER2 and VLDLR induces phosphorylation
      of Dab1, which binds to the intracellular domains of both receptors. Due to
      differential splicing, several isoforms of ApoER2 differing in their ligand
      binding and intracellular domains exist. One isoform harbors four binding repeats
      plus an adjacent short 13 amino acid insertion containing a furin cleavage site.
      It is not known whether furin processing of this ApoER2 variant actually takes
      place and, if so, whether the produced fragment is secreted. Here we demonstrate
      that cleavage of this ApoER2 variant does indeed take place, and that the
      resulting receptor fragment consisting of the entire ligand-binding domain is
      secreted as soluble polypeptide. This receptor fragment inhibits Reelin signaling
      in primary neurons, indicating that it can act in a dominant-negative fashion in
      the regulation of Reelin signaling during embryonic brain development.

PMID- 12426373
TI  - Altered aggregation properties of mutant gamma-crystallins cause inherited
      cataract.
AB  - Protein inclusions are associated with a diverse group of human diseases ranging
      from localized neurological disorders through to systemic non-neuropathic
      diseases. Here, we present evidence that the formation of intranuclear inclusions
      is a key event in cataract formation involving altered gamma-crystallins that are
      un likely to adopt their native fold. In three different inherited murine
      cataracts involving this type of gamma-crystallin mutation, large inclusions
      containing the altered gamma-crystallins were found in the nuclei of the primary
      lens fibre cells. Their formation preceded not only the first gross morphological
      changes in the lens, but also the first signs of cataract. The inclusions
      contained filamentous material that could be stained with the amyloid-detecting
      dye, Congo red. In vitro, recombinant mutant gammaB-crystallin readily formed
      amyloid fibrils under physiological buffer conditions, unlike wild-type protein.
      These data suggest that this type of cataract is caused by a mechanism involving
      the nuclear targeting and deposition of amyloid-like inclusions. The mutant gamma
      crystallins initially disrupt nuclear function, but then this progresses to a
      full cataract phenotype.

PMID- 12426374
TI  - Spindle-kinetochore attachment requires the combined action of Kin I-like Klp5/6
      and Alp14/Dis1-MAPs in fission yeast.
AB  - Fission yeast Klp5 and Klp6 belong to the microtubule-destabilizing Kin I family.
      In klp5 mutants, spindle checkpoint proteins Mad2 and Bub1 are recruited to
      mitotic kinetochores for a prolonged duration, indicating that these kinetochores
      are unattached. Further analysis shows that there are kinetochores to which only
      Bub1, but not Mad2, localizes. These kinetochores are likely to have been
      captured, yet lack tension. Thus Klp5 and Klp6 play a role in a spindle-
      kinetochore interaction at dual steps, capture and generation of tension. The
      TOG/XMAP215 family, Alp14 and Dis1 are known to stabilize microtubules and be
      required for the bivalent attachment of the kinetochore to the spindle. Despite
      apparent opposing activities towards microtubule stability, Klp5/Klp6 and
      Alp14/Dis1 share an essential function, as either dis1klp or alp14klp mutants are
      synthetically lethal, like alp14dis1. Defective phenotypes are similar to each
      other, characteristic of attachment defects and chromosome mis-segregation.
      Furthermore Alp14 is of significance for kinetochore localization of Klp5. We
      propose that Klp5/Klp6 and Alp14/Dis1 play a collaborative role in bipolar
      spindle formation during prometaphase through producing spindle dynamism.

PMID- 12426375
TI  - RNA editing by ADARs is important for normal behavior in Caenorhabditis elegans.
AB  - Here we take advantage of the well-characterized and simple nervous system of
      Caenorhabditis elegans to further our understanding of the functions of RNA
      editing. We describe the two C.elegans ADAR genes, adr-1 and adr-2, and
      characterize strains containing homozygous deletions in each, or both, of these
      genes. We find that adr-1 is expressed in most, if not all, cells of the
      C.elegans nervous system and also in the developing vulva. Using chemotaxis
      assays, we show that both ADARs are important for normal behavior. Biochemical,
      molecular and phenotypic analyses indicate that ADR-1 and ADR-2 have distinct
      roles in C.elegans, but sometimes act together.

PMID- 12426376
TI  - Cell numbers and leaf development in Arabidopsis: a functional analysis of the
      STRUWWELPETER gene.
AB  - The struwwelpeter (swp) mutant in Arabidopsis shows reduced cell numbers in all
      aerial organs. In certain cases, this defect is partially compensated by an
      increase in final cell size. Although the mutation does not affect cell cycle
      duration in the young primordia, it does influence the window of cell
      proliferation, as cell number is reduced during the very early stages of
      primordium initiation and a precocious arrest of cell proliferation occurs. In
      addition, the mutation also perturbs the shoot apical meristem (SAM), which
      becomes gradually disorganized. SWP encodes a protein with similarities to
      subunits of the Mediator complex, required for RNA polymerase II recruitment at
      target promoters in response to specific activators. To gain further insight into
      its function, we overexpressed the gene under the control of a constitutive
      promoter. This interfered again with the moment of cell cycle arrest in the young
      leaf. Our results suggest that the levels of SWP, besides their role in pattern
      formation at the meristem, play an important role in defining the duration of
      cell proliferation.

PMID- 12426377
TI  - Nuclear import of PKCdelta is required for apoptosis: identification of a novel
      nuclear import sequence.
AB  - We have shown previously that protein kinase Cdelta (PKCdelta) is required for
      mitochondrial-dependent apoptosis. Here we show that PKCdelta is imported into
      the nucleus of etoposide-treated cells, that nuclear import is required for
      apoptosis and that it is mediated by a nuclear localization signal (NLS) in the C
      terminus of PKCdelta. Mutation of the caspase cleavage site of PKCdelta inhibits
      nuclear accumulation in apoptotic cells, indicating that caspase cleavage
      facilitates this process. Expression of the PKCdelta catalytic fragment (CFdelta)
      in transfected cells results in nuclear localization and apoptosis. We show that
      the PKCdelta NLS is required for nuclear import of both full-length PKCdelta and
      CFdelta, and drives nuclear localization of a multimeric green fluorescent
      protein. Mutations within the NLS of CFdelta prevent nuclear accumulation and
      block apoptosis. Conversely, nuclear expression of a kinase-negative catalytic
      fragment (KN-CFdelta) protects cells from etoposide-induced apoptosis. Mutation
      of the NLS blocks the ability of KN-CFdelta to protect against etoposide-induced
      apoptosis. These results indicate that PKCdelta regulates an essential nuclear
      event(s) that is required for initiation of the apoptotic pathway.

PMID- 12426378
TI  - Dissection of c-MOS degron.
AB  - c-MOS, a MAP kinase kinase kinase, is a regulator of oocyte maturation. The
      concentration of c-MOS is controlled in part through its conditional degradation.
      Previous studies proposed the "second-codon rule", according to which the N
      terminal proline (Pro) of c-MOS is a destabilizing residue that targets c-MOS for
      degradation. We analyzed the degradation signal (degron) of c-MOS in Xenopus
      oocytes, found it to be a portable degron, and demonstrated that, contrary to the
      model above, the N-terminal Pro residue of c-MOS is entirely dispensable for its
      degradation if Ser-2 (encoded Ser-3) of c-MOS is replaced by a small non
      phosphorylatable residue such as Gly. The dependence of c-MOS degradation on N
      terminal Pro is shown to be caused by a Pro-mediated downregulation of the net
      phosphorylation of Ser-2, a modification that halts c-MOS degradation in oocytes.
      Thus, the N-terminal Pro residue of c-MOS is not a recognition determinant for a
      ubiquitin ligase, in agreement with earlier evidence that Pro is a stabilizing
      residue in the N-end rule.

PMID- 12426379
TI  - Clathrin light and heavy chain interface: alpha-helix binding superhelix loops
      via critical tryptophans.
AB  - Clathrin light chain subunits (LCa and LCb) contribute to regulation of coated
      vesicle formation to sort proteins during receptor-mediated endocytosis and
      organelle biogenesis. LC binding to clathrin heavy chain (HC) was characterized
      by genetic and structural approaches. The core interactions were mapped to HC
      residues 1267-1522 (out of 1675) and LCb residues 90-157 (out of 228), using
      yeast two-hybrid assays. The C-termini of both subunits also displayed
      interactions extending beyond the core domains. Mutations to helix breakers
      within the LCb core disrupted HC association. Further suppressor mutagenesis
      uncovered compensatory mutations in HC (K1415E or K1326E) capable of rescuing the
      binding defects of LCb mutations W127R or W105R plus W138R, thereby pinpointing
      contacts between HC and LCb. Mutant HC K1415E also rescued loss of binding by LCa
      W130R, indicating that both LCs interact similarly with HC. Based on circular
      dichroism data, mapping and mutagenesis, LCa and LCb were represented as alpha
      helices, aligned along the HC and, using molecular dynamics, a structural model
      of their interaction was generated with novel implications for LC control of
      clathrin assembly.

PMID- 12426380
TI  - Syndapins integrate N-WASP in receptor-mediated endocytosis.
AB  - Syndapins are potential links between the cortical actin cytoskeleton and
      endocytosis because this family of dynamin-associated proteins can also interact
      with the Arp2/3 complex activator N-WASP. Here we provide evidence for
      involvement of N-WASP interactions in receptor-mediated endocytosis. We reveal
      that the observed dominant-negative effects of N-WASP are dependent exclusively
      on the proline-rich domain, the binding interface of syndapins. Our results
      therefore suggest that syndapins integrate N-WASP functions in endocytosis. Both
      proteins co-localize in neuronal cells. Consistent with a crucial role for
      syndapins in endocytic uptake, co-overexpression of syndapins rescued the
      endocytosis block caused by N-WASP. An in vivo reconstitution of the syndapin-N
      WASP interaction at cellular membranes triggered local actin polymerization.
      Depletion of endogenous N-WASP by sequestering it to mitochondria or by
      introducing anti-N-WASP antibodies impaired endocytosis. Our data suggest that
      syndapins may act as important coordinators of N-WASP and dynamin functions
      during the different steps of receptor-mediated endocytosis and that local actin
      polymerization induced by syndapin-N-WASP interactions may be a mechanism
      supporting clathrin-coated vesicle detachment and movement away from the plasma
      membrane.

PMID- 12426381
TI  - The Erv41p-Erv46p complex: multiple export signals are required in trans for
      COPII-dependent transport from the ER.
AB  - Erv41p and Erv46p form an integral membrane protein complex that cycles between
      the endoplasmic reticulum (ER) and Golgi. Both proteins contain a large lumenal
      domain and short N- and C-terminal tail sequences exposed to the cytosol. The
      coat protein complex II (COPII) packages the Erv41p-Erv46p complex into ER
      derived vesicles for delivery to the Golgi. We determined signals in the Erv41p
      Erv46p complex that are required for COPII-dependent export from the ER. Mutants
      lacking the Erv41p or Erv46p C-terminus accumulated in the ER and were not
      packaged efficiently into vesicles. We identified an isoleucine-leucine sequence
      in the Erv41p tail that was required for COPII binding and inclusion of the
      complex into vesicles. This signal was sufficient for COPII binding but not for
      ER export. The Erv46p tail contains a phenylalanine-tyrosine sequence required
      together with the isoleucine-leucine signal in Erv41p for export of the complex.
      Surprisingly, Erv41p- Erv46p tail-swapped chimeras were not exported from the ER,
      indicating that signals in both the Erv41p and the Erv46p tail sequences are
      required in a specific orientation for efficient packaging of the Erv41p-Erv46p
      complex.

PMID- 12426382
TI  - Cargo selection into COPII vesicles is driven by the Sec24p subunit.
AB  - Transport of secretory proteins out of the endoplasmic reticulum (ER) is mediated
      by vesicles generated by the COPII coat complex. In order to understand how cargo
      molecules are selected by this cytoplasmic coat, we investigated the functional
      role of the Sec24p homolog, Lst1p. We show that Lst1p can function as a COPII
      subunit independently of Sec24p on native ER membranes and on synthetic
      liposomes. However, vesicles generated with Lst1p in the absence of Sec24p are
      deficient in a distinct subset of cargo molecules, including the SNAREs, Bet1p,
      Bos1p and Sec22p. Consistent with the absence of any SNAREs, these vesicles are
      unable to fuse with Golgi membranes. Furthermore, unlike Sec24p, Lst1p fails to
      bind to Bet1p in vitro, indicating a direct correlation between cargo binding and
      recruitment into vesicles. Our data suggest that the principle role of Sec24p is
      to discriminate cargo molecules for incorporation into COPII vesicles.

PMID- 12426383
TI  - Structural basis for the Golgi membrane recruitment of Sly1p by Sed5p.
AB  - Cytosolic Sec1/munc18-like proteins (SM proteins) are recruited to membrane
      fusion sites by interaction with syntaxin-type SNARE proteins, constituting
      indispensable positive regulators of intracellular membrane fusion. Here we
      present the crystal structure of the yeast SM protein Sly1p in complex with a
      short N-terminal peptide derived from the Golgi-resident syntaxin Sed5p. Sly1p
      folds, similarly to neuronal Sec1, into a three-domain arch-shaped assembly, and
      Sed5p interacts in a helical conformation predominantly with domain I of Sly1p on
      the opposite site of the nSec1/syntaxin-1-binding site. Sequence conservation of
      the major interactions suggests that homologues of Sly1p as well as the
      paralogous Vps45p group bind their respective syntaxins in the same way.
      Furthermore, we present indirect evidence that nSec1 might be able to contact
      syntaxin 1 in a similar fashion. The observed Sly1p-Sed5p interaction mode
      therefore indicates how SM proteins can stay associated with the assembling
      fusion machinery in order to participate in late fusion steps.

PMID- 12426384
TI  - Rab-alphaGDI activity is regulated by a Hsp90 chaperone complex.
AB  - The Rab-specific alphaGDP-dissociation inhibitor (alphaGDI) regulates the
      recycling of Rab GTPases. We have now identified a novel alphaGDI complex from
      synaptic membranes that contains three chaperone components: Hsp90, Hsc70 and
      cysteine string protein (CSP). We find that the alphaGDI-chaperone complex is
      dissociated in response to Ca(2+)-induced neurotransmitter release, that
      chaperone complex dissociation is sensitive to the Hsp90 inhibitor geldanamycin
      (GA) and that GA inhibits the ability of alphaGDI to recycle Rab3A during
      neurotransmitter release. We propose that alphaGDI interacts with a specialized
      membrane-associated Rab recycling Hsp90 chaperone system on the vesicle membrane
      to coordinate the Ca(2+)-dependent events triggering Rab-GTP hydrolysis with
      retrieval of Rab-GDP to the cytosol.

PMID- 12426385
TI  - Protein import into chloroplasts involves redox-regulated proteins.
AB  - Pre-protein translocation into chloroplasts is accomplished by two distinct
      translocation machineries in the outer and inner envelope, respectively. We have
      isolated the translocon at the inner envelope membrane (Tic complex) by blue
      native PAGE and describe a new Tic subunit, Tic62. Tic62, together with Tic110
      and Tic55, forms a core translocation unit. The N-terminus of Tic62 shows strong
      homologies to NAD(H) dehydrogenases in eukaryotes and to Ycf39-like proteins
      present in cyanobacteria and non-green algae. The stromal-facing C-terminus of
      Tic62 contains a novel, repetitive module that interacts with a ferredoxin
      NAD(P)(+) oxidoreductase. Ferredoxin-NAD(P)(+) oxidoreductase catalyses the final
      electron transfer of oxygenic photosynthesis from ferredoxin to NAD(P).
      Substrates that interfere with either NAD binding, such as deamino-NAD, or
      influence the ratio of NAD(P)/NAD(P)H, such as ruthenium hexamine trichloride,
      modulate the import characteristics of leaf-specific ferredoxin-NAD(P)(+)
      oxidoreductase isologues differently. We conclude that the Tic complex can
      regulate protein import into chloroplasts by sensing and reacting to the redox
      state of the organelle.

PMID- 12426386
TI  - From chloroplasts to photosystems: in situ scanning force microscopy on intact
      thylakoid membranes.
AB  - Envelope-free chloroplasts were imaged in situ by contact and tapping mode
      scanning force microscopy at a lateral resolution of 3-5 nm and vertical
      resolution of approximately 0.3 nm. The images of the intact thylakoids revealed
      detailed structural features of their surface, including individual protein
      complexes over stroma, grana margin and grana-end membrane domains. Structural
      and immunogold-assisted assignment of two of these complexes, photosystem I (PS
      I) and ATP synthase, allowed direct determination of their surface density,
      which, for both, was found to be highest in grana margins. Surface rearrangements
      and pigment- protein complex redistribution associated with salt-induced membrane
      unstacking were followed on native, hydrated specimens. Unstacking was
      accompanied by a substantial increase in grana diameter and, eventually, led to
      their merging with the stroma lamellae. Concomitantly, PS IIalpha effective
      antenna size decreased by 21% and the mean size of membrane particles increased
      substantially, consistent with attachment of mobile light-harvesting complex II
      to PS I. The ability to image intact photosynthetic membranes at molecular
      resolution, as demonstrated here, opens up new vistas to investigate thylakoid
      structure and function.

PMID- 12426387
TI  - Editing site recognition and nucleotide insertion are separable processes in
      Physarum mitochondria.
AB  - Insertional RNA editing in Physarum polycephalum is a complex process involving
      the specific addition of non-templated nucleotides to nascent mitochondrial
      transcripts. Since all four ribonucleotides are substrates for the editing
      activity(s), both the site of insertion and the identity of the nucleotide to be
      added at a particular position must be specified, but the signals for these
      events have yet to be elucidated. Here we report the occurrence of sporadic
      errors in RNAs synthesized in vitro. These mistakes, which include omission of
      encoded nucleotides as well as misinsertions, occur only on templates that
      support editing. The pattern of these misediting events indicates that editing
      site recognition and nucleotide addition are separable events, and that the
      recognition step involves features of the mitochondrial template that are
      required for editing. The larger deletions lack all templated nucleotides between
      editing sites, suggesting that the transcription/editing apparatus can "jump"
      from one insertion site to another, perhaps mediated by interactions with editing
      determinants, while smaller omissions most likely reflect misalignment of the
      transcript upon resumption of templated RNA synthesis.

PMID- 12426388
TI  - Nutrient control of gene expression in Drosophila: microarray analysis of
      starvation and sugar-dependent response.
AB  - We have identified genes regulated by starvation and sugar signals in Drosophila
      larvae using whole-genome microarrays. Based on expression profiles in the two
      nutrient conditions, they were organized into different categories that reflect
      distinct physiological pathways mediating sugar and fat metabolism, and cell
      growth. In the category of genes regulated in sugar-fed, but not in starved,
      animals, there is an upregulation of genes encoding key enzymes of the fat
      biosynthesis pathway and a downregulation of genes encoding lipases. The highest
      and earliest activated gene upon sugar ingestion is sugarbabe, a zinc finger
      protein that is induced in the gut and the fat body. Identification of potential
      targets using microarrays suggests that sugarbabe functions to repress genes
      involved in dietary fat breakdown and absorption. The current analysis provides a
      basis for studying the genetic mechanisms underlying nutrient signalling.

PMID- 12426389
TI  - A novel nuclear zinc finger protein EZI enhances nuclear retention and
      transactivation of STAT3.
AB  - A novel cDNA EZI isolated as an oncostatin M- inducible gene encoded a protein
      containing 12 C2H2-type zinc fingers. EZI was found to transactivate the
      promoters that are also responsive to STAT3 and activated the acute phase
      response element (APRE) synergistically with STAT3. Co-immunoprecipitation
      demonstrated the association of EZI with STAT3, which was mediated by the N
      terminal region (1-183) of EZI. The EZI mutant lacking this region showed reduced
      transcriptional activity, indicating that EZI and STAT3 function cooperatively
      through physical interaction. While EZI predominantly localized in the nucleus
      and enhanced the nuclear localization of STAT3, the EZI mutant lacking 11 zinc
      finger motifs failed to translocate into the nucleus and also inhibited nuclear
      localization of STAT3 as well as STAT3-mediated transactivation. These results
      indicate that EZI is a novel nuclear zinc finger protein that augments STAT3
      activity by keeping it in the nucleus.

PMID- 12426390
TI  - The phi29 transcriptional regulator contacts the nucleoid protein p6 to organize
      a repression complex.
AB  - The nucleoid protein p6 of Bacillus subtilis phage phi29 binds to DNA,
      recognizing a structural feature rather than a specific sequence. Upon binding to
      the viral DNA ends, p6 generates an extended nucleoprotein complex that activates
      the initiation of phi29 DNA replication. Protein p6 also participates in
      transcription regulation, repressing the early C2 promoter and assisting the
      viral regulatory protein p4 in controlling the switch from early to late
      transcription. Proteins p6 and p4 bind cooperatively to an approximately 200 bp
      DNA region located between the late A3 and the early A2c promoters, generating an
      extended nucleoprotein complex that helps to repress the early A2c promoter and
      to activate the late A3 promoter. We show that stable assembly of this complex
      requires interaction between protein p6 and the C-terminus of protein p4.
      Therefore, at this DNA region, stable polymerization of protein p6 relies on p4
      specified signals in addition to the structural features of the DNA. Protein p4
      would define the phase and boundaries of the p6-DNA complex.

PMID- 12426391
TI  - Decrease in hnRNP A/B expression during erythropoiesis mediates a pre-mRNA
      splicing switch.
AB  - A physiologically important alternative pre-mRNA splicing switch, involving
      activation of protein 4.1R exon 16 (E16) splicing, is required for the
      establishment of proper mechanical integrity of the erythrocyte membrane during
      erythropoiesis. Here we identify a conserved exonic splicing silencer element
      (CE(16)) in E16 that interacts with hnRNP A/B proteins and plays a role in
      repression of E16 splicing during early erythropoiesis. Experiments with model
      pre-mRNAs showed that CE(16) can repress splicing of upstream introns, and that
      mutagenesis or replacement of CE(16) can relieve this inhibition. An affinity
      selection assay with biotinylated CE(16) RNA demonstrated specific binding of
      hnRNP A/B proteins. Depletion of hnRNP A/B proteins from nuclear extract
      significantly increased E16 inclusion, while repletion with recombinant hnRNP A/B
      restored E16 silencing. Most importantly, differentiating mouse erythroblasts
      exhibited a stage-specific activation of the E16 splicing switch in concert with
      a dramatic and specific down-regulation of hnRNP A/B protein expression. These
      findings demonstrate that natural developmental changes in hnRNP A/B proteins can
      effect physiologically important switches in pre-mRNA splicing.

PMID- 12426392
TI  - Exp5 exports eEF1A via tRNA from nuclei and synergizes with other transport
      pathways to confine translation to the cytoplasm.
AB  - Importin beta-type transport receptors mediate the vast majority of transport
      pathways between cell nucleus and cytoplasm. We identify here the translation
      elongation factor 1A (eEF1A) as the predominant nuclear export substrate of
      RanBP21/exportin 5 (Exp5). This cargo-exportin interaction is rather un usual in
      that eEF1A binds the exportin not directly, but instead via aminoacylated tRNAs.
      Exp5 thus represents the second directly RNA-binding exportin and mediates tRNA
      export in parallel with exportin-t. It was suggested recently that 10-15% of the
      cellular translation would occur in the nucleus. Our data rule out such a
      scenario and instead suggest that nuclear translation is actively suppressed by
      the nuclear export machinery. We found that the vast majority of translation
      initiation factors (eIF2, eIF2B, eIF3, eIF4A1, eIF5 and eIF5B), all three
      elongation factors (eEF1A, eEF1B and eEF2) and the termination factor eRF1 are
      strictly excluded from nuclei. Besides Exp5 and importin 13, CRM1 and as yet
      unidentified exportins also contribute to the depletion of translation factors
      from nuclei.

PMID- 12426393
TI  - Exportin-5-mediated nuclear export of eukaryotic elongation factor 1A and tRNA.
AB  - Transport of proteins and RNA into and out of the cell nucleus is mediated
      largely by a family of RanGTP-binding transport receptors. Export receptors
      (exportins) need to bind RanGTP for efficient loading of their export cargo. We
      have identified eukaryotic elongation factor 1A (eEF1A) and tRNA as RanGTP
      dependent binding partners of exportin-5 (Exp5). Exp5 stimulates nuclear export
      of eEF1A when microinjected into the nucleus of Xenopus laevis oocytes.
      Surprisingly, the interaction between eEF1A and Exp5 is dependent on tRNA that
      can interact directly with Exp5 and, if aminoacylated, recruits eEF1A into the
      export complex. These data suggested to us that Exp5 might support tRNA export.
      Indeed, not only the canonical tRNA export receptor, exportin-t, but also Exp5
      can drive nuclear export of tRNA. Taken together, we show that there exists an
      alternative tRNA export pathway which can be exploited to keep eEF1A out of the
      cell nucleus.

PMID- 12426394
TI  - "Super p53" mice exhibit enhanced DNA damage response, are tumor resistant and
      age normally.
AB  - The tumor suppressor p53 is critical in preventing cancer due to its ability to
      trigger proliferation arrest and cell death upon the occurrence of a variety of
      stresses, most notably, DNA damage and oncogenic stress. Here, we report the
      generation and characterization of mice carrying supernumerary copies of the p53
      gene in the form of large genomic transgenes. Prior to this, we demonstrate that
      the p53 transgenic allele (p53-tg), when present in a p53-null genetic
      background, behaves as a functional replica of the endogenous gene. "Super p53"
      mice, carrying p53-tg alleles in addition to the two endogenous alleles, exhibit
      an enhanced response to DNA damage. Importantly, "super p53" mice are
      significantly protected from cancer when compared with normal mice. Finally, in
      contrast to previously reported mice with constitutively active p53, "super p53"
      mice do not show any indication of premature aging, probably reflecting the fact
      that p53 is under normal regulatory control. Together, our results prove that
      cancer resistance can be enhanced by a simple genetic modification and in the
      absence of undesirable effects.

PMID- 12426395
TI  - MDM2-HDAC1-mediated deacetylation of p53 is required for its degradation.
AB  - The tumor suppressor p53 is stabilized and activated in response to cellular
      stress through post-translational modifications including acetylation. p300/CBP
      mediated acetylation of p53 is negatively regulated by MDM2. Here we show that
      MDM2 can promote p53 deacetylation by recruiting a complex containing HDAC1. The
      HDAC1 complex binds MDM2 in a p53-independent manner and deacetylates p53 at all
      known acetylated lysines in vivo. Ectopic expression of a dominant-negative HDAC1
      mutant restores p53 acetylation in the presence of MDM2, whereas wild-type HDAC1
      and MDM2 deacetylate p53 synergistically. Fibroblasts overexpressing a dominant
      negative HDAC1 mutant display enhanced DNA damage-induced p53 acetylation,
      increased levels of p53 and a more pronounced induction of p21 and MDM2. These
      results indicate that acetylation promotes p53 stability and function. As the
      acetylated p53 lysine residues overlap with those that are ubiquitylated, our
      results suggest that one major function of p53 acetylation is to promote p53
      stability by preventing MDM2-dependent ubiquitylation, while recruitment of HDAC1
      by MDM2 promotes p53 degradation by removing these acetyl groups.

PMID- 12426397
TI  - Solution structure and DNA-binding properties of the C-terminal domain of UvrC
      from E.coli.
AB  - The C-terminal domain of the UvrC protein (UvrC CTD) is essential for 5' incision
      in the prokaryotic nucleotide excision repair process. We have determined the
      three-dimensional structure of the UvrC CTD using heteronuclear NMR techniques.
      The structure shows two helix-hairpin-helix (HhH) motifs connected by a small
      connector helix. The UvrC CTD is shown to mediate structure-specific DNA binding.
      The domain binds to a single-stranded-double-stranded junction DNA, with a strong
      specificity towards looped duplex DNA that contains at least six unpaired bases
      per loop ("bubble DNA"). Using chemical shift perturbation experiments, the DNA
      binding surface is mapped to the first hairpin region encompassing the conserved
      glycine-valine-glycine residues followed by lysine-arginine-arginine, a
      positively charged surface patch and the second hairpin region consisting of
      glycine-isoleucine-serine. A model for the protein-DNA complex is proposed that
      accounts for this specificity.

PMID- 12426396
TI  - Localization of DNA polymerases eta and iota to the replication machinery is
      tightly co-ordinated in human cells.
AB  - Y-family DNA polymerases can replicate past a variety of damaged bases in vitro
      but, with the exception of DNA polymerase eta (poleta), which is defective in
      xeroderma pigmentosum variants, there is little information on the functions of
      these polymerases in vivo. Here, we show that DNA polymerase iota (poliota), like
      poleta, associates with the replication machinery and accumulates at stalled
      replication forks following DNA-damaging treatment. We show that poleta and
      poliota foci form with identical kinetics and spatial distributions, suggesting
      that localization of these two polymerases is tightly co-ordinated within the
      nucleus. Furthermore, localization of poliota in replication foci is largely
      dependent on the presence of poleta. Using several different approaches, we
      demonstrate that poleta and poliota interact with each other physically and that
      the C-terminal 224 amino acids of poliota are sufficient for both the interaction
      with poleta and accumulation in replication foci. Our results provide strong
      evidence that poleta targets poliota to the replication machinery, where it may
      play a general role in maintaining genome integrity as well as participating in
      translesion DNA synthesis.

PMID- 12426398
TI  - MinCD-dependent regulation of the polarity of SpoIIIE assembly and DNA transfer.
AB  - During Bacillus subtilis sporulation, the SpoIIIE DNA translocase moves a trapped
      chromosome across the sporulation septum into the forespore. The direction of DNA
      translocation is controlled by the specific assembly of SpoIIIE in the mother
      cell and subsequent export of DNA into the forespore. We present evidence that
      the MinCD heterodimer, which spatially regulates cell division during vegetative
      growth, serves as a forespore-specific inhibitor of SpoIIIE assembly. The
      deletion of minCD increases the ability of forespore-expressed SpoIIIE to
      assemble and translocate DNA, and causes otherwise wild-type cells to reverse the
      direction of DNA transfer, producing anucleate forespores. We propose that two
      distinct mechanisms ensure the specific assembly of SpoIIIE in the mother cell,
      the partitioning of more SpoIIIE molecules into the larger mother cell by
      asymmetric cell division and the MinCD-dependent repression of SpoIIIE assembly
      in the forespore. Our results suggest that the ability of MinCD to sense
      positional information is utilized during sporulation to regulate protein
      assembly differentially on the two faces of the sporulation septum.

PMID- 12426400
TI  - Elliptic Yang-Mills equation.
AB  - We discuss some recent progress on the regularity theory of the elliptic Yang
      Mills equation. We start with some basic properties of the elliptic Yang-Mills
      equation, such as Coulomb gauges, monotonicity, and curvature estimates. Next we
      discuss singularity of stationary Yang-Mills connections and compactness theorems
      on Yang-Mills connections with bounded L(2) norm of curvature. We also discuss in
      some detail self-dual solutions of the Yang-Mills equation and describe a
      compactification of their moduli space.

PMID- 12426399
TI  - Functional interaction between DNA-PKcs and telomerase in telomere length
      maintenance.
AB  - DNA-PKcs is the catalytic subunit of the DNA-dependent protein kinase (DNA-PK)
      complex that functions in the non-homologous end-joining of double-strand breaks,
      and it has been shown previously to have a role in telomere capping. In
      particular, DNA-PKcs deficiency leads to chromosome fusions involving telomeres
      produced by leading-strand synthesis. Here, by generating mice doubly deficient
      in DNA-PKcs and telomerase (Terc(-/-)/DNA-PKcs(-/-)), we demonstrate that DNA
      PKcs also has a fundamental role in telomere length maintenance. In particular,
      Terc(-/-)/DNA-PKcs(-/-) mice displayed an accelerated rate of telomere shortening
      when compared with Terc(-/-) controls, suggesting a functional interaction
      between both activities in maintaining telomere length. In addition, we also
      provide direct demonstration that DNA-PKcs is essential for both end-to-end
      fusions and apoptosis triggered by critically short telomeres. Our data predict
      that, in telomerase-deficient cells, i.e. human somatic cells, DNA-PKcs
      abrogation may lead to a faster rate of telomere degradation and cell cycle
      arrest in the absence of increased apoptosis and/or fusion of telomere-exhausted
      chromosomes. These results suggest a critical role of DNA-PKcs in both cancer and
      aging.

PMID- 12426401
TI  - An Arabidopsis histidine kinase is essential for megagametogenesis.
AB  - Cytokinin-Independent 1 (CKI1) belongs to a group of putative plant histidine
      kinases whose members do not appear to act as ethylene receptors. The deduced
      protein structure, combined with the observation that Arabidopsis callus cultures
      overexpressing CKI1 exhibit a "cytokinin-independent" cell division and greening
      phenotype, led to the hypothesis that CKI1 is involved in cytokinin signaling,
      perhaps acting as a cytokinin receptor. To test the function of CKI1, we used a
      reverse-genetic approach to identify plants carrying T-DNA insertions in CKI1.
      Two independent alleles were identified, which produce the same developmental
      phenotype. Analyses of populations segregating for the cki1-5 or cki1-6 T-DNA
      insertion alleles failed to reveal any homozygous cki1 plants, indicating that
      the homozygous mutant condition was lethal. Based on segregation distortion,
      transmission studies, a microscopy-based examination of developing female
      gametophytes, and mRNA expression data, we suggest that CKI1 function is required
      for megagametophyte development. Our work with CKI1 mutants indicates that signal
      transduction by means of a HisAsp phosphorelay system may play an important and
      previously unsuspected role in female gametophyte development in Arabidopsis.

PMID- 12426402
TI  - The systemin precursor gene regulates both defensive and developmental genes in
      Solanum tuberosum.
AB  - Transformation of Solanum tuberosum, cv. Desiree, with the tomato prosystemin
      gene, regulated by the 35S cauliflower mosaic virus promoter, resulted in
      constitutive increase in defensive proteins in potato leaves, similar to its
      effects in tomato plants, but also resulted in a dramatic increase in storage
      protein levels in potato tubers. Tubers from selected transformed lines contained
      4- to 5-fold increases in proteinase inhibitor I and II proteins, >50% more
      soluble and dry weight protein, and >50% more total nitrogen and total free amino
      acids than found in wild-type tubers. These results suggest that the prosystemin
      gene plays a dual role in potato plants in regulating proteinase inhibitor
      synthesis in leaves in response to wounding and in regulating storage protein
      synthesis in potato tubers in response to developmental cues. The results
      indicated that components of the systemin signaling pathway normally found in
      leaves have been recruited by potato plants to be developmentally regulated to
      synthesize and accumulate large quantities of storage proteins in tubers.

PMID- 12426403
TI  - The mechanism of topoisomerase I poisoning by a camptothecin analog.
AB  - We report the x-ray crystal structure of human topoisomerase I covalently joined
      to double-stranded DNA and bound to the clinically approved anticancer agent
      Topotecan. Topotecan mimics a DNA base pair and binds at the site of DNA cleavage
      by intercalating between the upstream (-1) and downstream (+1) base pairs.
      Intercalation displaces the downstream DNA, thus preventing religation of the
      cleaved strand. By specifically binding to the enzyme-substrate complex,
      Topotecan acts as an uncompetitive inhibitor. The structure can explain several
      of the known structure-activity relationships of the camptothecin family of
      anticancer drugs and suggests that there are at least two classes of mutations
      that can produce a drug-resistant enzyme. The first class includes changes to
      residues that contribute to direct interactions with the drug, whereas a second
      class would alter interactions with the DNA and thereby destabilize the drug
      binding site.

PMID- 12426404
TI  - A simple alfalfa seedling infection model for Pseudomonas aeruginosa strains
      associated with cystic fibrosis shows AlgT (sigma-22) and RhlR contribute to
      pathogenesis.
AB  - A sensitive plant infection model was developed to identify virulence factors in
      nontypeable, alginate overproducing (mucoid) Pseudomonas aeruginosa strains
      isolated from cystic fibrosis (CF) patients with chronic pulmonary disease.
      Nontypeable strains with defects in lipopolysaccharide O-side chains are common
      to CF and often exhibit low virulence in animal models of infection. However,
      1,000 such bacteria were enough to show disease symptoms in the alfalfa
      infection. A typical mucoid CF isolate, FRD1, and its isogenic mutants were
      tested for alfalfa seedling infection. Although defects in the global regulators
      Vfr, RpoS, PvdS, or LasR had no discernable effect on virulence, a defect in RhlR
      reduced the infection frequency by >50%. A defect in alginate biosynthesis
      resulted in plant disease with >3-fold more bacteria per plant, suggesting that
      alginate overproduction attenuated bacterial growth in planta. FRD1 derivatives
      lacking AlgT, a sigma factor required for alginate production, were reduced >50%
      in the frequency of infection. Thus, AlgT apparently regulates factors in FRD1,
      besides alginate, important for pathogenesis. In contrast, in a non-CF strain,
      PAO1, an algT mutation did not affect its virulence on alfalfa. Conversely, PAO1
      virulence was reduced in a mucA mutant that overproduced alginate. These
      observations suggested that mucoid conversion in CF may be driven by a selection
      for organisms with attenuated virulence or growth in the lung, which promotes a
      chronic infection. These studies also demonstrated that the wounded alfalfa
      seedling infection model is a useful tool to identify factors contributing to the
      persistence of P. aeruginosa in CF.

PMID- 12426405
TI  - Tissue factor deficiency causes cardiac fibrosis and left ventricular
      dysfunction.
AB  - Exposure of blood to tissue factor (TF) activates the extrinsic (TF:FVIIa) and
      intrinsic (FVIIIa:FIXa) pathways of coagulation. In this study, we found that
      mice expressing low levels of human TF ( approximately 1% of wild-type levels) in
      an mTF(-/-) background had significantly shorter lifespans than wild-type mice,
      in part, because of spontaneous fatal hemorrhages. All low-TF mice exhibited a
      selective heart defect that consisted of hemosiderin deposition and fibrosis.
      Direct intracardiac measurement demonstrated a 30% reduction (P < 0.001) in left
      ventricular function in 8-month-old low-TF mice compared with age-matched wild
      type mice. Mice expressing low levels of murine FVII ( approximately 1% of wild
      type levels) exhibited a similar pattern of hemosiderin deposition and fibrosis
      in their hearts. In contrast, FIX(-/-) mice, a model of hemophilia B, had normal
      hearts. Cardiac fibrosis in low-TF and low-FVII mice appears to be caused by
      hemorrhage from cardiac vessels due to impaired hemostasis. We propose that TF
      expression by cardiac myocytes provides a secondary hemostatic barrier to protect
      the heart from hemorrhage.

PMID- 12426406
TI  - The expanding role of imaging in prion disease.

PMID- 12426407
TI  - Executive control function: a review of its promise and challenges for clinical
      research. A report from the Committee on Research of the American
      Neuropsychiatric Association.
AB  - This report reviews the state of the literature and opportunities for research
      related to "executive control function" (ECF). ECF has recently been separated
      from the specific cognitive domains (memory, language, and praxis) traditionally
      used to assess patients. ECF impairment has been associated with lesions to the
      frontal cortex and its basal ganglia-thalamic connections. No single putative ECF
      measure can yet serve as a "gold standard." This and other obstacles to
      assessment of ECF are reviewed. ECF impairment and related frontal system lesions
      and metabolic disturbances have been detected in many psychiatric and medical
      disorders and are strongly associated with functional outcomes, disability, and
      specific problem behaviors. The prevalence and severity of ECF deficits in many
      disorders remain to be determined, and treatment has been attempted in only a few
      disorders. Much more research in these areas is necessary.

PMID- 12426408
TI  - Transcranial magnetic stimulation: a new investigational and treatment tool in
      psychiatry.
AB  - Transcranial magnetic stimulation (TMS) is a new investigational technique used
      to explore various neural processes and treat a variety of neuropsychiatric
      illnesses. The most notable advantage of TMS is its ability to directly stimulate
      the cortex with little effect on intervening tissue. Single-pulse stimulation
      techniques can measure cortical inhibition, facilitation, connectivity,
      reactivity, and cortical plasticity, providing valuable insights into the
      cortical physiology. Repetitive TMS (rTMS) is currently being used to investigate
      cognitive processes and as a treatment tool in disorders such as depression and
      schizophrenia. Both TMS and rTMS are safe and well tolerated. The most serious
      side effect of high-frequency rTMS is seizures. TMS represents an exciting new
      frontier in neuroscience research, providing insights into the pathophysiology
      and treatment of various neuropsychiatric disorders.

PMID- 12426409
TI  - Traumatic brain injury and atrophy of the cingulate gyrus.
AB  - The medial surface areas of the cingulate gyrus (CG) and other midline structures
      (corpus callosum, thalamus, lateral ventricle) were examined in 27 traumatically
      brain injured (TBI) and 12 age- and gender-matched control subjects from an
      established TBI data base. Significant atrophy, primarily in the posterior CG,
      was found in TBI patients. Degree of atrophy was related to severity of injury.
      TBI subjects also had significantly reduced corpus callosum and thalamic cross
      sectional surface areas with associated increased lateral ventricular volume, as
      well as reduced brain volume and increased ventricle-to-brain ratio. Despite
      significant atrophy of the posterior CG, neuropsychological performance was not
      related to changes in CG cross-sectional surface area in the TBI subjects. This
      apparent discrepancy is discussed.

PMID- 12426411
TI  - Determining levels of unawareness in dementia research.
AB  - Clinical methods used to determine unawareness in dementia exist; however, their
      applicability to empirical research is limited. The authors present a
      statistically derived approach to determining unawareness that addresses these
      limitations. Dementia patients (n=32) completed an awareness questionnaire. On an
      identical questionnaire, collateral sources (relatives or friends; n=32) provided
      their best estimate of participants' abilities. The authors compared cluster
      analysis, the proposed empirical approach, to a currently used standard deviation
      cutoff score approach. Cluster analysis included all participants, displayed
      sound statistical properties, and was more sensitive to between-group differences
      in psychotic symptoms than standard deviation cutoff. Cluster analysis appears
      more appropriate for understanding the overall spectrum of unawareness in
      dementia research.

PMID- 12426410
TI  - Neuropsychiatric features of frontotemporal dementia: evaluation of consensus
      criteria and review.
AB  - Neuropsychiatric features characterize frontotemporal dementia (FTD). The authors
      evaluated the neuropsychiatric features of 53 FTD patients and retrospectively
      applied the Consensus Criteria for this disorder. Only one-third of the patients
      met Consensus Criteria for FTD on presentation. Most had early disengagement with
      poor insight; however, more than half retained socially appropriate interpersonal
      conduct and emotional expression. Supportive features, including compulsive-like
      acts and speech changes, were common presenting features, and 20% developed the
      Kluver-Bucy syndrome on 2-year follow-up. Consensus Criteria for FTD offer
      guidelines for diagnosis, but further refinement is needed, particularly for
      patients who lack early changes in social interpersonal conduct.

PMID- 12426412
TI  - Clinical features and comorbidity of mood fluctuations in Parkinson's disease.
AB  - Parkinson's disease (PD) patients commonly develop fluctuations in their motor
      responses to levodopa within several years of initiation of treatment; some also
      develop nonmotor fluctuations. The authors performed a case-control study
      comparing the frequency of comorbid symptoms in 70 PD patients who experienced
      clinically apparent mood changes during their motor "on" or "off" states with two
      control groups with no mood fluctuations. Mood fluctuators had significantly
      younger age at onset and longer disease duration and were significantly more
      likely to have dementia, psychosis, clinical depression, and motor complications.
      This association remained after removing effects of age and disease duration.

PMID- 12426413
TI  - A magnetization transfer analysis of the thalamus in schizophrenia.
AB  - The authors investigated the thalamus in schizophrenia by using magnetization
      transfer ratio (MTR), a novel structural magnetic resonance technique sensitive
      to subtle neuropathological abnormalities. The dorsomedial nucleus (DMN) and
      pulvinar were selected because of their connections to limbic, prefrontal, and
      temporal regions, putatively relevant in schizophrenia. Volume (intracranial;
      thalamic) and MTR (whole thalamus; DMN; pulvinar) were determined in 25 patients
      with chronic schizophrenia by DSM-IV criteria and 25 control subjects. There were
      no significant differences between patients and control subjects in thalamic
      volume (corrected for intracranial volume) or MTR in whole thalamus, DMN, or
      pulvinar. No volumetric or MTR abnormalities could be detected in the thalamus of
      patients with schizophrenia. The findings suggest that abnormalities, if present,
      are very subtle and beyond the power of resolution of these techniques.

PMID- 12426414
TI  - Association of obsessions and compulsions in schizophrenia with neurocognition
      and negative symptoms.
AB  - It is unclear whether obsessions and compulsions in schizophrenia spectrum
      disorders are associated with a unique pattern of symptoms and deficits.
      Accordingly, the present study compared symptom levels and neurocognitive
      function of participants with schizophrenia or schizoaffective disorder with
      (n=11) and without (n=52) significant obsessive-compulsive symptoms. Analyses of
      variance revealed that the obsessive-compulsive group performed more poorly on
      measures of executive function and vigilance and had higher levels of negative
      and emotional discomfort symptoms. Unexpectedly, the obsessive-compulsive group
      also demonstrated superior performance on a measure of visual memory. The
      implications of these clinical correlates of obsessive-compulsive phenomena in
      schizophrenia spectrum disorders are discussed.

PMID- 12426415
TI  - Differential effects of olanzapine and risperidone on cognition in schizophrenia?
      A saccadic eye movement study.
AB  - Recent studies suggest that novel antipsychotics have positive effects on certain
      cognitive functions in schizophrenia. The present study investigated this claim
      by means of saccadic paradigms, which provide a selective index of cognitive
      function. Thirty-three first-episode schizophrenic patients were randomly
      assigned to either olanzapine or risperidone treatment and compared with healthy
      control subjects for three saccadic paradigms. The influence of symptom profile,
      extrapyramidal symptoms, age, education, gender, hospitalization, and medication
      dose on cognitive performance was also investigated. Although the two patient
      groups did not differ from each other in task performance, both patient groups
      showed substantial problems in inhibitory control of saccades. A high level of
      education appeared to be protective for this impairment.

PMID- 12426416
TI  - Methylphenidate treats apathy in Parkinson's disease.

PMID- 12426417
TI  - A blind man with Parkinson's disease, visual hallucinations, and Capgras
      syndrome.

PMID- 12426418
TI  - Donepezil for cognitive deficits following traumatic brain injury: a case report.

PMID- 12426419
TI  - Paroxetine for treatment of somatization disorder.

PMID- 12426421
TI  - Premorbid psychiatric risk factors for postictal psychosis.

PMID- 12426422
TI  - A case series of D-cycloserine added to donepezil in the treatment of Alzheimer's
      disease.

PMID- 12426424
TI  - On addiction denial and cognitive dysfunction in alcoholics.

PMID- 12426425
TI  - Parietal circuits and conversion seizures.

PMID- 12426428
TI  - Two-wave longitudinal findings from the Berlin aging study: introduction to a
      collection of articles.
AB  - We provide background information for a collection of articles that describe two
      wave longitudinal findings derived from the first intensive follow-up of
      participants of the Berlin Aging Study (BASE). Multidisciplinary data were
      collected during 1995-1996 from 206 survivors approximately 4 years after
      baseline assessment (1990-1993). The strengths of the initial BASE design, in
      terms of a focus on very old age, multidisciplinary intensive assessment, and an
      examination of selectivity issues, were maintained in this longitudinal extension
      of the study.

PMID- 12426429
TI  - Longitudinal selectivity in aging populations: separating mortality-associated
      versus experimental components in the Berlin Aging Study (BASE).
AB  - The authors examined 3.7-year selectivity in the Berlin Aging Study by comparing
      the T1 parent sample (N = 516) with the T3 sample (N = 206). Selectivity was
      partitioned into a mortality-associated component, reflecting the degree to which
      individuals still alive at T3 (T3 survivors, N = 313) differ from the T1 parent
      sample (N = 516) from which they originated, and an experimental component,
      reflecting the degree to which the T3 sample (N = 206) differed from T3 survivors
      (N = 313). Across 48 variables representing medical, sensorimotor, cognitive,
      personality-related, and socioeconomic domains, the mortality-associated
      component accounted for 64% of total selectivity, and the experimental component
      for 36% (0.18 vs 0.10 SD units; t = 7.20, p <.01). Except for age and
      intelligence, experimental selectivity effects regarding means and prevalence
      rates were generally small. Partitioning selectivity into mortality-associated
      and experimental components is a useful tool in the longitudinal study of aging
      populations.

PMID- 12426430
TI  - Perceiving control: a double-edged sword in old age.
AB  - Although control beliefs are thought to be pivotal contributors to emotional well
      being in old age, questions remain about the specific and long-term emotional
      implications of different types of control beliefs. We examined three generalized
      beliefs about control (personal control over desirable outcomes, personal
      responsibility for undesirable outcomes, perceived others' control) and their
      associations with emotional well-being (positive and negative affect) using cross
      sectional (N = 516) and longitudinal (N = 206) samples from the Berlin Aging
      Study (age range = 70-103 years). Relationships between control beliefs and
      emotional well-being were dependent on the type of control belief and the
      dimension of emotional well-being considered, the sample investigated, and on
      whether individual differences at a given point in time or individual differences
      in intraindividual changes over time were examined. Despite these complexities,
      findings suggest that perceived control over desirable outcomes is associated
      with high emotional well-being, whereas perceived others' control is an emotional
      risk factor in old age.

PMID- 12426431
TI  - The dynamics of possible selves in old age.
AB  - Future-oriented motives are thought to be cast off in old age. Transcripts of the
      hopes and fears of participants in the 4-year longitudinal sample of the Berlin
      Aging Study (N = 206, 70-100+ years) were coded for central domains and motives
      (e.g., gain, maintenance, avoiding loss) and evaluated for the amount and
      direction of change. Domains of personal characteristics, health, and social
      relationships predominated together with gain motives. Over time, 72% of
      participants added new domains of hopes and 53% added new fears. Individual
      differences in stability and change in matched hopes and fears about health and
      personal identity were associated with changes in physical and functional health.
      People who added matched possible selves about health, focused on maintenance,
      and added few new domains of hopes declined in life satisfaction. Overall, these
      findings indicate that possible selves are a dynamic system during old age.

PMID- 12426432
TI  - Adapting to aging losses: do resources facilitate strategies of selection,
      compensation, and optimization in everyday functioning?
AB  - Previous cross-sectional research has shown that older people who are rich in
      sensorimotor-cognitive and social-personality resources are better functioning in
      everyday life and exhibit fewer negative age differences than resource-poor
      adults. Longitudinal data from the Berlin Aging Study was used to examine these
      findings across a 4-year time interval and to compare cross-sectional indicators
      of adaptive everyday functioning among survivors and nonsurvivors. Apart from
      their higher survival rate, resource-rich older people (a) invest more social
      time with their family members, (b) reduce the diversity of activities within the
      most salient leisure domain, (c) sleep more often and longer during daytime, and
      (d) increase the variability of time investments across activities after 4 years.
      Overall, findings suggest a greater use of selection, compensation, and
      optimization strategies in everyday functioning among resource-rich older adults
      as compared with resource-poor older adults.

PMID- 12426433
TI  - Social participation in very old age: cross-sectional and longitudinal findings
      from BASE. Berlin Aging Study.
AB  - Social participation, defined as socially oriented sharing of individual
      resources, is often regarded as an important criterion of quality of life in old
      age. We distinguished three types of participation with respect to content,
      context, and resources required to participate: collective, productive, and
      political participation. Data from the multidisciplinary Berlin Aging Study were
      used to describe social participation of a very old population and to examine
      individual differences and changes over time. Analyses showed that social
      participation is cumulative. Individuals who engaged in political activities also
      took part in the other two types, and those who engaged in productive activities
      also participated in collective activities. Although many persons changed their
      social participation over the 4-year period, the cumulative pattern within the
      population remained unchanged. Educational and occupational resources were
      positively related to the intensity of social participation in old age, but
      changes in social participation could be better explained by age and health.

PMID- 12426434
TI  - The exchange of emotional support with age and its relationship with emotional
      well-being by age.
AB  - This study tested three hypotheses derived from the application of socioemotional
      selectivity theory and exchange theory to the exchange of emotional support with
      age and its relationship with positive and negative affect by age. Data are from
      the Midlife in the United States study of 3,032 U.S. adults between the ages of
      25 and 74. The social contact hypothesis predicts that hours of emotional support
      given and received should decrease with age. The exchange hypothesis predicts
      that the discrepancy between the hours of emotional support given and received
      should decrease with age to reflect more balanced exchanges with age. The goal
      hypothesis predicts that unequal exchanges of support should predict higher
      negative and lower positive affect with age. Findings supported each hypothesis.
      Hours of emotional support given and received decreased as chronological age
      increased. Although adults of all ages gave more support than they received, the
      discrepancy between hours of emotional support given and received became more
      balanced with age. Compared with equal exchanges, unequal exchanges predicted
      worse emotional well-being profiles only among the oldest adults in this study
      (i.e., those aged 55-64 and 65-74). Findings contribute to the growing literature
      on the changing nature of the quantity and quality of interpersonal exchanges
      with age.

PMID- 12426435
TI  - Age and the understanding of emotions: neuropsychological and sociocognitive
      perspectives.
AB  - Sociocognitive approaches suggest that the ability to understand emotions should
      be well maintained in adult aging. However, neuropsychological evidence suggests
      potential impairments in processing emotions in older adults. In the current
      study, 30 young adults (aged 20-40 years) and 30 older adults (aged 60-80 years)
      were tested on a range of emotional ability measures. There were no age effects
      on the ability to decode emotions from verbal material. Older people were less
      able to identify facial expressions of anger and sadness, and showed poorer
      ability to identify theory of mind from pictures of eyes. The results indicate
      specific age-related deficits in identifying some aspects of emotion from faces,
      but no age effects on the understanding of emotions in verbal descriptions.

PMID- 12426436
TI  - Compensating for losses in perceived personal control over health: a role for
      collective self-esteem in healthy aging.
AB  - Collective self-esteem (CSE) refers to an individual's self-evaluation of his or
      her social identity. We speculate that a positive social identity, or high CSE,
      facilitates accommodation to negative health-related circumstances in later life,
      especially when one feels unable to alter these circumstances directly.
      Accordingly, we hypothesized that CSE would be associated with fewer chronic
      conditions and greater perceived health for those with low perceived control.
      Hierarchical regression analyses of data from 1,267 respondents (60% women, aged
      69-101) in the 1996 Aging in Manitoba survey confirmed the predicted CSE x
      Perceived Control interaction on both measures of health status. These findings
      persisted when respondents' self-rated loneliness was controlled. CSE may
      compensate to protect the health of older adults whose perceived personal control
      over health is low. Secondary control and alternative mechanisms for this
      protective effect are discussed.

PMID- 12426437
TI  - The activation of aging stereotypes in younger and older adults.
AB  - The activation of ageism and aging stereotypes in younger and older adults was
      investigated by manipulating both the valence and the stereotypicality of trait
      stimuli. Participants completed a lexical decision task in which the stimulus
      onset asynchronies (SOAs) between the prime and target stimuli were varied to
      examine the effects of automatic and controlled processing (300 and 2,000 ms,
      respectively). Both younger and older adults demonstrated strong stereotype
      activation for elderly stereotypes but relatively weak activation for young
      stereotypes. Both younger and older adults also demonstrated a positive bias
      toward older people, which was not moderated by SOA. These findings suggest that
      younger and older adults do not differ in their accessibility to aging
      stereotypes or to their age-based biases, which appear to be positive toward
      elderly people.

PMID- 12426438
TI  - Education and sex differences in the mini-mental state examination: effects of
      differential item functioning.
AB  - Years of completed education is a powerful correlate of performance on mental
      status assessment. This analysis evaluates differences in cognitive performance
      attributable to level of education and sex. We analyzed Mini-Mental State
      Examination responses from a large community sample (Epidemiologic Catchment Area
      study, N = 8,556), using a structural equation analytic framework grounded in
      item response theory. Significant sex and education group differential item
      functioning (DIF) were detected. Those with low education were more likely to err
      on the first serial subtraction, spell world backwards, repeat phrase, write,
      name season, and copy design tasks. Women were more likely to err on all serial
      subtractions, men on spelling and other language tasks. The magnitude of detected
      DIF was small. Our analyses show that failing to account for DIF results in an
      approximately 1.6% overestimation of the magnitude of difference in assessed
      cognition between high- and low-education groups. In contrast, nearly all (95%)
      of apparent sex differences underlying cognitive impairment are due to DIF.
      Therefore, item bias does not appear to be a major source of observed differences
      in cognitive status by educational attainment. Adjustments of total scores that
      eliminate education group differences are not supported by these results. Our
      results have implications for future research concerning education and risk for
      dementia.

PMID- 12426439
TI  - Stress and depressive symptoms among Mexican American elders.
AB  - Although social stressors have successfully predicted depressive symptomatology
      in a number of populations, few studies have examined the relevance of stressors
      for Mexican American elders. Results are reported here from a multistage
      probability sample of 3,050 Mexican Americans aged 65 and older drawn from a 5
      state region. Participants reported low levels of education and income, and most
      reported difficulty in reading or writing in English. Deaths, illness of close
      other, and financial problems were the three most frequent life events, and many
      reported financial strains. Depressive symptoms were then regressed on
      demographic indicators, cognitive status, linguistic acculturation, social
      supports, and three types of stressors. Being a woman, lower income, decreased
      income, chronic financial strain, and several health stressors were associated
      with greater symptomatology. Results identified a cluster of economic stressors
      and conditions that may play a critical role in the etiology of depressive
      symptoms in this minority population.

PMID- 12426440
TI  - The study of productive aging.

PMID- 12426441
TI  - Later life education in the 1990s: increasing involvement and continuing
      disparity.
AB  - OBJECTIVES: We examine age differences in adults' participation in, perceived
      barriers to, and institutional support for educational activities provided by
      schools, businesses, and community organizations in the 1990s. METHODS: We
      conduct descriptive and logistic regression analyses on a sample of respondents
      aged 30 to 74 from the National Household Education Surveys. RESULTS: Adult
      education participation rates increased for all ages over the 1990s, but gains
      were proportionately largest among people in later phases of the life course.
      Although age was a weaker predictor of engaging in educational activities at the
      end of the 1990s than it was at the beginning of the decade, older adults
      continue to be less likely than younger ones to participate in education and
      training provided by businesses and schools. Some of this age discrepancy occurs
      because employers are more likely to provide financial support for training to
      younger employees. Older adults, however, are less likely than younger adults to
      perceive obstacles to their participation in education and training. DISCUSSION:
      Although age-graded roles of student, worker, and retiree are becoming
      increasingly blurred, Americans' pursuit of education at the end of the twentieth
      century was still guided by age-related role expectations.

PMID- 12426442
TI  - Church-based social support and health in old age: exploring variations by race.
AB  - OBJECTIVES: A conceptual model is evaluated that explores the relationship
      between church-based support and health. In the process, an effort is made to see
      if the relationships in this model differ for older White and African American
      people. METHODS: Interviews were conducted with a national sample of 748 older
      White and 752 older Black people. The responses of 1,126 of these study
      participants are used in the analyses presented herein. Survey measures were
      administered to assess church-based social ties and health. RESULTS: Empirical
      support was provided for the following theoretical linkages: Older people who
      attend church often feel their congregations are more cohesive; older people in
      highly cohesive congregations receive more spiritual and emotional support from
      their fellow parishioners; older respondents who receive more church-based
      support have a more personal relationship with God; older people who feel more
      closely connected with God are more optimistic; and older people who are more
      optimistic enjoy better health. Data further reveal that older Black people are
      more likely than older White people to reap the health-related benefits of
      religion. DISCUSSION: The findings contribute to research on religion and health
      by specifying how the salubrious effects of religion may arise.

PMID- 12426443
TI  - Assessment of patient preferences: integrating treatments and outcomes.
AB  - OBJECTIVES: The purpose of this study was to develop a patient-centered measure
      of treatment preference applicable across a range of diseases and treatment
      decisions. METHODS: Instrument development was based on previous research
      supplemented by open-ended interviews and focus groups. Psychometric properties
      of the instrument were determined by administration to 125 persons aged 60 or
      older with a limited life expectancy secondary to congestive heart failure,
      chronic obstructive pulmonary disease, or cancer. Test-retest and inter-rater
      reliability were established using intraclass correlation coefficients. Construct
      validity was established by examining associations of the measure with a single
      item question regarding treatment goals and with age, ethnicity, and functional
      impairment, characteristics known to be associated with preferences. The
      Willingness to Accept Life-Sustaining Treatment instrument (WALT) consists of 6
      scenarios in which respondents weigh treatment burden against treatment outcomes
      expressed in terms of the likelihood of different health states and length of
      life following treatment. RESULTS: Inter-rater reliability ranged from .73 to .95
      and test-retest reliability from .49 to .93. WALT scores were significantly
      associated with a simpler measure of preference and with age, ethnicity, and
      functional impairment. CONCLUSIONS: The WALT measures patients' treatment
      preferences, assessed in the context of treatment burden and multiple aspects of
      treatment outcome with sound psychometric properties.

PMID- 12426444
TI  - Short-term change in physical function and disability: the Women's Health and
      Aging Study.
AB  - OBJECTIVES: Although measures of physical function are predictive of future
      disability, little is known about the short-term impact of changes in physical
      function on disability. METHODS: Data from 93 of the 102 women who participated
      in the Weekly Substudy of the Women's Health and Aging Study (WHAS) were used to
      explore the association of changes in physical function with disability. The WHAS
      Substudy included 24 weekly assessments of three standard performance tests and
      self-reported disability in activities of daily living (ADLs) and basic mobility.
      RESULTS: Using random-effects models, we found small but significant (ps <.01)
      changes in ADL and mobility disability during weekly follow-up. Baseline
      performance scores were significantly associated with both ADL and mobility
      disability (ps <.001), accounting for 27% and 36% of the between-person
      variability in each type of disability, respectively. After adjustment for
      baseline scores, change in performance scores was significantly associated with
      ADL disability (beta = 0.08, p <.01) and mobility disability (beta = 0.12, p
      <.001), but accounted only for a small proportion (<10%) of the variability in
      the rate of change in disability outcomes. There was no evidence for an
      additional effect on either type of disability because of having a single episode
      of a higher or lower than usual performance score, or because of periods of at
      least 4 consecutive higher or lower than usual performance test scores.
      DISCUSSION: Basic physical functions account for a substantial proportion of the
      heterogeneity in ADL and mobility disability among older disabled women, but have
      a relatively small impact on short-term changes in either type of disability.
      Effective prevention of disability may require attention to a wider array of risk
      factors than just limitations in basic physical functions.

PMID- 12426445
TI  - Use, type, and efficacy of assistance for disability.
AB  - OBJECTIVES: Personal and equipment assistance are often used to reduce
      disability. This study predicts use of assistance, type of assistance, and its
      efficacy (improvement with assistance) for disabilities in personal care and
      household management tasks. METHODS: U.S. community-dwellers aged 55+ are studied
      using the 1994-1995 National Health Interview Survey Disability Supplement. Three
      types of assistance are considered: Personal Only, Equipment Only, and Both.
      Efficacy is measured by comparing the degree of difficulty doing a task with
      versus without assistance. RESULTS: Severe disability in a task and poor overall
      health/disability status increase use of assistance for the task, and especially
      both types rather than one. For people using one type of assistance, poor
      health/disability status is linked with personal help, but high severity is
      linked with equipment use. These results reflect high needs for assistance and
      limited potential for physiological improvement, joined possibly by a strong
      desire for self-sufficiency among persons who are severely disabled. Controlling
      for factors that route people to different types of assistance, equipment is more
      efficacious than personal assistance. Equipment may have distinctive technical
      and psychological advantages; for example, it can be tailored to a person's
      specific needs, is available when needed, and maintains self-sufficiency.
      DISCUSSION: The results about equipment give impetus to policies that promote
      development and dissemination of assistive technology.

PMID- 12426446
TI  - Protein chemistry and the development of allosterism: Jeffries Wyman.

PMID- 12426448
TI  - The truth about medical codes: it's more than a bunch of numbers.

PMID- 12426447
TI  - On being a healing coach.

PMID- 12426449
TI  - A one- or two-piece pouching system?

PMID- 12426450
TI  - Re-introducing honey in the management of wounds and ulcers - theory and
      practice.
AB  - Dressing wounds with honey, a standard practice in past times, went out of
      fashion when antibiotics came into use. Because antibiotic-resistant bacteria
      have become a widespread clinical problem, a renaissance in honey use has
      occurred. Laboratory studies and clinical trials have shown that honey is an
      effective broad-spectrum antibacterial agent that has no adverse effects on wound
      tissues. As well as having an antibacterial action, honey also provides rapid
      autolytic debridement, deodorizes wounds, and stimulates the growth of wound
      tissues to hasten healing and start the healing process in dormant wounds. Its
      anti-inflammatory activity rapidly reduces pain, edema, and exudate and minimizes
      hypertrophic scarring. It also provides a moist healing environment for wound
      tissues with no risk of maceration of surrounding skin and completely prevents
      adherence of dressings to the wound bed so no pain or tissue damage is associated
      with dressing changes. Using appropriate dressing practice overcomes potential
      messiness and handling problems.

PMID- 12426451
TI  - Topical hyperbaric oxygen and electrical stimulation: exploring potential
      synergy.
AB  - Treatment of chronic wounds involves interventions ranging from dressings to
      surgery. Modalities gaining popularity in clinical settings include topical
      hyperbaric oxygen and electrical stimulation. A prospective, uncontrolled study
      was conducted to obtain preliminary observations and data about the effects of
      topical hyperbaric oxygen therapy and topical hyperbaric oxygen used with
      electrical stimulation on the healing of chronic wounds. All subjects were
      geriatric residents of long-term care facilities with Stage III or Stage IV
      pressure ulcers. Topical hyperbaric oxygen was applied daily to the wounds of
      eight subjects; three also received electrical stimulation. Initial wound size
      ranged from 87.75 cm2 to 7.04 cm2 with an average size of 30.1 +/- 28.5 (mean +/-
      sd) cm2. Healing times ranged from 8 to 49 weeks. After 4 weeks of treatment with
      topical hyperbaric oxygen, wound size decreased an average of 34.4% +/- 22.9%.
      Incidentally, the wounds of five of the eight subjects decreased more than 20%,
      for an average of 51.8% +/- 17.9%. No significant differences in healing were
      observed between patients receiving topical hyperbaric oxygen alone and those
      receiving topical hyperbaric oxygen/electrical stimulation. Preliminary data
      indicate that topical hyperbaric oxygen facilitates wound healing and full
      closure for pressure ulcers in patients with and without diabetes mellitus. A
      multicenter, prospective, randomized, double-blind controlled study is currently
      under way.

PMID- 12426452
TI  - Ultraviolet light C in the treatment of chronic wounds with MRSA: a case study.
AB  - The prevalence of antibiotic-resistant bacteria such as methicillin-resistant
      Staphylococcus aureus is rapidly increasing in healthcare facilities and
      spreading to the community. Methicillin-resistant S. aureus colonize the skin and
      open wounds and can interfere with wound healing. Recent studies have shown that
      ultraviolet light C can kill antibiotic-resistant strains of bacteria such as
      methicillin-resistant S. aureus in both laboratory cultures and animal tissue.
      This clinical report describes the effects of ultraviolet light C on wound
      bioburden and closure in three people with chronic ulcers infected with
      methicillin-resistant S. aureus. In all three patients, ultraviolet light C
      treatment reduced wound bioburden and facilitated wound healing. Two patients had
      complete wound closure following 1 week of ultraviolet light C treatment. This
      case study suggests that ultraviolet light C is a promising adjunctive therapy
      for chronic wounds containing antibiotic-resistant bacteria such as methicillin
      resistant S. aureus.

PMID- 12426453
TI  - Mind-body techniques in wound healing.
AB  - Even the most skilled and resourceful wound care provider encounters stagnation
      of wound healing from time to time. Patients with chronic, nonhealing wounds
      often display negative thought patterns and behavioral tendencies that, in turn,
      hinder biological and emotional healing. An increasing body of research supports
      the negative effect of stress on wound healing. The impact of deeper, emotion
      based "wounds" as complicating factors in conventional wound healing are being
      further explored. It is theorized that emotions such as lack of self worth,
      guilt, and anger are strongly correlated to the chronic, nonhealing wound. Mind
      body techniques such as affirmations, creative visualization, relaxation, and
      conscious breathing are suggested for incorporation into the treatment program.
      These techniques seek to empower and engage the patient by promoting greater
      personal awareness and assertion in the healing process. Wound care providers are
      seen as facilitators of the innate healing potential inside each individual. Mind
      body techniques are offered as a complement for a more comprehensive wound
      healing strategy.

PMID- 12426454
TI  - [Congenital nephrotic syndrome].
AB  - In strict sense, the term "congenital nephrotic syndrome" (CNS) refers to those
      cases of the nephrotic syndrome in which clinical symptoms, e.g. massive
      proteinuria, hypoalbuminemia and oedema are present at birth. However, the term
      is often extended to babies presenting with nephrotic syndrome before 3 months of
      age in whom proteinuria is likely to be present earlier, before the signs of the
      nephrotic syndrome become clinically manifest. The most common and probably the
      most severe type of CNS is the congenital nephrotic syndrome of the Finnish type
      (CNF), which is considered as the prototype of CNS. On the basis of this syndrome
      the clinical course, diagnosis and complex treatment strategy are described. A
      well-documented case of Denys-Drash syndrome - a rare type of congenital
      nephrotic syndrome is also presented.

PMID- 12426455
TI  - [Bone alkaline phosphatase: characteristic and its clinical applications].
AB  - Bone alkaline phosphatase (BALP) is one of the most frequently used biochemical
      markers of bone formation. The presented paper describes the enzyme's
      specificity, physiological values during normal growth and development as well as
      its clinical applications in various diseases. The main interest concerns the
      ability of BALP to predict bone loss in primary (postmenopausal and senile
      osteoporosis) and secondary osteoporosis associated with metabolic diseases
      (galactosemia, cystic fibrosis, celiac disease), renal osteodystrophy, Paget
      disease and others. The determination of BALP activity seems to be also helpful
      in diagnosis of the diseases and in monitoring of antiresorptive therapy. Further
      studies on BALP are needed to elucidate whether this bone formation marker
      reflect the therapy outcome of individual patients with primary osseus tumours
      and metastases.

PMID- 12426456
TI  - [Dietetic treatment in infants with food allergy].
AB  - Prevalence of food allergy and variability of symptoms in infants is described.
      Proposals concerning dietetic treatment underlining the importance of
      breastfeeding, indications for proteins hydrolysate and for meat-vegetable diet
      introduction are presented. Feeding schedule for infants with food allergy is
      also included.

PMID- 12426457
TI  - [Vitamin E status in hypercholesterolemic children].
AB  - The prime role of oxidized low-density lipoprotein in the pathogenesis of
      atherosclerosis is almost universally accepted. Fat soluble antioxidant vitamin E
      associated with lipoproteins, appears to have antiatheroma properties. In the
      presented studies concentration of vitamin E and the relationship between
      tocopherol and lipids were studied in blood of hypercholesterolemic children.
      Level of vitamin E was determined by high-performance liquid chromatography
      (HPLC) method. Compared with normocholesterolemic children, hypercholesterolemic
      patients had a significantly lower red blood cell vitamin E content (2.55 +/-
      0.19 micromol/l vs 3.15+/- 0.33 micromol/l; p<0.005) in spite of their higher
      plasma vitamin E concentration (27.9 +/- 8.3 micromol/l vs 21.01 +/- 3.6
      micromol/l; pl;0.001). In the group of patient tocopherol-to-total cholesterol
      and tocopherol-to-lipids ratio was statistically lower compared to those in the
      control group. In hypecholesterolemic children vitamin E positively correlated
      with total cholesterol (r=0.43; p<0.02), LDL-C (low-density lipoprotein
      cholesterol) (r=0.42; p<0.02) and lipids (triglycerides + total cholesterol)
      (r=0.45; p<0.02). This study demonstrates that total plasma vitamin E
      concentration is not a suitable predictor of cell vitamin E status. Our results
      suggested that the tocopherol of erythrocytes and vitamin E to lipids ratio in
      plasma, could be more meaningful indicators to evaluate the vitamin E status in
      hypercholesterolemic children.

PMID- 12426458
TI  - [Drugs and breastfeeding].
AB  - Most drugs taken by the mother reach breast milk and are ingested by the nursing
      infant. Most of the drugs are detected in breast milk at low concentrations, so
      breastfeeding by women taking these drugs is possible. The effect of some drugs
      on the nursing infant is unknown and further studies are needed. Some drugs may
      achieve significant infant plasma concentrations and may be unsafe for the
      infant. In these cases the infant should be carefully monitored for any clinical
      side effects and whenever observed, breastfeeding should be discontinued. Despite
      the confirmed benefits of breastfeeding, there are certain drugs which are
      absolutely contraindicated; in these cases interruption of breastfeeding is
      necessary. This review summarises the current scientific knowledge on
      compatibility of drugs with breastfeeding, focusing on drugs that are
      contraindicated and of which use in breastfeeding remains controversial.

PMID- 12426459
TI  - [Cord blood reticulocytes and reticulocyte subtypes in normal and complicated
      pregnancy].
AB  - Reticulocyte analysis using flow cytometry increases the precision of
      reticulocyte enumeration and can evaluate the maturation of reticulocytes.
      Reticulocytes count and their subtypes may reflect function of hematopoesis,
      especially during hypoxia. This study was aimed to establish reticulocyte count
      and reticulocyte maturation profile in cord blood during normal pregnancy and
      pregnancy complicated by chronic intrauterine hypoxia. For this purpose we
      analysed 233 cord blood specimens derived from uneventful pregnancy and 58 cord
      blood specimens from complicated pregnancy. The gestational age ranged from 26 to
      42 weeks. The following measurements were obtained (mean +/- standard deviation):
      reticulocyte absolute count - 268 +/- 63 10(9)/l, reticulocyte percentage - 6.4
      +/- 1.5; high fluorescence reticulocyte HFR - 11.3 +/- 3.8%; medium reticulocyte
      fraction MFR - 18.1 +/- 4.7%; low reticulocyte fraction LFR - 70.7 +/- 7%;
      immature reticulocyte fraction IFR - 29.3 +/- 7%. The percentage values of
      reticulocytes decreased in cord blood according to gestational age increase, but
      maturation subpopulations did not change significantly. Reticulocyte fractions in
      normal pregnancy were different compared to complicated pregnancy.

PMID- 12426460
TI  - [Toxocariasis - an underestimated problem in paediatrics].
AB  - Aspects of Toxocara spp. epidemiology and paratenic infestation of children are
      described. Human toxocariasis is caused by infestation of zoonotic roundworms of
      dogs and cats. Soil sampling showes widespread contamination of the environment,
      particularly parks and playgrounds, with the eggs of Toxocara spp. Toxocara
      seroprevelance values in children vary between 3.5% in the West Poland and 19% in
      the South-East Poland. Children more frequently have clinical symptoms o the
      disease because of the closer contact with contaminated soil in sand-boxes and
      relatively frequent geophagia. A 3 years old girl with covert toxocariasis is
      described. As this case illustrates, this disease can be present without its
      classic visceral, ocular or neurological manifestations. On admission to the
      hospital the results of blood tests were as follows: white blood cells count,
      43x10(3)/ mm3 (norm <13x10(3)) and hyperosinophilia, 81%. The girl was treated
      with albendazole 15 mg/kg for five days, after one year the treatment was
      repeated. The patient was followed with blood samples throughout a period of one
      and half year. During that time results of serological tests for Toxocara canis
      were strongly positive. The lowest blood count was 20.0x10(3)/mm3 and
      eosinophilia, 19%. Possible association between high eosinophilia in toxocariasis
      and development of allergic and cardiovascular diseases is discussed.

PMID- 12426461
TI  - New cases of inter-community infanticide by male chimpanzees at Ngogo, Kibale
      National Park, Uganda.
AB  - Infanticide by males has been recorded in four chimpanzee populations, including
      that in Kibale National Park, Uganda. Some infanticidal attacks occur during
      inter-community aggression. The sexual selection hypothesis does not easily
      explain these attacks because they may not directly increase male mating
      opportunities. However, females in the attackers' community may benefit by
      expanding their foraging ranges and thereby improving their reproductive success;
      thus infanticide may increase male reproductive success indirectly. We report two
      new cases of infanticide by male chimpanzees at Ngogo, Kibale National Park. Like
      two previous cases, these occurred during a boundary patrol and were almost
      certainly between-community infanticides. The patrolling males attacked despite
      the proximity of males from the victims' presumed community. This probably
      explains why, unlike the earlier cases, they did not completely cannibalize their
      victims. Such attacks seem to be relatively common at Ngogo and infanticide may
      be an important source of infant mortality in neighboring communities. Our
      observations cannot resolve questions about the sexual selection hypothesis.
      However, they are consistent with the range expansion hypothesis: the
      infanticides occurred during a period of frequent encounters between communities
      associated with a mast fruiting event, and Ngogo community members greatly
      increased their use of areas near the attack site during another mast fruiting
      event one year later. Our observations contribute to growing evidence that lethal
      intergroup aggression is a common characteristic of wild chimpanzee populations.

PMID- 12426462
TI  - The seasonal daily travel in a group of Sichuan snub-nosed monkey (Pygathrix
      roxellana) in Shennongjia Nature Reserve, China.
AB  - The seasonal daily travel of a group of snub-nosed monkey (Pygathrix roxellana)
      was investigated using the group's straight-line distance method. The group was
      followed from dawn to dusk for 30 consecutive days during each season to
      encompass all aspects of daily travel patterns. The results showed that in Summer
      and Autumn, the mean daily travel distance (m) was significantly longer than in
      Winter and Spring. There was no significant difference in the mean daily travel
      distance between Summer and Autumn or between Winter and Autumn. The mean travel
      distance (m/hr) during daytime was significantly higher in Summer and Autumn than
      in Spring, and in Autumn than in Winter. The travel of the group in all seasons
      had similar patterns. Traveling showed morning and afternoon peaks, with a rest
      period at the noon in a day. Seasonal food availability, length of daytime, and
      mean travel distance (m/hr) during daytime might have contributed to the
      different daily travel distances in different seasons.

PMID- 12426463
TI  - The function of male aggressive displays towards females in mountain gorillas.
AB  - In groups of Gorilla g. beringei, male aggression towards females regularly takes
      the form of male display. This paper examines male display towards females in two
      Karisoke study groups (Group 5 and Group BM) in 1989, a period when none of the
      females were new immigrants. Results are based on 259 hr of focal observations
      and 121 hr of ad libitum observations on male behaviors towards females. The goal
      is to see if the data are compatible with four non-mutually exclusive hypotheses
      to explain male displays towards females: (1) demonstration of male fighting
      abilities to influence female long term residence decision; (2) decrease
      potential competitive inequities between females; (3) provision to females of an
      occasion to confirm their subordinance to a male; and (4) short term influence on
      mating. First, male-female proximity was tested against proportion of male
      displays, to rule out the possibility that males display towards females simply
      because they happen to be close by. There was no association between proximity
      and male display. Dominant males were responsible for a higher proportion of
      displays than subordinate males. This is consistent with the idea that males
      display to demonstrate their fighting abilities, or their qualities as protector,
      since dominant males are the ones offering long term protection against
      infanticide and predators. Females that were in a position to transfer did not
      receive a higher proportion of male display, however. Long term resident dominant
      females received a higher proportion of displays from the dominant males, which
      is consistent with the idea that males attempt to decrease potential competitive
      inequities between females. There was an association between female appeasement
      reactions and male displays, which suggests that males display to create
      occasions for the females to confirm their subordinance to them. Estrous females
      did not receive a higher proportion of male displays, and there was no
      association between male display and copulation, suggesting that male displays
      are not a form of courtship aggression aimed at influencing mating in the short
      term.

PMID- 12426464
TI  - Population and social dynamics changes in ring-tailed lemur troops at Berenty,
      Madagascar between 1989 - 1999.
AB  - In the present study, we recorded all births, immigrations, deaths, and
      emigrations for a population of ring-tailed lemurs at Berenty Reserve,
      Madagascar, between September 1989 and August 1999. In September 1989, three
      troops (C, B, and T) inhabited the study area of 14.2 ha. During the 10-year
      period, eight troop divisions, six evictions of females, and three troop
      takeovers of ranges by other troops occurred in and around the study area.
      Consequently, in August 1999, the number of troops in the same area increased to
      six (CX, C1, C2A, C2B, T1, and T2). The number of lemurs aged > 1 year increased
      from 63 to 82, which resulted from 204 births, 58 immigrations, 125 deaths, and
      118 emigrations. Of the 204 newborn lemurs during the study period, 103 died, 44
      emigrated outside the study area, and 57 remained within the study area. The
      total number of lemurs that emigrated from natal troops was 69 (54 males and 15
      females). Natal males left their troops around the age of 3. Non-natal males
      changed troops after a tenure varying from 1 to 7 years. Survival curves showed a
      fall in survival rates of both sexes to < 0.5 between the ages of 2 and 3. For
      females, the survival rate gradually decreased to < 0.2 at the age of 9. On the
      other hand, due to emigration, the survival rate of males could not be determined
      after the age of 5 yr. Since some males attained high-rank at the age of 6 - 10
      yr, the prime age for male ring-tailed lemurs is thought to be around 7 - 10 yr.
      Ring-tailed lemurs are essentially female philopatric, because all cases of
      females leaving natal troops resulted from troop divisions or forced evictions.
      Such social changes may have resulted from competition among females. All cases
      of troop divisions or evictions occurred in larger troops consisting of >or=20
      lemurs, and only a few females could rejoin their troops. When males joined such
      a female-group, a new troop was formed. Although promoted by an increase in
      population, frequent emigrations of females from original troops are the
      characteristics of ring-tailed lemurs at Berenty.

PMID- 12426466
TI  - Circadian rhythm in circulating CD16-positive natural killer (NK) cells in
      macaque monkeys, implication of plasma cortisol levels.
AB  - The daily change in both percentage and absolute number of circulating major
      lymphocyte subset was determined with young Japanese monkeys and rhesus monkeys.
      The blood sample was collected at four hour-intervals beginning at 16:00 for 24
      hours under the condition of applying tethering system by which blood samples
      could be collected without restraint. During the dark period (from 20:00 to
      08:00), the number of peripheral lymphocytes increased and that of granulocytes
      decreased, resulting in no significant change in the number of total peripheral
      white blood cells. The absolute number of CD4+ T, CD8+ T, and CD20+ B cells
      showed the significant daily change similar to that in number of peripheral
      lymphocytes, indicating no proportional change in these subsets. The typical
      proportional change was observed in CD16+ natural killer (NK) cells and the
      percentage of CD16+ cells decreased during dark period (from 20:00 to 04:00) and
      increased in the morning (from 08:00 to 12:00). The NK activity determined by
      killing K562 target cells showed the same changing pattern as that of percentage
      in CD16+ NK cells. The changing pattern of both percentage and activity of NK
      cells was consistent with that of plasma cortisol levels. In addition, the
      intravenous injection of 300  g/kg of cortisol induced increase in plasma
      cortisol levels and decrease in percentage of CD16+ NK cells during the first 60
      min after cortisol injection. These results strongly suggest that the levels of
      peripheral functional CD16+ NK cells might be directly regulated by plasma
      cortisol level in macaque monkeys.

PMID- 12426465
TI  - Population subdivision and gene flow among wild orangutans.
AB  - Genetic variability among populations of orangutans from Borneo and Sumatra was
      assessed using seven SSR loci. Most SSR loci were highly polymorphic and their
      allele frequencies exhibited substantial variation across subpopulations. While
      significant genetic subdivision was observed among the island populations,
      genetic distance did not increase with geographic distance and sufficient gene
      flow persists to prevent marked genetic subdivision. Since it is unlikely that
      the Bornean Orangutans dispersed naturally among locations separated by such
      formidable geographic barriers, human assistance might already have altered their
      genetic structure. Our data suggests that there may be at least two subspecific
      clades of orangutans within Borneo while Central Kalimantan animals may have
      become more genetically related to animals in Sumatra due to human intervention.

PMID- 12426467
TI  - Interspecific interaction and predator avoidance behavior in response to tayra
      (Eira barbara) by mantled howler monkeys (Alouatta palliata).
AB  - This paper reports the response of one howler monkey group (Alouatta palliata) to
      a group of potential predators, the tayra (Eira barbara). The apparently
      successful predator avoidance behavior of the monkeys was recorded in detail. We
      observed a group of four adult tayras moving around the Alouatta group displaying
      a species-typical aggressive behavioral pattern. The two adult females of the
      howler group successfully chased the tayras away by repeatedly moving closer to
      the mustelids and even following them until the predators moved off.

PMID- 12426468
TI  - Molecular evolution of IgG subclass among nonhuman primates: implication of
      differences in antigenic determinants among Apes.
AB  - The cross-reactivity of five different rabbit polyclonal antibodies to human IgG
      and IgG subclass (IgG1, IgG2, IgG3, and IgG4) was determined by competitive ELISA
      with nine nonhuman primate species including five apes, three Old World monkeys,
      and one New World monkey. As similar to those previously reported, the reactivity
      of anti-human IgG antibody with plasma from different primate species was closely
      related with phylogenic distance from human. Every anti-human IgG subclass
      antibody showed low cross-reactivity with plasma from Old World and New World
      monkeys. The plasma from all apes except for gibbons (Hylobates spp.) showed 60
      to 100% of cross-reactivity with anti-human IgG2 and IgG3 antibodies. On the
      other hand, chimpanzee (Pan troglodytes and Pan paniscus) and orangutan (Pongo
      pygmaeus) plasma showed 100% cross-reactivity with anti-human IgG1 antibody, but
      gorilla (Gorilla gorilla) and gibbon plasma showed no cross-reactivity. The
      chimpanzee and gorilla plasma cross-reacted with anti-human IgG4 antibody at
      different reactivity, 100% in chimpanzee and 50% in gorilla, but no cross
      reactivity was observed in orangutan and gibbon plasma. These results suggest the
      possibilities that the divergence of "human-type" IgG subclasses might occur at
      the time of divergence of Homo sapience from Hylobatidae, and that the molecular
      evolution of IgG1 as well as IgG4 is different from that of IgG2 and IgG3 in
      great apes, this is probably caused by different in development of immune
      function in apes during the course of evolution.

PMID- 12426469
TI  - Central nervous system-specific expression of G protein alpha subunits in the
      ascidian Ciona intestinalis.
AB  - Heterotrimeric G proteins play crucial roles as mediators of signaling by many
      extracellular stimuli. The receptors that activate G proteins constitute the
      largest and most diverse family of cell surface molecules involved in signal
      transmission of metazoan cells. To investigate G protein signaling in the central
      nervous system (CNS) of chordates, we isolated cDNA fragments encoding five
      different G protein alpha subunits (CiGalpha(x), CiGalpha(q), CiGalpha(i1a),
      CiGalpha(i1b), and CiGalpha(i2)) from larvae of the ascidian, a simple chordate,
      Ciona intestinalis. In situ hybridization analysis revealed that each isoform had
      distinct patterns of spatial distribution in embryos. Among them, CiGalpha(i1a)
      and CiG alpha(i1b) mRNAs were specifically expressed in the CNS of the larva,
      whereas CiGalpha(q) transcripts were expressed in small parts of the trunk
      epidermis and the tip of the tail, but not in the CNS. The CiGalpha(x) expression
      was widely observed throughout the trunk and tail of the embryos, and the signals
      were stronger in the epidermis, mesenchyme, and tail muscle cells. Comparison of
      cDNA sequences and the exon-intron organization indicate that CiGalpha(i1a) and
      CiGalpha(i1b) are produced by alternative splicing of transcripts from a single
      gene, CiGalpha(i1). In the cleavage and gastrula stages, transcripts of
      CiGalpha(i1) were widely distributed in embryos, and the expression then became
      restricted to the CNS of tailbud embryos and larvae. An exhaustive search has
      failed to find transducin-type alpha subunits in C. intestinalis. Since
      CiGalpha(i1) is expressed in the ocellus, CiGalpha(i1) may mediate signals from
      Ci-opsin1, a visual pigment of the ocellus photoreceptor cells.

PMID- 12426470
TI  - Cytokinesis arrest and nuclear fission in low density populations of trichomonad
      protozoan.
AB  - Cell growth of anaerobic protozoan Tritrichomonas foetus was analyzed. This
      protozoan usually proliferates in extremely high density, but protozoan parasites
      were dispersed uniformly in F-bouillon medium and cell division stopped
      temporarily. However, nuclear fission continued and giant polynucleated cells
      formed. Later, cell division resumed and cells returned to normal form. In
      conditioned medium, cytokinesis of the dispersed parasites did not stop. Results
      indicated that T. foetus cells secreted an extracellular factor that influenced
      cytokinesis.

PMID- 12426471
TI  - Chromosomes of Japanese starfishes.
AB  - We developed a method for preparing starfish chromosomes from embryos. Blastulae
      were treated with colchicine (0.2-4.0 mg/ml), dissociated into single blastomeres
      by pippeting, swollen with 7% sodium citrate, and fixed with methanol: acetic
      acid (3:1). The fixed cells were dropped on a slide and air-dried. We examined
      the chromosome number in five species of asteroids belonging to 4 families
      (Luidiidae, Astropectinidae, Asterinidae, and Asteriidae), and all had a diploid
      number of 44. We analyzed the karyotype in 4 of the species, and all were
      different. We visualized the nucleolus organizer regions of an Asterina species
      and an Asterias species and found them to be quite different from each other.

PMID- 12426472
TI  - Retinoic acid isomers produce malformations in postembryonic development of the
      Japanese flounder, Paralichthys olivaceus.
AB  - We previously reported that characteristic deformities were induced by retinoic
      acid (RA) treatment of the Japanese flounder, Paralichthys olivaceus, at 6-9 days
      post-hatching (dph). To evaluate the toxic potency of nuclear retinoid receptors
      in induction of deformities by RA, we here investigated the effects of retinoic
      acid isomers on postembryonic development of this species. Larvae were exposed to
      either 25 nM of all-trans RA (atRA), 9-cis RA (9cRA) or 13-cis RA (13cRA) at 6-9
      dph. All RA isomers induced deformities in the lower jaw, caudal fin and
      vertebrae. In the lower jaw, growth retardation of the dentary was evident. In
      the vertebrae, the major abnormalities were hypertrophy of the centrum, central
      fusion, and an increase in the number of abdominal vertebrae. Caudal fin
      deformities included deformity of caudal bone complex and absence of the entire
      caudal fin. The absence of the hypural primordium at 12 dph was the first sign of
      abnormality in caudal fin development, and resulted in complete blocking of the
      caudal fin development. Among the RA isomers, atRA induced the most severe
      deformity in all skeletons examined. Retinoic acid receptor (RAR) expression was
      activated by atRA and 9cRA, and pitx2 expression was inhibited in the lower jaw
      by atRA and 9cRA. Vitamin D receptor (VDR) expression was specifically inhibited
      by atRA treatment, suggesting that RA inhibits the lower jaw growth by
      suppressing the expression of these genes. These results suggest that RA exerted
      toxic effects on the skeletal systems, mainly through the RAR pathway.

PMID- 12426473
TI  - Conserved expression pattern of BMP-2/4 in hemichordate acorn worm and echinoderm
      sea cucumber embryos.
AB  - The auricularia larva of sea cucumbers and tornaria larva of acorn worms share
      striking developmental and morphological similarities. They are regarded as not
      only an archetype of the nonchordate deuterostome larva, but also an archetype of
      the origin of chordates. Here we report the characterization and spatial
      expression patterns of the BMP-2/4 genes of a hemichordate acorn worm (Pf-bmp2/4)
      and an echinoderm sea cucumber (Sj-bmp2/4). Both the Pf-bmp2/4 and Sj-bmp2/4
      genes exhibited apparently conserved expression in the region of the coelomopore
      complex. This is in agreement with the homology between their basic larval body
      plans with respect to coelomogenesis and allows us to discuss the evolutionary
      counterparts of the coelomopore complex in chordates.

PMID- 12426474
TI  - Anatomy of the planarian Dugesia japonica I. The muscular system revealed by
      antisera against myosin heavy chains.
AB  - The planarian Dugesia japonica has two genes encoding myosin heavy chain, DjMHC-A
      and B (Kobayashi et al., 1998). We produced antibodies specifically recognizing
      each myosin heavy chain protein using their carboxyl terminal regions expressed
      in E. coli as antigens. Immunohistochemical analyses of sections and whole-mount
      specimens revealed the detailed structure and distribution of each type of muscle
      fiber in the planarian. In general, the MHC-A muscle fibers were distributed
      beneath the epithelial layers, namely, they were observable in the pharynx, the
      mouth, the intestine, the eyes and the body wall. In the pharynx, only MHC-A
      muscle fibers were present. In contrast, the MHC-B muscle fibers were distributed
      in the mesenchyme as dorso-ventral and transverse muscles, and in the body wall.
      The body-wall muscles were composed of an outer layer of circular MHC-A muscles
      and inner longitudinal and intermediate diagonal MHC-B muscle layers. Thus, two
      types of muscle fibers were distinguished by their distribution in the planarian.

PMID- 12426475
TI  - Colony composition, social behavior and some ecological characteristics of the
      Korean wood-feeding cockroach (Cryptocercus kyebangensis).
AB  - Korean populations of the genus Cryptocercus occur in forested mountains
      throughout South Korea. They live in monogamous associations in which parents
      care for their young in complex woody galleries. Single paired adults (23.2%) and
      one or both parents with their offspring (28.1%) were found most frequently in
      the field. Among single-parent families adult females (6.7%) were observed more
      frequently than adult males (1.4%). In families with single or both parents, the
      mean brood size was 21.6+/-9.4. Oothecae were observed from mid-June to the late
      July. Oothecae were found in the galleries of only paired adults and never found
      in families with nymphs. The mean number of eggs per female was 73.7+/-29.8. Most
      of neonates grew to the third or fourth instar prior to the winter. During the
      winter, C. kyebangensis in the field remained almost frozen in their galleries,
      but ones kept in the laboratory continued to grow during winter. Some
      characteristics of proctodeal feeding behavior are also described based on
      laboratory observations. We propose that the cold temperate climate, especially
      of the winter season, is one of the most important causes for the evolution of
      unusual life history of Cryptocercus including delayed development of nymphs.

PMID- 12426476
TI  - Population structure and genetic diversity in insular populations of Nasutitermes
      takasagoensis (Isoptera: Termitidae) analyzed by AFLP markers.
AB  - Dispersal ability and degree of inbreeding in a population can indirectly be
      assessed using genetic markers. In general, it was suggested that winged termites
      are not able to fly distances greater than several hundred meters. Here,
      amplified fragment length polymorphism (AFLP) was used to analyze genetic
      diversity, population substructure, and gene flow among insular populations of
      the termite Nasutitermes takasagoensis (Isoptera: Termitidae) in the Yaeyama
      Islands, Okinawa, Japan. Samples were collected from 77 nests on seven islands of
      the Yaeyama Group. Using three primer combinations a total of 155 bands were
      generated with 78 (50%) polymorphic bands. Genetic distance and G(st) values
      among insular populations were calculated. Relatively high genetic diversity and
      low values of G (st), suggest there is moderate subpopulation structure. Based on
      these results, we discussed two possibilities; first, winged termites are able to
      fly over distances of several kilometers, and second, these results were obtained
      because insular populations share a recent common origin.

PMID- 12426477
TI  - Revision, phylogeny and biogeography of the groundwater amphipods
      Salentinellidae. I. Description of Salentinella anae nov. sp. from Spain with
      remarks on the genera Salentinella and Parasalentinella.
AB  - A new species of the groundwater amphipod Salentinella (Crustacea,
      Salentinellidae), S. anae, is described from Spain. This species is characterised
      by spines on the antennula peduncle, the absence of retinaculae on the pleopods,
      and the morphology of the coxal plate 1. Different morphological characters are
      evaluated before a phylogenetic study of the family. Salentinella prognatha is
      assigned as a synonym of S. petiti. The description of the genus
      Parasalentinella, as well as the diagnosis of the Salentinellidae are completed.

PMID- 12426478
TI  - Intraspecific variation of cuticular hydrocarbon composition in Formica japonica
      Motschoulsky (Hymenoptera: Formicidae).
AB  - Cuticular hydrocarbons and morphological features were compared among 80 Formica
      japonica colonies collected in Japan. Although a few morphological differences
      were found in workers among the colonies, four different types of cuticular
      hydrocarbon composition were observed. This was supported by a principal
      component analysis. We further compared the cuticular hydrocarbons among a total
      of approximately 400 F. japonica colonies, and categorized the hydrocarbon
      components into four types based on the result of discriminant analyses for the
      first 80 colonies. Type 1 was observed in colonies mainly collected in southern
      Honshu, Shikoku, and Kyushu. Types 2, 3, and 4 were from colonies with primary
      collections in Southern Honshu, central and Pacific coast northern Honshu, and
      the Sea of Japan coasts of northern Honshu and Hokkaido, respectively. The
      occurrence of four distinct types of CHC composition suggests that the colonies
      that produce them are separate species.

PMID- 12426479
TI  - A new species of the genus Rimicaris (Alvinocarididae: Caridea: Decapoda) from
      the active hydrothermal vent field, "Kairei Field," on the Central Indian Ridge,
      the Indian Ocean.
AB  - Rimicaris kairei new species (Alvinocarididae: Caridea: Decapoda) is described
      based on materials, from the active hydrothermal vent field, "Kairei Field," on
      the Central Indian Ridge, the Indian Ocean. The new species is clearly
      distinguishable from the unique congener, R. exoculata Williams & Rona, 1986,
      which is known from the Atlantic Ocean. The following morphological differences
      were identified: (1) all punctations on carapace strongly ornamented by tufts of
      short stiff setae in R. exoculata, whereas without any setae in R. kairei; (2)
      antennal flagella in R. exoculata shorter than in R. kairei; (3) walking legs in
      R. exoculata more robust than in R. kairei.

PMID- 12426480
TI  - Comments on the taxonomic status of Ikeda taenioides (Ikeda, 1904) with some
      amendments in the classification of the phylum Echiura.
AB  - Examination of thin sections of trunk wall in an old specimen of Ikeda taneioides
      from Misaki, Sagami Bay revised previous false information about the wall
      musculature, actually consisting of outer circular, middle longitudinal, and
      inner-most oblique layers, like all other echiurans. This finding, together with
      the reexamination of relevant museum specimens, led to some taxonomic changes.
      These include that the definition of the genus Ikeda was amended to be a senior
      synonym of Prashadus; the family Ikedidae was regarded as a junior synonym of the
      family Echiuridae; and the order Heteromyota, erected virtually for I.
      taenioides, was abolished. Non-discovery of males and some other features in the
      amended genus Ikeda were noted with reference to its possible relationship with
      the family Bonelliidae.

PMID- 12426481
TI  - Morphological studies on the bathyal ascidian, Megalodicopia hians Oka 1918
      (Octacnemidae, Phlebobranchia), with remarks on feeding and tunic morphology.
AB  - Megalodicopia hians Oka is a solitary ascidian belonging to the family
      Octacnemidae inhabiting the bathyal /abyssal zone as well as other octacnemid
      ascidians. The phylogenetic relationship of octacnemids is open to argument
      because of its extraordinary morphological features due to habitat adaptation,
      e.g., a pharynx lacking ciliated stigmata. Aggregations of M. hians were
      discovered by the manned submersible Shinkai 2000 in the bathyal seafloor of
      Toyama Bay, Japan Sea, in 2000; this was the first in situ observation of M.
      hians in the Japanese coastal waters. In 2001, a total of 36 M. hians specimens
      were collected from the bay (592 to approximately 978 m deep). In situ
      observation indicated that M. hians usually opens its large oral apertures to
      engulf the drifting food particles in the water current. Microscopical
      observation of the gut contents also showed that M. hians is a non selective
      macrophagous feeding on small crustaceans, diatoms, detritus, and so on. Along
      with the position of the intestinal loop and gonad, the morphological
      characteristics of the tunic (integument of ascidians) suggest that M. hians is
      closely related to Cionidae and/or Corellidae. Some symbiotic/parasitic organisms
      were occasionally found in the tunic, including rod-shaped bacteria, fungi-like
      multicellular structure, and spawns of unknown animals.

PMID- 12426482
TI  - Mate discrimination and cuticular hydrocarbons in Drosophila elegans and D.
      gunungcola.
AB  - In Drosophila elegans, two morphs are known, the brown-morph occurring from
      southern China to Indonesia and the black-morph occurring in the Ryukyu Islands,
      Japan, and Taiwan, and brown-morph populations at high altitudes in Indonesia at
      least sympatrically occur with a sibling species D. gunungcola. Sexual isolation
      has developed between the two morphs of D. elegans to some extent; females of the
      black-morph have a higher concentration of pentacosenes on cuticle than those of
      the brown-morph, and males of these morphs discriminate between the females based
      on this difference. In this study, it was examined whether sympatry and allopatry
      with D. gunungcola have resulted in the differentiation of mate recognition
      system in D. elegans. No significant difference was observed in the degree of
      mate discrimination between a sympatric pair of D. elegans and D. gunungcola and
      their allopatric pairs. Thus, no support was obtained for the above notion. Males
      of the brown- and black-morphs of D. elegans discriminate between females of own
      morphs and D. gunungcola. However, brown-morph males did not discriminate between
      females of the black-morph and D. gunungcola, and also black-morph males did not
      discriminate between females of the brown-morph and D. gunungcola. This may be
      attributed to that D. gunungcola females retained an intermediate level of
      pentacosenes between brown- and black-morph females.

PMID- 12426484
TI  - Use of epidermal equivalents generated from follicular outer root sheath cells in
      vitro and for autologous grafting of chronic wounds.
AB  - During wound healing, outer root sheath (ORS) cells of hair follicles can
      substitute for interfollicular epidermal keratinocytes and thus act as precursor
      cells for interfollicular epidermal keratinocytes. Owing to improved culture
      techniques, ORS cells can be induced to develop highly differentiated epidermal
      equivalents, which are close to the normal human epidermis in terms of
      histological, ultrastructural, biochemical and immunohistological criteria. Such
      epidermal equivalents provide a versatile system for various applications in
      vitro, e.g. the study of epidermal homeostasis, cell interactions, pigmentation
      as well as toxicity testing and metabolism of xenobiotics. The easy and repeated
      availability of ORS cells, their successful multiplication in culture
      irrespective of the age of the hair follicle donor as well as the extended tissue
      normalization of epidermal equivalents prepared with ORS cells prompted us to
      test the usefulness of autologous epidermal equivalents for the treatment of
      recalcitrant chronic wounds. Autologous grafting of such epidermal equivalents in
      more than 50 recalcitrant leg ulcers of a mainly vascular origin resulted in an
      initial take rate of around 90%, with subsequent complete closure of the ulcers
      in about 45% and a significant size reduction in another 40% within 8 weeks.
      These positive results are probably due to the large compartment of proliferative
      cells as well as to the well-developed horny layer, which prevents rapid
      disintegration of the grafts. Practical advantages of this technology are its
      noninvasiveness and thus repeated availability, the fact that surgical facilities
      are not necessary and the short immobilization period after grafting, allowing a
      strategy of sequential application in an outpatient setting as an alternative to
      surgical autografting.

PMID- 12426485
TI  - Reaction of keratinocytes to exogenous DNA.
AB  - Keratinocytes have the ability to take up oligonucleotides (ODN) and plasmid DNA
      probably by receptor-mediated endocytosis or macropinocytosis. Despite the use of
      DNA for antisense and gene therapy, little is known about the regulation of genes
      following exposure to nucleic acids. To systematically identify gene regulation
      in keratinocytes upon exposure to ODN, we screened human cytokine DNA arrays
      containing 383 different genes and found interleukin-1 alpha (IL-1 alpha), IL-1
      beta, integrin beta1, alpha-tubulin and follistatin greatly induced, while most
      genes were unaffected. The time course and concentration dependence for IL-1
      alpha and follistatin was confirmed by the standard Northern blot technique and
      found to be induced by picomolar or femtomolar concentrations of ODN. ODN of
      different length and sequence induced comparable amounts of IL-1 alpha and
      follistatin. Their induction was independent of the negative charge and of
      several proinflammatory compounds and proteins such as lipopolysaccharides, IL-1
      beta or IFN-gamma, but was partly inhibited by activin A. In summary, our study
      revealed several genes of the acute phase protein family that were induced in a
      non-sequence-specific manner following the exposure of normal human keratinocytes
      to ODN. Therefore, it is tempting to speculate that, upon internalization, ODN
      bind to an intracellular receptor (e.g. Toll-like receptor 9), which mediates
      signaling.

PMID- 12426486
TI  - Skin genetically engineered as a bioreactor or a 'metabolic sink'.
AB  - Genetically manipulated human keratinocytes can produce and secrete medically
      relevant proteins to the circulation. Genetically modified skin may also function
      as a 'metabolic sink' detoxifying the body of metabolites which accumulate in
      certain metabolic diseases. At the National Institutes of Health (NIH), Bethesda,
      Md., a clinical trial investigating the treatment of an ocular disease using the
      skin as a 'metabolic sink' for ornithine accumulating in gyrate atrophy patients
      is being prepared. The trial will involve the transplantation of a small patch of
      autologous keratinocytes, transduced ex vivo, onto the thighs of patients with
      gyrate atrophy. We are now investigating other diseases where this technology may
      be applicable such as in the treatment of hyperphenylalaninemia or
      hypercholesterolemia.

PMID- 12426487
TI  - Treatment of chronic wounds: state of the art and future concepts.
AB  - The morbidity and mortality from chronic wounds of varying etiology present a
      significant health care problem. Multiple local disturbances and systemic disease
      can impair wound healing. Recently, experiments with tissue cultures and animal
      models have revolutionized the understanding of wound healing and the
      pathophysiological processes involved. In cooperation with clinicians and
      industrial partners novel therapeutic concepts including the topical application
      of growth factors and cell therapies have been developed. Cytokines that have
      been tested in clinical studies include epidermal growth factor, platelet-derived
      growth factor and fibroblast growth factor. These studies showed that an
      important aspect of the growth factor wound healing paradigm is the effective
      delivery of these polypeptides to the wound site. Current drug delivery
      strategies suffer from the inherent loss of drug activity due to the combined
      effects of physical inhibition and biological degradation. A molecular genetic
      approach in which genetically modified cells synthesize and deliver the desired
      growth factor in a time-regulated manner is a powerful means to overcome the
      limitations associated with the topical application of recombinant growth factor
      proteins.

PMID- 12426488
TI  - Gene therapy in soft tissue reconstruction.
AB  - Gene therapy is defined as the introduction of a therapeutic gene into a cell,
      whose expression can lead to a cure of a disease or offer a transient advantage
      for tissue growth and regeneration. The delivery of genes can be undertaken for a
      number of purposes, usually it is attempted to enhance or add a function to a
      cell or a tissue or to delete or reduce another function. In this brief overview
      we describe various vehicles and techniques that have been developed to deliver
      therapeutic genes into cells, such as viral vectors and physical/chemical gene
      delivery methods including naked DNA and particle-mediated gene transfer, the
      microseeding technique and the application of lipids. Furthermore we review the
      potential utility of gene therapy from the perspective of a reconstructive
      surgeon. Several tissues will be discussed, particularly muscle, tendon, nerve,
      bone, skin and wounds.

PMID- 12426489
TI  - Apoptotic genes in cancer therapy.
AB  - Induction of apoptosis in malignant cells is a major goal of cancer therapy in
      general and of certain cancer gene therapy strategies in particular. Numerous
      apoptosis-regulating genes have been evaluated for this purpose. Besides the most
      prominent p53 gene others include p16, p21, p27, E2F genes, FHIT, PTEN and
      CASPASE genes. Recently, the potential for therapy of an adenoviral gene, E1A,
      known for a long time for its apoptosis-inducing activity, has been discovered.
      In experimental settings, these genes have proven their tumor-suppressive and
      apoptosis-inducing activity. Clinical trials are currently being performed with
      selected genes. By far the most studies transfer the p53 gene using retro- or
      adenoviral vectors. Disease stabilization or other benefits were observed in a
      limited number of patients when p53 was applied alone or in combination with
      cytotoxic drugs. A second proapoptotic gene that has entered clinical trials is
      adenovirus E1A. Here, too, disease stabilization as well as/or local regression
      in one case have been demonstrated in selected patients. In all cases, side
      effects were tolerable. To further improve E1A as a therapeutic transgene, we
      have deleted transforming domains from the adenovirus 5 and 12 13S cDNAs. Mutants
      were derived which had completely lost their transforming activity in combination
      with the E1B oncogene but retained a pronounced tumor-suppressive activity. Cells
      transduced with these constructs showed a highly reduced ability to grow in soft
      agar, and tumor growth in nude mice could be substantially suppressed. Outgrowing
      tumors had lost E1A expression when analyzed in Western blots. These E1A
      constructs may represent valuable tools for cancer gene therapy in the future.

PMID- 12426490
TI  - Gene therapy for sarcoma.
AB  - Soft tissue sarcomas are mesenchymal tumors which respond poorly to systemic
      therapy. Recent studies suggest a higher response rate with an increased
      doxorubicin dosage. However, this was parallel with a profound hematotoxicity in
      75% of patients. Transfer of the human multidrug resistance 1 (MDR1) gene to
      normal hematopoietic stem cells and transplantation may significantly reduce the
      hematotoxicity of anthracyclin-based chemotherapy. To test this concept of
      supportive gene therapy in advance of a clinical study, we transduced mobilized
      peripheral blood progenitor cells (PBPC) with the retroviral vector SF91m3
      containing the human MDR1 gene, transplanted these cells to immune-deficient
      mice, allowed 6 weeks for engraftment to occur and treated the animals with MDR1
      based chemotherapy. In the MDR1-transduced group the human leukocytes were
      significantly protected from the toxicity of chemotherapy (p < 0.05). While the
      gene transfer rate was in the range of 10% and thus comparable to recent clinical
      trials, the gene expression was 59% of transduced cells and thus significantly
      higher than previously reported for less-advanced vectors. On the other hand,
      ifosfamide, a drug which has been used successfully for stem cell mobilization,
      is active in soft tissue sarcoma. Due to these favorable characteristics sarcoma
      is an attractive target to test the efficacy of MDR1 gene therapy in a clinical
      setting. Gene therapeutic strategies may also be used to directly target sarcoma
      cells, e.g. by transfer of suicide genes. We found that adenoassociated virus 2
      (AAV-2) vectors efficiently transduce human HS-1 and HT1080 sarcoma cells (>90%)
      while other tumor cell lines and primary human PBPC were less susceptible. The
      thymidine kinase (TK) suicide gene was cloned into an AAV-2 vector and a complete
      kill of TK-transduced HS-1 and HT1080 cells was observed following exposure to
      aciclovir or ganciclovir (GCV), while >90% of mock-transduced HS-1 cells survived
      at these dosages. Transplantation of those sarcoma cells to nonobese diabetic
      (NOD)/LtSz-severe-combined immunodeficient (scid)/scid (NOD/SCID) mice resulted
      in a survival of >5 months in the AAV-TK-transduced/GCV-treated group, while the
      mice in the mock-transduced/GCV-treated group had died after 3 weeks. These data
      show that soft tissue sarcomas are a particularly suitable model system for the
      development and clinical testing of new gene therapeutic concepts.

PMID- 12426491
TI  - Indirectly formed matrix for multiple composite core restorations: two clinical
      treatments illustrating an expanded technique.
AB  - The technique described in this report is an expansion of a previously reported
      intraoral procedure for directly developing a matrix for the fabrication of
      composite cores. The expanded method allows a matrix to be created indirectly
      after the involved teeth are trimmed or restored on a cast into slightly
      oversized crown preparations before the treatment visit. The cast may serve for
      both the matrix and the interim fixed restoration, enabling fabrication by the
      dental laboratory. A semirigid (occlusal registration) elastomeric material is
      used to form the matrix. The matrix is used to apply the composite and shape the
      cores after the abutment teeth have been prepared, pins or posts have been
      placed, and adhesive procedures have been implemented. The elastomeric matrix can
      be modified for use as the impression matrix. The described technique allows the
      simultaneous formation of multiple composite cores. An alternative method in
      which light-polymerized core composite is used with a vacuum-formed, dual
      laminate transparent matrix is described and compared with the semirigid
      elastomeric matrix.

PMID- 12426492
TI  - New approach to bonding all-ceramic adhesive fixed partial dentures: a clinical
      report.
AB  - This clinical report describes the use of intraoral silica coating and
      silanization in an alternative bonding procedure for a 3-unit, all-ceramic, resin
      bonded fixed partial denture.

PMID- 12426493
TI  - Retrieval and replacement of a malpositioned dental implant: a clinical report.
AB  - This clinical report describes the retrieval of a malpositioned mandibular
      implant with a severe lingual inclination. A replacement implant was inserted
      with an emphasis on its relationship with the maxillary antagonist, resulting in
      a buccal inclination of approximately 10 degrees. The treatment review highlights
      the importance of thorough communication among all members of the dental implant
      team.

PMID- 12426494
TI  - Prosthetic treatment for severely misaligned implants: a clinical report.
AB  - This clinical report describes a procedure that allows for prosthetic use of
      severely misaligned implants resulting from surgical placement.

PMID- 12426495
TI  - Susceptibility of Candida albicans isolates from the oral cavities of HIV
      positive patients to histatin-5.
AB  - STATEMENT OF PROBLEM: Oral surfaces, including the denture-fitting surface, may
      serve as a reservoir for disseminated candidal infections, particularly in
      immunocompromised hosts such as patients with AIDS. Histatins are a group of
      small, cationic antifungal peptides present in human saliva. There is limited
      information on the antifungal activity of peptides against Candida albicans
      isolates from HIV-positive patients. PURPOSE: This study investigated the
      fungicidal effects of histatin-5 against oral isolates of C. albicans from HIV
      positive and HIV-negative patients. MATERIAL AND METHODS: An isolate of C.
      albicans from each of 2 HIV-positive patients (both male) and 3 HIV-negative
      patients (2 male and 1 female) was obtained. American Type Culture Collection
      90028 served as a reference strain. All isolates were identified with sugar
      assimilation tests and the germ tube test. Fungicidal assays were performed on
      exponential C. albicans cells in the presence or absence of 0.315 to 50 microm of
      histatin-5. Numerical data were subjected to 1-way analysis of variance and
      Tukey's multiple range test (P<.05). RESULTS: Histatin-5 (50 microm) killed more
      than 95% of C. albicans isolates from HIV-negative patients and more than 90% of
      isolates from the reference strain. The same treatment induced 75.3% and 66.1%
      loss of viability in C. albicans isolates taken from HIV-positive patients (A1
      and A2 cells, respectively). The difference between the fungicidal effects in the
      HIV-positive and HIV-negative groups was significant. (P<.05). CONCLUSION: Within
      the limited population of this study, C. albicans isolates from the oral cavities
      of HIV-positive patients were less sensitive to histatin-5 than oral isolates
      from HIV-negative patients.

PMID- 12426496
TI  - Wettability, imbibition, and mass change of disinfected low-viscosity impression
      materials.
AB  - STATEMENT OF PROBLEM: There is an ongoing effort by dental manufacturers to
      create impression materials with improved wetting properties. Disinfection
      solutions may alter the surface characteristics of these newer materials.
      PURPOSE: This study compared wettability, imbibition, and mass change of various
      recently introduced automixed low-viscosity addition silicone and polyether
      materials before and after immersion disinfection. MATERIAL AND METHODS: The
      Wilhelmy technique was used for deriving wetting properties of 5 addition
      silicone materials (Clinician's Choice Affinity, Clinician's Choice
      Superhydrophilic [experimental], Kerr's Take One, 3M's Imprint II, and Dentsply's
      Aquasil LV) and 2 polyether materials (ESPE's Permadyne Garant and Impregum
      Garant). Conditions included a control with no disinfection (0 hours), as well as
      (1/2) hour of immersion disinfection in a full-strength solution of 2% acid
      glutaraldehyde disinfectant (Banicide). Weight changes before and after
      disinfection and weight loss in air were measured over an 18-hour period to
      detect imbibition and mass change over time. The data were analyzed with a 1-way
      analysis of variance at alpha=0.05, with n = 3 for advancing (ACA) and receding
      (RCA) contact angles and n = 2 for imbibition and mass change. RESULTS:
      Statistical significant differences in wettability (P<.001) were found among
      nondisinfection control groups, as well as among (1/2)-hour disinfection groups.
      Polyethers were the most wettable materials overall. Impregum Garant polyether
      demonstrated significantly lower RCA for the control (48.4 degrees) and at (1/2)
      hour of disinfection (51.8 degrees). The 2 polyethers and Take One lost mass,
      whereas Aquasil LV gained mass in air; however, all materials exhibited some
      degree of imbibition during disinfection. CONCLUSION: Within the limitations of
      this study, the 2 polyether materials tested exhibited significantly lower ACA's
      and RCA's compared with the 5 addition silicones tested. Imbibition for the 2
      polyether materials was significantly higher (P<.001). Polyether materials lost
      significantly more (0.6% to 0.8%) and Aquasil LV gained significantly more (0.6%)
      mass in air.

PMID- 12426497
TI  - Shear bond strength of resin cements to both ceramic and dentin.
AB  - STATEMENT OF PROBLEM: All ceramic restorations benefit from resin cement bonding
      to the tooth. However, the literature is unclear on which cement, ceramic
      conditioning treatment, and dentin bonding agent produce the highest and longest
      lasting bond strength. PURPOSE: This in vitro study evaluated immediate and 6
      month shear bond strengths between a feldspathic ceramic and 4 different resin
      cements with the use of 6 different surface-conditioning treatments. Shear bond
      strengths between the 4 resin cements and dentin also were measured. MATERIAL AND
      METHODS: Four hundred eighty discs (10 mm in diameter and 4 mm thick) of Ceramco
      II porcelain were randomly divided into 6 main groups (n = 80). The ceramic
      specimens received 6 different surface conditioning treatments before the
      application of resin cement. These surface treatments were sanding with 600-grit
      silicon carbide paper, microetching with aluminum oxide, sanding followed by
      silane application, microetching followed by silane application, hydrofluoric
      acid-etching, and hydrofluoric acid-etching followed by silane application. Each
      group then was subdivided into 4 subgroups (n = 20) for the application of 1 of 4
      cements: Nexus, Panavia 21, RelyX ARC, and Calibra. All cemented specimens were
      tested under shear loading until fracture on a universal testing machine; the
      load at fracture was reported in MPa as the bond strength. Bond strengths were
      determined at 24 hours and after 6 months of specimen storage in a saline
      solution. For dentin-resin cement shear bond strength testing, dentin specimens
      were treated with dentin bonding agents, and a thin layer of resin cement was
      applied according to the manufacturer's directions. Prodigy composite was bonded
      to the cement. Shear bond strengths were determined as above and reported in MPa
      at fracture. Data were analyzed with 3-way analysis of variance (P<.01). RESULTS:
      Hydrofluoric acid-etching followed by silane application produced bond strengths
      (15.0 +/- 7.4 to 21.8 +/- 5.8 MPa) in the highest statistical group with all 4
      cements at both 24 hours and 6 months (P<.01). Sanding with 600-grit silicon
      carbide paper and microetching with aluminum oxide produced the lowest bond
      strengths (0.0 to 4.0 +/- 3.5 MPa). At 24 hours and 6 months, there were no
      significant differences among the 4 cements when hydrofluoric acid-etching was
      followed by silane application. Both auto- and light-polymerized dentin bonding
      agents bonded better to dentin than dual-polymerized bonding agents. CONCLUSION:
      Within the limitations of this study, hydrofluoric acid-etching followed by
      silane application produced the best bonds at 24 hours and 6 months with all 4
      cements. Auto- and light-polymerized adhesives were associated with higher bond
      strengths to dentin than dual-polymerized adhesives.

PMID- 12426498
TI  - Effect of a new tension system, used in acrylic resin flasking, on the
      dimensional stability of denture bases.
AB  - STATEMENT OF PROBLEM: The pressure of final closure may be released when the
      flask is removed from the mechanical or pneumatic press and placed in the spring
      clamp. This release in pressure may result in dimensional changes that distort
      the denture base. PURPOSE: The purpose of this study was to investigate
      differences between the dimensional stability of standardized simulated denture
      bases processed by traditional moist heat-polymerization and those processed by
      use of a new tension system. MATERIAL AND METHODS: A metal master die was
      fabricated to simulate an edentulous maxillary arch without irregularities in the
      alveolar ridge walls. A silicone mold of this metallic die was prepared, and 40
      stone casts were formed from the mold with type III dental stone. The casts were
      randomly assigned to 4 test groups (A-D) of 10 specimens each. A uniform denture
      base pattern was made on each stone cast with a 1.5-mm thickness of base-plate
      wax, measured with a caliper. The patterns were invested for traditional hot
      water processing. A polymethyl methacrylate dough was prepared and packed for
      processing. The flasks in groups A and B were closed with the traditional
      pressure technique and placed in spring clamps after final closure. The flasks in
      groups C and D were pressed between the metallic plates of the new tension system
      after the final closure. The group A and C flasks were immediately immersed in
      the water processing unit at room temperature (25 degrees +/- 2 degrees C). The
      unit was programmed to raise the temperature to 74 degrees C over 1 hour, and
      then maintained the temperature at 74 degrees C for 8 hours. The group B and D
      flasks were bench stored at room temperature (25 degrees +/- 2 degrees C) for 6
      hours and were then subjected to the same moist heat polymerization conditions as
      groups A and C. All processed dentures were bench cooled for 3 hours. After
      recovery from the flasks, the base-cast sets were transversally sectioned into 3
      parts (corresponding to 3 zones): (1) distal of the canines, (2) mesial of the
      first molars, and (3) mesial of the posterior palate). These areas had been
      previously established and standardized by use of a pattern denture in the sawing
      device to determine the sections in each base-cast set. Base-cast gaps were
      measured at 5 predetermined points on each section with an optical micrometer
      that had a tolerance of 0.001 mm. Collected data were analyzed with analysis of
      variance and Tukey's test. RESULTS: Denture bases processed with the new tension
      system exhibited significantly better base adaptation than those processed with
      traditional acrylic resin packing. Immediately after polymerization (Groups A and
      C), mean dimensional change values were 0.213 +/- 0.055 mm for the traditional
      packing technique and 0.173 +/- 0.050 mm for new tension system. After delayed
      polymerization (Groups B and D), the values were 0.216 +/- 0.074 mm for the
      traditional packing technique and 0.164 +/- 0.032 mm for new tension system. With
      both techniques, dimensional changes in the posterior palatal zone were greater
      (conventional = 0.286 +/- 0.038 mm; new system = 0.214 +/- 0.024 mm) than those
      elsewhere on the base-cast set. CONCLUSION: Within the limitations of this study,
      the new tension packing system was associated with decreased dimensional changes
      in the simulated maxillary denture bases processed with heat-polymerization.

PMID- 12426499
TI  - Comparative study of circumferential clasp retention force for titanium and
      cobalt-chromium removable partial dentures.
AB  - STATEMENT OF PROBLEM: The interest in using titanium to fabricate removable
      partial denture (RPD) frameworks has increased, but there are few studies to
      support its use. PURPOSE: The objective of this study was to compare
      circumferential RPD clasps made of commercially pure titanium and identical
      clasps made of 2 different cobalt (Co)-chromium (Cr) alloys by testing
      insertion/removal and radiographically inspecting the casts for defects. MATERIAL
      AND METHODS: On refractory casts that represent a partially edentulous mandibular
      right hemi-arch segment, 36 frameworks were cast from commercially pure titanium
      (n = 12) and 2 Co-Cr alloys (n = 12 each) with identical prefabricated patterns
      and the manufacturer-designated investment and casting technique. Each group was
      divided into 2 subgroups, corresponding to .25-mm and .50-mm undercuts,
      respectively. No polishing procedures were performed to ensure uniformity. Only
      nodules and burs were carefully removed with tungsten burs under magnification
      when necessary. The specimens were radiographed and subjected to an
      insertion/removal test simulating 5 years of framework use. The data were
      subjected to analysis of variance and the Tukey complementary test (P<.01) to
      compare the retentive forces of RPDs made with the different materials. The
      Student t test (P<.01) was used to compare the retentive forces of RPDs
      fabricated with the same alloy with different undercuts. RESULTS: A total of 20%
      of the titanium specimens demonstrated porosity, showing casting difficulties,
      and any defect detected on the clasps determined the sample replacement. For Co
      Cr alloys, casting difficulties were not found. The data were subjected to
      analysis of variance and the Tukey complementary test to compare materials for
      the same undercut. For the .25-mm undercut, no significant difference was found
      between Magnum and Rematitan alloys; they were both different from the Remanium
      alloy (P<.01). For the.50-mm undercut, no significant difference was found
      between Co-Cr alloys; they were both different from Rematitan alloy (P<.01). The
      Student t test used to compare the same alloys with different undercuts showed no
      significant difference between Remanium with .25-mm and .50-mm undercuts. For
      Magnum and Rematitan alloys, there was a significant difference between different
      undercuts (P=.01). CONCLUSION: Within the limitations of this simulation study,
      the results suggest that commercially pure titanium clasps maintained retention
      over a simulated 5-year period, with lower retention force than identical Co-Cr
      clasps.

PMID- 12426500
TI  - Three-year clinical comparison of survival of endodontically treated teeth
      restored with either full cast coverage or with direct composite restoration.
AB  - STATEMENT OF PROBLEM: Little information exists regarding the outcome of crown
      build-ups on endodontically treated teeth restored with metal-ceramic crowns or
      with only a direct-placed composite. PURPOSE: The aim of this study was to
      evaluate the clinical success rate of endodontically treated premolars restored
      with fiber posts and direct composite restorations and compare that treatment
      with a similar treatment of full-coverage with metal-ceramic crowns. MATERIAL AND
      METHODS: Subjects included in this study had one maxillary or mandibular premolar
      for which endodontic treatment and crown build up was indicated and met specific
      inclusion/exclusion criteria. Only premolars with Class II carious lesions and
      preserved cusp structure were included. Subjects were randomly assigned to 1 of
      the following 2 experimental groups: (1) teeth endodontically treated and
      restored with adhesive techniques and composite or (2) teeth endodontically
      treated, restored with adhesive techniques and composite, and then restored with
      full-coverage metal-ceramic crowns. Sixty teeth were included in the first group
      and 57 in the second. All restorations were performed by one operator. Causes of
      failure were categorized as root fracture, post fracture, post decementation,
      clinical and/or radiographic evidence of marginal gap between tooth and
      restoration, and clinical and/or radiographic evidence of secondary caries
      contiguous with restoration margins. Subjects were examined for the listed
      clinical and radiographic causes of failure by 2 calibrated examiners at
      intervals of 1, 2, and 3 years. Exact 95% confidence intervals for the difference
      between the 2 experimental groups were calculated. RESULTS: At the 1-year recall,
      no failures were reported. The only failure modes observed at 2 and 3 years were
      decementations of posts and clinical and/or radiographic evidence of marginal gap
      between tooth and restoration. There was no difference in the failure frequencies
      of the 2 groups (95% confidence interval, -17.5 to 12.6). There was no difference
      between the number of failures caused by post decementations and the presence of
      marginal gaps observed in the 2 groups (95% confidence intervals, -9.7 to 16.2
      and -17.8 to 9.27). CONCLUSION: Within the limitations of this study, the results
      upheld the research hypothesis that the clinical success rates of endodontically
      treated premolars restored with fiber posts and direct composite restorations
      after 3 years of service were equivalent to a similar treatment of full coverage
      with metal-ceramic crowns.

PMID- 12426501
TI  - Effect of core stiffness on the in vitro fracture of crowned, endodontically
      treated teeth.
AB  - STATEMENT OF PROBLEM: Dentin and core materials that substitute for missing
      dentin are dissimilar materials. A core material with a lower elastic modulus may
      deform more under applied stress and therefore result in reduced stress
      concentration at the core/dentin junction. PURPOSE: This in vitro study examined
      the effect of core stiffness on the fracture resistance and failure
      characteristics of a crowned, endodontically treated tooth under simulated
      occlusal load. MATERIAL AND METHODS: Forty extracted human mandibular premolars
      were divided equally into 4 groups and prepared for posts and cast crowns as
      follows: group 1 = cast post and core, cast crown; group 2 = preformed metal
      post, composite core, and cast crown; group 3 = preformed metal post, amalgam
      core, and cast crown; and group 4 (control) = preformed metal post, no core, and
      cast crown. All prepared teeth had 2 mm of sound dentin on which the cemented
      crown rested. A continuous load (kg) was applied to the buccal cusp at a 30
      degree angle to the long axis of each tooth at a crosshead speed of 2 mm/min
      until failure. Collected data were subjected to 1-way analysis of variance with
      the Welch modification to compare groups (P<.05). RESULTS: Failure loads for the
      4 test groups were as follows: 98.1 +/- 34.6 kg (group 1), 94.4 +/- 41.8 kg
      (group 2), 105.5 +/- 18.6 kg (group 3), and 101.1 +/- 55.3 kg (group 4). No
      significant difference in failure load values was found among the 4 groups. The
      primary mode of failure (80%) in all groups was an oblique radicular fracture,
      either apical to the post or at the post level. Horizontal fracture of the root
      and post was found in groups 1, 2, and 3 (20%). Loosening of the crown, post, and
      core was found only in group 2(20%). CONCLUSION: Within the limitations of this
      study, core stiffness did not affect the failure resistance of teeth restored
      with posts and cores and complete-coverage cast metal crowns. The dominant
      pattern of failure was unrepairable root fracture. Only the composite core
      exhibited repairable fractures.

PMID- 12426502
TI  - Fracture toughness of packable and conventional composite materials.
AB  - STATEMENT OF PROBLEM: The introduction of packable composite has expanded the
      choices of materials for the restoration of posterior teeth. Few independent
      studies are available on the fracture toughness (K(IC)) of the presently
      available packable composites compared with more conventional composite
      alternatives. PURPOSE: This investigation evaluated the relative fracture
      toughness of 3 packable composites, 2 conventional composites, and 1 laboratory
      processed composite. MATERIALS AND METHODS: Six composite materials were tested
      in this study. These included: 3 packable composites (Alert, SureFil and
      Solitaire), 2 conventional composites (Herculite and Heliomolar), and 1
      laboratory-processed composite (Belleglass). K(IC) was determined by preparing 8
      mini-compact test specimens (8.2 mm diameter x 2 mm thickness) for each composite
      in a polytetrafluoroethylene split-mold with introduced precracks created with a
      razor blade. Specimens were stored in distilled water at 37 degrees +/- 2 degrees
      C for 7 days. Testing was performed on a universal testing machine at a
      displacement rate of 0.5 mm/min until fracture. Analysis of variance (P<.0001)
      and Ryan-Einot-Gabriel-Welsch multiple range tests (P<.05) were performed on all
      data. RESULTS: The mean fracture toughness of Alert (1.57 Mpa x m(1/2)) was
      significantly greater than any of the other composites tested. Solitaire, a
      packable composite, exhibited a mean fracture toughness (0.67 MPa x m(1/2)) that
      was significantly lower than any of the other materials tested. No significant
      difference was noted between Belleglass (1.27 MPa x m(1/2)), SureFil (1.25 MPa x
      m(1/2)) and Herculite (1.16 MPa x m(1/2)). CONCLUSION: Within the limitations of
      this study, the glass fiber-reinforced packable composite exhibited improved
      fracture toughness when compared with the other composite materials tested.

PMID- 12426503
TI  - Secondary caries in crowned teeth: correlation of clinical and radiographic
      findings.
AB  - STATEMENT OF PROBLEM: The diagnostic value of radiographs for interproximal
      caries detection on nonrestored teeth is well investigated. However, little is
      known about the use of radiographs in the diagnosis of secondary caries localized
      at crown margins. PURPOSE: The aim of this study was to correlate clinical
      findings with regard to secondary caries with the findings of a radiographic
      evaluation. MATERIALS AND METHODS: One hundred randomly selected patients who
      underwent restorations with fixed prostheses and were exhibiting at least one
      secondary carious lesion were included in the study. A total of 820 restorations
      (test group, 730 interproximal surfaces of 365 single crowns and 910
      interproximal surfaces of 455 fixed partial denture retainer crowns) and 1024
      interproximal surfaces of 512 nonrestored teeth (control group) were investigated
      clinically, with the use of modified California Dental Association criteria, and
      radiographically for interproximal carious lesions. The extension of the lesions
      was rated to be initial (with no cavitation), early (with cavitation limited to
      orthodentin), or deep (with cavitation). The data were statistically analyzed for
      normal distribution, and the frequency of the findings was calculated in absolute
      numbers and as a percentage. Statistically significant differences were
      determined by use of the chi(2) test (P<.05). A linear regression model was
      applied for the correlation between the percentage of secondary caries and the
      duration of the crowns in situ. RESULTS: Secondary caries was diagnosed
      clinically in 11.2% of 1640 interproximal surfaces but only in 8.3%
      radiographically. In contrast, the frequency of interproximal carious lesions
      diagnosed clinically in nonrestored teeth increased with the use of radiographs
      from 3.3% to 4.1%. CONCLUSION: Within the limits of this study, the results
      confirm that radiographs improve the diagnostic sensitivity for interproximal
      caries in nonrestored teeth. However, for the diagnosis of secondary caries in
      crowned teeth, the clinical examination is more reliable than the radiographic
      evaluation.

PMID- 12426504
TI  - Iatrogenic tooth abrasion comparisons among composite materials and finishing
      techniques.
AB  - STATEMENT OF PROBLEM: Many different rotary instruments are available for shaping
      composite restorations. Whether use of these instruments causes undesirable
      iatrogenic abrasion of either the tooth surface or the composite restorative
      material is unknown. Assuming that damage occurs, which technique is least
      damaging is unknown. PURPOSE: This in vitro study quantified the loss of surface
      enamel and dentin surrounding Class V preparations during composite shaping and
      finishing procedures. The susceptibility of 2 types of composites to tooth
      abrasion was also examined. MATERIALS AND METHODS: Standardized Class V cavities
      were prepared at the amelodentinal junction of 36 human molar teeth. The teeth
      were randomly assigned to 6 groups of 6 teeth each. They were restored with
      either a low- or high-viscosity composite (Revolution or Prodigy Condensable,
      respectively) and finished with aluminum oxide disks, tungsten carbide burs, or
      ultrafine finishing diamond burs. The preparations were profiled before and after
      restoration. After each finishing procedure, morphological measurements of
      surface changes in the dentin and enamel were made and reported as volume (in
      cubic millimeters); maximum depth, mean maximum depth, and mean depth (in
      micrometers); and surface area (in square millimeters). The results were
      subjected to a 2-way analysis of variance for restorative material and finishing
      technique (P<.05). RESULTS: Aluminum oxide disks removed significantly less
      enamel than tungsten carbide burs or ultrafine finishing diamond burs, as
      measured by volume, maximum depth, mean maximum depth, mean depth, and surface
      area (P<.05). Conversely, aluminum oxide disks removed significantly greater
      dentin than either tungsten carbide burs or ultrafine finishing burs as measured
      by loss of volume, mean depth, and surface area (P<.05). There was no significant
      difference in the loss of surrounding tooth substance based on resin type (low or
      high viscosity). CONCLUSION: Within the limitations of this study, the 3
      finishing systems tested resulted in varying degrees of iatrogenic abrasion of
      enamel and dentin. The composite material used had no significant effect on
      abrasion of the surrounding enamel or dentin.

PMID- 12426505
TI  - Verification jig for implant-supported prostheses: A comparison of standard
      impressions with verification jigs made of different materials.
AB  - STATEMENT OF PROBLEM: Implant verification jigs are routinely used during the
      fabrication of implant-supported prostheses. The dimensional accuracy of these
      jigs is unknown. PURPOSE: The purposes of this study were to (1) compare the
      dimensional accuracy of verification jigs with that of conventional impression
      procedures and (2) measure the dimensional accuracy of 3 resin materials used to
      fabricate verification jigs. MATERIALS AND METHODS: Thirty verification jigs and
      20 impressions were made of 3 externally hexed Steri-Oss implants in a master
      stone base according to the following groups (n = 10 per group): (Group 1) Jig:
      GC pattern resin; (Group 2) Jig: Duralay resin; (Group 3) Jig: Triad gel resin;
      (Group 4) Impression: closed-tray impression copings; and (Group 5) Impression:
      open-tray impression copings. A stone base was fabricated for each experimental
      jig and impression. Master stone base and experimental stone bases were measured
      with the following methods: X and Y coordinates of each implant center were
      obtained with a traveling microscope by averaging the X and Y coordinates of the
      implant external hex corners. The origins of the coordinates during measurement
      of each base were arbitrary. Distances between implant center points were
      calculated by use of the Pythagorean theorem. Vertical measurements (Z-plane)
      were obtained with a digital caliper at the 2 terminal-implant locations.
      Interimplant distances and vertical measurements were subtracted from those of
      the master base, and the resultant distortion values were analyzed with analysis
      of variance and Tukey Studentized range tests. Statistical significance was set
      at P<.05. RESULTS: Verification jigs were not significantly more accurate than
      standard impression procedures. Open-tray impressions showed a significantly
      greater vertical distortion (Z-R location: 262 +/- 158 microm; P=.0001; Z-L
      location 333 +/- 189; P=.0001) compared with the other groups. Triad gel jigs
      showed a significantly greater distortion in one interimplant distance (C-L) than
      closed-tray impressions (P=.04), whereas Duralay jigs exhibited significant
      greater distortion than closed-tray and open-tray impressions in the interimplant
      distance R-C (P=.006). Although not significantly different from other groups,
      the closed-tray group showed the lowest mean distortion values in all
      measurements. CONCLUSION: Within the limitations of this study, the accuracy
      provided by verification jigs was not significantly superior to standard
      impression procedures. The results suggest that jig fabrication does not improve
      the dimensional accuracy of stone casts. Open-tray impressions showed a
      significantly greater inaccuracy in the vertical plane.

PMID- 12426506
TI  - The impact of saliva on patient care: A literature review.
AB  - Decreased salivary flow results in a clinically significant oral imbalance that
      may manifest as increased caries, susceptibility to oral candidosis, altered
      taste sensation, or a host of other problems. This article reviews the role of
      saliva in oral health, highlights the causes and consequences of xerostomia, and
      outlines treatment modalities for patients with xerostomia. Journal articles were
      investigated through Medline, and relevant textbooks and handbooks were
      consulted. A summary of the literature pertinent to clinical prosthodontics is
      presented.

PMID- 12426507
TI  - Can we assess quality of life in patients with head and neck cancer? A
      preliminary report from the American Academy of Maxillofacial Prosthetics.
AB  - Survival statistics alone may no longer be valid when used as evidence of
      effective outcomes. Patient satisfaction is an end point that needs further
      evaluation and should be included in the outcomes assessment. A 133-item
      questionnaire has been designed by a special committee of the American Academy of
      Maxillofacial Prosthetics (AAMP) to assess the quality of life of patients with
      head and neck cancer impacting the orofacial region. This survey will be
      distributed to the entire population of 7 geographically dispersed treatment
      centers in the United States for a 2-year period. Patients will be stratified
      into several subgroups, including radiation/nonradiation, maxillary/mandibular,
      and surgical reconstruction/prostheses. Separate analyses will be conducted for
      each subgroup, and comparisons will be made within subgroups to test the
      sensitivity of the questionnaire to a known difference. A revised version of the
      AAMP questionnaire, limited to 50 items of interest to patients, will be
      validated against 2 established head and neck cancer questionnaires. This article
      provides background on previous quality-of-life studies and reviews the need for
      and aims of the AAMP assessment instrument.

PMID- 12426508
TI  - Simplified technique for retrieving cemented implant restorations.
AB  - The retrieval of cemented implant restorations can be a difficult problem for
      patients and clinicians. This article describes an accurate method of locating
      the implant abutment access chamber and abutment retaining screw so that the
      implant restoration can be retrieved without damage.

PMID- 12426510
TI  - Improving peer review: a guide for reviewers of biomedical research.

PMID- 12426509
TI  - Magnetic attachment for esthetic management of an overdenture.
AB  - Magnetic attachments are a popular means of retaining removable overdentures and
      maxillofacial prostheses.(1) When used in anterior regions, these attachments
      often are not esthetic because the metallic color of the cast coping or
      attachment can be seen directly or through the denture base. An esthetic magnetic
      attachment with a composite facing can be fabricated to overcome this problem.

PMID- 12426511
TI  - Sex-related differences in the clearance of cytochrome P450 3A4 substrates may be
      caused by P-glycoprotein.

PMID- 12426512
TI  - Single-dose and steady-state pharmacokinetics of celecoxib in children.
AB  - BACKGROUND AND OBJECTIVE: Celecoxib is a member of a novel group of agents that
      selectively inhibit cyclooxygenase 2 (COX-2). COX-2 inhibitors have emerged as an
      important class of drugs because of the lower incidence of side effects when
      compared with traditional nonsteroidal anti-inflammatory drugs, which inhibit
      both cyclooxygenase 1 and COX-2. Because children often differ from adults with
      respect to drug disposition, the objective of this study was to determine the
      single-dose and steady-state pharmacokinetics of celecoxib in pediatric patients.
      METHODS: Celecoxib plasma concentrations were determined at intervals over 12
      hours after a 250-mg/m(2) dose and again 1 week later after twice-daily dosing
      (steady state). RESULTS: Peak plasma concentrations (1234 +/- 528 microg/L) were
      achieved 3 hours after drug administration. The area under the celecoxib plasma
      concentration-time curve was 7709 +/- 3176 microg/L x h, the elimination half
      life (t(1/2)) was 3.7 +/- 1.1 hours, the apparent volume of distribution was 7.9
      +/- 7.8 L/kg, and the lower oral clearance of the drug was 1.4 +/- 1.0 L x h(-1)
      x kg(-1). Statistical analysis revealed a significantly lower [corrected]
      apparent oral clearance and longer t(1/2) (P <.05) at steady state compared with
      pharmacokinetics after a single dose. In addition, when the results were compared
      in children and adults, the drug was cleared approximately twice as fast in
      children and had a t(1/2) that was approximately half as long. CONCLUSIONS: This
      is the first report of celecoxib pharmacokinetics in children, and the results
      indicate that there are significant differences between children and adults with
      respect to celecoxib disposition; hence these data may have implications when
      dosing schedules are planned for this population.

PMID- 12426513
TI  - Pharmacokinetics of C1-inhibitor protein in patients with acute myocardial
      infarction.
AB  - OBJECTIVES: C1-inhibitor protein (C1-INH) purified from pooled human plasma is
      used for the treatment of patients with hereditary angioedema. Recently, the
      beneficial effects of high-dose C1-INH treatment on myocardial ischemia or
      reperfusion injury have been reported in various animal models and in humans. We
      investigated the pharmacokinetic behavior of C1-INH in patients with acute
      myocardial infarction to calculate the amount of C1-INH required for optimal
      efficacy. METHODS: Twenty-two patients received an intravenous loading dose,
      followed by 48 hours of continuous infusion of C1-INH. Changes in the endogenous
      production of C1-INH were evaluated in 16 control patients with acute myocardial
      infarction. A 2-compartment model was used to estimate the fractional catabolic
      rate constant (FCR), transcapillary escape rate constant (TER), and extravascular
      return rate constant (ERR) of C1-INH. Software designed to analyze and fit
      measured data to unknown parameters in a system of differential equations was
      used to fit the experimental data against the 3-parameter model. RESULTS: With
      fixed TER and ERR values (0.014 h(-1) and 0.018 h(-1), respectively), 20 of the
      22 cases yielded well-determined FCR values, and simultaneous fitting resulted in
      a median FCR of 0.011 h(-1) (95% confidence interval, 0.010 to 0.012 h(-1))
      versus 0.025 h(-1) as reported in healthy control patients. Simultaneous
      estimation of TER, ERR, and FCR demonstrated weakly defined TER and ERR values,
      whereas the median FCR value remained unchanged. The use of a 2-compartment model
      resulted in a significantly better fit compared with the 1-compartment model.
      Physiologic explanations are offered for discrepancies in the literature.
      CONCLUSIONS: Dose calculation of C1-INH in patients treated with massive doses of
      C1-INH requires turnover parameters that differ from those found in healthy
      subjects, possibly because of suppression of continuous C1-INH consumption by
      target proteases.

PMID- 12426514
TI  - Rifampin markedly decreases plasma concentrations of praziquantel in healthy
      volunteers.
AB  - BACKGROUND AND OBJECTIVE: Praziquantel is extensively metabolized by the hepatic
      cytochrome P450 (CYP) enzymes. The CYP3A isoforms are likely to be major enzymes
      responsible for praziquantel metabolism. Rifampin (INN, rifampicin), a potent
      enzyme inducer of CYP-mediated metabolism (especially CYP2C9, CYP2C19, and
      CYP3A4), is known to markedly decrease plasma concentrations and effects of a
      number coadministered drugs. The aim of this investigation was to study the
      possible pharmacokinetic interaction between rifampin and praziquantel. METHODS:
      An open, randomized, 2-phase crossover design was used in each study of single or
      multiple doses. In the single-dose study, 10 healthy Thai male volunteers
      ingested single doses of 40 mg/kg praziquantel alone (phase 1) or after
      pretreatment with 600 mg of oral rifampin once daily for 5 days (phase 2). In the
      multiple-dose study, all participants received multiple doses of 25 mg/kg
      praziquantel alone (phase 1) or after 5-day pretreatment with 600 mg of oral
      rifampin once daily (phase 2). Plasma concentrations of praziquantel in each
      phase were determined by the HPLC method. RESULTS: In the single-dose study,
      rifampin decreased plasma praziquantel concentrations to undetectable levels in 7
      of 10 subjects, whereas praziquantel concentrations were reduced by rifampin to
      undetectable levels in 5 of 10 subjects in the multiple-dose study. In 3 subjects
      with measurable concentrations in the single-dose study, rifampin significantly
      decreased the mean maximum plasma concentration (C(max)) and area under the
      plasma concentration-time curve from 0 to 24 hours [AUC(0-24)] of praziquantel by
      81% (P <.05) and 85% (P <.01), respectively, whereas rifampin significantly
      decreased the mean C(max) and AUC(0-24) of praziquantel by 74% (P <.05) and 80%
      (P <.01), respectively, in 5 subjects with measurable concentrations in the
      multiple-dose study. The mean C(max) and AUC(0-24) of praziquantel in subjects
      whose praziquantel concentrations could not be detected in the single-dose study
      (7 subjects) after rifampin pretreatment were reduced by approximately 99% (P
      <.001) and 94% (P <.001), respectively, and in the multiple-dose study (5
      subjects), they were reduced by 98% (P <.05) and 89% (P <.01), respectively.
      CONCLUSIONS: Rifampin greatly decreased plasma concentrations of single and
      multiple oral doses of praziquantel to levels lower than that of the minimum
      therapeutic concentration. Because praziquantel and rifampin are widely used in
      the treatment of liver flukes (Opisthorchis viverrini) and Mycobacterium
      tuberculosis, respectively, in Thailand and in some other countries in southeast
      Asia, the possibility of one drug influencing the pharmacokinetics of the other
      must be considered. Therefore simultaneous use of rifampin and praziquantel must
      be avoided in medical practice to optimize the therapeutic efficacy of
      praziquantel.

PMID- 12426515
TI  - Pharmacokinetic and pharmacodynamic interaction between grapefruit juice and
      halofantrine.
AB  - BACKGROUND: Halofantrine, an antimalarial drug that prolongs the QT interval, is
      metabolized into N-debutyl-halofantrine by cytochrome P450 (CYP) 3A4. Grapefruit
      juice increases the bioavailability of several orally administered CYP3A4
      substrates by inhibiting CYP3A4 at the enterocyte level and could therefore
      increase the risk of halofantrine-induced QT interval prolongation. We studied
      the effect of grapefruit juice on halofantrine bioavailability and on QT interval
      prolongation associated with its oral administration. METHODS: Twelve healthy
      male and female volunteers received 500 mg of halofantrine with 250 mL of water,
      orange juice, or grapefruit juice (250 mL once a day of regular strength for 3
      days and once at 12 hours before halofantrine administration), in a random order,
      during a crossover study. Plasma pharmacokinetics of halofantrine and N-debutyl
      halofantrine and QTc interval duration were studied during the following 168
      hours. RESULTS: Compared with water, grapefruit juice increased halofantrine area
      under the plasma concentration versus time curve (AUC) and peak plasma
      concentration by 2.8-fold +/- 1.5-fold (P <.0001) and 3.2-fold +/- 1.3-fold (P
      <.0001), respectively. There was a concomitant 2.4-fold +/- 1.6-fold decrease in
      N-debutyl-halofantrine AUC (P <.01) but no significant change in halofantrine
      elimination half-life. Maximum QTc interval prolongation increased from 17 +/- 6
      ms when halofantrine was administered with water to 31 +/- 12 ms when it was
      administered with grapefruit juice (P <.0005). Multiple regression analysis
      showed that QTc interval prolongation was better correlated with halofantrine
      (partial r = 0.432; P <.0001) than with N-debutyl-halofantrine (partial r =
      0.117; P <.01) concentrations. There was no significant difference between the
      water and orange juice study periods. CONCLUSIONS: Grapefruit juice increases
      halofantrine bioavailability and halofantrine-induced QT interval prolongation.
      Grapefruit juice should be contraindicated during administration of halofantrine.

PMID- 12426516
TI  - Cytochrome P450 3A4 and P-glycoprotein mediate the interaction between an oral
      erythromycin breath test and rifampin.
AB  - BACKGROUND: The intravenous (14)C-erythromycin breath test (ERMBT(IV)) does not
      measure aggregate liver and intestinal cytochrome P450 (CYP) 3A4 activity.
      Accordingly, we evaluated an oral stable-labeled ((13)C) formulation of the test
      (ERMBT(oral)) as an alternative CYP3A4 phenotyping probe. METHODS: After an
      overnight fast, 14 young healthy volunteers (5 women and 9 men) received the
      ERMBT(IV) (0.07 micromol, 3 muCi), followed by the ERMBT(oral) (500 mg). The next
      morning, the CYP3A4 inhibitor troleandomycin (500 mg) was given, and both ERMBTs
      were repeated. After at least 24 hours, the CYP3A4 and P-glycoprotein inducer
      rifampin (600 mg; INN, rifampicin) was given daily for 7 days, and both ERMBTs
      were repeated 24 hours after the last dose of rifampin. Plasma samples were
      collected for 10 hours with each administration of the ERMBT(oral), and
      erythromycin levels were measured by liquid chromatography-mass spectrometry.
      Finally, the effect of troleandomycin on erythromycin transport was examined in
      Caco-2 cell monolayers. RESULTS: Compared with baseline values, the median
      ERMBT(IV) and ERMBT(oral) results and erythromycin apparent oral clearance (CL/F)
      all significantly decreased, by at least 70%, with troleandomycin treatment (P
      =.001 for each comparison). With rifampin treatment, the median ERMBT(IV) result
      and CL/F increased 2-fold (P < or =.01), but the median ERMBT(oral) result was
      unchanged (P =.30). There were no rank-order correlations between the ERMBT(IV)
      and ERMBT(oral) results or between either ERMBT result and CL/F within each
      treatment group (P > or =.07). In addition, troleandomycin had no effect on
      erythromycin transport in Caco-2 cells (P > or =.20). CONCLUSIONS: The
      ERMBT(oral) was influenced by processes in addition to intestinal and hepatic
      CYP3A4 activity and therefore did not provide a straightforward measure of
      aggregate CYP3A4 phenotype. The erythromycin-rifampin interaction cannot be
      attributed to CYP3A4 induction alone and probably also reflected intestinal P
      glycoprotein induction.

PMID- 12426517
TI  - Disposition of nasal, intravenous, and oral methadone in healthy volunteers.
AB  - OBJECTIVE: Nasal administration of many opioids demonstrates rapid uptake and
      fast onset of action. Nasal administration may be an alternative to intravenous
      and oral administration of methadone and was therefore studied in human
      volunteers. METHODS: The study was approved by the Institutional Review Board of
      the University of Washington, Seattle. Eight healthy volunteers (6 men and 2
      women) aged 19 to 33 years were enrolled after informed written consent was
      obtained. Subjects received 10 mg methadone hydrochloride nasally, orally, or
      intravenously on 3 separate occasions in a crossover design. Nasal methadone (50
      mg/mL in aqueous solution) was given as a 100-microL spray in each nostril
      (Pfeiffer BiDose sprayer). Blood samples for liquid chromatography-mass
      spectrometry analyses of methadone and the metabolite 2-ethyl-1,5-dimethyl-3,3
      diphenylpyrrolinium were drawn for up to 96 hours. The methadone effect was
      measured by noninvasive infrared pupilometry coincident with blood sampling.
      RESULTS: Nasal uptake of methadone was rapid, with maximum plasma concentrations
      occurring within 7 minutes. The maximum effects of intravenous, nasal, and oral
      methadone, on the basis of dark-adapted pupil diameter, were reached in about 15
      minutes, 30 minutes, and 2 hours, respectively. The respective durations were 24,
      10, and 8 hours. Both nasal and oral bioavailabilities were 0.85. Subjects
      reported that nasal methadone caused a burning sensation. CONCLUSIONS: Nasal
      administration of methadone results in rapid absorption and onset of effect and
      high bioavailability, which was greater than that reported for other nasal
      opioids, with a similar duration of effect. Nasal administration may be an
      alternative route of methadone administration; however, improved formulations are
      desirable to reduce nasal irritation.

PMID- 12426518
TI  - Pharmacokinetics and pharmacodynamics of darbepoetin alfa and epoetin in patients
      undergoing dialysis.
AB  - OBJECTIVE: The aim of this multicenter, randomized, open-label study was to
      compare the pharmacokinetic and pharmacodynamic profiles of darbepoetin alfa, a
      new erythropoiesis-stimulating protein, and recombinant human erythropoietin
      (epoetin) after repeated intravenous dosing in patients with chronic kidney
      disease receiving hemodialysis. METHODS: Forty-seven patients were randomized to
      receive darbepoetin alfa administered once weekly (n = 17) or 3 times weekly (n =
      15) or epoetin administered 3 times weekly (n = 15) for up to 52 weeks.
      Pharmacokinetic profiles were measured during weeks 1 and 12 and at hemoglobin
      steady state (defined as a hemoglobin concentration within the target range for 4
      consecutive weeks after week 12 with no change in study drug dose) or between
      weeks 36 and 40, whichever occurred first. RESULTS: At each of the 3 time points
      evaluated, the terminal half-life of darbepoetin alfa was 2 to 3 times longer and
      the clearance approximately 4 times slower than those of epoetin. At week 12, the
      terminal half-life was 23.4 hours with darbepoetin alfa once weekly, 18.3 hours
      with darbepoetin alfa 3 times weekly, and 8.0 hours with epoetin 3 times weekly.
      The pharmacokinetics of darbepoetin alfa was not dependent on dose or time. Mean
      hemoglobin values at steady state were all approximately 11 g/dL, within the
      target range of 9.0 to 13.0 g/dL. Safety analyses revealed no differences between
      darbepoetin alfa and epoetin. CONCLUSIONS: The pharmacokinetic and
      pharmacodynamic profiles and safety data for darbepoetin alfa demonstrate that it
      can be administered less frequently than epoetin in patients with chronic kidney
      disease receiving hemodialysis, thus simplifying anemia management.

PMID- 12426519
TI  - Nimodipine: drug pharmacokinetics and plasma adenosine levels in patients
      affected by cerebral ischemia.
AB  - BACKGROUND AND OBJECTIVE: Nimodipine is a dihydropyridine calcium channel blocker
      used in the treatment of ischemic damage in subarachnoid hemorrhage. Recent
      investigations have shown that it is able to inhibit adenosine transport in human
      red blood cells and parietal cortex neurons. In this study we investigated the
      pharmacokinetics of nimodipine and the effect on plasma adenosine levels in
      patients affected by cerebral ischemia. METHODS: Twelve patients with cerebral
      ischemia (9 men and 3 women; mean age, 68.8 +/- 11.2 years; mean weight, 67.9 +/-
      9.3 kg) were admitted to the study. They received nimodipine intravenously (a
      bolus of 0.03 mg/kg) and orally (single doses of 30, 60, and 90 mg) during
      different sessions. Blood samples for adenosine and nimodipine were collected at
      fixed intervals up to 480 minutes. Adenosine and nimodipine plasma levels were
      detected by HPLC methods. RESULTS: Both the intravenous and oral administrations
      induced a statistically significant increase in plasma adenosine levels (P
      <.001), which appeared to be related to the dose and route of drug
      administration. In particular, a 67.8% increase was observed after intravenous
      administration, and increases of 28.9%, 43.6%, and 60.2% were observed after 30
      mg, 60 mg, and 90 mg of nimodipine, respectively. The pharmacokinetic parameters
      of nimodipine after intravenous administration were as follows: peak
      concentration (C(max)), 319.6 +/- 38.9 ng/mL at the first sampling time; area
      under the curve (AUC), 239 +/- 25 ng. h/mL; and terminal half-life, 3.12 +/- 0.97
      hours. After oral administration, the drug kinetics was linear in the
      administered dose range and the pharmacokinetic parameters were as follows:
      C(max)(30 mg), 46.1 +/- 5.8 ng/mL; C(max)(60 mg), 81.7 +/- 14.6 ng/mL; C(max)(90
      mg), 131.6 +/- 16.3 ng/mL; AUC(30 mg), 119 +/- 25 ng. h/mL; AUC(60 mg), 256 +/-
      48 ng. h/mL; and AUC(90 mg), 389 +/- 54 ng. h/mL. The half-life was similar to
      the values observed after intravenous administration, whereas the bioavailability
      ranged between 2% and 5.9%. CONCLUSIONS: Our data indicate that the
      administration of nimodipine induces an increase in plasma adenosine levels, and
      we hypothesize that the drug activity could be associated, at least partially,
      with adenosine mediation.

PMID- 12426520
TI  - Evaluation of cytochrome P4502C9 metabolic activity with tolbutamide in CYP2C91
      heterozygotes.
AB  - OBJECTIVES: Multiple single-nucleotide polymorphisms in the gene encoding
      cytochrome P450 (CYP) 2C9 have been identified, but the functional significance
      of the various putative defective genotypes in humans merits further study.
      METHODS: Using tolbutamide as a probe of CYP2C9 activity, we evaluated CYP2C9
      phenotype in 15 healthy individuals expressing the CYP2C9(*)1/(*)1, (*)1/(*)2,
      and (*)1/(*)3 genotypes (n = 5 per group). CYP2C9 genotype was determined by
      polymerase chain reaction-restriction fragment length polymorphism methods.
      Subjects received 500 mg of tolbutamide, with plasma and urine collected over a
      24-hour period. Plasma tolbutamide and urinary tolbutamide, 4'
      hydroxytolbutamide, and carboxytolbutamide concentrations were determined by an
      HPLC method. RESULTS: Tolbutamide area under the plasma concentration-time curve
      from time zero to infinity [AUC(0- infinity )] significantly increased by 1.5
      fold and 1.9-fold, respectively, in subjects expressing the CYP2C9(*)1/(*)2 and
      (*)1/(*)3 genotypes compared with (*)1/(*)1 subjects. Statistically significant
      reductions in tolbutamide oral clearance (29% and 48%) and formation clearance
      (38% and 56%) were detected in the (*)1/(*)2 and (*)1/(*)3 individuals,
      respectively, compared with (*)1/(*)1 subjects. The increases in AUC(0- infinity)
      and decreases in oral clearance observed in the (*)1/(*)3 individuals were also
      significantly greater than those expressing the (*)1/(*)2 genotype (P <.05). The
      amount of urinary 4'-hydroxytolbutamide and carboxytolbutamide excreted in the 0-
      to 12-hour and 6- to 12-hour collection intervals was significantly less in
      (*)1/(*)2 and (*)1/(*)3 individuals compared with (*)1/(*)1 subjects. With
      tolbutamide used as a CYP2C9 probe, CYP2C9 genotype was the major determinant of
      CYP2C9 phenotype (r(2) = 0.77). CONCLUSIONS: CYP2C9 activity was significantly
      reduced in (*)1 heterozygotes compared with (*)1 homozygotes, and metabolism was
      more severely impaired in (*)1/(*)3 individuals compared with those expressing
      (*)1/(*)2.

PMID- 12426521
TI  - The effects of the human MDR1 genotype on the expression of duodenal P
      glycoprotein and disposition of the probe drug talinolol.
AB  - BACKGROUND AND OBJECTIVES: A single-nucleotide polymorphism (SNP) of the human
      multidrug-resistance gene in wobble position of exon 26 reportedly predicts
      expression and function of P-glycoprotein in human enterocytes and lymphocytes.
      Several other allelic variants of MDR1 have been identified, some of which lead
      to amino acid exchange with as yet unknown functional relevance. METHODS: In
      healthy white volunteers, we investigated the influence of the hereditary
      variants C3435T in exon 26 and G2677T/A (Ala893Ser/Thr) in exon 21 and the
      influence of 7 frequent or putative functional SNPs on duodenal MDR1 messenger
      ribonucleic acid (n = 32) and immunoreactive P-glycoprotein (n = 37) expression.
      Moreover, the disposition of the probe drug talinolol was evaluated in 55
      subjects after oral administration (100 mg) and in 23 subjects after intravenous
      administration(30 mg). RESULTS: Duodenal MDR1 messenger ribonucleic acid and P
      glycoprotein, as assessed by real-time polymerase chain reaction (TaqMan) and
      immunostaining, were not influenced by any MDR1 polymorphism studied. Talinolol
      disposition was not affected by the exon 26 mutation C3435T. In carriers of the
      TT/TA variants of G2677T/A, the area under the serum concentration-time curve
      values of oral talinolol were slightly but significantly elevated compared with
      those in carriers of at least 1 wild-type allele (P <.05, Kruskal-Wallis test; P
      =.014, Mann-Whitney U test). However, multiple comparisons with combinations of
      putative functional SNPs did not confirm a significant influence of the MDR1
      genotype on talinolol disposition. CONCLUSIONS: We did not identify any influence
      of MDR1 genotypes on duodenal expression of P-glycoprotein and disposition of
      talinolol in humans.

PMID- 12426522
TI  - Modulation of steady-state kinetics of digoxin by haplotypes of the P
      glycoprotein MDR1 gene.
AB  - OBJECTIVE: We investigated the effect of polymorphisms in the P-glycoprotein (P
      gp) MDR1 gene on steady-state pharmacokinetics of digoxin in Caucasians.
      According to earlier data, homozygous TT of the exon 26 complementary
      deoxyribonucleic acid (cDNA) 3435C>T polymorphism was associated with low P-gp
      expression in the human intestine. METHODS: Eight healthy male homozygous
      carriers of the wild-type exon-26 3435C>T (CC), 8 heterozygous subjects (CT), and
      8 homozygous mutant (TT) subjects were selected. Seven further MDR1 polymorphisms
      were determined. Digoxin was administered orally twice daily on the first two
      study days; on days 3 to 5, 0.25 mg was given in the morning. On day 5, kinetic
      parameters were analyzed for genotype-phenotype and haplotype-phenotype
      relationships. RESULTS: The area under the plasma concentration-time curve from
      time zero to 4 hours [AUC(0-4)] (P =.042) and C(max) (P =.043) values of digoxin
      were higher in subjects with the 3435TT genotype than in those with the 3435CC.
      No influence of other single nucleotide polymorphisms (SNPs) on digoxin
      parameters was detected. Comparison of genotypes deduced from SNPs 2677G>T (exon
      21) and 3435C>T revealed significant differences for AUC(0-4) (P =.034) and
      C(max) (P =.039), which were substantiated by haplotype analysis. Haplotype 12
      (2677G/3435T), which had a frequency of 13.3% in a randomly drawn Caucasian
      sample (n = 687), was associated (Mann-Whitney test) with higher AUC(0-4) values
      (P =.009) than were found in noncarriers (mean +/- SD, 5.7 +/- 0.9 microg. h/L [n
      = 7] versus 4.8 +/- 0.9 microg. h/L [n = 17]). Haplotype 11 (2677G/3435C) had
      lower AUC(0-4) values (P =.013) compared with those of noncarriers (mean +/- SD,
      4.7 +/- 0.9 microg. h/L [n = 16] versus 5.6 +/- 0.9 microg. h/L [n = 8]). Results
      of haplotype analysis match data of other MDR1 studies. CONCLUSION: Haplotype 12
      codes for high values of AUC(0-4) and C(max) of orally administered digoxin.
      Analysis of MDR1 haplotypes is superior to unphased SNP analysis to predict MDR1
      phenotype.

PMID- 12426523
TI  - The efficacy of simvastatin is not influenced by CYP2D6 polymorphism.

PMID- 12426524
TI  - Hepatotoxicity associated with nimesulide: data from the Spanish
      Pharmacovigilance System.

PMID- 12426526
TI  - Recent advances in the evaluation and treatment of shoulder instability:
      anterior, posterior, and multidirectional.

PMID- 12426527
TI  - Meniscal surgery 2002 update: indications and techniques for resection, repair,
      regeneration, and replacement.

PMID- 12426528
TI  - Complex issues in anterior cruciate ligament surgery: open physes, graft
      selection, and revision surgery.

PMID- 12426529
TI  - Fundamental principles of shoulder rehabilitation: conservative to postoperative
      management.

PMID- 12426530
TI  - PCL 2002: indications, double-bundle versus inlay technique and revision surgery.

PMID- 12426531
TI  - Practice management: update on coding, ancillary services, and the new Stark
      laws.

PMID- 12426532
TI  - Comprehensive evaluation and treatment of the shoulder in the throwing athlete.

PMID- 12426534
TI  - Arthroscopic management of massive rotator cuff tears.

PMID- 12426533
TI  - Complex knee reconstruction: osteotomies, ligament reconstruction, transplants,
      and cartilage treatment options.

PMID- 12426535
TI  - Approach to the osteoarthritic knee in the aging athlete: debridement to
      osteotomy.

PMID- 12426537
TI  - Associated injuries in pediatric and adolescent anterior cruciate ligament tears:
      does a delay in treatment increase the risk of meniscal tear?
AB  - PURPOSE: To evaluate the incidence of associated injuries and meniscal tears in
      children and adolescents with anterior cruciate ligament (ACL) tears, we
      performed a retrospective review of patients, age 14 and younger, who were
      treated surgically at our institution. TYPE OF STUDY: Retrospective review.
      METHODS: We reviewed 39 patients (30 girls, 9 boys) with an average age of 13.6
      years (range, 10 to 14 years) who underwent surgical treatment of the ACL; 24
      right knees and 15 left knees were treated. Of the injuries treated, 24 occurred
      by a twisting mechanism, 10 were the result of contact, and 5 occurred from
      hyperextension. Thirty-five injuries occurred during sports activities, and 2
      were sustained in motor vehicle accidents. The mean duration from injury to
      operative treatment was 101 days (range, 7 to 696 days). Injuries were classified
      as acute (n = 17) if surgery was performed within 6 weeks of injury and chronic
      (n = 22) if surgery was performed after 6 weeks from injury. Relationships
      between medial and lateral meniscal injuries and the time from injury to surgery
      were analyzed, and the 2 groups, acute and chronic, were compared. Finally, the
      patterns of meniscal injury were compared. RESULTS: Twenty-six patients had
      associated injuries (10 medial meniscal tears, 15 lateral meniscal tears, 3
      medial collateral ligament tears, and 1 fractured femur). The association between
      medial meniscal tears and time from injury to surgery was highly statistically
      significant (P =.0223). There was no statistical significance between the
      incidence of lateral meniscal tears and time. Medial meniscal tears were more
      common in the chronic group (36%) than in the acute group (11%), whereas lateral
      meniscal tears were found with equal frequency. Medial meniscal tears that
      required surgical treatment (either partial excision or repair) were more common
      in the chronic group, and lateral meniscal tear patterns were equally
      distributed. CONCLUSIONS: Evidence from this study supports the contention that
      associated injuries are common in young individuals with ACL tears. Furthermore,
      the data also show that a delay in surgical treatment was associated with a
      higher incidence of medial meniscal tears.

PMID- 12426538
TI  - The effect of soft-tissue graft fixation in anterior cruciate ligament
      reconstruction on graft-tunnel motion under anterior tibial loading.
AB  - PURPOSE: To compare the motion of an anterior cruciate ligament (ACL) replacement
      graft within the femoral bone tunnel (graft- tunnel motion) when a soft-tissue
      graft is secured either by a titanium button and polyester tape (EndoButton
      fixation; Acufex, Smith & Nephew, Mansfield, MA) or by a biodegradable
      interference screw (Biointerference fixation; Endo-fix; Acufex, Smith & Nephew)
      An additional purpose was to evaluate the effect of the graft-tunnel motion on
      the kinematics of ACL-reconstructed knees and in situ force of the ACL
      replacement graft. TYPE OF STUDY: Biomechanical experiment using an in vitro
      animal model. METHODS: ACL reconstruction with a flexor tendon autograft was
      performed in 8 cadaveric knees of skeletally mature goats. The knee kinematics
      and the in situ force in the ACL replacement graft in response to anterior tibial
      loads were evaluated using the robotic/universal force-moment sensor testing
      system. The longitudinal and transverse graft-tunnel motion during anterior
      tibial loading was determined based on radiographic measurements parallel and
      perpendicular to the femoral bone tunnel, respectively. RESULTS: In response to
      an anterior tibial load of 100 N, the longitudinal graft-tunnel motion for
      EndoButton fixation and Biointerference fixation was 0.8 +/- 0.4 mm and 0.2 +/-
      0.1 mm, respectively (P <.05), whereas the transverse graft-tunnel motion was 0.5
      +/- 0.2 mm and 0.1 +/- 0.1 mm, respectively (P <.05). Furthermore, the anterior
      tibial translation for EndoButton fixation (5.3 +/- 1.2 mm) was also
      significantly larger than that for Biointerference fixation (4.2 +/- 0.9 mm) (P
      <.05). With both fixations, however, no significant difference between the in
      situ forces in the ACL replacement graft and that in the intact ACL could be
      detected. CONCLUSIONS: EndoButton fixation of a soft-tissue graft via an elastic
      material resulted in significantly larger graft-tunnel motion, and consequently,
      greater anterior knee laxity compared with more rigid fixation using an
      interference screw closer to the intra-articular entrance of the bone tunnel. In
      terms of force distribution, the ACL replacement graft in both fixations still
      functioned as a primary restraint to an anterior tibial load close to the intact
      ACL.

PMID- 12426539
TI  - Accuracy of anterior cruciate ligament tunnel placement with an active robotic
      system: a cadaveric study.
AB  - PURPOSE: The objective of this study was to evaluate the accuracy of tunnel
      placement for ACL reconstruction performed with an active robotic system. TYPE OF
      STUDY: Cadaveric analysis. METHODS: A reference screw containing 4 fiducials was
      placed in the femur and tibia of 13 fresh-frozen cadaveric knees. A preoperative
      plan was developed using images from 3-dimensional computed tomography
      reconstructions of the knee. The active robotic system then drilled the tunnels.
      The location and direction of each planned tunnel in the femur and tibia were
      determined from the preoperative plan. To compare these parameters
      postoperatively, a mechanical digitizer and a tunnel plug were used. The
      deviation in location and direction between the planned and drilled tunnel was
      determined. RESULTS: In preliminary trials, the tibial tunnel was located
      inaccurately because slippage of the drill bit occurred on the bone at the start
      of tunnel drilling. This was minimized by decreasing the feed rate of the robot
      by 75%. For the remaining 10 knees, deviations with respect to the preoperative
      plan were found of 2.0 +/- 1.2 mm and 1.1 degrees +/- 0.7 degrees for the intra-
      articular tibial tunnel location and direction, respectively. For the femur, the
      deviations were 1.3 +/- 0.9 mm for the tunnel location (intra-articular) and 1.0
      degrees +/- 0.6 degrees for the tunnel direction. CONCLUSIONS: The active robotic
      system is highly accurate for tunnel placement during ACL reconstruction, meaning
      that the robot drills the tunnels very close to the surgeon's plan. Comparison to
      a control group of surgeons could not be made because no preoperative plan is
      usually created in traditional surgery. However, accuracy values in this study
      were found to be below the values for precision of repeated tunnel placements
      reported in the literature.

PMID- 12426540
TI  - Arthroscopic anterior cruciate ligament reconstruction using the double press-
      fit technique: an alternative to interference screw fixation.
AB  - PURPOSE: Patellar tendon autograft fixation in arthroscopic anterior cruciate
      ligament reconstruction is commonly accomplished using interference screws.
      However, improper insertion of the screws may reduce primary stability, injure
      the posterior femoral cortex, or displace hardware into the joint. Even if placed
      properly, metallic screws interfere with postoperative magnetic resonance
      imaging. In case of revision surgery, removing screws may be difficult and leaves
      bone defects. TYPE OF STUDY: Retrospective study. METHODS: An arthroscopic
      technique was developed that achieves patellar tendon autograft fixation by press
      fit without any supplemental internal fixation. Forty patients were examined
      clinically and by KT-1000 arthrometer 28.7 months (range, 22 to 40 months)
      postoperatively. RESULTS: The mean difference in side-to-side laxity was 1.3 mm
      (SD 2.2) and the results according to the IKDC score were as follows: 7 A, 28 B,
      5 C, and 0 D. CONCLUSIONS: The double press-fit technique we present avoids all
      complications related to the use of interference screws and creates an ideal
      environment for osseous integration of the bone-patellar tendon-bone autograft.
      Concurrently, it achieves a stable fixation of the autograft and allows early
      functional rehabilitation. However, fixation strength depends on bone quality and
      the arthroscopic procedure is demanding.

PMID- 12426541
TI  - A survey of the tension applied to a doubled hamstring tendon graft for
      reconstruction of the anterior cruciate ligament.
AB  - PURPOSE: Currently there is no consensus regarding the amount of tension to apply
      to a graft when reconstructing the anterior cruciate ligament (ACL). We undertook
      a study to determine whether sports trained orthopedic surgeons tension hamstring
      tendon grafts maximally during ACL reconstruction, and also whether surgeons tend
      to load their grafts within a narrow range of tensions. TYPE OF STUDY: Cross
      sectional study. METHODS: One fresh-frozen cadaveric knee with appropriately
      placed femoral and tibial tunnels and five pairs of preconditioned semitendinosus
      and gracilis tendons were used. Custom-made computer software and a custom-made,
      load measurement device was employed. Thirteen orthopedic sports medicine
      physicians from our community took part in the study. Surgeons were asked to
      tension the graft as they would in surgery and were then asked to tension the
      graft maximally. RESULTS: The mean and standard deviation of the normal tension
      (14.8 +/- 7.2 lb) was significantly less (P =.005) than the mean maximal tension
      (22.3 +/- 6.9 lb). CONCLUSIONS: This study shows that most ACL surgeons do not
      tension their graft maximally. Moreover, graft tensioning is highly variable
      among sports medicine orthopedists. These findings revisit the question as to
      whether tension should be more accurately measured and controlled for
      intraoperatively.

PMID- 12426542
TI  - Meniscal allograft replacement: a 1-year to 6-year experience.
AB  - PURPOSE: Progressive degenerative arthritis leading to premature pain and
      functional loss in the postmeniscectomy state is a well- recognized and
      debilitating condition. Meniscal allograft replacement may be a suitable, early
      treatment alternative for this population at risk. The purpose of this study was
      to examine the potential benefits of meniscal allograft replacement on relieving
      pain and restoring function. TYPE OF STUDY: Retrospective clinical review.
      METHODS: From 1993 to 1999, 29 menisci were implanted in 28 patients. Of these,
      25 patients (26 menisci) were available for review. All patients had a minimum of
      12 months of follow-up, with an average of 33 months. Study participants included
      17 men and 8 women with primary symptoms of pain or instability at study onset.
      Eighteen patients had grades I through III Outerbridge chondromalacia changes and
      7 demonstrated grade IV changes in the affected compartment. Data were collected
      using the International Knee Documentation Committee (IKDC), Lysholm II, and
      Tegner scoring systems as well as a visual analogue scale (VAS) for pain
      measurement. RESULTS: Our findings revealed that following meniscal allograft
      replacement, pain was significantly reduced and function was improved (P <.001).
      In addition, IKDC scores for activity were reported as normal or nearly normal in
      17 subjects and abnormal in 8 participants. Outerbridge grade had a significant
      impact on final outcome; only 3 of 7 with grade IV changes achieved normal or
      nearly normal scores versus 14 of 18 in those with lesser Outerbridge changes.
      Isolated implants fared the same as those combined with an ACL reconstruction.
      Overall satisfaction reported by the subjects averaged 83%. Ten second-look
      procedures revealed 5 normal menisci, 3 with shrinkage, and 2 with recurrent
      tears. CONCLUSIONS: Earlier results from this population of patients indicated
      substantial pain relief and improved function. The durability of these early
      results has not met the test of time for those with exposed subchondral bone.
      However, statistically significant early and midterm improvements in pain,
      symptoms, and functional status continue to be noteworthy in the properly
      selected patient.

PMID- 12426543
TI  - Structural analysis of meniscal allografts after immediate and delayed
      transplantation in rabbits.
AB  - PURPOSE: To compare long-term performance of meniscal allografts transplanted
      immediately after meniscectomy and allografts transplanted 6 weeks after
      meniscectomy. TYPE OF STUDY: Experimental study. METHODS: Twenty-one rabbits were
      subjected to meniscectomy and divided into 3 groups of 7 animals. Immediate
      meniscal transplantation was performed in group A (6-week follow-up) and group B
      (1-year follow-up). Group C underwent delayed transplantation 6 weeks after
      meniscectomy. One animal in group B developed infective arthritis and was not
      included. Six nonoperated knees served as controls. Four other knees were
      subjected to a sham procedure. Menisci were examined macroscopically and
      histologically at 6 weeks (group A and 2 sham- operated animals) and 1 year
      (group B, C, controls, and 2 sham-operated animals). RESULTS: Capsular ingrowth
      was observed in all allografts. At 1 year, osteoarthritic changes in the delayed
      transplant group were more pronounced than in the immediate transplant group.
      Menisci in nonoperated controls and sham-operated knees appeared normal. No
      differences in shrinkage of allografts were observed between groups A and B.
      Group C showed significantly more shrinkage than allografts in both group A (P
      =.004) and group B ( P =.005). Two allografts in group C were completely
      degenerated. Differences in architecture of the allografts were not found between
      groups A, B, and C. In both the peripheral and central areas of transplanted
      menisci, the number of cells was frequently increased because of repopulation
      even at 6-week follow-up. CONCLUSIONS: Delayed meniscal allograft transplantation
      causes distinct structural damage to menisci in comparison with immediate
      transplantation.

PMID- 12426544
TI  - Arthroscopic biceps tenodesis: a new technique using bioabsorbable interference
      screw fixation.
AB  - PURPOSE: To report a new technique of arthroscopic biceps tenodesis using
      bioabsorbable interference screw fixation and the early results. TYPE OF STUDY:
      Prospective, nonrandomized study. METHODS:  TECHNIQUE: The principle of
      arthroscopic biceps tenodesis is simple: after biceps tenotomy, the tendon is
      exteriorized and doubled on a suture; the biceps tendon is then pulled into a
      humeral socket (7 or 8 mm x 25 mm) drilled at the top of the bicipital groove,
      and fixed using a bioabsorbable interference screw (8 or 9 mm x 25 mm) under
      arthroscopic control. PATIENTS: 43 patients treated with this technique between
      1997 and 1999 were followed-up for at least 1 year. The technique was indicated
      in 3 clinical situations: (1) with arthroscopic cuff repair (3 cases), (2) in
      case of isolated pathology of the biceps tendon with an intact cuff (6 cases),
      and (3) as an alternative to biceps tenotomy in patients with massive,
      degenerative and irreparable cuff tears (34 cases). The biceps pathology was
      tenosynovitis (4 cases), prerupture (15 cases), subluxation (11 cases), and
      luxation (13 cases). RESULTS: The absolute Constant score improved from 43 points
      preoperatively to 79 points at review (P <.005). There was no loss of elbow
      movement and biceps strength was 90% of the strength of the other side. Two
      patients, operated on early in the series, presented with a rupture of the
      tenodesis. In both cases the bicipital tendon was very friable and the diameter
      of the screw proved to be insufficient (7 mm). No neurologic or vascular
      complications occurred. CONCLUSIONS: Arthroscopic biceps tenodesis using
      bioabsorbable screw fixation is technically possible and gives good clinical
      results. This technique can be used in cases of isolated pathologic biceps tendon
      or a cuff tear. A very thin, fragile, almost ruptured biceps tendon is the
      technical limit of this arthroscopic technique.

PMID- 12426545
TI  - Failure of suture material at suture anchor eyelets.
AB  - PURPOSE: In the repair of soft tissue to bone using suture anchors, failure of
      the suture material can occur at the anchor eyelet. This study examines the load
      strength at which suture material fails with different metallic suture anchor
      eyelets. TYPE OF STUDY: Biomechanical study. METHODS: Suture material (Ethibond
      No. 2, Ethicon, Norderstedt, Germany) was pulled out from 22 metallic suture
      anchor models at 60 mm/min, and tensile load at failure and failure mode were
      recorded. Tests were performed either by simultaneous pulling on 2 suture limbs
      in 3 different directions (straight, at 45 degrees, and at 45 degrees rotated by
      90 degrees to the suture anchor axis) or by pulling on 1 suture limb while
      measuring the resulting force on the second limb. All tests were performed until
      suture failure. Pulling was performed in single tests on an Instron materials
      testing machine (High Wycombe, UK), with the anchors held by a vise. RESULTS: In
      all cases, the suture failed at the anchor eyelet. Failure load at straight
      loading ranged from 116 +/- 5 N to 226 +/- 5 N and from 69 +/- 5 N to 193 +/- 7 N
      when loaded at an angle of 45 degrees. The best results were found with the
      Statak 5.2-mm (Zimmer, Warsaw, IN): 177 N; Corkscrew 6.5-mm anchor (Arthrex,
      Naples, FL): 174 N; and PeBA 4.0-mm anchor (OBL Orthopaedic Biosystems,
      Scottsdale, AZ): 169 N. With each eyelet, sutures failed preferentially in 1
      direction, depending on the presence of sharp edges. CONCLUSIONS: Suture material
      can be cut at suture anchor eyelets. Failure load depends on sharp edges on the
      eyelet and occurs at forces up to 73% below the breaking strength of the suture
      material on a smooth hook. Anchors with suture-protecting channels are
      particularly sensitive to the orientation in which the sutures are loaded.

PMID- 12426546
TI  - Arthroscopically treated proximal humeral fracture malunion.
AB  - Articles describing the treatment of proximal humerus malunion are limited.
      Although in most of the cases, shoulder arthroplasty is the treatment of choice,
      when the articular surface of the humeral head is intact, other techniques can be
      considered and successfully used as well. Using arthroscopic techniques for
      proximal humerus malunion treatment is rarely reported in the literature. We
      could find only a few cases in which arthroscopic subacromial decompression was
      used to treat greater tuberosity malunion. Arthroscopic debridement and
      capsulotomy are also considered in the treatment of proximal humeral malunion
      cases with shoulder joint stiffness. This case report describes the completely
      arthroscopic treatment of a 4-part proximal humeral fracture malunion associated
      with pain and restricted range of motion. The main deformity in our case was
      medially displaced malunited lesser tuberosity that was blocking the internal
      rotation of the humerus. Isolated displaced lesser tuberosity fractures are rare
      injuries. Open techniques are usually the treatment of choice. We did not find
      any reports of arthroscopic treatment of lesser tuberosity malunion as a separate
      entity or as a component of a proximal humerus malunion. The early result in our
      case strongly encourages using arthroscopic techniques for lesser tuberosity
      malunion treatment as well as expanding the indications for shoulder arthroscopy
      in proximal humerus malunion cases.

PMID- 12426547
TI  - Dissecting a popliteal cyst after failed unicompartmental knee arthroplasty.
AB  - This report documents the first case of a popliteal cyst in a knee with failed
      unicompartmental knee arthroplasty (UKA). The cyst was treated successfully with
      the creation of a small communication hole between the posteromedial compartment
      and the popliteal cyst under direct arthroscopic visualization. This was followed
      by the replacement of a worn polyethylene insert via a small arthrotomy. Three
      months later, the popliteal mass had disappeared. This case suggests that a
      dissecting popliteal cyst may occur after UKA as one of the signs of a
      malfunction. It also suggests that treatment should be directed toward the joint
      and not the cyst itself.

PMID- 12426548
TI  - The bubble sign: an arthroscopic indicator of an intratendinous rotator cuff
      tear.
AB  - Intratendinous tears of the rotator cuff are, by definition, difficult to
      diagnose due to the absence of overt tendon disruption on both the bursal and
      articular surface of the rotator cuff. The authors describe the bubble sign, a
      bulging expansion of the rotator cuff tendon following injection of saline into
      the suspected lesion, as a useful indicator of an intratendinous tear of the
      rotator cuff.

PMID- 12426549
TI  - Interactive stereotaxic teleassistance of remote experts during arthroscopic
      procedures.
AB  - This article describes the technical setup for stereotaxic telesurgical
      assistance for arthroscopic procedures. It also outlines the current state,
      limitations, and feasibility of this technical development. Teleassistance or
      teleconsultation implemented in endoscopic or arthroscopic procedures have not
      yet been reported. In this study, 7 computer-assisted arthroscopies of the
      temporomandibular joint were supported by extramural experts via interactive
      stereotaxic teleconsultation from distant locations. The external experts were
      supplied with close to real-time video, audio, and stereotaxic navigation data
      directly from the operation site. This setup allows the surgeons and external
      experts to interactively determine portals, target structures, and instrument
      positions relative to the patient's anatomy and to discuss any step of the
      procedures. Optoelectronic tracking interfaced to computer- based navigation
      technology allowed precise positioning of instruments for single or multiple
      temporomandibular joint punctures. The average error of digitizing probe
      measurements was 1.3 mm (range, 0.0 to 2.5 mm) and the average standard deviation
      was 0.7 mm (range, 0.4 to 0.9 mm). Evaluation of the reliability and accuracy of
      this technique suggests that it is sufficient for controlled navigation, even
      inside the small temporomandibular joint, a fact that encourages further
      applications for arthroscopy in general. The minimum requirement for high-quality
      video transmission for teleassisted procedures are integrated services digital
      network (ISDN) connections. Conventional ISDN-based videoconferencing can be
      combined with computer-aided intraoperative navigation. Transmission control
      protocol/internet protocol (TCP/IP)-based stereotaxic teleassistance data
      transmission via ATM or satellite seem to be promising techniques to considerably
      improve the field of arthroscopy.

PMID- 12426550
TI  - Arthroscopic biceps tenodesis.
AB  - Surgical treatment of symptomatic pathology of the long head of the biceps tendon
      generally consists of either biceps tenotomy or tenodesis. Biceps tenodesis is
      generally recommended for younger patients and has been well described using open
      techniques. With advancements in arthroscopic ability and equipment, new
      arthroscopic techniques have recently been reported. These techniques can be
      especially useful when used in conjunction with other arthroscopic procedures
      such as distal clavicle resection, rotator cuff repair, and subacromial
      decompression. We present a modification of the techniques suggested by other
      researchers. In this technique, a bone anchor is used as a pulley at the bottom
      of the tunnel to pull the tendon into position. This is followed by interference
      screw fixation. To our knowledge, this technique has not been previously
      described.

PMID- 12426551
TI  - Laser-assisted arthroscopic ulnar shortening.
AB  - The purpose of this study is to evaluate arthroscopic ulnar shortening with the
      holmium:yttrium-aluminum-garnet (Ho:YAG) laser for the treatment of ulnocarpal
      abutment syndrome (UAS). This is a retrospective review of the experience of a
      single surgeon using this technique between 1994 and 2000. Unloading the
      ulnocarpal joint is the recognized treatment of UAS. Ulnar shortening via a
      diaphyseal osteotomy and plating (USO) has been used with good results; however,
      nearly 50% of patients will require hardware removal. Researchers have reported
      similar results between open distal ulnar resection (the wafer procedure) and USO
      for the treatment of UAS. Researchers have also reported similar results with
      mechanical arthroscopic distal ulnar resections (arthroscopic wafer distal ulnar
      resection [AWP]) for UAS. Eleven patients who underwent Ho:YAG laser-assisted
      arthroscopic distal ulnar resection were retrospectively evaluated. The average
      follow-up time was 31 months, with a range of 7 to 61 months. Evaluation using
      Darrow' s criteria revealed 64% excellent (7 of 11), 18% good (2 of 11), 9% fair
      (1 of 11), and 9% poor (1 of 11) results. The average return to work time was 4.7
      months, with a range of 1.5 to 16 months. Complications included 1 repeat surgery
      for ulnocarpal scar formation, 2 cases of transient tendonitis, and 1 portal site
      erythema without drainage that was treated with antibiotics. One patient (the one
      with a poor result) has not returned to work for unrelated reasons. chi- square
      analysis (P <.05) was unable to identify a statistical difference between the
      reported results of arthroscopic wafer procedures, USOs, and open wafer
      procedures. We concluded that Ho:YAG laser-assisted arthroscopic ulna shortening
      procedures show similar results to those reported for arthroscopic wafer
      procedures, open wafer procedures, and USOs. Return to work times are similar to
      those reported by other researchers, as is the return to preoperative occupation
      rate. There is no need for late removal of hardware, as is sometimes associated
      with USO. Our experience has been that the Ho:YAG laser removes hyaline cartilage
      and subchondral bone rapidly and with little debris, and thus facilitates the
      ulna shortening procedure.

PMID- 12426552
TI  - A long journey. Presidential address.

PMID- 12426553
TI  - Attrition sign in impingement syndrome.
AB  - Extrinsic compression of the rotator cuff by the coracoacromial arch has been
      accepted as a major factor in the etiology of bursitis, cuff tendonitis, and
      rotator cuff tears. Other etiologies for rotator cuff syndrome have also been
      proposed in various patient populations. These include repetitive microtrauma and
      underlying instability with tensile overload, particularly in the younger
      (younger than 35) athletic population. In this evolving field, the arthroscopist
      must to be able to recognize arthroscopic signs of impingement syndrome.
      Therefore, this paper discusses evaluating rotator cuff syndromes and reviews the
      signs of subacromial impingement found at bursoscopy. We also offer several tips
      to maximize visualization during shoulder bursoscopy.

PMID- 12426554
TI  - Bone wax as a way to prevent hematoma after arthroscopic anterior cruciate
      ligament reconstruction.
AB  - After the intra-articular drain placed during an arthroscopic anterior cruciate
      ligament reconstruction is removed, cannulated interference screws can function
      as a new drain, leading to blood leakage in the pretibial tissue. Sealing the
      lumen of the cannulated screw with bone wax may prevent this complication.

PMID- 12426555
TI  - An arthroscopic technique for confirming intra-articular subluxation of the long
      head of the biceps tendon: the ramp test.
AB  - The purpose of this technical note is to introduce the ramp test and explain this
      arthroscopic technique. The ramp test is used to test the integrity of the soft
      tissue restraint to intra-articular subluxation of the long head of the biceps
      tendon. Injury to the soft tissue restraint, the hidden lesion, has been proposed
      as occurring in conjunction with a full-thickness rotator cuff tear. Both
      cadaveric dissections and arthroscopic patient assessments were conducted to
      develop the ramp test. In this study, 17 patients also presented with refractory
      anterior shoulder pain and underwent arthroscopy to further characterize the ramp
      test. An abnormal examination result showed that the long head of the biceps
      tendon translated medially and inferiorly across the humeral head. In addition,
      this subgroup of 17 patients all had an abnormal ramp test but did not have a
      full-thickness rotator cuff tear. The ramp test is now applied to all
      arthroscopic procedures by the senior author, and we recommend its use for
      arthroscopic confirmation of intra-articular subluxation of the long head of the
      biceps tendon. Thus, we advocate that an abnormal ramp test result indicates
      pathology and warrants the surgical removal of the long head of the biceps tendon
      from the glenohumeral joint.

PMID- 12426556
TI  - Histologic findings with a bioabsorbable anterior cruciate ligament interference
      screw explant after 2.5 years in vivo.
AB  - We retrieved a high-molecular-weight poly-L-lactic) (PLLA) anterior cruciate
      ligament (ACL) interference screw (Arthrex, Naples, FL) after 30 months in vivo
      during revision ACL surgery. Gross, histologic, histomorphometric, and molecular
      weight measurements were carried out on the implant and the surrounding bone.
      These studies showed a 75% decrease in the molecular weight of the screw, with
      implant fragmentation and new bone formation adjacent to the screw and graft.
      Healing of the graft within the bony tunnel with no significant inflammatory
      reaction had occurred. The clinical implications of these findings are that this
      implant dissolves slowly, and it was physically present at 30 months in vivo. It
      is a safe, nonreactive alternative to traditional metal interference screws used
      for ACL graft fixation. It will eventually be substituted by bone and will
      eliminate some of the problems associated with metallic devices.

PMID- 12426557
TI  - Echinococcal synovitis of the knee joint.
AB  - Bone lesions are present in 1% to 2% of cases of hydatid disease. Hydatid
      synovitis can usually be identified due to secondary extension from the adjacent
      bone, or infrequently after hematogenous spread. We present an extremely rare
      case of hydatid synovitis without bony involvement. A 74-year-old man with
      diagnosed hydatid disease was admitted to our department because of left knee
      swelling. Neither physical examination nor laboratory studies revealed any
      remarkable findings. Radiographic evaluation of the knee joint was
      noncontributory. The patient underwent an arthroscopically assisted synovectomy,
      and the biopsy revealed an echinococcus contamination. No complications occurred
      during the postoperative period.

PMID- 12426558
TI  - Arthroscopic repair of dorsal radiocarpal ligament tears.
AB  - Various authors have highlighted the importance of the dorsal radiocarpal (DRC)
      ligament in normal carpal kinematics. It is a secondary stabilizer of the lunate
      and has a role in midcarpal stability. Disruption of the DRC ligament has been
      implicated in the development of static VISI and DISI deformities, prompting some
      authors to perform an open reattachment of the dorsal capsule if there is an
      associated scapholunate ligament tear. The management of these tears is still
      evolving. The contribution of a DRC ligament tear to the development of wrist
      pain remains uncertain when combined with additional wrist pathology. An isolated
      DRC ligament tear was responsible for chronic dorsal wrist pain in 2 patients. A
      previously undescribed inside-out repair method of the DRC ligament using a volar
      wrist portal was successful in relieving the pain. Recognition of this condition
      and further research into treatment methods is needed.

PMID- 12426559
TI  - Costimulatory molecule-targeted antibody therapy of a spontaneous autoimmune
      disease.
AB  - Humans and mice deficient in Fas, a tumor necrosis factor (TNF)-receptor family
      member, cannot induce apoptosis of autoreactive cells, and consequently develop
      progressive lymphoproliferative disorders and lupus-like autoimmune diseases.
      Previous studies have shown that short-term administrations of agonistic
      monoclonal antibodies against CD137, another TNF-receptor family member, activate
      T cells and induce rejection of allografts and established tumors. Here we report
      that treatment with an agonistic monoclonal antibody to CD137 (2A) blocks
      lymphadenopathy and spontaneous autoimmune diseases in Fas-deficient MRL/lpr
      mice, ultimately leading to their prolonged survival. Notably, 2A treatment
      rapidly augments IFN-gamma production, and induces the depletion of autoreactive
      B cells and abnormal double-negative T cells, possibly by increasing their
      apoptosis through Fas- and TNF receptor-independent mechanisms. This study
      demonstrates that agonistic monoclonal antibodies specific for costimulatory
      molecules can be used as novel therapeutic agents to delete autoreactive
      lymphocytes and block autoimmune disease progression.

PMID- 12426560
TI  - T cells require TRAIL for optimal graft-versus-tumor activity.
AB  - Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member
      of the TNF superfamily that exhibits specific tumoricidal activity against a
      variety of tumors. It is expressed on different cells of the immune system and
      plays a role in natural killer cell-mediated tumor surveillance. In allogeneic
      hematopoietic-cell transplantation, the reactivity of the donor T cell against
      malignant cells is essential for the graft-versus-tumor (GVT) effect. Cytolytic
      activity of T cells is primarily mediated through the Fas-Fas ligand and perforin
      granzyme pathways. However, T cells deficient for both Fas ligand and perforin
      can still exert GVT activity in vivo in mouse models. To uncover a potential role
      for TRAIL in donor T cell-mediated GVT activity, we compared donor T cells from
      TRAIL-deficient and wild-type mice in clinically relevant mouse bone-marrow
      transplantation models. We found that alloreactive T cells can express TRAIL, but
      the absence of TRAIL had no effect on their proliferative and cytokine response
      to alloantigens. TRAIL-deficient T cells showed significantly lower GVT activity
      than did TRAIL-expressing T cells, but no important differences in graft-versus
      host disease, a major complication of allogeneic hematopoietic cell
      transplantation, were observed. These data suggest that strategies to enhance
      TRAIL-mediated GVT activity could decrease relapse rates of malignancies after
      hematopoietic cell transplantation without exacerbation of graft-versus-host
      disease.

PMID- 12426561
TI  - Hypothalamic insulin signaling is required for inhibition of glucose production.
AB  - Circulating insulin inhibits endogenous glucose production. Here we report that
      bidirectional changes in hypothalamic insulin signaling affect glucose
      production. The infusion of either insulin or a small-molecule insulin mimetic in
      the third cerebral ventricle suppressed glucose production independent of
      circulating levels of insulin and of other glucoregulatory hormones. Conversely,
      central antagonism of insulin signaling impaired the ability of circulating
      insulin to inhibit glucose production. Finally, third-cerebral-ventricle
      administration of inhibitors of ATP-sensitive potassium channels, but not of
      antagonists of the central melanocortin receptors, also blunted the effect of
      hyperinsulinemia on glucose production. These results reveal a new site of action
      of insulin on glucose production and suggest that hypothalamic insulin resistance
      can contribute to hyperglycemia in type 2 diabetes mellitus.

PMID- 12426562
TI  - Cell-free hemoglobin limits nitric oxide bioavailability in sickle-cell disease.
AB  - Although the deleterious vasoconstrictive effects of cell-free, hemoglobin-based
      blood substitutes have been appreciated, the systemic effects of chronic
      hemolysis on nitric oxide bioavailability have not been considered or quantified.
      Central to this investigation is the understanding that nitric oxide reacts at
      least 1,000 times more rapidly with free hemoglobin solutions than with
      erythrocytes. We hypothesized that decompartmentalization of hemoglobin into
      plasma would divert nitric oxide from homeostatic vascular function. We
      demonstrate here that plasma from patients with sickle-cell disease contains cell
      free ferrous hemoglobin, which stoichiometrically consumes micromolar quantities
      of nitric oxide and abrogates forearm blood flow responses to nitric oxide donor
      infusions. Therapies that inactivate plasma hemoglobin by oxidation or nitric
      oxide ligation restore nitric oxide bioavailability. Decompartmentalization of
      hemoglobin and subsequent dioxygenation of nitric oxide may explain the vascular
      complications shared by acute and chronic hemolytic disorders.

PMID- 12426563
TI  - Indirect activation of naive CD4+ T cells by dendritic cell-derived exosomes.
AB  - Dendritic cells (DCs) secrete vesicles of endosomal origin, called exosomes, that
      bear major histocompatibility complex (MHC) and T cell costimulatory molecules.
      Here, we found that injection of antigen- or peptide-bearing exosomes induced
      antigen-specific naive CD4+ T cell activation in vivo. In vitro, exosomes did not
      induce antigen-dependent T cell stimulation unless mature CD8alpha- DCs were also
      present in the cultures. These mature DCs could be MHC class II-negative, but had
      to bear CD80 and CD86. Therefore, in addition to carrying antigen, exosomes
      promote the exchange of functional peptide-MHC complexes between DCs. Such a
      mechanism may increase the number of DCs bearing a particular peptide, thus
      amplifying the initiation of primary adaptive immune responses.

PMID- 12426564
TI  - NKG2D recruits two distinct adapters to trigger NK cell activation and
      costimulation.
AB  - NKG2D is a receptor on natural killer (NK) cells and cytotoxic T lymphocytes that
      binds major histocompatibility complex (MHC) class I-like ligands expressed
      primarily on virally infected and neoplastic cells. In vitro studies indicate
      that NKG2D provides costimulation through an associated adapter, DAP10, which
      recruits phosphatidylinositol-3 kinase. Here we show that in DAP10-deficient
      mice, CD8+ T cells lack NKG2D expression and are incapable of mounting tumor
      specific responses. However, DAP10-deficient NK cells express a functional NKG2D
      receptor due to the association of NKG2D with another adapter molecule, DAP12
      (also known as KARAP), which recruits protein tyrosine kinases. Thus, NKG2D is a
      versatile receptor that, depending on the availability of adapter partners,
      mediates costimulation in T cells and/or activation in NK cells.

PMID- 12426565
TI  - Selective associations with signaling proteins determine stimulatory versus
      costimulatory activity of NKG2D.
AB  - Optimal lymphocyte activation requires the simultaneous engagement of stimulatory
      and costimulatory receptors. Stimulatory immunoreceptors are usually composed of
      a ligand-binding transmembrane protein and noncovalently associated signal
      transducing subunits. Here, we report that alternative splicing leads to two
      distinct NKG2D polypeptides that associate differentially with the DAP10 and
      KARAP (also known as DAP12) signaling subunits. We found that differential
      expression of these isoforms and of signaling proteins determined whether NKG2D
      functioned as a costimulatory receptor in the adaptive immune system (CD8+ T
      cells) or as both a primary recognition structure and a costimulatory receptor in
      the innate immune system (natural killer cells and macrophages). This strategy
      suggests a rationale for the multisubunit structure of stimulatory
      immunoreceptors.

PMID- 12426566
TI  - Restoration of type VII collagen expression and function in dystrophic
      epidermolysis bullosa.
AB  - Dystrophic epidermolysis bullosa (DEB) is a family of inherited mechano-bullous
      disorders caused by mutations in the human type VII collagen gene (COL7A1).
      Individuals with DEB lack type VII collagen and anchoring fibrils, structures
      that attach epidermis and dermis. The current lack of treatment for DEB is an
      impetus to develop gene therapy strategies that efficiently transfer and stably
      express genes delivered to skin cells in vivo. In this study, we delivered and
      expressed full-length type VII collagen using a self-inactivating minimal
      lentivirus-based vector. Transduction of lentiviral vectors containing the COL7A1
      transgene into recessive DEB (RDEB) keratinocytes and fibroblasts (in which type
      VII collagen was absent) resulted in persistent synthesis and secretion of type
      VII collagen. Unlike RDEB parent cells, the gene-corrected cells had normal
      morphology, proliferative potential, matrix attachment and motility. We used
      these gene-corrected cells to regenerate human skin on immune-deficient mice.
      Human skin regenerated by gene-corrected RDEB cells had restored expression of
      type VII collagen and formation of anchoring fibrils at the dermal-epidermal
      junction in vivo. These studies demonstrate that it is possible to restore type
      VII collagen gene expression in RDEB skin in vivo.

PMID- 12426567
TI  - Mutations in two adjacent novel genes are associated with epidermodysplasia
      verruciformis.
AB  - Epidermodysplasia verruciformis (OMIM 226400) is a rare autosomal recessive
      genodermatosis associated with a high risk of skin carcinoma that results from an
      abnormal susceptibility to infection by specific human papillomaviruses (HPVs).
      We recently mapped a susceptibility locus for epidermodysplasia verruciformis
      (EV1) to chromosome 17q25. Here we report the identification of nonsense
      mutations in two adjacent novel genes, EVER1 and EVER2, that are associated with
      the disease. The gene products EVER1 and EVER2 have features of integral membrane
      proteins and are localized in the endoplasmic reticulum.

PMID- 12426568
TI  - Apc modulates embryonic stem-cell differentiation by controlling the dosage of
      beta-catenin signaling.
AB  - The Wnt signal-transduction pathway induces the nuclear translocation of membrane
      bound beta-catenin (Catnb) and has a key role in cell-fate determination. Tight
      somatic regulation of this signal is essential, as uncontrolled nuclear
      accumulation of beta-catenin can cause developmental defects and tumorigenesis in
      the adult organism. The adenomatous polyposis coli gene (APC) is a major
      controller of the Wnt pathway and is essential to prevent tumorigenesis in a
      variety of tissues and organs. Here, we have investigated the effect of different
      mutations in Apc on the differentiation potential of mouse embryonic stem (ES)
      cells. We provide genetic and molecular evidence that the ability and sensitivity
      of ES cells to differentiate into the three germ layers is inhibited by increased
      doses of beta-catenin by specific Apc mutations. These range from a severe
      differentiation blockade in Apc alleles completely deficient in beta-catenin
      regulation to more specific neuroectodermal, dorsal mesodermal and endodermal
      defects in more hypomorphic alleles. Accordingly, a targeted oncogenic mutation
      in Catnb also affects the differentiation potential of ES cells. Expression
      profiling of wildtype and Apc-mutated teratomas supports the differentiation
      defects at the molecular level and pinpoints a large number of downstream
      structural and regulating genes. Chimeric experiments showed that this effect is
      cell-autonomous. Our results imply that constitutive activation of the Apc/beta
      catenin signaling pathway results in differentiation defects in tissue
      homeostasis, and possibly underlies tumorigenesis in the colon and other self
      renewing tissues.

PMID- 12426569
TI  - Functional SNPs in the lymphotoxin-alpha gene that are associated with
      susceptibility to myocardial infarction.
AB  - By means of a large-scale, case-control association study using 92,788 gene-based
      single-nucleotide polymorphism (SNP) markers, we identified a candidate locus on
      chromosome 6p21 associated with susceptibility to myocardial infarction.
      Subsequent linkage-disequilibrium (LD) mapping and analyses of haplotype
      structure showed significant associations between myocardial infarction and a
      single 50 kb halpotype comprised of five SNPs in LTA (encoding lymphotoxin
      alpha), NFKBIL1 (encoding nuclear factor of kappa light polypeptide gene enhancer
      in B cells, inhibitor-like 1) and BAT1 (encoding HLA-B associated transcript 1).
      Homozygosity with respect to each of the two SNPs in LTA was significantly
      associated with increased risk for myocardial infarction (odds ratio = 1.78,
      chi(2) = 21.6, P = 0.00000033; 1,133 affected individuals versus 1,006 controls).
      In vitro functional analyses indicated that one SNP in the coding region of LTA,
      which changed an amino-acid residue from threonine to asparagine (Thr26Asn),
      effected a twofold increase in induction of several cell-adhesion molecules,
      including VCAM1, in vascular smooth-muscle cells of human coronary artery.
      Moreover, the SNP, in intron 1 of LTA, enhanced the transcriptional level of LTA.
      These results indicate that variants in the LTA are risk factors for myocardial
      infraction and implicate LTA in the pathogenesis of the disorder.

PMID- 12426570
TI  - Long-range chromatin regulatory interactions in vivo.
AB  - Communication between distal chromosomal elements is essential for control of
      many nuclear processes. For example, genes in higher eukaryotes often require
      distant enhancer sequences for high-level expression. The mechanisms proposed for
      long-range enhancer action fall into two basic categories. Non-contact models
      propose that enhancers act at a distance to create a favorable environment for
      gene transcription, or act as entry sites or nucleation points for factors that
      ultimately communicate with the gene. Contact models propose that communication
      occurs through direct interaction between the distant enhancer and the gene by
      various mechanisms that 'loop out' the intervening sequences. Although much
      attention has focused on contact models, the existence and nature of long-range
      interactions is still controversial and speculative, as there is no direct
      evidence that distant sequences physically interact in vivo. Here, we report the
      development of a widely applicable in situ technique to tag and recover chromatin
      in the immediate vicinity of an actively transcribed gene. We show that the
      classical enhancer element, HS2 of the prototypical locus control region (LCR) of
      the beta-globin gene cluster, is in close physical proximity to an actively
      transcribed HBB (beta-globin) gene located over 50 kb away in vivo, suggesting a
      direct regulatory interaction. The results give unprecedented insight into the in
      vivo structure of the LCR-gene interface and provide the first direct evidence of
      long-range enhancer communication.

PMID- 12426571
TI  - Population coding of shape in area V4.
AB  - Shape is represented in the visual system by patterns of activity across
      populations of neurons. We studied the population code for shape in area V4 of
      macaque monkeys, which is part of the ventral (object-related) pathway in primate
      visual cortex. We have previously found that many macaque V4 neurons are tuned
      for the curvature and object-centered position of boundary fragments (such as
      'concavity on the right'). Here we tested the hypothesis that populations of such
      cells represent complete shapes as aggregates of boundary fragments. To estimate
      the population representation of a given shape, we scaled each cell's tuning peak
      by its response to that shape, summed across cells and smoothed. The resulting
      population response surface contained 3-8 peaks that represented major boundary
      features and could be used to reconstruct (approximately) the original shape.
      This exemplifies how a multi-peaked neural population response can represent a
      complex stimulus in terms of its constituent elements.

PMID- 12426572
TI  - Early consolidation of instrumental learning requires protein synthesis in the
      nucleus accumbens.
AB  - It is widely held that long-term memories are established by consolidation of
      newly acquired information into stable neural representations, a process that
      requires protein synthesis and synaptic plasticity. Plasticity within the nucleus
      accumbens (NAc), a major component of the ventral striatum, is thought to mediate
      instrumental learning processes and many aspects of drug addiction. Here we show
      that the inhibition of protein synthesis within the NAc disrupts consolidation of
      an appetitive instrumental learning task (lever-pressing for food) in rats. Post
      trial infusions of anisomycin immediately after the first several training
      sessions prevented consolidation, whereas infusions delayed by 2 or 4 hours had
      no effect. However, if the rats were allowed to learn the task, the behavior was
      not sensitive to disruption by intra-accumbens anisomycin. Control infusions into
      the medial NAc shell or the dorsolateral striatum did not impair learning; in
      fact, an enhancement was observed in the latter case. These results show that de
      novo protein synthesis within the NAc is necessary for the consolidation, but not
      reconsolidation, of appetitive instrumental memories.

PMID- 12426573
TI  - Region-specific generation of cholinergic neurons from fetal human neural stem
      cells grafted in adult rat.
AB  - Pluripotent or multipotent stem cells isolated from human embryos or adult
      central nervous system (CNS) may provide new neurons to ameliorate neural
      disorders. A major obstacle, however, is that the majority of such cells do not
      differentiate into neurons when grafted into non-neurogenic areas of the adult
      CNS. Here we report a new in vitro priming procedure that generates a nearly pure
      population of neurons from fetal human neural stem cells (hNSCs) transplanted
      into adult rat CNS. Furthermore, the grafted cells differentiated by acquiring a
      cholinergic phenotype in a region-specific manner. This technology may advance
      stem cell-based therapy to replace lost neurons in neural injury or
      neurodegenerative disorders.

PMID- 12426574
TI  - A p75(NTR) and Nogo receptor complex mediates repulsive signaling by myelin
      associated glycoprotein.
AB  - Myelin-associated glycoprotein (MAG), an inhibitor of axon regeneration, binds
      with high affinity to the Nogo-66 receptor (NgR). Here we report that the p75
      neurotrophin receptor (p75(NTR)) is a co-receptor of NgR for MAG signaling. In
      cultured human embryonic kidney (HEK) cells expressing NgR, p75(NTR) was required
      for MAG-induced intracellular Ca2+ elevation. Co-immunoprecipitation showed an
      association of NgR with p75(NTR) that can be disrupted by an antibody against
      p75(NTR) (NGFR5), and extensive coexpression was observed in the developing rat
      nervous system. Furthermore, NGFR5 abolished MAG-induced repulsive turning of
      Xenopus axonal growth cones and Ca2+ elevation, both in neurons and in
      NgR/p75(NTR)-expressing HEK cells. Thus we conclude that p75(NTR) is a co
      receptor of NgR for MAG signaling and a potential therapeutic target for
      promoting nerve regeneration.

PMID- 12426575
TI  - Synthetic shuffling expands functional protein diversity by allowing amino acids
      to recombine independently.
AB  - We describe synthetic shuffling, an evolutionary protein engineering technology
      in which every amino acid from a set of parents is allowed to recombine
      independently of every other amino acid. With the use of degenerate
      oligonucleotides, synthetic shuffling provides a direct route from database
      sequence information to functional libraries. Physical starting genes are
      unnecessary, and additional design criteria such as optimal codon usage or known
      beneficial mutations can also be incorporated. We performed synthetic shuffling
      of 15 subtilisin genes and obtained active and highly chimeric enzymes with
      desirable combinations of properties that we did not obtain by other directed
      evolution methods.

PMID- 12426576
TI  - Growth factor engineering by degenerate homoduplex gene family recombination.
AB  - There is great interest in engineering human growth factors as potential
      therapeutic agonists and antagonists. We approached this goal with a synthetic
      DNA recombination method. We aligned a pool of "top-strand" oligonucleotides
      incorporating polymorphisms from mammalian genes encoding epidermal growth factor
      (EGF) using multiple polymorphic "scaffold" oligonucleotides. Top strands were
      then linked by gap filling and ligation. This approach avoided heteroduplex
      annealing in the linkage of highly degenerate oligonucleotides and thus achieved
      completely random recombination. Cloned genes from a human-mouse chimeric library
      captured every possible permutation of the parental polymorphisms, creating an
      apparently complete recombined gene-family library, which has not been previously
      described. This library yielded a chimeric protein whose agonist activity was
      enhanced 123-fold. A second library from five mammalian EGF homologs possessed
      the highest reported recombination density (1 crossover per 12.4 bp). The five
      homolog library yielded the strongest-binding hEGF variant yet reported. In
      addition, it contained strongly binding EGF variants with antagonist properties.
      Our less biased approach to DNA shuffling should be useful for the engineering of
      a wide variety of proteins.

PMID- 12426577
TI  - Targeting autoantigen-specific T cells and suppression of autoimmune
      encephalomyelitis with receptor-modified T lymphocytes.
AB  - We demonstrate here the feasibility of antigen-specifically redirecting T cells
      against autoreactive T lymphocytes and thereby treating a model autoimmune
      disease. We created and transgenically expressed on T cells a heterodimeric
      chimeric receptor that genetically links an autoantigenic peptide, its
      restricting MHC, and the signal transduction domain of the T-cell receptor (TCR)
      zeta-chain. Engagement of the chimeric receptor by the TCR of autoreactive T
      cells activated the receptor-modified T cells in vitro and in vivo, inducing
      proliferation and cytolysis. Adoptively transferred receptor-modified T cells
      prevented and treated a model autoimmune disease, experimental allergic
      encephalomyelitis (EAE), even after epitope spreading had diversified the
      autoantigenic response. Treatment reduced disease severity and increased survival
      of affected animals, and was durable for >75 days. The receptor-modified cells
      acted both by strongly attenuating T-cell response to autoantigen as well as by
      shifting the residual response from an immunopathologic Th1 to a protective Th2
      format.

PMID- 12426578
TI  - Systemically delivered antisense oligomers upregulate gene expression in mouse
      tissues.
AB  - Systemically injected 2'-O-methoxyethyl (2'-O-MOE)-phosphorothioate and PNA-4K
      oligomers (peptide nucleic acid with four lysines linked at the C terminus)
      exhibited sequence-specific antisense activity in a number of mouse organs.
      Morpholino oligomers were less effective, whereas PNA oligomers with only one
      lysine (PNA-1K) were completely inactive. The latter result indicates that the
      four-lysine tail is essential for the antisense activity of PNA oligomers in
      vivo. These results were obtained in a transgenic mouse model designed as a
      positive readout test for activity, delivery, and distribution of antisense
      oligomers. In this model, the expressed gene (EGFP-654) encoding enhanced green
      fluorescence protein (EGFP) is interrupted by an aberrantly spliced mutated
      intron of the human beta-globin gene. Aberrant splicing of this intron prevented
      expression of EGFP-654 in all tissues, whereas in tissues and organs that took up
      a splice site-targeted antisense oligomer, correct splicing was restored and EGFP
      654 expression upregulated. The sequence-specific ability of PNA-4K and the 2'-O
      MOE oligomers to upregulate EGFP-654 provides strong evidence that systemically
      delivered, chemically modified oligonucleotides affect gene expression by
      sequence-specific true antisense activity, validating their application as
      potential therapeutics.

PMID- 12426579
TI  - Starch content and yield increase as a result of altering adenylate pools in
      transgenic plants.
AB  - Starch represents the most important carbohydrate used for food and feed
      purposes. With the aim of increasing starch content, we decided to modulate the
      adenylate pool by changing the activity of the plastidial adenylate kinase in
      transgenic potato plants. As a result, we observed a substantial increase in the
      level of adenylates and, most importantly, an increase in the level of starch to
      60% above that found in wild-type plants. In addition, concentrations of several
      amino acids were increased by a factor of 2-4. These results are particularly
      striking because this genetic manipulation also results in an increased tuber
      yield. The modulation of the plastidial adenylate kinase activity in transgenic
      plants therefore represents a potentially very useful strategy for increasing
      formation of major storage compounds in heterotrophic tissues of higher plants.

PMID- 12426580
TI  - BMP4 initiates human embryonic stem cell differentiation to trophoblast.
AB  - The excitement and controversy surrounding the potential role of human embryonic
      stem (ES) cells in transplantation therapy have often overshadowed their
      potentially more important use as a basic research tool for understanding the
      development and function of human tissues. Human ES cells can proliferate without
      a known limit and can form advanced derivatives of all three embryonic germ
      layers. What is less widely appreciated is that human ES cells can also form the
      extra-embryonic tissues that differentiate from the embryo before gastrulation.
      The use of human ES cells to derive early human trophoblast is particularly
      valuable, because it is difficult to obtain from other sources and is
      significantly different from mouse trophoblast. Here we show that bone
      morphogenetic protein 4 (BMP4), a member of the transforming growth factor-beta
      (TGF-beta) superfamily, induces the differentiation of human ES cells to
      trophoblast. DNA microarray, RT-PCR, and immunoassay analyses demonstrate that
      the differentiated cells express a range of trophoblast markers and secrete
      placental hormones. When plated at low density, the BMP4-treated cells form
      syncytia that express chorionic gonadotrophin (CG). These results underscore
      fundamental differences between human and mouse ES cells, which differentiate
      poorly, if at all, to trophoblast. Human ES cells thus provide a tool for
      studying the differentiation and function of early human trophoblast and could
      provide a new understanding of some of the earliest differentiation events of
      human postimplantation development.

PMID- 12426581
TI  - Allosteric inhibition via R-state destabilization in ATP sulfurylase from
      Penicillium chrysogenum.
AB  - The structure of the cooperative hexameric enzyme ATP sulfurylase from
      Penicillium chrysogenum bound to its allosteric inhibitor, 3'-phosphoadenosine-5'
      phosphosulfate (PAPS), was determined to 2.6 A resolution. This structure
      represents the low substrate-affinity T-state conformation of the enzyme.
      Comparison with the high substrate-affinity R-state structure reveals that a
      large rotational rearrangement of domains occurs as a result of the R-to-T
      transition. The rearrangement is accompanied by the 17 A movement of a 10-residue
      loop out of the active site region, resulting in an open, product release-like
      structure of the catalytic domain. Binding of PAPS is proposed to induce the
      allosteric transition by destabilizing an R-state-specific salt linkage between
      Asp 111 in an N-terminal domain of one subunit and Arg 515 in the allosteric
      domain of a trans-triad subunit. Disrupting this salt linkage by site-directed
      mutagenesis induces cooperative inhibition behavior in the absence of an
      allosteric effector, confirming the role of these two residues.

PMID- 12426582
TI  - Structural analysis of the adaptor protein ClpS in complex with the N-terminal
      domain of ClpA.
AB  - In Escherichia coli, protein degradation is performed by several proteolytic
      machines, including ClpAP. Generally, the substrate specificity of these machines
      is determined by chaperone components, such as ClpA. In some cases, however, the
      specificity is modified by adaptor proteins, such as ClpS. Here we report the 2.5
      A resolution crystal structure of ClpS in complex with the N-terminal domain of
      ClpA. Using mutagenesis, we demonstrate that two contact residues (Glu79 and Lys
      84) are essential not only for ClpAS complex formation but also for ClpAPS
      mediated substrate degradation. The corresponding residues are absent in the
      chaperone ClpB, providing a structural rationale for the unique specificity shown
      by ClpS despite the high overall similarity between ClpA and ClpB. To determine
      the location of ClpS within the ClpA hexamer, we modeled the N-terminal domain of
      ClpA onto a structurally defined, homologous AAA+ protein. From this model, we
      proposed a molecular mechanism to explain the ClpS-mediated switch in ClpA
      substrate specificity.

PMID- 12426583
TI  - Sculpting of the spliceosomal branch site recognition motif by a conserved
      pseudouridine.
AB  - Pairing of a consensus sequence of the precursor (pre)-mRNA intron with a short
      region of the U2 small nuclear (sn)RNA during assembly of the eukaryotic
      spliceosome results in formation of a complementary helix of seven base pairs
      with a single unpaired adenosine residue. The 2' OH of this adenosine, called the
      branch site, brings about nucleophilic attack at the pre-mRNA 5' splice site in
      the first step of splicing. Another feature of this pairing is the phylogenetic
      conservation of a pseudouridine (psi) residue in U2 snRNA nearly opposite the
      branch site. We show that the presence of this psi in the pre-mRNA branch-site
      helix of Saccharomyces cerevisiae induces a dramatically altered architectural
      landscape compared with that of its unmodified counterpart. The psi-induced
      structure places the nucleophile in an accessible position for the first step of
      splicing.

PMID- 12426584
TI  - Proceedings of the 8th International Symposium on Schistosomiasis. Recife,
      Brazil, 2-5 December, 2001.

PMID- 12426585
TI  - Schistosomiasis mansoni in areas of low transmission: epidemiological
      characterization of Venezuelan foci.
AB  - Severe schistosomiasis is a rare event in Venezuela nowadays, after a successful
      national campaign by the Schistosomiasis Control Program. Unfortunately, this
      program has practically disappeared, and snail surveillance in field is not a
      priority, anymore. Thus, schistosomiasis has become a neglected disease in this
      country. However, surveys in different populations from the endemic area have
      shown particular epidemiological features described herein. In five communities
      we evaluated 2,175 persons and searched for the presence of Biomphalaria glabrata
      snails. Some markers were used for classifying schistosomiasis foci: mean age of
      the persons with Schistosoma mansoni eggs in the stools, serological tests,
      presence of B. glabrata snails, and intensity of infection. Places without B.
      glabrata snails and with few schistosomiasis cases were defined as "past
      transmission sites"; a site with abundant snails but few cases was defined as
      "potential risk"; "new transmission" foci were characterized by the presence of
      infected snails and young people passing eggs in the stools. A "re-emergent"
      focus has shared these last features, showing in addition a place where
      schistosomiasis had been reported before. Recent evidences of active transmission
      with the increasing dispersion of B. glabrata snails, point out the necessity for
      the re-establishment of the Schistosomiasis Control Program in Venezuela.

PMID- 12426586
TI  - Experimental evidence and ecological perspectives for the adaptation of
      Schistosoma mansoni Sambon, 1907 (Digenea: Schistosomatidae) to a wild host, the
      water-rat, Nectomys squamipes Brants, 1827 (Rodentia: Sigmodontinae).
AB  - Due to the semi aquatic habits and the overlap of the geographical distribution
      of the water-rat, Nectomys spp., with schistosomiasis endemic areas, these wild
      rodents are very likely to acquire Schistosoma mansoni infection in their daily
      activities. The role of the water-rat in the S. mansoni cycle would be
      substantiated if one could prove that these rodents acquire the parasite during
      their own activity time, a completely independent time schedule of human
      activities. To pursue this goal, we performed two field experiments in the
      municipality of Sumidouro, State of Rio de Janeiro, Brazil, a schistosomiasis
      endemic area where N. squamipes is found naturally infected. One experiment was
      devised as a series of observations of activity time of the water-rat. The other
      experiment was a test of the occurrence of late transmission of S. mansoni to the
      water-rat. The daily activity pattern showed that the water-rat is active chiefly
      just after sunset. At both diurnal and late exposition essays the water-rat
      sentinels got infected by S. mansoni. These findings clarify ecological and
      behavioral components necessary to the adaptation of S. mansoni to the water-rat
      as a non human definitive host and the existence of a transmission cycle
      involving this animals as a reservoir.

PMID- 12426587
TI  - Schistosomiasis mansoni in Bananal (State of Sao Paulo, Brazil): IV. Study on the
      public awareness of its risks in the Palha District.
AB  - A rather high prevalence of mansoni schistosomiasis has been observed in some
      localities of Bananal, State of Sao Paulo, during the past decade. The highest
      prevalence of schistosomiasis was found in the Palha District; it was thus
      considered adequate for an evaluation of public awareness of the risks involved
      in acquiring schistosomiasis, a likely outcome of certain behavior patterns. We
      interviewed 542 district-dwellers. The 5-to-39 age-group constituted 65.5% of the
      whole sample. Concerning the infection, 69.2% had hearsay information; 46.1% know
      the infection; 69.6% know how it is acquired; 31.5% know about the symptoms and
      57.1% know what can be done to avoid infection; 17.7% declared to have acquired
      the infection at least once in their lifetime; 62.3% reported total or partial
      immersion in collections of water of Bananal, once or twice a week, 53.9% of
      these for bathing or fishing. Although most (91.7%) households have treated
      running water, are connected to the sewage network or have septic tanks, 9% of
      the people interviewed use to defecate on the field. It became clear that the
      educational messages aimed at this population had not been adequate, having
      failed to fulfil any expectations. The local people received only piecemeal and
      subjective information about their problem. The control of schistosomiasis
      requires an integrated practice, which includes the analysis of macro-determinant
      factors, such as basic sanitation, habitation, education and health care. In
      short, we require a multidisciplinary vision of the mechanisms of transmission of
      the infection, which depends upon adequate planning and well trained personnel,
      intent on their educational work, to attain satisfactory results.

PMID- 12426588
TI  - Schistosomiasis mansoni in Bananal (State of Sao Paulo, Brazil): III.
      Seroepidemiological studies in the Palha District.
AB  - The Palha district, municipality of Bananal, State of Sao Paulo, Brazil, had
      10.3% cases of Schistosoma mansoni diagnosed from 1994 to 2000 by coproscopy:
      about three times the municipality average. The immunofluorescent antibody test
      was used to assess gut-associated IgM antibody titers of samples from 452
      inhabitants. It disclosed 129 (28.5%) positive cases. Subjects were classified
      according to age, sex, birthplace, and period of residence. Titers varied from 8
      to 4,096 (geometric mean: 170.2). Seropositives were aged from 6 to 69 years
      (average: 24.5), 75% of them aged 34 or less, predominantly males (78 or 60.5%).
      Of all subjects, 65.7% were born and had been living in Bananal since; 24.2% came
      from neighboring municipalities and are residing in Bananal from two months to 89
      years (average: 22.7 years). Further Kato-Katz coproscopy from 97 seropositives
      (geometric mean titer, 619) revealed S. mansoni eggs in 11 subjects (11.3%).
      Serology was deemed useful in screening subjects to be further investigated by
      coproscopy, considering that blood collection had better acceptance than
      supplying fecal samples. Higher than average serological titers may indicate new
      cases in endemic areas. Longitudinal studies associated with epidemiological
      investigation, including titer evolution are advised, as isolated data are
      difficult to interpret.

PMID- 12426589
TI  - Sequencing of simple sequence repeat anchored polymerase chain reaction
      amplification products of Biomphalaria glabrata.
AB  - Simple sequence repeat anchored polymerase chain reaction amplification (SSR-PCR)
      is a genetic typing technique based on primers anchored at the 5' or 3' ends of
      microsatellites, at high primer annealing temperatures. This technique has
      already been used in studies of genetic variability of several organisms, using
      different primer designs. In order to conduct a detailed study of the SSR-PCR
      genomic targets, we cloned and sequenced 20 unique amplification products of two
      commonly used primers, CAA(CT)6 and (CA)8RY, using Biomphalaria glabrata genomic
      DNA as template. The sequences obtained were novel B. glabrata genomic sequences.
      It was observed that 15 clones contained microsatellites between priming sites.
      Out of 40 clones, seven contained complex sequence repetitions. One of the
      repeats that appeared in six of the amplified fragments generated a single band
      in Southern analysis, indicating that the sequence was not widespread in the
      genome. Most of the annealing sites for the CAA(CT)6 primer contained only the
      six repeats found within the primer sequence. In conclusion, SSR-PCR is a useful
      genotyping technique. However, the premise of the SSR-PCR technique, verified
      with the CAA(CT)6 primer, could not be supported since the amplification products
      did not result necessarily from microsatellite loci amplification.

PMID- 12426590
TI  - First report on the presence of Biomphalaria straminea in the municipality of
      Jaboticatubas, State of Minas Gerais, Brazil.
AB  - This is the first report on occurrence of Biomphalaria straminea in the district
      of Sao Jose de Almeida (municipality of Jaboticatubas) State of Minas Gerais,
      Brazil. The presence of B. glabrata and B. tenagophila had already been reported
      in this area. Such municipality is part of the metropolitan region of Belo
      Horizonte and comprises 60% of the Tourist Complex of Serra do Cipo. Since the
      1950s throughout the 1990s, a schistosomiasis prevalence ranging from 15 to 40%
      has been observed. Although no B. straminea specimen has been found naturally
      infected in the region, descendants of these snails collected in the area, showed
      to be experimentally susceptible to Schistosoma mansoni infection reaching rates
      from 14.6 to 28.6%. Even not being found naturally infected, in the State of
      Minas Gerais, the possibility that the species B. straminea may keep endemicity
      foci of schistosomiasis should be regarded, as in the Northeastern region of
      Brazil where the high density of this planorbid and the social-economic and
      sanitary conditions enable to the transmission.

PMID- 12426591
TI  - Identification of snails within the Bulinus africanus group from East Africa by
      multiplex SNaPshot trade mark analysis of single nucleotide polymorphisms within
      the cytochrome oxidase subunit I.
AB  - Identification of populations of Bulinus nasutus and B. globosus from East Africa
      is unreliable using characters of the shell. In this paper, a molecular method of
      identification is presented for each species based on DNA sequence variation
      within the mitochondrial cytochrome oxidase subunit I (COI) as detected by a
      novel multiplexed SNaPshotTM assay. In total, snails from 7 localities from
      coastal Kenya were typed using this assay and variation within shell morphology
      was compared to reference material from Zanzibar. Four locations were found to
      contain B. nasutus and 2 locations were found to contain B. globosus. A mixed
      population containing both B. nasutus and B. globosus was found at Kinango.
      Morphometric variation between samples was considerable and UPGMA cluster
      analysis failed to differentiate species. The multiplex SNaPshotTM assay is an
      important development for more precise methods of identification of B. africanus
      group snails. The assay could be further broadened for identification of other
      snail intermediate host species.

PMID- 12426592
TI  - Schistosomiasis mansoni in Bananal (State of Sao Paulo, Brazil): II. Intermediate
      hosts.
AB  - We conducted monthly snail captures in Bananal, State of Sao Paulo, Brazil,
      between March 1998 and February 2001, to identify Schistosoma mansoni vectors,
      estimate seasonal population changes, and delimit foci. We also evaluated the
      impact of improvements in city water supply and basic sanitation facilities. We
      identified 28,651 vector specimens, 28,438 as Biomphalaria tenagophila, 49 of
      them (0.2%) infected with S. mansoni, and 213 as B. straminea, none of the latter
      infected. Vectors predominated in water bodies having some vegetation along their
      banks. Neither population density nor local vegetation could be linked to vector
      infection. We found the first infected snails in 1998 (from March to May).
      Further captures of infected snails ocurred, without exception, from July to
      December, when rainfall was least. Irrespective of season, overall temperature
      ranged from 16.5 degrees C to 21 degrees C; pH values, from 6.0 to 6.8. Neither
      factor was associated with snail population density. Frequent contact of people
      with the river result from wading across it, extracting sand from its bottom,
      fishing, washing animals, etc. Despite a marked reduction in contamination,
      cercaria shedding persists. Whatever the location along its urban course, contact
      with river Bananal, particularly of the unprotected skin, entails risks of
      infection.

PMID- 12426593
TI  - Freshwater snails and Schistosomiasis mansoni in the state of Rio de Janeiro,
      Brazil: III--Baixadas Mesoregion.
AB  - In this paper, the third of a series dealing with the survey of freshwater
      gastropods of the state of Rio de Janeiro, the results of collections carried out
      in the Mesoregion Baixadas from 2000 to 2002 are presented. Twenty-two species,
      belonging to seven families, were found. As to the snail intermediate hosts of
      Schistosoma mansoni, the most frequent species was Biomphalaria tenagophila
      besides some new findings of Biomphalaria straminea. No specimens were found
      harboring larval forms of S. mansoni although different kinds of cercariae had
      been observed.

PMID- 12426594
TI  - Polymerase chain reaction and restriction fragment length polymorphism of
      cytocrome oxidase subunit I used for differentiation of Brazilian Biomphalaria
      species intermediate host of Schistosoma mansoni.
AB  - The intermediate hosts of Schistosoma mansoni, in Brazil, Biomphalaria glabrata,
      B. tenagophila and B. straminea, were identified by restriction fragment length
      polymorphism analysis of the mitochondrial gene cytochrome oxidase I (COI). We
      performed digestions with two enzymes (AluI and RsaI), previously selected, based
      on sequences available in Genbank. The profiles obtained with RsaI showed to be
      the most informative once they were polymorphic patterns, corroborating with much
      morphological data. In addition, we performed COI digestion of B. straminea
      snails from Uruguay and Argentina.

PMID- 12426595
TI  - Genetic markers between Biomphalaria glabrata snails susceptible and resistant to
      Schistosoma mansoni infection.
AB  - The analysis of the genetic variability related to susceptibility to Schistosoma
      mansoni infection in the vector of the genus Biomphalaria is important in terms
      of a better understanding of the epidemiology of schistosomiasis itself, the
      possible pathological implications of this interaction in vertebrate hosts, and
      the formulation of new strategies and approaches for disease control. In the
      present study, the genetic variability of B. glabrata strains found to be
      resistant or susceptible to S. mansoni infection was investigated using DNA
      amplification by random amplified polymorphic DNA-polymerase chain reaction (RAPD
      PCR). The amplification products were analyzed on 8% polyacrylamide gel and
      stained with silver. We selected 10 primers, since they have previously been
      useful to detect polymorphism among B. glabrata and/or B. tenagophila. The
      results showed polymorphisms with 5 primers. Polymorphic bands observed only in
      the susceptible strain. The RAPD-PCR methodology represents an adequate approach
      for the analysis of genetic polymorphisms. The understanding of the genetic
      polymorphisms associated to resistance may contribute to the future
      identification of genomic sequences related to the resistance/susceptibility of
      Biomphalaria to the larval forms of S. mansoni and to the development of new
      strategies for the control of schistosomiasis.

PMID- 12426596
TI  - Susceptibility of Biomphalaria straminea (Dunker, 1848) from Serra da Mesa Dam,
      Goias, Brazil to infection with three strains of Schistosoma mansoni Sambon,
      1907.
AB  - Ecological changes from water resources development projects often affect the
      epidemiology of water-associated diseases. In order to investigate the occurrence
      and distribution of freshwater snails of medical and veterinary importance in the
      area of influence of the Serra da Mesa Hydroelectric a survey has been performed
      since 1997 and revealed the occurrence of well-established populations of
      Biomphalaria straminea (Dunker, 1848) in the 8 municipalities surrounding the
      lake. Areas of epidemiologic risk for schistosomiasis were selected and studies
      of parasite-mollusc compatibility were undertaken using specimens from 19
      populations of B. straminea and 3 strains (CM, EC and PB) originally isolated
      from B. straminea. Among 1,135 specimens used 15 became infected (infection index
      of 1.3%) and 8 populations were susceptible to the schistosome strains: B.
      straminea from Campinorte (Castelao, susceptible to CM and EC strains, and
      Planeta Agua, EC strain), Colinas (Tocantinzinho river, CM and EC strains),
      Minacu (Canabrava river, EC strain), Niquelandia (Codemin, CM and PB strains, and
      Almas river, CM strain), Uruacu (touristic area, PB strain) and Santa Rita do
      Novo Destino (Maranhao river, CM and EC strains). These results, associated with
      marked social and ecological changes occurred, strongly suggest the possibility
      of B. straminea coming to act as a vector of schistosomiasis in the studied area.

PMID- 12426597
TI  - Clustering of Schistosoma mansoni mRNA sequences and analysis of the most
      transcribed genes: implications in metabolism and biology of different
      developmental stages.
AB  - The study of the Schistosoma mansoni genome, one of the etiologic agents of human
      schistosomiasis, is essential for a better understanding of the biology and
      development of this parasite. In order to get an overview of all S. mansoni
      catalogued gene sequences, we performed a clustering analysis of the parasite
      mRNA sequences available in public databases. This was made using softwares PHRAP
      and CAP3. The consensus sequences, generated after the alignment of cluster
      constituent sequences, allowed the identification by database homology searches
      of the most expressed genes in the worm. We analyzed these genes and looked for a
      correlation between their high expression and parasite metabolism and biology. We
      observed that the majority of these genes is related to the maintenance of basic
      cell functions, encoding genes whose products are related to the cytoskeleton,
      intracellular transport and energy metabolism. Evidences are presented here that
      genes for aerobic energy metabolism are expressed in all the developmental stages
      analyzed. Some of the most expressed genes could not be identified by homology
      searches and may have some specific functions in the parasite.

PMID- 12426598
TI  - Characterization of new Schistosoma mansoni microsatellite loci in sequences
      obtained from public DNA databases and microsatellite enriched genomic libraries.
AB  - In the last decade microsatellites have become one of the most useful genetic
      markers used in a large number of organisms due to their abundance and high level
      of polymorphism. Microsatellites have been used for individual identification,
      paternity tests, forensic studies and population genetics. Data on microsatellite
      abundance comes preferentially from microsatellite enriched libraries and DNA
      sequence databases. We have conducted a search in GenBank of more than 16,000
      Schistosoma mansoni ESTs and 42,000 BAC sequences. In addition, we obtained 300
      sequences from CA and AT microsatellite enriched genomic libraries. The sequences
      were searched for simple repeats using the RepeatMasker software. Of 16,022 ESTs,
      we detected 481 (3%) sequences that contained 622 microsatellites (434 perfect,
      164 imperfect and 24 compounds). Of the 481 ESTs, 194 were grouped in 63 clusters
      containing 2 to 15 ESTs per cluster. Polymorphisms were observed in 16 clusters.
      The 287 remaining ESTs were orphan sequences. Of the 42,017 BAC end sequences,
      1,598 (3.8%) contained microsatellites (2,335 perfect, 287 imperfect and 79
      compounds). The 1,598 BAC end sequences 80 were grouped into 17 clusters
      containing 3 to 17 BAC end sequences per cluster. Microsatellites were present in
      67 out of 300 sequences from microsatellite enriched libraries (55 perfect, 38
      imperfect and 15 compounds). From all of the observed loci 55 were selected for
      having the longest perfect repeats and flanking regions that allowed the design
      of primers for PCR amplification. Additionally we describe two new polymorphic
      microsatellite loci.

PMID- 12426599
TI  - Cis-acting elements, CArG-, E-, CCAAT- and TATA-boxes may be involved in sexually
      regulated gene transcription in Schistosoma mansoni.
AB  - Schistosomes undergo various morphological and metabolic changes during their
      development, reflected in a finely tuned regulation of protein and/or gene
      expression. The mechanisms involved in the control of gene expression during the
      development of the parasite are not understood. Two actin genes had been
      previously cloned and observed to be differentially expressed during the
      maturation of the parasite. The SmAct gene contains four putative cis-regulatory
      elements (TATA-, CCAAT-, E- and CArG-boxes). Our objective was to investigate in
      greater detail the expression pattern of two actin genes and verify if the
      binding of nuclear proteins to the promoter elements of SmAct correlated with the
      expression profile observed. We detected little variation in the expression of
      actin genes during the first seven days of schistosomula culture in vitro.
      However, we observed significantly higher levels of expression in males compared
      to female adults. CArG and CCAAT elements bound to a greater extent and formed
      distinct complexes with male in comparison to female nuclear extracts. In
      contrast, female extracts bound weakly to the E-box probe while no binding was
      observed with male extracts. Taken together these results describe cis-acting
      elements that appear to be involved in sexually regulated gene expression in
      Schistosoma mansoni.

PMID- 12426600
TI  - Partial molecular characterization of Sm8, a tegumental antigen of Schistosoma
      mansoni.
AB  - Sm8 is a major tegumental antigen of Schistosoma mansoni. The partial cDNA was
      isolated and analyzed. Sequence analysis revealed transmembrane compatible
      hydrophobic domains and a putative leucine zipper pattern. The mRNA and the
      protein are predominantly expressed in adult worms.

PMID- 12426601
TI  - A Multiplex-PCR approach to identification of the Brazilian intermediate hosts of
      Schistosoma mansoni.
AB  - Due to difficulties concerning morphological identification of planorbid snails
      of the genus Biomphalaria, and given a high variation of characters and in the
      organs with muscular tissue, we designed specific polymerase chain reaction (PCR)
      primers for Brazilian snail hosts of Schistosoma mansoni from available sequences
      of internal transcribed spacer 2 (ITS2) of the ribosomal RNA gene. From the
      previous sequencing of the ITS2 region, one primer was designed to anchor in the
      5.8S conserved region and three other species-specific primers in the 28S region,
      flanking the ITS2 region. These four primers were simultaneously used in the same
      reaction (Multiplex-PCR), under high stringency conditions. Amplification of the
      ITS2 region of Biomphalaria snails produced distinct profiles (between 280 and
      350 bp) for B. glabrata, B. tenagophila and B. straminea. The present study
      demonstrates that Multiplex-PCR of ITS2-DNAr showed to be a promising auxiliary
      tool for the morphological identification of Biomphalaria snails, the
      intermediate hosts of S. mansoni.

PMID- 12426602
TI  - Antigenic community between Schistosoma mansoni and Biomphalaria glabrata: on the
      search of candidate antigens for vaccines.
AB  - We have previously confirmed the presence of common antigens between Schistosoma
      mansoni and its vector, Biomphalaria glabrata. Cross-reactive antigens may be
      important as possible candidates for vaccine and diagnosis of schistosomiasis.
      Sera from outbred mice immunized with a soluble Biomphalaria glabrata antigen
      (SBgA) of non-infected B. glabrata snails recognized molecules of SBgA itself and
      S. mansoni AWA by Western blot. Recognition of several molecules of the SBgA were
      inhibited by pre-incubation with AWA (16, 30, 36, 60 and 155 kDa). The only
      specific molecule of AWA, inhibited by SBgA, was a 120 kDa protein. In order to
      determine which epitopes of SBgA were glycoproteins, the antigen was treated with
      sodium metaperiodate and compared with non-treated antigen. Molecules of 140, 60
      and 24 kDa in the SBgA appear to be glycoproteins. Possible protective effects of
      the SBgA were evaluated immunizing outbred mice in two different experiments
      using Freund's Adjuvant. In the first one (12 mice/group), we obtained a
      significant level of protection (46%) in the total worm load, with a high
      variability in worm recovery. In the second experiment (22 mice/group), no
      significant protection was observed, neither in worm load nor in egg production
      per female. Our results suggest that SBgA constitutes a rich source of candidate
      antigens for diagnosis and prophylactic studies.

PMID- 12426603
TI  - Protective immunity of single and multi-antigen DNA vaccines against
      schistosomiasis.
AB  - We evaluated the usefulness of the combination of three plasmids encoding
      tegumental (pECL and pSM14) and muscular (pIRV5) antigens of the Schistosoma
      mansoni on improving the protective immunity over the use of a single antigen as
      DNA vaccines. Female BALB/c mice were inoculated twice with 25 micro g DNA
      plasmid within two weeks interval. The challenge was performed with 80 cercarias
      of a regional isolate of S. mansoni (SLM) one week after the last immunization.
      Six weeks after challenge, all mice were perfused for worm load determination.
      The following groups were analyzed: saline; empty vector; monovalent formulations
      of pECL; pSM14 and pIRV5 and also double combinations of pECL/pIRV5 and
      pIRV5/pSM14 and a triple combination of pECL/pIRV5/pSM14. The protection was
      expressed as a percentage of worm loads in each group compared with the saline
      group. The results obtained were 41% (p < 0.05); 52% (p < 0.05); 51% (p < 0.05);
      48% (p < 0.05); 55% (p < 0.05); 45% (p < 0.05); 65% (p < 0.05) for each group
      respectively.

PMID- 12426604
TI  - Antibody isotype responses to egg antigens in human chronic Schistosomiasis
      mansoni before and after treatment.
AB  - In the present communication we analyzed the levels of IgG1, IgG2, IgG3, IgG4 and
      IgE isotypes to soluble egg antigen of Schistosoma mansoni by ELISA in
      individuals from an endemic area for schistosomiasis in Northeast Brazil. The
      analysis was performed before and after treatment to evaluate the age-dependent
      pattern, and to identify differences in the reactivities to antigens. Our results
      suggest that schistosomiasis treatment would not interfere with this sort of
      immune response.

PMID- 12426605
TI  - Studies on the production and regulation of interleukin, IL-13, IL-4 and
      interferon-gamma in human Schistosomiasis mansoni.
AB  - The production and regulation of interleukin (IL) IL-13, IL-4 and interferon
      gamma was evaluated in different clinical forms of human schistosomiasis. The
      mechanisms of immune regulation are apparently different in the various clinical
      stages of the disease, some of them being antigen specific.

PMID- 12426606
TI  - Characterization of Sm14 related components in different helminths by sodium
      dodecyl sulphate-polyacrylamide gel electrophoresis and Western blotting
      analysis.
AB  - Sm14 was the first fatty acid-binding protein homologue identified in helminths.
      Thereafter, members of the same family were identified in several helminth
      species, with high aminoacid sequence homology between them. In addition, immune
      crossprotection was also reported against Fasciola hepatica infection, in animals
      previously immunized with the Schistosoma mansoni vaccine candidate, r-Sm14. In
      the present study, data on preliminary sodium dodecyl sulphate-polyacrylamide gel
      electrophoresis and Western blotting analysis of nine different helminth extracts
      focusing the identification of Sm14 related proteins, is reported. Out of these,
      three extracts - Ascaris suum (males and females), Echinostoma paraensei, and
      Taenia saginata - presented components that comigrated with Sm14 in SDS-PAGE, and
      that were recognized by anti-rSm14 policlonal serum, in Western blotting tests.

PMID- 12426607
TI  - Intestinal fibrovascular nodules caused by Schistosoma mansoni infection in
      Calomys callosus Rengger, 1830 (Rodentia: Cricetidae): a model of concomitant
      fibrosis and angiogenesis.
AB  - Human schistosomiasis develops extensive and dense fibrosis in portal space,
      together with congested new blood vessels. This study demonstrates that Calomys
      callosus infected with Schistosoma mansoni also develops fibrovascular lesions,
      which are found in intestinal subserosa. Animals were percutaneously infected
      with 70 cercariae and necropsied at 42, 45, 55, 80, 90 and 160 days after
      infection. Intestinal sections were stained for brightfield, polarization
      microscopy, confocal laser scanning, transmission and scanning electron
      microscopies. Immunohistological analysis was also performed and some nodules
      were aseptically collected for cell culture. Numerous intestinal nodules,
      appearing from 55 up to 160 days after infection, were localized at the interface
      between external muscular layer and intestinal serosa, consisting of
      fibrovascular tissue forming a shell about central granuloma(s). Intranodular new
      vessels were derived from the vasculature of the external vascular layer and were
      positive for laminin, chondroitin-sulfate, smooth muscle alpha-actin and FVIII
      RA. Fibroblastic cells and extracellular matrix components (collagens I, III and
      VI, fibronectin and tenascin) comprised the stroma. Intermixed with the
      fibroblasts and vessels there were variable number of eosinophils, macrophages
      and haemorrhagic foci. In conclusion, the nodules constitute an excellent and
      accessible model to study fibrogenesis and angiogenesis, dependent on S. mansoni
      eggs. The fibrogenic activity is fibroblastic and not myofibroblastic-dependent.
      The angiogenesis is so prominent that causes haemorrhagic ascites.

PMID- 12426608
TI  - Natural Schistosoma mansoni infection in Nectomys squamipes: histopathological
      and morphometric analysis in comparison to experimentally infected N. squamipes
      and C3H/He mice.
AB  - Histopathologic and morphometric (area, perimeter, major and minor diameters)
      analysis of hepatic granulomas isolated from twelve naturally infected Nectomys
      squamipes were compared to four experimentally infected ones and six C3H/He mice.
      Liver paraffin sections were stained for cells and extracellular matrix. Both
      groups of N. squamipes presented peculiar granulomas consisting predominantly of
      large macrophages, full of schistosome pigment, characterizing an exudative
      macrophage granuloma type, smaller than the equivalent granuloma type in mouse.
      Naturally infected animals exhibited granulomas in different stages of
      development, including large number of involutional types. Morphometric analysis
      showed that all measurements were smaller in naturally infected animals than in
      other groups. The results demonstrated that both N. squamipes groups reproduced,
      with small variations, the hepatic granuloma aspects already described in
      cricetidium (Calomys callosus), showing a genetic tendency to set up strong
      macrophage responses and small granulomas. Unexpectedly, natural infection did
      not engender distinguished histopathological characteristics distinct from those
      derived from experimental single infection, showing changes predominantly
      secondary to the duration of infection. It appears that the variability of the
      inocula (and the number of infections?) interfere more with the quantity than
      with the quality of the pathological changes, denoting some morpho-functional
      determinism in the response to schistosomal infection dependent on the animal
      species.

PMID- 12426609
TI  - Parasitological characteristics of Schistosoma mansoni infection in swiss mice
      with underlying malnutrition.
AB  - The effects of a protein-restricted diet (8% protein, 81% carbohydrate and 11%
      lipids) on Schistosoma mansoni infectivity, fecal egg excretion and intestinal
      egg distribution in Swiss (SW) mice were studied. Pregnant mice received a
      deficient diet from the middle of gestation until delivery. Seven-days-old mice
      were exposed to 50 cercariae (BH strain, Brazil). Offspring mice had a free
      access to the deficient diet since lactation until adulthood. The controls were
      fed with a commercial mice diet. A parasitological examination was performed
      between six and eight weeks post-infection while both groups were necropsied one
      week later. Mice on the experimental diet showed a significant loss in body
      weight. There was no significant difference (p > 0.05) in pre-patent period,
      kinetics of egg excretion and worm recovery from mice on either diet. Significant
      differences (p < 0.05) were found concerning to the percentage of deposited eggs
      in the distal segment of the small intestine from hosts on the experimental diet.
      Our data suggest that experimental malnutrition induced for a long term has no
      detrimental effect on the acute schistosomiais infection in SW mice.

PMID- 12426610
TI  - Ultrasound monitoring of structural urinary tract disease in Schistosoma
      haematobium infection.
AB  - A major advance in our understanding of the natural history of Schistosoma
      haematobium-related morbidity has come through the introduction of the portable
      ultrasound machines for non-invasive examination of the kidneys and bladder. With
      the use of generators or battery packs to supply power in non-clinical field
      settings, and with the use of instant photography or miniaturized thermal
      printers to record permanent images, it is possible to examine scores of
      individuals in endemic communities every day. Broad-based ultrasound screening
      has allowed better definition of age-specific disease risks in urinary
      schistosomiasis. Results indicate that urinary tract abnormalities are common
      (18% overall prevalence) in S. haematobium transmission areas, with a 2-4% risk
      of either severe bladder abnormality or advanced ureteral obstruction. In
      longitudinal surveys, ultrasound studies have shown that praziquantel and
      metrifonate therapy are rapidly effective in reversing urinary tract
      abnormalities among children. The benefits of treating adults are less well
      known, but research in progress should help to define this issue. Similarly, the
      prognosis of specific ultrasound findings needs to be clarified, and the ease of
      sonographic examination will make such long-term follow-up studies feasible. In
      summary, the painless, quick, and reproducible ultrasound examination has become
      an essential tool in the study of urinary schistosomiasis.

PMID- 12426611
TI  - Schistosomiasis mansoni in low transmission areas: abdominal ultrasound.
AB  - In endemic areas with low prevalence and low intensity of infection, the
      diagnosis of hepatic pathology due to the Schistosoma mansoni infection is very
      difficult. In order to establish the hepatic morbidity, a double-blind study was
      achieved in Venezuelan endemic areas, with one group of patients with
      schistosomiasis and the other one of non-infected people, that were evaluated
      clinically and by abdominal ultrasound using the Cairo classification.
      Schistosomiasis diagnosis was established based on parasitologic and serological
      tests. The increase of the hepatic size at midclavicular and midsternal lines (in
      hepatometry) and the hard liver consistency were the clinical parameters able to
      differentiate infected persons from non infected ones, as well as the presence of
      left lobe hepatomegaly detected by abdominal ultrasound. The periportal
      thickening, especially the mild form, was frequent in all age groups in both
      infected and uninfected patients. There was not correlation between the intensity
      of infection and ultrasound under the current circumstances. Our data suggest
      that in Venezuela, a low endemic area of transmission of schistosomiasis, the
      hepatic morbidity is mild and uncommon. The Cairo classification seems to
      overestimate the prevalence of periportal pathology. The specificity of the
      method must be improved, especially for the recognition of precocious pathology.
      Other causes of hepatopathies must be investigated.

PMID- 12426612
TI  - Retinal fluorescein contrast arrival time of young patients with the
      hepatosplenic form of the Schistosomiasis mansoni.
AB  - Schistosoma mansoni is responsible for lesions that can alter the hemodinamic of
      the portal venous circulation, lung arterial and venous sistemic systems.
      Therefore, hemodinamic changes in the ocular circulation of mansonic
      schistosomotic patients with portal hypertension and hepatofugal venous blood
      flow is also probable. The purpose of this study was to determine the fluorescein
      contrast arrival time at the retina of young patients with the hepatosplenic form
      of schistosomiasis, clinically and surgically treated. The control group included
      36 non schistosomotic patients, mean age of 17.3 years, and the case group was
      represented by 25 schistosomotic patients, mean age of 18.2 years, who were cared
      for at The University Hospital (Federal University of Pernambuco, Brazil), from
      1990 to 2001. They underwent digital angiofluoresceinography and were evaluated
      for the contrast arrival time at the early retinal venous phase of the exam. Both
      groups were ophthalmologically examined at the same hospital (Altino Ventura
      Foundation, Recife, Brazil), using the same technique. There was retardation of
      the retinal contrast arrival time equal or more than 70 sec in the eyes of three
      schistosomotic patients (12%) and in none of the control group, however, the mean
      contrast arrival time between the two groups were not statistically different.
      These findings lend support to the hypothesis that there could be a delay of the
      eye venous blood flow drainage.

PMID- 12426613
TI  - Surgical indication in Schistosomiasis mansoni portal hypertension: follow-up
      from 1985 to 2001.
AB  - The study had the objective to evaluate the benefits of surgical indication for
      portal hypertension in schistosomiasis patients followed from 1985 to 2001.
      Schistosoma mansoni eggs were confirmed by at least six stool examinations or
      rectal biopsy. Clinical examination, abdominal ultrasonography, and digestive
      endoscopy confirmed the diagnosis of esophageal varices. A hundred and two
      patients, 61.3% male (14-53 years old) were studied. Digestive hemorrhage,
      hypersplenism, left hypochondrial pain, abdominal discomfort, and hypogonadism
      were, in a decreasing order, the major signs and symptoms determining surgical
      indication. Among the surgical techniques employed, either splenectomy associated
      to splenorenal anastomosis or azigoportal desvascularization, esophageal gastric
      descompression and esophageal sclerosis were used. Follow-up of patients revealed
      that, independent on the technique utilized, a 9.9% of death occurred, caused
      mainly by digestive hemorrhage due to the persistence of post-treatment varices.
      The authors emphasize the benefits of elective surgical indication allowing a
      normal active life.

PMID- 12426614
TI  - Laboratory diagnosis of Schistosomiasis in areas of low transmission: a review of
      a line of research.
AB  - After 57 years of successful control of schistosomiasis in Venezuela, the
      prevalence and intensity of infection have declined. Approximately 80% of the
      individuals eliminate less than 100 eggs/g of stools, therefore morbidity is mild
      and the majority are asymptomatic. The sensitivity of Kato-Katz decreases to
      approximately 60%. Available serological methods for the detection of circulating
      antigens only reach a 70% of sensitivity. Tests based on the detection of
      antibodies by immunoenzymatic assays have been improved. The circumoval
      precipitine test has shown a high sensitivity (97%), specificity (100%), and
      correlation with oviposition, being considered the best confirmatory diagnostic
      test. Additionally to the classical immunoenzymatic assays, the development of
      the alkaline phosphatase immunoassay, allowed to reach a 100% specificity with an
      89% sensitivity. Recently, we have developed a modified ELISA in which the
      soluble egg antigen is treated with sodium metaperiodate (SMP-ELISA) in order to
      eliminate the glycosilated epitopes responsible for the false positive reactions.
      The specificity and sensitivity reaches 97% and 99%, respectively. Synthetic
      peptides from the excretory-secretory enzymes, cathepsin B (Sm31) legumain (Sm32)
      and cathepsin D (Sm45), have been synthesized. The combination of two peptides
      derived from the Sm31 have been evaluated, reaching a sensitivity of 96% when
      analyzed independently and with a 100% specificity. Antibodies raised in rabbits
      against peptides derived from the Sm31 and Sm32 are currently evaluated in two
      different antigen-capture-based assays. The development of a simple, cheap and
      reliable test that correlates with parasite activity is a major goal.

PMID- 12426615
TI  - Recent advances in the diagnosis of Schistosoma infection: the detection of
      parasite DNA.
AB  - As Schistosoma sp. control programs are chiefly based on treatment of infected
      population, adequate case finding has a crucial role. The available diagnostic
      methods are far from ideal, since the search for eggs in stools and the detection
      of circulating antigens lack sensitivity in low prevalence and post-treatment
      situations and antibody detection lacks specificity. In most endemic foci,
      repeated treatment of infected people leaves a number of non-diagnosed and
      consequently non-treated persons, enough to maintain a persistent residue of 5 to
      10% prevalence. In an attempt to surpass these diagnostic limitations we have
      developed a polymerase chain reaction (PCR) for the detection of Schistosoma sp.
      in feces that, in a first population study, has shown to be more sensitive than
      three-repeated stool Kato-Katz examination. The PCR may constitute a valuable
      tool for the diagnosis of the Schistosoma sp. infection in special situations,
      when high sensitivity and specificity are required and infrastructure is
      available.

PMID- 12426616
TI  - The effect of treatment on the age-antibody relationship in children infected
      with Schistosoma mansoni and Schistosoma haematobium.
AB  - The effect of praziquantel treatment on the age-antibody relationship was studied
      in 174 children aged between 6 and 17 years from a schistosome endemic area in
      Zimbabwe. The children were co-infected with Schistosoma mansoni and S.
      haematobium with infection prevalences of 74% and 53% respectively. Antibody
      levels for the isotypes IgA, IgE, IgM, IgG1, IgG2, IgG3 and IgG4, directed
      against soluble egg antigen were measured using an indirect ELISA assay.
      Treatment resulted in a significant increase in levels of IgG2 and IgG3 while
      levels of IgA decreased significantly. In untreated children there were
      significant decreases in levels of IgG4. Treatment also resulted in significant
      alteration in the age-antibody profiles for the isotypes IgE, IgM, IgG1 and IgG2
      in treated children but not in untreated children. The results are discussed in
      the context of factors believed to give rise to the age-antibody relationship;
      i.e. age-related exposure patterns, age-related development of acquired immunity,
      age-related hormonal changes and age-related changes in innate susceptibility to
      infection.

PMID- 12426617
TI  - Schistosomiasis mansoni in Bananal (State of Sao Paulo, Brazil): I. Efficiency of
      diagnostic and treatment procedures.
AB  - Bananal is an important focus of Schistosoma mansoni in the State of Sao Paulo.
      Accordingly, programmed active search for human cases, annual coproscopic surveys
      and treatment of infected cases were started in 1998, aiming at producing a sharp
      prevalence rate drop by the year 2000. S. mansoni eggs were searched for in two
      Kato-Katz slides per patient. Cases were followed up according to the routine of
      the local Family Health Program. In 1998, 130 samples out of 3,860 showed S.
      mansoni eggs; in 1999, 105 out of 3,550, and in 2000, 64 out of 3,528. Prevalence
      rates were 3.4%, 2.9%, and 1.8%, and average egg-counts 59, 64, and 79 eggs per
      gram of feces respectively. Prevalence rates decreased steadily after treatment,
      but persistently positive cases showed no significant decrease in parasite
      burdens. Egg count variation depended on sex and age bracket. Persistent residual
      cases admittedly preclude the eradication of this infection by only searching for
      and treating carriers. In addition, resistance to therapy and low sensitivity of
      fecal examinations, can not be ignored. Moderate to heavy worm burdens,
      frequently associated with hepatomegaly elsewhere, produced no serious cases in
      Bananal.

PMID- 12426618
TI  - Achievements of schistosomiasis control in China.
AB  - The control of schistosomiasis has been spectacularly successful in terms of
      controlling endemicity and severity of the disease during the last 50 years. It
      can be categorized into two stages. From 1955 through 1980, the transmission
      control strategy had been widely and successfully carried out. By the end of
      1980, the epidemic of schistosomiasis was successfully circumscribed in certain
      core regions including areas at the middle and low reaches of the Yangtze River
      and some mountainous areas in Sichuan and Yunnan provinces, where control of
      schistosomiasis had been demonstrated to be very difficult to be sustained.
      Therefore, since 1980, schistosomiasis control in China has been modified to
      employ a stepwise strategy, based on which morbidity control has been given
      priorities and if possible transmission control has been pursued. However, since
      snail-ridden areas remain unchanged so far, reinfections occur frequently. This
      necessitates a maintenance phase to consolidate the achievements in the control
      of schistosomiasis. In the mean time, we are challenged with some environmental,
      social and economical changes in terms of controlling schistosomiasis.
      Successfully controlling schistosomiasis in China is still a long-term task but
      will be achieved without doubt along with the economic development and the
      promotion of living and cultural standard of people.

PMID- 12426623
TI  - The role of CD8+ T cells during allograft rejection.
AB  - Organ transplantation can be considered as replacement therapy for patients with
      end-stage organ failure. The percent of one-year allograft survival has increased
      due, among other factors, to a better understanding of the rejection process and
      new immunosuppressive drugs. Immunosuppressive therapy used in transplantation
      prevents activation and proliferation of alloreactive T lymphocytes, although not
      fully preventing chronic rejection. Recognition by recipient T cells of
      alloantigens expressed by donor tissues initiates immune destruction of
      allogeneic transplants. However, there is controversy concerning the relative
      contribution of CD4+ and CD8+ T cells to allograft rejection. Some animal models
      indicate that there is an absolute requirement for CD4+ T cells in allogeneic
      rejection, whereas in others CD4-depleted mice reject certain types of
      allografts. Moreover, there is evidence that CD8+ T cells are more resistant to
      immunotherapy and tolerance induction protocols. An intense focal infiltration of
      mainly CD8+CTLA4+ T lymphocytes during kidney rejection has been described in
      patients. This suggests that CD8+ T cells could escape from immunosuppression and
      participate in the rejection process. Our group is primarily interested in the
      immune mechanisms involved in allograft rejection. Thus, we believe that a better
      understanding of the role of CD8+ T cells in allograft rejection could indicate
      new targets for immunotherapy in transplantation. Therefore, the objective of the
      present review was to focus on the role of the CD8+ T cell population in the
      rejection of allogeneic tissue.

PMID- 12426624
TI  - A mathematical framework for group analysis of von Willebrand factor multimeric
      composition following luminography.
AB  - The objective of the present study was to establish a method for quantitative
      analysis of von Willebrand factor (vWF) multimeric composition using a
      mathematical framework based on curve fitting. Plasma vWF multimers from 15
      healthy subjects and 13 patients with advanced pulmonary vascular disease were
      analyzed by Western immunoblotting followed by luminography. Quantitative
      analysis of luminographs was carried out by calculating the relative densities of
      low, intermediate and high molecular weight fractions using laser densitometry.
      For each densitometric peak (representing a given fraction of vWF multimers) a
      mean area value was obtained using data from all group subjects (patients and
      normal individuals) and plotted against the distance between the peak and IgM
      (950 kDa). Curves were constructed for each group using nonlinear fitting.
      Results indicated that highly accurate curves could be obtained for healthy
      controls and patients, with respective coefficients of determination (r2) of
      0.9898 and 0.9778. Differences were observed between patients and normal subjects
      regarding curve shape, coefficients and the region of highest protein
      concentration. We conclude that the method provides accurate quantitative
      information on the composition of vWF multimers and may be useful for comparisons
      between groups and possibly treatments.

PMID- 12426625
TI  - Plasma free and total carnitine measured in children by tandem mass spectrometry.
AB  - Free and total carnitine quantification is important as a complementary test for
      the diagnosis of unusual metabolic diseases, including fatty acid degradation
      disorders. The present study reports a new method for the quantification of free
      and total carnitine in dried plasma specimens by isotope dilution electrospray
      tandem mass spectrometry with sample derivatization. Carnitine is determined by
      looking for the precursor of ions of m/z = 103 of N-butylester derivative, and
      the method is validated by comparison with radioenzymatic assay. We obtained an
      inter- and intra-day assay coefficient of variation of 4.3 and 2.3, respectively.
      Free and total carnitine was analyzed in 309 dried plasma spot samples from
      children ranging in age from newborn to 14 years using the new method, which was
      found to be suitable for calculating reference age-related values for free and
      total carnitine (less than one month: 19.3 +/- 2.4 and 23.5 +/- 2.9; one to
      twelve months: 28.8 +/- 10.2 and 35.9 +/- 11.4; one to seven years: 30.7 +/- 10.3
      and 38.1 +/- 11.9; seven to 14 years: 33.7 +/- 11.6, and 43.1 +/- 13.8 micro M,
      respectively). No difference was found between males and females. A significant
      difference was observed between neonates and the other age groups. We compare our
      data with reference values in the literature, most of them obtained by
      radioenzymatic assay. However, this method is laborious and time consuming. The
      electrospray tandem mass spectrometry method presented here is a reliable, rapid
      and automated procedure for carnitine quantitation.

PMID- 12426626
TI  - The decrease in uroporphyrinogen decarboxylase activity induced by ethanol
      predisposes rats to the development of porphyria and accelerates xenobiotic
      triggered porphyria, regardless of hepatic damage.
AB  - We evaluated the porphyrinogenic ability of ethanol (20% in drinking water) per
      se, its effect on the development of sporadic porphyria cutanea tarda induced by
      hexachlorobenzene in female Wistar rats (170-190 g, N = 8/group), and the
      relationship with hepatic damage. Twenty-five percent of the animals receiving
      ethanol increased up to 14-, 25-, and 4.5-fold the urinary excretion of delta
      aminolevulinate, porphobilinogen, and porphyrins, respectively. Ethanol
      exacerbated the precursor excretions elicited by hexachlorobenzene. Hepatic
      porphyrin levels increased by hexachlorobenzene treatment, while this parameter
      only increased (up to 90-fold) in some of the animals that received ethanol
      alone. Ethanol reduced the activities of uroporphyrinogen decarboxylase, delta
      aminolevulinate dehydrase and ferrochelatase. In the ethanol group, many of the
      animals showed a 30% decrease in uroporphyrinogen activity; in the ethanol +
      hexachlorobenzene group, this decrease occurred before the one caused by
      hexachlorobenzene alone. Ethanol exacerbated the effects of hexachlorobenzene,
      among others, on the rate-limiting enzyme delta-aminolevulinate synthetase. The
      plasma activities of enzymes that are markers of hepatic damage were similar in
      all drug-treated groups. These results indicate that 1) ethanol exacerbates the
      biochemical manifestation of sporadic hexachlorobenzene-induced porphyria cutanea
      tarda; 2) ethanol per se affects several enzymatic and excretion parameters of
      the heme metabolic pathway; 3) since not all the animals were affected to the
      same extent, ethanol seems to be a porphyrinogenic agent only when there is a
      predisposition, and 4) hepatic damage showed no correlation with the development
      of porphyria cutanea tarda.

PMID- 12426627
TI  - Clinical assessment of the effect of digital filtering on the detection of
      ventricular late potentials.
AB  - Ventricular late potentials are low-amplitude signals originating from damaged
      myocardium and detected on the body surface by ECG filtering and averaging.
      Digital filters present in commercial equipment may interfere with the ability of
      arrhythmia stratification. We compared 40-Hz BiSpec (BI) and classical 40- to 250
      Hz band-pass Butterworth bidirectional (BD) filters in terms of impact on time
      domain variables and diagnostic properties. In a transverse retrospective age
      adjusted case-control study, 221 subjects with sinus rhythm without bundle branch
      block were divided into three groups after signal-averaged ECG acquisition: GI (N
      = 40), clinically normal controls, GII (N = 158), subjects with coronary heart
      disease without sustained monomorphic ventricular tachycardia (SMVT), and GIII (N
      = 23), subjects with heart disease and documented SMVT. Conventional variables
      analyzed from vector magnitude data after averaging to 0.3 micro V final noise
      were obtained by application of each filter to the averaged signal, and evaluated
      in pairs by numerical comparison and by diagnostic agreement assessment, using
      conventional and optimized thresholds of normality. Significant differences were
      found between BI and BD variables in all groups, with diagnostic results showing
      significant disagreement between both filters [kappa value of 0.61 (P<0.05) for
      GII and 0.31 for GIII (P = NS)]. Sensitivity for SMVT was lower with BI than with
      BD (65.2 vs 91.3%, respectively, P<0.05). Filters provided significantly
      different numerical and diagnostic results and the BI filter showed only limited
      clinical application to risk stratification of ventricular arrhythmia.

PMID- 12426628
TI  - Antimicrobial resistance among invasive Haemophilus influenzae strains: results
      of a Brazilian study carried out from 1996 through 2000.
AB  - A total of 1712 strains of Haemophilus influenzae isolated from patients with
      invasive diseases were obtained from ten Brazilian states from 1996 to 2000. beta
      Lactamase production was assessed and the minimum inhibitory concentrations (MIC)
      of ampicillin, chloramphenicol, ceftriaxone and rifampin were determined using a
      method for broth microdilution of Haemophilus test medium. The prevalence of
      strains producing beta-lactamase ranged from 6.6 to 57.7%, with an overall
      prevalence of 18.4%. High frequency of beta-lactamase-mediated ampicillin
      resistance was observed in Distrito Federal (25%), Sao Paulo (21.7%) and Parana
      (18.5%). Of the 1712 strains analyzed, none was beta-lactamase negative,
      ampicillin resistant. A total of 16.8% of the strains were resistant to
      chloramphenicol, and 13.8% of these also presented resistance to ampicillin, and
      only 3.0% were resistant to chloramphenicol alone. All strains were susceptible
      to ceftriaxone and rifampin and the MIC90 were 0.015 micro g/ml and 0.25 micro
      g/ml, respectively. Ceftriaxone is the drug of choice for empirical treatment of
      bacterial meningitis in pediatric patients who have not been screened for drug
      susceptibility. The emergence of drug resistance is a serious challenge for the
      management of invasive H. influenzae disease, which emphasizes the fundamental
      role of laboratory-based surveillance for antimicrobial resistance.

PMID- 12426629
TI  - Nitric oxide, cholesterol oxides and endothelium-dependent vasodilation in plasma
      of patients with essential hypertension.
AB  - The objective of the present study was to identify disturbances of nitric oxide
      radical (.NO) metabolism and the formation of cholesterol oxidation products in
      human essential hypertension. The concentrations of.NO derivatives (nitrite,
      nitrate, S-nitrosothiols and nitrotyrosine), water and lipid-soluble antioxidants
      and cholesterol oxides were measured in plasma of 11 patients with mild essential
      hypertension (H: 57.8 +/- 9.7 years; blood pressure, 148.3 +/- 24.8/90.8 +/- 10.2
      mmHg) and in 11 healthy subjects (N: 48.4 +/- 7.0 years; blood pressure, 119.4 +/
      9.4/75.0 +/- 8.0 mmHg). Nitrite, nitrate and S-nitrosothiols were measured by
      chemiluminescence and nitrotyrosine was determined by ELISA. Antioxidants were
      determined by reverse-phase HPLC and cholesterol oxides by gas chromatography.
      Hypertensive patients had reduced endothelium-dependent vasodilation in response
      to reactive hyperemia (H: 9.3 and N: 15.1% increase of diameter 90 s after
      hyperemia), and lower levels of ascorbate (H: 29.2 +/- 26.0, N: 54.2 +/- 24.9
      micro M), urate (H: 108.5 +/- 18.9, N: 156.4 +/- 26.3 micro M), beta-carotene (H:
      1.1 +/- 0.8, N: 2.5 +/- 1.2 nmol/mg cholesterol), and lycopene (H: 0.4 +/- 0.2,
      N: 0.7 +/- 0.2 nmol/mg cholesterol), in plasma, compared to normotensive
      subjects. The content of 7-ketocholesterol, 5alpha-cholestane-3beta,5,6beta-triol
      and 5,6alpha-epoxy-5alpha-cholestan-3alpha-ol in LDL, and the concentration of
      endothelin-1 (H: 0.9 +/- 0.2, N: 0.7 +/- 0.1 ng/ml) in plasma were increased in
      hypertensive patients. No differences were found for.NO derivatives between
      groups. These data suggest that an increase in cholesterol oxidation is
      associated with endothelium dysfunction in essential hypertension and oxidative
      stress, although.NO metabolite levels in plasma are not modified in the presence
      of elevated cholesterol oxides.

PMID- 12426630
TI  - Prevalence of diarrheogenic Escherichia coli and rotavirus among children from
      Botucatu, Sao Paulo State, Brazil.
AB  - In a one-year prospective study carried out to define the role of rotavirus and
      Escherichia coli in local childhood diarrhea, we determined the prevalence of
      both agents in 54 diarrheic children attending a health center in Botucatu.
      Diarrheogenic E. coli (DEC) strains were characterized by O:H serotyping, a
      search for virulence genetic markers, and assays of adherence to HEp-2 cells.
      Except for enteroaggregative E. coli (EAEC), no other DEC category was detected
      in the children's stools. Both EAEC and rotavirus were isolated from 22 of the 54
      (41.0%) diarrheic children as single agents or in combination with other
      enteropathogens. However, when considering the presence of a single agent, EAEC
      was dominant and isolated from 20.4% of the patients, whereas rotavirus was
      detected in 14.8%. These results indicate that rotavirus and EAEC play a
      significant role as agents of childhood diarrhea in the local population.

PMID- 12426631
TI  - Urinary iron excretion induced by intravenous infusion of deferoxamine in beta
      thalassemia homozygous patients.
AB  - The purpose of the present study was to identify noninvasive methods to evaluate
      the severity of iron overload in transfusion-dependent beta-thalassemia and the
      efficiency of intensive intravenous therapy as an additional tool for the
      treatment of iron-overloaded patients. Iron overload was evaluated for 26 beta
      thalassemia homozygous patients, and 14 of them were submitted to intensive
      chelation therapy with high doses of intravenous deferoxamine (DF). Patients were
      classified into six groups of increasing clinical severity and were divided into
      compliant and non-compliant patients depending on their adherence to chronic
      chelation treatment. Several methods were used as indicators of iron overload.
      Total gain of transfusion iron, plasma ferritin, and urinary iron excretion in
      response to 20 to 60 mg/day subcutaneous DF for 8 to 12 h daily are useful to
      identify iron overload; however, urinary iron excretion in response to 9 g
      intravenous DF over 24 h and the increase of urinary iron excretion induced by
      high doses of the chelator are more reliable to identify different degrees of
      iron overload because of their correlation with the clinical grades of secondary
      hemochromatosis and the significant differences observed between the groups of
      compliant and non-compliant patients. Finally, the use of 3-9 g intravenous DF
      for 6-12 days led to a urinary iron excretion corresponding to 4.1 to 22.4% of
      the annual transfusion iron gain. Therefore, continuous intravenous DF at high
      doses may be an additional treatment for these patients, as a complement to the
      regular subcutaneous infusion at home, but requires individual planning and close
      monitoring of adverse reactions.

PMID- 12426632
TI  - A new model for the immobilization of the rat hind limb.
AB  - An alternative device for the immobilization of the hind limb of the rat was
      developed to study the effects of chronic disuse on the soleus and tibialis
      anterior muscles, maintained for 3 weeks in the shortening and the stretching
      positions, respectively. The proposed device is made of steel mesh and cotton
      materials, and has some advantages when compared to cast or plaster cast: it is
      cheaper, lighter (12 g or 4% of the body weight of the rat) and the same unit can
      be easily adjusted and used several times in the same animal or in animals of
      similar size. Immobilization is also useful to restrain the movements of the hip,
      knee, and ankle joints. Male rats (291 +/- 35 g and aged 14 +/- 2 weeks) were
      used to develop and test the model. The soleus muscle of 18 rats was maintained
      in a shortened position for 21 consecutive days and lost 19 +/- 7% of its length
      (P = 0.008) and 44 +/- 6% of its weight (P = 0.002) compared to the contralateral
      intact muscle. No difference (P = 0.67) was found in the stretched tibialis
      anterior of the same hind limb when compared to the contralateral muscle. No
      ulcer, sore or foot swelling was observed in the animals. Immobilization was
      effective in producing chronic muscle disuse in the hind limbs of rats and is an
      acceptable alternative to the traditional methods of immobilization such as cast
      or plaster cast.

PMID- 12426633
TI  - CCR5 genotype and plasma beta-chemokine concentration of Brazilian HIV-infected
      individuals.
AB  - The 32-bp deletion in the HIV-1 co-receptor CCR5 confers a high degree of
      resistance to HIV-1 infection in homozygous individuals for the deleted allele
      and partial protection against HIV-1 during disease progression in heterozygotes.
      Natural ligands for CCR5, MIP-1alpha, MIP-1beta and RANTES, have been shown to
      inhibit HIV replication in CD4+ T cells. In the present study, we examined the
      CCR5 genotype by PCR and the plasma levels of RANTES and MIP-1alpha by ELISA
      among blood donors (N = 26) and among HIV-1-infected individuals (N = 129). The
      control group consisted of healthy adult volunteers and HIV-1-infected subjects
      were an asymptomatic and heterogeneous group of individuals with regard to
      immunologic and virologic markers of HIV-1 disease. The frequency of the CCR5
      mutant allele (Delta32ccr5) in this population was 0.032; however, no Delta32ccr5
      homozygote was detected. These results could be related to the intense ethnic
      admixture of the Brazilian population. There was no correlation between
      circulating beta-chemokines (MIP-1alpha, RANTES) and viral load in HIV-infected
      individuals. RANTES concentrations in plasma samples from HIV+ patients carrying
      the homozygous CCR5 allele (CCR5/CCR5) (28.23 ng/ml) were higher than in the
      control samples (16.07 ng/ml; P<0.05); however, this HIV+ patient group (mean
      26.23 pg/ml) had significantly lower concentrations of MIP-1alpha than those
      observed in control samples (mean 31.20 pg/ml; P<0.05). Both HIV-1-infected and
      uninfected individuals heterozygous for the Delta32ccr5 allele had significantly
      lower concentrations of circulating RANTES (mean 16.07 and 6.11 ng/ml,
      respectively) than CCR5/CCR5 individuals (mean 28.23 and 16.07 ng/ml,
      respectively; P<0.05). These findings suggest that the CCR5 allele and beta
      chemokine production may affect the immunopathogenesis of HIV-1.

PMID- 12426634
TI  - Potentiation of carbon tetrachloride hepatotoxicity by pentosan polysulfate in
      rats.
AB  - Few data are available in the literature regarding the effect of pentosan
      polysulfate (PPS) on normal and fibrotic rat livers. In addition, the combination
      of PPS and carbon tetrachloride (CCl4) has not been studied so far. The objective
      of this study was to assess the effect of PPS on rat livers treated or not with
      CCl4 for the induction of liver fibrosis. The study consisted of four stages: 1)
      hepatic fibrosis induction with CCl4 (N = 36 rats); 2) evaluation of the effect
      of PPS on CCl4-induced hepatic fibrosis (N = 36 rats); 3) evaluation of the
      effect of higher doses of PPS in combination with CCl4 (N = 50 rats); 4)
      evaluation of the presence of an enzymatic inductor effect by PPS (N = 18 rats)
      using the sodium pentobarbital test which indirectly evaluates hepatic microsomal
      enzyme activity in vivo. Adult (60 to 70 days) male Wistar rats weighing 180 to
      220 g were used. All animals receiving 0.5 ml 8% CCl4 (N = 36) developed hepatic
      fibrosis, and after 8 weeks they also developed cirrhosis. No delay or prevention
      of hepatic fibrosis was observed with the administration of 5 mg/kg PPS (N = 8)
      and 1 mg/kg PPS (N = 8) 1 h after the administration of CCl4, but the increased
      hepatotoxicity resulting from the combination of the two substances caused
      massive hepatic necrosis in most rats (N = 45). PPS (40 mg/kg) alone caused
      hepatic congestion only after 8 weeks, but massive hepatic necrosis was again
      observed in association with 0.5 ml CCl4 after 1 to 4 weeks of treatment.
      Unexpectedly, sleeping time increased with time of PPS administration (1, 2, or 3
      weeks). This suggests that PPS does not function as an activator of the hepatic
      microsomal enzymatic system. Further studies are necessary in order to clarify
      the unexpected increase in hepatotoxicity caused by the combination of CCl4 and
      high doses of PPS, which results in massive hepatic necrosis.

PMID- 12426635
TI  - Kinetics of TNF-alpha and IFN-gamma mRNA expression in islets and spleen of NOD
      mice.
AB  - Insulin-dependent diabetes mellitus is caused by autoimmune destruction of
      pancreatic beta cells. Non-obese diabetic (NOD) mice spontaneously develop
      diabetes similar to the human disease. Cytokines produced by islet-infiltrating
      mononuclear cells may be directly cytotoxic and can be involved in islet
      destruction coordinated by CD4+ and CD8+ cells. We utilized a semiquantitative RT
      PCR assay to analyze in vitro the mRNA expression of TNF-alpha and IFN-gamma
      cytokine genes in isolated islets (N = 100) and spleen cells (5 x 10(5) cells)
      from female NOD mice during the development of diabetes and from female CBA-j
      mice as a related control strain that does not develop diabetes. Cytokine mRNAs
      were measured at 2, 4, 8, 14 and 28 weeks of age from the onset of insulitis to
      the development of overt diabetes. An increase in IFN-gamma expression in islets
      was observed for females aged 28 weeks (149 +/- 29 arbitrary units (AU), P<0.05,
      Student t-test) with advanced destructive insulitis when compared with CBA-j
      mice, while TNF-alpha was expressed in both NOD and CBA-j female islets at the
      same level at all ages studied. In contrast, TNF-alpha in spleen was expressed at
      higher levels in NOD females at 14 weeks (99 +/- 8 AU, P<0.05) and 28 weeks (144
      +/- 17 AU, P<0.05) of age when compared to CBA-j mice. The data suggest that IFN
      gamma and TNF-alpha expression in pancreatic islets of female NOD mice is
      associated with beta cell destruction and overt diabetes.

PMID- 12426636
TI  - Contrast sensitivity to radial frequencies modulated by Jn and jn Bessel
      profiles.
AB  - We measured human contrast sensitivity to radial frequencies modulated by
      cylindrical (Jo) and spherical (jo) Bessel profiles. We also measured responses
      to profiles of jo, j1, j2, j4, j8, and j16. Functions were measured three times
      by at least three of eight observers using a forced-choice method. The results
      conform to our expectations that sensitivity would be higher for cylindrical
      profiles. We also observed that contrast sensitivity is increased with the j n
      order for n greater than zero, having distinct orderly effects at the low and
      high frequency ends. For n = 0, 1, 2, and 4 sensitivity tended to occur around
      0.8-1.0 cpd while for n = 8 and 16 it seemed to shift gradually to 0.8-3.0 cpd.
      We interpret these results as being consistent with the possibility that spatial
      frequency processing by the human visual system can be defined a priori in terms
      of polar coordinates and discuss its application to study face perception.

PMID- 12426637
TI  - Effect of cocaine on periadolescent rats with or without early maternal
      separation.
AB  - Cocaine-induced behavioral sensitization and weight loss were investigated in
      periadolescent Wistar rats kept with their mothers or subjected to repeated
      maternal separation. Litters allocated to the separation procedure were placed in
      a temperature-controlled (33 degrees C) chamber for 3 h per day from postnatal
      day 6 (P6) to P20. Non-handled rats were left undisturbed until weaning.
      Treatments were started on P30-31 and the test was performed on P36-37. Animals
      received injections of saline or cocaine (10 mg/kg, sc) twice daily for 5 days.
      On day 6 all animals received saline. On day 7 animals were challenged with 10
      mg/kg cocaine and their locomotion was evaluated in activity cages. A third group
      received saline throughout the 7-day period. Body weights were recorded on P30-31
      and P36-37. Two-way ANOVA on body weights showed a main effect of treatment group
      (F(1,35) = 10.446, P = 0.003; N = 10-12). Non-handled rats treated with cocaine
      for 5 days gained significantly less weight, while no significant effect was
      observed in maternally separated rats. Two-way ANOVA revealed a main effect of
      drug treatment on locomotor activity (F(2,32) = 15.209, P<0.001; N = 6-8), but
      not on rearing condition (F(1,32)<0.001, P = 0.998). Animals pretreated with
      cocaine showed a clear behavioral sensitization relative to the saline group. No
      difference in the magnitude of sensitization was found between separated and non
      handled animals. Only the effect of cocaine on weight gain was significantly
      affected by repeated episodes of early maternal separation during the pre-weaning
      period.

PMID- 12426638
TI  - Sleep-wake pattern of medical students: early versus late class starting time.
AB  - The sleep-wake cycle of students is characterized by delayed onset, partial sleep
      deprivation and poor sleep quality. Like other circadian rhythms, the sleep-wake
      cycle is influenced by endogenous and environmental factors. The aim of the
      present study was to determine the effects of different class starting times on
      the sleep-wake pattern of 27 medical students. The data were collected during two
      medical school semesters having different class starting times. All subjects
      answered the Portuguese version of the Horne and Ostberg Morningness/Eveningness
      Questionnaire, the Pittsburgh Sleep Quality Index (PSQI) and kept a sleep diary
      for two weeks during each semester. Better sleep quality (PSQI = 5.3 vs 3.4),
      delayed sleep onset (23:59 vs 0:54 h) and longer sleep duration (6 h and 55 min
      vs 7 h and 25 min) were observed with the late schedule. We also found reduced
      sleep durations during weekdays and extended sleep durations during weekends.
      This pattern was more pronounced during the semester with the early class
      schedule, indicating that the students were more sleep deprived when their
      classes began earlier in the morning. These results require further investigation
      regarding the temporal organization of our institutions.

PMID- 12426639
TI  - Protective role of antioxidant vitamin E and catechin on idarubicin-induced
      cardiotoxicity in rats.
AB  - Idarubicin is an anthracycline antibiotic extensively used in acute leukemia. In
      the present study we investigated whether vitamin E and catechin can reduce the
      toxic effects of idarubicin. Vitamin E (200 IU kg(-1) week(-1)), catechin (200 mg
      kg(-1) week(-1)), idarubicin (5 mg kg(-1) week(-1)), idarubicin + vitamin E (200
      IU kg(-1) week(-1)), and idarubicin + catechin (200 mg kg(-1) week(-1))
      combinations were given to male Sprague-Dawley rats weighing 210 to 230 g (N =
      6/group). Idarubicin-treated animals exhibited a decrease in body and heart
      weight, a decrease in myocardial contractility, and changes in ECG parameters
      (P<0.01). Catechin + idarubicin- and vitamin E + idarubicin-treated groups
      exhibited similar alterations, but changes were attenuated in comparison to those
      in cardiac muscle of idarubicin-treated rats (P<0.05). Superoxide dismutase and
      catalase activity was reduced in the idarubicin-treated group (P<0.05).
      Glutathione peroxidase levels were decreased in the idarubicin-treated group
      (P<0.05) and reached maximum concentrations in the catechin- and catechin +
      idarubicin-treated groups compared to control (P<0.01). Malondialdehyde activity
      was decreased in the catechin + idarubicin-treated groups compared to control and
      increased in the other groups, reaching maximum concentrations in the vitamin E
      treated group (P<0.01). In electron microscopy studies, swelling of the
      mitochondria and dilatation of the sarcoplasmic reticulum of myocytes were
      observed in the idarubicin-treated groups. In groups that were given idarubicin +
      vitamin E and idarubicin + catechin, the only morphological change was a weak
      dilatation of the sarcoplasmic reticulum. We conclude that catechin and vitamin E
      significantly reduce idarubicin-induced cardiotoxicity in rats.

PMID- 12426640
TI  - Determination of anaerobic threshold in rats using the lactate minimum test.
AB  - The break point of the curve of blood lactate vs exercise load has been called
      anaerobic threshold (AT) and is considered to be an important indicator of
      endurance exercise capacity in human subjects. There are few studies of AT
      determination in animals. We describe a protocol for AT determination by the
      "lactate minimum test" in rats during swimming exercise. The test is based on the
      premise that during an incremental exercise test, and after a bout of maximal
      exercise, blood lactate decreases to a minimum and then increases again. This
      minimum value indicates the intensity of the AT. Adult male (90 days) Wistar rats
      adapted to swimming for 2 weeks were used. The initial state of lactic acidosis
      was obtained by making the animals jump into the water and swim while carrying a
      load equivalent to 50% of body weight for 6 min (30-s exercise interrupted by a
      30-s rest). After a 9-min rest, blood was collected and the incremental swimming
      test was started. The test consisted of swimming while supporting loads of 4.5,
      5.0, 5.5, 6.0 and 7.0% of body weight. Each exercise load lasted 5 min and was
      followed by a 30-s rest during which blood samples were taken. The blood lactate
      minimum was determined from a zero-gradient tangent to a spline function fitting
      the blood lactate vs workload curve. AT was estimated to be 4.95 +/- 0.10% of
      body weight while interpolated blood lactate was 7.17 +/- 0.16 mmol/l. These
      results suggest the application of AT determination in animal studies concerning
      metabolism during exercise.

PMID- 12426641
TI  - Measuring higher order optical aberrations of the human eye: techniques and
      applications.
AB  - In the present paper we discuss the development of "wave-front", an instrument
      for determining the lower and higher optical aberrations of the human eye. We
      also discuss the advantages that such instrumentation and techniques might bring
      to the ophthalmology professional of the 21st century. By shining a small light
      spot on the retina of subjects and observing the light that is reflected back
      from within the eye, we are able to quantitatively determine the amount of lower
      order aberrations (astigmatism, myopia, hyperopia) and higher order aberrations
      (coma, spherical aberration, etc.). We have measured artificial eyes with
      calibrated ametropia ranging from +5 to -5 D, with and without 2 D astigmatism
      with axis at 45 degrees and 90 degrees. We used a device known as the Hartmann
      Shack (HS) sensor, originally developed for measuring the optical aberrations of
      optical instruments and general refracting surfaces in astronomical telescopes.
      The HS sensor sends information to a computer software for decomposition of wave
      front aberrations into a set of Zernike polynomials. These polynomials have
      special mathematical properties and are more suitable in this case than the
      traditional Seidel polynomials. We have demonstrated that this technique is more
      precise than conventional autorefraction, with a root mean square error (RMSE) of
      less than 0.1 micro m for a 4-mm diameter pupil. In terms of dioptric power this
      represents an RMSE error of less than 0.04 D and 5 degrees for the axis. This
      precision is sufficient for customized corneal ablations, among other
      applications.

PMID- 12426642
TI  - Prospective assessment of different indices of cardiac risk for patients
      undergoing noncardiac surgeries.
AB  - OBJECTIVE: To compare the accuracy of 4 different indices of cardiac risk
      currently used for predicting perioperative cardiac complications. METHODS: We
      studied 119 patients at a university-affiliated hospital whose cardiac assessment
      had been required for noncardiac surgery. Predictive factors of high risk for
      perioperative cardiac complications were assessed through clinical history and
      physical examination, and the patients were followed up after surgery until the
      4th postoperative day to assess the occurrence of cardiac events. All patients
      were classified according to 4 indices of cardiac risk: the Goldman risk-factor
      index, Detsky modified risk index, Larsen index, and the American Society of
      Anesthesiologists' physical status classification and their compared accuracies,
      examining the areas under their respective receiver operating characteristic
      (ROC) curves. RESULTS: Cardiac complications occurred in 16% of the patients. The
      areas under the ROC curves were equal for the Goldman risk-factor index, the
      Larsen index, and the American Society of Anesthesiologists' physical status
      classification: 0.48 (SEM +/- 0.03). For the Detsky index, the value found was
      0.38 (SEM +/- 0.03). This difference in the values was not statistically
      significant. CONCLUSION: The cardiac risk indices currently used did not show a
      better accuracy than that obtained randomly. None of the indices proved to be
      significantly better than the others. Studies to improve our ability to predict
      such complications are still required.

PMID- 12426643
TI  - A multicenter, open-label study of the efficacy and safety of telmisartan in mild
      to moderate hypertensive patients.
AB  - OBJECTIVE: To evaluate the efficacy and tolerability of telmisartan, given once a
      day to patients with mild to moderate hypertension, as well as to assess the 24
      hour blood pressure profile with ABPM. METHODS: Initially, 163 patients over 18
      were selected, regardless of sex, with blood pressure levels >140/90mmHg at visit
      1, which was confirmed at visit 2. One hundred thirty-four patients completed the
      study. After a 4-week placebo run-in phase, telmisartan 40mg/daily was given for
      6 weeks. In those patients whose blood pressure (BP) levels were lower than
      140/90mmHg, the same dosage was kept for an additional period of 6 weeks. For
      those who had BP higher than 140/90mmHg, the dosage was increased to 80mg/daily.
      Sixty-two patients were included in a subgroup that underwent ABPM 3 different
      times during the study. RESULTS: In the overall group, blood pressure reduction
      ranged from 162.3+/-14.5/101.3+/-5.75 mmHg (baseline) to 147.3+/-20.1/90.8+/-10.9
      mmHg (week 12) (p<0.05). Mean blood pressure decreases were 14.4mmHg for systolic
      BP and 10.3mmHg for diastolic BP, after 12 weeks of active treatment. A
      subanalysis showed that 47 (35%) patients took telmisartan 40mg throughout the
      study and 81 (65%) had the dosage increased to 80mg daily. Using ABPM, an 8-mmHg
      reduction in systolic BP as well as a 5-mmHg reduction in diastolic BP were
      observed, when compared with baseline values in the final 6 hours (18-24 hours
      after the last dose of study medication). CONCLUSION: Our results confirm that
      telmisartan given once a day is effective in reducing blood pressure levels in
      mild to moderate hypertensive patients. This reduction occurs in a sustained and
      gradual manner during a 24-hour period confirmed by ABPM.

PMID- 12426644
TI  - Benefits of exercise training in the treatment of heart failure: study with a
      control group.
AB  - OBJECTIVE: Exercise training programs have been proposed as adjuncts to treatment
      of heart failure. The effects of a 3-month-exercise-training-program with 3
      exercise sessions per week were assessed in patients with stable systolic chronic
      heart failure. METHODS: We studied 24 patients with final left ventricle
      diastolic diameter of 70+/-10mm and left ventricular ejection fraction of 37+/
      4%. Mean age was 52+/-16 years. Twelve patients were assigned to an exercise
      training group (G1), and 12 patients were assigned to a control group (G2).
      Patients underwent treadmill testing, before and after exercise training, to
      assess distance walked, heart rate, systolic blood pressure, and double product.
      RESULTS: In G2 group, before and after 3 months, we observed, respectively
      distance walked, 623+/-553 and 561+/- 460m (ns); peak heart rate, 142+/-23 and
      146+/- 33b/min (ns); systolic blood pressure, 154+/-36 and 164+/-26 mmHg (ns);
      and double product, 22211+/- 6454 and 24293+/-7373 (ns). In G1 group, before and
      after exercise, we observed: distance walked, 615+/-394 and 970+/- 537m (p<0.003)
      peak heart rate, 143+/-24 and 143+/-29b/min (ns); systolic blood pressure, 136+/
      33 and 133+/-24 mmHg (ns); and double product, 19907+/- 7323 and 19115+/-5776,
      respectively. Comparing the groups, a significant difference existed regarding
      the variation in the double product, and in distance walked. CONCLUSION: Exercise
      training programs in patients with heart failure can bring about an improvement
      in physical capacity.

PMID- 12426645
TI  - Acute myocardial infarction in elderly patients: comparative analysis of the
      predictors of mortality. The elderly versus the young.
AB  - OBJECTIVE: To study the in-hospital evolution of patients aged 65 years and
      older, with acute myocardial infarction, who were treated by direct coronary
      angioplasty with no fibrinolytic therapy. METHODS: We studied 885 patients
      divided into 2 groups as follows: group I (GI) - 293 (33.4%) patients aged >/= 65
      years (72+/-5 years), and group II (GII) - 592 patients aged < 65 years (57+/-9
      years). Multivessel disease was more frequent in GI (63.5% x 49.7%; p=0.001). A
      greater number of GII patients were class I or II of the clinical Killip-Kimball
      classification (K) (80.2% x 67.2%; p=0.00002), while a significant number of GI
      patients were KIII and KIV (24.3% x 12.8%; p=0.00003). RESULTS: Group I had a
      lower index of success (84.6% x 94%; p=0.0002) and a greater in-hospital
      mortality (12.2% x 4.7%; p=0.00007). The predictors of mortality in GI were as
      follows: previous infarction (20.5% x 6.3%; p=0.02), anterior location (13.4% x
      6.4%; p=0.03), and male sex (10.4% x 4.4%; p=0.007). CONCLUSION: Elderly patients
      had more severe acute myocardial infarction and more extensive disease, a lower
      index of success, and greater in-hospital mortality. Previous infarction,
      anterior location and male sex were identified as predictors of mortality in the
      elderly group (GI).

PMID- 12426646
TI  - Epidemiological aspects of adherence to the treatment of hypertension.
AB  - OBJECTIVE: To analyze the reasons given by patients for interrupting their
      pharmacological treatment of hypertension. METHODS: We carried out an
      observational cross-sectional study, in which a questionnaire was applied and
      blood pressure was measured in 401 patients in different centers of the state of
      Bahia. The patients selected had been diagnosed with hypertension and were not on
      antihypertensive treatment for at least 60 days. Clinical and epidemiological
      characteristics of the groups were analyzed. RESULTS: Of the 401 patients, 58.4%
      were females, 55.6% of whom white; 60.5% of the males were white. The major
      reasons alleged for not adhering to treatment were as follows (for males and
      females respectively): normalization of blood pressure (41.3% and 42.3%); side
      effects of the medications (31.7% and 24.8%); forgetting to use the medication
      (25.2% and 20.1%); cost of medication (21.6% and 20.1%); fear of mixing alcohol
      and medication (23.4% and 3.8%); ignoring the need for continuing the treatment
      (15% and 21.8%); use of an alternative treatment (11.4% and 17.1%); fear of
      intoxication (9.6% and 12.4%); fear of hypotension (9.6% and 12%); and fear of
      mixing the medication with other drugs (8.4% and 6.1%). CONCLUSION: Our data
      suggest that most factors concerning the abandonment of the treatment of
      hypertension are related to lack of information, and that, despite the
      advancement in antihypertensive drugs, side effects still account for most
      abandonments of treatment.

PMID- 12426647
TI  - Comparison between tilt-table testing results performed during different periods
      of the day.
AB  - OBJECTIVE: To evaluate the influences of circadian variations on tilt-table
      testing (TTT) results by comparing the positivity rate of the test performed
      during the morning with that of the test performed in the afternoon and to
      evaluate the reproducibility of the results in different periods of the day.
      METHODS: One hundred twenty-three patients with recurrent unexplained syncope or
      near-syncope referred for TTT were randomized into 2 groups. In group I, 68
      patients, TTT was performed first in the afternoon and then in the morning. In
      group II, 55 patients, the test was performed first in the morning and then in
      the afternoon. RESULTS: The TTT protocol was the prolonged passive test, without
      drug sensitization. Twenty-nine (23.5%) patients had a positive result in at
      least one of the periods. The positivity rate for each period was similar: 20
      (16.2%) patients in the afternoon and 19 (15.4%) in the morning (p=1.000). Total
      reproducibility (positive/positive and negative/negative) was observed in 49
      (89%) patients in group I and in 55 (81%) in group II. Reproducibility of the
      results was obtained in 94 (90.4%) patients with first negative tests but in 10
      (34%) patients with first positive tests. CONCLUSION: TTT could be performed
      during any period of the day, and even in the 2 periods to enhance positivity.
      Considering the low reproducibility rate of the positive tests, serial TTT to
      evaluate therapeutic efficacy should be performed during the same period of the
      day.

PMID- 12426648
TI  - Metabolic and hemodynamic effects of saline infusion to maintain volemia on
      temporary abdominal aortic occlusion.
AB  - OBJECTIVE: To analyze hemodynamic and metabolic effects of saline solution
      infusion in the maintenance of blood volume in ischemia-reperfusion syndrome
      during temporary abdominal aortic occlusion in dogs. METHODS: We studied 20 dogs
      divided into 2 groups: the ischemia-reperfusion group (IRG, n=10) and the
      ischemia-reperfusion group with saline solution infusion aiming at maintaining
      mean pulmonary arterial wedge pressure between 10 and 20 mmHg (IRG-SS, n=10). All
      animals were anesthetized with sodium thiopental and maintained on spontaneous
      ventilation. Occlusion of the supraceliac aorta was obtained with inflation of a
      Fogarty catheter inserted through the femoral artery. After 60 minutes of
      ischemia, the balloon was deflated, and the animals were observed for another 60
      minutes of reperfusion. RESULTS: IRG-SS dogs did not have hemodynamic instability
      after aortic unclamping, and the mean systemic blood pressure and heart rate were
      maintained. However, acidosis worsened, which was documented by a greater
      reduction of arterial pH that occurred especially due to the absence of a
      respiratory response to metabolic acidosis that was greater with the adoption of
      this procedure. CONCLUSION: Saline solution infusion to maintain blood volume
      avoided hemodynamic instability after aortic unclamping. This procedure, however,
      caused worsening in metabolic acidosis in this experimental model.

PMID- 12426649
TI  - Primary coronary angioplasty in 9,434 patients during acute myocardial
      infarction: predictors of major in- hospital adverse events from 1996 to 2000 in
      Brazil.
AB  - OBJECTIVE: To verify the results after the performance of primary coronary
      angioplasty in Brazil in the last 4 years. METHODS: During the first 24 hours of
      acute myocardial infarction onset, 9,434 (12.2%) patients underwent primary PTCA.
      We analyzed the success and occurrence of major in-hospital events, comparing
      them over the 4-year period. RESULTS: Primary PTCA use increased compared with
      that of all percutaneous interventions (1996=10.6% vs. 2000=13.1%; p<0.001).
      Coronary stent implantation increased (1996=20% vs. 2000=71.9%; p<0.001). Success
      was greater (1998=89.5% vs. 1999=92.5%; p<0.001). Reinfarction decreased
      (1998=3.9% vs. 99=2.4% vs. 2000=1.5%; p<0.001) as did emergency bypass surgery
      (1996=0.5% vs. 2000=0.2%; p=0.01). In-hospital deaths remained unchanged
      (1996=5.7% vs. 2000=5.1%, p=0.53). Balloon PTCA was one of the independent
      predictors of a higher rate of unsuccessful procedures (odds ratio 12.01 [CI=95%]
      1.58-22.94), and stent implantation of lower mortality rates (odds ratio 4.62
      [CI=95%] 3.19-6.08). CONCLUSION: The success rate has become progressively higher
      with a significant reduction in reinfarction and urgent bypass surgery, but in
      hospital death remains nearly unchanged. Coronary stenting was a predictor of a
      lower death rate, and balloon PTCA was associated with greater procedural
      failure.

PMID- 12426650
TI  - [Coronary heart disease paradox].

PMID- 12426651
TI  - [Case 5/2002 - A 73 year-old man with cardiac tamponade three days after a
      coronary angioplasty (Instituto do Coracao do Hospital das Clinicas da FMUSP, Sao
      Paulo)].

PMID- 12426652
TI  - [Caso 10/2002 - Instituto do Coracao do Hospital das Clinicas da FMUSP].

PMID- 12426653
TI  - [Intracoronary thrombectomy. An alternative in the management of the acute
      ischemic syndromes].

PMID- 12426654
TI  - [Effects of aerobic and of strength physical exercises on HDL and LDL
      lipoproteins and lipoprotein(a)].

PMID- 12426655
TI  - [From the aesculapian staff to the mercurial caduceus].

PMID- 12426656
TI  - [The interpretation of a test under an epidemiological view point. Test
      efficiency].

PMID- 12426658
TI  - Treatment of tendopathies with tropisetron.
AB  - A comparison between a local anesthetic drug and the 5-hydroxytryptamine 3 (5
      HT3) receptor antagonist tropisetron in treating tendopathies or
      periarthropathies revealed that tropisetron has a longer effect on resting pain
      and pain on movement than the local anesthetic drug. The most likely explanation
      for this effect probably is a blocking of stimulated 5-HT3 receptors at the
      nociceptors in conjunction with an inhibited release of substance P and other
      neurokines because of this blockage. Further studies will have to show whether
      the action of tropisetron in tendopathies is as favorable as that of
      corticosteroids.

PMID- 12426659
TI  - Effect of caffeic acid phenethyl ester on cartilage in experimental
      osteoarthritis.
AB  - Activation of nuclear factor kappa B (NF-kappaBeta) in synovial cells is seen in
      RA and OA patients. Caffeic acid phenethyl ester (CAPE) is a specific and potent
      inhibitor of NF-kappaBeta. We aimed to determine the in vivo effects of intra
      articular injections of CAPE on cartilage in an experimental rabbit
      osteoarthritis (OA) model. Two groups of six New Zealand white rabbits underwent
      unilateral anterior cruciate ligament transection (ACLT). Four weeks after ACLT,
      the test group was injected with 150 micro g/kg CAPE in 0.5% ethanol once daily
      for 2 weeks and the control group was injected the same amount of 0.5% ethanol
      intra-articularly. All rabbits were killed 2 weeks after the last injection, and
      cartilage tissue was evaluated morphologically. A histological score totaling 7
      points was determined for each knee. The CAPE group showed significantly
      decreased cartilage destruction and reduced loss of matrix proteoglycans. The
      histological score for cartilage tissue was significantly better in the CAPE
      group than in the control group (3.0+/-0.25 vs 5.3+/-0.55, P=0.005). This study
      suggests that intra-articular injection of CAPE may protect cartilage against the
      development of experimentally induced OA.

PMID- 12426661
TI  - Malignant lymphoma-associated autoimmune diseases--a descriptive epidemiological
      study.
AB  - Lymphoproliferative disorders and autoimmune diseases have some common aspects in
      their clinical appearance. We reviewed 940 patient charts with malignant
      lymphomas to assess the rate of associated autoimmune diseases. Of 421 non
      Hodgkin's lymphoma (NHL) patients (230 males, 191 females), 32 (7.6%) had an
      autoimmune disease (26 females, six males, mean age 48.3 years). The most common
      diagnosis was Sjogren's syndrome. The other cases were autoimmune skin diseases
      (5), thyroiditis (3), polymyositis (2), scleroderma (2), other musculoskeletal
      disorders (2), rheumatoid arthritis (1), vasculitis (1), undifferentiated
      collagenosis (1), colitis ulcerosa (1), autoimmune hepatitis (1), Addison's
      disease (1), and autoimmune hemolytic anemia (1). Of 519 Hodgkin's lymphoma
      patients (308 males, 211 females), an associated autoimmune disease occurred in
      45 (8.6%) (25 females, 20 males, mean age 39.2 years). In 31 cases, we found
      autoimmune thyroid disorders, then came glomerulonephritis (3), immune
      thrombocytopenia (3), insulin-dependent diabetes mellitus (2), autoimmune
      hemolytic anemia (1), seronegative spondylarthritis (1), systemic lupus
      erythematosus (1), mixed connective tissue disease (1), scleroderma (1), and
      vasculitis (1). We also analyzed histology, choice of treatment, and sequence of
      appearance of the disease types. We found a difference between NHL and Hodgkin's
      lymphoma patients, since in NHL autoimmunity - mostly from Sjogren's syndrome -
      preceded the lymphoma diagnosis (70%), but in Hodgkin's the autoimmunity
      developed mainly after the treatment of malignancy. The relatively high
      prevalence of autoimmune diseases in malignant lymphomas has several
      explanations. Clinicians have to consider autoimmunity when treating
      lymphoproliferative disorders.

PMID- 12426660
TI  - Treatment of psoriatic arthritis and psoriasis vulgaris with the tumor necrosis
      factor inhibitor infliximab.
AB  - OBJECTIVE: The aim was to evaluate the efficacy and safety of multiple infusions
      with achimeric, anti-tumor necrosis factor (TNF)alpha monoclonal antibody
      (infliximab) in patients with psoriatic arthritis (PsA) and psoriasis vulgaris.
      METHODS: Over 22 weeks, nine patients with both active psoriasis and PsA received
      five infusions of 3 mg/kg infliximab. The endpoints included changes in the
      swollen and tender joints counts, American College of Rheumatology (ACR)
      preliminary criteria for improvement response rates 20, 50, and 70, and
      improvement in the psoriasis area and severity index (PASI). RESULTS: The swollen
      count (SJC) and tender joint count (TJC) fell from means of 5.33+/-2.22 and
      17.80+/-4.21 to 1.44+/-1.09 and 9.77+/-0.92, respectively, by week 2 ( P=0.02,
      P=0.02). This benefit was sustained through week 22 (2.00+/-1.12/7.77+/-3.68,
      P=0.05/ P=0.002). The ACR 20/50/70 response was achieved in 89%/56%/22% of cases.
      The mean PASI score improved from 19.04+/-5.41 to 4.91+/-2.51 ( P=0.002).
      CONCLUSION: Multiple infusions of infliximab were effective and well tolerated in
      patients with active psoriasis and PsA.

PMID- 12426662
TI  - Impaired antioxidant status and decreased dietary intake of antioxidants in
      patients with systemic lupus erythematosus.
AB  - OBJECTIVE: This study compared plasma antioxidant/oxidant status and the dietary
      nutrient intake of patients with systemic lupus erythematosus (SLE) to those of
      healthy controls. PATIENTS AND METHODS: The study included 97 consecutive
      patients with SLE and 97 age- and sex-matched healthy controls. Blood samples
      from 19 patients and 19 controls were subjected to analyses of plasma
      concentrations of alpha-tocopherol and malone dialdehyde and the activities of
      superoxide dismutase and glutathione peroxidase in the plasma. All patients and
      controls were interviewed using a semiquantitative food-frequency questionnaire.
      RESULTS: The plasma alpha-tocopherol concentration was lower in patients, but
      this difference was not statistically significant. Plasma superoxide dismutase
      and glutathione peroxidase activities were significantly lower in patients than
      in controls, and the plasma malone dialdehyde level was significantly higher in
      patients than in controls. The intake of all major dietary antioxidants,
      including vitamin A, beta-carotene, and vitamin C, but not retinol, was lower in
      patients than in controls, but this difference was significant only for vitamin A
      and beta-carotene. CONCLUSIONS: These results show that plasma antioxidant status
      is impaired and dietary antioxidant intake is decreased in patients with SLE.

PMID- 12426663
TI  - Hypersensitivity vasculitis and cytokines.
AB  - OBJECTIVE: Hypersensitivity vasculitis (HSV) is secondary vasculitis due to an
      immune response to exogenous substances. Because of the relative rarity of the
      vasculitides there are no reports on the role cytokines. This report evaluates
      some of cytokines which might be involved in pathophysiological events of HSV.
      MATERIAL AND METHODS: Patients with HSV ( n=20) were classified as active ( n=12)
      ornd inactive ( n=8) according to a vasculitis activity index for systemic
      necrotizing vasculitis (VAI). All the patients were males. A control group was
      formed from 20 healthy male employees of our department. We performed tests for
      serum interleukins 6, IL-10, sIL-2 receptor, tumor necrosis factor (TNF) alpha, C
      reactive protein (CRP) levels using enzyme-linked immunosorbent assay and
      erythrocyte sedimentation rate (ESR). RESULTS: The mean ESR value, CRP, and
      fibrinogen levels were significantly different in both active and inactive HSV
      from those in the healthy group; they were also significantly higher in the
      active than in the inactive group. There was no significant difference between
      healthy and inactive groups for serum IL-10, IL-6, sIL-2 receptor, and TNFalpha
      levels. However, it was also significantly higher for in active HSV patients than
      in the healthy group. Similar results were obtained comparing active and inactive
      groups, namely, all cytokine levels were significantly higher for all patients.
      The most striking finding is the high correlation of ESR (also for CRP,
      fibrinogen) with serum levels of TNFalpha and IL-10, but not with IL-6 and IL2R.
      CONCLUSIONS: These data show that serum TNFalpha and IL-10 levels can be studied
      in comparison to traditional markers of inflammation such as sedimentation rate
      or C-reactive protein. This may lead to new approaches to treating or managing
      HSV.

PMID- 12426664
TI  - Diffuse idiopathic skeletal hyperostosis in a patient with idiopathic
      retroperitoneal fibrosis: a case report.
AB  - Idiopathic retroperitoneal fibrosis (IRF) is a rare rheumatologic disease with
      obscure pathogenesis. Its manifestations depend upon the structures involved.
      Diffuse idiopathic skeletal hyperostosis (DISH) is usually seen in male patients
      over 45 years of age and characterized by new bone formation at the entheses. The
      dorsal spine is most commonly involved, but radiographic findings in both the
      spine and extraspinal structures suggest a generalized disorder of ossification
      rather than a localized spinal disease. The association of IRF and DISH has not
      been reported before. There is proliferation of connective tissue in both of
      these diseases, and they may share a common etiopathogenetic basis. We describe a
      patient having features of both IRF and DISH.

PMID- 12426665
TI  - Aplastic anemia complicating systemic lupus erythematosus--report of a case and
      review of the literature.
AB  - Aplastic anemia is a very unusual feature of systemic lupus erythematosus (SLE).
      A 32-year-old lady presented with generalized purpuric lesions and was diagnosed
      as having immune thrombocytopenic purpura. Fourteen months later, she developed
      progressive pancytopenia, arthritis of small joints, and oral ulcers.
      Investigations confirmed SLE with aplastic anemia. High-dose methylprednisolone
      therapy had been unsuccessful in controlling the pancytopenia. She had a
      progressive course and died due to septicemia. Even though pancytopenia is common
      in SLE, a bone marrow examination should be done in all cases of persistent
      pancytopenia to exclude bone marrow aplasia. This will help in tailoring the
      treatment with more aggressive immunosuppressants.

PMID- 12426666
TI  - The prevailing diagnosis of a painful lymph node.

PMID- 12426667
TI  - Identification of quantitative trait loci for prepulse inhibition in rats.
AB  - INTRODUCTION: Schizophrenia is a common and debilitating psychiatric disorder
      that is partially under genetic control. Because of difficulties in mapping the
      genes that influence susceptibility to schizophrenia in humans, there has been
      substantial interest in mapping genes that control endophenotypes for
      schizophrenia in both human and rodent populations. Deficient prepulse inhibition
      (PPI) of the startle response has shown promise as an endophenotype for
      schizophrenia, as well as several other psychiatric disorders. METHODS: Brown
      Norway (BN/SsNHsd) and Wistar Kyoto (WKY/lj-cr) rats were used because they show
      a large, unconfounded difference in PPI. We used interval mapping methods to
      identify quantitative trait loci (QTL) for PPI in a backcross population.
      RESULTS: We identified a QTL on chromosome 2 with a LOD score of 3.63 and a
      suggestive QTL on chromosome 18 with a LOD score of 2.71. CONCLUSIONS: Both of
      the identified regions contain several candidate genes. Furthermore, the
      implicated rat chromosomes are syntenic with human chromosomal regions that have
      been reported to contain QTL for schizophrenia, bipolar disorder, and Tourette's
      syndrome. These results identify the chromosomal location of gene(s) that
      modulate an endophenotype for schizophrenia, and other psychiatric disorders, and
      may provide a shortcut to identifying specific genes and/or biochemical pathways
      involved in human psychiatric diseases.

PMID- 12426668
TI  - Simultaneous analyses of the neurochemical and behavioral effects of the
      norepinephrine reuptake inhibitor reboxetine in a rat model of antidepressant
      action.
AB  - RATIONALE: The forced swimming test (FST) is a rodent behavioral assay widely
      used to predict clinical efficacy of putative antidepressants. Few studies have
      examined the effects of the FST on neurotransmitter levels and how antidepressant
      drug treatment may alter neurotransmitter levels and behavior simultaneously
      during the performance of a stressful task. OBJECTIVES: The present study
      examined the role of norepinephrine in mediating active behaviors in the FST
      after treatment with reboxetine, a selective norepinephrine reuptake inhibitor.
      METHODS: High-pressure liquid chromatography was used to analyze microdialysis
      samples collected from awake, freely moving rats before, during and after
      exposure to the FST. Reboxetine (10 mg/kg) was given three times over a 24-h
      period prior to the test swim. Behavioral responses, including immobility,
      swimming and climbing, were counted during the 5-min test on day 1 and day 2.
      RESULTS: The first exposure to swim stress elicited a 65% increase in
      extracellular norepinephrine (NE). A second exposure on day 2 elicited a 52%
      increase of NE and a behavioral profile characterized by increased immobility and
      a reduction of active behaviors. A subchronic course (three injections over 24 h)
      of treatment with reboxetine between the two swim exposures resulted in
      antidepressant-like activity, i.e., decreased immobility and increased climbing
      behavior on day 2. A significantly greater increase in extracellular NE (112%)
      was observed in the group of animals that received reboxetine injections.
      CONCLUSIONS: Treatment with reboxetine in a schedule commonly used in the FST
      resulted in a potentiated noradrenergic response to the swim challenge
      concomitant with behavioral alterations consistent with antidepressant-like
      activity.

PMID- 12426669
TI  - [A population-based study on variations in the use of adjuvant radiotherapy in
      breast cancer patients].
AB  - AIM: The assessment of the compliance with consensus recommendations for adjuvant
      radiation therapy among women with breast cancer. The study is based on data
      obtained in a population-based cohort-study, which was performed to evaluate the
      quality of health care for patients with breast cancer. PATIENTS AND METHODS:
      About one million inhabitants live in the study region Eastern Thuringia, 2,031
      cases with invasive breast cancer without distant metastasis (MO) or inflammatory
      spread were registered from 1995 to 2000. Out of these 1,700 with complete
      documentation of covariates were included in multivariate analysis. To examine
      the simultaneous influence of all clinical factors and "caseload" on the
      likelihood to receive adjuvant radiation therapy a logistic regression model was
      fitted for radiation therapy after mastectomy. In order to describe the impact of
      each individual clinic on treatment decision as "caseload" was replaced by the
      clinics with more than 30 primary treatments. RESULTS: Following breast
      conserving therapy (BCT) 90.6% of the patients received adjuvant radiation
      therapy. In the univariate analysis older age was negatively associated with the
      use of radiation therapy among women with BCT (Table 1). Furthermore, comorbid
      conditions were negatively associated with the use of radiation therapy. For all
      other cofactors no associations were found. Subsequent to mastectomy 33.0% of the
      women underwent radiation therapy (Table 2). Associations between the use of
      radiation therapy and age, tumor category, number of positive lymph nodes,
      multiple tumors, histologic differentiation grade, residual tumor as well as
      hormone receptor status were found. In the multivariate analysis only older age
      (>/= 70 years) was identified as negative indicator for the utilization of
      radiation therapy. Among patients with mastectomy increasing tumor size was a
      positive predictor on radiation therapy (Table 3). In addition more than three
      positive lymph nodes, multiplicity, poor histologic differentiation grade (G3/4),
      medial localization, and younger age (35-49 years) were positive predictors for
      the application of radiation therapy. For R-classification, hormone receptor
      status and comorbidity no influence on the use of radiation therapy was observed.
      Among clinics adjusted for case-mix variations in the compliance of treatment
      recommendation both following BCT and mastectomy were found (Figure 1).
      CONCLUSION: Following BCT compliance with treatment recommendations regarding
      radiation therapy was high. Women in older age or with comorbidities received
      less often radiation therapy. Subsequent to mastectomy indicators for the use of
      radiation therapy were identified. Among clinics differences in the adherence to
      treatment recommendations were observed.

PMID- 12426670
TI  - Radiotherapy confined to the tumor bed following breast conserving surgery
      current status, controversies, and future projects.
AB  - BACKGROUND: The standard technique of radiotherapy (RT) after breast conserving
      surgery (BCS) is to treat the entire breast up to a total dose of 45-50 Gy with
      or without tumor bed boost. The majority of local recurrences occur in close
      proximity to the tumor bed. Thus, the necessity of whole breast radiotherapy has
      been questioned, and several centers have evaluated the feasibility and efficacy
      of sole tumor bed irradiation. The aim of this study was to review the current
      status, controversies, and future prospects of tumor bed irradiation alone after
      breast conserving surgery. MATERIAL AND METHODS: Published prospective trials
      evaluating the feasibility and efficacy of radiotherapy confined to the tumor bed
      following breast conserving surgery were reviewed in order to analyze treatment
      results. RESULTS: In three earlier studies, using tumor bed radiotherapy for
      unselected patients, the incidence of intra-breast relapse was reported in the
      range of 15.6-37%. However, in nine prospective phase I-II trials, sole
      brachytherapy (BT) with different dose rates, strict patient selection, and
      meticulous quality assurance, resulted in 95.6-100% local control rates. To date,
      only one phase III protocol has been initiated comparing the efficacy of tumor
      bed brachytherapy alone with conventional whole breast radiotherapy. The ideal
      extend of the planning target volume (PTV) for tumor bed radiotherapy alone has
      not been established yet. In most series, PTV was defined as the excision cavity
      with generous (1-3 cm) safety margins. Minimal requirement for PTV localization
      is the use of titanium clips to mark the walls of the excision cavity
      intraoperatively, but the combination of clip demarcation and three-dimensional
      (3-D) visual information obtained from cross-sectional images seems to be the
      best method to determine the target volume. 3-D virtual brachytherapy is also a
      promising method to minimize the chance of geographic miss. Recently developed
      techniques, such as intraoperative radiotherapy (IORT), as well as accelerated 3
      D conformal external beam radiation therapy (3-D-CRT) were also found to be
      feasible for tumor bed radiotherapy alone. CONCLUSIONS: In spite of the existing
      arguments against limiting radiotherapy to the tumor bed after breast conserving
      surgery, results of phase I-II studies suggest that tumor bed radiotherapy alone
      might be an appropriate treatment option for selected breast cancer patients.
      Whole breast radiotherapy remains the standard radiation modality used in the
      treatment of breast cancer, and brachytherapy as the sole modality should be
      considered as investigational. Further phase-III trials are suggested to
      determine the equivalence of sole tumor bed radiotherapy, compared with whole
      breast radiotherapy. Preliminary results with recently developed techniques (CT
      image based conformal brachytherapy, 3-D virtual brachytherapy, IORT, 3-D-CRT)
      are promising. However, more experience is required to define whether these
      methods might improve outcome for patients treated with tumor bed radiotherapy
      alone.

PMID- 12426671
TI  - 5-year results of pulsed dose rate brachytherapy applied as a boost after breast
      conserving therapy in patients at high risk for local recurrence from breast
      cancer.
AB  - PURPOSE: The aim of this study was to evaluate effect, toxicity, and cosmesis of
      a prospectively applied pulsed dose rate (PDR) brachytherapy boost schedule in
      patients with stage I/II/IIIa invasive breast cancer. PATIENTS AND METHODS: A
      total of 113 patients were treated after breast-conserving surgery (BCS) and
      external beam radiotherapy (median 50 Gy, range 46-52). The boost dose was graded
      in accordance to the pathologic tumor characteristics: 20-25 Gy: incomplete
      resection (n = 34), vascular invasion (n = 27), close margin resection (n = 41);
      15 Gy: T2G3 stage (n = 11). PDR brachytherapy (37 GBq, (192)Ir source) was
      carried out after geometric volume optimization with 1 Gy/pulse/h. The
      implantation and dose specification were performed similar to the rules of the
      Paris system. RESULTS: The overall local failure rate after a median follow-up of
      61 months was 4.4% (5/113). The actuarial 5- and 8-year local recurrence-free
      survival rates were 95% and 93%, respectively. Cosmesis was rated by 90% of the
      patients as excellent or good. 14/113 patients experienced grade III (all caused
      by planar telangiectasia) and none of the patients grade IV late toxicity of the
      skin (RTOG/EORTC). A boost dose of 25 Gy resulted in a significantly higher rate
      of late toxicity (Fisher's exact test, p < 0.01). CONCLUSIONS: PDR brachytherapy
      is safe, effective, and provides good cosmesis. A CLDR breast boost can be
      replaced by PDR brachytherapy without significant loss of therapeutic ratio.

PMID- 12426672
TI  - Electron and high-dose-rate brachytherapy boost in the conservative treatment of
      stage I-II breast cancer first results of the randomized Budapest boost trial.
AB  - BACKGROUND AND AIMS: To evaluate the effect of electron and high-dose-rate
      brachytherapy (HDR BT) boost on local tumor control (LTC), side effects and
      cosmesis after breast-conserving surgery (BCS) in a prospective randomized study.
      PATIENTS AND METHODS: 207 women with stage I-II breast cancer who underwent BCS
      were treated by 50 Gy irradiation to the whole breast and then randomly assigned
      to receive either a boost to the tumor bed (n = 104) or no further radiotherapy
      (n = 103). Boost treatments consisted of either 16 Gy electron irradiation (n =
      52) or 12-14,25 Gy HDR BT (n = 52). Breast cancer-related events, side effects,
      and cosmetic results were assessed. RESULTS: At a median follow-up of 5.3 years,
      the crude rate of local recurrences was 6.7% (7/104) with and 15.5% (16/103)
      without boost. The 5-year probability of LTC, relapse-free survival (RFS), and
      cancer-specific survival (CSS) was 92.7% vs. 84.9% (p = 0.049), 76.6% vs. 66.2%
      (p = 0.044), and 90.4% vs. 82.1% (p = 0.053), respectively. There was no
      significant difference in LTC between patients treated with electron or HDR BT
      boost (94.2% vs. 91.4%; p = 0.74). On multivariate analysis, patient age < 40
      years (RR: 4.53), positive margin status (RR: 4.17), and high mitotic activity
      index (RR: 3.60) were found to be significant risk factors for local recurrence.
      The incidence of grade 2-3 side effects was higher in the boost arm (17.3% vs.
      7.8%; p = 0.03). However, the rate of excellent/good cosmetic results was similar
      for the two arms (85.6% vs 91.3%; p = 0.14). Cosmesis was rated as excellent/good
      in 88.5% of patients treated with HDR BT and 82.7% of patients with electron
      boost (p = 0.29). CONCLUSIONS: Boost dose significantly improves LTC and RFS in
      patients treated with BCS and radiotherapy. In spite of the higher incidence of
      late side effects in the boost arm, boost dose is strongly recommended for
      patients at high risk for local recurrence. Positive or close margin status, high
      mitotic activity index, and young patient age should be viewed as absolute
      indications for tumor bed boost. LTC and cosmesis are excellent and similar to
      patients boosted with either HDR BT or electrons.

PMID- 12426673
TI  - Postmastectomy electron-beam-rotation irradiation in locally advanced breast
      cancer prognostic factors of locoregional tumor control.
AB  - BACKGROUND: Different radiotherapy techniques are used for postmastectomy
      irradiation. We review the results with the electron-beam-rotation technique in
      advanced breast cancer patients. Main endpoint was local tumor control. PATIENTS
      AND METHODS: From 1990 to 1998 119 patients with adverse pathology features (pT3
      17% of patients, pT4 42%, multicentricity 36%, pN >/= 3 positive nodes and/or
      pN1biii 81%, close margins 30%) underwent electron-beam-rotation irradiation of
      the chest wall with daily fractions of 2.0-2.5 Gy per day to 50 Gy total dose
      after modified radical mastectomy and axillary lymph node dissection. A local
      boost of 10 Gy and/or irradiation of locoregional lymph nodes were applied
      depending on the completeness of resection and lymph node involvement. RESULTS:
      After a median follow-up of 73 months for patients at risk the 5-year local tumor
      control, local tumor control first event, disease-free, and overall survival were
      82%, 92%, 57%, and 63% (Kaplen Meier analysis), respectively. Significant
      predictors of poor local tumor control were maximal tumor diameter >/= 5 cm (p =
      0.01), "close margins" or residual tumor (p < 0.01), four or more involved
      axillary lymph nodes (p = 0.02), two or more involved lymph node levels (p =
      0.04), negative estrogen receptor status (p = 0.03), and high-grade
      histopathology (GIIb-III, p < 0.01). The subgroup analysis showed a high local
      failure rate of 37% for high-grade (GIIb-III) and estrogen receptor negative
      tumors, whereas no local recurrence was found in low-grade (GI-Iia) and receptor
      positive tumors (p = 0.01). The multivariate analysis revealed maximal tumor
      diameter >/= 5 cm, four or more involved axillary lymph nodes and high-grade
      histopathology (GIIb-III) as independent predictors of poor local tumor control.
      CONCLUSION: In high-risk breast cancer patients postmastectomy irradiation with
      the electron-beam-rotation technique is an effective therapy, resulting in a 5
      year local failure rate of 8%. Intensified local therapy needs further
      investigation in subgroups of patients with additional risk factors.

PMID- 12426674
TI  - Perioperative brachytherapy for pretreated chest wall recurrence of breast
      cancer.
AB  - PURPOSE: To demonstrate the technical aspects of high-dose-rate afterloading (HDR
      AL) brachytherapy for isolated local chest wall recurrence of breast cancer
      pretreated with mastectomy and axillary node dissection plus postoperative
      radiotherapy. CASE REPORT: A 63-year-old female patient with left ductal breast
      cancer, pT2pN1biM0, was reoperated for an isolated local chest wall recurrence 13
      years after primary treatment (mastectomy, axillary dissection, and 50 Gy
      postoperative irradiation). Radical surgery would have involved extreme
      mutilation. Reoperative surgical margins of 3 mm width were involved, and four
      parallel afterloading catheters were placed intraoperatively in this
      histologically positive margin site. Perioperative HDR-AL (Ir-192 stepping
      source, 370 GBq activity, dose rate: reference air kerma rate at 1 m 40.84 mGy/h
      kg) was performed. Dose per fraction: 6 Gy to the reference line, two fractions
      per week, total dose 30 Gy. Follow-up after secondary treatment: 5 years.
      RESULTS: Firm local control and 5-year disease-free survival were obtained with
      perioperative HDR-AL therapy; staging procedures (clinical exam, MRI, abdominal
      ultrasound, and bone scan) showed no evidence of disease. The development of
      radiodermatitis did not exceed grade 2 level and healed spontaneously within 6
      weeks. CONCLUSIONS: Isolated local chest wall relapse can be effectively
      controlled by wide surgical excision and perioperative reirradiation with HDR-AL.
      This technique may represent a treatment alternative to ultraradical surgery,
      with equal healing probability and a better quality of life. Small-volume
      irradiation of the postoperative scar can be performed with HDR-AL brachytherapy,
      and long-term local control can be achieved with a total dose of 30 Gy.

PMID- 12426675
TI  - [Inversely planned intensity modulated radiotherapy for irradiation of a woman
      with breast cancer and funnel chest].
AB  - BACKGROUND: A 44-year old woman with breast cancer was transferred to our
      institution for irradiation. Due to a pronounced funnel chest no satisfying dose
      distribution was obtained by conventional techniques. Thus an intensity-modulated
      radiotherapy (IMRT) based on inverse optimisation was carried out. IMRT was
      compared to conventional techniques regarding dose distribution and feasibility.
      PATIENT AND METHODS: Tumor site was in the right middle lower quadrant. Target
      volume included the right breast and the parasternal lymph nodes. Target dose was
      50.4 Gy. Based on inverse optimisation irradiation was carried out in "step-and
      shoot"-technique with twelve intensity modulated beams with six intensity steps.
      Additionally, treatment plans were calculated using conventional techniques
      (technique A with two tangential wedged 6-MV photon beams, technique B with
      additional oblique 15-MeV electron portal). We analysed conformality and
      homogeneity of target volume and dose distribution within normal tissue. RESULTS:
      Dose conformality was substantially improved by IMRT. Dose homogeneity was
      slightly decreased compared to technique A. Lung volume irradiated with a dose
      higher than 20 Gy was reduced from 56.8% with technique A and 40.1% with
      technique B, respectively to 22.1% with IMRT. Treatment was tolerated well by the
      patient without relevant side effects. Mean treatment time was 19.5 min.
      CONCLUSION: The inversely planned IMRT using multiple beam directions is suitable
      for breast irradiation following breast conserving surgery. In the present case
      of a woman with funnel chest lung dose was substantially reduced without
      reduction of target dose. In which was the complex treatment technique leads to a
      clinically detectable advantage is examined at present, in the context of a
      study.

PMID- 12426676
TI  - Accuracy of 3-d needle navigation in interstitial brachytherapy in various body
      regions.
AB  - BACKGROUND: Precise immobilisation of a patient during extracranial stereotactic
      3-D navigation is essential in order to minimize the patient's movement during CT
      data recording and needle application. In this paper we report the first results
      of needle positioning accuracy in various body regions, using a 3-D navigation
      system for brachytherapy and a new patient immobilisation system. PATIENTS AND
      METHODS: Six patients with different manifestations of neoplastic diseases were
      immobilized by a special vacuum system and treated with stereotactic 3-D
      navigational interstitial brachytherapy. RESULTS: The comparison of the simulated
      stereotactic needle positions with the actual needle positions resulted in a mean
      positioning deviation varying from 3.4 to 6.5 mm for 29 needles. The maximum
      positioning deviation lay between 5.7 and 13 mm. CONCLUSION: The results of our
      study show that, despite effective patient immobilisation, an increase in needle
      positioning accuracy is limited by the method of stereotactic 3-D navigation.
      Effects such as modification of body shape caused by the needle application
      morphologic alterations, and inherent inaccuracies within the navigation system
      have an important influence upon accuracy, which it is not yet possible to
      calculate.

PMID- 12426677
TI  - Intraindividual comparison of conventional three-dimensional radiotherapy and
      intensity modulated radiotherapy in the therapy of locally advanced non-small
      cell lung cancer a planning study.
AB  - BACKGROUND: Local failure is the one of the most frequent cause of tumor related
      death in locally advanced non-small cell lung cancer (LAD-NSCLC). Dose escalation
      has the promise of increased loco-regional tumor control but is limited by the
      tolerances of critical organs. PATIENTS AND METHODS: To evaluate the potential of
      IMRT in comparison to conventional three-dimensional conformal planning (3DCRT)
      dose constraints were defined: Maximum dose (D(max)) to spinal cord < 48 Gy, mean
      lung dose </= 24 Gy, D(max) esophagus > 70 Gy in not more than 5 cm of the total
      length. For ten patients two plans were compared: (1) 3DCRT with 5 weekly
      fractions (SD) of 2 Gy to a total dose (TD) of 50 Gy to the planning target
      volume of second order (PTV2). If the tolerance of the critical organs was not
      exceeded, patients get a boost plan with a higher TD to the PTV1. (2) IMRT:
      concomitant boost with 5 weekly SD of 2 Gy (PTV1) and 1.5 Gy to a partial (p)PTV
      (pPTV=PTV2 profile of a line PTV1) to a TD of 51 Gy to the pPTV and 68 Gy to the
      PTV1. If possible, patients get a boost plan to the PTV1 with 5 weekly SD of 2 Gy
      to the highest possibly TD. RESULTS: Using 3DCRT, 3/10 patients could not be
      treated with TD > 50 Gy, but 9/10 patients get higher TD by IMRT. TD to the PTV1
      could be escalated by 16% on average. The use of non-coplanar fields in IMRT lead
      to a reduction of the irradiated lung volume. There is a strong correlation
      between physical and biological mean lung doses. CONCLUSION: IMRT gives the
      possibility of further dose escalation without an increasing mean lung dose
      especially in patients with large tumors.

PMID- 12426678
TI  - Myogenin--a more specific target for RT-PCR detection of rhabdomyosarcoma than
      MyoD1.
AB  - BACKGROUND: MyoD1 and myogenin are differentially expressed in early myogenesis
      and have been identified in rhabdomyosarcoma (RMS). This study evaluates reverse
      transcriptase-polymerase chain reaction (RT-PCR) for MyoD1 and myogenin mRNA as
      diagnostic markers of RMS, and the potential application of this method for the
      detection of small volume disease in bone marrow (BM) and peripheral blood (PB).
      PROCEDURE: Expression of MyoD1 and myogenin mRNA was examined by RT-PCR in RMSs
      (9 alveolar RMS, 10 embryonal RMS, 1 pleomorphic RMS), and 21 other paediatric
      tumor samples (10 neuroblastoma, 10 Ewing sarcomas, and 1 Sarcoma (not otherwise
      specified) (S(NOS)). BM (n = 19) and PB (n = 22) samples from the same RMS study
      population were also examined for MyoD1 and myogenin mRNA expression. RESULTS:
      Positive expression of both markers was demonstrated in adult muscle, but not in
      normal PB. Myogenin mRNA was expressed in 16/18 and MyoD1 mRNA in 12/12 RMSs
      studied. Myogenin was not expressed in 10/10 neuroblastomas, but was present in
      2/10 Ewing sarcomas. However, MyoD1 mRNA was detected in 10/10 Ewing sarcomas and
      7/10 neuroblastomas. Myogenin mRNA was detected in two BM samples from children
      with histologically negative BM and in 1/22 PB samples. Detection of MyoD1 mRNA
      in BM and PB was compromised by the amplification of a similar sized, non
      specific product. CONCLUSIONS: Myogenin mRNA is a more specific marker than MyoD1
      for the diagnosis of RMS. Myogenin mRNA is potentially a useful target for the
      assessment of small volume disease in RMS.

PMID- 12426679
TI  - Markers of endothelial function in pediatric stem cell transplantation for acute
      leukemia.
AB  - BACKGROUND: Endothelial cells and leukocytes intimately interact in inflammation
      and coagulation processes, so that dysregulation of their function may lead to
      both cellular damage and thrombosis, which may occur as complications of bone
      marrow transplantation (BMT). Partially conflicting evidence about endothelial
      markers and their relationships with clinical complications after BMT has been
      reported in the literature. Since almost all studies were carried out in adults,
      we evaluated some recent available markers of endothelial cell function in
      pediatric patients undergoing stem cell transplantation (SCT) for acute leukemia.
      PROCEDURE: We studied the variation in circulating serum endothelial-selectin
      (ES), leukocyte-selectin (LS), thrombomodulin (TM), von Willebrand factor (vWF),
      nitrate + nitrite (NO(2) (-)/NO(3) (-)), endothelin-1 (EN), and tissue factor
      (TF) in 21 pediatric patients undergoing SCT for acute leukemia. RESULTS: ES and
      LS significantly lowered following SCT and returned to pre-SCT levels 4 weeks
      after the procedure. NO(2) (-)/NO(3) (-) markedly increased following SCT. Also,
      TM and vWF increased, although such changes did not reach statistical
      significance. EN and TF did not appreciably change. A strong correlation was
      observed between white blood cell (WBC) count and both ES and LS, as well as
      between such selectins. TM significantly correlated with both selectins and NO(2)
      (-)/NO(3) (-). The pre-conditioning levels of TM and vWF in patients undergoing
      major complications, considered altogether, were significantly lower and higher,
      respectively, than in uncomplicated patients. NO(2) (-)/NO(3) (-) levels 3 and 4
      weeks post-SCT were significantly lower in patients suffering from veno occlusive
      disease. Both selectins were significantly higher in allo- than in auto
      transplanted patients 4 weeks after SCT. CONCLUSIONS: Our data support the
      hypothesis of severe endothelial damage after conditioning and SCT, particularly
      allogeneic. However, the increase in TM, which has strong anticoagulant
      properties, and metabolites of NO, involved also in protective actions, may
      reflect regeneration of the anti-thrombotic endothelial function. This could take
      place after transitory functional impairment, rather than pure endothelial
      damage.

PMID- 12426680
TI  - B-Cell lymphoproliferative disorder not associated with Epstein-Barr Virus in a
      child with relapsed acute lymphoblastic leukemia.
AB  - Lymphoproliferative disorder (LPD) is described in only a few children receiving
      chemotherapy for cancer. In all of them, an association between LPD and EBV
      (Epstein-Barr Virus) was found. We report on a patient who developed LPD not
      associated with EBV while receiving chemotherapy for relapsed acute lymphoblastic
      leukemia (ALL). Despite discontinuation of chemotherapy, administration of
      intravenous immunoglobulins and surgery the patient died. Growing experience with
      this disorder may allow better treatment options in the future and will show
      whether LPD not associated with EBV requires different therapeutic strategies.

PMID- 12426681
TI  - The role of biopsy in the diagnosis of renal tumors of childhood: Results of the
      UKCCSG Wilms tumor study 3.
AB  - BACKGROUND: The United Kingdom Children's Cancer Study Group (UKCCSG) Wilms Tumor
      Study 3 has adopted preoperative chemotherapy for Wilms tumors (WT), but required
      prechemotherapy biopsy for histologic diagnosis. The aims of this review were to
      assess the usefulness and safety of prechemotherapy biopsy and to compare
      histologic features of WT before and after chemotherapy. PROCEDURE: There were
      286 eligible patients but only 241 biopsies and 226 nephrectomy case slides were
      submitted for panel review. The presence of different histologic components of WT
      before and after chemo therapy was retrospectively assessed. RESULTS: Among the
      241 cases, the biopsy material in 9 (4%) was not diagnostic, in 28 (12%) that
      were clinically and radiologically consistent with WT, the biopsy revealed tumors
      other than WT, and in the remaining 204 (85%) WT was confirmed. Of 188 WT
      suitable cases, blastema was found in 89% of tumors at biopsy, but in only 50% at
      nephrectomy; the remainder were either completely necrotic (17%) or showed only
      epithelial and/or stromal elements (33%). Of 182 children who had percutaneous
      cutting needle biopsy (PCNB), a fall in haemoglobin (20% of cases) and local pain
      (19%) were the most common complications. One child required emergency
      nephrectomy due to massive intratumoral bleeding, another had tumor rupture and
      subsequently died, and a third developed a needle track recurrence 8 months after
      the biopsy. CONCLUSIONS: A number of renal tumors (12%) can have the correct
      histologic diagnosis made by PCNB. Preoperative chemo therapy markedly decrease
      in the number of samples with preserved blastema. The morbidity associated with
      PCNB is small. Needle biopsy of any renal mass prior to initiation of
      chemotherapy is recommended.

PMID- 12426682
TI  - Long term survival of children with Burkitt lymphoma in Malawi after
      cyclophosphamide monotherapy.
AB  - BACKGROUND: Between 1991 and 1997, limited funding at times restricted available
      treatment for children with Burkitt lymphoma (BL) to cyclophosphamide (CPM)
      monotherapy at Lilongwe Central Hospital, Malawi. Our objective was to assess
      long-term survival in Malawian children with Burkitt lymphoma (BL) who had
      received one or more treatments with intravenous CPM at 40 mg/kg/dose at 14-day
      intervals. PROCEDURE AND RESULTS: The study population consisted of 92 children
      in whom BL had been confirmed on fine needle aspirates (FNA), a home address had
      been documented on discharge from hospital, and the treatment records could be
      verified. Only the clinical site(s) of disease had been recorded. The M:F ratio
      was 1.4 and median age 8 years. A clinical officer on motorcycle attempted to
      locate the given addresses and interview parents or other sources. In 19
      patients, the address was incorrect. Of 73 evaluable patients, 40 children are
      alive at a mean follow-up time of 59 (range: 29-104) months. The survival rate
      was 63.5% in 52 children with BL of the head only, and 33.3% in 21 children with
      primary disease involving the abdomen or other sites. Survivors had received a
      median number of 6 (range: 1-12), non-survivors 4 (range: 1-12), and untracable
      children 3 (range: 1-11) courses of CPM. CONCLUSIONS: We confirmed that CPM could
      cure children with facial and abdominal BL. The unavoidable bias in the selection
      of patients and the variable amount of CPM given, precludes accurate survival
      estimates. A prospective study with proper staging, assessment of FNA, marrow and
      cerebrospinal fluid with modern techniques, a standard treatment protocol, and
      adequate follow-up will better define the current therapeutic value of CPM
      monotherapy. CPM can be purchased at about 3 US dollars per 500 mg.

PMID- 12426683
TI  - Cognitive deficits in long-term survivors of childhood brain tumors:
      Identification of predictive factors.
AB  - BACKGROUND: To describe cognitive function and to evaluate the association
      between potentially predictive factors and cognitive outcome in an unselected
      population of survivors of childhood brain tumors. PROCEDURE: We studied a
      consecutive sample of 133 patients (76 had received radiotherapy (RT)) who had a
      brain tumor diagnosed before the age of 15 years and were treated during the
      period January 1970 through February 1997 in the Eastern part of Denmark.
      Biologic effective dose of irradiation (BED) was assessed in 71 patients. One
      hundred twenty-seven patients were able to cooperate to WISC-R and WAIS-R.
      Multiple regression models were constructed to evaluate relationships between
      possible risk factors and cognitive outcome. RESULTS AND CONCLUSIONS: The mean
      intelligence (IQ) scores were substantially lower than the expected means of the
      general population. Younger age at diagnosis, tumor site in cerebral hemisphere,
      hydrocephalus treated with shunt, and treatment with RT were found to be
      significant predictors of lower cognitive functions. RT was the most important
      risk factor for impaired intellectual outcome. The mean observed full scale IQ
      was 97.1 (SD = 14.3) for the non-irradiated patients and 78.8 (SD = 14.3) for the
      irradiated patients (adjusted P < 0.001). Verbal IQ, but not performance and full
      scale IQ, had a significant negative correlation to BED to the tumor site (P <
      0.05). These results can be used to identify subgroups of children who are at
      increased risk for cognitive deficits allowing early and goal-directed
      intervention.

PMID- 12426684
TI  - Childhood cancer etiology: recent reports.

PMID- 12426685
TI  - Vincristine neurotoxicity in the presence of hereditary neuropathy.

PMID- 12426686
TI  - Is KL-6 a serum indicator of early pulmonary fibrosis in childhood cancer
      patients?

PMID- 12426687
TI  - Subacute leukencephalopathy after low-dose intrathecal methotrexate in an
      adolescent heterozygous for the MTHFR C677T polymorphism.

PMID- 12426688
TI  - True histiocytic lymphoma following acute lymphoblastic leukemia.

PMID- 12426689
TI  - Mediastinal yolk sac tumor ten years after treatment of intracranial germinoma.

PMID- 12426690
TI  - Congenital intracranial teratoma: prenatal diagnosis and postnatal successful
      resection.

PMID- 12426691
TI  - Resistance to a beta-lactam antibiotic appearing during therapy for enterobacter
      cloacae sepsis in a child.

PMID- 12426692
TI  - Concentration of soluble CD44 standard and soluble CD44 variant V5 in the serum
      of patients with malignant bone tumors.

PMID- 12426693
TI  - Childhood Hodgkin disease treated with COPP/ABV hybrid chemotherapy: a progress
      report.

PMID- 12426694
TI  - A three-year-old girl with a yolk sac tumor in the orbit/maxillary sinus.

PMID- 12426695
TI  - Palliative and terminal care for dying children.

PMID- 12426696
TI  - The Food and Drug Administration's experimental drug approval system: is it good
      for your health?

PMID- 12426697
TI  - Harvesting organs from cadavers: an ethical challenge.

PMID- 12426698
TI  - A cautionary tale: can Catholic health are maintain its identity and integrity
      while meeting the challenges of the marketplace?

PMID- 12426699
TI  - Body, cure thyself.

PMID- 12426700
TI  - The end of abortion and the meanings of "Christian America".

PMID- 12426701
TI  - Life, but not as we know it.

PMID- 12426702
TI  - The profit motive behind too much medical research.
AB  - A conflict of interest in scientific and medical research "between the
      investigation and correct treatment of illness ... and the financial objective of
      making a profit" was addressed in a papal message to an April 5-6 international
      conference on conflicts of interest in science and medicine sponsored by the
      Polish Academy of Sciences. The Vatican released the papal message April 11,
      which was addressed as a letter to Archbishop Jozef Kowalczyk, apostolic nuncio
      to Poland. The pope said that "there is a risk that science-based businesses and
      health care structures can be set up not in order to provide the best possible
      care for people in accordance with their human dignity but in order to maximize
      profits and increase business, with a predictable lowering in the quality of
      service of those unable to pay." For example, the pope said, the pharmaceutical
      industry, "driven by the pursuit of profit and catering to what could be called
      'medicine of desires' ... has favored research which as already placed on the
      world market products contrary to the moral good, including products which are
      not respectful of procreation and even suppress human life already conceived."
      The pope expressed concern about how priorities are set for pharmaceutical
      research, as well as about cost-containment imperatives in hospital medical care.
      His letter was written in English. The text follows.

PMID- 12426703
TI  - Physician-assisted suicide; terminal illness; state constitution.

PMID- 12426704
TI  - Living will; nutrition, hydration; persistent vegetative state; clear and
      convincing evidence.

PMID- 12426705
TI  - The Americans with Disabilities Act: implications for managed care for persons
      with mental illness and addiction disorders.
AB  - This Issue Brief, prepared for the Substance Abuse and Mental Health Services
      Administration, examines the Americans with Disabilities Act ("the ADA") and its
      application to managed care. The ADA provides important protections for persons
      with disabilities who are members of managed care arrangements, regardless of
      whether their membership is sponsored by an employer, Medicare, or Medicaid or is
      purchased privately. The interaction between the ADA and managed care is complex,
      and different issues can arise under publicly and privately sponsored plans.

PMID- 12426706
TI  - Selected key issues in the development and drafting of public managed behavioral
      health care carve-out contracts.
AB  - The development of managed behavioral health care carve-out contracts covering a
      discrete subset of benefits available for use by persons with mental health
      and/or substance abuse disorders poses major challenges for public purchasers.
      This Issue Brief explores several key issues that arise when drafting such
      agreements. Many of the issues that arise in the drafting of carve-out agreements
      will require the public purchaser to resolve basic policy questions well before
      the drafting of requests for proposals or contracts can proceed. Analyses of
      public sector managed behavioral health care contracts by attorneys at the Center
      for Health Policy Research suggest that there are four essential areas that must
      be addressed if mental health and substance abuse services are carved-out (either
      by the purchaser or by a comprehensive managed health care entity): (1) what
      population is eligible for enrollment; (2) what services is the contractor
      expected to furnish; (3) what triggers a duty on the part of the mental health or
      substance abuse carve-out contractor to provide services; and (4) how are
      services furnished by the managed behavioral health care contractor integrated
      with or coordinated with services furnished by a beneficiary's primary health
      care provider, with pharmaceutical benefits, and with other services that may be
      available to a beneficiary through a fee-for-service or other mechanism. However
      a purchaser chooses to resolve these four issues, it is essential that parallel
      clarifying clauses are also built into the contracts of primary health care
      providers and other entities providing needed services for persons whose mental
      health and substance abuse service needs are covered by the carve-out. Underlying
      all of these issues is the fact that ambiguity, vagueness, or failure to define
      terms and responsibilities can create unexpected and unwelcome clinical and
      financial liabilities to purchasers.

PMID- 12426707
TI  - Cultural competence in Medicaid managed care purchasing: general and behavioral
      health services for persons with mental and addiction-related illnesses and
      disorders.

PMID- 12426708
TI  - Designing a complaint and grievance system and other member assistance services
      under Medicaid managed care.

PMID- 12426709
TI  - Coverage decisions versus the quality of care: an analysis of recent ERISA
      judicial decisions and their implications for employer-insured individuals.

PMID- 12426710
TI  - An evaluation of agreements between managed care organizations and community
      based mental illness and addiction disorder treatment and prevention providers.
AB  - This Issue Brief, prepared for the Substance Abuse and Mental Health Services
      Administration (SAMHSA), examines contracts between managed care organizations
      (MCOs) and community-based providers of mental illness and addiction disorder
      treatment and prevention services (MI/AD providers). Building upon initial
      research published in 1997, this brief explores in depth one of the most hidden
      aspects of managed care: the relationship between the managed care organizations
      and health care providers.

PMID- 12426711
TI  - [Autonomic dysfunction in cardiopulmonary diseases].

PMID- 12426712
TI  - [Autonomic functions in healthy probands. Autonomic control of the cardiovascular
      system and lung function and their coordination].

PMID- 12426713
TI  - [Autonomic dysfunction and orthostatic intolerance].

PMID- 12426714
TI  - [Autonomic dysfunction in heart diseases and diabetes mellitus. Monitoring and
      diagnosis].

PMID- 12426715
TI  - [The autonomic nervous system and cardiac arrhythmias].

PMID- 12426716
TI  - [Autonomic nervous system and the respiratory system].

PMID- 12426717
TI  - [Sleep apnea, autonomic dysfunction and cardiovascular morbidity].

PMID- 12426718
TI  - [Autonomic dysfunction in critically ill patients].

PMID- 12426719
TI  - [Skin efflorescences in infectious diseases. I: Skin efflorescences in viral
      diseases].

PMID- 12426720
TI  - [Phenotypic healing of factor II deficiency by liver transplantation].

PMID- 12426721
TI  - [48-year-old patient with right sided flank pain and hypertension of recent
      onset. Secondary hypertension caused by embolic renal infarcts due to dissecting
      renal artery aneurysms].

PMID- 12426722
TI  - [Sharing patient medical records with the referred physician].

PMID- 12426723
TI  - [Recommendations for prevention of thromboembolism in elderly internal medicine
      patients].

PMID- 12426724
TI  - [Acute hepatitis C. Therapy with interferon alpha-2b].

PMID- 12426725
TI  - [BSE and vCJD. New infectious prion diseases].

PMID- 12426726
TI  - [Epidemiology of BSE and vCJD].

PMID- 12426727
TI  - [Etiology, pathology and diagnosis of prion diseases in humans].

PMID- 12426728
TI  - [Clinical aspects, diagnosis and therapeutic possibilities of human prion
      diseases].

PMID- 12426729
TI  - [Clinical aspects of risk assessment and prevention of nosocomial transmission of
      classical and variant CJD].

PMID- 12426730
TI  - [Glomerulonephritis].

PMID- 12426732
TI  - [Somnolent patient with progressive metabolic acidosis, increased osmotic gap and
      acute renal failure. Ethylene glycol poisoning].

PMID- 12426731
TI  - [Recurrent aspiration, vomiting and coordination disorders. Neurogenic
      deglutition disorder in Fahr disease. HP-positive gastritis].

PMID- 12426733
TI  - [Hepatitis B vaccination strategy of health personnel].

PMID- 12426734
TI  - [Modern pain therapy].

PMID- 12426735
TI  - [Screening with diagnostic imaging--challenge for radiologists].

PMID- 12426736
TI  - [Screening from the epidemiological viewpoint].
AB  - The scope of screening is to identify disease in a clinically inapparent stage in
      order to treat more effectively. However, the required application of a test to
      large subsets of the population implies risks which cannot be ignored. Thus, the
      introduction of a test for use in screening without previously established
      evidence of a benefit which exceeds potential harm by far cannot be justified.
      With regard to cancer, evidence of effectiveness has been proven for screening on
      cervical (Papsmear), breast (mammography) and colorectal (faecal occult blood
      test) cancer. The routine application of a screening procedure which has been
      proven effective provides the benefit in terms of mortality reduction seen in the
      trials only if the entire screening chain, from the test over potentially
      required assessment to treatment, is offered with highest quality and is under
      permanent quality control.

PMID- 12426737
TI  - [Cost effectiveness of screening procedures for early detection of prostatic
      carcinoma: an overview].
AB  - PURPOSE: The authors attempted to provide an overview of current concepts and the
      status of research in the field of cost effectiveness analysis (CEA) of screening
      for prostate cancer (PCA). MATERIAL AND METHODS: Basic concepts and methods of
      CEA were reviewed. Examples of CEA-related studies of PCA were obtained from
      pertinent literature through medical databases. RESULTS: Screening for PCA has so
      far been restricted to limited groups of health care recipients, usually within
      the framework of clinical trials. In those trials, screening for PCA usually
      results in higher numbers of PCAs being detected at lower average stages in a
      given population. As a consequence of screening, the rate of potentially curable
      PCAs increases. However, it has not yet been demonstrated that screening for PCA
      decreases PCA-related mortality or morbidity from metastatic PCA. On the other
      hand, additional costs are associated with the screening measure and with
      increased use of resources for diagnosis and treatment of the additional PCAs
      detected through screening. CONCLUSIONS: Throughout the European Union and North
      America, mass screening for PCA has not been implemented. This may chiefly be due
      to the current lack of information on long term benefits of PCA screening,
      particularly disease-specific survival. Currently, major studies are underway to
      assess the effects of PCA screening and its cost effectiveness. These studies
      include the US-American prostate, lung, colon and ovary trials (PLCO) and the
      European randomised study of Screening for Prostate Cancer (ERSPC).

PMID- 12426738
TI  - [Early lung cancer detection with low-dose CT: an update].
AB  - Lung cancer is the leading cause of death from malignancy. Due to a lack of early
      symptoms patients usually undergo therapy at advanced tumor stages when prognosis
      is poor. Feasibility studies of low-dose spiral CT screening of heavy smokers
      have shown that many small, resectable lung cancers can be diagnosed at early
      stages using simple diagnostic algorithms based on size and attenuation of
      detected pulmonary nodules with a small proportion of invasive procedures for
      benign lesions. Preliminary results of repeat screening confirms small size and
      favourable stage distribution of detected cancers, using even simpler diagnostic
      algorithms: additional diagnostic procedures are only required in new or growing
      nodules whereas follow-up with low-dose CT is sufficient in nodules that appear
      unchanged to exclude slow growth. However, mortality reduction by lung cancer
      screening with low-dose CT has yet to be demonstrated. Several randomised
      controlled trials are under way to assess possible mortality reduction by
      comparison of mortalities in a screening group and a control group. It is hoped
      that through international cooperation data from these trials can be pooled to
      allow for statistically significant conclusions as early as possible.

PMID- 12426739
TI  - [Ultrasound screening of renal cell carcinomas].
AB  - The increasing number of incidentally by ultrasound detected small renal cell
      carcinomas raises the question of the practicability and efficacy of a systematic
      screening for renal cell carcinoma by ultrasound. A two year screening program
      for renal cell carcinoma (RCC) was established for the general population (age >
      40 years) in two cities, Mainz and Wuppertal. In cooperation with different
      health insurers, the organizers recruited general practitioners, internists and
      urologists in private practice who were experienced in and equipped for
      performing renal ultrasound. The screening was offered in the form of a cost free
      renal ultrasound in the first year and a re-examination in the second year. For
      any equivocal/positive renal mass, a reference ultrasound was provided the
      urology departments at the two university hospitals. 9959 volunteers participated
      in the screening program (49% male, 51% female) in the first year. The mean age
      was 61 (40-94) years. 79% of these participants returned for re-examination in
      the second year. Thirteen (0.1%) subjects were found to have a renal mass, of
      which nine were RCC. The sensitivity of the program was 82% (one year of follow
      up). The predictive value was 2% for equivocal findings on initial exam and 50%
      for positive findings. The incidence of other abnormal findings was 12%. The
      screening program was well accepted by physicians in private practice and by the
      eligible population. The method proved effective, especially if equivocal
      findings were re-studied by reference sonography before further imaging studies
      such as CT and MRI were performed.

PMID- 12426740
TI  - [Virtual colonoscopy--chances for a screening procedure?].
AB  - In principle, virtual colonoscopy is capable to be used as method for early
      detection of colorectal cancer (CRC), even if the accuracy of the method and
      radiation exposure are matters discussion in the radiological community. Virtual
      colonoscopy is able to detect any pathology which is relevant for early detection
      of CRC especially when using multislice CT, but also with single slice CT. The
      diagnosis of small lesions, less than 7 mm in diameter (polyps and flat lesions)
      is still problematic as it is in conventional colonoscopy. The exposure to x-rays
      in asymptomatic patients, without any increased risk of developing cancer is
      highly problematic and should be reduced to a minimum. Using special post
      processing filters on the volume dataset it can be shown that a tube current of
      20 mAs is sufficient without any loss in accuracy. Measurements on the Alderson
      phantom showed, that an effective dose exposure of 1.2 mSv is obtained using
      these reduced mAs values. It has to be differentiated between virtual colonoscopy
      for early detection of polyps and CRC in individual patients or as a screening
      examination of a large population. Virtual colonoscopy as a screening examination
      necessitates reduction of radiation dose, a high degree of automatization in 3D
      reconstructions as well as the assessment of the entire mucosa. High risk
      patients, whom refuse fibreoptic colonoscopy should undergo virtual colonoscopy.
      Virtual colonoscopy has a good chance to become an accepted tool for general
      screening, if efficient dose reduction, complete visualization of the colon
      mucosa and automatization of the post processing procedures can be achieved.

PMID- 12426741
TI  - [Prevention without radiation--a strategy for comprehensive early detection using
      magnetic resonance tomography].
AB  - Recent advances in hardware technology, noninvasiveness, lack of radiation and
      high diagnostic accuracy combine to allow the usage of magnetic resonance imaging
      (MRI) for disease screening in asymptomatic people. 175 volunteers were examined
      by means of a comprehensive 60-minute MR-screening-protocol covering four organ
      systems: the brain, the arterial vasculature, the heart and the colon. In 28% of
      the cases vascular pathology (cerebral, peripheral or cardiovascular) was
      detected. In up to 17% of the single examination parts relevant incidental
      findings were seen. The outlined comprehensive MR-protocol is an accurate and
      patient-friendly imaging tool for the detection of vascular pathology as well as
      colonic polyps. The socio-economic relevance of this screening exam has to be
      further investigated in larger patient cohorts.

PMID- 12426742
TI  - [Pre- and postnatal kidney screening compared: an analysis of 34,450 newborn
      infants of the Mainz model birth register].
AB  - Malformations of the internal urogenital system are common. The birth registry
      "Mainz Model" reflects population-based prevalence of renal malformations,
      calculates sensitivity rates of the prenatal ultrasonographic findings and
      demonstrates rates of surgery needed. METHOD AND MATERIAL: During the study
      period (1990-2001) all newborns of the area of Mainz were examined according to a
      standardized procedure including ultrasonography of the kidneys. Pathology
      reports were reviewed for stillbirth, abortions (> 15.SSW) and induced abortions.
      Beside these clinical findings, since 1996 (after implementation of a special
      ultrasonographic malformation screening according to the german maternity
      guidelines) the results of prenatal as well as postnatal ultrasonographic
      examinations of the kidney were recorded. All children with pathologic diagnoses
      of the kidneys were retrospectively analysed. Data about the follow up and
      surgery if needed, were collected. RESULTS: During the study period from 1990
      2001 34.450 newborns were examined. 407 of the neonates (1.2%) had a malformation
      of the kidney. During the study period from 1996-2001 13.162 neonates were
      examined. 194 neonates (1.5%) had pathologic and 225 neonates (2.07%) had
      controllable findings. The most common diagnoses were supernumerary kidney,
      hydronephroses und megaureter. 22 neonates (12.8%) underwent surgery. The
      sensitivity of the prenatal ultrasonography was 36% and the specificity was 99%.
      CONCLUSION: Both, the prenatal as well as the postnatal ultrasonographic
      screening of the kidneys are ingenious examinations. The prenatal examination
      detects life threatening malformations of the kidneys. The postnatal examination
      completes early diagnosis of renal defects by uncovering the malformations, which
      have been missed prenatally. The prevalence of malformations of the kidney is
      comparable to the one of hip dislocation. We therefore conclude, that
      ultrasonographic screening of the kidneys is needed.

PMID- 12426743
TI  - [Ultrasound screening of the infant hip].
AB  - The sonographic screening of the hip has led to a marked decrease in treatment of
      children with developmental dysplasia of the hip (ddh) as inpatients. The
      prognosis for this disorder has greatly improved in the past few years due to
      early diagnosis and correspondingly early beginning of therapy, in many cases by
      using simple therapeutic methods. This undisputed success has been achieved with
      a high treatment rate in comparison with international practice (6.4%). The
      expectancy of reducing the number of checks, and thus costs, by deciding on the
      4th to 6th week of life as the time for screening has not been met.

PMID- 12426744
TI  - [Contrast-enhanced multislice CT in detection and evaluation of abdominal
      neoplasms].
AB  - PURPOSE: Demonstration of clinical value of contrast-enhanced multislice CT (MS
      CT) for evaluating abdominal neoplasias with focus on primary liver tumors,
      pancreatic carcinoma and colorectal carcinoma. MATERIAL AND METHODS: Optimized
      examination protocols for multislice CT are presented using oral and intravenous
      application of contrast agent. RESULTS: For primary liver tumors like
      hepatocellular carcinoma and cholangiocellular carcinoma diagnostic accuracies
      are achieved from 82 to 94% and for pancreatic carcinomas from 85 to 96%. For
      diagnosis of colorectal carcinoma results are relevant for staging of primary
      tumor, lymph node metastases and further metastases in liver and lung. The
      results achieve values from 86 to 92% for sensitivity, specificity and diagnostic
      accuracy. CONCLUSION: Contrast-enhanced multislice CT proves to be a quick and
      reliable examination technique for detection and staging of abdominal neoplasms
      with a focus on the epigastric region and colorectal carcinoma.

PMID- 12426745
TI  - [Apical pulmonary coin lesion. Sarcoidosis].

PMID- 12426746
TI  - [Functional magnetic resonance tomography (fMRI). 1: Basic principles and
      measuring techniques].

PMID- 12426747
TI  - [The anterior cruciate ligament as focus of interest].

PMID- 12426748
TI  - [History of surgery of the anterior cruciate ligament].
AB  - Early comments on the anterior cruciate ligament were found in ancient
      literature, and the first scientific reports were published in the nineteenth
      century. The first surgical treatment of a ruptured anterior cruciate ligament
      was carried out in 1895 by Robson performing a primary suture of the torn
      ligament. In 1903 F. Lange suggested a complete replacement of the injured
      ligament using silk ligaments and in 1914 Grekow was probably the first who
      recommended autogenous transplants by using a fascia lata strip. In 1917 Hey
      Groves presented his surgical technique that was the fundament for reconstruction
      surgery in the following years. Today, the autogenous transplant is accepted to
      be the golden standard for replacement of the injured anterior cruciate ligament.
      The bone-tendon-bone transplant of the patellar ligament and the semitendinosus
      or gracilis tendon are recommended by most surgeons. In the history of anterior
      cruciate ligament surgery, the surgical technique of the operative procedures has
      also changed. The evolution started with open arthrotomy followed by mini
      arthrotomy and led to arthroscopically assisted replacement of the anterior
      cruciate ligament.

PMID- 12426749
TI  - [Anatomy and function of the anterior cruciate ligament].
AB  - The anterior cruciate ligament originates at the medial wall of the lateral
      femoral condyle and inserts into the middle of the intercondylar area. It
      contributes significantly to the stabilization and kinematics of the knee joint.
      The femoral origin is oval and is located in the posterior aspect of the lateral
      femoral condyle. Therefore, it is difficult to visualize the femoral origin
      arthroscopically. This might be one reason for anterior malpositioning of the
      femoral bone tunnel during anterior cruciate ligament reconstruction. The
      position of the femoral origin is behind the center of rotation of the knee
      joint; therefore, it becomes tense when the knee is extended. The tibial
      insertion is oval and its center is nearly in the middle of the tibial plateau.
      Definite landmarks for tibial tunnel placement in anterior cruciate ligament
      reconstruction are the distance between the central insertion point at the
      intercondylar floor and the posterior cruciate ligament (7-8 mm) and the anterior
      horn of the lateral meniscus. The anterior cruciate ligament consists of multiple
      small fiber bundles. From a functional point of view, one can differentiate the
      anteromedial and posterolateral fiber bundles. The anteromedial fibers are tense
      during a greater range of motion than the posterolateral fibers. The main part of
      the anterior cruciate ligament consists of type I collagen-positive dense
      connective tissue. The longitudinal fibrils of type I collagen are divided into
      small bundles by thin type III collagen-positive fibrils. In the distal third,
      the structure of the tissue varies from the typical structure of a ligament. In
      this region, the structure of the tissue resembles fibrocartilage. Oval-shaped
      cells surrounded by a metachromatic extracellular matrix lie between the
      longitudinal collagen fibrils. The femoral origin and the tibial insertion have
      the structure of a chondral apophyseal enthesis. Near the anchoring region at the
      femur and tibia, there should be various mechanoreceptors, which might have an
      important function for the kinematics of the knee joint. The blood supply of the
      anterior cruciate ligament arises from the middle geniculate artery. The ligament
      is covered by a synovial fold where the terminal branches of the middle and the
      inferior geniculate artery form a periligamentous network. From the synovial
      sheath, the blood vessels penetrate the ligament in a horizontal direction and
      anastomose with a longitudinally orientated intraligamentous network. The
      distribution of blood vessels within the anterior cruciate ligament is not
      homogeneous. We detected three avascular areas within the ligament: Both
      fibrocartilaginous entheses of the anterior cruciate ligament are devoid of blood
      vessels. A third avascular zone is located in the distal zone of fibrocartilage
      adjacent to the roof of the intercondylar fossa.

PMID- 12426750
TI  - [Diagnosis of rupture of the anterior cruciate ligament].
AB  - Clinical examination has remained the key for diagnosis of meniscal and ligament
      lesions of the knee. Economical use of imaging techniques is based on adequate
      clinical examination. Standard radiographic examination is still a simple and
      valuable method. Magnetic resonance tomography has made great progress during the
      past few decades. For this reason, this article centers on this imaging modality.

PMID- 12426751
TI  - [Transplant selection for primary replacement of the anterior cruciate ligament].
AB  - Various graft choices have evolved over the past few decades for the primary
      reconstruction of the anterior cruciate ligament (ACL). Three predominant
      autologous graft choices exist today: patellar, hamstring, and quadriceps
      tendons. Clinical studies have as yet failed to demonstrate significant
      differences in clinical outcome among these grafts, irrespective of their varying
      fixation techniques. Therefore, other factors such as graft harvest morbidity
      have become more important when comparing different grafts. These factors can
      differ substantially between the grafts, depending on the type of patients'
      activities, the injury pattern, and the associated injuries of the knee joint. A
      basic knowledge of these factors and the parameters that affect the mechanical
      and biological behavior of the reconstructed ACL can help to find the appropriate
      graft choice for each individual patient. Factors such as harvest site morbidity,
      fixation techniques, osseous integration, and tunnel widening are discussed based
      on current clinical and basic science studies. Finally, an outlook is given for
      future alternatives with evolving techniques for tissue-engineered grafts,
      allografts, or the transplantation of xenogeneic donor tissue.

PMID- 12426752
TI  - [Bore canal site in surgical reconstruction of the anterior cruciate ligament.
      Position--placement errors--anatomic measurement].
AB  - The goal of surgical reconstruction of the anterior cruciate ligament (ACL) is
      restoration of its function as closely as possible to a physiological roll-and
      glide mechanism. Clinical success means knee joint stability, physiological joint
      biomechanics, and full range of motion. Anatomical placement of the graft
      insertion points and anatomical direction of the drilled tunnels are necessary to
      obtain isometric (anatometric) conditions. Despite technical advances in
      (arthroscopic) surgery, it is not yet possible to obtain absolute "isometricity"
      for ACL grafts. However a "physiological" or "relative" isometricity seems to be
      sufficient for successful clinical results. In 1986 Werner Muller proposed the
      term "anatometrics" in ACL reconstruction to describe this graft behavior and
      function. The knee joint is a complex motion system including many active and
      passive stabilizing elements (ligaments, tendons, muscles) as well as a
      proprioceptive function of the central column ligaments. Reconstruction of this
      "system" required the surgeon to have good surgical skills and a well-based
      knowledge of knee anatomy and function. Wrong placement of insertion points and
      bone tunnels carry the risk for ensuing graft insufficiency and resultant joint
      instability. The knee "prefers" a destroyed graft over an overconstrained
      biomechanical situation! Intraoperative factors for failure may be technical
      mistakes and intraoperative measuring devices for isometry, which might not
      guarantee true relations in a ligamentous deficient knee. Therefore,
      visualization of insertion points (and drilling) under direct arthroscopic view
      is still preferred over generalized rules and distances as proposed by many
      commercially available rulers and tapers. Recently, navigation and computer
      assisted placement techniques have been developed. The clinical standards of
      those techniques are still under investigation. At our institution, an
      arthroscopic approach (visualization, palpation) for ACL reconstruction with a
      bone-patellar-tendon-bone graft technique is used.

PMID- 12426753
TI  - [Replacement of the anterior cruciate ligament with a patellar tendon
      transplant].
AB  - The bone-patellar tendon-bone graft (BTPB) was the most commonly used graft for
      many years. The scientific database is more complete than for every other graft
      option. This review article presents the surgical techniques of ACL
      reconstruction with the BPTB graft, aspects of rehabilitation, clinical results,
      and postoperative problems with special emphasis on donor site morbidity.

PMID- 12426754
TI  - [Anterior cruciate ligament reconstruction with the semitendinosus-gracilis
      tendon transplant].
AB  - ACL reconstruction using autogenous semitendinosus and gracilis tendons has
      become more popular in the past, mainly because of less frequent donor site
      morbidity and a high level of patient acceptance. Numerous tibial and femoral
      fixation techniques have been described, which differ considerably with respect
      to the site of fixation (cortical, tunnel, near the joint line) and biomechanical
      parameters. Most commonly used femoral fixation techniques include fixation
      buttons (EndoButton), interference screws (titanium or biodegradable), or
      transfixation techniques. For tibial fixation, biodegradable interference screws,
      often in combination with a tibial fixation button or a suture over a bone
      bridge, are used most commonly. Each fixation technique has specific
      disadvantages, which cannot be completely overcome even with a precise operative
      procedure. Therefore, combined fixation techniques (hybrid fixation) have been
      developed to enhance biological healing of the graft while simultaneously
      providing sufficient initial mechanical strength. Furthermore, an atraumatic
      graft harvest and preparation depending on the desired fixation technique is
      essential. Most fixation techniques exhibit less initial mechanical strength
      compared to bone-tendon-bone grafts, which should be considered in a moderate
      rehabilitation program.

PMID- 12426755
TI  - [Complex instability of the anterior knee].
AB  - Complex knee instability involves the anterior cruciate ligament (ACL) and one or
      more major stabilizers of the knee [medial collateral ligament (MCL), lateral
      collateral ligament (LCL), posterior cruciate ligament (PCL)]. The medial side
      has a high healing potential and does not need operative treatment in most cases
      if ACL reconstruction is performed. Reconstruction of the medial ligament complex
      is indicated in gross instability of the medial meniscus fixation, dislocation of
      the MCL into the joint, and large dislocated bony avulsions. Injuries on the
      lateral side do not heal spontaneously and require acute operative treatment
      (first 2 weeks). Frank knee dislocations and gross multiligament injuries should
      be reduced acutely, and the integrity of the vascular structures must be examined
      closely. In a European multicenter study, operative treatment with reconstruction
      of both cruciate ligaments and functional rehabilitation gave better results than
      conservative treatment with immobilization of the joint.

PMID- 12426756
TI  - [Revision of failed anterior cruciate ligament reconstruction].
AB  - Failures of ACL reconstruction still occur despite improved arthroscopic methods
      and new technical instruments. The reasons for failures, which are mostly related
      to technical surgical errors, must be recognized, analyzed, and considered for
      the planning and execution of revision ACL surgery. This review article describes
      the reasons for failed ACL reconstructions, indications, preoperative evaluation,
      planning, and performance of the operative procedure as well as the issue of
      rehabilitation. The strategies are evaluated for graft selection, staging of the
      revision, and the steps of the operative procedure including hardware removal,
      tunnel placement, graft fixation, or additional operations. Special attention is
      given to the dilemma of arthrofibrosis and its management in ACL revision cases.
      Since the results are worse after revision than following primary ACL surgery,
      the operative procedure has to be tailored to the needs of the patient, planned
      carefully, and performed by an experienced knee surgeon.

PMID- 12426757
TI  - [Arthrofibrosis].
AB  - Arthrofibrosis represents a severe complication in joints after trauma and
      surgery, with loss of motion due to an excessive fibrotic response in the repair
      process. Patients with primary arthrofibrosis suffer from a general fibrotic
      healing response after injury or surgery, while patients with secondary
      arthrofibrosis exhibit loss of motion due to a local fibrotic healing response.
      Nonisometric positioning of cruciate ligament grafts, notch impingement, or
      hardware problems may lead to secondary arthrofibrosis. In contrast, the etiology
      of primary arthrofibrosis is still unknown. There are alterations of the
      extracellular matrix with an increase of collagen type VI expression similar to
      other local or systemic fibrotic disorders. A chronic inflammatory process may
      play a crucial role in the mechanism of primary arthrofibrosis and may indicate
      an immune response. It may be reasonable to assume that primary arthrofibrosis is
      an independent disease while secondary arthrofibrosis represents a true
      complication in joints resulting from trauma and surgery. Secondary
      arthrofibrosis can commonly be managed by arthroscopic procedures. Treatment of
      primary arthrofibrosis should usually include resection of dense fibrotic tissue
      in the anterior compartment of the knee and open posterior capsulotomy to allow
      full extension of the knee joint.

PMID- 12426758
TI  - [Rehabilitation after anterior cruciate ligament reconstruction].
AB  - The "Frankfurt rehabilitation regimen" following anterior cruciate ligament
      reconstruction is presented. ACL rehabilitation is discussed in the light of
      knowledge on knee biomechanics and proprioception as well as clinical results of
      reconstruction. Special emphasis is given to exercise therapy.

PMID- 12426759
TI  - [Gene transfer in cruciate ligament surgery. Natural science-based principles and
      possible clinical applications].
AB  - Current challenges in anterior cruciate ligament surgery include graft remodeling
      and tendon-to-bone healing. The development over the past few decades of methods
      for delivering genes to musculoskeletal tissues has stimulated interest in its
      application for orthopedic problems, including anterior cruciate ligament
      surgery. Despite substantial progress, a number of technical issues need to be
      addressed before gene transfer might be considered as an approach to improve the
      structural and functional properties of anterior cruciate ligament grafts. The
      aim of this review is to illustrate the principles of somatic gene transfer and
      to apply them to the cells that constitute the anterior cruciate ligament.
      Special characteristics that dictate the experimental strategies will be
      outlined.

PMID- 12426761
TI  - The new world of medicine: prospecting for health.
AB  - Throughout past millennia, human beings have shared the common goal of improving
      health for longevity. However, different cultures around the world have developed
      their own approaches to achieve this goal. Various traditions have emerged,
      rendering distinct medical systems such as Ayurveda, Yoga, Chinese-Japanese
      medicine, shamanism, and Native American healing. Traditional medicine involves a
      holistic approach to the human body to integrate healing with culture,
      environment, and tradition. Modern allopathic medicine originated from Greco
      Roman Medicine and Northern European traditions and is built on the science of
      anatomy, physiology, and biochemistry and the structure-function relationship
      between cells, tissues, and organs. This foundation focuses on diagnosis,
      treatment, and cure for acute illnesses via potent pharmaceutical drugs, surgery,
      radiation, and other treatment modalities. Within this past century, we have
      doubled the life-span of human beings. Genomic medicine, including stem cell
      research, cloning, and gene therapy, will increase our capability to treat even
      more diseases. In the new millennium, we face more chronic illnesses related to
      aging, environment, and lifestyle, such as cancer, diabetes. osteoporosis, and
      cardiovascular diseases. Thus, health care providers face the challenge of
      prospecting for health and disease prevention. Modern science and medical
      advancements provide the rationale for the integration of various traditional
      healing techniques, which have been termed Alternative and Complementary
      Medicine, to promote healing, health, and longevity. Advances in medicine must
      include the holistic approach of traditional medicine to face the current
      challenges in health care. Therefore, the New World of Medicine must fuse the
      antiquity of ancient healing with the innovations of modern medicine to increase
      life-expectancy and improve quality of life throughout the world.

PMID- 12426762
TI  - Lessons from a career as a physician scientist--looking back and looking forward.

PMID- 12426763
TI  - Joy of scientific pursuance and medical practice, an art.

PMID- 12426760
TI  - [Meniscus lesions].

PMID- 12426764
TI  - Molecular cloning of two guinea pig liver gap junction proteins, connexin32 and
      connexin26.
AB  - Intercellular coupling of hepatocytes through gap junctions facilitates exchange
      of small metabolites or ions, and contributes to maintenance of tissue
      homeostasis. As protein constituents of the liver gap junction channels,
      connexin32 (Cx32) and Cx26 have been identified. By use of rat cDNA probes, we
      cloned cDNAs for guinea pig homologs of Cx32 and Cx26, and compared their amino
      acid sequences with those of other species. The deduced primary structure of
      guinea pig Cx32 was 283 amino acids long and contained 98% identical amino acids
      to the rat and human Cx32. Only six amino acid exchanges were detected between
      the guinea pig and rat Cx32. On the contrary, the deduced amino acid sequence of
      guinea pig Cx26 (226 amino acids long) was 91 and 89% identical to the rat and
      human Cx26, respectively. Twenty-one amino acid exchanges were found between the
      guinea pig and rat, and the divergence was mostly located in cytoplasmic domains
      of Cx26. These results suggest that Cx26 shows structural diversity between
      species, while Cx32 is highly conserved.

PMID- 12426765
TI  - A Japanese case of severe refractory adult Still's disease: serum interleukin-18
      is a possible marker of the response to low-dose cyclosporin A therapy.
AB  - A 22-year-old man was admitted to our hospital with a high fever, fatigue, mild
      arthritis, and bilateral pleural effusions. Laboratory tests revealed a high ESR,
      leukocytosis, high serum C-reactive protein level, and high serum ferritin level.
      Various antibiotics had been given by a local hospital with no response. He was
      diagnosed as having severe refractory adult Still's disease and was subsequently
      treated with high-dose steroid therapy and low-dose cyclosporin A. The serum
      interleukin-18 level was monitored throughout treatment and was found to be a
      potentially useful marker of disease activity as well as of the response to
      cyclosporin A therapy.

PMID- 12426766
TI  - The role of particle size distribution on bioavailability of cyclosporine: novel
      drug delivery system.
AB  - During the long period of cyclosporine-containing dosage forms development a lot
      of significant findings have been done especially in the field of drug delivery
      systems. Currently available drugs are based, from technological point of view,
      on self-dispersible drug delivery systems, which contain cyclosporine solved in
      pharmaceutically acceptable vehicle. One can find difference among particular
      systems a) at particle size distribution after dispergation, b) at composition
      and c) at bioavailability of cyclosporine. As far as improvement of
      bioavailability between original brand leader formulation Sandimmune and recent
      brand leader formulation Neoral was followed by significant improvement in
      particle size distribution it was generally assumed that the reason for this
      improvement have been found. Several other formulations e.g. Consupren or SangCyA
      -self-dispersible systems, more or less correspond with above mentioned theory
      that smaller is better and by this principle bridged liquid based dosage forms
      with solid dosage forms. Bioavailability of novel drug delivery system which
      gives coarse dispersion with average particle size between 1-150 microns when
      dispersed have been tested on healthy volunteers. No difference among
      pharmacokinetic parameters of novel drug delivery system and microemulsion system
      have been observed in spite of fact that average particle size of novel system is
      almost 1000x bigger.

PMID- 12426767
TI  - The effect of particle size on bioavailability in cyclosporine preparations based
      on submicron dispersions.
AB  - The effect of particle size on bioavailability of 9 different formulations with
      cyclosporine A was studied. A common feature of all the formulations was the
      ability to form submicron dispersions under dilution. The composition of
      individual formulations was chosen in such a way that they were based on same or
      similar excipients. For each formulation, pharmacokinetic study was carried out
      in beagle dogs. On groups of 10 dogs, the average AUC was evaluated. Particle
      size of formulations under dilution in water was measured by laser scattering
      method. According to the results of particle size measurement, the formulations
      were sorted out into groups of similar particle size distribution by use of two
      methods of multivariate statistical analysis. The average AUC within groups and
      between-groups was compared, and the effect of particle size on bioavailability
      was evaluated.

PMID- 12426768
TI  - Lipid-based vehicle for oral drug delivery.
AB  - With an increasing number of lipophilic drugs under development, homolipids and
      heterolipids have gained renewed interests as excipients for oral drug delivery
      systems. Oral administration has many advantages for chronic drug therapy. It is
      relatively safe, convenient for the patient and allows self administration. This
      article is not intended to review the broad area of lipid-based vehicle for oral
      drug delivery comprehensively. The rationale behind choosing lipids materials for
      pharmaceutical dosage forms and their applications is discussed. It also comments
      on the methods for monitoring the physicochemical properties of vehicles and
      formulations and describes a range of pharmacopoeial excipients suitable for
      these purposes. The excipients selected here are pharmacopoeial in European
      Pharmacopoeia 4th Ed., United States Pharmacopoeia 24th Ed./National Formulary
      19th Ed. and Japanese Pharmacopoeia 13th Ed. or are drafted in Pharmaeuropa and
      Pharmacopoeial Forum. Widening availability of lipidic excipients with specific
      characteristics offer flexibility of application with respect to improving the
      bioavailability of poorly water-soluble drugs and manipulating release profiles.

PMID- 12426769
TI  - Interactions of warfarin.
AB  - In this article, the author reviews and updates the basis of interactions with
      warfarin, illustrated with appropriate examples. The interactions with drugs,
      medicinal herbs and foods are summarised.

PMID- 12426771
TI  - Neonatal rat cardiomyocytes--a model for the study of morphological, biochemical
      and electrophysiological characteristics of the heart.
AB  - The neonatal rat cardiomyocyte model enables heart researchers to study and
      understand the morphological, biochemical and electrophysiological
      characteristics of the heart. This model offers a broad spectrum of experiments,
      such as studies of contraction, ischaemia, hypoxia and the toxicity of various
      compounds. This review examines the methodology for the isolation and cultivation
      of primary neonatal rat cardiomyocyte cultures, considers possible problems and
      pitfalls, and presents an optimized protocol for cardiomyocyte preparation.

PMID- 12426770
TI  - Stress proteins: nomenclature, division and functions.
AB  - The heat shock response, characterized by increased expression of heat shock
      proteins (Hsps) is induced by exposure of cells and tissues to extreme conditions
      that cause acute or chronic stress. Hsps function as molecular chaperones in
      regulating cellular homeostasis and promoting survival. If the stress is too
      severe, a signal that leads to programmed cell death, apoptosis, is activated,
      thereby providing a finely tuned balance between survival and death. In addition
      to extracellular stimuli, several nonstressfull conditions induce Hsps during
      normal cellular growth and development. The enhanced heat shock gene expression
      in response to various stimuli is regulated by heat shock transcription factors.

PMID- 12426772
TI  - Cell suspensions, cell cultures, and tissue slices--important metabolic in vitro
      systems.
AB  - In vitro subcellular and cellular systems have important and irreplaceable roles
      in the metabolic investigations that precede the development of new potential
      drugs. Of these model systems, tissue slices are probably the nearest to in vivo
      conditions. From the experimental and complexity points of view, perfused organs
      lie midway between tissue slices and whole organism. Preparation and working with
      liver slices is quick and easy, and, excess material can be cryopreserved and
      stored untill the next experiment. Slices can be prepared from a wide variety of
      organs and it is possible to co-incubate them. Another important feature is the
      possibility of interspecies comparison of slices. Different experiments can be
      run both in the short-term as well as long-term incubations. Each in vitro system
      has an important place for example, in the development of new medicaments. It is
      therefore important to compare and supplement experimental results from different
      in vitro systems when extrapolating to in vivo situations is done.

PMID- 12426773
TI  - Osteoprotegerin, RANK, RANKL.
AB  - Osteoprotegerin, RANK (Receptor Activator of Nuclear factor kappa B) and RANKL
      (Receptor Activator of Nuclear faktor kappa B ligand) became the aim of intensive
      research. RANK is considered as a hematopoietic surface receptor controlling
      osteoclastogenesis and calcium metabolism. RANKL may promote osteoresorption by
      induction of cathepsin K gene expression. The present paper summarizes the most
      significant data in osteoprotegerin, RANK and RANKL problems obtained.

PMID- 12426774
TI  - Role of apoptosis and proliferation in differentiation of human retina, regio
      olfactoria and regio respiratoria.
AB  - Apoptosis and proliferation are very important processes during central nervous
      system development. In our study we concentrated on human fetus retina, regio
      respiratoria and olfactoria. The aims of our work were to evaluate a
      proliferative activity proved by PCNA and KI-67 gene expressions, to measure an
      expression of anti-apoptotic gene bcl-2, and finally to compare levels of
      apoptosis and proliferation in the areas investigated. Altogether we studied 29
      fetuses between the 5th to 13th week of gestation (WG). Parallel sections were
      elaborated by using standard methods of immunohistochemistry for the detection of
      proteins PCNA, Bcl-2 and Ki-67. Apoptotic cells were detected by two methods:
      TUNEL (for the detection of DNA fragmentation) and Apostain (for evidence of
      ssDNA). The results of semiquantitative evaluation show that expressions of
      proteins PCNA and KI-67 begins after the 6th WG, from the 8th to 13th WG they are
      very high in all investigated areas. Occurrence of apoptotic cells in regio
      respiratoria is sporadic between the 5th to 9th WG, while later it is widely
      spread. Apoptosis in regio olfactoria appears after the 9th WG and it is also
      very extensive. In the retina we found a higher frequency of apoptotic cells only
      in the 11th to 13th WG. The results of both methods for detection of apoptosis
      were concordant. Anti-apoptotic gene bcl-2 was detectable in all examined areas,
      but it followed no orderly pattern. We conclude, that the expression of apoptosis
      increases with the age from the 7th to 13th WG, and that both apoptosis and
      proliferation participate in the morphogenesis of fetuses between the 5th to 13th
      WG.

PMID- 12426775
TI  - Application of cationic propyl gallate as inducer of thrombocyte aggregation for
      evaluation of effectiveness of antiaggregation therapy.
AB  - INTRODUCTION AND AIM OF THE STUDY: Acetylsalicylic acid (ASA) is one of basic
      preparations used in the therapy of cardiovascular diseases. Application of ASA
      leads to irreversible reduction of platelet aggregation. The aim of the present
      study was to verify monitoring of effectiveness of ASA therapy using the
      measurement of platelet aggregability in vitro after induction by cationic propyl
      gallate (CPG), which is considered to be a highly potent inducer of aggregation.
      METHODS: We examined a group of 27 healthy volunteers, divided into two subgroups
      (n = 19, n = 8). The first subgroup was examined for thrombocyte aggregation
      before and 24 hours after administration of 400 mg of ASA after induction by ADP,
      collagen, adrenalin and CPG. The second subgroup was examined for thrombocyte
      aggregation before and after a three-day administration of ASA in a dose of 100
      mg/day. RESULTS AND CONCLUSION: In the group of 27 healthy volunteers we
      determined normal values of aggregability for individual inducers. Low stability
      of the used methods was proved (weak or insignificant correlation of results of
      the same method before and after administration of ASA). The most advantageous
      parameter for monitoring of effectiveness of 400 and 100 mg of ASA was CPG slope
      (paired t test, p < 0.00000002, resp. p < 0.001). The parameter of CPG slope we
      determined in both subgroups the cut-off value (< 53s), by means of which it is
      possible to discriminate probands according to ASA therapy (in contrast to other
      routinely used inducers). The obtained results indicate that measurement of
      thrombocyte aggregation after CPG induction reveals a significantly lower
      percentage of ASA non-responders ASA than after other inducers. Measurement of
      thrombocyte aggregation after CPG induction is predicted to be highly promising
      for monitoring the effectiveness of anti-aggregation therapy.

PMID- 12426776
TI  - Osteoprotegerin and bone density.
AB  - Aim of study was determine if a correlation exists between bone mass density and
      concentration of osteoprotegerin. We examined the group of 199 patients of mean
      age of 63 years. Of the group under study, 31 patients had normal bone density (T
      score > -1 and < 1) and 168 probands had osteopenia or osteoporosis (T < -1).
      Persons with normal BMD values had median values of OPG 60.8 ng/l, while patients
      with reduced bone density had median values of 73 ng/l OPG. Cut-off for reduction
      of bone density was 128 ng/l OPG. We demonstrated that OPG concentrations vary
      inversely with bone density values (correlation coefficient -0.31). These results
      suggest that determination of OPG could allow discrimination of individuals with
      normal bone density and those with reduced bone density.

PMID- 12426777
TI  - Hydatid cyst of the uterine cervix.
AB  - I report and discuss a very rare case of primary involvement of the uterine
      cervix by hydatid cyst a parasitic disease caused by Echinococcus granulosus,
      whose first and most important site is the liver. The case was misdiagnosed as an
      ovarian cyst until the time of operation. And this is to alert the gynaecologist
      to the possibility of hydatid cyst when a septated mass is found in the pelvis.

PMID- 12426778
TI  - Spontaneous rupture of a previously scared uterus. A case report and an overview
      of risk factors in Yemen Republic.
AB  - Maternal mortality is a significant public health problem. In Yemen it is
      attributable to socioeconomic, reproductive, health-status and health-services
      factors, as well as to medical causes. Direct obstetrical causes account for 61%
      of maternal deaths in Yemen 75% after delivery. Hemorrhage has been found as the
      second cause of maternal death in Yemen, accounting for 23.68% of all causes,
      while ruptured uterus accounts for 14.19% of maternal deaths in particular. The
      high percentage of ruptured uterus as a cause of maternal mortality prompted me
      to report the case below hoping it would shed light on the influence of factors,
      which can lead to this serious situations in Yemen.

PMID- 12426779
TI  - Determination of total antioxidant capacity in plasma by cyclic voltammetry. Two
      case reports.
AB  - The cyclic voltammetry (CV) was used for the measurement of the plasma total
      antioxidant capacity from two types of patients. The first one consisted of 29
      volunteers (men aged 18-21 years) who were administered placebo or silymarin at a
      dose of 858 mg/day. After two months of silymarine administration, CV revealed a
      statistically significant increase in total antioxidant capacity compared to
      placebo. No statistically significant changes in TBARS, SH-groups, creatininin,
      urea, and uric acid concentrations were found. The second group under study
      comprised 49 patients with chronic renal disease during dialysis therapy. After
      dialysis, CV revealed a decrease of total antioxidant capacity in the plasma,
      which was equivalent to a decrease in creatinine, urea and uric acid. CV was
      performed using a system consisting of a working glassy carbon electrode, an
      auxiliary platinum electrode, and a reference saturated calomel electrode; a
      linear change of voltage of 200 mV/s was applied. CV is a simple and relatively
      reliable method for assessment of body antioxidant status. It is also time and
      cost effective.

PMID- 12426780
TI  - Sonographic examination of the eyeball using whole body use equipment in
      children: potential and clinical significance.
AB  - The aim of this study was to evaluate the potential of eyeball examination using
      whole body USG equipment for patients up to 18 years of age. The sonographic
      findings were compared with ophthalmoscopic results and clinical progress; follow
      up sonographic examinations were carried out in many cases. Serious clinical
      states were operated and it was then possible to compare sonographic findings
      with surgical reports. Results obtained by other imaging methods, i.e. CT and/or
      MR examination, if these were carried out, were also used for comparison and for
      determination of the diagnostic yield of the sonographic examination of the
      eyeball. Using whole body USG equipment the most frequent pathological lesions of
      the posterior segment of the eyeball were unambiguously visualised. The results
      were statistically analysed. The results justify the thesis that the sonographic
      examination of the eyeball is the most useful, and most frequently, also the
      definitive imaging method for infant patients and its contribution, for example
      to differential-diagnostic judgments regarding vague findings on papilla, has a
      far-reaching consequence. Last but not least, it is necessary to mention the cost
      effectiveness of USG examination in comparison with both CT and MR examination.

PMID- 12426781
TI  - Mathematical model of the male urinary tract.
AB  - The paper presents a simplified (but not trivial) mathematical model of the
      interaction between the urine flow and the male urethra and bladder,
      respectively. Urine is assumed to be a Newtonian fluid. The flow is considered to
      be non-stationary, isothermal and turbulent. The urethra and bladder wall,
      featuring elastic properties, experience large displacements and strains. The
      dynamic forces are included in the urethra wall motion. When fully extended the
      urethra attains the shape of an axisymetric tube. An iterative method based on
      the uncoupled approach is developed.

PMID- 12426782
TI  - Performance of the health care system in the Czech Republic as compared to EU
      countries and other EU candidate countries.
AB  - This paper summarizes the results of a comparative study focused on health care
      system performance in EU countries and candidate states in Central and Eastern
      Europe.

PMID- 12426783
TI  - [A hundred years of Gedeon Richter Ltd].
AB  - The Company founded by Gedeon Richter in 1901 produced formerly medicines for
      organotherapeutical treatments, later purified hormones were prepared for
      therapy. The factory from the fifties developed gradually into the biggest
      pharmaceutical company in Hungary. Richter produces today mainly synthetic drugs
      and medicines. Its special field is the steroid synthesis on industrial scale.
      One tenth of the active ingredients of oral contraceptives of the world is made
      by Richter.

PMID- 12426784
TI  - [Zinc-hyaluronate: ana original organotherapeutic compound of Gedeon Richter
      Ltd].
AB  - Manufacturing of organotherapeutic products is the most long-standing activity of
      Gedeon Richter Ltd dating back to the establishment of the company in 1901. By
      the 1940s the company had manufactured and marketed about one hundred
      preparations containing tissue extracts from animals. As a result of the
      development of synthetic molecules, organic therapy fell into the background
      after World War II. Although the company followed this tendency, it continued
      manufacturing some organotherapeutic products as well in accordance with the
      requirements of the time. Since the 1950s the researchers of the company have
      worked on the research of glycosaminoglycans introducing the manufacture of
      heparin, and followed by the research of hyaluronic acid (hyaluronan) in the
      middle of the 1980s. In the human body hyaluronan is one of the main components
      of the extracellular matrix, where both in passive and active manner it affects
      the cellular functions through its viscoelastic molecular property and hyaluronan
      receptors of cells. In certain therapeutic fields such as dermatology,
      ophthalmology, surgery and rheumatology, these biological features of hyaluronan
      are used. Although most of the hyaluronan products contain sodium-hyaluronate (Na
      Hy), Richter's researchers found that another metal salt of hyaluronic acid such
      as zinc-hyaluronate (Zn-Hy) might be more favourable in some therapeutic areas
      than Na-Hy. Based on this theory, Gedeon Richter Ltd. developed its original zinc
      associate of hyaluronic acid. It is marketed under the trade name of Curiosin
      intended for dermatological application including promoting of wound healing.
      According to the results of preclinical studies on wound healing the
      pharmacological profile of Zn-Hy was more favourable than that of Na-Hy, proving
      the free radical scavenging, antioxidant, proinflammatory effects of Zn-Hy as
      well as the acceleration of chronic wound healing. In clinical studies Curiosin
      showed its efficacy in the healing of chronic and acute wounds.

PMID- 12426785
TI  - [Investigation of vasoactive agents with indole skeletons at Richter Ltd].
AB  - Investigation of agents with indol skeleton was started in Richter Ltd. 50 years
      ago. This paper presents the results obtained by Richter's scientists. At first,
      a vasoactive alcaloid, vincamine was extracted from the leaves of Vinca minor in
      industrial quantity in 1955. This agent selectively improves the cerebral blood
      supply. Vincamine (Devincan) is used for the treatment of cerebrovascular
      disorders from 1959. Vinpocetine (Cavinton), the most powerful vasoactive
      compound was produced by transforming the chemical structure of vincamine.
      Cavinton is a cis(3S,16S)-derivate of vincamine having antianoxic, antiischaemic
      and neuroprotective properties. Therefore, it is frequently used in the therapy
      of cerebral disorders of vascular origin. Cavinton was introduced into clinical
      practice in 1978. At present, Cavinton tablets are approved in 47 countries. The
      third compound, vintoperol is a trans(3S,16R)-derivate of vincamine. Vintoperol
      proved to be a powerful enhancer of blood flow in the lower extremities. Because
      of its toxic side effects the agent is not used in clinical practice.

PMID- 12426786
TI  - [Investigation of neuromuscular blocking agents at Richter Ltd].
AB  - Investigation of new neuromuscular blocking agents was started 30 years ago in
      Richter Ltd. This paper presents the results obtained by Richter's scientists. 2
      compounds out of 100 bisquaternary ammonio steroid having androstane skeleton
      were selected for further pharmacological study. One of these agents,
      pipecuronium bromide (Arduan) elicited long-lasting block of neuromuscular
      transmission without cardiovascular side effects in both animal experiments and
      clinical studies. Arduan is a powerful competitive antagonist of acetylcholine,
      since it can bind pre- and postsynaptic (N1) receptors of the transmitters. It
      has no remarkable cumulative effect. Neostigmine rapidly and completely
      antagonized the neuromuscular blockade caused by pipecuronium. Arduan was
      introduced into clinical practice. The second compound, RGH-4201 (Duador) evoked
      a neuromuscular block of short duration. It showed slight atropin-like cardio
      vagolytic effect in animal experiments. In the clinical studies, however, the
      cardiovascular side effects were found to be too strong. Therefore, it was not
      introduced in clinical practice.

PMID- 12426787
TI  - [Mydeton: a centrally acting muscle relaxant drug from Gedeon Richter LTD].
AB  - Since its introduction in 1959 tolperisone hydrochloride (Mydeton) is still one
      of the leading products of Gedeon Richter Ltd. It has been successfully applied
      for treating different painful muscle spasms. The compound is successfully
      marketed also by several foreign, mostly Japanese, pharmaceutical companies, as a
      central muscle relaxant agent. The present summary overviews the pharmacology of
      tolperisone, with special emphasize on its still partly understood way of action.
      Data from the scientific literature as well as our own experimental results
      strongly support the hypothesis that inhibition of voltage gated sodium channels
      is a major component of the mechanism of action of tolperisone. The paper also
      summarizes the clinical results with tolperisone and the perspectives of the
      therapeutic use of centrally acting muscle relaxants.

PMID- 12426788
TI  - [TRH analogs at Gedeon Richter Ltd.: highlights of experimental and clinical
      efficacy of posatirelin].
AB  - The chemical research for dissociation of the central nervous system effects of
      thyrotropin-releasing hormone (TRH) from its hormonal activity resulted in the
      selection of RGH-2202 (posatirelin) for further development. Posatirelin showed
      stronger vigilance enhancing effect than TRH in a variety of commonly used neuro
      psychopharmacological model in mice, rats and cats. This drug had positive
      effects in animal models of disturbed consciousness, and counteracted the decline
      of learning and memory capacity shown by aged or memory impaired rats.
      Posatirelin had a trophic effect on neurons both 'in vitro' and 'in vivo' as
      well. Activation of various neurotransmission systems has been demonstrated, but
      the "modulatory" action of this neuropeptide-like compound is too complex to be
      explained by a single mechanism. Posatirelin practically had no hormonal activity
      or other significant side effects either in animal studies or in clinical trials.
      The arousal level increasing and the neuronotrophic effects appeared in part in
      trials of human brain injuries and cerebral infarction. Patients suffering in
      dementia syndromes of either vascular or degenerative origin and treated
      chronically with posatirelin showed significant improvement in intellectual
      performance, in orientation, motivation and memory function in all well
      controlled trials.

PMID- 12426789
TI  - [Endre Koros, academician at the Hungarian Academy of Sciences (interview by Bela
      Noszal)].

PMID- 12426790
TI  - [Duty to promote, in a just manner, one's personal health and that of others].

PMID- 12426791
TI  - [Intervention of the hospital social service concerning the aged].

PMID- 12426792
TI  - [Psychotherapy. Approach to the subject through a behavioral model].

PMID- 12426793
TI  - [The burnout syndrome].

PMID- 12426794
TI  - [Euthanasia in Holland].

PMID- 12426795
TI  - [The need,,,, Palliative treatment].

PMID- 12426796
TI  - [Prophylaxis of hepatitis B in newborn infants].

PMID- 12426797
TI  - [Care of the aged: the care that we give, the persons that we are!].

PMID- 12426798
TI  - [A need to correct the weight of the aged?].

PMID- 12426799
TI  - Guidelines for the management of rheumatoid arthritis: 2002 update.
AB  - Rheumatoid arthritis (RA) is a progressive polyarthritis that is responsible for
      over nine million office visits annually. It is likely that most nurse
      practitioners will care for one or more patients with RA because approximately 1%
      of the adult population is affected by this disabling disorder. The guideline
      reviewed in this month's column describes the recommended care of patients who
      have been previously diagnosed with RA.

PMID- 12426800
TI  - The state Children's Health Insurance Program (CHIP).
AB  - PURPOSE: To provide an overview of the Children's Health Insurance Program
      (CHIP), along with implications for practice as it applies to nurse
      practitioners. DATA SOURCES: Extensive review of the on-line and published
      literature on CHIP. CONCLUSIONS: Congress established CHIP in an effort to reduce
      the high number of uninsured children in America. Each state administers its own
      program and children who are under age 19, 200% below federal poverty levels, and
      ineligible for Medicaid may qualify. Even though CHIP has made health care
      possible for over 3 million children, there are still many obstacles that need to
      be overcome to ensure that access to healthcare is a reality for America's
      children. IMPLICATIONS FOR PRACTICE: Although CHIP has made healthcare accessible
      for many low income children, there are still hundreds of children left without
      health insurance. Many children who could qualify for CHIP remain without access
      to healthcare. Nurse practitioners have the opportunity to make healthcare a
      reality for children by becoming knowledgeable about this plan in order to refer
      patients to the program who are eligible and by advocating for future legislation
      that will ensure its long term success.

PMID- 12426801
TI  - Implications of self-administered St. John's wort for depression symptom
      management.
AB  - PURPOSE: To provide nurse practitioners (NPs) with a greater understanding of the
      complex issues surrounding St. John's wort as a self-treatment for depression; to
      review laws regulating the production and sale of herbal products in the United
      States (U.S.); and to review clinical and practice implications for the self
      administration of St. John's wort and herbal treatments. DATA SOURCES: Federal
      regulations pertaining to herbal products, current research literature, and
      anecdotal and consumer reports. CONCLUSIONS: Current research findings suggest
      that St. John's wort may be an effective treatment for mild depression; however,
      evidence of significant adverse drug interactions with St. John's wort should not
      be overlooked. IMPLICATIONS FOR PRACTICE: Clinical assessment of the mildly
      depressed patient wishing to self-administer St. John's wort requires basic
      knowledge of this herbal supplement including regulation and risk information. An
      open NP-patient relationship helps to ensure patient disclosure of self
      administered St. John's wort.

PMID- 12426802
TI  - The advanced practice nurse's role regarding women's delay in seeking treatment
      with myocardial infarction.
AB  - PURPOSE: To synthesize nursing literature on reasons women delay in seeking
      treatment for signs and symptoms of an acute myocardial infarction (AMI), to
      hypothesize upon the primary reason(s) for this delay, and to propose advanced
      practice nurse (APN) interventions to reduce this delay. DATA SOURCES: Utilizing
      Stetler's Model of Research Utilization, all reports published in nursing
      journals within the last 10 years specifically examining prehospital delay
      related to gender factors were analyzed. CONCLUSIONS: Women, especially those in
      advanced age, delay longer before seeking treatment for signs and symptoms of
      AMI. Effective treatment is time dependent; mortality and morbidity rise with
      increased prehospital delay. The reasons identified in the literature for this
      delay included severity, specificity, atypical presentation of symptoms,
      differences in event perception according to gender roles, and the interpretation
      and attribution of symptoms. IMPLICATIONS FOR PRACTICE: Identifying and teaching
      women at highest risk for delay, dispelling internal and external gender bias,
      increasing one's perception of patient vulnerability to AMI, and developing one's
      awareness of atypical presentations are the major factors that are likely to
      impact APN practice and consequently reduce prehospital delays for women at risk.

PMID- 12426803
TI  - Asthma: a case study, review of pathophysiology, and management strategies.
AB  - PURPOSE: To review the pathophysiology of asthma, present a case study, and
      provide management strategies for treating this common, yet complex disorder in
      children and adults. DATA SOURCES: Selected clinical guidelines, clinical
      articles, and research studies. CONCLUSIONS: Asthma is a chronic inflammatory
      airway disorder with acute exacerbations that currently affects approximately 14
      million-15 million children and adults in the United States. Costs for asthma are
      staggering and nurse practitioners (NPs) are frequently presented with management
      decisions for the acute treatment and chronic management of this disorder.
      Disparities exist with the occurrence of asthma between race and gender.
      Additionally, there is an increased incidence in acute exacerbations resulting
      from poor long-term control and follow-up care among the socioeconomically
      disadvantaged. IMPLICATIONS FOR PRACTICE: Standards of care, along with new and
      emerging treatment strategies, guide NPs in providing the most comprehensive care
      to those affected with this chronic disorder. Knowledge about the pathophysiology
      of asthma and correlated to the case presentation enhances understanding
      treatment strategies for NPs who are often faced with providing care for patients
      with this chronic disorder that may sometimes present in an acute exacerbation.

PMID- 12426804
TI  - Exploring telehealth opportunities in domestic violence shelters.
AB  - PURPOSE: To determine the degree of interest in using a computer for the purpose
      of accessing services from a nurse practitioner (NP) at domestic violence
      shelters (DVSs); and to identify issues of privacy and confidentiality that might
      arise from participation by victims of intimate partner violence (IPV) in a
      Telehealth intervention. DATA SOURCES: Focus groups with 19 women residing in two
      DVSs. Interviews were recorded, transcribed and themes were identified that
      answered the questions posed in the interviews. CONCLUSIONS: Most of the women
      understood the term NP and were favorably inclined to seek services from one.
      Over half of the women were not familiar with computer use, but were willing to
      learn in order to receive health care services, both for episodic needs and for
      maintenance of chronic conditions. After learning of the method proposed to allow
      them to access an NP through the internet while still protecting their privacy
      and confidentiality, the women felt comfortable with this approach to meeting
      their health care needs. IMPLICATIONS FOR PRACTICE: Results from this study can
      be used to support the development and testing of Telehealth interventions for
      these victims of IPV.

PMID- 12426805
TI  - Structure and process of outcomes research for nurse practitioners.
AB  - PURPOSE: To present a framework for nurse practitioners (NPs) who wish to engage
      in outcomes research. DATA SOURCE: Review of scientific literature on the design
      of outcomes research. CONCLUSION: The structure and process of outcomes research
      includes both the research protocol and the decisions related to designing and
      implementing a study. Each identified step of the presented framework
      incorporates issues related to decision making relevant for that specific
      component of the research protocol. IMPLICATIONS FOR PRACTICE: Practical advice
      guides the NP in beginning to identify researchable problems within the clinical
      setting suited to outcomes research. Using a framework to design an outcomes
      study assists the NP in making key study decisions.

PMID- 12426806
TI  - ANA, CMAs help nurses become better prepared to respond to disasters.

PMID- 12426807
TI  - ANA files amicus brief in Iowa case: criminal investigation vs. privacy rights.
      Supports planned parenthood in protection of patients' records.

PMID- 12426812
TI  - Making a difference: Oklahoma nurse program recognized for assisting community.
      Interview by Susan Trossman.

PMID- 12426813
TI  - Spectrophotometric determination of terbinafine in presence of its
      photodegradation products.
AB  - Spectrophotometric methods have been developed for the quantitative determination
      of terbinafine hydrochloride in presence of its photodegradation products. The
      methods make use of the first spectral derivation (1D) and the first derivative
      of the ratio spectra (1DD) of the named drug and its photodegradates at different
      justified wavelengths. Good linearity was observed in the range of 10-100 mg.ml-1
      with low LOD (> or = 1.11 mg.ml-1) and LOQ (> or = 3.36 mg.ml-1). The proposed
      methods showed good linearity, precision and reproducibility.

PMID- 12426814
TI  - Potentiometric and thermodynamic studies of 5-(p-aminophenylazo)-8
      hydroxyquinoline and its metal complexes.
AB  - Proton-ligand dissociation constant of 5-(p-aminophenylazo)-8-hydroxyquinoline
      (HL) and metal-ligand stability constants of their complexes with bivalent (Mn2+,
      Co2+, Ni2+ and Cu2+) metal ions have been determined potentiometrically in 0.1 M
      KCl and 30% (v/v) dimethyl formamide (DMF)-water mixture. The order of the
      stability constants of the formed complexes was found to be Mn2+ < Co2+ < Ni2+ <
      Cu2+. The effect of temperature was studied and the corresponding thermodynamic
      parameters (delta G, delta H and delta S) were derived and discussed. The
      dissociation process is nonspontaneous, endothermic and entropically unfavorable.
      The formation of the metal complexes has been found to be spontaneous,
      endothermic and entropically favorable.

PMID- 12426815
TI  - Charge-oriented modelling in charge-transfer systems.
AB  - Various mechanisms are often used toxplain the charge-transfer interactions
      between various electron donors and acceptors. Commonly accepted mechanisms are
      those in witch the acceptors forms a weak interaction of the Lewis acid--Lewis
      base type. A modelling approach is applied in this study to examine this
      mechanism as well as other mechanism. A charge-oriented mechanism is proposed in
      solvent systems that may not favour this mechanism of interaction.

PMID- 12426816
TI  - Risks and benefits of PVC in medical applications.
AB  - The safety of using PVC in the medical field has been recently challenged due to
      the toxic activity it allegedly exerts on exposed patients. The environmental
      repercussions of disposing of PVC, once its use has terminated, represent an
      additional point of debate, used to sustain the advisability of abolishing PVC.
      The reasons that have led some to request the abolition of PVC involve valid
      questions of principle, perhaps, but they lack a technical evaluation of the
      benefit-risk ratio and the possible consequences this action would have on
      patients and on healthcare personnel. The purpose of this paper is therefore to
      help bring the terms of the question back into the realm of evidence and proof,
      attempting to formulate a brief picture of what is known, in terms of PVC uses in
      the clinical field, evaluating the benefits and risks to human health and to the
      environment, also in relation to possible alternatives, and discussing the
      margins of uncertainty that emerge. Evidence supports the conclusion that PVC is
      an important weapon in the complex arsenal medicine has at its disposal to care
      for patients and cure diseases. Though its use can be considered safe, recent
      surveys have identified in some patients possibility of risks associated with
      DEHP, the principal plasticizer of PVC for medical applications. Studies are in
      progress to eliminate these margins of risk and increase the safety for patients.

PMID- 12426817
TI  - Possibilities of the application of regression analysis and analysis of variance.
      II. Assessment and comparison of acute toxicity: presentation and practical
      application of the interactive computer program "LD50-MORTALITY".
AB  - The paper presents the interactive computer program "LD50-MORTALITY", written in
      the program language BASIC and used for the assessment of the acute toxicity
      (calculation of LD50 and other LD values) based on the algorithm of the Finney's
      probit analysis method. The correctness of the program execution has been shown
      on the test-example of assessment the acute toxicity (LD50 an LD90) of
      insecticide rotenone on Macrosiphonelia sanborni (the example is taken from the
      literature on probit analysis presentation). The results obtained by the program
      execution have been identical or similar to those given in the example. The
      results of the assessment and comparison of LD50 have also been presented.

PMID- 12426818
TI  - Spectrophotometric determination of nikethamide by charge--transfer complexation
      with chloranilic acid.
AB  - A Spectrophotometric method is described for assay of nikethamide which was based
      on charge transfer complexation between it and chloranilic acid. They form a
      complex with stoichiometric ratio of 1:1 and showed l-max at 535 nm. Maximum
      complexation occurred 30 min after mixing the reactants and was stable for 12 hr.
      The molar absorptivity, association constant and free energy for the complex were
      1.05 x 1.0(2), 4.40 x 10(-2) litre mole-1 and 1819.02 kcal respectively.
      Conformity to Beer's Law was within the concentration range of 1-2.5 x 10(-4),
      which enabled the assay of dosage forms of the drug at microquantities.

PMID- 12426819
TI  - Synthesis and pharmacological studies of some 2-t-amino and 2,3-di-t-amino
      substituted 1,4-naphthoquinones and related compounds.
AB  - Series of 2-t-amino and 2,3-di-t-amino substituted-1,4-naphthoquinones have been
      synthesised from corresponding 1,4-naphthoquinones by reaction with secondary
      amines. The compounds have been evaluated for their broad spectrum antimicrobial,
      antiviral and anticancer activity. In the preliminary screening results 8a and 9a
      have shown profile of an antimicrobial agent.

PMID- 12426820
TI  - Spectrophotometric determination of sulphacetamide.
AB  - A new rapid selective spectrophotometric method for the determination of
      sulphacetamide is described. The drug forms a orange-yellow colored complex with
      Cerium(IV) in sulfuric acid media which is extracted into ethyl acetate. The
      complex exhibits a maximum absorbance at 440 nm with a molar absorptivity of 3 x
      10(2) 1 mol-1 cm-1. The system obeys Beer's law in the concentration range of
      0.07-1.1 mg of sulphacetamide. The various parameters for the optimum extraction
      conditions are discussed. The method is applied to the determination of
      sulphacetamide in dosage forms.

PMID- 12426821
TI  - Detection of alpha-methyldopa on thin-layer plates using pi-acceptors in 1,4
      dioxane.
AB  - pi-Acceptors (P-chloranil and chloranilic acid) in 1,4-dioxane were used to
      detect alpha-methyldopa on thin layer plates. Thin layer plates coated to a
      thickness of 0.25 mm with silica gel G60 were spotted with solution of alpha
      methyldopa from drug formulations and pure alpha-methyldopa solution. The plates
      were developed in a solvent system of methanol: glacial acetic acid: water
      (14:5:3). The developed plates were dried and sprayed with pi-acceptors, and
      further were counter-sprayed with dimethylformamide (DMF). P-Chloranil gave an
      immediate blue green complex with alpha-methyldopa which intensified on counter
      sprayed with DMF. alpha-methyldopa (reference sample and those from drug
      formulations) gave Rf of 0.85 and excipients from the drug formulations did not
      interfere with the result.

PMID- 12426822
TI  - [Guidelines of the European Resuscitation Council 2000 for immediate life-saving
      treatment of adults. Position of the Basic Life Support and Automated External
      Defibrillation Working Group, after dismissal by the Execute Committee of the
      European Resuscitation Council].

PMID- 12426823
TI  - [Traveler's thrombosis].
AB  - It is pathophysiologically conceivable that prolonged sitting in a tight space
      (e.g., in airplane or other transport vehicle) may lead to leg vein thrombosis.
      The association between the incidence of venous thromboembolism and long travel
      has not been sufficiently documented but seems probable. However, this
      association is only weak and the incidence of symptomatic thromboembolism much
      lower than the impression given by the recent publicity. In a healthy person, the
      risk of suffering a clinically relevant leg vein thrombosis solely because of a
      flight is extreme low. In persons with risk factors for venous thromboembolism,
      the flight represents an additional, as yet not quantifiable risk. This risk
      increases with the duration of the travel. The most important cause of thrombosis
      during long journeys seems to be venostasis due to relative immobilization. It is
      not clear whether flight travel represents a higher risk of thrombosis compared
      to other transport vehicles with comparable duration and immobilization. Until
      more exact information becomes available, it seems reasonable to recommend simple
      isometric and isotonic leg exercises during long travel. More aggressive measures
      must be considered for persons with risk factors for thromboembolism, but these
      measures should be individualized.

PMID- 12426824
TI  - A porcine coronary stent model of increased neointima formation in the left
      anterior descending coronary artery.
AB  - BACKGROUND: Clinical trials suggest an increased frequency of restenosis after
      coronary intervention in left anterior descending (LAD) compared to the left
      circumflex or right coronary arteries. Experimental studies correlate stent
      induced arterial injury and the extent of neointima formation. This study
      investigates whether the coronary artery affects the relationship between
      arterial injury and neointima hyperplasia in the porcine stent model. METHODS:
      Non-lipemic farm pigs underwent stent placement in the LAD (n = 26) and the right
      coronary artery (RCA; n = 30). Quantitative coronary angiography (QCA) was
      performed before and after stent placement, and at follow-up; quantitative
      histomorphometry and injury score were analyzed at 30-day follow-up. RESULTS:
      Initial procedure balloon/artery ratios (LAD 1.17 +/- 0.11 vs RCA 1.17 +/- 0.09,
      P = NS), and minimal stent lumen diameters (MLD; LAD 2.91 +/- 0.31 vs RCA: 2.93
      +/- 0.28 mm, P = NS) were similar suggesting no difference in deployment
      technique. At follow-up there was more restenosis in the LAD (diameter stenosis:
      55.0 +/- 26.4% vs 37.3 +/- 18.1%, and MLD: 1.24 +/- 0.78 mm vs. 1.71 +/- 0.57 mm,
      P < 0.05 for both comparisons). No differences were seen for injury score (1.09
      +/- 0.51 vs 1.01 +/- 0.57; LAD vs RCA) or stent area (6.13 +/- 0.99 vs 6.55 +/-
      1.42 mm2). Histomorphometry demonstrated smaller lumen area (2.15 +/- 0.94 vs
      2.96 +/- 1.29 mm2) and thicker neointima (0.63 +/- 0.25 vs 0.51 +/- 0.17 mm; all
      P < 0.05) in the LAD. Multiple linear regression analysis identified the LAD as
      an independent predictive factor for increased neointima formation. CONCLUSIONS:
      These observations establish an animal model that is consistent with clinical
      experience showing that restenosis after stenting is more common in the LAD. The
      findings may be useful for understanding and developing systemic and local
      antirestenotic strategies.

PMID- 12426825
TI  - Undiagnosed diabetes mellitus among patients with prior myocardial infarction.
AB  - OBJECTIVE: To determine the prevalence of undiagnosed diabetic subjects in a
      group of long-term myocardial infarction (MI) survivors and to investigate their
      cardiovascular risk factors and medical care. METHODS: Glucose tolerance (OGTT
      WHO 1985), cardiovascular risk factors (blood pressure, lipids, urinary albumin),
      and primary medical care during the previous year were assessed among 244
      patients without previously known diabetes (mean age +/- SD: 70.5 +/- 6.9 yrs;
      75% males; time since incident infarction: 6.5 years (median), inter-quartile
      range: 4-9 years) from the population-based MONICA myocardial infarction registry
      in Augsburg (Germany). RESULTS: Proportion of undiagnosed diabetes among MI
      registry patients was 29/244, 12% (95%CI: 8-17%); impaired glucose tolerance was
      found in 27% (22-34%). Using fasting glucose according to ADA 1997 criteria, 11%
      (7-16%) had diabetes and 17% (12-22%) impaired fasting glucose. MI registry
      patients with newly detected diabetes (WHO or ADA) showed a more adverse risk
      factor profile (higher triglycerides, lower HDL-cholesterol, increased urinary
      albumin) than subjects with normal glucose tolerance after controlling for
      possible confounders (age, sex, time since MI, antihypertensive and lipid
      lowering medication). No significant differences were observed for self-reported
      medical care during the previous year among diabetic compared to non-diabetic
      subjects (number of physician visits and basic investigations). CONCLUSIONS:
      There was a high prevalence of undiagnosed diabetes mellitus among the selected
      elderly long-term MI survivors. Because mortality rate after MI has been
      previously shown to be increased in diabetic patients, screening for glucose
      intolerance appears to be as essential as for standard cardiovascular risk
      factors.

PMID- 12426826
TI  - [Neointimal hyperplasia by luminal cell recruitment and not be transmural
      migration. The role of Bcl-2 and HSP47 after balloon angioplasty].
AB  - Restenosis post angioplasty remains the major limitation of several therapeutic
      interventions including stent implantation. This explains the ongoing interest in
      its basic pathogenic mechanisms and factors. The aim of the present study was to
      assess the localization and maximal expression of Bcl-2, a central antiapoptotic
      protooncogene, and of heat shock protein 47 (HSP47), a marker of early collagen
      synthesis, in the context with hyperplastic neointima formation as well as
      concomitant transmural remodeling processes following angioplasty. 0, 4, 24 and
      48 hours, 4, 7 and 14 days post balloon traumatization by use of a rat carotid
      artery model, specific vascular wall compartments were evaluated concerning area,
      cell density as well as Bcl-2 and HSP47 expression by immunohistochemistry and
      morphometry, supplemented by electron microscopy (TEM). Neointimal cell
      accumulation was detected 4 days post angioplasty, characterized by luminal cells
      adherent to the internal elastic lamina, associated with maximal Bcl-2 and HSP47
      expression amounting to 49% and 41%, respectively. With ongoing neointimal
      formation, a luminal prevalence of both key determinants and a decreasing
      expression in basal neointimal areas were found. In the media, a temporally
      reduced cell density was observed significant at 48 hours post trauma.
      Constitutive HSP47 expression of the media was constant during the entire
      observation period, whereas sparse Bcl-2 signalling was induced post angioplasty
      maximal on day 2 with 3% and on day 14 with 5%. The adventitia demonstrated a
      transient structural separation between day 4 and 7, exhibiting an inner layer
      with sparse cellularity and an outer layer with extremely high cell density as
      well as pronounced neovascularization. In this outer adventitia layer, a high
      frequency of signals for both Bcl-2 and HSP47 were observed amounting to 29% and
      57%, respectively. Complementary TEM analysis gave no evidence of transmural
      migratory events propagated by adventitial cells and thereby supports early
      neointimal formation by luminal cell recruitment and marked co-expression of anti
      apoptotic Bcl-2 and matrix-generating HSP47 as important survival factors.
      Clinical implications of these findings may be seen in the integration of
      proapoptotic substances with temporal efficacy in order to prevent restenosis,
      e.g., by use of coated stents.

PMID- 12426828
TI  - [Detection of coronary calcinosis with multislice spiral computerized tomography:
      an alternative to electron beam tomography].
AB  - Electron-beam CT (EBT) has been used for years as the gold standard to quantify
      coronary artery calcification as a marker of coronary atherosclerosis. With the
      introduction of Multi-Slice Spiral CT (MSCT) technology in 1999, EBT is now
      challenged in the determination of coronary calcium. The aim of this study was to
      determine the diagnostic accuracy of MSCT for the assessment of coronary calcium,
      comparing this new technique to EBT. The study population consisted of 54 male
      patients, aged 58 +/- 11 years with suspected coronary artery disease. For EBT,
      40 axial slices (scan time = 100 ms, slice thickness = 3 mm) were acquired in one
      breath-hold (35 +/- 5 s) using an ECG-trigger at 80% of the RR interval. For
      MSCT, simultaneous acquisition of four axial slices (scan time = 250 ms, slice
      thickness = 2.5 mm) allowed the entire heart (40 slices) to be covered in one
      breath-hold (25 +/- 5 s) using a prospective ECG-trigger (R--450 ms). For
      quantification of coronary calcium the Agatston and the Volumetric calcium score
      (VCS) were applied. Mean Agatston score of the study group was calculated as 88
      +/- 111 (median = 45), which is between the 25th and 75th age-corrected
      percentile of asymptomatic patients. For the Volumetric calcium score, number of
      lesions, calcium mass and density, no statistical difference was found between
      both imaging modalities. Agatston and Volumetric calcium score were statistically
      different between and within both scans. Mean variability of VCS of the two
      methods was calculated as 24% and was in the range of repeated EBT studies (14
      44.9%). The Multi-Slice Spiral CT scanner is equivalent to EBT for the
      determination of coronary calcium and can, therefore, be used for calcium
      screening. Using a prospective ECG-trigger technique, the application of the
      Agatston method delivers statistically different results in comparison to EBT.
      With the application of the spiral mode technique, retrospective ECG-trigger and
      thinner slice thickness, further improvement in variability can be expected, thus
      allowing for follow-up studies to determine progression or regression of
      atherosclerosis with high accuracy.

PMID- 12426827
TI  - [Day-night variability of the prehospital phase of acute myocardial infarct].
AB  - While a circadian rhythm in the onset of acute myocardial infarction (AMI) is
      well established, little is known about the variability of prehospital delay and
      decision processes. Seven hundred and thirty-nine consecutive AMI patients
      (median age 65.3 years; 30.2% women) with a median decision time of 60 min and a
      total prehospital delay of 180 min were studied. In 30.9% of patients onset of
      AMI symptoms was at night (10.00 p.m.-06.00 a.m.). At night patient decision time
      was significantly longer than during daytime (120 vs 45 min, difference 75 min; p
      < 0.001), total prehospital delay was prolonged accordingly (240 vs 170 min,
      difference 70 min; p < 0.001). The relative risk (RR; 95% confidence interval,
      CI) for a late decision (> 1 h) to seek medical care at night was significantly
      increased in females (RR 1.96; CI 1.07-3.61, p = 0.028), non-smokers (RR 2.49; CI
      1.42-4.39, p = 0.001) and patients with radiation of anginal pain (RR 2.34; CI
      1.32-4.15; p = 0.003). Of all patients with a late decision to seek medical care
      at night, 95.6% belonged to one of these groups. These variables were not
      significant for early or late decisions during daytime. Decision processes of AMI
      patients may be different during daytime and at night. In conclusion, in AMI
      patients, decision time to seek medical help is prolonged at night. Simple
      clinical variables (female sex, non-smokers, radiation of anginal pain) identify
      patients at high risk for a late decision at night. This information should be
      included into public and individualized education campaigns.

PMID- 12426829
TI  - [Cardiac and cerebral manifestations of antiphospholipid syndrome].
AB  - We describe cardiac and cerebral manifestations in 27 patients with the
      antiphospholipid syndrome and give a review of the literature. PATIENTS AND
      METHODS: We studied 27 patients with either cardiac, cerebral or both
      manifestations, who also were diagnosed with the antiphospholipid syndrome (APS).
      All patients fulfilled the proposed classification criteria for the APS according
      to the Scientific Standardisation Committee of the International Society of
      Thrombosis and Haemostasis (1). Three patients died. RESULTS: Eighteen of the 27
      patients had coronary artery disease with either thrombotic coronary occlusions,
      high grade stenosis or complete vessel occlusion. In three patients the left main
      artery was involved. Ten patients had involvement of the left anterior descending
      artery (LAD), 6 patients of the circumflex artery (RCX) and 5 patients had
      involvement of the right coronary artery (RCA). As valvular lesions have been
      described in association with the APS it should be noted that in 16 cases there
      was mitral- and/or aortic valve disease and in 3 cases tricuspid valve disease.
      Four patients underwent mitral- and/or aortic- and/or tricuspid valve
      replacement. 7 patients presented with a history of cerebrovascular involvement;
      5 of these patients had cerebral infarction, one patient recurrent cerebral
      bleeding under oral anticoagulation and another patient presented with cognitive
      disorders. Three of the 7 patients had a prior history of myocardial infarction,
      whereas 3 patients underwent mitral or aortic valve replacement. CONCLUSION: The
      frequent occurrence of coronary disease, cardiac valvular disease and cerebral
      disease in patients diagnosed with APS may suggest a causative relationship
      between the presence of PL antibodies and vascular disease.

PMID- 12426830
TI  - [Occlusion by catheter intervention in patent foramen ovale via additional
      transseptal puncture].
AB  - In patients with a cryptogenic cerebral ischemia, the percutaneous closure of a
      patent foramen ovale (PFO) has gained increasing acceptance as an alternative
      strategy to prevent paradoxical embolism. Promising data with low recurrence
      rates have been reported for several self-expanding double disk devices. The
      implantation of the device is usually performed by passing the PFO. However, in
      one patient with a TIA (m, 43 years) transesophageal echocardiography (TEE)
      revealed an atrial septum abnormality with a hypermobile septum and a very small
      distance (approximately 12 mm) between the PFO channel and the anterior mitral
      valve leaflet, which was too short to accommodate the regular implantation
      procedure of the device via the PFO-channel itself. In this particular case the
      device (PFO-Star TSD) was advanced to the left atrium via an additional
      transseptal puncture--performed under TEE guidance--to allow for complete closure
      of the PFO without impairment of the mitral valve function. No periinterventional
      complications were observed. During the follow-up period of 9 months the patient
      was completely asymptomatic with no functional impairment of the mitral valve and
      no residual intracardiac shunt.

PMID- 12426831
TI  - ["Memory, speak....". Observations on integration problems].

PMID- 12426832
TI  - [Interdisciplinary therapy of childhood ependymomas].
AB  - BACKGROUND: Ependymomas represent about 10% of CNS tumors in children. The
      proportion of cases defined as anaplastic is about 25%. Prognosis depends on
      extent of resection, and postoperative radiotherapy, the overall survival rate is
      30-60%. Further investigations should clarify the impact of chemotherapy,
      histological grading, dose, and volume of radiotherapy. MATERIAL AND METHOD:
      Based on historical reports, the recent literature, present guidelines, and
      ongoing trials an overview is provided for the management of ependymomas in
      childhood. RESULTS: Local tumor control is the most important aim. Recurrences
      occur predominantly at the primary tumor region. The main instrument is surgery
      to effect maximal tumor resection. The addition of radiotherapy could improve
      survival significantly from 10% to 50%. Regarding the volume of irradiation there
      is confidence today that local fields are sufficient for all non-disseminated
      ependymomas. Local dose escalation has been introduced using hyperfractionated
      schedules. In recent studies this has been shown to increase local control up to
      70%. Regarding chemotherapy in ependymomas trials have shown limited efficacy to
      date. For metastatic disease standard treatment has shown to be insufficient and
      high dose chemotherapy regimens to increase survival are in study. In younger
      children radiotherapy should be delayed using early chemotherapy. With pre
      irradiation chemotherapy survival rates of 63.3% for children under age of 3 were
      achieved. CONCLUSIONS: At present the cooperating clinicians are optimizing
      treatment procedures to improve results and to reduce toxicity. In radiotherapy
      reduction of target volume to the involved field for all non-disseminated
      ependymomas as well as the introduction of hyperfractionated schedules and
      conformal therapy with dose escalation are important developments.

PMID- 12426833
TI  - Highly conformal therapy using proton component in the management of meningiomas.
      Preliminary experience of the Centre de Protontherapie d'Orsay.
AB  - AIMS: To evaluate the efficacy and the tolerance of an escalated dose of external
      conformal fractionated radiation therapy combining photons and protons in the
      treatment of intracranial meningiomas. PATIENTS AND METHODS: Between December
      1995 and December 1999, 17 patients received a treatment by 201-MeV proton beam
      at the Centre de Protontherapie d'Orsay (CPO) for a meningioma. Five patients
      presented a histologically atypical or malignant meningioma, twelve patients a
      benign one that was recurrent or rapidly progressive. In two cases radiotherapy
      was administered in the initial course of the disease and in 15 cases at the time
      of relapse. A highly conformal approach was used combining high-energy photons
      and protons for approximately 2/3 and 1/3 of the total dose. The median total
      dose delivered within gross tumor volume was 61 Cobalt Gray Equivalent CGE (25
      69). RESULTS: Median follow-up was 37 months (17-60). The 4-year local control
      and overall survival rates were 87.5 +/- 12% and 88.9 +/- 11%, respectively. One
      patient failed locally within the clinical tumor volume. One patient died of
      intercurrent disease. A complete or partial clinical improvement was seen in most
      of patients. Radiologically, there were eleven stable diseases and five partial
      responses. In 12/15 recurrent cases, the free interval after radiotherapy is
      longer than that achieved by the initial surgery. This radiotherapy was well
      tolerated. CONCLUSIONS: In both benign and more aggressive meningiomas, the
      combination of conformal photons and protons with a dose escalated by 10-15%
      offers clinical improvements in most patients as well as radiological long-term
      stabilization.

PMID- 12426834
TI  - Combined radiochemotherapy with paclitaxel in the treatment of malignant glioma.
AB  - BACKGROUND: Paclitaxel is a radiosensitizing agent that shows a synergistic
      effect with radiation in malignant glioma cells. A phase I/II trial was performed
      in order to evaluate both feasibility and outcome of combined radiochemotherapy
      in malignant glioma. PATIENTS AND METHODS: 56 patients were included in the
      trial. Paclitaxel was administered on days 1-4, 15-18 and 29-32 18 to 24 hours
      prior to irradiation. Radiotherapy with 60 Gy in conventional fractionation was
      initiated on day 2.31 patients were included in a dose-escalation trial starting
      with 20 mg/m2/d and increasing up to 60 mg/m2/d in 10-mg steps. Additional 25
      patients were treated with 50 mg/m2/d. RESULTS: The regimen was very well
      tolerated with minimal subjective impairment such as sickness or weakness.
      Maximal tolerable dose was 50 mg/m2/d, with neutropenia being the dose-limiting
      toxicity. There were four allergic reactions and five thromboembolisms;
      furthermore, one patient with a normal blood count died due to pneumonia. The
      median survival was 12 months, and significantly favorable factors were a young
      age, a lower tumor grade (grade 3) and a complete resection. Varying the
      paclitaxel dose had no influence on outcome. CONCLUSIONS: Combined
      radiochemotherapy with paclitaxel in the treatment of malignant glioma was well
      tolerated. Maximal tolerable dose was 50 mg/m2/d. There was no increase in
      survival compared with results reported in the literature.

PMID- 12426835
TI  - Radiosensitivity and TP 53, EGFR amplification and LOH10 analysis of primary
      glioma cell cultures.
AB  - AIM: Determination of in-vitro radiosensitivity and genetic alterations of cell
      cultures derived from human glioma biopsy tissue and established glioma cell
      lines. MATERIAL AND METHODS: Fresh brain tumor specimens of six patients were
      processed to early passage cell cultures. In addition the cell lines D 384 and
      Gli 6 were used. Cell cultures were irradiated with doses from 2 to 10 Gy.
      Following irradiation, cell survival was determined by clonogenic assay and
      survival curves were generated. The surviving fractions after 2 Gy (SF2) and 4 Gy
      (SF4) were used as radiosensitivity parameters. Genetic analysis included
      determination of the mutational and loss of heterozygosity (LOH) status of TP 53
      (exons 5-8), the LOH 10- and epidermal growth factor receptor gene (EGFR)
      amplification status. RESULTS: The SF2 and SF4 values ranged from 0.54 to 0.88
      (mean: 0.70) and from 0.13 to 0.52 (mean: 0.32), respectively. Genetic
      alterations were found in the Gli 6 cell line and in two primary cell cultures.
      The genetic profile of Gli 6 showed LOH but no TP 53 mutation, complete LOH 10
      and no EGFR amplification. The VU 15 cell culture showed TP 53 mutation but no
      LOH 10 or EGFR amplification, while VU 24 showed incomplete LOH 10, EGFR
      amplification and no TP 53 mutation. In the other four cell cultures and D 384
      cell line no genetic alterations were diagnosed. Histopathological classification
      of glioblastoma multiforme and/or genetic alterations resulted in lower
      radiosensitivity. CONCLUSION: In this small series of early passage glioma cell
      cultures low radiosensitivity and alterations in cell regulatory genes were seen.
      Further testing of biological behavior in larger series of patient-derived
      material is ongoing.

PMID- 12426836
TI  - Combined effect of topotecan and irradiation on the survival and the induction of
      chromosome aberrations in vitro.
AB  - BACKGROUND: Topotecan demonstrated radiosensitizing effects in vivo and in vitro,
      which are schedule- and cell line dependent. The underlying mechanisms are not
      fully understood. Topotecan interferes with DNA replication, transcription, and
      repair and may thus increase the frequency of radiation-induced lethal chromosome
      aberrations. MATERIAL AND METHODS: U-373 MG glioblastoma cells, WiDr colon adeno
      carcinoma cells, as well as normal human fibroblasts and lymphocytes were
      irradiated (0-6 Gy) and exposed to varying topotecan doses (0.01-10 microM)
      always 15 minutes before and either 1 hour after (short-term) or 24 hours after
      (long-term) irradiation. Survival was measured by colony-forming assays, and
      chromosome aberrations were scored in Giemsa-stained metaphase spreads.
      Unirradiated cells served as specific controls. RESULTS: Topotecan alone reduced
      the clonogenic cell survival in a concentration- and time-dependent manner, and
      radiosensitization was observed for all cell lines tested. There was no
      correlation between clonogenic cell survival and the frequencies of treatment
      induced chromosomal aberrations, neither in tumor cells nor in fibroblasts. In
      contrast, in lymphocytes increased frequencies of radiation-induced dicentric
      chromosomes were seen after the combined treatment. CONCLUSION: In certain cell
      types combined radiation/topotecan treatment may lead to increased frequencies of
      lethal chromosome aberrations. However, there is no evidence that the increased
      formation of lethal chromosome aberrations plays an important role in the
      topotecan-induced radiosensitization of human tumors.

PMID- 12426837
TI  - The influence of bromodeoxyuridine on the induction and repair of DNA double
      strand breaks in glioblastoma cells.
AB  - AIMS: To examine the dose response of DNA damage and its modification by the
      radiosensitizer, 5-bromo-2'-deoxyuridine (BrdU). The sensitizing mechanism is
      analyzed with regard to its influence on the induction and repair of DNA double
      strand breaks (DSBs). MATERIAL AND METHODS: Cells from three different human
      glioblastoma lines, A7, LH and U87MG, were X-irradiated with and without exposure
      to BrdU. DNA fragments were separated by field-inversion gel electrophoresis
      (FIGE) and quantified by fluorometry immediately and 24 h after irradiation.
      RESULTS: In all cell lines, the dose response followed a linear-quadratic rather
      than a purely linear function. BrdU-treated cells exhibited a significantly
      higher amount of mobile DNA. In repair experiments with and without BrdU, the
      amount of mobile DNA fell close to control values within 24 h. CONCLUSIONS: The
      linear-quadratic model appropriately describes the X-ray-induced fragmentation of
      DNA. BrdU sensitizing acts predominantly by increasing DNA fragility, and not by
      impairing damage repair. The amount of DSBs persistent after 24 h of repair is
      minimal, even after highly cytotoxic doses. However, it appears to depend on the
      extent of initial damage, causing sensitized cells to retain more DSBs than
      unsensitized cells.

PMID- 12426838
TI  - [Dissection or irradiation of the axilla in postmenopausal patients with breast
      cancer? Long-term results and long-term effects in 655 patients].
AB  - BACKGROUND: Until 1993 postmenopausal women with breast cancer did not receive
      adjuvant chemotherapy in our institution even if axillary nodes were involved. So
      in these patients axillary dissection had no diagnostic value for further
      treatment. Therefore we started a prospective study in which dissection of
      axillary nodes was replaced by irradiation in postmenopausal cN0 patients.
      PATIENTS AND METHODS: From 1986 to 1993 we irradiated 655 patients with breast
      cancer after breast conserving surgery (BET). In all 144 cN1- and all 209
      premenopausal cN0-patients axillary dissection was recommended. Of 302
      postmenopausal cN0 patients 129 had breast surgery in our institution. In a total
      of 129 patients axillary dissection was replaced by irradiation (AxRT-group).
      They were compared with all 173 patients referred from other hospitals for
      irradiation after both breast conserving surgery and axillary dissection (AxOP
      group). Dissected patients with gross tumor involvement of the axilla or less
      than eight nodes removed had additional axillary irradiation. Patients age, tumor
      size, vessel-, muscle- or skin invasion and grading were similar in both groups
      (Table 1). However, in the AxRT-group there were more patients with negative
      hormone receptors, multifocal and medial sited tumors. Late complications after
      dissection and/or irradiation of the axilla were evaluated in 502 patients free
      of locoregional relapse and with a minimal follow up of 3 years (median 9.5
      years). RESULTS: After 5, 10 and 15 years tumor free survival rates were 90%, 82%
      and 79% in the AxOP-group vs 91%, 82% and 80% in the AxRT-group, respectively (p
      = 0.95) (Figure 1). Overall survival (p = 0.98) (Figure 2), local (p = 0.47) and
      axillary control (p = 0.12) were equal in both groups (Figures 3 and 4). However,
      serious problems like lymphedema of the arm, pain, mobility impairment occurred
      in 26% patients following axillary dissection but only in 1% after axillary
      irradiation. No difference in late sequelae after axillary dissection with or
      without irradiation could be detected (26 vs 27%) (Table 2). CONCLUSION: In
      postmenopausal cN0-patients axillary dissection should be replaced by axillary
      irradiation, since it offers the same chance for cure with much lower morbidity.

PMID- 12426839
TI  - Inverse treatment planning and stereotactic intensity-modulated radiation therapy
      (IMRT) of the tumor and lymph node levels for nasopharyngeal carcinomas.
      Description of treatment technique, plan comparison, and case study.
AB  - PURPOSE: Inverse treatment planning and intensity-modulated radiation therapy
      (IMRT) promise advantages in the treatment of tumors of the head and neck region.
      Currently published studies use IMRT only in the treatment of the primary tumor.
      In these studies, the lymph nodes of the neck were treated using conventional
      techniques. The feasibility of an IMRT technique which allows treatment of the
      complete target volume, including the primary tumor and lymph nodes, without a
      beam split is described. PATIENT AND METHOD: For inverse treatment planning, the
      KonRad planning system was used. The primary as well as the secondary PTV
      (bilateral lymph node levels) were treated with one intensity-modulated primary
      plan. To increase the dose in the primary PTV and suspicious lymph nodes, an
      intensity-modulated boost plan was performed. The "step and shoot" IMRT technique
      was used. A plan comparison between the described IMRT approach and an IMRT
      approach using a split-beam technique was performed focusing on the treatment
      time. A patient with a carcinoma of the nasopharynx was treated with curative
      intent by a combined radiochemotherapy. RESULTS: The median total dose to the
      primary PTV was 70 Gy, to suspicious lymph nodes > or = 66.0 Gy, and to the
      secondary PTV 52 Gy. The defined maximum doses to the organs at risk were not
      exceeded, and the median dose to the protected parotid gland amounted to 21 Gy.
      Comparison of the treatment time between both IMRT approaches revealed only a
      slightly shorter treatment time (1-3 min) for the split-beam IMRT technique
      without considering the remaining conventional treatment parts of the split-beam
      IMRT technique. The patient achieved a complete response, and 18 months after
      treatment no signs of recurrent disease are visible. CONCLUSIONS: IMRT allows the
      treatment of the target volumes with high doses combined with an excellent
      sparing of the organs at risk. The IMRT approach presented here makes the
      treatment of the whole target volume with a single-beam arrangement feasible and
      does not increase the treatment time compared to a split-beam IMRT technique.
      Treatment time was comparable to a conventional three-field technique combined
      with electrons. This IMRT technique can prevent over- or underdosage at field
      matchlines in the head and neck region and, moreover, is able to spare parotid
      glands and therefore better avoid xerostomia compared to conventional techniques.

PMID- 12426840
TI  - [New laboratory diagnosis in rheumatology].

PMID- 12426841
TI  - [New aspects in autoantibody diagnosis in collagen diseases].
AB  - Distinct, especially non-organ specific autoantibodies are closely associated
      with connective tissue diseases and in many cases are vital elements of the
      laboratory diagnostics of these disorders. Their inclusion into the common
      classification criteria is quite heterogeneous. None of the autoantibodies is
      100% specific for a certain disease, and diagnostic specificity is usually
      reduced when application of the test is broadened and when more sensitive methods
      are used. In individual patients with scleroderma and/or myositis related
      diseases, typical autoantibodies usually exclude each other; however, there are
      characteristical exceptions from that rule. Evidence is accumulating that
      autoantibodies are detectable early during disease course and often even in
      preclinical stages. Variations of antibody levels during disease course are
      different in different systems and in some cases have been shown to correlate
      with disease activity. Negative results in sensitive screening assays are often
      essential to exclude a connective tissue disease. Although it has certain
      drawbacks and is being disputed, the indirect immunofluorescence assay with HEp-2
      cells still serves as a standard first step in connective tissue disease-related
      antibody detection. In case of positive results in this assay, further steps
      should be performed carefully, considering the signs and symptoms of the
      suspected disease as well as the immunofluorescence pattern, and being aware of
      the peculiarities and limitations of the assay methods used.

PMID- 12426842
TI  - [New aspects of antineutrophil cytoplasmic antibody (ANCA) diagnosis in
      vasculitis].
AB  - Anti-Neutrophil Cytoplasmic Antibodies (ANCA) are a heterogenous group of
      autoantibodies with a broad spectrum of clinically associated diseases. The
      diagnostic value is established of Proteinase 3 (PR3)-ANCA for Wegener's
      granulomatosis (WG) as well as Myeloperoxidase (MPO)-ANCA for microscopic
      polyangiitis (MPA). Within the last 20 years these antibodies were subject of
      intensive studies and a growing body of evidence arose for a distinct role of
      ANCA in the pathogenesis of the ANCA associated vasculitides WG and MPA. Our
      current concept of whether ANCA directly or indirectly contribute to vascular
      damage (ANCA-Cytokine-Sequence-Theory) was mainly developed from in vitro
      studies. It is plausible and it is supported by data from clinical investigations
      as well as animal models. Nevertheless our knowledge of the etiological and
      pathogenetic pathways remains incomplete.

PMID- 12426843
TI  - [New aspects of bacteriological pathogen diagnosis in rheumatic diseases].
AB  - Microbiological diagnosis for rheumatic diseases is increasingly used as part of
      the diagnostic work-up in rheumatological practice due to growing knowledge about
      bacteria-induced rheumatic diseases. This review's focus lies on rheumatic
      diseases, which in contrast to septic-infectious arthritis, are characterized by
      the inability to culture bacteria from the inflammed joint. These reactive
      arthritides occur after primary extraarticular bacterial infection. The
      etiological diagnosis of reactive arthritis is based on the detection of a
      previous or ongoing bacterial infection. Diagnosis is performed by serology or
      direct detection of the bacterial organism or parts thereof at the site of entry
      and recently by molecularbiology-based detection of the bacteria in the inflamed
      joint. This review reflects the current diagnostic approaches and formulates
      diagnostic algorithms for specific and well-directed microbiological diagnosis.

PMID- 12426844
TI  - [Cytometric analyses in systemic autoimmune diseases].
AB  - A number of autoantibodies play a significant role in collagen vascular diseases
      and represent diagnostic markers of some of these entities. Despite increasing
      knowledge of these serological findings, data are limited about potential
      disturbances of precursor cells that finally lead to the autoantibody producing
      plasma cells. Recent evidence of disturbed B cell homeostasis indicates that the
      peripheral B cell compartments in systemic lupus erythematodes (SLE) and
      Sjogren's syndrome are characteristically different to normal. Although the
      identification of autoreactive B cells in peripheral blood is still subject of
      ongoing studies, the differences in B cell subsets add to the understanding of
      the immunopathogenesis of these diseases and may provide new diagnostic clues and
      therapeutical avenues of these entities.

PMID- 12426845
TI  - [New aspects of molecular biology diagnosis. Array technology and expression
      profile for characterization of rheumatic diseases].
AB  - Increasing availability of high throughput technologies, exponentially growing
      information about the human genome and gene expression, and the growing global
      network of databases on systematic biomedical information will change our view on
      inflammatory rheumatic diseases in a revolutionary way. Several research
      laboratories have already generated initial extensive datasets on gene expression
      analysis. Application of this technique has demonstrated that in addition to a
      precise analysis, verification and validation of the results also on the level of
      cell populations, a meticulous characterization of the patients according to
      current conventional clinical, laboratory, imaging and histological standards is
      essential. For functional interpretation, in vitro tests, animal models and
      therapeutic studies will provide further information. Bioinformatic structuring
      and development is needed for the large amounts of data. After an initial genome
      wide screening, the objective is to identify those genes, which will allow
      characterization of the disease, classification according to molecular
      pathophysiology, evaluation of the prognosis and prediction of the correct and
      most potent therapeutic regimen. Derived from the improved knowledge about the
      molecular mechanisms, new and--as to expect--the crucial approaches for an
      effective therapy against chronic inflammation, organ destruction and
      pathological immune response in rheumatic diseases will emerge.

PMID- 12426846
TI  - [Structural quality of acute internal medicine rheumatology clinics--Project
      Group of the Association of Rheumatologic Acute Clinics].
AB  - A study group representing the VRA (Association of Rheumatology Clinics in
      Germany) has worked out the structural quality paper presented here. Five
      guidelines for structural quality have been established by the VRA and are laid
      out in this paper. Required space and personnel for implementing these guidelines
      are considered. A highly competent, multi-disciplinary team must be available to
      ensure the long-term quality of in-patient treatment of rheumatic patients, the
      majority of whom are chronically ill and are suffering from chronic pain of
      varying intensity which restricts their daily activities. The necessity for such
      in-patient treatment is reflected in a 6-point-questionnaire (draft) adapted to
      the Appropriateness Evaluation Protocol. Considering the introduction of a flat
      rate fee system (DRG-system) the structural quality paper describes the
      implementation of a specified electronic data processing documentation which is
      linked to a central hospital information system. According to the concept of
      benchmarking, the paper takes into account future developments of the German
      health system. It will be adjusted continuously to changing political guidelines
      for health services.

PMID- 12426847
TI  - [Technical aspects and value of arthrosonography in rheumatologic diagnosis. 4:
      Ultrasound of the elbow].
AB  - Musculoskeletal ultrasonography is an important imaging technique in the
      diagnosis of rheumatic diseases especially for early manifestation. It allows
      sensitive detection of small joint fluid collections as well as differentiation
      of soft tissue lesions and bone lesions. The following standard scans are
      suggested for sonographic evaluation of the elbow: 1) anterior humeroradial
      longitudinal scan, 2) anterior humeroulnar longitudinal scan to detect effusions,
      synovial proliferation, loose joint bodies, bone lesions
      (osteoarthritis/arthritis), 3) anterior transverse scan over the trochlea to
      evaluate these structures in an additional dimension, 4) posterior longitudinal
      scan and 5) posterior transverse scan of the olecranon fossa with flexed/extended
      elbow to evaluate the same objectives as the above mentioned scans and
      additionally to detect olecranon bursitis, and optional 6) distal dorsal
      longitudinal scan to differentiate soft tissue lesions such as rheumatoid nodules
      or gout tophi, 7) anterior transverse scan over the radius head to evaluate
      lesions of the radius head, tendopathy, calcinosis, 8) lateral humeroradial
      longitudinal scan to evaluate epicondylitis, 9) medial humeroulnar longitudinal
      scan to evaluate calcinosis, epicondylitis, signs of compression of the ulnar
      nerve. A linear transducer with a frequency of about 5-7.5 MHz is recommendable.
      The anterior distance between trochlea and the capitulum of the humerus between
      the bone and the joint-capsule of the elbow is > or = 2 mm in probable and > or =
      3 mm in definite synovitis or effusions. Synovitis or effusions are probable if
      the difference between the right and left elbow is 1 mm, and they are definite if
      the difference is > or = 2 mm.

PMID- 12426848
TI  - [Long-term follow-up and prognosis of work capacity in the early stage of chronic
      polyarthritis].
AB  - OBJECTIVES: Work disability (WD) in early rheumatoid arthritis (RA) has not been
      extensively evaluated in Germany. Therefore, the occurrence of WD pension within
      the first seven years of RA and prognostic indicators of the first year including
      the duration of sick leave (SL) were analyzed. PATIENTS AND METHODS: Within the
      first year of RA according to the ACR 1987 criteria, 141 gainfully employed
      patients were entered into a prospective multicenter study (61% females, mean age
      47 +/- 9 years, mean disease duration 6 +/- 3.5 months). One hundred and ten
      patients (78%) participated in a reevaluation (postal questionnaire) after a mean
      follow-up of 6.1 +/- 0.4 years. Predictors of WD pension were identified in
      univariate analyses and in backward multivariate Cox regression analyses (p <
      0.05) with Hazard-ratios [H-R] as measures of WD risk. RESULTS: Of 110 patients
      53 (48%) were still employed at reexamination. WD due to RA occurred in 5% after
      one year disease duration, in 15% after 2 years, in 20% after 3 years, and in 28%
      after 6.5 years. Other reasons for leaving the labor force were found in 24%.
      High pain intensity, radiographic erosions, comorbidity and the pain behavior of
      avoidance were associated with WD only in univariate analyses. Age > 45 years [H
      R 6.3] and the following job-related prognostic indicators were identified in the
      multivariate analyses: working under pressure of time [H-R 9.0], limited joint
      motion interferring with job tasks [H-R 5.9], feeling overworked [H-R 3.8] and
      work status (unskilled blue-collar workers vs white-collar professionals and self
      employed persons) [H-R 3.4]. In an alternative final Cox-regression model the
      variables feeling overworked and work status were replaced by SL duration > 8
      weeks within the first year of RA [H-R 7.1]. CONCLUSIONS: Since WD frequently
      occurs already within the first 3 years (20%) adequate interventions resulting
      from the prognostic indicators have to begin early in the course of RA. Apart
      from the rheumatological treatment and rehabilitation focusing on the reduction
      of pain, improved coping with pain, reduced joint destruction and improved
      mobility particularly working under pressure of time should be avoided and the
      work place has to be adjusted in case of limited joint motion interferring with
      job tasks. SL of several weeks duration already within the first year of RA is a
      red flag for impending WD.

PMID- 12426849
TI  - [Functional capacity and cartilage oligomeric protein (COMP) in serum of patients
      with maturity-onset polyarthritis].
AB  - OBJECTIVE: To compare late onset with adult onset rheumatoid arthritis. METHODS:
      Fifty-eight patients with late onset rheumatoid arthritis (LORA) were compared to
      117 patients with adult onset rheumatoid arthritis (AORA) with respect to
      clinical and functional parameters. Furthermore, in 104 patients serum cartilage
      oligomeric matrix protein (COMP) was measured. Results were compared by means of
      ANOVA and possible influences of age, gender and clinical parameters were
      evaluated by Spearman rank correlation. RESULTS: Except a different distribution
      in gender (40% males in the LORA group) and a higher ESR, no differences could be
      found with respect to clinical parameters. However, a significantly higher HAQ
      score and significantly higher serum-COMP levels could be shown in the LORA
      group. HAQ scores correlated not only with disease activity parameters (C
      reactive protein, disease activity score) but also with the age. Serum-COMP
      levels did show a correlation with the age as well, but not with disease
      activity. CONCLUSION: It is concluded that the higher serum-COMP levels in late
      onset rheumatoid arthritis could be due to concomitant osteoarthritic processes
      in larger joints, which are not symptomatic. The age dependence of the HAQ score
      is only weak, but may be the reason why patients with LORA show a worse
      functional capacity compared to patients with adult onset rheumatoid arthritis.

PMID- 12426850
TI  - Behcet's syndrome coexisting with clinically occult ankylosing spondylitis.
AB  - The case of a 36-year old man with Behcet's disease (BS) for 16 years had low
      back pain and stiffness in the cervical and lumbar spine. He was diagnosed as
      having ankylosing spondylitis (AS). In this report we wish to emphasize the
      clinically occult co-existence of AS in BS and revelation of AS after a long time
      of BS diagnose.

PMID- 12426851
TI  - [Presentation of the Center of Competence in Berlin].

PMID- 12426852
TI  - [Primary septic arthritis of the knee caused by Salmonella enteritidis in
      systemic lupus erythematosus].

PMID- 12426853
TI  - [Autoantibodies and the complement system--significance for pathogenesis of
      rheumatoid arthritis?].

PMID- 12426854
TI  - [Remicade in therapy of rheumatoid arthritis and Crohn diseases--no reason for
      panic].

PMID- 12426855
TI  - [Victor Rudolf Ott (1914-1986): European pioneer and and fighter].

PMID- 12426856
TI  - [Which possibilities of nuclear medicine therapy in general practice are
      available (RSO, Ra-224)?].

PMID- 12426857
TI  - [Benign prostatic hyperplasia syndrome--drugs instead of operation?].

PMID- 12426859
TI  - [Drug therapy of benign prostatic hyperplasia syndrome with alpha 1-receptor
      blockers. Basic principles and clinical results].
AB  - This article reviews the structure and function of the sympathetic nervous system
      controlling the myogenic tone of the bladder outlet. Therefore, the sympathetic
      nervous system is partially responsible for urinary outflow resistance. The alpha
      1-adrenoceptor antagonists alfuzosin, doxazosin, tamsulosin, or terazosin are
      able to reduce bladder outflow resistance, which leads to significant relief of
      LUTS (20-65%) and improvement of urinary flow (1-4.3 ml/s) in patients with
      symptomatic BPH. Alpha 1-blocker treatment works irrespective of the severity of
      symptoms, degree of subvesical obstruction, or prostate size. A significant
      reduction of residual urine was observed only occasionally, but at least
      alfuzosin is able to reduce the incidence of acute urinary retention. This
      article presents the results of 39 randomized, placebo-controlled trials with
      14,924 patients as well as trials with alpha 1-blockers and plant extracts or
      finasteride. The results of these trials indicate that all alpha 1-blockers are
      equally effective. However, tolerability of alfuzosin or tamsulosin is superior
      to doxazosin or terazosin. Furthermore, treatment of hypertension with doxazosin
      or terazosin is no longer recommended due to the increased frequency of
      cardiovascular side effects seen in the ALLHAT Study. As alpha 1-blockers can
      relieve symptoms and improve urinary flow more effectively than plant extracts or
      finasteride, alpha 1-blockers are the treatment of first choice in patients with
      symptomatic BPH without or with a minor degree of subvesical obstruction.

PMID- 12426858
TI  - [Dihydrotestosterone and the role of 5 alpha-reductase inhibitors in benign
      prostatic hyperplasia].
AB  - The genesis of benign prostate hyperplasia (BPH) depends on two factors:
      testicular androgen and the aging process. The most important androgen in the
      prostate is dihydrotestosterone (DHT). In the aging male the level of DHT in the
      prostate remains largely constant although the plasma level of testosterone
      decreases. DHT is formed by the reduction of testosterone by the enzyme 5-alpha
      reductase, which has two isoenzymes. The 5-alpha-reductase type 2 is the
      predominant isoenzyme in genital tissue and thus also in the prostate.
      Finasteride is a 5-alpha-reductase inhibitor, which is applied in the treatment
      of BHP and male baldness. In the doses used finasteride acts mainly by inhibiting
      the 5-alpha-reductase type 2, thereby reducing the serum level of DHT by
      approximately 70% and by about 85-90% in the prostate. Indeed the effect of
      finasteride in BPH was proven in clinical studies. However, the circulating and
      intraprostatic DHT could be further reduced by a more effective dual 5-alpha
      reductase inhibitor, which would be efficacious in the treatment of benign
      prostate hyperplasia and other DHT-related disorders.

PMID- 12426860
TI  - [Drug therapy of benign prostatic hyperplasia. Is combination therapy with 5
      alpha-reductase inhibitors and alpha-receptor blockers effective?].
AB  - 5 alpha-reductase inhibitors and alpha 1-receptor blockers are the two main drug
      therapies used in the management of symptomatic benign prostatic hyperplasia. As
      alpha-reductase inhibitors and alpha 1-receptor blockers act through different
      mechanisms, a combination of the two agents might be promising. The potential
      benefits of combination therapy with selective alpha 1-receptor blockers and
      finasteride, a 5 alpha-reductase inhibitor, are currently being evaluated in
      several placebo-controlled prospective multicenter studies (VA Study, ALFIN
      Study, PREDICT Study, and MTOPS Study). The data from these studies available so
      far demonstrate a statistically significant benefit for the study groups
      receiving alpha 1-receptor blockers and combination therapy vs placebo and
      finasteride monotherapy in terms of symptom scores and peak urine flow rates.
      However, none of the studies yielded a statistically significant advantage of
      combination therapy over treatment with alpha 1-receptor blockers. These results
      should be interpreted with reference to the prostatic volume, which in the
      studies mentioned above was relatively low. From the results of all these
      studies, it can be concluded that in symptomatic patients with prostate volumes
      of up to 40-45 ml a combination of 5 alpha-reductase inhibitors with alpha 1
      receptor blockers does not appear to provide any benefit. Yet, it can be assumed
      that in symptomatic patients with prostate volumes of more than 60 ml combination
      therapy may indeed prove more effective.

PMID- 12426862
TI  - [alpha 1-receptor blockade in therapy of benign prostatic hyperplasia syndrome.
      Correct dosing for optimal effectiveness].
AB  - Four alpha 1-adrenoceptor antagonists are currently available for the medical
      treatment of lower urinary tract symptoms suggestive of benign prostatic
      obstruction in Germany: alfuzosin, doxazosin, tamsulosin, and terazosin. Indirect
      comparison based on randomized, placebo-controlled trials as well as several
      direct comparative studies have shown equal efficacy of all four drugs on urinary
      flow and symptom relief if suggested dosing regimens are applied. A dosing
      regimen below this recommendation should be restricted to those patients who have
      a proven satisfactory response to a lower dose.

PMID- 12426861
TI  - [Phytotherapy of benign prostatic hyperplasia. Current evidence-based
      evaluation].
AB  - Despite its popularity as a medication in various European countries or as a
      nutritional supplement in the United States, the role of plant extracts for the
      treatment of LUTS due to BPH remains controversial. Only a few randomized
      clinical trials that meet standard criteria of evidence-based medicine but with
      relatively short follow-up times and some meta-analyses mainly regarding Serenoa
      repens and Pygeum Africanum as well as more recent studies on pumpkin seeds have
      shown clinical effects and good tolerability. To better judge the therapeutic
      potential of these plant extracts, additional randomized placebo-controlled
      clinical trials with sufficient follow-up are needed.

PMID- 12426863
TI  - [Significance of endorectal nuclear magnetic resonance tomography and transrectal
      ultrasound diagnosis in local staging of prostatic carcinoma].
AB  - METHODS: We assessed the staging accuracy of endorectal magnetic resonance
      imaging (eMRI) and transrectal ultrasonography (TRUS) for localized prostate
      cancer. 54 patients with biopsy proven prostate cancer underwent TRUS and eMRI
      prior to radical retropubic prostatectomy. The MR images were prospectively
      interpreted by two radiologists. These findings were compared with the
      histopathological results. RESULTS: Overall accuracy of eMRI in defining local
      tumor stage was 93% by radiologist A and 56% by radiologist B. Overall accuracy
      by TRUS was 63%. Analysis of interobserver agreement showed a poor correlation
      regarding MRI studies. Endorectal MRI was more sensitive than TRUS for detecting
      capsular penetration and seminal vesicle involvement. TRUS revealed a relatively
      high specificity and was superior to eMRI in this regard. CONCLUSION: This series
      shows the current limited value of TRUS and eMRI for planning treatment in
      patients with clinically localized prostate cancer.

PMID- 12426864
TI  - [Acceptance of silicone testicular prostheses in long-term follow-up].
AB  - The loss of a testicle is a psychological trauma, in particular for young men.
      The cosmetic defect can be corrected by implantation of a silicone testicular
      prosthesis (STP). The recurring discussion regarding the problems of silicone
      implants mainly concerns breast implants. STPs are made of equivalent material.
      Since we have been using STPs for 20 years, we wanted to research the opinion of
      our patients regarding these issues. Between 1978 and 1998, 51 STPs were
      implanted--37 times by groin incision and 14 times by scrotal incision--in 51
      patients. The average age of the patients at the time of the operation was 23.3
      years (14.3-55.4). Three implants had to be removed early. A questionnaire was
      distributed to all patients with STPs; 39 of the questionnaires were returned
      completed. The results--10.1 years postoperative--showed no serious late
      complications, an acceptance rate of 97% by the patients and about 50% by their
      female partners. Therefore, we will continue to offer the option for implantation
      of STP to our patients.

PMID- 12426865
TI  - [Prospective study of effectiveness. Reoperation (re-TUR) in superficial bladder
      carcinoma].
AB  - To assess the rate of residual cancer after transurethral resection (TUR) of
      superficial bladder cancer, a prospective study was carried out. All patients
      with transitional cell cancer (TCC) stage pTa-pT1 underwent a repeat TUR (ReTUR)
      within 6-8 weeks. Sites and rates of tumors found during ReTUR were documented as
      well as the morbidity of the ReTUR. Of a total of 192 TUR, superficial TCC was
      found in 124 cases; 83 underwent ReTUR according to the study protocol. Residual
      tumor was detected in 27% of pTa and 53% of pT1 tumors. Worsening of grading or T
      stage was found in 8%. Of the tumors detected by ReTUR, 81% were localized at the
      site of the first TUR. In this prospective study, residual tumor formation was
      detected in a high percentage. Routine ReTUR is therefore recommended in
      superficial bladder cancer except solitary pTaGI lesions.

PMID- 12426866
TI  - [Molecular genetic changes in renal cell carcinomas].
AB  - Over the last decade several genetic alterations involved in the pathogenesis and
      progression of renal cell carcinoma have been identified. These findings will
      have a wide implication for the diagnosis and management of renal cell
      carcinomas. This review provides a discussion of general principles of tumor
      development as well as the specific mechanisms underlying renal carcinogenesis.

PMID- 12426867
TI  - [Ambulatory radiosurgery in cerebral metastatic renal cell carcinoma. 5-year
      outcome in 58 patients].
AB  - Brain metastases (BM) indicate an advanced stage of renal cell cancer (RCC). They
      pose an increasing challenge to urologists as a result of improved survival due
      to modern therapy. Median survival of untreated patients with BM who often suffer
      from neurological deficits is 3 months. Radiosurgery with the Gamma Knife (GK)
      has increased in use as an alternative to whole brain radiation therapy (WBRT)
      and/or surgery. This study reports the results of a consecutive series of RCC
      patients treated for BM by GK radiosurgery during a 5-year period. Between 1994
      and 1999, 58 patients with a total of 277 BM and 3.0 (1-19) BM/patient were
      treated. Because of recurrent BM, 23 (40%) patients received repeated (multiple)
      GK sessions. The median tumor volume was 3.4 cm3 (0.1-19.1). The median interval
      between diagnosis of RCC and GK treatment was 2.2 years (0.1-17.2). Symptomatic
      side effects were detected in 9 (16%) of 58 patients. The median actuarial
      survival time was 9.9 months. Local tumor control could be achieved in 95% of
      patients. The GK therapy induced a significant tumor remission accompanied by
      rapid neurological improvement in 70% of patients. Compared to standard
      radiotherapy, GK radiosurgery is more effective, less time consuming, and can be
      repeated. Compared to surgery, radiosurgery is less invasive and better suited to
      treat multiple metastases in one single session. Surgery and radiosurgery,
      however, are supplementary methods that are highly effective to control
      intracerebral metastasizing RCC.

PMID- 12426868
TI  - [Telerobotic surgery between Baltimore and Munich].
AB  - The rapid development of laparoscopy in urology necessitates the training of
      specialists to guarantee the high standard of patient care. The real-time data
      communication of medical information between physicians in different locations is
      known as telemedicine. Telementoring describes the assistance of an experienced
      surgeon, while telerobotics requires the use of robots. Two robots, the
      established AESOP and the PAKY + RCM developed at the Johns Hopkins Hospital
      (JHH), were used to perform a telerobotic laparoscopic renal cyst ablation in
      cooperation between Baltimore and Munich. The telementor maneuvered the robots
      over a distance of 8000 km using eight ISDN lines and a PC. AESOP moved the
      camera, while PAKY allowed the use of a fan retractor in the abdomen. The
      telerobotic operation was performed without complications or system and
      communication failures. Telementoring can be used for training purposes but also
      for consultation between specialists in emergency settings.

PMID- 12426869
TI  - [Surgical therapy of scrotal edema in elephantiasis congenita hereditaria (Meige
      type)].
AB  - The underlying cause of primary lymphedema is a malformation of the lymph vessel
      system. Secondary lymphedemas can be due to infections, recurrent inflammation,
      hypoproteinemia, tumors, operations, or irradiation. As a reaction to persistent
      edema and interstitial macromolecules, fibrosis occurs. Recurrent inflammations
      of the indurated and edematous tissue are clinically impressive. The massive form
      of the scrotal lymphedema leads to painful tautness and sexual dysfunction. A
      concurrent penile edema can cause dysuria. The deformity of the affected
      extremities and organs not only leads to restriction of mobility but also to
      psychological stress due to the disfigurement, even as far as to social
      deprivation. We report on a surgical technique for treating pronounced scrotal
      edema by resection and neoscrotal reconstruction using ventral pedunculated
      scrotal skin flaps in cases of congenital hereditary elephantiasis of the Meige
      type.

PMID- 12426870
TI  - [Urinary calculi. 1: Epidemiology, laboratory diagnosis, genetics and
      infections].

PMID- 12426871
TI  - [Intergenerational relations and intragenerational conditions].

PMID- 12426872
TI  - [Intergenerational relations and intragenerational conditions. Observations from
      the viewpoint of statutory pension insurance].
AB  - The future development of all German pension systems will be determined by
      decisive challenges. The demographic development, the increasing number and
      length of interruptions of the employment period and the change in the
      distribution of functions in partnerships are just three aspects. The statutory
      pension insurance organizes the relationship between the generations as well as
      the balancing within one generation. The structure of statutory pension insurance
      must guarantee a fair equalization of burdens in both regards. The following
      article describes the challenges and the contribution of statutory pension
      insurance to stable social relationships.

PMID- 12426873
TI  - [Intergenerational contract and intergenerational justice].
AB  - Intergenerational justice dominates the discussion about public pension systems.
      Especially the implicit tax rate, the internal return, and the generational
      accounts as measures of intergenerational redistribution have brought the debate
      from the scientific community to the headlines of the political debate. Each of
      the three measures came to the result that there is too high of a burden for the
      younger generations as a result of the given demographic change. If
      intergenerational justice is understood as a equal treatment of different
      generations, an improvement of the relation between contributions and benefits
      for the younger generations becomes a necessary item of social policy. To achieve
      such a situation the introduction of a funded pillar into the public pension
      system is, according to most economists, the solution. The pension reform of the
      year 2000/01 in Germany took this into account. The effects of this reform on the
      relation between the contributions and benefits, and as a result on the
      intergenerational justice will be investigated in this paper.

PMID- 12426874
TI  - [Pension insurance and intergenerational justice following pension reform].
AB  - Against the background of the demographic development, the question is whether an
      old age income security system which is based on the pay-as-you-go principle is
      still in accordance with the principle of intergenerational solidarity. The
      article examines significant dimensions of a fair distribution of income between
      different generations and asks for the respective implications of the German
      pension reform 2001. The article finishes by concluding that even an old age
      income security system on a private basis which is based on the capital stock
      system cannot prevent future cohorts of younger generations from having a higher
      burden.

PMID- 12426875
TI  - [Promoting competition and improving quality. Accepting the intergenerational
      contract by stabilizing health care reform].
AB  - The challenge of demographic transition requires a health care reform which
      strengthens competition and quality in health care. With this, important
      contributions in stabilizing intergenerational relations, especially
      intergenerational solidarity in the public health care system, can be achieved.
      The reform proposal by an expert group, invited by the Friedrich-Ebert-Foundation
      to develop a concept of health care reform, takes these considerations into
      account.

PMID- 12426876
TI  - The politics of intergenerational relations.
AB  - The main purpose of this article is to emphasise the critical role of politics
      and political ideology in determining the nature of intergenerational relations.
      This is not the only source of influence on intergenerational relations but it
      has been under-emphasised in scientific inquiry. Social policies embodying
      political ideology have an impact at both micro and macro levels. The article
      summarises the ethical basis of generational solidarity, the nature of the social
      contract, the changes taking place in relations between the generations and the
      recent impact of political ideology on the social contract. The main point of
      reference is the UK.

PMID- 12426877
TI  - [Are the "elderly" living at the expense of the "young"? Remarks on the burden
      distribution between "generations" in an aging population from the economic
      perspective].
AB  - Public and scientific discussion on the effects of an aging population is often
      biased: aging is primarily seen as an economic burden. Increasing contribution
      rates in pension schemes, health and long-term care insurance are highlighted.
      This paper tries to provide a more balanced view. The distinction between a cross
      sectional and a longitudinal view already gives different information on
      distributional effects. Labeling older people as "economically inactive" is a
      much too narrow perspective focused on the activity on the labor market only.
      Other types of work are neglected such as caring for children or frail elderly as
      well as economic activities from wealth, consumption as well as paying taxes to
      finance public expenditure. The approach of "generational accounting" is also
      narrow, focusing on public expenditure, social insurance contributions and only
      some types of taxes, but not dealing with private, especially intrafamily
      transfers. In economic terms, a comprehensive approach is needed regarding the
      effect of institutions and measures on the economic situation of cohorts. The
      role of investment in human capital is mentioned as a decisive factor for
      productivity in a country. Further education and retraining of older workers is
      one important element. An integrative approach dealing with the different fields
      of activities is needed when analyzing the intergenerational as well as the
      intragenerational distribution. This requires an elaborated and differentiated
      reporting of distributional effects. This important precondition, however, does
      not exist in Germany.

PMID- 12426878
TI  - [Intergenerational communication by age-integrating structures? Remarks on on
      gerontologic utopia].
AB  - In their "aging and society" paradigm Riley and collaborators conceptualize the
      ideal type of an age-integrated society in which the social segregation of
      different age groups is removed. They claim that in the future the life-world
      areas of education, work and leisure will no longer exclusively follow the triple
      division of the life course but will be visited repeatedly in different phases of
      life. Therefore, they argue, age barriers would be dissolved in many areas, which
      would lead to more contact and cooperation and to a greater solidarity between
      the generations. This conception shall be rejected as an utopia because it
      contradicts central functional mechanisms of modern societies; at best it might
      be imagined as a "reflexive modernization" of age-segregated structures. A
      certain distance and alienation between the generations remains a direct, though
      unintended product of the modernization process and cannot be reversed without
      welfare losses. A dialogue of generations as a societal project, therefore,
      implies that the functional differentiation into age groups and life stages will
      be accepted without referring to pre-modern idealizations of generational
      relationships.

PMID- 12426879
TI  - [Generative potential in advanced age. Sociological intergenerational
      considerations of an old topic].
AB  - The concept of generativity--at first related to middle age--is increasingly used
      to describe developmental processes at higher ages. In previous discussions,
      however, the concept of generativity has been used without clear references
      either to stages in later life (independent retirement versus dependent old age)
      or to different concepts of generations. A stage-oriented approach--based on
      ideas developed by Margret Baltes--indicates that the dimensions of generativity
      change with aging (more active generativity for younger retired people, more
      passive and compensating generativity among fragile and dependent persons). A
      generational approach--looking at different concepts of generations (family
      generations, societal generations, welfare generations)--shows that generativity
      within family generations is underlined by social norms, whereas generativity
      concerning welfare generations or societal generations remains an unstructured or
      even anomic developmental task.

PMID- 12426880
TI  - [Importance of family for quality of life of the elderly in a social and cultural
      comparison].
AB  - This paper explores the role of the family and its contribution to quality of
      life in old age under a comparative perspective, looking at different European
      welfare states (Norway, Germany, Spain and Israel). The literature demonstrates a
      consistent association between well-being and social networks in old age.
      Intergenerational family relations seem to be of special relevance in their
      contribution to health and well-being of older family members. Key features of
      intergenerational relationships include association, help, and support. However,
      in modern welfare states, certain tasks traditionally performed by families are
      covered by services. To assess the relative impact of families and the welfare
      state and to understand the interaction between them both a comparative
      perspective is needed analyzing diverse cultures and welfare regimes. Cultural
      and societal contexts are of central importance in exploring and understanding
      the complex association between family relations and the quality of life of the
      elderly. It is hypothesized that there is an interaction between family structure
      and welfare state transfers. This hypothesis states that the relationship between
      family structure and quality of life depends on the type of welfare state and
      welfare state transfers and services. Hence, the relationship between quality of
      life and family support should be strong only in those cases where welfare state
      transfers are low. The empirical results partly confirm the theoretical
      assumptions of welfare state regime dependence of the children's effect on the
      elder's quality of life. Three out of the four analyzed countries show results
      that strongly support the hypothesis of an intervening effect of welfare state
      systems on the connection between family and overall quality of life in old age.
      However, further analyses are needed. First, more sensitive indicators of parent
      child relations have to be used. Second, needs and their intervening effects on
      the direct linkages between children and quality of life have to be taken into
      account in more complex analyses. Third, more elaborated indicators of "quality
      of life" should be used in future analyses.

PMID- 12426881
TI  - [Disembedding and remoralization. Old age security and intergenerational
      relations in globalized welfare capitalism].
AB  - The article reconstructs the changes in provision for old age since the 19th
      century with regard to the ensuing change in intergenerational relationships. The
      first finding is a broadening of the arenas of provision for old age, a
      historical cumulation of family (which is still relevant), welfare state and,
      increasingly, private provision in financial markets, adding up to a 'welfare
      mix' in old age. This implies a complexification of intergenerational
      relationships. The second finding is an ambivalent qualitative change: on the one
      hand relationships between generations become more anonymous and disembedded from
      primary social relationships; on the other hand they are politicized (they become
      a public issue) and remoralized. This ambivalence applies to bureaucratic
      provision for old age in the welfare state, i.e., to social insurance. The main
      thesis is that--contrary to neoliberal belief--private old-age security in global
      financial markets cannot be seen as individualistic and moral-free but
      constitutes an anonymous exchange relationship between generations on financial
      markets that also raises issues of intergenerational justice. We can expect that
      these abstract relationships between generations will be politicized and
      remoralized as a consequence. Welfare state and financial markets offer solutions
      to problems of previous forms of provision for old age but they also produce new
      problems of intergenerational relationships.

PMID- 12426882
TI  - [Impact of hospital diagnostic related groups on geriatric rehabilitation
      facilities].
AB  - The introduction of the DRGs (diagnosis related groups) for paying hospitals in
      Germany in 2003 will result in changes in quality, quantity and financial flows
      foremost for the hospital sector but also for the important sector of the
      geriatric rehabilitation. This geriatric sector will experience a growth in total
      patient numbers, an enhanced and altered service range and a change in the market
      relationship towards the hospitals. The introduction of case-related payments
      also for the geriatric rehabilitation could, on the one hand, reduce the negative
      spillover effects from the hospital sector and, on the other hand, guaranty an
      efficient service provision. Furthermore, there would be a good comparability
      among the geriatric rehabilitation facilities and between costs in institutions
      of geriatric rehabilitation and hospitals. If hospital and geriatric
      rehabilitation services were payed by case-related payments, efficiency of health
      care services could be further improved by a broad definition of cases (complex
      case-based reimbursement), including care in the hospital as well as the care in
      the rehabilitation clinic afterwards. If rehabilitation would be financed by case
      based reimbursement as well as by of a complex case-based reimbursement, a
      quality assurance program would be necessary.

PMID- 12426883
TI  - [Resource allocation and justice in distribution of services in medical
      management of elderly patients].
AB  - This paper presents the most important arguments in medical allocation based on
      an analysis of the relevant literature. The main arguments of rationing scarce
      medical resources are scrutinized. Especially the use of age limit considerations
      are critically reviewed. The discussion takes place against a backdrop of
      aggravating pressure on old people as cost factors. As a basis for further
      discussion, the authors give a brief history of theories of justice in
      philosophy. Finally minimum requirements for a constructive and responsible
      discussion are stated.

PMID- 12426884
TI  - Response: HIV/AIDS among older persons (a growing problem).

PMID- 12426885
TI  - HIV rates increase.

PMID- 12426886
TI  - African unions slam UK HIV.

PMID- 12426887
TI  - Celebrating the year of the outback.

PMID- 12426888
TI  - The Victorian nurse practitioner project.

PMID- 12426889
TI  - [Conclusions with consequences].

PMID- 12426890
TI  - [Can specialists be used in a better way?].

PMID- 12426891
TI  - [Is the last bastion falling down?].

PMID- 12426892
TI  - [Protein-creatinine ratio--a simple method for proteinuria assessment in clinical
      practice].
AB  - BACKGROUND: Proteinuria is an indicator of renal disease. Measurement of protein
      excretion is important for diagnosis and follow-up of renal disease, but
      measuring 24-hour protein excretion is a cumbersome procedure. MATERIAL AND
      METHODS: A simplified validated method for measuring excretion is obtained by
      measuring urine protein/creatinine concentration in a spot urine sample. RESULTS:
      We have implemented such ratios for clinical routine measurements of proteinuria
      at Rikshospitalet University Hospital in Oslo. Whenever protein or albumin in
      urine is requested, the laboratory also measures urine creatinine and reports the
      ratio in mg protein/mmol creatinine. 24-hour excretion is approximately 10 times
      the ratio. The rationale for using the ratio is given and proteinuria
      pathophysiology and potential risks and treatment options are discussed.
      INTERPRETATION: Our experience is that use of the urine protein/creatinine ratio
      is a significant improvement. Measurements are now routinely made whereas
      quantification was rarely performed when 24-hour urine samples were used. We
      recommend that physicians and laboratories implement the use of this ratio in
      their daily routines.

PMID- 12426893
TI  - [Lung edema follows inspiratory stridor--another pitfall for the
      anesthesiologist].
AB  - BACKGROUND: Patients with heart failure or elevated intracranial pressure are at
      risk of developing lung oedema when anaesthesized. Lung oedema may develop in
      patients with airway obstructions as well. MATERIAL AND RESULTS: We refer to a
      four-year-old boy anaesthesized for elective adenotomia and paracentesis. After
      being extubated, he developed a moderate inspiratory stridor lasting for hours.
      Clinically he normalized in two hours on a therapy with oxygen in a mask with
      continuous positive airway pressure (CPAP) and finally bronchodilator therapy
      with epinephrine and salbutamol. Successive lung X-rays showed lung oedema almost
      normalizing in 48 hours. INTERPRETATION: The triggering mechanism of lung oedema
      in airway obstruction is the negative intrathoracal pressure generated because of
      forced inspiratory effort. This pressure is transformed to a negative
      interstitial hydrostatic pressure that according to Starling's hypothesis on
      capillary filtration may generate a lung oedema. We conclude that our patient
      with nasal polyps had a lowered threshold for developing lung oedema faced with
      postextubatory complications causing inspiratory stridor. Pathogenic mechanisms
      are discussed.

PMID- 12426894
TI  - [Universal neonatal hearing screening of infants with otoacoustic emissions].
AB  - BACKGROUND: The incidence of congenital hearing impairment is 1-2/1,000--higher
      than for congenital hypothyroidism and phenylketonuria combined. Universal
      screening of hearing impairment has been introduced in many countries with
      portable otoacoustic emission (OAE) and/or automated auditory brainstem response
      (AABR), but not in Norway. This is the first Norwegian report on universal
      hearing screening of newborns before hospital discharge. MATERIALS AND METHODS:
      All newborns in Ostfold County (n = 5,712) in 2000 and 2001 were offered an OAE
      test on the second day in nursery by a two-step model. After two tests without
      OAE signals bilaterally, the infants were referred to the audiology clinic.
      RESULTS: 98.8% of the newborns were tested. Of these, 97.0% had a pass response
      after two tests. 169 (3.0%) were referred to the audiology clinic; 15 were
      withdrawn from follow-up examination by their parents. 23 infants had auditory
      brainstem response audiometry done, and sensorineural hearing impairment was
      found in six (1.0/1,000). Three infants (0.6/1,000) had conductive hearing
      impairment. INTERPRETATION: Our screening model was appropriate and cost
      effective. The incidence of congenital hearing impairment was similar to that
      reported by others. The number of parental refusals should be reduced. This may
      be achieved by adding an AABR to the two OAE tests.

PMID- 12426895
TI  - [Screening for congenital hearing loss--a pilot project].
AB  - BACKGROUND: Until recently in Norway, congenital hearing loss has on average been
      diagnosed at 2.8 years of age. Delayed diagnosis is associated with loss of
      valuable opportunities for auditory habilitation and speech development. MATERIAL
      AND METHODS: Since September 1999 we have carried out universal screening for
      congenital hearing loss in both healthy and sick newborns. During the first
      screening period, all newborns were screened with automated auditory brainstem
      response audiometry. In the second period all healthy infants were screened
      primarily with otoacoustic emission audiometry, with automated auditory brainstem
      response audiometry as a second stage screening for those who failed the
      otoacoustic emission test. 3,996 infants were screened from start-up until
      December 2001. RESULTS: Hearing loss was confirmed in 25 patients (11 unilateral
      and 14 bilateral). A further two patients were referred but found to have normal
      hearing. The incidence of congenital hearing loss was 0.16% in presumed healthy
      infants and 2.2% in infants admitted to the intensive care nursery.
      INTERPRETATION: Screening for congenital hearing loss can be carried out with a
      very low rate of referrals and a low rate of false positive tests, particularly
      if there is access to otoacoustic emission as well as automated auditory
      brainstem response testing. In our opinion, Norway now needs to legislate for
      universal screening for congenital hearing loss in the neonatal period. Our
      departments of audiology should be given the opportunity and resources to upgrade
      their skills in relation to this new group of patients.

PMID- 12426896
TI  - [Early diagnosis of deafness and severe hearing loss].
AB  - BACKGROUND: Universal neonatal hearing screening can now be done by practical
      application of hearing physiology and automated techniques for registration of
      otoacoustic emissions and auditory brainstem responses. MATERIAL AND METHODS:
      This review gives the theoretical and practical background for implementation of
      neonatal hearing screening in Norway. RESULTS: With the diagnostic methods used
      up to now, age at diagnosis of permanent hearing loss and start of habilitation
      has not been lowered during the last decades. Based on early diagnosis,
      habilitation of permanent hearing impairment can now be improved to an earlier
      unknown extent. The importance of continued efforts for diagnosis of postnatal
      hearing loss through infancy and adolescence is stressed. Disapproval of neonatal
      hearing screening based on methodological problems and possible parental concern
      is largely non-existent. INTERPRETATION: The benefits of early diagnosis of
      hearing loss outweigh the costs and efforts invested in screening.

PMID- 12426897
TI  - [Use of specialist health care by the population].
AB  - BACKGROUND: Equitable use of specialist health care is a central goal of
      Norwegian health policy. It is, however, claimed that use of health care
      facilities are more determined by easy access than by need; hence that equity is
      not achieved. This article examines the impact on the use of health services of
      self-assessed health on the one hand and degree of access on the other. MATERIAL
      AND METHODS: Data from a national survey of quality of life were merged with data
      on capacity/access to primary and specialist health care. The data sets include
      individual characteristics of 3,449 persons. Binominal logistic analysis was
      applied. RESULTS: When compared to persons with self-assessed poor or very poor
      health, those with self-assessed medium-level health are less likely to use
      hospital inpatient and outpatient services, but not less likely to use private
      specialists. Furthermore, we find significant effects of accessibility on the
      utilization of private specialists, but not on hospitalization. INTERPRETATION:
      Use of hospital services is rationed according to patients' health status, and
      not affected by patients' access, as aimed at in national health policy. On the
      other hand, the use of private specialists seems to function as an alternative to
      general practitioner. The finding represents a challenge for national health
      policy.

PMID- 12426898
TI  - [Drugs and thyroid gland function].

PMID- 12426899
TI  - [Drug treatment of schizophrenia].
AB  - BACKGROUND: Drug treatment is important, though only part of the treatment and
      support that most schizophrenic patients need. The aim of this article is to
      present current knowledge and opinion concerning start of treatment, drug of
      first choice, treatment of refractory schizophrenia, treatment of co-morbidity,
      treatment during pregnancy and lactation, and the proper time to stop medication.
      MATERIAL AND METHODS: The article is based on a review of recent literature and
      contact with experts in the field. Literature was identified through searches on
      Medline and Web of Science. RESULTS AND INTERPRETATION: The antipsychotic effect
      of the second-generation, atypical neuroleptics is comparable to the effect of
      conventional drugs. Clozapine is still the drug of choice for refractory
      conditions. The new antipsychotics seem to have properties that improve cognition
      and reduce the risk of motor side effects; hence they have some advantages over
      conventional drugs.

PMID- 12426900
TI  - [Does individual psychotherapy have a place in the treatment of schizophrenia?].
AB  - Psychotherapy of schizophrenia has caused considerable debate. In 1990 prominent
      researchers proposed "a moratorium" on such treatment. It is now generally
      accepted that neuroleptic drugs cannot eliminate the need for comprehensive
      training in practical and social skills in patients with schizophrenia and that
      most patients need help to acknowledge, bear and put into perspective actual
      emotions and life events. Psychotherapy cannot replace treatment with
      neuroleptics, but neuroleptics alone will remain insufficient. These patients
      need integrated, comprehensive treatment programmes.

PMID- 12426901
TI  - [Interdisciplinary cooperation between the cultural sector and the health
      sector].

PMID- 12426902
TI  - [Celecoxib and the CLASS study--a statement].

PMID- 12426903
TI  - [Celecoxib and the CLASS study--worse and worse...].

PMID- 12426904
TI  - [...bad example of a miserable "research on order"].

PMID- 12426905
TI  - [Sex differences in the risk for coronary heart disease].

PMID- 12426906
TI  - [Hot confusion about estrogen and breast cancer].

PMID- 12426907
TI  - [Must the patient himself quality-control health service's supply?].

PMID- 12426908
TI  - Physiotherapy research in Ukraine: a subjective view from the inside.

PMID- 12426909
TI  - Are cervical physical outcome measures influenced by the presence of
      symptomatology?
AB  - BACKGROUND AND PURPOSE: Outcome measures must be repeatable over time to judge
      changes as a result of treatment. It is unknown whether the presence of neck pain
      can affect measurement reliability over a time period when some change could be
      expected as a result of an intervention. The present study investigated the
      reliability of two measures, active cervical range of movement (AROM) and
      pressure pain thresholds (PPTs), in symptomatic and asymptomatic subjects.
      METHOD: A repeated-measures study design with one week between testing sessions
      was used. Nineteen healthy asymptomatic subjects and 19 subjects with chronic
      neck pain participated in the study. The neck movements measured were: flexion,
      extension, right and left lateral flexion, and axial rotation. PPTs were measured
      over six bilateral sites, both local and remote to the cervical spine. RESULTS:
      The between-week intra-class correlation coefficients (ICCs2,1) for AROM ranged
      from 0.67 to 0.93 (asymptomatic group) and from 0.64 to 0.88 (chronic neck pain
      group). Standard error of measurement (SEM) was similar in both groups, from 2.66
      degrees to 5.59 degrees (asymptomatic group) and from 2.36 degrees to 6.72
      degrees (chronic neck pain group). ICCs2,1 for PPTs ranged from 0.70 to 0.91
      (asymptomatic group) and from 0.69 to 0.92 (chronic neck pain group). SEM ranged
      from 11.14 to 87.71 kPa (asymptomatic group) and from 14.25 to 102.95 kPa
      (chronic neck pain group). CONCLUSIONS: The findings of moderate to very high
      between-week reliability of measures of AROM and PPTs in both asymptomatic and
      chronic neck pain subjects suggest the presence of symptomatology does not
      adversely affect reliability of these measures. The results support the use of
      these measures for monitoring change in chronic neck pain conditions.

PMID- 12426910
TI  - Vertebral artery atherosclerosis: a risk factor in the use of manipulative
      therapy?
AB  - BACKGROUND AND PURPOSE: Vertebrobasilar insufficiency, a direct result of
      compromised blood flow in the vertebrobasilar circulation, may be caused by
      stretching and/or compression of the vertebral arteries, particularly if
      superimposed on underlying atherosclerosis of the vessels. This is an important
      consideration when using manipulative therapy techniques. The aim of the present
      study was to investigate the incidence of atherosclerosis and to calculate the
      relative associated decrease in blood flow in the third and fourth parts of the
      vertebral artery, in a sample of the adult population. METHOD: A laboratory-based
      experimental investigation was used to study 362 vertebral arteries from embalmed
      adult cadavers that were routinely processed for light microscopic study. The
      incidence of each grade of atherosclerosis in the vessels was recorded.
      Atherosclerosis was classified as grades 0-5, where Grade 0 represented no
      atherosclerosis and Grade 5 a fully developed plaque occluding more than 75% of
      the vessel lumen. From mean measurements of 188 of these arteries, the estimated
      decrease in luminal cross-sectional area and the relative decrease in blood flow
      in the atherosclerotic vessels were calculated. RESULTS: The highest incidence of
      atherosclerosis found was Grade 3 (third part of the vertebral artery (VA3):
      42.0%; fourth part of the vertebral artery (VA4): 35.2%). An estimated decrease
      in artery luminal cross-sectional area to 6.2% of normal in Grade 5
      atherosclerosis was found. Because blood flow is proportional to the fourth power
      of the vessel radius, relative decreases in blood flow in grades 1-5
      atherosclerosis from 100% to 0% (with critical closing pressure in vessels),
      respectively, are likely to occur. CONCLUSIONS: These data suggest that, as
      significant numbers of the sample showed marked (Grade 3+) atherosclerosis,
      concomitant with decreased blood flow in the vertebral arteries, this population
      is at risk for developing vertebrobasilar insufficiency. Because other Western
      populations may be similarly at risk, particular care should be taken when
      considering the use of rotational manipulative therapy techniques in treatments
      of the cervical spine.

PMID- 12426911
TI  - The effect of measurement protocol on active cervical motion in healthy subjects.
AB  - BACKGROUND AND PURPOSE: Although the assessment of cervical motion is routinely
      performed in clinical practice, no standard protocol for this procedure has ever
      been established formally. The specific aim of the present study was to select
      from four different measurement protocols the one which was most stable in terms
      of reproducibility and was appropriate for clinical and/or medicolegal
      applications. METHOD: A repeated measurement, test-retest of cervical motion
      study design using an ultrasound-based system for three-dimensional (3D) motion
      analysis; cervical range of motion was measured along the six primary directions:
      flexion; extension; right and left rotation; and right and left lateral flexion,
      in 20 healthy subjects who were tested twice over a period of lasting from one to
      four weeks. 'Protocol A' (reciprocal--intermittent testing) consisted of moving
      the head along a given primary direction, return to the neutral position, a pause
      and then motion to the opposite primary direction and return to neutral position.
      These movements were repeated three times. 'Protocol B' (reciprocal--continuous
      testing) was identical to Protocol A, but without the pause between the primary
      directions. 'Protocol C' consisted of three repetitions of the same primary
      direction with a break between two consecutive primary directions. Three sets of
      six randomly ordered primary directions constituted 'Protocol D'. RESULTS:
      Protocol D was associated with a significantly smaller range of motion and with
      the least intra-test reproducibility, as indicated by the coefficient of
      variation. The differences between the other protocols were largely negligible.
      CONCLUSION: In routine clinical practice, either of protocols A, B or C may be
      applied.

PMID- 12426912
TI  - Reliability of detecting 'onset of pain' and 'submaximal pain' during neural
      provocation testing of the upper quadrant.
AB  - BACKGROUND AND PURPOSE: Conflicting results have been reported with regard to the
      reliability of neural tissue provocation tests and it is unclear whether repeated
      testing affects the test results. In the present study, the stability and
      reliability of the occurrence of 'onset of pain' and 'submaximal pain' throughout
      the range of motion during neurodynamic testing was analysed, in both a
      laboratory and a clinical setting. METHOD: A repeated-measures study design
      within and between sessions was used. In the laboratory and clinical settings,
      the base neurodynamic test for the median nerve was performed during a single
      session on a total of 27 patients with neurogenic cervico-brachial pain. In
      addition, the base test and three common variations were performed on two
      occasions by two examiners on 10 asymptomatic subjects in laboratory conditions
      only. Patients indicated the moment of 'submaximal pain' occurrence, whereas
      asymptomatic subjects indicated 'onset of pain' and 'submaximal pain'.
      Corresponding angles at the elbow were recorded by use of an electrogoniometer.
      RESULTS: In the asymptomatic group, the intra- and inter-tester reliability
      within the same session was excellent (intraclass correlation coefficient (ICC2.1
      > or = 0.95; standard error of measurement (SEM) < or = 4.9 degrees). Reliability
      after a 48-hour interval was moderate (ICC2.1 > or = 0.69; SEM < or = 9.9
      degrees). The reliability coefficients for the symptomatic group within the same
      session were comparable with the excellent results of the asymptomatic group, for
      both the laboratory (ICC2.1 = 0.98; SEM = 2.8 degrees) and clinical settings
      (ICC2.1 > or = 0.98; SEM < or = 3.4 degrees). Consequently, from a statistical
      perspective, improvements in range of motion as small as approximately 7.5
      degrees may be interpreted meaningfully. No significant trend due to repeated
      testing could be observed when three consecutive repetitions were analysed.
      CONCLUSIONS: Pain provocation during neurodynamic testing is a stable phenomenon
      and the range of elbow extension corresponding with the moment of 'pain onset'
      and 'submaximal pain' may be measured reliably, both in laboratory and clinical
      conditions.

PMID- 12426913
TI  - An evaluation of a single chest physiotherapy treatment on mechanically
      ventilated patients with acute lung injury.
AB  - BACKGROUND AND PURPOSE: Acute lung injury is a lung pathology that presents
      frequently on the intensive care unit. Chest physiotherapy, in the form of
      endotracheal suction, alternate side-lying and manual hyperinflation, is usually
      given to patients with this condition with the intention of removing retained
      pulmonary secretions and recruiting collapsed distal lung units. Despite this
      common practice there is insufficient research on the effects of chest
      physiotherapy in patients with acute lung injury being ventilated mechanically.
      The aim of the present study was to further understanding of the effects of three
      modes of treatment in chest physiotherapy in an acute lung injury patient group.
      METHOD: This randomized, controlled trial investigated all mechanically
      ventilated patients with acute lung injury admitted to the adult intensive care
      unit at Guy's and St Thomas' NHS Trust between August 1996 and July 1997, who
      matched the inclusion criteria. Patients were randomized into one of three
      treatment groups: Group 1 (suctioned only); Group 2 (positioned and suctioned);
      and Group 3 (positioned, manually hyperinflated and suctioned). Baseline and 10,
      30 and 60 minutes' post-treatment data were recorded for dynamic pulmonary
      compliance, arterial blood gases and haemodynamic variables. Results were
      analysed by use of an SPSS software package with a repeated-measures analysis of
      variance (ANOVA). RESULTS: Eighteen patients fitted the inclusion criteria.
      Significant changes were observed in both PaCO2 (p = 0.026) and dynamic
      compliance (p = 0.019) over time for all three groups. The arterial oxygen to
      fraction of inspired oxygen ratio (PaO2:FiO2) did not alter significantly in any
      of the groups. With respect to other oxygenation parameters, mixed venous oxygen
      saturation (SvO2) showed a significant difference between the groups. Heart rate
      (HR) and systemic blood pressure (BP) showed statistically significant, but not
      clinically significant differences over time. CONCLUSIONS: Patients with acute
      lung injury are notably complex to nurse and may require protracted physiotherapy
      intervention, which may take many forms. As de-recruitment was the single most
      important event that occurred in the present study population, a prescriptive
      chest physiotherapy approach to treating mechanically ventilated patients with
      acute lung should be questioned and adapted accordingly.

PMID- 12426914
TI  - Physiotherapists' use of touch in inpatient settings.
AB  - BACKGROUND AND PURPOSE: Although touch is a basic element in the practice of
      physiotherapy, no research has been done to establish the type and purpose of
      practitioner touch in clinical settings. The purpose of the present study was to
      determine how physiotherapists use touch in inpatient acute and rehabilitation
      settings. METHOD: Fifteen physiotherapists with three or more years' experience
      were videotaped treating two to three patients. The participant physiotherapists
      reviewed a videotape of themselves and described the types of touch used and
      their intent behind each touch. Cross-case analysis was used to determine common
      themes in the descriptions. Mutually exclusive categories of touch were then
      refined, based on the cases. RESULTS: The most common types of touch used by
      physiotherapists included assistive touch, touch used to prepare the patient,
      touch to provide information, caring touch, touch to provide a therapeutic
      intervention, and touch used to perceive information. The physiotherapists also
      used 33 different combinations of touch, that is, a single touch used for more
      than one purpose. CONCLUSIONS: Inpatient physiotherapists clearly perform in a
      'high touch' arena. Clinical experience was reported as the strongest factor in
      developing the physiotherapists' sensitivity to patient needs and their skill in
      using specific types of touch. Further research is needed concerning the way
      patients perceive and respond to the presence or absence of these various forms
      of practitioner touch.

PMID- 12426915
TI  - Stoking the fire.

PMID- 12426916
TI  - Heart failure: new data and guidelines.
AB  - Heart failure is a common clinical problem, affecting at least 5 million
      Americans. There have been substantial advances in the understanding and
      treatment of heart failure in the last several years. We review current concepts
      for the evaluation and treatment of the various manifestations of patients with
      heart failure.

PMID- 12426917
TI  - An update on the epidemiology, pathogenesis and management of infective
      endocarditis with emphasis on Staphylococcus aureus.
AB  - The incidence of infective endocarditis (IE) is thought to be around 4/100,000
      person years in the general population, and 15/100,000 over the age of 50 years.
      The risk of acquiring IE is higher among patients with valvular heart disease
      (e.g., rheumatic valves, bicuspid aortic valves, myxomatous degeneration, etc.),
      congenital heart disease (e.g., coarctation, patent ductus arteriosus,
      ventricular septal defect, etc.), prosthetic cardiac valves, and among
      intravenous drug abusers. Staphylococcus aureus is one of the most common
      infective agents of IE, and most commonly originates from nosocomial sources,
      e.g., intravenous and arterial catheters, pacemaker leads, and prosthetic valves.
      Endocarditis caused by S aureus has a mortality rate of approximately 20% to 40%.
      In up to 40% of patients, IE caused by S aureus is associated with embolic
      complications. The risk of death increases with the development of complications.
      The epidemiology and microbiology of S aureus are changing rapidly, and
      resistance to antibiotics, especially methicillin, is becoming more widespread.
      In this review we will focus on the epidemiology, microbiology, and pathogenesis
      of S aureus IE, and also summarize the current guidelines for diagnosis,
      treatment, and prophylaxis of this clinical condition.

PMID- 12426918
TI  - A comparison of cardiovascular disease risk factors in farm and non-farm
      residents: the Wisconsin Rural Women's Health Study.
AB  - OBJECTIVES: The purpose of this paper is to describe the baseline difference in
      cardiovascular disease risk factors between farm and non-farm women in the Rural
      Women's Health Study. METHODS: Women aged 25 to 75 years were recruited from the
      Central Marshfield Epidemiologic Study Area, a geographically defined area
      surrounding Marshfield, Wis. (population 19,000), where more than 95% of
      residents seek their health care from the Marshfield Clinic. The baseline
      examination included measurements of blood pressure, skin folds, height, weight,
      fasting blood lipids, and blood glucose. Health behavior information collected
      included smoking, dietary intake, reproductive health, physical activity, medical
      history, social support, occupational strain and symptoms of anxiety and
      depression. RESULTS: Between 1995 and 2001, 825 non-farm residents and 675 farm
      residents were examined (58% of eligible women). The farm residents were similar
      in age to the non-farm residents (mean 47.6 years and 47.0 years, t-test = -0.91,
      P value = 0.36). The total number of modifiable risk factors for atherosclerosis
      ranged theoretically from 0 to 6, and actually from 0 to 5, with a small
      percentage of women having either none or 5 risk factors. The percentage of women
      with 3 or more modifiable risk factors was 26.1% (95% CL = 23.9, 28.4). The
      median number of total risk factors was 2 and the frequency distribution was not
      significantly different between farm and non-farm residents (chi 2 5 df = 4.6, P
      = 0.47). The prevalence of current cigarette smoking was significantly higher in
      the non-farm residents, while the prevalence of hypertension and obesity was
      significantly higher in the farm residents. Overall, obesity prevalence is
      significantly higher in the study cohort than US women in general (35% versus
      23%). Only 5 (0.7%) of the farm residents and 10 (1.2%) of the non-farm residents
      reported a previous myocardial infarction. CONCLUSIONS: These data suggest that
      the prevalence of risk factors for atherosclerosis, and hence future coronary
      heart disease, is very high in rural women. Obesity prevention through increased
      physical activity would be appropriate for both farm and non-farm residents,
      while quit smoking campaigns should be specifically targeted towards non-farm
      resident women.

PMID- 12426919
TI  - Clinical cardiac manifestations of HIV infection: a review of current literature.
AB  - New cases of Human Immunodeficiency Virus (HIV) infection are becoming more
      prevalent in Wisconsin. As advances in HIV treatment have improved patient
      survival, more individuals are living with this disease. Consequently, previously
      uncommon manifestations, such as cardiac complications, are likely to be
      encountered in clinical practice more often. In general, cardiac manifestations
      in patients with HIV infection are clinically subtle in their initial stages.
      Symptoms are usually nonspecific; however, dyspnea is very common and may be
      overlooked or attributed to pulmonary diseases and opportunistic infections.
      Cardiac abnormalities in HIV infection may involve any of the structures of the
      heart including pericardium, myocardium, and endocardium. Furthermore, HIV
      infection is associated with pulmonary hypertension, cardiac neoplasms, and use
      of potentially cardiotoxic medications. This article reviews the clinical cardiac
      manifestations currently seen in patients with HIV infection. Most of the cardiac
      complications were identified in the era before highly-active antiretroviral
      therapy, however, new complications have also been observed. To further reduce
      morbidity and mortality caused by HIV, early recognition and prompt intervention
      of cardiac diseases is extremely important. Further delineation of the natural
      history and clinical trials of the treatment of cardiac complications in patients
      with HIV infection are need given recent advances in antiretroviral therapy.

PMID- 12426920
TI  - Incidence of myocardial infarction in a general population: the Marshfield
      Epidemiologic Study Area.
AB  - BACKGROUND: Much of what is known about the occurrence of myocardial infarction
      (MI) in populations is derived from mortality data. International heart disease
      registries and recent population-based studies provide only limited incidence
      data from selected areas of the United States. METHODS: The Marshfield
      Epidemiologic Study Area (MESA), a defined geographic region where nearly all
      residents receive their health care from the Marshfield Clinic and affiliated
      hospitals, is a resource for estimating disease incidence in a general
      population. MI incidence rates and time trends from 1992 to 1998 were evaluated
      in MESA. RESULTS: A total of 1691 MESA residents had their first MI during the
      study period (age-adjusted rate, 292.4 per 100,000 per year). Rates in MESA were
      similar to some, and higher than other, incidence rates reported from US
      populations. About 20% of first MIs were detected only on death certificates.
      Overall incidence did not change much over time (-0.4% per year, P = 0.68),
      although rates declined 2.3% per year among women (P = 0.07). CONCLUSIONS: This
      is the first report of MI incidence in a general population from Wisconsin. The
      fairly steady incidence trend and the large number of incident events detected
      through death certificates demonstrate the continued need for primary prevention.

PMID- 12426921
TI  - Rhabdomyolysis from the combination of a statin and gemfibrozil: an uncommon but
      serious adverse reaction.
AB  - We report a patient with renal insufficiency who developed rhabdomyolysis 1 month
      after initiating cerivastatin and gemfibrozil for hyperlipidemia. Myopathy caused
      by HMG-CoA reductase inhibitors (statins) alone is rare, but occurs more
      frequently when a statin is used with gemfibrozil, a medication that likely has a
      direct toxic effect on muscles. Predisposing factors to the development of
      myopathy from the combination include use of medications affecting statin
      metabolism, higher doses of statins, renal insufficiency, diuretics, and
      hypothyroidism. It has been proposed that alternate-day therapy with a statin and
      fibrate, spacing of doses in a single day, or use of lower doses of statins may
      prevent the development of myopathy. Currently, no predictable method to
      determine who is at risk for myopathy exists, nor is there a reliable screening
      test. Therefore, patients should be advised to watch for generalized muscle pain
      or weakness, and if it occurs, stop medications and report symptoms immediately.

PMID- 12426922
TI  - Endoleak: the achilles heel of endovascular abdominal aortic aneurysm exclusion-
      a case report.
AB  - Endovascular exclusion of abdominal aortic aneurysms (EAAA) is an alternative
      treatment to open surgical repair in patients with suitable anatomy. The
      development of endoluminal vascular procedures has allowed aneurysm exclusion via
      remote arterial access techniques. Aneurysm exclusion by these methods revealed
      the phenomenon of endoleak, a unique complication characterized by an
      extravasation of blood into the aneurysm sac after stent-graft deployment. We
      present a patient treated for an endoleak following EAAA repair and review the
      endoleak classification system and management.

PMID- 12426923
TI  - Workplace AED resuscitation of a patient with a rare congenital anomalous
      coronary circulation.
AB  - We describe the case of a 44-year-old male with anomalous pulmonary artery origin
      of the left main coronary artery who was successfully resuscitated after sudden
      cardiac death with use of an automated external defibrillator (AED) in the
      workplace. The diagnosis was made on emergency cardiac catheterization and
      treated with surgical intervention. This case illustrates: 1) that congenital
      anomalies, although rare, must continue to be considered in the differential
      diagnosis of sudden cardiac death, and 2) that AEDs in the workplace can be a
      crucial, lifesaving intervention in the time-dependent condition of sudden
      cardiac death.

PMID- 12426924
TI  - Myocardial infarction temporally related to ephedra--a possible role for the
      coronary microcirculation.
AB  - Myocardial infarction has been reported with ephedrine and pseudoephedrine use.
      It has been suggested that these agents may induce coronary artery spasm,
      hypercoagulable states, or oxygen demand imbalance. We report a 25-year-old male
      with myocardial infarction after receiving a diet pill containing ephedra.
      Coronary angiography revealed normal coronary arteries with very slow flow,
      suggestive of microcirculation abnormalities. The flow responded promptly to
      intracoronary verapamil.

PMID- 12426925
TI  - Prosthetic heart valve thrombosis: an overview.
AB  - BACKGROUND: Valvular heart disease represents a significant burden to patients
      with cardiovascular diseases. Surgical treatment of diseased heart valves
      represents a significant advancement for these patients. However, there are
      specific complications related to prosthetic valves, including valve thrombosis.
      METHODS: Review article. RESULTS: Thrombosis of a prosthetic heart valve can
      present with gradual cardiac decline, embolic phenomena, or frank cardiogenic
      shock. The diagnosis of prosthetic valve thrombosis is by history, physical
      examination, and by an imaging modality. Treatment of the thrombosed valve is
      either surgical or with thrombolysis. Both modalities have significant morbidity
      and mortality. CONCLUSION: Treatment of valvular heart disease does not remove
      the patient from significant risks. Inherent to a prosthetic heart valve is the
      risk for valvular thrombosis. Prompt recognition and treatment of prosthetic
      valve thrombosis is important.

PMID- 12426926
TI  - A drug is not a drug is not a drug: a commentary.

PMID- 12426927
TI  - Postmarketing drug dosage changes of 499 FDA-approved new molecular entities,
      1980-1999.
AB  - PURPOSE: Risks and benefits of marketed drugs can be improved by changing their
      labels to optimize dosage regimens for indicated populations. Such postmarketing
      label changes may reflect the quality of pre-marketing development, regulatory
      review, and postmarketing surveillance. We documented dosage changes of FDA
      approved new molecular entities (NMEs), and investigated trends over time and
      across therapeutic groups, on the premise that improved drug development methods
      have yielded fewer postmarketing label changes over time. METHODS: We compiled a
      list of NMEs approved by FDA from 1 January 1980 to 31 December 1999 using FDA's
      website, Freedom of Information Act request, and PhRMA (Pharmaceutical Research
      and Manufacturers of America) database. Original labeled dosages and indicated
      patient populations were tracked in labels in the Physician's Desk Reference.
      Time and covariate-adjusted risks for dosage changes by 5-year epoch and
      therapeutic groups were estimated by survival analysis. RESULTS: Of 499 NMEs, 354
      (71%) were evaluable. Dosage changes in indicated populations occurred in 73 NMEs
      (21%). A total of 58 (79%) were safety-motivated, net dosage decreases.
      Percentage of NMEs with changes by therapeutic group ranged from 27.3% for
      neuropharmacologic drugs to 13.6% for miscellaneous drugs. Median time to change
      following approval fell from 6.5 years (1980-1984) to 2.0 years (1995-1999).
      Contrary to our premise, 1995-1999 NMEs were 3.15 times more likely to change in
      comparison to 1980-1984 NMEs (p = 0.008, Cox analysis). CONCLUSIONS: Dosages of
      one in five NMEs changed, four in five changes were safety reductions. Increasing
      frequency of changes, independent of therapeutic group, may reflect intensified
      postmarketing surveillance and underscores the need to improve pre-marketing
      optimization of dosage and indicated population.

PMID- 12426928
TI  - Changes in prescribed drug doses after market introduction.
AB  - PURPOSE: The establishment of recommended dosing regimens has always been a
      difficult aspect of drug development. This paper examines the extent to which
      postmarketing prescribing deviates from initially recommended dosing regimens. We
      used the World Health Organization's (WHO) periodically updated compilation of
      the 'Defined Daily Dose' (DDD) to reflect prevailing patterns of prescribing in
      national markets. The aim of this study was to evaluate DDD changes over time
      (1982-2000) and to identify possible determinants of these changes. METHODS: Data
      on DDD changes were obtained from the WHO's Oslo Collaborating Centre. We
      performed a case-control analysis in which we compared drugs with (cases) and
      without (controls) postmarketing changes in DDD on possible determinants
      associated with DDD change. RESULTS: We found 115 instances of a change of DDD in
      the period 1982-2000 (45 (39.1%) increases and 70 (60.9%) decreases). Antibiotics
      showed the greatest number of changes in DDD: predominantly increases in the
      1980s, while the 1990s were dominated by decreases in DDD of mostly
      cardiovascular drugs. CONCLUSION: Changes in DDD reflect the outcome of a melange
      of forces, including misconceptions of dose requirements during pre-market
      development of drug and postmarketing changes in pharmacotherapeutic knowledge,
      clinical concepts, economic forces, and, in the case of anti-infective agents,
      changing patterns of resistance/sensitivity of target microorganisms to the anti
      infective agent(s) in question.

PMID- 12426929
TI  - Ayurvedic medicines.

PMID- 12426930
TI  - Pattern of use of complementary/alternative medicine (CAM) in epileptic patients
      in a tertiary care hospital in India.
AB  - PURPOSE: Many patients use complementary/alternative medicine (CAM) for their
      health problems especially where long-term treatment is required. Epilepsy is the
      most prevalent neurological disorder requiring long-term treatment and
      compliance. The purpose of the study was to establish the pattern of use of CAM
      in epileptic patients. METHODS: 1000 patients with seizure disorder visiting the
      Neurology outpatient department were interviewed regarding use of
      complementary/alternative medicine (CAM) in the past. The pattern of use, persons
      who recommended CAM and the reasons for trying these therapies and sequence of
      seeking them was noted in these patients. RESULTS: Overall 32% of patients had
      used CAM. Ayurvedic medicine was used most frequently, either alone (43%) or in
      combination (38%) with other CAM therapies followed by homeopathy (12.5%). Use of
      CAM was seen among all age groups and at all levels of education and was most
      frequent in the rural population (67%). Influence of family and friends (50%) was
      the most common reason for trying these therapies. Most patients (57%) sought CAM
      providers first before seeking the services of a medical doctor in our study.
      CONCLUSION: As more and more patients use CAM, physicians should ask their
      patients whether they use these therapies and should discuss these practices with
      their patients in order to safeguard their health.

PMID- 12426931
TI  - Birth defect classification by organ system: a novel approach to heighten
      teratogenic signalling in a pregnancy registry.
AB  - The Antiretroviral Pregnancy Registry (APR) is an ongoing international
      prospective exposure-registration cohort study that monitors outcomes of
      pregnancies exposed to marketed antiretroviral medications. The population of
      women exposed to antiretrovirals remains relatively small, which limits the power
      of the registry. In order to maximize identification of a teratogenic signal, a
      special birth defect classification system was devised. Birth defects were
      organized based upon organ system and embryology, using the Metropolitan Atlanta
      Congenital Defects Program as a model. Grouping defects that share embryology and
      pathogenesis increases the likelihood that a teratogenic effect will be apparent.
      The result is a three-tiered system: organ system, preferred defect term, and
      reported defect term. This system is text based, which eliminates the need to
      memorize codes and allows use by anyone familiar with medical terminology. Once
      established, the new APR Organ System Classification retains enough flexibility
      that categories may be collapsed or expanded as experience grows. Standardized
      nomenclature also minimizes variation introduced by collecting defect reports
      from many different sources.

PMID- 12426932
TI  - Serious ventricular arrhythmias among users of cisapride and other QT-prolonging
      agents in the United States.
AB  - PURPOSE: To evaluate the risk of serious ventricular arrhythmia (SVA) with
      cisapride use in the United States. METHODS: The study population included 28,078
      patients under the age of 65 years who received cisapride between 1993 and 1998
      with no history of antiarrhythmia treatment. Each follow-up day was classified
      according to use of cisapride and other factors. Outcomes of SVAs were identified
      using medical claims records and National Death Index search, and confirmed by
      medical record review. Rates of events were calculated for time on and off
      cisapride. Poisson regression analysis was used to calculate adjusted rate
      ratios. RESULTS: There were 23 cases of SVAs; 10 during periods of cisapride use
      and 13 during periods of non-use. The adjusted rate ratio comparing SVA events in
      cisapride use time to non-use time was 1.60 (95% CI: 0.67-3.82), and that
      identified for the other QT-prolonging drugs was 1.60 (95% CI: 0.65-3.98).
      CONCLUSIONS: The evidence for an increased risk of SVAs associated with cisapride
      was equivocal after taking observation time on and off cisapride into account,
      and adjusting for risk factors, though we cannot exclude the possibility of a 3.8
      fold increased risk. Overall, the plausible risks of cisapride were similar to
      those of other QT-prolonging drugs.

PMID- 12426933
TI  - Calcium channel blockers and myocardial infarction: a case--control study in a
      Japanese hospital.
AB  - PURPOSE: To examine the relationship of the use of calcium channel blockers
      (CCBs) in hypertensive patients to myocardial infarction in Japan, where CCBs are
      prescribed much more frequently than in Europe and America. DESIGN: We conducted
      a nested case-control study using a hospital information system in Japan.
      SUBJECTS: Cases were hypertensive patients who were repeat visitors to Tokyo
      University Hospital as of April 1996 and had an incidence of fatal or non-fatal
      myocardial infarction between 1996 and 1999. Controls were hypertensive patients
      individually matched to cases by sex, age and history of angina pectoris.
      RESULTS: The study consisted of 16 cases, who were matched to 80 controls. Of the
      80 control patients, 54 (68%) received CCBs. On the other hand, all but one of 16
      cases received CCBs and the crude odds ratio of myocardial infarction associated
      with the use of calcium channel blockers was as high as 7.0 (0.9-55.3). The odds
      ratio was reduced to 4.9 (0.6-42.4) when adjusted by diabetes and diastolic blood
      pressure. CONCLUSIONS: Although the crude odds ratio of myocardial infarction
      associated with CCBs was high, the ratio was reduced when adjusted by known
      confounding factors, suggesting a mechanism of confounding by indication. In
      addition, the results obtained in this study using records from a single hospital
      should not be generalized.

PMID- 12426934
TI  - Use of calcium channel blockers as antihypertensives in relation to mortality and
      cancer incidence: a population-based observational study.
AB  - PURPOSE: Treatment with blood pressure lowering drugs may reduce morbidity and
      mortality. However, the efficacy and effectiveness may differ between
      antihypertensive agents. The current investigation aimed to compare mortality and
      cancer incidence in hypertensive patients treated with calcium channel blockers
      (CCB) or with other antihypertensive drugs (AHD). METHODS: All patients in two
      outpatient clinics treated with AHD who underwent an annual check-up during 1989
      or 1990 were selected. Fatal events were identified through 1997 and incident
      cancers through 1998. RESULTS: Two hundred and fourteen patients on CCB and 1029
      on other AHD were identified. Overall mortality and the combined mortality from
      myocardial infarction and stroke were higher in CCB users; hazard ratios adjusted
      for sex, age, comorbidity and other and risk factors were 1.84 (95% CI 1.25-2.72)
      and 2.37 (95% CI 1.27-4.44), respectively. The risk estimates for cancer
      mortality and for cancer incidence did not differ significantly. CONCLUSIONS:
      Results from clinical trials as well as observational studies, including the
      present one, indicate a higher mortality risk and a higher cardiovascular
      morbidity risk associated with use of CCB. Accordingly, CCB should not be
      regarded as first line drugs in hypertension.

PMID- 12426935
TI  - Presence of pharmacoepidemiology in three bibliographic databases: Medline, IPA
      and SCI.
AB  - OBJECTIVE: The objective of this study is to make a comparative description of
      the evolution and distribution of international research into
      pharmacoepidemiology, using three bibliographic databases, in order to select the
      most appropriate for future bibliometric studies. METHODS: Bibliographic searches
      were performed using the following databases: Medline (1966-99), IPA (1970-99)
      and SCI (1990-99), using the term 'pharmacoepidemiology'. On the basis of these
      searches, the number of original articles per year and per journal title were
      noted. The growth of the output of scientific writing was found to fit Price's
      law. RESULTS: A total of 845 original articles were recovered: 467 from IPA, 219
      from Medline and 159 from SCI. The highest mean number of original articles per
      year (33.4) was obtained with the IPA database. Price's exponential growth
      pattern was observed among all three databases. The total numbers of journals in
      which the original articles were published were 102 in Medline, 65 in IPA and 60
      in SCI. The journals providing a single original article comprised 65% of the
      Medline titles and 61% of those in IPA and SCI. CONCLUSIONS: International
      research into pharmacoepidemiology presents an exponential growth pattern, in
      accordance with Price's law. There is a large degree of publishing dispersion.
      IPA was found to be the bibliographic database that recovered the greatest number
      of original articles, nearly half of which were published in Pharmacoepidemiology
      and Drug Safety. We therefore consider the latter database appropriate for
      bibliometric studies in the field of pharmacoepidemiology.

PMID- 12426936
TI  - Pharmacovigilance of over-the-counter products based in community pharmacy:
      methodological issues from pilot work conducted in Hampshire and Grampian, UK.
AB  - PURPOSE: The incidence of serious adverse events from non-prescription medicines
      remains to be established. The aim of this initial pilot work, using an
      observational cohort design, was to determine the feasibility of conducting a
      pharmacovigilance study of a non-prescription medicine, based in community
      pharmacies. METHOD: Community pharmacists from Grampian, Scotland, and Hampshire,
      England, recruited user-purchasers of ibuprofen. Exposure data were collected
      from a series of self-completed questionnaires. Outcome data were any new
      symptoms, use of concomitant medication and subsequent health-care utilization.
      RESULTS: A total of 1021 eligible customers were recruited, 6.4% (466/7320) and
      48.2% (555/1152) by the Hampshire and Grampian networks respectively. The cohorts
      differed with regard to age, smoking and socio-economic status, reason for
      purchase and recommendation, and duration of use. The two cohorts reported
      different use of concomitant medication (46.0 and 65.5%), asthma (7.2 and 10.5%),
      stomach/peptic ulcer (3.5 and 2.1%), a higher prevalence of gastrointestinal
      symptoms post-compared to pre-purchase (12.9 vs. 7.2%, p = 0.0006 and 8.8 vs.
      5.8%, p = 0.034), ingestion of doses in excess of the licensed non-prescription
      dose by 5.1 and 3.9%, and discontinuation of treatment because the medicine upset
      them by 4.5 and 3.1%, respectively. Most participants did not seek medical advice
      for their symptoms. CONCLUSION: Greater vigilance is required for adverse events
      that may be attributable to non-prescription product use. Development of
      pharmacovigilance models using community pharmacies is one means of
      systematically collecting information regarding drug safety. Further work is
      needed to identify a method which maximizes patient recruitment whilst
      maintaining acceptable follow-up rates.

PMID- 12426937
TI  - Variations in antidepressant prescribing practice: clinical need or market
      influences?
AB  - OBJECTIVE: To assess the antidepressant prescribing patterns of community
      psychiatrists, and the prescriptions issued by general practitioners and private
      physicians during 1999 in order to analyse and discuss the intensity and sources
      of variations between doctors. METHODS: All reimbursed prescriptions for
      antidepressants written in 1999 by community psychiatrists and general
      practitioners working for the Canary Islands Health Service at Santa Cruz de
      Tenerife were collected from official sources. Prescriptions were available
      individualized for each psychiatrist but were collected globally for the others.
      Drugs were classified according to the Anatomic Therapeutic Chemical (ATC-1999
      edition) System and use was quantified in terms of defined daily doses (DDDs). As
      an indicator of the quality of drug prescribing, the DU90% was used. RESULTS: The
      total use of antidepressant in Tenerife was 21.4 DDD/1000 inhabitants/day. The
      most frequently prescribed substances were fluoxetine, paroxetine and sertraline,
      which accounted for 58% of all prescriptions. Each psychiatrist used between 10
      and 20 different substances and between 15 and 26 different trade names.
      Prescribing by general practitioners mirrored that of psychiatrist, and private
      doctors (mainly psychiatrist) were found to have a different pattern of
      prescribing with higher use of new and uncommon antidepressants. Psychiatrists
      acknowledge the pressures of promotion by the pharmaceutical industry and half of
      them recognize a personal relationship with some 'company representatives'.
      CONCLUSION: There is a remarkable degree of variation in antidepressant
      prescribing by psychiatrists and general practitioners, this is due to economic
      and social factors as much as to morbidity differences.

PMID- 12426938
TI  - Introducing ethics in hospital drug resource allocation decisions: keep
      expectations modest and beware of unintended effects. Part I: An explorative
      overview.

PMID- 12426939
TI  - Pharmacoepidemiology and drug safety.

PMID- 12426940
TI  - [ECG-diagnosis 2, What is your diagnosis? Infero-posterior myocardial infarct
      with inferior aneurysm in occlusion of a dominant right coronary artery].

PMID- 12426941
TI  - [Fecal incontinence: evaluation, treatment concept and new therapeutic
      approaches].
AB  - Faecal incontinence is more frequent than generally assumed. The
      pathophysiological ground for faecal incontinence are injuries as well as
      infraclinic post childbirth injuries. However, faecal incontinence is frequently
      ideopathic by women probably due to weakness of the pelvic floor muscles.
      Interdisciplinary diagnosis include endoluminal-sonography, sphincter-manometry
      and in selected cases MR video-defaecography. Results of surgical sphincter
      repair combined with anterior anal repair may be excellent in up to 70% of the
      cases, however long-term results may become disappointing. Dynamic gracilis
      plastic is today a recognized therapy as sphincter replacement. However, provided
      that the sphincter-muscles remain intact, permanent sacral nerve-stimulation is a
      very promising emerging therapy. The initial results are very encouraging with
      recovery from faecal incontinence in up to 70-80% of the treated cases.

PMID- 12426942
TI  - [Gastrointestinal motility disorders relevant to general practice].
AB  - Gastroesophageal reflux disease, achalasia and esophageal spasms are the most
      frequent esophageal motility disorders and are associated with dysphagia and non
      cardiac chest pain. The diagnosis of achalasia is based on manometric criteria.
      Pneumatic dilatation, laparoscopic myotomy, and the minimal invasive injection of
      botulinum toxin are therapeutic options. Long-term-pH-metry is the gold standard
      to diagnose gastroesophageal reflux disease. Proton pump inhibitors (PPI) are the
      first-line therapy in reflux disease. Esophageal manometry and pH-metry are
      essential investigations prior to an antireflux operation. The evaluation of
      chronic constipation refractory to medical treatment should include anal
      manometry, and MR-defecography for the diagnosis of anorectal outlet obstruction
      such as anismus which could be treated successfully by biofeedback therapy.

PMID- 12426943
TI  - [Diarrhea].
AB  - Diarrhea is not a single disease, but only a symptom of different diseases.
      Diarrhea is characterized by an increase in bowel movements (more than three per
      day) and an increased liquidity of stools. Acute diarrheas are defined as those
      that last less than four weeks, whereas chronic diarrheas persist for more than
      four weeks. The pathophysiological basis of diarrhea is a disturbed enteral water
      and electrolyte balance, which can be caused by an increased secretion of
      osmotically active electrolytes (secretory diarrhea) or the increased ingestion
      of osmotically active substances (osmotic diarrhea). The stool characteristics
      allows to distinguish watery, bloody and fatty diarrhea. Acute diarrheas are
      mostly caused by an infectious agent (viruses, bacteria and parasites), whereas
      the differential diagnosis of chronic diarrhea is considerably larger and
      therefore the diagnostic work-up is more complex.

PMID- 12426944
TI  - [Syncope].
AB  - Syncope may be due to cardiac, vascular or cerebral disease. The cause of syncope
      is not established in up to 50-60% of cases. Where a diagnosis is possible, the
      patient's history, physical examination, ECG and prolonged ECG monitoring serve
      to establish the underlying disease in most cases. Additional diagnostic tests
      should only be performed in patients with possible cardiac syncope, since these
      cases show a higher mortality rate during follow-up than patients with non
      cardiac syncope. Finally, newer therapeutical approaches, including permanent
      cardiac pacing in recurrent vasovagal syncope, are discussed.

PMID- 12426945
TI  - pH-sensitive liposomes: mechanism of triggered release to drug and gene delivery
      prospects.
AB  - A growing amount of literature describes the development and applications of
      novel targeting and/or release triggering schemes to improve the therapeutic
      index of drugs encapsulated within liposomes. The composition of liposomal
      systems can be modified to facilitate site specific release in response to
      environmental conditions, namely at the gross anatomical level, at the cellular
      or sub-cellular level. They are designed in order to release their contents in
      response to acidic pH within the endosomal system while remaining stable in
      plasma thus improving the cytoplasmic delivery of various polar materials and
      macromolecules such as anti-tumor drugs, toxins, proteins and DNA. This review
      covers various aspect of research on pH-sensitive liposomes.

PMID- 12426946
TI  - [3-nitrobenzylidene-2,3(3H,5H)-furandione in the Hantzsch pyridine synthesis. 1.
      A new approach to furo(3,4-b)pyridines].
AB  - The nitrobenzylidenefurandiones 7 react with acetoacetic ester (8) and ammonium
      acetate or 3-aminocrotonic esters (9a, b) and 2-amino-pent-2-en-4-on (9c),
      respectively heating in acetic acid to yield the tetrahydrofuro[3,4-b]pyridines
      10. The dehydrogenation of 10 using nitric acid or activated manganese dioxide
      leads to the dihydrofuro[3,4-b]pyridines 12. When the reaction is carried out
      with the tetronic acid derivatives 7 and the enaminocarbonyl compounds 9 at 30
      degrees C in tert-butanol the hexahydro-7a-hydroxyfuro[3,4-b]pyridines 11 are
      obtained. Treating the N,O-acetales 11 with acetic anhydride in pyridine affords
      the annulated lactones 10.

PMID- 12426947
TI  - [3-(Nitrobenzylidene)-2,4(3H,5H)-furandione in the Hantzsch-pyridine synthesis 2.
      6,7-Dihydrophthalide].
AB  - Melting the 3-(o- and p-nitrobenzylidene)tetronic acids 2a and 2c with the
      enaminocarbonyl compounds 1 at 70-90 degrees C yields the hexahydro-7a
      hydroxyfuro[3,4-b]-pyridines 3, while with the m-nitro compound 2b at 100 degrees
      C the 6,7-dihydrophthalides 4 are obtained. Dehydrogenation of the dihydro
      derivatives 4 with activated manganese dioxide affords the phthalides 5.

PMID- 12426948
TI  - Thermodynamic study of the enantiomeric resolution of flurbiprofen by HPLC using
      Chiralpak AD-RH column.
AB  - The chiral resolution of (+/-)-flurbiprofen was achieved using water-acetonitrile
      (60:40, v/v) containing 0.1% acetic acid on a Chiralpak AD-RH column at 20
      degrees C. The enantio-resolution was studied with different percentages of
      acetonitrile. Thermodynamic parameters (enthalpy, entropy and free energy) were
      calculated by carrying out the enantio-resolution experiments at 0 to 60 degrees
      C. The enantio-resolution was found to be exothermic in nature. Attempts have
      been made to explain the mechanism of chiral resolution of flurbiprofen on the
      Chiralpak AD-RH column.

PMID- 12426949
TI  - Determination of aristolochic acid I and II in North American species of Asarum
      and Aristolochia.
AB  - Wild ginger, Asarum canadense, which has folk uses as a medicinal and food plant,
      has been reported to contain aristolochic acid I. Rhizomes of North American
      species of Aristolochiaceae were surveyed for the presence of aristolochic acids
      by HPLC. Aristolochic acid I (1) and aristolochic acid II (2) were present in
      Aristolochia species and Hexastylis; 1 alone was detected in multiple accessions
      of A. canadense and Asarum caudatum, though not in Asarum wagneri. Concentrations
      in A. canadense were highly variable, reaching as much as 0.037 percent of dry
      weight.

PMID- 12426950
TI  - Influence of storage time and temperature on the stability of indomethacin
      Pluronic F-127 gels.
AB  - The stability of 20 topical gel formulations containing drug, 1% w/w indomethacin
      (IND), and 20% w/w Pluronic (PF-127) as a gel-forming agent, hexylene glycol (HG)
      and polyethylene glycol 300 (PEG) in different amounts (16, 20 and 24% w/w) as
      solvents and 1% w/w polyvinyl pyrrolidone (PVP, K-25) and Tween as excipients was
      determined by appearance and consistency of the gels, microscopy, pH and
      rheological measurements after 1 and 4 weeks storage, at 6 degrees C, 20 +/- 2
      degrees C and 45 degrees C. Viscosity values were determined from rheograms by a
      Haake Rotovisco sensor at shear rates of 1000 to 10,000 l/s. The relationship
      between effectors (temperature and storage time) and response (viscosity) was
      determined using multiple regression analysis. All formulations were stable at
      room temperature (20 +/- 2 degrees C). The consistency of the gels containing HG
      and PEG decreased during storage at 6 degrees C. Storing the gels at 6 degrees C
      resulted in the precipitation of IND, but when PVP was incorporated into the IND
      PF-127 gels, the stability of the gels was improved. All IND gels sustained their
      pseudoplastic flow behaviour. The viscosity decreased as storage time increased.
      A statistically significant model was obtained, showing that the effect of
      storage temperatures on the viscosity was much less than the effect of storage
      time.

PMID- 12426951
TI  - Preparation and evaluation of poly (D, L-lactic acid) (PLA) or D, L
      lactide/glycolide copolymer (PLGA) microspheres with estradiol.
AB  - PLA/PLGA was used for biodegradable and biocompatible carriers to achieve
      sustained release of estradiol. Microspheres were formed by an emulsification
      solvent evaporation method, and then their properties and in vitro drug release
      behavior were examined including amongst others the effects of the concentration
      of PVA in the aqueous phase, the concentration of PLA in the organic phase, the
      stirring speed, the volume ratio of O/W, the weight ratio of E2/PLA fed, and the
      type and molecular weight of the polymers.

PMID- 12426952
TI  - Analgesic principle from the bark of Careya arborea.
AB  - Bioactivity guided isolation of the bark of Careya arborea afforded piperine--an
      alkaloid chemically known as 1-[5-(1,3-benzodioxol-5-yl)-1-oxo-2,4
      pentadienyl]piperidine, which was found to possess significant central and
      peripheral analgesic activity. At oral doses of 10, 20 and 30 mg/kg body weight,
      piperine exhibited 41 (p < 0.01), 45 (p < 0.01) and 53% (p < 0.001) inhibition of
      acetic acid induced writhing in mice respectively. At doses of 20 and 30 mg/kg
      body weight, the compound also showed 31.8 (p < 0.05) and 52.4% (p < 0.01)
      prolongation of tail flicking time of mice 30 min after the treatments determined
      by the radiant heat method.

PMID- 12426953
TI  - Polyphenols of Egyptian Rosaceae plants--two new flavonoid glycosides from
      Sanguisorba minor Scop.
AB  - Two new flavonol glycosides, 8-methoxyquercetin-3-O-beta-glucosyl-(1'"-2")-O-beta
      glucoside and kaempferol-3-O-[2'"-galloyl-O-beta-glucosyl-(1'"-2")-O-beta
      glucoside)], together with five known quercetin and kaempferol 3-O-mono
      glycosides, were isolated and identified from the aerial parts of Sanguisorba
      minor Scop. (Rosaceae). All structures were determined by routine methods of
      analysis and confirmed mostly by negative ESI-MS, 1H- and 13C NMR.

PMID- 12426954
TI  - Two new prosapogenins from Albizia adianthifolia.
AB  - Two new triterpenoidal prosapogenins 1 and 2 were obtained from the mild alkaline
      hydrolysate of the crude saponin fraction of Albizia adianthifolia (Mimosaceae)
      roots. Their structures were mainly determined by spectral analyses as acacic
      acid 3-O-beta-D-xylopyranosyl-(1-->2)-beta-D-fucopyranosyl-(1-->6)- 2-acetylamino
      2-deoxy-beta-D-glucopyranoside (1) and acacic acid 3-O-(beta-D-xylopyranosyl-(1-
      >2)-beta-D-fucopyranosyl-(1-->6)- [beta-D-glucopyranosyl-(1-->2)]-beta-D
      glucopyranosyl)-21-O-(6(S)-2- hydroxymethyl-6-methyl-6-O-(beta-D
      quinovopyranosyl)-2,7-octadienoyl) ester (2). Furthermore, the known julibroside
      A3 was isolated from the crude saponin mixture. Compounds 1 and 2 did not show
      any ability to potentiate in vitro cisplatin cytotoxicity in a human colon cancer
      cell line.

PMID- 12426955
TI  - Triumfettoside, a new alkaloidal steroid glycoside and triumfettosterol, a new
      sterol from Triumfetta flavescens.
AB  - The aerial parts of Triumfetta flavescens H. (N. O. Tiliaceae) afforded a new
      alkaloidal steroid glycoside, characterized as stigma 5(6)-ene-7,22-dione-25
      methylamino-3 beta,23 beta-diol-3-O-beta-D- glucoside and designated as
      triumfettoside (1); and a new sterol identified as stigma 5(6)-ene-7,22-dione-3
      beta,23 beta-diol, designated as triumfettosterol (2). Their structures were
      elucidated on the basis of chemical and spectral analysis.

PMID- 12426956
TI  - Indigoferabietone, a novel abietane diterpenoid from Indigofera longeracemosa
      with potential antituberculous and antibacterial activity.
AB  - From the stems of Indigofera longeracemosa, a novel abietane diterpenoid,
      indigoferabietone was isolated. The structure was established by spectral
      techniques. The inhibitory activity of indigoferabietone (1) tested against
      Mycobacterium tuberculosis and Candida albicans, and the antibacterial activity
      tested against Staphylococcus aureus, Proteus vulgaris, and Escherichia coli were
      found to be significant.

PMID- 12426957
TI  - A new pregnane glycoside and a furostanol glycoside from Digitalis cariensis.
AB  - Chemical investigation of the aerial parts of Digitalis cariensis Boiss. ex Jaub.
      & Spach resulted in the isolation of a new pregnane glycoside, cariensisoside (1)
      and a furostanol glycoside, uttroside A (2), along with the two known
      phenylethanoid glycosides, lugrandoside (3) and maxoside (4). On the basis of
      spectral (UV, IR, NMR, MS) and chemical methods, compounds 1 and 2 were
      identified as digifologenin-3-O-beta-glucopyranosyl-(1-->4)-beta
      oleandropyranoside and 3-O-(beta-lycotetraosyl)-26-O-(beta-glucopyranosyl)-(25R)
      22 alpha-methoxy-5-furostane-3 beta,26-diol, respectively.

PMID- 12426958
TI  - Impact of drug policy on the use of parenteral cephalosporins in Italy.
AB  - OBJECTIVE: To evaluate the effects of the 1998 revision of CUF Note 55 on
      doctors' prescribing behaviour and drug costs with regard to intramuscularly
      administered cephalosporins. METHOD: National data on drug use between January
      1998 and June 2000 were provided by the Drug Utilisation Monitoring Centre of the
      Ministry of Health. The Anatomic Therapeutic Chemical classification and the
      Defined Daily Dose methodology, as well as population estimates obtained from the
      Italian National Statistics Institute were used to define consumption as the
      number of defined daily doses per 1000 inhabitants per day. The cost of these
      antibiotic medications was determined using the wholesale price reported in
      Informatore Farmaceutico. Italian inflation rates were used to annuitize the
      expenditure. "STATA 6.0" software was used for all statistical analyses. RESULTS:
      The use of cefonicid rose dramatically after the revision (+ 136.3%), whereas the
      utilisation of the other active ingredients decreased. A decrease of 5.6% in the
      expenditure for all parenteral cephalosporins was observed in this period while
      the same figure increased by 2.3% after one year. CONCLUSION: The exclusion of
      cefonicid from a restricted list appears to have significantly affected doctors'
      prescribing practices, while the effect on drug expenditure was contradictory.

PMID- 12426959
TI  - Using the Internet to develop an international learning community of pharmacists.
AB  - Until recent years, the level of interaction across a profession, necessary to
      provide for an optimum learning environment which supports professional
      development, has only been significantly possible in face-to-face interaction and
      has therefore been place and time dependent. With the explosive development of
      the internet, communication barriers are breaking down and international
      interaction, networking and collaboration is becoming increasingly possible. This
      short report describes the manner in which an Internet-based postgraduate study
      programme, entitled "Enhancing Pharmacy Practice" has made use of these
      communication opportunities to develop an international learning community of
      pharmacists. Programme evaluation data collected from surveys completed online by
      participants and content analysis of online discussion groups during the first
      four modules of the programme, demonstrates that there is a high level of
      interaction amongst participants. It also suggests that this interaction has
      contributed to the learning experience and professional growth of the
      participants and impacted positively upon their practice.

PMID- 12426960
TI  - Toxicity to topical dimethyl sulfoxide (DMSO) when used as an extravasation
      antidote.
AB  - DMSO is a dipolar, aprotic, hygroscopic solvent for which a large number of
      pharmacologic properties have been claimed. Topical DMSO is considered an
      effective and safe antidote to be used with topical cooling after extravasations
      of vesicant drugs. A case of toxicity after its use as an antidote is described.
      Furthermore, the increasing importance of DMSO pharmacology, as its use in
      haematologic patients is spreading, is reviewed.

PMID- 12426961
TI  - Measuring the impact of medicines information services on patient care:
      methodological considerations.
AB  - INTRODUCTION: Medicines information services (MISs) aim to promote the safe,
      effective and economic use of medicines. Results from published studies suggest
      that they provide effective information, which in many cases results in improved
      patient outcome. However, there are several methodological issues that are
      important in the interpretation of such studies. AIM: To address methodological
      issues in the evaluation of MISs. OBJECTIVES: To carry out a critical appraisal
      of papers assessing the impact on patient outcome of passive information given to
      health care professionals, to identify the key methodological issues and to make
      recommendations for future research in Europe. METHODS: Literature search to
      identify relevant papers meeting the inclusion criteria, critical evaluation of
      the methods used. RESULTS: Most studies have been conducted in the United States.
      Various methodological considerations were identified: study design, sampling,
      data collection, choice of outcome measures, and validity. The results of each
      study are interpreted in view of the methods used. In addition, the implications
      of the methods selected on the validity, reliability and generalisability of the
      results are discussed. Finally, suggestions for future studies are provided, in
      order to maximise validity and reliability.

PMID- 12426962
TI  - The identification of barriers preventing the successful implementation of a
      surgical prophylaxis protocol.
AB  - AIM: The aim of this study was to introduce a protocol for the use of
      antimicrobials in surgical prophylaxis for the described procedures in Antrim
      Area Hospital. METHOD: Historical data of antimicrobial use were obtained from
      retrospective analysis of patients' charts, for those patients identified as
      having one of the following 'clean/contaminated' surgical procedures over the
      previous six months; cholecystectomy or abdominal hysterectomy. These data were
      analysed, and a protocol was introduced providing guidelines for the choice of
      antimicrobial agent, its administration time, route, dose, duration and frequency
      of treatment. MAIN OUTCOME MEASURE: The main outcome measure was the success of
      the uptake of the protocol following its implementation. RESULTS: There was a
      total of 285 patients identified, 105 prior to and 180 post implementation.
      Overall, 68% of patients received some form of prophylaxis in the first cycle,
      and 72% in the second. CONCLUSION: Although the introduction of the protocol led
      to slight improvements in compliance with standard prescribing procedures, with
      an increase in single-dose prophylaxis, and a reduction in prolonged prophylactic
      treatment, the improvements did not reach expectations. This paper attempts to
      identify the possible barriers to protocol implementation.

PMID- 12426963
TI  - Survey of drug use practices and antibiotic prescribing pattern at a general
      hospital in Nigeria.
AB  - OBJECTIVE: To describe the current drug use practices at the institution, and
      gather baseline data, which can serve as a basis for designing an appropriate
      intervention to improve the drug use profile. METHOD: A retrospective audit of in
      and out-patient prescriptions, generated during the period January-March 1999.
      Indicators of drug use pattern include: average number of drugs prescribed per
      encounter (ANDPE), average number of antibiotics prescribed per encounter
      (ANAPE), % encounter with antibiotics (PEA), percent of antibiotic prescriptions
      based on microbial sensitivity test results (MCST). Additionally, a "knowledge,
      attitude and practice" (KAP) survey of prescribers and dispensers was performed.
      Indicators of prescribing and dispensing quality include: sources of
      drug/prescribing information, availability and use of the hospital formulary,
      knowledge of the prescribing process and the adequacy of the drug supply
      management system. RESULTS: A total of 9984 outpatient prescriptions and 127 in
      patient case notes were audited. The total number of prescribers and dispensers
      surveyed were 88 and 13 respectively. The ANDPE was found to be 3.16 for out
      patients and 9.7 for in-patients, ANAPE was 1.1 and 2.4 for out-patients and
      inpatients respectively. The PEA was 50.3% for out-patients and 96.7% for in
      patients. Only 4.2% of in-patient antibiotic prescriptions were based on MCST and
      percent encounter with switches in antimicrobial therapy was 52.1% while the
      average number of switches per encounter was 1.35. In 18.5% of the in-patient
      encounters there was evidence of drug incompatibilities. The KAP survey revealed
      that prescribers and dispensers in the hospital rely on different sources for
      their drug information needs (MIMS vs Martindale Extrapharmacoepia). None of the
      prescribers surveyed was able to correctly enumerate all the 4 steps involved in
      the prescribing process, about 25% got at least 2 steps correctly, and only 9.1%
      of the dispensers surveyed could accurately define a hospital formulary. The drug
      supply management system was found to be inadequate. CONCLUSION: The survey
      revealed that appreciable gaps in knowledge with respect to rational drug use,
      still exists among these cadre of healthcare professionals. The foregoing
      suggests an urgent need for review of current policies and systems in the
      hospital with the view of enhancing the drug use practices of the health
      providers. Specifically it is recommended that there should be an intervention
      program involving concerted continuing education (to influence the KAP of the
      various cadre of healthcare providers) and the establishment of a hospital
      formulary/standard treatment guidelines.

PMID- 12426964
TI  - The lay user perspective on the quality of pharmaceuticals, drug therapy and
      pharmacy services--results of focus group discussions.
AB  - BACKGROUND: This article presents the results of a study on quality of pharmacy
      services and perceived risk of pharmaceuticals. The results presented here are
      part of a multi-study evaluation of major changes in drug distribution in
      Iceland. OBJECTIVES: This sub-study addressed the question: what is the lay user
      perspective on pharmaceuticals and pharmacy services, including their perception
      of risk? METHODS: To answer this question, seven focus group discussions were
      conducted with pharmacy customers in different locations in Iceland following new
      drug distribution legislation in 1996. RESULTS: The lay perspective emphasizes a
      definite split between lay and expert views on the value and quality of
      pharmaceuticals, drug therapy and pharmacy services, as well as in their
      assessment of risk. Participants voiced spontaneous criticism of the roles of
      both physicians and pharmacists in drug therapy; and expressed concern about the
      quality and safety of pharmaceuticals. Some scope for shared values was noted
      between the legislative goals and the lay user perspective, despite the fact that
      the public was in no way involved in the drafting of the new legislation.
      CONCLUSION: The results of this study raise questions about the nature and extent
      of the perceived gap between the medical and pharmacy professions on the one side
      and the lay public and health policy decision-makers on the other side in their
      views on the quality and safety of pharmaceuticals and pharmacy services.

PMID- 12426965
TI  - The potential interaction between oral anticoagulants and acetaminophen in
      everyday practice.
AB  - OBJECTIVE: The drug-drug interaction between oral anticoagulants (especially
      warfarin) and acetaminophen has been described, but evidence is conflicting and
      evidence for a similar interaction between acenocoumarol or phenprocoumon and
      acetaminophen is limited. Therefore, a study was performed to determine the
      influence of acetaminophen on oral anticoagulation with acenocoumarol or
      phenprocoumon in everyday practice. METHOD: Included were patients from two Dutch
      anticoagulant clinics who had used oral anticoagulants for at least three months
      and who started with acetaminophen (case group) or benzodiazepines (control
      group). RESULTS: Fifty-four patients were included who had a first prescription
      of acetaminophen in their pharmacy record (during oral anticoagulant use) and
      twenty patients with a first prescription of a benzodiazepine (during oral
      anticoagulant use). The INR (International Normalized Ratio) difference before
      and after acetaminophen use was not statistically significant between the two
      groups and showed no dose dependency. CONCLUSION: These data do not demonstrate
      that acetaminophen, in the dosages used in everyday practice, has a clinically
      relevant influence on the INR in patients using acenocoumarol or phenprocoumon.

PMID- 12426966
TI  - Desire for information about drugs: relationships with patients' characteristics
      and adverse effects.
AB  - INTRODUCTION: Adverse effects of drugs are known to cause problems both in
      hospital and general practice settings, contributing to longer stays in a
      hospital, and increased costs of hospitalisation. By developing both a greater
      understanding of adverse drug reactions and effects and developing ways to reduce
      them will assist pharmacists in managing medicines more effectively. The aim of
      this study was to explore the relationships between patient characteristics,
      information requirements and perceptions about adverse drug effects to assist
      pharmacists in identifying patients most at risk of ADRs. METHODS: The study took
      place on medical wards at a London teaching hospital during an eight week period
      in Autumn 2000. Patients were recruited using convenience sampling during the
      recruitment period. Once eligible patients consented to take part, standardised
      interviews were conducted at their bedside. The interviews included the use of
      the previously validated scale which measures the extent of information desired
      (EID), patient characteristics including age, gender, socio-economic status etc
      and the presence of an adverse drug effect was assessed using the Naranjo
      algorithm. Patients were also asked semi-structured questions to explore past and
      present experiences of adverse drug effects. RESULTS: 82 patients were recruited,
      80 were eligible for adverse effects of drugs assessment. Fifteen percent (12/80)
      of patients were assessed as having "definite" and "probable" adverse drug
      effects, based on the Naranjo algorithm. The previously validated EID scale was
      found to be both valid and reliable in this patient sample. There was an
      association between high scores on the EID scale and the presence of an adverse
      drug effect (chi-squared = 4.97, p = 0.02). CONCLUSION: The results show an
      association between the occurrence of an adverse drug effect on admission
      (identified by the Naranjo scale), the experience of an adverse drug effect in
      the past and a patient's desire for information. The EID-scale could be developed
      into a useful tool for assessing and addressing patients' drug information needs
      for pharmacists to use when assessing adverse drug effects in everyday practice.

PMID- 12426967
TI  - Evidence-based health promotion practice.

PMID- 12426968
TI  - Global conferences for solving social problems: are the gains sufficient?

PMID- 12426969
TI  - A contextual model for reproductive health education: fertility and family
      planning in Jordan.

PMID- 12426970
TI  - The Cochrane Health Promotion and Public Health Field--expanding and promoting
      the evidence base.

PMID- 12426971
TI  - Effectiveness of a resource on the Australian health care system among the Sydney
      Chinese-speaking community.

PMID- 12426972
TI  - Radio programming for health and social development in Mongolia.

PMID- 12426973
TI  - [Concerning residency, will the entropy end?].

PMID- 12426974
TI  - [Do the guidelines for clinical practice enable to improve the quality of care?
      (interview by Veronique Girault)].

PMID- 12426975
TI  - [Patentability of living material: public health concerns (1/2)].
AB  - A TOPICAL SUBJECT: The patentability of living material provokes debate in the
      scientific and medical world, but also concerns the political and legal circles.
      REGARDING PATENTS: Laws govern intellectual property rights and patients. There
      are contradictory arguments advanced by those who are in favour or who are
      opposed to patents, and particular problems related to the patenting of living
      organisms, particularly since the progress made in genomic research. ESSENTIAL
      PUBLIC HEALTH REQUIREMENTS: It is important to underline the limits imposed by
      the protection of intellectual property, regarding the access by all to any
      progress issued from research. The provisions must be widened in order to bypass
      the patents, when the health and nutrition of populations are at stake. It is
      essential to come to the universal accessibility, particularly in developing
      countries, to all innovations and that all knowledge be shared.

PMID- 12426976
TI  - [Sinusal penetration of amoxicillin-clavulanic acid. Formulation 1 g./125 mg.,
      twice daily versus formulation 500 mg./125 mg., three times daily].
AB  - INTRODUCTION: In order to meet the evolution of pneumococcus resistance to beta
      lactam antibiotics, a new formulation of amoxicillin (AMX) and clavulanic acid
      (CA), with twice as much AMX (1 g/125 mg vs. 500 mg/125 mg) was developed for the
      treatment of acute pneumonia in patients at risk. This formulation can also be
      used in the treatment of acute maxillary sinusitis using a 1 g/125 mg regimen
      twice-daily. OBJECTIVES: Compare the sinusal penetration of AMX and CA (1 g/125
      mg twice-daily vs. 500 mg/125 mg three times a day) when administered at both
      regimens to demonstrate equivalent pharmacokinetic and pharmacodynamic behaviour
      of the former when compared to the latter. METHODS: Concentrations of AMX and CA
      were measured in the anterior ethmoid, maxillary, posterior ethmoid sinus and in
      the middle nasa concha in 62 patients undergoing surgery for nasosinusal polyps.
      Patients randomised in two groups corresponding to 2 oral regimens, received
      either 1 g/125 mg twice a day or 500 mg/125 mg three times a day for 4 days. The
      last dose in both groups was administered 1 h 30, 3, 5 or 8 hrs prior to surgery.
      Serum samples were taken simultaneously to tissue samples. AMX and CA were
      measured by high performance liquid chromatography. Exogenous and above all
      endogenous blood contamination were taken into account with the hematocrit as
      well as blood and tissue haemoglobin concentrations. Comparisons of tissue
      concentrations were made for each sampling time, according to values obtained for
      a specific tissue with both doses on one hand, and on the other to values
      obtained with a specific dose in different tissues. The calculated
      pharmacodynamic parameters, which are considered to be predictive for
      bacteriological and clinical efficacy, result directly from tissue concentrations
      of AMX. tissue inhibitory quotients (IQtissue = Tissue concentration/MIC). time
      above MICs for serum and tissue concentrations (T > MIC). RESULTS: As regards
      AMX, whatever the dose, at 1 h 30 and at 3 hrs, tissue concentrations did not
      differ significantly whatever the tissue studied (from 1.1 to 2.5 micrograms/g).
      Conversely, at 5 and 8 hrs, they were greater than after the 1 g/125 mg regimen
      given twice-daily (0.06-0.7 vs. 0.7-1.8 micrograms/g). If we consider a given
      dose, the comparison between the various tissues showed identical concentrations
      in the four tissues studied at each sampling time, except in two cases with the
      dose of 500 mg/125 mg 3 times a day. T > MIC for serum and tissue showed higher
      values than those required for AMX/pneumococcus association (40-50%) with,
      nevertheless, greater tissue values for the 1 g/125 mg dose given twice-daily
      when MIC was of 1 microgram/ml (40-52% vs. 50-66%). The maximum tissue inhibitory
      quotients were also greater with the twice-daily 1 g/125 mg dose, when calculated
      with MIC 50 or 90 of S. Pneumoniae, H. influenzae, M. catarrhalis or S. pyogenes.
      As for CA, concentrations were equivalent for both doses at each sampling time
      and greater than those required in vitro during respectively 4 and 5 hours for
      beta-lactamases H. influenzae and M. catarrhalis. DISCUSSION-CONCLUSION: A least
      an equivalence between both dose regimens was observed, with occasionally a
      superiority of the twice-daily 1 g/125 mg dose, in terms of pharmacokinetics,
      tissue penetration and pharmacodynamics for both AMX and CA. This new regimen
      therefore appears more appropriate for the treatment of acute maxillary sinusitis
      in adults.

PMID- 12426977
TI  - [Association of type 1 neurofibromatosis and primary hyperparathyroidism].
AB  - INTRODUCTION: The combination of neurofibromatosis type I with
      hyperparathyroidism is classical but rare. OBSERVATION: Our report is on the
      original observation of a patient affected with Von Recklinghausen's disease
      complicated by chronic restrictive breathing deficiency. After an intense
      breathing decompensation and a spreading convulsive attack, hyperparathyroidism
      was diagnosed. DISCUSSION: The similarity of the bone lesions seen in type I
      neurofibromatosis and in hyperparathyroidism strongly suggests a genetic link
      between these two pathologies. Hence, hyperparathyroidism should be searched for
      in all patients affected with Von Recklinghausen's disease, since the adjustment
      of hypercalcemia can lead to partial reversibility of the bone abnormalities.

PMID- 12426978
TI  - [Cytomegalovirus infection, a risk when adopting a child abroad].

PMID- 12426979
TI  - [Evaluation of the quality of life in ophthalmology].
AB  - THE IMPORTANCE OF VISUAL FUNCTION IN THE ASSESSMENT OF QUALITY OF LIFE: The
      notion of visual function is related to visual acuity but also to many other
      parameters such as the visual field, perception of colour, contrasts, and the
      resistance to blinding. These factors are difficult to measure during routine
      ophthalmic examination but can be assessed during questionnaires on quality of
      life. MARKERS OF QUALITY OF LIFE IN OPHTHALMOLOGY: Various quality of life
      questionnaires have been developed in ophthalmology because the non-specific
      generic instruments appear inadequate. The SF 36 and SF 20 scales, which are
      generic instruments widely used in many fields, do not adequately explore the
      problems related to vision. The first efficient instrument is the VF 14, which is
      a questionnaire specific to ophthalmic diseases, developed by C. Mangione in
      1992. This self-administered questionnaire permits calculation of a 0 to 100
      score exploring 5 dimensions (long-sight acuity, near-sight acuity, unclear
      sight, and driving during the day and at night) during 14 activities with 18
      questions. It was translated and adapted into French by Gresset in 1997. Today it
      is the most commonly used questionnaire in ophthalmology, particularly in the
      assessment of efficacy and impact in surgery. Along the other specific
      questionnaires developed, there is the NEI-VQF which was created in 1995 to
      assess vision and the impact of visual problems on the quality of life of
      patients, independently of an ophthalmic pathology. Many studies have been
      conducted on various diseases that affect vision, such as diabetes or
      hypertension. THE LIMITS OF EXISTING INSTRUMENTS: The specific scales appear far
      more sensitive and specific than generic scales with regard to ophthalmic
      problems, but they provide less information on the general status of the patient,
      except for the NEI-VQF. They are limited in some parameters and do not,
      unfortunately, take into account the patient's age. No specific scale has been
      developed for children or adolescents, although the impact of vision on daily
      life is fundamental. The complexity of vision means that the elaboration of an
      ideal instrument is difficult. However, in the meantime, it is essential that the
      practitioners continue to use and to test the instruments available in order to
      improve with regard to pathologies, or in particular sub-groups of the
      population.

PMID- 12426980
TI  - [Treatment of pulmonary fibrosis].
AB  - A RECENTLY MODIFIED CONCEPT: Idiopathic pulmonary fibrosis (IPF) is characterized
      by dyspnea on exertion, diffuse radiological infiltrates and alterations in
      respiratory function. The approach to IPF has recently changed with a more
      precise definition of the histological diagnostic criteria (hence excluding other
      disorders such as non-specific interstitial pneumonia), and with the hypothesis
      that fibro-proliferation and abnormalities in epithelial repair may have a
      greater physiopathological role than inflammation. DEBATABLE RESULTS FOR
      CORTICOSTEROIDS: To date, no treatment has demonstrated its efficacy in this
      disorder and few randomised studies are available. Although early observations
      showed some benefit of corticosteroids, it is now well established that these
      studies in fact included a proportion of other corticosteroid-sensitive diseases,
      such as non-specific interstitial pneumonia. In more recent studies, in which the
      diagnosis of IPF was made more rigorously, no convincing demonstration of the
      efficacy of corticosteroids or of immunosuppressive treatments (cyclophosphamide,
      azathioprine) was made. A trial of corticosteroid therapy for a period of 3 to 6
      months (possibly combined with immunosuppressors) is still recommended in the
      absence of contraindications, but with rigorous and objective assessment of the
      efficacy, and careful monitoring of the side effects. TREATMENTS UNDER STUDY:
      Treatments aimed at limiting fibrogenesis have also been proposed. However,
      clinical studies have not confirmed the initial results obtained with colchicine.
      Nevertheless, encouraging results have been obtained with other "anti-fibrosing"
      agents (such as pirfenidone) or immunomodulators (interferon-gamma-1b); such
      treatment should be further evaluated by larger, randomised, controlled trials in
      order to know whether these results are applicable to a less selected population.
      BETWEEN SYMPTOMATIC CARE AND TRANSPLANTATION: In the absence of effective
      treatment, the management of IPF, the diagnosis of which has been confirmed by
      rigorous criteria (ideally lung biopsy) is primarily symptomatic. Young patients
      should be assessed with a view of pulmonary transplantation.

PMID- 12426981
TI  - [Vascular risk factors].

PMID- 12426982
TI  - EMA+ cells in dermatofibrosarcoma protuberans. A study of 11 tumors suggesting
      perineurial cell differentiation.
AB  - Expression of epithelial membrane antigen (EMA) was found in 11 of 57 (19%) cases
      of dermatofibrosarcoma protuberans (DFSP). These tumors with EMA+ cells showed
      the following histological features: classical storiform pattern in all 11 cases,
      myxoid areas in three cases, Bednar tumor pattern in one case, and fibrosarcoma
      like areas in one case. The EMA+ cells had a tendency to occur in moderately
      cellular and collagen-rich areas with parallel cell arrangement (4 cases) and in
      perivascular areas (3 cases). In such parts, a nuclear palisading and a wavy
      appearance of the nuclei were seen focally. One tumor contained perineurioma-like
      areas with whorled cell arrangement and EMA+ cells. The EMA+ cells were also
      found in ordinary storiform areas (6 cases), but here they were isolated and
      scarce. In two cases, the EMA+ cells were juxtaneural; therefore their origin
      from a sheath of preexisting nerves can not be excluded. Expression of EMA may
      reflect true perineurial cell differentiation in DFSP, as suggested previously in
      several ultrastructural and cytogenetic studies. The knowledge of occasional EMA
      positivity in DFSP is needed for a differential diagnosis between DFSP and other
      EMA+ soft tissue lesions.

PMID- 12426984
TI  - [Hairy-cell leukemia].
AB  - Presented is on overview of hairy cell leukemia problems in diagnostics. Methods
      of diagnosis--both clinical (clinical course, laboratory findings) and
      histopathologic are described in detail. There are also immunophenotypic findings
      described. Furthermore, differential diagnosis together with therapeutic methods,
      and the prognosis of the disease are depicted, too.

PMID- 12426983
TI  - [Primary mediastinal (thymus) large B-cell lymphoma: clinically defined type of
      tumors and morphologic variants].
AB  - In the WHO lymphoma classification, primary mediastinal (thymic) large B-cell
      lymphoma (PMVBL) is defined as a subtype of diffuse large B-cell lymphoma (DLBCL)
      showing typical clinical manifestation. The patterns related to variability of
      tumor cell morphology were analyzed in the setting of 15 bioptically verified
      PMVBL cases. In the majority of the cases (n = 12), the tumor showed pleomorphic
      blastic morphology with individual cell patterns resembling those of polymorphic
      centroblastoma of the Kiel classification. In addition, some of the cases had
      clear-cell and/or lacunar appearance (5/12), while distinctive anaplastic
      appearance was rare (1/12). Other cases (n = 3) showed a monotonous morphology of
      uniform smaller-sized blasts with monocytoid-like cytoplasm. The described
      morphologic variants of PMVBL might be related to the known genotypic variability
      of DLBCL, although monotypic c-Ig expression verified in some of the cases would
      support post-follicular stage of the tumor cell development. In the absence of
      clinical data and within the described morphologic variability, it is recommended
      to prefer a diagnosis of DLBCL and to include the tumor into a clinically defined
      subtype of PMVBL only in cases with well defined and typical clinical
      presentation and progression of the disease.

PMID- 12426985
TI  - [Fibrillary glomerulonephritis].
AB  - Fibrillary glomerulonephritis (FGN) is a rare cause of nephrotic syndrome. In
      three patients (65-year-old male; 57- and 38-year-old females) FGN was diagnosed
      by percutaneous renal biopsy. Clinically, the disease manifested itself with long
      term proteinuria and nephrotic syndrome without any associated systemic disorder.
      Histologically, glomeruli showed deposition of PAS+, fuchsinophilic and Orange G+
      material in the mesangium and basal membranes. Strong granular immunofluorescence
      IgG, C3 and weak kappa and lambda light chains mesangial and peripheral
      deposition were observed in two patients. Electronmicroscopically, deposition of
      fibrillary material into mesangium and basal membranes was found. Randomly
      distributed nonbranching fibrils were 18-28 nm thick. After 10 to 13 months of
      follow-up, the therapy with corticosteroids and immunosuppressives was without
      effect, and the disease progressed into chronic renal failure in two patients;
      the third patient did well.

PMID- 12426986
TI  - [What is your diagnosis? Answer: renal oncocytoma with filamentous globules].

PMID- 12426987
TI  - [Secondary changes in the thyroid gland induced by aspiration cytology].
AB  - Due to the introduction of fine needle aspiration cytology (FNAC) to the routine
      clinical preoperative examination surgical pathologists are faced with thyroid
      gland specimens with FNAC-induced secondary changes. These changes can cause
      diagnostic difficulties and be a source of incorrect diagnosis. Authors present a
      review of FNAC-induced changes with differential diagnostic criteria helpful in
      these pitfalls. FNAC-induced changes can be schematically divided into two major
      groups--recent ones (intranodal bleeding and/or necrosis) and subacute/late ones
      (proliferation of granulation tissue with predominance of myofibroblasts or
      endothelial cells, resorptive pseudoxantomathous granulomas, formation of sarcoid
      like granulomas, capsular pseudoinvasion and scarring). Pathologists should be
      informed about the previously performed FNAC and must be aware of these lesions
      to prevent their misinterpretation.

PMID- 12426988
TI  - [Plant tissues in biopsies].
AB  - A short communication demonstrates examples of plant tissues or their derivates
      in biopsies. Diagnostic pitfalls are emphasized.

PMID- 12426989
TI  - [Toxins from the aspect of international control programs].
AB  - Toxins, chemical substances produced by practically all forms of life, represent
      a chemically broad group of compounds. Many of them are very toxic for human and
      represent a serious jeopardy because they may be misused through chemical warfare
      or terrorist attacks. This danger has been increasing recently because toxins are
      more and more available due to modern synthetic methods and application of
      genetic engineering. Therefore the international community adopted multilateral
      conventions and control regimes, which regulate handling with toxins. These
      fundamentals are implemented into the Czech system of law too.

PMID- 12426990
TI  - [Pharmacokinetics of ethyl alcohol and its importance for forensic calculations
      of blood alcohol levels].
AB  - Calculations of blood alcohol concentration for forensic purposes are based on
      several simplified assumptions (linear pharmacokinetics of ethanol, constant rate
      of ethanol elimination within full range of time, constant rate of alcohol
      absorption and constant time of peak blood alcohol levels achievement which is by
      convention depending only on type of a beverage and quantity of food consumed).
      Simplified and idealized assumptions mentioned above significantly restrict
      possibility of back-extrapolations of blood alcohol concentrations from the
      observed values and calculations based on them exclude the absorption phase of
      blood alcohol curve from being estimated. In this work there are designs of more
      advanced models of alcohol pharmacokinetics describing blood alcohol
      concentrations within full ranges of blood alcohol curves. Their possible
      benefits for forensic medicine and practical aspects are discussed.

PMID- 12426991
TI  - Locally-applied collagenase and regeneration of transsected and repaired rat
      sciatic nerves.
AB  - The possible effects of collagenase on peripheral nerve regeneration were
      evaluated after epineurial repair of rat sciatic nerves. In the control group the
      repair site was covered by fibrin adhesive and infused with isotonic saline and
      in the experimental group collagenase was infused into the fibrin adhesive. In
      the short term study the regeneration distance was measured by a pinch test four,
      six, or eight days postoperatively. In the long term study the evaluation of
      nerve regeneration and recovery of motor function was made by testing the tetanic
      contraction force of the anterior tibial muscle three months postoperatively.
      There were no significant differences between the two groups in either the short
      or long term. We conclude that locally-applied collagenase had no effect on
      peripheral nerve regeneration.

PMID- 12426992
TI  - Cross-linked hyaluronan for augmentation of the posterior pharyngeal wall: an
      experimental study in rats.
AB  - Velopharyngeal insufficiency can be treated in different ways. Augmentation
      injections of various space-filling materials have been tried, but a substance
      that has the ideal properties--easy to inject, non-toxic, and not immunogenic,
      and having a lasting effect--has not yet been found. Hylan b gel, a double cross
      linked hyaluronan solution, is a new tissue augmentor that is not immunogenic and
      is easy to use. The purpose of this study was to evaluate the persistence of and
      the tissue reaction to hylan b gel injected into the posterior pharyngeal wall of
      12 rats. Six rats acted as controls. A light immediate, and no late, inflammatory
      reaction developed in the pharyngeal mucosa after injection. Six months after
      injection, the gel was still present and the substance had been invaded by and
      surrounded by newly-formed, loose connective tissue. These results indicate that
      hylan b gel may be an appropriate substance in the augmentation of mild
      velopharyngeal insufficiency in man. However, further studies are needed to
      evaluate its long-term effects.

PMID- 12426993
TI  - Colour Doppler ultrasound evaluation of haemodynamic changes in free tram flaps
      and their donor sites.
AB  - Colour Doppler ultrasound (US) was used to measure the blood flow in the donor
      and recipient arteries as well as in the deep superior epigastric artery of 10
      patients having free transverse rectus abdominis myocutaneous (TRAM) flaps. The
      peak, minimum and mean velocities, the diameter of the vessel, and the resistance
      index of both the deep superior and inferior epigastric arteries and
      thoracodorsal arteries were recorded preoperatively and at 4-6 and 15-30 days
      postoperatively. Colour Doppler US showed increased minimum velocity and
      decreased resistance index in the pedicle (p < 0.05) throughout the follow-up
      when compared with the baseline. In the ipsilateral superior epigastric artery
      the mean and minimum velocities increased (p < 0.05) while the resistance index
      decreased (p < 0.05) during the first month postoperatively. No changes were
      recorded in the opposite epigastric arteries or in the control vessel (opposite
      thoracodorsal artery). In all patients the diameter of the deep inferior
      epigastric artery was larger than that of the superior epigastric and remained so
      after the transfer. From the fourth to the thirtieth postoperative day blood flow
      increased in the free TRAM flap, presumably because of decreased vascular
      resistance. Blood flow also increased in the superior epigastic artery on the
      donor side after free TRAM transfer as expected (indicating the delay
      phenomenon), but harvesting the flap did not affect the circulation in the
      opposite rectus abdominis muscle. The inferior epigastric arterial system was
      dominant in all patients.

PMID- 12426994
TI  - Results of the latissimus dorsi and teres major tendon transfer on to the rotator
      cuff for brachial plexus palsy at birth.
AB  - Brachial plexus palsy at birth remains a serious problem. Although most cases
      resolve during the first few months by spontaneous regeneration, several
      operations have been used to correct the residual deformity. In the present study
      we describe the results of the latissimus dorsi and teres major tendons transfer
      on to the rotator cuff to improve shoulder function. Six patients were included
      in the study: three girls and three boys; four right shoulders, and two left. The
      types of palsy were four Erb's palsy (C5, C6) and two C5-C7 palsy. The median age
      at the time of operation was 11 years and 1 month and the median follow-up period
      was 54.2 months. Median preoperative passive external rotation was 51 degrees,
      and active abduction 67 degrees. Median postoperative active external rotation
      was 72 degrees, and postoperative active abduction 109 degrees. This procedure
      increased the ranges of external rotation and abduction, and provided
      considerable improvement in shoulder function.

PMID- 12426995
TI  - Reduction mammaplasty and the use of dextran against thromboembolism.
AB  - A retrospective study was conducted on 98 consecutive patients who had reduction
      mammaplasty done by different techniques during 1995, to find out the effect of
      dextran 70 on operative blood loss and postoperative complications. The most
      common procedure was reduction with a laterally based flap (n = 67) followed by a
      Lejour vertical mammaplasty (n = 15) and a medially based flap (n = 12). Four had
      other operations. Dextran 70 was given peroperatively to 64 patients and their
      median (range) blood loss was 350 (30-1000) ml and drainage volume 80 (10-465)
      ml. In 33 patients not treated with dextran 70 the median (range) blood loss was
      200 (25-650) ml and the drainage volume 40 (0-115) ml. Ten patients developed
      major complications and 16 minor complications and there was no difference in the
      complication rate between those given dextran 70 (18/64, 28%) and those who were
      not (8/33, 24%), p = 0.8. Complications were no more common in smokers,
      overweight patients or those whose breasts were reduced by more than 1500 g, but
      there was a tendency to find more complications after the Lejour vertical
      mammaplasty. In conclusion, the study shows that patients undergoing mammaplasty
      and given Dextran 70 have an acceptable blood loss and drainage. In patients with
      a high risk of developing thromboembolism there is a need for a prophylactic
      agent and this study shows that dextran 70 may safely be used during reduction
      mammaplasty.

PMID- 12426996
TI  - Threshold of tactile perception after nipple-sharing: a prospective study.
AB  - Reconstruction of the nipple-areola complex is the final procedure of a breast
      reconstruction. The method of choice in our department for nipple reconstruction
      is nipple-sharing and tattooing of the areola. Some patients are reluctant to use
      a part of the healthy nipple, as it is not fully known how the sensibility in the
      remaining donor nipple is affected by surgery. Twenty patients admitted to the
      hospital for nipple-sharing were invited to participate in the study. The tactile
      perception threshold of the donor nipple was assessed using von Frey
      monofilaments preoperatively, and 1, 6, and 12 months postoperatively. The
      patients' subjective impressions one year postoperatively were also evaluated.
      The donor nipple had regained sensibility to touch six months after nipple
      sharing. All patients reported that the nipple felt the same as before surgery
      and could become erect. We therefore recommend the nipple-sharing technique for
      completion of a breast reconstruction.

PMID- 12426997
TI  - Origins of the dorsal metatarsal arteries in humans.
AB  - The foot is indispensable for man's daily activities and the integrity of its
      structure depends on its irrigation. The number of bypass operations for its
      arteries therefore increases as well as the use of vascularised flaps to cover
      defects in its dorsal region. To find out more details about the irrigation of
      the dorsum of foot, the formation of dorsal metatarsal arteries (DMA) was
      examined in 50 feet of 25 fixed cadavers of Brazilian adults of both sexes. The
      feet arteries were injected with neoprene latex dyed red, and then dissected. The
      first DMA originated from the dorsalis pedis artery in 86%, from the plantar
      network in 10% and the origin was mixed in 4%. The second DMA originated from the
      arcuate artery exclusively in 10%, the third DMA in 6%, and the fourth DMA in
      10%. In its absence (48%), the lateral tarsal arteries and the proximal
      perforating branches were responsible for the formation of the second DMA in 52%,
      of the third DMA in 54%, and of the fourth DMA in 72%. The proximal perforating
      branches made an important contribution to the formation of such arteries,
      contributing partially or totally to the second DMA in 90%, to the third DMA in
      92%, and to the fourth DMA in 86%.

PMID- 12426998
TI  - Unstable distal radial fractures treated by external fixation: an analytical
      review.
AB  - A "Hoffman type 2" external fixator was applied in 33 patients being treated for
      distal radial fractures that were classified according to the three basic types
      of the AO/ASIF system. Thirty fractures were suitable for statistical evaluation.
      Fixators were used alone (n = 10) or in combination with internal fixation of the
      intra-articular component. Fixators were removed sooner when they were combined
      with internal devices and these patients had significantly less pain. There was
      no relation between pain, classification, primary displacement, function,
      position on the radiograph, and Green and O'Brien score. Primary displacement was
      more important in patients over 50 years of age. Reflex sympathetic dystrophy was
      associated with fractures of the ulnar head. Ulnar styloid fractures were not
      related to increased laxity or symptoms at the distal radioulnar joint. There
      were no signs of intracarpal "instability" in patients less than 50 years of age
      and the condition caused no specific symptoms. Maintenance of stability was
      better when grafts were used, but not significantly so. Green and O'Brien scoring
      was no more informative than a simple ordinal pain ranking system.

PMID- 12426999
TI  - Intramuscular benign lipoma of the temporalis muscle.
AB  - An intramuscular lipoma within the musculature of the head and neck is unusual.
      Most of them are infiltrating lipomas, and we know of no description of a well
      circumscribed lipoma of the temporalis muscle. We present a 64-year-old woman who
      had a non-pulsatile, soft, mobile mass in the right temporal fossa. The lesion 11
      x 8 x 3 cm in size was diagnosed using magnetic resonance imaging, it was
      resected, and she has recovered well with a good cosmetic result.

PMID- 12427000
TI  - Transient granulomatous inflammation of the hand.
AB  - We present a granulomatous inflammatory tumour of the hand in a fit 26-year-old
      man. The lesion resolved spontaneously within a month of presentation. Whilst the
      true nature of this inflammatory lesion remains unknown the case highlights the
      importance of thorough investigation of all deep-seated soft tissue tumours of
      the hand prior to committing a patient to surgery.

PMID- 12427001
TI  - Osteoid osteoma of the metacarpal bone presenting after an injury.
AB  - We present a case of osteoid osteoma of the right third metacarpal bone in a 23
      year-old man. He had an apparent history of initial injury, followed by pain and
      swelling. He was initially treated for post-traumatic periostosteitis, so that
      the diagnosis of osteoid osteoma was delayed. Computed tomography and histology
      confirmed the latter diagnosis. En bloc resection of the nidus was followed by
      complete resolution of his symptoms. This case report emphasises the difficulties
      in diagnosis, particularly after an injury, and illustrates its effective
      treatment.

PMID- 12427002
TI  - Rupture of flexor tendons after arthrodesis of the basal joint of the thumb.
AB  - We report a case of rupture of the flexor tendons to the index finger after
      arthrodesis of the basal joint of the thumb. The tendons ruptured as a result of
      the Kirschner wires having penetrated in the carpal tunnel. This unusual
      complication was treated by tendon graft of the palmaris longus tendon.

PMID- 12427003
TI  - Ruptures of flexor tendons at the wrist as a complication of fracture of the
      distal radius.
AB  - We report two cases of rupture of flexor tendons after fracture of the distal
      radius. The first case was a rupture of the flexor digitorum profundus and
      superficialis tendon to the index finger that happened 20 years after the
      fracture. The second was a rupture of the flexor pollicis longus tendon that
      occurred two years after, and the flexor profundus tendon to the index finger
      that occurred four years after the fracture. In the first case, the ruptures were
      caused by the bony protuberance of the radius after long interval without
      interference of the ulnar head.

PMID- 12427004
TI  - Restoration of the first dorsal interosseous muscle by transfer of the abductor
      pollicis longus tendon.
AB  - We used Neviaser's procedure, transfer of the abductor pollicis longus tendon, to
      restore the first dorsal interosseous muscle in two patients who had lost muscle
      function as a result of injury or resection of a tumour. The patients were
      satisfied with the increased strength and stability in pinch. There were no
      complications.

PMID- 12427006
TI  - On the stethoscope.

PMID- 12427005
TI  - Delaware doctors.

PMID- 12427007
TI  - Protein hydration, thermodynamic binding, and preferential hydration.

PMID- 12427008
TI  - The Werner syndrome helicase/exonuclease (WRN) disrupts and degrades D-loops in
      vitro.
AB  - The loss of function of WRN, a DNA helicase and exonuclease, causes the premature
      aging disease Werner syndrome. A hallmark feature of cells lacking WRN is genomic
      instability typified by elevated illegitimate recombination events and
      accelerated loss of telomeric sequences. In this study, the activities of WRN
      were examined on a displacement loop (D-loop) DNA substrate that mimics an
      intermediate formed during the strand invasion step of many recombinational
      processes. Our results indicate that this model substrate is specifically bound
      by WRN and efficiently disrupted by its helicase activity. In addition, the 3'
      end of the inserted strand of this D-loop structure is readily attacked by the 3'
      ->5' exonuclease function of WRN. These results indicate that D-loop structures
      are favored sites for WRN action. Thus, WRN may participate in DNA metabolic
      processes that utilize these structures, such as recombination and telomere
      maintenance pathways.

PMID- 12427009
TI  - Kinetic modeling and determination of reaction constants of Alzheimer's beta
      amyloid fibril extension and dissociation using surface plasmon resonance.
AB  - To establish the kinetic model of the extension and dissociation of beta-amyloid
      fibrils (f(A)beta) in vitro, we analyzed these reactions using a surface plasmon
      resonance (SPR) biosensor. Sonicated f(A)beta were immobilized on the surface of
      the SPR sensor chip as seeds. The SPR signal increased linearly as a function of
      time after amyloid beta-peptides (Abeta) were injected into the f(A)beta
      immobilized chips. The extension of f(A)beta was confirmed by atomic force
      microscopy. When flow cells were washed with running buffer, the SPR signal
      decreased with time after the extension reaction. The curve fitting resolved the
      dissociation reaction into the fast exponential and slow linear decay phases.
      Kinetic analysis of the effect of Abeta/f(A)beta concentrations on the reaction
      rate indicated that both the extension reaction and the slow linear phase of the
      dissociation were consistent with a first-order kinetic model; i.e., the
      extension/dissociation reactions proceed via consecutive association/dissociation
      of Abeta onto/from the end of existing fibrils. On the basis of this model, the
      critical monomer concentration ([M](e)) and the equilibrium association constant
      (K) were calculated, for the first time, to be 20 nM and 5 x 10(7) M(-1),
      respectively. Alternatively, [M](e) was directly measured as 200 nM, which may
      represent the equilibrium between the extension reaction and the fast phase of
      the dissociation. The SPR biosensor is a useful quantitative tool for the kinetic
      and thermodynamic study of the molecular mechanisms of f9A)beta formation in
      vitro.

PMID- 12427010
TI  - Metal binding to Saccharomyces cerevisiae ferrochelatase.
AB  - Ferrochelatase is the terminal enzyme in the heme biosynthetic pathway. It
      catalyzes the insertion of ferrous iron into protoporphyrin IX to produce
      protoheme IX. The crystal structures of ferrochelatase from Saccharomyces
      cerevisiae in free form, in complex with Co(II), a substrate metal ion, and in
      complex with two inhibitors, Cd(II) and Hg(I), are presented in this work. The
      enzyme is a homodimer, with clear asymmetry between the monomers with regard to
      the porphyrin binding cleft and the mode of metal binding. The Co(II) and Cd(II)
      complexes reveal the metal binding site which consists of the invariant amino
      acids H235, E314, and S275 and solvent molecules. The shortest distance to the
      metal reveals that amino acid H235 is the primary metal binding residue. A second
      site with bound Cd(II) was found close to the surface of the molecule,
      approximately 14 A from H235, with E97, H317, and E326 participating in metal
      coordination. It is suggested that this site corresponds to the magnesium binding
      site in Bacillus subtilis ferrochelatase. The latter site is also located at the
      surface of the molecule and thought to be involved in initial metal binding and
      regulation.

PMID- 12427011
TI  - Radical formation at Tyr39 and Tyr153 following reaction of yeast cytochrome c
      peroxidase with hydrogen peroxide.
AB  - The formation of yeast cytochrome c peroxidase (CcP) compound I has been
      recognized for many years to be associated with formation of two protein-centered
      radicals. One of these radical sites is located at Trp191 and is directly
      involved in catalytic oxidation of ferrocytochrome c (Sivaraja, M., Goodin, D.
      B., Smith, M., Hoffman, B. M. (1989) Science 245, 738-740). The second radical
      has been proposed to arise from one or more tyrosyl residues of CcP. However, the
      tyrosyl residue (or residues) capable of forming this radical has not been
      identified, and the functional role of this radical remains poorly understood. In
      the present work, this issue has been addressed through the combined use of the
      spin-trapping reagent 2-methyl-2-nitrosopropane and peptide mapping by
      electrospray mass spectrometry to identify Tyr39 and Tyr153 as two tyrosyl
      residues that are capable of forming radical centers upon reaction of CcP with
      hydrogen peroxide. The implications of this observation to the catalytic
      mechanism of CcP are addressed with reference to the three-dimensional structure
      of CcP.

PMID- 12427012
TI  - A new approach to the study of protein-protein interaction by FTIR: complex
      formation between cytochrome P450BM-3 heme domain and FMN reductase domain.
AB  - We describe a new approach to the study of protein-protein interaction using
      Fourier transform infrared spectroscopy (FTIR). This approach is based on the
      combination of FTIR technique with both protein titration experiments and the
      principal component analysis (factor analysis) of the IR absorption spectra in
      the 1500-1800 cm(-1) region for the protein mixtures. We have applied this
      approach to the interaction of the heme domain with the FMN domain of bacterial
      monooxygenase cytochrome P450BM-3 (CYP102A1). The analysis reveals that the first
      principal component reflects the protein-protein complex formation because the
      loading factors show a clear systematic dependence on the concentration of the
      heme domain according to a titration curve with a dissociation constant of
      approximately 5 microM. The spectrum of the first principal component has been
      assigned to structural changes in the secondary structure (increase of beta-sheet
      and alpha-helix and decrease of turn structures), amino acid side chains
      (protonation of aspartate and C-terminal COO group), and deprotonation of a
      propionic acid COOD group in the heme.

PMID- 12427013
TI  - Light-driven translocation of the protein phosphatase 2A complex regulates
      light/dark dephosphorylation of phosducin and rhodopsin.
AB  - In steps of protein purification of bovine retinal protein phosphatase 2A (PP2A),
      phosducin dephosphorylation activity peaks coelute with a PP2A enzyme complex,
      shown by peptide sequence analysis to contain a B' subunit, B56 epsilon. Other
      PP2A complexes with a slightly larger (56.5 kDa) B' subunit (sequenced to be B56
      alpha) or with the B alpha regulatory subunit have no phosducin dephosphorylation
      activity. Upon exposure to light, a significant increase in the immunoreactive
      protein level of the A, C, and B56 epsilon PP2A subunits is observed in the
      cytosolic fraction of mouse retina, the phosducin dephosphorylation of which
      occurs rapidly. During dark exposure, these subunits translocate to the membrane
      fraction where rhodopsin is slowly dephosphorylated. This PP2A redistribution
      occurs in less than 1.5 min and is dependent upon light and not upon an intrinsic
      circadian rhythm. Forty times more of the A subunit (approximately 20 ng/mouse
      retina) and 9 times more of the C subunit (approximately 4 ng/mouse retina) than
      of the B56 epsilon subunit (approximately 0.45 ng/mouse retina) redistribute,
      which suggests that the predominant form of the PP2A enzyme complex on the
      membrane in the dark is a dimer, consisting of only A and C subunits. We observe
      that the dimer favors phosphorylated opsin as a substrate, while the trimer,
      particularly the enzyme complex with the B56 epsilon subunit, greatly prefers
      phosphorylated phosducin, with an activity several hundred times those of other
      substrates that were tested. This light-driven PP2A translocation provides a
      potential mechanism for efficient dephosphorylation of two critical photoreceptor
      transduction proteins, cytosolic phosducin and membrane-bound rhodopsin, by the
      same enzyme.

PMID- 12427014
TI  - Amyloid fibril formation by a synthetic peptide from a region of human
      acetylcholinesterase that is homologous to the Alzheimer's amyloid-beta peptide.
AB  - A region near the C-terminus of human acetylcholinesterase (AChE) is weakly
      homologous with the N-terminus of the Alzheimer's disease amyloid-beta peptide.
      We report that a 14-amino acid synthetic polypeptide whose sequence corresponds
      to residues 586-599 of the human synaptic or T form of AChE assembles into
      amyloid fibrils under physiological conditions. The fibrils have all the
      classical characteristics of amyloid: they have a diameter of 6-7 nm and bind
      both Congo red and thioflavin-T. Furthermore, the kinetics of assembly indicate
      that fibril formation proceeds via a two-step nucleation-dependent polymerization
      pathway, and a transition in the peptide conformation from random coil to beta
      sheet is observed during fibril formation using far-UV circular dichroism
      spectroscopy. We also show that the peptide in aggregated fibrillar form has a
      toxic effect upon PC-12 cells in vitro. AChE normally resides mainly on
      cholinergic neuronal membranes, but is abnormally localized to senile plaques in
      Alzheimer's disease. Recently, an in vitro interaction between AChE and A beta,
      the principal constituent of the amyloid fibrils in senile plaques, has been
      documented. The presence of a fibrillogenic region within AChE may be relevant to
      the interaction of AChE with amyloid fibrils formed by Abeta.

PMID- 12427015
TI  - Characterization of the role of the N-loop of MIP-1 beta in CCR5 binding.
AB  - MIP-1beta is a CC-chemokine that plays a role in inflammation and host defense
      mechanisms by interacting with its specific receptor CCR5. CCR5 is a major
      coreceptor for macrophage-tropic human immunodeficiency virus (HIV), and as a
      consequence, MIP-1beta can inhibit HIV entry. It is therefore of interest to
      understand how MIP-1beta and other CCR5 ligands bind to their receptor, as such
      understanding could lead to the rational design of more efficient HIV entry
      blockers. We have previously demonstrated the importance of Phe13, and of basic
      residues of the 40's loop, in mediating high-affinity binding of MIP-1beta to
      CCR5. We have now investigated further the relative contribution of other MIP
      1beta residues in the interaction of the chemokine with CCR5, by studying the
      functional consequences of point mutations within the N-loop and the 3(10) turn
      of MIP-1beta, affecting the charge, size, and H-bonding properties of the side
      chains. Our data suggest that, in addition to Phe13, three amino acids of the N
      loop and 3(10) turn (Arg18, Lys19, and Arg22) interact with CCR5 through their
      positive charge. We also found that Pro21 contributes to the CCR5 binding
      properties of MIP-1beta. Moreover, NMR spectroscopy has revealed that the
      presence of Tyr at position 15 is necessary for the proper folding of the
      chemokine. Our results therefore demonstrate that the binding determinants of MIP
      1beta consist of residues arranged on one surface of the protein, including most
      of the basic residues in MIP-1beta, as well as two key hydrophobic groups. The
      good correlation observed between the potency of the mutants in a functional
      assay and their binding affinity strongly argues that basic residues Arg18,
      Lys19, and Arg22 of MIP-1beta are essential for its CCR5 binding properties,
      without a primary effect on CCR5 activation.

PMID- 12427016
TI  - Probing the hirudin-thrombin interaction by incorporation of noncoded amino acids
      and molecular dynamics simulation.
AB  - Thrombin is a primary target for the development of novel anticoagulants, since
      it plays two important and opposite roles in hemostasis: procoagulant and
      anticoagulant. All thrombin functions are influenced by Na+ binding, which
      triggers the transition of this enzyme from an anticoagulant (slow) form to a
      procoagulant (fast) form. In previous studies, we have conveniently produced by
      chemical synthesis analogues of the N-terminal fragment 1-47 of hirudin HM2
      containing noncoded amino acids and displaying up to approximately 2700-fold more
      potent antithrombin activity, comparable to that of full-length hirudin. In the
      work presented here, we have exploited the versatility of chemical synthesis to
      probe the structural and energetic properties of the S3 site of thrombin through
      perturbations introduced in the structure of hirudin fragment 1-47. In
      particular, we have investigated the effects of systematic replacement of Tyr3
      with noncoded amino acids retaining the aromatic nucleus of Tyr, as well as
      similar hydrophobic and steric properties, but possessing different electronic
      (e.g., p-fluoro-, p-iodo-, or p-nitro-Phe), charge (p-aminomethyl-Phe), or
      conformational (homo-Phe) properties. Our results indicate that the affinity of
      fragment 1-47 for thrombin is proportional to the desolvation free energy change
      upon complex formation, and is inversely related to the electric dipole moment of
      the amino acid side chain at position 3 of hirudin. In this study, we have also
      identified the key features that are responsible for the preferential binding of
      hirudin to the procoagulant (fast) form of thrombin. Strikingly, shaving at
      position 3, by Tyr --> Ala exchange, abolishes the differences in the affinity
      for thrombin allosteric forms, whereas a bulkier side chain (e.g., beta
      naphthylalanine) improves binding preferentially to the fast form. These results
      provide strong, albeit indirect, evidence that the procoagulant (fast) form of
      thrombin is in a more open and accessible conformation with respect to the less
      forgiving structure it acquires in the slow form. This view is also supported by
      the results of molecular dynamics simulations conducted for 18 ns on free
      thrombin in full explicit water, showing that after approximately 5 ns thrombin
      undergoes a significant conformational transition, from a more open conformation
      (which we propose can be related to the fast form) to a more compact and closed
      one (which we propose can be related to the slow form). This transition mainly
      involves the Trp148 and Trp60D loop, the S3 site, and the fibrinogen binding
      site, whereas the S1 site, the Na+-binding site, and the catalytic pocket remain
      essentially unchanged. In particular, our data indicate that the S3 site of the
      enzyme is less accessible to water in the putative slow form. This structural
      picture provides a reasonable molecular explanation for the fact that
      physiological substrates related to the procoagulant activity of thrombin
      (fibrinogen, thrombin receptor 1, and factor XIII) orient a bulky side chain into
      the S3 site of the enzyme. Taken together, our results can have important
      implications for the design of novel thrombin inhibitors, of practical utility in
      the treatment of coagulative disorders.

PMID- 12427017
TI  - Nitric oxide-mediated inhibition of Hdm2-p53 binding.
AB  - It has become increasingly evident that nitric oxide exerts its effects, in part,
      by S-nitrosylation of cysteine residues. We tested in vitro whether nitric oxide
      may indirectly control p53 by S-nitrosylation and inactivation of the p53
      negative regulator, Hdm2. Treatment of Hdm2 with a nitric oxide donor inhibits
      Hdm2-p53 binding, a critical step in Hdm2 regulation of p53. The presence of
      excess amounts of cysteine or dithiothreitol blocks this inhibition of binding.
      Moreover, nitric oxide inhibition of Hdm2-p53 binding was found to be reversible.
      Sulfhydryl sensitivity and reversibility are consistent with nitrosylation.
      Finally, we have identified a critical cysteine residue that nitric oxide
      modifies to disrupt Hdm2-p53 binding. This cysteine is proximal to the Hdm2-p53
      binding interface and is conserved across species from zebrafish to humans.
      Mutation of this residue from a cysteine to an alanine does not interfere with
      binding but rather eliminates the sensitivity of Hdm2 to nitric oxide
      inactivation.

PMID- 12427018
TI  - Molecular recognition of oligosaccharide epitopes by a monoclonal Fab specific
      for Shigella flexneri Y lipopolysaccharide: X-ray structures and thermodynamics.
AB  - The antigenic recognition of Shigella flexneri O-polysaccharide, which consists
      of a repeating unit ABCD [-->2)-alpha-L-Rhap-(1-->2)-alpha-L-Rhap-(1-->3)-alpha-L
      Rhap-(1-->3)-beta-D-GlcpNAc-(1-->], by the monoclonal antibody SYA/J6 (IgG3,
      kappa) has been investigated by crystallographic analysis of the Fab domain and
      its two complexes with two antigen segments (a pentasaccharide Rha A-Rha B-Rha C
      GlcNAc D-Rha A' and a modified trisaccharide Rha B-Rha C-GlcNAc D in which Rha C*
      is missing a C2-OH group). These complex structures, the first for a Fab specific
      for a periodic linear heteropolysaccharide, reveal a binding site groove (between
      the V(H) and V(L) domains) that makes polar and nonpolar contacts with all the
      sugar residues of the pentasaccharide. Both main-chain and side-chain atoms of
      the Fab are used in ligand binding. The charged side chain of Glu H50 of CDR H2
      forms crucial hydrogen bonds to GlcNAc of the oligosaccharides. The modified
      trisaccharide is more buried and fits more snugly than the pentasaccharide. It
      also makes as many contacts (approximately 75) with the Fab as the
      pentasaccharide, including the same number of hydrogen bonds (eight, with four
      being identical). It is further engaged in more hydrophobic interactions than the
      pentasaccharide. These three features favorable to trisaccharide binding are
      consistent with the observation of a tighter complex with the trisaccharide than
      the pentasaccharide. Thermodynamic data demonstrate that the native tri- to
      pentasaccharides have free energies of binding in the range of 6.8-7.4 kcal mol(
      1), and all but one of the hydrogen bonds to individual hydroxyl groups provide
      no more than approximately 0.7 kcal mol(-1). They further indicate that
      hydrophobic interactions make significant contributions to binding and, as the
      native epitope becomes larger across the tri-, tetra-, pentasaccharide series,
      entropy contributions to the free energy become dominant.

PMID- 12427019
TI  - Solution structure and characterization of the heme chaperone CcmE.
AB  - The covalent attachment of the heme cofactor in c-type cytochromes is a
      surprisingly complex process, which in bacteria involves a number of different
      proteins. Among the latter, the ccmE gene product is known to perform a key role
      in the heme delivery pathway in Gram-negative bacteria. The solution structure of
      the soluble domain of apo-CcmE from Shewanella putrefaciens was determined
      through NMR spectroscopy on a 13C,15N-labeled sample. The structure is
      characterized by a compact core with large regions of beta structure, while the N
      terminal and C-terminal regions are essentially unstructured. The overall folding
      is similar to that of the so-called oligo-binding proteins (OB fold). Solvent
      exposed aromatic residues, conserved in all CcmE homologues, have been found in
      the proximity of His131, the putative heme-binding residue, that could have a
      role in the interaction with heme. No interaction between CcmE and heme, as well
      as between CcmE and holocytochrome c, could be detected in vitro by electronic
      spectroscopy or by NMR. The data available suggest that the heme transfer process
      is likely to involve a heterooligomeric protein complex and occur under a tight
      enzymatic control.

PMID- 12427020
TI  - Light-induced global conformational change of photoactive yellow protein in
      solution.
AB  - The light-induced global conformational change of photoactive yellow protein was
      directly observed by small-angle X-ray scattering (SAXS). The N-terminal 6, 15,
      or 23 amino acid residues were enzymatically truncated (T6, T15, or T23,
      respectively), and their near-UV intermediates were accumulated under continuous
      illumination for SAXS measurements. The Kratky plot demonstrated that
      illumination induced partial loss of globularity. The change in globularity was
      marked in T6 but very small in T15 and T23, suggesting that structural change in
      positions 7-15 mainly reduces the globularity. The radius of gyration (R(g))
      estimated by Guinier plot was increased by 1.1 A for T6 and 0.7 A for T15 and T23
      upon illumination. As T23 lacks most of the N-terminal loop, structural change in
      the main part composed of the PAS core, helical connector, and beta-scaffold
      caused an increase of R(g) by 0.7 A. The structural change of positions 7-15
      caused an additional increase by 0.4 A. The decrease of R(g) upon truncation of
      positions 7-15 for dark state was 0.3 A, while that for the intermediate was 0.7
      A, suggesting that this region moves outward on formation of the intermediate.
      These results indicate that a light-induced structural change of PYP takes place
      in the main part and N-terminal 15 amino acid residues. The former induces only
      dimensional increase, but the latter results in additional change in shape.

PMID- 12427021
TI  - Binding of hsp90-associated immunophilins to cytoplasmic dynein: direct binding
      and in vivo evidence that the peptidylprolyl isomerase domain is a dynein
      interaction domain.
AB  - FKBP52 is a steroid receptor-associated immunophilin that binds via a
      tetratricopeptide repeat (TPR) domain to hsp90. FKBP52 has also been shown to
      interact either directly or indirectly via its peptidylprolyl isomerase (PPIase)
      domain with cytoplasmic dynein, a motor protein involved in retrograde transport
      of vesicles toward the nucleus. The functional role for the PPIase domain in
      receptor movement was demonstrated by showing that expression of the PPIase
      domain fragment of FKBP52 in 3T3 cells inhibits dexamethasone-dependent nuclear
      translocation of a green fluorescent protein-glucocorticoid receptor chimera.
      Here, we show that cytoplasmic dynein is co-immunoadsorbed with two other TPR
      domain proteins that bind hsp90 (the cyclophilin CyP-40 and the protein
      phosphatase PP5). Both proteins possess PPIase homology domains, and co
      immunoadsorption of cytoplasmic dynein with each is blocked by the PPIase domain
      fragment of FKBP52. Using purified proteins, we show that FKBP52, PP5, and the
      PPIase domain fragment bind directly to the intermediate chain of cytoplasmic
      dynein. PP5 colocalizes with both cytoplasmic dynein and microtubules, and
      expression of the PPIase domain fragment of FKBP52 in 3T3 cells disrupts its
      cytoskeletal localization. We conclude that the PPIase domains of the hsp90
      binding immunophilins interact directly with cytoplasmic dynein and that this
      interaction with the motor protein is responsible for the microtubular
      localization of PP5 in vivo.

PMID- 12427022
TI  - Deciphering the role of individual acyl chains in the interaction network between
      phosphatidylserines and a single-spanning membrane protein.
AB  - PMP1 is a small single-spanning membrane protein functioning as a regulatory
      subunit of the yeast plasma membrane H(+)-ATPase. This protein forms a unique
      helix and exhibits a positively charged cytoplasmic domain that is able to
      specifically segregate phosphatidylserines (PSs). A marked groove formed at the
      helix surface is thought to play a major role in the related lipid-protein
      interaction network. Mutational analysis and (1)H NMR experiments were therefore
      performed on a synthetic PMP1 fragment using DPC-d(38) micelles as a membrane
      like environment, in the presence of small amounts of POPS. A mutation designed
      for altering the helix groove was shown to disfavor the POPS binding specificity
      as much as that affecting the electrostatic interaction network. From POPS
      titration experiments monitored by a full set of one- and two-dimensional NOESY
      spectra, the association between the phospholipids and the PMP1 peptide has been
      followed. Our data reveal that the clustering of POPS molecules is promoted from
      a stabilized framework obtained by coupling the PMP1 helix groove to a POPS sn-2
      chain. To our knowledge, the NOE-based titration plots displayed in this report
      constitute the first NMR data that directly distinguish the role of the sn-1 and
      sn-2 acyl chains in a lipid-protein interaction. The results are discussed while
      taking into account our accurate knowledge of the yeast plasma membrane
      composition and its ability to form functional lipid rafts.

PMID- 12427023
TI  - Determining the membrane topology of proteins: insertion pathway of a
      transmembrane helix of annexin 12.
AB  - We describe a sensitive method for determining the bilayer topology of single
      site cysteine-linked NBD fluorescent labels on membrane proteins. Based upon a
      method developed for peptides [W. C. Wimley and S. H. White (2000) Biochemistry
      39, 161-170], it utilizes a novel fluorescence quencher, lysoUB, comprised of a
      single acyl chain attached to a UniBlue chromophore. The enhanced sensitivity of
      the method arises from the brightness of the NBD fluorescence and the quenching
      efficiency of lysoUB, which is not fluorescent. In the course of validating the
      method, we examined the insertion topology of the D-E helical region of repeat 2
      of annexin 12, known to adopt a transbilayer orientation at mildly acidic pH
      [Langen et al. (1998) Proc. Natl. Acad. Sci. USA 95, 14060-14065]. In the final
      membrane-inserted state, an NBD label attached to the single-cysteine mutant
      D134C was found to be in the outer (cis) leaflet, while the one attached to D162C
      was found in the trans leaflet. But kinetic measurements of NBD fluorescence
      suggested the existence of a transient intermediate insertion state whose
      lifetime could be increased by increasing the fraction of anionic lipids in the
      vesicles. Indeed, the lifetime could be increased for times sufficient for the
      completion of lysoUB-NBD topology measurements. Such measurements revealed that
      the D-E region adopts an interfacial topology in the intermediate state with both
      ends on the cis side of the membrane, consistent with the general concept of
      interface-directed membrane insertion of proteins [White et al. (2001) J. Biol.
      Chem. 276, 32395-32398].

PMID- 12427024
TI  - Studies of the mechanism of phenol hydroxylase: effect of mutation of proline 364
      to serine.
AB  - An active site residue in phenol hydroxylase (PHHY), Pro364, was mutated to
      serine to investigate its role in enzymatic catalysis. In the presence of phenol,
      the reaction between the reduced flavin of P364S and oxygen is very fast, but
      only 13% of the flavin is utilized to hydroxylate the substrate, compared to
      nearly 100% for the wild-type enzyme. The oxidative half-reaction of PHHY using m
      cresol as a substrate is similarly affected by the mutation. Pro364 was suggested
      to be important in stabilizing the transition state of the oxygen transfer step
      by forming a hydrogen bond between its carbonyl oxygen and the C4a
      hydroperoxyflavin [Ridder, L., Mullholland, A. J., Rietjens, I. M. C. M., and
      Vervoort, J. (2000) J. Am. Chem. Soc. 122, 8728-8738]. The P364S mutation may
      weaken this interaction by increasing the flexibility of the peptide chain;
      hence, the transition state would be destabilized to result in a decreased level
      of hydroxylation of phenol. However, when the oxidative half-reaction was studied
      using resorcinol as a substrate, the P364S mutant form was not significantly
      different from the wild-type enzyme. The rate constants for all the reaction
      steps as well as the hydroxylation efficiency (coupling between NADPH oxidation
      and resorcinol consumption) are comparable to those of the wild-type enzyme. It
      is suggested that the function of Pro364 in catalysis, stabilization of the
      transition state, is not as important in the reaction with resorcinol, possibly
      because the position of hydroxylation is different with resorcinol than with
      phenol and m-cresol.

PMID- 12427025
TI  - Binding of dioxygen to non-metal sites in proteins: exploration of the importance
      of binding site size versus hydrophobicity in the copper amine oxidase from
      Hansenula polymorpha.
AB  - Copper amine oxidases (CAOs) contain 2,4,5-trihydroxyphenylalanyl quinone (TPQ)
      and a copper ion in their active sites, catalyzing amine oxidation to aldehyde
      and ammonia concomitant with the reduction of molecular oxygen to hydrogen
      peroxide. Kinetic studies on the CAO from bovine serum (BSAO) [Su and Klinman
      (1999) Biochemistry 37, 12513-12525] and the recent reports on the cobalt
      substituted form of the enzyme from Hansenula polymorpha (HPAO) [Mills and
      Klinman (2000) J. Am. Chem. Soc. 122, 9897-9904, and Mills et al. (2002)
      Biochemistry, 41, 10577-10584] support pre-binding of molecular oxygen prior to a
      rate-limiting electron transfer from the reduced form of TPQ (p-aminohydroquinone
      form) to dioxygen. Although there is significant sequence homology between BSAO
      and HPAO, k(cat)/K(m)(O2) for BSAO under the optimal condition is one order of
      magnitude lower than that for HPAO. From a comparison of amino acid sequences for
      BSAO and HPAO, together with the X-ray crystal structure of HPAO, a plausible
      dioxygen pre-binding site has been identified that involves Y407, L425, and M634
      in HPAO; the latter two residues are altered in BSAO to A490 and T695. To
      determine which of these residues plays a greater role in dioxygen chemistry,
      k(cat)/K(m)(O2) was determined in HPAO for the M634 --> T and L425 --> A mutants.
      The L425 --> A mutation does not alter k(cat)/K(m)(O2) to a large extent, whereas
      the M634 --> T decreased k(cat)/K(m)(O2) by one order of a magnitude, creating a
      catalyst that is similar to BSAO. A series of mutants at M634 (to F, L, and Q)
      were, therefore, prepared in HPAO and characterized with regard to
      k(cat)/K(m)(O2) as a function of pH. Structure reactivity correlations show a
      linear relationship of rate with side chain volume, rather than hydrophobicity,
      indicating that dioxygen reactivity increases with the bulk of the residue at
      position 634. This site also shows specificity for O2, in relation to the co-gas
      N2, since substitution of the inert gas N2 by either Ar or He has no effect on
      measured rates. In particular, He gas is expected to have little affinity for
      protein at 1 atmospheric pressure, implying little or no binding by N2 as well.

PMID- 12427026
TI  - Identification of a binding site for ganglioside on the receptor binding domain
      of tetanus toxin.
AB  - The carboxyl-terminal region of the tetanus toxin heavy chain (H(C) fragment)
      binds to di- and trisialylgangliosides on neuronal cell membranes. To determine
      which amino acids in tetanus toxin are involved in ganglioside binding, homology
      modeling was performed using recently resolved X-ray crystallographic structures
      of the tetanus toxin H(C) fragment. On the basis of these analyses, two regions
      in tetanus toxin that are structurally homologous with the binding domains of
      other sialic acid and galactose-binding proteins were targeted for mutagenesis.
      Specific amino acids within these regions were altered using site-directed
      mutagenesis. The amino acid residue tryptophan 1288 was found to be critical for
      binding of the H(C) fragment to ganglioside GT1b. Docking of GD1b within this
      region of the toxin suggested that histidine 1270 and aspartate 1221 were within
      hydrogen bonding distance of the ganglioside. These two residues were mutagenized
      and found also to be important for the binding of the tetanus toxin H(C) fragment
      to ganglioside GT1b. In addition, the H(C) fragments mutagenized at these
      residues have reduced levels of binding to neurites of differentiated PC-12
      cells. These studies indicate that the amino acids tryptophan 1288, histidine
      1270, and aspartate 1221 are components of the GT1b binding site on the tetanus
      toxin H(C) fragment.

PMID- 12427027
TI  - Opening the KcsA K+ channel: tryptophan scanning and complementation analysis
      lead to mutants with altered gating.
AB  - The properties of the KcsA channel were investigated using a combination of
      tryptophan scanning of the two transmembrane helices followed by random
      mutagenesis at targeted residues. The tryptophan mutants were subjected to two
      screens: oligomeric stability and ability to complement the K+ uptake deficiency
      of the TK2420 Escherichia coli strain. Oligomeric stability is affected primarily
      by mutations at sites that border on and interact with the selectivity filter,
      while the complementation assays identified residues at the crossing point of the
      inner helices. Sites identified by the complementation assay in the tryptophan
      screen were subjected to random mutagenesis and selection by complementation. We
      have found two mutants, A108S and A108T, which have dramatically increased open
      probability while retaining the basic property of oligomeric stability.

PMID- 12427028
TI  - A highly conserved arginine is critical for the functional folding of inhibitor
      of apoptosis (IAP) BIR domains.
AB  - The inhibitor of apoptosis (IAP) proteins are found in all animals and regulate
      apoptosis (programmed cell death) by binding and inhibiting caspase proteases.
      This inhibition is overcome by several apoptosis stimulators, including
      Drosophila Hid and mammalian Smac/DIABLO, which bind to 65-residue baculovirus
      IAP repeat (BIR) domains found in one to three copies in all IAPs. Virtually all
      BIRs contain three Cys and a His that bind zinc, a Gly in a tight turn, and an
      Arg. The functional and structural role of the Arg was investigated in isolated
      BIR domains from the baculovirus Orgyia pseudotsugata Op-IAP and the Drosophila
      DIAP1 proteins. Mutation of the Arg to either Ala or Lys abolished Hid and Smac
      binding to BIRs, despite the Hid/Smac binding site being located on the opposite
      side of the BIR domain from the Arg. The mutant BIR domains also exhibited
      weakened zinc binding, increased sensitivity to limited proteolysis, and altered
      circular dichroism spectra indicative of perturbed domain folding. Examination of
      known BIR structures indicates that the Arg side chain makes simultaneous
      bridging hydrogen bonds and a cation-pi interaction for which the Arg guanidino
      group is uniquely well suited. These interactions are likely critical for
      stabilizing the tertiary fold of BIR domains in all IAPs, explaining the
      conservation of this residue.

PMID- 12427029
TI  - Ligand-induced structural changes in adenosine 5'-phosphosulfate kinase from
      Penicillium chrysogenum.
AB  - Adenosine 5'-phosphosulfate (APS) kinase catalyzes the second reaction in the two
      step, ATP-dependent conversion of inorganic sulfate to 3'-phosphoadenosine 5'
      phosphosulfate (PAPS). PAPS serves as the sulfuryl donor for the biosynthesis of
      all sulfate esters and also as a precursor of reduced sulfur biomolecules in many
      organisms. Previously, we determined the crystal structure of ligand-free APS
      kinase from the filamentous fungus, Penicillium chrysogenum [MacRae et al. (2000)
      Biochemistry 39, 1613-1621]. That structure contained a protease-susceptible
      disordered region ("mobile lid"; residues 145-170). Addition of MgADP and APS,
      which together promote the formation of a nonproductive "dead-end" ternary
      complex, protected the lid from trypsin. This report presents the 1.43 A
      resolution crystal structure of APS kinase with both ADP and APS bound at the
      active site and the 2.0 A resolution structure of the enzyme with ADP alone
      bound. The mobile lid is ordered in both complexes and is shown to provide part
      of the binding site for APS. That site is formed primarily by the highly
      conserved Arg 66, Arg 80, and Phe 75 from the protein core and Phe 165 from the
      mobile lid. The two Phe residues straddle the adenine ring of bound APS. Arg 148,
      a completely conserved residue, is the only residue in the mobile lid that
      interacts directly with bound ADP. Ser 34, located in the apex of the P-loop,
      hydrogen-bonds to the 3'-OH of APS, the phosphoryl transfer target. The structure
      of the binary E.ADP complex revealed further changes in the active site and N
      terminal helix that occur upon the binding/release of (P)APS.

PMID- 12427030
TI  - Tyr266 in the sixth transmembrane domain of the yeast alpha-factor receptor plays
      key roles in receptor activation and ligand specificity.
AB  - To identify interactions between Ste2p, a G protein-coupled receptor of the yeast
      Saccharomyces cerevisiae, and its tridecapeptide ligand, alpha-factor
      (WHWLQLKPGQPMY), a variety of alpha-factor analogues were used in conjunction
      with site-directed mutagenesis of a targeted portion of Ste2p transmembrane
      domain six. Alanine substitution of residues in the 262-270 region of Ste2p did
      not affect pheromone binding or signal transduction, except for the Y266A mutant,
      which did not transduce signal yet exhibited only a small decrease in alpha
      factor binding affinity. Substitutions with Ser, Leu, or Lys at Y266 also
      generated signaling-defective receptors. In contrast, Phe or Trp substitution at
      Y266 retained receptor function, suggesting that aromaticity at this position was
      critical. When coexpressed with WT receptor, the Y266A receptor exhibited a
      strong dominant-negative phenotype, indicating that this mutant bound G protein.
      A partial tryptic digest revealed that, in the presence of agonist, a different
      digestion profile for Y266A receptor was generated in comparison to that for WT
      receptor. The difference in trypsin-sensitive sites and their negative dominance
      indicated that the Y266A receptor was not able to switch into an "activated"
      conformation upon ligand binding. In comparison to WT Ste2p, the mutantY266A
      receptor showed increased binding affinity for N-terminal, alanine-substituted
      alpha-factor analogues (residues 1-4) and the antagonist [desW(1),desH(2)]alpha
      factor. A substantial decrease in affinity was observed for alpha-factor
      analogues with Ala substitutions from residues 5-13. The results suggest that
      Y266 is part of the binding pocket that recognizes the N-terminal portion of
      alpha-factor and is involved in the transformation of Ste2p into an activated
      state upon agonist binding.

PMID- 12427031
TI  - Characterization and membrane assembly of the TatA component of the Escherichia
      coli twin-arginine protein transport system.
AB  - Proteins bearing a signal peptide with a consensus twin-arginine motif are
      translocated via the Tat pathway, a multiprotein system consisting minimally of
      the integral inner membrane proteins TatA, TatB, and TatC. On a molar basis, TatA
      is the major pathway component. Here we show that TatA can be purified
      independently of the other Tat proteins as a 460 kDa homooligomeric complex.
      Homooligomer formation requires the amino-terminal membrane-anchoring domain of
      TatA. According to circular dichroism spectroscopy, approximately half of the
      TatA polypeptide forms alpha-helical secondary structure in both detergent
      solution and proteoliposomes. An expressed construct without the transmembrane
      segment is largely unstructured in aqueous solution but is able to insert into
      phospholipid monolayers and interacts with membrane bilayers. Protease
      accessibility experiments indicate that the extramembranous region of TatA is
      located at the cytoplasmic face of the cell membrane.

PMID- 12427032
TI  - Isoprenoids influence expression of Ras and Ras-related proteins.
AB  - Mevalonate depletion by inhibition of hydroxymethylglutaryl coenzyme A reductase
      impairs post-translational processing of Ras and Ras-related proteins. We have
      previously shown that this mevalonate depletion also leads to the upregulation of
      Ras, Rap1a, RhoA, and RhoB. This upregulation may result from global inhibition
      of isoprenylation or depletion of key regulatory isoprenoid species. Studies
      utilizing specific isoprenoid pyrophosphates in mevalonate-depleted cells reveal
      that farnesyl pyrophosphate (FPP) restores Ras processing and prevents RhoB
      upregulation while geranylgeranyl pyrophosphate (GGPP) restores Rap1a processing
      and prevents RhoA and RhoB upregulation. Either FPP or GGPP completely prevents
      lovastatin-induced upregulation of RhoB mRNA. Inhibition of FPP or squalene
      synthase allowed for the further identification of the putative regulatory
      species. Studies involving the specific isoprenyl transferase inhibitors FTI-277
      and GGTI-286 demonstrate that selective inhibition of protein isoprenylation does
      not mimic lovastatin's ability to increase Ras and RhoA synthesis, decrease Ras
      and RhoA degradation, increase RhoB mRNA, or increase total levels of Ras, Rap1a,
      RhoA, and RhoB. In aggregate, these findings reveal a novel role and mechanism
      for isoprenoids to influence levels of Ras and Ras-related proteins.

PMID- 12427033
TI  - Spontaneous transfer of phospholipid and cholesterol hydroperoxides between cell
      membranes and low-density lipoprotein: assessment of reaction kinetics and
      prooxidant effects.
AB  - Under oxidative pressure in the vascular circulation, erythrocytes and phagocytic
      cells may accumulate membrane lipid hydroperoxides (LOOHs), including cholesterol
      and phospholipid-derived species (ChOOHs, PLOOHs). LOOH translocation from cells
      to low-density lipoprotein (LDL) might sensitize the latter to free radical
      mediated oxidative modification, an early event associated with atherogenesis. To
      test this, we examined the spontaneous transfer kinetics of various ChOOH species
      (5 alpha-OOH, 6 alpha-OOH, 6 beta-OOH, 7 alpha/7 beta-OOH) and various PLOOH
      groups (PCOOH, PEOOH, PSOOH, SMOOH) using photoperoxidized erythrocyte ghosts as
      model donors and freshly prepared LDL as an acceptor. LOOH departure or uptake
      was monitored by reverse-phase HPLC with reductive electrochemical detection.
      Mildly peroxidized ghost membranes transferred overall ChOOH and PLOOH to LDL
      with apparent first-order rate constants approximately 60 and approximately 35
      times greater than those of the respective parent lipids. Individual ChOOH rate
      constants decreased in the following order: 7 alpha/7 beta-OOH > 5 alpha-OOH > 6
      alpha-OOH > 6 beta-OOH. Kinetics for reverse transfer from LDL to ghosts followed
      the same trend, but rates were significantly higher for all species and their
      combined activation energy was lower (41 vs 85 kJ/mol). PLOOH transfer rate
      constants ranged from 4- to 15-fold lower than the composite ChOOH constant,
      their order being as follows: PCOOH approximately PEOOH approximately PSOOH >
      SMOOH. Similar PLOOH transfer kinetics were observed when LDL acceptor was
      replaced by unilamellar liposomes, consistent with desorption from the donor
      membrane being the rate-limiting step. The susceptibility of transfer LOOH
      enriched LDL to Cu2+-induced chain peroxidative damage was assessed by monitoring
      the accumulation of conjugated dienes and products of free radical-mediated
      cholesterol oxidation. In both cases, transfer-acquired LOOHs significantly
      reduced the lag time for chain initiation relative to that observed using
      nonperoxidized ghosts. These findings are consistent with the idea that LDL can
      acquire significant amounts of "seeding" LOOHs via translocation from various
      donors in the circulation.

PMID- 12427034
TI  - Proteolytic cleavage of the developmentally important cadherin BT-R1 in the
      midgut epithelium of Manduca sexta.
AB  - BT-R1 (M(r) = 210 kDa) represents a new type of insect cadherin that is expressed
      specifically in the midgut epithelium during growth and development of Manduca
      sexta larvae. It also is a target receptor for the Cry1A toxins of the
      entomopathogenic bacterium Bacillus thuringiensis. Expression of BT-R1, which
      varies during larval development, correlates with the abundance of the protein
      and with the differential cleavage of the molecule at each developmental stage.
      The cleavage of BT-R1 is calcium dependent, and consequently, Ca2+ directly
      influences the structural integrity of BT-R1. Indeed, removal of calcium ions by
      chelating agents promotes cleavage of the BT-R1 ectodomain, resulting in
      formation of fragments that are similar to those observed during larval
      development. Partial purification of proteins from brush border membrane vesicles
      (BBMVs) by gel filtration chromatography hinders the cleavage of BT-R1 in the
      presence of EDTA and EGTA, indicating that there is specific proteolytic activity
      associated with the BBMV. This specific proteolytic cleavage of BT-R1 not only
      alters the integrity of BT-R1 but it most likely is implicated in cell adhesion
      events during differentiation and development of M. sexta midgut epithelium. We
      propose a model for calcium-dependent protection of BT-R1 as well as a cleavage
      pattern that may modulate the molecular interactions and adhesive properties of
      its ectodomain. Molecular characterization of such a protection mechanism should
      lead to a better understanding of how the function of specific cadherins is
      modulated during tissue differentiation and insect development.

PMID- 12427035
TI  - The beta 5' loop of the pancreatic lipase C2-like domain plays a critical role in
      the lipase-lipid interactions.
AB  - The structural similarities between the C-terminal domain of human pancreatic
      lipase (C-HPL) and C2 domains suggested a similar function, the interaction with
      lipids. The catalytic N-terminal domain (N-HPL) and C-HPL were produced as
      individual proteins, and their partitioning between the water phase and the
      triglyceride-water interface was assessed using trioctanoin emulsions (TC8). N
      HPL did not bind efficiently to TC8 and was inactive. C-HPL did bind to TC8 and
      to a phospholipid monolayer with a critical surface pressure of penetration
      similar to that of HPL (15 mN m(-1)). These experiments, performed in the absence
      of colipase and bile salts, support an absolute requirement of C-HPL for
      interfacial binding of HPL. To refine our analysis, we determined the
      contribution to lipid interactions of a hydrophobic loop (beta 5') in C-HPL by
      investigating a HPL mutant in which beta 5' loop hydrophobicity was increased by
      introducing the homologous lipoprotein lipase (LPL) beta 5' loop. This mutant
      (HPL-beta 5'LPL) penetrated into phospholipid monolayers at higher surface
      pressures than HPL, and its level of binding to TC8 was higher than that of HPL
      in the presence of serum albumin (BSA), an inhibitory protein that competes with
      HPL for interfacial adsorption. The beta 5' loop of LPL is therefore tailored for
      an optimal interaction with the surface of triglyceride-rich lipoproteins (VLDL
      and chylomicrons) containing phospholipids and apoproteins. These observations
      support a major contribution of the beta 5' loop in the interaction of LPL and
      HPL with their respective substrates.

PMID- 12427036
TI  - Spectroelectrochemical evaluation of redox potentials of cysteine
      tryptophylquinone and two hemes c in quinohemoprotein amine dehydrogenase from
      Paracoccus denitrificans.
AB  - Quinohemoprotein amine dehydrogenase (QH-AmDH) from Paracoccus denitrificans has
      a novel cofactor cysteine tryptophylquinone (CTQ) in the smallest gamma subunit
      and two hemes c in the largest alpha subunit [Datta, S., Mori, Y., Takagi, K.,
      Kawaguchi, K., Chen, Z., Okajima, T., Kuroda, S., Ikeda, T., Kano, K., Tanizawa,
      K., and Mathews, F. S. (2001) Proc. Natl. Acad. Sci. U.S.A. 98, 14268-14273]. The
      spectral change of QH-AmDH was assigned to the redox reaction of the hemes c
      alone. The redox potentials of the two hemes c with His and Met as the second
      axial ligands, respectively, were determined to be 0.149 and 0.235 V versus SHE
      at pH 7.0 by a mediator-assisted continuous-flow column electrolytic
      spectroelectrochemistry (MCES). The monomeric gamma subunit of QH-AmDH was
      isolated from urea-treated QH-AmDH. The fully oxidized and reduced forms of the
      gamma subunit exhibited a unique absorption band centered at 380 nm and a
      shoulder band around 315 nm, respectively, at neutral pH. The two-electron redox
      potential of CTQ in the isolated gamma subunit was evaluated to be 65 mV at pH
      7.0 by MCES. The redox reaction was linked to the two-proton transfer at pH <8.6
      and to a single-proton transfer at pH >8.6. The pK(a) value (K(a) being the acid
      dissociation constant) of 8.6 was assigned to one of the phenolic OH groups of
      the quinol form. Upon deprotonation, the red shift of the shoulder band was
      observed. The gamma subunit adsorbed on a glassy carbon electrode, and gave a
      direct but quasi-reversible electrochemical signal. Intra- and interprotein
      electron transfers of QH-AmDH are discussed from thermodynamic and structural
      points of view.

PMID- 12427037
TI  - From two-state to three-state: the effect of the P61A mutation on the dynamics
      and stability of the factor for inversion stimulation results in an altered
      equilibrium denaturation mechanism.
AB  - Factor for inversion stimulation (FIS) is a 22 kDa homodimeric protein found in
      enteric bacteria that is involved in the stimulation of certain DNA recombination
      events and transcription regulation of many genes. FIS has a central helix with a
      20 degrees kink, which is only reduced by 4 degrees after a proline 61 to alanine
      mutation (P61A). This mutation appears to have little effect on FIS function, yet
      it is striking that proline 61 is highly conserved among fis genes. Therefore, we
      studied the role of proline 61 on the stability and flexibility of FIS. The urea
      induced equilibrium denaturation of P61A FIS was monitored by circular dichroism
      and fluorescence anisotropy. Despite the apparent two-state transition, the
      concentration dependence of the transition slope (m value) shows that a two-state
      model, as seen for wild-type (WT) FIS, did not adequately describe the
      denaturation of P61A FIS. Global fitting of the data indicates that the
      denaturation of P61A FIS occurs via a three-state process involving a dimeric
      intermediate and has an overall DeltaG(H2O) for unfolding of 18.6 kcal/mol, 4
      kcal/mol higher than that for WT FIS. Limited trypsin proteolysis experiments
      show that the DNA binding C-terminus of P61A FIS is more labile to cleavage than
      that of WT FIS, suggesting an increased flexibility of this region in P61A FIS.
      In contrast, the resulting dimeric core (residues 6-71) of P61A FIS is more
      resistant to proteolysis, consistent with the presence of a dimeric intermediate
      not seen in WT FIS. Model transition curves generated using the parameters
      obtained by global fitting predicted a two-state-like transition at low P61A
      concentrations that becomes less cooperative with increasing protein
      concentration, as was experimentally observed. At concentrations of P61A FIS much
      higher than are experimentally feasible, a biphasic transition is predicted.
      Thus, this work demonstrates that a single mutation may be sufficient to alter a
      protein's denaturation mechanism and underscores the importance of analyzing the
      denaturation mechanism of oligomeric proteins over a wide concentration range.
      These results suggest that proline 61 in FIS may be conserved in order to
      optimize the global stability and the dynamics of the functionally important C
      terminus.

PMID- 12427038
TI  - Zinc is required for the catalytic activity of the human deubiquitinating
      isopeptidase T.
AB  - Two recombinant human isopeptidase T isoforms, ISOT-S and ISOT-L, differing by an
      insertion of 23 amino acids in ISOT-L, were previously classified as thiol
      proteases. Both contain one Zn2+-binding site of high-affinity, which is part of
      a cryptic nitrilo-triacetate-resistant pocket (site 1). A second Zn2+ site (site
      2) was disclosed when both isoforms of the holoenzyme were incubated with an
      excess of Zn2+. The firmly bound Zn2+ of site 1 could be removed either slowly by
      dialysis against 1,10-phenanthroline at pH 5.5 or rapidly by treatment at pH 3.0
      in the presence of 6 M urea followed by gel filtration at neutral pH. Zn2+ in
      site 1, but not in site 2, is essential for proteolytic activity because
      apoproteins were inactive. Inhibition of the catalytic activity was not due to a
      loss of ubiquitin binding capacity. CD spectra of both isoforms disclosed no
      major structural differences between the apo- and holoenzymes. The reconstitution
      of apoenzyme with Zn2+ under nondenaturing conditions at pH 5.5 completely
      restored enzymatic activity, which was indistinguishable from the reconstitution
      carried out in urea at pH 3.0. Thus, both human ISOTs are either thiol proteases
      with a local structural Zn2+ or monozinc metalloproteases that might use in
      catalysis a Zn2+-activated hydroxide ion polarized by Cys335.

PMID- 12427039
TI  - Biochemical and mass spectrometric evidence for quaternary structure
      modifications of plant threonine deaminase induced by isoleucine.
AB  - Arabidopsis thaliana threonine deaminase (TD) is a tetramer composed of identical
      approximately 59600 Da subunits. TD activity has been shown to be inhibited by
      isoleucine. This effect is reversed by a large excess of valine. Nondenaturant
      gel filtration, polyacrylamide gel electrophoresis, and mass spectrometry
      experiments demonstrated that binding of isoleucine on TD induces dimerization of
      the enzyme, whereas tetramerization is restored by addition of a high valine
      concentration. Nondenaturant gel filtration and electrospray ionization mass
      spectrometry of the enzyme in the presence of increasing amounts of isoleucine
      suggest a fast equilibrium between the tetramer and the dimer. Finally, study of
      TD mutants allowed us to focus on the specific role of each isoleucine-binding
      site.

PMID- 12427040
TI  - Substrate binding and catalytic mechanism in ascorbate peroxidase: evidence for
      two ascorbate binding sites.
AB  - The catalytic mechanism of recombinant soybean cytosolic ascorbate peroxidase
      (rsAPX) and a derivative of rsAPX in which a cysteine residue (Cys32) located
      close to the substrate (L-ascorbic acid) binding site has been modified to
      preclude binding of ascorbate [Mandelman, D., Jamal, J., and Poulos, T. L. (1998)
      Biochemistry 37, 17610-17617] has been examined using pre-steady-state and steady
      state kinetic techniques. Formation (k1 = 3.3 +/- 0.1 x 10(7) M(-1) s(-1)) of
      Compound I and reduction (k(2) = 5.2 +/- 0.3 x 10(6) M(-1) s(-1)) of Compound I
      by substrate are fast. Wavelength maxima for Compound I of rsAPX (lambda(max)
      (nm) = 409, 530, 569, 655) are consistent with a porphyrin pi-cation radical.
      Reduction of Compound II by L-ascorbate is rate-limiting: at low substrate
      concentration (0-500 microM), kinetic traces were monophasic but above
      approximately 500 microM were biphasic. Observed rate constants for the fast
      phase overlaid with observed rate constants extracted from the (monophasic)
      dependence observed below 500 microM and showed saturation kinetics; rate
      constants for the slow phase were linearly dependent on substrate concentration
      (k(3-slow)) = 3.1 +/- 0.1 x 10(3) M(-1) s(-1)). Kinetic transients for reduction
      of Compound II by L-ascorbic acid for Cys32-modified rsAPX are monophasic at all
      substrate concentrations, and the second-order rate constant (k(3) = 0.9 +/- 0.1
      x 10(3) M(-1) s(-1)) is similar to that obtained from the slow phase of Compound
      II reduction for unmodified rsAPX. Steady-state oxidation of L-ascorbate by rsAPX
      showed a sigmoidal dependence on substrate concentration and data were
      satisfactorily rationalized using the Hill equation; oxidation of L-ascorbic acid
      by Cys32-modified rsAPX showed no evidence of sigmoidal behavior. The data are
      consistent with the presence of two kinetically competent binding sites for
      ascorbate in APX.

PMID- 12427041
TI  - Structural and functional implications of C-terminal regions of alpha-synuclein.
AB  - Aggregation of alpha-synuclein is thought to play a major role in the
      pathogenesis of Parkinson's disease (PD), which is characterized by the presence
      of intracytoplasmic Lewy bodies (LB) in the brain. alpha-Synuclein and its
      deletion mutants are largely unfolded proteins with random coil structures as
      revealed by CD spectra, fluorescence spectra, gel filtration chromatography, and
      ultracentrifugation. On the basis of its highly unfolded and flexible
      conformation, we have investigated the chaperone-like activity of alpha-synuclein
      in vitro. In our experiments, alpha-synuclein inhibited the aggregation of model
      substrates and protected the catalytic activity of alcohol dehydrogenase and
      rhodanese during heat stress. In addition, alpha-synuclein inhibited the initial
      aggregation of reduced/denatured lysozyme on the refolding pathway.
      Interestingly, deletion of the C-terminal regions led to the abolishment of
      chaperone activity, although largely unstructured conformations are maintained.
      Moreover, alpha-synuclein could inhibit the aggregation of various Escherichia
      coli cellular proteins during heat stress, and C-terminal deletion mutants could
      not provide any protection to these cellular proteins. Results with synthetic C
      terminal peptides and C-terminal deletion mutants suggest that the second acidic
      repeat, (125)YEMPSEEGYQDYEPEA(140), is important for the chaperone activity of
      alpha-synuclein, and C-terminal deletion leads to the facilitated aggregation
      with the elimination of chaperone activity.

PMID- 12427042
TI  - Robustness of the long-range structure in denatured staphylococcal nuclease to
      changes in amino acid sequence.
AB  - A nativelike low-resolution structure has been shown to persist in the Delta 131
      Delta denatured fragment of staphylococcal nuclease, even in the presence of 8 M
      urea. In this report, the physical-chemical basis of this structure is addressed
      by monitoring changes in structure reflected in residual dipolar couplings and
      diffusion coefficients as a function of changes in amino acid sequence. Ten large
      hydrophobic residues, previously shown to play dominant roles in the stability of
      the native state, are replaced with polar residues of similar shape. Modest
      increases in the Stokes radius determined by NMR methods result from replacement
      of five isoleucine/valine residues with threonine, one leucine with glutamine,
      and oxidation of four methionines to the sulfoxides. Yet in the presence of all
      ten hydrophobic to polar substitutions and 8 M urea, the NMR signature of a
      native-like topology is still largely intact. In addition, removal of 30 residues
      from either the N-terminus (which deletes a three-strand beta meander) or C
      terminus (a long extended segment and the final alpha helix) produces only very
      small changes in long-range structure. These data indicate that both the general
      shape of the denatured state and the angular relationships of individual bond
      angles to the axes describing the spatial distribution of the protein chain are
      insensitive to large changes in the amino acid sequence, a finding consistent
      with the conclusion that the long-range structure of denatured proteins is
      encoded primarily by local steric interactions between side chains and the
      polypeptide backbone.

PMID- 12427043
TI  - The conformations of filamentous and soluble tau associated with Alzheimer paired
      helical filaments.
AB  - Paired helical filaments (PHF) occur in Alzheimer's diseased brains and are known
      to be composed of the microtubule-associated protein, tau. In the present report,
      circular dichroism (CD) spectroscopy and transmission electron microscopy (TEM)
      were used to characterize PHF suspended in Tris-buffered saline (TBS), sodium
      acetate buffer, and water. In TBS the CD spectrum of PHF was observed to have a
      spectral pattern consistent with 31-37% alpha-helix, 15-20% beta-sheet, 20-23%
      turn, and 26-29% unordered structure. The TBS sample was found to undergo a
      cooperative thermal transition between 70 and 75 degrees C, consistent with the
      changes observed in filament morphology, and it suggests that filamentous tau in
      the PHF (PHF-tau) makes a substantial contribution to the overall CD. Observed
      changes in the CD spectrum following removal of PHF by centrifugation suggest
      that PHF-tau possesses a higher fraction of alpha-helical structure than soluble
      tau. In acetate buffer, where only straight filaments were observed, the CD was
      consistent with a marked decrease in the fraction of alpha-helix and an increase
      in the fraction of beta-sheet relative to the sample in TBS. In water, where only
      rudimentary filaments remain, the CD was consistent with a Type II or II' beta
      turn conformation. Only noncooperative thermal transitions were observed for the
      PHF samples in acetate buffer and water, consistent with the presence of a
      heterogeneous population of folded structures. Taken cumulatively, the results
      are consistent with immunological data showing the presence of folded forms of
      tau and suggest that phosphorylation or nonproteinaceous components are able to
      induce conformations of tau other than the random coil conformation previously
      reported for cloned or purified human tau.

PMID- 12427044
TI  - Stabilization of protein by replacement of a fluctuating loop: structural
      analysis of a chimera of bovine alpha-lactalbumin and equine lysozyme.
AB  - Equine lysozyme is a calcium-binding lysozyme and an evolutional intermediate
      between non-calcium binding c-type lysozyme and alpha-lactalbumin. We constructed
      a chimeric protein by substituting the fluctuating loop of bovine alpha
      lactalbumin with the D-helix of equine lysozyme. The substitution affects the
      protection factors not only in the fluctuating loop but also in the antiparallel
      beta-sheet, the A- and B-helices, and the loop between the B-helix and the beta
      sheet. Amide protons in these regions of the chimera are more protected from
      exchange than are those of bovine alpha-lactalbumin. We used model-free analysis
      based on 15N nuclear magnetic resonance relaxation measurements to investigate
      the dynamics of the main chain of the chimera and showed that the fluctuating
      loop of the chimera is as rigid as three major helices. When we analyzed the
      chemical shift deviations and backbone HN-H(alpha) scalar coupling constants, we
      found that the chimera showed an alpha-helical tendency in residues around the
      fluctuating loop. Our results suggest that the replacement of a highly
      fluctuating loop in a protein with a rigid structural element in a homologous one
      may be useful to stabilize the protein structure.

PMID- 12427045
TI  - Temperature dependence of the internal dynamics of a calmodulin-peptide complex.
AB  - The temperature dependence of the fast internal dynamics of calcium-saturated
      calmodulin in complex with a peptide corresponding to the calmodulin-binding
      domain of the smooth muscle myosin light chain kinase is examined using 15N and
      2H NMR relaxation methods. NMR relaxation studies of the complex were carried out
      at 13 temperatures that span 288-346 K. The dynamics of the backbone and over
      four dozen methyl-bearing side chains, distributed throughout the calmodulin
      molecule, were probed. The side chains show a much more variable and often
      considerably larger response to temperature than the backbone. A significant
      variation in the temperature dependence of the amplitude of motion of individual
      side chains is seen. The amplitude of motion of some side chains is essentially
      temperature-independent while many show a simple roughly linear temperature
      dependence. In a few cases, angular order increases with temperature, which is
      interpreted as arising from interactions with neighboring residues. In addition,
      a number of side chains display a nonlinear temperature dependence. The
      significance of these and other results is illuminated by several simple
      interpretative models. Importantly, analysis of these models indicates that
      changes in generalized order parameters can be robustly related to corresponding
      changes in residual entropy. A simple cluster model that incorporates features of
      cooperative or conditional motion reproduces many of the unusual features of the
      experimentally observed temperature dependence and illustrates that side chain
      interactions result in a dynamically changing environment that significantly
      influences the motion of internal side chains. This model also suggests that the
      intrinsic entropy of interacting clusters of side chains is only modestly reduced
      from that of independent side chain motion. Finally, estimates of protein heat
      capacity support the view that the major contribution to the heat capacity of
      protein solutions largely arises from local bond vibrations and solvent
      interactions and not from torsional oscillations of side chains.

PMID- 12427046
TI  - Mutagenesis by acrolein-derived propanodeoxyguanosine adducts in human cells.
AB  - Acrolein, which is widely spread in the environment and is produced by lipid
      peroxidation in cells, reacts with DNA to form two exocyclic 1,N2
      propanodeoxyguanosine (PdG) adducts. To establish their relative contribution to
      the acrolein mutagenicity, the genotoxic properties of alpha-OH-PdG and gamma-OH
      PdG together with their model DNA adduct, PdG, were studied in human cells. DNA
      adducts were incorporated site-specifically into a SV40/BK virus origin-based
      shuttle vector and replicated in xeroderma pigmentosum complementation group A
      (XPA) cells. Analysis of progeny plasmid revealed that alpha-OH-PdG and PdG
      strongly block DNA synthesis and that both adducts induced base substitutions
      with G --> T transversions predominating. Primer extension studies, catalyzed by
      the 3'-->5' exonuclease-deficient Klenow fragment of Escherichia coli pol I,
      revealed limited extension from the 3' primer termini opposite these two adducts.
      In contrast, gamma-OH-PdG did not strongly block DNA synthesis or miscode in XPA
      cells. Primer extension from a dC terminus opposite gamma-OH-PdG was much more
      efficient than that opposite alpha-OH-PdG or PdG. These results indicate that the
      minor alpha-OH-PdG adduct is more genotoxic than the major gamma-OH-PdG.
      Furthermore, experiments using a HeLa whole cell extract indicate that all three
      DNA adducts are not efficiently removed from DNA by base excision repair.

PMID- 12427047
TI  - Identification of the first fungal NADP-GAPDH from Kluyveromyces lactis.
AB  - Deletion of the phosphoglucose isomerase gene, PGI1, in Saccharomyces cerevisiae
      leads to a phenotype for which glucose is toxic. This is related to
      overproduction of NADPH through the oxidative part of the pentose phosphate
      pathway and the incompetence of S. cerevisiae to deal with this overproduction. A
      similar deletion (rag2) in Kluyveromyces lactis does not lead to such a
      phenotype. We transformed a genomic library of K. lactis in a yeast vector to a
      S. cerevisiae strain with a pgi1 deletion and screened for growth on glucose. We
      found a gene (GDP1) which encodes a phosphorylating glyceraldehyde-3-phosphate
      dehydrogenase, NADP-GAPDH (EC 1.2.1.13), that accepts both NADP and NAD. This is
      the first report of a eukaryotic, nonplant, NADP-linked GAPDH. Presumably,
      operation of this enzyme in the reverse direction enabled the transformed S.
      cerevisiae pgi1 deletion mutant to reoxidize the excess NADPH produced when
      glucose catabolism was forced through the pentose pathway. On the other hand,
      transcription of the gene in K. lactis was upregulated during growth on D-xylose,
      which suggests that in K. lactis the enzyme is involved in regeneration of NADPH
      needed for xylose assimilation, but transcription was not detected in a rag2
      mutant grown on glucose. The presence of an asparagine (Asn46 in NADP-GAPDH)
      instead of the conserved aspartate found in related but NAD-specific enzymes may
      explain the ability of NADP-GAPDH to work with NADP as well as NAD.

PMID- 12427048
TI  - Chloride cofactor in the photosynthetic oxygen-evolving complex studied by
      fourier transform infrared spectroscopy.
AB  - Fourier transform infrared (FTIR) spectroscopy, using midfrequency S2/S1 FTIR
      difference spectra, has been applied to studies of chloride cofactor in the
      photosynthetic oxygen-evolving complex (OEC) to determine the effects of Cl(-)
      depletion and monovalent anion substitution. Cl(-) depletion resulted in the
      disappearance of a large part of the amide I and II vibrational modes, and
      induced characteristic modification in the features of the stretching modes of
      the carboxylate ligands of the Mn cluster. The normal spectral features were
      largely restored by replenishment of Cl(-) except for some changes in amide
      bands. The overall features of Br(-) -, I(-) -, or NO3(-) -substituted spectra
      were similar to those of the Cl(-) -reconstituted spectrum, consistent with their
      ability to support oxygen evolution. In contrast, the spectrum was significantly
      altered by the replacement of Cl(-) with F- or CH3COO(-), which resulted in
      marked suppression and distortion of both the carboxylate and amide bands. The
      activity of oxygen evolution restored by NO3(-) was as high as that by Cl(-) when
      measured under limited light conditions, indicating that the NO3(-) -substituted
      OEC is fully active in oxygen evolution, although with a slow turnover rate. The
      double-difference spectrum between the 14NO3(-) -substituted and 15NO3- 
      substituted S2/S1 difference spectrum showed isotopic bands for asymmetric NO
      stretching mode in the region of 1400-1300 cm(-1) due to NO3(-) bound to the Cl(
      ) site. This demonstrated structural coupling between the Cl(-) site and the Mn
      cluster. A proposed model for the isotopic bands suggested that Cl(-) as well as
      NO3(-) is not directly associated with the Mn cluster and exists in a more
      symmetric configuration and weaker binding state in the S2 state than in the S1
      state. These results also suggest that Cl(-) is required for changes in the
      structure of the specific carboxylate ligand of the Mn cluster as well as the
      peptide backbone of protein matrixes upon the transition from S1 to S2.

PMID- 12427049
TI  - Core temperature measurement: methods and current insights.
AB  - Climatic injuries, including hypothermia, hyperthermia and heat stroke, are
      common in many sports activities. Body core temperature (T(c)) measurement for
      the sportsperson can influence individual performance and may help to prevent
      injuries. Monitoring internal body T(c) accurately requires invasive methods of
      measurement. The mercury thermometer, most commonly used to measure oral
      temperature (T(oral)), has been almost exclusively the only instrument for
      measuring T(c) since the 18th century. Rectal (T(re)) and oesophageal
      temperatures (T(oes)) have been the most preferred measurement sites employed in
      thermoregulatory investigations. However, these measurement sites (T(re), T(oes),
      T(oral)), and the methods used to measure T(c) at these sites, are not
      convenient. T(oral) measurements are not always possible or accurate. T(oes) is
      undesirable because of the difficulty of inserting the thermistor, irritation to
      nasal passages and general subject discomfort. T(re) is not suitable under many
      circumstances as it is labour intensive and has a prolonged response time.
      However, T(re) remains the most accurately available method for monitoring T(c)
      in thermal illness that occurs during sports activities. In addition, T(re) and
      T(oes) require wire connections between the thermistor and the monitoring device.
      The purpose of this paper is to review the various existing methods of T(c)
      measurements in order to focus on the breakthrough needed for a simple,
      noninvasive, universally used device for T(c) measurement which is essential for
      preventing climatic injuries during sports events.

PMID- 12427050
TI  - Dietary recommendations and athletic menstrual dysfunction.
AB  - Exercise-induced or athletic menstrual dysfunction (amenorrhoea, oligomenorrhoea,
      anovulation, luteal phase deficiency, delayed menarche) is more common in active
      women and can significantly affect health and sport performance. Although
      athletic amenorrhoea represents the most extreme form of menstrual dysfunction,
      other forms can also result in suppressed estrogen levels and affect bone health
      and fertility. A number of factors, such as energy balance, exercise intensity
      and training practices, bodyweight and composition, disordered eating behaviours,
      and physical and emotional stress levels, may contribute to the development of
      athletic menstrual dysfunction. There also appears to be a high degree of
      individual variation with respect to the susceptibility of the reproductive axis
      to exercise and diet-related stresses. The dietary issues of the female athlete
      with athletic menstrual dysfunction are similar to those of her eumenorrhoeic
      counterpart. The most common nutrition issues in active women are poor energy
      intake and/or poor food selection, which can lead to poor intakes of protein,
      carbohydrate and essential fatty acids. The most common micronutrients to be low
      are the bone-building nutrients, especially calcium, the B vitamins, iron and
      zinc. If energy drain is the primary contributing factor to athletic menstrual
      dysfunction, improved energy balance will improve overall nutritional status and
      may reverse the menstrual dysfunction, thus returning the athlete to normal
      reproductive function. Because bone health can be compromised in female athletes
      with menstrual dysfunction, intakes of bone-building nutrients are especially
      important. Iron and zinc are typically low in the diets of female athletes if
      meat products are avoided. Adequate intake of the B vitamins is also important to
      ensure adequate energy production and the building and repair of muscle tissue.
      This review briefly discusses the various factors that may affect athletic
      menstrual dysfunction and two of the proposed mechanisms: the energy-drain and
      exercise-intensity hypotheses. Because energy drain can be a primary contributor
      to athletic menstrual dysfunction, recommendations for energy and the macro- and
      micronutrients are reviewed. Methods for helping the female athlete to reverse
      athletic menstrual dysfunction are discussed. The health consequences of trying
      to restrict energy intake too dramatically while training are also reviewed, as
      is the importance of screening athletes for disordered eating. Vitamins and
      minerals of greatest concern for the female athlete are addressed and
      recommendations for intake are given.

PMID- 12427052
TI  - Injuries to the pectoralis major.
AB  - Pectoralis major injuries typically occur in active individuals participating in
      manual labour or sports. While these injuries are rarely reported, the actual
      incidence of pectoralis tears among all shoulder injuries is unknown. Diagnosis
      can usually be made based on a patient's history and physical examination.
      However, ultrasound and magnetic resonance imaging are helpful tools for
      diagnosis and pre-operative planning. Specific treatment options should be based
      on the severity of the injury and the patient's individual needs. Nonoperative
      management consisting of immobilisation and physical therapy can offer a
      functional result with return of shoulder motion and activities of daily living.
      In recent studies, operative repair of pectoralis major rupture has been shown to
      restore normal chest-wall muscle contours and pre-operative strength (even in
      competitive athletes). Although complications such as re-rupture, infection, and
      heterotopic ossification do occasionally occur, favourable results should be
      expected when surgical repair is performed either acutely or in a delayed
      fashion.

PMID- 12427053
TI  - Tests of cycling performance.

PMID- 12427055
TI  - The role of apoptosis in age-related macular degeneration.
AB  - OBJECTIVE: To investigate apoptosis in human age-related macular degeneration
      (AMD). METHODS: Postmortem retinas with AMD and normal retinas were studied by
      terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) to identify
      dying cells, and by immunocytochemistry with cell-specific antibodies to identify
      rods and cones. Sections were also labeled for Fas, a cell surface receptor that
      triggers apoptosis in other cell types. The maculas with AMD had geographic
      atrophy (GA) or exudative AMD. RESULTS: Maculas with AMD had statistically
      significant increases in TUNEL-positive cells in the inner choroid, retinal
      pigment epithelium (RPE), photoreceptors, and inner nuclear layers compared with
      normal retinas. In eyes with GA, TUNEL-positive rod and RPE cell nuclei were
      present near edges of RPE atrophy. Photoreceptors in the maculas of eyes with AMD
      were strongly Fas-positive, while normal photoreceptors were only weakly labeled.
      CONCLUSIONS: Evidence in this study suggests that in human AMD, RPE,
      photoreceptors, and inner nuclear layer cells die by apoptosis. Most TUNEL
      positive RPE and photoreceptor cells were at edges of atrophy, correlating with
      clinically observed expansion of atrophic areas with vision loss in patients with
      GA. Increased Fas labeling in AMD photoreceptors indicates that the Fas/Fas
      ligand system may be involved in photoreceptor apoptosis. This information is
      essential for developing rational therapy for AMD.

PMID- 12427056
TI  - Verteporfin therapy of subfoveal choroidal neovascularization in patients with
      age-related macular degeneration: additional information regarding baseline
      lesion composition's impact on vision outcomes-TAP report No. 3.
AB  - OBJECTIVE: To explore how baseline lesion composition influenced vision outcomes
      in patients with age-related macular degeneration (AMD) undergoing photodynamic
      therapy with verteporfin (Visudyne) for subfoveal choroidal neovascularization
      (CNV) in the Treatment of Age-Related Macular Degeneration With Photodynamic
      Therapy Investigation. METHODS: Patients with subfoveal lesions secondary to AMD
      with evidence of classic CNV were categorized into 2 subgroups based on baseline
      color photographs and fluorescein angiograms assessed by graders at the Wilmer
      Photograph Reading Center (The Johns Hopkins University School of Medicine)
      before any outcome analyses as follows: (1) predominantly classic CNV (area of
      classic CNV >/=50% of the area of the entire lesion) or (2) minimally classic CNV
      (area of classic CNV <50% but >0% of the area of the entire lesion). Additional
      exploratory analyses were performed in the predominantly classic subgroup to
      investigate the effects of visual acuity, lesion size, prior laser
      photocoagulation, phakic status, micronutrient use, and presence of occult CNV on
      vision outcomes. MAIN OUTCOME MEASURES: Subgroup analyses of vision and
      fluorescein angiographic outcomes at 1 and 2 years after study enrollment were
      examined in an intent-to-treat analysis from 2 multicenter, double-masked,
      placebo-controlled, randomized clinical trials. RESULTS: Compared with patients
      who had minimally classic CNV, patients with predominantly classic CNV had a
      worse initial mean visual acuity and smaller lesions and were more likely to have
      lesions that included blood or blocked fluorescence. When evaluated by treatment
      assignment and lesion composition, 84% to 88% completed the month 24 examination.
      In the subgroup with predominantly classic lesions, visual acuity outcomes were
      consistently better in verteporfin-treated patients. Outcomes for patients with
      predominantly classic lesions without occult CNV tended to be better than
      outcomes for patients with predominantly classic lesions with occult CNV,
      although the former tended to have smaller lesions and lower levels of visual
      acuity at baseline. Contrast sensitivity and fluorescein angiographic outcomes
      (total lesion size, progression of classic CNV, and absence of classic CNV) were
      better in verteporfin-treated patients than in placebo-treated patients in the
      predominantly classic and the minimally classic CNV subgroups. In patients with
      predominantly classic CNV, no interaction of the treatment benefit by phakic
      status, micronutrient use, or prior laser photocoagulation therapy was noted.
      CONCLUSIONS: Verteporfin therapy can safely reduce the risk of moderate and
      severe vision loss in patients with subfoveal lesions that are predominantly
      classic CNV secondary to AMD. While this benefit seemed to be even greater in the
      absence of occult CNV, the effect may be related to the smaller lesions and worse
      visual acuity associated with predominantly classic lesions without occult CNV
      and not solely to the lesion composition itself. These analyses support initial
      reports that verteporfin therapy should be used to treat patients with AMD who
      have predominantly classic CNV, with or without occult CNV, but suggest that
      further investigations should be performed to determine if lesions with a
      minimally classic composition might benefit when they are smaller and have lower
      levels of visual acuity.

PMID- 12427057
TI  - Pneumatic retinopexy: results in eyes with classic vs relative indications.
AB  - OBJECTIVE: To compare the results of pneumatic retinopexy in 3 groups of eyes
      with rhegmatogenous retinal detachment. METHODS: In this retrospective,
      consecutive study, 44 eyes of 44 patients who underwent pneumatic retinopexy were
      divided into 3 groups: eyes with vitreoretinal abnormalities (group A),
      pseudopakic or aphakic eyes (group B), and phakic eyes without vitreoretinal
      abnormalities (group C). RESULTS: Single retinopexy success was achieved in 10
      (71%) of 14 eyes in group A, 7 (64%) of 11 eyes in group B, and 16 (84%) of 19
      eyes in group C (P=.42). Final success after reoperation was achieved in 13 (93%)
      of 14 eyes in group A, 10 (91%) of 11 eyes in group B, and in all 19 eyes in
      group C (P=.44). In group B, the rate of single retinopexy success using
      cryotherapy was significantly higher (5/5; 100%) than when laser photocoagulation
      was used (1/5; 20%) (P=.015). The final visual outcome obtained in the 3 groups
      was similar. There were no significant intergroup differences in either early or
      late complications. CONCLUSIONS: The best results were achieved in eyes with
      classic indications for pneumatic retinopexy, though the differences between
      these results and those in the nonclassic indications were not significant. In
      pseudophakic or aphakic eyes, the rate of single operation success after cryopexy
      was significantly higher than the rate after laser photocoagulation.

PMID- 12427058
TI  - Rate of resolution of exudative retinal detachment after plaque radiotherapy for
      uveal melanoma.
AB  - OBJECTIVES: To determine the clinical relevance of exudative retinal detachment
      (ERD) and the rate of ERD resolution after plaque radiotherapy of posterior uveal
      melanomas. METHODS: Retrospective, nonrandomized study of 135 consecutive
      patients with posterior uveal melanoma treated by iodine 125 plaque radiotherapy.
      Extent of ERD and tumor thickness were assessed before radiotherapy and at
      postoperative follow-up visits. Local tumor control was assessed at each follow
      up visit. RESULTS: An ERD was present in 71 patients (53%) and was a risk factor
      for local treatment failure (P =.03). The ERD resolved after radiotherapy in 59
      (83%) of the 71 patients. The ERD resolved within 1 year in 64 patients (90%)
      (mean time to resolution, 5.6 months). The rate of ERD resolution correlated with
      the rate of decrease in tumor thickness (P =.004). The ERD did not resolve and
      the tumor thickness continued to increase in 5 patients, who required further
      intervention. A recurrent retinal detachment developed in 5 patients, who were
      diagnosed as having rhegmatogenous retinal detachment (3 patients) and lipid
      exudation secondary to tumor vasculopathy (2 patients). Two patients with local
      tumor recurrence did not develop a recurrent ERD. Local tumor control was
      achieved in 130 patients (96%). CONCLUSIONS: An ERD may be a risk factor for
      local failure after plaque radiotherapy for uveal melanoma. If an ERD does not
      resolve within 9 to 12 months of radiotherapy and the tumor is not regressing,
      treatment failure should be suspected. A recurrent ERD does not necessarily
      represent local tumor recurrence.

PMID- 12427059
TI  - Evidence-based screening criteria for retinopathy of prematurity: natural history
      data from the CRYO-ROP and LIGHT-ROP studies.
AB  - BACKGROUND: The Multicenter Trial of Cryotherapy for Retinopathy of Prematurity
      (CRYO-ROP) demonstrated the efficacy of treatment for threshold ROP and indicated
      the need for worldwide ROP screening. Previous guidelines for ROP screening have
      been largely based on clinical impression; we can now develop evidence-based
      screening recommendations. OBJECTIVE: To define the appropriate ages and retinal
      ophthalmoscopic signs that determine when to commence and conclude acute phase
      ROP screening. DESIGN: Analysis of data from 2 prospective randomized controlled
      trials: CRYO-ROP (January 1, 1986, to November 30, 1987) and Light Reduction in
      ROP (LIGHT-ROP) (July 1, 1995, to March 31, 1997). SETTING: Neonatal intensive
      care units in 23 study centers in the United States for CRYO-ROP and 3 centers
      for LIGHT-ROP. PATIENTS: Eyes were examined sequentially in 4099 infants with
      birth weight less than 1251 g (CRYO-ROP study) and in 361 infants with birth
      weight less than 1251 g and gestational age less than 31 weeks (LIGHT-ROP study).
      RESULTS: In 99% of infants, retinal conditions indicating a risk of poor outcome
      were not observed before 31 weeks' postmenstrual age or 4 weeks' chronologic age.
      Signs indicating that the risk of visual loss from ROP was minimal or had passed
      were the infant's attainment of 45 weeks' postmenstrual age without the
      development of prethreshold ROP or worse, progression of retinal vascularization
      into zone III without previous zone II ROP, and full vascularization.
      CONCLUSIONS: The initial eye examination should be conducted by 31 weeks'
      postmenstrual age or 4 weeks' chronologic age, whichever is later. Acute phase
      ROP screening can be discontinued when any of the 3 signs is present, indicating
      that the risk of visual loss from ROP is minimal or passed.

PMID- 12427051
TI  - Oral creatine supplementation and skeletal muscle metabolism in physical
      exercise.
AB  - Creatine is the object of growing interest in the scientific literature. This is
      because of the widespread use of creatine by athletes, on the one hand, and to
      some promising results regarding its therapeutic potential in neuromuscular
      disease on the other. In fact, since the late 1900s, many studies have examined
      the effects of creatine supplementation on exercise performance. This article
      reviews the literature on creatine supplementation as an ergogenic aid, including
      some basic aspects relating to its metabolism, pharmacokinetics and side effects.
      The use of creatine supplements to increase muscle creatine content above
      approximately 20 mmol/kg dry muscle mass leads to improvements in high-intensity,
      intermittent high-intensity and even endurance exercise (mainly in
      nonweightbearing endurance activities). An effective supplementation scheme is a
      dosage of 20 g/day for 4-6 days, and 5 g/day thereafter. Based on recent
      pharmacokinetic data, new regimens of creatine supplementation could be used.
      Although there are opinion statements suggesting that creatine supplementation
      may be implicated in carcinogenesis, data to prove this effect are lacking, and
      indeed, several studies showing anticarcinogenic effects of creatine and its
      analogues have been published. There is a shortage of scientific evidence
      concerning the adverse effects following creatine supplementation in healthy
      individuals even with long-term dosage. Therefore, creatine may be considered as
      a widespread, effective and safe ergogenic aid.

PMID- 12427060
TI  - Self-management of age-related macular degeneration and quality of life: a
      randomized controlled trial.
AB  - OBJECTIVE: To assess the effectiveness of an age-related macular degeneration
      (AMD) self-management program, consisting of health education and enhancement of
      problem-solving skills, to improve quality of life as shown by measures of mood
      and function. METHODS: Two hundred thirty-one community-dwelling cognitively
      intact volunteers (mean age, 80.6 years) with advanced macular degeneration were
      randomly assigned to a 12-hour self-management program (n = 86), a series of 12
      hours of tape-recorded health lectures (n = 74), or to a waiting list (n = 72).
      MAIN OUTCOME MEASURES: The primary outcome measure was emotional distress
      (Profile of Mood States). Secondary outcome measures included function (National
      Eye Institute Visual Function Questionnaire), social support (Duke Social Support
      Index), outlook on life (Life Optimism Test-Revised), and self-confidence to
      handle AMD-specific challenges in daily life (AMD Self-Efficacy Questionnaire).
      Clinical depression was determined in accord with the Structured Clinical
      Interview for the Diagnostic and Statistical Manual of Mental Disorders, Axis I,
      Fourth Edition, Research Version. RESULTS: The self-management group showed
      significant improvement in measures of mood and function compared with controls.
      These changes were significantly greater for the depressed than for the
      nondepressed subjects. Decreased emotional distress was associated with increased
      self-efficacy, while improvements in function were associated with increases in
      self-efficacy and perceived social support. CONCLUSIONS: These findings suggest
      that the AMD self-management program was an effective intervention to enhance
      well-being in older persons with poor eyesight due to AMD, particularly in those
      who were initially depressed.

PMID- 12427061
TI  - Intracameral tissue plasminogen activator use in a large series of eyes with
      valved glaucoma drainage implants.
AB  - OBJECTIVE: To describe the efficacy and complications of intracameral tissue
      plasminogen activator (tPA) in a large series of glaucomatous eyes with valved
      glaucoma drainage implants (GDIs). METHODS: A retrospective analysis of 620 Ahmed
      and Krupin aqueous shunts implanted between December 1992 and May 2001 identified
      36 eyes treated with intracameral tPA for total or imminent tube obstruction by
      fibrin and/or blood. For a successful ocular outcome, tPA use must prevent the
      need for additional glaucoma surgery to replace or revise an occluded drainage
      implant. RESULTS: Intracameral tPA successfully cleared or prevented tube
      occlusion by fibrin/blood clots in 32 (88.9%) of 36 eyes. Multiple tPA injections
      were administered in 38.9% of eyes, and the mean number of injections required to
      achieve successful outcomes was 1.6. The mean +/- SD tPA dose per injection was
      9.8 +/- 3.1 micro g, and the mean +/- SD total tPA dose required to achieve
      successful outcomes was 15.5 +/- 9.9 micro g. For injections to be successful in
      totally occluded tubes (n = 31), the mean +/- SD intraocular pressure change 24
      hours after tPA administration was -21.2 +/- 15.6 mm Hg. Significant
      complications, including severe hyphema, profound hypotony, and anterior chamber
      flattening, occurred after 10.9% of tPA administrations. CONCLUSION: Intracameral
      tPA clears and prevents obstruction of valved GDIs by fibrin and/or blood clots.

PMID- 12427062
TI  - Visual field loss in patients with glaucoma who have asymmetric peripapillary
      focal arteriolar narrowing.
AB  - OBJECTIVE: To evaluate the relationship between peripapillary focal arteriolar
      narrowing and visual field defects. METHODS: From our institutional practice, we
      identified 31 patients with glaucoma who had peripapillary focal arteriolar
      narrowing in only one eye and compared visual field data between the two eyes.
      Mean deviation (MD) and corrected pattern standard deviation (CPSD) were recorded
      using Humphrey visual field testing at the time proximal narrowing was apparent
      on the fundus photograph. Visual field data from subsets of patients with mild
      and severe narrowing were also compared. RESULTS: The MD and CPSD were
      significantly worse in eyes with peripapillary focal arteriolar narrowing. The
      eyes with narrowing exhibited a mean MD of -8.77 +/- 8.27 dB and a mean CPSD of
      5.01 +/- 3.42 dB. Eyes without narrowing displayed a mean MD of -4.52 +/- 6.64 dB
      and a mean CPSD of 3.01 +/- 2.68 dB (P =.003 for both). There was no significant
      difference in severity of the visual field defect between eyes with mild and
      severe arteriolar narrowing. CONCLUSION: To our knowledge, this is the first
      study to show that the presence of peripapillary focal arteriolar narrowing is
      related to the severity of visual field loss in patients with glaucoma.

PMID- 12427063
TI  - Intractable diplopia after strabismus surgery in adults.
AB  - OBJECTIVES: To investigate the incidence of persistent intractable diplopia in
      adults undergoing surgery for long-standing, constant strabismus and to define
      tests that may be useful for identifying patients at risk for developing this
      complication. METHODS: A retrospective medical record review of adults without
      diplopia undergoing surgery for constant strabismus. RESULTS: Medical records of
      424 adult patients undergoing strabismus surgery were studied. Of these patients,
      143 (34%) experienced diplopia when tested preoperatively with prisms to simulate
      the desired surgical outcome. Only 40 patients (9%) had temporary diplopia after
      surgery, which resolved in all cases by 6 weeks postoperatively. Three patients
      (0.8%) developed persistent intractable diplopia. Experiencing diplopia with
      preoperative prism testing was significantly more likely to result in
      postoperative diplopia than if diplopia was not present preoperatively (P<.001
      and P =.04 for temporary and persistent postoperative diplopia, respectively).
      Preoperative testing had a sensitivity and negative predictive value for
      temporary postoperative diplopia of 100%, a specificity of 73%, and a positive
      predictive value of 28%. Similar values were found for persistent diplopia after
      surgery with the exception of the positive predictive value, which was only 2%.
      Patients who did not see double during preoperative testing with prisms never
      developed diplopia after surgery. However, the presence of preoperative diplopia
      with prism testing (including a prolonged trial with Fresnel prisms) was
      infrequently predictive of postoperative diplopia. CONCLUSIONS: Intractable
      diplopia after strabismus surgery in adults without previous diplopia is very
      rare. The diagnostic use of prisms prior to surgery may identify some patients
      who have little or no risk of postoperative diplopia, as well as a group of
      patients with a small but definite risk of intractable postoperative diplopia.

PMID- 12427064
TI  - A contribution to the natural history of optic nerve sheath meningiomas.
AB  - OBJECTIVE: To describe the natural history of patients with primary optic nerve
      sheath meningioma (ONSM) who were cared for without intervention. METHODS: A
      retrospective review of the medical records of 42 patients identified in the
      database of an academic neuro-ophthalmology unit who had been diagnosed with a
      unilateral ONSM. Twenty-five had been referred after treatment had been
      implemented, and 1 was blind at referral. The remaining 16 patients who were
      followed up with observation only are the focus of this study. RESULTS: The study
      subjects were followed up for a mean of 6.2 years (range, 2-18 years). The mean
      follow-up from the time of the first symptom was 10.2 years (range, 3-28 years).
      No patient died or incurred neurological deficits other than vision loss. At
      diagnosis, 12 of 16 had a visual acuity of 20/100 or better; 11 had a visual
      acuity of 20/30 or better. At follow-up, 8 of 16 had a visual acuity of 20/100 or
      better; 6 had a visual acuity of 20/30 or better. Three patients had slight
      improvement. Visual fields remained stable in 4 patients and improved in the 3
      patients whose visual acuity also improved. CONCLUSIONS: Some patients with ONSM
      have a stable course for many years, and a few may even show slight improvement.
      The routine application of radiation therapy may unnecessarily expose some
      patients to complications and should be reserved for those patients whose visual
      function declines under observation.

PMID- 12427065
TI  - The effect of visual field defects on driving performance: a driving simulator
      study.
AB  - OBJECTIVES: To investigate the effect of visual field defects on driving
      performance, and to predict practical fitness to drive. METHODS: The driving
      performance of 87 subjects with visual field defects due to ocular abnormalities
      was assessed on a driving simulator and during an on-road driving test. OUTCOME
      MEASURES: The final score on the on-road driving test and simulator indexes, such
      as driving speed, viewing behavior, lateral position, time-headway, and time to
      collision. RESULTS: Subjects with visual field defects showed differential
      performance on measures of driving speed, steering stability, lateral position,
      time to collision, and time-headway. Effective compensation consisted of reduced
      driving speed in cases of central visual field defects and increased scanning in
      cases of peripheral visual field defects. The sensitivity and specificity of
      models based on vision, visual attention, and compensatory viewing efficiency
      were increased when the distance at which the subject started to scan was taken
      into account. CONCLUSIONS: Subjects with visual field defects demonstrated
      differential performance on several driving simulator indexes. Driving examiners
      considered reduced speed and increased scanning to be valid compensation for
      central and peripheral visual field defects, respectively. Predicting practical
      fitness to drive was improved by taking driving simulator indexes into account.

PMID- 12427066
TI  - The effect of frontal air bags on eye injury patterns in automobile crashes.
AB  - OBJECTIVE: To investigate eye injuries resulting from frontal automobile crashes
      and to determine the effects of frontal air bags. METHODS: The National
      Automotive Sampling System database files from January 1, 1993, through December
      31, 1999, were examined in a 3-part study that included an investigation of 22
      236 individual crashes that occurred in the United States. A new 4-level eye
      injury severity scale that quantifies injuries based on recovery time, need for
      surgery, and possible loss of sight was developed. RESULTS: Of all occupants who
      were exposed to an air bag deployment, 3% sustained an eye injury. In contrast,
      2% of occupants not exposed to an air bag deployment sustained an eye injury. A
      closer examination of the type of eye injuries showed that there was a
      statistically significant increase in the risk of corneal abrasions for occupants
      who were exposed to an air bag compared with those who were not (P =.03). Of
      occupants exposed to an air bag deployment, 0.5% sustained a corneal abrasion
      compared with 0.04% of occupants who were not exposed to an air bag. CONCLUSIONS:
      Using the new injury levels, it was shown that although occupants exposed to an
      air bag deployment had a higher risk of sustaining minor eye injuries, the air
      bag appears to have provided a beneficial exchange by reducing the number of
      severe eye injuries.

PMID- 12427067
TI  - Consistency between visual acuity scores obtained at different test distances:
      theory vs observations in multiple studies.
AB  - OBJECTIVE: To investigate the consistency of visual acuity (VA) scores measured
      at 2 different distances in patients with or at risk for choroidal
      neovascularization. METHODS: Best-corrected VA scores measured at 2 distances for
      the same eyes at the same examinations were collected from 4 sets of randomized
      clinical trials among patients with or at risk of choroidal neovascularization.
      Within each trial, the pairs of VA scores were compared and their relationship
      was explored. RESULTS: After adjustment for test distance, VA scores obtained at
      the closer distance were found to be systematically lower than those obtained at
      the farther distance in all data sets. In the Submacular Surgery Trials pilot
      study, the average discrepancy between 2- and 0.5-m VA scores was 7.5 letters. In
      an ancillary study of the Macular Photocoagulation Study, the discrepancy between
      10-ft and 5-ft VA scores was 3.1 letters. In the Laser to Drusen Trial pilot
      study, the discrepancy between 3.2- and 1-m VA scores was 7.3 letters. In the
      Treatment of Age-Related Macular Degeneration With Photodynamic Therapy Study, in
      which the VA scores at the closer test distance were censored, the estimated
      discrepancy between 2- and 1-m VA scores was 8.2 letters. Reduction in visual
      angle at closer test distance did not explain the discrepancy completely.
      Features of the macular lesion, poor accommodation of the elderly population with
      age-related macular degeneration, or the test charts did not account for the
      discrepancies. CONCLUSION: The VA scores at distances less than 2 m were lower
      than expected in all 4 studies. The observed discrepancy was consistent with
      findings from a study among healthy young subjects, suggesting that the
      phenomenon is real and common.

PMID- 12427069
TI  - Expression of somatostatin receptors 1 and 2 in human choroid plexus and
      arachnoid granulations: implications for idiopathic intracranial hypertension.
AB  - OBJECTIVE: To investigate the localization of somatostatin receptor types 1 and 2
      in human choroid plexus (CP) and arachnoid granulations (AGs) by
      immunohistochemistry. METHODS: A prospective study was performed in an
      institutional setting. Immunohistochemistry was performed on 15 samples of CP and
      12 samples of AGs from 15 patients who died with no signs or symptoms of
      intracranial disease (age range, 52-81 years). The CP samples were dissected from
      the lateral ventricles and AG samples were dissected from the superior sagittal
      sinus. RESULTS: We demonstrated the presence of both somatostatin receptor types
      1 and 2 in all samples of normal human CP and AGs. CONCLUSIONS: Analogous to
      their demonstration and to their function in kidney and ocular tissues, these
      receptors may be involved in the processes of cerebrospinal fluid production and
      absorption, and may play a role in the increased intracranial pressure of
      idiopathic intracranial hypertension. CLINICAL RELEVANCE: Somatostatin analogues
      have been used to treat idiopathic intracranial hypertension, a disorder of
      cerebrospinal fluid homeostasis. Data are scarce regarding the cell-specific
      distribution of somatostatin receptors in normal human CP and AGs, the sites of
      cerebrospinal fluid production and egress.

PMID- 12427068
TI  - Real-time quantitative polymerase chain reaction diagnosis of infectious
      posterior uveitis.
AB  - OBJECTIVE: To validate a real-time polymerase chain reaction (PCR) assay allowing
      rapid and sensitive detection and quantitation of 4 common infectious posterior
      uveitis pathogens. METHODS: A real-time PCR assay using previously validated
      primer sets for cytomegalovirus, herpes simplex virus, varicella-zoster virus,
      and Toxoplasma gondii was developed. A standard curve for quantitation of
      pathogen load was generated for each pathogen using SYBR Green I fluorescence
      detection. Ocular samples from patients with posterior uveitis and from negative
      control samples were assayed and compared with standards to identify pathogens
      and quantify infectious load. RESULTS: Sensitivity for detection of purified
      pathogen DNA by PCR was not reduced by application of the real-time method.
      Standard curves for the quantitation of pathogen loads showed sensitivity to
      fewer than 10 organisms for all pathogens. The technique was applied to 2
      clinical problems. First, sensitivities of existing monoplex and multiplex PCR
      were compared by real-time PCR. No significant difference in sensitivity was
      observed between multiplex and monoplex techniques. Second, pathogen loads of
      vitreous specimens from patients previously diagnosed as having infectious
      posterior uveitis were calculated. Pathogen loads were found to be generally
      higher for patients with disease caused by varicella-zoster virus than those
      caused by cytomegalovirus or herpes simplex virus. CONCLUSIONS: Real-time PCR may
      be applied to infectious agents responsible for posterior uveitis. This technique
      will likely prove useful for the diagnosis of posterior uveitis as well as the
      linkage of pathogen to disease. CLINICAL RELEVANCE: Real-time PCR provides a
      rapid technique for quantitatively evaluating ocular samples for the presence of
      infectious pathogens.

PMID- 12427070
TI  - Visual acuity impairment and mortality in US adults.
AB  - OBJECTIVE: To examine the associations between reported visual impairment (VI)
      and mortality in a nationally representative sample of US adults. METHODS: The
      National Health Interview Survey is a multistage probability survey of the US
      civilian population. Adults within households were administered questions about
      VI and selected eye diseases (n = 116 796). Mortality linkage data with more than
      96% of the 1986-1994 survey participants were available through December 31,
      1997. Statistical analyses included Cox proportional hazards regression analysis.
      MAIN OUTCOME MEASURES: All-cause, cardiovascular disease-related, and cancer
      related mortality. RESULTS: A total of 327 participants (0.3%) had severe
      bilateral VI; an additional 4754 (4%) had some VI and/or severe VI in at least
      one eye. Mortality linkage identified 8949 deaths. After controlling for survey
      design, age, race, marital status, educational level, reported health status,
      glaucoma, cataract, and retinopathy, women, but not men, with reported severe
      bilateral VI were at a significantly increased risk of death relative to their
      counterparts without VI (hazard ratio [95% confidence interval], 2.21 [1.61-3.02]
      and 1.33 [0.96-1.84], respectively); risk of mortality was also slightly but
      significantly elevated in women and men with some reported VI compared with those
      reporting no VI. Similar patterns of associations were found for cardiovascular
      disease-related mortality. Risk of cancer-related mortality was not associated
      with VI. CONCLUSION: Reported severe bilateral VI and, to a smaller extent, less
      severe VI are associated with an increased risk of all-cause mortality and
      cardiovascular disease-related mortality in US women; there is weaker evidence
      for an association between VI and mortality in US men.

PMID- 12427071
TI  - The association of cataract and cataract surgery with the long-term incidence of
      age-related maculopathy: the Beaver Dam eye study.
AB  - OBJECTIVE: To examine the association between cataract and cataract surgery and
      the 10-year incidence of age-related maculopathy (ARM). METHODS: A population
      based cohort study of persons aged 43 to 86 years at baseline, living in Beaver
      Dam, Wis, of whom 3684 participated in a 5-year and 2764 in a 10-year follow-up.
      We used standardized protocols for physical examination, blood collection, health
      history, slitlamp and retroillumination photography of the lenses to determine
      the presence of cataract, and stereoscopic color fundus photography to determine
      the presence of ARM. We used the Kaplan-Meier (product-limit) survival approach
      and discrete linear logistic regression in analyses. MAIN OUTCOME MEASURES: The
      risk ratios (RRs) of persons with cataract or cataract surgery at baseline.
      RESULTS: While controlling for age, sex, systolic blood pressure, history of
      heavy drinking and smoking, and vitamin use, cataract at baseline was associated
      with incidence of early ARM (RR, 1.30; 95% confidence interval [CI], 1.04-1.63),
      soft indistinct drusen (RR, 1.38; 95% CI, 1.08-1.75), increased retinal pigment
      (RR, 1.38; 95% CI, 1.07-1.79), and progression of ARM (RR, 1.37; 95% CI, 1.06
      1.77). We found no association with the incidence of late ARM. In contrast,
      cataract surgery before baseline was associated with incidence of late ARM (RR,
      3.81; 95% CI, 1.89-7.69), increased retinal pigment (RR, 1.89; 95% CI, 1.18
      3.03), retinal pigment epithelial depigmentation (RR, 1.95; 95% CI, 1.17-3.25),
      pure geographic atrophy (RR, 3.18; 95% CI, 1.33-7.60), exudative macular
      degeneration (RR, 4.31; 95% CI, 1.71-10.9), and progression of ARM (RR, 1.97; 95%
      CI, 1.29-3.02), but not with the incidence of early ARM. CONCLUSIONS: These
      findings indicate an association of cataract with subsequent risk for early ARM.
      Cataract surgery increased the risk for late ARM.

PMID- 12427072
TI  - Infantile cataract in the collaborative perinatal project: prevalence and risk
      factors.
AB  - OBJECTIVES: To estimate the prevalence of 4 categories of infantile cataract in
      subjects surviving the neonatal period in a US cohort, and to investigate risk
      factors for isolated infantile cataract. DESIGN: Prospective study of 55 908
      pregnancies enrolled in the Collaborative Perinatal Project from 1959 to 1965 at
      12 university medical centers. METHODS: We gathered data on demographic,
      lifestyle, and prenatal and perinatal obstetrical and postnatal factors using a
      standardized protocol. Pediatricians and neurologists examined infants at birth,
      4 months, 1 year, and 7 years. We used exact logistic regression methods to
      compare putative risk factors in infants with isolated cataract with those in
      infants with no history of cataract. OUTCOME MEASURES: Infantile cataract as
      diagnosed using a standardized dilated ophthalmic examination. RESULTS: Infantile
      cataract occurred in 13.6 per 10 000 infants (95% confidence interval [CI], 10.7
      17.1). Isolated infantile cataract occurred 3.8 times as often among infants born
      at weights at or below 2500 g than among those born at or above 2500 g (95% CI,
      1.5-8.6; P<.001), after controlling for a set of covariates; we observed similar
      results for bilateral isolated cataract (odds ratio = 4.4; 95% CI, 1.2-13.9). No
      risk factor identified in bivariate analyses was independently associated with
      the odds of developing isolated unilateral infantile cataract. CONCLUSIONS:
      Infantile cataract is a rare disorder occurring during childhood. Prevalence
      estimates reported here are within the limits of those from large-cohort studies
      in economically developed nations. Infants born at weights at or below 2500 g
      have a 3- to 4-fold increased odds of developing infantile cataract.

PMID- 12427073
TI  - Paternal uniparental heterodisomy with partial isodisomy of chromosome 1 in a
      patient with retinitis pigmentosa without hearing loss and a missense mutation in
      the Usher syndrome type II gene USH2A.
AB  - OBJECTIVE: To evaluate a form of nonmendelian inheritance in a patient with
      retinitis pigmentosa (RP). METHODS: Direct DNA sequencing of the USH2A coding
      region and microsatellite analysis of polymorphic markers from chromosome 1 and
      other chromosomes. RESULTS: A patient with RP without hearing loss caused by the
      homozygous mutation Cys759Phe in the USH2A gene on chromosome 1q was found to be
      the daughter of a noncarrier mother and a father who was heterozygous for this
      change. Further evaluation with microsatellite markers revealed that the patient
      had inherited 2 copies of chromosome 1 from her father and none from her mother.
      The paternally derived chromosome 1's were heteroallelic from the centromere of
      chromosome 1 to the proximal short and long arms. The distal regions of the short
      and long arms of chromosome 1 were homoallelic, including the region of 1q with
      the mutant USH2A allele. This genetic pattern is compatible with a phenomenon of
      uniparental primary heterodisomy with regions of homozygosity arising through a
      nondisjunction event during paternal meiosis I and subsequent trisomy rescue or
      gamete complementation. A paternal second cousin of the patient also had RP and
      also had an identical heterozygous mutation in the USH2A gene in the same codon.
      However, the analysis of an isocoding polymorphism 20 base pairs away and closely
      linked microsatellite markers in the patient and family members indicated that
      the 2 mutant alleles are unlikely to be identical by descent and that the 2
      relatives fortuitously had RP and a mutation in the same codon of the USH2A gene.
      CONCLUSION: This family illustrates that recessive RP without hearing loss can
      rarely be inherited from only 1 unaffected carrier parent in a nonmendelian
      manner. CLINICAL RELEVANCE: The genetic counseling of families with recessively
      inherited eye diseases must take into consideration the possibility that an
      unaffected heterozygous carrier can have an affected offspring homozygous for the
      same mutation, even if the carrier's spouse has wild-type alleles at the disease
      locus.

PMID- 12427074
TI  - The challenge of presbyopia.

PMID- 12427075
TI  - Helping low-income patients obtain prescription medications.
AB  - Low-income patients without prescription medication insurance coverage may be
      forced to choose between essential medications and food. Programs are available
      to help low-income patients obtain prescription medications at no cost.

PMID- 12427076
TI  - Early prints depicting eyeglasses.
AB  - Much of the history of eyeglasses has been gleaned from studies of paintings and
      prints that illustrate them. A few prints from the first century of printing
      include spectacles and are reproduced in this article. In addition to showing
      their form and method of use, these prints also illustrate their symbolic value.

PMID- 12427077
TI  - Capsulorrhexis in capsular delamination.

PMID- 12427078
TI  - Optic nerve teratoma and odontogenic dermoid cyst in a neonate with persistent
      fetal vasculature.

PMID- 12427079
TI  - Scleral ulceration after preoperative injection of mitomycin C in the pterygium
      head.

PMID- 12427080
TI  - An ectopic site of lacrimal gland secretion mimicking epiphora.

PMID- 12427081
TI  - Optical coherence tomography in the diagnosis of foveal hypoplasia.

PMID- 12427082
TI  - Apparent disappearance of choroidal neovascularization after initial photodynamic
      therapy with verteporfin.

PMID- 12427083
TI  - Chronic subdural hematoma: an unusual sequela of laser photocoagulation of the
      retina at the slitlamp.

PMID- 12427084
TI  - Blade defect responsible for a severe laser-assisted in situ keratomileusis
      complication.

PMID- 12427085
TI  - Avulsed retinal vessel with operculated retinal break.

PMID- 12427086
TI  - Roth spots.

PMID- 12427087
TI  - Ophthalmomyiasis interna.

PMID- 12427088
TI  - Suture laser-assisted in situ keratomileusis flaps after epithelial ingrowth
      removal.

PMID- 12427090
TI  - Omitted references on color scanning laser ophthalmoscopy.

PMID- 12427092
TI  - High-dose supplements for age-related macular degeneration: did you leave out
      centrum?

PMID- 12427093
TI  - Cell signalling and Trypanosoma cruzi invasion.
AB  - Mammalian cell invasion by the protozoan pathogen Trypanosoma cruzi is critical
      to its survival in the host. To promote its entry into a wide variety of non
      professional phagocytic cells, infective trypomastigotes exploit an arsenal of
      heterogenous surface glycoproteins, secreted proteases and signalling agonists to
      actively manipulate multiple host cell signalling pathways. Signals initiated in
      the parasite upon contact with mammalian cells also function as critical
      regulators of the invasion process. Whereas the full spectrum of cellular
      responses modulated by T. cruzi is not yet known, mounting evidence suggests that
      these pathways impinge on a number of cellular processes, in particular the
      ubiquitous wound-repair mechanism exploited for lysosome-mediated parasite entry.
      Furthermore, differential engagement of host cell signalling pathways in a cell
      type-specific manner and modulation of host cell gene expression by T. cruzi are
      becoming recognized as essential determinants of infectivity and intracellular
      survival by this pathogen.

PMID- 12427094
TI  - Molecular interactions between Plasmodium and its insect vectors.
AB  - Our understanding of the intricate interactions between the malarial parasite and
      the mosquito vector is complicated both by the number and diversity of parasite
      and vector species, and by the experimental inaccessibility of phenomena under
      investigation. Steady developments in techniques to study the parasite in the
      mosquito have recently been augmented by methods to culture in their entirety the
      sporogonic stages of some parasite species. These, together with the new
      saturation technologies, and genetic transformation of both parasite and vector
      will permit penetrating studies into an exciting and largely unknown area of
      parasite-host interactions, an understanding of which must result in the
      development of new intervention strategies. This microreview highlights key areas
      of current basic molecular interest, and identifies numerous lacunae in our
      knowledge that must be filled if we are to make rational decisions for future
      control strategies. It will conclude by trying to explain why in the opinion of
      this reviewer understanding malaria-mosquito interactions may be critical to our
      future attempts to limit a disease of growing global importance.

PMID- 12427095
TI  - Two CCAAT/enhancer binding protein sites are cis-activator elements of the
      Entamoeba histolytica EhPgp1 (mdr-like) gene expression.
AB  - Here, we show the relevance of promoter regions (-74 to +24, -167 to -75 and -259
      to -168 bp) in the transcriptional activation of the multidrug resistance gene
      EhPgp1 in Entamoeba histolytica, using mutated plasmids and transfection assays.
      We also demonstrate that both CCAAT/enhancer binding protein sites (-54 to -43 bp
      and -198 to -186 bp) are cis-activating elements of gene expression in the drug
      resistant (clone C2) and -sensitive (clone A) trophozoites. Nuclear proteins from
      trophozoites of both clones and C/EBP sequences of the core promoter formed
      specific complexes, which were abolished by anti-human C/EBPbeta antibodies. UV
      cross-linking and Western blot assays revealed 25 and 65 kDa bands in urea
      treated and untreated proteins respectively. The nuclear factors that bind to
      C/EBP sites were semi-purified by affinity chromatography. They were
      immunodetected by anti-human C/EBPbeta antibodies and formed a specific complex
      with the C/EBP probe. The antibodies recognized proteins in the cytoplasm,
      nucleus and EhkO organelles in immunofluorescence and confocal microscopy
      experiments. Based on our results, we propose that the C/EBP site at -54 bp
      stabilizes the transcription pre-initiation complex, whereas the other site at 
      198 bp may be involved in the formation of a multiprotein complex, which provokes
      DNA folding and promotes the EhPgp1 gene transcription.

PMID- 12427096
TI  - Identification of a NIPSNAP homologue as host cell target for Salmonella
      virulence protein SpiC.
AB  - Salmonella enterica uses a type III secretion system encoded by SPI-2 to target
      specific virulence factors into the host cytosol of macrophages to inhibit the
      phagosomal-lysosomal maturation pathway. This ensures survival of Salmonella
      inside its intracellular niche, the Salmonella-containing vacuole (SCV). One such
      virulence factor is SpiC, which was previously shown to interfere with
      intracellular vesicular trafficking. In this study we have used a yeast two
      hybrid assay to identify a NIPSNAP homologue as host cell target for SpiC that we
      have termed TassC. In vitro and in vivo co-purification of SpiC and TassC confirm
      the specificity of this interaction. Suppression of TassC production compensates
      a SpiC production deficit and allows spiC-Salmonella to survive within
      macrophages at levels comparable to wild-type Salmonella. We hypothesize that
      TassC is a host cell factor that determines vesicular trafficking in macrophages
      and is inactivated by Salmonella SpiC.

PMID- 12427097
TI  - The alpha C protein mediates internalization of group B Streptococcus within
      human cervical epithelial cells.
AB  - Group B Streptococcus (GBS) is the leading cause of bacterial chorioamnionitis
      and neonatal pneumonia, sepsis, and meningitis. Deletion of the alpha C protein
      gene (bca) attenuates the virulence of GBS in an animal model; significant
      survival differences in the first 24 h of infection suggest a pathogenic role for
      the alpha C protein early in the infection process. We examined the role of alpha
      C protein in the association between GBS and mucosal surfaces using a human
      cervical epithelial cell line, ME180. Fluorescent and confocal microscopy and
      flow cytometry demonstrated that 9-repeat alpha C protein binds to the surface of
      ME180 cells. Isolated N-terminal region of this protein also binds to these cells
      and competitively inhibits binding of the full protein. Wild-type GBS strain A909
      and the bca-null isogenic mutant JL2053 bound similarly to the surface of ME180
      cells. However, A909 entered these cells threefold more. Internalization of A909
      was inhibited with 2- and 9-repeat alpha C and with N-terminal region alone but
      not by repeat region-specific peptide. Translocation across polarized ME180
      membranes was fivefold greater for A909 than for JL2053. These findings suggest a
      role for the alpha C protein in interaction with epithelial surfaces and
      initiation of infection.

PMID- 12427098
TI  - Staphylococcus aureus clumping factor B (ClfB) promotes adherence to human type I
      cytokeratin 10: implications for nasal colonization.
AB  - Staphylococcus aureus is an important cause of sepsis in both community and
      hospital settings, a major risk factor for which is nasal carriage of the
      bacterium. Eradication of carriage by topical antibiotics reduces sepsis rates in
      high-risk individuals, an important strategy for the reduction of nosocomial
      infection in targeted patient populations. Understanding the mechanisms by which
      S. aureus adheres to nasal epithelial cells in vivo may lead to alternative
      methods of decolonization that do not rely on sustained antimicrobial
      susceptibility. Here, we demonstrate for the first time that the S. aureus
      surface-expressed protein, clumping factor B (ClfB), promotes adherence to
      immobilized epidermal cytokeratins in vitro. By expressing a range of S. aureus
      adhesins on the surface of the heterologous host Lactococcus lactis, we
      demonstrated that adherence to epidermal cytokeratins was conferred by ClfB.
      Adherence of wild-type S. aureus was inhibited by recombinant ClfB protein or
      anti-ClfB antibodies, and S. aureus mutants defective in ClfB adhered poorly to
      epidermal cytokeratins. Expression of ClfB promoted adherence of L. lactis to
      human desquamated nasal epithelial cells, and a mutant of S. aureus defective in
      ClfB had reduced adherence compared with wild type. ClfB also promoted adherence
      of L. lactis cells to a human keratinocyte cell line. Cytokeratin 10 molecules
      were shown by flow cytometry to be exposed on the surface of both desquamated
      nasal epithelial cells and keratinocytes. Cytokeratin 10 was also detected on the
      surface of desquamated human nasal cells using immunofluorescence, and
      recombinant ClfB protein was shown to bind to cytokeratin K10 extracted from
      these cells. We also showed that ClfB is transcribed by S. aureus in the human
      nares. We propose that ClfB is a major determinant in S. aureus nasal
      colonization.

PMID- 12427099
TI  - Genes in the Salmonella pathogenicity island 2 and the Salmonella virulence
      plasmid are essential for Salmonella-induced apoptosis in intestinal epithelial
      cells.
AB  - Intestinal epithelial cells are an important site of the host's interaction with
      enteroinvasive bacteria. Genes in the chromosomally encoded Salmonella
      pathogenicity island 2 (SPI 2) that encodes a type III secretion system and genes
      on the virulence plasmid pSDL2 of Salmonella enteritica serovar Dublin (spv
      genes) are thought to be important for Salmonella dublin survival in host cells.
      We hypothesized that genes in those loci may be important also for prolonged
      Salmonella growth and the induction of apoptosis induced by Salmonella in human
      intestinal epithelial cells. HT-29 human intestinal epithelial cells were
      infected with wild-type S. dublin or isogenic mutants deficient in the expression
      of spv genes or with SPI 2 locus mutations. Neither the spv nor the SPI 2
      mutations affected bacterial entry into epithelial cells or intracellular
      proliferation of Salmonella during the initial 8 h after infection. However, at
      later periods, bacteria with mutations in the SPI 2 locus or in the spv locus
      compared to wild-type bacteria, manifested a marked decrease in intracellular
      proliferation and a different distribution pattern of bacteria within infected
      cells. Epithelial cell apoptosis was markedly increased in response to infection
      with wild-type, but not the mutant Salmonella. However, apoptosis of epithelial
      cells infected with wild-type S. dublin was delayed for approximately 28 h after
      bacterial entry. Apoptosis was preceded by caspase 3 activation, which was also
      delayed for approximately 24 h after infection. Despite its late onset, the
      cellular commitment to apoptosis was determined in the early period after
      infection as inhibition of bacterial protein synthesis during the first 6 h after
      epithelial cell infection with wild-type S. dublin, but not at later times,
      inhibited the induction of apoptosis. These studies indicate that genes in the
      SPI 2 and the spv loci are crucial for prolonged bacterial growth in intestinal
      epithelial cells. In addition to their influence on intracellular proliferation
      of Salmonella, genes in those loci determine the ultimate fate of infected
      epithelial cells with respect to caspase 3 activation and undergoing death by
      apoptosis.

PMID- 12427107
TI  - Iron absorption: biochemical and molecular insights into the importance of iron
      species for intestinal uptake.
AB  - Recent advances in cloning of proteins involved in intestinal iron absorption can
      inform design and understanding of therapeutic iron preparations. Redox chemistry
      of iron is particularly important in iron metabolism, both as a potential source
      of toxic intermediates and as an essential requirement for efficient iron
      transport. The initial step in iron absorption (uptake from lumen to mucosa) is
      particularly important and several pathways involving Fe(III) reduction or
      transport and Fe(II) transport have been identified. Novel genes associated with
      iron uptake include Dcytb, a putative iron-regulated reductase and DMT1, a Fe(II)
      carrier in the brush border membrane. Other mechanisms may also operate, however.
      We review the recent findings and apply this to understanding the absorption of
      Fe(III) pharmaceuticals.

PMID- 12427108
TI  - Watercress has no Importance for the elimination of ethanol by CYP2E1 inhibition.
AB  - Watercress, a cruciferous vegetable, is known to inhibit the metabolism of
      several CYP2E1 substrates such as paracetamol and chlorzoxazone. Since ethanol
      and its metabolite, acetaldehyde, are CYP2E1 substrates, the influence of
      watercress on ethanol and acetaldehyde was investigated in healthy human
      volunteers. According to a randomized cross-over design, ethanol and acetaldehyde
      pharmacokinetic parameters were determined in 9 persons at 3 occasions: without
      watercress and after watercress ingestion preceding ethanol consumption from 1 or
      10.5 hr, respectively. Ethanol tmax occurred significantly later when watercress
      was ingested 1 hr before ethanol ingestion. Likewise, acetaldehyde Cmax was
      significantly higher whereas acetaldehyde AUCs were increased by watercress but
      not significantly. All other ethanol and acetaldehyde pharmacokinetic parameters
      were similar between the 3 treatments. In healthy volunteers, no major watercress
      effect was observed on ethanol clearance but a weak inhibiting effect on
      acetaldehyde metabolism is possible. Ethanol absorption is also delayed by single
      ingestion of watercress immediately preceding ethanol consumption.

PMID- 12427109
TI  - Multiple thrombotic occlusions of vessels after Russell's viper envenoming.
AB  - Systemic bleeding due to consumption coagulopathy and thrombocytopenia due to
      activation of procoagulants is the leading manifestation and cause of death in
      Russell's viper systemic envenoming. Thrombotic occlusion of the blood vessels is
      rare in cases of snakebite. In this report, two adult patients with Russell's
      viper systemic envenoming presented multiple cerebral infarctions, digital
      gangrenes and ischaemic organs in addition to typical clinical manifestations of
      bleeding diathesis and renal involvement. Our findings in these two special cases
      suggest that the venom-induced coagulopathy and endothelium damage, predisposed
      by toxin-induced vasoconstriction, might be the possible mechanism of multiple
      thrombotic vascular occlusions in systemic envenoming of Formosan Russell's
      viper.

PMID- 12427110
TI  - Separate effects of 1,25-dihydroxyvitamin D and calcium on renal calbindin-D28k
      and intestinal calbindin-D9k.
AB  - The effects of normal, low and high plasma concentrations of 1,25-(OH)2vitamin D
      (1,25-(OH)2D) combined with normal, low and high concentrations of plasma calcium
      on renal calbindin-D28k and intestinal calbindin-D9k were examined in rats. We
      found that the expression of renal calbindin-D28k was significantly (P<0.05)
      increased by high levels of 1,25-(OH)2D, but was not affected by a 50% reduction
      in 1,25-(OH)2D. In contrast the intestinal calbindin-D9k responded significantly
      (P<0.005) to both high and low 1,25-(OH)2D levels. The effect of 1,25-(OH)2D on
      intestinal calbindin-D9k was modulated by plasma calcium concentrations.
      Increased plasma calcium levels did not affect the renal calbindin-D28k
      concentrations, but suppressed intestinal calbindin-D9k (P<0.05). The effect of
      calcium was not mediated by calciotropic hormones. This suggests the existence of
      a calcium-sensing mechanism in the proximal duodenum. It is concluded that
      intestinal calbindin-D9k is more sensitive than renal calbindin-D28k to changes
      in 1,25-(OH)2D and that intestinal calbindin-D9k in contrast to renal calbindin
      D28k is sensitive to changes in plasma calcium concentrations.

PMID- 12427111
TI  - Glutamate uptake is inhibited by tamoxifen and toremifene in cultured retinal
      pigment epithelial cells.
AB  - The systemic drugs chloroquine and tamoxifen have caused retinal defects in human
      eye. The aim of our study was to investigate the effects of the amphiphilic drug
      tamoxifen, of its homologue toremifene, and of chloroquine on the glutamate
      uptake in retinal pigment epithelial (RPE) cells. Cultured human RPE cell line
      D407 and pig RPE cells were used in the study. Glutamate uptake was characterised
      and the glutamate transporters of pig RPE cells and the human RPE cell line D407
      were compared to each other. The uptake of glutamate was studied using L
      [3H]glutamate as a tracer. The radioactivity in the solubilised RPE was measured
      with a liquid scintillation counter. In the uptake experiments, the cells were
      exposed to the test drugs, to the selected glutamate receptor antagonists, and to
      the glutamate transporter inhibitors. Both RPE cell types exhibited a high
      affinity transport system for glutamate. The glutamate transporter in RPE
      exhibited features characteristic of the uptake systems of neurotransmitters. The
      transport was Na+-dependent, and L- and D-aspartate were transported into the
      cell by the same transporter. Chloroquine had no effect on glutamate uptake, but
      tamoxifen and toremifene decreased the glutamate uptake of RPE cells dose
      dependently both in pig RPE cells and in human RPE cell line. The IC50 values of
      tamoxifen and toremifene were lower for pig RPE cells, compared to the human RPE
      cell line D407. The glutamate uptake was a sensitive target for the effects of
      tamoxifen and toremifene, and disturbances in this function could be considered
      as one of the possible mechanisms of retinal defects.

PMID- 12427112
TI  - Antidiabetogenic effect of fusidic acid in diabetes prone BB rats: a sex
      dependent organ accumulation of the drug is seen.
AB  - Fusidic acid and its sodium salt (fusidin) are widely used antistaphylococcal
      drugs which possesses immunomodulatory properties. This prompted us to
      investigate whether high concentrations of fusidin could lower the diabetes
      incidence in diabetes-prone BB (BioBreeding) rats. As fusidin has previously been
      claimed to be poorly absorbed in rats after oral administration we wanted to
      measure the activity of the drug in various organs. Three groups of BB rats were
      used: 63 rats received fusidin dissolved in drinking water; 65 rats received chow
      containing fusidin; and 72 rats served as controls. The content of fusidin in the
      organs were examined microbiologically. The incidence of diabetes was
      significantly lower in the two fusidin-treated groups compared to the control
      group. The incidence was lower for male than for female rats in both experimental
      groups while no gender difference was seen in the control group. The female rats
      had a substantially higher content of fusidin in their organs than the males
      regardless of the administration way and regardless of diabetes outbreak or not.
      Interestingly, the fusidin treated non-diabetic rats displayed a lower random
      blood glucose level than the controls. In conclusion, fusidin is well absorbed
      after oral administration and it significantly reduces the diabetes incidence in
      BB rats. Fusidin accumulates substantially more in female rats which may be due
      to the steroid structure of fusidin. Whether the same phenomenon takes place in
      human beings is not known.

PMID- 12427113
TI  - Influence of chloramphenicol on rat hepatic microsomal components and biomarkers
      of oxidative stress: protective role of antioxidants.
AB  - The effects of chloramphenicol and antioxidant vitamins on in vivo and in vitro
      indices of microsomal drug oxidizing system were examined in rats.
      Chloramphenicol at doses of 28 mg/kg, 57 mg/kg and 86 mg/kg body weight
      administered for 10 consecutive days resulted in a dose-dependent decrease in
      body weight, liver weight, relative liver weight and protein content compared to
      control. Chloramphenicol treatment also resulted in a dose-dependent decrease in
      microsomal phospholipid and a significant increase in cholesterol content causing
      an increase in cholesterol/phospholipid molar ratio. The drug produced a
      significant reduction in the activity of aniline hydroxylase, aminopyrine N
      demethylase, p-nitroanisole O-demethylase and ethoxyresorufin O- deethylase.
      Activity of ethoxyresorufin O-deethylase was little affected by the drug.
      Chloramphenicol ranging from 10-4-10-6 M similarly produced a concentration
      dependent inhibition in the activities of the enzymes. Kinetic studies revealed
      that chloramphenicol inhibited the enzymes non-competitively. alpha-Tocopherol,
      beta-carotene and ascorbic acid decreased the chloramphenicol inhibition of the
      enzymes within the range of 70 to 81%, 45-63% and 55 to 75% respectively. Also,
      the antioxidant vitamins attenuated the chloramphenicol-induced formation of
      malondialdehyde by 60%, 53% and 56% and lipid hydroperoxide by 60%, 54%, and 54%
      respectively The results indicate that the effect of chloramphenicol on
      cytochrome P450 drug oxidizing enzyme components is related to the action of the
      drug presumably, via free radical mechanism and that co-administration with
      antioxidant vitamins can attenuate its toxic action.

PMID- 12427114
TI  - Effects of lithium carbonate on apomorphine-induced sniffing behaviour in rats.
AB  - Effects of lithium carbonate (Li2CO3) on sniffing induced by apomorphine have
      been tested in rats. Intraperitoneal administration of different doses of
      apomorphine (0.25, 0.5 and 1 mg/kg) induced a dose-dependent sniffing response.
      Chronic Li2CO3 exposure (0.1% in drinking water for 30-35 days) but not acute
      administration of the drug (320 mg/kg, intraperitoneally) decreased the response
      of apomorphine. The response to chronic Li2CO3 exposure was observed when
      apomorphine was injected 60 min., 24 hr or 72 hr after Li2CO3withdrawal, with
      maximum effect observed when the drug was administered 72 hr after withdrawal of
      Li2CO3. Blockade of sniffing induced by apomorphine by the D1 dopamine receptor
      antagonist, SCH23390 (0.005 mg/kg, intraperitoneally) or the D2 dopamine receptor
      antagonist, sulpiride (25 mg/kg, intraperitoneally) was not increased in acute
      Li2CO3-treated animals. In animals which were treated chronically with Li2CO3,
      the blockade of apomorphine response by sulpiride but not by SCH23390 was
      potentiated. It is concluded that chronic treatment of animals with Li2CO3 is
      able to alter D2 dopamine receptors response.

PMID- 12427115
TI  - Ambroxol inhibits peroxynitrite-induced damage of alpha1-antiproteinase and free
      radical production in activated phagocytic cells.
AB  - The present study examined the effect of ambroxol on toxic action of
      peroxynitrite and the respiratory burst in activated phagocytic cells. Ambroxol
      decreased the inactivation or destruction of alpha1-antiproteinase induced by
      peroxynitrite (ONOO-) or hypochlorous acid (HOCl), which was similar to
      penicillamine and glutathione and was greater than diclofenac sodium and naproxen
      sodium. Ambroxol significantly decreased ONOO--mediated tyrosine nitration and
      iron plus EDTA-mediated degradation of 2-deoxy-D-ribose. Ambroxol significantly
      attenuated the production of superoxide, hydrogen peroxide, HOCl, and nitric
      oxide in fMLP- or IL-1-activated phagocytic cells, while the inhibitory effects
      of antiinflammatory and thiol compounds were only observed in HOCl production.
      Ambroxol and antiinflammatory drugs did not show a cytotoxic effect on
      macrophages. The results suggest that ambroxol protects tissue components against
      oxidative damage by an action different from antiinflammatory drugs. Ambroxol may
      interfere with oxidative damage of alpha1-antiproteinase through a scavenging
      action on ONOO- and HOCl and inhibition of the respiratory burst of phagocytic
      cells.

PMID- 12427116
TI  - Hepatic phospholipid changes induced by sustained oxygen supplementation.

PMID- 12427117
TI  - Cardiovascular autonomic dysfunction in uremia.
AB  - Cardiovascular morbidity and mortality is common in chronic renal failure
      patients, and may be explained in part by abnormalities in cardiovascular
      autonomic regulation. This review discusses the results of cardiovascular
      autonomic function studies in chronic renal failure patients. While covering most
      methods of assessing autonomic function, we focus particularly on power spectral
      analysis methods. These newer techniques are non-invasive, reproducible, and
      allow the rapid assessment of the integrity of cardiovascular autonomic reflexes
      at the bedside. The abnormalities of parasympathetic, sympathetic and cardiac
      baroreceptor function seen in dialysis-dependent patients are highlighted, and
      their significance in intra-dialytic hypotension and cardiovascular mortality as
      well as the effects of dialysis and transplantation on these parameters examined.
      Importantly, studies of cardiovascular autonomic dysfunction in pre-dialysis
      chronic renal failure patients, when abnormalities may be amenable to
      intervention to prevent progression and premature cardiovascular morbidity and
      mortality, are reviewed.

PMID- 12427118
TI  - Globotriaosylceramide accumulation in the Fabry kidney is cleared from multiple
      cell types after enzyme replacement therapy.
AB  - BACKGROUND: Fabry disease, a lysosomal storage disease caused by deficient
      lysosomal alpha-galactosidase A activity, is characterized by
      globotriaosylceramide (GL-3) accumulation in multiple cell types, particularly
      the vasculature, leading to end organ failure. Accumulation in the kidney is
      responsible for progressive decline in renal function in male patients with the
      classical phenotype, resulting in renal failure in their third to fifth decades
      of life. With the advent of recombinant protein synthesis technology, enzyme
      replacement therapy has become a viable alternative to dialysis or renal
      transplantation, previously the only available treatment options for end-stage
      renal disease. METHODS: The pre- and post-treatment renal biopsies were analyzed
      from fifty-eight Fabry patients enrolled in a Phase 3 double-blind, randomized,
      placebo-controlled trial followed by a six-month open label extension study of
      the recombinant human enzyme, alpha-galactosidase A (r-halphaGalA), administered
      IV at 1 mg/kg biweekly. The purpose of this investigation was to detail the
      pathologic changes in glycosphingolipid distribution and the pattern of post
      treatment clearance in the kidney. RESULTS: Baseline evaluations revealed GL-3
      accumulations in nearly all renal cell types including vascular endothelial
      cells, vascular smooth muscle cells, mesangial cells and interstitial cells, with
      particularly dense accumulations in podocytes and distal tubular epithelial
      cells. After 11 months of r-halphaGalA treatment there was complete clearance of
      glycolipid from the endothelium of all vasculature as well as from the mesangial
      cells of the glomerulus and interstitial cells of the cortex. Moderate clearance
      was noted from the smooth muscle cells of arterioles and small arteries.
      Podocytes and distal tubular epithelium also demonstrated evidence for decreased
      GL-3, although this clearance was more limited than that observed in other cell
      types. No evidence of immune complex disease was found by immunofluorescence
      despite circulating anti-r-halphaGalA IgG antibodies. CONCLUSIONS: These findings
      indicate a striking reversal of renal glycosphingolipid accumulation in the
      vasculature and in other renal cell types, and suggest that long-term treatment
      with r-halphaGalA may halt the progression of pathology and prevent renal failure
      in patients with Fabry disease.

PMID- 12427119
TI  - Atubular glomeruli in a rat model of polycystic kidney disease.
AB  - BACKGROUND: Autosomal-dominant polycystic kidney disease (ADPKD) is associated
      with a progressive decline in glomerular filtration rate (GFR) that often leads
      to end-stage renal disease. The basis for this decline in GFR is poorly
      understood. METHODS: Glomeruli in heterozygous Han:SPRD rats with ADPKD and their
      normal litter mates were studied by light microscopy, using serial sectioning
      techniques. The connections of the renal corpuscles to proximal tubules were
      classified as normal, atrophied, or absent (atubular glomerulus). Renal
      corpuscles also were examined by scanning electron microscopy. Single nephron
      glomerular blood flows were determined using microspheres. RESULTS: In the
      kidneys of six-month-old rats with ADPKD, 50% of the glomeruli were atubular and
      another 26% were associated with atrophied neck segments; these glomeruli were
      most often smaller in size than normal. About 16% of the glomeruli were
      hypertrophied and had normal connections to proximal tubules. Sclerotic changes
      in cystic kidney glomeruli were usually mild or moderate, and belied the failure
      of glomerular function. Glomerular blood flow in the cystic kidneys averaged half
      of normal and was markedly heterogeneous; the majority of small glomeruli
      displayed very low blood flows and a few showed relatively high blood flows.
      Fewer glomerular abnormalities were found in rats treated for five months with
      potassium citrate in their drinking water. CONCLUSIONS: The diminished GFR in the
      rat with ADPKD can be accounted for largely by the formation of atubular
      glomeruli. Compensatory glomerular hypertrophy also is present and may contribute
      to the progression of the renal disease.

PMID- 12427120
TI  - A strategy for in vitro propagation of rat nephrons.
AB  - BACKGROUND: Recent advances in the understanding of the molecular biology of
      rodent renal development have lead to the ability to culture the components of
      the developing rat kidney-the ureteric bud (UB) and the metanephric mesenchyme
      (MM)-in isolation from one another. Here we here describe a method for
      subculturing and propagating either whole rat metanephric rudiments or isolated
      rat UBs. Exploiting the branching program intrinsic to the UB, propagated rat UBs
      can be recombined with fresh rat mesenchyme to form a large number of rat
      "neokidneys" derived from a single progenitor that may be amenable to site
      specific modulation of function. METHODS: Whole rat metanephric rudiments or
      isolated rat UBs were cultured and subdivided through several generations. Both
      cultured progenitor and subsequent generations of isolated rat UBs were
      recombined with freshly isolated rat metanephric mesenchyme. The tubules of these
      rat neokidneys were examined for expression of epithelial markers. RESULTS:
      Isolated rat UBs and whole rat metanephric rudiments could be propagated through
      several generations and appeared morphologically identical to their progenitors.
      Generations of isolated rat UB could be recombined with fresh rat mesenchyme and
      the resultant neokidney displayed the same morphologic appearance as the whole
      rat kidney rudiment. The UB-derived and MM-derived portions of the tubules of
      these rat neokidneys appear contiguous. CONCLUSIONS: The recombination of
      cultured and propagated rat UB with rat mesenchyme yielded rat neokidneys with
      tubular structures that appeared morphologically identical to whole rat kidney.
      In vitro propagation of rat metanephric rudiments and recombination of rat UB and
      MM suggest the possibility of designing nephrons that possess specific desirable
      functions that can be propagated in vitro.

PMID- 12427121
TI  - Ligand-regulatable erythropoietin production by plasmid injection and in vivo
      electroporation.
AB  - BACKGROUND: The development of an in vivo gene transfer approach to deliver
      physiologic levels of recombinant proteins to the systemic circulation would
      represent a significant advance in the treatment of protein deficiency disorders.
      However, the ability to regulate transgene expression is of paramount importance
      for safe and effective gene transfer therapy. METHODS: We developed two plasmids,
      one encoder of chimeric GeneSwitch protein, and the other an inducible transgene
      for human erythropoietin (Epo). The level of secretion of Epo into the serum was
      modulated by intraperitoneal administration of mifepristone (MFP). Rats were
      divided into four groups: one group administered Epo plasmid with MFP for 50
      days, a second group administered Epo plasmid with MFP for 15 days and then again
      from day 30 to day 50, a third group administered Epo plasmid without MFP, and a
      fourth group administered control plasmid. A pair of electrodes was inserted into
      the muscle of the right thigh, 100 mg of each plasmid was injected, and in vivo
      electroporation (8 pulses at 100 V for 50 msec) was performed. RESULTS: The
      presence of vector-derived Epo mRNA was detected by RT-PCR only in the Epo
      plasmid and MFP(+) groups. The hematocrit levels increased continuously, from the
      pre-injection level of 41.2% to 55.0% on day 30 and 53.8% on day 50 in the Epo
      plasmid and MFP(+) groups. In the MFP re-challenged group, the hematocrit levels
      rose up to day 15, fell after 20 to 30 days, and then rose again after MFP re
      administration. The serum Epo levels increased only in the Epo plasmid and MFP(+)
      groups. There were no significant changes in hematocrit levels and Epo levels in
      the Epo plasmid and MFP(-) group. CONCLUSION: Epo gene transfer with the
      GeneSwitch system by in vivo electroporation is a useful procedure for efficient
      drug-regulated delivery of Epo.

PMID- 12427122
TI  - Endocytosis of light chains induces cytokines through activation of NF-kappaB in
      human proximal tubule cells.
AB  - BACKGROUND: In proteinuric states increased cytokine production through
      endocytosis of filtered proteins by proximal tubule cells (PTCs) has been
      proposed as a major mechanism mediating tubulointerstitial injury and progressive
      kidney disease. We studied the effects of six different light chains (LCs) on the
      production of cytokines in cultured human PTCs. METHODS: LCs were isolated and
      purified from the urine of patients with myeloma and human PTCs were exposed to
      either LC or human serum albumin (HSA) for up to 24 hours. LC endocytosis was
      monitored by immunocytochemistry. Cytokines were determined by enzyme-linked
      immunosorbent assay (ELISA) in the supernatants and activation of nuclear factor
      kappa B (NF-kappaB) was detected by electrophoretic mobility shift assays (EMSA)
      and immunocytochemistry. RESULTS: Endocytosis of LCs induced the release of
      interleukins (IL) IL-6, IL-8 and monocyte chemoattractant protein-1 (MCP-1);
      however, there was considerable variability among the six different LCs. In
      contrast, HSA had no effect on cytokine production even at very high
      concentrations. Removal of LC-containing media resulted in cessation of IL-6
      release. LC-induced cytokine release was associated with nuclear translocation of
      NF-kappaB subunits p50 and p65, as demonstrated by both EMSA and
      immunocytochemistry. Inhibitors of NF-kappaB, aspirin and
      pyrrolidineditiocarbamate (PDTC) markedly suppressed LC-induced cytokine
      production. CONCLUSION: LC endocytosis leads to production of inflammatory
      cytokines through activation of NF-kappaB. This may be an important mechanism of
      chronic tubulointerstitial inflammation process commonly seen in multiple
      myeloma. These findings also point out a potential role by filterable low
      molecular-weight proteins, like LCs, in PTC injury during all proteinuric
      diseases.

PMID- 12427123
TI  - Estradiol reverses TGF-beta1-induced mesangial cell apoptosis by a casein kinase
      2-dependent mechanism.
AB  - BACKGROUND: The slower rate of progression of chronic renal disease in women than
      in men is explained in part by the ability of estradiol to reverse the
      stimulatory effect of transforming growth factor-beta1 (TGF-beta1) on collagen IV
      synthesis at the level of casein kinase 2 activation. Casein kinase 2 also
      phosphorylates and activates the pro-apoptotic protein, p53. We hypothesized that
      estradiol would reverse TGF-beta1-induced mesangial cell apoptosis by
      antagonizing the stimulatory effects of TGF-beta1 on casein kinase 2 activity,
      thereby preventing p53 activation. METHODS: The effects of TGF-beta1 on mesangial
      cell apoptosis, p53 phosphorylation, Bax and Bcl-2 levels, caspase 9 activity,
      and cleavage of PARP were examined. The abilities of estradiol and a specific
      inhibitor of CK2 (5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole) (DRB) to
      modulate the effects of TGF-beta1 on these processes were also examined. RESULTS:
      TGF-beta1 (2 ng/mL), which up-regulates CK2 activity, induces apoptosis in murine
      mesangial cells together with p53 serine389 phosphorylation, up-regulation of
      Bax, suppression of Bcl-2, destabilization of mitochondrial permeability
      transition pores, stimulation of caspase 9 activity and activation of PARP. TGF
      beta1-induced p53 activation and all the intermediary steps leading to mesangial
      cell apoptosis were reversed by estradiol (10-9 mol/L) and by DRB, potent
      inhibitors of CK2 activity, but not by inhibitors of the p38 MAPK, ERK or JNK
      signaling cascades. In contrast, TGF-beta1 failed to induce apoptosis in p53
      knockout mesangial cells. CONCLUSIONS: Our data suggest that CK2 mediates the
      stimulatory effects of TGF-beta1 on mesangial cell apoptosis via a p53-dependent
      mechanism. The ability of estradiol to reverse TGF-beta1-induced apoptosis may
      contribute to the protective effects of female gender on the course of chronic
      renal disease.

PMID- 12427124
TI  - P-cresol, a uremic toxin, decreases endothelial cell response to inflammatory
      cytokines.
AB  - BACKGROUND: Infectious diseases are among the most morbid events in uremia. The
      uremic toxin p-cresol may play a role in the immunodeficiency of uremia by
      depressing phagocyte functional capacity. Leukocyte adhesion to endothelium, a
      key event in the immune response, is mediated by endothelial adhesion molecules.
      These include intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion
      molecule-1 (VCAM-1) and E-selectin, which are induced by various inflammatory
      cytokines. We asked whether p-cresol alters endothelial adhesion molecule
      expression and modifies endothelial/leukocyte adhesion. METHODS: Human umbilical
      vein endothelial cells (HUVEC) were incubated with p-cresol in the presence or
      absence of tumor necrosis factor (TNF) or interleukin-1beta (IL-1beta).
      Thereafter, the endothelial molecules ICAM-1, VCAM-1, and E-selectin were
      quantitated and the monocyte (THP-1) adhesion to HUVEC measured. RESULTS: P
      cresol decreased cytokine-induced protein and mRNA expression of ICAM-1 and VCAM
      1. In addition, p-cresol significantly decreased the adhesion of THP-1 to
      cytokine-stimulated HUVEC. CONCLUSIONS: P-cresol may play a role in the immune
      defect of uremic patients by inhibiting cytokine-induced endothelial adhesion
      molecule expression and endothelium/monocyte adhesion.

PMID- 12427126
TI  - Nitric oxide production in renal cells by immune complexes: Role of kinases and
      nuclear factor-kappaB.
AB  - BACKGROUND: Interaction of deposited immune complexes (IC) with Fc receptors
      (FcR) on tissue cells elicits the release of inflammatory mediators leading to
      tissue damage. Nitric oxide (NO) radicals generated by inducible NO synthase
      (iNOS) are important mediators in inflammatory processes. To analyze the role of
      NO in IC-mediated glomerular inflammation, we studied the in vitro and in vivo
      expression of iNOS in renal cells [resident mesangial cells (MC), and
      infiltrating monocytes] induced by IC, and the possible intermediate steps
      between FcR occupancy and iNOS induction. METHODS: MC and monocytes were
      stimulated with IgG- and IgA-containing IC, and NO production (nitrite
      accumulation), iNOS transcription (luciferase assay) and their expression was
      measured by RT-PCR and Western blot. The involvement of FcR, transcription factor
      nuclear factor-kappaB (NF-kappaB), and protein kinases was assessed by using Fc
      fragments and specific inhibitors. Immune glomerulonephritis was induced in rats,
      and iNOS expression and NF-kappaB activation were analyzed. RESULTS: In MC and
      monocytes, IC enhanced iNOS transcription/expression and NO generation, which
      were attenuated by specific inhibitors of NF-kappaB. In addition, mitogen
      activated protein kinase (MAPK) inhibitors decreased NO production, but did not
      interfere with NF-kappaB activity, suggesting that both pathways may converge
      downstream in the induction of iNOS. In experimental immune glomerulonephritis,
      increased iNOS expression correlated with proteinuria levels, and appeared
      colocalized with NF-kappaB in glomerular and infiltrating cells. Treatment of
      animals and cells with Fc fragments prevented iNOS induction and NF-kappaB
      activation by IC. CONCLUSIONS: These results indicate that IC, through activation
      of FcR, induce iNOS expression in renal resident and recruited cells by
      mechanisms involving MAPK and NF-kappaB, and support the idea of the important
      role of local NO generation in IC-mediated glomerular injury.

PMID- 12427125
TI  - Decay-accelerating factor expression in the rat kidney is restricted to the
      apical surface of podocytes.
AB  - BACKGROUND: Decay-accelerating factor (DAF) has inhibitory activity toward
      complement C3 and C5 convertases. DAF is present in human glomeruli and on
      cultured human glomerular visceral epithelial cells (GEC). We studied the
      distribution and function of rat DAF. METHODS: Function-neutralizing antibodies
      (Abs) were raised against DAF. The distribution of DAF in vivo was determined by
      immunoelectron microscopy. Functional studies were performed in cultured GEC and
      following IV injection of anti-DAF Abs into rats. RESULTS: DAF was present
      exclusively on the apical surfaces of GEC, and was not present on the basal
      surfaces of GEC, nor other glomerular or kidney cells. DAF was functionally
      active on cultured GEC, and served to limit complement activation in concert with
      CD59, an inhibitor of C5b-9 formation. Upon injection into normal rats, anti-DAF
      F(ab')2 Abs bound to GEC in vivo, yet there was no evidence for complement
      activation and animals did not develop abnormal albuminuria. Anti-megalin
      complement-activating IgG Abs were "planted" on GEC, which activated complement
      as evidenced by the presence of C3d on GEC. Attempts to inhibit DAF function with
      anti-DAF Abs did not affect the quantity of complement activation by these anti
      megalin Abs, nor did it lead to development of abnormal albuminuria. In contrast,
      in the puromycin aminonucleoside model of GEC injury and proteinuria, anti-DAF
      Abs slowed the recovery from renal failure that occurs in this model. CONCLUSION:
      In cultured rat GEC, DAF is an effective complement regulator. In vivo, DAF is
      present on GEC apical surfaces. Yet, it appears that DAF is not essential to
      prevent complement activation from occurring under normal circumstances and in
      those cases in which complement-activating Abs are present on the basal surfaces
      of GEC in vivo. However, in proteinuric conditions, DAF appears to be protective
      to GEC.

PMID- 12427127
TI  - Dual effects of Escherichia coli alpha-hemolysin on rat renal proximal tubule
      cells.
AB  - BACKGROUND: alpha-Hemolysin (HlyA) producing Escherichia coli is a common cause
      of pyelonephritis and subsequent renal scarring. Recent studies have suggested
      that toxin secreted from HlyA E. coli may not only have a lytic effect, but also
      may activate a calcium signaling pathway in renal tubule cells. A dose dependent
      study was performed on the interaction between HlyA E. coli secretions and rat
      renal proximal tubule (PT) cells with regards to calcium signaling and cell
      morphology. The site of interaction between HlyA secretion and PT cells was
      examined by using an antagonist to a common binding motif in bacterial proteins.
      METHODS: Supernatant from an overnight culture of HlyA was freshly prepared for
      each experiment. Renal PT cells from infant rats were cultured for three days and
      exposed for 30 minutes to four hours to supernatant or purified HlyA. Effects on
      cell morphology were studied semiquantitatively with light microscopy.
      Intracellular calcium was measured ratiometrically in the presence or absence of
      drugs. RESULTS: Renal PT cells incubated with low doses of HlyA supernatant
      responded within five minutes with calcium oscillations. Morphology appeared
      unchanged after four hours of incubation. In contrast, high doses of HlyA caused
      a sustained increase in intracellular calcium and majority of cells were lysed
      within four hours. Calcium oscillations caused by lower doses of HlyA supernatant
      were highly regular and slow in the 10 to 12 minute range. Oscillations were
      abolished by 6-cyano-7-nitroquinoxaline-2, 3-dione (CNQX), indicating that HlyA
      is interacting with a QPB/LAOBP-motif. CONCLUSION: HlyA secreted from
      uropathogenic E. coli exerts a dual action on renal PT cells. Sublytical
      concentrations induce a response that may serve as a host defense, while high
      concentrations cause irreversible cell damage. The data emphasize the importance
      of high diuresis in urinary tract infection.

PMID- 12427128
TI  - Platelet-derived growth factor-D expression in developing and mature human
      kidneys.
AB  - BACKGROUND: Platelet-derived growth factor (PDGF) is a family of growth
      regulatory molecules composed of sulfide-bonded dimeric structures. Two well
      studied PDGF peptides (PDGF-A and PDGF-B) have been shown to mediate a wide range
      of biological effects. PDGF-D is a newly recognized member of the PDGF family.
      Initial studies of the PDGF-D gene found its expression in cells of the vascular
      wall, suggesting that it could participate in vascular development and pathology.
      However, its localization in human kidney tissues has never been studied.
      METHODS: PDGF-D expression in fetal (N = 30) and adult (N = 25) human kidney
      tissues was examined by immunohistochemistry using an affinity-purified antibody
      raised to human PDGF-D. Antibody absorption with the immunizing peptide was
      employed to confirm the specificity of this antibody. PDGF-D protein and gene
      expression in human kidneys also were demonstrated by Western blotting and
      reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: In the
      developing kidney, PDGF-D was first expressed by epithelial cells of comma- and S
      shaped structures of the developing nephron, and most consistently in the
      visceral epithelial cells in the later stages of glomerular differentiation. In
      addition, PDGF-D could be found in mesenchymal, presumptively fibroblast cells in
      the interstitium of developing renal pelvis and in fetal smooth muscle cells in
      arterial vessels. In the adult normal kidney, PDGF-D was expressed by the
      visceral epithelial cells. There was persistent expression in arterial smooth
      muscle cells as well as in some neointimal smooth muscle cells of
      arteriosclerotic vessels, and expression in smooth muscle cells of vasa rectae in
      the medulla. PDGF-D could be identified at the basolateral membrane of some
      injured tubules in areas of chronic tubulointerstitial injury routinely
      encountered in aging kidneys. Western blotting of homogenates of adult kidneys
      demonstrated monospecific bands at 50 kD corresponding to previously established
      size parameter for this protein. RT-PCR of human kidney RNA resulted in a 918
      basepair band, the sequence of which corresponded to human PDGF-D (Genbank number
      AF336376). CONCLUSIONS: To our knowledge, these are the first studies to localize
      PDGF-D in human kidneys and suggest that PDGF-D may have a role in kidney
      development. PDGF-D was shown to bind to PDGF beta receptor, which localizes to
      mesangial cells, parietal epithelial cells, and interstitial fibroblasts,
      suggesting potential paracrine interactions between those cells and the visceral
      epithelium.

PMID- 12427129
TI  - Cyclosporine A-induced hypercalciuria in calbindin-D28k knockout and wild-type
      mice.
AB  - BACKGROUND: It is known that cyclosporine A (CsA) treatment induces high bone
      turnover osteopenia and hypercalciuria. It has been proposed that down-regulation
      of renal calbindin-D28k by CsA results in renal calcium wasting. We investigated
      the role of the kidney and bone in CsA-induced hypercalciuria in calbindin-D28k
      knockout (KO) and wild-type (WT) mice. METHODS: Two sets of experiments were
      performed. In experiment 1, KO and WT mice were treated with CsA 20 mg/kg/day
      intraperitoneally (IP) for 7 days. In experiment 2, to eliminate the CsA effect
      on bone resorption, pamidronate (APD) 2.5 mg/kg IP was given every 4 days with
      the first dose given 4 days prior to the 7-day course of CsA. Serum levels of
      creatinine, calcium, and osteocalcin, as well as renal calcium excretion were
      measured to assess CsA's effects on calcium homeostasis. Effects of CsA on the
      expression of calbindin-D28k, and two calcium channels in the apical membrane of
      the distal tubule, epithelial calcium channel (ECaC) and alpha1G-subunit of a
      voltage-dependent Ca channel (alpha1G), in the kidney were examined by
      semiquantitative reverse transcription polymerase chain reaction (RT-PCR).
      RESULTS: KO mice had a threefold increase in renal calcium excretion when
      compared with WT mice at the baseline. This difference disappeared when calcium
      load was reduced by overnight fasting. After the CsA treatment, both WT and KO
      mice had a significant increase of renal calcium excretion (urine Ca/Cr ratio in
      WT, 0.11 +/- 0.01 to 1.29 +/- 0.17; in KO, 0.39 +/- 0.04 to 1.18 +/- 0.13; both P
      < 0.01). CsA treatment decreased renal calbindin-D28k mRNA by 61%, but did not
      affect the expression of ECaC and alpha1G. Baseline serum osteocalcin level of KO
      mice was significantly lower than that of WT mice. After CsA treatment, both
      groups had a 50% increase in the serum osteocalcin level, indicating increased
      bone turnover. When mice were treated with both CsA and APD, the increase in
      serum osteocalcin level was prevented, and renal calcium excretion was
      significantly lower than that in mice treated with CsA alone. However, there was
      still a significant increase in the urine Ca/Cr ratio in WT and KO mice compared
      with pretreatment levels (urine Ca/Cr in WT, 0.11 +/- 0.01 to 0.76 +/- 0.05, P <
      0.01; in KO, 0.39 +/- 0.05 to 0.79 +/- 0.06; P < 0.01). CONCLUSION: Calbindin
      D28k KO mice have diet-dependent hypercalciuria and a lower bone turnover rate.
      CsA treatment suppresses the expression of calbindin-D28k in mice, but has no
      effects on ECaC and alpha1G gene expression at the mRNA level. The pathogenesis
      of CsA-induced hypercalciuria involves both down-regulation of calbindin-D28k
      with subsequent impaired renal calcium reabsorption and CsA-induced high turnover
      bone disease. Additionally, our results suggest that mechanism(s) independent of
      calbindin-D28k within the kidney also may contribute to the CsA-induced calcium
      leak.

PMID- 12427130
TI  - Presence of lipids in urine, crystals and stones: implications for the formation
      of kidney stones.
AB  - BACKGROUND: Cell membranes and their lipids play critical roles in calcification.
      Specific membrane phospholipids promote the formation of calcium phosphate and
      become a part of the organic matrix of growing calcification. We propose that
      membrane lipids also promote the formation of calcium oxalate (CaOx) and calcium
      phosphate (CaP) containing kidney stones, and become a part of their stone
      matrix. METHODS: Human urine, crystals of CaOx and CaP produced in the urine of
      healthy individuals, and urinary stones containing struvite, uric acid, CaOx and
      CaP crystals for the presence of membrane lipids were analyzed. Crystallization
      of CaOx monohydrate at Langmuir monolayers of dipalmitoylphosphatidylglycerol
      (DPPG), dipalmitoylphosphatidylcholine (DPPC), dipalmitoylphosphatidylserine
      (DPPS), dioleoylphosphatidylglycerol (DOPG), palmitoyloleoylphosphatidylglycerol
      (POPG) and dimyristoylphosphatidylglycerol (DMPG) was investigated to directly
      demonstrate that phospholipid assemblies can catalyze CaOx nucleation. RESULTS:
      Urine as well as CaOx and CaP crystals made in the urine and various types of
      urinary stones investigated contained some lipids. Urine of both CaOx and uric
      acid stone formers contained significantly more cholesterol, cholesterol ester
      and triglycerides than urine of healthy subjects. However, urine of CaOx stone
      formers contained more acidic phospholipids. The organic matrix of calcific
      stones contained significantly more acidic and complexed phospholipids than uric
      acid and struvite stones. For each Langmuir monolayer precipitation was
      heterogeneous and selective with respect to the orientation and morphology of the
      CaOx crystals. Crystals were predominantly monohydrate, and most often grew
      singly with the calcium rich (10-1) face toward the monolayer. The number of
      crystals/mm2 decreased in the order DPPG> DPPC and was inversely proportional to
      surface pressure and mean molecular area/molecule. CONCLUSIONS: Stone forming
      conditions in the kidneys greatly impact their epithelial cells producing
      significant differences in the urinary lipids between healthy and stone forming
      individuals. Altered membrane lipids promote face selective nucleation and
      retention of calcium oxalate crystals, and in the process become a part of the
      growing crystals and stones.

PMID- 12427131
TI  - Localization of SPARC in developing, mature, and chronically injured human
      allograft kidneys.
AB  - BACKGROUND: The matricellular protein SPARC (secreted protein acidic and rich in
      cysteine) is expressed during development, tissue remodeling and repair. It
      functions as an endogenous inhibitor of cell proliferation, regulates
      angiogenesis, regulates cell adhesion to extracellular matrix, binds cytokines
      such as platelet derived growth factor and stimulates transforming growth factor
      beta (TGF-beta) production. This study describes the expression of SPARC during
      human renal development, in normal kidneys and during renal allograft rejection.
      METHODS: A total of 60 renal specimens, including normal areas from tumor
      nephrectomies (N = 24), fetal kidneys (N = 27) and explanted renal allografts (N
      = 9), were included in the study. SPARC protein was localized by
      immunohistochemistry using two different antibodies. On consecutive sections
      SPARC mRNA was detected by in situ hybridization. RESULTS: In the normal adult
      kidney SPARC protein was expressed by visceral and parietal epithelial cells,
      collecting duct epithelium (CD), urothelium, smooth muscle cells of muscular
      arteries and focally in interstitial cells. During renal development immature
      glomeruli demonstrated a polarized SPARC expression in visceral epithelial cells
      at their surface abutting the capillary basement membranes. In the fully
      differentiated glomeruli the expression pattern mirrored that of the adult
      kidney. Furthermore, SPARC was abundantly expressed by derivatives of the
      ureteric bud, and smooth muscle cells of arterial walls. During chronic allograft
      rejection SPARC is expressed in neointimal arterial smooth muscle cells,
      infiltrating inflammatory cells as well as by interstitial myofibroblasts in
      areas of interstitial fibrosis. SPARC mRNA synthesis detected by in situ
      hybridization mirrored these protein expression patterns. CONCLUSION: These
      studies co-localize SPARC to several sites of renal injury previously shown to be
      sites of PDGF B-chain expression and/or activity. We speculate that SPARC could
      function as an accessory molecule in chronic PDGF-mediated sclerosing
      interstitial and vascular injury. SPARC localization to glomerular epithelial
      cells corresponds to similar findings in rodents, and may reflect its role in
      cell adhesion and /or regulation of cell shape.

PMID- 12427132
TI  - Nephrotoxic nephritis is mediated by Fcgamma receptors on circulating leukocytes
      and not intrinsic renal cells.
AB  - BACKGROUND: There is evidence that mesangial cells express Fcgamma receptors in
      vitro, but the in vivo relevance of this is not known. FcRgamma-/- mice lack the
      gamma chain signaling subunit and therefore do not express the activator Fcgamma
      receptors (FcgammaRI and FcgammaRIII) or the high affinity IgE receptor,
      FcepsilonRI. FcRgamma-/- mice were protected from renal inflammation following
      the induction of accelerated nephrotoxic nephritis using sheep anti-mouse
      glomerular basement membrane anti-serum in mice sensitized to sheep IgG. METHODS:
      In order to test whether Fcgamma receptors had a role on intrinsic renal cells
      during nephritis, bone marrow cells were transplanted between wild-type (WT) mice
      and mice with a gene-targeted deletion of FcRgamma. Donor marrow reconstitution
      was confirmed by flow cytometric analysis of peripheral blood for FcgammaRIII,
      and the susceptibility of the transplanted mice to accelerated nephrotoxic
      nephritis was tested. RESULTS: Following the induction of nephrotoxic nephritis,
      FcRgamma-/- mice transplanted with WT bone marrow developed as much renal disease
      as WT mice transplanted with WT bone marrow. In contrast, WT mice transplanted
      with FcRgamma-/- marrow were completely protected from glomerular crescents,
      thrombosis, albuminuria and renal impairment, as were FcRgamma-/- mice
      transplanted with FcRgamma-/- marrow. Mice with FcRgamma-/- marrow had prolonged
      survival, but by day 28 after nephrotoxic serum injection they had developed
      mesangial hypercellularity and a macrophage influx caused by non-FcRgamma
      dependent mechanisms. CONCLUSION: Despite previous evidence that mesangial cells
      express Fcgamma receptors in vitro, they have no role in an FcRgamma-dependent
      model of glomerulonephritis in vivo.

PMID- 12427133
TI  - Large-scale preparation of sodium-potassium ATPase from kidney outer medulla.
AB  - BACKGROUND: Large amounts of Na,K-ATPase are needed for studies involving protein
      chemistry. Preparation of Na,K-ATPase from kidney by the widely used, rapid
      procedure of Jorgensen (Biochim Biophys Acta 356:36-52, 1974; Methods Enzymol
      156:29-43, 1988) includes labor-intensive dissection of tissue from the outer
      medulla and centrifugation into a step gradient of sucrose solution. METHODS: In
      a large-scale modification presented here, tissue was dissected with a surgical
      instrument, a rongeur, and centrifugation was simply a five times repeated
      differential centrifugation. The procedure took seven days and 68 person-hours of
      work. RESULTS: The yield of activity from 26 kg of whole kidneys was 6600 units
      (micromol Pi/min) in one preparation. The amount of protein was 240 mg and the
      specific activity was 28 micromol Pi/min per mg protein. CONCLUSIONS: There is a
      significant saving of labor to obtain a product with a specific activity similar
      to that commonly obtained. The microsomal fraction may be useful for preparing
      other membrane proteins from the outer medulla.

PMID- 12427134
TI  - Agmatine inhibits arginine vasopressin-stimulated urea transport in the rat inner
      medullary collecting duct.
AB  - BACKGROUND: Agmatine, a putative endogenous ligand for imidazoline receptors,
      induces numerous biological effects. The agonist clonidine binds to alpha-2
      (alpha2) adrenoceptors and imidazoline receptors, and inhibits arginine
      vasopressin (AVP)-stimulated urea permeability (Pu) in the rat inner medullary
      collecting duct (IMCD). Dexmedetomidine, a selective alpha2 agonist, does not
      inhibit AVP-stimulated Pu. This study was conducted to determine if agmatine
      affects Pu in the rat IMCD and to investigate the possibility of an imidazoline
      mediated mechanism. METHODS: The isolated-perfused tubule technique was used to
      measure Pu in IMCDs from Wistar rats. AVP at 220 pmol/L or 8-chlorophenylthio
      cyclic adenosine monophosphate (8CPT cAMP) was used to stimulate Pu. Agmatine and
      other agents were added to the bath. RESULTS: Agmatine at 1 micromol/L inhibited
      AVP-stimulated Pu by 50%. Agmatine-induced inhibition could not be separated
      completely from inhibition produced by the non-imidazoline, catecholamine
      epinephrine. Of three antagonists selective for alpha2 adrenoceptors
      (rauwolscine, yohimbine, and RX821002), only rauwolscine reversed inhibition,
      whereas each of the three imidazoline-selective antagonists tested (atipamezole,
      idazoxan, and BU239) produced a significant reversal. Agmatine did not affect
      basal Pu or inhibit 8CPTcAMP-stimulated Pu. CONCLUSION: Our results indicate that
      agmatine inhibits AVP stimulated Pu by a cAMP-dependent mechanism. Imidazoline
      receptors are probably not involved. The possibility exists of an unknown
      agmatine-selective receptor modulating urea transport in the rat IMCD.

PMID- 12427135
TI  - Regulation of the expression of the Cl-/anion exchanger pendrin in mouse kidney
      by acid-base status.
AB  - BACKGROUND: Pendrin belongs to a superfamily of Cl-/anion exchangers and is
      expressed in the inner ear, the thyroid gland, and the kidney. In humans,
      mutations in pendrin cause Pendred syndrome characterized by sensorineural
      deafness and goiter. Recently pendrin has been localized to the apical side of
      non-type A intercalated cells of the cortical collecting duct, and reduced
      bicarbonate secretion was demonstrated in a pendrin knockout mouse model. To
      investigate a possible role of pendrin in modulating acid-base transport in the
      cortical collecting duct, we examined the regulation of expression of pendrin by
      acid-base status in mouse kidney. METHODS: Mice were treated orally either with
      an acid or bicarbonate load (0.28 mol/L NH4Cl or NaHCO3) or received a K+
      deficient diet for one week. Immunohistochemistry and Western blotting was
      performed. RESULTS: Acid-loading caused a reduction in pendrin protein expression
      levels within one day and decreased expression to 23% of control levels after one
      week. Concomitantly, pendrin protein was shifted from the apical membrane to the
      cytosol, and the relative abundance of pendrin positive cells declined.
      Similarly, in chronic K+-depletion, known to elicit a metabolic alkalosis,
      pendrin protein levels decreased and pendrin expression was shifted to an
      intracellular pool with the relative number of pendrin positive cells reduced. In
      contrast, following oral bicarbonate loading pendrin was found exclusively in the
      apical membrane and the relative number of pendrin positive cells increased.
      CONCLUSIONS: These results are in agreement with a potential role of pendrin in
      bicarbonate secretion and regulation of acid-base transport in the cortical
      collecting duct.

PMID- 12427137
TI  - Bicarbonate reabsorption and NHE-3 expression: abundance and activity are
      increased in Henle's loop of remnant rats.
AB  - BACKGROUND: The bulk of bicarbonate reabsorption along the loop of Henle (LOH) is
      localized at the level of the thick ascending limb (TAL) and is mainly dependent
      on the presence of luminal Na+-H+ exchanger (NHE-3). We investigated whether the
      reduction of renal mass is associated with alterations in LOH bicarbonate
      transport coupled to changes in NHE-3 gene expression and in vivo activity.
      METHODS: Sham-operated and remnant rats (4/6 nephrectomy) were studied 15 days
      after the surgery. To measure net bicarbonate reabsorption (JHCO3-) superficial
      loops were perfused by in vivo micropuncture. Perfusate was an end-like proximal
      solution containing 3H-methoxy-inulin. NHE-3 gene expression was quantified by
      competitive PCR using an internal standard of cDNA that differed from the wild
      type NHE-3 by a deletion of 76 bp. Western blot experiments were performed on TAL
      suspension using anti-NHE-3 antibodies. RESULTS: At various LOH bicarbonate
      loads, JHCO3- was constantly larger in remnant rats as compared to sham-operated
      animals. NHE-3 mRNA abundance was estimated to be 0.339 +/- 0.031 attomoles
      (amol)/ng-1 total RNA in sham-operated (N = 5) and it increased to 0.465 +/-
      0.023 in remnant rats (N = 5, P < 0.01). Western blot experiments showed a
      significant increase of NHE-3 protein abundance in TAL of remnant rats as
      compared to sham-operated animals. Finally, by means of a specific NHE-3
      inhibitor, S-3226, in vivo microperfusion experiments demonstrated that NHE-3 in
      vivo activity along the LOH was substantially increased in remnant rats in
      addition to the non-NHE-3 bicarbonate transport. CONCLUSIONS: These data indicate
      that the reduction of renal mass increases mRNA, protein abundance and in vivo
      activity of NHE-3 along the TAL. This may explain, at least in part, the
      augmented transepithelial bicarbonate transport along the LOH. Such an effect
      will counterbalance the increased glomerular bicarbonate load, thus preventing
      urinary bicarbonate loss and mitigating the ensuing metabolic acidosis.

PMID- 12427136
TI  - Effects of cardiac glycosides on sodium pump expression and function in LLC-PK1
      and MDCK cells.
AB  - BACKGROUND: The decreases in proximal tubule sodium reabsorption seen with
      chronic renal failure and volume expansion have been ascribed to circulating
      digitalis-like substances (DLS). However, the circulating concentrations of DLS
      do not acutely inhibit the sodium pump to a degree consistent with the observed
      changes in proximal tubule sodium reabsorption. METHODS: We examined how cell
      lines that simulated proximal (LLC-PK1) and distal tubule (MDCK) cells responded
      to acute (30 min) and long-term (up to 12 hours) Na+,K+-ATPase inhibition with
      DLS. RESULTS: In LLC-PK1, but not MDCK cells, low concentrations of ouabain
      decreased 86Rb uptake profoundly in a time and dose dependent manner. In LLC-PK1
      cells grown to confluence, transcellular 22Na flux was markedly reduced in
      concert with the decreases in 86Rb uptake. Similar findings were observed with
      marinobufagenin (MBG) and deproteinated extract of serum derived from patients
      with chronic renal failure. However, inhibition of the Na+,K+-ATPase with low
      extracellular potassium concentrations did not produce any of these effects.
      Western and Northern blots detected no change in alpha1 Na+,K+-ATPase protein and
      message RNA, respectively, in LLC-PK1 cells treated with ouabain for 12 hours.
      However, the decrease in enzymatic activity of Na+,K+-ATPase of these cells was
      comparable to observed decreases in 86Rb uptake. Differential centrifugation as
      well as biotinylation experiments demonstrated a shift of the Na+,K+-ATPase from
      the plasmalemma with prolonged ouabain treatment. CONCLUSIONS: The results show
      that binding of cardiac glycosides by proximal (but not distal) tubular cells
      results in internalization of Na+,K+-ATPase with the net effect to amplify
      inhibition of the Na+,K+-ATPase. As the circulating concentrations of DLS
      increase with chronic renal failure and volume expansion, we suggest that this
      phenomenon explains some of the decreased sodium reabsorption by the proximal
      tubule seen in these conditions.

PMID- 12427138
TI  - Hemodynamics of early tubuloglomerular feedback resetting during reduced proximal
      reabsorption.
AB  - BACKGROUND: Carbonic anhydrase inhibition with benzolamide reduces proximal
      reabsorption and activates tubuloglomerular feedback (TGF). In rats, TGF
      activation for 30 to 60 minutes locally suppresses renin secretion and resets TGF
      rightward to accommodate increased late proximal flow. After 24 hours of TGF
      activation, there is upward resetting of GFR and increased activity of macula
      densa nitric oxide synthase I (NOS I). METHODS: We studied renal hemodynamics
      during early TGF resetting with attention to the importance of renin suppression
      and NOS I activation. Left kidney blood flow (RBF, pulse Doppler) and glomerular
      filtration rate (GFR; inulin clearance or Fick method) were measured before and
      during benzolamide infusion (5 mg/kg bolus followed by 5 mg/kg/h IV) in Wistar
      rats concurrently receiving the converting enzyme inhibitor, enalaprilat (0.3
      mg/kg/h IV) or NOS-I blocker S-methyl-thiocitrulline (SMTC; 2.7 mg/kg/h IV).
      RESULTS: Activating TGF initially reduced RBF and GFR in all groups as expected.
      During continuous benzolamide, RBF gradually increased toward baseline in control
      and enalaprilat-treated rats, but not in NOS I-blocked rats. After the initial
      decline, GFR did not change further during one hour of benzolamide in any group.
      CONCLUSIONS: During one hour of persistent TGF stimulation, RBF increases toward
      normal, but GFR does not. This requires an overall decrease in renal vascular
      resistance and a decrease in the ratio of efferent/afferent arteriolar resistance
      (RE/RA), implying a major decrease in RE. NOS I, but not angiotensin-converting
      enzyme (ACE), is required for RBF to increase during TGF resetting. Although the
      hemodynamic changes during TGF resetting resemble the response to blocking the
      renin-angiotensin system, these data fail to show that the increase in RBF during
      early TGF resetting is mediated by renin suppression.

PMID- 12427139
TI  - pH dependence of Na+/myo-inositol cotransporters in rat thick limb cells.
AB  - BACKGROUND: To balance medullary interstitium hypertonicity generated by
      transepithelial NaCl absorption, medullary thick ascending limb (MTAL) cells
      accumulate myo-inositol (MI). Expression of Na+-MI cotransporter (SMIT) mRNA in
      TAL is correlated with the NaCl absorption rate. Our present study aimed to
      determine the plasma membrane location and functional properties of the Na+-MI
      cotransporter in MTAL cells. METHODS: Preparation of basolateral (BLMV) and
      luminal (LMV) membrane vesicles were simultaneously isolated from purified rat
      MTAL suspension, and uptake of [3H]myo-inositol ([3H]MI) was used to assess Na+
      MI cotransport activity. RESULTS: In the presence of an inside-negative membrane
      potential, imposing an inwardly-directed Na+-gradient versus tetramethylammonium
      (TMA) stimulated the initial [3H]MI uptake in BLMV and LMV. Phlorizin inhibited
      Na+ gradient-dependent initial [3H]MI uptake in both preparations, with IC50
      values of 565 and 29 micromol/L in BLMV and LMV, respectively. 2-0,C-methylene
      myo-inositol (MMI), a competitive inhibitor of MI transport, only inhibited the
      BLMV Na+-MI cotransporter. Phlorizin-sensitive Na+ gradient-dependent initial
      [3H]MI uptake showed Michaelis-Menten kinetics in both preparations, with similar
      Vmax but different Km values of 51 and 107 micromol/L in BLMV and LMV,
      respectively. Finally, BLMV but not LMV Na+-MI cotransporter exhibited a marked
      pH dependence with sigmoidal patterns of activation, as intravesicular pH (pHi)
      was decreased from 8.0 to 6.0 at extravesicular pH (pHe) 8.0, and as pHe was
      increased from 6.0 to 8.0 at pHi 6.0. Maximal activation was observed at pHi 6.5
      and pHe 7.5. CONCLUSIONS: In rat MTAL cells, Na+-MI cotransporter activity is
      present in both BLM and LM, and has markedly different functional properties,
      indicating the presence of distinct transporters. Basolateral Na+-MI
      cotransporter activity is maximal at physiological pH values of MTAL cells and
      interstitium, and a powerful modulation of the transporter activity may be
      exerted by pHe and pHi.

PMID- 12427140
TI  - Association between hypertension and variation in the alpha- and beta-adducin
      genes in a white population.
AB  - BACKGROUND: The substitution of tryptophan for glycine at amino acid 460
      (Gly460Trp polymorphism) of the alpha-subunit of the heterodimeric cytoskeleton
      protein adducin increases renal sodium reabsorption and may be involved in the
      pathophysiology of essential hypertension. In the present study, we investigated
      in multivariate analyses whether the risk of hypertension was associated with the
      C1797T polymorphism of the beta-adducin gene. METHODS: A total of 1848 subjects
      randomly selected from a white population were genotyped. Study nurses measured
      blood pressure at the participants' homes. RESULTS: The frequencies of the alpha
      adducin Trp and beta-adducin T alleles were 0.23 and 0.11, respectively. In men
      (N = 904), the beta-adducin T allele was not associated with hypertension
      [adjusted relative risk (RR) vs. CC homozygotes 0.94, P = 0.77], but T allele
      carriers had lower plasma renin activity (PRA) and 24-hour urinary aldosterone
      excretion (P < 0.04). In all women (N = 944), beta-adducin T allele carriers had
      a higher risk of hypertension than CC homozygotes (RR 1.81, CI 1.18-2.77, P =
      0.007), but similar PRA and 24-hour urinary aldosterone excretion (P> 0.29). In
      345 post-menopausal women and 190 users of oral contraceptives, the RRs of
      hypertension were 2.47 (CI 1.34-4.64, P = 0.003) and 2.56 (CI 0.83-7.86, P =
      0.10), respectively. For systolic pressure in women, there was a significant
      interaction (P = 0.02) between the alpha- and beta-adducin polymorphisms. Only in
      female carriers of the mutated alpha-adducin Trp allele was the systolic pressure
      significantly higher in beta-adducin T allele carriers compared with CC
      homozygotes (+3.8 mm Hg, P = 0.02). Furthermore, in the presence of the mutated
      alpha-adducin Trp allele, the RRs associated with the beta-adducin T allele were
      2.35 (P = 0.01) in all women, 2.92 (P = 0.03) in post-menopausal subjects, and
      3.79 (P = 0.09) in users of oral contraceptives. CONCLUSIONS: The 1797T allele of
      the beta-adducin gene is associated with increased risk of hypertension in post
      menopausal women and in users of oral contraceptives, particularly in the
      presence of the mutated alpha-adducin Trp allele. We hypothesize that inhibition
      of the renin-aldosterone system in men and absence of such a compensatory
      mechanism in women may explain, at least to some extent, the sexual dimorphism of
      the blood pressure phenotype in relation to the C1797T beta-adducin polymorphism.

PMID- 12427141
TI  - Bone histology and bone mineral density after correction of acidosis in distal
      renal tubular acidosis.
AB  - BACKGROUND: The association between chronic metabolic acidosis and alterations in
      bone cell functions has been demonstrated in vitro and in animal studies.
      However, the causal role of acidosis and the effects of alkaline therapy on bone
      histology and bone mineral density in chronic metabolic acidosis have never been
      systematically demonstrated in humans. This study was conducted to examine the
      alterations in bone mineral density and bone histology before and after
      correction of acidosis among patients with distal renal tubular acidosis (dRTA)
      METHODS: Correction of metabolic acidosis by potassium citrate was done in non
      azotemic dRTA patients, 6 females and 4 males, who had never received long-term
      alkaline therapy before enrolling into this study. Blood chemistries, serum
      intact parathyroid hormone, and 24-hour urine collection for the determination of
      urinary calcium, phosphate, sodium, potassium, bone mineral density
      determination, and transiliac bone biopsy were done in all patients at baseline
      and after one year of potassium citrate therapy. RESULTS: Significant elevations
      in serum bicarbonate (16.5 +/- 3.0 vs. 24.6 +/- 2.8 mEq/L, P < 0.05) and urinary
      potassium excretion (35.2 +/- 7.9 vs. 55.4 +/-3.5 mEq/L, P < 0.05) were observed
      after potassium citrate therapy. No significant alterations in other serum and
      urine electrolytes were found after the therapy. Serum intact parathyroid hormone
      level was also significantly elevated after one year of treatment (12.8 +/- 7.3
      vs. 26.2 +/- 8.7 pg/mL, P < 0.05). Bone formation rate was significantly
      suppressed at baseline and was normalized by the treatment (0.02 +/- 0.02 vs.
      0.06 +/- 0.03 microm(3)/microm(2)/day, P < 0.05). There were non-significant
      elevations in trabecular bone volume, osteoblastic and osteoclastic numbers. Bone
      mineral densities in dRTA patients were also significantly decreased below normal
      values in most studied areas at baseline and were significantly elevated at the
      trochanter of femur (0.677 +/- 0.136 vs. 0.748 +/- 0.144 g/c m(2), P < 0.05) and
      total femur (0.898 +/- 0.166 vs. 0.976 +/- 0.154 g/c m(2), P < 0.05) after the
      treatment. CONCLUSIONS: This study demonstrates that alkaline therapy corrects
      abnormal bone cell function and elevates bone mineral density in dRTA patients,
      indicating the causal role of acidosis in the alterations of bone cell functions
      and reduction in bone mineral density. Parathyroid gland activity also may be
      involved in the adaptation of the body to chronic metabolic acidosis.

PMID- 12427142
TI  - Randomized trial of darbepoetin alfa for treatment of renal anemia at a reduced
      dose frequency compared with rHuEPO in dialysis patients.
AB  - BACKGROUND: Darbepoetin alfa is a glycoprotein with a three-fold longer terminal
      half-life than recombinant human erythropoietin (rHuEPO). We aimed to determine
      whether darbepoetin alfa is as effective and well tolerated as rHuEPO for
      treating renal anemia in dialysis patients when administered at a reduced dose
      frequency. METHODS: A total of 522 European and Australian hemodialysis and
      peritoneal dialysis patients receiving stable rHuEPO therapy by either the
      intravenous (IV) or subcutaneous (SC) route were randomized, open-label in a 1:2
      ratio to continue rHuEPO or to receive an equivalent dose of darbepoetin alfa at
      a reduced dose frequency. Patients receiving rHuEPO once weekly changed to once
      every other week darbepoetin alfa, and those receiving rHuEPO two or three times
      weekly changed to once-weekly darbepoetin alfa. The doses of rHuEPO and
      darbepoetin alfa were titrated to maintain hemoglobin close to the patient's
      baseline level for up to 52 weeks. The primary endpoint was the change in
      hemoglobin between baseline and the evaluation period at weeks 25 to 32 of
      treatment. RESULTS: The mean change in hemoglobin from baseline to the evaluation
      period was similar in the darbepoetin alfa (-0.03 g/dL; SE 0.11) and rHuEPO (
      0.06 g/dL; SE 0.13) groups, and the difference between the two treatments was
      0.03 g/dL (95% CI -0.16, 0.21). This was not a statistically significant or
      clinically relevant difference, despite the reduced frequency of darbepoetin alfa
      administration. At the end of the evaluation period, >/=95% of patients had their
      hemoglobin successfully maintained on their assigned dose frequency for
      darbepoetin alfa (once weekly and once every other week) and rHuEPO (once, twice
      and three times weekly). The safety profiles of darbepoetin alfa and rHuEPO were
      similar, and no antibodies to either treatment were detected. CONCLUSIONS:
      Darbepoetin alfa maintains hemoglobin as effectively as rHuEPO, but with a
      reduced dose frequency.

PMID- 12427143
TI  - Gene for susceptibility to diabetic nephropathy in type 2 diabetes maps to
      18q22.3-23.
AB  - BACKGROUND: Diabetic nephropathy is the major cause of end-stage renal failure in
      patients with diabetes mellitus types 1 and 2. Epidemiological studies have
      suggested a genetic susceptibility to diabetic nephropathy. The aim of this study
      was to localize the gene(s) responsible for susceptibility to diabetic
      nephropathy. METHODS: A genetic linkage analysis was performed in 18 large
      Turkish families with type 2 diabetes mellitus and diabetic nephropathy. The
      result was checked in 101 affected sibling pairs of Pima Indians. RESULTS: A
      highly significant LOD score of 6.1 on chromosome 18q22.3-23 between the markers
      D18S469 and D18S58 was obtained in multipoint analysis. There was no indication
      for locus heterogeneity. In Pima Indians, linkage to the markers D18S469 and
      D18S58 was confirmed (P = 0.033), using the affected sib-pair method. The genetic
      model that fit best was a dominant mode of inheritance with an almost complete
      penetration in the Turkish population. CONCLUSIONS: There is strong evidence for
      the localization of a gene responsible for diabetic nephropathy in Turkish type 2
      diabetes mellitus patients. This locus maps to chromosome 18q22.3-23, between
      D18S43 and D18S50, an interval of 8.5 cM.

PMID- 12427144
TI  - Depletion of clusterin in renal diseases causing nephrotic syndrome.
AB  - BACKGROUND: Clusterin is a lipoprotein that has anti-complement effects in
      membranous nephropathy (MN). In focal segmental glomerulosclerosis (FSGS), it
      inhibits permeability plasma factor activity and could influence proteinuria.
      Moreover, with aging, knockout mice for clusterin develop a progressive
      glomerulopathy with sclerosis. METHODS: Since little is known about clusterin
      metabolism in humans, we determined clusterin levels and composition in the sera
      and urine of 23 patients with MN, 25 with FSGS and 23 with steroid-responsive
      nephrotic syndrome (NS). Renal localization was evaluated by immunofluorescence
      and morphometry. RESULTS: Serum clusterin was markedly reduced in active MN, in
      FSGS and in children with NS compared to controls; after stable remission of
      proteinuria, nearly normal levels were restored. Among various biochemical
      variables, serum clusterin was inversely correlated with hypercholesterolemia.
      Urinary clusterin, representing a 0.01 fraction of serum, was higher in the urine
      from normal subjects and FSGS patients in remission with proteinuric MN, FSGS and
      idiopathic NS; clusterin was inversely correlated with proteinuria. In all cases,
      urinary and serum clusterin was composed of the same 80 kD isoforms. Finally, a
      decrease in focal segmental or global clusterin staining was found in FSGS
      glomeruli, especially in areas of sclerosis. Instead, in MN an overall increment
      of staining was observed that ranged from mild/focal to very intense/diffuse.
      CONCLUSIONS: The overall pool of clusterin is reduced in glomerular diseases
      causing nephrotic syndrome, with hypercholesterolemia appearing as the unifying
      feature. Depletion of clusterin should negatively affect the clinical outcome in
      nephrotic patients and efforts should be aimed at normalizing clusterin overall
      pool.

PMID- 12427145
TI  - Evidence for elevated pulse pressure in patients on chronic hemodialysis: a case
      control study.
AB  - BACKGROUND: Few analyses have compared pulse pressure (PP) values in hemodialysis
      patients with healthy individuals, and they have provided only limited data. We
      retrospectively examined PP in a large cohort of hemodialysis patients and
      healthy control subjects. METHODS: The relationships of systolic blood pressure
      (SBP), diastolic blood pressure (DBP), and PP to mean arterial pressure (MAP)
      levels were investigated in 234 chronic hemodialysis patients and in 682 control
      subjects matched for age, sex, diabetes mellitus, and body mass index. RESULTS:
      In both control and patients, PP was positively correlated with MAP, and the two
      regression lines were parallel (beta of control subjects = 0.52; beta of
      hemodialysis patients = 0.57, P = 0.48). According to the regression line, at any
      MAP level, the PP in hemodialysis patients was significantly higher than that in
      control subjects: the mean PP difference between control and patients was 19.2 mm
      Hg (95% CI, 17.2 to 21.1 mm Hg, P < 0.0001). When the relationships between MAP
      and SBP and that between MAP and DBP were analyzed, the regression lines were
      also parallel. However, at any MAP level, SBP was higher and DBP was lower in
      hemodialysis patients than control subjects; the mean SBP difference was 12.8 mm
      Hg (95% CI, 11.5 to 14.1 mm Hg, P < 0.0001) and mean DBP difference was 6.4 mm Hg
      (95% CI, 5.7 to 7.0 mm Hg, P < 0.0001). CONCLUSIONS: At any MAP level,
      hemodialysis patients had a higher SBP, lower DBP, and higher PP values than
      those control subjects with a normal renal function who were matched for age,
      sex, diabetes mellitus, and body mass index. Further study is needed to determine
      whether preventing or reducing an elevated PP improves the prognosis for
      hemodialysis patients.

PMID- 12427146
TI  - A randomized controlled trial of N-acetylcysteine to prevent contrast nephropathy
      in cardiac angiography.
AB  - BACKGROUND: Contrast nephropathy (CN) is a common cause of renal dysfunction
      after cardiac angiography. Recently, N-acetylcysteine (NAC) has been found to
      reduce the risk of CN after CT imaging with contrast enhancement. The purpose of
      the current study was to evaluate the efficacy of NAC for the prevention of CN in
      the setting of cardiac angiography. METHODS: Eligible patients were those
      undergoing cardiac angiography with serum creatinine>1.7 mg/dL. Patients were
      randomized to one of two groups: Group 1, IV hydration and NAC, 1200 mg one hour
      before angiography, and a second dose 3 hours after; Group 2, IV hydration and
      placebo. CN was defined as an increase of 0.5 mg/dL in serum creatinine. RESULTS:
      Seventy-nine patients completed the study. There were no significant differences
      between the groups in baseline characteristics, duration of angiography, mean
      volume of dye infused or mean IV hydration. Contrast nephropathy developed in
      24.0% of subjects, 26.3% NAC, and 22.0% placebo (P = NS). Among subjects with
      diabetes mellitus, there was no significant difference in the rate of CN between
      the groups (42.1% NAC, 27.8% placebo; P = 0.09). The independent predictors of CN
      risk were diabetes mellitus and preexisting chronic renal insufficiency.
      CONCLUSIONS: NAC was not effective for the prevention of CN after cardiac
      angiography.

PMID- 12427147
TI  - Serum C-reactive protein and leptin as predictors of kidney disease progression
      in the Modification of Diet in Renal Disease Study.
AB  - BACKGROUND: In vitro and in vivo data suggest that markers of inflammation and
      nutritional status may be risk factors for the progression of chronic kidney
      disease. METHODS: We investigated whether higher levels of C-reactive protein
      (CRP) and leptin were risk factors for progression of chronic kidney disease in
      the Modification of Diet in Renal Disease (MDRD) Study. Frozen samples were
      assayed for high sensitivity C-reactive protein (CRP) or leptin in 804 patients.
      CRP and leptin were then evaluated as risk factors for glomerular filtration rate
      (GFR) decline using univariate and multivariable analyses. RESULTS: At baseline,
      the mean (median) CRP in Study A (GFR between 25 and 55 mL/min/1.73 m2) and Study
      B (GFR between 13 and 24 mL/min/1.73 m2) were 0.48 (0.25) and 0.46 (0.20) mg/dL,
      respectively, while the mean (median) leptin in Study A and Study B were 15.2
      (9.80) and 15.1 (7.80) ng/mL, respectively. Mean follow-up time was 2.2 years.
      The mean GFR decline was -4.33 and -3.65 mL/min/year in Study A and B,
      respectively. There was no significant association between the rate of GFR
      decline with the level of CRP or leptin in multivariable analysis in Study A
      [0.08 (-0.14, 0.30) mL/min/year slower GFR decline per twofold increase in CRP
      level; and 0.14 (-0.13, 0.40) mL/min/year slower GFR decline per twofold increase
      in leptin level], or in multivariable analysis in Study B [-0.05 (-0.28, 0.18)
      mL/min/year faster GFR decline per twofold increase in CRP level; and -0.12 (
      0.42, 0.19) mL/min/year faster GFR decline per twofold increase in leptin level].
      CONCLUSIONS: Higher serum levels of CRP and leptin are not independent risk
      factors for progression of non-diabetic kidney disease.

PMID- 12427148
TI  - Cost savings of home nocturnal versus conventional in-center hemodialysis.
AB  - BACKGROUND: Home nocturnal hemodialysis (HNHD) can improve clinical and
      biochemical factors in people with renal failure, but its cost-effectiveness
      relative to conventional in-center hemodialysis (IHD) is uncertain. We
      hypothesized that HNHD would provide more dialysis treatments at a lower total
      cost than IHD. METHODS: A prospective one-year descriptive costing study was
      performed at two centers in Toronto, Canada, involving patients enrolled from a
      HNHD program (N = 33), and a matched cohort from an IHD program (N = 23). All
      costs are expressed as mean weekly amount in Canadian year 2000 dollars. A
      projected mean annual cost (PMA) was calculated also. RESULTS: The mean number of
      treatments per week was much higher with HNHD (5.7 vs. 3.0, P = 0.004). Cost
      categories found to be less expensive for HNHD were staffing (weekly $210 vs.
      $423, P < 0.001, PMA $10,932 vs. $22,056) and overhead and support (weekly $80
      vs. $238, P < 0.001, PMA $4179 vs. $12,393). There was a trend toward lower costs
      for hospital admissions and procedures (weekly $23 vs. $134, P = 0.355, PMA $1173
      vs. $6997) and for medications ($172 vs. $231, P = 0.082, PMA $8989 vs. $12,029).
      Costs found to be more expensive for HNHD were the cost of direct hemodialysis
      materials (weekly $318 vs. $126, P < 0.001, PMA $16,587 vs. $6575) and capital
      costs (weekly $118 vs. $17, P < 0.001, PMA $6139 vs. $871), with a trend toward
      higher cost for laboratory tests (weekly $33 vs. $26, P = 0.094, PMA $1744 vs.
      $1364). Physician costs were the same at $128 per week (PMA $6650). The weekly
      mean total cost for health care delivery was 20% less for HNHD ($1082 vs. $1322,
      P = 0.006), with projected mean annual costs more than $10,000 lower ($56,394 vs.
      $68,935). CONCLUSIONS: HNHD provides about three times as many treatment hours at
      nearly a one-fifth lower cost, with savings evident even when only program and
      funding-specific costs are considered.

PMID- 12427149
TI  - Significance of the fractional excretion of urea in the differential diagnosis of
      acute renal failure.
AB  - BACKGROUND: Fractional excretion of sodium (FENa) has been used in the diagnosis
      of acute renal failure (ARF) to distinguish between the two main causes of ARF,
      prerenal state and acute tubular necrosis (ATN). However, many patients with
      prerenal disorders receive diuretics, which decrease sodium reabsorption and thus
      increase FENa. In contrast, the fractional excretion of urea nitrogen (FEUN) is
      primarily dependent on passive forces and is therefore less influenced by
      diuretic therapy. METHODS: To test the hypothesis that FEUN might be more useful
      in evaluating ARF, we prospectively compared FEUN with FENa during 102 episodes
      of ARF due to either prerenal azotemia or ATN. RESULTS: Patients were divided
      into three groups: those with prerenal azotemia (N = 50), those with prerenal
      azotemia treated with diuretics (N = 27), and those with ATN (N = 25). FENa was
      low only in the patients with untreated plain prerenal azotemia while it was high
      in both the prerenal with diuretics and the ATN groups. FEUN was essentially
      identical in the two pre-renal groups (27.9 +/- 2.4% vs. 24.5 +/- 2.3%), and very
      different from the FEUN found in ATN (58.6 +/- 3.6%, P < 0.0001). While 92% of
      the patients with prerenal azotemia had a FENa <1%, only 48% of those patients
      with prerenal and diuretic therapy had such a low FENa. By contrast 89% of this
      latter group had a FEUN <35%. CONCLUSIONS: Low FEUN (</=35%) was found to be a
      more sensitive and specific index than FENa in differentiating between ARF due to
      prerenal azotemia and that due to ATN, especially if diuretics have been
      administered.

PMID- 12427150
TI  - Antibody to oxidized low-density lipoprotein and cardiovascular mortality in end
      stage renal disease.
AB  - BACKGROUND: Immune response to oxidized low-density lipoprotein (oxLDL) may
      modulate the process of atherogenesis and cardiovascular disease. METHODS: We
      performed a prospective, observational cohort study in 249 patients with end
      stage renal disease (ESRD) to examine whether the serum titer of anti-oxLDL
      antibody can predict cardiovascular mortality. RESULTS: The median anti-oxLDL
      antibody titer was 320 mU/mL at baseline. During the follow-up (63 +/- 23
      months), 72 deaths including 34 cardiovascular deaths occurred. When the subjects
      were divided into two groups by the median titer, the high titer group showed a
      lower risk for cardiovascular mortality (P = 0.040 by Kaplan-Meier analysis and
      log-rank test). Multivariate Cox proportional hazards model indicated that the
      lower risk of cardiovascular death in the high titer group remained significant
      (hazard ratio of 0.46, 95%CI 0.23-0.95, P = 0.037) and independent of age,
      presence of vascular complications, presence of diabetes mellitus, and elevated C
      reactive protein. In contrast, anti-oxLDL antibody titer was not associated with
      non-cardiovascular mortality. CONCLUSIONS: These results demonstrate, to our
      knowledge for the first time, that serum anti-oxLDL antibody titer is an
      independent predictor of cardiovascular mortality in a cohort of patients with
      ESRD.

PMID- 12427151
TI  - Mortality risk in hemodialysis patients and changes in nutritional indicators:
      DOPPS.
AB  - BACKGROUND: Nutritional status is strongly associated with outcomes among
      hemodialysis patients. We analyzed the independent predictive value of several
      readily measured nutritional indicators, including a modified subjective global
      assessment (mSGA), body mass index (BMI), serum albumin, serum creatinine,
      normalized protein catabolic rate (nPCR), serum bicarbonate, lymphocyte count,
      and neutrophil count, using baseline and six-month follow-up measurements.
      METHODS: The study sample consisted of 7719 U.S. adult hemodialysis patients
      enrolled in the international Dialysis Outcomes and Practice Patterns Study
      (DOPPS), a prospective observational study that includes a random sample of
      hemodialysis patients from 145 dialysis facilities in the United States. Cox
      regression was used to estimate the relative risk of mortality associated with
      differences in measurements at baseline and six months later. Each analysis was
      adjusted for age, race, sex, and 15 summary comorbid conditions. RESULTS: Lower
      baseline measurements of mSGA, BMI, serum albumin, serum creatinine, and
      lymphocyte count were independently associated with significantly higher risk of
      mortality. During six-month follow-up, decreases in BMI, serum albumin, and serum
      creatinine were also associated with significantly higher mortality risk. The
      risk of mortality increased with higher baseline and six-month increases in
      neutrophil count. CONCLUSIONS: This study confirms that several readily-measured
      nutritional indicators predict mortality among hemodialysis patients and that
      changes in indicator values over six months provide additional important
      prognostic information. Interventions that modify these indicators of nutritional
      status may have an important impact on the survival of hemodialysis patients.

PMID- 12427152
TI  - Distribution of plasma folate forms in hemodialysis patients receiving high daily
      doses of L-folinic or folic acid.
AB  - BACKGROUND: We have previously reported that a daily oral high dose of l-folinic
      acid for the treatment of hyperhomocysteinemia in hemodialysis patients does not
      provide significantly greater reduction in fasting total homocysteine (tHcy)
      levels than an equimolar dose of folic acid. The present study uses the
      affinity/HPLC method to analyze the distribution of plasma folate forms in
      patients who received l-folinic acid versus those who received folic acid. This
      was done to investigate claims that renal insufficiency is associated with
      impaired folate interconversion, a stance that is supportive of the premise that
      tHcy lowering in these patients is more efficacious with folinic acid and other
      reduced folates, than folic acid. METHODS: Forty-eight chronic and stable
      hemodialysis patients were block-randomized, based on their screening predialysis
      tHcy levels, sex, and dialysis center, into two groups treated for 12 weeks with
      oral folic acid at 15 mg/day or an equimolar amount (20 mg/day) of oral l-folinic
      acid. All 48 subjects also received 50 mg/day of oral vitamin B6 and 1 mg/day of
      oral vitamin B12. Folate distribution was determined in plasma of 46 participants
      (Folinic acid group, N = 22; Folic acid group, N = 24) by using the affinity/HPLC
      method, with electrochemical (coulometric) detection. RESULTS: Both groups had
      similar baseline geometric means of plasma total folate and similar folate forms
      distribution. Following treatment, both groups demonstrated similar marked
      elevation in plasma total folate (geometric mean of the increase: Folinic acid
      group, +337 ng/mL; Folic acid group, +312 ng/mL; P = 0.796). In the folinic acid
      treated group, practically all of the increase in total folate was due to 5
      methyltetrahydrofolate. In the folic acid-treated group 5-methyltetrahydrofolate
      accounted for 35% of the increase in total folate and the remainder was
      unmethylated folic acid. CONCLUSIONS: Data from the present findings suggest that
      defects in folate absorption or impairment in folate interconversion are not the
      cause of the persistent hyperhomocysteinemia in hemodialysis patients.

PMID- 12427153
TI  - Hospitalized avascular necrosis after renal transplantation in the United States.
AB  - BACKGROUND: The national incidence of and risk factors for hospitalized avascular
      necrosis (AVN) in renal transplant recipients has not been reported. METHODS:
      This historical cohort study consisted of 42,096 renal transplant recipients
      enrolled in the United States Renal Data System (USRDS) between 1 July 1994 and
      30 June 1998. The data source was USRDS files through May 2000. Associations with
      hospitalizations for a primary diagnosis of AVN (ICD-9 codes 733.4x) within three
      years after renal transplant were assessed in an intention-to-treat design by Cox
      regression analysis. RESULTS: Recipients had a cumulative incidence of 7.1
      episodes/1000 person-years from 1994 to 1998. The two-year incidence of AVN did
      not change significantly over time. Eighty-nine percent of the cases of AVN were
      due to AVN of the hip (733.42) and 60.2% of patients with AVN underwent total hip
      arthroplasty (THA); these percentages did not change significantly over time. In
      the Cox regression analysis, an earlier year of transplant, African American race
      [adjusted hazard ratio (AHR), 1.65, 95% confidence interval (CI) 1.33 to 2.03],
      allograft rejection (AHR 1.67, 95% CI 1.35 to 2.07), peritoneal dialysis (vs.
      hemodialysis; AHR 1.44, 95% CI 1.15 to 1.81), and diabetes (AHR 0.41, 95% CI 0.27
      to 0.64) were the only factors independently associated with hospitalizations for
      AVN. CONCLUSIONS: The incidence of AVN did not decline significantly over time in
      the renal transplant population. Patients with allograft rejection, African
      American race, peritoneal dialysis and earlier date of transplant were at the
      highest risk of AVN, while diabetic recipients were at a decreased risk.

PMID- 12427154
TI  - Expression of TGF-beta and fibrogenic genes in transplant recipients with
      tacrolimus and cyclosporine nephrotoxicity.
AB  - BACKGROUND: Long-term treatment with cyclosporine (CsA) or tacrolimus (Tac)
      results in chronic nephrotoxicity. Transforming growth factor-beta (TGF-beta) and
      other pro-fibrogenic molecules have been known to contribute to this side effect.
      A comparison of intrarenal expression of TGF-beta and other fibrogenic genes in
      biopsies from patients with either CsA or Tac nephrotoxicity have not been
      documented. This study compared the expression of TGF-beta, collagen,
      fibronectin, metalloproteinases (MMP-2, -9), tissue inhibitors of
      metalloproteinases (TIMP-2) and osteopontin in renal biopsies obtained from renal
      transplant recipients treated with either CsA or Tac as primary immunosuppressive
      agents. METHODS: Using RT-PCR, intrarenal expression of TGF-beta, collagen,
      fibronectin, MMP-2, MMP-9 and TIMP-2 were studied in renal biopsies from patients
      with histological diagnosis of CsA or Tac nephrotoxicity and acute rejection. TGF
      beta protein expression was studied by staining section of biopsies with anti-TGF
      beta antibody. RESULTS: Intrarenal expression of TGF-beta, collagen, fibronectin,
      MMP-2, TIMP-2, and osteopontin were significantly increased in patients treated
      with Tac nephrotoxicity compared with CsA nephrotoxicity. The intrarenal mRNA
      expression of these genes was higher in patients diagnosed with Tac/CsA
      nephrotoxicity compared to acute rejection. CONCLUSIONS: This study compares the
      intrarenal expression of TGF-beta and profibrogenic genes in renal transplant
      recipients treated with Tac and CsA. The results show that patients diagnosed
      with Tac nephrotoxicity exhibit increased expression of profibrogenic genes
      compared to CsA nephrotoxicity.

PMID- 12427155
TI  - Renal replacement therapies in the aftermath of the catastrophic Marmara
      earthquake.
AB  - BACKGROUND: Renal replacement therapy is of vital importance in the treatment of
      crush syndrome victims, who are frequently encountered after catastrophic
      earthquakes. The Marmara earthquake, which struck Northwestern Turkey in August
      1999, was characterized by 477 victims who needed dialysis. METHOD: Within the
      first week of the disaster, questionnaires containing 63 clinical and laboratory
      variables were sent to 35 reference hospitals that treated the victims.
      Information considering the features of dialyses obtained through these
      questionnaires was submitted to analysis. RESULTS: Overall, 639 casualties with
      renal complications were registered, 477 of whom (mean age 32.3 +/- 13.7 years,
      269 male) needed dialysis. Among these, 452 were treated by a single dialysis
      modality (437 intermittent hemodialysis, 11 continuous renal replacement therapy
      and 4 peritoneal dialysis), while 25 victims needed more than one type of
      dialysis. In total, 5137 hemodialysis sessions were performed (mean 11.1 +/- 8.0
      sessions per patient) and mean duration of hemodialysis support was 13.4 +/- 9.0
      days; this duration was shorter in the non-survivors (7.0 +/- 8.7 vs. 10.0 +/-
      9.8 days, P = 0.005). Thirty-four victims who underwent continuous renal
      replacement therapy had higher mortality rates (41.2 vs. 13.7%, P < 0.0001). Only
      eight victims were treated by peritoneal dialysis, four of whom also required
      hemodialysis or continuous renal replacement therapy. The mortality rate in the
      dialyzed victims was 17.2%, a significantly higher figure compared to the
      mortality rate of the non-dialyzed patients with renal problems (9.3%; P =
      0.015). CONCLUSION: Substantial amounts of dialysis support may be necessary for
      treating the victims of mass disasters complicated with crush syndrome. Dialyzed
      patients are characterized by higher rates of morbidity and mortality.

PMID- 12427156
TI  - Aggressive venous neointimal hyperplasia in a pig model of arteriovenous graft
      stenosis.
AB  - BACKGROUND: Vascular access dysfunction is the most important cause of morbidity
      and hospitalization in the hemodialysis population in the United States at a cost
      of well over one billion dollars per annum. Venous neointimal hyperplasia
      characterized by stenosis and subsequent thrombosis, is the major cause of
      polytetrafluoroethylene (PTFE) dialysis graft failure. Despite the magnitude of
      the problem, there are currently no effective therapies for the prevention or
      treatment of venous neointimal hyperplasia in PTFE dialysis grafts. We believe
      that this is partly due to the lack of a validated large animal model of
      arteriovenous stenosis that could be used to test out novel interventions.
      METHODS: Seven-centimeter PTFE loop grafts were placed between the femoral artery
      and vein of domestic pigs. The grafts were removed at 2, 4, 7, 14 and 28 days
      after surgery and subjected to a detailed histological and immunohistochemical
      examination. RESULTS: Significant neointimal hyperplasia and venous stenosis
      developed by 28 days at the graft-vein anastomosis. There was minimal neointimal
      hyperplasia at the graft-artery anastomosis. Venous neointimal hyperplasia (VNH)
      was characterized by (a) the presence of smooth muscle cells/myofibroblasts; (b)
      angiogenesis within both the neointima and adventitia; and (c) the presence of an
      active macrophage cell layer lining the PTFE graft material. These results are
      very similar to the human lesion previously described by us in dialysis patients.
      CONCLUSIONS: We have developed and validated a pig model of venous neointimal
      hyperplasia that is very similar to the human lesion. We believe that this is an
      ideal model in which to test out novel interventions for the prevention and
      treatment of clinical hemodialysis vascular access dysfunction.

PMID- 12427157
TI  - Hypertension as a determinant of survival for patients treated with home
      dialysis.
AB  - BACKGROUND: Previous studies of the risks of hypertension for dialysis patients
      have yielded conflicting results. The aim of this study was to investigate, in a
      home dialysis population with low rates of diabetes and antihypertensive drug
      use, whether blood pressure (BP) was an independent risk factor for survival.
      METHODS: The outcome of 168 consecutive patients (94 male, 88% Caucasian), aged
      48 years (SD 16), who began home hemodialysis (HD; N = 124) or home continuous
      ambulatory peritoneal dialysis (CAPD; N = 44) between January 1, 1985 and
      December 31, 1994 were analyzed retrospectively. Only 4.7% of patients took
      antihypertensive drugs while on dialysis. The patients were followed to December
      31, 1998 with the primary outcome being all-cause mortality. Censoring events
      were transplantation, transfer to another center and treatment modality change.
      The Cox proportional hazard model was used with baseline predictors. RESULTS:
      Seventy-one patients died and the median overall survival was 4.2 years (5.6 on
      HD, 2.2 on CAPD, P < 0.0001). Mean BP at start of dialysis predicted survival on
      its own (P = 0.0009) and in the joint Cox model (P = 0.047). Other significant
      predictors in the joint model were age [10 year increase, relative hazard (RH) =
      1.55, P = 0.0008], albumin (10 g/L decrease, RH = 2.05, P = 0.007), diabetes (RH
      = 3.42, P = 0.015) and peripheral vascular disease (RH = 2.19, P = 0.02) but not
      dialysis modality (RH = 1.63, P = 0.13). High and low mean blood pressure (BP)
      values at the start of dialysis were associated with the highest mortality.
      CONCLUSIONS: Among the home dialysis patients, most of whom did not require
      antihypertensive drugs, hypertension was a risk factor for survival and patients
      with mid-range BP values survived the longest.

PMID- 12427158
TI  - Comparison of three methods to quantify urinary aquaporin-2 protein.
AB  - BACKGROUND: Urinary excretion of aquaporin-2 (AQP2) is measurable, and is
      regulated by renal vasopressin action in the principal cells of the collecting
      duct. To date, two methods [radioimmunoassay (RIA) and quantitative immunoblot
      analysis (IB)] have been used for quantitation of urinary AQP2 protein. However,
      the actual amount of urinary AQP2 measured has not been directly compared by the
      RIA and IB. Recently, we have established an enzyme-linked immunosorbent assay
      (ELISA) for quantitation of urinary AQP2. The purpose of our current study was to
      compare three different immunoassay methods for measurement of urinary AQP2.
      METHODS: After overnight dehydration, five normal subjects ingested an oral water
      load (20 mL/kg). Urine was collected at 0, 1, 2, 3, and 4 hours after oral water
      loading. Urinary AQP2 protein was quantitated in each sample by using the RIA,
      IB, and ELISA, and the correlation coefficients were compared among three
      different methods. RESULTS: Values of urinary AQP2 at 0, 1, 2, 3, and 4 hours
      after oral water loading for RIA, IB, and ELISA were, respectively (fmol/mg
      creatinine): 0 h: 266 +/- 28, 405 +/- 74, 294 +/- 41; 1 h: 159 +/- 59, 267 +/-
      147, 195 +/- 95; 2 h: 48 +/- 17, 19 +/- 10, 38 +/- 18; 3 h: 79 +/- 18, 70 +/- 24,
      80 +/- 15; 4 h: 147 +/- 21, 161 +/- 31, 136 +/- 15. All values were shown as
      means +/- SEM. There was a significant positive correlation between: the IB and
      ELISA (r = 0.91, P < 0.0001); the IB and RIA (r = 0.75, P < 0.0001); and the RIA
      and ELISA (r = 0.67, P < 0.0002). The correlation between the IB and ELISA was
      therefore the best. Also, urinary AQP2 was positively correlated with urine
      osmolality among all three methods. CONCLUSIONS: The results indicate that the
      newly developed IB and ELISA methods are useful for measurement of urinary AQP2
      and have an excellent correlation.

PMID- 12427159
TI  - A simple method for the specific detection of Ren-1 renin.
AB  - BACKGROUND: Ren-1 and Ren-2 renin are expressed in the kidneys of all mice and in
      the submandibular gland of several mouse strains. The present study determined
      the usefulness of modified periodic acid silver-methenamine (PAM) staining for
      the specific detection of Ren-1 renin. METHODS: Conventional paraffin sections
      were prepared from kidneys of ICR, BALB/cA, C57BL/6Cr, C3H/HeN, DBA/2Cr,
      angiotensin II type 1a receptor gene knockout (AT1aKO) mice, Wistar rats and a
      human, and submandibular glands of C57BL/6Cr and DBA/2Cr mice. Sections were
      analyzed for the presence of renin using PAM and immunohistochemistry. PAM
      reactions were terminated at generally or weakly intense (weak PAM staining; W
      PAM). In addition, kidneys of DBA/2Cr mice were fixed using various fixatives
      (formalin, PFA, PLP, Zamboni's, Bouin's, or Carnoy's) and treated using identical
      procedures. RESULTS: Although PAM-positive reactions were observed in
      juxtaglomerular (JG) cells, W-PAM reactions were particularly specific for these
      cells. These findings were observed in all mouse strains. Immunohistochemistry
      using mirror sections suggested that a W-PAM-positive reaction detected renin.
      This hypothesis was confirmed by the results from AT1aKO mice. Briefly, W-PAM
      detected an expansion of renin-positive areas in AT1aKO mice. Rat and human
      kidneys and mouse submandibular glands were negative for W-PAM. Levels of JG cell
      detection by W-PAM were similar in samples fixed in formalin, PFA, PLP, or
      Zamboni's. CONCLUSIONS: The present findings show that W-PAM can identify Ren-1
      renin, but not Ren-2, rat or human renin. The W-PAM method is useful for the
      specific detection of Ren-1 renin.

PMID- 12427160
TI  - Hyperbaric oxygen therapy in the treatment of calciphylaxis? Yes, more than hope.

PMID- 12427162
TI  - Treatment of primary focal segmental glomerulosclerosis.

PMID- 12427166
TI  - Responsiveness to staff support: evaluating the impact of individual
      characteristics on the effectiveness of active support training using a
      conditional probability approach.
AB  - BACKGROUND: Active support training was fully conducted in 38 community houses
      accommodating 106 adults with intellectual disabilities (ID; group 1), but not in
      a further 36 accommodating 82 adults with ID (group 2). The aims of the present
      study were to analyse whether staff became more effective in supporting resident
      activity after the implementation of active support, and whether there was
      evidence of differential responsiveness by people with differing status in
      relation to adaptive behaviour, psychiatric diagnosis, challenging behaviour or
      autism. METHODS: Observations of staff:resident interaction and resident
      engagement in activity were taken before and after active support training.
      Changes in Yule's Q statistics, indicating the likelihood that resident
      engagement in activity followed staff giving residents verbal instruction or non
      verbal assistance, were compared for the two groups. In addition, changes in
      similar statistics were compared for residents within group 1: (1) with Adaptive
      Behaviour Scale (ABS) scores above and below 180; and (2) with and without severe
      challenging behaviour, the triad of social impairments and mental illness.
      RESULTS: Yule's Q for engagement given non-verbal assistance significantly
      increased post-training among group 1, but not among group 2. Similar significant
      increases were found among group 1 residents with ABS scores below 180 without
      challenging behaviour, with and without the triad of social impairments, and
      without mental illness, but not with an ABS score above 180, with challenging
      behaviour and with mental illness. CONCLUSION: The present analysis reinforces
      previous studies on the effectiveness of active support training for adults with
      more severe ID (i.e. with ABS scores below 180). Active support was as effective
      for people with the triad of social impairments as for those without it. However,
      the effectiveness of support offered to people with challenging behaviour or
      mental illness did not significantly increase.

PMID- 12427165
TI  - Specialist health services for people with intellectual disability in Scotland.
AB  - BACKGROUND: People with intellectual disability (ID) are known to have a high
      prevalence of health needs, and to require access to specialist health services
      in addition to primary care and generic secondary care health services. However,
      there is no national database of each locality's specialist health service
      provision. Such a record would highlight variation in provision and enable
      benchmarking. METHOD: A 15-item questionnaire was developed which included
      questions on ID health services and staffing levels. This was sent to the chief
      executive of each of the 15 identified National Health Service primary care
      trusts/health boards which provide ID services in Scotland. The same
      questionnaire was also sent to the lead clinician/clinical director of each
      service. The results were converted to per 100 000 population per trust and
      presented in cumulative frequency tables to allow benchmarking. RESULTS: A
      response rate of 100% was achieved. The results show a wide range in the type of
      services provided by each locality in Scotland. Only three services (21%) have
      completed the process of resettlement. There was a wide-ranging variability in
      the number of beds/day places and professionals employed per 100 000 population
      per trust. CONCLUSIONS: There is widespread diversity in the service provision
      between different parts of Scotland. Geographical distances and responsibilities
      for service provision to remote and rural communities did not appear to account
      for these differences.

PMID- 12427167
TI  - A pilot study of the reliability and validity of the Caregiver Activity Survey -
      Intellectual Disability (CAS-ID).
AB  - BACKGROUND: People with Down's syndrome (DS) are at increased risk of Alzheimer
      type dementia (AD) when compared to the general population. Despite AD being a
      serious progressive disorder, little attention has been paid to the impact of the
      illness on formal caregivers. In the general population, the Caregiver Activity
      Survey (CAS) is used to measure time spent by family caregivers assisting people
      with AD in their day-to-day activities of living. In order to plan appropriate
      models of health and social care effectively for people with AD and DS, it is
      imperative that the care requirements of individuals at different stages of
      dementia are realized. An amended version of this survey, the Caregiver Activity
      Survey - Intellectual Disability (CAS-ID), was developed and tested for use by
      professional caregivers in the present study. METHODS: The CAS-ID was
      administered to 30 people with DS and their caregivers. Convergent validity was
      tested by comparing the results of the CAS-ID to other validated tests for
      cognitive and functional impairment in individuals with DS. Test-retest and inter
      rater reliability were investigated. RESULTS: The final version of the CAS-ID
      consists of eight items: dressing, bathing/showering, grooming, toileting, eating
      and drinking, housekeeping, nursing care-related activities, and supervision/
      behaviour management. The scale had excellent test-retest reliability, and
      correlated strongly with the Down Syndrome Mental Status Examination (DSMSE; r = 
      0.770), the Test for Severe Impairment (TSI; r = -0.881) and the Daily Living
      Skills Questionnaire (DLSQ; r = -0.855). CONCLUSIONS: The present authors provide
      preliminary evidence for the validity and reliability of the CAS-ID. This
      instrument offers a means of identifying and measuring care and resources
      requirements as this population experiences symptoms of dementia. Such
      information may help assist healthcare professionals in planning supports and
      services to address the care challenges evidenced at different stages of the
      disease process.

PMID- 12427168
TI  - Word-length effect in verbal short-term memory in individuals with Down's
      syndrome.
AB  - BACKGROUND: Many studies have indicated that individuals with Down's syndrome
      (DS) show a specific deficit in short-term memory for verbal information. The aim
      of the present study was to investigate the influence of the length of words on
      verbal short-term memory in individuals with DS. METHODS: Twenty-eight children
      with DS and 10 control participants matched for memory span were tested on verbal
      serial recall and speech rate, which are thought to involve rehearsal and output
      speed. RESULTS: Although a significant word-length effect was observed in both
      groups for the recall of a larger number of items with a shorter spoken duration
      than for those with a longer spoken duration, the number of correct recalls in
      the group with DS was reduced compared to the control subjects. The results
      demonstrating poor short-term memory in children with DS were irrelevant to
      speech rate. In addition, the proportion of repetition-gained errors in serial
      recall was higher in children with DS than in control subjects. CONCLUSIONS: The
      present findings suggest that poor access to long-term lexical knowledge, rather
      than overt articulation speed, constrains verbal short-term memory functions in
      individuals with DS.

PMID- 12427169
TI  - Behaviour problems in adult women with Rett syndrome.
AB  - BACKGROUND: Despite considerable interest in the genetic, physical and
      neurological aspects of Rett syndrome (RS), there have been few studies of
      associated behavioural and emotional features. Furthermore, few case studies or
      surveys have included adult women with RS. The main aim of the present study was
      to compare behaviour problems in a sample of women with RS against data from
      normative samples. METHODS: The primary carers of 50 women with RS completed the
      community version of the Aberrant Behavior Checklist. RESULTS: Women with RS were
      rated as having lower levels of irritability, hyperactivity and inappropriate
      speech behaviours than normative samples of adults with intellectual disability.
      CONCLUSIONS: A number of factors may affect the presentation of behaviour
      problems in women with RS (e.g. cognitive impairments or physical disabilities).
      Therefore, more research is needed in order to generate information about the
      behavioural phenotype of RS. The implications of the present data for future
      research are also discussed.

PMID- 12427173
TI  - Removing barriers to optimize the delivery of pain management.

PMID- 12427170
TI  - Residential care in the community for adults with intellectual disability: needs,
      characteristics and services.
AB  - BACKGROUND: The pattern of residential services for people with intellectual
      disability in England has changed dramatically since 1971, with many more places
      being made available in residential homes in the community. The aim of the
      present study was to assess the needs and characteristics of residents and
      features of all the residential homes provided by a national charity. METHOD:
      Assessments of adaptive behaviour, problem behaviour and social impairment were
      completed by staff who knew residents well; information about costs and staffing
      was provided from central records. RESULTS: A significant proportion of residents
      have important care needs relating to their skills, their behaviour and their
      social abilities. Residents with these needs are dispersed throughout services,
      so that a large majority of services include one or more residents with
      relatively complex needs. CONCLUSIONS: Compared with services in the late 1980s,
      these services care for a much more disabled client group. Since individuals with
      high levels of particular needs are typically distributed throughout services, a
      very high proportion of services require staff who have relatively advanced
      skills. Current national plans do not adequately address this need and case
      management arrangements may encourage the re-creation of more institutional
      services. DECLARATION OF INTEREST: The first author is a Trustee of the charity.

PMID- 12427174
TI  - Educating nurses about pain management: the way forward.
AB  - Nurse education does not appear to be preparing nurses to manage pain in the
      clinical area. A number of studies have demonstrated that nurses continue to have
      educational deficits in this context. Several studies have found no change in
      knowledge or behaviours following education about pain management. Others have
      found that changes in behaviour do occur. It is possible that innovative teaching
      strategies need to be used. The literature in this area is reviewed and
      recommendations made.

PMID- 12427175
TI  - White coat hypertension: understanding the concept and examining the
      significance.
AB  - Because the concept of white coat hypertension is evolving, a variety of
      definitions appear in the literature. There has also been continuing debate as to
      whether white coat hypertension is a benign clinical condition or is associated
      with increased hypertensive complications. This paper summarizes and evaluates
      the literature on white coat effect/hypertension, with a focus on the following
      aspects of the concepts: (1) alternative definitions, (2) prevalence and
      predictors, (3) prognostic significance, and (4) implications for clinical
      practice. The evidence suggests that white coat hypertension is not a harmless
      phenomenon. It is frequently associated with increased target-organ damage and
      often coexists with other cardiovascular risk factors. The extent of the presence
      of other risk factors may determine the risks associated with white coat
      hypertension. It is important for clinicians to understand the concept, learn to
      diagnose it properly, and develop strategies for evaluating risk levels so that
      patients receive the proper treatment.

PMID- 12427176
TI  - Cox proportional hazards model.

PMID- 12427177
TI  - Observation of pain assessment and management--the complexities of clinical
      practice.
AB  - Pain assessment and management are complex issues that embrace physiological,
      emotional, cognitive, and social dimensions. This observational study sought to
      investigate nurse-patient interactions associated with pain assessment and
      management in hospitalized postsurgical patients in clinical practice settings.
      Twelve field observations were carried out on Registered Nurses' activities
      relating to pain with their assigned patients. All nurses were involved in direct
      patient care in one surgical unit of a metropolitan teaching hospital in
      Melbourne, Australia. Six observation times were identified as key periods for
      activities relating to pain, which included change of shift and high activity
      periods. Each observation period lasted 2 hours and was examined on two
      occasions. Four major themes were identified as barriers to effective pain
      management: nurses' responses to interruptions of activities relating to pain,
      nurses' attentiveness to patient cues of pain, nurses' varying interpretations of
      pain, and nurses' attempts to address competing demands of nurses, doctors and
      patients. These findings provide some understanding of the complexities impacting
      on nurses' assessment and management of postoperative pain. Further research
      using this observational methodology is indicated to examine these influences in
      more depth. This knowledge may form the basis for developing and evaluating
      strategic intervention programmes that analyse nurses' management of
      postoperative pain and, in particular, their administration of opioid analgesics.

PMID- 12427178
TI  - Nursing documentation of postoperative pain management.
AB  - Previous studies have shown that nursing documentation is often deficient in its
      recording of pain assessment and treatment. In Sweden, documentation of the care
      process, including assessment, is a legal obligation. The aim of this study was
      to describe nursing documentation of postoperative pain management and nurses'
      perceptions of the records in relation to current regulations and guidelines. The
      sample included nursing records of postoperative care on the second postoperative
      day from 172 patients and 63 Registered Nurses from surgical wards in a central
      county hospital in Sweden. The records were reviewed for content and
      comprehensiveness based on regulations and guidelines for postoperative pain
      management. Three different auditing instruments were used. The nurses were asked
      if the documentation concurred with current regulations and guidelines. The
      result showed that pain assessment was based mainly on patients' self-report, but
      less than 10% of the records contained notes on systematic assessment with a pain
      assessment instrument. Pain location was documented in 50% of the records and
      pain character in 12%. About 73% of the nurses reported that the documentation
      concurred with current regulations and guidelines. The findings indicate that
      significant flaws existed in nurses' recording of postoperative pain management,
      of which the nurses were not aware.

PMID- 12427179
TI  - Refusing analgesics: using continuous improvement to improve pain management on a
      surgical ward.
AB  - Despite advances in pain control many patients experience moderate to severe pain
      whilst in hospital. Contributory factors include inadequate assessment and
      documentation of pain, as well as patient and professional misconceptions. A 28
      bedded surgical ward in a District General Hospital in the South of England was
      the setting for the project. A small preliminary audit of pain on this ward
      indicated that some patients experienced postoperative pain, which was not
      effectively controlled. A 'continuous improvement' framework was used to increase
      understanding of the problem and identify an aim for the project, which was to
      reduce the number of patients refusing analgesics when offered by nurses. An
      audit to ascertain how many patients refused analgesia revealed that, of 133
      patients offered, 93 (70%) refused. Using the 'Model for Improvement' (Langley et
      al., 1996) a number of changes were introduced, including a patient information
      sheet, regular documented pain assessment and an innovative staff education
      programme. To evaluate if the changes in practice had been successful, further
      audit data were collected from 167 patients. Sixty-three (44%) accepted
      analgesics, indicating a significant decrease in the number refusing (P = 0.005).
      This small project demonstrated that continuous improvement methodology can
      improve the management of pain and quality of care for patients. Such an approach
      brings practitioner and patient into meaningful understanding and offers
      solutions which are realistic, achievable and sustainable over time. Despite
      finite resources and increased pressure on staff it is possible to motivate
      people when they feel they have ownership and change is meaningful. Continuous
      improvement methods offer an exciting, feasible, patient-centred approach to
      improving care.

PMID- 12427180
TI  - A pain workshop: an approach to eliciting the views of young people with chronic
      pain.
AB  - Chronic pain is complex and there is still much to discover about the burden that
      it places on children and their families. The aim of this study was to explore
      the way in which the experience of chronic pain impacts on the lives of young
      people. Through the use of a pain workshop that involved a series of guided
      activities and a focus group, young people were able to share their experiences
      with each other and the facilitators/researchers. Data were analysed using a
      theoretical coding technique supported by Atlas.ti. Five key interlinked themes
      emerged from the data and each theme is expressed in the words of the young
      people themselves: 'no one's pain's the same', 'getting on with it', 'it's hard
      'cos...', 'keeping with the dream', and 'it depends ... some are OK'. The young
      people did experience significant disruption in their lives as a result of their
      pain. Pain was experienced as if it was both a separate entity as well as an
      intrinsic part of them and, to a degree, blighted their future. Based on the
      experiences shared by the young people, professionals need to develop insight and
      strategies into the challenges young people with chronic pain face on a daily
      basis.

PMID- 12427181
TI  - Documenting diabetes care: the diabetes nurse specialists' perspective.
AB  - Diabetes Nurse Specialists (DNSs) are often the hub of the communications network
      for the entire diabetes multiprofessional health care team, patients and their
      families. Frequently they liaise between primary and secondary care and have a
      key role in the provision of a 'seamless service'. To work effectively and
      efficiently they need a foolproof system of documentation and communication. The
      aim of the study was to investigate the means by which DNSs document patient care
      in order to provide baseline information about ongoing record-keeping practices.
      The study comprised a cross-sectional survey in which data were obtained by
      questionnaire. All DNSs in the UK registered with the British Diabetic
      Association were invited to participate in the study. A 70.3% response rate was
      achieved (n = 545). The results indicated that manual profession-specific records
      were used by 65.3% of DNSs, 21.1% used shared/integrated records, 12.8% used
      computerized records and only 0.7% made use of patient-held records. Whilst
      almost all DNSs felt that a good record-keeping system was essential in providing
      'seamless care' to patients, not all felt their system was efficient. Of those
      using a computerized system 65.7% rated it as efficient, compared with only 28.1%
      of those using a profession-specific system and 26.1% of those using a manual
      shared system. A high percentage of DNSs (65.9%) felt that the provision of
      'seamless care' was hindered by communication problems with members of other
      professional groups. The findings from this study indicate that computers alone
      cannot bridge the gap between primary and secondary care, but 'seamless care' may
      become more of a reality with computerized record-keeping systems and
      participation by all members of the multidisciplinary team.

PMID- 12427182
TI  - Improving glycaemic control of insulin-treated diabetic patients--a structured
      audit of specialist nurse intervention.
AB  - Insulin-treated diabetic patients with poor glycaemic control are frequently
      referred to diabetes specialist nurses, but little data exist as to the
      effectiveness of this practice. We therefore analysed the progress of 43
      prospectively referred insulin-treated patients with glycosylated haemoglobin
      (HbA1c) levels > 7.5%. Diabetes nurse intervention involved re-education, dietary
      advice and insulin dose adjustment. Improvement in control was defined as a final
      HbA1c < 7.0% or a fall of HbA1c of > 1.0% at 6 months post-intervention. Almost
      two-thirds (63%) of patients achieved improvement status, with no increase in
      body weight or hypoglycaemic episodes. Disappointingly, however, the 'non
      improver' group (37%) showed a mean deterioration in HbA1c. In conclusion,
      diabetes nurse intervention for poorly controlled insulin-treated diabetic
      patients is generally effective, but intervention may be best targeted to
      responsive patients. The factors which influence diabetic patients'
      'responsiveness to change' require further investigation.

PMID- 12427183
TI  - Psychosocial maturity among people with diabetes mellitus.
AB  - There is a relationship between coping with chronic illness and a person's
      psychosocial development. The aim of this study was to describe dimensions of
      psychosocial development based on results of a previous factor analysis of the
      Modified Erikson Psychosocial Stage Inventory among people with type 2 diabetes.
      Interviews were carried out with 10 people with diabetes. The transcribed
      interviews were analysed by qualitative content analysis into main categories,
      categories and themes. The categories were trust, lack of trust, positive
      identity, identity confusion, integrity and lack of integrity. Themes that
      permeated the categories in a positive way were 'activity' and 'involvement',
      while themes that permeated the categories in a negative way were 'passivity' and
      'alienation'. Our interpretation is that the category 'trust' is the basis for
      'identity', and together 'trust' and 'identity' are the basis for maturity and
      'integrity'. A conclusion is that positive psychosocial maturity has to do with
      attaining trust, identity and integrity through activity and involvement.
      Qualities important for maturation through trust, identity and integrity are
      understanding, capacity, purposefulness and fortitude. Our interpretation of
      maturity is considered as being an important and interesting focus in nursing,
      while the above related qualities are closely connected to coping with diabetes.

PMID- 12427184
TI  - Being a palliative care nurse in an academic hospital: a qualitative study about
      nurses' perceptions of palliative care nursing.
AB  - The original philosophy of palliative care emphasizes the importance of the
      integration of compassion and medical science. The meaning palliative care nurses
      assign to their relationships with patients has been described in several
      studies. This qualitative research was undertaken in order to elicit the way
      nurses working on a palliative care ward in an academic hospital perceive their
      role and gain insight into the problems they encounter. The findings present two
      different perceptions held by nurses about the nature of their work. The first,
      the more prominent, is 'striving to adopt a well-organized and purposeful
      approach as a nurse on an academic ward'; the second is 'striving to enhance the
      well-being of the patient'. Nurses should be supported in the development of
      their palliative care approach and be assisted in reflecting on their practice in
      terms of a model of 'reflective practice' and in the development of 'moral
      imagination'.

PMID- 12427185
TI  - Management of relatives of patients who are dying.
AB  - Previous research in a retrospective community-based study suggested that some
      relatives had difficulty coping with their bereavement when the pre-bereavement
      period had not been managed well. This prospective study in a hospital setting
      explored the issues further to include the views and needs of staff as well as
      relatives. Staff were interviewed in focus groups and relatives were interviewed
      individually. Analysis of data was qualitative using thematic analysis. Findings
      demonstrated that staff often felt ill-equipped for providing support for
      relatives when a patient is dying. Training is required to help nurses support
      and care for the relatives of dying patients.

PMID- 12427186
TI  - Developing palliative care practice in nursing and residential care homes: the
      role of the clinical nurse specialist.
AB  - The development of practice is but one aspect of Clinical Nurse Specialists'
      (CNSs) work, and a number of factors act to shape the extent to which CNSs are
      able to work with and develop practice with nursing and residential care homes. A
      postal survey of 730 community CNSs in palliative care working in the UK was
      undertaken to explore the involvement of these nurses with nursing and
      residential care homes. Much of the focus of the involvement was reactive work
      meeting the direct clinical needs of residents, primarily with cancer. Although
      the CNSs perceived that there were some educational and care deficits in these
      care settings, the amount of proactive work undertaken to improve practice was
      limited. The development work undertaken was focused on educational initiatives
      and establishing link nurse systems. There is potential to develop palliative
      care practice in nursing and residential care homes through practice development
      initiatives.

PMID- 12427187
TI  - Clinical group supervision in an intensive care unit: a space for relief, and for
      sharing emotions and experiences of care.
AB  - Much has been written about models, aims and the concept of clinical group
      supervisional, although few studies are empirical or focus on intensive care. The
      aim of the study was to illuminate the process and describe, using qualitative
      content analysis, the content of conversations carried out during the course of
      clinical group supervision sessions among Registered Nurses (RN) and enrolled
      nurses (EN) working in an intensive care unit (ICU). During the supervision
      sessions, ENs talked about their life-world from a caring perspective, while RNs
      focused on their professional development. Both ENs and RNs regarded the
      supervision sessions as a space for relief and for sharing emotions and caring
      experiences, which helped to manage complex nursing care. The findings are viewed
      in the light of Roach's theoretical framework describing the attributes of
      professional care as five Cs. Clinical group supervision is interpreted as
      supportive in developing interpersonal skills and a sensitive nursing practice.

PMID- 12427188
TI  - Attitudes toward patient aggression amongst mental health nurses in the 'zero
      tolerance' era: associations with burnout and length of experience.
AB  - UK government policy now officially encourages an attitude of 'zero tolerance'
      towards aggression against health care staff. This study examines levels of such
      tolerance amongst a group of mental health care staff and associations between
      tolerance and other occupational and stress factors. Thirty-seven staff completed
      a Tolerance Scale (from the Perceptions of Aggression Scale) and the Maslach
      Burnout Inventory. Tolerance for aggression was higher amongst more experienced
      staff (P < 0.01) and high tolerance was associated with low emotional exhaustion,
      low depersonalization and high personal accomplishment (P < 0.01). Some staff
      endorse positive statements about patient aggression and a tolerant attitude may
      be linked to low burnout. Nurse attitudes to patient aggression therefore are
      complex and do not necessarily equate with an approach of 'zero tolerance'.

PMID- 12427189
TI  - Effects of normal saline on endotracheal suctioning.
AB  - This study was designed to determine the effects of saline solution administered
      prior to endotracheal suctioning by nurses working in intensive care on
      oxygenation, heart rate and long-term pulmonary hygiene. The study was carried
      out on an experimental basis in the Intensive Care Unit of a university hospital
      in Turkey. A total of 20 patients were included, who were mechanically ventilated
      because of pulmonary or cardiovascular problems or trauma. Data were collected
      using a data form. Each patient was monitored for 5 minutes following suctioning
      with or without saline solution and findings of heart rate, SpO2, and blood gas
      measurements were recorded. Data were analysed using percentage calculations, the
      student's t-test and the Friedman test. The study showed that most of the
      patients were between 60 and 69 years and were intubated because of respiratory
      insufficiency. Evaluation of blood gases following suctioning with or without
      saline solution showed partial decreases in pO2, pCO2, HCO3, and oxygen
      saturation (SaO2), which did not reach a significant level. No significant
      difference was found between pH levels recorded prior to and 5 minutes after
      suctioning without saline solution; however, the increase in pH following
      suctioning with saline solution was significant. Patients undergoing suctioning
      with saline solution exhibited significantly increased heart rates in the fourth
      and fifth minutes, whereas no increases were detected in these undergoing
      suctioning without saline solution. SpO2 values obtained by pulse oxymeter did
      not show significant differences. Saline solution administered with suctioning
      resulted in undesirable, although not significant, alterations in oxygen
      saturation and arterial blood gas levels.

PMID- 12427190
TI  - Uncertain terms of sedation in ICU. How nurses and physicians manage and describe
      sedation for mechanically ventilated patients.
AB  - Sedation which is used for intubated patients may prolong mechanical ventilation
      by increasing the risk of complications. The aim of the study was to illuminate
      the specific terminology and unrecognized contextual factors which may influence
      nurses' and physicians' sedation practices. The main research questions were: How
      do nurses and physicians describe sedation? and How does the level of nursing
      skill relate to the level of sedation? The hypotheses were that sedation
      practices are inconsistent and that experienced nurses provide a better quality
      of sedation than less experienced nurses. The hypotheses were supported by the
      study. The research strategy was case study research with triangulation of
      sources and methods and a multicentre multiple-case design. Four university
      hospitals in Copenhagen, Denmark, and 14 cases were included in the study. The
      findings were based on secondary analysis of observation, interviews and chart
      review. The theoretical framework for the study was the problem-solving model, in
      which sedation was assumed to be provided according to indication (clinical
      problem), intervention (clinical decision) and expected outcome (clinical end
      point). Indications could be patient-related, ventilator-related, or patient
      ventilator related. Interventions could be related to the choice of agent, dose
      or administration method and the outcome was the level of sedation. Sedative
      therapy was prescribed by physicians and administered by nurses. The four sites
      in the study did not use guidelines for sedation and did not use sedation level
      assessment tools. The study shows that when the terminology is unclear, the
      indications, interventions and outcomes become unclear.

PMID- 12427191
TI  - Post-operative patients in severe pain but satisfied with pain relief.

PMID- 12427192
TI  - Spirituality in nursing care: evidence of a gap between theory and practice.

PMID- 12427193
TI  - Physiological effects of two temperature settings in preterm infants on nasal
      continuous airway pressure ventilation.

PMID- 12427197
TI  - Sports dentistry and dental traumatology.
AB  - Sports dentistry had its origins in the 1980s. More recently, the Academy for
      Sports Dentistry joined forces with the International Association of Dental
      Traumatology in cosponsoring the World Congress on Sports Dentistry and Dental
      Traumatology. It is the intent of the present paper to introduce readers to the
      arena of sports dentistry, suggest future areas for collaborative research, and
      stimulate authors to submit high quality, scientifically based manuscripts on
      sports dentistry to Dental Traumatology.

PMID- 12427198
TI  - The esthetic outcome of autotransplanted premolars replacing maxillary incisors.
AB  - Autotransplantation of developing premolars to replace maxillary incisors has
      been documented to provide physiologically sound results, but comprehensive
      studies of the esthetic outcome have not been made previously. In order to assess
      the applicability of this approach and to identify factors important for planning
      of treatment, 22 autotransplanted premolars reshaped to incisor morphology were
      compared to their natural, contralateral maxillary incisors by scoring of
      features considered important for esthetics (color, soft tissue appearance, tooth
      morphology, and position). The sum of scores for each feature was used to place
      the reshaped transplant in one of three categories - Match, Deviate, Mismatch.
      The 22 patients were asked to fill in a questionnaire which addressed the same
      features that were examined professionally, and the responses were categorized as
      either Satisfied, Acceptable, or Dissatisfied. Eleven of the 22 patients had
      received orthodontic treatment with fixed appliances following the
      transplantation. Most of the transplanted premolars matched the contralateral
      incisor, and the majority of patients were satisfied with the appearance of the
      transplant. Fourteen percentage of the transplants were categorized as Mismatch
      and 18% of patients reported dissatisfaction. The distribution in categories
      assessed professionally and by the patients was not significantly different. The
      color and gingival width of the transplanted tooth were scored as different from
      the natural incisor in about half of the bilateral comparisons. For those teeth
      categorized professionally as Mismatch and by patients as Dissatisfied, a
      potential for esthetic improvement could be identified, as allocation to these
      categories was primarily due to suboptimal positioning and restorative build-up
      of the transplant. Inter-disciplinary planning is important for successful
      esthetic results.

PMID- 12427199
TI  - Allo- and autotransplantation of mature teeth in monkeys: a sequential time
      related histoquantitative study of periodontal and pulpal healing.
AB  - Root resorption is known to be the most relevant complication determining the
      long-term prognosis of allotransplanted teeth, and it is initiated during the
      first few postoperative months. The aim of the present study was to
      quantitatively assess the dynamics of the periodontal ligament (PDL) and pulpal
      healing reactions during the first 8 weeks after allotransplantation of mature
      teeth. The material comprised 112 maxillary central and mandibular lateral
      incisors of 28 mature green Vervet monkeys, immunogenetically untested, and only
      matched according to the size of the grafts. Donors and recipients exchanged
      simultaneously both maxillary incisors and one mandibular incisor, whereas the
      contralateral mandibular incisors were autotransplanted as controls. At random,
      every second maxillary allograft was endodontically treated preoperatively.
      Histoquantitative analysis of the PDL and pulpal healing reactions was carried
      out after 1, 2, 4 and 8 weeks on serial cross-sections of the grafts in 6, 6, 6
      and 8 monkeys, respectively. Necrosis zones in the PDL were prominent in both
      auto- and allografts after 1 week. Inflammation in the PDL dominated healing in
      all types of grafts 1 week after transplantation, whereas it subsided
      significantly after 2 weeks in autografts compared to allografts (P = 0.005).
      Inflammatory resorption (IR) became prominent after 4 weeks in autografts and
      this remained stationary. In contrast, IR initiated significantly earlier in
      allografts compared to autografts after 2 weeks (P = 0.007), and this type of
      resorption was further increasing in allografts after 4 and 8 weeks. Endodontic
      treatment, however, reduced IR nearly totally in the allografts with time.
      Replacement resorption (RR) was nearly absent in autografts. In contrast,
      allografts showed increasing appearance of RR with time, initiating at 4 weeks.
      By removing IR from the allografts by endodontic treatment, RR was unmasked
      significantly at 4 weeks (P = 0.02) and dominated most of the periodontal
      ligament (70%) after 8 weeks (P = 0.0004). Within the 8 postoperative weeks
      autografts showed healing with increasing amount of normal PDL reaching
      significantly higher levels compared to allografts already after 2 weeks (P =
      0.02), with increasing differences thereafter. In most allografts, the normal PDL
      occupied less than 10% of the entire root surface and was located in the supra
      alveolar cervical region. Downgrowth of periodontal pocket epithelium was absent
      or found very infrequently in all groups irrespective of type, time and
      treatment. In conclusion, the healing of allo- and autotransplanted mature teeth
      differed significantly on several aspects during the first 8 postoperative weeks.
      The recorded differences included a higher amount of inflammation in the PDL of
      allografts after 2 weeks, inflammatory resorption from the second week, and
      replacement resorption dominating in the eighth week, indicated that an
      immunologic stimulus for root resorption existed in the allogenic PDL apart from
      the pulp. Furthermore, specific healing reactions was found in the cervical
      region with almost identical gingival healing in auto- and allografts.

PMID- 12427200
TI  - PCNA-expression of cementoblasts and fibroblasts on the root surface after
      extraoral rinsing for decontamination.
AB  - Periodontal cells capable of proliferation were studied immunohistochemically on
      extracted human teeth after 2-min irrigation with saline or ozonized water and
      marking of Proliferating Cell Nuclear Antigen (PCNA). All specimens expressed
      PCNA. The labelling index (LI), i.e. the number of positive cells compared to the
      total number of cells, was 6.6% after irrigation with saline and 7.8% after
      irrigation with ozone. There was no difference in number and distribution of PCNA
      positive cells from the coronal to the apical thirds of the roots. Irrigation
      with ozonized water showed higher labelling indices in comparison with saline,
      but this could not be statistically substantiated (P = 0.24). Ozonized water, not
      being isotonic, had no negative effect on periodontal cells remaining on the
      tooth surface after irrigation for 2 min.

PMID- 12427201
TI  - Clinical response to experimental forces and non-surgical therapy of teeth with
      various alveolar bone loss.
AB  - Firm lateral force is necessary for the thorough removal of calculus during
      scaling and root planning (SRP) with hand instruments. However, this firm lateral
      force should be applied to root surfaces without considering the tooth's loss of
      supporting tissues. The purpose of the present study was two-fold: firstly, to
      evaluate the initial pain response of periodontally diseased non-molar teeth with
      two different levels of alveolar bone loss (ABL) to experimental lateral and
      vertical pull forces; and secondly, to examine the clinical response of these
      teeth to non-surgical therapy. Twenty patients with chronic periodontitis were
      specifically selected in two groups according to the level of ABL at non-molar
      teeth. Group I consisted of 10 patients who have 141 non-molar teeth with a
      radiographic evidence of 40-65% ABL. Group II consisted of 10 patients who have
      132 non-molar teeth with a radiographic evidence of > or =70% ABL. All patients
      were systemically healthy, free of pain, and reported no current medication
      usage. Starting from 0 and gradually increasing an experimental lateral force
      with digital force gauge, and also an experimental vertical pull force with
      mechanical force gauge were applied to each tooth and measured. As a result of a
      single experimental force applied to each non-molar tooth, the initial pain
      response emerged in the patients was determined by means of electronic bell
      system used by patients themselves. Each patient was treated with SRP using
      specific hand instruments under local anesthesia. Plaque index (PI), gingival
      index (GI), probing depth (PD), clinical attachment level (CAL) and periotest
      values (PV scores) were compared in both groups at initial and at month 3. A mean
      experimental lateral force of 24.6 N and a mean experimental vertical pull force
      of 48.3 N caused initial pain response in group I. Initial pain response occurred
      with a mean experimental lateral force of 5.3 N and a mean experimental vertical
      pull force of 19.4 N in group II. Only group I showed statistically significant
      decrease in PI, GI, PD and a significant attachment gain at month 3 (P < 0.05).
      There was a decrease of 6 PV in group I at month 3 (P < 0.05), whereas an
      increase of 4 PV was observed in group II (P > 0.05). This study showed that
      lateral and vertical forces required for effective SRP do not cause any problem
      in the group with 40-65% ABL. However, they may cause trauma in the group with
      approximately 70% ABL. Thus, the results suggest that the degree of healing would
      be different in the group with > or =70% ABL and in the group with 40-65% ABL.

PMID- 12427202
TI  - Comfort and discomfort of dental trauma splints - a comparison of a new device
      (TTS) with three commonly used splinting techniques.
AB  - The present experimental study compared four dental trauma splints in 10
      volunteers. The evaluated splints included a wire-composite splint (WCS), a
      button-bracket splint (BS), a resin splint (RS), and the newly developed titanium
      trauma splint (TTS). All splints were bonded to the labial surfaces of the
      maxillary lateral and central incisors and left in place for 1 week. After splint
      removal, the next splint was placed after a 1-week rest period. The sequence of
      splint application was randomized for each individual. The following subjective
      parameters were assessed using a visual analogue scale: sensitiveness of splinted
      teeth, irritation of the gingival margin, irritation of the lips, impairment of
      speech, eating and oral hygiene. The results show that the application of BS
      leads to a significantly higher irritation of the lips and greater impairment of
      speech compared to other splints (P < 0.05). The RS leads to an increased and
      significantly higher irritation of the gingiva (P < 0.05) owing to a significant
      increase in cleaning difficulties (P < 0.05). In conclusion, WCS and TTS appear
      to be more accepted splints according to a subjective assessment by 10
      volunteers.

PMID- 12427203
TI  - Clinical procedures for the immediate reattachment of a tooth fragment.
AB  - Uncomplicated crown fractures are frequent dental injuries, especially in young
      patients. It is beneficial to quickly restore the function and the aesthetics of
      the traumatized tooth. The immediate fragment reattachment is a therapeutic
      choice for uncomplicated anterior crown fractures, when the tooth is not luxated
      and the fragment is correctly stored. The aim of this article is to present the
      clinical procedures for the immediate fragment reattachment by accurate bonding
      procedures. The immediate fragment reattachment is a very conservative treatment:
      it allows the restoration of the original dental anatomy, thus rehabilitating
      function and aesthetics in a short time, by preserving dental tissues.

PMID- 12427205
TI  - Outcomes in lower respiratory tract infections and the impact of antimicrobial
      drug resistance.
AB  - Numerous published studies have documented the rapid rise in antimicrobial drug
      resistance among common respiratory pathogens, particularly Streptococcus
      pneumoniae. Yet, surprisingly few studies have evaluated the impact of these in
      vitro findings on clinical outcomes. Outcomes research is the measurement of the
      impact of illness and the effect of treatment on clinically relevant end-points.
      Studies of patients with community-acquired pneumonia have established certain
      expected rates of outcomes, including mortality, clinical complications, and time
      to resolution of symptoms. Recent studies have identified specific processes of
      care and treatment choices that have an impact upon these outcomes. However,
      there are no well-controlled studies that provide definitive estimates of the
      magnitude of the impact of antimicrobial therapy on these outcomes for patients
      with community-acquired pneumonia or other respiratory tract infections, such as
      acute exacerbations of chronic bronchitis. Most studies of the impact of drug
      resistance on outcomes for patients with respiratory tract infections have
      focused on the impact of beta-lactam drug resistance on outcomes for patients
      with community-acquired pneumococcal pneumonia. In general, these studies have
      demonstrated that outcomes are not affected by current levels of drug resistance,
      but most studies are hampered by small sample size, inability to control
      adequately for severity of illness and concordance of therapy, and inclusion of
      few subjects with high-level drug resistance. Additional studies are urgently
      needed to assess better whether the current empiric treatment guidelines are
      adequate or will need to be adjusted as patterns of resistance continue to
      evolve.

PMID- 12427206
TI  - Surveillance of resistance in bacteria causing community-acquired respiratory
      tract infections.
AB  - Bacterial resistance to antibiotics in community-acquired respiratory tract
      infections is a serious problem and is increasing in prevalence world-wide at an
      alarming rate. Streptococcus pneumoniae, one of the main organisms implicated in
      respiratory tract infections, has developed multiple resistance mechanisms to
      combat the effects of most commonly used classes of antibiotics, particularly the
      beta-lactams (penicillin, aminopenicillins and cephalosporins) and macrolides.
      Furthermore, multidrug-resistant strains of S. pneumoniae have spread to all
      regions of the world, often via resistant genetic clones. A similar spread of
      resistance has been reported for other major respiratory tract pathogens,
      including Haemophilus influenzae, Moraxella catarrhalis and Streptococcus
      pyogenes. To develop and support resistance control strategies it is imperative
      to obtain accurate data on the prevalence, geographic distribution and antibiotic
      susceptibility of respiratory tract pathogens and how this relates to antibiotic
      prescribing patterns. In recent years, significant progress has been made in
      developing longitudinal national and international surveillance programs to
      monitor antibiotic resistance, such that the prevalence of resistance and
      underlying trends over time are now well documented for most parts of Europe, and
      many parts of Asia and the Americas. However, resistance surveillance data from
      parts of the developing world (regions of Central America, Africa, Asia and
      Central/Eastern Europe) remain poor. The quantity and quality of surveillance
      data is very heterogeneous; thus there is a clear need to standardize or validate
      the data collection, analysis and interpretative criteria used across studies. If
      disseminated effectively these data can be used to guide empiric antibiotic
      therapy, and to support-and monitor the impact of-interventions on antibiotic
      resistance.

PMID- 12427207
TI  - The patient's role in the spread and control of bacterial resistance to
      antibiotics.
AB  - As the ultimate consumers, patients play an important role in the emergence,
      spread and control of bacterial resistance to antibiotics. Improved knowledge of
      antibiotics and the problem of resistance, as well as a better understanding of
      beliefs, pressures/concerns, and expectations, from both the patient's and
      physician's perspectives, are fundamental for controlling antibiotic use. There
      is growing evidence to suggest that empowering patients through implementation of
      patient-centered health-care strategies, such as shared decision-making, in
      conjunction with educational initiatives help to change attitudes and behavior,
      and improve access to and completion of appropriate antimicrobial therapy. This,
      in turn, may help to control the development and spread of resistance to
      antibiotics.

PMID- 12427208
TI  - A critical assessment of published guidelines and other decision-support systems
      for the antibiotic treatment of community-acquired respiratory tract infections.
AB  - Guidelines are an important means by which professional associations and
      governments have sought to improve the quality and cost-effectiveness of disease
      management for infectious diseases. Prescribing of initial antibiotic therapy for
      community-acquired respiratory tract infections (RTIs) is primarily empiric and
      physicians may often have a limited appreciation of bacterial resistance. Recent
      guidelines for managing RTIs have adopted a more evidence-based approach. This
      process has highlighted important gaps in the existing knowledge base, e.g.
      concerning the impact of resistance on the effectiveness of oral antibiotics for
      outpatient community-acquired pneumonia and the level of resistance that should
      prompt a change in empiric prescribing. In upper RTIs, the challenge is to
      identify patients in whom antibiotic therapy is warranted. Concentrated,
      sustained efforts are needed to secure physicians' use of guidelines. The
      information should be distilled into a simple format available at the point of
      prescribing and supported by other behavioral change techniques (e.g. educational
      outreach visits). Advances in information technology offer the promise of more
      dynamic, computer-assisted forms of guidance. Thus, RTI prescribing guidelines
      and other prescribing support systems should help control bacterial resistance in
      the community. However, their effect on resistance patterns is largely unknown
      and there is an urgent need for collaborative research in this area. Rapid, cost
      effective diagnostic techniques are also required and new antibiotics will
      continue to have a role in disease management.

PMID- 12427209
TI  - Moving from recommendation to implementation and audit: part 1. Current
      recommendations and programs: a critical commentary.
AB  - Growing concern over the spread of resistance to antibiotics and other
      antimicrobials has prompted a plethora of recommendations for its control.
      Strategic programs for resistance containment have been initiated in various
      countries, particularly in Western Europe and North America. The World Health
      Organization and the European Union have responded to the need for international
      action by publishing guidance and encouraging collaboration. These
      recommendations rightly focus on controlling resistance in the community. They
      agree on the importance of surveillance of resistance patterns and antibiotic
      usage and the need to encourage judicious antibiotic usage (especially through
      education of prescribers and the public). Yet there remains a pressing need for
      the implementation of effective actions to address these issues. Important
      considerations given less attention include infection prevention (e.g. through
      immunization), the use of rapid diagnostic tests to reduce antibiotic usage,
      audit of implemented actions, and the provision of feedback. Furthermore,
      research is necessary to fill the substantial gaps in our knowledge. Notably, the
      reversibility or containment of resistance with the optimization of antibiotic
      usage has yet to be definitely established. For now, antimicrobial management
      programs should focus on ensuring the most appropriate use of antimicrobials
      rather than simply on limiting choices. Finally, developed countries must
      recognize that a truly global approach to resistance containment will require
      greater support for developing countries.

PMID- 12427210
TI  - Moving from recommendation to implementation and audit: part 2. Review of
      interventions and audit.
AB  - There are multiple interventions available that may help to control the
      development and spread of resistance to antimicrobial agents in bacteria
      implicated in community-acquired respiratory tract infections. Unfortunately,
      very few studies have assessed the effectiveness of these interventions using
      objective end-points, such as reduction in resistance rates and improvement in
      clinical outcomes. Most interventions are centered on reducing inappropriate or
      unnecessary use of antibiotics; others focus on reducing disease burden and
      bacterial colonization. With regard to antibiotic use, efforts should be
      concentrated at both the prescriber and consumer levels. Interventions that
      target prescribers include: provision of educational materials; strategies and
      tools to improve diagnosis; implementation of practice guidelines; personalized
      interactive sessions with feedback on the practice profile; and use of delayed
      prescription and alternative prescribing strategies. Optimal results are usually
      obtained when these interventions are combined with consumer education.
      Regulatory interventions (e.g. licensing regulations and controlled access to
      drugs), restrictions in the use of agents for growth promotion in animals, and
      use of nonantimicrobial therapies (e.g. probiotics) may help further to reduce
      inappropriate antibiotic use and thereby decrease the selective pressure for
      development of resistance. Infection-control strategies, public health measures,
      vaccination programs, and new antibiotics all have a role in minimizing the
      spread of resistant organisms. Ideally, resistance-control programs should
      include predefined criteria for success and integral audit processes based on
      objective end-points (antibiotic use, resistance trends, and health outcomes).
      Standardization of data collection is imperative so that the relative merits of
      various interventions can be compared. Effective implementation and audit of
      interventions is often difficult in developing countries owing to poor health
      care infrastructures, lack of resources, poor education/training, and minimal
      regulatory controls on the supply and quality of antimicrobials. Substantial
      support from governments and health-care organizations across the globe is
      required to initiate and sustain effective intervention programs to control
      antimicrobial resistance.

PMID- 12427214
TI  - Tuberculosis in children-is PCR the diagnostic solution?
AB  - Polymerase chain reaction (PCR) has been recently incorporated as a diagnostic
      tool for the diagnosis of tuberculosis. The benefit of rapid results and greater
      sensitivity compared with traditional microbiological methods makes PCR a
      suitable technique in childhood tuberculosis, especially when diagnosis is
      difficult or when urgent diagnosis is needed. However, the possibility of false
      positive results must be considered, especially if the clinical and epidemiologic
      context of the child make the diagnosis of tuberculosis improbable. The
      commercial 'Amplicor PCR test' lacks good sensitivity and specificity and it
      would be necessary to develop other commercial easy-to-use PCR kits that provides
      better yield.

PMID- 12427215
TI  - Clinical management of catheter-related infections.
AB  - Central venous catheters represent a major source of nosocomial bloodstream
      infections, which cause considerable excess morbidity. It is currently unknown to
      what extent these infections contribute to mortality. Most catheter-related
      infections (CRIs) are caused by Gram-positive organisms (mainly coagulase
      negative staphylococci). Definite diagnosis of CRI necessitates removal of the
      catheter in most cases. However, the recently described technique of differential
      time to positivity may allow diagnosis of CRI with the catheter left in place.
      Removal of the catheter has been standard clinical practice for the management of
      CRI in the past and is still recommended in many cases. In specific situations,
      such as infections of implanted catheters with coagulase-negative staphylococci,
      a trial of catheter salvage may be justified. In catheter-related bloodstream
      infection Staphylococcus aureus and Candida spp., the catheter should be removed
      immediately, due to the high risk of metastatic infection and increased
      mortality. A clinical work-up for the detection of additional foci (including
      transesophageal echocardiography in S. aureus infections) is advisable in these
      cases. All CRIs should be treated with antibiotics to which the causative agent
      has been shown to be susceptible. In addition to systemic antimicrobial therapy,
      antibiotic lock therapy may be applied, especially in patients with implanted
      long-term catheters if catheter salvage is attempted.

PMID- 12427216
TI  - Friendly fire: redirecting herpes simplex virus-1 for therapeutic applications.
AB  - Herpes simplex virus-1 (HSV-1) is a relatively large double-stranded DNA virus
      encoding at least 89 proteins with well characterized disease pathology. An
      understanding of the functions of viral proteins together with the ability to
      genetically engineer specific viral mutants has led to the development of
      attenuated HSV-1 for gene therapy. This review highlights the progress in
      creating attenuated genetically engineered HSV-1 mutants that are either
      replication competent (viral non-essential gene deleted) or replication defective
      (viral essential gene deleted). The choice between a replication-competent or 
      defective virus is based on the end-goal of the therapeutic intervention.
      Replication-competent HSV-1 mutants have primarily been employed as antitumor
      oncolytic viruses, with the lytic nature of the virus harnessed to destroy tumor
      cells selectively. In replacement gene therapy, replication-defective viruses
      have been utilized as delivery vectors. The advantages of HSV-1 vectors are that
      they infect quiescent and dividing cells efficiently and can encode for
      relatively large transgenes.

PMID- 12427217
TI  - Natural antibiotic susceptibility of Enterobacter amnigenus, Enterobacter
      cancerogenus, Enterobacter gergoviae and Enterobacter sakazakii strains.
AB  - OBJECTIVE: To investigate the natural susceptibility to 69 antimicrobial agents
      of 107 Enterobacter strains comprising E. amnigenus (n = 18), E. cancerogenus (n
      = 26), E. gergoviae (n = 28) and E. sakazakii (n = 35). METHODS: Minimal
      inhibitory concentrations (MICs) were determined with a microdilution procedure
      in Isosensitest broth and cation-adjusted Mueller-Hinton broth. RESULTS: All the
      species were naturally sensitive or intermediate to tetracyclines, amino
      glycosides, numerous beta-lactams (acylureidopenicillins, ticarcillin,
      ampicillin/sulbactam, several cephalosporins, carbapenems, aztreonam),
      quinolones, antifolates, chloramphenicol and nitrofurantoin. Natural resistance
      was found to penicillin G, oxacillin, several macrolides, lincosamides,
      streptogramins, glycopeptides, rifampicin and fusidic acid. Species-related
      differences in natural susceptibility were found to some beta-lactams,
      azithromycin and fosfomycin. Whereas E. gergoviae was the most susceptible
      species to azithromycin, E. cancerogenus was most susceptible to fosfomycin and
      was the only species showing natural resistance to amoxicillin,
      amoxicillin/clavulanic acid, cefaclor, cefazoline, loracarbef and cefoxitin.
      There were only minor medium-dependent differences in susceptibility to most
      antibiotics. CONCLUSIONS: The present study establishes a database concerning the
      natural susceptibility of recently established Enterobacter species to a wide
      range of antibiotics, which can be applied for the validation of routine
      susceptibility test results. beta-Lactam susceptibility patterns indicate the
      expression of species-specific beta-lactamases expressed at high or low levels in
      all the species except E. sakazakii.

PMID- 12427218
TI  - Transferable plasmid mediating resistance to multiple antimicrobial agents in
      Klebsiella pneumoniae isolates in Greece.
AB  - OBJECTIVE: To investigate the underlying resistance mechanisms in 10 Klebsiella
      pneumoniae isolates. METHODS: Ten K. pneumoniae strains according to distinct
      bacteriocin typing and REP-PCR, were examined for their plasmid content, their
      ability to transfer their resistance to aminoglycosides and third-generation
      cephalosporins, and their production of aminoglycoside-modifying enzymes and beta
      lactamases. RESULTS: Transfer of resistance to the above-mentioned antibiotics as
      well as to co-trimoxazole and tetracycline in Escherichia coli strain RC 85 at a
      frequency of 5-106 was achieved for all strains by conjugation. Similar strains
      harbor a self-transferable multiresistant plasmid (80 kb) with similar EcoRI and
      HindIII restriction patterns. This plasmid encodes an extended-spectrum beta
      lactamase which confers high-level resistance to third-generation cephalosporins
      and aztreonam. It produces SHV-5 beta-lactamase, as demonstrated by isoelectric
      focusing and DNA sequencing. Aminoglycoside resistance was co-transferred, and
      AAC(6')-I, mediating resistance to gentamicin, tobramycin, netilmicin and
      amikacin, and AAC(3)-I, mediating resistance to gentamicin and sisomycin, were
      encoded in all isolates and their transconjugants, while APH(3')-I, mediating
      resistance to kanamycin and neomycin, was encoded in seven strains. CONCLUSIONS:
      It appears that a multiresistant transferable plasmid encoding the SHV-5 beta
      lactamase, causing unusually high resistance to ceftazidime and aztreonam, and
      the combination AAC(6')-I + AAC(3)-I of acetylating enzymes causing, also
      resistance to all clinically available aminoglycosides, is established in K.
      pneumoniae in Greece.

PMID- 12427219
TI  - Factors related to the chronicity and evolution of hepatitis C infection in
      patients co-infected by the human immunodeficiency virus.
AB  - OBJECTIVES: This work analyses the influence of immune status, serum human
      immunodeficiency virus (HIV) load and hepatitis C virus (HCV) genotypes on the
      probability of resolution of HCV infection in HIV-co-infected patients, as well
      as the evolution of HCV viremia after antiretroviral therapy. PATIENTS AND
      METHODS: Forty-five patients with anti-HIV and anti-HCV antibodies were
      classified into two groups as a function of the positivity or persistent
      negativity of HCV RNA detection (active or recovered HCV infection,
      respectively). They were treated with highly active antiretroviral therapy
      (HAART). Serum HCV RNA was quantified by the reverse transcription-polymerase
      chain reaction. HCV genotypes were detected by line probe assay or by detection
      of type-specific antibodies. RESULTS: HCV RNA was detectable in 30 (66.6%) out of
      45 HIV-infected patients. CD4+ T-cell counts, HIV viremia, or HCV genotypes were
      similar in patients with active or recovered HCV infection. Patients with active
      HCV infection had a non-significant decrease of HCV viremia during a follow-up of
      12 months (from 6.15 +/- 6.32 to 5.96 +/- 6.05 log copies/mL). This was not
      influenced by baseline HCV or HIV viral load, HCV genotype, or CD4+ T-cell count.
      The non-significant decrease was present in patients with or without an
      immunological response to HAART. CONCLUSION: HCV genotypes, immune status, or
      serum HIV load did not influence the resolution or chronicity of HCV infection in
      HIV-co-infected individuals. A non-significant decrease of HCV viremia in these
      patients treated with combinations including antiproteases could be expected.

PMID- 12427220
TI  - Prevalence of antibiotic resistance of Helicobacter pylori isolates in Estonia
      during 1995-2000 in comparison to the consumption of antibiotics used in
      treatment regimens.
AB  - OBJECTIVE: To find a possible relation between the dynamics of antibiotic
      resistance of Helicobacter pylori isolates and the consumption of antibiotics
      during the last several years in Estonia. METHODS: Helicobacter pylori isolates
      were collected from the gastric mucosa of patients with peptic ulcer (153) and
      gastritis (68) and isolated on the Columbia Agar Base. From 1995 to 1997 the disk
      diffusion method was used for testing of H. pylori susceptibility to
      metronidazole (115 isolates), erythromycin (119 isolates), tetracycline (119
      isolates) and amoxicillin (119 isolates). From 1998 to 2000 the susceptibility of
      H. pylori to metronidazole (106 isolates), amoxicillin (30 isolates),
      clarithromycin (106 isolates) and ciprofloxacin (30 isolates) was assessed by E
      tests. Data from the Estonian State Agency of Medicines were used to determine
      the antibiotic consumption rate. RESULTS: Up to the year 2000 all the
      investigated H. pylori isolates were susceptible to ciprofloxacin; the resistance
      to clarithromycin, tetracycline, amoxicillin and erythromycin was 3%, 1.7%, 0.7%
      and 2.5%, respectively. Forty-six percent of H. pylori isolates were resistant to
      metronidazole. During 1995-2000 the consumption of amoxicillin, erythromycin and
      ciprofloxacin increased and the consumption of tetracycline decreased. The
      increasing consumption of amoxicillin reached a level 5.7 times than that of the
      consistent use of metronidazole. The resistance to amoxicillin appeared to be
      very low and resistance to metronidazole was continuously high. The increase of
      clarithromycin consumption (from 0.002 to 1.119 defined daily doses/1000) during
      three years was associated with the appearance of the first clarithromycin
      resistant isolates in 2000. CONCLUSION: No relation was observed between the
      antibiotic consumption rate and the resistance pattern of H. pylori to
      metronidazole, amoxicillin, erythromycin, tetracycline and ciprofloxacin during
      recent years among the in population.

PMID- 12427221
TI  - Diagnosis at first glance: bladder parachute in an HIV-infected patient.

PMID- 12427222
TI  - Death from cumulative sodium stibogluconate toxicity on Kala-Azar.

PMID- 12427223
TI  - Pseudomonas oryzihabitans peritonitis in a patient on continuous ambulatory
      peritoneal dialysis.

PMID- 12427224
TI  - Comparison of two transport media and three culture media for primary isolation
      of Helicobacter pylori from gastric biopsies.

PMID- 12427226
TI  - New professionalism and the society journal.

PMID- 12427227
TI  - Pars plana vitrectomy in the management of retained lens material following
      cataract surgery.

PMID- 12427228
TI  - Endophthalmitis.
AB  - Australia and New Zealand continue to be at the forefront of endophthalmitis
      research. In this Clinical Controversy, an ophthalmologist from each country
      presents different approaches to the management of a 72-year-old patient with
      routine endophthalmitis following cataract surgery. Mark Elder concludes that
      this case needs aqueous and vitreous aspirates for culture and the initial
      treatment of choice is intracameral vancomycin and amikacin. The evidence for
      intravitreal steroids is equivocal. Systemic antibiotics are indicated if there
      is a possibility of a bacterial biofilm present on the intraocular lens. Nigel
      Morlet concludes that timely intervention with appropriate antibiotics delivered
      in the right concentration to the vitreous cavity is the crux of successful
      management of endophthalmitis. Aggressive treatment of the inflammatory response
      is also required to further reduce the damage to the intraocular structures. Both
      ophthalmologists agree that vitrectomy is not necessarily the most appropriate
      treatment option.

PMID- 12427229
TI  - Pars plana vitrectomy in the management of retained intravitreal lens fragments
      after cataract surgery.
AB  - PURPOSE: To assess the outcome of patients who underwent pars plana vitrectomy
      for retained lens fragments after cataract surgery. METHODS: A retrospective
      study of all consecutive cases with pars plana vitrectomy performed for retained
      lens fragment was conducted. Twenty-seven eyes of 27 patients were included in
      the study. RESULTS: Twenty-four (89.9%) eyes received phacoemulsification. Pars
      plana vitrectomy was performed at the same sitting, or ranged from day 1-70 after
      cataract surgery. The mean follow up was 31.1 months. Final visual acuity of 6/12
      or better was achieved in 15 (55.6%) patients. After excluding patients with pre
      existing eye diseases, 68.4% of patients had visual acuity 6/12 or better.
      Complications after pars plana vitrectomy included glaucoma (22.2%), retinal
      detachment (11.1%) and surgically induced necrotizing scleritis (3.7%).
      CONCLUSION: Ocular complications with poor visual outcome can occur after removal
      of intravitreal retained lens fragments complicating cataract surgery.

PMID- 12427230
TI  - Low vision rehabilitation in patients with age-related macular degeneration at a
      tertiary eye care centre in southern India.
AB  - PURPOSE: To evaluate the specific needs and types of low vision devices (LVDs) in
      patients with age-related macular degeneration (AMD) so as to use the residual
      vision effectively. METHODS: One hundred consecutive patients with diagnosis of
      AMD were evaluated to ascertain the degree of visual disability. Different LVDs
      were used to suit the specific needs of individual patients. The distribution of
      LVDs for distance and near and other rehabilitation measures were stratified for
      vision >or=6/18 and <6/18. Statistical analysis was performed using chi2
      test/Fisher's exact test and paired t-test. RESULTS: The percentage of patients
      with visual acuity <6/18 reduced from 72.2% (26/36) to 47.2% (17/36) with the use
      of standard spectacles (P = 0.03). Similarly, the percentage of patients with
      visual acuity <6/18 reduced from 85.7% (6/7) to 14.3% (1/7) with the use of a
      telescope (P = 0.029). The optical devices for near tasks included spectacle
      magnifiers (n = 59), stand magnifiers (n = 19), and hand magnifiers (n = 18).
      With these LVDs, the near vision improved from 0.13 (decimal notations) to 0.39
      (P < 0.001). Eighty-six patients were given at least one of the LVDs and 20% were
      prescribed more than one near device (bifocals, spectacle magnifiers, hand
      magnifiers, stand magnifiers). Additionally, patients also needed counselling (n
      = 89) and training on eccentric viewing (n = 39), coin identification (n = 45),
      and independent mobility (n = 41). CONCLUSION: The overall management of a
      patient with AMD must include counselling, prescription of appropriate LVDs and
      training to utilize the residual vision to its fullest advantage. This is
      expected to improve the patient's quality of life.

PMID- 12427231
TI  - Effect of peripapillary chorioretinal atrophy on GDx parametersin patients with
      degenerative myopia.
AB  - PURPOSE: To determine the effect of peripapillary chorioretinal atrophy in
      degenerative myopia on the retinal nerve fibre layer (RNFL) thickness
      measurements performed by scanning laser polarimetry. METHODS: Polarimetric RNFL
      analysis was done in 41 degenerative myopic eyes of 25 patients with spherical
      refractive errors between -7.50 and -22.00 D (mean -12.50 D;SD 3.5). Analysis was
      also performed on 46 eyes of 24 age-matched healthy subjects with spherical
      refractive errors between -1.00 and +1.00 D (mean -0.25 D; SD 0.50) with GDx
      Nerve Fiber Analyzer (Version 1.0.12). All of the myopic patients had clinically
      evident peripapillary chorioretinal atrophy in their fundus examination. RESULTS:
      In myopic patients most of the GDx parameters were statistically different from
      the control group (P < 0.05). Although average thickness, ellipse average,
      number, inferior maximum and inferior average were found to be higher than the
      healthy subjects,the modulation parameters and the ratio-based parameters were
      significantly decreased in degenerative myopic patients (P < 0.05). The TSNIT
      (temporal, superior, nasal, inferior, temporal) graph showed irregular high
      spikes with loss of the regular double hump pattern, especially in quadrants with
      large chorioretinal atrophy and visible sclera. CONCLUSION: Peripapillary
      chorioretinal atrophy increased retardation values, which might be explained by
      the high reflectivity of the bare sclera in these areas.

PMID- 12427232
TI  - Management of rhegmatogenous retinal detachment without detectable breaks.
AB  - PURPOSE: To evaluate the causes of failure to find retinal breaks, the anatomical
      and functional outcomes of patients with rhegmatogenous retinal detachment (RD)
      without detectable breaks (Group I), to compare the results with detectable
      breaks (Group II). METHODS: Forty-five out of 258 eyes that had RD without
      detectable breaks were analysed retrospectively. RESULTS: The causes of failure
      to find retinal breaks were aphakia/pseudophakia in 22 eyes, small pupil without
      any eye disease in four eyes, corneal opacity in two eyes, cataract in two eyes,
      vitreous haze in two eyes, choroidal detachment in one eye, and unknown cause in
      12 eyes. After a single scleral buckling procedure, anatomical re-attachment of
      the retina successfully occurred in 62.2% of group I and 78.9% of group II
      patients. After repeated surgery, final anatomical success rates were 87.2% and
      90.2%, respectively. The best corrected visual acuity was 6/60 or better in 53.9%
      in Group I and 52.5% in Group II. CONCLUSION: The main cause of failure to find
      the retinal break was aphakia or pseudophakia. Although the rates of retinal
      reattachment in eyes without detectable breaks in primary buckling surgery was
      lower than detectable breaks and reoperations were required more frequently,
      final success rates were satisfactory and similar in both groups.

PMID- 12427233
TI  - Analysis of the Arg345Trp disease-associated allele of the EFEMP1 gene in
      individuals with early onset drusen or familial age-related macular degeneration.
AB  - BACKGROUND: A single base change within the EFEMP1 gene has been associated with
      malattia leventinese and Doyne honeycomb retinal dystrophy, two dominantly
      inherited macular diseases with early onset drusen. The aim of this study was to
      determine whether the same disease allele was also associated with other forms of
      early onset drusen or familial cases of age-related macular degeneration.
      METHODS: Thirteen index cases of early onset drusen together with 15 other family
      members were examined. In addition, 54 familial cases of age-related macular
      degeneration were examined. Blood was taken for DNA analysis and screened for the
      Arg345Trp disease-associated allele of the EFEMP1 gene. Twenty-four cases of
      malattia leventinese or Doyne honeycomb retinal dystrophy were also screened as
      positive controls. Another 150 ethnicity- and age-matched individuals acted as
      controls. RESULTS: The Arg345Trp disease-associated allele in the EFEMP1 gene was
      confirmed in individuals with malattia leventinese and Doyne honeycomb retinal
      dystrophy. However, involvement of this allele was not evident in either early
      onset drusen or familial age-related macular degeneration. CONCLUSIONS: The
      Arg345Trp disease-associated allele of the EFEMP1 gene does not appear to be
      associated with cases of early onset drusen that fall outside the diagnosis of
      malattia leventinese or Doyne honeycomb retinal dystrophy, nor does it appear to
      play a role in familial age-related macular degeneration. These findings do not
      exclude the involvement of other alleles of the EFEMP1 gene in either phenotype.
      The genetic mechanisms involved in the heterogeneous group of early onset drusen
      remain to be elucidated but should lead to insights into the genetic causes of
      macular diseases.

PMID- 12427235
TI  - Orbital abscess following uncomplicated phacoemulsification cataract surgery.
AB  - The case is presented of an 80-year-old woman who developed an orbital abscess
      after undergoing routine phaco-emulsification cataract surgery to her right eye.
      She was treated by drainage via an anterior orbitotomy and a sensitive
      Staphylococcus aureus was cultured. The presenting signs and symptoms resolved
      and final visual acuity was 6/9 in the right eye. One possible aetiology was the
      introduction of skin flora to orbital tissues during the peribulbar
      administration of local anaesthetic for the cataract surgery. Alternatively,
      secondary haemorrhage with secondary infection may have occurred.

PMID- 12427234
TI  - Neuropeptide Y expression in a mouse model of oxygen-induced retinopathy.
AB  - BACKGROUND: Neuropeptide Y (NPY) is a potent vaso-constrictor and angiogenic
      agent that is found in the retina. The goal of this study was to determine the
      expression of NPY and its receptors, NPY Y1 and NPY Y2, in a mouse model of
      oxygen-induced retinopathy. METHODS: Retinal NPY, NPY Y1, and NPY Y2 mRNA
      expression were evaluated using reverse transcriptase-polymerase chain reaction.
      Neuropeptide Y cellular localization was determined using immunohistochemistry.
      RESULTS: Retinal NPY mRNA expression was increased by 2.3-fold from P7 to P12,
      and 2.8-fold from P7 to P17 in oxygen-reared animals. Retinal NPY Y1 was
      increased 1.9-fold from P7 to P12 in room-air-reared animals. There was no change
      in NPY Y1 expression following exposure to oxygen. Retinal NPY Y2 expression in
      oxygen-reared animals increased by 2.8-fold from P7 to P12 and by 2.7-fold from
      P12 to P17. There was no change in NPY Y2 expression in room-air-reared animals.
      Retinal NPY and NPY Y2 expression increased concomitant with vasoconstriction and
      neovascularization seen in this model by evaluation of retinal whole mounts.
      Neuropeptide Y protein was detectable by immunohistochemistry mainly between the
      inner and outer nuclear layers and increased with hyperoxic exposure at P12 and
      also increased during the period of relative retinal hypoxia at P17. CONCLUSIONS:
      Retinal NPY and NPY Y2 receptor expression are altered in the development of
      oxygen-induced retinopathy of the mouse, during both the hyperoxic
      vasoconstrictive phase and the period of retinal neovascularization. Alteration
      in the production of NPY and the NPY Y2 receptor may be avenues for potential
      modification in the development of retinopathy.

PMID- 12427236
TI  - Talc retinopathy.
AB  - A 45 year old man presented with talc retinopathy that had been present for
      decades. The static nature of this condition indicates that, in the absence of
      ongoing intravenous drug use, ophthalmological follow up is not necessary

PMID- 12427237
TI  - Optic disc swelling in an adolescent with insulin dependent diabetes mellitus.
AB  - A 14-year-old Ukrainian girl with uncontrolled insulin dependent diabetes
      developed bilateral optic disc swelling when diabetic treatment was instituted.
      There was no retinal ischaemia. The disc swelling resolved completely over 8
      months without specific ocular therapy. Disc swelling in juvenile diabetics must
      be differentiated from disc neovascularization. These patients may develop
      retinal ischaemia and neovascularization after the disc changes resolve.

PMID- 12427238
TI  - Serpiginous choroidopathy: an unusual association with Crohn's disease.
AB  - Serpiginous choroidopathy, an inflammatory chorioretinopathy characterized by
      areas of choroidal atrophy and scarring, has previously been described in
      association with various systemic granulomatous disorders, but has not been
      linked to Crohn's disease. There are reports of ocular posterior segment
      abnormalities in patients with this chronic, granulomatous, inflammatory bowel
      disease, but these have not included serpiginous choroidopathy. This is the first
      report suggesting a link between serpiginous choroidopathy and Crohn's disease. A
      22-year-old woman presented with serpiginous choroidopathy in whom Crohn's
      disease was diagnosed soon after. After starting treatment with oral
      prednisolone, no further visual loss or progression of the chorioretinal lesions
      occurred. The T-cell mediated nature of both inflammatory disorders and the
      temporal association in their onset suggests a possible link between serpiginous
      choroidopathy and Crohn's disease.

PMID- 12427239
TI  - Methotrexate-induced optic neuropathy.
AB  - A 53-year-old Caucasian woman with long-standing, well controlled, severe
      rheumatoid arthritis, treated with methotrexate, salazopyrin, naprosyn,
      prednisone and plaquenil, presented with progressive visual loss in each eye. She
      had a past history of non-necrotizing anterior scleritis that was treated with
      increased doses of prednisone. She developed left then right central scotomas,
      reduced vision and optic atrophy. Eventually a diagnosis of methotrexate-induced
      optic atrophy was made.

PMID- 12427240
TI  - Dislocation of the lens: a complication after cyclocryotherapy.
AB  - An unusual complication is reported of a case of complete dislocation of the lens
      after cyclocryotherapy in a patient with neovascular glaucoma. To the best of the
      authors' knowledge, no case of lens dislocation following cyclocryotherapy has
      previously been reported.

PMID- 12427241
TI  - Morbidity of conjunctival suturing in short scleral tunnel phacoemulsification
      surgery.

PMID- 12427242
TI  - Evaluation of Indian intraocular lenses flawed.

PMID- 12427244
TI  - Septic superior ophthalmic vein thrombosis: to coagulate or not to coagulate?

PMID- 12427245
TI  - Septic superior ophthalmic vein thrombosis: enoxaparin needs to be monitored.

PMID- 12427247
TI  - Effect of alcohol on saccades.

PMID- 12427249
TI  - Vision standards for safe driving.

PMID- 12427251
TI  - Nitric oxide inhibits irreversibly P815 cell proliferation: involvement of
      potassium channels.
AB  - Nitric oxide (NO) has been shown to inhibit both normal and cancer cell
      proliferation. Potassium channels are involved in cell proliferation and, as NO
      activates these channels, we investigated the effect of NO on the proliferation
      of murine mastocytoma cell lines and the putative involvement of potassium
      channels. NO (in the form of NO donors) caused dose-dependent inhibition of cell
      proliferation in the P815 cell line inducing growth arrest in the mitosis phase.
      Incubation with NO donor for 4 or 24 h had a similar inhibitory effect on cell
      proliferation, indicating that this effect is irreversible. The inhibitory effect
      of NO was completely prevented by the blockade of voltage- and calcium-dependent
      potassium channels, but not by blockade of ATP-dependent channels. NO inhibition
      of cell proliferation was unaffected by guanylate cyclase and by cytoskeleton
      disruptors. Therefore, NO inhibits cell proliferation irreversibly via a
      potassium channel-dependent but guanylate cyclase-independent pathway in murine
      mastocytoma cells.

PMID- 12427252
TI  - Elevated Ki-67 expression is correlated with TNFalpha- and IFNgamma-induced
      apoptosis in tumour cells.
AB  - The expression of Ki-67 in tumour cells induced to apoptosis by tumour-necrosis
      factor alpha (TNFalpha) and interferon gamma (IFNgamma) was studied. Ki-67 is
      known as a proliferation marker which is expressed in cycling cells, but not in
      resting quiescent or Go cells. In numerous studies, the proportion of tumours
      expressing Ki-67 was determined and related to tumour grade or prognosis. A high
      percentage of Ki-67 expressing cells and a low apoptotic index were regarded as
      an indication of a progressive tumour. This implied that Ki-67 expression and
      apoptosis were contrary traits. In this study, the level of Ki-67 expression in
      human tumour cells in culture was measured after induction of apoptosis. The Ki
      67 level was determined by flow cytometry and apoptosis was measured by various
      methods including PARP degradation (western blot) in detached and floating cells.
      While the floating cells were all apoptotic, more than 80% of the attached cells
      showed no apoptotic signs. The Ki-67 level of apoptotic cells was elevated about
      3-fold compared to viable attached control cells. However, the cytokine-treated
      attached cells also expressed Ki-67 at similar high levels to the apoptotic
      floating cells, depending on sensitivity. The plot of Ki-67 level vs. remaining
      cells after treatment revealed a strong correlation between the level of Ki-67
      expression and the sensitivity to cytokine-induced apoptosis. This implies that
      proliferation pathways and apoptotic signal transduction are connected.

PMID- 12427253
TI  - A mathematical model of the impact of infused targeted cytotoxic agents on brain
      tumours: implications for detection, design and delivery.
AB  - Motivated by the recent development of highly specific agents for brain tumours,
      we develop a mathematical model of the spatio-temporal dynamics of a brain tumour
      that receives an infusion of a highly specific cytotoxic agent (e.g. IL-4-PE, a
      cytotoxin comprised of IL-4 and a mutated form of Pseudomonas exotoxin). We
      derive an approximate but accurate mathematical formula for the tumour cure
      probability in terms of the tumour characteristics (size at time of detection,
      proliferation rate, diffusion coefficient), drug design (killing rate, loss rate
      and convection constants for tumour and tissue), and drug delivery (infusion
      rate, infusion duration). Our results suggest that high specificity is necessary
      but not sufficient to cure malignant gliomas; a nondispersed spatial profile of
      pretreatment tumour cells and/or good drug penetration are also required. The
      most important levers to improve tumour cure appear to be earlier detection,
      higher infusion rate, lower drug clearance rate and better convection into
      tumour, but not tissue. In contrast, the tumour cure probability is less
      sensitive to a longer infusion duration and enhancements in drug potency and drug
      specificity.

PMID- 12427254
TI  - Tuning the cell cycle: a model based on averaging.
AB  - The ability of intercellular communication and the basement membrane to revert
      the phenotypic behaviour of malignant cells suggests that such cells can be tuned
      to behave more benignly. In addition, the large variation in cell doubling times
      observed in tumour cells poses the question of whether or not cell doubling
      times, and hence, patient survival, can be lengthened by therapeutic
      intervention. In both cases, the understanding may be enhanced by obtaining a
      parsimonious and tractable model of the cell cycle which behaves appropriately
      and suggests a philosophical framework for addressing these complex issues. We
      introduce a simple two-dimensional model based on averaging cyclin and maturation
      promotion factor over a fast oscillating subsystem that exhibits the basic
      features of cellular division, and discuss the ramifications of the model.

PMID- 12427255
TI  - Establishment of a triploid V79 cell line from tetraploid cells obtained through
      polyploidization using K-252a.
AB  - Triploid V79 cells were established from tetraploid cells. Diploid V79 cells were
      polyploidized by K-252a, an inhibitor of protein kinases, and then released from
      the drug for 10 days. At that time, the cell population was a mixture of diploid
      and tetraploid cells. Triploid cells were obtained through the cloning of
      tetraploid cells. They had 33 chromosomes (1.5 times the diploid number) and
      showed a karyotype of three homologueous chromosomes. The duration of the G1, S
      and G2/M phases was almost the same as for diploid cells. The cell volume of
      triploid V79 cells was about two times that of the diploid cells. An explanation
      for the diploid-tetraploid-triploid transition is proposed.

PMID- 12427256
TI  - Long-term result of Memokath urethral sphincter stent in spinal cord injury
      patients.
AB  - BACKGROUND: Memokath urethral sphincter stents are used to facilitate bladder
      emptying in patients with spinal cord injury, but long term follow-up has not
      been reported. METHODS: Case series of ten men with spinal cord injury who
      underwent insertion of Memokath stents and were followed for up to nine years.
      RESULTS: Within four years, the stent had to be removed in nine out of ten
      patients because of: extensive mucosal proliferation causing obstruction to the
      lumen of the stent; stone around the proximal end of the stent, incomplete
      bladder emptying, and recurrent urinary infections; migration of the stent into
      the bladder related to digital evacuation of bowels; large residual urine;
      concretions within the stent causing obstruction to flow of urine, and partial
      blockage of the stent causing frequent episodes of autonomic dysreflexia. In one
      patient the stent continued to function satisfactorily after nine years.
      CONCLUSIONS: The Memokath stent has a role as a temporary measure for treatment
      of detrusor-sphincter dyssynergia in selected SCI patients who do not get
      recurrent urinary infection and do not require manual evacuation of bowels.

PMID- 12427257
TI  - CT features in abdominal tuberculosis: 20 years experience.
AB  - BACKGROUND: Abdominal tuberculosis (TB) is endemic in the developing world and is
      reemerging in the West. Since computed tomography (CT) has the ability to
      demonstrate changes in the peritonium, mesentry, lymphnodes, bowel and solid
      organs and is being increasingly used for primary evaluation of abdominal
      conditions, it is important to be familiar with the CT features of the disease.
      METHODS: CT findings were retrospectively analysed in 49 patients with proved
      abdominal TB. Patients with genitourinary TB and with AIDS/HIV were not included
      in the study. RESULTS: Peritoneal involvement was the most common feature (77.5%)
      with ascites (wet peritonitis) seen in more than half the cases (55.2%). The rest
      showed peritoneal, mesenteric or omental thickening or mass formation but no
      ascites (dry peritonitis). Other findings included lymphadenopathy (46.9% mainly
      of diffuse nature, bowel wall thickening (38%) and solid organ involvement
      (20.4%). CONCLUSIONS: CT reliably demonstrates the entire range of findings which
      need interpretation in the light of clinical and laboratory data.

PMID- 12427258
TI  - Recognition of secretory proteins in Escherichia coli requires signals in
      addition to the signal sequence and slow folding.
AB  - BACKGROUND: The Sec-dependent protein export apparatus of Escherichia coli is
      very efficient at correctly identifying proteins to be exported from the
      cytoplasm. Even bacterial strains that carry prl mutations, which allow export of
      signal sequence-defective precursors, accurately differentiate between
      cytoplasmic and mutant secretory proteins. It was proposed previously that the
      basis for this precise discrimination is the slow folding rate of secretory
      proteins, resulting in binding by the secretory chaperone, SecB, and subsequent
      targeting to translocase. Based on this proposal, we hypothesized that a
      cytoplasmic protein containing a mutation that slows its rate of folding would be
      recognized by SecB and therefore targeted to the Sec pathway. In a Prl suppressor
      strain the mutant protein would be exported to the periplasm due to loss of
      ability to reject non-secretory proteins from the pathway. RESULTS: In the
      current work, we tested this hypothesis using a mutant form of lambda repressor
      that folds slowly. No export of the mutant protein was observed, even in a prl
      strain. We then examined binding of the mutant lambda repressor to SecB. We did
      not observe interaction by either of two assays, indicating that slow folding is
      not sufficient for SecB binding and targeting to translocase. CONCLUSIONS: These
      results strongly suggest that to be targeted to the export pathway, secretory
      proteins contain signals in addition to the canonical signal sequence and the
      rate of folding.

PMID- 12427261
TI  - Sara in her fourth analytic year.

PMID- 12427259
TI  - Impact of in utero exposure to EtOH on corpus callosum development and paw
      preference in rats: protective effects of silymarin.
AB  - BACKGROUND: Using a rat model we have found that the bioflavonoid silymarin (SY)
      ameliorates some of the negative consequences of in utero exposure to ethanol
      (EtOH). In the current study our aim was to determine if laterality preference
      and corpus callosum development were altered in rat offspring whose mothers were
      provided with a concomitant administration of SY with EtOH throughout gestation.
      METHODS: We provided pregnant Fisher/344 rats with liquid diets containing 35%
      ethanol derived calories (EDC) throughout the gestational period. A
      silymarin/phospholipid compound containing 29.8% silybin was co administered with
      EtOH to a separate experimental group. We tested the offspring for laterality
      preference at age 12 weeks. After testing the rats were sacrificed and their
      brains perfused for later corpus callosum extraction. RESULTS: We observed
      incomplete development of the splenium in the EtOH-only offspring. Callosal
      development was complete in all other treatment groups. Rats from the EtOH-only
      group displayed a left paw preference; whereas control rats were evenly divided
      between right and left paw preference. Inexplicably both SY groups were largely
      right paw preferring. CONCLUSIONS: The addition of SY to the EtOH liquid diet did
      confer some ameliorative effects upon the developing fetal rat brain.

PMID- 12427262
TI  - Indeterminacy & compromise formation: implications for a psychoanalytic theory of
      mind.
AB  - The meanings of communications between analyst and analysand are replete with
      alternative interpretations and ambiguity. Interpersonal meaning is inherently
      indeterminate, and so too is intrapsychic meaning. Indeterminacy of meaning, in
      fact, is an intrinsic feature of all psychic experience. In the clinical domain,
      indeterminate meaning is the psychic basis for forming and sustaining neurotic
      patterns of behaviour. This recognition has important implications for effective
      psychoanalytic intervention. Despite the inherent indeterminacy of meaning, it is
      not true that 'anything goes' when trying to make sense of the data that comprise
      psychic experience. Wittingly or not, analysts employ specific operational
      constraints to decide which among numerous alternative, competing interpretive
      schemes is the one that we accept as the 'accurate' and 'true' understanding of
      our experience. These constraints are employed by all rational systems and are
      important components of scientific theories and other explanatory domains.
      Neurotic symptoms and compromise formations do not recognise these constraints.
      They make freer use of indeterminate meaning to satisfy simultaneously the
      multiple competing demands of mental existence. Indeterminacy underlies the
      intense gratification afforded by neurotic symptoms and other transitional
      phenomena, in that it allows us to gratify simultaneously and as fully as
      possible our potentially contradictory desires that conflict with social and
      moral proscriptions. This simultaneous gratification afforded by compromise
      formation is why neurotic symptoms are so intractable to treatment. If conflict
      is one defining feature of the mind, then indeterminacy and compromise formation
      are the others.

PMID- 12427263
TI  - Some thoughts on psychoanalysis and ethics.
AB  - The author attempts to establish a framework for understanding the contribution
      of psychoanalysis to ethics through examining the work of certain philosophers,
      especially Kant. After reviewing the development of Freudian thought and going
      beyond the 'psychoanalysis and/or psychiatry?' question, he asserts that the
      space of the psychoanalytical cure revolves around an ethical problem. Thus, the
      limits of analysis should be determined by the subject's capacity for developing
      a structure of belief in the unconscious, with the concomitant capacity to go
      beyond equivocation in respect of an ethical conflict that underlies all cases
      where psychical suffering is manifested. Indeed, only human beings are called
      upon to deal with an ethical paradox-equally a logical one-which could be stated
      thus: there is Good in Evil and Evil in Good. This ethical paradox is the
      consequence of human subjection to the constituent laws of the Oedipus complex,
      which distances the human being, in his/her dealings with Evil and with Good,
      from any naturalist stance. In respect of the cure, then, we must take into
      account that Evil does not proceed from any particular drive-based
      characteristic, but is rather the expression of specific subjection to an
      unconscious Other, towards which it directs its affects. Finally, the author
      proposes a principle that emerges from the preceding discussion: let us not
      impute to or place in the Other our own subjective splitting or pain at existing.

PMID- 12427264
TI  - Explicating the implicit: the local level and the microprocess of change in the
      analytic situation.
AB  - This paper proposes a method of examining the micro-events of the analytic
      process that borrows heavily from developmental research. The increasing
      importance of illuminating the microprocess of interaction to understanding the
      process of change in analytic treatment is emphasised. A set of constructs and
      terminology is proposed for the study of the moment-to-moment interactive process
      in psychoanalytic therapy referred to as the local level. A theory of therapeutic
      action based on 'local-level' process is then explicated. Its central element
      involves a step-by-step process of 'fitting together', which leads to changes in
      implicit knowing through alteration of emotional procedures.

PMID- 12427265
TI  - A brief history of illusion: Milner, Winnicott and Rycroft.
AB  - Illusion is a word that Raymond Williams might have included among his list of
      keywords of British culture, since it is a word that discloses 'both continuity
      and discontinuity, and also deep conflicts of value and belief' within its
      intellectual and political history (1983, p. 23). It is a banner under which the
      meaning of that culture has frequently been contested. The author indicates some
      of the more significant of these contests, with occasional glances at the wider
      European context and with special reference to the history of psychoanalysis,
      where the conflicts that characterise the larger history of the word have been
      interestingly re-enacted. In particular, the author explores its significance for
      the English psychoanalysts Marion Milner and Charles Rycroft and, more centrally,
      for Donald Winnicott, not least because in Winnicott's case it is a word that has
      been treated only peripherally in the two books that are organised around the
      study of his language, Alexander Newman's Non-Compliance in Winnicott's Words
      (1995) and Jan Abram's The Language of Winnicott (1996).

PMID- 12427266
TI  - An essay on dreaming, psychical working out and working through.
AB  - In this paper the author attempts to expand the idea put forward by Freud who
      considered dreams as a special form of unconscious thinking. It is the author's
      contention that the psychical working-out function performed by dreams is a form
      of unconscious thinking, which transforms affects into memories and mental
      structures. He also attempts to clarify the way in which meaning is built and
      transformed in mental life. In that respect the unconscious internal world is
      seen as a form of unconscious thinking, a private theatre where meaning is
      generated and transformed. He focuses on what happens to feelings in dreams in
      connection with the meanings as a result of and an expression of the several
      stages of working through. The dream world is described as the setting where the
      mind gives expressive pictorial representation to the emotions involved in a
      conflict: a first step towards thinkability. The dreamwork also constitutes a
      process through which meaning is apprehended, built on and transformed at an
      expressive non-discursive level, based on representation through
      figurative/pictorial images. The author draws on Meltzer's formulation to
      conjecture that the working-through function of dreams, mainly in response to
      interpretations, is performed by a process of progression in formal qualities of
      the representations made available by dreaming in the form he has called
      affective pictograms. It is through progression in formal qualities of the
      representation that the thinking capabilities of the affective life develop and
      become part of the process of what is called metaphorically the metabolisation of
      emotional life. This process takes place through migration of meaning across
      various levels of mental process. In this perspective the analyst's
      interpretations of dreams effect what linguists call transmutation of the
      symbolic basis, a process that is necessary to help the mind to improve its
      capacity to think. Something expressed on the evocative plane and condensed into
      a pictographic image is then transformed into verbal language that expresses
      meaning. These conceptions are illustrated by a detailed clinical case.

PMID- 12427267
TI  - Recrimination in the analytic situation. A hypothesis about its influence on
      psychoanalytical groups.
AB  - This paper deals with certain distortions in communication generated by mutual
      recrimination that is the result of disturbances in the ideal agencies of both
      parties. Although the ideal ego, superego and ego ideal participate equally in
      reproach, it is the latter which is the most decisive. In clinical experience,
      recrimination may easily colour the analytic dialogue. In such cases,
      interpretation loses its sense of clarification and another type of dialogue
      replaces it. There, words are used to take possession of the other, for its
      autonomy is a threat to the static character of the pathology of mourning. The
      problem of recrimination has also tainted the development of psychoanalysis, to
      the point of disrupting the process of discovery itself. This paper deals with
      repercussions in the psychoanalytic movement and also in the elements that
      constitute its structure. Finally, different variations and disturbances in the
      psychoanalytic ideal are considered, as well as the involvement of the
      psychoanalytic institution in preserving or transforming the ideal. Here the
      importance of institutions and institutional ideals is emphasised. Finally, we
      suggest that ideals either encourage or hinder the working through of individual
      and collective mourning.

PMID- 12427268
TI  - Parents and their child--and the analyst in the middle.
AB  - The first part of this paper explains how the transgenerational mandate
      influences the mental activity of the child. When a child acts the denied
      suffering of the parental couple, the analyst risks being imprisoned by the
      transgenerational mandate. Frequently the analyst is unconsciously asked by the
      parents to cure without curing because the child's psychological birth, still in
      the making, threatens the defensive equilibrium of the parents. The analyst is
      thus caught between the parents and the child and must find his/her own way
      forward in order to free the child from the burden of the mandate. In the second
      part of the paper, an analysis of a 5-year-old child is presented. The author
      shows how a transgenerational mandate may hold a traumatic potential because it
      can impair heavily the child's capacity to think. The author also describes the
      way in which she works with the parents and how she manages the setting and the
      style of the interpretation. She insists in particular on the need to sustain the
      child's perceptions in order to gradually allow the child to take roots in
      his/her experiences and therefore develop his/her own identity.

PMID- 12427269
TI  - A Lacanian look at English elegance: some reflections on Ian McEwan's enduring
      love.
AB  - This paper makes use of certain thought-provoking ideas from Lacan's seminars in
      the years between 1959 and 1962 in order to engage with the very subtly conveyed
      inner drama that subtends the plot of Ian McEwan's novel Enduring Love. Freud, in
      his 1914 paper 'On narcissism', had referred to theories on the earliest moments
      of subjectivity as 'nebulous, scarcely imagined concepts'. In 1959 Lacan created
      a concept that he called the o-object to make incursions into theories on the
      lasting impact of the anxiety-ridden passage of the small pre-subject into
      subjective existence. In particular, the seminar on Anxiety (1962-3), for all the
      convolutions of syntax and sense that render it so difficult to read, opens up
      reflections on this topic that are not dissimilar to those stimulated by McEwan's
      accomplished prose. Both Lacan and McEwan explore the problematic dissolution of
      the everyday distinction between subjectivity and objectivity attendant on the
      upsurge of anxiety driven by unconscious forces.

PMID- 12427270
TI  - Psychology and literature: the question of reading otherwise.
AB  - By making literature the partner of a dialogue with psychology, with the aim of
      better understanding the psyche, psychoanalysis has truly altered our way of
      understanding the literary phenomenon. Thus, Freud resorted to literature in an
      attempt to validate his theories. At the same time, though, in striving for
      natural-scientific status, he shifted the emphasis away from any possible deep
      comprehension of the literature. However, psychoanalysis, trying to delve deeper
      into literature, has elaborated a whole theory regarding the literary meaning
      that is still prevalent today. In this paper, the author examines the Freudian
      conception of literature that points beyond the intrapsychic and moves towards
      intersubjectivity.

PMID- 12427271
TI  - On Georges Abraham 'The psychodynamics of orgasm'.

PMID- 12427274
TI  - Nontargeted metabolome analysis by use of Fourier Transform Ion Cyclotron Mass
      Spectrometry.
AB  - Advanced functional genomic tools now allow the parallel and high-throughput
      analyses of gene and protein expression. Although this information is crucial to
      our understanding of gene function, it offers insufficient insight into
      phenotypic changes associated with metabolism. Here we introduce a high-capacity
      Fourier Transform Ion Cyclotron Mass Spectrometry (FTMS)-based method, capable of
      nontargeted metabolic analysis and suitable for rapid screening of similarities
      and dissimilarities in large collections of biological samples (e.g., plant
      mutant populations). Separation of the metabolites was achieved solely by ultra
      high mass resolution; Identification of the putative metabolite or class of
      metabolites to which it belongs was achieved by determining the elemental
      composition of the metabolite based upon the accurate mass determination; and
      relative quantitation was achieved by comparing the absolute intensities of each
      mass using internal calibration. Crude plant extracts were introduced via direct
      (continuous flow) injection and ionized by either electrospray ionization (ESI)
      or atmospheric pressure chemical ionization (APCI) in both positive or negative
      ionization modes. We first analyzed four consecutive stages of strawberry fruit
      development and identified changes in the levels of a large range of masses
      corresponding to known fruit metabolites. The data also revealed novel
      information on the metabolic transition from immature to ripe fruit. In another
      set of experiments, the method was used to track changes in metabolic profiles of
      tobacco flowers overexpressing a strawberry MYB transcription factor and altered
      in petal color. Only nine masses appeared different between transgenic and
      control plants, among which was the mass corresponding to cyanidin-3
      rhamnoglucoside, the main flower pigment. The results demonstrate the feasibility
      and utility of the FTMS approach for a nontargeted and rapid metabolic
      "fingerprinting," which will greatly speed up current efforts to study the
      metabolome and derive gene function in any biological system.

PMID- 12427275
TI  - Metabolomics of plant saponins: bioprospecting triterpene glycoside diversity
      with respect to mammalian cell targets.
AB  - One of the goals of cancer chemotherapy and prevention is the discovery of
      compounds that are relatively selective to tumor cells and, therefore, have
      reduced effects on normal cell growth. In previously published studies, it was
      shown that certain triterpene saponins (called avicins) from a desert tree,
      Acacia victoriae, are selectively toxic to tumor cells at very low doses (IC(50):
      0.2 microg/mL for Jurkat cells). To extend this research to human clinical
      studies, we needed to find a reliable supply of avicins and have developed a
      transformed "hairy root" culture as a means of biomass production. Protocols were
      optimized for A. victoriae micropropagation; after a boiling water treatment, A.
      victoriae seeds were maintained under in vitro conditions on defined media.
      Embryo-axis explants from shoot tips were removed and infected with Agrobacterium
      rhizogenes Conn (R 1000) for hairy root induction. Plasmid integration was
      confirmed by PCR analysis with a primer set for a segment of the rol B gene.
      Culture conditions have been optimized for root biomass production, and various
      inducers have been investigated for enhancement of avicin production. Hairy root
      cultures were compared with intact pod tissue from field-grown sources for avicin
      content following partial purification of triterpene glycosides and HPLC
      separation of the secondary metabolites. From bioassays of the collected HPLC
      fractions, we have identified putative triterpene "metabolic clusters" with
      enhanced activity against tumor cells. This now provides a system for both
      production of clinical trial lots of active samples, but also a means to
      correlate structure of individual triterpene glycosides with specific cellular
      target activity in mammalian cells.

PMID- 12427276
TI  - Suspected utility of enzymes with multiple activities in the small genome
      Mycoplasma species: the replacement of the missing "household" nucleoside
      diphosphate kinase gene and activity by glycolytic kinases.
AB  - The small genome Mollicutes whose DNAs are completely sequenced (Mycoplasma
      genitalium, Mycoplasma pneumoniae, Mycoplasma pulmonis, and Ureaplasma
      urealyticum [parvum]) lack a gene (ndk) for the presumably essential nucleoside
      diphosphate kinase (NDPK). We hypothesized that other activities might replace
      NDPK activity. We found in M. genitalium G37(T), Mycoplasma pneumoniae FH(T),
      Mycoplasma fermentans PG18(T), and Mycoplasma capricolum subsp. capricolum Kid(T)
      that their 6-phosphofructokinases (6-PFKs), phosphoglycerate kinases (PGKs),
      pyruvate kinases (PKs), and acetate kinases (AKs), besides reactant ADP/ATP,
      could use other ribo- and deoxyribo-purine and pyrimidine NDPs and NTPs. These
      activities could compensate for the absence of an orthologous ndk gene in the
      Mycoplasmataceae. They suggest a metabolically varied and consequential role for
      unrelated and perhaps unsuspected "replacement" or compensatory enzymes that may
      confound metabolic prediction. We partially purified and biochemically
      characterized the PKs, 6-PFKs, PGKs, and AKs from M. capricolum subsp. capricolum
      Kid(T) and M. fermentans PG18(T).

PMID- 12427277
TI  - %(G+C) variation and prediction by a model of bacterial gene transfer and codon
      adaptation.
AB  - The %(G + C) of bacterial genomes ranges from 25% in Mycoplasma to 75% in
      Micrococcus. Our model for horizontal gene flow enabled a theoretical study of
      the adaptation of relative codon frequency to match the pattern of the tRNA set
      of a new host. This study explored the dynamic relationship of %(G + C) to
      vectors of relative codon frequency (F(gamma)), relative amino acid coding
      frequency (F(alpha)), and absolute codon frequency (F(|gamma|)) in chromosomes of
      nine, fully sequenced bacterial genomes that varied widely in %(G + C). At
      constant F(alpha), the theoretical maximum average range possible was %(G + C) =
      37.4 +/- 0.9%. In simulations of F(gamma) adaptation to a new host following
      hypothetical gene transfer, we modeled %(G + C) as a function of F(gamma) and
      F(alpha). The simulation revealed that %(G + C) is dependent on F(gamma) and
      F(alpha) in an explicit relationship described in this paper. We conclude that
      (1) F(gamma) and F(alpha) determine %(G + C), and (2) the degree of adaptation of
      %(G + C) in a transferred gene depends upon the degree of F(gamma) equilibration
      and the similarity of F(alpha) of the transferred gene to that of the new host.

PMID- 12427278
TI  - Two overlapping divergent transcription units in the human genome: the
      FEN1/C11orf10 locus.
AB  - Flap endonuclease 1 (FEN-1) is a nuclear enzyme involved in DNA metabolism, such
      as replication, repair, and recombination. Here, we report the comparative
      genomic organization of the chicken, mouse, and human FEN1 genes as well as the
      comparative organization of a small gene (C11orf10) located immediately upstream
      of the FEN1 gene in reverse orientation. Immunostaining revealed that the
      C11orf10 protein, unlike FEN-1, is located in the cytoplasm, suggesting that
      these two proteins do not form a physical complex. Importantly, in the human
      genome, the two mRNAs are overlapping (14 bp) in their 5' ends. Thus, the
      FEN1/C11orf10 locus is a new example of two overlapping, divergent transcription
      units in the human genome.

PMID- 12427281
TI  - Robert C. Gallo, M.D. [Interview by Vicki P Glaser].

PMID- 12427282
TI  - Toward cellular-based therapies for HIV infection.
AB  - Infection with HIV-1 progressively erodes immune function, leading ultimately to
      multiple hematopoietic cytopenias. In advanced HIV disease, anemia, neutropenia,
      and thrombocytopenia occur in a large fraction of patients and are reflective of
      a striking inability of the bone marrow to accomplish a compensatory increase in
      production. No failure of compensatory production is greater than that of the T
      lymphoid system, where despite apparently effective control of HIV replication,
      restoration of anti-HIV immunity does not occur. Recent technical developments
      have provided considerable insight into hematopoietic dysfunction in HIV disease
      and, in particular, in vivo T cell generation. This article will review some of
      the mechanisms participating in immune regeneration, the stakes involved in
      effectively accomplishing full reconstitution, and potential approaches to
      enhance the limited endogenous regenerative process.

PMID- 12427283
TI  - Stem cell transplantation and gene therapy for HIV-related lymphomas.
AB  - The treatment of patients with HIV-related non-Hodgkin's lymphoma (NHL) and
      Hodgkin's disease (HD) is less successful than in the non-HIV setting, in part
      due to the aggressive character of these lymphomas but also due to the underlying
      HIV infection. High-dose therapy with stem cell transplantation has been used
      with success in the HIV-negative lymphoma setting for high-risk or relapsed
      disease. However, for patients with HIV-NHL and HIV-HD, ultimately the chance for
      long-term lymphoma-free survival also depends on successful control of the HIV
      infection. Gene therapy approaches may provide the opportunity for this long-term
      control. Herein, we describe the use of high-dose chemotherapy with stem cell
      rescue in conjunction with current and future gene therapy approaches for the
      treatment of HIV-associated lymphomas.

PMID- 12427284
TI  - Immune recovery in HIV disease: role of the thymus and T cell expansion in immune
      reconstitution strategies.
AB  - While the progressive depletion of CD4(+) T cells is the hallmark of the impact
      of HIV on the immune system, considerable data also point to the loss of T cell
      function. The question is: Can the immune system recover from this insult and
      what are the therapeutic strategies available to us to mediate this immune
      recovery? This review will focus on our current knowledge of immune recovery
      following treatment with highly active antiretroviral therapy (HAART).
      Enhancement of thymic function in generating de novo T cell synthesis post-HAART
      has also emerged as a viable immune recovery strategy. Advances in molecular (T
      cell receptor excision circle assay) and conventional (computed tomography scans
      of the thymus) approaches to evaluate the role of the thymus in immune recovery
      as well as potential agents that might enhance thymic output (interleukin-7, IL
      7) will contribute greatly to the assessment of the success of these approaches
      as immune recovery strategies. In this review, we will integrate this new
      information in the context of the current strategies for HIV therapy leading to
      long-term immune reconstitution.

PMID- 12427285
TI  - An expanding role for CD40L and other tumor necrosis factor superfamily ligands
      in HIV infection.
AB  - Immunostimulatory members of the tumor necrosis factor (TNF) superfamily (TNFSF)
      of ligands are known to be important regulators of the immune system. These
      trimeric molecules interact with members of the TNF receptor superfamily (TNFRSF)
      to stimulate immune cells. Of the TNFSF molecules, CD40 ligand (CD40L, also
      called CD154 or TNFSF5) is the most crucial molecule for activating antigen
      presenting cells (APCs) and thereby initiating the immune response. Evidence has
      accrued indicating that HIV infection either selectively depletes those CD4(+) T
      cells that express CD40L in response to antigen or down-regulates CD40L
      expression by these cells. Because CD40L expression is necessary for the immune
      defense against HIV and opportunistic infections, an insufficiency of CD40L could
      contribute to the progression of AIDS. CD40L contributes to the antiviral
      mechanisms of the host by inducing anti-HIV beta-chemokines and activating CD8(+)
      T cells. However, CD40L stimulation can lead to enhanced HIV replication under
      certain experimental conditions, due to its immune activating properties and the
      need for cellular activation for high-level HIV production. On balance, it is
      believed that reversing the relative CD40L deficiency seen in HIV infection will
      be important for immune restoration in AIDS. In addition, adding CD40L to a
      therapeutic or preventative vaccine could lead to strengthened antiviral
      immunity. Because of the complexities in delivering this molecule, a number of
      forms of CD40L have been developed, and one form of soluble CD40L has been tested
      in humans. New strategies are being developed to translate the profoundly
      immunostimulatory effects of CD40L found in animal models to humans with HIV
      infection.

PMID- 12427286
TI  - Interleukin-7 and immunorestoration in HIV: beyond the thymus.
AB  - One of the hallmarks of untreated HIV infection is a progressive loss of
      effective immunity to both HIV-associated and non-HIV antigens. Combination
      antiretroviral therapy can frequently control viral replication, resulting in
      variable levels of immune reconstitution, but has not resulted in restoration of
      effective immunity to the virus. Understanding the limitations of immune
      reconstitution following highly active antiretroviral therapy (HAART) and
      identifying approaches to enhance immunity in this context may not only improve
      outcome for patients with HIV infection but could also provide insight for immune
      reconstitution in other conditions associated with T cell depletion.

PMID- 12427287
TI  - Gene therapy-based treatment for HIV-positive patients with malignancies.
AB  - Gene therapy for the treatment of HIV has long been a goal of many investigators.
      The majority of trials have involved the use of lymphocytes transduced with
      vectors promoting resistance to HIV infection or replication. Unfortunately, the
      results have been less than encouraging with low-level marking and, more
      importantly, clearance of these lymphocytes from the circulation. Conversely,
      gene-modified hematopoietic stem cells appear able to introduce foreign
      transgenes while avoiding immunologic clearance. Furthermore, the use of less
      toxic conditioning regimens for allogeneic transplantation provides an attractive
      approach to conferring HIV resistance while allowing treatment of HIV-related
      disorders such as malignancies. This combination of nonmyeloablative allogeneic
      transplantation using gene-modified hematopoietic stem cell theoretically
      overcomes the high transplant mortality associated with traditional conditioning
      regimens in patients with HIV as well as providing a self-renewing source of HIV
      resistant cells. To assess the safety and feasibility of such an approach, a
      clinical protocol was initiated in those patients infected with HIV with a
      hematologic malignancy meeting the standard indications for allogeneic
      transplantation and provided here is an update to the previously published
      original report. Only patient 1 received genetically modified cells. Both
      patients tolerated the procedure with no effect on viral load and improved CD4
      counts, and patient 1 remains in complete remission from acute myelogenous
      leukemia 3 years post transplant. Patient 2 also achieved clinical remission from
      chemorefractory Hodgkin's disease but died of relapsed disease 12 months after
      transplantation. Vector-transduced cells remain detectable at low levels more
      than 3 years post-transplantation, suggesting the potential for gene therapy as a
      reasonable goal for the treatment of HIV.

PMID- 12427288
TI  - Trans-activated interferon-alpha2 delivered to T cells by SV40 inhibits early
      stages in the HIV-1 replicative cycle.
AB  - Several lines of evidence suggest a potential major role for interferon (IFN) in
      controlling HIV-1 replication. However, this inhibition is moderate and is
      reversible upon IFN removal. To achieve prolonged high concentrations of IFN at
      the site of infection, we devised an SV40-based vector, SV[HIVLTR]IFN, to direct
      the synthesis of human IFN-alpha2, by employing a virus-trans-activated human IFN
      alpha2 gene to be transcribed in response to HIV-1 infection. Expression of IFN
      alpha2 was confirmed by Northern and Western blotting, in SV[HIVLTR]IFN
      transduced, HIV-1-challenged human lymphocyte lines and primary human
      lymphocytes. SV[HIVLTR]IFN-transduced cells showed no evidence of HIV-1-related
      cytophatic effects when challenged with high doses of HIV-1(NL4-3). As measured
      by supernatant HIV-1 p24 antigen concentration, IFN-alpha2-expressing cell lines
      and peripheral blood lymphocytes (PBL) were protected from high-dose challenges
      of HIV-1. rSV40-delivered IFN-alpha2 inhibited gp120 protein synthesis and
      expression of HIV-1 mRNAs. Finally, Southern analysis revealed that levels of
      proviral DNA were markedly reduced in SV[HIVLTR]IFN-transduced cells compared to
      control cultures. IFN-alpha2 expression driven by HIVLTR delivered by an rSV40
      vector thus strongly inhibits HIV-1 replication, probably by blocking a
      preintegration step in HIV-1 infection. Targeted expression of IFN-alpha2
      delivered by SV40 can thus repress HIV-1 replication, and may be a useful
      approach to HIV-1 treatment.

PMID- 12427289
TI  - HIV-1 gp120 modulates the immunological function and expression of accessory and
      co-stimulatory molecules of monocyte-derived dendritic cells.
AB  - Initiation of a primary immune response requires antigen specific CD4(+) T helper
      (T(h)) cells to assist in priming of CD8(+) cytotoxic T cell (CTL) activity. This
      is optimal when T(h) cells and CTL recognize antigen when presented to them by a
      dendritic cell (DC) in the context of major histocompatibility complex (MHC)
      class I and class II complexes. We have hypothesized that human DC exposed to HIV
      1 gp120 IIIB envelope glycoprotein may activate or alter the immunological
      activation of DCs. Our findings have led us to conclude that HIV-1 gp120 LAV/IIIB
      activates monocyte-derived DC when they are in their immature state while HIV-1
      gp120 exhibits highly selective effects on mature DC. We have observed that
      following maturation of DCs with lipopolysaccharide (LPS) that they are less
      susceptible to the modulatory effects of gp120. Although HIV-1 gp120 activates
      immature DC, it does so in a manner that abrogates their normal function in host
      immune responses and consequently disturbs the homeostatic balance of host immune
      response to infection. We suggest that HIV-1 gp120 may support sustained
      productive infection and transinfection of activated T cells that cluster with
      gp120-activated DC. We believe that these are promoted by mechanisms that are
      dependent, at least in part, on altered cytokine responses, enhanced expression
      of cellular adhesion molecules and augmented DC-mediated activation of T cells in
      nonspecific and antigen-specific immune reactivities. Consequently, HIV-1 gp120
      may actively contribute to the immunopathogenesis of AIDS.

PMID- 12427290
TI  - Epilogue: a journey with blood cells and viruses.

PMID- 12427291
TI  - Who's nervous now?

PMID- 12427292
TI  - Treatment of pediatric anxiety disorders: an open-label extension of the research
      units on pediatric psychopharmacology anxiety study.
AB  - BACKGROUND: An 8-week placebo-controlled study, the Research Units on Pediatric
      Psychopharmacology Anxiety Study, documented beneficial effects of fluvoxamine in
      the treatment of pediatric social anxiety, separation anxiety, or generalized
      anxiety disorders. Following completion of this study, participants were invited
      to enter a 6-month open-label treatment phase designed to examine three issues:
      (a) long-term maintenance of response in fluvoxamine responders, (b) acute
      response to fluoxetine in fluvoxamine nonresponders, and (c) acute response to
      fluvoxamine in placebo nonresponders. METHODS: Participants aged 6-17 years
      meeting criteria for social anxiety, separation anxiety, or generalized anxiety
      disorders previously treated in an 8-week placebo-controlled trial (n = 128) were
      offered open treatment. Changes in symptoms of anxiety during open treatment were
      assessed in three groups: (a) fluvoxamine responders maintained on fluvoxamine,
      (b) fluvoxamine nonresponders changed to fluoxetine, and (c) placebo
      nonresponders changed to fluvoxamine. Response was defined based on Clinical
      Global Impression criteria. RESULTS: During 6 months of continued open treatment,
      anxiety symptoms remained low in 33 of 35 (94%) subjects who initially responded
      to fluvoxamine. Among 14 fluvoxamine nonresponders switched to fluoxetine,
      anxiety symptoms appeared significantly improved in 10 (71%) subjects. Finally,
      among 48 placebo nonresponders, 27 (56%) showed clinically significant
      improvement in anxiety on fluvoxamine. CONCLUSION: The current findings
      concerning extended treatment of pediatric anxiety disorders are only
      preliminary, because treatment was uncontrolled. Results suggest that an initial
      fluvoxamine response is likely to be retained with continued treatment, that some
      fluvoxamine nonresponders may respond to fluoxetine, and that some placebo
      nonresponders may respond to fluvoxamine.

PMID- 12427293
TI  - Treating children and adolescents with selective serotonin reuptake inhibitors:
      how long is appropriate?
AB  - This article addresses a key question on the use of selective serotonin reuptake
      inhibitors (SSRIs) among children and adolescents. As briefly reviewed, recent
      randomized controlled trials have established the safety and efficacy of SSRIs in
      the acute treatment of major depression and anxiety disorders among children and
      adolescents. Major questions emerge in light of these data concerning the
      potential risks and benefits of long-term SSRI use among children and adolescents
      who receive significant short-term benefits from SSRI treatment. The current
      review summarizes research on longitudinal outcomes, neuroscience, and
      psychopharmacology to formulate a set of preliminary recommendations on long-term
      SSRI use. A review of data in these areas supports three conclusions. First, for
      children who achieve marked reduction in anxiety or depressive symptoms on an
      SSRI, clinicians should consider recommending a medication-free trial. Second,
      when indicated, this medication-free trial should coincide with the first low
      stress period occurring after 1 year of continual SSRI treatment. Third, SSRI
      treatment should be reinitiated in children who exhibit signs of relapse during
      this medication-free trial.

PMID- 12427294
TI  - Treatment of mood lability and explosive rage with minerals and vitamins: two
      case studies in children.
AB  - A micronutrient supplement containing a broad range of dietary minerals and
      vitamins is being examined for the treatment of mood lability in both adults and
      children (Kaplan et al. 2001; Popper 2001). During pilot work, two medication
      free boys with mood lability and explosive rage were studied in an open-label
      treatment followed by reversal and retreatment. One child was an 8-year-old with
      atypical obsessive-compulsive disorder, and the other was a 12-year-old with
      pervasive developmental delay. Both boys were monitored using the mood and temper
      items from the Conners Parent Rating Scale, as well as the Child Behavior
      Checklist. In addition, the boy with atypical obsessive-compulsive disorder was
      monitored with the child version of the Yale-Brown Obsessive Compulsive Scale.
      Both boys benefited from the micronutrient supplement when examined in ABAB
      designs: mood, angry outbursts, and obsessional symptoms improved when initially
      treated, returned when not taking the supplement, and remitted when the
      micronutrient supplement was reintroduced. Both boys have been followed and are
      stable on the nutritional supplement for over 2 years. These cases suggest that
      mood lability and explosive rage can, in some cases, be managed with a mixture of
      biologically active minerals and vitamins, without using lithium or other
      traditional psychopharmacologic agents.

PMID- 12427295
TI  - Trends in antipsychotic use in a Texas medicaid population of children and
      adolescents: 1996 to 2000.
AB  - The purpose of this study was to examine the current trends in prescribing
      antipsychotics to children and adolescents within the Texas Medicaid Program.
      Total enrollments of children and adolescents, ranging from infants to 19-year
      olds, in the Texas Medicaid Program were determined for each calendar year from
      1996 to 2000. Prevalence was defined as the number of children and/or adolescents
      with at least one Medicaid prescription claim for an antipsychotic per 1,000
      enrollees. Trends in prevalence were assessed over a 5-year period using annual
      descriptive analyses. In addition, total expenditures for antipsychotics were
      evaluated within this population. Over the 5-year period, an additional 12.25
      children and adolescents per 1,000 enrollees (+160%) were prescribed
      antipsychotics. The prevalence of atypical antipsychotics increased by 13.29 per
      1,000 enrollees (+494%) over the same period. In children and adolescents above 2
      years of age, the prevalence of antipsychotic use increased in all groups.
      Antipsychotic usage was more common in children and adolescents between the ages
      of 10 and 14 years compared to other age groups. Male and female antipsychotic
      prevalence rates increased during the 5-year period. The increase in total
      expenditures was related to the increased utilization of atypical antipsychotics.

PMID- 12427296
TI  - Can diabetes mellitus be induced by medication?
AB  - The possible relation between diabetes mellitus and the use of psychotropic
      medications in adult psychiatric patients has been discussed in the literature.
      In child and adolescent psychiatry, however, there have been only two previous
      case reports of an adolescent who developed diabetes mellitus while receiving
      psychotropic medications. We present three adolescents who developed diabetes
      mellitus after combined treatment with divalproex sodium and atypical
      antipsychotics. All were African American, obese, and had a family history of
      diabetes mellitus. We discuss each case and examine the possibility of
      psychotropic medication-induced diabetes mellitus in adolescents.

PMID- 12427297
TI  - A retrospective open trial of adjunctive donepezil in children and adolescents
      with autistic disorder.
AB  - In light of the recently reported neuropathologic and neurochemical abnormalities
      of the cholinergic pathways in autism, donepezil, a cholinesterase inhibitor, is
      a potentially useful agent in the treatment of cognitive and behavioral symptoms
      observed in this disorder. A retrospective pilot study was conducted to determine
      whether donepezil is effective in the treatment of children and adolescents with
      autism. Eight patients (mean age = 11.0 +/- 4.1 years; range 7-19 years) who met
      Diagnostic and Statistical Manual of Mental Disorders (4th edition) criteria for
      autistic disorder were openly treated with donepezil. All patients were on
      concomitant psychoactive medications. Four of these patients (50%) demonstrated
      significant improvement as assessed by the Aberrant Behavior Checklist and the
      Clinical Global Impression Scale. Decreases in the Irritability and Hyperactivity
      subscales were observed, but no changes in the Inappropriate Speech, Lethargy,
      and Stereotypies subscales were noted. Limited and transient side effects were
      reported, with one patient experiencing gastrointestinal disturbances and another
      reporting mild irritability. Double-blind, placebo-controlled investigations are
      needed to provide further evidence of the potential benefits of donepezil to
      patients with autistic disorder.

PMID- 12427298
TI  - A retrospective assessment of citalopram in children and adolescents with
      pervasive developmental disorders.
AB  - Although selective serotonin reuptake inhibitors have been used to treat symptoms
      of aggression and anxiety in children and adolescents with pervasive
      developmental disorders (PDDs), there are no published reports of the use of
      citalopram in this population. The purpose of this study was to examine the
      benefits and adverse effects of citalopram in a group of children and adolescents
      with PDDs. Target behaviors included aggression, anxiety, stereotypies, and
      preoccupations. Seventeen patients with PDDs (14 with autistic disorder, three
      with Asperger's disorder) (mean age = 9.4 +/- 2.9 years; range 4-15 years) were
      treated with citalopram for at least 2 months (mean duration of treatment = 7.4
      +/- 5.3 months; range 1-15 months). Treatment was initiated at a low dose (5 mg
      daily) and was increased by 5 mg weekly as tolerated and as necessary. The mean
      final dose was 19.7 +/- 7.8 mg (range 5-40 mg). Outcome was based on a consensus
      between clinician and parents, using the Improvement item of the Clinical Global
      Impressions Scale as a guide. Ten (59%) children were judged to be much improved
      or very much improved regarding target behaviors. Core symptoms of PDDs (social
      interactions, communication) did not show clinically significant improvement.
      Citalopram was generally well tolerated, although four patients developed
      treatment-limiting adverse effects: two with increased agitation, one with
      insomnia, and one with possible tics. The results of this case series suggest
      that citalopram has beneficial effects on some interfering behaviors associated
      with PDDs with few adverse effects. Controlled trials are warranted.

PMID- 12427299
TI  - Amantadine treatment of psychotropic-induced weight gain in children and
      adolescents: case series.
AB  - OBJECTIVE: The purpose of this study was to explore whether amantadine would slow
      or reverse significant weight gain in children and adolescents treated with
      antipsychotics and/or mood stabilizers that may promote increases in weight.
      METHODS: Eight boys and one girl ages 9-16 years and their parents consented to
      an open trial of amantadine 100 mg po bid or tid for weight gain in children.
      Side effects and body mass index were determined at baseline and during
      amantadine treatment. RESULTS: A mean weight gain of 10.5 kg (19.9% mean increase
      in body weight) occurred from baseline to the beginning of amantadine treatment.
      Amantadine trial length averaged 14.5 weeks (range 4-33 weeks). A planned
      comparison using repeated measures analysis of variance demonstrated strong
      support for a "slowing weight gain" mechanism (p = 0.001) for weight gain and
      body mass. Weight loss was strongly correlated with length of amantadine
      treatment (p = < 0.05). One child experienced orthostatic hypotension with
      concomitant stimulant medication. No other side effects or exacerbation of
      psychiatric symptoms was reported. CONCLUSIONS: Amantadine appears to stabilize
      weight gain related to psychotropic medications. Decreased weight and body mass
      index may occur with continued amantadine usage. Controlled trials of amantadine
      in children and adolescents taking weight-gain-inducing psychotropics are
      warranted.

PMID- 12427300
TI  - Obsessive-compulsive disorder secondary to brain dysgerminoma in an adolescent
      boy: a positron emission tomography case report.
AB  - The neuroanatomical model involved in the pathophysiology of obsessive-compulsive
      disorder (OCD) postulates a hyperactivation of orbitofrontal, limbic, and basal
      ganglia circuits. We report a case of OCD secondary to brain dysgerminoma
      affecting this circuit in an adolescent who responded to citalopram. The patient
      is a 16-year-old-boy with a midline germinal tumor (dysgerminoma) affecting the
      caudate nuclei; left lenticular, right internal capsule's genu; and bilateral
      involvement of the interventricular septum close to the interventricular
      foramina. He had OCD symptoms and elevated tumor markers when he had a tumor
      relapse, and fluorodeoxyglucose positron emission tomography showed caudate
      nuclei involvement. He responded to citalopram that had to be titrated gradually
      to 80 mg/day.

PMID- 12427301
TI  - Neuroleptic withdrawal versus serotonergic syndrome in an 8-year-old child.
AB  - There appears to be considerable symptomatic overlap between neuroleptic
      withdrawal reactions and the serotonin syndrome. This case report is of an 8-year
      old boy who developed symptoms compatible with both conditions while
      discontinuing pimozide and starting fluoxetine. It illustrates how the use of
      neuroleptic medication in young children is not without the risk of serious
      adverse drug events and can complicate diagnostic issues. This case report
      supports the suggestion that adverse drug reactions related to neuroleptics and
      serotonergic agents could be part of the same clinical and neurophysiological
      spectrum.

PMID- 12427302
TI  - Topiramate plus risperidone for controlling weight gain and symptoms in preschool
      mania.

PMID- 12427303
TI  - Medication interaction causing seizures in a patient with bipolar disorder and
      cystic fibrosis.

PMID- 12427304
TI  - A new scalable method for the purification of recombinant adenovirus vectors.
AB  - Recombinant adenovirus vectors continue to be the preferred vectors for many
      types of gene therapy. However, issues regarding production and safety as well as
      the development of a scalable process for these vectors remain a challenge.
      Additionally, any process must address the well-documented immune and toxicologic
      responses to these vectors. Some alternatives to classic CsCl-gradient
      purification based on column chromatography have been developed, but these first
      generation processes are still limited in potential application. We report the
      development of a tandem column chromatography process incorporating two resins;
      anion-exchange and PolyFlo (Puresyn, Inc., Malvern, PA). PolyFlo is used in a
      novel manner as a polishing step to remove additional host and viral proteins not
      removed by the anion-exchange capture step. By using the beta-galactosidase
      reporter vector, H5.CMV-lacZ, the purity of the product is improved compared to
      the same vector purified by 2x CsCl or anion-exchange alone as determined by high
      performance liquid chromatography (HPLC), sodium dodecyl sulfate-polyacrylamide
      gel electrophoresis (SDS-PAGE; silver stain), Western analysis, electron
      microscopy, and particle:infectious (VP:IU) unit ratio. The recovery over the
      entire process is significantly better than 2x CsCl and higher than other first
      generation tandem chromatography processes. This new process is reproducible and
      scalable to 10(15) input viral particles per run. Furthermore, the purified
      adenovirus product remains intact after multiple freeze/thaw cycles and is stable
      at 4 degrees C, -20 degrees C, and -75 degrees C. The process described here
      permits purification of adenovirus particles at a high concentration at large
      scale without centrifugation.

PMID- 12427305
TI  - Insect cells as a factory to produce adeno-associated virus type 2 vectors.
AB  - Recombinant adeno-associated viruses (rAAV) are produced transiently in mammalian
      cells usually by cotransfecting two or three plasmids containing AAV genes,
      adenovirus helper genes, and a vector genome. Expansion and transfection of
      adherent cells limit the scale of rAAV production. Efficient transfection is
      performed with cells on solid support media such as tissue culture plates. A
      large animal study or a human clinical trial may require 10(15) particles of
      vector, depending on dose. To generate this quantity of rAAV by transfection,
      more than 10(11) HEK293 cells may be needed, which would require about 5000 x 175
      cm(2) flasks. The ability to scale up rAAV production by these methods severely
      restricts the commercialization and use of AAV vectors. A recombinant baculovirus
      derived from the Autographa californica nuclear polyhedrosis virus is widely
      employed for large-scale production of heterologous proteins in cultured insect
      cells and may provide an attractive alternative. Toward this goal, we have
      explored the production of rAAV in invertebrate cells. Sf9 cells may be
      coinfected in suspension cultures with three recombinant baculoviruses (a Rep
      baculovirus, a VP-baculovirus, and an AAV ITR vector genome baculovirus) and, 3
      days later, rAAV is recovered. The particles produced are indistinguishable from
      293 cell-produced rAAV, as determined on the basis of physical properties and
      biologic activities. Particles produced by either method were composed of similar
      proteins and nucleic acid. The yield of genome-containing particles produced per
      Sf9 cell approached 5 x 10(4), thus, 1000 ml of cultured Sf9 cells produced the
      equivalent of between 500 to 1000 x 175 cm(2) flasks of 293 cells. This robust
      system provides a simple, cost-effective method for AAV vector production.

PMID- 12427306
TI  - Recovery of airway cystic fibrosis transmembrane conductance regulator function
      in mice with cystic fibrosis after single-dose lentivirus-mediated gene transfer.
AB  - The potential for gene therapy to be an effective treatment for cystic fibrosis
      (CF) airway disease has been limited by inefficient gene transfer vector particle
      delivery and lack of persistent gene expression. We have developed an airway
      conditioning process that, when combined with a human immunodeficiency virus
      (HIV)-derived lentivirus (LV) vector, resulted in persistent in vivo expression
      of transgenes in airway epithelium. Pretreatment of mouse nasal epithelium with
      the detergent lysophosphatidylcholine (LPC) prior to instillation of a single
      dose of an LV vector carrying the LacZ marker gene produced significant LacZ gene
      expression in nasal airway epithelium for at least 92 days. Transduction of the
      cystic fibrosis transmembrane conductance regulator (CFTR) gene using the same LV
      vector system resulted in partial recovery of electrophysiologic function in the
      nasal airway epithelium of CF mice (cftr(tm1Unc) knockout) for at least 110 days.
      This first demonstration of LV-mediated in vivo recovery of CFTR function in CF
      airway epithelium illustrates the potential of combining a preconditioning of the
      airway surface with a simple and brief LV vector exposure to produce therapeutic
      gene expression in airway.

PMID- 12427307
TI  - Redirecting migration of T cells to chemokine secreted from tumors by genetic
      modification with CXCR2.
AB  - T-cell-based immunotherapies provide a promising means of cancer treatment
      although durable antitumor responses are infrequent. A potential reason for these
      shortcomings may lie in the observed lack of trafficking of specific T cells to
      tumor. Our increasing knowledge of the process of trafficking involving adhesion
      molecules and chemokines affords us the opportunity to intervene and correct
      deficiencies in this process. Chemokines can be expressed by a range of tumors
      and may serve as suitable targets for directing specific T cells toward tumor. We
      initially sought to identify which chemokines were produced by a range of human
      tumor cell lines, and which chemokines and chemokine receptors were expressed by
      cultured T cells. We identified two chemokines: Growth-Regulated Oncogene-alpha
      (Gro-alpha; CXCL1) and Regulated on Activation Normal T Cell-Expressed and
      Secreted (RANTES; CCL5), to be secreted by several human tumor cell lines.
      Expression was also detected in fine-needle aspirates of melanoma from patients.
      In addition, we determined the expression of several chemokine receptors on
      cultured human T cells including CCR1, CCR2, CCR4, CCR5, CXCR3, and CXCR4.
      Cultured, activated human T cells expressed the chemokines lymphotactin (XCL1),
      RANTES, macrophage inflammatory protein-1 alpha (MIP-1 alpha; CCL3) and MIP-1
      beta (CCL4), but no appreciable Gro-alpha. In a strategy to direct T cells toward
      chemokines expressed by tumors we chose Gro-alpha as the target chemokine because
      it was produced by tumor and not by T cells themselves. However, T cells did not
      express the receptor for Gro-alpha, CXCR2, and therefore, T cells were transduced
      with a retroviral vector encoding CXCR2. Calcium ion mobilization, an important
      first step in chemokine receptor signaling, was subsequently demonstrated in
      transduced T cells in response to Gro-alpha. In addition, Gro-alpha was
      chemotactic for T cells expressing CXCR2 in vitro toward both recombinant protein
      and tumor-derived chemokine. Interestingly we demonstrate, for the first time,
      that Gro-alpha was able to induce interferon-gamma (IFN-gamma) secretion from
      transduced T cells, thereby extending our knowledge of other potential functions
      of CXCR2. This study demonstrates the feasibility of redirecting the migration
      properties of T cells toward chemokines secreted by tumors.

PMID- 12427309
TI  - Transferrin-facilitated lipofection gene delivery strategy: characterization of
      the transfection complexes and intracellular trafficking.
AB  - We previously showed that mixing transferrin with a cationic liposome prior to
      the addition of DNA, greatly enhanced the lipofection efficiency. Here, we report
      characterization of the transfection complexes in formulations prepared with
      transferrin, lipofectin, and DNA (pCMVlacZ) in various formulations. DNA in all
      the formulations that contain lipofectin was resistant to DNase I treatment.
      Transfection experiments performed in Panc 1 cells showed that the standard
      formulation, which was prepared by adding DNA to a mixture of transferrin and
      lipofectin, yielded highest transfection efficiency. There was no apparent
      difference in zeta potential among these formulations, but the most efficient
      formulation contained complexes with a mean diameter of three to four times that
      of liposome and the complexes in other gene delivery formulations. Transmission
      electron microscopic examination of the standard transfection complexes
      formulated using gold-labeled transferrin showed extended circular DNA decorated
      with transferrin as compared to extensively condensed DNA found in lipofectin-DNA
      complexes and heterogeneous structures in other formulations. By confocal
      microscopy, DNA and transferrin were found to colocalize at the perinuclear space
      and in the nucleus, suggesting cotransportation intracellularly, including
      nuclear transport. We propose that transferrin enhances the transfection
      efficiency of the standard lipofection formulation by preventing DNA
      condensation, and facilitating endocytosis and nuclear targeting.

PMID- 12427308
TI  - Dose-dependent neuroprotective effect of ciliary neurotrophic factor delivered
      via tetracycline-regulated lentiviral vectors in the quinolinic acid rat model of
      Huntington's disease.
AB  - The ability to regulate gene expression constitutes a prerequisite for the
      development of gene therapy strategies aimed at the treatment of neurologic
      disorders. In the present work, we used tetracycline (Tet)-regulated lentiviral
      vectors to investigate the dose-dependent neuroprotective effect of human ciliary
      neurotrophic factor (CNTF) in the quinolinic acid (QA) model of Huntington's
      disease (HD). The Tet system was split in two lentiviruses, the first one
      containing the CNTF or green fluorescent protein (GFP) cDNAs under the control of
      the Tet-response element (TRE) and a second vector encoding the transactivator
      (tTA). Preliminary coinfection study demonstrated that 63.8% +/- 2.0% of infected
      cells contain at least two viral copies. Adult rats were then injected with CNTF-
      and GFP-expressing viral vectors followed 3 weeks later by an intrastriatal
      administration of QA. A significant reduction of apomorphine-induced rotations
      was observed in the CNTF-on group. In contrast, GFP-treated animals or CNTF-off
      rats displayed an ipsilateral turning behavior in response to apomorphine. A
      selective sparing of DARPP-32-, choline acetyltransferase (ChAT)-, and NADPH-d
      positive neurons was observed in the striatum of CNTF-on rats compared to GFP
      animals and CNTF-off group. Enzyme-linked immunosorbent assay (ELISA) performed
      on striatal samples of rats sacrificed at the same time point indicated that this
      neuroprotective effect was associated with the production of 15.5 +/- 4.7 ng CNTF
      per milligram of protein whereas the residual CNTF expression in the off state
      (0.54 +/- 0.02 ng/mg of protein) was not sufficient to protect against QA
      toxicity. These results establish the proof of principle of neurotrophic factor
      dosing for neurodegenerative diseases and demonstrate the feasibility of
      lentiviral-mediated tetracycline-regulated gene transfer in the brain.

PMID- 12427310
TI  - Implications of BSE infection screening data for the scale of the British BSE
      epidemic and current European infection levels.
AB  - The incidence of confirmed clinical cases of bovine spongiform encephalopathy
      (BSE) in Great Britain continues to decline, but the recent discovery of cases in
      previously unaffected countries (including Israel, Japan, Poland, Slovenia and
      Spain) has heightened concerns that BSE transmission was more intense and
      widespread than previously thought. We use back-calculation methods to undertake
      an integrated analysis of data on infection prevalence in apparently healthy
      cattle and the incidence of confirmed clinical disease. The results indicate
      substantial underascertainment of clinical cases over the course of the British
      epidemic, and consequently that two- to fourfold more animals were infected than
      previously estimated. Upper bounds on the predicted size of the new variant
      Creutzfeldt-Jakob Disease (vCJD) epidemic are unaffected, as the prediction
      methods employed fit to observed vCJD mortality data, and are not sensitive to
      estimates of the absolute magnitude of past human exposure to BSE-infected
      cattle, only to relative changes in exposure through time. We also estimate the
      per-head incidence of infection in cattle born between 1993 and 1997 in other
      European Union countries, using data on the testing of apparently healthy cattle
      slaughtered for consumption. Infection incidence for cattle born after mid-1996
      was highest in Greece, Italy and Belgium, with Spain and The Netherlands having
      intermediate levels, and estimates for Great Britain, Germany and France being
      comparably low.

PMID- 12427311
TI  - Size symmetry of competition alters biomass-density relationships.
AB  - As crowded populations of plants develop, the growth of some plants is
      accompanied by the death of others, a process called density-dependent mortality
      or 'self-thinning'. During the course of density-dependent mortality, the
      relationship between total population biomass (B) and surviving plant density (N)
      is allometric: B = aN(b). Essentially, increasing population biomass can be
      achieved only through decreasing population density. Variation in the allometric
      coefficient a among species has been recognized for many years and is important
      for management, assessment of productivity and carbon budgets, but the causes of
      this variation have not been elucidated. Individual-based models predict that
      size-dependent competition causes variation in the allometric coefficient. Using
      transgenic Arabidopsis with decreased plasticity, we provide experimental
      evidence that morphological plasticity of wild-type populations decreases the
      size asymmetry of competition for light and thereby decreases density-dependent
      mortality. This decrease in density-dependent mortality results in more biomass
      at a given density under size-symmetric compared with size-asymmetric
      competition.

PMID- 12427312
TI  - A plant pathogen reduces the enemy-free space of an insect herbivore on a shared
      host plant.
AB  - An important mechanism in stabilizing tightly linked host-parasitoid and prey
      predator interactions is the presence of refuges that protect organisms from
      their natural enemies. However, the presence and quality of refuges can be
      strongly affected by the environment. We show that infection of the host plant
      Silene latifolia by its specialist fungal plant pathogen Microbotryum violaceum
      dramatically alters the enemy-free space of a herbivore, the specialist noctuid
      seed predator Hadena bicruris, on their shared host plant. The pathogen arrests
      the development of seed capsules that serve as refuges for the herbivore's
      offspring against the specialist parasitoid Microplitis tristis, a major source
      of mortality of H. bicruris in the field. Pathogen infection resulted both in
      lower host-plant food quality, causing reduced adult emergence, and in twofold
      higher rates of parasitism of the herbivore. We interpret the strong oviposition
      preference of H. bicruris for uninfected plants in the field as an adaptive
      response, positioning offspring on refuge-rich, high-quality hosts. To our
      knowledge, this is the first demonstration that plant-inhabiting micro-organisms
      can affect higher trophic interactions through alteration of host refuge quality.
      We speculate that such interference can potentially destabilize tightly linked
      multitrophic interactions.

PMID- 12427313
TI  - Human female attractiveness: waveform analysis of body shape.
AB  - Two putative cues to female physical attractiveness are body mass index (BMI) and
      shape (particularly the waist-hip ratio or WHR). To determine the relative
      importance of these cues we asked 23 male and 23 female undergraduates to rate a
      set of 60 pictures of real women's bodies in front-view for attractiveness. In
      our set of images, the relative ranges of BMI and WHR favoured WHR. We based
      these ranges on a sample of 457 women. We did not limit the WHR range, although
      we kept the BMI range to 0.5 s.d. either side of the sample means. As a result,
      WHR averaged 1.65 s.d. either side of its sample mean. However, even with these
      advantages, WHR was less important than BMI as a predictor of attractiveness
      ratings for bodies. BMI is far more strongly correlated with ratings of
      attractiveness than WHR (BMI approximately 0.5, WHR approximately 0.2). To
      further explore the relative importance of BMI and WHR, we deliberately chose a
      subset of these images that demonstrated an inverse correlation of BMI and WHR
      (i.e. a group in which as images get heavier they also become more curvaceous).
      If WHR is the most important determinant of attractiveness, then the more
      curvaceous (but higher BMI) images should be judged most attractive. However, if
      BMI is a better predictor, then the opposite should be true. We found that the
      more curvaceous (but higher BMI) images were judged least attractive, thereby
      inverting the expected rating pattern. This strongly suggests that viewers'
      judgements were influenced more by BMI than WHR. Finally, it is possible that
      body shape is an important cue to attractiveness, but that simple ratios (such as
      WHR) are not adequately capturing it. Therefore, we treated the outline of the
      torso as a waveform and carried out a set of waveform analyses on it to allow us
      to quantify body shape and correlate it with attractiveness. The waveform
      analyses address the complexity of the whole torso shape, and reveal innate
      properties of the torso shape and not shape elements based on prior decisions
      about arbitrary physical features. Our analyses decompose the waveform into
      objective quantified elements whose importance in predicting attractiveness can
      then be tested. All of the components that were good descriptors of body shape
      were weakly correlated with attractiveness. Our results suggest that BMI is a
      stronger predictor of attractiveness than WHR.

PMID- 12427314
TI  - Positive genetic correlation between female preference and offspring fitness.
AB  - In many species, females display preferences for extreme male signal traits, but
      it has not been determined if such preferences evolve as a consequence of females
      gaining genetic benefits from exercising choice. If females prefer extreme male
      traits because they indicate male genetic quality that will enhance the fitness
      of offspring, a genetic correlation will evolve between female preference genes
      and genes that confer offspring fitness. We show that females of Drosophila
      serrata prefer extreme male cuticular hydrocarbon (CHC) blends, and that this
      preference affects offspring fitness. Female preference is positively genetically
      correlated with offspring fitness, indicating that females have gained genetic
      benefits from their choice of males. Despite male CHCs experiencing strong sexual
      selection, the genes underlying attractive CHCs also conferred lower offspring
      fitness, suggesting a balance between sexual selection and natural selection may
      have been reached in this population.

PMID- 12427315
TI  - Determinants of loss of mammal species during the Late Quaternary 'megafauna'
      extinctions: life history and ecology, but not body size.
AB  - Extinctions of megafauna species during the Late Quaternary dramatically reduced
      the global diversity of mammals. There is intense debate over the causes of these
      extinctions, especially regarding the extent to which humans were involved. Most
      previous analyses of this question have focused on chronologies of extinction and
      on the archaeological evidence for human-megafauna interaction. Here, I take an
      alternative approach: comparison of the biological traits of extinct species with
      those of survivors. I use this to demonstrate two general features of the
      selectivity of Late Quaternary mammal extinctions in Australia, Eurasia, the
      Americas and Madagascar. First, large size was not directly related to risk of
      extinction; rather, species with slow reproductive rates were at high risk
      regardless of their body size. This finding rejects the 'blitzkrieg' model of
      overkill, in which extinctions were completed during brief intervals of selective
      hunting of large-bodied prey. Second, species that survived despite having low
      reproductive rates typically occurred in closed habitats and many were arboreal
      or nocturnal. Such traits would have reduced their exposure to direct interaction
      with people. Therefore, although this analysis rejects blitzkrieg as a general
      scenario for the mammal megafauna extinctions, it is consistent with extinctions
      being due to interaction with human populations.

PMID- 12427316
TI  - Life-history correlates of maximum population growth rates in marine fishes.
AB  - Theory predicts that populations of animals with late maturity, low fecundity,
      large body size and low body growth rates will have low potential rates of
      population increase at low abundance. If this is true, then these traits may be
      used to predict the intrinsic rate of increase for species or populations, as
      well as extinction risks. We used life-history and population data for 63 stocks
      of commercially exploited fish species from the northeast Atlantic to test
      relationships between life-history parameters and the rate of population increase
      at low abundance. We used cross-taxonomic analyses among stocks and among
      species, and analyses that accounted for phylogenetic relationships. These
      analyses confirmed that large-bodied, slow-growing stocks and species had
      significantly lower rates of recruitment and adult production per spawning adult
      at low abundance. Furthermore, high ages at maturity were significantly
      correlated with low maximum recruit production. Contrary to expectation,
      fecundity was significantly negatively related to recruit production, due to its
      positive relationship with maximum body size. Our results support theoretical
      predictions, and suggest that a simply measured life-history parameter can
      provide a useful tool for predicting rates of recovery from low population
      abundance.

PMID- 12427317
TI  - Frequency-dependent numerical dynamics in mosquitofish.
AB  - Altering the genetic composition of a population can alter several aspects of its
      numerical dynamics. Whether natural populations routinely contain the genetic
      variation capable of affecting the stability of those dynamics is less clear.
      Here we report a study of experimental populations of mosquitofish (Gambusia
      holbrooki), designed to examine this issue. The experiment examined the numerical
      effects of varying the initial relative frequency of a rare male genotype. A
      higher relative frequency of the rare, melanic genotype produced higher mortality
      rates in melanic males, higher mortality rates in females, higher juvenile
      abundance, and fewer fluctuations in the numbers of females across time. This
      work demonstrates that a natural population can harbour genetic variants in a
      single gender that are capable of inducing qualitative differences in the
      numerical dynamics of the opposite gender, through the effects of negative
      frequency-dependent selection.

PMID- 12427318
TI  - Sex differences in yolk hormones depend on maternal social status in Leghorn
      chickens (Gallus gallus domesticus).
AB  - Maternal hormones are known to be present in avian eggs and can have beneficial
      effects on chick development. Recently, differences in avian yolk steroid
      concentrations between the sexes have been demonstrated, and in this context
      steroids have been proposed to be part of the avian sex-determining mechanism. In
      our study, we show that it is very unlikely that androgen concentrations alone
      are the decisive part of the sex-determining mechanism. We found that sex
      specific differences in the yolk hormones strongly depend on the social rank of
      the mother. First, dominant females, but not subdominant females, allocated
      significantly more testosterone to male eggs than to female eggs. Second,
      subordinate females increased the testosterone concentrations of female eggs.
      This pattern of yolk hormone deposition can be functionally explained. In
      polygynous species such as the chicken, reproductive success is more variable in
      males than in females. Parental investment in sons or daughters is therefore
      expected to occur in direct relation to parental rearing capacities. We found
      that the social status of a hen was indeed negatively correlated with her
      maternal capacities (for example, body mass, egg mass). Differential androgen
      deposition might thus provide a mechanism for adaptive maternal investment
      depending on both the sex of the egg and the social status of the mother.

PMID- 12427319
TI  - The distribution of Wolbachia in fig wasps: correlations with host phylogeny,
      ecology and population structure.
AB  - We surveyed for the presence and identity of Wolbachia in 44 species of chalcid
      wasps associated with 18 species of Panamanian figs. We used existing detailed
      knowledge of the population structures of the host wasps, as well as the
      ecological and evolutionary relationships among them, to explore the relevance of
      each of these factors to Wolbachia prevalence and mode of transmission. Fifty
      nine per cent of these wasp species have Wolbachia infections, the highest
      proportion reported for any group of insects. Further, neither the presence nor
      the frequency of Wolbachia within hosts was correlated with the population
      structure of pollinator hosts. Phylogenetic analyses of wsp sequence data from 70
      individuals representing 22 wasp species show that neither the close phylogenetic
      relationship nor close ecological association among host species is consistently
      linked to close phylogenetic affinities of the Wolbachia associated with them.
      Moreover, no genetic variation was detected within any Wolbachia strain from a
      given host species. Thus, the spread of Wolbachia within host species exceeds the
      rate of horizontal transmission among species and both exceed the rate of
      mutation of the wsp gene in Wolbachia. The presence and, in some cases, high
      frequency of Wolbachia infections within highly inbred species indicate that the
      Wolbachia either directly increase host fitness or are frequently horizontally
      transferred within these wasp species. However, the paucity of cospeciation of
      Wolbachia and their wasp hosts indicates that Wolbachia do not persist within a
      given host lineage for long time-periods relative to speciation times.

PMID- 12427320
TI  - Mechanisms linking diversity, productivity and invasibility in experimental
      bacterial communities.
AB  - Decreasing species diversity is thought to both reduce community productivity and
      increase invasibility to other species. However, it remains unclear whether
      identical mechanisms drive both diversity-productivity and diversity-invasibility
      relationships. We found a positive diversity-productivity relationship and
      negative diversity-invasibility and productivity-invasibility relationships using
      microcosm communities constructed from spatial niche specialist genotypes of the
      bacterium Pseudomonas fluorescens. The primary mechanism driving these
      relationships was a dominance (or selection) effect: more diverse communities
      were more likely to contain the most productive and least invasible type.
      Statistical elimination of the dominance effect greatly weakened the diversity
      invasibility relationship and eliminated the diversity-productivity relationship,
      but also revealed the operation of additional mechanisms (niche complementarity,
      positive and negative interactions) for particular combinations of niche
      specialists. However, these mechanisms differed for invasibility and productivity
      responses, resulting in the invasibility-productivity relationship changing from
      strongly negative to weakly positive. In the absence of the dominance effect,
      which may be an experimental artefact, decreasing diversity can have unexpected
      or no effects on ecosystem properties.

PMID- 12427321
TI  - Roller coasters, g forces, and brain trauma: on the wrong track?
AB  - There has been enormous attention in the general press on the possibility that
      high G force roller coasters are inducing brain injury in riders. Armed with a
      handful of anecdotal case reports of brain injuries, the U.S. Congress has
      recently proposed legislation to regulate the level of G forces of roller
      coasters. However, high G forces are well tolerated during many activities and,
      therefore, are a poor measure for the risk of brain injury. Rather, accelerations
      of the head that can be caused by G forces are the key to producing injury. To
      determine the extent of head accelerations during roller coaster rides, we
      acquired G force data from three popular high G roller coasters. We used the
      highest recorded G forces in a simple mathematical model of head rotational
      acceleration, with the head rigidly pivoting from the base of the skull at a
      radius representing typical men and women. With this model, we calculated peak
      head rotational accelerations in three directions. Even for a conservative worst
      case scenario, we found that the highest estimated peak head accelerations
      induced by roller coasters were far below conventional levels that are predicted
      for head injuries. Accordingly, our findings do not support the contention that
      current roller coaster rides produce high enough forces to mechanically deform
      and injure the brain.

PMID- 12427322
TI  - Waiver of consent in studies of acute brain injury.
AB  - A multicenter trial of hypothermia in patients with acute brain injury, designed
      to accrue 140 patients per year and randomizing in less than 6 h from injury,
      enrolled 392 patients. The design was to achieve 33 degrees C within 8 h after
      injury. For the first 9 months of the trial, the only consent mechanism permitted
      by federal regulations was prospective, informed consent. In the subsequent 33
      months, after a change in federal regulations, waiver of consent could be used
      when family could not be located. Waiver of consent was used in 62% of patients
      enrolled. In the first 9 months of the trial, accrual was 65 patients. In the
      subsequent 3 years, an average yearly accrual was 127 patients. In the first 9
      months, time from injury to randomization was 4.5 +/- 1.2 h; time to achievement
      of target temperature was 11.7 +/- 2.6 h. In years when waiver of consent was
      permitted, randomization time was 4.1 +/- 1.1 h, and time to target temperature
      was 7.9 +/- 2.7 h. For all years of the study, waiver of consent was used for 53%
      of minorities, 47% of unskilled workers, 33% of nonminorities, and 29% of skilled
      or professional workers. Minorities were underrepresented by 30% in the first 9
      months of the study. We conclude that it is impracticable and unjust to perform
      studies of acute brain injury without use of waiver of consent when the treatment
      window is less than 6 h.

PMID- 12427323
TI  - Continuous cerebral autoregulation monitoring by cross-correlation analysis.
AB  - In order to validate cross-correlation analysis between spontaneous slow
      oscillations of arterial blood pressure (aBP) and intracranial pressure (ICP) or
      flow velocity as a means to assess the status of cerebral autoregulation
      continuously, we compared its results with different autoregulation bedside
      tests. The second aim was to check the method's stability over longer time
      periods. aBP, ICP, and flow velocity in the middle cerebral artery (FV(MCA)) was
      measured continuously in 13 critically ill comatose patients. Cross-correlation
      analysis was performed online and offline between aBP and ICP (CC [aBP --> ICP])
      and aBP/FV(MCA) (CC [aBP --> FV(MCA)]). Three different autoregulation bedside
      tests (cuff deflation, transient hyperemic response, orthostatic hypotension)
      were performed immediately before a 29-min cross-correlation test period. In
      addition, continuous cross-correlation autoregulation monitoring was performed
      over multiple hours (in order to analyze for stability and to assess the
      influence of other factors). Cluster analysis revealed two main clusters. Cluster
      1 (indicative for disturbed autoregulation) showed a centroid at t = -0.21 +/-
      3.32 sec, r = 0.43 +/- 0.18 for CC [aBP --> ICP], and t = 0 +/- 3.14 sec, r =
      0.44 +/- 0.18 for CC [aBP --> FV(MCA)]. Cluster 2 (indicative for normal
      autoregulation) revealed a centroid at t = 4.94 +/- 3.74 sec, r =- 0.4 +/- 0.16
      for CC [aBP --> ICP], and t = 3.38 +/- 4.44 sec, r = -0.38 +/- 0.18 for CC [aBP -
      > FV(MCA)]. Comparison between the cross-correlation test results and the bedside
      tests showed a sensitivity of 44-73% for CC [aBP --> FV(MCA)], whereas CC [aBP -
      > ICP] was more specific (60-80%). Long-term monitoring revealed stable cross
      correlation tests in about 45% of the measurement time. It is concluded that
      cross-correlation between aBP, ICP, and FV(MCA) is a valid means to monitor the
      autoregulation status continuously, although further improvement of sensitivity
      and specificity is needed to make it reliable for clinical decision making.

PMID- 12427324
TI  - Effect of traumatic brain injury and nitrone radical scavengers on relative
      changes in regional cerebral blood flow and glucose uptake in rats.
AB  - Changes in regional cerebral blood flow (rCBF) and glucose metabolism are
      commonly associated with traumatic brain injury (TBI). Reactive oxygen species
      (ROS) have been implicated as key contributors to the secondary injury process
      after TBI. Here, pretreatment with the nitrone radical scavengers (alpha-phenyl-N
      tert-butyl nitrone (PBN) or its sulfonated analogue sodium 2-sulfophenyl-N-tert
      butyl nitrone (S-PBN) were used as tools to study the effects of ROS on rCBF and
      glucose metabolism after moderate (2.4-2.6 atm) lateral fluid percussion injury
      (FPI) in rats. S-PBN has a half-life in plasma of 9 min and does not penetrate
      the blood-brain barrier (BBB). In contrast, PBN has a half-life of 3 h and
      readily penetrates the BBB. Regional cerebral blood flow (rCBF) and glucose
      metabolism was estimated by using (99m)Tc-HMPAO and [(18)F]Fluoro-2-deoxyglucose
      (FDG) autoradiography, respectively, at 42 min (n = 37) and 12 h (n = 34) after
      the injury. Regions of interest were the parietal cortex and hippocampus
      bilaterally. As expected, FPI produced an early (42-min) hypoperfusion in
      ipsilateral cortex and an increase in glucose metabolism in both cortex and
      hippocampus, giving way to a state of hypoperfusion and decreased glucose
      metabolism at 12 h postinjury. On the contralateral side, a hypoperfusion in the
      cortex and hippocampus was seen at 12 h only, but no significant changes in
      glucose metabolism. Both S-PBN and PBN attenuated the trauma-induced changes in
      rCBF and glucose metabolism. Thus, the early improvement in rCBF and glucose
      metabolism correlates with and may partly mediate the improved functional and
      morphological outcome after TBI in nitrone-treated rats.

PMID- 12427325
TI  - Multiple caspases are activated after traumatic brain injury: evidence for
      involvement in functional outcome.
AB  - Caspase-3 is a cysteine protease that is strongly implicated in neuronal
      apoptosis. Activation of caspase-3 may be induced by at least two major initiator
      pathways: a caspase-8-mediated pathway activated through cell surface death
      receptors (extrinsic pathway), and a caspase-9-mediated pathway activated by
      signals from the mitochondria that lead to formation of an apoptosomal complex
      (intrinsic pathway). In the present studies, we compare the activation of
      caspases-3, -8, and -9 after lateral fluid-percussion traumatic brain injury
      (TBI) in rats. Immunoblot analysis identified cleaved forms of caspases-3 and -9,
      but not caspase-8, at 1, 12, and 48 h after injury. Immunocytochemistry specific
      for cleaved caspases-3 and -9 revealed their expression primarily in neurons.
      These caspases were also frequently localized in TUNEL-positive cells, some of
      which demonstrated morphological features of apoptosis. However, caspases-3 and 
      9 were also found in neurons that were not TUNEL-positive, and other TUNEL
      positive cells did not show activated caspases. In contrast to caspases-3 or -9,
      caspase-8 expression was only minimally changed by injury. An increase in
      expression of this caspase was undetectable by immunoblotting methods, and
      appeared as positive immunostaining restricted to a few cells within the injured
      cortex. Treatment with the pan-caspase inhibitor z-VAD-fmk at 15 min after TBI
      improved performance on motor and spatial learning tests. These data suggest that
      several caspases may be involved in the pathophysiology of TBI and that pan
      caspase inhibition strategies may improve neurological outcomes.

PMID- 12427326
TI  - Axonal injury in children after motor vehicle crashes: extent, distribution, and
      size of axonal swellings using beta-APP immunohistochemistry.
AB  - The brains of 32 children (3 months to 16 years) who died as a result of motor
      vehicle collisions were examined for axonal injury using beta-APP
      immunohistochemistry. The extent and distribution of axonal injury was assessed
      and quantified throughout the forebrain, brainstem and cerebellum. The mean
      diameter of immunoreactive axons in the corpus callosum was measured for this
      pediatric group and, for comparison, a small adult sample. beta-APP
      immunoreactivity was seen in 14 pediatric cases (survival 35 mins to 87 h), most
      frequently in the parasagittal white matter (12/14), the corpus callosum (11/14),
      the brainstem (10/14) and cerebellum (9/14). In 2 cases, axon swelling was
      visualized in the internal capsule after only 35-45-min survival, earlier than
      has previously been reported. No immunoreactivity was seen in the remaining 18
      cases who died within 1 h. The extent and distribution of axonal injury
      throughout the brain showed a rapid early increase with increasing survival time
      and then a slower progression. The diameter of individual callosal axons
      increased with increasing survival times, rapidly over the first 24 h and then
      more slowly. There was no statistical difference (p < 0.05) for callosal axon
      diameters at different survival times between the children and the adults sampled
      here. The extent and distribution of axonal injury throughout the brain appears
      to be similar in children to that previously reported in adults. The spatial and
      temporal spread of axonal damage suggests there may be therapeutic potential for
      the process to be arrested or slowed in its early stages.

PMID- 12427327
TI  - Simple morphometry of axonal swellings cannot be used in isolation for dating
      lesions after traumatic brain injury.
AB  - Disruption of fast axonal transport as a result of traumatic brain injury is
      characterized by the accumulation of beta-amyloid precursor protein (APP) in
      axonal swellings. A recent report has suggested a correlation between the size of
      axonal swellings and survival time up to about 85 h after blunt head injury. The
      authors of the report concluded that this correlation, in conjunction with other
      evidence, might be useful in forensic science for timing injuries. To test this
      hypothesis we have used image analysis software to measure a number of different
      morphological parameters of axonal swellings. Paraffin sections from 63 cases of
      fatal head injury were stained with an antibody raised against the N-terminus of
      APP and counterstained with haematoxylin. Three different measurements were made
      of the APP-immunoreactive axonal swellings from the corpus callosum: (i) minimum
      and (ii) maximum Feret diameters, and (iii) area. Linear regression revealed a
      significant correlation between survival time and the minimum Feret diameter (p <
      0.0001) and the area (p < 0.001) of axonal swellings. Our findings are in
      agreement with the previous study in that there is a significant correlation
      between axonal swelling size and survival time. However, we would suggest that
      the large variability in swelling size within individual cases and the
      heterogeneity of the original trauma seriously compromise the utility of such
      information in the timing of lesions.

PMID- 12427328
TI  - Age-dependent NOC/oFQ contribution to impaired hypotensive cerebral hemodynamics
      after brain injury.
AB  - Previous studies have observed that the newly described opioid,
      nociceptin/orphanin FQ (NOC/oFQ), contributed to age dependent reductions in
      cerebral blood flow (CBF) and pial artery diameter after fluid percussion brain
      injury (FPI). Unrelated studies have noted a similar age dependency in impaired
      hypotensive cerebral autoregulation after FPI. This study was designed to compare
      the role of NOC/oFQ in impaired hypotensive cerebral autoregulation after FPI in
      newborn and juvenile pigs equipped with a closed cranial window. Ten minutes of
      hemorrhagic hypotension (10-15 mL blood/kg) decreased mean arterial blood
      pressure uniformly in both groups ( approximately 44%). In the newborn,
      hypotensive pial artery dilation was blunted within 1 h of FPI but partially
      protected by pretreatment with the NOC/oFQ antagonist, [F/G] NOC/oFQ (1-13) NH(2)
      (1 mg/kg, i.v.) (34 +/- 1 vs. 8 +/- 1 vs. 20 +/- 2% for sham control, FPI, and
      FPI-[F/G] NOC/oFQ (1-13) NH(2), respectively). CBF was reduced during
      normotension by FPI, further reduced by hypotension, but both were partially
      protected by this antagonist in the newborn (63 +/- 4, 34 +/- 2, and 20 +/- 2 vs.
      65 +/- 4, 47 +/- 2, and 29 +/- 2 mL/min.100 g for normotension, normotension-FPI
      and hypotension-FPI in the absence and presence of [F/G] NOC/oFQ (1-13) NH(2),
      respectively). In contrast, blunted hypotensive pial artery dilation was
      protected significantly less by this NOC/oFQ antagonist in the juvenile (32 +/- 2
      vs. 7 +/- 2 vs. 13 +/- 2% for sham control, FPI and FPI-NOC/oFQ antagonist,
      respectively). Similarly, [F/G] NOC/oFQ (1-13) NH(2) had less protective effect
      on normotensive and hypotensive CBF values post FPI in the juvenile. These data
      indicate that NOC/oFQ contributes to impaired hypotensive cerebral hemodynamics
      following brain injury in an age-dependent manner.

PMID- 12427329
TI  - Peripheral nerve grafts and aFGF restore partial hindlimb function in adult
      paraplegic rats.
AB  - The purpose of this study was to evaluate the degree of functional recovery in
      adult rats with completely transected spinal cord following experimental
      treatment regimens that include implantation of peripheral nerve segments and
      local application of acidic fibroblast growth factor (aFGF). Rats were randomly
      divided to five groups: (1) spinal cord transection, (2) spinal cord transection
      and aFGF treatment, (3) spinal cord transection and peripheral nerve grafts, (4)
      spinal cord transection, aFGF treatment, and peripheral nerve grafts, and (5)
      sham control (laminectomy only). The locomotor behavior of all rats was analyzed
      by the Basso, Beattie and Bresnahan (BBB) open field locomotor test over the six
      months survival time. Immunohistochemisty for neurofilament protein, and
      somatosensory (SSEP) and motor evoked potentials (MEP) were used to evaluate axon
      growth across the damage site following the different treatments. The results
      show four principal findings: (1) Only the combination of peripheral nerve grafts
      and aFGF treatment improved hindlimb locomotor function after spinal cord
      transection. (2) The SSEP and MEP demonstrated electrophysiological evidence of
      both sensory and motor information crossing the damaged site, but only in the
      combined nerve grafts and aFGF treatment rats. (3) Immunostaining demonstrated
      neurofilament positive axons extending through the graft area and into distal end
      of spinal cord, but only in the group with combined nerve grafts and aFGF
      treatment. (4) Retransection of group 4 rats eliminated the behavioral recovery,
      MEP, and SSEP responses, indicating that the improvement of hindlimb locomotor
      activity came from supraspinal control. These results demonstrate the ability of
      the repair strategy combining peripheral nerve grafts and aFGF treatment to
      facilitate the regeneration of spinal ascending and descending tracts and also
      recovery of motor behavior following spinal cord injury.

PMID- 12427330
TI  - Recruitment of spinal motor pools during voluntary movements versus stepping
      after human spinal cord injury.
AB  - We investigated the activation of lower limb motor pools by supraspinal and
      spinal networks after human spinal cord injury (SCI). We compared
      electromyographic (EMG) activity from six muscles during voluntarily attempted
      non-weight-bearing single-joint movements, multijoint movements approximating
      stepping in a supine position, and weight-bearing stepping on a treadmill with
      body weight support (BWST) in seven clinically incomplete and three clinically
      complete SCI subjects. Seven SCI subjects had previously completed Laufband
      therapy (a specific step training using variable levels of body weight support
      and manual assistance). Significant coactivation of agonists and antagonists and
      multijoint flexion or extension movements of the entire limb occurred during
      attempts at isolated knee or ankle single-joint movements in clinically
      incomplete SCI subjects. Further, some muscles that were not recruited during
      voluntary attempts at single-joint movements were activated during voluntary step
      like multijoint movements (5/16 comparisons). This suggests that the residual
      voluntary motor control in incomplete SCI subjects evokes more generalized motor
      patterns (limb flexion or extension) rather than selective activation of
      individual muscles. Clinically incomplete and clinically complete SCI subjects
      could achieve greater activation of motor pools and more reciprocal patterns of
      activity between agonists and antagonists during weight bearing stepping than
      during non-weight-bearing voluntary movements. The EMG mean amplitudes were
      higher during stepping than during voluntary movements in 50/60 muscles studied
      (p < 0.05). These results suggest that stepping with knee and hip extension and
      flexion and alternating lower limb loading and unloading provides proprioceptive
      inputs to the spinal cord that increases motor recruitment and improves
      reciprocity between agonists and antagonists compared to voluntary efforts.

PMID- 12427331
TI  - Velocity-dependent ankle torque in rats after contusion injury of the midthoracic
      spinal cord: time course.
AB  - Progressive neurophysiological changes in the excitability of the pathways that
      subserved ankle extensor stretch reflexes were observed following midthoracic
      contusion. The purpose of the present study was to determine the nature and time
      course of velocity-dependent changes in the excitability of the ankle stretch
      reflex following T(8) contusion injury. These studies were conducted in adult
      Sprague-Dawley rats using a 10-g 2.5-cm weight drop onto the exposed thoracic
      spinal cord (using an NYU injury device and a MASCIS protocol). Velocity
      dependent ankle torques and triceps surae EMGs were measured in awake animals
      over a broad range of rotation velocities (49-612 deg/sec) using instrumentation
      and protocol previously reported. EMGs and ankle torques were measured before and
      at weekly intervals following injury. Statistical tests of the data included
      within group repeated measures ANOVA and between group one-way ANOVA comparisons
      with time-matched control animals. An alternating pattern of significant increase
      followed by significant decrease in velocity-dependent ankle torque was observed
      during the first postinjury month. An increase of 33% in the peak torque and 24%
      in peak EMG magnitude at 612 deg/sec was observed in the first week. EMG burst
      amplitudes, that were timed-locked to the dynamic phase of the rotation, were
      observed to increase and decrease in a manner, which indicated that the changes
      in torque included stretch-evoked active contractions of the ankle extensors.
      During the second and third postinjury months, consistent 24-40% increases in the
      peak torques and 17-107% increases in the EMG magnitudes at the highest velocity
      were observed. No significant increases in torques were observed in the slowest
      rotation velocity in these periods.

PMID- 12427332
TI  - A statistical method for analyzing rating scale data: the BBB locomotor score.
AB  - The Basso, Beattie and Bresnahan (BBB) locomotor rating scale is widely used to
      test behavioral consequences of spinal cord injury (SCI) to the rat. Sensitivity
      of this rating scale can differentiate hind limb locomotor skills over a wide
      range of injury severities. While the 21-point BBB scale is ordinal in nature,
      the present discussion recommends the use of parametric statistics to evaluate
      the locomotor results. Specifically, it defines appropriate statistical analysis
      of these data in order to facilitate interpretation of results between
      laboratories and to provide a common methodology for the correct interpretation
      of SCI behavioral data.

PMID- 12427333
TI  - Temporal profile of changes in brain tissue extracellular space and extracellular
      ion (Na(+), K(+)) concentrations after cerebral ischemia and the effects of mild
      cerebral hypothermia.
AB  - Cerebral ischemic cellular swelling occurs primarily in astrocytes. This water
      influx into the intracellular space is believed to result from osmotic water
      movement after disruption of membrane ionic homeostasis. However, cellular
      swelling occurs earlier than expected after ischemia and new ionic and water
      channels have been discovered. This study examined the temporal profile of the
      water and ionic movement across the cell membrane after global ischemia by
      measuring the changes in extracellular space (ECS), extracellular K(+) and Na(+)
      ion concentrations ([K(+)](e) and [Na(+)](e)) using a high resolution tissue
      impedance probe and ion selective micropipettes in the rat cortex. The effect of
      mild cerebral hypothermia (31.5 +/- 2.6 degrees C brain temperature) on these
      parameters was also examined. The ECS started to decrease at 34 +/- 8 sec after
      global ischemia and reached half the maximum change at 61 +/- 17 sec. [K(+)](e)
      started to increase initially at 33 +/- 11 sec (phase 1) and then increased
      rapidly at 62 +/- 25 sec (phase 2), and [Na(+)](e) started to decrease at 88 +/-
      27 sec after ischemia. With mild hypothermia, the ECS started to decrease at 75
      +/- 35 sec after ischemia and reached half the maximum change at 123 +/- 44 sec,
      [K(+)](e) started to increase initially at 80 +/- 24 sec (phase 1) and then
      increased rapidly at 120 +/- 32 sec (phase 2), and [Na(+)](e) started to decrease
      at 172 +/- 70 sec. The present study shows that ischemic cellular swelling
      (decreased ECS) occurs concomitantly with the phase 1 increase of [K(+)](e) but
      precedes the disruption of ionic membrane homeostasis (phase 2). Mild hypothermia
      prolongs the onset of these phenomena but does not affect the magnitude of the
      changes in ECS and ion concentrations.

PMID- 12427334
TI  - Failure of a low virulence Streptococcus gallolyticus serotype 1 strain to
      immunize pigeons against streptococcosis.
AB  - Ten pigeons were inoculated intravenously with the low virulence Streptococcus
      gallolyticus strain PDH 827, which belongs to serotype 1, supernatant phenotype
      A(-)T2. The birds did not develop clinical disease but shed S. gallolyticus in
      their faeces, and antibodies against the bacterium were detected in post
      inoculation plasma samples of all birds. Seven weeks later, these pigeons, as
      well as 14 control pigeons, were challenged intravenously with the highly
      virulent S. gallolyticus strain STR 357, which also belongs to serotype 1 but to
      the supernatant phenotype A(+)T1. Post-inoculation morbidity in the immunized
      group amounted to 90%, demonstrating that no protective immunity had been built
      up after the first infection. These findings indicate that serotype-specific
      antigens are not, or at least not solely, involved in induction of protection
      against S. gallolyticus septicaemia in pigeons.

PMID- 12427335
TI  - Idiopathic hepatic fibrosis with cholestasis in broiler chickens:
      immunohistochemistry of hepatic stellate cells.
AB  - Immunohistochemical examinations of hepatic stellate cells (HSCs) were performed
      on six enlarged livers from broiler chickens with malformation of the
      extrahepatic biliary tract (group 1) and on eight broiler livers affected with
      naturally occurring cholangiohepatitis without biliary malformation (group 2).
      The livers from both groups were grossly enlarged, firm and tan-coloured, and
      histologically revealed severe diffuse fibrosis with proliferation of bile
      ductules. HSCs positive for muscle actin and desmin actively proliferated in the
      perisinusoidal space and around newly formed bile ductules. There was no
      difference in the immunohistochemical reactivities and location of HSCs between
      the two groups. The findings suggest that the diffuse hepatic fibrosis found in
      group 2 as well as group 1 results from reactive proliferation of HSCs.

PMID- 12427336
TI  - Amelia/ectromelia in association with scoliosis in three commercial layer hens
      (Gallus gallus forma domestica).
AB  - Three wingless "healthy" pullet hens were serendipitously discovered at a grow
      out facility for an egg-production ranch. Two of the birds were amelic and one
      was ectromelic. The defect in these chickens differs from the previously reported
      wingless mutations in that all three affected birds also had scoliosis. The birds
      also differed from previously reported scolitic mutant chickens in that they were
      wingless. Although the combination of amelia and scoliosis has been reported in
      humans, this is the first report of the combination in an animal species.

PMID- 12427337
TI  - Occurrence of subgroup J avian leukosis virus in Taiwan.
AB  - There are three grandparent farms for three different chicken breeds in Taiwan.
      One of these farms, populated by breast meat yield chickens (yield type),
      suffered from a severe subgroup J avian leukosis virus (ALV-J) infection in mid
      1997. The affected flocks at that farm had a weekly mortality of more than 1% and
      a 15% drop in egg production. The broilers from that breed had a 10% condemnation
      rate during the first week of age, and 5% of the remaining broilers were stunted
      afterwards. Some chickens had myeloid leukosis lesions at 6 weeks old. Their
      survivability was about 85%. However, chickens at the other two grandparent
      farms, populated with non-yield chickens (regular type), were also infected by
      ALV-J and showed myeloid leukosis. However, chickens at these farms produced
      progeny whose survivability reached more than 95%. ALV-J caused greater economic
      loss in yield type chickens than in regular type chickens in Taiwan.

PMID- 12427338
TI  - Helminth and arthropod parasites of the brown pelican, Pelecanus occidentalis, in
      Puerto Rico, with a compilation of all metazoan parasites reported from this host
      in the Western Hemisphere.
AB  - Seven species of helminths and six species of arthropods are reported from 23 of
      40 brown pelicans, Pelecanus occidentalis, collected from various localities in
      Puerto Rico. Helminth parasites include three nematodes (Contracaecum
      multipapillatum, Contracaecum mexicanum, and Eustrongylides sp.), three
      trematodes (Galactosomum darbyi, Mesostephanus appendiculatoides, and Ribeiroia
      ondatrae), and one cestode (Tetrabothrium sulae). Arthropod parasites include
      Colpocephalum occidentalis, Neottialges apunctatus, Ornithodoros capensis,
      Phalacrodectus pelecani, Phalacrodectus punctatissimus, and Phalacrodectus sp.
      The presence of R. ondatrae in the brown pelican is a new species host record,
      and P. pelecani, P. punctatissimus and N. apunctatus are new subspecies host
      records. C. multipapillatum, C. mexicanum, G. darbyi and M. appendiculatoides are
      new locality records for Puerto Rico, and N. apunctatus, P. pelecani, P.
      punctatissimus and T. sulae are new locality records for the Caribbean. Necrosis
      produced by C. multipapillatum, C. mexicanum, and R. ondatrae may have
      contributed to the emaciation and death of the brown pelicans examined in the
      present study.

PMID- 12427340
TI  - Characterization of the antigenic, immunogenic, and pathogenic variation of
      infectious bursal disease virus due to propagation in different host systems
      (bursa, embryo, and cell culture). I. Antigenicity and immunogenicity.
AB  - In vitro and in ovo virus neutralization assays were conducted to assess the role
      of different host systems in infectious bursal disease virus (IBDV) antigenic and
      immunogenic variation. Four different strains, two variant (1084 E and GLS) and
      two standard (Edgar and STC), were propagated separately in the bursa of
      Fabricius and embryos, and were compared with cell culture-adapted preparations
      of the homologous strains. Chicken polyclonal antisera were prepared against each
      IBDV and neutralizing antibody titres were determined. Normalized IBDV antibody
      concentrations were used in neutralization assays against homologous and
      heterologous IBDVs in 10-day-old specific pathogen free embryos. Both antigenic
      and immunogenic changes occurred in IBDVs evaluated, as evidenced by differences
      in the ability of normalized antibody to neutralize IBDV propagated in different
      host systems. Antibody induced by bursal-derived IBDV neutralized all isolates
      equally well, whereas antibody induced by cell culture-derived virus neutralized
      bursal-derived IBDV much less effectively.

PMID- 12427339
TI  - Immunosuppressive effects of Marek's disease virus (MDV) and herpesvirus of
      turkeys (HVT) in broiler chickens and the protective effect of HVT vaccination
      against MDV challenge.
AB  - Much of the impact of Marek's disease in broiler chickens is considered to be due
      to immunosuppression induced by Marek's disease virus (MDV). The present study
      evaluates the effects of an Australian isolate of pathogenic MDV (strain MPF 57)
      and a non-pathogenic vaccinal strain of herpesvirus of turkeys (HVT) (strain FC
      126) on the immune system of commercial broiler chickens for 35 days following
      challenge at days 0 or 3 of age. It also investigates the extent of protection
      provided by HVT vaccine against MDV-induced immunosuppression. Immune system
      variables, including relative lymphoid organ weight, blood lymphocyte phenotype
      (CD45+/CD3+, putatively T, and CD45+/LC+, putatively B) and antibody production
      following vaccination against infectious bronchitis (IB) at hatch, were used to
      assess the immune status of chickens. Immunosuppression was also assessed by
      susceptibility to secondary challenge with pathogenic Escherichia coli on day 29
      post-MDV challenge. MDV infection reduced the weight of the thymus and bursa of
      Fabricius, the numbers of circulating T lymphocytes and B lymphocytes, and IB
      antibody titre. The timing of these effects varied. MDV infection greatly
      increased susceptibility to E. coli infection. HVT alone caused mild depletion of
      T and B lymphocytes but no effect on immune organ weight or IB titre. Vaccination
      with HVT provided good protection against most of the immunosuppressive effects
      of MDV but not against MDV-induced growth impairment and reduced responsiveness
      to IB vaccination, suggesting that recent Australian strains of MDV may be
      evolving in virulence to overcome the protective effects of HVT.

PMID- 12427341
TI  - Characterization of the antigenic, immunogenic, and pathogenic variation of
      infectious bursal disease virus due to propagation in different host systems
      (bursa, embryo, and cell culture). II. Antigenicity at the epitope level.
AB  - Antigenic variation of infectious bursal disease virus (IBDV) due to propagation
      in different host systems (bursa of Fabricius, embryos, or cell cultures) was
      determined by enzyme-linked immunosorbent assay (indirect and antigen capture)
      and western blot analysis. To conduct this study, we used 27 non-neutralizing
      anti-VP(2) monoclonal antibodies, a reference panel of nine neutralizing
      monoclonal antibodies, and 13 neutralizing anti-IBDV chicken polyclonal
      antibodies. Changes occurred in neutralizing, cross-reactive, conformation
      dependent epitopes on the VP(2) protein of IBDV. Interestingly, non-neutralizing,
      cross-reactive, conformation-dependent and confirmation-independent epitopes also
      changed on VP(2). These epitope changes were directly associated with the method
      used to propagate IBDV. These results demonstrate that different host systems may
      play an important role in the antigenicity of IBDV.

PMID- 12427342
TI  - Characterization of the antigenic, immunogenic, and pathogenic variation of
      infectious bursal disease virus due to propagation in different host systems
      (bursa, embryo, and cell culture). III. Pathogenicity.
AB  - Differences in the relative pathogenicity of variant (1084 E and GLS) and
      standard (Edgar and STC) infectious bursal disease virus (IBDV) strains were
      observed after propagation in the bursa of Fabricius, embryos, or cell cultures.
      Bursa-derived IBDV induced the most severe lesions in the bursa of Fabricius when
      compared with strains propagated in embryos or cell cultures. Embryo-derived IBDV
      induced moderate gross bursal lesions, whereas cell culture-derived IBDV did not
      damage the bursa grossly. A high frequency of virus re-isolations was obtained
      from bursal, spleen, and thymic samples collected from birds inoculated with
      bursa-derived or embryo-derived IBDV. Virus re-isolation occurred much less
      frequently from birds inoculated with cell culture-adapted IBDV. Serological
      evaluations demonstrated that bursa-derived IBDV strains induced a higher
      neutralizing antibody response than did embryo-derived or cell culture-derived
      strains. These results document that the relative pathogenicity and
      immunogenicity of IBDV is reduced following propagation in embryos or cell
      cultures.

PMID- 12427343
TI  - Detection and differentiation of pathogenicity of avian paramyxovirus serotype 1
      from field cases using one-step reverse transcriptase-polymerase chain reaction.
AB  - Amplification of avian paramyxovirus serotype 1 (APMV-1)-specific nucleic acid
      fragments, followed by restriction endonuclease analysis (REA) using BglI, was
      carried out to type strains according to their virulence. Primer sequences were
      used to amplify a 202 base pair fragment, encompassing the fusion protein
      cleavage site, in a one-step reverse transcriptase-polymerase chain reaction (RT
      PCR) test for detection of a range of field cases and reference strains of APMV
      1. Subsequent REA of the amplified fragments enabled differentiation of low
      virulent lentogenic field and vaccine strains from more virulent mesogenic and
      velogenic field strains of APMV-1, including pigeon PMV-1. In the present paper,
      we report the development and application of a one-step RT-PCR test coupled with
      REA as a fast, specific method for both the detection and typing of APMV-1 from
      field samples.

PMID- 12427344
TI  - Salmonella enterica serovar Pullorum requires the Salmonella pathogenicity island
      2 type III secretion system for virulence and carriage in the chicken.
AB  - Functional mutations were made in the type III secretion systems encoded by
      Salmonella pathogenicity island 1 (SPI 1) and Salmonella pathogenicity island 2
      (SPI 2) of Salmonella enterica serovar Pullorum, the cause of pullorum disease in
      poultry. Their role in cell invasion in vitro, and in virulence in vivo was
      determined. The SPI 1 mutant showed decreased invasiveness for chicken cells but
      was capable of causing disease in orally infected 1-day-old chicks, although it
      showed some reduction in virulence. The SPI 2 mutant showed no reduction in
      invasiveness, but was fully attenuated for virulence in 1-day-old chicks, and was
      not detected following oral infection in 1-week-old chickens. Following
      intravenous infection, the SPI 2 mutant was also attenuated and cleared more
      rapidly than the parent strain. This indicates that S. Pullorum requires SPI 2
      for virulence and persistence but SPI 1 appears to contribute to, but is not
      essential for, the virulence of S. Pullorum.

PMID- 12427345
TI  - An in vitro and in vivo evaluation of the virulence of Newcastle disease virus
      and vaccines for the chicken reproductive tract.
AB  - The virulence of two vaccine strains and two field strains of Newcastle disease
      virus (NDV) for the female reproductive tract of chickens was assessed using
      oviduct organ cultures (OOC) prepared from precociously-induced oviducts in young
      chicks by oestrogen treatment. Ciliostasis, haemagglutination and virus isolation
      from infected OOC supernatants, histopathology and immunoperoxidase test results
      indicated the pathogenic nature of both vaccine and virulent NDVs for the
      precocious oviducts. The virulent viruses, mesogenic and lentogenic vaccines
      caused damage in that order of magnitude and the uterus had a higher
      susceptibility than oviducts. One virulent and the mesogenic strain of NDV were
      used for in vivo trials. The pathogenicity was assessed in oestrogen-treated
      infected chickens using histopathology and immunoperoxidase test. The vaccine
      virus produced transient damage up to 6 days post-infection, while the damage
      with the virulent isolate persisted for at least 9 days post-infection. This
      technique could be a pointer to possible variations in virulence of NDV vaccine
      and field strains, and warrants further investigation. The potential value of OOC
      from young chickens for testing the possibility of NDV vaccines causing damage by
      themselves and offering protection against damage of the reproductive tract
      caused by virulent isolates is emphasized.

PMID- 12427346
TI  - Evolution of pigeon Newcastle disease virus strains.
AB  - Twenty-seven Newcastle disease virus isolates obtained during the years 1998 and
      1999 from racing pigeons were shown to be antigenically indistinguishable from
      the pigeon paramyxovirus type 1 (PPMV-1) viruses isolated in the years 1983 and
      1984. Partial sequencing of 240 base pairs of the F gene demonstrated at least
      94.7% identity at the nucleotide level between isolates from 1983 and 1984, and
      more recent viruses isolated in 1998 and 1999. Most of the nucleotide changes
      observed were silent mutations as only six amino acid changes were observed.
      Three amino acid substitutions were observed in the F2/F1 cleavage site. The
      sequence of the F2/F1 cleavage site of all isolates was typical for pathogenic
      paramyxovirus 1 viruses. Amino acids at the F2/F1 cleavage site changed from
      (112)GRQKRF(117) to (112)RRQKRF(117), (112)RRKKRF(117) or (112)RRRKRF(117). The
      motif (112)RRQKRF(117) was present in the majority of the isolates but the
      intracerebral pathogenicity indexes of PPMV-1 isolates having this motif was
      highly variable but largely lower (mean, 0.69) than that reported for PPMV-1
      viruses isolated in the years 1983 and 1984 (mean, 1.44).

PMID- 12427348
TI  - Evaluation of different scales for measurement of perceived physical strain
      during performance of manual tasks.
AB  - The main objective of this study was to evaluate different scales of perceived
      strain during the performance of various physical tasks. A total of 52 male and
      female participants took part in 4 experiments to achieve the study objective.
      The results suggest that a bipolar comfort-discomfort scale is a more appropriate
      instrument than a discomfort scale for assessing cumulative physical stresses at
      work, especially at the beginning of the shift. For assessing discomfort at the
      end of the work shift, a unipolar scale may also be used. On the basis of the
      obtained results, red, green, and yellow zones are suggested to establish
      priorities for work redesign efforts in ergonomic control programs.

PMID- 12427349
TI  - Ergonomic program effectiveness: ergonomic and medical intervention.
AB  - The implementation of a successful ergonomic and medical intervention program
      designed to reduce the number and severity of injuries and illnesses and the
      associated levels of discomfort in the workplace is presented. Because of the
      recent activity concerning the on-again-off-again Occupational Safety and Health
      Administration (OSHA) Ergonomic Program Standard questions have been raised as to
      the value and effectiveness of an organization's ergonomics program. In light of
      these concerns, the immense cost associated with work-related injury and illness,
      and the related pain and suffering associated with such injuries and illnesses,
      it is important to present a workable and effective ergonomic and medical
      intervention program. The results of this applied study demonstrate that through
      the application of an ergonomic and medical intervention program, workplace
      related injuries and illnesses can be reduced or eliminated.

PMID- 12427350
TI  - Interaction of physical and mental work.
AB  - The objective of the research was to determine the effect of mental load on the
      physical capacity of an individual. An experiment involving 9 combinations of
      lifting tasks, 1 lowering task, and 3 treadmill tasks was conducted. Heart rate
      was measured and maximum acceptable weight of lift was determined using the
      psychophysical method. A simple multiplication task was used as the mental load.
      The output variables were determined with and without the mental task. The
      results indicate that the individual's physical capacity decreased with the
      mental task while lifting from floor to knuckle and shoulder to reach lifting
      heights.

PMID- 12427351
TI  - The effects of worksite stress management intervention on changes in coping
      styles.
AB  - In this study the effects of a worksite stress management intervention on changes
      in coping styles were examined. Ninety-five participants were randomly assigned
      to an experimental group participating in the intervention or to a control group
      with a delayed intervention. The stress management intervention was structured on
      enhancing so-called positive coping styles focused on problem solving and social
      diversion and on decreasing negative-emotion-focused and distraction-coping. The
      results showed that in the experimental group the level of positive coping styles
      significantly increased. The effect of decreased negative coping styles due to
      the intervention was observed only in the group of participants with a high level
      of negative affectivity.

PMID- 12427352
TI  - Combining psychophysical measures of discomfort and electromyography for the
      evaluation of a new automotive seating concept.
AB  - The purpose of this study was to determine if the advantages and disadvantages of
      a new automotive seating concept, known as the micro-adjuster control system,
      could be reliably evaluated using both a physiological assessment technique
      (i.e., electromyography [EMG]) and a subjective questionnaire. The results
      indicate that psychophysical measures of discomfort and the root mean squared
      (RMS) activity of the EMG are statistically related, r (8) = -.788, p =.020. More
      specifically, subjective perceptions of comfort were found to improve with
      decreasing levels of muscle activity. This implies that seat comfort can be
      evaluated on the basis of physiological as well as subjective responses to
      prolonged driving. This finding should drastically improve automobile seat design
      efforts.

PMID- 12427353
TI  - Permeability of medical gloves to mono- and dimethacrylate monomers in dental
      restorative materials.
AB  - Dental personnel manually handle methacrylate-based restorative materials, which
      can cause skin irritation and allergies. The protection given by different types
      of medical gloves is not well known. Breakthrough time (BTT, min) was used as a
      measure of protection according to a European standard, using 2 test mixtures
      consisting of respectively 3 and 5 monomers. Fourteen gloves representing natural
      rubber latex, synthetic rubber, and synthetic polymeric material were tested. The
      BTT ranged from some minutes to more than 2 hrs for the 4 monomers with a
      molecular mass less than 300. The longest protection was recorded for Nitra Touch
      (nitrile rubber), Tactylon (synthetic rubber), and Metin (PVC).

PMID- 12427354
TI  - Three-dimensional lifting model for non-homogeneous loads.
AB  - A 3-dimensional model and analysis methodology is suggested for treating lifting
      tasks when unbalanced loads are involved. The paper describes the biomechanical
      equations that are coupled with the worker's posture geometry, to address a
      practical problem of non-symmetric lifting. The analysis has a dominant
      biomechanical modeling scope, as it contains a breakdown of the internal lifting
      forces resulting from posture and external loads acting on the body. The load
      model represents the acting forces due to unbalanced lifting, which is commonly
      found in industrial situations. The suggested model allows the user to simulate
      the influence of the practical load distribution, aiding safe design of a lifting
      job.

PMID- 12427355
TI  - Lifter, a computerized lifting analysis technique.
AB  - A computer driven technique to analyze lifting forces, in non-homogeneous load
      situations, is described and tested. Analysis is based on a dynamic algorithm
      aimed to evaluate unconstrained lifting posture and non-homogeneous content of
      loads. For inputs we use actual geometrical body postures in the form of 3
      dimensional co-ordinates obtained from pictures taken at a work site. The outputs
      show a good match between the findings and pre-study assumptions for balanced and
      non-balanced load lifting practice. The results of the experiments show a good
      degree of correlation with results reported by researchers for symmetrical
      lifting tasks and with National Institute for Occupational Health (NIOSH) lifting
      guidelines. It is believed that the technique can serve as the proper choice for
      industrial and safety analysts of lifting activities.

PMID- 12427356
TI  - Driver workload response to in-vehicle device operations.
AB  - A central concern of Intelligent Transportation Systems (ITS) is the effect of in
      vehicle devices (e.g., cell phones, navigation systems, radios, etc.) on driver
      performance and safety. As diverse and innovative technologies are designed and
      implemented for in-vehicle use, questions regarding the presence and use of these
      devices assume progressively greater importance. Further concerns for advanced
      driver training require us to develop and validate reliable and effective
      procedures for assessing such effects. This work examines a number of candidate
      procedures, in particular the evaluation of change in cognitive workload as a
      strategy by which such goals might be achieved.

PMID- 12427357
TI  - Clinical trials for pediatric scleroderma.
AB  - Progressive systemic sclerosis (PSS), or scleroderma, is a rare disease in the
      pediatric population. Many children with PSS have significant involvement of
      their internal organs, which leads to decreased survival. Because of the
      infrequency of the condition and delayed diagnosis, there are no large studies to
      evaluate therapy for PSS in children. Treatment is controversial in the adult
      literature, and its applicability to children is unclear. Only through
      collaborative efforts will researchers be able to clearly delineate the
      etiopathogenesis of PSS, and gather information from multicenter studies to
      ultimately provide appropriate and effective care for children with PSS.

PMID- 12427358
TI  - Cytokines and juvenile idiopathic arthritis.
AB  - Cytokines are a large group of polypeptides and small proteins that are effector
      molecules for cells involved in immune and inflammatory responses. There are
      agonists and antagonists that interact with each other to maintain a dynamic
      equilibrium, and ensure eventual recovery of any perturbation, for example, by
      trauma or infection, of the network toward inflammation. The imbalance between
      pro- and anti-inflammatory cytokines and the T helper cell subtypes is considered
      important in the pathogenesis of autoimmune diseases, including juvenile
      idiopathic arthritis. The measurement of cytokines and chemotactic cytokines in
      body fluids and synovial tissue has provided insight into the type of immune and
      inflammatory reaction and the possible presence or absence of regulation.
      Differences between subtypes of juvenile idiopathic arthritis have been
      identified with these measurements. But cytokine measurements in serum are not
      useful for diagnostic purposes, because of the variability during 24 hours, the
      collection and assay methods, as well as the ease of degradation for most
      cytokines. The recent interest in the genetic polymorphisms of cytokine genes and
      their association with juvenile idiopathic arthritis has provided association
      with a number of cytokine alleles. Confirmation of linkage with disease is only
      available for tumor necrosis factor and interleukin-6 at present. These genetic
      variants may be the basis of genetic susceptibility to the persistent imbalance
      in the inflammatory and immune networks, and determine the phenotype and severity
      of disease.

PMID- 12427359
TI  - Gastrointestinal issues in children with rheumatologic disease.
AB  - Distinctive arthritic patterns, some of which may parallel or even precede
      intestinal disease activity, are seen in inflammatory bowel disease. Some
      spondyloarthropathies are associated with transient ileocolic inflammation.
      Vasculitis frequently affects the gastrointestinal tract, predominantly
      manifesting with abdominal pain. In severe cases, intestinal ischemia and
      perforation may occur. Various arthritides are thought to be associated with
      other gastrointestinal diseases, such as celiac disease and hepatitis. The
      association between intestinal disease and arthritis is still being investigated.
      Interactions between the inflammatory intestinal cells and inflamed synovial
      cells have been demonstrated. Certain intestinal bacteria such as Klebsiella
      pneumoniae are suspected to play a role as triggers for the development of
      arthropathies. Genetic factors, especially human leukocyte antigen associations,
      are also being increasingly investigated for better characterization of the types
      of arthritis and possible prognostic implications. Various therapies, including
      nonsteroidal anti-inflammatory drugs, used to treat rheumatologic diseases have
      the potential to cause gastrointestinal complications.

PMID- 12427360
TI  - Heat shock proteins in juvenile idiopathic arthritis: keys for understanding
      remitting arthritis and candidate antigens for immune therapy.
AB  - Juvenile idiopathic arthritis (JIA) is in a majority of the cases of self
      limiting, and sometimes even a self-remitting, disease. A growing amount of data
      suggests that active T cell regulation determines, at least partly, the clinical
      outcome of JIA. In experimental models of arthritis, a group of highly conserved
      microbial proteins, heat shock proteins (hsps), can be used to effectively
      prevent and treat arthritis. This protection is mediated through the induction of
      cross-reactive T cell responses to self-hsps. In JIA, naturally occurring T cell
      immune responses to hsps are associated with disease remission in restricted
      oligoarticular JIA. Moreover, those responses are associated with the induction
      of T cells with a regulatory phenotype. Taken together, these data imply that
      immune modulation with hsps can be an effective way to restore natural occurring
      T cell responses, and, thus, treat JIA and rheumatoid arthritis.

PMID- 12427361
TI  - Update on the treatment of Kawasaki disease in childhood.
AB  - Intravenous immunoglobulin (IVIG) treatment for Kawasaki disease (KD), first
      discovered almost 20 years ago, dramatically changed the management and prognosis
      of the condition. Although standard Japanese Ministry of Health criteria suggest
      that current treatment is more than 95% effective at preventing coronary artery
      changes, echocardiographic measurements adjusted for body size, imply a far
      higher incidence of coronary artery dilitation despite prompt therapy. If one
      also considers data on chronic alterations in endothelial function after KD, then
      more effective approaches to the management of acute and recurrent KD are needed.
      A variety of possible adjunct therapies--most notably high-dose corticosteroids-
      currently are being studied to determine whether better long-term outcomes may be
      achieved than with IVIG alone.

PMID- 12427363
TI  - Treatment of ankylosing spondylitis by inhibition of tumor necrosis factor-alpha.

PMID- 12427362
TI  - Immunodeficiency and genetic conditions that cause arthritis in childhood.
AB  - Many conditions can cause or be associated with arthritis in childhood. The
      authors of this paper will review the situations in which underlying
      immunodeficiency or defective regulation of lymphocyte homeostasis must be
      suspected, and discuss, for some of these diseases, the genetic bases and
      pathogenesis. In the second part of this article, the authors will focus on other
      diseases that can cause arthritis in childhood, often with other symptoms, and
      for which evidence of an association with genetic abnormalities has been recently
      discovered. Finally, the authors will discuss the implications of recent findings
      regarding the role of some genes as causing or modulating factors in juvenile
      idiopathic arthritis and related disorders, as well as observations made in
      adults and in animal models of inflammation and autoimmunity.

PMID- 12427364
TI  - Intravenous pamidronate in treatment of non-steroidal anti-inflammatory drug
      refractory ankylosing spondylitis.

PMID- 12427365
TI  - Advances in the understanding of entheseal inflammation.
AB  - The importance of enthesitis in the pathogenesis of spondyloarthropathy (SpA) is
      now well recognized. Several entheses comprise more than simply the insertion
      site, and they are part of a complex biomechanical organ to resist shear and
      compression. It is also evident that tendons that wrap around bony pulleys form
      an integral part of joint capsules, and share, along with imaging abnormalities
      and histopathologic changes, common anatomic, histologic, and biomechanical
      features with classically defined entheses. Researchers have called these regions
      of tendons functional entheses. Furthermore, certain synovial joints have much in
      common with classic entheses--most notably those lined with fibrocartilage rather
      than hyaline cartilage. These observations provide a unifying anatomic basis for
      SpA. Enthesitis is associated with underlying osteitis, whether mechanically
      induced or inflammatory-related--with the extent of osteitis determined by the
      human leukocyte antigen-B27 gene. Until recently, there was no effective therapy
      for resistant enthesitis, but it is now evident that enthesitis responds well to
      biologic blockade with anti-tumor necrosis factor. Unraveling the pathogenic
      basis of enthesitis will have important implications for understanding and
      defining therapies in SpA.

PMID- 12427366
TI  - Animal models of ankylosing spondylitis.
AB  - The pathology of ankylosing spondylitis (AS) and related spondyloarthropathies
      (SpA) characteristically involve a sacroiliitis and inflammation of the
      intervertebral discs (IVD) in the lumbar spine, and an enthesitis at sites of
      ligamentous insertions into bone. The proteoglycans aggrecan and versican are
      large molecules that aggregate with hyaluronic via a globular 1 domain. These
      domains share significant homology at the level of B and T cell epitope
      recognition. Both proteoglycans are present in the intervertebral disc and
      hyaline cartilages of the sacroiliac joint, as well as in entheses. Whereas
      aggrecan is most concentrated in the nucleus of the IVD and in articular
      cartilages and endplates, versican is generally absent from these tissues except
      in the sacroiliac joint, but is concentrated in ligaments and the annulus.
      Immunity to these molecules in BALB/c mice results in an AS-like pathology,
      including sacroiliitis, enthesitis, and discitis. The pathology of AS is closely
      associated with the expression of the class I molecule human leukocyte antigen
      B27. Rats bearing this transgene develop an AS-like pathology, as well as other
      various signs of autoimmunity. Ankylosing spondylitis is characterized by an
      ankylosing pathology whereby bone formation in the annulus leads to
      intervertebral fusion. Mice bearing the ank/ank defect gene develop a bony
      ankylosis of the spine like that seen in advanced AS and related SpA. These three
      animal models provide insight into the pathogenesis of SpA, and opportunities to
      investigate their pathology in relationship to human disease where investigation
      of the pathobiology is very difficult, because of restricted access to involved
      tissues.

PMID- 12427367
TI  - Mechanisms of bone resorption and new bone formation in spondyloarthropathies.
AB  - Spondyloarthropathies (SpA) share clinical features such as sacroiliitis, axial
      immobility, and peripheral arthropathies. They also share a strong association
      with human leukocyte antigen-B27, implicating T cells and antigen-presenting
      cells in the disease process. Inflammation seems to underlie the pathogenesis of
      SpA, particularly in the axial skeleton and entheses. Pathologic bone loss and
      formation occur simultaneously in inflamed regions, suggesting an inflammation
      induced dysregulation of osteoclast and osteoblast activity. Pro-inflammatory
      cytokines such as tumor necrosis factor-alpha (TNFa) appear to be central to the
      disease, because TNFa blockade has been shown to effectively improve clinical
      outcome. Other cytokines such as transforming growth factor-beta, interferon
      gamma (IFNg), and interleukin-18 are also likely to be important in SpA.
      Activated T cells have been shown to produce cytokines such as IFNg and receptor
      activator of nuclear-factor- kappaB ligand, with direct effects on
      osteoclastogenesis. The dual role of T cells in immunobiology and skeletal
      biology provides a possible link between human leukocyte antigen-B27, pro
      inflammatory cytokines, and bone cells in SpA.

PMID- 12427368
TI  - The role of infection in the pathogenesis of spondyloarthropathies with special
      reference to human leukocyte antigen-B27.
AB  - Spondyloarthropathies consist of many inflammatory diseases that are closely
      associated with human leukocyte antigen (HLA)-B27. One of these diseases is
      reactive arthritis (ReA), which is a joint inflammation that occurs after
      infections that are caused by certain gram-negative bacteria. The importance of
      these infections as causative agents of ReA has been clearly established. It is
      not clear, however, whether these infections contribute to the development of
      other forms of spondyloarthropathies. The exact mechanism by which HLA-B27
      influences disease susceptibility in spondyloarthropathies remains to be
      determined. The role of HLA-B27 as an antigen-presenting molecule is certainly
      important in the pathogenesis of these diseases; however, recent data indicate
      that this molecule may exhibit other functions unrelated to antigen presentation,
      which may be important in the pathogenesis of ReA. In this paper, the authors
      summarize the current knowledge of the role of infection in the
      spondyloarthropathies.

PMID- 12427370
TI  - [World diabetes day].

PMID- 12427371
TI  - [Perception of professionals' quality of life in the Asturias a Health Care Area,
      Spain].
AB  - AIM: To report on the perceived quality of life of professionals in the health
      services sector. DESIGN: Descriptive, cross-sectional study. SETTING: Directorate
      of Primary Care of Health Care Area VIII in Asturias, Spain. PARTICIPANTS: Two
      hundred thirty-seven professionals in the health care sector and other sectors.
      MAIN MEASURES: Internal mail was used to send all employees the CV-35 self
      administered questionnaire, which measures perceived professional quality of
      life, understood as the balance between work demands and the capacity to cope
      with them. The instrument consists of 35 items that evaluate three dimensions:
      perception of demands, emotional support received from superiors, and intrinsic
      motivation. Each item was scored on a quantitative scale of 1 to 10. RESULTS: One
      hundred thirty-five completed questionnaires were received (59.5%). Mean
      professional quality of life was 5.35 (5.12-5.58); there were no significant
      differences between age groups, sexes or employment status. Mean score for
      perceived demands at the workplace was 6.03 (5.89-6.17), and mean score for
      emotional support received from superiors was 4.78 (4.63-4.97). This support was
      valued most highly by employees who held a position of responsibility. Mean score
      for intrinsic motivation was 7.45 (7.34-7.56). CONCLUSIONS: Employees in Health
      Care Area VIII in Asturias perceived their professional quality of life to be
      moderately good, perceived a moderate degree of support received, and had a high
      level of intrinsic motivation to cope with high demands at the workplace.

PMID- 12427369
TI  - Gut inflammation and spondyloarthropathies.
AB  - Spondyloarthropathies (SpA) are a group of related disorders with common clinical
      and genetic characteristics. The prototype disease in this group is ankylosing
      spondylitis; other entities include reactive arthritis, psoriatic arthritis, and
      arthritis in patients with inflammatory bowel disease. Over recent years, there
      has been a special interest in the relation between spondylitis/synovitis and gut
      inflammation in patients with SpA. Two thirds of patients with undifferentiated
      SpA show histologic signs of gut inflammation, and a fraction of these patients
      go on to develop clinically overt Crohn's disease. In this review, the authors
      will focus on 1) the growing evidence that has been provided that gut
      inflammation in SpA is immunologically related to Crohn's disease, based on the
      molecular characterization of the inflammation (lymphocyte homing markers and
      ligands, T cell cytokines, macrophage markers, and serology); and 2) on the
      therapeutic implications resulting from this concept. The recent introduction and
      positioning of anti-tumor necrosis factor-alpha therapy in patients with
      ankylosing spondylitis and other types of SpA is, in large part, based on this
      concept.

PMID- 12427372
TI  - [Dental fillings in school-children from the Alcala la Real-Martos Health
      District (Jaen)].
AB  - OBJECTIVE: To evaluate 4-6 years later the state of dental fillings in 6-8 year
      old school-children treated at a health centre. DESIGN: Monitoring of a cohort
      with intervention. SETTING: Alcala la Real Health Centre (Jaen). PATIENTS: In the
      school years 94-95 and 95-96 a total de 88 second-year EPO (compulsory primary
      education) students received at least one occlusal silver amalgam filling in
      their first permanent molars. 4-6 years later, 78 students, who had had 157
      fillings, were examined. INTERVENTIONS: Silver amalgam fillings in first
      permanent molars. MAIN MEASUREMENTS AND RESULTS: The success or failure of the
      fillings was measured. The failure rate was 11.5% (95% CI, 6.0-17.0), with
      authentic failures (marginal infiltration, recurrent caries, broken filling and
      broken tooth) (58.8%) predominating over false failures (caries elsewhere)
      (41.2%). Neither sex, age when the filling was inserted, dental arch (upper or
      lower), nor the index of temporary caries at the start were statistically linked
      to the failure of fillings. CONCLUSIONS: In clinical terms, the health centre has
      an adequate level of efficacy 4-6 years after inserting simple silver amalgam
      fillings in 6-8 year old school-children.

PMID- 12427373
TI  - [Study of the validity of "rapid" serology in diagnosing Helicobacter pylori
      infection].
AB  - OBJECTIVE: To evaluate prospectively the validity of a <<rapid>> serology
      diagnosis method (using capillary blood) in our ambit, taking for reference a
      combination of standard diagnostic methods. DESIGN: Prospective. The endoscopist,
      pathologist and those responsible for interpreting the rapid urease test, the
      breath test and <<rapid>> serology did not know the results of the other
      diagnostic methods. SETTING: Gastro-enterology service of a tertiary
      hospital.Participants. 30 consecutive patients with symptoms attributable to the
      upper digestive tract and who underwent an oral gastroscopy. Main measurements.
      Gastric biopsies for histology examination and for the rapid urease test and a
      breath test with 13C-urea were conducted. For <<rapid>> serology, the commercial
      SureStep HP WB test kit was used. A patient was considered infected when at least
      two of the three validated techniques (rapid urease test, histology, breath test)
      were positive; and not infected, when all three were negative. RESULTS: 30
      patients, 30% male, with a mean age of 51, were included. The reference standard
      indicated 61% prevalence of infection, with two cases classed as undetermined.
      <<Rapid>> serology was positive in 8 patients and negative in 22. Sensitivity,
      specificity, positive predictive value and negative predictive value were,
      respectively, 41% (95% CI, 18-65), 91% (74-100), 87% (65-100) and 50% (28-72).
      The positive probability quotient was 4.5; and the negative, 0.65. CONCLUSION:
      The <<rapid>> serology used in the current study has deficient diagnostic
      accuracy. Therefore, it should not be used in clinical practice to identify H.
      pylori infection.

PMID- 12427374
TI  - [Genetics and primary care. Implications].

PMID- 12427375
TI  - [Accreditation system in primary care (SaAP) (II): challenges of ongoing
      training].

PMID- 12427376
TI  - [Immunisation: leaps into the future. Viral hepatitis].

PMID- 12427378
TI  - [Why do our patients really stop smoking?].

PMID- 12427379
TI  - [Development of tuberculosis after a slimming diet].

PMID- 12427380
TI  - [Rise in creatine kinase and prostate adenocarcinoma].

PMID- 12427381
TI  - [Dysphonia and laryngeal tubercolosis: presentation of two cases and review of
      the literature].

PMID- 12427382
TI  - [Antibiotics policy in primary and specialist care. Two separate policies?].

PMID- 12427384
TI  - [Culpability and fibromyalgia].

PMID- 12427385
TI  - Irreducibility and efficiency of ESIP to sample marker genotypes in large
      pedigrees with loops.
AB  - Markov chain Monte Carlo (MCMC) methods have been proposed to overcome
      computational problems in linkage and segregation analyses. This approach
      involves sampling genotypes at the marker and trait loci. Among MCMC methods,
      scalar-Gibbs is the easiest to implement, and it is used in genetics. However,
      the Markov chain that corresponds to scalar-Gibbs may not be irreducible when the
      marker locus has more than two alleles, and even when the chain is irreducible,
      mixing has been observed to be slow. Joint sampling of genotypes has been
      proposed as a strategy to overcome these problems. An algorithm that combines the
      Elston-Stewart algorithm and iterative peeling (ESIP sampler) to sample genotypes
      jointly from the entire pedigree is used in this study. Here, it is shown that
      the ESIP sampler yields an irreducible Markov chain, regardless of the number of
      alleles at a locus. Further, results obtained by ESIP sampler are compared with
      other methods in the literature. Of the methods that are guaranteed to be
      irreducible, ESIP was the most efficient.

PMID- 12427386
TI  - Precision of methods for calculating identity-by-descent matrices using multiple
      markers.
AB  - A rapid, deterministic method (DET) based on a recursive algorithm and a
      stochastic method based on Markov Chain Monte Carlo (MCMC) for calculating
      identity-by-descent (IBD) matrices conditional on multiple markers were compared
      using stochastic simulation. Precision was measured by the mean squared error
      (MSE) of the relationship coefficients in predicting the true IBD relationships,
      relative to MSE obtained from using pedigree only. Comparisons were made when
      varying marker density, allele numbers, allele frequencies, and the size of full
      sib families. The precision of DET was 75-99% relative to MCMC, but was not
      simply related to the informativeness of individual loci. For situations
      mimicking microsatellite markers or dense SNP, the precision of DET was > or =
      95% relative to MCMC. Relative precision declined for the SNP, but not
      microsatellites as marker density decreased. Full-sib family size did not affect
      the precision. The methods were tested in interval mapping and marker assisted
      selection, and the performance was very largely determined by the MSE. A multi
      locus information index considering the type, number, and position of markers was
      developed to assess precision. It showed a marked empirical relationship with the
      observed precision for DET and MCMC and explained the complex relationship
      between relative precision and the informativeness of individual loci.

PMID- 12427387
TI  - Genetic parameters for lactation traits of milking ewes: protein content and
      composition, fat, somatic cells and individual laboratory cheese yield.
AB  - The effects of some environmental variation factors and the genetic parameters
      for total milk traits (fat content, protein content, casein content, serum
      protein content, lactation mean of individual laboratory cheese yield (LILCY),
      lactation mean of somatic cell count (LSCC), and milk yield) were estimated from
      the records of 1,111 Churra ewes. Genetic parameters were estimated by
      multivariate REML. Heritability for fat content was low (0.10) as is usually
      found in the Churra breed. Heritabilities for protein content, casein content,
      serum protein content, LILCY, milk yield and somatic cell count were 0.31, 0.30,
      0.22, 0.09, 0.26 and 0.11, respectively. The highest heritability estimates were
      for protein and casein contents. Casein content is not advisable as an
      alternative to protein content as a selection criterion for cheese yield
      improvement; it does not have any compelling advantages and its measurement is
      costly. Our results for LSCC indicated that efforts should focus on improving the
      level of management rather than selecting for somatic cells, in the actual
      conditions of the Churra breed.

PMID- 12427388
TI  - Selection responses for the number of fertile eggs of the Brown Tsaiya duck (Anas
      platyrhynchos) after a single artificial insemination with pooled Muscovy
      (Cairina moschata) semen.
AB  - A seven-generation selection experiment comprising a selected (S) and a control
      (C) line was conducted with the objective of increasing the number of fertile
      eggs (F) of the Brown Tsaiya duck after a single artificial insemination (AI)
      with pooled Muscovy semen. Both lines consisted of about 20 males and 60 females
      since parents in each generation and each female duck was tested 3 times, at 26,
      29 and 32 weeks of age. The fertile eggs were measured by candling at day 7 of
      incubation. The selection criterion in the S line was the BLUP animal model value
      for F. On average, 24.7% of the females and 15% of the males were selected. The
      direct responses to the selection for F, and correlated responses for the number
      of eggs set (Ie), the number of total dead embryos (M), the maximum duration of
      fertility (Dm) and the number of hatched mule ducklings (H) were measured by
      studying the differences across the generations of selection between the
      phenotypic value averages in the S and C lines. The predicted genetic responses
      were calculated by studying the differences between the S and C lines in averaged
      values of five traits of the BLUP animal model. The selection responses and the
      predicted responses showed similar trends. There was no genetic change for Ie.
      After seven generations of selection, the average selection responses per
      generation were 0.40, 0.33, 0.42, 0.41 genetic standard deviation units for F, M,
      Dm, and H respectively. Embryo viability was not impaired by this selection. For
      days 2-8 after AI, the fertility rates (F/Ie) were 89.2% and 63.8%, the
      hatchability rates (H/F) were 72.5% and 70.6%, and (H/Ie) were 64.7% and 45.1% in
      the S and C lines respectively. It was concluded that upward selection on the
      number of fertile eggs after a single AI with pooled Muscovy semen may be
      effective in ducks to increase the duration of the fertile period and the
      fertility and hatchability rates with AI once a week instead of twice a week.

PMID- 12427389
TI  - Assessing the contribution of breeds to genetic diversity in conservation
      schemes.
AB  - The quantitative assessment of genetic diversity within and between populations
      is important for decision making in genetic conservation plans. In this paper we
      define the genetic diversity of a set of populations, S, as the maximum genetic
      variance that can be obtained in a random mating population that is bred from the
      set of populations S. First we calculated the relative contribution of
      populations to a core set of populations in which the overlap of genetic
      diversity was minimised. This implies that the mean kinship in the core set
      should be minimal. The above definition of diversity differs from Weitzman
      diversity in that it attempts to conserve the founder population (and thus
      minimises the loss of alleles), whereas Weitzman diversity favours the
      conservation of many inbred lines. The former is preferred in species where
      inbred lines suffer from inbreeding depression. The application of the method is
      illustrated by an example involving 45 Dutch poultry breeds. The calculations
      used were easy to implement and not computer intensive. The method gave a ranking
      of breeds according to their contributions to genetic diversity. Losses in
      genetic diversity ranged from 2.1% to 4.5% for different subsets relative to the
      entire set of breeds, while the loss of founder genome equivalents ranged from
      22.9% to 39.3%.

PMID- 12427390
TI  - History of Lipizzan horse maternal lines as revealed by mtDNA analysis.
AB  - Sequencing of the mtDNA control region (385 or 695 bp) of 212 Lipizzans from
      eight studs revealed 37 haplotypes. Distribution of haplotypes among studs was
      biased, including many private haplotypes but only one haplotype was present in
      all the studs. According to historical data, numerous Lipizzan maternal lines
      originating from founder mares of different breeds have been established during
      the breed's history, so the broad genetic base of the Lipizzan maternal lines was
      expected. A comparison of Lipizzan sequences with 136 sequences of domestic- and
      wild-horses from GenBank showed a clustering of Lipizzan haplotypes in the
      majority of haplotype subgroups present in other domestic horses. We assume that
      haplotypes identical to haplotypes of early domesticated horses can be found in
      several Lipizzan maternal lines as well as in other breeds. Therefore, domestic
      horses could arise either from a single large population or from several
      populations provided there were strong migrations during the early phase after
      domestication. A comparison of Lipizzan haplotypes with 56 maternal lines
      (according to the pedigrees) showed a disagreement of biological parentage with
      pedigree data for at least 11% of the Lipizzans. A distribution of haplotype
      frequencies was unequal (0.2%-26%), mainly due to pedigree errors and haplotype
      sharing among founder mares.

PMID- 12427391
TI  - Maternal and perinatal outcome in varying degrees of anemia.
AB  - OBJECTIVES: To analyze the maternal and perinatal outcome in varying degrees of
      anemia. METHODS: A total of 447 pregnant women were divided into group I (Hb>11
      g%, n=123 women), group II (Hb 9-10.9 g%, n=214 women), group III (Hb 7-8.9 g%,
      n=79 women) group IV (Hb<7 g%, n=31 women). Their maternal and perinatal outcome,
      mode of delivery, duration of labor and postpartum complications were noted and
      analyzed using multiple logistic regression to calculate odds ratios (95% CI) for
      duration of labor, mode of delivery and low birth babies. Chi square or Fisher's
      exact test was employed for difference in proportions and Student's t-test for
      testing difference between means. RESULTS: Mean age (27+/-4.25 years) and number
      of women with parity >3 were highest in group IV. The patients with Hb<8.9 g% had
      a 4-6-fold higher risk of prolonged labor compared to Hb>11 g%. The odds ratios
      for abnormal delivery (cesarean and operative vaginal deliveries) showed a 4.8
      fold higher risk (95% CI 1.82, 12.7) in patients with Hb </=7.5 g%. The mean
      birth weight was maximum in the 9.6-10.5 g% category that fell with both
      increasing and decreasing hemoglobin values, being lowest in Group IV. Women in
      Group II had lowest number of low birth weight and IUGR babies, no stillbirths
      and neonatal deaths, lowest induction and operative delivery rates. CONCLUSIONS:
      Mild anemia fared best in maternal and perinatal outcome. Severe anemia was
      associated with increased low birth weight babies, induction rates, operative
      deliveries and prolonged labor.

PMID- 12427392
TI  - Cesarean section as a cause of chronic pelvic pain.
AB  - OBJECTIVE: To determine if the history of cesarean section was associated with
      chronic pelvic pain, independent of the presence of other conditions such as
      pelvic adhesions, endometriosis, sequelae of pelvic inflammatory disease,
      leiomyoma and pelvic varices. METHODS: Retrospective case-control study conducted
      on 199 patients consecutively admitted from January 1998 to January 2000, 116 of
      them submitted to laparoscopy for the diagnosis of chronic pelvic pain and 83
      asymptomatic patients submitted to tubal ligation by laparoscopy. A logistic
      regression analysis was used to verify the association between chronic pelvic
      pain and the history of previous cesarean section. RESULTS: In women with chronic
      pelvic pain, a history of cesarean section was observed in 67.2% of cases,
      adhesions in 51.7%, endometriosis in 33.6%, sequelae of pelvic inflammatory
      disease in 31.9%, leiomyoma in 6.9% and pelvic varices in 11.2%. In asymptomatic
      women, a history of cesarean section was observed in 38.5%, adhesions in 24.1%,
      endometriosis in 9.6%, sequelae of pelvic inflammatory disease in 4.8%, leiomyoma
      in 7.2% and pelvic varices in 3.6%. In a logistic model, chronic pelvic pain was
      associated with a history of cesarean section (O.R.=3.7), as well as with
      endometriosis (O.R.=8.5), sequelae of pelvic inflammatory disease (O.R.=10.5).
      CONCLUSIONS: In the present study cesarean section was associated with chronic
      pelvic pain. This fact may be the cause of a public health problem in the coming
      years, due to the raised rates of cesarean section in Brazilian women.

PMID- 12427393
TI  - Endoscopy in hyperemesis gravidarum and Helicobacter pylori infection.
AB  - OBJECTIVES: To establish a relationship between hyperemesis gravidarum (HG) and
      Helicobacter pylori (H. Pylori) infection by histologic testing. METHODS: Twenty
      patients with severe HG (Group I) and 10 volunteer pregnant women without gastric
      complaints (Group II) were included in the study. Endoscopic evaluations were
      done in both groups and biopsies were obtained from the antrum and corpus for the
      histopathologic diagnosis of H. pylori. The groups were compared with the chi(2)
      test and Fisher's exact test where appropriate. RESULTS: H. pylori was diagnosed
      in 19 (95%) of 20 patients in Group I and 5 (50%) of 10 patients in group II. H.
      pylori densities in the antrum and corpus were higher in Group I and the
      differences between the two groups were statistically significant. The biopsy
      specimens revealed significant inflammation and H. pylori activation processes in
      patients with HG, and in 18 of 19 patients inflammation scores were greater than
      +2 on the scale. Pangastritis was demonstrated by endoscopic examination in 17 of
      20 patients with HG. Enterogastric reflux was also diagnosed in 10 patients. In
      the control group, three patients had antral gastritis. CONCLUSIONS: We suggest
      that in patients with intractable nausea and vomiting during pregnancy,
      pangastritis and enterogastric reflux are the main endoscopic findings and that
      these findings are closely associated with H. pylori infection, which can be
      diagnosed histologically. The degree of gastric complaints may be associated with
      the density of H. pylori infection.

PMID- 12427395
TI  - Pregnancy outcomes in urban teenagers.
AB  - OBJECTIVES: To compare pregnancy outcomes for teenagers with those for older
      gravidas. METHODS: A retrospective case control study was undertaken to compare
      teenagers who delivered between January 1996 and October 1999 at a public urban
      hospital with a group of older gravidas. RESULTS: Young pregnant teenagers were
      more likely to be nulliparous. They weighed less and gained less in pregnancy.
      More teen pregnancies occurred among Hispanics than other ethnic groups. The
      younger the teenager, the more likely for her infant to be of low or very low
      birth weight or growth restricted. There were fewer postmature deliveries,
      macrosomic fetuses and cesarean deliveries in young gravidas. Perinatal mortality
      was unaffected by maternal age. CONCLUSIONS: This investigation demonstrates
      that, while pregnancy outcomes in teenagers have improved in recent years
      relative to historical patterns, teenagers face continuing problems requiring
      special attention by care givers.

PMID- 12427394
TI  - Cytomegalovirus infection in pregnancy.
AB  - OBJECTIVES: To investigate the effects of intrauterine human cytomegalovirus
      (HCMV) infection on pregnancy outcomes and infant development. METHODS: The study
      group consisted of the HCMV-IgM-positive offspring of 75 pregnant women, and a
      control group of the non-infected offspring of 73 pregnant women. Chorionic
      villi, amnionic fluid, and umbilical blood were obtained to detect HCMV-late mRNA
      with a reverse transcriptase-polymerase chain reaction (RT-PCR) assay. The
      pregnancy outcomes were followed up. For all offspring, neurological development
      was evaluated with neurosonography, audiologic development with the brainstem
      auditory evoked potential (BAEP), and psychomotor development with the Beyley
      Scale of Infant Development (BSID). RESULTS: In the study group the positive rate
      of late mRNA was 50% in the chorionic villi and 67.65% in the amnionic fluid and
      the umbilical blood; the incidence of abnormal pregnancy outcomes (abortion,
      preterm delivery, stillbirth, etc.) was much higher than in the control group
      (40% vs. 6.57%; chi(2)=24.06; P=0.001); the abnormal rate of neurosonography
      results at birth and 3 months after birth was higher in the study group than in
      the control group (P<0.05), as were BAEP values 4 months after birth
      (chi(2)=8.960; P=0.003). Scores for the Infant Mental Development Index (MDI)
      were apparently lower than in the control group. When congenitally infected
      children were tested at the age of 5.5-6.5 years with the Wechsler Preschool and
      Primary Scale of Intelligence (WPPSI), their rate of mental retardation was still
      found to be approximately 20%. CONCLUSIONS: Intrauterine HCMV infection is
      closely related to abnormal pregnancy outcomes, infant neurological damage,
      mental retardation, and hearing loss.

PMID- 12427396
TI  - Biochemical markers for the prediction of spontaneous pre-term birth.
AB  - OBJECTIVES: The aim of this study was to identify predictive biochemical markers
      for preterm labor. METHODS: In this prospective study we included 225
      asymptomatic Caucasian women consecutively enrolled at 24 weeks of gestation. The
      following data were collected only once at 24 weeks of gestation: vaginal pH,
      vaginal fFN, cervical and serum concentration of IL-6, IL-8 and TNFalpha,
      maternal blood serum, ferritin. Student's t-test, the chi(2)-test and multiple
      linear regression were used as statistical methods. RESULTS: There were no
      differences between the age of patients, parity and gestational age at sampling
      between women who delivered at term and those who delivered pre-term (<37 weeks'
      gestation). There was a significant increase of cervical IL-6 (pre-term 608+/
      1595 pg/l vs. at term 58.9+/-112 pg/l) and serum ferritin (pre-term microg/l
      74.4+/-1.1 vs. at term 26.3+/-56.5 microg/l) in pregnant women who delivered pre
      term (P<0.05). No differences in cervical IL-8 and cervical TNFalpha between pre
      term and term deliveries were found. Multiple linear regression confirmed that
      the vaginal pH value and cervical fFN test were the best predictive biochemical
      markers of pre-term birth (standardized coefficient Beta=0.33 and 0.22,
      respectively). CONCLUSIONS: In order to evaluate pregnancies for pre-term labor,
      the presence of pH>4.5 and a positive fFN test seems to be predictive of
      subsequent pre-term delivery.

PMID- 12427397
TI  - Misoprostol in second and early third trimester for termination of pregnancies
      with fetal anomalies.
AB  - OBJECTIVES: To assess the effectiveness of a prostaglandin E1 analog,
      misoprostol, using different regimens compared with dinoprostone in termination
      of pregnancies in second and early third trimester complicated by either
      congenital fetal anomalies or intrauterine fetal demise. METHODS: A retrospective
      review of 59 pregnancies between 15 and 30 weeks was performed which were
      terminated due to congenital fetal anomalies or intrauterine fetal demise. In
      group 1 (n=29) 400 microg oral and 600 microg vaginal misoprostol, in group 2
      (n=12) 600 microg vaginal misoprostol and in group 3 (n=18) 0.5 mg dinoprostone
      gel were given for the termination of the pregnancies. All these groups were
      evaluated for demographic characteristics and delivery findings. Statistical
      analysis were performed by one-way ANOVA, Kruskal-Wallis and chi(2)-test.
      RESULTS: No significant statistical difference was observed in terms of age,
      gravidity, parity, previous abortion, gestational week, frequency of
      prostaglandin usage, and birth weights among the three groups. The time intervals
      between the first administration and delivery were 20.3 h for oral vaginal
      misoprostol, 17.3 h for vaginal misoprostol and 22.5 h for the dinoprostone group
      (P=0.594). Evacuation rates after single doses were similar in all groups (83%,
      73% and 72%, respectively). Uterine tachysystole was the only major side effect
      encountered in the oral-vaginal misoprostol group. CONCLUSIONS: All three
      regimens yielded similar results for termination of pregnancies in second and
      third trimester. The major advantage of misoprostol was the cost.

PMID- 12427398
TI  - Infertility in rural Ghana.
AB  - OBJECTIVES: This study measured the prevalence of self-reported infertility, as
      well as the level of knowledge of causes of infertility. Infertility was defined
      as failure to achieve conception after a minimum of 12 months of exposure.
      METHODS: Prevalence and knowledge of infertility were assessed in a
      representative community-based survey using a structured questionnaire in a rural
      district in Ghana among a random sample of 2,179 men and women from 15 to 49
      years. RESULTS: The prevalence of infertility was 11.8% among women and 15.8%
      among men. The knowledge of causes of infertility was limited; only 46.5% of the
      respondents reported any cause. Most respondents failed to identify reproductive
      tract infections as causes of infertility. CONCLUSIONS: Infertility in Ghana and
      other sub-Saharan countries deserves more recognition as a public health problem.
      Prevention and treatment of infertility should be incorporated in reproductive
      health programs, while male participation in reproductive health programs and
      research needs to be encouraged. Public education about the causes of infertility
      is recommended.

PMID- 12427399
TI  - Clinical equivalence of intranasal estradiol and oral estrogens for
      postmenopausal symptoms.
AB  - OBJECTIVES: The aim was to demonstrate the equivalent efficacy of intranasal
      estradiol (Aerodiol Servier, Istanbul, Turkey) 300 mg/day relative to a standard
      oral estradiol therapy of 2 mg/day and to assess the therapeutic value of the
      potential benefits of Aerodiol. METHODS: Two hundred and one postmenopausal women
      with severe menopausal symptoms were recruited to the trial. Women received
      either intranasal Aerodiol 300 microg/day (one spray delivery of 150 microg per
      nostril) or an oral estradiol 2 mg for 24 weeks. Severity of symptoms were
      compared based on the Kupperman index (KI) at the end of 24 weeks. RESULTS: The
      KI score decreased markedly in both groups between W0 and W24. At W24, the two
      treatments were shown to be statistically equivalent (P<0.001). The incidence of
      adverse events was very similar in both groups; those related to treatment were
      of mild or moderate intensity in 95% of cases for the nasal group and 90% for the
      oral group. CONCLUSIONS: In conclusion, pulsed estrogen therapy using Aerodiol is
      safe, easily used and highly efficient in alleviating postmenopausal symptoms
      with a dose of 300 microg. The dose of 300 microg in one administration per day
      offers the optimal therapy whilst being easily adaptable to each patient's
      clinical response.

PMID- 12427400
TI  - Congenital absence of the uterus.

PMID- 12427401
TI  - Celiac disease and polycystic ovary syndrome.

PMID- 12427402
TI  - A critical appraisal of cesarean section rates at teaching hospitals in India.
AB  - OBJECTIVES: To obtain an estimate of cesarean section rates and examine the
      indications and consequences at teaching hospitals in India. METHODS: Information
      was obtained on total number of normal and cesarean deliveries during 1993-1994
      and 1998-1999 from 30 medical colleges/teaching hospitals. In addition,
      prospective data were recorded for a period of 2 months on 7017 consecutive
      cesarean sections on indications for cesarean delivery, associated complications
      and mortality. RESULTS: The overall rate of cesarean section increased from 21.8%
      in 1993-1994 to 25.4% in 1998-1999. Among the 7,017 cesarean section cases, 42.4%
      were primigravidas, 31% had come from rural areas, 20.8% were referred including
      8% with history of interference, 66% were booked cases, period of gestation was
      less than 37 weeks in 21.7% and in 18% the surgery was elective. Major
      indications for cesarean section included dystocia (37.5%), fetal distress with
      or without meconium aspiration (33.4%), repeat section (29.0%), malpresentation
      (14.5%) and PIH (12.5%). Maternal and perinatal mortality was 299/100,000 and
      493/1,000 deliveries, respectively, and is high in spite of the increase in the
      cesarean section rates. CONCLUSIONS: There is need for standardized collection of
      information on all aspects of childbirth to ascertain the incidence and
      indications of cesarean section nationally so that comparison and improvements of
      care can take place.

PMID- 12427403
TI  - Domestic violence and postnatal depression in a Chinese community.
AB  - OBJECTIVES: To study the relationship between domestic violence and postnatal
      blues/depression in a Chinese community. METHODS: This was a prospective cohort
      study on 838 women after delivery in a local university teaching hospital.
      Between October, 2000 and February, 2001, all Chinese speaking women after
      delivery were invited to be interviewed by a designated research nurse using the
      Abuse Assessment Screen (AAS) to detect the incidence of domestic violence, the
      nature of violence and the perpetrator of abuse. Demographic data, pregnancy
      outcome, Stein's Daily Scoring System (SDSS) scores on day 2 or 3 postdelivery,
      Edinburgh Postnatal Depression Scale (EPDS) scores on day 2 or 3 postdelivery, 1
      2 days after discharge from hospital and at 6 weeks postdelivery were compared
      between the abused and non-abused groups using Student's t-test, chi(2)-test and
      Fisher's exact test as appropriate. RESULTS: A total of 139 women (16.6%) had
      been abused in the last year (the abused group). Of these, 87 (10.4%) had been
      abused during the current pregnancy. The nature of abuse was mainly verbal.
      Fourteen women (1.7%) had been sexually abused in the last year. The
      husband/boyfriend, mother-in-law and employer/colleague were the most common
      perpetrators of abuse. Socio-demographic factors did not differ between the two
      groups except that pregnancy was more likely to be unplanned in the abused group
      (P=0.002). The pregnancy outcome did not differ. However, the abused group had
      significantly higher SDSS and EPDS scores at all stages of screening (P=0.003,
      P=0.000, P=0.010 and P=0.001, respectively). CONCLUSION: The findings supported
      our hypothesis that the effect of domestic violence on Chinese pregnant women is
      mainly on their psychological well-being.

PMID- 12427404
TI  - Physiologically assessed coronary collateral flow and adverse cardiac ischemic
      events: a follow-up study in 403 patients with coronary artery disease.
AB  - OBJECTIVES: We sought to evaluate whether coronary collateral flow is clinically
      relevant for future cardiac ischemic events. BACKGROUND: The link between good
      collateral supply related to less myocardial damage and fewer cardiac events has
      not been established prospectively beyond doubt. METHODS: In 403 patients with
      stable angina pectoris undergoing percutaneous transluminal coronary angioplasty
      (PTCA) and quantitative collateral assessment, the occurrence of major adverse
      cardiac events ([MACE] cardiac death, myocardial infarction, unstable angina
      pectoris) and stable angina pectoris was monitored during follow-up. Collateral
      flow index (CFI) was determined using intracoronary pressure or Doppler
      guidewires. Mean aortic ([P(ao)] mm Hg) and distal coronary artery occlusive
      pressure ([P(occl)] mm Hg) during balloon angioplasty (PTCA), or distal coronary
      flow velocity time integral during ([V(occl)] cm) and after ([V(o-occl)] cm) PTCA
      were measured continuously. Pressure-derived CFI was calculated as follows:
      (P(occl) - 5)/(P(ao) - 5). Doppler-derived CFI: V(occl)/V(o-occl). Patients were
      subdivided into a group with well (CFI > or = 0.25) and poorly developed
      collaterals (CFI < 0.25). RESULTS: Average follow-up was 94 +/- 56 (15 to 202)
      weeks. There were 134 patients with CFI >or =0.25 (61 +/- 11 years) and 269 with
      CFI <0.25 (61 +/- 10 years). The overall cardiac ischemic event rate (MACE and
      stable angina pectoris) during follow-up was 23% in patients with CFI > or =0.25
      and 20% in patients with CFI <0.25 (p = NS). However, only 2.2% of patients with
      good collateral flow suffered a major cardiac ischemic event, compared with 9.0%
      among patients with poorly developed collaterals (p = 0.01). The incidence of
      stable angina pectoris was significantly higher in patients with well developed
      collaterals than in those with poorly developed collaterals (21% vs. 12%; p =
      0.01). CONCLUSIONS: In this relatively large population with chronic stable
      coronary artery disease undergoing quantitative collateral measurement, the
      beneficial impact of well developed collateral vessels on the occurrence of
      future major cardiac ischemic events is clearly demonstrated.

PMID- 12427405
TI  - Coronary collaterals, stenoses, and stents: is a new era of physiologic-guided
      percutaneous revascularization emerging?

PMID- 12427406
TI  - Percutaneous coronary intervention versus coronary bypass graft surgery for
      diabetic patients with unstable angina and risk factors for adverse outcomes with
      bypass: outcome of diabetic patients in the AWESOME randomized trial and
      registry.
AB  - OBJECTIVES: This study compared survival after percutaneous coronary intervention
      (PCI) with survival after coronary artery bypass graft surgery (CABG) among
      diabetics in the Veterans Affairs AWESOME (Angina With Extremely Serious
      Operative Mortality Evaluation) study randomized trial and registry of high-risk
      patients. BACKGROUND: Previous studies indicate that CABG may be superior to PCI
      for diabetics, but no comparisons have been made for diabetics at high risk for
      surgery. METHODS: Over five years (1995 to 2000), 2,431 patients with medically
      refractory myocardial ischemia and at least one of five risk factors (prior CABG,
      myocardial infarction within seven days, left ventricular ejection fraction
      <0.35, age >70 years, or an intra-aortic balloon being required to stabilize)
      were identified. A total of 781 were acceptable for CABG and PCI, and 454
      consented to be randomized. The 1,650 patients not acceptable for both CABG and
      PCI constitute the physician-directed registry, and the 327 who were acceptable
      but refused to be randomized constitute the patient-choice registry. Diabetes
      prevalence was 32% (144) among randomized patients, 27% (89) in the patient
      choice registry, and 32% (525) in the physician-directed registry. The CABG and
      PCI survival rates were compared using Kaplan-Meier curves and log-rank tests.
      RESULTS: The respective CABG and PCI 36-month survival rates for diabetic
      patients were 72% and 81% for randomized patients, 85% and 89% for patient-choice
      registry patients, and 73% and 71% for the physician-directed registry patients.
      None of the differences was statistically significant. CONCLUSIONS: We conclude
      that PCI is a relatively safe alternative to CABG for diabetic patients with
      medically refractory unstable angina who are at high risk for CABG.

PMID- 12427407
TI  - Frequency and correlates of coronary stent thrombosis in the modern era: analysis
      of a single center registry.
AB  - OBJECTIVES: The study examined the frequency, correlates, and outcome of patients
      with stent thrombosis within 30 days of stent placement. BACKGROUND: Patients in
      trials evaluating stents or dual antiplatelet therapy to prevent coronary stent
      thrombosis have generally had narrow inclusion criteria; the extent to which
      stent thrombosis rates in such trials represent current practice, particularly
      with the availability of newer stents, is unclear. METHODS: We performed a
      retrospective analysis of the Mayo Clinic Percutaneous Coronary Intervention
      database and identified all patients who received at least one coronary stent and
      dual antiplatelet therapy (aspirin and ticlopidine or clopidogrel for two to four
      weeks). RESULTS: Four thousand five hundred nine patients underwent successful
      coronary stent implantation and were treated with dual antiplatelet therapy
      between July 1, 1994, and April 30, 2000. Stent thrombosis occurred in 23
      patients (0.51%; 95% confidence interval 0.32%, 0.76%) within 30 days of stent
      placement. Multivariate analysis using bootstrap model selection to avoid over
      fitting the model indicated that only the number of stents placed was an
      independent correlate of stent thrombosis (odds ratio 1.80, p < 0.001). The
      frequency of death and frequency of nonfatal myocardial infarction (MI) among the
      23 patients with stent thrombosis were 48% and 39%, respectively. CONCLUSIONS:
      Stent thrombosis is even more rare in the current era than in earlier trials.
      Number of stents placed was an independent correlate of stent thrombosis. Most
      patients who suffer stent thrombosis either die or suffer MI.

PMID- 12427408
TI  - Relationship between residual atheroma burden and neointimal growth in patients
      undergoing stenting: analysis of the atherectomy before MULTI-LINK improves lumen
      gain and clinical outcomes trial intravascular ultrasound substudy.
AB  - OBJECTIVES: The objective of this study was to examine the relationship between
      quantitative volumetric and cross-sectional measures of residual atheroma burden
      and neointimal growth after coronary stenting. BACKGROUND: Previous intravascular
      ultrasound (IVUS) studies have demonstrated a correlation between residual
      atheroma burden and neointimal growth after coronary stenting. However,
      postmortem studies contradict this finding. METHODS: The study population
      included 34 patients who underwent IVUS six to eight months after stent
      placement, including 26 patients who underwent IVUS immediately after stent
      placement and at six to eight months follow-up. Using manual planimetry, the
      lumen cross-sectional area (LA), stent cross-sectional area (SA) and external
      elastic membrane cross-sectional area (EEM) were measured at 1-mm intervals after
      the procedure and at follow-up. Percent neointimal area (NA) and atheroma area
      (AA) were calculated as: percent neointimal area = ([SA - LA]/SA) x 100; percent
      AA = ([EEM - SA]/EEM) x 100 in the entire cross section and in individual
      quadrants. Postinterventional atheroma volume and neointimal volume at follow-up
      were calculated using Simpsons's rule. RESULTS: In pooled analyses using all
      cross sections and cross-sectional quadrants, there was a weak correlation
      between percent AA and NA (r = 0.11 and 0.12, respectively). Analysis in
      individual patients demonstrated no significant relationship between total or
      quadrant measurements of percent AA and NA (p = 0.47 and 0.4, respectively). No
      relationship between atheroma volume postintervention and neointimal volume at
      follow-up was observed (r = 0.1, p = 0.62). CONCLUSIONS: This study failed to
      demonstrate a clinically significant relationship between quantitative volumetric
      and cross-sectional measures of residual atheroma burden and subsequent
      neointimal growth.

PMID- 12427409
TI  - Multicentric inflammation in epicardial coronary arteries of patients dying of
      acute myocardial infarction.
AB  - OBJECTIVES: We sought to test the hypothesis of whether inflammatory cell
      infiltration in patients dying of an acute myocardial infarction (MI) is a
      multifocal event involving multiple coronary branches. BACKGROUND: Coronary
      instability is thought to reflect local disruption of a single vulnerable plaque.
      However, previous postmortem studies have not addressed the question of whether
      activation of inflammatory cells, particularly T lymphocytes, is limited to the
      culprit lesion only or rather diffuse in the coronary circulation. METHODS: We
      performed a systematic flow cytometric study in three groups of autopsied
      patients (group 1 = acute MI; group 2 = old MI; group 3 = no ischemic heart
      disease). Cell suspensions of enzymatically digested coronary arteries were
      stained for flow cytometry with CD3, CD68, alpha-smooth muscle actin, and human
      leukocyte antigen (HLA)-DR antibodies. RESULTS: The coronary plaques showed: 1) a
      higher proportion of inflammatory cells in groups 1 and 2 than in group 3; 2) a
      higher percentage of T lymphocytes in group 1 than in group 2 (11.67 +/- 0.70%
      vs. 5.67 +/- 0.74%, p = 0.001) and in group 2 than in group 3 (p = 0.008); and 3)
      diffuse cell activation in the whole coronary tree of group 1, but not of group 2
      subjects. CONCLUSIONS: Our study suggests that lymphocytes may play a key role in
      coronary instability by determining activation of various cellular types
      throughout the coronary circulation. Activated T lymphocytes and their products
      may well represent a new target in both the treatment and prevention of acute
      coronary syndromes.

PMID- 12427410
TI  - Outpatient adherence to beta-blocker therapy after acute myocardial infarction.
AB  - OBJECTIVES: This study was designed to determine adherence to outpatient beta
      blocker therapy following acute myocardial infarction (AMI). BACKGROUND: The
      importance of beta-blocker therapy after AMI is widely recognized. Outpatient
      adherence with this recommendation, however, is not well described. METHODS: Data
      on 846 patients surviving AMI were studied. Factors associated with filling a
      beta-blocker prescription within 30 days postdischarge and the proportion of
      patients who were or were not discharged on beta-blockers who filled
      prescriptions for them by 30, 180, and 365 days post-AMI discharge were assessed.
      RESULTS: Patients with a discharge order for beta-blocker therapy were more
      likely to fill a prescription in the first 30 days postdischarge (hazard ratio
      [HR] 15.82, 95% confidence interval [CI], 10.75 to 23.26). Patients older than
      age 75 years were less likely than those age <65 years to fill a prescription (HR
      0.63, 95% CI 0.42 to 0.93). Gender, race, and being an ideal candidate did not
      affect beta-blocker use. Among patients who were discharged on beta-blockers, 85%
      of survivors had filled a prescription by 30 days postdischarge, and 63% and 61%
      were current users at 180 and 365 days, respectively. In contrast, only 8% of
      those patients with no discharge order for beta-blockers had filled such a
      prescription by 30 days, and 13% and 12% of patients were current users at 180
      and 365 days, respectively. CONCLUSIONS: Patients not discharged on beta-blockers
      are unlikely to be started on them as outpatients. For patients who are
      discharged on beta-blockers after AMI, there is a significant decline in use
      after discharge. Quality improvement efforts need to be focused on improving
      discharge planning and to continue these efforts after discharge.

PMID- 12427411
TI  - Beneficial neurohormonal profile of spironolactone in severe congestive heart
      failure: results from the RALES neurohormonal substudy.
AB  - OBJECTIVES: We sought to evaluate the effects of spironolactone on neurohormonal
      factors in patients with severe congestive heart failure (CHF). BACKGROUND: In
      the Randomized ALdactone Evaluation Study (RALES), spironolactone, an aldosterone
      receptor antagonist, significantly reduced mortality in patients with severe CHF.
      However, the mechanism of action and neurohormonal impact of this therapy remain
      to be clarified. METHODS: The effects of spironolactone (25 mg/day; n = 54) or
      placebo (n = 53) on plasma concentrations of the N-terminal portion of atrial
      natriuretic factor (N-proANF), brain natriuretic peptide (BNP), endothelin-1 (ET
      1), norepinephrine (NE), angiotensin II (AII), and aldosterone were assessed in a
      subgroup of 107 patients (New York Heart Association functional class III to IV;
      mean ejection fraction 25%) at study entry and at three and six months. RESULTS:
      Compared with the placebo group, plasma levels of BNP (-23% at 3 and 6 months; p
      = 0.004 and p = 0.05, respectively) and N-proANF (-19% at 3 months, p = 0.03; 
      16% at 6 months, p = 0.11) were decreased after spironolactone treatment. Over
      time, spironolactone did not modify the plasma levels of NE and ET-1. Angiotensin
      II increased significantly in the spironolactone group at three and six months (p
      = 0.003 and p = 0.001, respectively). As expected, a significant increase in
      aldosterone levels was observed over time in the spironolactone group (p =
      0.001). CONCLUSIONS: Spironolactone administration in patients with CHF has
      opposite effects on circulating levels of natriuretic peptides (which decrease)
      and aldosterone and AII (which increase). The reduction in natriuretic peptides
      might be related to changes in left ventricular diastolic filling pressure and/or
      compliance, whereas the increase in AII and aldosterone probably reflects
      activated feedback mechanisms. Further studies are needed to link these changes
      to the beneficial effects on survival and to determine whether the addition of an
      AII antagonist could be useful in this setting.

PMID- 12427412
TI  - Selective low-level leg muscle training alleviates dyspnea in patients with heart
      failure.
AB  - OBJECTIVES: The purpose of this study was to demonstrate in patients with
      moderate to severe heart failure that exertional dyspnea can be alleviated by
      improving muscle function. BACKGROUND: Dyspnea is a frequent limiting symptom in
      patients with chronic heart failure (CHF). This sensation may originate from
      activation of receptors in the musculature rather than the lung. METHODS: To
      investigate whether dyspnea could be alleviated by selective changes in leg
      muscle function, we performed isolated lower-limb training in 17 patients with
      severe CHF. Eight patients learned guided imagery relaxation techniques and
      served as an active control group. Exercise training consisted of three months of
      low-level bicycle and treadmill exercise such that minute ventilation was <25
      l/min. Leg calisthenics were also performed. Maximal and submaximal exercise
      performance, respiratory and quadriceps muscle strength and endurance and quality
      of-life and dyspnea scales were measured before and after each intervention.
      Metabolic stress testing (VO(2)), pulmonary function tests and isokinetic
      strength testing were also performed. RESULTS: In the active control group, no
      changes in leg muscle function, pulmonary function, maximal and submaximal
      exercise performance or quality-of-life questionnaires were observed. In the
      training group, peak torque of leg flexors (pre: 39 +/- 15 ft-lb; post: 50 +/- 13
      ft-lb; p < 0.002) increased and the fatigue ratio decreased, indicating improved
      strength and endurance of the leg muscles. Maximal inspiratory and expiratory
      mouth pressures and maximum voluntary ventilation were unchanged. Peak VO(2) was
      increased (pre:12 +/- 2.2 ml/kg/min; post: 14 +/- 2.6 ml/kg/min) as well as the
      duration of exercise at 70% peak VO(2) increased (pre: 11.5 +/- 3.1 min; post:
      21.5 +/- 5.4 min; p < 0.003). Perceived dyspnea during the submaximal testing was
      decreased. Minnesota Living with Heart Failure Score, Guyatt Dyspnea Scale, and
      the Transitional Dyspnea Index were all improved with training (all p < 0.05).
      CONCLUSIONS: We concluded that improvement of limb muscle function alleviates
      dyspnea and improves exercise performance in patients with CHF.

PMID- 12427413
TI  - Comparative beneficial effects of simvastatin and pravastatin on cardiac
      allograft rejection and survival.
AB  - OBJECTIVES: We sought to evaluate the relative effects of low doses of
      pravastatin (20 mg/day) and simvastatin (10 mg/day) on indices of cardiac
      allograft rejection. We further examined the relative efficacy and safety of
      these two drugs on lipid-lowering in heart transplantation. BACKGROUND: The
      immunomodulatory effects of hydroxy methyl glutaryl-coenzyme A reductase
      inhibitors have been increasingly recognized. Previous studies have demonstrated
      an ameliorative influence of pravastatin on hemodynamically compromising
      rejection after heart transplantation. A recent observational trial suggested
      that simvastatin 20 mg/day was associated with trends to lower survival and more
      adverse effects than pravastatin 40 mg/day. METHODS: In a 12-month prospective,
      open-label study, 50 heart transplant recipients received either open-label
      pravastatin 20 mg daily (n = 24) or simvastatin 10 mg daily (n = 26) within four
      weeks of transplantation. Indices of allograft rejection including treated
      rejection, rejection with hemodynamic compromise, noncellular rejection, and mean
      one-year biopsy score were compared between the two cohorts, as well as with a
      statin-naive control population (n = 37). Lipid levels, safety, and post
      transplant outcomes were also assessed as secondary end points. RESULTS: We found
      no significant differences in any allograft rejection parameter between the two
      groups. However, total low-density lipoprotein (LDL), but not high-density
      lipoprotein cholesterol or triglycerides, were lower in the simvastatin arm (-23%
      vs. -11%, p = 0.02). No cases of rhabdomyolysis or myositis occurred in either
      group. Survival at one year was similar in both treatment groups (91% for
      patients on pravastatin and 92% for patients on simvastatin). Both groups had
      better survival compared with the statin-naive control group (80%, p = 0.04).
      CONCLUSIONS: Simvastatin (10 mg/day) and pravastatin (20 mg/day) are associated
      with similar beneficial effects on cardiac allograft rejection and one-year
      survival. At these doses, simvastatin decreases LDL cholesterol more so than
      pravastatin with no increase in adverse effects in heart transplantation.

PMID- 12427414
TI  - Cardiac resynchronization therapy tailored by echocardiographic evaluation of
      ventricular asynchrony.
AB  - OBJECTIVES: The value of interventricular and intraventricular echocardiographic
      asynchrony parameters in predicting reverse remodeling after cardiac
      resynchronization therapy (CRT) was investigated. BACKGROUND: Cardiac
      resynchronization therapy has been suggested as a promising strategy in patients
      with severe heart failure and left bundle branch block (LBBB), but the entity of
      benefit is variable and no criteria are yet available to predict which patients
      will gain. METHODS: Interventricular and intraventricular mechanical asynchrony
      was evaluated in 20 patients (8 men and 12 women, 63 +/- 10 years) with advanced
      heart failure caused by ischemic (n = 4) or nonischemic dilated cardiomyopathy (n
      = 16) and LBBB (QRS duration of at least 140 ms) using echocardiographic Doppler
      measurements. Left ventricular end-diastolic volume index (LVEDVI) and left
      ventricular end-systolic volume index (LVESVI) were calculated before and one
      month after CRT. Patients with a LVESVI reduction of at least 15% were considered
      as responders. RESULTS: Cardiac resynchronization therapy significantly improved
      ventricular volumes (LVEDVI from 150 +/- 53 ml/m(2) to 119 +/- 37 ml/m(2), p <
      0.001; LVESVI from 116 +/- 43 ml/m(2) to 85 +/- 29 ml/m(2), p < 0.0001). At
      baseline, the responders had a significantly longer septal-to-posterior wall
      motion delay (SPWMD), a left intraventricular asynchrony parameter; only QRS
      duration and SPWMD significantly correlated with a reduction in LVESVI (r = 
      0.54, p < 0.05 and r = -0.70, p < 0.001, respectively), but the accuracy of SPWMD
      in predicting reverse remodeling was greater than that of the QRS duration (85%
      vs. 65%). CONCLUSIONS: In patients with advanced heart failure and LBBB, baseline
      SPWMD is a strong predictor of the occurrence of reverse remodeling after CRT,
      thus suggesting its usefulness in identifying patients likely to benefit from
      biventricular pacing.

PMID- 12427415
TI  - Prognostic significance of the location of wall motion abnormalities during
      exercise echocardiography.
AB  - OBJECTIVES: Our aim was to determine whether location of wall motion
      abnormalities (WMAs) during exercise echocardiography provides independent
      prognostic value. BACKGROUND: The effect of the location of WMAs during stress
      echocardiography on prognostic outcome is unknown. METHODS: We studied 4,347
      patients (mean age, 61 +/- 12 years; 2,230 men) with known or suspected coronary
      artery disease by symptom-limited exercise echocardiography. An abnormal result
      was defined as resting or exercise-induced WMA. End points were cardiac death and
      nonfatal myocardial infarction (MI). RESULTS: There were 133 cardiac events (54
      cardiac deaths and 79 nonfatal MIs) during follow-up (median, three years). In a
      multiple-stepwise multivariate analysis model, clinical and exercise
      electrocardiography predictors of cardiac events were age, gender, hypertension,
      typical chest pain, previous MI, smoking, and resting ejection fraction. The
      percentage of ischemic segments at peak exercise provided additional information
      to the model (p = 0.0001). The presence of abnormalities in the left anterior
      descending (LAD) coronary artery distribution had an additional independent
      effect for the prediction of cardiac events (p = 0.001). Among patients with
      exercise echocardiographic abnormalities in a single vascular region, those with
      abnormalities in the left anterior descending coronary artery distribution had a
      higher event rate than patients with abnormalities elsewhere (3.2% vs. 2.1% at
      three years and 10.8% vs. 2.1% at five years; p = 0.009). CONCLUSIONS; Exercise
      WMAs in the distribution of the LAD coronary artery are associated with an
      increased risk of cardiac death and nonfatal MI. This risk is independent of the
      resting ejection fraction and the extent of WMAs during exercise.

PMID- 12427416
TI  - Compensatory changes in atrial volumes with normal aging: is atrial enlargement
      inevitable?
AB  - OBJECTIVES: The aim of this study was to evaluate left atrial volume and its
      changes with the phases (active and passive) of atrial filling, and to examine
      the effect of normal aging on these parameters and pulmonary vein (PV) flow
      patterns. BACKGROUND: Atrial volume change with normal aging has not been
      adequately described. Pulmonary vein flow patterns have not been volumetrically
      evaluated in normal aging. Combining atrial volumes and PV flow patterns obtained
      using transthoracic echocardiography could estimate shifts in left atrial
      mechanical function with normal aging. METHODS: A total of 92 healthy subjects,
      divided into two groups: Group Y (young <50 years) and Group O (old > or =50
      years), were prospectively studied. Maximal (Vol(max)) and minimal (Vol(min))
      left atrial volumes were measured using the biplane method of discs and by three
      dimensional echocardiographic reconstruction using the cubic spline interpolation
      algorithm. The passive filling, conduit, and active emptying volumes were also
      estimated. Traditional measures of atrial function, mitral peak A-wave velocity,
      velocity time integral (VTI), atrial emptying fraction, and atrial ejection force
      were measured. RESULTS: As age increased, Vol(max), Vol(min), and total atrial
      contribution to left ventricle (LV) stroke volume were not significantly altered.
      However, the passive emptying volume was significantly higher (14.2 +/- 6.4 ml
      vs. 11.6 +/- 5.7 ml; p = 0.03) whereas the active emptying volume was lower (8.6
      +/- 3.7 ml vs. 10.2 +/- 3.8 ml; p = 0.04) in Group Y versus Group O. Pulmonary
      vein flow demonstrated an increase in peak diastolic velocity (Group Y vs. Group
      O) with no corresponding change in diastolic VTI or systolic fraction.
      CONCLUSIONS: Normal aging does not increase maximum (end-systolic) atrial size.
      The atrium compensates for changes in LV diastolic properties by augmenting
      active atrial contraction. Pulmonary vein flow patterns, although diastolic
      dominant using peak velocity, demonstrated no volumetric change with aging.

PMID- 12427417
TI  - Left ventricular diastolic dysfunction as a predictor of the first diagnosed
      nonvalvular atrial fibrillation in 840 elderly men and women.
AB  - OBJECTIVES: The objective of this study was to determine whether diastolic
      dysfunction is associated with increased risk of nonvalvular atrial fibrillation
      (NVAF) in older adults with no history of atrial arrhythmia. BACKGROUND: Few data
      exist regarding the relationship between diastolic function and NVAF. METHODS:
      The clinical and echocardiographic characteristics of patients age > or =65 years
      who had an echocardiogram performed between 1990 and 1998 were reviewed.
      Exclusion criteria were history of atrial arrhythmia, stroke, valvular or
      congenital heart disease, or pacemaker implantation. Patients were followed up in
      their medical records to the last clinical visit or death for documentation of
      first AF. RESULTS: Of 840 patients (39% men; mean [+/- SD] age, 75 +/- 7 years),
      80 (9.5%) developed NVAF over a mean (+/- SD) follow-up of 4.1 +/- 2.7 years.
      Abnormal relaxation, pseudonormal, and restrictive left ventricular diastolic
      filling were associated with hazard ratios of 3.33 (95% confidence interval [CI],
      1.5 to 7.4; p = 0.003), 4.84 (95% CI, 2.05 to 11.4; p < 0.001), and 5.26 (95% CI,
      2.3 to 12.03; p < 0.001), respectively, when compared with normal diastolic
      function. After a number of adjustments, diastolic function profile remained
      incremental to history of congestive heart failure and previous myocardial
      infarction for prediction of NVAF. Age-adjusted Kaplan-Meier five-year risks of
      NVAF were 1%, 12%, 14%, and 21% for normal, abnormal relaxation, pseudonormal,
      and restrictive diastolic filling, respectively. CONCLUSIONS; The presence and
      severity of diastolic dysfunction are independently predictive of first
      documented NVAF in the elderly.

PMID- 12427418
TI  - Long-term follow-up of arrhythmias in patients with myotonic dystrophy treated by
      pacing: a multicenter diagnostic pacemaker study.
AB  - OBJECTIVES: We hypothesized that pacemaker (PM) implantation in patients with
      myotonic dystrophy (MD) with a prolonged HV interval, even asymptomatic, may
      protect them against sudden death related to atrioventricular (AV) block. We
      sought to prospectively document the true incidence of AV block episodes in this
      high-risk population and accurately trace, in the long term, by the PM, the
      occurrence of arrhythmias that may remain undetected during conventional follow
      up. BACKGROUND: Myotonic dystrophy is associated with a high risk of sudden
      death, commonly attributed to AV block or ventricular arrhythmias, but cardiac
      pacing is only recommended as a secondary prevention. METHODS: Patients with MD
      with an HV interval > or =70 ms, even in the absence of related symptoms,
      prospectively received a cardiac PM, including an algorithm capable of diagnosing
      episodes of bradycardia and tachyarrhythmias. RESULTS: The population consisted
      of 49 patients (45.5 +/- 8.9 years old) followed for 53.5 +/- 27.2 months.
      Paroxysmal arrhythmias were recorded in 41 patients (83.7%), consisting of
      complete AV block (n = 21), sino-atrial block (n = 4), or atrial (n = 25) or
      ventricular (n = 13) tachyarrhythmias. No patient died of AV block during follow
      up, but 10 deaths occurred, 4 of them sudden. An arrhythmic cause could be
      excluded by postmortem PM interrogation in two cases of typical sudden death.
      CONCLUSIONS: Arrhythmias are common in patients with MD with infrahisian
      conduction abnormalities. The prophylactic implantation of a pacing system when
      the HV interval is > or =70 ms seems appropriate. The PM protects the patient
      against the clinical consequences of paroxysmal profound bradycardia and
      facilitates the diagnosis and management of frequent paroxysmal tachyarrhythmias.

PMID- 12427419
TI  - Safety and efficacy of advanced atrial pacing therapies for atrial
      tachyarrhythmias in patients with a new implantable dual chamber cardioverter
      defibrillator.
AB  - OBJECTIVES: This study evaluated the safety and efficacy of atrial pacing
      therapies for the treatment and prevention of atrial tachycardia (AT) or atrial
      fibrillation (AF) in a new dual chamber implantable cardioverter defibrillator
      (ICD). BACKGROUND: Patients with an ICD may also experience AT or AF that is
      amenable to pace termination. METHODS: The efficacy of atrial antitachycardia
      pacing (ATP) therapies for atrial tachycardia or atrial fibrillation (AT/AF) was
      determined in 151 patients after implantation of a GEM III AT ICD (Medtronic
      Inc., Minneapolis, Minnesota). The percentage of episodes successfully terminated
      was adjusted for multiple episodes per patient. RESULTS: A total of 717 of 728
      (96%) episodes classified as AT or AF were judged to be appropriate detections.
      By device classification, atrial ATP terminated 187 of 383 (40% adjusted)
      episodes classified as AT compared with 65 of 240 episodes classified as AF (26%
      adjusted, p = 0.013). Atrial Ramp or Burst+ ATP terminated 184 of 378 episodes of
      AT (39% adjusted), whereas 50-Hz Burst pacing therapy terminated only 12 of 109
      episodes of AT (12% adjusted) and 65 of 240 episodes of AF (26% adjusted). If
      efficacy was defined as termination of AT/AF within 20 s of delivery of the
      pacing therapy, ATP therapies terminated 139 of 383 (32% adjusted) episodes of AT
      compared with 34 of 240 episodes of AF (15% adjusted, p = 0.003). Efficacy was
      dependent on AT cycle length. Frequent transitions between AT and AF predicted
      inefficacy of atrial ATP (p < 0.001). Ventricular proarrhythmia secondary to
      atrial ATP was not observed. CONCLUSIONS: Atrial ATP therapies terminate many
      episodes of AT without ventricular proarrhythmia. The addition of 50-Hz Burst
      pacing has minimal efficacy for AT/AF.

PMID- 12427420
TI  - Thrombolytic therapy of pulmonary embolism: a meta-analysis.
AB  - OBJECTIVES: We sought to assess the efficacy and safety of thrombolytic therapy
      in patients with an acute pulmonary embolism (PE). BACKGROUND: Thrombolytic
      therapy is approved for the treatment of acute PE; however, the safety and
      efficacy of this therapy remain debated. METHODS: A meta-analysis of randomized,
      controlled trials comparing thrombolytic agents with intravenous heparin in
      patients with acute PE was performed. Trials were identified through a combined
      search of the MEDLINE, EMBASE, and Current Contents databases. Three outcome
      measures were assessed: 1) mortality, 2) recurrence of PE, and 3) major
      hemorrhage. RESULTS: Nine trials including 461 patients were identified. Compared
      with intravenous heparin, thrombolytic therapy had no significant effect on
      mortality (relative risk [RR] 0.63, 95% confidence interval [CI] 0.32 to 1.23) or
      the recurrence of PE (RR 0.59, 95% CI 0.30 to 1.18), but was associated with an
      increased risk of major hemorrhage (RR 1.76, 95% CI 1.04 to 2.98). These results
      were homogeneous and largely unaffected by the formulation of thrombolytic agent,
      the clinical severity of PE, the extent of vascular obstruction determined
      radiologically, or the methodologic quality of the included trials. CONCLUSIONS:
      Compared with intravenous heparin, thrombolytic therapy does not appear to have
      therapeutic benefit in unselected patients with acute PE, but it is associated
      with an increased risk of major hemorrhage. Given the small number of patients
      included in the randomized trials thus far, the negative results in terms of the
      efficacy outcomes should be interpreted with caution. Definitive evidence of the
      utility of thrombolytic therapy in this setting requires a large, randomized,
      controlled trial.

PMID- 12427421
TI  - Cardiac manifestations of Anderson-Fabry disease in heterozygous females.
AB  - OBJECTIVES: We sought to define the prevalence of cardiac involvement in female
      patients with Anderson-Fabry disease (AFD). BACKGROUND: Anderson-Fabry disease is
      a rare inborn X-linked lysosomal storage disorder. Globotriaosylceramide (Gb(3)),
      the major substrate of the deficient alpha-galactosidase A enzyme, accumulates
      progressively in vulnerable cells, including the cardiovascular system. It has
      been believed that heterozygous females have less cardiac involvement than
      hemizygous males with AFD. METHODS: We performed two-dimensional
      echocardiographic examinations of female patients heterozygous for AFD. RESULTS:
      Since 1997, a total of 55 female patients (mean age, 39.6 years; range, 6.1 to
      70.8 years) with proven AFD have been investigated prospectively at our hospital.
      Of these, 13 (23.6%) had normal left ventricular (LV) geometry and LV mass (LVM).
      Seven patients (12.7%) had concentric remodeling, 29 patients (52.7%) concentric
      LV hypertrophy (LVH), and 6 patients (10.9%) eccentric LVH (2 with subaortic
      pressure gradients). There was a strong correlation between age and the severity
      of LVH (r(2) = 0.905; p < 0.0001), and all patients older than 45 years had LVH.
      With increasing LVM, there was a significant age-independent decrease in systolic
      and diastolic LV function. Mild thickening of the aortic valve leaflets was
      present in 25.5% of patients, with the same percentage demonstrating mild
      thickening of the mitral valve leaflets. Mild mitral valve prolapse was
      documented in 10.9% of patients. CONCLUSIONS: Cardiac involvement, with LVH and
      structural valve abnormalities, is very common and worsens with age in females
      who are heterozygous for AFD, and they should therefore be considered candidates
      for enzyme replacement therapy.

PMID- 12427422
TI  - Left ventricular dysfunction is a risk factor for sudden cardiac death in adults
      late after repair of tetralogy of Fallot.
AB  - OBJECTIVES: The purpose of this study was to determine if left ventricular (LV)
      systolic dysfunction was also a predictor of sudden cardiac death (SCD) in adults
      late after repair of tetralogy of Fallot (TOF). BACKGROUND: Previous studies
      looking at risk factors for SCD in adults with repair of TOF have focused on the
      right ventricle (RV). METHODS: A retrospective chart review of patients assessed
      at the Toronto Congenital Cardiac Centre for Adults was performed. Twelve adult
      patients with repaired TOF and SCD were identified (SCD group). A total of 125
      living adult patients with repaired TOF were randomly selected for comparison
      (control group). RESULTS: Patients with SCD were more likely to exhibit moderate
      or severe pulmonary regurgitation (92% vs. 51%, p = 0.02), have a history of
      sustained ventricular tachycardia (42% vs. 6%, p < 0.01), and have a QRS > or
      =180 ms (56% vs. 13%, p = 0.02). Moderate or severe LV systolic dysfunction was
      also significantly more common in patients with SCD than in the control group
      (42% vs. 9%, p < 0.01) with a positive predictive value of 29%. The combination
      of moderate or severe LV systolic dysfunction and QRS > or =180 ms had a positive
      and negative predictive value for SCD of 66% and 93%, respectively. CONCLUSIONS:
      Moderate or severe LV systolic dysfunction is significantly more common in adult
      patients with repaired TOF and SCD. The combination of QRS > or =180 ms and
      significant LV systolic dysfunction has high positive and negative predictive
      value for SCD. The implication of the role of prophylactic antiarrhythmic
      implantable cardiac defibrillator insertion in these patients needs further
      elucidating.

PMID- 12427423
TI  - Cardiac catheterization of patients supported by extracorporeal membrane
      oxygenation.
AB  - OBJECTIVES: The goal of this study was to describe the clinical outcomes of
      patients undergoing cardiac catheterization while supported with extracorporeal
      membrane oxygenation (ECMO). BACKGROUND: Extracorporeal membrane oxygenation is
      an important mechanical support for the failing circulation. There are diagnostic
      and therapeutic indications for cardiac catheterization in patients on ECMO, but
      no large series has been reported. METHODS: We performed a retrospective review
      of the indications and outcomes of patients catheterized on ECMO from a single,
      large pediatric tertiary care center. RESULTS: At our institution, 192 patients
      with cardiac disease have undergone a total of 216 courses of ECMO; 60
      catheterizations were performed on 54 patients (28%). Indications for
      catheterization included assessment of surgical repair (21 patients), left heart
      decompression (12 patients), myocarditis/cardiomyopathy assessment (10 patients),
      non-post-operative hemodynamic assessment (8 patients), planned catheter-based
      interventions (6 patients), and arrhythmia ablation (3 patients). An intervention
      was undertaken either during or after 50 of the catheterizations (83%); 29
      occurred at catheterization, 17 in the operating room (OR), and 4 both during
      catheterization and in the OR. Complications during catheterization were two
      myocardial perforations that were treated with pericardial drains (3%). Overall
      outcomes included successful decannulation of 39 patients, survival to hospital
      discharge of 26 (48%) patients, and longer-term survival of 23 (43%) patients
      (median follow-up, 35 months; range, 1 to 180 months). Fifteen patients were
      withdrawn from ECMO support due to severe neurologic impairment or lack of
      myocardial recovery. CONCLUSIONS: Cardiac catheterization can be performed safely
      on patients supported with ECMO. Catheterization during ECMO enables the
      diagnosis of residual lesions and can facilitate important therapeutic
      interventions.

PMID- 12427424
TI  - Influence of propranolol, enalaprilat, verapamil, and caffeine on adenosine A(2A)
      receptor-mediated coronary vasodilation.
AB  - OBJECTIVES: The study was done to determine the effects of propranolol,
      enalaprilat, verapamil, and caffeine on the vasodilatory properties of the
      adenosine A(2A)-receptor agonist ATL-146e (ATL). BACKGROUND: ATL is a new
      adenosine A(2A)-receptor agonist proposed as a vasodilator for myocardial stress
      perfusion imaging. Beta-blockers, angiotensin-converting enzyme (ACE) inhibitors,
      and calcium blockers are commonly used for the treatment of coronary artery
      disease (CAD), and their effect on ATL-mediated vasodilation is unknown. Dietary
      intake of caffeine is also common. METHODS: In 19 anesthetized, open-chest dogs,
      hemodynamic responses to bolus injections of ATL (1.0 microg/kg) and adenosine
      (60 microg/kg) were recorded before and after administration of propranolol (1.0
      mg/kg, ATL only), enalaprilat (0.3 mg/kg, ATL only), caffeine (5.0 mg/kg, ATL
      only), and verapamil (0.2 mg/kg bolus, ATL and adenosine). RESULTS: Neither
      propranolol nor enalaprilat attenuated the ATL-mediated vasodilation (225 +/- 86%
      and 237 +/- 67% increase, respectively, p = NS vs. control). Caffeine had an
      inhibitory effect (97 +/- 28% increase, p < 0.05 vs. control). Verapamil blunted
      both ATL- and adenosine-induced vasodilation (63 +/- 20% and 35 +/- 7%,
      respectively, p < 0.05 vs. baseline), and also inhibited the vasodilation induced
      by the adenosine triphosphate-sensitive potassium (K(ATP)) channel activator
      pinacidil. CONCLUSIONS: Beta-blockers and ACE inhibitors do not reduce the
      maximal coronary flow response to adenosine A(2A)-agonists, whereas verapamil
      attenuated this vasodilation through inhibition of K(ATP) channels. The
      inhibitory effect of verapamil and K(ATP) channel inhibitors like glybenclamide
      on pharmacologic stress using adenosine or adenosine A(2A)-receptor agonists
      should be evaluated in the clinical setting to determine their potential for
      reducing the sensitivity of CAD detection with perfusion imaging.

PMID- 12427425
TI  - Impact of hydroxymethylglutaryl coenzyme a reductase inhibition on left
      ventricular remodeling after myocardial infarction: an experimental serial
      cardiac magnetic resonance imaging study.
AB  - OBJECTIVES: We sought to assess the influence of long-term hydroxymethylglutaryl
      coenzyme A reductase inhibition (statin) therapy on left ventricular (LV)
      remodeling after myocardial infarction (MI) by use of serial cardiac magnetic
      resonance imaging (CMRI) studies. BACKGROUND: Statin therapy has been shown to
      reduce cardiac hypertrophy in vitro and in vivo, but the influence on LV post-MI
      remodeling is largely unknown. METHODS: The CMRI measurements were taken four and
      12 weeks after left coronary artery ligation in a 7.05-tesla Biospec. The MI
      size, LV mass and volumes, cardiac output (CO), and ejection fraction were
      determined. Rats were treated for 12 weeks with either placebo (P), cerivastatin
      (C; 0.6 mg/kg body weight per day) as a dietary supplement, or cerivastatin plus
      the nitric oxide synthase (NOS) inhibitor N-methyl-L-arginine methyl ester (L
      NAME, 76 mg/100 ml) and hydralazine (8 mg/100 ml) in drinking water (CLH) to
      assess the contribution of endogenous nitric oxide formation. RESULTS:
      Administration of cerivastatin attenuated hypertrophy after MI, and this effect
      was completely abolished by NOS inhibition (increase of LV mass from 4 to 12
      weeks after MI: 235.3 +/- 33.7 mg with P vs. 59.8 +/- 20.5 mg with C vs. 239.5 +/
      16.0 mg with CLH; p < 0.05 vs. P and CLH). Left ventricular dilation was not
      changed (increase of end-diastolic volume from 4 to 12 weeks after MI: 108.7 +/-
      28.8 with P vs. 126.6 +/- 20.5 with C vs. 173.7 +/- 25.1 with CLH; p = NS). The
      CO was higher in the cerivastatin group (12 weeks: 76.1 +/- 2.9 ml/min with P vs.
      95.8 +/- 4.8 ml/min with C; p < 0.05). The effects of cerivastatin were abolished
      by NOS inhibition in the CLH group (CO at 12 weeks: 69.3 +/- 2.8 ml/min, p < 0.05
      vs. C). CONCLUSIONS: Left ventricular remodeling was profoundly changed by statin
      treatment. Hypertrophy was attenuated, and global function was improved. These
      positive effects were abolished by NOS inhibition.

PMID- 12427426
TI  - International cardiology.

PMID- 12427427
TI  - ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and
      Antiarrhythmia Devices--summary article: a report of the American College of
      Cardiology/American Heart Association Task Force on Practice Guidelines
      (ACC/AHA/NASPE Committee to Update the 1998 Pacemaker Guidelines).

PMID- 12427429
TI  - Echo-planar and gradient-echo diffusion MRI of normal brain iron in the globus
      pallidus.
AB  - The purpose of this study was to investigate effects of normal brain iron on
      proton diffusion and its quantification by diffusion MRI. The studies were
      undertaken in 24 cases ages ranging from 15 to 74 years (mean=45 years) with
      normal iron deposition in the globus pallidus to characterize the appearances on
      diffusion imaging with differing b values and on apparent diffusion coefficient
      (ADC) maps. Diffusion MRI was obtained by the spin-echo echo-planar imaging
      sequence (n=20 patients) or by the gradient-echo diffusion sequence, PSIF (n=4).
      In the PSIF sequence, pixel lens calculations were performed. In the echo-planar
      sequence, ADC value calculations were performed by using Stejskal-Tanner formula
      and by direct reading from automatically generated ADC maps. ADC values obtained
      from the normal appearing parenchyma were used as controls. Twenty patients with
      acute cerebral infarction were included for comparison of ADC values with those
      of iron deposition. The mean ADC value in the normal cerebral parenchyma was
      0.85+/-0.11 x 10(-3) mm(2)/s. In the globus pallidus, mean ADC value was 48+/
      0.12 x 10(-3) mm(2)/s. That of regions with acute infarction was 0.34+/-0.11 x
      10(-3) mm(2)/s. On b=0 or 50, b=500 and b=1000 s/mm(2) images of the echo-planar
      diffusion imaging globus pallidus appeared hypointense compared to surrounding
      parenchymal structures. Low signal and low pixel values were evident on the PSIF
      imaging. This study indicates that, on diffusion MRI, normal iron deposition
      reveals prominent low signal on all the images of the echo-planar diffusion
      imaging sequence with differing b values, as well as on the gradient-echo
      diffusion, PSIF sequence. Low signal on ADC maps and low ADC values are evident.
      These represent characteristic diffusion MRI features of normal iron deposition
      in the brain, reflecting susceptibility effects.

PMID- 12427428
TI  - Susceptibility-induced changes in signal intensity from spin-echo versus gradient
      echo sequences.
AB  - This manuscript describes a study of the evaluation of T2 and T2* changes in a
      hypervascular tumor model (hemodialyzer phantom) under conditions simulating
      dynamic perfusion study. The measured 1/T2* was strongly dependent on the
      compartmentalization of contrast material within the model, whereas the observed
      1/T2 was not. Gradient-echo magnetic resonance (MR) imaging may be more suitable
      than a spin-echo MR imaging for the evaluation of tumor vascularity.

PMID- 12427430
TI  - MR imaging determination of the normal level of conus medullaris.
AB  - The location of conus medullaris according to age and sex was retrospectively
      evaluated with a 0.5-T magnetic resonance (MR) imaging system. A total of 639
      subjects without any conspicuous spinal canal pathology on the lumbar MR imaging
      examination were selected. The level of conus medullaris was most commonly
      located at the T(12)-L(1) intervertebral disc level in the whole population. Our
      results do not correlate with the previous studies. No significant difference in
      the conus level was found with increasing age.

PMID- 12427431
TI  - Similar TIAs and corresponding alterations in regional cerebral perfusion in
      Caucasian monozygotic twins with moyamoya disease.
AB  - We previously reported the first Caucasian monozygotic twins with moyamoya
      disease (MMD). In both patients, hyperventilation induced similar transient onset
      of left arm and hand paresthesias. Cerebral single photon emission computerized
      tomography (SPECT) showed overlapping perfusion abnormalities in the left
      parietal areas. Similarly, EEG showed high amplitude, bilateral, anterior, slow
      wave activity in the delta range during hyperventilation and rebuild-up
      phenomenon in both twins. Similar clinical symptoms mirrored alterations in
      regional cerebral perfusion by SPECT and EEG in our Caucasian monozygotic twins
      with MMD.

PMID- 12427432
TI  - Epidural hematoma as a complication of sphenoid sinusitis and epidural abscess: a
      case report and literature review.
AB  - Imaging is of paramount importance in early diagnosis of epidural abscess and its
      intracranial complications. Typical CT imaging features of an epidural abscess
      include a hypodense lentiform extra-axial collection with rim enhancement. We
      present a case of epidural abscess that was hyperdense on CT scan due to the
      presence of associated epidural hematoma. The literature is reviewed regarding
      this unusual complication of epidural abscess.

PMID- 12427433
TI  - Aneurysmal bone cyst of the orbit: a case of rare location and review of the
      literature.
AB  - Aneurysmal bone cysts (ABCs) are benign fibrosseous lesions, very rarely
      occurring in the orbit. Seventeen cases of ABCs involving the orbit were reported
      in the literature. MRI pictures of a 7-year-old female patient with ABC involving
      the orbit are presented here. The clinical findings were left-sided painless
      proptosis, diplopia, papilledema and partial loss of the vision. MRI study showed
      a well-circumscribed mutliloculated expansile lesion of the orbital roof. We
      additionally make a review of the literature for these rare lesions.

PMID- 12427434
TI  - CT and MR findings of bilateral lacrimal gland enlargement in Sjogren syndrome.
AB  - Two women with primary Sjogren syndrome underwent computed tomography (CT) and
      magnetic resonance (MR) imaging because of bilateral lacrimal gland enlargement.
      Histopathologic confirmation was obtained in both patients. Of the four lacrimal
      glands, one had lymphoepithelial disease, two had pseudolymphoma and one had
      mucosa-associated lymphoid tissue (MALT) lymphoma, respectively. From the imaging
      findings, however, it was not possible to differentiate benign
      lymphoproliferative disorders and malignant lymphoma.

PMID- 12427435
TI  - Lumpy silicone-injected breasts: enhanced MRI and microscopic correlation.
AB  - Clinical images emphasizing on magnetic resonance imaging (MRI) characteristics
      of silicone-injected breasts with microscopic correlation were presented. A total
      of 16 patients with a history of silicone injection breast augmentation received
      MRI examinations due to palpable masses were reviewed. MRI enables the
      demonstration of the characteristic MR intensities in silicone-injected breasts.
      Four breast cancers were accurately detected by the enhancement technique
      including the cancers admixing within the fibrosis and silicone granuloma. This
      article can document the excellent ability of MRI with high microscopic
      correlation in examining these clinical, mammographic and ultrasonographic
      difficult cases. Understanding the MRI features is helpful to approach these
      patients. On the other hand, these illustrations indicated the importance of
      enhancement technique in detecting the cancers and in differentiating the
      angiogenic lesions from nonenhanced silicone granulomas.

PMID- 12427436
TI  - Is unenhanced CT sufficient for evaluation of acute abdominal pain?
AB  - BACKGROUND: To determine whether intravenous contrast improves the ability of
      radiologists to establish the cause of acute abdominal pain after nondiagnostic
      or normal unenhanced CT. METHODS: Out of 164 consecutive emergency department
      patients presenting with less than 48 h of nontraumatic, acute abdominal pain, a
      confident diagnosis for cause of pain was made prospectively in 71/164 (43%)
      patients on these unenhanced scans by the monitoring radiologist. In the other 93
      patients, our study sample, intravenous contrast-enhanced CT was obtained. At a
      later date, retrospectively, two experienced abdominal CT radiologists
      independently evaluated unenhanced CT scans alone for potential causes of pain
      and diagnostic confidence level on a 1-3 scale. At least 2 weeks later,
      intravenous enhanced and unenhanced scans were read side-by-side for the same
      assessment. RESULTS: There was no significant difference in diagnostic confidence
      levels comparing unenhanced CT alone (2.59) vs. intravenous enhanced and
      unenhanced CT together (2.64). Chi-square analysis found no significant
      difference in finding a cause for pain when intravenous contrast was added
      compared to the initial unenhanced scan alone. CONCLUSIONS: Intravenous contrast
      did not significantly improve the ability of CT to establish a cause of abdominal
      pain after a negative or nondiagnostic unenhanced CT.

PMID- 12427437
TI  - Intravenous glucagon: does it optimize evaluation of the gastrointestinal tract
      on helical CT?
AB  - Forty outpatients were randomized into two groups of 20. Twenty patients received
      1 mg of intravenous glucagon and the other 20 did not. Three radiologists
      evaluated the bowel using a qualitative score and mean scores for each bowel
      level were compared. A different radiologist measured the maximal diameter of
      bowel at seven levels. There were no significant differences in qualitative or
      quantitative data for the two groups. Intravenous glucagon is therefore not
      routinely recommended for helical CT of the abdomen.

PMID- 12427438
TI  - Hepatic abscess caused by Brucella US, CT and MRI findings: case report and
      review of the literature.
AB  - The authors describe the findings detected by ultrasonography (US), computed
      tomography (CT) and magnetic resonance imaging (MRI) in a 42-year-old patient
      with a hepatic abscess due to brucellosis. This localization by Brucella (hepatic
      brucelloma) is quite rare and very often is asymptomatic. A review of the medical
      literature shows only 40 cases of an hepatic abscess due to brucellosis. The
      findings demonstrated by US, CT and MRI can offer important diagnostic elements,
      albeit not specific, which should, together with a positive serologic test,
      confirm the diagnosis.

PMID- 12427439
TI  - Hepatic angiomyolipoma: demonstration by out of phase MRI.
AB  - Hepatic angiomyolipoma is a rare liver pathology. In this case report, we
      describe MRI features of a hepatic angiomyolipoma with a high fat content, which
      was indeterminate on CT. In phase and out of phase T1-weighted spoiled gradient
      echo technique, T2-weighted fat suppressed fast spin echo technique and dynamic
      enhanced T1-weighted in phase gradient echo technique were used. Out of phase
      gradient echo sequence was the most sensitive technique identifying the fat
      content of the lesion in its mixed tissue composition.

PMID- 12427443
TI  - Linearization of the relationship between serum sodium, potassium concentration,
      their ratio and time since death in Chandigarh zone of north-west India.
AB  - A strong relationship was established between the ratio of postmortem serum
      sodium and potassium concentrations and time since death by Querido in wistar
      rats. Henceforth, the present study was carried out to substantiate this
      inclination in humans. Flame photometric estimation of sodium and potassium
      concentration in postmortem blood of 474 subjects revealed a highly significant
      relationship between logarithm serum sodium as well as potassium concentration,
      logarithm of their ratio and the logarithim of the time since death during the
      first 3-58 h of death. Nonetheless, postmortem interval can be predicted from
      alteration in postmortem serum sodium, potassium concentration and from their
      ratio with S.E. estimate of 3.2, 5.7 and 4.6 h, respectively but environmental
      temperature and cause of death modulate these changes significantly.

PMID- 12427444
TI  - Lethal child neglect.
AB  - The jurisdiction of the Hannover Institute of Legal Medicine recently experienced
      an unusually high incidence of lethal child neglect, with three cases in a 5
      month period in 1999. Case 1: A girl received an inappropriate and inadequate
      diet of tea and oatmeal. The child was never breastfed, nor did it ever receive
      any other formula. The parents report the infant to have been healthy until she
      suddenly began projectile vomiting at the age of 13 weeks. For the next 3 days
      the infant was not able to maintain an adequate intake. The mother reports
      finding the child dead in its bed on the morning of the fourth day. Attempts by
      medical personnel to revive the child were unsuccessful. Case 2: A mother began
      spoon-feeding the infant puree on the fourth day of life, which according to the
      manufacturer's specifications is suitable for children between 4 and 8 months of
      age. At the age of 5 weeks, the infant was reported to have vomited half the just
      previously ingested meal, after which she took a nap. Some time later the parents
      observed the infant to be quite pale, however, assumed this was a result of
      sleep. When the mother finally did pick her up, the child was lifeless, and the
      parents brought her to the hospital. Medical personnel could however, only
      declare the infant dead, documenting a rectal temperature of 30 degrees C. Case
      3: A 3.5-year-old girl died after her mother left the locked apartment and did
      not return for several weeks. The body of the child was found lying dressed on
      the floor in a state of advanced decay and mummification. Common findings in all
      three cases include lack of prenatal care, home birth without the help of a
      midwife, low socioeconomic status or maternal alcohol abuse, body weights below
      the 3rd percentile, extreme dehydration, fatty hepatic degeneration, thymic
      atrophy and signs of aspiration.

PMID- 12427445
TI  - Evaluation of a simplified method of the conduction system analysis in 110
      forensic cases.
AB  - A simplified method of the His bundle analysis is evaluated by the study of 110
      forensic cases. The atrioventricular node or its part were observed in 96 cases
      (87.3%), penetrating bundle in 92 cases (83.6%), branching and left bundles
      branch in 109 cases (99.1%) and right bundle branch in 73 cases (66.4%). The
      changes such as fibrosis and fatty infiltration show statistically significant
      differences (P<0.01) between progressive age groups confirming their degenerative
      and age-related nature. The study included as well nine cases of sudden
      unexpected death and two cases of sudden infant death syndrome (SIDS), for which
      the autopsy with histological examination and toxicological analysis resulted
      negative. For nine of these cases, pathological lesions were found which can even
      explain the fatal issue. Moreover, in the cases with known cause of death,
      potentially lethal changes were noticed. This simple, low cost technique could be
      proposed to forensic pathologists as easy to fit into the routine processing of
      autopsy material, allowing the detection of major abnormalities with minimal
      effort. The authors also consider the difficulties related to the interpretation
      of the pathological findings in the conduction system.

PMID- 12427446
TI  - Detection of the calcium antagonist nicardipine and its metabolites by gas
      chromatography-mass spectrometry.
AB  - An 89-year-old male patient, hospitalized with Parkinson's syndrome, suddenly
      died shortly after an intravenous drug injection. The conditions indicated that
      an overdose of nicardipine (1.3 mg/(mlkg)) may be given to the patient. At the
      autopsy, no pathological changes were noted. With a capillary gas chromatograph
      with mass spectrometer (GC-MS), nicardipine (4.97 microg/ml) and its pyridine
      metabolite (M-5, 5.0 microg/ml) were detected in the heart blood of the deceased.
      This result indicated that an overdose of intravenous nicardipine caused a sudden
      death of a patient in a poor condition.

PMID- 12427447
TI  - Position of superciliare in relation to the lateral iris: testing a suggested
      facial approximation guideline.
AB  - It has been suggested in the literature that superciliare is located directly
      above the most lateral point of the iris and that this association may be of use
      in facial approximation. However, the relationship between the lateral iris and
      superciliare has not been tested and its accuracy remains unknown. This study
      aims to determine the accuracy of this relationship using metric and non-metric
      analysis. The horizontal distance from superciliare to the lateral iris was
      measured, using photogrammetric methods, in Australians of European extraction
      (27 males, 48 females), central/south-east Asian extraction (20 males, 19
      females) and individuals from other population groups (7 males, 7 females).
      Results indicate that superciliare position is best approximated by the lateral
      iris in females. On average, superciliare fell lateral to the lateral iris by 4.8
      mm, S.D. 3.4 mm in males, and 1.2 mm, S.D. 5.4mm in females. In approximately 70
      80% of the sample, the superciliare fell between the exocanthion and the pupil
      center on both sides. It is suggested that the proposed guideline that the
      lateral iris is equal to superciliare is not very accurate, especially for males.
      Also the large standard deviations indicate that the position of superciliare is
      highly variable. The above measures should, on average, give a more accurate
      prediction of superciliare in contrast to the lateral iris border, and therefore,
      they should be used in facial approximation. However, the large variation in
      superciliare position should be acknowledged.

PMID- 12427448
TI  - Quantitative analysis of tropane alkaloids in biological materials by gas
      chromatography-mass spectrometry.
AB  - A simple and rapid method for quantitation of tropane alkaloids in biological
      materials has been developed using an Extrelut column with gas chromatography
      mass spectrometry (GC-MS). Biological materials (serum and urine) were mixed with
      a borate buffer and then applied to an Extrelut column. The adsorbed tropane
      alkaloids were eluted with dichloromethane before a GC-MS analysis. Atropine-d(3)
      was used as an internal standard. The extracted tropane alkaloids were converted
      to trimethylsilyl derivatives prior to GC analysis, to improve the instability of
      tropane alkaloids from heating and the property of them for a GC column. The
      recoveries of the compounds, which had been spiked to biological materials, were
      more than 80%. The GC separation of the derivatives from endogenous impurities
      was generally satisfactory with the use of a semi-polar capillary column. Tropane
      alkaloids showed excellent linearity in the range of 10-5000 ng/ml and the limit
      of detection was 5.0 ng/ml for biological materials. The present method is simple
      and more rapid than those previously reported, and was applied to a poisoning
      case. It is useful for the routine analysis of tropane alkaloids in cases of
      suspected tropane alkaloids poisoning.

PMID- 12427449
TI  - Suicide by sodium tetraoxoselenate(VI) poisoning.
AB  - Selenium is one of the most toxic elements necessary for the life of mammals.
      Only a narrow range separates therapeutic (connected with a protective effect)
      and toxic doses. Selenium incorporated into animal or human tissues in larger
      amounts can exceed normal human levels and may be toxic (only elemental selenium
      and selenium sulphide are poorly absorbed). Acute poisonings with selenium or its
      compounds, especially fatal ones, occur extremely rarely in humans. Levels of
      selenium in four fatal cases are reviewed, and the levels in a fatal poisoning
      with sodium tetraoxoselenate(VI) are evaluated. Postmortem tissue selenium
      contents in the latter case were the following: brain, 1.45 and 1.60 microg/g;
      stomach, 6.12 and 6.37 microg/g; small intestine, 4.37 and 4.13 microg/g; large
      intestine, 4.53 and 4.43 microg/g; liver, 4.20 and 4.35 microg/g; kidney, 3.35
      and 3.60 microg/g; lung, 1.80 and 1.60 microg/g; blood, 1.43 and 1.41 microg/ml
      measured by the use of ETA-AAS and fluorimetric methods, respectively.

PMID- 12427450
TI  - Fatal versus non-fatal heroin "overdose": blood morphine concentrations with
      fatal outcome in comparison to those of intoxicated drivers.
AB  - The study was performed to distinguish fatal from non-fatal blood concentrations
      of morphine. For this purpose, blood levels of free morphine and total morphine
      (free morphine plus morphine conjugates) in 207 cases of heroin-related deaths
      were compared to those in 27 drivers surviving opiate intoxication. The majority
      of both survivors and non-survivors were found to show a concomitant use of
      depressants including alcohol or stimulants. Blood morphine levels in both groups
      varied widely, with a large area of overlap between survivors (free morphine: 0
      128 ng/ml, total morphine: 10-2,110 ng/ml) and non-survivors (free morphine: 0
      2,800 ng/ml, total morphine: 33-5,000 ng/ml). Five (18.5%) survivors and 87
      (42.0%) non-survivors exhibit intoxication only by morphine. In these cases, too,
      both groups overlapped (survivors-free morphine: 28-93 ng/ml, total morphine: 230
      1,451 ng/ml; non-survivors-free morphine: 0-2,800 ng/ml, total morphine: 119
      4,660 ng/ml). Although the blood levels of free or total morphine do not allow a
      reliable prediction of survival versus non-survival, the ratio of free/total
      morphine may be a criterion to distinguish lethal versus survived intoxication.
      The mean of the ratio of free to total morphine for all lethal cases (N=207) was
      0.293, for those that survived (N=27) 0.135, in cases of intoxication only by
      morphine 0.250 (N=87) and 0.080 (N=5), respectively. Applying a cut-off of 0.12
      for free/total morphine and performing ROC analyses, fatal outcome can be
      predicted in 80% of the cases correctly, whereas 16% of the survivors were
      classified as dead. Nevertheless, in this study, all cases with a blood
      concentration of 200 ng/ml and more of free morphine displayed a fatal outcome.

PMID- 12427451
TI  - Population genetics of 10 STR loci in a population of Central Poland.
AB  - Allele frequencies for the 10 short tandem repeats (STRs) included in AmpFlSTR
      SGM Plus amplification kit (D3S1358, vWA, D16S539, D2S1338, D8S1179, D21S11,
      D18S51, D19S433, TH01, FGA) were estimated from a sample of 500 unrelated
      individuals born in Central Poland.

PMID- 12427452
TI  - Genetic polymorphism at 15 STR loci among three important subpopulation of Bihar,
      India.
AB  - Genotype polymorphism studies at 15 highly polymorphic short tandem repeat (STR)
      loci were carried out in three genetically important minor caste groups (Yadav,
      Kurmi and Baniya) of Bihar, a eastern state of India to evaluate their
      significance in human identification and population genetics study. The selected
      communities practice endogamy. Despite of same geographical area, the physical
      features of Yadavs and Baniyas resemble North Indian Indo-Caucasoids whereas
      Kurmis resemble more to Indo-Austroloids. Among the chosen 15 loci, two are penta
      nucleotide repeat: Penta-D and Penta-E, and 13 are tetra-nucleotide repeat: vWA
      D8S1179, TPOX, FGA, D5S818, D13S317, D7S820, D16S539, D3S1358, THO1, CSF1PO,
      D21S11, D18S51 and are validated for other population of India and world for
      forensic testing and human population study. Thirteen of these STR loci are
      present in the combined DNA index system (CODIS) [J. Forensic Sci. 44 (1999)
      1277] and world-wide data is available.

PMID- 12427453
TI  - High levels of mitochondrial DNA heteroplasmy in human hairs by Budowle et al.

PMID- 12427455
TI  - Taking the rough with the smooth: foraging for particulate food in continuous
      time.
AB  - This paper describes the development of the general dynamical model of foraging
      developed by Ollason (1980, Theoret. Popul. Biol. 18, 44-65) to predict foraging
      for particulate food in three different types of environment. In an environment
      containing particles of different types of food, the model predicts the selection
      of an approximately optimal diet; in an environment in which the particles occur
      in patches, the model predicts a time budget of patch occupancy that approximates
      to the optimal time budget; and in an environment containing patches of particles
      that regenerate by the addition of particles of food at constant rates, the model
      predicts that animals will dispose themselves among the patches approximately as
      predicted by the ideal free distribution. Where the predictions of the model
      depart from the predictions of optimal foraging theory, they are qualitatively
      similar to the observed departures of the behaviour of real animals from the
      predictions of optimal foraging theory. The model provides a general
      representation of the foraging decisions of animals whether they feed strictly
      continuously or discontinuously on particles of food, and does so without
      explicit reference to optimization processes.

PMID- 12427456
TI  - Metapopulations, community assembly, and scale invariance in aspect space.
AB  - The hierarchical competition model has been a useful tool in investigating the
      mechanisms of coexistence between competing species, and thus for understanding
      the foundations of biodiversity. Here we show that the geometric picture of
      community assemblage found by Nowak and May for the constant-fecundity version of
      this model can be extended to a whole family of tradeoffs between fecundity and
      mortality. In this picture, the proportion of the remaining space used by a
      species can be related to the amount of free space (in aspect space) behind the
      "competitive shadow" of the adjacent superior competitor, and in turn to the size
      of the competitive shadow cast by the species itself. We show that this geometric
      model is scale invariant in the rescaled aspect space and use this fact to
      investigate the limits to diversity and explore how communities assemble under
      this model.

PMID- 12427457
TI  - A vectorized method of importance sampling with applications to models of
      mutation and migration.
AB  - An importance-sampling method is presented for computing the likelihood of the
      configuration of population genetic data under general assumptions about
      population history and transitions among states. The configuration of the data is
      the number of chromosomes sampled that are in each of a finite set of states.
      Transitions among states are governed by a Markov chain with transition
      probabilities dependent on one or more parameters. The method assumes that the
      joint distribution of coalescence times of the underlying gene genealogy is
      independent of the genetic state of each lineage. Given a set of coalescence
      times, the probability that a pair of lineages is chosen to coalesce in each
      replicate is proportional to the contribution that the coalescence event makes to
      the probability of the data. This method can be applied to gene genealogies
      generated by the neutral coalescent process and to genealogies generated by other
      processes, such as a linear birth-death process which provides a good
      approximation to the dynamics of low-frequency alleles. Two applications are
      described. In the first, the fit of allele frequencies at two microsatellite loci
      sampled in a Sardinian population to the one-step mutation model is tested. The
      one-step model is rejected for one locus but not for the other. The second
      application is to low-frequency alleles in a geographically subdivided
      population. The geographic location is the allelic state, and the alleles are
      assumed to be sufficiently rare that their dynamics can be approximated by a
      linear birth-death process in which the birth and death rates are independent of
      geographic location. The analysis of eight low-frequency allozyme alleles found
      in the glaucous-winged gull, Larus glaucescens, illustrates how geographically
      restricted dispersal can be detected.

PMID- 12427458
TI  - The effects of genetic drift in experimental evolution.
AB  - Experimental evolution is characterized by exponential or logistic growth and
      periodic population bottlenecks. The fate of a rare beneficial mutation in these
      systems is influenced both by the bottleneck effect and by genetic drift. This
      paper explores the effects of incorporating genetic drift into models of fixation
      probability in populations with periodic bottlenecks. To model the inherent
      stochasticity during the growth phase in these populations, we assume a Poisson
      distribution of offspring. An analytical solution is developed to calculate the
      fixation probability and a computer simulation is used to verify the results. We
      find that the fixation rate of a favourable mutant is significantly lower when
      genetic drift is considered; fixation probability is reduced by over 25% for
      realistic experimental protocols. Our method is valid for both weak and strong
      selection; since very large selection coefficients have been reported in the
      experimental literature, this is an important improvement over previous results.

PMID- 12427459
TI  - On the minimum number of topologies explaining a sample of DNA sequences.
AB  - In this article I derive an alternative algorithm to Hudson and Kaplan's
      (Genetics 111, 147-165) algorithm that gives a lower bound to the number of
      recombination events in a sample's history. It is shown that the number, T(M),
      found by the algorithm is the least number of topologies required to explain a
      set of DNA sequences sampled under the infinite-site assumption. Let Tao =
      (T(1),...,T(r)) be a list of topologies compatible with the sequences, i.e., T(k)
      is compatible with an interval, I(k), of sites in the alignment. A
      characterization of all lists having T(M) topologies is given and it is shown
      that T(M) relates to specific patterns in the alignment, here called chain
      series. Further, a number of theorems relating general lists of topologies to the
      number T(M) is presented. The results are discussed in relation to the true
      minimum number of recombination events required to explain an alignment.

PMID- 12427460
TI  - Evolution of cannibalistic traits: scenarios derived from adaptive dynamics.
AB  - The evolution of cannibalistic traits in consumer populations is studied in this
      paper with the approach of adaptive dynamics theory. The model is kept at its
      minimum complexity by eliminating some environmental characteristics, like
      heterogeneity and seasonalities, and by hiding the size-structure of the
      population. Evolutionary dynamics are identified through numerical bifurcation
      analysis, applied both to the ecological (resident-mutant) model and to the
      canonical equation of adaptive dynamics. The result is a rich catalog of
      evolutionary scenarios involving evolutionary stable strategies and branching
      points both in the monomorphic and dimorphic dynamics. The possibility of
      evolutionary extinction of highly cannibalistic populations is also ascertained.
      This allows one to explain why cannibalism can be a transient stage of evolution.

PMID- 12427461
TI  - A novel cathepsin B active site motif is shared by helminth bloodfeeders.
AB  - This study compared specific protein sequence motifs present within cathepsin B
      like cysteine proteases from a number of helminth parasites. We have focused our
      efforts on cathepsin B-like proteases of Haemonchus contortus, Caenorhabditis
      elegans, Schistosoma mansoni, Schistosoma japonicum, Ostertagia ostertagi, and
      Ancylostoma caninum. The goal of this work is to correlate specific features, or
      proposed roles, of the cathepsin B-like proteases with primary sequence motifs
      discovered within the proteins. We report here a general motif for the
      identification of cathepsin B enzymes, and more significantly, a motif within
      this pattern that is found, with one exception, only in cathepsin B-like
      proteases of helminth bloodfeeders. We suggest that the "hemoglobinase" motif
      arose evolutionarily in a minimum of three independent events as a specialized
      response to increase the efficiency of hemoglobin degradation by these cathepsin
      B-like enzymes. This motif should be useful in identifying additional helminth
      hemoglobinases and may provide a specific target for drug design efforts.

PMID- 12427462
TI  - Plasmodium falciparum: in vitro activity of sulfadoxine and dapsone in field
      isolates from Kenya: point mutations in dihydropteroate synthase may not be the
      only determinants in sulfa resistance.
AB  - We have determined the relationship between point mutations in the gene that
      encodes the sulfa target, dihydropteroate synthase (DHPS) and the
      chemosensitivity profile to sulfadoxine and dapsone in 67 isolates from Kilifi,
      Kenya. We assessed the presence of mutations at codons 436, 437, 540, 581, and
      613 of dhps. The results showed that the dhps genotype had a strong influence on
      the sensitivity to sulfadoxine and dapsone, but that the correlation was far from
      perfect. Eleven isolates carried a wild-type dhps allele, but were resistant to
      sulfadoxine (IC(50) values >10 microg/ml), and 4/28 isolates were classed as
      sensitive to sulfadoxine (IC(50) values <10 microg/ml), but carried a triple
      mutant (436/437/613) allele of dhps. These data show that in low folate medium in
      vitro, the dhps genotype alone did not account completely for sulfadoxine or
      dapsone resistance; other factors such as the utilisation of exogenous folate
      must also be considered.

PMID- 12427463
TI  - Comparison of tissue culture and animal models for assessment of Cryptospridium
      parvum infection.
AB  - The current increased interest for using tissue culture as a surrogate for mouse
      infection to assess Cryptospridium viability suggests that a comparison of the
      two models is essential for data interpretation. Therefore, a need remains for a
      statistical comparison that can demonstrate if infection and inactivation
      predicted by new tissue culture models are comparable with those predicted by
      animal models. Data from a total of 31 dose-response trials using both tissue
      culture and mouse models to assess C. parvum infectivity were compared. The dose
      needed to infect 50% of the tissue cultures (ID(50)) was also compared to each
      ID(50) in mice. Average ID(50)s developed using the logit dose-response method
      for tissue culture and mice were 8 and 107, respectively, suggesting that tissue
      culture was more sensitive to infection. However, correlation (r) between tissue
      culture and mouse infectivity was statistically significant (0.9167 [95%
      CI=0.8428 to 0.9594, p<0.0001]). Comparison of oocyst disinfection by UV and
      chlorine dioxide showed no significant difference between inactivation predicted
      by tissue culture and mouse models (p=0.8893; t=0.0141; n=21). These results
      demonstrate that tissue culture can successfully be used to measure C. parvum
      infection and can be used for determining inactivation in disinfection studies.

PMID- 12427464
TI  - A Rho-like small GTPase of Entamoeba histolytica contains an unusual amino acid
      residue in a conserved GDP-stabilization region and is not a substrate for C3
      exoenzyme.
AB  - The Entamoeba histolytica small GTP-binding protein EhRho1 has an unusual amino
      acid residue at a conserved site found in all known Ras superfamily proteins.
      EhRho1 has an isoleucine at position 45, which corresponds to position 28 of
      human Ras and Rac and position 30 of human Rho and Cdc42. All other known small
      GTPases have an aromatic residue (typically phenylalanine) at this position, and
      mutation to a leucine renders other Ras proteins constitutively active by reason
      of diminished affinity for GDP. It was determined that the EhRho1 protein has a
      half-time of GDP dissociation similar to that of a human Rho protein, HsRhoA, and
      therefore an isoleucine at this site in EhRho1 is not likely to render EhRho1
      constitutively active. It was also found that EhRho1 is not a substrate for the
      Rho-specific C3 exoenzyme. Thus EhRho1 appears to be an unusual member of the Ras
      family.

PMID- 12427465
TI  - Plasmodium falciparum: analysis of transcribed var gene sequences in natural
      isolates from the Brazilian Amazon region.
AB  - Parasite isolates from Brazilian Western Amazonian patients suffering from
      uncomplicated falciparum malaria were matured in vitro and their var gene
      transcripts were analysed by RT-PCR and sequencing. Additionally, the
      cytoadherence patterns of these isolates were determined by panning techniques
      using transfected CHO cell lines expressing different surface receptors. All of
      the isolates tested showed between 4 and 13 different var gene transcripts per
      isolate. Several of these transcripts were present in more than one isolate and
      three sequences appeared to be preferentially expressed in natural infections. In
      most of the isolates, cytoadherence occurred to the receptors ICAM-1 and CD36.
      Several isolates showed a multiadherent profile. Analysis of MSP1 and MSP2
      allelic polymorphism indicated polyclonal infections, that could be responsible
      for the multiadherent phenotype.

PMID- 12427466
TI  - Plasmodium chabaudi: rosetting in a rodent malaria model.
AB  - Rosetting is a property of many malaria parasite species that has been linked to
      virulence in the major species infecting humans, Plasmodium falciparum. Here, the
      basic properties of rosettes in the rodent malaria laboratory model, P. chabaudi,
      were studied with a view to future studies on the role of rosetting in malaria
      parasite virulence and transmission. Rosetting occurred in 14 out of the 15 P.
      chabaudi clones studied, varied consistently between clones, and ranged between 9
      and 37% at full parasite maturity. Rosetting frequency markedly declined after
      the mouse reached peak parasitemia, possibly due to host immunity. Consistent
      with P. falciparum and P. vivax, rosettes in P. chabaudi were disrupted by
      treatment with trypsin and EDTA. However, P. chabaudi rosettes were insensitive
      to sulfated glycoconjugates (heparin, heparan sulfate and fucoidan). The
      molecular basis of rosetting in P. chabaudi is unknown at present, but the
      results suggest that the molecules involved may differ from those in human
      infecting species.

PMID- 12427467
TI  - Trypanosoma cruzi: in vitro phosphorylation of tubulin by a protein kinase CK2
      like enzyme.
AB  - One predominant 55-kDa polypeptide was phosphorylated in vitro in Trypanosoma
      cruzi homogenates prepared from three differentiation stages: epimastigotes,
      trypomastigotes, and spheromastigotes. Anti-alpha and anti-beta tubulin
      monoclonal antibodies immunoprecipitated the phosphorylated 55-kDa polypeptide
      from epimastigote extracts. Phosphoserine was the only residue phosphorylated in
      vitro in the 55-kDa polypeptide and in immunoprecipitated alpha tubulin. The
      phosphorylation of both the 55-kDa polypeptide and exogenously added casein was
      inhibited with GTP, heparin, and 2,3-bisphosphoglycerate in a dose-dependent
      manner, indicating the involvement of a CK2-like protein kinase. Moreover, when
      tubulin was isolated from an epimastigote homogenate by ultracentrifugation,
      followed by DEAE-Sephacel chromatography, a protein kinase that phosphorylated
      tubulin and casein co-purified with this cytoskeletal component. This result
      suggests an association between tubulin and its corresponding protein kinase in
      T. cruzi.

PMID- 12427468
TI  - Identification of extrinsic blood coagulation pathway inhibitors from the tick
      Ornithodoros savignyi (Acari: Argasidae).
AB  - The salt BaSO(4) selectively adsorbs two proteins from crude Ornithodoros
      savignyi salivary gland extract. They co-purify during reversed-phase HPLC, but
      can be separated by hydrophobic-interaction chromatography. Their molecular
      masses are 9333 and 9173Da. The 9.3kDa protein was designated BSAP1 and the
      9.1kDa protein BSAP2. Their amino acid compositions show significant differences,
      in particular the presence of seven and eight cysteine residues in BSAP1 and
      BSAP2, respectively. The proteins do not contain gamma-carboxyglutamic acid,
      hydroxyproline, or hydroxylysine. The proteins do not inhibit the intrinsic
      coagulation cascade, but inhibit the extrinsic pathway. The observed inhibition
      is not due to inhibition of factor VII. Both proteins bind to membranes. BSAP1
      binds neutral and negatively charged membranes more strongly than BSAP2. Its
      affinity for negative membranes is, however, much lower than for neutral
      membranes. In contrast, BSAP2 binds both membranes equally strongly. The binding
      of the proteins to the membranes was significantly lowered upon pre-incubation
      with Ca(2+).

PMID- 12427469
TI  - Immune suppression of Galleria mellonella (Insecta, Lepidoptera) humoral defenses
      induced by Steinernema feltiae (Nematoda, Rhabditida): involvement of the
      parasite cuticle.
AB  - Immune depression of Galleria mellonella larvae was evaluated a short time after
      infection with the entomopathogenic nematode Steinernema feltiae. In the host the
      activity of the enzymatic cascade known as the proPO system was significantly
      reduced by the presence of either live or dead parasites. The presence of
      parasites decreased the LPS-elicited proPO system activity. In addition, this
      process seems to be related to a decrease in the activity of hemolymph proteases,
      more than to phenoloxidase damage. proPO inhibition was also achieved by injected
      isolated cuticle fragments, suggesting that the parasite body surface plays an
      important role in the early parasitation phase.

PMID- 12427470
TI  - Entamoeba histolytica: sequence conservation of the Gal/GalNAc lectin from
      clinical isolates.
AB  - The Gal/GalNAc lectin gene of Entamoeba histolytica is a major amebic virulence
      protein responsible for interaction with host tissues. We investigated sequence
      differences in the Gal/GalNAc lectin heavy subunit in three isolates from
      Bangladesh and one isolate from Georgia, each of which was determined to be
      genetically distinct by SREHP AluI digestion. Interestingly, we observed only
      slight genetic diversity in the lectin gene as compared with the HM1:IMSS
      laboratory strain, originally a clinical isolate from Mexico. Genetic
      conservation of the Gal/GalNAc lectin between isolates may reflect that the
      lectin is under strong functional selection or possibly, that E. histolytica is a
      clonal population. Sequence conservation of the lectin indicates that immune
      responses against it should be cross-protective.

PMID- 12427471
TI  - Schistosoma mansoni: identification of a possible daughter sporocyst alkaline
      phosphatase.

PMID- 12427473
TI  - Inhibitors of neuronal regeneration: mediators and signaling mechanisms.
AB  - Neuritogenesis and its inhibition are opposite and balancing processes during
      development as well as pathological states of adult neuron. In particular, the
      inability of adult central nervous system (CNS) neurons to regenerate upon injury
      has been attributed to both a lack of neuritogenic ability and the presence of
      neuronal growth inhibitors in the CNS environment. I review here recent progress
      in our understanding of neuritogenic inhibitors, with particular emphasis on
      those with a role in the inhibition of neuronal regeneration in the CNS, their
      signaling cascades and signal mediators. Neurotrophines acting through the
      tropomyosin-related kinase (Trk) family and p75 receptors promote neuritogenesis,
      which appears to require sustained activation of the mitogen activated protein
      (MAP) kinase pathway, and/or the activation of phosphotidylinositol 3-kinase (PI3
      kinase). During development, a plethora of guidance factors and their receptors
      navigate the growing axon. However, much remained to be learned about the
      signaling receptors and pathways that mediate the activity of inhibitors of CNS
      regeneration. There is growing evidence that neuronal guidance molecules,
      particularly semaphorins, may also have a role as inhibitors of CNS regeneration.
      Although direct links have not yet been established in many cases, signals from
      these agents may ultimately converge upon the modulators and effectors of the Rho
      family GTPases. Rho-family GTPases and their effectors modulate the activities of
      actin modifying molecules such as cofilin and profilin, resulting in cytoskeletal
      changes associated with growth cone extension or retraction.

PMID- 12427474
TI  - Decrease of PKC precedes other cellular signs of calpain activation in area CA1
      of the hippocampus after transient cerebral ischemia.
AB  - One of the specific features of severe brain injury is an activation of calcium
      dependent proteolysis by calpains. We have observed a significant increase of
      activity as early as 3 h after the insult in a well defined model of delayed
      ischemic neuronal death in gerbil hippocampus. At 24 h, the enzymatic activity
      transiently normalized, then increased again, following the place and time of
      selective cellular death in the CA1 region of hippocampus. The enhanced
      postischemic proteolysis resulted in concomitant cleavage of calpain-specific
      endogenous substrates like protein kinase C (PKC), fodrin and microtubule
      associated protein-2 (MAP2). These effects were also time-dependent and
      restricted to the vulnerable, CA1 pyramidal neurons-containing the dorsal part
      (DP) of the hippocampus. We have also characterized the postischemic changes of
      six different isoforms of PKC. The vulnerable dorsal part of the hippocampus, but
      not its relative resistant abdominal part (AbP), exhibited a loss of PKCalpha,
      beta, gamma, and delta isoforms as early as 3 h after ischemic insult. However,
      at this time, solely in the soluble fraction of homogenate. Later (72 h), a
      further loss of the enzyme proteins, comprised the particulate fraction as well
      and resulted in an about 50% decrease of total PKCs in the vulnerable DP region.
      In the case of PKCalpha, the immunostaining pattern showed, in addition to the
      disappearance of the enzyme from the injured area, an extensive translocation
      into nuclei of the survived, ischemia-resistant neurones. The early decreases of
      PKC isoforms in the cytosol paralleled the transient calpain activation at 3h
      postischemia but substantially preceded the proteolysis of any other classical
      calpain substrates, such as fodrin and MAP2, being evidenced not earlier than 48
      72 h after the insult and restricted also to the vulnerable dorsal part. In
      conclusion, our results of the time-dependent effects of transient global
      cerebral ischemia on the calpain activity, levels and localization of its several
      substrates suggest, that calpain-mediated proteolysis is specifically involved in
      the early (induction) as well as in the late (execution) phases of delayed
      ischemic neuronal death in the CA1 hippocampus.

PMID- 12427472
TI  - Comparative EST analyses provide insights into gene expression in two asexual
      developmental stages of Eimeria tenella.
AB  - The protozoan parasite Eimeria tenella has a complex life cycle that includes two
      major asexual developmental stages, the merozoite and the sporozoite. The
      expressed sequence tag (EST) approach has been previously used to study gene
      expression of merozoites. We report here the generation and analysis of 556 ESTs
      from sporozoites. Comparative analyses of the two datasets reveal a number of
      transcripts that are preferentially expressed in a specific stage, including
      previously uncharacterised sequences. The data presented indicate the invaluable
      potential of the comparative EST analysis for providing information on gene
      expression patterns in the different developmental stages of E. tenella.

PMID- 12427475
TI  - A chemiluminescent serotonin assay.
AB  - A chemiluminescent serotonin assay is described, which is based on a reaction
      given by some indolic compounds in alkaline dimethyl sulfoxide (DMS). When
      coupled to a rapid serotonin extraction procedure the assay may be used for
      measuring the serotonin content of different brain areas, and the release of this
      transmitter.

PMID- 12427476
TI  - PF 9601N [N-(2-propynyl)-2-(5-benzyloxy-indolyl) methylamine], a new MAO-B
      inhibitor, attenuates MPTP-induced depletion of striatal dopamine levels in
      C57/BL6 mice.
AB  - Monoamine oxidase isoform B (MAO-B) is involved in Parkinson's disease (PD)
      induced by the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxin (MPTP) in human
      and non-human-primate. MAO-B inhibitors, such as L-deprenyl have shown to prevent
      against MPTP-toxicity in different species, and it has been used in Parkinson
      therapy, however, the fact that it is metabolized to (-)-methamphetamine and (-)
      amphetamine highlights the need to find out new MAO-B inhibitors without a
      structural amphetaminic moiety. In this context we herein report, for the first
      time, anywhere a novel non-amphetamine-like MAO-B inhibitor, PF 9601N, N-(2
      propynyl)-2-(5-benzyloxy-indolyl) methylamine. This attenuates the MPTP-induced
      striatal dopamine depletion in young-adult and adult-old C57/BL mice, using
      different schedules of administration, and which behave "ex vivo" as a slightly
      more potent and selective MAO-B inhibitor than L-deprenyl, assayed for
      comparative purposes in the same experimental conditions. The MAO-B ID(50) values
      were calculated from the total MAO-B activity measured against [14C]
      phenylethylamine (22 microM) as substrate, at each inhibitor concentration. The
      MAO-B ID(50) values resulted to be 381 and 577 nmol/kg for PF 9601N and L
      deprenyl, respectively. The intraperitoneally (i.p.) co-administration to young
      adult C57/BL6 mice of MPTP (30 mg/kg), with different concentrations of PF 9601N
      or L-deprenyl (29.5-0.357 micromol/kg) showed a dose-dependent protective effect
      against striatal dopamine depletion, measuring the dopamine contents and its
      metabolites by HPLC. The ED(50) value proved to be 3.07 micromol/kg without any
      significant differences between either MAO-B inhibitor. Nevertheless, lower doses
      of PF 9601N (1.5 micromol/kg) were necessary to get almost total protection,
      without any change in the DOPAC and HVA content, when administered 2 h before
      MPTP (30 mg/kg), whereas partial protection (45%) against dopamine depletion was
      observed in the case of L-deprenyl. In both cases, MAO-B inhibition was a
      necessary condition in order to observe the protective effect. When adult-old (8
      10 months) C57/BL6 mice were used, MPTP (25 mg/kg) administration induced 25 days
      later, an irreversible dopamine depletion. In these conditions, chronic
      administration with 0.15 micromol/kg of PF 9601N, before the toxin, every 24 h
      for 10 days, rendered almost total protection of dopamine depletion, whereas L
      deprenyl yielded only 50% protection of the dopamine content, assayed in the same
      conditions. It is worth remarking, that in both cases MAO-B was not affected.
      From these results, it can be concluded that PF 9601N attenuates MPTP
      neurotoxicity "in vivo" better than L-deprenyl through different mechanisms, with
      special relevance to the protective effect, independent of MAO-B inhibition,
      observed in the irreversibly MPTP-lesioned adult-old mice. Therefore, this novel
      non-amphetamine MAO-B inhibitor could be potentially effective in PD therapy.

PMID- 12427477
TI  - Anterograde axonal transport of endopeptidase 24.15 in rat sciatic nerves.
AB  - Axonal transport of endopeptidase 24.15 (EP24.15), a putative neuropeptide
      degrading-enzyme, was examined in the proximal, middle, and distal segments of
      rat sciatic nerves using a double ligation technique. At 48h after ligation, a
      significant amount of the axonal transport of EP24.15 activity was found in the
      proximal segment, while axonal transport of deamidase activity, a lysosomal
      enzyme, increased in both proximal and distal segments. Western blot analysis of
      EP24.15 showed that EP24.15 immunoreactivity in the proximal segment was 1.8-fold
      higher than that in the middle segment. The immunohistochemical analysis of the
      segments also showed an increase in the immunoreactive EP24.15 in the proximal
      segment in comparison with that in the middle segment. In the distal segment, no
      axonal transport of EP24.15 was found in all methods examined, indicating that
      EP24.15 is mainly transported by an anterograde axonal flow. These observations
      suggest that EP24.15 may be involved in the metabolism of neuropeptides in nerve
      terminals or synaptic clefts.

PMID- 12427478
TI  - The altered expression of GABA shunt enzymes in the gerbil hippocampus before and
      after seizure generation.
AB  - In the present study, the distribution of succinic semialdehyde dehydrogenase
      (SSADH) and succinic semialdehyde reductase (SSAR) in the hippocampus of the
      Mongolian gerbil and its association with various sequelae of spontaneous seizure
      were investigated in order to identify the roles of GABA shunt in the
      epileptogenesis and the recovery mechanisms in these animals. Both SSADH and SSAR
      immunoreactivities in the GABAergic neurons were significantly higher in the pre
      seizure groups of seizure sensitive (SS) gerbil as compared to those seen in the
      seizure resistant (SR) gerbils. The distributions of both SSADH and SSAR
      immunoreactivities in the hippocampus showed significant differences after the on
      set of seizure. At 3 h postictal, when compared to the pre-seizure group of SS
      gerbils, a decline in the immunoreactivities in the perikarya was observed. At 12
      h after seizure on-set, the densities of both SSADH and SSAR immunoreactivities
      were begun to recover to the pre-seizure level of SS gerbils. These results
      suggest that the GABAergic neurons in the hippocampal complex of the SS gerbil
      may be highly activated. In addition, the imbalance of GABA shunt expressions in
      the GABAergic neurons may imply a malfunction of the metabolism of GABAergic
      neurons in the SS gerbils, and this defect may trigger seizure on-set. Therefore,
      the initiation of seizure, at least in gerbils, may be the result of a
      malfunction in GABA shunt in the GABAergic neurons.

PMID- 12427479
TI  - DNQX-induced toxicity in cultured rat hippocampal neurons: an apparent AMPA
      receptor-independent effect?
AB  - To evaluate the involvement of AMPA receptor activation in neuronal cell death
      and survival, rat hippocampal neurons in culture were treated with AMPA receptor
      antagonists. A 46 h treatment with 6,7-dinitroquinoxaline-2,3-dione (DNQX), added
      2 h after cell plating, induces a dose-dependent neurotoxicity. Similar effects
      are also observed in more mature hippocampal neurons (treatment at 14 days in
      vitro). DNQX toxic effect is neuron-specific since cultured hippocampal glial
      cells are unaffected. Attempts to characterise the site of action of DNQX suggest
      that ionotropic glutamate receptors would not be implicated. Indeed, (i) other
      AMPA receptor antagonists are either ineffective or only moderately efficient in
      mimicking DNQX effects; (ii) AMPA alone or in the presence of cyclothiazide, as
      well as, other AMPA receptor agonists, do not reverse DNQX action; (iii) DNQX
      neurotoxicity is not likely to involve blockade of NMDA receptor glycine site,
      since this effect is neither mimicked by 7-chlorokynurenate nor reversed by D
      serine. Thus, DNQX toxicity in cultured hippocampal neurons is apparently
      mediated through an ionotropic glutamate receptor-independent way.

PMID- 12427480
TI  - Effects of ketamine on exocytotic and non-exocytotic noradrenaline release.
AB  - To characterise ketamine-induced sympathomimetic action, we examined the effects
      of ketamine on in vivo cardiac sympathetic nerve endings function. Using adult
      cats given anaesthesia with pentobarbital, dialysis probes were implanted in the
      left ventricular myocardium and dialysate noradrenaline (NA) concentrations were
      measured as an indicator of NA output at the cardiac sympathetic nerve endings.
      Ketamine was locally administered through the dialysis probe, and dialysate NA
      responses were obtained in the following conditions. (1) In the resting state,
      ketamine (10 mM) increased dialysate NA concentration. This increase in dialysate
      NA was not altered by addition of omega-conotoxin GVIA (N-type Ca(2+) channel
      blocker) or desipramine (membrane NA uptake blocker). (2) Sympathetic activation
      by electrical stimulation of the stellate ganglia (ES-SG; exocytotic NA release):
      ES-SG caused an increase in dialysate NA, which was further augmented by addition
      of desipramine. During co-administration of desipramine and ketamine, dialysate
      NA response to ES-SG was smaller than with desipramine alone. Further, there was
      no significant difference in the dialysate NA response to ES-SG between ketamine
      and ketamine + desipramine. These data suggested that both exocytosis and NA
      uptake function were impaired by ketamine. (3) Non-exocytotic NA release by
      ouabain: ouabain caused increases in dialysate NA. These increases in dialysate
      NA were suppressed by ketamine, which impaired the membrane outward NA transport
      evoked by ouabain. We conclude that ketamine impaired exocytotic and non
      exocytotic NA release. However, ketamine spontaneously evoked NA efflux that was
      independent of exocytosis and insensitive to NA transporter.

PMID- 12427481
TI  - Neuropeptides in the nervous system of Drosophila and other insects: multiple
      roles as neuromodulators and neurohormones.
AB  - Neuropeptides in insects act as neuromodulators in the central and peripheral
      nervous system and as regulatory hormones released into the circulation. The
      functional roles of insect neuropeptides encompass regulation of homeostasis,
      organization of behaviors, initiation and coordination of developmental processes
      and modulation of neuronal and muscular activity. With the completion of the
      sequencing of the Drosophila genome we have obtained a fairly good estimate of
      the total number of genes encoding neuropeptide precursors and thus the total
      number of neuropeptides in an insect. At present there are 23 identified genes
      that encode predicted neuropeptides and an additional seven encoding insulin-like
      peptides in Drosophila. Since the number of G-protein-coupled neuropeptide
      receptors in Drosophila is estimated to be around 40, the total number of
      neuropeptide genes in this insect will probably not exceed three dozen. The
      neuropeptides can be grouped into families, and it is suggested here that related
      peptides encoded on a Drosophila gene constitute a family and that peptides from
      related genes (orthologs) in other species belong to the same family. Some
      peptides are encoded as multiple related isoforms on a precursor and it is
      possible that many of these isoforms are functionally redundant. The distribution
      and possible functions of members of the 23 neuropeptide families and the insulin
      like peptides are discussed. It is clear that each of the distinct neuropeptides
      are present in specific small sets of neurons and/or neurosecretory cells and in
      some cases in cells of the intestine or certain peripheral sites. The
      distribution patterns vary extensively between types of neuropeptides. Another
      feature emerging for many insect neuropeptides is that they appear to be
      multifunctional. One and the same peptide may act both in the CNS and as a
      circulating hormone and play different functional roles at different central and
      peripheral targets. A neuropeptide can, for instance, act as a coreleased signal
      that modulates the action of a classical transmitter and the peptide action
      depends on the cotransmitter and the specific circuit where it is released. Some
      peptides, however, may work as molecular switches and trigger specific global
      responses at a given time. Drosophila, in spite of its small size, is now
      emerging as a very favorable organism for the studies of neuropeptide function
      due to the arsenal of molecular genetics methods available.

PMID- 12427482
TI  - Quercetin significantly decreased cyclosporin oral bioavailability in pigs and
      rats.
AB  - Cyclosporin, an immunosuppressant with a narrow therapeutic window, is a
      substrate for both CYP3A4 and P-glycoprotein (Pgp). Quercetin is an inhibitor of
      CYP3A4 and a modulator of Pgp. This study aimed to measure the effect of
      quercetin on the absorption and disposition of cyclosporin in pigs and rats.
      Cyclosporin (Sandimmune, 10 mg/kg) was orally administered with and without a
      concomitant dose of quercetin (50 mg/kg) to pigs and rats. Cyclosporin
      concentrations in blood samples were determined by a specific monoclonal
      fluorescence polarization immunoassay. The pharmacokinetic parameters were
      calculated by noncompartmental analysis using WINNONLIN. A paired Student's t
      test was conducted for statistical comparison. A study using the everted
      intestinal sac was carried out to evaluate the effect of quercetin on the
      function of intestinal Pgp. The coadministration of quercetin significantly
      decreased cyclosporin AUC(0-3) (area under the concentration-time curve from time
      zero to 3 h) by 56% and AUC(0-t) (area under the concentration-time curve from
      time zero to the last point) by 43% in pigs and rats, respectively, indicating
      that the coadministration of quercetin significantly decreased cyclosporin oral
      bioavailability. However, the inverted sac study showed that quercetin
      significantly inhibited the function of intestinal Pgp. It is suggested that
      concurrent use of quercetin or quercetin-containing dietary supplement or herbs
      with cyclosporin or other medications whose absorption and metabolism are
      mediated by Pgp and/or CYP3A4 should require close monitoring.

PMID- 12427483
TI  - Chemotoxicity and survival of tumor-bearing mice under exposure to randomized
      photoperiodic regimen.
AB  - Although disruption of the circadian rhythm had been traditionally considered as
      a pathological sign, there is an increasing recognition that an existence of
      internal disorder (or chaos) in the organism's homeostasis is, to some degree,
      essential to the organism's well being. In this study we explored the effects of
      rhythm scrambling by exposure to random light/dark (RLD) alternation or by
      hydrocortisone administration. The variables measured were the toxicity of
      Adriamycin, Vincristin, Cisplatinum and Cyclophosphamide in C57Bl/6J mice and the
      survival of EL4 lymphoma-bearing mice, before and after chemotherapy. Rhythm
      alterations were determined by WBC counts and plasma Alkaline Phosphatase
      activity. Injections of Adriamycin, Cisplatinum and Vincristin in RLD conditions
      resulted in a better survival than in control groups of mice kept in LD
      illumination regimen, although the differences between the groups were
      significant only for injection of Adriamycin. RLD conditions imposed a
      "protective" effect on survival of tumor-bearing mice. On the 94th day, 20% of
      the injected mice in RLD conditions still survived while, there were no survivors
      beyond 38 days in control group. Chemotherapy had a more prominent beneficial
      effect on survival in RLD group, as compared to LD group. The injections of
      hydrocortisone had detrimental effect on survival in both illumination schedules.
      However, the survival in the RLD group was still better than in the LD group.
      These experiments indicate that temporal disorganization has beneficial effects
      on lymphoma-bearing mice and could be used for development of new therapeutic
      modalities.

PMID- 12427484
TI  - Effect of FK506 on osteoinduction by recombinant human bone morphogenetic protein
      2.
AB  - FK506 is an immunosuppressant that is used widely in organ transplantation, and
      it has recently been recognized as effective for promoting the growth of bone
      grafts [J. Bone Miner. Res. 15 (2000) 1147]. In this study, we evaluated the
      influence of FK506 on osteoinduction by recombinant human bone morphogenetic
      protein-2 (rhBMP-2) using atelopeptide type I collagen as a carrier. We
      administered FK506 (1 mg/kg/day intramuscularly) on days -2 to 0, -2 to 7, and -2
      to sacrifice. rhBMP-2 was implanted into the calf muscle of Wistar rats (thirty
      per group) and the implant was sampled on days 7, 14, and 21. Radiographic
      evaluation, histological examination, and biochemical analysis were performed. It
      was found that FK506 promoted the early stage of osteoinduction after short-term
      administration. However, long-term administration of this agent accelerated both
      bone formation and bone resorption. In order to use FK506 effectively for
      promoting bone growth, we must further examine the appropriate dose, method, and
      period of administration.

PMID- 12427485
TI  - Anti-proliferative and differentiation-inducing activities of the green tea
      catechin epigallocatechin-3-gallate (EGCG) on the human eosinophilic leukemia EoL
      1 cell line.
AB  - A novel approach for the treatment of leukemia is the differentiation therapy in
      which immature leukemia cells are induced to attain a mature phenotype when
      exposed to differentiation inducers, either alone or in combinations with other
      chemotherapeutic or chemopreventive drugs. Over the past decade, numerous studies
      indicated that green tea catechins (GTC) could suppress the growth and induce
      apoptosis on a number of human cancer cell lines. However, the differentiation
      inducing activity of GTC on human tumors remains poorly understood. In the
      present study, the effect of the major GTC epigallocatechin-3-gallate (EGCG) on
      the proliferation and differentiation of a human eosinophilc leukemic cell line,
      EoL-1, was examined. Our results showed that EGCG suppressed the proliferation of
      the EoL-1 cells in a dose-dependent manner, with an estimated IC(50) value of
      31.5 microM. On the other hand, EGCG at a concentration of 40 microM could
      trigger the EoL-1 cells to undergo morphological differentiation into mature
      eosinophil-like cells. Using RT-PCR and flow cytometry, it was found that EGCG
      upregulated the gene and protein expression of two eosinophil-specific granule
      proteins, the major basic protein (MBP) and eosinophil peroxidase (EPO), in EoL-1
      cells. Taken together, our findings suggest that EGCG can exhibit anti-leukemic
      activity on a human eosinophilic cell line EoL-1 by suppressing the proliferation
      and by inducing the differentiation of the leukemia cells.

PMID- 12427486
TI  - Identification of a tachykinin NK(2) receptor splice variant and its expression
      in human and rat tissues.
AB  - The tachykinins substance P, neurokinin A and neurokinin B are implicated in
      different diseases and play an important role in neuroimmunomodulation. These
      peptides interact with three distinct types of tachykinin receptors termed NK(1),
      NK(2) and NK(3). While most mammalian genes encoding G protein-coupling cell
      membrane receptors are intron-less, the three tachykinin receptors contain
      introns in their genomic structures. In the present study, we have identified a
      splice variant of the tachykinin NK(2) receptor that results from skipping of
      exon 2 in the processing of the tachykinin NK(2) receptor mRNA. By using reverse
      transcription-polymerase chain reaction analysis, we observed that the tachykinin
      NK(2) receptor splice variant, that we named NK(2)beta, appeared in different
      human and rat tissues that also express the wild type, tachykinin NK(2)alpha
      isoform. Compared to tachykinin receptor NK(2)alpha isoform mRNA levels, the
      NK(2)beta isoform was strongly expressed in human and rat uteri, expressed in a
      moderate degree in the rat urinary bladder, colon, duodenum and stomach and
      unexpressed in the rat cerebral cortex, kidney, thoracic aorta, skeletal muscle
      and heart. These data describe the first known tachykinin receptor splice variant
      and suggest that the variety of tachykinin receptors may be further expanded
      through the generation of splicing isoforms. The presence of the truncated
      isoform may have a physiological significance in the regulation of tachykinin
      NK(2) receptor protein levels.

PMID- 12427487
TI  - The botanical extracts of Achyrocline satureoides and Ilex paraguariensis prevent
      methylglyoxal-induced inhibition of plasminogen and antithrombin III.
AB  - Endogenously produced dicarbonyls, such as methylglyoxal (MG), are involved in
      advanced glycation end-product formation and thus linked to the pathophysiology
      of diabetic chronic complications. While the search for synthetic new
      antiglycation agents continues, little attention has been paid to putative
      antiglycation agents in natural compounds. Given the link between glycation and
      oxidation, in this work, we study the effects of methylglyoxal on two model
      systems; plasminogen and antithrombin III (AT III), then we set out to unravel a
      possible antiglycation effect for extracts of the flavonoid-rich common herbal
      species Achyrocline satureoides (AS) and Ilex paraguariensis (IP). Using SAR-PRO
      ARG-pNA as a specific thrombin substrate, we show that incubation of plasma with
      MG decreases heparin activation of AT III by up to a 70%, in a dose-dependent
      manner. A parallel dose-dependent decrease in plasminogen activity reaching more
      than 50% was shown using D-BUT-CHT-lys-pNA as a plasmin-specific substrate.
      Extracts of AS and IP display a dose dependent inhibition of the action of the
      dicarbonyl, already significant at a 1/100 dilution of the herbal infusions. The
      inhibition was comparable to that obtained by using millimolar concentrations of
      known AGE inhibitors such as aminoguanidine and carnosine as well as micromolar
      concentrations of the antioxidant ascorbic acid. We believe our system of whole
      plasma glycation over 16 h with micromolar concentrations of MG, coupled with the
      measurement of activities of plasminogen and AT III by specific substrates
      provides a straightforward, practical method for monitoring the action of
      putative antiglycation agents. If predictably milder glycated forms of AT III and
      plasminogen were to be secreted in vivo, the loss of activities shown here could
      act synergistically to generate hyperthrombicity.

PMID- 12427488
TI  - Protamine is a low molecular weight polycationic amine that produces actions on
      cardiac muscle.
AB  - Protamine is a polycationic amine used clinically to reverse heparin overdose.
      Here we characterized the actions of protamine on the cardiovascular system of
      anesthetized rats and in isolated Langendorff rat hearts in order to define a
      possible mechanism of action on cardiovascular tissue. In anesthetized rats,
      protamine reduced blood pressure in a dose-dependent fashion and reduced heart
      rate. Only at a dose of 32 mg/kg did protamine increase the Q-aT interval of the
      electrocardiogram (EKG) to 62 +/- 6 msec from a control of 54 +/- 5 msec (p <
      0.05). Protamine dose-dependently reduced cardiac output by 74 +/- 5% and stroke
      volume by 62 +/- 15 %, suggesting that it directly affects cardiac contractility.
      An analysis of blood chemistry suggests that protamine does not alter plasma
      electrolyte or serum enzyme levels at the doses administered. Protamine produced
      aberrant rhythms in normal rat hearts when administered between 1-32 mg/kg. The P
      Q segment of the EKG for each of the arrhythmic complexes was reduced to 24 +/- 1
      msec compared to 32 +/- 3 msec in normal EKG complexes suggestive of anomalous
      atrio-ventricular or pre-excitation conduction. Isolated rat heart studies
      confirmed that protamine produced a reduction in cardiac contractility. Our
      studies suggest that the cardiovascular depressant actions of protamine result
      from a direct effect on the heart and that protamine may produce aberrant
      conduction within the heart which may result in deleterious effects in heart
      function, especially conditions associated with myocardial disease.

PMID- 12427489
TI  - SR 142801, a tachykinin NK(3) receptor antagonist, prevents beta(2)-adrenoceptor
      agonist-induced hyperresponsiveness to neurokinin A in guinea-pig isolated
      trachea.
AB  - We investigated whether fenoterol was able to enhance contractile responsiveness
      to neurokinin A (NKA) on the guinea-pig isolated trachea. We then studied the
      effects of two inhibitors of nuclear factor kappa B (NFkappaB), gliotoxin and
      pyrrolidine dithiocarbamate, and of the tachykinin NK(1), NK(2) and NK(3)
      receptor antagonists, SR 140333, SR 48968 and SR 142801 and determined whether
      tachykinin receptor gene expression was up-regulated in the trachea after
      exposure to fenoterol. Fenoterol (0.1 microM, 15 h, 21 degrees C) induced an
      increased contractile response to NKA (mean of difference in maximal tension
      between control and fenoterol +/- S.E.M; +0.47 +/- 0.14 g, n = 26, P < 0.01).
      This hyperresponsiveness was strongly reduced by co-incubation with gliotoxin
      (0.1 microg/ml) or pyrrolidine dithiocarbamate (0.1 mM) and abolished by SR
      140333 (0.1 microM) and SR 142801 (0.1 microM). SR 48968 (0.1 microM) diminished
      the tracheal contractility to NKA but failed to reduce the hyperreactivity
      induced by fenoterol. Tachykinin NK(1) receptor (NK(1)R), NK(2) receptor (NK(2)R)
      and NK(3) receptor (NK(3)R) gene expression was analyzed by semiquantitative RT
      PCR. Compared to control tissues, NK(1)R and NK(2)R mRNA expression was increased
      by about 1.6-fold and 1.4-fold, respectively, in tissues treated with fenoterol.
      We were unable to detect the presence of NK(3)R mRNA in the guinea-pig trachea.
      In conclusion, fenoterol induces tracheal hyperresponsiveness to NKA and an up
      regulation of NK(1)R and NK(2)R gene expression. The hyperresponsiveness
      implicates the NFkappaB pathway and is abolished by tachykinin NK(1) (SR 140333)
      and NK(3) (SR 142801) receptor antagonists.

PMID- 12427490
TI  - Singlet oxygen trapping by DRD156 in micellar solutions.
AB  - Recently, 4.4'-bis(1-p-carboxyphenyl-3-methyl-5-dydroxyl)-pyrazol (DRD156) has
      been developed as a new sensitive reagent that reacts specifically with singlet
      oxygen. The specificity of DRD156 for singlet oxygen in a biomimetic solution
      (micellar solution) and the effects of its coexistence with other reagent were
      examined with electron spin resonance (ESR). Singlet oxygen was generated using
      photosensitization reaction. The ESR spectrum of the radical derived from DRD156
      after the reaction with singlet oxygen in phosphate buffered salines (PBS) was
      comprised of twenty-nine lines, whereas that in cetyltrimethylammonium bromide
      (CTAB) micelles was comprised of nine lines. Both 2,2,6,6-tetramethyl-4
      piperidine (TMPD) and 1,3-diphenyl-isobenzofuran (DPBF) reduced the singlet
      oxygen-DRD156 signal intensity, and TMPD-mediated decrease in PBS (to 62%) was
      almost the same as that in CTAB micelle (to 65%). In contrast, DPBF reduced the
      DRD156 signal intensity more effectively in CTAB micelle (to 12%) than PBS (to
      38%). These results indicate that the specificity of DRD156 for singlet oxygen is
      dependent on microenvironment.

PMID- 12427491
TI  - An aqueous extract of Rubus chingii fruits protects primary rat hepatocytes
      against tert-butyl hydroperoxide induced oxidative stress.
AB  - Different in vitro free radical generating systems were used to assess the
      antioxidative activity of aqueous extracts of the five herbal components of Wu-zi
      yan-zong-wan, a traditional Chinese medicinal formula with a long history of use
      for tonic effects. Fructus Rubi [Rubus chingii (Rosaceae) fruits] was found to be
      the most potent. It was further investigated using the primary rat hepatocyte
      system. tert-Butyl hydroperoxide (t-BHP) was used to induce oxidative stress.
      Being a short chain analog of lipid hydroperoxide, t-BHP is metabolized into free
      radical intermediates by the cytochrome P450 system in hepatocytes, which in
      turn, initiate lipid peroxidation, glutathione depletion and cell damage. Pre
      treatment of hepatocytes with Fructus Rubi extract (50 microg/ml to 200
      microg/ml) for 24 h significantly reversed t-BHP-induced cell viability loss,
      lactate dehydrogenase leakage and the associated glutathione depletion and lipid
      peroxidation. The amount of reactive oxygen species formed was also decreased as
      visualized by the fluorescence probe 2',7'-dichlorofluorescin diacetate. These
      results suggested that Fructus Rubi was useful in protecting against t-BHP
      induced oxidative damage and may also be capable of attenuating cytotoxicity of
      other oxidants.

PMID- 12427492
TI  - A longitudinal study of gastric emptying and upper gastrointestinal symptoms in
      patients with diabetes mellitus.
AB  - PURPOSE: To evaluate the natural history of gastric emptying and upper
      gastrointestinal symptoms in patients with diabetes mellitus. SUBJECTS AND
      METHODS: We enrolled 20 patients (6 men, 14 women) with diabetes mellitus (16
      with type 1 diabetes, 4 with type 2 diabetes). Each had measurements of gastric
      emptying of a solid (100 g of ground beef) and liquid (150 mL of 10% dextrose)
      meal using scintigraphy, glycemic control (glycosylated hemoglobin [HbA(1c)] and
      mean blood glucose levels), upper gastrointestinal symptoms, and autonomic nerve
      function at baseline and after a mean (+/- SD) of 12.3 +/- 3.1 years of follow
      up. RESULTS: There were no differences in mean gastric emptying of the solid
      component (retention at 100 minutes at baseline: 56% +/- 19% vs. follow-up: 51%
      +/- 21%, P = 0.23) or the liquid component (time for 50% to empty at baseline: 33
      +/- 11 minutes vs. follow-up: 31 +/- 12 minutes, P = 0.71) during follow-up. Mean
      blood glucose (17.0 +/- 5.6 mmol/L vs. 13.8 +/- 4.9 mmol/L, P = 0.007) and
      HbA(1c) (8.4% +/- 2.3% vs. 7.6% +/- 1.3%, P = 0.03) levels were lower at follow
      up. There was no difference in symptom score (baseline: 3.9 +/- 2.7 vs. follow
      up: 4.2 +/- 4.0, P = 0.78). There was evidence of autonomic neuropathy in 7
      patients (35%) at baseline and 16 (80%) at follow-up. CONCLUSION: In patients
      with diabetes mellitus, we did not observe any marked changes in either gastric
      emptying or upper gastrointestinal symptoms during a 12-year period.

PMID- 12427493
TI  - Nephrology consultation in acute renal failure: does timing matter?
AB  - PURPOSE: Patients who develop acute renal failure in the intensive care unit
      (ICU) have extremely high rates of mortality and morbidity. The goals of this
      study were to identify correlates of the timing of nephrology consultation in
      acute renal failure, and to explore the relation between timing of consultation
      and outcomes. METHODS: We explored associations among timing of nephrology
      consultation and in-hospital mortality, lengths of hospital and ICU stay, and
      recovery of renal function in 215 ICU patients with acute renal failure at four
      U.S. teaching hospitals. We used multivariable logistic regression and propensity
      scores to adjust for confounding and selection effects. RESULTS: Nephrology
      consultation was delayed (>or=48 hours) in 61 patients (28%) (median time to
      consultation, 4 days). Lower serum creatinine levels (P <0.0001) and higher urine
      output (P = 0.002) were associated with delayed consultation. Delayed
      consultation was associated with increased mortality among dialyzed (31/42 [74%]
      vs. 50/103 [49%], P = 0.006) and nondialyzed patients (10/19 [53%] vs. 11/51
      [22%], P = 0.01), and increases in lengths of hospital (median, 19 days vs. 16
      days, P = 0.01) and ICU stay (17 days vs. 6 days, P <0.0001). The association
      between delayed consultation and mortality was attenuated by covariate
      adjustment, and was no longer statistically significant after adjustment for
      propensity score (odds ratio = 2.0; 95% confidence interval: 0.8 to 5.1).
      CONCLUSION: In acute renal failure, delayed nephrology consultation was
      associated with increased mortality and morbidity, whether or not dialysis was
      ultimately required. Using observational data, we cannot determine whether these
      findings reflect residual confounding, selection bias, adverse effects of delayed
      recognition of acute renal failure, or the benefits of nephrology consultation.

PMID- 12427494
TI  - Novel risk factors for peripheral arterial disease in young women.
AB  - PURPOSE: To investigate traditional and novel risk factors (homocysteine and C
      reactive protein levels, and exposure to infections) for peripheral arterial
      disease in young women. SUBJECTS AND METHODS: In a multicenter, population-based,
      case-control study, 212 young women (mean [+/- SD] age, 48.2 +/- 7.0 years) with
      peripheral arterial disease and 475 healthy control women (mean age, 45.5 +/- 8.1
      years) completed a standardized questionnaire and provided blood samples.
      Peripheral arterial disease was angiographically confirmed if a stenotic lesion
      (more than 50% reduction of the lumen) was present in at least one major
      peripheral artery. Hyperhomocysteinemia was defined as a nonfasting plasma
      homocysteine level exceeding the 90th percentile of the control group. History of
      infectious diseases was determined by questionnaire. RESULTS: Elevated C-reactive
      protein levels were associated with an increased likelihood of peripheral
      arterial disease (odds ratio [OR] = 3.9; 95% confidence interval [CI]: 1.8 to 8.5
      for women in the third quartile; OR = 3.1; 95% CI: 1.4 to 6.8 for women in the
      fourth quartile; both comparisons with women in the first quartile).
      Hyperhomocysteinemia was not associated with a significantly increased risk of
      peripheral arterial disease (OR = 1.6; 95% CI: 0.9 to 3.0). A history of
      chickenpox, shingles, mumps, pneumonia, chronic bronchitis, peptic ulcer, or
      periodontitis was independently related to peripheral arterial disease, with
      adjusted odds ratios varying from 1.7 (95% CI: 1.0 to 3.1) for mumps to 3.4 (95%
      CI: 1.5 to 7.7) for peptic ulcer. The risk of peripheral arterial disease
      increased with the number of these infections; exposure to five or more
      infections increased the odds 3.7-fold (95% CI: 1.7 to 8.2). This association was
      not affected by the level of C-reactive protein. CONCLUSION: Our results do not
      support a strong relation between homocysteine and peripheral arterial disease in
      young women. However, an elevated C-reactive protein level and several types of
      symptomatic infection were associated with peripheral arterial disease.

PMID- 12427495
TI  - Syncope in acute aortic dissection: diagnostic, prognostic, and clinical
      implications.
AB  - BACKGROUND: Syncope is a well-recognized symptom of acute aortic dissection,
      often indicating the development of dangerous complications such as cardiac
      tamponade. SUBJECTS AND METHODS: We identified consecutive patients with acute
      aortic dissection at 18 referral centers in six countries. Data on key clinical
      findings and outcomes were collected via extensive questionnaires. Multiple
      logistic regression models were used to determine the association between syncope
      and in-hospital mortality, adjusting for demographic characteristics, dissection
      type, comorbid conditions, and complications (e.g., cardiac tamponade). RESULTS:
      Syncope was reported in 96 (13%) of 728 patients. Patients with syncope were more
      likely to die in the hospital (34% [n = 33 deaths]) than were those without
      syncope (23% [144/632], P = 0.01). They were also more likely to have cardiac
      tamponade (28% [n = 27] vs. 8% [n = 49], P <0.001), stroke (18% [n = 17] vs. 4%
      [n = 27], P <0.001), and other neurologic deficits (25% [n = 24] vs. 14% [n =
      88], P = 0.005). After multivariate adjustment, clinical factors independently
      associated with the occurrence of syncope included a proximal dissection (odds
      ratio [OR] = 5.5; 95% confidence interval [CI]: 2.5 to 12; P <0.001), cardiac
      tamponade (OR = 3.1; 95% CI: 1.7 to 5.4; P <0.001), and stroke (OR = 3.5; 95% CI:
      1.7 to 7.2; P = 0.001). There was a significant association between in-hospital
      death and syncope after adjustment for demographic characteristics alone (OR =
      2.0; 95% CI: 1.2 to 3.5; P = 0.01), but not after adjustment for dissection type,
      comorbid conditions, and complications. CONCLUSION: Patients with dissections
      complicated by cardiac tamponade or stroke are significantly more likely to
      present with syncope. If these complications are excluded, syncope alone does not
      appear to increase the risk of death independently.

PMID- 12427496
TI  - Prevalence of coronary heart disease associated with HFE mutations in adults
      attending a health appraisal center.
AB  - PURPOSE: Mutations of the HFE gene that cause hereditary hemochromatosis may be
      associated with an increased risk of cardiovascular disease. We examined the
      relation between two HFE mutations (C282Y and H63D), indicators of iron
      homeostasis, and the prevalence of coronary heart disease in a large population
      of white adults. SUBJECTS AND METHODS: We conducted a cross-sectional study of
      30,916 white adults aged 25 to 98 years who attended a health appraisal center
      and underwent screening for HFE mutations. Coronary heart disease and
      cardiovascular risk factors were ascertained by questionnaire and medical
      records. RESULTS: Overall, 12% (1798/15,362) of men and 7% (1074/15,554) of women
      had a history of coronary heart disease. Of 10 HFE genotypes tested (five
      genotypes by sex), only men with the C282Y/H63D genotype (compound heterozygotes)
      had a significantly higher prevalence of coronary heart disease compared with men
      with no HFE mutations (odds ratio = 1.6; 95% confidence interval: 1.1 to 2.4; P =
      0.01) after adjusting for cardiovascular risk factors. Elevated serum ferritin
      levels (>250 ng/mL) were associated with a lower prevalence of coronary heart
      disease in men (10% [255/2209] vs. 12% [1515/12,461] in controls, P = 0.008),
      which was not significant after adjusting for use of aspirin and anticoagulants.
      There were no significant associations between elevated transferrin saturation in
      either men or women, or between elevated serum ferritin levels or HFE mutations
      in women, and the prevalence of coronary heart disease. CONCLUSION: The results
      do not support a consistent association between HFE mutations or serum iron
      indicators and the prevalence of coronary heart disease.

PMID- 12427497
TI  - Effects of nosocomial candidemia on outcomes of critically ill patients.
AB  - PURPOSE: To determine whether nosocomial candidemia is associated with increased
      mortality in intensive care unit (ICU) patients. SUBJECTS AND METHODS: We
      performed a retrospective (1992 to 2000) cohort study of 73 ICU patients with
      candidemia and 146 matched controls. Controls were matched based on disease
      severity as measured by the Acute Physiology and Chronic Health Evaluation
      (APACHE) II score (+/- 1 point), diagnostic category, and length of ICU stay
      before onset of candidemia. RESULTS: In comparison with the control group,
      patients with candidemia developed more acute respiratory failure (97% [n = 71]
      vs. 88% [n = 129], P = 0.03) during their ICU stay. They were mechanically
      ventilated for a longer period (29 +/- 26 days vs. 19 +/- 19 days, P<0.01) and
      had a longer stay in the ICU (36 +/- 33 days vs. 25 +/- 23 days, P = 0.02) as
      well as in the hospital (77 +/- 81 days vs. 64 +/- 69 days, P = 0.04). There was
      no difference in in-hospital mortality between the groups (48% [n = 35] vs. 43%
      [n = 62], P = 0.44), a difference of 5% (95% confidence interval [CI]: -8% to
      19%). In a multivariate analysis, older age (hazard ratio [HR] = 1.13 per 10
      years; 95% CI: 1.04 to 1.23; P = 0.004), acute renal failure (HR = 1.4; 95% CI:
      1.1 to 2.0; P = 0.02), and unfavorable APACHE II scores (HR = 1.10 per 5 points;
      95% CI: 1.00 to 1.20; P = 0.05) were independent predictors of mortality.
      Candidemia was not associated with mortality in a model that adjusted for these
      factors (HR = 0.9; 95% CI: 0.7 to 1.2; P = 0.53). CONCLUSION: Nosocomial
      candidemia does not adversely affect the outcome in ICU patients in whom
      mortality is attributable to age, the severity of underlying disease, and acute
      illness.

PMID- 12427498
TI  - U.S. military weight standards: what percentage of U.S. young adults meet the
      current standards?
AB  - PURPOSE: Each branch of the U.S. military enforces maximum allowable weight
      standards that must be met to join the military. We wanted to determine what
      percentage of U.S. civilians between the ages of 17 and 20 years met these
      standards. METHODS: The height and weight of adults between the ages of 17 and 20
      years, as measured in the nationally representative sample of the Third National
      Health and Nutritional Examination Survey, were matched against the height/weight
      charts of the military services. The percentage of men and women in each
      population subgroup who weighed more than the maximum allowable weight was
      calculated. RESULTS: The percentage of young adults whose weight exceeded the
      military weight standard ranged from 13% to 18% for men and 17% to 43% for women.
      When stratified by race, 15% to 20% of non-Hispanic white men and 12% to 36% of
      non-Hispanic white women were over the weight standards, 11% to 19% of non
      Hispanic black men and 35% to 56% of non-Hispanic black women were over the
      standards, and 13% to 24% of Mexican American men and 26% to 55% of Mexican
      American women exceeded the military weight standards. CONCLUSION: A large
      percentage of the young adult population from which the U.S. volunteer military
      is drawn is over the military weight standards, particularly among minorities,
      who comprise a disproportionately large proportion of the military. There is a
      marked discrepancy between the weight standards for men and women, and the
      appropriateness of these standards needs to be assessed.

PMID- 12427499
TI  - Cost-effectiveness of gastric bypass for severe obesity.
AB  - PURPOSE: To estimate the cost-effectiveness of gastric bypass in the treatment of
      severe obesity. SUBJECTS AND METHODS: We performed a cost-effectiveness analysis
      of gastric bypass versus no treatment from the payer perspective. We discounted
      quality-adjusted life-years (QALYs), life-years, and cost during the patient's
      lifetime. Our target group comprised women and men aged 35 to 55 years with a
      body mass index between 40 and 50 kg/m(2), and who did not have cardiovascular
      disease and in whom conservative bariatric therapies had been unsuccessful.
      RESULTS: The base case cost-effectiveness ratios ranged from 5000 dollars to
      16,100 dollars per QALY for women and from 10,000 dollars to 35,600 dollars per
      QALY for men, depending on age and initial body mass index. In a few subgroups of
      older, less obese men, variation in parameters such as loss of excess weight,
      obesity-related quality of life, complication rates, and perioperative mortality
      affected the cost-effectiveness ratios. Parameter variation did not result in
      meaningful changes in the remaining patients. CONCLUSION: Gastric bypass is a
      cost-effective alternative to no treatment, providing substantial lifetime
      benefits in patients who are severely obese.

PMID- 12427500
TI  - Screening for esophageal adenocarcinoma: an evidence-based approach.
AB  - Adenocarcinoma of the esophagus and the gastroesophageal junction is the
      twentieth most common malignancy in the United States. In developed countries,
      the incidence of esophageal adenocarcinoma is increasing 5% to 10% per year.
      Despite the use of endoscopy for earlier detection, mortality from esophageal
      adenocarcinoma has not declined. Using an evidence-based approach, we review
      screening methods for esophageal adenocarcinoma, including the use of a symptom
      questionnaire, identification of patients with a family history of Barrett's
      esophagus, peroral or transnasal endoscopy, barium swallow, fecal occult blood
      testing, and brush and balloon cytology. Screening has not been shown to reduce
      rate of progression of Barrett's esophagus to esophageal cancer. Many treatment
      options for dysplastic Barrett's esophagus or early carcinoma appear effective,
      but long-term follow-up data are not available. There is currently insufficient
      evidence supporting population-based screening for Barrett's esophagus. Several
      risk factors, including severe reflux symptoms, male sex, and obesity, may
      identify patients with gastroesophageal reflux disease who are at the greatest
      risk of the development of cancer.

PMID- 12427501
TI  - Milk thistle for the treatment of liver disease: a systematic review and meta
      analysis.
AB  - PURPOSE: Milk thistle, an herbal compound, is the dietary supplement taken most
      frequently by patients with chronic liver disease. We performed a systematic
      review of the literature to determine the efficacy and safety of this herb for
      the treatment of liver disease. METHODS: We searched English and non-English
      reports through July 1999 using thirteen databases and reference lists, and
      contacting manufacturers and technical experts. Reviewers independently screened
      all reports to identify randomized placebo-controlled trials that evaluated milk
      thistle for the treatment of liver disease. Outcomes of primary interest included
      mortality, histological findings on liver biopsy specimens, serum
      aminotransferase and albumin levels, and prothrombin times. RESULTS: Fourteen
      trials met inclusion criteria. Four trials reported outcomes for mortality among
      433 participants. The overall summary odds ratio for mortality in the milk
      thistle group compared with placebo was 0.8 (95% confidence interval [CI]: 0.5 to
      1.5; P = 0.6). Three trials assessed histology on liver biopsy; study quality was
      inversely associated with the likelihood of histological benefit for milk thistle
      compared with placebo. There were no differences in serum alanine
      aminotransferase, aspartate aminotransferase, or albumin levels, or prothrombin
      times, among participants assigned to milk thistle compared with those assigned
      to placebo. The only statistically significant difference was a greater reduction
      in alanine aminotransferase levels among patients with chronic liver disease
      assigned to milk thistle (-9 IU/L, 95% CI: -18 to -1 IU/L; P = 0.05), but this
      reduction was of negligible clinical importance and no longer statistically
      significant after limiting analyses to studies of longer duration or of higher
      quality. The frequency of adverse effects was low and, in clinical trials,
      indistinguishable from placebo. CONCLUSION: Treatment with milk thistle appears
      to be safe and well tolerated. We found no reduction in mortality, in
      improvements in histology at liver biopsy, or in biochemical markers of liver
      function among patients with chronic liver disease. Data are too limited to
      exclude a substantial benefit or harm of milk thistle on mortality, and also to
      support recommending this herbal compound for the treatment of liver disease.

PMID- 12427502
TI  - Interferon alpha and ribavirin for membranoproliferative glomerulonephritis and
      hepatitis C infection.

PMID- 12427503
TI  - Comparison of polymerase chain reaction with adenosine deaminase activity in
      pericardial fluid for the diagnosis of tuberculous pericarditis.

PMID- 12427504
TI  - Cases from the Osler Medical Service at Johns Hopkins University. Pseudoachalasia
      due to esophageal adenocarcinoma.

PMID- 12427505
TI  - Prognosis is favorable for most diabetic patients with delayed gastric emptying.

PMID- 12427506
TI  - Proving and improving the value of consultations.

PMID- 12427507
TI  - Acute foreign body reaction to synthetic dural graft.

PMID- 12427508
TI  - Rectus sheath hematoma eroding into the bladder wall causing extraperitoneal
      bladder rupture and vesico-hematoma fistula.

PMID- 12427510
TI  - Human herpesvirus 6 and adult-onset Still's disease.

PMID- 12427509
TI  - Severe bleeding associated with use of low molecular weight heparin and selective
      serotonin reuptake inhibitors.

PMID- 12427511
TI  - Expanding geriatrics into subspecialty internal medicine healthcare, research and
      education: caring for older adults and the T. Franklin Williams Career
      Development Awards.

PMID- 12427512
TI  - Hyperekplexia: a treatable neurogenetic disease.
AB  - Hyperekplexia is primarily an autosomal dominant disease characterized by
      exaggerated startle reflex and neonatal hypertonia. It can be associated with, if
      untreated, sudden infant death from apnea or aspiration pneumonia and serious
      injuries and loss of ambulation from frequent falls. Different mutations in the
      alpha1 subunit of inhibitory glycine receptor (GLRA1) gene have been identified
      in many affected families. The most common mutation is Arg271 reported in at
      least 12 independent families. These mutations uncouple the ligand binding and
      chloride channel function of inhibitory glycine receptor and result in increased
      excitability in pontomedullary reticular neurons and abnormal spinal reciprocal
      inhibition. Three mouse models from spontaneous mutations in GLRA1 and beta
      subunit of inhibitory glycine receptor (GLRB) genes and two transgenic mouse
      models are valuable for the study of the pathophysiology and the genotype
      phenotype correlation of the disease. The disease caused by mutation in GLRB in
      mice supports the notion that human hyperekplexia with no detectable mutations in
      GLRA1 may harbor mutations in GLRB. Clonazepam, a gamma aminobutyric acid (GABA)
      receptor agonist, is highly effective and is the drug of choice. It enhances the
      GABA-gated chloride channel function and presumably compensates for the defective
      glycine-gated chloride channel in hyperekplexia. Recognition of the disease will
      lead to appropriate treatment and genetic counseling.

PMID- 12427513
TI  - A survey of Japanese patients with mitochondrial fatty acid beta-oxidation and
      related disorders as detected from 1985 to 2000.
AB  - A clinical survey of Japanese patients with mitochondrial fatty acid beta
      oxidation and related disorders (FAODs) was performed with questionnaires sent to
      187 institutions, where inborn errors of metabolism could be managed in Japan,
      including a search of related literature published between 1985 and 2000. Sixty
      four patients with ten types of FAODs were found. Carnitine palmitoyltransferase
      2 deficiency and glutaric aciduria type 2 were most common (17 and 14 patients,
      respectively). As of 2000, there were no patients with medium-chain acyl-CoA
      dehydrogenase deficiency, which is common in Caucasians. Age at onset was under 2
      years in 38 (59%) of the patients. Eight (13%) patients had neonatal onset.
      Twenty-one (55%) of the 38 children with an initial attack under 2 years of age
      had acute encephalopathy or a Reye syndrome-like illness. Half of the patients
      presented within 2 years of birth died or were handicapped. On the other hand, 19
      (79%) of the 24 with onset after 2 years of age had muscle symptoms and 23 (96%)
      of the 24 grew and developed normally. Though the precise incidence of FAODs in
      Japan is still unknown, as a consequence of the development of diagnostic
      procedures the number of FAOD cases being diagnosed appears to have increased.
      Mass screening for FAODs during the neonatal period will greatly aid in
      prevention of attacks and related effects.

PMID- 12427514
TI  - Abnormalities in event-related potential and brainstem auditory evoked response
      in children with nocturnal enuresis.
AB  - To evaluate central nervous system functioning involvement in nocturnal enuresis,
      P300 and N200 event-related brain potentials and brainstem auditory-evoked
      potentials (BAER) were assessed in a group of 35 enuretic boys aged 7-9 years.
      The measurements of enuretic group were compared to those of age and sex matched
      non-enuretics. P300 latency in the enuretic group was significantly longer than
      in non-enuretic group (420 ms at parietal scalp (Pz), 414 ms at central scalp
      (Cz) versus 386 ms at Pz, 376 ms at Cz; P < 0.01 and P < 0.01, respectively).
      Both enuretic and non-enuretic subjects were divided into three subgroups his
      age. There was no significant difference in terms of both P300 amplitude and N200
      latency and N200 amplitude between non-enuretic age subgroups. But, P300 latency
      over central scalp in 8 years old non-enuretic subgroup was significantly longer
      than in 9 years old non-enuretic subgroup (P < 0.01). No significant difference
      was found in latency and amplitude of P300 and N200 latency between enuretic
      subgroups. However, N200 amplitude at Cz in 8 years old enuretic subgroup was
      significantly lower than both in 7 years old enuretic subgroup and in 9 years old
      enuretic subgroup (P < 0.01 and P < 0.01, respectively). There were significant
      topographical differences in latency and amplitude of P300 and in N200 latency in
      enuretic age subgroups, only. There was no significant difference in interpeak
      latencies I-III, I-V and III-V and wave latencies I, III and V of BAERs between
      enuretic group and non-enuretic subgroup. Longer interpeak and wave latencies of
      BAERs were found both in 8 years old enuretic subgroup and 8 years old non
      enuretic subgroup. CONCLUSION: Longer P300 latency in primer enuretics compare to
      non-enuretics is an evidence of a maturational delay of central nervous system
      functioning.

PMID- 12427515
TI  - Increased prevalence of pervasive developmental disorders in children with slight
      arylsulfatase A deficiency.
AB  - Arylsulfatase A deficiency (less than 15% of controls) is responsible for a
      neurological disorder known as metachromatic leukodystrophy. Nonetheless, low
      levels of the enzyme (15-50% of controls, higher than in metachromatic
      leukodystrophy) in adult patients have been related to neuropsychiatric
      disorders. On the other hand, there are only few and controversial data on the
      significance of reduced arylsulfatase A activity in children. This led us to
      perform the present study. Various classes of arylsulfatase A activity in
      children have been related with different groups of neuropsychiatric disorders
      and compared with a similar number of healthy children. We found a high
      percentage of reduced arylsulfatase A (less than 50% of controls) in children
      with pervasive developmental disorders (10.25%). Unexpectedly, raising the
      threshold level for considering arylsulfatase A deficiency up to 70% of controls
      resulted in a marked increase in the incidence of pervasive developmental
      disorders. This new class, arylsulfatase A slight deficiency, contained the
      highest number of patients affected by psychiatric symptoms. This suggests that
      arylsulfatase A slight deficiency could be a marker of a subclass of pervasive
      developmental disorders.

PMID- 12427516
TI  - Cerebral hemodynamics during early neonatal period in preterm infants with
      periventricular leukomalacia.
AB  - We prospectively investigated the relation among cerebral blood flow,
      periventricular leukomalacia (PVL) and hypocarbia using Doppler ultrasonography
      in 53 preterm infants with gestational age between 27 and 34 weeks who required
      mechanical ventilation during the first 72 h of life. Cerebral blood flow of
      pericallosal artery was assessed by Doppler ultrasonography at the first and the
      third day of life. Mean velocity (MV) and Resistance index (RI) of anterior
      cerebral artery were calculated from the data obtained by Doppler
      ultrasonography. The diagnosis of PVL was made in 12 infants on the basis of the
      results of ultrasonography and MRI. Hypocarbia was judged as positive when both
      arterial blood gas analyses before and after the ultrasonography revealed PaCO(2)
      values < 25 mmHg. On the first day of life, RI was 0.62 +/- 0.022 in infants with
      PVL and 0.71 +/- 0.014 in those without PVL. On the third day of life, RI was
      0.60 +/- 0.032 in infants with PVL and 0.66 +/- 0.013 in those without PVL. There
      was a significant difference in RI between the two groups at either point. MV was
      not significantly different between the two groups at either point. There was no
      significant difference in RI or MV between infants with and without hypocarbia at
      either point. RI was significantly lower in infants with PVL during the first 72
      h of life, which is suggestive of vasoparalysis in such infants at the level of
      major cerebral arteries. However, RI or MV was no different between infants with
      and without hypocarbia.

PMID- 12427517
TI  - Combination of neonatal electroencephalography and ultrasonography: sensitive
      means of early diagnosis of periventricular leukomalacia.
AB  - This study was performed to assess the predictive value of ultrasonography and
      electroencephalography (EEG) in order to identify infants with periventricular
      leukomalacia (PVL) during the early neonatal period, especially non-cystic cases,
      and to clarify the combination of ultrasonographic and EEG findings that are the
      most useful. We studied 288 eligible infants, whose gestational ages ranged
      between 27 and 32 weeks. PVL was observed in 49 infants (26 cystic PVL and 23 non
      cystic PVL). On ultrasonography, 31 infants with PVL were detected on the basis
      of definite periventricular echodensity (PVE). Thirty-seven infants had at least
      one of equivocal or definite PVE or cystic changes, but the other 12 did not have
      any of them. The sensitivity and specificity were 0.76 and 0.81, respectively. In
      EEG findings, acute stage abnormalities (ASA) of grade II or more were recognized
      in 31 infants with PVL. The sensitivity and specificity were 0.63 and 0.91,
      respectively. Equivocal or definite chronic stage abnormalities (CSA) were seen
      in 43 infants, the sensitivity and specificity being 0.88 and 0.84. The
      sensitivity of CSA was higher than that of ASA, and the specificity of ASA was
      higher than that of CSA. When these EEG findings were combined, 45 infants with
      PVL were detected. The sensitivity, specificity, positive predictive value, and
      negative predictive value were 0.92, 0.77, 0.45, and 0.98, respectively.
      Moreover, ultrasonographic and EEG findings were combined, 46 out of the 49
      infants with PVL were detected with a sensitivity of 0.94 and a specificity of
      0.64. The results indicated that EEG may be suitable for detecting infants at
      risk for development of PVL on the basis of its high sensitivity, and
      ultrasonography may be useful for confirming the presence of PVL on the grounds
      of its high specificity. Appropriate use of these measurements will make an early
      diagnosis of infants with PVL possible, even in non-cystic cases.

PMID- 12427518
TI  - Mismatch negativity of the color modality during a selective attention task to
      auditory stimuli in children with mental retardation.
AB  - Event-related potentials (ERPs) in response to a stimulus change in the visual
      color modality were recorded in normal subjects and children with mental
      retardation (MR) under selective attention conditions with auditory stimuli. The
      paradigm included the presentation of a standard (blue color screen, B) or
      deviant (red, R, or greenish blue color screen, GB) visual stimulus, and a target
      or non-target tone burst stimulus. In Experiment 1, negativity of the subtracted
      waveform in response to visual stimuli with a latency of 250-280 ms was clearly
      observed in the ERPs of normal adults. These potentials prominently appeared at
      posterior sites in one condition, for which the deviant was GB, but were frontal
      site-dominant for the other condition. A P300 response to visual deviance was not
      observed in the GB-B paradigm and the subtracted negativity for this paradigm
      seemed to be more evident than that for the R-B paradigm. The subtracted
      negativities could be detected in the range of 180-400 ms after the stimulus
      onset in control children for the GB-B paradigm. The grand average waves of
      subtracted ERPs in normal children showed a similar distribution to that in
      normal adults. Similar subtracted potentials could be recorded with the same
      paradigm in children with MR, however, the negativities were different in
      waveform and spatial distribution than in controls. Therefore, the subtracted
      negativity of the present visual modality represented the analogue of the
      auditory mismatch negativity (MMN), and so-called 'visual MMN' was detectable in
      children and even in MR patients when the selective attention was directed to
      other stimuli.

PMID- 12427519
TI  - Abnormal white matter lesions with sensorineural hearing loss caused by
      congenital cytomegalovirus infection: retrospective diagnosis by PCR using
      Guthrie cards.
AB  - We report on two patients with congenital cytomegalovirus (CMV) infection
      asymptomatic at birth that was diagnosed retrospectively by polymerase chain
      reaction (PCR) of CMV DNA using blood stored on Guthrie cards. Neuroimaging
      studies showed abnormal myelination without any gray matter abnormalities. In the
      differential diagnosis of patients with abnormal white matter lesions and
      sensorineural hearing loss, one should consider congenital CMV infection. When
      investigating the etiology of patients with behavioral problems, migrational
      disorder, or white matter disease, PCR analysis of CMV DNA using blood stored on
      Guthrie cards might be helpful.

PMID- 12427520
TI  - Prenatal diagnosis of Menkes disease by genetic analysis and copper measurement.
AB  - Carrier detection for 12 women and prenatal diagnosis for six fetuses in Japanese
      families with a patient with Menkes disease (MNK) were performed by gene analysis
      and/or measurement of the copper concentration in cultured cells. Six out of
      eight mothers of MNK patients were carriers while two (25%) were not carriers.
      Two unrelated patients showed the same mutation (R986X): one patient's mother was
      a carrier while the other was not. One male and three female fetuses did not have
      the same mutant allele as the respective MNK proband and have been healthy since
      birth. One female fetus had the same mutant allele as her affected brother. Gene
      analysis is very useful and reliable, although such examination is only indicated
      in families in which a mutation has been identified. In one family in which a
      mutation in ATP7A was not found, cultured amniocytes from a male fetus had a high
      copper concentration. Thus after his birth, the biochemical findings confirmed
      the presence of MNK and early treatment was started. As his early treatment with
      parenteral copper-histidine prevented the neurological disorders effectively,
      prenatal diagnosis is very important.

PMID- 12427521
TI  - Are the strokes in moyamoya syndrome associated with Down syndrome due to protein
      C deficiency?
AB  - Moyamoya syndrome has occasionally been seen in association with Down syndrome.
      We report a child with moyamoya syndrome and Down syndrome who was admitted with
      repeated episodes of strokes; his magnetic resonance imaging and magnetic
      resonance angiography findings confirmed the presence of occlusive
      cerebrovascular disease with basal collateral vessels. His protein C levels were
      significantly decreased during the stroke. Complete clinical recovery was seen
      during follow-up. This raises the possibility of a link between protein C
      deficiency and Down syndrome with moyamoya syndrome.

PMID- 12427522
TI  - MR imaging and 1H-MR spectroscopy in a case of juvenile Alexander disease.
AB  - The serial MR image and MR spectroscopy in the brain were examined in a young
      male diagnosed as having juvenile Alexander disease. He had megalencephaly,
      psychomotor retardation, seizures, and increasing elevation of increasing alpha-B
      crystallin and heat shock protein 27 in the cerebrospinal fluid. Serial MR images
      demonstrated increased demyelination of the bilateral frontal region to left
      occipital region over several years. The myo-inositol/creatine ratio was
      significantly increased in both the demyelinated white matter and normal area in
      the MR spectroscopy. These results suggested that demyelination very slowly
      progressed from the frontal to occipital region and that glial degeneration may
      occur even in the unaffected white matter of patients with juvenile Alexander
      disease.

PMID- 12427523
TI  - Phenomenon of Schwann cell apoptosis in a case of congenital hypomyelinating
      neuropathy with basal lamina onion bulb formation.
AB  - We analyzed a sural nerve biopsy of a child with congenital hypomyelinating
      neuropathy. A lack of normally myelinated fibres, abnormal architecture of
      premyelin fibres and basal lamina onion bulbs were identified. The most prominent
      pathological finding was the appearance of significant death of Schwann cells
      with apoptotic morphology. This new finding may suggest that abnormal premyelin
      fibres are susceptible to death and that their disappearance is responsible for
      empty basal lamina onion bulb formation.

PMID- 12427524
TI  - Infantile progressive bulbar palsy with deafness.
AB  - A 12-month-old boy with progressive cranial nerve palsies followed by ventilatory
      failure demanding artificial ventilation, generalized muscle weakness, and rapid
      progression to death at the age of 21 months is described. The patient had normal
      early development and also apparently normal hearing at presentation of illness
      but, after 6 months of the onset of the disease, hearing loss was documented by
      brainstem auditory evoked potentials (BAEP). Although the initial clinical and
      laboratory findings of this infant could fit with the diagnosis of progressive
      childhood bulbar palsy or Fazio-Londe (FL) disease, the subsequent appearance of
      hearing loss suggests that this patient represents a case of progressive bulbar
      palsy with perceptive deafness or Brown-Vialetto-Van Laere (BVVL) syndrome. To
      our knowledge, this case of BVVL syndrome with severe clinical features and rapid
      deterioration leading to death is the youngest one reported in the literature.
      Furthermore, this case emphasizes the need for repeated auditory examinations,
      including the performance of BAEP in all cases, especially infants and young
      children with progressive bulbar palsy.

PMID- 12427526
TI  - Special mutation research volume dedicated to Dr. Bryn Bridges. DNA repair and
      human health.

PMID- 12427527
TI  - Unfinished business: an essay on finally leaving the bench.

PMID- 12427528
TI  - Endogenous mutagenesis and cancer.
AB  - Mutations in DNA accrue relentlessly, largely via stochastic processes. Random
      changes accumulate, eventually disabling genetic components which result in the
      formation of the cancer phenotype. Given the infrequency of measured nucleotide
      changes and the requirement for several mutations to occur in the same cell, it
      has been postulated that the rate of mutation must become elevated early in the
      course of evolution of the cancer. Recently, large scale sequencing of tumor DNA
      has sought to directly measure random mutations. We discuss the implications of
      these findings and the factors that must be considered in order for fruitful
      determination of whether a mutator phenotype is a necessary precursor for cancer.

PMID- 12427529
TI  - Replication of damaged DNA in mammalian cells: new solutions to an old problem.
AB  - All cells need not only to remove damage from their DNA, but also to be able to
      replicate DNA containing unrepaired damage. In mammalian cells, the major process
      by which cells are able to replicate damaged templates is translesion synthesis,
      the direct synthesis of DNA past altered bases. Crucial to this process is a
      series of recently discovered DNA polymerases. Most of them belong to a new
      family of polymerases designated the Y-family, which have conserved sequences in
      the catalytic N-terminal half of the proteins. These polymerases have different
      efficiencies and specificities in vitro depending on the type of damage in the
      template.One of them, DNA polymerase eta, is defective in xeroderma pigmentosum
      variants, and overwhelming evidence suggests that this is the polymerase that
      carries out translesion synthesis past UV-induced cyclobutane pyrimidine dimers
      in vivo. DNA polymerase eta is localised in replication factories during DNA
      replication and accumulates at sites of stalled replication forks. Many studies
      have been carried out on the properties of the other polymerases in vitro, but
      there is as yet very little evidence for their specific roles in vivo.

PMID- 12427530
TI  - RecQ helicases and cellular responses to DNA damage.
AB  - The faithful replication of the genome is essential for the survival of all
      organisms. It is not surprising therefore that numerous mechanisms have evolved
      to ensure that duplication of the genome occurs with only minimal risk of
      mutation induction. One mechanism of genome destabilization is replication fork
      demise, which can occur when a translocating fork meets a lesion or adduct in the
      template. Indeed, the collapse of replication forks has been suggested to occur
      in every replicative cell cycle making this a potentially significant problem for
      all proliferating cells. The RecQ helicases, which are essential for the
      maintenance of genome stability, are thought to function during DNA replication.
      In particular, RecQ helicase mutants display replication defects and have
      phenotypes consistent with an inability to efficiently reinitiate replication
      following replication fork demise. Here, we review some current models for how
      replication fork repair might be effected, and discuss potential roles for RecQ
      helicases in this process.

PMID- 12427531
TI  - Recombinational DNA repair and human disease.
AB  - We review the genes and proteins related to the homologous recombinational repair
      (HRR) pathway that are implicated in cancer through either genetic disorders that
      predispose to cancer through chromosome instability or the occurrence of somatic
      mutations that contribute to carcinogenesis. Ataxia telangiectasia (AT), Nijmegen
      breakage syndrome (NBS), and an ataxia-like disorder (ATLD), are chromosome
      instability disorders that are defective in the ataxia telangiectasia mutated
      (ATM), NBS, and Mre11 genes, respectively. These genes are critical in
      maintaining cellular resistance to ionizing radiation (IR), which kills largely
      by the production of double-strand breaks (DSBs). Bloom syndrome involves a
      defect in the BLM helicase, which seems to play a role in restarting DNA
      replication forks that are blocked at lesions, thereby promoting chromosome
      stability. The Werner syndrome gene (WRN) helicase, another member of the RecQ
      family like BLM, has very recently been found to help mediate homologous
      recombination. Fanconi anemia (FA) is a genetically complex chromosomal
      instability disorder involving seven or more genes, one of which is BRCA2. FA may
      be at least partially caused by the aberrant production of reactive oxidative
      species. The breast cancer-associated BRCA1 and BRCA2 proteins are strongly
      implicated in HRR; BRCA2 associates with Rad51 and appears to regulate its
      activity. We discuss in detail the phenotypes of the various mutant cell lines
      and the signaling pathways mediated by the ATM kinase. ATM's phosphorylation
      targets can be grouped into oxidative stress-mediated transcriptional changes,
      cell cycle checkpoints, and recombinational repair. We present the DNA damage
      response pathways by using the DSB as the prototype lesion, whose incorrect
      repair can initiate and augment karyotypic abnormalities.

PMID- 12427532
TI  - DNA repair during organogenesis.
AB  - DNA damage caused by genotoxic agents can impact on virtually any cellular
      process due to its ability to affect gene expression and subsequent gene
      products. The importance of repairing damaged DNA is evidenced by the variety of
      DNA repair pathways that have evolved in all living organisms, and the human
      syndromes caused by a lack of this repair ability. This review focuses on the
      expression and activity of DNA repair pathways during mammalian organogenesis,
      and the role of these pathways in ensuring the stability of the conceptal genome.
      DNA repair capacity may play a role also in the response of the conceptus to
      genotoxic agents that may induce malformations; the consequences of exposure to a
      genotoxic agent during organogenesis depend on the extent of the damage and on
      the ability of the embryo to respond by repairing DNA or arresting cell division.
      The four main repair pathways (nucleotide excision repair, base excision repair,
      mismatch repair, and recombination repair) are expressed to various degrees
      during organogenesis, as are members of the genotoxic stress-activated cell cycle
      checkpoint pathways. Developmental-stage-specific alterations in transcript
      levels, protein levels, as well as activity, indicate that the regulation of DNA
      repair pathways during development is complex. The importance of DNA repair
      pathways in endogenous damage control is illustrated by the sensitivity of
      development to their disruption if some of these genes are mutated. Furthermore,
      the conceptus has a limited capacity to alter DNA repair responses following
      exposure to genotoxic agents.

PMID- 12427533
TI  - DNA repair in neural cells: basic science and clinical implications.
AB  - As one part of a distinguished scientific career, Dr. Bryn Bridges focused his
      attention on the issue of DNA damage and repair in stationary phase bacteria. His
      work in this area led to his interest in DNA repair and mutagenesis in another
      non-dividing cell population, the neurons in the mammalian nervous system. He has
      specifically taken an interest in the magnocellular neurons of the central
      nervous system, and the possibility that somatic mutations may be occurring in
      these neurons. As part of this special issue dedicated to Bryn Bridges upon his
      retirement, I will discuss the various DNA repair pathways known to be active in
      the nervous system. The importance of DNA repair to the nervous system is most
      graphically illustrated by the neurological abnormalities observed in patients
      with hereditary diseases associated with defects in DNA repair. I will consider
      the mechanisms underlying the neurological abnormalities observed in patients
      with four of these diseases: xeroderma pigmentosum (XP), Cockayne's syndrome
      (CS), ataxia telangectasia (AT) and AT-like disorder (ATLD). I will also propose
      a mechanism for one of the observations indicating that somatic mutation can
      occur in the magnocellular neurons of the aging rat brain. Finally, as a parallel
      to Bridges inquiry into how much DNA synthesis is going on in stationary phase
      bacteria, I will address the question of how much DNA synthesis in going on in
      neurons, and the implications of the answer to this question for recent studies
      of neurogenesis in adult mammals.

PMID- 12427534
TI  - Immunological disorders and DNA repair.
AB  - Cellular DNA continuously incurs damage and a range of damage response mechanisms
      function to maintain genomic integrity in the face of this onslaught. During the
      development of the immune response, the cell utilises three defined processes,
      V(D)J recombination, class switch recombination and somatic hypermutation, to
      create genetic diversity in developing T and B cells. Curiously, the damage
      response mechanisms employed to maintain genomic stability in somatic cells have
      been exploited and adapted to help generate diversity during immune development.
      As a consequence of this overlap, there is mounting evidence that disorders
      attributable to impaired damage response mechanisms display associated
      immunodeficiency. Since double strand breaks (DSB) are created during at least
      two of the mechanisms used to create immunoglobulin diversity, namely V(D)J
      recombination and class switch recombination, it is not surprising that disorders
      associated with defects in the response to double strand breaks are those most
      associated with immunodeficiency. Here, we review the steps involved in the
      generation of genetic diversity during immune development with a focus on the
      damage response mechanisms employed and then consider human immunodeficiency
      disorders associated with impaired damage response mechanisms.

PMID- 12427535
TI  - Mitochondrial DNA repair and aging.
AB  - The mitochondrial electron transport chain plays an important role in energy
      production in aerobic organisms and is also a significant source of reactive
      oxygen species that damage DNA, RNA and proteins in the cell. Oxidative damage to
      the mitochondrial DNA is implicated in various degenerative diseases, cancer and
      aging. The importance of mitochondrial ROS in age-related degenerative diseases
      is further strengthened by studies using animal models, Caenorhabditis elegans,
      Drosophila and yeast. Research in the last several years shows that mitochondrial
      DNA is more susceptible to various carcinogens and ROS when compared to nuclear
      DNA. DNA damage in mammalian mitochondria is repaired by base excision repair
      (BER). Studies have shown that mitochondria contain all the enzymes required for
      BER. Mitochondrial DNA damage, if not repaired, leads to disruption of electron
      transport chain and production of more ROS. This vicious cycle of ROS production
      and mtDNA damage ultimately leads to energy depletion in the cell and apoptosis.

PMID- 12427536
TI  - Assessing DNA damage and health risk using biomarkers.
AB  - Carcinogenesis is a multi-stage and prolonged process. At the present time, our
      knowledge of biological activities along the process is incomplete, therefore, a
      variety of experimental data are used to assess health risk from exposure to
      environmental chemicals. However, experimental approaches may not be adequate
      unless human data are available to support the assessment. In this brief review,
      benzene (CAS No. 71-43-2), a well-established human leukemogen, will be used as
      an example to illustrate the challenge in assessing toxicological mechanisms and
      cancer risk. Benzene has been shown to form DNA-adducts in experimental animals
      but the adducts have proved elusive of detection in human. Several toxic
      metabolites of benzene have been identified but the metabolite(s) responsible for
      the carcinogenic activities is unknown. Furthermore, the significant differences
      between rodents and human in response to benzene exposure are not understood.
      Therefore, the bone marrow specificity for the induction of leukemia in human by
      benzene remains to be elucidated. These complications illustrate the complexity
      of the assessment process and identify serious information gaps. These
      information gaps can be viewed as research opportunities to provide more precise
      data for assessment of toxicological effects and health risk.

PMID- 12427537
TI  - Rapid assessment of repair of ultraviolet DNA damage with a modified host-cell
      reactivation assay using a luciferase reporter gene and correlation with
      polymorphisms of DNA repair genes in normal human lymphocytes.
AB  - As DNA repair plays an important role in genetic susceptibility to cancer,
      assessment of the DNA repair phenotype is critical for molecular epidemiological
      studies of cancer. In this report, we compared use of the luciferase (luc)
      reporter gene in a host-cell reactivation (HCR) (LUC) assay of repair of
      ultraviolet (UV) damage to DNA to use of the chloramphenicol (cat) gene-based HCR
      (CAT) assay we used previously for case-control studies. We performed both the
      assays on cryopreserved lymphocytes from 102 healthy non-Hispanic white subjects.
      There was a close correlation between DNA repair capacity (DRC) as measured by
      the LUC and CAT assays. Although these two assays had similar variation, the LUC
      assay was faster and more sensitive. We also analyzed the relationship between
      DRC and the subjects' previously determined genotypes for four polymorphisms of
      two nucleotide-excision repair (NER) genes (in intron 9 of xeroderma pigmentosum
      (XP) C and exons 6, 10 and 23 of XPD) and one polymorphism of a base-excision
      repair gene in exon 10 of X-ray complementing group 1 (XRCC1). The DRC was
      significantly lower in subjects homozygous for one or more polymorphisms of the
      two NER genes than in subjects with other genotypes (P=0.010). In contrast, the
      polymorphic XRCC1 allele had no significant effect on DRC. These results suggest
      that the post-UV LUC assay measures NER phenotype and that polymorphisms of XPC
      and XPD genes modulate DRC. For population studies of the DNA repair phenotype,
      many samples need to be evaluated, and so the LUC assay has several advantages
      over the CAT assay: the LUC assay was more sensitive, had less variation, was not
      radioactive, was easier to perform, and required fewer cryopreserved cells. These
      features make the LUC-based HCR assay suitable for molecular epidemiological
      studies.

PMID- 12427538
TI  - Coding variants in human double-strand break DNA repair genes.
AB  - DNA repair is essential for the maintenance of genomic integrity. Consequently,
      altered repair capacity may impact individual health in such areas as aging and
      susceptibility to certain diseases. Defects in some DNA repair genes, for
      example, have been shown to increase cancer risk, accelerate aging and impair
      neurological functions. Now that over 115 genes directly involved in human DNA
      repair have been characterized at the DNA sequence level, the identification of
      single nucleotide polymorphisms (SNPs) in DNA repair genes is becoming a reality.
      This information will likely lead to the identification of alleles, or
      combinations of alleles that affect disease predisposition. This communication
      summarizes SNPs identified to date in the coding region of 24 human double-strand
      break repair (DSBR) genes. SNP data for four of these genes were obtained by
      screening at least 100 individuals in our laboratory. For each SNP, the codon
      number, amino acid substitution, allele frequency and population information is
      supplied.

PMID- 12427539
TI  - Polymorphisms in DNA repair and environmental interactions.
AB  - The repair of damage to DNA is critical to the survival of a cell. However, not
      all organisms nor all individuals express a similar response to challenges to
      their genetic material. Numerous polymorphisms in genes involved in DNA repair
      have been found in individuals with DNA repair-related disease as well as in the
      general population. Studies of these variants are critical in understanding the
      response of the cell to DNA damage. In some cases, these changes predispose the
      carrier to a greatly increased risk of cancer. In other cases, the effects are
      subtler and depend on interactions between the alleles of several genes, or with
      environmental factors. Consequently, the health effects of exposure to genotoxic
      or carcinogenic compounds or agents can depend on the variations in these genes.
      This review will highlight some of the effects that variants, found in many of
      the genes involved in human DNA repair pathways, have on the response to damage,
      and their role in susceptibility of the cell and organism to environmental
      genotoxins. This review will concentrate on the mismatch repair, nucleotide
      repair, base excision repair, strand break repair, and direct alkyl repair
      pathways.

PMID- 12427540
TI  - Genetic reversion of inherited skin disorders.
AB  - Human epidermis is a squamous stratified epithelium whose integrity relies on
      balanced processes of cell attachment, proliferation, and differentiation. In
      monogenic skin dermatoses, such as mecano-bullous diseases, or DNA repair
      deficiencies such as the xeroderma pigmentosum (XP), alterations of skin
      integrity may have devastating consequences as illustrated by the extremely high
      epidermal cancer proneness of XP patients. The lack of efficient pharmacological
      treatments, the easy accessibility of skin, and the possibility of long term
      culture and genetic manipulations ex vivo of epidermal keratinocytes, have
      encouraged approaches toward gene transfer and skin therapy prospects. We review
      here some of the human genetic disorders that exhibit major traits in skin, as
      well as requirements and difficulties inherent to approaches aimed at stable
      phenotypic correction.

PMID- 12427541
TI  - Enhanced DNA repair of cyclobutane pyrimidine dimers changes the biological
      response to UV-B radiation.
AB  - The goal of DNA repair enzyme therapy is the same as that for gene therapy: to
      rescue a defective proteome/genome by introducing a substitute protein/DNA. The
      danger of inadequate DNA repair is highlighted in the genetic disease xeroderma
      pigmentosum. These patients are hypersensitive to sunlight and develop multiple
      cutaneous neoplasms very early in life. The bacterial DNA repair enzyme T4
      endonuclease V was shown over 25 years ago to be capable of reversing the
      defective repair in xeroderma pigmentosum cells. This enzyme, packaged in an
      engineered delivery vehicle, has been shown to traverse the stratum corneum,
      reach the nuclei of living cells of the skin, and enhance the repair of UV
      induced cyclobutane pyrimidine dimers (CPD). In such a system, changes in DNA
      repair, mutagenesis, and cell signaling can be studied without manipulation of
      the genome.

PMID- 12427542
TI  - Synergistic regulation of human cystathionine-beta-synthase-1b promoter by
      transcription factors NF-YA isoforms and Sp1.
AB  - Cystathionine-beta-synthase (CBS) catalyzes the condensation of serine and
      homocysteine to form cystathionine, an intermediate step in the synthesis of
      cysteine. We previously described essential transactivating roles for specificity
      protein 1 (Sp1), Sp3, nuclear factor Y (NF-Y), and USF-1 in the regulation of the
      CBS-1b promoter. Differential binding of Sp1/Sp3 to the CBS-1b promoter due to
      differences in Sp1/Sp3 phosphorylation, and Sp1/Sp3 synergism with NF-Y might, in
      part, explain cell-specific patterns of CBS expression. In this report, the roles
      of various NF-YA isoforms in influencing cell-specific differences in CBS gene
      expression were determined in HT1080 and HepG2 cells. Seven unique NF-YA isoforms
      were detected in HT1080 by reverse transcriptase-PCR (RT-PCR) and DNA sequencing,
      characterized by deletions in the glutamine-rich and/or serine/threonine-rich
      domains. Only four of the seven NF-YA isoforms were found in HepG2 cells. The six
      alternatively spliced NF-YA isoforms all showed significantly less synergistic
      transactivation of the CBS-1b promoter with Sp1 than wild-type NF-YA, as
      determined by cotransfections in Drosophila SL2 cells with NF-YB and NF-YC.
      Further, all six alternatively spliced NF-YA isoforms inhibited the synergistic
      transactivation of the CBS-1b promoter by wild-type NF-Y and Sp1. Thus, the
      cellular distributions of these alternatively spliced NF-YA isoforms could impart
      an important cell-specific component to CBS transcriptional regulation, by virtue
      of their abilities to directly synergize with Sp1/Sp3 and interfere with
      transactivation of the CBS-1b promoter by wild-type NF-Y. Characterization of CBS
      promoter structure and function should clarify the molecular bases for variations
      in CBS gene expression in genetic diseases and the relationship between CBS and
      Down's syndrome (DS).

PMID- 12427543
TI  - Characterization of the rat RALDH1 promoter. A functional CCAAT and octamer motif
      are critical for basal promoter activity.
AB  - Retinal dehydrogenase type 1 (RALDH1) catalyzes the oxidation of retinal to
      retinoic acid (RA), a metabolite of vitamin A important for embryogenesis and
      tissue differentiation. Rat RALDH1 is expressed to high levels in developing
      kidney, and in stomach, intestine epithelia. To understand the mechanisms of the
      transcriptional regulation of rat RALDH1, we cloned a 1360-base pair (bp) 5'
      flanking region of RALDH1 gene. Using luciferase reporter constructs transfected
      into HEK 293 and LLCPK (kidney-derived) cells, basal promoter activity was
      associated with sequences between -80 and +43. In this minimal promoter region,
      TATA and CCAAT cis-acting elements as well as SP1, AP1 and octamer (Oct)-binding
      sites were present. The CCAAT box and Oct-binding site, located between positions
      -72 and -68 and -56 and -49, respectively, were shown by deletion analysis and
      site-directed mutation to be critical for promoter activity. Nuclear extracts
      from kidney cells contain proteins specifically binding the Oct and CCAAT
      sequences, resulting in the formation of six complexes, while different patterns
      of complexes were observed with non-kidney cell extracts. Gel shift assays using
      either single or double mutations of the Oct and CCAAT sequences as well as super
      shift assays demonstrated single and double occupancy of these two sites by Oct-1
      and CBF-A. In addition, unidentified proteins also bound the Oct motif
      specifically in the absence of CBF-A binding. These results demonstrate specific
      involvement of Oct and CCAAT-binding proteins in the regulation of RALDH1 gene.

PMID- 12427544
TI  - The BSP30 salivary proteins from cattle, LUNX/PLUNC and von Ebner's minor
      salivary gland protein are members of the PSP/LBP superfamily of proteins.
AB  - Saliva influences rumen function in cattle, yet the biochemical role for most of
      the bovine salivary proteins (BSPs) has yet to be established. Two cDNAs (BSP30a
      and BSP30b) from bovine parotid salivary gland were cloned and sequenced, each
      coding for alternate forms of a prominent protein in bovine saliva. The BSP30
      cDNAs share 96% sequence identity with each other at the DNA level and 83% at the
      amino acid level, and appear to arise from separate genes. The predicted BSP30a
      and BSP30b proteins share 26-36% amino acid identity with parotid secretory
      protein (PSP) from mouse, rat and human. BSP30 and PSP are in turn more distantly
      related to a wider group of proteins that includes lung-specific X protein, also
      known as palate, lung, and nasal epithelium clone (LUNX/PLUNC), von Ebner's minor
      salivary gland protein (VEMSGP), bactericidal permeability increasing protein
      (BPI), lipopolysaccharide binding protein (LBP), cholesteryl ester transfer
      protein (CETP), and the putative olfactory ligand-binding proteins RYA3 and
      RY2G5. Bovine cDNAs encoding homologs of LUNX/PLUNC and VEMSGP were isolated and
      sequenced. Northern blot analysis showed that LUNX/PLUNC, BSP30 and VEMSGP are
      expressed in bovine salivary tissue and airways, and that they have non-identical
      patterns of expression in these tissues. The expression of both BSP30a and BSP30b
      is restricted to salivary tissue, but within this tissue they have distinct
      patterns of expression. The proximity of the human genes coding for the PSP/LBP
      superfamily on HSA20q11.2, their similar amino acid sequence, and common exon
      segmentation strongly suggest that these genes evolved from a common ancestral
      gene. Furthermore, they imply that the BSP30a and BSP30b proteins may have a
      function in common with other members of this gene family.

PMID- 12427545
TI  - Structure and regulation of the murine gamma-casein gene.
AB  - The murine casein locus consists of five genes, which are coordinately regulated
      during mammary development. The levels of casein-specific mRNAs in mammary
      epithelial cells increase during the second half of pregnancy and remain high
      during lactation. The murine gamma-casein gene, which corresponds to the alphaS2
      casein gene in ruminants, was isolated from a mouse bacterial artificial
      chromosome (BAC) library (strain 129SV). The gene contains 14 exons, which are
      distributed over 14 kb of DNA sequence. The expression pattern of the murine
      gamma-casein gene mimics that of the neighbouring beta-casein gene in terms of
      developmental induction in vivo. In cell culture, both the beta- and gamma-casein
      promoter are synergistically induced by prolactin and glucocorticoids.
      Glucocorticoid induction is critically dependent on prolactin-mediated activation
      of STAT5 in both promoters. Several consensus STAT5 binding sites were identified
      in the gamma-casein promoter, some of which may have an additive effect on
      prolactin induction. mRNA levels of gamma- and beta-casein are similar in
      lactating mammary tissue. However, promoter segments derived from the gamma
      casein gene are significantly less active in cell culture than comparable
      fragments of the beta-casein promoter. Promoter hybrids between the gamma- and
      beta-casein promoters revealed that the critical sequences which are responsible
      for the different in vitro activity are located in a short promoter proximal
      region.

PMID- 12427546
TI  - Characterization of a human sphingosine-1-phosphate receptor gene (S1P5) and its
      differential expression in LGL leukemia.
AB  - Large granular lymphocyte (LGL) leukemia is a lymphoproliferative disorder often
      associated with autoimmune disease. A central feature of this disease is
      dysregulation of apoptosis. In order to identify differentially expressed genes
      in LGL leukemia, microarray analysis was performed. We found many differentially
      expressed genes including several expression sequence tags (ESTs). As a
      systematic study, we selected one up-regulated EST (GenBank Accession number
      N47089) and further investigated. An LGL leukemia library was screened using this
      EST as a probe and a full-length sequence for a novel gene was identified. The
      deduced amino acid sequence revealed that the novel gene encodes a G-protein
      coupled receptor gene that exhibits 86% identity with rat sphingosine-1-phosphate
      receptor (edg-8/nrg-1). This gene is present in brain, spleen, and peripheral
      blood mononuclear cells (PBMC) and is overexpressed in leukemic LGL.

PMID- 12427547
TI  - Isoenzyme-directed selection and characterization of anti-creatine kinase single
      chain Fv antibodies from a human phage display library.
AB  - Epitopes differing among isoenzymes of creatine kinase (CK) are apparently
      limited in number and poorly immunogenic in vivo. Especially for the BB-CK
      isoenzyme, very few monoclonal antibodies (mAb) are available. Here, we use in
      vitro selection with a synthetic human phage display antibody library and develop
      isoenzyme competition and peptide panning strategies to obtain human single chain
      Fv (scFv) antibodies against specific CK isoenzymes. We isolated and
      characterized seven scFv clones that recognize native as well as denatured
      cytosolic BB-CK in ELISA, immunoblot, immunofluorescence histochemistry and
      surface plasmon resonance (SPR) spectroscopy. To a variable but minor degree,
      they also react with cytosolic MM-CK, but not with mitochondrial CK isoenzymes.
      Epitope mapping revealed that the scFv antibodies recognize different BB-CK
      epitopes, including the N-terminus and the isoenzyme-specific box, a highly
      conserved sequence of unknown function for which no mAb were available so far.
      With a K(D) of 3.5-9.6 x 10(-7) M, the isolated scFv compare favorably with mouse
      mAb and may overcome certain of their limitations. Our results demonstrate the
      advantages of in vitro antibody selection for the generation of isoenzyme
      specific antibodies.

PMID- 12427548
TI  - Expression of the rice vdac isoform2: histochemical localization and expression
      level.
AB  - The voltage-dependent anion-selective channel (VDAC) is a mitochondrial outer
      membrane ion channel. The putative promoter of the rice vdac isoform2 (osvdac2)
      was isolated by screening a rice genomic library. Computer-based analyses
      predicted a TATA box, a putative transcription start and several transcription
      factor-binding sites including pollen specific elements. The promoter region was
      fused to the gus reporter gene and introduced into rice by Agrobacterium-mediated
      transformation. Histochemical and cell-type localizations indicated an overall
      expression of this promoter with a strong expression in actively growing lateral
      roots and in the pollen grains. Quantitative experiments showed that the osvdac2
      promoter has a strong specific activity in both root and shoot. Thus, the osvdac2
      promoter could be a good alternative to viral promoters (e.g. CaMV 35S) to
      overexpress genes in transgenic Poaceae.

PMID- 12427549
TI  - The interaction of cisplatin and analogues with DNA in reconstituted chromatin.
AB  - The influence of chromatin structure on cis-diamminedichloroplatinum(II)
      (cisplatin) DNA damage was investigated in a reconstituted nucleosome system.
      Nucleosomes were reconstituted on the somatic 5S rRNA gene from Xenopus borealis
      using the octamer transfer method of reconstitution. Footprinting techniques,
      utilising bleomycin and DNase I as the damaging agents, were employed to
      establish the precise location of positioned nucleosomes with respect to the DNA
      sequence. Reconstituted nucleosomal DNA was treated with cisplatin and drug
      induced DNA adduct formation was quantitatively analysed with a polymerase stop
      assay using Taq DNA polymerase. A densitometric comparison of the relative damage
      band intensities between purified and reconstituted DNA revealed regions of
      relative protection corresponding to the sites of the positioned nucleosome
      cores. This indicated that the preferred site of cisplatin DNA binding was in the
      linker region of the nucleosome. Statistical analysis showed significant
      protection from cisplatin DNA damage in the core region of the nucleosome. Three
      cisplatin analogues were also investigated in this reconstituted nucleosome
      system. These analogues, cis-diammine(1,1-cyclobutanedicarboxylato)platinum(II)
      (carboplatin), cis-dichlorobis(cyclohexylamine)platinum(II) (cis
      [PtCl(2)(C(6)H(11)NH(2))(2)]) and dichloro(N-[3-[(2-aminoethyl)
      amino]propyl]acridine-4-carboxamide)platinum(II) (ac-PtenCl(2)(n3)), were also
      found to target the linker region of the nucleosome. The latter DNA-targeted
      acridine-platinum complex gave rise to the most predominant footprints of all the
      Pt compounds tested.

PMID- 12427550
TI  - Organization of the human PTK7 gene encoding a receptor protein tyrosine kinase
      like molecule and alternative splicing of its mRNA.
AB  - Protein tyrosine kinase-7 (PTK7) is a receptor protein tyrosine kinase (RPTK)
      like molecule that contains a catalytically inactive tyrosine kinase domain. We
      report here the genomic structure of the human PTK7 gene by screening a BAC
      library and DNA sequencing. The PTK7 gene is organized into 20 exons. All of the
      splicing junctions followed the conserved GT/AG rule. The exon-intron structure
      of the PTK7 gene in the region that encodes the catalytic domain was distinct
      from those of other RPTKs with strong homology. The 5'-flanking sequence of the
      PTK7 gene contains two GC boxes that concatenate Sp1 binding motifs, but does not
      contain either the TATA or CAAT consensus sequence. Using a luciferase reporter
      assay, it was demonstrated that the 883-bp 5'-flanking sequence is functional as
      a promoter of the PTK7 gene. We identified four new splicing variants in testis
      that could be derived from alternative splicing of exons 8-10, 10, a part of 12
      13, and 16. The expression patterns of the splicing variants in the hepatoma and
      colon cancer cells were different from those of the testis. Our findings suggest
      that PTK7 is evolutionarily distinct from other RPTKs, and that the alternative
      splicing of PTK7 mRNA may contribute to its diverse function in cell signaling.

PMID- 12427551
TI  - Genetics and differential expression of NADH:ubiquinone oxidoreductase B8 subunit
      in brains of genetic strains of mice differing in voluntary alcohol consumption.
AB  - Inbred strains of mice remain a valuable resource for genetic dissection of
      complex traits including responses to drugs and chemicals, particularly alcohol.
      As a novel source of candidate genes for further analysis, we have used mRNA
      differential displays to identify genes with differential expression in the
      brains of ethanol-preferring (C57BL/6J) vs. ethanol-avoiding (A/J, BALB/c, and
      DBA/2J) strains, with and without ethanol i.p. treatments (4 g/kg). We report on
      one such gene, NADH:ubiquinone oxidoreductase B8 subunit, that has a higher
      expression in the C57BL/6J. Further, its expression also increases following
      ethanol treatment as compared to the three alcohol-avoiding strains. This
      regulatory feature follows three single nucleotide polymorphisms (SNPs) in the
      promoter region across the four strains studied. The four strains represent only
      two haplotypes, one C57BL/6J-specific and the other found in the three alcohol
      avoiding strains. Interestingly, one of the observed SNPs (-687 A/G) is located
      in the putative TFIID binding site with potential to regulate the expression of
      this gene and contribute to genotype-specific alcohol responses and effects
      involving reactive oxygen species (ROS).

PMID- 12427552
TI  - Molecular cloning and characterization of prokineticin receptors.
AB  - Recent studies have identified two novel biofunctional proteins, termed
      prokineticin 1/EG-VEGF and prokineticin 2, which were mammalian homologues of
      mamba MIT1 and frog Bv8. Prokineticins have been demonstrated to exert their
      physiological functions through G-protein coupled receptors (GPCRs). In this
      study, we report the molecular identification of two endogenous prokineticin
      receptors, designated PK-R1 and PK-R2, through a search of the human genomic DNA
      database. PK-R1, locating in chromosome 2, and PK-R2, locating in chromosome
      20p13, shared 87% homology, which was an extremely high value among known GPCRs.
      In functional assays, mammalian cells expressing PK-Rs responded to prokineticins
      in a concentration-dependent manner. Tissue distribution analysis revealed that
      expression of PK-R1 was observed in the testis, medulla oblongata, skeletal
      muscle and skin, while that of PK-R2 showed preferential expression in the
      central nervous system. The tissue distribution of PK-Rs reported in this paper
      suggests that the prokineticins play multifunctional roles in vivo.

PMID- 12427553
TI  - Functional characterization of the human spermidine/spermine N(1)
      acetyltransferase gene promoter.
AB  - Spermidine/spermine N(1)-acetyltransferase (SSAT), the key enzyme of polyamine
      catabolism, is induced by antiproliferative stresses. We analyzed the 5' flanking
      region of the human SSAT gene, and clarified that the binding of Sp1 to the GC
      box located 42 to 51 bp upstream from the transcription start site is essential
      for transcription in HeLa S3 cells. A polyamine-responsive element (PRE) seemed
      to be responsible for the elevated transcription after X-ray irradiation.

PMID- 12427554
TI  - cDNA cloning and mRNA expression of Transformer 2 (Tra 2) in chicken embryo.
AB  - We report the cloning of a chicken Transformer 2 (Tra 2) cDNA that encodes a
      protein of 289 amino acids which are 97.9% identical to those of mammalian
      splicing factor, Tra 2. Tra 2 mRNA was expressed in chicken embryonic tissues and
      was observed as a band of 1.5 kb by Northern blot analysis. Whole mount in situ
      hybridization showed an mRNA expression of Tra 2 in telencephalon, mandible,
      hyoid arch, wing and leg buds as early as day 3.5 of incubation. These results
      suggest that the Tra 2 gene may play a role in organogenesis in the chicken
      embryo.

PMID- 12427555
TI  - Cloning and characterization of a novel synaptosome-enriched mRNA that encodes 31
      kDa protein.
AB  - Although a subpopulation of mRNAs has been identified as translocated to the
      dendrites or the synaptic regions of neurons, the translocational mechanism has
      not been elucidated. To find mRNAs enriched in synapses, we compared the
      synaptosomal mRNAs with those from whole forebrain using differential display
      (DD). We cloned one of these mRNAs, which encoded a novel 31 kDa protein (PMES
      2). PMES-2 mRNA was specifically transcribed in the brain and was present in the
      dendrites of the hippocampal neurons. PMES-2 protein was partly localized in the
      postsynaptic density. Although this protein is very similar to human NABC1
      protein, its function is still unknown.

PMID- 12427556
TI  - The Shiga-toxin VT2-encoding bacteriophage varphi297 integrates at a distinct
      position in the Escherichia coli genome.
AB  - The plaque-forming VT2-encoding lambdoid bacteriophage varphi297 was isolated
      from a Belgian clinical Escherichia coli O157:H7 isolate. PCR walking, starting
      from the int gene of phage varphi297, demonstrated that the varphi297 prophage
      integrated in the yecE gene of a lysogenic E. coli K12 strain. This integration
      site, in E. coli K12 and in the original clinical O157:H7 isolate, was confirmed
      by PCR using primers flanking this site. The excisionase protein of phage
      varphi297 is identical to the excisionase of VT1-encoding phage VT1-Sakai, while
      the integrases, which are 82% identical, show significant sequence divergence in
      the central and C-terminal region. This can explain the different integration
      sites of both prophages. The activity of the integrase was proven by its ability
      to mediate the integration of a suicide plasmid, carrying the attachment site of
      varphi297, at the appropriate position in the E. coli chromosome.

PMID- 12427557
TI  - Sequence of goat cyclin T1 cDNA, gene organisation and expression analysis.
AB  - The cyclin T1 (Cyc T1) protein has been recently identified, associated with the
      cyclin-dependent kinase 9 (CDK 9), as to be involved in the transcriptional
      activation of the Human Immunodeficiency Virus type 1 (HIV-1) by the Tat protein.
      In this study, the sequence of the 7 kb goat Cyc T1 cDNA is reported as well as
      the exon/intron structure of the gene. Its observed ubiquitous expression is
      consistent with the promoter structure.

PMID- 12427558
TI  - Gene expression of the POU factor Brn-3a is regulated by two different promoters.
AB  - Expression of the POU transcription factor Brn-3a is regulated spatially and
      temporally during embryogenesis and can be detected in a particular subset of
      neurons and neuronal tumors. In the present study, we investigated the
      transcriptional regulation of Brn-3a expression. The human promoter is TATA-less
      and contains two bona fide mRNA start sites spread over 500 nucleotides 5' of the
      ATG translation initiation codon. Furthermore, a second TATA-less promoter was
      detected in the first intron of the Brn-3a gene and our data suggest that this
      promoter regulates expression of the shorter isoform of the Brn-3a gene.
      Transcriptional activity from this promoter was found in neuronal cell lines but
      not in epithelial cells. The activity of this promoter was strongly enhanced upon
      deletion of a 24 base pair (bp) DNA element downstream of the transcription
      initiation sites. In addition, this DNA element was able to repress transcription
      from a heterologous promoter suggesting a function as a transcriptional silencer.
      The more distal upstream Brn-3a promoter directing the expression of the longer
      Brn-3a isoform is not affected by the presence of this putative 24 bp DNA
      element. We propose therefore that the existence of two promoters in the Brn-3a
      gene offers a possibility for the observed differential and cell type-specific
      expression of the gene.

PMID- 12427559
TI  - Cloning and characterization of human and mouse DDA3 genes.
AB  - We have previously reported the identification of the mouse DDA3 as a p53- and
      p73-inducible gene that encodes a protein capable of suppressing cell growth when
      ectopically expressed. We now report the cloning of the DDA3 cDNA of human as
      well as the genomic DDA3 DNA of human and mouse. Human DDA3 contains a 1002-bp
      open reading frame encoding a protein of 333 amino acids that shares 68.2%
      identity in amino acid sequence to the mouse protein. Expression of the human
      DDA3 transcript was detectable in various adult and fetal tissues examined, and
      was most abundantly expressed in the adult brain and fetal thymus. The DDA3 genes
      for human (7.7 kb) and mouse (6.7 kb) were sequenced; both contained eight exons,
      the genomic organization and the exon-intron junction sequences were highly
      conserved. The human DDA3 is located on chromosome 1p13.1, and the mouse gene is
      mapped to a syntenic region of chromosome 3. Analysis of a 300-kb genomic regions
      surrounding the mouse and human DDA3 genes revealed that the composition and
      orders for flanking genes were identical. Together, these results indicate that
      the newly cloned human gene is an orthologue of the mouse DDA3.

PMID- 12427560
TI  - Identification and characterization of UEV3, a human cDNA with similarities to
      inactive E2 ubiquitin-conjugating enzymes.
AB  - Recent studies have shown that ubiquitination is an essential factor in endosomal
      sorting and virus assembly. The human TSG101 gene has been demonstrated to belong
      to a group of genes coding for apparently inactive E2 ubiquitin-conjugating
      enzymes, which exert regulatory effects on E2 activity in cellular ubiquitination
      processes. In this study, a novel human cDNA (UEV3) encoding a putative protein
      of 379 amino acids was isolated from a human placenta library that may represent
      a partial paralogue of human TSG101. The predicted protein contains an N-terminal
      domain homologous to the catalytic domain of ubiquitin-conjugating enzymes (Ubc),
      which is fused to a sequence showing significant homology to members of the
      lactate dehydrogenase protein family. The UEV3 gene is located on chromosome 11
      closely adjacent to TSG101 and LDH-C. Northern blot and UEV3-specific reverse
      transcription/polymerase chain reaction (RT/PCR) analyses of various colon
      carcinoma cell lines as well as both normal and tumor samples from colon revealed
      an expression of the UEV3 cDNA in all tested samples.

PMID- 12427561
TI  - Multimodal visual-somatosensory integration in saccade generation.
AB  - Neurophysiological studies have demonstrated multisensory interaction effects in
      the neural structures involved in saccade generation when visual, auditory or
      somatosensory stimuli are presented bimodally. Visual-auditory interaction
      effects have been demonstrated in numerous behavioural studies of saccades but
      little is known about interaction effects involving somatosensory stimuli. The
      present study examined visual-somatosensory interaction effects on saccade
      generation using a multisensory paradigm, whereby task-irrelevant distractors
      appeared spatially-coincident with, or remote from the designated saccade target.
      Somatosensory distractors reduced the latency of saccades when presented before
      the visual target and the greatest facilitation effect was observed with
      spatially-coincident stimuli. Visual distractors spatially-coincident with a
      somatosensory target reduced latency (and increased peak velocity) when presented
      before and after the target. Visual distractors contralateral to somatosensory
      targets increased saccade latency and produced high error rates of saccades made
      to the distractor. The high error rates and latency modulation with visual
      distractors is consistent with a bias for visual stimuli in the saccadic system.
      In the visual target condition, saccade latency was modulated by a somatosensory
      distractor that was entirely task-irrelevant and this effect was always greatest
      with spatially-coincident distractors. The multisensory distractor effects are
      discussed in terms of saccades being programmed to the non-target modality, the
      early triggering of a non-spatial saccade 'when' signal, and multisensory
      neuronal enhancement effects.

PMID- 12427562
TI  - A case for case: handling letter case selection in written spelling.
AB  - This study reports the unusual writing performance of a 72-year-old woman, Pp,
      who was unable to maintain her writing within a particular case, and made
      numerous case mixing errors (e.g. insTEAd). Her oral spelling was flawless, but
      when tested using a written spelling task (including words and non-words), a
      picture description task, a sentence writing task and a transcription task (from
      upper case to lower case, and vice versa), she showed a high proportion of case
      mixing errors, though spelling per se was correct. The problem, although less
      severe, was also present when spelling with letter cards. Despite a spared
      ability to select the correct letters in the stimulus, specify the correct number
      of letters and place them in the correct order, she had a specific problem in
      selecting the appropriate case. This impairment is indicative of peripheral
      dysgraphia. She appeared to have intact orthographic representations, but
      selection of the appropriate allographic codes for upper and lower case was
      impaired. Her longitudinal neuropsychological profile and MRI evidence suggest
      that Pp suffers from mild vascular dementia with more severe impairments in
      attentional functions. Her writing deficits may be accounted for by a model that
      incorporates an inhibitory mechanism, which is responsible for maintaining the
      appropriate case and inhibiting the inappropriate one, subsequent to case
      selection in writing. Failure of this mechanism would explain the pattern of case
      mixing shown by Pp.

PMID- 12427563
TI  - Simulating unilateral neglect in normals using prism adaptation: implications for
      theory.
AB  - Rightward deviation on line bisection is considered one of the most classic
      clinical signs of unilateral visual neglect--a cognitive disorder of spatial
      processing that commonly follows right brain damage. Recently, short-term
      adaptation to wedge prisms has been shown to significantly reduce neglect on this
      and other conventional diagnostic tasks. Our previous study has shown that
      visuomotor adaptation in normals produces a similar pattern of directional bias
      on a line bisection task. Based on the good working knowledge of how neglect
      patients perform on different versions of the standard diagnostic task, we showed
      here that using leftward-deviating prisms in normals, it is possible to produce:
      (1) a reliable bias on line bisection, (2) a rightward specific deviation, (3) a
      modulation of rightward deviation, which depends on the relative spatial location
      of the target lines and (4) a line length effect. A final experiment confirmed
      that these after-effects are specific to prism adaptation rather than passive
      prism exposure. Collectively, these findings confirm that adaptation to left
      deviating prisms in normals produces a reliable right-sided bias and as shown by
      a previous visuospatial judgement task, these findings cannot be adequately
      explained by the symmetric sensori-motor effects of prism adaptation. Taken
      together with the improvement of spatial neglect shown by right-deviating prisms
      only, the present study suggests that low level sensori-motor adaptations play a
      greater role in right hemisphere organisation for spatial cognition than
      previously thought.

PMID- 12427564
TI  - Neural correlates of retrieval processing in the prefrontal cortex during
      recognition and exclusion tasks.
AB  - Event-related fMRI was employed to contrast the neural activity elicited in
      prefrontal cortex during recognition memory and exclusion tests. The study phases
      preceding each memory test were identical, involving the presentation of study
      items (visually presented words) in one of two study contexts. For the
      recognition test subjects were required to respond positively to all old items
      regardless of study context, and to respond negatively to new items. For the
      exclusion task, positive responses were required to old items presented in one of
      the study contexts only; negative responses were required both to unstudied items
      and studied items from the alternative context (non-targets). No prefrontal
      region demonstrated greater activity for new items in the exclusion task. Thus,
      there was no evidence that retrieval cues were processed differently according to
      the specificity of the sought-for information. In several regions, most notably
      bilateral anterior prefrontal cortex, activity was greater for old than for new
      items regardless of task. Activity in right dorsolateral prefrontal cortex was
      also greater for old than for new items; these effects however were larger in the
      exclusion task. The findings are consistent with previous reports that activity
      in anterior prefrontal cortex elicited by recognition retrieval cues is sensitive
      to retrieval success, and extend these findings to the exclusion task. The
      findings for the right dorsolateral cortex add further weight to the proposal
      that this region supports post-retrieval monitoring of retrieved information.

PMID- 12427565
TI  - Word-category specific deficits after lesions in the right hemisphere.
AB  - A speeded lexical decision task was used to investigate word-category deficits in
      patients suffering from lesions in the right hemisphere and in neurological
      controls without cortical lesion. In all patients from one group (n = 12), the
      right frontal lobe was affected causing a left-sided hemiparesis. In the second
      group (n = 6), lesions primarily affected areas in the right inferior temporo
      occipital lobes. Patients with motor deficits due to lesions in the spinal cord
      or in the periphery served as neurological controls (n = 9). Processing of three
      categories of words was investigated: verbs referring to actions (action verbs
      (acVs)); nouns with strong visual associations (visually-related nouns (viNs));
      and nouns with both strong action and visual associations (bimodal nouns (biNs)).
      Stimulus categories were matched for word length and normalized lexical
      frequency. Error scores revealed a significant word category by patient group
      interaction. Patients with lesions in the right frontal lobe showed most severe
      deficits in processing action verbs, whereas those with lesions in their right
      temporo-occipital areas showed most severe deficits in processing visually
      related nouns. Neurological controls did not show any differences between word
      categories. The double dissociation of the processing impairments seen in frontal
      versus temporo-occipital patients demonstrates that specific word-category
      deficits can arise from lesions in the right non-dominant hemisphere. An account
      for these results in terms of distributed neuronal systems representing words is
      offered.

PMID- 12427566
TI  - Role of the anterior temporal lobe in repetition and semantic priming: evidence
      from a patient with a category-specific deficit.
AB  - Neuroimaging studies in healthy participants have implicated anterior temporal
      lobe regions and the fusiform gyrus in repetition priming and semantic priming.
      Only the investigation of patients with selective lesions, however, can establish
      the necessity of these particular regions. To this end, we administered three
      tests of repetition priming (pseudoword identification; masked-form priming;
      category-exemplar generation) and a test of semantic priming to a patient (J.P.)
      with a category-specific deficit stemming from bilateral damage to the anterior
      fusiform gyrus and anterior temporal regions. On all of the repetition priming
      tasks, J.P. showed priming effects within 1 S.D. of 10 age- and education-matched
      CON; ANOVAs indicated no interaction between group and prime condition. These
      findings suggest that the anterior fusiform and anterior temporal lobe are not
      required for these priming effects. J.P. also showed normal repetition priming
      even for items that he had never been able to name or to provide semantic
      information about. On the semantic priming task, J.P. showed normal levels of
      priming across categories. When we separately analyzed his priming for items he
      could never name or access information about versus items that he had been able
      to name on at least two testing sessions, we found priming for the latter items,
      but not for the former. This result suggests that category-specific deficits
      resulting from damage to the anterior temporal lobes may disrupt the automatic,
      rapid access of semantic information of some items.

PMID- 12427567
TI  - Neural systems underlying lexical retrieval for sign language.
AB  - Positron emission tomography was used to investigate whether signed languages
      exhibit the same neural organization for lexical retrieval within classical and
      non-classical language areas as has been described for spoken English. Ten deaf
      native American sign language (ASL) signers were shown pictures of unique
      entities (famous persons) and non-unique entities (animals) and were asked to
      name each stimulus with an overt signed response. Proper name signed responses to
      famous people were fingerspelled, and common noun responses to animals were both
      fingerspelled and signed with native ASL signs. In general, retrieving ASL signs
      activated neural sites similar to those activated by hearing subjects retrieving
      English words. Naming famous persons activated the left temporal pole (TP),
      whereas naming animals (whether fingerspelled or signed) activated left
      inferotemporal (IT) cortex. The retrieval of fingerspelled and native signs
      generally engaged the same cortical regions, but fingerspelled signs in addition
      activated a premotor region, perhaps due to the increased motor planning and
      sequencing demanded by fingerspelling. Native signs activated portions of the
      left supramarginal gyrus (SMG), an area previously implicated in the retrieval of
      phonological features of ASL signs. Overall, the findings indicate that similar
      neuroanatomical areas are involved in lexical retrieval for both signs and words.

PMID- 12427568
TI  - Acquired mirror writing and reading: evidence for reflected graphemic
      representations.
AB  - Mirror writing occurs when individual letters and whole word strings are produced
      in reverse direction. By analogy, mirror reading refers to the preference to read
      mirror reversed over normally written words. These phenomena appear rarely after
      brain damage and offer insight into the nervous system's organization of visual
      spatial and visual-motor representations. We present the case of a 51-year-old
      patient with persistent mirror writing and reading following traumatic brain
      injury. She preferred to write in the mirror direction with either hand. She drew
      asymmetric pictures with the same directional bias as normal right-handed
      subjects, and she did not exhibit left-right confusion regarding other pictures.
      By contrast, on picture-word matching and lexical decision tasks, she was faster
      and more accurate with mirrored than normally written words. This pattern of
      performance suggests that her behavior was not accounted for by reflected motor
      programs, or by the mirroring of visual-spatial representations in general.
      Rather, we suggest that her behavior was produced by privileged access to
      mirrored graphemes. Furthermore, because she seemed better able to read irregular
      words in mirrored than in normal formats, we suggest that mirrored
      representations may exist at the whole word level and not simply at the letter
      level.

PMID- 12427569
TI  - Implicit learning deficit in children with developmental dyslexia.
AB  - Several neuropsychological deficits have been reported as characteristic of the
      cognitive profile of dyslexic children. Phonological and visual processing are
      often impaired as well as auditory processing, attention and information
      processing speed. We investigated whether implicit learning, is impaired in
      dyslexic children and adolescents. Tests of implicit and declarative learning
      were administered to 18 clinically defined dyslexics and 18 similar age controls.
      Dyslexics showed a reduced learning rate in the implicit but not in the
      declarative task, suggesting a specific deficit of implicit learning. Although
      alternative hypothesis cannot be ruled out, considering that implicit learning is
      a cognitive function primarily processed by the cerebellum and that recent
      neurological and physiological data suggest a cerebellar dysfunction in dyslexia,
      the present results suggest an impairment of cerebellar system in reading
      disabilities.

PMID- 12427571
TI  - Biomarkers: from bedside to bench and back again.

PMID- 12427572
TI  - Enhancing pathways to therapeutic development with clinical biomarkers.

PMID- 12427573
TI  - Alcohol use in later life: scourge, solace, or safeguard of health?

PMID- 12427574
TI  - Biomarkers in psychiatry: methodological issues.
AB  - Particularly in psychiatry, biological measures are increasingly sought to detect
      exposure to toxic agents, to assist in early identification of illness, and to
      enhance diagnostic certainty, provide prognostic information, and permit the
      mapping of outcome in a variety of disorders. The authors explore the fundamental
      criteria necessary to designate a biological measure as a "biomarker" and discuss
      the potential applications, limitations, and hazards of such markers. Authors
      discuss methods for establishing the validity of a biomarker. Finally, they
      convey a word of caution about overinterpreting the clinical or scientific value
      of any biological measure.

PMID- 12427575
TI  - Biological markers in Alzheimer disease.
AB  - Biological markers are important tools in identifying predisposing factors to
      disease, as diagnostic tests, and in monitoring disease progression. Alzheimer
      disease is believed to have a long preclinical phase, followed by mild cognitive
      impairment, and, finally, dementia. Detecting alterable predisposing factors or
      identifying patients in preclinical or early-stage illness offers the greatest
      potential to modifying disease course. The authors focus on: 1) predisposing
      factors, such as genetic risk factors and homocysteine; 2) laboratory markers,
      such as amyloid beta and tau protein; and 3) diagnostic markers, such as
      structural and functional neuroimaging. Many markers have been tested but have
      not been confirmed in subsequent studies. Other tests require complex and
      expensive laboratory evaluation or expertise, thereby limiting their use at
      present. Still others are markers only useful in later-stage illness.
      Nonetheless, the search for markers has increased our understanding of the
      biology of illness and has led to exciting new directions, with diagnostic as
      well as treatment implications.

PMID- 12427576
TI  - Biomarkers in psychotropic drug development.
AB  - The authors review the use of biomarkers in the development of novel psychotropic
      agents. They briefly review clinical drug development, emphasizing the importance
      of incorporating biomarkers. For the development of psychotropic agents,
      biomarkers are particularly useful for assessing central nervous system exposure
      and effects and for serving as surrogate measures for safety and efficacy.
      Collectively, biomarkers allow for more accurate estimation of doses for clinical
      trials as drug development progresses. For drugs that target the pathophysiology
      of Alzheimer disease, several promising biomarkers are becoming available that
      may allow improved signal detection in clinical trials. Procedures for developing
      new drugs are evolving rapidly. Technical advances in the field are making it
      possible to shift from empirically-based methods to mechanistically-driven
      schemes. Biomarkers enhance the quality and safety of clinical drug development
      and reduce its cost and duration.

PMID- 12427577
TI  - Frontostriatal and limbic dysfunction in late-life depression.
AB  - Studies using diverse methods have documented frontostriatal and limbic
      dysfunction occurring in late-life depression. Although such impairments may
      result from aging-induced brain changes unrelated to depression, there are at
      least two reasons to suggest that they play a pathogenetic role in geriatric
      depression. First, frontostriatal dysfunction has been identified in at least
      some younger depressed subjects without known neurological abnormalities. Second,
      frontostriatal dysfunction may be associated with poor short- and long-term
      outcomes of late-life depression. Relating frontostriatal and limbic dysfunction
      to the course of late-life depression is an appropriate way for investigating its
      pathophysiological relevance, given that no biological test can be used as a
      validating criterion. However, this approach has experimental limitations.
      Studies of the course of late-life depression may be influenced by selective
      survival of depressed patients with favorable prognosis; factors peripherally
      related to the biology of depression, for example, physical handicaps; and
      clinical factors with unclear relationship to specific biological abnormalities,
      for example, personality disorders. Nonetheless, studies comparing depressed
      patients with control subjects complemented with studies of course of illness can
      bring to bear the rapidly evolving cognitive-neuroscience and brain-imaging
      techniques in an investigation of the networks responsible for predisposing,
      precipitating, and perpetuating late-life depression.

PMID- 12427578
TI  - Evaluating the consistency of pharmacotherapy exposure by use of state-of-the-art
      techniques.
AB  - OBJECTIVE: The authors examine the usefulness of population pharmacokinetics
      coupled with electronic compliance monitoring in evaluating consistency of
      exposure to pharmacotherapy. Adherence to pharmacotherapy can have a significant
      impact on drug response, especially in the treatment of schizophrenia and
      depression. Previous studies evaluating antipsychotics identified schizophrenic
      individuals with poor pharmacotherapy adherence as having a higher risk of
      rehospitalization. Other investigators have shown a relationship between pattern
      of taking selective serotonin-reuptake inhibitors (SSRIs) and probability of a
      positive outcome. Therefore, it is important to measure adherence patterns in
      clinical trials evaluating these treatments and to incorporate this information
      into the research findings. METHODS: Two multisite trials with atypical
      antipsychotics and antidepressants were simulated to evaluate, by use of
      population pharmacokinetic methods, the impact of electronic monitoring on
      measuring consistency of exposure to pharmacotherapy. One of the trials is
      ongoing and evaluates exposure to atypical antipsychotics, and the other is a
      proposed trial that examines exposure to an SSRI. RESULTS: Erratic exposure
      patterns were detected with population pharmacokinetic techniques in the absence
      of Electronic Medication Event Monitoring (MEMS) data. In our simulations, the
      use of electronic monitoring improved the identification of atypical exposure by
      population pharmacokinetics both for the atypical antipsychotics and SSRIs.
      CONCLUSION: Our simulations demonstrate the potential usefulness of the
      combination of population pharmacokinetics with electronic monitoring as a robust
      method for accurately and precisely capturing both magnitude and consistency of
      pharmacotherapy exposure.

PMID- 12427579
TI  - Verification of scale sub-domains in elderly patients with dementia: a
      confirmatory factor-analytic approach.
AB  - OBJECTIVE: Use of cognitive, psychiatric and behavioral domains to assess the
      effectiveness of a pharmacological or behavioral intervention in the treatment of
      neurodegenerative disorders (e.g., Alzheimer disease) aids the identification of
      specific types of impairment or distress in behavioral status and quality-of-life
      issues in this population. With confirmatory approaches to subscale development
      readily available, we can obtain a more precise understanding of the sub
      components of a scale, potentially providing the basis for selecting behavioral
      and/or quality-of-life outcome measures that may be more sensitive to the effects
      of pharmacological or behavioral interventions. METHODS: The authors illustrate
      the use of a confirmatory factor-analytic approach to verify scale sub-domains of
      the Neurobehavioral Rating Scale (NBRS) in elderly patients with dementia. With
      data collected from two groups of patients being treated for significant
      psychiatric and behavioral symptoms, authors investigated the relationships among
      scale items in order to test several competing models, including a general one
      factor model, a first-order multifactor model, and a second-order factor model.
      RESULTS: The first-order model, with seven factors, provided the best fit to the
      correlations among items in the NBRS, indicating the multidimensionality of
      problematic behaviors and symptoms exhibited by dementia patients. CONCLUSION:
      Authors advocate the use of a confirmatory factor-analytic approach to verify
      scale sub-domains in other, more widely used rating scales for patients with
      dementia.

PMID- 12427581
TI  - Informant reports of changes in personality predict dementia in a population
      based study of elderly african americans and yoruba.
AB  - OBJECTIVE: The authors conducted a longitudinal, population-based survey of
      African Americans in Indianapolis, Indiana, and Yoruba in Ibadan, Nigeria, using
      the Community Screening Interview for Dementia to assess the predictive value of
      informant reports of changes in personality on incident dementia and Alzheimer
      disease. METHODS: In all, 3,021 subjects had informants' reports of changes in
      personality and dementia status (2,084 subjects residing in Ibadan and 937
      subjects residing in Indianapolis). RESULTS: After adjusting for demographic,
      cognitive, and functional characteristics in two markedly different populations,
      socioeconomically and culturally, subjects with changes in personality had
      approximately twice the odds of having dementia as subjects with no change in
      personality. CONCLUSION: The finding that in two markedly different populations,
      personality change is a significant predictor of future dementia, independent of
      cognition and functional status, should make clinicians particularly sensitive to
      these reports when they occur in their elderly patients.

PMID- 12427580
TI  - Acute and chronic effects of citalopram on cerebral glucose metabolism in
      geriatric depression.
AB  - OBJECTIVE: In vivo studies of serotonin function have been limited by the lack of
      safe and selective pharmacologic agents and availability of suitable
      radiotracers. In the present study, the authors evaluated the cerebral metabolic
      effects of acute and continued administration of the selective serotonin reuptake
      inhibitor citalopram in patients with geriatric depression as a potential marker
      of serotonin dysfunction. METHODS: Six patients with geriatric depression and
      five comparison subjects underwent two resting positron emission tomography (PET)
      studies, performed after administration of a placebo infusion (Day 1) and a
      citalopram infusion (40 mg, Day 2). The patients were re-scanned after 8 weeks of
      treatment with the oral medication. RESULTS: The elderly comparison subjects
      demonstrated greater right-hemisphere cortical decreases than the patients. The
      depressed patients demonstrated greater left-hemisphere cortical decreases than
      comparison subjects. The depressed patients demonstrated greater increases in the
      right putamen and left occipital cortex. After 8 weeks of citalopram treatment,
      regional decreases and increases in metabolism were observed. CONCLUSION: These
      findings suggest regional deficits and also compensatory responses in the acute
      metabolic response to citalopram in the patients. These preliminary results
      suggest that the cerebral metabolic response to citalopram may be a useful marker
      of the pathophysiology of serotonin function in geriatric depression.

PMID- 12427582
TI  - Older offenders, substance abuse, and treatment.
AB  - OBJECTIVE: The adoption of more stringent truth-in-sentencing laws and the aging
      of the United States population in general has led to an increase in the
      proportion of prison inmates age 55 years and older. Recent judicial rulings
      require prisoners to receive adequate medical and mental health care. Care for
      substance abuse is often included to reduce recidivism. However, little
      systematic research has been conducted on the mental health and substance abuse
      treatment needs of older prisoners. METHODS: The authors examined age differences
      in substance abuse history provided by 10,952 offenders as part of their
      orientation and evaluation on entry into prison. Trained substance abuse
      counselors interviewed each offender and recorded data in an institutional
      database. RESULTS: Seventy-one percent of older inmates reported a substance
      abuse problem. When compared with younger inmates, older offenders were more
      likely to abuse alcohol only. Those older inmates with abuse problems had used
      substances for over 40 years, yet more than one-third had never received
      treatment. CONCLUSION: Like younger inmates, most older offenders would benefit
      from substance abuse treatment. The treatment may need to be tailored to age and
      lack of previous treatment experience and should be sensitive to this high-risk
      group's additional medical needs.

PMID- 12427583
TI  - Alcoholism treatment adherence: older age predicts better adherence and drinking
      outcomes.
AB  - OBJECTIVE: Adherence to treatment has been demonstrated to be an important factor
      for remission from alcohol dependence. The authors compared therapy and
      medication adherence for treatment of alcohol dependence in older adults with
      adherence in younger adults. METHODS: All subjects were participants in a
      randomized, double-blind, placebo-controlled efficacy trial of naltrexone for the
      treatment of alcohol dependence. All subjects received a medically-based
      psychosocial intervention focused on motivating patients to change and on
      adherence to treatment. The therapy is nonconfrontational and is delivered by a
      nurse-practitioner. RESULTS: Compared with younger adults, older adults had
      greater attendance at therapy sessions and greater adherence to the medication.
      Age-group was the only pretreatment factor associated with adherence. The greater
      adherence in older adults translated to less relapse than in younger adults.
      CONCLUSION: Treatment for alcohol dependence can be effective for older adults.
      Older adults appear to respond well to a medically-oriented program that is
      supportive and individualized. In fact, findings from this study suggest that
      older adults can be treated in mixed-age treatment settings when
      psychotherapeutic strategies are used that are age-appropriate and delivered on
      an individual basis.

PMID- 12427584
TI  - Alcohol use among older persons in a rural state.
AB  - OBJECTIVE: Older individuals are vulnerable to adverse consequences from
      alcoholism; unfortunately, alcohol-related problems are often under-identified in
      this group. METHODS: We characterized the demographic features of alcohol use
      among older adults (over age 65) in a statewide community survey. RESULTS:
      Approximately 15% were at risk for alcoholism. As a group, the at-risk
      individuals were younger than the remaining sample. Twenty percent indicated that
      they had previously tried unsuccessfully to stop drinking, but only 10% had
      received any type of treatment. CONCLUSION: This low rate of treatment
      intervention implies a need for enhanced recognition of alcoholism among older
      adults in rural settings.

PMID- 12427585
TI  - Alcohol misuse among elderly psychiatric patient referrals.

PMID- 12427586
TI  - Use of topiramate as an adjunctive medication in an elderly patient with
      treatment-resistant bipolar disorder.

PMID- 12427589
TI  - Alkaline pH shifts Ca2+ sparks to Ca2+ waves in smooth muscle cells of
      pressurized cerebral arteries.
AB  - The effects of external pH (7.0-8.0) on intracellular Ca(2+) signals (Ca(2+)
      sparks and Ca(2+) waves) were examined in smooth muscle cells from intact
      pressurized arteries from rats. Elevating the external pH from 7.4 to 7.5
      increased the frequency of local, Ca(2+) transients, or "Ca(2+) sparks," and, at
      pH 7.6, significantly increased the frequency of Ca(2+) waves. Alkaline pH
      induced Ca(2+) waves were inhibited by blocking Ca(2+) release from ryanodine
      receptors but were not prevented by inhibitors of voltage-dependent Ca(2+)
      channels, phospholipase C, or inositol 1,4,5-trisphosphate receptors. Activating
      ryanodine receptors with caffeine (5 mM) at pH 7.4 also induced repetitive Ca(2+)
      waves. Alkalization from pH 7.4 to pH 7.8-8.0 induced a rapid and large
      vasoconstriction. Approximately 82% of the alkaline pH-induced vasoconstriction
      was reversed by inhibitors of voltage-dependent Ca(2+) channels. The remaining
      constriction was reversed by inhibition of ryanodine receptors. These findings
      indicate that alkaline pH-induced Ca(2+) waves originate from ryanodine receptors
      and make a minor, direct contribution to alkaline pH-induced vasoconstriction.

PMID- 12427590
TI  - Inhibitors of gap junctions attenuate myogenic tone in cerebral arteries.
AB  - The effects of two structurally distinct inhibitors of gap junction communication
      were studied by using three different forms of vasoconstriction in pressurized
      rat middle cerebral arteries. The sensitivity of myogenic tone (at 60 mmHg),
      vasopressin-induced tone (10 nM, at 20 mmHg), and depolarizing solution-induced
      tone (80 mM K(+), at 20 mmHg) to inhibition by heptanol (1.0 microM to 3.0 mM) or
      18alpha-glycyrrhetinic acid (18alpha-GA, 1.0 to 50 microM) were determined.
      Pressure-induced myogenic tone was inhibited by heptanol (IC(50) = 0.75 +/- 0.09
      mM) and 18alpha-GA ( approximately 30 microM). Vasopressin-induced
      vasoconstriction was also inhibited by heptanol (IC(50) = 0.4 +/- 0.3 mM) and
      18alpha-GA (>1 microM). Depolarizing solution-induced vasoconstriction was less
      sensitive to inhibition by heptanol compared to vasopressin (P < 0.01) or
      pressure-induced constriction (P < 0.05). However, 18alpha-GA did not inhibit
      depolarization-induced constriction. Sharp microelectrode experiments on isolated
      arteries revealed stable membrane potentials, with no detectable effect of
      heptanol (1 mM) or 18alpha-GA (20-30 microM) on the average membrane potential at
      20 mmHg. However, approximately 20% of impaled cells (5 of 28) exhibited
      uncharacteristic oscillations in membrane potential after pharmacological
      uncoupling. At 60 mmHg a approximately 7- to 9-mV hyperpolarization and
      corresponding vasodilation (approximately 50%) was observed, and the frequency of
      membrane potential oscillations doubled (9 of 23 cells). These data indicate that
      gap junctions play an important role in the maintenance and modulation of
      membrane potential and tone in cerebral resistance arteries.

PMID- 12427591
TI  - On the role of mechanosensitive mechanisms eliciting reactive hyperemia.
AB  - We hypothesized that changes in hemodynamic forces such as pressure (P) and flow
      (F) contribute importantly to the development of reactive hyperemia. To exclude
      the effects of vivo factors, isolated rat skeletal muscle arterioles (
      approximately 130 microm) were utilized. We found that changes in P or P + F
      following occlusions elicited reactive dilations (RD). The peak of RD (up to
      approximately 45 microm), but not the duration of RD, increased to changes in P
      (80 to 10, then back to 80 mmHg) as a function of the length of occlusions (30,
      60, and 120 s). However, changes in P + F (80-10 -80 mmHg + 25-0-25 microl/min)
      increased both the peak and duration of RD (from approximately 25 to 90 s) with
      longer occlusions. When only P changed, inhibition of nitric oxide synthesis or
      endothelium removal (E-) reduced only the peak of RD, whereas when P + F were
      changed, both the peak and duration of RD became reduced. Inhibition of stretch
      activated cation channels by gadolinium reduced the peak but enhanced the
      duration of RD (both to P or P + F) that was unaffected by N(G)-nitro-l-arginine
      methyl ester (l-NAME) or by E-. When only P changed, inhibition of tyrosine
      kinases by genistein reduced peak RD but did not affect the RD duration. However,
      when P + F changed, genistein reduced both the peak and the duration of RD,
      additional l-NAME reduced the peak RD, but did not affect the duration of RD.
      Thus in isolated arterioles an RD resembling the characteristics of reactive
      hyperemia can be generated that is elicited by deformation, stretch, pressure,
      and flow/shear stress-sensitive mechanisms and is, in part, mediated by nitric
      oxide.

PMID- 12427592
TI  - Different roles of PKC and MAP kinases in arteriolar constrictions to pressure
      and agonists.
AB  - Protein kinase C (PKC) and mitogen-activated protein (MAP) kinases have been
      implicated in the modulation of agonist-induced contractions of large vessels.
      However, their role in pressure- and agonist-induced constrictions of skeletal
      muscle arterioles, which have a major role in regulating peripheral resistance,
      is not clearly elucidated. Thus constrictions of isolated rat gracilis muscle
      arterioles (approximately 80 microm in diameter) to increases in intraluminal
      pressure and to norepinephrine (NE) or angiotensin II (ANG II) were assessed in
      the absence or presence of chelerythrine, PD-98058, and SB-203580 (inhibitors of
      PKC, p42/44 and p38 MAP kinase pathways, respectively). Arteriolar constriction
      to NE and ANG II were significantly reduced by chelerythrine (by approximately
      90%) and unaffected by SB-203580, whereas PD-98058 decreased only ANG II-induced
      constrictions (by approximately 60%). Pressure-induced increases in wall tension
      (from 0.1 to 0.7 N/m) resulted in significant arteriolar constrictions (50%
      maximum) that were abolished by chelerythrine without altering smooth muscle
      intracellular Ca(2+) concentration ([Ca(2+)](i)) (fura 2 microfluorimetry). PD
      98058 and SB-203580 significantly decreased the magnitude of myogenic tone (by
      20% and 60%, respectively) and reduced the sensitivity of the myogenic mechanism
      to wall tension, causing a significant rightward shift in the wall tension
      myogenic tone relationship without affecting smooth muscle [Ca(2+)i]. MAP kinases
      were demonstrated with Western blotting. Thus in skeletal muscle arterioles 1)
      PKC is involved in both myogenic and agonist-induced constrictions, 2) PD-98058
      sensitive p42/44 MAP kinases modulate both wall tension-dependent and ANG II
      induced constrictions, whereas 3) a SB-203580-sensitive p38 MAP kinase pathway
      seems to be specifically involved in the mechanotransduction of wall tension.

PMID- 12427593
TI  - Transfection of human endothelial cells with HIV-1 tat gene activates NF-kappa B
      and enhances monocyte adhesion.
AB  - Human immunodeficiency virus (HIV)-1 Tat released from HIV-1-infected monocytes
      is believed to enter other cells via an integrin-facilitated pathway, resulting
      in altered gene expression. Indeed, exogenous Tat protein can increase cell
      adhesion molecule gene expression in human endothelial cells. Signaling pathways
      initiated by Tat in endothelial cells are not known. We evaluated the ability of
      endogenous tat to stimulate monocyte adhesion via activation of nuclear factor
      kappaB (NF-kappaB) within human umbilical vein endothelial cells. Transfection
      with pcTat, but not control vector DNA, increased NF-kappaB binding activity, NF
      kappaB luciferase reporter activity, and monocyte adhesion. pcTat also increased
      kappaB-dependent HIV-1-LTR-CAT reporter activity 28-fold compared with a 3-fold
      increase produced by transfection with an equivalent amount of pcTax (from human
      leukemia virus). The pcTat-induced increase in pNF-kappaB-Luc activity and
      monocyte adhesion to endothelial cells was blocked by cotransfection with
      dominant-negative mutant IkappaBalpha and by incubation with 10 mM aspirin. We
      conclude that monocyte adhesion to human endothelial cells stimulated by pcTat is
      mediated via an NF-kappaB-dependent mechanism. Furthermore, inhibition studies
      using aspirin suggest that pcTat-stimulated NF-kappaB activation and monocyte
      adhesion occur via a redox-sensitive mechanism.

PMID- 12427594
TI  - Effects of acute reduction of temperature on ventricular fibrillation activation
      patterns.
AB  - Because of its electrophysiological effects, hypothermia can influence the
      mechanisms that intervene in the sustaining of ventricular fibrillation. We
      hypothesized that a rapid and profound reduction of myocardial temperature
      impedes the maintenance of ventricular fibrillation, leading to termination of
      the arrhythmia. High-resolution epicardial mapping (series 1; n = 11) and
      transmural recordings of ventricular activation (series 2; n = 10) were used to
      analyze ventricular fibrillation modification during rapid myocardial cooling in
      Langendorff-perfused rabbit hearts. Myocardial cooling was produced by the
      injection of cold Tyrode into the left ventricle after induction of ventricular
      fibrillation. Temperature and ventricular fibrillation dominant frequency decay
      fit an exponential model to arrhythmia termination in all experiments, and both
      parameters were significantly correlated (r = 0.70, P < 0.0001). Termination of
      the arrhythmia occurred preferentially in the left ventricle and was associated
      with a reduction in conduction velocity (-60% in left ventricle and -54% in right
      ventricle; P < 0.0001) and with activation maps predominantly exhibiting a single
      wave front, with evidence of wave front extinction. We conclude that a rapid
      reduction of temperature to <20 degrees C terminates ventricular fibrillation
      after producing an important depression in myocardial conduction.

PMID- 12427595
TI  - Female rats are protected against fructose-induced changes in metabolism and
      blood pressure.
AB  - The objective of this study was to determine whether the effects of a fructose
      diet, which causes hyperinsulinemia, insulin resistance, and hypertension in male
      rats, are dependent on sex. Blood pressure was measured via the tail-cuff method,
      and oral glucose tolerance tests were performed to assess insulin sensitivity.
      Blood pressure in female rats did not differ between fructose-fed and control
      rats at any time point (126 +/- 5 and 125 +/- 3 mmHg at week 9 for fructose-fed
      and control rats, respectively) nor was there a difference in any metabolic
      parameter measured. Furthermore, the vascular insulin resistance that is present
      in male fructose-fed rats was not observed. After ovariectomy, fructose caused a
      significant change in systolic blood pressure from baseline compared with
      fructose-fed ovary-intact rats (change of 21 +/- 5 vs. -2 +/- 4 mmHg). The
      results demonstrate that females do not develop hypertension or hyperinsulinemia
      upon fructose feeding except after ovariectomy, suggesting that female sex
      hormones may confer protection against the effects of a fructose diet.

PMID- 12427596
TI  - Effects of changes in left ventricular contractility on indexes of contractility
      in mice.
AB  - Measurement of left ventricular (LV) function is often overlooked in murine
      studies, which have been used to analyze the effects of genetic manipulation on
      cardiac phenotype. The goal of this study was to address the effects of changes
      in LV contractility on indexes of contractility in mice. LV function was assessed
      in vivo in closed-chest mice by echocardiography and by LV catheterization using
      a conductance pressure-volume (P-V) catheter with three different interventions
      that alter contractility by 1) atrial pacing to increase inotropy by augmentation
      of the force-frequency relation (modest increment of inotropy), 2) dobutamine to
      maximize inotropy, and 3) esmolol infusion to decrease contractility. Load
      independent parameters derived from P-V relations, such as slope of end-systolic
      P-V relations (ESPVR) and slope of the first maximal pressure derivative over
      time (dP/dt(max))-end-diastolic volume relation (dP/dt-EDV), and standard
      echocardiographic parameters were measured. The dP/dt-EDV changed the most among
      parameters after atrial pacing and dobutamine infusion (percent change, 162.8 +/-
      95.9% and 271.0 +/- 44.0%, respectively). ESPVR was the most affected by a
      decrease in LV contractility during esmolol infusion (percent change, -49.8 +/-
      8.3%). However, fractional shortening failed to detect changes in contractility
      during atrial pacing and esmolol infusion and its percent change was <20%. This
      study demonstrated that contractile parameters derived from P-V relations change
      the most during a change in LV contractility and should therefore best detect a
      small change in contractility in mice. Heart rate has a modest but significant
      effect on P-V relationship-derived indexes and must be considered in the
      evaluation of murine cardiac physiology.

PMID- 12427597
TI  - PH-induced changes in calcium: functional consequences and mechanisms of action
      in guinea pig portal vein.
AB  - The effects of changing extracellular (pH(o)) and intracellular pH (pH(i)) on
      force and the mechanisms involved in the guinea pig portal vein were investigated
      to better understand the control of tone in this vessel. When pH(o) was altered,
      the effects on force and calcium were the same irrespective of whether force had
      been produced spontaneously by high-K depolarization or by norepinephrine;
      alkalinization increased tone, and acidification reduced it. Because pH(o)
      changes also lead to changes in pH(i), we determined whether the effects on force
      could be explained by these induced pH(i) changes. It was found, however, that
      only with spontaneous activity did intracellular alkalinization increase force.
      In depolarized preparations, force was decreased, and, with norepinephrine, force
      was initially decreased and then increased. Thus the effects of pH(o) cannot be
      explained solely by changes in pH(i). The role of the sarcoplasmic reticulum (SR)
      and surface membrane Ca(2+)-ATPase on the mechanism were investigated and shown
      not to be involved. Therefore, it is concluded that both pH(o) and pH(i) can have
      powerful modulatory effects on portal vein tone, that these effects are not
      identical, and that they are likely to be due to effects of pH on ion channels
      rather than the SR or plasma membrane Ca(2+)-ATPase.

PMID- 12427598
TI  - Thyroid hormone regulation of cardiac bioenergetics: role of intracellular
      creatine.
AB  - The effect of thyroid hormone (T(3)) on the content of myocardial creatine (Cr),
      Cr phosphate (CrP), and high-energy adenine nucleotides and on cardiac function
      was examined. In the hearts of control and T(3)-treated rats perfused in vitro,
      while "low" and "high" contractile work was performed, T(3) treatment resulted in
      a approximately 50% reduction in CrP, Cr, total Cr content (Cr + CrP), and in the
      CrP-to-Cr ratio. In addition, there was a slight fall in myocardial content of
      ATP and a large rise in calculated free ADP (fADP), resulting in a significant
      decrease in the ATP-to-fADP ratio in the hearts of hyperthyroid compared with
      euthyroid rats. Moreover, there was a substantial decrease in the level of ATP in
      hearts of T(3)-treated rats under high work conditions. Importantly, the ratio of
      cardiac work to oxygen consumption was not altered by thyroid status. Treatment
      with T(3) also resulted in an almost threefold reduction in the content of
      Na(+)/Cr transporter mRNA in the ventricular myocardium and skeletal muscle but
      not in the brain. We conclude with the following: 1) changes in the expression of
      the Na(+)/Cr transporter mRNA correlate with Cr + CrP in the myocardium; 2)
      hearts of hyperthyroid rats contain lower levels of ATP and higher levels of fADP
      under both low and high work conditions but no reduction in efficiency of work
      output; and 3) the reduction in Cr and ATP in hearts of hyperthyroid rats may be
      the basis for the reduced maximal work capacity of the hyperthyroid heart.

PMID- 12427599
TI  - Comparison of three rat models of cerebral vasospasm.
AB  - A substantial number of rat models have been used to research subarachnoid
      hemorrhage-induced cerebral vasospasm; however, controversy exists regarding
      which method of selection is appropriate for this species. This study was
      designed to provide extensive information about the three most popular
      subarachnoid hemorrhage rat models: the endovascular puncture model, the single
      hemorrhage model, and the double-hemorrhage model. In this study, the basilar
      artery and posterior communicating artery were chosen for histopathological
      examination and morphometric analysis. Both the endovascular puncture model and
      single-hemorrhage model developed significant degrees of vasospasm, which were
      less severe when compared with the double-hemorrhage model. The endovascular
      puncture model and double-hemorrhage model both developed more vasospasms in the
      posterior communicating artery than in the basilar artery. The endovascular
      puncture model has a markedly high mortality rate and high variability in
      bleeding volume. Overall, the present study showed that the double-hemorrhage
      model in rats is a more suitable tool with which to investigate mechanism and
      therapeutic approaches because it accurately correlates with the time courses for
      vasospasm in humans.

PMID- 12427600
TI  - Alpha 2-Adrenergic stimulation is protective against ischemia-reperfusion-induced
      ventricular arrhythmias in vivo.
AB  - We previously reported that alpha(2)-adrenergic receptor (alpha(2)-AR)
      stimulation in Purkinje fibers in vitro prolongs action potential duration and
      suppresses beta-adrenergic-induced delayed afterdepolarizations and sustained
      triggered activities. We examined the effects of alpha(2)-AR stimulation on
      reperfusion-induced ventricular arrhythmias [ventricular tachycardia/ventricular
      fibrillation (VT/VF)] in vivo. Arterial blood pressure, heart rate, surface
      electrocardiogram, and renal sympathetic nerve activities were recorded
      simultaneously in Sprague-Dawley rats. The incidence of VT/VF was 87.5% for
      controls, 50% for the beta-blocker group, 72% for the alpha(1)-blocker group, and
      12.5% for the alpha(1) + beta-blockers group (unopposed alpha(2)-adrenergic
      activation). Direct alpha(2)-AR stimulation with UK-14304 also prevented VT/VF.
      These effects were reversed by the alpha(2)-adrenergic antagonist yohimbine.
      Increases in renal sympathetic nerve activity were associated with left anterior
      descending coronary artery ligation and reperfusion (33 +/- 1.5 and 62 +/- 1.7%
      over baseline, respectively) in controls. Similar patterns were observed among
      all experimental groups irrespective of the incidence of VT/VF on reperfusion. We
      conclude that alpha(2)-AR stimulation has a potent antiarrhythmic effect on
      ischemia-reperfusion-induced VT/VF in vivo and that this effect is not centrally
      mediated.

PMID- 12427601
TI  - Adenoviral-mediated overexpression of catalase inhibits endothelial cell
      proliferation.
AB  - Although hydrogen peroxide (H(2)O(2)) induces proliferation of vascular smooth
      muscle cells, its role in endothelial cell proliferation is unclear. Our aim was
      to study the role of hydrogen peroxide in endothelial cell proliferation by
      overexpressing catalase. Human aortic endothelial cells were transduced with
      adenoviral vectors encoding beta-galactosidase (Adbetagal) or catalase (AdCat) or
      were exposed to diluent alone (control). Transgene expression was demonstrated by
      beta-galactosidase staining, Western analysis, and significantly increased enzyme
      activity in AdCat-transduced cells. Overexpression of catalase decreased DNA
      synthesis in AdCat compared with control and Adbetagal-transduced cells (536.8 +/
      31 vs. 1,875.1 +/- 132.9 vs. 1,347.5 +/- 93.7 dpm/well, respectively; P < 0.05
      vs. control and Adbetagal). Six days after transduction with AdCat (multiplicity
      of infection = 50), cell numbers were significantly reduced (AdCat: 38 +/- 1.8%
      of cell counts in control, P < 0.05; and 45 +/- 2% of cell count in Adbetagal, P
      < 0.05). Incubation with aminotriazole 10 mmol/l, an inhibitor of catalase,
      prevented this effect. The number of apoptotic cells was increased one- and
      threefold 2 and 4 days, respectively, after transduction with AdCat. Exogenous
      administration of low concentrations of H(2)O(2) (50 microM) significantly
      increased cell proliferation, whereas it was inhibited by higher concentrations.
      These results suggest that H(2)O(2) is an important modulator of endothelial cell
      proliferation.

PMID- 12427602
TI  - ATP stimulates chemically sensitive and sensitizes mechanically sensitive
      afferents.
AB  - We examined whether ATP stimulation of P2X purinoceptors would raise blood
      pressure in decerebrate cats. Femoral arterial injection of the P2X receptor
      agonist alpha,beta-methylene ATP into the blood supply of the triceps surae
      muscle induced a dose-dependent increase in arterial blood pressure. The maximal
      increase in mean arterial pressure (MAP) evoked by 0.1, 0.2, and 0.5 mM
      alpha,beta-methylene ATP (0.5 ml/min injection rate) was 6.2 +/- 2.5, 22.5 +/-
      4.4, and 35.2 +/- 3.9 mmHg, respectively. The P2X receptor antagonist pyridoxal
      phosphate-6-azophenyl-2',4'-disulfonic acid (2 mM ia) attenuated the increase in
      MAP elicited by intra-arterial alpha,beta-methylene ATP (0.5 mM), whereas the P2Y
      receptor antagonist reactive blue 2 (2 mM ia) did not affect the MAP response to
      alpha,beta-methylene ATP. In a second group of experiments, we tested the
      hypothesis that ATP acting through P2X receptors would sensitize muscle afferents
      and, thereby, augment the blood pressure response to muscle stretch. Two
      kilograms of muscle stretch evoked a 26.5 +/- 4.3 mmHg increase in MAP. This MAP
      response was enhanced when 2 mM ATP or 0.1 mM alpha,beta-methylene ATP (0.5
      ml/min) was arterially infused 10 min before muscle stretch. Furthermore, this
      effect of ATP on the pressor response to stretch was attenuated by 2 mM pyridoxal
      phosphate-6-azophenyl-2',4'-disulfonic acid (P < 0.05) but not by the P1
      purinoceptor antagonist 8-(p-sulfophenyl)-theophylline (2 mM). These data
      indicate that activation of ATP-sensitive P2X receptors evokes a skeletal muscle
      afferent-mediated pressor response and that ATP at relatively low doses enhances
      the muscle pressor response to stretch via engagement of P2X receptors.

PMID- 12427603
TI  - Shear properties of passive ventricular myocardium.
AB  - We examined the shear properties of passive ventricular myocardium in six pig
      hearts. Samples (3 x 3 x 3 mm) were cut from adjacent regions of the lateral left
      ventricular midwall, with sides aligned with the principal material axes. Four
      cycles of sinusoidal simple shear (maximum shear displacements of 0.1-0.5) were
      applied separately to each specimen in two orthogonal directions. Resulting
      forces along the three axes were measured. Three specimens from each heart were
      tested in different orientations to cover all six modes of simple shear
      deformation. Passive myocardium has nonlinear viscoelastic shear properties with
      reproducible, directionally dependent softening as strain is increased. Shear
      properties were clearly anisotropic with respect to the three principal material
      directions: passive ventricular myocardium is least resistant to simple shear
      displacements imposed in the plane of the myocardial layers and most resistant to
      shear deformations that produce extension of the myocyte axis. Comparison of
      results for the six different shear modes suggests that simple shear deformation
      is resisted by elastic elements aligned with the microstructural axes of the
      tissue.

PMID- 12427604
TI  - Characterization of Ca2+ channels involved in ET-1-induced transactivation of EGF
      receptors.
AB  - The purpose of this study was to demonstrate the involvement of Ca(2+) influx
      through voltage-independent Ca(2+) channels (VICCs) in endothelin-1 (ET-1)
      induced transactivation of epidermal growth factor receptor protein tyrosine
      kinase (EGFR PTK) using the Ca(2+) channel blockers LOE-908 and SK&F-96365 in
      rabbit internal carotid artery vascular smooth muscle cells. ET-1-induced EGFR
      PTK transactivation was completely inhibited by AG-1478, which is a specific
      inhibitor of EGFR PTK. In the absence of extracellular Ca(2+), the magnitude of
      EGFR PTK transactivation was near the basal level. Based on sensitivity to
      nifedipine, which is a specific blocker of voltage-operated Ca(2+) channels
      (VOCCs), VOCCs have minor roles in EGFR PTK transactivation. In contrast, Ca(2+)
      influx through VICCs plays an important role in EGFR PTK transactivation.
      Moreover, based on the sensitivity of VICCs to SK&F-96365 and LOE-908, VICCs were
      shown to consist of two types of Ca(2+)-permeable nonselective cation channels
      (NSCCs), which are designated NSCC-1 and NSCC-2, and a store-operated Ca(2+)
      channel. In summary, Ca(2+) influx through VICCs plays an essential role in ET-1
      induced EGFR PTK transactivation in rabbit internal carotid artery vascular
      smooth muscle cells.

PMID- 12427605
TI  - Alterations of systolic left ventricular twist after acute myocardial infarction.

PMID- 12427606
TI  - Reinterpretation of head and neck scans: massive can of worms or call to action?

PMID- 12427607
TI  - Detection of residual disease of lymph node metastases in the neck, which is
      treated by (chemo)radiation.

PMID- 12427608
TI  - Vertebroplasty for vertebral fractures with intravertebral clefts.

PMID- 12427609
TI  - Diskography in the popular press.

PMID- 12427610
TI  - Reinterpretation of cross-sectional images in patients with head and neck cancer
      in the setting of a multidisciplinary cancer center.
AB  - BACKGROUND AND PURPOSE: Patients referred to tertiary care centers frequently
      arrive with images obtained at outside institutions; these images require
      reinterpretation. We assessed the clinical value of reinterpreting cross
      sectional imaging studies of patients with head and neck cancer, in the setting
      of a multidisciplinary cancer center. METHODS: Outside CT and MR images of 136
      patients with known or presumed head and neck cancer were reinterpreted by a
      neuroradiologist. Clinical history and findings on physical examination were
      available. Reinterpretation was performed before review of outside reports, which
      were subsequently compared with those generated at the cancer center. Changes in
      interpretation were noted, and their effects on TNM staging, patient care, and
      prognosis were assessed. Reliability and statistical significance of rates of
      change in diagnosis were analyzed with 95% confidence intervals (CIs) and the
      sign test, respectively. Verification of change in diagnosis was confirmed by
      pathologic analysis (75%), characteristic radiologic findings (18%), or clinical
      and imaging follow-up (7%). RESULTS: Change in interpretation occurred in 56
      patients (41%) (95% CI: 33-49%, P <.001). Forty-six patients (34%) had a change
      in T, N, and/or M staging (26-42%, P <.001). Change in T stage occurred in 27
      cases (20%) (13-27%, P <.001) (upstaged in 22, downstaged in five), and a change
      in N stage in 26 cases (19%) (12-26%, P <.001) (upstaged in 20, downstaged in
      six). Two patients (1.5%) had missed systemic metastases. Three patients with an
      initial diagnosis of cancer were found to be cancer-free, and six patients had a
      diagnosis of new second primary cancers that were missed at original
      interpretation. One patient had a missed middle cerebral artery aneurysm. Changes
      in image interpretation altered treatment in 55 (98%) of 56 patients and affected
      prognosis in 53 patients (95%) (P <.001). CONCLUSION: Reinterpretation of cross
      sectional images in the setting of a multidisciplinary cancer center has a
      significant effect on staging, management, and prognosis in patients with head
      and neck cancer.

PMID- 12427611
TI  - Lymph nodes of patients with regional metastases from head and neck squamous cell
      carcinoma as a predictor of pathologic outcome: size changes at CT before and
      after radiation therapy.
AB  - BACKGROUND AND PURPOSE: Viable tumor in a neck dissection specimen is important
      in predicting prognosis and directing treatment. Our purpose was to clarify the
      importance of size changes of regional metastases from head and neck squamous
      cell carcinoma on CT scans obtained before and after radiation therapy (RT) as a
      predictor of pathologic outcome. METHODS: Thirty-seven heminecks in 34 patients
      who underwent pre-RT CT, RT, post-RT CT, and post-RT neck dissection were
      reviewed. Thirteen hemineck specimens were pathologically positive. Decrease
      ratios of the largest axial dimension of the lymph nodes between the pre- and
      post-RT CT studies were calculated. RESULTS: Six of 37 heminecks had a decrease
      ratio greater than 50%. These yielded negative specimens after planned neck
      dissection. In two of 37 heminecks, the largest axial dimension of the largest
      node increased between studies, resulting in negative decrease ratio. One
      (decrease ratio, -20%) had a positive specimen, and the other (decrease ratio, 
      3%) had a negative specimen. No interval change in size in the largest node was
      noted in one of the 37 heminecks; its specimen was positive. Average decrease
      ratios were 41.2% (range, -3% to 62%) in the negative specimen group (n = 24) and
      27.2% (range, -20% to 50%) in the positive specimen group (n = 13). Univariate
      analysis revealed that the decrease ratio was not a significant predictor of a
      positive surgical specimen (P =.154). CONCLUSION: Heminecks in which the decrease
      ratio was greater than 50% tended to have a negative surgical specimen. However,
      this trend was not statistically significant.

PMID- 12427612
TI  - CT and MR imaging of solitary extramedullary plasmacytoma of the nasal tract.
AB  - BACKGROUND AND PURPOSE: Solitary extramedullary plasmacytoma (SEP) is rare. The
      purpose of this study was to determine the CT and MR imaging features of SEP of
      the nasal tract. METHODS: We retrospectively reviewed three CT and two MR images
      of three histologically proved cases in two men and one woman aged 43-66 years.
      RESULTS: The plasmacytomas predominantly involved the nasopharynx in two cases
      and the nasal cavity in one. Two of the tumors were bulky solid masses, whereas
      the third showed infiltrative features. They were predominantly masses or
      infiltrative lesions with soft-tissue attenuation on CT scans. The lesions were
      isointense and hyperintense on T1- and T2-weighted MR images, respectively. The
      tumors revealed moderate-to-marked contrast enhancement and may have been
      associated with lytic bone destruction. CONCLUSION: The imaging features of SEP
      are nonspecific. However, this entity should be included in the differential
      diagnosis of tumors in the nasopharynx and nasal cavity.

PMID- 12427613
TI  - Laryngeal neurofibroma associated with neurofibromatosis type 2.
AB  - We present a case of laryngeal neurofibroma associated with neurofibromatosis
      type 2. Although laryngeal neurofibromas have previously been reported in cases
      of neurofibromatosis type 1, their presence has never been described in a patient
      with neurofibromatosis type 2.

PMID- 12427614
TI  - Radiologic and cytologic findings in a case of thyrolipoma.
AB  - Thyrolipomas are rare capsulated mass lesions containing fat and thyroid tissue.
      We herein report the case of a 60-year-old man who had goitre for 10 years, with
      rapid enlargement of the gland during the last several months before
      presentation. Sonography, scintigraphy, CT, MR imaging, and sonography-guided
      fine needle aspiration were performed. Sonography and scintigraphy revealed an
      unusual mass of the thyroid. The diagnosis of thyrolipoma was based on CT and MR
      imaging findings and fine needle aspiration cytology.

PMID- 12427615
TI  - Intravertebral clefts opacified during vertebroplasty: pathogenesis, technical
      implications, and prognostic significance.
AB  - BACKGROUND AND PURPOSE: Intravertebral clefts have long been considered as
      pathognomonic for avascular necrosis and as a rare cause of compression fracture.
      We have observed unsuspected clefts opacifying frequently during vertebroplasty.
      Our purpose in this study was to determine the incidence of these clefts in
      symptomatic osteoporotic compression fractures, assess the sensitivity of MR
      imaging and conventional radiography in the detection of these clefts, and
      determine whether there is any prognostic significance of these clefts in
      patients treated with vertebroplasty. METHODS: Retrospective chart reviews were
      conducted of 135 vertebroplasty procedures performed during a 2-year period. MR
      images and conventional radiographs were reviewed for the presence of clefts
      defined as fluid-filled cavities on MR images or gas-filled cavities on
      conventional radiographs. Digital radiographs obtained at the time of the
      procedure were inspected for the presence of opacified clefts. Imaging findings
      were correlated with subjective pain scores documented before the procedure and
      at 1 week, 1 month, 6 months, and 12 months after vertebroplasty. RESULTS: Two
      hundred thirty-six osteoporotic compression fractures were treated with
      polymethylmethacrylate in 125 patients. Thirty-one and eight-tenths percent of
      the fractures were noted to contain clefts at the time of vertebroplasty. Fluid
      filled clefts were detected on preoperative MR images in only 52.8% of the
      fractures with opacified clefts at vertebroplasty. Gas-filled clefts were evident
      on preoperative conventional radiographs in only 11.4% of the fractures with
      opacified clefts at vertebroplasty. No significant difference was noted in
      numerical pain scores between the two populations at baseline or 1 week or 1
      month after the procedure. Pain scores at 6 and 12 months after vertebroplasty
      showed a trend toward greater pain relief in patients with clefts, although the
      difference was not statistically significant. A sustained, statistically
      significant decrease in pain scores after treatment (P <.01) was noted in both
      groups. CONCLUSION: Intravertebral clefts are much more common than previously
      described and probably represent fracture nonunions. Imaging is not sensitive in
      detecting these clefts before vertebroplasty. We advocate complete filling of the
      cleft with cement during vertebroplasty to maximize stabilization of the fracture
      fragments. There is a trend toward greater pain relief being achieved 6 and 12
      months after the procedure in patients with clefts that are opacified at the time
      of vertebroplasty.

PMID- 12427616
TI  - Ex vivo biomechanical comparison of hydroxyapatite and polymethylmethacrylate
      cements for use with vertebroplasty.
AB  - BACKGROUND AND PURPOSE: Little is known about the mechanical stabilization
      afforded by new materials proposed for use with vertebroplasty. This comparative
      ex vivo biomechanical study was designed to determine the strength and stiffness
      of osteoporotic vertebral bodies (VBs) subjected to compression fractures and
      stabilized with bipedicular injections of Cranioplastic altered in a manner
      consistent with the practice of vertebroplasty or BoneSource cement. METHODS: VBs
      T8-T10 and L2-L4 from 10 fresh spines were harvested from female cadavers (aged
      91.5 years +/- 3.9 at death). These were screened for bone density (t score, -4.9
      +/- 1.4; bone mineral density, 0.61 g/cm(2) +/- 0.19), disarticulated, and
      compressed to determine initial strength and stiffness. The fractured VBs were
      stabilized with bipedicular injections of a predetermined quantity and type of
      cement and then re-crushed. RESULTS: At both the thoracic and lumbar levels, VBs
      repaired with altered Cranioplastic resulted in significantly greater strength (P
      <.05) than that in their prefracture states, whereas those repaired with
      BoneSource were restored to their initial strength. Cranioplastic resulted in
      significantly stronger repairs than BoneSource in the thoracic region; however,
      repair strengths in the lumbar region were not significantly different. The
      repaired stiffness was significantly lower than the initial stiffness in all
      treatments and in both regions. Differences in the repaired stiffness between the
      treatment groups in either region and differences in the mechanical parameters
      obtained by adding an additional 2 mL of BoneSource were not significant.
      CONCLUSION: Both materials in the volumes used either restored or increased VB
      strength, but none restored stiffness.

PMID- 12427617
TI  - Contrast between scar and recurrent herniated disk on contrast-enhanced MR
      images.
AB  - BACKGROUND AND PURPOSE: Ionic solutes diffuse more slowly in cartilage than do
      nonionic ones. The purpose of this study was to test the hypothesis that the
      contrast between scar and recurrent herniated disk fragment on MR images is
      greater after the IV administration of an ionic rather than a nonionic contrast
      medium. METHODS: Patients who had undergone previous laminectomy and who had MR
      imaging evidence of recurrent herniated disk were enrolled in the study and
      underwent lumbar MR imaging with the nonionic medium gadodiamide and on a
      subsequent day with the ionic contrast medium gadopentetate dimeglumine.
      Enhancement of scar and disk was measured by one of the investigators as the
      ratio of signal intensity change from baseline to the baseline signal intensity
      and was plotted as a function of time. Differences in enhancement for scar and
      disk fragment for the two contrast media were tested for significance by using
      the Student t test of the means. RESULTS: Eight patients were enrolled in the
      study and were studied with the two contrast media within 4 weeks. The average
      enhancement of the disk fragment at 5 minutes was 0.1 with the ionic medium and
      0.4 with the nonionic medium. The difference was significant at P <.05. Contrast
      between scar tissue and disk tissue was greater with the ionic than with the
      nonionic medium at both 5 and 20 minutes because of the lower concentration of
      ionic contrast medium in the disk fragment. CONCLUSION: With clinical imaging of
      patients with recurrent herniated disks, disk fragments enhance less after the
      administration of an ionic rather than a nonionic medium. Contrast between disk
      fragment and scar tissue is greater after the use of an ionic contrast medium
      than a nonionic one.

PMID- 12427618
TI  - The therapeutic benefit of repeat percutaneous vertebroplasty at previously
      treated vertebral levels.
AB  - BACKGROUND AND PURPOSE: Recurrent pain after vertebroplasty is relatively common,
      usually representing a new fracture at a different vertebral level. In a small
      cohort described herein, clinical and imaging findings indicated that recurrent
      pain arose from abnormality of the previously treated level. Our purpose was to
      demonstrate that repeat percutaneous vertebroplasty performed within the same
      fractured vertebra can offer therapeutic benefit for patients with recurrent pain
      after initial treatment. METHODS: We conducted a retrospective review of
      consecutive vertebroplasty procedures performed at our institution to define a
      patient population that underwent repeat vertebroplasty for recurrent pain at
      previously treated vertebral levels. We identified six such patients over an 8
      year period, and clinical outcomes were assessed through quantitative
      measurements of pre- and postoperative levels of pain and mobility. RESULTS:
      Initial vertebroplasty resulted in substantial improvement in pain in all six
      patients. Patients developed recurrent pain between 8 days and 167 days after
      initial vertebroplasty. After repeat vertebroplasty, five of the six patients
      reported a reduction of at least 3 points in their rating of pain, with a mean
      reduction of 6.5 points and a mean postoperative pain level of 3.5 points (11
      point scale). Four of six patients reported impaired mobility before repeat
      vertebroplasty, and all four demonstrated a postoperative improvement in
      mobility. Mean increase in mobility was 1.50 points, and the mean postoperative
      mobility impairment was 0.25 points (5-point scale). CONCLUSION: The clinical
      outcomes of the patients within this case series suggest that repeat percutaneous
      vertebroplasty performed at previously treated vertebral levels for recurrent
      pain offer therapeutic benefit.

PMID- 12427619
TI  - Lumbar disk pseudotumor: an unusual presentation of lumbar spinal fracture and
      stenosis.
AB  - We present an unusual case of a primary lumbar disk-space mass that presumably
      developed secondary to a chronic hyperextension spinal fracture associated with
      spinal stenosis. This injury resulted in the appearance of a lumbar
      intervertebral disk-space mass or pseudotumor. The pseudotumor most likely
      resulted from a prior spinal fracture, leading to a fused hyperextension
      deformity in a patient with underlying chronic degenerative spinal disease.

PMID- 12427620
TI  - Radiologic appearance of a rare primary vertebral lymphangioma.
AB  - A 41-year-old patient with a history of low back pain underwent conventional
      radiography, CT, digital subtraction angiography (DSA), and MR imaging. An
      inhomogeneous sclerotic-lytic lumbar vertebra with slightly thickened spongiotic
      structure and intense contrast enhancement were compatible with an L4 vertebral
      hemangioma. Embolization and posterior surgical osseous decompression was
      performed. Histologic analysis of osseous parts revealed a vertebral lymphangioma
      instead of a hemangioma.

PMID- 12427621
TI  - Terminal zones of myelination: MR evaluation of children aged 20-40 months.
AB  - BACKGROUND AND PURPOSE: MR imaging is the method of choice for assessment in vivo
      of the development of myelination of the human central nervous system. During the
      first months of life, the myelination process follows well-defined steps, whereas
      little information exists about the later phases of myelination. To improve our
      understanding of this aspect and to identify the specific sites involved in the
      process of myelination in its terminal phase, we evaluated normal MR brain
      studies in children aged 20-40 months. METHODS: We retrospectively evaluated 85
      MR brain studies of 81 children aged 20-40 months who were without diseases
      potentially affecting white matter. The MR studies were performed with a 1.5-T
      system, with T2-weighted spin-echo and turbo spin-echo sequences. Subjective
      analysis of the signal intensity of the white matter was made in four areas:
      subcortical frontal, temporal, and parietal lobes and peritrigonal region.
      Extension of myelination was graded on an ordinal scale; 0 indicated the absence
      of myelin, and the maximum value indicated complete myelination. RESULTS: A
      persistent T2 hyperintensity of the subcortical areas was noted after 20 months
      of age. With advancing age, a progressive increase in the grade of myelination
      was noted in these regions, and at about 40 months of age myelination was
      complete. However, in most of our patients aged 20 months, myelination in the
      peritrigonal areas appeared complete. CONCLUSION: The only area that can still
      exhibit a persistent T2 hyperintensity on MR images at about 2 years of age is
      considered to be the peritrigonal region: the so-called terminal zone. At this
      age in our patients, however, a persistent T2 hyperintensity was noted in the
      frontotemporal subcortical regions. In these areas, the myelination appeared
      complete at 36-40 months of age. The so-called terminal zones were the
      subcortical areas rather than the peritrigonal area, and complete myelination
      took place by about age 3 years.

PMID- 12427622
TI  - Incidental findings on pediatric MR images of the brain.
AB  - BACKGROUND AND PURPOSE: Previous studies have addressed the prevalence of
      incidental findings in symptomatic and healthy adult populations. Our study aims
      to elucidate the prevalence of incidental findings in a healthy pediatric
      population. METHODS: We retrospectively reviewed 225 conventional brain MR
      imaging studies obtained during structural and functional brain imaging research
      in a cohort of neurologically healthy children (100 boys [44%] and 125 girls
      [56%]) ranging in age from younger than 1 month to 18 years. All MR images were
      reviewed, and two board-certified neuroradiologists categorized the findings by
      consensus. RESULTS: Incidental abnormalities were detected in 47 subjects (21%),
      while 79% of the images were normal. Of the 47 abnormalities detected, 17 (36%)
      required routine clinical referral; a single lesion (2%) required urgent
      referral. The occurrence of these findings in the male cohort was twice that of
      the female cohort; however, the percentage of subjects requiring either routine
      or urgent referral did not differ by sex (male subjects, 34%; female subjects,
      39%). CONCLUSION: Although the frequency of clinically important incidental
      abnormalities was not high in the sample of children studied, the presence and
      variety of findings in any pediatric group is particularly important for both the
      welfare of the subject and for research in which knowledge of the subject's
      neurologic status is vital to the interpretation of the results. Despite the
      limitations of the study in terms of the age and ethnic distribution, this work
      highlights the need for the routine involvement of trained radiologists in these
      studies to ensure that such incidental findings are detected and that appropriate
      follow-up is provided.

PMID- 12427624
TI  - Advanced MR imaging of cortical dysplasia with or without neoplasm: a report of
      two cases.
AB  - We herein describe two cases of patients with epilepsy with occipital lobe
      cortical dysplasia who were studied with both MR spectroscopy and MR diffusion
      imaging in addition to conventional MR imaging. Greater diffusion abnormalities,
      as well as more marked decreases in N-acetylaspartate, were observed to occur in
      the patient harboring a low grade neoplasm within an area of cortical dysplasia
      than in the patient with cortical dysplasia alone.

PMID- 12427623
TI  - Reproducibility of proton MR spectroscopic imaging (PEPSI): comparison of
      dyslexic and normal-reading children and effects of treatment on brain lactate
      levels during language tasks.
AB  - BACKGROUND AND PURPOSE: We repeated a proton echo-planar spectroscopic imaging
      (PEPSI) study to test the hypothesis that children with dyslexia and good readers
      differ in brain lactate activation during a phonologic judgment task before but
      not after instructional treatment. METHODS: We measured PEPSI brain lactate
      activation (TR/TE, 4000/144; 1.5 T) at two points 1-2 months apart during two
      language tasks (phonologic and lexical) and a control task (passive listening).
      Dyslexic participants (n = 10) and control participants (n = 8) (boys and girls
      aged 9-12 years) were matched in age, verbal intelligence quotients, and valid
      PEPSI voxels. In contrast to patients in past studies who received combined
      treatment, our patients were randomly assigned to either phonologic or
      morphologic (meaning-based) intervention between the scanning sessions. RESULTS:
      Before treatment, the patients showed significantly greater lactate elevation in
      the left frontal regions (including the inferior frontal gyrus) during the
      phonologic task. Both patients and control subjects differed significantly in the
      right parietal and occipital regions during both tasks. After treatment, the two
      groups did not significantly differ in any brain region during either task, but
      individuals given morphologic treatment were significantly more likely to have
      reduced left frontal lactate activation during the phonologic task. CONCLUSION:
      The previous finding of greater left frontal lactate elevation in children with
      dyslexia during a phonologic judgment task was replicated, and brain activation
      changed as a result of treatment. However, the treatment effect was due to the
      morphologic component rather than the phonologic component.

PMID- 12427625
TI  - The effect of hydroxyurea on vasculopathy in a child with sickle cell disease.
AB  - We report serial CNS findings in a girl with sickle cell disease and stroke.
      Religious considerations precluded transfusion and bone marrow transplantation;
      therefore, she received single-agent hydroxyurea therapy for almost 6 years. MR
      angiography showed that vascular patency improved, although diffuse cerebral
      atrophy slowly worsened. Hydroxyurea can be effective in treating vasculopathy,
      but it might not prevent the progression of parenchymal damage in advanced
      disease.

PMID- 12427626
TI  - Mycotic aneurysms as lethal complication of brain pseudallescheriasis in a near
      drowned child: a CT demonstration.
AB  - Intracranial true mycotic aneurysms are rare and generally lethal. We report a
      case of a near-drowned child with brain abscesses due to Pseudallescheria boydii,
      a saprophytic fungus, who died after subarachnoid hemorrhage occurred. CT showed
      contrast-enhancing lesions indicative of aneurysms of basilar and right posterior
      cerebral arteries that could not be appreciated 2 days before. P. boydii is often
      resistant to commonly used antimycotic drugs. Because CNS infection is frequently
      associated with near-drowning, early diagnosis and specific therapy are strongly
      recommended for these patients.

PMID- 12427627
TI  - Assessment of the interventional neuroradiology workforce in the United States: a
      review of the existing data.

PMID- 12427628
TI  - Cerebral aneurysm perforations complicating therapy with Guglielmi detachable
      coils: a meta-analysis.
AB  - BACKGROUND AND PURPOSE: The risk of intraprocedural aneurysm perforation in
      patients with previously ruptured aneurysms tends to be higher than that of
      patients with previously unruptured aneurysms, but a statistically significant
      difference has not been shown. Our purpose was to define the rates of occurrence
      and of morbidity and mortality associated with aneurysmal perforation associated
      with coil embolization. METHODS: A meta-analysis of the results from 17 published
      retrospective reports of aneurysm perforations complicating therapy with
      Guglielmi detachable coils (GDCs) was performed. Rates of perforation and
      associated morbidity and mortality in previously ruptured and unruptured
      aneurysms were calculated. The mechanism of perforation was noted. RESULTS: The
      risk of intraprocedural perforation was significantly higher in patients with
      ruptured aneurysms compared with patients with unruptured aneurysms (4.1% vs
      0.5%; P <.001). The combined risk of permanent neurologic disability and death
      associated with intraprocedural aneurysm perforation was 38% for ruptured
      aneurysms and 29% for unruptured aneurysms. The morbidity and mortality rates
      with perforations caused by coils (39%) and microcatheters (33%) were similar.
      The morbidity and mortality rate for microguidewire perforations was considerably
      lower (0%, n = 4) than the rates for coils and microcatheters, but number of
      cases was too low to indicate statistical significance. CONCLUSION: The risk of
      aneurysm perforation during GDC therapy is much higher in patients with
      previously ruptured aneurysms than in those with unruptured aneurysms. The
      morbidity and mortality rates are substantial for perforations caused by coils
      and microcatheters, whereas they seem to be much lower for perforations caused by
      microguidewires.

PMID- 12427629
TI  - Endovascular treatment of experimental wide neck aneurysms: comparison of results
      using coils or cyanoacrylate with the assistance of an aneurysm neck bridge
      device.
AB  - BACKGROUND AND PURPOSE: Endovascular treatment of wide neck aneurysms often
      results in incomplete occlusion or aneurysm recurrence. The two goals of the
      present study were to compare results of coil embolization with or without the
      assistance of an aneurysm neck bridge device (ANBD) and to explore the use of
      this instrument to control cyanoacrylate embolization. METHODS: Wide necked
      bifurcation aneurysms were constructed in 28 dogs. Coil embolization of the
      aneurysms was performed 2 to 4 weeks later, with (n = 11) or without (n = 10)
      ANBD assistance. In seven other animals, embolization was performed with
      cyanoacrylate, injected under the protection of ANBDs. Angiographic results were
      compared immediately after and at 3 and 12 weeks. Neointima formation at the neck
      was also compared between groups at 12 weeks. RESULTS: Initial angiographic
      results and recurrences at 12 weeks were not significantly different in aneurysms
      coiled with or without ANBDs. Neointimal scores were also similar. The use of one
      ANBD at the neck was not sufficient to safely deliver cyanoacrylate into
      aneurysms. Cyanoacrylate embolization led to improved angiographic results (P
      =.05) and to better neointimal sealing of the neck of the aneurysms at 12 weeks
      (P =.004). CONCLUSION: ANBDs did not prevent recanalization and recurrences after
      coil embolization of wide neck aneurysms in this animal study. ANBD-assisted
      cyanoacrylate embolization was unsafe but could decrease recurrences at 12 weeks.

PMID- 12427630
TI  - Vein of Galen aneurysmal malformation: diagnosis and treatment of 13 children
      with extended clinical follow-up.
AB  - BACKGROUND AND PURPOSE: We herein present our experience in diagnosing and
      treating 13 children with vein of Galen aneurysmal malformations (VGAM), with an
      emphasis on possible prognostic indicators, endovascular strategies, factors
      affecting treatment during the neonatal period, and long-term follow-up. With
      this review, we hope to identify those factors that have the most significant
      prognostic value in determining long-term outcomes in children with VGAM.
      METHODS: We retrospectively reviewed the radiology studies, hospital charts, and
      outpatient clinic chart notes (when applicable) of 13 children evaluated and
      treated for VGAM at a single tertiary care pediatric hospital. Clinical
      presentation, diagnostic methods, treatment strategies, and outcome were
      documented for each child. The present neurologic status and level of function of
      each patient was determined by review of the outpatient charts and direct contact
      with the clinicians who were conducting the follow-up. Outcome was graded on a 5
      point scale, ranging from 0 (death) to 4 (normal), taking into account only
      neurologic and developmental characteristics. RESULTS: Eight of 13 patients
      presented as neonates with congestive heart failure. The other five patients
      ranged in age from 4 months to 13 years at the time of presentation. The five
      patients presenting outside of the neonatal period achieved normal or near-normal
      outcomes. Two of the eight patients presenting during the neonatal period
      achieved normal or near-normal outcomes, one experienced significant impairment,
      and the other five died. We were unable to identify significant differences in
      outcome on the basis of differences in treatment strategies. CONCLUSION: Our
      experience confirms that children with VGAM presenting during the neonatal period
      have a generally much worse prognosis than do those presenting later in
      childhood. Complicating factors in the management and treatment of these children
      are discussed in light of their impact on outcome.

PMID- 12427631
TI  - Endovascular treatment using low-power ultraviolet laser for delayed vasospasm in
      the rabbit carotid artery model.
AB  - BACKGROUND AND PURPOSE: We previously reported that pretreatment with external
      ultraviolet (UV) irradiation at 325 nm before blood exposure prevented the
      development of chronic vasospasm in rabbit common carotid arteries. The purpose
      of this study was to investigate the preventive effect of endovascular UV light
      on vasospasm after blood immersion by using the same animal model. METHODS: The
      right common carotid arteries in 63 rabbits were enclosed in silicon cuffs on day
      0. Sheaths were empty or filled with clotted blood. Thirty minutes after the
      placement of the sheaths, either alone or with blood, the common carotid arteries
      were subjected to UV or visible light (442 nm) irradiation via an endovascular
      approach at a fluence rate of 0.17 W/cm(2). The animals were killed on day 2, 9,
      or 30. Digital subtraction angiography was performed on days 0 and 2 and at the
      end point to evaluate the degree of vasospasm. RESULTS: UV treatment
      significantly prevented the development of vasospasm on day 2. On days 9 and 30,
      there were no significant differences between UV-treated animals and control
      animals. The preventive effect reached an approximate plateau with an irradiation
      time of 10 s. No severe vascular injury, such as perforation, occurred in
      response to UV treatment during the observation period. UV light was
      significantly more effective than visible light in preventing vasospasm (P
      <.001). CONCLUSION: These results suggest that endovascular UV irradiation after
      blood exposure has a prophylactic effect on vasospasm and suggest a dependence on
      irradiation wavelength and duration of irradiation.

PMID- 12427632
TI  - Does streaming affect the cerebral distribution of infraophthalmic intracarotid
      chemotherapy?
AB  - BACKGROUND AND PURPOSE: The development of new non-ocular-toxic drugs has enabled
      infraophthalmic chemotherapeutic infusion. We assessed whether streaming occurs
      with infraophthalmic, high cervical internal carotid artery (ICA) delivery of
      chemotherapeutic agents by means of conventional angiographic catheters. METHODS:
      Six patients with high-grade gliomas treated with monthly carotid intraarterial
      chemotherapy were studied. Chemotherapy delivery and distribution was modeled by
      technetium 99m hexylmethyl-propyleneamine oxine (HMPAO), a first-pass agent. Each
      patient received 0.5 mCi (18.5 MBq) of (99m)Tc-HMPAO in 50-mL of saline
      intraarterially in the ICA at the C1-C2 level. Injections were given twice, at
      two different injection rates: 0.08 mL/s at one therapeutic session and 6 mL/s a
      month later. The slow injection rate modeled the slowest rate used in the
      delivery of chemotherapy into the ICA. The higher rate was selected to avoid any
      possibility of uneven mixing, by replacing intracarotid blood completely and by
      using a turbulent injection rate that destroys laminar flow and intraarterial
      streaming. Single photon emission CT (SPECT) was performed 2 hours after
      injection. For each patient, the corresponding SPECT sections at the two
      injection rates were compared. RESULTS: No differences were noted in (99m)Tc
      HMPAO distribution between the two injection rates in any of the patients.
      However, some of the rapid injection rate SPECT scans showed extension of the
      (99m)Tc-HMPAO uptake into adjacent watershed territories. CONCLUSION: There was
      no evidence, in humans, of substantial streaming during slow infraophthalmic
      intracarotid injections. Slow rates of infusion are as good as high rates for
      infraophthalmic intracarotid drug delivery. This is of special importance for
      drugs that are not tolerated at high injection rates. Moreover, infraophthalmic
      intracarotid chemotherapeutic infusion does not require special injectors or
      catheters.

PMID- 12427633
TI  - Carotid cavernous fistula: embolization via a bilateral superior ophthalmic vein
      approach.
AB  - We report the case of a 74-year-old woman with a complex indirect (Barrow D)
      carotid cavernous sinus fistula. The patient was treated incrementally and
      finally cured by a rarely reported bilateral retrograde direct transvenous
      approach via the superior ophthalmic vein. The treatment of the complex carotid
      cavernous fistula with multiple bilateral fistula points showed additional
      complexity due to a partially thrombosed left superior ophthalmic vein, which
      required a combined microsurgical and endovascular treatment, showing that
      treatment can be achieved, if necessary, by catheterization of a thrombosed
      orbital vein.

PMID- 12427634
TI  - Normal structures in the intracranial dural sinuses: delineation with 3D contrast
      enhanced magnetization prepared rapid acquisition gradient-echo imaging sequence.
AB  - BACKGROUND AND PURPOSE: The potential pitfalls in the diagnosis of dural sinus
      thrombosis include the presence of arachnoid granulations, intrasinus fibrotic
      bands (so-called septa), and hypoplasia or aplasia of the dural sinuses. The
      purpose of this study was to assess the appearance, distribution, and prevalence
      of arachnoid granulations and septa in the dural sinuses by using a high
      resolution 3D contrast-enhanced magnetization prepared rapid acquisition gradient
      echo (MPRAGE) imaging sequence. METHODS: Conventional MR images and contrast
      enhanced MPRAGE images of 100 consecutive patients who had no abnormalities of
      the dural sinuses were retrospectively reviewed. The incidence, site, number,
      size, signal intensity, and shape of arachnoid granulations and septa within the
      sinuses and their relationship with adjacent veins were recorded. RESULTS: With
      3D contrast-enhanced MPRAGE imaging, 433 round, oval, or lobulated focal filling
      defects were found in a total of 90 patients. Curvilinear septa were observed in
      92 patients. Sixty-nine patients had round, oval, or lobulated defects in the
      transverse sinus, 59 had such defects in the superior sagittal sinus, and 47 had
      such defects in the straight sinus. All except two of the above defects were
      isointense relative to CSF on all images. These structures were presumed to be
      arachnoid granulations. Of 431 arachnoid granulations, 233 (53.8%) were located
      in the superior sagittal sinus, 122 (28.1%) in the transverse sinus, and 76
      (17.6%) in the straight sinus. One or more veins were seen to enter arachnoid
      granulations in 414 (96%) instances. CONCLUSION: The contrast-enhanced 3D MPRAGE
      imaging sequence showed a much higher prevalence and a different distribution of
      arachnoid granulations and septa within dural sinuses than have been observed in
      previous radiologic studies. Arachnoid granulations were closely related
      spatially to veins.

PMID- 12427635
TI  - The substantia nigra in Parkinson disease: proton density-weighted spin-echo and
      fast short inversion time inversion-recovery MR findings.
AB  - BACKGROUND AND PURPOSE: A reduction in the area of the substantia nigra (SN) has
      been shown in patients with Parkinson disease. The substantia nigra is
      anteroinferolateral to the red nucleus, and it is important to precisely locate
      its true anatomic location to accurately measure SN area. Our purpose was to
      determine the exact location of the substantia nigra by correlating imaging and
      anatomic findings. We also attempted to quantitate SN area in patients with
      Parkinson disease compared with that in healthy control subjects on the basis of
      proton density-weighted spin-echo (SE) and fast short inversion time inversion
      recovery (STIR) MR imaging findings. METHODS: In four healthy volunteers, dual
      echo SE and fast STIR MR images were obtained in three orthogonal planes and an
      oblique coronal plane. These images were correlated with anatomic specimens to
      determine the location of the SN. The area of the SN was also measured on oblique
      coronal fast STIR images obtained at a plane perpendicular to the SN in 22
      patients with Parkinson disease and in 22 age- and sex-matched healthy
      volunteers. RESULTS: The true anatomic location of the SN, anteroinferolateral to
      the red nucleus, was accurately identified, not on T2-weighted images, but on
      proton density-weighted SE images and fast STIR images as an area of hyperintense
      gray matter. The hypointense area seen on T2-weighted images corresponded to the
      anterosuperior aspect of the SN and to the adjacent crus cerebri. No
      statistically significant differences were noted in the size of the SN when the
      oblique coronal images of patients with Parkinson disease were compared with
      those of the control groups. CONCLUSION: The SN is located mainly beneath the red
      nucleus. Its location cannot be determined on the basis of T2-weighted imaging
      results but rather on the basis of proton density-weighted SE or fast STIR
      findings. SN volume loss is not found in Parkinson disease, and this finding is
      compatible with that of recent pathology reports in the literature.

PMID- 12427636
TI  - Fragile X premutation carriers: characteristic MR imaging findings of adult male
      patients with progressive cerebellar and cognitive dysfunction.
AB  - BACKGROUND AND PURPOSE: Our purpose was to characterize the findings of MR
      imaging of the brain of adult male fragile X premutation carriers with a recently
      identified disorder characterized by ataxia, tremor, rigidity, and cognitive
      dysfunction. METHODS: MR imaging studies of the brain of 17 male patients were
      characterized for signal intensity and for size of ventricles, cerebral and
      cerebellar sulci, and brain stem. Comparison was made with age- and sex-matched
      control participants. Southern blot and/or polymerase chain reaction methods were
      used to analyze CGG trinucleotide repeats in the fragile X mental retardation 1
      gene. RESULTS: Fifteen of 17 patients showed symmetrically decreased T1 and
      increased T2 signal intensity in cerebellar white matter lateral, superior, and
      inferior to the dentate nuclei. Fourteen of 17 had similar signal intensity
      alterations in the middle cerebellar peduncles. Cerebellar cortical atrophy was
      present in 16 of 17 and cerebral atrophy in 17 of 17. Evan's Index as a measure
      of ventricular size averaged 0.35 (range, 0.25-0.46), with that for age-matched
      control participants averaging 0.28 (range, 0.24-0.31) (P <.005). The mean third
      ventricle width was 11 mm (for control participants, 6 mm; P <.01). Corpus
      callosum was thinned in 14 of 16 participants. Middle cerebellar peduncles were
      atrophic when compared with those of control participants (P <.005). Pontine
      transverse dimension was 25 mm (for control participants, 31 mm; P <.005), and
      rostral-caudal length averaged 26 mm (for control participants, 29 mm; P <.005).
      CGG repeats clustered in the low to mid premutation range (86 +/- 10 CGG repeats)
      in the 17 patients. CONCLUSION: MR imaging findings in symptomatic male fragile X
      premutation carriers are characteristic of this disorder. Recognition of these
      alterations may support a specific diagnosis and may have implications for the
      potential occurrence of fragile X syndrome in the children of reproductive age
      female relatives.

PMID- 12427637
TI  - Preoperative assessment of intracranial tumors with perfusion MR and a volumetric
      interpolated examination: a comparative study with DSA.
AB  - BACKGROUND AND PURPOSE: In evaluating intracranial tumors, a safe low-cost
      alternative that provides information similar to that of digital subtraction
      angiography (DSA) may be of interest. Our purpose was to determine the utility
      and limitations of a combined MR protocol in assessing (neo-) vascularity in
      intracranial tumors and their relation to adjacent vessels and to compare the
      results with those of DSA. METHODS: Twenty-two consecutive patients with an
      intracranial tumor who underwent preoperative stereoscopic DSA were examined with
      contrast-enhanced dynamic T2*-weighted perfusion MR imaging followed by a T1
      weighted three-dimensional (3D) MR study (volumetric interpolated brain
      examination [VIBE]). The maximum relative cerebral blood volume (rCBV) of the
      tumor was compared with tumor vascularity at DSA. Critical vessel structures were
      defined in each patient, and VIBE images of these structures were compared with
      DSA findings. For full exploitation of the 3D data sets, maximum-intensity
      projection algorithms reconstructed in real time with any desired volume and
      orientation were used. RESULTS: Tumor blush scores at DSA were significantly
      correlated with the rCBV measurements (r = 0.75; P <.01, Spearman rank
      correlation coefficient). In 17 (77%) patients, VIBE provided all relevant
      information about the venous system, whereas information about critical arteries
      were partial in 50% of the cases and not relevant in the other 50%. CONCLUSION: A
      fast imaging protocol consisting of perfusion MR imaging and a volumetric MR
      acquisition provides some of the information about tumor (neo-) vascularity and
      adjacent vascular anatomy that can be obtained with conventional angiography.
      However, the MR protocol provides insufficient visualization of distal cerebral
      arteries.

PMID- 12427638
TI  - Discrepant MR spectroscopic and perfusion imaging results in a case of malignant
      transformation of cerebral glioma.
AB  - We present serial MR perfusion and spectroscopic findings of a pathologically
      proved low grade glioma, which evolved into glioblastoma multiforme in 2 years in
      a 24-year-old man. The initial MR imaging studies, including enhanced
      conventional T1-weighted and perfusion imaging, were characteristic of a benign
      glioma with the only exception being that multi-voxel proton MR spectroscopy
      showed malignant features with a high choline:phosphocreatine ratio.
      Postoperative follow-up MR imaging revealed findings consistent with malignant
      glioma, with increased angiogenesis on perfusion images and heterogeneous
      enhancement on contrast-enhanced T1-weighted images that were further confirmed
      by second surgery. We suggest conducting close MR imaging follow-up of patients
      with glioma who have discrepant MR spectroscopic and perfusion results after
      treatment.

PMID- 12427639
TI  - Time-of-flight MR angiography of carotid artery stenosis: does a flow void
      represent severe stenosis?
AB  - BACKGROUND AND PURPOSE: Time-of-flight (TOF) magnetic resonance angiography (MRA)
      is commonly used to visualize the carotid arteries; however, flow void artifacts
      can appear. Our purpose was to determine the frequency and diagnostic meaning of
      flow voids by using real patient data, as part of a larger study of MRA compared
      with the criterion standard, digital subtraction angiography (DSA). METHODS: In
      1997-2000, 390 consecutive patients with sonographic findings suggestive of
      carotid artery stenosis were included in this study. All patients subsequently
      underwent three-dimensional (3D) TOF MRA and conventional DSA. The frequency of
      flow void artifacts on 3D TOF MRA images were compared with stenosis measurements
      on DSA images. RESULTS: We recorded 107 flow voids (16%) during 3D TOF MRA of 662
      carotid arteries. DSA images were available for comparison in 102 cases. The
      median percentage of stenosis in this subgroup of flow voids on MRA images was
      80%, compared with measurements on DSA images according to the North American
      Symptomatic Carotid Endarterectomy Trial (NASCET) criteria. Stenoses ranged from
      36% to 100% (occlusion). Three flow voids (2.9%) were in the 0-49% range; 11
      (10.8%), in the 50-69% range; and 86 (84.3%), in the 70-99% range. Two flow voids
      (2.0%) represented occlusions. The positive predictive value of a flow void
      artifact for the presence of severe (70-99%) stenosis was 84.3% (95% CI: 77.3%,
      91.4%). CONCLUSION: Flow void artifacts represented severe stenosis in most of
      the arteries. According to our data, the assumption that flow voids on 3D TOF MRA
      images represent severe stenosis is justified.

PMID- 12427640
TI  - Predicting cerebral ischemic infarct volume with diffusion and perfusion MR
      imaging.
AB  - BACKGROUND AND PURPOSE: Diffusion and perfusion MR imaging have proved useful in
      the assessment of acute stroke. We evaluated the utility of these techniques in
      detecting acute ischemic infarction and in predicting final infarct size.
      METHODS: Diffusion and hemodynamic images were obtained in 134 patients within a
      mean of 12.3 hours of onset of acute ischemic stroke symptoms. We retrospectively
      reviewed patient radiology reports to determine the presence or absence of lesion
      identification on initial diffusion- (DW) and perfusion-weighted (PW) images.
      Radiologists were not blinded to the initial clinical assessment. For
      determination of sensitivity and specificity, the final discharge diagnosis was
      used as the criterion standard. Neurologists were not blinded to the DW or PW
      imaging findings. In 81 patients, acute lesions were compared with final infarct
      volumes. RESULTS: Sensitivities of DW imaging and cerebral blood volume (CBV),
      cerebral blood flow (CBF), and mean transit time (MTT) perfusion parameters were
      94%, 74%, 84%, and 84%, respectively. Specificities of DW imaging, CBV, CBF, and
      MTT were 96%, 100%, 96%, and 96%, respectively. Results were similar in 93
      patients imaged within 12 hours. In 81 patients with follow-up, regression
      analysis yielded r(2) = 0.9, slope = 1.24 for DW imaging; r(2) = 0.84, slope =
      1.22 for CBV; r(2) = 0.35, slope = 0.44 for CBF; and r(2) = 0.22, slope = 0.32
      for MTT, versus follow-up volume. A DW-CBV mismatch predicted additional lesion
      growth, whereas DW-CBF and DW-MTT mismatches did not. Results were similar in 60
      patients imaged within 12 hours. CONCLUSION: Diffusion and hemodynamic images are
      sensitive and specific for detecting acute infarction. DW imaging and CBV best
      predict final infarct volume. DW-CBV mismatch predicts lesion growth into the CBV
      abnormality. CBF and MTT help identify additional tissue with altered perfusion
      but have lower correlation with final volume.

PMID- 12427641
TI  - MR imaging-related heating of deep brain stimulation electrodes: in vitro study.
AB  - BACKGROUND AND PURPOSE: Recent work has shown a potential for excessive heating
      of deep brain stimulation electrodes during MR imaging. This in vitro study
      investigates the relationship between electrode heating and the specific
      absorption rate (SAR) of several MR images. METHODS: In vitro testing was
      performed by using a 1.5-T MR imaging system and a head transmit-receive coil,
      with bilateral deep brain stimulation systems positioned in a gel saline-filled
      phantom, and temperature monitoring with a fluoroptic thermometry system.
      Standardized fast spin-echo sequences were performed over a range of high,
      medium, and low SAR values. Several additional, clinically important MR imaging
      techniques, including 3D magnetization prepared rapid acquisition gradient-echo
      imaging, echo-planar imaging, quantitative magnetization transfer imaging, and
      magnetization transfer-suppressed MR angiography, were also tested by using
      typical parameters. RESULTS: A significant, highly linear relationship between
      SAR and electrode heating was found, with the temperature elevation being
      approximately 0.9 times the local SAR value. Minor temperature elevations, <1
      degrees C, were found with the fast spin-echo, magnetization prepared rapid
      acquisition gradient-echo, and echo-planar clinical imaging sequences. The high
      dB/dt echo-planar imaging sequence had no significant heating independent of SAR
      considerations. Sequences with magnetization transfer pulses produced temperature
      elevations in the 1.0 to 2.0 degrees C range, which was less than theoretically
      predicted for the relatively high SAR values. CONCLUSION: A potential exists for
      excessive MR imaging-related heating in patients with deep brain stimulation
      electrodes; however, the temperature increases are linearly related to SAR
      values. Clinical imaging sequences that are associated with tolerable temperature
      elevations in the <or=2.0 degrees C range at the electrode tips can be performed
      safely within an SAR range <2.4 W/kg local (0.9 W/kg whole body averaged).

PMID- 12427642
TI  - Proton MR spectroscopy of Wernicke encephalopathy.
AB  - Two patients with acute thiamine deficiency were examined with thalamic single
      voxel proton MR spectroscopy. T2-weighted images exhibited increased signal
      intensity. N-acetylaspartate (NAA)/creatine (Cr) ratios were low without
      detectable lactate. Owing to substantially decreased choline (Cho) T2, the Cho/Cr
      ratio was not decreased. After thiamine therapy, the NAA/Cr ratio increased,
      paralleling clinical improvement and reduction in the areas of signal-intensity
      changes.

PMID- 12427643
TI  - Advances in the understanding of the blood-brain barrier in neuro-oncology.

PMID- 12427645
TI  - Low-density lipoprotein, non-high-density lipoprotein, and apolipoprotein B as
      targets of lipid-lowering therapy.

PMID- 12427646
TI  - Effect of diet and exercise intervention on blood pressure, insulin, oxidative
      stress, and nitric oxide availability.
AB  - BACKGROUND: Diet and exercise can affect blood pressure and atherosclerotic risk.
      METHODS AND RESULTS: The present study was designed to examine the effects of a
      short-term, rigorous diet and exercise intervention on blood pressure,
      hyperinsulinemia, and nitric oxide (NO) availability. Men (n=11) were placed on a
      low-fat, high-fiber diet combined with daily exercise for 45 to 60 minutes for 3
      weeks. Pre- and post fasting blood was drawn for serum lipid, insulin, 8
      isoprostaglandin F(2alpha) (8-iso-PGF(2alpha)), and glucose measurements.
      Anthropometric parameters, blood pressure (BP), and 24-hour urinary NO metabolite
      excretion (NO(X)), a marker of NO bioavailability, were measured. Systolic
      (P<0.01) and diastolic BP (P<0.01) and 8-iso-PGF(2alpha) decreased (P<0.05),
      whereas urinary NO(X) increased (P<0.05). There was a significant reduction in
      fasting insulin (P<0.01) and a significant correlation between the decrease in
      serum insulin and the increase in urinary NO(X) (r2=0.68, P<0.05). All fasting
      lipids decreased significantly, and the total cholesterol to high-density
      lipoprotein cholesterol ratio improved. Although body weight and body mass index
      (P<0.01) decreased, obesity was still present and there were no correlations
      between the change in body mass index and the change in insulin, BP, or urinary
      NO(X). CONCLUSIONS: This intervention resulted in dramatic improvements in BP,
      oxidative stress, NO availability, and the metabolic profile within 3 weeks,
      mitigating the risk for atherosclerosis progression and its clinical sequelae.

PMID- 12427647
TI  - Sympathetic neural activation in visceral obesity.
AB  - BACKGROUND: Muscle sympathetic nerve activity (MSNA) is elevated in obese humans.
      However, the potential role of abdominal visceral fat as an important adipose
      tissue depot linking obesity to elevated MSNA has not been explored. Accordingly,
      we tested the hypothesis that MSNA would be increased in men (age=18 to 40 years,
      body mass index < or =35 kg/m2) with higher abdominal visceral fat (HAVF; n=13,
      abdominal visceral fat=118.1+/-15.8 cm2) compared with their age- (28.7+/-2.4
      versus 25.5+/-2.0 years, P>0.05), total fat mass-matched (20.6+/-2.1 versus
      20.8+/-2.4 kg, P>0.05) and abdominal subcutaneous fat-matched (230.6+/-24.9
      versus 261.4+/-34.8 cm(2), P>0.05) peers with lower abdominal visceral fat levels
      (LAVF; n=13, visceral fat= 73.0+/-6.0 cm2). METHODS AND RESULTS: MSNA
      (microneurography), body composition (dual energy x-ray absorptiometry), and
      abdominal visceral and subcutaneous fat (computed tomography) were measured in 37
      sedentary men across a wide range of adiposity. MSNA was approximately 55% higher
      in men with HAVF compared with men with LAVF (33+/-4 versus 21+/-2 bursts/min,
      P<0.05). Furthermore, MSNA was more closely associated with the level of
      abdominal visceral fat (r=0.65, P<0.05) than total fat mass (r=0.323, P<0.05) or
      abdominal subcutaneous fat (r=0.27, P=0.05). The relation between MSNA and
      abdominal visceral fat was independent of total body fat (r=0.61, P<0.05).
      CONCLUSIONS: The results of our study indicate that MSNA is elevated in men with
      visceral obesity. Our observations are consistent with the idea that abdominal
      visceral fat is an important adipose tissue depot linking obesity with
      sympathetic neural activation in humans. Furthermore, these findings may have
      important implications for understanding the increased risk of developing
      cardiovascular diseases in individuals with visceral obesity.

PMID- 12427648
TI  - Non-high-density lipoprotein cholesterol levels predict five-year outcome in the
      Bypass Angioplasty Revascularization Investigation (BARI).
AB  - BACKGROUND: Current National Cholesterol Education Program guidelines recommend
      that non-high-density lipoprotein cholesterol (non-HDL-C) be considered a
      secondary target of therapy among individuals with triglycerides >2.26 mmol/L. It
      is not known whether non-HDL-C relates to prognosis among patients with coronary
      heart disease. METHODS AND RESULTS: Lipid levels were available at baseline among
      1514 patients (73% men; mean age, 61 years) enrolled in the Bypass Angioplasty
      Revascularization Investigation (BARI); all had multivessel coronary artery
      disease. Patients were followed for 5 years. Outcomes of death, nonfatal
      myocardial infarction, and death or myocardial infarction were modeled using
      univariate and multivariate time-dependent proportional hazards methods; angina
      pectoris at 5 years was modeled using univariate and multivariate logistic
      regression. Non-HDL-C was a strong and independent predictor of nonfatal
      myocardial infarction (multivariate relative risk, 1.049 [95% confidence
      intervals, 1.006 to 1.093] for every 0.26 mmol/L increase) and angina pectoris
      (multivariate odds ratio, 1.049 [95% confidence intervals, 1.004 to 1.096] for
      every 0.26 mmol/L increase), but it did not relate to mortality. HDL-C and LDL-C
      did not predict events during follow-up. CONCLUSIONS: Among patients with lipid
      values in BARI, non-HDL-C is a strong and independent predictor of nonfatal
      myocardial infarction and angina pectoris at 5 years, even after consideration of
      powerful clinical variables. Our data suggest that non-HDL-C is an appropriate
      treatment target among patients with coronary heart disease.

PMID- 12427649
TI  - Low-density lipoprotein level reduction by the 3-hydroxy-3-methylglutaryl
      coenzyme-A inhibitor simvastatin is accompanied by a related reduction of F2
      isoprostane formation in hypercholesterolemic subjects: no further effect of
      vitamin E.
AB  - BACKGROUND: Both statins and vitamin E, by reducing the rate of lipid
      peroxidation, may interfere with oxidative stress, but the impact of their
      combination is unknown. METHODS AND RESULTS: We randomized 43
      hypercholesterolemic patients (21 men, 22 women, age 63+/-11 years) to either
      simvastatin, to achieve >20% reduction of total cholesterol, or simvastatin plus
      600 mg/d vitamin E for 2 months. Patients were then crossed over to the
      alternative treatment. Lipid parameters documented patients' compliance to
      simvastatin, whereas plasma levels of vitamin E documented compliance and
      absorption of vitamin E. We assessed urinary excretion of the isoprostane 8-iso
      prostaglandin F(2alpha) (8-iso-PGF(2alpha)) as an in vivo index of oxidative
      stress at baseline and after each month of therapy. 8-Iso-PGF(2alpha) was
      significantly reduced by simvastatin, from 361+/-148 pg/mg creatinine (mean+/-SD)
      at baseline to 239+/-124 pg/mg creatinine after 1 month. The addition of vitamin
      E did not reduce such levels any further (256+/-125 after 1 month). Linear
      regression analysis showed a weak inverse relationship of 8-iso-PGF(2alpha) with
      vitamin E levels but a much stronger relationship with LDL cholesterol
      (R(2)=0.162; P<0.001). CONCLUSIONS: In hypercholesterolemic patients, LDL
      cholesterol is a major correlate of oxidative stress. Concomitant with LDL
      cholesterol reduction, simvastatin causes a drastic reduction of oxidative stress
      to a level that is not further reduced by the addition of vitamin E. Results of
      clinical trials with vitamin E may have been hampered by inadequate knowledge of
      the background level of lipid peroxidation, which is a major determinant of
      vitamin E bioactivity.

PMID- 12427650
TI  - Ability of recombinant factor VIIa to reverse the anticoagulant effect of the
      pentasaccharide fondaparinux in healthy volunteers.
AB  - BACKGROUND: The novel anticoagulant fondaparinux proved to be effective and safe
      in the postoperative prevention of venous thrombosis. Current phase III trials
      with this synthetic selective factor Xa inhibitor focus on its use in the
      treatment of patients with venous and arterial thrombosis. As with any
      anticoagulant therapy, there is a risk of bleeding complications; hence, a
      strategy to reverse the effects of fondaparinux is desirable. The aim of this
      study was to investigate whether recombinant factor VIIa (rFVIIa) could
      neutralize the anticoagulant effects of subcutaneously administered fondaparinux.
      METHODS AND RESULTS: In a randomized, placebo-controlled design, 16 healthy male
      subjects received either a single subcutaneous dose of fondaparinux (10 mg) and a
      single intravenous bolus of rFVIIa (90 microg/kg; n=8), fondaparinux and placebo
      (n=4), or placebo and rFVIIa (n=4). Fondaparinux (or placebo) was administered 2
      hours before rFVIIa (or placebo). Injection of rFVIIa after fondaparinux
      normalized the prolonged activated partial thromboplastin and prothrombin times
      and reversed the decrease in prothrombin activation fragments 1+2 (F(1+2)), as
      observed with fondaparinux alone. Thrombin-generation time and endogenous
      thrombin potential, which were inhibited by fondaparinux, normalized up to 6
      hours after rFVIIa injection. CONCLUSIONS: rFVIIa is capable of normalizing
      coagulation times and thrombin generation during fondaparinux treatment. The
      duration of this effect ranged from 2 to 6 hours after rFVIIa injection. These
      results suggest that rFVIIa may be useful to reverse the anticoagulant effect of
      fondaparinux in case of serious bleeding complications or need for acute surgery
      during treatment with fondaparinux.

PMID- 12427651
TI  - Lung function and cardiovascular risk: relationship with inflammation-sensitive
      plasma proteins.
AB  - BACKGROUND: The inverse relationship between pulmonary function and incidence of
      cardiovascular disease remains largely unexplained. This prospective study
      explored the hypothesis of a relationship with inflammation-sensitive plasma
      proteins. METHODS AND RESULTS: Forced vital capacity (FVC) and plasma levels of
      fibrinogen, alpha(1)-antitrypsin, haptoglobin, ceruloplasmin, and orosomucoid
      were determined in 5064 healthy men aged 28 to 61 years. All-cause mortality,
      cardiovascular mortality, and incidence of myocardial infarction were monitored
      over a mean follow-up period of 18.4 years. Low FVC (fourth quartile) was
      associated with higher protein levels and with increased incidences of myocardial
      infarction and cardiovascular death. Adjustments for protein levels reduced the
      age-adjusted relative risks (RRs) for myocardial infarction (from 1.99, 95% CI
      1.5 to 2.6, to 1.70, 95% CI 1.3 to 2.2) and cardiovascular death (from 2.71, 95%
      CI 1.9 to 3.9, to 2.28, 95% CI 1.6 to 3.3) among men with low FVC, corresponding
      to approximately 25% of the excess risk. The risk factor-adjusted RRs were
      reduced from 1.45 (95% CI 1.1 to 1.9) to 1.38 (95% CI 1.1 to 1.8) and from 1.96
      (95% CI 1.4 to 2.8) to 1.85 (95% CI 1.3 to 2.7) for myocardial infarction and
      cardiovascular death, respectively, corresponding to approximately 10% to 15% of
      the excess risk. Among men with low FVC, the risk factor-adjusted RR for
      myocardial infarction was 2.5 (95% CI 1.7 to 3.6) for those with high protein
      levels (> or =2 proteins in top quartile) and 1.7 (95% CI 1.1 to 2.4) for those
      with low protein levels (< or =1 protein in top quartile; reference, top quartile
      of FVC and low protein levels). CONCLUSIONS: FVC is significantly and inversely
      associated with plasma levels of inflammation-sensitive plasma proteins. This
      relationship contributes to but cannot fully explain the increased cardiovascular
      risk among men with low FVC.

PMID- 12427652
TI  - Arterial stiffness and endothelial function in patients with beta-thalassemia
      major.
AB  - BACKGROUND: Increased iron store has been linked to risk of cardiovascular
      disease. Structural alterations of arteries in beta-thalassemia major patients
      and in vitro functional disturbance of vascular endothelial cells by thalassemic
      serum have been described. We sought to determine whether arterial stiffness and
      endothelial function are altered in vivo. METHODS AND RESULTS: Thirty thalassemia
      patients (16 male) aged 22.2+/-7.4 years were recruited. Left ventricular (LV)
      mass and function were assessed echocardiographically. Carotid and brachioradial
      artery stiffness was assessed by stiffness index and pulse-wave velocity (PWV),
      respectively. Brachial artery endothelial function was assessed by vascular
      response to reactive hyperemia (flow-mediated dilation [FMD]) and sublingual
      glyceryl trinitrate. These indexes were compared with those of 30 age- and sex
      matched controls. None of the patients had LV systolic or diastolic dysfunction.
      When compared with controls, patients had greater absolute (113.8+/-38.0 versus
      109.0+/- 32.6 g, P=0.04) and indexed (82.4+/-17.5 versus 66.7+/-12.7 g/m(2),
      P<0.001) LV mass, carotid artery stiffness index (8.1+/-3.5 versus 5.5+/-1.6,
      P<0.001), and brachioradial PWV (8.9+/-2.4 versus 7.9+/-1.7 m/s, P= 0.03). Their
      FMD was impaired (3.5+/-3.3% versus 8.8+/-3.9%, P<0.001), whereas glyceryl
      trinitrate- mediated dilation was preserved (17.9+/-7.6% versus 16.3+/-6.1%,
      P=0.40). Both stiffness index and PWV correlated inversely with magnitude of FMD
      (r=-0.40, P=0.03; r=-0.41, P=0.03) and positively with indexed LV mass (r=0.50,
      P=0.005; r=0.40, P=0.027). Nonetheless, no significant correlation existed
      between ferritin level and carotid stiffness, PWV, or FMD. CONCLUSIONS: Increased
      arterial stiffness, endothelial dysfunction, and LV hypertrophy occur in patients
      with beta-thalassemia major, which may result in reduction of mechanical
      efficiency of the heart.

PMID- 12427653
TI  - Analysis of cardiovascular phenotype and genotype-phenotype correlation in
      individuals with a JAG1 mutation and/or Alagille syndrome.
AB  - BACKGROUND: Cardiovascular anomalies are among the most common features of
      Alagille syndrome (AGS). Mutations of JAG1 are found in most individuals with
      AGS. This study was undertaken to determine the spectrum of cardiovascular
      phenotypes associated with a JAG1 mutation and/or AGS, investigate potential
      genotype-phenotype correlations, and begin to correlate clinical outcome with
      genetic pathogenesis. METHODS AND RESULTS: We reviewed the records of 200
      individuals with a JAG1 mutation or AGS. A total of 187 (94%) subjects had
      evidence of cardiovascular involvement. Cardiovascular anomalies were identified
      by imaging in 150 subjects (75%), and 37 (19%) had a peripheral pulmonary
      stenosis murmur with either a normal echocardiogram or no imaging study. Of the
      150 subjects with anomalies confirmed by imaging, right-sided anomalies were
      present in 123 and left-sided anomalies in 22, with both in 12. Seventeen
      subjects had other anomalies. The most common abnormality was stenosis/hypoplasia
      of the branch pulmonary arteries (PAs), which was documented by imaging (n=111)
      or inferred from a peripheral pulmonary stenosis murmur (n=41) in 76% of
      subjects. Tetralogy of Fallot was present in 23 subjects and was accompanied by
      pulmonary atresia in 8. Branch PA phenotype differed between individuals with and
      without a JAG1 mutation. Among subjects with a JAG1 mutation, there was no
      correlation between the type or location of mutation and the frequency or type of
      cardiovascular anomaly. CONCLUSIONS: More than 90% of individuals with a JAG1
      mutation or AGS have cardiovascular anomalies, with branch PA stenosis the most
      common abnormality. Cardiovascular phenotype does not correlate with the type or
      location of JAG1 mutation.

PMID- 12427654
TI  - Coronary artery pattern and outcome of arterial switch operation for
      transposition of the great arteries: a meta-analysis.
AB  - BACKGROUND: Prior studies of coronary pattern and outcome after arterial switch
      operation (ASO) for transposition of the great arteries (TGA) have been hindered
      by limited statistical power. This meta-analysis assesses the effect of coronary
      anatomy on post-ASO mortality, both overall and adjusted for time. METHODS AND
      RESULTS: A literature search revealed 9 independent series that reported post-ASO
      mortality by coronary pattern in a total of 1942 patients. Odds ratios comparing
      all-cause mortality in patients with usual versus variant coronary patterns were
      calculated and combined by use of an empirical Bayesian model. Single coronary
      patterns, both of which loop around the great vessels, were associated with
      significant mortality (OR 2.9, 95% CI 1.3 to 6.8), whereas looping patterns that
      arose from 2 separate ostia were not (OR 1.2, 95% CI 0.8 to 1.9). This latter
      group includes patients with the most common variant, circumflex from right
      coronary artery. Patients with an intramural coronary artery had the greatest
      mortality (OR 6.5, 95% CI 2.9 to 14.2). Overall, patients with any variant
      coronary pattern had nearly twice the mortality seen in those with the usual
      pattern (OR 1.7, 95% CI 1.3 to 2.4). Single ostium patterns and intramural
      coronary arteries remained associated with significant added mortality after
      adjustment for time-trend effects. CONCLUSIONS: Over the past 2 decades, patients
      with common coronary variants have undergone ASO without added mortality compared
      with those with the usual coronary pattern. Those with intramural or single
      coronary arteries have significant added mortality that has persisted over time.

PMID- 12427655
TI  - Enzymatically modified nonoxidized low-density lipoprotein induces interleukin-8
      in human endothelial cells: role of free fatty acids.
AB  - BACKGROUND: Treatment of low-density lipoprotein (LDL) with a protease and
      cholesterolesterase transforms the lipoprotein to an entity that resembles
      lipoprotein particles in atherosclerotic lesions, which have a high content of
      free cholesterol, reflecting extensive de-esterification in the intima. Because
      de-esterification would occur beneath the endothelium, we examined the effects of
      enzymatically modified LDL (E-LDL) on cultured endothelial cells. METHODS AND
      RESULTS: Incubation of endothelial cells with E-LDL provoked selective
      accumulation of interleukin (IL)-8 mRNA and production of the cytokine. Chemical
      analyses and depletion experiments indicated that the effect was caused by the
      presence of free fatty acids in the altered lipoprotein. Reconstitution studies
      demonstrated that the oleic and linoleic acids associated with E-LDL are
      particularly effective IL-8 inducers. The effects of E-LDL on endothelial cells
      could be abrogated with albumin. CONCLUSION: IL-8 is required for rolling
      monocytes to adhere firmly to the endothelium; thus, the findings reveal a link
      between subendothelial entrapment of LDL, cleavage of cholesterol esters, and
      monocyte recruitment into the lesion.

PMID- 12427656
TI  - Hypotension caused by extracorporeal circulation: serotonin from pump-activated
      platelets triggers nitric oxide release.
AB  - BACKGROUND: Cardiopulmonary bypass and hemodialysis often cause hypotension. We
      investigated a possible role of pump-induced platelet activation with consequent
      serotonin release. METHODS AND RESULTS: In rats, a heparin-coated extracorporeal
      shunt was placed between the proximal part of a carotid artery and the distal
      part of a femoral artery. Autoperfusion did not affect platelets or hemodynamics.
      Pump perfusion, however, immediately elicited strong platelet aggregation,
      whereas aortic pressure rapidly fell to 60+/-12% (mean+/-SD) of its prepump
      value, partially recovered, and then progressively decreased to 70+/-12% at 2
      hours. Femoral resistance doubled and then decreased to 59+/-11%. The initial
      changes in aortic pressure and femoral resistance were proportional to the amount
      of platelet aggregation, were accompanied by a rise (6-fold) in plasma serotonin
      levels downstream of the pump, but not in the aorta, and could be mimicked by
      serotonin-infusion into the leg. All hemodynamic changes were prevented or
      largely reduced by blockade of 5-hydroxytryptamine (5-HT)2 receptors with
      pizotifen or ritanserin. The hypotension and femoral resistance decrease could
      also be prevented or abolished by inhibiting the production of nitric oxide (NO),
      an intermediate in 5-HT(2B) receptor-induced vasodilation. When the
      extracorporeal blood was pumped into the aortic arch instead of the femoral
      artery, the hypotensive effect was similar and also NO dependent, but it was
      absent with venous return. CONCLUSIONS: Pump perfusion with arterial return of
      the blood causes hypotension by endothelial NO-release, which in turn is
      triggered by serotonin from activated platelets.

PMID- 12427657
TI  - Reverse ventricular remodeling reduces ischemic mitral regurgitation: echo-guided
      device application in the beating heart.
AB  - BACKGROUND: In ischemic mitral regurgitation (MR), mitral leaflet closure is
      restricted by ventricular remodeling with displacement of the papillary muscles
      (PMs). Therapy is uncertain because ring annuloplasty does not alleviate PM
      displacement. We tested the hypothesis that echo-guided PM repositioning using an
      external device can reduce MR without compromising left ventricular (LV)
      function. METHODS AND RESULTS: We studied 10 sheep with ischemic MR produced by
      circumflex ligation with inferior infarction, 6 acutely and 4 eight weeks after
      myocardial infarction (MI). A Dacron patch containing an inflatable balloon was
      placed over the PMs and adjusted under echo guidance to reverse LV remodeling and
      reposition the infarcted PM. 3D echo assessed mitral valve geometric changes. In
      7 sheep, sonomicrometry and Millar catheters assessed changes in end-systolic and
      end-diastolic pressure-volume relationships, and microspheres were injected to
      assess coronary flow. Moderate MR after MI resolved with patch application alone
      (n=3) or echo-guided balloon inflation, which repositioned the infarcted PM,
      decreasing the PM tethering distance from 31.1+/-2.5 mm after MI to 26.8+/-1.8
      with patch (P<0.01; baseline=25.5+/-1.5). LV contractility was unchanged (end
      systolic slope=3.4+/-1.6 mm Hg/mL with patch versus 2.8+/-1.6 after MI). Although
      there was a nonsignificant trend for a mild increase in stiffness constant
      (0.07+/-0.05 mL(-1) versus 0.05+/-0.03 after MI, P=0.06), LV end-diastolic
      pressure was unchanged as MR resolved. Coronary flow to noninfarcted regions was
      not reduced. CONCLUSIONS: An external device that repositions the PMs can reduce
      ischemic MR without compromising LV function. This relatively simple technique
      can be applied under echo guidance in the beating heart.

PMID- 12427658
TI  - Preoperative glutamine administration induces heat-shock protein 70 expression
      and attenuates cardiopulmonary bypass-induced inflammatory response by regulating
      nitric oxide synthase activity.
AB  - BACKGROUND: Heat-shock protein 70 (HSP70) plays a major role in the
      pathophysiology of inflammation, and the induction of HSP70 before the onset of
      inflammation can reduce organ damage through a self-protective system. Glutamine
      is known to be an inducer of HSP70, and its preoperative administration seems
      useful in attenuating cardiopulmonary bypass (CPB)-induced inflammatory response.
      METHODS AND RESULTS: Adult male Sprague-Dawley rats (group G, received 100 mg/kg
      of glutamine via the right jugular vein 3 times per day for 1 week and just
      before the initiation of CPB; group C served as control) underwent CPB (60
      minutes, 100 mL/kg per minute, 34 degrees C) and were killed 3 hours after the
      termination of CPB. Group G showed significantly lower plasma concentrations of
      interleukin-6 and interleukin-8 after CPB termination. Myocardial and respiratory
      damages were significantly attenuated in group G, as evidenced by Langendorff
      perfusion, respiratory index, and neutrophil adherence. HSP70 expressions in the
      heart, lung, and liver were detected only in group G before CPB and were markedly
      stronger in group G 3 hours after CPB termination. Although plasma
      nitrate+nitrite concentrations were not significantly different between the
      groups, endothelial-constitutive nitric oxide synthase (NOS) activity was
      markedly preserved and inducible NOS activity was markedly attenuated in the
      tissues of group G. CONCLUSIONS: These results suggest that preoperative
      glutamine administration induces HSP70 expression before CPB and attenuates CPB
      induced inflammation by regulating NOS activity, which may be a prospective
      management for conferring tolerance to CPB-induced inflammatory response through
      a self-protective mechanism.

PMID- 12427660
TI  - Update on myocardial bridging.

PMID- 12427659
TI  - CD14-deficient mice are protected against lipopolysaccharide-induced cardiac
      inflammation and left ventricular dysfunction.
AB  - BACKGROUND: The molecular mechanisms responsible for sepsis-induced myocardial
      dysfunction remain undefined. CD14 mediates the inflammatory response to
      lipopolysaccharide (LPS) in various organs including the heart. In this study we
      investigated the role of CD14 in LPS-induced myocardial dysfunction in vivo.
      METHODS AND RESULTS: Wild-type and CD14-deficient (CD14-D) mice were challenged
      with Escherichia coli LPS. Myocardial tumor necrosis factor, interleukin-1beta
      (IL-1beta), and NOS2 induction was measured before and 6 hours after LPS
      challenge. Echocardiographic parameters of left ventricular function were
      measured before and 6 hours after LPS administration. LPS challenge induced a
      significant increase in myocardial tumor necrosis factor and IL-1beta mRNA and
      protein expression in wild-type mice. In contrast, mRNA and protein levels for
      TNF and IL-1beta were significantly blunted in CD14-D mice. An increase in NOS2
      protein was noted within 6 hours of LPS provocation only in the hearts of wild
      type mice. This was associated with an increase in ventricular cGMP levels.
      Activation of nuclear factor-kappaB was observed within 30 minutes of LPS in the
      hearts of wild-type mice but not in CD14-D mice. In wild-type mice, LPS
      significantly decreased left ventricular fractional shortening, velocity of
      circumferential shortening, and dP/dt(max). LPS-treated CD14-D mice maintained
      normal cardiac function. CONCLUSIONS: These results suggest that CD14 is
      important in mediating the proinflammatory response induced by LPS in the heart
      and that CD14 is necessary for the development of left ventricular dysfunction
      during LPS-induced shock in vivo.

PMID- 12427661
TI  - Medication errors in acute cardiac care: An American Heart Association scientific
      statement from the Council on Clinical Cardiology Subcommittee on Acute Cardiac
      Care, Council on Cardiopulmonary and Critical Care, Council on Cardiovascular
      Nursing, and Council on Stroke.

PMID- 12427662
TI  - Report of the American Heart Association Task Force on Strategic Research
      Direction: executive summary.

PMID- 12427663
TI  - Cardiology patient pages. Treatment of blood clots.

PMID- 12427664
TI  - Passage of inhaled particles into the blood circulation in humans.

PMID- 12427665
TI  - No-reflow phenomenon.

PMID- 12427666
TI  - Further in vivo evidence that cellular senescence is implicated in vascular
      pathophysiology.

PMID- 12427667
TI  - Circulating and exhaled markers of nitric oxide and antioxidant activity after
      smoking.

PMID- 12427668
TI  - Angiotensin-(1-7) attenuates the development of heart failure after myocardial
      infarction in rats.

PMID- 12427669
TI  - Misinformation on plant proteins.

PMID- 12427670
TI  - Task Force on Strategic Research Direction: Basic Science Subgroup key science
      topics report.

PMID- 12427671
TI  - Task Force on Strategic Research Direction: Clinical Science Subgroup key science
      topics report.

PMID- 12427672
TI  - Task Force on Strategic Research Direction:
      Population/Outcomes/Epidemiology/Social Science Subgroup key science topics
      report.

PMID- 12427674
TI  - Selective expression of doublecortin and LIS1 in developing human cortex suggests
      unique modes of neuronal movement.
AB  - The genes doublecortin (DCX) and LIS1 are required for proper cortical neuronal
      migration and differentiation in humans. Here, we study the expression pattern of
      the encoded proteins of these genes in developing human brain. LIS1 stained
      virtually all migrating neurons throughout periods of development. Initially, DCX
      extensively overlapped with Reelin in early preplate stage in radially oriented
      columns of cells in the ventricular zone, whereas at later stages, the majority
      of DCX-positive cells were horizontally oriented. During the cortical plate
      stage, two opposite patterns of DCX expression were found: in radially oriented
      apical processes, presumably of pyramidal cells in the cortical plate, and in non
      radially oriented mono- or bipolar neurons with migratory morphologies in the
      deep compartments of the cerebral wall. The extensive co-localization of DCX and
      Calretinin in non-radially oriented neurons suggested a non-pyramidal phenotype.
      These cells assumed a more vertical orientation upon entering the subplate. In
      addition, DCX was expressed by cells in the subpial granular layer and by Cajal
      Retzius cells. In a 19 week human fetal cortex with a LIS1 mutation, the number
      of Reelin-expressing Cajal-Retzius cells was reduced and their morphology was
      abnormal. DCX was expressed by cells in all regions, but in extremely low
      numbers, suggesting that LIS1 deficiency adversely affects the migration and
      differentiation of DCX- and Reelin-positive neurons.

PMID- 12427675
TI  - Radial organization of developing preterm human cerebral cortex revealed by non
      invasive water diffusion anisotropy MRI.
AB  - Cerebral cortical development involves a complex cascade of events which are
      difficult to visualize in intact, living subjects. In this study, we apply
      diffusion tensor imaging (DTI) to the evaluation of cortical development in human
      infants ranging from 26 to 41 weeks gestational age (GA). Apparent diffusion of
      water in cortex is maximally anisotropic at 26 weeks GA and anisotropy values
      approach zero by 36 weeks GA. During this period, the major eigenvector of the
      diffusion tensor in cerebral cortex is oriented radially across the cortical
      plate, in accord with a predominately radial deployment of its neuronal
      constituents. Values for the rotationally averaged water diffusion coefficient
      increase between 26 and 32 weeks GA, then decrease thereafter. These changes in
      DTI parameters are specific to cerebral cortex and reflect changes in underlying
      cortical architecture and formation of neuronal connections. Because of its
      correlation with tissue microstructure and non-invasive nature, DTI offers unique
      insight into cortical development in preterm human newborns and, potentially,
      detection of derangements of its basic cytoarchiteture.

PMID- 12427676
TI  - Retinoic acid synthesis in the postnatal mouse brain marks distinct developmental
      stages and functional systems.
AB  - Retinoic acid (RA) affects development and function of the brain, but little is
      known about how much is made locally and where it is distributed. To identify RA
      sensitive neural processes, we mapped the RA-synthesizing retinaldehyde
      dehydrogenases (RALDHs) during postnatal brain formation of the mouse. High and
      stable RALDH expressions mark the basal ganglia, olfactory bulbs, hippocampus and
      auditory afferents as major sites of RA actions in the functional brain. During
      the early postnatal period, transient and very high RALDH3 expressions
      distinguish two developmental events: (i) the colonization of the nucleus
      accumbens and the olfactory bulbs by neuronal precursors and (ii) the maturation
      of selected parts of the cerebral cortex. In the cortex, RALDH3 is transiently
      activated in postmigratory layer II/III neurons during formation of their
      dendritic arbors and it is transported in their axons across the corpus callosum.
      RALDH3-expressing cortical regions include most of the limbic lobe, with
      strongest expression in the anterior cingulate cortex, medial and lateral
      secondary visual cortices, auditory cortical areas, the secondary motor cortex
      and some association areas. The transient cortical expression points to a brief
      RA-critical period during differentiation of the cortical network that serves in
      the coordination of sensory-motor activity with emotional and recently learned
      information.

PMID- 12427677
TI  - The frontal cortex of the rat and visual attentional performance: dissociable
      functions of distinct medial prefrontal subregions.
AB  - A previous study using a rodent five-choice test of attention found poor choice
      accuracy and increased perseverative responding following medial prefrontal
      cortex (mPFC) lesions. As this rat cortical area includes at least two
      anatomically distinguishable subregions, the present study investigated their
      specific contributions to performance of this task. Rats were trained on the five
      choice task prior to receiving excitotoxic lesions or sham surgery. In the first
      experiment, lesions of the dorsal mPFC (Zilles's Cg1) resulted in poor accuracy,
      but no changes in perseverative responding. Introducing variable delays for
      stimulus presentation abolished these accuracy deficits, suggesting that Cg1
      lesioned rats were impaired at using temporal cues to guide performance. In the
      second experiment, lesions of the ventral mPFC increased perseverative
      responding, but had only short-lasting effects on accuracy. Rats with complete
      mPFC lesions had both choice accuracy impairments and increased perseverative
      responding. Additional evidence of the functional dissociation of dorsal and
      ventral mPFC came from the analysis of the spatial and temporal distribution of
      the correct and incorrect responses. Only rats with ventral mPFC lesions showed
      delay-dependent deficits and bias towards a location that had recently been
      associated with reward. Taken together, these results suggest dissociable
      'executive' functions of mPFC subregions. Circuits centred on Cg1 are critical
      for the temporal organization of behaviour, while networks involving the ventral
      mPFC are important for maintaining behavioural flexibility.

PMID- 12427678
TI  - Adult experience-dependent plasticity of S1 barrel cortex in the normal and
      monoamine oxidase-A knockout (Tg8) mouse.
AB  - By restricted use of D2 and D3 whiskers for 3-20 days at maturity (whisker
      pairing, WP), receptive field plasticity of adult D2 barrel cortex cells was
      compared in vivo for Tg8 mutant and normal (NOR) mice. Little plasticity was
      achieved until 20 days of WP in both mice. For Tg8, which lacks segregation of
      thalamocortical (TC) terminals into barrels, the first relay (TC) responses in
      layer IV to the principal whisker were potentiated more than in NOR mice by 20
      days of WP. In parallel, secondary discharges were reduced more in Tg8 than NOR.
      It is suggested that both TC excitation and feed-forward inhibition in Tg8 are
      greater and potentiated more by WP than in NOR mice. Similar differences were
      reflected in supragranular (SG) cells. For Tg8 but not NOR mice, first latencies
      of one in five cells in layer IV to an adjacent surround whisker matched those of
      the principal whisker, increasing to one in three by 20 days of WP experience.
      Converse decreases occurred for the deprived surround whisker. Changes were
      similar but smaller for SG cells. Lack of TC segregation in Tg8, therefore,
      allows substantial overlapping TC terminals of immediate surround whiskers to
      activate neighbouring D2 column cells directly with potentiated relay to a
      whisker paired input and weakened relay to a deprived input. Although differing
      from NOR mice, experiential plasticity was not strongly compromised in Tg8 mice.
      Differences in WP plasticity from rat barrel cortex are discussed.

PMID- 12427679
TI  - Areal organization of the posterior parietal cortex of the ferret (Mustela
      putorius).
AB  - On grounds of electrophysiological mapping, cytoarchitecture, myeloarchitecture
      and callosal and thalamic connectivity, we have identified two cortical areas in
      the posterior parietal cortex of the ferret: posterior parietal caudal and
      rostral (PPc and PPr). These areas occupy the lateral and suprasylvian gyri, from
      the cingulate sulcus (medially) to the suprasylvian sulcus (laterally) and lie
      between visual areas 18 and 21 (posteriorly) and the somatosensory areas
      (anteriorly). Within both areas a coarse representation of the visual field was
      found and within PPr there was also a representation of the body. Each
      representation mirrors those within neighboring areas. Cytoarchitectonic and
      myeloarchitectonic fields within this cortical region did not correspond in any
      simple way to the physiological representations. The architectonic differences
      correlate to differential callosal connectivity, with predominant connectivity
      corresponding to the upper hemifield/head representations. PPr and PPc receive
      thalamic projections from a different, but overlapping, complement of thalamic
      nuclei. The superimposition of somatic and visual maps in PPr might relate to the
      probable role of this area in transforming retinal-centered to body-centered
      spatial coordinates. The organization of the parietal areas in the ferret
      resembles that of the flying fox and might unveil a common organizational plan
      from which the primate posterior parietal cortex evolved.

PMID- 12427680
TI  - Reelin immunoreactivity in the adult primate brain: intracellular localization in
      projecting and local circuit neurons of the cerebral cortex, hippocampus and
      subcortical regions.
AB  - Reelin is a large secretable protein which is widely expressed by specific
      neuronal populations. In the embryonic brain, Reelin plays a signaling role
      critical for the correct positioning of migrating neuroblasts. Reelin is also
      expressed in the adult mammalian brain, including humans; however, its function/s
      there remain poorly understood. To gain insight into which neuronal populations
      and specific circuits may be influenced by Reelin in the adult, we have conducted
      a light and electron microscope analysis of Reelin-immunoreactive neuron types in
      the cerebral cortex and subcortical regions of adult macaque monkeys. Results
      show that the great majority of brain neurons, including interneurons and
      projection neurons, are immunoreactive for Reelin although some neuronal
      populations do not contain Reelin. The immunoreactive protein is located
      intracellularly, mainly in neuronal somata. Reelin is also present in gray matter
      neuropil as well as in some long axonal pathways and their terminal
      arborizations, suggesting that it can be axonally transported over long
      distances. The staining patterns in the labeled neurons are remarkably diverse.
      Our observations reveal a wider distribution of Reelin in the adult macaque brain
      than in any other species investigated to date. The data show that Reelin is in a
      position to influence most brain circuits in the adult primate brain.

PMID- 12427681
TI  - Frontal and parietal lobe activation during transitive inference in humans.
AB  - Cortical areas engaged in knowledge manipulation during reasoning were identified
      with functional magnetic resonance imaging (MRI) while participants performed
      transitive inference (TI) on an ordered list of 11 items (e.g. if A < B and B <
      C, then A < C). Initially, participants learned a list of arbitrarily ordered
      visual shapes. Learning occurred by exposure to pairs of list items that were
      adjacent in the sequence. Subsequently, functional MR images were acquired as
      participants performed TI on non-adjacent sequence items. Control tasks consisted
      of height comparisons (HT) and passive viewing (VIS). Comparison of the TI task
      with the HT task identified activation resulting from TI, termed 'reasoning',
      while controlling for rule application, decision processes, perception, and
      movement, collectively termed 'support processes'. The HT-VIS comparison revealed
      activation related to support processes. The TI reasoning network included
      bilateral prefrontal cortex (PFC), pre-supplementary motor area (preSMA),
      premotor area (PMA), insula, precuneus, and lateral posterior parietal cortex. By
      contrast, cortical regions activated by support processes included the bilateral
      supplementary motor area (SMA), primary motor cortex (M1), somatic sensory
      cortices, and right PMA. These results emphasize the role of a prefrontal
      parietal network in manipulating information to form new knowledge based on
      familiar facts. The findings also demonstrate PFC activation beyond short-term
      memory to include mental operations associated with reasoning.

PMID- 12427682
TI  - Neural basis of mental scanning of a topographic representation built from a
      text.
AB  - Humans have the ability to build and to inspect an internal visual image of an
      environment built from a verbal description. We used positron emission tomography
      (PET) to investigate the brain areas engaged in the mental scanning of a map that
      subjects built from the reading of a descriptive text. This task engaged a
      parieto-frontal network known to deal with spatial representations. Additional
      activations were evidenced in the angular gyrus and in Broca's and Wernicke's
      areas. In order to examine the neural impact of the learning modality, these PET
      results were compared to those obtained in another group of six subjects who
      performed a similar mental scanning task on a topographic representation built
      from visual inspection of a map. Both scanning tasks engaged the parieto-frontal
      network. However, the bilateral activation of the angular gyrus as well as the
      involvement of language areas appeared specific to the mental scanning of the
      topographic representation built from textual information. On the other hand, the
      right medial temporal lobe was activated only when a map had been visually
      learned. These results suggest that although both tasks involved visuo-spatial
      internal representation, a trace of the learning modality remained present in the
      brain.

PMID- 12427683
TI  - A computational morphometric MRI study of schizophrenia: effects of
      hallucinations.
AB  - Quantitative magnetic resonance imaging (MRI) studies in patients with
      schizophrenia have shown reliable deficits in global tissue volume as well as
      some regionally specific changes, particularly in the temporal and frontal lobes.
      Recent technical advances have enabled automated voxel-wise analyses, which have
      the advantage of facilitating whole brain coverage without the restrictions of
      anatomically defined regions of interest and imperfect rater reliability. We used
      such a method to estimate voxel composition from segmentation of bivariate, dual
      echo spin-echo data in 72 men with schizophrenia. Of these, 41 had a prominent
      history of auditory-verbal hallucinations and 31 had no such history. The
      patients were compared with 32 age, gender, handedness and IQ matched healthy
      controls. The study revealed localized areas of reduced grey-matter tissue
      proportion aggregating around the medial temporal lobes, the insulae, orbito
      frontal cortex including anterior cingulate, and the precuneus (and lingual)
      gyri, in the schizophrenia patients as a whole. There were also reductions in
      white-matter tissue proportion extending along much of the large anterior
      posterior frontal tracts in the right hemisphere. Small regions of increased grey
      matter were also noted in the right inferior parietal lobe. A contrast between
      the hallucinator and non-hallucinator patient groups showed a single region of
      reduced grey-matter tissue proportion affecting the left insula and adjacent
      temporal lobe. These data confirm the utility of voxel-based morphometric methods
      in schizophrenia research and point towards disruption to a 'paralimbic' neural
      network, as underlying schizophrenic psychopathology in general, with
      abnormalities of the left insula specifically related to hallucinations.

PMID- 12427684
TI  - Volumetry of temporopolar, perirhinal, entorhinal and parahippocampal cortex from
      high-resolution MR images: considering the variability of the collateral sulcus.
AB  - Researchers in clinical and basic neuroscience frequently target structures of
      the human medial temporal lobe (MTL) for volumetric analysis with magnetic
      resonance imaging (MRI). In neurodegenerative diseases, a precise volumetric
      analysis of MTL structures can assist in differential diagnosis and can be used
      in guiding early treatment. Also, in functional neuroimaging, exact localization
      is crucial for the correct interpretation of focal MTL activations with respect
      to specific memory functions. In presently available protocols, precise and
      consistent volumetric analysis of MTL structures is compromised in numerous ways.
      Most importantly, in order to cover all structures of the MTL, the researcher is
      presently forced to combine independently developed segmentation protocols for
      different structures from different laboratories. This approach limits anatomical
      precision because these protocols are based on different anatomical guidelines
      and descriptions that cannot easily be integrated. The segmentation approach
      presented in this paper was designed to address this issue by presenting
      segmentation guidelines for all major structures of the parahippocampal gyrus
      (PHG). It was developed directly to complement a volumetric protocol for
      hippocampus and amygdala (Pruessner et al., 2000, Cereb Cortex 10:433-442), thus
      allowing volumetric assessment of all major MTL structures in an integrated and
      consistent manner. Furthermore, it takes into consideration the neuroanatomical
      appearance of the collateral sulcus by presenting a method to correct the volumes
      of the surrounding cortices for the variability of this sulcus. The protocol was
      validated using MR images of 40 healthy normal control subjects (20 men and 20
      women, age range 18-42 years). Intra- and interrater coefficients are presented,
      together with mean values for the volumes of all PHG structures, correlations
      with age and sex, and tests for hemispheric differences.

PMID- 12427686
TI  - Prison optics.

PMID- 12427689
TI  - Caution with breast-conserving surgery.

PMID- 12427690
TI  - Stop trivializing MD workforce problems.

PMID- 12427693
TI  - Stop trivializing MD workforce problems.

PMID- 12427695
TI  - Restricted access for PPIs not a panacea.

PMID- 12427696
TI  - Telephone stroke.

PMID- 12427697
TI  - Reserving judgement on HRT.

PMID- 12427698
TI  - Physicians' prescribing information: not for sale.

PMID- 12427701
TI  - Causes of death among people in custody in Ontario, 1990-1999.
AB  - BACKGROUND: People in custody are more likely to die prematurely, especially of
      violent causes, than similar people not in custody. Some of these deaths may be
      preventable. In this study we examined causes of death (violent and natural)
      among people in custody in Ontario. We also compared the causes of deaths in 3
      custodial systems (federal penitentiaries, provincial prisons and police cells).
      METHODS: We examined all available files of coroners' inquests into the deaths of
      people in custody in federal penitentiaries, provincial prisons and police cells
      in Ontario from 1990 to 1999. Data collected included age, cause of death, place
      of death, history of psychiatric illness and history of substance abuse. Causes
      of death were categorized as violent (accidental poisoning, suicide or homicide)
      or natural (cancer, cardiovascular disease or "other"). Crude death rates were
      estimated for male inmate populations in federal and provincial institutions.
      There were inadequate numbers for women and inadequate denominator estimates for
      police cells. RESULTS: A total of 308 inmates died in custody during the study
      period; data were available for 291 (283 men, 8 women). Of the 283 deaths
      involving men, over half (168 [59%]) were from violent causes: suicide by
      strangulation (n = 90), poisoning or toxic effect (n = 48) and homicide (n = 16).
      Natural causes accounted for 115 (41%) of the deaths among the men,
      cardiovascular disease being the most common (n = 62 cases) and cancer the second
      most common (n = 18). Most (137 [48%]) of the deaths among the men occurred in
      federal institutions; 88 (31%) and 58 (21%) respectively occurred in provincial
      institutions and police cells. The crude rate of death among male inmates was
      420.1 per 100,000 in federal institutions and 211.5 per 100 000 in provincial
      institutions. Compared with the Canadian male population, male inmates in both
      federal and provincial institutions had much higher rates of death by poisoning
      and suicide; the same was true for the rate of death by homicide among male
      inmates in federal institutions. The rates of death from cardiovascular disease
      among male inmates in federal and provincial institutions -- 102.7 and 51.7 per
      100,000 respectively -- were also higher than the national average.
      INTERPRETATION: Violent causes of death, especially suicide by strangulation and
      poisoning, predominate among people in custody. Compared with the Canadian male
      population, male inmates have a higher overall rate of death and a much higher
      rate of death from violent causes.

PMID- 12427685
TI  - 2002 clinical practice guidelines for the diagnosis and management of
      osteoporosis in Canada.
AB  - OBJECTIVE: To revise and expand the 1996 Osteoporosis Society of Canada clinical
      practice guidelines for the management of osteoporosis, incorporating recent
      advances in diagnosis, prevention and management of osteoporosis, and to identify
      and assess the evidence supporting the recommendations. OPTIONS: All aspects of
      osteoporosis care and its fracture complications - including classification,
      diagnosis, management and methods for screening, as well as prevention and
      reducing fracture risk - were reviewed, revised as required and expressed as a
      set of recommendations. OUTCOMES: Strategies for identifying and evaluating those
      at high risk; the use of bone mineral density and biochemical markers in
      diagnosis and assessing response to management; recommendations regarding
      nutrition and physical activity; and the selection of pharmacologic therapy for
      the prevention and management of osteoporosis in men and women and for
      osteoporosis resulting from glucocorticoid treatment. EVIDENCE: All
      recommendations were developed using a justifiable and reproducible process
      involving an explicit method for the evaluation and citation of supporting
      evidence. VALUES: All recommendations were reviewed by members of the Scientific
      Advisory Council of the Osteoporosis Society of Canada, an expert steering
      committee and others, including family physicians, dietitians, therapists and
      representatives of various medical specialties involved in osteoporosis care
      (geriatric medicine, rheumatology, endocrinology, obstetrics and gynecology,
      nephrology, radiology) as well as methodologists from across Canada. BENEFITS,
      HARM AND COSTS: Earlier diagnosis and prevention of fractures should decrease the
      medical, social and economic burdens of this disease. RECOMMENDATIONS: This
      document outlines detailed recommendations pertaining to all aspects of
      osteoporosis. Strategies for identifying those at increased risk (i.e., those
      with at least one major or 2 minor risk factors) and screening with central dual
      energy x-ray absorptiometry at age 65 years are recommended. Bisphosphonates and
      raloxifene are first-line therapies in the prevention and treatment of
      postmenopausal osteoporosis. Estrogen and progestin/progesterone is a first-line
      therapy in the prevention and a second-line therapy in the treatment of
      postmenopausal osteoporosis. Nasal calcitonin is a second-line therapy in the
      treatment of postmenopausal osteoporosis. Although not yet approved for use in
      Canada, hPTH(1-34) is expected to be a first-line treatment for postmenopausal
      women with severe osteoporosis. Ipriflavone, vitamin K and fluoride are not
      recommended. Bisphosphonates are the first-line therapy for the prevention and
      treatment of osteoporosis in patients requiring prolonged glucocorticoid therapy
      and for men with osteoporosis. Nasal or parenteral calcitonin is a first-line
      treatment for pain associated with acute vertebral fractures. Impact-type
      exercise and age-appropriate calcium and vitamin D intake are recommended for the
      prevention of osteoporosis. VALIDATION: All recommendations were graded according
      to the strength of the evidence; where the evidence was insufficient and
      recommendations were based on consensus opinion alone, this is indicated. These
      guidelines are viewed as a work in progress and will be updated periodically in
      response to advances in this field.

PMID- 12427702
TI  - Health-related quality of life and mobility of patients awaiting elective total
      hip arthroplasty: a prospective study.
AB  - BACKGROUND: Waits for elective total hip arthroplasty for osteoarthritis are
      common in publicly funded health care systems, but they may lead to poorer
      postoperative outcomes and loss of health-related quality of life (HRQOL) through
      progressive pain and immobility during the wait. These issues have not been
      examined from the time of referral for surgery. Our primary objective was to test
      whether a longer wait was associated with poorer postoperative HRQOL. METHODS:
      Patients needing possible total hip arthroplasty for osteoarthritis were
      identified upon referral to a surgeon in London, Ont. Outcome measures, including
      the Western Ontario McMaster (WOMAC) Osteoarthritis Index and mobility in the 6
      Minute Walk, were assessed at baseline and every 3-6 months thereafter until at
      least 3 months after the surgery. RESULTS: Of 553 potentially eligible patients
      referred for surgical assessment, 123 were placed on a waiting list for total hip
      arthroplasty; 114 underwent the procedure, and 99 of them returned for
      postoperative assessment. No significant differences in HRQOL or mobility were
      seen postoperatively between patients with short waits and those with long waits
      (a priori definitions < or = 6 months and > 6 months respectively). At referral,
      however, patients with short waits had poorer HRQOL and were less mobile than
      those with long waits (p = 0.002 for WOMAC Osteoarthritis Index total score,
      0.001 for pain, 0.009 for stiffness and 0.008 for function; p = 0.006 for 6
      Minute Walk results). Patients with short waits experienced larger gains in these
      measures from the time of referral until the postoperative assessment than did
      patients with long waits (p = 0.002 for WOMAC Osteoarthritis Index total score, <
      0.001 for pain, 0.005 for stiffness and 0.005 for function; p = 0.06 for 6-Minute
      Walk results). For patients with long waits, increases in the WOMAC
      Osteoarthritis Index total score exceeded 10% and losses in walking distance
      exceeded 30 m from the time of referral to surgery. INTERPRETATION: The length of
      wait for elective total hip arthroplasty is not associated with postoperative
      HRQOL and mobility. However, patients who undergo the procedure within 6 months
      after referral have greater disability at referral, and realize greater gains in
      HRQOL and mobility after surgery, than patients waiting more than 6 months.
      Clinically important losses in HRQOL and mobility occur in patients waiting more
      than 6 months.

PMID- 12427703
TI  - Initial patterns of use of COX-2 inhibitors by elderly patients in Ontario:
      findings and implications.

PMID- 12427704
TI  - Death behind bars.

PMID- 12427705
TI  - The double-edged sword of COX-2 selective NSAIDs.
AB  - The launch of the cyclooxygenase-2 (COX-2) selective NSAIDs was based on 2
      hypotheses: (1) the major adverse effects limiting the usefulness of nonselective
      NSAIDs are gastrointestinal in nature and (2) COX-2 selective NSAIDs are
      associated with fewer gastrointestinal adverse effects than nonselective NSAIDs.
      At the time of the launch, neither of these hypotheses had been proven and, as
      documented in this review, both remain uncertain. The increased incidence of
      total and nongastrointestinal serious adverse events, with the COX-2 selective
      NSAIDs as compared with nonselective NSAIDs, in the Celecoxib Long-term Arthritis
      Safety Study (CLASS) and the Vioxx Gastrointestinal Outcomes Research (VIGOR)
      study remains a major concern. The increased morbidity associated with the COX-2
      selective NSAIDs may be a manifestation of the COX-2 selectivity of rofecoxib and
      celecoxib or the supramaximal doses of these drugs used in the trials. Proof that
      the increased harm was not caused by the COX-2 selectivity of the drugs depends
      on demonstration in a randomized controlled trial that COX-2 selective NSAIDs at
      usual doses are as effective as nonselective NSAIDs and cause fewer
      gastrointestinal serious adverse events without increasing the incidence of total
      nongastrointestinal serious adverse events.

PMID- 12427707
TI  - Resurgence of Bordetella pertussis infection.

PMID- 12427706
TI  - The 2002 Canadian bone densitometry recommendations: take-home messages.

PMID- 12427709
TI  - Smallpox vaccination advice.

PMID- 12427708
TI  - Mefloquine: contraindicated in patients with mood, psychotic or seizure
      disorders.

PMID- 12427710
TI  - A rare site for tuberculosis.

PMID- 12427715
TI  - Methadone maintenance expands inside federal prisons.

PMID- 12427716
TI  - Firing public health MD over pro-Kyoto comments a no-no, Alberta learns.

PMID- 12427722
TI  - Ontario's ambitious primary care reform plan slow in attracting MDs.

PMID- 12427724
TI  - No shortage of teaching opportunities in Johannesburg trauma unit.

PMID- 12427726
TI  - Class of '94 results point to family medicine's declining popularity.

PMID- 12427729
TI  - Cell cycle differences in DNA damage-induced BRCA1 phosphorylation affect its
      subcellular localization.
AB  - Phosphorylation of BRCA1 tumor suppressor protein is regulated during the cell
      cycle and in response to DNA damage. Several Ser/Thr kinases have been implicated
      in BRCA1 phosphorylation, including ATM/ATR, cdk2, and hChk2 kinases. In this
      study, phospho-Ser-specific antibodies recognizing Ser-988, -1423, -1497, and 
      1524 residues of BRCA1 were employed to study BRCA1 phosphorylation during the S
      and G2/M phases under conditions of DNA damage. We observed that IR (ionizing
      radiation) treatment induced phosphorylation of Ser-988/Ser-1524 during the S
      phase and of Ser-988/Ser-1423 during the G2/M phase. UV treatment induced
      phosphorylation of Ser-988 during the S phase and of Ser-1423 during the G2/M
      phase. Phosphorylation of serines 1423 and -1524 was not induced in HCC1937
      breast cancer cells, which contain mutant BRCA1 protein. Confocal microscopy
      revealed that unphosphorylated BRCA1 localizes on chromosomes from metaphase
      through telophase, whereas Ser-988-phosphorylated BRCA1 resides in the inner
      chromosomal structure, centrosome, and the cleavage furrow during prophase
      through telophase. We also found that Ser-988-phosphorylated BRCA1 relocalizes to
      the perinuclear region when cells are subjected to IR or UV radiation in the S
      phase. These results reinforce a model wherein phosphorylation of specific
      residues of BRCA1 after DNA damage affects its localization and function.

PMID- 12427730
TI  - G protein-coupled receptor Kinase 2/G alpha q/11 interaction. A novel surface on
      a regulator of G protein signaling homology domain for binding G alpha subunits.
AB  - G protein-coupled receptors (GPCRs) transduce cellular signals from hormones,
      neurotransmitters, light, and odorants by activating heterotrimeric guanine
      nucleotide-binding (G) proteins. For many GPCRs, short term regulation is
      initiated by agonist-dependent phosphorylation by GPCR kinases (GRKs), such as
      GRK2, resulting in G protein/receptor uncoupling. GRK2 also regulates signaling
      by binding G alpha(q/ll) and inhibiting G alpha(q) stimulation of the effector
      phospholipase C beta. The binding site for G alpha(q/ll) resides within the amino
      terminal domain of GRK2, which is homologous to the regulator of G protein
      signaling (RGS) family of proteins. To map the Galpha(q/ll) binding site on GRK2,
      we carried out site-directed mutagenesis of the RGS homology (RH) domain and
      identified eight residues, which when mutated, alter binding to G alpha(q/ll).
      These mutations do not alter the ability of full-length GRK2 to phosphorylate
      rhodopsin, an activity that also requires the amino-terminal domain. Mutations
      causing G alpha(q/ll) binding defects impair recruitment to the plasma membrane
      by activated G alpha(q) and regulation of G alpha(q)-stimulated phospholipase C
      beta activity when introduced into full-length GRK2. Two different protein
      interaction sites have previously been identified on RH domains. The G alpha
      binding sites on RGS4 and RGS9, called the "A" site, is localized to the loops
      between helices alpha 3 and alpha 4, alpha 5 and alpha 6, and alpha 7 and alpha
      8. The adenomatous polyposis coli (APC) binding site of axin involves residues on
      alpha helices 3, 4, and 5 (the "B" site) of its RH domain. We demonstrate that
      the G alpha(q/ll) binding site on the GRK2 RH domain is distinct from the "A" and
      "B" sites and maps primarily to the COOH terminus of its alpha 5 helix. We
      suggest that this novel protein interaction site on an RH domain be designated
      the "C" site.

PMID- 12427731
TI  - Nak1, an essential germinal center (GC) kinase regulates cell morphology and
      growth in Schizosaccharomyces pombe.
AB  - We have identified and characterized Nak1, a 652- amino acid NH(2)-terminal
      kinase belonging to the group II germinal center kinase (GCK) family, in
      Schizosaccharomyces pombe. We found that nak1 is essential for cell
      proliferation. Furthermore, partial repression of nak1, under regulation of an
      integrated nmt1 promoter, resulted in an aberrant round cellular morphology,
      actin and microtubule mislocalization, slow growth, and cell division defects.
      Overexpression of either a kinase-inactive mutant (Nak1(K39R)) or the non
      catalytic domain resulted in similar phenotypes, suggesting dominant-negative
      effects. By deletion analysis, we mapped the region responsible for this dominant
      negative effect to the COOH-terminal 99 residues. Furthermore, we found that
      deletion of the COOH-terminal 99 residues inhibited Nak1 autophosphorylation, and
      expression of a partially inactive (Nak1(T171A)) or truncated (Nak1(1-562))
      protein only weakly suppressed morphological and growth phenotypes, indicating
      that both kinase and COOH-terminal regions are important for Nak1 function. GFP
      Nak1 localized uniformly throughout the cytoplasm, unlike many other proteins
      which influence cell polarity that preferentially localize to cell ends.
      Together, our results implicate Nak1 in the regulation of cell polarity, growth,
      and division and suggest that the COOH-terminal end plays an important role in
      the regulation of this kinase.

PMID- 12427732
TI  - Regulation of expression of the phospholipid hydroperoxide/sperm nucleus
      glutathione peroxidase gene. Tissue-specific expression pattern and
      identification of functional cis- and trans-regulatory elements.
AB  - A sperm nucleus glutathione peroxidase (snGPx), which is closely related to the
      phospholipid hydroperoxide glutathione peroxidase (phGPx), was recently
      discovered in late spermatids. Both GPx isoforms originate from a joint ph/snGPx
      gene, but their N-terminal peptides are encoded by alternative first exons. The
      expression of the two enzymes is differentially regulated in various cells, but
      little is known about the regulatory mechanisms. To explore the tissue-specific
      regulation of expression of the two isoenzymes, we first investigated their
      tissue distribution. Whereas phGPx is expressed at low levels in many organs,
      snGPx was only detected in testis, kidney, and in the human embryonic kidney cell
      line HEK293. Subcellular fractionation studies and immunoelectron microscopy
      revealed a cytosolic localization. To explore the mechanistic reasons for the
      differential expression pattern, we first tested the activity of the putative
      phGPx and snGPx promoters. The 5'-flanking region of the joint ph/snGPx gene
      exhibits strong promoter activity. In contrast, the putative snGPx promoter,
      which comprises 334 bp of intronic sequences, lacks major promoter activity.
      However, it strongly suppresses the activity of the ph/snGPx promoter. These data
      suggest negative regulatory elements in the first intron of the ph/snGPx gene,
      and DNase protection assays revealed the existence of several protein-binding
      sites. The corresponding trans-regulatory proteins (SP1, ERG1, GATA1, SREBP1,
      USF1, and CREBP1) were identified, and in vivo binding of EGR1 and SREBP1 was
      shown by chromatin immunoprecipitation. These data indicate for the first time
      somatic expression of the snGPx and provide evidence for the existence of
      intronic negative cis-regulatory elements in the ph/snGPx gene. Our failure to
      detect an alternative snGPx promoter suggests that transcription of the ph/snGPx
      gene may be regulated by a joint basic promoter. The decision, which GPx isoform
      is expressed in a given cell, appears to be made by alternative splicing of a
      joint primary transcript.

PMID- 12427733
TI  - The transmembrane domain of Vam3 affects the composition of cis- and trans-SNARE
      complexes to promote homotypic vacuole fusion.
AB  - It is presently not clear how the function of SNARE proteins is affected by their
      transmembrane domains. Here, we analyzed the role of the transmembrane domain of
      the vacuolar SNARE Vam3 by replacing it by a lipid anchor. Vacuoles with mutant
      Vam3 fuse poorly and have increased amounts of cis-SNARE complexes, indicating
      that they are more stable. As a consequence efficient cis-SNARE complex
      disassembly that occurs at priming as a prerequisite of fusion requires addition
      of exogenous Sec18. trans-SNARE complexes in this mutant accumulate up to 4-fold
      over wild type, suggesting that the transmembrane domain of Vam3 is required to
      transit through this step. Finally, palmitoylation of Vac8, a reaction that also
      occurs early during priming is reduced by almost one-half. Since palmitoylated
      Vac8 is required beyond trans-SNARE complex formation, this may partially explain
      the fusion deficiency.

PMID- 12427734
TI  - Recognition and hydrolysis of noncrystalline cellulose.
AB  - Cellulase Cel5A from alkalophilic Bacillus sp. 1139 contains a family 17
      carbohydrate-binding module (BspCBM17) and a family 28 CBM (BspCBM28) in tandem.
      The two modules have significantly similar amino acid sequences, but amino acid
      residues essential for binding are not conserved. BspCBM28 was obtained as a
      discrete polypeptide by engineering the cel5A gene. BspCBM17 could not be
      obtained as a discrete polypeptide, so a family 17 CBM from endoglucanase Cel5A
      of Clostridium cellulovorans, CcCBM17, was used to compare the binding
      characteristics of the two families of CBM. Both CcCBM17 and BspCBM28 recognized
      two classes of binding sites on amorphous cellulose: a high affinity site (K(a)
      approximately 1 x 10(6) M(-1)) and a low affinity site (K(a) approximately 2 x
      10(4) M(-1)). They did not compete for binding to the high affinity sites,
      suggesting that they bound at different sites on the cellulose. A polypeptide,
      BspCBM17/CBM28, comprising the tandem CBMs from Cel5A, bound to amorphous
      cellulose with a significantly higher affinity than the sum of the affinities of
      CcCBM17 and BspCBM28, indicating cooperativity between the linked CBMs. Cel5A
      mutants were constructed that were defective in one or both of the CBMs. The
      mutants differed from the wild-type enzyme in the amounts and sizes of the
      soluble products produced from amorphous cellulose. This suggests that either the
      CBMs can modify the action of the catalytic module of Cel5A or that they target
      the enzyme to areas of the cellulose that differ in susceptibility to hydrolysis.

PMID- 12427735
TI  - Signaling states of rhodopsin. Formation of the storage form, metarhodopsin III,
      from active metarhodopsin II.
AB  - Vertebrate rhodopsin consists of the apoprotein opsin and the chromophore 11-cis
      retinal covalently linked via a protonated Schiff base. Upon photoisomerization
      of the chromophore to all-trans-retinal, the retinylidene linkage hydrolyzes, and
      all-trans-retinal dissociates from opsin. The pigment is eventually restored by
      recombining with enzymatically produced 11-cis-retinal. All-trans-retinal release
      occurs in parallel with decay of the active form, metarhodopsin (Meta) II, in
      which the original Schiff base is intact but deprotonated. The intermediates
      formed during Meta II decay include Meta III, with the original Schiff base
      reprotonated, and Meta III-like pseudo-photoproducts. Using an intrinsic
      fluorescence assay, Fourier transform infrared spectroscopy, and UV-visible
      spectroscopy, we investigated Meta II decay in native rod disk membranes. Up to
      40% of Meta III is formed without changes in the intrinsic Trp fluorescence and
      thus without all-trans-retinal release. NADPH, a cofactor for the reduction of
      all-trans-retinal to all-trans-retinol, does not accelerate Meta II decay nor
      does it change the amount of Meta III formed. However, Meta III can be
      photoconverted back to the Meta II signaling state. The data are described by two
      quasi-irreversible pathways, leading in parallel into Meta III or into release of
      all-trans-retinal. Therefore, Meta III could be a form of rhodopsin that is
      stored away, thus regulating photoreceptor regeneration.

PMID- 12427736
TI  - Protein-protein interactions in the bacteriophage T4 replisome. The leading
      strand holoenzyme is physically linked to the lagging strand holoenzyme and the
      primosome.
AB  - The bacteriophage T4 replication complex is composed of eight proteins that
      function together to replicate DNA. This replisome can be broken down into four
      basic units: a primosome composed of gp41, gp61, and gp59; a leading strand
      holoenzyme composed of gp43, gp44/62, and gp45; a lagging strand holoenzyme; and
      a single strand binding protein polymer. These units interact further to form the
      complete replisome. The leading and lagging strand polymerases are physically
      linked in the presence of DNA or an active replisome. The region of interaction
      was mapped to an extension of the finger domain, such that Cys-507 of one subunit
      is in close proximity to Cys-507 of a second subunit. The leading strand
      polymerase and the primosome also associate, such that gp59 mediates the contact
      between the two complexes. Binding of gp43 to the primosome complex causes
      displacement of gp32 from the gp59.gp61.gp41 primosome complex. The resultant
      species is a complex of proteins that may allow coordinated leading and lagging
      strand synthesis, helicase DNA unwinding activity, and polymerase nucleotide
      incorporation.

PMID- 12427737
TI  - Essential role of A-kinase anchor protein 121 for cAMP signaling to mitochondria.
AB  - A-Kinase anchor proteins (AKAPs) immobilize and concentrate protein kinase A
      (PKA) isoforms at specific subcellular compartments. Intracellular targeting of
      PKA holoenzyme elicits rapid and efficient phosphorylation of target proteins,
      thereby increasing sensitivity of downstream effectors to cAMP action. AKAP121
      targets PKA to the cytoplasmic surface of mitochondria. Here we show that
      conditional expression of AKAP121 in PC12 cells selectively enhances cAMP.PKA
      signaling to mitochondria. AKAP121 induction stimulates PKA-dependent
      phosphorylation of the proapoptotic protein BAD at Ser(155), inhibits release of
      cytochrome c from mitochondria, and protects cells from apoptosis. An AKAP121
      derivative mutant that localizes on mitochondria but does not bind PKA down
      regulates PKA signaling to the mitochondria and promotes apoptosis. These
      findings indicate that PKA anchored by AKAP121 transduces cAMP signals to the
      mitochondria, and it may play an important role in mitochondrial physiology.

PMID- 12427738
TI  - Structural consequences of a cancer-causing BRCA1-BRCT missense mutation.
AB  - The integrity of the carboxyl-terminal BRCT repeat region is critical for BRCA1
      tumor suppressor function; however, the molecular details of how a number of
      clinically derived BRCT missense mutations affect BRCA1 function remain largely
      unknown. Here we assess the structural response of the BRCT tandem repeat domain
      to a well characterized, cancer-associated single amino acid substitution, Met
      1775 --> Arg-1775. The structure of BRCT-M1775R reveals that the mutated side
      chain is extruded from the protein hydrophobic core, thereby altering the protein
      surface. Charge-charge repulsion, rearrangement of the hydrophobic core, and
      disruption of the native hydrogen bonding network at the interface between the
      two BRCT repeats contribute to the conformational instability of BRCT-M1775R.
      Destabilization and global unfolding of the mutated BRCT domain at physiological
      temperatures explain the pleiotropic molecular and genetic defects associated
      with the BRCA1-M1775R protein.

PMID- 12427739
TI  - NFATc1 mediates vascular endothelial growth factor-induced proliferation of human
      pulmonary valve endothelial cells.
AB  - Mice deficient for the transcription factor NFATc1 fail to form pulmonary and
      aortic valves, a defect reminiscent of some types of congenital human heart
      disease. We examined the mechanisms by which NFATc1 is activated and translocated
      to the nucleus in human pulmonary valve endothelial cells to gain a better
      understanding of its potential role(s) in post-natal valvular repair as well as
      valve development. Herein we demonstrate that activation of NFATc1 in human
      pulmonary valve endothelial cells is specific to vascular endothelial growth
      factor (VEGF) signaling through VEGF receptor 2. VEGF-induced NFATc1 nuclear
      translocation was inhibited by either cyclosporin A or a calcineurin-specific
      peptide inhibitor; these findings suggest that VEGF stimulates NFATc1 nuclear
      import in human pulmonary valve endothelial cells by a calcineurin-dependent
      mechanism. Importantly, both cyclosporin A and the calcineurin-specific peptide
      inhibitor reduced VEGF-induced human pulmonary valve endothelial cell
      proliferation, indicating a functional role for NFATc1 in endothelial growth. In
      contrast, VEGF-induced proliferation of human dermal microvascular and human
      umbilical vein endothelial cells was not sensitive to cyclosporin A. Finally,
      NFATc1 was detected in the endothelium of human pulmonary valve leaflets by
      immunohistochemistry. These results suggest VEGF-induced NFATc1 activation may be
      an important mechanism in cardiac valve maintenance and function by enhancing
      endothelial proliferation.

PMID- 12427740
TI  - The methyl-CpG-binding protein MeCP2 links DNA methylation to histone
      methylation.
AB  - DNA methylation plays an important role in mammalian development and correlates
      with chromatin-associated gene silencing. The recruitment of MeCP2 to methylated
      CpG dinucleotides represents a major mechanism by which DNA methylation can
      repress transcription. MeCP2 silences gene expression partly by recruiting
      histone deacetylase (HDAC) activity, resulting in chromatin remodeling. Here, we
      show that MeCP2 associates with histone methyltransferase activity in vivo and
      that this activity is directed against Lys(9) of histone H3. Two characterized
      repression domains of MeCP2 are involved in tethering the histone
      methyltransferase to MeCP2. We asked if MeCP2 can deliver Lys(9) H3 methylation
      to the H19 gene, whose activity it represses. We show that the presence of MeCP2
      on nucleosomes within the repressor region of the H19 gene (the differentially
      methylated domain) coincides with an increase in H3 Lys(9) methylation. Our data
      provide evidence that MeCP2 reinforces a repressive chromatin state by acting as
      a bridge between two global epigenetic modifications, DNA methylation and histone
      methylation.

PMID- 12427741
TI  - An atypical protein disulfide isomerase from the protozoan parasite Leishmania
      containing a single thioredoxin-like domain.
AB  - In higher eukaryotes, secretory proteins are under the quality control of the
      endoplasmic reticulum for their proper folding and release into the secretory
      pathway. One of the proteins involved in the quality control is protein disulfide
      isomerase, which catalyzes the formation of protein disulfide bonds. As a first
      step toward understanding the endoplasmic reticulum quality control of secretory
      proteins in lower eukaryotes, we have isolated a protein disulfide isomerase gene
      from the protozoan parasite Leishmania donovani. The parasite enzyme shows high
      sequence homology with homologs from other organisms. However, unlike the four
      thioredoxin-like domains found in most protein disulfide isomerases, of which two
      contain an active site, the leishmanial enzyme possesses only one active site
      present in a single thioredoxin-like domain. When expressed in Escherichia coli,
      the recombinant parasite enzyme shows both oxidase and isomerase activities.
      Replacement of the two cysteins with alanines in its active site results in loss
      of both enzymatic activities. Further, overexpression of the mutated/inactive
      form of the parasite enzyme in L. donovani significantly reduced their release of
      secretory acid phosphatases, suggesting that this single thioredoxin-like domain
      protein disulfide isomerase could play a critical role in the Leishmania
      secretory pathway.

PMID- 12427742
TI  - Escherichia coli RecX inhibits RecA recombinase and coprotease activities in
      vitro and in vivo.
AB  - In Escherichia coli the RecA protein plays a pivotal role in homologous
      recombination, DNA repair, and SOS repair and mutagenesis. A gene designated recX
      (or oraA) is present directly downstream of recA in E. coli; however, the
      function of RecX is unknown. In this work we demonstrated interaction of RecX and
      RecA in a yeast two-hybrid assay. In vitro, substoichiometric amounts of RecX
      strongly inhibited both RecA-mediated DNA strand exchange and RecA ATPase
      activity. In vivo, we showed that recX is under control of the LexA repressor and
      is up-regulated in response to DNA damage. A loss-of-function mutation in recX
      resulted in decreased resistance to UV irradiation; however, overexpression of
      RecX in trans resulted in a greater decrease in UV resistance. Overexpression of
      RecX inhibited induction of two din (damage-inducible) genes and cleavage of the
      UmuD and LexA repressor proteins; however, recX inactivation had no effect on any
      of these processes. Cells overexpressing RecX showed decreased levels of P1
      transduction, whereas recX mutation had no effect on P1 transduction frequency.
      Our combined in vitro and in vivo data indicate that RecX can inhibit both RecA
      recombinase and coprotease activities.

PMID- 12427743
TI  - Regulation of channel gating by AMP-activated protein kinase modulates cystic
      fibrosis transmembrane conductance regulator activity in lung submucosal cells.
AB  - Cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel activity
      is important for fluid and electrolyte transport in many epithelia including the
      lung, the site of most cystic fibrosis-associated morbidity. CFTR is unique among
      ion channels in requiring ATP hydrolysis for its gating, suggesting that its
      activity is coupled to cellular metabolic status. The metabolic sensor AMP
      activated kinase (AMPK) binds to and phosphorylates CFTR, co-localizes with it in
      various tissues, and inhibits CFTR currents in Xenopus oocytes (Hallows, K. R.,
      Raghuram, V., Kemp, B. E., Witters, L. A. & Foskett, J. K. (2000) J. Clin.
      Invest. 105, 1711-1721). Here we demonstrate that this AMPK-CFTR interaction has
      functional implications in human lung epithelial cells. Pharmacologic activation
      of AMPK inhibited forskolin-stimulated CFTR short circuit currents in polarized
      Calu-3 cell monolayers. In whole-cell patch clamp experiments, the activation of
      endogenous AMPK either pharmacologically or by the overexpression of an AMPK
      activating non-catalytic subunit mutant (AMPK-gamma1-R70Q) dramatically inhibited
      forskolin-stimulated CFTR conductance in Calu-3 and CFTR-expressing Chinese
      hamster ovary cells. Plasma membrane expression of CFTR, assessed by surface
      biotinylation, was not affected by AMPK activation. In contrast, the single
      channel open probability of CFTR was strongly reduced in cell-attached patch
      clamp measurements of Calu-3 cells transfected with the AMPK-activating mutant,
      an effect due primarily to a substantial prolongation of the mean closed time of
      the channel. As a metabolic sensor in cells, AMPK may be important in tuning CFTR
      activity to cellular energy charge, thereby linking transepithelial transport and
      the maintenance of cellular ion gradients to cellular metabolism.

PMID- 12427744
TI  - The absence of fucose but not the presence of galactose or bisecting N
      acetylglucosamine of human IgG1 complex-type oligosaccharides shows the critical
      role of enhancing antibody-dependent cellular cytotoxicity.
AB  - An anti-human interleukin 5 receptor (hIL-5R) humanized immunoglobulin G1 (IgG1)
      and an anti-CD20 chimeric IgG1 produced by rat hybridoma YB2/0 cell lines showed
      more than 50-fold higher antibody-dependent cellular cytotoxicity (ADCC) using
      purified human peripheral blood mononuclear cells as effector than those produced
      by Chinese hamster ovary (CHO) cell lines. Monosaccharide composition and
      oligosaccharide profiling analysis showed that low fucose (Fuc) content of
      complex-type oligosaccharides was characteristic in YB2/0-produced IgG1s compared
      with high Fuc content of CHO-produced IgG1s. YB2/0-produced anti-hIL-5R IgG1 was
      subjected to Lens culinaris aggulutin affinity column and fractionated based on
      the contents of Fuc. The lower Fuc IgG1 had higher ADCC than the IgG1 before
      separation. In contrast, the content of bisecting GlcNAc of the IgG1 affected
      ADCC much less than that of Fuc. In addition, the correlation between Gal and
      ADCC was not observed. When the combined effect of Fuc and bisecting GlcNAc was
      examined in anti-CD20 IgG1, only a severalfold increase of ADCC was observed by
      the addition of GlcNAc to highly fucosylated IgG1. Quantitative PCR analysis
      indicated that YB2/0 cells had lower expression level of FUT8 mRNA, which codes
      alpha1,6-fucosyltransferase, than CHO cells. Overexpression of FUT8 mRNA in YB2/0
      cells led to an increase of fucosylated oligosaccharides and decrease of ADCC of
      the IgG1. These results indicate that the lack of fucosylation of IgG1 has the
      most critical role in enhancement of ADCC, although several reports have
      suggested the importance of Gal or bisecting GlcNAc and provide important
      information to produce the effective therapeutic antibody.

PMID- 12427745
TI  - Kruppel-like factor 4 mediates p53-dependent G1/S cell cycle arrest in response
      to DNA damage.
AB  - The tumor suppressor p53 is required for the maintenance of genomic integrity
      following DNA damage. One mechanism by which p53 functions is to induce a block
      in the transition between the G(1) and S phase of the cell cycle. Previous
      studies indicate that the Kruppel-like factor 4 (KLF4) gene is activated
      following DNA damage and that such activation depends on p53. In addition,
      enforced expression of KLF4 causes G(1)/S arrest. The present study examines the
      requirement of KLF4 in mediating the p53-dependent cell cycle arrest process in
      response to DNA damage. We show that the G(1) population of a colon cancer cell
      line, HCT116, that is null for the p53 alleles (-/-) was abolished following
      gamma irradiation compared with cells with wild-type p53 (+/+). Conditional
      expression of KLF4 in irradiated HCT116 p53-/- cells restored the G(1) cell
      population to a level similar to that seen in irradiated HCT116 p53+/+ cells.
      Conversely, treatment of HCT116 p53+/+ cells with small interfering RNA (siRNA)
      specific for KLF4 significantly reduced the number of cells in the G(1) phase
      following gamma irradiation compared with the untreated control or those treated
      with a nonspecific siRNA. In each case the increase or decrease in KLF4 level
      because of conditional induction or siRNA inhibition, respectively, was
      accompanied by an increase or decrease in the level of p21(WAF1/CIP1). Results of
      our study indicate that KLF4 is an essential mediator of p53 in controlling
      G(1)/S progression of the cell cycle following DNA damage.

PMID- 12427746
TI  - Complex formation by the human Rad51B and Rad51C DNA repair proteins and their
      activities in vitro.
AB  - The human Rad51 protein is essential for DNA repair by homologous recombination.
      In addition to Rad51 protein, five paralogs have been identified: Rad51B/Rad51L1,
      Rad51C/Rad51L2, Rad51D/Rad51L3, XRCC2, and XRCC3. To further characterize a
      subset of these proteins, recombinant Rad51, Rad51B-(His)(6), and Rad51C proteins
      were individually expressed employing the baculovirus system, and each was
      purified from Sf9 insect cells. Evidence from nickel-nitrilotriacetic acid pull
      down experiments demonstrates a highly stable Rad51B.Rad51C heterodimer, which
      interacts weakly with Rad51. Rad51B and Rad51C proteins were found to bind single
      and double-stranded DNA and to preferentially bind 3'-end-tailed double-stranded
      DNA. The ability to bind DNA was elevated with mixed Rad51 and Rad51C, as well as
      with mixed Rad51B and Rad51C, compared with that of the individual protein. In
      addition, both Rad51B and Rad51C exhibit DNA-stimulated ATPase activity. Rad51C
      displays an ATP-independent apparent DNA strand exchange activity, whereas Rad51B
      shows no such activity; this apparent strand exchange ability results actually
      from a duplex DNA destabilization capability of Rad51C. By analogy to the yeast
      Rad55 and Rad57, our results suggest that Rad51B and Rad51C function through
      interactions with the human Rad51 recombinase and play a crucial role in the
      homologous recombinational repair pathway.

PMID- 12427747
TI  - Functional analysis of a divergent system II protein, Ccs1, involved in c-type
      cytochrome biogenesis.
AB  - The Ccs1 gene, encoding a highly divergent novel component of a system II type c
      type cytochrome biogenesis pathway, is encoded by the previously defined CCS1
      locus in Chlamydomonas reinhardtii. phoA and lacZalpha bacterial topological
      reporters were used to deduce a topological model of the Synechocystis sp. 6803
      Ccs1 homologue, CcsB. CcsB, and therefore by analogy Ccs1, possesses a large
      soluble lumenal domain at its C terminus that is tethered in the thylakoid
      membrane by three closely spaced transmembrane domains in the N-terminal portion
      of the protein. Molecular analysis of ccs1 alleles reveals that the entire C
      terminal soluble domain is essential for Ccs1 function and that a stromal loop
      appears to be important in vivo, at least for maintenance of Ccs1. Site-directed
      mutational analysis reveals that a single histidine (His(274)) within the last
      transmembrane domain, preceding the large lumenal domain, is required for c-type
      cytochrome assembly, whereas an invariant cysteine residue (Cys(199)) is shown to
      be non-essential. Ccs1 is proposed to interact with other Ccs components based on
      its reduced accumulation in ccs2, ccs3, ccs4, and ccsA strains.

PMID- 12427748
TI  - Dampening of cytosolic Ca2+ oscillations on propagation to nucleus.
AB  - Ca(2+) signals may regulate gene expression. The increase of the cytosolic Ca(2+)
      concentration ([Ca(2+)](c)) promotes activation and/or nuclear import of some
      transcription factors, but others require the increase of the nuclear Ca(2+)
      concentration ([Ca(2+)](N)) for activation. Whether the nuclear envelope may act
      as a diffusion barrier for propagation of [Ca(2+)](c) signals remains
      controversial. We have studied the spreading of Ca(2+) from the cytosol to the
      nucleus by comparing the cytosolic and the nuclear Ca(2+) signals reported by
      targeted aequorins in adrenal chromaffin, PC12, and GH(3) pituitary cells. Strong
      stimulation of either Ca(2+) entry (by depolarization with high K(+) or
      acethylcholine) or Ca(2+) release from the intracellular Ca(2+) stores (by
      stimulation with caffeine, UTP, bradykinin, or thyrotropin-releasing hormone
      (TRH)) produced similar Ca(2+) signals in cytosol and nucleus. In contrast, both
      spontaneous and TRH-stimulated oscillations of cytosolic Ca(2+) in single GH(3)
      cells were considerably dampened during propagation to the nucleus. These results
      are consistent with the existence of a kinetic barrier that filters high
      frequency physiological [Ca(2+)](c) oscillations without disturbing sustained
      [Ca(2+)](c) increases. Thus, encoding of the Ca(2+) signal may allow differential
      control of Ca(2+)-dependent mechanisms located at either the cytosol or the
      nucleus.

PMID- 12427749
TI  - An alternative domain containing a leucine-rich sequence regulates nuclear
      cytoplasmic localization of protein 4.1R.
AB  - In red blood cells, protein 4.1 (4.1R) is an 80-kDa protein that stabilizes the
      spectrin-actin network and anchors it to the plasma membrane. The picture is more
      complex in nucleated cells, in which many 4.1R isoforms, varying in size and
      intracellular location, have been identified. To contribute to the
      characterization of signals involved in differential intracellular localization
      of 4.1R, we have analyzed the role the exon 5-encoded sequence plays in 4.1R
      distribution. We show that exon 5 encodes a leucine-rich sequence that shares key
      features with nuclear export signals (NESs). This sequence adopts the topology
      employed for NESs of other proteins and conserves two hydrophobic residues that
      are shown to be critical for NES function. A 4.1R isoform expressing the leucine
      rich sequence binds to the export receptor CRM1 in a RanGTP-dependent fashion,
      whereas this does not occur in a mutant whose two conserved hydrophobic residues
      are substituted. These two residues are also essential for 4.1R intracellular
      distribution, because the 4.1R protein containing the leucine-rich sequence
      localizes in the cytoplasm, whereas the mutant protein predominantly accumulates
      in the nucleus. We hypothesize that the leucine-rich sequence in 4.1R controls
      distribution and concomitantly function of a specific set of 4.1R isoforms.

PMID- 12427750
TI  - NAB2, a corepressor of EGR-1, inhibits vascular endothelial growth factor
      mediated gene induction and angiogenic responses of endothelial cells.
AB  - In this study we have investigated the role of a specific corepressor of EGR-1,
      NAB2, to down-regulate vascular endothelial growth factor (VEGF)-induced gene
      expression in endothelial cells and to inhibit angiogenesis. Firstly, we show a
      reciprocal regulation of EGR-1 and NAB2 following VEGF treatment. During the
      initial phase EGR-1 is rapidly induced and NAB2 levels are down-regulated. This
      is followed by a reduction of EGR-1 and a concomitant increase of NAB2. Secondly,
      using the tissue factor gene as a readout for VEGF-induced and EGR-1-regulated
      gene expression we demonstrate that NAB2 can completely block VEGF-induced tissue
      factor reporter gene activity. Thirdly, by adenovirus-mediated expression we show
      that NAB2 inhibits up-regulation of tissue factor, VEGF receptor-1, and urokinase
      plasminogen activator mRNAs even when a combination of VEGF and bFGF is used for
      induction. In addition, NAB2 overexpression significantly reduced tubule and
      sprout formation in two different in vitro angiogenesis assays and largely
      prevented the invasion of cells and formation of vessel-like structures in the
      murine Matrigel model. These data suggest that NAB2 regulation represents a
      mechanism to guarantee transient EGR-1 activity following exposure of endothelial
      cells to VEGF and that NAB2 overexpression could be used to inhibit signals
      involved in the early phase of angiogenesis.

PMID- 12427751
TI  - Characterization of homoisocitrate dehydrogenase involved in lysine biosynthesis
      of an extremely thermophilic bacterium, Thermus thermophilus HB27, and
      evolutionary implication of beta-decarboxylating dehydrogenase.
AB  - Although the presence of an enzyme that catalyzes beta-decarboxylating
      dehydrogenation of homoisocitrate to synthesize 2-oxoadipate has been postulated
      in the lysine biosynthesis pathway through alpha-aminoadipate (AAA), the enzyme
      has not yet been analyzed at all, because no gene encoding the enzyme has been
      identified until recently. A gene encoding a protein with a significant amino
      acid sequence identity to both isocitrate dehydrogenase and 3-isopropylmalate
      dehydrogenase was cloned from Thermus thermophilus HB27. The gene product
      produced in recombinant Escherichia coli cells demonstrated homoisocitrate
      dehydrogenase (HICDH) activity. A knockout mutant of the gene showed an AAA
      auxotrophic phenotype, indicating that the gene product is involved in lysine
      biosynthesis through AAA. We therefore named this gene hicdh. HICDH, the gene
      product, did not catalyze the conversion of 3-isopropylmalate to 2
      oxoisocaproate, a leucine biosynthetic reaction, but it did recognize isocitrate,
      a related compound in the tricarboxylic acid cycle, as well as homoisocitrate as
      a substrate. It is of interest that HICDH catalyzes the reaction with isocitrate
      about 20 times more efficiently than the reaction with the putative native
      substrate, homoisocitrate. The broad specificity and possible dual function
      suggest that this enzyme represents a key link in the evolution of the pathways
      utilizing citrate derivatives. Site-directed mutagenesis study reveals that
      replacement of Arg(85) with Val in HICDH causes complete loss of activity with
      isocitrate but significant activity with 3-isopropylmalate and retains activity
      with homoisocitrate. These results indicate that Arg(85) is a key residue for
      both substrate specificity and evolution of beta-decarboxylating dehydrogenases.

PMID- 12427753
TI  - Novel bacterial polar lipids containing ether-linked alkyl chains, the structures
      and biological properties of the four major glycolipids from Propionibacterium
      propionicum PCM 2431 (ATCC 14157T).
AB  - Propionibacterium propionicum belongs to the "acnes group" of propionibacteria,
      which is currently considered as clinically important because of its growing
      potential in infections, in particular with those connected with immune system
      dysfunctions. Propionibacteria are thought to be actinomycete-like microorganisms
      and may still cause diagnostic difficulties. The chloroform-methanol extracts of
      the cell mass of P. propionicum (type strain) gave in TLC analysis the
      characteristic glycolipid profile containing four major glycolipids, labeled G(1)
      through G(4). These polar lipids were found to be useful chemotaxonomic markers
      to differentiate P. propionicum from other cutaneous propionibacteria, in
      particular from strains of the acnes group. Glycolipids G(1)-G(4) were isolated
      and purified using gel-permeation chromatography, TLC, and high performance
      liquid chromatography, and their structures were elucidated by compositional and
      methylation analyses, specific chemical degradations, MALDI-TOF mass
      spectrometry, and (1)H NMR and (13)C NMR spectroscopy, including HMBC, TOCSY,
      HMQC, and NOESY experiments. Glycolipids G(2) and G(3) possess as backbone alpha
      d-Glcp-(1 --> 3)-alpha-d-Glcp-(1 --> 1)-Gro (Gro, glycerol), in which position O
      2 of the glycerol residue is acylated by a fatty acid (mainly C(15):0) while O-3
      is substituted by an alkyl ether chain. In glycolipid G(3), an additional fatty
      acyl chain was linked to O-6 of the terminal glucose residue. Glycolipid G(4) was
      structurally related to G(2) but devoid of one glucose residue. Glycolipid G(1)
      was isolated in small amounts, and its structure was therefore deduced from MALDI
      TOF-MS experiments alone, which revealed that it possessed the structure of G(2)
      but was lacking one fatty acid residue. In studies on the biological properties
      of P. propionicum glycolipids, the anti-P. propionicum rabbit antisera reacted in
      dot enzyme-immunoblotting test with G(2) and G(3). Glycolipid G(3) was able to
      induce the delayed type of hypersensitivity. The results indicated that these
      novel ether linkage-containing polar glycolipids are immunogenic and possibly
      active in hypersensitivity, and thus, in pathogenesis.

PMID- 12427752
TI  - NUDT9, a member of the Nudix hydrolase family, is an evolutionarily conserved
      mitochondrial ADP-ribose pyrophosphatase.
AB  - We have recently characterized the protein product of the human NUDT9 gene as a
      highly specific ADP-ribose (ADPR) pyrophosphatase. We now report an analysis of
      the human NUDT9 gene and its potential alternative transcripts along with
      detailed studies of the enzymatic properties and cell biological behavior of
      human NUDT9 protein. Our analysis of the human NUDT9 gene and twenty-two distinct
      cloned NUDT9 transcripts indicates that the full-length NUDT9 alpha transcript is
      the dominant form, and suggests that an alternative NUDT9 beta transcript occurs
      as the result of a potentially aberrant splice from a cryptic donor site within
      the first exon to the splice acceptor site of exon 2. Computer analysis of the
      predicted protein of the NUDT9 alpha transcript identified an N-terminal signal
      peptide or subcellular targeting sequence. Using green fluorescence protein
      tagging, we demonstrate that the predicted human NUDT9 alpha protein is targeted
      highly specifically to mitochondria, whereas the predicted protein of the NUDT9
      beta transcript, which is missing this sequence, exhibits no clear subcellular
      localization. Investigation of the physical and enzymatic properties of NUDT9
      indicates that it is functional as a monomer, optimally active at near neutral
      pH, and that it requires divalent metal ions and an intact Nudix motif for
      enzymatic activity. Furthermore, partial proteolysis of NUDT9 suggests that NUDT9
      enzymes consist of two distinct domains: a proteolytically resistant C-terminal
      domain retaining essentially full specific ADPR pyrophosphatase activity and a
      proteolytically labile N-terminal portion that functions to enhance the affinity
      of the C-terminal domain for ADPR.

PMID- 12427754
TI  - Phosphorylation and hsp90 binding mediate heat shock stabilization of p53.
AB  - The p53 tumor suppressor is stabilized and activated by diverse stress signals.
      In this study, we investigated the mechanism of p53 activation by heat shock. We
      found that heat shock inhibited p53 ubiquitination and caused accumulation of p53
      at the post-transcriptional level. Heat shock induced phosphorylation of p53 at
      serine 15 in an ATM kinase-dependent fashion, which may contribute partially to
      heat-induced p53 accumulation. However, p53 accumulation also occurred after heat
      shock in ATM-deficient cells. Heat shock induced conformational change of wild
      type p53 and binding to hsp90. Inhibition of hsp90-p53 interaction by
      geldanamycin prevented p53 accumulation partially in ATM-wild type cells and
      completely in ATM-deficient cells. Therefore, phosphorylation and interaction
      with hsp90 both contribute to stabilization of p53 after heat shock.

PMID- 12427755
TI  - Construction of a deep-rough mutant of Burkholderia cepacia ATCC 25416 and
      characterization of its chemical and biological properties.
AB  - Burkholderia cepacia is a bacterium with increasing importance as a pathogen in
      patients with cystic fibrosis. The deep-rough mutant Ko2b was generated from B.
      cepacia type strain ATCC 25416 by insertion of a kanamycin resistance cassette
      into the gene waaC encoding heptosyltransferase I. Mass spectrometric analysis of
      the de-O-acylated lipopolysaccharide (LPS) of the mutant showed that it consisted
      of a bisphosphorylated glucosamine backbone with two 3-hydroxyhexadecanoic acids
      in amide-linkage, 4-amino-4-deoxyarabinose (Ara4N) residues on both phosphates,
      and a core oligosaccharide of the sequence Ara4N-(1 --> 8) D-glycero-D-talo-oct-2
      ulosonic acid (Ko)-(2 --> 4)3-deoxy-D-manno-oct-2-ulosonic acid (Kdo). The mutant
      allowed investigations on the biosynthesis of the LPS as well as on its role in
      human infection. Mutant Ko2b showed no difference in its ability to invade human
      macrophages as compared with the wild type. Furthermore, isolated LPS of both
      strains induced the production of tumor necrosis factor alpha from macrophages to
      the same extent. Thus, the truncation of the LPS did not decrease the biological
      activity of the mutant or its LPS in these aspects.

PMID- 12427756
TI  - Regulation of myeloid zinc finger protein 2A transactivation activity through
      phosphorylation by mitogen-activated protein kinases.
AB  - The myeloid zinc finger protein (MZF)-2 is a C(2)H(2) zinc finger transcription
      factor that is expressed in myeloid cells and involved in the growth,
      differentiation, and tumorigenesis of myeloid progenitors. Here we describe a
      novel isoform of MZF-2, designated MZF-2A, and show that it is phosphorylated by
      the mitogen-activated protein (MAP) kinases. An in vitro phosphorylation
      experiment revealed that the transactivation domain (TAD) of MZF-2A was
      phosphorylated strongly by extracellular signal-regulated kinase (ERK) and
      phosphorylated weakly by p38 MAP kinase but not by Jun N-terminal kinase.
      Experiments using "add-back" mutants showed that three serine residues (Ser(257),
      Ser(275), and Ser(295)) in the TAD were phosphorylated in vitro by ERK. In
      myeloid LGM-1 cells, various extracellular stimuli induced the phosphorylation of
      these serine residues, which was differentially inhibited by the protein kinase
      inhibitors U0126 and SB203580. Substitution of these phosphorylation sites with
      alanines resulted in a strong enhancement of the ability of MZF-2A to activate
      transcription in a luciferase reporter assay. Taken together, these results
      indicate that MZF-2A is a novel target for the ERK and p38 MAP kinase signaling
      pathways, and its transactivation activity is negatively regulated by MAP kinase
      mediated phosphorylation of the TAD.

PMID- 12427757
TI  - Direct interaction between nucleolin and hepatitis C virus NS5B.
AB  - Hepatitis C virus (HCV) NS5B is an RNA-dependent RNA polymerase (RdRP), a central
      catalytic enzyme in HCV replication. While studying the subcellular localization
      of a NS5B mutant lacking the C-terminal membrane-anchoring domain, NS5Bt, we
      found that expression of the green fluorescent protein (GFP)-fused form was
      exclusively nucleolar. Interestingly, the distribution of endogenous nucleolin
      changed greatly in the cells expressing GFP-NS5B, with nucleolin colocalized with
      GFP-NS5B in perinuclear regions in addition to the nucleolus, suggesting that
      NS5B retains the ability to bind nucleolin. The interaction between nucleolin and
      NS5B was demonstrated by GST pull-down assay. GST pull-down assay results
      indicated that C-terminal region of nucleolin was important for its binding to
      NS5B. Scanning clustered alanine substitution mutants library of NS5B revealed
      two sites on NS5B that binds nucleolin. NS5B amino acids 208-214 and 500-506 were
      both found to be indispensable for the nucleolin binding. We reported that the
      latter sequence is essential for oligomerization of NS5B, which is a prerequisite
      for the RdRP activity. C-terminal nucleolin inhibited the NS5B RdRP activity in a
      dose-dependent manner. Taken together, this indicates the binding ability of
      nucleolin may be involved in NS5B functions.

PMID- 12427758
TI  - Down-regulation of hydrogen peroxide-induced PKC delta activation in N
      acetylglucosaminyltransferase III-transfected HeLaS3 cells.
AB  - N-acetylglucosaminyltransferase III (GnT-III) is a key enzyme that inhibits the
      extension of N-glycans by introducing a bisecting N-acetylglucosamine residue.
      Our previous studies have shown that modification of N-glycans by GnT-III affects
      a number of intracellular signaling pathways. In this study, the effects of GnT
      III on the cellular response to reactive oxygen species (ROS) were examined. We
      found that an overexpression of GnT-III suppresses H(2)O(2)-induced apoptosis in
      HeLaS3 cells. In the case of GnT-III transfectants, activation of Jun N-terminal
      kinase (JNK) following H(2)O(2) treatment was markedly reduced compared with
      control cells. Either the depletion of protein kinase C (PKC) by prolonged
      treatment with phorbol 12-myristate 13-acetate or the inhibition of PKC by the
      specific inhibitor H7 attenuated the H(2)O(2)-induced activation of JNK1 and
      apoptosis in control cells but not in the GnT-III transfectants. Furthermore, we
      found that H(2)O(2)-induced phosphorylation of PKC delta was markedly suppressed
      in GnT-III transfectants. Rottlerin, a specific inhibitor of PKC delta,
      significantly inhibited H(2)O(2)-induced activation of JNK1 in control cells,
      indicating that PKC delta is involved in the pathway. These findings suggest that
      the overexpression of GnT-III suppresses H(2)O(2)-induced activation of PKC delta
      JNK1 pathway, resulting in inhibition of apoptosis.

PMID- 12427759
TI  - In vivo interaction between the polyprenol phosphate mannose synthase Ppm1 and
      the integral membrane protein Ppm2 from Mycobacterium smegmatis revealed by a
      bacterial two-hybrid system.
AB  - Dolichol phosphate-mannose (Dol-P-Man) is a mannose donor in various eukaryotic
      glycosylation processes. So far, two groups of Dol-P-Man synthases have been
      characterized based on the way they are stabilized in the endoplasmic reticulum
      membrane. Enzymes belonging to the first group, such as the yeast Dpm1, are
      typical integral membrane proteins harboring a transmembrane segment (TMS) at
      their C terminus. In contrast, mammalian Dpm1, enzymes of the second group, lack
      the typical TMS and require the association with the small hydrophobic proteins
      Dpm3 to be properly stabilized in the endoplasmic reticulum membrane. In
      Mycobacterium tuberculosis, the Polyprenol-P-Man synthase MtPpm1 is involved in
      the biosynthesis of the cell wall-associated glycolipid lipoarabinomannan. MtPpm1
      is composed of two domains. The C-terminal catalytic domain is homologous to
      eukaryotic Dol-P-Man synthases. The N-terminal domain of MtPpm1 contains six TMS
      that anchor the enzyme in the cytoplasmic membrane. In contrast, in Mycobacterium
      smegmatis, orthologs of the two domains of MtPpm1 are encoded by two distinct
      open reading frames, Msppm1 and Msppm2, organized as an operon. No TMS are
      predicted in MsPpm1, and subcellular fractionation experiments indicate that this
      enzyme is cytosolic when produced in Escherichia coli. Computer-assisted topology
      predictions and alkaline phosphatase insertions showed that MsPpm2 is an integral
      membrane protein. Using a recently developed bacterial two-hybrid system, it was
      found that MsPpm2 interacts with MsPpm1 to stabilize the synthase MsPpm1 in the
      bacterial membrane. This interaction is reminiscent of that of mammalian Dpm1
      with Dpm3 and mimics the structure of MtPpm1 as demonstrated by the capacity of
      the two domains of MtPpm1 to spontaneously interact when co-expressed in E. coli.

PMID- 12427760
TI  - Structure-function analysis of invasion plasmid antigen C (IpaC) from Shigella
      flexneri.
AB  - Shigella flexneri causes a self-limiting gastroenteritis in humans, characterized
      by severe localized inflammation and ulceration of the colonic mucosa.
      Shigellosis most often targets young children in underdeveloped countries.
      Invasion plasmid antigen C (IpaC) has been identified as the primary effector
      protein for Shigella invasion of epithelial cells. Although an initial model of
      IpaC function has been developed, no detailed structural information is available
      that could assist in a better understanding of the molecular basis for its
      interactions with the host cytoskeleton and phospholipid membrane. We have
      therefore initiated structural studies of IpaC, IpaC I', (residues 101-363
      deleted), and IpaC Delta H (residues 63-170 deleted). The secondary and tertiary
      structure of the protein was examined as a function of temperature, employing
      circular dichroism and high resolution derivative absorbance techniques. ANS (8
      anilino-1-napthalene sulfonic acid) was used to probe the exposure of the
      hydrophobic surfaces under different conditions. The interaction of IpaC and
      these mutants with a liposome model (liposomes with entrapped fluorescein) was
      also examined. Domain III (residues 261-363) was studied using linker-scanning
      mutagenesis. It was shown that domain III contains periodic, sequence-dependent
      activity, suggesting helical structure in this section of the protein. In
      addition to these structural studies, investigation into the actin nucleation
      properties of IpaC was conducted, and actin nucleation by IpaC and some of the
      mutants was exhibited. Structure-function relationships of IpaC are discussed.

PMID- 12427761
TI  - Binding of the priming nucleotide in the initiation of transcription by T7 RNA
      polymerase.
AB  - Unlike DNA polymerases, an RNA polymerase must initiate transcription de novo,
      that is binding of the initiating (+1) nucleoside triphosphate must be achieved
      without benefit of the cooperative binding energetics of an associated primer.
      Since a single Watson-Crick base pair is not stable in solution, RNA polymerases
      might be expected to provide additional stabilizing interactions to facilitate
      binding and positioning of the initiating (priming) nucleoside triphosphate at
      position +1. Consistent with base-specific stabilizing interactions, of the 17 T7
      RNA polymerase promoters in the phage genome, 15 begin with guanine. In this
      work, we demonstrate that the purine N-7 is important in the utilization of the
      initial substrate GTP. The fact that on a template encoding AG as the first two
      bases in the transcript (as in the remaining two of the T7 genome) transcription
      starts predominantly (but not exclusively) at the G at position +2 additionally
      implicates the purine O-6 as an important recognition element in the major
      groove. Finally, results suggest that these interactions serve primarily to
      position the initiating base in the active site. It is proposed that T7 RNA
      polymerase interacts directly with the Hoogsteen side of the initial priming GTP
      (most likely via an interaction with an arginine side chain in the protein) to
      provide the extra stability required at this unique step in transcription.

PMID- 12427762
TI  - Novel cell-specific and dominant negative anti-apoptotic roles of p73 in
      transformed leukemia cells.
AB  - Although extensive homology exists between related genes p53 and p73, recent data
      suggest that the family members have divergent roles. We demonstrate that the
      differential regulatory roles of p53 family member p73 are highly cell-context
      and promoter-specific. Full-length p73 expressed in the transformed leukemia cell
      line Jurkat behaves as a specific dominant negative transcriptional repressor of
      the cell cycle inhibitor gene p21 and blocks p53-mediated apoptosis. These
      findings provide evidence for a new mechanism in oncogenesis through which the
      functional properties of p73 can be altered in an inheritable and cell-specific
      fashion independent of transcriptional coding.

PMID- 12427763
TI  - Cloning and functional characterization of the smooth muscle ether-a-go-go
      related gene K+ channel. Potential role of a conserved amino acid substitution in
      the S4 region.
AB  - The human ether-a-go-go-related gene (HERG) product forms the pore-forming
      subunit of the delayed rectifier K(+) channel in the heart. Unlike the cardiac
      isoform, the erg K(+) channels in native smooth muscle demonstrate gating
      properties consistent with a role in maintaining resting potential. We have
      cloned the smooth muscle isoform of HERG, denoted as erg1-sm, from human and
      rabbit colon. erg1-sm is truncated by 101 amino acids in the C terminus due to a
      single nucleotide deletion in the 14th exon. Sequence alignment against HERG
      showed a substitution of alanine for valine in the S4 domain. When expressed in
      Xenopus oocytes, erg1-sm currents had much faster activation and deactivation
      kinetics compared with HERG. Step depolarization positive to -20 mV consistently
      produced a transient outward component. The threshold for activation of erg1-sm
      was -60 mV and steady-state conductance was approximately 10-fold greater than
      HERG near the resting potential of smooth muscle. Site-directed mutagenesis of
      alanine to valine in the S4 region of erg1-sm converted many of the properties to
      that of the cardiac HERG, including shifts in the voltage dependence of
      activation and slowing of deactivation. These studies define the functional role
      of a novel isoform of the ether-a-go-go-related gene K(+) channel in smooth
      muscle.

PMID- 12427764
TI  - Angiopoietin-1 and angiopoietin-2 share the same binding domains in the Tie-2
      receptor involving the first Ig-like loop and the epidermal growth factor-like
      repeats.
AB  - Angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) have been identified as ligands
      with different effector functions of the vascular assembly and maturation
      mediating receptor tyrosine kinase Tie-2. To understand the molecular
      interactions of the angiopoietins with their receptor, we have studied the
      binding of Ang-1 and Ang-2 to the Tie-2 receptor. Enzyme-linked immunosorbent
      assay-based competition assays and co-immunoprecipitation experiments analyzing
      the binding of Ang-1 and Ang-2 to truncation mutants of the extracellular domain
      of Tie-2 showed that the first Ig-like loop of Tie-2 in combination with the
      epidermal growth factor (EGF)-like repeats (amino acids 1-360) is required for
      angiopoietin binding. The first Ig-like domain or the EGF-like repeats alone are
      not capable of binding Ang-1 and Ang-2. Concomitantly, we made the surprising
      finding that Tie-2 exon-2 knockout mice do express a mutated Tie-2 protein that
      lacks 104 amino acids of the first Ig-like domain. This mutant Tie-2 receptor is
      functionally inactive as shown by the lack of ligand binding and receptor
      phosphorylation. Collectively, the data show that the first 104 amino acids of
      the Tie-2 receptor are essential but not sufficient for angiopoietin binding.
      Conversely, the first 360 amino acids (Ig-like domain plus EGF-like repeats) of
      the Tie-2 receptor are necessary and sufficient to bind both Ang-1 and Ang-2,
      which suggests that differential receptor binding is not likely to be responsible
      for the different functions of Ang-1 and Ang-2.

PMID- 12427765
TI  - Acidification of the malaria parasite's digestive vacuole by a H+-ATPase and a H+
      pyrophosphatase.
AB  - As it grows within the human erythrocyte, the malaria parasite, Plasmodium
      falciparum, ingests the erythrocyte cytosol, depositing it via an endocytotic
      feeding mechanism in the "digestive vacuole," a specialized acidic organelle. The
      digestive vacuole is the site of hemoglobin degradation, the storage site for
      hemozoin (an inert biocrystal of toxic heme), the site of action of many
      antimalarial drugs, and the site of proteins known to be involved in antimalarial
      drug resistance. The acidic pH of this organelle is thought to play a critical
      role in its various functions; however, the mechanisms by which the pH within the
      vacuole is maintained are not well understood. In this study, we have used a
      combination of techniques to demonstrate the presence on the P. falciparum
      digestive vacuole membrane of two discrete H(+) pumping mechanisms, both capable
      of acidifying the vacuole interior. One is a V-type H(+)-ATPase, sensitive to
      concanamycin A and bafilomycin A(1). The other is a H(+)-pyrophosphatase, which
      was inhibited by NaF and showed a partial dependence on K(+). The operation of
      the H(+)-pyrophosphatase was dependent on the presence of a Mg(2+)-pyrophosphate
      complex, and kinetic experiments gave results consistent with free pyrophosphate
      acting as an inhibitor of the protein. The presence of the combination of a H(+)
      ATPase and a H(+)-pyrophosphatase on the P. falciparum digestive vacuole is
      similar to the situation in the acidic tonoplasts (vacuoles) of plant cells.

PMID- 12427766
TI  - Essential histidine and tryptophan residues in CcsA, a system II polytopic
      cytochrome c biogenesis protein.
AB  - Three distinct systems (I, II, and III) for catalysis of heme attachment to c
      type apocytochromes are known. The CcsA and Ccs1 proteins are required in system
      II for the assembly of bacterial and plastid cytochromes c. A tryptophan-rich
      signature motif (WWD), also occurring in CcmC and CcmF found in system I, and
      three histidinyl residues, all strictly conserved in CcsA suggest a function in
      heme handling. Topological analysis of plastid CcsA in bacteria using the PhoA
      and LacZalpha reporters placed the WWD motif, the conserved residues His(212) and
      His(347) on the lumen side of the membrane, whereas His(309) was assigned a
      location on the stromal side. Functional analysis of CcsA through site-directed
      mutagenesis enabled the designation of the initiation codon of the ccsA gene and
      established the functional importance of the WWD signature motif and the absolute
      requirement of all three histidines for the assembly of plastid c-type
      cytochromes. In a ccsA mutant, a 200-kDa Ccs1-containing complex is absent from
      solubilized thylakoid membranes, suggesting that CcsA operates together with
      Ccs1. We propose a model where the WWD motif and histidine residues function in
      relaying heme from stroma to lumen and we postulate the existence of a cytochrome
      c assembly machinery containing CcsA, Ccs1 and additional components.

PMID- 12427767
TI  - BAFF AND APRIL: a tutorial on B cell survival.
AB  - BAFF, a member of the TNF family, is a fundamental survival factor for
      transitional and mature B cells. BAFF overexpression leads to an expanded B cell
      compartment and autoimmunity in mice, and elevated amounts of BAFF can be found
      in the serum of autoimmune patients. APRIL is a related factor that shares
      receptors with BAFF yet appears to play a different biological role. The BAFF
      system provides not only potential insight into the development of autoreactive B
      cells but a relatively simple paradigm to begin considering the balancing act
      between survival, growth, and death that affects all cells.

PMID- 12427768
TI  - Role of nerves in enteric infection.
AB  - Peripheral and central effects of enteric infection are considered. Nerves play a
      vital part in the immediate response to enteric infection, promoting pathogen
      expulsion by orchestrating intestinal secretion and propulsive motor patterns.
      Laboratory studies indicate that therapeutic agents aimed at modulating the
      neural response can profoundly alter the outcome of infection. As our
      understanding of the role of nerves increases, exciting new targets for
      therapeutic intervention will emerge in both acute and chronic disorders induced
      by enteric infection.

PMID- 12427769
TI  - Argon plasma coagulation therapy for ablation of Barrett's oesophagus.

PMID- 12427770
TI  - Appendix redux.

PMID- 12427771
TI  - Risk of pancreatic ductal adenocarcinoma in chronic pancreatitis.

PMID- 12427772
TI  - Breast milk against coeliac disease.

PMID- 12427773
TI  - The NFkappaB luciferase mouse: a new tool for real time measurement of NFkappaB
      activation in the whole animal.

PMID- 12427774
TI  - Effect of chronic and acute cigarette smoking on the pharyngoglottal closure
      reflex.
AB  - BACKGROUND: Injection of water into the pharynx at a threshold volume induces
      vocal cord adduction--the pharyngoglottal closure reflex (PGCR). This reflex
      together with other supraoesophageal reflexes may be helpful in preventing
      aspiration. Cigarette smoking has an adverse affect on the pharyngo-upper
      oesophageal sphincter contractile reflex and reflexive pharyngeal swallow. The
      effect of smoking on PGCR has not been studied previously. AIMS: To elucidate the
      effect of chronic and acute cigarette smoking on PGCR. SUBJECTS: We studied 10
      chronic smokers and 10 non-smokers before and after real/simulated smoking,
      respectively. METHODS: Using concurrent recordings, glottal function was
      monitored by video endoscopy, swallowing by electromyography, and PGCR was
      triggered by rapid and slow pharyngeal water injections. RESULTS: The threshold
      volume to trigger PGCR during rapid injection was significantly higher in chronic
      smokers (non-smoker 0.20 (SEM 0.02) ml, smoker 0.36 (0.02) ml; p<0.001). In six
      of 10 smokers, acute smoking abolished this reflex during slow water injection.
      CONCLUSIONS: Smoking adversely affects stimulation of PGCR. This finding may have
      implications in the development of reflux related respiratory complications in
      smokers.

PMID- 12427775
TI  - Efficacy and one year follow up of argon plasma coagulation therapy for ablation
      of Barrett's oesophagus: factors determining persistence and recurrence of
      Barrett's epithelium.
AB  - INTRODUCTION: Barrett's epithelium (BE) has malignant potential. Neither acid
      suppression nor antireflux surgery produce consistent or complete regression of
      the metaplastic epithelium. Endoscopic thermoablation with argon plasma
      coagulation (APC) offers a different approach but factors influencing its outcome
      have not been systematically examined. AIM: To assess the efficacy of APC and
      factors influencing initial and one year outcome. METHODS: Fifty patients, mean
      age 61.4 years, mean BE length 5.9 cm (range 3-19), underwent APC therapy at four
      weekly intervals while receiving proton pump inhibitor (PPI) therapy. BE margins
      were marked by India ink tattooing and extent was documented by grid drawings,
      photography, and 2 cm interval quadrantic jumbo biopsies. Twenty four hour
      ambulatory oesophageal pH studies were done while on PPIs before and after APC
      therapy, and Bilitec bilirubin monitoring after APC completion. RESULTS: A total
      of 68% of patients achieved >90% BE ablation after a median of four APC sessions.
      Persistent BE (>10% original BE area) was associated with longer initial BE
      length despite more APC sessions. Persistent acid and bile reflux on PPIs,
      although commoner in this group, were not significantly different from those
      successfully ablated. Fifteen of 34 patients (44%) with successful macroscopic
      clearance had buried glands, present in 8.3% of a total of 338 biopsies. At the
      one year follow up, only 32% of those with initial successful ablation showed no
      recurrence. BE recurred or increased in most with mean segment length increases
      of 1.1 cm and 1.6 cm, respectively, in patients with previous full ablation and
      those with persistent BE. The presence of buried glands did not predict BE
      recurrence. Patients who reduced their PPI dose had significantly greater BE
      recurrence. CONCLUSIONS: APC is most effective for shorter segment BE ablation
      but "buried" glands do occur. Recurrence of BE is common at one year, especially
      in those with initial persistent and/or long segment BE and those who reduce
      their PPI dose.

PMID- 12427776
TI  - SPECT imaging of the stomach: comparison with barostat, and effects of sex, age,
      body mass index, and fundoplication. Single photon emission computed tomography.
AB  - BACKGROUND: Impaired gastric accommodation may lead to dyspeptic symptoms. A non
      invasive method using single photon emission computed tomography (SPECT) has been
      developed to measure gastric volumes. AIMS AND METHODS: Our aims were: to assess
      the accuracy of SPECT with three dimensional image analysis to measure balloon
      volumes in vitro; to compare gastric barostat balloon volumes measured post-meal
      and post-distension with total gastric volumes measured simultaneously with
      SPECT; to present normal gastric volume data for healthy adults; and to compare
      SPECT data in health with symptomatic post-fundoplication patients. RESULTS: In
      vitro balloon volumes measured by SPECT were highly accurate (R(2)=0.99). When
      measured simultaneously by gastric barostat and SPECT, postprandial/fasting
      volume ratios (2.2 (0.12) (mean (SEM)) v 2.3 (0.15), respectively; p=0.6) and
      post-distension volume ratios (1.4 (0.1) v1.3 (0.1); p=0.2) were highly
      comparable. In females, postprandial gastric volumes (675 (14) v 744 (20) ml for
      males; p=0.004) and changes in gastric volumes (464 (14) ml v 521 (20) ml for
      males; p=0.01) measured by SPECT were significantly lower than in males. No
      effects of age or body mass index were noted. The postprandial/fasting gastric
      volume ratio by SPECT was lower in post-fundoplication patients (2.7 (0.2)) than
      in healthy controls (3.4 (0.1); p=0.003). CONCLUSIONS: SPECT provides a non
      invasive estimate of the effect of a meal on total gastric volume that is
      comparable to changes in balloon volume observed with the gastric barostat. The
      SPECT technique is promising for investigation of gastric volumes in health and
      disease and the effects of pharmacological agents.

PMID- 12427777
TI  - Human transforming growth factor alpha (TGF-alpha) is digested to a smaller (1
      43), less biologically active, form in acidic gastric juice.
AB  - BACKGROUND: Transforming growth factor alpha (TGF-alpha) is a 50 amino acid
      peptide with potent proliferative and cytoprotective activity present in gastric
      mucosa and juice. AIMS: To determine the forms and biological activity of natural
      and recombinant TGF-alpha following incubation with acid pepsin. PATIENTS: Human
      gastric juice was obtained under basal conditions from patients taking acid
      suppressants and from volunteers undergoing intragastric neutralisation. METHODS:
      Samples were analysed using mass spectroscopy and/or high pressure liquid
      chromatography with radioimmunoassay. Biological activity was determined using
      thymidine incorporation into rat hepatocytes and an indomethacin/restraint
      induced gastric damage rat model. RESULTS: TGF-alpha(1-50) is cleaved to TGF
      alpha(1-43) by acid pepsin and this is the predominant form in normal gastric
      juice. However, intragastric neutralisation or taking acid suppressants caused
      the predominant form to be TGF-alpha(1-50). TGF-alpha(1-43) had only half of the
      ability to maximally stimulate [(3)H]thymidine incorporation into primary rat
      hepatocytes (28 177 (1130) DPM/well for 2.16 nM TGF-alpha(1-43) v 63 184 (3536)
      DPM/well for TGF-alpha(1-50); p<0.001). A similar reduced potency was seen when
      used in an indomethacin induced rat gastric damage model (0.18 micro mol/kg/h of
      TGF-alpha(1-43) reduced ulcer area by 19% whereas TGF-alpha(1-50) reduced area by
      62%; p<0.001). CONCLUSIONS: TGF-alpha(1-50) is cleaved to the TGF-alpha(1-43)
      form by acid pepsin, causing 2-5-fold loss of biological activity. Such changes
      may have relevance to the actions of acid suppressants and the importance of this
      peptide in both normal and abnormal growth.

PMID- 12427778
TI  - Polyclonal nature of diffuse proliferation of interstitial cells of Cajal in
      patients with familial and multiple gastrointestinal stromal tumours.
AB  - BACKGROUND: Diffuse proliferation of interstitial cells of Cajal (ICCs) in the
      myenteric plexus layer of the intestine has been described in patients with
      familial and multiple gastrointestinal stromal tumours (GISTs). However, it is
      not fully understood whether proliferation is polyclonal or monoclonal. AIMS: To
      evaluate the clonal nature of diffuse ICC proliferation in familial and multiple
      GIST cases, we carried out clonal analysis using inactivation at the human
      androgen receptor (HUMARA) locus. MATERIALS AND METHODS: Diffuse ICC
      proliferation tissues from three female patients were microdissected using a
      laser capture microdissection (LCM) system. Normal intestinal mucosal tissues
      were also microdissected for polyclonal controls and GIST tissues for monoclonal
      controls from the same patients, and genomic DNA was extracted. After digestion
      by restriction enzyme HhaI, the HUMARA locus was amplified by a fluorescent
      polymerase chain reaction (PCR) procedure and the PCR products were analysed.
      RESULTS: One case was uninformative because it was homozygous at the HUMARA
      locus. In the two other cases, PCR products from the diffuse ICC proliferation
      showed two alleles as well as those from normal intestinal mucosal tissues,
      indicating that ICC proliferation was polyclonal. In contrast, PCR products from
      associated GIST tissues showed only one allele, indicating that GISTs were
      monoclonal. CONCLUSION: The results suggested that diffuse ICC proliferation in
      familial and multiple GIST cases was non-neoplastic hyperplasia.

PMID- 12427779
TI  - Characterisation of colorectal cancers showing hypermethylation at multiple CpG
      islands.
AB  - BACKGROUND AND AIMS: A subgroup of colorectal cancers (CRC) referred to as the
      CpG island methylator phenotype (CIMP+) shows simultaneous methylation of
      multiple CpG islands. The clinicopathological and molecular characteristics of
      this phenotype remain uncertain however. METHODS: We analysed methylation of CpG
      islands in the p16 and MDR1 genes and MINT-2 clone in 275 stage II/III CRCs.
      RESULTS: Concurrent methylation of two or more CpG islands was observed in 32% of
      cases and was considered to represent CIMP+. These were often poorly
      differentiated, had less TP53 mutations, and originated frequently in the
      proximal or higher stage CRC compared with CIMP- tumours (p<0.05 for each). CIMP+
      had no prognostic significance in stage II or stage III CRC treated by surgery
      alone. hMLH1 methylated tumours comprised the majority (81%) of cases with
      microsatellite instability, were frequently observed in older female patients,
      were often poorly differentiated or CIMP+, and contained wild-type K-ras (p<0.05
      for each). Females who were heterozygous or homozygous for the C677T MTHFR
      polymorphism were at increased risk of developing CIMP+ CRC (odds ratio 2.17, 95%
      confidence interval 1.03-4.57; p=0.037). CONCLUSIONS: These observations made in
      a relatively large unselected series of CRC support the notion that CIMP+
      characterises a subgroup of tumours with distinctive phenotypic features.

PMID- 12427780
TI  - Effects of appendicectomy on the course of ulcerative colitis.
AB  - BACKGROUND: Appendicectomy reduces the risk of having ulcerative colitis.
      However, its effect on the natural history of ulcerative colitis remains
      uncertain. AIM: To determine whether appendicectomy reduces the overall severity
      of ulcerative colitis. PATIENTS AND METHODS: Appendicectomy status and smoking
      habits were specified by direct interview in 638 patients seen consecutively
      between 1997 and 2000. Severity of ulcerative colitis was assessed by reviewing
      therapeutic needs from the onset of colitis. Additionally, the annual incidence
      of flare up was assessed prospectively between 1997 and 2000 in patients who had
      not been colectomised. RESULTS: The 10 year risk of colectomy was 16 (7)% in
      previously appendicectomised patients (n=49) compared with 33 (2)% in non
      appendicectomised patients (n=589, p=0.05). Cox regression showed that previous
      appendicectomy and current smoking were independent factors protecting against
      colectomy (adjusted hazard ratio and 95% confidence intervals: 0.40 (0.20-0.78)
      and 0.60 (0.40-0.95), respectively). The respective proportions of
      appendicectomised and non-appendicectomised patients who required oral steroids
      and immunosuppressive therapy were not significantly different (67% v 70% and 27%
      v 19%, respectively). Between 1997 and 2000, ulcerative colitis was active for
      48% of the time in appendicectomised patients (47 of 98 patient years) and for
      62% of the time in non-appendicectomised patients (631 of 1024 patient years;
      p<0.01). CONCLUSION: Previous appendicectomy is associated with a less severe
      course of ulcerative colitis. The beneficial effect of appendicectomy on the risk
      of colectomy is additive to that of current smoking.

PMID- 12427782
TI  - No seasonality in month of birth of inflammatory bowel disease cases: a
      prospective population based study of British under 20 year olds.

PMID- 12427781
TI  - Protective role of appendicectomy on onset and severity of ulcerative colitis and
      Crohn's disease.
AB  - BACKGROUND AND AIMS: Recent studies on appendicectomy rates in ulcerative colitis
      and Crohn's disease have generally not addressed the effect of appendicectomy on
      disease characteristics. The aims of this study were to compare appendicectomy
      rates in Australian inflammatory bowel disease patients and matched controls, and
      to evaluate the effect of prior appendicectomy on disease characteristics.
      METHODS: Patients were ascertained from the Brisbane Inflammatory Bowel Disease
      database. Controls matched for age and sex were randomly selected from the
      Australian Twin Registry. Disease characteristics included age at diagnosis,
      disease site, need for immunosuppression, and intestinal resection. RESULTS: The
      study confirmed the significant negative association between appendicectomy and
      ulcerative colitis (odds ratio (OR) 0.23, 95% confidence interval (CI) 0.14-0.38;
      p<0.0001) and found a similar result for Crohn's disease once the bias of
      appendicectomy at diagnosis was addressed (OR 0.34, 95% CI 0.23-0.51; p<0.0001).
      Prior appendicectomy delayed age of presentation for both diseases and was
      statistically significant for Crohn's disease (p=0.02). In ulcerative colitis,
      patients with prior appendicectomy had clinically milder disease with reduced
      requirement for immunosuppression (OR 0.15, 95% CI 0.02-1.15; p=0.04) and
      proctocolectomy (p=0.02). CONCLUSIONS: Compared with patients without prior
      appendicectomy, appendicectomy before diagnosis delays disease onset in
      ulcerative colitis and Crohn's disease and gives rise to a milder disease
      phenotype in ulcerative colitis.

PMID- 12427783
TI  - Effect of Pentavac and measles-mumps-rubella (MMR) vaccination on the intestine.
AB  - BACKGROUND: The safety of infant vaccination has been questioned in recent years.
      In particular it has been suggested that the measles, mumps, and rubella (MMR)
      vaccination leads to brain damage manifesting as autism consequent to the
      development of an "enterocolitis" in the immediate post-vaccination period. AIM:
      To assess if MMR vaccination is associated with subclinical intestinal
      inflammation, which is central to the autistic "enterocolitis" theory. METHODS:
      We studied 109/58 infants, before and two and four weeks after immunisation with
      Pentavac and MMR vaccines, for the presence of intestinal inflammation (faecal
      calprotectin). RESULTS: Neither vaccination was associated with any significant
      increase in faecal calprotectin concentrations. CONCLUSIONS: The failure of the
      MMR vaccination to cause an intestinal inflammatory response provides evidence
      against the proposed gut-brain interaction that is central to the autistic
      "enterocolitis" hypothesis.

PMID- 12427784
TI  - Colonic epithelial cells are a major site of macrophage inflammatory protein
      3alpha (MIP-3alpha) production in normal colon and inflammatory bowel disease.
AB  - BACKGROUND AND AIM: Macrophage inflammatory protein 3alpha (MIP-3alpha) is a
      recently described lymphocyte directed C-C chemokine expressed predominately at
      extralymphoid sites, including the intestine. The aim of this study was to
      determine whether colonic epithelial cells produce MIP-3alpha and whether its
      expression is upregulated in inflammatory bowel disease. METHODS AND RESULTS: We
      found that interleukin 1beta and tumour necrosis factor alpha dose dependently
      stimulated MIP-3alpha production in Caco-2 and HT-29 intestinal epithelial cells.
      In cytokine treated Caco-2 and HT-29 cells, a significant increase in MIP-3alpha
      protein production was observed after three hours and continued for at least 24
      hours. Analysis of colonic tissues by quantitative real time polymerase chain
      reaction and ELISA revealed significantly elevated MIP-3alpha mRNA levels (7.9
      fold; p<0.05) and protein levels (8.9-fold; p<0.05) in Crohn's disease compared
      with controls or ulcerative colitis. MIP-3alpha immunoreactivity in normal colon
      and inflammatory bowel disease was principally associated with crypt and surface
      epithelial cells. Moreover, MIP-3alpha protein levels were elevated in primary
      epithelial cells isolated from patients with inflammatory bowel disease.
      CONCLUSIONS: These findings indicate that increased enterocyte MIP-3alpha
      production may play an important role in lymphocyte activation and recruitment to
      the colonic epithelium in Crohn's disease and ulcerative colitis.

PMID- 12427785
TI  - A prospective randomised study of the probiotic Lactobacillus plantarum 299V on
      indices of gut barrier function in elective surgical patients.
AB  - BACKGROUND: Bacterial translocation occurs in surgical patients and may
      predispose to postoperative septic morbidity. Many factors are thought to
      influence the prevalence of bacterial translocation, one of which is the
      composition of the gut microflora. The aim of this prospective and randomised
      study was to assess the effect of the probiotic Lactobacillus plantarum 299v on
      the incidence of bacterial translocation, gastric colonisation, and septic
      complications in elective surgical patients. METHODS: Patients undergoing
      elective major abdominal surgery were randomised to either a treatment or control
      group. The treatment group received an oral preparation containing Lactobacillus
      plantarum 299v (Proviva) for at least one week preoperatively and also in the
      postoperative period. Bacterial translocation was determined by culture of a
      mesenteric lymph node and serosal scraping obtained at laparotomy. Gastric
      colonisation was assessed by microbiological culture of nasogastric aspirates.
      All postoperative septic complications were recorded. RESULTS: A total of 129
      patients completed the study (probiotic group n=64). There was no significant
      difference between the two groups in terms of bacterial translocation (12% v 12%;
      p=0.82), gastric colonisation with enteric organisms (11% v 17%; p=0.42), or
      septic morbidity (13% v 15%; p=0.74). CONCLUSIONS: Administration of
      Lactobacillus plantarum 299v in elective surgical patients does not influence the
      rate of bacterial translocation, gastric colonisation, or incidence of
      postoperative septic morbidity.

PMID- 12427786
TI  - Trends in indigenous foodborne disease and deaths, England and Wales: 1992 to
      2000.
AB  - BACKGROUND: Commitment to food safety is evidenced by high profile governmental
      initiatives around the globe. To measure progress towards targets, policy makers
      need to know the baseline from which they started. AIM: To describe the burden
      (mortality, morbidity, new presentations to general practice, hospital
      admissions, and hospital occupancy) and trends of indigenous foodborne disease
      (IFD) in England and Wales between 1992 and 2000. METHODS: Routinely available
      surveillance data, special survey data, and hospital episode statistics were
      collated and arithmetic employed to estimate the burden and trends of IFD in
      England and Wales. Adjustments were made for underascertainment of disease
      through national surveillance and for foreign travel. The final estimates were
      compared with those from the USA. RESULTS: In 1995 there were an estimated
      2,365,909 cases, 21,138 hospital admissions, and 718 deaths in England and Wales
      due to IFD. By 2000 this had fallen to 1,338,772 cases, 20,759 hospital
      admissions, and 480 deaths. In terms of disease burden the most important
      pathogens were campylobacters, salmonellas, Clostridium perfringens,
      verocytotoxin producing Escherichia coli (VTEC) O157, and Listeria monocytogenes.
      The ratio of food related illness in the USA to IFD in England and Wales in 2000
      was 57:1. Taking into account population rates, this ratio fell to 11:1 and
      converged when aetiology and disease severity were considered. CONCLUSION:
      Reducing IFD in England and Wales means tackling campylobacter. Lowering
      mortality rates however also requires better control and prevention of
      salmonellas, Cl perfringens, L monocytogenes, and VTEC O157.

PMID- 12427787
TI  - Lipopolysaccharide modulation of normal enterocyte turnover by toll-like
      receptors is mediated by endogenously produced tumour necrosis factor alpha.
AB  - BACKGROUND: Circulating levels of endotoxin (or lipopolysaccharide (LPS)) and
      anti-endotoxin antibodies are increased in patients with inflammatory bowel
      disease, supporting the hypothesis of a role for endogenous bacterial products in
      the pathogenesis of these disorders. AIM: The aim of this study was to analyse
      the direct effects of LPS on intestinal epithelial cell turnover. METHODS AND
      RESULTS: LPS significantly inhibited growth of the human non-transformed immature
      crypt cell line (HIEC), whereas IEC-6 cell proliferation was stimulated by LPS.
      As LPS is a physiological inducer of tumour necrosis factor alpha (TNFalpha) in
      various cell systems and this cytokine exerted similar anti-proliferative (HIEC)
      or growth stimulatory (IEC-6 cells) effects, the study thus tested the hypothesis
      that endogenously produced TNFalpha in response to LPS mediates this growth
      modulatory effect in an autoparacrine/paracrine way. Therefore, during LPS
      stimulation, the biological activity of TNFalpha was blocked using neutralising
      anti-TNFalpha antibodies, as well as inhibitory, antagonistic antibodies directed
      against the p55 TNF receptor, signalling the antimitotic TNFalpha effect in HIEC.
      Both experimental approaches completely abolished the growth modulatory effects
      of LPS in HIEC/IEC-6 cells. Production and secretion of TNFalpha by HIEC/IEC-6
      cells in response to LPS was confirmed on mRNA and protein level by reverse
      transcription polymerase chain reaction (RT-PCR) and enzyme linked immunosorbent
      assay. LPS signalling was independent of CD14 in HIEC, as these cells lack this
      receptor. However, HIEC expressed TLR4 and MD2 resulting in a fully functional
      signalling complex as demonstrated by RT-PCR, western blot, and
      immunofluorescence analyses. CONCLUSION: These results support the hypothesis
      that LPS induced changes of intestinal epithelial cell turnover may directly
      contribute to the pathogenesis of inflammatory epithelial cell lesions by
      endogenous TNFalpha production by enterocytes.

PMID- 12427788
TI  - Risk of pancreatic adenocarcinoma in chronic pancreatitis.
AB  - BACKGROUND: The risk of pancreatic cancer in patients with chronic pancreatitis
      (CP) is difficult to assess. Previous studies, mostly case control studies or
      studies relying on data case registers, reported relative risks varying from 2.3
      to 18.5. METHODS: We studied a prospective, single centre, medical-surgical
      cohort of 373 consecutive patients (322 (86%) men, median age 40 years) with
      proven CP (alcoholic origin 85%) and a follow up of at least two years (median
      follow up 9.2 years; range 2.0-34.8) in order to exclude pancreatitis revealing
      pancreatic cancer. We calculated the age and sex standardised incidence ratio
      (SIR) as the ratio of the number of observed cases of pancreatic cancer in this
      cohort to the number of expected cases, as provided by the French National Cancer
      Register. RESULTS: Four cases of pancreatic adenocarcinoma (1.1% of patients)
      were observed in 3437 patient years (expected number of cases 0.15; SIR 26.7, 95%
      confidence interval (CI) 7.3-68.3; p=0.00002). In a second analysis in which
      patients lost to follow up were considered to be followed up until the end point
      without having developed pancreatic adenocarcinoma (4762 patient years), SIR was
      19.0 (CI 5.2-48.8; p=0.00007). CONCLUSION: Patients with CP have a markedly
      increased risk of pancreatic cancer compared with the general population.

PMID- 12427789
TI  - Hepatopulmonary syndrome: prevalence and predictive value of various cut offs for
      arterial oxygenation and their clinical consequences.
AB  - BACKGROUND: The hepatopulmonary syndrome (HPS) is defined as the triad of liver
      disease, arterial deoxygenation, and pulmonary vascular dilatation. The reported
      prevalence of HPS in cirrhotic patients varies between 4% and 19%, and various
      threshold values defining arterial deoxygenation have been used and recommended
      previously. However, it is not known how the prevalence of HPS differs using
      different cut off values for arterial deoxygenation. METHODS: We studied 127
      patients for the presence of HPS using transthoracic contrast echocardiography
      for detection of pulmonary vasodilation, pulmonary function tests, and blood gas
      analysis. RESULTS: Ninety eight patients were included in the study, of whom 33
      (34%) had a positive contrast echocardiography. Using an increased alveolar
      arterial difference for the partial pressure of oxygen (AaDO(2)) as an indication
      of hypoxaemia, the prevalence of HPS was considerably higher (>15 mm Hg, 32%; >20
      mm Hg, 31%; and >age related threshold, 28%) than using reduced partial pressure
      of arterial oxygen (PaO(2)) as a threshold (<80 mm Hg, 19%; <70 mm Hg, 15%; and
      <age related threshold, 15%). For AaDO(2) as the cut off, the positive predictive
      value for a diagnosis of HPS was low (34%, 37%, and 53%, respectively). In
      contrast, PaO(2) as a cut off had considerably higher positive predictive values
      (44%, 93%, and 94%, respectively). Introducing PaO(2) <65 mm Hg as the cut off,
      the positive predictive value increased to 100%. Dyspnoea was more often present
      in patients with "clinically significant" HPS (57%) compared with "subclinical
      HPS" (8%), and patients without HPS (6%). The Child-Pugh score correlated
      significantly with the severity of HPS. Two of five liver transplanted patients
      with "subclinical HPS" had embolic brain infarcts, possibly induced by venous
      emboli passing through dilated intrapulmonary vessels. CONCLUSIONS: Defining
      arterial hypoxaemia in HPS by different, previously used, cut off values for
      arterial oxygenation leads to a wide variation in the prevalence of HPS in the
      same sample of cirrhotic patients.

PMID- 12427790
TI  - Comparison of the hepatic clearances of campesterol, sitosterol, and cholesterol
      in healthy subjects suggests that efflux transporters controlling intestinal
      sterol absorption also regulate biliary secretion.
AB  - BACKGROUND: Recently identified ABCG5/8 transporters are responsible in part for
      the different absorption rates of campesterol, sitosterol, and cholesterol. These
      transporters are also expressed in the liver and might regulate biliary sterol
      secretion. AIMS: This study was therefore conducted to determine the biliary
      secretion rates and hepatic clearances of campesterol, sitosterol, and
      cholesterol. SUBJECTS: Six healthy, male volunteers. METHODS: Deuterium labelled
      sitosterol and campesterol, and unlabelled sitostanol were constantly infused
      together with a liquid formula using a duodenal perfusion technique. Biliary
      secretion and hepatic clearance rates were calculated from hourly bile and plasma
      samples. RESULTS: Plasma concentrations of cholesterol, campesterol, and
      sitosterol averaged 167.5 (50) mg/dl (SD), 0.50 (0.22) mg/dl, and 0.30 (0.10)
      mg/dl, respectively. Sitosterol showed a significantly higher biliary secretion
      rate (1.23 (0.87) mg/h) than campesterol (0.76 (0.54) mg/h, p=0.0321), but both
      plant sterols had significantly lower biliary secretion rates compared with
      cholesterol (47.7 (17.5) mg/h; p=0.001 for both). Hepatic clearance of
      cholesterol (0.31 (0.18) dl/h) was significantly lower compared with campesterol
      (2.11 (2.51) dl/h) and sitosterol (4.97 (4.70) dl/h; p=0.028 for both), and the
      clearance of campesterol was significant lower compared with sitosterol
      (p=0.028). CONCLUSION: The observed inverse relation between hepatic clearance
      and known intestinal absorption of cholesterol, campesterol, and sitosterol
      supports the hypothesis that the ABCG5/8 transporters regulating intestinal
      sterol absorption might also be involved in biliary sterol excretion.

PMID- 12427791
TI  - Retreatment with interferon plus ribavirin of chronic hepatitis C non-responders
      to interferon monotherapy: a meta-analysis of individual patient data.
AB  - BACKGROUND AND AIMS: Retreatment with a combination of alpha interferon (IFN)
      plus ribavirin of patients with chronic hepatitis C who did not respond to IFN
      monotherapy has not been assessed in large controlled studies. METHODS: To assess
      the effectiveness and tolerability of IFN/ribavirin retreatment of non-responders
      to IFN and to identify predictors of complete (biochemical and virological)
      sustained response, we performed a meta-analysis of individual data on 581
      patients from 10 centres. Retreatment with various IFN schedules (mean total dose
      544 mega units) and a fixed ribavirin dose (1000-1200 mg/daily depending on body
      weight) was given for 24-60 (mean 39.5) weeks. RESULTS: Biochemical end of
      treatment and sustained responses were observed in 271/581 (46.6%; 95% confidence
      interval (CI) 42.6-50.7%) and in 109/581 (18.7%; 95% CI 15.6-22.0%) cases,
      respectively. Two hundred and six of 532 patients (38.7%; 95% CI 34.6-42.9%) had
      an end of treatment complete response to retreatment while a complete sustained
      response occurred in 88 of 559 (15.7%; 95% CI 12.8-18.8%). Fifty four of 581
      patients (9.2%; 95% CI 7.0-11.7%) stopped retreatment due to adverse effects. By
      logistic regression, complete sustained response was predicted independently by
      age <45 years (p=0.04), by normal pretreatment gamma-glutamyltransferase levels
      (p=0.01), and by a second course total IFN dose of at least 432 mega units
      (p=0.008). CONCLUSIONS: The overall low probability of effectiveness argues
      against indiscriminate retreatment of all IFN monotherapy non-responders with
      IFN/ribavirin. Patients less than 45 years old with normal gamma
      glutamyltransferase levels who were retreated with high dose long course
      combination therapy had a complete sustained response rate of 30%.

PMID- 12427792
TI  - Mechanisms of hyperinsulinaemia in Child's disease grade B liver cirrhosis
      investigated in free living conditions.
AB  - AIMS: Human liver cirrhosis is commonly associated with increased fasting and
      glucose induced insulin concentrations. However, whether the hyperinsulinaemia is
      a consequence of increased pancreatic insulin secretion, decreased hepatic
      insulin removal, or impaired feedback regulation of insulin secretion is still
      doubtful. To investigate these issues, insulin secretion-during 24 hours of
      standardised living conditions-insulin sensitivity, and hepatic insulin
      extraction were assessed in cirrhotic patients compared with matched healthy
      subjects. PATIENTS: Nine Child's disease grade B cirrhotic patients and seven
      healthy volunteers, participated in the study. The subjects were studied on two
      separate days, one for the assessment of insulin secretion during a standardised
      24 hour life period (calorimetric chamber), and one for the determination of
      insulin sensitivity. METHODS: Insulin secretion rates were reconstructed from
      plasma C peptide concentrations by deconvolution, and indices of beta cell
      function were derived using a mathematical model describing the functional
      dependence of insulin secretion on plasma glucose concentrations. Insulin
      sensitivity was determined using the euglycaemic hyperinsulinaemic clamp
      technique. RESULTS: Cirrhotic patients showed a marked hypersecretory response,
      both in absolute terms (mean (SEM) 295 (53) versus 138 (11) nmol/m(2), p<0.02),
      and in relation to glucose (175 (26) versus 57 (5) pmol/min/m(2), p<0.02). In
      particular, the beta cell dose-response function was shifted upward compared with
      controls. The sensitivity of insulin secretion to the rate of glucose change was
      also increased. Insulin sensitivity, markedly reduced in cirrhosis (157 (10)
      versus 296 (30) ml/min/m(2), p<0.002), was strongly inversely correlated (r=0.89,
      p<0.002) in these patients with insulin secretion at 5 mM glucose. Insulin
      clearance and hepatic insulin extraction were not reduced. A frank
      hypermetabolism with increased lipid oxidation was found in this series.
      CONCLUSIONS: This study suggests that hyperinsulinaemia, at least in Child's
      disease grade B cirrhotic patients, is the consequence of increased beta cell
      sensitivity to glucose, while hepatic insulin extraction does not seem to play a
      significant part.

PMID- 12427793
TI  - Prospective study of liver dysfunction in pregnancy in Southwest Wales.
AB  - BACKGROUND: Liver dysfunction in pregnancy has serious consequences. Its
      frequency and characteristics have not been systematically documented in Britain.
      We have prospectively determined incidence, causes, and outcome of liver
      dysfunction in pregnancy in an obstetric unit in Southwest Wales, UK. METHODS: A
      central laboratory identified all abnormal liver tests (bilirubin >25 micro
      mol/l, aspartate transaminase >40 U/l, or gamma glutamyl transpeptidase >35 U/l)
      from patients in antenatal clinics and wards of an obstetric unit serving a
      population of 250 000. Patients with abnormal liver tests were assessed and
      followed throughout and after pregnancy [corrected]. Medical advice was provided
      to obstetric teams. FINDINGS: There were 4377 deliveries during the 15 month
      study. A total of 142 patients had abnormal liver tests. There were 206
      contributing diagnoses, the great majority being pregnancy specific. Among the
      most important were pre-eclampsia (68), HELLP (haemolysis, elevated liver
      enzymes, low platelets) syndrome (30), obstetric cholestasis (23), hyperemesis
      gravidarum (11), acute fatty liver of pregnancy (five), and hepatic infarct
      (one). Sepsis, postoperative factors, and placental pathology (51) were not
      uncommonly responsible but incidental or pre-existing hepatobiliary disease was
      infrequent (17). Sixty five patients were delivered early by induction or
      caesarean section because of liver dysfunction. Despite substantial liver related
      morbidity, there were no maternal deaths and only two intrauterine deaths.
      CONCLUSIONS: Liver dysfunction was seen in 3% of deliveries during a 15 month
      prospective study and was usually directly related to pregnancy with spontaneous
      recovery in the puerperium. Incidence of the most serious conditions, acute fatty
      liver of pregnancy and HELLP syndrome, was much greater than previously reported.
      Profound effects on maternal and infant health were observed but close medical
      and obstetric collaboration ensured low mortality.

PMID- 12427794
TI  - Sacral nerve stimulation for faecal incontinence due to systemic sclerosis.
AB  - BACKGROUND: Faecal incontinence occurs in over one third of patients with
      systemic sclerosis. The aetiology is multifactorial. Conventional treatment is
      often unsuccessful. Sacral nerve stimulation is a new effective treatment for
      resistant faecal incontinence. AIMS: To evaluate sacral nerve stimulation in
      patients with systemic sclerosis. PATIENTS: Five women, median age 61 years (30
      71), with scleroderma associated faecal incontinence were evaluated. All had
      failed maximal conventional treatment. Median number of preoperative weekly
      episodes of incontinence was 15 (7-25), median duration of incontinence was five
      years (5-9), and scleroderma 13 years (4-29). METHODS: All patients were screened
      with temporary stimulation. Those who benefited underwent permanent implantation.
      At baseline and after stimulation a bowel diary, the SF-36 quality of life
      assessment, endoanal ultrasound, and anorectal physiology were performed.
      RESULTS: Four patients were continent at a median follow up of 24 months (6-60).
      One patient failed temporary stimulation and was not permanently implanted. The
      weekly episodes of incontinence decreased from 15, 11, 23, and 7 to 0. Urgency
      resolved (median time to defer <1 minute (0-1) v 12.5 minutes (5-15)). Quality of
      life, especially social function, improved. Endoanal ultrasound showed an
      atrophic internal anal sphincter (median width 1.0 mm (0-1.6)). Anorectal
      physiology showed an increase in median resting pressure (37 pre v 65 cm H(2)O
      post) and squeeze pressure (89 v 105 cm H(2)O). Stimulation produced enhanced
      rectal sensitivity to distension. There were no major complications. CONCLUSIONS:
      Sacral nerve stimulation is a safe and effective treatment for resistant faecal
      incontinence secondary to scleroderma. The benefit is maintained in the medium
      term.

PMID- 12427795
TI  - Accessory left biliary duct draining into the lesser curve of the stomach.

PMID- 12427796
TI  - Functional heartburn: the stimulus, the pain, and the brain.
AB  - Functional heartburn is a common disorder and appears to be composed of several
      distinct subgroups. Identifying the different subgroups based on clinical history
      only is not achievable at present. The mechanisms responsible for pain, clinical
      characteristics, and the optimal therapeutic approach remain poorly understood.
      Response to potent antireflux treatment is relatively limited. Current and future
      treatment strategies for functional heartburn patients who have failed standard
      dose proton pump inhibitors (PPIs) include increased PPI dose in some, as well as
      addition of pain modulators in others.

PMID- 12427797
TI  - Distinction between "high grade MALT" and diffuse large B cell lymphoma. Mucosa
      associated lymphoid tissue.

PMID- 12427798
TI  - Cytokeratin immunoreactivity of intestinal metaplasia.

PMID- 12427799
TI  - Mortality with oesophageal varices: different things to different people.

PMID- 12427800
TI  - Serrated adenomas in FAP. Familial adenomatous polyposis.

PMID- 12427801
TI  - Timing and sampling in surveillance of premalignant gastric lesions.

PMID- 12427802
TI  - Coeliac disease and the risk of autoimmune disorders.

PMID- 12427803
TI  - Non-alcoholic steatohepatitis (NASH): why biopsy?

PMID- 12427804
TI  - Risk of gastric carcinoma in patients with atrophic gastritis and intestinal
      metaplasia.

PMID- 12427805
TI  - Quality improvement guidelines for angiography, angioplasty, and stent placement
      in the diagnosis and treatment of renal artery stenosis in adults.

PMID- 12427806
TI  - Chronic renal ischemia: pathophysiologic mechanisms of cardiovascular and renal
      disease.
AB  - Chronic renal ischemia caused by renal artery stenosis (RAS) elicits a complex
      biologic response. Although the traditional pathophysiologic pathways underlying
      renal ischemia have been well studied, there is emerging evidence that additional
      mechanisms may be responsible for producing many of the hemodynamic alterations
      and end-organ injury seen in patients with RAS, including persistent
      hypertension, renal insufficiency, and cardiac disturbance syndromes. A better
      understanding of these mechanisms may allow earlier identification of RAS,
      provide markers to predict the response to revascularization, or allow unique
      therapeutic targets for drug development. This and a subsequent article will
      explore the pathophysiologic and clinical implications of chronic renal ischemia.

PMID- 12427807
TI  - Declining-dose study of reteplase treatment for lower extremity arterial
      occlusions.
AB  - PURPOSE: To prospectively determine the technical success and complication rates
      of three different reteplase dosing regimens during catheter-directed arterial
      thrombolysis. MATERIALS AND METHODS: Prospective data were obtained from three
      groups of patients who underwent lower extremity arterial thrombolysis with three
      different regimens of reteplase: 0.5 U/h, 0.25 U/h, and 0.125 U/h. A total of 101
      thrombosed lower extremity arterial occlusions in 87 patients were treated. A
      subtherapeutic intravenous heparin dose of 400-500 U/h was administered. All
      limbs were viable at presentation. Thrombolytic success was defined as 95%
      thrombolysis of the occluded artery or graft with restored distal antegrade flow.
      Thirty-day mortality and amputation rates were calculated. Bleeding complications
      and need for transfusions were recorded. Laboratory values recorded included
      fibrinogen level, platelet count, hematocrit level, hemoglobin level, and
      prothrombin time. RESULTS: Thrombolytic success was achieved in 86.7% of patients
      in the 0.5-U/h dose group, 83.8% of patients in the 0.25-U/h dose group, and
      85.3% of patients in the 0.125-U/h dose group. The major bleeding and transfusion
      rates were 13.3% in the 0.5-U/h dose group, 5.4% in the 0.25-U/h dose group, and
      2.9% in the 0.125-U/h dose group. The 30-day amputation-free survival rates were
      90% in the 0.5-U/h dose group, 97.3% in the 0.25-U/h dose group, and 94.1% in the
      0.125-U/h dose group. Pre- and postprocedural fibrinogen levels and the
      fibrinogen nadir were not statistically different between the groups. No
      differences in total infusion times were found between the 0.5-U/h dose and 0.25
      U/h dose groups. However, the infusion time in the 0.125-U/h dose group was
      significantly longer than in the other two groups (42 h vs 30 h; P <.05).
      CONCLUSION: All dosing regimens were equally effective in the treatment of acute
      lower extremity occlusions. The infusion times were longer with the 0.125-U/h
      dose. Significantly fewer major bleeding complications were encountered with the
      0.25-U/h and 0.125-U/h dose regimens than with the 0.5-U/h dose regimen.

PMID- 12427808
TI  - Thrombolysis of occluded peripheral arteries and veins with tenecteplase: a pilot
      study.
AB  - PURPOSE: To prospectively assess the feasibility, risk profile, and effect on
      fibrinogen levels of tenecteplase in transcatheter thrombolysis for peripheral
      arterial and venous occlusive disease. MATERIALS AND METHODS: Between March 2001
      and January 2002, 18 consecutive patients (14 men, four women) with arterial (n =
      13) or venous (n = 5) occlusive disease were treated with tenecteplase infusions
      of 0.25 mg/h. Technical success was defined as restoration of antegrade flow and
      removal of more than 95% of thrombus. Clinical success was defined in arterial
      cases as immediate limb salvage and relief of ischemic rest pain and in venous
      cases as resolution or improvement in extremity pain and swelling. Major bleeding
      was defined as an intracranial bleeding episode, bleeding that resulted in death,
      or bleeding that required transfusion, surgery, or cessation of thrombolytic
      therapy. RESULTS: Technical success was achieved in all 18 patients (100%).
      Clinical success was achieved in 11 of 13 arterial cases (85%) and in four of
      five (80%) venous cases. The mean duration of thrombolysis treatment was 21.5
      hours +/- 6.2 (range, 7-35 h), with total tenecteplase doses of 7.1 mg +/- 4.3
      (range, 1.75-18.75 mg). Major bleeding occurred in one patient (5.5%) because of
      slow oozing from bilateral femoral groin access sites, which caused a 25%
      decrease in hematocrit level. There were no deaths, intracranial hemorrhages,
      remote sites of bleeding, or minor bleeding complications. The serum fibrinogen
      level dropped to a mean of 77.4% +/- 19.2% of baseline. CONCLUSION: In this
      initial study, tenecteplase was shown to be a feasible treatment for peripheral
      arterial and venous thrombolysis with only moderate effect on fibrinogen levels.

PMID- 12427809
TI  - Evaluation of a model to predict poor survival in patients undergoing elective
      TIPS procedures.
AB  - PURPOSE: To validate a previously published model to predict the probability of
      patient death within 3 months after an elective transjugular intrahepatic
      portosystemic shunt (TIPS) procedure. The model is implemented with use of a
      nomogram or a formula. MATERIALS AND METHODS: Patients who underwent an elective
      TIPS procedure between May 1, 1999, and May 1, 2001, were selected. Patients who
      underwent emergency TIPS creation and patients with serum creatinine levels
      greater than 3.0 mg/dL were excluded. A total of 72 patients met the inclusion
      criteria. The patients were divided into two groups: group A (ethanol-induced
      cirrhosis; n = 23) and group B (non-ethanol-induced cirrhosis; n = 49). The model
      was applied and the predicted probability of death was compared to actual patient
      survival. A high risk score (R > or = 1.8) is associated with a high risk of
      death within 3 months after TIPS creation. Survival curves were estimated with
      use of Kaplan-Meier product limit estimates and were compared with use of the log
      rank test. The model's accuracy was evaluated with use of the c-statistic. P
      values lower than.05 indicated statistical significance. RESULTS: The technical
      success rate was 98.7%. The 3-month survival rate for the whole group was 79.7%.
      The predicted mortality rate was higher than the observed mortality rate. The c
      statistic was 0.65 for the formula and 0.66 for the nomogram. Patients with a
      risk score of at least 1.8 had a 3-month survival rate of 54.6% and patients with
      a risk score lower than 1.8 had a 3-month survival rate of 84.9% (P =.037).
      CONCLUSION: These results confirm that, after an elective TIPS procedure,
      patients with risk scores of at least 1.8 have a significantly lower 3-month
      survival rate than patients with risk scores lower than 1.8.

PMID- 12427810
TI  - Arterial problems associated with dysfunctional hemodialysis grafts: evaluation
      of patients at high risk for arterial disease.
AB  - PURPOSE: To retrospectively review the incidence and types of arterial problems
      associated with dysfunctional hemodialysis grafts in patients who are at high
      risk for peripheral arterial disease. MATERIALS AND METHODS: During the 1-year
      period from February 2001 to February 2002, 40 patients with
      polytetrafluoroethylene hemodialysis grafts underwent upper extremity
      arteriography to evaluate arterial inflow to the vascular access. The indication
      for arteriography was based on the presence of at least two of the following risk
      factors for peripheral vascular disease: diabetes mellitus, hypertension, and age
      greater than 65 years. Thirty-three of the 40 patients were women and the median
      age was 65 years. Thirty-three patients had forearm loop-configuration grafts and
      seven had upper-arm grafts. RESULTS: Upper extremity arteriography revealed 13
      arterial inflow lesions in 11 of the 40 patients (28%). Ten patients had stenoses
      at the arterial anastomosis. Two of these patients also had stenoses in the
      brachial artery. One patient had a single stenosis in the brachial artery. Eight
      of the 11 patients (73%) underwent angioplasty of seven arterial anastomotic
      stenoses and three brachial artery stenoses. Comparative analysis revealed that
      the presence of risk factors for atherosclerotic disease did not correlate with
      an increased incidence of arterial inflow problems. Surprisingly, patients with
      diabetes mellitus had a decreased likelihood (P =.03) of having an arterial
      abnormality. CONCLUSION: Although the incidence of arterial anastomotic stenoses
      in our study group was higher than previously reported, patients undergoing
      hemodialysis who have risk factors for peripheral vascular disease do not have a
      high prevalence of native arterial lesions.

PMID- 12427811
TI  - Initial results of endovascular repair of abdominal aortic aneurysms with a self
      expanding stent-graft.
AB  - PURPOSE: This study was performed to evaluate the authors' experience with the
      endovascular treatment of abdominal aortic aneurysm (AAA) with use of a self
      expanding nitinol stent covered with a polyester fabric device and to report the
      implant's technical features, the immediate results, and the outcome 30 days
      after device implantation. MATERIALS AND METHODS: From June 1997 to December
      2001, we admitted 169 patients diagnosed with AAA. Of these, 134 were suitable to
      undergo endovascular repair with use of the Talent stent-graft. In one patient,
      it was technically impossible to proceed with the implantation procedure.
      Therefore, a total of 133 patients were treated with use of this technique
      (78.7%). The average age was 70.7 years (range, 52-88 y). There were 119 men and
      14 women. Computed tomographic follow-up was done between the 15th and 30th
      postoperative days. RESULTS: The stent-grafts were successfully implanted in all
      133 patients. Complications during the procedure included three type-I endoleaks
      (2.3%) and four iliac artery ruptures (3.0%), which were effectively treated by
      means of aortic or iliac extension grafts, respectively. The average surgical
      time was 2.92 hours (from 1.67 h to 7 h). Of the stent-grafts used, 125 were
      bifurcated (94.0%), two were straight tube grafts (1.5%), and six were conical
      aortouniiliac grafts (4.5%). Custom-made grafts were used in 62 patients (46.6%)
      and standard grafts were used in 71 (53.4%). Suprarenal fixation was performed in
      117 patients (88%). One female patient developed a serious pulmonary embolism.
      Eight patients (6.0%) developed serious systemic inflammatory syndrome; two died
      of disseminated intravascular coagulopathy. There were two additional deaths, one
      from refractory shock and one suddenly from an unknown cause (total mortality
      rate, 3.0%). During the postoperative period, 70.3% of the patients developed
      mild fever (37.6 degrees C-38.9 degrees C). The average length of stay in the
      intensive care unit was 1.3 days (ranging from 1 d to 12 d) and the total
      hospitalization time was 4.2 days. Six type-II endoleaks were observed: two were
      corrected by video laparoscopy-assisted inferior mesenteric artery interruption
      and the other four were clinically followed up. CONCLUSIONS: The exclusion of AAA
      by endovascular techniques with use of the Talent device was possible in the
      majority of cases with a low incidence of complications. The most common serious
      postprocedural complication was systemic inflammatory syndrome.

PMID- 12427812
TI  - Embolization of high flow arteriovenous malformations: experience with use of
      superabsorbent polymer microspheres.
AB  - PURPOSE: To determine efficacy, safety, and requirements for adjunctive
      embolization or surgery in the treatment of symptomatic arteriovenous
      malformations (AVMs) with superabsorbent polymer microsphere (SAP-MS) particles.
      MATERIALS AND METHODS: SAP-MS particles (sodium acrylate and vinyl alcohol
      copolymer) are nonbiodegradable spheres with a precisely calibrated diameter. SAP
      MS particles swell by absorbing fluids and become soft and deformable. Twenty
      five patients (16 men, nine women; mean age, 32 y; range 12-66 y) with
      symptomatic facial (n = 5), upper- (n = 8) and lower- (n = 12) extremity AVMs
      were treated primarily (n = 23) or preoperatively (n = 2) by transarterial
      embolization (TAE) treatment with use of SAP-MS particles. Direct puncture
      embolization (DPE; n = 4) and/or surgical intervention (n = 5; ie, skin graft,
      resection, or amputation) were required. Surgical specimens from the resected (n
      = 2) and the amputated (n = 2) patients were evaluated histologically. Follow-up
      study, including clinical findings and imaging studies, was performed at
      intervals ranging from 3 months to 1 year. Clinical outcome was evaluated
      retrospectively, depending on the subjective improvement of symptoms and signs,
      according to the medical records. RESULTS: Seventy-two TAEs (range, 1-11; mean,
      2.8) and 12 DPEs (range, 1-3; mean, 2.4) were performed during the mean follow-up
      period of 38 months (range, 7-110 mo). Twenty patients (80%) experienced symptom
      improvement by embolotherapy alone (n = 17) or in combination with surgery (n =
      3). One lip and two finger AVMs were totally removed by surgical excision or
      amputation after TAE treatment. In diffuse upper- (n = 1) and lower- (n = 1)
      extremity AVMs, the symptoms were uncontrolled. No nerve injury or skin necrosis
      was observed after TAE treatment with SAP-MS particles. Mucosal necrosis was
      induced by DPE with ethanol in one patient. Histologically, SAP-MS particles
      penetrated intralesional vessels and conformed to the vessel lumen, resulting in
      tight vessel occlusion. Minimal perivascular reaction was observed. CONCLUSION:
      SAP-MS particles were used safely in TAE treatment of AVM. TAE treatment with use
      of SAP-MS particles was suitable for certain symptomatic AVMs, but diffuse AVMs
      remain a challenge and a combination of alternative methods will be necessary for
      further strategy.

PMID- 12427813
TI  - Lack of preoperative spinous process tenderness does not affect clinical success
      of percutaneous vertebroplasty.
AB  - PURPOSE: Some operators use the lack of point tenderness over compression
      fractures to exclude patients from undergoing percutaneous vertebroplasty
      procedures. The purpose of this study was to determine whether this lack of
      tenderness portends a poorer clinical outcome after vertebroplasty than is
      achieved in patients with such tenderness. MATERIALS AND METHODS: The authors
      conducted a retrospective review of consecutive percutaneous vertebroplasty
      procedures performed at their institution to define two populations. Group 1
      included 90 patients with tenderness to palpation over the spinous process of the
      fractured vertebra, whereas group 2 included 10 patients without such tenderness.
      This second group presented with back pain and demonstrated tenderness distant
      from the fracture (n = 5), tenderness lateral to the fracture (n = 4), or no
      focal tenderness at all (n = 1). All were treated because of edema seen on
      magnetic resonance (MR) imaging and/or increased activity on bone scan. Clinical
      outcomes were assessed by quantitative measurements of pre- and postoperative
      levels of pain (11-point scale) and mobility (five-point scale). RESULTS: Pain
      improvement of three points or greater occurred in 77 of the 85 patients (91%) in
      group 1 who complied with follow-up and nine of nine such patients (100%) in
      group 2, with mean postoperative pain levels of 1.82 and 0.33 points,
      respectively (P =.14). Forty of 45 patients (89%) in group 1 with impaired
      preoperative mobility reported improvement postoperatively, as did two of three
      such patients (67%) in group 2. Mean levels of postoperative impaired mobility
      for groups 1 and 2 were 0.27 and 0.67 points, respectively (P =.27). CONCLUSION:
      Pain on palpation over the fractured vertebra is not a necessary requirement in
      selecting patients who will benefit from percutaneous vertebroplasty. Other
      factors, such as MR evidence of edema or increased uptake on bone scan, should be
      weighed considerably in the decision to treat a patient.

PMID- 12427814
TI  - Management of unremitting chylothorax by percutaneous embolization and blockage
      of retroperitoneal lymphatic vessels in 42 patients.
AB  - PURPOSE: To demonstrate the applicability, technique, and efficacy of
      percutaneous transabdominal catheter embolization or needle disruption of
      retroperitoneal lymphatic vessels in the treatment of high-output or unremitting
      chylothorax. MATERIALS AND METHODS: Forty-two patients (21 men, 21 women; mean
      age, 56 y; range, 19-80 y) who had chylothorax with various etiologies were
      referred from the thoracic surgery department for treatment as soon as
      chylothorax was documented. The thoracic duct was punctured and catheterized via
      a peritoneal cannula to facilitate embolization with use of microcoils,
      particles, or glue; if there were no lymph trunks that could be catheterized,
      attempts were made to disrupt lymph collaterals with use of needles. RESULTS: The
      thoracic duct was catheterized in 29 patients and embolized in 26 patients. In
      patients with lymph trunks that could be catheterized, treatment resulted in cure
      within 7 days in 16 patients and partial response with cure within 3 weeks in six
      patients. In the patients with lymph trunks that could not be catheterized (n =
      16), disruption with use of needles resulted in cure in five patients and partial
      response in two patients. Cure and partial response rates after thoracic duct
      embolization and needle disruption were 73.8%, with no morbidity. Surgical
      thoracic duct ligation was performed in seven patients. The nonprocedural
      mortality rate was 19%. Follow-up was 3 months or longer. CONCLUSIONS: Effective
      percutaneous treatment of high-output or medically uncontrollable chylothorax was
      performed promptly and safely in more than 70% of referred cases. This procedure
      should be attempted, especially if patients are very ill, before riskier surgical
      thoracic duct ligation is considered.

PMID- 12427815
TI  - The effect of pelvic MR imaging on the diagnosis and treatment of women with
      presumed symptomatic uterine fibroids.
AB  - PURPOSE: To determine if magnetic resonance (MR) imaging significantly alters the
      diagnostic thinking and treatment plans of interventional radiologists during the
      evaluation of women for uterine fibroid embolization (UFE) for presumed uterine
      fibroids. MATERIALS AND METHODS: At a single institution, interventional
      radiologists prospectively completed questionnaires (n = 60) before and after MR
      imaging was performed in their evaluation of women presenting for potential UFE.
      The questionnaires asked these physicians the probability (0%-100%) of their most
      likely diagnosis before MR imaging and after receiving the MR imaging
      information. They were also asked their anticipated and final treatment plans.
      Diagnostic confidence gains and the proportion of patients with changed initial
      diagnoses or anticipated management were calculated. The Wilcoxon signed-rank
      test was used to assess gains in diagnostic confidence. RESULTS: MR imaging
      caused a mean gain in diagnostic confidence of 22% (P <.0001). MR imaging changed
      initial diagnoses in 11 patients (18%). Immediate clinical management changed in
      13 patients (22%). UFE was not performed in 11 of 57 women (19%) who were
      anticipated before MR imaging to receive UFE. CONCLUSIONS: MR imaging
      significantly alters the diagnoses and treatment plans of interventional
      radiologists evaluating women with presumed symptomatic fibroids. MR imaging
      should be considered in all patients before UFE.

PMID- 12427816
TI  - Value of CT volume imaging for optimal placement of radiofrequency ablation
      probes in liver lesions.
AB  - PURPOSE: To determine the value of multiplanar and volume-rendered modes of
      analysis versus axial imaging for the optimal placement of probes in spiral image
      computed tomography (CT)-guided radiofrequency (RF) ablation of liver lesions.
      MATERIALS AND METHODS: Thirty-two malignant hepatic lesions in 21 patients with
      hepatocellular carcinoma (n = 10) or metastases (n = 11) were treated with
      percutaneous RF ablation. After axial CT-guided placement (biopsy mode) of the
      probe in the tumor, a contrast-enhanced spiral image set was obtained and data
      were viewed in contiguous axial sections and the multiplanar and volume-rendered
      modes. The position of the probe was characterized as "central," "marginal," or
      "outside," corresponding with its position in the lesion. Outside positioning was
      corrected before ablation was performed and, in cases of "marginal" positioning,
      the probe was redirected after initial ablative therapy in the same session.
      RESULTS: Multiplanar and volume-rendered analysis reclassified the needle
      position before 14 of 32 RF ablation procedures (44%; P =.0034, McNemar test). In
      10 cases, probe positions considered "central" on biopsy-mode images were found
      to be "marginal" with multiplanar/volume-rendered analysis. In three cases, probe
      positions considered "marginal" on biopsy-mode images were found to be "outside"
      with multiplanar/volume-rendered analysis. In one lesion, multiplanar/volume
      rendered analysis upgraded the probe position from "marginal" to "central."
      Comparison of multiplanar and volume-rendered analysis revealed no difference in
      probe positioning. The time requirements to obtain additional data were 159
      seconds +/- 49 for multiplanar analysis and 434 seconds +/- 78 for volume
      rendered analysis. CONCLUSION: A contrast-enhanced spiral CT image data set with
      multiplanar reformations to verify an optimal probe location after axial CT
      guided needle placement should be obtained before RF ablation of liver lesions.

PMID- 12427817
TI  - Influence of a new prophylactic antibiotic therapy on the incidence of liver
      abscesses after chemoembolization treatment of liver tumors.
AB  - Intrahepatic abscess is a complication of transcatheter arterial
      chemoembolization (TACE) treatment in patients who have a history of biliary
      reconstructive surgery. This study followed eight patients who underwent
      chemoembolization after biliary surgery. These patients were divided into two
      groups. Patients in group one (n = 4) were administered intravenous cephalexin
      for prophylaxis. Patients in group two (n = 4) were administered bowel
      preparation and tazobactam/piperacillin. All patients in group one developed
      hepatic abscesses, which were treated with percutaneous catheter drainage and
      antibiotics. None of the patients in group two developed abscesses. Aggressive
      antibiotic prophylaxis with bowel preparation may provide protection against
      intrahepatic abscesses after chemoembolization in patients who have a history of
      biliary reconstructive surgery.

PMID- 12427818
TI  - Midaortic syndrome associated with fetal alcohol syndrome.
AB  - Midaortic syndrome (MAS) is an uncommon condition characterized by progressive
      narrowing of the abdominal aorta and its branches and impressive formation of
      collateral circulation. It affects children and young adults and presents
      predominantly as untreatable hypertension. Fetal alcohol syndrome (FAS) refers to
      a constellation of physical, behavioral, and cognitive abnormalities secondary to
      alcohol exposure in utero. The authors present an unusual association between a
      hypoplastic abdominal aorta and fetal alcohol syndrome. The patient discussed in
      this article presented with severe hypertension that was successfully treated
      with renal angioplasty.

PMID- 12427819
TI  - Role of thalamocortical sensory suppression during arousal: focusing sensory
      inputs in neocortex.
AB  - The thalamus serves as a gate that regulates the flow of sensory inputs to the
      neocortex, and this gate is controlled by neuromodulators from the brainstem
      reticular formation that are released during arousal. We found recently that
      sensory-evoked responses are suppressed in the neocortex during arousal. This
      sensory suppression results from the activity-dependent depression of the
      thalamocortical connection caused by increased tonic firing of thalamocortical
      cells during arousal. In the present study, the functional consequences of
      thalamocortical suppression during arousal were investigated using the vibrissae
      system of rodents. The results show that thalamocortical suppression is
      associated with a strong reduction in the spread of sensory inputs through the
      cortex, thus reducing the size of sensory representations. In addition, when the
      responses of single cells to principal and adjacent whiskers are compared, the
      response to the adjacent whiskers was found to be strongly suppressed, much more
      so than that of principal whiskers. Consequently, the receptive fields of
      cortical neurons become more focused to the principal whisker. The results
      indicate that thalamocortical suppression during arousal serves to focus sensory
      inputs to their appropriate representations in neocortex, which may be
      computationally helpful for the spatial processing of sensory information.

PMID- 12427820
TI  - Transfer of motor learning across arm configurations.
AB  - It has been suggested that the learning of new dynamics occurs in intrinsic
      coordinates. However, it has also been suggested that elements that encode hand
      velocity, and hence act in an extrinsic frame of reference, play a role in the
      acquisition of dynamics. To reconcile claims regarding the coordinate system
      involved in the representation of dynamics, we have used a procedure involving
      the transfer of force-field learning between two workspace locations. Subjects
      made point-to-point movements while holding a two-link manipulandum. Subjects
      were first trained to make movements in a single direction at the left of the
      workspace. They were then tested for transfer of learning at the right of the
      workspace. Two groups of subjects were defined. For the subjects in group j,
      movements at the left and right workspace locations were matched in terms of
      joint displacements. For the subjects in group h, movements in the two locations
      had the same hand displacements. Workspace locations were chosen such that for
      group j, the paths (for training and testing) that were identical in joint space
      were orthogonal in hand space. The subjects in group j showed good transfer
      between workspace locations, whereas the subjects in group h showed poor
      transfer. These results are in agreement with the idea that new dynamics are
      encoded in intrinsic coordinates and that this learning has a limited range of
      generalization across joint velocities.

PMID- 12427821
TI  - Inverse relationship between release probability and readily releasable vesicles
      in depressing and facilitating synapses.
AB  - We tested the hypothesis that the probability of vesicular exocytosis at synapses
      is positively correlated with the pools of readily releasable synaptic vesicles,
      as shown for mammalian neurons grown in tissue culture. We compared synapses of
      two identified glutamatergic neurons: phasic (high-output, depressing) and tonic
      (low-output, facilitating) crustacean motor neurons, which differ 100- to 1000
      fold in quantal content. Estimates of vesicles available for exocytosis were made
      from depletion during forced release and from electron microscopic observation of
      vesicles docked at synaptic membranes near active zones. Both measurements showed
      a significantly larger pool of readily releasable vesicles in facilitating
      synapses, despite their much lower quantal output during stimulation. Thus, the
      probability for release of docked vesicles is very much lower at facilitating
      synapses, and the presence of more docked vesicles does not predict higher
      synaptic release probability in these paired excitatory neurons.

PMID- 12427822
TI  - Properties of unitary granule cell-->Purkinje cell synapses in adult rat
      cerebellar slices.
AB  - The cerebellar cortex contains huge numbers of synapses between granule cells and
      Purkinje cells. These synapses are thought to be a major storage site for
      information required to execute coordinated movements. To obtain a quantitative
      description of this connection, we recorded unitary synaptic responses between
      granule cell and Purkinje cell pairs in adult rat cerebellar slices. Our results
      are consistent with parallel fiber-->Purkinje cell synapses having high release
      probabilities and modest paired pulse facilitation. However, a wide range of
      response amplitudes was observed. Indeed, we detected many fewer parallel fiber
      connections (7% of the granule cells that were screened) than expected (54%),
      leading us to suggest that up to 85% of parallel fiber-->Purkinje cell synapses
      do not generate detectable electrical responses. We also investigated the
      possible role of granule cell ascending axons by recording granule cells near the
      Purkinje cell. A high proportion (up to 50%) of local granule cells generated
      detectable synaptic responses. However, most of these connections were
      indistinguishable from parallel fiber connections, suggesting that powerful
      ascending axon connections are rare. The existence of many very weak synapses
      would provide a mechanism for Purkinje cells to extract information selectively
      from the mass provided by parallel fibers.

PMID- 12427823
TI  - Two distinct signaling pathways upregulate NMDA receptor responses via two
      distinct metabotropic glutamate receptor subtypes.
AB  - Molecular processes regulating the gain of NMDA receptors modulate diverse
      physiological and pathological responses in the CNS. Group I metabotropic
      glutamate receptors (mGluRs), which neighbor NMDA receptors and which can be
      coactivated by synaptically released glutamate, couple to several different
      second messenger pathways, each of which could target NMDA receptors. In CA3
      pyramidal cells we show that the activation of mGluR1 potentiates NMDA current
      via a G-protein-independent mechanism involving Src kinase activation. In
      contrast, mGluR5-mediated enhancement of NMDA current requires G-protein
      activation, triggering a signaling cascade including protein kinase C and Src.
      These results indicate that one neurotransmitter, glutamate, can activate two
      distinct and independent signaling systems to target the same effector. These two
      pathways are likely to contribute significantly to the highly differentiated
      control of NMDA receptor function.

PMID- 12427824
TI  - NMDA receptor 2 (NR2) C-terminal control of NR open probability regulates
      synaptic transmission and plasticity at a cerebellar synapse.
AB  - The C-terminal domain of NMDA receptor 2 (NR2) subunits has been proposed to play
      a critical role in regulating NMDA receptor localization and function in
      postsynaptic densities. However, the mechanism of this regulation is not
      completely understood. In this paper we show that C-terminal truncation of NR2A
      and NR2C subunits in mice (NR2A/C(DeltaC/DeltaC)) impairs synaptic transmission
      and plasticity at the cerebellar mossy fiber-granule cell relay. Activation of
      synaptic NMDA receptors could be distinguished from that of extrasynaptic
      receptors by using the glutamate scavenger glutamate pyruvate transaminase and
      the open channel blocker MK801. NR2A/C(DeltaC/DeltaC) mice exhibited a specific
      reduction in synaptic NMDA receptor activation attributable to a severalfold
      decrease in channel open probability but not channel conductance. Immunodetection
      revealed normal developmental expression of NR subunit proteins. Quantitative
      immunogold analyses with an antibody to NR1 indicated that the reduction in
      receptor activation is not attributed to a reduced number of NR1-containing
      receptors in postsynaptic densities. Thus, NR2A/NR2C subunits and particularly
      their C termini regulate synaptic NMDA receptor activation and function by
      enhancing channel open probability, which is critical for long-term potentiation
      induction.

PMID- 12427825
TI  - Regional differences in distribution and functional expression of small
      conductance Ca2+-activated K+ channels in rat brain.
AB  - Small-conductance Ca2+-activated K+ (SK) channels are important for excitability
      control and afterhyperpolarizations in vertebrate neurons and have been
      implicated in regulation of the functional state of the forebrain. We have
      examined the distribution, functional expression, and subunit composition of SK
      channels in rat brain. Immunoprecipitation detected solely homotetrameric SK2 and
      SK3 channels in native tissue and their constitutive association with calmodulin.
      Immunohistochemistry revealed a restricted distribution of SK1 and SK2 protein
      with highest densities in subregions of the hippocampus and neocortex. In
      contrast, SK3 protein was distributed more diffusely in these brain regions and
      predominantly expressed in phylogenetically older brain regions. Whole-cell
      recording showed a sharp segregation of apamin-sensitive SK current within the
      hippocampal formation, in agreement with the SK2 distribution, suggesting that
      SK2 homotetramers underlie the apamin-sensitive medium afterhyperpolarizations in
      rat hippocampus.

PMID- 12427826
TI  - Limit on the role of activity in controlling the release-ready supply of synaptic
      vesicles.
AB  - Typical fast chemical synapses in the brain weaken transiently during normal high
      frequency use after expending their presynaptic supply of release-ready vesicles.
      Although it takes several seconds for the readily releasable pool (RRP) to refill
      during periods of rest, it has been suggested that the replenishment process may
      be orders of magnitude faster when synapses are active. Here, we measure this
      replenishment rate at active Schaffer collateral terminals by determining the
      maximum rate of release that can still be elicited when the RRP is almost
      completely exhausted. On average, we find that spent vesicles are replaced at a
      maximum unitary rate of 0.24/sec during periods of intense activity. Because the
      replenishment rate is similar during subsequent periods of rest, we conclude that
      no special mechanism accelerates the mobilization of neurotransmitter in active
      terminals beyond the previously reported, several-fold, residual calcium-driven
      modulation that persists for several seconds after bouts of intense synaptic
      activity. In the course of this analysis, we provide new evidence supporting the
      hypothesis that a simple enzymatic step limits the rate at which reserve synaptic
      vesicles become ready to undergo exocytosis.

PMID- 12427827
TI  - SynGAP regulates ERK/MAPK signaling, synaptic plasticity, and learning in the
      complex with postsynaptic density 95 and NMDA receptor.
AB  - At excitatory synapses, the postsynaptic scaffolding protein postsynaptic density
      95 (PSD-95) couples NMDA receptors (NMDARs) to the Ras GTPase-activating protein
      SynGAP. The close association of SynGAP and NMDARs suggests that SynGAP may have
      an important role in NMDAR-dependent activation of Ras signaling pathways, such
      as the MAP kinase pathway, and in synaptic plasticity. To explore this issue, we
      examined long-term potentiation (LTP), p42 MAPK (ERK2) signaling, and spatial
      learning in mice with a heterozygous null mutation of the SynGAP gene (SynGAP(
      /+)). In SynGAP(-/+) mutant mice, the induction of LTP in the hippocampal CA1
      region was strongly reduced in the absence of any detectable alteration in basal
      synaptic transmission and NMDAR-mediated synaptic currents. Although basal levels
      of activated ERK2 were elevated in hippocampal extracts from SynGAP(-/+) mice,
      NMDAR stimulation still induced a robust increase in ERK activation in slices
      from SynGAP(-/+) mice. Thus, although SynGAP may regulate the ERK pathway, its
      role in LTP most likely involves additional downstream targets. Consistent with
      this, the amount of potentiation induced by stimulation protocols that induce an
      ERK-independent form of LTP were also significantly reduced in slices from
      SynGAP(-/+) mice. An elevation of basal phospho-ERK2 levels and LTP deficits were
      also observed in SynGAP(-/+)/H-Ras(-)/- double mutants, suggesting that SynGAP
      may normally regulate Ras isoforms other than H-Ras. A comparison of SynGAP and
      PSD-95 mutants suggests that PSD-95 couples NMDARs to multiple downstream
      signaling pathways with very different roles in LTP and learning.

PMID- 12427828
TI  - Tau-mediated cytotoxicity in a pseudohyperphosphorylation model of Alzheimer's
      disease.
AB  - Aggregation and increased phosphorylation of tau at selected sites
      ("hyperphosphorylation") are histopathological hallmarks of Alzheimer's disease
      (AD). However, it is not known whether the tau pathology has a primary role
      during neuronal degeneration. To determine the role of tau hyperphosphorylation
      in AD, pseudohyperphosphorylated tau (PHP-tau) that simulates disease-like
      permanent, high stoichiometric tau phosphorylation and mimics structural and
      functional aspects of hyperphosphorylated tau was expressed in neural cells. In
      differentiated PC12 cells, PHP-tau exhibited reduced microtubule interaction and
      failed to stabilize the microtubule network compared with exogenously expressed
      wild-type tau (wt-tau). During longer culture, PHP-tau exerted a cytotoxic
      effect, whereas wt-tau was neutral. PHP-tau-mediated cytotoxicity was associated
      with an induction of apoptotic cell death as characterized by chromatin
      condensation, DNA fragmentation, and caspase-3 activation in the absence of
      detectable protein aggregates. Furthermore, PHP-tau expression specifically
      sensitized the cells for other apoptotic stimuli (colchicine and staurosporine).
      Herpes simplex virus-mediated overexpression of PHP-tau induced degeneration
      associated with an induction of apoptotic mechanisms also in terminally
      differentiated human CNS model neurons. Partially pseudophosphorylated constructs
      caused an intermediate toxicity. The data provide evidence for a neurotoxic "gain
      of function" of soluble tau during AD as a result of structural changes that are
      induced by a cumulative, high stoichiometric tau phosphorylation. PHP-tau
      expressing cells and organisms could provide a useful system to identify
      mechanisms that contribute to tau-mediated toxicity.

PMID- 12427829
TI  - Cannabinoids promote oligodendrocyte progenitor survival: involvement of
      cannabinoid receptors and phosphatidylinositol-3 kinase/Akt signaling.
AB  - Cannabinoids exert pleiotropic actions in the CNS, including the inhibition of
      inflammatory responses and the enhancement of neuronal survival after injury.
      Although cannabinoid receptors are distributed widely in brain, their presence
      has not been investigated previously in oligodendrocytes. This study examined the
      expression of cannabinoid type 1 (CB1) receptors in rat oligodendrocytes in vivo
      and in culture and explored their biological function. Expression of CB1
      receptors by oligodendrocytes was demonstrated immunocytochemically in postnatal
      and in adult white matter as well as in oligodendrocyte cultures. Reverse
      transcription-PCR and Western blotting further confirmed the presence of CB1
      receptors. Oligodendrocyte progenitors undergo apoptosis with the withdrawal of
      trophic support, as determined by TUNEL assay and caspase-3 activation, and both
      the selective CB1 agonist arachidonyl-2'-chloroethylamide/(all Z)-N-(2
      cycloethyl)-5,8,11,14-eicosatetraenamide (ACEA) and the nonselective cannabinoid
      agonists HU210 and (+)-Win-55212-2 enhanced cell survival. To investigate
      intracellular signaling involved in cannabinoid protection, we focused on the
      phosphatidylinositol-3 kinase (PI3K)/Akt pathway. HU210, (+)-Win-55212-2, and
      ACEA elicited a time-dependent phosphorylation of Akt. Pertussis toxin abolished
      Akt activation, indicating the involvement of G(i)/G(o)-protein-coupled
      receptors. The CB1 receptor antagonist SR141716A partially inhibited Akt
      phosphorylation in response to HU210 and (+)-Win-55212-2 and abolished the
      effects of ACEA. Trophic support deprivation downregulated Akt activity, and
      cannabinoids recovered phospho-Akt levels. Inhibition of PI3K abrogated the
      survival action and the recovery of Akt activity in response to cannabinoids.
      SR141716A prevented only the protection conferred by ACEA. Nevertheless,
      SR141716A and the selective CB2 receptor antagonist SR144528 in combination
      inhibited the prosurvival action of HU210, which is in accordance with the
      finding of CB2 receptor expression by oligodendroglial cells. These data identify
      oligodendrocytes as potential targets of cannabinoid action in the CNS.

PMID- 12427830
TI  - Increased expression of brain-derived neurotrophic factor induces formation of
      basal dendrites and axonal branching in dentate granule cells in hippocampal
      explant cultures.
AB  - During limbic epileptogenesis in vivo the dentate granule cells (DGCs) exhibit
      increased expression of brain-derived neurotrophic factor (BDNF), followed by
      striking morphologic plasticities, namely the formation of basal dendrites and
      the sprouting of mossy fibers. We hypothesized that increased expression of BDNF
      intrinsic to DGCs is sufficient to induce these plasticities. To test this
      hypothesis, we transfected DGCs in rat hippocampal slice cultures with BDNF or
      nerve growth factor (NGF) via particle-mediated gene transfer, and we visualized
      the neuronal processes with cotransfected green fluorescent protein. Transfection
      with BDNF produced significant increases in axonal branch and basal dendrite
      number relative to NGF or empty vector controls. Structural changes were
      prevented by the tyrosine kinase inhibitor K252a. Thus increased expression of
      BDNF within DGCs is sufficient to induce these morphological plasticities, which
      may represent one mechanism by which BDNF promotes limbic epileptogenesis.

PMID- 12427831
TI  - Amyloid-beta induces Smac release via AP-1/Bim activation in cerebral endothelial
      cells.
AB  - Insoluble fibrils of amyloid-beta peptide (Abeta) are the major component of
      senile and vascular plaques found in the brains of Alzheimer's disease (AD)
      patients. Abeta has been implicated in neuronal and vascular degeneration because
      of its toxicity to neurons and endothelial cells in vitro; some of these cells
      die with characteristic features of apoptosis. We used primary cultures of murine
      cerebral endothelial cells (CECs) to explore the mechanisms involved in Abeta
      induced cell death. We report here that Abeta(25-35), a cytotoxic fragment of
      Abeta, induced translocation of the apoptosis regulator termed second
      mitochondria-derived activator of caspase (Smac) from the intramembranous
      compartment of the mitochondria to the cytosol 24 hr after exposure. In addition,
      we demonstrated that X chromosome-linked inhibitor-of-apoptosis protein (XIAP)
      coimmunoprecipitated with Smac, suggesting that the two proteins bound to one
      another subsequent to the release of Smac from the mitochondria. Abeta(25-35)
      treatment also led to rapid AP-1 activation and subsequent expression of Bim, a
      member of the BH3-only family of proapoptotic proteins. Bim knockdown using an
      antisense oligonucleotide strategy suppressed Abeta(25-35)-induced Smac release
      and resulted in attenuation of CEC death. Furthermore, AP-1 inhibition, with
      curcumin or c-fos antisense oligonucleotide, reduced bim expression. These
      results suggest that Abeta activates an apoptotic cascade involving AP-1 DNA
      binding, subsequent bim induction, followed by Smac release and binding to XIAP,
      resulting in CEC death.

PMID- 12427832
TI  - Increased severity of stroke in CB1 cannabinoid receptor knock-out mice.
AB  - Endogenous cannabinoid signaling pathways have been implicated in protection of
      the brain from hypoxia, ischemia, and trauma, but the mechanism for these
      protective effects is uncertain. We found that in CB1 cannabinoid receptor knock
      out mice, mortality from permanent focal cerebral ischemia was increased, infarct
      size and neurological deficits after transient focal cerebral ischemia were more
      severe, cerebral blood flow in the ischemic penumbra during reperfusion was
      reduced, and NMDA neurotoxicity was increased compared with wild-type
      littermates. These findings indicate that endogenous cannabinoid signaling
      pathways protect mice from ischemic stroke by a mechanism that involves CB1
      receptors, and suggest that both blood vessels and neurons may be targets of this
      protective effect.

PMID- 12427833
TI  - Rab11a and myosin Vb regulate recycling of the M4 muscarinic acetylcholine
      receptor.
AB  - Agonist-induced internalization followed by subsequent return to the cell surface
      regulates G-protein-coupled receptor (GPCR) activity. Because the cellular
      responsiveness to ligand depends on the balance between receptor degradation and
      recycling, it is crucial to identify the molecules involved in GPCR recovery to
      the cell surface. In this study, we identify mechanisms involved in the recycling
      of the M4 subtype of muscarinic acetylcholine receptor. M4 is highly expressed in
      the CNS, plays a role in locomotor activity, and is a novel therapeutic target
      for neurologic and psychiatric disorders. Previous studies show that, after
      cholinergic stimulation, M4 internalizes from the cell surface to endosomes in
      cell culture and the rat brain. Here, we show that, after activation, M4 traffics
      to transferrin receptor- and Rab11a-positive perinuclear endosomes. Expression of
      the constitutively GDP-bound, inactive mutant Rab11aS25N inhibits M4 trafficking
      to recycling endosomes. Expression of the C-terminal tail of myosin Vb, a Rab11a
      effector, enhances M4 accumulation in perinuclear endosomes. Both Rab11aS25N and
      the myosin Vb tail impair M4 recycling. The results demonstrate that GPCR
      recycling is mediated through a discrete pathway using both Rab11a and myosin Vb.

PMID- 12427834
TI  - Evidence that synaptically released beta-amyloid accumulates as extracellular
      deposits in the hippocampus of transgenic mice.
AB  - A neuropathological hallmark of Alzheimer's disease is the deposition of amyloid
      beta (Abeta) peptides in senile plaques in the hippocampus and cerebral cortex.
      Abeta is derived from larger integral membrane proteins termed amyloid precursor
      proteins (APP). We demonstrated previously that APP, synthesized by neurons in
      the entorhinal cortex, is transported via the perforant pathway to presynaptic
      terminals in the dentate gyrus. We reported that, although full-length APP and
      membrane-tethered, C-terminal APP derivatives (APP-CTFs) accumulate at terminal
      fields, the production of Abeta peptides at these sites was indeterminate. To
      test the hypothesis that APP-CTFs, generated from axonally transported APP, are
      further metabolized to Abeta peptides that are subsequently released and
      deposited proximal to nerve terminals, we created unilateral knife lesions of the
      perforant pathway of transgenic mice that exhibit hippocampal amyloid deposits.
      We observed pronounced reductions in amyloid burden in the ipsilateral dentate
      gyrus, findings that lead us to conclude that axonally transported APP gives rise
      to Abeta peptides that are released from presynaptic sites in the dentate gyrus
      and deposited in extracellular plaques. Moreover, our findings are consistent
      with the view that Abeta deposits are dynamic structures and that the perforant
      path lesion alters the equilibrium between Abeta production-deposition toward
      clearance as a consequence of blocked axonal transport of APP from the entorhinal
      cortex to terminal fields in the hippocampus.

PMID- 12427835
TI  - Disruption of corticocortical connections ameliorates amyloid burden in terminal
      fields in a transgenic model of Abeta amyloidosis.
AB  - We demonstrated previously that amyloid precursor protein (APP) is anterogradely
      transported from the entorhinal cortex (ERC) to the dentate gyrus via axons of
      the perforant pathway. In the terminal fields of these inputs, APP undergoes
      proteolysis to generate C-terminal fragments containing the entire amyloid beta
      peptide (Abeta) domain. The present study was designed to test the hypothesis
      that APP derived from ERC neurons is the source of the Abeta peptide deposited in
      the hippocampal dentate gyrus in Alzheimer's disease (AD) and in transgenic mice
      with Abeta amyloidosis. We used mice harboring two familial AD-linked genes
      (human APP Swedish and presenilin1-DeltaE9), in which levels of Abeta (especially
      Abeta(42)) are elevated, leading to the formation of amyloid plaques, and
      lesioned the ERC to interrupt the transport of APP from ERC to hippocampus. Our
      results show that, on the side of ERC lesion, numbers of APP-immunoreactive
      dystrophic neurites and Abeta burden were significantly reduced by approximately
      40 and 45%, respectively, in the dentate gyrus compared with the contralateral
      side. Reductions in APP and Abeta were more substantial in the molecular layer of
      the dentate, i.e., a region that contains the ERC terminals, and were associated
      with a parallel decrease in total APP and Abeta measured by Western blot and
      ProteinChip immunoassays. Silver and thioflavine staining confirmed the reduction
      of amyloid plaques on the side of deafferentation. These results are consistent
      with the hypothesis that ERC may be the primary source of amyloidogenic Abeta in
      the dentate gyrus, and they suggest an important role of corticocortical and
      corticolimbic forward connections in determining patterns of amyloid deposition
      in AD.

PMID- 12427836
TI  - p73 is required for survival and maintenance of CNS neurons.
AB  - Here, we show that the p53 family member, p73, is necessary for survival and long
      term maintenance of CNS neurons, including postnatal cortical neurons. In p73-/-
      animals, cortical neuron number is normal at birth but decreases significantly by
      postnatal day 14 (P14)-P16 because of enhanced apoptosis. This decrease continues
      into adulthood, when p73-/- animals have approximately one-half as many cortical
      cells as their wild-type littermates. Cortical neurons express the DeltaNp73alpha
      protein, and overexpression of DeltaNp73 isoforms rescues cortical neurons from
      diverse apoptotic stimuli. Thus, DeltaNp73 isoforms are survival proteins in
      cortical neurons, and their deletion causes a gradual loss of cortical neurons in
      the weeks and months after birth. This decrease in CNS neuron number in p73-/-
      animals is not limited to the cortex; facial motor neuron number is decreased,
      and postnatal development of the olfactory bulb is greatly perturbed. These
      findings, together with our previous work showing that DeltaNp73 is essential for
      survival of peripheral sympathetic neurons (Pozniak et al., 2000), indicate that
      p73 isoforms are essential survival proteins in CNS as well as PNS neurons, and
      that they likely play a role not only during developmental cell death but also in
      the long-term maintenance of at least some adult neurons.

PMID- 12427837
TI  - Ammonium-induced impairment of axonal growth is prevented through glial creatine.
AB  - Hyperammonemia in neonates and infants affects brain development and causes
      mental retardation. We report that ammonium impaired cholinergic axonal growth
      and altered localization and phosphorylation of intermediate neurofilament
      protein in rat reaggregated brain cell primary cultures. This effect was
      restricted to the phase of early maturation but did not occur after
      synaptogenesis. Exposure to NH4Cl decreased intracellular creatine,
      phosphocreatine, and ADP. We demonstrate that creatine cotreatment protected
      axons from ammonium toxic effects, although this did not restore high-energy
      phosphates. The protection by creatine was glial cell-dependent. Our findings
      suggest that the means to efficiently sustain CNS creatine concentration in
      hyperammonemic neonates and infants should be assessed to prevent impairment of
      axonogenesis and irreversible brain damage.

PMID- 12427838
TI  - Subpallial dlx2-expressing cells give rise to astrocytes and oligodendrocytes in
      the cerebral cortex and white matter.
AB  - The precise origins of postnatal subventricular zone (SVZ) cells are not known.
      Furthermore, the gliogenic potential of progenitors expressing Dlx genes that
      migrate ventrodorsally from the ganglionic eminences has not been explored in
      vivo. Here, we identify the embryonic origins of two distinct populations of
      postnatal SVZ cells: SVZ border cells, which express Zebrin II, and migratory
      cells in the central SVZ, which are generally devoid of Zebrin II expression
      (Staugaitis et al., 2001). Zebrin II is expressed by all cells of the
      telencephalic primordium, with its expression becoming restricted to astrocytes
      in the mature telencephalon. As the neuroepithelium folds during corticostriatal
      sulcus formation (embryonic day 13-15), a wedge of Zebrin II+ cells is created at
      the presumptive site of the dorsolateral SVZ. At this time, Dlx2-expressing cells
      and their progeny begin to migrate ventrodorsally along a medial path from the
      ganglionic eminences. These migratory subpallial cells invade the wedge of Zebrin
      II+ cells to form the central region of the SVZ. We used a Dlx2/tauLacZ knock-in
      to perform a short-term lineage analysis of Dlx2-expressing cells throughout SVZ
      formation and the postnatal peak of gliogenesis. Dlx2/tauLacZ [beta-galactosidase
      (beta-gal)]-expressing cells populate the central SVZ, whereas Zebrin II
      expressing cells form its borders. Furthermore, beta-gal expression demonstrates
      a lineage relationship between Dlx2-expressing cells and glia residing in the
      dorsal telencephalon. We propose a model for the formation of the postnatal SVZ
      and demonstrate that subpallium-derived Dlx2-expressing cells give rise to
      astrocytes and oligodendrocytes in the white matter and cerebral cortex.

PMID- 12427840
TI  - Dopamine-dependent desensitization of dopaminergic signaling in the developing
      mouse striatum.
AB  - The dynamics of dopamine receptor signaling efficacy were characterized in
      developing mice by measuring striatal c-Fos expression after dopaminergic agonist
      treatment at postnatal day 4 (P4) to P18. Control mice and mutant mice, in which
      dopamine production is inactivated in dopaminergic neurons by gene targeting,
      were treated with saline; a synthetic dopamine precursor, L-3,4
      dihydroxyphenylalanine (L-DOPA) methyl ester; a direct dopamine D(1) receptor
      agonist, N-allyl-SKF 38393; or a dopamine reuptake inhibitor, cocaine. L-DOPA
      methyl ester treatment failed to induce striatal c-Fos immunoreactivity in
      control and mutant mice deficient in dopamine production at P4 and P6 compared
      with saline treatment. However, at P10 through P18 it induced abundant c-Fos
      expression in mutants. At these later stages, c-Fos expression remained at basal
      levels in control mice after L-DOPA methyl ester treatment. Control and mutant
      mice responded to D1 receptor agonist administration to a similar degree at P4
      and P6, but the responses were greatly enhanced in mutants at later stages.
      Cocaine treatment elicited expression in control mice at P10 through P18 but not
      at P4 and P6. Mutant mice were largely unresponsive to cocaine treatment. The
      results suggest that striatal dopamine receptors are capable of transducing
      extracellular signals at P4 and P6, but dopaminergic neurotransmission begins
      thereafter. Dopaminoceptive neurons appear to reduce their sensitivity to
      dopamine as dopaminergic terminals innervate the striatum and functional
      neurotransmission begins.

PMID- 12427839
TI  - A novel cytokine pathway suppresses glial cell melanogenesis after injury to
      adult nerve.
AB  - The neural crest gives rise to numerous cell types, including Schwann cells,
      neurons, and melanocytes. The extent to which adult neural crest-derived cells
      retain plasticity has not been tested previously. We report that cutting adult
      mouse sciatic nerve induces pigmentation around nerve fascicles, among muscle
      bundles, and in the hypodermis. Pigmented cells are derived from adult nerve,
      because pigmentation occurs even when nerve fragments are grafted into tyrosinase
      null albino mice. Pigmentation defects are pervasive in patients with
      neurofibromatosis type 1 (NF1). Mice hemizygous for Nf1 mutations show enhanced
      pigmentation after nerve lesion and occasionally form pigmented and unpigmented
      tumors. The Nf1 nerve and the Nf1 host environment both contribute to enhanced
      pigmentation. Grafted purified Nf1 mutant glial cells [S100(+)-p75NGFR(+)-GFAP(+)
      EGFR(+) or S100(+)-p75NGFR(+)-GFAP(+)-EGFR(-)] mimic nerve-derived pigmentation.
      The NF1 protein, neurofibromin, is a Ras-GAP that acts downstream of a few
      defined receptor tyrosine kinases, including [beta-common (beta(c))] the shared
      common receptor for granulocyte and monocyte colony-stimulating factor,
      interleukin-3 (IL3), and IL5. Cytokines in the environment have the potential to
      suppress pigmentation as shown by nerve injury experiments in null mice; when is
      beta(c) absent or Nf1 is mutant, melanogenesis is increased. Thus, the adult
      nerve glial cell phenotype is maintained after nerve injury by response to
      cytokines, through neurofibromin.

PMID- 12427841
TI  - Internal shearing within the hearing organ evoked by basilar membrane motion.
AB  - The vibration of the hearing organ that occurs during sound stimulation is based
      on mechanical interactions between different cellular structures inside the organ
      of Corti. The exact nature of these interactions is unclear and subject to
      debate. In this study, dynamic structural changes were produced by stepwise
      alterations of scala tympani pressure in an in vitro preparation of the guinea
      pig temporal bone. Confocal images were acquired at each level of pressure. In
      this way, the motion of several structures could be observed simultaneously with
      high resolution in a nearly intact system. Images were analyzed using a novel
      wavelet-based optical flow estimation algorithm. Under these conditions, the
      reticular lamina moved as a stiff plate with a center of rotation in the region
      of the inner hair cells. Despite being enclosed in several types of supporting
      cells, the inner hair cells, together with the adjacent inner pillar cells, moved
      in a manner signifying high compliance. The outer hair cells displayed radial
      motion indicative of cellular bending. Together, these results show that shearing
      motion occurs between several parts of the organ, and that structural
      relationships within the organ change dynamically during displacement of the
      basilar membrane.

PMID- 12427842
TI  - Selective mediation of nerve injury-induced tactile hypersensitivity by
      neuropeptide Y.
AB  - Prevention of nerve injury-induced tactile, but not thermal, hypersensitivity is
      achieved by ipsilateral lesions of the dorsal columns or lidocaine microinjection
      into the nucleus gracilis (n. gracilis). These and other data support the
      possibility that tactile hyperresponsiveness after nerve injury may be
      selectively mediated by a low-threshold myelinated fiber pathway to the n.
      gracilis. Here we identify a transmitter that might selectively mediate such
      injury-induced tactile hypersensitivity. Neuropeptide Y (NPY), normally not
      detected in the dorsal root ganglion (DRG) or in the n. gracilis of rats, became
      markedly upregulated at both sites and in the spinal cord after spinal nerve
      injury. Injury-induced NPY-IR occurred predominately in large-diameter DRG cells,
      and the NPY-IR in the n. gracilis was blocked by dorsal rhizotomy or dorsal
      column lesion. NPY microinjection into the n. gracilis of uninjured rats elicited
      reversible tactile, but not thermal, hypersensitivity only in the ipsilateral
      hindpaw. Administration of anti-NPY antiserum, but not control serum or
      preabsorbed serum, into the n. gracilis ipsilateral to nerve injury reversed
      tactile, but not thermal, hypersensitivity. Similarly, microinjection of the NPY
      antagonists NPY(18-36) and (R)-N-[[4-(aminocarbonylaminomethyl)-phenyl]methyl]-N2
      (diphenylacetyl)-argininamide trifluoroacetate, into the n. gracilis ipsilateral
      to the injury reversed tactile, but not thermal, hypersensitivity. Antagonist
      administration into the contralateral n. gracilis had no effect on injury-induced
      hypersensitivity. These data suggest the selective mediation of nerve injury
      induced tactile hypersensitivity by upregulated NPY via large fiber input to n.
      gracilis. Selective reversal of injury-induced tactile allodynia by NPY receptor
      antagonists would have significant implications for human neuropathic conditions.

PMID- 12427843
TI  - Localization of phosphorylated cAMP response element-binding protein in immature
      neurons of adult hippocampus.
AB  - Neurogenesis continues to occur in the adult hippocampus, although many of the
      newborn cells degenerate 1-2 weeks after birth. The number and survival of
      newborn cells are regulated by a variety of environmental stimuli, but very
      little is known about the intracellular signal transduction pathways that control
      adult neurogenesis. In the present study, we examine the expression of the
      phosphorylated cAMP response element-binding protein (pCREB) in immature neurons
      in adult hippocampus and the role of the cAMP cascade in the survival of new
      neurons. The results demonstrate that virtually all immature neurons, identified
      by triple immunohistochemistry for bromodeoxyuridine (BrdU) and polysialic acid
      neural cell adhesion molecule (PSA-NCAM), are also positive for pCREB. In
      addition, upregulation of cAMP (via pharmacological inhibition of cAMP breakdown
      or by antidepressant treatment) increases the survival of BrdU-positive cells. A
      possible role for pCREB in the regulation of PSA-NCAM, a marker of immature
      neurons involved in neuronal remodeling and neurite outgrowth, is supported by
      cell culture studies demonstrating that the cAMP-CREB pathway regulates the
      expression of a rate-limiting enzyme responsible for the synthesis of PSA-NCAM.
      These findings indicate that the cAMP-CREB pathway regulates the survival, and
      possibly the differentiation and function, of newborn neurons.

PMID- 12427844
TI  - Saccadic target selection deficits after lateral intraparietal area inactivation
      in monkeys.
AB  - We investigated the contribution of the lateral intraparietal area (LIP) to the
      selection of saccadic eye movement targets and to saccade execution using
      muscimol-induced reversible inactivation and compared those effects with
      inactivation of the adjacent ventral intraparietal area (VIP) and with sham
      injections of saline into LIP. Three types of tasks were used: saccades to single
      visual or memorized targets, saccades to synchronous and asynchronous bilateral
      targets, and visual search of a target among distractors. LIP inactivation failed
      to produce deficits in the latency or accuracy of saccades to single targets, but
      it dramatically reduced the frequency of contralateral saccades in the presence
      of bilateral targets, and it increased search time for a contralateral target
      during serial visual search. In the latter task, the observed deficits might
      reflect either an ispilateral bias in saccadic search strategy or an attentional
      impairment in locating a target among flanking distractors within the
      contralateral field. No effects were observed on any of these tasks after VIP
      inactivation. These results suggest that one important contribution of LIP to
      oculomotor behavior is the selection of targets for saccades in the context of
      competing visual stimuli.

PMID- 12427845
TI  - Thalamocortical bursts trigger recurrent activity in neocortical networks: layer
      4 as a frequency-dependent gate.
AB  - Sensory information reaches the cortex via thalamocortical (TC) synapses in layer
      4. Thalamic relay neurons that mediate information flow to cortex operate in two
      distinct modes, tonic and burst firing. Burst firing has been implicated in
      enhancing reliability of information flow between individual neurons. However,
      little is known about how local networks of neocortical neurons respond to
      different temporal patterns of TC activity. We studied cortical activity patterns
      evoked by stimulating TC afferents at different frequencies, using a combination
      of electrophysiology and calcium imaging in TC slices that allowed for the
      reconstruction of spatiotemporal activity with single-cell resolution.
      Stimulation of TC axons at low frequencies triggered action potentials in only a
      small number of layer 4 neurons. In contrast, brief high-frequency stimulus
      trains triggered widespread recurrent activity in populations of neurons in layer
      4 and then spread into adjacent layers 2/3 and 5. Recurrent activity had a clear
      threshold, typically lasted 300 msec, and could be evoked repetitively at
      frequencies up to 0.5 Hz. Moreover, the spatial extent of recurrent activity was
      controlled by the TC pattern of activity. Recurrent activity triggered within the
      highly interconnected networks of layer 4 might act to selectively amplify and
      redistribute transient high-frequency TC inputs, filter out low-frequency inputs,
      and temporarily preserve a record of past sensory activity.

PMID- 12427846
TI  - Rewarding effects of the cholinergic agents carbachol and neostigmine in the
      posterior ventral tegmental area.
AB  - Rats learned to lever-press for microinjections of the cholinergic agonist
      carbachol (30-500 pmol per infusion) or the acetylcholinesterase inhibitor
      neostigmine (7.5-75 pmol per infusion) into the posterior ventral tegmental area
      (VTA) of the brain. Intracranial carbachol self-administration was site-specific.
      Carbachol was not reliably self-administered into a site just dorsal to the VTA
      or into the adjacent substantia nigra and was self-administered only weakly into
      the adjacent anterior VTA or interpeduncular nucleus. Carbachol produced
      conditioned place preferences when injected into the posterior but not into the
      anterior VTA or sites dorsal to the posterior VTA. Rats self-administered
      carbachol less when it was co-infused with the muscarinic cholinergic receptor
      antagonist scopolamine or the nicotinic cholinergic receptor antagonist dihydro
      beta-erythroidine, and also when the rats were pretreated with the D1 dopamine
      antagonist SCH 23390. These findings implicate both nicotinic and muscarinic
      cholinergic neurotransmission in ventral tegmental reward function and suggest
      special involvement of the posterior portion of the VTA in cholinergic reward
      function.

PMID- 12427847
TI  - Conditional rescue of protein kinase C epsilon regulates ethanol preference and
      hypnotic sensitivity in adult mice.
AB  - Conventional gene targeting is a powerful tool to study the influence of specific
      genes on behavior. However, conclusions relevant for adult animals are limited by
      consequences of gene loss during development. Mice lacking protein kinase C
      epsilon (PKCepsilon) consume less alcohol and show greater acute sensitivity to
      alcohol than do wild-type mice. There are no selective inhibitors of PKCepsilon
      that can be administered systemically and cross the blood-brain barrier to test
      whether these phenotypes result from loss of PKCepsilon during development or in
      adulthood. Here we used conditional expression of PKCepsilon in the basal
      forebrain, amygdala, and cerebellum to rescue wild-type responses to alcohol in
      adult PKCepsilon(-/-) mice. Subsequent suppression of transgenic PKCepsilon
      restored PKCepsilon(-/-) behaviors. These findings establish that PKCepsilon
      signaling in the adult brain regulates alcohol consumption and sensitivity. If
      this extends to humans, then PKCepsilon inhibitors might prove useful as novel
      therapeutics for alcoholism.

PMID- 12427848
TI  - Mechanisms of amygdala modulation of hippocampal plasticity.
AB  - Basolateral amygdala (BLA) activation by emotional arousal modulates memory
      related processes in the hippocampus. We have shown (Akirav and Richter-Levin,
      1999b) that activating the BLA before perforant path (PP) tetanization has a
      biphasic effect on hippocampal plasticity; priming the BLA immediately before PP
      tetanization results in the enhancement of dentate gyrus (DG) long-term
      potentiation (LTP) (an "emotional tag"), whereas stimulation in a spaced interval
      results in the suppression of DG-LTP. Here, we aimed to elucidate the mechanisms
      underlying BLA modulation of DG-LTP and specifically to examine whether the
      stress hormones norepinephrine (NE) and corticosterone (CORT) are main mediators
      of the BLA biphasic effects. We found that the BLA affects hippocampal plasticity
      in a complex manner; BLA priming enhanced DG-LTP, and both NE and CORT mediated
      this effect. Furthermore, we found that ipsilateral BLA spaced activation (2 hr
      before PP tetanization) suppressed DG-LTP and that this suppressive effect was
      also mediated by NE and CORT. Priming the contralateral BLA enhanced DG-LTP
      similarly to the ipsilateral enhancement, but neither NE nor CORT mediated this
      effect. The spaced activation of the contralateral BLA did not suppress DG-LTP.
      Taken together, these results suggest that differential mechanisms underlie the
      ipsilateral and contralateral BLA effects on hippocampal plasticity. Hence, the
      BLA modulates hippocampal memory processes, presumably via the mediation of the
      stress hormones NE and CORT, to establish a diverse memory of the experience.
      Possibly, at the onset of an emotional event the stress hormones permissively
      mediate plasticity. However, their prolonged presence in the system may suppress
      the cognitive response to stress.

PMID- 12427849
TI  - Divergent GABA(A) receptor-mediated synaptic transmission in genetically seizure
      prone and seizure-resistant rats.
AB  - Recent evidence suggests that abnormal expression of GABA(A) receptors may
      underlie epileptogenesis. We observed previously that rats selectively bred to be
      seizure-prone naturally overexpressed, as adults, GABA alpha subunits (alpha2,
      alpha3, and alpha5) seen at birth, whereas those selected to be seizure-resistant
      overexpressed the adult, alpha1 subunit. In this experiment, we gathered GABA
      miniature IPSCs (mIPSCs) from these strains and correlated their attributes with
      the subunit expression profile of each strain compared with a normal control
      strain. The mIPSCs were collected from both cortical pyramidal and nonpyramidal
      neurons. In seizure-prone rats, mIPSCs were smaller and decayed more slowly than
      in normal rats, which in turn were smaller and slower than in seizure-resistant
      rats. A detailed analysis of individual mIPSCs revealed two kinds of postsynaptic
      responses (those with monoexponential vs biexponential decay) that were
      differentially altered in the three strains. The properties of monoexponentially
      decaying mIPSCs did not differ between pyramidal and nonpyramidal neurons within
      a strain but differed between strains. In contrast, an interaction was observed
      between cell morphology and strain for biexponentially decaying mIPSCs. Here, the
      mIPSCs of pyramidal neurons in the seizure-resistant rats formed a distinct
      subpopulation compared with the seizure-prone rats; yet in the latter rats, it
      was the mIPSCs of the nonpyramidal neurons that were unique. Given these
      differences, we were surprised to find that the total inhibitory charge transfer
      between the strains was similar. This suggests that the timing of inhibition,
      particularly slow inhibitory neurotransmission between nonpyramidal neurons, may
      be a contributing factor in seizure genesis.

PMID- 12427850
TI  - Theta-frequency synaptic potentiation in CA1 in vitro distinguishes cognitively
      impaired from unimpaired aged Fischer 344 rats.
AB  - Hippocampal-dependent learning and memory deficits have been well documented in
      aging rodents. The results of several recent studies have suggested that these
      deficits arise from weakened synaptic plasticity within the hippocampus. In the
      present study, we examined the relationship between hippocampal long-term
      potentiation (LTP) in vitro and spatial learning in aged (24-26 months) Fischer
      344 rats. We found that LTP induced in the CA1 region using theta-frequency
      stimulation (5 Hz) is selectively impaired in slices from a subpopulation of aged
      rats that had shown poor spatial learning in the Morris water maze. LTP at 5 Hz
      in aged rats that did not show learning deficits was similar to that seen in
      young (4-6 months) controls. We also found that 5 Hz LTP amplitude strongly
      correlated with individual learning performance among aged rats. The difference
      in 5 Hz LTP magnitude among aged rats was not attributable to an altered response
      to 5 Hz stimulation or to differences in the NMDA receptor-mediated field EPSP.
      In addition, no performance-related differences in LTP were seen when LTP was
      induced with 30 or 70 Hz stimulation protocols. Finally, both 5 Hz LTP and
      spatial learning in learning-impaired rats were enhanced with the selective
      muscarinic M2 antagonist BIBN-99 (5,11-dihydro-8-chloro-11-[[4-[3-[(2,2-dimethyl
      1-oxopentyl)ethylamino]propyl]-1-piperidinyl]acetyl]-6H-pyrido[2,3
      b][1,4]benzodiazepin-6-one). These findings reinforce the idea that distinct
      types of hippocampal LTP offer mechanistic insight into age-associated cognitive
      decline.

PMID- 12427851
TI  - Expansion of the tonotopic area in the auditory cortex of the blind.
AB  - A part of the core area of the auditory cortex was examined in nine blind and 10
      sighted individuals by magnetic source imaging and was found to be enlarged by a
      factor of 1.8 in the blind compared with the sighted humans. Moreover, the
      latency of the N1m component of the auditory-evoked magnetic response was
      significantly decreased in the blind. The development of use-dependent cortical
      reorganization may be a consequence of the absence of visual input in combination
      with enhanced auditory activity generated by the long-term concentration by blind
      individuals on nonvisual cues to interact appropriately with the environment. It
      is consistent with and well suited to mediate the demonstrated increased ability
      of the blind to accurately localize acoustic sources in peripheral auditory
      fields and to decode speech.

PMID- 12427852
TI  - Processing of natural temporal stimuli by macaque retinal ganglion cells.
AB  - This study quantifies the performance of primate retinal ganglion cells in
      response to natural stimuli. Stimuli were confined to the temporal and chromatic
      domains and were derived from two contrasting environments, one typically
      northern European and the other a flower show. The performance of the cells was
      evaluated by investigating variability of cell responses to repeated stimulus
      presentations and by comparing measured to model responses. Both analyses yielded
      a quantity called the coherence rate (in bits per second), which is related to
      the information rate. Magnocellular (MC) cells yielded coherence rates of up to
      100 bits/sec, rates of parvocellular (PC) cells were much lower, and short
      wavelength (S)-cone-driven ganglion cells yielded intermediate rates. The
      modeling approach showed that for MC cells, coherence rates were generated almost
      exclusively by the luminance content of the stimulus. Coherence rates of PC cells
      were also dominated by achromatic content. This is a consequence of the stimulus
      structure; luminance varied much more in the natural environment than
      chromaticity. Only approximately one-sixth of the coherence rate of the PC cells
      derived from chromatic content, and it was dominated by frequencies below 10 Hz.
      S-cone-driven ganglion cells also yielded coherence rates dominated by low
      frequencies. Below 2-3 Hz, PC cell signals contained more power than those of MC
      cells. Response variation between individual ganglion cells of a particular class
      was analyzed by constructing generic cells, the properties of which may be
      relevant for performance higher in the visual system. The approach used here
      helps define retinal modules useful for studies of higher visual processing of
      natural stimuli.

PMID- 12427853
TI  - Firing properties of identified interneuron populations in the mammalian hindlimb
      central pattern generator.
AB  - Little is known about the network structure of the central pattern generator
      (CPG) controlling locomotor movements in mammals. The present experiments aim at
      providing such knowledge by focusing on commissural interneurons (CINs) involved
      in left-right coordination. During NMDA and 5-HT-initiated locomotor-like
      activity, we recorded intracellularly from caudally or descending projecting L2
      and L3 CINs (dCINs) located in the ventromedial area of the lumbar spinal cord in
      newborn rats. This region is crucial for rhythmic motor output and left-right
      coordination. The overall sample of dCINs represented a heterogenous population
      with neurons that fired in all phases of the locomotor cycle and exhibited
      varying degrees of rhythmicity, from strongly rhythmic to nonrhythmic. Among the
      rhythmic, putative CPG dCINs were populations that fired in-phase with the
      ipsilateral or with the contralateral L2 locomotor-like activity. There was a
      high degree of organization in the dorsoventral location of rhythmic dCINs, with
      neurons in-phase with the ipsilateral L2 activity located more ventrally. Spikes
      of rhythmically active dCINs were superimposed on membrane oscillations that were
      generated predominantly by synaptic input, with little direct contribution from
      the intrinsic pacemaker hyperpolarization-activated inward current. For both
      ipsilaterally and contralaterally firing dCINs the dominant synaptic drive was in
      phase with the ipsilateral L2 motor activity. This study provides the first
      characterization of putative CPG interneurons in the mammalian spinal cord. Our
      results suggest an anatomical and physiological separation of CPG commissural
      interneurons in the ventral horn and demonstrate that it is possible to target
      specific interneuron subpopulations in the mammalian locomotor network.

PMID- 12427854
TI  - Propagation of neuronal activity along the neocortical-perirhinal-entorhinal
      pathway in the guinea pig.
AB  - The study of synaptic interactions within the parahippocampal region is crucial
      to understand the integrative functions performed by this region during memory
      information processing. Despite the extensive anatomical studies, the intrinsic
      physiology of the parahippocampal area has been poorly investigated. We describe
      here the organization pattern of the synaptic network formed by the temporal
      neocortex, areas 36 and 35 of the perirhinal cortex (PRC) and the entorhinal
      cortex (EC), in the in vitro isolated guinea-pig brain. Current source density
      analysis of laminar field potential profiles was performed with multichannel
      silicon probes positioned in different parahippocampal subfields. Stimulation of
      the temporal neocortex induced monosynaptic and polysynaptic potentials in areas
      35 and 36, respectively. Area 36 stimulation evoked monosynaptic responses within
      areas 36 and 35. Stimuli in area 35 induced responses that propagated
      longitudinally along area 35 itself. No local field responses were observed in
      the EC after stimulation of both neocortex and areas 35/36. Despite the absence
      of a local extracellular response, intracellular recordings demonstrated that
      subpopulations of superficial layer neurons in medial and lateral EC showed
      polysynaptic EPSPs after stimulation of area 35 and area 36. The results
      demonstrate that the propagation of neuronal activity across the rhinal sulcus in
      the direction from the PRC to the EC is finely and diffusely distributed. In
      agreement with previous reports, these findings suggest that the PRC-EC pathway
      is highly regulated by inhibitory network interactions.

PMID- 12427855
TI  - The role of spinal neuroimmune activation in morphine tolerance/hyperalgesia in
      neuropathic and sham-operated rats.
AB  - Hypersensitivity resulting from nerve injury or morphine tolerance/hyperalgesia
      is predicted to involve similar cellular and molecular mechanisms. One expected
      but incompletely explored mechanism is the activation of central neuroimmune
      responses associated with these conditions. To begin to address this, we
      undertook three separate studies: First, we determined the acute antinociceptive
      action of morphine, the rate of development of opioid tolerance, and withdrawal
      induced hyperalgesia/allodynia in nerve-injured and sham-operated rats using
      noxious (thermal and mechanical) and non-noxious (mechanical allodynia)
      behavioral paradigms. Second, we investigated the impact of chronic morphine
      treatment on spinal glial activation and cytokine expression after L5 spinal
      nerve transection or sham surgery. Third, we examined the consequences of spinal
      administration of cytokine inhibitors on the development of morphine tolerance
      and morphine withdrawal-induced hyperalgesia and allodynia. Results demonstrated
      that after nerve injury, the antinociceptive effect of acute morphine was
      significantly decreased, and the rate of development of tolerance and opioid
      withdrawal-induced hyperalgesia/allodynia was significantly enhanced compared
      with that after sham surgery. Chronic administration of morphine to sham-operated
      rats activated spinal glia and upregulated proinflammatory cytokines [interleukin
      (IL)-1beta, IL-6, and tumor necrosis factor-alpha]. This neuroimmune activation
      was further enhanced in nerve-injured rats after chronic morphine treatment.
      Spinal inhibition of proinflammatory cytokines restored acute morphine
      antinociception in nerve-injured rats and also significantly reversed the
      development of morphine tolerance and withdrawal-induced hyperalgesia and
      allodynia in nerve-injured or sham-operated rats. Targeting central cytokine
      production and glial activation may improve the effectiveness of morphine and
      reduce the incidence of morphine withdrawal-induced hyperalgesia and allodynia in
      neuropathic pain conditions.

PMID- 12427856
TI  - Time course of error detection and correction in humans: neurophysiological
      evidence.
AB  - Using event-related brain potentials, the time course of error detection and
      correction was studied in healthy human subjects. A feedforward model of error
      correction was used to predict the timing properties of the error and corrective
      movements. Analysis of the multichannel recordings focused on (1) the error
      related negativity (ERN) seen immediately after errors in response- and stimulus
      locked averages and (2) on the lateralized readiness potential (LRP) reflecting
      motor preparation. Comparison of the onset and time course of the ERN and LRP
      components showed that the signs of corrective activity preceded the ERN. Thus,
      error correction was implemented before or at least in parallel with the
      appearance of the ERN component. Also, the amplitude of the ERN component was
      increased for errors, followed by fast corrective movements. The results are
      compatible with recent views considering the ERN component as the output of an
      evaluative system engaged in monitoring motor conflict.

PMID- 12427857
TI  - Synchronization of motor neurons during locomotion in the neonatal rat:
      predictors and mechanisms.
AB  - We describe here the robust synchronization of motor neurons at a millisecond
      time scale during locomotor activity in the neonatal rat. Action potential
      activity of motor neuron pairs was recorded extracellularly using tetrodes during
      locomotor activity in the in vitro neonatal rat spinal cord. Approximately 40% of
      motor neuron pairs recorded in the same spinal segment showed significant
      synchronization, with the duration of the central peak in cross-correlograms
      between motor neurons typically ranging between approximately 30 and 100 msec.
      The percentage of synchronized motor neuron pairs was considerably higher for
      pairs with similar locomotor-related activity and strong rhythmic modulation. We
      also found synchronization between the activities of different motor pools, even
      if located several segments apart. Such distant synchronization was abolished in
      the absence of chemical synapses, although local coupling between motor neurons
      persisted. On the other hand, both local and distant coupling between motor
      neurons were preserved after antagonism of gap junction coupling between motor
      neurons. These results demonstrate that motor neuron activity is strongly
      synchronized at a millisecond time scale during the production of locomotor
      activity in the neonatal rat. These results also demonstrate that chemical
      synaptic inputs, in addition to electrical synapses, contribute to this
      synchronization, suggesting the existence of multiple mechanisms underlying motor
      neuron synchronization in the neonatal rat. The fast synchronization described
      here might be involved in activity-dependent processes during development or in
      the coordination of individual motor neurons into a functional population
      underlying behavior.

PMID- 12427858
TI  - Vestibular information is required for dead reckoning in the rat.
AB  - Dead reckoning is an on-line form of spatial navigation used by an animal to
      identify its present location and return directly to a starting location, even
      after circuitous outward trips. At present, it is not known which of several self
      movement cues (efferent copy from movement commands, proprioceptive information,
      sensory flow, or vestibular information) are used to compute homeward
      trajectories. To determine whether vestibular information is important for dead
      reckoning, the impact of chemical labyrinthectomy was evaluated in a test that
      demanded on-line computation of a homeward trajectory. Rats were habituated to
      leave a refuge that was visible from all locations on a circular table to forage
      for large food pellets, which they carried back to the refuge to eat. Two
      different probe trials were given: (1) the rats foraged from the same spatial
      location from a hidden refuge in the light and so were able to use visual cues to
      navigate; (2) the same procedure took place in the dark, constraining the animals
      to dead reckon. Although control rats carried food directly and rapidly back to
      the refuge on both probes, the rats with vestibular lesions were able to do so on
      the hidden refuge but not on the dark probe. The scores of vestibular reflex
      tests predicted the dead reckoning deficit. The vestibular animals were also
      impaired in learning a new piloting task. This is the first unambiguous
      demonstration that vestibular information is used in dead reckoning and also
      contributes to piloting.

PMID- 12427859
TI  - Expression and physiological actions of cholecystokinin in rat taste receptor
      cells.
AB  - Gustatory perception arises not only from intracellular transduction cascades
      within taste receptor cells but also from cell-to-cell communication among the
      cells of the taste bud. This study presents novel data demonstrating that the
      brain-gut peptide cholecystokinin (CCK) is expressed in subsets of taste receptor
      cells, and that it may play a signaling role unknown previously within the taste
      bud. Immunocytochemistry revealed positively stained subsets of cells within
      taste buds throughout the oral cavity. These cells typically displayed round
      nuclei with full processes, similar to those classified as light cells. Peptide
      expression was verified using nested PCR on template cDNA derived from mRNA
      extracted from isolated posterior taste buds. Multiple physiological actions of
      cholecystokinin on taste receptor cells were observed. An outward potassium
      current, recorded with the patch-clamp technique, was inhibited by exogenous
      application of sulfated cholecystokinin octapeptide in a reversible and
      concentration-dependent manner. Pharmacological analysis suggests that this
      inhibition is mediated by CCK-A receptors and involves PKC phosphorylation. An
      inwardly rectifying potassium current, typically invariant to stimulation, was
      also inhibited by cholecystokinin. Additionally, exogenous cholecystokinin was
      effective in elevating intracellular calcium as measured by ratiometric
      techniques with the calcium-sensitive dye fura-2. Pharmacology similarly
      demonstrated that these calcium elevations were mediated by CCK-A receptors and
      were dependent on intracellular calcium stores. Collectively, these observations
      suggest a newly discovered role for peptide neuromodulation in the peripheral
      processing of taste information.

PMID- 12427860
TI  - Involvement of the neuropeptide nociceptin/orphanin FQ in kainate seizures.
AB  - The neuropeptide nociceptin/orphanin FQ (N/OFQ) has been shown to modulate
      neuronal excitability and neurotransmitter release. Previous studies indicate
      that the mRNA levels for the N/OFQ precursor (proN/OFQ) are increased after
      seizures. However, it is unclear whether N/OFQ plays a role in seizure
      expression. Therefore, (1) we analyzed proN/OFQ mRNA levels and NOP (the N/OFQ
      receptor) mRNA levels and receptor density in the kainate model of epilepsy,
      using Northern blot analysis, in situ hybridization, and receptor binding assay,
      and (2) we examined susceptibility to kainate seizure in mice treated with 1
      [(3R, 4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1, 3-dihydro
      benzimidazol-2-one (J-113397), a selective NOP receptor antagonist, and in
      proN/OFQ knock-out mice. After kainate administration, increased proN/OFQ gene
      expression was observed in the reticular nucleus of the thalamus and in the
      medial nucleus of the amygdala. In contrast, NOP mRNA levels and receptor density
      decreased in the amygdala, hippocampus, thalamus, and cortex. Mice treated with
      the NOP receptor antagonist J-113397 displayed reduced susceptibility to kainate
      induced seizures (i.e., significant reduction of behavioral seizure scores).
      N/OFQ knock-out mice were less susceptible to kainate seizures compared with
      their wild-type littermates, in that lethality was reduced, latency to
      generalized seizure onset was prolonged, and behavioral seizure scores decreased.
      Intracerebroventricular administration of N/OFQ prevented reduced susceptibility
      to kainate seizures in N/OFQ knock-out mice. These data indicate that acute
      limbic seizures are associated with increased N/OFQ release in selected areas,
      causing downregulation of NOP receptors and activation of N/OFQ biosynthesis, and
      support the notion that the N/OFQ-NOP system plays a facilitatory role in kainate
      seizure expression.

PMID- 12427861
TI  - Enhanced locomotor, reinforcing, and neurochemical effects of cocaine in
      serotonin 5-hydroxytryptamine 2C receptor mutant mice.
AB  - Brain serotonin [5-hydroxytryptamine (5-HT)] systems substantially influence the
      effects of cocaine; however, the contributions of individual 5-HT receptor
      subtypes to the regulation of cocaine responses are unclear. A line of mutant
      mice devoid of 5-HT2C receptors was used to examine the contribution of this
      receptor subtype to the serotonergic modulation of cocaine responses. Mutants
      display enhanced exploration of a novel environment and increased sensitivity to
      the locomotor stimulant effects of cocaine. In an operant intravenous self
      administration model under a progressive ratio schedule of reinforcement, mutants
      display elevated levels of lever pressing for cocaine injections, indicating that
      the drug is more reinforcing in these mice. Moreover, mutants exhibit enhanced
      cocaine-induced elevations of dopamine (DA) levels in the nucleus accumbens, a
      brain region implicated in the stimulant and rewarding properties of cocaine. In
      contrast, phenotypic differences in dorsal striatal DA levels were not produced
      by cocaine treatment. These findings strongly implicate 5-HT2C receptors in the
      serotonergic suppression of DA-mediated behavioral responses to cocaine and as a
      potential therapeutic target for cocaine abuse.

PMID- 12427862
TI  - Diminished anxiety- and depression-related behaviors in mice with selective
      deletion of the Tac1 gene.
AB  - The tachykinin neuropeptide substance P and its receptor neurokinin 1 have been
      implicated in the regulation of many physiological and pathological processes,
      including the control of emotional behaviors. The present study examines mice
      with a targeted deletion of the Tac1 gene, which encodes the neuropeptides
      substance P and neurokinin A, in animal models relevant to depressive illness and
      anxiety. In depression-related paradigms, Tac1-deficient mice were more active in
      the Porsolt's forced-swimming test and the tail-suspension test, and they did not
      become hyperactive after bulbectomy. Tac1 mutant mice were also less fearful in
      several animal models of anxiety. They were more active and less affected by the
      light conditions in the central area of the open-field arena; they showed more
      social interactions in an aversive environment, they were more active in the open
      areas of an elevated zero-maze, and they had a reduced latency to feed in the
      Thatcher-Britton conflict paradigm. These results demonstrate that tachykinins
      are powerful mediators of depression-like or anxiety-related behaviors in mice.
      The tachykinin system therefore may play an important role in the regulation of
      emotional states and the development of anxiety disorders and depression.

PMID- 12427863
TI  - A synaptic explanation of suppression in visual cortex.
AB  - The responses of neurons in the primary visual cortex (V1) are suppressed by mask
      stimuli that do not elicit responses if presented alone. This suppression is
      widely believed to be mediated by intracortical inhibition. As an alternative, we
      propose that it can be explained by thalamocortical synaptic depression. This
      explanation correctly predicts that suppression is monocular, immune to cortical
      adaptation, and occurs for mask stimuli that elicit responses in the thalamus but
      not in the cortex. Depression also explains other phenomena previously ascribed
      to intracortical inhibition. It explains why responses saturate at high stimulus
      contrast, whereas selectivity for orientation and spatial frequency is invariant
      with contrast. It explains why transient responses to flashed stimuli are
      nonlinear, whereas spatial summation is primarily linear. These results suggest
      that the very first synapses into the cortex, and not the cortical network, may
      account for important response properties of V1 neurons.

PMID- 12427864
TI  - Unchain my heart, baby let me go--the entry and intracellular transport of HIV.
AB  - In this issue, McDonald et al. describe the itinerary of the incoming human
      immunodeficiency virus (HIV) during its travels to the host nucleus. They show
      that subviral particles tagged with the green fluorescent protein (GFP) are
      propelled along microtubules (MTs) by minus-end-directed and presumably plus-end
      directed MT motors. The tracked particles correspond to functional units, since
      they no longer include a viral envelope, but do include viral matrix protein,
      Vpr, capsid protein, and reverse transcription activity.

PMID- 12427865
TI  - Signal recognition particle RNA localization within the nucleolus differs from
      the classical sites of ribosome synthesis.
AB  - The nucleolus is the site of ribosome biosynthesis, but is now known to have
      other functions as well. In the present study we have investigated how the
      distribution of signal recognition particle (SRP) RNA within the nucleolus
      relates to the known sites of ribosomal RNA synthesis, processing, and nascent
      ribosome assembly (i.e., the fibrillar centers, the dense fibrillar component
      (DFC), and the granular component). Very little SRP RNA was detected in fibrillar
      centers or the DFC of the nucleolus, as defined by the RNA polymerase I-specific
      upstream binding factor and the protein fibrillarin, respectively. Some SRP RNA
      was present in the granular component, as marked by the protein B23, indicating a
      possible interaction with ribosomal subunits at a later stage of maturation.
      However, a substantial portion of SRP RNA was also detected in regions of the
      nucleolus where neither B23, UBF, or fibrillarin were concentrated. Dual probe in
      situ hybridization experiments confirmed that a significant fraction of nucleolar
      SRP RNA was not spatially coincident with 28S ribosomal RNA. These results
      demonstrate that SRP RNA concentrates in an intranucleolar location other than
      the classical stations of ribosome biosynthesis, suggesting that there may be
      nucleolar regions that are specialized for other functions.

PMID- 12427867
TI  - Rootletin, a novel coiled-coil protein, is a structural component of the ciliary
      rootlet.
AB  - The ciliary rootlet, first recognized over a century ago, is a prominent
      structure originating from the basal body at the proximal end of a cilium.
      Despite being the largest cytoskeleton, its structural composition has remained
      unknown. Here, we report a novel 220-kD protein, designated rootletin, found in
      the rootlets of ciliated cells. Recombinant rootletin forms detergent-insoluble
      filaments radiating from the centrioles and resembling rootlets found in vivo. An
      mAb widely used as a marker for vertebrate rootlets recognizes an epitope in
      rootletin. Rootletin has a globular head domain and a tail domain consisting of
      extended coiled-coil structures. Rootletin forms parallel in register homodimers
      and elongated higher order polymers mediated by the tail domain alone. The head
      domain may be required for targeting to the basal body and binding to a kinesin
      light chain. In retinal photoreceptors where rootlets appear particularly robust,
      rootlets extend from the basal bodies to the synaptic terminals and anchor ER
      membranes along their length. Our data indicate that rootlets are composed of
      homopolymeric rootletin protofilaments bundled into variably shaped thick
      filaments. Thus, rootletin is the long-sought structural component of the ciliary
      rootlet.

PMID- 12427866
TI  - Mutant DMPK 3'-UTR transcripts disrupt C2C12 myogenic differentiation by
      compromising MyoD.
AB  - Myotonic dystrophy (DM) is caused by two similar noncoding repeat expansion
      mutations (DM1 and DM2). It is thought that both mutations produce pathogenic RNA
      molecules that accumulate in nuclear foci. The DM1 mutation is a CTG expansion in
      the 3' untranslated region (3'-UTR) of dystrophia myotonica protein kinase
      (DMPK). In a cell culture model, mutant transcripts containing a (CUG)200 DMPK 3'
      UTR disrupt C2C12 myoblast differentiation; a phenotype similar to what is
      observed in myoblast cultures derived from DM1 patient muscle. Here, we have used
      our cell culture model to investigate how the mutant 3'-UTR RNA disrupts
      differentiation. We show that MyoD protein levels are compromised in cells that
      express mutant DMPK 3'-UTR transcripts. MyoD, a transcription factor required for
      the differentiation of myoblasts during muscle regeneration, activates
      differentiation-specific genes by binding E-boxes. MyoD levels are significantly
      reduced in myoblasts expressing the mutant 3'-UTR RNA within the first 6 h under
      differentiation conditions. This reduction correlates with blunted E-box-mediated
      gene expression at time points that are critical for initiating differentiation.
      Importantly, restoring MyoD levels rescues the differentiation defect. We
      conclude that mutant DMPK 3'-UTR transcripts disrupt myoblast differentiation by
      reducing MyoD levels below a threshold required to activate the differentiation
      program.

PMID- 12427868
TI  - EGF controls the in vivo developmental potential of a mammary epithelial cell
      line possessing progenitor properties.
AB  - The bilayered mammary epithelium comprises a luminal layer of secretory cells and
      a basal layer of myoepithelial cells. Numerous data suggest the existence of self
      renewing, pluripotent mammary stem cells; however, their molecular
      characteristics and differentiation pathways are largely unknown. BC44 mammary
      epithelial cells in culture, display phenotypic characteristics of basal
      epithelium, i.e., express basal cytokeratins 5 and 14 and P-cadherin, but no
      smooth muscle markers. In vivo, after injection into the cleared mammary fat pad,
      these cells gave rise to bilayered, hollow, alveolus-like structures comprising
      basal cells expressing cytokeratin 5 and luminal cells positive for cytokeratin 8
      and secreting beta-casein in a polarized manner into the lumen. The persistent
      stimulation of EGF receptor signaling pathway in BC44 cells in culture resulted
      in the loss of the in vivo morphogenetic potential and led to the induction of
      active MMP2, thereby triggering cell scattering and motility on laminin 5. These
      data (a) suggest that BC44 cells are capable of asymmetric division for self
      renewal and the generation of a differentiated progeny restricted to the luminal
      lineage; (b) clarify the function of EGF in the control of the BC44 cell
      phenotypic plasticity; and (c) suggest a role for this phenomenon in the mammary
      gland development.

PMID- 12427869
TI  - A novel role for p120 catenin in E-cadherin function.
AB  - Indirect evidence suggests that p120-catenin (p120) can both positively and
      negatively affect cadherin adhesiveness. Here we show that the p120 gene is
      mutated in SW48 cells, and that the cadherin adhesion system is impaired as a
      direct consequence of p120 insufficiency. Restoring normal levels of p120 caused
      a striking reversion from poorly differentiated to cobblestone-like epithelial
      morphology, indicating a crucial role for p120 in reactivation of E-cadherin
      function. The rescue efficiency was enhanced by increased levels of p120, and
      reduced by the presence of the phosphorylation domain, a region previously
      postulated to confer negative regulation. Surprisingly, the rescue was associated
      with substantially increased levels of E-cadherin. E-cadherin mRNA levels were
      unaffected by p120 expression, but E-cadherin half-life was more than doubled.
      Direct p120-E-cadherin interaction was crucial, as p120 deletion analysis
      revealed a perfect correlation between E-cadherin binding and rescue of
      epithelial morphology. Interestingly, the epithelial morphology could also be
      rescued by forced expression of either WT E-cadherin or a p120-uncoupled mutant.
      Thus, the effects of uncoupling p120 from E-cadherin can be at least partially
      overcome by artificially maintaining high levels of cadherin expression. These
      data reveal a cooperative interaction between p120 and E-cadherin and a novel
      role for p120 that is likely indispensable in normal cells.

PMID- 12427870
TI  - Hsc70 is required for endocytosis and clathrin function in Drosophila.
AB  - By screening for Drosophila mutants exhibiting aberrant bride of sevenless (Boss)
      staining patterns on eye imaginal disc epithelia, we have recovered a point
      mutation in Hsc70-4, the closest homologue to bovine clathrin uncoating ATPase.
      Although the mutant allele was lethal, analysis of mutant clones generated by
      FLP/FRT recombination demonstrated that the Sevenless-mediated internalization of
      Boss was blocked in mutant Hsc70-4 eye disc epithelial cells. Endocytosis of
      other probes was also greatly inhibited in larval Garland cells. Immunostaining
      and EM analysis of the mutant cells revealed disruptions in the organization of
      endosomal/lysosomal compartments, including a substantial reduction in the number
      of clathrin-coated structures in Garland cells. The Hsc70-4 mutation also
      interacted genetically with a dominant-negative mutant of dynamin, a gene
      required for the budding of clathrin-coated vesicles (CCVs). Consistent with
      these phenotypes, recombinant mutant Hsc70 proteins exhibited diminished clathrin
      uncoating activity in vitro. Together, these data provide genetic support for the
      long-suspected role of Hsc70 in clathrin-mediated endocytosis, at least in part
      by inhibiting the uncoating of CCVs.

PMID- 12427872
TI  - Penfield revisited? Understanding and modifying behavior by deep brain
      stimulation for PD.

PMID- 12427871
TI  - ECM regulates MT1-MMP localization with beta1 or alphavbeta3 integrins at
      distinct cell compartments modulating its internalization and activity on human
      endothelial cells.
AB  - Regulation of membrane-type 1 matrix metalloproteinase (MT1-MMP) by different
      extracellular matrices (ECMs) on human endothelial cells (ECs) has been
      investigated. First, MT1-MMP is found at the intercellular contacts of confluent
      ECs grown on beta1 integrin-dependent matrix such as type 1 collagen (COL I),
      fibronectin (FN), or fibrinogen (FG), but not on gelatin (GEL) or vitronectin
      (VN). The novel localization of MT1-MMP at cell-cell contacts is assessed by
      confocal videomicroscopy of MT1-MMP-GFP-transfected ECs. Moreover, MT1-MMP
      colocalizes with beta1 integrins at the intercellular contacts, whereas it is
      preferentially found with alphavbeta3 integrin at motility-associated structures
      on migrating ECs. In addition, clustered integrins recruit MT1-MMP and
      neutralizing anti-beta1 or anti-alphav integrin mAb displace MT1-MMP from its
      specific sites, pointing to a biochemical association that is finally
      demonstrated by coimmunoprecipitation assays. On the other hand, COL I, FN, or FG
      up-regulate cell surface MT1-MMP on confluent ECs by an impairment of its
      internalization, whereas expression and internalization are not modified on GEL
      or VN. In addition, MT1-MMP activity is diminished in confluent ECs on COL I, FN,
      or FG. Finally, MT1-MMP participates and cooperates with beta1 and alphavbeta3
      integrins in the migration of ECs on different ECM. These data show a novel
      mechanism by which ECM regulates MT1-MMP association with beta1 or alphavbeta3
      integrins at distinct cellular compartments, thus modulating its internalization,
      activity, and function on human ECs.

PMID- 12427873
TI  - Wine, flavonoids, and the "water of life".

PMID- 12427874
TI  - Damage control: the influence of environment on recovery from brain injury.

PMID- 12427876
TI  - Amount and type of alcohol and risk of dementia: the Copenhagen City Heart Study.
AB  - OBJECTIVE: To assess whether amount or type of alcohol is associated with risk of
      dementia. METHODS AND SUBJECTS: Case-control nested in a cohort study among
      participants in the third Copenhagen City Heart Study (1991 to 1994), aged 65
      years or more, who where screened using the Mini-Mental State Examination and
      subsequently examined for dementia. There were 83 subjects diagnosed with
      dementia and the remaining 1,626 nondemented subjects were included as controls.
      The two groups were compared with regard to alcohol intake and type of alcohol
      assessed 15 years before. RESULTS: Average weekly total alcohol intake had no
      significant effect on risk of dementia. Monthly and weekly intake of wine was
      significantly associated with a lower risk of dementia. For beer and spirits,
      only a monthly intake of beer was significantly associated with an increased risk
      of dementia. The effect of alcohol on risk of dementia did not differ between men
      and women. CONCLUSIONS: Monthly and weekly intake of wine is associated with a
      lower risk of dementia. The results do not indicate that people should start
      drinking or increase wine consumption to avoid dementia, but instead suggest that
      certain substances in wine may reduce the occurrence of dementia.

PMID- 12427877
TI  - Cognitive impairments in advanced PD without dementia.
AB  - OBJECTIVE: To determine the nature and frequency of cognitive impairments in
      nondemented patients with advanced PD and their relationship to other variables
      potentially predictive of neuropsychological performance. METHODS: The
      neuropsychological performance of nondemented, nondepressed patients with
      idiopathic PD (n = 61) was quantified with respect to clinically available
      normative data. The relationship of neuropsychological measures to motor
      symptoms, age, years of education, disease duration, age at disease onset,
      disease deterioration rate, and dopaminergic therapy was assessed. RESULTS:
      Impairment was most frequent on measures sensitive to frontal lobe function (67%
      on Wisconsin Card Sorting Test number of categories, 30% on letter fluency, 30%
      on verbal learning). Poorer performance on multiple neuropsychological measures
      was related to greater overall motor abnormality (total Unified Parkinson's
      Disease Rating Scale score), increased bradykinesia on medication, older age,
      longer disease duration, and reduced education. CONCLUSIONS: Even in the absence
      of dementia or depression, patients with advanced PD are likely to show
      clinically significant impairments on neuropsychological measures sensitive to
      changes in dorsolateral prefrontal regions participating in cognitive basal
      ganglia-thalamocortical circuits.

PMID- 12427878
TI  - Weight loss in early stage of Huntington's disease.
AB  - BACKGROUND: Huntington's disease (HD) is an autosomal dominant disease with
      neurologic manifestations. In transgenic mouse models of HD, weight loss is
      recognized as a feature associated with the disease onset. It is unclear whether
      a similar pattern occurs in humans. METHODS: Data from the Huntington Study Group
      were used to evaluate whether HD is associated with lower body mass index (BMI)
      at the earliest stage of the disease. There were 361 case subjects in whom HD had
      been diagnosed with an independence scale rating of 100 (no special care needed),
      a total functional capacity score of >or=11, and HD duration of <4 years. For
      each case subject, five sex- and age-matched control subjects were selected from
      the National Heart, Lung, and Blood Institute Family Heart Study or the
      Framingham Offspring Study. RESULTS: Among case subjects, neither disease
      duration, nor dystonia, nor chorea score was significantly associated with BMI.
      BMI was significantly lower among case than among control subjects. Among men,
      age-adjusted BMI (+/-SE) was 25.90 +/- 0.34 kg/m(2) for case subjects with HD and
      27.68 +/- 0.16 kg/m(2) for control subjects. Among women, corresponding values
      were 24.34 +/- 0.43 for case subjects with HD and 26.63 +/- 0.21 kg/m(2) for
      control subjects. CONCLUSIONS: At an early stage of the disease, subjects with
      Huntington's disease had lower body mass index than matched controls from the
      general population. The cause of weight loss is unknown but the parallel to
      observations in Huntington's disease transgenic mice suggests that it is a
      significant hallmark of Huntington's disease gene expression.

PMID- 12427879
TI  - Presymptomatic testing in Huntington's disease and autosomal dominant cerebellar
      ataxias.
AB  - OBJECTIVE: To report a 7-year experience of presymptomatic testing in persons at
      risk for Huntington disease (HD) and to compare their characteristics and
      outcomes with those of persons at risk for a less disabling condition, autosomal
      dominant cerebellar ataxias (ADCA). METHODS: The authors collected data on
      presymptomatic testing for HD (n = 712) and ADCA (n = 46) in 10 French centers.
      RESULTS: The characteristics of applicants were similar in HD and ADCA, revealing
      a predominance of women, a low rate of completing the presymptomatic testing
      program, and a high rate of follow-up. The frequency of serious events was low
      (2% for HD, 5% for ADCA), but such events were also found after favorable
      results. Family planning was a more frequent reason for seeking presymptomatic
      testing in ADCA than in HD. Prenatal diagnosis was performed in only half of the
      pregnancies in HD carriers (n = 35) but in all of those in ADCA carriers (n = 4).
      CONCLUSION: Counseling in multistep and multidisciplinary teams is important not
      only for presymptomatic testing in HD but also for less disabling diseases.

PMID- 12427880
TI  - Dose-related neurocognitive effects of marijuana use.
AB  - BACKGROUND: Although about 7 million people in the US population use marijuana at
      least weekly, there is a paucity of scientific data on persistent neurocognitive
      effects of marijuana use. OBJECTIVE: To determine if neurocognitive deficits
      persist in 28-day abstinent heavy marijuana users and if these deficits are dose
      related to the number of marijuana joints smoked per week. METHODS: A battery of
      neurocognitive tests was given to 28-day abstinent heavy marijuana abusers.
      RESULTS: As joints smoked per week increased, performance decreased on tests
      measuring memory, executive functioning, psychomotor speed, and manual dexterity.
      When dividing the group into light, middle, and heavy user groups, the heavy
      group performed significantly below the light group on 5 of 35 measures and the
      size of the effect ranged from 3.00 to 4.20 SD units. Duration of use had little
      effect on neurocognitive performance. CONCLUSIONS: Very heavy use of marijuana is
      associated with persistent decrements in neurocognitive performance even after 28
      days of abstinence. It is unclear if these decrements will resolve with continued
      abstinence or become progressively worse with continued heavy marijuana use.

PMID- 12427881
TI  - Abnormal brain activation on functional MRI in cognitively asymptomatic HIV
      patients.
AB  - BACKGROUND/OBJECTIVES: A previous fMRI study demonstrated increased brain
      activation during working memory tasks in patients with HIV with mild dementia.
      The current study aims to determine whether patients who are HIV-1 positive and
      have normal cognitive function also show increased brain activation on fMRI.
      METHODS: Blood oxygenation level-dependent (BOLD) fMRI was performed in 10
      patients with HIV (CD <500) and 10 age-, sex-, education-, and handedness-matched
      seronegative subjects. Each subject performed a battery of neuropsychological
      tests and fMRI with three tasks (0-back, 1-back, and 2-back) that required
      different levels of attention for working memory. RESULTS: Compared with control
      subjects, patients with HIV showed greater magnitude of brain activation (BOLD
      signal intensity changes, p <or= 0.001) in the lateral prefrontal cortex, with
      normal performance during fMRI and on a battery of neuropsychological tests. The
      patients with HIV also showed increased activated brain volume in the lateral
      prefrontal cortex (p = 0.007) but not in other activated regions, including the
      posterior parietal cortex, supplementary motor area, thalamus, caudate, and
      occipital cortex. The increase in activated brain volume was independent of task
      difficulty. CONCLUSION: Increased brain activation in subjects who are positive
      for HIV precedes clinical signs or deficits on cognitive tests. Early injury to
      the neural substrate may necessitate increased usage of brain reserve to maintain
      normal cognitive function. BOLD fMRI appears to be more sensitive than clinical
      and neuropsychological evaluations for detecting early HIV-associated brain
      injury.

PMID- 12427882
TI  - Role of the urokinase plasminogen activator system in patients with bacterial
      meningitis.
AB  - BACKGROUND: The urokinase plasminogen activator system has the potency to promote
      leukocyte recruitment and blood-CSF barrier breakdown, and thus may play an
      important pathophysiologic role in bacterial meningitis. METHODS: CSF and serum
      concentrations of urokinase-plasminogen activator (urokinase [uPA]), uPA receptor
      (uPAR), and PA inhibitor-1 (PAI-1) were quantified by ELISA in 12 patients with
      bacterial meningitis, control patients (n = 10) with noninflammatory neurologic
      diseases, and 10 patients with Guillain-Barre syndrome (GBS), a disease in which
      blood-CSF barrier disruption occurs without CSF pleocytosis. Casein zymography
      was used to determine PA-dependent plasminogen activation in the CSF. RESULTS: A
      marked increase in uPA-dependent plasminogen activation was detected in the CSF
      of patients with bacterial meningitis vs CSF of patients with GBS and controls.
      Accordingly, ELISA analysis of CSF revealed intrathecal upregulation of uPA
      protein in patients with bacterial meningitis. CSF concentrations of uPAR and PAI
      1 were also elevated in these patients. The serum of patients with bacterial
      meningitis showed elevated protein levels of uPA, but not uPAR or PAI-1. Positive
      correlations were found between blood-CSF barrier breakdown and CSF uPA
      concentrations, and between CSF pleocytosis and CSF/serum ratios of the potent
      chemokine uPAR in patients with bacterial meningitis. Furthermore, an adverse
      clinical outcome in these patients correlated with serum uPA concentrations.
      CONCLUSION: In bacterial meningitis, the urokinase plasminogen activator system
      is involved in leukocyte recruitment and breaching of the blood-CSF barrier, and
      this may contribute to an unfavorable clinical outcome.

PMID- 12427883
TI  - Life after death?

PMID- 12427884
TI  - Beneficial effects of enriched environment following status epilepticus in
      immature rats.
AB  - BACKGROUND: There is increasing evidence that enriching the environment can
      improve cognitive and motor deficits following a variety of brain injuries.
      Whether environmental enrichment can improve cognitive impairment following
      status epilepticus (SE) is not known. OBJECTIVE: To determine whether the
      environment in which animals are raised influences cognitive function in normal
      rats and rats subjected to SE. METHODS: Rats (n = 100) underwent lithium
      pilocarpine-induced SE at postnatal (P) day 20 and were then placed in either an
      enriched environment consisting of a large play area with toys, climbing objects,
      and music, or in standard vivarium cages for 30 days. Control rats (n = 32) were
      handled similarly to the SE rats but received saline injections instead of
      lithium-pilocarpine. Rats were then tested in the water maze, a measure of visual
      spatial memory. A subset of the rats were killed during exposure to the enriched
      or nonenriched environment and the brains examined for dentate granule cell
      neurogenesis using bromodeoxyuridine (BrdU) and phosphorylated cyclic AMP
      response element binding protein (pCREB) immunostaining, a brain transcription
      factor important in long-term memory. RESULTS: Both control and SE rats exposed
      to the enriched environment performed significantly better than the nonenriched
      group in the water maze. There was a significant increase in neurogenesis and
      pCREB immunostaining in the dentate gyrus in both control and SE animals exposed
      to the enriched environment compared to the nonenriched groups. Environmental
      enrichment resulted in no change in SE-induced histologic damage. CONCLUSIONS:
      Exposure to an enriched environment in weanling rats significantly improves
      visual-spatial learning. Even following SE, an enriched environment enhances
      cognitive function. An increase in neurogenesis and activation of transcription
      factors may contribute to this enhanced visual-spatial memory.

PMID- 12427885
TI  - Creutzfeldt-Jakob disease in Australia 1970-1999.
AB  - OBJECTIVE: To ascertain all persons who developed a transmissible spongiform
      encephalopathy (TSE) within Australia during the 30-year period 1970 to 1999
      through a comprehensive national surveillance program and subject the group to
      detailed epidemiologic analysis. METHODS: Cases were ascertained through reviews
      of morbidity separation coding data from all university-affiliated tertiary
      referral hospitals, as well as the centralized data bases of state and territory
      health departments, regular national death certificate searches, and semiannual
      mailout questionnaires to all neurologists and pathologists throughout Australia.
      Prospective monitoring commenced in September 1993. RESULTS: A total of 387
      patients were confirmed as having TSE during this epoch. The majority of cases
      were sporadic Creutzfeldt-Jakob disease (CJD) (90.7%), with 7.2% heredofamilial
      and 2.1% iatrogenic. Over this 30-year period, the national average annual
      sporadic CJD incidence rate per million progressively increased from 0.31 for the
      decade 1970 through 1979 to 0.77 for 1980 through 1989, reaching 1.03 for 1990
      through 1999. Death certificates were found to have a false-positive rate of
      11.5% and sensitivity of 83.0% for sporadic CJD. CONCLUSIONS: Within Australia,
      there has been a gradual increase in the incidence of transmissible spongiform
      encephalopathy over the three-decade period 1970 through 1999, peaking in 1999 at
      1.4/million/year for sporadic Creutzfeldt-Jakob disease. This increase is
      believed secondary to improved case ascertainment. Variant Creutzfeldt-Jakob
      disease was not identified during this period. Age- and sex-adjusted comparisons
      showed a decline in incidence rates in the elderly in both sexes, usually from
      age 74 years. Death certificates were a useful but imperfect method of case
      detection.

PMID- 12427886
TI  - Sleep deprivation does not affect seizure frequency during inpatient video-EEG
      monitoring.
AB  - OBJECTIVE: To determine whether acute sleep deprivation facilitates seizures
      during inpatient monitoring in a controlled protocol. METHODS: Eighty-four
      patients with medically refractory partial epilepsy undergoing inpatient
      monitoring were assigned in consecutive blocks to either sleep deprivation every
      other night or to normal sleep. In both groups, subjects were requested to stay
      awake during the day, from 6 AM to 10 PM. In the sleep deprivation group,
      patients also stayed awake between 10 PM and 6 AM every other night beginning
      with Day 2. Patients were removed from sleep deprivation if they had two or more
      secondarily generalized seizures within 24 hours. Patients were removed from the
      normal sleep group and were sleep deprived if they did not have a complex partial
      or secondarily generalized seizure by Day 6 of monitoring. In these patients
      removed from sleep deprivation or from normal sleep, data were analyzed up to and
      including the day of removal from the protocol. RESULTS: The sleep deprivation
      and normal sleep subjects did not differ in age, sex, seizure localization, or
      percent dosage reduction in antiepileptic drugs from baseline at days 1 to 3 of
      monitoring. Protocol duration was 6.5 +/- 2.4 days (mean +/- SD) for the sleep
      deprivation group and 5.8 +/- 2.0 days for the normal sleep group. Seizures per
      day for complex partial, secondarily generalized, and combined complex partial
      and secondarily generalized, calculated from admission until end of protocol, did
      not differ significantly between the two groups. CONCLUSION: Acute sleep
      deprivation did not affect seizure frequency during inpatient monitoring in our
      patients with intractable complex partial seizures with secondary generalization.

PMID- 12427887
TI  - Homocysteine and cognitive function in the elderly: the Rotterdam Scan Study.
AB  - BACKGROUND: Elevated plasma total homocysteine (tHcy) concentrations are
      associated with AD and vascular dementia, but the relation with cognitive
      performance in nondemented elderly people is not known. OBJECTIVE: To examine the
      association of tHcy and cognitive function in the elderly, and assess whether
      this may be mediated by structural brain changes on MRI. METHODS: The Rotterdam
      Scan Study is a population-based study of 1,077 nondemented elderly. Cognitive
      performance was assessed, and compound scores were constructed for psychomotor
      speed, memory function, and global cognitive function. Cerebral infarcts, white
      matter lesions, and generalized brain atrophy were measured on MRI. The cross
      sectional relationship between tHcy levels and neuropsychological test scores was
      assessed by multiple regression. RESULTS: Mean tHcy level was 11.5 micro mol/L
      (SD 4.1). Increasing tHcy levels were associated with lower scores for
      psychomotor speed, memory function, and global cognitive function, and this was
      largely due to the association with tHcy levels in the upper quintile (>14 micro
      mol/L). Adjusted differences between test scores of participants in the upper
      quintile as compared with the lower four quintiles of tHcy were -0.26 (95% CI: 
      0.37; -0.14) for psychomotor speed, -0.13 (95% CI: -0.27; 0.01) for memory
      function, and -0.20 (95% CI: -0.30; -0.11) for global cognitive function. These
      associations were not mediated by structural brain changes on MRI. CONCLUSION:
      Elevated tHcy levels are associated with decreased cognitive performance in
      nondemented elderly people, and the relation was most marked for psychomotor
      speed. This association was independent of structural brain changes on MRI.

PMID- 12427888
TI  - Is diffusion imaging appearance an independent predictor of outcome after
      ischemic stroke?
AB  - BACKGROUND: MR diffusion-weighted imaging (DWI) in ischemic stroke can be
      quantified by calculating the apparent diffusion coefficient (ADC) or measuring
      lesion volume. OBJECTIVE: To clarify the association between DWI lesion
      parameters, clinical stroke severity at baseline, and the relationship with
      functional outcome. METHODS: Consecutive patients with stroke were categorized
      for stroke type (Oxford Community Stroke Project Classification [OCSP]) and
      severity (Canadian Neurologic Scale [CN Scale]) before DWI. The ratio of the
      trace of the apparent diffusion tensor in the ischemic lesion to the mirror image
      area in the contralateral hemisphere was calculated (<ADC>r). The volume of the
      visible lesion on DWI was measured. Any visible lesion on T2-weighted imaging
      (T2WI) was noted. All assessments were blind to all other information. A blinded
      observer obtained a 6-month Rankin score. Univariate and multivariate analyses
      were performed to test for independent associations with outcome. RESULTS: In 108
      patients, those with lower (i.e., more abnormal) <ADC>r values had more severe
      strokes according to the CN Scale (p = 0.01) and the OCSP stroke type (p =
      0.002), a large lesion on DWI (p = 0.05), a visible lesion on T2WI (p = 0.001),
      and poor 6-month functional outcome (p = 0.009). However, on logistic regression,
      neither <ADC>r nor DWI lesion volume were independent predictors of 6-month
      outcome over and above age and stroke severity. CONCLUSION: The <ADC>r is
      associated with functional outcome, but that is because it and DWI lesion volume
      are also associated with stroke severity. Although DWI lesion features are
      univariate surrogate outcome predictors, the authors were unable to show that
      they were independent outcome predictors in the current study. Differences
      between these and other results may be due to differences in study design, sample
      size, and case mix.

PMID- 12427889
TI  - Megalencephaly in NF1: predominantly white matter contribution and mitigation by
      ADHD.
AB  - BACKGROUND: Megalencephaly is a frequent CNS manifestation in neurofibromatosis
      type 1 (NF1); however, its tissue composition, modification by attention deficit
      hyperactivity disorder (ADHD), and relationship with unidentified bright objects
      (UBO) remain controversial. METHODS: Eighteen male patients with NF1, seven of
      whom had ADHD (NF1+ADHD), were compared with 18 age- and sex-matched controls in
      terms of MRI-, Talairach-based brain, cerebral, lobar, and sublobar gray and
      white matter volumes. Twelve subjects with NF1 had UBO in the centrencephalic
      region, whereas six had no UBO or exclusively infratentorial lesions. RESULTS:
      Patients with NF1 without ADHD (NF1-pure) had the largest total cerebral, gray,
      and white matter volumes with larger parietal/somatosensory white matter volumes
      than controls, particularly if UBO were present in the basal ganglia. All
      subjects with NF1 (including NF1+ADHD) had larger total and frontal white matter
      volumes than controls. Smaller frontal/right prefrontal gray matter volumes were
      found in NF1+ADHD when compared with NF1-pure patients. CONCLUSIONS: The increase
      in frontal and parietal white matter volumes in male patients with NF1, including
      the preferential centrencephalic distribution, supports the hypothesis that NF1's
      white matter pathology encompasses but is not limited to visible UBO. Male
      patients with NF1+ADHD, as compared with NF1-pure patients, showed frontal
      reductions that are largely consistent with those found in idiopathic ADHD.

PMID- 12427890
TI  - Clinical and genetic study of a large Italian family linked to SPG12 locus.
AB  - BACKGROUND: Seven loci for autosomal dominant hereditary spastic paraplegia
      (ADHSP) have been mapped. To date, two families of SPG12 (chromosome 19q13) have
      been analyzed; however, there is not enough clinical information on SPG12 to
      establish locus-phenotype correlations. METHODS: The authors studied 60
      individuals from a large Italian family with ADHSP, in which 16 members in four
      generations were affected. They performed genetic linkage analysis with DNA
      markers from currently known ADHSP loci. After database searching, one candidate
      gene for SPG12 was analyzed by sequencing. RESULTS: The patients in this family
      showed an early onset and rapid progression of symptoms, resulting in severe
      disability, with a large proportion of affected members requiring use of a
      wheelchair. By age 16, most patients had sensory disturbance. Evidence for
      linkage to the SPG12 locus was obtained. Obligate recombination events observed
      in this family have narrowed the SPG12 locus from the 16.1 cM to 11.3 cM region
      between markers D19S416 and D19S412. In combination with previous genetic
      studies, the SPG12 locus was further narrowed to the 3.3 cM region between
      D19S416 and D19S220. A homologue of the AAA (ATPases associated with a variety of
      cellular activities) protein family, proteasome 26S subunit ATPase mapped near
      D19S220, was excluded by sequencing. CONCLUSIONS: This study refined the SPG12
      region between D19S416 and D19S220 and revealed several clinical characteristics
      early onset, rapid progression, and involvement of sensory disturbance-that may
      be unique to SPG12. Suggestive evidence of genetic anticipation was obtained, but
      should be confirmed in other SPG12 families.

PMID- 12427891
TI  - Mitochondrial disorders: a proposal for consensus diagnostic criteria in infants
      and children.
AB  - BACKGROUND: In 1996 diagnostic criteria were published for adults with
      respiratory chain disorders. Modified criteria for children were also recently
      proposed. OBJECTIVE: To facilitate and standardize diagnosis of respiratory chain
      disorders in children. METHODS: A new classification has been developed, the
      Mitochondrial Disease Criteria (MDC), for the diagnosis of respiratory chain
      disorders in infants and children. It considers clinical, metabolic, imaging, and
      histopathologic features vs biochemical investigations of skeletal muscle. The
      criteria were applied to a group of 30 children. RESULTS: The modified adult
      criteria and the MDC gave similar results, with 17 patients having a definite
      respiratory chain disorder. No patients reached this category using the original
      adult criteria. CONCLUSIONS: The proposed Mitochondrial Disease Criteria
      classification allows more precise definition of clinical and metabolic items and
      the independent scoring of muscle biochemical investigations before combining all
      findings to determine the overall diagnostic certainty.

PMID- 12427892
TI  - Diagnostic criteria for respiratory chain disorders in adults and children.
AB  - BACKGROUND: Respiratory chain (RC) disorders are clinically, biochemically, and
      molecularly heterogeneous. The lack of standardized diagnostic criteria poses
      difficulties in evaluating diagnostic methodologies. OBJECTIVE: To assess
      proposed adult RC diagnostic criteria that classify patients into "definite,"
      "probable," or "possible" categories. METHODS: The authors applied the adult RC
      diagnostic criteria retrospectively to 146 consecutive children referred for
      investigation of a suspected RC disorder. Data were collected from hospital,
      genetics, and laboratory records, and the diagnoses predicted by the adult
      criteria were compared with the previously assigned assessments. RESULTS: The
      authors identified three major difficulties in applying the adult criteria:lack
      of pediatric-specific criteria; difficulty in segregating continuous data into
      circumscribed major and minor criteria; and lack of additivity of clinical
      features or enzyme tests. They therefore modified the adult criteria to allow for
      pediatric clinical and histologic features and for more sensitive coding of RC
      enzyme and functional studies. Reanalysis of the patients' data resulted in
      congruence between the diagnostic certainty previously assigned by the authors'
      center and that defined by the new general RC diagnostic criteria in 99% of
      patients. CONCLUSIONS: These general diagnostic criteria appear to improve the
      sensitivity of the adult criteria. They need further assessment in prospective
      clinical and epidemiologic studies.

PMID- 12427893
TI  - Eight-year follow-up study of brain atrophy in patients with MS.
AB  - OBJECTIVE: To characterize whole-brain atrophy in relapsing-remitting MS (RRMS)
      patients over an 8-year period. The specific goals of this study were to
      determine if brain atrophy is related to subsequent disability status and to
      identify MRI correlates of atrophy progression. METHODS: A follow-up study was
      conducted to reassess patients from a phase III trial of interferon beta-1a
      (IFNbeta-1a) 8 years after randomization. Clinical and MRI data from 172 patients
      followed over 2 years in the original trial were used as baseline data. Follow-up
      data were obtained on 160 patients, including 134 patients with follow-up MRI
      examinations. Brain atrophy was estimated by automated calculation of brain
      parenchymal fraction. The relation between atrophy during the original trial and
      disability status at follow-up was determined. Correlations were also determined
      between lesion measurements from the original trial and the brain parenchymal
      fraction at follow-up. RESULTS: Brain atrophy was correlated with subsequent
      disability status. Atrophy rate during the original trial was the most
      significant MRI predictor of disability status at follow-up. Brain atrophy at
      follow-up was related to lesion volumes measured during the original trial.
      CONCLUSIONS: The relation between atrophy progression and subsequent neurologic
      disability status suggests that atrophy progression during RRMS is clinically
      relevant. Therefore, atrophy progression may be a useful marker for disease
      progression in clinical trials. The relation between lesions and subsequent
      atrophy indicates that brain atrophy may be related to focal tissue damage at
      earlier points in time, but important predisposing or other factors contributing
      to atrophy remain undefined.

PMID- 12427894
TI  - Spinal schwannoma mimicking lower limb SMA.

PMID- 12427895
TI  - Mania following deep brain stimulation for Parkinson's disease.
AB  - Three patients with PD developed manic behavior after bilateral implantation of
      electrodes for deep-brain stimulation (DBS). Common to all three patients were
      manic symptoms unremitting after levodopa reduction or stimulation "off," lower
      electrodes positioning caudal to the subthalamic nucleus area, postoperative DBS
      with the lower contacts (0) of the quadripolar electrodes, and resolution of the
      manic episodes coinciding with stimulation through higher contacts.

PMID- 12427896
TI  - Aggressive behavior induced by intraoperative stimulation in the triangle of
      Sano.
AB  - The authors report a patient with advanced PD, successfully treated by bilateral
      stimulation of the subthalamic nucleus, who developed acute transient aggressive
      behavior during intraoperative electrical test stimulation. The electrode
      responsible for this abnormal behavior was located within the lateral part of the
      posteromedial hypothalamic region (triangle of Sano). The authors suggest that
      affect can be dramatically modulated by the selective manipulation of deep brain
      structures.

PMID- 12427897
TI  - Effect on mood of subthalamic DBS for Parkinson's disease: a consecutive series
      of 24 patients.
AB  - A series of 24 consecutive PD patients were prospectively studied prior to and
      within 6 months postoperatively for mood, motor, and cognitive status to
      investigate the effects on mood of subthalamic deep brain stimulation (DBS) in
      PD. In six patients (25%), mood state worsened significantly, and three were
      transiently suicidal despite clear motor improvement. Caregivers and patients
      should be educated about the potential impact of this neurosurgical procedure on
      mood.

PMID- 12427898
TI  - Effect of glatiramer acetate on MS lesions enhancing at different gadolinium
      doses.
AB  - This baseline-vs-treatment study of 20 patients with relapsing-remitting MS
      investigated whether glatiramer acetate (GA) has a graduated effect on MS
      inflammatory activity, which was measured using monthly, standard, and triple
      dose gadolinium (Gd)-enhanced MRI. GA significantly reduced the mean numbers of
      enhancing lesions/patient/month on both standard dose and triple dose scans,
      without interactions with the Gd dose. GA is effective in reducing MS activity,
      independent of the severity of the MRI-detectable inflammatory process.

PMID- 12427899
TI  - Postictal psychosis after temporal lobectomy.
AB  - Three of 282 consecutive patients who had temporal resections for intractable
      epilepsy developed postoperative postictal psychosis. These three patients had
      seizure recurrence contralateral to the resection, whereas none of the patients
      with ipsilateral seizure recurrence developed any psychiatric symptoms after
      surgery. Two had left amygdalo-hippocampectomy and one right temporal lobectomy.
      The de novo occurrence of postoperative postictal psychosis is a well-defined
      complication of surgery for temporal lobe epilepsy, and may relate to
      contralateral epileptogenesis.

PMID- 12427900
TI  - Singing seizures.
AB  - Automatisms are commonly seen in epilepsy, either ictally or postictally.
      However, most automatisms are simple, with hand movements, mouth smacking, nose
      rubbing, repetition of a single word, or coughing, grunting, or screeching.
      Complex automatisms are less common and striking. The authors report two cases of
      seizure-associated singing where song expression may be recognizable.

PMID- 12427901
TI  - Epileptic monocular nystagmus.
AB  - The authors describe a case of epileptic monocular nystagmus in a cognitively
      intact adult with normal vision. Focal seizures originated in the occipital lobe
      contralateral to the involved eye, and an associated structural lesion was
      thought to represent a forme fruste of Sturge-Weber syndrome. It is hypothesized
      that the seizure discharge either activated a cortical saccade region and caused
      simultaneous supranuclear inhibition of ipsilateral eye movement or triggered
      monocular eye movement commands.

PMID- 12427902
TI  - Intratympanic gentamicin injections for Meniere disease: vestibular hair cell
      impairment and regeneration.
AB  - The authors treated 22 patients with intratympanic gentamicin. Vestibular
      function was measured using caloric and head impulse tests and vestibular evoked
      myogenic potentials induced by high amplitude sounds and short duration galvanic
      currents. Roughly one-third of the patients, after initially losing their caloric
      responses and displaying refixation saccades to head impulse tests, recovered
      within 2 years of the lesion. Vertigo did not recur in patients in whom the
      galvanic response was abolished.

PMID- 12427903
TI  - Ptosis as a remote effect of therapeutic botulinum toxin B injection.
AB  - The authors report a patient with cervical dystonia, previously treated with
      botulinum toxin A (BTX-A), who developed bilateral ptosis and difficulty with
      accommodation only after botulinum toxin B (BTX-B). High-frequency repetitive
      nerve stimulation of the abductor digiti minimi demonstrated a 34% increment in
      compound muscle action potential. No increment in 20 people injected with BTX-A
      and no cases of ptosis in a chart review of 1,606 BTX-A injections for cervical
      dystonia were found. The authors conclude that systemic spread of BTX-B can cause
      symptomatic involvement of autonomic neurons.

PMID- 12427904
TI  - N-acetylcysteine and Unverricht-Lundborg disease: variable response and possible
      side effects.
AB  - Serum glutathione levels were assessed in a patient with genetically proven
      Unverricht-Lundborg disease (ULD) before and during treatment with the
      antioxidant N-acetylcysteine (NAC). Glutathione levels were low before treatment,
      and increased during treatment. This increase was mirrored by an improvement in
      seizures, but not in myoclonus or ataxia. Three other patients with clinically
      determined ULD showed a variable response and some notable side effects during
      treatment with NAC.

PMID- 12427905
TI  - Sensitization of trigeminal nociception specific for migraine but not pain of
      sinusitis.
AB  - Trigeminal pain processing was studied in 14 patients with unilateral migraine
      attacks and 14 age- and sex-matched patients with comparable unilateral headache
      from frontal sinusitis. Using a nociception-specific blink reflex method (nBR), a
      facilitation of nBR responses predominantly on the headache side was observed in
      migraine, but not in sinusitis. The facilitation of trigeminal nociception may be
      specific for migraine rather than a consequence of peripheral pain such as
      frontal sinusitis.

PMID- 12427906
TI  - CNS demyelination associated with copper deficiency and hyperzincemia.
AB  - CNS demyelination is not a previously reported feature of acquired copper
      deficiency. The authors report two patients with idiopathic hypocupremia and
      hyperzincemia, hematologic changes of copper deficiency, and extensive CNS
      demyelination. Hematologic recovery followed copper supplementation, both
      initially and after relapse off copper therapy, while serum zinc levels remained
      high and the neurologic abnormalities only stabilized.

PMID- 12427907
TI  - Survival and respiratory decline are not related to homozygous SMN2 deletions in
      ALS patients.
AB  - The presence of the SMN2 deletion in 124 patients with ALS was investigated.
      Eleven patients had the homozygous deletion of SMN2 (8.8%) in comparison with 20
      of 200 (10%) of the healthy control population. No significant differences in
      sex, age at onset, initial symptoms, form of inheritance, decline in ventilatory
      function, or survival time were found between patients with and without the
      deletion. The hypothesis that SMN2 is a prognostic factor in sporadic or familial
      ALS was not confirmed in this study.

PMID- 12427908
TI  - Fulminant ascending paralysis as a delayed sequela of diethylene glycol (Sterno)
      ingestion.
AB  - The authors report a 57-year-old man who survived 18 days after swallowing an 8
      oz. can of Sterno in a suicide attempt. Two days after ingestion, he developed
      confusion and acute renal failure requiring hemodialysis, followed on day 8 by a
      delayed but rapidly evolving ascending paralysis. Pathologic examination showed
      severe demyelination, with lesser axonal damage, of virtually all cranial and
      peripheral nerves sampled and sparing of central myelin. The diethylene glycol in
      the Sterno was considered responsible for this intoxication.

PMID- 12427910
TI  - Tumoral nature of intrathoracic meningocele in neurofibromatosis 1.

PMID- 12427909
TI  - SMN1 gene study in three families in which ALS and spinal muscular atrophy co
      exist.
AB  - Spinal muscular atrophy (SMA) is caused by SMN1 gene deletions or mutations, and
      ALS is the most frequent motor neuron condition in adults. The authors describe
      three families in which ALS and SMA coexist. The authors found that no SOD1
      mutation was found within these families; all three ALS cases had at least two
      SMN1 copies; and an abnormal SMN1 gene locus did not explain the co-occurrence of
      these two motor neuron disorders in these families.

PMID- 12427911
TI  - Pentoxifylline-induced aseptic meningitis in a patient with mixed connective
      tissue disease.

PMID- 12427912
TI  - Postural vertigo and impaired vasoreflexes caused by a posterior inferior
      cerebellar artery infarct.

PMID- 12427913
TI  - Hereditary neuropathy with liability to pressure palsies emerging during
      vincristine treatment.

PMID- 12427914
TI  - Jaw drop in Kennedy's disease.

PMID- 12427915
TI  - The minimally conscious state: definition and diagnostic criteria.

PMID- 12427916
TI  - MRI measures of entorhinal cortex versus hippocampus in preclinical AD.

PMID- 12427917
TI  - Homocysteine, vitamin B6, and vascular disease in patients with AD.

PMID- 12427918
TI  - Dementia with Lewy bodies and AD are not associated with occipital lobe atrophy
      on MRI.

PMID- 12427919
TI  - Models on stickiness of replicated Escherichia coli oriC.

PMID- 12427920
TI  - Active expression of soluble methane monooxygenase from Methylosinus
      trichosporium OB3b in heterologous hosts.

PMID- 12427921
TI  - Expression of soluble methane monooxygenase genes.

PMID- 12427922
TI  - What does a bacterial genome sequence represent? Mis-assignment of MAFF 303099 to
      the genospecies Mesorhizobium loti.

PMID- 12427923
TI  - MprF-mediated lysinylation of phospholipids in Bacillus subtilis--protection
      against bacteriocins in terrestrial habitats?

PMID- 12427924
TI  - Genotypic vs. phenotypic biodiversity in Lactococcus lactis.

PMID- 12427925
TI  - Protein transport in the halophilic archaeon Halobacterium sp. NRC-1: a major
      role for the twin-arginine translocation pathway?

PMID- 12427926
TI  - Bovicin HC5, a bacteriocin from Streptococcus bovis HC5.
AB  - Previous work indicated that Streptococcus bovis HC5 had significant
      antibacterial activity, and even nisin-resistant S. bovis JB1 cells could be
      strongly inhibited. S. bovis HC5 inhibited a variety of Gram-positive bacteria
      and the spectrum of activity was similar to monensin, a commonly used feed
      additive. The crude extracts (ammonium sulfate precipitation) were inactivated by
      Pronase E and trypsin, but the activity was resistant to heat, proteinase K and
      alpha-chymotrypsin. Most of the antibacterial activity was cell associated, but
      it could be liberated by acidic NaCl (100 mM, pH 2.0) without significant cell
      lysis. When glycolysing S. bovis JB1 cells were treated with either crude or
      acidic NaCl extracts, intracellular potassium declined and this result indicated
      the antibacterial activity was mediated by a pore-forming peptide. The peptide
      could be purified by HPLC and matrix-assisted laser desorption ionization time-of
      flight analysis indicated that it had a molecular mass of approximately 2440 Da.
      The terminal amino acid sequence was VGXRYASXPGXSWKYVXF. The unnamed amino acid
      residues (designated by X) had approximately the same position as dehydroalanines
      found in some lantibiotics, but samples that were reduced and alkylated prior to
      Edman degradation did not have cysteine residues. The only other bacteriocin that
      had significant similarity was the lantibiotic precursor of Streptococcus
      pyogenes SF370, but the identity was only 55%. Based on these results, the
      bacteriocin of S. bovis HC5 appears to be novel and the authors now designate it
      as bovicin HC5.

PMID- 12427927
TI  - Glycogen-accumulating organisms in laboratory-scale and full-scale wastewater
      treatment processes.
AB  - Laboratory-scale sequencing batch reactors (SBRs) as models for wastewater
      treatment processes were used to identify glycogen-accumulating organisms (GAOs),
      which are thought to be responsible for the deterioration of enhanced biological
      phosphorus removal (EBPR). The SBRs (called Q and T), operated under alternating
      anaerobic-aerobic conditions typical for EBPR, generated mixed microbial
      communities (sludges) demonstrating the GAO phenotype. Intracellular glycogen and
      poly-beta-hydroxyalkanoate (PHA) transformations typical of efficient EBPR
      occurred but polyphosphate was not bioaccumulated and the sludges contained 1.8%
      P (sludge Q) and 1.5% P (sludge T). 16S rDNA clone libraries were prepared from
      DNA extracted from the Q and T sludges. Clone inserts were grouped into
      operational taxonomic units (OTUs) by restriction fragment length polymorphism
      banding profiles. OTU representatives were sequenced and phylogenetically
      analysed. The Q sludge library comprised four OTUs and all six determined
      sequences were 99.7% identical, forming a cluster in the gamma-Proteobacteria
      radiation. The T sludge library comprised eight OTUs and the majority of clones
      were Acidobacteria subphylum 4 (49% of the library) and candidate phylum OP10
      (39% of the library). One OTU (two clones, of which one was sequenced) was in the
      gamma-Proteobacteria radiation with 95% sequence identity to the Q sludge clones.
      Oligonucleotide probes (called GAOQ431 and GAOQ989) were designed from the gamma
      Proteobacteria clone sequences for use in fluorescence in situ hybridization
      (FISH); 92% of the Q sludge bacteria and 28% of the T sludge bacteria bound these
      probes in FISH. FISH and post-FISH chemical staining for PHA were used to
      determine that bacteria from a novel gamma-Proteobacteria cluster were
      phenotypically GAOs in one laboratory-scale SBR and two full-scale wastewater
      treatment plants. It is suggested that the GAOs from the novel cluster in the
      gamma-Proteobacteria radiation be named 'Candidatus Competibacter phosphatis'.

PMID- 12427928
TI  - Genetic and physiological characterization of rpoB mutations that activate
      antibiotic production in Streptomyces lividans.
AB  - Antibiotic production in Streptomyces lividans can be activated by introducing
      certain mutations (rif) into the rpoB gene that confer resistance to rifampicin.
      Working with the most typical (rif-17) mutant strain, KO-417, the rif-17 mutation
      was characterized. The rif-17 mutation was shown to be responsible for activating
      antibiotic production and for reducing the growth rate of strain KO-417, as
      demonstrated by gene-replacement experiments. Gene-expression analysis revealed
      that introduction of rif into S. lividans elevates expression of the pathway
      specific regulatory gene actII-ORF4 to nearly the same level seen in Streptomyces
      coelicolor. The rif effect on antibiotic production was still evident in the
      genetic background of relC, indicating that the rif mutation can provoke its
      effect without depending on ppGpp. Accompanying the restoration of antibiotic
      production, rif mutants also exhibited a lower rate of RNA synthesis compared to
      the parental strain when grown in a nutritionally rich medium, suggesting that
      the mutant RNA polymerases may behave like 'stringent' RNA polymerases. These
      results indicate that the rif mutation can alter the gene-expression pattern
      independent of ppGpp. The impaired growth of strain KO-417 (rif-17) was largely
      restored by introducing the second rif mutation (rif-18) just adjacent to the rif
      17 position. Proteome analysis using two-dimensional PAGE revealed that the rif
      mutant strain KO-418 (rif-17 rif-18) displayed a temporal burst of expression
      especially of two enzymes, glutamine synthetase (type II) and oxidoreductase,
      during the late growth phase.

PMID- 12427929
TI  - Characterization of mutations in aclacinomycin A-non-producing Streptomyces
      galilaeus strains with altered glycosylation patterns.
AB  - In this study a set of Streptomyces galilaeus ATCC 31615 mutants was
      characterized, which are incapable of synthesizing some or all of the deoxyhexose
      sugars of aclacinomycin A. Complementation experiments with the the mutant
      strains H026, H038, H039, H054, H063, H065 and H075 were carried out with
      glycosylation genes previously derived from the wild-type S. galilaeus. Mutations
      in strains H038, H063 and H075 were complemented with single PCR-amplified genes.
      Furthermore, amplification and sequencing of the corresponding genes from the
      mutant strains revealed single point mutations in the sequences. First, in H038 a
      transition mutation in aknQ, encoding a putative dTDP-hexose 3-ketoreductase,
      causes an amino acid substitution from glycine to aspartate, suppressing the
      biosynthesis of both 2-deoxyfucose and rhodinose and thus leading to the
      accumulation of aclacinomycin T with rhodosamine as its only sugar. Second, in
      H063, which accumulates aklavinone without a sugar moiety, amino acid
      substitution occurs, with threonine being substituted by isoleucine in dTDP
      glucose synthase, the first enzyme participating in deoxyhexose biosynthesis,
      encoded by aknY. Third, a nonsense mutation in aknP leads to truncated dTDP
      hexose 3-dehydratase in H075, which is incapable of synthesizing rhodinose. In
      addition, mutants H054 and H065, which accumulate aclacinomycins without
      aminosugars, were complemented by a gene for an aminotransferase, aknZ.
      Characterization of the nature of the mutations adds to the usefulness and value
      of the mutants in the analysis of gene function and in the creation of novel
      compounds by combinatorial biosynthesis. Furthermore, these results strengthen
      the assignments of akn gene products and enlighten the biosynthetic pathway for
      deoxyhexoses.

PMID- 12427930
TI  - Streptococcus mutans biofilm formation: utilization of a gtfB promoter-green
      fluorescent protein (PgtfB::gfp) construct to monitor development.
AB  - The glucosyltransferases of Streptococcus mutans are recognized as important
      virulence factors for this cariogenic bacterium. To study the expression of the
      gtfB gene of S. mutans in biofilms, a gtfB promoter (PgtfB)-green fluorescent
      protein (GFP) reporter system was developed. A Streptococcus-Escherichia coli
      shuttle vector harbouring a PGTFB::gfp cassette was introduced into S. mutans GS
      5, and the expression of GFP by the transformed S. mutans cells was confirmed by
      fluorescence microscopy. Furthermore, confocal laser scanning microscopy was
      carried out on biofilms attached to polystyrene plates; enhanced gtfB expression
      was observed in various microcolonies across these biofilms. To further test the
      hypothesis that gtfB expression is upregulated in biofilms, flow cytometry
      analysis was done on planktonic and biofilm cells; this analysis showed an
      approximately five-fold increase in gtfB expression in the biofilm cells relative
      to the planktonic cells. Real-time (TaqMan) PCR analysis confirmed that gtfB
      expression in the biofilm cells was enhanced relative to the planktonic cells.
      Previously, it has been suggested that the S. mutans gtfC gene might be co
      transcribed with gtfB. Therefore, RT-PCR analysis was performed on gtfB
      expressing S. mutans; this analysis demonstrated that gtfC was co-transcribed
      with gtfB. These results indicated that GFP expression can be utilized to examine
      gene regulation in S. mutans biofilm formation.

PMID- 12427931
TI  - Structural characterization of the fusobacterial non-specific porin FomA suggests
      a 14-stranded topology, unlike the classical porins.
AB  - Native and recombinant FomA proteins were extracted by detergent from the cell
      envelopes of Fusobacterium nucleatum and Escherichia coli, and purified to near
      homogeneity by chromatography. Circular dichroism analysis revealed that the FomA
      protein consists predominantly of beta-sheets, in line with the previously
      proposed 16-stranded beta-barrel topology model. Results obtained by trypsin
      treatment of intact cells and cell envelopes of F. nucleatum, and from limited
      proteolysis of purified FomA protein, indicated that the N-terminal part of the
      FomA protein is not an integral part of the beta-barrel, but forms a periplasmic
      domain. Based on these results a new topology model is proposed for the FomA
      protein, where the C-terminal part forms a 14-stranded beta-barrel separate from
      the periplasmic N-terminal domain.

PMID- 12427932
TI  - Growth of Bacillus subtilis on citrate and isocitrate is supported by the Mg2+
      citrate transporter CitM.
AB  - Bacillus subtilis 168 was assayed for its growth on tricarboxylic acid (TCA)
      cycle intermediates and related compounds as the sole carbon sources. Growth of
      the organism was supported by citrate, D-isocitrate, succinate, fumarate and L
      malate, whereas no growth was observed in the presence of cis-aconitate,2
      oxoglutarate, D-malate, oxaloacetate and tricarballylate. Growth of the organism
      on the tricarboxylates citrate and D-isocitrate required the presence of
      functional CitM, an Mg(2+)-citrate transporter, whereas its growth on succinate,
      fumarate and L-malate appeared to be CitM-independent. Interestingly, the
      naturally occurring enantiomer D-isocitrate was favoured over L-isocitrate by the
      organism. Like citrate, D-isocitrate was shown to be an inducer of citM
      expression in B. subtilis. The addition of 1 mM Mg(2+) to the growth medium
      improved growth of the organism on both citrate and D-isocitrate, suggesting that
      D-isocitrate was taken up by CitM in complex with divalent metal ions.
      Subsequently, the ability of CitM to transport D-isocitrate was demonstrated by
      competition experiments and by heterologous exchange in right-side-out membrane
      vesicles prepared from E. coli cells expressing citM. None of the other TCA cycle
      intermediates and related compounds tested were recognized by CitM. Uptake
      experiments using radioactive (63)Ni(2+) provided direct evidence that D
      isocitrate is transported in complex with divalent metal ions.

PMID- 12427933
TI  - Cell-wall proteinases PrtS and PrtB have a different role in Streptococcus
      thermophilus/Lactobacillus bulgaricus mixed cultures in milk.
AB  - The manufacture of yoghurt relies on the simultaneous utilization of two
      starters: Streptococcus thermophilus and Lactobacillus delbrueckii subsp.
      bulgaricus (Lb. bulgaricus). A protocooperation usually takes place between the
      two species, which often results in enhanced milk acidification and aroma
      formation compared to pure cultures. Cell-wall proteinases of Lactococcus lactis
      and lactobacilli have been shown to be essential to growth in milk in pure
      cultures. In this study, the role of proteinases PrtS from S. thermophilus and
      PrtB from Lb. bulgaricus in bacterial growth in milk was evaluated; a negative
      mutant for the prtS gene of S. thermophilus CNRZ 385 was constructed for this
      purpose. Pure cultures of S. thermophilus CNRZ 385 and its PrtS-negative mutant
      were made in milk as well as mixed cultures of S. thermophilus and Lb.
      bulgaricus: S. thermophilus CNRZ 385 or its PrtS-negative mutant was associated
      with several strains of Lb. bulgaricus, including a PrtB-negative strain. The pH
      and growth of bacterial populations of the resulting mixed cultures were
      followed, and the Lactobacillus strain was found to influence both the extent of
      the benefit of Lb. bulgaricus/S. thermophilus association on milk acidification
      and the magnitude of S. thermophilus population dominance at the end of
      fermentation. In all mixed cultures, the sequential growth of S. thermophilus
      then of Lb. bulgarius and finally of both bacteria was observed. Although
      proteinase PrtS was essential to S. thermophilus growth in milk in pure culture,
      it had no effect on bacterial growth and thus on the final pH of mixed cultures
      in the presence of PrtB. In contrast, proteinase PrtB was necessary for the
      growth of S. thermophilus, and its absence resulted in a higher final pH. From
      these results, a model of growth of both bacteria in mixed cultures in milk is
      proposed.

PMID- 12427934
TI  - Static growth of mucoid Pseudomonas aeruginosa selects for non-mucoid variants
      that have acquired flagellum-dependent motility.
AB  - When mucoid (alginate-producing) Pseudomonas aeruginosa FRD1 is grown under low
      oxygen conditions in liquid culture (static), non-mucoid variants appear and
      eventually predominate. This conversion is not readily observed in aerobic,
      shaken cultures or static cultures containing the alternative electron acceptor
      nitrate. In this study, it is shown that the non-mucoid variants that arise under
      static growth conditions are almost exclusively algT mutants. It has been shown
      that AlgT not only positively regulates alginate biosynthesis, but also directly
      or indirectly negatively regulates flagellum synthesis. Indeed, during static
      growth, conversion to the non-mucoid phenotype is accompanied by the acquisition
      of flagellum-mediated motility. Surprisingly, by using a reporter gene fusion
      with the fliC promoter (pfliC::xylE), it was found that fliC expression begins
      within hours of static growth and is reversible after returning the culture to
      shaking conditions. The ability of the strain to produce alginate seems to be
      irrelevant to this phenomenon, as an AlgT(+) deltaalgD strain showed identical
      results. Thus, it is suggested that the first effect of static growth is to
      induce motility as an adaptive measure in the presence of wild-type algT. This
      may afford P. aeruginosa the ability to swim towards areas of higher oxygen
      concentrations. Subsequent to this, algT mutations are likely to secure the
      motile phenotype.

PMID- 12427935
TI  - Novel insights into the interplay between peripheral reactions encoded by xyl
      genes and the chlorocatechol pathway encoded by tfd genes for the degradation of
      chlorobenzoates by Ralstonia eutropha JMP134.
AB  - Many bacteria can grow on chloroaromatic pollutants because they can transform
      them into chlorocatechols, which are further degraded by enzymes of a specialized
      ortho-cleavage pathway. Ralstonia eutropha JMP134 is able to grow on 3
      chlorobenzoate by using two pJP4-encoded, ortho-cleavage chlorocatechol
      degradation gene clusters (tfdC(I)D(I)E(I)F(I) and tfdD(II)C(II)E(II)F(II)). Very
      little is known about the acquisition of new catabolic genes encoding enzymes
      that lead to the formation of chlorocatechols in R. eutropha JMP134. The effect
      on the catabolic properties of an R. eutropha JMP134 derivative that received the
      xylS-xylXYZL gene module, encoding the xylS-regulated expression of the broad
      substrate-range toluate 1,2-dioxygenase (xylXYZ) and the 1,2-dihydro-1,2
      dihydroxytoluate dehydrogenase (xylL) from pWW0, which allows the transformation
      of 4-chlorobenzoate into 4-chlorocatechol, was studied. Such a derivative could
      efficiently grow on 4-chlorobenzoate. Unexpectedly, this derivative also grew on
      3,5-dichlorobenzoate, a substrate for XylXYZL but not an inducer of the XylS
      regulatory protein. The ability to grow on 4-chlorobenzoate or 3,5
      dichlorobenzoate was also observed in derivatives of strain JMP134 containing the
      xyl gene module but lacking xylS, indicating the presence of an xylS-like element
      in R. eutropha with an inducer profile different from that of the pWW0-encoded
      regulator. Growth on 4-chlorobenzoate was also observed after introduction of the
      xyl gene module into strain JMP222, a JMP134 derivative lacking pJP4, but only if
      multiple copies of tfdC(I)D(I)E(I)F(I) or tfdD(II)C(II)E(II)F(II) were present.
      However, only the derivative containing multiple copies of
      tfdD(II)C(II)E(II)F(II) was able to grow on 3,5-dichlorobenzoate. These
      observations indicate that although the acquisition of new catabolic genes
      actually enhances the catabolic abilities of R. eutropha JMP134, these new
      properties are strongly influenced by the dosage of the tfd genes, the presence
      of a chromosomal xylS-like regulatory element and the different contributions of
      the tfd gene clusters.

PMID- 12427936
TI  - Genome-wide transcriptional profiling of the Bacillus subtilis cold-shock
      response.
AB  - The transcriptome of Bacillus subtilis was analysed at different time points (30,
      60 and 90 min) after a temperature downshift from 37 to 18 degrees C using DNA
      macroarrays. This approach allowed the identification of around 50 genes
      exhibiting an increased mRNA level and around 50 genes exhibiting a decreased
      mRNA level under cold-shock conditions. Many of the repressed genes encode
      enzymes involved in the biosynthesis of amino acids, nucleotides and coenzymes,
      indicating metabolic adaptation of the cells to the decreased growth rate at the
      lower temperature. The strongest cold-inducible gene encodes fatty acid
      desaturase, which forms unsaturated fatty acids from saturated phospholipid
      precursors, thereby increasing membrane fluidity. The cold-shock-induced increase
      of mRNA levels of the classical cold-shock genes cspB, cspC and cspD could be
      verified. Furthermore, besides many genes encoding proteins of unknown function,
      some genes encoding ribosomal proteins were transcriptionally up-regulated, which
      points to an adaptive reprogramming of the ribosomes under cold-shock conditions.
      Interestingly, the amount of mRNA specified by the operon ptb-bcd-buk-lpd-bkdA1
      bkdA2-bkdB, which encodes enzymes involved in degradation of branched-chain amino
      acids, also increases after a temperature downshift. As cells utilize the
      isoleucine and valine degradation intermediates alpha-methylbutyryl-CoA and
      isobutyryl-CoA for synthesis of branched-chain fatty acids, this finding reflects
      the adaptation of membrane lipid composition, ensuring the maintenance of
      appropriate membrane fluidity at low temperatures. The results of the DNA array
      analyses were verified for several selected genes by RNA slot-blot analysis and
      compared with two-dimensional PAGE analyses.

PMID- 12427937
TI  - Transcriptional analysis of the gene encoding peptidyl-tRNA hydrolase in
      Escherichia coli.
AB  - Gene pth encodes peptidyl-tRNA hydrolase (Pth), an enzyme that cleaves peptidyl
      tRNAs released abortively from ribosomes during protein synthesis. In the
      Escherichia coli chromosome, pth is flanked by ychH and ychF, two genes of
      unknown function. Pth is essential for cell viability, especially under
      conditions leading to overproduction of peptidyl-tRNA. In an attempt to unveil
      the elements that affect pth expression, the transcriptional features of the pth
      region were investigated. Northern blot experiments showed that both pth and
      ychF, the 3'-proximal gene, are cotranscribed in a bicistronic transcript.
      However, transcripts containing each of the individual messages were also
      detected. Accordingly, two transcriptional promoters were identified by primer
      extension experiments: one located upstream of pth, which presumably gives rise
      to both the mono and bicistronic pth transcripts, and the other, preceding ychF,
      which generates its monocistronic message. Deletion analysis indicates that pth
      transcript stability depends on ychF integrity. Also, a defect in RNase E
      activity resulted in Pth overproduction. It is proposed that RNase E processing
      within ychF in the bicistronic message limits pth expression.

PMID- 12427938
TI  - Catabolism of mannitol in Lactococcus lactis MG1363 and a mutant defective in
      lactate dehydrogenase.
AB  - Mannitol metabolism in Lactococcus lactis MG1363 and in a derivative strain
      deficient in lactate dehydrogenase (LDH(d)) was characterized. Both strains had
      the ability to grow on mannitol as an energy source, although this polyol was a
      poorer substrate for growth than glucose. When compared to glucose, the
      metabolism of mannitol caused an NADH burden due to formation of an additional
      NADH molecule at the reaction catalysed by mannitol-1-phosphate dehydrogenase
      (Mtl1PDH). This resulted in a prominent accumulation of mannitol 1-phosphate
      (Mtl1P) both in growing and resting cells, suggesting the existence of a severe
      bottleneck at Mtl1PDH. Growth on mannitol induced the activity of Mtl1PDH in both
      the LDH(d) and MG1363 strains. The lower accumulation of Mtl1P in mannitol-grown
      cells when compared to glucose-grown LDH(d) cells, as monitored by in vivo (13)C
      NMR, reflects this induction. A clear shift towards the production of ethanol was
      observed on mannitol, indicating pressure to regenerate NAD(+) when this
      substrate was used. A strategy to obtain a mannitol-overproducing strain is
      proposed.

PMID- 12427939
TI  - Lack of cable pili expression by cblA-containing Burkholderia cepacia complex.
AB  - The Burkholderia cepacia complex consists of several closely related bacterial
      species (or genomovars) which although generally not pathogenic for healthy
      individuals, contribute significantly to morbidity and mortality among persons
      with cystic fibrosis (CF). Certain B. cepacia complex strains are more frequently
      recovered from CF sputum cultures than are others, and these typically reside in
      genomovar III. The ET12 clone is a genomovar III strain that predominates among
      CF patients in Canada and the United Kingdom and is characterized by distinctive
      cblA-encoded pili that have a cable-like morphology. In a previous survey of B.
      cepacia complex isolates recovered from 606 CF patients in the US, a single
      genomovar III ET12 isolate (isolate AU0007) was identified; several cblA
      containing genomovar I isolates, however, were also detected. In the study
      reported here, analysis by PFGE revealed several distinct strain types among
      these genomovar I isolates, and sequence analysis of their cblA genes
      demonstrated 87.8-88.4% identity to the ET12 cblA sequence. Southern analysis
      indicated that the cblA variant from each genomovar I isolate resides on a 4 kbp
      EcoRI fragment, in contrast to ET12 isolates, in which cblA localizes to a 5 kbp
      EcoRI fragment. Western blot assay indicated expression of the 16 kDa major pilin
      subunit by ET12 isolates, including AU0007, but neither whole-cell nor surface
      protein extracts of the genomovar I reacted. Electron microscopy revealed the
      complete absence of pili expression by the genomovar I isolates. In contrast to
      typical ET12 isolates, AU0007 appeared to be hyperpiliated with rigid pili that
      lacked the cable morphology and did not bind cytokeratin 13, which has been
      previously identified as the epithelial cell receptor for the ET12 cable-pili
      associated adhesin.

PMID- 12427940
TI  - The inner-core lipopolysaccharide biosynthetic waaE gene: function and genetic
      distribution among some Enterobacteriaceae.
AB  - To determine the function of the waaE gene in the biosynthesis of the inner-core
      LPS of Klebsiella pneumoniae, a waaE non-polar mutant has been constructed. Data
      obtained from the comparative chemical analysis of LPS samples obtained from the
      wild-type, the mutant strain and the complemented mutant demonstrated that the
      waaE gene is involved in substitution of alpha-L-glycero-D-manno-heptopyranose I
      (L,D-HeppI) at the O-4 position by a beta-D-glucopyranose (beta-D-Glcp) residue.
      In addition, DNA amplification and nucleotide sequence determination studies
      revealed that waaE homologues located between the waaA and coaD genes are present
      in clinical isolates of Enterobacteriaceae containing the structure beta-D-Glcp
      (1-->4)-alpha-L,D-HeppI (K. pneumoniae, Proteus mirabilis and Yersinia
      enterocolitica), as well as in strains of Serratia marcescens and Enterobacter
      aerogenes of unknown LPS-core structures. Complementation studies using non-polar
      waaE mutants prove that all the waaE homologues perform the same function.
      Furthermore, K. pneumoniae, Ser. marcescens and P. mirabilis non-polar waaE
      mutants showed reduced adhesion and pathogenicity. In addition, the Ser.
      marcescens and P. murabilis waaE mutants showed reduced swarming motility and
      ability to form biofilms in vitro. All these characteristics were rescued by
      reintroduction of the waaE gene independently of its origin. An easy DNA
      amplification method to detect this gene was established, which also helps in
      finding the potential presence of this structural feature [beta-D-Glcp-(1-->4)
      alpha-L,D-HeppI] in the inner-core LPS of Enterobacteriaceae members with unknown
      LPS-core structures.

PMID- 12427941
TI  - TonB of Escherichia coli activates FhuA through interaction with the beta-barrel.
AB  - FhuA is a multifunctional protein in the outer membrane of Escherichia coli that
      actively transports Fe(3+)-ferrichrome and the antibiotics albomycin and
      rifamycin CGP 4832, and serves as a receptor for the unrelated phages T5, T1,
      phi80 and UC-1, colicin M and microcin J25. The energy source for active
      transport is the proton-motive force of the cytoplasmic membrane, which is
      required for all FhuA functions except infection by phage T5, and is thought to
      be mediated to the outer-membrane receptor FhuA by the TonB protein. The crystal
      structure of FhuA consists of a beta-barrel that is closed by a globular domain.
      The proximal region carries the TonB box (residues 7-11), for which genetic
      evidence exists that it interacts with the region around residue 160 of TonB.
      However, deletion of the TonB box along with the globular domain results in a
      protein, FhuAdelta5-160, that still displays TonB-dependent active ferrichrome
      transport across the outer membrane and confers sensitivity to the FhuA ligands.
      In this study synthetic nonapeptides identical in sequence to amino acids 150
      158, 151-159, 152-160, 153-161 and 158-166 of TonB were shown to reduce
      ferrichrome transport of cells via wild-type FhuA and the corkless derivative
      FhuAdelta5-160, which suggests that this TonB region is involved in the
      interaction of TonB with the beta-barrel of FhuA. TonB missense mutants reduced
      the activity of FhuA and FhuAdelta5-160. TonB proteins of different
      Enterobacteriaceae activated FhuA and FhuAdelta5-160 to a similar degree. TonB of
      Pantoea agglomerans displayed low activity in an E. coli tonB mutant. Sequencing
      of the tonB gene of P. agglomerans revealed differences from E. coli TonB in the
      region around residue 160 of the deduced protein; these differences might
      contribute to the lower activity of the P. agglomerans TonB protein when coupled
      to the E. coli FhuA protein. The data support the theory that the beta-barrel
      receives the energy from the cytoplasmic membrane via TonB and responds to the
      energy input and thus represents the transporting domain of FhuA.

PMID- 12427942
TI  - Physiological analysis of the role of truB in Escherichia coli: a role for tRNA
      modification in extreme temperature resistance.
AB  - The truB gene of Escherichia coli encodes the pseudouridine-55 (psi55) synthase
      and is responsible for modifying all tRNA molecules in the cell at the U55
      position. A truB null mutant grew normally on all growth media tested, but
      exhibited a competitive disadvantage in extended co-culture with its wild-type
      progenitor. The mutant phenotype could be complemented by both the cloned truB
      gene and by a D48C, catalytically inactive allele of truB. The truB mutant also
      exhibited a defect in survival of rapid transfer from 37 to 50 degrees C. This
      mutant phenotype could be complemented by the cloned truB gene but not by a D48C,
      catalytically inactive allele of truB. The temperature sensitivity of truB
      mutants could be enhanced by combination with a mutation in the trmA gene,
      encoding an m(5)U-methyltransferase, modifying the universal U54 tRNA nucleoside,
      but not by mutations in trmH, encoding the enzyme catalysing the formation of
      Gm18. The truB mutant proteome contained altered levels of intermediates involved
      in biogenesis of the outer-membrane proteins OmpA and OmpX. The truB mutation
      also reduced the basal expression from two sigma(E) promoters, degP and rpoHP3.
      Three novel aspects to the phenotype of truB mutants were identified. Importantly
      the data support the hypothesis that TruB-effected psi55 modification of tRNA is
      not essential, but contributes to thermal stress tolerance in E. coli, possibly
      by optimizing the stability of the tRNA population at high temperatures.

PMID- 12427943
TI  - The mcrA gene as an alternative to 16S rRNA in the phylogenetic analysis of
      methanogen populations in landfill.
AB  - Inferred amino acid sequences of the methyl coenzyme-M reductase (mcrA) gene from
      five different methanogen species were aligned and two regions with a high degree
      of homology flanking a more variable region were identified. Analysis of the DNA
      sequences from the conserved regions yielded two degenerate sequences from which
      a forward primer, a 32-mer, and a reverse primer, a 23-mer, could be derived for
      use in the specific PCR-based detection of methanogens. The primers were
      successfully evaluated against 23 species of methanogen representing all five
      recognized orders of this group of Archaea, generating a PCR product between 464
      and 491 bp. Comparisons between the mcrA and 16S small subunit rRNA gene
      sequences using PHYLIP demonstrated that the tree topologies were strikingly
      similar. Methods were developed to enable the analysis of methanogen populations
      in landfill using the mcrA gene as the target. Two landfill sites were examined
      and 63 clones from a site in Mucking, Essex, and 102 from a site in Odcombe,
      Somerset, were analysed. Analysis revealed a far greater diversity in the
      methanogen population within landfill material than has been seen previously.

PMID- 12427944
TI  - Periplasmic maltose- and glucose-binding protein activities in cell-free extracts
      of Thermotoga maritima.
AB  - In this study, high-affinity maltose- and glucose-binding activities in cell-free
      extracts of Thermotoga maritima were detected; these activities were distinct and
      specific. At the gross level, the expression of binding-protein activities was
      repressed by growth of T. maritima in the presence of the cognate sugar. Growth
      of the organism in the presence of maltose reduced maltose-binding activity but
      not glucose-binding activity, while growth in the presence of glucose reduced
      glucose-binding activity but not maltose-binding activity. In competition assays,
      these binding activities showed distinct patterns of substrate specificity:
      whereas the maltose-binding activity showed specificity for alpha-linked
      glucosides, the glucose-binding activity showed a broader specificity. All
      maltose- and glucose-binding activity was found in the supernatant retrieved
      following centrifugation (100,000 g) of the cell-free extracts prepared by French
      pressure-cell treatment; no activity was found in an octyl-glucoside-treated
      extract of the membrane fraction. The maltose-binding-protein activity was
      recovered from the periplasmic fraction by selective release of the periplasmic
      contents of T. maritima cells using a newly developed freeze-thaw procedure.
      Annotation of the complete genome sequence of T. maritima suggests that there may
      be at least two maltose-binding proteins, MalE1 and MalE2, encoded in the genome.
      The maltose-binding activity corresponded to a protein of 43 kDa, which was
      consistent in size with either of the putative proteins. These data demonstrate
      that the hyperthermophilic bacterium T. maritima possesses separate maltose- and
      glucose-binding-protein activities that are freely soluble in its periplasm, in
      contrast to the membrane-bound sugar-binding proteins found in archaeal
      hyperthermophiles.

PMID- 12427945
TI  - Six GTP-binding proteins of the Era/Obg family are essential for cell growth in
      Bacillus subtilis.
AB  - GTP-binding proteins are found in all domains of life and are involved in various
      essential cellular processes. With the recent explosion of available genome
      sequence data, a widely distributed bacterial subfamily of GTP-binding proteins
      was discovered, represented by the Escherichia coli Era and the Bacillus subtilis
      Obg proteins. Although only a limited number of the GTP-binding proteins
      belonging to the subfamily have been experimentally characterized, and their
      function remains unknown, the available data suggests that many of them are
      essential to bacterial growth. When the complete genomic sequence of B. subtilis
      was surveyed for genes encoding GTP-binding proteins of the Era/Obg family, nine
      such genes were identified. As a first step in elucidating the functional
      networks of those nine GTP-binding proteins, data presented here indicates that
      six of them are essential for B. subtilis viability. Additionally, it is shown
      that the six essential proteins are able to specifically bind GTP and GDP in
      vitro. Experimental depletion of the essential GTP-binding proteins was examined
      in the context of cell morphology and chromosome replication, and it was found
      that two proteins, Bex and YqeH, appeared to participate in the regulation of
      initiation of chromosome replication. Collectively, these results suggest that
      members of the GTP-binding Era/Obg family are important proteins with precise,
      yet still not fully understood, roles in bacterial growth and viability.

PMID- 12427946
TI  - Characterization of the norCBQD genes, encoding nitric oxide reductase, in the
      nitrogen fixing bacterium Bradyrhizobium japonicum.
AB  - The genes norCBQD that encode the bc-type nitric oxide reductase from
      Bradyrhizobium japonicum USDA110 have been isolated and characterized. norC and
      norB encode the cytochrome c-containing subunit II and cytochrome b-containing
      subunit I of nitric oxide reductase, respectively. norQ encodes a protein with an
      ATP/GTP-binding motif, and the predicted norD gene product shows similarity with
      NorD from other denitrifiers. Mutational analysis indicates that the two
      structural norC and norB genes are required for microaerobic growth under nitrate
      respiring conditions. A mutant strain lacking a functional norC gene also lacked
      the 16 kDa c-type cytochrome that is normally detectable by haem-staining of
      proteins from membranes of microaerobically grown wild-type cells. Expression of
      a transcriptional fusion of the nor promoter region to the reporter gene lacZ
      (P(norC)-lacZ) was not detected in aerobically grown cells of USDA110, but the
      fusion was induced threefold when the cells were cultured under microaerobic
      conditions (1% O(2)) with either nitrite or nitric oxide, and about 18-fold when
      nitrate was the N oxide present in the medium. The P(norC)-lacZ fusion was not
      expressed in the B. japonicum fixK(2) mutant strain 9043, but complementation of
      the mutant with the fixK(2) gene restored beta-galactosidase activity to levels
      similar to those found in the parental strain. The promoter region of the norCBQD
      genes has been characterized by primer extension. A major transcript initiates
      45.5 bp downstream of the centre of a putative binding site for the transcription
      factor FixK(2).

PMID- 12427947
TI  - NisB is required for the dehydration and NisC for the lanthionine formation in
      the post-translational modification of nisin.
AB  - Nisin produced by Lactococcus lactis subsp. lactis is a 34-residue antibacterial
      polypeptide and belongs to a group of post-translationally modified peptides,
      lantibiotics, with dehydrated residues and cyclic amino acids, lanthionines.
      These modifications are supposed to be made by enzymes encoded by lanB and lanC
      genes, found only in biosynthetic operons encoding lantibiotics. To analyse the
      extent of modification, His-tagged nisin precursors were expressed in nisB and
      nisC mutant strains. The His-tagged nisin precursors were purified from the
      cytoplasm of the cells, as lack of NisB or NisC activity impaired translocation
      of the nisin precursor. The purified His-tagged polypeptides were analysed with
      trypsin digestion followed by nisin bioassay, SDS-PAGE, N-terminal sequencing and
      mass spectroscopy. According to the results, nisin precursors from the strain
      lacking NisB activity were totally unmodified, whereas nisin precursors from the
      strain lacking NisC activity, but having NisB activity, were dehydrated and
      devoid of normal lanthionine formation. This is the first experimental evidence
      showing that NisB is required for dehydration and NisC for correct lanthionine
      formation in nisin maturation.

PMID- 12427948
TI  - Tn5041-like transposons: molecular diversity, evolutionary relationships and
      distribution of distinct variants in environmental bacteria.
AB  - A detailed study on the geographic distribution, molecular diversity and
      evolutionary relationships of 24 closely related variants of the Tn5041
      transposon found among 182 mercury resistant environmental Gram-negative strains
      from the IMG-Hg Reference Collection is reported here. RFLP analysis, followed by
      the determination of partial DNA sequences, identified 14 distinct types of these
      transposons, which differed from each other by 1-7 single-event DNA
      polymorphisms. No polymorphisms were detected at the right arm of the transposons
      except an insertion of a new mobile DNA element carrying a mer operon (named the
      mer2 cassette) within the Tn5041 mer operon. According to the model presented
      here, the insertion occurred via homologous recombination with a circular form of
      the mer2 cassette. A total of 8 point mutations, 1 internal deletion, 2 end
      involving deletions, 3 mosaic regions and 2 insertions were detected at the left
      arm of the transposons. The insertions were a transposon closely related to Tn21
      but lacking the integron and a new group II intron (named INT5041C). Inspection
      of the geographic distribution of the Tn5041 variants suggested that at least
      three long-distance waves of dissemination of these variants had occurred,
      accompanied by homologous recombination between different Tn5041 lineages.
      Movements of circular DNAs by homologous recombination as a source of mosaic
      genes and new mer genes, and formation of unusual mosaics ending or beginning at
      the Tn5041 att site are discussed.

PMID- 12427949
TI  - A new regulatory DNA motif of the gamma subclass Proteobacteria: identification
      of the LexA protein binding site of the plant pathogen Xylella fastidiosa.
AB  - Escherichia coli LexA protein is the repressor of a gene network whose members
      are directly involved in the repair of damaged DNA and in the survival of
      bacterial cells until DNA lesions have been eliminated. The lexA gene is widely
      present in bacteria, although the sequences of only three LexA-binding sites are
      known: Gram-positive, alpha Proteobacteria and some members of gamma
      Proteobacteria represented by E. coli. Taking advantage of the fact that the
      genome sequence of the plant-pathogenic bacterium Xylella fastidiosa has been
      determined, its lexA gene has been cloned and overexpressed in E. coli to purify
      its product. After demonstration that X. fastidiosa lexA and recA genes are co
      transcribed, gel mobility shift assays and directed mutagenesis experiments using
      the promoter of the lexA-recA transcriptional unit demonstrated that the X.
      fastidiosa LexA protein specifically binds the imperfect palindrome
      TTAGN(6)TACTA. This is the first LexA binding sequence identified in the gamma
      Proteobacteria differing from the E. coli-like LexA box. Although a computational
      search has revealed the presence of TTAGN(6)TACTA-like motifs upstream of X.
      fastidiosa genes other than lexA, X. fastidiosa LexA only binds the promoter of
      one of them, XF2313, encoding a putative DNA-modification methylase. Moreover, X.
      fastidiosa LexA protein does not bind any of the other genes whose homologues are
      regulated by the LexA repressor in E. coli (uvrA, uvrB, ssb, ruvAB, ftsK, dinG,
      recN and ybfE). RT-PCR quantitative analysis has also demonstrated that lexA-recA
      and XF2313 genes, as well as the X. fastidiosa genes which are homologues to
      those of E. coli belonging to the LexA regulon, with the exception of ssb, are
      DNA damage-inducible in X. fastidiosa.

PMID- 12427950
TI  - cis-Acting elements that regulate the low-pH-inducible urease operon of
      Streptococcus salivarius.
AB  - Differential expression of the Streptococcus salivarius 57.I urease operon in
      response to pH is effected by repression of transcription from a proximal
      promoter, PUREI: To localize the cis-acting elements involved in the regulation
      of the urease operon, the intact promoter region and its derivatives were
      generated and fused to a promoterless chloramphenicol acetyltransferase (cat)
      gene. The promoter-cat fusions were established in the lacZ gene of S. salivarius
      by using a newly constructed integration vector. CAT-specific activities were
      examined in batch-grown cells at pH 7.5 and 5.5. The results indicated that a 21
      bp region immediately 5' to the -35 element was required for efficient repression
      of PureI at neutral pH and that the 39 bp (-57 to -95) 5' to this region
      contained sequences required for optimal expression of PUREI: A potential
      secondary repressor-binding site was tentatively identified further upstream of
      the -35 element (-96 to -115). To further analyse the cis-acting elements, base
      changes were introduced into two AT-rich repeats within the primary repressor
      binding site. One such derivative, S. salivarius M1, with five base substitutions
      immediately 5' to the -35 element, expressed 20-fold more CAT-specific activity
      at neutral pH than the strain carrying wild-type PureI-cat. Also, the pH
      sensitivity of strain M1 was greatly reduced, suggesting that this AT-rich region
      is crucial for repression of the urease operon. Deletion of three consecutive 15-
      or 16-base segments from -52 to -96 in the S. salivarius M1 background resulted
      in lower activities compared to strain M1, confirming the presence of sequences
      required for optimal expression of the operon. All of the PureI-cat fusions were
      also integrated into the gtfG gene of Streptococcus gordonii DL1, a non-ureolytic
      oral Streptococcus sp. Repression of PureI was observed at neutral pH in S.
      gordonii and the effects of the various mutations of the repressor-binding site
      largely paralleled those seen in S. salivarius, suggesting that the cis-elements
      may be a target for a global regulatory circuit that controls gene expression in
      streptococci in response to pH.

PMID- 12427951
TI  - The role of multiple SOS boxes upstream of the Mycobacterium tuberculosis lexA
      gene--identification of a novel DNA-damage-inducible gene.
AB  - Four potential binding sites for LexA were identified upstream of the
      Mycobacterium tuberculosis lexA gene. A mutational analysis of these sites in a
      lexA-lacZ reporter construct revealed that only one of these SOS boxes was
      required for DNA-damage-mediated regulation of lexA expression. A novel DNA
      damage-inducible gene, Rv2719c, was identified that was divergently transcribed
      relative to lexA; the other three SOS boxes were found to be involved in
      regulating expression of this novel mycobacterial-specific gene. The SOS boxes
      lay in the respective promoter regions of the genes that they regulated.

PMID- 12427952
TI  - Molecular analysis of the soluble butane monooxygenase from 'Pseudomonas
      butanovora'.
AB  - 'Pseudomonas butanovora' is capable of growth with butane via the oxidation of
      butane to 1-butanol, which is catalysed by a soluble butane monooxygenase (sBMO).
      In vitro oxidation of ethylene (an alternative substrate for sBMO) was
      reconstituted in the soluble portion of cell extracts and was NADH-dependent.
      Butane monooxygenase was separated into three components which were obligately
      required for substrate oxidation. The N-terminal sequences of the peptides
      associated with butane monooxygenase led to the cloning and sequencing of the
      5797 nucleotide bmo gene cluster. Comparisons of the deduced amino acid sequences
      with other multicomponent monooxygenases suggest that sBMO is a multimeric
      hydroxylase with 61, 45 and 19 kDa subunits encoded by bmoXYZ, a 40 kDa
      oxidoreductase encoded by bmoC, and a 15 kDa regulatory protein encoded by bmoB.
      A sixth structural gene (bmoD) encodes a 9.6 kDa protein with similarity
      exclusively to mmoD (orfY), a putative metal centre assembly protein of the
      soluble methane monooxygenases. Insertional inactivation of bmoX resulted in a
      mutant 'P. butanovora' strain incapable of growth with butane. A putative
      promoter element characteristic of promoters associated with sigma(54)-dependent
      transcription initiation was located upstream of the bmo genes. Expression of all
      six genes was detected in butane-induced cells. Butane monooxygenase from 'P.
      butanovora' aligns most closely with non-haem carboxylate-bridged diiron
      monooxygenases and, moreover, contains the characteristic iron-binding motif. The
      structural and mechanistic implications of the high sequence identity (up to 64%)
      between the peptides of butane monooxygenase and methane monooxygenases are
      discussed.

PMID- 12427953
TI  - Specificity of respiratory pathways involved in the reduction of sulfur compounds
      by Salmonella enterica.
AB  - The tetrathionate (Ttr) and thiosulfate (Phs) reductases of Salmonella enterica
      LT2, together with the polysulfide reductase (Psr) of Wolinella succinogenes, are
      unusual examples of enzymes containing a molybdopterin active-site cofactor since
      all formally catalyse sulfur-sulfur bond cleavage. This is in contrast to the
      oxygen or hydrogen transfer reactions exhibited by other molybdopterin enzymes.
      Here the catalytic specificity of Ttr and Phs has been compared using both
      physiological and synthetic electron-donor systems. Ttr is shown to catalyse
      reduction of trithionate but not sulfur or thiosulfate. In contrast, Phs cannot
      reduce tetrathionate or trithionate but allows whole cells to utilize elemental
      sulfur as an electron acceptor. Mechanisms are proposed by which the bacterium is
      able to utilize an insoluble sulfur substrate by means of reactions at the
      cytoplasmic rather than the outer membrane.

PMID- 12427954
TI  - Legionella pneumophila induces apoptosis via the mitochondrial death pathway.
AB  - Legionella pneumophila has been shown to induce apoptosis within macrophages,
      monocytic cell lines and alveolar epithelial cells. The mechanisms and
      significance of L. pneumophila-associated apoptosis are not well understood. It
      has been speculated that L. pneumophila may induce apoptosis through ligation of
      death receptors by bacterial surface components or by secreted bacterial factors.
      Translocation of apoptotic factor(s) through the Dot/Icm secretion machinery
      followed by direct activation of caspases within the cytosol is discussed as
      another possible mechanism of apoptosis induction by L. pneumophila. Here, it is
      shown that L. pneumophila induced the mitochondrial release of cytochrome c in
      CD95 (Fas/Apo-1)-negative monocytic Mono Mac 6 cells, indicating that Legionella
      induced apoptosis is mediated via the mitochondrial signalling pathway. In
      addition, blocking of the death receptor pathway at distinct stages using CD95-,
      FADD- or caspase-8-deficient Jurkat cells did not affect induction of apoptosis
      by L. pneumophila. Conversely, inhibition of the mitochondrial death pathway by
      overexpression of the anti-apoptotic protein Bcl-2 potently inhibited the
      processing of caspases and the induction of apoptosis. Therefore, these findings
      support a model in which the induction of apoptosis by L. pneumophila is mediated
      by activation of the intrinsic mitochondrial death pathway in the absence of
      external death receptor signalling.

PMID- 12427955
TI  - Analysis of 16S libraries of mouse gastrointestinal microflora reveals a large
      new group of mouse intestinal bacteria.
AB  - Total genomic DNA from samples of intact mouse small intestine, large intestine,
      caecum and faeces was used as template for PCR amplification of 16S rRNA gene
      sequences with conserved bacterial primers. Phylogenetic analysis of the
      amplification products revealed 40 unique 16S rDNA sequences. Of these sequences,
      25% (10/40) corresponded to described intestinal organisms of the mouse,
      including Lactobacillus spp., Helicobacter spp., segmented filamentous bacteria
      and members of the altered Schaedler flora (ASF360, ASF361, ASF502 and ASF519);
      75% (30/40) represented novel sequences. A large number (11/40) of the novel
      sequences revealed a new operational taxonomic unit (OTU) belonging to the
      Cytophaga-Flavobacter-Bacteroides phylum, which the authors named 'mouse
      intestinal bacteria'. 16S rRNA probes were developed for this new OTU. Upon
      analysis of the novel sequences, eight were found to cluster within the
      Eubacterium rectale-Clostridium coccoides group and three clustered within the
      Bacteroides group. One of the novel sequences was distantly related to
      Verrucomicrobium spinosum and one was distantly related to Bacillus mycoides.
      Oligonucleotide probes specific for the 16S rRNA of these novel clones were
      generated. Using a combination of four previously described and four newly
      designed probes, approximately 80% of bacteria recovered from the murine large
      intestine and 71% of bacteria recovered from the murine caecum could be
      identified by fluorescence in situ hybridization (FISH).

PMID- 12427956
TI  - Comparative studies of immunity proteins of pediocin-like bacteriocins.
AB  - Genes encoding pediocin-like bacteriocins are usually co-transcribed with a gene
      encoding a cognate immunity protein. To investigate the functionality and
      specificity of immunity proteins, immunity genes belonging to the bacteriocins
      curvacin A, enterocin A, enterocin P, leucocin A, pediocin PA-1 and sakacin P, as
      well as a putative immunity gene, orfY, were expressed in three bacteriocin
      sensitive lactic acid bacteria (Lactobacillus sake, Carnobacterium piscicola and
      Enterococcus faecalis). The transformed indicator strains, each containing one of
      the immunity genes, were tested for sensitivity towards seven different purified
      bacteriocins (curvacin A, enterocin A, enterocin P, leucocin A, leucocin C,
      pediocin PA-1 and sakacin P). Cross-immunity was observed almost exclusively in
      situations where either the bacteriocins or the immunity proteins belonged to the
      same sequence-based subgroup. In a few cases, the functionality of immunity
      proteins was strain-dependent; e.g. the leucocin A immunity gene provided
      immunity to enterocin A, pediocin PA-1 and leucocin A in Ent. faecalis, whereas
      in the other two indicators, this gene provided immunity to leucocin A only. The
      orfY gene, which is transcribed without a cognate bacteriocin, was shown to
      encode a functional immunity protein that expands the bacteriocin resistance of
      the strain possessing this gene. The results show that the bacteriocin
      sensitivity of a lactic acid bacterium strain can depend on (1) the presence of
      immunity genes in connection with its own bacteriocin production, (2) the
      presence of extra immunity genes and (3) more general properties of the strain
      such as the membrane composition or the presence of receptors.

PMID- 12427957
TI  - Identification of strain-specific genes located outside the plasticity zone in
      nine clinical isolates of Helicobacter pylori.
AB  - Helicobacter pylori is a Gram-negative bacterium that is associated with the
      development of peptic ulcers and gastric carcinoma in humans. This species
      appears to be one of the most genetically variable bacteria described to date.
      The overall level of heterogeneity within strains of this organism was determined
      by comparing the genome sequences of two reference strains, J99 and 26695. The
      aim of this study was to measure the genetic diversity within strains of H.
      pylori by looking for strain-specific genes in nine H. pylori strains isolated
      from patients suffering from chronic gastritis (n=3), duodenal ulcers (n=3) or
      gastric cancer (n=3). Seven loci that contained strain-specific genes in strains
      J99 and 26695 were studied. These regions were subsequently amplified from most
      of the clinical isolates studied and their sequences were determined. ORFs were
      predicted from the sequence data and were compared to sequences within the
      databases. The results showed that the genes flanking the ORFs specific to either
      strain J99 or strain 26695 were also present in a similar configuration in the
      genomes of the nine clinical isolates. Moreover, in most regions, ORFs homologous
      to those found in the corresponding loci in the two reference strains were
      detected. However, in 10 regions, genes similar to those located at another locus
      in the genome of J99 or 26695 were found. Finally, six strain-specific genes were
      identified in three regions of three of the H. pylori strains isolated from
      patients with duodenal ulcers (n=2) and gastric cancer (n=1). Of these six genes,
      five were putative genes and one was an orthologue of a gene encoding a
      transposase in Thermotoga maritima. However, no association with disease was
      found for these genes.

PMID- 12427958
TI  - Characterization of a novel Vibrio pathogenicity island (VPI-2) encoding
      neuraminidase (nanH) among toxigenic Vibrio cholerae isolates.
AB  - Acquisition of virulence genes encoded on mobile genetic elements has played an
      important role in the emergence of pathogenic isolates of Vibrio cholerae, the
      causative agent of the diarrhoeal disease cholera. The genes encoding cholera
      toxin (ctxAB), the main cause of profuse secretory diarrhoea in cholera, are
      encoded on a filamentous bacteriophage CTXphi. The toxin coregulated pilus (TCP),
      an essential intestinal colonization factor, was originally designated as part of
      a pathogenicity island named the Vibrio pathogenicity island (VPI), but this
      island has more recently been proposed to be the genome of a filamentous phage,
      VPIphi. In this study, it is shown that nanH, which encodes neuraminidase, maps
      within a novel pathogenicity island designated VPI-2. The 57.3 kb VPI-2 has all
      of the characteristic features of a pathogenicity island, including the presence
      of a bacteriophage-like integrase (int), insertion in a tRNA gene (serine) and
      the presence of direct repeats at the chromosomal integration sites.
      Additionally, the G+C content of VPI-2 (42 mol%) is considerably lower than that
      of the entire genome (47 mol%). VPI-2 encodes several gene clusters, such as a
      restriction modification system (hsdR and hsdM) and genes required for the
      utilization of amino sugars (nan-nag region) as well as neuraminidase. To
      determine the distribution of VPI-2 among V. cholerae, 78 natural isolates were
      examined using PCR and Southern hybridization analysis for the presence of this
      region. All toxigenic V. cholerae O1 serogroup isolates examined contained VPI-2,
      whereas non-toxigenic isolates lacked the island. Of 14 V. cholerae O139
      serogroup isolates examined, only one strain, MO2, contained the entire 57.3 kb
      island, whereas 13 O139 isolates contained only a 20.0 kb region with most of the
      5' region of VPI-2 which included nanH deleted in these strains.

PMID- 12427959
TI  - Peptide methionine sulfoxide reductase (MsrA) is not a major virulence
      determinant for the oral pathogen Actinobacillus actinomycetemcomitans.
AB  - Actinobacillus actinomycetemcomitans is an oral pathogen that is a causative
      agent for periodontal disease as well as other non-oral infections. The chronic
      inflammation associated with periodontal diseases suggests that the bacterium
      must be able to neutralize oxygen intermediates to survive in the host tissues.
      Methionine sulfoxide reductase (MsrA) is an enzyme that has been demonstrated to
      have a role in protection against oxidative damage and has also been identified
      to be required for the proper expression or maintenance of functional adhesins on
      the surface of several pathogenic bacteria. The A. actinomycetemcomitans
      homologue of msrA has been isolated and a chromosomal insertion mutant
      constructed by allele replacement mutagenesis. Inactivation of the gene led to a
      complete loss of enzymic activity toward a synthetic substrate. However, the
      isogenic mutant was not more sensitive to oxidative stress or less adherent to
      epithelial cells as compared with the parent strain. These data suggest that this
      strain of A. actinomycetemcomitans has redundant systems that compensate for the
      MsrA activities ascribed for other organisms.

PMID- 12427960
TI  - Copper- and zinc-containing superoxide dismutase (Cu/ZnSOD) is required for the
      protection of Candida albicans against oxidative stresses and the expression of
      its full virulence.
AB  - Copper- and zinc-containing superoxide dismutase (Cu/ZnSOD) is suspected to be
      one of the anti-oxidant enzymes and virulence determinants active in some
      pathogenic micro-organisms. To elucidate the role of Cu/ZnSOD in the major human
      fungal pathogen Candida albicans, its gene, designated SOD1, was disrupted by the
      URA-blaster technique. The resulting sod1/sod1 mutant showed delayed hyphal
      growth on Spider medium but could still form hyphae on other solid media or in
      liquid media, particularly in response to serum. Moreover, the sod1/sod1 mutant
      was more sensitive to menadione, a redox-cycling agent, than the isogenic wild
      type strain, although it still showed an adaptive oxidative stress response.
      Furthermore, the sod1/sod1 mutant cells exhibited slow growth in minimal medium
      when compared to the wild-type cells, but their growth was restored by the
      addition of lysine to the medium. Interestingly, C. albicans cells lacking
      Cu/ZnSOD showed increased susceptibility to macrophage attack and had attenuated
      virulence in mice. Thus, these results suggest that Cu/ZnSOD is required for the
      protection of C. albicans against oxidative stresses and for the full virulence
      of the organism to be expressed.

PMID- 12427961
TI  - Cycles of mitochondrial energization driven by the ultradian clock in a
      continuous culture of Saccharomyces cerevisiae.
AB  - A continuous culture of Saccharomyces cerevisiae IFO 0233, growing with glucose
      as the major carbon and energy source, shows oscillations of respiration with a
      period of 48 min. Samples taken at maxima and minima indicate that (i) periodic
      changes do not occur as a result of carbon depletion, (ii) intrinsic differences
      in respiratory activity occur in washed organisms and (iii) a respiratory
      inhibitor accumulates during respiratory oscillations. Plasma membrane and inner
      mitochondrial membranes generate transmembrane electrochemical potentials;
      changes in these can be respectively assessed using anionic or cationic
      fluorophores. Thus flow cytometric analyses indicated that an oxonol dye
      [DiBAC(4)(3); bis(1,3-dibutylbarbituric acid)trimethine oxonol] was excluded from
      yeasts to a similar extent (in >98% of the population) at all stages, showing
      that the plasma membrane potential was maintained at a steady value. However,
      uptake of Rhodamine 123 was greatest at that phase characterized by a low
      respiratory rate. Addition of uncouplers of energy conservation [CCCP (m
      chlorocarbonylcyanide phenylhydrazone) or S-13(5-chloro-3-t-butyl-2-chloro-4(1)
      nitrosalicylanilide)] to the continuous cultures increased the respiration, but
      had only a transient effect on the period of the oscillation. Electron microscopy
      showed changes in mitochondrial ultrastructure during the respiratory
      oscillation. At low respiration the cristae were more clearly defined due to
      swelling of the matrix; this corresponds to the 'orthodox' conformation. When
      respiration was high the mitochondrial configuration was 'condensed'. It has been
      shown previously that a temperature-compensated ultradian clock operates in S.
      cerevisiae. It is proposed that mitochondria undergo cycles of energization in
      response to energetic demands driven by this ultradian clock output.

PMID- 12427962
TI  - YlBMH1 encodes a 14-3-3 protein that promotes filamentous growth in the dimorphic
      yeast Yarrowia lipolytica.
AB  - Most pathogenic fungi have the ability to alternate between a unicellular yeast
      form and different filamentous forms (hyphae and pseudohyphae). This attribute is
      generally regarded as an important virulence factor and has also attracted
      attention because of its implications in the study of eukaryotic cell
      differentiation. To identify genes that are involved in the regulation of these
      events, chemical mutagenesis of the dimorphic yeast Yarrowia lipolytica was
      performed and morphological mutants that were unable to form hyphal cells were
      isolated. Screening of a Y. lipolytica genomic DNA library for genes able to
      complement this defect led to the isolation of YlBMH1, a gene encoding a 14-3-3
      protein and whose transcription levels are increased during the yeast-to-hypha
      transition. Remarkably, overexpression of YlBMH1 was able to enhance pseudohyphae
      formation in a strain lacking functional YlRAC1 but caused no visible effects in
      deltamhy1 and deltabem1 cells, thus suggesting that YlBMH1 is involved in the
      regulation of both hyphal and pseudohyphal growth in Y. lipolytica. The
      identification of YlBMH2, a gene encoding a second 14-3-3 protein (YlBmh2p) that
      contains a 19 aa insertion absent in all other members of the 14-3-3 family, is
      also reported. Differently from YlBMH1, the transcription levels of YlBMH2 do not
      show any apparent variation during the induction of hyphal growth, and its
      overexpression has no effects on cells lacking functional MHY1, YlRAC1 or YlBEM1.
      Taken together, these observations suggest that, in spite of their high
      conservation, YlBmh1p and YlBmh2p have different cellular functions.

PMID- 12427963
TI  - Naphthalene, an insect repellent, is produced by Muscodor vitigenus, a novel
      endophytic fungus.
AB  - Muscodor vitigenus is a recently described endophytic fungus of Paullinia
      paullinioides, a liana growing in the understorey of the rainforests of the
      Peruvian Amazon. This fungus produces naphthalene under certain cultural
      conditions. Naphthalene produced by M. vitigenus was identified by gas
      chromatography/mass spectrometry. Its chromatographic and mass spectral
      properties were identical to authentic naphthalene. Agar plugs supporting growth
      of the fungus and producing known amounts of naphthalene effectively repelled the
      adult stage of the wheat stem sawfly, Cephus cinctus, in Y-tube bioassay tests.
      Authentic naphthalene, at comparable concentrations to those in tests involving
      the fungus itself, mimicked the insect repellency of the fungus. Although other
      Muscodor spp. produce volatile antimicrobials, M. vitigenus is unique in its
      ability to produce naphthalene almost exclusively. This report also describes the
      potential practical implications of M. vitigenus.

PMID- 12427964
TI  - Differential secretion of Sap4-6 proteins in Candida albicans during hyphae
      formation.
AB  - Secreted aspartyl proteinases (Saps) from Candida albicans are encoded by a multi
      gene family and are considered to be putative virulence factors for candidiasis.
      SAP4-6 mRNAs were first detected during hyphae formation and were assumed to play
      roles in the development of disseminated candidiasis. Recombinant Sap proteins
      (Sap2-6) were prepared and specific antibodies were generated against Sap2-6. The
      presence of Sap4, Sap5 and Sap6, but not Sap2 or Sap3, was demonstrated in
      culture supernatants of C. albicans after induction of hyphae formation. In
      parallel to hyphae formation, Sap5 (approximately 40 kDa) was detected as early
      as approximately 6 h after induction at neutral pH, and Sap4/6 (approximately 43
      kDa) were detected after approximately 24 h when the culture medium became
      acidic. The differential secretion of Sap5 and Sap4/6 was affected when the
      culture medium pH was buffered at pH 6.5 or pH 4.5. In addition, intracellular
      pools of Sap4-6 seem to exist, and protein is not necessary for Sap4-6 induction.
      This study provides the first evidence that Sap4-6 proteins in C. albicans are
      differentially produced and secreted during hyphae formation.

PMID- 12427965
TI  - Crystalline variational methods.
AB  - A surface free energy function is defined to be crystalline if its Wulff shape
      (the equilibrium crystal shape) is a polyhedron. All the questions that one
      considers for the area functional, where the surface free energy per unit area is
      1 for all normal directions, can be considered for crystalline surface free
      energies. Such questions are interesting for both mathematical and physical
      reasons. Methods from the geometric calculus of variations are useful for
      studying a number of such questions; a survey of some of the results is given.

PMID- 12427966
TI  - NCX-1015, a nitric-oxide derivative of prednisolone, enhances regulatory T cells
      in the lamina propria and protects against 2,4,6-trinitrobenzene sulfonic acid
      induced colitis in mice.
AB  - NCX-1015 is a nitric oxide (NO)-releasing derivative of prednisolone. In this
      study we show NCX-1015 protects mice against the S. A. development and induces
      healing of T helper cell type 1-mediated experimental colitis induced by
      intrarectal administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS). The
      beneficial effect of NCX-1015 was reflected in increased survival rates,
      improvement of macroscopic and histologic scores, a decrease in the mucosal
      content of T helper cell type 1 cytokines (protein and mRNA), and diminished
      myeloperoxidase activity in the colon. In contrast to its NO derivative, only
      very high doses of prednisolone were effective in reproducing these beneficial
      effects. NCX-1015 was 10- to 20-fold more potent than the parent compound in
      inhibiting IFN-gamma secretion by lamina propria mononuclear cells. Protection
      against developing colitis correlated with inhibition of nuclear translocation of
      p65Rel A in these cells. In vivo treatment with NCX-1015 potently stimulated IL
      10 production, suggesting that the NO steroid induces a regulatory subset of T
      cells that negatively modulates intestinal inflammation.

PMID- 12427967
TI  - Circular dichroism spectra of short, fixed-nucleus alanine helices.
AB  - Very short alanine peptide helices can be studied in a fixed-nucleus, helix
      forming system [Siedlicka, M., Goch, G., Ejchart, A., Sticht, H. & Bierzynski, A.
      (1999) Proc. Natl. Acad. Sci. USA 96, 903-908]. In a 12-residue sequence taken
      from an EF-hand protein, the four C-terminal peptide units become helical when
      the peptide binds La(3+), and somewhat longer helices may be made by adding
      alanine residues at the C terminus. The helices studied here contain 4, 8, or 11
      peptide units. Surprisingly, these short fixed-nucleus helices remain almost
      fully helical from 4 to 65 degrees C, according to circular dichroism results
      reported here, and in agreement with titration calorimetry results reported
      recently. These peptides are used here to define the circular dichroism
      properties of short helices, which are needed for accurate measurement of helix
      propensities. Two striking properties are: (i) the temperature coefficient of
      mean peptide ellipticity depends strongly on helix length; and (ii) the intensity
      of the signal decreases much less rapidly with helix length, for very short
      helices, than supposed in the past. The circular dichroism spectra of the short
      helices are compared with new theoretical calculations, based on the
      experimentally determined direction of the NV(1) transition moment.

PMID- 12427968
TI  - Increased rates of cerebral glucose metabolism in a mouse model of fragile X
      mental retardation.
AB  - In humans, failure to express the fragile X mental retardation protein (FMRP)
      gives rise to fragile X syndrome, the most common form of inherited mental
      retardation. A fragile X knockout (fmr1 KO) mouse has been described that has
      some of the characteristics of patients with fragile X syndrome, including
      immature dendritic spines and subtle behavioral deficits. In our behavioral
      studies, fmr1 KO mice exhibited hyperactivity and a higher rate of entrance into
      the center of an open field compared with controls, suggesting decreased levels
      of anxiety. Our finding of impaired performance of fmr1 KO mice on a passive
      avoidance task is suggestive of a deficit in learning and memory. In an effort to
      understand what brain regions are involved in the behavioral abnormalities, we
      applied the [(14)C]deoxyglucose method for the determination of cerebral
      metabolic rates for glucose (CMR(glc)). We measured CMR(glc) in 38 regions in
      adult male fmr1 KO and WT littermates. We found CMR(glc) was higher in all 38
      regions in fmr1 KO mice, and in 26 of the regions, differences were statistically
      significant. Differences in CMR(glc) ranged from 12% to 46%, and the greatest
      differences occurred in regions of the limbic system and primary sensory and
      posterior parietal cortical areas. Regions most affected are consistent with
      behavioral deficiencies and regions in which FMRP expression is highest. Higher
      CMR(glc) in fragile X mice may be a function of abnormalities found in dendritic
      spines.

PMID- 12427969
TI  - Multiple subnuclear targeting signals of the leukemia-related AML1/ETO and ETO
      repressor proteins.
AB  - Leukemic disease can be linked to aberrant gene expression. This often is the
      result of molecular alterations in transcription factors that lead to their
      misrouting within the nucleus. The acute myelogenous leukemia-related fusion
      protein AML1ETO is a striking example. It originates from a gene rearrangement
      t(8;21) that fuses the N-terminal part of the key hematopoietic regulatory factor
      AML1 (RUNX1) to the ETO (MTG8) repressor protein. AML1ETO lacks the intranuclear
      targeting signal of the wild-type AML1 and is directed by the ETO component to
      alternate nuclear matrix-associated sites. To understand this aberrant subnuclear
      trafficking of AML1ETO, we created a series of mutations in the ETO protein.
      These were characterized biochemically by immunoblotting and in situ by
      immunofluorescence microscopy. We identified two independent subnuclear targeting
      signals in the N- and C-terminal regions of ETO that together direct ETO to the
      same binding sites occupied by AML1ETO. However, each segment alone is targeted
      to a different intranuclear location. The N-terminal segment contains a nuclear
      localization signal and the conserved hydrophobic heptad repeat domain
      responsible for protein dimerization and interaction with the mSin3A
      transcriptional repressor. The C-terminal segment spans the nervy domain and the
      zinc finger region, which together support interactions with the corepressors N
      CoR and HDACs. Our findings provide a molecular basis for aberrant subnuclear
      targeting of the AML1ETO protein, which is a principal defect in t(8;21)-related
      acute myelogenous leukemia.

PMID- 12427971
TI  - Ultrafast surface hydration dynamics and expression of protein functionality:
      alpha -Chymotrypsin.
AB  - We report studies of hydration dynamics at the surface of the enzyme protein
      bovine pancreatic alpha-chymotrypsin. The probe is the well known 1
      anilinonaphthalene-8-sulfonate, which binds selectively in the native state of
      the protein, not the molten globule, as shown by x-ray crystallography. With
      femtosecond time resolution, we examined the hydration dynamics at two pHs, when
      the protein is physiologically in the inactive state (pH 3.6) or the active state
      (pH 6.7); the global structure and the binding site remain the same. The
      hydration correlation function, C(t), whose decay is governed by the rotational
      and translational motions of water molecules at the site, shows the behavior
      observed in this laboratory for other proteins, Subtilisin Carlsberg and
      Monellin, using the intrinsic amino acid tryptophan as a probe for surface
      hydration. However, the time scales and amplitudes vary drastically at the two
      pHs. For the inactive protein state, C(t) decays with an ultrafast component,
      close to bulk-type behavior, but 50% of the C(t) decays at a much slower rate,
      tau = 43 ps. In contrast, for the active state, the ultrafast component becomes
      dominant (90%) and the slow component changes to a faster decay, tau = 28 ps.
      These results indicate that in the active state water molecules in the hydration
      layer around the site have a high degree of mobility, whereas in the inactive
      state the water is more rigidly structured. For the substrate-enzyme complex, the
      function and dynamics at the probe site are correlated, and the relevance to the
      enzymatic action is clear.

PMID- 12427970
TI  - Adoptive T cell therapy using antigen-specific CD8+ T cell clones for the
      treatment of patients with metastatic melanoma: in vivo persistence, migration,
      and antitumor effect of transferred T cells.
AB  - Adoptive T cell therapy, involving the ex vivo selection and expansion of antigen
      specific T cell clones, provides a means of augmenting antigen-specific immunity
      without the in vivo constraints that can accompany vaccine-based strategies. A
      phase I study was performed to evaluate the safety, in vivo persistence, and
      efficacy of adoptively transferred CD8+ T cell clones targeting the tumor
      associated antigens, MART1MelanA and gp100 for the treatment of patients with
      metastatic melanoma. Four infusions of autologous T cell clones were
      administered, the first without IL-2 and subsequent infusions with low-dose IL-2
      (at 0.25, 0.50, and 1.0 x 10(6) unitsm(2) twice daily for the second, third, and
      fourth infusions, respectively). Forty-three infusions of MART1MelanA-specific or
      gp100-specific CD8+ T cell clones were administered to 10 patients. No serious
      toxicity was observed. We demonstrate that the adoptively transferred T cell
      clones persist in vivo in response to low-dose IL-2, preferentially localize to
      tumor sites and mediate an antigen-specific immune response characterized by the
      elimination of antigen-positive tumor cells, regression of individual metastases,
      and minor, mixed or stable responses in 8 of 10 patients with refractory,
      metastatic disease for up to 21 mo.

PMID- 12427972
TI  - Kidney-specific chloride channel, OmClC-K, predominantly expressed in the
      diluting segment of freshwater-adapted tilapia kidney.
AB  - The kidney plays an important role in osmoregulation in freshwater teleosts,
      which are exposed to the danger of osmotic loss of Na(+) and Cl(-). However, ion
      transport mechanisms in the kidney are poorly understood, and ion transporters of
      the fish nephron have not been identified thus far. From Mozambique tilapia,
      Oreochromis mossambicus, we have cloned a chloride channel, which is a homologue
      of the mammalian kidney-specific chloride channel, ClC-K. The cDNA of the
      channel, named OmClC-K, encodes a protein whose amino acid sequence has high
      homology to Xenopus and mammalian ClC-K (Xenopus ClC-K, 41.8%; rat ClC-K2, 40.9%;
      rat ClC-K1, 40.1%). The mRNA of OmClC-K was expressed exclusively in the kidney,
      and the expression level of mRNA was increased more in freshwater-adapted fish
      than seawater-adapted fish. The immunohistochemical study using a specific
      antibody showed that OmClC-K-positive cells were specifically located in the
      distal nephron segments. Immunoelectron microscopy further showed that
      immunoreaction of OmClC-K was recognizable on the structure of basolateral
      membrane infoldings in the distal tubule cells. The localization of OmClC-K and
      its induction in hypoosmotic media suggest that OmClC-K is involved in Cl(-)
      reabsorption in the distal tubule of freshwater-adapted tilapia.

PMID- 12427973
TI  - Crystal structure of a human aminoacyl-tRNA synthetase cytokine.
AB  - The 20 aminoacyl-tRNA synthetases catalyze the first step of protein synthesis
      and establish the rules of the genetic code through aminoacylation reactions.
      Biological fragments of two human enzymes, tyrosyl-tRNA synthetase (TyrRS) and
      tryptophanyl-tRNA synthetase, connect protein synthesis to cell-signaling
      pathways including angiogenesis. Alternative splicing or proteolysis produces
      these fragments. The proangiogenic N-terminal fragment mini-TyrRS has IL-8-like
      cytokine activity that, like other CXC cytokines, depends on a Glu-Leu-Arg motif.
      Point mutations in this motif abolish cytokine activity. The full-length native
      TyrRS lacks cytokine activity. No structure has been available for any mammalian
      tRNA synthetase that, in turn, might give insight into why mini-TyrRS and not
      TyrRS has cytokine activities. Here, the structure of human mini-TyrRS, which
      contains both the catalytic and the anticodon recognition domain, is reported to
      a resolution of 1.18 A. The critical Glu-Leu-Arg motif is located on an internal
      alpha-helix of the catalytic domain, where the guanidino side chain of R is part
      of a hydrogen-bonding network tethering the anticodon-recognition domain back to
      the catalytic site. Whereas the catalytic domains of the human and bacterial
      enzymes superimpose, the spatial disposition of the anticodon recognition domain
      relative to the catalytic domain is unique in mini-TyrRS relative to the
      bacterial orthologs. This unique orientation of the anticodon-recognition domain
      can explain why the fragment mini-TyrRS, and not full-length native TyrRS, is
      active in cytokine-signaling pathways.

PMID- 12427974
TI  - Targeting the Mycobacterium tuberculosis 30/32-kDa mycolyl transferase complex as
      a therapeutic strategy against tuberculosis: Proof of principle by using
      antisense technology.
AB  - We have investigated the effect of sequence-specific antisense phosphorothioate
      modified oligodeoxyribonucleotides (PS-ODNs) targeting different regions of each
      of the 3032-kDa protein complex (antigen 85 complex) encoding genes on the
      multiplication of Mycobacterium tuberculosis. Single PS-ODNs to one of the three
      mycolyl transferase transcripts, added either once or weekly over the 6-wk
      observation period, inhibited bacterial growth by up to 1 log unit. A combination
      of three PS-ODNs specifically targeting all three transcripts inhibited bacterial
      growth by approximately 2 logs; the addition of these PS-ODNs weekly for 6 wk was
      somewhat more effective than a one-time addition. Targeting the 5' end of the
      transcripts was more inhibitory than targeting internal sites; the most effective
      PS-ODNs and target sites had minimal or no secondary structure. The effect of the
      PS-ODNs was specific, as mismatched PS-ODNs had little or no inhibitory activity.
      The antisense PS-ODNs, which were highly stable in M. tuberculosis cultures,
      specifically blocked protein expression by their gene target. PS-ODNs targeting
      the transcript of a related 24-kDa protein (mpt51) had little inhibitory effect
      by themselves and did not increase the effect of PS-ODNs against the three
      members of the 3032-kDa protein complex. The addition of PS-ODNs against the
      transcripts of glutamine synthetase I (glnA1) and alanine racemase (alr) modestly
      increased the inhibitory efficacy of the 3032-kDa protein complex-specific PS
      ODNs to approximately 2.5 logs. This study shows that the three mycolyl
      transferases are highly promising targets for antituberculous therapy by using
      antisense or other antimicrobial technologies.

PMID- 12427975
TI  - Elucidation of the methylerythritol phosphate pathway for isoprenoid biosynthesis
      in bacteria and plastids. A metabolic milestone achieved through genomics.

PMID- 12427976
TI  - Chromatin-remodeling and memory factors. New regulators of plant development.

PMID- 12427977
TI  - Brefeldin A: deciphering an enigmatic inhibitor of secretion.

PMID- 12427978
TI  - Global changes in gene expression in response to high light in Arabidopsis.
AB  - A range of environmental conditions can lead to oxidative stress; thus, a prompt
      and effective response to oxidative stress is crucial for the survival of plants.
      Microarray and northern-blot analyses were performed toward the identification of
      the factors and signaling pathways that enable plants to limit oxidative damage
      caused by exposure to high light (HL). Arabidopsis plants grown under moderate
      light (100 micromol m(-2) s(-1)) were exposed to HL (1,000 micromol m(-2) s(-1))
      for 1 h. The microarray analyses revealed that exposure of Arabidopsis to HL
      caused an increase in known antioxidant genes, as well as several unknown genes.
      Some of these unknown genes had homologies to possible regulatory genes and
      metabolic enzymes. Furthermore, it was found that a range of chaperones were up
      regulated in the HL treatment and that this induction was specifically due to the
      HL stress. The temporal expression under HL and different oxidative stress
      conditions of a subset of HL-responsive genes was confirmed via northern-blot
      analysis. Results from the arrays were also compared with publicly available
      microarray data sets from a range of different stress conditions at the
      Arabidopsis Functional Genomics Consortium. This cross comparison enabled the
      identification of genes that may be induced by changes in redox poise. Finally,
      to determine if the genes that were differentially expressed by HL stress were
      under similar transcriptional control, we analyzed the promoter sequences for the
      presence of common motifs.

PMID- 12427979
TI  - Function of a plant stress-induced gene, HVA22. Synthetic enhancement screen with
      its yeast homolog reveals its role in vesicular traffic.
AB  - Expression of the barley (Hordeum vulgare) HVA22 gene is induced by environmental
      stresses, such as dehydration, salinity, and extreme temperatures, and by a plant
      stress hormone, abscisic acid. Genes sharing high level of sequence similarities
      with HVA22 exist in diverse eukaryotic organisms, including animals, plants, and
      fungi, but not in any prokaryotic organisms. The yeast (Saccharomyces cerevisiae)
      HVA22 homolog, Yop1p, has been shown to interact with the GTPase-interacting
      protein, Yip1p. Deletion of YOP1 led to only a modest reduction of the stationary
      phase titer at 37C. A synthetic enhancement mutant screen was performed in the
      yop1 deletion background to identify genes interacting with YOP1. The open
      reading frame YOR165W (renamed SEY1 for synthetic enhancement of YOP1) was
      identified as a YOP1-dependent complementation gene. The yeast SEY1 is a homolog
      of the Arabidopsis RHD3 gene whose mutations cause the accumulation of transport
      vesicles near the tips of defective root hairs. The yeast double mutant of yop1
      and sey1 is defective in vesicular traffic as evidenced by the accumulation of
      transport vesicles and the decrease in invertase secretion. Based on these
      observations, we suggest that Yop1p/HVA22 regulates vesicular traffic in stressed
      cells either to facilitate membrane turnover, or to decrease unnecessary
      secretion.

PMID- 12427980
TI  - LeCTR1, a tomato CTR1-like gene, demonstrates ethylene signaling ability in
      Arabidopsis and novel expression patterns in tomato.
AB  - LeCTR1 was initially isolated by both differential display reverse transcriptase
      polymerase chain reaction screening for tomato (Lycopersicon esculentum) fruit
      ethylene-inducible genes and through homology with the Arabidopsis CTR1 cDNA.
      LeCTR1 shares strong nucleotide sequence homology with Arabidopsis CTR1, a gene
      acting downstream of the ethylene receptor and showing similarity to the Raf
      family of serine/threonine protein kinases. The length of the LeCTR1 transcribed
      region from ATG to stop codon (12,000 bp) is more than twice that of Arabidopsis
      CTR1 (4,700 bp). Structural analysis reveals perfect conservation of both the
      number and position of introns and exons in LeCTR1 and Arabidopsis CTR1. The
      introns in LeCTR1 are much longer, however. To address whether this structural
      conservation is indicative of functional conservation of the corresponding
      proteins, we expressed LeCTR1 in the Arabidopsis ctr1-1 (constitutive triple
      response 1) mutant under the direction of the 35S promoter. Our data clearly show
      that ectopic expression of LeCTR1 in the Arabidopsis ctr1-1 mutant can restore
      normal ethylene signaling. The recovery of normal ethylene sensitivity upon
      heterologous expression of LeCTR1 was also confirmed by restored glucose
      sensitivity absent in the Arabidopsis ctr1-1 mutant. Expression studies confirm
      ethylene responsiveness of LeCTR1 in various tissues, including ripening fruit,
      and may suggest the evolution of alternate regulatory mechanisms in tomato versus
      Arabidopsis.

PMID- 12427981
TI  - The combined effect of drought stress and heat shock on gene expression in
      tobacco.
AB  - In nature, plants encounter a combination of environmental conditions that may
      include stresses such as drought or heat shock. Although drought and heat shock
      have been extensively studied, little is known about how their combination affect
      plants. We used cDNA arrays, coupled with physiological measurements, to study
      the effect of drought and heat shock on tobacco (Nicotiana tabacum) plants. A
      combination of drought and heat shock resulted in the closure of stomata,
      suppression of photosynthesis, enhancement of respiration, and increased leaf
      temperature. Some transcripts induced during drought, e.g. those encoding
      dehydrin, catalase, and glycolate oxidase, and some transcripts induced during
      heat shock, e.g. thioredoxin peroxidase, and ascorbate peroxidase, were
      suppressed during a combination of drought and heat shock. In contrast, the
      expression of other transcripts, including alternative oxidase, glutathione
      peroxidase, phenylalanine ammonia lyase, pathogenesis-related proteins, a WRKY
      transcription factor, and an ethylene response transcriptional co-activator, was
      specifically induced during a combination of drought and heat shock.
      Photosynthetic genes were suppressed, whereas transcripts encoding some
      glycolysis and pentose phosphate pathway enzymes were induced, suggesting the
      utilization of sugars through these pathways during stress. Our results
      demonstrate that the response of plants to a combination of drought and heat
      shock, similar to the conditions in many natural environments, is different from
      the response of plants to each of these stresses applied individually, as
      typically tested in the laboratory. This response was also different from the
      response of plants to other stresses such as cold, salt, or pathogen attack.
      Therefore, improving stress tolerance of plants and crops may require a
      reevaluation, taking into account the effect of multiple stresses on plant
      metabolism and defense.

PMID- 12427982
TI  - Isolation and characterization of a rice dwarf mutant with a defect in
      brassinosteroid biosynthesis.
AB  - We have isolated a new recessive dwarf mutant of rice (Oryza sativa L. cv
      Nipponbare). Under normal growth conditions, the mutant has very short leaf
      sheaths; has short, curled, and frizzled leaf blades; has few tillers; and is
      sterile. Longitudinal sections of the leaf sheaths revealed that the cell length
      along the longitudinal axis is reduced, which explains the short leaf sheaths.
      Transverse sections of the leaf blades revealed enlargement of the motor cells
      along the dorsal-ventral axis, which explains the curled and frizzled leaf
      blades. In addition, the number of crown roots was smaller and the growth of
      branch roots was weaker than those in the wild-type plant. Because exogenously
      supplied brassinolide considerably restored the normal phenotypes, we designated
      the mutant brassinosteroid-dependent 1 (brd1). Further, under darkness, brd1
      showed constitutive photomorphogenesis. Quantitative analyses of endogenous
      sterols and brassinosteroids (BRs) indicated that BR-6-oxidase, a BR biosynthesis
      enzyme, would be defective. In fact, a 0.2-kb deletion was detected in the
      genomic region of OsBR6ox (a rice BR-6-oxidase gene) in the brd1 mutant. These
      results indicate that BRs are involved in many morphological and physiological
      processes in rice, including the elongation and unrolling of leaves, development
      of tillers, skotomorphogenesis, root differentiation, and reproductive growth,
      and that the defect of BR-6-oxidase caused the brd1 phenotype.

PMID- 12427983
TI  - Phosphorus effects on metabolic processes in monoxenic arbuscular mycorrhiza
      cultures.
AB  - The influence of external phosphorus (P) on carbon (C) allocation and metabolism
      as well as processes related to P metabolism was studied in monoxenic arbuscular
      mycorrhiza cultures of carrot (Daucus carota). Fungal hyphae of Glomus
      intraradices proliferated from the solid minimal medium containing the colonized
      roots into C-free liquid minimal medium with different P treatments. The fungus
      formed around three times higher biomass in P-free liquid medium than in medium
      with 2.5 mM inorganic P (high-P). Mycelium in the second experiment was harvested
      at an earlier growth stage to study metabolic processes when the mycelium was
      actively growing. P treatment influenced the root P content and [(13)C]glucose
      administered to the roots 7 d before harvest gave a negative correlation between
      root P content and (13)C enrichment in arbuscular mycorrhiza fungal storage
      lipids in the extraradical hyphae. Eighteen percent of the enriched (13)C in
      extraradical hyphae was recovered in the fatty acid 16:1omega5 from neutral
      lipids. Polyphosphate accumulated in hyphae even in P-free medium. No influence
      of P treatment on fungal acid phosphatase activity was observed, whereas the
      proportion of alkaline-phosphatase-active hyphae was highest in high-P medium. We
      demonstrated the presence of a motile tubular vacuolar system in G. intraradices.
      This system was rarely seen in hyphae subjected to the highest P treatment. We
      concluded that the direct responses of the extraradical hyphae to the P
      concentration in the medium are limited. The effects found in hyphae seemed
      instead to be related to increased availability of P to the host root.

PMID- 12427985
TI  - Maize leaves turn away from neighbors.
AB  - In commercial crops, maize (Zea mays) plants are typically grown at a larger
      distance between rows (70 cm) than within the same row (16-23 cm). This
      rectangular arrangement creates a heterogeneous environment in which the plants
      receive higher red light (R) to far-red light (FR) ratios from the interrow
      spaces. In field crops, the hybrid Dekalb 696 (DK696) showed an increased
      proportion of leaves toward interrow spaces, whereas the experimental hybrid 980
      (Exp980) retained random leaf orientation. Mirrors reflecting FR were placed
      close to isolated plants to simulate the presence of neighbors in the field. In
      addition, localized FR was applied to target leaves in a growth chamber. During
      their expansion, the leaves of DK696 turned away from the low R to FR ratio
      signals, whereas Exp980 leaves remained unaffected. On the contrary, tillering
      was reduced and plant height was increased by low R to FR ratios in Exp980 but
      not in DK696. Isolated plants preconditioned with low R/FR-simulating neighbors
      in a North-South row showed reduced mutual shading among leaves when the plants
      were actually grouped in North-South rows. These observations contradict the
      current view that phytochrome-mediated responses to low R/FR are a relic from
      wild conditions, detrimental for crop yield.

PMID- 12427984
TI  - A novel nucleus-targeted protein is expressed in barley leaves during senescence
      and pathogen infection.
AB  - The barley (Hordeum vulgare) cDNA HvS40 represents a gene with enhanced mRNA
      level during leaf senescence. Biolistic transformation of onion (Allium cepa)
      epidermal cell layers with a glucuronidase fusion protein construct provided
      evidence that the 15.4-kD protein encoded by HvS40 is localized to the nucleus.
      Expression of the gene is induced by jasmonate and salicylic acid; both are known
      to act as signaling compounds during senescence and defense toward pathogens.
      Transcript levels of HvS40 were observed to be particularly high in leaf sectors
      that undergo necrosis and chlorosis after infection with Pyrenophora teres. This
      pathogen-related expression is, in contrast, clearly reduced in transgenic barley
      plants expressing a stilbene synthase from grape (Vitis vinifera), whereas the
      mRNA level of a gene encoding the pathogen-related protein HvPR1 is unaffected.
      In situ hybridization with HvS40 antisense RNA revealed that during leaf
      senescence, the HvS40 transcript predominantly accumulates in the mesophyll.
      Taken together, the findings suggest a connection between the nuclear protein
      encoded by HvS40 and the degeneration of chloroplasts occurring during senescence
      and during infection of barley wild-type plants with P. teres.

PMID- 12427986
TI  - Dynamic 1-aminocyclopropane-1-carboxylate-synthase and -oxidase transcript
      accumulation patterns during pollen tube growth in tobacco styles.
AB  - In flowering plants, pollination of the stigma sets off a cascade of responses in
      the distal flower organs. Ethylene and its biosynthetic precursor 1
      aminocyclopropane-1-carboxylate (ACC) play an important role in regulating these
      responses. Because exogenous application of ethylene or ACC does not invoke the
      full postpollination syndrome, the pollination signal probably consists of a more
      complex set of stimuli. We set out to study how and when the pollination signal
      moves through the style of tobacco (Nicotiana tabacum) by analyzing the
      expression patterns of pistil-expressed ACC-synthase and -oxidase genes. Results
      from this analysis showed that pollination induces high ACC-oxidase transcript
      levels in all cells of the transmitting tissue. ACC-synthase mRNA accumulated
      only in a subset of transmitting tract cells and to lower levels as compared with
      ACC-oxidase. More significantly, we found that although ACC-oxidase transcripts
      accumulate to uniform high levels, the ACC-synthase transcripts accumulate in a
      wave-like pattern in which the peak coincides with the front of the ingrowing
      pollen tube tips. This wave of ACC-synthase expression can also be induced by
      incongruous pollination and (partially) by wounding. This indicates that wounding
      like features of pollen tube invasion might be part of the stimuli evoking the
      postpollination response and that these stimuli are interpreted differently by
      the regulatory mechanisms of the ACC-synthase and -oxidase genes.

PMID- 12427987
TI  - Regulation of the distribution of chlorophyll and phycobilin-absorbed excitation
      energy in cyanobacteria. A structure-based model for the light state transition.
AB  - The light state transition regulates the distribution of absorbed excitation
      energy between the two photosystems (PSs) of photosynthesis under varying
      environmental conditions and/or metabolic demands. In cyanobacteria, there is
      evidence for the redistribution of energy absorbed by both chlorophyll (Chl) and
      by phycobilin pigments, and proposed mechanisms differ in the relative
      involvement of the two pigment types. We assayed changes in the distribution of
      excitation energy with 77K fluorescence emission spectroscopy determined for
      excitation of Chl and phycobilin pigments, in both wild-type and state transition
      impaired mutant strains of Synechococcus sp. PCC 7002 and Synechocystis sp. PCC
      6803. Action spectra for the redistribution of both Chl and phycobilin pigments
      were very similar in both wild-type cyanobacteria. Both state transition-impaired
      mutants showed no redistribution of phycobilin-absorbed excitation energy, but
      retained changes in Chl-absorbed excitation. Action spectra for the Chl-absorbed
      changes in excitation in the two mutants were similar to each other and to those
      observed in the two wild types. Our data show that the redistribution of
      excitation energy absorbed by Chl is independent of the redistribution of
      excitation energy absorbed by phycobilin pigments and that both changes are
      triggered by the same environmental light conditions. We present a model for the
      state transition in cyanobacteria based on the x-ray structures of PSII, PSI, and
      allophycocyanin consistent with these results.

PMID- 12427988
TI  - Induction of jasmonate biosynthesis in arbuscular mycorrhizal barley roots.
AB  - Colonization of barley (Hordeum vulgare cv Salome) roots by an arbuscular
      mycorrhizal fungus, Glomus intraradices Schenck & Smith, leads to elevated levels
      of endogenous jasmonic acid (JA) and its amino acid conjugate JA-isoleucine,
      whereas the level of the JA precursor, oxophytodienoic acid, remains constant.
      The rise in jasmonates is accompanied by the expression of genes coding for an
      enzyme of JA biosynthesis (allene oxide synthase) and of a jasmonate-induced
      protein (JIP23). In situ hybridization and immunocytochemical analysis revealed
      that expression of these genes occurred cell specifically within arbuscule
      containing root cortex cells. The concomitant gene expression indicates that
      jasmonates are generated and act within arbuscule-containing cells. By use of a
      near-synchronous mycorrhization, analysis of temporal expression patterns showed
      the occurrence of transcript accumulation 4 to 6 d after the appearance of the
      first arbuscules. This suggests that the endogenous rise in jasmonates might be
      related to the fully established symbiosis rather than to the recognition of
      interacting partners or to the onset of interaction. Because the plant supplies
      the fungus with carbohydrates, a model is proposed in which the induction of JA
      biosynthesis in colonized roots is linked to the stronger sink function of
      mycorrhizal roots compared with nonmycorrhizal roots.

PMID- 12427989
TI  - Two putative BIN2 substrates are nuclear components of brassinosteroid signaling.
AB  - GSK3 is a highly conserved kinase that negatively regulates many cellular
      processes by phosphorylating a variety of protein substrates. BIN2 is a GSK3-like
      kinase in Arabidopsis that functions as a negative regulator of brassinosteroid
      (BR) signaling. It was proposed that BR signals, perceived by a membrane BR
      receptor complex that contains the leucine (Leu)-rich repeat receptor-like kinase
      BRI1, inactivate BIN2 to relieve its inhibitory effect on unknown downstream BR
      signaling components. Using a yeast (Saccharomyces cerevisiae) two-hybrid
      approach, we discovered a potential BIN2 substrate that is identical to a
      recently identified BR-signaling protein, BES1. BES1 and its closest homolog,
      BZR1, which was also uncovered as a potential BR-signaling protein, display
      specific interactions with BIN2 in yeast. Both BES1 and BZR1 contain many copies
      of a conserved GSK3 phosphorylation site and can be phosphorylated by BIN2 in
      vitro via a novel GSK3 phosphorylation mechanism that is independent of a priming
      phosphorylation or a scaffold protein. Five independent bes1 alleles containing
      the same proline-233-Leu mutation were identified as semidominant suppressors of
      two different bri1 mutations. Over-expression of the wild-type BZR1 gene
      partially complemented bin2/+ mutants and resulted in a BRI1 overexpression
      phenotype in a BIN2(+) background, whereas overexpression of a mutated BZR1 gene
      containing the corresponding proline-234-Leu mutation rescued a weak bri1
      mutation and led to a bes1-like phenotype. Confocal microscopic analysis
      indicated that both BES1 and BZR1 proteins were mainly localized in the nucleus.
      We propose that BES1/BZR1 are two nuclear components of BR signaling that are
      negatively regulated by BIN2 through a phosphorylation-initiated process.

PMID- 12427990
TI  - Molecular characterization of plant ubiquitin-conjugating enzymes belonging to
      the UbcP4/E2-C/UBCx/UbcH10 gene family.
AB  - The anaphase promoting complex or cyclosome is the ubiquitin-ligase that targets
      destruction box-containing proteins for proteolysis during the cell cycle.
      Anaphase promoting complex or cyclosome and its activator (the fizzy and fizzy
      related) proteins work together with ubiquitin-conjugating enzymes (UBCs) (E2s).
      One class of E2s (called E2-C) seems specifically involved in cyclin B1
      degradation. Although it has recently been shown that mammalian E2-C is regulated
      at the protein level during the cell cycle, not much is known concerning the
      expression of these genes. Arabidopsis encodes two genes belonging to the E2-C
      gene family (called UBC19 and UBC20). We found that UBC19 is able to complement
      fission yeast (Schizosaccharomyces pombe) UbcP4-140 mutant, indicating that the
      plant protein can functionally replace its yeast ortholog for protein degradation
      during mitosis. In situ hybridization experiments were performed to study the
      expression of the E2-C genes in various tissues of plants. Their transcripts were
      always, but not exclusively, found in tissues active for cell division. Thus, the
      UBC19/20 E2s may have a key function during cell cycle, but may also be involved
      in ubiquitylation reactions occurring during differentiation and/or in
      differentiated cells. Finally, we showed that a translational fusion protein
      between UBC19 and green fluorescent protein localized both in the cytosol and the
      nucleus in stable transformed tobacco (Nicotiana tabacum cv Bright Yellow 2)
      cells.

PMID- 12427992
TI  - Variation in its C-terminal amino acids determines whether endo-beta-mannanase is
      active or inactive in ripening tomato fruits of different cultivars.
AB  - Endo-beta-mannanase cDNAs were cloned and characterized from ripening tomato
      (Lycopersicon esculentum Mill. cv Trust) fruit, which produces an active enzyme,
      and from the tomato cv Walter, which produces an inactive enzyme. There is a two
      nucleotide deletion in the gene from tomato cv Walter, which results in a frame
      shift and the deletion of four amino acids at the C terminus of the full-length
      protein. Other cultivars that produce either active or inactive enzyme show the
      same absence or presence of the two-nucleotide deletion. The endo-beta-mannanase
      enzyme protein was purified and characterized from ripe fruit to ensure that cDNA
      codes for the enzyme from fruit. Immunoblot analysis demonstrated that non
      ripening mutants, which also fail to exhibit endo-beta-mannanase activity, do so
      because they fail to express the protein. In a two-way genetic cross between
      tomato cvs Walter and Trust, all F(1) progeny from both crosses produced fruit
      with active enzyme, suggesting that this form is dominant and homozygous in
      tomato cv Trust. Self-pollination of a plant from the heterozygous F(1)
      generation yielded F(2) plants that bear fruit with and without active enzyme at
      a ratio appropriate to Mendelian genetic segregation of alleles. Heterologous
      expression of the two endo-beta-mannanase genes in Escherichia coli resulted in
      active enzyme being produced from cultures containing the tomato cv Trust gene
      and inactive enzyme being produced from those containing the tomato cv Walter
      gene. Site-directed mutagenesis was used to establish key elements in the C
      terminus of the endo-beta-mannanase protein that are essential for full enzyme
      activity.

PMID- 12427991
TI  - Characterization of AtCDC48. Evidence for multiple membrane fusion mechanisms at
      the plane of cell division in plants.
AB  - The components of the cellular machinery that accomplish the various complex and
      dynamic membrane fusion events that occur at the division plane during plant
      cytokinesis, including assembly of the cell plate, are not fully understood. The
      most well-characterized component, KNOLLE, a cell plate-specific soluble N
      ethylmaleimide-sensitive fusion protein (NSF)-attachment protein receptor
      (SNARE), is a membrane fusion machine component required for plant cytokinesis.
      Here, we show the plant ortholog of Cdc48p/p97, AtCDC48, colocalizes at the
      division plane in dividing Arabidopsis cells with KNOLLE and another SNARE, the
      plant ortholog of syntaxin 5, SYP31. In contrast to KNOLLE, SYP31 resides in
      defined punctate membrane structures during interphase and is targeted during
      cytokinesis to the division plane. In vitro-binding studies demonstrate that
      AtCDC48 specifically interacts in an ATP-dependent manner with SYP31 but not with
      KNOLLE. In contrast, we show that KNOLLE assembles in vitro into a large
      approximately 20S complex in an Sec18p/NSF-dependent manner. These results
      suggest that there are at least two distinct membrane fusion pathways involving
      Cdc48p/p97 and Sec18p/NSF that operate at the division plane to mediate plant
      cytokinesis. Models for the role of AtCDC48 and SYP31 at the division plane will
      be discussed.

PMID- 12427993
TI  - Functional analysis of an Arabidopsis T-DNA "knockout" of the high-affinity
      NH4(+) transporter AtAMT1;1.
AB  - NH(4)(+) acquisition by plant roots is thought to involve members of the NH(4)(+)
      transporter family (AMT) found in plants, yeast, bacteria, and mammals. In
      Arabidopsis, there are six AMT genes of which AtAMT1;1 demonstrates the highest
      affinity for NH(4)(+). Ammonium influx into roots and AtAMT1;1 mRNA expression
      levels are highly correlated diurnally and when plant nitrogen (N) status is
      varied. To further investigate the involvement of AtAMT1;1 in high-affinity
      NH(4)(+) influx, we identified a homozygous T-DNA mutant with disrupted AtAMT1;1
      activity. Contrary to expectation, high-affinity (13)NH(4)(+) influx in the
      amt1;1:T-DNA mutant was similar to the wild type when grown with adequate N.
      Removal of N to increase AtAMT1;1 expression decreased high-affinity (13)NH(4)(+)
      influx in the mutant by 30% compared with wild-type plants, whereas low-affinity
      (13)NH(4)(+) influx (250 microM-10 mM NH(4)(+)) exceeded that of wild-type
      plants. In these N-deprived plants, mRNA copy numbers of root AtAMT1;3 and
      AtAMT2;1 mRNA were significantly more increased in the mutant than in wild-type
      plants. Under most growth conditions, amt1;1:T-DNA plants were indistinguishable
      from the wild type, however, leaf morphology was altered. However, when grown
      with NH(4)(+) and sucrose, the mutant grew poorly and died. Our results are the
      first in planta evidence that AtAMT1;1 is a root NH(4)(+) transporter and that
      redundancies within the AMT family may allow compensation for the loss of
      AtAMT1;1.

PMID- 12427994
TI  - Localization, ion channel regulation, and genetic interactions during abscisic
      acid signaling of the nuclear mRNA cap-binding protein, ABH1.
AB  - Abscisic acid (ABA) regulates developmental processes and abiotic stress
      responses in plants. We recently characterized a new Arabidopsis mutant, abh1,
      which shows ABA-hypersensitive regulation of seed germination, stomatal closing,
      and cytosolic calcium increases in guard cells (V. Hugouvieux, J.M. Kwak, J.I.
      Schroeder [2001] Cell 106: 477-487). ABH1 encodes the large subunit of a dimeric
      Arabidopsis mRNA cap-binding complex and in expression profiling experiments was
      shown to affect mRNA levels of a subset of genes. Here, we show that the dimeric
      ABH1 and AtCBP20 subunits are ubiquitously expressed. Whole-plant growth
      phenotypes of abh1 are described and properties of ABH1 in guard cells are
      further analyzed. Complemented abh1 lines expressing a green fluorescent protein
      ABH1 fusion protein demonstrate that ABH1 mainly localizes in guard cell nuclei.
      Stomatal apertures were smaller in abh1 compared with wild type (WT) when plants
      were grown at 40% humidity, and similar at 95% humidity. Correlated with stomatal
      apertures from plants grown at 40% humidity, slow anion channel currents were
      enhanced and inward potassium channel currents were decreased in abh1 guard cells
      compared with WT. Gas exchange measurements showed similar primary humidity
      responses in abh1 and WT, which together with results from abh1/abi1-1 double
      mutant analyses suggest that abh1 shows enhanced sensitivity to endogenous ABA.
      Double-mutant analyses of the ABA-hypersensitive signaling mutants, era1-2 and
      abh1, showed complex genetic interactions, suggesting that ABH1 and ERA1 do not
      modulate the same negative regulator in ABA signaling. Mutations in the RNA
      binding protein sad1 showed hypersensitive ABA-induced stomatal closing, whereas
      hyl1 did not affect this response. These data provide evidence for the model that
      the mRNA-processing proteins ABH1 and SAD1 function as negative regulators in
      guard cell ABA signaling.

PMID- 12427995
TI  - Nitric oxide synthase-mediated phytoalexin accumulation in soybean cotyledons in
      response to the Diaporthe phaseolorum f. sp. meridionalis elicitor.
AB  - Phytoalexin biosynthesis is part of the defense mechanism of soybean (Glycine
      max) plants against attack by the fungus Diaporthe phaseolorum f. sp.
      meridionalis (Dpm), the causal agent of stem canker disease. The treatment of
      soybean cotyledons with Dpm elicitor or with sodium nitroprusside (SNP), a nitric
      oxide (NO) donor, resulted in a high accumulation of phytoalexins. This response
      did not occur when SNP was replaced by ferricyanide, a structural analog of SNP
      devoid of the NO moiety. Phytoalexin accumulation induced by the fungal elicitor,
      but not by SNP, was prevented when cotyledons were pretreated with NO synthase
      (NOS) inhibitors. The Dpm elicitor also induced NOS activity in soybean tissues
      proximal to the site of inoculation. The induced NOS activity was Ca(2+)- and
      NADPH-dependent and was sensitive to the NOS inhibitors N(G)-nitro-L-arginine
      methyl ester, aminoguanidine, and L-N(6)-(iminoethyl) lysine. NOS activity was
      not observed in SNP-elicited tissues. An antibody to brain NOS labeled a 166-kD
      protein in elicited and nonelicited cotyledons. Isoflavones (daidzein and
      genistein), pterocarpans (glyceollins), and flavones (apigenin and luteolin) were
      identified after exposure to the elicitor or SNP, although the accumulation of
      glyceollins and apigenin was limited in SNP-elicited compared with fungal
      elicited cotyledons. NOS activity preceded the accumulation of these flavonoids
      in tissues treated with the Dpm elicitor. The accumulation of these metabolites
      was faster in SNP-elicited than in fungal-elicited cotyledons. We conclude that
      the response of soybean cotyledons to Dpm elicitor involves NO formation via a
      constitutive NOS-like enzyme that triggers the biosynthesis of antimicrobial
      flavonoids.

PMID- 12427996
TI  - Endophytic fungal beta-1,6-glucanase expression in the infected host grass.
AB  - Mutualistic fungal endophytes infect many grass species and often confer benefits
      to the hosts such as reduced herbivory by insects and animals. The physiological
      interactions between the endophytes and their hosts have not been well
      characterized. Fungal-secreted proteins are likely to be important components of
      the interaction. In the interaction between Poa ampla and the endophyte
      Neotyphodium sp., a fungal beta-1,6-glucanase is secreted into the apoplast, and
      activity of the enzyme is detectable in endophyte-infected plants. Sequence
      analysis indicates the beta-1,6-glucanase is homologous to enzymes secreted by
      the mycoparasitic fungi Trichoderma harzianum and Trichoderma virens. DNA gel
      blot analysis indicated the beta-1,6-glucanase was encoded by a single gene. As a
      secreted protein, the beta-1,6-glucanase may have a nutritional role for the
      fungus. In culture, beta-1,6-glucanase activity was induced in the presence of
      beta-1,6-glucans. From RNA gel blots, similar beta-1,6-glucanases were expressed
      in tall fescue (Festuca arundinacea Schreb.) and Chewings fescue (Festuca rubra
      L. subsp. fallax [Thuill] Nyman) infected with the endophyte species Neotyphodium
      coenophialum and Epichloe festucae, respectively.

PMID- 12427997
TI  - Characterization of a NifS-like chloroplast protein from Arabidopsis.
      Implications for its role in sulfur and selenium metabolism.
AB  - NifS-like proteins catalyze the formation of elemental sulfur (S) and alanine
      from cysteine (Cys) or of elemental selenium (Se) and alanine from seleno-Cys.
      Cys desulfurase activity is required to produce the S of iron (Fe)-S clusters,
      whereas seleno-Cys lyase activity is needed for the incorporation of Se in
      selenoproteins. In plants, the chloroplast is the location of (seleno) Cys
      formation and a location of Fe-S cluster formation. The goal of these studies was
      to identify and characterize chloroplast NifS-like proteins. Using seleno-Cys as
      a substrate, it was found that 25% to 30% of the NifS activity in green tissue in
      Arabidopsis is present in chloroplasts. A cDNA encoding a putative chloroplast
      NifS-like protein, AtCpNifS, was cloned, and its chloroplast localization was
      confirmed using immunoblot analysis and in vitro import. AtCpNIFS is expressed in
      all major tissue types. The protein was expressed in Escherichia coli and
      purified. The enzyme contains a pyridoxal 5' phosphate cofactor and is a dimer.
      It is a type II NifS-like protein, more similar to bacterial seleno-Cys lyases
      than to Cys desulfurases. The enzyme is active on both seleno-Cys and Cys but has
      a much higher activity toward the Se substrate. The possible role of AtCpNifS in
      plastidic Fe-S cluster formation or in Se metabolism is discussed.

PMID- 12427998
TI  - Microarray analysis of brassinosteroid-regulated genes in Arabidopsis.
AB  - Brassinosteroids (BRs) are steroidal plant hormones that are essential for growth
      and development. Although insights into the functions of BRs have been provided
      by recent studies of biosynthesis and sensitivity mutants, the mode of action of
      BRs is poorly understood. With the use of DNA microarray analysis, we identified
      BR-regulated genes in the wild type (WT; Columbia) of Arabidopsis and in the BR
      deficient mutant, det2. BR-regulated genes generally responded more potently in
      the det2 mutant than in the WT, and they showed only limited response in a BR
      insensitive mutant, bri1. A small group of genes showed stronger responses in the
      WT than in the det2. Exposure of plants to brassinolide and brassinazole, which
      is a specific inhibitor of BR biosynthesis, elicited opposite effects on gene
      expression of the identified genes. The list of BR-regulated genes is constituted
      of transcription factor genes including the phytochrome-interacting factor 3,
      auxin-related genes, P450 genes, and genes implicated in cell elongation and cell
      wall organization. The results presented here provide comprehensive view of the
      physiological functions of BRs using BR-regulated genes as molecular markers. The
      list of BR-regulated genes will be useful in the characterization of new mutants
      and new growth-regulating compounds that are associated with BR function.

PMID- 12427999
TI  - Rubisco small subunit, chlorophyll a/b-binding protein and sucrose:fructan-6
      fructosyl transferase gene expression and sugar status in single barley leaf
      cells in situ. Cell type specificity and induction by light.
AB  - We describe a highly efficient two-step single-cell reverse transcriptase
      polymerase chain reaction technique for analyzing gene expression at the single
      cell level. Good reproducibility and a linear dose response indicated that the
      technique has high specificity and sensitivity for detection and quantification
      of rare RNA. Actin could be used as an internal standard. The expression of
      message for Rubisco small subunit (RbcS), chlorophyll a/b-binding protein (Cab),
      sucrose (Suc):fructan-6-fructosyl transferase (6-SFT), and Actin were measured in
      individual photosynthetic cells of the barley (Hordeum vulgare) leaf. Only Actin
      was found in the non-photosynthetic epidermal cells. Cab, RbcS, and 6-SFT genes
      were expressed at a low level in mesophyll and parenchymatous bundle sheath (BS)
      cells when sampled from plants held in dark for 40 h. Expression increased
      considerably after illumination. The amount of 6-SFT, Cab, and RbcS transcript
      increased more in mesophyll cells than in the parenchymatous BS cells. The
      difference may be caused by different chloroplast structure and
      posttranscriptional control in mesophyll and BS cells. When similar single-cell
      samples were assayed for Suc, glucose, and fructan, there was high correlation
      between 6-SFT gene expression and Suc and glucose concentrations. This is
      consistent with Suc concentration being the trigger for transcription. Together
      with earlier demonstrations that the mesophyll cells have a higher sugar
      threshold for fructan polymerization, our data may indicate separate control of
      transcription and enzyme activity. Values for the sugar concentrations of the
      individual cell types are reported.

PMID- 12428000
TI  - The procambium specification gene Oshox1 promotes polar auxin transport capacity
      and reduces its sensitivity toward inhibition.
AB  - The auxin-inducible homeobox gene Oshox1 of rice (Oryza sativa) is a positive
      regulator of procambial cell fate commitment, and its overexpression reduces the
      sensitivity of polar auxin transport (PAT) to the PAT inhibitor 1-N
      naphthylphthalamic acid (NPA). Here, we show that wild-type rice leaves formed
      under conditions of PAT inhibition display vein hypertrophy, reduced distance
      between longitudinal veins, and increased distance between transverse veins,
      providing experimental evidence for a role of PAT in vascular patterning in a
      monocot species. Furthermore, we show that Oshox1 overexpression confers
      insensitivity to these PAT inhibitor-induced vascular-patterning defects.
      Finally, we show that in the absence of any overt phenotypical change, Oshox1
      overexpression specifically reduces the affinity of the NPA-binding protein
      toward NPA and enhances PAT and its sensitivity toward auxin. These results are
      consistent with the hypothesis that Oshox1 promotes fate commitment of procambial
      cells by increasing their auxin conductivity properties and stabilizing this
      state against modulations of PAT by an endogenous NPA-like molecule.

PMID- 12428001
TI  - Rapid induction of regulatory and transporter genes in response to phosphorus,
      potassium, and iron deficiencies in tomato roots. Evidence for cross talk and
      root/rhizosphere-mediated signals.
AB  - Mineral nutrient deficiencies constitute major limitations for plant growth on
      agricultural soils around the world. To identify genes that possibly play roles
      in plant mineral nutrition, we recently generated a high-density array consisting
      of 1,280 genes from tomato (Lycopersicon esculentum) roots for expression
      profiling in nitrogen (N) nutrition. In the current study, we used the same array
      to search for genes induced by phosphorus (P), potassium (K(+)), and iron (Fe)
      deficiencies. RNA gel-blot analysis was conducted to study the time-dependent
      kinetics for expression of these genes in response to withholding P, K, or Fe.
      Genes previously not associated with P, K, and Fe nutrition were identified, such
      as transcription factor, mitogen-activated protein (MAP) kinase, MAP kinase
      kinase, and 14-3-3 proteins. Many of these genes were induced within 1 h after
      withholding the specific nutrient from roots of intact plants; thus, RNA gel-blot
      analysis was repeated for specific genes (transcription factor and MAP kinase) in
      roots of decapitated plants to investigate the tissue-specific location of the
      signal triggering gene induction. Both genes were induced just as rapidly in
      decapitated plants, suggesting that the rapid response to the absence of P, K, or
      Fe in the root-bathing medium is triggered either by a root-localized signal or
      because of root sensing of the mineral environment surrounding the roots. We also
      show that expression of Pi, K, and Fe transporter genes were up-regulated by all
      three treatments, suggesting coordination and coregulation of the uptake of these
      three essential mineral nutrients.

PMID- 12428002
TI  - Stomatal constraints may affect emission of oxygenated monoterpenoids from the
      foliage of Pinus pinea.
AB  - Dependence of monoterpenoid emission and fractional composition on stomatal
      conductance (G(V)) was studied in Mediterranean conifer Pinus pinea, which
      primarily emits limonene and trans-beta-ocimene but also large fractions of
      oxygenated monoterpenoids linalool and 1,8-cineole. Strong decreases in G(V)
      attributable to diurnal water stress were accompanied by a significant reduction
      in total monoterpenoid emission rate in midday. However, various monoterpenoids
      responded differently to the reduction in G(V), with the emission rates of
      limonene and trans-beta-ocimene being unaffected but those of linalool and 1,8
      cineole closely following diurnal variability in G(V). A dynamic emission model
      indicated that stomatal sensitivity of emissions was associated with
      monoterpenoid Henry's law constant (H, gas/liquid phase partition coefficient).
      Monoterpenoids with a large H such as trans-beta-ocimene sustain higher
      intercellular partial pressure for a certain liquid phase concentration, and
      stomatal closure is balanced by a nearly immediate increase in monoterpene
      diffusion gradient from intercellular air-space to ambient air. The partial
      pressure rises also in compounds with a low H, but more than 1,000-fold higher
      liquid phase concentrations of linalool and 1,8-cineole are necessary to increase
      intercellular partial pressure high enough to balance stomatal closure. The
      system response is accordingly slower, and the emission rates may be transiently
      suppressed by low G(V). Simulations further suggested that linalool and 1,8
      cineole synthesis rates also decreased with decreasing G(V), possibly as the
      result of selective inhibition of various monoterpene synthases by stomata. We
      conclude that physicochemical characteristics of volatiles not only affect total
      emission but also alter the fractional composition of emitted monoterpenoids.

PMID- 12428003
TI  - The voltage-independent cation channel in the plasma membrane of wheat roots is
      permeable to divalent cations and may be involved in cytosolic Ca2+ homeostasis.
AB  - A voltage-independent cation (VIC) channel has been identified in the plasma
      membrane of wheat (Triticum aestivum) root cells (P.J. White [1999] Trends Plant
      Sci 4: 245-246). Several physiological functions have been proposed for this
      channel, including roles in cation nutrition, osmotic adjustment, and charge
      compensation. Here, we observe that Ca(2+) permeates this VIC channel when
      assayed in artificial, planar lipid bilayers, and, using an energy barrier model
      to describe cation fluxes, predict that it catalyzes Ca(2+) influx under
      physiological ionic conditions. Thus, this channel could participate in Ca(2+)
      signaling or cytosolic Ca(2+) homeostasis. The pharmacology of (45)Ca(2+) influx
      to excised wheat roots and inward cation currents through the VIC channel are
      similar: Both are insensitive to 20 microM verapamil or 1 mM tetraethylammonium,
      but inhibited by 0.5 mM Ba(2+) or 0.5 mM Gd(3+). The weak voltage dependency of
      the VIC channel (and its lack of modulation by physiological effectors) suggest
      that it will provide perpetual Ca(2+) influx to root cells. Thus, it may effect
      cytosolic Ca(2+) homeostasis by contributing to the basal Ca(2+) influx required
      to balance Ca(2+) efflux from the cytoplasm through ATP- and proton-coupled
      Ca(2+) transporters under steady-state conditions.

PMID- 12428004
TI  - Expression of alpha-expansin and expansin-like genes in deepwater rice.
AB  - Previously, we have studied the expression and regulation of four alpha- and 14
      beta-expansin genes in deepwater rice (Oryza sativa). We now report on the
      structure, expression, and regulation of 22 additional alpha-expansin (Os-EXP)
      genes, four expansin-like (Os-EXPL) genes, and one expansin-related (Os-EXPR)
      gene, which have recently been identified in the expressed sequence tag and
      genomic databases of rice. Alpha-expansins are characterized by a series of
      conserved Cys residues in the N-terminal half of the protein, a histidine
      phenylalanine-aspartate (HFD) motif in the central region, and a series of
      tryptophan residues near the carboxyl terminus. Of the 22 additional alpha
      expansin genes, five are expressed in internodes and leaves, three in
      coleoptiles, and nine in roots, with high transcript levels in the growing
      regions of these organs. Transcripts of five alpha-expansin genes were found in
      roots only. Expression of five alpha-expansin genes was induced in the internode
      by treatment with gibberellin (GA) and by wounding. The wound response resulted
      from excising stem sections or from piercing pinholes into the stem of intact
      plants. EXPL proteins lack the HFD motif and have two additional Cys residues in
      their C- and N-terminal regions. The positions of conserved tryptophan residues
      at the C-terminal region are different from those of alpha- and beta-expansins.
      Expression of the Os-EXPL3 gene is correlated with elongation and slightly
      induced by applied GA. However, the expression of the Os-EXPL1 and Os-EXPL2 genes
      showed limited correlation with cell elongation and was not induced by GA. We
      found no expression of the Os-EXPR1 gene in the organs examined.

PMID- 12428005
TI  - Interaction of sulfate assimilation with carbon and nitrogen metabolism in Lemna
      minor.
AB  - Cysteine synthesis from sulfide and O-acetyl-L-serine (OAS) is a reaction
      interconnecting sulfate, nitrogen, and carbon assimilation. Using Lemna minor, we
      analyzed the effects of omission of CO(2) from the atmosphere and simultaneous
      application of alternative carbon sources on adenosine 5'-phosphosulfate
      reductase (APR) and nitrate reductase (NR), the key enzymes of sulfate and
      nitrate assimilation, respectively. Incubation in air without CO(2) led to severe
      decrease in APR and NR activities and mRNA levels, but ribulose-1,5-bisphosphate
      carboxylase/oxygenase was not considerably affected. Simultaneous addition of
      sucrose (Suc) prevented the reduction in enzyme activities, but not in mRNA
      levels. OAS, a known regulator of sulfate assimilation, could also attenuate the
      effect of missing CO(2) on APR, but did not affect NR. When the plants were
      subjected to normal air after a 24-h pretreatment in air without CO(2), APR and
      NR activities and mRNA levels recovered within the next 24 h. The addition of Suc
      and glucose in air without CO(2) also recovered both enzyme activities, with OAS
      again influenced only APR. (35)SO(4)(2-) feeding showed that treatment in air
      without CO(2) severely inhibited sulfate uptake and the flux through sulfate
      assimilation. After a resupply of normal air or the addition of Suc,
      incorporation of (35)S into proteins and glutathione greatly increased. OAS
      treatment resulted in high labeling of cysteine; the incorporation of (35)S in
      proteins and glutathione was much less increased compared with treatment with
      normal air or Suc. These results corroborate the tight interconnection of
      sulfate, nitrate, and carbon assimilation.

PMID- 12428006
TI  - Stoichiometry of the photosynthetic apparatus and phycobilisome structure of the
      cyanobacterium Plectonema boryanum UTEX 485 are regulated by both light and
      temperature.
AB  - The role of growth temperature and growth irradiance on the regulation of the
      stoichiometry and function of the photosynthetic apparatus was examined in the
      cyanobacterium Plectonema boryanum UTEX 485 by comparing mid-log phase cultures
      grown at either 29 degrees C/150 micromol m(-2) s(-1), 29 degrees C/750 micromol
      m(-2) s(-1), 15 degrees C/150 micromol m(-2) s(-1), or 15 degrees C/10 micromol
      m(-2) s(-1). Cultures grown at 29 degrees C/750 micromol m(-2) s(-1) were
      structurally and functionally similar to those grown at 15 degrees C/150 micromol
      m(-2) s(-1), whereas cultures grown at 29 degrees C/150 micromol m(-2) s(-1) were
      structurally and functionally similar to those grown at 15 degrees C/10 micromol
      m(-2) s(-1). The stoichiometry of specific components of the photosynthetic
      apparatus, such as the ratio of photosystem (PS) I to PSII, phycobilisome size
      and the relative abundance of the cytochrome b(6)/f complex, the plastoquinone
      pool size, and the NAD(P)H dehydrogenase complex were regulated by both growth
      temperature and growth irradiance in a similar manner. This indicates that
      temperature and irradiance may share a common sensing/signaling pathway to
      regulate the stoichiometry and function of the photosynthetic apparatus in P.
      boryanum. In contrast, the accumulation of neither the D1 polypeptide of PSII,
      the large subunit of Rubisco, nor the CF(1) alpha-subunit appeared to be
      regulated by the same mechanism. Measurements of P700 photooxidation in vivo in
      the presence and absence of inhibitors of photosynthetic electron transport
      coupled with immunoblots of the NAD(P)H dehydrogenase complex in cells grown at
      either 29 degrees C/750 micromol m(-2) s(-1) or 15 degrees C/150 micromol m(-2)
      s(-1) are consistent with an increased flow of respiratory electrons into the
      photosynthetic intersystem electron transport chain maintaining P700 in a reduced
      state relative to cells grown at either 29 degrees C/150 micromol m(-2) s(-1) or
      15 degrees C/10 micromol m(-2) s(-1). These results are discussed in terms of
      acclimation to excitation pressure imposed by either low growth temperature or
      high growth irradiance.

PMID- 12428007
TI  - Mutations in the gravity persistence signal loci in Arabidopsis disrupt the
      perception and/or signal transduction of gravitropic stimuli.
AB  - Gravity plays a fundamental role in plant growth and development, yet little is
      understood about the early events of gravitropism. To identify genes affected in
      the signal perception and/or transduction phase of the gravity response, a mutant
      screen was devised using cold treatment to delay the gravity response of
      inflorescence stems of Arabidopsis. Inflorescence stems of Arabidopsis show no
      response to gravistimulation at 4 degrees C for up to 3 h. However, when
      gravistimulated at 4 degrees C and then returned to vertical at room temperature
      (RT), stems bend in response to the previous, horizontal gravistimulation (H.
      Fukaki, H. Fujisawa, M. Tasaka [1996] Plant Physiology 110: 933-943). This
      indicates that gravity perception, but not the gravitropic response, occurs at 4
      degrees C. Recessive mutations were identified at three loci using this cold
      effect on gravitropism to screen for gravity persistence signal (gps) mutants.
      All three mutants had an altered response after gravistimulation at 4 degrees C,
      yet had phenotypically normal responses to stimulations at RT. gps1-1 did not
      bend in response to the 4 degrees C gravity stimulus upon return to RT. gps2-1
      responded to the 4 degrees C stimulus but bent in the opposite direction. gps3-1
      over-responded after return to RT, continuing to bend to an angle greater than
      wild-type plants. At 4 degrees C, starch-containing statoliths sedimented
      normally in both wild-type and the gps mutants, but auxin transport was abolished
      at 4 degrees C. These results are consistent with GPS loci affecting an aspect of
      the gravity signal perception/transduction pathway that occurs after statolith
      sedimentation, but before auxin transport.

PMID- 12428008
TI  - Continuous measurement of macronutrient ions in the transpiration stream of
      intact plants using the meadow spittlebug coupled with ion chromatography.
AB  - A method is described for continuous, nondestructive analysis of xylem-borne
      mineral nutrients in intact transpiring plants. The method uses the xylem-feeding
      insect the meadow spittlebug (Philaenus spumarius L. [Homoptera: Cercopidae]).
      This insect will feed from a wide range of plant species and organs. Insect
      excreta can be collected at all times of the day and night, and its mineral ion
      content can be analyzed rapidly, and without purification, by ion chromatography.
      The excreta will have a mineral content virtually identical to that of xylem sap.
      Cages suitable for containing the insects and collecting excreta from any desired
      location on plants in both laboratory and greenhouse are described. Even in the
      greenhouse, evaporation had only a minor effect on the sample ion content.
      Example results are presented which illustrate dynamics, over several days, in
      the xylem concentrations of sodium (Na(+)), potassium (K(+)), NH(4)(+), magnesium
      (Mg(2+)), calcium (Ca(2+)), chloride (Cl(-)), NO(3)(-), PO(4)(3-), and SO(4)(2-).
      These data were collected from young plants growing in pots of compost in the
      laboratory and from fully mature pepper (Capsicum annuum L. cv Bellboy) plants
      growing in hydroponics (rockwool) in the greenhouse. This method should
      facilitate studies of macronutrient uptake and transport in a range of plants and
      environments.

PMID- 12428009
TI  - Salt stress inhibits the repair of photodamaged photosystem II by suppressing the
      transcription and translation of psbA genes in synechocystis.
AB  - Light stress and salt stress are major environmental factors that limit the
      efficiency of photosynthesis. However, we have found that the effects of light
      and salt stress on photosystem II (PSII) in the cyanobacterium Synechocystis sp.
      PCC 6803 are completely different. Strong light induced photodamage to PSII,
      whereas salt stress inhibited the repair of the photodamaged PSII and did not
      accelerate damage to PSII directly. The combination of light and salt stress
      appeared to inactivate PSII very rapidly as a consequence of their synergistic
      effects. Radioactive labeling of cells revealed that salt stress inhibited the
      synthesis of proteins de novo and, in particular, the synthesis of the D1
      protein. Northern- and western-blotting analyses demonstrated that salt stress
      inhibited the transcription and the translation of psbA genes, which encode D1
      protein. DNA microarray analysis indicated that the light-induced expression of
      various genes was suppressed by salt stress. Thus, our results suggest that salt
      stress inhibits the repair of PSII via suppression of the activities of the
      transcriptional and translational machinery.

PMID- 12428010
TI  - Induction of the arginine decarboxylase ADC2 gene provides evidence for the
      involvement of polyamines in the wound response in Arabidopsis.
AB  - Polyamines are small ubiquitous molecules that have been involved in nearly all
      developmental processes, including the stress response. Nevertheless, no direct
      evidence of a role of polyamines in the wound response has been described. We
      have studied the expression of genes involved in polyamine biosynthesis in
      response to mechanical injury. An increase in the expression of the arginine
      decarboxylase 2 (ADC2) gene in response to mechanical wounding and methyl
      jasmonate (JA) treatment in Arabidopsis was detected by using DNA microarray and
      RNA gel-blot analysis. No induction was observed for the ADC1 gene or other genes
      coding for spermidine and spermine synthases, suggesting that ADC2 is the only
      gene of polyamine biosynthesis involved in the wounding response mediated by JA.
      A transient increase in the level of free putrescine followed the increase in the
      mRNA level for ADC2. A decrease in the level of free spermine, coincident with
      the increase in putrescine after wounding, was also observed. Abscisic acid
      effected a strong induction on ADC2 expression and had no effect on ADC1
      expression. Wound-induction of ADC2 mRNA was not prevented in the JA-insensitive
      coi1 mutant. The different pattern of expression of ADC2 gene in wild-type and
      coi1 mutant might be due to the dual regulation of ADC2 by abscisic acid and JA
      signaling pathways. This is the first direct evidence of a function of polyamines
      in the wound-response, and it opens a new aspect of polyamines in plant biology.

PMID- 12428011
TI  - Characterization of the genes encoding the cytosolic and plastidial forms of ADP
      glucose pyrophosphorylase in wheat endosperm.
AB  - In most species, the synthesis of ADP-glucose (Glc) by the enzyme ADP-Glc
      pyrophosphorylase (AGPase) occurs entirely within the plastids in all tissues so
      far examined. However, in the endosperm of many, if not all grasses, a second
      form of AGPase synthesizes ADP-Glc outside the plastid, presumably in the
      cytosol. In this paper, we show that in the endosperm of wheat (Triticum
      aestivum), the cytosolic form accounts for most of the AGPase activity. Using a
      combination of molecular and biochemical approaches to identify the cytosolic and
      plastidial protein components of wheat endosperm AGPase we show that the large
      and small subunits of the cytosolic enzyme are encoded by genes previously
      thought to encode plastidial subunits, and that a gene, Ta.AGP.S.1, which encodes
      the small subunit of the cytosolic form of AGPase, also gives rise to a second
      transcript by the use of an alternate first exon. This second transcript encodes
      an AGPase small subunit with a transit peptide. However, we could not find a
      plastidial small subunit protein corresponding to this transcript. The protein
      sequence of the purified plastidial small subunit does not match precisely to
      that encoded by Ta.AGP.S.1 or to the predicted sequences of any other known gene
      from wheat or barley (Hordeum vulgare). Instead, the protein sequence is most
      similar to those of the plastidial small subunits from chickpea (Cicer arietinum)
      and maize (Zea mays) and rice (Oryza sativa) seeds. These data suggest that the
      gene encoding the major plastidial small subunit of AGPase in wheat endosperm has
      yet to be identified.

PMID- 12428012
TI  - Mutations affecting light regulation of nuclear genes encoding chloroplast
      glyceraldehyde-3-phosphate dehydrogenase in Arabidopsis.
AB  - Expression of nuclear genes that encode the A and B subunits of chloroplast
      glyceraldehyde-3-phosphate dehydrogenase (GAPA and GAPB) of Arabidopsis is known
      to be regulated by light. We used a negative selection approach to isolate
      mutants that were defective in light-regulated expression of the GAPA gene. Two
      dominant mutants belonging to the same complementation group, uga1-1 and uga1-2,
      were then characterized. These two mutants showed a dramatic reduction in GAPA
      mRNA level in both mature plants and seedlings. Surprisingly, mutations in uga1-1
      and uga1-2 had no effect on the expression of GAPB and several other light
      regulated genes. In addition, we found that the chloroplast glyceraldehyde-3
      phosphate dehydrogenase enzyme activity of the mutants was only slightly lower
      than that of the wild type. Western-blot analysis showed that the GAPA protein
      level was nearly indistinguishable between the wild-type and the uga mutants.
      These results suggested that posttranscriptional control was involved in the up
      regulation of the GAPA protein in the mutants. The uga1-1 mutation was mapped to
      the bottom arm of chromosome V of the Arabidopsis genome.

PMID- 12428013
TI  - Functional analysis of regulatory elements in the gene promoter for an abscission
      specific cellulase from bean and isolation, expression, and binding affinity of
      three TGA-type basic leucine zipper transcription factors.
AB  - Site-directed mutagenesis was used to identify cis-acting elements that control
      hormonal and abscission-specific expression of the bean (Phaseolus vulgaris)
      abscission cellulase (BAC) promoter. Auxin inhibition of BAC promoter expression
      is at least in part controlled by a negatively regulated element and ethylene
      induction by a positively regulated element. One of a series of 15 different 10
      bp mutations created in a 2.9-kb BAC promoter reduced reporter gene expression by
      60%. The native sequence for this 10-bp mutation includes a TGA-type basic
      leucine zipper (bZIP) motif. Tandem ligation of three 18-bp BAC elements (Z-BAC),
      which includes the bZIP motif to a minimal -50 35S cauliflower mosaic virus
      promoter, enhanced expression in abscission zones (AZs) 13-fold over that of the
      minimal promoter alone. The native forward orientation of the Z-BAC elements was
      essential for high expression levels. Expression of the Z-BAC minimal construct
      was 3-fold greater in AZ than stems when compared with the expression levels of
      an internal control with an enhanced 35S cauliflower mosaic virus promoter.
      Polymerase chain reaction was used to identify three TGA-type bZIP transcription
      factors in an AZ cDNA library. One of these factors was of the class I type and
      two of the class II type. RNA-blot analysis was completed for these genes and
      electrophoretic mobility shift assays used to confirm their binding to the Z-BAC
      element. Electrophoretic mobility shift assay-binding affinity was greatest for
      the class I TGA-type bZIP factor. The results indicate a complex interaction of
      negative and positive regulating transcription factors that control BAC gene
      expression.

PMID- 12428014
TI  - Induction of glutathione S-transferases in Arabidopsis by herbicide safeners.
AB  - Herbicide safeners increase herbicide tolerance in cereals but not in
      dicotyledenous crops. The reason(s) for this difference in safening is unknown.
      However, safener-induced protection in cereals is associated with increased
      expression of herbicide detoxifying enzymes, including glutathione S-transferases
      (GSTs). Treatment of Arabidopsis seedlings growing in liquid medium with various
      safeners similarly resulted in enhanced GST activities toward a range of
      xenobiotics with benoxacor, fenclorim, and fluxofenim being the most effective.
      Safeners also increased the tripeptide glutathione content of Arabidopsis
      seedlings. However, treatment of Arabidopsis plants with safeners had no effect
      on the tolerance of seedlings to chloroacetanilide herbicides. Each safener
      produced a distinct profile of enhanced GST activity toward different substrates
      suggesting a differential induction of distinct isoenzymes. This was confirmed by
      analysis of affinity-purified GST subunits by two-dimensional sodium dodecyl
      sulfate-polyacrylamide gel electrophoresis. AtGSTU19, a tau class GST, was
      identified as a dominant polypeptide in all samples. When AtGSTU19 was expressed
      in Escherichia coli, the recombinant enzyme was highly active toward 1-chloro-2,4
      dinitrobenzene, as well as chloroacetanilide herbicides. Immunoblot analysis
      confirmed that AtGSTU19 was induced in response to several safeners. Differential
      induction of tau GSTs, as well as members of the phi and theta classes by
      safeners, was demonstrated by RNA-blot analysis. These results indicate that,
      although Arabidopsis may not be protected from herbicide injury by safeners, at
      least one component of their detoxification systems is responsive to these
      compounds.

PMID- 12428015
TI  - Arabidopsis brassinosteroid-insensitive dwarf12 mutants are semidominant and
      defective in a glycogen synthase kinase 3beta-like kinase.
AB  - Mutants defective in the biosynthesis or signaling of brassinosteroids (BRs),
      plant steroid hormones, display dwarfism. Loss-of-function mutants for the gene
      encoding the plasma membrane-located BR receptor BRI1 are resistant to exogenous
      application of BRs, and characterization of this protein has contributed
      significantly to the understanding of BR signaling. We have isolated two new BR
      insensitive mutants (dwarf12-1D and dwf12-2D) after screening Arabidopsis ethyl
      methanesulfonate mutant populations. dwf12 mutants displayed the characteristic
      morphology of previously reported BR dwarfs including short stature, short round
      leaves, infertility, and abnormal de-etiolation. In addition, dwf12 mutants
      exhibited several unique phenotypes, including severe downward curling of the
      leaves. Genetic analysis indicates that the two mutations are semidominant in
      that heterozygous plants show a semidwarf phenotype whose height is intermediate
      between wild-type and homozygous mutant plants. Unlike BR biosynthetic mutants,
      dwf12 plants were not rescued by high doses of exogenously applied BRs. Like bri1
      mutants, dwf12 plants accumulated castasterone and brassinolide, 43- and 15-fold
      higher, respectively, providing further evidence that DWF12 is a component of the
      BR signaling pathway that includes BRI1. Map-based cloning of the DWF12 gene
      revealed that DWF12 belongs to a member of the glycogen synthase kinase 3beta
      family. Unlike human glycogen synthase kinase 3beta, DWF12 lacks the conserved
      serine-9 residue in the auto-inhibitory N terminus. In addition, dwf12-1D and
      dwf12-2D encode changes in consecutive glutamate residues in a highly conserved
      TREE domain. Together with previous reports that both bin2 and ucu1 mutants
      contain mutations in this TREE domain, this provides evidence that the TREE
      domain is of critical importance for proper function of DWF12/BIN2/UCU1 in BR
      signal transduction pathways.

PMID- 12428016
TI  - The as-1 promoter element is an oxidative stress-responsive element and salicylic
      acid activates it via oxidative species.
AB  - The activation sequence-1 (as-1)-like element found in the promoter of some
      glutathione S-transferase (GST) genes, has been previously described as a
      salicylic acid (SA)- and auxin-responsive element. In this paper, we tested the
      hypothesis that the activating effect of SA on the as-1 element is mediated by
      oxidative species. Supporting this hypothesis, our results show that the
      antioxidants dimethylthiourea (DMTU) and 3-t-butyl-4-hydroxy-anizole (BHA)
      inhibit the SA-induced transcription of genes controlled by as-1 elements in
      tobacco (Nicotiana tabacum) plants [i.e. GNT35 gene coding for a GST and (as
      1)(4)/beta-glucuronidase (GUS) reporter transgene]. DMTU and BHA also inhibit SA
      activated as-1-binding activity in nuclear extracts. Further support for the
      hypothesis that the as-1 element is activated by oxidative species comes from our
      result showing that light potentiates the SA-induced activation of the as-1
      element. Furthermore, methyl viologen, a known oxidative stress inducer in
      plants, also activates the as-1 element. Increasing H(2)O(2) levels by incubation
      with H(2)O(2) or with the catalase inhibitor 3-amino-1,2,5-triazole does not
      activate the (as-1)(4)/GUS gene. On the contrary, 3-amino-1,2,5-triazole inhibits
      the activating effect of SA on the (as-1)(4)/GUS gene. These results suggest that
      oxidative species other than H(2)O(2) mediate the activation of the as-1 element
      by SA. Our results also suggest that even though the as-1 binding activity is
      stimulated by oxidative species, this is not sufficient for the transactivation
      of genes controlled by this element. The complex interplay between SA and
      reactive oxygen species in the transcriptional activation of defense genes is
      discussed.

PMID- 12428017
TI  - Supplementary ultraviolet-B radiation induces a rapid reversal of the
      diadinoxanthin cycle in the strong light-exposed diatom Phaeodactylum
      tricornutum.
AB  - A treatment of the diatom Phaeodactylum tricornutum with high light (HL) in the
      visible range led to the conversion of diadinoxanthin (Dd) to diatoxanthin (Dt).
      In a following treatment with HL plus supplementary ultraviolet (UV)-B, the Dt
      was rapidly epoxidized to Dd. Photosynthesis of the cells was inhibited under HL
      + UV-B. This is accounted for by direct damage by UV-B and damage because of the
      UV-B-induced reversal of the Dd cycle and the associated loss of photoprotection.
      The reversal of the Dd cycle by UV-B was faster in the presence of
      dithiothreitol, an inhibitor of the Dd de-epoxidase. Our results imply that the
      reversal of the Dd cycle by HL + UV-B was caused by an increase in the rate of
      gross Dt epoxidation, whereas the de-epoxidation of Dd was unaffected by UV-B.
      This is further supported by our finding that the in vitro de-epoxidation
      activity and the affinity toward the cosubstrate ascorbic acid of the Dd de
      epoxidase were both unaffected by UV-B pretreatment of intact cells. We provide
      evidence that Dt epoxidation is normally down-regulated by a high pH gradient
      under HL. It is proposed that supplementary UV-B affected the pH gradient across
      the thylakoid membrane, which disrupted the down-regulation of Dt epoxidation and
      led to the observed increase in the rate of Dt epoxidation.

PMID- 12428018
TI  - Differential production of meta hydroxylated phenylpropanoids in sweet basil
      peltate glandular trichomes and leaves is controlled by the activities of
      specific acyltransferases and hydroxylases.
AB  - Sweet basil (Ocimum basilicum) peltate glandular trichomes produce a variety of
      small molecular weight phenylpropanoids, such as eugenol, caffeic acid, and
      rosmarinic acid, that result from meta hydroxylation reactions. Some basil lines
      do not synthesize eugenol but instead synthesize chavicol, a phenylpropanoid that
      does not contain a meta hydroxyl group. Two distinct acyltransferases, p
      coumaroyl-coenzyme A:shikimic acid p-coumaroyl transferase and p-coumaroyl
      coenzyme A:4-hydroxyphenyllactic acid p-coumaroyl transferase, responsible for
      the production of p-coumaroyl shikimate and of p-coumaroyl 4
      hydroxyphenyllactate, respectively, were partially purified and shown to be
      specific for their substrates. p-Coumaroyl-coenzyme A:shikimic acid p-coumaroyl
      transferase is expressed in basil peltate glands that are actively producing
      eugenol and is not active in glands of noneugenol-producing basil plants,
      suggesting that the levels of this activity determine the levels of synthesis of
      some meta-hydroxylated phenylpropanoids in these glands such as eugenol. Two
      basil cDNAs encoding isozymes of cytochrome P450 CYP98A13, which meta
      hydroxylates p-coumaroyl shikimate, were isolated and found to be highly similar
      (90% identity) to the Arabidopsis homolog, CYP98A3. Like the Arabidopsis enzyme,
      the basil enzymes were found to be very specific for p-coumaroyl shikimate.
      Finally, additional hydroxylase activities were identified in basil peltate
      glands that convert p-coumaroyl 4-hydroxyphenyllactic acid to its caffeoyl
      derivative and p-coumaric acid to caffeic acid.

PMID- 12428019
TI  - Role of the arginyl-glycyl-aspartic motif in the action of Ptr ToxA produced by
      Pyrenophora tritici-repentis.
AB  - A fundamental problem of plant science is to understand the biochemical basis of
      plant/pathogen interactions. The foliar disease tan spot of wheat (Triticum
      aestivum), caused by Pyrenophora tritici-repentis, involves Ptr ToxA, a
      proteinaceous host-selective toxin that causes host cell death. The fungal gene
      ToxA encodes a 17.2-kD pre-pro-protein that is processed to produce the mature
      13.2-kD toxin. Amino acids 140 to 142 of the pre-pro-protein form an arginyl
      glycyl-aspartic (RGD) sequence, a motif involved in the binding of some animal
      proteins and pathogens to transmembrane receptor proteins called integrins.
      Integrin-like proteins have been identified in plants recently, but their role in
      plant biology is unclear. Our model for Ptr ToxA action predicts that toxin
      interacts with a putative host receptor through the RGD motif. Mutant clones of a
      ToxA cDNA, created by polymerase chain reaction such that the RGD in the pro
      toxin was changed to arginyl-alanyl-aspartic or to arginyl-glycyl-glutamic, were
      expressed in Escherichia coli. Extracts containing mutated forms of toxin failed
      to cause host cell death, but extracts from E. coli expressing both a wild-type
      pro-protein cDNA and a control mutation away from RGD were active in cell death
      development. In competition experiments, 2 mM RGD tripeptide reduced the level of
      electrolyte leakage from wheat leaves by 63% when co-infiltrated with purified
      Ptr ToxA (15 microg mL(-1)) obtained from the fungus, but the control peptide
      arginyl-glycyl-glutamyl-serine provided no protection. These experiments indicate
      that the RGD motif of Ptr ToxA is involved with toxin action, possibly by
      interacting with a putative integrin-like receptor in the host.

PMID- 12428020
TI  - Mechanisms of arsenic hyperaccumulation in Pteris vittata. Uptake kinetics,
      interactions with phosphate, and arsenic speciation.
AB  - The mechanisms of arsenic (As) hyperaccumulation in Pteris vittata, the first
      identified As hyperaccumulator, are unknown. We investigated the interactions of
      arsenate and phosphate on the uptake and distribution of As and phosphorus (P),
      and As speciation in P. vittata. In an 18-d hydroponic experiment with varying
      concentrations of arsenate and phosphate, P. vittata accumulated As in the fronds
      up to 27,000 mg As kg(-1) dry weight, and the frond As to root As concentration
      ratio varied between 1.3 and 6.7. Increasing phosphate supply decreased As uptake
      markedly, with the effect being greater on root As concentration than on shoot As
      concentration. Increasing arsenate supply decreased the P concentration in the
      roots, but not in the fronds. Presence of phosphate in the uptake solution
      decreased arsenate influx markedly, whereas P starvation for 8 d increased the
      maximum net influx by 2.5-fold. The rate of arsenite uptake was 10% of that for
      arsenate in the absence of phosphate. Neither P starvation nor the presence of
      phosphate affected arsenite uptake. Within 8 h, 50% to 78% of the As taken up was
      distributed to the fronds, with a higher translocation efficiency for arsenite
      than for arsenate. In fronds, 49% to 94% of the As was extracted with a phosphate
      buffer (pH 5.6). Speciation analysis using high-performance liquid chromatography
      inductively coupled plasma mass spectroscopy showed that >85% of the extracted As
      was in the form of arsenite, and the remaining mostly as arsenate. We conclude
      that arsenate is taken up by P. vittata via the phosphate transporters, reduced
      to arsenite, and sequestered in the fronds primarily as As(III).

PMID- 12428021
TI  - Alternate energy-dependent pathways for the vacuolar uptake of glucose and
      glutathione conjugates.
AB  - Through the development and application of a liquid chromatography-mass
      spectrometry-based procedure for measuring the transport of complex organic
      molecules by vacuolar membrane vesicles in vitro, it is shown that the mechanism
      of uptake of sulfonylurea herbicides is determined by the ligand, glucose, or
      glutathione, to which the herbicide is conjugated. ATP-dependent accumulation of
      glucosylated chlorsulfuron by vacuolar membrane vesicles purified from red beet
      (Beta vulgaris) storage root approximates Michaelis-Menten kinetics and is
      strongly inhibited by agents that collapse or prevent the formation of a
      transmembrane H(+) gradient, but is completely insensitive to the phosphoryl
      transition state analog, vanadate. In contrast, ATP-dependent accumulation of the
      glutathione conjugate of a chlorsulfuron analog, chlorimuron-ethyl, is
      incompletely inhibited by agents that dissipate the transmembrane H(+) gradient
      but completely abolished by vanadate. In both cases, however, conjugation is
      essential for net uptake because neither of the unconjugated parent compounds are
      accumulated under energized or nonenergized conditions. That the attachment of
      glucose to two naturally occurring phenylpropanoids, p-hydroxycinnamic acid and p
      hydroxybenzoic acid via aromatic hydroxyl groups, targets these compounds to the
      functional equivalent of the transporter responsible for chlorsulfuron-glucoside
      transport, confirms the general applicability of the H(+) gradient dependence of
      glucoside uptake. It is concluded that H(+) gradient-dependent, vanadate
      insensitive glucoside uptake is mediated by an H(+) antiporter, whereas vanadate
      sensitive glutathione conjugate uptake is mediated by an ATP-binding cassette
      transporter. In so doing, it is established that liquid chromatography-mass
      spectrometry affords a versatile high-sensitivity, high-fidelity technique for
      studies of the transport of complex organic molecules whose synthesis as
      radiolabeled derivatives is laborious and/or prohibitively expensive.

PMID- 12428022
TI  - Interactions of nitrate and CO2 enrichment on growth, carbohydrates, and rubisco
      in Arabidopsis starch mutants. Significance of starch and hexose.
AB  - Wild-type (wt) Arabidopsis plants, the starch-deficient mutant TL46, and the near
      starchless mutant TL25 were grown in hydroponics under two levels of nitrate, 0.2
      versus 6 mM, and two levels of CO(2), 35 versus 100 Pa. Growth (fresh weight and
      leaf area basis) was highest in wt plants, lower in TL46, and much lower in TL25
      plants under a given treatment. It is surprising that the inability to synthesize
      starch restricted leaf area development under both low N (N(L)) and high N
      (N(H)). For each genotype, the order of greatest growth among the four treatments
      was high CO(2)/N(H) > low CO(2)/N(H), > high CO(2)/N(L), which was similar to low
      CO(2)/N(L). Under high CO(2)/N(L), wt and TL46 plants retained considerable
      starch in leaves at the end of the night period, and TL25 accumulated large
      amounts of soluble sugars, indicative of N-limited restraints on utilization of
      photosynthates. The lowest ribulose-1,5-bisphosphate carboxylase/oxygenase per
      leaf area was in plants grown under high CO(2)/N(L). When N supply is limited,
      the increase in soluble sugars, particularly in the starch mutants, apparently
      accentuates the feedback and down-regulation of ribulose-1,5-bisphosphate
      carboxylase/oxygenase, resulting in greater reduction of growth. With an adequate
      supply of N, growth is limited in the starch mutants due to insufficient
      carbohydrate reserves during the dark period. A combination of limited N and a
      limited capacity to synthesize starch, which restrict the capacity to use
      photosynthate, and high CO(2), which increases the potential to produce
      photosynthate, provides conditions for strong down-regulation of photosynthesis.

PMID- 12428023
TI  - Alveolar type I cells: molecular phenotype and development.
AB  - Understanding of the functions and regulation of the phenotype of the alveolar
      type I epithelial cell has lagged behind studies of its neighbor the type II cell
      because of lack of cell-specific molecular markers. The recent identification of
      several proteins expressed by type I cells indicates that these cells may play
      important roles in regulation of cell proliferation, ion transport and water
      flow, metabolism of peptides, modulation of macrophage functions, and signaling
      events in the peripheral lung. Cell systems and reagents are available to
      characterize type I cell biology in detail, an important goal given that the
      cells provide the extensive surface that facilitates gas exchange in the intact
      animal.

PMID- 12428024
TI  - Neuroprotection and antiepileptogenesis: overview, definitions, and context.

PMID- 12428025
TI  - Seizure-induced neuronal injury: animal data.
AB  - One of the oldest questions in epilepsy is whether seizures are a cause or a
      result of brain damage. Animal data have provided us with insights into the
      relationship between seizures and subsequent brain damage. It is now recognized
      that seizures can be caused by brain injury and that, in certain conditions, can
      cause brain damage. Whether seizures result in brain damage depends on a number
      of variables, including age of the animal, seizure type and duration, etiology of
      the seizures, and genetic substrate on which the seizures occur. Seizures lasting
      for hours can cause injury to the brain regardless of whether they are
      generalized or focal in onset. The cell loss that occurs after the seizure is
      secondary to excessive excitability, with seizures causing massive depolarization
      of neurons leading to excessive glutamate release. This glutamate release results
      in increased intracellular calcium, causing a cascade of changes that ultimately
      result in cell death. Hypoxia and ischemia can exacerbate the injury. However,
      even in animals that are well ventilated and oxygenated, prolonged seizures can
      lead to cell loss and subsequent reorganization of synaptic networks. Although
      prolonged seizures at any age can result in cell loss, the immature brain fares
      much better than the mature brain with regard to cell loss after a prolonged
      seizure. Evidence that prolonged seizures result in neuronal loss is firmly
      established. It is less clear how detrimental recurrent seizures are. Although
      cell loss and synaptic reorganization have been reported in recurrent seizure
      models, such as kindling, it is generally modest compared to status epilepticus.
      When seizure-induced changes do occur, the pathologic patterns in the brain
      differ from those in status epilepticus.

PMID- 12428026
TI  - Animal models of epileptogenesis.
AB  - Advances in our understanding of the molecular biology of human epileptogenesis
      and secondary hyperexcitability have resulted in part from the development and
      characterization of animal models of mesial temporal lobe epilepsy, trauma
      induced epilepsy, and age-specific models of febrile seizures and neonatal
      hypoxia-induced seizures. Each of these models displays similarities to and
      differences from their human counterparts and will undoubtedly prove useful for
      evaluating novel therapies aimed at preventing the development, or halting the
      progression, of epilepsy or insult-induced secondary hyperexcitability. This
      article briefly reviews those models that most closely parallel human mesial
      temporal lobe epilepsy, trauma-induced epilepsy, febrile seizures, and hypoxia
      induced seizures. Particular attention is paid to the underlying pathology, the
      presence or absence of a latent period, and development of spontaneous seizures.

PMID- 12428027
TI  - Seizure-induced neuronal injury: human data.
AB  - Evidence that recurrent epileptic seizures may cause neuronal injury in some
      patients has been inferred from clinical observation, neuropsychological
      assessments, and neuroimaging studies. Cross-sectional investigations have
      yielded conflicting results and it is not possible to draw conclusions regarding
      causation, rather than merely association, from such designs. However, there is
      also evidence from in vivo biochemical studies that seizures may cause neuron
      injury. The heterogeneity of the epilepsies, epileptic seizures, co-morbidities,
      treatment regimens, and individual patient susceptibility all complicate the
      picture and inhibit the drawing of conclusions that are uniformly applicable.
      Longitudinal neuroimaging studies have the potential to objectively identify
      structural changes in the brain that are markers of neuronal injury. Such studies
      are a major undertaking, requiring age-matched control groups and consistent
      image acquisition and analysis techniques. One needs to analyze not only changes
      in group means but also the number of patients who show significant changes in
      imaging parameters that exceed the limits of test-retest reliability and changes
      in age-matched controls. Quantitative analysis of MRI T(1)-weighted volumetric
      datasets can reliably identify changes in cerebral and hippocampal volumes of 1
      3% in individual subjects. The sensitivity of such quantitative analysis of
      structural data to identify functionally significant changes is not yet certain.
      Functional imaging techniques such as MR spectroscopy, PET, and SPECT may be more
      sensitive for detecting cerebral abnormalities, but their test-retest reliability
      is inferior. Other MRI tools, such as diffusion tensor imaging, may be useful for
      evaluating secondary cerebral damage after seizures, both acutely and
      chronically. Present evidence suggests that, to detect significant treatment
      effects, longitudinal studies of putative neuroprotective agents, using
      neuroimaging methods as a surrogate end point, would require at least a 3-year
      observation period, include large numbers of patients, and provide stratification
      for important clinical variables.

PMID- 12428028
TI  - Epilepsy after brain insult: targeting epileptogenesis.
AB  - Seizures and epilepsy are common sequelae of acute brain insults such as stroke,
      traumatic brain injury, and central nervous system infections. Early, or acute
      symptomatic, seizures occur at the time of the brain insult and may be a marker
      of severity of injury. A cascade of morphologic and biologic changes in the
      injured area over months to years leads to hyperexcitability and epileptogenesis.
      After a variable latency period, late unprovoked seizures and epilepsy occur. The
      latent period may offer a therapeutic window for the prevention of
      epileptogenesis and the development of unprovoked seizures and epilepsy.
      Administration of anticonvulsant drugs following acute brain insults has thus far
      failed to prevent late epilepsy. Proper choice of disease models and target
      populations will aid in the development of putative antiepileptogenic agents. The
      incidence, timing, and pathophysiology of common epileptogenic brain injuries,
      including head trauma, cerebrovascular disease, brain tumors, neurosurgical
      procedures, neurodegenerative conditions, status epilepticus, and febrile
      seizures, are reviewed.

PMID- 12428029
TI  - Drug-mediated neuroprotection and antiepileptogenesis: animal data.
AB  - Seizures have a partial onset in approximately two-thirds of epilepsy patients.
      In most of these cases epilepsy is a consequence of a brain-damaging insult such
      as head trauma, stroke, brain infection, brain surgery, or status epilepticus.
      The epileptic process consists of three phases: initial insult U27AA; latency
      period (epileptogenesis) U27AA; recurrent seizures (symptomatic epilepsy). The
      treatment of epilepsy focuses exclusively on preventing or suppressing seizures,
      which are the end products of the epileptic process. The challenge is whether
      epileptogenesis can be prevented by therapeutic intervention. If not, can the
      disease process be modified in such a way that epilepsy will be easier to treat?
      Achieving these goals is becoming more realistic now that there is a better
      understanding of the neurobiology of the epileptic process and the factors that
      predict the risk for progression in individual patients. These data provide new
      opportunities for the design of neuroprotective and antiepileptogenic treatments
      for patients who, if untreated, could develop drug-refractory epilepsy associated
      with cognitive decline. Here we review the available data on neuroprotective,
      antiepileptogenic, and disease-modifying effects of antiepileptic drugs and other
      treatments at different phases of the epileptic process. Analysis of these data
      suggests that by using compounds currently available, beneficial effects on the
      outcome can be achieved by modification of the epileptogenic insult at the acute
      phase and by modification of circuitry reorganization that is induced/maintained
      by brief seizures after the diagnosis of epilepsy. Discontinuation or
      modification of epileptogenesis in patients who experienced an epileptogenic
      insult months or years before is more complicated. However, molecular screening
      of candidate epileptogenesis-related genes has revealed novel mechanisms
      underlying network reorganization and will undoubtedly provide exciting avenues
      for the development of true antiepileptogenic and disease-modifying agents.

PMID- 12428030
TI  - Drug-mediated antiepileptogenesis in humans.
AB  - The goal of pharmacologic therapy for patients with epilepsy is to suppress
      seizures without side effects. There is growing interest in developing
      antiepileptogenic drugs capable of preventing the onset of seizures in patients
      at high risk and inducing a permanent remission of seizures in patients with
      epilepsy, i.e., a cure. Whether any anticonvulsant drugs in current use have
      antiepileptogenic properties is the subject of this overview.

PMID- 12428031
TI  - Neuroprotection and antiepileptogenesis: where are we now?

PMID- 12428032
TI  - Violence prevention and control through environmental modifications.
AB  - Violence traditionally had been considered a problem exclusively within the
      criminal justice domain, although it is now widely viewed as a public health
      issue as well. Public health has brought new and complementary tools for
      understanding and preventing violence. Whereas public health has long recognized
      the environment as a determinant of disease and injury, it has paid less
      attention to the environment when considering violence prevention strategies. For
      several decades though, some criminologists and others have been researching
      environmental factors in crime prevention. This article aims to discuss the main
      environmental crime-prevention strategies, provide examples of promising
      interventions, review public health literature that uses these strategies,
      discuss what public health can contribute, and suggest public health research to
      test the hypothesis that violence can be prevented and controlled through
      environmental modifications.

PMID- 12428033
TI  - Health issues of air travel.
AB  - Every day in the United States the airline industry boards over 1.7 million
      passengers for a total of 600 million passengers per year. As these passengers
      enter the cabin of their aircraft few are aware of the artificial environment
      that will protect them from the hazards of flight. Passengers are exposed to
      reduced atmospheric pressure, reduced available oxygen, noise, vibration, and are
      subject to below zero temperatures that are only a quarter inch away-the
      thickness of the aircraft's skin. Over the past decade there have been both
      technical and lay articles written on the perception of poor cabin air quality.
      Studies have, in part, supported some of those concerns, but, in general, the air
      quality exceeds that found in most enclosed spaces on terra firma. Since the
      events of September 11th, passengers have not only been exposed to the physical
      stress of flight, but also to social and emotional stress preceding departure.
      There has been a significant increase in air rage on board aircraft, which poses
      a threat to flight safety and a fear of harm to passengers and crew. The phrase
      "economy class syndrome" has received popular press attention and refers to the
      possibility of deep vein thrombosis (DVT) in the tight confines of an aircraft
      cabin. Studies have been conducted that demonstrate DVT can occur in flight just
      as it occurs in other modes of transportation or with prolonged sitting. In part,
      because of the stress related to commercial flight it is not a mode of
      transportation for everyone. Certain cardiovascular, pulmonary, and
      neuropsychiatric conditions are best left on the ground. Although medical
      problems and death are rare in flight, they do occur, and one major airline
      reported 1.52 medical diversions per billion revenue passenger miles flown. To
      provide medical support at 36,000 ft (11,000 m) most airlines now carry on-board
      medical kits as well as automatic external defibrillators. A recent survey
      conducted by a major airline revealed that there was at least one physician on
      85% of all its flights. Both passenger and cargo aircraft have proven to be
      vectors of disease in that they transport humans, mosquitoes, and other insects
      and animals who, in turn, transmit disease. Transmission to other passengers has
      occurred with tuberculosis and influenza. Vectors for yellow fever, malaria, and
      dengue have been identified on aircraft. Although there are numerous health
      issues associated with air travel they pale in comparison to the enormous
      benefits to the traveler, to commerce, to international affairs, and to the
      public's health.

PMID- 12428035
TI  - Oxygen therapy for acute respiratory infections in young children.

PMID- 12428034
TI  - Supporting informed consumer health care decisions: data presentation approaches
      that facilitate the use of information in choice.
AB  - To make informed choices and navigate within a complex health care system,
      consumers must have easily available, accurate, and timely information, and they
      must use it. Contrary to the consumer-driven approach, however, the evidence
      demonstrates that having an abundance of information does not always translate
      into its being used to inform choices. The challenge is not merely to communicate
      accurate information to consumers, but to understand how to present and target
      that information so that it is actually used in decision-making. This paper
      reviews what is known from studies of human judgment and decision-making and
      discusses their implications for supporting informed consumer choice. We
      delineate the types of decisions that consumers and patients are making, the
      barriers to using information effectively in choice, and draw upon the evidence
      for the efficacy of different presentation strategies to propose an initial
      framework for evaluating and choosing comparative information presentation
      approaches.

PMID- 12428036
TI  - Diagnosis and outcome of acute bacterial meningitis in early childhood.
AB  - OBJECTIVE: To estimate frequency of acute bacterial meningitis (ABM) in early
      childhood in hospital admissions, to describe clinical and diagnostic features,
      and to analyze mortality, complications and long term sequelae. DESIGN:
      Prospective study. SETTING: Pediatric wards and Rehabilitation Center of KEM
      Hospital, Pune. METHOD: Study subjects between the ages of 1 months to 5 years
      with ABM were recruited. Clinical details were recorded. CSF was analysed by
      routine biochemical methods, antigen detection tests (Latex agglutination LAT)
      and microbiological studies on special media. Management was as per standard
      protocols. Survivors were followed up long term with neurodevelopmental studies
      and rehabilitation programmes. RESULTS: In a study period of 2 years, 54 children
      (1.5% of all admissions) satisfied the criteria of ABM in early childhood; 78%
      were below one year and 52% were under the age of six months. Chief presentation
      was high fever, refusal of feeds, altered sensorium and seizures. Meningeal signs
      were present in only 26%. CSF C-reactive protein was positive in 41%, gram stain
      was positive in 67% LAT in 78% and cultures grew causative organisms in 50% of
      the cases. The final etiological diagnosis (as per LAT and/or cultures) were
      Streptococcus pneumoniae 39% Hemophilus influenzae type b 26% and others in 35%
      The others included one case of Neisseria meningitidis and 10 who were LAT
      negative and culture sterile. 39% patients developed acute neurological
      complications during the hospital course. 31% children with ABM died in hospital
      or at home soon after discharge. Six were lost to follow up. Of the 31 children,
      available for long term follow up (1-3 years), 14 (45%) had no sequelae. The
      remaining had significant neurodevelopmental handicaps ranging from isolated
      hearing loss to severe mental retardation with multiple disabilities. CONCLUSION:
      ABM in early childhood has a considerable mortality, morbidity and serious long
      term sequelae. Neurodevelopmental follow up and therapy should begin early.
      Etiological diagnosis can be enhanced by LAT and good culture media. H.
      influenzae b and S. pneumoniae account for more than 60% of ABM in early
      childhood.

PMID- 12428037
TI  - Atopic dermatitis.

PMID- 12428038
TI  - Outcome in juvenile dermatomyositis.
AB  - The clinical features, outcome and complications of juvenile dermatomyositis were
      studied in a tertiary care hospital by retrospective analysis of case records.
      Nineteen patients were treated over an 11-year period. Median age at diagnosis
      was 12 years (2.5-16 years). Median duration of disease prior to diagnosis was 12
      months (2-96 months). Proximal muscle weakness was seen in all 19 cases, neck
      muscle weakness in 14, pharyngeal muscle involvement in 5 and respiratory muscle
      involvement in 3 cases. Heliotrope rash was seen in 9 and Gottrons rash in 8
      patients. Myocarditis and GI bleed were seen in 1 each while interstitial lung
      disease was seen in 2 patients. All except one patient received prednisolone.
      Methotrexate was used in 13 and azathioprine in 3 patients. Eight patients are in
      complete remission (CR), 8 partial remission and 2 patients had no response.
      Complications were calcinosis in 5, contractures in 2, TB in 4 and pyogenic
      infections in 4 patients. Juvenile dermatomyositis needs to be recognised early
      and treated aggressively to improve outcome.

PMID- 12428039
TI  - Prevalence of hepatitis A in children and adolescents in Adana, Turkey.
AB  - The present study was aimed at determining the seroprevalence of anti-HAV in
      children and adolescents in the city of Adana, Turkey. The overall prevalence of
      anti-HAV was 44.4% (316/711). The prevalence increased with advancing age i.e.
      28.8% (2.1-6 yr), 49.8% (6.1-12 yr), and 68% (12.1-16.5 yr) (P < 0.0001).
      Seroprevalence was significantly lower in children less than 6 years and
      belonging to higher socioeconomic status.

PMID- 12428040
TI  - Isosporiasis in children.
AB  - The clinical, laboratory and therapeutic data of patients with diarrhea in Human
      immunodeficiency virus (HIV) antibody positive, immunocompromised and
      immunocompetent individuals were studied especially to look for prevalence of
      intestinal coccidiosis. During a study period of one decade, Isospora belli were
      identified in the stool samples of seven children with diarrhea. Diarrhea
      persisted for a little longer period in HIV-seropositive children compared to
      sero-negatives but the clinical picture did not differ significantly in either
      HIV infected or HIV uninfected individuals.

PMID- 12428041
TI  - Phenobarbitone prophylaxis for neonatal jaundice in babies with birth weight 1000
      1499 grams.
AB  - Management of neonatal jaundice is simple but in sick, very low birth weight
      babies poses additional hemodynamic insult. Role of prophylactic postnatal
      phenobarbitone (two different dosage regimens) was evaluated prospectively on
      occurrence of neonatal jaundice and the need for therapy in 150 babies with birth
      weight 1000-1499 grams. Phenobarbitone in the dose of 10mg/kg given within 6
      hours of life followed by 5mg/kg/day till day 5 of life intravenously
      significantly decreased the need for exchange transfusion and duration of
      phototherapy in babies with birth weight of 1000-1499 grams. This dosage schedule
      was better than dose of 5mg/kg for 5 days in significantly reducing the duration
      of phototherapy

PMID- 12428042
TI  - Febrile episodes in childhood malignancies.
AB  - The objectives of the present report were to study the site of infections and
      pathogenic organisms during febrile episodes in different childhood malignant
      conditions, to correlate febrile episode with Absolute Neutrophil Count (ANC) and
      to know the sensitivity pattern of bacteria to different antibiotics so as to
      know the most appropriate antibiotic regimen in these children. The study
      material comprised of forty two febrile episodes occurring in children aged lt 12
      years with various malignancies. All the episodes were worked up in detail
      including complete history, physical examination and relevant hematological,
      microbiological and radiological investigations. Out of the 42 episodes, 15 (36%)
      occurred in children with acute leukemias, 20 (48%) in children with lymphomas
      and 7(17%) in children with solid tumors. 26 (62%) episodes were seen in children
      during chemotherapy, while 12% each in freshly diagnosed and remission and 14% in
      relapse cases. 12 (28%) episodes occurred in children with ANC < 500/mm3. 36%
      were microbiologically confirmed. Klebsiella species was the commonest organism
      isolated followed by E. coli. Maximum sensitivity (75%) was seen with
      ciprofloxacin against both Klebsiella species and E.coli.

PMID- 12428043
TI  - Thoracoscopy in management of empyema thoracis in children.
AB  - The usual treatment for empyema in children varies from a simple thoracocentesis
      to thoracotomy and open decortication. We studied the role of thoracoscopy in the
      management of empyema thoracis in 10 immunocompetent children after failure of
      medical management. All children recovered well with an early removal of
      intercostal tube and reduced postoperative hospital stay and showed complete
      resolution of empyema on follow up. Thoracoscopy has come as a new ray of hope
      for the patients with empyema, with the advantages of complete evacuation,
      minimal pulmonary dysfunction, reduced pain and hospital stay.

PMID- 12428044
TI  - Leucocyte adhesion deficiency-1.

PMID- 12428045
TI  - Von Voss-Cherstvoy syndrome.

PMID- 12428046
TI  - Congenital syphilis.

PMID- 12428047
TI  - Cyclopia.

PMID- 12428048
TI  - Bilateral congenital chylothorax with Noonan syndrome.

PMID- 12428049
TI  - Endobronchial tuberculosis and the surgeon.

PMID- 12428050
TI  - Efficacy of nimesulide in pain relief after day care surgery.

PMID- 12428052
TI  - Duchenne muscular dystrophy in a female child.

PMID- 12428054
TI  - First dose of hepatitis B vaccine in infants.

PMID- 12428057
TI  - Relactation in mothers of high risk infants.

PMID- 12428058
TI  - Conducting a CME Program.

PMID- 12428060
TI  - Unmasking the anti-La/SSB response in sera from patients with Sjogren's syndrome
      by specific blocking of anti-idiotypic antibodies to La/SSB antigenic
      determinants.
AB  - BACKGROUND: Autoantigen La/SSB is molecular target of humoral autoimmunity in
      patients with primary Sjogren's Syndrome (pSS) and systemic lupus erythematosus
      (SLE). In this study, we investigated the existence and possible influence of
      anti-idiotypic response to anti-La/SSB antibodies. MATERIALS AND METHODS:
      Synthetic peptide analogs (pep) of the major antigenic determinants of La/SSB
      (289-308 aa and 349-364 aa) were prepared. Based on "molecular recognition"
      theory, complementary peptides (cpep), derived by anti-parallel readings of the
      noncoding strand of La/SSB DNA encoding for its antigenic determinants, were
      constructed. Sera from 150 patients with anti-La/SSB antibodies, 30 patients
      without anti-La/SSB antibodies, and 42 normal individuals were tested against all
      four peptides. F(ab')(2) fragments from anti-peptide IgG were prepared and
      F(ab')(2) - IgG interactions were evaluated using a specific anti-idiotypic
      ELISA. RESULTS: All four peptides were recognized by anti-La positive sera (83%
      and 51% for pep and cpep 349-364 and 51% and 28% for pep and cpep289-308,
      respectively). Anti-cpep F(ab')(2 )bound to a common idiotype (Id) located within
      or spatially close to the antigen combining site of anti La/SSB (anti-pep)
      antibodies. Homologous and cross-inhibition experiments further confirmed this
      relation. The anti-idiotypic antibodies inhibited the anti-La/SSB antibody
      binding to recombinant La/SSB by 91%. To overcome the anti-idiotypic interference
      in anti-La/SSB detection, a specific assay was developed. Sera were heated for
      dissociation of Id-anti-Id complexes, anti-Id antibodies blocked with cpep, and
      anti-La/SSB reactivity was recovered. Application of this method to anti-Ro
      positive-anti-La/SSB "negative" sera showed that all anti-Ro/SSA positive
      autoimmune sera also possess anti-La/SSB antibodies. This reaction was not
      observed in 14 anti-Ro negative- anti-Sm/RNP positive sera from patients with
      SLE. CONCLUSIONS: Autoimmune sera from patients with pSS and SLE contain anti
      idiotypic antibodies targeting a common anti-La/SSB idiotype. These antibodies
      can be detected using complementary peptides of La/SSB epitopes. The
      antiidiotypic antibodies mask the anti-La/SSB response. Hidden anti-La/SSB
      antibodies can be released and detected using complementary epitope analogs.

PMID- 12428061
TI  - Fabry disease: twenty novel alpha-galactosidase A mutations and genotype
      phenotype correlations in classical and variant phenotypes.
AB  - BACKGROUND: Fabry disease (OMIM 301500) is an X-linked inborn error of
      glycosphingolipid metabolism resulting from mutations in the alpha-galactosidase
      A (alpha-Gal A) gene. The disease is phenotypically heterogeneous with classic
      and variant phenotypes. To assess the molecular heterogeneity, define
      genotype/phenotype correlations, and for precise carrier identification, the
      nature of the molecular lesions in the alpha-Gal A gene was determined in 40
      unrelated families with Fabry disease. MATERIALS AND METHODS: Genomic DNA was
      isolated from affected males or obligate carrier females and the entire alpha-Gal
      A coding region and flanking sequences were amplified by PCR and analyzed by
      automated sequencing. Haplotype analyses were performed with polymorphisms within
      and flanking the alpha-Gal A gene. RESULTS: Twenty new mutations were identified
      (G43R, R49G, M72I, G138E, W236X, L243F, W245X, S247C, D266E, W287C, S297C, N355K,
      E358G, P409S, g1237del15, g10274insG, g10679insG, g10702delA, g11018insA, g11185
      delT), each in a single family. In the remaining 20 Fabry families, 18 previously
      reported mutations were detected (R49P, D92N, C94Y, R112C [two families], F113S,
      W162X, G183D, R220X, R227X, R227Q, Q250X, R301X, R301Q, G328R, R342Q, E358K,
      P409A, g10208delAA [two families]). Haplotype analyses indicated that the
      families with the R112C or g10208delAA mutations were not related. The proband
      with the D266E lesion had a severe classic phenotype, having developed renal
      failure at 15 years. In contrast, the patient with the S247C mutation had a
      variant phenotype, lacking the classic manifestations and having mild renal
      involvement at 64 years. CONCLUSIONS: These results further define the
      heterogeneity of alpha-Gal A mutations causing Fabry disease, permit precise
      heterozygote detection and prenatal diagnosis in these families, and provide
      additional genotype/phenotype correlations in this lysosomal storage disease.

PMID- 12428062
TI  - Inhibition by yeast killer toxin-like antibodies of oral Streptococci adhesion to
      tooth surfaces in an ex vivo model.
AB  - BACKGROUND: Monoclonal (KTmAb) and recombinant (KTscFv) anti-idiotypic
      antibodies, representing the internal image of a yeast killer toxin, proved to be
      microbicidal in vitro against important eukaryotic and prokaryotic pathogens such
      as Candida albicans, Pneumocystis carinii, Mycobacterium tuberculosis,
      Staphylococcus aureus, S. haemolyticus, Enterococcus faecalis, E. faecium, and
      Streptococcus pneumoniae, including multidrug-resistant strains. KTmAb and KTscFv
      exerted a strong therapeutic effect in well-established animal models of
      candidiasis and pneumocystosis. Streptococcus mutans is the most important
      etiologic agent of dental caries that might result from the metabolic end
      products of dental plaque. Effective strategies to reduce the disease potential
      of dental plaque have considered the possibility of using antibiotics or
      antibodies against oral streptococci in general and S. mutans in particular. In
      this study, the activity of KTmAb and KTscFv against S. mutans and the inhibition
      and reduction by KTmAb of dental colonization by S. mutans and other oral
      streptococci in an ex vivo model of human teeth were investigated. MATERIALS AND
      METHODS: KTscFv and KTmAb were used in a conventional colony forming unit (CFU)
      assay against a serotype C strain of S. mutans, and other oral streptococci (S.
      intermedius, S. mitis, S. oralis, S. salivarius). An ex vivo model of human teeth
      submerged in saliva was used to establish KTmAb potential of inhibiting or
      reducing the adhesion to dental surfaces by S. mutans and other oral
      streptococci. RESULTS: KTmAb and KTscFv kill in vitro S. mutans and other oral
      streptococci. KTmAb inhibit colonization of dental surfaces by S. mutans and oral
      streptococci in the ex vivo model. CONCLUSIONS: Killer antibodies with antibiotic
      activity or their engineered derivatives may have a potential in the prevention
      of dental caries in vivo.

PMID- 12428063
TI  - Gene expression of ABC proteins in hepatocellular carcinoma, perineoplastic
      tissue, and liver diseases.
AB  - BACKGROUND: The development of hepatocellular carcinoma (HCC) is a frequent event
      during the natural history of cirrhosis. Effective treatment is, however,
      hampered by drug resistance related to the expression of multidrug resistance
      (MDR) proteins belonging to the ABC family transporters. Studying expression of
      genes coding for these proteins may help to explain the potential sensitivity of
      HCC to chemotherapy. MATERIAL AND METHODS: The expression of MRP1, MRP2, MRP3,
      MDR1, and MDR3 was investigated by quantitative RT-PCR analyses in paraffin
      embedded tissues obtained from 9 cases of HCC, 16 cases of cirrhosis, 10 cases of
      chronic extrahepatic cholestasis, and 16 cases of normal liver. In HCC cases,
      gene expression was assessed both in neoplastic and perineoplastic tissue after
      microscopically assisted microdissection. RESULTS: MRP1 was significantly and
      similarly overexpressed in HCC and perineoplastic tissue. MRP2 and MDR1 were also
      increased in HCC, but the level of expression did not correlate with that of
      perineoplastic tissue. The level of expression was either reduced or normal in
      cirrhotic liver and during chronic cholestasis. Expression of MDR3 was unchanged
      in all conditions investigated. CONCLUSIONS: The genetic expression of multi-drug
      resistance proteins, in particular MRP1, MRP2, and MDR1, is increased during HCC.
      In the case of MRP1, the extent of expression is similar in neoplastic and
      perineoplastic tissue, but this is not the case for MRP2 and MDR1. The assessment
      of ABC protein expression pattern may provide important information for the
      diagnosis and treatment of HCC.

PMID- 12428064
TI  - Human mitochondrial transcription factor A reduction and mitochondrial
      dysfunction in Hashimoto's hypothyroid myopathy.
AB  - BACKGROUND: Mitochondrial changes have been described in muscle tissue in
      acquired hypothyroidism. Among the molecular mechanisms by which thyroid hormones
      regulate expression of nuclear genes encoding for regulatory proteins of
      mitochondrial respiratory function, the mitochondrial transcription factor A (h
      mtTFA) has been proposed to be a target of thyroid hormone action. The aim of
      this study has been to relate h-mtTFA levels in the skeletal muscle of patients
      affected by Hashimoto's hypothyroidism and myopathy (HHM) to muscle disease and
      thyroid status. PATIENTS AND METHODS: Eleven HHM patients underwent complete
      thyroid status and neurologic assessment, along with determination of exercise
      lactate anaerobic threshold (LT) and muscle biopsy in which h-mtTFA levels were
      measured and mtDNA was analyzed. RESULTS: Decreased exercise lactate threshold,
      presence of cytochrome c oxidase negative fibers, reduction of cytochrome c
      oxidase activity, and mitochondrial DNA copy number at muscle biopsy were
      indicative of mitochondrial involvement in these patients. Furthermore, muscle h
      mtTFA levels were reduced to a variable extent in comparison with a group of
      euthyroid controls. The h-mtTFA levels were inversely correlated with TSH and LT
      lactate, and positively correlated with FT4. CONCLUSIONS: These results indicate
      that low levels of the h-mtTFA occur in skeletal muscle of HHM and suggest that
      abnormal h-mtTFA turnover may be implicated in the pathogenesis of mitochondrial
      alterations in this disease.

PMID- 12428065
TI  - The clinical importance of proton pump inhibitor pharmacokinetics.
AB  - Achieving the optimal clinical response for patients with upper gastrointestinal
      peptic disease is important. This response depends on the pathology treated as
      well as on the choice of proton pump inhibitor. Here, we identify factors in
      specific disease therapy and proton pump inhibitor (PPI) pharmacokinetic and
      pharmacodynamic characteristics that help us achieve this goal. These include
      differences in PPI bioavailability and acid-suppressive effects. Available data
      indicate that PPIs appear to have similar potency on a milligram basis, and that
      omeprazole and lansoprazole are more frequently double dosed than pantoprazole.
      The lower propensity for double dosing with pantoprazole may also result in lower
      medication acquisition costs and a reduction in physician visits due to
      ineffective therapy with the standard dosing of these other agents.

PMID- 12428066
TI  - The role of the autonomic nervous system in liver regeneration and apoptosis-
      recent developments.
AB  - Hepatocytes have a great replicative capacity and are capable of repopulating the
      liver. Previous studies have suggested that the autonomic nervous system
      regulates liver regeneration and apoptosis. Moreover, the central nervous system
      modulates them through the autonomic nervous system. The lateral hypothalamus
      (LH) area and the ventromedial hypothalamus (VMH) nucleus have been studied for
      their role in the integration of neurohumoral information. The LH is part of the
      parasympathetic system, while the VMH belongs to the sympathetic system. Lesions
      of the LH reportedly induced an increase in sympathetic nerve activity, while
      those in the VMH produced facilitation of vagus nerve activity. Moreover, VMH or
      LH lesions facilitate hepatic regeneration after partial hepatectomy.
      Furthermore, the hypothalamus mediates hepatic apoptosis through the autonomic
      nervous system. Although further studies are needed to define the role clearly,
      the autonomic nervous system is one of the important factors that regulate liver
      regeneration and apoptosis.

PMID- 12428067
TI  - Helicobacter species are not detectable by 16S rDNA PCR in bile from Dutch
      patients with common bile duct stones.
AB  - BACKGROUND: Some Helicobacter species colonize the intestinal tract. To explore
      the possible relation between Helicobacter spp. and gallbladder disorders, we
      have investigated their presence in bile of patients with biliary obstruction and
      dilatation of the bile ducts. METHODS: Bile was sampled from 31 Dutch patients
      with biliary obstruction identified by jaundice and dilatation of the bile ducts
      on ultrasound. Samples (n = 31) were obtained immediately following cannulation
      of the common bile duct (CBD) by endoscopic retrograde cholangiopancreatography
      (ERCP) (n = 29) or by peri-operative puncture of the gallbladder (n = 2). DNA was
      isolated from bile by binding to diatoms. Helicobacter spp. were detected by a
      sensitive (detection limit 1 CFU per reaction tube) 16S rDNA PCR with genus
      specific primers. Duplicate samples were spiked with Helicobacter pylori DNA and
      subjected to PCR in order to check for inhibition. RESULTS: 28 patients had CBD
      stones (bile collected by ERCP (n = 26) or operatively (n = 2)), 2 had a
      pancreatic head tumor, and in 1 no abnormalities were found. In 1 of 21
      amplifiable bile samples (10/31 inhibited) from Dutch patients with CBD stones,
      H. pylori 16S rDNA was found. CONCLUSION: Our data indicate that CBD stones in
      Dutch patients are not associated with the presence of Helicobacter spp. in bile.

PMID- 12428068
TI  - Effect of Helicobacter pylori eradication or of ranitidine plus metoclopramide on
      Helicobacter pylori-positive functional dyspepsia. A randomized, controlled
      follow-up study.
AB  - BACKGROUND: A definitive treatment for functional dyspepsia (FD), and the role of
      Helicobacter pylori eradication on the course of this disease are controversial.
      AIM: To investigate the effect of a combination of acid-suppressing and
      prokinetic drugs or eradication therapy on the course of H. pylori-positive FD.
      METHOD: A total of 157 patients with endoscopically-proven H. pylori-positive FD
      and no response to 4 weeks of antacid therapy were randomly divided into 2
      groups. 84 were placed on bismuth subnitrate plus metronidazole and amoxicillin
      (group A) and 73 received ranitidine and metoclopramide for 4 weeks (group B).
      The severity of symptoms (7 items) were assessed on a 6-point categorical scale.
      Group B patients who failed to respond to their medication underwent eradication
      therapy after 3 months. All patients were followed and assessed for 9 months
      after the end of therapy by the same clinicians who initiated the therapy.
      RESULTS: At the end of the medication period, symptom's score decreased
      significantly, and to the same extent. At 3-month follow-up moderate or complete
      response was achieved in 27.4% (group A) and 19.2% (group B) by intention-to
      treat analysis. 34 patients of group B, not responding to treatment, underwent
      eradication therapy and followed as group A. Eradication of H. pylori was
      successful in 60 of 110 controlled patients (54%). After 9-month follow-up,
      complete or moderate response was observed in only 30% of 60 patients in whom H.
      pylori had been eradicated (intention-to-treat analysis), compared to 38% in 50
      noneradicated cases (p > 0.05, 95% CI: 19-43 vs. 24-52). CONCLUSION: Eradication
      therapy with bismuth compound is effective as ranitidine plus metoclopramide in a
      subgroup of patients with FD not responding to antacid therapy. There is no
      difference in improvement between patients cured or not cured from H. pylori
      infection. This suggests that bismuth compounds were effective in FD when used in
      the eradication regimen. Combination therapy with acid-suppressing drugs plus
      prokinetic and bismuth seems to hold promise for FD.

PMID- 12428069
TI  - Efficacy of vascular endothelial growth factor in the treatment of experimental
      gastric injury.
AB  - BACKGROUND/AIMS: Studies indicate that angiogenesis is important in tissue
      healing. However, the role of vascular endothelial growth factor (VEGF) in tissue
      healing has not been established. The aim of the study is to determine whether
      VEGF has a gastroprotective role in experimental gastric injury. METHODS: Acute
      gastric injury was induced in Sprague-Dawley rats by intragastric administration
      of 100% ethanol. Expression of gastric VEGF was determined in tissue homogenates
      by enzyme-linked immunosorbent assay and in paraffin-embedded sections by
      immunohistochemistry. The effect of systemic administration of anti-VEGF
      antibodies and recombinant VEGF on injury severity was assessed macroscopically
      and microscopically. RESULTS: Gastric VEGF concentrations peaked at 6 h and again
      3 days after acute injury. The presence of VEGF was demonstrated in epithelial
      cells and in mononuclear cells. Blocking endogenous VEGF effects with anti-VEGF
      antibodies exacerbated mucosal injury. Administration of recombinant VEGF after
      the onset of injury reduced the severity of mucosal injury, irrespective of the
      timing of initial treatment with VEGF. Immunohistochemical detection of vascular
      endothelial cells revealed that the VEGF-induced mucosal repair is closely
      related to the degree of angiogenesis. CONCLUSION: The results provide strong
      evidence for the role of VEGF in the repair of tissue damage induced by ethanol.
      The results also show how VEGF may be used in a clinical setting to treat some
      acute gastric lesions.

PMID- 12428070
TI  - Cutaneous electrical stimulation of acupuncture points may enhance gastric
      myoelectrical regularity.
AB  - BACKGROUND/AIM: Cutaneous electrical stimulation has been reported to be as
      effective as electroacupuncture. The aim of this study was to test whether
      cutaneous electrical stimulation had the same effect as electroacupuncture to
      enhance the regularity of myoelectrical activity. METHODS: Fifteen healthy male
      volunteers were enrolled for this study. Electrogastrography (EGG) was performed
      for 30 min at the baseline, 30 min during electroacupuncture or cutaneous
      electrical stimulation, and for an additional 30 min thereafter. RESULTS: During
      3 Hz of electroacupuncture on the Zusanli point, there was a significant increase
      in the percentage of normal frequency. The percentage of normal frequency in the
      post-acupuncture period was also increased, but it was not statistically
      significant when compared to the baseline. There was a significant decrease in
      the tachygastric and bradygastric rhythm during electroacupuncture on the Zusanli
      points. There were similar changes of EGG parameters with cutaneous electrical
      stimulation on the Zusanli points. The percentage of normal frequency during
      cutaneous electrical stimulation increased significantly. However, the percentage
      of normal frequency in the post-cutaneous electrical stimulation period was
      similar to the baseline. There was a significant decrease in the percentage of
      tachygastric rhythm during cutaneous electrical stimulation on the Zusanli
      points. However, there was no significant change in the percentage of
      bradygastric rhythm during and after the cutaneous electrical stimulation
      periods. CONCLUSIONS: The effect of cutaneous electrical stimulation on the
      percentage of normal frequency and tachygastria is similar to electroacupuncture.
      Nonetheless, the changes of the percentage in bradygastria are not significant.

PMID- 12428071
TI  - Intestinal resection- and steroid-associated alterations in gene expression were
      not accompanied by changes in lipid uptake.
AB  - BACKGROUND/AIMS: Glucocorticosteroids alter the morphology and transport function
      of the intestine of adult rats. This study was undertaken to assess the possible
      effect on intestinal lipid uptake of the locally acting steroid budesonide, or
      the systemically active prednisone or dexamethasone. METHODS: Sprague-Dawley rats
      underwent intestinal transection or 50% intestinal resection. Budesonide,
      prednisone, dexamethasone, or control vehicle was given for 2 weeks from the time
      of surgery. Uptake was measured using ring uptake technique. RESULTS: Resection
      had no effect on the mRNA expression for the early response genes, for
      proglucagon, or for the ileal lipid binding protein (ILBP), but was associated
      with reduced jejunal ornithine decarboxylase (ODC) mRNA and with reduced jejunal
      mRNA for the liver fatty acid binding protein (L-FABP). All three steroids
      reduced jejunal mRNA for proglucagon and c-jun, and did not affect the mRNA for L
      FABP or for ILBP. These resection- and steroid-associated changes in gene
      expression were not associated with alterations in the intestinal uptake of long
      chain fatty acids or cholesterol. CONCLUSIONS: The resection-associated
      alterations in the RNA expression of ODC and L-FABP and the steroid-associated
      changes in mRNA expression of c-jun and proglucagon were not accompanied by
      variations in lipid uptake.

PMID- 12428072
TI  - Candidate genes colocalized to linkage regions in inflammatory bowel disease.
AB  - BACKGROUND/AIMS: The genes encoding for tumor necrosis factor-alpha (TNF-alpha),
      epidermal growth factor receptor (EGFR) and the vitamin D receptor (VDR) are
      colocalized to inflammatory bowel disease-associated linkage regions on
      chromosomes 6, 7 and 12. An association study of these gene polymorphisms with
      ulcerative colitis or Crohn's disease and a stratification according to disease
      phenotypes was performed in order to identify genetically homogenous subgroups.
      PATIENTS AND METHODS: 119 healthy, unrelated controls, 95 patients with Crohn's
      disease and 93 patients with ulcerative colitis were genotyped for the (G to A) 
      308 TNF-alpha promoter polymorphism on chromosome 6, the codon 497 EGFR
      polymorphism on chromosome 7 and the TaqI polymorphism of the VDR gene on
      chromosome 12. After genotyping, patients were stratified according to the
      respective disease phenotype. RESULTS: A disequilibrium in the distribution of
      the VDR genotypes was found in patients with ulcerative colitis compared to
      controls (p = 0.024). In fistulizing and fibrostenotic Crohn's disease the 'TT'
      genotype was significantly reduced compared with other phenotypes (p = 0.006),
      whereas the 'tt' genotype was found more frequently (p = 0.04). The frequency of
      the WT allele of the EGFR gene was significantly higher in ulcerative colitis (p
      = 0.04) than in controls. Further significant differences, concerning the
      associations of the different polymorphisms and disease susceptibility or
      clinical phenotypes, were not observed. CONCLUSIONS: Regardless of the disease
      phenotype, the associations between the polymorphisms and inflammatory bowel
      disease investigated herein are modest, even after stratification for the disease
      phenotypes. Hence, these polymorphisms are unlikely to confer the reported
      linkage between inflammatory bowel disease and chromosomes 6, 7 and 12.

PMID- 12428073
TI  - Improved quality of life in patients with refractory or recidivant ascites after
      insertion of transjugular intrahepatic portosystemic shunts.
AB  - BACKGROUND: We have recently shown that the transjugular intrahepatic
      portosystemic shunt (TIPS) is more effective than paracentesis in the treatment
      of cirrhotic patients with severe ascites and can prolong survival in selected
      patients. Although an improved quality of life (QOL) has been suggested in these
      patients after the TIPS procedure, so far there are no data available to
      substantiate this assumption. Therefore, the aim of this study was to determine
      the effect of TIPS on the QOL in cirrhotic patients with refractory or recidivant
      ascites. METHODS: 21 cirrhotic patients who underwent TIPS for refractory or
      recidivant ascites were investigated. All patients were pretreated with repeated
      paracentesis for at least 1 year. Before the procedure and at 3 and 6 months
      during follow-up, the patients themselves rated QOL, fatigue and physical
      performance on a visual analogue scale (range 0-100). Furthermore, QOL was
      determined by the QOL index (range 0-10) according to Spitzer. RESULTS: Patients'
      rating of the QOL on the visual analogue scale significantly increased from 35 +/
      25 (baseline) to 64 +/- 28 (3 months), and 66 +/- 24 (6 months; p = 0.02).
      Similarly, the QOL index significantly increased from 6.9 +/- 2.0 (baseline) to
      8.3 +/- 2.1 (3 months), and 8.6 +/- 1.7 (6 months; p < 0.001). The increase of
      QOL was more pronounced in patients with complete response to TIPS. CONCLUSIONS:
      We demonstrate that TIPS for refractory or recidivant ascites improves the QOL in
      patients with cirrhosis. Our data indicates that this improvement is dependent on
      the response to therapy.

PMID- 12428074
TI  - Contribution of nutrition to child health.

PMID- 12428075
TI  - Global patterns of child health: the role of nutrition.
AB  - Almost two-thirds of the deaths of children around the world are directly or
      indirectly associated with nutritional deficiencies. Both protein-energy
      malnutrition and micronutrient deficiencies increase the risk of death from
      common diseases such as acute gastroenteritis, pneumonia and measles. Iron
      deficiency anemia is estimated to affect almost 25% of the world's population
      (equivalent to 3.5 billion people) resulting in high economic costs by adding to
      the burden on healthcare services, affecting learning in school and reducing
      adult productivity. Dietary practices frequently seen in older children and
      adolescents from industrialized countries, leading to frequent consumption of
      often nutrient-poor foods, may also put them at risk of micronutrient
      deficiencies. Marginal nutrient deficiencies in the developed world are
      increasingly accepted as risk factors for the development of chronic disease such
      as cardiovascular disease or some cancers.

PMID- 12428076
TI  - Impact of micronutrient deficiencies on growth: the stunting syndrome.
AB  - Stunting is a process that can affect the development of a child from the early
      stages of conception and until the third or fourth year of life, when the
      nutrition of the mother and the child are essential determinants of growth.
      Failure to meet micronutrient requirements, a challenging environment and the
      inadequate provision of care, are all factors responsible for this condition that
      affects almost 200 million children under 5 years of age. The timing and duration
      of the nutritional insult leads to different physiological consequences. Growth
      retardation is however just one feature of a complex syndrome including
      developmental delay, impaired immune function, reduced cognitive function and
      metabolic disturbances leading to increased prospective risk of obesity and
      hypertension. Prevention is possible by undertaking interventions at all stages
      of the life cycle, and mainly involves the promotion of exclusive breast-feeding
      until the age of 6 months and the provision of complementary foods and family
      foods with adequate micronutrient density. Treatment is possible, at least until
      the age of 5, and can lead to reversal of all the symptoms, although further
      research is required to clarify whether accelerating growth velocity might also
      lead to an increased risk of metabolic syndrome.

PMID- 12428077
TI  - Establishing dietary habits during childhood for long-term weight control.
AB  - OBJECTIVE: To review psychosocial research with respect to relevance for the
      development of nutritional education strategies for optimal weight control during
      childhood and the longer term. RESULTS: Recent decades have witnessed changes in
      the social context of eating, with a trend away from family meals towards grazing
      and eating alone. At the same time, the prevalence of overweight and obesity is
      increasing amongst both children and adults, with even young children
      deliberately practising weight control measures, ranging from selective food
      choice to self-induced vomiting. Such behaviour is motivated by unrealistic
      perceptions of healthy body weight and shape. Successful long-term management of
      healthy body weight is supported by flexible control of eating behaviour and long
      term educational strategies. Children are interested in learning about a wide
      range of nutrition topics. However, to be effective, nutrition education should
      be appropriate to the stage of cognitive development according to the age of the
      child, and be placed in the context of the direct, perceivable and immediate
      benefits resulting from good nutrition. CONCLUSION: Educational strategies should
      focus on consumption of a balanced diet, coupled with provision of a variety of
      foods, including a range of nutrient-dense "healthy" food and encouraging
      children to taste unfamiliar dishes. They should provide a stable and predictive
      pattern of social eating occasions to promote the social meaning and importance
      of eating, and to enable social learning of food preferences. Educational
      strategies should provide orientation and reassurance regarding the range of
      healthy and acceptable body weights and shapes. They should also encourage
      flexible control of eating behaviour to enable children to maintain their weight
      within this healthy range.

PMID- 12428078
TI  - Diet, breakfast, and academic performance in children.
AB  - OBJECTIVE: To determine whether nutrient intake and academic and psychosocial
      functioning improve after the start of a universal-free school breakfast program
      (USBP). METHODS: Information was gathered from 97 inner city students prior to
      the start of a USBP and again after the program had been in place for 6 months.
      Students who had total energy intakes of <50% of the recommended daily allowance
      (RDA) and/or 2 or more micronutrients of <50% of RDA were considered to be at
      nutritional risk. RESULTS: Prior to the USBP, 33% of all study children were
      classified as being at nutritional risk. Children who were at nutritional risk
      had significantly poorer attendance, punctuality, and grades at school, more
      behavior problems, and were less likely to eat breakfast at school than children
      who were not at nutritional risk. Six months after the start of the free school
      breakfast programs, students who decreased their nutritional risk showed
      significantly greater: improvements in attendance and school breakfast
      participation, decreases in hunger, and improvements in math grades and behavior
      than children who did not decrease their nutritional risk. CONCLUSION:
      Participation in a school breakfast program enhanced daily nutrient intake and
      improvements in nutrient intake were associated with significant improvements in
      student academic performance and psychosocial functioning and decreases in
      hunger.

PMID- 12428079
TI  - Determinants of nutrient intake among children and adolescents: results from the
      enKid Study.
AB  - BACKGROUND: Although adequacy of nutrient intake has been studied considerably in
      children and adolescents across Europe, the factors associated with nutritional
      risk have rarely been addressed. This study was developed in order to explore the
      nutritional intakes of Spanish children and the factors influencing the risk of
      nutritional inadequacy. OBJECTIVES: To evaluate socio-economic and lifestyle
      variables associated with nutritional adequacy in Spanish children and
      adolescents. METHODS: A cross-sectional study utilising face-to-face interviews.
      A random sample of 3,534 individuals aged 2-24 years were interviewed by a team
      of 43 dieticians in the subjects' homes. Interviews included two 24-hour recalls
      (a second 24-hour recall in 25% of the sample) and other questions, including
      lifestyle. Weight and height were measured in all subjects. Under-reporters (18%)
      were excluded from the present analysis. An unconditional logistic regression
      analysis was used to identify variables associated with greater nutritional risk.
      RESULTS: The participation rate was 68%. Twenty percent of males and 50% of
      females were classified as being at high nutritional risk. Variables associated
      with increased nutritional risk were: age between 14 and 24 years, being female,
      low social class, low educational level of the mother, having more than one
      sibling, smoking, watching TV during meals, sedentary habits at leisure time,
      infrequent meals and a poor quality breakfast. One dietary factor closely
      associated with nutritional risk was a failure to consume ready-to-eat cereals.
      CONCLUSIONS: Nutritional risk during infancy and adolescence is associated with
      socio-economic and educational variables of the family, and some lifestyle
      factors including physical activity and the quality of the breakfast meal.

PMID- 12428080
TI  - Avoiding overanticoagulation: knowing your antibiotics.

PMID- 12428081
TI  - Overanticoagulation associated with combined use of antibacterial drugs and
      acenocoumarol or phenprocoumon anticoagulants.
AB  - BACKGROUND: Several case reports associated combined use of coumarins and
      antibacterial drugs with overanticoagulation. Despite the fact that these drugs
      are frequently prescribed concurrently, there is little quantitative information
      on the risks of such complications. OBJECTIVE: To study which antibacterial drugs
      are associated with overanticoagulation during therapy with coumarins. DESIGN:
      Population-based cohort study in a sample of the Rotterdam Study. SUBJECTS: All
      patients who were treated with acenocoumarol or phenprocoumon in the study period
      from April 1, 1991 through December 31, 1998 and for whom INR data were
      available. METHODS: Patients were followed until an INR >/= 6.0, the end of their
      treatment, death or end of the study period. Proportional hazards regression
      analysis was used to estimate the risk of an INR >/= 6.0 in relation to
      concomitant use of an oral anticoagulant and antibacterial drugs after adjustment
      for several potentially confounding factors such as age, gender, hepatic
      dysfunction, malignancies, and heart failure. RESULTS: Of the 1,124 patients in
      the cohort, 351 developed an INR >/= 6.0. The incidence rate was 6.9 per 10,000
      treatment days. Sulfamethoxazole combined with trimethoprim most strongly
      increased the risk of overanticoagulation with an adjusted relative risk of 20.1
      (95% CI: 10.7-37.9). Stratification showed that the induction period of
      overanticoagulation varied between different antibacterial drugs. CONCLUSION: In
      this study among outpatients of an anticoagulation clinic using acenocoumarol or
      phenprocoumon, several antibacterial drugs strongly increased the risk of
      overanticoagulation. Awareness of these drug interactions and more frequent
      monitoring of INR values during the initial stages of antibacterial drug therapy
      are warranted to minimize the risk of bleeding complications.

PMID- 12428082
TI  - Aspirin resistance in cardiovascular disease: a review of prevalence, mechanisms,
      and clinical significance.

PMID- 12428083
TI  - Acquired activated protein C resistance associated with anti-protein S antibody
      as a strong risk factor for DVT in non-SLE patients.
AB  - Anti-phospholipid (aPL) antibodies (Abs) are well known to be associated with
      thromboembolic events in patients with systemic lupus erythematosus (SLE).
      However, the clinical relevance of a PL Abs in patients without SLE (non-SLE) who
      have venous thromboembolism remains unclear. We evaluated 143 non-SLE patients
      with a first episode of clinically suspected deep vein thrombosis (DVT) by using
      objective tests for diagnosing DVT and laboratory tests including the activated
      protein C resistance (APC-R) test, the factor V Leiden test, and various aPL Abs.
      The prevalence of acquired APC-R, in which case there was no factor V Leiden
      mutation, was significantly higher in patients with DVT (15/58 cases, 25.9%, p <
      0.0001) than in those without DVT (3/80 cases, 3.7%), and confirmed that acquired
      APC-R was a strong risk factor for DVT (odds ratio [OR], 8.95; 95% confidence
      intervals [CI], 2.45-32.7; p < 0.001). Multivariate logistic analysis revealed
      that the presence of LA, aCL, anti-beta2-glycoprotein I, anti-prothrombin and
      anti-protein C Abs was not reliable as a risk factor for DVT in non-SLE patients,
      and that the presence of anti-protein S Abs was the most significant risk factor
      for DVT (OR, 5.88; 95% CI, 1.96-17.7; p < 0.002). Furthermore, the presence of
      anti-protein S Abs was strongly associated with acquired APC-R (OR, 57.8; 95% CI,
      8.53-391; p < 0.0001). These results suggest that acquired APC-R may reflect
      functional interference by anti-protein S Abs of the protein C pathway, which
      action may represent an important mechanism for the development DVT in non-SLE
      patients.

PMID- 12428084
TI  - Interaction between hyperhomocysteinemia, mutated
      methylenetetrahydrofolatereductase (MTHFR) and inherited thrombophilic factors in
      recurrent venous thrombosis.
AB  - Venous thrombosis is a multicausal disease involving acquired and genetic
      factors. In this study we investigated a possible interaction between
      hyperhomocysteinemia (fasting or postload) and factor V Leiden or prothrombin
      G20210A on the risk of recurrent venous thrombosis. We also looked at the risk
      due to mutations in the MTHFR-gene (C677T and A1298C). We performed a case
      control study in 171 patients with a history of recurrent venous thrombosis and
      461 control subjects from the general population. Hyperhomocysteinemia (fasting
      or 6 h after an oral methionine load) was defined as a homocysteine concentration
      above the 90th percentile of the distributions in the control group. The odds
      ratio (adjusted for age and sex) for recurrent venous thrombosis was 1.8 (95% CI:
      1.1 to 3.0) for fasting hyperhomocysteinemia, 5.1 (95% CI: 3.0 to 8.6) for factor
      V Leiden and 1.8 (95% CI: 0.7 to 4.2) for prothrombin G20210A. We found 14
      patients and 3 controls with both hyperhomocysteinemia and factor V Leiden, which
      yielded an odds ratio of 11.6 (95% CI: 3.2 to 42.5). We found no interaction
      between hyperhomocysteinemia and prothrombin G20210A. The relative risk for MTHFR
      677CT was 1.6 (95% CI: 1.1 to 2.4) and for MTHFR 677TT was 1.4 (95% CI: 0.7 to
      2.8). The combined risk for MTHFR 677TT and factor V Leiden was 18.7 (95% CI: 3.3
      to 108). We conclude that hyperhomocysteinemia and factor V Leiden are risk
      factors for recurrent venous thrombosis. The risk of thrombosis appeared high for
      individuals who had both risk factors.

PMID- 12428085
TI  - Anti-beta2-glycoprotein I and anti-prothrombin antibodies in antiphospholipid
      negative patients with thrombosis: a case control study.
AB  - We performed a case-control study to assess whether anti-beta2-glycoprotein I and
      anti-prothrombin antibodies are independent risk factors of thrombosis. Cases
      were 79 patients with arterial and/or venous thrombosis without lupus
      anticoagulants, anticardiolipin antibodies and systemic lupus erythematosus;
      controls were 85 normal subjects. The prevalences and titers of IgG and IgM anti
      beta2-glycoprotein I and anti-prothrombin antibodies were similar in both groups.
      Cases were analyzed with respect to the arterial or venous type of thrombosis and
      to the presence of congenital or acquired risk factors for thrombosis: no
      statistically significant relationships with the presence of anti-beta2
      glycoprotein I and anti-prothrombin antibodies were found. Our data indicate that
      anti-beta2-glycoprotein I and anti-prothrombin antibodies are not risk factors
      for thrombosis independent of lupus anticoagulants and anticardiolipin
      antibodies. Their measurement, therefore, is not warranted in the laboratory
      screening of patients with arterial and/or venous thrombosis.

PMID- 12428086
TI  - Antithrombotic effects of DX-9065a, a direct factor Xa inhibitor: a comparative
      study in humans versus low molecular weight heparin.
AB  - BACKGROUND: Recent evidence suggests that TF may play a causal role in acute
      coronary syndromes, and may be an important therapeutic target. Several
      inhibitors of TF, coagulation factors VIIa and Xa are under investigation as
      novel antithrombotic approaches. We compared the antithrombotic effects of DX
      9065a, a new FXa inhibitor, vs. enoxaparin. METHODS AND RESULTS: The protocol was
      an open-label crossover study. Subjects (n = 6) participated in 3 consecutive
      study-arms: a) enoxaparin + ASA (1 mg/Kg s. c + 162 mg/day x 3 days), b) three
      escalating doses of DX-9065a (1 mg bolus + 0.25 mg/h x 2 h, followed by an
      additional 1 mg bolus + 0.625 mg/h x 2 h and, a final 1 mg bolus + 1.25 mg/h x 2
      h), and c) the same doses of DX-9065a in Arm 2 plus ASA pre-treatment. The
      antithrombotic effects were assessed using the Badimon perfusion chamber at each
      dose level. The administration of DX-9065a whether alone or combined with ASA
      significantly inhibited thrombus formation at high and low shear rate conditions
      while enoxaparin did not have a significant effect. Furthermore, these
      antithrombotic effects were obtained without significant prolongations of the
      standard coagulation parameters as those induced by enoxaparin. CONCLUSIONS: The
      direct inhibition of FXa by DX-9065a appears to be a safe and effective new
      approach for preventing the thrombotic complications of atherosclerotic disease.
      The clinical effectiveness of the direct FXa inhibitors should be further
      investigated.

PMID- 12428087
TI  - Patients with coronary artery disease who present with chest pain have
      significantly elevated platelet contractile force and clot elastic modulus.
AB  - Rapid laboratory markers that correlate with patient risk would facilitate the
      decision making regarding admission of patients with chest pain (CP). Platelet
      contractile force (PCF) and clot elastic modulus (CEM) are elevated in patients
      undergoing coronary bypass grafting. This study assessed PCF, CEM, and platelet
      aggregation in patients presenting to the emergency department with chest pain
      (CP). Results were compared with fifty normal controls. Both the total group of
      CP patients (n = 100) and the subset of patients (n = 36) with documented
      coronary artery disease (CAD) had significantly elevated PCF and CEM, and
      significantly decreased platelet aggregation relative to normal (p <0.001 for the
      total group, p </=0.008 for patients with CAD). Patients with
      electrocardiographic evidence of ischemia had the highest PCF and CEM values of
      any patient group. Increased PCF and CEM were not due to higher platelet counts,
      and PCF did not differ by race.

PMID- 12428088
TI  - Coagulation markers predict survival in cancer patients.
AB  - In order to prospectively evaluate the predictive value of coagulation markers
      such as the fibrin Ddimer for survival of cancer patients, we analyzed their role
      in a prospective study at a University Hospital Institute of Medical Oncology.
      268 consecutive outpatients with cancer were included, 72 in remission and 196
      with active disease. All cause mortality in relation to the marker levels was
      measured. 99/268 patients died during the observation period of 4,484 patient
      months (mean: 17 months). Patients with active disease had a significant, 1.5-5
      fold increased marker concentration compared to patients in remission. When
      analyzed in quartiles, the data showed a lower than predicted death rate in the
      first quartile and a significantly elevated mortality in the fourth marker
      quartile. The odds ratio for death predicted by the fibrin monomer (FM) in the
      fourth vs. the first quartile was 4.1 (95% C.I.: 1.7-9.7) and p = 0.005 for the
      multivariate analysis of the markers. We conclude that a single determination of
      coagulation markers, particularly of TAT, FM, and Ddimer is sufficient to
      strongly predict survival in cancer patients over the following 1-3 years.

PMID- 12428089
TI  - Two naturally occurring mutations on FVII gene (S363I-W364C) altering intrinsic
      catalytic activity.
AB  - Factor VII (FVII) requires the cleavage of an internal peptide bond and the
      association with tissue factor (TF) to attain its fully active FVIIa
      conformation. This event alone leaves FVIIa in a zymogen-like state of relatively
      low specific activity. The TF-induced allosteric enhancement of FVIIa's activity
      contributes to the procoagulant activity of the complex. We have characterized
      two naturally occurring mutations (S363I - W364C) on FVII gene. Both homozygous
      patients for each mutation have a normal FVII: Ag level associated to an
      undetectable FVII coagulant activity. The patient carrying the allele 364C had a
      more severe hemorrhagic diathesis than the S363I mutant. To understand the
      mechanism of these deficiency, in vitro expression analysis with further
      biochemical characterization of recombinant proteins of both mutants FVII-363I,
      FVII-364C and wild type (WTFVII) FVII constructs were done. The results
      recapitulated the patients' plasma data with normal Ag level and no detectable
      coagulant activity. The D-F-Pip-R-pNA and CH(3)SO(2)-D-CHA-A-But-R chromogenic
      substrates were used to evaluate the amidolytic activity of WT and mutant FVII in
      presence and absence of recombinant tissue factor (rTF). Binding of FVII to rTF
      by a solid phase binding assay was done using recombinant human rTF. The results
      of amidolytic assays showed that rTF enhances 28 fold the value of the
      specificity of constant (kcat/K(m)) in WT but no activity was detectable in
      either mutant constructs under any condition. The equilibrium dissociation
      constant of rTF-FVIIa interaction showed Kd equal to 4.4 +/- 0.2nM, 4.9 +/- 0.5nM
      and 6 +/- 0.9 of WT, 363I and 364C FVII forms, respectively. The K(d) values of
      the non activated forms were equal to 24.7 +/- 3.3, 24.4 +/- 3.1 and 20.6 +/-
      4nM, respectively. These data demonstrate that, compared to the WT form, FVII
      363I and FVII-364C have no significant affinity change for TF and that the
      detrimental effect of these two mutations is attributable to the loss of an
      efficient catalytic machinery in the FVII molecule causing a severe deficiency of
      coagulant activities.

PMID- 12428090
TI  - The role of the factor X activation peptide: a deletion mutagenesis approach.
AB  - To understand the role of the factor X (fX) activation peptide (AP), a deletion
      mutagenesis approach was employed. Two single-chain, variant enzymes were
      generated in which 41 residues were deleted from the AP: fX (des-137-183) and
      fX(des-137-183;N191A), which lacks a carbohydrate moiety at Asn191 due to an
      alanine substitution. Deletion of the fX AP did not impact fXa catalytic
      activity. Activation of the variant zymogens, however, was altered. Neither
      mutant enzyme was activated by the fX coagulant protein from Russell's viper
      venom (RVV-X(1)). Activation by factor VIIa (fVIIa) and fVIIa in the presence of
      cofactor, lipidated tissue factor (TF), occurred at an accelerated rate for both
      variants as compared to wild-type fX (WTfX). Similar to fVII, the mutants auto
      activated in a cofactor-independent manner, which was characterized by a lag
      period and accelerated dose-dependently by plasma fXa (kcat/Km, 0.046 +/- 0.004
      micro M(-1) s(-1)). Both mutants were also found to be activated by fVIIa (0.31
      +/- 0.03 micro M(-1) s(-1)), fIXa (0.30 +/- 0.03 micro M(-1) s(-1)), and thrombin
      (0.00078 +/- 0.00015 micro M(-1) s(-1)). In all cases, the rate of activation was
      faster for fX(des-137-183;N191A) as compared to fX(des-137-183). We propose that
      the fX AP and Asn191 carbohydrate serve primarily as negative autoregulation
      mechanisms to prevent spurious activation of fX and secondarily in cofactor
      dependence and activator specificity.

PMID- 12428091
TI  - Polymorphic changes in the 5' flanking region of factor VII have a combined
      effect on promoter strength.
AB  - Polymorphic differences in the 5' flanking region of the gene encoding
      procoagulant protein Factor VII (FVII) are associated with variations in FVII
      coagulant activity (FVII:C) and FVII antigen (FVII:Ag) levels. A decanucleotide
      insert polymorphism (CCTATATCCT) at 323 bp upstream of the start site of
      translation correlates with a decrease of approximately 20% FVII: C levels per
      allele containing this insert. However, linkage disequilibrium of the
      decanucleotide polymorphism with two single nucleotide polymorphisms (SNPs) at 
      122 and -401 have made it difficult to pinpoint the functional role, if any, of
      these genetic changes in lowering FVII levels. In vitro reporter gene studies in
      HepG2 cells analyzing the 8 possible combinations of polymorphic sites at -401, 
      323, and -122 reveal the necessity of the presence of the three concurrent
      polymorphic changes to maximally decrease promoter strength. In addition, these
      in vitro results are supported by in vivo studies in 89 individuals of African
      heritage, 34% of whom display a new haplotype that shows the polymorphic changes
      at -323 and -401 but lacks the change at -122.

PMID- 12428092
TI  - The in vitro analysis of the coagulation mechanism of activated factor VII using
      thrombelastogram.
AB  - We investigated the effects of addition of recombinant activated coagulation
      factor VII (rFVIIa) to coagulation factor-deficient plasma and whole blood, using
      thrombelastograms (TEGs). The addition of rFVIIa to factor II- or X-deficient
      plasma did not correct hemostatic parameters, whereas it produced partial
      responses in factor V-, VIII- or IX-deficient plasma and good responses in factor
      VII-, XI- or XII-deficient plasma. Furthermore, the addition of rFVIIa and
      platelets (30-100 x 10(3)/ micro l) to platelet-poor plasma produced marked
      corrections, producing TEGs similar to those of platelet-rich plasma. These
      results indicate that factors II and X are essential for the hemostatic effects
      of rFVIIa, and that factors V and VIII promote these effects. We believe that
      TEGs are, at present, one of the most useful tools for evaluating in vitro
      hemostatic effects of rFVIIa.

PMID- 12428093
TI  - Rapid-SF: a rapid whole-blood screen for soluble fibrin monomer.
AB  - Thrombosis accounts for a high proportion of disability and death in the West.
      Although soluble fibrin (SF) assays have been shown to be good predictors of
      thrombosis, current quantitative assays are too complex or lengthy to provide
      timely results, while simpler methods are qualitative and lack sensitivity. We
      here describe a rapid, new, protamine-based whole-blood screening method for SF
      which is quantitative and suitable for point-of-care use. Citrated whole blood is
      mixed with reagent under controlled conditions and the time until development of
      an SF precipitate is measured. Negative samples remain precipitate-free for 300
      seconds. Strongly positive samples develop precipitate in as little as 10
      seconds. SF times are mathematically converted to arbitrary SF units (SFU). This
      Rapid-SF test provides a simple and reliable means of detecting the presence of
      SF, and is well-suited for whole-blood rapid screening in the emergency
      department, operating room or clinic.

PMID- 12428094
TI  - Hemophilia A mutations within the factor VIII A2-A3 subunit interface destabilize
      factor VIIIa and cause one-stage/two-stage activity discrepancy.
AB  - Thrombin-activated factor VIII (FVIIIa) is a heterotrimer with the A2 subunit in
      a weak ionic interaction with the A1 and A3-C1-C2 subunits. Dissociation of the
      A2 subunit correlates with inactivation of FVIIIa. A homology model (Blood
      89:2413, 1997) of the triplicated A domains of factor VIII (FVIII) predicts a
      pseudo-threefold axis at the tightly packed hydrophobic core with several
      interdomain interactions. These lie at the interface of A1-A2, A2-A3 and A1-A3.
      We have previously demonstrated that hemophilia A mutations (R531H, A284E, S289L)
      within the predicted A1-A2 and A1-A3 interface disrupt potential intersubunit
      hydrogen bonds and have the molecular phenotype of increased rate of inactivation
      of FVIIIa due to increased rate of A2 subunit dissociation. Patients with these
      mutations exhibit a clinical phenotype where the FVIII activity by one-stage(1
      st) assay is at least two-fold higher than by two-stage(2-st) assay. We have now
      also explored mutations within the predicted A2-A3 interface (N694I, R698W and
      R698L) that also have the phenotype of 1-st/2-st activity discrepancy. These
      mutations exhibit the same molecular mechanism of increased instability of FVIIIa
      as those mutations described along the A1-A2 and A1-A3 interfaces. This suggests
      that the entire tightly packed hydrophobic core within the predicted pseudo
      threefold axis contributes to stabilization of FVIIIa.

PMID- 12428095
TI  - Phosphorotioated oligonucleotides trigger synthesis of human coagulation serine
      proteases.
AB  - RATIONALE: CpG containing phosphorotioated oligonucleotides (ODN) are efficient
      adjuvants able to enhance macrophage and B cell activities. Their impact in the
      generation of coagulation and fibrinolytic factors has not been analysed.
      OBJECTIVES: Production of coagulation and fibrinolytic proteins by human
      peripheral blood mononuclear cells (PBMC) treated with ODN was assessed.
      FINDINGS: ODN induced in vitro generation of tissue factor (TF), thrombin and
      plasminogen, by PBMC. Synthesis of TF and thrombin occurred mostly in monocytes,
      while plasminogen was produced by both monocytic and lymphocytic cell
      populations. Generation of these proteins stimulated by CpG was totally blocked
      by cycloheximide, indicating the requirement of ongoing protein synthesis.
      Protein synthesis was equally pronounced at stimulation with cytosine-phosphate
      guanosine (CpG)- and GpC-containing ODN, and depended on the presence of the
      phosphorotioate moiety backbone in the ODN. Plasminogen, synthesized by monocytes
      and lymphocytes, was shown to be the primary product of ODN activation, leading
      subsequently to the expression of TF and thrombin generation. CONCLUSIONS: Our
      findings should be taken into consideration when assessing advantages and
      drawbacks of immunotherapy and gene therapy.

PMID- 12428096
TI  - Diurnal variation in PAI-1 activity predominantly confined to the 4G-allele of
      the PAI-1 gene.
AB  - We examined the diurnal pattern in Plasminogen Activator Inhibitor-type 1 (PAI-1)
      activity and Plasminogen activator (t-PA) in relation to the 4G/5G-polymorphism
      in the promoter of the PAI-1 gene. The analyses were performed in the Arnhem
      Elderly Study, a population-based study of 598 elderly. A single blood sample was
      drawn and the time of blood sampling was recorded (between 8 a.m. and 5.30 p.m.).
      Plasma PAI-1 activity was strongly associated with time of blood sampling,
      showing the highest values in the early morning. The diurnal pattern was clearly
      present in the 4G/4G (n = 184) and 4G/5G (n = 275) genotypes, but not in the
      5G/5G-genotype (n = 139). T-PA antigen showed a weak diurnal variation, which did
      not differ across the variants of the 4G/5G-polymorphism. Our findings raise the
      hypothesis that 5G-homozygotic persons may be relatively protected from diurnal
      variation in the occurrence of coronary events.

PMID- 12428097
TI  - Association between increased homocysteine levels and impaired fibrinolytic
      potential: potential mechanism for cardiovascular risk.
AB  - BACKGROUND: Elevated homocysteine levels increase cardiovascular risk although
      the mechanism is not well understood. Since thrombosis plays an important role in
      plaque development and acute coronary syndromes, hyperhomocysteinemia may
      increase risk by increasing the thrombotic potential. METHODS AND RESULTS:
      Hemostatic risk factors were measured in 3,216 individuals (1,451 men and 1,765
      women) free of cardiovascular disease who participated in cycle 5 of the
      Framingham Offspring Study. An increase in homocysteine level was associated with
      a rise in plasminogen activator inhibitor (PAI-1), tissue plasminogen activator
      (TPA) antigen, von Willebrand factor and fibrinogen level. After regression
      analyses adjusting for covariates, there remained significant associations
      between homocysteine and PAI-1 and TPA antigen. CONCLUSION: Increasing
      homocysteine levels are associated with impaired fibrinolytic potential, as
      indicated by increased PAI-1 and TPA antigen levels. These data suggest that
      folic acid and other homocysteine lowering therapies may decrease cardiac events
      through a reduction in thrombotic tendency.

PMID- 12428098
TI  - Influence of plasminogen deficiency on the contribution of polymorphonuclear
      leucocytes to fibrin/ogenolysis: studies in plasminogen knock-out mice.
AB  - Plasminogen knock-out (PG(-/-)) mice provide an unique opportunity for the study
      of alternative mediators of fibrinolysis. Polymorpho-nuclear leucocytes (PMNs)
      contain non-plasmin fibrinolytic proteases, however the degree to which these
      cells contribute to fibrin(ogen) degradation in these animals is not known.
      Thrombi were generated in carotid arteries and jugular veins of PG(-/-) and wild
      type (PG(+/+)) mice following adventitial application of a 20% ferric chloride
      solution. PMNs, identified histologically on H&E staining and by
      immunohistochemistry using anti-mouse PMN RB6-8C5 antibody, accumulated within
      the thrombus by 6 h after the injury and peaked at 24 h. There was significantly
      greater retention of PMNs within the thrombi of PG(-/-) mice from 48 to 72 h than
      in the PG(+/+) controls (at 72 h: PG(-/-)255 +/- 41 cell/mm(2) (n = 5), PG(+/+)
      61 +/- 10 cell/mm(2) (n = 5), p<0.01 in the arterial thrombi; PG(-/-) 252 +/- 50
      cell/mm(2) (n = 5), PG(+/+) 100 +/- 36 cell/mm(2) (n = 5), p<0.05 in the venous
      thrombi), providing potential for more PMN derived fibrinolytic enzymes to be
      present at late times after a thrombotic challenge in PG(-/-) mice relative to
      the PG(+/+) controls. Intact PMNs were elicited from the peritoneal cavities of
      PG(-/-) and PG(+/+) mice following 4% thioglycolate stimulation. In vitro studies
      showed PMNs from PG(-/-) mice to release greater quantities of 10%
      trichloroacetic acid (TCA)-soluble fibrinopeptides from I(125)-labeled
      fibrinogen, than cells from PG(+/+) controls although these differences did not
      become apparent until after 24 h of incubation (at 72 h incubation: PG(-/-) 918
      n/10 x 10(6) cells/0.5 ml, PG(+/+) 589 ng/10 10(6) cells/0.5 ml p = 0.005).
      Furthermore, autoradiographic analysis of the I(125)-labeled fibrinogen
      degradation products showed the cleavage pattern by PG(-/-) PMNs to be distinct
      from that produced by PG(+/+) PMNs. These data suggest that a relatively greater
      role for PMNs-initiated fibrinolysis exists in the setting of plasminogen
      deficiency, although this prominence only becomes evident more than 24 h after
      the thrombotic insult. In addition, mechanisms responsible for the process in PG(
      /-) mice may be distinct from those primarily responsible for the process in PMNs
      from PG(+/+) mice.

PMID- 12428099
TI  - Characterization of a ligand-attenuated binding site on glycoprotein IIb/IIIa.
AB  - We describe an epitope on the platelet integrin, GPIIb/IIIa, identified by the
      monoclonal antibody, 4F8, which is attenuated by small-molecule GPIIb/IIIa
      ligands. 4F8 did not bind to the ligand binding pocket as it did not compete with
      a radiolabelled antagonist, (3)H-SC-52012. This indicates that the 4F8 epitope
      behaves as a ligand-attenuated binding site (LABS). Ligand-induced attenuation of
      4F8 was an active process as it was prevented by pretreating platelets with
      cytochalasin D and reduced by prostaglandin E(1) or inhibition of protein kinase
      C. Disappearance of the epitope was required for full platelet activation as 4F8
      prevented platelet aggregation without inhibiting fibrinogen binding. These
      results suggest a model where disappearance of the 4F8 epitope is a secondary
      event required for full "outside-in" signaling through GPIIb/IIIa.

PMID- 12428100
TI  - Platelet aggregation and activation under complex patterns of shear stress.
AB  - Arterial stenosis results in a complex pattern of blood flow containing an
      extremely fast flow in the throat of stenosis and a post-stenosis low flow. The
      fast flow generates high shear stress that has been demonstrated in vitro to
      activate and aggregate platelets. One potential problem of these in vitro studies
      is that platelets are invariably exposed to a high shear stress for a period that
      is significantly longer than they would have experienced in vivo. More
      importantly, the role of the post-stenosis low flow in platelet activation and
      aggregation has not been determined. By exposing platelets to a shear profile
      that contains both high and low shear segments, we found that platelets aggregate
      when they are exposed to a high shear stress of 100 dyn/cm(2) for as short as 2.5
      s, a period that is significantly shorter than those previously reported (30-120
      s). Platelet aggregation under this condition requires a low shear exposure
      immediately after a high shear pulse, suggesting that post-stenosis low flow
      enhances platelet aggregation. Furthermore, platelet aggregation under this
      condition is not activation-dependent because the CD62P expression of sheared
      platelets is significantly less than that of platelets treated with ADP. Based on
      these findings, we propose that shear-induced platelet aggregation may be a
      process of mechanical crosslinking of platelets, requiring minimal platelet
      activation. This process may function as a protective mechanism to prevent in
      vivo irreversible platelet activation and aggregation under temporary high shear.

PMID- 12428101
TI  - Local shear conditions and platelet aggregates regulate the incorporation and
      activity of circulating tissue factor in ex-vivo thrombi.
AB  - The presence of thrombogenic blood-borne or circulating tissue factor (cTF) has
      recently been demonstrated. These observations have implicated cTF to be a key
      determinant of thrombus propagation by depositing on platelets in nascent
      thrombi. Previously, we detected cTF by detergent solubilization and addition of
      phospholipids. We now report the direct demonstration of TF activity in ex-vivo
      thrombi. Collagen-coated substrates were exposed to native blood at shear rates
      of 0, 650, and 2,000 s(-1) for 10 min in a modified rotating Teflon cone and
      plate viscometer. Substrates were then gently rinsed to remove 'loose'
      (unadherent) components of blood. cTF activity was measured by adding a solution
      containing 10 nM FVIIa, 100 nM FX, and 5 mM CaCl(2) to the substrates exposed to
      blood. Samples of this mixture were obtained at intervals for 30 min and the
      amount of Xa generated was quantified by adding a chromogenic substrate,
      Spectrozyme Xa, and measuring the increase in OD at 405 nm. Our studies show that
      a minimal amount of generated Xa (approximately 1nM) can be measured from ex-vivo
      thrombi. Static and shear samples generated the same amount of Xa, with the
      exception of blood subjected to 650 s(-1) shear. At 650 s(-1) shear rate, the
      amount of Xa generated reached a maximum of 4 nM at 5 min and then decreased to
      approximately 1 nM. Immunohistological stains and fluorescent images demonstrate
      the presence of cTF antigen at 650 s(-1) wall shear rate.

PMID- 12428102
TI  - Physical and enzymatic perturbation of the architecture of the Tunica media
      destroys its inherent thromboresistance.
AB  - The media layer of the arterial cryo-cross sections, is defective for vWf
      dependent platelet adhesion. Exposure of the same layer by stripping off the most
      inner portions of the vessel wall results in a highly thrombogenic surface.
      Stripping or balloon dilation was applied to porcine arteries prior to functional
      assays. Cryosections of treated or untreated arteries were perfused with porcine
      blood at 3,350 s(-1) and platelet deposition was detected by indirect
      immunofluorescence. Following balloon dilation, vWf-dependent platelet deposition
      increased; covering 9.08 +/- 1.36% of the total media surface area, this value
      for untreated vessels was 0.88 +/- 0.14%. A 10-fold increase was also found in
      the binding of vWf-coated fluorescent beads to the media. In addition to
      mechanical procedures, treatment by serine-proteases like trypsin, chymotrypsin
      and proteinase 3, or by chondroitinase ABC, but not by heparitinase also resulted
      in a 7-10-fold increase in platelet coverage over the media. Collagen in the
      media may be complexed with another vessel wall component shielding the vWf
      binding sites. Mechanical or biochemical processes unmask these sites, and
      increase the thrombogenicity of the vessel wall.

PMID- 12428103
TI  - Trophic effects of platelets on cultured endothelial cells are mediated by
      platelet-associated fibroblast growth factor-2 (FGF-2) and vascular endothelial
      growth factor (VEGF).
AB  - In addition to their role in primary hemostasis, platelets serve to support and
      maintain the vascular endothelium. Platelets contain numerous growth factors
      including the potent angiogenic inducers VEGF and FGF-2. To characterize the
      function of these two platelet-associated growth factors, the effects of the
      addition of purified platelets to cultured endothelial cells were examined. The
      survival and proliferation of endothelial cells were markedly stimulated (2-3
      fold and 5-15-fold respectively) by the addition of gel-filtered platelets.
      Acetylsalicylic acid-treated or lyophilized fixed-platelets were ineffective in
      supporting endothelial cell proliferation. In Transwell assays, the stimulatory
      effect of platelets on endothelial cells was preserved, consistent with an effect
      mediated by secreted factors. The combined inhibition of VEGF and FGF-2 by
      neutralizing antibodies, in contrast to inhibition of either alone, abrogated
      both platelet-induced endothelial cell survival and proliferation. FGF-2 isoforms
      were detected in platelet lysates, as well as in the releases of agonist
      stimulated platelets. Megakaryocytes generated by ex vivo expansion of
      hematopoietic progenitor cells with kit ligand and thrombopoietin were analyzed
      for expression of FGF-2. Punctate cytoplasmic staining but no nuclear staining
      was observed by immunocytochemistry consistent with possible localization of the
      growth factor to cytoplasmic granules. The addition of platelets to cultured
      endothelial cells activated extracellular signal-regulated kinase (ERK) in a dose
      and time-dependent manner. This effect was abrogated by both anti-FGF-2 and anti
      VEGF antibody. Since FGF-2 and VEGF are potent angiogenic factors and known
      endothelial cell survival factors, their release by platelets provides a
      plausible mechanism for the platelet support of vascular endothelium.

PMID- 12428104
TI  - F11-receptor (F11R/JAM) mediates platelet adhesion to endothelial cells: role in
      inflammatory thrombosis.
AB  - The F11 receptor (F11R) is a cell adhesion molecule (CAM), member of the
      immunoglobulin superfamily found on the surface of human platelets, and
      determined to play a role in platelet aggregation, secretion, adhesion and
      spreading. The same molecule is present also at tight junctions of endothelial
      cells (EC) where it is known as JAM and acts as a CAM through homophilic
      interactions. The role of F11R/JAM in the interaction of platelets with
      endothelial cells was investigated in the current studies. We report here that
      washed human platelets adhere specifically to a matrix made of immobilized,
      recombinant sF11R. Furthermore, platelets adhere to cytokine- (TNF-alpha, INF
      gamma) stimulated human umbilical vein endothelial cells (HUVEC), and
      approximately 40-60% of the adhesive force is exerted by homophilic interactions
      between the F11R of platelets and EC. This is evidenced by the inhibition of
      platelet adhesion to endothelial cells by recombinant soluble form of the F11R,
      and by two F11R peptides with amino acid sequences of the N-terminal region, and
      in the 1(st) Ig fold of the F11R, respectively. This study suggests a role for
      F11R in the adhesion of platelets to cytokine-inflamed endothelial cells and thus
      in thrombosis and atherosclerosis induced in non-denuded blood vessels by
      inflammatory processes. Agents that block the F11R-mediated adhesion of platelets
      to EC may be of therapeutic value in controlling thrombosis and preventing heart
      attacks and stroke.

PMID- 12428105
TI  - NFkappaB is an essential intermediate in the activation of endothelial cells by
      anti-beta(2)-glycoprotein 1 antibodies.
AB  - Antiphospholipid antibodies (aPLA) are associated with thrombophilia and
      recurrent pregnancy loss. They bind directly to anionic phospholipids or via
      phospholipid-binding proteins such as beta(2)-glycoprotein 1 (beta(2)GP1). The
      underlying mechanisms by which aPLA induce a thrombophilic phenotype are not well
      understood. The present work was done to determine whether antibodies to
      beta(2)GP1 activate endothelial cells (EC) and whether NFkappaB is involved in
      this activation. Incubation of EC with these antibodies resulted in a
      redistribution of NFkappaB from the cytoplasm to the nucleus after a delay of
      several hours. This was accompanied by an increased expression of tissue factor
      and of the leukocyte adhesion molecules ICAM-1, VCAM-1 and E-selectin. Inhibition
      of the nuclear translocation of NFkappaB abolished the response to these
      antibodies. In comparison to anti-beta(2)GP1 antibodies, incubation of EC with
      TNF resulted in a more rapid (within 30 minutes) redistribution of NFkappaB and a
      more pronounced expression of tissue factor and of the leukocyte adhesion
      molecules. The slower response to the antibodies as compared to TNF suggests that
      the NFkappaB response to anti-beta(2)GP1 antibodies is indirect. Taken together
      our results imply that NFkappaB is an essential intermediate in the activation of
      EC by anti-beta(2)GP1 antibodies.

PMID- 12428106
TI  - Blockade of platelet GPIIB-IIIA (Integrin alphaII(b)beta(3)) in flowing human
      blood leads to passivation of prothrombotic surfaces.
AB  - We examined the impact of platelet activation on platelet adhesion to collagen in
      flowing human blood. ADP activation of platelets in ex vivo flowing blood
      resulted in paradoxical inhibition of platelet deposition on collagen. Blockade
      of fibrinogen binding to platelets by Lamifiban, a competitive antagonist of
      GPIIb-IIIa (integrin alpha(IIb)beta(3)), reversed this inhibition, leading to a
      marked increase in integrin alpha(2)beta(1)-dependent platelet adhesion. Analysis
      of integrin alpha(2)beta(1)-dependent platelet adhesion to collagen indicated
      that ADP-induced suppression of platelet adhesion is the result of trans-dominant
      inhibition of integrin alpha(2)beta(1) caused by fibrinogen binding to integrin
      GPIIb-IIIa. Lamifiban blocked fibrinogen binding, reversing the trans-dominant
      inhibition of alpha(2)beta(1) dependent adhesion to collagen. The GPIIb-IIIa
      antagonist resulted in the formation of a non-thrombogenic, passivated surface
      comprised of an adherent platelet monolayer. This unexpected consequence of
      blocking fibrinogen binding to GPIIb-IIIa may explain the long-term benefits of
      short-term GPIIb-IIIa antagonist treatment of Acute Coronary Syndrome patients.

PMID- 12428107
TI  - Ultrasound improves tissue perfusion in ischemic tissue through a nitric oxide
      dependent mechanism.
AB  - Ultrasound accelerates enzymatic fibrinolysis in vitro and in animal models and
      may be used as an adjunct to thrombolytic therapy. Ultrasound can also affect
      vascular tone directly, and we have now investigated the effect of ultrasound on
      tissue perfusion in a rabbit model of acute muscle ischemia to characterize the
      magnitude and temporal course of vasodilation and determine its mechanism. After
      ligation of the femoral artery of rabbits, tissue perfusion in the gracilis
      muscle as determined using a laser Doppler probe declined by 53% from 13.7 +/-
      0.3 U to 6.4 +/- 0.2 U. The tissue became acidotic as pH declined from normal to
      7.05 +/- 0.2. Application of 40 kHz ultrasound at intensities from 0.25 to 0.75
      W/cm(2) progressively improved perfusion over 60 min and reversed acidosis, but
      these effects were both completely blocked by pre-treatment with the nitric oxide
      synthase inhibitor L-NAME. Nitric oxide synthase activity in muscle was measured
      using an assay based on the conversion of radiolabeled L-arginine to L-citrulline
      and demonstrated an increase of 3.6-fold following ultrasound exposure. This
      effect was greatest at locations close to the transducer and declined
      progressively away from it. Histologic examination showed greater capillary
      circumference in ultrasound exposed muscle compared to unexposed tissue with no
      other histologic changes. We conclude that the application of 40 kHz at low
      intensity improves perfusion and reverses acidosis in acutely ischemic muscle
      through a nitric oxide dependent mechanism.

PMID- 12428108
TI  - A collagen binding assay: an additional method for von Willebrand factor activity
      in therapeutic concentrates.

PMID- 12428109
TI  - Fg12 prothrombinase activity?

PMID- 12428110
TI  - Allele frequency of CYP2C9 gene polymorphisms in Iran.

PMID- 12428111
TI  - Allele frequencies of tissue factor pathway inhibitor polymorphisms in African
      American, Hispanic and Caucasian populations.

PMID- 12428112
TI  - Plasma prothrombin levels are not associated with mutations in the promoter
      region of the prothrombin gene.

PMID- 12428113
TI  - Suppression of fibrinolytic activity and obesity in young patients with
      myocardial infarction.

PMID- 12428114
TI  - D-dimers testing is not recommended for the exclusion of deep vein thrombosis in
      outpatients with lower limb erysipelas.

PMID- 12428115
TI  - Is smoking a risk factor for venous thromboembolism?

PMID- 12428116
TI  - The fibrinolytic system and obesity.

PMID- 12428117
TI  - Nitric oxide and prostacyclin are released by cultured apoptotic human umbilical
      vein endothelial cells consistent with an anti-micro-thrombotic potential.

PMID- 12428118
TI  - Enoxaparin and unfractionated heparin in acute coronary syndromes without ST
      segment elevation.

PMID- 12428121
TI  - Functional MRI in symptomatic proliferative angiopathies.
AB  - Seizures, the main expression of cerebral arteriovenous malformations (AVMs) can
      be difficult to control medically. We studied fMRI in correlation with clinical
      findings cerebral activation clusters patterns in relation with singular AVMs
      (proliferative angiopathy). We carried out blood oxygen-level dependent
      functional MRI (fMRI) in seven patients with language problems due to capillary
      ectasia with verbal fluency and repetition language tasks in box-car paradigms.
      fMRI maps were calculated with cross-correlation coefficients and superimposed on
      brain anatomy. Five patients had perimalformative and/or contralateral areas of
      ipsi- and contralateral activation clusters redistribution. One patient who
      underwent fMRI after a severe focal post-ictal deficit had total hemisphere
      contralateral activation clusters redistribution.

PMID- 12428122
TI  - Inaudible functional MRI using a truly mute gradient echo sequence.
AB  - We performed functional MRI experiments using a mute version of a gradient echo
      sequence on adult volunteers using either a simple visual stimulus (flicker
      goggles: 4 subjects) or an auditory stimulus (music: 4 subjects). Because the
      mute sequence delivers fewer images per unit time than a fast echo planar imaging
      (EPI) sequence, we explored our data using a parametric ANOVA test and a non
      parametric Wilcoxon-Mann-Whitney test in addition to performing a cross
      correlation analysis. All three methods were in close agreement regarding the
      location of the BOLD contrast signal change. We demonstrated that, using
      appropriate statistical analysis, functional MRI using an MR sequence that is
      acoustically inaudible to the subject is feasible. Furthermore compared with the
      "silent" event-related procedures involving an EPI protocol, our mGE protocol
      compares favourably with respect to experiment time and the BOLD signal.

PMID- 12428123
TI  - CT in acute stroke: improved detection of dense intracranial arteries by varying
      window parameters and performing a thin-slice helical scan.
AB  - We evaluated the possibility of improving detection of a dense intracranial
      artery on CT in acute stroke by narrowing window width, varying window level and
      performing a thin-slice helical scan for the circle of Willis, in some cases
      followed by postprocessing maximum-intensity projections. We carried out 32
      examinations of 31 patients with a documented cerebral ischaemic attack,
      performing cranial CT within 6 h of the onset of symptoms. Patients with
      intracranial haemorrhage were excluded, as were patients who went on to
      thrombolytic therapy. Varying window width and centre level on standard 5 mm
      thick contiguous axial slices, we detected a dense proximal middle cerebral
      artery (MCA) in a higher proportion of patients. A 1.1 mm thick helical scan
      through the circle of Willis improved recognition of a dense distal horizontal
      segment and the temporoinsular branches of the MCA and of a dense posterior
      cerebral artery.

PMID- 12428124
TI  - A characteristic feature of acute haematomas in the brain on echo-planar
      diffusion-weighted imaging.
AB  - Diffusion-weighted MRI (DWI) is used in the diagnosis of acute ischaemic disease
      of the brain, but it is not clear whether or not it can be used to differentiate
      an acute haematoma from an infarct. Our purpose was to identify any
      characteristic feature of acute haematomas which can be recognised on DWI and to
      evaluate the usefulness of DWI in acute cerebral stroke. We examined nine
      patients with acute haemorrhage using CT and MRI including DWI. We measured the
      volume and apparent diffusion coefficient (ADC) of the haematomas. All showed
      heterogeneous signal on DWI, and the centre of the large (>20 ml) haematomas
      especially a mixed pattern with high and low signal. The characteristic feature
      of acute haematomas was a peripheral low-signal region, found in all subjects
      regardless of the size of the haematoma; acute infarcts did not show this. This
      low-signal rim on DWI may be useful for differentiating an acute haematoma from
      an infarct.

PMID- 12428125
TI  - Unusually quick resorption of an intracerebral hemorrhage in congenital
      afibrinogenemia.
AB  - Neuroimaging diagnostics of cerebral hemorrhage in congenitally afibrinogenic
      patients may be compromised by different pitfalls. We describe the case of a 28
      year-old patient with the diagnosis of congenital afibrinogenemia who suffered a
      large intracerebral hemorrhage. Initial cerebral computed tomography showed
      typical bleeding, but follow-up cerebral CT scans 1 and 2 weeks later revealed an
      unusually quick and subtotal resorption of hemorrhage with only a small hypodense
      lesion within the former bleeding area left. Imaging findings and differential
      diagnosis are discussed with respect to previous reports about intracerebral
      hemorrhage in afibrinogenemia.

PMID- 12428126
TI  - MRI of secondary changes in the thalamus following a cerebral infarct.
AB  - We investigated acute secondary degeneration in the thalamus following a cerebral
      infarct in 21 patients with an infarct in the territory of the middle cerebral
      artery, using serial MRI at various time after the stroke. Secondary degeneration
      in the ventral nuclei of the thalamus was seen as regions of slightly low signal
      on proton-density and/or T2-weighted images, mostly obtained a few weeks after
      the onset. An area of slightly high signal was observed in the dorsomedial
      nucleus of the thalamus on T2-weighted images about 6 weeks after the onset.
      Damage to the superior and anterior thalamic radiation caused degeneration in the
      ventral and dorsomedial nucleus, respectively. Thus, the time of detection and
      the abnormalities seen on MRI in secondary degeneration vary depending upon which
      area of the thalamus is involved. The mechanism underlying the degeneration is
      therefore also likely to differ in these areas.

PMID- 12428127
TI  - Posterior alien hand syndrome: case report.
AB  - The alien hand syndrome (AHS) is involuntary uncontrolled movement of an arm with
      a sense of estrangement from the limb itself. AHS was initially used to describe
      interhemispheric disconnection phenomena in patients with lesions in the anterior
      corpus callosum, but it has been found in patients with posterior cerebral
      lesions without involvement of the corpus callosum, for example parietal infarcts
      or corticobasal degeneration. The posterior alien hand syndrome is less frequent
      and presents with nonpurposive behaviour like lifting the arm or writhing
      fingers. We report an 80-year-old woman with a posterior AHS of the dominant
      right hand. MRI showed atrophy of the pre- and postcentral gyri without
      involvement of the corpus callosum. We discuss the aetiology of the posterior AHS
      and the differences from the anterior varieties.

PMID- 12428128
TI  - Neuroimaging supports the clinical diagnosis of methanol poisoning.
AB  - In addition to visual loss, methanol intoxication can cause brain damage that is
      revealed by neuroimaging. We report on a 34-year-old man whose visual acuity
      deteriorated dramatically during his journey round the world, shortly after an
      evening with excessive alcohol consumption. Two months after the start of visual
      disturbances he returned to Finland. At examination, poor visual acuity and
      glaucomatously cupped pale optic discs were detected. The history and clinical
      findings indicated possible methanol intoxication, which was supported by both CT
      and MRI. The MRI findings are discussed in the light of the MRI appearance of the
      pallidum nuclei among patients of different age groups.

PMID- 12428129
TI  - Cerebral venous and sinus thrombosis with cerebrospinal fluid circulation block
      after the first methotrexate administration by lumbar puncture.
AB  - We report a patient treated for small lymphocytic lymphoma/leukemia with cerebral
      venous and sinus thrombosis (CVST) after lumbar puncture with intrathecal
      administration of methotrexate (MTX). He also developed a cerebrospinal fluid
      flow block. This is the first report of an association between lumbar puncture
      and intrathecally administered MTX and the development of CVST. Intrathecal
      treatment in this patient was discontinued and he was successfully treated with
      high-dose low-molecular-weight heparin subcutaneously.

PMID- 12428130
TI  - Hypertrophic nerve roots in a case of Roussy-Levy syndrome.
AB  - Hypertrophic radiculopathy is a rare feature of neuropathies. Single cases of
      enlarged nerve roots have been described in hereditary motor sensory neuropathies
      (HMSN) and chronic inflammatory demyelinating diseases (CIDP). This is the first
      description of hypertrophied nerve roots in a patient with Roussy-Levy syndrome.
      MRI did not show contrast enhancement of the enlarged nerve roots or nodular
      lesions.

PMID- 12428131
TI  - Perfusion MRI abnormalities in the absence of diffusion changes in a case of
      moyamoya-like syndrome in neurofibromatosis type 1.
AB  - We report on a 12-year-old boy with neurofibromatosis type 1 who suffered a
      transient ischemic attack. Angiography revealed occlusion of intracranial
      arteries, moyamoya vessels and leptomeningeal collaterals. The conventional T2
      weighted and the diffusion-weighted MRI images demonstrated no pathology. Dynamic
      first-pass postgadolinium T2* perfusion-weighted MRI depicted altered
      hemodynamics in the vascular territory of the left middle cerebral artery, which
      defined this region as ischemic tissue at risk. The patient suffered a repeat
      transient ischemic attack 5 days later.

PMID- 12428132
TI  - Outcome after endovascular therapy of ruptured intracranial aneurysms: morbidity
      and impact of rebleeding.
AB  - We evaluated midterm functional outcome after endovascular occlusion of aneurysms
      in patients with subarachnoid haemorrhage (SAH) and determined the incidence of
      late rebleeding as an additional prognostic parameter. We treated 79 consecutive
      patients with SAH from an intracranial aneurysm admitted from a neurological
      intensive care unit by the endovascular route between 1993 and 1997 and 52
      survivors were followed up in 1999-2000. The mean interval between SAH and follow
      up was 41 months (range 13-74 months). Outcome was determined by the Glasgow
      outcome (GOS) and Rankin (RS) scales and by questions concerning
      neuropsychological disorders. The patients were analysed according to Hunt and
      Hess (H & H) grades I-III or IV-V on admission. We observed two episodes of
      rebleeding (3%) with impact on outcome at 907 and 2010 days after SAH,
      respectively. A complete recovery (GOS 5) was achieved in 53% of H & H grade I
      III and 17% of grade IV-V patients; with death rates 19% and 50%, and morbidity
      according to the RS (5-2) 18% and 29%, respectively. Midterm morbidity after
      endovascular therapy is thus low. Rebleeding with an impact on outcome can be
      observed up to 2010 days after SAH, suggesting that long-term angiographic follow
      up is indispensable.

PMID- 12428133
TI  - Endovascular treatment of experimental aneurysms in rabbits using Guglielmi
      detachable coils -- a feasibility study.
AB  - The Guglielmi detachable coil (GDC) has been generally accepted for treatment of
      intracranial aneurysms. Preclinical testing of new coil developments requires
      animal models of aneurysms which imitate human aneurysms in size, configuration
      and neck morphology. We assessed in detail the technical requirements and steps
      for transfemoral treatment of experimentally induced aneurysms at the top of the
      brachiocephalic trunk (TBC) in rabbits. We created aneurysms in five rabbits by
      distal ligation and intraluminal incubation of the right common carotid artery
      with elastase. All animals were treated successfully 2-3 weeks after induction of
      the aneurysm, with dense packing of the coils. No complications related to the
      procedures occurred. The study demonstrates that our animal model can be a
      suitable method for testing the biocompatibility and occlusion rate of new
      embolic materials.

PMID- 12428134
TI  - Percutaneous vertebroplasty: long-term clinical and radiological outcome.
AB  - We assessed radiographic and functional outcome in 13 patients with a minimum of
      5 years follow-up from a prospectively monitored series of 17 patients who
      underwent percutaneous vertebroplasty (PPV). A visual analogue scale (VAS) and
      the short McGill questionnaire (MPQ) were used to assess average symptoms. The
      VAS showed significant improvement after treatment: the initial score was 9.07+/
      0.6 (mean+/-SD), falling to 2.07 (1.14) on the third day, 1.07 (1.07) by the
      third month and 2.15 (2.6) at 5 years. Pain reduction was statistically
      significant ( P<0.001). The MPQ showed a significant improvement after treatment
      ( P<0.001), but had worsened by the last follow-up. All patients were "very" or
      "somewhat satisfied" with the procedure. We saw no further collapse of the
      vertebrae injected or migration or changes in the shape of the cement. A new
      fracture was seen in three patients, affecting four vertebrae, only two of which
      were adjacent to the treated level. On CT following the procedure, there was
      cement in the epidural veins adjacent to the vertebra in 48% of cases, but only
      patient developed a transitory neuritis.

PMID- 12428135
TI  - Involvement of NMDA receptors and a p21Ras-like guanosine triphosphatase in the
      constitutive activation of nuclear factor-kappa-B in cortical neurons.
AB  - The transcription factor nuclear factor-kappa-B (NF-kappaB) is now recognised as
      a key mediator of physiological and pathological plasticity in the central
      nervous system (CNS), and ionotropic glutamate receptor stimulation potently
      triggers NF-kappaB activation. This study was designed to identify the mechanisms
      responsible for the high basal levels of activated NF-kappaB present in neurons
      in the cerebral cortex. In cultured cortical neurons, the basal levels of
      activated NF-kappaB were reduced by the glutamate receptor antagonists MK801 and
      6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), but were not affected by exposure to
      a mitogen-activated protein (MAP) kinase kinase (MEK) inhibitor, a p38 MAP kinase
      inhibitor or a cyclic guanosine monophosphate (cGMP)-dependent protein kinase
      inhibitor. However, activated NF-kappaB levels were reduced by a guanylate
      cyclase inhibitor, the Src-family tyrosine kinase inhibitor PP1, or the farnesyl
      transferase inhibitors manumycin and farnesyl transferase (Ftase) inhibitor 1.
      There was no additive effect when MK801 was applied together with manumycin.
      These results suggest that the basal levels of activated NF-kappaB in cortical
      neurons are maintained partially by synaptic activity involving N-methyl- D
      aspartate (NMDA) and AMPA/kainate glutamate receptors, coupled to activation of
      an Src-family tyrosine kinase and a p21(Ras)-like guanosine triphosphatase
      (GTPase) in a cGMP-dependent manner. The results are intriguing in the light of
      the recent identification of a synaptic p21(Ras) activator stimulated by cGMP.

PMID- 12428136
TI  - Altering the visuomotor gain. Evidence that motor plans deal with vector
      quantities.
AB  - Two experiments investigated the effects of providing nonveridical knowledge of
      the results (KR) in a visuomanual task in which participants pointed to briefly
      (200 ms) presented targets without seeing their hand. By showing after each trial
      the movement endpoint displaced radially with respect to its true position, we
      were able to alter progressively the gain of the visuomanual loop. In experiment
      1, the KR was provided only for transversal movements and for one target
      distance, but the effect generalized to all directions and all distances.
      Moreover, it also generalized to the other hand that had never been biased. In
      experiment 2, nonveridical KR was supplied for movements along the two major
      diagonals which require sharply different muscle synergies. The transfer to other
      directions and to the other hand was equally substantial. It is argued that the
      results support the vector coding hypothesis, which holds that the input to the
      motor execution stage is supplied by specifying independently the amplitude and
      the direction of the vector from the initial to the final position in an
      extrinsic frame of reference. We also discuss the possible brain structures
      involved in the biasing action of the KR.

PMID- 12428137
TI  - Nitric oxide controls the light adaptive chromatic difference in receptive field
      size of H1 horizontal cell network in carp retina.
AB  - In carp retina, the receptive field size of the H1-type horizontal cell (HC)
      network is known to be chromatically selective, as electrophysiological signals
      are generated by short-wavelength (SW) light stimuli, which spread much less than
      those for long-wavelength (LW). We have shown previously that the signalling
      mechanism underlying this chromatic difference operates only in the light-adapted
      retina and that it involves cGMP as an intermediary messenger. In the present
      study, the possible role of nitric oxide (NO) as such a control mechanism was
      investigated. Application of a NO donor (SNP or SNOG) to dark-adapted retinae
      produced a chromatic difference in the receptive field size, such as in the light
      adapted state. This effect was due mainly to a reduction in the spread of signals
      generated by SW stimuli; LW signalling spread was not altered. No such effect was
      observed in light-adapted retinae where a chromatic difference in receptive field
      size was already present. On the other hand, application of the NO 'scavenger'
      haemoglobin to light-adapted retinae suppressed the chromatic difference. These
      results are consistent with NO being a light-adaptive retinal neuromodulator
      involved in the generation of the chromatic difference in H1 cell receptive field
      size. These results are discussed in the context of two different hypotheses.

PMID- 12428138
TI  - Manual asymmetries in the directional coding of reaching: further evidence for
      hemispatial effects and right hemisphere dominance for movement planning.
AB  - Directional coding of hand movements is of primary importance in the proactive
      control of goal-directed aiming. At the same time, manual reaction times are
      known to be asymmetric when reaching at lateralized targets. Generally,
      ipsilateral movements and left hand advantages are interpreted using the
      classical model of interhemispheric transmission for simple visuomotor
      integration, but the use of this model was recently challenged when applied to
      reaching movements, arguing that attentional and biomechanical effects could also
      account for such asymmetries. In this work, we aimed at controlling both visual
      attention orienting and movement mechanical constraints in order to clarify the
      origin of manual reaction time asymmetries and hemispatial effects in the
      directional coding of reaching. Choice reaction time pointing tasks were assessed
      in two experiments in which identical movements were compared in different
      conditions of target lateralization and different conditions of head, eye and
      hand position. Results suggested that biomechanical constraints could account for
      hemispatial effects for movement execution but not for movement direction coding.
      These results are discussed in the light of models of interhemispheric
      cooperation and the right hemisphere dominance for spatial processing.

PMID- 12428139
TI  - Voluntary toe-walking gait initiation: electromyographical and biomechanical
      aspects.
AB  - This study was carried out to investigate the biomechanical constraints of toe
      walking gait initiation and the associated changes in motor program compared to
      the well documented heel-toe walking gait initiation. Seven healthy subjects
      volunteered for this study. Gait was initiated on a force platform, at three self
      selected speed conditions, from an erect spontaneous posture in the control
      situation (CS) and from a posture with heels raised in the test situation (TS).
      Surface electromyographical (EMG) activities of muscles soleus (Sol) and tibialis
      anterior (TA) were recorded on both limbs. We analysed the consequences of the
      heel-off posture on EMG patterns and biomechanical activities. Whatever the speed
      condition, the centre of foot pressure was initially located more ahead of the
      ankle axis in TS than in CS, with an increased Sol and TA EMG activity. The EMG
      pattern which expresses the motor program governing gait initiation was modified
      in TS in comparison to CS and induced adaptations of the anticipatory postural
      adjustments (APA) that precede toe-off of the stepping limb. A lengthening of the
      APA duration allowed the subjects in TS to reach a gait velocity similar to the
      one obtained in CS at the end of the anticipatory movements and also at the end
      of the first step. In TS, the velocity of the centre of gravity at time of toe
      off covaried, as in CS, with CG velocity at the end of the first step, still
      resulting from TA muscular actions during the APA but also probably from other
      combined muscular actions.

PMID- 12428140
TI  - Simultaneous repetitive movements following pallidotomy or subthalamic deep brain
      stimulation in patients with Parkinson's disease.
AB  - Patients with Parkinson's disease (PD) commonly exhibit difficulties performing
      simultaneous tasks and levodopa has been shown to improve the performance of
      these movements to a greater extent than movements performed in isolation. The
      aim of this study was to compare the effects of acute unilateral pallidal lesions
      (nine patients) and bilateral deep brain stimulation (DBS) of the subthalamic
      nucleus (STN) (eight patients) with levodopa therapy (ten patients) on the
      performance of isolated versus bilateral simultaneous repetitive movements. The
      STN group was assessed with and without DBS both on and off levodopa. The two
      tasks employed were maximally paced button tapping (Tap) and wrist pronation
      supination (WPS) movements. During the off drug state (12-14 h after the last
      oral dose of levodopa), the performance of simultaneous Tap and WPS movements in
      all three groups was significantly slower and more irregular than when each
      movement was performed in isolation. For example, WPS velocity decreased by at
      least 37% (P<0.05) with concomitant Tap. Following levodopa, pallidotomy or STN
      DBS, WPS velocity was increased during the simultaneous task to a greater extent
      than in the isolated task. All treatments also improved WPS velocity and
      increased the regularity of movement during concomitant Tap (P<0.01). The
      findings indicate that, like levodopa, surgical therapies can improve the
      performance of simultaneous tasks more than isolated tasks. These observations
      suggest that the excessive neuronal activity and/or abnormal firing patterns in
      the globus pallidus internus that is found in parkinsonian patients contribute to
      difficulties in the execution of complex motor tasks.

PMID- 12428141
TI  - Enhancement of visual perception by crossmodal visuo-auditory interaction.
AB  - Neurophysiological studies have shown in animals that a sudden sound enhanced
      perceptual processing of subsequent visual stimuli. In the present study, we
      explored the possibility that such enhancement also exists in humans and can be
      explained through crossmodal integration effects, whereby the interaction occurs
      at the level of bimodal neurons. Subjects were required to detect visual stimuli
      in a unimodal visual condition or in crossmodal audio-visual conditions. The
      spatial and the temporal proximity of multisensory stimuli were systematically
      varied. An enhancement of the perceptual sensitivity (d') for luminance detection
      was found when the audiovisual stimuli followed a rather clear spatial and
      temporal rule, governing multisensory integration at the neuronal level.

PMID- 12428142
TI  - Further evidence that a shared efferent collicular pathway drives separate
      circuits for smooth eye movements and saccades.
AB  - The aim of the present study was to find out whether smooth eye movements (SEMs)
      evoked by superior colliculus (SC) stimulation are, as suggested by Breznen et
      al. (1996), artefactual eye movements resulting from a non-physiological response
      of the saccadic generator. This question was reinvestigated in head-restrained
      cats. Long-lasting SC stimulation was found to evoke, in a comparable proportion,
      either a single saccade followed by an uninterrupted SEM or a staircase of two or
      three saccades interleaved with SEMs. These two different patterns of eye
      movements could be elicited at a near-threshold current and at low stimulation
      frequencies. In most cases, SEM direction clearly differed from that of the
      preceding saccade. This difference between SEM and saccade directions varied in a
      systematic way as a function of the initial saccade direction. As demonstrated by
      computer simulation, this observation can be explained if the neural circuit
      controlling SEMs reaches a saturation level earlier than the saccadic burst
      generator. Our results in cats were reminiscent of those reported by Breznen et
      al. (1996) in the monkey only in some instances, when high frequency stimulation
      (400-600 Hz) was applied. Indeed, in the case of near-threshold stimulation
      elicited staircase saccades, increasing the stimulation frequency led to a
      progressive disappearance of the smaller subsequent saccades that were
      substituted by uninterrupted SEM-like movements. Altogether, the present results
      confirm the view that SEMs are genuine eye movements. These results rule out the
      hypothesis that SEMs result from a saturation of the saccadic generator and
      strengthen the hypothesis that SEMs and saccades are distinct movements. We
      suggest that the same collicular efferent cells carry out the motor command to
      saccadic and SEM circuits and that the position error originating from the SC may
      be distributed amongst separate downstream motor systems.

PMID- 12428143
TI  - Suramin reduces infarct volume in a model of focal brain ischemia in rats.
AB  - Extracellular adenosine 5'-triphosphate (ATP) provides excitatory transmission in
      the central nervous system. Stimulation by ATP of ionotropic ligand-gated ion
      channel purinoceptors (P(2X)) leads to increased intracellular calcium levels,
      and activation of P(2X) receptors may be involved in the process of excitotoxic
      neuronal injury caused by stroke. Suramin, as an agent that is known to block
      P(2X) receptors at a specific concentration, was assessed for its neuroprotective
      potential in a model of experimental stroke in the rat. We propose that the
      effectiveness of suramin is limited to those concentrations where it is an
      effective P(2X) receptor antagonist. Focal brain ischemia was produced by
      unilateral occlusion and transection of the middle cerebral artery (MCAT) and
      bilateral occlusion of the common carotid arteries (CCA). Thirty-four male
      Sprague-Dawley rats were randomly separated into five groups. Changes in regional
      cerebral blood flow in the ischemic region were verified by laser Doppler
      flowmetry. All rats received, over a period of 30 min before MCAT, a dose of
      suramin at 0 (saline), 25, 50, 100, or 250 mg/kg intravenously in a volume of 1
      ml using an infusion pump. Six hours after ischemia onset, evaluation of the
      neurologic status and cerebral blood flow was followed by morphometric analysis
      of infarct volume. During the surgical procedure mean arterial pressure, blood
      gases (PaCO(2), PaO(2)), and pH were monitored. A dose-dependent decrease in
      infarct volume (slope -0.049, SE 0.009, P<0.001) was observed in groups treated
      over the dose range of 0 to 100 mg/kg (r(2)=0.55). Suramin at a dose of 100 mg/kg
      significantly decreased infarct volume (n=9, P<0.001) and edema volume (P=0.003).
      The neuroprotective effect of suramin at a dose of 100 mg/kg was supported by an
      improved neurologic score in this group (median 0) compared with a median of 3 in
      control animals (P=0.02). These findings indicate that suramin at 100 mg/kg is an
      effective pre-treatment neuroprotective agent. As the estimated brain
      concentration of 10 microM (from McNally et al., 2000, Life Sci 67:1847-1857) is
      the IC(50) for suramin-mediated P(2X) antagonism, these results suggest that
      interference with the ATP excitatory system could provide neuroprotection from
      brain ischemia.

PMID- 12428144
TI  - Fast gamma oscillations in areas MT and MST occur during visual stimulation, but
      not during visually guided manual tracking.
AB  - We studied the incidence of oscillatory activity in the gamma range (35-110 Hz)
      in single cell and multi-unit activity recorded from extrastriate areas MT
      (middle temporal) and MST (superior middle temporal) while rhesus monkeys
      performed different behavioural tasks. During full field stimulation by coherent
      motion of random dots, we observed gamma oscillations in approximately 20% of the
      cells. The average oscillation frequencies differed considerably between both
      animals (60 Hz vs 100 Hz). In both animals, oscillatory modulation was
      particularly strong at sites that showed a strong directional bias to visual
      stimulation. The amount of oscillatory activity was roughly the same whether
      stimulus movement was presented during fixation or whether the animal had to
      perform pursuit movements across a stationary visual pattern. If cells were
      engaged in gamma oscillations during visual stimulation, the amount of
      oscillatory modulation was dependent on stimulus direction, stimulus velocity and
      stimulus contrast. During a visually guided manual tracking task no gamma
      activity was detectable. Cells with clear oscillatory modulation during the full
      field stimulation failed to show oscillatory activity when the animal was
      involved in a motor task in which the visual motion information had to be
      evaluated for the correct movement of the hand. Our results reaffirm the
      ubiquitous presence of stimulus-induced gamma oscillation in extrastriate areas
      MT and MST of the awake monkey during various stimulus conditions, but they fail
      to support the notion that high-frequency gamma oscillations in this area play a
      specific role during cortical control of a motor response to visual stimulation.

PMID- 12428145
TI  - Gradual and reversible central vestibular reorganization in frog after selective
      labyrinthine nerve branch lesions.
AB  - Postlesional reorganization of vestibular afferent and commissural inputs onto
      second-order vestibular neurons was studied in the isolated brain after
      unilateral section of the N.VIII, of the ramus anterior (RA) of N.VIII, of the
      utricular (UT) or of the anterior vertical and horizontal canal nerves in
      combination. RA nerve section eliminated the inputs from utricular, anterior
      vertical and horizontal canal organs. In the first set of experiments we recorded
      field potentials on the operated side of the vestibular nuclei 2 months after RA
      nerve section. These responses were evoked by electrical stimulation of the RA
      nerve or of the posterior vertical canal nerve on the operated or on the intact
      side. The amplitudes of afferent field potentials evoked by stimulation of the
      spared posterior vertical canal nerve were increased. The amplitudes of afferent
      field potentials evoked by stimulation of the axotomized RA nerve remained
      unaltered. After N.VIII section the commissural, but not the afferent, field
      potentials increased significantly on the operated side following stimulation of
      N.VIII on the intact and on the operated side, respectively. After UT nerve
      section no change in commissural but an increase in the amplitude of afferent
      field potentials from each of the three intact canal nerves was observed on the
      operated side. In the context of earlier results these findings imply that second
      order vestibular neurons, disfacilitated due to afferent nerve section, became
      receptive to additional, excitatory synaptic inputs, preferentially from intact
      vestibular nerve afferent fibers. The reduced excitation via afferent nerve
      inputs was thereby replaced by other afferent nerve inputs from spatially
      inadequate vestibular end-organs. The synaptic terminals of inactivated afferent
      nerve fibers were maintained and not repressed. The process of central
      reorganization after vestibular nerve lesion was activity related, the expansion
      of signals restricted to inputs from intact fibers, its extent graded and its
      onset delayed with respect to the onset of corresponding spinal changes and to
      the onset of postural recovery after the same type of nerve lesion. After the
      section of RA nerve or of an individual nerve branch the labyrinthine end-organs
      remained intact and were not removed as after unilateral labyrinthectomy (UL).
      Peripheral reinnervation of the end-organs was thus excluded after UL, but
      expected after one of the former types of lesion. Functional reinnervation of the
      utricular macula was mirrored behaviorally by the reappearance of severe postural
      deficits following a second RA nerve section. These lesion-induced postural
      deficits began to reappear if the repeated RA nerve section was delayed with
      respect to the first by about 3 months. We therefore studied postlesional
      reorganization in the brainstem 3 months after the first RA nerve section.
      Reinnervation of the utricular macula was accompanied by a rapid decline of the
      increased amplitudes of afferent and commissural vestibular field potentials
      towards control values, suggesting the reversibility of the lesion-induced
      central reorganization.

PMID- 12428146
TI  - Differential cerebral responses to aversive auditory arousal versus muscle pain:
      specific EEG patterns are associated with human pain processing.
AB  - The specificity of electroencephalogram (EEG) activity in relation to processing
      of human pain needs further elucidation. This study was designed to determine if
      nociceptive input and general arousal responses to external stimulation exert
      different effects on EEG activity. Continuous aversive auditory stimuli (90 dB
      for 2 min) and painful injection of hypertonic saline (5.8%, 0.2 ml) into the
      left brachioradialis muscle were administered to 12 male subjects during separate
      sessions in a counterbalanced design. Intensity, arousal and unpleasantness were
      assessed during the muscle pain and auditory stimulation using a visual analogue
      scale and arousal-affective scales. The EEG data (32 channels) was acquired
      before, during and after application of painful and aversive auditory stimuli.
      Aversive auditory stimulation and intramuscular injection of hypertonic saline
      induced similar degrees of arousal and unpleasantness associated with a
      similarity of intensity of sensation of pain and auditory sensation. However,
      muscle pain induced a significant decrease of alpha-1 activity (8-14 Hz) at T6,
      PC2, PC6, Pz, P4, O2 and POz sites compared to the baseline, but aversive
      auditory stimulation did not produce any significant changes in alpha-1 activity
      compared to baseline. The alpha-1 EEG powers at P3, Pz, P4, PC1, PC2 and POz, and
      alpha-2 at Pz and POz sites were significantly decreased during muscle pain when
      compared with aversive noise stimulation. These results indicate that specific
      EEG patterns are associated with human pain processing.

PMID- 12428147
TI  - Attentional effects in the visual pathways: a whole-brain PET study.
AB  - Attentional effects in the visual pathways were investigated by contrasting the
      distribution of regional cerebral blood flow (rCBF) measured by H(2)(15)O
      positron emission tomography (PET) during performance of a shape-matching task
      with the distribution of rCBF during a less demanding color-matching task. The
      two tasks were performed using the same stimuli: pairs of colored random shapes
      shown at a fixed rate (2 s per pair). In the shape-matching task, the subjects
      determined whether the two stimuli were the same in shape regardless of
      differences in size or color. In the color-matching task, the subjects determined
      whether the two stimuli were the same in color regardless of differences in size
      or shape. Mean reaction time for shape-matching exceeded mean reaction time for
      color-matching by nearly 200 ms. The corresponding shape-color comparison showed
      extensive bilateral increases in rCBF in visual areas in the occipital and
      parietal lobes, including the primary visual cortex. Subcortical activations were
      found in cerebellum (particularly the vermis) and in the thalamus with the focus
      in a region comprising the lateral geniculate nucleus, the pulvinar, and adjacent
      parts of the reticular nucleus. Frontal activations were found in a region that
      seems implicated in visual short-term memory (posterior parts of the superior
      sulcus and the middle gyrus). The reverse, color-shape comparison showed
      bilateral increases in rCBF in the anterior cingulate gyri, superior frontal
      gyri, and superior and middle temporal gyri. The attentional effects found by the
      shape-color comparison in the thalamus and the primary visual cortex may have
      been generated by feedback signals preserving visual representations of selected
      stimuli in short-term memory.

PMID- 12428148
TI  - Convergence of the anterior semicircular canal and otolith afferents on cat
      single vestibular neurons.
AB  - The convergence between the anterior semicircular canal (AC) and utricular (UT)
      inputs, as well as the convergence between the AC and saccular (SAC) inputs in
      single vestibular neurons of decerebrated cats were investigated. Postsynaptic
      potentials were recorded intracellularly after selective stimulation of each pair
      of vestibular nerves AC/UT or AC/SAC. Neurons were recorded from the central
      parts of the vestibular nuclei, where the otolith afferents mainly terminate. Of
      a total of 105 neurons that were activated after stimulation of the AC and UT
      nerves, 42 received convergent inputs. Thirty-eight of these neurons received
      excitatory inputs from both afferents. Convergent neurons were further classified
      into vestibulospinal (n=28) and vestibulooculospinal (n=6) neurons by antidromic
      activation from the border between the C1 and C2 spinal cord and the oculomotor
      or trochlear nucleus. Eight neurons that were not antidromically activated from
      either site were classified as vestibular neurons. Forty three percent of the
      convergent vestibulospinal neurons and most of the convergent
      vestibulooculospinal neurons projected to the spinal cord through the medial
      vestibulospinal tract. The remaining vestibulospinal and vestibulooculospinal
      neurons descended through the ipsilateral lateral vestibulospinal tract. Of a
      total of 118 neurons that were activated after stimulation of the AC and/or SAC
      nerves, 51 received convergent inputs (27 vestibulospinal, 4
      vestibulooculospinal, 5 vestibuloocular and 15 vestibular neurons). Forty-two of
      the convergent neurons received excitatory inputs from both afferents. Thirty
      seven percent of the convergent vestibulospinal neurons and all of the convergent
      vestibulooculospinal neurons projected to the spinal cord through the medial
      vestibulospinal tract. The remaining vestibulospinal and vestibulooculospinal
      neurons descended through the ipsilateral lateral vestibulospinal tract.

PMID- 12428151
TI  - Alcoholism, anxiety, and opioid-dopaminergic interactions.

PMID- 12428152
TI  - Field study for degradation of methyl parathion in apples cultivated with
      integrated crop management system.

PMID- 12428150
TI  - Prepulse inhibition during withdrawal from an escalating dosage schedule of
      amphetamine.
AB  - RATIONALE: Psychomotor stimulants can induce psychotic states in humans that
      closely resemble those observed in patients with idiopathic schizophrenia.
      Attentional and sensorimotor gating impairments are observed in schizophrenic
      patients using the latent inhibition (LI) and prepulse inhibition (PPI)
      behavioral assays, respectively. Our previous studies demonstrated that after 4
      days of withdrawal from a period of amphetamine (AMPH) administration, animals
      exhibited disrupted LI but normal PPI. OBJECTIVE: The aim of the present study
      was to test PPI in AMPH-withdrawn rats under experimental conditions similar to
      those used to best demonstrate locomotor sensitization following AMPH withdrawal.
      METHODS: We examined the effects on PPI of (1) pairing drug injections with PPI
      test-associated cues, (2) administration of a low-dose dopamine agonist challenge
      and (3) testing following longer withdrawal periods (23, 30, 60 days). RESULTS:
      Although none of these conditions revealed a disruption of PPI in AMPH-withdrawn
      rats, we did observe that the acoustic startle response was reduced during a
      restricted time period following AMPH withdrawal. Similar to our previous
      findings, AMPH-withdrawn animals showed disrupted LI on day 16 of withdrawal and
      locomotor sensitization to a challenge injection of AMPH after 62 days of
      withdrawal. CONCLUSION: We conclude that the effects of repeated AMPH on PPI are
      not modulated by the same experimental parameters known to be important for
      eliciting locomotor sensitization and that withdrawal from the schedule of AMPH
      administration used in this study models only specific cognitive dysfunctions
      linked to schizophrenic symptoms, since LI was disrupted but PPI was not
      affected.

PMID- 12428153
TI  - Restoration of the slow biodegradation of isoxaben in the soil of a fruit orchard
      after interruption of repeated isoxaben applications.

PMID- 12428154
TI  - Soil persistence and mobility in corn fields of flumetsulam applied at low doses.

PMID- 12428155
TI  - Chemical ratios and groundwater contamination in East Texas.

PMID- 12428156
TI  - Investigation of polychlorobiphenyls and organochlorine pesticides in tissues of
      tuna ( thunnus thunnus thynnus) from the Mediterranean Sea in 1999.

PMID- 12428157
TI  - Leaching of arsenic, chromium, and copper in a contaminated soil at a wood
      preserving site.

PMID- 12428158
TI  - Transfer of 134Cs and 85Sr to Pleurotus eryngii fruiting bodies under laboratory
      conditions: a compartmental model approach.

PMID- 12428159
TI  - Cadmium accumulation in fetus and placenta of bank voles ( Clethrionomys
      glareolus, Schreber 1780).

PMID- 12428160
TI  - Degradation of aromatic and asphaltenic fractions by Serratia liquefasciensand
      bacillus sp.

PMID- 12428161
TI  - Comparison of asbestos exposure in a containment system with and without
      employment of glovebags.

PMID- 12428162
TI  - Alternative strategies for PCB risk reduction from contaminated seafood: options
      for children as susceptible populations.

PMID- 12428163
TI  - Cigarette smoking and secondary smoke in Turkey: effect on placental aryl
      hydrocarbon hydroxylase (AHH), infant birth weight, and size.

PMID- 12428164
TI  - Antiestrogenic and antiprogesteronic activity of tire extracts with yeast-based
      steroid hormone receptor gene transcription assay.

PMID- 12428165
TI  - Alkaline pretreatment of kraft mill sludge to improve its anaerobic digestion.

PMID- 12428166
TI  - Occurrence of shell deformities in green-lipped mussel Perna viridis (Linnaeus)
      collected from Malaysian coastal waters.

PMID- 12428167
TI  - Exposure of the frog Rana ridibunda to copper: impact on two biomarkers, lipid
      peroxidation, and glutathione.

PMID- 12428168
TI  - Superoxide dismutase and lipid peroxidation levels in fish from the Ethiope River
      in southern Nigeria.

PMID- 12428169
TI  - Combined effect of mercuric chloride and selenium dioxide on the growth of the
      cyanobacteria, Anacystis nidulans.

PMID- 12428170
TI  - Influence of pesticide-fertilizer combination on food intake, growth, and
      conversion efficiencies of Oreochromis mossambicus.

PMID- 12428171
TI  - Glycemic index in chronic disease: a review.
AB  - AIM: The intent of this review is to critically analyze the scientific evidence
      on the role of the glycemic index in chronic Western disease and to discuss the
      utility of the glycemic index in the prevention and management of these disease
      states. BACKGROUND: The glycemic index ranks foods based on their postprandial
      blood glucose response. Hyperinsulinemia and insulin resistance, as well as their
      determinants (eg high energy intake, obesity, lack of physical activity) have
      been implicated in the etiology of diabetes, coronary heart disease and cancer.
      Recently, among dietary factors, carbohydrates have attracted much attention as a
      significant culprit, however, different types of carbohydrate produce varying
      glycemic and insulinemic responses. Low glycemic index foods, characterized by
      slowly absorbed carbohydrates, have been shown in some studies to produce
      beneficial effects on glucose control, hyperinsulinemia, insulin resistance,
      blood lipids and satiety. METHOD: Studies on the short and long-term metabolic
      effects of diets with different glycemic indices will be presented and discussed.
      The review will focus primarily on clinical and epidemiological data, and will
      briefly discuss in vitro and animal studies related to possible mechanisms by
      which the glycemic index may influence chronic disease.

PMID- 12428172
TI  - L-amino acid sensing by the calcium-sensing receptor: a general mechanism for
      coupling protein and calcium metabolism?
AB  - Cellular sensing of L-amino acids is widespread and controls diverse cellular
      responses regulating, for example, rates of hormone secretion, amino acid uptake,
      protein synthesis and protein degradation (autophagy). However, the nature of the
      sensing mechanisms involved has been elusive. One important sensing mechanism is
      selective for branched chain amino acids, acts via mTOR (mammalian target of
      rapamycin) and regulates the rates of insulin and IGF-1 secretion as well as
      hepatic, and possibly muscle, autophagy. A second sensing mechanism is selective
      for aromatic L-amino acids and regulates the rate of gastric acid secretion and
      other responses in the gastro-intestinal tract. Interactions between calcium and
      protein metabolism, including accelerated urinary calcium excretion in subjects
      consuming high-protein diets and secondary hyperparathyroidism in subjects
      consuming low-protein diets, suggest an additional amino acid sensing mechanism
      linked to the control of urinary calcium excretion and parathyroid hormone (PTH)
      release. New data demonstrating L-amino acid-dependent activation of the calcium
      sensing receptor (CaR), which regulates PTH secretion and urinary calcium
      excretion, suggests an unexpected explanation for these links between calcium and
      protein metabolism. Furthermore, expression of the CaR in gastrin-secreting G
      cells and acid-secreting parietal cells, together with data indicating that the
      CaR exhibits selectivity for aromatic amino acids, would appear to provide a
      molecular explanation for amino acid sensing in the gastrointestinal tract. This
      review examines what is known about the CaR as a gene, a receptor, a
      physiological regulator and, now, as an amino acid sensor. Possible new roles for
      the CaR are also considered.

PMID- 12428173
TI  - Abdominal vs buttock adipose fat: relationships with children's serum lipid
      levels.
AB  - OBJECTIVE: To explore the extent to which the reported unfavorable fatty acid
      content of abdominal depots in adults is also true for children. In addition, the
      present study aims to assess the relative importance of abdominal vs buttock
      adipose tissue fat in the prediction of serum lipid levels in children. DESIGN: A
      cross-sectional study of children from the island of Crete. SETTING: The study
      was conducted between October 1999 and January 2000 in the Municipality of St
      Nikolas, Crete. SUBJECTS: A total of 475 children (aged 11-18) participated in
      the study. Data were obtained on children's anthropometry, serum lipids, physical
      activity and abdominal and buttock adipose tissue fatty acids. In total 138
      children (aged 11-16) had complete data in all of the variables studied. RESULTS:
      Abdominal depots have elevated proportions of saturated fatty acids (P<0.001) and
      trans fatty acids (P<0.001), and reduced proportions of monounsaturated (P<0.001)
      and polyunsaturated fatty acids (P<0.001) in comparison to buttock depots.
      Buttock adipose tissue monounsaturated fat correlated negatively to serum LDL-C
      (P<0.05). Abdominal adipose tissue polyunsaturated fat had negative correlations
      with serum total cholesterol (P<0.05) and LDL-C (P<0.05). Regression analyses
      indicated that children's serum total cholesterol (P<0.05) and LDL-C (P<0.05)
      were inversely related to abdominal adipose tissue polyunsaturated fat. Body mass
      index was positively related to serum triglycerides (P<0.01) and LDL-C (P<0.01),
      and negatively to serum HDL-C (P<0.05). Age was negatively related to serum HDL-C
      (P<0.05). CONCLUSIONS: It appears that, similar to adults, children's fatty acid
      composition of abdominal adipose tissue is less favorable than that of the
      buttock. Abdominal depots have elevated proportions of saturated fatty acids and
      reduced proportions of monounsaturated and polyunsaturated fat in comparison to
      buttock depots. Moreover, children's abdominal depots appear to have higher trans
      fatty acid contents than buttock depots. Children's adipose polyunsaturated fat,
      a biomarker of long-term polyunsaturated fatty acid intake, is inversely related
      to serum total cholesterol and LDL-C. It appears that abdominal adipose tissue
      fatty acids are more strongly related to serum lipids than buttock adipose tissue
      fatty acids. This may be attributed to the reported higher lipolysis rates in
      abdominal as opposed to buttock depots. SPONSORSHIP: Funding was provided by the
      Municipality of St Nikolas, Crete, Greece.

PMID- 12428174
TI  - Biochemical deficiency of pyridoxine does not affect interleukin-2 production of
      lymphocytes from patients with Sjogren's syndrome.
AB  - BACKGROUND: There is evidence that pyridoxine deficiency may alter the immune
      response. It is not known whether a deficiency of this vitamin is evident in
      subjects with primary Sjogren's syndrome (SS). OBJECTIVE: We studied whether
      subjects with primary SS showed a biochemical deficiency of pyridoxine, and if it
      is associated with abnormal production of interleukin-2 from lymphocytes
      stimulated in vitro with phytohemagglutinin (PHA). DESIGN: Two studies were
      conducted, (i) biochemical and nutritional assessments were performed in a cross
      over study in subjects with primary SS, who were supplemented with 25 mg/day of
      pyridoxine or placebo for 3 months. After 1 month washout, they were supplemented
      for 3 months with placebo, (ii) patients with SS and matched controls received
      pyridoxine or placebo for 45 days, and a blood sample was obtained to study IL-2
      production and expression in T-lymphocytes stimulated with PHA. RESULTS: Subjects
      with primary SS showed limited dietary intake of pyridoxine and biochemical
      deficiency of this vitamin assessed through the activation coefficient of the
      erythrocyte aspartate aminotransferase. The biochemical deficiency did not affect
      production nor mRNA expression of IL-2 from T-lymphocytes stimulated in vitro
      with PHA compared with the control group. Supplementation of subjects with
      primary SS with 25 mg/day with pyridoxine for 45 days did not produce any
      significant change as compared to those patients supplemented with placebo.
      CONCLUSIONS: Subjects with primary SS showed biochemical deficiency of
      pyridoxine, possibly due to limited intake of this vitamin which was corrected by
      supplementation with pyridoxine. However, IL-2 production and mRNA expression
      from stimulated lymphocytes were unaffected by supplementation, probably because
      the deficiency was not severe enough to affect the immune system. SPONSORSHIP:
      This work was supported by the National Council of Science and Technology
      (CONACYT), Mexico, grant no. 212226-5-0902PM.

PMID- 12428175
TI  - The effect of vegetable oil-based cheese on serum total and lipoprotein lipids.
AB  - OBJECTIVE: To investigate the effect of rapeseed oil-based cheese (milk-fat
      substituted by rapeseed oil) on serum total and lipoprotein lipid concentrations
      and blood pressure in reference to ordinary, milk-fat-based cheese in subjects
      with mildly to moderately elevated serum cholesterol concentration. DESIGN:
      Randomized, controlled, single-blind, cross-over clinical trial. SETTINGS:
      Outpatient dietary intervention with free-living subjects in Eastern Finland.
      INTERVENTIONS: The study began with a 2 week pre-trial period followed by two 4
      week intervention periods. During the intervention study subjects replaced their
      ordinary cheese or cold cuts with 65 g of rapeseed oil-based or milk-fat-based
      control cheese. The type of test cheese was switched at 4 weeks of intervention.
      Altogether 31 subjects completed the study. RESULTS: Compared with the control
      cheese period the mean serum total cholesterol concentration was 6.7% (95% Cl 
      9.9 to -3.5%) lower after 2 weeks and 5.0% (95% Cl -7.5 to -2.5%) lower after 4
      weeks of use of rapeseed oil-based cheese. Respectively, LDL cholesterol
      concentration was 7.0% (95% Cl -11.7 to -2.6%) lower after 2 weeks use and 6.4%
      (95% Cl -10.0 to -2.8%) lower after 4 weeks' use of rapeseed oil-based cheese.
      CONCLUSIONS: The present study showed that the rapeseed oil-based cheese reduces
      serum total and LDL cholesterol concentrations in mildly to moderately
      hypercholesterolemic subjects when replacing ordinary milk-fat-based cheese in
      the diet. SPONSORSHIP: Mildola Ltd, Tuusula, Finland and Kyronmaan Juustomestarit
      Ltd, lsokyro, Finland.

PMID- 12428176
TI  - Boron supplementation and activated factor VII in healthy men.
AB  - OBJECTIVE: The aim of the present study was to determine whether postprandial
      concentrations of the active component of serine protease coagulation factor VII
      (VIIa) were lowered by acute boron supplementation in vivo. DESIGN: An acute,
      randomized, placebo-controlled, double blind, cross-over study. SETTING: Free
      living population. SUBJECTS: Fifteen apparently healthy men, aged 45-65 y.
      INTERVENTIONS: Subjects visited the centre on two occasions, with the study days
      separated by a minimum of 2 weeks. Following collection of a fasting blood
      sample, subjects received either placebo or acute bolus of 11.6 mg boron (given
      as 102.6 mg sodium tetraborate decahydrate) together with a standard fat-rich
      meal. Blood samples were obtained at 1, 2, 4 and 6 h after the administration of
      the test meal, during which time subjects were at liberty to consume deionized
      water only. Blood samples were assayed for concentrations of insulin, glucose,
      lipids and boron. Measurement of the concentration of activated factor VIIa and
      of factor VII antigen, and of the activity of coagulation factors VII, IX and X
      was also carried out. RESULTS: Plasma boron concentrations were significantly
      higher following consumption of the boron supplement compared with placebo
      (0.124+/-0.02 vs 0.008+/-0.01 mg/l; P< or =0.001). There was no significant
      effect of acute boron supplementation on plasma insulin and glucose concentration
      or on blood lipid or coagulation factor profile. Factor VIIa rose significantly
      following consumption of the high fat meal (1.05+/-0.07 vs 1.26+/-0.07; P< or
      =0.001), but this increase was not altered by boron supplementation. CONCLUSIONS:
      Results from this study suggest that acute boron supplementation (at 11.6 mg
      boron) does not alter the activity of factor VIIa following consumption of a high
      fat meal. SPONSORSHIP: This work was funded by Borax Europe Ltd.

PMID- 12428177
TI  - Anthropometric assessment of nutritional status in adolescent populations in
      humanitarian emergencies.
AB  - OBJECTIVE: To outline the difficulties and suggest potential solutions in
      anthropometric assessment of adolescents during humanitarian emergencies. DESIGN:
      Literature review. SETTING: Multiple settings in which the nutritional status of
      adolescents has been assessed using anthropometric measurements. SUBJECTS:
      Adolescents in multiple populations. INTERVENTIONS: None. RESULTS: The use of
      anthropometry may be more difficult in adolescents than in other age groups
      because anthropometric indices in normally nourished adolescents change with age
      and sexual development. Moreover, survey and reference populations may differ in
      the age at which certain pubertal landmarks are attained, requiring adjustment
      for differences between survey and reference populations. Adolescent populations
      may also differ by ethnicity in various body proportions that affect
      anthropometric indices. Adjustment may be required when the body proportions of
      adolescents in the reference population differ from those in the population
      assessed. CONCLUSIONS: Although no definitive recommendation can be made
      regarding which anthropometric indices are the most appropriate for adolescents,
      some revisions may improve current practices. Weight-for-height could be used for
      prepubertal adolescents and body mass index could be used for postpubertal
      adolescents. Because cut-off points are age-specific, age should be collected as
      accurately as possible for all adolescents measured during screening or survey
      activities. The WHO-recommended reference population of US adolescents is
      inappropriate in most populations of adolescents. Adolescents should never
      undergo nutritional assessment in isolation; other population subgroups should be
      included, and other health, nutrition and food data should be collected at the
      same time. SPONSORSHIP: The United Nations Administrative Committee on
      Coordination/Sub-Committee on Nutrition.

PMID- 12428178
TI  - Diet and nutritional status of rural adolescents in India.
AB  - OBJECTIVE: To study the current diet and nutritional status of rural adolescents
      in India. DESIGN: Cross-sectional study with household as the unit of
      randomization. SETTING: National Nutrition Monitoring Bureau collected
      information in the rural areas of the nine States. METHODS: In each State, 120
      villages were selected from eight districts. From each of the selected villages,
      20 households (HHs) were selected from five clusters. The information on socio
      demographic profile was collected in all the 20 HHs, while anthropometric data
      such as weight, height and clinical signs of nutritional deficiency was collected
      on all the available adolescents in the selected households. In every fourth
      sampled household, ie five HHs, dietary information on all the members was
      collected using 24 h dietary recall. The outcome measures for nutritional status
      were proportion of underweight (<median -2 s.d. of NCHS standards of weight for
      age), stunted (<median -2 s.d. of NCHS standards of height for age) and body mass
      index. The nutrient intakes were compared with recommended dietary allowances
      (RDA). RESULTS: Anthropometric and socio-economic information on 12 124
      adolescent boys and girls and dietary information on 2579 individuals in 1996
      1997 was available for the analysis. The major occupation of the heads of the
      households surveyed was agriculture. More than a third (37.3%) of the families
      with adolescents did not possess any land. The per capita income per month was
      about Rs 250/- at 1996-1997 prices. About 23% of the adolescent girls were
      married before the age of 18 y. About a quarter of the married adolescent girls
      had short stature and 18.6% were underweight. They considered as 'at risk'. About
      39% of the adolescents were stunted (<Median -2 s.d. of NCHS height for age)
      irrespective of sex. The prevalence of undernutrition (<median -2 s.d. of NCHS
      weight for age) is higher (53.1%) in boys than in girls (39.5%). The extent of
      stunting was higher (42.7%) among adolescents belonging to the scheduled caste
      community. In the case of girls, the extent of underweight was considerably less
      in each age group than their male counterparts. About 70% of adolescents consumed
      more than 70% of RDA for energy. The intakes of micronutrients such as vitamin A
      and riboflavin were woefully inadequate. CONCLUSIONS: The extent of
      undernutrition was high among adolescents and was higher among boys than girls.
      Adolescent girls in the rural areas could be at greater risk of nutritional
      stress because of early marriage and early conception before completion of their
      physical growth.

PMID- 12428179
TI  - Postsurgery enteral nutrition in head and neck cancer patients.
AB  - OBJECTIVE: Patients with head and neck cancer undergoing surgery have a high
      incidence of postoperative complications. The aim of our study was to investigate
      whether postoperative nutrition of head and neck cancer patients, using an
      arginine-enriched diet, could improve nutritional variables as well as clinical
      outcomes. DESIGN: Randomized clinical trial. SETTING: Tertiary care. SUBJECTS: A
      population of 47 patients with oral and laryngeal cancer were enrolled.
      INTERVENTIONS: At surgery patients were randomly allocated to two groups: (a)
      patients receiving an enteral diet supplemented with arginine and fiber (group
      I); (b) patients receiving an isocaloric, isonitrogenous enteral formula (group
      II). RESULTS: No significant intergroup differences in the trend of the three
      plasma proteins and lymphocytes were detected. Gastrointestinal tolerance
      (diarrhea) of both formulas was good (17.4% group I and 8.3% group II; NS).
      During the 3 months after hospital discharge five patients died; no differences
      were detected between groups (13% group I and 8.3% group II; NS). The incidences
      postoperative infection complications were similar (nine patients) in both groups
      (21.7% group I and 16.7% group II; NS). Fistula were less frequent in enriched
      nutrition group (0% group I and 20.8% group II; P<0.05); wound infection was more
      frequent in group II, but without statistical difference (4.3% group I and 12.5%
      group II; NS). The length of postoperative stay was 22.8+/-11.8 days in the
      enriched group and 31.2+/-19.1 days in the control group (P=0.07). CONCLUSIONS:
      In conclusion, enriched formula improves local wound complications in
      postoperative head and neck cancer patients. Our results suggest that these
      patients could benefit from an immunonutrient-enhanced enteral formula.

PMID- 12428180
TI  - Moderate alcohol consumption reduces plasma C-reactive protein and fibrinogen
      levels; a randomized, diet-controlled intervention study.
AB  - OBJECTIVE: To evaluate the effect of moderate alcohol consumption on the acute
      phase proteins C-reactive protein and fibrinogen. DESIGN: Randomized, diet
      controlled, cross-over study. SETTING: The study was performed at TNO Nutrition
      and Food Research, Zeist, The Netherlands. SUBJECTS: Ten middle-aged men and 10
      postmenopausal women, all apparently healthy, non-smoking and moderate alcohol
      drinkers, were included. One women dropped out because of a treatment-unrelated
      cause. The remaining 19 subjects finished the experiment successfully.
      INTERVENTIONS: Men consumed four glasses and women consumed three glasses of beer
      or no-alcohol beer (control) with evening dinner during two successive periods of
      3 weeks. The total diet was supplied to the subjects and had essentially the same
      composition during these 6 weeks. Before each treatment there was a 1 week
      washout period to compensate for possible carry-over effects. RESULTS: Plasma C
      reactive protein and fibrinogen levels were decreased by 35% (P=0.02) and 12.4%
      (P< or =0.001), respectively, after 3 weeks' consumption of beer, as compared to
      no-alcohol beer consumption. CONCLUSIONS: Moderate alcohol consumption
      significantly decreased plasma C-reactive protein and fibrinogen levels. An anti
      inflammatory action of alcohol may help explain the link between moderate alcohol
      consumption and lower cardiovascular disease risk. SPONSORSHIP: Dutch Foundation
      for Alcohol Research (SAR).

PMID- 12428181
TI  - Coenzyme Q10 improves blood pressure and glycaemic control: a controlled trial in
      subjects with type 2 diabetes.
AB  - OBJECTIVE: Our objective was to assess effects of dietary supplementation with
      coenzyme Q10 (CoQ) on blood pressure and glycaemic control in subjects with type
      2 diabetes, and to consider oxidative stress as a potential mechanism for any
      effects. SUBJECTS AND DESIGN: Seventy-four subjects with uncomplicated type 2
      diabetes and dyslipidaemia were involved in a randomised double blind placebo
      controlled 2x2 factorial intervention. SETTING: The study was performed at the
      University of Western Australia, Department of Medicine at Royal Perth Hospital,
      Australia. INTERVENTIONS: Subjects were randomly assigned to receive an oral dose
      of 100 mg CoQ twice daily (200 mg/day), 200 mg fenofibrate each morning, both or
      neither for 12 weeks. MAIN OUTCOME MEASURES: We report an analysis and discussion
      of the effects of CoQ on blood pressure, on long-term glycaemic control measured
      by glycated haemoglobin (HbA(1c)), and on oxidative stress assessed by
      measurement of plasma F2-isoprostanes. RESULTS: Fenofibrate did not alter blood
      pressure, HbA(1c), or plasma F2-isoprostanes. There was a 3-fold increase in
      plasma CoQ concentration (3.4+/-0.3 micro mol/l, P<0.001) as a result of CoQ
      supplementation. The main effect of CoQ was to significantly decrease systolic (
      6.1+/-2.6 mmHg, P=0.021) and diastolic (-2.9+/-1.4 mmHg, P=0.048) blood pressure
      and HbA(1c) (-0.37+/-0.17%, P=0.032). Plasma F2-isoprostane concentrations were
      not altered by CoQ (0.14+/-0.15 nmol/l, P=0.345). CONCLUSIONS: These results show
      that CoQ supplementation may improve blood pressure and long-term glycaemic
      control in subjects with type 2 diabetes, but these improvements were not
      associated with reduced oxidative stress, as assessed by F2-isoprostanes.
      SPONSORSHIP: This study was supported by a grant from the NH&MRC, Australia.

PMID- 12428182
TI  - Accuracy of an eight-point tactile-electrode impedance method in the assessment
      of total body water.
AB  - OBJECTIVE: To establish the accuracy of an eight-polar tactile-electrode
      impedance method in the assessment of total body water (TBW). DESIGN: Transversal
      study. SETTING: University department. SUBJECTS: Fifty healthy subjects (25 men
      and 25 women) with a mean (s.d.) age of 40 (12) y. METHODS: TBW measured by
      deuterium oxide dilution; resistance (R) of arms, trunk and legs measured at
      frequencies of 5, 50, 250 and 500 kHz with an eight-polar tactile-electrode
      impedance-meter (InBody 3.0, Biospace, Seoul, Korea). RESULTS: An algorithm for
      the prediction of TBW from the whole-body resistance index at 500 kHz (height
      (2)/R(500) where R is the sum of the segmental resistances of arms, trunk and
      legs) was developed in a randomly chosen subsample of 35 subjects. This algorithm
      had an adjusted coefficient of determination (r2(adj)) of 0.81 (P<0.0001) and a
      root mean square error (RMSE) of 3.6 l (9%). Cross-validation of the predictive
      algorithm in the remaining 15 subjects gave an r2(adj) of 0.87 (P<0.0001) and an
      RMSE of 3.0 l (8%). The precision of eight-polar BIA, determined by measuring R
      three times a day for five consecutive days in a fasting subject, was < or =2.8%
      for all segments and frequencies. CONCLUSION: Eight-polar BIA is a precise method
      that offers accurate estimates of TBW in healthy subjects. This promising method
      should undergo further studies of precision and its accuracy in assessing
      extracellular water and appendicular body composition should be determined.
      SPONSORSHIP: Modena and Reggio Emilia University.

PMID- 12428183
TI  - Identification and quantitation of major carotenoids in selected components of
      the Mediterranean diet: green leafy vegetables, figs and olive oil.
AB  - OBJECTIVE: To characterize the carotenoid content of selected components of the
      Mediterranean diet commonly eaten by Greek migrants to Melbourne, a population
      group maintaining a traditional dietary regimen, and who exhibit relatively high
      circulating carotenoid concentrations and low cardiovascular disease mortality.
      DESIGN AND SPECIMENS: Opportunistic sampling of wild (sow thistle, amaranth,
      purslane and dandelion, collected from roadsides and home gardens) and
      commercially available (chicory, endive) green leafy vegetables and figs in
      season. Foods were selected on the basis that they are commonly eaten by Greek
      migrants but not by Anglo-Celtic persons, and had not previously been well
      characterized with respect to their carotenoid contents. Extra virgin, cold
      pressed olive oil and 'extra light' olive oil were obtained from commercial
      sources. Specimens were extracted with tetrahydrofuran (or chloroform:methanol
      for olive oil) and carotenoid contents were quantified using HPLC with UV
      detection. Two to six specimens of greens and figs were analysed. Dietary intake
      was assessed by food frequency questionnaire. RESULTS: Wild green vegetables
      contained high concentrations of lutein (sow thistle>amaranth>purslane>dandelion)
      and beta-carotene (sow thistle>amaranth>purslane=dandelion). Sow thistle and
      amaranth contained lutein (15 and 13 mg/100 g, respectively) and beta-carotene
      (3.3 and 4.0 mg/100 g, respectively) at concentrations greater than that seen in
      the commercially available species of chicory and endive. Figs contained all
      major carotenoids appearing in plasma, albeit at low concentrations. Extra virgin
      cold-pressed olive oil contained substantial quantities of lutein and beta
      carotene, but the more-refined 'extra light' olive oil did not. CONCLUSIONS:
      These components of the traditional Mediterranean diet contribute to the higher
      circulating concentrations of carotenoids in Greek migrants compared to Anglo
      Celtic Australians. SPONSORSHIP: This study largely funded by the National Health
      and Medical Research Council of Australia (grant no. 974098). Extra virgin olive
      oil donated by Picuba Foods, Marrickville, NSW, Australia.

PMID- 12428184
TI  - The two faces of medical evidence.
AB  - The dictionary definition of "evidence" is given. The meaning of evidence in the
      history of science is described. Clinical examples are presented to illustrate
      different aspects of evidence, i.e. the mechanistic versus the semiotic points of
      view. Evidence is explained in the light of constructivism, and suggestions are
      presented as to how evidence can be applied in a biopsychosocial model of
      medicine.

PMID- 12428185
TI  - Genetics of familial cardiomyopathies and arrhythmias.
AB  - Molecular cardiology has become an important tool in understanding the aetiology,
      pathogenesis and development of familial cardiomyopathies and arrhythmias. The
      knowledge of genotype-phenotype correlations in certain pathologies has changed
      the concepts of therapy. In monogenic diseases, genetic testing offers a new
      complementary diagnostic approach. A genetic test can be used to confirm a
      clinically determined diagnosis, predict prognosis in a clinically affected
      patient, or provide options for therapy in patients and in clinically unaffected
      relatives of a patient with the disease producing mutation. In pure forms of
      familial hypertrophic cardiomyopathy mutations in several genes coding for
      sarcomeric proteins have been identified, indicating wide locus heterogeneity.
      Various disease genes are implicated in familial dilated cardiomyopathy in the
      pure form or in combination with other diseases. In the long QT syndrome and
      Brugada syndrome, mutations in ion channel genes can cause the disease; one of
      those genes is also implicated in progressive cardiac conduction defect. In other
      familial diseases like the arrhythmogenic right ventricular cardiomyopathy,
      anyone of the numerous chromosomal loci can be involved, but only one gene has
      been identified so far. The same gene is also involved in catecholaminergic
      polymorphic ventricular tachycardia. From genotype-phenotype studies,
      correlations between gene-mutations and the clinical course of the disease have
      become clear. As only a few families with the same mutations have been studied,
      data have to be considered as preliminary and any conclusion must be regarded as
      tentative. This emphasizes the need to study genotype-phenotype correlations in a
      large number of families.

PMID- 12428186
TI  - Cytokines that regulate autoimmune myocarditis.
AB  - A growing body of evidence suggests that autoimmune responses are involved in the
      pathogenesis of myocarditis and postinfectious cardiomyopathy. Autoimmunity may
      also arise after ischaemic or traumatic damage to heart tissue. Myocarditis
      leading to heart failure can be mimicked in rodents by immunisation with cardiac
      alpha myosin and peptides derived from it. Cytokines and chemokines, produced
      mainly by T-cells and antigen-presenting cells, control immune responses by
      acting as either potentiating or inhibitory agents. Gene targeting and
      experiments with antibodies and/or antagonists blocking cytokines and their
      receptors have uncovered mechanisms whereby such regulatory molecules are
      involved in the pathogenesis of myocarditis. Identification of regulatory key
      cytokines and the associated pro- or anti-inflammatory pathways involved in the
      pathogenesis of cardiac inflammation may have important implications for
      therapeutic strategies and vaccine design in the future.

PMID- 12428187
TI  - Inhibition of the TNF-pathway: use of infliximab and etanercept as remission
      inducing agents in cases of therapy-resistant chronic inflammatory disorders.
AB  - OBJECTIVE: To examine the potential of the two tumour necrosis factor (TNF)
      inhibitors infliximab and etanercept as remission-inducing agents in chronic
      therapy-resistant inflammatory disorders of immune or non-immune pathogenesis.
      METHODS: 14 patients with adult Still's disease/macrophage activation syndrome
      (4), Wegener's disease (3), Behcet's disease (3), keratoscleritis (1),
      lymphomatous tracheo-bronchitis (1) Cogan's syndrome (1), and rapidly destructive
      crystal arthropathy (1) were treated with infliximab (n = 10) and etanercept (n =
      4). All patients showed organ-threatening progression of their diseases with
      resistance to conventional immunosuppressive medication. Therapeutic benefit was
      assessed clinically and by documenting organ-specific functional and
      morphological alterations. Side effects were compared with the data of our
      clinic's rheumatoid arthritis (RA) patients treated by TNF inhibitors. RESULTS: A
      rapid and dramatic beneficial effect was documented in 9 patients and a moderate
      one in 5. Best responses (clinical and laboratory parameters) were seen in
      patients with macrophage activation syndrome/adult Still's disease and Behcet's
      disease, while the results were less impressive in those with Wegener's disease,
      Cogan's syndrome, idiopathic cerato-scleritis and lymphomatous tracheobronchitis.
      In all cases immunosuppressive agents and systemic glucocorticoids could be
      reduced or discontinued. CONCLUSIONS: TNF inhibition may be highly effective in
      patients with severe, therapy-resistant chronic inflammatory disorders.

PMID- 12428188
TI  - Remote control of pulmonary blood flow: a dream comes true.
AB  - The indication for pulmonary artery banding is currently limited by several
      factors. Previous attempts have failed to produce adjustable pulmonary artery
      banding with reliable external regulation. An implantable, telemetrically
      controlled, battery-free device (FloWatch) developed by EndoArt SA, a medical
      company established in Lausanne, Switzerland, for externally adjustable pulmonary
      artery banding was evaluated on minipigs and proved to be effective for up to 6
      months. The first human implant was performed on a girl with complete
      atrioventricular septal defect with unbalanced ventricles, large patent ductus
      arteriosus and pulmonary hypertension. At one month of age she underwent closure
      of the patent ductus arteriosus and FloWatch implantation around the pulmonary
      artery through conventional left thoracotomy. The surgical procedure was rapid
      and uneventful. During the entire postoperative period bedside adjustments
      (narrowing or release of pulmonary artery banding with echocardiographic
      assessment) were repeatedly required to maintain an adequate pressure gradient.
      The early clinical results demonstrated the clinical benefits of unlimited
      external telemetric adjustments. The next step will be a multi-centre clinical
      trial to confirm the early results and adapt therapeutic strategies to this
      promising technology.

PMID- 12428189
TI  - Dexamethasone/phenytoin interactions: neurooncological concerns.

PMID- 12428190
TI  - Evidence for prevention and screening: recommendations in adults.
AB  - A growing body of evidence supports preventive interventions in asymptomatic
      adults. Primary prevention, which includes counselling (in particular for smoking
      cessation) and review of immunisation status, has been shown to be more cost
      effective than secondary prevention. Evidence supports screening for
      hypertension, hyperlipidaemia, cervical cancer, colorectal cancer, breast cancer
      and obesity. Screening for lung, pancreatic and ovarian cancer has no effect on
      outcome and should not be performed. Controversial preventive interventions
      include general screening for diabetes mellitus, thyroid disorders and prostate
      cancer. Physicians should be aware of a possible hidden agenda in patients
      presenting for a checkup.

PMID- 12428191
TI  - Management of viral infections in immunocompromised cancer patients.
AB  - Immunocompromised cancer patients are at elevated risk for serious viral disease.
      The introduction into clinical use of potent antiviral agents and of rapid
      diagnostic tests resulted in the development of efficient management strategies
      for infections due to herpes simplex virus, varicellazoster virus, and
      cytomegalovirus. The emergence of herpesvirus resistance to acyclovir,
      ganciclovir, cidofovir, or foscarnet represents an important challenge. The new
      neuraminidase inhibitors zanamivir and oseltamivir are efficacious in the
      treatment of influenza in otherwise healthy adults, and need to be investigated
      among immunodeficient patients with malignancy. Preliminary data on pleconaril, a
      first broad-spectrum anti-picornaviral compound, are promising.

PMID- 12428192
TI  - Monotoring adherence to prescribed medication in type 2 diabetic patients treated
      with sulfonylureas.
AB  - BACKGROUND: Data on adherence to prescribed medication amongst diabetics are
      scarce. The purpose of this study was to collect information about the dynamics
      and patterns of compliance of elderly patients with type 2 diabetes mellitus on
      oral treatment by using different assessment techniques. METHODS: Adherence to
      prescribed sulfonylurea medication was prospectively assessed by Self-report
      (Sr), Pill count (Pc) and using a Medication Event Monitoring System (MEMS) over
      a period of 2 months in 19 elderly patients with type 2 diabetes mellitus. A
      pressure-activated microprocessor allowing the registration of each opening is
      located in the cap of the MEMS drug container. MEMS dosage adherence (MEMSd) was
      defined as the number of bottle openings divided by the number of doses
      prescribed), and MEMS regimen adherence (MEMSr) was defined as the percentage of
      days in which the dose regimen was taken as prescribed. RESULTS: Adherence rates
      were 96.8 +/- 19.6% for Pc, 92.6 +/- 19.9% for MEMSd and 78.6 +/- 28.3% for
      MEMSr. Adherence rates for Pc were 103.8 +/- 10.9% in once daily regimens and
      87.3 +/- 25.2% in bid/tid regimens (p = 0.0686). MEMSd was 101.0 +/- 4.8% in once
      daily regimens versus 81.0% +/- 26.8% in bid/tid regimens (p = 0.0255). MEMSr was
      93.6 +/- 5.7% in once daily regimens versus only 57.8 +/- 34.1% in bid/tid
      regimens (p = 0.0031). Assessed by MEMSd as many as 42.1% of the participants had
      adherence rates greater than 100%. Over-compliance was found primarily in once
      daily regimens. CONCLUSION: Adherence rates varied with different assessment
      techniques. Adherence rates were far from optimal. Once daily dosage led to
      significantly better adherence rates than two or three times daily regimens.
      However, over-compliance was surprisingly high and occurred more frequently on a
      once daily regimen.

PMID- 12428193
TI  - Septic deep venous thrombosis in intravenous drug users.
AB  - OBJECTIVE: To review diagnostic and therapeutic experience in seven patients with
      septic deep vein thrombosis (DVT) after intravenous use of illicit drugs.
      METHODS: Retrospective review of medical records and prospective data collection
      in intravenous drug users (IVDU) who presented with a confirmed diagnosis of DVT
      and sepsis during a period of 18 months in a single institution. RESULTS: Of
      seven long-term IVDU (age 24-40 years), who had repeatedly attempted venous
      access to proximal veins, five had femoral DVT and one each jugular and brachial
      DVT. All DVT were confirmed by contrast-enhanced helical CT or ultrasonography.
      Median C-reactive protein (CRP) was 215 mg/l (range 76-386). Multiple blood
      cultures grew Gram-positive bacteria in 7 of 8 patients, chiefly Staphylococcus
      aureus, confirming an intravascular infection with continuous bacteraemia.
      Therapy consisted of intravenous b-lactamase-resistant penicillin until
      normalisation of CRP (3-4 weeks), initially combined with an aminoglycoside for a
      few days. The mean defervescence time was 7.4 days (range 3-12). All patients
      were given intravenous heparin overlapping with oral anticoagulation without
      major side effects. Surgical exploration of the venous vasculature was never
      necessary. Mean hospital stay was 25.7 days (range 10-47). CONCLUSION: Septic DVT
      in IVDU is a potentially life-threatening disorder that may become more frequent
      as the number of long-term IVDU increases. Helical CT or colour-coded Doppler
      ultrasound is the confirmatory imaging procedure of choice. Empirical antibiotic
      therapy should include a ss-lactamase-resistant penicillin since S. aureus is the
      most common pathogen isolated. Anticoagulation can be safely initiated once the
      diagnosis of DVT is confirmed. Surgery is necessary only in rare instances of
      septic DVT.

PMID- 12428196
TI  - Molecular genetics of sex determination.
AB  - In humans, the choice between male or female development is genetically
      determined. Sex determination take place when the bipotential embryonic gonad
      becomes either testis or ovary. This process is directed by genes that have been
      discovered by genetic analysis of sex-reversed patients and confirmed by knockout
      experiments in mice. The testis-determining pathway is better known than the
      ovary pathway. SRY, a gene located on the Y chromosome, triggers a complex
      genetic cascade leading to testicular differentiation. In this cascade, two genes
      play a crucial role in male differentiation, SOX9 and FGF9, which contribute to
      testicular cord formation. However, only a minority of 46,XY sex-reversed
      patients can be explained by mutations in known genes such as SRY, SOX9, WTI, and
      SF1, suggesting that other genes influencing sex determination are yet to be
      discovered. In females, some rare genes that induce ovarian failure or female-to
      male sex reversal have been found through gene-targeted inactivation in mice or
      positional cloning of mutations in humans and goats. In both sexes, genetic
      analysis of sex-reversed individuals (XX males, XX and XY hermaphrodites, and XY
      with complete or partial dysgenesis) remains an approach of choice to isolate new
      genes involved in sex determination.

PMID- 12428197
TI  - Molecular endocrinology of sex differentiation.
AB  - Differentiation of a testis or an ovary from a bipotential gonad is a complex
      developmental process involving various genes and hormones. Similarly, internal
      and external genital organs develop from an indeterminate stage from the complex
      differentiation of Wolffian and Mullerian ducts. Differentiation of the Wolffian
      ducts, urogenital sinus, and external genitalia is androgen dependent. Female sex
      differentiation appears to be a more passive process that is independent of
      estrogen. This article reviews the process of differentiation of the gonads and
      the genitalia and the factors affecting it. In addition, a clinical approach to
      patients with sexual ambiguity or sex reversal is discussed.

PMID- 12428198
TI  - Ambiguous genitalia in the newborn.
AB  - Ambiguous genitalia in the newborn need immediate and rational management. This
      complex situation requires a strategy of clinical, hormonal, genetic, molecular,
      and radiographic investigation to determine the etiology of the intersex state
      and orient the therapeutic approach. Physical examination is key to diagnosis.
      Careful palpation to locate gonads at the genital folds or in the inguinal region
      provides the first element for diagnostic orientation. If gonads are absent, a
      diagnosis of female pseudohermaphroditism seems advisable; if gonads are
      palpated, a diagnosis of male pseudohermaphroditism is more appropriate.
      Karyotyping is systematic while polymerase chain reaction (PCR) analysis of the
      SRY gene provides information about the presence of a Y chromosome within 1 day.
      Hormonal investigation should be based on clinical and genetic orientation.
      Substantially elevated plasma 17-OH progesterone will confirm the diagnosis of
      congenital adrenal hyperplasia due to deficiency in 21-hydroxylase. Testicular
      stimulation with human chorionic gonadotropin (hCG) will determine the functional
      value of testicular tissue. Exploration of the genitourinary axis is principally
      carried out by ultrasound and genitography. By the end of these investigations,
      the medical team should be able to give a precise diagnosis. Female
      pseudohermaphroditism may be due to excess fetal androgens (congenital adrenal
      hyperplasia), increased androgen production of maternal origin, or placental
      androgen excess. In male pseudohermaphroditism, if testosterone rises normally
      after hCG stimulation, androgen resistance is indicated. If it does not rise
      after this test, either testicular dysgenesis or disturbance in testosterone
      biosynthesis may be responsible. The assignment of sex for rearing must be guided
      by the etiology of the genital malformation, the anatomic condition, and family
      considerations. In cases of female pseudohermaphroditism, the newborn should
      always be declared to be of female sex at birth. In cases of male
      pseudohermaphroditism, great care should be taken in the declaration of male sex:
      the potential for reconstructive surgery and the pubertal "programmed" response
      of the external genitalia to endogenous and exogenous testosterone are
      determinant. Management of ambiguous genitalia in the newborn requires an entire
      multidisciplinary team in every step of the diagnostic procedure, the choice of
      sex assignment, and the treatment strategy.

PMID- 12428199
TI  - Disorders of gonadal development.
AB  - The molecular mechanisms of gonadal development are a complex process, which
      involves the tightly regulated differentiation of a bipotential embryonic gonad
      into either testes or ovary. Once this has occurred, the phenotypic and gonadal
      sex of an individual has been genetically determined. This process, however, may
      not always be so straightforward. By studying individuals who are sex reversed or
      who have ambiguous genitalia, the discovery of the handful of sex-determining
      genes that we know of today was made possible. It was not until recently that the
      transcription factors SRY, DAX1, SOX9, SF-1, and WT1 were recognized to be
      involved in gonadal development. Dissecting the molecular pathway of mammalian
      sex determination will be crucial in understanding the development of the gonads
      and the pathophysiology of human disorders of sex determination.

PMID- 12428200
TI  - LH receptor defects.
AB  - In this article the role of LH receptor gene mutations in patients with aberrant
      sex differentiation is discussed. In a dominant autosomal familial form of
      precocious puberty in boys (familial male-limited precocious puberty) LH receptor
      gene mutations have been identified. These single amino acid changes, mostly
      found in the sixth transmembrane helix and the third intracellular loop of the
      transmembrane domain of the LH receptor, cause constitutive activation of LH
      receptor protein without the hormone present, resulting in precocious production
      of testosterone by the testicular Leydig cells. The large number of activating LH
      receptor mutations have allowed more precise molecular modeling of the LH
      receptor protein. In a rare hereditary form of 46,XY male pseudohermaphroditism
      known as Leydig cell hypoplasia, LH receptor gene mutations have been identified
      that completely or partially inactivate the LH receptor protein. Large gene
      deletions cause complete absence of the LH receptor protein, whereas other, more
      subtle missense mutations prevent the receptor from assuming an active
      conformation.

PMID- 12428201
TI  - Disorders of androgen biosynthesis.
AB  - Disorders of androgen biosynthesis are a relatively rare cause of sexual
      ambiguity in 46,XY genetic males, but genetic disorders characterized by
      excessive androgen synthesis are a common cause of virilization in 46,XX genetic
      females. Understanding of these disorders is relatively simple if one is familiar
      with the components of the various steroidogenic pathways. The biosynthesis of
      androgens requires the steroidogenic acute regulatory protein (StAR) and the
      steroidogenic enzymes P450scc, P450c17, 3betaHSDII, 17betaHSDIII, and 5alpha
      reductase. Deficiencies have been described in all of these, leading to male
      pseudohermaphroditism. Other steroidogenic enzymes not involved in androgen
      biosynthesis, such as P450c21, P450c11beta, and P450aro, must also be considered,
      as mutations in these can result in overproduction of androgens, resulting in
      female pseudohermaphroditism.

PMID- 12428202
TI  - Disorders of androgen action.
AB  - Disorders of androgen action are the main cause of male pseudohermaphroditism and
      include 5alphaR deficiency and androgen receptor defects. 5alphaR deficiency is
      characterized by female genitalia with some degree of masculinization,
      clitoromegaly, and severely bifid scrotum corresponding to the so-called
      pseudovaginal perineoscrotal hypospadias. At the onset of puberty, increased
      muscle mass, development of pubic hair, and phallic growth are associated with
      the acquisition of male gender identity. Normal or increased levels of
      testosterone and an elevated testosterone-to-dihydrotestosterone ratio after
      human chorionic gonadotropin stimulation testing suggest 5alphareductase
      deficiency, and the diagnosis can be ascertained by identifying the mutation in
      the 5alphaR-2 gene. Whatever the patient's age at diagnosis, psychological
      evaluation with 5alphaRD is vital. Androgen receptor defects encompass two
      clinical expressions: the complete and partial androgen insensitivity syndromes.
      Complete androgen insensitivity syndrome should be suspected at birth in the
      presence of inguinal hernia in a girl without genital ambiguity. At puberty, the
      sign of alert is primary amenorrhea with normal female phenotype and harmonious
      mammary development but no pubic hair growth. Partial androgen insensitivity
      syndrome covers a wide spectrum of undervirilized phenotypes ranging from
      clitoromegaly at birth to infertile men. In all cases, complementary
      investigations should include plasma testosterone and luteinizing hormone as well
      as androgen-binding capacity in cultured genital skin fibroblasts. Diagnosis is
      confirmed by identification of the androgen receptor gene mutation. Although
      patients with complete androgen insensitivity syndrome are raised as females,
      patients with partial androgen insensitivity syndrome should be managed according
      to age at diagnosis, response to treatment with exogenous androgens, and the
      presence of an androgen gene mutation. Gonadectomy in complete androgen
      insensitivity syndrome should be performed before puberty, and androgen
      substitution may improve the development of external genitalia in some patients
      with partial androgen insensitivity syndrome. Psychological follow-up is
      necessary.

PMID- 12428203
TI  - Congenital adrenal hyperplasia: 21-hydroxylase deficiency in the newborn and
      during infancy.
AB  - Congenital adrenal hyperplasia is a family of monogenic autosomal recessive
      disorders of steroidogenesis with protean clinical manifestations. The commonest
      form, 21-hydroxylase deficiency, is the most frequent cause of ambiguous
      genitalia in the newborn. The molecular features associated with abnormalities in
      the CYP21 gene are well characterized in relation to phenotypic manifestations.
      The concordance between genotype and phenotype is sufficiently robust as to be
      relevant and useful in planning treatment strategies. Thus, the dose of
      glucocorticoid replacement in the early years of life can be tailored according
      to the predicted degree of 21-hydroxylase enzyme deficiency in the anticipation
      that this may avoid hitherto excessive steroid replacement during the critical
      early years of growth and development. The means to prevent genital virilization
      in affected females is clearly demonstrated by the success of early dexamethasone
      administration to pregnant mothers at risk. Short-term outcome studies of
      children exposed to dexamethasone in utero indicate no significant adverse
      effects. Nevertheless, it is recommended that prenatal treatment programs to
      prevent a major congenital malformation of the urogenital system be conducted
      only as part of agreed national multicenter studies, which include a commitment
      to long-term outcome analyses.

PMID- 12428204
TI  - Nonclassic 21-hydroxylase deficiency.
AB  - The nonclassic form of adrenal hyperplasia (NCAH) has been increasingly
      recognized in adolescent or adult hyperandrogenic patients. It is now widely
      accepted that neither the clinical presentation nor the androgen plasma levels
      can be used for the screening or diagnosis of NCAH in hyperandrogenic women,
      especially those presenting with a phenotype like that in polycystic ovary
      syndrome. Therefore, the measurement of a follicular morning level of serum 17
      hydroxyprogesterone (17-HP) should be included in the initial investigation of
      all hyperandrogenic women, including those with premature pubarche. Levels of 17
      HP lower than 2 ng/mL (6.0 nmol/L) and greater than 4 ng/mL (12.0 nmol/L) have
      good predictive negative and positive values, respectively. The
      adrenocorticotropic hormone test is useful only when the morning follicular
      unsuppressed 17-HP level falls between 2 and 4 ng/mL (6 to 12 nmol/L). Adrenal
      insufficiency and adrenal hyperplasia are more theoretical than real
      complications of NCAH. On the other hand, the polycystic ovary syndrome and
      infertility are frequently associated with NCAH. For the treatment of
      hyperandrogenism, the conventional treatment by glucocorticoid therapy is
      challenged by cyproterone acetate, but it is still indicated when patients wish a
      pregnancy. It can be questioned whether the low risk of virilized female newborns
      in untreated women with NCAH justifies prenatal diagnosis and treatment.

PMID- 12428205
TI  - Congenital adrenal hyperplasia: 11beta-hydroxylase deficiency.
AB  - The most potent corticosteroids are 11beta-hydroxylated compounds. In humans, two
      cytochrome P450 isoenzymes with 11beta-hydroxylase activity, catalyzing the
      biosynthesis of cortisol and aldosterone, are present in the adrenal cortex.
      CYP11B1, the gene encoding 11beta-hydroxylase (P450c11), is expressed in high
      levels in the zona fasciculata and is regulated by adrenocorticotropic hormone
      (ACTH). CYP11B2, the gene encoding aldosterone synthase (P450c11Aldo), is
      expressed in the zona glomerulosa under primary control of the renin-angiotensin
      system. The substrate for P450c11 is 11-deoxycortisol. Mutations in CYP11B1 cause
      congenital adrenal hyperplasia (CAH) due to 11beta-hydroxylase deficiency. This
      disorder is characterized by androgen excess and hypertension and is autosomal
      recessively inherited. Classical and nonclassical forms of 11beta-hydroxylase
      deficiency can be distinguished. Studies in heterozygotes for classical 11beta
      hydroxylase deficiency show inconsistent results with no or only mild hormonal
      abnormalities (elevated plasma levels of 11-deoxycortisol after ACTH
      stimulation). Molecular genetic studies of the CYP11B1 gene in 11beta-hydroxylase
      deficiency have led to the identification of several mutations. Transfection
      experiments showed loss of enzyme activity in vitro. Molecular genetic studies
      have practical importance for the prenatal diagnosis of virilizing CAH forms.

PMID- 12428206
TI  - Congenital adrenal hyperplasia due to 3beta-hydroxysteroid dehydrogenase/Delta(5)
      Delta(4) isomerase deficiency.
AB  - The 3beta-hydroxysteroid dehydrogenase/Delta(5)-Delta(4)isomerase (3beta-HSD)
      isoenzymes are responsible for the oxidation and isomerization of Delta(5)-3beta
      hydroxysteroid precursors into Delta(4)-ketosteroids, thus catalyzing an
      essential step in the formation of all classes of active steroid hormones. The
      3beta-HSD gene family should have evolved to facilitate differential patterns of
      tissue- and cell-specific expression and regulation involving multiple signal
      transduction pathways, which are activated by several growth factors, steroids,
      and cytokines. In humans, there are two 3beta-HSD isoenzymes, which were
      chronologically designated type I and II encoded by HSD3B1 and HSD3B2 gene,
      respectively. HSD3B1 gene encodes the almost exclusive 3beta-HSD isoenzyme
      expressed in the placenta and peripheral tissues, whereas HSD3B2 gene encodes the
      predominant 3beta-HSD isoenzyme expressed in the adrenal gland, ovary, and testis
      and its deficiency is responsible for a rare form of congenital adrenal
      hyperplasia causing various degrees of salt-wasting in both sexes and incomplete
      masculinization of the external genitalia in genetic males. Although an elevated
      ratio of Delta(5)-Delta(4)-steroids was considered to be the best biological
      parameter for the diagnosis of this autosomal recessive disorder, the most
      accurate criteria now appears to be the plasma levels of 17-OH-pregnenolone
      greater than 100 nmol/L following ACTH stimulation. To date a total of 34
      mutations (including 5 frameshift, 4 nonsense, 1 in-frame deletion, 1 splicing,
      and 23 missense mutations) have been identified in the HSD3B2 gene in 56
      individuals from 44 families suffering from classical 3beta-HSD deficiency. In
      almost all the cases, the functional characterization of HSD3B2 mutations has
      provided a molecular explanation for the heterogeneous clinical presentation of
      this disorder. Indeed these experiments confirm that no functional 3betaHSD type
      II isoenzyme is expressed in the adrenals and gonads of the patients suffering
      from a severe salt-wasting form, whereas the non-salt-losing form results from
      specific missense mutation(s) in the HSD3B2 gene, which causes an incomplete loss
      of enzymatic activity thus leaving sufficient enzymatic activity to prevent salt
      wasting. Moreover, various mutations appear to have a drastic effect upon
      stability of the protein, therefore providing molecular evidence of a new
      mechanism involved in classical 3beta-HSD deficiency. Thus, the elucidation of
      the molecular basis of 3beta-HSD deficiency has highlighted the fact that
      mutations in the HSD3B2 gene can result in a wide spectrum of molecular
      repercussions, which are associated with the different phenotypic manifestations
      of classical 3beta-HSD deficiency and also provide valuable information
      concerning the structure-function relationships of the 3beta-HSD superfamily.

PMID- 12428207
TI  - The essential role of the aromatase/p450arom.
AB  - Aromatase (P450arom) catalyzes the conversion of testosterone to estradiol,
      androstenedione to estrone, and 16a-hydroxylated dehydroepiandrosterone to
      estriol. P450arom is encoded by the human CYP19 gene (15q21.1) spanning about 123
      kb with a coding region of 9 exons (about 30 kb, exon II to exon X). Although
      there are a number of alternative first exons and nine different transcriptional
      start sides with individual promoters that permit tissue-specific regulation of
      expression, the protein expressed in these various tissue sites (placenta,
      adipose tissue, brain, bone, ovary, etc.) always remains the same. As not only
      androgens but also estrogens are of importance particularly in male pubertal
      development including bone changes, which were classically considered androgen
      dependent, the features of the aromatase deficiency syndrome in affected boys and
      girls as well as adult males and females are discussed. There is growing
      awareness that androgens and estrogens have general metabolic roles that reach
      far beyond reproductive processes. For instance, estrogen has a significant
      impact on carbohydrate and lipid metabolism, vascular function, and
      arteriosclerosis. In addition, extragonadal estrogen biosynthesis plays an
      important but often underestimated physiological and pathophysiological role, for
      example, in breast cancer and endometriosis. Based on that knowledge, progress
      has been made as far as treatment and follow-up of this disorder are concerned.

PMID- 12428208
TI  - Psychological consequences.
AB  - Sex assignment of children born with ambiguous genitalia is a difficult and
      responsible decision based on limited empirical evidence regarding future
      development of gender identity/role, sexual orientation, and sexual functioning.
      Sex of assignment and rearing has appeared to be a prognosticator of future
      gender identity, usually better than the other criteria of sex (chromosomes,
      gonadal tissue, prenatal and postnatal hormonal profiles). The decision to assign
      a sex is guided by the prognosis of the "optimal" sex for the newborn, of which
      the elements are an overall sex-appropriate appearance with a stable gender
      identity; good sexual function, preferably combined with reproductive function if
      attainable; minimal medical procedures; and a reasonably happy life given the
      limitations. The limited follow-up studies indicate that this is a reasonable
      policy, although a limited number of subjects will experience gender dysphoria
      later in life and will cross over to the other sex. This is more often the case
      in subjects assigned to the female sex with considerable prenatal or postnatal
      androgen exposure. Children in this predicament must receive guidance well into
      adulthood. It may be difficult to engage in sexual relations when the anatomy of
      the genitalia (often operated upon) is not fully normal.

PMID- 12428209
TI  - Long-term perspectives for 46,XY patients affected by complete androgen
      insensitivity syndrome or congenital micropenis.
AB  - Controversy concerning optimal treatment for individuals affected by syndromes of
      abnormal sex differentiation can best be resolved with knowledge about long-term
      medical, surgical, and psychosexual outcomes of patients. Follow-up information
      has recently been gathered on older cohorts of the following patient groups: (1)
      those affected by complete androgen insensitivity syndrome (CAIS) raised female
      and (2) those affected by congenital micropenis raised male or female. As a
      group, women with CAIS were satisfied with their female gender and sexual
      function. However, a need for better patient education was identified for this
      specific population. Most patients with congenital micropenis, whether raised
      male or female, were satisfied with their gender. Regardless of sex of rearing,
      dissatisfaction with the appearance and function of the genitalia as judged by
      both physicians and subjects was evident. For patients with congenital
      micropenis, male sex of rearing was concluded to be optimal because genital
      reconstructive surgery is not required with this choice.

PMID- 12428210
TI  - Environmental endocrine disrupters and disorders of sexual differentiation.
AB  - Endocrine disrupters are exogenous substances that cause adverse effects in the
      endocrine system. Sexual differentiation is regulated by reproductive hormones.
      Male differentiation is critically dependent on normal androgen action, which in
      turn depends on normal production of luteinizing hormone. Other essential
      hormones include follicle-stimulating hormone, anti-Mullerian hormone, and
      insulin-like hormone 3 (insl-3). Estrogens influence transcription of insl-3 and
      affect sexual differentiation both directly and indirectly. Diethylstilbestrol is
      the best known endocrine disrupter and has caused abnormalities of sexual
      differentiation in both exposed male and female human fetuses. There is a growing
      group of chemicals that have weak estrogenic properties, but, in addition, there
      are several antiandrogenic compounds that have been shown to disturb sexual
      differentiation in experimental animals. It is a challenge for endocrinologists
      to find out whether or not these chemicals or mixtures of them are involved in
      any of the abnormalities of human sexual differentiation.

PMID- 12428211
TI  - The deficiency of PIP2 5-phosphatase in Lowe syndrome affects actin
      polymerization.
AB  - Lowe syndrome is a rare X-linked disorder characterized by bilateral congenital
      cataracts, renal Fanconi syndrome, and mental retardation. Lowe syndrome results
      from mutations in the OCRL1 gene, which encodes a phosphatidylinositol 4,5
      bisphosphate 5-phosphatase located in the trans-Golgi network. As a first step in
      identifying the link between ocrl1 deficiency and the clinical disorder, we have
      identified a reproducible cellular abnormality of the actin cytoskeleton in
      fibroblasts from patients with Lowe syndrome. The cellular abnormality is
      characterized by a decrease in long actin stress fibers, enhanced sensitivity to
      actin depolymerizing agents, and an increase in punctate F-actin staining in a
      distinctly anomalous distribution in the center of the cell. We also demonstrate
      an abnormal distribution of two actin-binding proteins, gelsolin and alpha
      actinin, proteins regulated by both PIP(2) and Ca(+2) that would be expected to
      be altered in Lowe cells. Actin polymerization plays a key role in the formation,
      maintenance, and proper function of tight junctions and adherens junctions, which
      have been demonstrated to be critical in renal proximal tubule function, and in
      the differentiation of the lens. These findings point to a general mechanism to
      explain how this PIP(2) 5-phosphatase deficiency might produce the Lowe syndrome
      phenotype.

PMID- 12428212
TI  - Transcription factor SOX3 is involved in X-linked mental retardation with growth
      hormone deficiency.
AB  - Physical mapping of the breakpoints of a pericentric inversion of the X
      chromosome (46,X,inv[X][p21q27]) in a female patient with mild mental retardation
      revealed localization of the Xp breakpoint in the IL1RAPL gene at Xp21.3 and the
      Xq breakpoint near the SOX3 gene (SRY [sex determining region Y]-box 3) (GenBank
      accession number NM_005634) at Xq26.3. Because carrier females with microdeletion
      in the IL1RAPL gene do not present any abnormal phenotype, we focused on the Xq
      breakpoint. However, we were unable to confirm the involvement of SOX3 in the
      mental retardation in this female patient. To validate SOX3 as an X-linked mental
      retardation (XLMR) gene, we performed mutation analyses in families with XLMR
      whose causative gene mapped to Xq26-q27. We show here that the SOX3 gene is
      involved in a large family in which affected individuals have mental retardation
      and growth hormone deficiency. The mutation results in an in-frame duplication of
      33 bp encoding for 11 alanines in a polyalanine tract of the SOX3 gene. The
      expression pattern during neural and pituitary development suggests that
      dysfunction of the SOX3 protein caused by the polyalanine expansion might disturb
      transcription pathways and the regulation of genes involved in cellular processes
      and functions required for cognitive and pituitary development.

PMID- 12428215
TI  - The elderly hypertensive population: what lies ahead of us?

PMID- 12428216
TI  - Specific aspects of high blood pressure in the elderly.

PMID- 12428213
TI  - myotilin Mutation found in second pedigree with LGMD1A.
AB  - Limb-girdle muscular dystrophy 1A (LGMD1A [MIM 159000]) is an autosomal dominant
      form of muscular dystrophy characterized by adult onset of proximal weakness
      progressing to distal muscle weakness. We have reported elsewhere a mutation in
      the myotilin gene in a large, North American family of German descent. Here, we
      report the mutation screening of an additional 86 families with a variety of
      neuromuscular pathologies. We have identified a new myotilin mutation in an
      Argentinian pedigree with LGMD1 that is predicted to result in the conversion of
      serine 55 to phenylalanine (S55F). This mutation has not been found in 392
      control chromosomes and is located in the unique N-terminal domain of myotilin,
      only two residues from the T57I mutation reported elsewhere. Both T57I and S55F
      are located outside the alpha-actinin and gamma-filamin binding sites within
      myotilin. The identification of two independent pedigrees with the same disease,
      each bearing a different mutation in the same gene, has long been the gold
      standard for establishing a causal relationship between defects in a gene and the
      resultant disease. As a description of the second known pedigree with LGMD1A,
      this finding constitutes that gold standard of proof that mutations in the
      myotilin gene cause LGMD1A.

PMID- 12428217
TI  - Special management needs of the elderly hypertensive patient.

PMID- 12428218
TI  - Cognitive decline and dementia in the elderly hypertensive.

PMID- 12428219
TI  - Organisation and functional role of the brain angiotensin system.

PMID- 12428220
TI  - Therapy in the elderly hypertensive.

PMID- 12428221
TI  - Et tu, acetaminophen?

PMID- 12428222
TI  - Predictors and outcomes of scleroderma renal crisis: data from the high-dose
      versus low-dose D-penicillamine in early diffuse systemic sclerosis trial.

PMID- 12428223
TI  - Long-term safety and maintenance of clinical improvement following treatment with
      anakinra (recombinant human interleukin-1 receptor antagonist) in patients with
      rheumatoid arthritis: extension phase of a randomized, double-blind, placebo
      controlled trial.
AB  - OBJECTIVE: To demonstrate the long-term efficacy of anakinra, a human recombinant
      interleukin-1 receptor antagonist, in patients with rheumatoid arthritis (RA),
      and to assess the long-term safety of anakinra at different daily doses. METHODS:
      The efficacy and safety of anakinra were previously demonstrated in a double
      blind, placebo-controlled, 24-week evaluation in 472 patients with active RA. Of
      345 patients who completed the placebo-controlled phase of the study, 309
      continued in a 52-week, multicenter, double-blind, parallel-group extension phase
      of the study. Patients received subcutaneous injections of anakinra (30, 75, or
      150 mg) once daily. Efficacy was assessed among the 309 patients for the first 24
      weeks of the extension phase (48 weeks total therapy), using the American College
      of Rheumatology composite score (ACR20), its components, and radiographs of the
      hands and wrists. Safety was assessed in all 472 patients over the entire 52-week
      extension phase (76 weeks total exposure). RESULTS: A total of 218 patients
      completed the extension phase. Of the 91 patients who withdrew prematurely, 46
      did so following adverse events, and 26 withdrew because of lack of efficacy.
      Among patients receiving anakinra who entered the extension phase, the level of
      improvement was maintained for 48 weeks. The ACR20 response was 51% at week 24
      and 46% at week 48, and this effect was consistent across all dose groups. The
      durability of the response to anakinra was further demonstrated in an evaluation
      of the sustained ACR20 response, which was similar during the first and second 24
      week periods (36% and 42%, respectively). At week 48, ACR50 and ACR70 responses
      were demonstrated in 18% and 3% of patients, respectively, who continued taking
      anakinra (all dose groups) and in 20% and 1% of patients, respectively, who were
      originally receiving placebo and then were randomized to all doses of anakinra.
      Anakinra was well tolerated for 76 weeks. The only side effects that appeared to
      be treatment-related were skin reactions at the injection site. There was no
      evidence of decreased tolerance, an increased number of withdrawals, or an
      increased incidence of clinical complications associated with extended anakinra
      therapy. CONCLUSION: The clinical benefits of treatment with daily self
      administered subcutaneous injections of anakinra in a cohort of patients with
      active RA were maintained for up to 48 weeks. Anakinra was well tolerated over 76
      weeks. These observations support the long-term use of anakinra for the treatment
      of patients with RA.

PMID- 12428225
TI  - Cell-derived microparticles in synovial fluid from inflamed arthritic joints
      support coagulation exclusively via a factor VII-dependent mechanism.
AB  - OBJECTIVE: To determine the cellular origin of synovial microparticles, their
      procoagulant properties, and their relationship to local hypercoagulation.
      METHODS: Microparticles in synovial fluid and plasma from patients with
      rheumatoid arthritis (RA; n = 10) and patients with other forms of arthritis (non
      RA; n = 10) and in plasma from healthy subjects (n = 20) were isolated by
      centrifugation. Microparticles were identified by flow cytometry. The ability of
      microparticles to support coagulation was determined in normal plasma.
      Concentrations of prothrombin fragment F(1+2) (by enzyme-linked immunosorbent
      assay [ELISA]) and thrombin-antithrombin (TAT) complexes (by ELISA) were
      determined as estimates of the coagulation activation status in vivo. RESULTS:
      Plasma from patients and healthy controls contained comparable numbers of
      microparticles, which originated from platelets and erythrocytes. Synovial
      microparticles from RA patients and non-RA patients originated mainly from
      monocytes and granulocytes; few originated from platelets and erythrocytes.
      Synovial microparticles bound less annexin V (which binds to negatively charged
      phospholipids) than did plasma microparticles, exposed tissue factor, and
      supported thrombin generation via factor VII. F(1+2) (median 66 nM) and TAT
      complex (median 710 microg/liter) concentrations were elevated in synovial fluid
      compared with plasma from the patients (1.6 nM and 7.0 microg/liter,
      respectively) as well as the controls (1.0 nM and 2.9 microg/liter,
      respectively). CONCLUSION: Synovial fluid contains high numbers of microparticles
      derived from leukocytes that are strongly coagulant via the factor VII-dependent
      pathway. We propose that these microparticles contribute to the local
      hypercoagulation and fibrin deposition in inflamed joints of patients with RA and
      other arthritic disorders.

PMID- 12428224
TI  - Association of baseline levels of markers of bone and cartilage degradation with
      long-term progression of joint damage in patients with early rheumatoid
      arthritis: the COBRA study.
AB  - OBJECTIVE: The known risk factors for radiologic progression in rheumatoid
      arthritis (RA) are not optimally discriminative in patients with early disease
      who do not have evidence of radiologic damage. We sought to determine whether
      urinary C-terminal crosslinking telopeptide of type I (CTX-I) and type II (CTX
      II) collagen (markers of bone and cartilage destruction, respectively) are
      associated with long-term radiologic progression in patients with early RA.
      METHODS: This was a prospective study of 110 patients with early RA who were
      participating in the COBRA (Combinatietherapie Bij Reumatoide Artritis) clinical
      trial and followup study, a randomized controlled trial comparing the efficacy of
      oral pulse prednisolone, methotrexate, plus sulfasalazine with sulfasalazine
      alone. We investigated the relationship between baseline levels of urinary CTX-I
      and CTX-II and the mean annual progression of joint destruction over a median of
      4 years, as measured by changes in the modified Sharp score (average of 2
      independent readers). RESULTS: In multivariate logistic regression analysis,
      baseline urinary CTX-I and CTX-II levels in the highest tertile were the
      strongest predictors of radiologic progression (Sharp score increase >2
      units/year; odds ratio 7.9 and 11.2, respectively), independently of treatment
      group, erythrocyte sedimentation rate (ESR), Disease Activity Score in 28 joints,
      rheumatoid factor (RF), and baseline joint damage (Sharp score). The likelihood
      ratios for a positive test were 3.8 and 8.0 for CTX-I and CTX-II, respectively,
      which compared favorably with the likelihood ratios for the ESR (3.0), baseline
      joint damage (1.6), and RF (1.8). When patients were grouped according to the
      presence (Sharp score >/=4, n = 49) and absence (Sharp score <4, n = 61) of joint
      damage at baseline, CTX-I and CTX-II levels were predictive only in those without
      baseline joint damage (odds ratio 14.9 and 25.7, respectively). CONCLUSION: High
      baseline levels of urinary CTX-I and CTX-II independently predict an increased
      risk of radiologic progression over 4 years in patients with early RA, especially
      those without radiologic joint damage. Urinary CTX-I and CTX-II may be useful for
      identifying individual RA patients at high risk of progression very early in the
      disease, before erosions can be detected radiographically. Such patients may be
      in special need of treatments that inhibit bone and cartilage degradation.

PMID- 12428226
TI  - Regulation of fibronectin and metalloproteinase expression by Wnt signaling in
      rheumatoid arthritis synoviocytes.
AB  - OBJECTIVE: The enhanced release of extracellular matrix proteins by fibroblast
      like synoviocytes (FLS) from rheumatoid arthritis (RA) patients is suggestive of
      joint remodeling. Because Wnt proteins play a critical role in joint development,
      we investigated whether up-regulated Wnt signaling plays a role in the enhanced
      synthesis of extracellular matrix proteins. The purpose of the present
      experiments was to determine the role of Wnt-1-like molecules in the expression
      of matrix proteins by RA FLS and to ascertain the effects of Wnt antagonists on
      RA FLS function and survival. METHODS: Transfection with a reporter plasmid
      (TOPflash) was performed to assess whether Wnt signaling is active in RA FLS. Wnt
      signaling was up-regulated in normal FLS by transfection with a Wnt-1 expression
      plasmid and was down-regulated in RA FLS by transfection with dominant-negative
      lymphoid enhancer factor 1 (LEF-1)/T cell factor 4 (TCF-4) and secreted Frizzled
      receptor protein 1 (sFRP-1) expression plasmids. Recombinant sFRP-1 and anti-Wnt
      1 antibody were also administered to RA FLS to block Wnt signaling. RESULTS: RA
      FLS had constitutive activation of the canonical Wnt signaling pathway.
      Transfection of normal FLS with a Wnt-1 expression vector enhanced not only
      fibronectin, but also pro-matrix metalloproteinase 3 (proMMP-3) expression. In a
      complementary manner, interference with Wnt signaling using anti-Wnt-1 antibody,
      the Wnt antagonist sFRP-1, or dominant-negative vectors that inhibited the
      transcription factors TCF-4/LEF-1 blocked the expression of fibronectin by RA FLS
      and reduced cell survival. Anti-Wnt-1 antibody and sFRP-1 also blocked the
      expression of proMMP-3. CONCLUSION: Our results indicate that the canonical Wnt
      pathway regulates fibronectin and metalloproteinase expression in RA FLS.

PMID- 12428227
TI  - Migration of CX3CR1-positive T cells producing type 1 cytokines and cytotoxic
      molecules into the synovium of patients with rheumatoid arthritis.
AB  - OBJECTIVE: Rheumatoid arthritis (RA) is characterized by chronic inflammation of
      multiple joints. Large numbers of T cells, which produce type 1 cytokines,
      infiltrate into RA synovium. Chemokines and chemokine receptors are considered to
      contribute to the T cell infiltration. In this study, we examined the role of
      CX3CL1/fractalkine and its receptor CX3C chemokine receptor 1 (CX3CR1) in the T
      cell migration into RA synovium. METHODS: Using flow cytometry,
      immunohistochemistry, and reverse transcription-polymerase chain reaction, we
      analyzed CX3CR1 expression by peripheral blood and synovial T cells, and CX3CL1
      expression in synovium from patients with RA. Cytokine and cytotoxic molecule
      expression by CX3CR1-positive T cells was analyzed by flow cytometry. RESULTS:
      CX3CR1 expression by peripheral CD4+ and CD8+ T cells was up-regulated in RA
      patients. The peripheral CD4+ and CD8+ T cells expressing CX3CR1 predominantly
      produced interferon-gamma and tumor necrosis factor alpha, and expressed
      cytotoxic molecules such as granzyme A and perforin. Furthermore, CX3CR1+,CD3+ T
      cells infiltrated into RA synovium. CX3CL1, the unique ligand of CX3CR1, was
      expressed by endothelial cells and synoviocytes in RA synovium, but not in
      osteoarthritis synovium. CONCLUSION: Our findings suggest that the interactions
      of CX3CL1 and CX3CR1 might contribute to the accumulation of CX3CR1+ T cells
      expressing type 1 cytokines and possessing cytotoxic granules in RA synovium.

PMID- 12428228
TI  - Risk factors for progressive cartilage loss in the knee: a longitudinal magnetic
      resonance imaging study in forty-three patients.
AB  - OBJECTIVE: To evaluate the rate of progression of cartilage loss in the knee
      joint using magnetic resonance imaging (MRI) and to evaluate potential risk
      factors for more rapid cartilage loss. METHODS: We evaluated baseline and
      followup MRIs of the knees in 43 patients (minimum time interval of 1 year, mean
      1.8 years, range 52-285 weeks). Cartilage loss was graded in the anterior,
      central, and posterior regions of the medial and lateral knee compartments. Knee
      joints were also evaluated for other pathology. Data were analyzed using analysis
      of variance models. RESULTS: Patients who had sustained meniscal tears showed a
      higher average rate of progression of cartilage loss (22%) than that seen in
      those who had intact menisci (14.9%) (P <or= 0.018). Anterior cruciate ligament
      (ACL) tears had a borderline significant influence (P <or= 0.06) on the
      progression of cartilage pathology. Lesions located in the central region of the
      medial compartment were more likely to progress to more advanced cartilage
      pathology (progression rate 28%; P <or= 0.003) than lesions in the anterior (19%;
      P <or= 0.564) and posterior (17%; P <or= 0.957) regions or lesions located in the
      lateral compartment (average progression rate 15%; P <or= 0.707). Lesions located
      in the anterior region of the lateral compartment showed less progression of
      cartilage degradation (6%; P <or= 0.001). No specific grade of lesion identified
      at baseline had a predilection for more rapid cartilage loss (P <or= 0.93).
      CONCLUSION: MRI can detect interval cartilage loss in patients over a short
      period (<2 years). The presence of meniscal and ACL tears was associated with
      more rapid cartilage loss. Cartilage lesions located in the central region of the
      medial compartment showed more rapid progression of cartilage loss than cartilage
      lesions in the anterior and posterior portions of the medial compartment. The
      findings in this study suggest that patients entering clinical trials
      investigating antiarthritis regimens may need to be randomized based on location
      of the lesion.

PMID- 12428229
TI  - Clinical benefit of joint distraction in the treatment of severe osteoarthritis
      of the ankle: proof of concept in an open prospective study and in a randomized
      controlled study.
AB  - OBJECTIVE: Osteoarthritis (OA) is a degenerative, disabling joint disease that
      affects >10% of the adult population. No effective disease-modifying treatment is
      available. In the present study, we used joint distraction, a relatively new
      treatment in which mechanical contact between the articular surfaces is avoided
      while intraarticular intermittent fluid pressure is maintained, to treat patients
      with severe OA of the ankle. METHODS: Patients with severe ankle OA (n = 57) who
      were being considered for joint fusion (arthrodesis) were treated with joint
      distraction in an open prospective study. In addition, a randomized trial was
      performed in 17 patients to determine whether joint distraction had a better
      outcome than debridement. A standardized evaluation protocol (physical
      examination, assessment of pain, mobility, and functional ability) was used, and
      changes in radiographic joint space width and subchondral sclerosis were
      measured. Thirty-eight patients in the open study have been followed up for >1
      year, with up to 5 years of followup in 7 of them (mean +/- SD followup 2.8 +/-
      0.3 years). Patients in the randomized study have been followed up for 1 year.
      RESULTS: Significant clinical benefit was found in three-fourths of the 57
      patients in the open prospective study. Most interestingly, the improvement
      increased over time. Radiographic evaluation showed increased joint space width
      and decreased subchondral sclerosis. Moreover, joint distraction showed
      significantly better results than debridement. CONCLUSION: The clinical benefit
      of joint distraction in the treatment of severe OA is proof of the concept.
      Although the followup remains relatively short and effects over time remain
      unpredictable, our study creates possibilities for the treatment of severe OA in
      general. Considering the high prevalence of OA and the lack of a cure for it,
      joint distraction as a treatment of severe OA may have great medical, social, and
      economic impact.

PMID- 12428230
TI  - Matrix homeostasis in aging normal human ankle cartilage.
AB  - OBJECTIVE: To study age-related (as opposed to arthritis-related) changes in
      collagen and proteoglycan turnover. METHODS: Macroscopically nondegenerate normal
      ankle cartilage obtained from 30 donors (ages 16-75 years) was processed for in
      situ hybridization to detect messenger RNA (mRNA) of type IIB collagen (CIIB);
      antibodies to the C-propeptide of type II collagen (CPII), to the type II
      collagen (CII) collagenase-generated cleavage neoepitope (Col2-3/4C(short)), and
      to the CII denaturation product (Col2-3/4m) were used for immunohistochemistry
      analysis and immunoassay. In addition, immunoblotting was used to detect the 4
      collagenases. Assays were also performed to detect glycosaminoglycan (GAG)
      content and the 846 epitope of aggrecan. RESULTS: There were no significant
      changes in CII, GAG, and the content of the 846 epitope after the age of 30
      years. Both mRNA for CIIB and the CPII were present in all zones, and CPII
      content did not change significantly with age. While the collagenase-cleaved CII
      showed a trend to increase with age, the denatured collagen did not. However, the
      molar ratio of cleaved versus denatured collagen was positively correlated with
      age. All 4 collagenases were detectable in the ankle cartilage but showed no
      identifiable changes in content with age. CONCLUSION: Synthesis and degradation
      of CII is associated with the pericellular matrix and is maintained at a steady
      state throughout life. The contents of CII and proteoglycan did not change. There
      was a significant reduction in the denaturation of CII with age, relative to
      collagenase-mediated cleavage. These observations reveal that, in aging of the
      intact ankle articular cartilage, there is no evidence of molecular degenerative
      changes of the kind observed in osteoarthritis, thereby distinguishing aging from
      the osteoarthritis process.

PMID- 12428231
TI  - Replicative aging of human articular chondrocytes during ex vivo expansion.
AB  - OBJECTIVE: To investigate the contribution of clinical ex vivo expansion
      protocols to replicative aging of human chondrocytes. METHODS: Primary human
      chondrocytes were cultured as monolayers after isolation from 7 articular
      cartilage specimens. Cells were passaged corresponding to 12-19 cell population
      doublings (cpd). Aliquots of the cells were collected from each passage and
      analyzed for telomere length and telomerase activity. RESULTS: The rate of
      telomere shortening was heterogeneous, ranging from 147 to 431 bp/cpd (mean +/-
      SD 305 +/- 122). Telomerase activity was detected at various time points during
      passaging in 5 of 7 primary chondrocytes analyzed, but not in native human
      articular cartilage specimens. According to our data, an 8-10-fold (
      approximately 3 cpd) ex vivo expansion of articular chondrocytes, as typically
      performed for transplantation procedures, leads to telomere erosion in the range
      of 900 bp. This is comparable with 30 years of aging based on the in vivo rate of
      telomere shortening of 30 bp/year recently found in chondrocytes. CONCLUSION: If
      telomere shortening is an important determinant of aging in human articular
      cartilage, an additional telomere loss due to ex vivo expansion might affect the
      incidence or time of onset of age-related cartilage disorders. However, given the
      limited extent of expansion performed in the clinical setting to date, a
      significant telomere-mediated increase in the risk of malignant transformation or
      replicative exhaustion of the transplanted cells seems unlikely.

PMID- 12428232
TI  - Hematopoietic stem cell transplantation for severe and refractory lupus. Analysis
      after five years and fifteen patients.
AB  - OBJECTIVE: To determine the safety and long-term efficacy of immune ablation and
      autologous hematopoietic stem cell transplantation (HSCT) in severe systemic
      lupus erythematosus (SLE). METHODS: Fifteen patients with persistently active SLE
      after intravenous (IV) cyclophosphamide (CYC) therapy underwent HSCT. Stem cells
      were mobilized with CYC (2.0 gm/m(2)) and granulocyte colony-stimulating factor
      (5 microg/kg/day). Lymphocytes were depleted from the graft by selection of CD34
      positive cells. The conditioning regimen used was CYC (200 mg/kg), antithymocyte
      globulin (90 mg/kg), and methylprednisolone (3 mg/kg). Outcome was evaluated by
      the SLE Disease Activity Index (SLEDAI), serum complement levels, serologic
      features, function of diseased organs, and immunosuppressive medication
      requirements. RESULTS: Fifteen patients with persistent, severe SLE, 7 of whom
      were critically ill, were treated. No deaths occurred following treatment. The
      median followup after HSCT has been 36 months (range 12-66 months). All patients
      demonstrated a gradual, but marked, improvement. The SLEDAI score has declined to
      <or=5 in 12 patients. Complement and anti-double-stranded DNA levels have
      normalized and marked improvements in end organ function have occurred in all
      subjects. Of the 12 patients followed up for >1 year after HSCT, 10 have
      discontinued immunosuppressive medications, and the prednisone dosage has been
      tapered to 15 mg/day in 1. Only 2 patients have demonstrated clinical evidence of
      recurrence of active lupus. One of these patients currently requires no
      immunosuppressive medication and has a normal performance status. The other
      patient is currently receiving IV CYC. CONCLUSION: In patients experiencing the
      persistence of organ-threatening lupus following standard, aggressive therapy,
      HSCT may be performed safely, with marked improvement and sustained withdrawal of
      all immunosuppressive medication for most patients. A phase III randomized trial
      is warranted to determine the relative efficacy and durability of remission of
      HSCT compared with standard therapies.

PMID- 12428233
TI  - Dehydroepiandrosterone treatment of women with mild-to-moderate systemic lupus
      erythematosus: a multicenter randomized, double-blind, placebo-controlled trial.
AB  - OBJECTIVE: To evaluate the efficacy and tolerability of dehydroepiandrosterone
      (DHEA) at a dosage of 200 mg/day in adult women with active systemic lupus
      erythematosus (SLE). METHODS: In a multicenter randomized, double-blind, placebo
      controlled trial, 120 adult women with active SLE received oral DHEA (200 mg/day;
      n = 61) or placebo (n = 59) for 24 weeks. The primary end point was the mean
      change from baseline in the Systemic Lupus Activity Measure (SLAM) score at 24
      weeks of therapy. Secondary end points included time to first flare, change in
      SLE Disease Activity Index (SLEDAI) score, and physician's and patient's global
      assessment scores at week 24. RESULTS: The two groups were well balanced for
      baseline characteristics. Mean reductions in SLAM scores from baseline were
      similar and were not statistically significantly different between treatment
      groups (DHEA -2.6 +/- 3.4 versus placebo -2.0 +/- 3.8, mean +/- SD). The number
      of patients with flares was decreased by 16% in the DHEA group (18.3% of DHEA
      treated patients versus 33.9% of placebo-treated patients; P = 0.044, based on
      time to first flare). The mean change in the patient's global assessment was
      statistically significant between the two groups (DHEA -5.5 versus placebo 5.4; P
      = 0.005). The number of patients with serious adverse events, most of which were
      related to SLE flare, was significantly lower in DHEA-treated patients compared
      with placebo-treated patients (P = 0.010). Expected hormonal effects, including
      increased testosterone levels and increased incidence of acne, were observed. No
      life-threatening reactions or serious safety issues were identified during this
      study. CONCLUSION: The overall results confirm that DHEA treatment was well
      tolerated, significantly reduced the number of SLE flares, and improved patient's
      global assessment of disease activity.

PMID- 12428234
TI  - Linkage and interaction of loci on 1q23 and 16q12 may contribute to
      susceptibility to systemic lupus erythematosus.
AB  - OBJECTIVE: Six recent genome scans of different systemic lupus erythematosus
      (SLE) multiplex family cohorts showed multiple putative susceptibility loci. In
      the present study, we examined 4 previously identified loci to replicate findings
      of significant linkage to 1q23 and 16q12, and to support findings of suggestive
      linkage to 14q21-23 and 20p12 in a cohort of 115 multiethnic nuclear families
      containing 145 SLE-affected sibpairs. METHODS: Model-free, multipoint linkage
      analyses (SIBPAL2, SAGE version 4.0) and exclusion mapping (GeneHunter) were
      performed. RESULTS: Linkages to 1q23 (peak at D1S2675, mean allele sharing [MAS]
      0.56; P = 0.003) and to 16q12 (peaks between D16S753 and D16S757, MAS 0.57; P =
      0.003) were confirmed, but linkage evidence at 20p12 was weak and inconsistent
      (MAS 0.52-0.56; from P = 0.005 to P not significant). Evidence for linkage to
      1q23 and 16q12 was stronger in 68 non-Caucasian affected sibpairs than in 77
      Caucasian affected sibpairs. Exclusion mapping ruled out linkage at 14q21-23
      (lambda(s) [sib recurrence risk or genotypic risk ratio] = 1.8). Because the
      pericentromeric region of chromosome 16 has been identified by genome scans in
      several autoimmune diseases, we postulated that it might harbor an autoimmune
      modifier gene. To explore this possibility, we tested for an interaction between
      16q12 and 1q23, and between 16q12 and 20p12. Haplotype sharing at 1q23 increased
      concomitantly with increased haplotype sharing at 16q12 (P = 0.008 by
      nonparametric Jonckheere-Terpstra exact statistical test). No evidence supporting
      an interaction between 16q12 and 20p12 was observed. Analysis of sibpairs sharing
      2 alleles at 16q12 also showed increased allele sharing at 1q23 (MAS from 0.56 to
      0.65). CONCLUSION: These data support the presence of SLE susceptibility genes at
      1q23 and 16q12, particularly in non-Caucasians. The skewed distribution of
      haplotypes suggests that genetic interaction of these two loci may affect SLE
      susceptibility.

PMID- 12428235
TI  - Stratification of pedigrees multiplex for systemic lupus erythematosus and for
      self-reported rheumatoid arthritis detects a systemic lupus erythematosus
      susceptibility gene (SLER1) at 5p15.3.
AB  - OBJECTIVE: Arthritis is a common manifestation in systemic lupus erythematosus
      (SLE), appearing in approximately 85% of patients. Often, the polyarthritis at
      presentation of SLE cannot be distinguished from rheumatoid arthritis (RA) by
      physical examination or history. Indeed, physicians initially tell many SLE
      patients that they have RA (one source of "self-reported RA"), only to have SLE
      established later. In addition, RA aggregates in families with an SLE proband. We
      predicted that pedigrees multiplex for both SLE and for self-reported RA would
      better isolate particular genetic effects. If this proved to be true, we would
      then use the increased genetic homogeneity to more easily reveal genetic linkage.
      METHODS: From a collection of 160 pedigrees multiplex for SLE, we selected 36
      pedigrees that also contained >or=2 members with self-reported RA (19 pedigrees
      were African American, 14 were European American, and 3 were of other ethnic
      origin). Data from a genome scan of 307 microsatellite markers were evaluated for
      SLE linkage by contemporary genetic epidemiologic techniques. RESULTS: The most
      significant evidence of linkage to SLE was obtained at 5p15.3 in the European
      American pedigrees by both parametric (logarithm of odds [LOD] score 6.2, P = 9.3
      x 10(-8)) and nonparametric (LOD score 6.9, P = 1.7 x 10(-8)) methods. The best
      fitting model for this putative SLE gene in this region was a recessive gene with
      a population frequency of 5% and with 50% penetrance in females and 15%
      penetrance in males at virtually 100% homogeneity. CONCLUSION: For a genetically
      complex disease phenotype, an unusually powerful linkage has been found with SLE
      at 5p15.3 in European American pedigrees multiplex for SLE and for self-reported
      RA. This result predicts the presence of a gene at the top of chromosome 5 in
      this subset of patients that is important for the pathogenesis of SLE.

PMID- 12428236
TI  - Autoimmune responses to proliferating cell nuclear antigen multiprotein complexes
      involved in cell proliferation are strongly associated with their structure and
      biologic function in patients with systemic lupus erythematosus.
AB  - OBJECTIVE: To analyze the reaction of lupus sera with proliferating cell nuclear
      antigen (PCNA) multiprotein complexes (PCNA complexes), which are part of the
      protein machinery involved in cell proliferation. METHODS: PCNA complexes were
      purified from rabbit thymus extract by affinity chromatography using anti-PCNA
      monoclonal antibodies (TOB7, TO17, and TO30); monomeric and trimeric PCNA forms
      (AK-PCNA) were purified using anti-PCNA serum AK. The reactions to these antigens
      of 10 anti-PCNA-positive and 40 anti-PCNA-negative sera selected from 560 lupus
      patients were tested by immunoblotting, immunoprecipitation, and enzyme-linked
      immunosorbent assays (ELISAs). RESULTS: With one exception (serum OK), anti-PCNA
      positive sera reacted exclusively with only the 34-kd polypeptide. In contrast,
      14 of 40 anti-PCNA-negative sera reacted with multiple proteins within PCNA
      complexes. Most anti-PCNA-positive sera probably recognize as epitopes the
      binding sites for other proteins on PCNA, which are likely hidden when PCNA is
      complexed with other proteins. As a consequence, only serum OK reacted with the
      PCNA complex in a series of ELISAs. Using AK-PCNA as a competitive inhibitor, it
      was determined that serum OK reacts with both the 58-kd polypeptide and the 34-kd
      PCNA within complexes. Together with the results of a longitudinal analysis,
      these results suggest that the immune system of patient OK likely recognized the
      complexed PCNA protein, after which the autoimmune response spread to other
      elements of the complexes. CONCLUSION: Intermolecular-intrastructural help,
      leading to the spread of autoimmune response from PCNA to other proteins
      associated with its biologic function, plays a crucial role in the induction of
      the autoimmune response seen in lupus patients.

PMID- 12428237
TI  - Autoantibodies to lipoprotein lipase and dyslipidemia in systemic lupus
      erythematosus.
AB  - OBJECTIVE: To demonstrate the binding of bovine lipoprotein lipase (LPL) by IgG
      from sera obtained from patients with systemic lupus erythematosus (SLE) and
      other rheumatic diseases, and the relationship of anti-LPL to triglyceride levels
      in SLE. METHOD: Binding of LPL by IgG from sera obtained from patients with SLE
      and other rheumatic diseases was measured by an enzyme-linked immunosorbent assay
      technique. Lipid profiles for fasting blood samples obtained from SLE patients
      and control subjects were determined. RESULTS: Sera obtained from 105 patients
      with SLE were assessed for reactivity with LPL, and 49 (47%) of the results were
      positive. Sera obtained from patients with rheumatoid arthritis (RA) (n = 80),
      Sjogren's syndrome (n = 30), polymyositis and dermatomyositis (n = 30), and
      progressive systemic sclerosis (n = 31) were also studied, and 10 (13%), 3 (10%),
      12 (40%), and 13 (42%), respectively, were positive for reactivity with LPL. It
      was determined that all affinity-purified anti-double-stranded DNA (dsDNA)
      antibodies and 4 of 5 monoclonal anti-dsDNA antibodies bound to LPL. The binding
      of IgG depleted of anti-dsDNA to LPL indicates a second anti-LPL activity in SLE.
      Measurements of fasting lipid levels in SLE patients with anti-LPL revealed a
      strong positive correlation of antibody levels and total serum triglycerides,
      apolipoprotein B, and apolipoprotein E concentrations. CONCLUSION: Antibodies to
      LPL occurred in 47% of SLE patients and in a similar percentage of patients with
      polymyositis or systemic sclerosis. The prevalence of these antibodies was less
      in patients with RA or Sjogren's syndrome. It is hypothesized that the elevated
      triglyceride levels in SLE patients are in part attributable to anti-LPL, and
      this lipid abnormality could contribute to the premature atherosclerosis known to
      be present in patients with SLE.

PMID- 12428238
TI  - Fast spin echo-T2-weighted sequences with fat saturation in dactylitis of
      spondylarthritis. No evidence of entheseal involvement of the flexor digitorum
      tendons.
AB  - OBJECTIVE: To establish by means of fast spin echo (FSE)-T2-weighted sequences
      with fat saturation if enthesitis of the flexor digitorum superficialis and
      profundus tendons is the primary lesion in spondylarthritis (SpA) finger
      dactylitis. METHODS: Eleven dactylitic fingers and their corresponding normal,
      contralateral fingers, belonging to 6 patients who met the Amor criteria for SpA,
      were studied by FSE-T2-weighted sequences with fat saturation. RESULTS: All
      dactylitic fingers showed moderate or severe fluid collection in the flexor
      tendon synovial sheaths. Involvement of the joint cavity was simultaneously
      present in at least one joint in 3 (27.3%) of the 11 fingers. A mild to moderate
      peritendinous soft tissue edema was observed in 5 (45.5%) of the 11 affected
      fingers. In no dactylitic finger was bone edema observed near the insertions of
      the flexor digitorum superficialis or profundus tendons or in other sites of the
      phalanges. No lesions were observed in the 11 contralateral, clinically normal
      fingers. CONCLUSION: In SpA dactylitis there is no evidence of enthesitis of the
      flexor digitorum tendons and joint capsules.

PMID- 12428239
TI  - Association of ankylosing spondylitis with HLA-B*1403 in a West African
      population.
AB  - OBJECTIVE: To investigate the contribution of HLA class I alleles in the
      susceptibility to primary ankylosing spondylitis (AS) in West African patients
      living in Togo. METHODS: A large epidemiologic analysis of 9,065 West African
      rheumatology patients living in Togo was performed in order to identify those who
      had AS. Eight Togolese patients with AS were identified. HLA was typed by
      polymerase chain reaction using sequence-specific oligonucleotide probes. DNA
      typing was also performed on a control population of 85 healthy subjects matched
      for ethnic background. RESULTS: A significant association between AS and B*14 was
      identified. This allele was found in 62.5% of the AS patients (odds ratio 69),
      but was carried by only 2% of the healthy controls. Analysis for B14 subtypes
      showed that B*1403 was the predominant allele in AS patients (odds ratio 171),
      and that this allele was absent in healthy controls. B27 was virtually absent,
      being observed in only 1 AS patient (B*2705). CONCLUSION: HLA-B*1403 shows the
      B27 "supertype" motif and may exert an effect on AS susceptibility according to
      the arthritogenic peptide model. The association of B*1403 with AS has not
      previously been reported in either population.

PMID- 12428240
TI  - Cell-surface expression and immune receptor recognition of HLA-B27 homodimers.
AB  - OBJECTIVE: HLA-B27 is capable of forming in vitro a heavy-chain homodimer
      structure lacking beta(2)-microglobulin. We undertook this study to ascertain if
      patients with spondylarthritis express beta(2)-microglobulin-free HLA-B27 heavy
      chains in the form of homodimers and receptors for HLA-B27 homodimers. METHODS:
      Expression of HLA-B27 heavy chains by mononuclear cells was analyzed by
      fluorescence-activated cell sorter staining, Western blotting with the monoclonal
      antibody HC-10, and 2-dimensional isoelectric focusing. Fluorescence-labeled
      tetrameric complexes of HLA-B27 heavy-chain homodimers were constructed in which
      each dimer comprised one His-tagged heavy chain and one biotinylated heavy chain,
      and were used to stain patient and control mononuclear cells and transfected cell
      lines. RESULTS: Patients with spondylarthritis expressed cell-surface HLA-B27
      homodimers. Populations of synovial and peripheral blood monocytes, and B and T
      lymphocytes from patients with spondylarthritis, and controls carried receptors
      for HLA-B27 homodimers. Experiments with transfected cell lines demonstrated that
      KIR3DL1 and KIR3DL2, and immunoglobulin-like transcript 4 (ILT4), but not ILT2,
      are receptors for HLA-B27 homodimers. CONCLUSION: Patients with spondylarthritis
      express both HLA-B27 heavy-chain homodimers and receptors for HLA-B27 homodimers.
      This may be of significance with regard to disease pathogenesis.

PMID- 12428241
TI  - Predictors and outcomes of scleroderma renal crisis: the high-dose versus low
      dose D-penicillamine in early diffuse systemic sclerosis trial.
AB  - OBJECTIVE: The reported frequency of scleroderma M01-R renal crisis (SRC) in
      diffuse systemic sclerosis (SSc; scleroderma) is 15-20%. Early use of angiotensin
      converting enzyme (ACE) inhibitors has markedly improved outcome. The present
      analysis reexamines the prognostic factors for and outcome of SRC in a
      prospective cohort of patients with early diffuse SSc. METHODS: We
      retrospectively evaluated the cohort of SSc patients who participated in the High
      Dose Versus Low-Dose D-Penicillamine in Early Diffuse SSc trial. Patients with
      diffuse cutaneous scleroderma were enrolled if their disease duration was <18
      months. Because the trial failed to show a difference between treatment groups,
      the data were pooled. RESULTS: One hundred thirty-four SSc patients entered the
      observation period a mean +/- SD of 0.8 +/- 0.3 years after onset of SSc. SRC
      occurred in 18 patients a mean +/- SD of 0.9 +/- 1.1 years after entry. During a
      mean +/- SD 4.0 +/- 1.1 years of followup after entry, 9 of the 18 patients died
      (mean +/- SD 0.6 +/- 0.9 years after SRC onset). Baseline characteristics that
      predicted SRC included a modified Rodnan skin thickness score of >or=20 (P <
      0.01), enlarged cardiac silhouette on radiograph (P = 0.04), large joint
      contractures (wrist, elbow, knee) (P = 0.008), and prednisone use at entry (P =
      0.01). Baseline characteristics that did not predict SRC included age, sex, race,
      Health Assessment Questionnaire score, fist closure, handspread, lung
      involvement, muscle weakness, erythrocyte sedimentation rate, and platelet count.
      In 5 of 10 subjects for whom at least 2 sequential skin scores were available,
      skin scores increased significantly (P = 0.012) in the 6 months before onset of
      SRC. CONCLUSION: SRC occurred in 13% of patients soon (mean 11 months) after
      entry into the cohort. Predictors of SRC identified in this study included higher
      than average skin score, prednisone use at study entry, large joint contractures,
      and heart enlargement. Our data suggest, however, that low-dose prednisone alone
      was not associated with the onset of SRC, except in the appropriate clinical
      setting. Although ACE inhibitors and dialysis are now readily available, SRC
      continues to be associated with poor survival (in this study, 50% of patients
      with SRC died).

PMID- 12428242
TI  - Association of novel polymorphisms with the expression of SPARC in normal
      fibroblasts and with susceptibility to scleroderma.
AB  - OBJECTIVE: Fibroblasts from patients with systemic sclerosis (SSc) have an
      activated phenotype characterized by increased synthesis of extracellular matrix
      (ECM) components. SPARC (secreted protein, acidic and rich in cysteine) regulates
      the deposition or assembly of ECM components. The aim of this study was to
      investigate the role of SPARC in SSc susceptibility by functional and genetic
      association studies. METHODS: Complementary DNA (cDNA) microarrays were used to
      obtain gene expression data on cultured dermal fibroblasts from SSc patients.
      SPARC protein levels were assessed by Western blotting. Five polymorphic
      microsatellite markers within 5 cM of the SPARC gene (chromosome 5q31-32) were
      genotyped in Choctaw Indians, a population previously shown to have a high
      prevalence of SSc. Discovery of single-nucleotide polymorphisms (SNPs) was
      accomplished by sequencing the SPARC cDNA. These SNPs were then genotyped in a
      multi-ethnic cohort of SSc patients to determine potential associations with
      disease susceptibility in a broader population of SSc patients, as well as with
      various clinical and immunologic features of SSc. The functional relevance of
      these SNPs with regard to transcript stability of SPARC was also assessed.
      RESULTS: Microarrays demonstrated increased expression of SPARC, along with other
      ECM genes, in SSc patients compared with normal controls. SSc fibroblasts also
      had increased SPARC protein levels. Three of 5 microsatellite markers near SPARC
      showed significant associations with SSc in the Choctaw SSc patients. Sequencing
      of SPARC cDNA revealed 3 novel SNPs in the 3'-untranslated region at +998 (C-
      >G), +1551 (C-->G), and +1922 (T-->G). Homozygosity for the C allele at SNP +998
      was significantly increased in SSc patients across ethnic lines. SPARC SNPs +1551
      and +1922 demonstrated correlations with Raynaud's phenomenon and pulmonary
      fibrosis, respectively. Functional studies of SPARC SNP +998 in normal fibroblast
      cultures suggested a correlation between the SNP +998 C allele polymorphism and
      an increased messenger RNA half-life. CONCLUSION: This study is the first to show
      that polymorphisms of the SPARC gene are associated with susceptibility to, and
      clinical manifestations of, SSc and that they may also be functionally important
      in influencing SPARC expression in skin fibroblasts.

PMID- 12428243
TI  - Transforming growth factor beta induces fibroblast fibrillin-1 matrix formation.
AB  - OBJECTIVE: Fibrillin, an extracellular matrix protein implicated in dermal
      fibrosis, is increased in the reticular dermis of systemic sclerosis (SSc) skin.
      We undertook this study to investigate the hypothesis that transforming growth
      factor beta (TGFbeta) or other cytokines regulate fibrillin matrix formation by
      normal and SSc fibroblasts. We further investigated the mechanism of TGFbeta
      induced fibrillin fibrillogenesis and its relationship to myofibroblasts.
      METHODS: Fibrillin and fibronectin matrix deposition and alpha-smooth muscle
      actin expression by fibroblast cultures from normal and SSc skin treated with
      TGFbeta or other cytokines were analyzed by immunofluorescence. Supernatant and
      extracellular matrix from normal and SSc fibroblasts treated with or without
      TGFbeta were evaluated by Western blot and Northern blot for fibrillin protein
      and messenger RNA (mRNA) expression, respectively. RESULTS: Immunofluorescence
      demonstrated increased fibrillin matrix formation by normal and scleroderma
      fibroblasts after TGFbeta treatment. Other cytokines, including tumor necrosis
      factor alpha, interleukin-1beta (IL-1beta), IL-4, granulocyte-macrophage colony
      stimulating factor, and platelet-derived growth factor, did not affect fibrillin
      fibrillogenesis. Fibrillin matrix formed in proximity to myofibroblasts and
      independently of up-regulation of fibronectin matrix or cell number. Western blot
      analysis of extracellular matrix confirmed increased fibrillin after TGFbeta
      stimulation of normal or scleroderma fibroblasts. However, TGFbeta did not alter
      the expression of either soluble fibrillin protein or fibrillin mRNA. CONCLUSION:
      Our data show that TGFbeta induces fibrillin protein incorporation into the
      extracellular matrix without affecting fibrillin gene expression or protein
      synthesis, suggesting that fibrillin matrix assembly is regulated
      extracellularly. TGFbeta might increase fibrillin matrix by activating
      myofibroblasts. Such TGFbeta-mediated effects could account for the increased
      fibrillin matrix observed in SSc skin.

PMID- 12428244
TI  - Interleukin-15 inhibits sodium nitroprusside-induced apoptosis of synovial
      fibroblasts and vascular endothelial cells.
AB  - OBJECTIVE: One of the pathologic hallmarks of juvenile rheumatoid arthritis (JRA)
      is a tumor-like expansion of inflamed synovial tissue, or pannus, which causes
      much of the joint damage in this disease. The expansion of pannus is supported by
      extensive formation of new blood vessels. We have previously shown that
      revascularization of minced JRA synovial tissues engrafted into SCID mice
      correlated with the intensity of inflammatory activity in the tissues and with
      interleukin-15 (IL-15) expression. Since synovial vascular endothelial cells
      (VECs) expressed IL-15 receptors, the present study was undertaken to investigate
      the hypothesis that IL-15 might play a role in neovascularization of the pannus.
      METHODS: To evaluate IL-15 for possible angiogenic activity, we assessed the
      ability of recombinant human IL-15 (rHuIL-15) to induce VEC growth directly and
      to stimulate synovial cells to produce endothelial growth factors. Since IL-15
      had been shown to inhibit apoptosis of certain immune cells, we were also
      interested in whether it might have similar effects on VECs. Apoptosis was
      induced by addition of sodium nitroprusside (SNP) at 1-2 mM to >80% confluent
      primary VECs, and numbers of apoptotic cells were determined by annexin V assay.
      RESULTS: Addition of rHuIL-15 at 10-100 ng/ml to primary synovial fibroblast
      cultures failed to up-regulate expression of vascular endothelial growth factor
      and angiopoietin 1 by these cells. Although rHuIL-15 failed to induce a mitogenic
      response of VECs, it promoted survival of these cells on Matrigel. Preincubation
      of VECs with rHuIL-15 at 50 ng/ml significantly reduced the proportion of VECs
      undergoing apoptosis. CONCLUSION: IL-15 promotes survival of VECs on Matrigel and
      inhibits SNP-induced apoptosis of endothelial cells. We hypothesize that this
      mechanism may be relevant to the stabilization of newly formed vascular
      structures in JRA synovium.

PMID- 12428245
TI  - Self epitopes shared between human skeletal myosin and Streptococcus pyogenes M5
      protein are targets of immune responses in active juvenile dermatomyositis.
AB  - OBJECTIVE: To identify self T cell epitopes associated with proinflammatory
      immune responses and clinically active juvenile dermatomyositis (juvenile DM).
      The target of our search for relevant epitopes was represented by amino acid
      sequences shared between human skeletal myosin and Streptococcus pyogenes M5
      protein. The long-term objective of the project is to identify suitable targets
      for immunotherapy of the disease. METHODS: We used computerized algorithms to
      identify putative agretopes on both the human myosin and Streptococcus M5
      proteins. Direct binding assays for homolog peptides were used to confirm such
      predictions. Antigenicity and functional cross-reactivity were evaluated by
      cytotoxicity assays and by measurement of cytokine levels. Specific T cells were
      isolated by T cell capture, and T cell receptor (TCR) V(beta) gene usage was
      identified by reverse transcriptase-polymerase chain reaction. RESULTS: We
      identified peptides that are targets of disease-specific cytotoxic T cell
      responses. T cell reactivity against the self peptides correlates with clinical
      signs of early, active myositis. Such reactivity is accompanied by production of
      proinflammatory cytokines, which may contribute to the damage. T cell cross
      recognition of bacterial and human homologs was shown functionally as well as by
      sorting peptide-specific T cells and identifying oligoclonal and largely
      overlapping TCR V(beta) gene usage. CONCLUSION: These findings represent the
      first identification of a self epitope in juvenile DM, providing a potential
      candidate for antigen-specific immune therapy.

PMID- 12428246
TI  - Safe disposal of inflammatory monosodium urate monohydrate crystals by
      differentiated macrophages.
AB  - OBJECTIVE: Although monosodium urate monohydrate (MSU) crystals have been
      recognized since the 18th century as the etiologic agent of gout, it is still
      unknown why certain hyperuricemic individuals remain asymptomatic, and how an
      acute attack of gout spontaneously resolves. We hypothesized that mononuclear
      phagocytes hold the key to these questions, and that the state of
      monocyte/macrophage differentiation is critical. METHODS: Human peripheral blood
      monocytes were differentiated for 1-7 days in vitro and examined with respect to
      1) uptake of MSU crystals, 2) expression of macrophage, dendritic cell, and
      activation markers, 3) secretion of tumor necrosis factor alpha (TNFalpha),
      interleukin 1beta (IL-1beta), IL-6, and IL-10, 4) activation of endothelial E
      selectin expression, and 5) enhancement of secondary neutrophil recruitment by
      endothelial cells. RESULTS: MSU crystals induced TNFalpha, IL-1beta, and IL-6
      (but not IL-10) secretion in undifferentiated monocytes, which in turn promoted
      endothelial cell E-selectin expression and secondary neutrophil capture under
      shear flow. In contrast, differentiation over 3-5 days led to development of a
      noninflammatory phenotype characterized by a lack of proinflammatory cytokine
      secretion, lack of endothelial cell activation, and lack of secondary neutrophil
      recruitment. Acquisition of the noninflammatory phenotype correlated with
      expression of macrophage antigen but not with expression of dendritic cell marker
      or activation marker. Monocytes and macrophages were similarly phagocytic, and a
      control particle, zymosan, elicited secretion of the full panel of cytokines in
      both cell types. However, coincubation with MSU led to a significant suppression
      of zymosan-induced TNFalpha secretion (P = 0.009) from macrophages but not
      monocytes. CONCLUSION: These findings imply that differentiated macrophages
      provide a safe-disposal mechanism for the removal of inflammatory urate crystals.
      This may be of clinical relevance to the maintenance of asymptomatic
      hyperuricemia and the resolution of acute gout.

PMID- 12428247
TI  - Ciprofloxacin enhances the stimulation of matrix metalloproteinase 3 expression
      by interleukin-1beta in human tendon-derived cells. A potential mechanism of
      fluoroquinolone-induced tendinopathy.
AB  - OBJECTIVE: To determine whether the fluoroquinolone antibiotic ciprofloxacin,
      which can cause tendon pain and rupture in a proportion of treated patients,
      affects the expression of matrix metalloproteinases (MMPs) in human tendon
      derived cells in culture. METHODS: Cell cultures were derived from 6 separate
      tendon explants, and were incubated in 6-well culture plates for 2 periods of 48
      hours each, with ciprofloxacin (or DMSO in controls) and interleukin-1beta (IL
      1beta), alone and in combination. Samples of supernatant medium from the second
      48-hour incubation were assayed for MMPs 1, 2, and 3 by Western blotting. RNA was
      extracted from the cells and assayed for MMP messenger RNA (mRNA) by
      semiquantitative reverse transcription-polymerase chain reaction, with
      normalization for GAPDH mRNA. RESULTS: Unstimulated tendon cells expressed low or
      undetectable levels of MMP-1 and MMP-3, and substantial levels of MMP-2. IL-1beta
      induced a substantial output of both MMP-1 and MMP-3 into cell supernatants,
      reflecting increases (typically 100-fold) in MMP mRNA, but had only minor effects
      on MMP-2 expression. Ciprofloxacin had no detectable effect on MMP output in
      unstimulated cells. Preincubation with ciprofloxacin potentiated IL-1beta
      stimulated MMP-3 output, reflecting a similar effect on MMP-3 mRNA expression.
      Ciprofloxacin also potentiated IL-1beta-stimulated MMP-1 mRNA expression, but did
      not potentiate the output of MMP-1, and had no significant effects on MMP-2 mRNA
      expression or output. CONCLUSION: Ciprofloxacin can selectively enhance MMP
      expression in tendon-derived cells. Such effects might compromise tendon
      microstructure and integrity.

PMID- 12428248
TI  - CARD15 mutations in familial granulomatosis syndromes: a study of the original
      Blau syndrome kindred and other families with large-vessel arteritis and cranial
      neuropathy.
AB  - OBJECTIVE: To analyze the CARD15 gene in families with heritable multi-organ
      granulomatoses, including the original Blau syndrome kindred as well as other
      families with related granulomatous conditions. METHODS: Linkage mapping was
      performed in 10 families. Observed recombination events were used to exclude
      regions centromeric or telomeric to 16q12.1, and the Blau gene critical region
      was refined to <3 cM, corresponding to a physical distance of 3.5 megabasepairs.
      Based on its known biochemical function, CARD15 was analyzed as a positional
      candidate for the Blau syndrome susceptibility gene, by direct DNA sequencing.
      RESULTS: These studies resulted in the identification, in 5 of the families, of 2
      sequence variants at position 334 of the gene product (R334W and R334Q). Affected
      family members from the original Blau syndrome kindred were heterozygous for the
      R334W missense mutation; mutations at the same position were also observed in
      several unrelated Blau syndrome families, some of whose phenotypes included large
      vessel arteritis and cranial neuropathy. The missense mutations segregated with
      the disease phenotype in the families, and were not seen in 208 control alleles.
      CONCLUSION: These findings demonstrate that CARD15 is an important susceptibility
      gene for Blau syndrome and for other familial granulomatoses that display
      phenotypic traits beyond those of classic Blau syndrome.

PMID- 12428249
TI  - Determinants and sequelae associated with utilization of acetaminophen versus
      traditional nonsteroidal antiinflammatory drugs in an elderly population.
AB  - OBJECTIVE: Acetaminophen is recommended as initial therapy for patients with
      arthritis, particularly those at increased risk of nonsteroidal antiinflammatory
      drug (NSAID)-induced gastrointestinal (GI) side effects. However, higher doses of
      acetaminophen inhibit prostaglandin synthesis and have been associated with GI
      events. This study was undertaken to compare the observed and adjusted rates of
      GI events (hospitalizations, ulcers, dyspepsia, GI prophylaxis) occurring with
      higher versus lower doses of acetaminophen. METHODS: This was a retrospective
      cohort study of subjects ages >or=65 years who received a prescription for
      acetaminophen or NSAID between 1994 and 1996. Pharmaceutical and medical records
      were reviewed for 1 year of historical data prior to the index prescription of
      acetaminophen or non-aspirin NSAID. Risk factors for GI events were identified
      based on the historical data. To further control for bias, patients were
      categorized by propensity score (the likelihood of receiving acetaminophen, given
      defined risk factor values). Records were then reviewed for the duration of the
      index prescription or 30 days, whichever was less, to generate data on the
      occurrence of GI events. Determinants of acetaminophen utilization were
      identified using logistic regression, and rates of GI events for each therapy
      were examined using Poisson regression analyses, controlling for duration of
      exposure, individual risk factors, and propensity scores. RESULTS: The study
      included 26,978 patients in the NSAID cohort and 21,207 in the acetaminophen
      cohort. Determinants of acetaminophen utilization compared with NSAIDs (odds
      ratio [95% confidence interval]) included recent hospitalization (8.6 [7.7-9.5]),
      concomitant anticoagulation therapy (3.2 [2.7-3.8]), age >85 years (2.3 [2.1
      2.4]), and history of prior GI events, especially those requiring hospitalization
      (14.6 [11.7-18.7]). Unadjusted rates of GI hospitalization, ulcer, and dyspepsia
      were higher for patients in the acetaminophen cohort than for those in the NSAID
      cohort. The occurrence of GI events in acetaminophen-treated patients was dose
      dependent, with rate ratios (compared with high-dose NSAIDs and adjusted for risk
      susceptibility) ranging from 0.6 (95% confidence interval 0.5-0.7) for <or=650
      mg/day to 1.0 (0.9-1.1) for >3,250 mg/day. CONCLUSION: In this cohort,
      acetaminophen utilization is more common in patients at higher risk of GI events.
      After adjustment for risk susceptibility, patients receiving higher doses of
      acetaminophen have higher rates of GI events compared with those receiving lower
      doses.

PMID- 12428250
TI  - Increase in expression of receptor activator of nuclear factor kappaB at sites of
      bone erosion correlates with progression of inflammation in evolving collagen
      induced arthritis.
AB  - OBJECTIVE: The receptor activator of nuclear factor kappaB (RANK)/RANK ligand
      (RANKL) pathway is critical in osteoclastogenesis and bone resorption and has
      been implicated in the process of focal bone erosion in arthritis. This study was
      undertaken to identify in vivo the hitherto-unknown origin and localization of
      RANK-expressing osteoclast precursor cells at sites of bone erosion in arthritis.
      METHODS: DBA-1 mice were immunized with bovine type II collagen/Freund's complete
      adjuvant and were given an intraperitoneal booster injection of type II collagen
      on day 21. Arthritis was monitored visually, and joint pathology was examined
      histologically. RANK and RANKL expression were analyzed using specific
      immunohistochemistry, and tartrate-resistant acid phosphatase (TRAP) staining was
      performed. In addition, TRAP and cathepsin K messenger RNA expression were
      analyzed by in situ hybridization. RESULTS: A marked increase in the number of
      cells expressing RANK correlated with the progression of synovial inflammation
      and clinical disease severity in evolving collagen-induced arthritis (CIA).
      Interestingly, RANK expression demonstrated a gradient pattern with increased
      numbers of RANK-positive cells within the synovial infiltrate in areas closer to
      periosteum and cortical bone. Cells expressing RANK included cells in synovial
      tissue, bone lining cells on the surface of trabecular bone at sites of erosion,
      and cells in periosteal areas adjacent to synovial inflammation. In areas where
      RANK-positive cells were abundant, TRAP-positive, multinucleated osteoclast-like
      cells were also present at sites of focal bone erosion, suggesting
      differentiation of synovially derived RANK-positive osteoclast precursor cells
      into osteoclasts. In addition, TRAP- and cathepsin K-double-positive osteoclast
      like cells were detected on the synovial side of cortical bone at sites of early
      and advanced cortical bone erosion. Sites of RANK expression also correlated well
      with sites of RANKL expression, and there was a close correlation of the temporal
      expression of the receptor-ligand pair. CONCLUSION: Cells expressing RANK
      increased in abundance with the progression of arthritis in evolving CIA, and
      sites of RANK-expressing cells correlated with sites of TRAP-positive,
      multinucleated osteoclast-like cells as well as with sites of RANKL expression.
      These data support the hypothesis that the RANK/RANKL pathway plays an important
      role in the process of bone erosion in CIA.

PMID- 12428251
TI  - Mechanisms of effects of complement inhibition in murine collagen-induced
      arthritis.
AB  - OBJECTIVE: To determine the mechanisms of amelioration of collagen-induced
      arthritis (CIA) in DBA/1J mice by inhibition of complement activation. METHODS:
      Mice received 2 intradermal injections of bovine type II collagen (CII), on days
      0 and 21. From day 21 (immediately after the second injection of CII) through day
      35, mice received intraperitoneal injections of either phosphate buffered saline
      (PBS), a monoclonal mouse antibody to murine C5 (anti-C5 antibody), or the C3
      convertase inhibitor Crry-Ig. RESULTS: On days 30 and 32, the clinical disease
      activity score was lower in mice treated with anti-C5 antibody than in those
      treated with Crry-Ig. Histopathologic evidence of joint damage was 75% lower in
      the mice treated with anti-C5 antibody than in those treated with either PBS or
      Crry-Ig. Spleen cells from mice receiving either form of complement inhibition
      exhibited decreased CII-stimulated proliferation, whereas increased proliferative
      responses were exhibited by lymph node cells from mice treated with Crry-Ig.
      Treatment with anti-C5 antibody decreased production of IgG1 anticollagen
      antibody, while production of IgG2a antibody was inhibited by both complement
      inhibitory treatments. CII-stimulated spleen cells from anti-C5-treated mice
      produced lower levels of tumor necrosis factor alpha (TNFalpha) and interleukin
      10 (IL-10) compared with those from mice treated with Crry-Ig. Lower steady-state
      messenger RNA (mRNA) levels for TNFalpha, interferon-gamma (IFNgamma), IL-18, and
      IL-6 were observed in the joints of anti-C5-treated mice, and for IFNgamma and IL
      6 in mice receiving Crry-Ig, all in comparison with PBS-treated mice. However,
      mRNA levels for IL-1beta and TNFalpha were lower in the joints after treatment
      with anti-C5 compared with Crry-Ig. CONCLUSION: These results indicate that
      inhibition of complement in CIA leads to decreased production of IgG2a antibody
      and suppressed CII-induced spleen cell proliferation. The greater inhibitory
      effects on CIA of anti-C5 antibody in comparison with Crry-Ig may be attributable
      primarily to decreased levels of IL-1beta and TNFalpha mRNA in the joints.

PMID- 12428253
TI  - Correlation of renal tubular epithelial cell-derived interleukin-18 up-regulation
      with disease activity in MRL-Faslpr mice with autoimmune lupus nephritis.
AB  - OBJECTIVE: MRL-Fas(lpr) mice spontaneously develop an autoimmune disease that
      mimics systemic lupus erythematosus in humans. Infiltrating T cells expressing
      interferon-gamma (IFNgamma) are responsible for the autoimmune kidney destruction
      in MRL-Fas(lpr) mice, and interleukin-18 (IL-18) released by mononuclear
      phagocytes stimulates T cells to produce the IFNgamma. Since MRL-Fas(lpr) T cells
      are characterized by an overexpression of the IL-18 receptor accessory chain, we
      sought to determine the impact of IL-18 on the progression of lupus nephritis in
      MRL-Fas(lpr) mice. METHODS: IL-18 expression in sera and kidney tissues from MRL
      Fas(lpr) mice was determined by enzyme-linked immunosorbent assay (ELISA),
      reverse transcription-polymerase chain reaction (RT-PCR), immunohistochemistry,
      and Western blotting. IL-18 production by primary cultured tubular epithelial
      cells (TECs) from MRL-Fas(lpr) and BALB/c mice were examined by RT-PCR, ELISA,
      and Western blotting. The interactions of TEC-derived IL-18 and MRL-Fas(lpr) T
      cells were studied in coculture assays. IL-18-related effects on TEC viability
      and adhesion molecule expression were determined by fluorescence-activated cell
      sorting and cell proliferation assays. RESULTS: Up-regulation of mature IL-18 was
      restricted to nephritic MRL-Fas(lpr) kidneys and increased in parallel with the
      severity of lupus nephritis. IL-18 expression was not confined to infiltrating
      monocytes but was primarily detected in TECs. Similarly, interleukin-1beta
      converting enzyme expression, which is required for the processing of precursor
      IL-18, was localized in TECs. De novo synthesis of IL-18 by MRL-Fas(lpr) TECs was
      confirmed by RT-PCR and Western blotting. Functional assays revealed that
      activated TECs induced IFNgamma production in MRL-Fas(lpr) T cells through IL-18.
      IL-18, in turn, increased apoptotic TEC death and up-regulation of intercellular
      adhesion molecule 1 and vascular cell adhesion molecule 1. CONCLUSION: Taken
      together, our findings suggest that IL-18-producing TECs may directly be involved
      in the pathogenesis of lupus nephritis.

PMID- 12428254
TI  - Tumor necrosis factor receptor type II (exon 6) and interleukin-6 (-174) gene
      polymorphisms are not associated with family history but tumor necrosis factor
      receptor type II is associated with hypertension in patients with rheumatoid
      arthritis from northern Sweden.

PMID- 12428252
TI  - Spinal adenosine receptor activation inhibits inflammation and joint destruction
      in rat adjuvant-induced arthritis.
AB  - OBJECTIVE: To examine the effect of spinal cord adenosine (Ado) receptor
      stimulation on rat adjuvant-induced arthritis (AIA). METHODS: Long-term
      intrathecal (IT) catheters were implanted into rats to provide spinal access for
      drug delivery. Animals were immunized with complete Freund's adjuvant at the tail
      base. Eight days later and every other day thereafter until day 20, rats were
      treated IT with the selective Ado A1 receptor agonist cyclohexyladenosine (CHA)
      or vehicle. In some experiments, animals received an additional daily
      intraperitoneal injection of the nonselective Ado antagonist theophylline. Paw
      swelling was measured by water displacement plethysmometry. The effect of IT CHA
      on the activation of activator protein 1 (AP-1) was determined by electromobility
      shift assay. Spinal cord c-Fos expression was determined by immunohistochemistry.
      RESULTS: Spinal CHA significantly inhibited inflammation in AIA, with a mean +/-
      SEM 20.9 +/- 16.9% increase in paw swelling in the IT CHA group compared with
      81.3 +/- 10.6% in the saline group. The antiinflammatory effect of CHA was
      mediated through Ado receptors since the effect was reversed by coadministration
      of systemic theophylline. In addition, radiographs showed significantly less bone
      and cartilage destruction in the CHA-treated animals. Synovial expression of AP
      1, which is a key regulator of metalloproteinase expression, was lower in IT CHA
      treated animals. C-Fos expression was localized to spinal laminae I-VI, with a
      modest decrease observed in the superficial laminae in IT CHA-treated rats.
      CONCLUSION: These data demonstrate that the spinal cord can regulate peripheral
      inflammation. Therapeutic strategies that target the central nervous system might
      be useful in arthritis.

PMID- 12428255
TI  - Comparison of a disease-specific and a generic instrument for measuring health
      related quality of life in ankylosing spondylitis.

PMID- 12428256
TI  - Detection of parvovirus B19 DNA by polymerase chain reaction in giant cell
      arteritis: a case-control study.

PMID- 12428257
TI  - Aspirin antiplatelet therapy and nonsteroidal antiinflammatory drugs: comment on
      the 2002 update of the American College of Rheumatology Guidelines for the
      Management of Rheumatoid Arthritis.

PMID- 12428258
TI  - Hidden hazards and practical problems: comment on the 2002 update of the American
      College of Rheumatology Guidelines for the Management of Rheumatoid Arthritis.

PMID- 12428261
TI  - Intolerance to caffeine may increase susceptibility to rheumatoid arthritis:
      comment on the article by Mikuls et al.

PMID- 12428262
TI  - Importance of T cells in rheumatoid synovitis: comment on the review by Firestein
      and Zvaifler.

PMID- 12428264
TI  - Genetic drift as an explanation for the reduced incidence of rheumatoid
      arthritis.

PMID- 12428265
TI  - Successful rechallenge with anti-tumor necrosis factor alpha for psoriatic
      arthritis after development of demyelinating nervous system disease during
      initial treatment: comment on the article by Mohan et al.

PMID- 12428267
TI  - A nonsense mutation in exon 2 of the DNase I gene is not present in UK subjects
      with systemic lupus erythematosus and Graves' disease: Comment on the article by
      Rood et al.

PMID- 12428268
TI  - Antioxidant treatment decreases the titer of circulating anticardiolipin
      antibodies: comment on the article by Sambo et al.

PMID- 12428269
TI  - Role of T cells in the pathogenesis of osteoarthritis.

PMID- 12428270
TI  - Benefit or risk of aspirin treatment of giant cell arteritis: comment on the
      article by Weyand et al.

PMID- 12428273
TI  - Mesenchymal stem cells.

PMID- 12428274
TI  - Effects of antibodies against protein S100b on synaptic transmission and long
      term potentiation in CA-1 hippocampal neurons in rats.
AB  - Effects of idiotypic and antiidiotypic antibodies against protein S100b on
      synaptic transmission and long-term potentiation of CA1 pyramidal neurons in rat
      hippocampus were studied. Idiotypic antibodies against protein S100b inhibited
      synaptic transmission from Schaffer collateral axons to pyramidal neurons, but
      had no effect on neuronal responses to antidromic stimulation. Antiidiotypic
      antibodies against protein S100b facilitated neuronal responses to orthodromic
      stimulation. Idiotypic antibodies against protein S100b suppressed changes in
      neuronal responses to orthodromic stimulation during long-term potentiation,
      while antiidiotypic antibodies facilitated these effects. Our findings suggest
      that the effects of idiotypic and antiidiotypic antibodies to protein S100b are
      associated with their regulatory influences on synaptic transmission. These
      mechanisms differ from mechanisms of synaptic plasticity involved in long-term
      potentiation.

PMID- 12428275
TI  - Effect of static and dynamic influences on receptors of equilibrium organ of
      Helix lucorum after 163-day orbital flight in "Mir" station.
AB  - A 163-day orbital flight increased the baseline impulse activity of statocyst
      receptor cells in terrestrial pulmonata snail Helix lucorum. The maximum of
      reaction to step static stimuli (changes in body position in the range from 0 to
      180 degrees) was significantly shifted by 30 degrees from gravitational vertical,
      while the reaction to dynamic stimuli (dumped sinusoidal oscillations) faded more
      rapidly than in control animals.

PMID- 12428276
TI  - Immunomodulation of inherent behavior in C57Bl/6 and BALB/c mice with antibodies
      to glutamate.
AB  - Immunization of BALB/c mice with glutamate-BSA conjugate reduced anxiety and
      improved passive avoidance retention, while in C57Bl/6 mice immunization
      disturbed passive avoidance retention, but had no effect on anxiety. Interstrain
      differences in the shuttle box behavior were found between control animals.

PMID- 12428277
TI  - Endogenous cannabinoids improve myocardial resistance to arrhythmogenic effects
      of coronary occlusion and reperfusion: a possible mechanism.
AB  - Stimulation of cannabinoid receptors with endogenous cannabinoid anandamide and
      its enzyme-resistant analogue R-(+)-methanandamide improved cardiac resistance to
      arrhythmias induced by coronary occlusion and reperfusion. This antiarrhythmic
      effect was not associated with activation of NO synthase, since pretreatment with
      NG-nitro-L-arginine methyl ester had no effect on the incidence of
      ischemia/reperfusion-induced arrhythmias. Blockade of ATP-dependent K+ channels
      with glybenclamide did not abolish the antiarrhythmic effect of R-(+)
      methanandamide. Antiarrhythmic activity of endogenous cannabinoids is probably
      associated with their direct effects on the myocardium.

PMID- 12428279
TI  - Changes in the count of pancreatic beta- and alpha-cells and blood glucose level
      in rats with alloxan-induced diabetes.
AB  - We estimated the count of pancreatic alpha- and beta-cells and blood glucose
      level at various stages of alloxan-induced diabetes in rats. Alloxan decreased
      the count of insulin-producing beta-cells, but increased the number of glucagon
      secreting alpha-cells in the pancreas (week 1 of diabetes). These changes were
      accompanied by hyperglycemia. The decrease in blood glucose level in diabetic
      rats was associated with an increase in beta-cell count against the background of
      high density of pancreatic alpha-cells.

PMID- 12428278
TI  - Activation of cannabinoid receptors decreases the area of ischemic myocardial
      necrosis.
AB  - We studied the possibility of decreasing the area of ischemic necrosis during
      myocardial infarction with HU-210, a selective cannabinoid receptor agonist.
      Activation of cannabinoid receptors with HU-210 had practically no effect on
      collateral blood flow in the myocardium, but considerably decreased the area of
      necrosis. There results indicate that cannabinoid receptor agonist HU-210
      possesses cardioprotective activity and delays the formation of necrotic zones
      during coronary occlusion and reperfusion.

PMID- 12428280
TI  - Effects of prenatal stress on formalin-induced acute and persistent pain in adult
      male rats.
AB  - Behavioral responses of 90-day-old male offspring from female Wistar rats exposed
      to restraint stress during the last week of pregnancy were studied in the
      formalin test. Specific biphasic behavioral response characterized acute (phase
      1) and persistent tonic pain (phase 2). The intensity of nociceptive responses
      (evaluated by the number of flexions + shakings and by the duration of paw
      licking) in prenatally stressed rats changed only during phase 2. During
      interphase, facilitation of the flexion + shakings pattern (but not the licking
      pattern) in response to nociceptive stimulation was seen. The response intensity
      during phase 1 and the duration of both phases remained unchanged. Our findings
      suggest that prenatal stress modulates nociceptive sensitivity in 90-day-old
      offspring: it affects the duration of tonic (inflammatory), but not of acute
      pain. It is concluded that different mechanisms are responsible for the effects
      of prenatal stress on acute and persistent pain in the formalin test.

PMID- 12428281
TI  - Protective effect of Biolan during ischemic damages to cultured cerebellar
      granular cells.
AB  - Biolan containing carnosine and delta sleep-inducing peptide produced a
      protective effect on cerebellar granular cells from 7-day-old rats exposed in
      culture to ischemia (oxygen and glucose deprivation) and cytotoxic influence of
      glutamate. These results indicate that Biolan holds much promise for correction
      of ischemic brain damages in clinical practice.

PMID- 12428282
TI  - Antioxidant effects of Bemitil during acute cerebral hypoxia.
AB  - Bemitil (25 mg/kg) prevented activation of lipid peroxidation and inhibition of
      the antioxidant system in rat brain during acute hypoxic hypoxia.

PMID- 12428283
TI  - Systemic endotoxemia during chronic viral hepatitis.
AB  - Incidence and severity of systemic endotoxemia in patients with chronic viral
      hepatitis B and C were studied using the limulus test. Healthy subjects and
      patients with acute viral hepatitis B and C comprised reference groups. The
      incidence of "physiological" systemic endotoxemia in healthy subjects was 31.3%,
      while in chronic hepatitis systemic endotoxemia was found in 69-84% patients and
      it was more severe in this case. A significant correlation was revealed between
      systemic endotoxemia with virus replication and the degree of basic clinical and
      laboratory signs in patients with chronic viral hepatitis B.

PMID- 12428284
TI  - Identification and characterization of serum protein in patients with ovarian
      cancer.
AB  - A 36 kDa protein was isolated from the sera of patients with ovarian cancer and
      rabbit antisera to this protein were prepared. Precipitation test with these
      antisera detected an antigen with electrophoretic mobility corresponding to alpha
      1-globulins and molecular weight of 36 kDa. Direct comparison of precipitating
      test systems showed that this antigen is not identical to the known
      carcinoembryonic, placental, and reactive proteins. Serum alpha-1-globulin was
      not detected in the sera of healthy humans, pregnant women, newborns, and in
      human adult and fetal visceral tissues at the level of precipitating test system
      sensitivity 1 mg/liter. It was detected in the sera of patients with ovarian
      cancer, in ovarian tumor (cancer) tissues, in the contents of ovarian tumor
      cavities, and in concentrated specimens of amniotic fluid. The antigen was not
      detected in ascitic fluid of patients with ovarian cancer, but it was present in
      75% serum samples from these patients. The antigen was called serum oncoovarian
      alpha-1-globulin. SDS-PAAG electrophoresis showed that this antigen is an
      oligomer consisting of subunits (monomers) with molecular weight of 36 kDa. Under
      denaturing conditions in the presence of 2-mercaptoethanol these monomers
      dissociate into polypeptide chains with a molecular weight of 18 kDa. The protein
      is liable to oligomerization. Comparative characteristics of serum oncoovarian
      alpha-1-globulin and CA-125 antigen are presented.

PMID- 12428285
TI  - Pathogenetic role of dysbacteriosis in the development of complications of type 1
      diabetes mellitus in children.
AB  - A relationship between enteric microbiocenosis and severity of type 1 diabetes
      mellitus was detected. Microbiological analysis showed II-IV degree
      dysbacteriosis in all diabetic children. Long-term therapy with probiotics aimed
      at eradication of opportunistic microflora resulted in recovery of
      microbiocenosis, which was paralleled by improvement of the clinical status,
      regression of complications in children who were ill for a long time, and
      prevention of complications in children with newly detected diabetes. These
      results indicate the leading role of chronic enteric toxic infectious process in
      the development of complications of type 1 diabetes. The significance of
      infection in the pathogenesis of other noninfectious diseases in man is
      discussed.

PMID- 12428286
TI  - Epithalon inhibits tumor growth and expression of HER-2/neu oncogene in breast
      tumors in transgenic mice characterized by accelerated aging.
AB  - Female transgenic FVB mice carrying breast cancer gene HER-2/neu were monthly
      injected with Vilon or Epithalon (1 microgram subcutaneously for 5 consecutive
      days) starting from the 2nd month of life. Epithalon markedly inhibited neoplasm
      development: the maximum size of breast adenocarcinomas was 33% lower than in the
      control (p < 0.05). The intensity of HER-2/neu mRNA expression in breast tumors
      of Epithalon-treated mice was 3.7 times lower than in control animals. These
      results indicate that Epithalon inhibits breast tumor development in transgenic
      mice, which is probably related to suppression of HER-2/neu expression.

PMID- 12428287
TI  - Bone mineralization in senescence-accelerated OXYS rats.
AB  - We compared age-related changes in the mineral composition of bone tissues in
      Wistar and senescence-accelerated OXYS rats. The mass concentrations of calcium,
      phosphorus, and magnesium were measured by atomic emission spectrometry. OXYS
      rats are characterized by early mineralization of the bone tissue, which peaked
      by the 6th month of life. Mineralization defects in 12-month-old OXYS rats
      included accumulation of iron and phosphorus, decrease in the Ca/P ratio, and
      increase in ash weight. These changes reflected early development and accelerated
      aging of these animals. Studies of the bone tissue in OXYS rats indicate that
      these animals can be used for evaluation of the mechanisms of involutional
      osteoporosis.

PMID- 12428288
TI  - Generation of reactive oxygen species by mitochondria in senescence-accelerated
      OXYS rats.
AB  - Chemiluminescence assay showed that oxygen reduction and production of superoxide
      anion and hydrogen peroxide by liver mitochondria in OXYS rats highly sensitive
      to oxidative stress were less intensive than in Wistar rats. Experiments with
      cytochrome c oxidase inhibitors showed that decreased O2-. generation in
      mitochondria of OXYS rats is probably associated with changes in complex III of
      the electron transport chain.

PMID- 12428289
TI  - Spontaneous infection of lower primates with hepatitis C virus.
AB  - We present serological and virological evidence of spontaneous infection in Old
      World lower monkeys with human hepatitis C virus or, maybe, antigenically related
      but genetically different simian virus strain. These data is of both theoretical
      and practical importance and can serve as the basis for further development of
      experimental model of hepatitis C on lower monkeys.

PMID- 12428290
TI  - Disturbances of saccadic eye movements in monkeys during development of MPTP
      induced syndrome.
AB  - Changes in the amplitude and dynamic parameters of purposive saccades were
      studied in monkeys with MPTP-induced Parkinson-like syndrome. Lengthening of
      saccade latency, decreased maximum velocity of eye movements, and impaired
      saccade accuracy were observed at the early stages MPTP-syndrome. Different
      disturbances of large- and small-scale saccades were found.

PMID- 12428291
TI  - Regulatory structures of cerebral and renal arteries in experimental hyper- and
      hypotension.
AB  - Brain and kidneys from 15 control and 70 experimental puppies with hemodynamic
      model of coarctation of the aorta were examined. The number of regulatory muscle
      formations was increased in the brain and decreased in the kidneys during
      modeling of aorta coarctation associated with hyper- and hypotension in the
      corresponding basins. The location of these structures in cerebral and renal
      distribution and resistance vessels is analyzed.

PMID- 12428292
TI  - Comparative evaluation of blood vessels in serous tumors of the ovaries by color
      Doppler mapping and morphometry.
AB  - Morphometric study of blood vessels in serous tumors of the ovaries was carried
      out. Vascularization of benign, borderline, and malignant tumors is different,
      which agrees with the data of color Doppler mapping. Pronounced morphological
      changes in vascular wall (degenerative changes, sclerosis, and hyalinosis) were
      detected mainly in borderline and malignant tumors.

PMID- 12428293
TI  - Experimental study of reparative regeneration processes in the wound treated with
      bioactive dressings.
AB  - Quantitative and structural functional analysis of granulation tissue cells
      during treatment with protein-polysaccharide dressing Collahit F was carried out.
      The preparation effectively cleansed the wound from detritus, prevented secondary
      infection due to stimulation of the functional activity of macrophages and due to
      the effect of its antiseptic component (furagin), and stimulated proliferative
      activity of fibroblasts and granulation tissue microvessels on day 5 of
      treatment, thus promoting repair processes in the wound.

PMID- 12428294
TI  - Thymic hormones in human fetal skin epidermis.
AB  - Thymic hormone thymalin is detected in young epidermal cells of human fetuses.
      Its content varies with gestation age. Maturation of keratinocytes in the
      epidermis is paralleled by a decrease in the population of young thymalin
      positive cells. By birth they are located on the basal membrane and in some
      adjacent layers. This regularity was seen in different parts of the body.

PMID- 12428295
TI  - A method for estimation of urease activity in gastric mucosa biopsy specimens and
      Helicobacter pylori cell suspensions.
AB  - A method for measuring urease activity in biopsy specimens and Helicobacter
      pylori cultures from these specimens is proposed. The method is based on
      measurement (with a portable pH-meter) of the rate of pH changes in a reaction
      mixture consisting of buffer, substrate (urea), and biopsy specimen or bacterial
      cells. This method revealed that urease activity of biopsy specimens correlated
      with that of H. pylori suspension in the same experiment. High urease activity
      was found in biopsy specimens containing the greatest number of Helicobacter
      cells; only one of 14 specimens free of H. pylori cells showed no urease
      activity. Introduction of this method into clinical practice will help to
      evaluate the contribution of H. pylori to the pathological process.

PMID- 12428296
TI  - Neuroprotective effect of hypoxic preconditioning: phenomenon and mechanisms.
AB  - We developed a new model of hypoxic preconditioning improving tolerance of
      complete global cerebral ischemia. The role of adenosine receptors in the
      realization of this effect and in the mechanisms of hypoxic tolerance is
      demonstrated. Preconditioning decreases of body temperature, which correlates
      with the neuroprotective effect, but this effect does not directly result from
      hypothermia.

PMID- 12428297
TI  - [Experimental study of the immunomodulator effect of pentoxifylline in bacterial
      translocation produced by lipid-free parenteral nutrition].
AB  - INTRODUCTION: Bacterial translocation (BT) leads to sepsis of intestinal origin
      and, despite current advances, there is a high level of mortality and morbidity
      as a result of this. We have attempted to investigate whether such an immunity
      modulating substance as Pentoxiphylline (PX) might diminish or inhibit BT. We
      have chosen PX because it has immunity modulation actions and inhibits the
      synthesis and action of TNF-alpha, which seems to be linked to the progress of
      these conditions towards multiple organ failures. MATERIAL AND METHOD: An
      experimental study was performed with 4 groups of 20 Wistar rats subjected to
      lipid-free parenteral nutrition (PN) over 7 days. Group A: PN; group B: PN + 50
      mg/kg of PX; group C: PN + 100 mg/kg; and group D: PN + 134 mg/kg. On day 7, a
      sterile extraction was effected to remove the mesenteric ganglial chain, liver,
      blood and intestine, and these samples were processed for the quantitative and
      qualitative microbiological study, the histological study of the intestinal
      mucosa and the quantification of TNF-alpha. The data obtained were subsequently
      analyzed statistically. RESULTS: The quantitative microbiological study revealed
      that, with statistically significant differences, more colonies grew in the
      lymphatic ganglion, liver and blood of animals belonging to group A. The germ
      most frequently identified was E. Coli. In the study of TNF-alpha, the greatest
      value corresponded to group A, again with statistically significant differences.
      In the histological study, it was observed that group A showed the greatest
      atrophy. CONCLUSIONS: Our experimental model is valid as a model of BT, in group
      A, without PX, a total of 16 BT occurred while in the groups with PX the number
      of BT fell, as did the serum figures for TNF-alpha.

PMID- 12428298
TI  - [Effect of changes in body weight on rest energy expenditure in critically ill
      patients].
AB  - AIM: Critically ill patients may present rapid and significant variations in body
      weight in excess of 20%, attributed to acute changes in the volume of
      extracellular water. These changes should not alter the level of metabolic
      activity, as the extracellular compartment is metabolically inactive. The purpose
      of this study has been to verify whether or not the rapid changes in body weight
      presented by critically ill patients over short periods of time alter the at-rest
      energy expenditure (GER in its Spanish acronym). PATIENTS: Out of a group of 55
      critically ill patients whose GER had been repeatedly measured, 15 were chosen as
      two of their GER measurements complied with the following clinical conditions: a
      difference in body weight of more than 5%, a time difference of less than 10 days
      between both measurements, a variation of less than 20% in the calorie intake, a
      difference in axillary temperature of less than 1 degree centigrade (degree C)
      and the same sedation and/or analgesia. All of the patients presented acute
      kidney failure. Their GER was measured with a system based on the bell spirometer
      (Calorimet). RESULTS: The variation in body weight was 7.3 +/- 2.12 kg. The
      difference between the GER with high and low body weight was, in absolute terms,
      154 +/- 162 kcal/day (p = 0.003) and, in terms of body weight, -0.6 +/- 1.9
      kcal/kg/day (p = 0.21). A statistically significant (r = 0.77 and p > 0.001)
      linear relationship was observed between the variations in body weight and the
      GER expressed as a percentage [[symbol: see text] GER (%) = -1.77 + [symbol: see
      text] peso (%)]. CONCLUSION: The variation in body weight presented by critically
      ill patients over short periods of time is associated with changes in the GER.

PMID- 12428299
TI  - [Nutritional evaluation in patients with total gastrectomy].
AB  - Gastric cancer continues to be the second cause of cancer-related mortality in
      the world. Surgery is the only potentially curative therapy, although the adverse
      effects of surgery are considerable and include digestive symptoms, loss of
      appetite and malnutrition. Our study included 45 patients subjected to
      gastrectomy who were under treatment at our unit during 2000. The data given here
      refer to their first visit following surgery. The most frequent complications
      were diarrhoea (31%), pain (29%) and early dumping (24%). Other complications
      found were late dumping, nausea/vomiting and dysphagia. Anorexia appeared in 49%
      and 29% presented a negative attitude towards food. These complications give rise
      to insufficient food intake, leading to malnutrition, mainly marasmic in nature.
      Only 7% of the patients were normonourished, with 86% presenting slight or
      moderate malnutrition and 7% severe malnutrition. The mean Body Mass Index (BMI)
      of these patients was 20 +/- 3 kg/m2. The most frequent analytical alterations
      were anaemia with ferropenia and b12 deficit, and a reduction in the levels of
      zinc and retinol transporting protein. Many patients had impaired quality of
      life; 43% did not leave home and only 13% were able to work. Three groups were
      established depending on the time that had passed since the gastrectomy was
      performed before the first nutritional assessment (less than 3 months, from three
      months to a year, and over one year), without significant differences being found
      in any of the parameters studied. In this article we include recommendations for
      the nutritional handling and treatment of patients following gastrectomy.

PMID- 12428300
TI  - [Use of lyophilized products in texture modified diets at a hospital].
AB  - BACKGROUND: Decrease in the capacity to deglutition solids and liquids is a
      problem in many people, this problem decreases quality of life. The objective of
      our study is to compare the acceptance of texture modifies courses against
      conventional courses. METHODS: A total of 70 patients were studied in our
      Hospital. First, 35 patients received a modified texture diet with conventional
      products and the next 35 patients received a modified texture diet with
      lyophilised products. All patients responded the next questions after to take the
      diets; texture, taste, smell and color. RESULTS: A total of 70 patients were
      studied (38 males and 32 females), the mean age was 74.9 +/- 16.8 years, no
      differences were detected between both groups (76.6 +/- 17.1 years vs 73.7 +/-
      16.67 years). Lyophilised diets had better medians than conventional diets in all
      parameters; taste, smell, color and texture. CONCLUSION: Acceptance of
      lyophilised dishes were better than conventional dishes. These products could
      improve nutritional state in these patients.

PMID- 12428301
TI  - [Anthropometric values in a very elderly institutionalized population].
AB  - The purpose of the present study has been to determine, in a population group
      over 80 years of age in a publicly-funded geriatric institution, the
      anthropometric parameters that represent reference values for the study of
      nutritional status. These parameters allow detection of alterations in the
      nutritional status which, once corrected, will contribute to maintaining an
      appropriate quality of life in a population group that is highly sensitive to the
      associated morbidity and mortality processes. In order to carry out this study, a
      sample of 56 healthy elderly individuals was selected (13 men and 43 women) with
      a mean age of 86.5 +/- 4.8 years and a range from 80 to 101 years. The parameters
      measured were: weight, height, tricipital fold, brachial perimeter and the
      following values calculated on the basis of these figures: body mass index,
      percentage of body fat, brachial muscular area, brachial muscular perimeter,
      brachial adipose area and the ratio of muscle to adipose tissue. These values
      were processed statistically with the assistance of the RSB-SIGMA computer
      software, with calculation of the percentiles, the mean, and the comparison
      between the sexes. The criterion for statistical significance was set at p <
      0.05. Our results confirm the presence of significant differences in the muscle
      parameters, which are greater in men than in women, whereas the fat parameters
      are higher in the latter. Thus, it is concluded that weight, height, brachial
      muscle area and brachial muscle perimeter are significantly higher in men whereas
      tricipital fold, percentage of body fat, the brachial adipose area and the muscle
      to adipose tissue ratio are significantly superior among women. There are no
      significant differences by gender in the body mass index and the brachial
      perimeter.

PMID- 12428302
TI  - [Survey on parenteral nutrition preparation variability in pediatrics].
AB  - The prescription and preparation of paediatric parenteral nutrition in Spain are
      subject to great variability. AIM: To identify how paediatric parenteral
      nutrition is prescribed and prepared in Spain. MATERIAL AND METHODS: During the
      first quarter of 2001, a telephone survey was carried out among most of the
      hospitals in which parenteral nutrition is habitually prepared. The survey
      included questions on who was in charge of the prescription, the use of different
      solutions, addition of supplements (carnitine, heparin and glutamine), as well as
      information on the shelf-life of the mixtures. Subsequently, the results of the
      survey were compared with the following guidance documents: "Enteral and
      parenteral nutrition in paediatrics", drafted under the auspices of the Spanish
      Association for Paediatric Gastroenterology, Hepatology and Nutrition (2000) and
      the "Guidelines for the use of parenteral and enteral nutrition in adult and
      paediatric patients"/"Nutrition support practice manual" from the American
      Society for Parenteral and Enteral Nutrition (1998). RESULTS: Of the 48 hospitals
      surveyed, paediatric parenteral nutrition was not prepared in 12 of them. the
      number of food bags prepared daily correlated directly with the size of the
      hospital. In all cases, the paediatricians were responsible for prescription. In
      87% of the centres, this prescription was customized (i.e. solutions adapted to
      each individual patient). All of the hospitals used dextrose as the source of
      carbohydrates and specific amino acid solutions for paediatric medicine.
      Basically, lipid emulsions with long chain triglycerides were used in 65% of
      cases and another 19% used physical mixtures of MCT and LCT. Only half of the
      hospitals routinely used all-in-one mixtures. Inorganic phosphate continued to be
      used in most cases (78%) versus sodium glycerol phosphate. Vitamins and trace
      elements were added daily in 65% of the hospitals, with alternate administration
      in the remainder. In half of the centres, heparin was added to the mixture and
      carnitine in 27%. For 40% of the centres responding to the survey, the solution
      had to be used within 24 hours of its preparation; 11% did not indicate the shelf
      life. CONCLUSIONS: Although parenteral nutrition is prescribed by the
      paediatricians on all occasions, the preparation protocols differ significantly
      between hospitals. Standardization is exceptional. It is noteworthy that all-in
      one mixtures are only used in half of the hospitals surveyed. We suggest the
      creation of a multidisciplinary working party (pharmacists, paediatricians,
      neonatologists) in order to draw up protocols for the preparation of paediatric
      parenteral nutrition.

PMID- 12428303
TI  - [Perception of sweet and salty flavors in different population groups].
AB  - The flavour perceived by humans when eating varies depending on age, gender,
      habits, emotional status, etc. The present study reflects the changes in the
      perception of sweet and salt flavours among different population groups depending
      on age, with an assessment, for each flavour, of the threshold concentration for
      the detection of these flavours. Triangular discrimination sensorial tests were
      performed in three groups, with thirty members in each, classified to represent
      young, adult and elderly age groups. With regard to sweet flavours, the groups of
      young people and adults distinguished the different sample at 0.1% of sugar for
      95% and 99% significance levels, whereas the elderly required the concentration
      to reach 1% at both levels before they could distinguish the sugar solution from
      water. In the case of salt flavours, young people are able to detect the
      different sample at the lowest concentration level, for both levels of
      significance. Adults significantly distinguished the sample containing 0.05% of
      salt, at the 95% significance level, whereas the elderly needed a concentration
      of 0.1% for both levels of significance. Age-dependent variations in response
      were observed. As age increases, greater concentrations are required in order to
      distinguish the salt or sweet solutions from the samples containing only water.

PMID- 12428304
TI  - Progress and tradition.

PMID- 12428305
TI  - Unusual dental erosion caused by a cola drink.

PMID- 12428306
TI  - 2002 JCO study of orthodontic diagnosis and treatment procedures. Part 1. Results
      and trends.

PMID- 12428307
TI  - JCO interviews Martin L. 'Bud' Schulman on success through sharing. Interview by
      Eugene L. Gottlieb.

PMID- 12428308
TI  - The distal jet simplified and updated.

PMID- 12428309
TI  - A simple method of molar uprighting with micro-implant anchorage.

PMID- 12428310
TI  - Flowable composites for bonding lingual retainers.

PMID- 12428311
TI  - [Serum and urinary inorganic fluoride concentrations with renal and hepatic
      functions after repeated sevoflurane anesthesia].
AB  - The purpose of this study is to examine changes in serum and urinary inorganic
      fluoride (F) concentrations with their effects on renal and hepatic functions
      after repeated sevoflurane anesthesia with relatively short time interval. Eight
      patients received sevoflurane anesthesia twice within 7 days for gynecological
      surgery. Serum and urine F levels before induction, 0.5 and 1 hour after
      induction, and 0.5 hour after anesthesia were compared between first and second
      anesthesia. There were no significant differences in serum and urine F
      concentrations at the same point between first and second anesthesia. Two obese
      patients exhibited peak concentrations greater than 50 mumol.l-1 of F. Laboratory
      findings of renal function remained stable throughout 2 operations, whereas
      hepatic function deteriorated in the two obese patients after the first
      anesthesia, and resolved within 14 days after the second anesthesia. In
      conclusion, it is suggested that the second exposure to sevoflurane within 7 day
      interval does not alter the sevoflurane metabolism. However, obesity may
      contribute to a rise in serum inorganic fluoride after repeated sevoflurane
      anesthesia.

PMID- 12428312
TI  - [Comparison of zopiclone and midazolam premedication for preoperative
      anxiolysis].
AB  - To compare the anxiolysis property of zopiclone (ZPC) and midazolam (MDZ), 117
      patients were given zopiclone 7.5 mg p.o. or midazolam 0.05 mg.kg-1 i.m. as
      premedication. In the study 1, patients were randomly allocated to 4 groups: ZZ
      group (n = 16) received ZPC in the night before operation and 2 h before
      operation, ZM group (n = 18) received ZPC in the night before operation and MDZ 1
      h before operation, Z group (n = 18) received ZPC 2 h before operation, and M
      group (n = 24) received MDZ 1 h before operation. The degree of anxiety was
      evaluated using the state-trait anxiety inventory (STAI) on the day before
      operation and after receiving premedication. ZPC showed a significant reduction
      in the STAI score in the ZZ and Z group, but premedication with MDZ showed no
      changes in the STAI score. In the study 2, patients were randomly allocated to 2
      groups: ZPC group (n = 22) received ZPC 2 h before operation, and M group (n =
      19) received MDZ 1 h before operation. The degree of anxiety was evaluated using
      the visual analog scale (VAS) on the day before operation and after receiving
      premedication. ZPC showed a significant reduction in the VAS score, but MDZ
      showed no changes in the VAS. It is concluded that ZPC (7.5 mg p.o.) is suitable
      to reduce the preoperative anxiety in patients who are to undergo surgery as
      compared to MDZ (0.05 mg.kg-1 i.m.).

PMID- 12428313
TI  - [Induced hypotension for endoscopic sinus surgery].
AB  - The purpose of the present investigation is to examine whether induced
      hypotension can improve the dryness of the surgical field in endoscopic sinus
      surgery (ESS). ASA physical status I and II adult patients with chronic sinutitis
      undergoing ESS were studied. All patients were not premedicated. Anesthesia was
      induced with propofol and maintained with sevoflurane and fentanyl. The patients
      were allocated randomly into two groups. In patients of Group C, mean arterial
      blood pressure (MAP) was maintained around 80 mmHg. In Group H, sodium
      nitroprusside was infused to maintain controlled hypotension with MAP around 60
      mmHg. Blood loss, dryness of the surgical field, volume of fluid infusion and
      urine output, and surgical as well as anesthetic time were compared. Blood loss
      and dryness of the surgical field were significantly different between the
      groups. Volume of infused fluid, urine output, and surgical as well as anesthetic
      time were not significantly different. Induced hypotension with sodium
      nitroprusside improved surgical conditions and decreased blood loss in ESS.

PMID- 12428314
TI  - [Spread of local anesthetic solutions in the thoracic epidural space].
AB  - The segmental spread of thoracic epidural analgesia was measured in 14 patients
      scheduled for elective surgery with ages ranging from 35 to 80 years. Epidural
      puncture was performed in the seventh or eighth thoracic intervertebral space
      using 17 gauge Tuohy needle with the patient in the left lateral position. The
      epidural space was identified using "loss of resistance technique". With the
      bevel of the needle pointing towards the head, 7-10 ml of 2% mepivacaine was
      injected at the rate of 1 ml.sec-1. Fifteen minutes after injection of
      anesthetic, the spinal segments anesthetized were determined by absence of cold
      sensation. A statistically significant correlation was found between age and a
      segmental dose (ml.seg-1) (r = -0.72), and between age and a segmental dose
      corrected by height (ml.seg-1.m-1) (r = -0.65).

PMID- 12428315
TI  - Flumazenil antagonizes respiratory depression caused by diazepam and induces
      expiratory excitation of hypoglossal nerve.

PMID- 12428316
TI  - [A case of bradycardia in a patient with secondary hypothyroidism].
AB  - A 68-year-old patient was scheduled for subtotal gastrectomy. Preoperative
      examination showed heart rate of 30-40 beats.min-1 caused by secondary
      hypothyroidism. Triiodothyronine and thyroid stimulating hormone concentrations
      were 1.9 pg.ml-1 and 0.17 microU.ml-1 respectively. To treat bradycardia, the
      patient was given isoproterenol hydrochloride (ISP: 0.01-0.03 microgram.kg-1.hr
      1) for 5 days before surgery. Heart rate recovered to 70-80 beats.min-1, and the
      dosage could be tapered off before surgery without return of bradycardia. The
      operation was performed successfully under general anesthesia. We reported the
      anesthetic management of this patient with severe bradycardia due to secondary
      hypothyroidism. This case suggests that preoperative treatment for the symptoms
      is important for anesthetic management of a patient with hypothyroidism.

PMID- 12428317
TI  - [A case of intraoperative repeated coronary artery spasm with ST-segment
      depression].
AB  - A 68-year-old man with good left ventricular function underwent subtotal
      gastrectomy for gastric cancer under general anesthesia. Twenty minutes after the
      start of surgery, ST-segment depression was noted on the electrocardiogram
      monitor without change in the hemodynamic state. Intravenous isosorbide dinitrate
      relieved the electrocardiographic signs of ischemia. Short episodes of the ST
      segment depression recurred 5 times despite intravenous isosorbide dinitrate and
      nicorandil. Echocardiography immediately after the surgery revealed hypokinesia
      of the anterior, septal and apical segments with an ejection fraction of 48%,
      suggesting acute myocardial infarction or the "Takotsubo"-shaped cardiomyopathy.
      However, a day after surgery, echocardiography showed improvement of regional
      wall motion with an ejection fraction of 57%. Coronary angiography showed normal
      coronary arteries on the 22nd day after the surgery. Patient manifested occlusive
      coronary artery spasm on ergonovine provocative test. We would like to stress
      that perioperative coronary artery spasm may demonstrate ST-segment depression
      and may result in severe consequences, regressive but relatively prolonged, in
      left ventricular function.

PMID- 12428318
TI  - [Skin burn after radiofrequency liver ablation of metastatic tumor].
AB  - Radiofrequency ablation (RFA) is used to treat unresectable liver tumor. The
      authors described a case of RFA complicated by skin burn around a ground pad. A
      70-year-old female underwent RFA of liver metastatic tumor under general
      anesthesia. Preoperatively, two ground pads were placed on the patient's right
      thigh and right calf after left lateral positioning. RFA was performed three
      times by 90 watts for 15 min each. At the end of surgery we noticed skin burn on
      the right thigh. It seems that electric current concentrated on the ground pad of
      the right thigh especially on the proximal side. In conclusion, two ground pads
      should be placed one on each thigh to distribute electric current.

PMID- 12428320
TI  - [Paravertebral block for labor analgesia in a parturient with idiopathic
      thrombocytopenia].
AB  - A parturient with idiopathic thrombocytopenia received labor analgesia with
      bilateral paravertebral blocks, because epidural analgesia was contraindicated
      due to her low platelet count (69,000.microliter-1) even after intravenous
      administration of freeze-dried sulfonated human normal globulin (400 mg.kg-1.day
      1) and transfusion of platelet (20 units.day-1). In spite of predonisolone (1
      mg.kg-1.day-1) p.o., her platelet counts could not increase at early gestation
      period. Prior to the induction of the labor, two catheters were inserted into T
      11 bilateral paravertebral spaces, then 0.2% ropivacaine 10 ml was administered
      in each side, followed by the infusion at 5 ml.hr-1 each for the management of
      first stage of labor pain. Labor was induced with oxytocin infusion at 2.5-5.0
      mU.min-1. As she requested additional analgesia in the second stage of labor,
      fentanyl 50 micrograms was administered twice intravenously. The labor course was
      uneventful with adequate analgesia, and the neonate (2,826 g) was vigorous with
      Apgar scores 9/10. Complications associated with this block such as hypotension,
      vascular or pleural punctures and pneumothorax were not seen. Bilateral
      paravertebral blocks may provide adequate analgesia as an alternative method for
      labor analgesia in a parturient with thrombocytopenia when conventional epidural
      analgesia is contraindicated.

PMID- 12428321
TI  - [Compartment syndrome in a young male caused by acute alcoholic rhabdomyolysis].
AB  - We report a case of young male who developed compartment syndrome of his left leg
      caused by rhabdomyolysis following a heavy binge of alcohol. The laboratory data
      on his admission revealed extremely elevated serum levels of CPK (108,021 IU.l
      1). The serum levels of potassium and creatinine were within normal ranges. He
      also had myoglobinuria. He required fasciotomy after admission. Diuretics and a
      large volume of fluids were given to prevent the renal failure. His postoperative
      course was uneventful. The direct toxic effects of alcohol and the prolonged
      ischemia of his lower leg induced by acute alcoholic intoxication, are thought to
      have played a major role in the triggering of the acute rhabdomyolysis. Acute
      alcoholic rhabdomyolysis should be considered in any intoxicated patient who
      presents muscle tenderness and weakness. The early recognition and prompt
      treatment are essential to prevent serious complications.

PMID- 12428322
TI  - [Rosai-Dorfman disease accompanying hypertrophic cranial pachymeningitis with an
      early symptom of right peripheral facial palsy].
AB  - We experienced a rare case of sinus histiocytosis with massive lymphoadenopathy
      (Rosai-Dorfman disease) accompanying hypertrophic cranial pachymeningitis. The
      patient is a 64-year-old woman with an early symptom of rt. peripheral facial
      palsy. She had a 4-month history of headache with a 5-week history of numbness in
      the rt. supraorbital nerve area, and lost her weight by 10 kg in 2 months. She
      developed rt. trochlea nerve palsy and numbness in the lt. mandibular nerve area.
      Laboratory findings showed that ALP, LDH and CRP were higher than normal. Of CT,
      MRI and MRA, the images of her head were normal. However, the Gd-enhanced MRI
      only showed a diffuse pachymeningeal enhancement. After about 3 months from the
      onset of rt. peripheral facial palsy, she died of DIC of unknown etiology. As a
      result of examinations in anatomical pathology, she was diagnosed as having sinus
      histiocytosis with massive lymphoadenopathy (Rosai-Dorfman disease). There were a
      large number of histiocytes on the pachymeninx. These findings suggest that
      hypertrophic cranial pachymeningitis caused multiple cranial neuropathy. We
      emphasize that use of Gd-enhanced MRI in the early stage is important for
      diagnosis.

PMID- 12428323
TI  - [Perioperative management for carotid endoarterectomy with induced mild
      hypothermia: a case report].
AB  - We report perioperative management for carotid endoarterectomy with induced mild
      hypothermia in a patient with severe stenosis of the bilateral carotid arteries.
      The patient was a 47 year-old male with familial hyperlipidemia and history of
      coronary artery bypass surgery. Angiography revealed severe stenotic lesions of
      the right internal carotid artery (ICA) and total occlusion of the left ICA.
      Endoarterectomy for the right ICA was planned. Anesthesia was induced and
      maintained with fentanyl, midazolam, pancuronium and sevoflurane.
      Electroencephalogram and near-infrared cerebral oxymetry were employed for
      monitoring intraoperatively. Temporary shunting was used during clamping of the
      right carotid artery because collateral blood flow could not be expected due to
      total occlusion of the left ICA. Furthermore, mild hypothermia down to 34 degree
      C was induced for brain protection with the use of a cooling blanket. After the
      surgery, the patient was transferred to ICU under deep anesthesia and controlled
      ventilation. Anesthesia was lightened gradually after rewarming to prevent
      postoperative shivering. The patient left ICU on the second postoperative day
      without any neurological deficits.

PMID- 12428324
TI  - [A case of gastrectomy under continuous subdural anesthesia].
AB  - Unintentional subdural block, while attempting epidural block, is known as a
      complication. The authors used a catheter which had happened to be introduced
      into the subdural space, for clinical anesthesia and postoperative pain relief.
      For a 75-year-old male patient, gastrectomy was scheduled under epidural
      anesthesia. Epidural puncture was at the T 7 and T 8 interspace using loss of
      resistance method with saline under fluoroscopic guidance. We examined the
      catheter position by injecting iopamidol and confirmed subdural catheterization
      by subsequent computed tomography. After obtaining informed consent and agreement
      from the patient, "subdural anesthesia" was conducted. Ten ml of 0.5% bupivacaine
      was injected with 20 mg ephedrine as an initial dose. Twenty min after the
      injection, pin pricking revealed that analgesia had extended from the C 5 to S 1
      dermatoms. Consciousness was clear and blood pressure was stable. Then, surgery
      was started. Since blood pressure tended to fall down gradually, we injected 40
      mg of ephedrine subcutaneously 45 min after the subdural injection. At a 2 hours
      interval from the initial subdural injection, 5 ml of 0.5% bupivacaine was
      additionally injected. Respiration was stable throughout the surgery and the
      surgery was finished uneventfully. Analgesic level was from C 5 through S 3 at
      the end of surgery. Bupivacaine 0.25% was continuously infused at a rate of 2
      ml.h-1 for 7 days for postoperative pain relief. The patient never complained of
      pain during the period. This report demonstrates that subdural block has a
      potential capability as an anesthesia for laparotomy as far as it is managed
      properly.

PMID- 12428325
TI  - [Efficacy of active core rewarming using fluid heating system HOTLINE before and
      during the operation in a patient with for panperitonitis in state of shock and
      hypothermia].
AB  - A 62-year-old man was transported to the emergency room. He was in the state of
      shock and hypothermia of 34.2 degrees C. Fluid therapy was started using a
      HOTLINE to raise the body temperature, with vasopressors, vitamin B1 and sodium
      bicarbonate after checking arterial blood gas. Diagnosis of panperitonitis was
      made and operation was started immediately. We used HOTLINE before and during the
      operation. Body temperature returned to normal ranges, and hemodynamic state was
      stabilized at the end of the operation. After the operation, he received
      controlled artificial ventilation and nutrition support with intravenous
      hyperalimentation. Though he was complicated with disseminated intravascular
      coagulation, he went to general ward 17 days, and was discharged at 47 days after
      the operation. Sepsis accompanied with hypothermia leads to poor prognosis. We
      used fluid therapy with rapid-heating, and obtained good outcome. HOTLINE is
      effective for hypothermia in an emergency patient, because its effect is sure and
      does not obstruct the examination and management.

PMID- 12428326
TI  - [Spinal anesthesia with 0.5% isobaric bupivacaine for a patient with alcoholic
      cardiomyopathy].
AB  - A 69-year-old male patient with alcoholic cardiomyopathy was scheduled for
      inguinal herniorrhaphy. Spinal anesthesia was performed with 1.5 ml of 0.5%
      isobaric bupivacaine at the L 2-3 interspace. The analgesic levels were at the
      eighth thoracic 15 minutes after injection and the fifth thoracic dermatome at
      the end of the operation, respectively. The hemodynamic status was stable during
      operation and his postoperative course was uneventful. This case suggests that
      spinal anesthesia with 0.5% isobaric bupivacaine is useful for inguinal
      herniorrhaphy in the patient with alcoholic cardiomyopathy.

PMID- 12428327
TI  - [Intraoperative awareness during propofol anesthesia with epidural anesthesia].
AB  - This report describes a case of awareness and recall during propofol anesthesia
      combined with epidural anesthesia in a 32-year-old woman scheduled for a
      resection of left ovarian tumor. After induction, anesthesia was maintained with
      propofol and epidural anesthesia. About one hour into maintenance, the patient
      was moving with haemodynamic signs suggesting inadequate analgesia. Immediately
      after extubation, the patient could recall the abdomen being touched during
      laparotomy. This case indicates that even if appropriate dose of propofol is
      administrated, intraoperative awareness may occur especially with inadequate
      analgesia.

PMID- 12428328
TI  - [Dibucaine for spinal anesthesia is a probable risk for cauda equina syndrome].
AB  - A 64-year-old man was scheduled for transure thral resection of the prostate. The
      patient's medical history showed borderline diabetic state and two uncomplicated
      surgeries under spinal anesthesia. Spinal anesthesia was performed at the L 3/4
      interspace using hyperbaric 0.24% dibucaine 2.2 ml, which was followed by general
      anesthesia because the anesthesia level had spread only to the lower left side of
      the body. On the next day, he complained of difficulty of defecation and
      urination combined with hypesthesia around the anus, which was diagnosed as cauda
      equina syndrome. The symptoms had not changed for three weeks. Then, there was a
      gradual recovery but slight hypesthesia remained even four months after the
      surgery. Speculation of this clinical etiology suggests that high concentration
      of dibucaine, having maldistributed inside the intrathecal space, affected cauda
      equina, which resulted in irreversible nerve damage. There were other risk
      factors for cauda equina syndrome in this patient such as lithotomy position,
      history of frequent spinal anesthesia, diabetes and advanced age. None of these
      are contraindication for spinal anesthesia. Many elderly patients particularly
      undergoing urological surgeries are likely to have such risk factors. Therefore
      at least dibucaine should be avoided for spinal anesthesia because of its high
      neurotoxicity compared with other local anesthetics.

PMID- 12428329
TI  - [Assessment of peripheral blood perfusion during open heart surgery with
      sublingual PCO2 measured by ISFET-PCO2 sensor].
AB  - Sublingual tissue PCO2 (PSLCO2) was continuously monitored with an ISFET-based
      PCO2 sensor during and after the open-heart surgery under cardiopulmonary bypass
      (CPB) in order to study the effect of CPB on the peripheral blood perfusion. In
      addition, PSLCO2 monitoring was carried out in several cases of off-pump CABG. In
      the cases of open-heart surgery with CPB, PSLCO2 increased from 35.0 +/- 5.6 mmHg
      at the induction of anesthesia to the maximum value of 55.7 +/- 6.0 mmHg during
      CPB. After declamping of the aorta, PSLCO2 decreased gradually to 49.0 +/- 4.0 mm
      Hg 6 hr after the admission to ICU. The value of arterial lactate as another
      index of peripheral blood perfusion also increased gradually after the start of
      CPB, reaching to the maximum value of 8.8 +/- 1.1 mmol.l-1 just after being
      admitted into ICU. In the case of off-pump CABG, PSLCO2 and arterial lactate
      showed a slight increase during the later part of the surgery, but the change was
      not so significant as in the case of open-heart surgery under CPB. Through this
      study, typical changing pattern of PSLCO2 during the open-heart surgery was
      recognized. The change of PSLCO2 always preceded that of arterial lactate. We
      also experienced one case in which early stage of hypoperfusion was detected
      through the monitoring of PSLCO2. These results suggest clinical advantages of
      PSLCO2 monitoring.

PMID- 12428330
TI  - [A portable sternal compressor for cardiac massage on a patient carried by a
      litter--Part 3: Applicability of the device tested by a recording manikin].
AB  - Effects of a portable sternal compressor developed by us was examined by 43
      medical students (28 males and 15 females) and 9 anesthesia residents using a
      recording manikin. Compression over a depth of 3.5 to 5.0 cm was classified as
      adequate. First, the examinee held the device affixed in front of the chest with
      a belt hanged over the shoulder and pulled the other handle back and forth at a
      rate of 100 per minute. The male students could perform adequate compression in
      92% of the total number of compression in the first one minute, while female
      students could in 65%. Though the anesthesia residents accomplished 99% of
      success rate in the first one minute, the rate fell to nearly 80% in the next
      minute and about 50% thereafter due to fatigue. When one handle was sustained on
      the floor with its fold-in stand and held between the knees of the examinee
      sitting on a chair, adequate compression was performed with the success rate of
      over 80% for 5 minutes. We conclude this device will be useful for cardiac
      massage on a patient either transported on a litter or lying on a soft bed.

PMID- 12428331
TI  - [Surgical management of acute empyema].
AB  - Basic principles apply to the management of all forms of acute empyema:
      investigation and treatment of the underlying infection, drainage of purulent
      collection, obliteration of the space, and treatment of the associated
      intercurrent medical conditions. From July 1999 to May 2001, we performed
      surgical treatment in 11 patients for acute empyema. There were 4 cases of the
      fibrinopurulent phase and 7 cases of the organizing phase. Surgical procedure was
      7 open thoracotomies and 4 thoracoscopies. The mean operating time was 154.2 +/-
      36.6 minutes and blood loss during surgery was 344.7 +/- 274.8 ml. There was no
      procedure-related morbidity. In conclusion, early aggressive surgical approach is
      a feasible method for treatment of acute empyema.

PMID- 12428332
TI  - [Early and mid-term results of all arterial graft coronary artery bypass grafting
      using bilateral internal thoracic and radial arterial conduits].
AB  - From March 1996 to May 2000, 41 patients [age 39-78 (mean 63.5 +/- 8.8) years,
      90.2% male] underwent all arterial multiple coronary artery bypass grafting
      (CABG) using bilateral internal thoracic (BiITA) and radial (RA) arterial
      conduits. The reason for using RA was that the right gastroepiploic artery (RGEA)
      was small or occluded on preoperative angiography, a history of upper abdominal
      surgery or disease, or the right coronary arterial lesion was proximal and mild.
      The BiITA were used as in situ grafts and the proximal anastomosis of RA was to
      the ascending aorta in all cases. All patients underwent conventional elective
      CABG with median sternotomy using cardiopulmonary bypass. The mean number of
      anastomoses was 3.3 +/- 0.5 branches and complete revascularization rate was
      80.5%. Postoperative follow-up averaged 20 months and the longest was 50 months.
      There was no early death, and overall graft patency 2-3 weeks after surgery was
      96.2% (LITA 94.0%, RITA 97.6%, RA 97.6%). Four-year actuarial survival rate was
      96.4 +/- 3.5% (1 patient: 9 months, no cardiac death), and cardiac event-free
      rate after surgery was 89.7 +/- 4.9% [4 patients: percutaneous transluminal
      coronary angioplasty (PTCA)]. However, once patients were discharged from
      hospital, cardiac event-free rate was 100%. These excellent results suggest that
      all arterial graft CABG was satisfactory, and RA can be used as a third suitable
      arterial bypass conduit, if RGEA cannot be used or is unsuitable for use.

PMID- 12428333
TI  - [Valvular heart surgery in osteogenesis imperfecta].
AB  - Osteogenesis imperfecta is a disease in which fragile bones readily cause
      fracture. Valvular disease concurrently develops. However, the surgery-related
      mortality rate is approximately 30%. In this study, we report 2 patients with
      osteogenesis imperfecta who underwent valvular heart surgery. Patient 1 was a 31
      year-old male. He had previously been diagnosed as having osteogenesis
      imperfecta. Echocardiography suggested aortic valve insufficiency, and aortic
      valve replacement was performed. Patient 2 was a 59-year-old male. During
      admission, osteogenesis imperfecta was diagnosed. Echocardiography suggested
      mitral valve insufficiency, and mitral valve plasty was performed. In the 2
      patients, intraoperative hemorrhage was marked. However, there were no fatal
      complications. We also reviewed the literature.

PMID- 12428334
TI  - [Concomitant lobectomy for lung cancer under intraaortic balloon pumping and
      coronary bypass grafting].
AB  - A 71-year-old man was admitted because of an abnormal shadow on the chest X-ray
      film. Chest computed tomography (CT) revealed a tumor in the right upper lobe.
      The diagnosis of lung cancer was made by transbronchial lung biopsy. He had
      suffered an infarction of the inferior myocardial wall at the age of 55 years.
      Preoperative coronary angiography revealed total occlusion of segment 1, 75%
      stenosis of segments 5 and 6, and 90% stenosis of segment 13. Since these
      coronary lesions could cause perioperative and postoperative myocardial
      infarction, the patient was scheduled to undergo surgery of both the heart and
      lung in a one-stage operation. Under intraaortic balloon pumping (IABP), we
      performed a right upper lobectomy of the lung, and coronary artery bypass
      grafting with cardiopulmonary bypass through median sternotomy. During the
      lobectomy and first postoperative day, a stable circulation was achieved with
      IABP. The postoperative course was uneventful. At present, that is 33 months
      after the operation, the patient presents no sighs of recurrence of lung cancer
      and has not suffered any anginal attack during follow-up. Lung cancer and
      coronary artery disease can be treated simultaneously by this procedure.

PMID- 12428335
TI  - [A new formula to calculate perfusion rate in advanced hemodilution and tepid
      cardiopulmonary bypass].
AB  - BACKGROUND: During cardiopulmonary bypass, perfusion flow rate is generally
      calculated only with the patient body surface. Recently, far advanced
      hemodilution during cardiopulmonary bypass and tepid bypass circulation are
      common. PURPOSE: We have arrived at an appropriate flow rate formula, in which
      factors like temperature, hemoglobin concentration, the target mixed venous
      oxygen saturation (SvO2), and the amount of oxygen consumption are included. Our
      formula was compared with the conventional one. MATERIAL AND METHOD: Seventy-four
      points of cardiopulmonary bypass data under total cardiopulmonary bypass in 33
      patients were studied. Our formula's validity was re-evaluated. Then, the SvO2
      values were predicted by applying the flow rate value as per conventional
      calculation in to our formula. RESULTS: The flow rate of our formula and the
      actual flow rate are well correlated (r = 0.9212). In the prediction of the SvO2
      by the conventional method, 36.5% were calculated to have a SvO2 of less than
      60%. Furthermore, with a hemoglobin concentration of 7 g/dl, 73.3% were
      calculated to have a SvO2 of less than 60%. With a body temperature of 34 degrees
      centigrade, 53.8% were calculated to have a SvO2 of less than 60%. On the other
      hand, to maintain SvO2 level at 70% by the conventional method, if the patient
      hemoglobin concentration was 10 g/dl, temperature should be maintained at 36
      degrees centigrade, and when hemoglobin concentration is 7 g/dl, the temperature
      should be maintained at 33 degrees centigrade. CONCLUSION: In advanced
      hemodilution or tepid cardiopulmonary bypass, use of appropriate flow rate
      formula is recommended, which takes into account the indispensable factors such
      as hemoglobin levels, temperature, and the target SvO2.

PMID- 12428336
TI  - [Surgically treated pancoast tumor].
AB  - A 40-year-old male was detected his right apical lung tumor by roentgenographic
      screening on January 1997, but he did not refer to a hospital since he had no
      symptom. He went a orthopedics because of his right chest, back, and arm pain on
      October 1997, and he received traction and physical therapy. He went
      roentgenographic screening again on January 1998 and he was pointed out that the
      tumor increased. He admitted our hospital. Biopsy using bronchofiberscopy
      revealed adenocarcinoma and induction radiotherapy (40 Gy) was performed. Right
      upper lobectomy with chest wall resection and lymph node dissection was performed
      under hook approach. This approach was useful to dissect the tumor from the
      invaded plexus brachialis. Postoperative radio-chemotherapy was added but the
      patient died 7-postoperative months because of multiple metastases. Early
      detection should be led to early starting of the therapy.

PMID- 12428337
TI  - [Inferior vena cava cannulation using Forgaty catheter for partial
      cardiopulmonary bypass].
AB  - Partial cardiopulmonary bypass is adopted in operation for aneurysm of descending
      aorta or DeBakey IIIb dissection. Cannulation from left common femoral vein to
      inferior vena cava (IVC) is often difficult because of operative position and
      anatomical relation of iliac veins to IVC. In this paper, IVC cannulation using
      Forgaty catheter is reported to be easy and safe for prevention of IVC
      perforation.

PMID- 12428338
TI  - [Lymphoscintigraphy for chylothorax after replacement of descending thoracic
      aortic aneurysm].
AB  - A 77-year-old female with Stanford B chronic aortic dissection, received elective
      replacement of descending aorta. The aorta distal to the aneurysm was encircled
      with a tape, and replaced using the double barrel technique. After the operation,
      chest X-ray showed effusion on the bilateral side. The amount of milky fluid from
      drain increased to 2,000 ml per day. The chemical profiles of the fluids were
      compatible with chylothorax. The Thoracic duct near the diaphragm was closed
      through left mini-thoracotomy. But the leakage of chyle did not cease. The
      lymphoscintigraphy showed a leakage to right lower intrathorax near the diaphragm
      and native aorta. A defect of the thoracic duct was closed, and chylothorax was
      cured. This case shows that though detailed anatomical structure of thoracic duct
      is not revealed, lymphoscintigraphy is useful for the localization of leakage in
      patients with chylothorax of post-cardiovascular-surgery.

PMID- 12428339
TI  - [Modified bentall operation using composite graft without resection of aortic
      valve].
AB  - A 27-year-old male whose diagnoses were aortic dissection (Stanford A), aortic
      regurgitation, annulo-aortic ectasia, and Marfan syndrome underwent modified
      Bentall operation using composite graft and total arch replacement. Modification
      of proximal suture without resection of aortic valve like intravalvular
      implantation might have resulted in good recovery without blood transfusion.
      Another 63-year-old male who suffered from spontaneous aortic rupture with aortic
      regurgitation also underwent modified Bentall operation in the similar manner as
      the first case with good result. Spontaneous aortic rupture reported here is a
      rare case, and operation is thought to be prerequisite for the patient who
      suffers from this disease to survive.

PMID- 12428341
TI  - [Surgical management of acute type A aortic dissection with a complaint of
      disturbance of consciousness; report of a case].
AB  - A 50-year-old female was admitted to our hospital with a chief complaint of
      disturbance of consciousness (DOC). Left-sided hemiparalysis was noted on
      examination and cerebral infarction was diagnosed with total occlusion of the
      right common carotid artery revealed by cerebral angiography. Pharmacological
      thrombolysis (urokinase 720,000 U) was performed. Dissection of the right common
      carotid artery was noted after successful thrombolytic therapy. Enhanced chest
      computed tomography (CT) showed the acute type A aortic dissection involving the
      cerebral artery. Ascending aortic replacement was performed 4 days after the
      thrombolytic therapy to avoid brain edema and hemorrhagic infarction during
      cardiopulmonary bypass. The postoperative course was uneventful. In the case of
      acute type A aortic dissection with DOC, proper indication and optimal timing of
      the operation may help to improve patient survival.

PMID- 12428340
TI  - [Minimally invasive direct coronary artery bypass in a patient with idiopathic
      thrombocytopenic purpura; report of a reoperative case].
AB  - A 77-year-old man who had undergone coronary artery bypass grafting (CABG) to
      segment 3, 7 and 12-14 with saphenous vein grafts (SVG) 15 years before, and
      ligation of coronary arteriovenous (AV) fistula 8 years before was admitted to
      our hospital, and diagnosed as acute heart failure and idiopathic
      thrombocytopenic purpura. Coronary angiography showed multiple stenosis of three
      vessels, and the grafts to segment 3 and 7 were occluded. The area of left
      anterior descending (LAD) had no viability, but the inferior wall had viability
      on dobutamine load echocardiography. The platelet count was about 5.0 x
      10(4)/mm3. Minimally invasive direct coronary artery bypass (MIDCAB) for right
      coronary artery (RCA) using right internal thoracic artery (RITA) was performed
      through right parasternotomy. Operative and postoperative bleeding was slight,
      and postoperative course was uneventful. Reoperative MIDCAB can be safely
      performed in a patient with idiopathic thrombocytopenic purpura, and should be
      considered a viable alternative for highrisk patients.

PMID- 12428342
TI  - [Right atrial lipoma with calcification in ascending aorta; report of a case].
AB  - A 67-year-old male was diagnosed to have a right atrial tumor by echocardiography
      incidentally. Computed tomography (CT) indicated a mass which showed very low
      radiodensity and magnetic resonance imaging (MRI) [T1-weighted] showed the high
      signal intensity of tumor. We could predict the mass as lipoma. Tumor removal was
      performed under cardio-pulmonary bypass and under ventricular fibrillation
      because of the calcification in ascending aorta. Microscopically the tumor was
      consisted of mature adipose tissue. The postoperative course was uneventful.
      Cardiac lipomas are rare tumors. CT and MRI are better investigations for
      preoperative diagnosis. After surgical excision the prognosis is excellent.

PMID- 12428343
TI  - [Three-channeled aortic dissection; report of a case].
AB  - The formation of 2 adjacent lumens is rarely observed in aortic dissection. We
      report herein a case of ruptured 3-channeled aortic dissection in a short time of
      hospitalization. A 58-year-old man who had been followed up for aortic dissection
      (Stanford type B) was admitted to Kumamoto National Hospital with an abdominal
      pain and a lumbago. A computed tomography (CT) revealed that a 3-channeled aortic
      dissection from the aortic arch to the right common iliac artery. An intramural
      hematoma was generated in the abdominal aorta and the left kidney was not
      enhanced. We initially adopted conservative therapies. But on the next day, he
      suddenly complained a severe back pain and died. At autopsy, the thoracic aorta
      was found to have ruptured into the mediastinum, and massive hematoma was formed.

PMID- 12428344
TI  - [DeBakey IIIb type dissecting aneurysm with adrenal myelolipoma; report of a
      case].
AB  - We report a case of DeBakey IIIb type dissecting aneurysm with adrenal myelo
      lipoma in a 50-year-old woman. The patient was referred to our hospital for
      severe back pain with severe hypertension. The chest computed tomography (CT)
      scans and aortography showed the DeBakey IIIb type dissecting aneurysm. And the
      round-shaped masses on her both side adrenal glands were detected by abdominal CT
      scans. First, the thoracic aneurysm was replaced with a 26 mm woven dacron graft
      under cardiopulmonary bypass. Six months later a right adrenal tumor was removed
      under a postero lateral approach. Her postoperative course was uneventful. And
      her blood pressure control was good with no antihypertensive drug. Pathological
      findings for the resected tumor was diagnosed as myelolipoma. To our knowledge, a
      dissecting aneurysm with adrenal myelolipoma has not been previously reported.

PMID- 12428345
TI  - [Nodular pulmonary amyloidosis with bullae; report of a case].
AB  - A 53-year-old male was admitted to the hospital because of progressive paralysis
      of inferior limb. Chest X-ray film and chest computed tomography (CT) on
      admission showed a small nodule with bullae in the right lower lung field. After
      CT-guided marking, partial lung resection including the nodule was performed. The
      cut surface of the resected specimen showed a tumor (10 mm in diameter) in a
      bullae measuring 14 mm in diameter. The tumor was diagnosed as amyloidosis.
      Fourty-six cases of primary localized pulmonary amyloidosis were reported in
      Japan. However, primary localized pulmonary amyloidosis with bullae is extremely
      rare, only 3 cases have been reported.

PMID- 12428346
TI  - [Pleomorphic adenoma of the lung; report of a case].
AB  - A 67-year-old woman was admitted because of an abnormal shadow on the chest X-ray
      film. Chest computed tomography (CT) film revealed a peripheral mass in the
      middle lower lobe of the lung. We performed open lung biopsy and diagnosed as a
      benign epithelial adenoma but not ruled out adenocarcinoma completely by
      intraoperative examination of frozen sections. We operated right middle lobectomy
      and mediastinal lymph nodes dissections. Histological examination confirmed
      pleomorphic adenoma. We examined salivary glands, but didn't find the focus of
      that. The patient had been well for three years postoperatively.

PMID- 12428347
TI  - [Thoracoscopic pericardial fenestration for persistent pericardial effusion after
      radiotherapy for esophageal cancer; report of a case].
AB  - We performed thoracoscopic pericardial fenestration for persistent pericardial
      effusion after radiotherapy for esophageal cancer. An 85-year-old man who had
      radiation therapy (70.2 Gy) for esophageal cancer was admitted for shortness of
      breath. Chest computed tomography showed a pericardial effusion. During the 6
      months prior to this admission, the patient had undergone percutaneous
      pericardial drainage 3 times for cardiac tamponade. We performed thoracoscopic
      partial pericardiectomy with creation of a pleuropericardial window via one
      access port. Histopathologically, no malignant cells were found in either the
      resected pericardium or the pericardial effusion. Therefore, we believe the
      persistent pericardial effusion was secondary to radiotherapy. There was no
      recurrence of the pericardial effusion for 7 months postoperatively. In summary,
      thoracoscopic pericardial fenestration is useful in both the diagnosis and
      treatment of persistent pericardial effusion.

PMID- 12428348
TI  - [Contralateral pneumothorax after pneumonectomy for bronchogenic carcinoma;
      report of a case].
AB  - A case of contralateral pneumothorax after pneumonectomy was reported.
      Intrathoracic drainage was performed and pneumothorax was healed. Recurrent
      pneumothorax was occurred in this patient and intrathoracic drainage was
      performed again and pneumothorax was healed. We suspected that bulla was the
      cause of pneumothorax and thought that contralateral pneumothorax after
      pneumonectomy must be carefully follow-up.

PMID- 12428349
TI  - [Petroclival meningioma].

PMID- 12428350
TI  - [Transluminal visualization of intra-aneurysmal blood flow with transluminal flow
      imaging of three-dimensional MR angiography].
AB  - As a preliminary investigation, we report transluminal flow imaging with
      perspective volume rendering of magnetic resonance angiography in patients with
      unruptured cerebral aneurysms. Selective change in signal intensities, based on
      using a square curve, was superimposed onto the transluminal image of the vessel
      and aneurysmal walls. This imaging technique provided direct visualization of
      flow-related information within the aneurysm in relation to its morphologic
      features. Transluminal flow imaging of three-dimensional magnetic resonance
      angiography may be a useful adjunct for the evaluation of intra-aneurysmal blood
      flow in clinical cases.

PMID- 12428351
TI  - [BIS monitoring is useful for reliable intraoperative cortical mapping during
      brain tumor operations].
AB  - Poor detection of muscle motor evoked potential (m-MEP) by electrical cortical
      stimulation has often been encountered during neurosurgical operations, although
      widely known optimal factors for reliable detection have been put into practice.
      We hypothesized that the depth of anesthesia influenced the detection of m-MEP.
      Bispectral Index (BIS) monitoring was used to assess the depth of anesthesia for
      16 patients during brain tumor operations. The doses of intravenous anesthetics,
      propofol, were titrated according to BIS indices during operations. When BIS
      indices were 40 or below, detection was difficult and higher intensities of
      electrical stimulation were necessary to evoke m-MEPs. Furthermore, risk of
      seizure was relatively high due to stronger electrical stimulation. Our results
      suggested that a BIS index above 50 and below 70 was optimal range. BIS
      monitoring is a useful method for setting the optimal dose of anesthetics for
      reliable intraoperative cortical mapping.

PMID- 12428352
TI  - [A ruptured aneurysm in the bifurcation of the proximal anterior cerebral artery
      and the frontopolar artery: case report].
AB  - We report a case of ruptured aneurysm in the bifurcation of the proximal anterior
      cerebral artery and the frontopolar artery. A 49-year-old woman complained of
      sudden onset of severe headache on December 24, 2000. She was admitted to our
      hospital and CT scan revealed subarachnoid hemorrhage. Cerebral angiography on
      the next day revealed an aneurysm in the bifurcation of the frontopolar artery
      and the proximal anterior cerebral artery. She was operated on using the left
      pterional approach and complete neck clipping was performed. The post-operative
      course was uneventful. She was discharged with no neurological deficit two months
      after the operation.

PMID- 12428353
TI  - [A case of a ruptured dermoid cyst in the sylvian fissure].
AB  - A 22-year-old woman was admitted to our department after developing a headache.
      The neurological findings were unremarkable on her first visit, but CT
      demonstrated a lot of low-density masses in the subarachnoid space. The largest
      mass was in the right sylvian fissure. These lesions appeared hyper-intense in
      T1, T2 and diffusion-weighted MR images. A right frontotemporal craniotomy was
      performed to remove the main mass lesion in the right sylvian fissure. During
      surgery, thickening of the arachnoid membrane and floating oily globules were
      seen in the subarachnoid space. The histopathological examination revealed that
      the tumor was a dermoid cyst. Follow-up MRI revealed that some of the small
      lesions had moved since the operation. These findings suggested that the tumor
      was a ruptured dermoid cyst. The patient's postoperative course was uneventful
      and her headache disappeared completely.

PMID- 12428354
TI  - [Giant, invasive sacral schwannoma extending to the 4th lumbar spine].
AB  - In this report, we describe a case with giant sacral schwannoma, which invasively
      extended to the 4th lumbar spine and to the surrounding sacral and iliac bone. A
      26-year-old female was admitted to our hospital because of numbness and transient
      weakness of the right leg, and dysuria. Radiological examinations revealed that a
      giant sacral tumor, associated with multiple cystic formations, had invasively
      extended to the 4th lumbar spine, sacrum, and iliac bone. She underwent partial
      removal of the tumor, followed by irradiation. Pathological diagnosis was
      schwannoma. Subsequently, she underwent a second operation because of tumor
      regrowth 15 months later, and the tumor was totally removed. Numbness of the
      right leg resolved after surgery. No tumor recurrence has been noted during 5
      year follow-up period. Previously, only 5 cases have been reported of invasive
      sacral schwannoma extending to the lumbar spine. Our experience in this rare case
      strongly suggests that aggressive resection should be aimed to improve long-term
      outcome.

PMID- 12428355
TI  - [A ruptured mycotic aneurysm, simultaneously associated with acute subdural
      hematoma and intracerebral hemorrhage: case report and review of the literature].
AB  - A case is reported of a patient with simultaneous subdural hematoma and
      intracerebral hemorrhage associated with a ruptured intracranial mycotic
      aneurysm. A 65-year-old woman, with a history of low grade fever for over a
      month, presented with disturbance of consciousness. A CT showed bilateral acute
      subdural hematomas and parenchymal hematomas in the occipital lobes. Cerebral
      angiography demonstrated a distal middle cerebral aneurysm. Cardiac
      ultrasonography showed a verruca at the mitral valve. The incidence of ruptured
      mycotic aneurysm presenting with acute subdural hematoma is extremely rare. To
      our knowledge, there have been only seven cases. The present case is discussed
      with reference to a review of the literature.

PMID- 12428356
TI  - [Dejerine-Roussy syndrome following endovascular parent artery occlusion for an
      unruptured posterior cerebral artery aneurysm (P2 segment): case report].
AB  - A right posterior cerebral artery (PCA) fusiform aneurysm was incidentally
      discovered in a 53-year-old man. Although the aneurysm was asymptomatic,
      treatment of the aneurysm was indicated to avoid possible hemorrhage and/or mass
      effect. Since the patient tolerated temporary balloon occlusion of the right PCA
      at P1-P2 segments and sufficient collateral flow to the right temporo-occipital
      region was observed during such occlusion, parent artery occlusion as well as
      intraluminal occlusion of the aneurysm was performed with Guglielmi detachable
      coils. The patient did not develop neurological deficit immediately after
      embolization. However, he subsequently developed Dejerine-Roussy syndrome due to
      an infarction in the territory of the thalamogeniculate artery. Parent artery
      occlusion together with intraluminal aneurysmal obliteration is an useful
      treatment for a fusiform aneurysm of the PCA. However, ischemic complication in
      the territory of the perforating artery can not be predicted.

PMID- 12428357
TI  - [A case of solitary neurocysticercosis of unknown transmission route].
AB  - We report a case of solitary neurocysticercosis of unknown transmission route. A
      26-year-old male was taken to our hospital with a history of general convulsions.
      On admission, physical and neurological findings were normal. On the basis of
      neuroimaging (computed tomography scan and magnetic resonance imaging), initial
      diagnosis was brain abscess and the patient was treated with antibiotics. Two
      months later, the patient, at times, presented a loss of consciousness. The
      follow-up MRI revealed that the enhanced lesion became enlarged and perifocal
      edema became evident, so the patient was surgically treated. By histopathological
      examination, the lesion was diagnosed as a cysticercus. The immunoserologic assay
      gave a positive result for the disease. Postoperatively, the symptoms improved.
      Cerebral cysticercosis is the most common parasitic disease of the central
      nervous system, but rare in Japan. Therefore its diagnosis remains difficult,
      especially in the case of solitary cerebral cysticercosis, which has been
      reported only 7 times in Japan. The pathological examination or the
      immunoserologic assay should be taken into consideration to obtain definitive
      diagnosis of cerebral cysticercosis.

PMID- 12428358
TI  - [Training in neurovascular intervention].

PMID- 12428359
TI  - [CNS infection and prion diseases, no. 5 in series of articles: basic knowledge
      of neuropathology for neurosurgeons].

PMID- 12428360
TI  - [Problems and proposals from neurosurgical practice., no. 9 in series of
      articles: controversy and reform proposals concerning insured medical care in
      neurosurgery].

PMID- 12428361
TI  - [Tau gene mutation].

PMID- 12428362
TI  - [Posttranslational modifications of microtubule associated protein tau].

PMID- 12428363
TI  - [Tau isoforms and neurodegenerative disorders].

PMID- 12428364
TI  - [Tau protein abnormality and dementia: the mechanisms of neurodegeneration].

PMID- 12428365
TI  - [Current clinical advancements of meningoencephalitis in Japan].

PMID- 12428366
TI  - [Cortical control of saccadic eye movements: a clinical electrophysiological
      study of antisaccades].
AB  - An antisaccadic paradigm in which saccades are directed towards the mirror
      location opposite to that of target appearance has been thought to reflect
      frontal lobe function and a saccade-inhibitory mechanism. In order to clarify now
      the cortical mechanism differs between antisaccades (AS) and reflexive visually
      guided saccades (VS), we measured scalp EEG potentials preceding AS and VS in 9
      young normal subjects, as well as the magnetic brain activities during AS and VS
      in 1 of them. Prior to the right and left saccades in both paradigms, our
      measurements revealed the appearance of a slowly developing negative potential,
      the presaccadic negativity (PSN), and then a steeper negative potential, the
      presaccadic steep negativity (PSSN). The onset of PSSN was significantly earlier
      and the maximum amplitude of PSSN was significantly greater in AS than in VS. The
      peak amplitude of PSSN at each middle electrode (Fz, Cz, Pz) was generally
      greater in AS than in VS in both directions of saccades. In one normal subject,
      the difference between AS and VS in the magnetic field distribution just prior to
      saccades in both directions was demonstrated as current dipoles on the bilateral
      frontal areas. Our results suggest that the activation of the bilateral frontal
      lobes is greater prior to AS than it is prior to VS.

PMID- 12428367
TI  - [Predictors of long-term institutionalization in patients with Alzheimer's
      disease: role of caregiver burden].
AB  - BACKGROUND AND PURPOSE: The decision of long-term institutionalization of
      patients with Alzheimer's disease (AD) is based on multiple patients' and
      caregivers' characteristics. It is very important to find out factors associated
      with institutionalization for the timely institutionalization, i.e. for the
      prevention of premature institutionalization. Among those factors, caregiver
      burden is reportedly one of the most important factors in Europe and North
      America. However, no studies have been carried out in Japan. In order to address
      this issue, we studied outcome of patients with AD. SUBJECTS AND METHODS:
      Subjects were 211 patients who fulfilled the criteria of the National Institute
      of Neurological Disease and Stroke/Alzheimer's Disease and Related Disorders
      Association for probable AD. Diagnosis of AD was made through extensive
      examinations including MRI and PET/SPECT of the brain. The patients included 149
      women and 62 men; the mean age was 73.1 +/- 8.0 (SD) years. The Japanese version
      of Zarit Caregiver Burden Interview (ZBI), which is a validated tool for
      assessment of the burden of caregivers for dementia patients, was used to
      evaluate caregivers' burden through the interview of a principal caregiver by
      trained nurses. Cognitive, functional, and neuropsychiatric impairments were
      assessed with standardized instruments of the Mini-Mental State Examination
      (MMSE), Hyogo Activities of Daily Living Scale (HADLS), Neuropsychiatric
      Inventory (NPI), respectively. We annually sent a questionnaire to the caregivers
      to collect information on the patients' status. It included questions whether and
      when they died or were institutionalized and whether they had used formal social
      supports such as home care, day care, and respite care services. MAIN OUTCOME
      MEASURE: Time to death or institutionalization. RESULTS: One-hundred and fifty
      subjects were followed for at least one year and 51 of them met either end point.
      The Cox proportional hazard model demonstrated that the baseline caregiver burden
      was a significant predictor of the end point even after controlling possible
      confounders. Among these, the use of day care and home care services during the
      course were significant protective factors. The baseline cognitive and functional
      disturbances but not neuropsychiatric manifestations were significantly
      associated with the end point. CONCLUSIONS: The caregiver burden is a significant
      predictor for the death or institutionalization of the patients with AD. The
      caregiver education which decrease the caregiver burden and prompt the usage of
      the social care services are necessary to protect premature institutionalization.

PMID- 12428368
TI  - [A case of brachial plexus neuropathy who presented with acute paralysis of the
      hand after sleep].
AB  - We report a 46-year-old woman who presented with acute paresis of the right hand
      and arm. She was well until when she noted a paresis and dysesthesia in her right
      hand in the morning. Neurological examination revealed weakness in the muscles
      which were supplied by lower cervical segments, with increased deep tendon
      reflexes in the right arm. Allen's test and Wright's test were positive. The
      nerve conduction studies disclosed a reduced CMAPs more severely by right median
      than ulnar nerve stimulation. The frequency and amplitude of the F waves was also
      reduced. Needle electromyogram showed a mild neurogenic pattern in the right hand
      muscles. Digital subtraction angiography revealed a tapering of the subclavian
      artery when the right arm was abducted. She underwent decompression surgery. A
      remarkable improvement of the symptoms was observed after surgery. Our patient
      suggests that brachial plexus neuropathy should be considered in the acute
      paresis of the hand after sleep, and that surgical procedure would lead to a
      successful outcome.

PMID- 12428369
TI  - [Frontal lobe hematoma associated with transcortical motor aphasia: case report].
AB  - An 81-year-old woman with left medial frontal lobe hematoma, which involved the
      supplementary motor area, is reported. She was right-handed and was initially
      mute for several hours after the onset. On admission, she exhibited mild paresis
      of the right lower extremity. Her spontaneous speech was sparse and not fluent,
      but her articulation and auditory comprehension were normal and repetition was
      good. She exhibited excellent performance in the confrontation naming task, but
      showed difficulty in recalling words from a given category during the word
      fluency task. On the basis of these clinical features, she was diagnosed as
      having transcortical motor aphasia. Our case may corroborate previous findings
      that the left medial frontal lobe is important in word fluency but not in
      confrontation naming.

PMID- 12428370
TI  - [Pitfall of three-dimensional CT angiography].

PMID- 12428371
TI  - [Intense pulse-synchronous tinnitus caused by dural arteriovenous fistula at the
      hypoglossal canal].

PMID- 12428372
TI  - [The membrane-anchored metalloproteinase inhibitor RECK].

PMID- 12428373
TI  - [Significance of adipocytokine, fat-derived hormones, in metabolic syndrome].

PMID- 12428374
TI  - [Creation of unnatural base pairs: the expansion of the genetic code].

PMID- 12428375
TI  - [Oscillatory mechanism of mammalian circadian rhythm].

PMID- 12428376
TI  - [Quality control of secretory pathway proteins by a ubiquitin ligase that
      recognizes sugar chains].

PMID- 12428377
TI  - [Analysis of the general transcription factor TFIID using the fission yeast
      Schizosaccharomyces pombe].

PMID- 12428378
TI  - [RNAi provides a new tool for functional analyses of the mammalian genes].

PMID- 12428379
TI  - [Developing computer models of cellular processes].

PMID- 12428380
TI  - Evaluation of T factor, surgical method, and prognostic factors in central type
      lung cancer.
AB  - OBJECTIVE: We report our experience in the diagnosis and surgical treatment of
      central type lung cancer (CTLC) and discuss the prognostic significance of
      clinicopathological factors including the T factor. METHODS: Subjects were 151
      patients with CTLC undergoing surgery from 1984 to 1999. Surgical procedures
      include lobectomy in 111, pneumonectomy in 35, and segmentectomy in 5.
      Bronchoplasty was done in 44, including sleeve lobectomy in 33, carinal resection
      in 8, and bronchoplasty without resection of pulmonary parenchyma in 3. Data on
      CTLC was compared to that on peripheral lung cancer during the same period.
      RESULTS: Compared to peripheral tumors, central lung tumors showed a higher ratio
      in male gender, pN1 in pN factors, squamous cell carcinoma in histology, and
      pneumonectomy and bronchoplasty in surgery. No statistical differences were seen
      between groups in surgical outcome, mean age, distribution pattern in pT factors,
      and extended surgery. The positive predictive cT factor has improved. No
      significant difference was seen in 5-year survival based on 8 factors--period, cT
      factors, tumor histology, bronchoplasty, extended surgery, cellular atypia,
      additional chemotherapy, and radiotherapy. Five-year survival differed
      significantly for 12 other factors--pT, cN, and pN factors; surgical method;
      number of resected organs in extended surgery; curability (complete/incomplete);
      tumor size; N1 and N2 station metastasis; p factor, and blood vessel and
      lymphatic invasion. Multivariable analysis indicated only 2 independent
      prognostic factors--cN and p factor. CONCLUSIONS: CTLC appears to belong to a
      subgroup other than peripheral tumors, requiring a more accurate diagnosis of cT
      factors, particularly in the proximal bronchus, because cT and cN factors are the
      only 2 used preoperatively.

PMID- 12428381
TI  - Thoracoscopic right upper mediastinal dissection for left lung cancer.
AB  - OBJECTIVE: In left lung cancer, left and right mediastinum lymphatic spread occur
      equally frequently. We evaluated the safety and effectiveness of thoracoscopic
      right upper mediastinal dissection, implemented prior to left lung resection for
      left lung cancer. METHODS: Between January 1999 and May 2000, 17 patients with
      left lung cancer underwent thoracoscopic right upper mediastinal dissection prior
      to resection of the left lung and left mediastinal dissection for left lung
      cancer. These patients had either enlarged left hilar or bilateral mediastinal
      nodes, or either a tumor at least 3 cm in diameter or tumor extension to the
      hilum, mediastinum, or chest wall. Tumor and lymph nodes were examined with
      hematoxylin and eosin and immunohistochemical staining of cytokeratin for
      micrometastasis. RESULTS: In 3 patients (17.6%), metastasis occurred in right
      paratracheal nodes. The 30-day mortality was 0% and morbidity 35.3% (6/17).
      Postoperative complications occurred in 3 of 4 patients (75%) undergoing
      induction chemotherapy, but none were lethal. CONCLUSION: Thoracoscopic right
      upper mediastinal dissection is safe and feasible in treating advanced left lung
      cancer.

PMID- 12428382
TI  - Lymph node metastasis, recurrence, and prognosis in small peripheral lung
      adenocarcinoma. Analysis based on replacement.
AB  - OBJECTIVE: We studied clinical and pathological features of small peripheral
      adenocarcinoma of the lung, focusing on tumor typing based on Noguchi's
      classification of small adenocarcinoma and determining whether these tumors grew
      by replacing alveolar lining cells. METHODS: Subjects were 51 patients with small
      peripheral adenocarcinoma 2 cm or less in diameter resected between 1994 and
      2001. Mediastinal and hilar lymph node dissection was done in 37 (72.5%).
      Patients were divided into 2 groups by replacement or nonreplacement tumors. We
      compared patient profiles, lymph node involvement, and recurrence and survival
      patterns. RESULTS: No significant difference was seen between groups in mean age,
      surgical procedure, or primary tumor location. Women predominated in replacement
      tumors at 71% vs 41%, p = 0.04. The incidence of lymph node metastasis at 40% vs
      4.5%, p = 0.007 and distant metastasis at 47% vs 2.9%, p < 0.001 was
      significantly higher in nonreplacement than replacement tumors. Replacements
      tumor thus showed significantly better disease-free survival at 95% vs 53%, p <
      0.001, and overall 3-year survival at 95.4% vs 62.7% than did nonreplacement
      tumors. CONCLUSION: We found distant metastasis and lymph node involvement to be
      more frequent in nonreplacement than replacement small peripheral adenocarcinoma,
      on suggesting that pretreatment tumor typing and accurate nodal status
      determination are essential to improve disease staging.

PMID- 12428383
TI  - Nicorandil ameliorates posttransplant dysfunction in cardiac allografts harvested
      from non-heart-beating donors.
AB  - OBJECTIVE: Warm ischemia is a major cause of cardiac allograft dysfunction in non
      heart-beating donors (NHBDs). We evaluated the cardioprotective effects of
      nicorandil, an adenosine triphosphate-sensitive potassium channel opener, on the
      early posttransplant left ventricular (LV) function of hearts harvested from
      asphyxiated canine NHBDs. METHODS: Hypoxic cardiac arrest was induced in 12 donor
      dogs. In 6, nicorandil was administered intravenously at 100 micrograms/kg + 25
      micrograms/kg/min after respiratory arrest and hearts were preserved with
      nicorandil-supplemented cardioplegic solution (nicorandil group). The remaining 6
      did not receive nicorandil at any time during the experiment (control group).
      Hearts were orthotopically transplanted after a mean myocardial ischemic time of
      4 hours. RESULTS: All 12 recipients were weaned from cardiopulmonary bypass
      without inotropic support. In the control group, posttransplant cardiac indices
      and left ventricular end-systolic pressure (LVESP) decreased significantly, while
      LV max-dP/dt and Tau increased over pretransplant values. No differences were
      seen in parameters between pretransplant and posttransplant values in the
      nicorandil group. Posttransplant cardiac indices, LVESP, and LV max + dP/dt were
      higher in the nicorandil group than in controls, while posttransplant LV max
      dP/dt in the nicorandil group was lower. CONCLUSIONS: Our results indicate that
      pretreatment with nicorandil during hypoxic perfusion before cardiac arrest and
      subsequent preservation with nicorandil-supplemented cardioplegia ameliorates
      early posttransplant LV dysfunction of hearts harvested from asphyxiated NHBDs.

PMID- 12428384
TI  - Aortic valve replacement after midline-crossed internal thoracic artery grafting.
AB  - In the presence of a midline-crossed internal thoracic artery graft, a median
      sternotomy may jeopardize the graft and compromise hemodynamics. We report
      successful aortic valve replacement using a "staircase" thoracotomy and
      hypothermic axillary perfusion with balloon aortic occlusion in 2 men who had
      patent right internal thoracic artery grafts that was previously anastomosed to
      the left anterior descending coronary artery.

PMID- 12428385
TI  - Video-assisted thoracoscopic bullectomy for spontaneous pneumothorax in a Swyer
      James syndrome patient.
AB  - We treated a 15-year-old patient with spontaneous pneumothorax associated with
      Swyer-James syndrome using video-assisted thoracoscopic surgery (VATS). Thoracic
      computed tomography showed hyperlucent areas in the bilateral lungs. Due to major
      air leakage continuing for a week, we conducted VATS bullectomy. Because the
      opposite lung suffered hypoplasia, intermittent bilateral pulmonary ventilation
      was required to sustain an adequate PaO2 in arterial blood gas analysis during
      surgery. Because of recurrent pneumothorax, we performed reoperation 10 months
      later, finding a few newly generated bullae. To the best of our knowledge, this
      is the first report of VATS used to treat a Swyer-James syndrome patient with
      pneumothorax.

PMID- 12428386
TI  - Surgical removal of an accufix pacing lead with a protruding J wire.
AB  - We report a patient with a fractured J wire protruding through the outer
      polyurethane sheath of an Accufix electrode in the subclavian vein and right
      atrium. The wire within the subclavian vein was removed transvenously, while the
      tip of the lead within the right atrium was removed surgically via a median
      sternotomy.

PMID- 12428387
TI  - Successful surgical repair of a ventricular septal defect and high take-off of
      the right coronary artery in an infant.
AB  - A 6-month-old boy was admitted in acute distress because of severe dyspnea and
      intractable congestive heart failure. With a diagnosis of the ventricular septal
      defect, pulmonary hypertension and deteriorated lung function due to the
      respiratory syncytial virus infection, he was taken to the operating room to
      undergo banding of the pulmonary artery. However, an intraoperative finding of
      the anomalous high take-off from the right coronary artery made us to discontinue
      the banding procedure. After intensive medical management, he underwent a
      successful surgical repair of the defect with no ischemic injury to the
      myocardium. Congenital cardiac defects having this particular subset of anomalies
      of the coronary artery need to be repaired primarily since the palliative
      procedure near the anomalous coronary artery has a potential hazard to compromise
      the flow of blood through this artery.

PMID- 12428388
TI  - Sudden death under successful medical management of sick sinus syndrome after
      cardiac pacing discontinuation.
AB  - Bacterial infection is a serious complication of permanent pacemaker
      implantation. A 52-year-old woman with sick sinus syndrome and vasospastic angina
      developed pacemaker infection 4 years after implantation, with methicillin
      resistant Staphylococcus aureus detected in arterial blood cultures. We treated
      the septicemia with antibiotics and removed the infected pacemaker. We treated
      sick sinus syndrome with intravenous nitroglycerin followed by oral maintenance
      isosorbide mononitrate. After cardiac pacing was discontinued following removal
      of the infected permanent pacemaker, the patient remained well, until her sudden
      death 3.5 years later. Although the precise cause of death was not clear, we
      suspected sick sinus syndrome or vasospastic angina, and now consider the outcome
      may have been more favorable if we had reimplanted a permanent pacemaker before
      she died.

PMID- 12428389
TI  - Successful thrombolytic therapy for acute massive pulmonary thrombosis after
      total cavo-pulmonary shunt.
AB  - A 4-year-old boy with massive pulmonary thrombosis after total cavo-pulmonary
      shunt was successfully treated by aggressive thrombolytic therapy. In the unique
      circulation involving total cavo-pulmonary shunt with azygous connection, the
      clinical manifestations of pulmonary thrombosis are somewhat different from those
      observed with ordinary biventricular circulation. The patient's hemodynamic
      state, including central venous pressure and systemic blood pressure, was
      relatively stable, but there was a dramatic decrease in oxygenation, possibly
      because azygous continuation allowed reversed blood flow from the superior vena
      cava to return to the atrium through collateral vessels between the azygous vein
      and the portal vein. Clinicians should be aware of this complication and unique
      circulation, and the importance of prompt diagnosis cannot be overemphasize. The
      effectiveness of the aggressive thrombolytic therapy in this case was noteworthy.

PMID- 12428390
TI  - Girdling and sparing effects in adynamic cardiomyoplasty.

PMID- 12428391
TI  - [beta 2-adrenoceptor polymorphism and effect of inhaled beta 2-stimulant
      (procaterol) on airway resistance measured by body plethysmography in healthy
      volunteers].
AB  - This study was designed to evaluate, in healthy volunteers, differences of
      bronchodilator responsiveness to a beta 2-agonist between those with the Arg
      16/Gly 16 allele and those with the Gly 16/Gly 16 allele at codon 16 of beta 2
      adrenoceptor polymorphism. Peak flow and pulmonary functions were measured by
      body plethysmography after the inhalation of procaterol. In the Arg 16/Gly 16
      group, the resulting acute increase of V 25 and acute decrease of airway
      resistance were greater, and the bronchodilator effect of a single inhaled beta 2
      agonist was longer, than those observed in the Gly 16/Gly 16 group. The present
      study showed that a single inhalation of procaterol has a varying bronchodilator
      effect on healthy adults, depending on the genotype of beta 2 adrenoceptor
      polymorphism at codon 16.

PMID- 12428392
TI  - [Usefulness of clinical pathway for community-acquired pneumonia as both an
      educational and a cost-management tool--an intervention study to compare the
      usefulness of management with a critical pathway to historical control of
      conventional management].
AB  - To delineate the usefulness of a clinical pathway for community-acquired
      pneumonia (CAP) as an educational tool as well as a cost management tool, we
      conducted a prospective controlled trial including a historical control group.
      Consecutive CAP patients classified under Category 3 of the American Thoracic
      Society and admitted to our hospital were evaluated. Using the clinical pathway
      method, 42 patients were managed between April and December 2000 as the
      intervention group, and 33 patients received conventional management between
      April and December 1999 as a historical control. For the intervention group, the
      clinical pathway, which was a time-task matrix formatted with consideration for
      guidance for disease treatment, laboratory tests, physical examinations, oxygen
      saturation monitoring, ambulation, diet, education for the patient and clinical
      outcomes, was implemented. We determined (1) educational effect, measured using
      reduction of delay caused by physicians; (2) quality of clinical practice,
      measured using the success rate of the initial antimicrobial therapy and
      readmission rate; and (3) economic efficacy, measured using health care cost and
      length of hospital stay. The delay caused by physicians was reduced by 16% in the
      Intervention Group (5% vs. 21%; p = 0.045). The success rates of initial
      antimicrobial therapy in the two groups were similar (85.7% vs. 84.8%). In the
      intention-to-treat set, the median value of health care cost was reduced by yen
      48,055 (yen 277,460 vs. yen 325,515; p = 0.017) and the median length of a
      hospital stay was shortened by 3 days (8 vs. 11 days; p = 0.0007) in the
      Intervention Group. In conclusion, the clinical pathway had an educational effect
      on physicians regarding the management of hospitalized patients with community
      acquired pneumonia as well as on the cost management.

PMID- 12428393
TI  - [Risk factors in development of sleep apnea syndrome--a large population study
      using a simple monitoring system].
AB  - We studied the risk factors in the development of sleep apnea syndrome (SAS) in
      779 patients (705 males and 74 females) using Apnomonitor R. The apnea index (AI)
      significantly correlated with the body mass index (BMI), and was higher in obese
      patients (BMI > or = 25 kg/m2) than in non-obese patients. The prevalence of SAS
      increased with patient age. Obesity was less common in older than in younger
      patients. The AI was significantly higher in smokers than in non-smokers, as was
      the prevalence of SAS. The AI and the prevalence of SAS were higher in smokers
      than in non-smokers in both obese and non-obese patients. The AI was
      significantly higher in males than in females, and so was the prevalence of SAS.
      The AI and the prevalence of SAS were always higher in male obese patients, non
      obese patients, smokers, and non-smokers than in female patients in the same
      categories. These results suggest that obesity, age, smoking, and gender were
      independent risk factors in the development of SAS.

PMID- 12428394
TI  - [A case of migratory air space infiltration after radiation therapy for breast
      cancer].
AB  - A 54-year-old woman underwent conserving surgery for right breast cancer, and
      received a cumulative dose of 50 Gy of radiation therapy to the remaining part of
      the right breast. About five months after the termination of irradiation, cough
      and low-grade fever developed. The chest radiograph showed an infiltrative shadow
      in the right lung field. Organizing pneumonia was identified in the
      transbronchial lung biopsy specimen. After prednisolone was given to the patient
      the clinical symptoms and infiltrates seen in the radiograph disappeared. In the
      course of tapering the prednisolone dose, new infiltrative shadows developed in
      the upper right lung and the left lung. The histologic changes were shown by
      transbronchial lung biopsy to be organizing pneumonia. The increased dose of
      prednisolone resulted in the rapid improvement of the clinical symptoms and chest
      radiograph abnormalities. This case suggests that breast radiation after
      conserving surgery for breast cancer may cause a pathologic process similar to
      that of bronchiolitis obliterans organizing pneumonia.

PMID- 12428395
TI  - [A case of suspected lung metastasis of pancreatic carcinoma with bronchorrhea
      similar to bronchioloalveolar carcinoma].
AB  - There have been only a few reports of bronchorrhea in patients with metastatic
      pulmonary carcinoma. We report a case of suspected lung metastasis of pancreatic
      carcinoma with bronchorrhea, which was radiologically similar to
      bronchioloalveolar carcinoma. A 67-year-old man who had previously undergone
      surgical resection of pancreatic carcinoma was admitted because of a progressive
      cough producing copious amounts of serous sputum. A chest radiograph on admission
      revealed an infiltrative shadow with air bronchograms and ground glass opacities
      in the left middle and lower lung fields. A chest CT scan revealed a
      consolidative shadow with air bronchograms and bubble-like lucencies similar to
      bronchioloalveolar carcinoma in the left lower lobe. The histopathological
      features of the specimen obtained by transbronchial biopsy revealed
      adenocarcinoma with a pattern identical to that of the pancreatic carcinoma.
      Immunohistochemical staining with anti-SP-A antibody was entirely negative but
      those with anti-CA 19-9, Dupan 2 and CA 50 were positive in both lung and
      pancreatic tumors. These results strongly suggest that the pulmonary carcinoma
      was a metastasis of cystic adenocarcinoma of the pancreas. In summary, for a
      definitive diagnosis of bronchioloalveolar carcinoma, extrapulmonary
      adenocarcinoma as a primary site should first be ruled out.

PMID- 12428396
TI  - [A case of racemose hemangioma of a bronchial artery complicated with atrial
      septal defect and localized peripheral ground-glass opacity].
AB  - We report a case of racemose hemangioma of the right bronchial artery complicated
      with an atrial septal defect (ASD) and ground-glass opacity localized in the
      right upper lung lobe. A 42-year-old woman was admitted for the pre-operative
      assessment of ASD. Aortography and selective angiography revealed that the right
      bronchial artery was markedly dilated and convoluted, draining into the right
      intercostal arteries and the right upper pulmonary vein. The patient was
      suffering from exertional dyspnea, but produced no bloody sputum. Since
      videobronchoscopy showed normal mucosal findings without bronchiectasis, primary
      racemose hemangioma of the right bronchial artery was diagnosed, and was treated
      by ligation of the bronchial artery and patch-closure of the ASD. The ground
      glass opacity observed preoperatively in the periphery of the right upper lung
      lobe vanished after surgery. This opacity was considered to have been localized
      pulmonary congestion due to augmented hydrostatic pressure in the right upper
      pulmonary vein, induced by increased pulmonary blood flow through the ASD and the
      drainage route of the racemose bronchial artery into right upper pulmonary vein.

PMID- 12428397
TI  - [A case of left diaphragmatic eventration treated by thoracoscopic plication].
AB  - A 59-year-old woman was admitted to our hospital because of left diaphragmatic
      eventration due to a left phrenic nerve injury following surgery for recurrent
      thyroid cancer. She underwent plication by thoracoscopic surgery followed by
      marked expansion of the left lung and improvement of pulmonary function and
      dyspnea on exercise. Thoracoscopic plication for diaphragmatic eventration is a
      useful minimally invasive surgical technique.

PMID- 12428398
TI  - [A case of acute sarcoidosis with polyarthralgia and erythema nodosum; Lofgren's
      syndrome].
AB  - A 49-year-old woman was admitted to our hospital with a dry cough and bilateral
      hilar lymphadenopathy. She had a history of acute arthralgia and erythema nodosum
      4 months before admission. Chest CT scans on admission revealed multiple
      mediastinal lymphadenopathy. Broncho-alveolar lavage showed CD4-dominant
      lymphocytosis. A biopsy specimen of the lung revealed non-caseating granuloma of
      epithelioid cells with giant cells, confirming the diagnosis of sarcoidosis. She
      recovered in one month, and has since remained well and free of the symptoms.
      Lofgren's syndrome is acute sarcoidosis, characterized by polyarthralgia,
      erythema nodosum and bilateral hilar lymphadenopathy. It is common in European
      countries, but very rare in Japan, from where only two case reports have
      appeared. This syndrome is closely related to HLA-B8, DR-3, and DR-17, but our
      case did not have these HLA loci. We report this case as the third case of
      Lofgren's syndrome in Japan.

PMID- 12428399
TI  - [A case of lung cancer with cyst formation].
AB  - A 70-year-old man was admitted with a nodule adjacent to a cystic lesion in the
      right lower lung field. Diagnosis of lung cancer was made by transbronchial
      biopsy. A series of chest radiographs revealed that a cystic lesion had presented
      8 years before, and that a nodule appeared on the hilar side of the cyst 5 years
      later. The cyst may have been formed by the check-valve mechanism due to the lung
      cancer.

PMID- 12428400
TI  - [A case of sarcoidosis complicated by primary Sjogren's syndrome].
AB  - A 35-year-old woman had been suffering for 10 years from a dry mouth and dry eyes
      without being medically examined. When she finally saw a doctor in September
      1996, a chest radiograph revealed bilateral hilar lymphadenopathy.
      Histopathological examination of the lung and scalene lymph nodes revealed non
      specific lymphadenitis. She was followed thereafter without any therapy. In 1997,
      she was referred to our hospital because of a high titer of antinuclear antibody.
      A diagnosis of Sjogren's syndrome was made on the basis of the results of
      sialography, lip biopsy, Schirmer's test, and the present of anti-SS-A antibody.
      Re-evaluation of the mediastinal lymph nodes and the lung by thoracoscopic biopsy
      revealed non-caseating epithelioid cell granulomas, which led to a diagnosis of
      sarcoidosis. Although the coexistence of Sjogren's syndrome and sarcoidosis has
      been reported occasionally, cases with histological proof of sarcoidosis have
      been rare. In a survey of 27 reported cases, the majority of the patients were
      female and in roentgenological stage I. In most cases, Sjogren's syndrome
      preceded sarcoidosis. The predominance of the Th 1 immune response at the site of
      each disease may be involved in the pathogenic mechanism by which these diseases
      coincide.

PMID- 12428401
TI  - [Usual interstitial pneumonia associated with psoriasis vulgaris].
AB  - The patient was a 56-year-old man who had received diagnoses of psoriasis
      vulgaris at the age of thirty-three and of nephrotic syndrome at forty-five, and
      had been treated with prednisolone. He consulted the outpatient clinic because of
      a cough, and interstitial pneumonia was diagnosed. He was admitted to our
      hospital because his symptoms and chest radiographic findings continued to worsen
      under treatment with antitussives. Chest radiography revealed a linear-reticular
      shadow in the lower lung fields. Chest computed tomography also revealed micro
      cystic lesions, reticular shadows and traction bronchiectasis underneath the
      pleura at the back of both lower lobes. His serum titer of antinuclear antibody
      was increased, but he had no other symptoms or autoantibodies. Surgical lung
      biopsy under thoracoscopy revealed usual interstitial pneumonia (UIP). The
      association of interstitial pneumonia with psoriasis vulgaris is rare.

PMID- 12428402
TI  - [An autopsy case of desmoplastic malignant mesothelioma].
AB  - On November 15, 2000, a 60-year-old man was admitted to our hospital with
      progressive dyspnea and right chest pain. He had a 40-year history of
      occupational asbestos exposure, which began when he was 20 years old. On
      admission, his chest radiographs showed pleural effusion on the right side, and
      asbestos bodies were detected in his sputum. Neither a cytological examination of
      the pleural effusion nor a histological examination of the pleura by percutaneous
      pleural biopsy revealed malignant cells. In addition, we could not find any other
      cause for the pleural effusion (such as tuberculosis, collagen disease, or heart
      failure). In May 2001, the patient also developed pleural thickening and pain in
      the right hypochondrium, and he was readmitted to our hospital on May 21, 2001.
      On readmission, an enhanced abdominal CT showed multiple liver tumors, and
      percutaneous pleural and liver biopsies were performed. The histological findings
      in the pleura and liver specimens revealed hypocellular collagen tissues without
      malignant cells. Thus, we could not determine the main cause either of the
      pleural effusion or of the patient's disease. However, his condition rapidly
      deteriorated, and he died on August 12, 2001. At the autopsy, bilateral pleural
      thickening, predominantly on the right side, and invasion of the lungs were
      observed. The histological findings in the pleural and hepatic tissues revealed
      hypocellular collagen fibers with a striate pattern and areas of neoplastic
      spindle cells. He was diagnosed as having malignant desmoplastic mesothelioma
      with liver metastasis. Cases of malignant desmoplastic mesothelioma have rarely
      been reported in Japan.

PMID- 12428403
TI  - [A case of mixed infection by Nocardia asteroides and Mycobacterium
      tuberculosis].
AB  - A 55-year-old man with diabetes mellitus was admitted to our hospital because of
      abnormal shadows in his chest radiographs. Both chest radiography and CT revealed
      infiltrative shadows in the right upper lung field. Repeated sputum smears showed
      no mycobacterium, so bronchoalveolar lavage (BAL) was performed bronchoscopically
      at the right B3b. The BAL fluid and the sputum obtained on the day after BAL
      contained acid-fast, branching filamentous structures. The microorganism was
      identified as Nocardia asteroides. Trimethoprim-sulfamethoxazole (ST) and SPFX
      were therefore administered. Later, Mycobacterium tuberculosis was detected in a
      6-week culture of the sputum and BAL fluid. This case was diagnosed as a mixed
      infection by Nocardia asteroides and Mycobacterium tuberculosis, so the three
      anti-tuberculosis agents INH, RFP and EB were added. After 6 months of the
      combined therapy, neither microorganism could be detected in the sputum, and the
      lesion in the CT scan had decreased markedly in size. Since such a mixed
      infection is very rare, no treatment strategy has yet been established. The
      combined therapy was judged to have been effective in this case.

PMID- 12428404
TI  - [Optic disc pits and maculopathy (electroretinography study)].
AB  - An ERG examination according to the international standard was made in 55
      patients with pits in the optic nerve disc. 19 of them suffered from concurrent
      maculopathy. Electroretinography revealed in scotopic responses a significant
      reduction of amplitudes of oscillatory potentials and reduction of potentials of
      the b wave in standard (maximal) reactions. Even more markedly the cone reactions
      and flicker were reduced--responses to intermittent (30 Hz) photostimulation. The
      authors consider maculopathies with pits a separate nosological unit with
      possible hereditary transmission. ERG signalizes a more extensive alteration of
      retinal structures than affection of the centre, probably on the basis of the
      circulation. Maculopathies with pits are also characterized by the fact that the
      dramatic drop of amplitudes is associated with the patient's age or the duration
      of the disease.

PMID- 12428405
TI  - [Effect of YAG capsulotomy of secondary cataracts on visual functions].
AB  - 1. 20 patients (20 eyes) with secondary cataract and best corrected visual acuity
      (BCVA) of 20/30 or 20/20 using Snellen charts were examined before Nd-YAG
      capsulotomy and 14 days postoperatively. 2. Contrast sensitivity (CS) was tested
      on a computerized system of the Contrast sensitivity 8010 type and on VCTS charts
      in 6 spatial frequencies, BCVA was measured on the logMAR charts with Landolt
      rings and influence of glare of 342.6 cd/m2 was tested using Brightness Acuity
      Tester (BAT). 3. BCVA (without and under glare) in patients before and after YAG
      capsulotomy was significantly lower compared to the control group (p < 0.001).
      Postoperative improvement of BCVA was markedly higher on logMAR charts (up to 6.6
      standardized lines) than using Snellen charts (1 line). 4. CS (without and under
      glare) using both methods in patients before and after YAG capsulotomy was
      significantly lower compared to the control group (p < 0.05 to p < 0.001) in
      spite of significant improvement postoperatively (p < 0.05 to p < 0.001), first
      of all at intermediate and high spatial frequencies. 5. Glare had only
      nonsignificant influence on BCVA and CS in all groups.

PMID- 12428406
TI  - [Spontaneous reduction and absorption of cataracts in childhood].
AB  - The authors give an account on spontaneous reduction and absorption of cataracts
      in nine children. The initial symptom where leukocoria predominated was as a rule
      detected already in infant age. In one case the affection was bilateral and was
      manifested by partial pseudoaphakia. The observation comprised also classical
      secondary aphakia in a 4-year-old girl. Resorption of lenticular masses of
      cataracts into the shape of membranous discs or reduced masses of a fibrous
      character took on average 18 months on seven eyes and this process was associated
      with vascular activity in four lenses. In two of these patients during resorption
      panuveitis was observed with a hyperergic response in humoral and cellular
      immunity without obvious general antigenic action which caused atrophy of the
      optic nerve. Surgical solution of cataract was used in four eyes, PC IOL was
      implanted in one patient which had a favourable effect on visual function.
      Histological examination was successful of the extracted reduced lens only in one
      case. Inside the lenticular capsule was a mixture of the original fibrotically
      altered cataract masses with ingrowing vascular tissue.

PMID- 12428407
TI  - [New views on aberrant innervation of oculomotor muscles ].
AB  - Aberrant innervations of oculomotor muscles are a special group of clinical
      entities, the common sign of which is an abnormal innervation of the oculomotor
      muscles with nerve fibres which originally were not meant for this purpose. The
      majority of these anomalies develops during the embryonic period of lesions at
      the level of nuclei of cranial nerves or peripheral fibres. Congenital
      aberrations affect most frequently n. VI, less frequently n. III and rarely n.
      IV. Acquired affections are most frequent in n. III. Abnormal innervation
      connections concern not only oculomotor muscles but also muscles engaged in
      mastication and those of the upper eyelid. Clinically they are manifested as
      eyelid and facial synkinesias. Among aberrant innervations which lack an uniform
      terminology belong according to the more recent classification the following
      clinical units: Duan's syndrome, synergic divergence, double-elevator palsy,
      misdirection syndrome, Marcus Gunn phenomenon, some forms of congenital fibrous
      syndrome, trigemino-abducens synkinesia, pseudohyperfunction of the lower oblique
      muscle, crocodile tears syndrome, and aberrant affection of n. III. The authors
      describe the course, possible etiology of these anomalies and demonstrate, based
      on their own observations, clinical cases which can be explained by these
      mechanisms.

PMID- 12428408
TI  - [Metastatic involvement of the iris in primary carcinoma of the lung].
AB  - The authors describe a quite unique case of metastatic affection of the iridial
      tissue in a 69-year-old female patient treated from 2000 for primary lung cancer.
      Before assessment of the ophthalmological diagnosis the patient reported pain and
      redness of the right eye persisting for two weeks. On examination extensive
      proliferating tissue in the area of the temporal part of the right iris was found
      and secondarily a painful glaucoma. Treatment with regard to the case-history and
      general condition of the patient involved enucleation of the affected eye.
      Histological examination confirmed subsequently the presence of a metastasis of a
      small cell spindle-shaped lung cancer into the iris with dissemination in the
      anterior chamber and corneal endothelium.

PMID- 12428409
TI  - [Evaluation of the quality of a donor cornea before transplantation].
AB  - Transplantation of the cornea is often the only possible treatment of many
      ophthalmological diseases and injuries. The quality of the donor cornea
      determines in a major way the success of transplantation and therefore the
      demands on its quality must be high. OBJECTIVE: Assess how the vitality of the
      endothelium changes in relation to the time which elapsed since the donor's death
      after storage of the cornea in the medium (death/preservation time, DPT). If the
      vitality of the endothelium is poor, the oedema of the cornea persists at room
      temperature. METHODS: The endothelium of the donor cornea was examined before
      transplantation under a specular microscope Bio Optics (USA). According to DPT
      the corneae were divided into three groups: 1st group--22 corneae where DPT is
      shorter than 5 hours 2nd group--33 corneae where DPT is 6-10 hours 3rd group--46
      corneae where DPT was longer than 10 hours. RESULTS: In the first group the
      corneae got rid of the oedema after 20 minutes at room temperature and
      endothelial cells could be observed in detail. In the second group the corneae
      got rid of the oedema after 20 minutes but there were rare oedematous sites where
      the endothelial function was not adequate. In the third group even after long
      time at room temperature the cornea did not get rid of the oedema, and on
      examination it was very difficult to find a group of endothelial cells for
      evaluation. CONCLUSION: Corneae from group 1 have a totally vital endothelium, in
      the second group there are sites on the cornea where the vitality of the
      endothelium is already impaired, in the third group the vitality of the entire
      endothelium is impaired. For transplantation corneae with a DPT shorter than 10
      hours are suitable. With a DPT longer than 10 hours they are less suitable or
      unsuitable for transplantation.

PMID- 12428410
TI  - [Refractive surgery in Slovakia].
AB  - Since 1991 the chief specialist evaluates different spheres of ophthalmology
      based on data provided by all departments in Slovakia. In the submitted article
      the author summarizes the 10-year period of refractive surgery in Slovakia.

PMID- 12428411
TI  - [Astigmatism after perforating keratoplasty. II. Management of the sutures in the
      astigmatism].

PMID- 12428412
TI  - [Transplantation of the amnionic membrane--its role in the treatment of
      pathologies of the ocular surface].

PMID- 12428413
TI  - [Autofluorescence as a diagnostic method].
AB  - The authors demonstrate the diagnostic possibilities of autofluorescence. They
      discuss its uses in diagnosing of the optic disc drusen and astrocytic hamartomas
      of the retina and the optic disc. They also show the influence of
      autofluorescence in interpreting fluorescein angiography.

PMID- 12428414
TI  - [Vincent Priessnitz and his treatment of eye diseases].

PMID- 12428415
TI  - [Hematopoiesis from the aspect of CD antigen expression].
AB  - The author summarized the expression of membrane markers (CD antigens) on
      haematopoietic cells. The proliferation and differentiation of cells in
      individual lineages from initial haematopoietic stem cell and their myeloid and
      lymphoid precursors is evaluated.

PMID- 12428416
TI  - [Hematopoietic cell lines and their importance in studies of leukemia and
      lymphoma etiopathogenesis].
AB  - Hematopoietic cell lines phenotypically and genotypically corresponding to
      original patient's leukemic or lymphoma cells are the powerful tools for studies
      of many aspects of malignant process and also for studies of normal and malignant
      hematopoesis. Until recently, permanent cell lines were derived from nearly all
      types of hematopoietic malignancies--leukemias and lymphomas. Availability of
      leukemia and lymphoma cell lines enabled the development of hybridoma technology
      for production of monoclonal antibodies and also discovery of the first human
      retroviruses HTLV-1,2 and HIV. Last but not least, leukemic cell lines are also
      used as standards for molecular diagnostics of leukemias and lymphomas. Leukemic
      and lymphoma cell lines have fully proved and extended their importance for
      modeling of malignant process ex vivo.

PMID- 12428417
TI  - [Role of cytokine signaling pathways of the transforming growth factor-beta (TGF
      beta) family in the regulation of hematopoiesis].
AB  - The transforming growth factor-beta (TGF-beta) family of cytokines consists of
      more than 30 secreted structurally related polypeptides including TGF-beta s,
      activins and bone morphogenetic proteins (BMP). This family regulates a broad
      spectrum of biological functions, including cell proliferation, differentiation,
      apoptosis, migration, and extracellular matrix production. Signaling by these
      cytokines occurs via binding to specific receptors with serine/threonine kinase
      activity and activation of specific downstream intracellular effectors (the
      receptor-regulated Smad transcription factors). TGF-beta is a regulator of all
      stages of hematopoiesis. Depending on the differentiation stage of the target
      cell, the local environment and the concentration of TGF-beta, TGF-beta can be
      positive or negative regulator of proliferation, apoptosis or differentiation of
      hematopoietic cells. TGF-beta inhibits the growth of primitive hemopoietic cells
      with a stem cell immunophenotype but has no effect or in some cases stimulates
      the growth of committed progenitors. Persistent loss of TGF-beta signaling in the
      hemopoietic stem cells and the primitive hemopoietic progenitor cells may
      possibly be involved in the development of malignant transformation.

PMID- 12428418
TI  - [Vaccinia virus as a vector for transduction of dendritic cells].
AB  - Dendritic cells (DC) are very heterogenous population of professional antigen
      presenting cells. Precursor cells migrate from bone marrow to peripheral tissues,
      where immature DC ingest pathogenic microorganisms and then migrate to secondary
      lymphoid organs. DC differentiate into mature cells that are capable to prime
      naive T lymphocytes. DC can be used for immunotherapy of cancer and infectious
      diseases. Transduction of DC by recombinant viral vectors expressing tumor
      associated antigens (TAA) can result in efficient antigen presentation to T
      lymphocytes. DC transduced with recombinant vaccinia virus expressing E7
      oncoprotein of human papilloma virus 16 are able to protect mice against the
      growth of syngeneic papillomavirus transformed tumor cells TC1. Antitumor effect
      was observed also with nonreplicating viruses.

PMID- 12428419
TI  - [DNA vaccines].
AB  - Immunization with plasmid DNA is a new trend in vaccine development that could
      enhance the safety and efficacy of currently used vaccines. Simultaneously, it
      will enable preparation of new vaccines that could not be developed by existing
      procedures. The main methods of plasmid-DNA application are intramuscular
      injection and intradermal delivery into skin by a gene gun. As a protein antigen
      is produced inside host cells, both humoral and cell-mediated immunity are
      significantly activated. The dominant role is played by dendritic cells
      presenting an antigen. The type and intensity of immune reaction induced can be
      influenced by various ways. Modification of gene coding for immunization antigen,
      combination with genes for immunostimulatory factors, and utilization of adjuvant
      effect of stimulatory CpG motifs are the major methods of improvement of
      immunization with plasmid DNA. Immune reactions against viral, bacterial, and
      parasitic infectious agents were successfully stimulated in many experimental
      systems. Other experiments are under way utilizing DNA vaccines for treatment of
      malignant tumors, autoimmune diseases, and allergy. The fast progress in DNA
      vaccine development resulted in continually increasing number of clinical trials.

PMID- 12428420
TI  - [Myelodysplastic syndrome--classification, prognosis and therapy].
AB  - BACKGROUND: The impact of classification, prognostic factors and treatment on
      survival and rate of leukemic transformation was analysed in 197 patients with
      primary myelodysplastic syndrome (MDS) treated in the Institute of Hematology and
      Blood Transfusion in the years 1980-2000. METHODS AND RESULTS: The patients were
      classified according to the FAB criteria and divided into risk groups according
      to the International Prognostic Scoring System (IPSS). A separate evaluation of
      34 patients who underwent stem cell transplantation and of 163 of those not
      transplanted was performed. Median survival of not transplanted patients with
      RAEB (10.0 months) and RAEB-T (12.0 months) was significantly shorter than
      survival of RA (62.4 months) and RARS (48.1 months, P < 0.001) patients as well
      as survival of patients included in intermediate II. (13.8 months) and high (10.8
      months) risk subgroups when compared to those with low (74.9 months) and
      intermediate I. risk (56.0 months, P < 0.001). A similar difference was observed
      in percentage of patients evolving towards acute leukemia and in estimated 3
      years survival (EFS). EFS of RA patients was 57% in contrast to 4% in RAEB-T
      group (P < 0.001) in the same way, EFS in low risk subgroup was 79% vs. 3% in
      high risk patients (P < 0.001). Chemotherapy alone did not significantly affect
      median survival of patients with advanced MDS when compared with supportive care.
      On the contrary, median survival of transplanted patients with RAEB and RAEB-T
      was 38.4 months in comparison to 11.5 months in those not transplanted (P <
      0.001) and 36.8 months vs. 12.0 months in transplanted and not transplanted
      patients with intermediate II. and high risk (P = 0.05). The difference in
      survival between transplanted and not transplanted patients with RA and in
      patients in low and intermediate I. risk subgroups was not statistically
      significant. CONCLUSIONS: We confirmed an adverse effect of excess of blasts on
      prognosis of patients with primary MDS. Stem cell transplantation had a
      significant beneficial effect on survival of patients with RAEB or RAEB-T as well
      as of patients included in intermediate II. or high risk subgroups. The impact of
      stem cell transplantation on survival of patients with RA or with low or
      intermediate I. risk was not significant. Therefore, further criteria should be
      taken in account for indication of stem cell transplantation in these subgroups
      of patients.

PMID- 12428421
TI  - [Rearrangements of 11q in patients with hematologic malignancies].
AB  - BACKGROUND: The aim of this study was to investigate the rearrangement of MLL
      gene in bone marrow cells of patients with hematological malignancies with
      various types of 11q aberrations. These aberrations have been observed in acute
      lymphoblastic and acute myeloid leukemias as well as in myelodysplasias and
      lymphomas. METHODS AND RESULTS: Correlations of clinical characteristics, type of
      aberrations, diagnoses and survival of patients were evaluated. Using classical
      cytogenetic techniques we found 11q aberration in 17 patients with different
      hematological malignancies. FISH with dual color locus specific probe for MLL
      gene was used to confirm or exclude the rearrangement of this gene. Whole
      chromosome painting probes and multicolor FISH were performed for identification
      of chromosomes involved in complex translocations. Balanced rearrangements of 11q
      were found in 3 patients, in 14 patients unbalanced aberrations were found with
      rearrangement (4), deletion (4) and amplification (2) of MLL gene. In 7 patients
      no rearrangement of MLL gene was found. CONCLUSIONS: Correlation between clinical
      characteristics, type of aberrations, diagnoses and survival of patients was not
      significant, therefore further studies of larger cohort of patients are necessary
      to evaluate the prognostic value of 11q rearrangement.

PMID- 12428422
TI  - [Use of photodynamic therapy for elimination of residual leukemic cells in
      autologous transplants of hematopoietic progenitor cells].
AB  - BACKGROUND: The increasing use of autologous hematopoietic cell support in
      various malignancies including leukemia and lymphoma currently bears the problem
      of tumor contamination of the graft with tumor cells which after re-infusion
      contribute to the disease relapses. It is therefore desirable to eradicate the
      cancer cell fraction of the graft without causing damage to the normal stem cell
      fraction. The purging processes based on photodynamic treatments appear to be
      perspective means for this purpose. METHODS AND RESULTS: We investigated the
      effects of 5-aminolevulinic acid (ALA)--based photodynamic treatment (ALA-PDT) on
      the proliferation of human leukemia cell lines HL60 (promyelocytic leukemia), ML2
      (myelomonocytic leukemia) and HEL (erythroleukemia) by 3H-thymidine incorporation
      into the cell DNA, on the viability of cell lines HL60, HEL, DAUDI (B-cell
      leukemia) and JURKAT (T-cell lymphoma) as well as of blast cells of acute myeloid
      leukemia (AML) patients by flow cytometry-propidium iodide assay, and on the
      clonogenic activities of normal human bone marrow cells by in vitro cloning
      assays. Under the conditions used (treatment with 1 mM ALA for 4 h at 37 degrees
      C followed by exposure to blue light dose of 18 J/cm2) the number of
      proliferating HL60 cells was reduced by 2.4 logs, of ML2 cells by 3.2 logs and of
      HEL cells by 1 log. From the mononuclear cell preparations of AML patients the
      blast cells were substantially reduced in eight out of ten patients. The
      clonogenic activities of normal bone marrow progenitor cells were largely spared:
      52.5 +/- 8.9% of colony-forming units--granulocytes macrophages (CFU-GM), and
      48.6 +/- 9.7% burst forming units--erythrocytes (BFU-E). CONCLUSIONS: ALA-PDT
      appears to be usable principle for the depletion of residual leukemic cells from
      autologous transplants.

PMID- 12428423
TI  - [Role of free radicals in blood platelet activation].
AB  - BACKGROUND: Free radicals and reactive oxygen containing substances are in
      addition to negative effects on biological systems important as signal molecules.
      Influencing their concentration by the action of antioxidants has a basic
      influence on the course of a number of cellular responses. The function of
      platelets is modulated in a significant way by the presence of vitamin E and
      resveratrol. The objective of the submitted paper is to assess the effect of
      Trolox (a stable analogue of vitamin E) and resveratrol sorbed by platelets on
      the aggregation response of washed platelets activated by collagen. METHODS AND
      RESULTS: To investigate the effects of the mentioned antioxidants on platelet
      aggregation washed platelets were prepared. The concentrations of the two
      antioxidants sorbed by platelets were assessed by the method of high performance
      liquid chromatography. From the total Trolox concentration (4200 microM) the
      platelets sorbed 33.5 nmol/10(9) platelets and from the total concentration of
      resveratrol (300 microM) the platelets sorbed 6.5 nmol/10(9) platelets. Inhibited
      aggregation by collagen was 57% for Trolox and 98% for resveratrol. CONCLUSIONS:
      The antioxidant capacity of both antioxidants is identical. The resveratrol
      concentration in platelets which led to almost complete inhibition of platelet
      aggregation by collagen was five times lower than for Trolox which caused a 57%
      inhibition of aggregation. Thus also other factors participate in the antioxidant
      activity of resveratrol. One of these factors is very probably the effect on
      arachidonic acid cycle.

PMID- 12428424
TI  - [Effect of oxidized cellulose on fibrin formation and blood platelets].
AB  - BACKGROUND: Haemostyptic materials initiate and hasten blood clotting at the site
      of their application. The properties of haemostyptic materials are used for
      treatment of capillary and parenchymatous haemorrhage along with surgical
      treatment. Celluloses one of the biopolymers studied for a long time, suitable
      because of its biocompatibility and non-toxicity. METHODS AND RESULTS: In the
      submitted study the authors used microdispersed calcium-sodium salt of oxidized
      cellulose which is formed by oxidation of cellulose in position C6 (patent
      Alltracel Pharmaceuticals). The authors investigated the effect of oxidized
      cellulose on fibrin formation and platelets. Using the optic method of the
      surface plasmon resonance they investigated the initial stage of interaction
      between fibrinogen and oxidized cellulose. Oxidized cellulose retards and reduces
      the interaction of the immobilized fibrin monomer with fibrinogen. Fibrin
      formation was investigated spectrophotometrically at 350 nm. In the presence of
      cellulose the period of formation of fibrin gel was prolonged and its turbidity
      increased, depending on the concentration of the cellulose used. The platelet
      activation by cellulose was assessed by measuring the released serotonin. For the
      activation of platelets by cellulose the presence of plasma is necessary, rinsed
      platelets were not activated by cellulose. It was revealed that direct,
      interaction of rinsed platelets or fibrinogen with cellulose plays a secondary
      role. CONCLUSIONS: These data and the retarded activation of platelets in plasma
      with factor XII deficiency indicate that due to negatively charged oxidized
      cellulose probably activation of the contact coagulation system occurs and this
      leads to the activation of platelets and fibrin formation.

PMID- 12428425
TI  - [Activation of the ribosomal gene during blast transformation of human
      lymphocytes].
AB  - BACKGROUND: Natural lectin, phytohemagglutinin, initiates the transformation of
      normally quiescent T lymphocytes into proliferating lymphoblast-like cells.
      Recently we have shown that the transformation is accompanied by strong promotion
      of ribosomal RNA synthesis and by phosphorylation of its activator, initiating
      factor UBF, both culminating in a synthetic phase of the first cell division
      cycle. In contrast we have revealed that the UBF gene was activated and its
      transcription culminated in the early G1 phase. We examined three possible
      delaying mechanisms: the kinetics of unwinding of rDNA chromatin, the kinetics of
      transcription of genes coding for the second initiating factor, SL1 complex, and
      the kinetics of the translation of UBF protein product. METHODS AND RESULTS: Up
      to 48 hrs following the addition of phytohemagglutinin to the growth medium, we
      monitored structural changes in the rDNA chromatin using indirect antiUBF
      immunofluorescence. The data indicated an increased number of separated
      transcriptional units during the G1 phase of the first cycle. In a time interval
      of up to 70 hrs we measured the mRNA levels of four constituents of SL1 complex:
      TAF110, TAF63, TAF48 and TBP using the RT-PCR method. We found a close
      correlation between the kinetics of the transcription of UBF and SL1 genes and
      the maximal rate in the early G1 phase. Using metabolic labelling with 35S
      methionine/cysteine we monitored the translation of UBF protein in PHA stimulated
      lymphocytes. The data suggested that UBF translation, starting in the S phase,
      paralleled chromosomal DNA replication. CONCLUSIONS: During the transformation of
      normal T lymphocytes into proliferating blast-like cells, the multicopy rDNA gene
      unwinds in the G1 phase of the first cycle forming individual transcriptional
      units. Genes coding for factors which initiate synthesis of ribosomal precursors
      are activated in the early G1 phase. The G1 synthesis of ribosomal RNA is
      accelerated by phosphorylation of the hypophosphorylated UBF pool. As blastic
      transformation develops UBF translation is triggered in the S phase and
      neosynthesized UBF, activated by phosphorylation, pushes the synthesis of
      ribosomal precursors to maximal efficiency. The process of blastic transformation
      interferes throughout the entire prolonged G1 phase of the first cell division
      cycle.

PMID- 12428426
TI  - Urbanization: an increasing risk factor for leishmaniasis.

PMID- 12428427
TI  - Studies on the antiplasmodial properties of some South African medicinal plants
      used as antimalarial remedies in Zulu folk medicine.
AB  - The parasite lactate dehydrogenase (pLDH) assay method, a recently developed in
      vitro enzymatic method for evaluating antimalarial compounds, was used to examine
      the antiplasmodial activities of the aqueous leaf, stem-bark and fruit extracts
      of some plants used for the treatment and/or prophylaxis of malaria in KwaZulu
      Natal province of South Africa. The in vitro antiplasmodial assay was carried out
      using a chloroquine-sensitive strain of malarial parasite, Plasmodium falciparum
      D10. A preliminary phytochemical analysis of the plant extracts was carried out
      using UV spectral analysis and thin-layer chromatography (TLC) to separate the
      chemical constituents of the extracts. Their chemical components were
      subsequently identified by treating the TLC plates with various spray reagents.
      Of the 14 plant extracts investigated, only 10 were found to have IC50 values of
      10-50 micrograms/ml. The two most active extracts were Psidium guajava stem-bark
      extract and Vangueria infausta leaf extract, both of which showed IC50 values of
      10-20 micrograms/ml. Phytochemical analysis of these two active plant extracts
      revealed the presence of anthraquinones, flavonoids, seccoirridoids and
      terpenoids.

PMID- 12428428
TI  - Activated polymorphonuclear leukocytes induce cardiomyocyte apoptosis and the
      protective effects of carvedilol.
AB  - Previous studies have shown that ischemia and reperfusion are potent stimuli for
      eliciting cardiomyocyte apoptosis, and that polymorphonuclear leukocytes (PMNs)
      are involved in the development of myocardial injury induced by ischemia and
      reperfusion. The present study examined whether PMN could directly induce
      cardiomyocyte apoptosis and, if so, it possible signal transduction pathways. In
      addition, we also investigated the effects of carvedilol, a potent antioxidant,
      on PMN-induced apoptosis. Cultured primary neonatal rat cardiomyocytes were
      exposed to PAF-activated PMNs at concentrations of 10(5), 3 x 10(5) and 10(6)
      cells/well for 48 h. Multiple detecting techniques, including electron
      microscopy, DNA gel electrophoresis. TUNEL assay and flow cytometry were used to
      identify myocyte apoptosis. All of these techniques demonstrated that activated
      PMNs directly induced cardiomyocyte apoptosis in a concentration-dependent
      manner, while unactivated PMNs showed no such effect. Activated PMN-induced
      apoptosis was partially inhibited by SB203580, a specific inhibitor of the p38
      MAPK signaling system. Carvedilol (at a dose range of 1-10 mumol/l) significantly
      prevented activated PMN-induced cardiomyocyte apoptosis. These results suggest
      that PMNs, when activated, directly induce cardiomyocyte apoptosis and that the
      p38-MAPK signaling pathway might be involved in this process. Carvedilol may
      prevent PMN-induced apoptosis possibly because of its antioxidant properties.

PMID- 12428429
TI  - Histaminergic modulation of stress-induced analgesia and cognitive dysfunction.
AB  - Physiological stress is known to produce analgesia and memory disruption. A large
      body of evidence favors the nonopiate mediation of stress-induced analgesia. It
      is suggested that brain histamine mediates nonopiate analgesia and participates
      in learning and memory in rodents. Histamine is released during stress, although
      the nature of histaminergic involvement in stress response is not clearly
      defined. Therefore, we studied the effect of L-histidine and histamine-receptor
      antagonists on antinociception and impaired retention induced by immobilization
      stress. In the present study, immobilization stress produced a naloxone-resistant
      analgesia that was potentiated by L-histidine and antagonized by pretreatment
      with the histamine receptor antagonists chlorpheniramine and cimetidine. L
      histidine attenuated the memory disruption induced by immobilization stress,
      which was significantly reversed by chlorpheniramine but not by cimetidine. Thus
      the involvement of the central histaminergic system, through histamine H1- and H2
      receptors, may be speculated in analgesia and cognitive deficit induced by
      immobilization stress.

PMID- 12428430
TI  - Protective effects of dextromethorphan and tizanidine on ouabain-induced
      arrhythmias.
AB  - The effects of the opioid agonist dextromethorphan and the alpha 2-adrenoceptor
      agonist tizanidine on ouabain-induced cardiac arrhythmias were investigated in
      rats. Ouabain (10 mg/kg i.v.) elicited ventricular arrhythmias in all of the
      control rats. Administration of dextromethorphan (25 mg/kg i.v.) and tizanidine
      (0.1 mg/kg i.v.) 30 min before ouabain treatment significantly reduced the
      incidence of arrhythmias. We suggest that dextromethorphan and tizanidine showed
      these effects by decreasing excitatory amino acid (EAA) activity. It can be
      speculated that opioids and other EAA antagonists may have antiarrhythmic actions
      through both their central and peripheral effects as well.

PMID- 12428431
TI  - Quality of life (Spain and France): validation of the chronic venous
      insufficiency questionnaire (CIVIQ).
AB  - A health-related quality of life (HRQOL) assessment is particularly necessary for
      patients with chronic venous insufficiency (CVI), as is an assessment of the
      objective signs (edema, dilated veins, ulceration and other lesions). A
      comprehensive 3-year research program was undertaken in France to construct and
      validate the Chronic Venous Insufficiency Questionnaire (CIVIQ), a questionnaire
      designed specifically to evaluate the quality of life for CVI sufferers. The next
      step was to implement a program of cross-cultural validation in several
      countries. Translation into Spanish was undertaken following international
      guidelines. Face validity was verified with a pilot test among 12 Spanish
      patients. Psychometric validation was performed in Spain (n = 476 patients with
      CVI). The Spanish CIVIQ demonstrated very good internal consistency, high
      reproducibility and responsiveness, as well as longitudinal clinical validity. It
      appears to be a valuable instrument for assessing improvement in patient quality
      of life in response to both therapy in clinical practice and clinical trials.

PMID- 12428432
TI  - Gateways to Clinical Trials.
AB  - Gateways to Clinical Trials is a guide to the most recent clinical trials in
      current literature and congresses. The data in the following tables has been
      retrieved from the Clinical Studies knowledge area of Prous Science Integrity,
      the drug discovery and development portal, http://integrity.prous.com. This issue
      focuses on the following selection of drugs: Adalimumab, aeroDose insulin
      inhaler, agomelatine, alendronic acid sodium salt, aliskiren fumarate, alteplase,
      amlodipine, aspirin, atazanavir; Bacillus Calmette-Guerin, basiliximab, BQ-788,
      bupropion hydrochloride; Cabergoline, caffeine citrate, carbamazepine,
      carvedilol, celecoxib, cyclosporine, clopidogrel hydrogensulfate, colestyramine;
      Dexamethasone, diclofenac sodium, digoxin, dipyridamole, docetaxel, dutasteride;
      Eletriptan, enfuvirtidie, eplerenone, ergotamine tartrate, esomeprazole
      magnesium, estramustine phosphate sodium; Finasteride, fluticasone propionate,
      fosinopril sodium; Ganciclovir, GBE-761-ONC, glatiramer acetate, gliclazide,
      granulocyte-CSF; Heparin sodium, human isophane insulin (pyr),
      Hydrochlorothiazide; Ibuprofen, inhaled insulin, interferon alfa, interferon beta
      1a; Laminvudine, lansoprazole, lisinopril, lonafarnib, losartan potassium,
      lumiracoxib; MAb G250, meloxicam methotrexate, methylprednisolone aceponate,
      mitomycin, mycophenolate mofetil; Naproxen sodium, natalizumab, nelfinavir
      mesilate, nemifitide ditriflutate, nimesulide; Omalizumab, omapatrilat,
      omeprazole, oxybutynin chloride; Pantoprazole sodium, paracetamol, paroxetine,
      pentoxifylline, pergolide mesylate, permixon, phVEGF-A165, pramipexole
      hydrochloride, prasterone, prednisone, probucol, propiverine hydrochloride;
      Rabeprazole sodium, resiniferatoxin, risedronate sodium, risperidone, rofecoxib
      rosiglitazone maleate, ruboxistaurin mesilate hydrate; Selegiline transdermal
      system, sertraline, sildenafil citrate, streptokinase; Tadalafil, tamsulosin
      hydrochloride, technosphere/Insulin, tegaserod maleate, tenofovir disoproxil
      fumarate, testosterone heptanoate, testosterone undecanoate, tipifarnib,
      tolterodine tartrate, topiramate, troglitazone; Ursodeoxycholic acid; Valdecoxib,
      valsartan, vardenafil, venlafaxine hydrochloride, VX-745.

PMID- 12428433
TI  - [Inflammatory and degenerative joint diseases].

PMID- 12428434
TI  - [Insight into the clinical epidemiology of arthrosis].
AB  - Osteoarthritis is one of the most important contributions to the burden of
      disease. 50% of those aged 65 and 80% of those aged 75 years show radiological
      signs of osteoarthritis. Risk factors for incidence and progression of
      osteoarthritis vary considerably according to the type of joint. There is only a
      modest relationship between the radiographic severity of joint damage and the
      incidence and severity of pain. Psychosocial and socioeconomic factors play an
      important role for the development of pain in osteoarthritis.

PMID- 12428435
TI  - [Joint pain of undetermined origin--evaluation method].
AB  - The most important diagnostic steps in the initial, non-specialist evaluation of
      joint pains are the careful anamnesis, clinical examination and laboratory tests
      for inflammations parameters and for infectious and autoimmune serologies. The
      arthrocentesis and consecutive analysis of synovial fluid, the interpretation of
      which, due to their complexity, lie in the hands of rheumatologists and most
      often allow the clear differentiation of non-inflammatory versus inflammatory
      causes. Conventional radiology is seldom diagnostic but a prerequisite for
      monitoring the course of the joint disease. Arthrosonography is cost-effective
      and often provides additional information besides clinical examination. More
      expensive diagnostic procedures such as arthroscopy, magnetic resonance imaging,
      scintigraphy and CT are reserved for more specific clinical situations.

PMID- 12428436
TI  - [Ultrasound diagnosis of the locomotor system].
AB  - Improvements of ultrasound technology with knew equipments allowed enormous
      advances in all fields of medicine during the last years. Several conditions
      concerning technical equipment and training of the operator have to be fulfilled
      to guarantee sufficient quality of the diagnostic information obtained in
      musculoskeletal ultrasound, Ultrasound is most commonly used in the assessment of
      soft tissue disease, detection of fluid collection, but can also be used to
      visualise structures such as cartilage and bone surfaces. Bone surface changes
      like erosions may be seen before they are apparent on plain x ray or even
      magnetic resonance imaging. Dynamic assessment of joint and tendon movements
      allows better understanding of the functional disorders than mainly static
      imaging methods. Advantages of ultrasound include its non-invasiveness,
      portability, relative inexpensiveness, lack of ionising radiation, and its
      ability to be repeated as often as necessary, making it particularly useful in
      the monitoring of treatment. Guidance of diagnostic aspiration, biopsy and
      injection treatment improves quality and security of these interventions. Newer
      ultrasound techniques including colour and power Doppler imaging, as well as
      bubble contrast agents and three dimensional reconstructions are promising tools
      for the future.

PMID- 12428438
TI  - [Seronegative spondyloarthropathies].
AB  - Seronegative spondyloarthropathies are characterized by bilateral or unilateral
      sacroiliitis, spondylitis, peripheral arthritides or extraarticular
      manifestations. The spondyloarthropathies are associated with a positive HLA-B27
      status. Genetic factors, repetitive biomechanical stress and the immune response
      to bacterial products lead to the inflammatory changes at typical anatomical
      sites. Diseases classified as spondyloarthropathies include ankylosing
      spondylitis, reactive arthritis, psoriatic arthritis, juvenile
      spondyloarthropathy and inflammatory bowel disease associated with spondylitis.
      The SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) syndrome is also
      considered a member of the spondyloarthropathy family. An otherwise unclassified
      HLA-B27-linked peripheral arthritis is often considered an undifferentiated
      spondyloarthropathy. Treatment consists of physical therapy including patient
      education, non-steroidal anti-inflammatory drugs and disease modifying anti
      rheumatic drugs.

PMID- 12428437
TI  - [Calcium pyrophosphate deposits--a chameleon].
AB  - Calcium Pyrophosphate Dihydrate (CPPD) crystals deposit in articular fibro- or
      hyaline cartilage (chondrocalcinosis), joint capsules, synovium, periarticular
      ligaments and tendons resulting in an age dependent prevalence. These
      calcifications may be asymptomatic or may manifest as acute pseudogout arthritis,
      pseudorheumatoid arthritis, bursitis, tenosynovitis, tendinitis, polymyalgic
      syndrome or chronic pyrophosphate arthropathy. The diagnosis is based on the
      presence of intracellular CPPD crystals in synovial fluid detected by polarizing
      microscopy, the characteristic radiological changes and the typical clinical
      presentations. The therapy is symptom oriented or disease specific in case of an
      underlying metabolic disease such as hemochromatosis, hyperparathyroidism,
      hypophosphatasia, hypomagnesemia or hypothyroidism.

PMID- 12428439
TI  - [Therapeutic use of "biologics" in inflammatory joint and spinal diseases].
AB  - At present, two principles of biologic treatment for rheumatoid arthritis and
      other chronic inflammatory joint and spine diseases (juvenile polyarticular
      idiopathic arthritis, spondarthritides) are available for use in clinical
      practice. These are the TNF-alpha antagonists etanercept and infliximab as well
      as the human recombinant IL-1 receptor antagonist anakinra. All three biologics
      have significant short and long-term therapeutic effects on clinical and humoral
      inflammatory activity compared to placebo treatment in controlled clinical trials
      and even radiological progression of rheumatoid arthritis can be with halted.
      Principally, safety and tolerability of TNF- and IL-1 antagonist are good.
      However, local skin reactions at injection sites and infections of the upper
      respiratory tract and urinary tract have to be considered. Severe infections are
      rare except for an increased frequency of tuberculous infection observed with
      infliximab worldwide. The induction of autoantibodies including antibodies to
      double-stranded DNA and neuralizing antibodies to etanercept and infliximab
      themselves can occur though their clinical significance is still upon debate. It
      is important to notice that the advantages of the use of biologics in individual
      patients has carefully to be balanced against their high costs and the increased
      risk of infectious side effects. Therefore, guidelines of international experts
      recommend the clinical use of biologics mostly for patients resistant or
      intolerable to conventional treatment.

PMID- 12428440
TI  - [Viscosupplementation in arthrosis].
AB  - Target of this paper is to focus on the current knowledge about
      viscosupplementation in the management of osteoarthritis. The molecular structure
      and the effects of hyaluronic acid derivates on mechanical, biochemical and
      cellular level are described. Since the exogenously introduced hyaluronic acid
      derivates stay on average only 10 to 20 hour in the synovial fluid and yet its
      effect continues over months, an additional effect is postulated: modulation of
      the activity of the different cells in the development and progression of the
      osteoarthritis (synoviocytes, chondrocytes, inflammatory cells), probably by
      direct effect on their specific receptors. These receptors play an important role
      in the migration, adhesion and activation of inflammatory cells, as well as
      maturation and differentiation of the chondrocytes for synthesizing the cartilage
      matrix. In experimental studies in vitro and in vivo an analgetic and anti
      inflammatory effect of hyaluronic acid derivates was proven. These results were
      confirmed in clinical studies. An amelioration of symptoms was shown and a delay
      of disease progression seems possible. This therapy is well tolerated and
      complications are few. Further studies to determine the optimal dosage and
      product (low or high-molecular preparation), the possible combination with other
      therapies in ideal sequence and the effect in the different subtypes of
      population are needed.

PMID- 12428442
TI  - Will living starter bacteria no longer be an argument for the quality of
      fermented products?

PMID- 12428441
TI  - [Endoprosthesis implantation in the elbow joint].
AB  - Previously used total elbow prostheses were mainly constrained hinged implants.
      Their early clinical results were favourable but they failed due to a high rate
      of loosening already a few years after implantation. The cause for the early
      loosening was the great forces across the elbow joint which were directly
      transmitted to the prosthesis-bone interface in these implants. Therefore, these
      implants were abandoned. Afterwards, unlinked, semiconstrained or non-constrained
      resurfacing devices were introduced. In these devices, the soft tissues constrain
      the joint and therefore absorb part of the transmitted forces. The rates of
      loosening were significantly improved and rarely the cause of early failure. But
      resurfacing implants require intact condyles and collateral ligaments. These
      implants can, therefore, only be used in a limited number of indications, and
      postoperative instabilities are known complications. The currently most
      frequently used device is the semiconstrained Coonrad-Morrey prosthesis. It is a
      floppy hinge which allows valgus-varus and rotational laxities. Therefore, a part
      of the forces across the elbow joint are absorbed by the soft tissues. The
      loosening rate is not a clinical problem any more, and is with 4% 10 years after
      implantation (rheumatoid arthritis) similar to that of total hip or knee
      replacement. Furthermore, this device is stabilised with a small anterior flange
      to the anterior cortex of the humeral shaft. Condyles and collateral ligaments
      are therefore not necessary neither for short nor for long-term stability. The
      Coonrad-Morrey total elbow prosthesis can therefore be used for almost every
      indication, such as severe destruction of the elbow joint and even in case of
      complete loss of the distal humerus. The long-term outcome with this prosthesis
      for the treatment of rheumatoid arthritis is favourable with 96% of very good and
      good results. Function is restored with an average flexion of 131 degrees, a mean
      loss of extension of 28 degrees, and an unrestricted pronation and supination.
      The rate of complications for patients with rheumatoid arthritis is 10%.
      Similarly, the results for Coonrad-Morrey total elbow replacement for
      posttraumatic arthrosis are favourable with 83% of satisfactory results. Most
      patients consider their elbow as improved compared to preoperatively, but pain
      relief is obtained only in three quarters of the patients. The rate of
      complications is high with 30%, indicating the total elbow replacement is
      contraindicated for strenuous labour and sports activities.

PMID- 12428443
TI  - Effect of ascorbic acid on the stability of beta-carotene and capsanthin in
      paprika (Capsicum annuum) powder.
AB  - The effect of ascorbic acid, light, and storage on the stability of the pigments
      beta-carotene and capsanthin in red pepper (Capsicum annuum) powder has been
      elucidated by determining the amount of pigment in samples treated by various
      concentrations of ascorbic acid. Determination of pigment concentration has been
      performed after different storage times using high-performance liquid
      chromatography. The dependence of the concentration of pigments on the
      concentration of ascorbic acid, presence of light and the storage time has been
      assessed by stepwise regression analysis. The concentration of pigments decreased
      at longer storage time and increased at higher concentration of ascorbic acid,
      beta-carotene being more sensitive towards storage time and concentration of
      ascorbic acid than capsanthin. Interaction between the effects of light and
      storage time, and light and concentration of ascorbic acid has been established.

PMID- 12428444
TI  - Effect of annealing and heat moisture conditioning on the physicochemical
      characteristics of Bambarra groundnut (Voandzeia subterranea) starch.
AB  - Isolated starch of Bambarra groundnut (Voandzeia subterranean) was subjected to
      hydrothermal modifications through annealing and heat moisture conditioning. Both
      annealing and heat moisture conditioning reduced the swelling power and
      solubility of the starch. Water binding capacity reduced after annealing heat
      moisture conditioning at 18% moisture level (HMB18) and heat moisture
      conditioning at 21% moisture level (HMB21). Both heat moisture conditioning at
      24% moisture level (HMB24) and heat moisture conditioning at 27% moisture level
      (HMB27) increased the water binding capacity. Hydrothermal modifications reduced
      the oil absorption capacity of the raw starch. Annealing and heat moisture
      conditioning reduced the peak viscosity (Pv), viscosity at 95 degrees C (Hv) and
      viscosity at 95 degrees C after 30 min holding (Hv30). However, viscosity
      increased on cooling down to 50 degrees C after annealing. Annealing and heat
      moisture treatments as revealed by scanning electron micrograph and light
      micrograph did not alter the shape and size of the raw starch. The results
      indicate a rearrangement within the starch granule following hydrothermal
      treatments.

PMID- 12428445
TI  - Antifungal activities of selected aromatic plants growing wild in Greece.
AB  - Essential oils of Origanum onites, Satureja thymbra, Salvia fruticosa (Greek
      sage), and Salvia pomifera subsp. calycina plants growing wild in Greece and
      their components carvacrol, camphor, and 1,8-cineole, were assayed for antifungal
      activity against 13 fungal species. Among the fungi tested were food poisoning,
      plant, animals and human pathogenic species. The oils presented various degrees
      of inhibition against all the fungi investigated. The highest and broadest
      activity was shown by the carvacrol content oils (O. onites and S. thymbra),
      while the oil of sage was the least effective. Carvacrol exhibited the highest
      and 1,8-cineole the lowest level of antifungal activity among the components
      tested.

PMID- 12428446
TI  - A recombinant Saccharomyces cerevisiae strain for efficient conversion of lactose
      in salted and unsalted cheese whey into ethanol.
AB  - For utilization of lactose in salted and unsalted cheese whey, intergeneric
      protoplast fusion between lactose nonfermenting, salt-tolerant Saccharomyces
      cerevisiae ATCC4126 and lactose fermenting Kluyveromyces lactis CBS683 was
      carried out. The fusion process gave rise to new hybrid yeast strains that
      revealed higher significant DNA contents than parental strains. The recombinants
      showed growth on either lactose or sucrose. The ethanol yields by some
      recombinants were 5.55% from sweet whey and 4.66% from salted whey containing up
      to 6% sodium chloride compared to 4.15 and 2.86% for parental K. lactis CBS683,
      respectively.

PMID- 12428447
TI  - Influence of gamma-irradiation and maize lipids on the production of aflatoxin B1
      by Aspergillus flavus.
AB  - The effect of gamma-irradiation and maize lipids on aflatoxin B1 production by
      Aspergillus flavus artificially inoculated into sterilized maize at reduced water
      activity (aw 0.84) was investigated. By increasing the irradiation doses the
      total viable population of A. flavus decreased and the fungus was completely
      inhibited at 3.0 kGy. The amounts of aflatoxin B1 were enhanced at irradiation
      dose levels 1.0 and 1.5 kGy in both full-fat maize (FM) and defatted maize (DM)
      media and no aflatoxin B1 production at 3.0 kGy gamma-irradiation over 45 days of
      storage was observed. The level in free lipids of FM decreased gradually, whereas
      free fatty acid values and fungal lipase activity increased markedly by
      increasing the storage periods. The free fatty acid values decreased by
      increasing the irradiation dose levels and there was a significant enhancement of
      fungal lipase activity at doses of 1.0 and 1.50 kGy. The ability of A. flavus to
      grow at aw 0.84 and produce aflatoxin B1 is related to the lipid composition of
      maize. The enhancement of aflatoxin B1 at low doses was correlated to the
      enhancement of fungal lipase activity.

PMID- 12428448
TI  - Cystone, an ayurvedic herbal drug imparts protection to the mice against the
      lethal effects of gamma-radiation: a preliminary study.
AB  - The effect of 5, 10, 20, 40, 60, 80, 100, 120, and 160 mg/kg body weight (b.wt.)
      of aqueous extract of cystone (an ayurvedic herbal medicine) administered
      intraperitoneally was studied on the radiation-induced mortality in mice exposed
      to 10 Gy of gamma-radiation. Treatment of mice with different doses of cystone,
      consecutively for five days before irradiation, delayed the onset of mortality
      and reduced the symptoms of radiation sickness when compared with the non-drug
      treated irradiated controls. The pretreatment of mice with different doses of
      cystone before exposure to 10 Gy of gamma-radiation resulted in a dose-dependent
      elevation in the survival up to 40 mg/kg b.wt., where the highest number of
      survival (55.55%) was observed by 30 days post irradiation, when compared with
      the 10 Gy irradiated control (6.66%). Thereafter, the number of survivors
      declined and reached a nadir at 160 mg/kg, where no survivors could be observed.
      The optimum protection against irradiation was observed for 40 mg/kg cystone,
      where the highest number of survivors were reported by 30 days post irradiation
      and it was 8.34-fold greater than that of the irradiated control group.

PMID- 12428449
TI  - Antibacterial activity of chitosan against Aeromonas hydrophila.
AB  - The effect of chitosan on growth and production of haemolysin by Aeromonas
      hydrophila was investigated as well as the effects of temperature, pH, salts and
      irradiation on the antibacterial activity of chitosan. It was found that chitosan
      affected growth and haemolysin production of A. hydrophila in varying degrees
      compared to the control. Growth and haemolysin production were clearly suppressed
      at 0.04% of chitosan. Suppression was more effective at pH 6.0 than at pH 7.0.
      The bactericidal effects of chitosan increased with increasing temperature and
      decreasing pH. Divalent cations at concentrations of 10 and 25 mM reduced the
      antibacterial activity of chitosan, in the order of Ba2+ > Ca2+ > Mg2+. Sodium
      ions at concentrations of 10 and 25 mM also reduced chitosan's activity.
      Irradiation of chitosan at 150 kGy under dry condition was effective in slightly
      increasing its activity.

PMID- 12428450
TI  - Distribution of aflatoxins in product and by-products during glucose production
      from contaminated corn.
AB  - Aflatoxins are known to be hepatotoxic, carcinogenic, and teratogenic. A positive
      correlation has been established between the consumption of aflatoxin
      contaminated foods and the increased incidence of liver cancer worldwide. A
      survey of Egyptian corn and corn-based products and by-products shows that the
      majority of the samples had higher limits of aflatoxin. We have conducted
      experiments to determine the fate and distribution of aflatoxin during wet
      milling process fractions and investigate the aflatoxin destruction during starch
      conversion to glucose syrup. The present results showed that about half of the
      aflatoxin content (48.1%) in the infected corn grain was found to be lost in
      steep liquor, depending upon the aflatoxin type, arranged in the order G1 > G2 >
      B1 > B2. After wet-milling aflatoxins were distributed into starch, gluten,
      fiber, and germ. Gluten, fiber, and germ were the most highly contaminated
      fractions. The loss of aflatoxin during process of starches reached 54.4% in
      steep water and water process. Although the gluten fraction represents only 9.6%
      of corn, the higher percentage (25.3%) of aflatoxin was found in this fraction,
      the fiber and germ account for nearly 29% of the milled corn and contain 11.6% of
      the aflatoxin. On the other hand, 8.7% of the total aflatoxins in start corn was
      found in starch fraction which accounts 61% of the milled corn. Aflatoxins G1 and
      G2 were found lost in higher concentrations compared to the aflatoxin B1 and B2.
      A higher percentage of AfG1 (86.35%) and AfG2 (78.36%) and a lower percentage of
      AfB1 (16.3%) and AfB2 (14.7%) were found in starch fraction. The conversion
      percent of contaminated starch was 89.5% compared with control starch. It can be
      concluded that aflatoxins were destroyed during starch conversion. Consequently,
      glucose syrup produced from contaminated starch was found aflatoxin-free.

PMID- 12428451
TI  - Butyric acid modulates activities of intestinal and renal disaccharidases in
      experimentally induced diabetic rats.
AB  - To elucidate the effect of feeding of butyric acid on disaccharidase activities,
      the specific activities of the disaccharidases were measured in the intestinal
      mucosa and kidney cortex of control and diabetic rats. Diabetes was induced in
      rats using streptozotocin. Rats were fed with basal diet containing wheat bran
      (5%) as a source of insoluble dietary fiber and guar gum (2.5%) as a source of
      soluble dietary fiber. The experimental group received butyric acid at 250, 500
      and 750 mg/kg body weight/day. Increased activities of intestinal maltase,
      sucrase and lactase in diabetic rats were significantly reduced in fiber-fed
      diabetic group. Supplementation of butyric acid at 500 mg/kg body weight/day
      showed a further decrease in their activities. The activity of disaccharidases in
      renal tissue was decreased in diabetic rats and was significantly improved in
      fiber-fed diabetic group. Butyric acid feeding at 500 mg/kg body weight/day
      showed further improvement in their activities.

PMID- 12428452
TI  - Development of a sample preparation method for the analysis of oxidized flavonols
      in onions and leek.
AB  - A method is presented for the determination of oxidized flavonols (i.e.,
      hydroxybenzoylbenzofuranones) in plant material. Onions and leek are investigated
      using a newly developed solid-phase extraction procedure for sample preparation
      prior to high-performance liquid chromatography (HPLC). It is shown that the
      addition of ascorbic acid as antioxidant is necessary to prevent the generation
      of the researched analytes during this procedure. Nevertheless, the plant
      extracts do under certain conditions catalyze the oxidation of flavonoles
      resulting in benzofuranones.

PMID- 12428453
TI  - Hydrophilic and lipophilic antioxidant activities of grapes.
AB  - The 2,2'-azino-bis-(3-ethylbenzthiazoline-6-sulfonic acid)/H2O2/horseradish
      peroxidase (ABTS/H2O2/HRP) decoloration method permits the evaluation of the
      antioxidant activity of complex food samples. This method is capable of
      determining both hydrophilic (in buffered media) and lipophilic (in organic
      media) antioxidant properties in the same sample. Its application to the study of
      the antioxidant properties of grapes, one white and two black, has permitted us
      to establish important differences in the antioxidant activity. The black grapes
      showed higher antioxidant activity than the white variety. The determination of
      hydrophilic antioxidant activity (HAA) and lipophilic antioxidant activity (LAA)
      in the three grapes showed that a minor contribution (4-13%) of total antioxidant
      activity (TAA) was due to LAA in all cases. The experimentally determined HAA
      could be approximated using the relative contributions of the calculated values
      of reference compounds (total phenols as gallic acid and anthocyanins as
      malvidin).

PMID- 12428454
TI  - Estimation of the main dill seeds odorant carvone by solid-phase microextraction
      and gas chromatography.
AB  - Solid-phase microextraction (SPME) was examined for its suitability for isolation
      of volatiles from seeds of dill in comparison with the traditional steam
      distillation procedure. Two main dill seeds volatiles, carvone and limonene, were
      taken into consideration. Two Supelco SPME fibers were used for the extraction:
      polyacrylic (PAc) and polydimethylsiloxane (PDMS). The time required to saturate
      the fibers was 3 min, while distillation took 3 h. Gas chromatography (GC)
      separation was reduced to 5 min by use of microcapillary column HP-5 cross-linked
      5% Ph Me Siloxane. The standards of limonene and carvone were used to prepare
      calibration curves. PAc fiber responses were described by quadratic curves while
      PDMS responded linearly. Six varieties of dill were examined by distillation and
      SPME with both fibers. The good results were achieved for carvone by SPME-PDMS
      with significant regression between distillation and SPME. This compound can be
      measured in dill seeds samples within 10 min. The SPME-PDMS were also tested for
      its application to chiral resolution of carvone and limonene enantiomers in dill
      seeds oil. The enantiomeric separation was done with two chiral columns. The
      enantiomeric ratios measured by SPME were just the same as with distillation.

PMID- 12428455
TI  - Genetically modified maize and soybean on the Egyptian food market.
AB  - The results of a survey study on food samples produced from genetically modified
      soybean and maize collected from the Egyptian market are presented. Forty samples
      of soybean and 40 samples of maize products have been gathered randomly from
      markets in Cairo and Giza. The genetic modification was detected by polymerase
      chain reaction (PCR) using official detection methods according to section 35 of
      the German Foodstuffs Act. Samples were investigated for the presence of material
      derived from the following genetically modified organisms (GMOs) all of which are
      approved for food use in Europe: Roundup Ready soybean (RRS) and maize lines
      Bt176, Bt11, T25 and MON810. In addition, samples were examined in qualitative
      and quantitative analysis for the presence of material derived from the
      transgenic maize line StarLink (Aventis) which was approved for animal feed use
      exclusively in the US. Twenty % of 40 investigated soy samples contained Roundup
      Ready soybean; 15% of 40 maize samples tested positive for Bt176 and 12.5%
      positive for Bt11 maize. Furthermore, the presence of StarLink maize could
      clearly be demonstrated in four samples mixed with Bt176 and Bt11. The percentage
      of StarLink was less than 1% in quantitative analysis. The maize lines T25 and
      MON810 were not detected.

PMID- 12428456
TI  - Effect of succinylation on the functional and physicochemical properties of alpha
      globulin, the major protein fraction from Sesamum indicum L.
AB  - alpha-Globulin the major protein fraction from Sesamum indicum was succinylated
      to different levels and the effect of the chemical modification was evaluated
      both on the functional and physicochemical properties. The results suggest that
      the pH of minimum solubility shifted to the more acidic side (pH approximately
      4.5-5.5) for the succinylated alpha-globulin whereas for control alpha-globulin
      the pH of minimum solubility was 6.5. Succinylation also increased emulsion
      activity and emulsion stability of the protein. The emulsion stability increased
      from a control value of 53 +/- 3 s to a value of 122 +/- 5 s. Bulk density, water
      absorption capacity, oil absorption capacity, foam capacity and foam stability
      were evaluated in phosphate buffer (pH 7.0) containing 0.5 M sodium chloride and
      all these properties showed increased values as a result of succinylation.
      Ultracentrifugation studies showed that the % composition of 7S component
      increases with concomitant decrease in that of 11S fraction with the increase in
      percentage of succinylation. Further increase in succinylation resulted in only
      2S component which is a dissociated form of 11S and/or 7S protein fractions. The
      fluorescence emission studies showed a decrease in the fluorescence emission
      intensity of alpha-globulin as a result of succinylation. The thermal stability
      of the protein molecule decreased due to progressive succinylation as indicated
      by decrease in the apparent thermal denaturation temperature from a control value
      of 84 to 62 degrees C at a succinylation level of 40%. These results suggest that
      succinylation improves the functional characteristics of alpha-globulin. Such
      changes in the functional properties have been attributed partly to the
      dissociation of the protein molecule at higher levels of succinylation and the
      increase in the net negative charge on the protein.

PMID- 12428457
TI  - Metallic content of wines from the Canary Islands (Spain). Application of
      artificial neural networks to the data analysis.
AB  - Eleven elements, K, Na, Ca, Mg, Fe, Cu, Zn, Mn, Sr, Li and Rb, were determined in
      dry and sweet wines bearing the denominations of origin of El Hierro, La Palma
      and Lanzarote islands (Canary Islands, Spain). Analyses were performed by flame
      atomic absorption spectrophotometry, with the exceptions of Li and Rb for which
      flame atomic emission spectrophotometry was used. The content in copper and iron
      did not present risks of cases. All samples presented a copper and zinc content
      below the maximum amount recommended by the Office International de la Vigne et
      du Vin (OIV) for these elements. Significant differences in the metallic content
      were found among the different islands. Thus, Lanzarote presented the highest
      mean content in sodium and lithium and the lowest mean content in rubidium, and
      La Palma presented the highest mean content in strontium and rubidium. Sweet
      wines from La Palma, elaborated as naturally sweet with over-ripe grapes,
      presented mean contents significantly higher with regard to dry wines from the
      same island in the majority of the analysed elements. Cluster analysis and
      Kohonen self-organising maps showed differences in wines according to the island
      of origin and the ripening state of the grapes. Back-propagation artificial
      neural networks showed better prediction ability than stepwise linear
      discriminant analysis.

PMID- 12428458
TI  - [Cerebral blindness].
AB  - In two patients, a 60-year-old woman and a 63-year-old man, cerebral blindness
      was diagnosed. The first patient developed the disorder shortly after cerebral
      angiography was carried out to diagnose a carotid-cavernous fistula. The symptoms
      disappeared after three days. The second patient suffered from a reversible
      posterior leuko-encephalopathy syndrome. He recovered his vision without specific
      treatment. Cortical or cerebral blindness is a form of blindness caused by a
      lesion in the cerebral part of the visual pathways. Although in itself rare,
      cerebral blindness occurs frequently as a complication of non-neurologic diseases
      or interventions. Physicians who are unaware of this syndrome tend to diagnose
      these patients as 'hysteric', since normal pupillary reactions and normal eye
      movements accompany the loss of vision. If the blindness is not caused by an
      ischaemic infarct, it is usually reversible.

PMID- 12428459
TI  - [Phenotypic variability: genetics and chance--deletion 22q11 and schizophrenia].
AB  - Haploinsufficiency syndromes, such as the deletion 22q11, the velo-cardio-facial
      or DiGeorge/Shprintzen syndrome characterised by chromosome 22q11 deletion, show
      marked variability in the clinical features. This variability may be due to
      chance fluctuations in expression of genes in the deleted segment, which tend to
      have more impact if only one copy of the gene is present. The apparent
      association between deletion 22q11 and schizophrenia indicates a role for a gene
      within the deletion in signal transduction in the brain.

PMID- 12428460
TI  - [Schizophrenia and the 22q11 deletion syndrome].
AB  - In 10-30% of the patients with the 22q11 deletion syndrome (22q11DS), a psychosis
      develops in adulthood, often schizophrenia. 22q11DS is a common genetic syndrome
      which is associated with an interstitial deletion at chromosome 22q11. The
      syndrome is characterised by a variable phenotype which includes cognitive and
      behavioural problems, in addition to congenital heart and facial anomalies. The
      presence of 22q11DS represents one of the highest risk factors for the
      development of schizophrenia. The study of 22q11DS offers a unique opportunity to
      increase the understanding of the pathogenesis of schizophrenia.

PMID- 12428461
TI  - [New insights in the classification of soft tissue tumors].
AB  - Soft tissue tumours are rare and form some of the most difficult pathological
      subjects in medicine. The diagnosis of a soft tissue tumour goes hand-in-hand
      with a number of clinically relevant questions related to the therapy and
      prognosis (what is the classifying diagnosis?, is the proliferation reactive or
      neoplastic?; in the case of neoplasia: is it benign or malignant?, what is the
      grade of malignancy?, what is the expected clinical course?). Due to new insights
      in tumour diversity at a morphologic level, developments in immunohistochemistry
      and increasing (cyto)genetic knowledge about tumour-specific abnormalities, the
      known histological groups of tumours have been better characterised at the
      clinicopathological level, new tumour entities have been defined, old terms have
      been abandoned and a better understanding of tumour histogenesis has been
      established.

PMID- 12428462
TI  - [Diagnostic image (111). A dyspnoeic man with fever and a sore throat. Lemierre's
      syndrome].
AB  - An 18-year-old man was admitted because of high fever, a sore throat and
      dyspnoea. Additional investigations revealed tonsillitis, lung abscesses and
      thrombophlebitis of the internal jugular vein. Lemierre's syndrome was diagnosed.

PMID- 12428463
TI  - [A bifid uvula in a patient with schizophrenia as a sign of 22q11 deletion
      syndrome].
AB  - A bifid uvula and nasal speech were observed in a 25-year-old woman who was
      referred because of psychotic complaints. Fluorescence in situ hybridisation
      (FISH) research for the 22q11 deletion was carried out and the deletion was
      found. The 22q11-deletion syndrome (22q11DS) is characterised by somatic
      abnormalities including cardiovascular defects, velopharyngeal anomalies and
      typical facial characteristics. There is an increasing interest in the cognitive
      and psychiatric consequences of 22q11DS. There is a high prevalence of learning
      disabilities and the delayed development of language and speech. Mild mental
      retardation or borderline intellectual functioning is often reported. A broad
      range of psychiatric symptoms have been reported; a consistent finding is the
      development of a psychosis in a considerable proportion of 22q11DS patients from
      early adulthood onwards. It is important to consider the possibility of 22q11DS
      in psychiatric patients, as then early intervention strategies for later
      psychopathological abnormalities are possible, as well as the provision of
      genetic counselling.

PMID- 12428464
TI  - [Gastrointestinal toxicity caused by irinotecan in the case of preexistent
      passage problems].
AB  - Two female patients, aged 50 and 62 years respectively, who were treated with
      irinotecan, fluorouracil and folinic acid (Saltz scheme) due to metastasised
      colorectal carcinoma, developed progressive abdominal pain, fever and leucopenia.
      One patient also exhibited intestinal obstruction. The main problem was
      differentiating between an acute abdomen and irinotecan toxicity. Both patients
      recovered without the need for an operative intervention. One patient was treated
      by means of colonic stent placement. The combination of gastrointestinal
      irinotecan toxicity and pre-existing passage problems is dangerous. However, in
      such cases restraint should be exercised with respect to operative interventions.

PMID- 12428465
TI  - [The term 'cause of death': an international comparison].
AB  - 'Cause of death' is an ambiguous concept. Terms such as 'immediate', 'underlying'
      or 'primary' cause of death are used, along with indications such as 'associated
      conditions' and 'contributing factors'. Furthermore, the terms 'mechanism',
      'manner' and 'method' of death are used internationally. The Dutch classification
      of the manner of death with just two categories (natural and unnatural death) is
      not used in other countries. Belgium, Germany, England and the USA use more or
      other categories. It is recommended that the Netherlands consistently use these
      terms in accordance with the international codes for both the death certificate
      as well as the registration form for the cause of death statistics. The
      circumstances of death of which the medical examiner needs to be notified should
      be explicitly stated on the death certificate.

PMID- 12428466
TI  - [The role of physicians in the case of death, and professional secrecy in the
      Netherlands, Belgium, Germany, England and the US].
AB  - The role of physicians in issuing a death certificate in the Netherlands differs
      from that in neighbouring countries and the US; there is also a difference in the
      degree to which professional secrecy plays a role in this respect. In the
      Netherlands, England and the US the external examination of the dead body is
      performed primarily by the attending physician, whereas in Belgium and Germany
      this may be performed by any physician. Competences and tasks of government
      appointed officials such as the medical examiner, forensic pathologist and
      coroner differ widely. In some countries many data concerning the deceased, the
      findings of the post-mortem examination, the post-mortal symptoms, the cause of
      death and the manner of death must be recorded on the death certificate, whilst
      in other countries, including the Netherlands, hardly any data are recorded. It
      is recommended that Dutch death certificates should state the points to be
      covered during a post-mortem as well as explicitly stating the circumstances in
      which the medical examiner should be called in.

PMID- 12428467
TI  - [Centenary of the Health Council of the Netherlands. VII. Influencing the human
      brain in the future].
AB  - On the occasion of its centenary, the Health Council of the Netherlands issued an
      advisory report on future possibilities for influencing the human brain. The
      Council foresees that, in the future, it will probably become possible to prevent
      or extensively delay diseases such as dementia and Parkinson's disease. The
      burden of many mental disorders will be markedly relieved by early detection and
      treatment. Developments are to be expected in the fields of function enhancement,
      pharmacotherapy, psychotherapy and electrostimulation. The promising developments
      aimed at the prevention of brain disorders have important ethical and societal
      implications which require uninterrupted attention.

PMID- 12428468
TI  - [Clinical reasoning and decision making in practice. Fever, purpura and
      hemiparesis in a 29-year-old female].

PMID- 12428469
TI  - [Clinical reasoning and decision making in practice. Fever, purpura and
      hemiparesis in a 29-year old female].

PMID- 12428470
TI  - [Clinical reasoning and decision making in practice. Fever, purpura and
      hemiparesis in a 29-year old female].

PMID- 12428471
TI  - [Clinical reasoning and decision making in practice. Fever, purpura and
      hemiparesis in a 29-year old female].

PMID- 12428472
TI  - [Clinical reasoning and decision making in practice. Fever, purpura and
      hemiparesis in a 29-year old female].

PMID- 12428473
TI  - [One hundred years of the Association of Surgeons in the Netherlands. VIII.
      Surgical oncology].

PMID- 12428474
TI  - Advantage for emotional words in immediate and delayed memory tasks: could it be
      explained in terms of processing capacity?
AB  - Emotional stimuli are better remembered and recognized than neutral ones. This
      advantage for emotional stimuli has been repeatedly obtained when testing long
      term retention. However, there are contradictory results concerning retention of
      emotional information when short retention intervals are used. The aim of the
      present study was, on the one hand, to test the effect of retention interval on
      memory for emotional stimuli (Experiment 1). The results showed that emotional
      information is better remembered than neutral information in both immediate and
      delayed memory tests, suggesting that the advantage for emotional information is
      not limited to long retention intervals. On the other hand, I tried to test the
      proposals made by Christianson and Nilsson (1984) and Bower (1992). These authors
      suggested that the advantage for emotional stimuli could be explained as
      emotional stimuli spending more processing capacity during acquisition, thus
      rendering less capacity available to encode simultaneously presented information
      (Experiments 2 and 3). Results showed that concurrent presentation of emotional
      stimuli did not inhibit the recall of neutral stimuli. These findings do not seem
      to support the proposals of Christianson and Nilsson (1984) and Bower (1992).
      According to these results, some mechanisms other than a greater spending of
      processing capacity have to be involved in the advantage for emotional
      information in memory.

PMID- 12428475
TI  - Effects of an intervention in active strategies for text comprehension and
      recall.
AB  - The aim of this study was to investigate the effects of an intervention program
      to promote active text-processing strategies (main-idea identification and
      summarization) at two developmental levels (12- and 16-year-olds). The
      independent variables were training condition (experimental and control) and
      school level (7th and 10th grades). Several measures were taken as dependent
      variables: reading span, reading time, construction of macrostructure, and
      structural recall. The hypothesis claimed that training would increase
      comprehension and recall significantly. Furthermore, as a result of the training
      program, a reduction in developmental differences in the experimental groups at
      posttest was also expected. Results supported the predictions, showing a
      significant improvement in the experimental groups' reading comprehension and
      recall. These results are discussed in terms of the importance of active and self
      controlled strategies for text comprehension and recall.

PMID- 12428476
TI  - Presentation of keywords by means of interactive drawings.
AB  - One of the main outstanding problems in keyword mnemotechnics is whether this
      technique is more effective when the subjects generate their own keywords, or
      when the keywords are supplied by the experimenter. Both methods have advantages
      and disadvantages. An alternative method has recently been suggested, in which
      the keywords are generated by the subjects' peers. In the present study we aimed
      to investigate whether immediate or delayed recall are affected by keyword
      generation method (experimenter or peer generation). We also aimed to determine
      whether the method of keyword generation affects imaging capacity as evaluated by
      questionnaires or spatial tests. A total of 377 secondary-school students were
      selected and divided into four groups. All subjects were presented with 30 Latin
      words. Additionally, the subjects in Group 1 were presented with bizarre images,
      while the subjects of Group 2 were presented with normal images, in both cases
      representing the keywords selected by peers as interacting with the Latin words.
      The subjects in Groups 3 and 4 were likewise presented with normal or bizarre
      images, respectively, but representing the keywords selected by the
      experimenters. The subjects' imaging capacity was evaluated by means of the
      Vividness of Visual Imagery Questionnaire (VVIQ) and the Spatial Test of Primary
      Mental Abilities (ST-PMA). The results were analysed by multivariate analysis of
      variance (MANOVA) with three factors (ST-PMA imaging capacity, 2 levels; VVIQ
      imaging capacity, 2 levels; and mnemotechnic method, 4 levels) and dependent
      variables immediate recall and delayed recall. All three factors influenced
      recall. Subsequent univariate analyses of variance indicated that subjects with
      high ST-PMA score and subjects with high VVIQ score showed better immediate and
      delayed recall than subjects with low ST-PMA score and subjects with low VVIQ
      score. Mnemotechnic method (i.e. whether keywords are generated by the
      experimenter or by peers) significantly affected immediate recall but not delayed
      recall.

PMID- 12428477
TI  - A sequential analysis of private and social speech in children's dyadic
      communication.
AB  - The purpose of this study was to perform a sequential analysis of private and
      social speech in children's dyadic communication. To investigate the
      communication patterns, a category system was applied to the communication of 64
      paired third (M = 8 years and 8 months) and fifth (M = 10 years and 8 months)
      graders, while playing with a Lego-set (construction material). The results
      revealed that: (a) at both grades, when one child addresses the other child about
      the task, it is highly probable that the latter will address the first child
      immediately afterwards and will adapt to task-related semantic content; (b) at
      both grades, children's private speech about the task stops them from
      communicating a task-related production to their partner immediately afterwards;
      (c) at third grade, task-relevant private speech favors the prolongation of the
      break in interpersonal communication and the use of inner speech by both
      children; and (d) at fifth grade, children are more able to distinguish private
      speech from social speech than at third grade.

PMID- 12428478
TI  - Are facial displays social? Situational influences in the attribution of emotion
      to facial expressions.
AB  - Observers are remarkably consistent in attributing particular emotions to
      particular facial expressions, at least in Western societies. Here, we suggest
      that this consistency is an instance of the fundamental attribution error. We
      therefore hypothesized that a small variation in the procedure of the recognition
      study, which emphasizes situational information, would change the participants'
      attributions. In two studies, participants were asked to judge whether a
      prototypical "emotional facial expression" was more plausibly associated with a
      social-communicative situation (one involving communication to another person) or
      with an equally emotional but nonsocial, situation. Participants were found more
      likely to associate each facial display with the social than with the nonsocial
      situation. This result was found across all emotions presented (happiness, fear,
      disgust, anger, and sadness) and for both Spanish and Canadian participants.

PMID- 12428479
TI  - Mental models in deductive reasoning.
AB  - We report research investigating the role of mental models in deduction. The
      first study deals with conjunctive inferences (from one conjunction and two
      conditional premises) and disjunctive inferences (from one disjunction and the
      same two conditionals). The second study examines reasoning from multiple
      conditionals such as: If e then b; If a then b; If b then c; What follows between
      a and c? The third study addresses reasoning from different sorts of conditional
      assertions, including conditionals based on if then, only if, and unless. The
      paper also presents research on figural effects in syllogistic reasoning, on the
      effects of structure and believability in reasoning from double conditionals, and
      on reasoning from factual, counterfactual, and semifactual conditionals. The
      findings of these studies support the model theory, pose some difficulties for
      rule theories, and show the influence on reasoning of the linguistic structure
      and the semantic content of problems.

PMID- 12428480
TI  - [First scientific meeting of CRI (Rheumatism and Inflammation Club) under the
      patronage of FNSIM (French National Society of Internal Medicine) and FSR(French
      Society of Rheumatology) Paris, May 4, 2002].

PMID- 12428481
TI  - [10th International Conference on Behcet Syndrome. Berlin, June 27-29, 2002].

PMID- 12428482
TI  - [Venous thromboembolism recurrence: is there a place for D-dimer?].

PMID- 12428483
TI  - [Kidney, lupus and pregnancy].

PMID- 12428484
TI  - [Relation between physical activity, muscle function and IGF-1, testosterone and
      DHEAS concentrations in the elderly].
AB  - OBJECTIVE: Lower amounts of circulating anabolic hormones are thought to
      accelerate the age related decline in muscle mass and function. Replacement
      therapies are promising interventions but there are problems with these
      therapies. Thus alternative strategies should be developed. The age related
      changes in hormonal status may be probably influenced by exercise. The purpose of
      this study was: a) to confirm with other methods, more adapted for elderly
      people, the results of a previous study that has shown relationship between
      physical activity (PA) and quadriceps muscle function with dehydroepiandrosterone
      sulphate (DHEAS), insulin like growth factor-1 (IGF-1). Quadriceps muscle power
      (Pmax) is measured in this new work with a recently developed leg extensor
      machine and, b) to complete the results of the first study examining
      simultaneously the relationship between PA, Pmax and cardiorespiratory fitness
      (VO2max) with DHEAS, IGF-1 and testosterone in a group of healthy elderly people.
      METHODS: Fifty independent, community dwelling elderly subjects (25 mens and 25
      womens) aged from 66 to 84 volunteered to participate in the study. PA was
      evaluated by the questionnaire and expressed using two activity indices: mean
      habitual daily energy expenditure (MHDEE) and the daily energy expenditure
      corresponding to leisure time sports activities (Sports Activity). Pmax and
      optimal shortening velocity (vopt) were measured on a Ergopower dynamometer. The
      Pmax was expressed relative to body mass, Pmax/kg (W kg-1), and relative to the
      mass of the two quadriceps muscles, Pmax/Quadr (W.kgQuadr-1). VO2max has been
      measured during a maximal treadmill exercise. RESULTS: In women, IGF-1 correlated
      significantly with MHDEE (r = 0.54, P = 0.004), Pmax/kg (r = 0.54, P = 0.004) and
      Pmax/Quadr (r = 0.46, P = 0.02), whereas DHEAS with MHDEE (r = 0.54, P = 0.004),
      Sports Activity (r = 0.65, P < 0.001), VO2max (r = 0.46, P = 0.02), Pmax/kg (r =
      0.46, P = 0.02) and Pmax/Quadr (r = 0.55, P = 0.004). No such correlation was
      found in men. CONCLUSION: These findings confirm that in healthy elderly women
      physical activity, cardiorespiratory fitness and quadriceps muscle function are
      similarly related to levels of circulating DHEAS and IGF-1 suggesting a
      favourable influence of exercise on anabolic hormonal production in the elderly.

PMID- 12428485
TI  - [Psychiatric complications of corticoid therapy in the elderly over 65 years of
      age treated for Horton disease].
AB  - OBJECTIVES: To analyse steroid psychiatric related complications in aged (> 65
      years old) with temporal arteritis (TA). METHODS: Retrospective cohort study.
      PATIENTS: In a cohort of 126 elderly patients with a diagnosis of TA and followed
      with a mean period of 64 months, clinical and biological presentations, outcome
      and corticoid adverse effects were recorded throughout the follow-up period.
      RESULTS: Twenty patients (16%), (mean age: 73 +/- 7.9 years, male n = 6)
      exhibited corticosteroid related psychiatric complications. Symptoms appear to be
      dose dependent and generally begin during the first month of treatment.
      Psychiatric disorders were as follow: mood disturbances (n = 8), depression (n =
      6), mania (n = 3), anxiety neurosis (n = 2) and dementia (n = 1). Three patients
      were hospitalized in psychiatric units and 2 in nursing home. Psychiatric adverse
      affects appears to be more frequent with prednisone than prednisolone (P < 0.05).

PMID- 12428487
TI  - [What do general practitioners expect from internal medicine? Results of postal
      survey].
AB  - SUBJECT: The place of internal medicine in the French health care system is a
      matter of debate. In the process of writing down a project for the department of
      internal medicine of a University hospital, we decided to assess the expectations
      of general practitioners toward internal medicine in general, and toward this
      department in particular. METHODS: We carried out a postal survey over a
      population of general practitioners working in the referral area of our
      University hospital. The answers of physicians familiar or not with our
      department were compared with a chi 2 test. RESULTS: 852 questionnaires were sent
      over and 49.5% were returned. The general practitioners as a whole acknowledge
      the classical features of internal medicine: medicine dealing with diagnosis and
      taking in charge unexplained symptoms; holistic medicine in cases of multiple
      illnesses; medicine dealing with systemic diseases as well as medicine of
      "niches" (incidentalomas, orphan diseases). The specific orientations of this
      department of internal medicine are also well known by most physicians: a great
      majority (94%) of them are satisfied with the help they receive; they stress the
      need on swift sending of letters (74%); above all, 94% of them wish to obtain
      rapid appointments for their patients at their request. CONCLUSION: These results
      are in complete accordance with our aim of setting a general internal medicine
      department at the disposal of general practitioners. They do confirm that
      outpatient consultation is the hardcore of internal medicine that must be readily
      available to the patients referred by their general practitioner.

PMID- 12428486
TI  - [Anticoagulation in permanent atrial fibrillation after 75 years of age].
AB  - PURPOSE: More than 10% of the population over 75 years old is concerned by non
      valvular permanent atrial fibrillation which is responsible for at least 30% of
      ischemic strokes. The indication of an anticoagulant therapy is discussed in two
      different situations: primary or secondary prevention of stroke and acute phase
      of stroke. CURRENT KNOWLEDGE AND KEY POINTS: Patients over 75 years old have a
      high risk of stroke (> 8% year). All the studies have demonstrated the benefit of
      a primary or secondary prevention by antivitamin K with an INR between 2 and 3
      (reduction of the relative risk of about 68%). Conversely, the efficacy of
      aspirin has not been proven in this population of elderly patients. Once stroke
      has occurred, it is not recommended to initiate an anticoagulation (unfractioned
      or low molecular weight heparin) within the first hours. Prevention of venous
      thrombosis remains necessary. FUTURE PROSPECTS AND PROJECTS: Currently, less than
      30% of the patients older than 75 years are given anticoagulation, the risk of
      the treatment being probably overestimated. The risk benefit ratio should be
      evaluated more properly for a given patient.

PMID- 12428488
TI  - [Main points in intensive care medicine].
AB  - PURPOSE: Progresses in intensive care medicine have concerned major syndromes
      associated with life threatening organ dysfunction, like the acute respiratory
      distress syndrome (ARDS) or septic shock. CURRENT KNOWLEDGE AND KEY POINTS: A
      better understanding of interactions between mechanical ventilation and the
      underlying lung lesions, has lead to define a so-called "lung protective
      ventilation", which resulted in an improved prognosis of ARDS. In numerous
      situations of acute respiratory failure, including acute exacerbation of chronic
      obstructive pulmonary disorder or immunosuppressed patients, endotracheal
      intubation can be avoided by the use of face mask ventilation, also called
      noninvasive ventilation. This approach results in a reduction of complications
      associated with mechanical ventilation or with the entire intensive care unit
      stay, including nosocomial infections. As a result, survival is increased when
      this kind of ventilation is feasible. In septic shock, pharmacological
      improvements have concerned effects of sepsis on coagulation, and the
      unexpectedly high frequency of relative adrenal insufficiency. Lastly,
      improvements have been made regarding the prevention and management of ventilator
      associated pneumonia.

PMID- 12428489
TI  - [ANCA associated glomerulonephritis related to benzylthiouracil].
AB  - INTRODUCTION: Vasculitis associated with antineutrophil cytoplasmic antibodies
      (ANCA) have been reported in patients suffering from Graves' disease treated with
      anti-thyroid drugs and especially propylthiouracil (PTU). EXEGESIS: We report a
      case of Graves' disease treated with benzylthiouracil (Basdene). This therapy was
      complicated by acute renal insufficiency due to crescentic glomerulonephritis
      associated with pANCA. After benzylthiouracil withdrawal and under
      corticosteroids, renal insufficiency, biological inflammation and pANCA levels
      decreased. CONCLUSION: Similar vasculitis associated with pANCA secondary to anti
      thyroid drugs, especially propylthiouracil, were described. This suggests a
      causal relation between drug and vasculitis. To our best knowledge, it is the
      first case of vasculitis secondary to benzylthiouracil.

PMID- 12428490
TI  - [Vasculitis with renal and pulmonary involvement in a patient receiving
      benzylthiouracil for Graves disease].
AB  - INTRODUCTION: Vasculitis is a rare complication of antithyroid drugs reported
      with propylthiouracil, carbimazole, methimazole and we describe the first case
      with benzylthyouracil. Renal involvement during thyroid auto-immune diseases and
      during vasculitis as complication of antithyroid drugs will be discussed.
      EXEGESIS: We present a case study of 28-year-old female patient with Graves'
      disease diagnosed in 1996 and treated by benzylthiouracil for 2 years. The
      thyroid function was poorly controlled, so surgical treatment was indicated in
      May 1998. One month later, she developed vasculitis with pulmonary and renal
      involvement. Her renal function deteriorated rapidly. On admission, the
      additional laboratory findings showed hematuria, proteinuria of 1.44 g/day and
      serum creatinine level at 1000 mumol/l. She had myeloperoxidase-anti neutrophil
      cytoplasmic antibody, antithyroglobulin and antimicrosome antibodies. A renal
      biopsy revealed pauci-immune crescentic glomerulonephritis with 75% sclerous
      crescents. Chest-X-ray showed unilateral alveolar shadowing and a bronchio
      alveolar lavage revealed lymphocytic alveolitis. She was treated with high dose
      of prednisolone and cyclophosphamide. After a follow-up of 18 months, the serum
      creatinine level decreased at 186 mumol/l and chest-X-ray returned to normal.
      CONCLUSION: Some cases of vasculitis associated with anti-thyroid drug treatment
      are reported.

PMID- 12428491
TI  - [Pancreatic metastasis of renal cell carcinoma: report of three cases].
AB  - INTRODUCTION: The pancreas is an uncommon site of metastasis from renal cell
      carcinoma. EXEGESIS: Three observations are described in this review which is
      aimed at reporting recent data on diagnosis, prognosis and therapeutic features
      of this kind of metastasis 0: The average space of time between nephrectomy and
      the diagnosis of the metastasis was 16 years. They have been fortuitously
      discovered in 2 cases, in patients who did not complain of any pancreatic
      symptom, during abdominal ultrasonography done for another reason. In the third
      case, pancreatic symptoms led to the diagnosis. Endoscopic ultrasonography (EUS)
      was useful to diagnose multiple lesions misdiagnosed on CT-scan or MRI imaging.
      EUS patterns are characteristic, but histological and cytological examinations of
      EUS-guided needle biopsies are difficult to study according to the
      hypervascularized character of these metastasis. CONCLUSION: The diagnosis of
      pancreatic metastasis must be suggested for patients suffering from a pancreatic
      mass with a previous medical history of late renal cell carcinoma. According to
      their hypervascularized character, the negativity of EUS-guided needle biopsies
      could strongly direct the diagnosis. When surgery is possible, the survival rate
      is better than in primary pancreatic adenocarcinoma and is even better than in
      pancreatic metastasis from other sites.

PMID- 12428492
TI  - [Digital ischaemia secondary to post traumatic subclavicular aneurysm].

PMID- 12428493
TI  - [Safety of monoclonal antibody anti-CD 20 in refractory thrombocytopenic
      idiopathic purpura].

PMID- 12428494
TI  - [Pulmonary localization of hairy cell leukemia].

PMID- 12428495
TI  - ["Psychosomatic medicine--progress in biopsychosocial public health"].

PMID- 12428496
TI  - [Psychosomatic medicine--historical models and current theories].
AB  - The term psychosomatic medicine has two meanings: first it represents a specific
      scientific approach in medicine that encompasses methodologies from natural
      sciences as well as social and human sciences. Second it denotes a clinical
      speciality that aims at applying this complex scientific background to diagnostic
      and therapeutic procedures. In this review partly contrasting concepts in
      medicine are outlined in order to discuss current psychosomatic theories and
      models. This reflection based on philosophy of science shows that the
      heterogeneity of the concepts in medicine expresses differences in the
      predominance of phenomenologic, dialectic, empiric-analytic and hermeneutic
      methodology. In psychosomatic medicine a critical evaluation and integration of
      the applied methodologies is regarded as scientific prerequisite and ethical
      demand. These hypotheses are also shared by medical anthropology (v. Weizsacker),
      theoretical pathology (Doerr and Schipperges), and by the concepts of Uexkull
      (Situationskreis) and Hahn (Methodenkreis); they also serve as the fundamental
      basis for this article.

PMID- 12428497
TI  - [General significance and quality standards in psychosomatic care].
AB  - The relevance of psychosomatic and psychotherapeutic in--and--out patient service
      is evident. Two important examples of psychosomatic care are described:
      somatoform and cardiovascular disorders. Quality assurance is necessary. There
      are data concerning the efficacy and the cost-benefit relation.

PMID- 12428498
TI  - [Epidemiology and management of psychosomatic patients in Austria].
AB  - The problem of epidemiological surveys of psychosomatic patients particularly in
      view of their requirements and willingness for treatment is discussed. Since
      there are no data available for Austria data from FRG are presented. These data
      are compared with the provision of psychotherapeutic and psychosomatic care in
      Austria. In addition the provision of in-patient treatment for psychosomatic
      patients is presented. Whereas the outpatient provision of care for psychosomatic
      patients can be considered acceptable in the big cities, there is a big gap in
      the rural areas and smaller towns. The provision of in-patient treatment is at
      present well below of what is considered necessary by the ministry of social
      affairs. From these data a serious lack of provision of care for psychosomatic
      patients in Austria can be deduced.

PMID- 12428499
TI  - [Relationship between psychosomatic medicine and psychotherapy in theory and
      practice].
AB  - Initially, the different operationalizations of 'psychosomatic' are presented.
      Etiological concepts of psychosomatic illness include stressful life events,
      developmental factors and the individual psychic structure. At the Department for
      Psychotherapy and Psychoanalysis of Vienna University, the initial diagnostic
      interview includes subjective illness theories as possible pathway to
      psychotherapy, motivational factors and the patient's ability to transfer the
      experience from this interview into psychotherapy proper. The psychotherapeutic
      method applied to psychosomatic patients should offer a theoretical concept
      concerning psychosomatic illness, as it is the case in psychoanalytic
      psychotherapy. Finally, the importance of supervision for psychotherapists
      working in an institutional setting with in-patients is stressed.

PMID- 12428500
TI  - [Development of psychosomatic medicine and psychotherapeutic medicine in
      Germany].
AB  - The following article comes from a historical description of the concept of
      psychosomatics and the psychotherapeutic system of supply. With reference to the
      memorandum of the situation of the psychosomatic medicine at German universities
      the developments of the psychotherapeutic system of supply, the guidelines, the
      psychotherapeutic procedures, settings and concepts of treatment are lined out.
      The criterions of the description of those specialists are explained as like as
      outpatient and inpatient treatment models. In the meantime there are many
      investigations available also to the need of treatment and the demands of this
      special field. Period of treatment, number of personal included and quality
      management are also part of the short survey.

PMID- 12428501
TI  - [A concept for the psychosomatic clinic in Bad Aussee].
AB  - For the first time in Austria a large psychosomatic hospital with 120 beds is in
      planning. It shall be closely connected to the newly constructed general hospital
      Bad Aussee. By applying a cooperative approach multiple economic, financial and
      technical-medical synergies are intended. Also middle- and long-term savings for
      the social insurance system are expected by specialised psychosomatic treatment
      programmes that should help reduce disease chronification as well as related
      health care costs. Such a treatment approach needs to take into account the
      patient's personal history, his value system, his various resources and
      intentions, psychodynamic factors and the course and severity of the disease.
      With this new hospital we strive for a psychosomatic department that is
      adequately equipped and adequately large to offer indication-specific treatment
      programmes for a broad range of psychosomatic disorders.

PMID- 12428502
TI  - [Developing a network for psychosomatic medicine and psychotherapy in Austria].
AB  - In Austria additional in-patient treatment facilities for psychosomatic patients
      are currently established. In this context an advisory board of the planned
      psychosomatic clinics suggests to develop a network for psychosomatics and
      psychotherapy. This suggestion focuses on four goals: further integration of
      specialised psychosomatic care into general medical care; further promotion of
      general psychosomatic care in primary health care; increasing acceptance of
      psychotherapy among psychosomatic patients in need of psychotherapeutic
      interventions; decreasing the number of chronic psychosomatic disorders by early
      and adequate treatment. The proposed network should involve three levels of
      cooperation: the primary care level, the specialised psychosomatic
      psychotherapeutic level and the institutional level of planning future structural
      developments according to the actual needs and demands. Such a network should
      also facilitate a common approach regarding the admission of patients, in-patient
      treatment and post-treatment care. A need inventory and an implementation
      analysis involving all levels of cooperation as well as the patients perspective
      are regarded as a prerequisite for the implementation of the network.

PMID- 12428503
TI  - [Quality criteria for psychosomatic consultation-liaison service].
AB  - Besides the integrated psychosomatic models in various medical specialities (e.g.
      Internal medicine, Obstetrics and Gynaecology or Paediatrics), specific models of
      cooperation in the form of consultation-liaison (C-L) service between specialised
      psychosomatic-psychotherapeutic departments and other medical departments play a
      crucial role in providing psychosomatic care to patients. The concept 'liaison'
      expresses a particularly close form of cooperative activity, going far beyond the
      classical model of consultation services. In this context, the psychosomatic
      consultant has not only a fixed organised presence in the provision of patient
      care, he/she also participates in case discussions, hospital rounds, ward
      discussions and continuing education programmes of the 'partner' department.
      Thus, the liaison service is not only patient-centred, but also team-centred.
      Such consultation-liaison services, in Austria, were first established at the
      University Hospitals. As a consequence of laws regulating psychotherapeutic care,
      according to which such care is to be offered in general hospitals, increasingly
      C-L services are becoming part of regular care provision in more and more
      hospitals. Consensus groups, international as well as in German-speaking
      countries, are currently working on establishing quality standards in the area of
      psychosomatic C-L services. A working group of the scientific medical
      representatives has recently published guidelines for the structure, process and
      results of quality control. A second group, of the European Association of
      Consultation Liaison Psychiatry and Psychosomatics, is currently working on
      guidelines for training consultation-liaison service providers. In the present
      article, an overview of these projects will be presented and the results
      discussed against the background of the specific health policy situation in
      Austria.

PMID- 12428504
TI  - [Contribution of psychosomatic medicine to relationship medicine: a catalog of
      claims in times of crisis].
AB  - The medical ideology being based on structure instead of function (specifically
      on the cgs-logic--centimetre, gram, second) instead of a patient-orientation, the
      patient's resources are rarely ever even touched. This is the basis for operating
      difficulties in self- and patient-management. Changes of this uneconomic approach
      should centre on training, focusing especially on how to increase the
      professional's sensitivity for the relationship with his patient. Unfortunately,
      Austria's situation is characterized by deficitary psychosomatic competence in
      medical professionals. In addition, the absence of universitary or other
      structures centering on psychosomatic training and co-ordination is to be
      criticized. An interuniversitary-psychosomatic structure in Austria is proposed
      as a starting-point to overcome these serious short-comings.

PMID- 12428505
TI  - [Prevention and health promotion].
AB  - Health as well as illness is not a state but a dynamic process. It depends among
      others on internal and external resources and possibilities which are given or
      not. Health behavior means the contribution of the individual to foster and
      develop their health. This includes all measures and behavior which contribute to
      early prevention or detection of illness. Traditional medicine engages in the
      investigation of causes and processes of disease and has not yet investigated
      prevention or health promoting behavior in the same way. This can also be seen in
      the concept of primary, secondary and tertiary prevention, which is disease
      oriented. Health promotion however--as stated in the Ottawa Charta in 1986 is the
      process of enabling people to increase control over and to improve their health.

PMID- 12428506
TI  - [Holistic thinking in medicine--do we need a medical philosophy? Current efforts
      to think beyond the limits of school medicine, needs for systematic
      standardization].
AB  - The increasing debate dealing with topics of medicine and with medicine itself
      necessitates a scientific and systematic approach to the reality of medicine as a
      whole. This can be accomplished by the philosophy of medicine. For the purpose of
      reorientation of this discipline a division into notices of medicine, aesthetics
      of medicine and ethics of medicine is proposed.

PMID- 12428507
TI  - Social Security's special minimum benefit.
AB  - Social Security's special minimum primary insurance amount (PIA) provision was
      enacted in 1972 to increase the adequacy of benefits for regular long-term, low
      earning covered workers and their dependents or survivors. At the time, Social
      Security also had a regular minimum benefit provision for persons with low
      lifetime average earnings and their families. Concerns were rising that the low
      lifetime average earnings of many regular minimum beneficiaries resulted from
      sporadic attachment to the covered workforce rather than from low wages. The
      special minimum benefit was seen as a way to reward regular, low-earning workers
      without providing the windfalls that would have resulted from raising the regular
      minimum benefit to a much higher level. The regular minimum benefit was
      subsequently eliminated for workers reaching age 62, becoming disabled, or dying
      after 1981. Under current law, the special minimum benefit will phase out over
      time, although it is not clear from the legislative history that this was
      Congress's explicit intent. The phaseout results from two factors: (1) special
      minimum benefits are paid only if they are higher than benefits payable under the
      regular PIA formula, and (2) the value of the regular PIA formula, which is
      indexed to wages before benefit eligibility, has increased faster than that of
      the special minimum PIA, which is indexed to inflation. Under the Social Security
      Trustees' 2000 intermediate assumptions, the special minimum benefit will cease
      to be payable to retired workers attaining eligibility in 2013 and later. Their
      benefits will always be larger under the regular benefit formula. As policymakers
      consider Social Security solvency initiatives--particularly proposals that would
      reduce benefits or introduce investment risk--interest may increase in restoring
      some type of special minimum benefit as a targeted protection for long-term low
      earners. Two of the three reform proposals offered by the President's Commission
      to Strengthen Social Security would modify and strengthen the current-law special
      minimum benefit. Interest in the special minimum benefit may also increase
      because of labor force participation and marital trends that suggest that
      enhancing workers' benefits may be a more effective means of reducing older
      women's poverty rates than enhancing spousal or widow's benefits. By
      understanding the Social Security program's experience with the special minimum
      benefit, policymakers will be able to better anticipate the effectiveness of
      other initiatives to enhance benefits for long-term low earners. This article
      presents the most recent and comprehensive information available about the
      special minimum benefit in order to help policymakers make informed decisions
      about the provision's future. Highlights of the current special minimum benefit
      include the following: Very few persons receive the special minimum benefit. As
      of December 2001, about 134,000 workers and their dependents and survivors were
      entitled to a benefit based on the special minimum. Of those, only about 79,000
      received a higher total benefit because of the special minimum; the other 55,000
      were dually entitled. (In effect, when persons are eligible for more than one
      type of benefit--that is, they are dually eligible--the highest benefit payable
      determines total benefits. If the special minimum benefit is not the highest
      benefit payable, it does not increase total benefits paid.) As of February 2000,
      retired workers who were special minimum beneficiaries with unreduced benefits
      and were not dually entitled were receiving, on average, a monthly benefit of
      $510 per month. That amount is approximately $2,000 less than the annual poverty
      threshold for an aged individual. Special minimum benefits provide small
      increases in total benefits. For special minimum beneficiaries who were not
      dually entitled as of December 2001, the average special minimum monthly PIA was
      just $39 higher than the regular PIA. Most special minimum beneficiaries are
      female retired workers. About 90 percent of special minimum beneficiaries are
      retired workers, and 77 percent of those retired workers are women. The special
      minimum benefit has never provided poverty-level benefits. Maximum payable
      special minimum benefits (unreduced for early retirement) equal 85 percent of the
      poverty level for aged persons, down from 96 percent at the provision's
      inception. Major public policy considerations raised by this analysis include the
      following: Social Security benefits alone do not protect all long-term low
      earners from poverty. Low earners with 30 years of earnings equal to the annual
      full-time minimum wage who retired in selected years from 1982 to 2000 received
      benefits that were 3.9 percent to 20.1 percent below the poverty threshold,
      depending on the year they retired. For 40-year earners, the range was 3.9
      percent to 15.3 percent below poverty. Furthermore, in 1993, 29.2 percent of
      retired-worker beneficiaries who were poor had 30 or more years of coverage. The
      size of the universe of persistently low earners with significant attachment to
      the covered workforce is unknown. Available research that examines two 28-month
      periods suggests that only 4 percent to 6 percent of full-time, full-period
      earners had below-minimum wages for more than 12 consecutive months. Targeting
      enhanced benefits only toward long-term, regular workers who are low earners is
      difficult under the current Social Security program. All else being equal, if
      total wage-indexed lifetime covered earnings are the same for both a full-career
      low earner and for a high earner who has worked only occasionally, then their
      Social Security benefits will be identical. Social Security has no information on
      number of hours worked, hourly wages, or other information that could distinguish
      between two such persons.

PMID- 12428508
TI  - Modeling SSI financial eligibility and simulating the effect of policy options.
AB  - This article simulates eligibility for Supplemental Security Income (SSI) among
      the elderly, analyzes factors affecting participation, and looks at the potential
      effects of various options to modify financial eligibility standards for the
      federal SSI program. We find that in the estimated noninstitutional elderly
      population of 30.2 million in the United States in 1991, approximately 2 million
      individuals aged 65 or older were eligible for SSI (a 6.6 percent rate of
      eligibility). Our overall estimate of the rate of participation among eligible
      elderly is approximately 63 percent, suggesting that more than a third of those
      who are eligible do not participate in the program. The results of our analysis
      of factors affecting participation among the eligible elderly show that expected
      SSI benefits and a number of demographic and socioeconomic variables are
      associated with the probability of participation. We also simulate the effects of
      various policy options on the poverty rate, poverty gap, annual program cost, the
      number of participants, and the average estimated benefits among participants.
      The simulations consider the potential effects of five policy alternatives:
      Increase the general income exclusion (GIE) from $20 to $80. Increase the earned
      income exclusion (EIE) from $65 to $260. Increase the federal benefit rate (FBR)
      by $50 for individuals and $75 for couples and eliminate the GIE. Increase the
      asset threshold to $3,000 for individuals and $4,500 for couples. Increase the
      asset threshold to $6,000 for individuals and $9,000 for couples. Using 1991
      microdata from the Survey of Income and Program Participation (SIPP) matched to
      Social Security Administration administrative records and making adjustments
      reflecting aggregate program statistics, we present the results of our
      simulations for December 1999. The results show substantial variation in the
      simulated effects of the five policy alternatives along the various outcome
      dimensions considered. The simulated effects on the poverty gap of the elderly
      population range from a 7.9 percent reduction ("Increase the GIE from $20 to
      $80") to a 0.1 percent reduction ("Increase the EIE from $65 to $260"). All
      simulated interventions are expected to increase the rate of SSI participation
      among the elderly from a high of 20.3 percent ("Increase the GIE from $20 to
      $80") to a low of 0.5 percent ("Increase the EIE from $65 to $260"). We also find
      that the interventions that have greater estimated effects in terms of increased
      participation and reduced poverty tend to cost more. At the high end, we estimate
      that increasing the GIE from $20 to $80 could raise annual federal SSI cash
      benefit outlays by about 46 percent, compared with only 0.9 percent for
      increasing the EIE from $65 to $260. Similar to the EIE intervention, raising the
      resource thresholds by 50 percent would reduce the overall poverty gap of the
      elderly by only 0.2 percent, would increase SSI participation only modestly (by
      1.3 percent), but would entail slightly higher program costs (by 1.4 percent).
      Increasing the asset threshold by 200 percent would have higher estimated effects
      on all three outcomes, but it would still be associated with relatively low
      increases in both costs and benefits. Finally, the simulated effects on the three
      key outcomes of increasing the FBR by $50 for individuals and $75 for couples,
      combined with eliminating the GIE, are relatively large but are clearly less
      substantial than increasing the GIE from $20 to $80. This work relies on data
      from the SIPP matched to administrative data on federal SSI benefits that provide
      a more accurate picture of SSI participation than has been feasible for previous
      studies. We simulate eligibility for federal SSI benefits by applying the program
      rules to detailed information on the characteristics of individuals and couples
      based on the rich array of demographic and socioeconomic data in the SIPP,
      particularly the comprehensive information SIPP provides on assets and monthly
      income. A probit model is estimated to analyze factors affecting participation
      among the eligible elderly. Finally, we conduct the policy simulations using
      altered program rules represented by the policy alternatives and predicted
      participation probabilities to estimate outcomes under simulated program rules.
      We compare those simulated outcomes to observed outcomes under current program
      rules. The results of our simulations are conditional on the characteristics of
      participants and eligibles in 1991, but they also reflect aggregate adjustments
      capturing substantial changes in overall participation and program benefit levels
      between 1991 and 1999.

PMID- 12428509
TI  - The Canada Pension Plan's experience with investing its portfolio in equities.
AB  - For the past few years, the Canada Pension Plan (CPP) has been investing some of
      its assets in equities. Without changes, an imbalance between revenues and
      outlays would exhaust the CPP reserve fund by 2015. Creating an entity that was
      independent of government was one of several changes the federal and provincial
      governments enacted to achieve fuller funding. The governments created an
      independent Investment Board (the CPP Investment Board, or "CPPIB") to oversee
      the new investments. Because the plan already owned a large government bond
      portfolio, the CPPIB decided to invest new CPP funds in broad equity indices in
      March 1999. In 2000, the CPPIB began actively investing a portion of the CPP
      funds. Key features of that policy and some observations about its implementation
      include the following: In addition to investing CPP revenues in equities, reform
      also included contribution rate increases, benefit reductions, and a financing
      stabilizer. The new investment policy accounted for 25 percent of the total
      effect of all the reforms. It is premature to know if the investments will
      achieve their long-term performance objective. The new equity investments are
      projected by the Chief Actuary, in his most recent Actuarial Report, to earn a
      4.5 percent real rate of return on Canadian equity and 5.0 percent real return on
      foreign equity for a blended real return of 4.65 percent based on an equity mix
      of 70 percent Canadian and 30 percent non-Canadian. However, it is too early to
      tell if the equity investments will achieve that goal over the long run. The
      Investment Board's mandate is to maximize returns. The Investment Board, which
      oversees the CPP's new investments, has broad discretion to pursue maximum
      returns on its assets without incurring undue risk of loss while keeping in mind
      the financial obligations and other assets of the CPP. Furthermore, it has
      developed into a professional investment organization staffed with private-sector
      experts in finance and investment. The board is designed to be independent of
      government. The federal and provincial governments designed the board to operate
      at arm's length from themselves. The process for selecting directors includes
      public- and private-sector participation, and the board is in compliance with
      several sets of governance guidelines for corporations. CPPIB management, with
      the support of its board of directors, has decided to implement a virtual
      corporation model involving a small team of senior executives setting strategies
      for implementation primarily by external professional firms. Consequently, as a
      virtual corporation, the board currently relies on external fund managers to make
      investments and vote proxies. Several measures are designed to ensure
      accountability to the public. The investment legislation subjects the board to
      overlapping layers of oversight to ensure accountability to the public. The
      features of this oversight include public meetings in each province as well as
      quarterly statements and annual reports to Parliament, the federal and provincial
      finance ministers, and the public. The 10 finance ministers review the CPPIB's
      mandate and regulations every 3 years, and the CPPIB is subject to a special
      examination every 6 years by an auditor appointed by the Federal Minister of
      Finance.

PMID- 12428510
TI  - Social Security: a financial appraisal for the median voter.
AB  - Several explanations have been proposed for why voters continue to support
      unfunded social security systems. Browning (1975) suggests that the extremely
      large unfunded pension systems of most democracies depend on the existence of a
      voting majority composed of middle-aged and older people who fail to fully
      internalize the cost of financing the system. In fact, when voting, economically
      rational workers consider only their current and future contributions to the
      system and their expected pension benefits--not their past contributions, which
      they regard as sunk costs. If, for a majority of voters, the expected
      continuation return from social security exceeds the return from alternative
      assets, an unfunded social security system is politically sustainable. This
      article explores the validity of Browning's proposition by quantifying the
      returns that U.S. voters in presidential elections from 1964 to 1996 have
      obtained, or expect to obtain, from Social Security. Did "investments" in Social
      Security outperform alternative forms of investment, such as mutual funds or
      pension funds, for a majority of the voters? What can be expected for the future?
      The U.S. Social Security system redistributes income within age cohorts on the
      basis of sex, income, and marital status. To account for some of these features,
      the median voter is represented by a family unit whose members--a husband who
      accounts for 70 percent of household earnings and a wife who accounts for 30
      percent--make joint economic and voting decisions. Thus, retirement and survival
      benefits paid out to the spouse of an insured worker can be included in the
      calculation of Social Security returns. Interval estimates of voters' family
      incomes from the U.S. Census Bureau were used to obtain the median voter's
      household earnings. The median voter's age is derived from the ages of those who
      voted in presidential elections, not from the ages of the entire electorate. The
      median voter's contributions to Social Security are the product of the joint
      employer/employee Old-Age and Survivors Insurance (OASI) tax rate and employee
      earnings. Data on actual contributions are available for median voters in the
      1964 to 1976 elections; Social Security Administration (SSA) estimates are used
      for future tax rates and average wage growth rates. Data on actual old-age,
      retirement, and survivor benefits, as well as estimates of future benefits, are
      also available from SSA. Analysis of ex-post returns from "investing" in Social
      Security and from a buy-and-hold strategy applied to three alternative assets-
      the Standard & Poor's Composite Index (S&P), the Dow Jones Industrial Average
      (DJIA), and U.S. government bonds--shows surprising results. In 1964 and 1968,
      Social Security largely outperformed the other three assets. In 1972, Social
      Security and the stock market performed almost equally. In 1976, however, the
      median voter would have been better off in the stock market. The expected returns
      for median voters in later elections cannot be directly compared with realized
      returns from alternative assets. However, estimates range from 5.7 percent in
      1984 to 7.0 percent in 1996 and thus compare favorably with average returns of
      5.6 percent for S&P, 5.3 percent for DJIA, and 2.1 percent for government bonds
      over the 1964-1996 period. Although these findings must be taken with caution
      since they compare ex-post returns, they show that, despite a continuous
      reduction in profitability, Social Security still represents a safe, high-return
      asset for a majority of families.

PMID- 12428511
TI  - Retirement and wealth.
AB  - The decision to retire is related to the decision to save and to a number of
      other decisions, including decisions of when to claim Social Security benefits
      and what share of assets to hold as pensions, Social Security, and in other
      forms. This article explores the relationships among these various decisions and
      then explains why it is important to take them into account when attempting to
      understand the effects of changing Social Security and related policies on
      retirement outcomes. To understand how Social Security benefits affect retirement
      behavior, and the implications of changing such features as the Social Security
      early retirement age, the Social Security Administration and others have begun to
      estimate and use single-equation models of retirement. We explain why the kind of
      simple model they use is likely to provide a misleading guide for policy. Even if
      one's primary interest is in the relationship between Social Security policy and
      the decision to retire, it is important to incorporate other key decisions into
      the analysis. These simple models relate the probability of retiring to measures
      of changes in the value of Social Security benefits when retirement is postponed.
      The basic problem is that because the omitted factors are related systematically
      both to retirement outcomes and to the measured reward to postponing retirement,
      a simple retirement equation credits the effects of the omitted factors to the
      included measures of changes in Social Security benefits. New policies will
      change the relationship between retirement and the increase in the value of
      Social Security benefits with postponed retirement, resulting in incorrect
      predictions of the effects of new policies. When we fit single-equation
      retirement models, we find a variety of evidence that important behaviors have
      been omitted. These models include variables measuring the age of the respondent.
      These age variables suggest there is a sharp increase in the probability of
      retirement at age 62. This is a sign that even though the equations include
      measures of the increase in the value of Social Security with delayed retirement,
      the cause of the increased retirement behavior at age 62 has not been included in
      the model. In addition, the estimated effect of a variable measuring the future
      value of Social Security and pensions on retirement suggests that if the Social
      Security early retirement age were to be abolished, more people would retire
      earlier rather than later--a counter-intuitive prediction. There is even more
      direct evidence of the need for a more comprehensive model of behavior. We show
      that if individuals' preferences for leisure time were unrelated to their
      preferences for saving, then a simple retirement equation would yield an unbiased
      estimate of the effects of Social Security on retirement. An implication of such
      a model is that those who retire earlier for particular reasons would also save
      more for those same reasons. But when we estimate an equation with wealth
      accumulated through 1992 as a dependent variable, together with the simple
      retirement equation, we do not observe that the factors associated with earlier
      retirement are also associated with higher saving. These and related findings
      suggest that those who wish to retire earlier also have a weaker preference for
      saving, a relationship that is ignored in the simple model and can only be
      measured in a more complex model. Still other evidence also warns of internal
      inconsistencies in the simple retirement equations that are being estimated.
      Social Security incentives are often measured by the increment in the value of
      benefits associated with deferred retirement, but the incremental value depends
      on when benefits are claimed. Our findings show that those who retire completely
      are claiming their benefits too early to be maximizing the expected value of the
      benefits. Yet the measures of Social Security benefit accrual used in these
      retirement models often include the increase in the value of benefits from
      deferred claiming in their measure of the gain to deferring retirement. On the
      one hand, early retirees are seen not to defer benefit acceptance despite the
      actuarial advantage. On the other hand, later retirees are said to defer their
      retirement in order to gain the advantage of deferring benefit acceptance. Our
      empirical analysis is based on data from the first four waves of the Health and
      Retirement Study (HRS), a longitudinal survey of 12,652 respondents from 7,607
      households with at least one respondent who was born from 1931 to 1941. Our
      analysis also uses linked pension and Social Security data together with
      respondents' records from the HRS. We also evaluate a number of specific features
      of retirement models and suggest improvements. We develop a measure of the future
      value of pensions and Social Security--the premium value--that is not subject to
      a problem plaguing other measures in that it handles the accrual of benefits
      under defined contribution plans very well. We also introduce a new definition of
      retirement status that blends information on objective hours worked with
      subjective self-reports of retirement status. Our findings also explore the
      effects of Social Security incentives on partial retirement and consider the
      importance of incorporating partial retirement in any study of the relation of
      Social Security to retirement behavior.

PMID- 12428512
TI  - Pension sponsorship and participation: trends and policy issues.
AB  - Employment sector and employer size account for substantial variation in workers'
      participation in employer-sponsored retirement plans. Other things being equal,
      employees in the public sector--that is, federal, state, and local governments-
      are much more likely to be offered a retirement plan than workers in the private
      sector. Within the private sector, workers in firms with 100 or more employees
      are significantly more likely than workers in smaller firms to have the
      opportunity to participate in a retirement plan. This situation has prompted
      Congress to seek ways of reducing small businesses' obstacles to pension
      coverage. For example, Congress has authorized retirement plans that have fewer
      reporting requirements and less stringent contribution rules than those imposed
      on larger employers. Evaluating the effect of these laws on pension coverage is
      complicated by the many other variables that affect an employer's decision to
      sponsor a retirement plan and a worker's decision to participate in it.
      Nevertheless, data collected in national surveys of employers and households can
      be used to establish a baseline against which future changes in retirement plan
      sponsorship and participation can be measured. Recent surveys of employers and
      households reveal that: During the 1990s, participation in retirement plans rose
      among workers in firms with fewer than 100 employees but remained steady among
      workers in larger firms. The 1990s saw a substantial shift from defined benefit
      retirement plans to defined contribution plans. Despite increases in
      participation, workers in firms with fewer than 100 employees are only about half
      as likely as those in larger firms to participate in an employer-sponsored
      retirement plan. In both the public and private sectors, part-year or part-time
      workers are much less likely than year-round, full-time workers to be offered an
      opportunity to participate in an employer-sponsored retirement plan.

PMID- 12428513
TI  - The widow(er)'s limit provision of Social Security.
AB  - Widow benefits have been a part of the Social Security program since the 1939
      amendments to the Social Security Act (widower benefits were added later). For
      many years, the Social Security law called for paying a widow(er) a fraction of
      the deceased worker's primary insurance amount (PIA). However, the worker--while
      alive--may have received the full PIA as his or her retirement benefit. Over
      time, arguments were made that a widow(er) should be treated as generously as his
      or her spouse was. The 1972 amendments to the Social Security Act allowed for a
      widow(er) to receive a full PIA, subject to actuarial reductions if the widow(er)
      benefit was claimed before the normal retirement age (NRA) and subject to a new
      provision of the law commonly referred to as the widow(er)'s limit. Generally,
      the widow(er)'s limit specifies that if a worker received reduced retirement
      benefits (because the worker claimed benefits before the NRA), then the worker's
      widow(er) cannot receive a monthly benefit equal to the full PIA. Rather, the
      widow(er)'s benefit is generally limited to the amount the worker would receive
      if he or she was still alive. The limit provision appears to be motivated by the
      overall intent of the 1972 Congress to pay a benefit to a widow(er) that was
      comparable with what the worker received. A number of changes to the limit
      provision have been discussed. This article looks at the following options:
      Abolishing the limit, Raising the limit by requiring that it never be set below
      the average PIA among all retired-worker beneficiaries. Adjusting the limit for
      some widow(er)s--that is, only persons who are widowed before the NRA (the ARLA
      option), Making a simpler adjustment to the limit by abolishing it for persons
      who are widowed before age 62 (the SARLA option), and A proposal by Robert J.
      Myers that would make modest adjustments to the limit for cases in which the
      worker died before the NRA. The most fundamental change--abolishing the limit-
      would increase benefits for about 2.8 million widow(er)s and would cost about
      $3.1 billion a year. Most of the additional government expenditures would not go
      to the poor and the near poor. Another change would be more successful in aiding
      low-income widow(er)s: requiring that the limit amount never be set below the
      average PIA among all retired-worker beneficiaries. About 58 percent of the
      government expenditures from that option would be received by the poor and the
      near poor. Overall, 1.2 million widow(er)s would be helped, and the cost would be
      about $816 million a year. Although the limit provision is consistent with the
      overall intent of the 1972 Congress, it can have effects that may have been
      unintended and that some policymakers might consider unusual. Persons who delay
      receipt of Social Security benefits usually receive higher monthly benefit
      amounts, but a widow(er) who faces a limit cannot increase his or her monthly
      benefit through delayed receipt of benefits. Thus, many persons who are widowed
      before the NRA face strong incentives to claim benefits early. That is somewhat
      unusual because the actuarial adjustments under Social Security are approximately
      fair, so there are no cost savings to the Social Security program from "forcing"
      a widow(er) to claim early benefits as opposed to allowing him or her to delay
      receipt of benefits in exchange for a higher monthly amount. And many widow(er)s
      would be better off if they could use the Social Security program to, in effect,
      save (that is, delay receipt of benefits in exchange for a higher amount later).
      This article analyzes two other options that would provide widow(er)s with
      additional filing options under Social Security. The ARLA option would ultimately
      help about 229,000 widow(er)s, and the cost would be small (about $69 million a
      year). The SARLA option would help about 117,000 widow(er)s, and the cost would
      be about $41 million a year. Robert J. Myers, a former Chief Actuary of Social
      Security, has offered a proposal that would provide relief from the widow(er)'s
      limit in cases in which the worker dies shortly after retirement. That proposal
      would help about 115,000 widow(er)s, and the cost would be low (about $57 million
      a year).

PMID- 12428514
TI  - Improving child support enforcement for children receiving SSI.
AB  - Less than half of all children who receive Supplemental Security Income (SSI)
      benefits and live in a single-parent home receive child support services.
      Although filing for child support is a condition of eligibility for income
      assistance programs such as Temporary Assistance for Needy Families (TANF), it is
      not a condition of eligibility for SSI benefits. Requiring single custodial
      parents applying for SSI on behalf of their children to pursue child support
      payments might result in more children on SSI receiving child support, and since
      the Social Security Administration (SSA) excludes one-third of child support when
      determining benefit amounts, increased receipt of child support would enhance the
      financial well-being of SSI children. Improving access to data on child support
      would enhance the integrity of the SSI program by reducing overpayments to
      children receiving child support. This article looks at the child support
      provisions in SSI and other means-tested programs and discusses policy options
      for improving receipt of child support and access to related data. Requiring
      cooperation with child support enforcement agencies would be consistent with the
      philosophy that the SSI program should serve as a program of last resort.
      Whenever possible, both parents should take primary responsibility for their
      children. While such a requirement has the potential to improve the financial
      status of children receiving SSI, factors such as their low-income status and
      their involvement with the TANF program raise questions about how much those
      children will actually benefit from such a requirement. Even if many additional
      children do not receive child support, the requirement demonstrates SSA's
      dedication to the stewardship of the SSI program. However, if custodial parents
      fail to comply with the requirement, children may be worse off as a result of the
      requirement. SSA should carefully pursue a requirement to induce cooperation
      while protecting children to the greatest extent possible. Improving access to
      child support data would enhance the integrity of the SSI program by reducing
      overpayments to children receiving child support. Given the reality of limited
      administrative resources as well as the apparent difficulties of gaining access
      to the needed child support data, SSA must decide which data matches to pursue
      and which requirements enhance the program enough to justify the additional
      resources. Although the options discussed in this article may be chosen
      independently, there are important interactions to consider. For example,
      although a requirement to pursue support might result in more children receiving
      child support, SSA would still rely on parents to report that income unless it
      was able to gain better access to child support data. Implementing the option to
      require cooperation with child support enforcement (CSE) agencies could improve
      verification of income from child support if field offices developed better
      communication with local CSE offices. However, by itself, it would not have as
      great an effect on overpayments as would having direct access to child support
      data. In a 1999 report, the General Accounting Office acknowledged that the
      potential benefit reductions would be offset by the cost for SSA to administer a
      child support cooperation requirement and by the costs to the CSE programs to
      provide services. The report suggested that the goals of promoting parental
      responsibility and increasing the income of children receiving SSI should be
      pursued despite the costs. Requiring cooperation may increase administrative
      costs by $6 million over 5 years and may result in program savings. Gaining
      access to data may be more expensive and may not prevent overpayments to the same
      extent as other data-matching workloads on which SSA has placed a priority. SSA
      should continue to work with federal child support enforcement and with
      individual states to develop a cost-effective way to identify child support
      income.

PMID- 12428515
TI  - Legislative history of title VIII of the Social Security Act.

PMID- 12428516
TI  - The U.S. study of work incapacity and reintegration.
AB  - In many countries, including the United States, the number of persons being
      awarded long-term or permanent disability benefits has risen dramatically in
      recent years. Government agencies, advocates for the disabled, and others are
      looking for ways to help persons with disabilities return to the labor force. The
      Work Incapacity and Reintegration (WIR) Study was developed to address that
      issue. The United States and five other countries--Germany, Denmark, Sweden,
      Israel, and the Netherlands--have participated in a cross-national study of work
      incapacity under the auspices of the International Social Security Association.
      The study had two objectives: to examine the factors that influence the pattern
      of work resumption among persons disabled by a back condition and to identify the
      medical and nonmedical interventions that are most effective in helping such
      persons reenter the labor force. Samples for the U.S. national study were drawn
      from four cohorts: Social Security Disability Insurance (DI) beneficiaries,
      Supplemental Security Income (SSI) beneficiaries, and recipients of temporary
      disability insurance (TDI) benefits from the states of California and New Jersey.
      Only the TDI recipients were included in the comparative study. This article
      discusses the study design and methodology and summarizes the findings of the
      U.S. national study. Findings from the U.S. study show significant differences
      between the two cohorts in terms of work resumption and other characteristics.
      The proportions of respondents from the TDI cohorts who were working at the third
      and final study contact ranged from 53 percent to 65 percent, compared with less
      than 5 percent of the DI and SSI respondents. Respondents from the DI and SSI
      cohorts were on average about 10 years older than the TDI respondents, were less
      well educated, and reported more physical demands in their usual work. They also
      reported lower levels of functional capacity, higher levels of pain, and a much
      greater tendency to have other chronic illnesses. The types of medical treatments
      provided were remarkably uniform across cohorts and, within cohorts, between
      those who did and did not resume working. Thus, no medical intervention was
      identified that showed a significantly higher success rate in terms of
      facilitating a return to work. However, changes made in the work environment by
      the employer were an important factor in work reintegration; about 80 percent of
      respondents who resumed working did so with the help of workplace accommodations.
      In addition, since respondents with fewer physical demands in their job were more
      likely to return to work, there appears to be some potential for job retraining
      as a means of promoting a return to work. The Social Security Administration
      should consider these findings in developing strategies to help disabled workers
      reenter the labor force.

PMID- 12428517
TI  - The Social Security Administration's Death Master File: the completeness of death
      reporting at older ages.
AB  - We examine the completeness of death reporting in the Social Security
      Administration's Death Master File (DMF) through comparison with deaths by year
      and age group reported in official U.S. vital statistics. For most years since
      1973, results suggest that the DMF includes 93 percent to 96 percent of deaths of
      individuals aged 65 or older. Although studies have shown that the National
      Center for Health Statistics' National Death Index provides superior coverage of
      deaths, for many researchers the DMF may be a desirable choice. Some advantages
      of the Death Master File are discussed.

PMID- 12428518
TI  - How policy variables influence the timing of applications for Social Security
      Disability Insurance.
AB  - This article analyzes the impact of policy variables--employer accommodations,
      state Social Security Disability Insurance (DI) allowance rates, and DI benefits-
      on the timing of an application for DI benefits by workers with a work-limiting
      health condition starting when their health condition first begins to bother
      them. The analysis uses a rich mixture of personal and employer characteristics
      from the Health and Retirement Study linked to Social Security administrative
      records. We find that most workers do not apply immediately for DI benefits when
      they are first bothered by a health condition. On the contrary, the median
      working-age man with a work-limiting condition waits 7 years after that time
      before applying, and the median working-age woman waits 8 years. Although the
      risk of applying for benefits is greatest in the year following onset, only 16
      percent of men and 13 percent of women in our sample apply within the first year,
      and the risk of application falls thereafter. That finding suggests that
      institutional factors, in addition to health factors, may play a role in the
      timing of DI applications. Using kernel density estimates of the distribution of
      application and nonapplication ordered by state allowance rates (the rate of
      acceptance per DI determination in each state), we find that both men and women
      who live in states with high allowance rates are disproportionately more likely
      to apply for benefits in the first year after their condition begins to bother
      them than are those in states with low allowance rates. Using life-table
      analysis, we also find that men and women who are accommodated by their employers
      are significantly less likely to apply for DI benefits in each of the first few
      years after their condition begins to bother them than are those who are not
      accommodated. On the basis of this evidence, we include these policy variables in
      a model of the timing of DI application that controls for other socioeconomic
      variables as well as health. Using a hazard model, we find that workers who live
      in states with higher allowance rates apply for DI benefits significantly sooner
      than those living in states with lower allowance rates following the onset of a
      work-limiting health condition. Workers who are accommodated following the onset
      of a work-limiting health condition, however, are significantly slower to apply
      for DI benefits. Using the mean values of all explanatory variables, we estimate
      the relative importance of changes in these policy variables on the speed with
      which workers apply for benefits after onset. We find that the mean time until
      application for men is 10.22 years. Universal accommodations following onset
      would delay application by 4.36 years. In contrast, a 20 percent decrease in
      state allowance rates would delay application by only 0.88 years. For working-age
      women, the average expected time until application once a condition begins to
      bother them is 10.58 years. Universal accommodations would delay that by 3.76
      years, and a 20 percent decrease in allowance rates would delay it by 1.47 years.
      A complication in this analysis is that the policy variables are to some degree
      endogenous. Accommodation is probably offered more often to workers who want to
      continue working. Allowance rates are chosen by states on the basis of federal
      policy and local choices and probably in part on the health condition of workers
      in the state. Therefore, our estimates are upper bounds of these policy effects.
      Still, we believe we provide evidence that the social environment faced by
      workers with work-limiting health conditions can significantly influence their
      decision to apply for DI benefits, holding their specific health conditions
      constant.

PMID- 12428519
TI  - Transitions from AFDC to SSI before welfare reform.
AB  - The Supplemental Security Income (SSI) and Aid to Families with Dependent
      Children (AFDC) programs serve populations with similar characteristics. SSI
      serves adults and children with disabilities who are in low-income families, and
      AFDC serves low-income families with children. Because of that overlap, policy
      changes in one program can affect the other. In 1996, Congress enacted the
      Personal Responsibility and Work Opportunity Reconciliation Act, which
      transformed AFDC into the Temporary Assistance for Needy Families (TANF) program.
      Many people have expected that implementing that welfare reform legislation would
      eventually increase SSI participation, for two reasons. First, TANF includes new
      work requirements and time limits that induce more AFDC/TANF recipients with
      disabilities to obtain SSI benefits. Second, the change in the funding mechanism-
      from open-ended funding on a matching basis for AFDC to cash assistance block
      grants for TANF--gives states a stronger incentive to shift welfare recipients to
      SSI. This article examines the interaction between the SSI and AFDC programs in
      the prereform period (1990 to 1996) and discusses the potential implications of
      welfare reform on that interaction. Using matched data from the Survey of Income
      and Program Participation and Social Security Administration (SSA) records, our
      analysis focuses on how the interaction of those programs affects young women
      (aged 18 to 40) and children (aged 0 to 17). We find a very strong link between
      AFDC and SSI for young women and children. Significant portions of young female
      and child SSI beneficiaries in the 1990-1993 period were in AFDC families or had
      received AFDC in the past. In addition, a substantial share of young women and
      children who received AFDC during that period eventually entered SSI. Because the
      SSI program is now serving a much larger population of families with young women
      and children than in the past, SSA might need to develop policies to better serve
      that group. The findings also suggest that the prereform period is a poor
      baseline against which to measure the impact of TANF, primarily because of the
      instability in programs and policies.

PMID- 12428520
TI  - Argentina's pension system.

PMID- 12428522
TI  - Conscious sedation: a perspective.

PMID- 12428521
TI  - Overcautiousness can be a disservice.

PMID- 12428524
TI  - Laser dentistry in South Africa.

PMID- 12428523
TI  - Posterior composite resin restorations. Part 4. Base liners and adhesive
      protocol.

PMID- 12428525
TI  - Pulp histology after Er:YAG laser cavity preparation in subhuman primates--a
      pilot study.
AB  - The aim of the study was to make a direct comparison of the pulpal effects of
      laser and turbine preparations in subhuman primates. One female baboon (Papio
      Ursinus ursinus), weighing 15 kg, was used. General anaesthesia was administered
      (ketamine 100 mg/ml/kg body weight) and maintained with acepromazine (10 mg/ml/kg
      body weight). Class V cavities were prepared buccally in a total of 28 teeth (7
      in each quadrant). Teeth in the upper right and lower left quadrants were
      prepared using a conventional 330 carbide bur in a high-speed fibre-optic
      handpiece with copious water spray. Teeth in the upper left and lower right
      quadrants were prepared using an Er:YAG laser drill (Fotona Twinlight, Llubljana,
      Slovenia) delivering 500 mJ at a pulse rate of 10 Hz and a wavelength of 2940 nm.
      The animal was sacrificed after 25 days. After general anaesthesia as described
      before, perfusion fixation of the head was accomplished with 10% neutral buffered
      formalin, pumped through a catheter inserted into the left carotid artery. The
      jaws were removed and, using a 330 carbide bur in a high speed handpiece, a
      continuous groove was cut through the bone and the roots at the level of the
      middle third of all the roots to promote thorough fixation of pulpal tissue.
      Decalcification and grading of the severity of the pulpal responses were
      conducted according to standard procedures. RESULTS: Owing to procedural errors
      seven teeth, FDI numbers 23, 24, 31, 34, 35, 44 and 45, had to be eliminated. The
      turbine-prepared teeth (N = 11) had a mean remaining dentine thickness (RDT) of
      0.77 mm (SD = 0.42) and the laser-prepared teeth (N = 10) had a mean RDT of 0.81
      mm (SD = 0.60). All pulps appeared normal except in one turbine-prepared tooth
      (12 with RDT = 0.20) and one laser-prepared tooth (27 with RDT = 0.30, where
      irreversible damage was caused. The only other deviations from normal were seen
      in the laser-treated 41 (RDT = 0.69) and the turbine-treated 36 (RDT = 0.77)
      where moderate hyperaemia was seen. Within the limitations of this study it can
      be concluded that there is no significant difference between dental pulp of teeth
      where Class V cavities were prepared with an Er:YAG laser drill compared with
      those prepared with a standard turbine drill.

PMID- 12428526
TI  - Thermal coagulation caused by different power settings of CO2 laser surgery.
AB  - The aim of this clinical research project was to evaluate histopathologically the
      zone of thermal effects along the cut margin of tissue specimens with the use of
      CO2 laser surgery regarding laser artifacts and diagnostic biopsy.

PMID- 12428527
TI  - The Er,Cr:YSGG hydrokinetic laser system for dentistry--clinical applications.

PMID- 12428528
TI  - Non-steroidal anti-inflammatory drugs in orofacial pain management--an update.

PMID- 12428529
TI  - Basic principles of allergic reactions.

PMID- 12428531
TI  - Time for new thinking.

PMID- 12428530
TI  - General practitioner's radiology case 4. Cleidocranial dysplasia.

PMID- 12428532
TI  - Lessons learned at Leicester.

PMID- 12428533
TI  - Legionnaires' disease blame can be unfair.

PMID- 12428534
TI  - Legal focus on legionella issues.

PMID- 12428535
TI  - Competition winning centre opens.

PMID- 12428536
TI  - Spotlight on fuel ionisation.

PMID- 12428537
TI  - Building simulation--design tool or gimmick?

PMID- 12428538
TI  - Pathogenesis of asthma.
AB  - There is now strong evidence that airway inflammation is a predominant underlying
      problem in patients with asthma, and it has been suggested that ongoing
      inflammation may lead to airway injury and remodeling. There is also recent
      evidence that longstanding asthma could be associated with loss of elastic
      recoil, which can enhance airway obstruction and worsen asthma control [82,83].
      Therefore, the use of anti-inflammatory therapy has been advocated in all
      guidelines, including the National Asthma Education and Prevention Program
      (NAEPP) Expert Panel Report [84] and its recent update [85] that recommended
      inhaled steroids as a first mode of therapy for patients with mild, moderate, or
      severe, persistent asthma. There is preliminary evidence that early institution
      of anti-inflammatory therapy might lead to disease modification and limit the
      progression of subepithelial fibrosis and airway remodeling. The pathogenesis of
      asthma clearly involves many cells and mediators, although the contribution of
      each individual factor is probably different from patient to patient depending on
      the setting and stimulus. Although currently available therapies are highly
      effective in controlling asthma symptoms and limiting exacerbations in the
      majority of patients, there is still a subset of patients that proceed to develop
      severe asthma with decreased lung function, lack of responsiveness to therapy, or
      frequent exacerbations. It is hoped that rapid progress in the area of asthma
      genetics and pharmacogenetics will yield a more precise and patient-specific
      understanding of asthma pathogenesis and allow practitioners to prescribe
      therapies that are designed for a particular patient or exacerbation. That will
      undoubtedly help to improve the care of asthma, limit its morbidity, and reduce
      the side effect of medications.

PMID- 12428539
TI  - Genetics of asthma.
AB  - As is becoming increasingly apparent, both atopy and asthma (however they are
      clinically defined) are a diverse group of related conditions, which are
      similarly disparate in their origins. Despite this, genetic factors are clearly
      operational. Speaking to their relatedness, linkages have been found between
      similar chromosomal sites for both atopy and asthma. Speaking to their
      divergence, there are also reports of the same phenotypes displaying linkage to
      different chromosomal areas. The likely explanation for this is that both the
      atopy and asthma phenotypes are polygenetic, requiring that multiple genes (some
      of them common to both) be expressed. For example, it may be that three genes,
      such as "a," "b," and "c," are involved in the development of skin test
      reactivity. Having only two of these genes, such as "a" and "b" or "b" and "c,"
      alone does not result in the development of the defined phenotype of skin test
      reactivity. At the same time, it may be that to develop asthma one also needs
      three genes, such as "c", "d," and "e." One gene "c" involved in atopy
      inflammation is needed for both asthma and skin test reactivity. Genes "a" and
      "b" are also needed to be present for skin test reactivity, and a different set
      of genes, "d" and "e," are needed for asthma to develop. These genes "a" and "b"
      may be needed to localize the process in the skin and "d" and "e" to localize the
      process in the lung (Fig. 1). In addition to having the genetic predisposition
      for atopy and its associated conditions, environmental interactions are involved.
      Environmental conditions may be the initiating trigger and cause a shift in the
      balance between the protection and susceptibility of getting the clinical
      picture. In summary, atopy and asthma seem to be related conditions, involving
      both environmental and genetic factors, most likely consisting of multiple genes,
      which may interact with each other and the environment. A deeper [figure: see
      text] understanding of these genetic bases and the roles that environmental
      factors play in the development and manifestations of these conditions will
      provide better methods of diagnosis and treatment.

PMID- 12428540
TI  - Occupational asthma.
AB  - Occupational asthma is a common yet all too frequently unnoticed form of adult
      asthma. Many agents can trigger disease by a variety of mechanisms, some of which
      are unknown. Awareness of high-risk occupations and knowledge that adults with
      persistent asthma may have an occupational trigger are vital in early
      identification and treatment of this population of patients where the stakes are
      high. Although the sensitivity and specificity of various tests are low, a
      multidimensional approach, which includes the cooperation of primary care
      physician, allergist-immunologist, pulmonologist, industrial hygienist,
      occupational medicine specialist, and industry (union and management), can lead
      to a successful outcome in a timely manner.

PMID- 12428541
TI  - Environmental controls in the management of allergic asthma.
AB  - Environmental allergen control is one of the four primary goals of good asthma
      management. The American Academy of Allergy, Asthma, and Immunology has published
      a position statement [78] that endorses the National Asthma Education and
      Prevention Program management guidelines [23] and recommends that every patient
      with persistent asthma be evaluated for environmental allergen sensitivity.
      Patients who have sensitivities should receive practical advice on allergen
      avoidance. An accumulating body of knowledge indicates that such measures, when
      strictly applied for a sufficient period of time, can indeed reduce asthma
      symptoms, need for medication, and airway hyperresponsiveness. Ongoing
      prospective trials in large numbers of patients are being conducted and should
      enhance the ability to make proper recommendations to patients.

PMID- 12428542
TI  - Beta-agonists.
AB  - Beta-Agonists are a mainstay of asthma treatment. Short-acting beta-agonists are
      the most effective bronchodilators for rescue or quick relief of symptoms. Long
      acting beta-agonists have a key role in long-term control when added to inhaled
      corticosteroid therapy, and are especially useful in the control of nocturnal
      asthma. Both types of beta-agonists may be used in the prophylaxis of exercise
      induced asthma with long-acting beta-agonists providing more prolonged
      protection. beta-Agonists have minimal side effects and are safe when used
      appropriately.

PMID- 12428543
TI  - Leukotriene modifiers.
AB  - Leukotrienes (LTs) are 5-lipoxygenase products formed from arachidonic acid
      metabolism. There is compelling evidence that LTs play an important role in the
      pathogenesis of asthma. LTs affect vascular permeability, mucus production, and
      smooth muscle constriction, and may contribute to airway remodeling. In mild-to
      moderate asthma, LT modifiers improve measures of airflow limitation and quality
      of life and reduce the frequency of asthma exacerbations and the need for short
      acting bronchodilator therapy. In moderate-to-severe asthma, an LT modifier in
      combination with an inhaled corticosteroid results in improvements in lung
      function and asthma control over that achieved with an inhaled corticosteroid
      alone. LT modifiers are effective in the treatment of exercise-induced
      bronchoconstriction and aspirin-induced asthma. There are few adverse effects of
      LT modifiers.

PMID- 12428544
TI  - The use of inhaled corticosteroids in adult asthma.
AB  - Inhaled corticosteroids modify some but not all features of airway inflammation
      seen in asthma. ICS remain the most effective class of medications currently
      available to treat persistent asthma and result in few clinically relevant
      adverse effects when used in low-moderate doses. ICS activity is enhanced when
      used in combination with LABA and, to a lesser degree, LTRAs. ICS are well
      tolerated in adults. Daily doses of ICS may not be required to exceed 200
      micrograms of FP equivalents. From an economic standpoint, ICS provide health
      care savings because of reductions in asthma hospitalization. The impact of early
      introduction of ICS in the disease course of asthma remains unresolved. The use
      of ICS in patients whose asthma is mild, with essentially normal lung function,
      and infrequent symptoms also remains unstudied. For the time being, ICS remain
      the first line of asthma treatment for adults with persistent disease.

PMID- 12428545
TI  - The evaluation and management of acute, severe asthma.
AB  - This article provides a systematic approach to the patient with acute, severe
      asthma. After a brief, focused evaluation prompt treatment with inhaled beta 2
      agonists and systemic corticosteroids remains the cornerstone of treatment.
      Ipratropium bromide is now recognized as a useful addition for both adult and
      pediatric populations, whereas consideration of intravenous MgSO4 and
      theophylline is warranted for refractory patients. Ongoing evaluation of
      antileukotriene agents offers a possibility of these agents as alternative
      bronchodilators. Further research with a number of potential acute asthma agents
      will further expand treatment options for rapid symptomatic airway improvement
      and prevention of progressing airway obstruction, hospitalization, and potential
      respiratory failure.

PMID- 12428546
TI  - Refractory asthma.
AB  - Treating patients with refractory asthma remains an ongoing challenge. Although
      most patients respond to large doses of systemic corticosteroid, the adverse
      effects associated with such a treatment limit its general use. Clinicians
      treating patients with refractory asthma must consider tapering systemic
      corticosteroid at every opportunity. Recent advances in the understanding of the
      pathogenesis of refractory asthma and corticosteroid resistance have fueled
      further study in the mechanisms of these processes and have prompted
      consideration of new treatment approaches. Unfortunately, most alternative
      approaches require more rigorous evidence to support their regular use.

PMID- 12428547
TI  - The use of anti-IgE in the treatment of allergic asthma.
AB  - Allergic sensitization plays a significant role in the development of asthma in
      many patients. IgE-mediated immune responses play a central role in the
      pathogenesis of this condition. The development of a treatment that interrupts
      this pathway is particularly desirable to prevent downstream events. Large-scale
      trials in patients ranging in age from 6 to 76 years have shown that omalizumab
      therapy is safe and effective in the treatment of severe allergic asthma. This is
      particularly true in patients who experience poor disease control despite high
      doses of inhaled steroids or need oral steroids for control of their disease.
      These patients are at risk for severe exacerbations despite recommended therapy,
      and anti-IgE therapy has proved to reduce these episodes. Early aggressive
      therapy of asthma is needed for maximum control in all age groups. Despite the
      efficacy of inhaled steroids there is a reluctance to use these agents,
      especially in younger children. Because of these concerns a long-acting treatment
      is especially desirable. Because of imperfect effort or technique limiting
      inhaled medications, introduction of an effective agent that could be
      administered parenterally at long intervals also is very important. Allergic
      rhinitis is a co-existing problem in many patients with allergic asthma.
      Immunotherapy trials have suggested that early intervention with immunotherapy
      and allergic rhinitis patients may actually prevent the development of asthma.
      Early treatment of patients with anti-IgE may also have benefits, particularly in
      those who have concomitant allergic rhinitis in addition to allergic asthma.
      Although omalizumab has not yet received Food and Drug Administration approval in
      the United States, it shows great promise in the management of patients requiring
      high doses of inhaled or oral corticosteroids for control of their disease and to
      prevent exacerbations of asthma in such patients. Reductions in high doses of
      inhaled or oral corticosteroids may prevent long-term complications of these
      treatments.

PMID- 12428548
TI  - Asthma: future directions.
AB  - Asthma continues to be a significant health care problem, as reflected by the
      increasing rise in disease morbidity and mortality. Because steroids are
      relatively safe, clinically effective, and easy to administer, they remain the
      gold standard of treatment. After many decades of use, however, it is apparent
      that inhaled corticosteroids have failed to halt the progression of the asthma
      epidemic. Newer, more effective drugs are being developed to combat this disease,
      and the interest in developing new medications to treat allergic disease and
      asthma has increased exponentially. The financial burden of asthma has also been
      a significant motivating factor in the development of new medications. It is
      estimated that in 1998 the total cost of asthma on society was $11 billion [175].
      This consideration has further intensified the quest to develop more effective
      asthma medications. Table 1 reviews the wide array of drugs currently being
      investigated. With the development and approval of novel asthma treatments,
      millions of asthma sufferers will undoubtedly have increased therapeutic options
      for control of their disease in the near future.

PMID- 12428550
TI  - [Medical problems of biological safety].

PMID- 12428549
TI  - [Human ecology: challenges of civilization, debt of society, responsibility of
      public health service].

PMID- 12428551
TI  - [Current problems of microbiological safety].

PMID- 12428552
TI  - [Basic science and problems of biological safety].

PMID- 12428553
TI  - [Food and biological safety].

PMID- 12428554
TI  - [Drug prevention to enhance population resistance to biological factors].

PMID- 12428555
TI  - [Significance of recurrent infections for biological safety].

PMID- 12428556
TI  - [HIV infection is a geo-political issue].

PMID- 12428557
TI  - [Zoonoses and biological safety].

PMID- 12428558
TI  - [Extremely dangerous infections].

PMID- 12428559
TI  - [Vaccine prevention during bioterrorism and biological catastrophes].

PMID- 12428560
TI  - [Use of biotest systems in the assurance of biological safety].

PMID- 12428561
TI  - [The specific features of the clinical picture, diagnosis and treatment of
      particularly hazardous infections at the present stage].

PMID- 12428562
TI  - [Nosocomial infections as a problem of biological safety].

PMID- 12428563
TI  - [Anaerobic surgical infection in emergencies].

PMID- 12428564
TI  - [Early adverse reactions after vaccination against influenza in chronically ill
      people].
AB  - The objective was to assess the early adverse reactions after vaccination against
      influenza with the use of Fluarix vaccine (SmithKline Beecham) in chronically ill
      people. 1010 people were selected to undergo vaccination. The group included 621
      women aged on average 44.2 years and 389 men aged on average 48.2. The
      vaccination was conducted simultaneously and the period of adverse reactions
      monitoring lasted 14 days. The vaccination was performed in accordance with
      recommendations of manufacturer. All the vaccinated people suffered from
      circulatory system disorders, bone system disorders, mental disorders and
      endocrinological problems. They were in the period of remission during the
      vaccination. The observed symptoms were classified into two categories: local and
      general. The local symptoms included swelling, reddening and pain in the
      vaccinated area. 67 people (6.6%) reported swelling, 85 (8.4%) reported
      reddening, 12 people (1.2%) reported pain in the vaccinated area. The general
      symptoms included headache, bad mood and temperature over 37.5 degrees C. 19
      people (1.9%) reported bad mood, 10 people (1%)--headache and 8 people (0.8%)
      reported temperature over 37.5 degrees C. Coexistence of two or three types of
      symptoms was present in 15 cases (1.5%). The low percentage of early adverse
      reactions encourages a wider use of vaccines against influenza in chronically ill
      people.

PMID- 12428565
TI  - [The influence of respiratory insufficiency on autonomic nervous system function
      in infants].
AB  - The aim of the study was to examine the influence of the respiratory
      insufficiency in infants treated conservatively or with the use of mechanical
      lung ventilation, on cardiovascular activity of the autonomic nervous system and
      interdependence of the sympathic and parasympathic system in infants. The
      cardiovascular autonomic nervous system functions were estimated by the power
      spectrum analysis of the heart rate variability (PS/HRV) using MEDEA HRV system.
      HRV spectrum analysis was limited to low (LF: 0.05-0.2 Hz) and high (HF: 0.2-0.6
      Hz) frequency components, which were indicators of the sinoatrial node modulation
      by sympathic (LF) or parasympathic (HF) nervous system. LF/HF ratio presents the
      independence of the sympathic and parasympathic nervous system activity, and the
      total power spectrum of the HRV is the whole vegetative system activity index.
      The medical research was carried out in 44 infants. They included 29 infants with
      respiratory insufficiency conservatively treated in intensive care unit and 15
      healthy control subjects. All infants with respiratory insufficiency were
      examined twice: during respiratory insufficiency and after recovery (40-64 days
      from first examination). Healthy infants were examined only once. According to
      the HRV parameters analysis it was proved that in infants respiratory
      insufficiency has significant influence on the increased cardiovascular activity
      of the parasympathic system, and increased cardiovascular activity of the
      autonomic nervous system. Respiratory insufficiency significantly changes
      relationship between cardiovascular activity of the sympathic and parasympathic
      nervous system. Regression of respiratory insufficiency symptoms causes the
      normalisation of both sympathic and parasympathic activity.

PMID- 12428566
TI  - [Influence of prognostic factors on the risk of recurrence in breast cancer
      patients after radical treatment].
AB  - The analysis includes 730 consecutive breast cancer patients operated radically.
      The impact on local and distant recurrences as well as the probability of 5-year
      disease free survival according to age, hormonal status, primary tumor and
      axillary nodes stage, number of involved nodes, presence of extracapsular
      invasion and histopathological grade was assessed. Results of this analysis
      showed the stage of axillary lymph nodes as the most important prognostic factor
      for the estimation of the risk of failure. It was also revealed that well-known,
      classic factors are often insufficient to determine appropriate prognosis.

PMID- 12428567
TI  - [Usefulness of serum calcitonin, CEA and AFP assays in the early detection of
      medullary thyroid carcinoma relapse].
AB  - The medullary thyroid carcinoma (MTC) occurs in the two major forms, the sporadic
      medullary carcinoma (SMTC) and hereditary medullary carcinoma, to which belong
      familial form (FMTC) and the element of Multiple Endocrine Neoplasia Syndrome MEN
      2A and 2B. The method-of-choice of treatment is total thyroidectomy with
      following radiotherapy in selected cases. Among the follow-up methods, there are
      two used the most frequently: the pentagastrin and omeprazole stimulation test of
      calcitonin (CT), and CEA antigen assay. The aim of this study is to evaluate
      usefulness of plasma CT, CEA and AFP assay in the early detection of relapse or
      metastasis of MTC. 18 patients (14 females and 4 males) were investigated. The
      following procedures were performed in all the patients: plasma CT assays in the
      basal conditions and after stimulation tests, CEA and AFP. The results were
      analysed according to TNM staging and neck USG results. Our conclusion is that
      calcitonin stimulation tests, and CEA assays are useful methods to estimate the
      presence of relapse or metastases in the patients after surgical treatment due to
      MTC. Assays of plasma AFP concentration are not useful in a follow-up of patients
      operated on MTC.

PMID- 12428568
TI  - [Comparison of effectiveness of endoscopic injection of autologous blood and
      conservative therapy in the treatment of bilateral primary vesicoureteral
      reflux].
AB  - Vesicoureteral reflux (VUR) is one of the most frequent diseases which leads to
      pyelonephritis and furthermore, renal damage. The treatment of VUR (surgical or
      endoscopic) remains a controversial topic. Autologous blood injection-
      autohemotherapy (AHT) is used in the endoscopic treatment of VUR. The aim of the
      research was the comparison of efficacy of AHT and conservative therapy in
      children with bilateral VUR grade III. 125 children were treated endoscopically.
      The results of the AHT were compared with the results of conservative treatment
      in 121 children with the same kind of disease. Complete disappearance of VUR
      after AHT was observed in 61.6% of children and in 59.5% after two years of
      medical treatment. These results were not significantly different (p > 0.73) in
      contrast to the results reached after one year of conservative therapy (p <
      0.01). After the conservative treatment in 33.5% of kidneys reflux nephropathy
      (NR) was observed. In the group treated by AHT NR developed in 25.2% of kidneys.
      The frequency of NR was significantly higher in children after conservative
      treatment (p < 0.001). 29.8% of children after conservative therapy and 8% of
      children after AHT were operated. The results of research proved that usefulness
      of intravesical autohemotherapy in the treatment of VUR. The method was safe with
      a low quantity of complications. The efficacy of AHT in the elimination of
      bilateral high grade VUR was comparable to this reached after two years of
      conservative treatment.

PMID- 12428569
TI  - [Preoperative analysis of vital lung capacity in female patients with flattened
      thyrotoxicosis].
AB  - Unbalanced hyperthyroidism leads to the feeling of dyspnea and to the decrease of
      vital lung capacity. Efficacious treatment of thyrotoxicosis relieves mentioned
      disorders and brings normalization of ventilation parameters. The main issue of
      this research was the analysis of vital lung capacity in female patients with
      properly treated hyperthyroidism and comparison of values of these parameters
      among patients with balanced thyrotoxicosis, non-toxic goitre and with non
      thyroid disorders. Research was conducted on 300 randomized female-patients (ASA
      I, II), aged 18 to 47 with surgically treated hyperthyroidism, non-toxic goitre
      or non-thyroid disorders. Vital lung capacity (VLC) was analyzed as absolute
      values and as a percent of predicted values. Statistical analysis revealed that
      patients in specified groups did not differ in age, weight and frequency of
      belonging to both ASA categories. Vital lung capacity and percent of predicted
      values were not significantly different in all groups. Vital lung capacity of
      female-patients with balanced hyperthyroidism did not differ significantly from
      vital lung capacity of patients with non-toxic goitre and non-thyroid disorders.

PMID- 12428570
TI  - [Clinical symptoms and signs in Kimmerle anomaly].
AB  - The aim of the study was to consider Kimmerle anomaly (ponticulus posterior of
      the atlas) as an anatomic variant, which can cause a set of clinical symptoms and
      signs. A hundred and eight patients, 58 females and 50 males at the age of 18-59
      years (M. 36.9 years, SD = 9.6) with radiologically verified Kimmerle anomaly
      were examined. A control group comprised 40 healthy subjects at the similar age
      range. The diagnosis of headaches was based on the criteria proposed by the IHS.
      A character of headaches, their localization, frequency, duration, number of days
      with headaches per year, circumstances associated with their onset and
      concomitant symptoms were evaluated. All the patients were subjected to
      electrophysiological studies (ENG, EEG and VEP). The results were statistically
      analyzed using a SPSS/PC+ computer system. It was revealed that clinical symptoms
      and signs in Kimmerle anomaly occurred most frequently in the third and fourth
      decade of life (65% of cases). These were most often tension-type headaches (50%
      of cases with headaches), vascular headaches (26% of cases) and neuralgia (24% of
      cases). Intensity of headaches was high. Headaches were accompanied by other
      complaints like vertigo (59% of cases) and in one third of cases--nausea. About
      10% of patients also suffered from vomiting, paresthesia, dizziness, short
      periods of loss of consciousness. Sporadically--tinitus, drop attack, and
      vegetative symptoms. In cases without pain the most frequent signs were short
      periods of loss of consciousness, dizziness, and also nausea and dizziness. The
      EEG examination revealed pathology in 40% of patients with Kimmerle anomaly. The
      ENG examination in more than 33% of anomaly cases showed injury in the central
      part of vestibular system. Improper answers were reported in about 75% of the
      patients during the VEP examination.

PMID- 12428571
TI  - [Symptoms of temporomandibular joint dysfunction in patients treated for the
      condylar fractures].
AB  - 124 patients at the age of 7 to 70 years with condylar fractures were treated in
      the Department of Dental and Maxillo-Facial Surgery in the years 1992-96. The
      authors carried out control clinical examinations and the radiographic
      investigations in 42 patients treated conservatively. Late results of treatment
      were assessed after 5 since post fracture. In the assessment the range of
      mandible abduction, function of temporomandibular joints, mandibular malposition
      following movements, occlusal disturbance, dislocation of the central line, and
      the acoustic symptoms in TMJ.

PMID- 12428572
TI  - [Imaging of adrenal glands--overview and examination techniques].
AB  - Imaging methods used in the diagnosis and differentiation of adrenal lesions are
      presented. For this purpose ultrasound, computed tomography (CT), scintigraphy
      and magnetic resonance imaging are employed. Ultrasound, because of its
      availability, allows the diagnosis of large number of adrenal tumors. Its
      usefulness is limited by difficulties in the diagnosis of small tumors and
      characterization of visualized lesions. Computed tomography is a primary method,
      performed without the administration of contrast. It allows the diagnosis of 95%
      of adrenal lesions and permits to characterize majority of them. Magnetic
      resonance has similar to CT accuracy of diagnosis and characterization of adrenal
      tumors similar to CT. Scintigraphy of adrenal cortex has not yet gained wide
      acceptance. Scintigraphic examination with MIBG is performed to search for
      extraadrenal sites of pheochromocytoma. Adrenal biopsy is indicated occasionally
      in patients with neoplastic disease and adrenal tumor, not characterized by CT
      and MRI.

PMID- 12428573
TI  - [Damage of mitochondrial DNA in selected pathologies].
AB  - The presence of separate genetic information in the mitochondria let consider
      them as semiautonomous structures. Changes of mitochondrial genetic material were
      detected in many pathologies; they have a number of common traits, but they also
      differ in terms of frequency of occurrence. This paper presents data concerning
      mtDNA and a review of most commonly encountered mutations and the associated
      pathologies.

PMID- 12428574
TI  - [Thyroid gland and pregnancy--physiology and pathology].
AB  - Changes in thyroid function and structure during pregnancy, including
      abnormalities in thyroid ultrasonography. Levels of thyroid stimulating hormone
      (TSH), free thyroxine (FT4), total thyroxine (TT4), total triiodothyronine (TT3),
      reverse triiodothyronine (rT3), thyroxin binding globulin (TBG) and thyroglobulin
      (Tg) as well as the changes in metabolism have been presented. Difficulties in
      the diagnostics of hyperthyroidism and hypothyroidism in pregnant women have been
      described. In addition modern ideas about the treatment of thyroid dysfunction in
      this period of woman life have been presented. Furthermore thyroid physiology and
      pathology in fetus and newborn have been described.

PMID- 12428575
TI  - [Extracellular matrix metalloproteinases--perspectives of their use in medicine].
AB  - Extracellular matrix turnover disturbances are implicated in many human diseases.
      Matrix Metalloproteinases (MMP) are believed to play a pivotal role in
      maintaining the intricate balance between extracellular matrix synthesis and
      degradation. These enzymes are active in the cleavage of many matrix proteins.
      There is evidence that matrix metalloproteinases activity changes in many
      pathological conditions, including inflammatory and degenerative disorders as
      well as tumour progression and metastases. This review focuses on the recent view
      on physiological and pathological function of MMPs. Authors aimed also to show
      the putative role of matrix metalloproteinases as a diagnostic tool in future
      medicine.

PMID- 12428576
TI  - [Dance therapy in the treatment of psychiatric and somatic disorders].
AB  - The article is an attempt of review of recent achievements in dance therapy. It
      presents possibilities of introducing dance into the treatment of psychiatric
      disturbances (psychoses, dementias, neurotic disorders) and somatic disorders
      (rheumatoid arthritis, osteoporosis, terminal stages). The authors basing on the
      contemporary literature describe positive results of dance therapy in various
      clinical situations.

PMID- 12428577
TI  - [Two cases of hearing loss following Hashimoto disease].
AB  - Hearing loss accompanies some of thyroid gland diseases especially those with
      hypothyroidism. Some authors state it correlates with autoimmune background of
      certain thyroid gland disturbances. We present two cases of patients with
      Hashimoto disease accompanied by fluctuating cochlear hearing loss and peripheral
      vestibular loss in one of the cases. FIRST CASE: there was unilateral worsening
      of bilateral hearing loss diagnosed previously after gentamycine treatment in 16
      year old female with Hashimoto disease. There was significant improvement
      confirmed in audiological tests when the child became euthyroid. Second case
      presenting hearing loss and vertigo: 16 year old female with hypothyroidism and
      diabetes mellitus type 1 with high blood concentration of anticytoplasmic
      immunoglobulins lasting for 2 years. Bilateral cochlear perceptive hearing loss
      was diagnosed. In summary an association of autoimmune process as well as thyroid
      hormones blood level with inner ear condition was suggested. Trying to find the
      reason of observed disturbances one should consider wide differential diagnostics
      in all the cases of perceptive seemingly idiopathic cochlear hearing loss. The
      presented problem needs to be further investigated in larger clinical material.

PMID- 12428578
TI  - [Combined pancreaticoduodenal injury after blunt trauma--case report].
AB  - The paper presents a patient with a traumatic combined injury of pancreas,
      duodenum and peripancreatic vessels successfully treated by performing
      duodenopancreatectomy with splenectomy. Severe complications developed in
      postoperative period: postoperative haemorrhage, intra-abdominal abscesses,
      biliary and intestinal fistula. The diagnostics and operative treatment of such
      injury were discussed.

PMID- 12428579
TI  - [Noonan syndrome coexisting with essential arterial hypertension in 8 year old
      boy].
AB  - In the paper some basic data concerning Noonan syndrome were reminded. Then the
      case of 8 year old boy suffering from above mentioned syndrome coexisting with
      essential arterial hypertension was described. Such coexistence has been probably
      reported for the first time. Arterial hypertension in the described case was
      successfully treated with atenolol.

PMID- 12428580
TI  - [Parotid metastases from breast cancer].
AB  - Metastatic tumours in parotid gland are very uncommon, and they usually reflect
      the lymphatic drainage from the head and neck region. The most frequent types of
      the metastatic tumours are squamous cell carcinoma and malignant melanoma.
      Metastases to parotid gland from subclavicular area are extremely rare. Two
      patients with breast cancer and metastases to parotid region are presented. One
      patient developed metastases in parotid gland 15 years after surgery and
      radiotherapy of breast cancer. In the latter patient parotid tumour was the first
      manifestation of the disease. Both patients underwent parotid surgery. None of
      the patients survived more than 6 months. Metastases in parotid region carry bad
      prognosis for the patients.

PMID- 12428581
TI  - [Ludwik Rydygier--homo creator. The 150th anniversary of the birth of Ludwik
      Rydygier].
AB  - The authors present biography of Ludwik Rydygier, the great Polish surgeon, with
      special emphasis on his medical and scientific activity as well as his role in
      the foundation of Polish surgical school.

PMID- 12428583
TI  - Suspended animation.

PMID- 12428582
TI  - Cross purposes.

PMID- 12428584
TI  - Primary care trusts. Mix and match.

PMID- 12428585
TI  - Nurse development. Tutor tonic.
AB  - Preceptorship programmes for newly qualified nurses can help ease the transition
      from training to work. Experience at two acute trusts found that some
      participants had difficulty in completing learning portfolios. Participants
      welcomed support on the wards and structured learning sessions.

PMID- 12428586
TI  - Histomorphometric analysis of rat alveolar wound healing with hydroxyapatite
      alone or associated to BMPs.
AB  - Several materials and techniques have been proposed to improve alveolar wound
      healing and decrease loss of bone height and thickness that normally follow
      dental extraction. The objective of this research was the histologic analysis of
      bone morphogenetic proteins implanted into dental alveoli of rats after
      extraction. A total of 45 adult male Wistar rats were divided into three groups
      of 15 animals each: control (no treatment), implanted with pure hydroxyapatite
      (HA, 3 mg) and implanted with hydroxyapatite plus bone morphogenetic proteins
      (HA/BMPs, 3 mg). Five animals from each group were sacrificed at 7, 21 and 42
      days after extraction for the histometric analyses of the osteoconductive
      potential of hydroxyapatite associated or not with BMPs. After dissection,
      fixation, decalcification and serial microtomy of 6-micron thick sections, the
      samples were stained with hematoxylin-eosin for histologic and histometric
      analyses. Both HA and HA/BMPs caused a delay in wound healing compared to control
      animals, evaluated by the percentage of bone tissue in the alveoli. The treatment
      with HA/BMPs had the greatest delay at 21 days, even though it produced values
      similar to the control group at 42 days. The materials did not improve alveolar
      repair in the normal period of wound healing and the association of HA/BMPs did
      not have osteoconductive properties with granulated hydroxyapatite as the
      vehicle.

PMID- 12428587
TI  - In vitro antimicrobial activity of calcium hydroxide pastes and their vehicles
      against selected microorganisms.
AB  - The aim of this study was to investigate in vitro the antimicrobial activity of
      calcium hydroxide in combination with several vehicles against some
      microorganisms commonly isolated from root canals. Antimicrobial activity was
      determined by the agar diffusion method. Stainless-steel cylinders were placed on
      each inoculated agar medium. The test medicaments and their controls were placed
      inside the cylinders. The zones of growth inhibition were measured and recorded
      after incubation for each plate and the results were analyzed statistically
      (ANOVA). The in vitro antimicrobial effects of the medications were ranked from
      strongest to weakest as follows: Ca(OH)2 + CMCP + glycerine, Ca(OH)2 + CMCP,
      Ca(OH)2 + glycerine, Ca(OH)2 + anesthetic, Ca(OH)2 + saline, Ca(OH)2 + H2O,
      Ca(OH)2 + polyethyleneglycol. The pastes with oily vehicles showed significantly
      larger mean zones of inhibition compared to those with aqueous or viscous
      vehicles. It was concluded that diffusion and antimicrobial activity of calcium
      hydroxide were affected by the type of vehicle used.

PMID- 12428589
TI  - In vitro analysis of effect of heat used in dental bleaching on human dental
      enamel.
AB  - From a cosmetic point-of-view, white teeth are important for integration of an
      individual into society. Thus, dental bleaching may be used to reach this
      objective. When analyzing several proposed techniques, it was observed that heat
      is frequently involved either in direct application or as a result of a chemical
      reaction. Taking into account the importance of preserving dental structures, the
      present study analyzed possible injuries to enamel when heat is used in the
      bleaching procedure. A colorimetric method was used and the results showed that
      there was no difference when heat was used. In only one case did the non
      communicating tufts become communicating.

PMID- 12428588
TI  - Effects of a 10% carbamide peroxide bleaching agent on rat oral epithelium
      proliferation.
AB  - The purpose of the present study was to evaluate the influence of short course
      topical application of carbamide peroxide on proliferating cell nuclear antigen
      (PCNA) immunohistochemical expression in the oral tongue mucosa of rats. Twelve
      male Wistar rats were submitted to topical application of 10% carbamide peroxide
      on one side of the dorsal tongue once a week for three consecutive weeks. Only
      distilled water was applied on the control side. The animals were killed on days
      0, 10, and 20 after the last application. The tongue was fixed in buffered
      formalin for 24 h and embedded in paraffin. Tissue blocks (3 microns) were
      subjected to the biotin-streptavidin amplified system for identification of PCNA.
      The percentage of epithelial-positive basal cells in each side of the tongue
      mucosa was calculated. The results demonstrated that topical application of 10%
      carbamide peroxide increases PCNA immunohistochemical expression on the basal
      layer of the oral mucosa epithelium of rats on day 0 after treatment. In
      conclusion, short-course use of carbamide peroxide induces transient epithelial
      cell proliferation of the oral mucosa of rats.

PMID- 12428590
TI  - Structure and microstructure of coronary dentin in non-erupted human deciduous
      incisor teeth.
AB  - The dentin structure of non-erupted human deciduous mandibular and maxillary
      central and lateral incisor teeth was studied employing light and scanning
      electron microscopy. For light microscopy, nitric-acid-demineralized and ground
      sections were used. The sections were stained by hematoxylin-eosin, picrosirius
      and azo-carmine methods, and ground specimens were prepared using a carborundum
      disk mounted in a handpiece. For SEM study, teeth were frozen in liquid nitrogen
      and fractured at longitudinal and transversal directions. Structurally,
      demineralization and ground methods revealed tubules with primary and secondary
      curvatures, canaliculi, giant tubules, interglobular dentin, predentin, and
      intertubular dentin. Scanning electron microscopy showed three-dimensional
      aspects of dentinal tubules, canaliculi, peritubular dentin, intertubular dentin,
      and predentin. This study contributes to knowledge about dentin morphology
      showing characteristics of teeth not yet submitted to mastication stress.

PMID- 12428591
TI  - Shear bond strength of enamel surface treated with air-abrasive system.
AB  - The aim of this study was to evaluate the shear bond strength of a composite
      resin to dental enamel, using three different surface treatments. Fifteen sound
      third molars were randomly assigned to three groups. The mesial and distal
      surfaces were flattened and covered using adhesive tape with a central orifice
      delimiting the adhesion area (7.07 mm2). Group I, the enamel surface was
      conditioned with 37% phosphoric acid for 15 s; group II, the surface was treated
      using air abrasion with aluminum oxide; group III, the enamel surface was treated
      using an association of air abrasion with aluminum oxide and 37% phosphoric acid.
      The Single Bond (3M) adhesive system was applied and a Teflon matrix was placed
      and filled with composite resin Z-100 (3M) and light-cured. The shear bond
      strength test was performed with a universal testing machine. The acid etching
      technique and air abrasion with aluminum oxide associated with acid etching had
      the highest shear bond strength values. Data were subjected to statistical
      analysis using ANOVA and the Turkey test, and no statistically significant
      difference in shear bond strength was observed between group I (12.49 +/- 2.85
      MPa) and group III (12.59 +/- 2.68 MPa). In contrast, both groups had
      statistically better shear bond strengths compared to group II (0.29 +/- 0.56
      MPa; p < 0.05). Air abrasion with aluminum oxide does not substitute acid
      etching. The association of these methods to obtain adequate adhesion to the
      substrate is necessary.

PMID- 12428592
TI  - Effect of surface roughness on amalgam repair using adhesive systems.
AB  - The objective of this in vitro study was to evaluate the effect of three surface
      treatments and two adhesive systems on the shear bond strength of old and freshly
      placed amalgam. The results suggested that the intact amalgam showed a
      significantly higher strength than repaired groups and the strongest repaired
      specimens were made when the amalgam surfaces were roughened with a diamond bur
      or microetcher. The adhesive systems showed no significant differences on bond
      strength with the same superficial texture.

PMID- 12428594
TI  - Effect of different EGTA concentrations on dentin microhardness.
AB  - The effect of 1%, 3% and 5% EGTA (ethylene glycol-bis-(beta-amino-ethyl ether)
      N,N,N',N'-tetra-acetic acid) on the microhardness of root dentin of the cervical
      third of human teeth was studied. Five newly extracted maxillary incisors were
      sectioned transversely at the cementoenamel junction, and the crowns were
      discarded. The roots were embedded in blocks of high-speed polymerized acrylic
      resin and cut transversely into 1-mm sections. The second section of the cervical
      third of the root of each tooth was sectioned and divided into four parts. Each
      part was placed on an acrylic disc that was used as a base for microhardness
      measurement. Fifty microliters of 1% EGTA, 3% EGTA, or 5% EGTA were applied to
      the dentin surface. Deionized and distilled water was used as control. Dentin
      microhardness was then measured with a load of 50 g for 15 s. Statistical
      analysis showed that the three concentrations of the chelating solution EGTA
      significantly reduced dentin microhardness when compared with water (ANOVA, p <
      0.01), and that there was a statistically significant difference among the three
      solutions (Tukey test, p < 0.05).

PMID- 12428593
TI  - In vitro evaluation of microleakage of a flowable composite in Class V
      restorations.
AB  - The aim of this study was to evaluate microleakage around class V restorations
      using a flowable composite compared to a hybrid composite. Forty class V cavities
      were prepared on buccal and lingual surfaces of 20 human teeth, with occlusal and
      cervical margins at the enamel and cementum/dentin levels, respectively.
      Specimens were divided into 2 groups with 10 samples each. Group 1: buccal
      cavities received Paama 2 (conventional bonding agent) + Wave (flowable
      composite); lingual cavities were restored with Paama 2 + Glacier (hybrid
      composite). Group 2: buccal cavities received Optibond Solo (self-priming bonding
      agent) + Wave; lingual cavities were restored with Optibond Solo + Glacier. After
      being stored in distilled water and finished, the teeth were thermocycled,
      immersed in a 50% silver nitrate solution and embedded in resin. They were
      sectioned and the depth of tracer penetration was scored. The results were
      analyzed using Kruskal-Wallis and Wilcoxon tests. The restorations with flowable
      composite and those with hybrid composite from the same group showed similar
      results of microleakage for both occlusal and cervical margins. Optibond Solo
      improved the sealing of the restorations when compared with Paama 2 (p < 0.01).
      None of the restorative materials completely sealed the tooth/restoration
      interface at the cervical margins.

PMID- 12428595
TI  - Bonding brackets to porcelain--in vitro study.
AB  - The aim of this research was to verify, in vitro, the effect of various porcelain
      surface treatment on the shear strength of orthodontic brackets bonded to
      porcelain and the mode of fracture after debonding. Eighty-eight samples of
      metallic supported feldspathic porcelain were randomly divided into four groups
      according to their surface preparation as follows: the porcelain was maintained
      intact (GI), roughened with a diamond bur (GII), etched with 10% hydrofluoric
      acid (GIII), or sandblasted with aluminum oxide (GIV). The specimens were treated
      with silane (Scotchprime) and brackets were bonded with Concise. Each sample was
      subjected to a shear load at a crosshead speed of 1 mm/min and a recording was
      made at the point of failure. Bond strengths, adequate to withstand the
      application of orthodontic forces, were achieved in all groups. The Kruskal
      Wallis statistical test showed no significant differences in bond strength
      between the groups (p > 0.05). However, many more porcelain fractures occurred on
      deglazed porcelain. This study indicates that with the appropriate material
      selection, the silane/composite procedure alone may be adequate for bonding.

PMID- 12428596
TI  - Changes in occlusal vertical dimension in microwave processing of complete
      dentures.
AB  - This study investigated the effect of different microwave curing cycles on the
      changes in occlusal vertical dimension of complete dentures. Four test groups
      with 12 maxillary dentures each were evaluated. Groups 1, 2 and 3 were
      polymerized with different cycles by microwave radiation and Group 4 was the
      control and cured by water bath. The average pin opening for all groups was less
      than 0.5 mm. There was no significant difference between the groups polymerized
      by the microwave method and the control group. However, analyses of the vertical
      dimension changes showed statistically significant differences between groups 2
      (0.276 +/- 0.141 mm) and 3 (0.496 +/- 0.220 mm).

PMID- 12428597
TI  - Evaluation of the reliability of computerized profile cephalometric analysis.
AB  - The use of computers as an auxiliary instrument for case evaluation and
      procedures in health sciences is not new, and their advantages are well known. A
      growing number of orthodontists are using computerized systems for cephalometric
      analysis. Thus, this study evaluated the reliability of both computerized and
      manual methods used for creating profile cephalograms. Fifty profile radiographs
      were selected from the files of the Post-Graduate Course in Orthodontics at the
      Dental School of the Federal University of Rio de Janeiro. The good quality of
      the material was the only necessary requirement for selection. Results were
      submitted to the interclass correlation coefficient and a reliable similarity
      between cephalometric data obtained through both evaluated methods was found.
      However, the clinical utilization of computerized cephalometric analysis is not
      absolutely reliable.

PMID- 12428598
TI  - Effect of intrinsic pigmentation on the flexural strength of a microwave-cured
      acrylic resin.
AB  - This study investigated the effect of intrinsic pigmentation on the transverse
      strength of a microwave-cured acrylic resin. Forty transverse strength specimens
      were fabricated according to ADA specification #12 and divided into 5 groups. No
      fibers were added to group I (GI, control group); acrylic stain (AS) was added to
      GII and GIII in concentrations of 0.5 and 1.5% w/w, respectively; acrylic fibers
      (AF) were added to groups GIV and GV in concentrations of 0.5 and 1.5% w/w,
      respectively. All specimens were irradiated in a microwave oven with a cycle of 3
      min at 360 W, followed by 4 min resting, then 3 min at 810 W. Flasks were bench
      cooled for 30 min at room temperature, followed by immersion in cold tap water
      for 30 min. After storage in distilled water at 37 degrees C for 48 h, all
      specimens were tested for flexural strength in a testing machine (EMIC-DL 500) at
      a crosshead speed of 0.5 cm/min. Mean and standard deviation (MPa) for the
      flexural strength test were: GI = 86.0 +/- 7.9; GII = 86.0 +/- 9.8; GIII = 86.6
      +/- 7.7; GIV = 84.9 +/- 5.3; GV = 84.9 +/- 5.2. No statistical differences were
      detected among the groups (ANOVA, p > 0.05). The addition of the acrylic fibers
      or the acrylic stain did not affect the transverse strength of the microwave
      cured acrylic resin.

PMID- 12428600
TI  - Nasolabial cyst: case report.
AB  - The nasolabial cyst is classified as a fissural cyst, found outside the bone, and
      on the region corresponding to the nasolabial furrow and alar nose. This cyst is
      frequently asymptomatic with the most usual sign being alar nose elevation. In
      spite of the low occurrence of nasolabial cysts, it is important to recognize the
      clinical characteristics of this lesion. The purpose of this paper is to review
      the literature and discuss the histomorphology and etiology of this condition,
      showing treatment by surgical excision.

PMID- 12428599
TI  - In vitro study of effect of solvent on root canal retreatment.
AB  - The aim of this study was to assess the effectiveness of five different solvents:
      xylol, eucalyptol, halothane, chloroform and orange oil on softening gutta-percha
      in simulated root canals. One drop of solvent was placed into a reservoir made in
      a simulated canal whose channel was previously instrumented and filled with gutta
      percha and N-Rickert sealer. After 5 min, softening was evaluated for each
      solvent by the penetration of a spreader while applying force with a 442 Instron
      apparatus to reach a depth of 5 mm. The results were analyzed statistically by
      the Kruskal-Wallis test. Xylol and orange oil were better in softening gutta
      percha than the other solvents. There was no significant difference between xylol
      and orange oil, but these were statistically different from eucalyptol, halothane
      and chloroform (p < 0.01).

PMID- 12428601
TI  - Proceedings of the 7th International Conference on Endothelin. Edinburgh, United
      Kingdom, 16-19 September 2001.

PMID- 12428602
TI  - Scientists unveil the next step in the human genome project.

PMID- 12428604
TI  - Patients should be sent copies of doctors' letters about them.

PMID- 12428605
TI  - Radioactive Isotopes in Clinical Medicine and Research. Abstracts of the 25th
      International Symposium. Bad Gastein, Austria, 8-11 January 2002.

PMID- 12428606
TI  - Children in the Gaza Strip suffer malnutrition.

PMID- 12428608
TI  - Canadians need to spend $C5bn more a year on health care.

PMID- 12428609
TI  - Italy cracks down on its drugs bill.

PMID- 12428607
TI  - NICE recommends greater use of thrombolytics in acute myocardial infarction.

PMID- 12428610
TI  - US government cannot revoke licences of doctors who recommend marijuana.

PMID- 12428611
TI  - Proceedings of the 2nd International Workshop on Therapeutic Filtration. London,
      United Kingdom, 6 July 2001.

PMID- 12428612
TI  - Suturing v conservative management of hand lacerations. Hand lacerations should
      be explored before conservative treatment.

PMID- 12428613
TI  - Suturing v conservative management of hand lacerations. Incisions are not
      lacerations.

PMID- 12428614
TI  - Risk factor thresholds. Hypothesis is dangerous nonsense.

PMID- 12428616
TI  - Weber's test demystified. . . . and a collaborative group of
      otorhinolaryngologists reports its findings.

PMID- 12428615
TI  - Risk factor thresholds. Pharmacological treatment should not be determined by age
      alone.

PMID- 12428617
TI  - Oral Manifestations of HIV in the Developing and Developed World. Proceedings and
      abstracts of the 4th International Workshop on Oral Manifestations of HIV
      Infection. Skukuza, South Africa, 4-8 July 2000.

PMID- 12428618
TI  - Working on working capital.

PMID- 12428619
TI  - Appearance of impropriety?

PMID- 12428621
TI  - Proceedings and abstracts of BIOMED8: Current materials and approaches in
      biomaterials and in hard tissue repair. Ankara, Turkey, 5-8 September 2001.

PMID- 12428620
TI  - The new (non-numeric) fingerprint evidence standard--it is pointless?

PMID- 12428622
TI  - The AJO: electronic augmentation on the Internet.

PMID- 12428623
TI  - Long-Term Care in the 21st Century: Perspectives from Around the Asia-Pacific
      Rim. Proceedings of a workshop. January 2000.

PMID- 12428625
TI  - Irish Endocrine Society 27th Annual Meeting. 8-9 November 2002. Abstracts.

PMID- 12428624
TI  - [III All-Russia Symposium on Slow Oscillatory Processes in the Human Body and
      Seminar on Nonlinear Dynamics in Physiology and Medicine. Novokuznestsk, May 21
      25, 2001].

PMID- 12428626
TI  - Abstracts of the First Pan-American/Iberian Meeting on Acoustics. Cancun, Mexico,
      2-6 December 2002.

PMID- 12428627
TI  - EVER 2002. European Association for Vision and Eye Research. 2-5 October 2002,
      Alicante, Spain. Abstracts.

PMID- 12428629
TI  - International Society for Pharmacoepidemiology annual conference. Amsterdam, The
      Netherlands, 16-19 October 2002. Abstracts.

PMID- 12428628
TI  - Abstracts, 2nd International Meeting, The platelet ADP receptors: biochemistry,
      physiology, pharmacology and clinical aspects. 3-5 October 2002, S. Margherita di
      Pula, Italy.

PMID- 12428630
TI  - Abstracts of the 11th Congress of the European Academy of Dermatology and
      Venereology. 2-6 October 2002, Prague, Czech Republic.

PMID- 12428631
TI  - Aspirin therapy now recommended for people at risk for heart disease.

PMID- 12428633
TI  - Majority of patients with serious mental illness do not receive minimum level of
      care.

PMID- 12428632
TI  - The biotic ligand model: a historical overview.
AB  - During recent years, the biotic ligand model (BLM) has been proposed as a tool to
      evaluate quantitatively the manner in which water chemistry affects the
      speciation and biological availability of metals in aquatic systems. This is an
      important consideration because it is the bioavailability and bioreactivity of
      metals that control their potential to cause adverse effects. The BLM approach
      has gained widespread interest amongst the scientific, regulated and regulatory
      communities because of its potential for use in developing water quality criteria
      (WQC) and in performing aquatic risk assessments for metals. Specifically, the
      BLM does this in a way that considers the important influences of site-specific
      water quality. This journal issue includes papers that describe recent advances
      with regard to the development of the BLM approach. Here, the current status of
      the BLM development effort is described in the context of the longer-term history
      of advances in the understanding of metal interactions in the environment upon
      which the BLM is based. Early developments in the aquatic chemistry of metals,
      the physiology of aquatic organisms and aquatic toxicology are reviewed first,
      and the degree to which each of these disciplines influenced the development of
      water quality regulations is discussed. The early scientific advances that took
      place in each of these fields were not well coordinated, making it difficult for
      regulatory authorities to take full advantage of the potential utility of what
      had been learned. However, this has now changed, with the BLM serving as a useful
      interface amongst these scientific disciplines, and within the regulatory arena
      as well. The more recent events that have led to the present situation are
      reviewed, and consideration is given to some of the future needs and developments
      related to the BLM that are envisioned. The research results that are described
      in the papers found in this journal issue represent a distinct milestone in the
      ongoing evolution of the BLM approach and, more generally, of approaches to
      performing ecological assessments for metals in aquatic systems. These papers
      also establish a benchmark to which future scientific and regulatory developments
      can be compared. Finally, they demonstrate the importance and usefulness of the
      concept of bioavailability and of evaluative tools such as the BLM.

PMID- 12428634
TI  - Hospital compliance with its safety recommendations is low, group says.

PMID- 12428636
TI  - Diabetes screening strategy holds potential for early treatment, savings.

PMID- 12428635
TI  - The in vitro effects of crystalloids and colloids on coagulation.
AB  - Classically haemodilution is regarded as causing coagulopathy. However,
      haemodilution with saline seems to cause a hypercoagulable state both in vivo and
      in vitro. The aim of the present study was to measure the effect of mild to
      severe haemodilution using thrombelastography. Blood samples were taken in 12
      healthy volunteers and divided into seven aliquots. One aliquot was undiluted and
      acted as control. The other six were diluted with normal saline, Ringer Acetate,
      4% albumin, Dextran 70, 6% and 10% hydroxyethylstarch to 10%, 20%, 40%, 50% and
      60% dilution. The dilution was checked by measuring the haemoglobin
      concentration. Each aliquot was placed in a temperature-controlled
      thrombelastography channel. Increased coagulation activity, as measured by
      thrombelastography changes, was detected at low and medium levels of dilution
      with all the tested solutions. At more than 40% dilution, coagulation returned to
      normal while in the case of dextran and hydroxyethylstarch coagulopathy
      developed. For crystalloids and albumin,dilution had to exceed 50% before
      coagulation was impaired. If these findings can be reproduced in vivo, they may
      have implications for transfusion practice and prophylaxis against thrombosis.

PMID- 12428637
TI  - Estimating unmeasured anions in critically ill patients: anion-gap, base-deficit,
      and strong-ion-gap.
AB  - We used 100 routine blood samples from critically ill patients to establish
      whether correcting the anion-gap and base-deficit for decreased plasma albumin
      improves agreement with the strong-ion-gap for estimating unmeasured anions and
      whether the modifications increase the proportion of samples with levels of anion
      gap or base-deficit above the reference ranges. We used Bland-Altman analyses to
      compare the methods of estimating unmeasured ions. Compared with the strong-ion
      gap, modification reduced the limits of agreement for both the anion-gap and the
      base-deficit. The bias for the base-deficit was also reduced but the bias for the
      anion-gap was increased. The proportion of samples with an anion-gap > 22 meq.l(
      1) increased from 4 to 29% (p < 0.001), and the proportion with a base-deficit >
      5 meq.l(-1) increased from 8 to 42% (p < 0.001). Consequently, metabolic acidosis
      from unmeasured ions in critically ill patients maybe more frequent than often
      recognised.

PMID- 12428638
TI  - Anaesthesia for cardioversion: a comparison of sevoflurane and propofol.
AB  - This study compared the induction time, haemodynamic changes, recovery
      characteristics and patient satisfaction for sevoflurane and propofol when used
      as the main anaesthetic agents for cardioversion. Sixty-one unpremedicated
      patients scheduled for elective cardioversion were anaesthetised with either
      inhaled sevoflurane 8% or an intravenous propofol target-controlled infusion set
      at 6 microg.ml(-1). There was no significant difference in induction time between
      the two groups: mean (SD) = 90.1(40) s in the sevoflurane group vs. 83.7(35) s in
      the propofol group. Mean (SD) time to recovery was significantly shorter in the
      sevoflurane group than in the propofol group: 318 (127) s vs.738 (355) s,
      respectively, p < 0.001. At recovery, the patients in the propofol group had
      significantly lower systolic and diastolic blood pressures than those in the
      sevoflurane group, p < 0.001. The incidence of complications was low in both
      groups, with similar patient satisfaction expressed after the procedure. We
      conclude that sevoflurane is a suitable choice for anaesthesia for cardioversion
      and may provide greater haemodynamic stability than a target-controlled infusion
      of propofol.

PMID- 12428639
TI  - Microvascular decompression for hemifacial spasm: a long-term follow-up of 1,169
      consecutive cases.
AB  - We analyzed the records of 1,169 patients with hemifacial spasm (HFS) who
      underwent microvascular decompression (MVD) and were followed up for more than 6
      months from January 1987. The mean follow-up duration was 23.8 months (6-145
      months). Excellent surgical outcome was obtained in 90.5% and good in 4.5%,
      giving an overall success rate of 95.0%. There was statistically significant
      relationship between vertebral artery (VA) shift and side of symptom. Permanent
      facial weakness and hearing impairment were 1.4% and 2.3%, respectively. There
      were no anatomical differences at the root entry zone (REZ) and significant
      differences of surgical outcome in young HFS (34 patients). Factors such as type
      of offender, severity of compression on the facial nerve root, and the degree of
      decompression of the REZ on postoperative MRI did not correlate with surgical
      outcome.

PMID- 12428640
TI  - The value of risks scores for predicting postoperative nausea and vomiting when
      used to compare patient group in a randomised controlled trial.
AB  - Whilst conducting a randomised controlled trial into the effects of combination
      anti-emetics, we endeavoured to confirm that our patient groups were matched
      using the predictive scoring systems for postoperative nausea and vomiting (PONV)
      and postoperative vomiting (POV) reported in the literature. One hundred and
      seventy-seven female patients attending for day case gynaecological surgery were
      studied and their individual risks of PONV and POV were calculated using four
      predictive models for PONV and two predictive models for POV. The scoring systems
      were then evaluated to see if agreement existed between them using the method
      described by Bland and Altman. Bias and 95% limits of agreement were calculated
      for each combination. Agreement between scoring systems was poor. As the scoring
      systems gave widely divergent predictions, we concluded that the predictive risk
      for PONV or POV would be dependent upon the scoring system chosen, thus limiting
      their usefulness in this role.

PMID- 12428641
TI  - Measurement of liver tissue oxygenation after orthotopic liver transplantation
      using a multiparameter sensor. A pilot study.
AB  - The currently used methods of monitoring liver perfusion and oxygenation after
      liver transplantation have major limitations in clinical use. We describe the use
      of a multiparameter sensor to enable continuous monitoring of liver tissue oxygen
      tension, carbon dioxide tension and hydrogen ion concentration in the early
      postoperative period in 12 patients after liver transplantation. The sensor was
      inserted under direct vision via the falciform ligament into the liver before
      skin closure. Tissue oxygen tension values decreased in the first 24 h and
      subsequently increased to a mean (SD) = 7.3 (2.8) kPa at 48 h after surgery. This
      was associated with a decrease in the degree of acidosis. There were no
      complications attributable to the sensor. This study demonstrates that continuous
      measurement of liver oxygen tension, carbon dioxide tension and pH is possible.
      This technique may be useful as a continuous monitor to help identify grafts at
      risk of ischaemia.

PMID- 12428642
TI  - Dental devices; classification for intraoral devices for snoring and/or
      obstructive sleep apnea. Final rule.
AB  - The Food and Drug Administration (FDA) is classifying the intraoral devices for
      snoring and/or obstructive sleep apnea into class II (special controls). These
      devices are used to control or treat simple snoring and/or obstructive sleep
      apnea. This classification is based on the recommendations of the Dental Devices
      Panel (the Panel), and is being taken to establish sufficient regulatory controls
      that will provide reasonable assurance of the safety and effectiveness of these
      devices. This action 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 Food and
      Drug Administration Modernization Act of 1997 (FDAMA). Elsewhere in this issue of
      the Federal Register, FDA is publishing a notice of availability of the guidance
      document that will serve as the special control for this final rule.

PMID- 12428643
TI  - Talk among yourselves. MGMA online networking case study regarding nurse staffing
      mix.

PMID- 12428644
TI  - Program and abstracts. Eighteenth Annual Meeting, American Society for
      Gravitational and Space Biology. November 6-9, 2002, Cape Canaveral, FL, USA.

PMID- 12428645
TI  - Aspirin intolerance and nasal polyposis.
AB  - Chronic rhinosinusitis with nasal polyposis usually develops in aspirin-sensitive
      patients with asthma Arachidonic acid metabolism appears to be abnormal in the
      nasal polyps of aspirin-sensitive patients with asthma. These abnormalities an
      characterized by a low production of prostaglandin E2 (PGE2) and a high release
      of cysteinyl leukotrienes. Moreover, cyclooxygenase-2 is markedly downregulated
      in polyps from aspirin-sensitive patients with asthma. This abnormality may
      explain the low production of PGE2 in nasal polyps and may account for the
      increased susceptibility to the inhibitory effects of aspirin. Nasal instillation
      or ingestion of aspirin induces a nasal reaction in most aspirin-sensitive
      patients with asthma. This reaction is accompanied by the influx of eosinophils
      and a concomitant increase in cysteinyl leukotrienes, tryptase, and eosinophil
      cationic protein release. The aspirin nasal challenge is a very safe test with a
      moderate sensibility and high specificity that can be used in the diagnosis of
      aspirin intolerance. The similarities in the reaction between the nose and
      airways in aspirin-sensitive patients provide compelling evidence for common
      pathogenic mechanisms for nasal polyps, chronic rhinosinusitis, and bronchial
      asthma.

PMID- 12428646
TI  - Decisions on euthanasia.

PMID- 12428648
TI  - Dominant frequency uncertainty analysis of EEG alpha activity in pilots with
      transient ischemic attacks.
AB  - Objective. To study the characteristics of EEG after transient ischemic attack
      and to offer reference for screening procedure of aircrew and astronaut
      selection. Method. The dominant frequency uncertainty of alpha band EEG in 12
      pilots (males; age 30 +/- 5) with transient ischemic episodes in middle cerebral
      artery (MCA) territories and in 20 normal healthy pilots was analyzed with
      frequency-fluctuation analysis. Result. The dominant probability of the main
      frequency coinciding with sites affected by transient ischemic attack (TIA) in
      patient pilots was higher than that in healthy pilots (P<0.01), and the dominant
      probability ratio logarithmic index I >or= 0 in all patient pilots with normal
      EEG, but I<0 in all healthy pilots. It was also found that not only I >or= 0, but
      the second component shifted to lower frequency (8 Hz) in patients with slight
      focal EEG alterations, i.e. slowing of frequency. The relative entropy values
      (percentage) were decreased significantly in pilots with TIA as compared with
      healthy pilots (P<0.05). Conclusion. The dominant frequency uncertainty analysis
      of alpha band showed clear superiority of computerized evaluation over routine
      visual assessment for the diagnosis of minor cerebral ischemia. It offers not
      only a possibility of studying pathophysiological functional parameter, but also
      the reference for screening procedure in aircrew and astronaut selection.

PMID- 12428647
TI  - Effects of tea polyphenols on cardiac function and myocardial ultrastructure in
      rats after repeated +Gz stress.
AB  - Objective. To observe the effects of tea polyphenols (TP) on cardiac function and
      myocardial ultrastructure in rats after repeated +10 Gz stress. Method. Twenty
      four male Wistar rats were randomly divided into three groups (n=8 each): group A
      (control), group B (+10 Gz), group C (+Gz with TP). Group B and C were repeatedly
      exposed to +10 Gz (each for 30 s, onset rate about 0.5 G/s, 3 times/d with +1 Gz
      1 min intervals, 3 d/wk, 4 weeks in total), but group A was only submitted to +1
      Gz. TP (200 mg kg-1) was given orally to group C about 1 h prior to the +Gz
      experiment, and distilled water was given to group A and B. Function of isolated
      rat working hearts and myocardial ultrastructure were observed. Result. A
      significant decrease of left ventricular systolic pressure (LVSP) and injury of
      myocardial structure in rats were demonstrated after repeated +10 Gz stress. But
      TP could remarkably elevate the LVSP and improve myocardial ultrastructural
      injury in +10 Gz stressed rats. Conclusion. These results indicated that repeated
      high G exposure may produce cardiac structural and functional injuries in rats
      which might be partly related to free radical metabolism; and antioxidant TP had
      significant protective effects on the hearts of +Gz stressed rats.

PMID- 12428649
TI  - Taking the road less traveled.

PMID- 12428650
TI  - [Echocardiographic assessment of left ventricular structure and function after
      simulated weightlessness in rats].
AB  - Objective. To investigate whether the changes in rat after simulated
      weightlessness are similar to those in astronaut after flight. Methods. The
      effects of 4 wk tail-suspension on left ventricular structure and function in
      rats were examined by echocardiography. Results. After 4 wk of simulated
      weightlessness, the thickness of both the anterior and posterior wall in left
      ventricle (LV) showed a general trend of decrease, but these changes were not
      statistically significant; the end-systolic and end-diastolic internal dimensions
      (ESD and EDD respectively) of LV decreased significantly; and the end-systolic
      volume, end-diastolic volume and stroke volume (ESV, EDV and SV respectively)
      were all reduced; so did the relevant indices of them. There were no significant
      differences in ejection fraction (EF) and fractional shortening (FS) between the
      tail-suspended and control groups. The left ventricular mass (LVM) and its index
      (LVMI) were decreased. The peak velocities of blood flow of aorta, pulmonary
      artery and mitral valve didn't show any significant change after simulated
      weightlessness. Conclusion. Medium-term simulated weightlessness may lead to a
      significant decrease in left ventricular internal dimension, ventricular volume,
      and mass, and a trend of decrease in mean left ventricular wall thickness. These
      changes in rats are similar to those observed in astronauts postflight.

PMID- 12428651
TI  - [Differentiated remodeling changes of medium-sized arteries from different body
      parts in tail-suspended rats and their reversibility].
AB  - Objective. The aim of the present study was to test whether medium-sized arteries
      in different body parts are differentially directed to achieve stimulus-specific
      remodeling to adapt local hemodynamic changes induced by tail-suspension, and to
      examine whether these structural changes are reversible. Method. Morphological
      changes of femoral, anterior tibial, common carotid, and basilar arteries from 4
      wk tail-suspended (SUS-4), 1 wk recovered (REC-1), and control (CON) rats were
      studied using van Gieson-Orcein staining method. Result. For the hindquarter
      arteries, like the femoral and anterior tibial arteries, the lumen diameter (d)
      and medial tissue area (A) of SUS-4 group were significantly decreased (P<0.05,
      P<0.01) as compared with that of CON group, and that of REC-1 group were not
      fully recovered though the differences were not significant. With respect to
      arteries in the neck region and the brain, the remodeling changes were just in an
      opposite direction. In SUS-4 group, the d and A of both common carotid and
      basilar arteries were significantly increased (P<0.05, P<0.01) as compared with
      that of CON, and not fully restored after 1 wk recovery. Conclusion. The
      structures of medium-sized arteries in different body parts remodel
      differentially in response to local hemodynamic changes during simulated
      weightlessness and these changes were reversible.

PMID- 12428652
TI  - [Countermeasuring effect of lower body negative pressure against orthostatic
      intolerance induced by 21 d -6 degrees head down tilt in humans].
AB  - Objective. To investigate whether LBNP during 21 d -6 degrees head-down tilt
      (HDT) would modify orthostatic tolerance. Method. 12 healthy males, age 23.7 +/-
      5.0, were exposed to -6 degrees HDT for 21 d. 6 of them received -4.0 kPa LBNP
      sessions for 1 h/d from 15th day to 21st day of HDT. The other 6 served as
      control. HUT + 75 degrees, 20 min orthostatic tolerance test were done before, on
      day 10 and on day 21 of HDT. Result. During HUT + 75 degrees, 20 min orthostatic
      tolerance test on day 10 of HDT, 5 subjects of the control group and 4 of the
      LBNP group presented presyncopal or syncopal signs and symptoms, the average
      standing time of both groups were shorter than those of the pre-HDT (p<0.05).
      During HUT + 75 degrees, 20 min orthostatic tolerance test on day 21 of HDT, 5
      subjects of the control group and one subject of the LBNP group presented
      presyncopal or syncopal signs and symptoms, the average standing time of control
      group reduced significantly as compared with those of pre-HDT(P<0.05), also
      significantly shorter than those of LBNP group (P<0.05). Conclusion. The present
      study clearly shows that the use of LBNP could alleviate the bed rest-induced
      orthostatic intolerance.

PMID- 12428653
TI  - Pain into gain.

PMID- 12428654
TI  - Effects of exercise on gastric volume and pH in the proximal portion of the
      stomach of horses.
AB  - OBJECTIVE: To assess effects of exercise on a treadmill with changes in gastric
      volume and pH in the proximal portion of the stomach of horses. ANIMALS: 3
      healthy adult horses. PROCEDURE: A polyester bag of approximately 1,600 mL was
      placed into the proximal portion of the stomach of each horse via a nasogastric
      tube. Changes in bag volume, determined by an electronic barostat, were recorded
      before, during, and after a training session on a treadmill with and without
      prior withholding of food. In separate experiments, pH in the proximal portion of
      the stomach was continuously recorded during exercise for fed and food-withheld
      conditions. Finally, changes in intra-abdominal and intragastric pressure were
      simultaneously recorded during a training session. RESULTS: Bag volume rapidly
      decreased to nearly zero during trotting and galloping. Conversely, a return to
      walking resulted in a sharp increase in volume and a return to pre-exercise
      values. Intragastric and intra-abdominal pressures increased almost in parallel
      with walking, trotting, galloping, and galloping on a slope. Gastric pH decreased
      rapidly to < 4 at the beginning of walking, continued to decrease during trotting
      and galloping, and remained low until a return to walking. CONCLUSIONS AND
      CLINICAL RELEVANCE: Increased intra-abdominal pressure during intense exercise in
      horses causes gastric compression, pushing acidic contents into the proximal,
      squamous-lined region of the stomach. Increased duration of acid exposure
      directly related to daily duration of exercise may be the reason that squamous
      lesions tend to develop or worsen when horses are in intensive training programs.

PMID- 12428655
TI  - Effects of initial handling and training on autonomic nervous function in young
      Thoroughbreds.
AB  - OBJECTIVE: To determine the effects of initial handling and training on autonomic
      nervous functions in young Thoroughbreds. ANIMALS: 63 healthy Thoroughbreds.
      PROCEDURE: All horses were trained to be handled and initially ridden in
      September of the yearling year and then trained until the following April by
      conventional training regimens. To obtain the heart rate (HR), electrocardiograms
      were recorded in the stable before initial handling and training and following 7
      months of training; variations in HR were then evaluated from the power spectrum
      in terms of the low frequency (LF; 0.01 to 0.07 Hz) power and high frequency (HF;
      0.07 to 0.6 Hz) power as indices of autonomic nervous activity. To evaluate the
      fitness, the V200 (velocity at HR of 200 beat/min), which is reflective of the
      aerobic capacity of the horse, was measured. RESULTS: Mean (+/- SE) resting HR
      decreased significantly from 41.5 +/- 0.8 to 38.7 +/- 0.4 beat/min following 7
      months of training. The LF power of horses increased significantly from 1,037 +/-
      128 milliseconds2 in September of the yearling year to 2,944 +/- 223
      milliseconds2 in the following April. Similarly, the HF power increased
      significantly from 326 +/- 30 milliseconds2 to 576 +/- 39 milliseconds2 at the
      corresponding time points. The V200 increased significantly following training.
      CONCLUSIONS AND CLINICAL RELEVANCE: Increases in LF and HF powers indicate that
      parasympathetic nervous activity increases in horses by 7 months of training. The
      decrease in resting HR may be dependent on the training-induced increase of
      parasympathetic nervous activity in Thoroughbreds.

PMID- 12428656
TI  - Results of thyroid function tests and concentrations of plasma proteins in dogs
      administered etodolac.
AB  - OBJECTIVE: To determine the effects of etodolac administration on results of
      thyroid function tests and concentrations of plasma proteins in clinically normal
      dogs. ANIMALS: 19 healthy random-source mixed-breed dogs. PROCEDURE: Blood
      samples for measurement of serum thyroxine (T4), 3,5,3'-triiodothyronine (T3),
      free T4 (fT4), and endogenous canine thyroid stimulating hormone (cTSH) were
      measured twice before as well as on days 14 and 28 of etodolac administration
      (mean dosage, 13.7 mg/kg, PO, q 24 h). Plasma total protein, albumin, and
      globulin concentrations and serum osmolality were measured once before as well as
      on days 14 and 28 of etodolac administration. RESULTS: Etodolac administration
      did not significantly affect serum T4, T3, fT4, or cTSH concentrations or serum
      osmolality. Significant decreases in plasma total protein, albumin, and globulin
      concentrations were detected on days 14 and 28 of administration. CONCLUSIONS AND
      CLINICAL RELEVANCE: Results of thyroid function tests are not altered when
      etodolac is administered for up to 4 weeks. Therefore, interpretation of results
      of these tests should accurately reflect thyroid function during etodolac
      treatment. Plasma total protein, albumin, or globulin concentrations that are
      less than the respective reference range in a dog administered etodolac for > or
      = 2 weeks may be an effect of treatment rather than an unrelated disease process.
      A decrease in plasma protein concentrations may reflect subclinical injury of the
      gastrointestinal tract.

PMID- 12428657
TI  - In vitro investigation of the effects of cyclooxygenase-2 inhibitors on
      contractile activity of the equine dorsal and ventral colon.
AB  - OBJECTIVE: To evaluate the effect of 2 cyclooxygenase (COX)-2 inhibitors on
      contractile activity of the circular smooth muscle layer of the equine dorsal and
      ventral colon. SAMPLE POPULATION: Samples of the dorsal and ventral colon
      obtained from 10 healthy horses. PROCEDURE: Full-thickness tissue samples were
      collected from the dorsal colon in the area of the diaphragmatic flexure and the
      ventral colon in the area of the sternal flexure. Samples were cut into strips
      oriented along the fibers of the circular muscle layer and mounted in a tissue
      bath system for determination of contractile strength. Incremental amounts of
      etodolac, nabumetone, and indomethacin were added, and contractile activity was
      recorded. RESULTS: Response of the dorsal and ventral colon to nonsteroidal anti
      inflammatory drugs (NSAIDs) was variable. Indomethacin induced the greatest
      reduction in contractile activity, followed by nabumetone. For etodolac, the
      difference from baseline values was only significantly reduced at the highest
      concentration used (1 X 10(5)M) for the ventral colon. CONCLUSIONS AND CLINICAL
      RELEVANCE: The NSAIDs that are designed to target the COX-2 isoform appeared to
      have variable effects on the contractile activity of the equine dorsal and
      ventral colon. Etodolac appeared to have the least effect on contractile
      activity, compared with the effects attributable to nabumetone, and would
      potentially have the fewest adverse effects relative to motility of the dorsal
      and ventral colon.

PMID- 12428658
TI  - Effect of immunosuppressive doses of cyclosporine on pancreatic beta cell
      function in pigs.
AB  - OBJECTIVE: To evaluate whether immunosuppressive doses of cyclosporine (CsA) have
      an adverse effect on the liver, kidney, and pancreatic beta cells of pigs.
      ANIMALS: 8 juvenile 8-week-old Landrace X Large White crossbred pigs. PROCEDURE:
      CsA (100 to 140 mg/kg) was administered orally to euglycemic pigs to reach whole
      blood trough concentrations of approximately 1500 ng/mL. To determine pancreatic
      beta cell function, plasma C-peptide and insulin concentrations were measured in
      response to i.v. administration of glucose, glucagon, arginine, and oral
      administration of glucose. Effects on liver and kidney were determined by
      monitoring serum measurements of liver function and serum creatinine
      concentrations, respectively. RESULTS: Plasma concentrations of C-peptide were
      significantly lower in euglycemic CsA-treated pigs, compared with control pigs,
      following i.v. administration of glucose, glucagon, arginine, and oral
      administration of glucose. Furthermore, the glucose clearance rate was decreased
      in euglycemic CsA-treated pigs, compared with control pigs. Serum creatinine
      concentrations and 4 of 7 serum measurements of liver function were not adversely
      affected by CsA administration. Serum concentrations of bilirubin and albumin
      were significantly increased, and serum alanine aminotransferase activity was
      significantly decreased in CsA-treated pigs, compared with control pigs.
      Histologic evaluation of liver and kidney sections revealed no pathologic
      findings in CsA-treated or control pigs. CONCLUSIONS AND CLINICAL RELEVANCE: In
      our study, immunosuppressive doses of CsA caused an impairment of porcine
      pancreatic beta cell function, but did not have toxic effects on the kidney.
      However, on the basis of changes in serum bilirubin and albumin concentrations
      and alanine aminotransferase activity, subclinical toxic effects on the liver did
      occur when immunosuppressive doses of CsA were administered.

PMID- 12428659
TI  - Epidemiologic investigation of Mycobacterium bovis in a population of cats.
AB  - OBJECTIVE: To determine whether cats exposed at a residence were infected with
      Mycobacterium bovis, whether the tuberculin skin test can identify cats infected
      with M bovis, and whether an ELISA could identify tuberculosis-infected cats.
      ANIMALS: 20 domestic cats exposed to a cat with laboratory-confirmed disseminated
      M bovis infection. PROCEDURE: Cats were administered a tuberculin skin test and
      monitored for 72 hours. Blood and fecal samples were collected. Cats were then
      euthanatized, and postmortem examinations were performed. Tissues were examined
      grossly and histologically for signs of mycobacteriosis. Pooled tissue samples
      and fecal samples were submitted for mycobacterial culture. Blood samples were
      examined for evidence of tuberculosis by use of a comparative ELISA. RESULTS: 4
      cats had positive responses for the ELISA, and 2 cats had suspicious responses.
      All tuberculin skin tests yielded negative results. No gross or histologic
      lesions of tuberculosis were detected in any tissues, and mycobacteria were not
      isolated from tissues or feces obtained from the 20 cats. CONCLUSIONS AND
      CLINICAL RELEVANCE: All cats that had positive or suspicious responses for the
      ELISA were offspring of the cat with tuberculosis. Evidence of tuberculosis was
      not seen in other cats at the residence, the owner, or the attending
      veterinarian. The most likely source of tuberculosis for the infected cat was
      through the consumption of M bovis-infected wildlife carcasses or offal. Because
      M bovis is endemic in wildlife in northeastern Michigan, there is a risk of
      exposure to tuberculosis in companion animals, their owners, and attending
      veterinarians.

PMID- 12428660
TI  - Effects of an adenosine kinase inhibitor and an adenosine deaminase inhibitor on
      accumulation of extracellular adenosine by equine articular chondrocytes.
AB  - OBJECTIVE: To investigate accumulation of extracellular adenosine (ADO) by equine
      articular chondrocytes and to compare effects of adenosine kinase inhibition and
      adenosine deaminase inhibition on the amount of nitric oxide (NO) produced by
      lipopolysaccharide (LPS)-stimulated chondrocytes. SAMPLE POPULATION: Articular
      cartilage from metacarpophalangeal and metatarsophalangeal joints of 14 horses.
      PROCEDURE: Chondrocytes were cultured as monolayers, and cells were incubated
      with LPS, the adenosine kinase inhibitor 5'-iodotubercidin (ITU), or the
      adenosine deaminase inhibitor erythro-9-(2-hydroxy-3-nonyl)adenine hydrochloride
      (EHNA). Concentrations of ADO in cell supernatants were measured by use of
      reverse-phase high-performance liquid chromatography. Effect of inhibition of
      enzymatic metabolism of ADO on induced NO production was evaluated by exposing
      cells to a combination of LPS and ITU or LPS and EHNA. RESULTS: Articular
      chondrocytes accumulated extracellular ADO when exposed to LPS or ITU.
      Chondrocytes exposed to ITU accumulated ADO in a time-dependent manner.
      Unstimulated chondrocytes did not accumulate ADO. Similarly, EHNA alone did not
      produce detectable ADO concentrations; however, addition of EHNA and ITU resulted
      in a synergistic effect on accumulation of ADO. Lipopolysaccharide-induced NO
      production was more effectively suppressed by exposure to ITU than to EHNA
      CONCLUSIONS AND CLINICAL RELEVANCE: Equine articular chondrocytes release ADO in
      response to the proinflammatory stimulus of bacterial LPS. Inhibition of the
      metabolism of ADO increases accumulation of extracellular ADO. Autocrine release
      of ADO from chondrocytes may play a role in the cellular response to tissue
      damage in arthritic conditions, and pharmacologic modulation of these pathways in
      joints of arthritic horses could be a potential method of therapy.

PMID- 12428661
TI  - In vitro biomechanical study of rotational stabilizers of the canine elbow joint.
AB  - OBJECTIVE: To develop a model for measuring rotary stability of the canine elbow
      joint and to evaluate the relative contribution of the anconeal process (AN),
      lateral collateral ligament (LCL), and medial collateral ligament (MCL). SAMPLE
      POPULATION: 18 forelimbs from 12 canine cadavers. PROCEDURE: Forelimbs were
      allocated to 3 experimental groups (6 forelimbs/group). Each intact forelimb was
      placed in extension at an angle of 135 degrees and cycled 50 times from -16
      degrees (pronation) to +28 degrees (supination) in a continuous manner at 2.0 Hz.
      Cycling was repeated following sectioning of the structure of interest (group 1,
      AN; group 2, LCL; and group 3, MCL). Torque at -12 degrees (pronation) and +18
      degrees (supination) was measured for each intact and experimentally sectioned
      limb. A Student t test was performed to compare torque values obtained from
      intact verses experimentally sectioned limbs and for comparison with established
      criteria for differentiation of primary (> or = 33%), secondary (10 to 33%), and
      tertiary rotational stabilizers (< 10%). RESULTS: In pronation, the AN was the
      only primary stabilizer (65%). For supination, the LCL was a primary stabilizer
      (48%), AN was a secondary stabilizer (24%), and MCL was a tertiary stabilizer
      (7%). CONCLUSIONS AND CLINICAL RELEVANCE: With the elbow joint in extension at an
      angle of 135 degrees, the AN is a primary rotational stabilizer in pronation, and
      the LCL is a primary stabilizer in supination. Disruption of the AN or LCL may
      affect rotary range of motion or compromise stability of the elbow joint in dogs.

PMID- 12428662
TI  - In vivo effects of meloxicam and aspirin on blood, gastric mucosal, and synovial
      fluid prostanoid synthesis in dogs.
AB  - OBJECTIVE: To evaluate in vivo activity in dogs of meloxicam or aspirin,
      previously shown in vitro to be a selective cyclooxygenase-2 (COX-2) inhibitor
      (COX-1 sparing drug), or a nonselective COX inhibitor, respectively. ANIMALS: 12
      male dogs with unilateral osteoarthritis of the stifle joint. PROCEDURE: Each dog
      was treated in a crossover design with aspirin or meloxicam for 21 days.
      Prostaglandin E2 (PGE2) concentrations were measured at days 0 (baseline), 7, and
      21 of each treatment period in lipopolysaccharide (LPS)-stimulated blood,
      synovial fluid collected by arthrocentesis, and endoscopic gastric mucosal biopsy
      specimens. Thromboxane B2 (TXB2) was evaluated in blood on days 0, 7, and 21 of
      each treatment period. RESULTS: Aspirin administration significantly suppressed
      PGE2 concentrations in blood, gastric mucosa, synovial fluid, and suppressed TXB2
      concentration in blood at days 7 and 21. Meloxicam administration significantly
      suppressed PGE2 concentrations in blood and synovial fluid at days 7 and 21, but
      had no effect on concentrations of TXB2 in blood or PGE2 in gastric mucosa.
      Suppression of LPS-stimulated PGE2 concentrations in blood and synovial fluid by
      aspirin and meloxicam administration is consistent with activity against the COX
      2 isoenzyme. Suppression of concentrations of PGE2 in the gastric mucosa and TXB2
      in blood by aspirin administration is consistent with activity against COX-1.
      Meloxicam, in contrast, had a minimal effect on functions mediated by COX-1.
      CONCLUSIONS AND CLINICAL RELEVANCE: Meloxicam acts in vivo in dogs as a COX-1
      sparing drug on target tissues by sparing gastric PGE2 synthesis while retaining
      antiprostaglandin effects within inflamed joints.

PMID- 12428663
TI  - Safety and immunologic effects after inoculation of inactivated and combined live
      inactivated dermatophytosis vaccines in cats.
AB  - OBJECTIVE: To determine antidermatophyte immunologic effects of an experimental
      combined live-inactivated dermatophytosis vaccine (CLIDV) and a commercial
      inactivated dermatophytosis vaccine (IDV) in cats and to evaluate adverse effects
      associated with administration of these vaccines. ANIMALS: 20 healthy juvenile
      domestic shorthair cats. PROCEDURE: Cats were injected with 2 doses of CLIDV at
      the standard dosage or 1 dose of CLIDV at 10 times the standard dosage; IDV was
      administered at the manufacturer-recommended dosage. Cats were observed for
      illness and reactions at inoculation sites. Periodically, samples were obtained
      for fungal culture, lymphocyte blastogenesis test (LBT) as an indicator of cell
      mediated immunity against dermatophyte antigens, and antidermatophyte IgG titers.
      Following vaccination, cats were challenge-exposed by topical application of
      Microsporum canis macroconidia and examined weekly for clinical signs of
      dermatophytosis. RESULTS: of 10 cats given CLIDV developed focal crusts at the
      injection site that resolved without treatment; these were areas of dermatophyte
      infection with the vaccine strain. Antidermatophyte IgG titers increased
      significantly with all vaccination protocols. Cellular immunity against M canis
      increased slightly and variably during the vaccination period and did not differ
      significantly between vaccinated and control cats. All cats developed
      dermatophyte infection after challenge exposure. Vaccination with CLIDV or IDV
      was associated with slightly reduced severity of initial infection. CONCLUSIONS
      AND CLINICAL RELEVANCE: Noculation with IDV or CLIDV did not provide prophylactic
      immunity against topical challenge exposure with M canis. Inoculation with either
      vaccine did not provide a more rapid cure of an established infection.

PMID- 12428664
TI  - Scanning electron microscopy of vascular corrosion casts and histologic
      examination of pulmonary microvasculature in dogs with dirofilariosis.
AB  - OBJECTIVE: To characterize structural changes in pulmonary vessels of dogs with
      dirofilariosis. ANIMALS: 8 dogs with dirofilariosis and 2 unaffected control
      dogs. PROCEDURE: Pulmonary artery pressure was measured in affected dogs, and
      dogs then were euthanatized. Scanning electron microscopy was used to examine
      vascular corrosion casts of pulmonary vasculature. Tissue sections of pulmonary
      vasculature were evaluated by use of histologic examination. RESULTS: Pulmonary
      artery pressure was higher in dogs with severely affected pulmonary vessels. In
      tissue sections, dilatation, as well as lesions in the tunica intima and
      proliferative lesions resulting in constriction or obstruction, were frequently
      observed in branches of the pulmonary artery. Numerous dilated bronchial arteries
      were observed around affected pulmonary arteries. Hyperplastic venous sphincters
      were observed in small pulmonary veins and venules. In corrosion casts, affected
      pulmonary lobar arteries had dilatation, pruning, abnormal tapering,
      constriction, and obstruction. In small arteries and arterioles, surface
      structures representing aneurisms and edema were seen. Bronchial arteries were
      well developed and extremely dilated, and they formed numerous anastomoses with
      pulmonary arteries at all levels, from the pulmonary trunk to peripheral vessels.
      Capillaries in the lungs were dilated with little structural change. Small
      pulmonary veins and venules had irregular annular constrictions that were caused
      by hyperplastic smooth muscle cells of venous sphincters. CONCLUSIONS AND
      CLINICAL RELEVANCE: Scanning electron microscopy of microvascular casts
      delineated links between the bronchial and pulmonary circulations in dogs with
      dirofilariosis. Results of scanning electron microscopy provided a structural
      explanation for the development of pulmonary circulatory disturbances and
      pulmonary hypertension in dogs affected by dirofilariosis.

PMID- 12428665
TI  - Binding of radiolabeled porcine motilin and erythromycin lactobionate to smooth
      muscle membranes in various segments of the equine gastrointestinal tract.
AB  - OBJECTIVE: To identify and characterize motilin receptors in equine duodenum,
      jejunum, cecum, and large colon and to determine whether erythromycin
      lactobionate competes with porcine motilin for binding to these receptors. SAMPLE
      POPULATION: Specimens of various segments of the intestinal tracts of 4 adult
      horses euthanatized for reasons unrelated to gastrointestinal tract disease.
      PROCEDURE: Cellular membranes were prepared from smooth muscle tissues of the
      duodenum, jejunum, pelvic flexure, and cecum. Affinity and distribution of
      motilin binding on membrane preparations were determined by use of 125I-labeled
      synthetic porcine motilin. Displacement studies were used to investigate
      competition between 125I-labeled synthetic porcine motilin and erythromycin
      lactobionate for binding to motilin receptors in various segments of bowel.
      RESULTS: Affinity of 125I-labeled synthetic porcine motilin for the equine
      motilin receptor was estimated to be 6.1nM. A significantly higher number of
      motilin receptors was found in the duodenum than in the pelvic flexure and cecum.
      The jejunum had a significantly higher number of motilin receptors than the
      cecum. Erythromycin lactobionate displacement of 125I-labeled porcine motilin
      from the equine motilin receptor did not differ significantly among various
      segments of bowel. CONCLUSIONS AND CLINICAL RELEVANCE: Motilin receptors were
      found in the duodenum, jejunum, pelvic flexure, and cecum of horses. The highest
      number of motilin receptors was in the duodenum, and it decreased in more distal
      segments of bowel. Erythromycin lactobionate competed with motilin binding in the
      equine gastrointestinal tract. This suggests that 1 of the prokinetic actions of
      erythromycin in horses is likely to be secondary to binding on motilin receptors.

PMID- 12428666
TI  - Quantitative assessment of nociception in horses by use of the nociceptive
      withdrawal reflex evoked by transcutaneous electrical stimulation.
AB  - OBJECTIVES: To evoke and measure the nociceptive withdrawal reflex (NWR) by use
      of electromyographic recordings and to score the behavioral nociceptive responses
      to electrical pulses in standing nonsedated horses. ANIMALS: 10 adult horses.
      PROCEDURE: The lateral palmar digital nerve of the forelimb was transcutaneously
      stimulated, and surface electromyographic responses were recorded from the
      ulnaris lateralis, extensor carpi radialis, and common digital extensor muscles.
      Stimuli consisted of a 25-millisecond train of 5 constant-current pulses
      delivered by a computer-controlled stimulator. The 80- to 250-milliseconds
      poststimulation interval was analyzed to detect the NWR. The current intensity
      was increased in steps of 0.5 mA until the NWR threshold intensity (lt) was
      reached. The stimulus at It was repeated twice. Latency and amplitude of the NWR,
      together with the behavioral reaction of horses, were analyzed. The latter was
      scored according to a scale from 0 (no reaction) to 5 (vigorous reaction).
      Finally, 3 suprathreshold stimuli at 1.2 X It were analyzed. RESULTS: The median
      It to elicit NWR was 2.5 mA. Median onset latency of the NWR was 96.0
      milliseconds at It and 89.6 milliseconds for suprathreshold stimuli. The
      amplitude of the reflexes was higher for suprathreshold stimulations, and
      behavioral reactions were slightly stronger when stimulus intensity increased.
      CONCLUSIONS AND CLINICAL RELEVANCE: Results of our study indicate that it is
      possible to record NWR in conscious standing horses, to define a reflex
      threshold, and to measure reflexes in response to increasing stimulus intensity.

PMID- 12428667
TI  - Evaluation of intravenous administration of meloxicam for perioperative pain
      management following stifle joint surgery in dogs.
AB  - OBJECTIVE: To compare preoperative administration of meloxicam and butorphanol to
      perioperative administration of butorphanol alone for control of postoperative
      signs of pain in dogs. ANIMALS: 40 client-owned dogs scheduled for surgical
      repair of a cranial cruciate ligament rupture. PROCEDURE: Group-1 dogs received
      butorphanol (0.2 mg/kg, IV) and meloxicam (0.2 mg/kg, IV) just prior to surgery.
      Group-2 dogs received butorphanol just prior to surgery (0.2 mg/kg, IV) and at
      incision closure (0.1 mg/kg, IV). Pain assessment began 1 to 2 hours before
      surgery and from extubation until 24 hours after surgery by obtaining the
      following measurements: the visual analog scale (VAS) score, cumulative pain
      score (CPS), adjusted cumulative pain score, modified cumulative pain score, and
      the adjusted modified cumulative pain score (AMCPS). Serum cortisol concentration
      was measured between 12 to 24 and between 1 to 2 hours prior to surgery, and at
      30 minutes, and 1, 2, 4, 8, 18, and 24 hours after extubation. RESULTS: No
      significant differences between treatment groups were observed in CPS or VAS
      score. At 8, 9, 10, and 11 hours after extubation, meloxicam-butorphanol-treated
      dogs had a significantly lower AMCPS, compared with butorphanol-alone-treated
      dogs. Total serum cortisol concentration (area under the curve) during the
      measurement period was significantly lower in meloxicam-butorphanol-treated dogs,
      compared with butorphanol-alone treated dogs. CONCLUSIONS AND CLINICAL RELEVANCE:
      Preoperative single dose administration of meloxicam-butorphanol is equivalent to
      or slightly better than the administration of 2 perioperative doses of
      butorphanol for the control of postoperative signs of pain in dogs.

PMID- 12428668
TI  - Factors regulating collagen synthesis and degradation during second-intention
      healing of wounds in the thoracic region and the distal aspect of the forelimb of
      horses.
AB  - OBJECTIVE: To determine significant molecular and cellular factors responsible
      for differences in second-intention healing in thoracic and metacarpal wounds of
      horses. ANIMALS: 6 adult mixed-breed horses. PROCEDURE: A full-thickness skin
      wound on the metacarpus and another such wound on the pectoral region were
      created, photographed, and measured, and tissue was harvested from these sites
      weekly for 4 weeks. Gene expression of type-I collagen, transforming growth
      factor (TGF)-beta1, matrix metalloproteinase (MMP)-1, and tissue inhibitor of
      metalloproteinase (TIMP)-1 were determined by quantitative in situ hybridization.
      Myofibroblasts were detected by immunohistochemical labeling with alpha-smooth
      muscle actin (alpha-SMA). Collagen accumulation was detected by use of
      picrosirius red staining. Tissue morphology was examined by use of H&E staining.
      RESULTS: Unlike thoracic wounds, forelimb wounds enlarged during the first 2
      weeks. Myofibroblasts, detected by week 1, remained abundant with superior
      organization in thoracic wounds. Type-I collagen mRNA accumulated progressively
      in both wounds. More type-I collagen and TGF-beta1 mRNA were seen in forelimb
      wounds. Volume of MMP-1 mRNA decreased from day 0 in both wounds. By week 3, TIMP
      1 mRNA concentration was greater in thoracic wounds. CONCLUSIONS AND CLINICAL
      RELEVANCE: Greater collagen synthesis in metacarpal than thoracic wounds was
      documented by increased concentrations of myofibroblasts, type-I collagen
      mRNA,TGF-beta1 mRNA, and decreased collagen degradation (ie, MMP-1). Imbalanced
      collagen synthesis and degradation likely correlate with development of exuberant
      granulation tissue, delaying healing in wounds of the distal portions of the
      limbs. Factors that inhibit collagen synthesis or stimulate collagenase may
      provide treatment options for horses with exuberant granulation tissue.

PMID- 12428669
TI  - Effect of oxytocin treatment in sows on umbilical cord morphology, meconium
      staining, and neonatal mortality of piglets.
AB  - OBJECTIVE: To evaluate the effect of 2 oxytocin products administered to sows at
      the onset of fetal expulsion on the integrity of umbilical cords, meconium
      staining, and piglet mortality. ANIMALS: 2099 neonatal pigs. PROCEDURE: 180
      parturient sows were randomly assigned to 3 stratified groups of 60 sows each.
      Two groups of sows were injected IM at the onset of fetal expulsion with 1 of 2
      oxytocin commercial products (20, 40, or 50 U for sows weighing 120 to 150 kg,
      151 to 250 kg, or > or = 251 kg, respectively). Control sows were treated IM with
      saline (0.9% NaCI) solution. Farrowing time, expulsion intervals, and numbers of
      stillborn and liveborn piglets were recorded for each sow. Piglets were evaluated
      for inspiratory effort, heart rates, and degree of meconium staining of skin
      (nonstained, and moderately or severely stained). Umbilical cords were classified
      as normal in appearance, edematous, congested, hemorrhagic, or ruptured. RESULTS:
      Oxytocin-treated sows had a significant decrease in farrowing time and expulsion
      intervals and also had a significantly higher number of stillborn piglets per
      litter, compared with control sows. The number of piglets per litter with
      ruptured and hemorrhagic umbilical cords was significantly greater in oxytocin
      treated sows, compared with control sows. In near-death stillborn piglets,
      oxytocin treatment significantly decreased inspiratory efforts at birth and
      increased the rate and severity of meconium staining, compared with saline
      treatment. CONCLUSIONS AND CLINICAL RELEVANCE: Oxytocin given to sows at the
      onset of fetal expulsion significantly increases the rate of fetal distress,
      anoxia, and intrapartum death in piglets.

PMID- 12428670
TI  - Distribution of viral antigen and development of lesions after experimental
      infection with highly virulent bovine viral diarrhea virus type 2 in calves.
AB  - OBJECTIVE: To correlate tissue distribution with development of lesions after
      experimental infection with a virulent strain of noncytopathic bovine viral
      diarrhea virus (BVDV) type 2 in calves. ANIMALS: Ten 14-day-old and two 2-month
      old colostrum-deprived calves. PROCEDURE: Calves were intranasally inoculated
      with BVDV type-2 strain 1373 from an outbreak of clinically severe bovine viral
      diarrhea (BVD). Two 14-day-old calves served as noninfected controls. Two calves
      each were euthanatized on postinoculation days 3, 6, and 12, and 1 each on days
      8, 9, 13, and 14. Tissues were collected for immunohistologic and histologic
      examination. RESULTS: Inoculated calves developed nonspecific clinical signs
      characterized by high fever and decreased numbers of leukocytes and thrombocytes.
      Viral antigen was detected focally in lymphoid tissues on day 3. On days 6, 8, 9,
      12, and 14, viral antigen became increasingly widespread throughout organs and
      tissues. Viral antigen in lymphoid tissues was associated with severe depletion
      of all compartments. Lesions in other tissues were not well correlated with
      distribution of viral antigen. Depletion of lymphoid tissues was observed in a
      calf on day 13, but viral antigen had been cleared from most tissues and was
      detected in vascular walls only. CONCLUSIONS AND CLINICAL RELEVANCE: Infection
      with a virulent BVDV strain resulted in wide dissemination of viral antigen in
      host tissues. Severe lymphoid depletion developed in lymphoid tissues, whereas
      viral antigen was generally not associated with lesions in other tissues.
      Findings suggest that development of lesions in acute BVD is not solely a
      function of viral replication and is also attributable to host reaction to
      infection.

PMID- 12428672
TI  - Aldose reductase activity and glucose-related opacities in incubated lenses from
      dogs and cats.
AB  - OBJECTIVE: To determine responses of canine and feline lenses to incubation in a
      medium with a high glucose concentration. SAMPLE POPULATION: Lenses from 35 dogs
      and 26 cats. PROCEDURE: Glucose concentrations were measured in paired lenses
      from 25 dogs and 17 cats after incubation for 14 days in high-glucose (30 mmol of
      glucose/L) or control (6 mmol of glucose/L) medium. Aldose reductase activity was
      measured spectrophotometrically in the incubated lenses and in freshly frozen
      lenses from 10 dogs and 9 cats. Two lenses of each group were studied
      histologically. RESULTS: Canine and feline lenses in high-glucose medium
      developed glucose-specific opacities of variable localization and extent. Canine
      lenses developed equatorial vacuoles, but severity of the lesions was not
      associated with the age of the dog. Lenses from young cats (< or = 4 years old)
      developed extensive posterior cortical opacities, whereas those from older cats
      (> 4 years old) did not. Glucose concentrations were similar in all lenses
      incubated in high-glucose medium; however aldose reductase activity was
      significantly lower in lenses from older cats, compared with lenses from young
      cats and from dogs. CONCLUSIONS AND CLINICAL RELEVANCE: High aldose reductase
      activity and glucose-related opacities suggest a central role for this enzyme in
      the pathogenesis of diabetic cataracts in dogs and cats. Because onset of
      diabetes mellitus usually occurs in cats > 7 years of age, low activity of aldose
      reductase in lenses of older cats may explain why diabetic cataracts are rare in
      this species despite hyperglycemia.

PMID- 12428671
TI  - Purification and partial characterization of canine pepsinogen A and B.
AB  - OBJECTIVE: To purify and partially characterize various isoforms of canine
      pepsinogen (PG) from gastric mucosa. SAMPLE POPULATION: Stomachs obtained from 6
      euthanatized dogs. PROCEDURE: Mucosa was scraped from canine stomachs, and a
      crude mucosal extract was prepared and further purified by use of weak anion
      exchange chromatography, hydroxyapatite chromatography, size-exclusion
      chromatography, and strong anion-exchange chromatography. Pepsinogens were
      characterized by estimation of molecular weights, estimation of their isoelectric
      points (IEPs), and N-terminal amino acid sequencing. RESULTS: Two different
      groups of canine PG were identified after the final strong anion-exchange
      chromatography: PG A and PG B. Pepsinogens differed in their molecular weights
      and IER Pepsinogen B appeared to be a dimer with a molecular weight of
      approximately 34,100 and an IEP of 4.9. Pepsinogen A separated into several
      isoforms. Molecular weights for the various isoforms of PG A ranged from 34,200
      to 42,100, and their IEPs ranged from 4.0 to < 3.0. The N-terminal amino acid
      sequence for the first 25 amino acid residues for PG A and B had good homology
      with the amino acid sequences for these proteins in other species. CONCLUSIONS
      AND CLINICAL RELEVANCE: Canine PG B and several isoforms of canine PG A have been
      purified. Availability of these PGs will facilitate development of immunoassays
      to measure PG in canine serum as a potential diagnostic marker for gastric
      disorders in dogs.

PMID- 12428673
TI  - Comparison of serologic tests for detection of Brucella infections in cattle and
      water buffalo (Bubalus bubalis).
AB  - OBJECTIVE: To estimate sensitivity and specificity of 4 commonly used brucellosis
      screening tests in cattle and domestic water buffalo of Trinidad, and to compare
      test parameter estimates between cattle and water buffalo. ANIMALS: 391 cattle
      and 381 water buffalo. PROCEDURE: 4 Brucella-infected herds (2 cattle and 2 water
      buffalo) and 4 herds (2 of each species) considered to be brucellosis-free were
      selected. A minimum of 100 animals, or all animals > 1 year of age, were tested
      from each herd. Serum samples were evaluated for Brucella-specific antibodies by
      use of standard plate agglutination test (SPAT), card test (CT), buffered plate
      agglutination test (BPAT), and standard tube agglutination test (STAT). A
      Bayesian approach was used to estimate sensitivity and specificity of diagnostic
      tests without the use of a gold standard, assuming conditional independence of
      tests. RESULTS: Sensitivity and specificity estimates in cattle, respectively,
      were SPAT, 66.7 and 98.9; CT, 72.7 and 99.6; BPAT, 88.1 and 98.1; and STAT, 80.2
      and 99.3. Corresponding test estimates in water buffalo, respectively, were SPAT,
      51.4 and 99.3; CT, 90.4 and 99.4; BPAT, 96.3 and 90.7; and STAT, 75.0 and 98.8.
      Sensitivity of the CT and specificity of the BPAT were different between cattle
      and water buffalo with at least 95% probability. CONCLUSIONS AND CLINICAL
      RELEVANCE: Brucellosis serologic test performance varied by species tested, but
      BPAT had the highest sensitivity for screening cattle and water buffalo.
      Sensitivity and specificity of more than 2 screening tests can be estimated
      simultaneously without a gold standard by use of Bayesian techniques.

PMID- 12428675
TI  - Arachidonic acid-derived oxidation products initiate apoptosis in vascular smooth
      muscle cells.
AB  - The mechanism of arachidonic acid (AA)-induced apoptosis in vascular smooth
      muscle cells (VSMCs) was studied in the A-10 rat aortic smooth muscle cell line.
      Treatment of serum-deprived VSMCs with 50 microM AA for 24 h resulted in a loss
      of cell viability. The apoptotic effect of AA was characterized by annexin V
      binding, sub-G1 population of cells, cell shrinkage and chromatin condensation.
      AA-induced VSMC death was attenuated by antioxidants alpha-tocopherol and
      glutathione, the hydrogen peroxide (H2O2) scavenger catalase and by serum
      proteins, albumin and gamma globulins. Moreover, the AA peroxidation products,
      12(S)-hydroperoxyeicosatetraenoic acid (HPETE), 15(S)-HPETE, 4-hydroxy-2-nonenal
      (HNE) and malondialdehyde (MDA) caused VSMC apoptosis. These data suggest an
      oxidative mechanism of AA-induced VSMC death. The apoptotic effect of AA was pH
      dependent, being inhibited by extracellular alkalinization to pH 8.0. AA
      inhibited serum-stimulated cell cycle progression in quiescent cells, but not in
      proliferating cells. In conclusion, AA, through its oxidation products causes
      VSMC apoptosis. Antioxidants, by inhibiting VSMC apoptosis, may prevent
      consequent pathological events such as atherosclerotic plaque rupture.

PMID- 12428676
TI  - Sequence analysis, frequency and ethnic distribution of VNTR polymorphism in the
      5'-untranslated region of the human prostacyclin synthase gene (CYP8A1).
AB  - The prostacyclin synthase enzyme (CYP8A1, EC 5.3.99.4) is the unique member of
      family 8 in the cytochrome P450 superfamily. Inheritable interindividual
      differences in prostacyclin production may be implicated in the pathogenesis of
      human vascular diseases. Recently, we functionally characterized a variable
      number of tandem repeat (VNTR) polymorphism in the 5'-proximal regulatory region
      of CYP8A1. In this study, we extended the CYP8A1 VNTR polymorphism analysis using
      a panel of DNA samples from distinct ethnic populations: Tunisians, Gaboneses and
      French Caucasians. A total of nine VNTR were detected, three of which represent
      new variants in the CYP8A1 promoter region. Differences among the three ethnic
      panels in the frequency of the VNTR variants were observed. This study represents
      the first multi-population-based analysis of the frequency and distribution of
      VNTR polymorphism affecting the CYP8A1 promoter.

PMID- 12428674
TI  - Pro-inflammatory effect of freshly solubilized beta-amyloid peptides in the
      brain.
AB  - It has recently been shown that the level of soluble beta-amyloid (Abeta)
      peptides correlates well with the severity of synaptic loss and the density of
      neurofibrillary tangles observed in Alzheimer's disease (AD) brain. However, the
      biological activity of soluble forms of Abeta peptides in the brain remains to be
      determined. We have investigated ex vivo the effect of freshly solubilized Abeta1
      40 peptides (fsAbeta) on prostaglandin E2 (PGE2) production in rat brain slices.
      PGE2 levels increased rapidly following treatment with fsAbeta, an effect that
      was prevented by SB202190, a selective inhibitor of p38 mitogen-activated protein
      kinase (p38 MAPK), and by NS-398, which preferentially inhibits cyclooxygenase-2
      (COX-2) compared to COX-1. In an attempt to determine the cellular systems of the
      brain responsible for prostaglandin production in response to fsAbeta, the effect
      of fsAbeta was tested on isolated brain microvessels, primary cultures of brain
      smooth muscle cells/pericytes and endothelial cells, and a human neuron-like cell
      line (IMR32). Our data show that fsAbeta ex vivo can stimulate prostaglandin
      accumulation in incubates of isolated rat brain microvessels. In addition,
      fsAbeta appears to cause a concentration-dependent enhancement of prostaglandin
      accumulation in primary cultures of brain microvessel-derived smooth muscle
      cells/pericytes but not of brain endothelial cells. Finally, fsAbeta also
      stimulated PGF2alpha accumulation in cultures of differentiated IMR32 cells, but
      to a lesser extent than in brain smooth muscle cell/pericyte cultures. Deposition
      of aggregated forms of Abeta in the brain has been thought to trigger an
      inflammatory response which accompanies the neuropathologic events of AD. Our
      data provide evidence that fsAbeta triggers a pro-inflammatory reaction in rat
      brain, and suggest that the cerebrovasculature may constitute an important source
      of pro-inflammatory eicosanoids.

PMID- 12428677
TI  - Role of contaminating platelets in thromboxane synthesis in primary cultures of
      human umbilical vein endothelial cells.
AB  - Previous studies suggested that cultured human endothelial cells metabolize
      arachidonic acid to thromboxane A2. When primary cultures of human umbilical vein
      endothelial cells were incubated with 14C-arachidonic acid and the 14C
      metabolites resolved by reverse phase high pressure liquid chromatography,
      radioactive products were observed that comigrated with 6-keto-prostaglandin
      F1alpha and thromboxane B2, the degradation products of prostacyclin and
      thromboxane A2, respectively. Since platelets synthesize thromboxane A2, the
      present study examined the hypothesis that adherent platelets may contaminate the
      primary cultures of human umbilical vein endothelial cells and be responsible for
      thromboxane B2 production. Confluent primary cultures or passaged cells were
      stimulated with histamine (10(-5) M). Incubation buffer was analyzed by specific
      radioimmunoassays for 6-keto-prostaglandin F1alpha and thromboxane B2. The
      production of thromboxane B2 decreased in the passaged cells (207 +/- 44 pg/ml
      versus 65 +/- 12 pg/ml; primary versus passaged cells). A moderate decrease in
      the yield of 6-keto-prostaglandin F1alpha was measured in the passaged cells
      compared to the primary cultures (3159 +/- 356 pg/ml versus 1678 +/- 224 pg/ml,
      primary versus passaged cells). If the primary cultures were incubated with human
      platelet-rich plasma for 30 min prior to stimulation with histamine, the amount
      of thromboxane B2 increased approximately 10-fold. In an additional experiment,
      sub-confluent primary cells were incubated with platelet-rich plasma for 30 min,
      washed to remove non-adherent platelets, and allowed to reach confluency.
      Confluent cells were then passaged and stimulated with histamine. The amount of
      thromboxane B2 was not significantly different from that obtained with passaged
      cells that had not been incubated with platelet-rich plasma during the primary
      culture (83 +/- 15 pg/ml versus 65 +/- 12 pg/ml, respectively). If the
      cyclooxygenase inhibitor indomethacin was included in the incubations, the
      amounts of both thromboxane B2 and 6-keto-prostaglandin F1alpha decreased. In
      contrast, the thromboxane A2 synthase inhibitor dazoxiben blocked thromboxane
      production and had no effect on the amount of 6-keto-prostaglandin F1alpha. Light
      microscopy revealed the presence of adherent platelets in primary cultures with
      and without platelet-rich plasma but no platelets were observed in any group of
      passaged cells. Histofluorescence for platelet serotonin indicated the presence
      of platelets only in primary cultures of human umbilical vein endothelial cells
      or in cultures pre-incubated with platelet-rich plasma. These studies suggest
      that primary cultures of human umbilical vein endothelial cells contain adherent
      platelets that contribute to thromboxane synthesis.

PMID- 12428678
TI  - 8-iso-prostaglandin F2alpha as a marker of tissue oxidative damage in bovine
      retained placenta.
AB  - Retention of foetal membranes (RFM) in cows is supposed to be associated with the
      imbalance between production and neutralisation of reactive oxygen species (ROS).
      The consequence of uncontrolled ROS increase is oxidative damage to tissues,
      cells, and macromolecules. 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha) is
      considered as a marker of oxidative tissue damage. The aim of the study was to
      investigate whether the concentrations of 8-iso-PGF2alpha, in caruncles and
      cotyledons from the bovine placenta differ between retained and properly released
      foetal membranes. Placentomes were collected immediately after either spontaneous
      delivery at term via the vagina or caesarean section before as well as at term
      through the incision and divided into six groups consisting of eight cows each as
      follows: A-preterm caesarean section without RFM, B-preterm caesarean section
      with RFM, C-term caesarean section without RFM, D-term caesarean section with
      RFM, E-term spontaneous delivery without RFM, F-term spontaneous delivery with
      RFM. The concentrations of free and total 8-iso-PGF2alpha, were determined in
      caruncles as well as cotyledons by enzyme immunoassay and expressed in picogram
      per gram of wet weight of tissue. The concentrations of free and total 8-iso
      PGF2alpha were lower (P < 0.05) in cotyledons than in caruncles in all groups
      examined, as well as they were higher (P < 0.05) in retained than in released
      placenta. The concentrations of both parameters were lower (P < 0.05) in term
      spontaneous delivery groups than in term caesarean section groups. The results
      indicate that oxidative tissue damage, which may be the result of ROS imbalance,
      appears during RFM. However, the dynamics of this damage requires further
      elucidation.

PMID- 12428679
TI  - Differential regulation of prostacyclin and thromboxane by dexamethasone and
      celecoxib during oxidative stress in newborn rabbits.
AB  - To compare the effects of dexamethasone (Dex) and celecoxib (Cel) on F
      isoprostane, prostacyclin (PGI2), and thromboxane A2 (TxA2) following hyperoxia,
      and hyperoxia followed by recovery in room air (RA), newborn rabbits were exposed
      to hyperoxia (80-100% oxygen) for 4 days, during which they were treated with
      saline (Sal, i.m.), Dex (i.m.), vehicle (Veh, PO), or Cel (PO, n = 12 per group).
      Six animals in each group were sacrificed immediately following hyperoxia, and
      the remainder allowed to recover in RA for 5 days. The control litters were
      treated simultaneously in RA with all conditions other than atmospheric oxygen
      being identical. Blood samples were assayed for 8-epi-prostaglandin F2alpha (8
      epi-PGF2alpha), 6-keto prostaglandin F1alpha (6-ketoPGF1alpha), and TxB2. Dex and
      Cel decreased 8-epi-PGF2alpha during hyperoxia and the recovery period. Dex
      increased 6-ketoPGF2alpha following hyperoxia, while similar increments were
      noted during recovery with Cel. Although TxB2 was decreased only during the
      recovery period, TxB2/6-ketoPGF1alpha ratio was lower during hyperoxia and
      recovery in both treated groups. The effect of Cel on 8-epi-PGF2. and TxA2/PGI2
      ratio confirm the formation of a COX-derived F2-isoprostane that is possibly
      linked to TxA2 receptors. Further studies are required to examine whether Cel can
      be used as a therapeutic alternative to Dex for oxygen-induced injury in the
      newborn.

PMID- 12428680
TI  - Desensitization of the mouse thromboxane A2 receptor (TP) by G protein-coupled
      receptor kinases (Grks).
AB  - GRKs play a key role in regulating G protein-coupled receptor (GPCR)
      responsiveness. To investigate the role of GRKs in desensitization of TP, we
      replaced threonines with favorable phosphorylation motifs for GRKs (positions 226
      and 230) with alanine. Mutant and wild-type receptors were expressed in cell
      culture models and clones expressing similar numbers of receptors were studied.
      We found that: (1) affinity and specificity of thromboxane A2 (TxA2) binding to
      mutant TP were identical to the wild-type, (2) replacement of threonines 226 and
      230 with alanines delayed the onset of agonist-induced desensitization, and (3)
      inhibition of endogenous GRK activity with a dominant-negative construct
      inhibited agonist-induced phosphorylation and enhanced responsiveness of wild
      type TP but had little effect on responsiveness of the receptor mutant. These
      data are consistent with the notion that GRKs contribute to desensitization of
      TP.

PMID- 12428681
TI  - Occupation of the prostaglandin E2-type 1 receptor increases rat atrial
      contractility via a Y-27632-sensitive pathway.
AB  - This study investigated whether rat left atria (LA) contain the prostaglandin E2
      type 1 receptor (EP1) and whether EP1 occupation induces positive inotropic
      responses in superfused LA. Western analysis demonstrated that LA contain EP1 and
      the EP1 splice variant. Exposing isolated, superfused LA to 17-phenyl trinor
      PGE2, an EP1 agonist, increased isometric contractile force and its corresponding
      dF/dTs to approximately 70% of the isoproterenol maximum with an EC50 of
      approximately 80 nM. In contrast, agonists for EP2, EP3, and EP4 caused little
      change in LA function. While the EP1 antagonists SC-51089 and SC-19220 blocked 17
      phenyl trinor PGE2-induced inotropy, neither prazosin, nadolol, atropine nor EI
      283, a pan-specific protein kinase C inhibitor, affected 17-phenyl trinor PGE2
      induced inotropy. However, Y-27632 and HA-1077, inhibitors of rho A-activated
      protein kinases, prevented and reversed the increase in LA contractility that
      occurred in the presence of 17-phenyl trinor PGE2. Thus, atria contain EP1 and
      EP1 occupation increases LA contractility via a pathway sensitive to inhibitors
      of rho A-activated protein kinases.

PMID- 12428682
TI  - Reduction in the extent of atherosclerosis in apolipoprotein E-deficient mice
      induced by electroporation-mediated transfer of the human plasma platelet
      activating factor acetylhydrolase gene into skeletal muscle.
AB  - The effect of increasing the activity of plasma platelet-activating factor (PAF)
      acetylhydrolase (AH) (PAF-AH) on the progression of atherosclerosis in
      apolipoprotein E-deficient (apoE(-/-)) mice was examined by gene delivery to
      skeletal muscle. The expression vector pcDNA3.1 containing either human PAF-AH
      cDNA (pcDNA/PAF-AH) or green fluorescent protein cDNA (pcDNA/GFP) was introduced
      into the skeletal muscle of both hind legs of 6-week-old apoE(-/-) mice by
      electroporation. The activity of PAH-AH in plasma was significantly increased 4
      16 weeks after electroporation of apoE(-/-) mice with 120 microg of pcDNA/PAF-AH;
      the maximal (2.5-fold) increase was apparent after 8 weeks. The mean thickness of
      the aortic wall, determined by 160 measurements in each mouse, was significantly
      reduced in apoE(-/-) mice 8-16 weeks after exposure to pcDNA/PAF-AH compared with
      that in corresponding control animals that received pcDNA/GFP. These results
      suggest that the electrotransfer of the plasma PAF-AH gene to skeletal muscle
      reduces the extent of atherosclerosis in apoE(-/-) mice.

PMID- 12428683
TI  - Oxytocin induces PGE2 release from bovine cervical mucosa in vivo.
AB  - Oxytocin receptor (OTR) concentrations in bovine cervical mucosa rise steeply a
      few days before estrus to high concentrations and fall rapidly after estrus. To
      study the physiological role of these OTR, the effect of OT on the release of
      PGE, from the cervical mucosa of periestrous cows in vivo was determined by
      inserting bags made of dialysis tubing containing isooncotic saline solution in
      the endocervix for two 2-h periods, a fresh bag for each period. During the first
      period no treatment was given, during the second period OT (100 IU) or saline was
      injected i.m. PGE2 content in the second bag was significantly greater in OT
      treated cows than in saline-treated cows. In a second experiment cervical
      resistance to stretch, achieved by distention of a balloon inside the cervical
      canal, was measured in periestrous cows before and 10 h after i.m. injection of
      OT, or endocervical application of 2.5mg PGE1 in a jelly, or the inactive jelly.
      A significant reduction in the resistance was achieved with both OT and PGE1; in
      the doses given the effect of PGE1 was longer lasting than that of OT.

PMID- 12428684
TI  - Selenium deficiency alters the formation of eicosanoids and signal transduction
      in rat lymphocytes.
AB  - Previous reports have shown that selenium (Se) nutrition alters the lipoxygenase
      pathway and mitogenic responses in bovine lymphocytes. In order to further
      understand how Se may alter lymphocyte function, we examined the effects of Se
      nutrition on arachidonic acid (AA) metabolism and phospholipase D (PLD)
      activation. Lymphocytes were isolated from the lymph nodes of rats fed either Se
      deficient diet (-Se) or Se-supplemented diet (+Se) for 12 weeks. Our results
      revealed that calcium ionophore A23187-stimulated lymphocytes derived from -Se
      rats produced significantly less prostaglandins (PGs) than those obtained from
      +Se rats. Phospholipase D (PLD) activation by 12-O-tetradecanoylphorbol-13
      acetate (TPA) was significantly lower in lymphocytes obtained from -Se rats when
      compared to cells from +Se rats. Furthermore, the addition of PGE2, PGD2 or
      PGF2alpha to suspended lymphocytes from -Se rats significantly enhanced PLD
      activity. The effects of TPA and PGE2 on PLD activation were additive. However,
      the addition of PGE2 abolished the significant difference in PLD activation
      between -Se and +Se cells observed in response to TPA alone. Based on these
      results, we postulate that dietary Se status plays an important role in the
      regulation of AA metabolism that subsequently affects PLD activation.

PMID- 12428685
TI  - Treatment with prostaglandin F2alpha increases expression of prostaglandin
      synthase-2 in the rat corpus luteum.
AB  - Recent studies indicate that the corpus luteum (CL) may be a source of
      prostaglandin F2alpha (PGF2alpha) for regression. We investigated expression of
      mRNA and protein for prostaglandin G/H synthase (PGHS) in the CL of immature
      superovulated rats following administration of PGF2alpha. We observed an increase
      in mRNA for PGHS-2, the induced isoform, at 1 h and protein at 8 and 24 h after
      treatment. One hour after PGF2alpha, there was also a progressive decrease in
      plasma progesterone concentration. There were no changes, however, in expression
      of PGHS-1, the constitutive isoform, over the 24 h sampling period. These results
      indicate that PGHS-2 increases following PGF2alpha treatment and that expression
      of this enzyme in the rat CL may contribute to the luteolytic mechanism.

PMID- 12428686
TI  - Renal pathology resulting from PGHS-2 gene ablation in DBA/B6 mice.
AB  - Kidneys of prostaglandin H synthase-2 (PGHS-2) null mice fail to develop
      normally, leading to renal insufficiency. We have found that in a mixed DBA/B6
      background, the lack of a functional PGHS-2 gene causes less severe renal
      pathology than was reported previously for PGHS-2 null mice in a B6 genetic
      background. The increase in blood urea nitrogen in the DBA/B6 strain of PGHS-2
      null mice was significantly lower than reported for B6 PGHS-2 null mice (200%
      versus 270%). Cystic changes in DBA/B6 PGHS-2 null mice were also less severe.
      The DBA/B6 PGHS-2 null adult mice did not die from renal failure, unlike their
      B6/PGHS-2 counterparts that showed excessive neonatal and adult deaths.
      Therefore, DBA/B6 PGHS-2 null may be highly suitable to study the functional
      consequences of the lack of PGHS-2 in the kidney due to their less severe
      pathology and greater survival.

PMID- 12428687
TI  - Induction of apoptosis dependent on caspase activities and growth arrest in HL-60
      cells by PGA2.
AB  - Prostaglandin (PG) A2 has been reported to inhibit the growth or induce apoptosis
      of various tumor cells. In the present study, PGA2 inhibited the growth of HL-60
      cells and concomitantly-induced nuclear condensation and DNA fragmentation,
      characteristics of apoptosis. Down-regulation of c-myc mRNA, and activation of
      caspase-3 were observed in the PGA2 -treated cells. PGA2-induced DNA
      fragmentation was completely abolished in the presence of zVAD-Fmk or zDEVD-Fmk.
      But, relative cell survival was not improved up to that of untreated cells by
      pretreatment of caspase inhibitors, and c-myc down-regulation was not recovered
      by caspase inhibitors, either. Moreover, cytochrome c release and activation of
      caspase-9 was also observed in apoptotic cells and a specific inhibitor of
      caspase-9 (zLEHD-Fmk) prevented both DNA fragmentation and activation of caspase
      3, but not relative cell survival, implying the upstream mitochondrial event of
      caspase-3 activation. In addition, antagonistic Fas antibody (ZB4) exerted no
      effect on the apoptosis. Taken together, these results suggest that PGA2 may
      induce the apoptosis as well as growth inhibition in HL-60 cells, and cytochrome
      c release and caspase activation seem to play a critical role in this apoptosis
      which might be independent or downstream of growth inhibition associated with c
      myc down-regulation.

PMID- 12428688
TI  - The prostaglandin E agonist, misoprostol, inhibits airway IL-5 production in
      atopic asthmatics.
AB  - BACKGROUND: Prostaglandin E2 is a potent immunomodulator that inhibits the early
      and late bronchoconstriction to inhaled allergen, as well as inhibiting the acute
      allergen-induced release of mediators into the human airway. To determine if the
      stable prostaglandin E agonist misoprostol could alter the late allergic
      formation of mediators we measured the appearance of eosinophils and key
      cytokines in the bronchoalveolar lavage fluid 24 h after allergen instillation.
      METHODS: Six atopic asthmatics underwent bronchoscopy, alveolar lavage and
      antigen instillation followed 24 h later by bronchoalveolar lavage. Eosinophil
      counts were done, together with measurements of IL-4, IL-5, eotaxin, RANTES and
      cysteinyl leukotrienes by immunoassay. The study was done in randomized blinded
      fashion while the volunteers took placebo or 600 microg of misoprostol four times
      a day (QID). RESULTS: Misoprostol significantly decreased the appearance of IL-5
      late after allergen challenge. Eotaxin levels were reduced, but not statistically
      significantly. Eosinophil number, RANTES, eosinophil cationic protein and
      cysteinyl leukotrienes were not altered by misoprostol. CONCLUSIONS: Misoprostol
      reduces the formation of IL-5 late after allergen challenge, perhaps by
      inhibiting eosinophil, mast cell, and/or T lymphocyte production of IL-5. Despite
      decreases in IL-5 and eotaxin, eosinophils were recruited and activated by
      allergen.

PMID- 12428689
TI  - Effect of mifepristone on pregnancy, pregnancy-specific protein B (PSPB),
      progesterone, estradiol-17beta, prostaglandin F2alpha (PGF2alpha) and
      prostaglandin E (PGE) in ovariectomized 90-day pregnant ewes.
AB  - The objective of this experiment was to determine the effect of mifepristone, a
      progesterone receptor antagonist, on pregnancy and secretion of steroids,
      pregnancy-specific protein B (PSPB) and prostaglandins at mid-pregnancy in ewes.
      Ninety-day pregnant ewes were ovariectomized (OVX) and treatments were initiated
      72 h post-OVX. Ewes received (1) vehicle, (2) prostaglandin F2alpha (PGF2alpha, 8
      mg/58 kg/bw, i.m.) 84 h post-OVX, (3) mifepristone (50 mg intrajugular at 72, 84,
      96, and 108 h post-OVX), (4) mifepristone (50mg) + PGF2alpha, (5) mifepristone
      (100 mg intrajugular at 72, 84, 96, and 108 h), and (6) mifepristone (100 mg) +
      PGF2alpha. Ewes treated with vehicle or PGF2alpha alone did not abort (P > or =
      0.05). But, 60, 80, 60, and 100% of ewes treated with mifepristone (50 mg),
      mifepristone (50 mg) + PGF2alpha, mifepristone (100 mg), and mifepristone (100
      mg) + PGF2alpha, respectively, aborted (P < or = 0.05). Profiles of progesterone,
      estradiol-17beta, prostaglandin E (PGE), or PSPB did not differ (P > or = 0.05)
      among treatment groups. Profiles of PGF2alpha of treatment groups receiving
      mifepristone with or without PGF2alpha differed (P < 0.05) from vehicle or
      PGF2alpha alone-treated ewes. It is concluded that progesterone actions are
      necessary to suppress uterine/placental secretion of PGF2alpha and that
      maintenance of critical progesterone: estradiol-17beta and PGE:PGF2alpha ratios
      are necessary for maintenance of pregnancy.

PMID- 12428690
TI  - Synthesis of platelet-activating factor (PAF) in transformed cell lines of a
      different origin.
AB  - Interest in the possible involvement of the platelet-activating factor (PAF) in
      tumor growth and invasiveness has been stimulated by the recognition that PAF
      influences various biological responses relevant to metastatic diffusion, such as
      angiogenesis, adhesiveness to endothelia and cellular motility. In the present
      study, we investigated the extent to which PAF is synthesized by a series of
      human and murine transformed cell lines of a different histotype. Synthesis of
      PAF was studied by combining the 14C-acetate incorporation into PAF with the
      quantitative analysis of PAF performed by a procedure based on gas chromatography
      mass spectrometry with a negative ion chemical ionization. In the presence of the
      Ca2+ ionophore A23187, cultures of human melanoma (Hs294T), fibrosarcoma (HT1080)
      and colon carcinoma (LS180) cell lines synthesized conspicuous amounts of PAF,
      comparable to those produced by resident peritoneal macrophages. Substantial
      quantities of PAF were also synthesized by the murine melanoma (F10-M3 cells).
      PAF synthesis was rather limited in RSV-transformed Balb/c3T3 (B77-3T3) cells and
      in one of their high metastatic variants (B77-AA6 cells), although it was more
      abundant in the latter. We also investigated whether certain cytokines, such as
      TNFalpha and IFNgamma might induce PAF synthesis in our systems of cell lines
      which we found to express mRNAs encoding receptors for these cytokines. We
      observed that PAF synthesis was enhanced in human melanoma and colon carcinoma
      cell lines and in the murine B77-AA6 cells to levels comparable to those obtained
      with the Ca2+ ionophore. Synthesis of PAF was not inducible by TNFalpha in murine
      F10-M3 melanoma cells. IFNgamma also stimulated PAF synthesis in human and murine
      melanoma lines, and in human LS180 colon carcinoma line, but not in the B77-AA6
      cells. PAF synthesis was also inducible by exogenous PAF in the human and murine
      melanoma lines, and in the human LS180 colon carcinoma line, all of which
      expressed cell surface PAF receptors. PAF synthesis was not inducible by
      exogenous PAF in the B77-AA6 cells, which do not express PAF receptors.

PMID- 12428691
TI  - Effect of misoprostol and indomethacin on cyclooxygenase induction and eicosanoid
      production in carrageenan-induced air pouch inflammation in rats.
AB  - Effects of misoprostol, a synthetic prostaglandin E1 (PGE1) analogue, on
      cyclooxygenase-2 (COX-2) protein level and exudate prostaglandin E2 (PGE2) and
      thromboxane B2 (TXB2) level were investigated in acute carrageenan-induced air
      pouch inflammation in rats. Treatment with misoprostol (12.5, 25, and 50
      microg/kg) has been started in separated groups, 30 min and 2 days before
      carrageenan injection and it was given twice a day (total of five doses) by
      orogastric route. Indomethacin, in doses of 0.5 and 5 mg/kg, and specific COX-2
      inhibitor SC-58236, in doses of 5, 10, and 20 mg/kg were given 1 h before
      carrageenan injection by the orogastric route. Misoprostol increased the levels
      of PGE2 and COX-2 protein at all doses applied. Despite indomethacin and SC-58236
      increased the level of COX-2 protein when they used alone, these drugs partially
      inhibited misoprostol-induced increase in the level of COX-2 protein. Partial
      inhibition of misoprostol-induced increase in the level of COX-2 protein by
      indomethacin or SC-58236 may indicate the modulatory roles of endogenous
      prostaglandins (PGs, especially, PGE2) on the COX-2 expression.

PMID- 12428692
TI  - Management of vaginal birth after cesarean.
AB  - OBJECTIVE: To raise the success rate of vaginal birth after cesarean (VBAC)
      without increasing maternal or perinatal morbidity and mortality rates. METHODS:
      Of 468 women with a prior scar, 365 gave valid informed consent for our
      management of VBAC at Akashi Municipal Hospital during 1986-1999. Trials of labor
      (TOL) were attempted in 322 cases principally by waiting for spontaneous labor
      onset and teaching the patients a breathing method to avoid straining until
      expulsion by vacuum extraction become possible, controlling the intrauterine
      pressure. Our selection criteria for TOL changed during the trial; from 1991-1999
      patients with a prior scar extending into fundus were excluded. RESULTS: Of the
      322 TOL, 88.2% were successful, and VBAC was successful in 77.8% (284 of the 365
      patients). Uterine rupture was observed in 2 cases (0.62%). Fetal death occurred
      in 1 case. Three women gave birth to neonates with a 1-minute Apgar score < or =
      6. CONCLUSION: The rate of VBAC was 77.8% in all women with a prior scar. During
      our management of VBAC, maternal or perinatal morbidity and mortality rates did
      not increase significantly.

PMID- 12428693
TI  - Sonographic features of trisomy 18 at midpregnancy.
AB  - OBJECTIVE: To evaluate the sonographic characteristics of the fetuses with
      trisomy 18 at 16-22 weeks of gestation. METHODS: The subjects were recruited from
      pregnant women undergoing prenatal sonographic examinations at 16-22 weeks of
      gestation and subsequently proven to be trisomy 18. The results of ultrasound
      findings were retrospectively reviewed in 25 cases with chromosomes which were
      confirmed as trisomy 18. RESULTS: All cases had at least one abnormal sonographic
      finding. There was only one case that had no structural abnormality, but fetal
      growth restriction was documented. The common sonographic findings included fetal
      growth restriction, choroid plexus cysts, cardiac anomalies, clenched hand,
      omphalocele and cleft lip. Fetal growth restriction was the most common finding
      demonstrated in nearly half of all cases. Other less common findings were
      diaphragmatic hernia, abnormal head shape, polyhydramnios, single umbilical
      artery. CONCLUSION: Nearly all fetuses with trisomy 18 had characteristic
      sonographic patterns of abnormalities demonstrated at midpregnancy. Detailed
      ultrasound at midpregnancy could effectively screen fetuses with trisomy 18 for
      further genetic testing.

PMID- 12428694
TI  - Thromboprophylaxis with low molecular weight heparin in thrombophilia-complicated
      pregnancy.
AB  - We treated three thrombophilia-complicated pregnant women (two antiphospholipid
      antibody syndrome, one protein C deficiency) with low molecular weight heparin
      (dalteparin). All three pregnancies including one twin pregnancy ended in live
      births without a decrease in bone mineral density. This treatment modality was
      effective and safe preventing thrombosis during their pregnancies.

PMID- 12428695
TI  - A case of successful management of maternal septic shock with multiple organ
      failure following amniocentesis at midgestation.
AB  - Maternal sepsis is an unusual but catastrophic complication of amniocentesis. We
      report a case of successful treatment of maternal septic shock and multiple organ
      failure following amniocentesis at midgestation, possibly due to needle puncture
      of the sigmoid colon, which was tightly adherent to the anterior surface of the
      pregnant uterus.

PMID- 12428696
TI  - Current status of prophylactic use of antimicrobial agents for cesarean section
      in Thailand.
AB  - AIMS: To evaluate actual practices and physician reasons for variation in
      prophylactic use of antimicrobial agents for cesarean section (CS). METHODS: The
      study combined a survey of 2726 medical records and an interview of 50 practicing
      physicians at the obstetric departments of a university, a regional and a general
      hospital in Songkhla Province, Southern Thailand. RESULTS: Practices that were
      consistent with systematic reviews were use in 94%, prescription after cord
      clamping in 86%, and choosing ampicillin in 91%, because physicians believed in
      the advantages of these practices. Indications for prophylactic use ranged from
      routine use for all cases to selective use for indicated cases such as ruptured
      membranes, vaginal examinations, labor, maternal obesity, or unplanned CS. Single
      dose practice was varied greatly across hospitals, from 9% to 84%. The reasons
      given by physicians for a multiple-dose regimen were personal experience in this
      regimen and belief in its superiority under their local conditions. This practice
      was less common where the hospital had practice recommendations. CONCLUSIONS: Not
      all evidence-based knowledge is adopted in practice. The prophylactic use of
      antimicrobial agents for CS varies among physicians. Past experience and personal
      beliefs in the limitation of research generalizability are the barriers to such
      adoption.

PMID- 12428697
TI  - Situation analysis of atypical squamous cells of undetermined significance smears
      in Songklanagarind Hospital.
AB  - OBJECTIVE: To review the incidence, management, follow-up rate and colposcopic
      diagnosis of atypical squamous cells of undetermined significance (ASCUS)
      detected on cervical smears in Songklanagarind Hospital, Thailand. METHODS: A
      retrospective study of ASCUS smears taken during January 2000 to March 2001 at
      Songklanagarind Hospital was performed. The type of management was classified and
      the follow-up rate was detected. Cases with colposcopy, tissue biopsy,
      endocervical curettage, conization and hysterectomy specimen were reviewed. In
      the cases without tissue biopsy, the final diagnoses were based on the
      colposcopic examination. RESULTS: Among the 25068 Pap smears examined, the
      incidence of ASCUS was 0.62%. Of these, only 56.13% received the further
      evaluation. The non-compliance rate was 18.71%. The incidences of cervical
      intraepithelial neoplasia (CIN) and invasive cancer among the cases who received
      colposcopy were 15.96% and 2.13%, respectively. The incidence of CIN or invasive
      cancer in ASCUS favor reactive and ASCUS favor neoplasia were not different
      statistically significant. CONCLUSIONS: Management of ASCUS smears by follow-up
      may be inappropriate. A practice guideline which consists of active management,
      intensive follow-up system and well-organized data management should be used to
      improve the situation.

PMID- 12428698
TI  - Plasma anti-oxidant status and lipid profile in non-gravida women with a history
      of pre-eclampsia.
AB  - OBJECTIVE: To investigate the total plasma anti-oxidant status, the plasma lipid
      profile and the uterine artery Doppler velocity waveform in formerly pre
      eclamptic women. METHODS: Thirty-two formerly pre-eclamptic, non-gravida women
      constituted the study group, while 28 age-matched non-gravida women who had never
      had pre-eclampsia served as control subjects. On days 17-19 of their menstrual
      cycle, fasting plasma samples were collected for total anti-oxidant status (TAS)
      and lipid profile evaluation, and uterine artery Doppler velocity waveform
      studies were performed. Results were analyzed with Mann-Whitney U-test and
      Pearson correlation analysis. RESULTS: There was no significant difference
      between the groups in means of the uterine artery Doppler velocity waveforms and
      the plasma lipid levels, but body mass index values were significant (P < 0.005).
      The TAS value was subnormal in 72% of the formerly pre-eclamptic group and in 35%
      of the control group. The mean plasma TAS value was 1.20 +/- 0.05 mmol/L and was
      significantly lower in the study group when compared with the control group (P <
      0.05). CONCLUSION: The current study reveals significantly decreased TAS in women
      with a history of pre-eclampsia, which may have an important role in
      pathophysiology.

PMID- 12428699
TI  - Usefulness of percutaneous intracardiac administration of colored microspheres in
      measuring blood flow distribution to the brain in 7-day-old rats.
AB  - OBJECTIVE: By using colored microsphere (CMS) technique in newborn rats, we
      explored the relationship between injection sites and blood flow distribution
      patterns in open-chest and in closed-chest models, with hopes that percutaneous
      left ventricle injection can be applicable to measure relative blood flow
      distribution to the brain. METHODS: Seven-day-old Wistar rats were used. In open
      chest models (n = 30), we exposed the heart and injected CMS (15 microm diameter,
      125000 spheres in 0.05 mL) to left and right ventricles, respectively. In closed
      chest models (n = 12), we percutaneously punctured the left ventricle to
      administer microspheres to see the difference in blood flow distribution between
      the right and left side of organs. Microsphere counts were compared between the
      left and right side of each organ by unpaired t-test (mean +/- SD). RESULTS: Open
      chest showed that right ventricle injection resulted in exclusive entrapment in
      the lungs, while left ventricle injection resulted in systemic distribution.
      According to this, one of 12 injections in the closed-chest was judged as right
      ventricle injection. The other 11 showed insignificant differences between the
      right and left side in the cortex, lung, and kidney. CONCLUSION: Right ventricle
      injection is differentiated from left ventricle injection and microsphere counts
      are the same between right and left side of the organs, suggesting that
      percutaneous microsphere injection is applicable for relative blood flow
      distribution in 7-day-old rat models.

PMID- 12428700
TI  - Newborns' preference for faces: what is crucial?
AB  - Three experiments investigated whether the presence of more elements in the upper
      part of a configuration (i.e., up-down asymmetry) plays a role in determining
      newborns' preference for facelike patterns. Newborns preferred a nonfacelike
      stimulus with more elements in the upper part over a nonfacelike stimulus with
      more elements in the lower part (Experiment 1), did not show a preference for a
      facelike stimulus over a nonfacelike configuration equated for the number of
      elements in the upper part of the configuration (Experiment 2), and preferred a
      nonfacelike configuration located in the upper portion of the stimulus over a
      facelike configuration in the lower portion of the pattern (Experiment 3).
      Results demonstrated that up-down asymmetry is crucial in determining newborns'
      face preference.

PMID- 12428701
TI  - Children's interpretation of generic noun phrases.
AB  - Generic utterances (e.g., "Cows say 'moo'") have 2 distinctive semantic
      properties: (a) Generics are generally true, unlike indefinites (e.g., "Bears
      live in caves" is generic; "I saw some bears in the cave" is indefinite), and (b)
      generics need not be true of all category members, unlike universal quantifiers
      (e.g., all, every, each). This article examined whether preschool children and
      adults appreciate both these features, using a comprehension task (Study 1) and
      an elicited production task (Study 2). In both tasks, 4-year-old children--like
      adults--treated generics as distinct from both indefinites ("some") and universal
      quantifiers ("all"). In contrast, 3-year-olds did not differentiate among
      generics, "all," and "some." By 4 years of age, generics emerge as a distinct
      semantic device.

PMID- 12428702
TI  - Processing speed in the 1st year of life: a longitudinal study of preterm and
      full-term infants.
AB  - Processing speed was assessed at 5, 7, and 12 months in full-term and preterm
      infants (birth-weight < 1,750 g). Speed was gauged directly in a new task by
      presenting infants with a series of paired faces, one that remained the same
      across trials and one that changed; trials continued until infants showed a
      consistent novelty preference. At all ages, preterms required about 20% more
      trials and 30% more time than full-terms to reach criterion. Among preterms,
      slower processing was associated with greater medical risk (e.g., respiratory
      distress syndrome). Developmental trajectories for speed (and attention) were
      similar for both groups. Thus, the deficits in processing speed previously found
      for preterms in childhood are already present in the 1st year of life.

PMID- 12428703
TI  - Predicting changes in children's self-perceptions of academic competence: a
      naturalistic examination of evaluative discourse among classmates.
AB  - Classroom discourse was examined as a predictor of changes in children's beliefs
      about their academic capabilities. Kindergarten, first-grade, and second-grade
      students (N = 106) participated in 2 waves of data collection, approximately 1
      year apart. During the 1st year of the study, children's verbal interactions with
      their classmates were observed and recorded. Children rated their self
      perceptions of academic competence during the 1st and 2nd years. Analyses
      revealed that changes over time in children's competence perceptions could be
      predicted from the types of statements that children made and had directed toward
      them by classmates. Examining sequences of child and classmate statements proved
      helpful in explaining the observed changes in children's perceptions of
      competence.

PMID- 12428704
TI  - The prehistory of discovery: precursors of representational change in solving
      gear system problems.
AB  - Microgenetic research has identified 2 different types of processes that produce
      representational change: theory revision and redescription. Both processes have
      been implicated as important sources of developmental change, but their relative
      status across development has not been addressed. The current study investigated
      whether (a) the process of representational change undergoes developmental change
      itself or (b) different processes occupy different niches in the course of
      knowledge acquisition. College, 3rd-, and 6th-grade students solved gear system
      problems over 2 sessions. For all grades, discovery of the physical principles of
      the gear system was consistent with theory revision, but discovery of a more
      sophisticated strategy, based on the alternating sequence of gears, was
      consistent with redescription. The results suggest that these processes may
      occupy different niches in the course of acquiring knowledge and that the
      processes are developmentally invariant across a broad age range.

PMID- 12428705
TI  - Oral language and code-related precursors to reading: evidence from a
      longitudinal structural model.
AB  - This study examined code-related and oral language precursors to reading in a
      longitudinal study of 626 children from preschool through 4th grade. Code-related
      precursors, including print concepts and phonological awareness, and oral
      language were assessed in preschool and kindergarten. Reading accuracy and
      reading comprehension skills were examined in 1st through 4th grades. Results
      demonstrated that (a) the relationship between code-related precursors and oral
      language is strong during preschool; (b) there is a high degree of continuity
      over time of both code-related and oral language abilities; (c) during early
      elementary school, reading ability is predominantly determined by the level of
      print knowledge and phonological awareness a child brings from kindergarten; and
      (d) in later elementary school, reading accuracy and reading comprehension appear
      to be 2 separate abilities that are influenced by different sets of skills.

PMID- 12428706
TI  - Object names and object functions serve as cues to categories for infants.
AB  - Can object names and functions act as cues to categories for infants? In Study 1,
      14- and 18-month-old infants were shown novel category exemplars along with a
      function, a name, or no cues. Infants were then asked to "find another one,"
      choosing between 2 novel objects (1 from the familiar category and the other
      not). Infants at both ages were more likely to select the category match in the
      function than in the no-cue condition. However, only at 18 months did naming the
      objects enhance categorization. Study 2 shows that names can facilitate
      categorization for 14-month-olds as well when a hint regarding the core meaning
      of the objects (the function of a single familiarization object) is provided.

PMID- 12428707
TI  - The importance of eyes: how infants interpret adult looking behavior.
AB  - Two studies assessed the gaze following of 12-, 14-, and 18-month-old infants.
      The experimental manipulation was whether an adult could see the targets. In
      Experiment 1, the adult turned to targets with either open or closed eyes.
      Infants at all ages looked at the adult's target more in the open- versus closed
      eyes condition. In Experiment 2, an inanimate occluder, a blindfold, was compared
      with a headband control. Infants 14- and 18-months-old looked more at the adult's
      target in the headband condition. Infants were not simply responding to adult
      head turning, which was controlled, but were sensitive to the status of the
      adult's eyes. In the 2nd year, infants interpreted adult looking as object
      directed--an act connecting the gazer and the object.

PMID- 12428708
TI  - Two-year-olds learn novel nouns, verbs, and conventional actions from massed or
      distributed exposures.
AB  - Two-year-old children were taught either 6 novel nouns, 6 novel verbs, or 6 novel
      actions over 1 month. In each condition, children were exposed to some items in
      massed presentations (on a single day) and some in distributed presentations
      (over the 2 weeks). Children's comprehension and production was tested at 3
      intervals after training. In comprehension, children learned all types of items
      in all training conditions at all retention intervals. For production, the main
      findings were that (a) production was better for nonverbal actions than for
      either word type, (b) children produced more new nouns than verbs, (c) production
      of words was better following distributed than massed exposure, and (d) time to
      testing (immediate, 1 day, 1 week) did not affect retention. A follow-up study
      showed that the most important timing variable was the number of different days
      of exposure, with more days facilitating production. Results are discussed in
      terms of 2 key issues: (a) the domain-generality versus domain-specificity of
      processes of word learning and (b) the relative ease with which children learn
      nouns versus verbs.

PMID- 12428709
TI  - Social provisions of real and imaginary relationships in early childhood.
AB  - Preschool-aged children's perceptions of their social relationships were
      examined, including those with parents, best friends, siblings, and imaginary
      companions. Sixty 4-year-old children participated in an interview designed to
      measure perceptions of the degree of conflict, nurturance, instrumental help, and
      power available in their relationships. Three groups were compared: children with
      (a) invisible friends, (b) companions who were personified objects (e.g., dolls),
      and (c) no imaginary companion. Results indicated that children differentiated
      the relationships in their social networks according to provisions. Parent-child
      relationships afforded instrumental help and siblings were associated with
      conflict. Provisions of real and imaginary friendships were similar, although
      imaginary friends were preferred as objects of nurturance. Results imply that 4
      year-old children have developed differentiated relationship schemas and that
      those of children with invisible friends may be particularly distinct.

PMID- 12428710
TI  - Children use whole-part juxtaposition as a pragmatic cue to word meaning.
AB  - When parents label novel parts of familiar objects, they typically provide
      familiar whole-object terms before offering novel part terms (e.g., "See this
      cup? This is the rim."). Such whole-part juxtaposition might help children to
      accurately interpret the meaning of novel part terms, but it can do so only if
      they recognize the conjunction as a potential cue to part meaning. Two studies
      examined (a) whether 3- to 4-year-olds use whole-part juxtaposition to accurately
      interpret novel part terms and (b) how they might do so. Study 1 confirmed that
      children indeed use juxtaposition to guide learning of novel part terms.
      Furthermore, 2 control conditions clarified that children's use of juxtaposition
      was not simply due to memory effects, such as the facilitation of lexical access,
      nor to recognition of the grammatical frame that typically accompanies
      juxtaposition. Study 2 revealed that children readily use juxtaposition in a
      novel, gestural format. Such flexibility in recognizing and utilizing novel
      variants of juxtaposition strongly suggests that pragmatic understanding lies at
      the heart of children's sensitivity to whole-part juxtaposition.

PMID- 12428711
TI  - Children's understanding of the knowledge prerequisites of drawing and
      pretending.
AB  - Many young children will claim that someone is pretending to be something even
      when the person does not know what that something is. To examine whether
      children's failure to take knowledge prerequisites into account is part of a more
      fundamental problem in recognizing how mental representations constrain external
      ones, the authors asked children whether an artist who did not know what
      something was, yet whose drawing bore resemblance to it, was drawing it. The same
      questions were asked regarding pretending. Children performed similarly on
      pretending and drawing questions, and performance on both questions improved when
      the protagonists' point of view was emphasized. Performance for drawing improved
      somewhat when alternative goals were stated. Further, cross-sectional data
      indicated that understanding how knowledge relates to producing external
      representations increases gradually from age 4 to age 8, suggesting that
      experiential factors may be crucial to this understanding.

PMID- 12428712
TI  - Statistical regularities in vocabulary guide language acquisition in
      connectionist models and 15-20-month-olds.
AB  - This research tested the hypothesis that young children's bias to generalize
      names for solid objects by shape is the product of statistical regularities among
      nouns in the early productive vocabulary. Data from a 4-layer Hopfield network
      suggested that the statistical regularities in the early noun vocabulary are
      strong enough to create a shape bias, and that the shape bias is overgeneralized
      to nonsolid stimuli. A 2nd simulation suggested that this overgeneralization is
      due to the dominance of names for shape-based categories in the early noun
      vocabulary. Two subsequent longitudinal experiments tested whether it is possible
      to create word learning biases in children. Children 15-20 months old were given
      intensive naming experiences with 12 noun categories typical of the types of
      categories children learn to name early. The children developed a precocious
      shape bias that was overgeneralized to naming nonsolid substances; they also
      showed accelerated vocabulary development. Children taught an atypical set of
      nouns or no new nouns did not develop a shape bias and did not show accelerated
      vocabulary development.

PMID- 12428713
TI  - Children's recognition of caricatures.
AB  - This study examined children's and adults' perception and recognition of facial
      stimuli that were either systematically exaggerated (caricatures) or de
      exaggerated (anticaricatures) relative to a norm face. The results showed that
      all age groups perceived caricatures as the most distinctive versions of a face
      and anticaricatures as the least distinctive, although the effect was smallest
      for 6-year-olds. In general, caricatures were identified as quickly as the
      veridical faces and faster than the anticaricatures. Across all age groups,
      participants' familiarity with the stimulus faces interacted with degree of
      caricature to determine speed of processing as well as choice of best likeness.
      The results are discussed in relation to the idea that distinctiveness
      information in a face is represented in relation to a norm.

PMID- 12428714
TI  - Confidence judgments in children's and adults' event recall and suggestibility.
AB  - The present work investigated the role of children's and adults' metacognitive
      monitoring and control processes for unbiased event recall tasks and for
      suggestibility. Three studies were conducted in which children and adults
      indicated their degree of confidence that their answers were correct after (Study
      1) and before (Study 2) answering either unbiased or misleading questions or
      (Study 3) forced-choice recognition questions. There was a strong tendency for
      overestimation of confidence regardless of age and question format. However,
      children did not lack the principal metacognitive competencies when these
      questions were asked in a neutral interview. Under misleading questioning, in
      contrast, children's monitoring skills were seriously impaired. Within each age
      group, better metacognitive differentiation was positively associated with recall
      accuracy in the suggestive interview.

PMID- 12428715
TI  - Parkinson's disease: current and future challenges.
AB  - In 15 years, we will mark the 200th anniversary of the James Parkinson's original
      description of the disease that now bears his name (An Essay on the Shaking
      Palsy, Sherwood, Neely and Jones London, 1817). Perhaps, one of the most exciting
      but daunting questions we face at this moment is whether or not we can unravel
      the etiology of the disease by that time. If we are to accomplish such an
      ambitious goal, we must determine the resources that will be required to make it
      happen, and identify the areas of scientific focus that should receive the
      greatest attention. One issue that will have great bearing on the allocation of
      research resources relates to the relative roles of genes versus environment in
      disease causation. For reasons that will become clear in this article, this has a
      remained surprisingly controversial area. Ironically, this controversy has even
      spilled over to the very definition of Parkinson's disease, and even whether or
      not it should be considered a disease entity. In this article, the enduring
      "genes versus environment" debate is reviewed, with a goal of putting it into a
      broader perspective. Issues surrounding disease definition and terminology are
      also addressed in detail, because of the need to have clarity of thought and
      vision if research on the cause is to proceed in an orderly (and hopefully
      expeditious) manner. Finally, issues relating future research directions are
      summarized, with the goal of identifying the pieces of the Parkinson's puzzle
      that are going to have to be put together if we are to solve this mysterious
      disease.

PMID- 12428716
TI  - Partnership for Parkinson's disease research: patient-researcher-clinician
      sponsor.
AB  - Parkinson's disease (PD) appears to arise from the interaction of three events-an
      individual's inherited genetic susceptibility, their subsequent environmental
      exposures, and their age. We clearly need to intensify efforts to understand the
      environmental triggers of PD, the importance of the timing of exposure to these
      triggers, and the interplay between these exposures and a persons underlying
      genetic constitution and susceptibilities. This knowledge, once generated, will
      lead to better detection of the earliest stages of PD, to improved therapeutics,
      and most importantly, to viable prevention strategies so that people need not
      suffer from environmentally-caused PD. Many promising lines of investigation are
      already supported by the National Institute of Environmental Health Sciences
      (NIEHS), National Institute of Neurological Disorders and Stroke (NINDS), and the
      National Institute of Aging (NIA) and other public and private organizations. In
      order to accelerate the pace of progress in this field, the NIEHS is developing a
      Consortium Centers Program that will provide a formal mechanism for "cross-talk"
      between PD clinicians, basic research scientists, and patient advocates. The
      Consortium will seek to identify and support novel approaches and research
      ventures that might not otherwise be pursued by scientists working in isolation.
      The NIEHS will also continue to explore ways to promote more mechanism-based
      research to understand putative environmental triggers for PD in concert with
      defined genetic susceptibilities.

PMID- 12428717
TI  - Parkinson's disease and related synucleinopathies are a new class of nervous
      system amyloidoses.
AB  - Parkinson's disease (PD) is the most common neurodegenerative movement disorder.
      While the classic clinical-neuropathological features of PD have been well
      established, mechanisms underlying brain degeneration in PD are unknown, and only
      partially effective symptomatic treatments for PD exist. Further, there are no
      therapeutic interventions that prevent PD or block the progression of this
      relentless neurodegenerative disorder. However, dramatic new insights into the
      role of alpha-synuclein (AS) in the pathobiology of PD have emerged recently, and
      this has led to the development of transgenic animal models of PD-like AS
      pathologies. Continuing advances in this research direction should advance
      understanding of PD and accelerate discovery of more effective therapies for this
      and related synucleinopathies.

PMID- 12428718
TI  - Development of new treatments for Parkinson's disease in transgenic animal
      models: a role for beta-synuclein.
AB  - Neuronal death in Parkinson's disease (PD), one of the most common
      neurodegenerative disorders in the adult and aging population is probably caused
      by misfolding of synaptic proteins such as alpha-synuclein. Although, some
      treatments are currently available to control some of the symptoms of PD, none of
      these approaches directly addresses the mechanisms of disease. With the advent of
      new experimental animal models for this disorder, the potential for development
      and discovery of new treatment has been significantly bolstered. Among them,
      overexpression of alpha-synuclein results in motor deficits. dopaminergic loss
      and formation of inclusion bodies. Co-expression of mutant amyloid precursor
      protein, accelerates alpha-synuclein aggregation and enhances the
      neurodegenerative pathology in these mice, providing a unique model where to
      investigate the interactions between Abeta1-42 and alpha-synuclein and to develop
      treatments for combined Alzheimer's disease and PD. Development of anti
      parkinsonian treatments based on these models includes: (i) anti-aggregation or
      pro-degradation compounds, (ii) neuroprotective compounds, and (iii) neurotrophic
      agents. Among them, we characterized beta-synuclein, the non-amyloidogenic
      homologue of alpha-synuclein, as an inhibitor of aggregation of alpha-synuclein.
      Our results raise the intriguing possibility that beta-synuclein might be a
      natural negative regulator of alpha-synuclein aggregation, and that a similar
      class of endogenous factors might regulate the aggregation state of other
      molecules involved in neurodegeneration. Such an anti-amyloidogenic property of
      beta-synuclein might also provide a novel strategy for the treatment of
      neurodegenerative disorders.

PMID- 12428719
TI  - Functional imaging of the dopamine system: in vivo evaluation of dopamine
      deficiency and restoration.
AB  - Dopamine deficiency causes a severe impairment in motor function in patients with
      Parkinson's disease (PD) and in experimental animal models. Recent developments
      in neuroimaging techniques provide a means to assess in vivo the state of the
      dopamine system. From a functional perspective, four levels need to be operative
      and integrated in the system: the dopamine cell (pre-synaptic), the striatal
      dopamine receptors (post-synaptic), adequate release of dopamine (intra
      synaptic), and the cortico-subcortical motor projections. Neuroimaging functional
      methods can be used to estimate, at these four levels, dopamine cell
      degeneration, adaptive responses to injury and, importantly, the effect of
      therapeutic interventions. In this respect, data from functional imaging studies
      at clinical and pre-clinical stages, support the idea that cell replacement
      therapy might achieve a more physiological restoration of the dopamine motor
      system than other therapies (such as ablative surgery, administration of
      precursor, deep brain stimulation) that currently are equally or more effective
      in relieving motor symptoms.

PMID- 12428720
TI  - Pre-treatment with R-lipoic acid alleviates the effects of GSH depletion in PC12
      cells: implications for Parkinson's disease therapy.
AB  - Oxidative stress is believed to play a key role in the degeneration of
      dopaminergic neurons in the substantia nigra (SN) of Parkinson's disease (PD)
      patients. An important biochemical feature of PD is a significant early depletion
      in levels of the thiol antioxidant compound glutathione (GSH) which may lead to
      the generation of reactive oxygen species (ROS), mitochondrial dysfunction, and
      ultimately to subsequent neuronal cell death. In earlier work from our
      laboratory, we demonstrated that depletion of GSH in dopaminergic PC12 cells
      affects mitochondrial integrity and specifically impairs the activity of
      mitochondrial complex I. Here we report that pre-treatment of PC12 cells with R
      lipoic acid acts to prevent depletion of GSH content and preserves the
      mitochondrial complex I activity which normally is impaired as a consequence of
      GSH loss.

PMID- 12428721
TI  - Environmental factors in Parkinson's disease.
AB  - Evidence discussed in this review article lends strong support in favor of an
      etiologic role of environmentalfactors in Parkinson's disease. First, thanks to
      the discovery of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), it is now
      clear that, by targeting the nigrostriatal system, neurotoxicants can reproduce
      the neurochemical and pathological features of idiopathic parkinsonism. The
      sequence of toxic events triggered by MPTP has also provided us with intriguing
      clues concerning mechanisms of toxicant selectivity and nigrostriatal
      vulnerability. Relevant examples are (i) the role of the plasma membrane dopamine
      transporter in facilitating the access of potentially toxic species into
      dopaminergic neurons; (ii) the vulnerability of the nigrostriatal system to
      failure of mitochondrial energy metabolism; and (iii) the contribution of
      inflammatory processes to tissue lesioning. Epidemiological and experimental data
      suggest the potential involvement of specific agents as neurotoxicants (e.g.
      pesticides) or neuroprotective compounds (e.g. tobacco products) in the
      pathogenesis of nigrostriatal degeneration, further supporting a relationship
      between the environment and Parkinson's disease. A likely scenario that emerges
      from our current knowledge is that neurodegeneration results from multiple events
      and interactive mechanisms. These may include (i) the synergistic action of
      endogenous and exogenous toxins (e.g. the ability of the pesticide
      diethyldithiocarbamate to promote the toxicity of other compounds); (ii) the
      interactions of toxic agents with endogenous elements (e.g. the protein alpha
      synuclein); (iii) the tissue response to an initial toxic insult; and, last but
      not least, (iv) the effects of environmental factors on the background of genetic
      predisposition and aging.

PMID- 12428722
TI  - Parkinson's genetics: molecular insights for the new millennium.
AB  - In idiopathic Parkinson's disease and familial parkinsonism, the limited number
      of overlapping clinical and pathological outcomes argue that a common underlying
      molecular pathway is perturbed. Genetic methods are a powerful approach to
      identify molecular components of disease. We summarize recent attempts to
      identify the genetic components of familial parkinsonism, without a priori
      assumptions about disease causation. Much effort has been expended on mapping in
      families with early-onset disease, in which parkinsonism appears inherited as a
      Mendelian trait. More recently, association methods have been employed in late
      onset disease using affected sib-pairs and population isolates. These findings
      have been extrapolated to Parkinson's disease in the community with some success.
      We review the molecular synthesis now emerging from a genetic perspective.

PMID- 12428723
TI  - Gender difference in the interaction of smoking and monoamine oxidase B intron 13
      genotype in Parkinson's disease.
AB  - We tested for gender-specific interactions between smoking and genetic
      polymorphisms of monoamine oxidase B (MAO-B) intron 13 (G or A allele), monoamine
      oxidase A (MAO-A) EcoRV (Yor N allele), and dopamine D2 recepor (DRD2) Taq1B (B1
      or B2 allele) in a case-control study of 186 incident idiopathic Parkinson's
      disease (PD) cases and 296 age- and gender-matched controls. The odds ratios
      (ORs) for PD risk for ever smokers versus never smokers were 0.27 (95% CI: 0.13
      0.58) for men of genotype G, and 1.26 (0.60-2.63) for men of genotype A
      (interaction chi2 = 8.14, P = 0.004). In contrast, for women, the OR for ever
      smokers versus never smokers were 0.62 (95% CI: 0.25-1.34) and 0.64 (95% CI: 0.18
      2.21) for women of genotype GG/GA and AA, respectively (interaction chi2 = 0.001,
      P = 0.975). No interactions were detected between smoking and either MAO-A EcoRV
      or DRD2 Taq1B genotypes. These results suggest that a strong gender difference
      exists with respect to the modifying effect of MAO-B genotype on the smoking
      association with PD.

PMID- 12428724
TI  - Progressive parkinsonism in a young experimental physicist following long-term
      exposure to methanol.
AB  - A case is described of an experimental physicist who developed parkinsonism,
      apparently as delayed toxic effect of long exposure to vapors of methanol in the
      laboratory. Clinical and magnetic resonance imaging (MRI) supported the
      diagnosis, after exclusion of hereditary diseases and primary degenerative
      diseases. Screening for heavy metals in urine and plasma ceruloplasmin was
      negative. This case illustrates the neurotoxic delayed effect of long-term
      exposure to methanol with no episodes of acute intoxication. The setting of a
      research laboratory with prolonged exposure to mixed single crystals and
      inhalation of methanol vapors may exist in other academic and hi-tech
      environments, and pose the risk of similar delayed toxic influences.

PMID- 12428725
TI  - Synergistic effects of pesticides and metals on the fibrillation of alpha
      synuclein: implications for Parkinson's disease.
AB  - Aggregation of alpha-synuclein has been implicated in the formation of
      proteinaceous inclusions in the brain (Lewy bodies, Lewy neurites) that are
      characteristic of neurodegenerative diseases, such as Parkinson's disease (PD)
      and dementia with Lewy bodies (DLBs). The etiology of PD is unknown, but recent
      work has shown that except in rare cases, there appears to be no direct genetic
      basis. However, several studies have implicated environmental factors, especially
      pesticides and metals. Here we show that certain pesticides and metals induce a
      conformational change in alpha-synuclein and directly accelerate the rate of
      formation of alpha-synuclein fibrils in vitro. In addition, the simultaneous
      presence of metal and pesticide led to synergistic effects on the rate of
      fibrillation. We propose a model in which environmentalfactors in conjunction
      with genetic susceptibility may form the underlying molecular basis for
      idiopathic PD.

PMID- 12428726
TI  - Selective effects of insecticides on nigrostriatal dopaminergic nerve pathways.
AB  - A degeneration of the nigrostriatal pathway is a primary component of Parkinson's
      disease (PD), and we have investigated the actions of insecticides on this
      pathway. For in vivo exposures, C57BL/6 mice were treated three times over a 2
      week period with heptachlor, the pyrethroids deltamethrin and permethrin, or
      chlorpyrifos. One day after the last treatment, we observed that heptachlor and
      the pyrethroids increased maximal [3H]dopamine uptake in striatal synaptosomes
      from treated mice, with dose-dependent changes in Vmax displaying a bell-shaped
      curve. Western blot analysis confirmed increased levels of dopamine transporter
      (DAT) protein in the striatum of mice treated with heptachlor and permethrin. In
      contrast, we observed a small, but statistically significant decrease in dopamine
      uptake by 100 mg/kg chlorpyrifos. For heptachlor, doses that upregulated DAT
      expression had little or no effect on serotonin transport. Permethrin did cause
      an upregulation of serotonin transport, but required a 30-fold greater dose than
      that effective on dopamine uptake. Other evidence of specificity was found in
      transmitter release assays, where heptachlor and deltamethrin released dopamine
      from striatal terminals with greater potency than other transmitter types. These
      findings confirm that insecticides possess specificity for effects on striatal
      dopaminergic neurotransmission.

PMID- 12428727
TI  - Catecholaminergic neuronal degeneration in rainbow trout assessed by skin color
      change: a model system for identification of environmental risk factors.
AB  - Genetic, neurochemical, and environmental factors have been implicated in
      neurodegenerative disease, and a combination of these factors is likely
      responsible for disease onset and progression. Environmental toxicants implicated
      in Parkinson's disease include organic compounds, reactive oxygen species, metal
      ions and others. Exposure to a combination of environmental toxicants may produce
      a synergistic insult leading to neuronal death, even though levels of individual
      toxicants may be below detection by conventional methods. Rodent models of
      toxicant-induced neurodegeneration are hampered by the high resistance of these
      animals to many environmental toxicants. Extensive literature on aquatic
      toxicology and the high homology between many human and fish neurotrophic factors
      makefish a useful model for investigating environmental toxicants and
      neurodegeneration. Skin color in salmonids is under catecholaminergic control;
      pigment-containing melanophores aggregate when stimulated, resulting in paling.
      We demonstrate that lesions to nerves innervating melanophores prevent
      aggregation and produce dark skin color. The time course for return of skin color
      corresponds to neuronal regeneration, a neurotrophin-dependent event.
      Observations from this model system may be useful for predicting risks associated
      with environmental toxicants and nervous system integrity, and may have important
      implications for the identification of risk factors.

PMID- 12428728
TI  - Conformational behavior of human alpha-synuclein is modulated by familial
      Parkinson's disease point mutations A30P and A53T.
AB  - Structural properties and response to changes in the environment of wild-type
      (WT), A30P and A53T alpha-synucleins, as well as their propensity to aggregate
      orform fibrils, were compared by a variety of biophysical methods, including far
      UV CD, FTIR, SAXS, static light scattering and Thioflavin T (TFT) fluorescence.
      All three proteins were natively unfolded under physiological conditions but
      adopted identical partially-folded conformations under conditions of acidic pH or
      high temperature. The initial kinetic event in the fibrillation of all three
      alpha-synucleins was shown to be the formation of a partially-folded intermediate
      with properties close to those described for these proteins at acidic pH or at
      high temperatures. Both mutants showed a greater propensity to form non-fibrillar
      aggregates than wild-type protein. All three proteins formed fibrils faster in
      the presence of heparin, although substantially higher concentrations were
      required for the A30P mutant. In contrast to the wild-type and A53T proteins, in
      which fibrillation was further accelerated by the presence of the pesticide
      diethyldithiocarbamate (DDC), the A30P mutant was inhibited by DDC. The mutant
      proteins had significantly lower affinity for DDC than the WT. A model of the
      effect of mutations on the aggregation behavior of alpha-synuclein is proposed,
      which explains the different effects of exogenous agents on the three proteins,
      based on different kinetic partitioning along pathways leading to fibrils and to
      non-fibrillar aggregates.

PMID- 12428729
TI  - Acute mitochondrial and chronic toxicological effects of 1-methyl-4
      phenylpyridinium in human neuroblastoma cells.
AB  - At low micromolar concentrations, 1-methyl-4-phenylpyridinium (MPP+), the toxic
      metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) selectively
      kills nigrostriatal dopaminergic neurons by mechanisms believed to involve
      impairment of mitochondrial complex I. A human neuroblastoma cell line expressing
      the dopamine transporter (DAT) was utilized to examine the effects of MPP+ on
      acute physiologic responses and subsequent cell death. Acute responses were
      measured by microphysiometry and by monitoring mitochondrial membrane potential
      with [3H]tetraphenylphosphonium (TPP+) uptake. MPP+ (10 microM) increased
      extracellular proton excretion in DAT-expressing cells within 2-3 min, but had no
      effect in untransfected cells. The lipophilic complex I inhibitor, rotenone,
      increased proton excretion in both cell lines. In DAT-expressing cells,
      mitochondrial membrane potential was reduced within I h of 10 microM MPP+
      exposure. Rotenone reduced mitochondrial membrane potential in both cell lines.
      MPP+ caused apoptotic death of DAT-transfected cells 2-3 days after drug
      application, but did not kill untransfected cells. Thus, MPP+ produces immediate
      mitochondrial impairment only in cells that express DAT, and these changes occur
      days before overt cellular toxicity. The magnitude, time course and nature of
      these changes were similar to those produced by rotenone, confirming the site of
      action of MPP+ as mitochondrial complex I. These immediate mitochondrial effects
      appear to be an accurate predictor of subsequent cell death.

PMID- 12428730
TI  - Nicotine and nicotinic receptors; relevance to Parkinson's disease.
AB  - The development of nicotinic agonists for therapy in neurodegenerative disorders
      such as Parkinson's disease is an area currently receiving considerable
      attention. The rationale for such work stems from findings that reveal a loss of
      nicotinic receptors in Parkinson's disease brains. These results, coupled with
      reports that nicotine treatment relieves some of the symptoms of this disorder,
      provides support for the contention that nicotine and/or nicotinic agonists may
      be beneficial for acute symptomatic treatment. Moreover, the observation that
      there is a decreased incidence of Parkinson's disease with tobacco use, possibly
      due to the nicotine in tobacco products, may imply that such drugs are useful for
      long-term neuroprotection. However, there are multiple nicotinic receptor
      populations in the brain with different functional properties. Identification of
      the subtypes involved in nigrostriatal dopaminergic activity is therefore
      critical for the rational use of selective therapeutic agents for symptomatic
      treatment and/or neuroprotection. Accumulating evidence, both in rodents and
      nonhuman primates now indicate that alpha6* nicotinic receptors are present on
      nigrostriatal dopaminergic neurons, and furthermore, that receptors containing
      this subunit may be most vulnerable to nigrostriatal damage, at least in nonhuman
      primates. These data suggest that nicotinic receptor ligands directed to alpha6*
      nicotinic receptors might be particularly relevant for Parkinson's disease
      therapeutics.

PMID- 12428731
TI  - Manganese causes differential regulation of glutamate transporter (GLAST) taurine
      transporter and metallothionein in cultured rat astrocytes.
AB  - Neurotoxicity due to excessive brain manganese (Mn) can occur due to
      environmental (air pollution, soil, water) and/ or metabolic aberrations
      (decreased biliary excretion). Manganese is associated with oxidative stress, as
      well as alterations in neurotransmitter metabolism with concurrent
      neurobehavioral deficits. Based on the few existing studies that have examined
      brain regional [Mn], it is likely that in pathological conditions it can reach
      100-500 microM. Amino acid (e.g. aspartate, glutamate, taurine), as well as
      divalent metal (e.g. zinc, manganese) concentrations are regulated by astrocytes
      in the brain. Recently, it has been reported that cultured rat primary astrocytes
      exposed to Mn displayed decreased glutamate uptake, thereby, increasing the
      excitotoxic potential of glutamate. Since the neurotoxic mechanism(s) Mn employs
      in terms of glutamate metabolism is unknown, a primary goal of this study was to
      link altered glutamate uptake in Mn exposed astrocytes to alterations in
      glutamate transporter message. Further, we wanted to examine the gene expression
      of metallothionein (MT) and taurine transporter (tau-T) as markers of Mn
      exposure. Glutamate uptake was decreased by nearly 40% in accordance with a 48%
      decrease in glutamate/aspartate transporter (GLAST) mRNA. Taurine uptake was
      unaffected by Mn exposure even though tau-T mRNA increased by 123%. MT mRNA
      decreased in these Mn exposed astrocytes possibly due to altered metal
      metabolism, although this was not examined. These data show that glutamate and
      taurine transport in Mn exposed astrocytes are temporally different.

PMID- 12428732
TI  - Alteration of intracellular structure and function of glyceraldehyde-3-phosphate
      dehydrogenase: a common phenotype of neurodegenerative disorders?
AB  - Recent evidence reveals that glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is
      not simply a classical glycolytic protein of little interest. Instead, it is a
      multifunctional protein with diverse cytoplasmic, membrane and nuclear
      activities. Significantly, each activity is separate and distinctfrom its role in
      energy production. Its nuclear activities include its emerging role in apoptosis
      especially in neuronal cells. GAPDH translocates into the nucleus during
      programmed cell death. Introduction of antisense GAPDH sequences reduces
      apoptosis and prevents its nuclear translocation. Independent analyses
      demonstrate that GAPDH may be involved in the cellular phenotype of age-related
      neurodegenerative disorders. GAPDH binds uniquely in vitro to the beta-amyloid
      precursor protein (betaAPP), to huntingtin as well as to other triplet repeat
      neuronal disorder proteins. In Parkinson's disease (PD) cells, immunofluorescent
      data suggests the co-l localization of GAPDH and alpha-synuclein in Lewy bodies.
      Drugs used to treat PD bind specifically to GAPDH. Our recent findings (Mazzola
      and Sirover, 2001) demonstrate a subcellular reduction in GAPDH glycolytic
      activity in Alzheimer's disease (AD) and in Huntington's disease (HD) cells. The
      latter may be due to intracellular alteration of GAPDH structure (Mazzola and
      Sirover 2002). We discuss the hypothesis that the intracellularformation of
      GAPDH: neuronal protein complexes may represent an emerging cellular phenotype of
      neurodegenerative disorders. The cytoplasmic binding of neuronal proteins to
      GAPDH could affect energy production. Nuclear interactions could affect its
      apoptotic activity. Other functions of this multidimensional protein may also be
      inhibited. Experimental paradigms to test this hypothesis are considered.

PMID- 12428733
TI  - L-DOPA does not cause neurotoxicity in VMAT2 heterozygote knockout mice.
AB  - One of the most useful treatments of Parkinson's disease (PD) is
      dihydroxyphenylalanine (L-DOPA) administration. However, L-DOPA has been
      suggested to be toxic to dopamine (DA) neurons and perhaps contribute to the
      progression of the disease. Sequestration of DA and dopaminergic neurotoxins into
      vesicles by the vesicular monoamine transporter 2 (VMAT2) is a key factor in
      preventing cellular damage. Mice with reduced expression of VMAT2 (VMAT2
      heterozygote knockout mice; VMAT2 (+/-)) are more sensitive to the neurotoxic
      effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and
      methamphetamine. In this study, we subjected VMAT2 (+/-) mice to subchronic
      administration of L-DOPA to determine if it was toxic in this model. VMAT2 wild
      type (VMAT2 (+/+)) and VMAT2 (+/-) mice were given i.p. injections of L
      DOPA:carbidopa (50:5 mg/kg) three times a day for 28 days. Biochemical analysis
      revealed a significant increase in striatal DA levels in both groups of mice
      treated with L-DOPA. L-DOPA treatment significantly decreased DAT levels in VMAT2
      (+/+) mice, but not in VMAT2 (+/-) mice. VMAT2 protein levels, an index of
      terminal integrity and the number of tyrosine hydroxylase (TH)-positive nigral
      cells remained unchanged after L-DOPA treatment. These data indicate that in an
      animal model that displays increased susceptibility to dopaminergic injury, a
      subchronic administration of L-DOPA does not induce toxicity.

PMID- 12428734
TI  - Developmental exposure to the pesticides paraquat and maneb and the Parkinson's
      disease phenotype.
AB  - Idiopathic Parkinson's disease (PD) is associated with advanced age, but it is
      still unclear whether dopaminergic neuronal death results from events initiated
      during development, adulthood, or represents a cumulative effect across the span
      of life. This study hypothesized that paraquat (PQ) and maneb (MB) exposure
      during critical periods of development could permanently change the nigrostriatal
      dopamine (DA) system and enhance its vulnerability to subsequent neurotoxicant
      challenges. C57BL/6 mice were treated daily with saline, 0.3 mg/kg PQ, 1 mg/kg MB
      or PQ + MB from post-natal (PN) days 5 to 19. At 6 weeks, a 20% decrease in
      activity was evident only in the PQ + MB group, with a further decline (40%)
      observed at 6 months. A subset of mice were re-challenged as adults with saline,
      10 mg/kg PQ, 30 mg/kg MB, or PQ + MB 2 x a week for 3 weeks. Mice exposed
      developmentally to PQ + MB and rechallenged as adults were the most affected,
      showing a 70% reduction in motor activity 2 weeks following the last rechallenge
      dose. Striatal DA levels were reduced by 37% following developmental exposure to
      PQ + MB only, butfollowing adult re-challenge levels were reduced by 62%. A
      similar pattern of nigral dopaminergic cell loss was observed, with the PQ + MB
      treated group exhibiting the greatest reduction, with this loss being amplified
      by adult re-challenge. Developmental exposure to PQ or MB alone produced minimal
      changes. However, following adult re-challenge, significant decreases in DA and
      nigral cell counts were observed, suggesting that exposure to either
      neurotoxicant alone produced a state of silent toxicity that was unmasked
      following adult re-exposure. Taken together, these findings indicate that
      exposure to pesticides during the PN period can produce permanent and progressive
      lesions of the nigrostriatal DA system, and enhanced adult susceptibility to
      these pesticides, suggesting that developmental exposure to neurotoxicants may be
      involved in the induction of neurodegenerative disorders and/or alter the normal
      aging process.

PMID- 12428735
TI  - Effect of high dietary manganese intake of neonatal rats on tissue mineral
      accumulation, striatal dopamine levels, and neurodevelopmental status.
AB  - Mn is an essential element, but may become neurotoxic at high levels. Recent
      reports of high Mn levels in hair of children with neurodevelopmental deficits
      suggest that these deficits could be due to Mn-induced neurotoxic effects on
      brain dopamine (DA) systems, although the mechanism is not well understood.
      Infant formulas contain considerably higher concentrations of Mn than human milk.
      Thus, formula-fed infants are exposed to high levels of Mn at a time when Mn
      homeostasis is incompletely developed. We studied the effects of dietary Mn
      supplementation of rat pups on tissue Mn accumulation, brain dopamine levels,
      infant neurodevelopmental status, and behavior at maturity. Newborn rats were
      supplemented daily with 0, 50, 250, or 500 microg Mn given orally from day 1 to
      day 20. Mineral analysis of small intestine and brain at day 14 showed a
      significant increase of tissue Mn in supplemented rats. Neurodevelopmental tests
      conducted at various ages showed significant delays as a function of Mn
      supplementation. At day 32, there was a significant positive relationship between
      passive avoidance errors and Mn supplementation levels. Brains of animals killed
      on day 40 showed a significant inverse relationship between Mn supplementation
      level and striatal dopamine concentration. These observations suggest that
      dietary exposure to high levels of Mn during infancy can be neurotoxic to rat
      pups and result in developmental deficits.

PMID- 12428736
TI  - Effects of neonatal dietary manganese exposure on brain dopamine levels and
      neurocognitive functions.
AB  - Neonatal exposure to high levels of manganese (Mn) has been indirectly implicated
      as a causal agent in attention deficit hyperactivity disorder (ADHD), since Mn
      toxicity and ADHD both involve dysfunction in brain dopamine (DA) systems. This
      study was undertaken to examine this putative relationship in an animal model by
      determining if levels of neonatal dietary Mn exposure were related to brain DA
      levels and/or behavioral tests of executive function (EF) when the animals
      reached maturity. We used 32 newborn male Sprague-Dawley rats and randomly
      assigned them to one of the four dietary Mn supplementation conditions: 0, 50,
      250 and 500 microg per day, administered daily in water from postnatal days 1-21.
      During days 50-64, the animals were given a burrowing detour test and a passive
      avoidance test. At day 65, the animals were killed and brains were assayed for
      DA. There was a statistically significant relationship (P = 0.003) between
      dietary Mn exposure and striatal DA. On the burrowing detour and passive
      avoidance, greater deficits were observed for animals subjected to higher Mn
      exposure, but these differences did not reach statistical significance. However,
      tests for heterogeneity of variance between groups were statistically significant
      for all measures, with positive relationship between Mn exposure and degree of
      within-group behavioral variability. Kendall's nonparametric test of the
      relationship between the three behavioral measures and striatal DA levels was
      also statistically significant (P = 0.02). These results lend support to the
      hypothesis that neonatal Mn exposure is related to brain DA levels and
      neurocognitive deficit in the rodent.

PMID- 12428737
TI  - Novel means to selectively identify Sertoli cell transplants.

PMID- 12428738
TI  - Identification of a specific Sertoli cell marker, Sox9, for use in
      transplantation.
AB  - The immunoprivileged environment of the testes was first described in the 1930s,
      and the Sertoli cell was later identified as the main cell type responsible for
      this phenomenon. Recent work has examined the possibility of recreating this
      immunoprivileged environment at heterotopic sites using isolated Sertoli cells.
      These studies have focused on protection of pancreatic islets and neuronal cells
      from immune destruction in the hopes of reversing type I diabetes and Parkinson's
      disease. The absence of a definitive marker for identifying Sertoli cells at the
      transplant site has been an obstacle to this research. The current study examines
      the presence of a nuclear transcription factor, Sox9, which is preferentially
      expressed in Sertoli cells. Syngeneic Lewis rat Sertoli cells were transplanted
      into the renal subcapsular space and a subcutaneous site in Lewis female rats and
      examined histologically 21 days later. In addition, porcine Sertoli cells were
      transplanted into the renal subcapsular space in female SCID mice. Control testes
      and the transplant sites were examined immunohistochemically using an antibody to
      Sox9. The results from the study demonstrate that Sox9 expression is restricted
      to the Sertoli cells of the neonatal rat and porcine testis, indicating high
      homology between species. In addition, Sox9 expression was also observed in the
      testicular-like tubules that formed in both syngeneic and xenogeneic heterotopic
      transplants in rats and SCID mice. The Sox9 expression was restricted to the
      regions where Sertoli cells would be found in the native testis. These results
      suggest that the Sox9 protein is a useful marker in identifying Sertoli cells in
      heterotopic transplants in a manner similar to insulin as a marker for pancreatic
      islets.

PMID- 12428739
TI  - A unique cytoplasmic marker for extratesticular Sertoli cells.
AB  - In the absence of a definitive cell marker for testis-derived Sertoli cells,
      their identification in cell culture or in Sertoli cell-facilitated cell
      transplantation protocols is difficult and limits the creditable evaluation of
      experimental results. However, the production by prepubertal Sertoli cells of
      Mullerian inhibiting substance (MIS) presents the possibility of specifically
      identifying extratesticular Sertoli cells as well as Sertoli cells in situ, by
      the immunodection of this unique glycoprotein. This study was designed to
      determine if isolated rat Sertoli cells could be identified by routine
      immunocytochemistry utilizing an antibody raised against MIS. Sertoli cells
      immunostained for MIS included Sertoli cells in situ and freshly isolated,
      cultured and cocultured Sertoli cells, and Sertoli cells structurally integrated
      with NT2 cells in simulated microgravity. Detection of MIS was also determined by
      Western blot analysis.

PMID- 12428740
TI  - Successful single donor islet allotransplantation in the streptozotocin diabetes
      rat model.
AB  - The objective of this study was to define pretransplant islet culture conditions
      for optimum tissue engraftment in the rat islet allotransplantation model. Lewis
      rat islets were cultured in TCM 199/5% fetal calf serum for I day at 37 degrees
      C, followed by 1 day of culture at 22 degrees C. When islets from single donors
      were allotransplanted intraportally into single streptozotocin-diabetic Wistar
      Furth rats, complete normoglycemia was restored within 1 day after
      transplantation in seven out of seven rats, and persisted up to immunological
      rejection about 1 week later. In five out of six rats receiving a posttransplant
      injection of antilymphocyte serum, plasma glucose was normalized for >100 days.
      These data demonstrate, for the first time, successful single-donor-to-single
      recipient transplantation of allogeneic rat pancreatic islets. Because islet
      engraftment may still be regarded as a main problem for clinical islet
      transplantation, the pretransplant islet culture regimen outlined in this article
      may lead to a more efficient use of donor pancreatic islet tissue in the clinical
      setting, as well.

PMID- 12428741
TI  - Gene transfection and expression of transforming growth factor-beta1 in nonobese
      diabetic mouse islets protects beta-cells in syngeneic islet grafts from
      autoimmune destruction.
AB  - Nonobese diabetic (NOD) mice develop diabetes and destroy syngeneic islet grafts
      through an autoimmune response. Because transforming growth factor (TGF)-beta1
      downregulates immune responses, we tested whether overexpression of TGF-beta1 by
      gene transfection of NOD mouse islets could protect beta-cells in islet grafts
      from autoimmune destruction. NOD mouse islet cells were transfected with an
      adenoviral DNA expression vector encoding porcine latent TGF-beta1 (Ad TGF-beta1)
      or the adenoviral vector alone (control Ad vector). The frequency of total islet
      cells expressing TGF-beta1 protein was increased from 12 +/- 1% in control Ad
      vector-transfected cells to 89 +/- 4% in Ad TGF-beta1-transfected islet cells,
      and the frequency of beta-cells that expressed TGF-beta1 was increased from 12 +/
      1% to 60 +/- 7%. Also, secretion of TGF-beta1 was significantly increased in
      islets that overexpressed TGF-beta1. Ad TGF-beta1-transfected NOD mouse islets
      that overexpressed TGF-beta1 prevented diabetes recurrence after transplantation
      into diabetic NOD mice for a median of 22 days compared with only 7 days for
      control Ad vector-transfected islets (p = 0.001). Immunohistochemical examination
      of the islet grafts revealed significantly more TGF-beta1+ cells and insulin+
      cells and significantly fewer CD45+ leukocytes in Ad TGF-beta1-transfected islet
      grafts. Also, islet beta-cell apoptosis was significantly decreased whereas
      apoptosis of graft-infiltrating leukocytes was significantly increased in Ad TGF
      beta1-transfected islet grafts. These observations demonstrate that
      overexpression of TGF-beta1, by gene transfection of NOD mouse islets, protects
      islet beta-cells from apoptosis and autoimmune destruction and delays diabetes
      recurrence after islet transplantation.

PMID- 12428742
TI  - Morphological and functional studies on submucosal islet transplants in normal
      and diabetic hamsters.
AB  - The long-term outcome of human islet allotransplantation is poor, and it remains
      to be seen if the Edmonton Protocol will make a positive impact upon the
      extension of posttransplant islet function. Hence, establishing an implantation
      site capable of sustaining islet allografts for a prolonged duration needs to be
      explored. In this study we investigated the submucosal space of the duodenum in
      Syrian golden hamsters. Following transplantation of more than 800 islets into
      streptozotocin (STZ)-induced diabetic hamsters, basal nonfasted blood glucose
      levels decreased from 403 +/- 14 to 143 +/- 10 mg/dl within 5 weeks
      posttransplantation. In these animals, in vivo islet function, as determined by
      intravenous glucose tolerance test (IVGTT), was similar to nondiabetic controls
      (K values: 1.16 +/- 0.12 vs. 0.95 +/- 0.06, respectively) and was significantly
      greater than diabetic controls (K value: 0.47 +/- 0.07). Islets transplanted into
      the submucosal space become richly vascularized within 2 weeks, and there is
      minimal host inflammatory infiltrate. The beta-cells of the graft remain well
      granulated with insulin for at least 129 days. We conclude that the submucosal
      space is an effective engraftment site for islets that warrants further
      development in a large-animal model.

PMID- 12428743
TI  - Comparison of size, viability, and function of fetal pig islet-like cell clusters
      after digestion using collagenase or liberase.
AB  - Liberase is a highly purified blend of collagenases that has been specifically
      developed to eliminate the numerous problems associated with the conventional use
      of crude collagenase when isolating islet-like cell clusters (ICCs) from
      pancreases of different species. The influence of Liberase on yield, size,
      viability, and function of ICCs has been documented when this enzyme was used to
      digest adult but not fetal pancreases. In this study, we compared the effects of
      collagenase and Liberase on fetal pig ICCs. A total of eight fetal pig pancreas
      digestions were analyzed. Fetuses were obtained from Large White Landrace pigs of
      gestational age 80 +/- 2.1 days. The pancreases were digested with either 3 mg/ml
      collagenase P or 1.2 mg/ml Liberase HI. The time taken to digest the pancreas was
      shorter for collagenase when compared with Liberase (22 +/- 2 vs. 31 +/- 2 min).
      The size of ICCs was similar for both collagenase (83 +/- 0.5 microm) and
      Liberase (79 +/- 0.4 microm) as was the number of ICCs produced per pancreas
      (7,653 +/- 1,297 vs. 8,101 +/- 1,177). Viability, as assessed using fluorescent
      markers, was slightly greater for Liberase (79 +/- 1% vs. 76 +/- 1%, p < 0.05).
      Responsiveness to beta-cell stimulus (20 mM KCl) was similar for both methods of
      isolation, as was the insulin content of the ICCs, both in vitro and at I month
      after transplantation of 1,500 ICCs beneath the renal capsule of
      immunoincompetent mice. Despite the high content of endotoxins in collagenase,
      the above results show that this enzyme was equally as efficient as Liberase in
      isolating functional ICCs from fetal pig pancreas.

PMID- 12428744
TI  - Development of an immunoprivileged site to prolong islet allograft survival.
AB  - Sertoli cells (SC) play a critical role in the maintenance of the
      immunoprivileged environment of the testis. We hypothesized that preengrafting SC
      would allow one to develop a vascularized immunoprivileged ectopic site that
      provides protection for mouse islet allografts. SC, prepared from 9-day Balb/c
      mice, were transplanted under the kidney capsule in adult Balb/c mice. After SC
      engraftment (approximately 30 days), mice were rendered diabetic and subsequently
      implanted with Balb/c or CBA/J islets directly adjacent to the established SC
      grafts. Preengrafted SC (5.7 +/- 0.2 x 106) had no adverse effect on syngeneic
      islet graft function. When allogeneic islets were transplanted into the
      immunoprivileged ectopic site created by preengrafting 6.4 +/- 0.3 x 10(6) SC,
      mean graft survival was slightly prolonged (32.4 +/- 6.0 days) compared with
      control mice that received allogeneic islets alone (16.3 +/- 1.5 days; p =
      0.329). In contrast, when 4.8 +/- 0.4 x 10(6) SC were preengrafted, islet
      allograft survival was significantly prolonged (66.1 +/- 9.8 days; p = 0.001).
      Four of eight mice, preimplanted with 4.8 +/- 0.4 x 10(6) SC, remained
      normoglycemic throughout the follow-up period (83.8 +/- 8.6 days) and returned to
      a diabetic state only when the kidneys bearing the composite grafts were removed.
      Transplantation of islets into an immunoprivileged ectopic site created by
      preengrafting SC did not affect islet function and, moreover, provided a means of
      developing an immunopriveliged ectopic site that permits prolonged islet
      allograft survival without systemic immunosuppression.

PMID- 12428745
TI  - Intrasplenic transplantation of encapsulated cells: a novel approach to cell
      therapy.
AB  - Cell therapy is likely to succeed clinically if cells survive at the
      transplantation site and are protected against immune rejection. We hypothesized
      that this could be achieved with intrasplenic transplantation of encapsulated
      cells because the cells would have instant access to oxygen and nutrients while
      being separated from the host immune system. In order to provide proof of the
      concept, primary rat hepatocytes and human hepatoblastoma-derived HepG2 cells
      were used as model cells. Rat hepatocytes were encapsulated in 100-kDa hollow
      fibers and cultured for up to 28 days. Rat spleens were implanted with hollow
      fibers that were either empty or contained I x 10(7) rat hepatocytes. Human HepG2
      cells were encapsulated using alginate/ poly-L-lysine (ALP) and also transplanted
      into the spleen; control rats were transplanted with free HepG2 cells. Blood
      human albumin levels were measured using Western blotting and spleen sections
      were immunostained for albumin. Hepatocytes in monolayer cultures remained viable
      for only 6-10 days, whereas the cells cultured in hollow fibers remained viable
      and produced albumin throughout the study period. Allogeneic hepatocytes
      transplanted in hollow fibers remained viable for 4 weeks (end of study). Free
      HepG2 transplants lost viability and function after 7 days, whereas encapsulated
      HepG2 cells remained viable and secreted human albumin at all time points
      studied. ALP capsules, with or without xenogeneic HepG2 cells, produced no local
      fibrotic response. These data indicate that intrasplenic transplantation of
      encapsulated cells results in excellent survival and function of the transplanted
      cells and that the proposed technique has the potential to allow transplantation
      of allo- and xenogeneic cells (e.g., pancreatic islets) without
      immunosuppression.

PMID- 12428746
TI  - Innocuous intracellular ice improves survival of frozen cells.
AB  - Extensive efforts to avoid intracellular ice formation (IF) during freezing have
      been central to current methods used for the preservation and long-term storage
      of cells and tissues. In this study, we examined the effect of intracellular ice
      formation on the postthaw survival of V-79W fibroblast and MDCK epithelial cells
      using convection cryomicroscopy and controlled-rate freezing. V-79W and MDCK
      cells were cultured as single attached cells or as confluent cell monolayers.
      Postthaw cell survival was assessed using three different indices: the presence
      of an intact plasma membrane, the ability to reduce alamarBlue, and the capacity
      to form colonies in culture. Regulating the isothermal nucleation temperature was
      used to control the incidence of IIF in the model systems. We report that the
      presence of intracellular ice in confluent monolayers at high subzero
      temperatures does not adversely affect postthaw cell survival. Further, we show
      that in the absence of chemical cryoprotectants, the formation of intracellular
      ice alone improves the postthaw survival of cultured V-79W fibroblast and MDCK
      epithelial cells. Improved long-term storage of cells and tissues will result by
      incorporating innocuous intracellular ice formation into current strategies for
      cryopreservation.

PMID- 12428747
TI  - Gene therapy: a lipofection approach for gene transfer into primary endothelial
      cells.
AB  - Despite the great potential of gene therapy to become a new treatment modality in
      future medicine, there are still many limitations to overcome before this gene
      approach can pass to the stage of human trial. The foremost obstacle is the
      development of a safe, efficient, and efficacious vector system for in vivo gene
      application. This study evaluated the efficacy of lipofection as a gene delivery
      vehicle into primary endothelial cells. Transfection efficiency of several lipid
      based reagents (Effectene, Fugene 6, DOTAP) was examined at experimental
      temperatures of 37 degrees C, 24 degrees C, and 6 degrees C. Human umbilical vein
      endothelial cells (HUVECs) were transfected with the enhanced green fluorescent
      protein (EGFP) using precise amounts of DNA (Effectene, 0.2 microg; Fugene 6, 0.5
      microg; DOTAP, 2.5 microg) and lipids (Effectene, 10 microl; Fugene 6, 6 microl;
      DOTAP, 15 microl) optimized in our laboratory. Duration of incubation in the
      DNA/lipid transfection mixture varied for each lipid transfectant as follows: 5 h
      for both Fugene 6 and DOTAP and 3 h for Effectene. Efficiency of transfection was
      quantified by microscopic evaluation of EFGP expression in a minimum of 100 cells
      per group. Transfection efficiencies achieved with these lipofection agents were
      34 +/- 1.3% (mean +/- SEM), 33 +/- 1.4%, and 18 +/- 1.5% for Effectene, Fugene 6,
      and DOTAP, respectively, at 37 degrees C. Transfection results were lower at 24
      degrees C with mean efficiencies of 26 +/- 2.4% for Effectene, 14 +/- 2.9% for
      Fugene 6, and 15 +/- 3.2% for DOTAP. Furthermore, mean efficiencies at 6 degrees
      C were 6 +/- 0.5%, 8 +/- 1.5%, and 6 +/- 0.0% for Effectene, Fugene 6, and DOTAP,
      respectively. Efficiency of transfection appeared to be temperature dependent
      (ANOVA; p < 0.0001). In spite of a significant decrease (37 degrees C vs. 24
      degrees C: p < 0.0001; 37 degrees C vs. 6 degrees C: p < 0.0001; 24 degrees C vs.
      6 degrees C: p < 0.0115) in transfection efficiency at low temperatures, the
      successful in vitro gene manipulation renders lipofection a potential gene
      delivery strategy for in vivo gene therapy.

PMID- 12428748
TI  - Vascular adventitia is a suitable compartment to transplant transduced vascular
      smooth muscle cells for ex vivo gene expression.
AB  - Vascular smooth muscle cells (VSMC) are ideal for systemic gene therapy because
      of their proximity to blood vessels and they have demonstrated long-term
      exogenous gene expression in vivo. However, the procedure generally followed to
      seed the transduced VSMC onto arteries denuded of endothelial cells usually
      induces stenosis and thrombosis, with a consequent high risk for use in humans.
      We demonstrate here that the vascular adventitia is a suitable place to introduce
      transduced VSMC and to secrete therapeutic proteins into the blood stream by a
      simple procedure, avoiding postoperative vascular complications. Transduced VSMC,
      with the retroviral vectors carrying the human growth hormone gene (hGH), were
      seeded into the adventitia of the rat abdominal aorta by single injection of a
      cell suspension. Based on the hGH and anti-hGH production in serum and on
      histological analysis of the removed aortas, we demonstrated hGH production over
      the 2-month experimental period. None of the animals used in the experiment
      showed stenosis, thrombosis, or other vascular or visible physiological
      abnormalities.

PMID- 12428749
TI  - Pharmacological, cell, and gene therapy strategies to promote spinal cord
      regeneration.
AB  - In this review, recent studies using pharmacological treatment, cell
      transplantation, and gene therapy to promote regeneration of the injured spinal
      cord in animal models will be summarized. Pharmacological and cell
      transplantation treatments generally revealed some degree of effect on the
      regeneration of the injured ascending and descending tracts, but further
      improvements to achieve a more significant functional recovery are necessary. The
      use of gene therapy to promote repair of the injured nervous system is a
      relatively new concept. It is based on the development of methods for delivering
      therapeutic genes to neurons, glia cells, or nonneural cells. Direct in vivo gene
      transfer or gene transfer in combination with (neuro)transplantation (ex vivo
      gene transfer) appeared powerful strategies to promote neuronal survival and
      axonal regrowth following traumatic injury to the central nervous system. Recent
      advances in understanding the cellular and molecular mechanisms that govern
      neuronal survival and neurite outgrowth have enabled the design of experiments
      aimed at viral vector-mediated transfer of genes encoding neurotrophic factors,
      growth-associated proteins, cell adhesion molecules, and antiapoptotic genes.
      Central to the success of these approaches was the development of efficient,
      nontoxic vectors for gene delivery and the acquirement of the appropriate
      (genetically modified) cells for neurotransplantation. Direct gene transfer in
      the nervous system was first achieved with herpes viral and El-deleted adenoviral
      vectors. Both vector systems are problematic in that these vectors elicit
      immunogenic and cytotoxic responses. Adeno-associated viral vectors and
      lentiviral vectors constitute improved gene delivery systems and are beginning to
      be applied in neuroregeneration research of the spinal cord. Ex vivo approaches
      were initially based on the implantation of genetically modified fibroblasts.
      More recently, transduced Schwann cells, genetically modified pieces of
      peripheral nerve, and olfactory ensheathing glia have been used as implants into
      the injured spinal cord.

PMID- 12428750
TI  - Neural transplantation in the new millenium.

PMID- 12428751
TI  - Basic biological research at the dawn of a new century.

PMID- 12428752
TI  - Molecular aspects of vertebrate retinal development.
AB  - The formation of retina from neural plate has been mapped extensively by
      anatomical and molecular methods. The major cascades of transcription factor
      expression have been identified, and deficits resulting from transcription factor
      knockouts are well characterized. There is extensive cross-regulation, both
      positive and negative, at the transcriptional level between transcription factors
      and this is vital in the formation of neural compartments. Many transcription
      factors are important at both early stages of optic cup formation and later
      stages of terminal differentiation of retinal cell types. The transcription
      factor cascades can be regulated by extrinsic factors, and some of the
      intracellular signaling pathways whereby this is achieved have been identified.
      Defining the quantitative interactions between regulatory molecules will be the
      next step in understanding this excellent model of vertebrate central nervous
      system (CNS) development.

PMID- 12428753
TI  - Reelin signaling and Cdk5 in the control of neuronal positioning.
AB  - Neuronal positioning is important for higher brain function because it is the
      architectural basis of the formation of precise synaptic circuits. Analysis of
      neurological mutant mice has led to dramatic progress in the identification and
      characterization of molecules important for neuronal positioning in the
      developing mammalian brain. Among these molecules, identification of signal
      pathways mediated by Reelin and Cdk5 kinase has provided a conceptual framework
      for exploring the molecular mechanisms underlying proper neuronal positioning in
      the developing mammalian brain. Recent evidence has implicated synergism between
      Reelin signaling and Cdk5 in contributing to the proper positioning of selective
      neuronal populations.

PMID- 12428754
TI  - Molecular constituents of the node of Ranvier.
AB  - The interaction between neurons and glial cells that results in myelin formation
      represents one of the most remarkable intercellular events in development. This
      is especially evident at the primary functional site within this structure, the
      node of Ranvier. Recent experiments have revealed a surprising level of
      complexity within this zone, with several components, including ion channels,
      sequestered with a very high degree of precision and sharply demarcated borders.
      We discuss the current state of knowledge of the cellular and molecular
      mechanisms responsible for the formation and maintenance of the node. In normal
      axons, Na+ channels are present at high density within the nodal gap, and voltage
      dependent K+ channels are sequestered on the internodal side of the paranode--a
      region known as the juxtaparanode. Modifying the expression of certain surface
      adhesion molecules that have been recently identified, markedly alters this
      pattern. There is a special emphasis on contactin, a protein with multiple roles
      in the nervous system. In central nervous system (CNS) myelinated fibers,
      contactin is localized within both the nodal gap and paranodes, and appears to
      have unique functions in each zone. New experiments on contactin-null mutant mice
      help to define these mechanisms.

PMID- 12428755
TI  - Alphaviral vectors for gene transfer into neurons.
AB  - Alphaviruses are small, enveloped positive-strand RNA viruses that have been
      successfully transformed into expression vectors in the case of Semliki Forest
      virus (SFV), Sindbis virus (SIN), and Venezuelan equine encephalitis virus.
      Compared to other viral vectors, their advantages are easy and fast generation of
      recombinant viral particles, rapid onset, and high-level transgene expression.
      When applied to neuronal tissue, SFV and SIN vectors possess the additional
      advantage of efficiently and preferentially transducing neurons rather than non
      neuronal cells. This article gives an overview of the biology of SFV and SIN,
      their generation into expression vectors, and their application in neurobiology,
      with particular emphasis on the transduction of hippocampal neurons. In addition,
      it describes the more recent development of alphaviral vectors with decreased or
      absent cytotoxicity and lowered transgene expression, temperature-controllable
      gene expression, and altered host-cell specificity in the central nervous system
      (CNS). Finally, the review evaluates the use of SFV and SIN vectors in
      hippocampal tissue cultures vs recombinant lentivirus, adenovirus type 5, adeno
      associated virus type 2, and measles virus.

PMID- 12428756
TI  - Regulation of GABAergic inhibition by serotonin signaling in prefrontal cortex:
      molecular mechanisms and functional implications.
AB  - Serotonergic neurotransmission in prefrontal cortex (PFC) plays a key role in
      regulating emotion and cognition under normal and pathological conditios.
      Increasing evidence suggests that serotonin receptors are involved in the complex
      regulation of GABAergic inhibitory transmission in PFC. Activation of
      postsynaptic 5-HT2 receptors in PFC pyramidal neurons inhibits GABAA-receptor
      currents via phosphorylation of GABAA receptor gamma2 subunits by RACK1-anchored
      PKC. In contrast, activation of postsynaptic 5-HT4 receptors produces an activity
      dependent bi-directional regulation of GABA-evoked currents in PFC pyramidal
      neurons, which is mediated through phosphorylation of GABAA-receptor beta
      subunits by anchored PKA. On the presynaptic side, GABAergic inhibition is
      regulated by 5-HT through the activation of 5-HT2, 5-HT1, and 5-HT3 receptors on
      GABAergic intereneurons. These data provide a molecular and cellular mechanism
      for serotonin to dynamically regulate synaptic transmission and neuronal
      excitability in the PFC network, which may underlie the actions of many
      antidepressant and antipsychotic drugs.

PMID- 12428757
TI  - Downloading central clock information in Drosophila.
AB  - Pigment-dispersing factor (PDF) neuropeptide is an important neurochemical that
      carries circadian timing information originating from the central oscillator in
      Drosophila. Several core-clock factors function as upstream pdf regulators; the
      dClock and cycle genes control pdf transcription, whereas the period and timeless
      genes regulate post-translational processes of PDF via unknown mechanisms. For a
      downstream neural path, PDF most likely acts as a local modulator, which binds to
      its receptors that are possibly linked to Ras/MAPK signaling pathways. PDF
      receptor-containing cells seem to localize in the vicinity of nerve terminals
      from pace-making neurons. Although PDF is likely to be a principal clock-output
      factor, our recent evidence predicts the presence of other neuropeptides with
      rhythm-relevant functions. Furthermore, recent microarray screens have identified
      numerous potential clock-controlled genes, suggesting that diverse physiological
      processes might be affected by the biological clock system.

PMID- 12428758
TI  - Structure of the sodium channel gene SCN11A: evidence for intron-to-exon
      conversion model and implications for gene evolution.
AB  - Exon/intron boundaries in the regions encoding the trans-membrane segments of
      voltage-gated Na channel genes are conserved, supporting their proposed evolution
      from a single domain channel, while the exons encoding the cytoplasmic loops are
      less conserved with their evolutionary heritage being less defined. SCN11A
      encodes the tetrodotoxin-resistant (TTX-R) sodium channel Nav1.9a/NaN, which is
      preferentially expressed in nociceptive primary sensory neurons of dorsal root
      ganglia (DRG) and trigeminal ganglia. SCN11A is localized to human chromosome 3
      (3p21-24) close to the other TTX-R sodium channel genes SCN5A and SCN10A. An
      alternative transcript, Nav1.9b, has been detected in rat DRG and trigeminal
      ganglion. Nav1.9b is predicted to produce a truncated protein due to a frame
      shift, which is introduced by the new sequence of exon 23c (E23c). In human and
      mouse SCN11A, divergent splicing signals prevent utilization of E23c. Unlike
      exons 5A/N in genes encoding TTX-sensitive sodium channels, which appear to have
      resulted from exon duplication, E23c might have evolved from the conversion of an
      intronic sequence. Although a functional role for Nav1.9b has yet to be
      established, intron-to-exon conversion may represent a mechanism for ion channels
      to acquire novel features.

PMID- 12428759
TI  - Mechanisms of GABAA receptor assembly and trafficking: implications for the
      modulation of inhibitory neurotransmission.
AB  - Fast synaptic inhibition in the brain is largely mediated by ionotropic GABA
      receptors, which can be subdivided into GABAA and GABAC receptors based on
      pharmacological and molecular criteria. GABAA receptors are important therapeutic
      targets for a range of sedative, anxiolytic, and hypnotic agents and are
      implicated in several diseases including epilepsy, anxiety, depression, and
      substance abuse. In addition, modulating the efficacy of GABAergic
      neurotransmission may play a key role in neuronal plasticity. Recent studies have
      begun to reveal that the accumulation of ionotropic GABAA receptors at synapses
      is a highly regulated process that is facilitated by receptor-associated proteins
      and other cell-signaling molecules. This review focuses on recent experimental
      evidence detailing the mechanisms that control the assembly and transport of
      functional ionotropic GABAA receptors to cell surface sites, in addition to their
      stability at synaptic sites. These regulatory processes will be discussed within
      the context of the dynamic modulation of synaptic inhibition in the central
      nervous system (CNS).

PMID- 12428760
TI  - A short history of LIM domains (1993-2002): from protein interaction to
      degradation.
AB  - The LIM domain is a cysteine-rich zinc-finger motif found in a large family of
      proteins. In LIM-homeodomain (LIM-hd) transcription factors and LIM-only (LMO)
      factors, the LIM domains are responsible for key interactions with co-activators,
      co-repressors, competitors, and other transcription factors, and are therefore of
      considerable importance for the regulation of associated transcriptional
      activity. In this review, the authors describe the progressive discoveries of
      NLI/Ldb/CLIM, LMO and RLIM, and discuss how the field was very recently updated
      by the finding that LIM-hd transcriptional activity is controlled by regulated
      degradation of cofactors and LIM-hd themselves.

PMID- 12428761
TI  - Hypoxia signaling to genes: significance in Alzheimer's disease.
AB  - Aberrations in neural signaling, converging to and diverging from oxidative
      metabolism and blood supply, contribute to the initiation and maintenance of
      inflammatory responses, neuronal degeneration, and age-related cognitive decline
      in Alzheimer's disease (AD). Hypoxia/ischemia triggers phospholipase A2, leading
      to the accumulation of free arachidonic and docosahexaenoic acids (AA, DHA), as
      well as that of lysophospholipids. Some of these bioactive lipid messengers in
      turn give rise to several downstream lipid messengers, such as platelet
      activating factor (PAF) and ecosanoids (prostaglandins and leukotrienes).
      Eicosanoid synthesis is highly regulated in hypoxia and in reperfusion subsequent
      to ischemia. As one of the consequences, mitochondrial function is disrupted and
      reactive oxygen species (ROS) both contribute to the expansion of cellular
      inflammatory responses and reduce the expression of genes required to maintain
      synaptic structure and function. On the other hand, pro-inflammatory genes are up
      regulated. One of these, the inducible cyclooxygenase-2 (COX-2), along with
      oxygen-starved mitochondria, comprise the major sources of ROS in the brain
      during hypoxia, ischemia, and reperfusion. One outcome is a sustained metabolic
      stress that drives progressive dysfunction, apoptosis and/or necrosis, and brain
      cell death. How hypoxia modulates oxygen-sensitive gene expression is not well
      understood. Pro-inflammatory gene families that contribute to neurodegeneration
      are transiently activated in part by the heterodimeric oxygen-sensitive DNA
      binding proteins nuclear factor for kappa B (NF-kappaB) and hypoxia-inducible
      factor-alpha (HIF-1alpha). Here the authors summarize current studies supporting
      the hypothesis that synaptically-derived lipid messengers play significant roles
      in ischemic stroke and that hypoxia is an important contributor to the onset and
      progression of AD neurodegeneration.

PMID- 12428762
TI  - Intracellular A-beta amyloid, a sign for worse things to come?
AB  - In this review the authors discuss the possible neuropathological role of
      intracellular amyloid-beta accumulation in Alzheimer's disease (AD) pathology.
      There is abundant evidence that at early stages of the disease, prior to A-beta
      amyloid plaque formation, A-beta peptides accumulate intraneuronally in the
      cerebral cortex and the hippocampus. The experimental evidence would indicate
      that intracellular amyloid-beta could originate both by intracellular
      biosynthesis and also from the uptake of amyloidogenic peptides from the
      extracellular milieu. Herein the aspects of the possible impact of intracellular
      amyloid-beta in human AD pathology are discussed, as well as recent observations
      from a rat transgenic model with a phenotype of intracellular accumulation of A
      beta fragments in neurons of the hippocampus and cortex, without plaque
      formation. In this model, the intracellular amyloid-beta phenotype is accompanied
      by increased MAPK/ERK activity and tau hyperphosphorylation. Finally, the authors
      discuss the hypothesis that, prior to plaque formation, intracellular A-beta
      accumulation induces biochemical and pathological changes in the brain at the
      cellular level priming neurons to further cytotoxic attack of extracellular
      amyloidogenic peptides.

PMID- 12428764
TI  - The spectrum of congenital myasthenic syndromes.
AB  - The past decade saw remarkable advances in defining the molecular and genetic
      basis of the congenital myasthenic syndromes. These advances would not have been
      possible without antecedent clinical observations, electrophysiologic analysis,
      and careful morphologic studies that pointed to candidate genes or proteins. For
      example, a kinetic abnormality of the acetylcholine receptor (AChR) detected at
      the single channel level pointed to a kinetic mutation in an AChR subunit;
      endplate AChR deficiency suggested mutations residing in an AChR subunit or in
      rapsyn; absence of acetylcholinesterase (AChE) from the endplate predicted
      mutations in the catalytic or collagen-tailed subunit of this enzyme; and a
      history of abrupt episodes of apnea associated with a stimulation dependent
      decrease of endplate potentials and currents implicated proteins concerned with
      ACh resynthesis or vesicular filling. Discovery of mutations in endplate-specific
      proteins also prompted expression studies that afforded proof of pathogenicity,
      provided clues for rational therapy, lead to precise structure function
      correlations, and highlighted functionally significant residues or molecular
      domains that previous systematic mutagenesis studies had failed to detect. An
      overview of the spectrum of the congenital myasthenic syndromes suggests that
      most are caused by mutations in AChR subunits, and particularly in the epsilon
      subunit. Future studies will likely uncover new types of CMS that reside in
      molecules governing quantal release, organization of the synaptic basal lamina,
      and expression and aggregation of AChR on the postsynaptic junctional folds.

PMID- 12428763
TI  - Acute neuronal injury, excitotoxicity, and the endocannabinoid system.
AB  - The endocannabinoid system is a valuable target for drug discovery, because it is
      involved in the regulation of many cellular and physiological functions. The
      endocannabinoid system constitutes the endogenous lipids anandamide, 2
      arachidonoylglycerol and noladin ether, and the cannabinoid CB1 and CB2 receptors
      as well as the proteins for their inactivation. It is thought that
      (endo)cannabinoid-based drugs may potentially be useful to reduce the effects of
      neurodegeneration. This paper reviews recent developments in the endocannabinoid
      system and its involvement in neuroprotection. Exogenous (endo)cannabinoids have
      been shown to exert neuroprotection in a variety of in vitro and in vivo models
      of neuronal injury via different mechanisms, such as prevention of excitotoxicity
      by CB1-mediated inhibition of glutamatergic transmission, reduction of calcium
      influx, and subsequent inhibition of deleterious cascades, TNF-alpha formation,
      and anti-oxidant activity. It has been suggested that the release of endogenous
      endocannabinoids during neuronal injury might be a protective response. However,
      several observations indicate that the role of the endocannabinoid system as a
      general endogenous protection system is questionable. The data are critically
      reviewed and possible explanations are given.

PMID- 12428767
TI  - Immediate antecedents of cigarette smoking: an analysis from ecological momentary
      assessment.
AB  - The authors assessed the association between smoking and situational cues,
      including affect, in real-world contexts. Using ecological momentary assessment,
      304 smokers monitored ad-lib smoking for 1 week, recording each cigarette on palm
      top computers. Generalized estimating equations contrasted 10,084 smoking and
      11,155 nonsmoking situations. After controlling for smoking restrictions, smoking
      was strongly related to smoking urges and modestly related to consumption of
      coffee and food, the presence of other smokers, and several activities. Smoking
      was unrelated to negative or positive affect or to arousal, although it was
      associated with restlessness. Thus, in daily life, affect appears to exert little
      influence over ad-lib smoking in heavy smoking adults.

PMID- 12428765
TI  - The neurobiology of apolipoproteins in psychiatric disorders.
AB  - A genetic contribution to the transmission of psychiatric disorders has been
      established and it is now accepted that several genes confer susceptibility to
      schizophrenia, and similar disorders, giving rise to a complex polygenic mode of
      inheritance. With the high-throughput molecular profiling techniques available,
      apolipoproteins have emerged as being important factors in psychiatric disorders.
      This review will focus on three apolipoproteins that have recently been shown to
      be elevated in neuropsychiatric disorders: apoD, apoE, and apoL. Furthermore, the
      authors discuss the role of apoD in the pathology and pharmacotherapy of
      schizophrenia and bipolar disorder.

PMID- 12428766
TI  - Post-genomic era and gene discovery for psychiatric diseases: there is a new art
      of the trade? The example of the HUMTH01 microsatellite in the Tyrosine
      Hydroxylase gene.
AB  - The microsatellite HUMTH01, located in the first intron of the Tyrosine
      Hydroxylase (TH) gene (encoding the rate-limiting enzyme in the synthesis of
      catecholamines), is characterized by a TCAT repeated motif and has been used in
      genetic studies of neuropsychiatric and other complex diseases, in which
      catecholaminergic neurotransmission is implicated. After reporting a positive
      association between HUMTH01 and bipolar disorder as well as schizophrenia, the
      authors established that HUMTH01 alleles display the features of regulatory
      elements. Thereafter, they cloned two proteins (ZNF191 and HBP1), specifically
      binding to HUMTH01, and demonstrated that allelic variations of HUMTH01 have a
      quantitative silencing effect on TH gene expression in vitro, and correlate with
      quantitative and qualitative changes in the binding by ZNF191. The authors aim to
      characterize the transduction pathway impinging on the HUMTH01 microsatellite and
      establish its relevance for TH gene regulation in vivo. Since the TCAT repeated
      sequence is widespread throughout the genome, their approach may lead to the
      dissection of the mechanisms underlying the quantitative expression of several
      genes implicated in complex genetic traits, both normal and pathological. Thus,
      these investigations on the possible contribution and potential role of the
      HUMTH01 microsatellite in neuro-pathological conditions may represent an example
      of the different approaches needed to validate genetic targets in the "post
      genomic era."

PMID- 12428768
TI  - Psychometric schizotypy and motor performance.
AB  - Motor abnormalities have long been a focus in discussions of schizophrenia. The
      present study used a newly developed line drawing task to examine fine motor
      performance and psychometrically assessed schizotypy in a large, randomly
      ascertained sample of young adults (N = 120) with no history of psychosis. Poor
      motor performance on the line drawing task, indexed by root-mean-square error
      (RMS), was significantly related to 4 separate psychometric measures of
      schizotypy in the overall sample. The psychometric schizotypy-RMS association
      remained significant for 2 of the schizotypy measures even when the effects of
      intellectual functioning, mental state factors, and sustained attention were
      statistically controlled in a regression analysis. The status of the line drawing
      index as a schizophrenia liability measure is discussed.

PMID- 12428769
TI  - Waxing and waning in concert: dynamic comorbidity of conduct disorder with other
      disruptive and emotional problems over 7 years among clinic-referred boys.
AB  - Six waves of structured diagnostic assessments were conducted of 168 clinic
      referred 7- to 12-year-olds, over 7 years. Wave-to-wave changes in the number of
      conduct disorder (CD) behaviors were paralleled by correlated changes in the
      numbers of symptoms of oppositional defiant disorder (ODD), attention
      deficit/hyperactivity disorder (ADHD), depression, and anxiety. In addition, CD
      in Wave 1 predicted levels of ODD, ADHD, depression, and anxiety in later waves
      when initial levels of those symptoms were controlled, but only ODD in Wave 1
      predicted CD in later waves when initial CD levels were controlled. These
      findings indicate a striking degree of dynamic comorbidity between CD and other
      types of psychopathology and provide an initial empirical framework for needed
      developmental models of comorbidity.

PMID- 12428770
TI  - Confluent paranoia in African American psychiatric patients: an empirical study
      of Ridley's typology.
AB  - This study examined Ridley's (1984) typology of paranoia in African Americans,
      which assumes orthogonal dimensions of culture and pathology in symptom
      expression. Median split of scores on the Cultural Mistrust Inventory and the
      scale of False Beliefs and Perceptions represented high and low levels of
      cultural paranoia and pathological paranoia, respectively. The 4 groups of Black
      patients were nonparanoia, cultural paranoia, pathological paranoia, and
      confluent paranoia. A Fenigstein Paranoia Scale manipulation check indicated that
      differences in paranoid symptom expression among the groups were partially
      supportive of Ridley's model, as were measures of perceptions of hostility and
      self-esteem. Omnibus tests of between-groups differences were significant for
      global assessment of functioning and number of symptoms recorded in patients'
      charts. Predicted pattern testing revealed a significant severity dimension in
      mean scores across paranoia groups for some measures of clinician-rated
      functioning but not others. SCID interviewers' ratings of cultural mistrust and
      number of times restrained (or secluded) were more consistent with a pattern
      representing a cultural dimension than a severity dimension across paranoia
      groups. Findings provide limited empirical validation of Ridley's typology of
      paranoia in African Americans.

PMID- 12428771
TI  - Age, gender, race, socioeconomic status, and birth cohort differences on the
      children's depression inventory: a meta-analysis.
AB  - A within-scale meta-analysis was performed on 310 samples of children (ages 8-16;
      N = 61,424) responding to the Children's Depression Inventory (CDI). Girls'
      depression scores stayed steady from ages 8 to 11 and then increased between ages
      12 and 16. Boys' CDI scores were stable from ages 8 to 16 except for a high CDI
      score at age 12. Girls' scores were slightly lower than boys' during childhood,
      but girls scored higher beginning at age 13. There were no socioeconomic status
      effects and no differences between White and Black samples. However, Hispanic
      samples scored significantly higher on the CDI. Analyses for birth cohort showed
      a slight decrease in boys' CDI scores over time and no change for girls.
      Longitudinal studies demonstrated a marked testing effect.

PMID- 12428772
TI  - Behavioral activation and inhibition systems and the severity and course of
      depression.
AB  - Theorists have proposed that depression is associated with abnormalities in the
      behavioral activation (BAS) and behavioral inhibition (BIS) systems. In
      particular, depressed individuals are hypothesized to exhibit deficient BAS and
      overactive BIS functioning. Self-reported levels of BAS and BIS were examined in
      62 depressed participants and 27 nondepressed controls. Clinical functioning was
      assessed at intake and at 8-month follow-up. Relative to nondepressed controls,
      depressed participants reported lower BAS levels and higher BIS levels. Within
      the depressed group, lower BAS levels were associated with greater concurrent
      depression severity and predicted worse 8-month outcome. Levels of both BIS and
      BAS showed considerable stability over time and clinical state. Overall, results
      suggest that BAS dysregulation exacerbates the presentation and course of
      depressive illness.

PMID- 12428773
TI  - Modeling individual differences in perceptual and attentional processes related
      to bulimic symptoms.
AB  - Attentional and perceptual differences between women with high and low levels of
      bulimic symptoms were studied with techniques adapted from cognitive science.
      Stimuli were pictures of young women varying in body size and facial affect. A
      multidimensional scaling analysis showed that the high-symptom women were
      significantly more attentive to information about body size and significantly
      less attentive to information about affect. In prototype classification tasks,
      the high-symptom women used significantly more information about body size and
      significantly less information about affect. There were strong associations
      between individual differences in attention in the similarity task and decision
      making in the classification tasks. The study shows the potential utility of
      cognitive science methods for the study of cognitive factors in psychopathology.

PMID- 12428774
TI  - Emotion among women with psychopathy during picture perception.
AB  - Emotional reactions in women with psychopathy were examined in a mixed-picture
      paradigm using psychophysiological measures. Startle probes were presented at 2.0
      or 4.5 s following onset of a 6-s picture presentation. At 2.0 s, nonpsychopaths
      exhibited the typical pattern of eyeblink reflex magnitude: unpleasant > neutral
      > pleasant. Psychopaths with high general levels of anxiety also exhibited this
      pattern. Psychopaths with lower anxiety exhibited attenuated reflex magnitudes
      during unpleasant pictures. Similarly, when focusing on psychopathy components,
      only individuals expressing high antisocial behavior and high emotional
      detachment exhibited smaller reflex magnitudes during unpleasant pictures. At 4.5
      s, all groups exhibited normal, potentiated reflex magnitudes during unpleasant
      pictures. Group differences were not observed for other measures.

PMID- 12428776
TI  - Reappraising the link between peritraumatic dissociation and PTSD symptom
      severity: evidence from a longitudinal study of community violence survivors.
AB  - Cross-lagged panel analysis of longitudinal data collected from young adult
      survivors of community violence was used to examine the relationship between
      recall of peritraumatic dissociation and posttraumatic stress disorder (PTSD)
      symptom severity. Recollections of peritraumatic dissociation assessed within
      days of exposure differed from recollections measured at 3- and 12-month follow
      up interviews. Peritraumatic dissociation was highly correlated with PTSD
      symptoms within each wave of data collection. Baseline recollections of
      peritraumatic dissociation were not predictive of follow-up PTSD symptom severity
      after controlling for baseline PTSD symptom severity. This pattern of results
      replicates previous work demonstrating a correlation between peritraumatic
      dissociation and subsequent symptom severity. However, findings are not
      consistent with the prevailing view that peritraumatic dissociation leads to
      increased PTSD symptom severity.

PMID- 12428775
TI  - Spatial frequency discrimination in schizophrenia.
AB  - Pathways within the visual system can be distinguished on the basis of
      selectivity for low or high spatial frequencies. Spatial frequency discrimination
      was evaluated in 17 medicated male patients with schizophrenia and 19 male
      control subjects. Subjects were required to discriminate whether pairs of high
      contrast, sinusoidally modulated gratings were the same or different in spatial
      frequency. Accuracy performance was compared at high, medium, and low spatial
      frequencies on tasks matched for control performance. Patients showed a greater
      performance decrement of 12% on low as compared with 4% on high spatial
      frequencies. These findings suggest a disturbance of right hemisphere mechanisms
      involved in spatial perception and attention in schizophrenia.

PMID- 12428777
TI  - Confirmatory factor analyses of posttraumatic stress symptoms in deployed and
      nondeployed veterans of the Gulf War.
AB  - Confirmatory factor analysis was used to compare 6 models of posttraumatic stress
      disorder (PTSD) symptoms, ranging from 1 to 4 factors, in a sample of 3,695
      deployed Gulf War veterans (N = 1,896) and nondeployed controls (N = 1,799). The
      4 correlated factors-intrusions, avoidance, hyperarousal, and dysphoria-provided
      the best fit. The dysphoria factor combined traditional markers of numbing and
      hyperarousal. Model superiority was cross-validated in multiple subsamples,
      including a subset of deployed participants who were exposed to traumatic combat
      stressors. Moreover, convergent and discriminant validity correlations suggested
      that intrusions may be relatively specific to PTSD, whereas dysphoria may
      represent a nonspecific component of many disorders. Results are discussed in the
      context of hierarchical models of anxiety and depression.

PMID- 12428778
TI  - Implicit and explicit alcohol-related cognitions in heavy and light drinkers.
AB  - Implicit and explicit alcohol-related cognitions were measured in 2 dimensions:
      positive-negative (valence) and arousal-sedation, with 2 versions of the Implicit
      Association Test (IAT; A. G. Greenwald, D. E. McGhee, & J. L. Schwartz) and
      related explicit measures. Heavy drinkers (n = 24) strongly associated alcohol
      with arousal on the arousal IAT (especially men) and scored higher on explicit
      arousal expectancies than light drinkers (n = 24). On the valence IAT, both light
      and heavy drinkers showed strong negative implicit associations with alcohol that
      contrasted with their positive explicit judgments (heavy drinkers were more
      positive). Implicit and explicit cognitions uniquely contributed to the
      prediction of 1-month prospective drinking. Heavy drinkers' implicit arousal
      associations could reflect the sensitized psychomotor-activating response to drug
      cues, a motivational mechanism hypothesized to underlie the etiology of addictive
      behaviors.

PMID- 12428779
TI  - Understanding the relations among gender, disinhibition, and disruptive behavior
      in adolescents.
AB  - This study examined whether disinhibition shows similar relations with attention
      deficit/hyperactivity disorder (ADHD) and conduct disorder (CD) symptomatology
      among male and female adolescents. The mixed-incentive or punishment condition of
      Newman's go/no-go task was administered to 172 adolescents. As expected, ADHD
      symptoms in boys and girls were predictive of disinhibition (i.e., commission
      errors) in the mixed-incentive but not punishment condition. Also consistent with
      expectations, CD symptoms in boys were predictive of disinhibition in the mixed
      incentive but not punishment condition. In contrast, CD symptoms in girls were
      not predictive of disinhibition in either condition. These findings are discussed
      in terms of implications for understanding sex differences in the etiology of
      ADHD and CD.

PMID- 12428780
TI  - The differential functions of imagery and verbal thought in insomnia.
AB  - Individuals with insomnia were exposed to a stressor (speech threat) prior to
      getting into bed and were instructed to think about the speech and its
      implications in either images (Image group, n = 14) or verbal thought (Verbal
      group, n = 17). Participants completed questionnaires about speech anxiety,
      arousal, and sense of resolution. Measures were taken of subjective (sleep diary
      estimates) and objective (actigraphy) sleep-onset latency. In the short term, the
      Image group reported more distress and arousal relative to those in the Verbal
      group. In the longer term, the Image group estimated that they fell asleep more
      quickly and, the following morning, reported less anxiety and more comfort about
      giving the speech compared with the Verbal group.

PMID- 12428781
TI  - Negative mood, depressive symptoms, and major depression after smoking cessation
      treatment in smokers with a history of major depressive disorder.
AB  - Negative mood, depressive symptoms, and major depressive episodes (MDEs) were
      examined in 179 smokers with a history of major depression in a trial comparing
      standard smoking cessation treatment to treatment incorporating cognitive
      behavioral therapy for depression (CBT-D). Early lapses were associated with
      relatively large increases in negative mood on quit date. Mood improved in the 2
      weeks after quit date among those returning to regular smoking but not among
      those smoking moderately. Continuous abstinence was associated with short- and
      long-term reductions in depressive symptoms. MDE incidence during follow-up was
      15.3% and was not associated with abstinence. Unexpected was that CBT-D was
      associated with greater negative mood and depressive symptoms and increased MDE
      risk. Results suggest complex bidirectional associations between affect and
      smoking outcomes.

PMID- 12428782
TI  - Frontal brain asymmetry in restrained eaters.
AB  - It is well known that the eating patterns that restrain chronic dieters
      (restrained eaters) can be disinhibited by anxiety, which in turn has been
      associated with relative right frontal brain activity in independent
      electroencephalographic (EEG) studies. Combining these two lines of evidence, the
      authors tested the hypothesis that chronic restrained eating is associated with
      relative right frontal asymmetry. Resting anterior brain asymmetry and self
      reported measures of anxiety and depression were collected in 23 restrained and
      32 unrestrained eaters. As hypothesized, groups differed in tonic frontal
      activity, with restrained eaters showing more relative right frontal activity.
      Furthermore, relative right frontal activity was associated with greater self
      reported restraint. Right-sided prefrontal asymmetry may thus represent a
      diathesis associated with increased vulnerability toward restrained eating.

PMID- 12428783
TI  - Turning a deaf ear to fear: impaired recognition of vocal affect in psychopathic
      individuals.
AB  - The processing of emotional expressions is fundamental for normal socialization
      and interaction. Reduced responsiveness to the expressions of sadness and fear
      has been implicated in the development of psychopathy (R. J. R. Blair, 1995). The
      current study investigates the ability of adult psychopathic individuals to
      process vocal affect. Psychopathic and nonpsychopathic adults, defined by the
      Hare Psychopathy Checklist-Revised (PCL-R; R. D. Hare, 1991), were presented with
      neutral words spoken with intonations conveying happiness, disgust, anger,
      sadness, and fear and were asked to identify the emotion of the speaker on the
      basis of prosody. The results indicated that psychopathic inmates were
      particularly impaired in the recognition of fearful vocal affect. These results
      are interpreted with reference to the low-fear and violence inhibition mechanism
      models of psychopathy.

PMID- 12428784
TI  - Nicotine and familial vulnerability to schizophrenia: a discordant twin study.
AB  - Tobacco use is significantly associated with schizophrenia. However, it is not
      clear if smoking is associated with the illness itself, treatment, or underlying
      vulnerability to the disease. Smoking was studied in a sample of schizophrenic
      probands (n = 24), their unaffected co-twins (n = 24), and controls (n = 3,347).
      Unaffected co-twins had higher rates of daily smoking than controls. Probands and
      co-twins were more frequently unsuccessful in attempts to quit than controls.
      Probands reported shaky hands and depression following smoking cessation more
      often than controls, whereas unaffected co-twins reported difficulty
      concentrating, drowsiness, nervousness, and headache following smoking cessation
      more often than controls. Results are consistent with the hypothesis that
      nicotine use is influenced by familial vulnerability to schizophrenia, not just
      clinical schizophrenia per se.

PMID- 12428785
TI  - Standardization of clinical immunohistochemistry: why, how, and by whom?

PMID- 12428786
TI  - Tissue array technology for testing interlaboratory and interobserver
      reproducibility of immunohistochemical estrogen receptor analysis in a large
      multicenter trial.
AB  - Semiquantitative immunohistochemical assessment of estrogen receptor (ER) is used
      to predict the likelihood of response to antiestrogen therapy in breast
      carcinoma. If semiquantitative immunohistochemical analysis leads to therapeutic
      decisions, the importance of standardization and quality control increases. ER
      assessment reproducibility was studied among 172 laboratories using tissue
      microarray slides with 20 tissue spots negative and 10 tissue spots expressing ER
      at low, medium, or high levels. More than 80% of the laboratories demonstrated ER
      positivity in the medium- and high-expressing tissue spots, but only about 43%
      succeeded with tissue spots with low expression. Poor interlaboratory agreement
      was based on insufficient retrieval efficacy as shown by additional tests using
      autoclave pretreatment. The immunohistochemical scores used to quantify
      therapeutic target molecules remain inconclusive as long as progress toward
      standardized immunohistochemical procedures and evaluation is not achieved.
      Tissue microarray technology has proved its suitability for large-scale
      immunohistochemical trials, giving rise to new dimensions in control assessment.

PMID- 12428787
TI  - Usefulness of p53 and Ki-67 immunohistochemical analysis for preoperative
      diagnosis of extremely well-differentiated gastric adenocarcinoma.
AB  - Of 987 cases of gastric adenocarcinoma seen at Nagoya University School of
      Medicine, we found 6 rare, extremely well-differentiated advanced gastric
      adenocarcinomas that could not be diagnosed as malignant tumors with only H&E
      staining, even with repeated biopsies under preoperative endoscopy. The aim of
      this study was to determine whether an immunohistochemical method using p53 and
      Ki-67 antibody would be helpfulfor preoperative pathologic diagnosis. The cancer
      control cases were 16 cases of ordinary well-differentiated advanced gastric
      adenocarcinoma, while the gastritis control cases were 22 cases of Helicobacter
      pylori-positive chronic gastritis. The p53 labeling index and the localization of
      Ki-67+ cells showed that the special adenocarcinomas in biopsy specimens were
      distinct from the surrounding normal mucosa and chronic gastritis, but not from
      the cancer control cases. These methods are useful markers for preoperative
      pathologic diagnosis of extremely well-differentiated gastric adenocarcinoma,
      which sometimes is confused with regenerative atypical glands before operation.

PMID- 12428788
TI  - Interobserver reproducibility of Her-2/neu protein overexpression in invasive
      breast carcinoma using the DAKO HercepTest.
AB  - Although there are criteria for interpretation of the staining results for Her
      2/neu in the DAKO HercepTest, the determination of staining intensity and
      percentage of complete membrane staining is subjective. We studied 46 cases of
      invasive breast carcinoma to evaluate interobserver reproducibility among 5
      pathologists. Complete agreement was achieved in 22 (48%) of46 cases. Generalized
      kappa values indicated substantial agreement (0.80). Discrepancies between
      negative (0, 1+) and positive (2+, 3+) results occurred in 2 cases (kappa =
      0.96). One was because of a tangential cut of the basal part of the tumor that
      mimicked complete membranous staining, and the other was a borderline case that
      revealedfocal (5%-15%) complete membranous staining. Distinguishing weakly (2+)
      from strongly (3+) positive results showed agreement in only 13 (59%) of 22
      positive cases (kappa = 0.38). If more than 50% of tumor cells revealing strong
      complete membrane staining were regarded as strongly positive, agreement would be
      improved (kappa = 0.78). While there was a high percentage (70%-80%) of negative
      cases during routine evaluation, the good interobserver agreement and high
      negative predictive value made immunohistochemical analysis an effective
      screening test to exclude negative cases.

PMID- 12428789
TI  - CD97, but not its closely related EGF-TM7 family member EMR2, is expressed on
      gastric, pancreatic, and esophageal carcinomas.
AB  - CD97 expression is related closely to the dedifferentiation and tumor stage in
      thyroid carcinomas. We systematically examined the role of CD97 and its closest
      relative, EMR2, in normal and malignant gastric, esophageal, and pancreatic
      tissue. The normal tissues were EMR2-, whereas CD97 was expressed slightly in the
      parietal cells of gastric mucosa and in exocrine pancreatic cells. Interestingly,
      intralobular and interlobular pancreatic ducts were CD97+. All tumors were EMR2-.
      CD97 was expressed by 44 of 50 gastric, 14 of 18 pancreatic, and 10 of 13
      esophageal carcinomas. Of the 44 gastric cancers, 27 showed disseminated or
      scattered tumor cells at the invasion front with stronger CD97 expression than
      tumor cells located in solid tumor formations. There was no correlation between
      CD97 levels in the tumors or soluble CD97 in the serum samples and the
      clinicopathologic features of the patients. Taken together, significant numbers
      of gastric, esophageal, and pancreatic carcinomas are CD97+, whereas its homolog,
      EMR2, does not have any role in such tumors.

PMID- 12428790
TI  - Usefulness of DNA ploidy measurement on liquid-based smears showing conflicting
      results between cytology and high-risk human papillomavirus typing.
AB  - To improve the positive predictive value (PPV) for high-risk human papillomavirus
      (HR-HPV) in primary screening, DNA ploidy was measured on the same liquid-based
      sample by image cytometry in 984 cases showing discrepancies between cytology and
      HR-HPV testing. Of the conflicting results, 14.5% corresponded to a cytologic
      lesion (from atypical squamous cells of undetermined significance to high-grade
      squamous intraepithelial lesion [HSIL]) without HPV detected, and 85.5% of smears
      were within normal limits but revealed an HR-HPV infection. A suspect DNA profile
      was associated significantly with a lesion. In 497 patients who underwent
      repeated HPV testing, a normal DNA profile at the first smear predicted the
      clearance of HPV infection (sensitivity, 81.5%; specificity, 45.4%; PPV, 69%;
      negative predictive value, 62.4%). In persistent HR-HPV infection, a suspect DNA
      profile at the first smear increased the PPVfrom 10.8% to 22.7% for the detection
      of a histologically proven HSIL with a sensitivity of 95.2%. DNA ploidy can be
      used to select smears with high risk of HSIL, especially in cases of persistent
      HR-HPV infection.

PMID- 12428791
TI  - ASCCP patient management guidelines: Pap test specimen adequacy and quality
      indicators.
AB  - Our objective was to provide management guidelines according to Papanicolaou
      (Pap) test specimen adequacy based on literature review and expert opinion. A
      task force named by the American Society for Colposcopy and Cervical Pathology
      (ASCCP) conducted a literature review and discussed appropriate management. The
      Steering Committee of the ASCCP and other experts reviewed the guidelines. The
      guidelines recommend a repeated Pap test in 12 months for most women undergoing
      routine annual/biennial screening if the current Pap test is negative but either
      lacks an endocervical/ transformation zone component or is partially obscured.
      Indications for considering an earlier repeat are also provided. The preferred
      managementfor unsatisfactory Pap tests is a repeated Pap test within a short
      interval of 2 to 4 months. The management guidelines will help promote optimal
      and uniform follow-up of women according to Pap test specimen adequacy.

PMID- 12428792
TI  - Chronic inactive gastritis and coccoid Helicobacter pylori in patients treated
      for gastroesophageal reflux disease or with H pylori eradication therapy.
AB  - Gastric biopsy specimens from 105 consecutive adults with persistent dyspepsia
      who did not have changes due to esophageal reflux disease changes or gastric or
      duodenal ulcers at endoscopy were scored using the updated Sydney gastritis
      classification system. The medication history of proton pump inhibitors (PPIs) or
      Helicobacter pylori eradication therapy during the month before endoscopy was
      retrieved. Of the patients, 72 (68.6%) had chronic inactive gastritis, and 7
      (6.7%) had antral-predominant, chronic mild active gastritis. H pylori infection
      was present in 36 patients (34.3%), of whom 29 had chronic inactive gastritis.
      Forty-six patients (43.8%) had a positive medication history, including 40 (56%)
      of 72 with chronic inactive gastritis. The most common morphologic feature
      associated with H pylori infection was moderate chronic inactive gastritis, which
      was found most often in patients who had received recent PPIs or H pylori
      eradication therapy. Pathologists should be aware of the extensive use of these
      medications, their association with chronic inactive gastritis, and rare H pylori
      thatfrequently are coccoid shaped. Modified Giemsa stain may not be the optimal
      method to detect H pylori in this group of patients.

PMID- 12428793
TI  - The efficacy of reprocessing unsatisfactory cervicovaginal ThinPrep specimens
      with and without glacial acetic acid: effect on Hybrid Capture II human
      papillomavirus testing and clinical follow-up.
AB  - We sought to determine the efficacy of remaking initially unsatisfactory
      cervicovaginal ThinPrep (Cytyc, Boxborough, MA) specimens with and without the
      addition of glacial acetic acid (GAA) and the effect on human papilloma virus
      (HPV) Hybrid Capture II (HC2; Digene, Gaithersburg, MD) testing. A total of 583
      initially unsatisfactory ThinPrep slide preparations were identified, and remakes
      were made with the residual in the PreservCyt (Cytyc) vials with (n = 455) or
      without (n = 128) GAA. Clinical follow-up information was obtained. The addition
      of GAA resulted in a 56.5% reduction in unsatisfactory cases, compared with a
      26.6% reduction without GAA. Neoplasia and atypia were detected in the
      reprocessed specimens. The addition of GAA resulted in false-positive HC2 test
      results in 10 of 10 cases. Neutralization of the specimen may reverse this
      effect. Reprocessing unsatisfactory ThinPrep specimens with GAA can substantially
      reduce the overall unsatisfactory rate and result in the detection of significant
      lesions. However, the addition of GAA can result in false-positive results on HC2
      HPV tests.

PMID- 12428794
TI  - Analysis of the molecular quality of human tissues: an experience from the
      Cooperative Human Tissue Network.
AB  - The scientific usefulness of the data obtained from tissue analysis is related to
      specimen quality, which may be affected by conditions that may contribute to the
      degradation of the specimen before processing and analysis. We determined the
      usability of nucleic acids extracted from banked human tissues for further
      molecular analyses. We assayed 151 tissue specimens, storedfor various times at 4
      divisions of the Cooperative Human Tissue Network, National Cancer Institute,
      Bethesda, MD, for DNA and RNA degradation. Simple electrophoresis, polymerase
      chain reaction (PCR), reverse-transcriptase (RT)-PCR, and Northern blot analysis
      were compared to determine the optimal quality control procedure. In addition, a
      time course degradation procedure was performed on human lung tissue. Gel
      electrophoresis was as informative as PCR, RT-PCR, and Northern blot analysis in
      determining the molecular usefulness of the human tissues. Overall, 80% of the
      stored human tissues had good-quality DNA, and 60% had good-quality RNA.
      Electrophoresis procedures for DNA and RNA offer a quick and valuable measure of
      the molecular quality of stored human tissues. The DNA and RNA degradation of one
      tissue type (lung) was stable for both nucleic acids for up to 5 hours after
      excision.

PMID- 12428795
TI  - Diagnosis of Wihipple disease by immunohistochemical analysis: a sensitive and
      specific method for the detection of Tropheryma whipplei (the Whipple bacillus)
      in paraffin-embedded tissue.
AB  - Whipple disease is a rare infection characterized clinically by diarrhea, fever,
      weight loss, arthralgia, malabsorption, and other systemic manifestations. The
      etiologic agent, Tropheryma whipplei, has been cultured only rarely. By using a
      polyclonal rabbit antibody produced against a cultured strain of T whipplei,
      tissue sections from 18 patients with Whipple disease were studied. Specimens
      from patients with histologic mimics and other infections served as control
      specimens. Immunostaining was identified in all 18 patients. Granular
      immunostaining was observed similar to that in periodic acid-Schiff (PAS) stains.
      In 2 patients, immunostaining was identified in specimens negative by H&E and PAS
      stains. In 4 patients studied before and after antibiotic therapy, immunostaining
      was retained but diminished in intensity and quantity. Immunostaining was not
      identified in any control specimen. Immunohistochemical analysis is a sensitive
      and specific method for the diagnosis of Whipple disease in paraffin-embedded
      tissue and may provide new opportunities to investigate the pathogenesis of the
      infection.

PMID- 12428796
TI  - Differences in the O-glycosylation patterns between lung squamous cell carcinoma
      and adenocarcinoma.
AB  - Mucins are highly O-glycosylated proteins synthesized by epithelial cells, and
      their glycosylation patterns can be altered during neoplastic transformation. The
      2 types of non-small cell lung cancer (NSCLC) display a similar pattern of mucin
      gene expression but different reactivity to periodic acid-Schiff diastase,
      suggesting that a higher number of carbohydrate chains are present in
      adenocarcinomas. We compared the expression of core (Tn, sialyl-Tn, T) and
      terminal fucosylated and sialylated (Lewis antigens) carbohydrate structures in
      lung tumors. Specific antibodies were usedfor immunohistochemical and Western
      blot assays. Results indicated that core and terminal structures are detected
      more frequently in adenocarcinoma than in squamous cell carcinoma, except Lewis
      y, which is expressed strongly in both types of NSCLC. These data suggest that in
      squamous cell carcinoma and adenocarcinoma, different sets of
      glycosyltransferases must be expressed and that different posttranslational
      modifications of the mucin genes can take place in these 2 tumor types.

PMID- 12428797
TI  - Comparison of immunophenotypes of small B-cell neoplasms in primary lymph node
      and concurrent blood or marrow samples.
AB  - Immunophenotyping of small B-cell neoplasms (SBCNs) may have a critical role in
      diagnosis. However, there are few data addressing whether the immunophenotypes of
      SBCNs in bone marrow (BM) and peripheral blood (PB) are representative of those
      in other tissue sites. We compared the immunophenotypic features of concurrently
      analyzed lymph node (LN) and BM/PB specimens using multiparameter flow cytometry.
      Fifty-five SBCNs were identified: 27 follicular lymphomas (FLs), 16 chronic
      lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLLs), and 12 mantle cell
      lymphomas (MCLs). Major (presence vs absence) or minor (alteration of intensity)
      variations in expression of individual antigens between LN and BM/PB were
      observed in up to 25% of cases within a particular SBCN category. All FLs and
      CLL/SLLs maintained characteristic immunophenotypes in BM/PB. Potentially
      misleading variations included 1 case of MCL that failed to express CD5 in BM and
      likely would have been immunophenotypically misclassified as a marginal zone
      lymphoma and another MCL that expressed moderate CD23 in PB and would have
      required additional studies for precise classification. The remaining major and
      minor variations would not have affected interpretation.

PMID- 12428798
TI  - The t(14;18) and bcl-2 expression are present in a subset of primary cutaneous
      follicular lymphoma: association with lower grade.
AB  - According to the European Organization for Research and Treatment of Cancer
      classification, primary cutaneous follicle center cell lymphoma is not associated
      with the t(14;18)(q32;q21) and only rarely expresses bcl-2 protein. To further
      investigate this issue, we evaluated a series of 20 patients (14 men, 6 women)
      with primary cutaneous follicular lymphoma (PCFL). The presenting skin lesion was
      located in the head and neck region in 16 of 20 patients. Most cases were grade 2
      (6/20) or grade 3 (13/20), and all had a follicular architecture.
      Immunohistochemical analysis demonstrated bcl-2 expression in 8 cases (40%), and
      expression was inversely related to the grade. Of 7 grade 1 or 2 cases, 5 (71%)
      were positive, whereas only 3 (23%) of 13 grade 3 cases were positive for bcl-2.
      Clonal immunoglobulin heavy chain gene rearrangements were detected in 9 (45%) of
      20 cases. In 4 (20%) of 20 cases, we identified the major breakpoint of the
      t(14;18) by polymerase chain reaction, 3 of which were grade 1 or 2. We conclude
      that bcl-2 protein expression and the t(14;18) are present in a subset of PCFL,
      particularly in lower grade cases.

PMID- 12428799
TI  - Clusterin is widely expressed in systemic anaplastic large cell lymphoma but
      fails to differentiate primary from secondary cutaneous anaplastic large cell
      lymphoma.
AB  - A recent study by Wellmann et al (Blood. 2000;96:398-404) detected clusterin
      expression in all 36 systemic anaplastic large cell lymphomas (ALCLs) tested, but
      not in any of 9 primary cutaneous ALCLs. Our purpose was to confirm the
      diagnostic usefulness of clusterin in systemic ALCL and to evaluate its efficacy
      in distinguishing primary cutaneous ALCL from secondary skin involvement by
      systemic ALCL. We examined clusterin expression by paraffin immunohistochemical
      analysis in 41 systemic ALCLs (18 ALK-1+ and 23 ALK-1-), 9 primary cutaneous
      ALCLs, and 4 secondary cutaneous ALCLs. Clusterin was positive in 95% of systemic
      ALCLs (39/41), including 100% (18/18) of the ALK-1+ cases and 91% (21/23) of the
      ALK-1- cases. Five (56%) of 9 primary and 3 (75%) of 4 secondary cutaneous ALCLs
      were positive for clusterin. Our observations confirm the diagnostic usefulness
      of clusterin in systemic ALCL, especially in the ALK-1- cases. However, our data
      fail to demonstrate its value in distinguishing primary from secondary cutaneous
      ALCL.

PMID- 12428800
TI  - Follicular pattern of bone marrow involvement by follicular lymphoma.
AB  - Five patterns of bone marrow infiltration by non-Hodgkin lymphoma or Hodgkin
      lymphoma are currently recognized, but a true follicular pattern of bone marrow
      involvement by follicular lymphoma has not been described. In 260 bone marrow
      trephine biopsy specimens involved by follicular lymphoma, we identified 12 cases
      with a follicular pattern of bone marrow involvement. The paratrabecular pattern
      was not present at all in 9, and it accounted for less than 10% of tumor burden
      in 3 cases. Malignant follicles in the bone marrow were similar to malignant
      follicles in the respective lymph nodes. Follicular dendritic cells were
      identified by immunohistochemical analysis. The true follicular pattern of bone
      marrow involvement by follicular lymphoma seems to be more frequent in women than
      in men. It is important to recognize this pattern of follicular lymphoma in the
      bone marrow because it is possible to misinterpret interstitial lymphoid
      aggregates as benign in the absence of the more characteristic paratrabecular
      pattern.

PMID- 12428801
TI  - How useful are CBC and reticulocyte reports to clinicians?
AB  - We surveyed 1,353 attending and 689 house staff physicians of the University
      Hospitals of Cleveland to ascertain the parameters of the CBC, leukocyte
      differential, and reticulocyte reports perceived as useful in clinical practice.
      The response rate was 33% for attending and 22% for house staff physicians. Only
      4 of 11 parameters routinely reported in the CBC battery were selected as
      frequently or always useful by more than 90% of physicians: hemoglobin,
      hematocrit, platelet count, and WBC count. Among primary care physicians, the
      mean cell volume also attained this level of usefulness for the evaluation of
      anemia. There were no differences between academic physicians and community
      physicians in the use of RBC indices; however, physicians who had been in
      practice for fewer than 10 years indicated higher use of the red cell
      distribution width than physicians practicing for more than 10 years. Most
      physicians prefer differentials reported as percentages rather than absolute
      counts. Among physicians who monitor reticulocyte counts, the immature
      reticulocyte fraction is not widely used. Our results indicate that many
      physicians do not use much of the data provided in routine CBC/differential and
      reticulocyte reports. Some modifications of report formats may facilitate
      physician perception of hematology laboratory results.

PMID- 12428802
TI  - Rapid and accurate identification of mycobacteria by sequencing hypervariable
      regions of the 16S ribosomal RNA gene.
AB  - We developed a method to identify mycobacteria by sequencing hypervariable
      regions of the polymerase chain reaction-amplified 16S ribosomal RNA gene. This
      method is nearly specific for mycobacteria and uses positive culture from liquid
      or solid medium without the needfor lengthy subculture. It shortens
      identification time to 3 days, which is much faster than the conventional
      biochemical method (mean, 8 weeks). It applies to all mycobacteria (approximately
      100 species), unlike current nucleic acid hybridization methods, which probe only
      4 species. The identifications are the same or are species specific for the well
      characterized mycobacteria (59/68 [87%]) or more accurate for recently proposed
      species (9/68 [13%]). The method requires a single sequencing reaction, which is
      efficient and cost-effective. Therefore, this method is clinically and
      academically useful.

PMID- 12428803
TI  - Quality control in Papanicolaou tests.

PMID- 12428804
TI  - Molecular diagnosis and recent therapeutic results of fatal infectious
      mononucleosis.

PMID- 12428805
TI  - Fast axonal transport misregulation and Alzheimer's disease.
AB  - Pathological alterations in the microtubule-associated protein (MAP) tau are well
      established in a number of neurodegenerative disorders, including Alzheimer's
      Disease (AD), frontotemporal dementia (FTD), progressive supranuclear palsy
      (PSP), and others. Tau protein and in some cases, neurofilament subunits exhibit
      abnormal phosphorylation on specific serine and threonine residues in these
      diseases. A large body of biochemical, genetic, and cell biological evidence
      implicate two major serine-threonine protein kinases, glycogen synthase kinase 3
      (GSK-3) and cyclin-dependent kinase 5 (CDK5) as major kinases responsible for
      both normal and pathological phosphorylation of tau protein in vivo. What remains
      unclear is whether tau phosphorylation and/or neurofibrillary tangle (NFT)
      formation are causal or secondary to initiation of neuronal pathology. In fact,
      many studies have indicated that tau misphosphorylation is not the causal event.
      Interestingly, some of these kinase and phosphatase activities have recently
      merged as key regulators of fast axonal transport (FAT). Specifically, CDK5 and
      GSK-3 have been recently shown to regulate kinesin-driven motility. Given the
      essential role of FAT in neuronal function, an alternate model for pathogenesis
      can be proposed. In this model, misregulation of FAT induced by an imbalance in
      specific kinase-phosphatase activities within neurons represents an early and
      critical step for the initiation of neuronal pathology. Such a model may explain
      many of the unique characteristics of late onset of neurological diseases such as
      AD.

PMID- 12428806
TI  - Synaptic vesicle endocytosis: the races, places, and molecular faces.
AB  - The classical experiments on synaptic vesicle recycling in the 1970s by Heuser
      and Reese, Ceccarelli, and their colleagues raised opposing theories regarding
      the speed, mechanisms, and locations of membrane retrieval at the synapse. The
      Heuser and Reese experiments supported a model in which synaptic vesicle
      recycling is mediated by the formation of coated vesicles, is relatively slow,
      and occurs distally from active zones, the sites of neurotransmitter release.
      Because heavy levels of stimulation were needed to visualize the coated vesicles,
      Ceccarelli's experiments argued that synaptic vesicle recycling does not require
      the formation of coated vesicles, is relatively fast, and occurs directly at the
      active zone in a "kiss-and-run" reversal of exocytosis under more physiological
      conditions. For the next thirty years, these models have provided the foundation
      for studies of the rates, locations, and molecular elements involved in synaptic
      vesicle endocytosis. Here, we describe the evidence supporting each model and
      argue that the coated vesicle pathway is the most predominant physiological
      mechanism for recycling synaptic vesicles.

PMID- 12428807
TI  - Alpha-synuclein and presynaptic function: implications for Parkinson's disease.
AB  - This article focuses on alpha-synuclein's role in normal and pathological axonal
      and presynaptic functions and its relationship to Parkinson's disease. It is not
      possible to mention all the contributions to aspects of this area. Readers
      interested in alpha-synuclein's relation to aggregation, Lewy lesions, and
      pathological modifications are referred to the many reviews (see Goldberg and
      Lansbury 2000; Galvin 2001a; Goedert 2001).

PMID- 12428808
TI  - Tau and axonopathy in neurodegenerative disorders.
AB  - The microtubule (MT)-associated protein (MAP) tau in neurons has been implicated
      as a significant factor in the axonal growth, development of neuronal polarity,
      and the maintenance of MT dynamics. Tau is localized to the axon, and is known to
      promote MT assembly and to stabilize axonal MTs. These functions of tau are
      primarily regulated by the activities of protein kinases and phosphatases. In
      Alzheimer's disease and other neurodegenerative disorders, abundant filamentous
      tau inclusions are found to be major neuropathological characteristics of these
      diseases. Both somato-dendritic and axonal tau lesions appear to be closely
      associated with axonal disruption. Furthermore, recent discoveries of pathogenic
      mutations on the tau gene suggest that abnormalities of tau alone are causative
      of neurodegeneration. Finally, analyses of transgenic mice that express human tau
      proteins have enabled in vivo quantitative assessments of axonal functions and
      have provided information about mechanistic relationships between pathological
      alteration of tau and axonal degeneration.

PMID- 12428809
TI  - Axonal transport, tau protein, and neurodegeneration in Alzheimer's disease.
AB  - The molecular causes and the genetic and environmental modifying factors of the
      sporadic form of Alzheimer's disease (AD) remain elusive. Extrapolating from the
      known mutations that cause the rare familial forms and from the typical post
      mortem pathological lesions in all AD patients--e.g., amyloid plaques and
      neurofibrillary tangles (NFTs)-the evident molecular candidates are amyloid
      precursor protein (APP), presenilin, and tau protein. To include ApoE4 as the
      only certain genetic modifier known leaves us to face the challenge of
      implementing these very different molecules into an evident pathological
      partnership. In more than one respect, the proposition of disturbed axonal
      transport appears attractive with more details becoming available on APP
      processing and microtubular transport and also of the pathology in the model
      systems--e.g., transgenic mice expressing APP or protein tau. Conversely, the
      resistance of APP-transgenic mice with full-blown amyloid pathology to also
      develop tau-related neurofibrillar pathology is a major challenge for this
      hypothesis. From the most relevant data discussed here, we conclude that the
      postulate of disturbed axonal transport as the primary event in AD is difficult
      to defend. On the other hand, failing axonal transport appears to be of major
      importance in the later stages in AD, by further compromising tau protein, APP
      metabolism, and synaptic functioning. Protein tau may thus be the central
      "executer" in the chain of events leading from amyloid neurotoxicity to tau
      hyperphosphorylation, microtubular destabilization, disturbed axonal transport,
      and synaptic failure to neurodegeneration. In order to identify normal
      physiological processes and novel pathological targets, definition is needed--in
      molecular detail--of the complex mechanisms involved.

PMID- 12428813
TI  - Matching resources to treatment decisions for patients with acute coronary
      syndromes.
AB  - Multiple dynamic forces are having an impact on the way cardiovascular disease is
      treated today and will be in the future. These forces include extended life
      expectancy, decreased disability, and accelerated improvement in the
      effectiveness of medical technology. All of these forces will lead to a
      predictable increase in health care costs. Cardiologists must also be cognizant
      of the rise in health care consumerism; patients are assuming a larger role in
      decisions about their medical care and treatment. All of these factors are
      driving the climate of evidence-based medicine, particularly in the
      cardiovascular field. Payers and the government are beginning to require the
      clinical community to define quality. In turn, these third parties are beginning
      to measure quality as defined by the profession and to hold providers accountable
      for the quality of what they do. Although the frontier of genetic prediction in
      therapeutics will serve as an intellectual focus for bringing these issues closer
      to the forefront in cardiovascular medicine, the fundamental provision of value
      in health care (high quality at reasonable cost) cannot wait on genomics. Because
      the amount of evidence in acute coronary syndromes (ACS) exceeds other areas of
      medicine, therapies for ACS will undergo increasingly intense scrutiny.

PMID- 12428811
TI  - Do apoptotic mechanisms regulate synaptic plasticity and growth-cone motility?
AB  - Signals between neurons are transduced primarily by receptors, and second
      messenger and kinase cascades, located in pre- and postsynaptic terminals. Such
      synaptic signaling pathways include those activated by neurotransmitters,
      cytokines, neurotrophic factors, and cell-adhesion molecules. Many of these
      signaling systems are also localized in the growth cones of axons and dendrites,
      where they control pathfinding and synaptogenesis during development. Although it
      has been known for decades that such signaling pathways can affect the survival
      of neurons, by promoting or preventing a form of programmed cell death known as
      apoptosis, we have discovered that apoptotic biochemical cascades can exert local
      actions on the functions and structural dynamics of growth cones and synapses. In
      this article, we provide a brief background on apoptotic biochemical cascades,
      and present examples of studies in this laboratory that have identified novel
      apoptotic and anti-apoptotic signaling mechanisms that are activated and act
      locally in synapses, growth cones, and dendrites to modify their structure and
      function. Apoptotic synaptic cascades that may play roles in neuronal plasticity
      include activation of caspases that can cleave certain types of ionotropic
      glutamate-receptor subunits and thereby modify synaptic plasticity. Caspases may
      also cleave cytoskeletal protein substrates in growth cones of developing neurons
      and may thereby regulate neurite outgrowth. Par-4 and the tumor-suppressor
      protein p53 are pro-apoptotic proteins that may also function in synaptic and
      developmental plasticity. Examples of anti-apoptotic signals that regulate the
      plasticity of growth cones and synapses include neurotrophic factor-activated
      kinase cascades, calcium-mediated actin depolymerization, and activation of the
      transcription factor NF-kappaB. The emerging data strongly suggest that many of
      the signaling mechanisms that control apoptosis are also involved in regulating
      the structural and functional plasticity of neuronal circuits under physiological
      conditions.

PMID- 12428814
TI  - Economics and quality of care for patients with acute coronary syndromes: the
      impending crisis.
AB  - Several factors are placing significant financial burdens on the health care
      system today. These include the growing older population, the obesity and type II
      diabetes epidemics, and the attendant increased prevalence of heart disease,
      which remains the leading cause of death in the United States. In response,
      cardiovascular medicine is undergoing sweeping change in the use of advanced
      technology and interventions. In addition, biomarkers, such as troponin, are
      emerging as critical predictors of responses to therapy, particularly for
      coronary stenting. Future trends in the treatment of acute coronary syndromes
      (ACS) will embrace the use of genomic solutions, such as gene expression
      profiling, to predict therapeutic outcomes. Careful consideration will need to be
      given to these innovative approaches to ensure they are cost effective.

PMID- 12428810
TI  - Presenilins and APP in neuritic and synaptic plasticity: implications for the
      pathogenesis of Alzheimer's disease.
AB  - A key neuropathological hallmark of Alzheimer's disease (AD) is the loss of
      neocortical and hippocampal synapses, which is closely correlated with the degree
      of memory impairment. Mutations in the genes encoding the amyloid
      precursorprotein (APP) and presenilins are responsible from some cases of early
      onset autosomal-dominant AD. This article reviews the current understanding of
      how alterations in the cellular functions of APP and presenilins may result in
      the dysfunction and degeneration of synapses in AD. APP mutations result in
      increased production/aggregation of amyloid beta-peptide (Abeta), which induces
      oxidative stress, resulting in the impairment of synaptic membrane ion,
      glutamate, and glucose transporters. APP mutations may also compromise the
      production and/or function of secreted forms of APP that are believed to play
      important roles in learning and memory processes. Presenilin (PS1) mutations
      result in a major defect in endoplasmic reticulum (ER) calcium regulation, which
      may perturb synaptic function in ways that lead to impaired synaptic plasticity
      and neuronal degeneration. Studies in transgenic mice that express APP and PS1
      mutations have provided evidence that the mutations result in altered cellular
      calcium homeostasis and synaptic plasticity, and impaired learning and memory.
      This article provides a brief review of the pathophysiological interactions of
      APP and presenilins with synaptic proteins, and discusses how AD-linked mutations
      in APP and PS1 may disrupt synaptic processes that contribute to memory
      formation.

PMID- 12428815
TI  - Defining the scope of evidence-based practice for low-molecular-weight heparin
      therapy in high-risk patients with unstable angina and non-ST-elevation
      myocardial infarction.
AB  - Various therapies have been utilized for the treatment of unstable angina and non
      ST-elevation myocardial infarction (NSTEMI). Each therapy has both advantages and
      disadvantages with regard to clinical outcomes and an increased risk of bleeding.
      One emerging primary therapy is low-molecular-weight heparin (LMWH). Concerns
      have emerged, however, over the use of LMWH in patients going to the
      catheterization laboratory or who receive platelet glycoprotein IIb/IIIa
      inhibitors. Available trial data point to the safety and efficacy of LMWH in
      these patients. Eventually, LMWH will probably replace unfractionated heparin
      (UFH) for the majority of patients with acute coronary syndromes (ACS). At
      present, however, practitioners need to consider individually how comfortable
      they are with the available data.

PMID- 12428812
TI  - Energetics and oxidative stress in synaptic plasticity and neurodegenerative
      disorders.
AB  - As in other cells, neurons use adenosine triphosphate (ATP) as an energy source
      to drive biochemical processes involved in various cell functions, and produce
      reactive oxygen species (ROS) as "by products" of oxidative phosphorylation.
      However, the electrical excitability and structural and synaptic complexity of
      neurons present unusual demands upon cellular systems that produce or respond to
      ATP and ROS. Mitochondria in axons and presynaptic terminals provide sources of
      ATP to drive the ion pumps that are concentrated in these structures to rapidly
      restore ion gradients following depolarization and neurotransmitter release.
      Mitochondria may also play important roles in the regulation of synaptic function
      because of their ability to regulate calcium levels and ROS production. ROS
      generated in response to synaptic activity are now known to contribute to the
      regulation of long-term structural and functional changes in neurons, and the
      best-known example is the nitric oxide radical. The high-energy demands of
      synapses, together with their high levels of ROS production, place them at risk
      during conditions of increased stress, which occur in aging, neurodegenerative
      disorders such as Alzheimer's and Parkinson's diseases, and after acute traumatic
      and ischemic insults. Energy depletion and/or increased oxidative damage to
      various synaptic proteins can result in a local dysregulation of calcium
      homeostasis and synaptic degeneration. Accordingly, recent studies have shown
      that dietary and pharmacological manipulations that improve energy efficiency and
      reduce oxyradical production can prevent synaptic degeneration and neuronal death
      in experimental models of neurodegenerative disorders. A better understanding of
      the molecular control of subcellular energy production and utilization, and of
      the functional relationships between energy metabolism, ion homeostasis, and
      cytoskeletal and vesicular dynamics, will provide novel insight into mechanisms
      of neuronal plasticity and disease.

PMID- 12428816
TI  - Defining optimal therapy for the thrombolysis-ineligible patient.
AB  - Not all patients presenting with acute coronary syndrome (ACS) are able to
      receive reperfusion therapy. These include patients who present late (after 12 h)
      or who have bleeding diathesis. Studies have found a number of factors affect the
      decision to reperfuse. Other treatment options are needed for those patients with
      acute ST-elevation myocardial infarction (STEMI). Low-molecular weight heparin,
      such as enoxaparin, now offers these patients the opportunity for successful
      intervention. Several clinical trials have determined its superiority over
      unfractionated heparin as an adjunct during thrombolytic therapy. Currently, a
      trial is underway to determine the effect of enoxaparin in combination with
      tirofiban in patients with STEMI ineligible for reperfusion therapy. Blinded data
      for the entire patient cohort shows excellent efficacy and safety in these
      patients.

PMID- 12428817
TI  - Defining standards of care for facilitated and direct percutaneous coronary
      intervention.
AB  - Interventional cardiologists have a variety of options when it comes to
      facilitated and direct percutaneous coronary intervention (PCI). Over the years,
      several controversies have surrounded the choices made before and during this
      process. Questions have been raised over the value of stenting all patients and
      the use of filters and thrombectomy devices. A number of important clinical
      trials have also investigated the efficacy of platelet glycoprotein IIb/IIIa
      inhibitors. Considerable interest is now taking place on how best to reduce
      reperfusion delays and to improve anticoagulation in the catheterization
      laboratory. Since direct PCI is often a slow process, better use of existing and
      future therapies, as well as advances in patient transport, are expected to
      improve patient outcomes.

PMID- 12428818
TI  - Randomized controlled trial of the Alexander technique for idiopathic Parkinson's
      disease.
AB  - OBJECTIVE: To determine whether the Alexander Technique, alongside normal
      treatment, is of benefit to people disabled by idiopathic Parkinson's disease.
      DESIGN: A randomized controlled trial with three groups, one receiving lessons in
      the Alexander Technique, another receiving massage and one with no additional
      intervention. Measures were taken pre- and post-intervention, and at follow-up,
      six months later. SETTING: The Polyclinic at the University of Westminster,
      Central London. SUBJECTS: Ninety-three people with clinically confirmed
      idiopathic Parkinson's disease. INTERVENTIONS: The Alexander Technique group
      received 24 lessons in the Alexander Technique and the massage group received 24
      sessions of massage. MAIN OUTCOME MEASURES: The main outcome measures were the
      Self-assessment Parkinson's Disease Disability Scale (SPDDS) at best and at worst
      times of day. Secondary measures included the Beck Depression Inventory and an
      Attitudes to Self Scale. RESULTS: The Alexander Technique group improved compared
      with the no additional intervention group, pre-intervention to post-intervention,
      both on the SPDDS at best, p = 0.04 (confidence interval (CI) -6.4 to 0.0) and on
      the SPDDS at worst, p = 0.01 (CI -11.5 to -1.8). The comparative improvement was
      maintained at six-month follow-up: on the SPDDS at best, p = 0.04 (CI -7.7 to
      0.0) and on the SPDDS at worst, p = 0.01 (CI -11.8 to -0.9). The Alexander
      Technique group was comparatively less depressed post-intervention, p = 0.03 (CI 
      3.8 to 0.0) on the Beck Depression Inventory, and at six-month follow-up had
      improved on the Attitudes to Self Scale, p = 0.04 (CI -13.9 to 0.0). CONCLUSIONS:
      There is evidence that lessons in the Alexander Technique are likely to lead to
      sustained benefit for people with Parkinson's disease.

PMID- 12428819
TI  - Cutaneous electrical stimulation may enhance sensorimotor recovery in chronic
      stroke.
AB  - OBJECTIVE: To investigate whether cutaneous electrical stimulation has a role in
      the enhancement of sensorimotor function in chronic stroke. SUBJECTS AND SETTING:
      Fifty-nine patients with chronic stroke received cutaneous stimulation during
      their three-week-long inpatient rehabilitation. Thirty-two received active
      treatment in the paretic hand and eight received no-current placebo treatment in
      the paretic hand. Nineteen patients received active stimulation of the paretic
      foot. None received stimulation in both upper and lower limbs. INTERVENTION:
      Cutaneous stimulation was delivered twice daily via a special glove/sock
      electrode. MAIN OUTCOME MEASURES: Modified Motor Assessment Scale, 10-metre
      walking test, paretic limb function, limb skin sensation and somatosensory evoked
      potentials (SEP) were performed before and after the treatment. RESULTS: Modified
      Motor Assessment Scale (p < 0.001), 10-metre walking test (p < 0.05), paretic
      hand function (p < 0.01), upper limb skin sensation (p < 0.01) and SEP normality
      classification of paretic upper limb (p < 0.01) and paretic lower limb (p < 0.5)
      improved significantly in the treatment group (n = 51) after three weeks of
      stimulation. When active hand treatment and placebo hand treatment were compared,
      a significant improvement in the sensory and motor function was observed only in
      the actively treated group. CONCLUSIONS: Cutaneous stimulation had positive
      effects in the motor performance, limb sensation and the configuration of SEP of
      the paretic limb in chronic stroke patients.

PMID- 12428820
TI  - Short-term effectiveness of intensive multidisciplinary rehabilitation for people
      with Parkinson's disease and their carers.
AB  - OBJECTIVE: To evaluate the short-term effectiveness of an intensive
      multidisciplinary rehabilitation programme for people with Parkinson's disease
      and their carers. DESIGN: Observational, with assessments before and after
      intervention. SETTING: An elderly care day unit in a district general hospital in
      south-east England. SUBJECTS: One hundred and eighteen people with Parkinson's
      disease and no cognitive impairment, and their carers. INTERVENTION: Participants
      attended the day hospital in groups of six patients with their carers for one day
      per week over six consecutive weeks. After assessment, they received individual
      treatment from a specialist team. Weekly group activities included relaxation and
      talks from experts. OUTCOME MEASURES: Patients and carers were assessed for:
      health-related quality of life, psychological well-being, social services need,
      perceptions of the programme. Patients were additionally assessed for mobility,
      gait and speech. Carers were assessed for strain. RESULTS: After treatment
      significant improvements were recorded in patients' mobility and gait (p < 0.05),
      speech (p < 0.001), depression (p = 0.029), health-related quality of life (p =
      0.001). People with more advanced disease at baseline gained significantly more
      from treatment (p < or = 0.04). Carers were less depressed and had higher health
      related quality of life than patients at baseline (p < 0.001) and no improvements
      in these indicators were recorded after treatment. A high unmet need for social
      services was identified in 31% of participants, and 10% of carers were found in
      danger of being unable to continue caring. Participants reported knowledge gains
      and high levels of satisfaction with both individual therapies and group
      activities. CONCLUSIONS: This intensive co-ordinated programme provided immediate
      benefits to people with Parkinson's disease and their carers.

PMID- 12428821
TI  - The associated reaction rating scale: a clinical tool to measure associated
      reactions in the hemiplegic upper limb.
AB  - OBJECTIVE: To determine what items should be included in a clinical assessment
      tool developed to measure associated reactions in the hemiplegic upper limb and
      to assess the reliability of the resultant measure. DESIGN: Development through a
      structured consultative process using focus group methodology. Evaluation of
      inter- and intra-rater reliability between two independent observers. SUBJECTS:
      Nineteen consecutive hemiplegic patients admitted to Northwick Park Hospital for
      rehabilitation following stroke. METHODS: Focus groups were conducted in two
      centres, comprising physiotherapists experienced in the clinical management of
      brain injury. The groups identified four key characteristics related to severity
      of associated reactions, which became the items of the rating scale. Evaluation
      of inter- and intra-rater reliability was undertaken by comparison of agreement
      between ratings of associated reactions occurring during a single standardized
      task (sit-to-stand), by two senior physiotherapists in 19 subjects. RESULTS:
      There were good correlations between the two raters in total (rho 0.89 p < 0.005)
      and modal scores (rho 0.88 p < 0.005). Reliability testing of each item revealed
      moderate to very good inter-rater agreement (weighted kappa values 0.43-0.85) and
      good to very good intra-rater agreement (weighted kappa values 0.61-0.87). A
      slight tendency for one rater to score more severely than the other only reached
      significance for one item (excursion). Overall (modal) severity scores showed a
      good level of agreement (kappa 0.76-0.81) both between and within raters.
      CONCLUSION: Items to be included in a clinical assessment tool to measure
      associated reactions in the hemiplegic upper limb were determined. Reliability of
      the resultant measure was found to be encouraging. These results however apply
      only to observations made during a specific standardized task (sit-to-stand) and
      further study of sensitivity to change and reproducibility in different tasks is
      required before the findings can be extrapolated into routine practice.

PMID- 12428822
TI  - Stroke patients entering nursing home care: a content analysis of discharge
      letters.
AB  - OBJECTIVE: To examine the information contained in medical and nursing staff
      hospital discharge letters for stroke patients entering nursing home care.
      DESIGN: A retrospective content analysis comparing case notes with discharge
      letters. SETTING: Nottingham (UK) hospitals. SUBJECTS: Thirty-eight stroke
      patients with a Barthel Activities of Daily Living Index score of less than 11/20
      at three months post stroke who were discharged into a nursing home. METHOD:
      Patients' medical case notes and medical and nursing discharge letters were
      subjected to the same structured content analysis. The three key areas were: self
      care ability (i.e. washing, dressing), nursing needs (i.e. diet, continence) and
      risk assessment (i.e. falls, pressure sores). RESULTS: Discharge letters were
      least likely to provide information on risk assessments, for example only 14
      (37%) documented the risk of pressure sores and 7 (18%) falls. Thirty discharge
      letters (79%) had information relating to self-care ability and nursing care,
      although a blanket term 'needs all care' was used to describe patient ability in
      20 (66%) of these. CONCLUSION: The results demonstrate that the completeness and
      accuracy of information is often poor, doing little to enhance the continuity of
      care for patients who are transferred from hospital to nursing homes.

PMID- 12428823
TI  - The influence of preparedness on rapid stepping in young and older adults.
AB  - OBJECTIVE: To investigate the influence of age and preparation level on postural
      muscle activation and step completion time during a rapid step task. DESIGN:
      Postural muscle onset times (EMG) and ground reaction forces were recorded from
      healthy young (n = 20, age 21 +/- 3 years) and older (n = 25, age 71 +/- 5 years)
      female adults during a choice reaction-time stepping paradigm. MAIN OUTCOME
      MEASURES: Onset times of six trunk and hip muscles, reaction time and components
      of the step (weight shift time, step time and task time) were recorded. RESULTS:
      Muscle activation was delayed and movement time was lengthened in both young and
      older adults when poorly prepared for a stepping task. While reduced preparation
      did not influence older adults to a greater extent than young adults, the slowest
      step response and completion time was evident in older adults when poorly
      prepared to move. CONCLUSIONS: A late postural response when poorly prepared to
      move may be a contributing factor to an increased risk of overbalancing in older
      adults. Future assessment of and intervention to improve postural stability in
      older adults should be expanded to incorporate tasks performed at various levels
      of preparation.

PMID- 12428824
TI  - Does four weeks of TENS and/or isometric exercise produce cumulative reduction of
      osteoarthritic knee pain?
AB  - OBJECTIVE: To evaluate the cumulative effect of repeated transcutaneous
      electrical nerve stimulation (TENS) on chronic osteoarthritic (OA) knee pain over
      a four-week treatment period, comparing it to that of placebo stimulation and
      exercise training given alone or in combination with TENS. DESIGN: Sixty-two
      patients, aged 50-75, were stratified according to age, gender and body mass
      ratio before being randomly assigned to four groups. INTERVENTIONS: Patients
      received either (1) 60 minutes of TENS, (2) 60 minutes of placebo stimulation,
      (3) isometric exercise training, or (4) TENS and exercise (TENS & Ex) five days a
      week for four weeks. MAIN OUTCOME MEASURES: Visual analogue scale (VAS) was used
      to measure knee pain intensity before and after each treatment session over a
      four-week period, and at the four-week follow-up session. RESULTS: Repeated
      measures ANOVA showed a significant cumulative reduction in the VAS scores across
      the four treatment sessions (session 1, 10, 20 and the follow-up) in the TENS
      group (45.9% by session 20, p < 0.001) and the placebo group (43.3% by session
      20, p = 0.034). However, linear regression of the daily recordings of the VAS
      indicated that the slope in the TENS group (slope = -2.415, r = 0.943) was
      similar to the exercise group (slope = -2.625, r = 0.935), which were steeper
      than the other two groups. Note that the reduction of OA knee pain was maintained
      in the TENS group and the TENS & Ex group at the four-week follow-up session, but
      not in the other two groups. CONCLUSIONS: The four treatment protocols did not
      show significant between-group difference over the study period. It was
      interesting to note that isometric exercise training of the quadriceps alone also
      reduced knee pain towards the end of the treatment period.

PMID- 12428825
TI  - Between-days reliability of electromyographic measures of paraspinal muscle
      fatigue at 40, 50 and 60% levels of maximal voluntary contractile force.
AB  - OBJECTIVE: To ascertain which percentage of maximal voluntary contractile force
      of the paraspinal muscles, when tested in a functional position, is most reliable
      for assessing electromyographic (EMG) fatigue changes. SUBJECTS: Ten healthy
      volunteers with no history of low back pain (six males). MAIN OUTCOME MEASURES:
      The surface EMG signal during 60-second isometric contractions of the paraspinal
      muscles at 40, 50 and 60% levels of maximal voluntary contractile force was
      captured and analysed. Each contraction level was assessed on two occasions, at
      least three days apart. The initial median frequency, the decline in median
      frequency slope and the increase in root mean square values were assessed for
      between-days reliability, using intraclass correlation coefficients (ICCs) and
      standard errors of measurements (SEM). Normalized median frequency and root mean
      square values were also assessed. RESULTS: At 40% of maximal voluntary
      contraction, little or no EMG fatigue changes occurred in any of the observed
      parameters. At 50% maximal voluntary contraction the initial mean frequency and
      root mean square changes proved highly reliable, with ICCs ranging from 0.74 to
      0.86 and 0.75 to 1.00 respectively. Normalizing the root mean square data reduced
      the reliability, but this was still acceptable with ICCs 0.70-0.83. The median
      frequency decline slope proved less reliable with ICCs 0.24-0.74 for raw and 0.26
      0.77 for normalized data. At 60% maximal voluntary contraction the initial mean
      frequency proved as reliable as initial median frequency at 50% with ICCs 0.70
      0.89. The raw and normalized root mean squares (ICCs 0.43-0.89 and 0.30-0.87
      respectively) and raw and normalized median frequency (ICCs 0.27-0.51 and 0.24
      0.53 respectively) changes were less reliable than at 50% MVC. Overall, the
      reliability is better at the L4/5 than at the L2/3 level. CONCLUSION: Outcome
      measures taken at 50% maximal voluntary contraction are the most reliable in
      functional testing the paraspinal muscles of healthy volunteers. With initial
      median frequency and root mean square values being more reliable parameters than
      median frequency decline. At the L4/5 level, however, all parameters were
      acceptably reliable at 50% of maximum effort. However the between-subject
      variability of the median frequency decline and root mean square incline slopes
      suggest that these parameters are not yet fully suitable for monitoring fatigue
      changes during prolonged isometric contraction.

PMID- 12428826
TI  - Maximal isometric muscle strength of the cervical spine in healthy volunteers.
AB  - OBJECTIVE: To describe the maximal isometric neck muscle strength in healthy
      Chinese volunteers, in six different directions, as measured by a Multi Cervical
      Rehabilitation Unit. DESIGN: A standardized cross-sectional observational study.
      SETTING: A university rehabilitation unit. SUBJECTS: Ninety-one healthy
      volunteers aged 20-84. METHODS: During the measurement the subject was instructed
      to do three consecutive steady contractions as hard as possible, with a 10-second
      rest in between each contraction and a 2-minute rest between different
      directions. The peak isometric strength for each of the six directions (flexion,
      extension, lateral flexions, protraction and retraction) was calculated. RESULTS:
      No significant difference was found in muscle strength between different age
      groups. Isometric muscle strength in the direction of right lateral flexion was
      significantly greater than that to the left in men (p = 0.030), but no difference
      was found in women (p = 0.297). Isometric strength in all directions in men was
      1.2-1.7 times that in women (all p < 0.028). Correlations between physical
      measurements (height and weight) and strength values were all insignificant in
      both genders. CONCLUSION: Men have approximately 20-70% greater isometric neck
      muscle strength than women. Both men and women can maintain high levels of
      cervical muscle strength in six different directions up to their seventh decade.
      There is no significant correlation between physical measurements and isometric
      neck muscle strength.

PMID- 12428827
TI  - A self-administered pain severity scale for patellofemoral pain syndrome.
AB  - OBJECTIVE: To develop a scale for estimating the severity of patellofemoral pain
      syndrome (PFPS) and to determine its reliability and validity. DESIGN: The PFPS
      Severity Scale (PSS) was developed following a literature search, input from
      clinicians, and pilot testing in people with PFPS. The final version of the
      instrument encompasses 10 statements regarding PFPS pain in a visual analogue
      format. Reliability and validity of the new scale were determined in a PFPS
      population. SETTING: All testing was performed at the Canadian Forces Base
      Kingston, Physiotherapy Department. SUBJECTS: Twenty-nine military subjects (7
      female) between the ages of 20 and 48 (32 years +/- 8.9) with subjective and
      objective findings consistent with PFPS were recruited. Twenty-four of the
      participants (6 female, 31.8 years +/- 9.4) participated in the reliability phase
      of the study. METHODS: Reliability of the PSS was determined by comparing the
      scores obtained on two test days (24 hours apart). Convergent validity of the PSS
      was determined by comparing data from the PSS with two established knee scales:
      the WOMAC (Western Ontario and McMaster Universities) Osteoarthritis Index and
      the Hughston Foundation subjective knee scale. RESULTS: Test-retest reliability
      was excellent (Spearman's rho = 0.95, p < 0.0001). The correlations between the
      PSS and the WOMAC and Hughston scales were strong (rho = 0.72 and 0.83, p < 0.001
      respectively). CONCLUSIONS: The PSS is reliable and has demonstrated convergent
      validity making it a useful tool for monitoring rehabilitative or surgical
      outcomes in clients with PFPS.

PMID- 12428828
TI  - The influence of local steroid injections, body weight and the length of symptoms
      in the treatment of painful subcalcaneal spurs with extracorporeal shock wave
      therapy.
AB  - OBJECTIVE: To evaluate the effectiveness of extracorporeal shock wave therapy
      (ESWT) for the treatment of painful subcalcaneal spurs and evaluate whether local
      steroid injections, body weight and the length of symptoms can affect the
      clinical results. DESIGN: Subjects were selected through clinical examination and
      heel radiograms according to diagnosis of painful subcalcaneal spurs. SUBJECTS:
      Sixty-four subjects were divided into two groups of treatment depending on their
      past history of previous local steroid injections. INTERVENTIONS: Each subject
      received a three-session ESWT (performed weekly). A rehabilitative programme was
      instituted, consisting of self-assisted plantar fascia and plantar flexors
      stretching exercises. MAIN OUTCOME MEASURES: The Mayo Clinical Scoring System
      (MCSS) was utilized to evaluate each subject before the treatment and at two- and
      ten-month follow-ups. In addition, standard radiograms were done both before the
      treatment and at the ten-month follow-up. RESULTS: Patients with no past
      treatment using steroids did not show any statistically significant improvement
      of the MCSS at the two-month follow-up. The statistical significance was obtained
      at the ten-month follow-up. Patients with past treatment using steroids did not
      show any statistically significant improvement of the MCSS at either follow-up.
      At the radiogram check, none of the subjects showed any modification of the heel
      spurs. CONCLUSIONS: According to the results of the present study ESWT should be
      considered as an effective treatment for painful subcalcaneal spurs. Previous
      local steroid injections may negatively affect the result of ESWT.

PMID- 12428829
TI  - The effect of a first vaginal delivery on the integrity of the pelvic floor
      musculature.
AB  - OBJECTIVE: To assess the specific effect of delivery of the first child on the
      integrity of the pelvic floor musculature. DESIGN: A prospective study of two
      groups of females with no symptoms of urinary incontinence. SETTING:
      Physiotherapy Department, Rotunda Lying In Hospital, Dublin. SUBJECTS: Two groups
      of healthy female physiotherapists (age range 20-28 years) were recruited for the
      study: group 1 consisted of nulliparous females (n = 10) and group 2 consisted of
      primiparous females who were 9-10 months post delivery (n = 10). INTERVENTION AND
      MAIN OUTCOME MEASURES: Assessment of the pelvic floor musculature was performed
      by digital assessment, electromyography and perineometry. RESULTS: For all data,
      the nulliparous group showed evidence of greater pelvic floor strength and
      endurance. Analysis of anterior and posterior electromyography data showed
      significantly stronger contractions in the nulliparous group (p = 0.0001 and
      0.044). During a maximum contraction of the pelvic floor muscles, the anterior
      resting EMG activity increased by 9 +/- 6 microV (mean +/- SD) in the primiparous
      group compared with an increment of 22.3 +/- 4.74 microV in the nulliparous
      group. Posterior EMG resting activity increased by 19.7 +/- 7.65 microV (mean +/-
      SD) in the nulliparous group compared with 13.8 +/- 8.19 microV in the
      primiparous group. There were significant differences between the two groups for
      the four types of digital muscle assessment (p < 0.0013). In addition, there was
      a greater increase in perineometry readings in the nulliparous group (increment =
      5.6 +/- 2.5, mean +/- SD) compared with the primiparous group (increment = 3.1 +/
      0.9; mean +/- SD). CONCLUSIONS: This study suggests that irrespective of lack of
      symptoms of urinary incontinence, it would appear advisable that all women should
      undertake a prescribed programme of pelvic floor rehabilitation exercises after
      childbirth.

PMID- 12428830
TI  - New treatments in scleroderma: the rheumatologic perspective.

PMID- 12428831
TI  - New treatments in scleroderma: dermatologic perspective.

PMID- 12428832
TI  - Collodion baby: what's new.

PMID- 12428833
TI  - Manifestation of cellulitis after saphenous venectomy for coronary bypass
      surgery.
AB  - A few cases of onset of cellulitis after saphenous venectomy for coronary by-pass
      surgery were first reported by Baddour and Bisno in 1982. We reviewed the dinical
      characteristics of 31 subjects followed up in our department following onset of
      manifestations of cellulitis after saphenous venectomy for coronary by-pass
      surgery. In all the subjects the cellulitis originated at the scar of the
      saphenous venectomy, and most presented ill-defined, mildly erythematous,
      slightly oedematous lesions. Mycologically confirmed tinea pedis was found in 25
      subjects. All the patients responded well to penicillins or cephalosporins. In
      this report we comment on the pathogenesis of this complication of saphenous
      venectomy based on the clinical features of the cases reviewed. We suggest that
      saphenous venectomy may destroy the lymphatics in the lower leg, that are located
      adjacent to the great saphenous vein, and thus microorganisms penetrating into
      the skin may easily cause cellulitis in areas with impaired lymphatic drainage.

PMID- 12428834
TI  - Dermatofibrosarcoma protuberans: a clinicopathological study of 20 cases.
AB  - AIM: To review the dinical and histological data of 20 cases of
      dermatofibrosarcoma protuberans presenting at two dermatology centres in Lisbon
      from 1978 to 1998. PATIENTS AND METHODS: The 20 subjects comprised nine males and
      11 females ranging in age from 25 to 79 years, with highest frequency of subjects
      in the 30-50 year olds. We reviewed the clinical features, histopathological
      aspects, including morphologic variants and immunohistochemical studies. RESULTS:
      Median age at diagnosis was 51 years and the trunk was the most frequent
      location. The characteristic histologic storiform pattern was seen in all cases.
      Three subjects presented fibrosarcomatous areas, one with myoid differentiation
      and another with multinucleated giant cells. Immunohistochemical stains revealed
      CD34 expression in the 18 specimens tested, FXIIIa was negative, and these two
      antigens proved important for the differential diagnosis of this neoplasm. Local
      wide excision was performed in 13 cases and seven patients underwent Moh's
      micrographic surgery. Follow-up ranged from 2 months to 17 years and three
      recurrences were recorded, two following classical surgery and one after Moh's
      surgery; there was no difference in the rate of local recurrence (15%) for the
      two kinds of treatment in our series.

PMID- 12428835
TI  - The image of a leper (?): a paradigm of hidden fears of contagious diseases
      (exemplified in a wall painting of Saint Elizabeth of Hungary).
AB  - This is a brief study on the popular ideas about leprosy based on an 18th century
      wall painting in north-western Croatia portraying Saint Elisabeth healing a sick
      man, possibly a leper. The analysis uses examples from the history of medicine,
      semantics, toponymy and iconography.

PMID- 12428836
TI  - Results of atopy patch tests with house dust mites in adults with 'intrinsic'
      and'extrinsic' atopic dermatitis.
AB  - BACKGROUND: The most frequently employed diagnostic criteria of atopic dermatitis
      (AD) can be fulfilled in the absence of elevated total circulating IgE or
      specific IgE to food allergens or environmental aeroallergens and/or in the
      absence of personal or familial history of atopy as well. Therefore a distinction
      between 'extrinsic' or 'allergic' and 'intrinsic' or 'non-allergic' AD has been
      suggested. Recently, a patch test with environmental aeroallergens, named atopy
      patch test (APT), has been proposed for use in the study of AD. OBJECTIVE The aim
      of this study was to investigate the reactivity to APT in patients with
      'extrinsic' and 'intrinsic' AD. PATIENTS, MATERIALS AND METHODS: Two groups of
      adult male subjects with AD were examined consecutively in our department
      (Department of Dermatology, Italian Navy Main Hospital, Taranto, Italy) andpatch
      tested with whole bodies of house dust mites (HDM) at a concentration of 20% in
      petrolatum (Dermatophagoides pteronyssinus 50%, D. farinae 50%). The groups
      included: (i) 95 patients affected by the adult clinical form of 'extrinsic' AD;
      (ii) 12 patients affected by the adult clinical form of 'intrinsic' AD; and (iii)
      a control group of 49 adult healthy male subjects with a negative anamnesis for
      eczema and atopy and negative skin prick test to aeroallergens/food allergens
      and/or normal level of total circulating IgE, also patch tested with the same
      allergen. The statistical differences were calculated by chi2 test and 95%
      confidence intervals (CI) were provided. RESULTS: The APT was positive in 47.4%
      (CI: 37-57%) of'extrinsic'AD, in 66.6% (CI: 41-93%) of'intrinsic' AD and in 12.2%
      (CI: 3-21%) of healthy subjects. The differences between the two AD subgroups and
      the control group were statistically significant (P < 0.001). CONCLUSIONS: APT
      positivity is more frequent in both 'extrinsic' and 'intrinsic' AD than in
      unaffected subjects. Other studies are needed to confirm our data and to explain
      why the APT is positive in the 'intrinsic' form.

PMID- 12428837
TI  - Are quality of family life and disease severity related in childhood atopic
      dermatitis?
AB  - BACKGROUND: Atopic dermatitis (AD) can be traumatizing to family life. Little is
      known about the relationship between quality of life in AD and disease severity.
      OBJECTIVE: To document family quality of life and relate this to severity of AD
      in children, for a 6-month period from a given point in time. STUDY DESIGN: These
      data are part of a longitudinal study conducted in two parts of the UK to
      investigate risk factors for AD severity and its impact on quality of life.
      SUBJECTS: and methods Thetargetedpopulation comprised children with AD aged 5-10
      years in a primary-care setting. The general practitioners identified potential
      subjects and the UK diagnostic criteria for AD were used to verify the diagnosis.
      Both the children and their parents were interviewed. Eczema severity was
      assessed using a modified form of the SCORAD (SCORe Atopic Dermatitis) Index
      (SCORAD-D) from which parents' score of itching and sleep loss were excluded. The
      quality of family life was quantified by the Dermatitis Family Impact (DFI)
      questionnaire. These two parameters were evaluated on two occasions 6 months
      apart. ANALYSIS: Multiple regression analysis was used to investigate the
      relationship between the quality of family life and the severity of the AD in the
      children, at a specific point in time and over the following 6-month period.
      RESULTS: Of the 116 children attending the first visit, mean age 8 years, 106
      attended the second visit (91%) and were included in the analysis. Quality of
      family life was shown to be significantly affected in 48 (45%) cases at the first
      visit and 38 (36%) cases at the second visit. The initial means of the DFI and
      SCORAD-D were 2.4 and 8.2, respectively. Six months later the mean final DFI and
      SCORAD-D were 1.9 and 7.7, respectively. Using multiple regression on the first
      and second visits, each unit increase in SCORAD-D was associated with 0.21 [95%
      confidence interval (CI) 0.06-0.37 P = 0.008] and 0.37 (95% CI 0.15-0.59, P =
      0.001) units increase in quality of family life, respectively. This relationship
      remained significant even after adjustment for potential confounders (black skin,
      social class, sex, child's age, family size and location) each unit increase in
      SCORAD-D led to a 0.25 unit (95% CI 0.11-0.4, P = 0.001) and 0.23 unit (95% CI
      0.05-0.42, P = 0.014) increase in DFI on the first and second visits,
      respectively. Changes in the DFI scores were significantly related to changes in
      the SCORAD-D scores (regression coefficient; 0.17 (95% CI 0.06-0.29, P = 0.002).
      CONCLUSIONS: We show that quality of family life is related to the severity of AD
      in children. This confirms the importance of parental assessment of the impact of
      the disease in the management of AD, because the disease affects the entire
      family. Also, these results show the response of DFI to change predictably with
      disease severity. This may imply that the DFI questionnaire could be used as an
      extra measure of outcome in everyday clinical practice as well as in research
      studies.

PMID- 12428838
TI  - Pityriasis alba: a study of pathogenic factors.
AB  - BACKGROUND: The aetiology of pityriasis alba (PA), a common dermatosis in
      childhood, is still controversial. The objective of this study was to assess the
      possible aetiopathogenic factors of this disease in infants. METHODS: Forty-four
      patients with PA and 31 healthy children were examined and compared. Personal
      hygiene habits, sun exposure, presence of Staphylococcus aureus in nasal fossae
      and presence of major or minor signs of atopy were assessed during anamnesis and
      physical examination. Susceptibility to ultraviolet (UV) B radiation was measured
      by the onset of a contact hypersensitivity reaction to diphenylcyclopropenone in
      individuals sensitized in previously irradiated areas. RESULTS: The prevalence of
      PA was higher in individuals with darker skin, in high phototype categories, as
      well as in males. The number of daily baths and sun exposure between 10.00 h and
      15.00 h were significantly higher in the PA group when compared with controls (P
      = 0.03 and P = 0.0015, respectively). The presence of atopy signs was more common
      in pityriasis patients (P = 0.002). Susceptibility to UVB radiation was 29.6% in
      the PA group vs. 29.0% in the control group; nevertheless, important differences
      were found after stratification in order to control possible confounding factors.
      The presence of S. aureus in the nostrils was equal in both groups. CONCLUSIONS:
      Our results confirm that PA, in our population, is more prevalent in males and in
      individuals in higher phototype categories. In those with inadequate personal
      hygiene and sun exposure habits the disease is more accentuated, demonstrating
      that the xerosis presenting in individuals with atopic diathesis is an important
      element in the development of the disease. S. aureus is not an important
      aetiopathogenic factor in PA. Susceptibility to UVB becomes important when
      related to the patient's phototype.

PMID- 12428839
TI  - Botulinum toxin A in anal fissures: a modified technique.
AB  - BACKGROUND: Anal fissures are common and painful. Botulinum toxin A (BTXA) is
      considered to be the most potent non-surgical treatment; however, no attention
      has been paid to associated hyperhidrosis. AIM: To compare traditional BTXA
      treatment of muscular spasticity in anal fissures with combined treatment of
      spasticity and focal hyperhidrosis of the anal fold and perianal skin. SETTING:
      Outpatient department of a dermatological hospital. PATIENTS AND METHODS: Ten
      patients with chronic anal fissures (of more than 6 months duration who failed to
      respond to conservative treatment and who had refused surgery) associated with
      focal hyperhidrosis as assessed by Minor's sweat test were investigated in an
      open, two-armed trial. Intramuscular injections of 20-25 U BTXA (Botox) were
      performed in group A (n = 5). In group B (n = 5) those injections were combined
      with intracutaneous injection of 30-50 U BTXA to treat focal hyperhidrosis. Mean
      follow-up was 5 months. RESULTS: Five of five patients in group B but only two of
      five patients in group A experienced a complete remission despite the fact that
      relief of pain was evident in eight of 10 patients within 2 weeks. Patient
      satisfaction with treatment was high but slightly better in group B. CONCLUSIONS:
      This open trial suggests that combined therapy of both muscular spasticity and
      focal hyperhidrosis may provide better results than intramuscular injections
      alone in anal fissure therapy with BTXA.

PMID- 12428840
TI  - Collodion baby: a follow-up study of 17 cases.
AB  - Seventeen cases of collodion baby are reported. Clinical aspects, complications,
      treatment, final outcome and family history were studied. We did not observe any
      clinical features in the collodion baby that could serve as a clue in predicting
      the final diagnosis. Infections were observed in nine, hypothermia in five and
      hypernatraemic dehydration in four cases. Skin infection mainly occurred in
      babies treated with emollients (petrolatum, lanolin and cetomacrogolis cream were
      used). We therefore recommend treating the collodion baby in a humidified
      incubator, if necessary with intravenous rehydration, but not to use emollients.
      The final outcome of these study patients was erythrodermic autosomal recessive
      lamellar ichthyosis in seven cases (41%), non-erythrodermic autosomal recessive
      lamellar ichthyosis in three cases (18%), Sjogren-Larsson in one case (6%),
      epidermolytic hyperkeratosis in one case (6%), acute neonatal variant of Gaucher
      disease in one case (6%) and normal skin in four cases (24%).

PMID- 12428841
TI  - Psychological features of androgenetic alopecia.
AB  - OBJECTIVE: To evaluate the psychological features of subjects with male (MAGA)
      and female androgenetic alopecia (FAGA). METHODS: We performed a retrospective
      study of 100 patients with FAGA and the same number of patients with MAGA based
      on the features registered in the personal history of individuals who attended
      our Trichology Unit (Hospital Universitario Virgen Macarena, Sevilla, Spain) from
      January 1993 to January 1995. RESULTS: Depression was more frequent in FAGA than
      in MAGA (55:3), but anxiety (78:41) and aggressiveness or hostility were more
      frequent in MAGA than in FAGA (22:3), and three men were considered anxious and
      depressive. Treatment resulted in improvement in 89% of FAGA and 76% of MAGA, and
      the subjects continued attending with periodic check-ups. There were requests for
      surgical treatment by 3% of FAGA and 12% of MAGA, and 6% of FAGA and 12% of MAGA
      did not return for follow-up consultation. All of the MAGA showed aggressiveness
      and lack of willingness to follow the correct treatment. CONCLUSIONS: In general,
      AGA patients tend to have elusive personalities and, although the individuals may
      go to the trichology centre accompanied they preferred to present alone to the
      desk or at least to the trichological examination room, except for subjects with
      depression who would often not agree to the physician removing hairs for the
      trichogram. Most subjects accepted the prescribed medical or surgical treatment,
      but several phoned before the second treatment session because the results of the
      first session were not as good as they had expected. The drop-out rate was higher
      in men (1 in 2), who were probably subjects showing aggressiveness.

PMID- 12428842
TI  - High-dose cytosine arabinoside-induced cutaneous reactions.
AB  - BACKGROUND: High-dose cytosine arabinoside (HDAC) is being used increasingly to
      treat haematological malignancies. The therapy is associated with various non
      haematological negative side-effects, frequently involving the skin. OBJECTIVE:
      Our aim was to evaluate the actual occurrence of adverse skin reactions to HDAC
      over the 10-year period from 1989 to 1999. METHODS: One hundred and seventy-two
      subjects, 118 with acute myelogenous leukaemia and 54 with acute lymphoblastic
      leukaemia, between 16 and 71 years of age were treated with 226 post-remission
      consolidation regimens with HDAC (54 subjects underwent two cycles of treatment).
      Treatment was combined with standard doses of other cytotoxic drugs. A
      prospective study of the skin changes was then performed. RESULTS: The overall
      incidence of cutaneous reactions was almost 53%, with rashes occurring in 72.7%
      and 40.6% of subjects who received total doses of 30 and 24 g/m2, respectively.
      In the group of subjects who received a second cycle of treatment not all of
      those who experienced exanthema after the first cycle (44.4%) experienced this
      reaction after the second cycle (only 33.3%). The most commonly observed
      reactions were morbilliform eruptions on the trunk and extremities and acral
      erythema, although severe reactions with swelling and generalized urticaria
      developed in some cases. CONCLUSIONS: HDAC-induced cutaneous reactions in 53% of
      subjects. The skin changes were found to be dose related and most cleared
      spontaneously without requiring treatment. A clinical grading of cutaneous
      toxicity has been proposed to allow better comparison of cutaneous adverse
      effects in different reports.

PMID- 12428843
TI  - Watering can perineum--a forgotten complication of gonorrhoea.
AB  - In the modern era of broad spectrum antibiotics, urethral fistulae (watering can
      perineum) is one of the forgotten sequelae of chronic gonococcal infection. We
      report a 20-year-old unmarried male with gonococcal urethritis and two sinuses in
      the scrotum (watering can perineum). The micturating and retrograde urethrogram
      revealed mucosal irregularity and extravasation of contrast medium at the
      junction of bulbous and membranous urethra. Recent worldwide emergence of
      multidrug resistant strains of gonococci give rise to alarm. In the present
      scenario of HIV pandemic, ineffective treatment of patient or partner with
      gonorrhoea may result in development of these complications.

PMID- 12428844
TI  - Skin necrosis from extravasation of vinorelbine.
AB  - Skin necrosis from intravenous infiltration of soft tissue is a rare but
      potentially devastating complication of intravenous therapy. Vinca alkaloids are
      among the intravenous drugs with the highest destructive power. We report two
      cases of skin necrosis from accidental extravasation of vinorelbine, a
      semisynthetic analogue of vinblastine, rarely described as being responsible for
      this event. Histopathologic study showed separation of the dermis from necrotic
      epidermis, associated with cytologic atypia, in both patients, and focal necrosis
      of eccrine glands in one of them. We consider that intravenous infusions of
      vinorelbine should be performed using the preventive measures and care applied
      for other chemotherapeutic agents with high potential for induction of skin
      necrosis due to extravasation.

PMID- 12428845
TI  - Lymphadenopathy detected by ultrasound examination as first diagnostic hint of
      chronic lymphocytic leukaemia in a patient with melanoma.
AB  - Recent reports indicate that patients with malignant melanoma might be at higher
      risk for developing a non-cutaneous unrelated second malignancy. We describe the
      case of a 46-year-old woman who had a malignant melanoma on her right shoulder
      that was treated in 1998 by surgical excision combined with axillary lymph node
      dissection. In 1999, ultrasound examination of peripheral lymph nodes revealed
      one suspicious echopoor structure in the woman's right axilla that was not
      palpable. Diagnostic excision and histopathological examination revealed a small
      B-cell lymphocytic lymphoma, and further investigations led to a diagnosis of
      chronic lymphocytic B-cell leukaemia (B-CLL). We would like to point out the
      value of high-resolution ultrasound examination in the follow-up of patients with
      malignant melanoma; this examination can detect early metastasis as well as other
      unrelated malignancies.

PMID- 12428846
TI  - Inoculation (tattoo) leprosy: a report of 31 cases.
AB  - Thirty-one female patients with leprosy lesions starting over tattoo marks
      observed over a period of 16 years are reported. All the patients belonged to the
      Chhattisgarh State, which is highly endemic for leprosy. Most of the patients
      were in the third decade of life. All of them had ornamental tattooing done by
      roadside tattoo artists, who used unsterile needles for tattooing a large
      gathering one after another with the same needles. In all of them, the first
      lesion of leprosy started over a tattoo mark. Twenty-five cases had only single
      lesion of leprosy exclusively confined to tattoo marks. The duration between
      tattooing and appearance of first lesion in most of the cases varied from 10 to
      20 years. Paucibacillary leprosy was the commonest type observed in 29 cases,
      while two had multibacillary leprosy. The diagnosis was confirmed by
      histopathology in all cases. The present report supports the hypothesis of
      transmission of leprosy in these cases through tattooing. To the best of our
      knowledge, such a large collection of leprosy cases subsequent to tattooing has
      not been reported so far.

PMID- 12428847
TI  - Erythema annulare centrifugum: report of a case with neonatal onset.
AB  - Darier's erythema annulare centrifugum (EAC) is often associated with infectious,
      autoimmune or neoplastic disease, nevertheless, most cases of EAC remain
      unexplained. We report a case of EAC with neonatal onset and a clinical course of
      over 20 years. The patient presented from the 6th day of life with erythematous
      papules that enlarged centrifugally to form figurate, annular or policyclic
      plaques involving the entire cutaneous surface. The clinical picture had a
      chronic course, disappearing only during unrelated febrile episodes. Histologic
      examination revealed a normal epidermis and a dense perivascular
      lymphohistiocytic infiltrate and numerous eosinophils in the superficial and
      reticular dermis. Today the patient is 24 years old and his lesions are still
      unchanged. Recently, clinical evaluation revealed a diffuse sderodermic
      induration. A second biopsy showed a diffuse thickening of collagen fibers in the
      dermis. To our knowledge, this is the second report of EAC with neonatal onset
      and such a long and peculiar clinical course.

PMID- 12428848
TI  - Lichen sclerosus--a keratotic variant.
AB  - We describe an unusual case of keratotic lichen sclerosus with extragenital and
      genital lesions in a 34-year-old Brazilian man. The disease was characterized by
      several erythematous and brownish keratotic papules on the man's back, trunk and
      extensor areas of the limbs; histologic findings were typical of lichen
      sclerosus. Others atypical extragenital forms of lichen sderosus are discussed.

PMID- 12428849
TI  - Recurrent lentigo maligna as amelanotic lentigo maligna melanoma.
AB  - Amelanotic lentigo maligna and lentigo maligna melanoma are extremely rare
      tumours. Even rarer is a recurrent amelanotic lentigo maligna or amelanotic
      lentigo maligna melanoma at the site of a previously removed pigmented lentigo
      maligna. We describe two cases of recurrent amelanotic lentigo maligna melanoma
      manifesting as erythematous plaques evolved from previously excised pigmented
      lentigo maligna.

PMID- 12428850
TI  - Verrucous herpes of the scrotum in a human immunodeficiency virus-positive man:
      case report and review of the literature.
AB  - We report a case of a 28-year-old human immunodeficiency virus-positive man. He
      presented with confluent verrucous papules and nodules on his scrotum that were
      due to herpes simplex infection.

PMID- 12428851
TI  - Granuloma annulare possibly triggered by antitetanus vaccination.
AB  - We report the case of a 6-year-old girl with granuloma annulare (GA) possibly
      related to antitetanus vaccinations. The first episode occurred 2 months after
      the girl had been vaccinated but the lesions were not located at the vaccination
      site. After 1 year of being free of lesions, she had a second episode unrelated
      to vaccination. After another 6-month lesion-free period, the girl was
      administered another antitetanus vaccination and a solitary lesion developed at
      the vaccination site within 3 days. A few lesions developed on her legs in the 2
      months following the appearance of the initial plaque. The literature includes
      two reports of cases with papular lesions limited to the hepatitis B vaccination
      site, both histopathologically consistent with necrobiotic granuloma, but
      clinically not suggestive of GA. To the best of our knowledge, GA following
      antitetanus vaccination and occurring at the vaccination site has not been
      reported before. Either the trauma alone from the injection or a vaccine-induced
      immunological reaction might have triggered the necrobiosis of collagen through
      some unexplained mechanisms.

PMID- 12428852
TI  - Myxoid plexiform fibrohistiocytic tumour.
AB  - Plexiform fibrohistiocytic tumour is a low-grade malignant mesenchymal neoplasm
      of myofibroblastic origin with the capacity for biphasic differentiation toward a
      fibroblastic or histiocyte-like morphology. We report a case of this rare tumour
      presenting as a tender subcutaneous nodule on the scalp of a 58-year-old man.
      Histopathological examination revealed multinodular biphasic proliferation of
      fibroblast-like and histiocyte-like cells with a few osteoclast-like giant cells.
      This case is notable for the rare myxoid changes, which may reflect a different
      behaviour of this tumour when occurring in older people.

PMID- 12428853
TI  - Eosinophilic pustular folliculitis.
AB  - Eosinophilic pustular folliculitis is a rase dermatosis and the treatment is
      difficult because the underlying pathogenic mechanism is unknown. The authors
      report a case of eosinophilic pustular folliculitis (Ofuji's disease) in a 50
      year-old man who died 9 years after onset of the disease.

PMID- 12428854
TI  - Transdermal application of prostaglandin E1 ethyl ester for the treatment of
      trophic acral skin lesions in a patient with systemic scleroderma.
AB  - An early dinical symptom in scleroderma patients is Raynaud's phenomenon. Later
      cutaneous manifestations of the disease include oedematous swelling in the
      extremities and in more extreme cases often very painful, refractory acral
      necroses. We report on a 56-year-old female patient who participated in a
      prospective, double-blind, multicentre comparative pilot study because of her
      severe Raynaud symptoms, with dystrophic skin lesions on both hands. The goal of
      the study was to evaluate the efficacy and safety of prostaglandin E1 ethyl ester
      in a transdermal drug delivery system compared with placebo in patients with
      secondary Raynaud's phenomenon associated with systemic scleroderma or mixed
      connective tissue disease. After 2 weeks of verum treatment the patient
      experienced a marked improvement of Raynaud's attacks, with increased capillary
      flow velocity, reduced blood stasis and dinical healing of the acral trophic
      lesions. For this patient the transdermal application of prostaglandin E1 ethyl
      ester in the form of a medicated patch proved to be a simple and effective
      therapy for the acral trophic skin lesions associated with systemic scleroderma.

PMID- 12428855
TI  - Cerebriform intradermal naevus (a rare form of secondary cutis verticis gyrata).
AB  - BACKGROUND: Acquired cerebriform intradermal naevus (CIN) is a rare form of
      pseudo cutis verticis gyrata. CASE REPORT: A case of acquired CIN of the scalp in
      a 46-year-old male patient is presented. The clinical and histopathological
      presentations of CIN are described and the therapeutic possibilities are
      discussed. CONCLUSIONS: In each individual case the physician must decide whether
      to do surgery or follow a wait-and-see policy. There is little risk of malignant
      change of CIN, and surgical excision of such lesions often involves evident
      mutilation.

PMID- 12428856
TI  - 'Deep' white superficial onychomycosis due to molds.

PMID- 12428857
TI  - Multiple keratoacanthomas arising on skin lesions of pseudoxanthoma elasticum.

PMID- 12428858
TI  - A case of syringocystadenoma papilliferum: an unusal localization on
      postoperative scar.

PMID- 12428859
TI  - Absence of Epstein-Barr virus and human herpesvirus-6 in pityriasis lichenoides
      and plaque parapsoriasis.

PMID- 12428860
TI  - An extraordinary case of subcutaneous invasive thymoma.

PMID- 12428861
TI  - D-penicillamine induced polymyositis and morphea in a woman with Hashimoto
      thyroiditis.

PMID- 12428862
TI  - Is demodex folliculorum larger in diabetic patients?

PMID- 12428863
TI  - Bakamjian's flap.

PMID- 12428864
TI  - Lichen planopilaris and scleroderma en coup de sabre.

PMID- 12428865
TI  - Annular leucocytoclastic vasculitis: response to dapsone.

PMID- 12428866
TI  - Herpes simplex virus associated erythema multiforme in a prepartum woman without
      involvement of the newborn.

PMID- 12428867
TI  - Pyoderma gangrenosum in pregnancy.

PMID- 12428868
TI  - Compromise of immune function in obstructive jaundice.

PMID- 12428869
TI  - Effect of tension induced by Shouldice repair on postoperative course and long
      term outcome.
AB  - OBJECTIVE: To record intraoperative tension during Shouldice hernioplasty and
      correlate it with postoperative course and long-term outcome. DESIGN: Prospective
      clinical trial. SETTING: University clinic, Germany. SUBJECTS: 20 male patients
      undergoing elective primary inguinal hernia repair by Shouldice technique.
      INTERVENTION: Measurement of intraoperative tension during hernioplasty (low 0
      2.0 N, moderate 2.1-4.0 N, high > 4.1 N). MAIN OUTCOME MEASURES: Postoperative
      pain measured by visual analogue scale (VAS) at rest and activity, pain-related
      change of ventilatory measurements (8, 24 and 48 hours after intervention),
      postoperative complications, length of stay in hospital, and recurrence rate at
      mean 46.7 (range 43-54) months after operation. Data are given as mean (SD).
      RESULTS: The results for 18 patients were analysed, 2 being lost to follow up.
      Mean pain score was 17.5 (15.6), 14.8 (15.6) and 12.3 (14.9) at rest 8 hours, 24
      hours and 48 hours after operation, during activity 42.0 (16.5), 36.4 (18.5) and
      33.7 (19.1) respectively. Most depression of ventilatory measurements was found 8
      hours after operation (vital capacity 88.4 (12.5)%. peak flow 81.3 (17.2)%)
      compared with preoperative values. Complications comprised one seroma, one
      subcutaneous wound infection, and 3 haematomas. Mean length of stay in hospital
      was 4.3 (range 2-7) days. At follow up, no recurrences were found. No correlation
      with intraoperatively-induced tension was found. CONCLUSIONS: Postoperative pain
      and recurrences depend on many factors, but induced intraoperative tension can be
      excluded. The reported advantages of tension-free procedures are not based on the
      avoidance of tension. The Shouldice repair can therefore continued to be used as
      a routine technique in uncomplicated primary inguinal hernia repair.

PMID- 12428870
TI  - Vertical Mayo repair of midline incisional hernia: suggested guidelines for
      selection of patients.
AB  - OBJECTIVE: To find out whether the vertical Mayo repair should be done for
      midline incisional hernias. DESIGN: Retrospective study. SETTING: University
      hospital, Austria. SUBJECTS: 208 patients who presented with a primary midline
      incisional hernia during the period January 1991 to December 1996. INTERVENTIONS:
      Incisional hernia repair using the vertical Mayo technique. MAIN OUTCOME
      MEASURES: Recurrence rates, risk factors, common practice. RESULTS: There were 60
      recurrences (29%) and median follow up was 6 years (range 4-8). Four risk factors
      (cirrhosis, chronic cough, obesity (BMI > 30), and hernia width > 4 cm) were
      identified, which were independently predictive of hernia recurrence. All 60
      patients with a recurrent hernia had at least two of the four risk factors. The
      remaining 148 patients who did not develop a recurrence had no risk factors, or
      only one. Recurrence could therefore be predicted with a sensitivity of 80% and a
      specificity of 96%. CONCLUSION: The vertical Mayo repair is a good method for the
      repair of incisional hernias if not more than one of the four significant risk
      factors is present. The presence of two or more risk factors is predictive of a
      high rate of recurrence, and other techniques, such as alloplastic mesh repair,
      should be considered.

PMID- 12428871
TI  - Resection for cancers of the pancreatic head in patients aged 70 years or over.
AB  - OBJECTIVE: To find out if resections of cancers of the head of pancreatic are
      justified in patients over the age of 70 years. DESIGN: Retrospective study.
      SETTING: University hospital, Germany. SUBJECTS: 519 patients with cancers of the
      pancreatic head, 93 (18%) of whom were aged 70 or over. MAIN OUTCOME MEASURES:
      Comparison of outcomes between those aged 70 or over, and those aged less than
      70. RESULTS: There were 247 ductal adenocarcinomas, 134 carcinomas of the papilla
      of Vater, 79 carcinomas of the distal common bile duct, and 59 miscellaneous
      tumours. Of all variables compared (age, sex, symptoms, operations, clinical and
      pathological stage. morbidity, mortality, and long-term survival) the only
      significant difference between the groups was that leaks from the
      pancreaticojejunostomy occured more often in the older age group (p = 0.02).
      However, this did not influence overall morbidity or mortality. CONCLUSION:
      Patients' age is not a limiting factor in attempts at curative resection of
      cancers of the head of pancreas. If the tumour is resectable and patient is
      motivated and well enough, resection is indicated whatever the age.

PMID- 12428872
TI  - Percutaneous cystogastrostomy in patients with pancreatic pseudocysts.
AB  - OBJECTIVE: To evaluate the results of percutaneous cystogastrostomy for
      pancreatic pseudocysts secondary to acute or chronic pancreatitis. DESIGN:
      Retrospective study with prospective follow-up. SETTING: University hospital,
      Sweden. PATIENTS: 16 patients with symptomatic pseudocysts (10 men and 6 women,
      mean age 56 (36-78) years) treated during the period 1993-1999. INTERVENTION:
      Pseudocystogastrostomy was created under local anaesthesia and fluoroscopic
      control by percutaneous insertion of a double pigtail catheter. RESULTS: The
      underlying diagnosis was acute pancreatitis in 10 and chronic pancreatitis in 6
      patients. 13 patients had one pseudocyst and 4 had 2 or more with a median
      diameter of 11 (5-20) cm. The procedure was successful in all but 2 patients, who
      were operated on. 2 patients experienced pain after the intervention that did not
      require specific treatment, otherwise no complications were noted. Median
      hospital stay was 2 days (range 1-60). The median follow-up was 45 (1-94) months.
      All but 2 patients had successful drainage during follow-up with resolution or
      regression of the pseudocyst and relief of symptoms (pain and abdominal
      discomfort). CONCLUSION: Pancreatic pseudocysts were treated by percutaneous
      cystogastrostomy with good results. Percutaneous cystogastrostomy is a safe,
      minimally invasive procedure that gives good results at long-term follow-up as
      well as in the short-term.

PMID- 12428873
TI  - Scoring and diagnostic laparoscopy for suspected appendicitis.
AB  - OBJECTIVE: To develop a reproducible scoring system to identify patients who
      present with a doubtful diagnosis of appendicitis and who would benefit from
      diagnostic laparoscopy. DESIGN: Prospective observational study. SETTING:
      Regional teaching hospital, The Netherlands. SUBJECTS: 577 consecutive patients
      during the period 1994-5, and 343 who presented during the period 1996-7.
      INTERVENTIONS: The variables that seemed to be predictive of acute appendicitis
      were abstracted from the earlier group. a logistic regression analysis applied,
      and score created. The score was validated on the 343 patients who presented
      during 1996-7, and then the groups were combined for further analysis. MAIN
      OUTCOME MEASURES: Reproducibility of the scoring system obtained by comparing
      odds ratios (OR) of the two groups; its effectiveness judged by comparing the
      delayed and normal appendicectomy rates. RESULTS: The following variables were
      significantly correlated with the presence of acute appendicitis: white cell
      count 10 x 10(9)/L or more (score 3), rebound tenderness and male sex (score 2
      each); and symptoms present for < 48 hrs and temperature 38 degrees C or more
      (score 1 each). The OR for the two groups were 1.80 and 1.76, respectively,
      indicating that score was reproducible. With a sensitivity of 93% and a
      specificity of 83% it would be at least as accurate as clinical judgment. The
      normal appendicectomy rate would be 7% instead of 9%. and the negative
      exploration rates (laparoscopy and primary appendicectomy) would both be 22%. The
      score would also result in a lower perforation rate (2% compared with 17%).
      CONCLUSION: The score can indicate when there is an indication for laparoscopy in
      patients with suspected appendicitis.

PMID- 12428874
TI  - Treatment of Budd-Chiari syndrome with inferior vena caval occlusion by
      mesoatrial shunt.
AB  - OBJECTIVE: To report the effectiveness of a mesoatrial shunt in the treatment of
      Budd-Chiari syndrome caused by combined hepatic vein and inferior vena caval
      block. DESIGN: Retrospective study. SETTING: Tertiary care hospital, India.
      PATIENTS: 10 patients (4 men and 6 women; mean age 28, range 18-45) who had
      operations for Budd-Chiari syndrome between 1994 and 2000. INTERVENTION:
      Mesoatrial shunt. MAIN OUTCOME MEASURES: Graft patency, survival, liver function
      and symptoms. RESULTS: One patient died. All grafts were patent over a mean
      follow up period of 40 months (range 6-71). All survivors have normal liver
      function and were symptom free at the time of writing. CONCLUSION: Mesoatrial
      shunt is effective in the treatment of Budd-Chiari syndrome caused by combined
      hepatic vein and vena caval occlusion.

PMID- 12428875
TI  - Injured moped riders who required admission to hospital in Sweden from 1987 to
      1994.
AB  - OBJECTIVES: To find out the incidence, extent of injury, medical consequences,
      and mortality rate of moped riders involved in crashes in Sweden. DESIGN:
      Retrospective case study. SETTING: The Swedish Hospital Discharge Register
      (SHDR). SUBJECTS: 4716 moped riders, a total of 5857 admissions to Swedish
      hospitals from 1987-94. INTERVENTIONS: Statistical analysis of the Register. MAIN
      OUTCOME MEASURES: Incidence of injured moped riders in Sweden, mortality rate,
      types of injuries, and medical consequences. RESULTS: From 1987 to 1994, Swedish
      hospitals admitted 4716 moped riders (5857 admissions) injured in crashes, which
      corresponds to a mean of 8.5 injured/100 000 population a year. Of these 3993
      were male (85%) and 723 female (15%), with a median age of 16 years (range 3-93).
      Twenty-four percent of those admitted to hospital spent more than a week there.
      The annual number of injured moped riders did not change significantly during
      this period. The total number of deaths in hospital was 59 (1%). Among those who
      died in hospital, 32 (54%) had head injuries, 16 (27%) fractures, and 5 (9%)
      abdominal or thoracic injuries. CONCLUSION: The number of injured moped riders in
      Sweden is low. Fractures of the extremities were most common, followed by
      injuries to the head and brain. The usual victim was a teenager or young man. Of
      the patients treated in hospital few died, most of whom were elderly men.

PMID- 12428877
TI  - Acute stridor secondary to recurrent multinodular goitre after previous subtotal
      thyroidectomy: compartment syndrome of the neck.

PMID- 12428876
TI  - Necrotising infections of soft tissues--a clinical profile.
AB  - OBJECTIVE: To study the clinical profile and outcome of patients with necrotising
      soft-tissue infections. DESIGN: Prospective study. SETTING: Teaching hospital,
      India. SUBJECTS: 75 patients (54 male and 21 female), mean age 40 years (range 8
      months-85 years). INTERVENTIONS: Patients were uniformly managed by initial
      resuscitation, debridement, topical wound care, systemic antibiotics, and enteral
      hyperalimentation. MAIN OUTCOME MEASURES: Morbidity and mortality. RESULTS:
      Aetiology of the infections included major and minor trauma, minor skin
      infections and postoperative infections. 22 patients were diabetic. The
      extremities were involved in 57 patients, the trunk in 26 and the perineum in 21.
      68 presented with local tenderness (91%), 74 with oedema (99%), 54 with erythema
      (72%), 55 with ulceration (73%), and 54 with a purulent or serous discharge
      (72%). beta-haemolytic streptococci were isolated from only 10 patients.
      Staphylococcus aureus was the most common bacteria isolated (n = 30, 46%)
      followed by Bacteroides fragilis and anaerobic cocci (n = 22, 34% each). Cultures
      grew fungi in 9 patients. 20 patients died giving a mortality of 27%. Jaundice
      and serum albumin were the only factors to have a significant influence on
      mortality. CONCLUSIONS: Necrotising soft tissue infections are potentially fatal.
      Early recognition and prompt aggressive debridement are the keys to successful
      management.

PMID- 12428878
TI  - Choosing fluids in traumatic hypovolemic shock: the role of crystalloids,
      colloids, and hypertonic saline.

PMID- 12428879
TI  - A comparison of thiopental, propofol, and diazepam-ketamine anesthesia for
      evaluation of laryngeal function in dogs premedicated with butorphanol
      glycopyrrolate.
AB  - Thiopental, propofol, and diazepam-ketamine were compared for evaluation of
      laryngeal function in dogs. There was no significant difference among the three
      protocols in time to observation of normal function after drug administration or
      in the occurrence of swallowing, laryngospasm, or breathing. Jaw tone was
      significantly greater with diazepam-ketamine. Exposure of the larynx was
      excellent in five dogs and moderate in three dogs, each receiving thiopental or
      propofol. Exposure was excellent in one dog, moderate in six dogs, and poor in
      one dog receiving diazepam-ketamine. Exposure of the larynx for laryngeal
      function evaluation is more readily accomplished with thiopental or propofol than
      with diazepam-ketamine.

PMID- 12428880
TI  - Comparison of the effects of buprenorphine, oxymorphone hydrochloride, and
      ketoprofen for postoperative analgesia after onychectomy or onychectomy and
      sterilization in cats.
AB  - In this prospective, randomized, blinded study, 68 clinically healthy cats that
      had onychectomy (n = 20), onychectomy and castration (n = 20), or onychectomy and
      ovariohysterectomy (n = 28) were randomly assigned to one of four postoperative
      analgesic treatment groups: buprenorphine (0.01 mg/kg body weight,
      intramuscularly [IM]), oxymorphone hydrochloride (0.05 mg/kg body weight, IM),
      ketoprofen (2 mg/kg body weight, IM), and placebo (physiological saline).
      Sedation scores, visual analog pain scores, cumulative pain scores, serum
      cortisol concentration, and appetite were used to assess postoperative analgesic
      effect. Buprenorphine demonstrated the highest efficacy with the lowest
      cumulative pain scores and serum cortisol levels.

PMID- 12428881
TI  - Cardiopulmonary effects of intrathoracic insufflation in dogs.
AB  - This study was designed to quantify the effects of incremental positive
      insufflation of the intrathoracic space on cardiac output (CO), heart rate (HR),
      arterial pressure (AP), central venous pressure (CVP), and percent saturation of
      hemoglobin with oxygen (SPO2) in anesthetized dogs. Seven healthy, adult dogs
      from terminal teaching laboratories were maintained under anesthesia with
      isoflurane delivered with a mechanical ventilator. The experimental variables
      were recorded before introduction of an intrathoracic catheter, at intrathoracic
      pressures (IP) of 0 mm Hg, 3 mm Hg insufflation, and additional increments of 1
      mm Hg insufflation thereafter until the SPO2 remained <85% despite increases in
      minute volume. Finally the variables were measured again at 0 mm Hg IP. The
      cardiac output and systolic and diastolic AP significantly (P < 0.05) decreased
      at 3 mm Hg IP. Significant decreases in SPO2 were seen at 10 mm Hg IP.
      Significant increase in CVP was noted at 6 mm Hg IP. Heart rate decreased
      significantly at 5 to 6 mm Hg IP but was not decreased above 6 mm Hg IP. Given
      the degree of CO decrease at low intrathoracic pressures, insufflation-aided
      thoracoscopy should be used with caution and at the lowest possible insufflation
      pressure. Standard anesthetic monitoring variables such as HR and AP measurements
      may not accurately reflect the animal's cardiovascular status.

PMID- 12428882
TI  - Indirect arterial blood pressure measurement in nonsedated Irish wolfhounds:
      reference values for the breed.
AB  - Arterial blood pressure measurements were obtained from 158 healthy Irish
      wolfhounds using the oscillometric technique to establish reference values for
      the breed. In contrast to other sight hounds, Irish wolfhounds have low arterial
      blood pressure. Mean systolic pressure for the group was 116.0 mm Hg. Mean
      diastolic pressure was 69.2 mm Hg, and the mean value for mean arterial pressure
      was 87.8 mm Hg. Blood pressure measurements were higher in older wolfhounds than
      in young dogs. There was no difference between systolic and mean arterial blood
      pressures in lateral recumbency compared to standing position. However, diastolic
      pressure was slightly lower when standing. Calm dogs had lower pressure than
      anxious wolfhounds. There was a significant interaction between the effects of
      age, gender, and mood on systolic, diastolic, and mean arterial blood pressure
      values.

PMID- 12428883
TI  - Temporary tube cystostomy as a treatment for urinary obstruction secondary to
      adrenal disease in four ferrets.
AB  - Adrenal neoplasia is a common problem in middle-aged to older ferrets. Male
      ferrets may present for stranguria and dysuria due to prostatic/paraurethral
      tissue enlargement secondary to elevation in androgens produced by the neoplastic
      tissue. Progressive urethral compression followed by complete urinary obstruction
      can result. Urinary obstruction can persist for days following surgery requiring
      urinary diversion. Four ferrets presenting with signs consistent with urinary
      obstruction secondary to adrenal disease were immediately treated with urethral
      catheterization or cystocentesis followed by adrenalectomy and temporary tube
      cystostomy. The tube cystostomy placement and use were associated with minimal
      complications and allowed recovery from surgery.

PMID- 12428884
TI  - Cervical expanding hematomas in dogs: five cases.
AB  - Five puppies were presented to the Alfort National Veterinary School for a
      rapidly expanding, well-demarcated, subcutaneous cervical mass of a few days'
      duration. In all cases, previous trauma was reported. Fine-needle aspiration of
      the mass in each case revealed a serosanguineous fluid containing mainly
      erythrocytes, with a total protein concentration ranging from 3.5 to 5.2 g/dL.
      Coagulation tests failed to reveal any coagulation disorder. En-bloc surgical
      removal of the fluid-filled mass associated with short-term postoperative
      drainage was curative in all cases. Histopathological examination of the mass
      revealed encapsulated hematoma. The disease resembles chronic expanding hematoma
      in humans.

PMID- 12428885
TI  - Detection of occult urinary tract infections in dogs with diabetes mellitus.
AB  - Dogs with diabetes mellitus may develop occult urinary tract infections. In this
      study, diabetic dogs with negative and positive bacterial urine cultures were
      compared. Records from 51 dogs with diabetes mellitus were reviewed at the
      University of Illinois. No difference was identified between the groups in urine
      specific gravity, pH, glucose, ketones, protein, red blood cells, white blood
      cells, or epithelial cells. Dogs with occult urinary tract infection did have an
      increased incidence of bacteriuria, but this was not a consistent finding.
      Therefore, the urine on all diabetic dogs should be cultured to accurately
      identify the presence or absence of bacterial urinary tract infections.

PMID- 12428886
TI  - Cutaneopulmonary fistula in a dog caused by migration of a toothpick.
AB  - A 6-year-old, neutered male, mixed-breed dog was presented for a chronic draining
      tract and cough. A contrast fistulogram demonstrated a cutaneopulmonary fistula.
      Excision of the fistulous tract retrieved a migrating foreign body (i.e., a
      toothpick) within the tract. Clinical signs resolved 2 weeks following surgery.
      Foreign body migration is a common problem seen in dogs, resulting in many
      different clinical syndromes. Definitive surgery depends upon complete removal of
      the foreign body and the diseased tissue. Sinography is an inexpensive, readily
      available diagnostic tool that can help define a draining tract and confirm a
      foreign body.

PMID- 12428887
TI  - Congenital factor XI deficiency in a domestic shorthair cat.
AB  - A 6-month-old, female, domestic shorthair cat was examined after onychectomy and
      ovariohysterectomy because of bleeding from the paws. Prolonged activated partial
      thromboplastin time was discovered, Coagulation factor analyses revealed
      deficiency of factor XI coagulant activity. Plasma mixing studies indicated
      factor deficiency or dysfunction rather than factor inhibition. Feline factor XI
      deficiency in one adult cat has been previously reported but was attributed to
      factor XI inhibitors. The signalment, lack of primary disease, and the finding of
      persistent factor XI deficiency in the absence of coagulation inhibitors were
      considered compatible with congenital factor XI deficiency in the cat of this
      report.

PMID- 12428888
TI  - Association of cauda equina compression on magnetic resonance images and clinical
      signs in dogs with degenerative lumbosacral stenosis.
AB  - Magnetic resonance imaging (MRI) was used to examine the lumbosacral spine of 27
      dogs with degenerative lumbosacral stenosis. Four normal dogs were also similarly
      imaged. Compression of the soft-tissue structures within the vertebral canal at
      the lumbosacral space was assessed in two ways: by measuring dorsoventral
      diameter on T1-weighted sagittal images and cross-sectional area on transverse
      images. The severity of the clinical signs was compared to the severity of cauda
      equina compression. No significant correlation was found. It is concluded that
      degree of compression as determined by MRI at time of presentation is independent
      of disease severity.

PMID- 12428889
TI  - External hydrocephalus in a dog with suspected bacterial meningoencephalitis.
AB  - An approximately 12-week-old, male fox terrier was presented for clinical and
      physical signs consistent with hydrocephalus. Diagnostic evaluation led to a
      diagnosis of external hydrocephalus and fibrinopurulent meningoencephalitis.
      Treatment consisted of antibiotics and the placement of a ventriculoperitoneal
      shunt. The dog improved neurologically and was alive and doing well 1 year
      following initial presentation. This is the first reported case of external
      hydrocephalus in the dog. The dog of this report exhibited clinical features
      consistent with a disorder termed hydrocephalus with periventricular
      encephalitis.

PMID- 12428890
TI  - Closure of median sternotomy in dogs: suture versus wire.
AB  - Twenty normal, large-breed dogs underwent median sternotomy. Median sternotomies
      were closed with 20-gauge orthopedic wire in 10 dogs and no. 2 polybutester in 10
      dogs. Closure with suture was faster than with wire (6.7 +/- 1.8 minutes versus
      9.1 +/- 1.9 minutes, respectively). Significant differences were not observed in
      degree of postoperative pain or wound complication rates. Sternotomies closed
      with wire showed a trend to be more stable and had significantly less
      displacement on radiographic evaluation at 28 days. All sterna closed with wire
      examined histopathologically showed evidence of chondral or osteochondral
      bridging, while sterna closed with suture only showed fibrous union.

PMID- 12428891
TI  - Maximize your publication potential by targeting your journal.

PMID- 12428892
TI  - Acceptance, cognitions, and resourcefulness in women with diabetes.
AB  - The coexistence of diabetes and depression occurs frequently among young and
      middle-age women. Unless one is resourceful, simultaneous management of the
      symptoms of both conditions is especially challenging. Skills constituting
      resourcefulness are learned throughout life and are important for the optimal
      performance of daily activities. Little is known about specific factors that
      influence resourcefulness. In this study contextual factors (diabetic and
      depressive symptoms) and cognitive factors (positive cognitions and acceptance of
      diabetes) were examined as antecedents of learned resourcefulness in 82 women
      with type 2 diabetes. Regression analyses showed that depressive symptoms and
      positive cognitions were significant antecedents of learned resourcefulness:
      Positive cognitions mediated the effects of depressive symptoms on learned
      resourcefulness. The findings suggest the need for interventions thatfocus on
      development of positive cognitions to better promote resourcefulness in women
      with type 2 diabetes who are at risk for depression.

PMID- 12428893
TI  - Korean women's breast cancer experience.
AB  - The purpose of this study was to explore cultural meanings of breast cancer among
      Korean women in South Korea. A descriptive longitudinal study using
      methodological triangulation was conducted, and only qualitative findings are
      presented in this article. Ten Korean women who were newly diagnosed with a plan
      of surgery and subsequent chemotherapy, who did have severe fatigue at the time
      of recruitment, were recruited through Seoul National University Hospital. Data
      were collected using in-depth, 2-hour interviews and analyzed using thematic
      analysis. The themes emerged through the analysis process included: (a) "I did
      wrong," (b) "I cannot ask male physicians." (c) "I don't want to show the
      operation site to my husband." and (d) "I do household tasks by myself." The
      overriding theme was marginalization of the women within the context of their
      patriarchal culture. The findings suggest that culture is an important context
      circumscribing women's health/illness experience.

PMID- 12428894
TI  - Social support and positive health practices.
AB  - The purpose of this study was to examine the relationships between positive
      health practices and social support, self-esteem, and optimism. The relationships
      between social support and self-esteem and between social support and optimism
      were also examined. Two alternative mediational models. with self-esteem in Model
      1 and optimism in Model 2, were tested to help explain the relationship between
      social support and positive health practices in middle-age adults. The sample of
      202 middle-age adults completed a demographic data sheet, the Personal Lifestyle
      Questionnaire, Personal Resource Questionnaire 85-Part 2, Rosenberg Self-Esteem
      Scale, and Revised Life Orientation Test. The five correlational hypotheses were
      supported. Social support, self-esteem, and optimism were all positively related
      to positive health practices, and social support was positively related to self
      esteem and optimism. The two mediational models tested with regression analyses
      were not supported.

PMID- 12428895
TI  - Impairing injuries among medical personnel.
AB  - Medically impairing injuries among medical personnel (n = 209) were analyzed
      based on data obtained from the Work-Related No-Fault Liability Insurance's (TFA)
      injury registration system. Almost half (98; 47%) were injured during patient
      care, of which 29 were injured as a result of physical trauma inflicted by the
      patient. When moving themselves between the homes of the patients and between
      different wards, 94 (45%) were injured (18 in vehicle crashes). The injuries most
      often resulting in medical impairment were sprains and/or strains (101; 48%) and
      fractures (67; 32%). The injuries primarily affected the upper extremities (48%).
      Fifteen percent had a medical impairment of 10% or more, and in about half of the
      cases, the impairment was 1% to 4%. Every injured person was on sick leave for 7
      months, on average, during the 2-year follow-up period. In 12% of the cases, the
      injury led to a disability pension.

PMID- 12428896
TI  - Aboriginal nurses' beliefs, attitudes, and values about sexuality in Taiwan.
AB  - The potential of risky sexual behaviors and adolescent unplanned pregnancy has
      become a primary issue in the health care system for aborigines in eastern
      Taiwan. Using aboriginal nurses to provide information on sexual behaviors may
      have potential in promoting healthy sexual practices among aborigines. The
      purposes of this study were to explore Taiwanese aboriginal nurses beliefs.
      attitudes, and values about sexuality. Several health centers in eastern Taiwan
      were randomly selected to recruit participants in the year 2000. A self-report
      questionnaire was administered to 206 female nurses (mean age = 28.4, SD = 7.4)
      who worked in various clinical units. The results revealed that aboriginal nurses
      hold moderately positive beliefs, attitudes, and values about sexuality. The
      conflict between aboriginal nurses' belief and value systems about sexuality was
      clear. A conflict between aboriginal nurses' value systems and patients behaviors
      also existed. Strategies to help aboriginal nurses to be more aware of their
      beliefs, attitudes, and values about sexuality should be an essential issue in
      the practice and education of nurses.

PMID- 12428897
TI  - A comparison of imputation techniques for handling missing data.
AB  - Researchers are commonly faced with the problem of missing data. This article
      presents theoretical and empirical information for the selection and application
      of approaches for handling missing data on a single variable. An actual data set
      of 492 cases with no missing values was used to create a simulated yet realistic
      data set with missing at random (MAR) data. The authors compare and contrast five
      approaches (listwise deletion, mean substitution, simple regression, regression
      with an error term, and the expectation maximization [EM] algorithm) for dealing
      with missing data, and compare the effects of each method on descriptive
      statistics and correlation coefficients for the imputed data (n = 96) and the
      entire sample (n = 492) when imputed data are inculded. All methods had
      limitations, although our findings suggest that mean substitution was the least
      effective and that regression with an error term and the EM algorithm produced
      estimates closest to those of the original variables.

PMID- 12428898
TI  - Biophysical aspects of using liposomes as delivery vehicles.
AB  - Liposomes are used as biocompatible carriers of drugs, peptides, proteins,
      plasmic DNA, antisense oligonucleotides or ribozymes, for pharmaceutical,
      cosmetic, and biochemical purposes. The enormous versatility in particle size and
      in the physical parameters of the lipids affords an attractive potential for
      constructing tailor-made vehicles for a wide range of applications. Some of the
      recent literature will be reviewed here and presented from a biophysical point of
      view, thus providing a background for the more specialized articles in this
      special issue on liposome technology. Different properties (size, colloidal
      behavior, phase transitions, and polymorphism) of diverse lipid formulations
      (liposomes, lipoplexes, cubic phases, emulsions, and solid lipid nanoparticles)
      for distinct applications (parenteral, transdermal, pulmonary, and oral
      administration) will be rationalized in terms of common structural, thermodynamic
      and kinetic parameters of the lipids. This general biophysical basis helps to
      understand pharmaceutically relevant aspects such as liposome stability during
      storage and towards serum, the biodistribution and specific targeting of cargo,
      and how to trigger drug release and membrane fusion. Methods for the preparation
      and characterization of liposomal formulations in vitro will be outlined, too.

PMID- 12428899
TI  - Towards an understanding of complex biological membranes from atomistic molecular
      dynamics simulations.
AB  - Computer simulation has emerged as a powerful tool for studying the structural
      and functional properties of complex biological membranes. In the last few years,
      the use of recently developed simulation methodologies and current generation
      force fields has permitted novel applications of molecular dynamics simulations,
      which have enhanced our understanding of the different physical processes
      governing biomembrane structure and dynamics. This review focuses on frontier
      areas of research with important biomedical applications. We have paid special
      attention to polyunsaturated lipids, membrane proteins and ion channels,
      surfactant additives in membranes, and lipid-DNA gene transfer complexes.

PMID- 12428900
TI  - NMR studies of drug interaction with membranes and membrane-associated proteins.
AB  - This review focuses on the recent developments in the study of drug interactions
      with biological membranes and membrane-associated proteins using nuclear magnetic
      resonance (NMR) spectroscopy and other spectroscopic techniques. Emphasis is
      placed on a class of low-affinity neurological agents as exemplified by volatile
      general anesthetics and structurally related compounds. The technical aspects are
      reviewed of how to prepare membrane-mimetic systems and of NMR approaches that
      are either in current use or opening new prospects. A brief literature survey
      covers studies ranging from drug distribution in simplified lipid matrix to
      specific drug interaction with neuronal receptors reconstituted in complicated
      synthetic membrane systems.

PMID- 12428901
TI  - Liposome clearance.
AB  - The clearance rate of liposomal drugs from the circulation is determined by the
      rate and extent of both drug release and uptake of liposomes by cells of the
      mononuclear phagocyte system (MPS). Intravenously injected liposomes initially
      come into contact with serum proteins. The interaction of liposomes with serum
      proteins is thought to play a critical role in the liposome clearance. Therefore,
      in this review, we focus on the role of serum proteins, so-called opsonins, that
      enhance the clearance of liposomes, when bound to liposomes. In addition to
      opsonin-dependent liposome clearance, opsonin-independent liposome clearance is
      also reviewed. As opposed to the conventional (non-surface modification)
      liposomes, we briefly address the issue of the accelerated clearance of PEGylated
      liposomes (sterically stabilized liposomes, long-circulating liposomes) on
      repeated injection, a process that has recently been observed.

PMID- 12428902
TI  - Controlling the physical behavior and biological performance of liposome
      formulations through use of surface grafted poly(ethylene glycol).
AB  - The presence of poly(ethylene glycol) (PEG) at the surface of a liposomal carrier
      has been clearly shown to extend the circulation lifetime of the vehicle. To this
      point, the extended circulation lifetime that the polymer affords has been
      attributed to the reduction or prevention of protein adsorption. However, there
      is little evidence that the presence of PEG at the surface of a vehicle actually
      reduces total serum protein binding. In this review we examine all aspects of PEG
      in order to gain a better understanding of how the polymer fulfills its
      biological role. The physical and chemical properties of the polymer are explored
      and compared to properties of other hydrophilic polymers. An evidence based
      assessment of several in vitro protein binding studies as well as in vivo
      pharmacokinetics studies involving PEG is included. The ability of PEG to prevent
      the self-aggregation of liposomes is considered as a possible means by which it
      extends circulation longevity. Also, a "dysopsonization" phenomenon where PEG
      actually promotes binding of certain proteins that then mask the vehicle is
      discussed.

PMID- 12428903
TI  - PEG-immunoliposome.
AB  - This review deals with the current status of newly developed pendant-type PEG
      immunoliposomes (Type C), carrying monoclonal antibodies or their fragments
      (Fab') at the distal ends of the PEG chains. In terms of target binding of Type
      C, two different anatomical compartments are considered. They are mouse lung
      endothelium as a readily accessible site via the intravascular route and the
      implanted solid tumor as a much less accessible target site reached via
      extravasation. Small unilamellar liposomes (90-130 nm in diameter) were prepared
      from phosphatidycholine and cholesterol (2:1, m/m) containing 6mol.% of DSPE-PEG
      COOH or DPPE-PEG-Mal. For targeting to the vascular endothelial surface in the
      lung, 34A antibody, which is highly specific to mouse pulmonary endothelial
      cells, was conjugated to PEG-liposomes (34A-Type C). The degree of lung binding
      of 34A-Type C in BALB/c mouse was significantly higher than that of 34A-Type A,
      which is an ordinary type of immunoliposome (without PEG derivatives). For
      targeting to solid tumor tissue, 21 B2 antibody (anti-human CEA) and its Fab'
      fragment were used. The targeting ability of Fab'-Type C was examined by using
      CEA-positive human gastric cancer strain MKN-45 cells inoculated into BALB/c
      nu/nu mice. Fab'-Type C showed low RES uptake and a long circulation time, and
      enhanced accumulation of the liposomes in the solid tumor was seen. The small
      Fab'-Type C predominantly passed through the leaky tumor endothelium by passive
      convective transport. These studies offer important insights into the potential
      of Type C liposomes for target-specific drug delivery.

PMID- 12428904
TI  - Tumor-directed targeting of liposomes.
AB  - Tumor-specific targeting is a critical goal in the research area of liposomal
      drug delivery. Identification of the specific interactions between ligands and
      target tumor cells is a principle prerequisite in achieving this goal. Generally,
      tumor cells aberrantly express tumor-associated antigens that can be utilized as
      appropriate target molecules. Monoclonal antibodies against tumor-associated
      antigens have been successfully adopted for targeting to various types of cancer
      cells. The incorporation of humanized monoclonal antibodies or single chain human
      antibodies, instead of rodent antibodies into immunoliposomes has resulted in
      better clinical applicability. Tumor-specific ligands other than monoclonal
      antibodies have also been investigated as in vivo tumor-directing molecules.
      However, the number of pre-clinical studies of anticancer treatments using tumor
      specific liposomal drugs reporting successful targeting and enhanced therapeutic
      efficacy has been limited. Further refinement of tumor-specific interactions and
      liposomal formulations will be necessary for the application of the tumor
      specific liposomal drug strategy for anticancer chemotherapy or gene therapy.

PMID- 12428905
TI  - Cationic liposome-mediated gene delivery in vivo.
AB  - Several improvements have been made in liposomal delivery, thus making this
      technology potentially useful for treatment of certain diseases in the clinic.
      Success in non-viral delivery is complicated and requires optimization of several
      components. These components include nucleic acid purification, plasmid design,
      formulation of the delivery vehicle, administration route and schedule, dosing,
      detection of gene expression, and others. With further improvements, broad use of
      non-viral delivery systems to treat human disorders should be possible.

PMID- 12428907
TI  - Complex roles of CpG in liposomal delivery of DNA and oligonucleotides.
AB  - Unmethylated CpG in bacterial DNA has recently been recognized as a danger signal
      to the mammalian immune system. This CpG signal can be greatly amplified when DNA
      is delivered via a lipidic vector. The CpG effects are affected by the
      administration route, and can be either beneficial or harmful. In this review, we
      will summarize our current understanding about the mechanism of action of the
      immunostimulatory motifs. Emphasis will be placed on the discussion of the
      complicated roles of CpG when CpG DNA or oligonucleotides are administered in
      vivo using liposomes as a delivery vehicle.

PMID- 12428906
TI  - Plasmid delivery in the rat brain.
AB  - Neurodegenerative diseases as a class do not have effective pharmacotherapies.
      This is due in part to a poor understanding of the pathologies of the disease
      processes, and the lack of effective medications. Gene delivery is an attractive
      possibility for treating these diseases. For the paradigm to be effective,
      efficient, safe and versatile vectors are required. In this study we evaluated
      three plasmid delivery systems for transgene expression in the rat hippocampus.
      Two of these systems were designed to have enhanced intracellular
      biodegradability. It was hypothesized that this system would be less toxic and
      could increase the free (non-vector) associated plasmids within the cell, leading
      to increased transgene activity. Polyethylenimine (PEI) and r-AAV-2 (recombinant
      adeno associated virus-2) were used as positive, non-viral and viral controls
      respectively, in the in vivo experiments. The results from the studies indicate
      there is a distinct difference between the various vectors in terms of total
      cells transfected, type of cell transfected, and toxicity. Non-viral systems were
      effective at transfecting both neurons and glia cells within the hippocampus,
      while the r-AAV-2 transfected mainly neurons. In summary, plasmid-mediated
      systems are effective for transgene expression within the brain and deserve
      further study.

PMID- 12428908
TI  - Delivery of protein antigens to the immune system by fusion-active virosomes: a
      comparison with liposomes and ISCOMs.
AB  - The induction of effective cellular and humoral immune responses against protein
      antigens is of major importance in vaccination strategies against infectious
      diseases and cancer. Immunization with protein alone in general does not result
      in efficient induction of cytotoxic T lymphocyte (CTL) and antibody responses.
      Numerous other immunization strategies have been explored. In this review we will
      discuss a number of lipid-based antigen delivery systems suitable for the
      induction of CTL responses. These systems comprise reconstituted virus envelopes
      (virosomes), liposomes, and immune-stimulating complexes (ISCOMs). We will
      concentrate on delivery of the protein antigen ovalbumin (OVA) since extensive
      studies with this antigen have been performed for all of the systems discussed,
      allowing direct comparison of antigen delivery efficiency. Stimulation of CTL
      activity requires processing of the antigen in the cytosol of antigen-presenting
      cells (APCs) and presentation of antigenic peptides on surface major
      histocompatibility class I complexes (MHC class I). In vitro, the ability of
      antigen delivery systems to induce MHC class I presentation indeed correlates
      with their capacity to deliver antigen to the cytosol of cells. This capacity
      appears to be less important for the induction of cytotoxic T lymphocytes in
      vivo. Instead, other properties of the antigen delivery system like activation of
      APCs and induction of T helper cells play a more prominent role. Fusion-active
      virosomes appear to be a very potent system for induction of CTL activity, most
      likely since virosomes combine efficient delivery of antigen with general
      stimulation of the immune system.

PMID- 12428909
TI  - Liposomal delivery of CTL epitopes to dendritic cells.
AB  - The induction of strong and long lasting T-cell response, CD4+ or CD8+, is a
      major requirement in the development of efficient vaccines. An important aspect
      involves delivery of antigens to dendritic cells (DCs) as antigen presenting
      cells (APCs) for the induction of potent antigen-specific CD8+ T lymphocyte
      (CTLs) responses. Protein or peptide-based vaccines become an attractive
      alternative to the use of live cell vaccines to stimulate CTL responses for the
      treatment of viral diseases or malignancies. However, vaccination with proteins
      or synthetic peptides representing discrete CTL epitopes have failed in most
      instances due to the inability for exogenous antigens to be properly presented to
      T cells via major histocompatibility complex (MHC) class I molecules. Modern
      vaccines, based on either synthetic or natural molecules, will be designed in
      order to target appropriately professional APCs and to co-deliver signals able to
      facilitate activation of DCs. In this review, we describe the recent findings in
      the development of lipid-based formulations containing a combination of these
      attributes able to deliver tumor- or viral-associated antigens to the cytosol of
      DCs. We present in vitro and pre-clinical studies reporting specific immunity to
      viral, parasitic infection and tumor growth.

PMID- 12428910
TI  - Antigen delivery to mucosa-associated lymphoid tissues using liposomes as a
      carrier.
AB  - Oral vaccination requires an antigen delivery vehicle to protect the antigen and
      to enhance translocation of the antigen to the mucosa-associated lymphoid tissue.
      A variety of antigen delivery vehicles including liposomes have been studied for
      mucosal immunization. The advantages of liposome formulations are their
      particulate form and the ability to accommodate immunomodulators and targeting
      molecules in the same package. Many conventional liposomes are variably unstable
      in acids, pancreatic juice and bile. Nevertheless, carefully designed liposomes
      have demonstrated an impressive efficacy in inducing mucosal IgA responses,
      compared to free antigens and other delivery vehicles. However, liposomes as an
      oral vaccine vehicle are not yet optimized. To design liposomes that are stable
      in the harsh intestinal environment and are efficiently taken up by the M cells
      remains a challenge. This review summarizes recent research efforts using
      liposomes as an antigen carrier for oral vaccines with practical attention to
      liposome designs and interaction with the M cells.

PMID- 12428911
TI  - Houston Conference: need for more fundamental knowledge in neuropsychology.
AB  - Two training models in neuropsychology have been recently proposed (Guidelines of
      the INS-Division 40 Task Force on Education, Accreditation, and Credentialing,
      Clin. Neuropsychol. 1: 29-34, 1987; Hannay, H. J. et al., Anh. Clin.
      Neuropsychol. 13: 157-250,1998). When comparing both educational models,
      similarities but also differences are found. According to the Houston Conference
      model--but not to the former model--neuropsychology represents a specialty of
      psychology. In the Houston Conference training model, applied knowledge is
      overtly emphasized, whereas fundamental or basic knowledge in neuropsychology
      appears weak. The proposed program does not seem to provide sufficient emphasis
      and background knowledge in (1) History of neuropsychology, (2)
      Neuropsychological syndromes, and (3) Neuropsychology theory.

PMID- 12428912
TI  - The Houston Conference: the road more traveled.

PMID- 12428913
TI  - An essay on the Houston Conference policy statement: static yet incomplete or a
      work in progress?
AB  - Ardila (Neuropsychol. Rev. 12: 3, 2002) criticizes the Policy Statement from the
      Houston Conference on Specialty Education and Training in Clinical
      Neuropsychology (Hannay et al., Arch. Clin. Neuropsychol. 13: 157-250, 1998) as
      possessing deficiencies in the training of clinical neuropsychologists in three
      fundamental knowledge areas: the history of the discipline, neuropsychological
      syndromes, and neuropsychological theory. These problems are seen here as a
      result of a more pervasive problem associated with the Houston Conference
      training model's emphasis on technical skill over science and the attempt to
      micromanage the training of the clinical neuropsychologist at the administrative
      level.

PMID- 12428914
TI  - The Houston Conference: the need for more discussion.

PMID- 12428916
TI  - Telomere shortening in mouse strains with constitutional chromosomal aberrations.
AB  - PURPOSE: To compare telomere length in mouse strains with constitutional
      chromosomal aberrations generated either by exposure of parents to ionizing
      radiation, a chemical mutagen or arising spontaneously with that of the
      karyotypically normal mouse from the same genetic background. MATERIALS AND
      METHODS: Telomere length was assessed in five independently derived strains of
      mouse with constitutional chromosomal aberrations and in the karyotypically
      normal control mouse using quantitative fluorescence in situ hybridization (Q
      FISH). Bone marrow cells obtained directly from the animals were used for the
      analysis. RESULTS: Chromosomal aberrations, one in each mouse strain, included
      three reciprocal translocations induced by ionizing radiation, one insertion
      induced by a chemical mutagen and one spontaneous Robertsonian translocation.
      There was no cytogenetically detectable loss of material in any of the strains
      and most mice were phenotypically normal. Telomeres were significantly shorter in
      all mouse strains with constitutional chromosomal aberrations in comparison with
      those originating from the karyatypically normal mouse from the same genetic
      background. Telomeres were significantly shorter at p-arms than at q-arms in all
      animals. The telomere length in individual chromosomes was variable and there was
      no single chromosome with consistently short telomeres in all animals.
      CONCLUSIONS: The presence of stable chromosomal aberrations, such as
      translocations or insertions, in the mouse genome may generate telomere
      shortening. This might have implications for understanding biological
      consequences or radiation-induced stable chromosomal aberrations.

PMID- 12428915
TI  - Neuropsychological functioning in chronic Lyme disease.
AB  - Lyme disease is currently the most common vector-borne illness in the United
      States. The disease is multisystemic, and chronic disease, in particular, may be
      associated with neuropsychological deficits. However, to date, only a few
      empirical studies exist, which examine the neuropsychological sequelae associated
      with chronic Lyme disease. A review of the literature shows that the deficits
      observed in adults with chronic Lyme disease are generally consistent with the
      deficits that can be seen in processes with primarily frontal systems
      involvement. These observations are generally consistent with neuroradiologic
      findings. The clinical presentation in chronic Lyme disease and the nature of the
      neuropsychological deficits are discussed, as are several central issues in
      understanding neuropsychological functioning in chronic Lyme disease, such as the
      impact of chronic illness, response to treatment, and the relationship between
      neuropsychological performance and depression, fatigue, and neurological
      indicators of disease.

PMID- 12428917
TI  - Higher frequency of chromosome aberrations in late-arising first-division
      metaphases than in early-arising metaphases after exposure of human lymphocytes
      to X-rays in G0.
AB  - PURPOSE: To determine whether metaphases arising at different times after mitogen
      stimulation of G0 lymphocytes differ in frequencies of X-ray-induced chromosome
      aberrations. MATERIALS AND METHODS: Human G0 lymphocytes from peripheral blood
      exposed to 0, 1.5 or 3.0 Gy X-rays were stimulated to divide with the mitogen
      phytohaemagglutinin (PHA). First-division metaphases were distinguished from
      second and third divisions by chromatid labelling with 5-bromodeoxvuridine (BUdR)
      and staining with Giemsa or DAPI. Cultures harvested 48, 70 and 94 h after
      mitogen stimulation were analysed for unstable aberrations on Giemsa-stained
      slides and for stable and unstable aberrations by fluorescence in situ
      hvbridization (FISH) with painting probes for chromosomes 1, 2 and 4. RESULTS:
      Frequencies of aberrations declined at the later culture periods, as expected on
      the basis of unstable aberrations being lost in mitotic division. Whe n scoring
      was restricted to firstdivision metaphases, however, aberration frequencies were
      higher in 94-h cultures than in 48-h cultures. CONCLUSIONS: Frequencies of
      radiation-induced chromosome aberrations in first-division metaphases increase
      with culture time after mitogen stimulation. Possible explanations for this
      finding are a delay of damaged cells in mitogenic response or progression through
      divisions and heterogeneity among lymphocytes in culture kinetics and
      radiosensitivity. The data argue against the common assumption that all first
      division cells are equivalent as indicators of radiation-induced chromosome
      aberrations.

PMID- 12428918
TI  - Decreased efficiency of gamma-ray-induced DNA double-strand break rejoining in
      malignant transformants of human bronchial epithelial cells generated by alpha
      particle exposure.
AB  - PURPOSE: To investigate the cytogenetic changes and DNA double-strand break (DSB)
      rejoining of transformed cell lines generated from human bronchial epithelial
      cells by alpha-particle exposure. MATERIALS AND METHODS: Transformed cell lines
      were derived from the HPV 18-immortalized human bronchial epithelial cell line
      BEP2D generated by 1.5 Gy of alpha-particles emitted by a 238Pu source. Two cell
      lines, BERP35T1 and BERP35T4, were investigated. Karyotypes were analyzed by
      trypsin/Giemsa banding. Cell survival was estimated by colony assay. PFGE was
      used to detect the DNA DSB. mRNA expression was analyzed by RT-PCR. RESULTS:
      Abnormal chromosomes 2 and 12 with elongated long arm and deletions of
      chromosomes 2, 12, 13 and 17 were observed in the transformed cell lines.
      BERP35T4 showed a much higher proportion of polyploid cells (40.5%) compared with
      parental BEP2D cells and the BERP35TI cell line (5%). BERP35T1 and BERP35T4
      showed a markedly lower capacity for rejoining of gamma-ray-induced DNA DSB and
      increased radiosensitivity compared with parental BEP2D cells. The analysis of
      mRNA levels revealed a 2.5- to 6.5-fold down-regulated expression of the DNA
      repair genes XRCC-2, XRCC-3 and Ku80 in BERP35T1 and BERP35T4 cells. CONCLUSION:
      The karyotypic changes of chromosomes 2, 12, 13 and 17 and the deficiency of DSB
      rejoining could be related to the malignant transformation processing of BEP2D
      cells initiated by alpha-particle exposure.

PMID- 12428919
TI  - Mutagenicity of low-filtered 30 kVp X-rays, mammography X-rays and conventional X
      rays in cultured mammalian cells.
AB  - PURPOSE: To measure the mutagenic effectiveness of low-filtered 30 kVp X-rays,
      mammography X-rays and conventional (200 kVp) X-rays in mammalian cells.
      MATERIALS AND METHODS: Two different cell lines and mutation assays were used.
      Exponentially growing SV40-transformed human fibroblasts were exposed to graded
      doses of mammography (29 kVp, tungsten anode, 50 microm Rh filter) or
      conventional X-rays and the frequency of 6-thioguanine-resistent HPRT-deficient
      mutants was determined. Exponentially growing hamster A(L) cells, which contain a
      single human chromosome 11 conferring the expression of the human surface protein
      CD59, were subjected to magnetic cell separation (MACS) in order to remove
      spontaneous mutants before irradiation with low-filtered 30 kVp (tungsten anode,
      0.5 mm Al filter) or conventional X-rays. Fractions of radiation-induced CD59-
      mutants were quantified by flow-cytometry after immunofluorescence labelling of
      CD59 proteins. RESULTS: Mammography X-rays were more effective than conventional
      X-rays at inducing killing of human fibroblasts, whereas 30 kVp X-rays and
      conventional X-rays were about equally effective at killing Al. cells. Mutant
      frequencies were linearly related to dose in both mutation assays. An RBE = 2.7
      was calculated for the yield of HPRT mutants in human fibroblasts exposed to
      mammography relative to conventional X-rays and an RBE = 2.4 was obtained for the
      CD59 mutant frequency in A(L) cells irradiated with low-filtered 30 kVp relative
      to conventional X-rays. CONCLUSIONS: Both low-filtered 30 kVp and mammography X
      rays are mutagenic in mammalian cells in vitro. It is unknown if and how the
      enhanced mutagenicity of mammography X-rays measured in human cells in vitro
      translates into breast cancer risk for predisposed women with an enhanced
      inherited risk for breast cancer. Although the ICRP guidelines attribute the same
      relative biological effectiveness to all radiations of low LET, including X- and
      gamma-radiations of all energies for radiobiological protection purposes
      including the assessment of risks in general terms, they also state that 'for the
      estimation of the likely consequences of an exposure of a known population, it
      will sometimes be better to use absorbed dose and specific data relating to the
      relative biological effectiveness of the radiations concerned and the probability
      coefficients relating to the exposed population' (ICRP 1991: 32). This latter
      statement may apply for the population of familial predisposed women. We hope
      that the presented data on the enhanced mutagenicity of mammography X-rays may
      stimulate a re-evaluation of the risk assessment of mammography for familial
      predisposed women. In the meantime, one should be cautious and avoid early and
      frequent mammography exposure of predisposed women. Alternative examination
      methods should be applied for these women with an inherited increased risk for
      breast cancer.

PMID- 12428920
TI  - Minisatellite and Hprt mutations in V79 cells irradiated with helium ions and
      gamma rays.
AB  - PURPOSE: To evaluate and compare cytotoxic and mutational effects of graded doses
      of gamma-rays and 4He++ ions at different LET values (nominally 80 and 123
      keV/microm) in V79 cells. MATERIALS AND METHODS: 4He++ ion beams at 80 and 123
      keV/microm were supplied by the 7 MV Van de Graaff CN accelerator of the INFN-LNL
      in the dose range 0.3 2.4 Gy at a dose rate of 1 Gy/min. Gamma-irradiation was
      performed by the 60Co 'gamma beam' of CNR-FRAE (at the INFN-LNL) in the dose
      range 0.5 6.0 Gy at a dose rate of 1 Gy/min. After irradiation, the cells were
      seeded to measure surviving fraction (SF) and mutant frequency (MF) at the Hprt
      locus on the basis of 6-thioguanine resistance. Alterations at minisatellite
      sequences (MS) of clones derived from irradiated and unirradiated cells were
      detected by Southern blot analysis using a multi-locus probe (DNA
      fingerprinting). RESULTS: Survival data from 4He++ irradiation at two LET values
      (80 and 123 keV/microm) yielded similar results: alpha = (1.08 +/- 0.04)/Gy and
      (0.90 +/- 0.03)/Gy, respectively. The best fit for mutant induction at the Hprt
      locus after 80keV/microm 4He++ was a linear function of the dose in the dose
      interval 0-1.5 Gy: alpha= (47.77 +/- 16.01) x 10(-6)/Gy. The best fit for mutant
      induction after 123 keV/microm 4He++ in the dose-interval 0-1.2 Gv was a linear
      quadratic function: alpha=(86.01 +/- 13.80) x 10(-6)/Gy; beta = (42.87 +/- 11.03)
      x 10(-6)/Gy2. For gamma-irradiation, the best fit of Hprt mutation data gave:
      alpha = (4.14+2.67)x 10(-6)/Gy: beta = (0.63 +/- 0.86) x 10(-6)/Gy2. The best
      fitting of MS alteration data with linear-quadratic or linear relationships gave:
      for gamma-rays, alpha = 0.56 mutants/Gy and beta = 0.52 mutants/Gy2; for 80
      keV/microm 4He++, alpha = 3.70 mutants/Gy and beta = 9.00 mutants/Gy2; for
      123keV/microm 4He++, alpha = 4.36 mutants/Gy. CONCLUSIONS: The results reported
      here confirmed the higher cytotoxic and mutagenic effects of helium ions in
      comparison with gamma-irradiation and the ability of DNA fingerprint analysis to
      investigate DNA damage induced by different ionizing radiations. The results of
      the mutagenic effects measured by the two tests are in agreement.

PMID- 12428921
TI  - Reduction of survival and induction of chromosome aberrations in tobacco
      irradiated by carbon ions with different linear energy transfers.
AB  - PURPOSE: To determine the relationship between linear energy transfer (LET) and
      the relative biological effectiveness (RBE) for survival reduction and chromosome
      aberration induction in plants. MATERIALS AND METHODS: Tobacco seeds were exposed
      to carbon ions having LET ranging from 92 to 260 keV microm(-1). Survival ratc
      was determined at 7 weeks after sowing. Chromosome aberrations were observed when
      the root length reached about 0.5 mm (immediately after radicle emergence), 3 and
      10 mm. RESULTS: The RBE for both endpoints increased with increasing LET and
      showed the highest value at 230 keV um(-1). The highest RBE was 65.0 for survival
      reduction and 52.5 for chromosome aberration induction. The types and yield ratio
      of chromosome aberrations such as fragments and bridges were not affected by
      radiation type at 0.5mm root length. As the roots elongated from 0.5 to 10 mm,
      the frequency of aberrant cells gradually decreased. The number of cells with
      fragments decreased faster than the number of cells with bridges. The decrement
      of chromosome aberrations appeared to be slower in roots irradiated by carbon
      ions than in roots irradiated by gamma-rays. CONCLUSIONS: The results show a
      close relationship between survival reduction and chromosome aberration induction
      in plants. The types and yield ratio of initial chromosome aberrations did not
      differ among gamma-rays and carbon ions with different LET.

PMID- 12428922
TI  - Radiation-induced apoptosis in human non-small-cell lung cancer cell lines is
      secondary to cell-cycle progression beyond the G2-phase checkpoint.
AB  - PURPOSE: To characterize the relationship between cell-cycle progression and
      radiation-induced apoptosis in NSCLC cell lines with different p53 status.
      MATERIALS AND METHODS: Cell lines with functional (H460, A549) and non-functional
      p53 (H661 and H520) were irradiated with 20 Gy. Multiparameter flow-cytometry was
      used to follow the progression of synchronized cells through the cell cycle after
      irradiation. RESULTS: Delayed apoptosis was observed after cell-cycle progression
      beyond the G2 block, either in the late G2/M-phase of the same cell cycle being
      irradiated (H661, H520) or in the G1-phase of the subsequent cell cycle (H460,
      A549). The apoptotic fraction in H661 and H520 was 60-80% at 144h after
      irradiation, higher than in A549 and H460 (5 and 35%, respectively). As an
      alternative to apoptosis in cells cycling beyond the G2 restriction point,
      hyperploid cells were generated by all cell lines. Inhibition of cell-cycle
      progression through the G2/M-phase efficiently reduced the induction of late
      apoptosis. After irradiation in S-phase, 50-60% of cells with functional p53
      remained arrested at the G2 restriction point until 144 h post-irradiation, while
      only 20% of the H661 or H520 did so. CONCLUSIONS: These data characterize
      radiation-induced apoptosis in NSCLC cell lines as a removal pathway of
      clonogenically inactivated cells secondary to cell-cycle progression beyond G2/M,
      and is unlikely to be a critical factor for cellular radiation sensitivity.

PMID- 12428923
TI  - Ceramide induces activation of the mitochondrial/caspases pathway in Jurkat and
      SCC61 cells sensitive to gamma-radiation but activation of this sequence is
      defective in radioresistant SQ20B cells.
AB  - PURPOSE: To clarify the molecular mechanisms leading to radiation-induced
      apoptosis or resistance, the kinetics (1-48 h) and sequence of events triggered
      in response to 10 Gy irradiation were investigated in three cell lines displaying
      a gradient of sensitivity to 7-rays. MATERIALS AND METHODS: Ceramide levels were
      measured by high performance liquid chromatography (HPLC). Mitochondrial function
      was evaluated in terms of transmembrane potential (delta(psi)m), reactive oxygen
      species (ROS) and glutathione levels analysed by flow cytometry or HPLC. Caspase
      activation was assessed by immunoblotting, and apoptosis by flow cytometry.
      RESULTS: In Jurkat radiosensitive cells and SCC61 adherent cells with
      intermediate radiosensitivity, the degree of delayed ceramide release was
      directly related to their propensity to undergo apoptosis. Transduction of the
      death signal was mediated by a drop in delta(psi)m and glutathione levels, ROS
      accumulation and activation of effector caspases. Experiments conducted with
      caspase inhibitors, bongkrekic acid, or DL-PDMP indicated that ceramide triggers
      mitochondrial collapse, followed by the activation of caspases-9, -8 and -3, and
      poly(ADP-ribose)polymerase cleavage. In SQ20B radioresistant cells, gamma
      radiation did not induce ceramide generation or subsequent activation of the
      mitochondrial/caspase apoptotic pathway. CONCLUSIONS: Ceramide appears to be a
      determining factor in the commitment phase of radiation-induced apoptosis. When
      ceramide is not generated, the whole pathway is ineffective and resistance to
      apoptosis may result.

PMID- 12428924
TI  - Nitric oxide-mediated bystander effect induced by heavy-ions in human salivary
      gland tumour cells.
AB  - PURPOSE: To investigate the signal factor and its function in the medium-mediated
      bystander effect during heavy-ion irradiation of human salivary gland (HSG)
      neoplastic cells. MATERIALS AND METHODS: Unirradiated recipient HSG cells were co
      cultivated with HSG donor cells irradiated with 290 MeV/u carbon beams having
      different LET values. Cell proliferation and micronucleus (MN) induction in
      recipient cells with and without treatment of a NO scavenger (PTIO) were measured
      and the concentration of nitrite in the co-culture medium was detected. As a
      direct control, the effects of a nitric oxide (NO) generator (sper/NO) on cell
      proliferation and MN induction were also examined. RESULTS: Increases in cell
      proliferation and MN induction were found in the recipient HSG cells as a result
      of co-culturing and cell proliferation was obviously enhanced during a further
      subculture. In comparison with 13keV/microm, 100keV/microm carbon-ion irradiation
      was found to be a more efficient inducer of the medium-mediated bystander effect.
      The treatment of cells by PTIO resulted in elimination of such effects, which
      supports a role for NO in the medium-mediated bystander effect. As an oxidization
      product of NO, nitrite was detected in the co-culture medium, and the dose
      response for its concentration was similar to that of cell proliferation and MN
      induction in the recipient cells. When the HSG cells were treated by sper/NO with
      a concentration of less than 20 microM cell proliferation was enhanced, whereas
      MN increased along with sper/NO concentration. CONCLUSION: NO participated in the
      medium-mediated bystander effects on cell proliferation and MN induction,
      depending on the LET of irradiation.

PMID- 12428925
TI  - Life span, cancer and non-cancer diseases in mouse exposed to a continuous very
      low dose of gamma-irradiation.
AB  - PURPOSE: To analyse the life-span and pathologies of mice living under a
      continuous very low-dose gamma-irradiation. MATERIAL AND METHODS: We exposed 300
      C57B1/6J female mice, 3 weeks old, to 10 cGy year(-1) gamma-rays while 300
      control mice lived in the same room. Irradiation was delivered continuously by
      thorium nitrate. We kept all the animals until natural death and performed
      autopsy. RESULTS: No difference was observed in life-span (mean lifespan +/-SE:
      805.2 +/- 9.62 days for controls and 815 +/- 9.57 days for irradiated mice),
      weight curves or food intake. At autopsy, cancer was present in 40.9% of controls
      and 37.9% of irradiated mice. They were mainly represented by lymphomas (23.7 and
      24.9%) and histiocytic sarcomas (12.6 and 8.7%, respectively, for controls and
      irradiated mice). Vascular diseases occurred in 24.1% of controls and 23% of
      irradiated mice. Infections were present at autopsy in 14.1 and 12.3%,
      respectively, of controls and irradiated animals. No statistical difference was
      observed at the end of the experiment for cancer or non-cancer diseases between
      the two groups. CONCLUSION: Continuous 10 cGy year(-1) gamma-irradiation had no
      adverse effect on malignant or non-malignant diseases in this strain of mouse.

PMID- 12428926
TI  - Dynamic analysis of chromosome aberrations in three victims of the Tokai-mura
      criticality accident.
AB  - PURPOSE: To investigate the dynamics of chromosome aberrations in the blood cells
      of three workers severely exposed to neutrons and gamma-rays in a criticality
      accident that occurred in Tokai-mura, Japan, in 1999. MATERIALS AND METHODS: The
      change with time of the frequency of' chromosome aberrations in the three
      patients was examined using a new analysis to score drug-induced prematurely
      condensed ring chromosomes (PCC-R) and a conventional meta-phase analysis.
      RESULTS: The frequencies and cellular distributions of PCC-R, dicentrics and
      rings did not change significantly among the samples obtained at 9-48h after the
      accident while the first depletion of lymphocytes occurred. The distributions of
      these aberrations in the cells of two patients showed a slight overdispersion
      compared with a Poisson distribution reflecting neutron and non-uniform
      exposures. The dose response curve of rings paralleled that of dicentrics, but
      not PCC-R. The half-lives of PCC-R (8.5 months) and of rings (8.7 months) were
      shorter than that of dicentrics (13.5 months). CONCLUSIONS: In the three patients
      of the Tokai-mura accident, lymphocytes in the circulating and extravascular
      pools had reached equilibrium at 9h, and highly damaged lymphocytes did not
      selectively move away from the circulatory system during the first rapid
      depletion of lymphocytes after exposure. Data on the in vivo half-life of PCC-R
      as well as dicentrics and rings obtained in the present study may be useful for
      retrospective dosimetry.

PMID- 12428927
TI  - The G2 chromosomal radiosensitivity assay.
AB  - Although requiring stringent experimental conditions to achieve good
      reproducibility, the G2 assay has potential as a sensitive marker for cancer
      susceptibility, and is particularly useful in population studies. Immediate
      culture of blood is preferable, but overnight storage of blood either at ambient
      temperature or at 4 degrees C does not appear significantly to affect G2 scores.
      Transport of blood may lead to additional variability in assay results and should
      be well controlled. Although reproducibility is generally good, G2 scores on
      blood from certain individuals appear to show significant variability in repeat
      samples. Thus, determination of an individual's radiosensitivity may require
      multiple assays on different occasions. While it is recognized that the
      distinction between aligned and mis-aligned discontinuities has no scientific
      basis, some laboratories have decided for the purpose of record-keeping to score
      all aligned discontinuities as gaps, and mis-aligned discontinuities as breaks.
      In all cases the final G2 score should comprise the sum of all gaps and breaks.

PMID- 12428928
TI  - A critique of 'Collaborative exercise on the use of FISH chromosome painting for
      retrospective biodosimetry of Mayak nuclear-industrial personnel'.

PMID- 12428929
TI  - Breastfeeding, amenorrhea and contraceptive practice among postpartum women in
      Zibo, China.
AB  - This paper reports a hospital-based longitudinal study that was conducted in
      Zibo, China, in June 1996. The objective was to investigate the existing patterns
      of breastfeeding, amenorrhea and contraceptive use among postpartum women in
      urban areas of China. Information was obtained from 492 newly parturient women.
      Follow-up interviews were done at 42 days. 4 months and 1 year after delivery.
      The results showed that the full breastfeeding rate (including exclusive and
      almost exclusive breastfeeding) was 78% and 43% at 42 days and 4 months after
      delivery, respectively. The mean reported length of abstinence from sexual
      intercourse after delivery was 71 days. The mean reported time to menses
      resumption was 184 days. Ninety-three per cent of women had resumed sexual
      intercourse at 4 months after delivery. Seventy-three per cent of women were
      using contraceptive methods when they resumed sexual activity after delivery.
      After childbirth, the majority ofthe women interviewed used condoms within 3
      months. Thereafter, most of them switched to intrauterine device (IUD)). Life
      table analysis shows that the continuation rates of full breastfeeding and
      amenorrhea at 4 months after delivery were 35% and 68%, respectively. This
      implies that if the full breastfeeding rate can be prolonged, it is feasible to
      use the lactational amenorrhea method (LAM) among Chinese postpartum women. The
      policy implications of this study are that quality care on contraceptive services
      and information for postpartum women in urban areas need to be improved further.

PMID- 12428930
TI  - Attitudes towards contraceptive pill use in two different populations in Thrace,
      Greece.
AB  - OBJECTIVE: To investigate the differentiation in attitudes towards contraceptive
      pill use in two different populations in Thrace, Greece. A retrospective study on
      representatives of the two major religious subgroups in Thrace: 127 Orthodox
      Christians and 120 Muslims. The questionnaire was designed to investigate women's
      opinions concerning the possible beneficial and adverse effects of the
      contraceptive pill. RESULTS: In comparison with Christians, a higher percentage
      of Muslims responded 'don't know' in questions about the pill's efficacy in
      regulating menses (p = 0.019), 'yes' concerning the inconvenience of daily uptake
      (p = 0.032) and the pill's contribution to nausea (p = 0.003), and 'maybe' in the
      question concerning the pill's contribution to depression and headaches (p <
      0.001). A higher percentage of Christians responded 'yes' concerning the pill's
      contribution to depression and headaches, and 'don't know' concerning the pill's
      contribution to nausea. There were no significant differences in the responses to
      the remaining questions, and it was clear that most women believed that use of
      the pill is correlated with increased risk of cardiovascular disease and cancer.
      CONCLUSIONS: Muslims appeared more reluctant than Christians to use the pill as a
      contraceptive method. Christians seemed to be better informed about the pill's
      phamacological actions and beneficial effects, but both populations were unaware
      of current information regarding the pill's safety. There is a need to promote
      information about these topics in Thrace.

PMID- 12428931
TI  - Factors leading to the removal of the intrauterine implant Gynefix.
AB  - OBJECTIVE: The objective of this study was to determine the incidence of
      expulsion of the Gynefix intrauterine implant, to analyze the variables
      associated with the above and to examine the efficacy of this intrauterine
      contraceptive model in users at the Municipal Family Planning Center-SERGAS in A
      Coruna, Spain. METHODS: A prospective observational study was performed on all
      women (n = 358) who had a Gynefix implant inserted from March 1998 to September
      2000. RESULTS: The accumulated incidence of implant expulsion was 6.7% (95%
      confidence interval (CI) 4.4-9.9) with a pregnancy rate of 0.6% (95% CI 0.09
      2.2). The probability of implant removal decreases with the rise in the number of
      implants that have been inserted by the professional. A multivariate analysis
      adjusted for age, number of implants and uterine position showed that the
      position of the uterus was the variable that independently determined the
      probability of removal. CONCLUSIONS: It is concluded that retroflexion of the
      uterus increases the probability of removal.

PMID- 12428932
TI  - Knowledge and use of emergency contraception in a tertiary referral unit in a
      developing country.
AB  - BACKGROUND: The promotion and availability of emergency contraception have the
      possibility of reducing the number of unwanted pregnancies, leading to fewer
      pregnancy terminations and possibly to reduced maternal morbidity and mortality.
      METHODS: The aims of the study were to determine the knowledge and use of
      emergency contraception in two groups of women: those requesting emergency
      contraception after sexual misadventure and another group of women requesting
      termination of pregnancy. A retrospective analysis was performed on all files of
      patients who requested emergency contraception over a 12-month period. Telephone
      interviews were conducted 1 year later. Structured questionnaires regarding
      knowledge and usage of emergency contraception were also administered to patients
      requesting termination of pregnancy. RESULTS: Seventy-six women requested
      emergency contraception over the 12-month period. Forty-one (53.9%) did not
      attend the follow-up visit. Only two patients used condoms. A total of 39
      patients were contacted by telephone after 1 year. Of these, 18 did not use any
      contraception, although five were sexually active. In the group of women who
      requested termination of pregnancy, 44% had not previously used contraception. In
      all, 40% did not know about emergency contraception, 36% had not used it
      previously and 24% had used it previously. CONCLUSIONS: Lack of knowledge
      concerning emergency contraception can contribute to the number of legal
      abortions requested. There is an urgent need to address current education for
      users and providers on the use of emergency contraception.

PMID- 12428933
TI  - Opinions of imams about family planning and their use of methods in Kayseri,
      Turkey.
AB  - OBJECTIVES: Imams are religious leaders who have significant influence on the
      social attitudes and behavior of a society. This study examined the views of
      imams on family planning and their personal preference of birth control methods.
      MATERIALS AND METHODS: Using a pre-prepared questionnaire, an on-site individual
      interview was conducted face-to-face with each of 164 imams at Kayseri, a city in
      Central Anatolia. RESULTS: All of the imams included in the study knew of at
      least one family planning method. Withdrawal was the most widely known method of
      family planning (84.2%). Among imams, 88.4% approved the use of birth control.
      While only 61.8% of the imams used at least one method of family planning, 20.1%
      used none at all. Of the family planning methods used, we considered 43.1%
      efficient (modem) and 18.7% inefficient (traditional). The most important factor
      affecting preference of traditional methods was religious suitability.
      CONCLUSION: Contrary to common belief, imams viewed family planning positively
      and used family planning methods at a rate similar to that of the general public.
      If provided with accurate information, we believe that imams may have a positive
      contribution to make in the development of family planning programs.

PMID- 12428934
TI  - What do women want? Counselling in contraception.
AB  - As Snowden (1) said nearly 20 years ago, 'The methods of fertility regulation
      from which most couples choose represent a choice among unpleasant alternatives.
      The choice is not so much a positive discrimination but a negative one, in that
      the methods not chosen are even more disliked than the method that is chosen. The
      contraceptive methods most people use are therefore the least unpleasant of the
      unpleasant set of alternatives. However, it is most important that this realistic
      summary is set against the other reality that consumers greatly prefer the
      available range of methods to no methods at all.' The choice of methods has now
      expanded but the decision process has not. Women want what everyone wants. They
      want their agenda to be addressed in a sensitive, considerate, complete and
      timely manner. They want to be given all relevant information in a way that they
      can understand by a person they like and who they can trust to advise them fully,
      correctly, confidentially and safely. They are quite happy to answer questions as
      long as they believe that they are necessary. They want the clinician to treat
      them with respect and to take into account their cultural and personal needs. The
      clinician must be able to advise them not only on contraceptive issues but also
      on all areas of sexual health. In short, just like all of us, women want to be
      treated as equals and trusted with information to enable them to make decisions
      about their life. Services can always improve and listening to our clients can
      help us aim for the sky. Let me share with you what they have to say.

PMID- 12428935
TI  - Oral contraception: patterns of non-compliance. The Coraliance study.
AB  - OBJECTIVES: To determine the number of times women failed to take their oral
      contraceptive medication and their behavior in response to a missed pill. Another
      objective was to determine the potential benefit provided by a continuously
      administered oral contraceptive compared with an oral contraceptive involving a
      pill-free interval during a 6-month period. METHODS: Healthy women were enrolled
      in a cohort study; their contraceptive practices were followed by their
      gynecologists. Data were collected at inclusion using cross-sectional method with
      retrospective data collection for the previous 6 months and, more specifically,
      on their previous or their current menstrual cycle. Women on the pill were asked
      to specify the number of times and precise time at which they missed one or more
      pills and what they did in response to missing a pill. RESULTS: A total of 617
      gynecologists enrolled and followed 3316 patients from six geographic areas
      throughout France. The mean age of patients was 30 years. Duration of oral
      contraceptive use was 8 years. During their previous cycle, 23% of women (n =
      737) missed a pill at least once. Among women on the pill involving a treatment
      free interval, 42% of instances of missing a pill occurred during the first week
      following the treatment-free interval. In response to missing a pill, patients
      read the product information leaflet (39%) or asked someone's advice (28%),
      mainly their gynecologist (63%) or their family physician (18%). Almost one-third
      of women did not take any specific measures. CONCLUSIONS: Patients on a
      discontinuous oral contraceptive regimen tended to miss a pill during the first
      week of treatment. Prescription of a continuous regimen without a treatment-free
      interval may improve compliance.

PMID- 12428936
TI  - Laparoscopic microsurgical tubal reanastomosis: a preliminary study.
AB  - OBJECTIVE: To determine the effect of laparoscopic reversal of tubal
      sterilization on pregnancy rate. METHODS: Eight patients who underwent
      laparoscopic tubal reversal between March 1999 and 31 December 2001 were
      evaluated. RESULTS: Four of eight patients who had had laparoscopic tubal
      reversal became pregnant. Three have delivered; pregnancy in the fourth woman is
      ongoing. To date, the other four patients are still not pregnant. Two ofthese
      four cases have tubal patency but have not achieved pregnancy; in the other two
      cases, the operation was unsuccessful and tubal patency did not occur.
      CONCLUSION: In our preliminary study, the pregnancy rate was 50%.

PMID- 12428937
TI  - Adolescent pregnancy and its consequences.
AB  - OBJECTIVES: This study was designed to evaluate the incidence, complications and
      follow-up of adolescent pregnancies. METHODS: The medical records of two
      university departments of obstetrics and gynecology, were evaluated for the
      period 1985-1998. RESULTS: From a total of 71,680 births, 5,398 (7.53%) occurred
      in adolescent mothers, aged 14-19 years old. Among the teenage pregnancies, 34%
      resulted in birth, 57% in abortions and 9% in miscarriage. The mean gestational
      age at delivery was 38 weeks and 3 days and the mean birth weight was 2,880 g.
      The mode of delivery was normal in 84% of cases, while 9.6% were delivered by
      Cesarean section and 6.4% by forceps delivery (mainly vacuum extraction). Seventy
      eight per cent of cases were primagravidas. Toxemia and anemia were seen in 1.2%
      and 0.23% of the cases, respectively. Premature separation of the placenta and
      placenta previa were seen in 1.08% and 1.29% of cases, respectively. Ectopic
      pregnancies were not seen. CONCLUSION: Although the teenage birth rate has
      decreased from 9.0% in 1985 to 5.6% in 1998, adolescent pregnancy still remains a
      medical and social problem. Most cases are unwanted pregnancies. The cases that
      have decided to proceed with the pregnancy have presented an insignificant number
      ofeomplications as assessed by adequate medical follow-up. It appears that formal
      sex education programs may increase knowledge about reproductive health and
      improve the use of methods to protect against pregnancy and sexually transmitted
      diseases.

PMID- 12428938
TI  - Spermicides 2002: an overview.
AB  - The first-ever written prescription for a contraceptive (barrier method) tampon
      can be found in the Ebers Papyrus, a compendium of medical practices written in
      1550 BC. Modern spermicides are produced in a variety of formulations, including
      gels, foams, creams, suppositories, pessaries, capsules, foaming tablets and
      films. Spermicides are relatively inexpensive and widely available over the
      counter. Most of the currently used spermicides contain the chemical agent (non
      ionic detergent) nonoxynol-9. The spermicide 'as a commonly used method' has a
      very high failure rate (one pregnancy in every four women using this method of
      contraception for 1 year). Implementation of other, much more effective methods
      of contraception has made spermicides less and less popular, but recently their
      potential properties against HIV and STI pathogens (a cause of sexually
      transmitted diseases) have led to new attention for these products. These
      properties have been widely evaluated in clinical trials, but the final
      conclusion does not favor spermicides as the tool for the global fight against
      HIV/AIDS. There is an urgent need for the invention of a chemical product that,
      for dual protection, would be administered vaginally before sexual intercourse to
      kill HIV and other STI pathogens, and at the same time disable or kill sperm. The
      new era for barrier methods should begin from the development of novel
      microbicides.

PMID- 12428939
TI  - Continuation and compliance of contraceptive use.
AB  - Choosing a method of contraception is an important decision as regards user
      satisfaction, continuation of use and compliance. The issues of continuation of
      and compliance with contraceptive use are presented. The continuation rate of a
      method of contraception is the indicator of the acceptability of that method. The
      highest continuation rates at the end of the first year are recorded for
      subdermal implants, intrauterine devices (IUD), the pill and Depo-Provera. Lower
      continuation rates are found for periodic abstinence, male condom, female condom,
      diaphragm and spermicides. Continuation rates are highest for methods not
      affected by compliance. Compliance indicates the degree to which the patient
      adheres to a prescribed regimen. Lack of compliance can lead to adverse effects
      of contraceptive use (unintended pregnancy, side-effects, diminished non
      contraceptive health benefits) and to discontinuation of the contraceptive
      method. Also, differences between method effectiveness and user effectiveness can
      largely be attributed to compliance with the prescribed contraceptive regimens.
      Health-care professionals have to empower the patient to increase compliance with
      the existing methods. In addition, the development and use of new contraceptive
      methods, which take into account the issues of non-compliance, should be
      encouraged.

PMID- 12428940
TI  - Research opportunities for bioactive natural constituents in agriculture and food
      prepared for the 50th anniversary of the Journal of Agricultural and Food
      Chemistry.
AB  - The Journal of Agricultural and Food Chemistry recently introduced a new subject
      matter category titled "Bioactive Constituents" to cover investigations of the
      composition of natural compounds and their biological activity in crops and
      foods. It is recognized by the Editors that a number of other journals specialize
      in various aspects of the chemistry of natural products, but the intent of this
      classification is to emphasize and stimulate submission of manuscripts in such
      areas of agricultural and food chemistry that have so far been neglected or under
      represented. Selected topics dealing with bioactive constituents are given as
      representative examples of the types of investigations that would be appropriate
      to the scope of the Journal.

PMID- 12428942
TI  - Determination of soyasaponins in soy with LC-MS following structural unification
      by partial alkaline degradation.
AB  - High-performance liquid chromatography coupled with electrospray ionization mass
      spectrometer was used to study the soyasaponins in soy. It was found that each
      soyasaponin belonging to group A existed mainly in their genuine acetylated
      forms. The partially to fully deacetylated structures coexisted in various
      proportions. Likewise, the soyasaponins belonging to group B in soy were detected
      as both 2,3-dihydro-2,5-dihydroxy-6-methyl-4-pyrone (DDMP) conjugated forms and
      non-DDMP forms. The structural diversity of soyasaponins hinders the separation
      and determination of the individual compounds in soy. In the present studies, the
      soyasaponins extracted from soy were treated with sodium hydroxide under mild
      conditions to cleave the acetyl groups from soyasaponins in group A as well as
      the DDMP from soyasaponins in group B, while the glycoside structures remained
      unaffected. By doing so, all soyasaponins originating from the same initial
      structures were unified into well-defined structures and then quantified
      individually using the selective ion recording of their [M-H](-) ions. The pure
      deacetyl and non-DDMP soyasaponins were used as the external standards. The
      quantification limits of soyasaponins in group A and group B were 1.74 and 1.89
      ng injected on column with recovery rates of 94.1% +/- 4.2% and 96.9% +/- 2.9%,
      respectively.

PMID- 12428941
TI  - FTIR spectra of whey and casein hydrolysates in relation to their functional
      properties.
AB  - Mid-infrared spectra of whey and casein hydrolysates were recorded using Fourier
      transform infrared (FTIR) spectroscopy. Multivariate data analysis techniques
      were used to investigate the capacity of FTIR spectra to classify hydrolysates
      and to study the ability of the spectra to predict bitterness, solubility,
      emulsifying, and foaming properties of hydrolysates. Principal component analysis
      revealed that hydrolysates prepared from different protein sources or with
      different classes of proteolytic enzymes are distinguished effectively on basis
      of their FTIR spectra. Moreover, multivariate regression analysis showed
      satisfactory to good prediction of functional parameters; the coefficient of
      determination (R(2)) varied from 0.60 to 0.92. The accurate prediction of
      bitterness and emulsion forming ability of hydrolysates by using only one
      uncomplicated and rapid analytical method has not been reported before. FTIR
      spectra in combination with multivariate data analysis proved to be valuable in
      protein hydrolysate fingerprinting and can be used as an alternative for
      laborious functionality measurements.

PMID- 12428943
TI  - Chromatographic determination of cyanoglycosides prunasin and amygdalin in plant
      extracts using a porous graphitic carbon column.
AB  - The determination of cyanogenic compounds in plants is often performed by HPLC.
      However, in this analysis, interferences due to compounds in the matrix, such as
      tannins and other pigments, are encountered, especially in roots and leaves. A
      new method is proposed for determining the cyanogenic glycosides amygdalin (D
      mandelonitrile beta-D-gentiobioside) and prunasin (D-mandelonitrile beta-D
      glucoside) in almond tree tissues, using poly(vinylpyrrolidone) or active carbon
      as scavengers for extracting cyanogenic compounds from roots or leaves,
      respectively. A new chromatographic approach for conducting the analysis is also
      discussed herein. The advantages of a Hypercarb column for the analysis of
      prunasin in roots are shown. The correlation coefficient with a reference method
      is high (>0.99), and statistical tests prove that the two methods are equivalent.
      In addition, the results provide evidence that prunasin is the only
      cyanoglycoside present in almond tree roots.

PMID- 12428944
TI  - Development of a solid-phase cleanup and portable rapid flow-through enzyme
      immunoassay for the detection of ochratoxin a in roasted coffee.
AB  - A membrane-based flow-through enzyme immunoassay (patent application pending) for
      the detection of ochratoxin A (OA) in roasted coffee was developed. First, an
      extraction and solid-phase cleanup method was developed. A high partition
      coefficient for OA in the mobile phase was achieved by using methanol/5% aqueous
      NaHCO(3) as the sample extraction and cleanup solvent. The solid-phase
      (aminopropyl) cleanup was developed to chromatographically elute OA but retain
      cross-reacting compounds. Without using aminopropyl cleanup, cross-reacting
      compounds resulted in 100% false positives for both flow-through enzyme
      immunoassay and HPLC methods. However, after cleanup with aminopropyl, no false
      positives were observed. The flow-through results were visually evaluated. The
      sensitivity achieved for the flow-through was 4 microg kg(-1) in spiked roasted
      coffee. The assay was used to screen roasted coffee samples. Results were
      confirmed with HPLC with a detection limit of 1 microg kg(-1).

PMID- 12428945
TI  - Optimizing conditions for the extraction of pigments in cochineals (Dactylopius
      coccus Costa) using response surface methodology.
AB  - A simple method was developed for the extraction and determination of color
      pigments in cochineals (Dactylopius coccus Costa). The procedure was based on the
      solvent extraction of pigments in insect samples using methanol:water (65:35,
      v:v) as extractant. Two-level factorial design was used in order to optimize the
      solvent extraction parameters: temperature, time, methanol concentration in the
      extractant mixture, and the number of extractions. The results suggest that the
      number of extractions is statistically the most significant factor. The
      separation and determination of the pigments was carried out by high-performance
      liquid chromatography with UV-visible detection. Because the absorption spectra
      of different pigments are different in the visible region, it is convenient to
      use a diode array detector to obtain chromatographic profiles that allow for the
      characterization of the extracted pigments.

PMID- 12428946
TI  - Antioxidant activity in common beans (Phaseolus vulgaris L.).
AB  - Beans were pearled to evaluate the feasibility of increasing antioxidant activity
      and phenolic antioxidants. Phenolics were concentrated mostly in the hull
      fraction at about 56 mg of catechin equivalents per gram of sample. The
      methanolic extracts of the pearled bean samples were screened for antioxidant
      potential using the beta-carotene-linoleate and the 1,1-diphenyl-2-picrylhydrazyl
      (DPPH) in vitro model systems. The pearled material, also referred to as milled
      samples, exhibited antioxidant activity that correlated with phenolic content and
      inhibited DPPH significantly in a dose-dependent manner. Phenolics and
      antioxidant activities were also examined in chromatographic fractions of
      methanolic extracts of manually obtained hulls that represented a model used
      previously to ascertain antimutagenic activity. Fractions extracted with ethyl
      acetate/acetone and acetone displayed antioxidant activity, which implies potent
      free radical scavenging activity with antimutagenic activity.

PMID- 12428947
TI  - Peptides with angiotensin I-converting enzyme (ACE) inhibitory activity from
      defibrinated, hydrolyzed bovine plasma.
AB  - Defibrinated bovine plasma (DBP) was treated with the microbial protease
      Flavourzyme to obtain protein hydrolysates with various degrees of hydrolysis
      (DH). The angiotensin I-converting enzyme (ACE) inhibiting activity of the
      hydrolyzed protein was assessed with hippuryl-His-Leu as the substrate. The
      amount of hippuric acid released, due to uninhibited ACE activity, was determined
      by high-performance liquid chromatography. ACE inhibiting (ACEI) activity was
      found to increase with increasing DH; the 43% DH hydrolysate exhibited the
      highest activity and had an IC(50) of 1.08 mg/mL. Peptide fractions with high
      ACEI activity were isolated using size exclusion chromatography. The fraction
      that possessed the highest ACEI activity contained peptides with GYP, HL(I), HPY,
      HPGH, L(I)F, SPY, and YPH sequence motifs, as determined by reversed-phase liquid
      chromatography-tandem mass spectrometry using a novel immonium precursor-ion
      scanning technique. Some of these motifs correspond to sequences found in bovine
      serum albumin, a potential source of ACEI peptides in bovine plasma.

PMID- 12428948
TI  - Antifungal constituents of the essential oil fraction of Artemisia dracunculus L.
      Var. dracunculus.
AB  - The isolation and structure elucidation of antifungal constituents of the steam
      distilled essential oil fraction of Artemisia dracunculus are described.
      Antifungal activities of 5-phenyl-1,3-pentadiyne and capillarin against
      Colletrotichum fragariae, Colletrotichum gloeosporioides, and Colletrotichum
      acutatum are reported for the first time. The relative abundance of 5-phenyl-1,3
      pentadiyne is about 11% of the steam-distilled oil, as determined by GC-MS.
      Methyleugenol was also isolated and identified as an antifungal constituent of
      the oil.

PMID- 12428949
TI  - Repellent activity of constituents identified in Foeniculum vulgare fruit against
      Aedes aegypti (Diptera: Culicidae).
AB  - The repellent activity of materials derived from the methanol extract of fruits
      from Foeniculum vulgareagainst hungry Aedes aegypti females was examined using
      skin and patch tests and compared with that of the commercial N,N-diethyl-m
      toluamide (deet) and (Z)-9-octadecenoic acid. The biologically active
      constituents of the Foeniculum fruits were characterized as (+)-fenchone and (E)
      9-octadecenoic acid by spectroscopic analyses. Responses varied according to
      compound, dose, and exposure time. In a skin test with female mosquitoes, at a
      dose of 0.4 mg/cm(2), (+)-fenchone and (Z)-9-octadecenoic acid exhibited moderate
      repellent activity at 30 min after treatment, whereas deet provided >1 h of
      protection against adult mosquitoes at 0.2 mg/cm(2). (Z)-9-Octadecenoic acid was
      a more potent repellent agent than (E)-9-octadecenoic acid. (+)-Fenchone and (E)
      9-octadecenoic acid merit further study as potential mosquito repellent agents or
      as lead compounds.

PMID- 12428950
TI  - Structural and functional characterization of pronyl-lysine, a novel protein
      modification in bread crust melanoidins showing in vitro antioxidative and phase
      I/II enzyme modulating activity.
AB  - Application of an in vitro antioxidant assay to solvent fractions isolated from
      bread crust, bread crumb, and flour, respectively, revealed the highest
      antioxidative potential for the dark brown, ethanol solubles of the crust,
      whereas corresponding crumb and flour fractions showed only minor activities. To
      investigate whether these browning products may also act as antioxidants in
      biological systems, their modulating activity on detoxification enzymes was
      investigated as a functional parameter in intestinal Caco-2 cells. The bread
      crust and, in particular, the intensely brown, ethanolic crust fraction induced a
      significantly elevated glutathione S-transferase (GST) activity and a decreased
      phase I NADPH-cytochrome c reductase (CCR) activity compared to crumb-exposed
      cells. Antioxidant screening of Maillard-type model mixtures, followed by
      structure determination, revealed the pyrrolinone reductones 1 and 2 as the key
      antioxidants formed from the hexose-derived acetylformoin and N(alpha)-acetyl-L
      lysine methyl ester or glycine methyl ester, chosen as model substances to mimic
      nonenzymatic browning reactions with the lysine side chain or the N terminus of
      proteins, respectively. Quantitation of protein-bound pyrrolinone reductonyl
      lysine, abbreviated pronyl-lysine, revealed high amounts in the bread crust (62.2
      mg/kg), low amounts in the crumb (8.0 mg/kg), and the absence of this compound in
      untreated flour. Exposing Caco-2 cells for 48 h to either synthetically
      pronylated albumin or purified pronyl-glycine (3) significantly increased phase
      II GST activity by 12 or 34%, respectively, thus demonstrating for the first time
      that "pronylated" proteins as part of bread crust melanoidins act as
      monofunctional inducers of GST, serving as a functional parameter of an
      antioxidant, chemopreventive activity in vitro.

PMID- 12428951
TI  - pH modulation of zopfiellin antifungal activity to Colletotrichum and Botrytis.
AB  - Zopfiellin, a novel cyclooctanoid natural product isolated from Zopfiella curvata
      No. 37-3, was evaluated in a 96-well microtiter assay for fungicidal activity
      against Botrytis cinerea, Colletotrichum acutatum, Colletotrichum fragariae,
      Colletotrichum gloeosporioides, and Fusarium oxysporum. Zopfiellin exhibited pH
      dependent activity, with the most mycelial growth inhibition demonstrated at pH
      5.0. Mass spectrometry and nuclear magnetic resonance spectroscopy studies
      indicated that zopfiellin undergoes structural changes with changes in pH. At pH
      5.0, zopfiellin showed the greatest activity against B. cinerea (IC(80) = 10
      microM), C. gloeosporioides (IC(80) = 10 microM), and C. fragariae (IC(80) = 10
      microM) and intermediate activity against C. acutatum (IC(80) = 30 microM), and
      was not active against F. oxysporum (IC(80) > 100 microM).

PMID- 12428952
TI  - Rat lens aldose reductase inhibitory activities of Coptis japonica root-derived
      isoquinoline alkaloids.
AB  - The inhibitory activity of Coptis japonica root-derived materials was evaluated
      against lens aldose reductase isolated from male Sprague-Dawley rats and compared
      to that of three commercially available isoquinoline alkaloids (berberine
      sulfate, berberine iodide, and palmatine chloride), as well as quercitrin as
      aldose reductase inhibitor. The biologically active constituents of C. japonica
      extract were characterized as the isoquinoline alkaloids, berberine chloride and
      palmatine iodide, by spectral analysis. The inhibitory effects varied with both
      chemical and concentration used. The IC(50) values of berberine chloride and
      palmatine iodide are 13.98 and 13.45 nM, respectively. Among three berberines and
      two palmatines, the inhibitory activity was much greater for the choridated and
      sulfated analogues than for those with iodide. Quercitrin was a much more potent
      inhibitor than berberines and palmatines. Nonetheless, berberines and palmatines
      may be useful as lead compounds and new agents for aldose reductase inhibition.

PMID- 12428953
TI  - Toxicity of (+)- and (-)-gossypol to the plant pathogen, Rhizoctonia solani.
AB  - The dimeric sesquiterpene gossypol occurs naturally in cottonseed and other parts
      of the cotton plant. Gossypol exists as enantiomers because of the restricted
      rotation around the central binaphthyl bond. The (-)-enantiomer is toxic to
      nonruminant animals while the (+)-enantiomer exhibits little, if any, toxicity to
      these animals. Developing cotton plants with low levels of the (-)-gossypol could
      expand the use of cottonseed as a feed source. Gossypol also may play a role in
      protecting the plant from pathogens. The relative toxicity of (+)- and (-)
      gossypol to plant pathogens has not been reported. We measured the concentration
      of (+)- and (-)-gossypol in roots from cotton seedlings that were treated with
      the biocontrol agent Trichoderma virens that induces biosynthesis of gossypol and
      related terpenoids in cotton roots. (-)-Gossypol was the minor enantiomer in
      control and treated roots, but levels were slightly higher in roots from T.
      virens-treated seed. We also determined the toxicity of the gossypol enantiomers
      and the racemate to the seedling disease pathogen Rhizoctonia solani. The (+)-
      and (-)-enantiomers of gossypol and the racemate are equally effective in
      inhibiting growth of this pathogen. The lethal doses of the gossypols required to
      kill the pathogen appeared to be similar, but their toxicities are significantly
      less than those of related cotton and kenaf sesquiterpenes. The results indicate
      that altering the enantiomeric ratio in cotton roots will not adversely affect
      the resistance of seedlings to the seedling pathogen R. solani.

PMID- 12428954
TI  - Black cohosh (Cimicifuga racemosa L.) protects against menadione-induced DNA
      damage through scavenging of reactive oxygen species: bioassay-directed isolation
      and characterization of active principles.
AB  - The roots/rhizomes of Cimicifuga racemosa L. (Nutt.) (black cohosh) have
      traditionally been used to treat menopausal symptoms through an unknown mechanism
      of action. In an effort to determine if black cohosh had additional health
      benefits, methanol extracts were investigated for their potential to scavenge
      reactive oxygen species and to protect against menadione-induced DNA damage.
      These extracts effectively scavenged 1,1-diphenyl-2-picrylhydrazyl (DPPH) free
      radicals. In addition, the extracts showed dose-dependent decreases in DNA single
      strand breaks and oxidized bases induced by the quinone menadione using the comet
      (single-cell gel electrophoresis assay) and fragment length associated repair
      enzyme assays, respectively. Bioassay-directed fractionation of the methanolic
      extracts using the DPPH assay as a monitor led to the isolation of nine
      antioxidant active compounds: caffeic acid (1), methyl caffeate (2), ferulic acid
      (3), isoferulic acid (4), fukinolic acid (5), cimicifugic acid A (6), cimicifugic
      acid B (7), cimicifugic acid F (8), cimiracemate A (9), and cimiracemate B (10).
      Six of these antioxidants were found to reduce menadione-induced DNA damage in
      cultured S30 breast cancer cells with the following order of potency: methyl
      caffeate (2) > caffeic acid (1) > ferulic acid (3) > cimiracemate A (9) >
      cimiracemate B (10) > fukinolic acid (5). These data suggest that black cohosh
      can protect against cellular DNA damage caused by reactive oxygen species by
      acting as antioxidants.

PMID- 12428955
TI  - Antifeedant effects of marine halogenated monoterpenes.
AB  - In this work the antifeedant effects of the halogenated monoterpenes 1-13 were
      tested against several divergent insect species. These compounds have been
      isolated from Plocamium cartilagineum (6 was isolated as an acetyl derivative),
      except for 4, which was isolated from Pantoneura plocamioides. We have also
      included the semisynthetic derivatives 1a, 2a, and 7. Compounds 1, 1a, 2, 4, 5,
      7, 8-10, and 13 were antifeedants against Leptinotarsa decemlineata with varying
      potencies. The aphids Myzus persicae and Ropalosiphum padi were strongly deterred
      in the presence of compounds 2, 12, and 13. This effect was correlated with the
      electronic recording of their probing behavior. Compounds 2 and 12 were toxic to
      L. decemlineata and had selective cytotoxicity to insect-derived Sf9 cells. None
      of the tested compounds showed phytotoxic effects. The antifeedant and cytotoxic
      effects of these compounds were compared with those of the polyhalogenated
      insecticide gamma-hexachlorocyclohexane (lindane).

PMID- 12428956
TI  - Nonenzymatic browning in food models in the vicinity of the glass transition:
      effects of fructose, glucose, and xylose as reducing sugar.
AB  - Effects of a reducing sugar, fructose, glucose, or xylose, and glass transition
      on the nonenzymatic browning (NEB) rate in maltodextrin (MD),
      poly(vinylpyrrolidone) (PVP), and water systems were studied. Glass transition
      temperatures (T(g)) were determined using DSC. Water contents were determined
      gravimetrically, and NEB rates were followed at several temperatures
      spectrophotometrically at 280 and 420 nm. Reducing sugar did not affect water
      contents, but xylose reduced the T(g) of the solid models. Sugars showed
      decreasing NEB reactivity in the order xylose > fructose > glucose in every
      matrix material. The NEB reactivity and temperature dependence of the single
      sugars varied in different matrices. The NEB rates of the solid models increased
      at temperatures 10-20 degrees C above the T(g), and nonlinearity was observed in
      Arrhenius plots in the vicinity of T(g). The temperature dependence of
      nonenzymatic browning could also be modeled using the WLF equation.

PMID- 12428957
TI  - Influence of fatty acids on wine foaming.
AB  - The influence of fatty acids (free and bound as ethyl esters) on wine foaming was
      studied in different white wines and the corresponding sparkling wines. Moreover,
      from three of these wines the foam formed by CO(2) injection was separated, and
      two fractions were then obtained: foam wine (FW) and remainder wine (RW). In
      these fractions and the sparkling wines produced from them, foam properties and
      fatty acids were also determined. The free fatty acids C8, C10, and C12 were
      negatively correlated with foamability (HM), whereas the ethyl esters of
      hexanoic, octanoic, and decanoic acids were positively related to HM. The value
      of HM was directly proportional to the ratio of esterified to unesterified fatty
      acids. This was confirmed by the changes that occur in the esterification ratio
      during the second fermentation and aging. No influence was observed on either the
      Bikerman coefficient or the stability time of foam.

PMID- 12428958
TI  - Chemical characterization of the high-molecular-weight material extracted with
      hot water from green and roasted robusta coffees as affected by the degree of
      roast.
AB  - The hot-water-soluble polymeric material from green and roasted Uganda robusta
      coffees submitted to different degrees of roasting was isolated and
      characterized, and the changes in structure and amount of galactomannans and
      arabinogalactans were determined and discussed in relation to the data already
      available for arabica coffees, obtained under the same experimental conditions.
      The content of arabinogalactans extracted from robusta green coffee was higher
      than that extracted from arabica. For roasted coffees, the amount of
      galactomannans extracted ranged from 0.66% to 0.92% (w/w). These values were near
      50% of those obtained from the arabica coffees using the same extraction
      procedure. However, the amount of arabinogalactans extracted from robusta coffees
      (0.56-0.72%) was in the range obtained from arabica. The structures of
      arabinogalactans and galactomannans extracted from green and roasted coffees were
      not sufficiently different between robusta and arabica coffees to explain the
      observed differences in extraction yields for the arabinogalactans from green
      coffees and for the galactomannans from roasted coffees. The total polysaccharide
      content and the structures of the galactomannans and arabinogalactans in the two
      green coffee varieties investigated were also very similar. These differences in
      the extraction of high-molecular-weight polysaccharides between arabica and
      robusta roasted coffees may be related to the different susceptibility of the
      cell walls during the roasting process, known to result in a different porosity
      between arabica and robusta roasted coffees.

PMID- 12428959
TI  - Evolution of phenolic compounds during an experimental aging in wood of Sherry
      vinegar.
AB  - Changes in the physicochemical composition of wine vinegars produced by submerged
      culture system and aged in wood were followed. Five Sherry wine vinegars and a
      model vinegar solution were aged in six new American oak butts of 16.6 L
      capacity. A total of 24 phenolic compounds were monitored during the maturation
      study (24 months), along with other physicochemical parameters (total extract,
      acidity, residual alcohol and total phenolic index). Multivariate statistical
      analysis was applied to the data. From the sixth month on, significant changes
      were produced in most of the phenolic compounds, mainly aromatic aldehydes and 5
      (hydroxymethyl)-2-furaldehyde. When all the phenolic compounds were considered as
      variables, cluster analysis grouped samples according to the wine substrate
      employed in the elaboration of vinegars under study. Within each subcluster,
      samples are arranged according to their aging status when phenolic compounds
      accounting significative changes at 180 days of aging are considered.
      Discriminant functions were constructed from the phenolic compounds data set. The
      validity of these functions was tested using 13 samples of aged commercial Sherry
      wine vinegars and 25 unaged vinegars. A total of 97.4% of the test samples was
      correctly classified within its respective group.

PMID- 12428960
TI  - Activity of octylthiotrifluoropropan-2-one, a potent esterase inhibitor, on
      growth, development, and intraspecific communication in Spodoptera littoralis and
      Sesamia nonagrioides.
AB  - A series of experiments were conducted to examine the effect of 3-octylthio-1,1,1
      trifluoro-2-propanone (OTFP) on growth, development, and behavior of the cotton
      leafworm, Spodoptera littoralis (Lepidoptera: Noctuidae), and the corn stalk
      borer, Sesamia nonagrioides (Lepidoptera: Noctuidae). The chemical behaved as an
      oviposition deterrent and, when added to the diet of the second-instar larvae of
      both insects, reduced diet consumption and growth, pupation, and adult emergence.
      Treatment of 100-5000 ng of the compound on fourth-instar larvae for 3-24 h,
      however, did not produce significant differences in the amount of diet ingested.
      Our results suggest that the effect of OTFP is long-lasting and that the
      inhibitor is not fully detoxified by the detoxification enzymes of the digestive
      tract of the insects. In behavioral assays, adult males which had been treated
      with the chemical at the larval stage were less attracted to the pheromone source
      than regular untreated males. When Sp. littoralis untreated females were used as
      the attractant source, treated males also displayed significantly fewer contacts
      with the cage-containing females than untreated or solvent-treated males. In the
      presence of treated females, only 27% of treated males successfully completed the
      flight in comparison to animals responding to solvent-treated females (54.5%). By
      contrast, when Se. nonagrioides females, whether they had been subjected or not
      to the treatment, were used as the attractant source, males were similarly
      attracted to them regardless of whether they had been treated or not at the
      larval stage. Analyses of gland extracts of Sp. littoralis treated females showed
      no difference from control insects in the qualitative or quantitative composition
      of the pheromone blend. The results obtained, in combination with other results
      previously reported by us (Riba, M.; Sans, A.; Bau, P.; Grolleau, G.; Renou, M.;
      Guerrero, A. J. Chem. Ecol. 2001, 27, 1879-1897), provide new and relevant
      information about the possible utility of these chemicals in future studies
      directed to the development of new approaches for pest control.

PMID- 12428961
TI  - Value assignment of nutrient concentrations in standard reference material 2384
      baking chocolate.
AB  - Standard Reference Material (SRM) Baking Chocolate was recently issued, and the
      process used for value assignment of nutrient concentrations is reported herein.
      SRM 2384 is intended for use as a primary control material for assigning values
      to in-house control materials and for validation of analytical methods for the
      measurement of fatty acids, proximates, vitamins, and elements in chocolate and
      similar high-fat matrices. The Certificate of Analysis for SRM 2384 provides
      assigned values for concentrations of fatty acids, proximates, vitamins,
      elements, and total dietary fiber, for which product labeling is required by the
      Nutrition Labeling and Education Act of 1990, as well as for catechins, caffeine,
      theobromine, and theophylline. These assigned values were based on measurements
      by NIST and/or collaborating laboratories.

PMID- 12428962
TI  - Rapid degradation of the Cry1F insecticidal crystal protein in soil.
AB  - The gene for the core Cry1F insecticidal crystal protein (ICP) from Bacillus
      thuringiensis Berliner (Bt) has been incorporated into the genome of maize
      plants, Zea mays L. Plants expressing this ICP are protected from attack by
      various Lepidopteran pests including the European corn borer, Ostrinia nubilalis
      (Hubner). The stability of the Cry1F ICP in soil was assessed in a laboratory
      study designed to determine the persistence of the active protein residue in soil
      over time, using insect bioassay as the analytical quantification method. The
      GI(50) (concentration estimated to inhibit growth by 50%) rose at each
      consecutive incubation interval, indicating a consistent decline in Cry1F
      activity over time. The residue data were poorly described by a first-order model
      when fit to either the full data or a truncated data set where the last interval
      (28 days) was excluded. Data were well described by a shift-log model, and this
      model predicted DT(50) (time until 50% decay) and DT(90) (time until 90% decay)
      values of 0.6 and 6.9 days, respectively. This rapid degradation rate was
      consistent with other Bt proteins evaluated in our laboratory.

PMID- 12428963
TI  - Mousy off-flavor of wine: precursors and biosynthesis of the causative N
      heterocycles 2-ethyltetrahydropyridine, 2-acetyltetrahydropyridine, and 2-acetyl
      1-pyrroline by Lactobacillus hilgardii DSM 20176.
AB  - The N-heterocyclic bases, 2-ethyltetrahydropyridine (1), 2-acetyl-1-pyrroline
      (2), and 2-acetyltetrahydropyridine (3) are associated with the occurrence of
      mousy off-flavor in wine. The biosynthesis of these N-heterocycles by the wine
      lactic acid bacterium, Lactobacillus hilgardii DSM 20176, was studied by high
      cell-density incubation in combination with a minimal chemically defined N
      heterocycle assay medium. The key components of the defined N-heterocycle assay
      medium included D-fructose, ethanol, L-lysine, L-ornithine, and mineral salts. N
      heterocycle formation was quantitatively determined by gas chromatography-mass
      spectrometry. The formation of 2 and 3 required the concomitant availability of a
      fermentable carbohydrate (D-fructose), ethanol, and iron (Fe(2+)). In addition, L
      ornithine stimulated the formation of 2 and repressed 3 formation, whereas L
      lysine stimulated the formation of 3 and repressed 2 formation. Incorporation of
      d(6)-ethanol into the acetyl side chain of 2 and 3, and of d(4)-acetaldehyde into
      the acetyl side chain of 3, confirmed that ethanol and acetaldehyde could serve
      as major side chain precursors. A pathway for the formation of 2 and 3 by
      heterofermentative lactic acid bacteria is proposed involving the interaction of
      accumulated C-2 intermediates from the heterolactic pathway and N-heterocyclic
      intermediates derived from the metabolism of L-ornithine and L-lysine.

PMID- 12428964
TI  - Influence of physicochemical interactions between amylose and aroma compounds on
      the retention of aroma in food-like matrices.
AB  - In food matrices, where starch is often used as a gelling or texturing agent, the
      occurrence of amylose-aroma complexes and their effect on the release of aroma
      compounds are difficult to determine. Indeed, thick or gelled systems are known
      to reduce the diffusion rate of flavor molecules, resulting in an increase of
      retention. Moreover, interactions between aroma compounds and matrix components
      might increase the retention of aroma compounds. The complexing behavior of three
      aroma compounds with amylose was studied by DSC and X-ray diffraction to
      determine the relative importance of these two factors. Their interaction
      properties were different: two of them formed complexes, and the third did not.
      These aroma compounds were added in food matrices containing different starches
      that induced different textures. Their retention was studied by static headspace
      analysis. The retention of aroma compounds appeared to depend on the
      amylose/amylopectin ratio of starch, both from the formation of complexes and by
      a viscosity effect.

PMID- 12428965
TI  - Nuclear magnetic resonance spectroscopic study of beta-lactoglobulin interactions
      with two flavor compounds, gamma-decalactone and beta-ionone.
AB  - Interactions between a well-characterized protein, beta-lactoglobulin, and two
      flavor compounds, beta-ionone and gamma-decalactone, were studied by 2D NMR
      spectroscopy. NMR spectra were recorded in aqueous solution (pH 2.0, 12 mM NaCl,
      10% D(2)O) under conditions such that beta-lactoglobulin is present in a
      monomeric state. TOCSY and NOESY spectra were recorded on the protein and the
      complexes between protein and ligands. The spectra of the NH-CH(alpha) region
      showed the cross-signals due to the coupling between N- and C-bonded protons in
      the polypeptide backbone. The observed chemical shift variations in the presence
      of ligands can be assigned to changes in the protein conformation. It appears
      that the side chains of several amino acids are affected by binding of gamma
      decalactone point into the central cavity (Leu46, Ile56, Met107, and Gln120),
      whereas binding of beta-ionone affects amino acids located in a groove near the
      outer surface of the protein (Leu104, Tyr120, and Asp129), as illustrated by
      molecular visualization. This NMR study provides precise information of the
      location of binding and confirms the existence of two different binding sites for
      aroma compounds on beta-lactoglobulin, which was suggested in previous
      competition studies by fluorometry or affinity chromatography and by structural
      information obtained from infrared spectroscopy.

PMID- 12428966
TI  - Sorption and vapor transmission properties of uncompressed and compressed
      microcellular starch foam.
AB  - Microcellular starch foams (MCFs) are made by a solvent-exchange process and
      consist of a porous matrix with pores generally ranging from approximately 2
      microm to submicrometer size. MCF may potentially be useful as a slow-release
      agent for volatile compounds because of its ability to sorb chemicals from the
      atmosphere and to absorb liquids into its porous structure, and because it can be
      compressed to form a starch plastic. MCF made of high-amylose corn and wheat
      starches was prepared with or without 2% (w/w) silicone oil (SO) or palmitic acid
      (PA). The MCF was loaded with 1% of various volatile compounds with vapor
      pressures ranging from 0.02 to 28 mm. The MCF depressed the vapor pressure from
      0.37 to 37% compared to a control containing no MCF. Incorporating SO or PA in
      the matrix of the MCF had little effect on sorption of volatiles. Compressing MCF
      at 1.4, 6.9, and 69 MPa made a starch plastic with varying porosity. The vapor
      transmission rate of various volatile compounds through MCF was positively
      correlated to the vapor pressure of the test compound but was inversely
      proportional to the compression force used to form the starch plastic. The
      results indicate that uncompressed and compressed MCFs could be effective slow
      release agents for a variety of volatile compounds, especially if used together.

PMID- 12428967
TI  - Influence of human saliva on odorant concentrations. 2. aldehydes, alcohols, 3
      alkyl-2-methoxypyrazines, methoxyphenols, and 3-hydroxy-4,5-dimethyl-2(5H)
      furanone.
AB  - The influence of human whole saliva on selected alcohols, aldehydes, 3-alkyl-2
      methoxypyrazines, and phenols in food-relevant concentrations was investigated.
      At pH 7.5-8 it was found that the alcohols, methoxyphenols, methoxypyrazines, and
      3-hydroxy-4,5-dimethyl-2(5H)-furanone remained unmodified by saliva, whereas
      aldehydes were reduced to their corresponding alcohols. Generally, the processes
      were found to be dependent on the salivary activity of the panelists as well as
      on the concentration of the applied odorants. Reduction of the aldehydes did not
      occur after thermal treatment of the saliva. These investigations are aimed at
      finding an explanation for longer lasting aftertaste in humans, as it is induced
      by some odor-active compounds after the consumption of food materials.

PMID- 12428968
TI  - Modeling of hydrogenation kinetics from triglyceride compositional data.
AB  - A mathematical model was developed to describe the reduction of soybean oil
      triglycerides during hydrogenation. The model was derived from reaction and
      transport mechanisms and formulated into a system of first-order irreversible
      rate expressions that included terms for temperature, hydrogen pressure, and
      catalyst concentration. The model parameters were estimated from experimental
      data, and the model was used to simulate the results of hydrogenation performed
      over the pressure range of 0.069-6.9 MPa. The model could be extended to include
      geometrical isomers formed during hydrogenation.

PMID- 12428969
TI  - Metal-catalyzed oxidation of a structured lipid model emulsion.
AB  - The effects of temperature, time, metal, citric acid, and tocopherol contents on
      the oxidation stability of a model oil-in-water emulsion prepared with
      enzymatically synthesized menhaden oil-caprylic acid structured lipid were
      evaluated by response surface methodology. The emulsions were stabilized by whey
      protein isolate. Oxidation was monitored by measuring lipid hydroperoxides and
      thiobarbituric acid reactive substances (TBARS). Cupric sulfate and ferrous
      sulfate were used to study the effect of metal concentration and type. A
      statistical model was developed to determine the relationships between all
      variables considered. The relationships differed depending on the type of metal
      catalyst used. For both metal types, the metal concentration had the highest
      positive effect on peroxide value. Citric acid had the highest negative effect on
      peroxide value for iron-containing emulsions, while tocopherol had the highest
      negative effects for copper-containing emulsions. Results from the TBARS test did
      not vary significantly enough to yield an acceptable model.

PMID- 12428970
TI  - Partitioning of exogenous delta-tocopherol between the triacylglycerol and
      membrane lipid fractions of chicken muscle.
AB  - The partitioning of exogenous delta-tocopherol, added dissolved in ethanol,
      between the neutral triacylglycerols and membranes of chicken leg muscles was
      investigated. The two lipid fractions were separated using differential
      ultracentrifugation techniques. Triacylglycerols were obtained after high-speed
      centrifugation of the minced muscle at 130000 g for 30 min. Membranes were
      collected from a muscle-buffer homogenate (pH 7.5) between 10000 g for 20 min and
      130000 g for 30 min. The triacylglycerols collected represented from 15 to 80% of
      the total triacylglycerols of the minced muscle, the yields increasing with
      increasing muscle triacylglycerol content. The phospholipids in the isolated
      membrane fraction represented from 20 to 35% of the total phospholipids of the
      muscle. At low muscle total lipid contents (3-5%), the added delta-tocopherol was
      present in approximately the same concentration in both muscle lipid fractions.
      At higher total lipid contents, achieved by adding exogenous triacylglycerols,
      the delta-tocopherol concentration in the membranes increased relative to that in
      the triacylglycerols.

PMID- 12428971
TI  - Influence of various phosphopeptides of caseins on iron absorption.
AB  - The influence of the origin and kind of caseinophosphopeptide (CPP) on iron
      absorption was assessed by comparing a commercially available CPP mixture (CPPs)
      and derived chromatographic fractions with the purified, chemically
      phosphopeptide of beta-casein [beta-CN(1-25)] using a perfused rat duodenal loop
      system; gluconate iron was used as control. Only iron complexed to beta-CN(1-25)
      displayed a better bioavailability than gluconate iron. The results obtained with
      various chromatographic fractions indicated that phosphopeptides of different
      origins (alpha(s)- versus beta-caseins) display specific effects. These findings
      contribute to the explanation of the discrepancy about the role of
      caseinophosphopeptides on mineral bioavailability in vivo.

PMID- 12428972
TI  - Impact of protein surface denaturation on droplet flocculation in hexadecane oil
      in-water emulsions stabilized by beta-lactoglobulin.
AB  - The influence of globular protein denaturation after adsorption to the surface of
      hydrocarbon droplets on flocculation in oil-in-water emulsions was examined. n
      Hexadecane oil-in-water emulsions (pH 7.0) stabilized by beta-lactoglobulin (1-wt
      % beta-Lg) were prepared by high-pressure valve homogenization. NaCl (0-150 mM)
      was added to these emulsions immediately after homogenization, and the evolution
      of the mean particle diameter (d) and particle size distribution (PSD) was
      measured by laser diffraction during storage at 30 degrees C for 48 h. No change
      in d or PSD was observed in the absence of added salt, which indicated that these
      emulsions were stable to flocculation. When 150 mM NaCl was added to emulsions
      immediately after homogenization, d increased rapidly during the following few
      hours until it reached a plateau value, while the PSD changed from monomodal to
      bimodal. Addition of N-ethylmaleimide, a sulfhydryl blocking agent, to the
      emulsions immediately after homogenization prevented (at 20 mM NaCl) or
      appreciably retarded (at 150 mM NaCl) droplet flocculation. These data suggests
      that protein unfolding occurred at the droplet interface, which increased the
      hydrophobic attraction and disulfide bond formation between droplets. In the
      absence of added salt, the electrostatic repulsion between droplets was
      sufficient to prevent flocculation, but in the presence of sufficient salt, the
      attractive interactions dominated, and flocculation occurred.

PMID- 12428973
TI  - Antioxidant synergy and regeneration effect of quercetin, (-)-epicatechin, and
      (+)-catechin on alpha-tocopherol in homogeneous solutions of peroxidating methyl
      linoleate.
AB  - Antioxidant interactions between flavonoids and alpha-tocopherol have been
      demonstrated by oximetry (oxygen concentration measured by ESR signal line
      width). In tert-butyl alcohol, a solvent in which flavonoids are weak retarders
      of peroxidation of methyl linoleate when initiated by alpha,alpha'
      azoisobutyronitrile, quercetin and (-)-epicatechin were found to act
      synergistically with the chain-breaking antioxidant alpha-tocopherol. In
      chlorobenzene, a solvent in which flavonoids are chain-breaking antioxidants,
      quercetin and (+)-catechin each regenerated alpha-tocopherol, resulting in a co
      antioxidant effect. The stoichiometric factor of the flavonoids as chain-breaking
      antioxidants in 1:1 mixtures with alpha-tocopherol was measured to be close to 1
      for quercetin and slightly smaller for the catechins. The apparent inhibition
      rate constant, k(inh), for the mixture quercetin/alpha-tocopherol was measured to
      be 4.1 x 10(5) and 2.6 x 10(6) M(-1) s(-1) in tert-butyl alcohol and
      chlorobenzene, respectively, at 50 degrees C. A k(inh) of 4.4 x 10(5) M(-1) s(-1)
      was measured for (+)-catechin alone in chlorobenzene at 50 degrees C.

PMID- 12428974
TI  - Influence of EDTA and citrate on physicochemical properties of whey protein
      stabilized oil-in-water emulsions containing CaCl2.
AB  - The influence of chelating agents (disodium ethylenediaminetetraacetate (EDTA)
      and sodium citrate) on the physicochemical properties of whey protein isolate
      (WPI)-stabilized oil-in-water emulsions containing calcium chloride was
      determined. The calcium-binding characteristics of EDTA and citrate at 30 degrees
      C were characterized in aqueous solutions (20 mM Tris buffer, pH 7.0) by
      isothermal titration calorimetry (ITC). EDTA and citrate both bound calcium ions
      in a 1:1 ratio, but EDTA had a much higher binding constant. Oil-in-water
      emulsions (pH 7.0) were prepared containing 6.94% (w/v) soybean oil, 0.35% (w/v)
      WPI, 0.02% (w/v) sodium azide, 20 mM Tris buffer, 10 mM CaCl(2), and 0-40 mM
      chelating agent. The particle size, apparent viscosity, creaming stability, free
      calcium concentration, and particle surface potential of the emulsions were
      measured. The chelating agents reduced or prevented droplet aggregation in the
      emulsions. When they were present above a certain concentration (>3.5 mM EDTA or
      >5 mM citrate), droplet aggregation was prevented. The reduction of aggregation
      was indicated by decreases in particle size, shear-thinning behavior, apparent
      viscosity, and creaming. Emulsions containing chelating agents had lower free
      calcium concentrations and more negatively charged droplets, indicating that the
      chelating agents improved emulsion stability by binding calcium ions. EDTA could
      be used at lower concentrations than citrate because of its higher calcium ion
      binding constant.

PMID- 12428975
TI  - Digestibility of food allergens and nonallergenic proteins in simulated gastric
      fluid and simulated intestinal fluid-a comparative study.
AB  - Information on the comparative digestibility of food allergens and nonallergenic
      proteins is crucial when stability to digestion is to be used as a criterion to
      assess the allergenic potential of novel proteins. In this work, we compared the
      digestive stability of a number of food allergens and proteins of unproven
      allergenicity and examined whether allergens possess a higher stability than
      nonallergenic proteins of similar cellular functions, and whether there is a
      correlation between protein digestibility and allergenicity. The stability of
      groups of storage proteins, plant lectins, contractile proteins, and enzymes,
      both allergens and proteins with unproven allergenicity, in a standard simulated
      gastric fluid and a standard simulated intestinal fluid was measured. Food
      allergens were not necessarily more resistant to digestion than nonallergenic
      proteins. There was not a clear relationship between digestibility measured in
      vitro and protein allergenicity.

PMID- 12428976
TI  - Kinetics and mechanism of free fatty acid formation on the surface of milled
      rice.
AB  - The presence of free fatty acid (FFA) is an important factor in determining rice
      quality for brewing. FFA formation in milled rice during storage was monitored,
      and a two-parameter semiempirical kinetic model giving product concentration as a
      function of time is proposed to describe FFA formation on milled rice during
      storage. The model was tested using sets of data obtained from partially milled
      rice samples stored at 24, 37, and 50 degrees C and fully milled rice stored at
      37 degrees C and 70% relative humidity. The predicted values provide very good
      fits (R(2) >or= 97%) of the experimental data at all storage temperatures. A two
      substrate reaction mechanism representing a two-phase process is also presented.
      Milled rice FFA at a given storage time varied with storage temperatures. The
      kinetic model and mechanisms proposed could be useful in describing and
      predicting FFA contents of milled rice during storage and transportation.

PMID- 12428977
TI  - Antioxidant properties of carnosine re-evaluated in a ferrylmyoglobin model
      system and in cooked pork patties.
AB  - The antioxidative effect of purified carnosine (i.e., separated from the common
      contaminant hydrazine) has been evaluated in two systems: (i) Carnosine was found
      to possess poor reducing properties toward the prooxidant ferrylmyoglobin; at pH
      approximately 5 the presence of carnosine did not increase the rate of reduction
      of MbFe(IV)=O compared to autoreduction, whereas at pH 7.4 the rate constant for
      reduction by carnosine was 0.010 +/- 0.002 M(-1).s(-1) (I = 0.16; 25.0 degrees
      C). (ii) In cooked pork patties prepared from meat (longissimus dorsi and
      masseter) with purified or nonpurified carnosine added, the effect of purified
      carnosine was insignificant when compared to control patties, whereas patties
      with carnosine contaminated with hydrazine had a lower oxidation level than
      patties with purified carnosine. Carnosine is concluded not to deactivate the
      prooxidant ferrylmyoglobin and not to have any antioxidative effect in cooked
      pork.

PMID- 12428978
TI  - Green tea polyphenols inhibit metalloproteinase activities in the skin, muscle,
      and blood of rainbow trout.
AB  - We have investigated the inhibitory effects of polyphenols from natural products,
      such as green tea, bilberry, grape, ginkgo, and apple, on rainbow trout
      gelatinase activities. Gelatinases from the skin, muscle, and blood of rainbow
      trout contained serine proteinase, metalloproteinase, and other proteinase
      activities as measured by gelatin zymography. The polyphenols of green tea caused
      the strong inhibition of some gelatinase activities when compared with those of
      the other products. This inhibition was quite similar to that of
      metalloproteinase by ethylenediaminetetraacetic acid, suggesting that the effects
      of green tea polyphenols on proteinase activities are specific for
      metalloproteinases. The major catechins of green tea polyphenols were then
      separated and identified by reverse-phase chromatography to be (-)
      epigallocatechin gallate (EGCG), (-)-epigallocatechin, (-)-epicatechin gallate,
      and (-)-epicatechin. The effects of these catechins on gelatinase activities were
      examined; the most potent inhibitor of metalloproteinase activities was found to
      be EGCG. These results have indicated that green tea polyphenols including EGCG
      are useful for regulating metalloproteinase activities of fish meat.

PMID- 12428979
TI  - Carotenoids and carotenoid esters in potatoes (Solanum tuberosum L.): new
      insights into an ancient vegetable.
AB  - The carotenoid pattern of four yellow- and four white-fleshed potato cultivars
      (Solanum tuberosum L.), common on the German market, was investigated using HPLC
      and LC(APCI)-MS for identification and quantification of carotenoids. In each
      case, the carotenoid pattern was dominated by violaxanthin, antheraxanthin,
      lutein, and zeaxanthin, which were present in different ratios, whereas
      neoxanthin, beta-cryptoxanthin, and beta,beta-carotene generally are only minor
      constituents. In contrast to literature data, antheraxanthin was found to be the
      only carotenoid epoxide present in native extracts. The total concentration of
      the four main carotenoids reached 175 microg/100 g, whereas the sum of carotenoid
      esters accounted for 41-131 microg/100 g. Therefore, carotenoid esters are
      regarded as quantitatively significant compounds in potatoes. For LC(APCI)-MS
      analyses of carotenoid esters, a two-stage cleanup procedure was developed,
      involving column chromatography on silica gel and enzymatic cleavage of residual
      triacylglycerides by lipases. This facilitated the direct identification of
      several potato carotenoid esters without previous isolation of the compounds.
      Although the unequivocal identification of all parent carotenoids was not
      possible, the cleanup procedure proved to be highly efficient for LC(APCI)-MS
      analyses of very low amounts of carotenoid esters.

PMID- 12428981
TI  - Historiography of a very fast gas reaction: a case history that spanned about 12
      decades.

PMID- 12428980
TI  - Tea enhances insulin activity.
AB  - The most widely known health benefits of tea relate to the polyphenols as the
      principal active ingredients in protection against oxidative damage and in
      antibacterial, antiviral, anticarcinogenic, and antimutagenic activities, but
      polyphenols in tea may also increase insulin activity. The objective of this
      study was to determine the insulin-enhancing properties of tea and its
      components. Tea, as normally consumed, was shown to increase insulin activity >15
      fold in vitro in an epididymal fat cell assay. Black, green, and oolong teas but
      not herbal teas, which are not teas in the traditional sense because they do not
      contain leaves of Camellia senensis, were all shown to increase insulin activity.
      High-performance liquid chromatography fractionation of tea extracts utilizing a
      Waters SymmetryPrep C18 column showed that the majority of the insulin
      potentiating activity for green and oolong teas was due to epigallocatechin
      gallate. For black tea, the activity was present in several regions of the
      chromatogram corresponding to, in addition to epigallocatechin gallate, tannins,
      theaflavins, and other undefined compounds. Several known compounds found in tea
      were shown to enhance insulin with the greatest activity due to epigallocatechin
      gallate followed by epicatechin gallate, tannins, and theaflavins. Caffeine,
      catechin, and epicatechin displayed insignificant insulin-enhancing activities.
      Addition of lemon to the tea did not affect the insulin-potentiating activity.
      Addition of 5 g of 2% milk per cup decreased the insulin-potentiating activity
      one-third, and addition of 50 g of milk per cup decreased the insulin
      potentiating activity approximately 90%. Nondairy creamers and soy milk also
      decreased the insulin-enhancing activity. These data demonstrate that tea
      contains in vitro insulin-enhancing activity and the predominant active
      ingredient is epigallocatechin gallate.

PMID- 12428982
TI  - The chemistry of organic polysulfanes R-S(n)-R (n > 2).

PMID- 12428983
TI  - Generation and reactions of organic radical cations in zeolites.

PMID- 12428984
TI  - Metal-mediated reductive hydrodehalogenation of organic halides.

PMID- 12428985
TI  - Chemical strategies to design textured materials: from microporous and mesoporous
      oxides to nanonetworks and hierarchical structures.

PMID- 12428986
TI  - Photoinduced motions in azo-containing polymers.

PMID- 12428987
TI  - Synthesis and solution properties of zwitterionic polymers.

PMID- 12428988
TI  - Reactions of ground state and electronically excited atoms of main group
      elements: a matrix perspective.

PMID- 12428989
TI  - Chemistry of aerogels and their applications.

PMID- 12428990
TI  - The thermodynamic properties of phosphorus and solid binary phosphides.

PMID- 12428991
TI  - Isolation and synthesis of biologically active carbazole alkaloids.

PMID- 12428992
TI  - Hormone replacement therapy: optimising the dose and route of administration.
AB  - Several new products and regimens for estrogen replacement in the postmenopausal
      woman have recently been introduced, giving physicians and patients greater
      choice not only in dose but also in route of administration. Estrogen treatment
      in the postmenopausal woman has several proven benefits for those who have
      vasomotor symptoms or problems related to urogenital atrophy. However, the most
      controversial area is in the long-term preventive benefits of estrogen against
      the development of osteoporosis and cardiovascular disease, particularly in women
      older than 60 years. It is in these areas that decisions on the dose and optimal
      route of administration of estrogen replacement therapy (ERT) must be made.
      Although adding a progestogen to an ERT regimen is mandatory, particularly in a
      woman with an intact uterus, discussion now focuses on which progestogen least
      attenuates the beneficial effects of estrogen. Emerging trends suggest that lower
      doses of estrogen (i.e. ethinylestradiol 5 microg/day, estradiol 0.25 mg/day or
      conjugated estrogens [CEE] 0.3 mg/day) continuously combined with lower doses of
      medroxyprogesterone (MPA) are equally effective at relieving vasomotor symptoms
      as the most commonly prescribed regimen in the US (CEE 0.625mg/MPA 2.5mg daily),
      with fewer adverse events, leading to greater patient acceptance and likelihood
      for continuation of therapy. This is especially important when therapy is
      initiated at an older age.

PMID- 12428993
TI  - Atrial fibrillation in the elderly: facts and management.
AB  - Although atrial fibrillation is not widely known by the general public, in
      developed countries it is the most common arrhythmia. The incidence increases
      markedly with advancing age. Thus, with the growing proportion of elderly
      individuals, atrial fibrillation will come to represent a significant medical and
      socioeconomic problem. The consequences of atrial fibrillation have the greatest
      impact. The risk of thromboembolism is well known; other outcomes of atrial
      fibrillation are less well recognised, such as its relationship with dementia,
      depression and death. Such consequences are responsible for diminished quality of
      life and considerable economic cost. Atrial fibrillation is characterised by
      rapid and disorganised atrial activity, with a frequency between 300 and 600
      beats/minute. The ventricles react irregularly, and may contract rapidly or
      slowly depending on the health of the conduction system. Clinical symptoms are
      varied, including palpitations, syncope, dizziness or embolic events. Atrial
      fibrillation may be paroxysmal, persistent or chronic, and a number of attacks
      are asymptomatic. Suspicion or confirmation of atrial fibrillation necessitates
      investigation and, as far as possible, appropriate treatment of underlying causes
      such as hypertension, diabetes mellitus, hypoxia, hyperthyroidism and congestive
      heart failure. In the evaluation of atrial fibrillation, cardiac exploration is
      invaluable, including electrocardiogram (ECG) and echocardiography, with the aim
      of detecting cardiac abnormalities and directing management. In elderly patients
      (arbitrarily defined as aged >75 years), the management of atrial fibrillation
      varies; it requires an individual approach, which largely depends on comorbid
      conditions, underlying cardiac disease, and patient and physician preferences.
      This management is essentially based on pharmacological treatment, but there are
      also nonpharmacological options. Two alternatives are possible: restoration and
      maintenance of sinus rhythm, or control of ventricular rate, leaving the atria in
      arrhythmia. Pharmacological options include antiarrhythmic drugs, such as class
      III agents, beta-blockers and class IC agents. These drugs have some adverse
      effects, and careful monitoring is necessary. The nonpharmacological approach to
      atrial fibrillation includes external or internal direct-current cardioversion
      and new methods, such as catheter ablation of specific foci, an evolving science
      that has been shown to be successful in a very select group of atrial
      fibrillation patients. Another serious challenge in the management of chronic
      atrial fibrillation in older individuals is the prevention of stroke, its primary
      outcome, by choosing an appropriate antithrombotic treatment (aspirin or
      warfarin). Several risk-stratification schemes have been validated and may be
      helpful to determine the best antithrombotic choice in individual patients.

PMID- 12428994
TI  - Practical management of psoriasis in the elderly: epidemiology, clinical aspects,
      quality of life, patient education and treatment options.
AB  - Psoriasis in the elderly will constitute a significant challenge for the
      practising physician in this new millennium. Special considerations for the
      elderly include drug-induced or drug-aggravated psoriasis, especially for
      patients receiving polypharmacy or with recent worsening or poor response to
      conventional therapy. Other frequently encountered forms of psoriasis in the
      elderly include psoriatic arthritis and its complications, inverse psoriasis and
      potentially life-threatening complications such as erythrodermic or acute
      pustular psoriasis, where early recognition and systemic therapy is critical.
      Faced with an array of topical and systemic drug therapy options, it is of
      paramount importance that the physician remains focused on the holistic
      management of the patient, in order to achieve optimal compliance and benefit.
      This can be achieved through careful attention to quality-of-life issues,
      especially since many elderly patients may have other medical, social and
      economic comorbidities that can further negatively affect their overall quality
      of life. It is also essential that the severity of psoriasis be assessed on a
      more balanced, holistic scale that incorporates both physical and psychological
      parameters, such as the Salford Psoriasis Index. The patient and caregiver
      education should be multi-faceted, regularly conducted and practically
      orientated. Treatment goals should be kept simple and individualised for each
      patient, based on concomitant comorbidities, potential adverse effects, existing
      quality of life, self-care capability, drug history, caregiver situation,
      financial needs, feasibility for follow-up and patient's preferences. Topically
      applied medications, such as topical corticosteroids, salicylic acid, tar and
      dithranol preparations, calcipotriol and tazarotene, are the favoured first-line
      therapeutic options in the elderly. Narrowband ultraviolet B phototherapy is also
      well established as a standard therapy for psoriasis. Systemic therapy with
      agents such as methotrexate, acitretin and cyclosporin should be judiciously
      reserved for severe, extensive cases in view of their lower therapeutic index in
      the elderly. The ambulatory psoriasis treatment centre is an integral part of the
      overall cost-effective management of patients with psoriasis that can function as
      a 'one-stop' treatment and resource centre for the elderly patient.

PMID- 12428995
TI  - Role of hormones in the pathogenesis and management of sarcopenia.
AB  - There is growing evidence to indicate that age-related declines in growth hormone
      (GH), insulin-like growth factor (IGF)-1, and androgen and estrogen production
      play a role in the pathogenesis of sarcopenia (an age-related decline in muscle
      mass and quality). Although GH supplementation has been reported to increase lean
      body mass in elderly individuals, the high incidence of adverse effects combined
      with a very high cost has limited the applicability of this form of therapy. The
      assessment of an alternative approach to enhance the GH/IGF-1 axis in the elderly
      by using GH-releasing hormone and other secretagogues is currently under way and
      is showing some promise. Testosterone replacement therapy may increase muscle
      mass and strength and decrease body fat in hypogonadal elderly men. Long-term
      randomised, controlled trials are needed, however, to better define the risk
      benefit ratio of this form of therapy before it can be recommended. Available
      data are currently insufficient to decide what role estrogen replacement therapy
      may play in the management of sarcopenia. Therefore, although the evidence
      linking age-related hormonal changes to the development of sarcopenia is rapidly
      growing, it is still too early to determine the clinical utility of hormonal
      supplementation in the management of sarcopenia.

PMID- 12428996
TI  - Potential interactions between herbal medicines and conventional drug therapies
      used by older adults attending a memory clinic.
AB  - OBJECTIVE: Herbal medicines and conventional drug therapies are often taken in
      combination. The objective of our study was to identify the range of natural
      health products and conventional drug therapies used by older adults (aged 65
      years and over) attending a memory clinic, and to specifically evaluate the
      frequency of potential interactions between herbal medicines and conventional
      drug therapies. DESIGN: We interviewed consecutive patients attending the Memory
      Disorders Clinic at the Baycrest Centre for Geriatric Care, a University of
      Toronto teaching hospital, between 4 July and 15 August 2000. Patients were asked
      to bring to their appointment all natural health products (i.e. herbal medicines,
      vitamins and minerals) and conventional drug therapies (i.e. prescription and
      over-the-counter) they were currently using. We collected information on current
      and previously used natural health products and current conventional drug
      therapies. Patients were classified as having the potential for an interaction if
      they were using a current herbal medicine in combination with a conventional drug
      therapy and the interaction had been reported previously in the medical
      literature. PARTICIPANTS: We interviewed 195 consecutive patients attending the
      Memory Disorders Clinic at the Baycrest Centre for Geriatric Care, Toronto,
      Ontario, Canada. RESULTS: Of the 195 patients in our sample, 33 (17%) were
      'current users', 19 (10%) were 'past users', and 143 (73%) were 'never users' of
      herbal medicines. Among the 52 patients who were 'current or past users', the
      most frequently used herbal medicines were ginkgo (Ginkgo biloba) [39 users],
      garlic (n = 10), glucosamine sulphate (n = 9) and echinacea (n = 8). Among the 33
      patients who were current users, the most commonly used herbal medicines were
      Ginkgo biloba (n = 22), glucosamine sulphate (n = 8) and garlic (n = 6). Among
      the 33 current users, we identified 11 potential herb-drug interactions in nine
      patients. The 11 herb-drug interactions we identified were between ginkgo and
      aspirin (acetylsalicylic acid) [n = 8], ginkgo and trazodone (n = 1), ginseng and
      amlodipine (n = 1) and valerian and lorazepam (n = 1). CONCLUSIONS: Herbal
      medicines are widely used. Almost one-third of current users of herbal medicines
      were at risk of a herb-drug interaction. The most common potential herb-drug
      interaction was between ginkgo and aspirin. This finding has important potential
      implications because both of these products are regularly used by older people.
      Physicians and other healthcare providers should be aware of potential herb-drug
      interactions and should monitor and inform their patients accordingly.

PMID- 12428997
TI  - The Cochrane Library: access for all Australians.

PMID- 12428998
TI  - Can we better meet the healthcare needs of Aboriginal and Torres Strait Islander
      women?
AB  - Listening and responding to women will improve cervical screening and other
      women's health programs.

PMID- 12428999
TI  - Primary open-angle glaucoma.
AB  - Early diagnosis of this otherwise progressive, asymptomatic process is essential.

PMID- 12429000
TI  - Epidural block and outcome after major surgery.
AB  - Patients at increased risk of postoperative respiratory complications may
      benefit.

PMID- 12429001
TI  - Licit psychostimulant consumption in Australia, 1984-2000: international and
      jurisdictional comparison.
AB  - OBJECTIVES: To examine trends in the licit consumption of the psychostimulants
      dexamphetamine and methylphenidate in Australia and nine other countries from
      1994 to 2000 and in each State and Territory of Australia from 1984 to 2000.
      DESIGN: Annual rates of consumption of psychostimulants were compared using
      Poisson regression models. All drug consumption was standardised to defined daily
      doses per 1000 population per day. MAIN OUTCOME MEASURES: Rates of consumption of
      each psychostimulant in each country and in each Australian State and Territory.
      RESULTS: For the 10 countries from 1994 to 2000, total psychostimulant
      consumption increased by an average 12% per year, with the highest increase from
      1998 to 2000. Australia and New Zealand ranked third in total psychostimulant use
      after the United States and Canada. Australia consumed significantly more than
      the United Kingdom, Sweden, Spain, the Netherlands, France or Denmark. In
      Australia, from 1984 to 2000, the rate of consumption of licit psychostimulants
      increased by 26% per year, with an 8.46-fold increase from 1994 to 2000. Western
      Australia ranked first, with nearly twice the consumption rate of total
      psychostimulants as New South Wales, which ranked second. Methylphenidate is the
      main psychostimulant consumed in the US and Canada, and dexamphetamine in
      Australia. CONCLUSIONS: The consumption of psychostimulants in Australia is high
      internationally and varies significantly between States and Territories. The
      results imply varied jurisdictional prescribing determinants and supply processes
      throughout Australia, which may require new national prescribing standards and
      access to online patient data for prescribers and dispensers.

PMID- 12429002
TI  - Participation in cervical cancer screening by women in rural and remote
      Aboriginal and Torres Strait Islander communities in Queensland.
AB  - OBJECTIVE: To investigate the extent of participation in cervical cancer
      screening among women who live in discrete rural and remote Indigenous
      communities in Queensland. DESIGN: Descriptive analysis of data from the
      Queensland Health Pap Smear Registry for the period March 1999 to February 2001.
      SUBJECTS: Women aged 20-69 years who had given their address of usual residence
      as one of 13 discrete rural and remote Indigenous communities in Queensland. MAIN
      OUTCOME MEASURES: Proportion of women who participated in cervical screening over
      a two-year period ("biennial participation percentage") and variation in
      participation across the 13 communities. RESULTS: Overall, the biennial
      participation percentage in the Indigenous communities was 41.1%. This was 30%
      lower (risk ratio, 0.70; 95% CI, 0.67-0.72) than that for the rest of Queensland.
      There was statistically significant variation among communities, with biennial
      participation percentage ranging from 19.9% to 63.5%. CONCLUSIONS: The variation
      in participation across the communities suggests that the problem of low
      participation among Indigenous women is not intractable. Achieving participation
      rates similar to the highest rates found in our study would be of major benefit
      to Indigenous women.

PMID- 12429003
TI  - Appropriateness of red blood cell transfusion in Australasian intensive care
      practice.
AB  - OBJECTIVE: To determine the incidence and appropriateness of use of allogenic
      packed red blood cell (RBC) transfusion in Australian and New Zealand intensive
      care practice. SETTING: Intensive care units of 18 Australian and New Zealand
      hospitals: March 2001. DESIGN: Prospective, observational, multicentre study.
      METHODS: All admissions to participating intensive care units were screened and
      all patients who received a transfusion of RBC were enrolled. The indications for
      transfusion were recorded and compared with Australian National Health and
      Medical Research Council guidelines. Transfusions conforming to these guidelines
      were deemed appropriate. MAIN OUTCOME MEASURES: RBC transfusion in intensive care
      and transfusion appropriateness. RESULTS: 1808 admissions to intensive care units
      were screened: 357 (19.8%) admissions (350 patients) received an RBC transfusion
      while in intensive care. Overall, 1464 RBC units were administered in intensive
      care on 576 transfusion days. The most common indications for transfusion were
      acute bleeding (60.1%; 880/1464) and diminished physiological reserve (28.9%;
      423/1464). The rate of inappropriate transfusion was 3.0% (44/1464). Diminished
      physiological reserve with haemogloblin level > or = 100 g/L was the indication
      in 50% (22/44) of inappropriate transfusions; no indication was provided for 31%
      (15/44). CONCLUSION: The rate of inappropriate transfusion in Australian and New
      Zealand intensive care units in 2001 was remarkably low.

PMID- 12429004
TI  - Fatal intravenous misuse of transdermal fentanyl.
AB  - The introduction of a transdermal delivery system for fentanyl means that it is
      now more readily available. We present the first documented fatality after
      intravenous injection of the contents of a transdermal fentanyl patch.
      Prescribers need to be aware of the potential for misuse of fentanyl patches.

PMID- 12429005
TI  - Attention deficit hyperactivity disorder in children: moving forward with
      divergent perspectives.
AB  - Current controversy about diagnosis and treatment of attention deficit
      hyperactivity disorder (ADHD) reflects the divergence between developmental and
      non-developmental approaches. While there is growing evidence for biological
      vulnerabilities associated with ADHD, we believe that environmental factors,
      including early problems in parental attachment, are also important in
      determining the type and timing of deficit that a child develops, the risk to
      academic and social performance and eventual outcome. We warn against labelling
      children with ADHD simply because they fulfil the cross-sectional diagnostic
      symptom criteria of the Diagnostic and statistical manual of mental disorders -
      4th edition (DSM-IV). We advocate an integrated biopsychosocial approach to
      diagnosis and management with a thorough developmental assessment to identify
      developmental factors, such as deficits in early attachment, contributing to the
      presentation.

PMID- 12429006
TI  - Chlamydia pneumoniae and cardiovascular disease.
AB  - Chlamydia pneumoniae has been detected in atherosclerotic plaques, while
      seropositivity to this organism confers a slightly increased risk of coronary
      events. However, no aetiological link has been established; a major difficulty
      when investigating this link is the lack of a gold standard for diagnosing
      chronic vessel infection. The outcomes of case-control studies and prospective
      trials of macrolides in treatment and prevention of cardiovascular disease have
      been ambiguous but suggest a short-term preventive effect. Whether this is due to
      the antimicrobial or anti-inflammatory activity of the macrolides is unknown.
      Larger and longer prospective trials currently under way may provide better
      insight into the association of C. pneumoniae with cardiovascular disease. At
      present, there is no justification for treating cardiovascular disease with
      antibiotics.

PMID- 12429007
TI  - Does preoperative radiotherapy improve outcome in patients with resectable rectal
      cancer?

PMID- 12429008
TI  - Randomisation in clinical trials.

PMID- 12429009
TI  - Pertussis: adults as a source in healthcare settings.

PMID- 12429010
TI  - Endemic invasive amoebiasis in northern Australia.

PMID- 12429011
TI  - The road to consensus: considerations for the safe use and prescribing of COX-2
      specific inhibitors.

PMID- 12429012
TI  - Guideline-discordant care in acute myocardial infarction: predictors and
      outcomes.

PMID- 12429013
TI  - A quality use of medicines program for continuity of care in therapeutics from
      hospital to community.

PMID- 12429014
TI  - Competing interests and careers.

PMID- 12429015
TI  - Activation of S6K1 (p70 ribosomal protein S6 kinase 1) requires an initial
      calcium-dependent priming event involving formation of a high-molecular-mass
      signalling complex.
AB  - The mitogen-stimulated protein kinase p70 ribosomal protein S6 kinase 1 (S6K1) is
      a key enzyme in the regulation of cell growth and proliferation. Activation of
      S6K1 requires a complex, ordered series of conformational changes and
      phosphorylation reactions. While the role of sequential, multi-site
      phosphorylation has been extensively detailed, characterization of the priming
      step required to initiate this cascade has remained elusive. In the present study
      we show for the first time that this priming process is dependent on calcium.
      Calcium-dependent regulation of S6K1 did not specifically target Thr-229 and Thr
      389, the key regulatory phosphorylation sites; rather, calcium chelation resulted
      in a global inhibition of S6K1 phosphorylation. Mutation of individual
      phosphorylation sites in the auto-inhibitory and hydrophobic domains to acidic
      residues (to mimic phosphorylation) yields a kinase that remains sensitive to
      calcium chelation, while the combined mutations alleviate the requirement for
      calcium. Furthermore, deletion of the C-terminal residues (398-502) also renders
      the kinase insensitive to calcium. We hypothesize that the initial calcium
      dependent process is required to release an inhibitory interaction between the C-
      and N-termini of S6K1, thus allowing phosphorylation of these key domains. The
      requirement for this priming step can only be overcome by mutations mimicking the
      phosphorylation of both the auto-inhibitory and hydrophobic domains. We further
      propose that the priming event involves formation of a calcium-dependent protein
      complex that releases the interaction between the N- and C-termini. S6K1 is then
      accessible for activation by the kinases that target the known regulatory
      phosphorylation sites. Consistent with this hypothesis, serum stimulation of S6K1
      activity is associated with its incorporation into a calcium-dependent high
      molecular-mass complex.

PMID- 12429016
TI  - Phosphorylation of myosin II regulatory light chain is necessary for migration of
      HeLa cells but not for localization of myosin II at the leading edge.
AB  - To investigate the role of phosphorylated myosin II regulatory light chain (MRLC)
      in living cell migration, these mutant MRLCs were engineered and introduced into
      HeLa cells. The mutant MRLCs include an unphosphorylatable form, in which both
      Thr-18 and Ser-19 were substituted with Ala (AA-MRLC), and pseudophosphorylated
      forms, in which Thr-18 and Ser-19 were replaced with Ala and Asp, respectively
      (AD-MRLC), and both Thr-18 and Ser-19 were replaced with Asp (DD-MRLC). Mutant
      MRLC-expressing cell monolayers were mechanically stimulated by scratching, and
      the cells were forced to migrate in a given direction. In this wound-healing
      assay, the AA-MRLC-expressing cells migrated much more slowly than the wild-type
      MRLC-expressing cells. In the case of DD-MRLC- and AD-MRLC-expressing cells, no
      significant differences compared with wild-type MRLC-expressing cells were
      observed in their migration speed. Indirect immunofluorescence staining showed
      that the accumulation of endogenous diphosphorylated MRLC at the leading edge was
      not observed in AA-MRLC-expressing cells, although AA-MRLC was incorporated into
      myosin heavy chain and localized at the leading edge. In conclusion, we propose
      that the phosphorylation of MRLC is required to generate the driving force in the
      migration of the cells but not necessary for localization of myosin II at the
      leading edge.

PMID- 12429017
TI  - Modulation of cytochrome c spin states by lipid acyl chains: a continuous-wave
      electron paramagnetic resonance (CW-EPR) study of haem iron.
AB  - This work is a systematic study, showing a clear correlation between the nature
      of the lipid acyl chain and the spin states of cytochrome c interacting with
      different types of lipid membranes. According to the lipid acyl chain type, and
      the head group charge present in the bilayer, three spin states of cytochrome c
      were observed in different proportions: the native cytochrome c low spin state
      with rhombic symmetry (spin 1/2, g axially=3.07 and g radially=2.23), a low spin
      state with less rhombic symmetry (spin 1/2, g(1)=2.902, g(2)=2.225, and
      g(3)=1.510) and the high spin state (spin 5/2, g axially=6.0 and g radially=2.0).
      The proportion of the spin states of cytochrome c bound to bilayers was also
      dependent on the lipid/protein ratio, suggesting the existence of two or more
      protein sites interacting with the lipids. The lipid-induced alterations in the
      symmetry and spin states of cytochrome c exhibited partial reversibility when the
      ionic strength was increased, which reinforces the crucial role played by the
      electrostatic interaction with the lipid bilayer. Different cytochrome c spin
      states exhibited corresponding modifications in the haemprotein UV/visible
      spectra, particularly in the Q-band associated with loss of the 695 nm band and
      appearance of a band in the region of 600-650 nm. The observed reactivity of
      cytochrome c with oxidized forms of unsaturated lipids reinforces the possibility
      of the acyl chain insertion in the haemprotein structure.

PMID- 12429018
TI  - Prostaglandin E2 mediates growth arrest in NFS-60 cells by down-regulating
      interleukin-6 receptor expression.
AB  - Interleukin-6 (IL-6), a potent myeloid mitogen, and the immunosuppressive
      prostanoid prostaglandin E2 (PGE2) are elevated following thermal injury and
      sepsis. We have previously demonstrated that bone marrow myeloid commitment
      shifts toward monocytopoiesis and away from granulocytopoiesis during thermal
      injury and sepsis and that PGE2 plays a central role in this alteration. Here we
      investigated whether PGE2 can modulate IL-6-stimulated growth in the
      promyelocytic cell line, NFS-60, by down-regulating IL-6 receptor (IL-6r)
      expression. Exposure of NFS-60 cells to PGE2 suppressed IL-6-stimulated
      proliferation as well as IL-6r expression. Receptor down-regulation is
      functionally significant since IL-6-induced signal transduction through
      activators of transcription (STAT)-3 is also decreased. Down-regulation of IL-6r
      correlated with the ability of PGE2 to arrest cells in the G0/G1 phase of the
      cell cycle. PGE2 appears to signal through EP2 receptors. Butaprost (EP2 agonist)
      but not sulprostone (EP3 agonist) inhibited IL-6-stimulated proliferation. In
      addition, an EP2 antagonist (AH6809) alleviated the anti-proliferative effects of
      PGE2. NFS-60 cells express predominantly EP2 and EP4 receptors. While PGE2 down
      regulated both the IL-6r protein and mRNA expression, it had no influence on EP2
      or EP4 mRNA expression. The present study demonstrates that PGE2 is a potent down
      regulator of IL-6r expression and thus may provide a mechanistic explanation for
      the granulocytopenia seen in thermal injury and sepsis.

PMID- 12429019
TI  - The three-dimensional structural surface of two beta-sheet scorpion toxins mimics
      that of an alpha-helical dihydropyridine receptor segment.
AB  - An alpha-helical II-III loop segment of the dihydropyridine receptor activates
      the ryanodine receptor calcium-release channel. We describe a novel manipulation
      in which this agonist's activity is increased by modifying its surface structure
      to resemble that of a toxin molecule. In a unique system, native beta-sheet
      scorpion toxins have been reported to activate skeletal muscle ryanodine receptor
      calcium channels with high affinity by binding to the same site as the lower
      affinity alpha-helical dihydropyridine receptor segment. We increased the
      alignment of basic residues in the alpha-helical peptide to mimic the spatial
      orientation of active residues in the scorpion toxin, with a consequent 2-20-fold
      increase in the activity of the alpha-helical peptide. We hypothesized that, like
      the native peptide, the modified peptide and the scorpion toxin may bind to a
      common site. This was supported by (i) similar changes in ryanodine receptor
      channel gating induced by the native or modified alpha-helical peptide and the
      beta-sheet toxin, a 10-100-fold reduction in channel closed time, with a < or = 2
      fold increase in open dwell time and (ii) a failure of the toxin to further
      activate channels activated by the peptides. These results suggest that diverse
      structural scaffolds can present similar conformational surface properties to
      target common receptor sites.

PMID- 12429020
TI  - Vitamin E (alpha-tocopherol) attenuates cyclo-oxygenase 2 transcription and
      synthesis in immortalized murine BV-2 microglia.
AB  - One of the immediate early microglial genes that are up-regulated in response to
      proinflammatory stimuli is cyclo-oxygenase 2 (COX-2). In the present study, we
      have investigated the effects of alpha-tocopherol (alpha TocH), an essential
      constituent of the nervous system, on the activation of COX-2 in
      lipopolysaccharide (LPS)-stimulated mouse BV-2 microglia. In unstimulated BV-2
      cells, COX-2 mRNA and protein were almost undetectable but were strongly up
      regulated in response to LPS. Activation of COX-2 protein synthesis in LPS
      stimulated BV-2 cells involved activation of the extracellular-signal-regulated
      kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (MAPK) pathway and
      was sensitive to the protein kinase C (PKC) inhibitors staurosporine and
      chelerythrine, and the MAP kinase/ERK kinase 1/2 inhibitors PD98059 and U0126.
      Supplementation of BV-2 cells with alpha TocH before LPS stimulation resulted in
      pronounced up-regulation of protein phosphatase 2A (PP2A) activity, down
      regulation of PKC activity, ERK1/2 phosphorylation and nuclear factor kappa B (NF
      kappa B) activation. As a result, COX-2 protein levels and prostaglandin E(2)
      production were significantly lower in alpha TocH-supplemented cells. The effects
      of alpha TocH on PKC activity could be reverted by calyculin A and okadaic acid,
      two PP inhibitors. In summary, our results suggest that alpha TocH activates
      microglial PP2A activity and thereby silences an LPS-activated PKC/ERK/NF kappa B
      signalling cascade resulting in significantly attenuated COX-2 protein synthesis.
      These in vitro results imply that alpha TocH could induce quiescence to pathways
      that are associated with acute or chronic inflammatory conditions in the central
      nervous system.

PMID- 12429021
TI  - Histone deacetylases (HDACs): characterization of the classical HDAC family.
AB  - Transcriptional regulation in eukaryotes occurs within a chromatin setting, and
      is strongly influenced by the post-translational modification of histones, the
      building blocks of chromatin, such as methylation, phosphorylation and
      acetylation. Acetylation is probably the best understood of these modifications:
      hyperacetylation leads to an increase in the expression of particular genes, and
      hypoacetylation has the opposite effect. Many studies have identified several
      large, multisubunit enzyme complexes that are responsible for the targeted
      deacetylation of histones. The aim of this review is to give a comprehensive
      overview of the structure, function and tissue distribution of members of the
      classical histone deacetylase (HDAC) family, in order to gain insight into the
      regulation of gene expression through HDAC activity. SAGE (serial analysis of
      gene expression) data show that HDACs are generally expressed in almost all
      tissues investigated. Surprisingly, no major differences were observed between
      the expression pattern in normal and malignant tissues. However, significant
      variation in HDAC expression was observed within tissue types. HDAC inhibitors
      have been shown to induce specific changes in gene expression and to influence a
      variety of other processes, including growth arrest, differentiation,
      cytotoxicity and induction of apoptosis. This challenging field has generated
      many fascinating results which will ultimately lead to a better understanding of
      the mechanism of gene transcription as a whole.

PMID- 12429022
TI  - Detection of bovine spongiform encephalopathy, ovine scrapie prion-related
      protein (PrPSc) and normal PrPc by monoclonal antibodies raised to copper
      refolded prion protein.
AB  - Prion-related protein (PrP) is a glycosylphosphatidylinositol-linked cell-surface
      protein expressed by a wide variety of cells, including those of the nervous
      system and the immune system. Several functions of normal cellular PrP (PrPc)
      have been proposed that may be associated with the capacity of this protein to
      bind copper. In the present study, we describe the generation of a panel of
      monoclonal antibodies raised to copper-refolded PrP, which may be used to analyse
      the normal and disease-associated forms of this protein. The anti-PrP monoclonal
      antibodies were reactive by Western blot and ELISA with recombinant murine PrPc
      refolded in the presence or absence of either copper or manganese, and with the
      disease-susceptible allelic form V136R154Q171 ('VRQ'; where single-letter amino
      acid notation has been used) and disease-resistant allelic form A136R154R171
      ('ARR') of recombinant ovine PrPc. FACS analysis of lymphoid cells using these
      monoclonal antibodies showed that wild-type non-activated mouse lymphocytes
      expressed little, if any, PrPc. These monoclonal antibodies were shown to react
      with the unglycosylated and monoglycosylated forms of PrPSc (abnormal disease
      specific conformation of PrP) in prion-infected tissue samples from all of the
      different species tested by Western blot. In addition, this analysis allowed one
      to make a distinction between bovine spongiform encephalopathy ('BSE') and
      scrapie PrPSc) isolates from experimentally infected sheep on the basis of their
      different electrophoretic mobilities.

PMID- 12429023
TI  - Cloning, expression and characterization of a mammalian Nudix hydrolase-like
      enzyme that cleaves the pyrophosphate bond of UDP-glucose.
AB  - A distinct UDP-glucose (UDPG) pyrophosphatase (UGPPase, EC 3.6.1.45) has been
      characterized using pig kidney ( Sus scrofa ). This enzyme hydrolyses UDPG, the
      precursor molecule of numerous glycosylation reactions in animals, to produce
      glucose 1-phosphate (G1P) and UMP. Sequence analyses of the purified enzyme
      revealed that, similar to the case of a nucleotide-sugar hydrolase controlling
      the intracellular levels of ADP-glucose linked to glycogen biosynthesis in
      Escherichia coli [Moreno-Bruna, Baroja-Fernandez, Munoz, Bastarrica-Berasategui,
      Zandueta-Criado, Rodri;guez-Lopez, Lasa, Akazawa and Pozueta-Romero (2001) Proc.
      Natl. Acad. Sci. U.S.A. 98, 8128-8132], UGPPase appears to be a member of the
      ubiquitously distributed group of nucleotide pyrophosphatases designated Nudix
      hydrolases. A complete cDNA of the UGPPase-encoding gene, designated UGPP, was
      isolated from a human thyroid cDNA library and expressed in E. coli. The
      resulting cells accumulated a protein that showed kinetic properties identical to
      those of pig UGPPase.

PMID- 12429025
TI  - Estrogen actions in the ovary revisited.
AB  - Estrogens are synonymous with fertility and infertility in mammals. Our knowledge
      of the biological actions of estrogens, however, is incomplete. Three recent
      developments have thrown new light on the actions of estrogens in mammalian
      reproduction that will lead to a greater understanding of their functions. They
      are (a) the identification of a second estrogen receptor, called ERbeta, (b) the
      identification of ligand-specific ER coactivators and (c) mouse models with
      targeted disruption of the genes encoding both ER and the aromatase enzyme. These
      models provide for the first time animals which are either unable to respond to
      endogenous or exogenous estrogens (ER 'knockouts'), or can respond to exogenous
      estrogen but do not make endogenous estrogen (aromatase 'knockout' or ArKO).
      Furthermore, the ArKO mouse has provided a model to study the effects on the
      ovary of exogenous estrogens of plant and synthetic origin that are of clinical
      relevance. The data show that estrogens are essential for fertility but not for
      survival after birth or for the formation of the reproductive tract. This
      commentary focuses on the roles of estrogen in folliculogenesis and in the
      maintenance of the ovarian somatic cell phenotype in the mouse. We also
      hypothesize that the ERalpha and ERbeta may subserve the proliferative and
      differentiative actions of estrogen, respectively, within a follicle. In summary,
      estrogen is obligatory for normal folliculogenesis beyond the antral stage and
      for the maintenance of the female phenotype of the somatic cells within the
      ovaries. This clearly demonstrates a major role for sex steroids in somatic cell
      differentiation in the gonads of eutherian mammals and challenges the central
      paradigm that the ovary is the default gonad, arising due to the absence of
      testicular defining signals. Evidence is also provided for the plasticity of the
      adult female gonad. Understanding the mechanisms of estrogen actions will provide
      an insight into the regulation of reproductive disorders afflicting women today,
      notably ovarian dysfunction and the menopause.

PMID- 12429026
TI  - Evidence for genomic and nongenomic actions of estrogen in growth plate
      regulation in female and male rats at the onset of sexual maturation.
AB  - Recently, both estrogen receptor (ER) alpha and beta were detected in growth
      plate chondrocytes of rats before sexual maturation, implying a role for estrogen
      at this stage. In this study, therefore, we investigated the effects of
      ovariectomy (OVX) or estrogen supplementation on parameters of longitudinal
      growth in 26-day-old rats, which were sexually immature at the start of the
      experiment. OVX caused an increase in body weight gain, tibial length and growth
      plate width due to an increased proliferating zone. This increase correlated with
      an increase in cell number, with a decrease in cell diameter and with increased
      proliferating cell nuclear antigen (PCNA) immunostaining compared with sham.
      Interestingly, the increase in proliferation was not caused by an increase in
      insulin-like growth factor-I (IGF-I) mRNA expression in the growth plate as
      assessed by real-time PCR. In contrast to OVX, 17beta-estradiol (E(2))
      supplementation (0.5 mg/21 days) of 26-day-old female rats caused a strong
      decrease in body weight gain, tibial length and growth plate width. The latter
      was explained by a reduction of the proliferating zone width, which correlated
      with a reduced number of PCNA-positive cells (not significant) and by a reduction
      of the hypertrophic zone width. In male rats supplemented with E(2), similar
      effects were observed compared with the females. ERalpha and beta immunostaining
      was found predominantly in late proliferating and early hypertrophic
      chondrocytes. OVX did not affect ER expression but E(2) supplementation strongly
      decreased immunostaining for both ERalpha and beta in both sexes. Besides E(2),
      desoxyestrone (DE), an activator of nongenomic estrogen-like signaling (ANGEL)
      and 2-methoxyestradiol (2-MeO-E(2)), a tissue-selective naturally occurring
      metabolite of E(2), were administered to female and male rats of the same age.
      Compared with E(2), these compounds had less pronounced, though significant,
      effects on some parameters of longitudinal growth in both sexes, especially on
      growth plate characteristics. In conclusion, E(2) may exert effects on
      longitudinal growth before and at the onset of sexual maturation, despite very
      low endogenous serum levels at these stages. There may be a role for nongenomic
      signaling in body weight gain, tibial length and growth plate width but genomic
      signaling prevails.

PMID- 12429024
TI  - Molecular cloning and characterization of CIDE-3, a novel member of the cell
      death-inducing DNA-fragmentation-factor (DFF45)-like effector family.
AB  - DNA fragmentation is one of the critical steps in apoptosis, which is induced by
      DNA fragmentation factor (DFF). DFF is composed of two subunits, a 40 kDa caspase
      activated nuclease (DFF40) and a 45 kDa inhibitor (DFF45). Recently a novel
      family of cell-death-inducing DFF45-like effectors (CIDEs) has been identified.
      Among CIDEs, two from human (CIDE-A and CIDE-B) and three from mouse (CIDE-A,
      CIDE-B and FSP27) have been reported. In this study human CIDE-3, a novel member
      of CIDEs, was identified upon sequence analysis of a previously unidentified cDNA
      that encoded a protein of 238 amino acids. It was shown to be a human homologue
      of mouse FSP27, and shared homology with the CIDE-N and CIDE-C domains of CIDEs.
      Apoptosis-inducing activity was clearly shown by DNA-fragmentation assay of the
      nuclear DNA of CIDE-3 transfected 293T cells. The expression pattern of CIDE-3
      was different from that of CIDE-B. As shown by Northern-blot analysis, CIDE-3 was
      expressed mainly in human small intestine, heart, colon and stomach, while CIDE-B
      showed strong expression in liver and small intestine and at a lower level in
      colon, kidney and spleen. Green-fluorescent-protein-tagged CIDE-3 was revealed in
      some cytosolic corpuscles. Alternative splicing of the CIDE-3 gene was also
      identified by reverse transcription PCR, revealing that two transcripts, CIDE-3
      and CIDE-3alpha, were present in HepG2 and A375 cells. CIDE-3 comprised a full
      length open reading frame with 238 amino acids; in CIDE-3alpha exon 3 was deleted
      and it encoded a protein of 164 amino acids. Interestingly the CIDE-3alpha
      isoform still kept the apoptosis-inducing activity and showed the same pattern of
      subcellular localization as CIDE-3. Consistent with its chromosome localization
      at 3p25, a region associated with high frequency loss of heterozygosity in many
      tumours, CIDE-3 may play an important role in prevention of tumorigenesis.

PMID- 12429027
TI  - The phytochemical lindleyin, isolated from Rhei rhizoma, mediates hormonal
      effects through estrogen receptors.
AB  - Some plant compounds or herb mixtures are popular alternatives to conventional
      therapies and contain organic compounds that bind to some nuclear receptors, such
      as the estrogen receptor (ER), to exert various biological effects. We studied
      the effect of various herbal extracts on ERalpha and ERbeta isoforms. One herbal
      extract, Rhei rhizoma (rhubarb), acts as an agonist to both ERalpha and ERbeta.
      The phytochemical lindleyin, a major component of rhubarb, might contribute to
      this estrogenic activity through ERalpha and ERbeta. 4-Hydroxytamoxifen, an ER
      antagonist, completely reversed the estrogenic activity of lindleyin. Lindleyin
      binds to ERalpha in vitro, as demonstrated using a fluorescent polarization
      assay. The in vivo effect of rhubarb extract was studied using a vitellogenin
      assay system in the freshwater fish, Japanese medaka (Oryzias latipes). There
      were marked increases in serum vitellogenin levels in male medaka exposed to
      rhubarb extract. We conclude that lindleyin, a component of some herbal
      medicines, is a novel phytoestrogen and might trigger many of the biological
      responses evoked by the physiological estrogens.

PMID- 12429028
TI  - Prevention of solely estrogen-induced mammary tumors in female aci rats by
      tamoxifen: evidence for estrogen receptor mediation.
AB  - There is increasing evidence that both endogenous and exogenously ingested
      estrogens play a primary role in sporadic breast cancer causation. To establish
      further that solely estrogen-induced mammary oncogenesis in female ACI rats is an
      estrogen receptor (ERalpha)-driven process, we show for the first time that
      concomitant treatment with the antiestrogen, tamoxifen citrate (TAMc), completely
      prevents the induction of 17beta-estradiol (E(2))-induced mammary gland tumors
      (MGTs). This finding is also supported by the reduced mammary gland (MG) lobulo
      alveolar development and proliferative activity observed in TAMc+E(2)-treated
      animals compared with MGs from animals treated with E(2) alone. These data also
      correlated with a marked decrease in the number of MG cells expressing ERalpha
      and progesterone receptor (PR) in immunostained MG tissue sections from TAMc+E(2)
      treated animals. Additionally, a marked decline in the level of expression of
      ERalpha 47, 56 and 66 kDa forms, and PR-A and PR-B was seen in TAMc+E(2)-treated
      MGs, compared with MGs treated solely with E(2). Thus, both ERalpha and PR MG
      profiles in TAMc+E(2)-treated rats essentially revert to their respective
      receptor profiles seen in untreated control and TAMc-alone-treated rats. The
      presence of 56 and 54 kDa isoforms in chronically E(2)-treated MGs and in MGTs
      respectively may contribute to fostering the enhanced E(2)-dependent growth
      response of both precursor and frank MGT epithelial cells. These findings are
      consistent with an ERalpha/PR-mediated mg cell proliferation, a prerequisite for
      generating the high frequency of chromosomal instability seen in E(2)-induced
      ductal carcinomas in situ and primary MGTs in female ACI rats reported by us
      previously.

PMID- 12429029
TI  - High stromal and epithelial human gh gene expression is associated with
      proliferative disorders of the mammary gland.
AB  - We have demonstrated and localized human GH (hGH) gene expression in surgical
      specimens of normal human mammary gland and in proliferative disorders of the
      mammary gland of increasing severity using sensitive in situ RT-PCR methodology.
      hGH mRNA identical to pituitary hGH mRNA was first detected by RT-PCR of RNA
      derived from samples of normal human mammary gland. Cellular localization of hGH
      gene expression in the normal mammary gland exhibited restriction to luminal
      epithelial and myoepithelial cells of the ducts and to scattered stromal
      fibroblasts. We subsequently examined the expression of the hgh gene in three
      progressive proliferative disorders of the human mammary gland, i.e. A benign
      lesion (fibroadenoma), a pre-invasive stage (intraductal carcinoma) and an
      invasive ductal carcinoma. hGH mRNA was readily detected in the tumoral and non
      tumoral epithelial components and also in cells of the reactive stroma including
      fibroblasts, myofibroblastic and myoepithelial cells, inflammatory infiltrate
      lymphocytes and endothelial cells in areas of neovascularization. In all three
      proliferative disorders examined, the intensity of the cellular labeling observed
      in both the epithelial and stromal compartments was always stronger compared with
      that in adjacent normal tissue. hGH protein was also present in significantly
      higher concentration in extracts derived from proliferative disorders of the
      mammary gland compared with extracts derived from normal mammary gland. We also
      examined hGH gene expression in axillary lymph nodes not containing and
      containing metastatic mammary carcinoma. hGH gene expression was evidenced in
      metastatic mammary carcinoma cells and in reactive stromal cells by both in situ
      hybridization and in situ RT-PCR. In contrast, in lymph nodes not containing
      metastatic mammary carcinoma, hGH mRNA was detected only by use of in situ RT
      PCR. Thus, increased expression of the hGH gene in the epithelial component and
      the de novo stromal expression in proliferative disorders of the mammary gland
      are suggestive of a pivotal role for autocrine hGH in neoplastic progression of
      the mammary gland.

PMID- 12429030
TI  - Raloxifene- and estradiol-mediated effects on uterus, bone and B lymphocytes in
      mice.
AB  - Raloxifene is a selective estrogen receptor modulator approved for the prevention
      of osteoporosis in postmenopausal women. It is selective by having estrogen
      agonistic effects on bone, vessels and blood lipids while it is antagonistic on
      mammary and uterine tissue. Our aim was to study the agonistic and antagonistic
      properties of the raloxifene analogue LY117018 (LY) on uterus, bone, B
      lymphopoiesis and B cell function. Oophorectomized and sham-operated animals were
      treated with s.c. injections of equipotent anti-osteoporotic doses of 17beta
      estradiol (E2) (0.1 mg/kg) or LY (3 mg/kg) or vehicle as controls. Effects on
      bone mineral density (BMD) were studied using peripheral quantitative computed
      tomography, uterine weight was examined, B lymphopoiesis was examined using flow
      cytometry and B cell function in bone marrow and spleen was studied by the use of
      an ELISPOT assay. E2 and LY had similar effects on BMD and bone marrow B
      lymphopoiesis, while LY had a clear antagonistic effect on endogenous estrogen in
      uterine tissue and no stimulating effect on the frequency of Ig-producing B cells
      in sham-operated animals. Our results are discussed in the context of estrogen
      receptor biology, relations between the immune system and bone metabolism and
      also with respect to the estrogen-mediated effects on rheumatic diseases.

PMID- 12429031
TI  - Effects of ovariectomy and oestradiol-17beta replacement on brain tyrosine
      hydroxylase in the catfish Heteropneustes fossilis: changes in in vivo activity
      and kinetic parameters.
AB  - In Heteropneustes fossilis, ovariectomy inhibited in vivo brain (hypothalamus
      pituitary, telencephalon and medulla oblongata) tyrosine hydroxylase (TH)
      activity with significant effects in weeks 2, 3, 4 and 5 of the gonadal resting
      phase and in weeks 3, 4 and 5 of the prespawning phase (P<0.05, Tukey's test).
      Oestradiol-17beta (OE(2)) replacement in 3-week ovariectomised fish produced
      biphasic responses in both seasons; the low dosages of 0.05 and 0.5 micro g/g
      body weight (BW) elevated TH activity, whereas the high dosages of 1.0 and 2.0
      micro g/g BW decreased it. The magnitude of the inhibition was higher in the
      resting phase than in the prespawning phase. The inhibitory effect of ovariectomy
      may be produced by elevating the apparent K(m) values (decreased affinity) of the
      enzyme for both L-tyrosine (substrate) and dimethyltetrahydropteridine (cofactor)
      and consequently decreasing the V(max). Significant changes (P<0.05) in both
      these parameters were noticed but showed minor differences with regard to the
      length of ovariectomy, season or brain regions. The biphasic effects of OE(2)
      replacement on TH activity seemed to be produced by differential effects on
      apparent K(m) and V(max). The stimulatory effect of the low dosages of OE(2)
      coincides with a decrease in the apparent K(m) values (increased affinity) for
      both substrate and cofactor and an increase in the V(max) of the enzyme. The
      inhibitory effect of the high dosages of OE(2) correlated with an increase in the
      apparent K(m) values (decreased affinity) for both substrate and cofactor, and a
      decrease in the V(max) compared with the lower dosage groups. The results
      strongly suggested that OE(2) can modulate brain catecholaminergic activity at
      the level of tyrosine hydroxylation which, in turn, may alter gonadotrophin
      secretion. OE(2) may elicit biphasic effects by differentially altering the
      enzyme affinity towards the substrate and cofactor.

PMID- 12429032
TI  - Rapid stimulation of cyclic AMP production by aldosterone in rat inner medullary
      collecting ducts.
AB  - Aldosterone stimulates sodium transport in the inner medullary collecting duct
      (IMCD) via the classic genomic pathway, but it is not known whether it also acts
      via a rapid, non-conventional pathway in this part of the nephron. The IMCD
      regulates the final sodium content of urine and expresses vasopressin receptors
      coupled to adenylate cyclase. The recently reported rapid, non-genomic actions of
      aldosterone have been associated mainly with an increase in intracellular Ca(2+);
      however, it has also been shown to stimulate camp generation. Thus the aim of
      this study was to determine whether aldosterone stimulates rapid generation of
      cAMP in isolated IMCD segments. IMCD segments were microdissected from Sprague
      Dawley rat kidneys and incubated at 37 degrees C for 4 min with aldosterone (10(
      12) to 10(-6) M), vasopressin (10(-12) to 10(-6) M), or a combination of hormones
      in the presence of a phosphodiesterase inhibitor. cAMP was measured by
      radioimmunoassay. While corticosterone and dexamethasone were ineffective,
      aldosterone stimulated a dose-dependent increase in cAMP within 4 min (P<0.05).
      This action of aldosterone was not inhibited by the MR antagonist spironolactone.
      Co-incubation of aldosterone with vasopressin resulted in a further increase in
      cAMP generation above that induced by the neurohypophysial hormone alone.
      Aldosterone-mediated cAMP generation was not inhibited by a vasopressin V(1) or
      V(2) receptor antagonist. These data support a novel and rapid, non-genomic
      effect of aldosterone in IMCD. Aldosterone does not apparently interact with the
      vasopressin receptor to stimulate cAMP generation.

PMID- 12429033
TI  - Expression of the progesterone receptor and progesterone- metabolising enzymes in
      the female and male human kidney.
AB  - Due to high binding affinity of progesterone to the human mineralocorticoid
      receptor (hMR), progesterone competes with the natural ligand aldosterone. In
      order to analyse how homeostasis can be maintained by mineralocorticoid function
      of aldosterone at the MR, especially in the presence of elevated progesterone
      concentrations during the luteal phase and pregnancy, we investigated protective
      mechanisms such as the decrease of free progesterone by additional binding sites
      and progesterone metabolism in renal cells. As a prerequisite for sequestration
      of progesterone by binding to the human progesterone receptor (hPR) we
      demonstrated the existence of hPR expression in female and male kidney cortex and
      medulla at the level of transcription and translation. We identified hPR RNA by
      sequencing the RT-PCR product and characterised the receptor by ligand binding
      and scatchard plot analysis. The localisation of renal hPR was shown
      predominantly in individual epithelial cells of distal tubules by
      immunohistology, and the isoform hPR-B was detected by Western blot analysis. As
      a precondition for renal progesterone metabolism, we investigated the expression
      of steroid-metabolising enzymes for conversion of progesterone to metabolites
      with lower affinity to the hMR. We identified the enzyme 17alpha-hydroxylase for
      renal 17alpha-hydroxylation of progesterone. For 20alpha-reduction, different
      hydroxysteroid dehydrogenases (HSDs) such as 20alpha-HSD, 17beta-HSD type 5
      (3alpha-HSD type 2) and 3alpha-HSD type 3 were found. Further, we detected the
      expression of 3beta-HSD type 2 for 3beta-reduction, 5alpha-reductase (Red) type 1
      for 5alpha-reduction, and 5beta-Red for 5beta-reduction of progesterone in the
      human kidney. Therefore metabolism of progesterone and/or binding to hPR could
      reduce competition with aldosterone at the MR and enable the mineralocorticoid
      function.

PMID- 12429034
TI  - Expression levels of Mullerian-inhibiting substance, GATA4 and 17alpha
      hydroxylase/17,20-lyase cytochrome P450 during embryonic gonadal development in
      two diverse breeds of swine.
AB  - Sexual differentiation and early embryonic/fetal gonad development is a tightly
      regulated process controlled by numerous endocrine and molecular signals. These
      signals ensure appropriate structural organization and subsequent development of
      gonads and accessory organs. Substantial differences exist in adult reproductive
      characteristics in Meishan (MS) and White Composite (WC) pig breeds. This study
      compared the timing of embryonic sexual differentiation in MS and WC pigs.
      Embryos/fetuses were evaluated on 26, 28, 30, 35, 40 and 50 days postcoitum
      (dpc). Gonadal differentiation was based on morphological criteria and on
      localization of GATA4, Mullerian-inhibiting substance (MIS) and 17alpha
      hydroxylase/17,20-lyase cytochrome P450 (P450(c17)). The timing of testicular
      cord formation and functional differentiation of Sertoli and Leydig cells were
      similar between breeds. Levels of GATA4, MIS and P450(c17) proteins increased
      with advancing gestation, with greater levels of MIS and P450(c17) in testes of
      MS compared with WC embryos. Organization of ovarian medullary cords and
      formation of egg nests was evident at similar ages in both breeds; however, a
      greater number of MS compared with WC embryos exhibited signs of ovarian
      differentiation at 30 dpc. In summary, despite breed differences in MIS and
      P450(c17) levels in the testis, which may be related to Sertoli and Leydig cell
      function, the timing of testicular differentiation did not differ between breeds
      and is unlikely to impact reproductive performance in adult boars. In contrast,
      female MS embryos exhibited advanced ovarian differentiation compared with WC
      embryos which may be related to the earlier reproductive maturity observed in
      this breed.

PMID- 12429035
TI  - How much LH do the Leydig cells see?
AB  - The purpose of this study was to assess the concentrations of LH that Leydig
      cells are exposed to upon in vivo stimulation of steroidogenesis. The
      concentrations of LH were measured in rats in testicular interstitial
      extracellular fluid, seminiferous tubular fluid and blood plasma from testicular
      veins from one testis before and from the other testis of the same rats after an
      intravenous injection of gonadotrophin-releasing hormone (GnRH) or saline, and
      compared with the concentrations in blood plasma from a peripheral vein. The
      concentrations of LH in interstitial fluid surrounding the Leydig cells before
      the injections were about 10% of the levels in blood plasma, and showed no
      significant rise at 15 min and a much smaller rise at later times in rats
      injected with GnRH than those seen in blood plasma from either of the two
      sources, which were similar. The concentrations of LH in tubular fluid were even
      lower and showed no change after GnRH. Testosterone concentrations in testicular
      cells, interstitial fluid and testicular venous blood plasma were significantly
      increased by 15 min after GnRH, when compared with saline-injected controls, with
      no change in the levels in tubular fluid. The rise in testosterone concentrations
      in testicular venous plasma after GnRH was smaller than those in the cells and
      interstitial fluid. In conclusion, the concentrations of LH reaching the
      testicular interstitial fluid were only about one-tenth of that measured in the
      circulation, presumably because the endothelial cells restrict access of the
      hormone to the interstitial fluid. This indicated that either the Leydig cells
      are extremely sensitive to LH stimulation or that testicular endothelial cells
      modulate the action of LH on the Leydig cells.

PMID- 12429036
TI  - Contrasting effects of different levels of food intake and adiposity on LH
      secretion and hypothalamic gene expression in sheep.
AB  - Body reserves (long-term) and food intake (short-term) both contribute
      nutritional feedback to the hypothalamus. Reproductive neuroendocrine output
      (GnRH/LH) is stimulated by increased food intake and not by high adiposity in
      sheep, but it is unknown whether appetite-regulating hypothalamic neurons show
      this differential response. Castrated male sheep (Scottish Blackface) with
      oestradiol implants were studied in two 4 week experiments. In Experiment 1,
      sheep were fed to maintain the initial body condition (BC) score of 2.0+/-0.00
      (lower BC (LBC), n=7) or 2.9+/-0.09 (higher BC (HBC), n=9), and liveweight of
      43+/-1.1 and 59+/-1.6 kg respectively. LBC and HBC sheep had similar mean plasma
      LH concentration, pulse frequency and amplitude, but HBC animals had higher mean
      plasma concentrations of insulin (P<0.01), leptin (P<0.01) and glucose (P<0.01).
      Gene expression (measured by in situ hybridisation) in the hypothalamic arcuate
      nucleus (ARC) was higher in LBC than HBC sheep for neuropeptide Y (NPY; 486% of
      HBC, P<0.01), agouti-related peptide (AGRP; 467%, P<0.05) and leptin receptor (OB
      Rb; 141%, P<0.05), but lower for cocaine- and amphetamine-regulated transcript
      (CART; 92%, P<0.05) and similar between groups for pro-opiomelanocortin (POMC).
      In Experiment 2, sheep with initial mean BC score 2.4+/-0.03 and liveweight 55+/
      0.8 kg were fed a liveweight-maintenance ration (low intake, LI, n=7) while sheep
      with initial mean BC score 2.0+/-0.03 and liveweight 43+/-1.4 kg were fed freely
      so that BC score increased to 2.5+/-0.00 and liveweight increased to 54+/-1.4 kg
      (high intake, HI, n=9). Compared with LI, HI sheep had higher mean plasma LH
      (P<0.05), baseline LH (P<0.01) and pulse amplitude (P<0.01) and showed a trend
      towards higher pulse frequency. Although there were no differences in final mean
      plasma concentrations, there were significant increases over time in mean
      concentrations of insulin (P<0.001), leptin (P<0.05) and glucose (P<0.001) in HI
      sheep. Gene expression for AGRP in the ARC was higher in HI than LI animals (453%
      of LI; P<0.05), but expression levels were similar for NPY, OB-Rb, CART and POMC.
      Thus, the hypothalamus shows differential responses to steady-state adiposity as
      opposed to an increase in food intake, in terms of both reproductive
      neuroendocrine activity and hypothalamic appetite-regulating pathways.
      Differences in hypothalamic gene expression were largely consistent with
      contemporary levels of systemic leptin and insulin feedback; however, increased
      nutritional feedback was stimulatory to GnRH/LH whereas constant high feedback
      was not. The hypothalamus therefore has the ability to retain a nutritional
      memory that can influence subsequent responses.

PMID- 12429037
TI  - Seasonal and dose-dependent effects of intracerebroventricular leptin on lh
      secretion and appetite in sheep.
AB  - The role of leptin in neuroendocrine appetite and reproductive regulation remains
      to be fully resolved. A series of three experiments was conducted using
      adequately nourished oestradiol-implanted castrated male sheep. In a cross-over
      design (n=6), responses to a single i.c.v. (third ventricle) injection of leptin
      (0.5, 1.0 and 1.5 mg ovine leptin (oLEP) and 1.0 mg murine leptin (mLEP)), N
      methyl-D-aspartate (NMDA, 20 micro g) or 0.9% saline (control) were measured in
      terms of LH secretion (4 h post-injection compared with 4 h pre-injection) and
      appetite (during 2 h post-injection) in autumn (Experiment 1). NMDA and 1.0 mg
      oLEP treatments were repeated in the same sheep in the following spring
      (Experiment 2). With an additional 12 sheep (n=18 in cross-over design),
      responses to low-dose 'physiological' i.c.v. infusion of leptin (8 ng/h for 12 h
      daily for 4 days), insulin (0.7 ng/h) and artificial cerebrospinal fluid were
      measured in the next spring (Experiment 3). LH was studied over 8 h and appetite
      over 1 h on days 1 and 4 of infusion. In Experiment 1 (autumn), oLEP overall
      increased LH pulse frequency by up to 110% (P<0.05), decreased LH pulse amplitude
      (P<0.05) and decreased appetite (P<0.05). mLEP reduced LH pulse amplitude
      (P<0.05) without significant effect on appetite, while NMDA reduced appetite
      (P<0.05) but had no effect on LH. In Experiment 2 (spring), LH responses were
      'surge-like' with highly significant increases in the moving average LH
      concentration after 1.0 mg oLEP (P<0.001) and after NMDA (P<0.001). Compared with
      similar analysis of experiment 1 results, the LH response in spring was greater
      than that in autumn for both 1.0 mg oLEP (P<0.05) and NMDA (P<0.005). Conversely,
      unlike in autumn (Experiment 1), there was no effect of 1.0 mg oLEP or NMDA on
      appetite in the spring (Experiment 2). In Experiment 3 (spring), 'physiological'
      i.c.v. infusion of oLEP or insulin increased LH pulse frequency by up to 100%
      (P<0.001) compared with the control infusion on both days 1 and 4, but there were
      no effects on appetite. These results indicate that intracerebral leptin both
      stimulates reproductive neuroendocrine output and decreases appetite in
      adequately nourished sheep. However, the responses of these two axes were dose
      dependent and differentially affected by the time of year, suggesting
      dissociation of the neural pathways involved.

PMID- 12429038
TI  - Leptin directly regulates bone cell function in vitro and reduces bone fragility
      in vivo.
AB  - Fat mass is an important determinant of bone density, but the mechanism of this
      relationship is uncertain. Leptin, as a circulating peptide of adipocyte origin,
      is a potential contributor to this relationship. Recently it was shown that
      intracerebroventricular administration of leptin is associated with bone loss,
      suggesting that obesity should be associated with low bone mass, the opposite of
      what is actually found. Since leptin originates in the periphery, an examination
      of its direct effects on bone is necessary to address this major discrepancy.
      Leptin (>10(-11) m) increased proliferation of isolated fetal rat osteoblasts
      comparably with IGF-I, and these cells expressed the signalling form of the
      leptin receptor. In mouse bone marrow cultures, leptin (>or=10(-11) m) inhibited
      osteoclastogenesis, but it had no effect on bone resorption in two assays of
      mature osteoclasts. Systemic administration of leptin to adult male mice (20
      injections of 43 micro g/day over 4 weeks) reduced bone fragility (increased work
      to fracture by 27% and displacement to fracture by 21%, P<0.001). Changes in
      tibial histomorphometry were not statistically significant apart from an increase
      in growth plate thickness in animals receiving leptin. Leptin stimulated
      proliferation of isolated chondrocytes, and these cells also expressed the
      signalling form of the leptin receptor. It is concluded that the direct bone
      effects of leptin tend to reduce bone fragility and could contribute to the high
      bone mass and low fracture rates of obesity. When administered systemically, the
      direct actions of leptin outweigh its centrally mediated effects on bone, the
      latter possibly being mediated by leptin's regulation of insulin sensitivity.

PMID- 12429039
TI  - Antibodies to pituitary surface antigens during various pituitary disease states.
AB  - Autoantibodies to cell surface antigens of human somatotropinoma (ASAS), human
      prolactinoma (ASAP) and rat adenohypophysis (ASARA) were assayed in the serum of
      patients with pituitary diseases associated with GH deficiency (GHD), such as
      pituitary dwarfism and primary empty sella syndrome (ESS), and in the serum of
      patients with hyperprolactinaemia of different etiologies: idiopathic
      hyperprolactinaemia, prolactinoma and ESS. The investigation was carried out with
      a cellular variant of an ELISA. Among children with GHD, the highest percentage
      of antibody-positive patients was found in the group with idiopathic isolated GHD
      (89% of ASAS(+) patients and 30% of ASARA(+) patients vs 33.3% and 0%
      respectively in the group with idiopathic combined pituitary hormone deficiency,
      and 33.3% and 9% in patients with pituitary hypoplasia associated with isolated
      GHD or combined pituitary hormone deficiency). Among hyperprolactinaemic
      patients, the highest ASAP and ASARA frequency was observed in patients with
      idiopathic hyperprolactinaemia (67.7% and 41.9% respectively) where it was twice
      as high as in the group of patients with prolactinoma. The proportion of ASAS(+)
      and ASARA(+) did not differ significantly between the groups of patients with ess
      with or without GHD. Similarly, there was no significant difference between the
      number of ESS ASAP(+) and ASARA(+) patients with or without hyperprolactinaemia.
      The data obtained suggested that autoimmune disorders may be primary, and
      responsible, at least in part, for pituitary dysfunction in the cases of
      idiopathic isolated GHD and idiopathic hyperprolactinaemia. At the same time, the
      autoimmune disorders in the patients with prolactinoma or ESS are probably
      secondary to the organic pituitary lesion and their significance in the
      development of the pituitary dysfunction is obscure.

PMID- 12429040
TI  - Inhibitory effects of antagonistic analogs of GHRH on GH3 pituitary cells
      overexpressing the human GHRH receptor.
AB  - GH3 rat pituitary tumor cells produce GH and prolactin (PRL), but lack the GHRH
      receptor (GHRH-R). We expressed human GHRH-R (hGHRH-R) in GH3 cells using
      recombinant adenoviral vectors and studied the effects of GHRH antagonists. The
      mRNA expression of the GHRH-R gene in the cells was demonstrated by RT-PCR. An
      exposure of the GH3 cells infected with hGHRH-R to 10(-10), 10(-9) and 10(-8) m
      hGHRH for 1 or 2 h in culture caused a dose-dependent elevation of the
      intracellular cAMP concentration and the cAMP efflux. Exposure to hGHRH also
      elicited dose-dependent increases in GH and PRL secretion from these cells.
      Neither the uninfected nor the antisense hGHRH-R-infected control cells exhibited
      cAMP, GH and PRL responses to GHRH stimulation. GHRH antagonists JV-1-38 and jv-1
      36 applied at 3x10(-8) m for 3 h, together with 10(-9) m GHRH, significantly
      inhibited the GHRH-stimulated cAMP efflux from the hGHRH-R-infected cells by 36
      and 80% respectively. The more potent antagonist JV-1-36 also decreased the
      intracellular cAMP levels in these cells by 55%. Exposure to JV-1-36 for 1 h
      nullified the stimulatory effect of GHRH on GH secretion and significantly
      inhibited it by 64 and 77% after 2 and 3 h respectively. In a superfusion system,
      GHRH at 10(-10), 10(-9) and 10(-8) m concentrations induced prompt and dose
      related high cAMP responses and smaller increases in the spontaneous GH secretion
      of the hGHRH-R-infected cells. Antagonists JV-1-36 and JV-1-38 applied at 3x10(
      8) m for 15 min, together with 10(-9) m GHRH, inhibited the GHRH-stimulated cAMP
      response by 59 and 35% respectively. This work demonstrates that GHRH antagonists
      can effectively inhibit the actions of GHRH on the hGHRH-R. Our results support
      the view that this class of compounds would be active clinically.

PMID- 12429041
TI  - Increased lactotrophs despite decreased somatotrophs in the dwarf (dw/dw) rat: a
      defect in the regulation of lactotroph/somatotroph cell fate?
AB  - The dwarf (dw/dw) rat differs from all other rodent models of GH deficiency in
      that its pituitary prolactin (PRL) content is normal or even increased. We have
      now studied this throughout postnatal development, using a combination of
      immunocytochemistry, RIA and fluorescence-activated cell sorting (FACS) and
      analysis. Compared with normal Albino Swiss (AS) rats, adult dw/dw rats showed a
      profound reduction in pituitary GH content accompanied by increased PRL content,
      significantly so in females (AS vs dw/dw; P<0.01). Somatotroph hypoplasia was
      evident in the adult dw/dw rats, with most GH(+ve) cells showing weak
      immunostaining, whereas many more strongly stained PRL cells were evident in
      pituitary sections from dw/dw rats. Facs analysis confirmed both somatotroph
      hypoplasia and relative lactotroph hyperplasia in dw/dw rats at all ages studied
      (9-144 days); the difference in somatotrophs increased with age whereas the
      difference in lactotrophs declined with age. At 9 days, the percentage of
      lactotrophs was 10-fold higher in dw/dw rats than in AS rats. Young dw/dw rats
      also had a higher proportion of mammosomatotrophs than AS rats, although this
      difference disappeared as the mammosomatotroph proportions increased with age in
      both strains. GHRH released GH from both dw/dw and as cells maintained in culture
      for 5 days. The sensitivity to GHRH and the amount of GH released was lower in
      the dw/dw cultures, mostly explained by their fewer GH cells and lower initial GH
      content. GHRH increased cAMP in as but not in dw/dw cultures, even when these
      were greatly enriched for dw/dw somatotrophs by FACS sorting prior to culture.
      These results suggest that GHRH-induced cAMP stimulation is required for trophic
      effects on GH synthesis and somatotroph proliferation, but is not required for
      GHRH-stimulated GH release. The inverse changes in somatotroph and lactotroph
      numbers suggest that the dw/dw mutation disturbs the mechanism that specifies and
      retains appropriate numbers of somatotrophs in their differentiated state, and
      results in a higher proportion of the remaining cells progressing to lactotrophs.
      The dw/dw phenotype is thus not confined to somatotrophs.

PMID- 12429042
TI  - Isolation and characterisation of the ovine gastrin-releasing peptide gene;
      abundant expression in the pregnant uterus and selective expression in fetal
      tissues.
AB  - High concentrations of a peptide related to gastrin-releasing peptide (GRP) are
      produced in the utero-placental unit of the human and sheep and secreted into the
      general circulation. This suggests an endocrine role in addition to its role as a
      neurotransmitter/neuromodulator. The GRP is larger than the previously described
      form GRP(1-27) but it is not known whether the larger form is the product of a
      related GRP-like gene or differences in post-translational processing. We have
      therefore cloned the gene for the sheep homologue of the GRP gene and determined
      its distribution. Only a single GRP gene was found in the sheep. This had a
      similar organisation to the human GRP gene with three exons and two introns. The
      larger form of GRP in the pregnant endometrium therefore appears to be the result
      of an alteration in processing of the GRP prohormone. The expression of GRP mRNA
      in the pregnant uterus was extraordinarily high comprising one-third of all mRNA
      synthesised by the pregnant endometrium. As the endometrial GRP mRNA arises
      solely from the glandular epithelium, the localised synthesis of GRP mRNA would
      be far higher. GRP mRNA was expressed in a wide variety of fetal tissues (fundus,
      colon, jejunum, ileum, duodenum, kidney, adrenal, lung, heart and pancreas) with
      a corresponding presence of GRP immunoreactivity. The expression of GRP in the
      fetal lung was biphasic with peaks at mid-term and near parturition but none in
      the adult supporting the concept of a specific developmental role of GRP in the
      lung.

PMID- 12429043
TI  - Characterization of a thyroid hormone-mediated short-loop feedback control of TSH
      receptor gene in an anaplastic human thyroid cancer cell line.
AB  - The expression of TSH receptor (TSHR) gene is frequently lost in thyroid cancers
      during the process of dedifferentiation that involves perturbation of several
      nuclear transcription factors. We have established that thyroid hormone receptor
      beta1 (TRbeta1) is associated with the loss of TSHR gene expression in an
      anaplastic human thyroid cancer cell line, ARO. To demonstrate that TRbeta1
      regulates TSHR gene expression, we performed electrophoresis mobility shift and
      3,5,3'-triiodothyronine (T3) transactivation assays. As expected, TRbeta1 bound
      the synthesized oligomer containing TSHR promoter sequence by heterodimerizing
      with retinoid X receptor. When a chimeric reporter pTRCAT5'-146 enclosing the
      minimal TSHR promoter was applied for T3 transactivation assay, two TRbeta1
      overexpressing transfectants of ARO cells (ARO1 and ARO2) demonstrated higher
      basal activity than their parental cells. Consequentially, T3 suppressed the
      reporter gene activity only in ARO1 and ARO2, but not in ARO cells. A point
      mutation creating a cAMP response element (CRE) in the reporter pTRCAT5'-146 CRE
      led to T3-induced suppression of the reporter gene in ARO cells without changing
      the basal or T3-induced activities in ARO1 and ARO2 cells. We conclude that the
      regulatory effect of T3 on TSHR gene expression is TR- and promoter DNA sequence
      determined.

PMID- 12429044
TI  - The endotoxin-induced increase of cytokines is followed by an increase of
      cortisol relative to dehydroepiandrosterone (DHEA) in healthy male subjects.
AB  - Dehydroepiandrosterone (DHEA) and DHEA sulphate (DHEAS) inhibit T-helper
      lymphocyte type 2 immune reactions and exert anti-inflammatory effects in some
      chronic inflammatory diseases. Both DHEA and, in particular, DHEAS levels are
      dramatically decreased in chronic inflammatory diseases whereas cortisol levels
      remain stable or are elevated. However, the time course of cortisol relative to
      DHEA production is not known. We tested whether administration of endotoxin to
      healthy male subjects can induce an early predominance of cortisol relative to
      DHEA and DHEAS. It is demonstrated that endotoxin induces a dose-dependent
      increase of cortisol in relation to DHEA (no effect at 0.2 ng endotoxin/kg body
      weight (b.w.), clear effect at 0.4 and 0.8 ng/kg b.w., p<0.05) and DHEAS (tested
      at 0.4 ng/kg b.w., P=0.014). The increase of cortisol relative to DHEA appears 4
      h after endotoxin injection and 2 h after a strong increase of interleukin (IL)-6
      relative to tumour necrosis factor (TNF). In addition, an increase of cortisol
      relative to 17OH-progesterone was observed. The ratio of serum IL-6/TNF was
      positively correlated with the ratio of serum cortisol/DHEA (R(Rank)=0.472,
      P=0.041) and serum cortisol/17OH-progesterone (R(Rank)=0.514, P=0.048). In
      conclusion, dissociation of cortisol relative to DHEA, DHEAS or 17OH-progesterone
      appears very early during a systemic inflammatory response which is associated
      with an increase of IL-6 relative to TNF. As in chronic inflammatory diseases,
      during an acute inflammatory response with endotoxin, these physiological hormone
      changes are probably necessary to achieve adequate cortisol levels at the expense
      of adrenal androgens.

PMID- 12429045
TI  - Apolipoprotein E-deficient mice created by systemic administration of antisense
      oligodeoxynucleotides: a new model for lipoprotein metabolism studies.
AB  - Atherosclerotic cardiovascular disease results from complex interactions among
      multiple genetic and environmental factors. Thus, it is important to elucidate
      the influence of each factor on cholesterol metabolism. For this purpose,
      transgenic/gene-targeting technology is a powerful tool for studying gene
      functions. However, this technology has several disadvantages such as being time
      consuming and expensive. Accordingly, we established new animal models using in
      vivo gene transfer technology. In this study, we examined the feasibility of the
      creation of a new animal model for the study of atherosclerosis. We hypothesized
      that apolipoprotein (apo) E-deficient mice can be created by systemic
      administration of antisense apo E oligodeoxynucleotides (ODN) coupled to the HVJ
      liposome complex. Initially, we examined the localization and cellular fate of
      FITC-labeled antisense ODN administered intravenously. FITC-labeled ODN
      transfection by the HVJ-liposome method resulted in fluorescence in the liver,
      spleen and kidney, but not in other organs such as brain. Moreover, fluorescence
      with the HVJ-liposome method was sustained for up to 2 weeks after transfection,
      which resulted in a striking difference from transfection of ODN alone or ODN in
      liposomes without HVJ, which showed rapid disappearance of fluorescence (within 1
      day). Given these unique characteristics of the HVJ-liposome method, we next
      examined transfection of antisense apo E ODN by intravenous administration.
      Transfection of antisense apo E ODN resulted in a marked reduction of apo E mRNA
      levels in the liver, but no change in apo B and beta-actin mRNA levels. In mice
      fed a normal diet, a transient increase in cholesterol and triglyceride levels
      was observed in the antisense apo E-treated group, but they returned to normal
      levels by 6 days after transfection. Similar findings were also found in mice fed
      a high cholesterol diet. Neither scrambled nor mismatched ODN resulted in any
      increase in cholesterol. To make chronic hypercholesterolemic mice, we therefore
      performed repeated injections of apo E antisense ODN. Whenever antisense apo E
      ODN were injected, mice showed a transient increase in cholesterol and
      triglyceride. Cumulative administration of antisense apo E ODN resulted in a
      sustained increase in cholesterol for up to 3 weeks after the last transfection.
      Finally, mice treated with repeated injections of antisense apo E every week
      developed sustained hypercholesterolemia and hypertriglyceridemia until
      withdrawal of injections. Apolipoprotein-deficient mice created by intravenous
      administration of antisense ODN are a promising new animal model to help
      understand the role of apolipoprotein in vivo and develop a new drug therapy
      targeting apolipoprotein.

PMID- 12429046
TI  - Inducible ablation of adipocytes in adult transgenic mice expressing the E. coli
      nitroreductase gene.
AB  - We describe the use of an enzyme prodrug system based on E. coli nitroreductase
      (NTR) to achieve the specific ablation of adipose tissue. Transgenic mice
      expressing the NTR gene specifically in the adipose tissue were generated using
      the adipocyte specific promoter aP2. After treatment with the prodrug CB1954
      these mice showed extensive cell depletion in all fat depots; this was directly
      correlated to both the dose of prodrug and the levels of NTR expression. Higher
      doses of CB1954 resulted in complete disappearance of visible adipose stores in
      some transgenic mice. These mice exhibited an impaired ability to thermoregulate
      body temperature. Lower doses of CB1954 resulted in a partial reduction of the
      adipose tissue leaving non-expressing cells that escape ablation. These animals
      show normal levels of blood glucose and triglycerides but have reduced leptin
      levels. After 30 days they were able to regenerate the fat depots and leptin
      levels returned to normal but, interestingly, no NTR-expressing cells were
      detectable. The present model provides a new approach to manipulate the number of
      adipocytes at different stages of mouse development and provides a new system for
      the study of fat metabolism especially in abnormal conditions such as obesity and
      its modulation through manipulation of the target cell population.

PMID- 12429047
TI  - Differential dimerization and association among resistin family proteins with
      implications for functional specificity.
AB  - Secreted by white adipose tissue as a hormone, resistin was identified as a
      possible link between obesity and insulin resistance. High circulating resistin
      levels were observed to correlate with obesity. Administration of resistin
      lowered the glucose tolerance threshold and impaired insulin activity; whereas
      anti-resistin antibodies had the opposite effects. However, contradictory data
      were subsequently reported in regard to the correlation between resistin
      expression level and obesity or type 2 diabetes. Two additional proteins that
      share a highly homologous C-terminus with resistin have been identified in mouse,
      and one in human, forming a resistin-related protein family. Resistin was shown
      to dimerize through a disulfide bond formed by the N-terminal-most cysteine
      (Cys26). Here we demonstrate that while Cys26 is both necessary and sufficient
      for homodimer formation, all three resistin family members can also interact with
      one another regardless of the presence of Cys26 through non-covalent
      interactions. Furthermore, protein crosslinking analysis indicated that resistin
      and resistin beta, but not resistin alpha, exist as multimers, probably with a
      dimer as the subunit. The multiple protein complex formation is obviously at a
      level higher than the Cys26 disulfide bonding. These results suggest the
      potential importance of considering intermolecular interactions among resistin
      family members in studying their functions.

PMID- 12429048
TI  - Production of cartilage link protein by human granulosa-lutein cells.
AB  - Link protein (LP), an extracellular matrix protein in cartilage, stabilizes
      aggregates of hyaluronic acid (HA) and proteoglycans, including aggrecan and
      inter-alpha-trypsin inhibitor (ITI). We have shown previously that cartilage LP
      is present in the maturing rat and mouse ovary. In the present study, we have
      employed immunohistochemistry to examine the anatomical distribution of cartilage
      LP in the human ovary. The expression of cartilage LP was selectively detected in
      the cells within the granulosa compartment of the preovulatory dominant follicle.
      The HA-positive granulosa-lutein cells were found to be a cartilage LP-positive
      subpopulation. We subsequently studied the in vitro expression of cartilage LP in
      cultured human granulosa-lutein cells obtained at oocyte retrieval for in vitro
      fertilization. Analysis of cultured cells by enzyme-linked immunoaffinity assay,
      Western blotting and immunofluorescence microscopy revealed that gonadotropin
      stimulates cartilage LP production. Time-course studies indicated that the
      cartilage LP production was induced as early as with gonadotropin stimulation for
      2 h, and the effect was sustained up to 8 h. Western blot analysis further
      revealed the presence of the macroaggregates composed of HA, ITI and cartilage LP
      in the gonadotropin-stimulated granulosa-lutein cell extracts. Collectively, the
      present results raise the possibility that cartilage LP forms extracellular
      structures that may have a regulatory function in the developing follicle in the
      human ovary.

PMID- 12429049
TI  - Parathyroid hormone-related peptide (38-94) amide stimulates ATP-dependent
      calcium transport in the Basal plasma membrane of the human syncytiotrophoblast.
AB  - The final step in the maternal-fetal transfer of calcium in the placenta involves
      transport against a concentration gradient across the syncytiotrophoblast basal
      plasma membrane (BM). Based on animal studies, it has been proposed that
      parathyroid hormone-related peptide (PTHrP) plays a major role in maintaining the
      maternal-fetal concentration gradient of calcium. In this study, we tested the
      hypothesis that a highly conserved mid-region fragment (38-94) of PTHrP directly
      affects the ATP-dependent calcium transport across BM isolated from full-term
      human placentas. PTHrP (38-94) stimulated ATP-dependent calcium transport at a
      concentration within the physiological range (5 pg/ml) and the effect (10-38%
      increase) was concentration dependent over the range 5 pg/ml to 5 ng/ml (n=8;
      P<0.05). In contrast, PTH, PTHrP (1-34), PTHrP (67-86) and calcitonin increased
      BM calcium transport only at concentrations much higher than physiological. The
      increased calcium uptake was inhibited by the protein kinase C (PKC) inhibitor
      chelerythrine (n=6; P<0.05). In addition, PTHrP (38-94) increased inositol
      trisphosphate (IP(3)) production and PKC phosphorylation in human placental BM
      (n=12; P<0.05). Our data indicate that PTHrP (38-94) stimulates Ca(2+)ATPase in
      the human syncytiotrophoblast BM vesicles by activating the IP(3)-DAG-PKC
      pathway. We suggest that PTHrP (38-94) is important in maintaining the calcium
      concentration gradient across the placental barrier in the human.

PMID- 12429050
TI  - Evidence that the major degradation product of glucose-dependent insulinotropic
      polypeptide, GIP(3-42), is a GIP receptor antagonist in vivo.
AB  - The incretin hormone glucose-dependent insulinotropic polypeptide (GIP) is
      rapidly degraded in the circulation by dipeptidyl peptidase IV forming the N
      terminally truncated peptide GIP(3-42). The present study examined the biological
      activity of this abundant circulating fragment peptide to establish its possible
      role in GIP action. Human GIP and GIP(3-42) were synthesised by Fmoc solid-phase
      peptide synthesis, purified by HPLC and characterised by electrospray ionisation
      mass spectrometry. In GIP receptor-transfected Chinese hamster lung fibroblasts,
      GIP(3-42) dose dependently inhibited GIP-stimulated (10(-7) M) cAMP production
      (up to 75.4+/-5.4%; P<0.001). In BRIN-BD11 cells, GIP(3-42) was significantly
      less potent at stimulating insulin secretion (1.9- to 3.2-fold; P<0.001),
      compared with native GIP and significantly inhibited GIP-stimulated (10(-7) M)
      insulin secretion with maximal inhibition (48.8+/-6.2%; P<0.001) observed at 10(
      7) M. In (ob/ob) mice, administration of GIP(3-42) significantly inhibited GIP
      stimulated insulin release (2.1-fold decrease; P<0.001) and exaggerated the
      glycaemic excursion (1.4-fold; P<0.001) induced by a conjoint glucose load. These
      data indicate that the N-terminally truncated GIP(3-42) fragment acts as a GIP
      receptor antagonist, moderating the insulin secreting and metabolic actions of
      GIP in vivo.

PMID- 12429051
TI  - Repeated maternal glucocorticoid administration and the developing liver in fetal
      sheep.
AB  - Prenatal glucocorticoid exposure has been associated with a reduction in birth
      weight and postnatal alterations in glucose homeostasis and hypothalamic
      pituitary-adrenal (HPA) axis function. The mechanisms underlying these responses
      are unknown, although changes in fetal hepatic development may play an important
      role. The fetal liver produces key regulators of fuel metabolism and of the
      developing HPA axis that are altered by glucocorticoids. The local availability
      of glucocorticoids is regulated, in part, by corticosteroid-binding protein
      (CBG), glucocorticoid receptors (GR) and by the enzyme 11beta-hydroxysteroid
      dehydrogenase (11betaHSD), but the effects of maternal glucocorticoid
      administration on the expression of these genes in the fetal liver are unknown.
      11betaHSD1 is the predominant form of this enzyme present in the liver and is
      responsible for the conversion of cortisone to cortisol. To determine if prenatal
      glucocorticoid exposure alters fetal hepatic regulation of CBG, 11betaHSD1 and
      GRs, we treated pregnant ewes with betamethasone (0.5 mg/kg) intramuscularly at
      104, 111 and 118 days of gestation (term 150 days). Animals were killed at 125 or
      146 days of gestation. Maternal betamethasone administration did not alter mean
      cord plasma glucose but significantly decreased cord plasma insulin levels
      (P<0.05) at 125 days of gestation. At 146 days of gestation, cord plasma glucose
      levels were significantly increased without alterations in insulin levels
      following maternal betamethasone treatment (P<0.05). Maternal betamethasone
      administration resulted in a significant increase in fetal hepatic 11betaHSD1
      mRNA and protein levels at 125 days of gestation (P<0.05). CBG mRNA levels were
      significantly elevated over control at 125 days although levels of CBG protein
      were not significantly different. GR protein levels were not statistically
      different at either 125 or 146 days of gestation following glucocorticoid
      administration. These data suggest that prenatal betamethasone exposure in the
      ovine fetus results in alterations in cord glucose and insulin levels as well as
      alterations in hepatic 11betaHSD1 mRNA and protein expression. These changes in
      11betaHSD1 increase the potential to generate local cortisol from circulating
      cortisone. We speculate that this could affect expression of glucocorticoid
      dependent hepatic enzymes involved with the regulation of glucose production and
      HPA responsiveness.

PMID- 12429052
TI  - Endocrinology trial design: adverse event reporting in randomised controlled
      trials of recombinant human GH in GH-deficient adults.
AB  - We have evaluated the reporting of withdrawals due to adverse effects and
      specific adverse effects in randomised controlled trials of recombinant human GH
      in adults. A systematic review was carried out of randomised controlled trials of
      the clinical effectiveness of recombinant human GH in adults with GH deficiency
      in relation to impact on quality of life. Trials were identified from searching
      electronic databases, bibliographies of related articles and consulting experts.
      There was reporting of withdrawals due to adverse effects and specific adverse
      effects. Rates of oedema and arthralgia were reported in included trials.
      Seventeen randomised controlled trials, published between 1990 and 1999, met the
      inclusion criteria for the review. Nine trials reported data on the effectiveness
      of GH on quality of life in adults. Only five trials (29%) reported both
      withdrawals from the study because of adverse events and specific adverse events
      with numbers per study arm and per type. Six further trials (35%) reported either
      withdrawal details or specific adverse event details or partial data on specific
      adverse events. Six trials (35%), however, did not report information on either
      withdrawals or specific adverse events. Ten of the 17 studies (59%) reported the
      number of patients who withdrew from the study due to adverse events per study
      arm and type of adverse event per study arm. Seven of the 17 trials (41%)
      reported the number of specific adverse events per study arm and six (35%)
      reported the type per study arm. The reporting of adverse events in randomised
      controlled trials of GH is variable and not consistent across trials. It is not
      possible to assess the impact that adverse events may have had on unblinding
      patients, and therefore the extent to which the effects of GH may have been
      overestimated. Therefore those conducting endocrinology trials in the future need
      to pay attention to the reporting of withdrawals due to adverse events and
      specific adverse events.

PMID- 12429053
TI  - Circulating ghrelin concentrations are lowered by intravenous glucose or
      hyperinsulinemic euglycemic conditions in rodents.
AB  - Ghrelin is a peptide secreted mainly by gastric parietal cells that may play a
      role in appetite regulation. Circulating ghrelin is abruptly lowered by food
      intake, but factors involved in ghrelin regulation remain unclear. The aim of
      this study was to determine whether intravenous glucose infusion lowers ghrelin,
      and to determine whether glucose, insulin or some measure of insulin action best
      predicts the effect of feeding on ghrelin. Rats were infused over 3 h with either
      A. saline (controls); B. dextrose to steady state blood glucose approximately
      16.7 mM, or C. insulin 7.5 mU/kg x min, plus dextrose as needed to clamp to
      euglycemic basal concentrations. During 3 h of infusion, group B had
      significantly greater (P<0.01) glucose, 17.4+/-0.3 mM, than groups A (6.6+/-0.3)
      or C (6.1+/- 0.2). Groups B and C had hyperinsulinemia at the end of the 3 h
      infusion (894+/-246, 804+/-156 pM) compared with saline-infused (222+/-24 pM,
      P<0.01). Ghrelin concentrations were reduced (P<0.01) in both hyperinsulinemic
      groups (B=85+/-2; C=103+/-0.6 pM) versus controls (163+/-9). Ghrelin was strongly
      correlated with insulin (r=-0.68), glucose infusion rate (r=-0.75) and free fatty
      acids (r=0.67), when all 3 groups were combined, although only the 2 latter
      variables were independent predictors of ghrelin. In conclusion, neither a rise
      in blood glucose nor presence of nutrient in the stomach is required for the
      effect of feeding on ghrelin. The data suggest that whole body insulin
      responsiveness plays either a direct or indirect role in meal-related ghrelin
      inhibition.

PMID- 12429054
TI  - The guards themselves.
AB  - If we agree that, in the present climate of fear of bioterrorism, some
      restrictions on the conduct and/or publication of certain types of biological
      research are likely, it is to our advantage to preempt government action by
      devising for ourselves restrictions that we can live with, then the inevitable
      question becomes: how should these restrictions be administered?

PMID- 12429055
TI  - Breaking barriers through collaboration: the example of the Cell Migration
      Consortium.
AB  - Understanding complex integrated biological processes, such as cell migration,
      requires interdisciplinary approaches. The Cell Migration Consortium, funded by a
      Large-Scale Collaborative Project Award from the National Institute of General
      Medical Science, develops and disseminates new technologies, data, reagents, and
      shared information to a wide audience. The development and operation of this
      Consortium may provide useful insights for those who plan similarly large-scale,
      interdisciplinary approaches.

PMID- 12429056
TI  - Mile-high view of plant biology.
AB  - A report on Plant Biology 2002, the annual meeting of the American Society of
      Plant Biologists, Denver, USA, 3-7 August 2002.

PMID- 12429057
TI  - Understanding biology through intelligent systems.
AB  - A report on the Tenth International Conference on Intelligent Systems for
      Molecular Biology (ISMB), Edmonton, Canada, 3-7 August 2002.

PMID- 12429058
TI  - Exploring the conditional coregulation of yeast gene expression through fuzzy k
      means clustering.
AB  - BACKGROUND: Organisms simplify the orchestration of gene expression by
      coregulating genes whose products function together in the cell. Many proteins
      serve different roles depending on the demands of the organism, and therefore the
      corresponding genes are often coexpressed with different groups of genes under
      different situations. This poses a challenge in analyzing whole-genome expression
      data, because many genes will be similarly expressed to multiple, distinct groups
      of genes. Because most commonly used analytical methods cannot appropriately
      represent these relationships, the connections between conditionally coregulated
      genes are often missed. RESULTS: We used a heuristically modified version of
      fuzzy k-means clustering to identify overlapping clusters of yeast genes based on
      published gene-expression data following the response of yeast cells to
      environmental changes. We have validated the method by identifying groups of
      functionally related and coregulated genes, and in the process we have uncovered
      new correlations between yeast genes and between the experimental conditions
      based on similarities in gene-expression patterns. To investigate the regulation
      of gene expression, we correlated the clusters with known transcription factor
      binding sites present in the genes' promoters. These results give insights into
      the mechanism of the regulation of gene expression in yeast cells responding to
      environmental changes. CONCLUSIONS: Fuzzy k-means clustering is a useful
      analytical tool for extracting biological insights from gene-expression data. Our
      analysis presented here suggests that a prevalent theme in the regulation of
      yeast gene expression is the condition-specific coregulation of overlapping sets
      of genes.

PMID- 12429059
TI  - Genomic functional annotation using co-evolution profiles of gene clusters.
AB  - BACKGROUND: The current speed of sequencing already exceeds the capability of
      annotation, creating a potential bottleneck. A large proportion of the genes in
      microbial genomes remains uncharacterized. Here we propose a new method for
      functional annotation using the conservation patterns of gene clusters. If
      several gene clusters show the same coevolution pattern across different genomes
      it is reasonable to infer they are functionally related. The gene cluster
      phylogenetic profile integrates chromosomal proximity information and
      phylogenetic profile information and allows us to infer functional dependences
      between the gene clusters even at great distance on the chromosome. RESULTS: As a
      proof of concept, we applied our method to the genome of Escherichia coli K12
      strain. Our method establishes functional relationships among 176 gene clusters,
      comprising 738 E. coli genes. The accuracy of pair phylogenetic profiles was
      compared with the single-gene phylogenetic profile and was shown to be higher. As
      a result, we are able to suggest functional roles for several previously unknown
      genes or unknown genomic regions in E. coli. We also examined the robustness of
      coevolution signals across a larger set of genomes and suggest a possible upper
      limit of accuracy for the phylogenetic profile methods. CONCLUSIONS: The higher
      order phylogenetic profiles, such as the gene-pair phylogenetic profiles, can
      detect functional dependences that are missed by using conventional single-gene
      phylogenetic profile or the chromosomal proximity method only. We show that the
      gene-pair phylogenetic profile is more accurate than the single-gene phylogenetic
      profiles.

PMID- 12429060
TI  - The PRC-barrel: a widespread, conserved domain shared by photosynthetic reaction
      center subunits and proteins of RNA metabolism.
AB  - BACKGROUND: The H subunit of the purple bacterial photosynthetic reaction center
      (PRC-H) is important for the assembly of the photosynthetic reaction center and
      appears to regulate electron transfer during the reduction of the secondary
      quinone. It contains a distinct cytoplasmic beta-barrel domain whose fold has no
      close structural relationship to any other well known beta-barrel domain.
      RESULTS: We show that the PRC-H beta-barrel domain is the prototype of a novel
      superfamily of protein domains, the PRC-barrels, approximately 80 residues long,
      which is widely represented in bacteria, archaea and plants. This domain is also
      present at the carboxyl terminus of the pan-bacterial protein RimM, which is
      involved in ribosomal maturation and processing of 16S rRNA. A family of small
      proteins conserved in all known euryarchaea are composed entirely of a single
      stand-alone copy of the domain. Versions of this domain from photosynthetic
      proteobacteria contain a conserved acidic residue that is thought to regulate the
      reduction of quinones in the light-induced electron-transfer reaction. Closely
      related forms containing this acidic residue are also found in several non
      photosynthetic bacteria, as well as in cyanobacteria, which have reaction centers
      with a different organization. We also show that the domain contains several
      determinants that could mediate specific protein-protein interactions.
      CONCLUSIONS: The PRC-barrel is a widespread, ancient domain that appears to have
      been recruited to a variety of biological systems, ranging from RNA processing to
      photosynthesis. Identification of this versatile domain in numerous proteins
      could aid investigation of unexplored aspects of their biology.

PMID- 12429061
TI  - Within the fold: assessing differential expression measures and reproducibility
      in microarray assays.
AB  - BACKGROUND: 'Fold-change' cutoffs have been widely used in microarray assays to
      identify genes that are differentially expressed between query and reference
      samples. More accurate measures of differential expression and effective data
      normalization strategies are required to identify high-confidence sets of genes
      with biologically meaningful changes in transcription. Further, the analysis of a
      large number of expression profiles is facilitated by a common reference sample,
      the construction of which must be carefully addressed. RESULTS: We carried out a
      series of 'self-self' hybridizations in which aliquots of the same RNA sample
      were labeled separately with Cy3 and Cy5 fluorescent dyes and co-hybridized to
      the same microarray. From this, we can analyze the intensity-dependent behavior
      of microarray data, define a statistically significant measure of differential
      expression that exploits the structure of the fluorescent signals, and measure
      the inherent reproducibility of the technique. We also devised a simple procedure
      for identifying and eliminating low-quality data for replicates within and
      between slides. We examine the properties required of a universal reference RNA
      sample and show how pooling a small number of samples with a diverse
      representation of expressed genes can outperform more complex mixtures as a
      reference sample. CONCLUSION: Analysis of cell-line samples can identify
      systematic structure in measured gene-expression levels. A general procedure for
      analyzing cDNA microarray data is proposed and validated. We show that pooled
      reference samples should be based not only on the expression of individual genes
      in each cell line but also on the expression levels of genes within cell lines.

PMID- 12429062
TI  - Phylogenetic analysis of 277 human G-protein-coupled receptors as a tool for the
      prediction of orphan receptor ligands.
AB  - BACKGROUND: G-protein-coupled receptors (GPCRs) are the largest and most diverse
      family of transmembrane receptors. They respond to a wide range of stimuli,
      including small peptides, lipid analogs, amino-acid derivatives, and sensory
      stimuli such as light, taste and odor, and transmit signals to the interior of
      the cell through interaction with heterotrimeric G proteins. A large number of
      putative GPCRs have no identified natural ligand. We hypothesized that a more
      complete knowledge of the phylogenetic relationship of these orphan receptors to
      receptors with known ligands could facilitate ligand identification, as related
      receptors often have ligands with similar structural features. RESULTS: A
      database search excluding olfactory and gustatory receptors was used to compile a
      list of accession numbers and synonyms of 81 orphan and 196 human GPCRs with
      known ligands. Of these, 241 sequences belonging to the rhodopsin receptor-like
      family A were aligned and a tentative phylogenetic tree constructed by neighbor
      joining. This tree and local alignment tools were used to define 19 subgroups of
      family A small enough for more accurate maximum-likelihood analyses. The secretin
      receptor-like family B and metabotropic glutamate receptor-like family C were
      directly subjected to these methods. CONCLUSIONS: Our trees show the overall
      relationship of 277 GPCRs with emphasis on orphan receptors. Support values are
      given for each branch. This approach may prove valuable for identification of the
      natural ligands of orphan receptors as their relation to receptors with known
      ligands becomes more evident.

PMID- 12429063
TI  - The society of genes: networks of functional links between genes from comparative
      genomics.
AB  - BACKGROUND: Comparative genomics provides at least three methods beyond
      traditional sequence similarity for identifying functional links between genes:
      the examination of common phylogenetic distributions, the analysis of conserved
      proximity along the chromosomes of multiple genomes, and observations of fusions
      of genes into a multidomain gene in another organism. We have previously
      generated the links according to each of these methods individually for 43 known
      microbial genomes. Here we combine these results to construct networks of
      functional associations. RESULTS: We show that the functional networks obtained
      by applying these methods have different topologies and that the information they
      provide is largely additive. In particular, the combined networks of functional
      links contain an average of 57% of an organism's complete genetic complement,
      uncover substantial portions of known pathways, and suggest the function of
      previously unannotated genes. In addition, the combined networks are
      qualitatively different from the networks obtained using individual methods. They
      have a dominant cluster that contains approximately 80%-90% of the genes,
      independent of genome size, and the dominant clusters show the small world
      behavior expected of a biological system, with global connectivity that is nearly
      random, and local properties that are highly ordered. CONCLUSIONS: When the
      information on functional linkage provided by three emerging computational
      methods is combined, the integrated network uncovers large numbers of conserved
      pathways and identifies clusters of functionally related genes. It therefore
      shows considerable utility and promise as a tool for understanding genomic
      structure, and for guiding high throughput experimental investigations.

PMID- 12429064
TI  - Improved analytical methods for microarray-based genome-composition analysis.
AB  - BACKGROUND: Whereas genome sequencing has given us high-resolution pictures of
      many different species of bacteria, microarrays provide a means of obtaining
      information on genome composition for many strains of a given species. Genome
      composition analysis using microarrays, or 'genomotyping', can be used to
      categorize genes into 'present' and 'divergent' categories based on the level of
      hybridization signal. This typically involves selecting a signal value that is
      used as a cutoff to discriminate present (high signal) and divergent (low signal)
      genes. Current methodology uses empirical determination of cutoffs for
      classification into these categories, but this methodology is subject to several
      problems that can result in the misclassification of many genes. RESULTS: We
      describe a method that depends on the shape of the signal-ratio distribution and
      does not require empirical determination of a cutoff. Moreover, the cutoff is
      determined on an array-to-array basis, accounting for variation in strain
      composition and hybridization quality. The algorithm also provides an estimate of
      the probability that any given gene is present, which provides a measure of
      confidence in the categorical assignments. CONCLUSIONS: Many genes previously
      classified as present using static methods are in fact divergent on the basis of
      microarray signal; this is corrected by our algorithm. We have reassigned
      hundreds of genes from previous genomotyping studies of Helicobacter pylori and
      Campylobacter jejuni strains, and expect that the algorithm should be widely
      applicable to genomotyping data.

PMID- 12429066
TI  - The discovery of novel neuropeptides takes flight.
AB  - Structural data are critical for the elucidation of how peptides are synthesized
      and how they function. Two recent studies have used nanoscale chromatography
      together with mass spectrometry to determine the structures of novel
      neuropeptides in rat and Drosophila. The results shed light on neuropeptide
      synthesis and function(s) in both vertebrates and insects.

PMID- 12429065
TI  - Finding signals that regulate alternative splicing in the post-genomic era.
AB  - Alternative splicing of pre-mRNAs is central to the generation of diversity from
      the relatively small number of genes in metazoan genomes. Auxiliary cis elements
      and trans-acting factors are required for the recognition of constitutive and
      alternatively spliced exons and their inclusion in pre-mRNA. Here, we discuss the
      regulatory elements that direct alternative splicing and how genome-wide analyses
      can aid in their identification.

PMID- 12429068
TI  - An improved RSP method to detect HpaI polymorphism in the apolipoprotein C-1 gene
      promoter.
AB  - BACKGROUND: An apolipoprotein C1 gene promoter polymorphism (CGTT insertion at
      position -317) is associated with familial dysbetalipoprotemia, cardiovascular
      diseases, and Alzheimer's disease. Restriction site polymorphism (RSP) assays
      were previously established to detect this polymorphism. In this study, we
      introduce an improved RSP assay to detect this polymorphism. METHODS: This method
      included newly designed primers and only one round of PCR amplification which
      yields one short and specific APOC1 fragment followed by HpaI digestion. Briefly,
      It consists of three steps: 1) one round of PCR amplification of DNA sample, 2)
      HpaI enzyme digestion of PCR products, and 3) electrophoresis on an agarose gel
      to visualize the genotypes. This improved RSP method was applied to genotype 92
      human samples collected from The Johns Hopkins Hospital. RESULTS: The observed
      allele frequencies for H1 and H2 from 92 genotyped human subjects were 0.707 and
      0.293 respectively. The H2 allele frequency in the black subjects (0.350) was
      significantly (p = 0.024) higher than that in the white subjects (0.177). This
      method was more economical and convenient than the methods previously reported to
      detect this mutation in the APOC1 gene. CONCLUSIONS: This assay will be readily
      applied to screen large sample sizes for population studies in a simple and cost
      effective way.

PMID- 12429067
TI  - The presenilins.
AB  - The presenilins are evolutionarily conserved transmembrane proteins that regulate
      cleavage of certain other proteins in their transmembrane domains. The clinical
      significance of this regulation is shown by the contribution of presenilin
      mutations to 20-50% of early-onset cases of inherited Alzheimer's disease.
      Although the precise molecular mechanism underlying presenilin function or
      dysfunction remains elusive, presenilins are thought to be part of a complex of
      proteins that has 'gamma-secretase cleavage' activity, which is clearly central
      in the pathogenesis of Alzheimer's disease. Mutations in presenilins increase the
      production of the longer isoforms of amyloid beta peptide, which are neurotoxic
      and prone to self-aggregation. Biochemical studies indicate that the presenilins
      do not act alone but operate within large heteromeric protein complexes, whose
      components and enzymatic core are the subject of much study and controversy; one
      essential component is nicastrin. The presenilin primary sequence is remarkably
      well conserved in eukaryotes, suggesting some functional conservation; indeed,
      defects caused by mutations in the nemotode presenilin homolog can be rescued by
      human presenilin.

PMID- 12429069
TI  - The transitive fallacy for randomized trials: if A bests B and B bests C in
      separate trials, is A better than C?
AB  - BACKGROUND: If intervention A bests B in one randomized trial, and B bests C in
      another randomized trial, can one conclude that A is better than C? The problem
      was motivated by the planning of a randomized trial, where A is spiral-CT
      screening, B is x-ray screening, and C is no screening. On its surface, this
      would appear to be a straightforward application of the transitive principle of
      logic. METHODS: We extended the graphical approach for omitted binary variables
      that was originally developed to illustrate Simpson's paradox, applying it to
      hypothetical, but plausible scenarios involving lung cancer screening, treatment
      for gastric cancer, and antibiotic therapy for clinical pneumonia. RESULTS:
      Graphical illustrations of the three examples show different ways the transitive
      fallacy for randomized trials can arise due to changes in an unobserved or
      unadjusted binary variable. In the most dramatic scenario, B bests C in the first
      trial, A bests B in the second trial, but C bests A at the time of the second
      trial. CONCLUSION: Even with large sample sizes, combining results from a
      previous randomized trial of B versus C with results from a new randomized trial
      of A versus B will not guarantee correct inference about A versus C. A three-arm
      trial of A, B, and C would protect against this problem and should be considered
      when the sequential trials are performed in the context of changing secular
      trends in important omitted variables such as therapy in cancer screening trials.

PMID- 12429070
TI  - Colony shape as a genetic trait in the pattern-forming Bacillus mycoides.
AB  - BACKGROUND: Bacillus mycoides Flugge, a Gram-positive, non-motile soil bacterium
      assigned to Bacillus cereus group, grows on agar as chains of cells linked end to
      end, forming radial filaments curving clock- or counter-clockwise (SIN or DX
      morphotypes). The molecular mechanism causing asymmetric curving is not known:
      our working hypothesis considers regulation of filamentous growth as the
      prerequisite for these morphotypes. RESULTS: SIN and DX strains isolated from the
      environment were classified as B. mycoides by biochemical and molecular biology
      tests. Growth on agar of different hardness and nutrient concentration did not
      abolish colony patterns, nor was conversion between SIN and DX morphotypes ever
      noticed. A number of morphotype mutants, all originating from one SIN strain,
      were obtained. Some lost turn direction becoming fluffy, others became round and
      compact. All mutants lost wild type tight aggregation in liquid culture. Growth
      on agar was followed by microscopy, exploring the process of colony formation and
      details of cell divisions. A region of the dcw (division cell wall) cluster,
      including ftsQ, ftsA, ftsZ and murC, was sequenced in DX and SIN strains as a
      basis for studying cell division. This confirmed the relatedness of DX and SIN
      strains to the B. cereus group. CONCLUSIONS: DX and SIN asymmetric morphotypes
      stem from a close but not identical genomic context. Asymmetry is established
      early during growth on agar. Wild type bacilli construct mostly uninterrupted
      filaments with cells dividing at the free ends: they "walk" longer distances
      compared to mutants, where enhanced frequency of cell separation produces new
      growing edges resulting in round compact colonies.

PMID- 12429072
TI  - The gynecologist: the competent counselor in breast health matters.

PMID- 12429073
TI  - Sexual side effects of SSRI medications: potential treatment strategies for SSRI
      induced female sexual dysfunction.
AB  - Depression often coexists with sexual dysfunction, and the medical treatment of
      depression can further worsen sexual symptoms or cause de novo sexual dysfunction
      in a person who did not experience it prior to treatment. There are many drugs
      that can adversely affect sexual response. Among antidepressants, this effect is
      commonly observed with selective serotonin-reuptake inhibitors (SSRI). Various
      strategies for the treatment of SSRI-related sexual dysfunction have been
      studied, including: awaiting spontaneous remission of sexual dysfunction;
      reducing the dose of medication; taking a "drug holiday"; adding another drug to
      help reverse sexual symptoms; changing antidepressants; or initially starting
      with a different antidepressant that is known to have fewer or no sexual side
      effects. Overall, it is important to address sexual health when caring for a
      patient--to improve drug compliance and the patient's well being.

PMID- 12429071
TI  - Haplotype analysis of the PPARgamma Pro12Ala and C1431T variants reveals opposing
      associations with body weight.
AB  - BACKGROUND: Variation at the PPARG locus may influence susceptibility to type 2
      diabetes and related traits. The Pro12Ala polymorphism may modulate receptor
      activity and is associated with protection from type 2 diabetes. However, there
      have been inconsistent reports of its association with obesity. The silent C1431T
      polymorphism has not been as extensively studied, but the rare T allele has also
      been inconsistently linked to increases in weight. Both rare alleles are in
      linkage disequilibrium and the independent associations of these two
      polymorphisms have not been addressed. RESULTS: We have genotyped a large
      population with type 2 diabetes (n = 1107), two populations of non-diabetics from
      Glasgow (n = 186) and Dundee (n = 254) and also a healthy group undergoing
      physical training (n = 148) and investigated the association of genotype with
      body mass index. This analysis has demonstrated that the Ala12 and T1431 alleles
      are present together in approximately 70% of the carriers. By considering the
      other 30% of individuals with haplotypes that only carry one of these
      polymorphisms, we have demonstrated that the Ala12 allele is consistently
      associated with a lower BMI, whilst the T1431 allele is consistently associated
      with higher BMI. CONCLUSION: This study has therefore revealed an opposing
      interaction of these polymorphisms, which may help to explain previous
      inconsistencies in the association of PPARG polymorphisms and body weight.

PMID- 12429074
TI  - Noncontraceptive applications of the levonorgestrel intrauterine system.
AB  - The introduction of an intrauterine system that releases 20 mg of levonorgestrel
      (LNG-IUS) directly to the uterine lining has ushered in a new era for the
      intrauterine device. The LNG-IUS reduces menstrual bleeding and dysmenorrhea, and
      is an effective nonsurgical treatment for idiopathic menorrhagia in premenopausal
      women. Women using the device experience significant reductions in menstrual flow
      and increases in hemoglobin. Abnormal uterine bleeding has become a primary
      indication for the use of this intrauterine device in Europe, and it is an
      emerging off-label indication in the United States. Women randomized to the use
      of the device experience a reduction in bleeding similar to that obtained by
      hysteroscopic procedures, and satisfaction with the results is high. The device
      also provides endometrial protection in combination with estrogen as
      postmenopausal hormone replacement therapy. In this paper, the growing literature
      on the emerging noncontraceptive indications for the LNG-IUS is reviewed.

PMID- 12429075
TI  - Ethical issues in gynecology: adolescent confidentiality, provider conscience and
      abortion, and patient choice of provider gender.
AB  - All medical specialists struggle with problems that cannot be solved with medical
      knowledge alone. The field of gynecology is not unique in medicine for the
      presence of ethical dilemmas, but the nature of the dilemmas are unique.
      Gynecologists commonly confront complex ethical questions in their practices that
      can be answered only through thoughtful consideration of the values, interests,
      rights, goals, and obligations of those involved. In this paper, three ethical
      issues that commonly arise in the practice of gynecology are presented:
      adolescent confidentiality regarding reproductive health services, physician
      conscience and provision of abortion services, and the question of accommodating
      patient choice of provider gender. Each topic is introduced with a case vignette
      followed by an analysis of the issues involved and recommendations for
      resolution.

PMID- 12429077
TI  - Menstrual nirvana: amenorrhea through the use of continuous oral contraceptives.
AB  - Medically induced amenorrhea has been used successfully in women who have medical
      conditions that worsen during menstruation. Menstrual suppression through the use
      of continuous oral contraceptives has been proven to be safe, effective, and
      extremely acceptable to women. Women without medical indications for menstrual
      suppression may find medically induced amenorrhea to be a significant improvement
      in their quality of life. Greater satisfaction with use of oral contraception may
      encourage compliance and increase the prevalence of pill-related health benefits.

PMID- 12429076
TI  - Anesthesia for office endometrial procedures: a review of the literature.
AB  - Providing anesthesia for office endometrial procedures is a clinical challenge.
      The available techniques include the traditional paracervical block, the deep
      paracervical block, intrauterine lidocaine, topical spray lignocaine, and
      conscious sedation. Each offers some benefit in providing anesthesia during these
      procedures and can contribute to a more comfortable experience for the patient.

PMID- 12429078
TI  - The health of adolescent girls: does the law support it?
AB  - The law provides protection and creates many policy options that could and do
      support the health of adolescent girls. Current legal protection pertains to
      consent for care, confidentiality of information, and insurance coverage; gaps in
      protection and policy options also exist. The extent to which the protection and
      options will remain in place and the gaps will be filled is uncertain. Additional
      issues of current interest and debate include financing treatment for
      increasingly pressing health concerns, such as eating disorders, obesity, and
      depression; new challenges concerning statutory rape reporting and enforcement of
      the laws related to it; and girls' access to emergency contraception.

PMID- 12429079
TI  - Adolescent preventive services for girls.
AB  - Adolescence is a complex and often confusing time in the life of a girl as she
      undergoes significant physical, emotional, and cognitive development. Because
      most causes of teen morbidity and mortality are behavioral, preventive health
      visits should address psychosocial issues such as substance abuse, sexuality, and
      emotional health in a confidential and age-appropriate manner. Assessment and
      management strategies for providing preventive health services for adolescent
      girls are offered in this article.

PMID- 12429080
TI  - Sexual orientation of adolescent girls.
AB  - It is important for healthcare providers to have a clear understanding of sexual
      orientation and other components of sexual identity (genetic gender, anatomic
      gender, gender identity, gender role, and sexual behavior). Knowledge of how a
      lesbian identity is formed will aide providers in guiding these girls through
      adolescence. Societal stigma often forces isolation that leads to many risky
      behaviors that affect health (alcohol and drug use; risky sexual behaviors;
      truancy and dropping out; running away and homelessness; and depression and
      suicide). Health providers need to ensure a safe and understanding environment
      for these girls, to enhance their physical, emotional, and social development to
      healthy adulthood.

PMID- 12429081
TI  - Eating disorders in adolescent girls.
AB  - Eating disorders affect a minority of adolescents, but represent a significant
      source of chronic illness in this age group. Treatment requires a
      multidisciplinary team approach and family involvement. The prognosis for
      adolescents is better than that for adult patients with eating disorders, but
      requires prompt diagnosis and referral to experienced providers. In this article,
      updates on the latest developments in the diagnosis and treatment of anorexia
      nervosa and bulimia are presented.

PMID- 12429082
TI  - Human papillomavirus and adolescent girls.
AB  - Human papillomavirus (HPV) infection is one of the most common sexually
      transmitted infections (STI) in young women. Infection frequently is
      asymptomatic, but may lead to anogenital condylomata and cervical squamous cell
      carcinoma. This article provides an overview of the recent literature on HPV
      infection and its clinical sequelae with a focus on issues pertinent to
      adolescents.

PMID- 12429083
TI  - Dehydrogenases, NAD, and transcription--what's the connection?
AB  - In the October issue of Molecular Cell, Kumar et al. demonstrate that the C
      terminal binding protein (CtBP) is an NAD-dependent dehydrogenase that links
      enzymatic activity to protein-protein contacts associated with transcriptional
      repression, and implicates a broader involvement of enzymes and NAD in the
      regulation of gene expression.

PMID- 12429084
TI  - The trypanosomal trans-sialidase: two catalytic functions associated with one
      catalytic site.
AB  - The structure of the trypanosomal trans-sialidase reveals a canonical sialidase
      catalytic site elaborated with a conformational switch that creates an adjacent
      binding pocket for lactose.

PMID- 12429085
TI  - A T cell receptor goes public.
AB  - The crystal structure of a human T cell receptor, which is used almost
      exclusively in the immune response to an Epstein-Barr virus protein, highlights
      the importance of noncontact residues in antigen recognition.

PMID- 12429086
TI  - Periplasmic chaperones--new structural and functional insights.
AB  - Although chaperones exist in the periplasmic compartment of Gram-negative
      bacterial cells, how they function is not well understood. New intriguing
      functional insights are provided by the solved crystal structure of the
      periplasmic chaperone SurA.

PMID- 12429087
TI  - Obg, a G domain with a beautiful extension.
AB  - The structure of Obg, a protein involved in a complicated genetic network that
      regulates stress response and sporulation in Bacillus subtilis, reveals a
      completely new type of guanine nucleotide binding protein and provides some hints
      about its function.

PMID- 12429089
TI  - The crystal structure of MT0146/CbiT suggests that the putative precorrin-8w
      decarboxylase is a methyltransferase.
AB  - The CbiT and CbiE enzymes participate in the biosynthesis of vitamin B12. They
      are fused together in some organisms to form a protein called CobL, which
      catalyzes two methylations and one decarboxylation on a precorrin intermediate.
      Because CbiE has sequence homology to canonical precorrin methyltransferases,
      CbiT was hypothesized to catalyze the decarboxylation. We herein present the
      crystal structure of MT0146, the CbiT homolog from Methanobacterium
      thermoautotrophicum. The protein shows structural similarity to Rossmann-like S
      adenosyl-methionine-dependent methyltransferases, and our 1.9 A cocrystal
      structure shows that it binds S-adenosyl-methionine in standard geometry near a
      binding pocket that could accommodate a precorrin substrate. Therefore,
      MT0146/CbiT probably functions as a precorrin methyltransferase and represents
      the first enzyme identified with this activity that does not have the canonical
      precorrin methyltransferase fold.

PMID- 12429090
TI  - Crystallographic structure of SurA, a molecular chaperone that facilitates
      folding of outer membrane porins.
AB  - The SurA protein facilitates correct folding of outer membrane proteins in gram
      negative bacteria. The sequence of Escherichia coli SurA presents four segments,
      two of which are peptidyl-prolyl isomerases (PPIases); the crystal structure
      reveals an asymmetric dumbbell, in which the amino-terminal, carboxy-terminal,
      and first PPIase segments of the sequence form a core structural module, and the
      second PPIase segment is a satellite domain tethered approximately 30 A from this
      module. The core module, which is implicated in membrane protein folding, has a
      novel fold that includes an extended crevice. Crystal contacts show that peptides
      bind within the crevice, suggesting a model for chaperone activity whereby
      segments of polypeptide may be repetitively sequestered and released during the
      membrane protein-folding process.

PMID- 12429091
TI  - Cocrystal structures of diaminopimelate decarboxylase: mechanism, evolution, and
      inhibition of an antibiotic resistance accessory factor.
AB  - Cocrystal structures of Methanococcus jannaschii diaminopimelate decarboxylase
      (DAPDC) bound to a substrate analog, azelaic acid, and its L-lysine product have
      been determined at 2.6 A and 2.0 A, respectively. This PLP-dependent enzyme is
      responsible for the final step of L-lysine biosynthesis in bacteria and plays a
      role in beta-lactam antibiotic resistance in Staphylococcus aureus. Substrate
      specificity derives from recognition of the L-chiral center of diaminopimelate
      and a system of ionic "molecular rulers" that dictate substrate length. A coupled
      enzyme assay system permitted measurement of kinetic parameters for recombinant
      DAPDCs and inhibition constants (K(i)) for azelaic acid (89 microM) and other
      substrate analogs. Implications for rational design of broad-spectrum
      antimicrobial agents targeted against DAPDCs of drug-resistant strains of
      bacterial pathogens, such as Staphylococcus aureus, are discussed.

PMID- 12429092
TI  - Monomeric structures of the zymogen and active catalytic domain of complement
      protease c1r: further insights into the c1 activation mechanism.
AB  - C1r is the serine protease (SP) that mediates autoactivation of C1, the complex
      that triggers the classical complement pathway. We have determined the crystal
      structure of two fragments from the human C1r catalytic domain, each encompassing
      the second complement control protein (CCP2) module and the SP domain. The wild
      type species has an active structure, whereas the S637A mutant is a zymogen. The
      structures reveal a restricted hinge flexibility of the CCP2-SP interface, and
      both are characterized by the unique alpha-helical conformation of loop E. The
      zymogen activation domain exhibits high mobility, and the active structure shows
      a restricted access to most substrate binding subsites. Further implications
      relevant to the C1r self-activation process are derived from protein-protein
      interactions in the crystals.

PMID- 12429093
TI  - The 1.5 A crystal structure of a highly selected antiviral T cell receptor
      provides evidence for a structural basis of immunodominance.
AB  - Despite a potential repertoire of >10(15) alphabeta T cell receptors (TcR), the
      HLA B8-restricted cytolytic T cell response to a latent antigen of Epstein-Barr
      virus (EBV) is strikingly limited in the TcR sequences that are selected. Even in
      unrelated individuals this response is dominated by a single highly restricted
      TcR clonotype that selects identical combinations of hypervariable Valpha, Vbeta,
      D, J, and N region genes. We have determined the 1.5 A crystal structure of this
      "public" TcR, revealing that five of the six hypervariable loops adopt novel
      conformations providing a unique combining site that contains a deep pocket
      predicted to overlay the HLA B8-peptide complex. The findings suggest a
      structural basis for the immunodominance of this clonotype in the immune response
      to EBV.

PMID- 12429094
TI  - Crystal structure of the human supernatant protein factor.
AB  - Supernatant protein factor (SPF) promotes the epoxidation of squalene catalyzed
      by microsomes. Several studies suggest its in vivo role in the cholesterol
      biosynthetic pathway by a yet unknown mechanism. SPF belongs to a family of lipid
      binding proteins called CRAL_TRIO, which include yeast phosphatidylinositol
      transfer protein Sec14 and tocopherol transfer protein TTP. The crystal structure
      of human SPF at a resolution of 1.9 A reveals a two domain topology. The N
      terminal 275 residues form a Sec14-like domain, while the C-terminal 115 residues
      consist of an eight-stranded jelly-roll barrel similar to that found in many
      viral protein structures. The ligand binding cavity has a peculiar horseshoe-like
      shape. Contrary to the Sec14 crystal structure, the lipid-exchange loop is in a
      closed conformation, suggesting a mechanism for lipid exchange.

PMID- 12429095
TI  - Structure of the DNA binding region of prospero reveals a novel homeo-prospero
      domain.
AB  - The Prospero transcription factor promotes neural differentiation in Drosophila,
      and its activity is tightly regulated by modulating its subcellular localization.
      Prospero is exported from the nucleus of neural precursors but imported into the
      nucleus of daughter cells, which is necessary for their proper differentiation.
      Prospero has a highly divergent putative homeodomain adjacent to a conserved
      Prospero domain; both are required for sequence-specific DNA binding. Here we
      show that the structure of these two regions consists of a single structural unit
      (a homeo-prospero domain), in which the Prospero domain region is in position to
      contribute to DNA binding and also to mask a defined nuclear export signal that
      is within the putative homeodomain region. We propose that the homeo-prospero
      domain coordinately regulates Prospero nuclear localization and DNA binding
      specificity.

PMID- 12429096
TI  - NMR structure of the heme chaperone CcmE reveals a novel functional motif.
AB  - The concept of metal chaperones involves transient binding of metallic cofactors
      by specific proteins for delivery to enzymes in which they function. Metal
      chaperones thus provide a protective, as well as a transport, function. We report
      the first structure of a heme chaperone, CcmE, which comprises these two
      functions. We propose that the covalent attachment of heme to an exposed
      histidine occurs after heme binding at the surface of a rigid molecule with a
      flexible C-terminal domain. CcmE belongs to a family of proteins with a specific
      fold, which all share a function in delivery of specific molecular cargo.

PMID- 12429097
TI  - Crystal structure of the priming beta-ketosynthase from the R1128 polyketide
      biosynthetic pathway.
AB  - ZhuH is a priming ketosynthase that initiates the elongation of the polyketide
      chain in the biosynthetic pathway of a type II polyketide, R1128. The crystal
      structure of ZhuH in complex with the priming substrate acetyl-CoA reveals an
      extensive loop region at the dimer interface that appears to affect the
      selectivity for the primer unit. Acetyl-CoA is bound in a 20 A-long channel,
      which placed the acetyl group against the catalytic triad. Analysis of the primer
      unit binding site in ZhuH suggests that it can accommodate acyl chains that are
      two to four carbons long. Selectivity and primer unit size appear to involve the
      side chains of three residues on the loops close to the dimer interface that
      constitute the bottom of the substrate binding pocket.

PMID- 12429098
TI  - Structural studies of Salmonella typhimurium ArnB (PmrH) aminotransferase: a 4
      amino-4-deoxy-L-arabinose lipopolysaccharide-modifying enzyme.
AB  - Lipid A modification with 4-amino-4-deoxy-L-arabinose confers on certain
      pathogenic bacteria, such as Salmonella, resistance to cationic antimicrobial
      peptides, including those derived from the innate immune system. ArnB catalysis
      of amino group transfer from glutamic acid to the 4"-position of a UDP-linked
      ketopyranose molecule to form UDP-4-amino-4-deoxy-L-arabinose represents a key
      step in the lipid A modification pathway. Structural and functional studies of
      the ArnB aminotransferase were undertaken by combining X-ray crystallography with
      biochemical analyses. High-resolution crystal structures were solved for two
      native forms and one covalently inhibited form of S. typhimurium ArnB. These
      structures permitted identification of key residues involved in substrate binding
      and catalysis, including a rarely observed nonprolyl cis peptide bond in the
      active site.

PMID- 12429099
TI  - Structural and biochemical analysis of the Obg GTP binding protein.
AB  - The Obg nucleotide binding protein family has been implicated in stress response,
      chromosome partitioning, replication initiation, mycelium development, and
      sporulation. Obg proteins are among a large group of GTP binding proteins
      conserved from bacteria to man. Members of the family contain two equally and
      highly conserved domains, a C-terminal GTP binding domain and an N-terminal
      glycine-rich domain. Structural analysis of Bacillus subtilis Obg revealed
      respective domain architectures and how they are coupled through the putative
      switch elements of the C-terminal GTPase domain in apo and nucleotide-bound
      configurations. Biochemical analysis of bacterial and human Obg proteins combined
      with the structural observation of the ppGpp nucleotide within the Obg active
      sight suggest a potential role for ppGpp modulation of Obg function in B.
      subtilis.

PMID- 12429100
TI  - Crystal structure of E. coli YhbY: a representative of a novel class of RNA
      binding proteins.
AB  - E. coli YhbY belongs to a conserved family of hypothetical proteins represented
      in eubacteria, archaea, and plants (Pfam code UPF0044). Three maize proteins
      harboring UPF0044-like domains are required for chloroplast group II intron
      splicing, and bioinformatic data suggest a role for prokaryotic UPF0044 members
      in translation. The crystal structure of YhbY has been determined. YhbY has a
      fold similar to that of the C-terminal domain of translation initiation factor 3
      (IF3C), which binds to 16S rRNA in the 30S ribosome. Modeling studies indicate
      that the same surface is highly basic in all members of UPF0044, suggesting a
      conserved RNA binding surface. Taken together, the evidence suggests that members
      of UPF0044 constitute a previously unrecognized class of RNA binding domain.

PMID- 12429101
TI  - Aggressive behavior while driving as predictor of self-reported car crashes.
AB  - PROBLEM: In Greece, there is a lack of scientific evidence on the relationship
      between aggressive behavior while driving and young drivers' involvement in car
      crashes; this study examined this potential relationship. METHODS: The randomly
      selected samples of 356 young drivers (18-24 years old) were interviewed through
      a questionnaire of self-reported car crash involvement, which mainly focused on
      their behavior on the road and the number of car crashes in which they had been
      involved. RESULTS: The statistical methods used were principal components
      analysis (PCA) and multiple regression analysis. Two factors relevant to
      aggressive driving emerged: (a) driving violations and (b) irritability while
      driving. The multivariate model suggested that driving just for fun (joyriding)
      and irritability were predictors of young drivers' involvement in car crashes. It
      was found that younger age was negatively associated with young drivers'
      involvement in car crashes. IMPACT ON GOVERNMENT AND INDUSTRY: The findings of
      this study can contribute in the formation of public policies aiming to prevent
      young drivers' car crashes. These findings can also be the starting point of some
      health promotion interventions trying to reduce car crashes and casualties on the
      road. Finally, the insurance companies may be interested in applying these
      findings into their field of interest.

PMID- 12429102
TI  - An analysis of motorcycle injury and vehicle damage severity using ordered probit
      models.
AB  - PROBLEM: Motorcycles constitute about 19% of all motorized vehicles in Singapore
      and are generally overrepresented in traffic accidents, accounting for 40% of
      total fatalities. METHOD: In this paper, an ordered probit model is used to
      examine factors that affect the injury severity of motorcycle accidents and the
      severity of damage to the vehicle for those crashes. Nine years of motorcycle
      accident data were obtained for Singapore through police reports. These data
      included categorical assessments of the severity of accidents based on three
      levels. Damage severity to the vehicle was also assessed and categorized into
      four levels. Categorical data of this type are best analyzed using ordered probit
      models because they require no assumptions regarding the ordinality of the
      dependent variable, which in this case is the severity score. Various models are
      examined to determine what factors are related to increased injury and damage
      severity of motorcycle accidents. RESULTS: Factors found to lead to increases in
      the probability of severe injuries include the motorcyclist having non
      Singaporean nationality, increased engine capacity, headlight not turned on
      during daytime, collisions with pedestrians and stationary objects, driving
      during early morning hours, having a pillion passenger, and when the motorcyclist
      is determined to be at fault for the accident. Factors leading to increased
      probability of vehicle damage include some similar factors but also show some
      differences, such as less damage associated with pedestrian collisions and with
      female drivers. In addition, it was also found that both injury severity and
      vehicle damage severity levels are decreasing over time.

PMID- 12429103
TI  - Changes in logging injury rates associated with use of feller-bunchers in West
      Virginia.
AB  - PROBLEM: It is well documented that logging is one of the most dangerous
      occupations and industries in which to work, and trees fellers are at greatest
      risk of injury. The objective of this study was to determine whether West
      Virginia (WV) logging companies experienced a reduction in injuries after
      beginning to use feller-bunchers (tree cutting machines, which replace some of
      the work done with a chainsaw) during harvesting operations. METHODS: WV workers
      compensation claims and employment data from 1995 to 2000 were used to calculate
      injury rates. Injury trends in the rest of the WV logging industry, not using
      feller-bunchers, were also assessed. RESULTS: For 11 companies, the pre-feller
      buncher injury claims rate was 19.4 per 100 workers and the post-feller-buncher
      rate was 5.2 per 100 workers. This was a significant difference, with an adjusted
      rate ratio of 2.8 (95% CI: 1.8-4.5) of pre to post claims. Struck by injuries
      also showed significant decline, with the pre-feller-buncher injury rate being
      3.8 (95% CI: 1.8-8.2) times as great as post-feller-buncher rate. During the time
      of the study, the injury rate rose in the rest of the WV logging industry. The
      average cost of a workers compensation claim in the WV logging industry during
      the time of the study was approximately $10,400. IMPACT ON INDUSTRY: As
      mechanization of logging tasks becomes more widespread, the WV logging industry
      as a whole may see substantial injury declines and a reduction in the total cost
      of injury claims. Struck by injuries, the most common and potentially fatal of
      logging injury types, appear to be particularly affected. However, logging
      operations in areas of very steep terrain where it is not possible to use these
      machines may need to rely on strategies other than feller-bunchers to reduce
      injuries.

PMID- 12429104
TI  - An evaluation of the implementation of ignition interlock in California.
AB  - PROBLEM: This study evaluates the degree to which courts have implemented
      California's ignition interlock program, and surveys judges and district/city
      attorneys to identify barriers to implementing a successful interlock program.
      METHOD: There are three parts to the evaluation. In the first, a sample of
      drivers arrested for driving on a driving under the influence (DUI)-suspended
      driver license was examined to calculate the rate at which courts order
      interlocks for DUI-suspended drivers, as required by California law. The second
      part of the study used Department of Motor Vehicle (DMV) records to count the
      statewide rate of court-ignition interlock device (IID) orders across time and
      jurisdictions. The final part surveyed judges, district/city attorneys, and
      offenders installing an interlock to obtain information about their use of
      interlock, barriers to implementing an interlock program, and the effectiveness
      of the devices in preventing drinking and driving. RESULTS: It was found that
      conviction rates for driving while suspended are low; that judges order
      interlocks for only a fraction of the convicted driving-while-suspended (DWS)
      offenders who should receive such an order; and that the majority of offenders
      who are ordered by the court to install an ignition interlock in their vehicle do
      not do so. IMPACT ON INDUSTRY: Any successful interlock program will need to find
      a way to balance the inability of many offenders to pay for the devices, with the
      need for the industry to remain economically viable.

PMID- 12429105
TI  - Fatality risk assessment and modeling of drivers responsibility for causing
      traffic accidents in Dubai.
AB  - INTRODUCTION: This paper examines crash and safety statistics from the Emirate of
      Dubai in an attempt to identify factors responsible for making this population at
      greater risk of crashes compared to other countries. PROBLEM: In developing
      countries such as the United Arab Emirates (U.A.E.), motor-vehicle-related
      mortalities frequently exceed those of the industrialized nations of North
      America and Europe. METHOD: Fatality and injury data used in the analysis mainly
      come from Dubai Emirate police reports and from other relevant international
      sources. Groups of the population are identified according to associated risk and
      exposure factors. Influence and strength of the most common risk factors are
      quantified using relative risk, the Lorenz curve, and the Gini index. Further
      analysis employed logit modeling, and possible predictors available in Dubai
      police reports, to estimate probability and odds ratios associated with drivers
      that are deemed responsible for causing traffic accidents. RESULTS: Traffic
      fatality risk was found to be higher in Dubai, compared to some developed
      nations, and to vary considerably between different classes of road users and
      groups of the resident population. The likelihood of a driver causing an accident
      is considerably higher for those driving goods vehicles, but it is also
      associated with other factors. IMPACT: Results provide epidemiological inferences
      about traffic mortality and morbidity, and suggest priorities and appropriate
      measures for intervention, targeting resident population.

PMID- 12429106
TI  - A model of fishing vessel accident probability.
AB  - PROBLEM: Commercial fishing is one of the least safe occupations. METHOD: The
      researchers develop a fishing vessel accident probability model for fishing areas
      off the northeastern United States using logit regression and daily data from
      1981 to 1993. RESULTS: The results indicate that fishing vessel accident
      probability declined over the study period. Higher wind speed is associated with
      greater accident probability. Medium-size vessels have the highest accident
      probability, while small vessels have the lowest. Within the study region,
      accident probability is lower in the southwestern section than in the
      northeastern section. Accidents are likely to occur closer to shore than
      offshore. Accident probability is lowest in spring. IMPACT ON INDUSTRY: The
      probability model is an important building block in development and quantitative
      assessment of management mechanisms related to safety in the commercial fishing
      industry.

PMID- 12429107
TI  - Occupational safety and health in Spain.
AB  - Occupational Health and Safety in Spain has improved considerably over the last
      decade, most likely due to a new concept where an overall concept of safety
      culture is defined. Important changes in industrial safety, hygiene, and
      psychosocial factors present an optimistic panorama for the future of Spain.
      Despite this general improvement, according to the European Convergence Program,
      Spanish statistics still offer far from good safety results. In fact, according
      to 1997 official statistics, Spain had the highest incidence rate for nonfatal
      occupational accidents of all European Union (EU) countries, and occupied third
      place for fatal accidents. This paper summarizes the organizational structure of
      the Spanish National System of Health & Safety at Work, its effective health and
      safety laws, and statistics on the Spanish work environment obtained from III
      Spanish National Survey on Work Conditions (1997). The researchers hope that the
      findings of this work will have an impact on Spanish industry that will
      subsequently bring about improvements in work conditions and develop assessment
      and intervention models in occupational health and safety, from a theoretical
      position integrating environmental, human, and organizational factors.

PMID- 12429109
TI  - Electrophysiology of mammalian Schwann cells.
AB  - Schwann cells are the satellite cell of the peripheral nervous system, and they
      surround axons and motor nerve terminals. The review summarises evidence for the
      ion channels expressed by mammalian Schwann cells, their molecular nature and
      known or speculated functions. In addition, the recent evidence for gap junctions
      and cytoplasmic diffusion pathways within the myelin and the functional
      consequences of a lower-resistance myelin sheath are discussed. The main types of
      ion channel expressed by Schwann cells are K(+) channels, Cl(-) channels, Na(+)
      channels and Ca(2+) channels. Each is represented by a variety of sub-types. The
      molecular and biophysical characteristics of the cation channels expressed by
      Schwann cells are closely similar or identical to those of channels expressed in
      peripheral axons and elsewhere. In addition, Schwann cells express P(2)X ligand
      gated ion channels. Possible in vivo roles for each ion channel type are
      discussed. Ion channel expression in culture could have a special function in
      driving or controlling cell proliferation and recent evidence indicates that some
      Ca(2+) channel and Kir channel expression in culture is dependent upon the
      presence of neurones and local electrical activity.

PMID- 12429110
TI  - Mechanical stress-induced apoptosis in the cardiovascular system.
AB  - All tissues in the body are subjected to physical forces originating either from
      tension, created by cells themselves, or from the environment. Particularly, the
      cardiovascular system is continuously subjected to haemodynamic forces created by
      blood flow and blood pressure. While biomechanical force at physiological levels
      is essential to develop and maintain organic structure and function, elevated
      mechanical stress may result in cell death leading to pathological conditions. In
      recent years, however, it has been widely recognized that cell death, namely
      apoptosis, is not just the response to an injury but a highly regulated and
      controlled process. Therefore, physical stimuli must be sensed by cells and
      transmitted through intracellular signal transduction pathways to the nucleus,
      resulting in cell apoptosis. Disturbances in the regulatory mechanisms of
      apoptosis often precede the development of a disease. Exploration of the
      molecular signalling mechanisms leading to mechanical stress-induced apoptosis in
      cardiovascular disorders revealed the crucial role of apoptosis in the
      pathogenesis of these diseases. For instance, heart failure, hypertension and
      atherosclerosis are believed to be related to sustained mechanical overloading or
      stress. In this review we summarize the recent data focusing on molecular
      mechanisms of mechanical stress-induced apoptosis and highlight the role of
      apoptosis in the development of cardiovascular disorders, which may lead to new
      therapeutic strategies for these diseases.

PMID- 12429111
TI  - Functional and phylogenetic analyses of a putative Drosophila melanogaster UDP
      glycosyltransferase gene.
AB  - Glucosidation plays a major role in the inactivation and excretion of a great
      variety of both endogenous and exogenous compounds. The recent determination of
      the complete genome sequence of Drosophila melanogaster has revealed the presence
      of over 30 putative UDP-glucosyltransferase (UGT) genes in this organism. We
      report here the molecular cloning and functional characterisation of one of these
      genes, named DmUgt37a1. The predicted protein comprises 525 amino acids and has
      about 30% overall amino acid identity with vertebrate members of the UGT family.
      The phylogenetic relationships of DmUgt37a1 with other members of the UGT family
      from D. melanogaster are discussed. DmUgt37a1 was expressed in lepidopteran
      insect cells and the ability of the enzyme to conjugate 38 potential substrates
      belonging to diverse chemical groups was assessed using UDP-glucose as sugar
      donor. However, no activity was detected with any compound under the conditions
      used and thus, the substrate specificity of the enzyme remains unknown.

PMID- 12429112
TI  - Chemical composition of the attachment pad secretion of the locust Locusta
      migratoria.
AB  - This study is the first attempt to characterise the chemical composition of the
      secretion of the smooth pads of the locust Locusta migratoria and to relate this
      to the composition of the cuticle coverage of the pads and the wings. Gas
      chromatography and mass-spectrometry (GC-MS) were the principal techniques used
      for the characterization of these materials. Secretion droplets were visualised
      and quantified with the aid of diverse microscopic techniques. The chemical
      composition of prints is shown to differ from the cuticle coverage, in
      particular, with respect to the fatty acid distribution: in the secretion,
      saturated and unsaturated fatty acids with chain lengths between C(16) and C(20)
      in both the free form and as glycerides predominate, whereas cuticle coverage
      contains waxes of long-chained fatty-acids bound to long-chain primary alcohols.
      The second important difference is the significant amount of glucose and other
      saccharides found in methanolyzates of the pad fluid. A considerable amount of
      the amino acids (up to 53%) was detected in the non-volatile portion of the
      fluid. Data obtained from the shock-freezing, carbon-platinum coating and replica
      preparation show that the secretory droplets contain nano-droplets on their
      surfaces. The results lead us to suggest that the pad secretion is an emulsion
      consisting of lipidic nano-droplets dispersed in an aqueous liquid. According to
      the chemical composition of the secretion, a high-viscosity of the fluid may be
      suggested. Presumably, the fluid is a kind of a coupling agent, promoting and
      strengthening adhesion between otherwise incompatible materials by providing the
      proximity of contact for intermolecular forces.

PMID- 12429113
TI  - Molecular cloning of lysozyme-encoding cDNAs expressed in the salivary gland of a
      wood-feeding termite, Reticulitermes speratus.
AB  - Two kinds of PCR-product cDNAs that encode premature lysozyme peptides (Rs-Lys1
      and Rs-Lys2) were cloned from workers of a Japanese damp-wood termite,
      Reticulitermes speratus. The Rs-Lys1 and Rs-Lys2 cDNAs encoded deduced sequences
      of 170 and 164 amino acids, respectively. Alignment of these sequences with those
      of other insect lysozymes showed that the cDNAs encode lysozyme homologues with
      putative signal peptides, insertions eight amino acids long, and a relatively
      long C-terminus (13-17 amino acids). A maximum likelihood tree, constructed using
      the cDNA sequences, indicated that the termite lysozymes are related to those of
      mosquitoes and lepidopterans. Southern-blotting analysis identified single copies
      of these lysozyme genes in the termite. Reverse transcript (RT)-PCR and in situ
      hybridization experiments showed that Rs-Lys1 and Rs-Lys2 are expressed in the
      salivary glands of worker termites. Here, we discuss the possible digestive
      function of these lysozymes.

PMID- 12429114
TI  - Ca(2+) as second messenger in PTTH-stimulated prothoracic glands of the silkworm,
      Bombyx mori.
AB  - Measurements of Ca(2+) influx and [Ca(2+)](i) changes in Fura-2/AM-loaded
      prothoracic glands (PGs) of the silkworm, Bombyx mori, were used to identify
      Ca(2+) as the actual second messenger of the prothoracicotropic hormone (PTTH) of
      this insect. Dose-dependent increases of [Ca(2+)](i) in PG cells were recorded in
      the presence of recombinant PTTH (rPTTH) within 5 minutes. The rPTTH-mediated
      increases of [Ca(2+)](i) levels were dependent on extracellular Ca(2+). They were
      not blocked by the dihydropyridine derivative, nitrendipine, an antagonist of
      high-voltage-activated (HVA) Ca(2+) channels, and by bepridil, an antagonist of
      low-voltage-activated (LVA) Ca(2+) channels. The trivalent cation La(3+), a non
      specific blocker of plasma membrane Ca(2+) channels, eliminated the rPTTH
      stimulated increase of [Ca(2+)](i) levels in PG cells and so did amiloride, an
      inhibitor of T-type Ca(2+) channels. Incubation of PG cells with thapsigargin
      resulted in an increase of [Ca(2+)](i) levels, which was also dependent on
      extracellular Ca(2+) and was quenched by amiloride, suggesting the existence of
      store-operated plasma membrane Ca(2+) channels, which can also be inhibited by
      amiloride. Thapsigargin and rPTTH did not operate independently in stimulating
      increases of [Ca(2+)](i) levels and one agent's mediated increase of [Ca(2+)](i)
      was eliminated in the presence of the other. TMB-8, an inhibitor of intracellular
      Ca(2+) release from inositol 1,4,5 trisphosphate (IP(3))-sensitive Ca(2+) stores,
      blocked the rPTTH-stimulated increases of [Ca(2+)](i) levels, suggesting an
      involvement of IP(3) in the initiation of the rPTTH signaling cascade, whereas
      ryanodine did not influence the rPTTH-stimulated increases of [Ca(2+)](i) levels.
      The combined results indicate the presence of a cross-talk mechanism between the
      [Ca(2+)](i) levels, filling state of IP(3)-sensitive intracellular Ca(2+) stores
      and the PTTH-receptor's-mediated Ca(2+) influx.

PMID- 12429115
TI  - Molecular characterization of Lma-p54, a new epicuticular surface protein in the
      cockroach Leucophaea maderae (Dictyoptera, oxyhaloinae).
AB  - The epicuticular surface protein Lma-p54 is imbedded in the "cuticular waxes"
      which cover the abdominal surface of the adult Leucophaea maderae. Natural Lma
      p54 was purified and the complete cDNA sequence was determined by RT-PCR using
      primers based on Edman degradation fragments. Northern blot and in situ
      hybridization analyses showed that Lma-p54 was expressed in the adult abdominal
      epidermis and in the chemical sense organs of both sexes. Sequence alignment
      indicates that Lma-p54 is closely related to aspartic proteases (EC 3.4.23).
      However, there are critical amino acid substitutions at the level of the active
      site and, since no proteolytic activity was detected in the abdominal secretion,
      the protein is likely inactive. As an inactive aspartic protease, Lma-p54 is
      related to pregnancy-associated glycoproteins (PAGs) which still present a
      peptide-binding ability. According to recent experiments using whole tergal
      protein secretions, a role in intraspecific contact recognition was proposed for
      this surface protein.

PMID- 12429116
TI  - The orphan nuclear receptors BmE75A and BmE75C of the silkmoth Bombyx mori:
      hornmonal control and ovarian expression.
AB  - The steroid hormone 20-hydroxyecdysone (20E) plays a key role in the stimulation
      of ovarian follicle development in the silkmoth, Bombyx mori. To understand
      better the mechanism by which 20E regulates silkmoth oogenesis, Bombyx homologs
      of the ecdysone-inducible orphan nuclear receptor E75 (BmE75) were cloned and
      their expression was analyzed in developing ovaries and staged follicles during
      metamorphosis. Of the two BmE75 isoforms isolated, only the A-isoform (BmE75A)
      has been identified previously in lepidopteran insects. BmE75C, on the other
      hand, shows significant sequence homology in its N-terminus to the Drosophila
      E75C isoform. Northern blot analysis shows unique expression patterns for each
      isoform mRNA during ovarian development. While the A-isoform seems to be mainly
      implicated in the earlier stages of the ecdysone response during
      previtellogenesis and vitellogenesis, expression of the C-isoform becomes
      strongly induced in an ecdysteroid-independent fashion at the transition from
      vitellogenesis to choriogenesis. Our data indicate a complex regulation of the
      expression of the BmE75 gene during oogenesis and postulate a new role for the
      BmE75C receptor at the end of vitellogenesis and the beginning of choriogenesis.

PMID- 12429117
TI  - Fusion proteins containing neuropeptides as novel insect contol agents: snowdrop
      lectin delivers fused allatostatin to insect haemolymph following oral ingestion.
AB  - The mannose-binding lectin from snowdrop (Galanthus nivalis agglutinin: GNA),
      when fed to insects, binds to the gut epithelium and passes into the haemolymph.
      The potential for GNA to act as a carrier protein to deliver an insect
      neuropeptide, Manduca sexta allatostatin (Manse-AS), to the haemolymph of
      lepidopteran larvae has been examined by expressing a GNA/Manse-AS fusion protein
      (FP) in Escherichia coli, and feeding purified FP to larvae of the tomato moth
      Lacanobia oleracea. FP, administered at 1.5 or 0.5% of dietary proteins, was
      found to strongly inhibit feeding and prevent growth of fifth stadium larvae,
      whereas neither GNA nor Manse-AS alone, nor a mixture of GNA and Manse-AS in
      control treatments, had deleterious effects at similar levels. Elevated levels of
      material reacting with anti-Manse-AS antibodies were detected in the haemolymph
      of insects fed diets containing FP, suggesting that transport of the peptide had
      occurred. Evidence for the delivery of intact FP to the haemolymph was provided
      by the co-elution of Manse-AS-like immunoreactivity with standard FP after size
      exclusion chromatography of haemolymph from FP-fed larvae. GNA/Manse-AS and
      similar fusion proteins offer a novel and effective strategy for delivering
      insect neuropeptides by oral administration, which could be used in conjunction
      with expression in transgenic plants to give crop protection in the field.

PMID- 12429118
TI  - Proventriculus-specific cDNAs characterized from the tsetse, Glossina morsitans
      morsitans.
AB  - Peritrophic matrix (peritrophic membrane or PM) is an important structure in the
      gut of most insects at some stage in their development. It is composed of chitin,
      proteins and proteoglycans. Multiple roles for the PM ranging from partitioning
      of digestive enzymes and food to protection of gut epithelial cells from viral
      and parasitic invasion have been proposed. While most adult members of Diptera
      have a Type I PM synthesized in response to a blood meal, the medically and
      agriculturally important vector insect, tsetse has a sleeve-like Type II PM which
      is constitutively synthesized by cells in the proventriculus (cardia). Using a
      differential hybridization approach, we have identified three abundant cDNAs from
      a proventriculus cDNA library of GLOSSINA MORSITANS MORSITANS: GmPro1, GmPro2 and
      GmPro3. DNA sequence analysis indicates that GmPro1 and GmPro2 share similarities
      with the peritrophin-15 family of larval PM proteins, while GmPro3 is a member of
      the serine protease family. Northern analysis indicates that transcripts for all
      three cDNAs are preferentially expressed in the proventriculus tissue. The
      expression profile of these genes in response to the presence of trypanosome
      indicates that transcription of GmPro1 is increased in the presence of parasites
      (immune sensitive), while the other two are not affected. Western analysis using
      antibodies developed against the recombinant GmPro2 shows its primary
      localization in the gut to be within the peritrophic matrix structure. We discuss
      the molecular characteristics of these proventriculus specific cDNAs and their
      products as well as their potential role for vector control studies.

PMID- 12429119
TI  - Parasitoid-host endocrine relations: self-reliance or co-optation?
AB  - High titers of juvenile hormone (JH) maintain developmental arrest in Manduca
      sexta larvae parasitized by Cotesia congregata. Parasitized hosts exhibit up to
      9.5 times greater amounts of total hemolymph JH (from 0.6+/-0.09 to 2.51+/
      0.43ng/ml) compared to non-parasitized controls. Elevated titers are observed
      throughout the fifth instar, even beyond egression of the parasitoids on day 5.
      GC-MS analysis revealed that in hemolymph of unparasitized control larvae, JH I
      is the major homolog and levels of JH III are negligible; in parasitized
      individuals the amounts of JH I, II, and III rise, and JH III predominates. Neck
      ligation ensured separation of M. sexta's corpora allata from the posterior
      section, which contained most of the parasitoids in the infected insects. When
      the posterior region was sampled, JHs were not detected in the non-parasitzed
      larvae, but in those parasitized, JH III was found (1.98+/-0.29ng/ml, 24 h post
      ligation). JH III was the only homolog produced and secreted by the parasitoid in
      in vitro culture. This is the first report stating that a parasitoid secretes JH
      III and may contribute, at least in part, to the circulating titer in the host
      hemocoel, concurrently promoting host production of JH I and II.

PMID- 12429120
TI  - A digestive beta-glucosidase from the salivary glands of the termite, Neotermes
      koshunensis (Shiraki): distribution, characterization and isolation of its
      precursor cDNA by 5'- and 3'-RACE amplifications with degenerate primers.
AB  - beta-Glucosidase activity [EC 3.2.1.21] was measured in the salivary glands and
      the gut of wood-eating termite, Neotermes koshunensis (Shiraki). 75% of the
      activity was detected in the salivary glands, whereas 15% of the activity was
      present in the hindgut, where numerous symbiotic flagellates reside. The salivary
      beta-glucosidase was partially purified by ion-exchange and gel filtration
      chromatography. The molecular weight of the salivary beta-glucosidase was 60 kDa,
      and the K(m) value on cellobiose was 2.5 mM. Its optimal pH was 5.6 and the
      activity was stable from 20 degrees C up to 45 degrees C. In addition to
      cellobiose, p-nitrophenyl-beta-D-fucopyranoside and laminaribiose were
      efficiently hydrolyzed by the salivary beta-glucosidase. Degenerate PCR using
      primers designed from N-terminal amino acid sequences of the salivary beta
      glucosidase resulted in a cDNA fragment of 1730 bp, encoding 498 amino acids and
      with sequence similarity to glycosyl hydrolase family 1. Reverse-transcription
      (RT)-PCR showed that this beta-glucosidase is produced only in the salivary
      glands.

PMID- 12429121
TI  - Salivary gland hyaluronidase in various species of phlebotomine sand flies
      (Diptera: psychodidae).
AB  - Hyaluronidase activity was detected and partially characterized in salivary gland
      extracts of females of six sand fly species. In Phlebotomus papatasi and
      Lutzomyia longipalpis the enzyme was active over a broad pH range; the pH optimum
      was 5.0. Besides high cleaving activity towards hyaluronic acid, it hydrolyzed
      chondroitin sulfates A and C. Hyaluronidases of various sand fly species differed
      in structure and sensitivity to reducing conditions. In the subgenera Phlebotomus
      (P. papatasi and P. duboscqi) and Adlerius (P. halepensis) the predominant active
      form of the enzyme was monomeric with the same apparent molecular weight under
      nonreducing and reducing conditions (around 65 kDa for P. papatasi and P.
      duboscqi and 110 kDa for P. halepensis). In P. sergenti the enzyme occurred as a
      putative homodimer but remained active under reducing conditions when separated
      into 60 kDa subunits. In L. longipalpis and P. perniciosus the activity was
      detectable under non-reducing conditions only. In P. duboscqi, low enzyme
      activity was found also in males. Salivary gland hyaluronidases of sand flies
      share characteristics with endo-N-acetyl-hexosaminidases of mammalian sperm cells
      and corresponding venom enzymes of Hymenoptera. Hypothetically, they facilitate
      blood meal acquisition but also may modulate immune reactions of the host and
      promote pathogen transmission.

PMID- 12429123
TI  - Identification of SNARE and cell trafficking regulatory proteins in the salivary
      glands of the lone star tick, Amblyomma americanum (L.).
AB  - Prostaglandin E(2) (PGE(2)) stimulates secretion of tick salivary gland proteins
      via a phosphoinositide signaling pathway and mobilization of intracellular Ca(2+)
      (). Highly conserved intracellular SNARE (soluble NSF attachment protein
      receptors) complex proteins are associated with the mechanism of protein
      secretion in vertebrate and invertebrate neuronal and non-neuronal cells.
      Proteins in the salivary glands of partially fed female lone star ticks cross
      react individually with antibodies to synaptobrevin-2 (vesicle (v)-SNARE),
      syntaxin-1A, syntaxin-2 and SNAP-25 (target (t)-SNAREs), cytosolic alpha/beta
      SNAP and NSF (N-ethylmaleimide-sensitive fusion protein), Ca(2+) sensitive
      synaptotagmin, vesicle associated synaptophysin, and regulatory cell trafficking
      GTPases Rab3A and nSec1. V-SNARE and t-SNARE proteins form an SDS-resistant,
      boiling sensitive core complex in the salivary glands. Antibodies to SNARE
      complex proteins inhibit PGE(2)-stimulated secretion of anticoagulant protein in
      permeabilized tick salivary glands. We conclude that SNARE and cell trafficking
      regulatory proteins are present and functioning in the process of PGE(2)
      stimulated Ca(2+) regulated protein secretion in tick salivary glands.

PMID- 12429122
TI  - Structured RNA upstream of insect cap distal iron responsive elements enhances
      iron regulatory protein-mediated control of translation.
AB  - Iron regulatory protein (IRP) blocks ribosomal assembly by binding to an iron
      responsive element (IRE) located proximal (<60 nts) to the mRNA cap, thereby
      repressing translation. Constructs with IREs located 60-100 nts from the cap
      permit ribosomal assembly but the ribosomes pause at IRE/IRP complexes resulting
      in partial repression of translation. However, insect ferritin mRNAs have cap
      distal IREs located 90-156 nts from the cap. Because iron can be toxic, it seems
      unlikely that insects would be unable to fully regulate ferritin synthesis at the
      level of translation. Calpodes ferritin consists of two subunits, S and G. In
      vitro translation of Calpodes ferritin and IRP1 from fat body mRNA yields only G
      subunits suggesting that IRP1 more efficiently represses translation of the S
      subunit than the G. When repression is removed by the addition of IRE competitor
      RNA, the synthesis of both subunits is greatly increased. S and G ferritin mRNAs
      have identical IREs in similar far cap-distal positions. While both ferritin
      mRNAs are predicted to have stem-loops between the IRE and the RNA cap, in
      general insect S mRNAs have more cap-proximal RNA structure than G mRNAs.
      Therefore, we examined the effect of upstream secondary structure on ribosomal
      assembly onto S ferritin mRNA constructs using sucrose gradient analysis of
      translation initiation complexes. We found no evidence for ribosomal assembly on
      wild type Calpodes S ferritin mRNA in the presence of IRP1 while constructs
      lacking the wild type secondary structure showed ribosomal pausing. Constructs
      with wild type secondary structure preceded by an unstructured upstream leader
      assemble ribosomes in the presence or absence of IRP1. Sequence and RNA folding
      analyses of other insect ferritins with cap-distal IREs failed to identify any
      common sequences or IRE-like structures that might bind to IRP1 with lower
      affinity or to another RNA binding protein. We propose that stem-loops upstream
      from the IRE act like pleats that shorten the effective distance between the IRE
      and cap and allow full translational repression by IRP1. In this way some cap
      distal IREs may function like cap-proximal ones.

PMID- 12429124
TI  - Presence of chitinase and beta-N-acetylglucosaminidase in the Aedes aegypti. a
      chitinolytic system involving peritrophic matrix formation and degradation.
AB  - Measurement of the hydrolysis of specific fluorogenic substrates by
      spectrophotometry as well as the substrate activity-SDS-PAGE gel analysis of the
      chitinolytic activity in Aedes aegypti guts showed that both chitinase and beta-N
      acetylglucosaminidase are present and physiologically active. Both enzymes were
      present even in guts from unfed insects, but the activities increased rapidly
      after feeding on blood or an artificial protein-free diet. Chitinase activity was
      predominantly of the 'endo'-type, reaching its maximum activity at 36 h and then
      declining to very low levels after the degradation of the peritrophic matrix
      (PM). Chitinase assay in gels after SDS-PAGE was a very sensitive method that
      allowed us to detect two chitinases with distinct molecular weights in the
      mosquito gut. Hydrolysis of a chitinase-specific substrate by chitinolytic
      activities in the mosquito guts was inhibited by allosamidin, a potent chitinase
      inhibitor. Allosamidin treatment led to the formation of an atypical thick PM,
      while the addition of exogenous chitinase completely blocked its formation. This
      chitinolytic system appears to operate both on the formation and degradation of
      the PM. Since the PM is involved in pathogen invasion, these results are
      important in facilitating a search for mechanisms that can block pathogen
      development in the mosquito vector.

PMID- 12429125
TI  - Biochemical and molecular characterizaton of house cricket (Acheta domesticus,
      Orthoptera: Gryllidae) Delta9 desaturase.
AB  - Studies of insect fatty acyl-CoA desaturases have heretofore concentrated on the
      Diptera and Lepidoptera. We report here the isolation and characterization of a
      fatty acyl-CoA Delta9 desaturase from the house cricket, Acheta domesticus
      (Orthoptera). Two desaturase cDNAs were isolated from a library, one of which
      contained two intron sequences. The clones were identical in their respective
      coding regions, but had divergent 5' and 3' untranslated regions. The cDNAs
      encode a 359 amino acid desaturase enzyme that could rescue a fatty acyl-CoA
      desaturase auxotrophic phenotype when expressed in yeast. Biochemical analysis of
      lipids from transformed yeast cells confirmed that the enzyme is a Delta9
      desaturase with activity on both palmitic and stearic acid substrates. Southern
      blotting indicated multiple Delta9 desaturase genes within the genome. A single
      message that was up-regulated in fed insects vs. starved insects was observed on
      northern blots, indicating transcriptional regulation in response to diet.

PMID- 12429126
TI  - Urea and amide-based inhibitors of the juvenile hormone epoxide hydrolase of the
      tobacco hornworm (Manduca sexta: Sphingidae).
AB  - A new class of inhibitors of juvenile hormone epoxide hydrolase (JHEH) of Manduca
      sexta and further in vitro characterization of the enzyme are reported. The
      compounds are based on urea and amide pharmacophores that were previously
      demonstrated as effective inhibitors of mammalian soluble and microsomal epoxide
      hydrolases. The best inhibitors against JHEH activity so far within this class
      are N-[(Z)-9-octadecenyl]-N'-propylurea and N-hexadecyl-N'-propylurea, which
      inhibited hydrolysis of a surrogate substrate (t-DPPO) with an IC(50) around 90
      nM. The importance of substitution number and type was investigated and results
      indicated that N, N'-disubstitution with asymmetric alkyl groups was favored.
      Potencies of pharmacophores decreased as follows:
      amide>urea>carbamate>carbodiimide>thiourea and thiocarbamate for N, N'
      disubstituted compounds with symmetric substituents, and urea>amide>carbamate for
      compounds with asymmetric N, N'-substituents. JHEH hydrolyzes t-DPPO with a K(m)
      of 65.6 microM and a V(max) of 59 nmol min(-1) mg(-1) and has a substantially
      lower K(m) of 3.6 microM and higher V(max) of 322 nmol min(-1) mg(-1) for JH III.
      Although none of these compounds were potent inhibitors of hydrolysis of JH III
      by JHEH, they are the first leads toward inhibitors of JHEH that are not
      potentially subject to metabolism through epoxide degradation.

PMID- 12429127
TI  - Use of subtracted libraries and macroarray to isolate developmentally specific
      genes from the mosquito, Aedes aegypti.
AB  - Subtracted cDNA libraries were screened with cDNA macroarrays to isolate larval
      and pupal stage-specific genes from Aedes aegypti. Of 103 partial cDNAs sequenced
      from the 4th instar subtracted cDNA library, 62 have counterpart genes in other
      organisms while 41 of them have no significant similarity to any known genes.
      Sequences of 116 partial cDNA clones from the pupal subtracted library revealed
      that 57 belong to unknown genes and 59 have homologous genes in other organisms.
      Results of cDNA macroarrays showed that 42-50% of randomly selected genes in the
      subtracted cDNA libraries were differentially expressed. Of the unknown genes,
      transcripts of 15-19% of the genes were detected in larval or pupal stages,
      respectively. The results indicate that a subtracted cDNA library in combination
      with a cDNA macroarray can be used effectively to identify genes expressed in a
      particular stage.

PMID- 12429128
TI  - Purification of pimplin, a paralytic heterodimeric polypeptide from venom of the
      parasitoid wasp Pimpla hypochondriaca, and cloning of the cDNA encoding one of
      the subunits.
AB  - We have previously detected a paralytic factor in gel filtration-separated venom
      from the endoparasitoid wasp Pimpla hypochondriaca which is active against the
      fly Musca domestica. Now we have further purified this factor, which we have
      called pimplin, by reverse phase chromatography, and established using SDS-PAGE
      that it has a molecular mass of approximately 22 kDa. A 40 ng dose of pimplin
      administered to adult M. domestica by intrahaemocoelic injection was sufficient
      to kill all flies tested. Treatment of pimplin with beta-mercaptoethanol prior to
      SDS-PAGE analysis resulted in the appearance of two polypeptides of approximately
      15 and 6 kDa, indicating that pimplin is a heterodimer whose polypeptides are
      linked through a disulphide bond. Subunit masses of 10.544 and 6.318 kDa were
      determined using MALDI-TOF analysis indicating that the larger subunit migrates
      anomalously in SDS-PAGE. Using an oligonucleotide probe designed from N-terminal
      sequence obtained for the 15 kDa polypeptide, we have isolated a cDNA (pim1)
      encoding this larger pimplin subunit. The N-terminal amino acid sequence of pim1
      occurred 28 residues beyond a predicted signal peptide cleavage site, indicating
      that pim1 is synthesised as a pre-propolypeptide which is secreted and
      proteolytically cleaved to yield the mature polypeptide stored in the venom sac.
      Beginning at the fourth residue of the mature pim1 venom polypeptide is a stretch
      of 46 residues consisting of alternating prolines, the significance of which is
      discussed in terms of possible host processing.

PMID- 12429129
TI  - Cloning of putative odorant-degrading enzyme and integumental esterase cDNAs from
      the wild silkmoth, Antheraea polyphemus.
AB  - Odorant-degrading enzymes have been postulated to participate in the fast
      deactivation of insect pheromones. These proteins are expressed specifically in
      the sensillar lymph of insect antennae in such low amounts that, hitherto,
      isolation and protein-based cDNA cloning has not been possible. Using degenerate
      primers based on conserved amino acid sequences of insect carboxylesterases and
      juvenile hormone esterases, we were able to amplify partial cDNA fragments, which
      were then used for the design of gene-specific primers for RACE. This
      bioinformatics approach led us to the cloning of cDNAs, encoding a putative
      odorant-degrading enzyme (Apol-ODE) and a putative integumental esterase (Apol
      IE) from the wild silkmoth, Antheraea polyphemus. Apol-ODE had a predicted
      molecular mass of 59,994 Da, pI of 6.63, three potential N-glycosylation sites,
      and a putative catalytic site Ser characterized by the sequence Gly(195)-Glu-Ser
      Ala-Gly-Ala. Apol-IE gave calculated molecular mass of 61,694 Da, pI of 7.49, two
      potential N-glycosylation sites, and a putative active site with the sequence
      Gly(214)-Tyr-Ser-Ala-Gly. The transcript of Apol-ODE was detected by RT-PCR in
      male antennae and branches (sensillar tissues), but not in female antennae and
      other control tissues. Apol-IE was detected in male and female antennae as well
      as legs.

PMID- 12429130
TI  - Mutations in the Bemisia tabaci para sodium channel gene associated with
      resistance to a pyrethroid plus organophosphate mixture.
AB  - The voltage-gated sodium channel is the primary target site of pyrethroid
      insecticides. In some insects, super knockdown resistance (super-kdr) to
      pyrethroids is caused by point mutations in the linker fragment between
      transmembrane segments 4 and 5 of the para-type sodium channel protein domain II
      (IIS4-5). Here, we identify two mutations in the IIS4-5 linker of the para-type
      sodium channel of the whitefly, BEMISIA TABACI: methionine to valine at position
      918 (M918V) and leucine to isoleucine at position 925 (L925I). Although each
      mutation was isolated independently from strains >100-fold resistant to a
      pyrethroid (fenpropathrin) plus organophosphate (acephate) mixture, only L925I
      was associated with resistance in strains derived from the field in 2000 and
      2001. The L925I mutation occurred in all individuals from nine different field
      collections that survived exposure to a discriminating concentration of
      fenpropathrin plus acephate. Linkage analysis of hemizygous male progeny of
      unmated heterozygous F1 females (L925Ixwild-type) shows that the observed
      resistance is tightly linked to the voltage-gated sodium channel locus. The
      results provide a molecular tool for better understanding, monitoring and
      managing pyrethroid resistance in B. tabaci.

PMID- 12429131
TI  - The role of Ins(1,4,5)P(3) in signal transduction of the metabolic neuropeptide
      Mem-CC in the cetoniid beetle, Pachnoda sinuata.
AB  - We have investigated the role of inositol triphosphate, Ins(1,4,5)P(3), in the
      transduction of the hypertrehalosaemic and hyperprolinaemic signal of the
      endogenous neuropeptide Mem-CC in the cetoniid beetle Pachnoda sinuata. Flight
      and injection of Mem-CC into the haemocoel of the beetle induce an increase of
      Ins(1,4,5)P(3) levels in the fat body of the beetle. When Mem-CC is co-injected
      with U 73122, which is an inhibitor of phospholipase C, this effect is abolished.
      Mem-CC also elevates Ins(1,4,5)P(3) concentration in fat body pieces in vitro.
      The increase in Ins(1,4,5)P(3) levels is tissue-specific and does not occur in
      brain and flight muscles. Elevation of the Ins(1,4,5)P(3) levels upon injection
      of Mem-CC is time- and dose-dependent: the maximum response is reached after 3
      min and a dose of 10 pmol is needed. Compounds that mimic the action of cAMP (cpt
      cAMP, forskolin) do not influence the concentration of Ins(1,4,5)P(3), while
      those that stimulate G-proteins (aluminium fluoride and cholera toxin) cause an
      increase of Ins(1,4,5)P(3) levels. The application (in vivo and in vitro) of F
      Ins(1,4,5)P(3), an Ins(1,4,5)P(3) analogue that penetrates the cell membrane,
      causes a mobilisation of carbohydrate reserves via the activation of glycogen
      phosphorylase but does not stimulate proline synthesis. In addition, U 73122
      abolishes the hypertrehalosaemic but not the hyperprolinaemic effect of Mem-CC.
      The results suggest that the hypertrehalosaemic signal of Mem-CC is mediated via
      an increase of Ins(1,4,5)P(3) levels in the fat body of P. sinuata.

PMID- 12429132
TI  - Binding and storage of heme by vitellin from the cattle tick, Boophilus
      microplus.
AB  - We have previously shown (, Curr. Biol. 9, 703-706) that the cattle tick
      Boophilus microplus does not synthesize heme, relying solely on the recovery of
      the heme from the diet to make all its hemeproteins. Here we present evidence
      that Vitellin (VN(1)), the main tick yolk protein, is a reservoir of heme for
      embryo development. VN was isolated from eggs at different days throughout
      embryogenesis. Immediately after oviposition, Boophilus VN contains approximately
      one mol of heme/mol of protein. During embryo development about one third of egg
      VN is degraded. The remaining VN molecules bind part of the heme released. These
      results suggest that VN functions as a heme reservoir, binding any free heme that
      exceeds the amount needed for development. In vitro measurement of the binding of
      heme to VN showed that each VN molecule binds up to 31 heme molecules. The
      association of heme with VN strongly inhibits heme-induced lipid peroxidation,
      suggesting that binding of heme is an important antioxidant mechanism to protect
      embryo cells from oxidative damage. This mechanism allows this hematophagous
      arthropod to safely store heme obtained from a blood meal inside their eggs for
      future use. Taken together our data suggest that, besides its known roles, VN
      also plays additional functions as a heme deposit and an antioxidant protective
      molecule.

PMID- 12429133
TI  - A molt-associated chitinase cDNA from the spruce budworm, Choristoneura
      fumiferana.
AB  - Chitinase (CfChitinase) cDNA from the spruce budworm, Choristoneura fumiferana,
      was cloned using reverse transcription PCR and cDNA library screening. The
      CfChitinase cDNA was determined to be 2856 nucleotides long with the longest open
      reading frame made up of 1671 nucleotides that encoded a protein that was 557
      amino acid long with a predicted molecular mass of 62 kDa. The deduced amino acid
      sequence showed 76-79% identity with other lepidopteran chitinases. Northern
      blots revealed that transcripts of CfChitinase appeared prior to each molt and
      peaked on the day of ecdysis from the second instar to the pupal stage but
      disappeared immediately after the molt. No transcripts could be detected in the
      early first instar prior to the spinning of the hibernaculum or in the diapausing
      second instars or during the intermolt periods of the other instars. Western blot
      analysis revealed that the protein appeared 12 h prior to ecdysis and disappeared
      12 h after ecdysis from the sixth instar to pupal stage. The 20-hydroxyecdysone
      analog, tebufenozide (RH5992), induced expression of CfChitinase in the early
      stage of the sixth instar and caused a precocious and incomplete molt into an
      extra larval stage. During the sixth instar to the pupal molt, transcripts could
      be detected only in the epidermis and fat bodies, but not in the midgut. Western
      blots showed that the protein was present in the epidermis and midgut, but not in
      the fat bodies. The recombinant protein expressed in Autographa californica
      multicapsid nucleopolyhedrovirus (AcMNPV) showed high levels of chitinolytic
      activity with an optimal pH range 6-9. Glycosylation appeared to be necessary for
      the chitinolytic activity and secretion of the recombinant protein.

PMID- 12429134
TI  - The pathogenesis of osteoporosis in older women and men: a review.

PMID- 12429135
TI  - Sp1 is essential for estrogen receptor alpha gene transcription.
AB  - The exact molecular mechanisms regulating estrogen receptor (ER)alpha expression
      in breast tumors are unclear, but studies suggest that the regulation is at least
      partly transcriptional. We therefore undertook a detailed analysis of ERalpha
      promoter activity in a number of breast cancer cell lines. We find that the
      majority of ERalpha promoter activity lies within the first 245bp of the 5'
      flanking region of the gene. Three elements essential for full ERalpha promoter
      transcriptional activity were identified within the -245 to -192bp region in
      transient transactivation assays using linker-scanner mutation analysis. These
      three elements include two binding sites for the Sp1 family of transcription
      factors as well as a non-consensus E box. We show that both Sp1 and Sp3 bind to
      this region using electrophoretic mobility shift assays. Exogenous expression of
      Sp1 or Sp3 in Sp1/3-negative Drosophila Schneider SL2 cells results in
      transactivation of the -245 to +212bp fragment of the ERalpha promoter. These
      data demonstrate that transcription of ERalpha is dependent upon the expression
      of members of the Sp1 family.

PMID- 12429136
TI  - Cloning of two mRNA variants of brain aromatase cytochrome P450 in rainbow trout
      (Oncorhynchus mykiss Walbaum).
AB  - This work describes the molecular cloning of the cDNA encoding the rainbow trout
      (Oncorhynchus mykiss Walbaum) brain cytochrome P450arom by means of reverse
      transcriptase and polymerase chain reaction (RT-PCR) and 5'- and 3'-rapid
      amplification of cDNA ends (RACE) analyses. The results obtained demonstrate
      that, as in other teleost fishes, the trout genome contains, besides the gene
      previously identified in the ovary, a second CYP19 gene (CYP19B) expressed at
      high level in the brain. Moreover, two P450aromB mRNAs, forms I and II, were
      found to be transcribed in trout. Form I (1816 sequenced nt) contains an open
      reading frame (ORF) of 1464b, a 5'-untranslated terminal region (UTR) of 124b and
      at least 228b in the 3'-UTR (incomplete, as the polyadenylation signal was not
      determined). Form II (1930 sequenced nt) contains an ORF of 1362b, a 5'-UTR of
      340b and the same 3'-UTR as form I. Form II lacks the first 34 amino acids of
      form I, corresponding to the membrane-anchoring segment, whereas the sequence of
      the remaining coding region is almost the same in the two forms, resulting in
      proteins of 454 and 488 amino acids, respectively. Whether the two transcripts
      derive from the same gene by alternative splicing or are encoded by different
      CYP19B genes remains to be clarified. On Northern blot analyses with brain and
      ovary specific ORF probes and poly(A)(+)-enriched RNAs from trout ovary and
      brain, a transcript of about 2.6kb was identified in the ovary, as expected,
      whereas the full-length mRNA of brain P450arom is about 3.8kb. The brain form is
      expressed in the brain and gonads, whereas expression in peripheral tissues is
      limited mostly to the gills. The two trout CYP19 genes are not equivalent in
      tissue-specific expression, indicating the possibility of distinct promoters and
      regulatory mechanisms.

PMID- 12429137
TI  - Activities of a non-classical estrogen, Z-bis-dehydrodoisynolic acid, with
      ERalpha and ERbeta.
AB  - (+/-)-Z-bis-Dehydrodoisynolic acid [(+/-)-Z-BDDA] is highly estrogenic in vivo,
      yet binds to estrogen receptor (ER) poorly. This paradox has raised the
      possibility of alternative ERs and/or molecular mechanisms. To address the
      possibility of high activities of Z-BDDA with ERbeta, we determined the
      activities of (+)-Z-BDDA and (-)-Z-BDDA, in cell culture and in vitro, comparing
      ERbeta to ERalpha. Transfectional analysis in Hela cells showed (-)-Z-BDDA is an
      agonist for gene activation with both ERalpha (EC(50) congruent with 0.3nM) and
      ERbeta (EC(50) congruent with 5nM), while little to no activity was observed with
      (+)-Z-BDDA. Similarly, in gene repression assays, (-)-Z-BDDA was active (EC(50)
      congruent with 0.2nM), but again minimal activity was exhibited by (+)-Z-BDDA.
      Binding to ERalpha and ERbeta in vitro used both competition and a direct binding
      assay. For ERalpha, the relative affinity of (-)-Z-BDDA was approximately 6% by
      competition and 1.7% by direct binding versus 17beta-estradiol (E2; 100%), while
      (+)-Z-BDDA also demonstrated binding, but with relative affinities of only 0.08%
      by competition and 0.3% by the direct assay. For ERbeta, the affinity of (-)-Z
      BDDA was approximately 7% by competition and 1.5% by the direct assay relative to
      E2 (100%), while (+)-Z-BDDA had lower affinity, approximately 0.2% that of E2 by
      both assays. The paradox of potent in vivo activity but lower activity in
      receptor binding and in cell culture reporter gene assays, previously seen with
      ERalpha is now also associated with ERbeta. The failure of ERbeta to explain the
      activity-binding paradox indicates the need for additional in vivo metabolic and
      pharmacokinetic studies and continued consideration of alternative mechanisms.

PMID- 12429138
TI  - Estrogenic effect of a series of bisphenol analogues on gene and protein
      expression in MCF-7 breast cancer cells.
AB  - Bisphenols constitute a family of compounds, which includes many substances that
      have as a common chemical structure two phenolic rings joined together through a
      bridging carbon. In the present study, we aimed to determine whether several
      events triggered by 17 beta-estradiol (E(2)) in MCF-7 breast cancer cells were
      also observed in response to various bisphenol-A (BPA) analogues. We studied the
      expression of estrogen controlled genes by measuring the induction of pS2 (mRNA
      and protein) and progesterone receptor (PgR) as well as the expression of a
      luciferase reporter gene transfected into MVLN cells. These data were compared to
      the cell proliferation potency and effectiveness as the latest expression of
      estrogen controlled functions. Bisphenols showed an agonistic effect in all our
      assays, suggesting that these compounds may act through all the response pathways
      triggered by the natural hormone. We found differences between the assays in the
      potency of bisphenols, defined as the minimum concentration required to produce a
      maximal effect. In the cell proliferation assay, all tested compounds needed a
      lower concentration than in the other assays to give maximal response. Our
      results suggest that the polarity and nature of the substituent in the central
      carbon determines the estrogenic potency. Presence of two propyl chains at the
      central carbon appears to confer the greatest potency in both gene and protein
      expression assays.

PMID- 12429139
TI  - Glucocorticoids enhance activation of the human type II 3beta-hydroxysteroid
      dehydrogenase/Delta5-Delta4 isomerase gene.
AB  - Glucocorticoids indirectly alter adrenocortical steroid output through the
      inhibition of ACTH secretion by the anterior pituitary. However, previous studies
      suggest that glucocorticoids can directly affect adrenocortical steroid
      production. Therefore, we have investigated the ability of glucocorticoids to
      affect transcription of adrenocortical steroid biosynthetic enzymes. One
      potential target of glucocorticoid action in the adrenal is an enzyme critical
      for adrenocortical steroid production: 3beta-hydroxysteroid dehydrogenase/Delta5
      Delta4 isomerase (3beta-HSD). Treatment of the adrenocortical cell line (H295R)
      with the glucocorticoid agonist dexamethasone (DEX) increased cortisol production
      and 3beta-HSD mRNA levels alone or in conjunction with phorbol ester. This
      increase in 3beta-HSD mRNA was paralleled by increases in Steroidogenic Acute
      Regulatory Protein (StAR) mRNA levels. The human type II 3beta-HSD promoter lacks
      a consensus palindromic glucocorticoid response element (GRE) but does contain a
      Stat5 response element (Stat5RE) suggesting that glucocorticoids could affect
      type II 3beta-HSD transcription via interaction with Stat5. Transfection
      experiments show enhancement of human type II 3beta-HSD promoter activity by
      coexpression of the glucocorticoid receptor (GR) and Stat5A and treatment with
      100nM dexamethasone. Furthermore, removal of the Stat5RE either by truncation of
      the 5' flanking sequence in the promoter or introduction of point mutations to
      the Stat5RE abolished the ability of DEX to enhance 3beta-HSD promoter activity.
      These studies demonstrate the ability of glucocorticoids to directly enhance the
      expression of an adrenal steroidogenic enzyme gene albeit independent of a
      consensus palindromic glucocorticoid response element.

PMID- 12429140
TI  - Studies on the catalytic function of aromatase: aromatization of 6-alkoxy
      substituted androgens.
AB  - To gain insight into the catalytic function of aromatase, we studied
      aromatization of a series of 6alpha- and 6beta-ether-substituted (methoxy,
      ethoxy, and n-butoxy) androst-4-ene-3,17-dione (AD) steroids (1 and 2) and their
      androsta-1,4-diene-3,17-dione (ADD) derivatives (3 and 4) with human placental
      aromatase by gas chromatography-mass spectrometry (GC-MS). Among the steroids
      examined, 6beta-methoxy and 6beta-ethoxyADDs (4a and 4b) are suicide substrates
      of aromatase. All of the steroids were found to be converted into the
      corresponding 6-alkoxy estrogens. Introduction of the alkoxy groups at C-6 of AD
      or ADD decreased the ability of these to serve as a substrate of aromatase. In
      6alpha-alkoxy steroid series, compounds 1 and 3, the aromatization rate increased
      by elongating the 6-methoxy group up to the n-butoxy group whereas, in the 6beta
      isomers series, 2 and 4, the rate decreased due to this structural modification.
      6beta-Alkoxy steroids, 2 and 4, including the suicide substrates, were extremely
      poor substrates for the aromatization reaction. Apparent K(m) values obtained for
      6alpha-alkoxy compounds 1 and 3 were similar to each other, ranging from 92 to
      111nM, as shown by their previously-obtained K(i) values. The findings indicate
      that the stereochemistry as well as the bulkiness of the 6-ether-substituent play
      an important role in the ability to serve as a substrate. It is also predicted
      that the aromatization reaction and the mechanism-based inactivation reaction
      would be related and have a definite partition number which is characteristic to
      the compound in a series of suicide substrates.

PMID- 12429141
TI  - Neonatal superior ovarian nerve transection disturbs the cyclic activity of the
      female rats.
AB  - The neural pathway most related with ovarian steroidogenesis has been identified
      as the superior ovarian nerve (SON). This work constitutes the first study of the
      effects of early ovarian SON transection, which was performed in rats of 4 days
      of age (SON-t rats) to magnify the effects of the denervation. The rats were
      studied at the prepubertal (30 days), peripubertal (41 days) and adult cyclic in
      dioestrus (60 days) reproductive stages. The SON-t rats showed a delay of vaginal
      opening, a notable disruption of oestrous cyclicity, and a large number of
      corpora lutea. In all the stages, the circulating levels of FSH, prolactin and
      growth hormone were lower in SON-t rats than in controls, whereas LH did not
      vary. Serum androstenedione levels were higher in SON-t rats at 30 days and lower
      at 41 days, compared with control animals while no difference was observed at 60
      days. Serum progesterone levels did not differ between control and SON-t, but
      serum oestradiol concentrations were higher in SON-t rats in all of the stages.
      At the peripubertal stage, there were fewer ovarian beta-adrenergic receptors in
      SON-t ovaries, associated with a rise in the ovarian content of norepinephrine,
      but no changes were observed in SON-t rats at 30 and 60 days with respect to the
      controls. The release of progesterone in vitro from luteal cell in SON-t rats at
      60 days was reduced in basal condition and under ovine LH or FSH stimulation,
      when compared with control animals; while no difference was observed in presence
      of isoproterenol or androstenedione in the culture medium. In corpora lutea of
      SON-t rats at 60 days, no change was observed in the activity of 3beta
      hydroxysteroid dehydrogenase (3beta-HSD), but the activity of 20alpha
      hydroxysteroid dehydrogenase (20alpha-HSD) was reduced, suggesting abnormal
      luteolysis in spite of the large number of corpora lutea. The interruption of
      innervation at an early age by SON transection is very important in the
      regulation of ovarian development in prepubertal and cyclic rats. The functional
      changes observed in the ovary suggest a possible alteration in the hypothalamic
      hypophyseal axis.

PMID- 12429142
TI  - A time-resolved fluoroimmunoassay for 18-oxocortisol and 18-hydroxycortisol.
      Development of a monoclonal antibody to 18-oxocortisol.
AB  - Patients with primary aldosteronism and with glucocorticoid-suppressible
      aldosteronism excrete in the urine excessive amounts of the hybrid steroids 18
      hydroxycortisol and 18-oxocortisol. The measurement of these steroids aids in the
      differential diagnosis of various adrenal disorders. We have produced mouse
      monoclonal antibodies against 18-oxocortisol and polyclonal antibodies against 18
      hydroxycortisol and describe a time-resolved fluoroimmunoassay (TR-FIA) technique
      for the measurement of these steroids in the urine. We have also compared this
      assay with an ELISA technique for these compounds. We also describe the
      preparation of in-house Eu(III)-labeled avidin and an enhancement solution and
      compared to a commercially available Eu(III)-labeled streptavidin and enhancement
      solutions. The monoclonal antibodies against 18-oxocortisol are sensitive and
      have a high level of specificity. The TR-FIA technique using in-house prepared
      reagents or commercial ones were indistinguishable from each other, but at a
      significant saving. The TR-FIA technique was more sensitive and had a greater
      precision than the ELISA technique for both steroids.

PMID- 12429143
TI  - Catalytic and immunochemical properties of NADPH-cytochrome P450 reductase from
      fungus Rhizopus nigricans.
AB  - Flavoprotein NADPH-cytochrome P450 reductase (CPR, EC 1.6.2.4) from filamentous
      fungus Rhizopus nigricans is a membrane bound enzyme which is involved in the
      reduction of cytochrome P450 during the hydroxylation of progesterone at 11alpha
      position. After purification of the enzyme from induced mycelia three forms of
      fungal CPR were detected on SDS-PAGE: a predominant form with an apparent
      molecular mass of 78kDa and two truncated forms. N-terminal sequences of all
      three forms were determined as well as some internal sequences of 78kDa form.
      Dose-dependent immunoinhibition of NADPH-cytochrome c reductase and progesterone
      11alpha-hydroxylase activities was observed with mouse anti-CPR antisera. No
      cross-reactions were obtained on Western blots between mouse anti-CPR antisera
      and protein preparations from noninduced mycelia and microsomal fraction from
      fungus Pleurotus osteatus, plant Ginkgo biloba or chicken liver. The kinetic
      mechanism of CPR was proposed on the basis of model reaction with cytochrome
      c(3+). Results obtained at high ionic strength suggest a nonclassical two-site
      ping pong mechanism and at low ionic strength a sequential mechanism of
      bisubstrate reaction.

PMID- 12429148
TI  - Fluorescence detection of bladder cancer: a review.
AB  - An effective therapeutic outcome in the treatment of bladder cancer is largely
      defined by its early detection. In this context, big expectations have been
      placed on the fluorescence-guided diagnosis of bladder cancer. This paper reviews
      the applications of endo- and exogenous fluorescence for early diagnosis of in
      situ carcinoma of the bladder. Despite certain advantages of autofluorescence,
      exogenous fluorescence, based on the intravesical instillation of fluorophores
      with the following visible light excitation, has been shown to be more effective
      in terms of sensitivity and specificity for detecting carcinoma in situ. The
      equipment consists of a slightly modified light source in order to choose between
      white (conventional endoscopy) or blue light (fluorescence endoscopy) excitation,
      and specific lenses, in order to enhance maximally the contrast between normal
      (blue) autofluorescence and red fluorescence from malignancies. Among exogenous
      fluorophores, a particular emphasis will be put on the 5-aminolevulinic acid
      (ALA), its ester derivative (h-ALA) and hypericin. These dyes demonstrated an
      excellent sensitivity above 90% and specificity ranging from 70% to 90%.

PMID- 12429149
TI  - What importance do women attribute to the size of the penis?
AB  - OBJECTIVE: A great deal of men consider that the size of the penis is directly
      proportional to its sexual power. Some men, who are worried that their penis is
      too small, wish to be considered for surgical lengthening or thickening
      procedures. The argumentation for this chiefly points in the direction of women.
      However, have women actually been asked about the extent to which they consider
      the size of the penis to be of importance from a sexual point of view? Or asked
      what they think about ideas surrounding the size of the penis in relation with
      actual sexual functioning? PATIENTS AND METHODS: To address these questions, 375
      sexually active women who had recently given birth at the University Hospital
      Groningen were asked a number of questions about sexual functioning and the
      importance they attach to the size of their partner's penis. RESULTS: A total of
      170 questionnaires were returned (response rate 45%); 20% of the women found the
      length of the penis important and 1% very important; 55% and 22% of the women
      found the length of the penis unimportant and totally unimportant, respectively.
      Opinions about the girth of the penis followed the same trend. Length was less
      important than girth: 21% and 32%, respectively. The women who found the girth of
      the penis important had the same opinion about the length of the penis
      (correlation 0.71, p=-0.001). Median division into two subgroups (girth
      important/unimportant; t-test) did not reveal any significant differences in
      relation with demographic data. Correlation analysis did not reveal any
      significant correlation between sexual functioning (measured with the NSF) and
      opinions about the girth of the penis. CONCLUSION: Although clearly in the
      minority, a nevertheless considerable percentage of the women respondents
      attached substantial importance to the size of the male sexual organ.

PMID- 12429150
TI  - A systematic review of the literature on the prevalence of sexual impairment in
      women with urinary incontinence and the prevalence of urinary leakage during
      sexual activity.
AB  - OBJECTIVE: To provide a synthesis of the literature concerning the impact of
      urinary incontinence on sexual lives of women and the prevalence of urinary
      incontinence during sexual activity. METHODS: Medline and PsycInfo were searched
      for all primary epidemiological articles reporting the prevalence of sexual
      incontinence or the impact of urinary incontinence on sexual function in women.
      Only papers written in English since 1980 and prior to December 2001 were
      included. RESULTS: Two studies had assessed the prevalence of sexual incontinence
      in randomly selected community samples and reported population prevalences of 2%.
      Reporting in clinical samples were varied with prevalences ranging from 10 to
      56%. Studies of impairment in sexual function were more varied and
      methodologically heterogeneous with reported prevalences of 0.6-64%. CONCLUSIONS:
      Further research is needed using standard definitions and measures of sexual
      incontinence and sexual impairment in order to establish reliable prevalence
      estimates.

PMID- 12429151
TI  - Current laparoscopic practice patterns in urology: results of a survey among
      urologists in Germany and Switzerland.
AB  - OBJECTIVES: A survey was performed to assess the current practice patterns in
      laparoscopy among urologists in Germany and Switzerland. METHODS: Using the
      database directory of the German and Swiss Urological Association urological
      departments were identified. A detailed questionnaire was designed and sent by
      postal service. Responding questionnaires were analyzed. RESULTS: The overall
      response rate was 64%. Fifty-four percent of respondents in Germany and 33% in
      Switzerland already perform laparoscopy; another 50% and 56% are planning to
      introduce laparoscopy. Thirty-six percent think that laparoscopy is economical
      and 77% await shortening of hospital stay. Major concerns are: Economical
      aspects, lengthy learning curve, investment, and lack of scientific data. The
      number of laparoscopic procedures during 12 months was registered for 19
      indications. More than 40 procedures for one indication are performed by only 6%
      of the departments. CONCLUSIONS: The survey reveals an increasing number of
      departments performing laparoscopy and broad acceptance of the technology but
      combined with some major concerns. Currently only a minority of the departments
      perform more than 40 procedures for one indication suggesting that at present
      laparoscopy is mainly a center-based technology.

PMID- 12429152
TI  - Laparoscopic radical nephroureterectomy: results of an international multicenter
      study.
AB  - OBJECTIVE: To report a multicenter analysis after laparoscopic radical
      nephroureterectomy for pathologically confirmed upper tract transitional cell
      carcinoma. MATERIALS AND METHODS: A total of 116 patients (72 males; mean age 68
      years) underwent laparoscopic radical nephroureterectomy at five international
      institutions: 51 transperitoneally, 65 retroperitoneally. Location of the primary
      tumor was pelvicalyceal in 70 patients (60%), ureteral in 27 (23%), and
      multifocal in 19 (17%). In 18 patients (15%), transurethral resection was
      performed for concomitant bladder tumor. The median follow-up time was 25 months
      (range 3-93). A minimum follow-up of 1 and 2 years was available in 77 and 41
      patients, respectively. RESULTS: Five patients (4%) were converted to open
      surgery. The specimen was extracted intact in all 116 patients: using an
      Endocatch bag in 78 patients, a Lapsac in 5, and manually in 33. Pathologic
      staging was pTis in 5 (4%), pTa in 41 patients (35%), pT1 in 31 (26%), pT2 in 18
      (15%), pT3 in 16 (13%), and pT4 in 5 (4%). Pathological grade was grade I in 26
      patients (23%), grade II in 41 (35%), grade III in 34 (29%) and grade IV in 15
      (12%). Histopathology revealed a positive surgical margin in five patients
      (4.5%): renal hilum (one), periureteral soft tissue (two), distal edge of the
      ureter/ bladder cuff (two). Local recurrence was noted in two patients (1.7%).
      Bladder recurrence was noted in 28 patients (24%) with a mean time to recurrence
      of 13.9+/-11.5 months. Distant metastases occurred in 11 patients (9%): lung (5),
      liver (3), bones (2), adrenal (1); mean time to metastasis was 13 months.
      Overall, 23 patients (20%) died. One-year and 2-year cancer-specific survival was
      92% and 87%, respectively. Two-year cancer-specific survival according to
      pathologic stage was 89% for patients with pT1 disease, 86% for pT2, 77% for pT3,
      and 0% for pT4 (p=0.0001). Two-year survival according to pathologic grade was
      88% for grade I, 90% for grade II, 80% for grade III, and 90% for grade IV
      (p>0.05). CONCLUSION: Laparoscopic radical nephroureterectomy appears to be an
      effective minimally invasive treatment for select patients with upper tract
      transitional cell carcinoma. Although the 2-year survival data reported herein
      are encouraging, longer follow-up is needed before laparoscopy can be considered
      as a standard treatment.

PMID- 12429153
TI  - A comparison of laparoscopic pyeloplasty performed with the daVinci robotic
      system versus standard laparoscopic techniques: initial clinical results.
AB  - PURPOSE: Laparoscopic pyeloplasty is an accepted therapy for primary
      ureteropelvic junction obstruction (UPJO), however difficulty associated with
      intracorporeal suturing has limited widespread clinical application. We report
      our initial experience of laparoscopic pyeloplasty performed with the daVinci
      robotic system matched to procedures performed with standard laparoscopic
      techniques. PATIENTS AND METHODS: From June 2001 until August 2001, six patients
      underwent definitive management of primary UPJO using the daVinci robotic system.
      In four patients an Anderson-Hynes pyeloplasty was performed, while in two
      patients Fengerplasty was performed. Using demographic and preoperative
      information, each patient in the daVinci-assisted group was matched to a
      corresponding patient with primary UPJO undergoing laparoscopic pyeloplasty with
      standard techniques between November 1999 and June 2001. Perioperative results
      and follow-up data were subsequently compared. RESULTS: Treatment groups were
      identical with regard to surgical procedure, gender, and side of UPJO. The length
      of hospitalization was 4 days for all patients, regardless of treatment group.
      Estimated blood loss was <50 cc in all cases. For Anderson-Hynes pyeloplasty, the
      mean overall operative and suturing times were 140 and 70 min using the daVinci
      system and 235 and 120 min using standard techniques, respectively. For the
      Fengerplasty, the mean overall operative and suturing times were 78 and 13
      minutes using the daVinci system and 100 and 28 minutes using standard
      techniques, respectively. No complications were observed and there were no open
      conversions. CONCLUSION: Anderson-Hynes pyeloplasty and Fengerplasty are feasible
      using either conventional laparoscopic techniques or the daVinci robotic system.
      In this initial pilot study, procedures performed with the daVinci robotic system
      resulted in overall decreased operative time, however factors responsible for the
      decreased operative time remain to be defined. Long-term prospective follow-up of
      procedures performed with or without the daVinci robotic system for surgeons with
      limited experience in laparoscopic management of UPJO is warranted to delineate
      the true efficacy of the device.

PMID- 12429155
TI  - Reduced thrombospondin-1 at presentation predicts disease progression in
      superficial bladder cancer.
AB  - OBJECTIVES: Superficial bladder cancer (SBC) presents a difficult clinical
      dilemma at diagnosis as only a small subgroup of patients will subsequently
      develop invasive disease. Study of cancer biology has found that angiogenesis is
      central to growth and spread. This study examines the relationship between the
      angiogenic inhibitory factor Thrombospondin-1 (TSP-1) at initial presentation and
      subsequent progression of SBC. METHODS: Using immunohistochemistry, 220 cases of
      SBC were examined for pattern and extent of expression of TSP-1 at initial
      presentation. RESULTS: TSP-1 was detected in perivascular tissue, at the
      epithelial-stromal junction, in the stroma and in tumour cells and reduced
      perivascular TSP-1 staining at presentation was an independent predictive factor
      for the subsequent development of muscle invasive or metastatic disease.
      CONCLUSION: This adds further weight to the theory that TSP-1 plays a major part
      in the biology of bladder cancer possibly through the control of angiogenesis.

PMID- 12429154
TI  - Value of immunohistochemistry in staging T1 urothelial bladder carcinoma.
AB  - PURPOSE: The subclassification of T1 bladder tumors into T1A and T1B has an
      important prognostic significance and a great impact on patient management.
      Unfortunately, staging T1 tumors is highly subject to interpathologist variation
      that can be critical for patients included in randomized clinical trials. To
      determine the value of immunohistochemistry (IHC), such as desmin and keratin, in
      comparison to hematoxylin-eosin (H&E) in classifying T1 stage disease, we
      retrospectively examined 93 consecutive cases diagnosed at our department.
      MATERIALS AND METHODS: The study was conducted in two phases (H&E then IHC), each
      in two time periods. First H&E, and then IHC slides were reviewed independently
      by two experienced pathologists and discrepant cases from each phase were
      discussed between the two pathologists to reach a final decision. RESULTS: The
      two methodologies (H&E and IHC) showed total agreement in 76 out of 93 cases. IHC
      downstaged seven cases, that is from T1B to T1A, upstaged four cases, that is
      from T1A to T1B, lowered the rate of imprecision and eliminated the disagreement
      between the two pathologists. However, IHC failed to subclassify T1 tumors in
      three cases. Finally, the discussion supported by the IHC was very useful in
      reaching the diagnosis in some cases. CONCLUSIONS: IHC appears to be a useful
      tool in staging T1 bladder cancer, especially in difficult cases where specimen
      orientation and artifact could create a major hindrance in reaching an accurate
      diagnosis.

PMID- 12429156
TI  - Keratinising squamous metaplasia of the bladder: natural history and
      rationalization of management based on review of 54 years experience.
AB  - OBJECTIVE: To review our experience of keratinising squamous metaplasia of the
      bladder as a predictor for the development of cancer and other complications, and
      formulate a policy for its management. MATERIALS AND METHODS: A retrospective
      review (1945-1999) identified 34 patients with histologically proven keratinising
      squamous metaplasia (27 males and 7 females, average age 50 years, range 13-80
      years). The histological criteria used to diagnose keratinising squamous
      metaplasia were squamous metaplasia of the urothelium with keratinisation and/or
      hyperkeratosis and/or acanthosis. Female patients with non-keratinising squamous
      metaplasia (vaginal metaplasia) were excluded. RESULTS: Four patients had
      synchronous bladder carcinoma (three advanced with early death; one localised,
      cured by cystectomy). Another 14 patients had extensive metaplasia (Group A, >50%
      of mucosal involvement). Three cases had cystectomy and cure. Six cases (out of
      11) developed subsequent cancer (4 advanced and early death, two localised and
      cured by cystectomy). One other case died of obstructive uropathy secondary to
      squamous metaplasia. Two cases died of unrelated causes. Sixteen patients had
      limited squamous metaplasia (Group B, <50% involvement mucosal surface). Twelve
      patients had endoscopic resection, extraction bladder calculus etc. with no
      further complications. Another two patients underwent urinary diversion. Two
      patients (out of 16) developed subsequent cancer both with advanced disease and
      early death. CONCLUSION: Keratinising squamous metaplasia of the bladder is a
      significant risk factor for vesical carcinoma and complications, such as bladder
      contracture and ureteral obstruction. This risk of complications increases with
      more extensive bladder mucosal involvement. The wide variation in lag time to the
      development of complications necessitates indefinite follow-up. Selected patients
      with extensive bladder involvement and long life expectancy should be offered
      cystectomy.

PMID- 12429157
TI  - Trace elements distribution in renal cell carcinoma depending on stage of
      disease.
AB  - OBJECTIVES: The aim of this study was to identify those trace elements which can
      be used to distinguish between normal and malignant tissue in renal cell cancer
      (RCC) kidney and to assess changes in trace elements concentration in tissue with
      progressing malignant disease. METHODS: In case control study, 36 cases of RCC
      were analyzed by Synchrotron Radiation Induced X-ray Emission (SRIXE) in order to
      establish the concentration of 19 elements. Patients with RCC were examined to
      obtain staging of disease after radical nephrectomy, which was performed in each
      case. Results were compared with 15 control kidney cortex tissue obtained during
      autopsy in which cause of death was trauma. RESULTS: The most relevant decrease
      was detected in Cd content: from 81 +/- 39.2 ppm in normal control samples to
      16.6 +/- 22.2 ppm concentration in RCC. We found that the concentrations of Ti,
      Pb and Rb were also lower in RCC tissue. On the other hand, the RCC tissue was
      rich in iron and zirconium. With the progress of malignant disease, assessed by
      TNM (UICC 1997) scale, lower concentration of S and higher concentration of Ca in
      both RCC and neoplastic kidney cortex can be seen. The same tendency is observed
      in Zn and Se concentrations. Cadmium shows raising concentration with progress of
      RCC only in cortex of neoplastic kidney. In all cases it was shown that the
      relatively high tissue concentration of iron in both investigated tissues is
      decreasing with the progress of disease. The zirconium has shown raising tissue
      concentration in advanced disease. CONCLUSION: Trace elements concentration is
      different in malignant tissue and surrounding macroscopically unchanged kidney
      cortex. Progress of the disease is connected with changes in trace elements
      concentration. This may reflect different biology of compared tissue with
      potential practical implication.

PMID- 12429158
TI  - Bicalutamide monotherapy versus flutamide plus goserelin in prostate cancer:
      updated results of a multicentric trial.
AB  - OBJECTIVES: To compare the efficacy of bicalutamide monotherapy to maximal
      androgen blockade in advanced prostatic cancer. PATIENTS AND METHODS: Previously
      untreated patients with histologically proven stage C or D (American Urological
      Association Staging System) disease were randomly allocated to either
      bicalutamide (B) or goserelin plus flutamide (G+F). After disease progression,
      patients treated with B were assigned to castration. The primary endpoint for
      this trial was overall survival. Prostate cancer-specific survival and
      progression were included among secondary endpoints. RESULTS: In total 108
      patients received B and 112 received G+F. At a median follow-up time of 54 months
      (range 1-89), 151 patients progressed and 113 died. There was no significant
      difference in the duration of either progression-free or overall survival.
      Hazards of progression, death and cancer-specific death, corrected by disease
      stage, tumor grade and baseline PSA level, showed that patients initially
      assigned to B had a higher risk of progression but a comparable risk of death and
      cancer-specific death with the exception of patients with G3 tumors who had an
      increased risk of death). CONCLUSIONS: In patients with well or moderately well
      differentiated tumors, B monotherapy followed by castration may offer the same
      survival chance as maximal androgen deprivation. In those patients it thus
      represents a reasonable choice that can avoid the side effects of androgen
      deprivation for considerable periods of time.

PMID- 12429159
TI  - The valuation of the International Prostate Symptom Score (IPSS) for use in
      economic evaluations.
AB  - OBJECTIVE: Lower Urinary Tract Symptoms (LUTS) suggestive of Benign Prostatic
      Obstruction (BPO) cause a reduction in quality of life, but the magnitude of that
      reduction cannot be estimated empirically. This is because survey instruments
      currently available merely sum the symptoms found, but do not value their impact
      on quality of life. It is therefore difficult to determine whether the effects of
      treatments for LUTS suggestive of BPO justify the costs. This complicates
      economic evaluations. METHODS: We valued the impact on quality of life of
      patients with LUTS suggestive of BPO, by valuing health states defined by the
      International Prostate Symptom Score (IPSS) using the time trade-off (TTO). TTO
      values ranged from 1.0 for perfect health to 0.0 for the value of death, and can
      be used to calculate Quality-Adjusted Life Years (QALYs), the preferred outcome
      measure in health economics. RESULTS: We reduced the number of health states
      defined by the IPSS using factor analysis. The resulting nine health states were
      valued by a representative sample of the general public (N=170) using TTO. The
      worst IPSS health state was valued at 0.87. CONCLUSION: The values for health
      states defined by the IPSS revealed that LUTS suggestive of BPO has a mild impact
      on quality of life. The valuation of the IPSS facilitates economic evaluations of
      treatments for LUTS suggestive of BPO, because QALYs (the preferred outcome
      measure in health economics) can be determined empirically.

PMID- 12429160
TI  - The relationships among filling, voiding subscores from International Prostate
      Symptom Score and quality of life in Japanese elderly men and women.
AB  - OBJECTIVES: Lower urinary tract symptoms (LUTS) are reported to influence the
      quality of life (QoL) of the elderly. The aim of this study was to elucidate the
      relationships among filling problems, voiding problems and QoL in elderly men and
      women. METHODS: A total of 450 males and 228 females, aged 50 years or older
      responded to a questionnaire, which included seven questions from the
      International Prostate Symptom Score (I-PSS) and 16 questions from the King's
      Health Questionnaire (KHQ). The relations among the filling, voiding subscores
      deliverable from I-PSS, and KHQ-QoL were investigated. RESULTS: The voiding
      subscore significantly correlated with the filling subscore with a considerably
      large standard deviation, and the filling subscore also significantly correlated
      with I-PSS in both genders. KHQ-QoL was significantly associated with the filling
      and voiding subscores in almost all domains of the KHQ. Multiple regression
      analyses demonstrated the filling, voiding subscores, and I-PSS explained the 55%
      or greater reduction in the QoL in six, four, six domains in men and four, three,
      four domains in women, respectively. CONCLUSIONS: The filling problems are
      slightly more associated with KHQ-QoL than voiding problems but filling problems
      did not appear to predominantly affect QoL as expected in both genders. We
      believe it valid to use I-PSS to evaluate voiding problems as well as filling
      problems in the elderly women.

PMID- 12429161
TI  - Pre-selection of patients for pressure-flow analysis based on the maximum flow
      rate.
AB  - OBJECTIVE: To study the effects of the application of flow rate prescreening to
      select men for invasive pressure-flow studies, notably the reduction of invasive
      pressure-flow measurements that can be achieved and the proportion of men in
      whom, on the basis of the application of a prescreening, an invasive measurement
      is unjustly not indicated (false negatives). In addition, the variables on which
      these effects depend are studied. MATERIALS AND METHODS: Two hundred and sixty
      two pressure-flow measurements in 131 patients (2 measurements/patient) and 89
      free-flow measurements that preceded the invasive measurements in some patients
      were studied. A mathematical model was developed based on the outcomes of the
      invasive measurements. By means of the model the effects of several flow rate
      prescreening scenarios were estimated. A comparison of the model predicted and
      actually observed effects of flow rate prescreening was made for those
      measurements that were preceded by a free-flow rate measurement. RESULTS: The
      application of a free-flow rate prescreening may result in a reduction of the
      number of invasive measurements of 20-30% at a 5% false negative rate. The
      reduction that may be achieved at an assumed constant false negative rate depends
      on the distribution of the maximum flow rate in the population and on the
      definition of bladder outlet obstruction used. When the measurement selection
      procedure was applied to the free-flow rate measurements that were available in
      89 patients, a 21% reduction in invasive measurement indications was found (25%
      expected). Four patients (4.5%) would have been unjustly excluded from invasive
      procedures (maximally 5% expected), three of these four patients were borderline
      obstructed. CONCLUSION: Considering the bother and risk to the patient and the
      cost of invasive measurements we think that a 20-30% gain in efficiency at a 5%
      risk of unjustly declaring a patient unobstructed makes a flow rate prescreening
      procedure cost effective in the diagnosis of bladder outlet obstruction.

PMID- 12429162
TI  - Retroperitoneoscopic nephrectomy in the prone position in children (point of
      technique).
AB  - We describe our initial experience with retroperitoneoscopic procedures in
      children in the prone position. Twelve children (five girls and seven boys; mean
      age 3.5 years) underwent nephrectomy, nephroureterectomy or
      heminephroureterectomy for obstruction or reflux within the non-functioning
      kidney, multicystic dysplastic kidney or upper pole dysplastic moiety. None of
      the operations were converted to an open procedure. The mean operative time for
      these procedures was 110 minutes. Blood loss was less than 20 ml.

PMID- 12429163
TI  - 'Batman excision' of ventral skin in hypospadias repair, clue to aesthetic repair
      (point of technique).
AB  - OBJECTIVE: In the hypospadiac penis the ventral skin is poorly developed, while
      dorsal skin is redundant. The classical Byars' flaps are a way to use the excess
      dorsal skin to cover the penile shaft. The appearance after Byars' flaps however
      is not natural. We use a more natural looking skin allocation with superior
      aesthetic results. METHOD: The clue in this reconstruction is an inverted
      triangle shaped excision of ventral skin expanding over the edges of the hooded
      prepuce (which makes it look like Batman). After excision of the ventral skin it
      is possible to close the penile skin in the midline, thus mimicking the natural
      raphe. In case of preputial reconstruction the excised ventral skin makes the
      prepuce look more natural. CONCLUSION: The trend of further refining aesthetic
      appearance of the hypospadiac penis often neglects the penile skin
      reconstruction. A technique is presented by which the total penile appearances
      after surgery ameliorates due to better skin reconstruction.

PMID- 12429166
TI  - Plant sterols...from research to practice.

PMID- 12429167
TI  - Plant sterol and stanols--comparison and contrasts. Sterols versus stanols in
      cholesterol-lowering: is there a difference?

PMID- 12429164
TI  - In vitro effects of a novel class of nitric oxide (NO) donating compounds on
      isolated human erectile tissue.
AB  - OBJECTIVES: The discovery of nitric oxide (NO) as one of the major effectors in
      penile erectile function has led to the development of various drugs which are
      able to elevate intracellular levels of cGMP. Recently, a novel class of NO
      donors have been developed, exemplified by S-nitroso-glutathione (GSNO) and S
      nitroso-N-acetylcysteine-ethylester (SNACET), as well as compounds combining both
      phosphodiesterase inhibitory and NO donating activity, such as NCX 911
      (sildenafil nitrate). In our study, we assessed the effects of GSNO, SNACET and
      NCX 911 on adrenergic tension and electrically induced relaxation of isolated
      human corpus cavernosum (HCC) and the in vitro formation of cGMP. Effects were
      compared to those of sodium nitroprusside (SNP) and sildenafil citrate. MATERIALS
      AND METHODS: Using the organ bath technique, drug effects were investigated on
      norepinephrine-induced tension and electrically induced relaxation of HCC. HCC
      strips were exposed to increasing concentrations of the compounds (0.01/0.1
      10/100 microM) and the accumulation of cGMP was determined by means of a
      radioimmunoassay. RESULTS: Relaxation of HCC induced by means of electrical field
      stimulation (EFS) was abolished by tetrotodoxin, guanylyl cyclase inhibitor ODQ
      and nitric oxide synthase inhibitor L-NNA. Adrenergic tension of HCC strips was
      dose-dependently reversed by the drugs. The rank order of potency was: SNP > GSNO
      > NCX911 > sildenafil > SNACET. Compounds also dose-dependently increased EFS
      induced amplitudes of relaxation (SNP > NCX911 > sildenafil > SNACET/GSNO).
      Relaxing effects of the drugs were paralleled by an increase in tissue levels of
      cGMP. CONCLUSION: Our results provide a rationale for future use of NCX 911 and S
      nitrosothiols in the pharmacotherapy of erectile dysfunction (ED). Since the
      compounds are assumed to exert no considerable hemodynamic effects, they might be
      developed into new oral treatments for ED.

PMID- 12429168
TI  - Efficacy and therapeutic potential of plant sterols.

PMID- 12429169
TI  - Importance of dietary management and practical patient counseling--US
      perspective.

PMID- 12429170
TI  - Importance of dietary management and practical patient counseling, the
      European/Australasian perspective.

PMID- 12429171
TI  - Temporary unilateral microembolization of the lung-a new approach to regional
      chemotherapy for pulmonary metastases.
AB  - BACKGROUND: Except in patients with resectable disease, treatment of pulmonary
      metastases is still disappointing. Regional chemotherapy may be a suitable method
      for delivering more effective doses to regionally confined tumors while
      minimizing systemic toxicity. We propose an unilateral chemoembolization of the
      lung applicable by endovascular method. MATERIALS AND METHODS: An unilateral
      microembolization of the lung with degradable starch microspheres (DSM) alone
      (group 1) and combined with carboplatin (group 2) was performed on Sprague-Dawley
      rats (n = 12). Microcirculatory parameters were studied by in vivo
      videomicroscopy and radiological pattern on pulmonary angiogram. RESULTS: After
      injection of DSM, mean embolization time in subpleural capillaries was 7.1 +/-
      2.3 min, followed by a mean flow retardation of 14.3 +/- 4.6 min; 21.4 +/- 4.7
      min after embolization, original flow of erythrocytes was observed demonstrating
      reperfusion and reversibility of microembolization. After reperfusion relative
      fluorescence measured in subpleural alveoli was 0.13 +/- 0.049 in group 1, 0.105
      +/- 0.016 in group 2, and 0.11 +/- 0.036 in control group (NS). Alveolar septal
      diameter was 17.3 +/- 1.13 microm in group 1, 16.8 +/- 1.25 microm in group 2,
      and 16.6 +/- 1.08 microm in control group (NS), demonstrating neither altered
      permeability nor pulmonary edema. Pulmonary angiogram confirmed patency of the
      central pulmonary artery. CONCLUSION: For the first time unilateral
      microembolization of the lung could be established in an experimental model. By
      injection of DSM, reversible embolization on arteriolar and capillary level could
      be demonstrated without occlusion of the main branches of the pulmonary arteries.
      Alveolar-capillary membrane disorder as symptom of early toxicity could not be
      detected even with additional application of carboplatin.

PMID- 12429172
TI  - Ulceration as a possible link between duodenogastric reflux and neoplasms in the
      stomach of rats.
AB  - BACKGROUND: Duodenogastric reflux predisposes to gastric cancer. This study
      investigates whether ulceration induced by duodenogastric reflux is associated
      with the development of neoplasms in the stomach. MATERIALS AND METHODS: In a rat
      experiment, duodenal fluid was directed into the corpus (jejunal reflux) or
      through the pylorus into the antrum (pyloric reflux). Sham-operated animals
      served as controls. The animals were sacrificed after 24, 36, or 52 weeks.
      RESULTS: Ulcerations and neoplasms occurred more frequently in the corpus than in
      the antrum. In the corpus, ulceration was observed significantly more often in
      animals with jejunal reflux (62, 55, and 53% at 24, 36, and 52 weeks,
      respectively) than in animals with pyloric reflux (15, 21, and 30%). The
      incidence of neoplasm in the corpus increased significantly with time from 38% at
      24 weeks to 89% at 52 weeks in animals with jejunal reflux and from 12 to 33% in
      animals with pyloric reflux. Ulceration and neoplasms shared location in the
      corpus adjacent to the gastrojejunostomy and by 24 weeks, all but one neoplasm in
      the jejunal reflux and one in pyloric reflux groups occurred adjacent to
      ulceration. In the antrum, 37% of the animals had a prepyloric ulceration after
      24 weeks of pyloric reflux and only one of these animals had a neoplasm. By 52
      weeks 20% of animals with pyloric reflux had a neoplasm that appeared in the
      prepyloric area. CONCLUSIONS: Ulceration and neoplasm occurred at the same sites
      in the stomach, and ulcerations preceded the development of neoplasms in the
      antrum and very likely in the corpus. The results suggest that ulceration plays
      an important role in the genesis of neoplasms in the stomach and that the
      vulnerability to duodenogastric reflux is more pronounced in the corpus than in
      the antrum mucosa.

PMID- 12429173
TI  - The possibility of nervus ilioinguinalis and nervus iliohypogastricus injury in
      lower abdominal incisions and effects on hernia formation.
AB  - AIM: The aim of this study was to determine the distances of nervus
      ilioinguinalis and nervus iliohypogastricus to McBurney's and paramedian
      incisions. MATERIALS AND METHODS: This study was performed on 12 adult cadavers.
      Right and left inguinal regions of the cadavers were dissected by inguinal
      incision. The points where the nerves perforated the internal obliquus muscles
      were determined, and the distances of these points to the spina iliaca anterior
      superior (SIAS) and to the umbilicus were measured. These distances were marked
      over a diagram, and distances of the nerves to McBurney's and paramedian
      incisions were measured by illustrating these incisions on the same diagram.
      FINDINGS: While the distance of the iliohypogastric nerve from the SIAS was 1.5-8
      cm on the right and 2.3-3.6 cm on the left, the distance of the ilioinguinal
      nerve from the SIAS was 3-6.4 cm on the right and 2-5 cm on the left. The
      distance of the ilioinguinal nerve from McBurney's incision was 0.2-6.1 cm on the
      right and 1.8-7.5 cm on the left, and that of the iliohypogastric nerve was 2.2
      6.9 cm on the right and 2.9-6.2 cm on the left. The distances of the nerves from
      paramedian incision were found to be 4.6-10 cm on the right and 6.4-11.2 cm on
      the left for the ilioinguinal nerve and 5-11.2 cm on the right and 7.4-11.6 cm on
      the left for the iliohypogastric nerve. CONCLUSION: Both nerves perforate the
      musculus obliquus internus, scattered in a wide area. Considering the distances,
      the paramedian incision seems to be more reliable with respect to the risk of
      nerve injury. Incisions performed in the lower abdomen carry the risk of injury
      to the ilioinguinal and iliohypogastric nerves.

PMID- 12429174
TI  - The importance of factor XIII as a component of fibrin sealants.
AB  - BACKGROUND: The need for factor XIII (FXIII) in fibrin sealant is subject to
      discussions. Some commercially available fibrin sealants (FS) contain high levels
      of FXIII (up to 70-80 U/mL) while others contain low levels or none. The
      objective of the present studies was to investigate the need for FXIII in FS.
      MATERIALS AND METHODS: Beriplast P, a commercial FS containing 40-80 U/mL FXIII,
      was compared with FS with different concentrations of FXIII or FXIII depleted FS.
      In Study 1, Beriplast P or FS with 4 U/mL FXIII was allowed to cross-link for
      0.25, 1, and 2 min and the resulting fibrin gamma- and beta-chains as well as
      gamma-gamma-chain dimers were analyzed by SDS-PAGE and densitometry. In Study 2,
      a series of six FS was prepared from fibrinogen containing 0 (FS-FXIII), 17.5,
      35, 70, 140, and 280 U/mL FXIII. The intrasealant strength was determined using a
      biomechanical test (twin-bottle test). In Study 3, 18 rabbits underwent bilateral
      partial kidney resection (acute model); right (n = 18) and left (n = 18) kidneys
      were treated with Beriplast P or FS with 4 U/mL FXIII (FS + 4U FXIII). In Study
      4, rabbits were randomly assigned to receive FXIII depleted FS (FS-FXIII) (n =
      15); FS + 3 U/mL FXIII (n = 10); FS + 10 U/mL FXIII (n = 10); or Beriplast P (n =
      15), after partial rabbit kidney resection (chronic model). The primary endpoint
      for Studies 3 and 4 was hemostasis. RESULTS: In Study 1, Beriplast P produced
      significantly more fibrin gamma-chain cross-linking in the observed period than
      FS with 4 U/mL FXIII. In Study 2, fibrin clot strength increased as a function of
      FXIII concentration with a maximum of 70 U/mL. In Study 3, significantly more
      animals achieved hemostasis in the Beriplast P treated group than in the FS + 4U
      FXIII group (P = 0.03 at 15 s; P < 0.001 at 1 and 2 min). In Study 4, FS
      containing FXIII (all concentrations) achieved more efficient hemostasis and
      reduced the need for respray compared with FS-FXIII. Beriplast P was associated
      with a lower incidence of postoperative adhesions compared with the other
      treatment groups. At autopsy, the majority of clots formed from FXIII containing
      FS exhibited mild to moderate clot lysis, whereas the majority of clots in the FS
      FXIII group showed severe lysis. CONCLUSIONS: FXIII, when added to fibrinogen
      concentrate in FS, improved fibrin cross-linking and clot strength. FXIII
      containing FS achieved more effective hemostasis than FXIII depleted FS. FXIII is
      an essential component of commercial FS and should be present in FS at an optimal
      concentration of about 40-80 U/mL.

PMID- 12429175
TI  - Dendritic cell-tumor cell fusion and staphylococcal enterotoxin B treatment in a
      pancreatic tumor model.
AB  - BACKGROUND: Surgical resection of pancreatic tumors removes gross disease but not
      metastases. Adjuvant therapy such as chemotherapy and radiation treatment is of
      little value in metastatic pancreatic cancer. The hypothesis of this
      investigation is that specific and effective immunotherapeutic vaccine
      (dendritic/tumor cell fusion) will activate cytotoxic T lymphocytes (CTLs),
      leading to the eradication of spontaneous pancreatic cancer. METHODS: We have
      developed a double transgenic mouse model (MET) that forms spontaneous pancreatic
      tumors and expresses the human MUC1 antigen. Seven-week-old MET mice (n = 8) were
      treated every 3 weeks with the vaccine. In addition, these mice received 50
      microg of superantigen staphylococcal enterotoxin B (SEB), a known T cell
      stimulant, prior to the first vaccination. A second treatment group received SEB
      alone (n = 8) and controls received no treatment (n = 9). MUC1-specific CTLs were
      measured by chromium release assay. At 10 weeks of age and at necropsy, MUC1
      serum levels were measured using a MUC1-specific ELISA. RESULTS: Mice were known
      to harbor microscopic foci of cancer at birth. Survival was enhanced in vaccine
      as well as SEB-treated mice (75% CI +/- 0.42) compared to controls (11% CI +/-
      0.28) and both groups of treated mice exhibited mature CTLs without in vitro
      stimulation. MUC1 serum levels of the vaccine group were 50% less than that of
      control (P < 0.04) at 10 weeks. MUC1 serum levels directly correlated with tumor
      weight at necropsy (r = 0.86). CONCLUSIONS: This is the first evidence that MUC1
      specific CTLs can be stimulated to enhance survival in a spontaneous tumor model.

PMID- 12429176
TI  - PDGF(BB) increases myocardial production of VEGF: shift in VEGF mRNA splice
      variants after direct injection of bFGF, PDGF(BB), and PDGF(AB).
AB  - BACKGROUND: Vascular endothelial growth factor (VEGF) plays an important role in
      angiogenesis. We hypothesized that a combination of recombinant angiogenic
      proteins might induce myocardial VEGF production and cause a shift in the mRNA
      signal produced. MATERIALS AND METHODS: The left ventricles of New Zealand white
      rabbits were injected with 500 microL of saline, basic fibroblast growth factor
      (bFGF), platelet-derived growth factor-AB (PDGF(AB)), platelet-derived growth
      factor-BB (PDGF(BB)), bFGF + PDGF(AB), or bFGF + PDGF(BB). Myocardial VEGF
      production was analyzed by ELISA while mRNA splice variants were analyzed by RT
      PCR 3 and 7 days after injection. RESULTS: PDGF(BB) alone caused the most
      pronounced induction of VEGF. Three days after injection the induction of VEGF by
      PDGF(BB) was significant compared to all treatment groups, except the bFGF +
      PDGF(BB) group. Induction of VEGF by PDGF(BB) was associated with a decrease in
      mRNA production of VEGF(121) within the myocardium. CONCLUSIONS: Injection of
      PDGF(BB) induces significant production of VEGF within the myocardium. This
      induction of VEGF production is associated with a shift toward other, less
      soluble forms of VEGF. These findings may allow more precise regulation of the
      myocardial response to therapeutic angiogenesis.

PMID- 12429177
TI  - Prediction of graft viability from non-heart-beating donor pigs using hepatic
      microdialysate hypoxanthine levels.
AB  - BACKGROUND: Non-heart-beating donors (NHBDs) are not yet acceptable in orthotopic
      liver transplantation (OLTX) because of the high frequency of primary graft
      nonfunction. In this study, we aimed to develop a new predictive method of graft
      viability in OLTX from NHBDs. MATERIALS AND METHODS: (1) Pigs were subjected to
      15 min of hepatic ischemia and reperfusion (I/R). (2) Porcine OLTX was performed
      using grafts obtained from NHBDs subjected to in situ warm ischemia (0, 30, and
      60 min). During both operations, hepatic hypoxanthine levels were measured by a
      microdialysis method. RESULTS: In the I/R model, hypoxanthine accumulated during
      ischemia and decreased after reperfusion, whereas marked xanthine and uric acid
      production were observed after reperfusion. In the NHBDs model, all of the 0-min
      group, 6 of 13 pigs in the 30-min group, and 1 of 6 pigs in the 60-min group
      survived more than 7 days. Significant increases of hypoxanthine levels were seen
      dependent on warm ischemic time. In the 30-min group, hypoxanthine levels were
      significantly higher in the pigs that died than in those that survived, and
      correlated with aspartate aminotransferase, lactate dehydrogenase, and adenosine
      triphosphate levels of recipients. Histological examination revealed that graft
      injury was severe in the pigs with higher hypoxanthine levels. CONCLUSIONS: It is
      suggested that hepatic microdialysate hypoxanthine levels during warm ischemia in
      NHBDs were correlated with graft viability in the recipient. By using of this
      technique, prediction of the graft viability may be possible during donor
      operation.

PMID- 12429178
TI  - Chymase inhibitor, BCEAB, suppressed peritoneal adhesion formation in hamster.
AB  - BACKGROUND: Mast cells are closely related to adhesion formation, while it has
      been unclear which factor in mast cells plays an important role in the
      development of adhesion formation. To clarify the role of chymase produced from
      mast cells in adhesion formation, we investigated the preventive effect of a
      specific chymase inhibitor, BCEAB, on adhesion formation in a hamster
      experimental model. MATERIALS AND METHODS: Hamsters were administered orally once
      daily with 100 mg/kg of BCEAB or placebo from the operated day to 1 week after
      the operation. The uterus was grasped and denuded by a swab. RESULTS: One week
      after the operation, the scores for adhesion formation in the chymase inhibitor
      treated group were significantly decreased in comparison with those in the
      placebo-treated group (placebo-treated group, 2.80 +/- 0.20; chymase inhibitor
      treated group 1.60 +/- 0.31: P < 0.01). The chymase activity in the injured
      uterus was also significantly suppressed in the chymase inhibitor-treated group
      (placebo-treated group, 17.3 +/- 2.69 mU/mg protein; chymase inhibitor-treated
      group 9.60 +/- 0.89: P < 0.05). After scraping the utelus, the level of
      transforming growth factor-beta in the peritoneal fluid was significantly
      increased in the placebo-treated group, while it was suppressed to 70% by the
      treatment with BCEAB. CONCLUSIONS: The specific chymase inhibitor BCEAB may be a
      useful drug for prevention of adhesion formation.

PMID- 12429179
TI  - Reasons for delayed discharge of trauma patients.
AB  - BACKGROUND: In the trauma population, increased length of stay is associated with
      age, comorbidities, and injury severity. We hypothesized that a significant
      contributor to a delay in length of stay was unrelated to these variables.
      MATERIALS AND METHODS: All trauma patients admitted for > 48 h with acute injury
      from 7/1/2000 to 9/30/2000 were evaluated daily for discharge readiness. Actual
      discharge time was recorded from the time discharge orders were written. A
      discharge-ready patient not discharged within 24 h was a Delay discharge.
      Discharge delay was categorized as availability of rehabilitation beds, family
      reasons, or system-related delay. Payer was classified as commercial, government,
      Medicare, or uninsured. Actual hospital costs were used. RESULTS: One hundred
      twenty-eight patients were evaluated; 30 patients had a delay in discharge. The
      average delay was 2 days (range 1-15 days). Mean hospital stay for Delay patients
      was 13.4 days, and 8.1 days for Timely patients (P < 0.05). Injury severity, age,
      and comorbidities were not different among groups. The main reason for delay was
      lack of a rehabilitation bed. Hospital costs were $39,013 per patient in the
      Delay group and $24,414 in the Timely group. Delay patients were more likely to
      be uninsured, have an orthopedic injury, and require ICU care. CONCLUSION:
      Discharge delays significantly lengthen hospital stay for nonmedical reasons in
      trauma patients. Improved efficiency in a trauma system will require changes from
      acute care to rehabilitation.

PMID- 12429180
TI  - Heat preconditioning attenuates oxygen free radical-mediated alterations in the
      intestinal brush border membrane induced by surgical manipulation.
AB  - BACKGROUND: The intestine is highly susceptible to free radical-induced damage
      and our earlier work has shown that surgical manipulation of the intestine
      results in generation of oxygen free radicals and mucosal damage along with
      alterations in the brush border membrane (BBM). Heat preconditioning is known to
      offer protection against various stresses including oxidative stress and this
      study looked at the effect of heat preconditioning on the intestinal BBM
      alterations following surgical manipulation. METHODS: Control and rats heat
      preconditioned were subjected to surgical manipulation by opening the abdominal
      wall and handling the intestine. BBM were isolated from the intestine and
      structural and functional alterations to these membranes were assessed. RESULTS:
      Surgical manipulation resulted in oxidative stress suggested by a decrease in
      alkaline phosphatase activity and alpha-tocopherol content, accompanied by an
      increase in lipid peroxidation. A decrease in glucose transport by the isolated
      BBM vesicles suggested functional impairment. Surgical manipulation resulted in
      phospholipid degradation with generation of arachidonic acid along with
      appearance of cPLA(2) in the membrane. These changes were prevented by heat
      preconditioning of the animal prior to surgical manipulation. CONCLUSION: These
      results suggest that heat preconditioning offers protection from damage to the
      intestinal BBM following surgical manipulation and mild whole body hyperthermia
      might prevent postsurgical complications.

PMID- 12429181
TI  - Changes in hepatic TNF-alpha levels, antioxidant status, and oxidation products
      after renal ischemia/reperfusion injury in mice.
AB  - BACKGROUND: Ischemia/reperfusion (I/R) injury induces an inflammatory response
      and production of reactive oxygen species (ROS), which affects the organs remote
      to the sites of I/R. The aim was to assess the hepatic changes after renal I/R
      injury. MATERIALS AND METHODS: Twenty mice were subjected to either sham
      operation or varying degrees of renal I/R injury. Hepatic TNF-alpha levels,
      myeloperoxidase (MPO), superoxide dismutase (SOD), and catalase (CAT) activities
      and reduced glutathione (GSH) levels, thiobarbituric acid-reactive substances
      (TBARS), and protein carbonyl levels were evaluated to show hepatic response to
      renal I/R injury. RESULTS: Hepatic tumor necrosis factor-alpha levels were found
      to be increased significantly after 30 min ischemia-1 h reperfusion and remained
      elevated through 60 min ischemia-1 h reperfusion. Supporting the neutrophil
      recruitment, about 10-fold increase in MPO activity was detected after 30 min
      ischemia-1 h reperfusion. Antioxidant enzymes were detected to be decreased after
      30 min ischemia-1 h reperfusion and reached to the minimum levels after 60 min
      ischemia-1 h reperfusion. Decreased levels of GSH and increased levels of TBARS
      and protein carbonyls after 60 min ischemia-1 h reperfusion supported the ROS
      mediated biomolecular alterations. CONCLUSIONS: A minumum of 30 min ischemia-1 h
      reperfusion is enough to elicit remote effects of renal I/R injury. Care should
      be taken to protect other organs remote from I/R sites especially during renal
      surgery.

PMID- 12429182
TI  - Differentiation of engrafted neuronal-restricted precursor cells is inhibited in
      the traumatically injured spinal cord.
AB  - Differentiation of pluripotent neural stem cells engrafted into the adult normal
      and injured spinal cord is restricted to the glial lineage, suggesting that in
      vitro induction toward a neuronal lineage prior to transplantation and/or
      modification of the host environment may be necessary to initiate and increase
      the differentiation of neurons. In the present study, we investigated the
      differentiation of neuronal-restricted precursors (NRPs) grafted into the normal
      and contused adult rat spinal cord. NRPs proliferated through multiple passages
      in the presence of FGF2 and NT3 and differentiated into only neurons in vitro in
      the presence of retinoic acid and the absence of FGF2. Differentiated NRPs
      expressed GABA, glycine, glutamate, and ChAT. Two weeks to 2 months after
      engraftment of undifferentiated NRPs into adult normal spinal cord, large numbers
      of surviving cells were seen in all of the animals. The majority differentiated
      into betaIII-tubulin-positive neurons. Some transplanted NRPs expressed GABA and
      small numbers were glutamate- and ChAT-positive. NRPs were also transplanted into
      the epicenter of the contused adult rat spinal cord. Two weeks to 2 months after
      transplantation, some engrafted NRPs remained undifferentiated nestin-positive
      cells. Small numbers were MAP2- or betaIII-tubulin-positive neurons. However, the
      expression of GABA, glutamate, or ChAT was not observed. These results show that
      NRPs can differentiate into different types of neurons in the normal adult rat
      spinal cord, but that such differentiation is inhibited in the injured spinal
      cord. Manipulation of the microenvironment in the injured spinal cord will likely
      be necessary to facilitate neuronal replacement.

PMID- 12429183
TI  - Grafted lineage-restricted precursors differentiate exclusively into neurons in
      the adult spinal cord.
AB  - Multipotent neural stem cells (NSCs) have the potential to differentiate into
      neuronal and glial cells and are therefore candidates for cell replacement after
      CNS injury. Their phenotypic fate in vivo is dependent on the engraftment site,
      suggesting that the environment exerts differential effects on neuronal and glial
      lineages. In particular, when grafted into the adult spinal cord, NSCs are
      restricted to the glial lineage, indicating that the host spinal cord environment
      is not permissive for neuronal differentiation. To identify the stage at which
      neuronal differentiation is inhibited we examined the survival, differentiation,
      and integration of neuronal restricted precursor (NRP) cells, derived from the
      embryonic spinal cord of transgenic alkaline phosphatase rats, after
      transplantation into the adult spinal cord. We found that grafted NRP cells
      differentiate into mature neurons, survive for at least 1 month, appear to
      integrate within the host spinal cord, and extend processes in both the gray and
      white matter. Conversely, grafted glial restricted precursor cells did not
      differentiate into neurons. We did not observe glial differentiation from the
      grafted NRP cells, indicating that they retained their neuronal restricted
      properties in vivo. We conclude that the adult nonneurogenic CNS environment does
      not support the transition of multipotential NSCs to the neuronal commitment
      stage, but does allow the survival, maturation, and integration of NRP cells.

PMID- 12429184
TI  - Combined inhibition of apoptosis and complement improves neural graft survival of
      embryonic rat and porcine mesencephalon in the rat brain.
AB  - To define potential mechanisms of cell death during neural cell transplantation,
      we investigated the role of intracellular caspase activation in combination with
      the activation of serum complement. We demonstrated that ventral mesencephalic
      (VM) cells are susceptible to complement-mediated cell lysis that can be blocked
      with an anti-C5 complement inhibitor (18A10). We also determined that incubating
      freshly isolated allogenic VM cells with the caspase inhibitor 1-3-Boc
      aspartyl(Ome)-fluoromethyl ketone (BAF), followed by immediate striatal
      implantation, led to a 2.5-fold increase in tyrosine hydroxylase (TH) cell
      survival 12 weeks postimplantation (P < 0.05). In contrast, overnight incubation
      with BAF followed by striatal implantation led to a 2-fold reduction in TH cell
      survival at 12 weeks (P < 0.05). Using the optimal BAF treatment and complement
      inhibition, we tested the hypothesis that these treatments would lead to
      increased cell survival in both allogeneic and xenogeneic transplantation models.
      We transplanted cell suspensions of (a) rat E14 VM or VM treated with (b) BAF
      alone, (c) anti-C5, or (d) a combination of BAF and anti-C5. There was a
      significant increase in the relative number of TH-positive cells in the BAF/anti
      C5 group versus control at 12 weeks posttransplantation. Similar results were
      achieved in a pig to rat xenotransplant paradigm. A neuronal xenograft marker (70
      kDa neurofilament) also demonstrated relative increases in graft volume in the
      BAF/anti-C5 treatment group. These studies indicate that more than one mechanism
      can mediate cell death during neural cell transplantation and that a combined
      treatment using caspase and complement inhibition can significantly improve cell
      survival.

PMID- 12429185
TI  - A-fiber sprouting in spinal cord dorsal horn is attenuated by proximal nerve
      stump encapsulation.
AB  - Peripheral nerve transection in the rat alters the spinal cord dorsal horn
      central projections from both small and large DRG neurons. Injured neurons with C
      fibers exhibit transganglionic degeneration of their terminations within lamina
      II of the spinal cord dorsal horn, while peripheral nerve injury of medium to
      large neurons induces collateral sprouting of myelinated A-fibers from lamina I
      and III/IV into lamina II in rats, cats, and primates. To date, it is not known
      what sequelae are responsible for the collateral sprouting of A-fibers after
      peripheral nerve injury, although target-derived factors are thought to play an
      important role. To determine whether target-derived factors are necessary for
      changes in A-fiber laminar terminations in rat spinal cord dorsal horn, we
      unilaterally transected the sciatic nerve and ensheathed the proximal nerve stump
      in a silicone cap. Three days before sacrifice of rat, the injured sciatic nerve
      was injected with cholera toxin beta-subunit conjugated to horseradish peroxidase
      (betaHRP) that effectively labels both peripheral and central A-fiber axons. The
      effect of the ligature, axotomy, and silicone cap treatment was evaluated by
      analyzing the extent of betaHRP-, Substance P-(SP-), and isolectin B4- (IB4-)
      immunoreactive (ir) fibers in the somatotopically appropriate spinal cord dorsal
      horn regions. In all animals, 2-5 weeks after nerve transection (treated or
      otherwise), IB4- and SP-ir is absent from lamina II. Animals without nerve cap
      treatment exhibited robust fiber sprouting into lamina II at 2 weeks. In sharp
      contrast, animals treated with silicone caps did not exhibit betaHRP-ir fibers in
      lamina II at 2 weeks. This observation was extended up to 5 weeks postinjury.
      These results suggest that axotomy-induced expansion of betaHRP-ir primary
      afferent central terminations in the spinal cord dorsal horn is dependent on
      factors produced in the injury site milieu. While our understanding of local
      repair mechanisms of injured peripheral nerves is incomplete, it is clear that
      the time-dependent production of growth factors in the nerve injury
      microenvironment favor nerve fiber outgrowth, both peripherally and centrally.

PMID- 12429186
TI  - Up-regulation of cadherin-2 and cadherin-4 in regenerating visual structures of
      adult zebrafish.
AB  - Cadherins are homophilic cell adhesion molecules that control development of a
      variety of tissues and maintenance of adult structures. In this study, we
      examined expression of zebrafish cadherin-2 (Cdh2, N-cadherin) and cadherin-4
      (Cdh4, R-cadherin) in the visual system of adult zebrafish after eye or optic
      nerve lesions using immunocytochemistry and immunoblotting. Both Cdh2 and Cdh4
      immunoreactivities were specifically up-regulated in regenerating retina and/or
      the optic pathway. Furthermore, temporal expression patterns of these two
      cadherins were distinct during the regeneration of the injured tissues. Cadherins
      have been shown to regulate axonal outgrowth in the developing nervous system,
      but this is the first report, to our knowledge, of increased cadherin expression
      associated with axonal regeneration in the vertebrate central nervous system. Our
      results suggest that both Cdh2 and Cdh4 may be important for regeneration of
      injured retinal ganglion cell axons.

PMID- 12429187
TI  - The role of NADPH oxidase and neuronal nitric oxide synthase in zinc-induced
      poly(ADP-ribose) polymerase activation and cell death in cortical culture.
AB  - In the present study, we examined the role and the mechanism of poly(ADP-ribose)
      polymerase (PARP) and poly(ADP-ribose) glycohydrolase (PARG) activation in zinc
      induced cell death in cortical culture. After brief exposure to 400 microM zinc,
      cortical cells exhibited DNA fragmentation, increased poly(ADP-ribosyl)ation, and
      decreased levels of nicotinamide adenine dinucleotide (NAD) and ATP and
      subsequently underwent cell death. Inhibitors of PARP/PARG attenuated both zinc
      induced NAD/ATP depletion and cell death, thereby implicating the PARP/PARG
      cascade in these processes. The zinc-inducible enzymes NADPH oxidase and neuronal
      nitric oxide synthase (nNOS) contributed to PARP activation as their inhibitors
      attenuated zinc-induced poly(ADP-ribosyl)ation. Levels of nitric oxide and
      nitrites increased following zinc exposure, consistent with NOS activation. In
      addition, Western blots and RT-PCR analysis revealed that protein and mRNA levels
      of nNOS specifically increased following zinc exposure in a manner similar to
      that of NADPH oxidase. The present study demonstrates that induction of NADPH
      oxidase and nNOS actively contributes to PARP/PARG-mediated NAD/ATP depletion and
      cell death induced by zinc in cortical culture.

PMID- 12429188
TI  - Elevated levels of neurotrophins in human biceps brachii tissue of amyotrophic
      lateral sclerosis.
AB  - Previous studies suggest that neurotrophins support regeneration and survival of
      injured motoneurons. Based on these findings, brain-derived neurotrophic factor
      (BDNF) has been clinically investigated for its therapeutic potential in
      amyotrophic lateral sclerosis (ALS), a rapidly progressing and fatal motoneuronal
      disease. We questioned whether imbalances of neurotrophic levels are indeed
      involved in the pathology of ALS. Therefore the expression of nerve growth factor
      (NGF), BDNF, neurotrophin-3 (NT-3), and neurotrophin-4/5 (NT-4/5) was
      investigated in postmortem muscle tissue of the biceps from 15 patients with
      neuropathologically confirmed sporadic ALS and 15 age-matched controls. Using
      mRNA analysis techniques and quantitative protein measurements, we have
      demonstrated that both mRNA and protein levels of all four neurotrophins are
      increased in muscle tissue of ALS patients. The production levels displayed a
      disease duration dependency and different expression patterns emerged for the
      four neurotrophins. Whereas the early phase of the disease was characterized by a
      strong upregulation of BDNF, levels of NGF, NT-3, and NT-4/5 gradually increased
      in the course of the disorder, peaking at later stages. We conclude that
      decreased neurotrophic support from muscle tissue is most likely not the cause of
      motoneuron degeneration in ALS. On the contrary, our results suggest that
      degenerating motoneurons in ALS are exposed to elevated levels of muscle-derived
      neurotrophins.

PMID- 12429189
TI  - Coordination and control of forces during multifingered grasping in Parkinson's
      disease.
AB  - In this study, we focused on how subjects with Parkinson's disease (PD) grasp and
      lift with five-digits of the hand. This task provided the opportunity to
      simultaneously examine (a) the coordination of multiple segments (i.e., digits),
      (b) the sequencing of multiple tasks (i.e., force development, object lift, and
      hold), and (c) the control of force output. We found that PD patients coordinated
      and controlled five-digit forces comparable to that of age-matched controls.
      Specifically, these groups developed and maintained similar force amplitudes and
      force sharing patterns across all grasping phases. In addition, PD patients
      demonstrated similar levels of variability both within and across trials. In the
      frequency domain, however, some differences were observed across groups,
      especially in PD patients exhibiting obvious action tremor (AT) at a single modal
      frequency. In these subjects (four of nine PD patients), there was a systematic
      disruption, i.e., a phase-shifting away from approximately 0 degrees, in-phase
      force synchronization patterns normally observed between digits. This disruption
      typically occurred at and around the AT frequency, while at many other
      frequencies synchronization patterns were maintained. The composite of these
      findings implies that although global features observed in five-digit grasping in
      PD patients are preserved, more subtle aspects of the coordination between
      digits, as revealed by frequency domain analysis, are not. These results are
      discussed in relation to the neural mechanisms that might underlie physiological
      synchronization of forces and its pathological disruption.

PMID- 12429190
TI  - Modulated generation of neuronal cells from bone marrow by expansion and
      mobilization of circulating stem cells with in vivo cytokine treatment.
AB  - The aim of the present study is to determine whether the expansion and
      mobilization of circulating bone marrow (BM) stem cells by in vivo treatment with
      granulocyte-colony stimulating factor (G-CSF) and stem cell factor (SCF) increase
      the amount of BM-derived neuronal cells in mouse brain. The presence of BM
      derived cells in the brain was traced by transplanting into lethally irradiated
      adults and newborns adult BM from transgenic mice that ubiquitously expressed
      enhanced green fluorescent protein (GFP). GFP+ and Y-chromosome+ donor-derived
      cells were present in several brain areas of all treated mice (cortical and
      subcortical areas, cerebellum, olfactory bulb). The presence of GFP+ cells
      expressing nuclear neural specific antigen (NeuN), neurofilament, and beta-III
      tubulin in cortical forebrain and olfactory bulb (OB) was higher in G-CSF-SCF
      treated groups (P < 0.05, analysis of variance, Fisher post hoc). We observed
      that overall the amount of double positive cells was higher in animals treated at
      birth than in adults and in OB than in forebrain areas (P < 0.05). Temporal
      cortical areas of cytokine-treated adult animals revealed a mean threefold
      increase in the number of GFP+ cells expressing the nuclear neural specific
      antigen (211 +/- 86 GFP+NeuN+/mm(3) in G-CSF + SCF treated mice and 66 +/- 33
      GFP+NeuN+/mm(3) in control animals). GFP+ cells coexpressing neuronal markers
      contain only one nucleus and have a DNA index (a measure of DNA ploidy) identical
      to that of surrounding neurons, thus excluding donor cell fusion with endogenous
      cells as a relevant phenomenon under these experimental conditions. Our results
      indicate that G-CSF and SCF administration modulates the availability of GFP+
      cells in the brain and enhances their capacity to acquire neuronal
      characteristics. Cytokine stimulation of autologous stem cells might be seen as a
      new strategy for neuronal repair in neurodegenerative diseases.

PMID- 12429191
TI  - Neuroinvasive Nocardia asteroides GUH-2 induces apoptosis in the substantia nigra
      in vivo and dopaminergic cells in vitro.
AB  - Neurodegenerative diseases such as Parkinson's disease are increasingly prevalent
      in the aging population worldwide. The causes of these disorders are unknown, but
      many studies have suggested that the etiology is likely multifactorial and may
      involve exposure to something in the environment combined with the normal aging
      process. Nocardia asteroides are bacteria commonly found in the soil, and
      neuroinvasive strains of nocardiae have been described. N. asteroides strain GUH
      2 invades the brains of experimentally infected animals and selectively affects
      dopaminergic neurons of the substantia nigra (SN), causing an L-DOPA-responsive
      movement disorder resembling parkinsonism. Furthermore, dopaminergic neurons
      undergo morphological changes characteristic of apoptosis following nocardial
      infection. Apoptosis has been implicated in dopaminergic neuronal dropout in
      Parkinson's patients as well as other parkinsonian models. Thus, in this study,
      in vivo and in vitro models were utilized to measure the ability of GUH-2 to
      induce the apoptotic death of dopaminergic cells. Following infection with GUH-2,
      dopaminergic apoptotic cells were identified in the SN of animals by in situ end
      labeling, which detects DNA fragmentation, combined with fluorescent
      immunolabeling of tyrosine hydroxylase-positive cells. In addition, apoptosis was
      observed in PC12 cell cultures incubated with GUH-2 by both in situ end labeling
      and the annexin V assay, which detects externalization of phosphatidylserine of
      the plasma membrane, indicating apoptotic death. Based on the results of these
      studies, it appears that experimental infection with N. asteroides provides a
      general model for studying apoptosis in parkinsonian disorders.

PMID- 12429192
TI  - Aberrant sprouting and downregulation of tyrosine hydroxylase in lesioned
      nigrostriatal dopamine neurons induced by long-lasting overexpression of glial
      cell line derived neurotrophic factor in the striatum by lentiviral gene
      transfer.
AB  - The effects of sustained (up to 9 months) striatal overexpression of glial cell
      line derived neurotrophic factor (GDNF) on lesioned nigrostriatal dopamine (DA)
      neurons was studied using a recombinant lentiviral (rLV) vector to deliver GDNF
      into the striatum 4 weeks prior to the creation of an intrastriatal 6
      hydroxydopamine lesion. The results of the amphetamine-induced rotation suggested
      an initial partial protection followed by a complete recovery, whereas the
      spontaneous motor behaviors remained impaired. There was a clear protection of
      the nigral tyrosine hydroxylase (TH)-positive neurons in the rLV-GDNF group
      compared to rats injected with the control vector encoding green fluorescent
      protein (GFP) (70 and 20% of the intact side, respectively). However, the
      striatal TH+ fiber density was equally reduced (to 20% of the intact side) in
      both groups. Further morphological analyses indicated that the nigrostriatal
      projections of the DA neurons were indeed preserved in the GDNF group. The axonal
      projections were visualized using two independent methods: First, retrograde
      labeling of the nigral cell bodies by intrastriatal Fluoro-Gold injections showed
      that the majority of rescued cells in the GDNF group had preserved axonal
      projections to striatum. Second, injections of a recombinant adeno-associated
      viral vector expressing GFP into the nigra was used to anterogradely fill the DA
      neurons and their projections with GFP protein. GFP immunostaining clearly
      demonstrated that the fibers of the nigral DA cells were preserved along the
      nigrostriatal pathway and innervated large parts of the striatum, but did not
      express TH at detectable levels. In addition, fiber sprouting was observed in the
      globus pallidus, entopeduncular nucleus, and substantia nigra, corresponding to
      areas where GDNF protein was released. The lack of functional recovery in the
      spontaneous motor behaviors may, at least in part, be explained by this extensive
      aberrant fiber sprouting in the downstream striatal target nuclei and/or
      decreased synthesis of dopamine in the striatum.

PMID- 12429193
TI  - Tau conformational changes correspond to impairments of episodic memory in mild
      cognitive impairment and Alzheimer's disease.
AB  - A multitiered strategy was adopted to assess tau conformational changes within
      fibrillar lesions during the progression of Alzheimer's disease (AD). Anti-tau
      monoclonal antibodies whose epitopes are distributed across much of the molecule
      were used to probe vulnerable brain regions in 37 clinically staged cases
      obtained from the Religious Orders Study. In this way, tau conformational changes
      were evaluated as the disease progressed from early cognitive decline to AD.
      These analyses revealed three main findings. First, the presence of
      granulovacuolar and fibrillar lesions correlates with several measures of
      episodic memory, suggesting that these lesions significantly contribute to
      cognitive dysfunction. Second, neuropil threads precede the appearance of
      neurofibrillary tangles that in turn precede the appearance of neuritic plaques.
      Third, tau structural changes, or "conformational signatures," emerged as a
      result of in situ reactivity to a subset of antibodies and nonreactivity to
      others, thereby reflecting the underlying status of the tau molecule within the
      fibrillar lesions. These signatures allowed us to document a sequence of tau
      conformational changes that occur during AD and to correlate these changes with
      episodic memory deficits. Furthermore, we were able to compare conformational
      signatures of tau among different lesion types and determine that the molecular
      profile of tau is lesion-specific.

PMID- 12429194
TI  - Effects of different anesthetics on the paired-pulse depression of the h reflex
      in adult rat.
AB  - Hyperreflexia is a common feature of spinal cord injury (SCI), and changes in
      reflex excitability have been reported to be useful in assessing treatments in
      animal models of cord damage. However, spinal reflexes are known to be dependent
      on anesthetic level. As a preliminary to its use in SCI, the excitability of the
      Hoffman reflex (H reflex) has been assessed under several commonly used
      anesthetics. The H reflex was recorded in the distal foot muscles (dorsal
      interossei) of adult rats, while the lateral plantar nerve was stimulated. Five
      different anesthetics were used: ketamine, halothane, Nembutal, Etomidate, and
      Saffan. Recording and stimulating electrodes were inserted directly through the
      skin to minimize the surgical procedure for each experiment, allowing repeated
      recording to be made in the same animal on a weekly basis. Suppression of the H
      reflex was tested using twin-pulse stimulation. Halothane and ketamine produced
      suppression of the H response when interpulse intervals were shortened to less
      than 1 s. The H-reflex suppression profiles recorded under Etomidate, Saffan, and
      Nembutal anesthesia were less sensitive to the stimulation rate, with little
      reduction until intervals were 200 ms or less. The suppression profiles of
      halothane and ketamine resemble that seen in unanesthetized humans, whereas that
      under the other anesthetics tried here resembles that observed in spinal-cord
      injured animals. The results suggest a preferential action of some anesthetics on
      descending pathways involved in reflex modulation and the importance of assessing
      reflex excitability under anesthetics such as ketamine or halothane.

PMID- 12429195
TI  - Suppression of absence seizures by electrical and pharmacological activation of
      the caudal superior colliculus in a genetic model of absence epilepsy in the rat.
AB  - Activation of the superior colliculus has been shown to reproduce the
      antiepileptic effect of the inhibition of the substantia nigra reticulata. A
      circuit involving neurons of the caudal deep layers of the superior colliculus
      has been suggested to control brain stem convulsive seizures. The present study
      was designed to examine whether a similar circuit is also involved in the control
      of absence seizures. For this, activation of either the rostral or caudal parts
      of the deep and intermediate layers of the superior colliculus was applied in a
      genetic model of absence seizures in the rat (GAERS). Single-shock (5 s)
      electrical stimulation of the rostral and caudal superior colliculus interrupted
      ongoing spike-and-wave discharges at an intensity (antiepileptic threshold)
      significantly lower than the intensity inducing behavioral effects. At this
      intensity, no interruption of licking behavior was observed in water-deprived
      rats. Repeated stimulations (5 s on/5 s off) at the antiepileptic threshold
      reduced absence seizures only during the first 10 min. Bilateral microinjection
      of a GABA antagonist (picrotoxin, 33 pmol/side) significantly suppressed spike
      and-wave discharges when applied in the caudal aspect of the superior colliculus.
      This antiepileptic effect appears dissociated from an anxiogenic effect, as
      tested in an elevated plus maze test. Finally, bilateral injection of picrotoxin
      (33 pmol/side) appeared more effective in the superficial and intermediate layers
      of the caudal superior colliculus, whereas such injections had only weak effects
      on absence seizures when applied in the deep layers. These results suggest that a
      specific population of neurons located in the intermediate and superficial layers
      of the caudal superior colliculus is involved in the inhibitory control of
      absence seizures. It may constitute an important relay for the control of absence
      seizures by the basal ganglia via the substantia nigra reticulata.

PMID- 12429196
TI  - Increased red blood cell polyamines in ALS and Parkinson's disease.
AB  - The polyamines spermidine (SPD) and spermine (SPM) are implicated in nerve cell
      degeneration and regeneration. Over 70% of circulating polyamines are associated
      with red blood cells (RBC). Against this background we have analysed RBC
      polyamines in two neurodegenerative disorders, amyotrophic lateral sclerosis
      (ALS) and Parkinson's disease (PD). Twenty patients with the sporadic form of
      ALS, 20 patients with PD, and 20 healthy controls were studied. The highest
      levels of SPD and SPM were found in the PD group where the mean values were 134
      and 115%, respectively, above those of the controls. The patients with PD also
      presented the lowest levels of the SPD precursor, putrescine (PUTR). In the
      patients suffering from ALS the SPD and SPM mean levels were increased by 46 and
      112%, respectively. The RBC SPD/SPM ratio in the patients suffering from PD was
      significantly elevated in comparison with that of ALS patient group, suggesting a
      different involvement of the polyamine system in these disorders. It is at
      present unknown if raised polyamine levels may contribute to induce the
      degeneration of susceptible neurons or if the increase represents a compensatory
      protective reaction, or simply an unspecific epiphenomenon.

PMID- 12429197
TI  - NFH-LacZ transgenic mice: regional brain activity of cytochrome oxidase.
AB  - Expression of the NFH-LacZ fusion protein in transgenic mice causes an early
      accumulation of neurofilament proteins in the cell bodies of neurons, as well as
      a reduction of motor neuron axonal caliber and Purkinje cell number in the
      cerebellum. Young (3 month old) and older (12-20 months) NFH-LacZ transgenic mice
      were compared to normal controls for regional brain metabolism, as assessed by
      cytochrome oxidase (CO) activity. Irrespective of age, CO activity was reduced in
      three cerebellar-related regions of NFH-LacZ transgenic mice: (1) the lateral
      reticular nucleus, (2) the parvicellular red nucleus, and (3) the superior
      colliculus, possibly as a secondary consequence of cerebellar Purkinje cell
      histopathology. Aged NFH-LacZ mice had lower CO activity relative to either age
      matched controls or young transgenic mice in the following regions: the motor
      nucleus of the vagus nerve, the trapezoid nucleus, the subiculum, the motor
      cortex, the superior olive, and the lateral dorsal thalamus. These results
      indicate regional and age-selective deficits of brain metabolism in a transgenic
      model with neurofilament maldistribution.

PMID- 12429198
TI  - Postischemic administration of basic fibroblast growth factor improves
      sensorimotor function and reduces infarct size following permanent focal cerebral
      ischemia in the rat.
AB  - Basic fibroblast growth factor (bFGF) is a polypeptide with potent trophic and
      protective effects on the brain. bFGF has been reported to exert neuroprotection
      against a wide variety of insults, including ischemic neuronal injury. To date,
      animal models of focal ischemia have not been translated to efficacy in stroke
      clinically with respect to testing of neuroprotective agents. Because functional
      outcome is the measurement of efficacy for putative neuroprotective agents in the
      clinic, we sought to evaluate the functional consequences of bFGF administration
      in rats subjected to focal ischemia. In this study, we assessed the effects of
      bFGF on functional outcome as well as infarct size in rats subjected to severe
      cerebral ischemia by permanent occlusion of the middle cerebral artery (MCAO).
      Male Sprague-Dawley rats were subjected to permanent MCAO by the intraluminal
      filament technique. Two hours following occlusion, rats were infused
      intravenously with either bFGF, at a dose of 150 microg/kg, or vehicle alone.
      Functional sensorimotor impairment, which was assessed by the accelerating
      rotarod test, was recorded at baseline and compared to performance assessed at 24
      h after MCAO. Permanent occlusion of the MCA caused marked impairment in rotarod
      performance in both groups. Treatment of rats with bFGF showed a significant 46%
      improvement in rotarod fall latency when compared with that from the animals
      treated with vehicle alone. The volume of cortical infarction was significantly
      reduced by 32% as a function of bFGF treatment. These results suggest that the
      delayed intravenous administration of bFGF improves sensorimotor function as well
      as reduces infarct size following permanent focal ischemia in rat.

PMID- 12429199
TI  - Mechanisms underlying suppression of protein synthesis induced by transient focal
      cerebral ischemia in mouse brain.
AB  - Transient global cerebral ischemia triggers suppression of the initiation step of
      protein synthesis, a process which is controlled by endoplasmic reticulum (ER)
      function. ER function has been shown to be disturbed after transient cerebral
      ischemia, as indicated by an activation of the ER-resident eIF2alpha kinase PERK.
      In this study, we investigated ischemia-induced changes in protein levels and
      phosphorylation states of the initiation factors eIF2alpha, eIF2B epsilon, and
      eIF4G1 and of p70 S6 kinase, proteins playing a central role in the control of
      the initiation of translation. Transient focal cerebral ischemia was induced in
      mice by occlusion of the left middle cerebral artery. Transient ischemia caused a
      long-lasting suppression of global protein synthesis. eIF2alpha was transiently
      phosphorylated after ischemia, peaking at 1-3 h of recovery. eIF2B epsilon and
      p70 S6 kinase were completely dephosphorylated during ischemia and
      phosphorylation did not recover completely following reperfusion. In addition,
      eIF2B epsilon, eIF4G1, and p70 S6 kinase protein levels decreased progressively
      with increasing recirculation time. Thus, several different processes contributed
      to ischemia-induced suppression of the initiation of protein synthesis: a long
      lasting dephosphorylation of eIF2B epsilon and p70 S6K starting during ischemia,
      a transient phosphorylation of eIF2alpha during early reperfusion, and a marked
      decrease of eIF2B epsilon, eIF4G1, and p70 S6K protein levels starting during
      vascular occlusion (eIF4G1). Study of the mechanisms underlying ischemia-induced
      suppression of the initiation step of translation will help to elucidate the role
      of protein synthesis inhibition in the development of neuronal cell injury
      triggered by transient cerebral ischemia.

PMID- 12429201
TI  - Quetiapine attenuates levodopa-induced motor complications in rodent and primate
      parkinsonian models.
AB  - The contribution of serotoninergic mechanisms to motor dysfunction in Parkinson's
      disease (PD) has yet to be fully elucidated. Recent clinical observations
      increasingly suggest that drugs able to block serotonin 5HT2A/C receptors can
      benefit patients with certain extrapyramidal movement disorders. To further
      explore the roles of these and other neurotransmitter receptors in the
      pathogenesis of parkinsonian signs and levodopa-induced dyskinesias; we evaluated
      the effects of quetiapine, an atypical antipsychotic with 5HT2A/C and D2/3
      antagonistic activity, on motor behavior in 6-hydroxydopamine-lesioned rats and
      MPTP-lesioned nonhuman primates. In hemiparkinsonian rats, quetiapine (5 mg/kg,
      po) reversed the shortened motor response to levodopa challenge produced by 3
      weeks of twice-daily levodopa treatment (P < 0.01). Quetiapine (5 mg/kg po) also
      normalized the shortened response to the acute injection of either a dopamine D1
      receptor agonist (SKF 38392) or a D2 agonist (quinpirole) in rats that had
      received chronic levodopa treatment. Quetiapine had no effect on parkinsonian
      dysfunction when given alone or with levodopa to parkinsonian rats and monkeys.
      Quetiapine (4 mg/kg, po) did, however, substantially reduce levodopa-induced
      dyskinesias when coadministered with levodopa (P < 0.05). These results suggest
      that quetiapine could confer therapeutic benefits to patients with levodopa
      induced motor complications. Moreover, our findings may indicate that 5HT2A/C
      receptor-mediated mechanisms, alone or in combination with other mechanisms,
      contribute to the pathogenesis of the altered motor responses associated with the
      treatment of PD.

PMID- 12429200
TI  - Neonatal ablation of the nigrostriatal dopamine pathway does not influence limb
      development in rats.
AB  - Hemiparkinson-hemiatrophy syndrome (HP-HA) is associated with skeletal
      hemiatrophy and the later development of parkinsonism. It is generally assumed
      that this phenotype is due to the combination of dysfunction of the basal ganglia
      (e.g., substantia nigra compacta and/or other related structures), causing
      parkinsonism, and of other areas (e.g., cerebral cortex), causing hemiatrophy.
      The occurrence of asymmetry of limb size in a patient with very asymmetric
      involvement of dopa-responsive dystonia encouraged Greene et al. (2000, Mov.
      Disord. 15: 537-541) to propose that lifelong deficits in nigrostriatal dopamine
      could account for limb asymmetry in HP-HA. The purpose of this study was to
      determine whether skeletal hemiatrophy could be produced in rats by unilateral,
      neonatal ablation of the nigrostriatal dopamine pathway. Infusion of 6
      hydroxydopamine into the striatum of rat neonates resulted in loss of dopamine
      neurons in the ipsilateral substantia nigra, reduced striatal dopamine levels,
      and stimulant-induced motor asymmetry. Saline infusions neither altered the
      number of dopamine neurons nor produced behavioral changes. Both groups incurred
      discrete lesions of the ipsilateral motor cortex surrounding the infusion site
      and atrophy of the corresponding cerebral peduncle. Cortical, but not
      nigrostriatal, lesions were associated with significant atrophy of ipsilateral
      femora, humeri, and innominate bones, as assessed radiographically. Skeletal
      hemiatrophy was not observed in naive animals or in experimental animals that did
      not exhibit corticospinal abnormalities. The results of this study indicate that
      early skeletal development in rats is not affected by loss of nigrostriatal
      dopamine per se, but is markedly attenuated by corticospinal lesions sustained
      during the neonatal period.

PMID- 12429202
TI  - Fimbria-fornix lesion does not affect APP levels and amyloid deposition in the
      hippocampus of APP+PS1 double transgenic mice.
AB  - The deposition of amyloid beta peptides (Abeta) and cholinergic dysfunction are
      two characteristic features of Alzheimer's disease. Several studies have
      suggested that a compromised cholinergic transmission can increase the amount of
      amyloid precursor protein (APP) in the denervated cortex (or hippocampus);
      however, whether this will increase Abeta production is unknown. To investigate
      the relation between cholinergic neurotransmission and APP metabolism, and the
      possible role of cholinergic dysfunction in the development of amyloid
      neuropathology, we lesioned the fimbria-fornix pathway in APP+PS1 double
      transgenic mice, at 5 and 7 months of age. Three months and 11 months postlesion,
      the mice were sacrificed for biochemical and histopathological analyses. The
      fimbria-fornix transection resulted in a substantial depletion of cholinergic
      markers in the hippocampus at both time points. Three months postlesion,
      hippocampal APP and Abeta levels were not significantly changed. At 11 months
      postlesion, the fimbria-fornix lesion did not result in an alteration in either
      the hippocampal Abeta levels or the extent of Abeta deposition, as assessed by
      amyloid plaque counts and image analysis of Abeta load in the 18-month-old
      APP+PS1 mice. Our findings indicate that APP metabolism in mice may be
      dissociated from cholinergic neurotransmission rather than related as previously
      suggested in other mammalian species.

PMID- 12429204
TI  - Oscillatory local field potentials recorded from the subthalamic nucleus of the
      alert rat.
AB  - Hitherto, high-frequency local field potential oscillations in the upper gamma
      frequency band (40-80 Hz) have been recorded only from the region of subthalamic
      nucleus (STN) in parkinsonian patients treated with levodopa. Here we show that
      local field potentials recorded from the STN in the healthy alert rat also have a
      spectral peak in the upper gamma band (mean 53 Hz, range 46-70 Hz). The power of
      this high-frequency oscillatory activity was increased by 30 +/- 4% (+/-SEM)
      during motor activity compared to periods of alert immobility. It was also
      increased by 86 +/- 36% by systemic injection of the D2 dopamine receptor agonist
      quinpirole. The similarities between the high-frequency activities in the STN of
      the healthy rat and in the levodopa-treated parkinsonian human argue that this
      oscillatory activity may be physiological in nature and not a consequence of the
      parkinsonian state.

PMID- 12429203
TI  - Both dorsal and ventral spinal cord pathways contribute to overground locomotion
      in the adult rat.
AB  - Identification of long tracts responsible for spontaneous locomotion is critical
      for spinal cord injury (SCI) repair strategies. We recently demonstrated that
      extensive demyelination of adult rat thoracic ventral columns, ventromedial, and
      ventrolateral white matter produces persistent, significant open-field hindlimb
      locomotor deficits. Locomotor movements resulting from stimulation of the
      pontomedullary locomotor region are inhibited by dorsolateral funiculus (DLF)
      lesions suggesting that important pathways for locomotion may also exist in the
      dorsal white matter. However, dorsal hemisections that interrupt dorsal
      columns/dorsal corticospinal tract (DC/CST) and DLF pathways do not produce
      persistent, severe locomotor deficits in the adult rat. We studied the
      contributions of myelinated tracts in the DLF and DC/CST to overground locomotion
      following complete conduction blockade of axons in the ventrolateral funiculus
      (VLF), a region important for locomotor movements and for transcranial magnetic
      motor-evoked potentials (tcMMEP). Animals received ethidium bromide plus photon
      irradiation to produce discrete demyelinating lesions sufficient to stop axonal
      conduction in the VLF, combined VLF + DLF, or combined VLF + DC/CST. Open-field
      BBB scores and tcMMEPs were studied at 1, 2, 3, and 4 weeks postlesion. VLF
      lesions resulted in mean BBB scores of 17 at 4 weeks. VLF + DC/CST and VLF + DLF
      lesions resulted in mean BBB scores of 15.9 and 11.1, respectively. TcMMEPs were
      absent in all lesion types confirming VLF conduction blockade throughout the
      study. Our data indicate that significant contributions to locomotion from
      myelinated pathways within the rat DLF can be revealed when combined with
      simultaneous compromise of the VLF.

PMID- 12429205
TI  - Suppression of insult-induced neurogenesis in adult rat brain by brain-derived
      neurotrophic factor.
AB  - In mammals, including humans, the subventricular zone of the lateral ventricle
      and the subgranular zone of the dentate gyrus contain neural stem cells, which
      continue to proliferate even in adulthood and give rise to new neurons.
      Neurogenesis in these areas is enhanced by brain insults. Brain-derived
      neurotrophic factor (BDNF) promotes neuronal survival and differentiation during
      the development of the nervous system. In the adult intact brain, BDNF
      administration in the lateral ventricle or ventricular zone stimulates
      neurogenesis in several forebrain areas. Here we show that intrahippocampal
      transduction of recombinant adeno-associated virus carrying the BDNF gene giving
      rise to levels of BDNF protein sufficient to induce a functional response
      inhibits the formation of new dentate granule cells triggered by global forebrain
      ischemia in rats. Our data indicate that long-term delivery of a neurotrophic
      factor, which is considered as a novel neuroprotective strategy for human brain
      diseases, may attenuate intrinsic neuroregenerative responses.

PMID- 12429206
TI  - Mice lacking glutathione peroxidase-1 activity show increased TUNEL staining and
      an accelerated inflammatory response in brain following a cold-induced injury.
AB  - The mechanisms leading to neurodegeneration are complex and multifactorial.
      Oxidative stress has been identified as an important constituent in this process
      and the use of transgenic and knockout mice has allowed the role of key
      components of the antioxidant pathway to be evaluated. In this study, we have
      used mice lacking the glutathione peroxidase-1 gene in order to determine the
      consequences of a reduced capacity to neutralize hydrogen peroxide toward the
      pathological outcomes following cold-induced brain injury. Analysis of brain
      cryosections using TUNEL staining revealed a significant increase in brain cell
      death in knockout mice compared to that seen in wild-type mice. Interestingly,
      cell death appeared to be uncoupled to a neuro-inflammatory response which was
      observed in both knockout and wild-type mice but which proceeded in an
      accelerated manner in glutathione peroxidase-1 knockout mice at 24 h, rapidly
      diminishing by 96 h postinjury. Our data suggest an important role for
      glutathione peroxidase-1 in modulating molecular pathways involved in both the
      level of cell death and inflammatory cascades in brain through its antioxidant
      capacity in regulating levels of oxygen species such as hydrogen peroxide.

PMID- 12429207
TI  - Interferon-gamma regulates oxidative stress during experimental autoimmune
      encephalomyelitis.
AB  - Experimental autoimmune encephalomyelitis (EAE) is an induced inflammatory and
      demyelinating disease of the central nervous system which shares many clinical
      and pathological features with and is considered the animal model of multiple
      sclerosis. There is extensive evidence that EAE is a Th1 disease eliciting
      secretion of proinflammatory cytokines like IFN-gamma or TNF-alpha, and it has
      been suggested that cytokine-induced oxidative stress could have a role in EAE
      neuropathology. However, the individual roles of these and other cytokines in the
      pathogenesis of the disease are still uncertain. Here we analyze the role of IFN
      gamma during EAE by using both IFN-gamma receptor-knockout (IFN-gamma R(-/-)) and
      wild-type mice, both strains immunized with peptide 40-55 from rat myelin
      oligodendrocyte glycoprotein. The levels of oxidative stress were determined
      through the analysis of immunoreactivity for inducible NO synthase,
      nitrotyrosine, and malondialdehyde, as well as through the expression of the
      tissue-protective antioxidant factors metallothionein I+II (MT-I+II). We also
      examined the number of cells undergoing apoptosis as judged by using the TUNEL
      technique. The levels of oxidative stress, MT-I+II, and apoptotic cell death by
      EAE were significantly increased in all mice, though more so in IFN-gamma R(-/-)
      mice compared with wild-type mice. These data support the notion that IFN-gamma
      has a protective role against EAE.

PMID- 12429208
TI  - Identification of the human cDNA for new survival/evasion peptide (DSEP): studies
      in vitro and in vivo of overexpression by neural cells.
AB  - We identified the human cDNA encoding a peptide that has been partially purified
      from the secretions of oxidatively stressed neural cell lines, murine
      adenocarcinoma cells, and group Abeta-hemolytic steptococci. We then genetically
      modified mouse and human neural cells to overexpress this peptide and found these
      modified cells to be remarkably hearty, surviving under conditions of severe
      oxidative stress, in xenocultures when exposed to activated macrophages, and as
      xenografts in the brain of rats that were not immunosuppressed. The peptide is
      called DSEP (dee-sep) for diffusible survival evasion peptide. Part of the
      survival advantage of DSEP overexpressors may be due to their attenuated response
      to all-trans-retinoic acid, which regulates differentiation and apoptosis of
      several cell types including neural and immune cells.

PMID- 12429209
TI  - Lipid-mediated glial cell line-derived neurotrophic factor gene transfer to
      cultured porcine ventral mesencephalic tissue.
AB  - Transplantation of dopaminergic ventral mesencephalic (VM) tissue into the basal
      ganglia of patients with Parkinson's disease (PD) shows at best moderate
      symptomatic relief in some of the treated cases. Experimental animal studies and
      clinical trials with allogenic and xenogenic pig-derived VM tissue grafts to PD
      patients indicate that one reason for the poor outcome of neural transplantation
      is the low survival and differentiation of grafted dopaminergic neurons. To
      improve dopaminergic cell survival through a gene-therapeutic approach we have
      established and report here results of lipid-mediated transfer of the gene for
      human glial cell line-derived neurotrophic factor (GDNF) to embryonic (E27/28)
      porcine VM tissue kept as organotypic explant cultures. Treatment of the
      developing VM with two mitogens, basic fibroblast growth factor and epidermal
      growth factor, prior to transfection significantly increased transfection yields.
      Expression of human GDNF via an episomal vector could be detected by in situ
      hybridization and by the measuring of GDNF protein secreted into the culture
      medium. When compared to mock-transfected controls, VM tissue expressing
      recombinant GDNF contained significantly higher numbers of tyrosine hydroxylase
      positive neurons in the cultured VM tissue. We conclude that lipid-mediated gene
      transfer employed on embryonic pig VM explant cultures is a safe and effective
      method to improve survival of dopaminergic neurons and may become a valuable tool
      to improve allo- and xenotransplantation treatment in Parkinson's disease.

PMID- 12429210
TI  - Neural stem cells spontaneously express dopaminergic traits after transplantation
      into the intact or 6-hydroxydopamine-lesioned rat.
AB  - The ability to differentiate neural stem cells (NSCs) into dopamine neurons is
      fundamental to their role in cell replacement therapies for neurodegenerative
      disorders such as Parkinson's disease. We show here that when a clonal line
      (C17.2) of undifferentiated NSCs is transplanted into the intact or 6
      hydroxydopamine-lesioned striatum, cells withdraw from the cell cycle (BrdU(-)),
      migrate extensively in the host striatum, and express markers associated with
      neuronal (beta-tubulin III(+), NSE(+), NeuN(+)) but not glial (GFAP(-), MBP(-),
      A2B5(-)) differentiation. Importantly, by 2-5 weeks postgrafting, in the majority
      of these transplants, nearly all engrafted cells express the dopamine
      synthesizing enzymes tyrosine hydroxylase and aromatic L-amino decarboxylase,
      sometimes resulting in changes in motor behavior. In contrast, no NSCs stain for
      dopamine-beta-hydroxylase, choline acetyltransferase, glutamic acid
      decarboxylase, or serotonin. We conclude that, following transplantation into the
      intact or 6-hydroxydopamine-lesioned rat, the adult brain contains intrinsic cues
      sufficient to direct the specific expression of dopaminergic traits in immature
      multipotential neural stem cells.

PMID- 12429211
TI  - Differences in host serotonin innervation of intrastriatal grafts are not
      determined by a glial scar or chondroitin sulfate proteoglycans.
AB  - Serotoninergic (5-HT) neurons of adult recipients provide a much denser
      innervation of striatal than ventral mesencephalic grafts implanted into the
      neostriatum of the rat. Moreover, grafts from both brain regions are more
      innervated by host 5-HT axons after implantation in neonatal than adult hosts. To
      test the hypothesis that differences in glial scarring or expression of the
      growth inhibitory molecules, chondroitin sulfate proteoglycans (CSPG), be
      responsible for these differences in 5-HT innervation of neural grafts, we
      examined the 5-HT innervation, the astroglial reaction and the expression of CSPG
      in ventral mesencephalic grafts implanted into newborn (1-5 days old), juvenile
      (15 days old), or adult rats and in striatal grafts implanted in adult rats,
      using immunohistochemistry against 5-HT, glial fibrillary acidic protein (GFAP)
      and CSPG. Immunostaining for GFAP showed a stronger initial gliosis (1-10 days
      after grafting) in neonatal than adult recipients of mesencephalic grafts, but
      this gliosis subsided gradually at later time points. Nevertheless, a glial scar
      formed at the graft-host interface in both neonatal and adult recipients, 5-10
      days after transplantation, although it decreased over a longer time course--up
      to 60 days--in adults. Immunostained astrocytes appeared first in the host brain
      tissue around the graft and then immunoreactive processes and perikarya gradually
      invaded the graft. Immunoreactivity for CSPG was similar in neonatal and adult
      hosts: it was strongly expressed inside the graft early after transplantation,
      and almost completely down-regulated at 60 days. The reaction of adult hosts to
      striatal and mesencephalic grafts was similar, although GFAP was more
      heterogeneously distributed and CSPG immunoreactivity remained in patches inside
      striatal grafts, even after 60 days. The 5-HT innervation of mesencephalic grafts
      was much denser after implantation in newborns than in adults. It was also
      stronger in striatal than in mesencephalic grafts implanted in adults. Thus, the
      presence of a glial scar or the expression of CSPG cannot totally account for the
      different degrees of 5-HT innervation in the various types of neural grafts.

PMID- 12429212
TI  - Hybrid tetanus toxin C fragment-diphtheria toxin translocation domain allows
      specific gene transfer into PC12 cells.
AB  - To study the mechanism by which genes can efficiently be transferred into
      specific cell types, we have constructed several novel, single-chain
      multicomponent proteins by recombining the nontoxic C fragment of tetanus toxin
      and the translocation domain of diphtheria toxin together with the DNA-binding
      fragment of GAL4 transcription factor, for transportation of plasmid DNA into
      neuronal cells. The C fragment of tetanus toxin provided neuronal selectivity,
      the translocation domain of diphtheria toxin permitted endosomal escape, and the
      GAL4 domain provided binding to DNA. To assess the cellular tasks of each
      component in gene transfer, different combinations of these fragments were
      produced by polymerase chain reaction, expressed in Escherichia coli, and
      purified under native conditions from the soluble proteins. We show that only
      fusion proteins bearing the C fragment of tetanus toxin bind to gangliosides and,
      followed by their specific binding to differentiated PC12 cells, are internalized
      within 10 min. These proteins delivered the green fluorescence protein gene to
      PC12 cells, with the highest transfection efficiency achieved with proteins
      containing both the C fragment and the translocation domain. Addition of
      chloroquine elevated the transfection efficiency, which was further increased by
      incorporation of a nuclear localization signal in the delivery system. In
      addition, the effect of different DNA-condensing materials (poly-L-lysine,
      protamine, lysine(n=8)-trytophan(n=2)-lysine(n=8)) on gene transfer was
      investigated.

PMID- 12429213
TI  - Heterogeneity of nigral and cortical Lewy bodies differentiated by amplified
      triple-labeling for alpha-synuclein, ubiquitin, and thiazin red.
AB  - Alpha-synuclein(alpha-S) and ubiquitin(Ub) are constituents of the Lewy bodies
      (LBs), composed of fibrillary structures. To clarify morphological heterogeneity
      of LBs, we looked for localization of these epitopes in relation to fibrillary
      structure possibly detectable by a fluorochrome, thiazin red (TR). On the
      sections of the substantia nigra (SN) and the cingulate gyrus (CG) obtained from
      Parkinson's disease brains, double amplification by CARD fluorescent
      immunohistochemistry with anti-alpha-S monoclonal (LB509) and anti-Ub polyclonal
      antibodies was performed, followed by staining with TR. These triple-labeled
      images were captured by a confocal laser microscope and subsequently stained with
      Campbell-Switzer method, a silver staining specific for LBs. Staining profiles of
      LBs were different between those in the SN and in the CG. Immunolabeling either
      with the anti-alpha-S or anti-Ub antibody was diffuse without halo structure in
      LBs of CG. In addition to this diffuse staining, a lot of LBs of SN exhibited a
      halo structure immunopositive for alpha-S and Ub, probably representing later
      stages of LB evolution. Irrespective of the presence of this halo structure, the
      TR signal was always concentrated in the center of LBs, as the silver-stained
      material was, suggesting that fibrillary components in the central portion of LBs
      undergo some conformational changes detectable by TR and the silver-staining.
      This technique reveals different epitopes in relation to LB evolution in vivo.
      Heterogeneity in staining profile of LBs, as clarified by this method, may
      represent evolutional changes of LBs, related to conformational states of their
      constituents.

PMID- 12429214
TI  - Acute neuroinflammation exacerbates excitotoxicity in rat hippocampus in vivo.
AB  - Accumulating evidence suggests that inflammation may play an important part in
      neurodegenerative diseases such as Alzheimer's disease. Inflammation itself,
      however, is insufficient to produce acute neurodegeneration in vivo. In this
      report, we determined whether inflammation increases excitotoxicity in
      hippocampal neurons. A proinflammagen, bacterial endotoxin lipopolysaccharide,
      was coinjected with ibotenate, an N-methyl-D-aspartate receptor agonist, into rat
      hippocampus. One week after coinjection, significant neuronal degeneration and
      severe tissue collapse were observed in the hippocampus. Astroglial and
      microglial infiltration were also detected. The neurodegeneration was suppressed
      by dizocilpine maleate, an N-methyl-D-aspartate receptor antagonist. We then
      examined whether microglial activation takes part in synergistic neuronal loss.
      One day after the lipopolysaccharide injection into the rat hippocampus,
      substantial microglial activation and induction of inducible nitric oxide
      synthase were observed, while neither neuronal nor astrocytic changes were
      detected. On the other hand, ibotenate injection at the same place 1 day after
      lipopolysaccharide injection in the hippocampus produced significant neuronal
      degeneration and gross microglial activation. These results suggest that
      inflammation by lipopolysaccharide might play an important role in
      ibotenate/lipopolysaccharide neurotoxicity.

PMID- 12429215
TI  - Death of preganglionic sympathetic neurons after surgical or immunologic lesion
      of peripheral processes.
AB  - Three months after systemic injection of antibody to acetylcholinesterase (AChE),
      there is a 60% decrease in the population of preganglionic sympathetic neurons
      expressing choline acetyltransferase (ChAT) in the intermediolateral (IML)
      nucleus of the rat spinal cord. In principle, the disappearance of identifiable
      cholinergic neurons might reflect either outright cell death or severe atrophy
      with downregulation of cholinergic markers. To distinguish between these
      possibilities, preganglionic neurons were labeled with the retrograde tracer dye,
      Fast Blue, 1 week before antibody injection or surgical transection of the
      cervical sympathetic trunk. Three months after either treatment, the thoracic IML
      contained 40-60% fewer Fast Blue-labeled neurons than in controls. Therefore,
      preganglionic sympathetic neurons do degenerate after antibody injection or
      axotomy. To clarify the role of axonal damage in this process, the effects of
      three different mechanical lesions were examined. A lumbar ganglionectomy
      designed to interrupt most sympathetic axons emanating from L2 IML caused 92%
      loss of ChAT-positive cells observed 10 weeks later at that site. In comparison,
      transection of the cervical sympathetic trunk, which spared some distally
      directed axonal branches from the thoracic IML, caused only a 46% loss of ChAT
      positive neurons at T1. Still smaller effects were seen after the same nerve was
      crushed, a lesion that is less destructive. Thus, the ability of central
      sympathetic neurons to survive a peripheral lesion may be related to the degree
      of axonal damage and to the opportunity for axonal regrowth.

PMID- 12429216
TI  - The case for the bulbospinal respiratory nitric oxide synthase-immunoreactive
      pathway in the dog.
AB  - Previous investigations from our laboratory have documented that the neuropil of
      the phrenic nucleus contains a dense accumulation of punctate nicotinamide
      adenine dinucleotide phosphate diaphorase staining. In this study we investigated
      the occurrence and origin of punctate nitric oxide synthase immunoreactivity in
      the neuropil of the phrenic nucleus in C3-C5 segments, supposed to be the
      terminal field of the premotor bulbospinal respiratory nitric oxide synthase
      immunoreactive pathway in the dog. As the first step, nitric oxide synthase
      immunohistochemistry was used to characterize nitric oxide synthase
      immunoreactive staining of the phrenic nucleus and nitric oxide synthase
      containing neurons in the dorsal and rostral ventral respiratory group and in the
      Botzinger complex of the medulla. Dense punctate nitric oxide synthase
      immunoreactivity was found on control sections in the neuropil of the phrenic
      nucleus. Several thin bundles of nitric oxide synthase-immunoreactive fibers were
      found to enter the phrenic nucleus from the lateral and ventral column. Nitric
      oxide synthase-containing neurons were revealed in the dorsal respiratory group
      of medulla corresponding to the ventrolateral nucleus of the solitary tract and
      in the rostral ventral respiratory group beginning approximately 1 mm caudal to
      the obex and reaching to 650 microm rostral to the obex. Axotomy-induced
      retrograde changes, consisting in a strong upregulation of nitric oxide synthase
      containing neurons, were found in the dorsal and rostral ventral respiratory
      group contralateral to the hemisection performed at the C2-C3 level.
      Concurrently, a strong depletion of the punctate nitric oxide synthase
      immunopositivity in the neuropil of the phrenic nucleus ipsilaterally with the
      hemisection was detected, thus revealing that a crossed premotor bulbospinal
      respiratory pathway contains a fairly high number of nitric oxide synthase
      immunopositive fibers terminating in the phrenic nucleus. The use of the
      retrograde fluorescent tracer Fluorogold injected into the phrenic nucleus and an
      analysis of sections cut through the dorsal and rostral ventral respiratory group
      and Botzinger complex of medulla and processed for nitric oxide synthase
      immunocytochemistry revealed that approximately 73.8% of crossed premotor
      bulbospinal respiratory nitric oxide synthase-immunoreactive axons originate in
      the rostral ventral respiratory group and 26.2% is given by nitric oxide synthase
      containing neurons of the dorsal respiratory group. A few premotor nitric oxide
      synthase-immunoreactive axons originating from the Botzinger complex were found.
      In summary, the present study provides evidence for a hitherto unknown premotor
      bulbospinal respiratory nitric oxide synthase-immunoreactive pathway connecting
      the bulbar respiratory centers with the motor neurons of the phrenic nucleus in
      the dog.

PMID- 12429217
TI  - Changes in immunoreactivity to calcium-binding proteins in the anterior olfactory
      nucleus of the rat after neonatal olfactory deprivation.
AB  - The effects of olfactory deprivation on the density of neuronal populations
      expressing the calcium-binding proteins calbindin D-28k, calretinin, and
      parvalbumin in the anterior olfactory nucleus of the rat were studied
      immunohistochemically in 60-day-old rats subjected to unilateral naris closure on
      the day of birth. The neuronal populations were characterized morphologically and
      topologically, and the density of each cell type was calculated in each
      subdivision of the anterior olfactory nucleus at seven rostrocaudal levels. Data
      were gathered into three groups: data from either the ipsilateral or
      contralateral anterior olfactory nucleus of experimental animals and data from
      control animals. Statistical analysis indicated that disruption of the normal
      afferent activity to one olfactory bulb affects the expression of the calcium
      binding proteins investigated in the anterior olfactory nucleus, as revealed by
      variations in the density of certain neuronal populations. The observed effects
      were very heterogeneous and could not be related to any specific neuronal type,
      location, or to the expression of a given calcium-binding protein. Nevertheless,
      as a general rule the most affected neuronal populations were those expressing
      calbindin D-28k located in the rostral subdivisions. These subdivisions are the
      latest to develop in mammals and are those that receive the largest amount of
      inputs from the olfactory bulb.

PMID- 12429218
TI  - Glucocorticoid exacerbation of gp120 neurotoxicity: role of microglia.
AB  - Gp120 protein, part of the HIV coat, may be a causative agent in AIDS-Related
      Dementia (ARD) because of its demonstrated neurotoxicity in vitro and in vivo.
      There are two possible mechanisms for this toxicity, namely through release of
      toxins from the microglia or through direct action on neuronal chemokine
      receptors. In tissue culture, glucocorticoids (GCs), the adrenal steroids
      released during stress, exacerbate gp120 neurotoxicity. In this paper, we examine
      the means by which GCs may increase toxicity, focusing on interactions with
      microglia and glia. Media from microglia treated with gp120 was toxic to neurons
      but not to glia. The effects of GCs upon the extent of gp120-induced release of
      toxins by microglia seemed to be dependent on the time of exposure to the
      hormone. Twenty-four-hour exposure of microglia to GCs decreased the toxicity of
      gp120-treated microglial conditioned media. In contrast, longer-term GC exposure
      enhanced neurotoxicity. There also appeared to be a component of gp120
      neurotoxicity in hippocampal cultures that was exacerbated by GCs, independent of
      the amount of microglia present. Thus, GCs appear to act at a number of different
      sites in the multi-cellular pathway to exacerbate the neurotoxic effects of
      gp120.

PMID- 12429219
TI  - Cell lines derived from hippocampal neurons of the normal and trisomy 16 mouse
      fetus (a model for Down syndrome) exhibit neuronal markers, cholinergic function,
      and functional neurotransmitter receptors.
AB  - We have established hippocampal cell lines from normal and trisomy 16 fetal mice,
      a model of human trisomy 21. Both cell lines, named H1b (derived from a normal
      animal) and HTk (trisomic) possess neuronal markers by immunohistochemistry
      (enolase, synaptophysin, microtubule associated protein-2, and choline
      acetyltransferase) and lack glial markers (glial fibrillary acidic protein and S
      100). Also, we evaluated intracellular Ca(2+) levels ([Ca(2+)](i)) in response to
      neurotransmitter agonists, in cells loaded with the fluorescent Ca(2+) indicators
      Indo-1 and Fluo-3. Both cell lines responded to glutamatergic stimuli induced by
      glutamate, N-methyl-D-aspartate, I-amino-2,3-dihydro-5-methyl-3-oxo-4-isoxazole
      propanoic acid or kainate. Glutamate responses were only partially prevented by
      addition of 5 mM EGTA and the metabotropic glutamate receptor agonist, trans
      (1S,3R)-1-amino-1,3-cyclopentanedicarboxylic acid (ACPD), increased [Ca(2+)](i)
      in both cell types. These results confirm the presence of glutamatergic
      metabotropic receptors. In glutamate-induced responses, HTk cells exhibited
      slower time-dependent decay kinetics than H1b cells. Cholinergic agonists
      (nicotine and muscarine) induced a rapid, transient increase in [Ca(2+)](i) in
      both cell types. Furthermore, some cells were sensitive to histamine and
      norepinephrine. All responses to the aforementioned agonists were prevented by
      addition of specific antagonists. We also studied incorporation and release of
      [(3)H]choline in the cells, and observed no differences in uptake parameters.
      However, release induced by K(+) and nicotine depolarization was greatly reduced
      in HTk cells. The results show that H1b and HTk cells retain neuronal
      characteristics and respond to specific neurotransmitter stimuli. The HTk
      differences could be related to neuronal pathophysiology in Down syndrome.

PMID- 12429220
TI  - Changes in visual response properties of cat retinal ganglion cells within two
      weeks after axotomy.
AB  - After optic nerve transection beta cells of cat retinal ganglion cells (RGCs)
      suffer from rapid cell death from 3 to 7 days, whereas alpha cells gradual cell
      death until 14 days. Here we report electrophysiological properties of Y-
      (morphological alpha) and X- (morphological beta) cells at 5 and 14 days after
      axotomy in comparison with those of intact Y- and X-cells. Most of the axotomized
      RGCs revealed characteristic visual response properties that enable us to
      classify them into Y- or X-cells. Physiological sampling ratio of X-cells sharply
      decreased from day 5 to 14 after axotomy, corresponding to the previous
      morphological results. As compared with intact RGCs, axotomized RGCs of both Y-
      and X-type revealed the following abnormalities: smaller receptive field centers,
      weaker visual responses and lower spontaneous activities. Intracellular
      injections of Lucifer yellow into axotomized and intact RGCs at eccentricities 0
      6 mm from the area centralis revealed no sign of shrinkage in dendritic field
      size of either alpha or beta cells on day 5 and day 14 after axotomy, revealing
      that observed smaller receptive field centers of axotomized RGCs on day 5 were
      not due to the change of dendritic field sizes. These results suggest that the
      major events occurring shortly after axotomy are significant loss of synaptic
      inputs from afferent neurons in the retina and/or changes of membrane properties
      of axotomized RGCs. These events can also explain lower spontaneous activities
      and weaker visual responses of axotomized RGCs.

PMID- 12429221
TI  - Role of TNF-alpha receptors in mice intoxicated with the parkinsonian toxin MPTP.
AB  - The loss of dopaminergic neurons in Parkinson's disease is associated with a
      glial reaction and the overproduction of proinflammatory cytokines such as tumor
      necrosis factor alpha (TNF-alpha). TNF-alpha acts via two different receptors,
      TNFR1 and TNFR2, and is believed to have both a neuroprotective and a deleterious
      role for neurons. In order to analyze the putative role of TNF-alpha in
      parkinsonism, we compared the effect of the parkinsonian drug 1-methyl-4-phenyl
      1,2,3,6-tetrahydropyridine (MPTP) in mice lacking TNFR1, TNFR2, or both receptors
      and in wild-type littermates. We show that MPTP does not affect spontaneous
      activity or anxiety in any of the groups and that it reduces motor activity on a
      rotarod in double knock out mice but not in mice lacking only one receptor.
      Postmortem analysis revealed no differences in the number of nigral dopaminergic
      neurons whatever the group. In contrast, striatal dopamine level was slightly
      decreased in double knock-out mice and more reduced by MPTP in this group than in
      the other groups of mice. In addition, dopamine turnover was significantly more
      increased in double knock out mice after MPTP injection. These data suggest that
      TNF-alpha does not participate in the death of dopaminergic neurons in
      parkinsonism but that it slightly alters dopamine metabolism or the survival of
      dopaminergic terminals by a mechanism involving both receptors.

PMID- 12429222
TI  - A light and electron microscopic study of divalent metal transporter-1
      distribution in the rat hippocampus, after kainate-induced neuronal injury.
AB  - An accumulation of iron occurs in the hippocampus of rats injected with kainate
      over time, but thus far whether this accumulation is associated with any changes
      in expression of iron transporters is not known. The present study was therefore
      carried out using an antibody to the divalent metal transporter-1 (DMT-1) and
      immunoblot and immunocytochemical analyses to elucidate possible changes in
      expression of the transporter in the rat hippocampus after kainate injections. A
      significant increase in density ratios of DMT-1/beta-actin bands was observed in
      Western blots in the 1-week, 1-month, and 2-months post-kainate-injected
      hippocampus, compared to uninjected and 1-day post-kainate-injected hippocampus.
      The increase in DMT-1 protein was paralleled by an increase in DMT-1
      immunoreactivity in astrocytes. Light staining for DMT-1 was observed in the
      uninjected, saline-injected, and 1-day post-kainate-injected rat hippocampus. In
      contrast, an upregulation of DMT-1 was observed in reactive glial cells at 1
      week, 1 month, and 2 months post-kainate injection. Electron microscopy confirmed
      that the glial cells had morphological features of astrocytes. DMT-1 is a
      cellular iron transporter responsible for transport of metal ions from the plasma
      membrane to endosomes. The observation that DMT-1 is present on astrocytic end
      feet in contact with blood vessels suggests that these cells may be involved in
      uptake of iron from endothelial cells.

PMID- 12429223
TI  - Synaptophysin in the cochlear nucleus following acoustic trauma.
AB  - Chinchillas are notable for a low-frequency hearing range similar to that of
      humans and a marked sensitivity to loud noise. A single noise exposure that
      produces cochlear damage may lead to progressive loss of synaptic endings in the
      cochlear nucleus, followed by new axonal growth. As an index of synaptic
      regulation during such changes, we have examined the expression of a synaptic
      vesicle protein, synaptophysin, in the cochlear nucleus following a damaging
      acoustic stimulus in adult chinchillas. With one ear protected by a plug,
      following a 3-h exposure to an octave-band noise of 108 dB sound pressure level,
      centered at 4 kHz, the unprotected cochlea and the cochlear nuclei exhibited
      degeneration of hair cells and axons over periods of 7, 14, 30, 90, and 150 days.
      Axonal degeneration, as revealed by a silver degeneration method, was heavy
      ipsilateral to the cochlear damage, but sparse degeneration also appeared on the
      contralateral, unexposed side. Synaptophysin immunostaining underwent a major,
      bilateral decline in the anteroventral and posteroventral cochlear nuclei,
      interrupted at intervening periods by transient increases in the numbers of
      stained structures. A distinction in staining between large perisomatic
      structures and smaller puncta in the neuropil and between the dorsal and the
      ventral zones of the ventral cochlear nuclei revealed some variations in the
      response and degree of recovery of synaptophysin staining. These findings could
      best be explained by degeneration of synaptic endings followed by new growth of
      terminals and by regulatory changes in the levels of synaptophysin expression and
      synaptic vesicle accumulation over time.

PMID- 12429224
TI  - L-4-chlorokynurenine attenuates kainate-induced seizures and lesions in the rat.
AB  - Blockade of the strychnine-insensitive glycine site of the NMDA receptor is
      considered an attractive strategy for the development of novel neuroprotective
      and anticonvulsive agents. 7-Cl-kynurenic acid (7-Cl-KYNA) is a potent, selective
      antagonist of the NMDA/glycine receptor but penetrates poorly through the blood
      brain barrier. Its prodrug, L-4-Cl-kynurenine (4-Cl-KYN), readily enters the
      brain from the circulation and provides antiexcitotoxic neuroprotection after
      systemic application. We now examined the effect of 4-Cl-KYN on seizures and
      neuronal loss caused by the systemic administration of the chemoconvulsant
      kainate (KA). 4-Cl-KYN (50 mg/kg, ip) was given 10 min before and 30, 120, and
      360 min after KA (10 mg/kg, sc). Microdialysis and tissue level measurements in 4
      Cl-KYN-treated rats showed increases in the concentration of 7-Cl-KYNA in several
      limbic brain regions of KA-injected animals. Continuous EEG recording for 24 h
      revealed that 4-Cl-KYN significantly delayed seizure onset and reduced the total
      time spent in seizures. Repeated 4-Cl-KYN administration also prevented KA
      induced lesions in the piriform cortex and provided protection of hippocampal
      pyramidal cells in area CA1. In contrast, neurons in the hilus and in layer III
      of the entorhinal cortex were not protected. Consistent with the in vivo results,
      in vitro application of 7-Cl-KYNA to brain slices containing hippocampus and
      entorhinal cortex preferentially blocked low Mg(2+)-induced seizure activity in
      hippocampal pyramidal cells. Taken together, these data suggest that a prodrug
      approach using 4-Cl-KYN might offer advantages in the treatment of temporal lobe
      epilepsy.

PMID- 12429225
TI  - Effect of 3-nitropropionic acid on kynurenine aminotransferase in the rat brain.
AB  - Activation of excitatory amino acid receptors by endogenous excitotoxins results
      in degenerative changes characteristic of neurodegenerative brain diseases such
      as Huntington's disease. Excitatory amino acid receptors are present in the
      highest concentration in the striatum, the hippocampal region, and the temporal
      lobe. The most potent, naturally occurring excitatory amino acid receptor
      antagonist is kynurenic acid (KYNA) which acts preferentially on N-methyl-D
      aspartate (NMDA) receptors. KYNA is produced from L-kynurenine, by the action of
      the enzymes kynurenine aminotransferases (KAT I and KAT II). Several inhibitors
      of mitochondrial energy metabolism result in an indirect excitotoxic neuronal
      degeneration. We examined whether systemic administration of the mitochondrial
      toxin 3-nitroproprionic acid (3-NP), an irreversible inhibitor of succinate
      dehydrogenase, which also acts by an indirect excitotoxic mechanism, would
      produce alterations in the immunohistochemical pattern of KAT I. Our present
      investigations demonstrate that after 15 days of administration of 3-NP, an
      inhibitor of mitochondrial Complex II, the most severe depletion of KAT I
      occurred in the striatum; less severe depletion occurred in other brain areas
      investigated, following a striatum > hippocampus > temporal cortex gradient. The
      alterations induced by 15 days of 3-NP treatment were less conspicuous in 6-week
      old (young) animals than in 3-month-old adults. In these adult animals, 3-NP
      induced necrotic cores in the striatum, characterized by destruction of neuronal
      and glial elements, similar to that seen in the histologic and neurochemical
      features of Huntington's disease. It appears that immunohistochemical depletion
      of KAT after administration of 3-NP to adult animals may contribute to the
      pathological processes that characterize Huntington's disease.

PMID- 12429226
TI  - FK506 treatment inhibits caspase-3 activation and promotes oligodendroglial
      survival following traumatic spinal cord injury.
AB  - The focus of this study is to examine the ability of FK506, an immunosuppressant
      that inhibits calcineurin activation, to limit caspase-3 activation in
      oligodendroglia following spinal cord injury (SCI). To better establish a role
      for calcineurin and caspase-3 activation in oligodendroglia following SCI, rats
      received a contusion injury to the spinal cord followed by treatment with FK506
      or rapamycin (another immunosuppressant with no detectable inhibitory action on
      calcineurin activation). Animals were then sacrificed at 8 days postinjury and
      spinal cord tissue was processed using immunofluorescence histochemistry to
      examine cellular caspase-3 activation in ventral and dorsal white matter. In all
      treatment groups, numerous oligodendroglia were found to express the activated
      form of caspase-3 in regions proximal and distal to the injury epicenter.
      However, our findings suggest that treatment with FK506, but not rapamycin
      reduces the number of oligodendroglia expressing activated caspase-3 and
      increases the number of surviving oligodendroglia in dorsal white matter. These
      results provide initial evidence that agents that reduce the actions of
      calcineurin and subsequent caspase-3 activation may prove beneficial in the
      treatment of traumatic SCI.

PMID- 12429227
TI  - Behavioral and anatomical effects of long-term L-dihydroxyphenylalanine (L-DOPA)
      administration in rats with unilateral lesions of the nigrostriatal system.
AB  - This study investigated behavioral and anatomical changes induced by long periods
      of L-DOPA treatment in the unilateral rat model of Parkinson's disease. After
      daily injections of L-DOPA (50 mg/kg, ip) given for 1, 4, 8, or 16 weeks,
      behavioral sensitization, expressed by contralateral turning and changes in its
      pattern, increased within the first week of treatment and remained unchanged
      thereafter. Dyskinetic movements, affecting the trunk and limbs of all treated
      rats, also developed within the first week of treatment and increased further
      during the 16 weeks of L-DOPA treatment. L-DOPA responsiveness was also
      accompanied by changes at the neuronal level, as shown by changes in the
      expression of c-fos in the dopamine-depleted striatum. Following 1 week of L-DOPA
      treatment there was a marked decrease in striatal c-fos expression, compared to
      single injections, especially evident in the medial and ventral regions and to a
      lesser extent in the dorsolateral regions of the striatum. This specific regional
      expression of c-fos was maintained throughout the 16 weeks of L-DOPA treatment.
      Overall, our results show that behavioral sensitization to L-DOPA starts
      relatively early during the treatment and include not only an increase in
      contralateral turning rate but also an increase in dyskinetic movements.
      Persisting c-fos expression in the dorsolateral striatum might be implicated in
      the development of dyskinesias when L-DOPA treatment is extended for periods
      longer than 1 week.

PMID- 12429228
TI  - Transplants of fibroblasts genetically modified to express BDNF promote axonal
      regeneration from supraspinal neurons following chronic spinal cord injury.
AB  - Transplants of fibroblasts genetically modified to express BDNF (Fb/BDNF) have
      been shown to promote regeneration of rubrospinal axons and recovery of forelimb
      function when placed acutely into the injured cervical spinal cord of adult rats.
      Here we investigated whether Fb/BDNF cells could stimulate supraspinal axon
      regeneration and recovery after chronic (4 week) injury. Adult female Sprague
      Dawley rats received a complete unilateral hemisection injury at the third
      cervical spinal cord segment (C3). Four-five weeks later the injury site was
      exposed and rats received transplants of unmodified fibroblasts (Fb/UM) or
      Fb/BDNF. Four-five weeks after transplantation, locomotor recovery was examined
      on a test of forelimb usage and regeneration of supraspinal axons was studied
      following injection of the anterograde tracer biotin dextran amine (BDA).
      Rubrospinal tract (RST), reticulospinal tract (ReST), and vestibulospinal tract
      (VST) axons regenerated into transplants of either Fb/UM or Fb/BDNF but the
      length of axonal growth was significantly different in the two groups. The
      absolute distance of ReST growth was 1.8-fold greater in Fb/BDNF than in Fb/UM
      and the absolute distance of growth of RST and VST axons showed a statistically
      significant 4-fold increase. All three types of regenerated axons occupied a
      greater proportional length of Fb/BDNF transplants than of Fb/UM transplants.
      Only VST axons extended into the host spinal cord caudal to the Fb/BDNF grafts,
      but these axons were sparse. Rats receiving Fb/BDNF used both forelimbs together
      to explore walls of a cylinder more often than rats receiving Fb/UM, indicating
      partial recovery of forelimb usage. These results demonstrate that fibroblasts
      genetically modified to express BDNF promote axon regeneration from supraspinal
      neurons in the chronically injured spinal cord with accompanying partial recovery
      of locomotor performance.

PMID- 12429229
TI  - The expression of GABA in mossy fiber synaptosomes coincides with the seizure
      induced expression of GABAergic transmission in the mossy fiber synapse.
AB  - Although the granule cells of the dentate gyrus are glutamatergic, they contain
      the machinery for the synthesis and vesiculation of GABA. Furthermore, glutamic
      acid decarboxylase and the vesicular GABA transporter mRNA are expressed in the
      granule cells and mossy fibers in an activity-dependent manner, suggesting that
      these cells release GABA in addition to glutamate. Supporting this hypothesis, we
      found that seizures induce simultaneous glutamatergic and GABAergic transmission
      in the mossy fiber projection. To further explore this expression of inhibition,
      we looked for the presence and expression of endogenous GABA in a synaptosomal
      preparation enriched with mossy fiber nerve endings of kindled rats. We also
      studied the capacity of this preparation to capture and release [(3)H]GABA under
      control conditions and after kindling epilepsy. In accordance with our hypothesis
      we show that the mossy fiber synaptosomal preparation of the kindled rats has a
      significantly higher content of endogenous GABA than controls. We also found that
      the protein content in the mossy fiber synaptosomal preparation of kindled rats
      was significantly augmented, which is consistent with mossy fiber sprouting. Due
      to this, the total [(3)H]GABA incorporated in the synaptosomal preparation was
      also augmented. However, [(3)H]GABA uptake (expressed in % radioactivity/mg
      protein) and its evoked release were similar in both groups. With the present
      results, we provide further support for the hypothesis of the emergence of
      GABAergic transmission in the mossy fiber synapse that can constitute a
      protective mechanism in response to seizures.

PMID- 12429230
TI  - Okadaic acid induces epileptic seizures and hyperphosphorylation of the NR2B
      subunit of the NMDA receptor in rat hippocampus in vivo.
AB  - Overactivation of N-methyl-D-aspartate (NMDA) glutamate receptors is closely
      related to epilepsy and excitotoxicity, and the phosphorylation of these
      receptors may facilitate glutamate-mediated synaptic transmission. Here we show
      that in awake rats the microinjection into the hippocampus of okadaic acid, a
      potent inhibitor of protein phosphatases 1 and 2A, induces in about 20 min
      intense electroencephalographic and behavioral limbic-type seizures, which are
      suppressed by the systemic administration of the NMDA receptor antagonist (+)-5
      methyl-10,11-dihydro-5H-dibenzo-[a,d]cyclohepten-5,10-imine hydrogen maleate and
      by the intrahippocampal administration of 1-(5-isoquinolinesulfonyl)-2
      methylpiperazine, an inhibitor of protein kinases. Two hours after okadaic acid,
      when the EEG seizures were intense, an increased serine phosphorylation of some
      hippocampal proteins, including an enhancement of the serine phosphorylation of
      the NMDA receptor subunit NR2B, was detected by immunoblotting. Twenty-four hours
      after okadaic acid a marked destruction of hippocampal CA1 region was observed,
      which was not prevented by the receptor antagonists. These findings suggest that
      hyperphosphorylation of glutamate receptors in vivo may result in an increased
      sensitivity to the endogenous transmitter and therefore induce neuronal
      hyperexcitability and epilepsy.

PMID- 12429231
TI  - Mnemonic deficits in animals depend upon the degree of cholinergic deficit and
      task complexity.
AB  - The role of cholinergic basal forebrain (CBF) neurons in mnemonic behaviors was
      investigated using the immunotoxin 192IgG-saporin. We assessed two routes of
      immunotoxin administration: intracerebroventricular (ICV) and intraparenchymal
      (INTRA). INTRA lesions of the medial septum (MS) and/or the nucleus basalis
      magnocellularis (NBM) were compared with ICV-lesions, INTRA-phosphate-buffered
      saline injected, and naive controls. The INTRA-NBM/MS and ICV NBM/MS lesions
      produced a similar depletion of choline acetyltransferase activity of 80% across
      all CBF projections. Water maze performance was similarly impaired for ICV- and
      INTRA-NBM/MS animals during various phases of testing, whereas animals with
      individual lesions of the NBM or MS performed at the level of controls. In
      contrast to the allocentric demands of water maze performance, the egocentric
      based T-maze task revealed a vast group difference between the ICV- and the INTRA
      NBM/MS animals. INTRA-NBM/MS animals showed a severe deficit in the non-match-
      and match-to-position version, whereas again, animals with single lesions were
      unimpaired. In addition, a dichotomy between animals with complete cholinergic
      deafferentation was observed in the inhibitory avoidance task. ICV-NBM/MS showed
      a diminished retention for the aversive stimulus while the INTRA-NBM/MS animals
      remembered well. During plus maze testing, only the INTRA-NBM/MS animals had a
      reduced level of anxiety. Although non-CBF regions may have been differently
      affected by the two routes of immunotoxin administration, global measures of
      arousal, motivation, and motor initiation did not reveal a different behavioral
      pattern. Our findings suggest that a dynamic interplay exists between the degree
      of cholinergic deficit and task demands revealing different types of mnemonic
      impairments.

PMID- 12429232
TI  - Therapeutic strategies targeting caspase inhibition following spinal cord injury
      in rats.
AB  - Apoptosis-modulating therapeutics using active-site mimetic peptide ketones (z
      VAD-fluoromethylketone (fmk)) have been reported to be efficacious in delaying
      the apoptotic response in central nervous system lesions. The purpose of the
      present study was to examine whether the caspase inhibitor z-VAD fmk prevents
      apoptosis and improves neurological deficit and tissue damage. One-hundred twenty
      female Sprague-Dawley rats were randomized into groups that were administered 25
      microg of z-VAD-fmk or vehicle 30 min and 24 h after moderate spinal cord
      contusion (NYU impactor, 12.5 mm at T10). Several routes of administration were
      tested: (1) via Gelfoam placed on the spinal cord, (2) into the cisterna magna
      via a subarachnoidal catheter, (3) intravenously via the external jugular vein,
      or (4) intraperitoneally. Another group was injected with 50 microg of zVAD-fmk
      or vehicle intraperitoneally 30 min, 24, 48, and 72 h after injury. Animals were
      evaluated for locomotor function (BBB score) at weekly intervals for 6 weeks
      after injury and treatment. Spinal cords were then processed for histological
      analysis to determine whether zVAD-fmk treatment decreased contusion volume.
      Other spinal cord samples were harvested 24 h after injury and examined for
      cleavage of XIAP by immunoblot analysis. There were no significant differences in
      the BBB scores, contusion volumes, and XIAP cleavage between animals receiving
      the broad specific caspase inhibitor by the various routes and animals receiving
      vehicle alone. These findings raise critical questions about the use of peptide
      ketone apoptotic inhibitors in improving functional and histopathological
      outcomes following spinal cord injury.

PMID- 12429233
TI  - CD4 and CD8 T cells, but not B cells, are critical to the control of murine
      experimental autoimmune neuritis.
AB  - Experimental autoimmune neuritis (EAN) is a T cell-mediated autoimmune disease of
      the peripheral nervous system that duplicates the clinical, pathological, and
      electrophysiological features of Guillain-Barre syndrome in humans. However, the
      molecular pathogenesis of EAN remains controversial. Therefore, for this study,
      we induced EAN with P0 protein peptide 180-199 in CD4(-/-), CD8(-/-), CD4(-)8(-),
      and B cell knockout (microMT) mice to further investigate the roles of these
      cells in EAN. Our results showed that the severity of clinical signs and
      histopathological manifestations of EAN and the T cell response to P0 peptide 180
      199 in CD4(-/-) mice were significantly lower than those in their wild-type
      counterparts. CD8(-/-) mice also had a milder clinical course, less
      histopathological change, and a diminished T cell response to P0 peptide 180-199.
      However, more severe clinical and histopathological manifestations, a stronger T
      cell response to P0 peptide 180-199, and enhanced IFN-gamma production in the
      spleen were observed in the EAN of CD4(-)8(-) and microMT mice, but these were
      not obviously different from those of wild-type mice. Levels of IgG production
      were similar in sera from CD4(-/-), CD8(-/-), and CD4(-)8(-), and wild-type mice.
      These findings suggest that the induction and control of murine EAN are dependent
      on both CD4(+) and CD8(+) T cells and that B cells apparently do not perpetuate
      the related inflammatory demyelination.

PMID- 12429234
TI  - Detection of a novel pattern of connexin 43 immunoreactivity responsive to
      dehydration in rat hypothalamic magnocellular nuclei.
AB  - Immunocytochemical expression of Connexin 43 (Cx 43) in the rat Supraoptic
      Nucleus was analyzed following dehydration, using sequence-specific anti-Cx 43
      antibodies (designated 13-8300, 71-0700, and sc-9059) that exhibit differential
      recognition of Cx 43. Punctate and longitudinally arranged immunostaining
      patterns of Cx 43 labeling, as evidenced by antibody sc-9059, was detected
      overlaying the nucleus of magnocellular neuroendocrine cells. This novel form of
      longitudinally arranged Cx 43 immunoreactivity was modified by dehydration and
      halothane exposure, but not lactation.

PMID- 12429235
TI  - In vitro isolation and expansion of human retinal progenitor cells.
AB  - Human retinal development proceeds with temporal and spatial precision. Although
      differentiation starts around the beginning of the third month of gestation, the
      majority of cells in the outer neuroblastic layer of human neural retina are
      still proliferating, as evidenced by their Ki-67 immunoreactivity. In the present
      study, the proliferating human retinal progenitor cells (HRPCs) were isolated and
      expanded in culture. They were capable of dividing for multiple generations (with
      passage 8, the latest tested) and differentiating to several retinal cell
      phenotypes. These findings indicate that human retina at the 10th-13th week of
      gestation harbors progenitor cells that can be maintained and expanded in vitro
      for multiple generations. The availability of such cells may have important
      implications with respect to human degenerative retinal diseases, as these HRPCs
      have the potential to be used therapeutically to replace damaged retinal neurons.

PMID- 12429236
TI  - Reaxotomy of chronically injured rubrospinal neurons results in only modest cell
      loss.
AB  - Among the most promising therapeutic strategies to facilitate axonal regeneration
      after spinal cord injury is the transplantation of various cellular substrates
      into the injury site. With the establishment of a glial scar and cyst at the
      injury site over time, the implantation of such cells in the chronic injury
      setting may require some resection of these nonpermissive elements, which could
      concomitantly reinjure already severed axons. This study evaluates the response
      of chronically injured rubrospinal neurons to such a second axotomy. Our findings
      indicate that the second axotomy does not lead to an accelerated loss of
      rubrospinal neurons, which represents an important finding for those who evaluate
      axonal regeneration of this motor system in chronic transplantation studies.

PMID- 12429237
TI  - Transplantation of M213-2O cells with enhanced GAD67 expression into the inferior
      colliculus alters audiogenic seizures.
AB  - The purpose of the present study was to examine the effects of GABA-producing
      cell transplants on audiogenic seizures (AGS). The M213-2O cell line was derived
      from fetal rat striatum and has GABAergic properties. This cell line was further
      modified to express human GAD(67) and produce elevated levels of GABA. The
      present study compares the effects of parent M213-2O cell transplants with those
      of GAD(67)-modified M213-2O cells in AGS-prone Long-Evans rats. Two weeks
      following implantation of engineered cells, latency to AGS-typical wild running
      was increased compared to nonimplanted subjects. Survival of the transplanted
      cells was confirmed by immunochemical labeling of GAD(67) and Epstein-Barr virus
      nuclear antigen. These findings support the use of GABA-producing cell lines to
      modify seizure activity.

PMID- 12429238
TI  - Expression of EMAP-II by activated monocytes/microglial cells in different
      regions of the rat hippocampus after trimethyltin-induced brain damage.
AB  - Endothelial monocyte-activating polypeptide-II (EMAP-II), a novel cytokine with
      proinflammatory and antiangiogenic properties, has previously been shown to be
      expressed by activated monocytes/microglial cells in the rat brain and was
      therefore considered a useful marker to stage microglial activation in
      inflammatory lesions. The aim of the present immunohistochemical study was to
      investigate expression of EMAP-II in the rat hippocampus after intoxication with
      the organotin compound trimethyltin (TMT). Administration of this neurotoxicant
      is known to produce brain damage mainly affecting the hippocampal formation, with
      severe neuronal cell loss being observed predominantly in regions CA-1 and CA-3.
      The maximum severity of TMT-induced brain damage is observed 21 days after a
      single ip administration. In this well-characterized model of neurodegeneration,
      activated microglial cells have been described to occur mainly in the early
      stages of TMT-induced neurotoxicity. Following TMT intoxication, we observed a
      significant increase in EMAP-II(+) monocytes/microglial cells in the CA-1 and the
      CA-3 regions. The CA-2 region, however, was largely spared. While appearance of
      single EMAP-II(+) microglial cells was observed already after 5 days, EMAP-II
      immunoreactivity reached its maximum after 21 days and persisted in some of the
      rats up to 35 days. These findings show a close correlation to the temporal and
      spatial pattern of neuronal damage described in the rat hippocampus after TMT
      administration previously. Thus, upregulation of EMAP-II by activated
      monocytes/microglial cells may serve as a sensitive marker of neurotoxic lesions
      in the rat brain.

PMID- 12429239
TI  - Pathologic myopia: where are we now?.
AB  - PURPOSE: To describe current concepts and available treatments for pathologic
      myopia. DESIGN: Review of experimental and clinical studies. METHODS: The
      demography, natural history, medical and surgical treatments for choroidal
      neovascular membrane, vitreoretinal interface disorders and future strategies for
      pathologic myopia are reviewed. RESULTS: Several medical and surgical modalities
      are currently available to treat various complications of pathologic myopia.
      Macular translocation appears to stabilize or improve visual function in many
      eyes with choroidal neovascularization. CONCLUSION: Newer strategies are emerging
      to better ameliorate or prevent the complications of pathologic myopia.

PMID- 12429240
TI  - Long-term follow-up after macular hole surgery with internal limiting membrane
      peeling.
AB  - PURPOSE: To report long-term anatomical and functional results after pars plana
      vitrectomy with peeling of the internal limiting membrane (ILM) for idiopathic
      macular hole. DESIGN: Prospective, nonrandomized, consecutive series. METHODS:
      Ninety-nine patients with a follow-up of at least 12 months were included. The
      surgical technique consisted of a standard pars plana vitrectomy, removal of the
      ILM, and an intraocular gas tamponade (15% hexafluoroethane [C(2)F(6)] gas
      mixture) followed by head-down positioning for at least 5 days. Follow-up
      examinations included a clinical examination, Goldmann perimetry, optical
      coherence tomography, and static microperimetry using a Rodenstock scanning laser
      ophthalmoscope (SLO-105). Stimulus size was 0.2 degrees (Goldmann II),
      intensities employed were 0 and 12 dB. Twenty-degree fields were used for all
      tests. RESULTS: Mean period of review was 32 months (median 34). Anatomic closure
      was achieved in 86 (87%) of 99 patients by one surgical procedure. Nine patients
      underwent a successful second operation with an improvement of visual acuity in 7
      patients. The closure rate after two surgical interventions was 96%. Best
      corrected visual acuity improved from a median of 20/100 preoperatively to a
      median of 20/40 postoperatively (P <.001). An improvement of visual acuity was
      achieved in 94% of patients. In 13 of 99 patients (13%) a combined vitrectomy and
      cataract surgery with intraocular lens implant was performed; 72 patients (73%)
      underwent cataract surgery later. Ninety of 99 patients (91%) were pseudophakic
      on last presentation. Paracentral scotomata did not change in size, density, or
      shape over time. Its incidence was not correlated with the stage of the macular
      hole. No postoperative epiretinal membrane formation or late reopening of the
      macular hole was observed. One patient presented with a peripheral visual field
      defect after vitrectomy. CONCLUSIONS: Macular hole surgery with peeling of the
      ILM without the use of adjuvants or ILM staining leads to good functional long
      term results. Paracentral scotomata remained subclinical in most cases and may be
      due to a mechanical trauma of the nerve fiber layer.

PMID- 12429241
TI  - Evaluation of successful macular hole surgery by optical coherence tomography and
      multifocal electroretinography.
AB  - PURPOSE: To evaluate successful macular hole surgery using optical coherence
      tomography (OCT) and multifocal electroretinography (MFERG). DESIGN:
      Interventional case series. METHODS: In a prospective study, 20 eyes of 20
      patients with successful surgery for stage II, III, or IV idiopathic macular hole
      were evaluated by best-corrected visual acuity (BCVA), ocular examination, OCT,
      and MFERG preoperatively and 1, 3, 6, and 12 months postoperatively. For
      statistical analysis, the paired t test and nonparametric methods were used, as
      well as the Spearman analysis. RESULTS: Postoperatively, all 20 eyes of 20
      patients had anatomic closure of the macular hole confirmed by OCT. The center of
      the fovea, measured by OCT from the retinal pigment epithelium to the inner
      retinal surface, had a mean +/- SD thickness of 116.5 +/- 30.9 microm (range, 68
      175 microm) 1 year postoperatively. Best-corrected visual acuity significantly
      improved (preoperative mean +/- standard deviation [SD] value, 0.131 +/- 0.081
      and 1 year postoperative mean +/- SD value, 0.407 +/- 0.193). Multifocal
      electroretinography values area 1 (0-2.8 degrees) and area 2 (2.8-9 degrees from
      the center of the fovea) significantly improved (preoperative mean +/- SD values
      3.10 +/- 1.334 nV/deg(2) and 3.573 +/- 1.545 nV/deg(2), respectively, and 1 year
      postoperative +/- SD mean values, 5.53 +/- 1.208 nV/deg(2) and 4.748 +/- 1.404
      nV/deg(2), respectively). The thickness of the fovea, measured by OCT,
      significantly correlated with the BCVA 1 year postoperatively. One year
      postoperative MFERG values areas 1 and 2 were not correlated with 12-month BCVA
      and OCT findings. CONCLUSIONS: Twelve months postoperatively BCVA and MFERG
      values significantly improved in this series of eyes with successful macular hole
      surgery. Optical coherence tomography findings were correlated to BCVA, but MFERG
      values were not correlated to BCVA and OCT findings, 1 year postoperatively.

PMID- 12429242
TI  - Optical coherence tomography findings in adult-onset foveomacular vitelliform
      dystrophy.
AB  - PURPOSE: The purpose of this article is to analyze cross-sectional images of a
      subretinal macular lesion, using optical coherence tomography (OCT) in eyes with
      adult-onset foveomacular vitelliform dystrophy (AOFVD), to compare thickness of
      the neurosensory retina over the lesion with best-corrected visual acuity (BCVA)
      of each eye, and to compare OCT tomograms of AOFVD patients with OCT of Best
      disease. DESIGN: Observational case series. METHODS: This is a retrospective
      study which took place in a clinical practice. Forty-three patients (72 eyes)
      with AOFVD and 12 patients (24 eyes) with Best's disease were studied. The
      observation procedures used were biomicroscopic fundus examination, fluorescein
      angiography (FA), indocyanine green angiography (ICGA), and optical coherence
      tomography (OCT). The main outcome measures were a description of the typical
      picture of AOFVD in OCT tomograms, the relationship between the neurosensory
      retinal thickness over the lesion, the BCVA expressed in decimal terms, and a
      comparison with description of OCT in Best disease. RESULTS: Of the 43 patients
      affected by AOFVD, 29 had bilateral macular lesions. Fluorescein angiography
      showed a central hypofluorescent spot surrounded by an irregular hyperfluorescent
      ring in 65 of the 72 eyes. Indocyanine green angiography demonstrated a central
      nonfluorescent spot and a hyperfluorescent area surrounding the central spot in
      22 of 27 eyes examined. In all 72 eyes of 43 patients, OCT showed a well-defined
      central region of thickening in the reflective band representing the retinal
      pigment epithelium (RPE). The relationship between the thickness of neurosensory
      retina over the lesion and BCVA was significant (P =.001, r(2) = 0.61). Optical
      coherence tomography in all 24 eyes with Best disease showed a well-defined
      central serous retinal detachment. CONCLUSION: In the 72 eyes with AOFVD, FA and
      ICGA presented different features. Instead, OCT tomograms showed a well-defined
      subretinal thickening of the RPE in all the eyes. The lack of difference in OCT
      patterns between cases with or without the hypofluorescent spot on angiography
      was useful for confirming the diagnosis of AOFVD. Moreover, a reduced visual
      acuity was evident in patients with a thinner neurosensory retinal layer over
      AOFVD lesion. Finally, OCT images were also useful for distinguishing AOFVD from
      Best disease.

PMID- 12429243
TI  - A controlled trial of povidone-iodine to treat infectious conjunctivitis in
      children.
AB  - PURPOSE: To report the efficacy of povidone-iodine as a treatment for
      conjunctivitis in pediatric patients. DESIGN: Double-masked, controlled,
      prospective clinical trial. METHODS: In an ophthalmology clinic in a general
      hospital in Manila, Philippines, 459 children (mean [SD] age 6.6 [6.6] years;
      range, 7 months-21 years) with acute conjunctivitis were studied. Infected eyes
      were cultured for bacteria and underwent immunofluorescent testing for Chlamydia
      trachomatis. Viral conjunctivitis was diagnosed if bacterial cultures were
      negative and diagnostic criteria were met. Subjects were alternated to receive
      povidone-iodine 1.25% or neomycin-polymyxin-B-gramicidin ophthalmic solution, one
      drop 4 times daily in the affected eye. Ocular inflammation was evaluated daily
      by the family or patient and weekly by an ophthalmologist. The main outcome
      measures were days until cured and proportion cured after 1 and 2 weeks of
      treatment. RESULTS: Despite adequate statistical power (power >80% for a 1-day
      difference and P <.05), there was no significant difference between treatment
      groups regarding the number of days to cure or proportion cured at 1 or 2 weeks
      whether caused by bacteria or virus (P =.133-.824 for the four comparisons).
      After 1 week of treatment, povidone-iodine cured marginally more chlamydial
      infections than the antibiotic (P =.057). By 2 weeks, fewer chlamydial infections
      were cured than those of viral or bacterial etiology (P =.0001). The younger the
      patient, the faster their conjunctivitis resolved (R = 0.13, P =.013).
      CONCLUSIONS: Povidone-iodine 1.25% ophthalmic solution was as effective as
      neomycin-polymyxin B-gramicidin for treating bacterial conjunctivitis, somewhat
      more effective against chlamydia, and as ineffective against viral
      conjunctivitis. Povidone-iodine ophthalmic solution should be strongly considered
      as treatment for bacterial and chlamydial conjunctivitis, especially in
      developing countries where topical antibiotics are often unavailable or costly.

PMID- 12429244
TI  - Keratocyte density in keratoconus. A confocal microscopy study(a).
AB  - PURPOSE: To estimate keratocyte density in human corneas with keratoconus by
      confocal microscopy. DESIGN: Prospective, observational cohort study. METHODS:
      Twenty-nine unscarred corneas of 19 patients with keratoconus and 29 corneas of
      19 controls matched for age (+/-3 years) and contact lens wear were examined by
      using confocal microscopy. Images were recorded from the full-thickness central
      cornea. A masked observer manually counted bright objects (keratocyte nuclei) in
      images without motion blur. Cell densities in anteroposterior stromal layers of
      keratoconus corneas were compared with densities in corresponding layers of
      control corneas. RESULTS: In keratoconus patients, age 40 +/- 15 years (mean +/-
      standard deviation), keratocyte density was 19% lower in those who wore contact
      lenses (16,894 +/- 4032 cell/mm(3), n = 12) than in those who did not wear
      contact lenses (20,827 +/- 4934 cell/mm(3), n = 17, P =.03). In control patients,
      age 39 +/- 16 years, there was no difference in keratocyte density between those
      who wore contact lenses (n = 12) and those who did not wear contact lenses (n =
      17, P =.80). Among contact lens wearers, keratocyte density was 25% lower in
      keratoconus corneas (16,894 +/- 4, 032 cell/mm(3), n = 12 [9 = rigid gas
      permeable lenses, 3 = soft lenses]) than in control corneas (22,579 +/- 2, 387
      cell/mm(3), n = 12 [3 = rigid gas-permeable lenses, 9 = soft lenses], P =.002),
      the result of cell density being lower in the most anterior keratocyte layer (P
      =.001) and the layers between 0% to 10% (P <.001), 67% to 90% (P <.001), and 91%
      to 100% (P <.001) of stromal thickness. Among noncontact lens wearers, there was
      no difference in cell density between keratoconus and controls (P =.41).
      CONCLUSION: Keratocyte density is decreased in the anterior and posterior stroma
      of keratoconus patients who wear contact lenses.

PMID- 12429245
TI  - Changes of axial length and keratometry after keratoplasty for keratoconus using
      the guided trephine system.
AB  - PURPOSE: The purpose of this study was to examine the cause of increasing myopia
      after penetrating keratoplasty for keratoconus with the guided trephine system.
      DESIGN: Prospective interventional study cohort. METHODS: Thirty eyes (28
      patients) after keratoplasty for keratoconus were examined. Preoperatively and 1,
      3, 6, 12, and 24 months postoperatively subjective refraction was evaluated.
      Keratometry was calculated with a computerized videokeratoscope (TMS-1). Axial
      length was measured using applanation ultrasonography before surgery and 2 years
      after surgery. Anterior chamber depth, lens thickness, and vitreous length were
      taken into consideration. RESULTS: The mean spherical equivalent was + 2.22 +/-
      3.47 diopters 1 month postoperatively and had a continuous myopic shift to -1.02
      +/- 2.65 diopters 2 years postoperatively. This was associated with a significant
      increase in mean keratometric levels from + 41.72 +/- 2.96 diopters 1 month
      postoperatively to + 43.77 +/- 2.29 diopters 2 years postoperatively (r(s) = 
      0.36, P =.05). Overall, no significant changes in axial length were observed.
      However, vitreous length showed a small but statistically significant increase.
      As expected, mean anterior chamber depth decreased significantly postoperatively
      (P </=.05). In eyes with a decrease in keratometric values (n = 8) a myopic shift
      was also observed. In this group a significant elongation of the axial length and
      the vitreous length was found. CONCLUSIONS: A study of eyes after keratoplasty
      for keratoconus demonstrated continuous myopic shift over time. Increasing myopia
      was associated with increasing keratometric values. Thus, the major cause of
      increasing myopia after keratoplasty in keratoconus eyes seems to be continuing
      keratectasia. However, ongoing bulbus growth may contribute to continuing myopia
      in some eyes.

PMID- 12429246
TI  - Corneal flap displacement and drift in LASIK: comparison of Hansatome and
      Automated Corneal Shaper microkeratomes.
AB  - PURPOSE: To describe and compare the displacement of corneal flaps created during
      laser in situ keratomileusis (LASIK) procedures performed with two different
      microkeratomes and analyze parameters (for example, pupil-to-hinge distance,
      drift during suction) that might affect the flap displacement or be influenced by
      flap displacement. DESIGN: This work was based on a cross-sectional study design.
      METHODS: Images copied from video recordings of 206 consecutive LASIK surgeries
      were analyzed to determine the distance from pupil center to corneal flap hinge
      (pupil-to-hinge distance), the hinge size, the distance from the center of the
      pupil to the margins of the flap, and the positions of the suction ring before
      and after vacuum in corneal flaps created by the Hansatome and the Automated
      Corneal Shaper (ACS) microkeratomes. Accurate measurements of all these variables
      could be obtained in 121 eyes (Hansatome: n = 66, right eye (OD) = 27 eyes, left
      eye (OS) = 39 eyes; ACS: n = 55, OD = 25 eyes, OS = 30 eyes), which were included
      in the analysis. Formulas were derived to calculate from the measurements the
      magnitude and direction of the drift of the suction ring during vacuum and the
      final displacement of the corneal flap. RESULTS: The mean +/- standard deviation
      (SD) drift of eyes during suction with the Hansatome was 0.27 +/- 0.02 mm and
      with the ACS was 0.12 +/- 0.02 mm (P <.001). The Hansatome induced, on average,
      more biased (temporal vs random) drift than did the ACS. The mean final
      displacement of the center of the flap from the center of the pupil was of equal
      magnitude for the two instruments (0.37 +/- 0.02 mm and 0.36 +/- 0.02 mm with the
      Hansatome and ACS, respectively). CONCLUSION: The drift induced by the Hansatome
      contributes to the horizontal component of the final decentration of the corneal
      flaps. This tendency for drift and the resultant decrease in pupil-to-hinge
      distance should be considered to minimize flap displacements during LASIK.

PMID- 12429247
TI  - Local anesthesia with intravenous sedation for surgical repair of selected open
      globe injuries.
AB  - PURPOSE: To report factors associated with the use of local anesthesia with
      intravenous sedation (local anesthesia/sedation) rather than general anesthesia
      for surgery for open globe injuries in adult reparable eyes. DESIGN:
      Retrospective, nonrandomized, comparative case series. METHODS: Medical records
      were reviewed of all patients with open globe injuries repaired at Bascom Palmer
      Eye Institute between 1995 and 1999. "Adult reparable eyes" (eyes in patients
      >/=18 years of age, not treated with primary enucleation or evisceration,
      followed up >/=2 months) were included. RESULTS: In all, 220 eyes of 218 patients
      met inclusion criteria. General anesthesia was employed in 80 of 200 (36%) and
      local anesthesia/sedation in 140 of 220 (64%). Patients who had local
      anesthesia/sedation were significantly more likely to have an intraocular foreign
      body (31% vs 14%; P =.010, chi-square test), better presenting visual acuity (1.8
      logMAR [logarithm of the minimum angle of resolution] units vs 2.5 logMAR units;
      P <.001, t test), more anterior wound location (75% corneal/limbal vs 65%; P
      =.003, chi-square), shorter wound length (6.3mm vs 10.8mm; P <.001, t test), and
      dehiscence of previous surgical wound (26% vs 12%; P =.021, chi-square) and were
      significantly less likely to have an afferent pupillary defect (22% vs 51%; P
      <.001, chi-square). There was no anesthesia-related complication in either group.
      The local anesthesia/sedation group had a shorter mean operating time than did
      the general anesthesia group (78 minutes vs 117 minutes; P <.001, t test). The
      general anesthesia group had a longer mean follow-up than the local
      anesthesia/sedation group (20.2 months vs 13.9 months, respectively; P =.002, t
      test). Change in visual acuity between the presenting and final examinations was
      similar for open globe injuries repaired with general anesthesia compared with
      local anesthesia/sedation (0.94 vs 0.72 logMAR units of visual acuity,
      respectively; P =.16, t test). CONCLUSIONS: Local anesthesia/sedation is a
      reasonable alternative to general anesthesia for selected patients with open
      globe injuries.

PMID- 12429248
TI  - Correctable visual impairment in an older population: the blue mountains eye
      study.
AB  - PURPOSE: To describe temporal changes in the characteristics of older persons
      with visual impairment in their better eye correctable by refraction. DESIGN:
      Study of two cross sections of a community 6 years apart. METHODS: The Blue
      Mountains Eye Study examined 3654 persons aged 49 to 97 during 1992 to 1994
      (cross-section 1) and 3509 persons (2335 cohort survivors plus 1174 persons who
      moved to the area and age group) during 1997 to 2000 (cross-section 2). Logarithm
      of minimal angle of resolution visual acuity was measured before and after
      refraction. Correctable visual impairment was defined as visual impairment <
      20/40 in the better eye before refraction that improved after refraction to no
      impairment (>/= 20/40). Factors associated with correctable visual impairment and
      persistent correctable impairment were determined. RESULTS: Cross-sections 1 and
      2 had similar age-gender distributions. In cross-section 1, 7.5% of participants
      had correctable visual impairment, 3.6% had noncorrectable visual impairment, and
      88.9% had no impairment. Corresponding rates in cross-section 2 were 5.6%, 2.7%,
      and 91.7%. In both cross sections, similar proportions (around 68%) of those
      visually impaired had correctable visual impairment and similar sociodemographic
      measures predicted correctable visual impairment. Cross-section 1 participants
      who were married, owned their home, had high job prestige, gained qualifications
      after high school, or were current drivers were less likely to have correctable
      visual impairment after controlling for age and gender. Adjusted odds for
      correctable visual impairment increased in those living alone, using community
      support services, dependent on others, with myopia, wearing distance glasses, or
      with low perceived health and heart disease. Histories of stroke, cancer, and
      diabetes were similar between groups with correctable and no visual impairment.
      CONCLUSION: Socioeconomic parameters, myopia, wearing distance glasses, reported
      health problems, and poor perceived health were associated with correctable
      visual impairment in this older population.

PMID- 12429249
TI  - Identification of a stop codon mutation in exon 2 of the collagen 2A1 gene in a
      large stickler syndrome family.
AB  - PURPOSE: To describe the clinical features and identify the mutation responsible
      for an autosomal dominant vitreoretinal degeneration occurring in a previously
      unreported large family. DESIGN: Cohort study. METHODS: Family members were
      evaluated clinically over a 30-year period. Genealogical investigation, genetic
      linkage to known vitreoretinal degenerations, and mutation screening of the
      COL2A1 gene were performed. RESULTS: We identified a single large family (2,384
      total family members) with vitreoretinal degeneration spanning 12 generations. We
      reviewed the clinical records of 165 family members (95 affected and 70
      unaffected). The common clinical findings in affected individuals included early
      onset posterior perivascular retinal degeneration, vitreous degeneration, and
      retinal detachment. The incidence of retinal detachment was 57% (95/165) and the
      mean age of onset was 15.2 years. Orofacial, skeletal, and auditory abnormalities
      were seen in 0%, 5%, and 7.5%, respectively, in a subset of 28 affected subjects.
      Linkage to the collagen COL2A1 locus was demonstrated and a cytosine to adenosine
      transition identified within exon 2, leading to the creation of a stop codon at
      position 86 (Cys86Stop). CONCLUSIONS: Identification of the mutation in this
      family enables diagnosis of individuals at risk for potentially blinding
      complications in this condition at an early age. Given the variability of the
      Stickler phenotype, mutation detection allows for more comprehensive genetic
      counseling and directs clinical monitoring to family members inheriting the
      disease gene.

PMID- 12429250
TI  - Radial perivascular retinal degeneration: a key to the clinical diagnosis of an
      ocular variant of Stickler syndrome with minimal or no systemic manifestations.
AB  - PURPOSE: To identify the genetic defect and present the ocular and extraocular
      findings in a large pedigree of predominantly ocular Stickler syndrome. DESIGN:
      Observational case series. METHODS: An eight-generation pedigree with hereditary
      retinal detachments was retrospectively and prospectively studied. Clinical
      information was obtained by medical records, telephone interviews, medical
      questionnaires, detailed ophthalmologic examinations, physical examinations, and
      personal observations. Linkage analysis of the COL2A1 gene was performed on 21
      family members, and mutation analysis was performed on three family members.
      RESULTS: The pedigree consisted of 100 affected individuals. The ocular findings,
      frequently bilateral, consisted of radial perivascular retinal degeneration
      (RPRD) (100%), vitreous syneresis (100%), high myopia (76%), retinal detachment
      (65%), presenile cataract development (occurring before 50 years of age; 78%),
      and glaucoma (18%). Most (70%) of the retinal detachments occurred between 4 and
      18 years of age. Extraocular manifestations, characteristic for Stickler
      syndrome, were detected in only four of 100 (4%) affected individuals. Linkage
      analysis with COL2A1 flanking markers showed evidence for linkage to the COL2A1
      locus. The COL2A1 gene analysis identified a mutation converting a codon TGC for
      cysteine(86) to a premature termination codon in the alternatively spliced exon
      2. CONCLUSIONS: A variant of Stickler syndrome, caused by mutations in exon 2 of
      COL2A1, may present in families with all of the ocular findings and no clinically
      identifiable extraocular findings associated with Stickler syndrome. The
      predominant ocular findings are a congenitally abnormal vitreous and an acquired
      radial perivascular retinal degeneration that may lead to complicated childhood
      and adult retinal detachment.

PMID- 12429251
TI  - The progression of refractive error in school-age children: Shunyi district,
      China.
AB  - PURPOSE: To assess the progression of refractive error and the incidence of
      myopia in school-age children in the Shunyi District of Beijing, China. DESIGN: A
      longitudinal cohort study. METHODS: A population-based sample of 4,662 children
      initially examined in 1998 at ages 5 to 13 years was reexamined between September
      and November, 2000. Refractive error was measured under cycloplegia with
      autorefraction. Age, sex, and baseline refractive error were evaluated as risk
      factors for progression. RESULTS: In 28.5 months, the average change in
      refractive error was -0.42 diopters (standard deviation, 0.68) in right eyes.
      Myopic shift of refractive error was associated with female sex, older age, and
      higher myopic or hyperopic refractive error at baseline. The average change in
      astigmatic error was essentially zero, with significant change in both directions
      more likely among those with higher baseline astigmatism. Findings were similar
      for left eyes. The cumulative incidence of myopia, defined as a spherical
      equivalent refractive error of -0.50 diopters or more in either eye, among
      initial emmetropes and hyperopes was 14.1% (95% confidence interval [CI], 11.8%
      16.5%) for male and 23.5% (95% CI, 20.8%-26.1%) for female subjects. Myopia
      incidence increased sixfold to sevenfold between baseline age 5 and 12, before
      decreasing at age 13, for both male and female subjects. CONCLUSIONS: In the
      design of cost-effective programs for the periodic screening and treatment of
      uncorrected refractive error, children initially found to require refractive
      correction should be targeted for relatively frequent rescreening, as should
      girls and older children. Further study is required to better understand
      environmental and genetic risk factors for myopia development and progression.

PMID- 12429252
TI  - The American Journal of Ophthalmology announces online submission and peer review
      process.

PMID- 12429253
TI  - Stickler syndrome: clinical care and molecular genetics.

PMID- 12429254
TI  - Systemic adverse effects of beta-adrenergic blockers: an evidence-based
      assessment.
AB  - PURPOSE: To present an evidence-based review of the systemic adverse effects of
      beta-adrenergic blockers and recommend safety guidelines for use of ophthalmic
      beta-adrenergic blockers. DESIGN: Literature review of published articles in peer
      reviewed journals and medical texts. METHODS: Pre-MEDLINE and MEDLINE search of
      relevant English language articles from 1966 to the present. Cardiovascular,
      pulmonary, endocrine/metabolic, central nervous system, sexual, exercise, and
      neuromuscular effects of systemic or ophthalmic beta-adrenergic blockers were
      reviewed. RESULTS: Systemic beta-adrenergic antagonists unequivocally reduce
      mortality in patients with mild, moderate, and even severe congestive heart
      failure. Development of symptomatic bradycardia on systemic or ophthalmic beta
      adrenergic blockers alone likely indicates underlying cardiac conduction
      disturbances. Beta 2-adrenergic blockade, regardless of route of administration,
      may exacerbate or trigger bronchospasm in patients with asthma or pulmonary
      disease associated with hyper-reactive airways. This review identifies no
      scientific studies supporting the development of worsening claudication,
      depression, hypoglycemic unawareness, or prolonged hypoglycemia in non-insulin
      dependent diabetes, sexual dysfunction, or impaired neuromuscular transmission
      with systemic or ophthalmic beta-adrenergic blockers. CONCLUSIONS: Many commonly
      presumed adverse beta-adrenergic blocker effects observed via systemic or ocular
      administration are not supported by published randomized clinical trials. Wide
      acceptance of such traditionally purported side effects has been largely due to
      propagation of isolated case reports and short series as well as personal
      communication felt to reflect expert opinion. Many more patients may be eligible
      to use these drugs. Obtaining a careful medical history and checking pulse rate
      and rhythm in the office should identify the vast majority of patients with
      potential cardiopulmonary contraindications.

PMID- 12429255
TI  - Loss of vision caused by expansion of intraocular perfluoropropane (C(3)F(8)) gas
      during nitrous oxide anesthesia.
AB  - PURPOSE: To report visual loss associated with nitrous oxide anesthesia in
      patients with intraocular perfluoropropane (C(3)F(8)) gas. DESIGN: Observational
      case series. METHODS: Three patients are described who lost vision in the eye
      with intraocular gas after subsequent nitrous oxide general anesthesia. RESULTS:
      Three patients, aged 75, 80, and 73 years, with intraocular C(3)F(8) gas in three
      eyes underwent nitrous oxide general anesthesia in three different medical
      centers for conditions unrelated to their ophthalmic surgery, ranging from 10
      days to 1 month after their vitreoretinal procedure. All three patients suffered
      visual loss due to presumed central retinal artery occlusion caused by expansion
      of the intraocular gas by nitrous oxide during general anesthesia. In two
      patients, there was no recovery of light perception. In one patient, there was
      moderate recovery of vision. CONCLUSIONS: Identification of patients with
      intraocular gas is critical when planning nitrous oxide anesthesia. This may be
      achieved by the use of a simple intraocular gas identification bracelet issued to
      patients at the time of their vitreoretinal procedure.

PMID- 12429256
TI  - Total en bloc excision: a modified vitrectomy technique for proliferative
      diabetic retinopathy.
AB  - PURPOSE: To report a modified vitrectomy technique for proliferative diabetic
      retinopathy. DESIGN: Interventional case series. METHODS: In the modified
      vitrectomy technique for proliferative diabetic retinopathy, core vitrectomy is
      performed, followed by separation of the glial ring from the optic disk using a
      hook or forceps. The posterior hyaloid membrane, including proliferative tissues,
      is lifted and peeled from the posterior to the peripheral retina without creating
      a window in the posterior hyaloid membrane. At any strong vitreoretinal adhesion
      site, the posterior hyaloid is partially removed, followed by membrane
      delamination. RESULTS: In the 18 eyes that underwent the modified technique,
      iatrogenic retinal breaks occurred less often compared with the 48 eyes that
      underwent the conventional technique. The difference was not statistically
      significant (P =.14), but the surgical time was significantly reduced (P =.0003).
      The glial ring and proliferative tissue arising from the optic disk can be
      readily separated, and other adhesion sites can be satisfactorily peeled after
      separating the posterior hyaloid membrane around the optic disk. CONCLUSIONS:
      This modified vitrectomy technique for proliferative diabetic retinopathy may be
      an alternative surgical technique to the conventional technique.

PMID- 12429257
TI  - Macular infarction after transpupillary thermotherapy for subfoveal choroidal
      neovascularization in age-related macular degeneration.
AB  - PURPOSE: To report the complication of macular infarction after transpupillary
      thermotherapy (TTT) for the treatment of subfoveal choroidal neovascularization
      (CNV) due to age-related macular degeneration (AMD). DESIGN: Interventional case
      reports. METHODS: Among 107 consecutive patients with subfoveal CNV due to AMD, a
      73-year-old woman with recurrent subfoveal classic choroidal neovascularization
      and a 76-year-old man with subfoveal occult choroidal neovascularization with
      adjacent areas of geographic retinal pigment epithelium atrophy noted a severe
      decrease in visual acuity and photopsias within hours of undergoing TTT. RESULTS:
      Both patients had marked whitening of the macula clinically and closure of the
      perifoveal capillaries on fluorescein angiography. Immediately after treatment
      their visual acuity decreased from 20/200 to 6/200 and from 20/400 to 2/200,
      respectively. Several months later, all exudation had resolved and their visual
      acuity had stabilized at 20/100 and 20/200, respectively. CONCLUSIONS: Macular
      infarction is a rare complication that occurred in two of 107 patients undergoing
      TTT for subfoveal CNV due to AMD. The presence of geographic retinal pigment
      epithelium atrophy or a previous laser treatment scar in the macular region may
      predispose patients to this complication.

PMID- 12429258
TI  - Bilateral anterior optic neuritis in adult measles infection without
      encephalomyelitis.
AB  - PURPOSE: To describe anterior optic neuritis in adult measles infection. DESIGN:
      Interventional case report. METHODS: A 31-year-old woman presented with bilateral
      visual loss 6 days after the onset of maculopapular rash. Complete ophthalmic and
      neurologic examinations, radiologic studies, and lumbar puncture were performed.
      RESULTS: Visual acuities were counting fingers in both eyes, with bilateral optic
      disk hyperemia and swelling noted. Neurologic examination was unremarkable, and
      computed tomography and magnetic resonance imaging of the brain were normal. The
      cerebrospinal fluid (CSF) was devoid of white cells, although measles
      immunoglobulin M (IgM) antibodies were detected in both CSF and serum.
      Intravenous corticosteroids were administered, and clinical findings resolved
      within 1 month. A fall in serum IgM and a rise in serum IgG titers were observed.
      CONCLUSIONS: Although rare, optic neuritis in the absence of encephalomyelitis
      may occur in measles. Whether treatment is effective is unknown.

PMID- 12429259
TI  - Removal of semitranslucent cactus spines embedded in deep cornea with the aid of
      a fiberoptic illuminator.
AB  - PURPOSE: To report a rare case of multiple cactus spines embedded deep in the
      cornea that were removed with the aid of a fiberoptic illuminator. DESIGN:
      Interventional case report. METHODS: A 20-year-old man had an accidental ocular
      injury of the right eye when he hit a household miniature cactus plant. There
      were 80 to 90 spiculated foreign bodies embedded in the cornea, some of them even
      penetrating the anterior chamber. RESULTS: Removal of the foreign bodies was
      performed with the aid of a fiberoptic illuminator, which was chosen because it
      provides superior visualization of the semitranslucent spines. No residual
      corneal spines were found postoperatively. CONCLUSIONS: Household miniature
      cactus plants can cause corneal injury, with multiple foreign bodies that can be
      difficult to localize and remove. The use of a fiberoptic illuminator in such a
      situation is simple and effective.

PMID- 12429260
TI  - Keratectasia after laser in situ keratomileusis (LASIK): evaluation of the
      calculated residual stromal bed thickness.
AB  - PURPOSE: To report corneal histopathology associated with keratectasia after
      laser in situ keratomileusis (LASIK) and to evaluate the thickness of the
      calculated residual stromal bed in two cases and those in the literature. DESIGN:
      Interventional case reports. METHODS: Three eyes of two patients developed
      keratectasia after LASIK. Corneal specimens after penetrating keratoplasty in one
      eye of each patient were studied histopathologically, and the residual stromal
      bed was directly measured. For comparison, residual stromal bed thicknesses were
      calculated from published cases of keratectasia. RESULTS: Two eyes of a 26-year
      old woman and one eye of a 22-year-old woman developed keratectasia after LASIK.
      Calculated residual stromal bed thicknesses were 210, 213, and 261 microm.
      Histologic sections revealed focal scarring in the flap plane. The cornea
      specimens measured 75 and 118 microm thinner than calculated values immediately
      after LASIK. Transmission electron microscopy of one case revealed an average
      lamellar thickness of 0.94 microm. In 28 (49%) of 57 previous cases of
      keratectasia, the calculated residual stromal bed thicknesses were greater than
      250 microm. CONCLUSIONS: Both the flap and the stromal bed of the cornea may thin
      after LASIK. A residual stromal bed thickness of 250 microm does not preclude the
      development of keratectasia after LASIK.

PMID- 12429261
TI  - Recurrence of retinoblastoma 12 years after brachytherapy.
AB  - PURPOSE: To report a case of retinoblastoma that recurred 12 years after
      brachytherapy. DESIGN: Interventional case report. METHODS: A 2-month-old boy
      presented in December 1983 with bilateral retinoblastoma and was treated with
      bilateral 198Au plaque radiotherapy, photocoagulation, and cryotherapy. He
      maintained a visual acuity of 20/200 in both eyes. In December 1995, he had a
      sudden decrease of vision in the right eye and vitreous hemorrhage with fluffy
      opacification. RESULTS: In January 1996, cytopathologic examination of large
      keratic precipitates in the right eye demonstrated cells consistant with
      retinoblastoma. The right eye was enucleated and diffuse retinoblastoma was noted
      histopathologically. Systemic chemotherapy was given, and there has been no local
      recurrence or extraocular metastasis for 5 years. CONCLUSIONS: This case
      emphasizes that long-term follow-up is essential for managing retinoblastoma
      after eye-preserving conservative therapy.

PMID- 12429262
TI  - Primary adrenal lymphoma with choroidal metastases.
AB  - PURPOSE: To describe a 71-year-old man with bilateral primary adrenal lymphoma
      with metastases to the choroid. DESIGN: Interventional case report. METHODS: A 71
      year-old man presented with decreased visual acuity in his left eye secondary to
      an exudative retinal detachment. Abdominal computed tomography and percutaneous
      biopsy revealed non-Hodgkin large-cell lymphoma involving both adrenal glands.
      RESULTS: Ocular and adrenal lesions resolved after six cycles of chemotherapy
      with cytoxan, adriamycin, vincristine, and prednisone. Seven years after his
      initial diagnosis, the patient reported no recurrence of either ocular or
      systemic lymphoma. CONCLUSIONS: To our knowledge, this is the first case report
      of bilateral primary adrenal lymphoma with apparent metastases exclusively to the
      eye.

PMID- 12429263
TI  - BB embolus causing monocular blindness in a 9-year-old boy.
AB  - PURPOSE: To report a case of monocular blindness resulting from intravascular
      bullet migration. DESIGN: Observational case report. METHODS: A 9-year-old boy
      presented to the emergency room with a penetrating BB gun injury to the chest.
      RESULTS: Carotid angiography localized the bullet to the right internal carotid
      artery. He subsequently suffered blindness in the right eye, a right pupil
      involving third nerve palsy, left hemiparesis, and a probable left homonymous
      hemianopia. CONCLUSION: BB gun injuries may result in devastating ophthalmologic
      as well as systemic consequences due to bullet embolization.

PMID- 12429264
TI  - Effect of acetazolamide on ocular hemodynamics in pseudotumor cerebri associated
      with inflammatory bowel disease.
AB  - PURPOSE: To describe the hemodynamic effect of oral acetazolamide administration
      on ocular perfusion in a patient with pseudotumor cerebri associated with Crohn
      disease. DESIGN: Interventional case report. METHODS: A 20-year-old woman with a
      5-year history of Crohn disease presented with a 2-week history of headache and
      blurred vision in both eyes. Ophthalmologic examination was normal. Fluorescein
      angiography showed a profound delay in retinal and choroidal perfusion. Lumbar
      puncture showed an opening pressure of 320 mm water. Therapy was initiated with
      oral acetazolamide 750 mg per day. RESULTS: A subjective improvement of symptoms
      was noted over 4 days. Repeat fluorescein angiography showed resolution of the
      ocular perfusion deficit. No recurrent symptoms were noted 19 months after
      cessation of therapy. CONCLUSIONS: Crohn disease may present with pseudotumor
      cerebri and severe ocular perfusion deficits that are reversible with oral
      acetazolamide therapy.

PMID- 12429265
TI  - Combined pharmacologic and surgical approach to acquired nystagmus due to
      multiple sclerosis.
AB  - PURPOSE: To describe a combined pharmacological and surgical approach to treating
      acquired nystagmus in a patient with multiple sclerosis. DESIGN: Interventional
      case report. METHODS: A 40-year-old patient with acquired horizontal and vertical
      nystagmus and severe oscillopsia secondary to multiple sclerosis had combined
      treatment with gabapentin and a vertical Kestenbaum-type procedure. RESULTS:
      After gabapentin treatment (3,000 mg orally daily) the horizontal nystagmus was
      significantly reduced, and the patient developed a marked chin-up position. The
      vertical nystagmus remained unchanged, dampening on downgaze. A recession of both
      inferior rectus muscles reduced the nystagmus significantly in primary position,
      the abnormal head position disappeared, and oscillopsia completely resolved.
      Treatment increased visual acuity from 6/24 in the right eye and 6/60 in the left
      eye to 6/9 in both eyes. CONCLUSIONS: Acquired nystagmus in multiple sclerosis
      can be significantly improved by using a combined pharmacological and surgical
      approach.

PMID- 12429266
TI  - The enhanced frontalis sling for blepharoptosis repair.
AB  - PURPOSE: To describe a simple modification of the frontalis sling procedure.
      DESIGN: Interventional case reports. METHODS: The fascia lata strips are passed
      superiorly with a Richard-Allan needle rather than trimmed at the central
      incision in the inferior forehead. RESULTS: Satisfactory and stable eyelid
      positions have been achieved in six patients. CONCLUSIONS: Increasing the area of
      contact between the fascia lata strips and the frontalis muscle should enhance
      the muscle's action in elevating the ptotic eyelid.

PMID- 12429267
TI  - Tourette syndrome and iatrogenic eye injury.
AB  - PURPOSE: To describe the circumstances associated with eye injury from an ocular
      examination of two patients with Tourette syndrome. DESIGN: Case reports.
      METHODS: A 21-year-old man and a 24-year-old man had sudden and unpredictable
      movement during an eye examination, causing conjunctival laceration and
      hemorrhage abrasion in the first patient and a corneal abrasion in the second
      patient. RESULTS: With topical antibiotics for both patients and patching of the
      eye for the 24-year-old patient, healing was uncomplicated. CONCLUSIONS: Patients
      with Tourette syndrome are at risk of eye injury when an unanticipated tic
      movement occurs during eye examination. Physician precautions, particularly
      mental preparedness for sudden jerking movement, should be taken when examining
      patients with Tourette syndrome.

PMID- 12429268
TI  - Metastatic synovial sarcoma to the skull base and orbit.
AB  - PURPOSE: To report a case of metastatic synovial sarcoma to the parasellar area
      and orbit. DESIGN: Interventional case report. METHODS: A 43-year-old woman with
      a history of a right forearm synovial sarcoma treated with excision, radiation,
      and chemotherapy 16 months previously presented with blurred vision of the right
      eye, pain with eye movement, epistaxis, and a right superior division cranial
      nerve III palsy. Magnetic resonance imaging showed a right parasellar and right
      orbital apex mass. RESULTS: Pathologic examination of the parasellar biopsy
      revealed metastatic synovial sarcoma. At 6-month follow-up, the neuro-ophthalmic
      examination was unchanged, and repeat magnetic resonance imaging showed no
      recurrence of the tumor. CONCLUSIONS: Metastatic synovial sarcoma should be added
      to the differential diagnosis of parasellar and orbital tumors.

PMID- 12429269
TI  - Use of a flap of extraocular muscle and fat during subtotal exenteration to
      repair bony orbital defects.
AB  - PURPOSE: To describe a technique for the primary repair of bony defects between
      the orbit and adjacent structures during subtotal exenteration. DESIGN:
      Interventional case reports. METHODS: A flap composed of orbital fat supported by
      an extraocular muscle pedicle was used to fill a defect between the orbit and the
      nasal cavity in one case, and to buttress a fascia lata graft covering exposed
      dura mater in one case. RESULTS: The exenterated socket healed satisfactorily
      without fistula formation in both cases. CONCLUSIONS: Primary repair of
      communications between the orbit and its surrounding cavities may prevent the
      development of postoperative fistulae or cerebrospinal fluid leakage.

PMID- 12429270
TI  - Retinal capillary hemangioma treated with verteporfin photodynamic therapy.
AB  - PURPOSE: To describe a case of exudative retinal capillary hemangioma treated
      with photodynamic therapy that resulted in an improvement in clinical appearance
      and visual acuity. DESIGN: Interventional case report. METHODS: A 55-year-old
      Asian man presented with a large exudative peripheral retinal capillary
      hemangioma of the left eye causing serous retinal detachment, cystoid macular
      edema, and a best-corrected visual acuity of 20/200. The hemangioma was treated
      with three successive sessions of verteporfin photodynamic therapy (PDT).
      RESULTS: With 10 months of follow-up after the initial treatment, involution of
      the hemangioma, reduction of subretinal fluid, and improvement of best-corrected
      visual acuity to 20/80 was seen. CONCLUSION: Photodynamic therapy may be an
      effective treatment option in select cases of exudative retinal capillary
      hemangioma.

PMID- 12429271
TI  - Photodynamic therapy for the treatment of choroidal neovascularization secondary
      to rubella retinopathy.
AB  - PURPOSE: To describe a patient for whom photodynamic therapy was used to treat
      subfoveal choroidal neovascularization secondary to rubella retinopathy. DESIGN:
      Interventional case report. METHODS: A 36-year-old man with subfoveal choroidal
      neovascularization secondary to rubella retinopathy was treated with photodynamic
      therapy using verteporfin. Outcome was followed up with subsequent fundus
      examinations, fluorescein angiography, and evaluations of best-corrected visual
      acuity. RESULTS: Two treatments of photodynamic therapy using verteporfin
      resulted in involution of the neovascular membrane, resolution of subretinal
      hemorrhage, and improvement in best-corrected visual acuity from 20/200 to 20/60
      2 months after the second treatment. Owing to recurrence of active choroidal
      neovascularization, the patient required two more treatments of photodynamic
      therapy in the next 6 months, after which his best-corrected visual acuity was
      restored to 20/60. CONCLUSION: Photodynamic therapy may be an effective treatment
      for subfoveal choroidal neovascularization secondary to rubella retinopathy.

PMID- 12429272
TI  - Immunologic graft reaction after allogenic penetrating keratoplasty.

PMID- 12429286
TI  - Timing of androgen deprivation for prostate cancer: benefits versus side effects-
      a patient-physician dialogue.

PMID- 12429287
TI  - Hormonal therapy for prostate cancer: primum non nocere.

PMID- 12429288
TI  - Pitfalls in the design of clinical trials for interstitial cystitis.

PMID- 12429289
TI  - New basic science concepts in the treatment of classic bladder exstrophy.

PMID- 12429290
TI  - Improved prostate cancer-specific survival and other disease parameters: impact
      of prostate-specific antigen testing.
AB  - OBJECTIVES: To determine how the implementation of prostate-specific antigen
      (PSA) testing has affected disease-specific survival and other characteristics of
      prostate cancer. METHODS: Data were collected on all patients with prostate
      cancer diagnosed between 1988 and 1998 and registered in the Center for Prostate
      Disease Research Database at Walter Reed Army Medical Center. Statistical
      analyses were used to summarize trends over time in survival, mortality, and
      clinical stage. RESULTS: Between 1988 and 1998, a total of 2042 patients with
      prostate cancer were registered at Walter Reed Army Medical Center. The 5-year
      disease-specific survival rate was 86.9% and 93.7% for patients diagnosed in the
      respective year groups of 1988 to 1991 and 1992 to 1994, with follow-up through
      December 1, 2000 (P < 0.001). Prostate cancer was the cause of death for 37.5% of
      the patients in 1988 to 1989 versus 15.4% in 1999 to 2000. Marked stage migration
      has occurred; from 1988 to 1998, the percentage of patients presenting with
      metastatic disease decreased from 14.1% to 3.3% (P < 0.001). CONCLUSIONS: A
      statistically significant improved 5-year disease-specific survival and a
      decreased chance of dying from prostate cancer has occurred after the widespread
      implementation of PSA. We suspect that PSA testing has resulted in fewer patients
      presenting with metastatic disease and more patients presenting with localized
      disease amenable to curative treatment. This portends well for the use of PSA
      screening to improve outcomes for prostate cancer. However, randomized trials are
      needed to confirm the improvements in survival and mortality.

PMID- 12429291
TI  - A functional thrombin receptor (PAR1) is expressed on bone-derived prostate
      cancer cell lines.
AB  - OBJECTIVES: To identify genes important in prostate cancer metastatic to bone.
      Bone-specific metastasis is a common feature of prostate cancer and a significant
      cause of morbidity. METHODS: To identify factors involved in organ-specific
      metastasis, we used cDNA microarray analysis to compare a bone-derived cell line,
      VCaP, with a soft tissue-derived cell line, DuCaP. Both cell lines were derived
      from the same patient and spontaneously passaged. RESULTS: Forty-five genes were
      differentially expressed, and only seven of these also had increased expression
      in VCaP compared with normal prostatic tissue. Of these, protease-activated
      receptor 1 (PAR1) was verified as having increased expression by reverse
      transcriptase-polymerase chain reaction and Northern blot analysis, as well as by
      immunohistochemistry. PAR1 expression in a panel of prostate cancer cell lines
      demonstrated increased expression in those cell lines derived from bone
      metastases. Alpha-thrombin stimulation of the VCaP cells produced a dose
      dependent mobilization of intracellular calcium compared with DuCaP, suggesting
      that PAR1 expressed on the VCaP prostate cancer cell line is functional.
      CONCLUSIONS: These data indicate that a functional PAR1 is expressed on prostate
      cancer cell lines. The prostate cancer cell lines expressing PAR1 appear to have
      an association with increased bone metastases.

PMID- 12429292
TI  - Urology practice patterns after residency training in radical perineal
      prostatectomy.
AB  - OBJECTIVES: To assess the impact of residency training in radical perineal
      prostatectomy (RPP) on subsequent use of RPP in urology practice. METHODS:
      Urologists who completed residency training at Tulane University and the
      University of California, San Diego, Medical Center from 1977 to 1999 were
      surveyed by anonymous questionnaire for their practice demographics, operative
      experience in RPP during residency, the role of RPP in their current practice,
      and the reasons they do or do not perform RPP. RESULTS: Of 91 former residents,
      61 (67%) responded. RPP was in current use by 41% of the urologists trained in
      RPP during residency and by 13% of those with no residency RPP training. Those
      who had performed 10 or more RPPs during residency reported a higher rate of
      current RPP use (53%) than did those who had performed fewer than 10 RPPs during
      residency (21%). Urologists trained in RPP during residency cited partner
      preference (28%) and inadequate exposure (26%) as reasons they did not perform
      RPP; respondents with no residency RPP training cited inadequate exposure (25%),
      difficulty of the operation (25%), and time required to perform the operation
      (25%). CONCLUSIONS: A urologist with residency training in RPP is more likely to
      perform RPP in practice than is a urologist without such training. The intensity
      of training, in the form of greater operative experience during residency, had a
      positive impact on the future use of this specialized surgical technique.

PMID- 12429293
TI  - Augmentation cystoplasty in renal transplantation: a good and safe option-
      experience with 25 cases.
AB  - OBJECTIVES: To assess the surgical and long-term results of renal transplantation
      in 25 patients with bladder dysfunction and augmentation cystoplasty. METHODS: We
      retrospectively reviewed the evolution and surgical outcome of 25 renal
      transplants in 24 recipients with augmentation cystoplasty. The mean patient age
      at transplantation was 27.6 years. The etiology of bladder dysfunction was
      neurogenic bladder with detrusor hyperreflexia (11 patients), tuberculosis (5
      patients), vesicoureteral reflux (4 patients), posterior urethral valves (3
      patients), and interstitial cystitis (1 patient). Seventeen transplants were from
      living donors. Augmentation cystoplasty was performed before transplantation in
      21 patients. The bowel segments used in the augmentation cystoplasty included
      ileum in 16, ileocecal segments in 2, and sigmoid in 5 patients. The donor ureter
      was anastomosed to the native bladder in 16 patients, to the bowel segment in 6,
      and to the native ureter in 3. RESULTS: Twenty kidneys (80%) were functioning at
      a mean follow-up of 53.2 months (range 6 to 118). The mean serum creatinine was
      1.56 mg/dL (range 0.7 to 2.6). Three patients died of unrelated causes and 1 of
      adenocarcinoma that originated at the vesicointestinal anastomosis. The actuarial
      graft survival at 1, 2, and 5 years was 96%, 92%, and 78%, respectively.
      Complications included symptomatic urinary infection, ureteral stenosis, and
      lymphocele. CONCLUSIONS: Augmentation cystoplasty is a safe and effective method
      to restore function in noncompliant bladders. Renal transplantation can be
      performed safely after augmentation cystoplasty.

PMID- 12429294
TI  - Impact of diabetes mellitus on the presentation and outcomes of Fournier's
      gangrene.
AB  - OBJECTIVES: To evaluate, in a population of patients with very high risk of
      diabetes, the natural history of Fournier's gangrene (FG) and to characterize the
      differences in presentation and outcome. METHODS: Patients with FG were
      identified during a 6-year period at two tertiary care institutions in San
      Antonio, Texas. The impact of diabetes on presentation and outcome were evaluated
      and compared with previous series. RESULTS: We identified 26 patients with FG, of
      whom 20 (76.9%) had diabetes. Diabetes was the most common risk factor identified
      and was associated with a younger age. The average hospital stay was not affected
      by the diagnosis of diabetes. Of 26 patients treated for FG, 3 (11%) died, 1 of
      whom had diabetes. Although the extent of debridement required was greater among
      diabetics, the average number of debridements required was not increased (2.55 in
      diabetic and 2.4 in nondiabetic patients). CONCLUSIONS: Although diabetes is a
      risk factor for FG, the outcome is not affected by this diagnosis.

PMID- 12429295
TI  - Primary and postoperative retroperitoneal fibrosis-experience with 18 cases.
AB  - OBJECTIVES: Retroperitoneal fibrosis (RPF) is an uncommon disease complicated by
      ureteral entrapment. Its etiology includes several medications, periaortic
      inflammation, abdominal and retroperitoneal operations, radiotherapy, and
      malignancy. We present 18 patients, 14 of whom developed RPF after surgery and
      radiotherapy. METHODS: During the past 12 years, we treated 7 women and 11 men.
      The diagnosis was based on intravenous urography, retrograde pyelography, and
      computed tomography features. Computed tomography-guided or intraoperative
      biopsies were taken to differentiate benign from malignant fibrosis. In all
      patients, percutaneous stent nephrostomies or internal stents were inserted
      before surgery. The operation included ureterolysis with an omental flap or
      ureteral reimplantation. Follow-up included renal function tests, intravenous
      urography, and computed tomography. RESULTS: The mean patient age was 57.3 years
      (range 36 to 85). Fourteen patients developed RPF after abdominal or
      retroperitoneal surgery. Three had primary RPF and one malignant RPF due to
      metastatic disease. Six patients also underwent radiotherapy. The mean time
      between the insults to the diagnosis of RPF was 18.6 months (range 1 to 96). Ten
      patients had bilateral obstruction. Fourteen patients underwent surgery and four
      were treated with stenting only. Of the 14 patients who underwent surgery, 10 had
      a normal intravenous urogram postoperatively and 4 had decreased function of the
      formerly obstructed kidney. In 1 patient, re-entrapment of the ureter appeared
      owing to pelvic recurrence of tumor. At last follow-up, 1 patient waits with
      stents. The mean follow-up time was 22 months (range 4 to 52). CONCLUSIONS: The
      etiology of RPF varies. The unique feature of our series was the high incidence
      of patients who developed RPF after surgery and radiotherapy to the
      retroperitoneum. Nephrostomy drainage and ureteral stenting facilitated surgery.
      Ureterolysis combined with wrapping the ureter with an omental flap or re
      implantation ensured good anatomic and functional results.

PMID- 12429296
TI  - Techniques to maximize flexible ureteroscope longevity.
AB  - OBJECTIVES: To assess methods to improve the longevity and durability of flexible
      ureteroscopes by using the ureteral access sheath, 200-microm holmium laser
      fiber, and nitinol baskets or graspers during routine ureteroscopic procedures.
      Despite adequate advances in fiberoptics and endoscope design, the decreased size
      of currently available flexible ureteroscopes makes damage inevitable after
      repeated use. However, new auxiliary tools may be able to enhance ureteroscope
      durability. METHODS: The indications for performing flexible ureteroscopy were
      proximal ureteral stones (n = 32), renal calculi (n = 59), treatment of upper
      tract transitional cell carcinoma (n = 3), evaluation of hematuria or filling
      defect (n = 7), and treatment of ureteral strictures or ureteropelvic junction
      obstruction (n = 8). Using four new 7.5F flexible ureteroscopes, we prospectively
      evaluated the number of passes of each ureteroscope until more than 20 optical
      fibers were broken, more than a 25 degrees loss of deflection in either direction
      had occurred, or the instrument sustained injury requiring repair by the
      manufacturer. RESULTS: One hundred nine flexible ureteroscopic procedures
      (average 27.5 procedures per instrument; range 19 to 34) were performed with the
      four new flexible ureteroscopes before being sent for repair. Adjuncts to reduce
      scope damage during these procedures were the use of the ureteral access sheath
      (n = 109), nitinol devices allowing lower pole stone retrieval (n = 27), and the
      200-microm holmium laser fiber for stone fragmentation, tumor ablation, and
      incision of ureteropelvic junction/ureteral stenoses (n = 91). The average number
      of passes until more than 20 optical fibers were broken was 15.3 (range 12 to
      20), until more than a 25 degrees loss of deflection occurred was 50.3 (range 42
      to 66), or until the scope required repair was 66.7 (range 46 to 82).
      CONCLUSIONS: Flexible ureteroscopy will be used increasingly to manage upper
      urinary tract pathologic findings. Historically, the number of procedures
      performed before a flexible ureteroscope requires repair averaged 6 to 15. By
      incorporating the new ureteroscopic accessories, such as nitinol devices, a
      ureteral access sheath, and the 200-microm holmium laser fiber into common
      practice, one can reduce the strain on these fragile 7.5F endoscopes, thereby
      maximizing their longevity.

PMID- 12429297
TI  - Biochemical distinction between hyperuricosuric calcium urolithiasis and gouty
      diathesis.
AB  - OBJECTIVES: To determine whether the biochemical presentation and urinary
      physicochemical environment of patients with hyperuricosuria presenting with
      calcium stones (hyperuricosuric calcium urolithiasis [HUCU]) differs from those
      of patients with gouty diathesis (GD) or idiopathic uric acid urolithiasis.
      METHODS: A total of 122 patients with HUCU and 68 patients with GD were
      identified from our "stone registry" of patients who underwent a full ambulatory
      evaluation. All patients with HUCU had urinary uric acid greater than 800 mg/day
      in men and greater than 750 mg/day in women and presented with calcium stones.
      Those with GD had pure uric acid stones or mixed uric acid-calcium stones and did
      not have secondary causes of uric acid urolithiasis. Data derived from the
      fasting serum and 24-hour urine samples collected on a random diet and on a diet
      restricted in calcium, sodium, and oxalate were compared between the two groups.
      RESULTS: Compared with patients with HUCU, those with GD had significantly higher
      serum uric acid and lower urinary uric acid and pH levels (mean value 5.38 and
      5.35 on random and restricted diets versus 6.09 and 6.14, respectively). The
      fractional excretion of urate and the discriminant score of the relationship
      between urinary pH and the fractional excretion of urate were significantly lower
      in those with GD than in those with HUCU. Patients with HUCU displayed a greater
      urinary saturation of sodium urate and calcium oxalate compared with those with
      GD, and those with GD had a higher urinary content of undissociated uric acid and
      lower urinary saturation of brushite (calcium phosphate). CONCLUSIONS: Patients
      with HUCU presented with normal urinary pH and hyperuricosuria, accompanied
      sometimes by hypercalciuria, which produced increased urinary saturation of
      sodium urate and calcium oxalate. In contrast, those with GD had a low fractional
      excretion of urate (that contributed to hyperuricemia) and low urinary pH (that
      led to increased amount of undissociated uric acid). The varying biochemical and
      physicochemical presentations of the two conditions can be ascribed to
      overindulgence with purine-rich foods in those with HUCU and underlying primary
      gout in those with GD.

PMID- 12429298
TI  - Evaluation of extracorporeal shock wave therapy in Peyronie's disease.
AB  - OBJECTIVES: To evaluate the results of extracorporeal shock wave therapy (ESWT)
      in patients with Peyronie's disease. METHODS: This study included 42 patients
      (mean age 55.4 years, range 32 to 72, SD 9.92) with Peyronie's disease. The mean
      duration of disease was 16.5 months (range 3 to 60, SD 13.31). Before treatment,
      the degree of angulation was assessed artificially by injection of 10 to 20
      microg alprostadil, and Polaroid photographs were taken. Patients were also
      questioned about pain on erection, whether sexual intercourse was possible, and
      the quality of erections. All were initially treated with three sessions of ESWT
      (3000 shock waves). After three sessions, patients who believed that improvement
      had resulted or who wanted to undergo additional treatment went on to have
      further sessions. The mean duration of follow-up was 5.9 months (range 2 to 18,
      SD 4.4), after which the results were analyzed. RESULTS: Those who believed that
      improvement in angulation had resulted were asked to provide Polaroid photographs
      to assess the improvement objectively. Six (14%) said that they had excellent
      results, 21 (50%) had significant improvement, 7 (17%) had slight improvement,
      and 8 (19%) had no change. Of the 25 who had pain on erection before treatment,
      21 (84%) reported complete or near complete relief after treatment. Five patients
      said that the quality of the erections had improved after treatment. Eight
      patients complained of mild and one of severe pain during or immediately after
      treatment; 2 of these 9 patients had both pain and bruising. CONCLUSIONS: The
      initial results with ESWT are promising, with minimal complications. The long
      term results need to be evaluated.

PMID- 12429302
TI  - Does adrenal mass size really affect safety and effectiveness of laparoscopic
      adrenalectomy?
AB  - OBJECTIVES: To evaluate the effectiveness and safety of laparoscopic
      adrenalectomy with regard to adrenal mass size, as well as to consider its
      clinical and pathologic patterns. Laparoscopy is today considered the first
      choice treatment of many adrenal diseases, although its use is still
      controversial for large adrenal masses and incidentally found adrenal cortical
      carcinoma. METHODS: A total of 125 patients underwent lateral transperitoneal
      laparoscopic adrenalectomy. The indications were either functioning or
      nonfunctioning adrenal masses, without any radiologic evidence of involvement of
      the surrounding structures. The correlation between the size and the operative
      times, estimated blood loss, incidence of intraoperative and postoperative
      complications, and length of hospital stay were studied with Pearson's
      correlation coefficient, Fisher's exact test, and the chi-square test. The
      analysis of variance test was used to evaluate any possible correlation between
      the size and clinicopathologic features and the results. RESULTS: A slight
      correlation was observed between the size and operative time (P = 0.004), but no
      correlation was observed between the size and the other parameters. Statistical
      analysis showed a significant correlation between the clinicopathologic patterns
      (nonfunctioning benign adrenal masses, Conn's adenoma, Cushing's adenoma,
      pheochromocytoma, adrenal cortical cancer, and other tumor metastasis) and the
      operative time (P = 0.011), but not with the other parameters. CONCLUSIONS:
      Laparoscopic adrenalectomy is also effective and safe for large lesions. The
      results of our series confirms that the risk of encountering an incidental
      adrenal cortical cancer is significantly increased for large lesions, and
      therefore, in these cases, additional attention is required to observe oncologic
      surgical principles.

PMID- 12429303
TI  - Sporadic renal cell carcinoma in young adults: presentation, treatment, and
      outcome.
AB  - OBJECTIVES: To present our institutional experience with young adult patients
      treated for sporadic renal cell cancer (RCC) during the past two decades.
      Sporadic RCC is rare in patients younger than 40 years old, accounting for only
      3.4% of cases. METHODS: A retrospective review of 101 patients with sporadic RCC
      between the ages of 20 and 40 years was performed. The mean age at diagnosis was
      33.7 +/- 5.5 years. Tumors were discovered incidentally in 40 patients (40%) and
      were symptomatic in 61 (60%). Sixteen patients (16%) had distant metastasis at
      diagnosis. For unilateral disease, 58 underwent radical nephrectomy and 31
      nephron-sparing surgery (NSS). For bilateral RCC, 2 patients underwent bilateral
      radical nephrectomy, 3 underwent bilateral NSS, and 7 underwent NSS on one side
      and a staged contralateral radical nephrectomy. The mean postoperative follow-up
      was 48 +/- 44 months. RESULTS: The overall and cancer-specific 5-year survival
      rate was 61% and 67%, respectively. Tumor stage (P < 0.001) and grade (P < 0.001)
      had a significant impact on survival. Incidentally discovered tumors were less
      likely to develop metastases and had improved cancer-specific survival compared
      with symptomatic tumors (P = 0.001). The 5-year cancer-specific survival rate by
      pathologic stage was 88% for T1N0M0, 64% for T2N0M0, 61% for T3N0M0, and 0% for
      N+ and M+ (P < 0.001). CONCLUSIONS: The results of our study show that RCC does
      not behave more aggressively in young adults younger than 40 years old than in
      older adults. The major determinants of patient survival are tumor stage and
      grade at presentation. Outcome is similar in select patients whether undergoing
      NSS or radical nephrectomy.

PMID- 12429304
TI  - Renovascular complications of laparoscopic donor nephrectomy.
AB  - OBJECTIVES: To review the operative renovascular injuries related to our
      laparoscopic donor nephrectomy experience, since management of intraoperative
      renovascular complications during laparoscopic nephrectomy can present a serious
      challenge. METHODS: During a 6-year period, 353 patients underwent laparoscopic
      donor nephrectomy. A retrospective chart review was performed to identify and
      evaluate the renovascular complications associated with the procedure. RESULTS:
      Eight cases (2.3%) of renovascular complications were identified. Vascular injury
      involved the renal artery in 6 cases and the renal vein in 2 cases. The
      etiologies included endovascular GIA stapling failure (n = 2), surgical clip
      dislodgment (n = 2), and vessel laceration during dissection or stapling (n = 4).
      Open conversion was necessary in 6 cases (75%). No patient mortality or allograft
      loss occurred. CONCLUSIONS: Laparoscopic donor nephrectomy is associated with a
      low incidence of renovascular complications. Laparoscopic or open surgical
      management may be required when problems arise to optimize donor safety and
      allograft survival.

PMID- 12429306
TI  - Association of cyclooxygenase-2 expression with prognosis of stage T1 grade 3
      bladder cancer.
AB  - OBJECTIVES: To determine whether the expression of cyclooxygenase-2 (COX-2) has
      prognostic significance in Stage T1G3 transitional cell carcinoma of the bladder,
      the most unfavorable subgroup in terms of recurrence and disease progression.
      METHODS: Thirty-seven consecutive patients with initial T1G3 transitional cell
      carcinoma, who had undergone complete transurethral resection, followed by 6
      weeks of intravesical instillation of bacille Calmette-Guerin (BCG), and with at
      least 1 year of follow-up, were enrolled in the study. Paraffin-embedded cancer
      tissue samples were immunohistochemically stained for COX-2, and possible
      correlations with clinicopathologic features, such as age, shape and multiplicity
      of tumor, recurrence, and progression were examined. RESULTS: The median follow
      up was 27 months (range 12 to 67). Sixteen patients (43.2%) experienced
      recurrence and 6 (16.2%) had progression defined as muscle invasion. Of 37
      specimens, 16 (43.2%) stained positive for COX-2, defined as 5% or greater of
      positively stained cancer cells. COX-2 expression was statistically significant
      in predicting both recurrence (P = 0.0493) and disease progression (P = 0.0272).
      Patient age and the shape and multiplicity of tumors were not significantly
      predictive of recurrence or progression. CONCLUSIONS: In a pathologically
      homogeneous group of T1G3 transitional cell carcinoma of the bladder, the
      expression of COX-2 correlated with recurrence and progression. Thus, patients
      with COX-2 positive superficial bladder cancer may need to be followed up more
      vigorously. Additional studies on the mechanistic implications of COX-2 with
      respect to recurrence and progression and the possible application of a COX-2
      inhibitor to prevent recurrence and progression of superficial bladder cancer are
      warranted.

PMID- 12429307
TI  - Impact of a second transurethral resection on the staging of T1 bladder cancer.
AB  - OBJECTIVES: To evaluate the impact of a second transurethral resection (TUR) on
      the pathologic stage in a unique patient population with T1 tumors. METHODS:
      Seventy-one patients with Stage T1 transitional cell carcinoma of the bladder
      were prospectively enrolled and underwent restaging TUR. Fifteen patients
      underwent immediate cystectomy and 56 patients were treated endoscopically. The
      patients who underwent immediate cystectomy were the subjects of this report.
      RESULTS: Fifteen patients underwent immediate cystectomy. At restaging TUR, 13
      patients had persistent T1, 1 patient had Tis, and 1 patient had no residual
      disease. The pathologic stage at cystectomy revealed the presence of residual
      disease in 12 of 15 patients, and 3 patients had pT0. Of the 12 patients with
      residual disease, 3 had residual pT1, 2 had pT1 with pTis, 5 had pTis alone, and
      2 had muscle-invasive tumors. Thirteen percent of the patients who underwent
      immediate cystectomy after restaging TUR had a pathologic stage greater than pT1.
      CONCLUSIONS: Understaging for T1 disease is negligible after restaging TUR.

PMID- 12429309
TI  - Complication rates and risk factors of 5802 transrectal ultrasound-guided sextant
      biopsies of the prostate within a population-based screening program.
AB  - OBJECTIVES: To evaluate the complication rates and possible risk factors of
      biopsy of the prostate, with the aim of improving patient counseling and the
      safety of the procedure. Biopsy of the prostate has to be a relatively safe
      procedure and the participants have to be well informed about the possible
      complications. METHODS: Within the biopsy protocol of the Rotterdam section of
      the European Randomized Study of Screening for Prostate Cancer, we evaluated 5802
      transrectal ultrasound-guided systematic sextant biopsies. All participants
      received prophylactic antibiotic therapy. RESULTS: We performed 5802 biopsies.
      Hematuria lasting longer than 3 days and hematospermia were present after 22.6%
      and 50.4% of the procedures, respectively. More severe complications were far
      less frequent. Two hundred participants (3.5%) developed fever after biopsy.
      Urinary retention was seen 20 times (0.4%), and hospitalization was needed in 27
      cases (0.5%). Twenty-five of these men were admitted because of signs of
      prostatitis and/or urosepsis. Risk factor analyses revealed that an earlier
      episode of prostatitis was significantly associated with hospital admission and
      pain after biopsy. Characteristics of prostatic hyperplasia, such as prostate
      volume, transition zone volume/total prostate volume ratio, and a higher
      International Prostate Symptom Score, were all predictors of urinary retention.
      CONCLUSIONS: Minor complications are frequently seen but major complications are
      rare after prostate biopsy. Assessment of the risk factors before biopsy can help
      to improve the adequacy of counseling, and precautionary measures can be taken to
      minimize the risk of complications after the procedure. Transrectal ultrasound
      guided sextant biopsy remains a safe procedure for the diagnosis of prostate
      cancer within the general population.

PMID- 12429310
TI  - Predicting the outcome of prostate biopsy in a racially diverse population: a
      prospective study.
AB  - OBJECTIVES: To develop a mathematical model to predict prostate biopsy outcome
      using readily available clinical variables. METHODS: A total of 319 men (78%
      African American) undergoing transrectal ultrasound-guided prostate biopsy were
      prospectively studied. The parameters collected included age, race, prostate
      specific antigen (PSA) level, PSA density (PSAD), digital rectal examination
      findings, biopsy history, prostate volume (by transrectal ultrasound), and
      ultrasound findings. Models were constructed using multivariate logistic
      regression (LR) analysis and back-propagation artificial neural networks (ANNs).
      Patient data were randomly split into five cross-validation sets and used to
      develop and validate the LR and ANN models. RESULTS: Of the 319 men, 39% had a
      positive biopsy. The mean patient age was 65.1 +/- 8.3 years, with a mean PSA
      level of 12.6 +/- 24.9 ng/mL and a mean PSAD of 0.31 +/- 0.66 ng/mL/cm(3).
      Univariate analysis indicated a significant difference in age, PSA level, PSAD,
      free PSA, digital rectal examination findings, TRUS lesion, and biopsy history
      between the positive and negative biopsy groups (P <0.01). The mean area under
      the receiver operating characteristic curve (AUROC) for the five LR models was
      0.76 +/- 0.04 (range 0.71 to 0.81). The median LR AUROC was 0.76, with a
      corresponding specificity of 0.13 at a sensitivity of 0.95. The mean AUROC for
      the five ANN models was 0.76 +/- 0.04 (range 0.71 to 0.83). The median ANN AUROC
      was 0.76, with a corresponding specificity of 0.21 at a sensitivity of 0.95.
      CONCLUSIONS: Two models (LR and ANN) that predict outcome with high efficiency
      (AUROC = 0.76) were constructed from a contemporary, prospective database. Such
      models may be useful to patients and physicians alike when assessing the
      diagnostic strategies available to detect prostate cancer.

PMID- 12429311
TI  - Predictors of cancer in repeat extended multisite prostate biopsy in men with
      previous negative extended multisite biopsy.
AB  - OBJECTIVES: To evaluate the factors influencing the cancer detection rate in men
      whose initial and repeat biopsies were both performed using an extended multisite
      biopsy scheme. Sextant biopsy of the prostate is associated with a significant
      false-negative rate, as evident from the high cancer detection rate after repeat
      prostate biopsy. Extended multisite biopsy schemes have therefore been
      recommended to maximize cancer detection. METHODS: Between June 1997 and August
      2001, 939 men underwent prostate biopsy for early detection of prostate cancer
      using the extended multisite scheme (10 or 11 cores incorporating the anterior
      horn of the peripheral zone with or without midline peripheral zone and/or the
      transition zone). Of these 939 men, 89 (9.5%) underwent a repeat extended
      multisite prostate biopsy. The median prostate-specific antigen level was 6.9
      ng/mL (range 0.7-36.1). Twenty-four men (27%) had an abnormal digital rectal
      examination at presentation. Most men (86%) in the group undergoing repeat biopsy
      had two or more risk factors for a positive biopsy. The median interval between
      biopsies was 4 months. RESULTS: Of the 89 men, 15 (17%) had prostate cancer in
      the repeat biopsy specimen. Seven cancers (47%) were found only in the alternate
      biopsy sites, 5 (33%) cancers were found only in the sextant sites, and 3 in both
      sextant and alternate sites. Cancer was present in only one biopsy core in 11
      (73%) of the 15 men, and the median Gleason score was 6 (range 6-8). On
      multivariate analysis, the presence of atypical glands suspicious for carcinoma
      (AGSC) was the only independent predictor of cancer in repeat biopsy (P <0.004).
      Of the 79 men without AGSC in the initial biopsy, 8 (10%) had a positive repeat
      biopsy. The total and percent free prostate-specific antigen level, digital
      rectal examination, ultrasound findings, and presence of high-grade prostatic
      intraepithelial neoplasia were not predictive of cancer detection. CONCLUSIONS:
      The probability of a positive result for a repeat prostate biopsy is lower after
      an initial extended multisite biopsy compared with an initial sextant biopsy. The
      presence of AGSC was the only significant predictor of cancer in the repeat
      biopsy. Because nearly 50% of cancers detected in the repeat biopsy were in
      alternate sites only, using a sextant biopsy scheme for repeat biopsy would have
      missed these cancers.

PMID- 12429312
TI  - Increasing the number of core samples taken at prostate needle biopsy enhances
      the detection of clinically significant prostate cancer.
AB  - OBJECTIVES: The number of cores obtained during transrectal ultrasound-guided
      prostate biopsy to detect cancer has increased from the previous standard of 6.
      Increasing the number of biopsy cores taken results in a higher prostate cancer
      detection rate. Because criteria for defining the clinical significance of
      localized prostate cancer has been proposed, the question may be asked whether
      the increased number of tumors found is clinically significant. METHODS: The
      Urology Service's surgical log database revealed 369 patients who underwent
      radical prostatectomy as primary therapy between January 1997 and March 2001.
      Only men who had had more than six core biopsies that included the standard
      sextant and lateral horns of the peripheral zone biopsies were considered. The
      hospital's clinical information system was then used to extract all additional
      data for age, clinical stage, pretreatment prostate-specific antigen level, and
      transrectal ultrasound-guided biopsy and subsequent whole mount pathology
      results, including pathologic stage, number of tumors, largest single and
      aggregate tumor volumes, highest tumor Gleason score, and tumor locations. A
      total of 127 men comprised our final group. RESULTS: Subgrouping based on the
      location of positive biopsy results yielded 40 (31.5%) in the standard sextant
      biopsy only, 31 (24.4%) in the lateral horns of the peripheral zone only, and 56
      (44.1%) of 127 tumors in both zones. The Gleason score was similar throughout.
      The margin-positive rate was 12.5% for the sextant-only positive biopsies, 12.9%
      for the lateral horn-only positive biopsies, and 42.9% for the both positive
      biopsies. The insignificant tumor rate for the group as a whole was 5.5% (7 of
      127). The insignificant tumor rate for the lateral horn-only positive biopsies
      was 3.2% (1 of 31). CONCLUSIONS: The addition of laterally directed biopsies
      increases the rate of prostate cancer detection, and the vast majority of these
      tumors are clinically significant.

PMID- 12429314
TI  - Prostate cancer diagnosed after initial biopsy with atypical small acinar
      proliferation suspicious for malignancy is similar to cancer found on initial
      biopsy.
AB  - OBJECTIVES: To compare matched clinical and prostatectomy data between (a) men
      with an initial biopsy diagnosis of atypical small acinar proliferation (ASAP)
      suspicious for malignancy whose cancer was diagnosed subsequently, and (b) men
      with a cancer diagnosis not preceded by an ASAP diagnosis. ASAP diagnoses apply
      to 1.5%-9.0% of prostatic biopsies and predict definite cancer in about 45% of
      repeat biopsies. METHODS: At our hospitals, during overlapping intervals from
      1990 to 2001, 7081 men underwent prostate biopsy, and 227 (3.2%) had an overall
      diagnosis (based on all cores sampled) of ASAP. We concurred with the ASAP
      diagnosis in 184 cases (81%). Repeat biopsy was performed in 129 (57%), with 22
      again having ASAP and 51 (40%) adenocarcinoma. Nineteen men underwent
      prostatectomy at our hospitals. The controls comprised men who underwent
      prostatectomy before and after each man with an initial ASAP diagnosis (2:1 match
      with cases). Findings included grade, pathologic stage, measured maximum
      dimension of tumor, resection margin status, patient age, and latest preoperative
      serum prostate-specific antigen. RESULTS: Men in the initial-ASAP group did not
      differ significantly from controls with respect to age (63 vs. 61, P = 0.08).
      Initial-ASAP and control groups had serum prostate-specific antigen levels of 5.9
      and 7.4 ng/mL (P = 0.32), respectively; mean Gleason scores were 6.2 and 6.6 (P =
      0.11); mean stages were pT2b and pT2b; and tumor size averaged 0.9 and 1.2 cm (P
      = 0.36). Fewer men with initial-ASAP diagnosis on biopsy had positive margins
      (5%) than did those in the control group (30%, P < 0.05). CONCLUSIONS: An ASAP
      diagnosis represents undersampled cancer in at least 40% of cases and places men
      at risk of prostate cancer with similar clinicopathologic findings as in other
      men with cancer.

PMID- 12429313
TI  - Acceptability and complications of prostate biopsy in population-based PSA
      screening versus routine clinical practice: a prospective, controlled study.
AB  - OBJECTIVES: To compare both the acceptability and the complications of prostate
      biopsy between men attending screening and hospital-referred symptomatic
      patients. A screening program cannot be successful unless the screening and
      diagnostic examinations are well tolerated and the willingness to participate is
      high. METHODS: A total of 200 men, comprising 100 participants in the Finnish
      prostate cancer screening trial and 100 hospital-referred patients with signs or
      symptoms suggestive of prostate cancer, were consecutively recruited and
      underwent transrectal ultrasound-guided prostate biopsies. Immediate
      complications were recorded at the time of examination. Acceptance and possible
      late complications of biopsy were requested through a self-administered
      questionnaire, which was returned by 97% of those screened and 84% of the
      hospital-referred controls. RESULTS: No major complications were seen immediately
      after biopsy, but one half of the men had minor rectal hemorrhage and, in a few
      cases, bleeding from the urethra. Most screened (58%) and hospital-referred (65%)
      subjects felt no distress before biopsy. The procedure was considered unpleasant
      by 69% of those screened and 61% of the controls. Correspondingly, 52% and 63% of
      men reported moderate pain at biopsy, but only 3 of those screened (3%) and 4
      controls (5%) experienced severe pain. Nevertheless, a great majority of men in
      both the screening (82%) and the control (86%) groups would be willing to undergo
      a repeated biopsy if needed. Persistent rectal bleeding and hematuria were common
      (13% to 35%, respectively), but less than one fourth considered this disturbing.
      No significant differences were seen either in complications or acceptability
      between the groups. CONCLUSIONS: The results of our study demonstrated that minor
      complications are equally frequent among men undergoing prostate biopsy for
      screening and other men. Despite the complications, prostate biopsy was regarded
      as acceptable. Nevertheless, such complications may impair the acceptability, and
      eventually, the effectiveness of screening.

PMID- 12429315
TI  - Radical prostatectomy: bladder neck preservation and puboprostatic ligament
      sparing--effects on continence and positive margins.
AB  - OBJECTIVES: To determine the effect of puboprostatic ligament sparing and bladder
      neck preservation on postoperative continence and positive margins after radical
      retropubic prostatectomy. METHODS: A total of 149 men with clinically localized
      prostate cancer underwent radical retropubic prostatectomy. A bladder neck
      preservation technique was used in 48 patients (group 1), puboprostatic ligament
      sparing in 51 patients (group 2), and both techniques in 50 men (group 3).
      Urinary continence and margin status were assessed. RESULTS: A statistically
      significant difference in the early return of continence was found 3 and 6 months
      postoperatively between groups 1 and 2 (P < 0.05), as well as between groups 2
      and 3 (P < 0.05), in favor of groups 1 and 3. However, the long-term continence
      rates recorded 1 year postoperatively did not differ, at 92%, 92%, and 94% for
      groups 1, 2, and 3, respectively. Positive margins were found in 10 patients
      (21%) from group 1, in 9 (18%) from group 2, and in 11 (22%) from group 3.
      Positive margins at the bladder neck were found in 3 (6%), 1 (2%), and 2 (4%)
      patients, respectively, in groups 1, 2, and 3. These were the sole sites found in
      1 patient (2%) in each of groups 1 and 3 and in none of group 2 (0%). Positive
      margins on the prostatic apex were found in 3 patients (6%) in group 1, 2
      patients (4%) in group 2, and 4 patients (8%) in group 3. The apex was the only
      site found in 0 (0%), 1 (2%), and 2 (4%) patients for groups 1, 2, and 3,
      respectively. No statistically significant difference was found in the margin
      status among the groups studied. CONCLUSIONS: The final continence rates did not
      differ among the three groups. However, bladder neck preservation offered an
      earlier return of continence compared with the puboprostatic ligament-sparing
      technique. The positive margin status was similar for all three groups.

PMID- 12429316
TI  - Laparoscopic radical prostatectomy: initial 70 cases at a U.S. university medical
      center.
AB  - OBJECTIVES: To report our experience with the first 70 cases of laparoscopic
      radical prostatectomy. Radical retropubic prostatectomy is an accepted therapy
      for the management of locally confined prostate cancer. Recently, laparoscopic
      prostatectomy has been introduced as a minimally invasive alternative to open
      radical prostatectomy. Several published series from Europe have demonstrated
      that laparoscopic radical prostatectomy is a safe and feasible approach to the
      management of localized prostate cancer. METHODS: From May 2000 to May 2001,
      transperitoneal laparoscopic radical prostatectomy was performed on 70 men, aged
      40 to 76 years, who were appropriate candidates for radical retropubic
      prostatectomy. Patient characteristics, surgical statistics, and pathologic
      results were prospectively collected. RESULTS: The mean preoperative prostate
      specific antigen level was 6.6 ng/mL (range 1.5 to 20.7). The preoperative
      Gleason sum was 6 in 53 patients (75.7%), 7 in 16 (22.9%), and 8 in 1 patient
      (1.4%). The mean operating time was 274 minutes (range 165 to 495). The estimated
      blood loss averaged 449 mL (range 50 to 2750), and 4 patients (5.7%) required
      blood transfusions. In 1 case, we converted to a standard retropubic approach.
      Two intraoperative (2.9%) and 14 (20%) overall postoperative complications
      occurred. Positive surgical margins were reported in 8 specimens (11.4%). At a
      minimum of 3 months' follow-up, 85% reported use of 0 or 1 pad per day. The
      operative times, amount of blood loss, and complication rate decreased
      dramatically with experience. CONCLUSIONS: Laparoscopic radical prostatectomy is
      a technically demanding procedure that is a feasible option for the surgical
      treatment of localized prostate cancer. The morbidity of this operation is
      significantly less than that of radical retropubic prostatectomy. The
      laparoscopic approach shows significant promise for reducing surgical morbidity
      and improving the anatomic radical prostatectomy.

PMID- 12429317
TI  - Prospective comparison of radical retropubic prostatectomy and robot-assisted
      anatomic prostatectomy: the Vattikuti Urology Institute experience.
AB  - OBJECTIVES: Robotic assistance may enhance the precision of anatomic dissection
      and increase the feasibility of performing laparoscopic radical prostatectomy for
      most surgeons. We performed a prospective comparison of 30 consecutive patients
      undergoing conventional radical retropubic prostatectomy (RRP) and 30 initial
      patients undergoing robot-assisted anatomic prostatectomy (RAP) at our
      institution. METHODS: The study design was a prospective nonrandomized comparison
      of anatomic RRP performed using the technique of Walsh and RAP performed with the
      da Vinci surgical system. We evaluated the baseline patient and tumor
      characteristics (age, body mass index, serum prostate-specific antigen, Gleason
      score, and clinical stage), intraoperative parameters (operative time, blood
      loss, and need for transfusion), postoperative parameters (pain score,
      hospitalization duration, catheter duration), histopathologic parameters, and
      complications in the two groups. RESULTS: The preoperative parameters were
      comparable for both groups of patients. The mean setup time for RAP was 0.95
      hours. The mean operating time was 2.3 hours for RRP and 4.8 hours for RAP (P
      <0.001). One patient required conversion from RAP to RRP because of a lack of
      progress. The mean blood loss was 970 mL for RRP and 329 mL for RAP (P <0.001).
      The drop in hemoglobin was greater in the RRP group (4.4 versus 1.2 g in RAP; P
      <0.05). The mean pain score on postoperative day 1 was 7 in the RRP group and 4
      in RAP group (P = 0.05). The mean hospital stay was 56 hours in the RRP group and
      36 hours in the RAP group (P value not significant). Sixty-three percent of the
      RAP and 0% of the RRP groups were discharged within 23 hours (P <0.001). The mean
      duration of postoperative catheterization was 14 days for the RRP and 11 days for
      the RAP groups (difference not significant). The pathologic stage, margin status,
      and prostate-specific antigen values were not different between the two groups.
      The setup time, operative time, blood loss amount, and catheterization duration
      were significantly reduced after the first 20 patients. CONCLUSIONS: Currently,
      RAP is a longer procedure than RRP. However, the blood loss is minimal and
      patients feel less pain and are discharged earlier from the hospital. In our
      hands, the margin status and complication rates were comparable for both
      techniques.

PMID- 12429319
TI  - Effect of catheter size on urodynamic assessment of bladder outlet obstruction.
AB  - OBJECTIVES: To examine the effect of cross-sectional catheter diameter on
      urodynamic measurement of bladder outlet obstruction as predicted by the Abrams
      Griffiths nomogram. METHODS: Thirty-one patients with symptomatic benign
      prostatic hyperplasia underwent free flow measurements followed by pressure-flow
      urodynamic evaluation using 5F and 10F urethral catheters in randomly assigned
      order. The measurements of voided volume, maximal flow rate (Qmax), postvoid
      residual volume, and detrusor pressure at maximal flow (PdetQmax) were compared.
      Data points were then plotted on the Abrams-Griffiths nomogram, and
      categorization of bladder outlet obstruction was assigned for each catheter size.
      RESULTS: The use of 10F catheters resulted in both a significant decrease in Qmax
      and increase in PdetQmax compared with the use of 5F catheters. Of 31 patients,
      10 (32%) were incorrectly categorized as obstructed according to the Abrams
      Griffiths nomogram when the larger sized catheter was used, and 17 (55%)
      experienced migration from a less obstructed to a more obstructed category.
      CONCLUSIONS: The use of 5F catheters allows for more accurate diagnosis of
      bladder outlet obstruction. In urodynamic evaluations, the larger size 10F
      catheters should be avoided, especially in patients with borderline symptoms.

PMID- 12429318
TI  - Impact of radical prostatectomy and TURP on the hypothalamic-pituitary-gonadal
      hormone axis.
AB  - OBJECTIVES: To assess the impact of prostate cancer (PCa) and benign prostatic
      hyperplasia (BPH) on the hypothalamic-pituitary hormone axis, we determined the
      endocrine changes after radical prostatectomy (RP) and transurethral resection of
      the prostate (TURP) for BPH and in a group of men with BPH followed up
      conservatively. METHODS: Patients with PCa before RP (n = 49), those who
      underwent TURP for BPH (n = 51), and men with lower urinary tract symptoms for
      whom a wait-and-see strategy was chosen (n = 46) were included. Serum levels of
      total testosterone, luteinizing hormone, and follicle-stimulating hormone were
      determined at baseline and 6 and 12 months later in all patients. RESULTS: No
      significant endocrine changes were observed in the wait-and-see and TURP groups 6
      and 12 months after baseline. In contrast, luteinizing hormone increased from 5.2
      to 8.9 mIU/mL (P = 0.0004) and follicle-stimulating hormone from 5.7 to 9.3
      mIU/mL (P = 0.0003) 12 months after RP. The rise of total testosterone from 3.9
      to 4.4 ng/mL failed to reach statistical significance (P = 0.18). Patients with
      Gleason score 2 to 6 PCa had higher testosterone values (4.2 ng/mL) at baseline
      than did those with Gleason score 7 to 10 PCa (2.2 ng/mL, P < 0.05). Although 12
      months after RP no changes in testosterone were observed in the low Gleason score
      group, the testosterone levels more than doubled in those with high-grade tumors.
      The increases in luteinizing hormone and follicle-stimulating hormone at 12
      months, however, were comparable in both groups. CONCLUSIONS: Our findings
      suggest a significant impact of PCa on the hypothalamic-pituitary axis that is
      more profound in high-grade cancer. Such an effect was not demonstrable for the
      transition zone in BPH.

PMID- 12429320
TI  - Sexual dysfunction in combat veterans with post-traumatic stress disorder.
AB  - OBJECTIVES: To evaluate the prevalence, clinical correlates, and severity of
      sexual dysfunction in combat veterans with and without post-traumatic stress
      disorder (PTSD) using a validated instrument for assessing sexual function. The
      results of recent studies have suggested that combat veterans with PTSD
      experience a higher rate of sexual dysfunction than do those without PTSD.
      METHODS: We administered the International Index of Erectile Function (IIEF) and
      a demographic and health questionnaire to male combat veterans undergoing
      treatment for PTSD and to age-comparable male combat veterans without PTSD.
      RESULTS: The mean total IIEF score was significantly lower in the 44 patients
      with PTSD than in the 46 controls (26.38 versus 40.86; P = 0.035). With respect
      to the individual IIEF domains, patients with PTSD had poorer scores on overall
      satisfaction and orgasmic function and showed trends toward poorer scores on
      intercourse satisfaction and erectile function. No statistically significant
      difference was observed for sexual desire. The rate of erectile dysfunction was
      85% in patients with PTSD and 22% in controls. Moderate to severe erectile
      dysfunction was present in 45% of the patients with PTSD and in only 13% of
      controls. Significantly more patients with PTSD (57%) than controls (17%) were
      using psychotropic medications. CONCLUSIONS: Combat veterans with PTSD experience
      a significantly higher rate of sexual dysfunction than do veterans without PTSD
      and show impairment in some, but not all, specific domains of sexual function.
      The IIEF may be useful in evaluating the response to treatment of erectile
      dysfunction. Clinicians should proactively address the sexual concerns of combat
      veterans with PTSD.

PMID- 12429321
TI  - Outcomes for vasectomy reversal performed after obstructive intervals of at least
      10 years.
AB  - OBJECTIVES: To determine the outcomes for vasectomy reversal performed after at
      least 10 years of obstruction. METHODS: We performed a retrospective review of
      three surgeons' experience with microsurgical vasectomy reversal for obstructive
      intervals of at least 10 years. RESULTS: The overall pregnancy rate was 37%. The
      patency/pregnancy rate for an obstructive interval of 10 to 15, 16 to 19, and 20
      or more years was 74%/40%, 87%/36%, and 75%/27%, respectively. The overall
      ongoing/delivered rate was 35%. The ongoing/delivered rates equaled the pregnancy
      rates, except in the 16 to 19-year group, for which the ongoing/delivered rate
      was 27%. Assuming a live delivery rate per cycle of 25% for intracytoplasmic
      sperm injection (ICSI), the delivery rate for vasectomy reversal would not be
      exceeded until an obstructive interval of at least 20 years. Assuming a live
      delivery rate of 28.6% per cycle for ICSI with obstructive azoospermia, the
      delivery rate for vasectomy reversal would not be exceeded until an obstructive
      interval of at least 15 years. CONCLUSIONS: Even after prolonged obstructive
      intervals, vasectomy reversal offers better or comparable success rates to ICSI.
      For each center, depending on their success rates, a threshold obstructive
      interval exists at which ICSI surpasses vasectomy reversal. Depending on their
      wishes, couples who have an obstructive interval that exceeds this threshold may
      be better served by ICSI. As with all infertile couples, close collaboration
      between the urologists and gynecologists is essential to provide the most
      appropriate care.

PMID- 12429322
TI  - Difference in stage and morphology-adjusted survival between young and elderly
      patients with a testicular germ cell tumor.
AB  - OBJECTIVES: To compare the relative survival in men younger and older than 50
      years with a testicular germ cell tumor. METHODS: Data on patients with
      testicular cancer diagnosed between 1973 and 1997 and registered by one of the
      nine population-based Surveillance, Epidemiology, and End Results (SEER) cancer
      registries in the United States were obtained from the National Cancer Institute
      public domain SEER*Stat 3.0 package. Survival rates adjusted for mortality owing
      to other causes (ie, relative survival) were calculated for men within each
      category of the American Joint Committee on Cancer staging system. RESULTS:
      Patients who developed a germ cell tumor before the age of 50 years had better 10
      year relative survival (90.8%, 95% confidence interval 90.6% to 91.0%) than those
      who developed one after the age of 50 years (84.0%, 95% confidence interval 81.9%
      to 86.1%). This difference remained after stratification by histologic type and
      stage, except for patients with localized seminomatous disease (97.9% versus
      98.0% for men younger and older than 50 years, respectively). The largest
      difference in 10-year relative survival was found in men with metastasized
      disease: seminomatous disease, 89.7% versus 69.6%, and nonseminomatous disease,
      76.9% versus 57.0%, for men younger and older than 50 years, respectively.
      CONCLUSIONS: Lower stage and morphology-adjusted relative survival rate was
      observed among patients older than 50 years of age with testicular cancer. This
      difference was more evident in metastasized disease. Whether the worse prognosis
      in testicular cancer can be explained by a lower tolerance to chemotherapy and/or
      to suboptimal treatment in the elderly has to be established.

PMID- 12429323
TI  - Prospective comparison and 1-year follow-up of a single endoscopic subureteral
      polydimethylsiloxane versus dextranomer/hyaluronic acid copolymer injection for
      treatment of vesicoureteral reflux in children.
AB  - OBJECTIVES: To compare, in a prospective study, the efficacy of a single
      injection of polydimethylsiloxane (Macroplastique) or dextranomer/hyaluronic acid
      copolymer (Deflux), a new biodegradable substance, and to assess the short-term
      and 1-year clinical effects concerning reflux resolution and the safety of these
      two bulking agents. Subureteral injection of bulking agents has recently
      demonstrated good success rates for endoscopic treatment of vesicoureteral
      reflux. Macroplastique has been one of the most popular bulking agents during the
      past years. Nevertheless, considering the synthetic property, new biodegradable
      substances have become more relevant. METHODS: From January 2000 to June 2001, 16
      boys and 56 girls (total of 114 ureters) with a mean age of 34.5 months were
      treated endoscopically for vesicoureteral reflux. A single subureteral
      Macroplastique or Deflux injection was performed in 34 children (58 ureters) and
      38 children (56 ureters), respectively. Both groups were comparable in terms of
      baseline parameters. Vesicoureteral reflux was grade II in 52, grade III in 57,
      and grade IV in 5 ureterorenal units. The procedure was performed on an
      outpatient basis, with the children under general anesthesia. In addition to the
      routine parameters, the follow-up evaluation consisted of renal ultrasonography
      and voiding cystourethrography at 3 and 12 months postoperatively. RESULTS:
      Endoscopic treatment was performed without any complications in all cases. At the
      3-month follow-up visit, reflux was corrected in 50 (86.2%) of 58 refluxing
      ureters in the Macroplastique group and in 40 (71.4%) of 56 refluxing ureters in
      the Deflux group. At 1 year of follow-up, reflux correction was maintained in
      80.9% of ureters in the Macroplastique group and in 67.6% of ureters in the
      Deflux group. No postoperative complications were observed in either group.
      CONCLUSIONS: A single subureteral injection of either polydimethylsiloxane
      (Macroplastique) or dextranomer/hyaluronic acid copolymer (Deflux) is an
      effective treatment modality for children with vesicoureteral reflux. The
      procedure was well tolerated, safe, and associated with low morbidity. Deflux, a
      new biocompatible, biodegradable substance, seems to be an alternative modality
      to other bulking agents for treating vesicoureteral reflux in children, with
      acceptable short-term and 1-year results.

PMID- 12429325
TI  - Simultaneous two-plane x-ray imaging for endoscopic recanalization of
      prostatomembranous urethral disruption.
AB  - We describe a technique that uses simultaneous two-plane images to facilitate
      endoscopic recanalization of prostatomembranous urethral disruption. This
      technique is very useful for identifying the true passage and to perform
      endoscopic recanalization safely.

PMID- 12429326
TI  - Maximizing ureteroscope deflection: "play it straight".
AB  - We studied simple maneuvers to optimize active deflection of the flexible
      ureteroscope. Up to 61 degrees of active deflection is lost if the ureteroscope
      is not kept in a straight alignment. Holding the ureteroscope taut, placing a
      super-stiff guidewire in the working channel, or using an access sheath maximizes
      active deflection.

PMID- 12429327
TI  - Novel modification of partial nephrectomy technique using porcine small intestine
      submucosa.
AB  - INTRODUCTION: To describe a novel partial nephrectomy technique that uses small
      intestine submucosa (SIS) to ensure a watertight closure of the collecting system
      and minimize parenchymal bleeding. The indications for nephron-sparing surgery
      have increased in recent years. The most prevalent complications after partial
      nephrectomy include urinary leakage/fistula and parenchymal bleeding. Porcine SIS
      has been used in animal models to reconstruct portions of the urinary tract
      successfully. TECHNICAL CONSIDERATIONS: Twenty-two consecutive patients underwent
      24 partial nephrectomies that required entry into the collecting system for
      presumed renal cell carcinoma. After temporary occlusion of the renal vessels and
      renal hypothermia, the tumor and a margin of normal parenchyma were excised. The
      cut surface was cauterized with an argon beam coagulator, and visible vessels
      were suture ligated. The collecting system was reapproximated with interrupted,
      absorbable sutures. A multilayer piece of hydrated SIS was sutured in place over
      the exposed collecting system and parenchymal defect with several figure-of-eight
      chromic sutures. With a mean follow-up of 18.4 months, none of the 22 patients
      experienced postoperative urinary leaks/fistulas or postoperative hemorrhage
      requiring transfusion. The serum creatinine returned to within 0.2 mg/dL of
      baseline in all patients after surgery. CONCLUSIONS: We describe a novel
      technique of partial nephrectomy using SIS, which, we believe, aids in closure of
      the collecting system and decreases parenchymal bleeding.

PMID- 12429328
TI  - Purple urine bag syndrome.

PMID- 12429329
TI  - Renal cell carcinoma with solitary metachronous metastasis to the urinary
      bladder.
AB  - We report a case of renal cell carcinoma with solitary metachronous metastasis to
      the urinary bladder occurring 6 years after radical nephrectomy. The patient was
      treated with partial cystectomy and survived for 60 months. Other cases like this
      one were reviewed in published reports, and the 3-year survival rate for patients
      with this type of cancer with solitary metastasis to the urinary bladder was
      found to be 80%. The follow-up duration of our case was the longest in the
      published studies. We suggest that urinary bladder metastasis of renal cell
      carcinoma should be resected because no effective treatment for metastatic renal
      cell carcinoma is available. A good prognosis may be expected, especially in
      patients with solitary metastasis to the urinary bladder.

PMID- 12429330
TI  - Orthotopic neobladder and subsequent renal transplantation.
AB  - Continent urinary diversion has become an attractive alternative to traditional
      conduits after cystectomy in select patients, including those awaiting renal
      transplantation. We report a case of a surgically anephric dialysis patient who
      underwent radical cystoprostatectomy with orthotopic ileal neobladder for
      recurrent superficial transitional cell carcinoma of the bladder and subsequent
      living-related renal transplantation 7 months later. We also discuss the
      perioperative adjuncts paramount to successful outcomes in such patients.

PMID- 12429331
TI  - Unusual bladder masses in children.
AB  - Benign and malignant bladder masses in children are extremely rare pathologic
      lesions. The presentation can include gross hematuria, irritable or obstructive
      voiding symptoms, and urinary infection. We present 2 cases in which large
      bladder masses suspicious for malignancy were diagnosed as benign lesions. One
      patient presented with abdominal pain and frequency 2 weeks after a minor bicycle
      accident and had a bladder wall abscess with sterile urine. Another child
      presented with gross hematuria and was found to have a giant cystitis glandularis
      lesion with no precipitating event or infection. The evaluation and differential
      diagnosis are discussed, and a review of the literature is presented.

PMID- 12429332
TI  - Intravesical migration of intrauterine device resulting in stone formation.
AB  - The intrauterine contraceptive device has been in use for many years, and
      migration of the device from the uterus to the pelvic cavity has been reported by
      many investigators. Although perforation of the uterus by an intrauterine
      contraceptive device is not uncommon, intravesical migration and secondary stone
      formation are rare complications. We report on a 27-year-old woman in whom an
      intrauterine contraceptive device (Copper-T) migrated from the uterus to the
      bladder and resulted in formation of a stone.

PMID- 12429333
TI  - Occurrence of polyorchidism in a young man.
AB  - Polyorchidism is an uncommon congenital anomaly of the genital tract defined as
      the presence of more than two testes. Polyorchidism is associated with maldescent
      testis, inguinal hernia, torsion, and an increased risk of malignancy. However,
      if a neoplasm is ruled out by ultrasonography, surgical exploration is not
      needed. We report a case of multiple testicular glands.

PMID- 12429334
TI  - Rhabdomyolysis after laparoscopic donor nephrectomy.
AB  - Rhabdomyolysis is a postoperative complication that may result in acute renal
      failure owing to excessive myoglobinuria. After uncomplicated laparoscopic left
      transperitoneal donor nephrectomy, a 32-year-old man developed anuric acute renal
      failure secondary to postoperative rhabdomyolysis that required intermittent
      hemodialysis for 2 weeks. The presumed risk factors in this case were the
      patient's high body mass index, intraoperative flank position with flexion, a
      solitary kidney, and the duration of surgery. Our current surgical technique has
      been modified to drop the kidney bridge early, immediately after visualization of
      the hilum.

PMID- 12429335
TI  - Transitional cell carcinoma in a single ectopic ureter opening into the
      ejaculatory duct.
AB  - The incidence of an ectopic ureter in male patients is low. The ectopic ureter in
      men often ends at the seminal tract in association with renal dysgenesis.
      Malignant transformation of this closed, nonfunctional urothelial system has been
      reported only once. To our knowledge, we report the first case of primary
      transitional cell carcinoma in a single ectopic ureter with a dysplastic kidney
      that terminated in the ejaculatory duct.

PMID- 12429336
TI  - Occlusion of an intraluminal endovascular stent graft after treatment of a
      ureteral-iliac artery fistula.
AB  - Ureteral-arterial fistulas are rare causes of intermittent and often massive
      hematuria. We report the case of a patient presenting with massive hematuria and
      shock caused by a ureteral-iliac fistula initially treated with a covered
      endovascular stent graft. Eight months after deployment, the stent occluded, and
      the patient required a femoral-femoral bypass. This is the first known case of
      endovascular stent graft occlusion when used for this purpose.

PMID- 12429337
TI  - GSTT1-null genotype is a protective factor against bladder cancer.
AB  - OBJECTIVES: To investigate the effects of homozygous deletions of GSTM1 and GSTT1
      and smoking on bladder cancer, we conducted a case-control and ecological study.
      METHODS: The case group consisted of 216 patients with bladder cancer and the
      control group of 449 healthy Koreans. Every subject was personally interviewed to
      obtain a detailed smoking history, and a multiplex polymerase chain reaction
      method was used to detect the presence or absence of the GSTM1 and GSTT1 genes.
      In the ecological study, age-standardized bladder cancer incidence and
      frequencies of GSTM1 and GSTT1-null types, estimated prevalence of cigarette
      smoking, and estimated per capita consumption of cigarettes per adult according
      to nationality and ethnicity were included. RESULTS: In the Korean case-control
      data, smoking history and the GSTT1-null genotype were significantly associated
      with bladder cancer, and the GSTM1-null genotype was not. In the univariate and
      multivariate analyses with the ecological data of various countries and ethnic
      groups, cigarette smoking positively, but the frequency of the GSTT1-null type
      negatively, correlated with the age-standardized bladder cancer incidence.
      CONCLUSIONS: These results suggest that the GSTT1-negative genotype might not be
      a risk factor but a protective factor of bladder cancer.

PMID- 12429338
TI  - Effect of flaxseed supplementation on prostatic carcinoma in transgenic mice.
AB  - OBJECTIVES: To investigate the effects of flaxseed supplementation on prostatic
      neoplasia in the transgenic adenocarcinoma mouse prostate (TRAMP) model. METHODS:
      A total of 135 male TRAMP mice 5 to 6 weeks old were randomized to a control
      group (AIN-76A diet) or an experimental group (AIN-76A diet plus 5% flaxseed by
      weight). One half of the mice in each group were treated for 20 weeks and the
      remainder for 30 weeks. At autopsy, urogenital tissues (four prostatic lobes,
      seminal vesicles, and emptied bladder), lungs, lymph nodes, and grossly abnormal
      tissues were collected for histologic evaluation. RESULTS: Of the control mice,
      100% developed prostate cancer versus 97% of the mice in the flaxseed group. The
      tumor/urogenital weight was 3.6 +/- 0.4 g in the controls versus 1.9 +/- 0.2 g in
      the flaxseed-treated mice (P = 0.0005). At 20 weeks, no significant difference in
      tumor grade was seen between the two groups; however, at 30 weeks, the flaxseed
      treated mice had significantly less aggressive tumors than did the controls (P =
      0.01). The prevalence of lung and lymph node metastases was 13% and 16%,
      respectively, in the control mice versus 5% and 12%, respectively, in the
      experimental group (difference not significant). After 20 weeks of treatment,
      cellular proliferation (Ki-67) differed significantly between the control and
      experimental groups (38.1 +/- 2.03 versus 26.2 +/- 2.03; P <0.0001), and the
      apoptotic index (deoxynucleotidyl transferase-mediated dUTP-digoxigenin nick end
      labeling) was 1.45 +/- 0.14 versus 3.3 +/- 0.31 (P <0.0001). Similar differences
      were seen after 30 weeks of treatment. CONCLUSIONS: A diet supplemented with 5%
      flaxseed inhibits the growth and development of prostate cancer in the TRAMP
      model.

PMID- 12429339
TI  - Comparison of endothelin-1-mediated tissue tension and calcium mobilization
      effects in isolated rabbit corpus cavernosum.
AB  - OBJECTIVES: To directly compare and contrast the effects of endothelin-1 (ET-1)
      and adrenoreceptor agonists norepinephrine and phenylephrine on eliciting calcium
      influx in primary rabbit corpus cavernosum cells and their ability to elicit
      tissue contractions. The potent vasoconstrictor peptide ET-1 and the alpha
      adrenoreceptor agonists are important modulators of smooth muscle tone in the
      penile corpus cavernosum. However, the mechanisms involved in maintaining smooth
      muscle tone and contraction are not clearly understood. METHODS: Intracellular
      calcium mobilization was measured in cultured corpus cavernosum smooth muscle
      cells using calcium-sensing dyes in conjunction with a fluorometric imaging plate
      reader. Tissue tension studies on rabbit corpus cavernosum were conducted using
      organ chambers. RESULTS: ET-1 at concentrations as low as 10 nM was sufficient to
      induce a transient increase of intracellular calcium in these cells. In contrast,
      concentrations of 1 mM and greater of norepinephrine and phenylephrine were
      required to elicit comparable calcium fluxes in cavernosum cells. Tissue bath
      studies indicated that ET-1 is a potent stimulator of corpus cavernosum smooth
      muscle contraction, with concentrations as low as 10 nM sufficient to initiate
      contraction. CONCLUSIONS: The potency of ET-1 in producing contraction on tissue
      strips and inducing calcium flux suggests that ET-1 might be an important
      mediator for modulating and maintaining corpus cavernosum smooth muscle tone.
      Therefore, additional exploration of the role of endothelins and their receptors
      in the tumescence and detumescence states of the penis would be extremely
      valuable.

PMID- 12429340
TI  - Ureteral replacement using porcine small intestine submucosa in a porcine model.
AB  - OBJECTIVES: To investigate an alternative technique using an onlay patch of
      porcine small intestine submucosa (SIS) allograft to bridge a ureteral defect.
      For ureteral strictures that fail endourologic management, few options are
      available for minimally invasive repair or reconstruction. Although laparoscopic
      interposition of a tubularized allograft of porcine SIS has great promise, animal
      studies have yielded mixed results. METHODS: In 9 anesthetized female pigs,
      cystoscopy and retrograde pyelography were performed, and a ureteral stent was
      placed. Transperitoneal laparoscopic access was obtained, and a segment of ureter
      2 cm long and encompassing one half the ureteral circumference was excised. An
      oval-shaped patch of SIS was sutured to the native ureter to cover the defect. In
      one control survival animal, the ureter was excised and a stent placed, but no
      SIS onlay was performed. Two pigs were killed immediately. In the survival group
      (6 pigs), the stents were removed at 1 week (n = 2), 2 weeks (n = 2), or 4 weeks
      (n = 2) and the corresponding animals were killed at 3 weeks (n = 2), 6 weeks (n
      = 2), and 9 weeks (n = 2). Intravenous urography was performed to evaluate renal
      function, and retrograde pyelography was performed after harvest to identify
      ureteral stricture or obstruction. The ureteral grafts were measured and examined
      histologically. RESULTS: All 6 kidneys from the survival group were grossly
      normal, appeared promptly on intravenous urography, and were patent on retrograde
      pyelography. The control animal demonstrated complete ureteral obstruction. By 9
      weeks, the SIS graft was replaced with ureteral tissue, including the muscle
      layers. The epithelium was primarily transitional epithelium, with focal
      intestinal metaplasia. The submucosa and ureteral musculature appeared
      histologically normal. CONCLUSIONS: In the porcine model, a patch graft technique
      using SIS appears to induce ureteral regrowth. Renal function remained intact,
      and no evidence of stricture was demonstrated on radiographic imaging. Before
      clinical application of this technique, evaluation in a stricture model is
      required.

PMID- 12429341
TI  - Vesicourethral anastomosis with 2-octyl cyanoacrylate adhesive in an in vivo
      canine model.
AB  - OBJECTIVES: To evaluate the effectiveness of 2-octyl cyanoacrylate adhesive (OCA)
      in the formation of vesicourethral anastomoses. METHODS: Open total prostatectomy
      was performed on 12 mongrel hounds. Of these, 8 had a vesicourethral anastomosis
      formed using OCA (4 with suture support and 4 sutureless). The remaining four
      anastomoses were conventionally formed using eight interrupted sutures. Acute
      leakage was tested intraoperatively. Before killing the hounds, the anastomosis
      of 1 animal in each group was assessed on postoperative days 3, 5, 7, and 14 by
      radiography. Each anastomotic specimen was then tested for leak pressure and
      examined histologically. RESULTS: At intraoperative testing, one small leak was
      found in the sutureless OCA group. All other anastomoses were watertight
      intraoperatively. Radiographically, two leaks occurred in the OCA group with
      suture support, three leaks in the sutureless OCA group, and only one small
      localized leak in the control group. Only one of the eight anastomoses using OCA
      achieved a physiologic leak pressure greater than 70 mm Hg (one of these,
      however, could not be tested because of injury at the time the specimen was
      retrieved). The leak pressures of all four control-group anastomoses were 70 mm
      Hg or greater. Histologically, no significant differences were found in healing
      between the control and OCA anastomoses. CONCLUSIONS: With or without suture
      support, OCA appears to be unsuitable for use in forming the large-diameter
      vesicourethral anastomosis required in radical prostatectomy.

PMID- 12429342
TI  - Treatment for interstitial cystitis.

PMID- 12429344
TI  - Cysteinyl leukotriene receptors.
AB  - Cysteinyl leukotrienes (CysLTs) are important inflammatory mediators in asthma
      and allergic disorders. Two types of CysLT receptors, CysLT(1) and CysLT(2),
      which were originally defined pharmacologically based on their sensitivity to
      CysLT(1) specific antagonists, are responsible for most of the known CysLT
      biological actions. The regulation of CysLT receptor expression and signaling in
      disease processes is largely unclear. Recent molecular cloning of both receptor
      subtypes from several different species will greatly facilitate future research
      in understanding CysLT signal transduction mechanisms. Expression of the
      relatively better-studied CysLT(1) is verified in lung tissues and peripheral
      blood cells. Elucidating how this receptor mediates airway inflammation will
      deepen our understanding of asthma etiology. On the other hand, detection of
      CysLT(2) in the heart, brain, and adrenal glands will inject new excitement into
      the search for novel CysLT functions. This review summarizes receptor cloning,
      ligand binding, expression, signaling, and functions in an effort to bridge early
      pharmacological studies to future studies at the molecular level.

PMID- 12429345
TI  - Identification of residues involved in the substrate specificity of human and
      murine dCK.
AB  - Deoxycytidine kinase (dCK) is a salvage pathway enzyme that can phosphorylate
      both pyrimidine and purine deoxynucleosides, including important antiviral and
      cytostatic agents. Earlier studies showed that there are differences in kinetic
      properties between human and murine dCK, which may explain differences in toxic
      effects of nucleoside analogs. To determine if certain substitutions in amino
      acid sequences between human and mouse dCK give these differences in substrate
      specificity the 14 mutants and hybrid forms of human dCK were studied. All
      variants were characterised with dCyd, dAdo and dGuo as phosphate acceptors and
      ATP and UTP as phosphate donor. The relative activities with dCyd, dAdo and dGuo
      were about 70, 20, 30%, respectively, with UTP as compared to ATP for human dCK
      and 40, 60, 70% for mouse dCK. Among all tested mutants only the triple
      combination of substitutions Q179R-T184K-H187N (RKN) had a kinetic behaviour very
      similar to mouse dCK. The kinetic patterns with several important nucleoside
      analogs, such as AraC, CdA, ddC and AraG have also been studied. Results
      demonstrated 50-70% low relative capacities of the recombinant mouse and triple
      mutant RKN to phosphorylate this nucleoside analogs compare with human dCK. A
      model for dCK was used to try to explain the functional role of these amino acid
      substitutions. According to this model the triple mutant RKN have altered amino
      acids in a region necessary for conformational changes during catalyses. This may
      affects the substrate selectivity both for the nucleosides and the phosphate
      donors.

PMID- 12429346
TI  - Endogenous drug transporters in in vitro and in vivo models for the prediction of
      drug disposition in man.
AB  - The epithelial canine and porcine kidney cell lines MDCK, MDCKII and LLC-PK1,
      respectively are employed to establish recombinant models of drug transport.
      Endogenous drug carriers in these cells may contribute to the activities of
      recombinant drug transporters, thus making it difficult to assess their
      properties. We analysed the expression of endogenous transporters in these cell
      lines by RT-PCR and by determining drug transporter activities. Concerning drug
      efflux, multidrug resistance protein 1 (MDR1) and MRP1 mRNAs were found in all
      lines. MRP2 mRNA was expressed in all cell lines except MDCK. Transepithelial
      transport of vinblastine and its modulation by a MDR1-specific inhibitor or by
      the MDR1- and MRP-inhibitor verapamil, indicated that MDCKII cells have, in
      comparisons to the other cell lines, relatively high levels of functional MDR1
      while vinblastine transport in MDCK cells is likely to be mediated more by MRP1.
      Notably, LLC-PK1 cells displayed little activity attributable to either MDR1 and
      MRP1, thus making them suitable for the expression of these efflux pumps. Of the
      drug uptake carriers, OATP-A mRNA was only expressed in MDCK cells. OATP-C mRNA
      was barely detectable in MDCK cells and absent in MDCKII and LLC-PK1 cells. In
      agreement with transcriptional profiling, the OATP-mediated uptake of either
      estradiol-glucuronide or estrone-sulfate was either absent or barely detectable
      in all cell lines thus implying that they are suitable to establish recombinant
      models for human OATP's. Transcriptional profiling was also performed on porcine
      and canine tissues and revealed that MRP1 was expressed in canine but not in
      human or porcine liver, whereas surprisingly OATP-C was expressed in canine
      kidney but only in human and porcine liver. The findings presented are relevant
      to the use of porcine and canine models for drug disposition.

PMID- 12429347
TI  - CYP2C8 polymorphisms in Caucasians and their relationship with paclitaxel 6alpha
      hydroxylase activity in human liver microsomes.
AB  - Published cDNA sequences suggest the existence of non-synonymous single
      nucleotide polymorphisms in the cytochrome P450 CYP2C8. To determine whether
      these polymorphisms could be confirmed in a Caucasian population and to
      investigate whether additional polymorphisms occur in the coding and upstream
      regions of this gene, we screened for previously described and for novel
      polymorphisms using PCR-RFLP and SSCP analysis. We confirmed the existence of two
      of the previously detected polymorphisms which give rise to the amino acid
      substitutions I264M and K399R, respectively, but failed to detect three others in
      our population. We also confirmed that a recently identified polymorphism (R139K)
      is linked to K399R (CYP2C8*3) in our study population. The allele frequencies for
      the I264M (CYP2C8*4 allele) and the CYP2C8*3 allele were 0.075 and 0.15,
      respectively. Three novel polymorphisms (T-370G, C-271A and T1196C/L390S) were
      also detected with the upstream polymorphisms showing allele frequencies of 0.061
      and 0.196, respectively, but the L390S polymorphism detected only in a single
      subject. An additional single subject was heterozygous for a polymorphism
      recently described in African-Americans (A805T; CYP2C8*2 allele). The functional
      significance of the two upstream polymorphisms and the CYP2C8*3 and CYP2C8*4
      alleles was investigated in human liver microsomes. Samples heterozygous for
      CYP2C8*3 showed significantly lower paclitaxel 6alpha-hydroxylase activity
      compared with wild-type samples. Median activity associated with CYP2C8*4 also
      appeared lower than the wild-type but the difference was not significant. There
      was no evidence that either upstream polymorphism gave rise to altered CYP2C8
      expression.

PMID- 12429348
TI  - Quercetin, apoptosis, heat shock.
AB  - The present study was designed to investigate the correlation between the
      expression level of Hsp27 and Hsp72 and induction of apoptosis in HeLa cells in
      response to quercetin treatment. Treatment of HeLa cells with quercetin or with
      1hr period of hyperthermia (42 degrees) increased the number of apoptotic cells.
      Inhibition of the expression of Hsp72 and Hsp27 in tumour cells by anti-sense
      oligonucleotides, enhanced the induction of apoptosis by quercetin. Heat shock
      itself had little effect on apoptotic cell death in these cells, but when
      combined with quercetin treatment, caused a significant increase in the number of
      apoptotic cells. These results suggest that the reduction of Hsps expression in
      the HeLa cell line promotes the induction of apoptosis by quercetin.

PMID- 12429349
TI  - A physiological threshold for protection against menadione toxicity by human
      NAD(P)H:quinone oxidoreductase (NQO1) in Chinese hamster ovary (CHO) cells.
AB  - NAD(P)H:quinone oxidoreductase 1 (NQO1) has often been suggested to be involved
      in cancer prevention by means of detoxification of electrophilic quinones. In the
      present study, a series of Chinese hamster ovary (CHO) cell lines expressing
      various elevated levels of human NQO1 were generated by stable transfection. The
      level of NQO1 over-expression ranged from 14 to 29 times the NQO1 activity in the
      wild-type CHO cells. This panel of cell lines, allowed investigation of the
      protective role of NQO1 in quinone cytotoxicity. It could be demonstrated that
      menadione toxicity was significantly reduced in all NQO1-transfected CHO clones
      compared to the wild-type cells, but the clones did not show differences in their
      level of protection against menadione. This observation pointed at a critical
      threshold concentration of NQO1 above which a further increase does not provide
      further protection against quinone cytotoxicity. Additional studies in which the
      NQO1 activity was inhibited by dicoumarol showed that only dicoumarol
      concentrations of about five times the EC(50) for NQO1 inhibition were able to
      reduce NQO1 levels below the apparent threshold, making the cells more sensitive.
      The level of this threshold was estimated to be in the range of base line NQO1
      activities observed in several tissues and species. Thus, the results of the
      present study indicate that beneficial effects of NQO1 induction by, for example,
      cruciferous vegetables might be absent or present depending on the NQO1 activity
      threshold for optimal protection and the basal level of NQO1 expression in the
      tissue and species of interest.

PMID- 12429350
TI  - Carbazolequinone induction of caspase-dependent cell death in Src-overexpressing
      cells.
AB  - We previously reported that RSV-transformed quail neuroretina cells (QNR-ts68)
      were highly resistant to apoptosis provoked by serum withdrawal, and that this
      property was due to v-Src kinase activity. The present study investigates the
      cytotoxic effect and the functional mechanism of carbazolequinone-mediated cell
      death in this system. QNR-ts68 cells were subjected to carbazolequinone treatment
      and both growth inhibition and cell death induction were examined using formazan
      assays. Cell death mechanism (both apoptosis and necrosis) was confirmed through
      phosphatidyl serine exposure and propidium iodide incorporation. Furthermore, the
      effect of active carbazolequinone was inhibited by a pan caspase inhibitor.
      Cytofluorimetric and immunofluorescence data demonstrated the activation of
      caspase-3 and the involvement of mitochondria. Therefore, this study clearly
      indicates that carbazolequinones could induce cell death in transformed cells
      displaying high levels of antiapoptotic tyrosine kinase activity. Further
      investigations would be necessary to elucidate the mechanisms by which these
      carbazolequinones act as antitumor agents.

PMID- 12429351
TI  - Cytotoxic and genotoxic effects of megazol, an anti-Chagas' disease drug,
      assessed by different short-term tests.
AB  - Cyto- and genotoxicity induced by drugs can limit the dose and duration of
      treatment, can adversely affect patient quality of life, and may be life
      threatening. Two drugs are currently being used for treatment of the acute phase
      of Chagas' disease and both have serious undesirable effects. In this research,
      cyto- and genotoxic activity of the nitroimidazole-tiadiazole derivative CL 64855
      2-amino-5-(1-methyl-5-nitro-2-imidazolyl)-1,3,4-thiadiazole (megazol), a
      promising alternative drug, was evaluated in vitro with different short-term
      tests: (a) induction of recombination events and mutation in the yeast
      Saccharomyces cerevisiae D7 strain, with and without induction of cytochrome P
      450; DNA damage (single and double strand breaks, alkali-labile sites, etc.) by
      the Comet assay in different mammalian cells. S. cerevisiae did not show a
      significant increase of mutant and recombinant event frequency, both with and
      without cytochrome P-450. On the other hand, the cytochrome complex appeared to
      detoxify the drug with respect to cytotoxicity. Results in rat and mouse fresh
      leukocytes showed a dose-response relation of drug-induced DNA damage. Findings
      in treated VERO cells suggested a complex treatment time-DNA damage relationship
      and the possible induction of repair mechanisms. Furthermore, bleomycin effects
      were increased in rat cells by simultaneous administration of megazol. Megazol
      shows different biological activity in relation to cellular types and
      experimental conditions (with or without cytochrome P-450, short/long time of
      exposure, with or without other genotoxins), thus suggesting a modulation of
      effectiveness by different physiological/biochemical conditions of cells. The
      findings could be useful to evaluate new megazol-derived compounds and to assess
      the risks/benefits relationship for each drug.

PMID- 12429352
TI  - Synergistic effects of troglitazone and oleate on the translatability of
      preproinsulin mRNA from INS-1 cells.
AB  - Glitazones are known to modulate fatty acid-induced effects on insulin secretion
      in the pancreatic beta-cell. The present study focused on combined effects of
      troglitazone and oleate on preproinsulin (PPI) biosynthesis. Insulin-producing
      INS-1 cells were incubated for 4 hr at 11.2mM glucose in the presence (O(+)) or
      absence (O(-)) of 200 microM oleate with (T(+)) or without (T(-)) 10 microM
      troglitazone. After cell lysis, cytoplasmic RNA was extracted and employed for
      Northern blotting and corresponding in vitro translation. Compared with untreated
      controls (CTRL=O(-)/T(-)), the cellular content of PPI-mRNA from cells which had
      been simultaneously treated by troglitazone and oleate (O(+)/T(+)) was
      significantly diminished (O(+)/T(+)=75+/-10% x CTRL; P=0.015). The PPI-mRNA
      content from those cells which had been exclusively exposed either to oleate
      (O(+)/T(-)) or troglitazone (O(-)/T(+)) did not significantly differ from that of
      the untreated controls. In spite of that decreased PPI-mRNA content, in vitro
      translation revealed the highest yield of newly synthesized PPI in RNA samples
      from those cells which had been simultaneously exposed to oleate and troglitazone
      before (O(+)/T(+)=1.6+/-0.3 x CTRL; P=0.01). It is concluded that troglitazone
      and oleate synergistically affect the translational rate at the level of the PPI
      mRNA molecule.

PMID- 12429354
TI  - Retinoic acid binding properties of the lipocalin member beta-lactoglobulin
      studied by circular dichroism, electronic absorption spectroscopy and molecular
      modeling methods.
AB  - Interaction between the Vitamin A derivative all-trans retinoic acid and the
      lipocalin member bovine beta-lactoglobulin (BLG) was studied by circular
      dichroism (CD) and electronic absorption spectroscopy at different pH values. In
      neutral and alkaline solutions achiral retinoic acid forms a non-covalent complex
      with the protein as indicated by the appearance of a negative Cotton effect
      around 347 nm associated to the narrowed and red shifted pi-pi(*) absorption band
      of the ligand. The induced optical activity is attributed to the helical
      distortion of the conjugated chain caused by the chiral protein binding
      environment. As the disappearing CD activity showed in the course of CD-pH
      titration experiment, retinoic acid molecules dissociate from BLG upon
      acidification but this release is completely reversible as proved by the
      reconstitution of the CD and absorption spectra after setting the pH back to
      neutral. This unique behavior of the complex is explained by the conformational
      change of BLG (Tanford transition) which involves a movement of the EF loop at
      the entrance of the central cavity from open to closed conformation in the course
      of pH lowering. From these results it was inferred that retinoic acid binds
      within the hydrophobic calyx of the beta-barrel.

PMID- 12429353
TI  - Influence of isolation procedure, extracellular matrix and dexamethasone on the
      regulation of membrane transporters gene expression in rat hepatocytes.
AB  - The influence of the isolation procedure of hepatocytes, extracellular matrix
      (ECM) configuration and incubation medium supplementation by dexamethasone (DEX)
      on the cell morphology and on the gene expression of membrane transporters was
      examined in rat hepatocytes. The mRNA levels were determined using
      oligonucleotide microarrays, in liver, in suspension and in primary culture in
      monolayer (CPC), and in collagen gels sandwich (SPC) in absence and presence of
      DEX (100 and 1000 nM). The results indicated pronounced morphological differences
      between CPC and SPC in response to DEX demonstrating that the hepatocytes re
      formed, as in vivo, multicellular arrays with extensive bile canalicular network
      only in SPC in presence of DEX. The mRNA levels of membrane transporters were not
      affected significantly during isolation procedure. However, plating hepatocytes
      in CPC resulted in a decrease of major basolateral transporters mRNA level
      whereas mRNA levels of mdr1b and mrp3 were increased (>100-fold). Similar
      observations were made in SPC in the absence of DEX demonstrating that the ECM
      configuration alone did not play a critical role in the regulation of membrane
      transporters. However, adding DEX to the incubation medium in SPC resulted in an
      up-regulation of mdr2, oatp2 and mrp2 in a concentration-dependent way for the
      two latter genes, whereas mdr1b and mrp3 expression were maintained to their
      baseline liver levels. These data suggested therefore that the combination of ECM
      and DEX supplementation is essential for the formation of the bile canalicular
      network and is a determinant factor in the regulation of membrane transporters in
      cultured rat hepatocytes.

PMID- 12429355
TI  - Antioxidant properties of ursodeoxycholic acid.
AB  - We have investigated potential antioxidant properties of the clinically relevant
      bile acid UDCA, which reaches therapeutic concentrations up to 0.09 and 29 mM,
      respectively, in human plasma and bile. UDCA was an excellent scavenger of
      OHz.rad; generated by FeCl(3)-EDTA, H(2)O(2) and ascorbate in the deoxyribose
      oxidation test, showing IC(min) and IC(50) values of 0.02 and 0.2 mM,
      respectively, and a second-order rate constant for reaction with OHz.rad; of 2+/
      0.1 x 10(10)M(-1)s(-1). Notably, the drug could enhance at 1.5 mM concentration
      the antioxidant capacity of human bile against OHz.rad;-induced deoxyribose
      oxidation. UDCA also showed antioxidant effects in the deoxyribose test performed
      with nonchelated iron ions, such as Fe(2+) plus H(2)O(2) (IC(min): 7 mM, IC(50):
      20 mM) or Fe(3+) plus H(2)O(2) and ascorbate (IC(min): 0.3 mM, IC(50): 5 mM), and
      inhibited ferrozine-Fe(2+) and desferrioxamine-Fe(3+) complexes formation with
      IC(50) values of, respectively, 12 and 0.3 mM, indicating that the drug interacts
      more with iron(III) than with iron(II). Moreover, UDCA significantly inhibited
      phospholipid liposome peroxidation induced by the OHz.rad;-generating system
      FeCl(3)-EDTA, H(2)O(2) and ascorbate (IC(min): 0.75 mM, IC(50): 3 mM), and by
      peroxyl radicals generated in the aqueous phase by AAPH (IC(min): 8 mM, IC(50):
      14 mM). UDCA, even at 25 mM concentration, was ineffective on the
      lipoperoxidation mediated by Fe(2+) alone, but at the same concentration
      counteracted significantly that by Fe(3+) plus ascorbate, further pointing to its
      preferential antioxidant interaction with iron(III). In conclusion, UDCA has
      direct antioxidant properties, which are especially relevant against Fe(3+)- and
      OHz.rad;-dependent biomolecular oxidative damage; such properties are evident at
      therapeutically relevant drug concentrations, suggesting that UDCA could act as
      an antioxidant in vivo.

PMID- 12429356
TI  - Depression and anxiety symptoms in relation to anthropometry and metabolism in
      men.
AB  - Depression is associated with an increased risk of developing cardiovascular
      disease and type 2 diabetes mellitus. Abdominal obesity is also a high risk
      factor for these diseases. Therefore, symptoms of depression and anxiety were
      examined in relation to abdominal obesity. A total of 59 middle-aged men
      volunteered for measurements with the Hamilton Depression Scale (HDS), the
      Montgomery-Asberg Depression Rating Scale (MADRS), the Beck Depression Inventory
      (BDI) and the Hamilton Anxiety Scale (HAS). These results were examined in
      relation to body mass index (BMI), waist/hip ratio (WHR) and sagittal abdominal
      diameter, a measurement of intra-abdominal fat mass, and metabolic variables. Men
      with WHR>1.0 (n=26) in comparison with men with normal WHR (<1.0, n=33) showed
      significantly higher sum scores in all the scales used. There were positive
      correlations between the sum scores of all the depression scales and the WHR or
      the sagittal abdominal diameter. BMI correlated comparatively weakly only with
      the HDS. The correlations with the WHR remained when the influence of BMI was
      eliminated, suggesting that obesity is less involved than centralization of body
      fat. Insulin and glucose were significantly related to the HDS. Morning cortisol
      levels were negatively related to the BDI and (borderline) to the MADRS,
      suggesting perturbations of the regulation of the hypothalamic-pituitary-adrenal
      axis. We conclude that men with abdominal obesity have symptoms of depression and
      anxiety.

PMID- 12429357
TI  - Epinephrine- and thrombin-stimulated high-affinity GTPase activity in platelet
      membranes from patients with psychiatric disorders.
AB  - Although heterotrimeric guanine nucleotide-binding regulatory (G) proteins have
      been implicated in the pathophysiology of mental illnesses (especially mood
      disorders), direct evidence has been scarce. This study was designed to reveal
      possible abnormalities of receptor-coupled G protein function in platelets in
      patients with psychiatric disorders such as depression and schizophrenia. The
      functional status of alpha(2A)-adrenergic receptor-coupled G(i2) and thrombin
      receptor-coupled G proteins (G(i2)+G(q)) was determined by the increase in high
      affinity GTPase activity in response to epinephrine and thrombin, respectively,
      in platelet membranes from 18 patients with mood disorders (15 unipolar and three
      bipolar subtype), 13 schizophrenic patients, four neurotic patients and 29
      healthy control subjects. Neither alpha(2A)-adrenergic receptor-coupled G(i2) nor
      thrombin receptor-coupled G(q) was functionally altered in platelets from
      psychiatric patients compared with control subjects. No significant correlation
      was observed between these biochemical measures in platelets and severity of
      psychopathological symptoms. The functional coupling efficiency of G proteins
      with receptors appears intact, at least between alpha(2A)-adrenergic receptors
      and G(i2), and between thrombin receptors and G(q), in platelets from patients
      with psychiatric disorders.

PMID- 12429358
TI  - Does adverse family environment or sex matter in the salivary cortisol responses
      to anticipatory stress?
AB  - We previously reported that in anticipation of a modest stressor, preadolescent
      sons of drug-dependent fathers (HR) demonstrated a diminished salivary cortisol
      response relative to comparison boys. No data were available concerning
      anticipatory salivary cortisol responses in preadolescent daughters of HR
      fathers. Additionally, we hypothesized that diminished stress responses in HR
      youth might be an adaptation to a stressful family environment. Consequently, in
      this report we have examined the role of family environment in the anticipatory
      salivary cortisol responses in both HR boys and girls as well as their
      association with a measure of distress in the family environment. Independent of
      sex, HR children had diminished anticipatory cortisol responses. Girls had
      significantly higher salivary cortisol concentrations, pre- and post-stressor.
      However, contrary to our expectation, we could not demonstrate an association
      between salivary cortisol responses and the measures of the family environment.
      These results suggest that there may be a sex difference in salivary cortisol
      dynamics in preadolescent children; however, the functional status of the current
      family environment does not appear to be related to cortisol reactivity.

PMID- 12429359
TI  - Specificity of quantitative EEG analysis in adults with attention deficit
      hyperactivity disorder.
AB  - Attention deficit hyperactivity disorder (ADHD) in children and adolescents is
      characterised by excessive restlessness and an extremely poor concentration span,
      resulting in impulsive and disruptive behaviour. Clinical observation of ADHD in
      adults suggests that the early hyperactivity is diminished in terms of its impact
      on social and academic function, while impulsive-type behaviours remain
      unchanged. EEG studies in children and adolescents with ADHD have reported
      significantly more low-frequency power (predominantly theta) and less high
      frequency power (predominantly beta) than in normal subjects. In normal children
      and adolescents, a decrease in theta power and an increase in beta power are
      found with increasing age, leading some researchers to interpret the EEG
      anomalies in ADHD as evidence of developmental delay. Studies of adults with ADHD
      compared with normal adult control subjects have found a reduction in the
      difference between the two groups, suggesting that the reduced beta activity
      apparent in ADHD children and adolescents changes with age. Adults with ADHD thus
      appear to have elevated low-frequency power as their predominant EEG difference
      from normal control subjects. The present study examined whether this EEG profile
      was specific to adult ADHD patients. Quantitative EEGs were recorded at rest in
      an eyes-open condition and used to compare 50 adult patients diagnosed with ADHD
      with 50 non-ADHD subjects (who presented for ADHD assessment but failed to meet
      the diagnostic criteria) and 50 control subjects. The ADHD group differed from
      both the non-ADHD and the control groups on the basis of elevated theta activity.
      The ADHD and control groups did not differ in beta activity, but relative theta
      was reduced and relative beta power was elevated in the non-ADHD group compared
      with both the ADHD and control groups. These results suggest that quantitative
      EEG may be used to differentiate ADHD adults from both normal adults and adults
      who display some of the symptoms of ADHD, but fail to meet the diagnostic
      criteria of ADHD.

PMID- 12429360
TI  - A comparison of paroxetine versus paroxetine plus amisulpride in the treatment of
      dysthymic disorder: efficacy and psychosocial outcomes.
AB  - Dysthymic disorder is a chronic depressive condition with considerable
      psychosocial impairment. Even if DD patients respond to various antidepressant
      medications, there has been little systematic study on antidepressant-refractory
      DD. Only a few trials have evaluated the effects of treatment on psychosocial
      functioning of dysthymic patients. In this 3-month, open-label study, 60
      outpatients with DSM-IV criteria for dysthymic disorder who failed to respond to
      3-month treatment with paroxetine 20 mg/day were randomly assigned to treatment
      with paroxetine 40 mg/day or paroxetine 20 mg/day plus amisulpride 50 mg/day. The
      effects of the two treatments were assessed for both mood symptoms (21-item
      Hamilton Rating Scale for Depression, Montgomery-Asberg Depression Rating Scale,
      Clinical Global Impression, severity and improvement) and psychosocial outcomes
      (DSM-IV Global Assessment of Functioning, Social Adaptation Self-evaluation
      Scale). Analysis of variance on all rating scales showed that both treatments
      were effective over this observation period. Response and remission rates did not
      differ in the treatment groups. A significantly greater psychosocial improvement
      was observed in the group receiving combined treatment compared with patients
      receiving paroxetine alone. Both treatments appeared to be effective in our
      sample of dysthymic subjects. Combined treatment with paroxetine and amisulpride
      resulted in a better outcome in terms of social functioning.

PMID- 12429361
TI  - A novel approach to assess inter-rater reliability in the use of the Overt
      Aggression Scale-Modified.
AB  - The ability of raters to apply measures of efficacy accurately and reproducibly
      in clinical trials of psychotropic medications is vital to the validity of study
      data. In a large, multi-center trial using the Overt Aggression Scale-Modified
      (OAS-M), inter-rater reliability was evaluated using standardized patients (SP)
      in a live 'mock' interview. Thirty raters experienced in the OAS-M each
      interviewed two actors trained to portray patients with intermittent explosive
      disorder, borderline and antisocial personality disorder, and/or post-traumatic
      stress disorder. Inter-rater reliability of OAS-M scores was evaluated using the
      intra-class correlation coefficient (ICC). The joint reliability of the raters in
      the study with an expert rater was also assessed by an ICC. The ICC was 0.96
      between the raters, and 0.98 between the raters and expert rater. Results suggest
      that SP can be utilized in rater assessment and that raters administering the OAS
      M in this model of rater reliability assessment demonstrate a high level of
      consistency and reliability. The method described here may be useful in future
      assessments of inter-rater reliability.

PMID- 12429362
TI  - The Life Functioning Questionnaire (LFQ): a brief, gender-neutral scale assessing
      functional outcome.
AB  - The Life Functioning Questionnaire (LFQ) is a 5-min, 14-item, gender-neutral self
      report questionnaire designed to assess role function over the preceding month in
      four domains: workplace, duties at home, leisure time with family and leisure
      time with friends. To validate the LFQ for use as an instrument assessing
      functional outcome in patients with a mood disorder, the LFQ was administered to
      three different samples of patients (N=87). Fifty-nine concurrently completed the
      self-report version of the Social Adjustment Scale (SAS-SR) and 32 concurrently
      had a Clinical Global Impression Scale for Bipolar Disorder (CGI-BP) assessment.
      The LFQ proved to have high internal consistency reliability, high test-retest
      reliability, excellent concurrent validity with the SAS-SR, and high validity as
      a measurement of severity of illness when compared with the CGI-BP. The LFQ
      provides a reliable, consistent and valid assessment of function at work and home
      in both male and female patients with a mood disorder.

PMID- 12429363
TI  - Olfaction and face encoding in humans: a magnetoencephalographic study.
AB  - Magnetic field changes were recorded while 20 healthy young participants
      performed a deep face encoding task. Some of the faces were randomly associated
      with a simultaneously presented odor. A recognition test, during which all faces
      were presented again together with the same number of new faces, followed. The
      task was to discriminate between repeated and new faces. During the recognition
      test no odor was presented. The recognition performance was significantly
      influenced by the simultaneously associated odor during the encoding phase. Faces
      associated with odor were less accurately recognized. In addition, we found
      significant physiological differences between 'encoded faces without odor' and
      'encoded faces with odor'. In particular, two effects occurred. Between about 200
      and 300 ms after stimulus onset 'encoded faces without odor' evoked higher brain
      activity than 'encoded faces with odor'. Between about 600 and 900 ms after
      stimulus onset 'encoded faces with odor' evoked higher brain activity than
      'encoded faces without odor'. Whereas the latter effect is interpreted as
      reflecting conscious olfactory information processing, the earlier effect is
      suggested to reflect an odor influence on face encoding. We suggest that the
      simultaneous odor association distracted face encoding resulting in a
      significantly reduced recognition performance. These findings are suggested to
      represent evidence of multimodal sensoric interactions between visual face
      processing and olfactory information.

PMID- 12429364
TI  - Differences in incidental and intentional learning of sensorimotor sequences as
      revealed by event-related brain potentials.
AB  - The present study investigated differences in sequential learning between
      subjects who were or were not informed of the presence of a repeating sequence
      (intentional or incidental group, respectively). Subjects had to learn a 16
      letter-long repeating sequence that was irregularly disrupted by deviating
      stimuli. Reaction times indicated that both groups learned the sequential
      regularities. Intentional learners showed a larger learning effect. Event-related
      brain potentials (ERPs) recorded during performance of the task showed a reliably
      enhanced amplitude for the N2b- and P3b-components for deviant letters for
      intentional learners, but not for incidental learners. These results are
      discussed in the context of models proposing that different neural structures are
      involved in implicit and explicit serial learning.

PMID- 12429365
TI  - Behavioural and electrophysiological correlates of visuomotor learning during a
      visual search task.
AB  - Visuomotor association learning involves learning specific motor responses to
      arbitrary cues, and is dependent on a distributed and highly flexible network in
      the brain. We investigated the behavioural and electrophysiological correlates of
      arbitrary visuomotor learning in 20 normal participants. An experimental group
      learned an arbitrary association between a visual stimulus and a motor response
      during a training block. Their performance was compared with that of untrained
      controls on a subsequent visual discrimination task in which the learned
      association was a crucial element. Event-related brain potentials (ERPs) were
      recorded from the scalp of each participant during learning and discrimination
      blocks. Reaction times to stimuli in the discrimination task were significantly
      faster in the trained group compared to controls. There was a corresponding
      difference in the ERP waveforms recorded during the task, with larger P3b
      amplitude for the trained group over midline and centroparietal scalp areas. A
      latency difference in P3b was also observed for trained targets compared to
      distractors. RTs during the training block decreased in a manner consistent with
      learning effects. We conclude that training of a visuomotor association
      facilitates subsequent performance on a related task, and that the waveform
      correlates found here may reflect the involvement of parts of the network
      underlying arbitrary association mapping.

PMID- 12429366
TI  - Parametric analysis of event-related potentials in semantic comprehension:
      evidence for parallel brain mechanisms.
AB  - In event-related potential (ERP) studies of cognitive processes, the
      electrophysiological responses are typically contrasted between experimental
      conditions that are taken to represent discrete categories (e.g. attended vs.
      unattended stimuli, or real vs. nonsense words). Because categorical variation is
      less powerful than continuous or parametric variation, a more effective method
      may be to relate continuous variation in the cognitive process with matching
      variation in the electrophysiological responses. We assessed continuous variation
      in the expectancy and meaningfulness of words in different sentence contexts by
      having subjects rate the words along these two dimensions. ERP averages were then
      created for each word by averaging the ERP across all subjects' responses to that
      word. A parametric principal components analysis was then conducted by
      multiplying the factor topographies from the temporal PCA by the parameter
      correlation maps for each rating parameter. This analysis showed that both
      expectancy and meaningfulness begin to influence lexical processing around 200
      ms. Source localization of the expectancy N2 (recognition potential) pointed to a
      source in the left fusiform gyrus region (visual word form area). Source
      localization of the meaningfulness N2 (meaning recognition potential) suggested a
      right inferior posterior source, such as in the right cerebellum or right
      fusiform area. Further research with parametric analysis of dense array ERPs may
      clarify the multiple neural mechanisms of word recognition.

PMID- 12429367
TI  - The role of visuospatial attention in developmental dyslexia: evidence from a
      rehabilitation study.
AB  - Shifting of visual attention induced by peripheral cues was studied in 24
      children with specific reading disorder (SRD) or dyslexia and was compared with
      that of 19 normal readers by means of a covert orienting paradigm. This paradigm
      presents participants with valid, neutral and invalid spatial cues preceding the
      presentation of a target stimulus. As compared to normal readers, in SRD children
      the inhibition effect (i.e. the difference between neutral and invalid cues) was
      absent. The 24 SRD children were divided into two groups matched for age, IQ and
      reading ability to study the efficacy of two different rehabilitation procedures.
      We assessed the effects on reading accuracy and speed over a 4-month treatment
      with visual hemisphere specific stimulation (VHSS; J. Learn Disabil. 25 (1992)
      102) vs. traditional speech training. The VHSS program trains participants to
      perform rapid endogenous attentional orienting by presenting briefly flashed
      words in the peripheral visual field. We found that children treated with VHSS
      showed significant changes in their attentional inhibition process, as indicated
      by increased costs for 'reorienting' the attentional focus. As this treatment
      program also proved to be highly efficient in improving the children's reading
      abilities, the possible causal relationship between reading and inhibition
      mechanisms of visuospatial attention was discussed.

PMID- 12429368
TI  - Is human sentence parsing serial or parallel? Evidence from event-related brain
      potentials.
AB  - In this ERP study we investigate the processes that occur in syntactically
      ambiguous German sentences at the point of disambiguation. Whereas most
      psycholinguistic theories agree on the view that processing difficulties arise
      when parsing preferences are disconfirmed (so-called garden-path effects),
      important differences exist with respect to theoretical assumptions about the
      parser's recovery from a misparse. A key distinction can be made between parsers
      that compute all alternative syntactic structures in parallel (parallel parsers)
      and parsers that compute only a single preferred analysis (serial parsers). To
      distinguish empirically between parallel and serial parsing models, we compare
      ERP responses to garden-path sentences with ERP responses to truly ungrammatical
      sentences. Garden-path sentences contain a temporary and ultimately curable
      ungrammaticality, whereas truly ungrammatical sentences remain so permanently--a
      difference which gives rise to different predictions in the two classes of
      parsing architectures. At the disambiguating word, ERPs in both sentence types
      show negative shifts of similar onset latency, amplitude, and scalp distribution
      in an initial time window between 300 and 500 ms. In a following time window (500
      700 ms), the negative shift to garden-path sentences disappears at right central
      parietal sites, while it continues in permanently ungrammatical sentences. These
      data are taken as evidence for a strictly serial parser. The absence of a
      difference in the early time window indicates that temporary and permanent
      ungrammaticalities trigger the same kind of parsing responses. Later differences
      can be related to successful reanalysis in garden-path but not in ungrammatical
      sentences.

PMID- 12429369
TI  - Short-term semantic retention during on-line sentence comprehension. Brain
      potential evidence from filler-gap constructions.
AB  - In filler-gap sentences, a phrase ('filler') is separated by intervening words
      from a subsequent phrase ('gap') with which it is integrated. The filler-gap
      interval provides a useful model for the study of short-term retention processes
      during sentence comprehension. Kluender and Kutas [J. Cogn. Neurosci. 5 (1993)
      29] used event-related brain potentials (ERPs) to show that a filler phrase
      places a demand on short-term retention processes in the filler-gap interval, but
      left the processing level at which this demand arises unspecified. Here we use
      ERPs to address the issue of whether the filler places a demand on the semantic
      component of short-term retention processes in the filler-gap interval.
      Participants read filler-gap sentences, which began with a filler phrase and, in
      the filler-gap interval, contained a subject and object that were either
      semantically related or unrelated. There was also a control condition in which
      the filler phrase was absent (i.e. less memory demand). The main result was that
      during the filler-gap interval, bilateral posterior electrodes displayed a larger
      positivity for unrelated than related words. Moreover, during the same interval,
      posterior electrodes displayed a larger positivity for filler-gap sentences than
      for control sentences. In the control condition (non-filler gap sentences),
      manipulation of semantic relatedness did not produce differences in ERP activity.
      Our results suggest that a filler phrase places a demand on the semantic
      component of verbal working memory during on-line sentence comprehension.

PMID- 12429370
TI  - Using ERPs to dissociate recollection from familiarity in picture recognition.
AB  - Dual process theories posit that separate recollection and familiarity processes
      contribute to recognition memory. Previous research, testing recognition memory
      for words, indicates that event-related brain potentials (ERPs) can be used to
      dissociate recollection from familiarity. It has been hypothesized that the FN400
      ERP old/new effect (300-500 ms) varies with stimulus familiarity, but the
      parietal ERP old/new effect (400-800 ms) varies with recollection. The results
      reported here are consistent with this hypothesis, extending it to the
      recognition of pictures when subjects had to discriminate between studied
      pictures, highly familiar lures (mirror-reversals of studied pictures), and new
      pictures. Furthermore, the parietal old/new effect showed significant
      recollection-related differences only for subjects with good behavioral
      discrimination between studied items and similar lures.

PMID- 12429371
TI  - Altered synaptophysin expression in the rat spinal cord after chronic
      constriction injury of sciatic nerve.
AB  - Injury to the peripheral nervous system can lead to spontaneous pain,
      hyperalgesia and allodynia. Previous studies have shown sprouting of Abeta-fibres
      into lamina II of the spinal cord dorsal horn after nerve injury and the
      formation of new synapses by these sprouts. Synaptophysin is a presynaptic
      vesicle protein, useful in the identification of synaptogenesis. Here we
      investigated whether synaptogenesis as measured by the expression of
      synaptophysin protein correlates with symptoms of neuropathic pain in rats with a
      chronic constriction injury (CCI) of the sciatic nerve. We used
      immunohistochemistry, Western immunoblotting and densitometry to study the
      distribution of synaptophysin and to quantify relative protein. Synaptophysin was
      increased in the ipsilateral dorsal horn with a peak level on day 14 and returned
      to baseline on day 21 post-CCI. Synaptophysin levels temporally correlated with
      thermal hyperalgesia but not with tactile allodynia. Our results indicate that
      thermal hyperalgesia in CCI significantly correlates with synaptogenesis within
      the superficial layers of the dorsal horn.

PMID- 12429372
TI  - Convulsive disorder and the genetics of signal transduction; a study of a low
      molecular weight protein tyrosine phosphatase in a pediatric sample.
AB  - Recent studies point to an involvement of kinases and phosphatases in ionic
      channel regulation and in physiopathologic mechanisms leading to convulsive
      disorders. Acid phosphatase locus 1 (ACP1), also named cytosolic low molecular
      weight phosphotyrosine phosphatase, is a highly polymorphic phosphatase that is
      especially abundant in the central nervous system and is known to be involved in
      several signal transduction pathways. We studied ACP1 in 122 children with
      idiopathic generalized tonic-clonic seizures, 80 children with febrile
      convulsions, and 417 controls from the population of Rome. Low activity
      phenotypes of ACP1 (*A/*A and *A/*B) were found to be over-represented while high
      activity phenotypes (*C/*C and *B/*C) were under-represented in generalized
      seizures cases compared to controls (P < 0.005). No significant difference was
      observed between febrile convulsion cases and controls. These observations
      suggest a protective role of the high activity ACP1 phenotypes against seizures
      in children.

PMID- 12429373
TI  - Consistent immunohistochemical detection of intracellular beta-amyloid42 in
      pyramidal neurons of Alzheimer's disease entorhinal cortex.
AB  - We compared the effects of three pretreatment immunohistochemical techniques (no
      pretreatment, pepsin predigestion and heat pretreatment (HEAT)) for detecting
      intracellular beta-amyloid42 (Abeta42) in pyramidal neurons of formalin-fixed
      Alzheimer's disease (AD) cortices (n = 25). Although all three protocols
      immunostained Abeta42 in amyloid plaques using four commercially-obtained Abeta42
      specific antibodies, only the HEAT protocol consistently detected prominent
      intracellular Abeta42 in pyramidal neurons. This suggests that the Abeta42
      present in amyloid plaques may be structurally distinct from that located within
      the neurons perhaps due to differential binding proteins coupling or a
      consequence of formalin fixation. Detection of an abundant intracellular Abeta42
      in neurons may provide alternate explanations for the origin of dense-core
      amyloid plaques in AD cortices other than the conventional chronic extracellular
      Abeta42 deposition hypothesis.

PMID- 12429374
TI  - Immunomodulation of experimental autoimmune encephalomyelitis in the Lewis rats
      by Lovastatin.
AB  - Previous studies have demonstrated the immunomodulatory potential of Lovastatin,
      a hydroxy methyl glutaryl-CoA reductase inhibitor, in lessening the clinical and
      histological manifestations in the neuroinflammatory animal model experimental
      autoimmune encephalomyelitis (EAE) (Neurosci. Lett., 269 (1999) 71, and J.
      Neurosci. Res., 66 (2001) 155). To determine the mechanism behind the observed
      amelioration of EAE by Lovastatin, we examined the cytokine profile of stimulated
      splenocytes from control, EAE and Lovastatin treated EAE rats. Splenocytes from
      Lovastatin-treated EAE rats showed decreased levels of interferon-gamma, a Th1
      type cytokine, while interleukin (IL)-10, a Th2 type cytokine, was markedly
      increased as compared to untreated EAE animals. In addition, we also observed
      reduced levels of IL-6 and nitric oxide production in lipopolysaccharide
      stimulated splenocytes isolated from Lovastatin-treated animals. This study
      documents for the first time that Lovastatin induces a bias towards Th2 cytokines
      ex vivo, and as a result may be of therapeutic value for cell-mediated diseases
      such as multiple sclerosis.

PMID- 12429375
TI  - Tyrosine kinase inhibitors suppress alpha1-adrenoceptor mediated contraction in
      human radial, internal mammary arteries and saphenous vein.
AB  - The aim of this study is to determine whether the tyrosine kinase plays a role in
      the contractile response of human radial artery (RA), internal mammary artery
      (IMA) and saphenous vein (SV) to alpha(1)-adrenoceptor (AR) stimulation. The
      tyrosine kinase inhibitors, genistein and tyrphostin, significantly inhibited
      alpha(1)-AR mediated contractile response in a dose-dependent and non-competitive
      manner. Genistein at 10 microM inhibited 39%, 54% and 72% of PE-induced maximum
      contraction, and tyrphostin at 50 microM inhibited 41%, 68% and 39% of the
      contraction in the human RA, IMA and SV respectively. These results suggest that
      tyrosine kinases participate in regulation of signal transduction that is
      associated with alpha(1)-AR mediated contractile response in human blood vessels.

PMID- 12429376
TI  - Responses of neurons to an amplitude modulated microwave stimulus.
AB  - In this study we investigated the effects of a pulsed radio frequency signal
      similar to the signal produced by global system for mobile communication
      telephones (900 MHz carrier, modulated at 217 Hz) on neurons of the avian brain.
      We found that such stimulation resulted in changes in the amount of neural
      activity by more than half of the brain cells. Most (76%) of the responding cells
      increased their rates of firing by an average 3.5-fold. The other responding
      cells exhibited a decrease in their rates of spontaneous activity Such responses
      indicate potential effects on humans using hand-held cellular phones.

PMID- 12429377
TI  - Protective effects of the 5-HT1A receptor agonist 8-hydroxy-2-(di-n
      propylamino)tetralin against traumatic brain injury-induced cognitive deficits
      and neuropathology in adult male rats.
AB  - To further investigate the efficacy of 5-HT(1A) receptor agonism on functional
      and histological outcome in traumatically-brain injured (TBI) rats, a single
      intraperitoneal injection of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT;
      0.1, 0.5, or 1.0 mg/kg) or vehicle was given 15 min after controlled cortical
      impact or sham injury. Function was assessed by established motor and cognitive
      tests on post-operative days 1-5 and 14-18, respectively. Cortical lesion volume
      and hippocampal CA(1)/CA(3) cell survival were quantified at 4 weeks. The
      administration of 8-OH-DPAT (0.5 mg/kg) attenuated spatial acquisition deficits
      and reduced hippocampal CA(3) cell loss vs. vehicle (P < 0.05). These data
      augment published reports that 5-HT(1A) receptor agonists confer neuroprotective
      effects after experimental TBI.

PMID- 12429378
TI  - Longitudinal cerebrospinal fluid tau load increases in mild cognitive impairment.
AB  - Cross-sectional cerebrospinal fluid (CSF) levels of tau and amyloid (A) beta
      (beta) are of diagnostic importance for Alzheimer's disease (AD) and mild
      cognitive impairment (MCI). However, most longitudinal studies of tau fail to
      demonstrate progression. Because predominantly brain-derived proteins such as
      tau, have higher ventricle to lumbar ratios, we hypothesized that adjusting for
      the ventricular enlargement of AD would correct for the dilution of tau, and
      improve detection of longitudinal change. Abeta which is not exclusively brain
      derived, shows a ratio <1, and no benefit was expected from adjustment. In a 1
      year longitudinal study of eight MCI and ten controls, we examined CSF levels of
      hyperphosphorylated (P) tau231, Abeta40, and Abeta42. In cross-section, MCI
      patients showed elevated Ptau231 and Abeta40 levels, and greater ventricular
      volumes. Longitudinally, only after adjusting for the ventricular volume and only
      for Ptau231, were increases seen in MCI. Further studies are warranted on
      mechanisms of tau clearance and on using imaging to interpret CSF studies.

PMID- 12429380
TI  - Reproduction of scalp acupuncture therapy on strokes in the model rats,
      spontaneous hypertensive rats-stroke prone (SHR-SP).
AB  - Scalp acupuncture (SA) therapy on strokes has been empirically established and
      widely used in clinics in China. SA is particularly effective at ameliorating
      paralyses and speech disturbances, and the recovery rate is twice that for those
      treated with medication alone. To investigate the effects of SA on a scientific
      basis, we have developed a new experimental system that provides reliable
      controls and excludes psychological effects by using a genetic strain of rats,
      spontaneous hypertensive rats-stroke prone. Here we report that SA indeed has
      rapid and powerful effects to remove limb paralyses caused either by cerebral
      infarct or by cerebral haemorrhage. This model is well suited to study the
      mechanism of the effects of SA in parallel with clinical studies, and to describe
      the whole recovery process after the stroke onset.

PMID- 12429379
TI  - Differential Akt phosphorylation at Ser473 and Thr308 in cultured neurons after
      exposure to glutamate in rats.
AB  - Akt kinase is involved in growth factor-mediated neuronal protection. In the
      present study, we found in cultured neurons exposed to glutamate, that
      phosphorylation at Ser473 was transiently induced, but the level of
      phosphorylation at Thr308 and Akt activity were unchanged. Inhibition of
      phosphoinositide 3-kinase with LY294002 decreased phosphorylation and Akt
      activity, however, pretreatment with LY294002 did not affect glutamate toxicity.
      Our findings suggested that the endogenous Akt pathway does not play a crucial
      role in cell survival after exposure to glutamate.

PMID- 12429381
TI  - Aged Fischer 344 rats exhibit altered locomotion in the absence of decreased
      locomotor activity: exacerbation by nomifensine.
AB  - A novel force plate actometer was used to measure locomotor activity and gait in
      young (6 months) versus aged (24 months) Fischer 344 rats. The actometer revealed
      altered gait in the aged rats in the absence of decreased locomotor activity. The
      catecholamine uptake inhibitor, nomifensine increased locomotor activity in both
      groups and exacerbated the gait alteration in the aged group. Analyses of whole
      brain tissue levels of dopamine (DA), 3,-4 dihydroxyphenylacetic acid (DOPAC),
      and homovanillic acid (HVA) in the substantia nigra and dorsal striatum revealed
      no significant differences between the two age groups. In the young (but not
      aged) rats, distance traveled was negatively correlated with striatal DOPAC +
      HVA/DA tissue ratios (a measure of DA turnover). In the aged (but not the young)
      rats, positive correlations were observed between distance traveled and DOPAC +
      HVA/DA ratios in the substantia nigra. Neither striatal nor nigral DA content was
      significantly correlated with distance traveled in either age group. These
      findings demonstrate that aged rats may exhibit functional changes in locomotor
      activity in the absence of quantitative changes in nigrostriatal DA content.

PMID- 12429382
TI  - Estrogen reduces vascular endothelial growth factor(164) expression in the mouse
      nucleus paraventricularis of the hypothalamus.
AB  - The aim of the present study was to establish whether estrogen and
      corticosteroids exert effects on vascular endothelial growth factor (VEGF)(164)
      expression in the hippocampus and nucleus paraventricularis of the hypothalamus
      by in situ hybridization. Female mice were ovariectomized and treated either with
      estradiol benzoate or vehicle and male mice were either adrenalectomized or sham
      operated. Ovariectomy plus estrogen reduced VEGF(164) expression in the nucleus
      paraventricularis but not in the hippocampus. Adrenalectomy did not influence
      VEGF(164) mRNA levels in the hippocampus and nucleus paraventricularis. Our
      results show for the first time an inhibitory effect of estrogen on VEGF(164)
      expression in the nucleus paraventricularis and suggest a role for estrogen in
      the regulation of VEGF(164) expression and function in the central nervous
      system.

PMID- 12429383
TI  - Different modes of manual acupuncture stimulation differentially modulate
      cerebral blood flow velocity, arterial blood pressure and heart rate in human
      subjects.
AB  - The psychophysiological effect of different modes of manual acupuncture
      stimulation was investigated in 12 healthy, right handed, male subjects (mean age
      29). The cerebral blood flow velocity (CBFV) in both middle cerebral arteries,
      arterial blood pressure (BP), heart rate (HR) and the perceived intensity of the
      stimulation were monitored while an acupuncture needle in the right dorsal thenar
      muscle (point Hegu, Li 4) was repetitively rotated with either high frequency (4
      8 Hz) and low amplitude (hf-la) or low frequency (1-2 Hz) and high amplitude (lf
      ha). Response patterns induced by hf-la and 1f-ha [corrected] stimulation
      differed significantly (P < 0.05) as tested by Student's t-test: (1), 1f-ha
      [corrected] stimulation was perceived as more intense and induced a more marked
      right hemispheric CBFV increase; (2), while hf-la stimulation lead to a slight
      decrease of BP and HR, lf-ha stimulation induced an initial pressor response
      (increase of BP, decrease of HR) and a more marked long term decrease of BP. Data
      indicate that the mode of manual acupuncture stimulation has a differential
      effect on the perceived stimulation intensity, the cerebral activation and the
      cardiovascular reflex response.

PMID- 12429384
TI  - Investigation of promoter variants of the histamine 1 and 2 receptors in
      schizophrenia and clozapine response.
AB  - We report the identification of four novel histamine 1 (H1-17-C/T, -974-C/A, 
      1023-A/G and -1536-G/C) and four novel histamine 2 promoter polymorphisms (H2-294
      A/G, -592-A/G, -1018-G/A and -1077-G/A) which we have investigated for
      involvement in susceptibility to schizophrenia, and in clinical response to
      clozapine treatment. We identified a weak independent association between
      variants at the H1-1536-G/C locus and schizophrenia, where an excess of the H1
      1536-C allele was observed amongst such patients (P = 0.036). However upon
      correction for multiple testing this relationship was no longer statistically
      significant. Similar investigation of the H2 receptor polymorphisms revealed
      association between genotype at the H2-1018-G/A locus and clinical response to
      clozapine treatment (P = 0.027), though upon correction for multiple testing this
      difference was no longer significant. We have concluded that the participation of
      these variants in the disorder is unlikely, particularly in view of their
      apparent lack of function and unlikely influence on receptor expression. However
      their nature alludes to the potential presence of other more important
      alterations further along these regions, where sequences encoding alternate
      promoters have recently been identified for each receptor that may yet be found
      to harbour such polymorphisms.

PMID- 12429385
TI  - A horseradish peroxidase-light and electron microscopic study of immunoliposomes
      utilized for intracellular delivery to the rat striatum.
AB  - Liposomes can deliver plasmid DNA, viruses, antisense oligonucleotides, and
      pharmacological agents to the central nervous system. Conjugation of antibodies
      to liposomes increases delivery specificity. Immunoliposomes created with Thy 1.1
      antibody have previously been shown to be effective for neuronal delivery. The
      intracellular delivery of these immunoliposomes is evaluated by light and
      electron microscopy. Thy 1.1 conjugated liposomes were loaded with horseradish
      peroxidase and stereotactically injected into rat striatum. On light microscopy,
      immunoliposomes were concentrated within 0.2 mm of the injection site 8 h
      following delivery but, 24 h post-operatively, had diffused more than 0.5 mm from
      the injection site. With transmission electron microscopy, immunoliposomes were
      observed entering numerous neurons and some astrocytes in a process distinct from
      the clathrin-coated pit mechanism. These findings suggest that Thy 1.1
      immunoliposomes are effective for intracellular delivery in vivo and their
      endocytosis occurs independently of a coated pit process. The research has helped
      to elucidate alternative mechanisms for immunoliposomal delivery. A more
      fundamental understanding of these attributes is needed to achieve the
      therapeutic potential of immunoliposomes.

PMID- 12429387
TI  - CS-US delay does not impair appetitive conditioning in Chasmagnathus.
AB  - Habituation and appetitive conditioning have been already described in the crab
      Chasmagnathus. The purpose of this work is to study whether associative learning
      can be obtained despite a long conditioned stimulus-unconditioned stimulus
      interval. Results of the first experiment show that the weakening of temporal
      contiguity does not prevent appetitive conditioning to occur while after a long 4
      h delay, conditioning wanes completely. A second experiment was conducted, after
      one and three days of training respectively, confirming the above results. Though
      initially neutral the context trace may be still available immediately after
      training and for the period of two but not after 4:00 h, demonstrating a forward
      limit for the conditioning window. After 3 days of training, a further decrease
      in the exploratory activity suggested that a longer training could increase the
      relative weight of habituation. Conditioning and habituation seem to work as
      opponent processes in the crab CHASMAGNATHUS GRANULATUS: if habituation training
      in the box is followed by the administration of reinforcement after a short
      period of time, appetitive conditioning will take place. However, as this
      interval is increased, habituation prevails. A persistent effect of the exposure
      to a given environment that may underlie trace conditioning in this crab is
      discussed in adaptive terms.

PMID- 12429386
TI  - Antipsychotic, antidepressant, anxiolytic, and anticonvulsant drugs induce type
      II nitric oxide synthase mRNA in rat brain.
AB  - Nitric oxide synthase inhibitors have been regarded as potentially beneficial for
      psychiatric disorders such as depression and schizophrenia, though little is
      known about how nitric oxide synthases are affected by psychotropic drugs in the
      brain. Using reverse transcription-polymerase chain reaction analysis, we
      investigated the effects of short- and long-term oral treatments with several
      psychotropics on type II nitric oxide synthase gene expression in the rat brain.
      With maprotiline and fluvoxamine, enzyme mRNA levels were higher after a 28 day
      treatment than after 1 and 4 day treatments. Zonisamide, carbamazepine and
      diazepam also increased mRNA, though differences in levels between 1, 4 and 28
      day treatments were not significant. These results suggest that psychotropics
      modulate the gene expression of type-II nitric oxide synthase in the brain.

PMID- 12429388
TI  - The role of vision and proprioception in the aversion of rats to the open arms of
      an elevated plus-maze.
AB  - The elevated plus-maze test is usually run with a short edge surrounding the open
      arms in order to prevent the rats from falling. The present experiment
      investigated the role of transparent edges differing in heights: 1 (used as
      control), 5, 10, 20 and 40 cm, the latter the same height as the closed arm
      walls. Additionally, this 40-cm high transparent edge was also studied covered by
      white translucent or black opaque paper. The data show that the time spent in the
      open arms was significantly greater when the edge height was 5, 10 or 40 cm
      covered by the white or black paper. However, there were no differences from the
      1-cm control edge when the height was 40 cm transparent. A similar effect was
      observed when entries in the open arms and total entries were analyzed. The facts
      that there were no differences when the open arms were surrounded by 1- or 40-cm
      transparent edges (which allow thigmotaxis) and that the same 40-cm edge caused
      increases in exploratory behavior when covered by papers indicate that vision
      triggers aversion to open spaces.

PMID- 12429389
TI  - Scent-marking behaviour by male prairie voles, Microtus ochrogaster, in response
      to the scent of opposite- and same-sex conspecifics.
AB  - We conducted an experiment using the prairie vole (Microtus ochrogaster) to test
      predictions associated with the proposed functions of scent marking as a sexual
      attractant, in reproductive competition, and as a self-advertisement. We allowed
      an oestrous female, an anoestrous female, and an adult male to scent mark three
      portions of a clean substrate and then exposed a second male to this substrate
      for secondary marking. We did not support a sexual attraction hypothesis in that
      males did not place more scent marks in response to oestrous than anoestrous
      females. Similarly, we did not support a reproductive competition hypothesis in
      that males did not place more scent marks in response to marks of males than to
      those of females or bare substrate. Males did not overmark the scent of males or
      females and thus we did not support a scent-masking or scent-blending hypothesis.
      In that males deposited scent similarly in response to males, females, and on
      bare substrate, our results suggest that the frequency and placement of scent
      marks by males function primarily to advertise individual identity in an area.

PMID- 12429390
TI  - Preference for mirror images and video image in Java sparrows (Padda oryzivora).
AB  - Java sparrows were exposed to a mirror and a frosted mirror, a mirror and a live
      bird, a mirror and a live bird with frosted screen, a closed circuit TV monitor
      and a TV program or the closed circuit monitor and an upside down monitor. The
      birds showed strong preference for the self-image on the mirror, the live bird
      and the self-image on the monitor. They preferred almost equally to the mirror
      and the frosted live bird. These results suggest that the Java sparrows saw the
      self-image on the mirror as conspecific image.

PMID- 12429391
TI  - The importance of paternal care on pup survival and pup growth in Peromyscus
      californicus when required to work for food.
AB  - We examined paternal care in the monogamous California mouse when wheel running
      was necessary to obtain food. Paternal and maternal care, pup survival and
      feeding were compared in litters with single females (Male Absent) and paired
      females (Male Present) under three different foraging requirements. When wheel
      running was required for obtaining food (Wheel Contingent), the male's presence
      significantly increased pup survival. There were no significant effects of the
      male's presence on pup survival in the No Wheel (standard laboratory housing with
      ad lib food) or Wheel Noncontingent (running wheel with ad lib food) groups.
      Males may have indirectly increased pup survival by helping generate food through
      wheel running and then subsequently spending less time eating than females. While
      females reduced the time spent in parental care as pups aged, males increased the
      time spent in parental care as pups aged. Thus as pups became larger and more
      expensive to rear, the male increased parental care. These results indicate that
      paternal care benefits pup survival more under conditions where the parents must
      forage to obtain food than when food is provided ad lib in the standard
      laboratory environment.

PMID- 12429392
TI  - Acquisition of dominance status affects maze learning in mice.
AB  - Learning is likely to be costly and thus subject to trade-off with other
      components of life history. An obvious prediction, therefore, is that investment
      in learning, and thus learning performance, will vary with individual life
      history strategy and the reproductive value of the learning outcome. We tested
      this idea in the context of social dominance in male laboratory mice, using a
      simple radial maze paradigm to compare the ability of high- and low-ranking male
      mice to track changing food location. We tested animals in randomly selected
      pairs before and after establishing aggressive rank relationships to distinguish
      intrinsic differences in learning ability from those attributable to acquiring
      high or low rank. There was no difference in learning between later dominants and
      subordinates prior to establishing rank relationships. After pairing, however,
      dominants showed a significantly greater percentage of correct responses, with
      the difference being greatest earlier in a sequence of trials. The percentage of
      correct responses also increased with the amount of aggression initiated during
      pairing. The results thus appeared to reflect a state-dependent change in
      learning associated with the aggressive social relationships formed during
      pairing.

PMID- 12429393
TI  - Latent inhibition as a function of CS intensity in taste aversion learning.
AB  - An experiment is reported in which the relationship between the intensity of a
      preexposed stimulus and latent inhibition was investigated, using the taste
      aversion learning paradigm in rats. Two concentrations of a saline solution
      (high, 1%; and low, 0.25%) were used during preexposure and conditioning phases
      in a factorial design. Two control conditions without preexposure were added, one
      for each stimulus concentration during conditioning. The known effect of
      conditioned stimulus (CS) intensity during conditioning was confirmed: the more
      concentrated the solution used in conditioning, the higher the acquisition rate.
      A direct relationship was observed between the CS intensity used during
      preexposure and the latent inhibition effect: the more concentrated the solution
      during preexposure, the lower the acquisition rate of conditioning. The
      implications of these results for latent inhibition theories are considered.

PMID- 12429394
TI  - The role of the laterodorsal nucleus of the thalamus in spatial learning and
      memory in the rat.
AB  - The anterior thalamic nuclei appear to play an important role in learning and
      memory. Connectionally and structurally, the lateral dorsal nucleus is similar to
      the anterior nuclei. This study tested the hypothesis that the laterodorsal
      thalamic nucleus (LD) also contributes to these functions. Adult Sprague-Dawley
      rats received bilateral ibotenic acid lesions of LD, and 2 weeks later the rats
      were tested in a repeated acquisition water maze task. The control groups
      displayed a short final escape latency and showed a preference for the correct
      quadrant in the probe trial. Rats with a lesion restricted to LD (LDL) were
      mildly impaired in the task, but rats with lesions that destroyed LD and also
      significantly (50%) damaged the adjacent anterior thalamic nuclei (LDL+) were
      severely impaired, displaying no improvement in performing the spatial task. In a
      second experiment, training in the same paradigm for 2 weeks resulted in improved
      final performance by LDL and control rats but not by LDL+ rats. These findings
      support the hypothesis that together with the anterior thalamic nuclei, LD plays
      a role in spatial learning and memory.

PMID- 12429395
TI  - Variation in visual acuity within pigmented, and between pigmented and albino rat
      strains.
AB  - Many researchers assume that laboratory rats have poor vision, and accordingly,
      that they need not consider differences in the visual function of rats as a
      consequence of strain or experience. Currently, it is not specifically known
      whether rat domestication has negatively affected the visual function of
      laboratory rat strains, what the effects of strain albinism are on rat visual
      function, or whether there are strain differences in the visual function of
      laboratory rats that are independent of pigmentation. In order to address these
      questions, we measured psychophysically the vertical grating acuity of three
      pigmented (Dark Agouti, Fisher-Norway, Long-Evans) and three albino (Fisher-344,
      Sprague-Dawley, Wistar) strains of laboratory rats, and compared their acuity
      with that of wild rats. The grating thresholds of Dark Agouti, Long-Evans and
      wild strains clustered around 1.0 cycle/degree (c/d) and did not significantly
      differ from one another. Fisher-Norway rats, however, had a significantly higher
      threshold of 1.5 c/d. The grating thresholds of Fisher-344, Sprague-Dawley, and
      Wistar strains, which were clustered around 0.5 c/d, were significantly lower
      than those of the pigmented strains. These data demonstrate that there is
      significant strain variability in the visual function of laboratory rats.
      Domestication of Long-Evans and Dark Agouti strains does not appear to have
      compromised visual acuity, but in the case of Fisher-Norway rats, selective
      breeding may have enhanced their acuity. Strain selection associated with
      albinism, however, appears to have consistently impaired visual acuity.
      Therefore, a consideration of strain differences in visual function should
      accompany the selection of a rat model for behavioral tasks that involve vision,
      or when comparing visuo-behavioral measurements across rat strains.

PMID- 12429396
TI  - Effect of tryptophan depletion on impulsive behavior in men with or without a
      family history of alcoholism.
AB  - This study investigated the effects of acute serotonin depletion on two measures
      of impulsive behavior in healthy men with a family history of alcoholism.
      Serotonin has been implicated in several forms of impulsive behavior, as well as
      in the etiology of Type II alcoholism. The present study was designed to
      determine if an acute disturbance of serotonin function would increase impulsive
      responding on two behavioral indices of impulsivity, and whether this effect
      would be greater in individuals with a genetic predisposition to alcoholism.
      Forty healthy men, half of whom had an alcoholic father, participated in a two
      session study. Subjects ingested a tryptophan-depleting diet on one session and a
      balanced diet on the other session, and completed tasks measuring behavioral
      inhibition and delay discounting. Tryptophan depletion impaired performance on
      the behavioral inhibition task in the males with a positive family history,
      relative to the males without alcoholic relatives, whereas it improved behavioral
      inhibition in the family history negative group. Tryptophan depletion had
      negligible effects on mood, and it did not alter performance on the delay
      discounting task. The results provide partial support for the hypothesis that
      impulsive behavior is related to low serotonin function, and further suggests
      that the role of serotonin depends on genetic factors related to alcoholism. The
      results complement the results of a parallel study investigating the effects of
      serotonin depletion on a similar behavioral inhibition procedure in rats.
      Parallel studies in rats and humans are important to validate the large body of
      neurobiological research with non-human species to humans.

PMID- 12429397
TI  - Dopamine release in human ventral striatum and expectation of reward.
AB  - Using the ability of [11C]raclopride to compete with dopamine for D(2)/D(3)
      receptors, we investigated by positron emission tomography the effect of placebo
      (saline) injection on dopamine release in the ventral striatum of patients with
      Parkinson's disease. We found evidence for placebo-induced dopamine release of
      similar magnitude to that reported in healthy volunteers after amphetamine
      administration. However, in contrast to the dorsal striatum, there were no
      differences in [11C]raclopride binding potential changes between patients who
      experienced the reward (those who reported placebo-induced clinical benefit) and
      those who did not. We conclude that the release of dopamine in the ventral
      striatum (nucleus accumbens) is related to the expectation of reward and not to
      the reward itself. These observations have potential implications for the
      treatment of drug addiction.

PMID- 12429398
TI  - Physical but not emotional stress induces a delay in behavioural coping responses
      in rats.
AB  - Physical stress (PS) and emotional stress (ES) have opposite long-term effects on
      open field behaviour. PS consisted of a repeated mild foot shock treatment, which
      the ES animals witnessed. PS caused a long-term decrease in locomotor activity
      and exploration behaviours and increased immobility. ES induced an increase in
      locomotor activity. These changes in open field behaviour could be the result of
      several factors such as increased anxiety, a shift in coping strategy or simply a
      change in locomotor activity. To investigate the effect of the PS and ES
      treatment on these separate factors, the following behavioural tests were
      performed: defensive withdrawal, shock prod bury, large open field and social
      interaction. PS animals initially showed immobility in the shock prod bury test
      and the large open field, while the differences measured over the entire test
      period were small or not present. PS did not induce differences in the defensive
      withdrawal and the social interaction tests. ES and control animals did not
      differ significantly in any of the tests. The effects of PS in the shock prod
      bury test in particular can be interpreted as an indication of a passive coping
      style. However, PS animals showed the same behaviour as controls, but started
      displaying the behaviour after the initial immobility response. It is concluded
      that neither PS nor ES affects the coping style and anxiety level of the rats. PS
      induces a delay in behavioural responding and ES induces locomotor activation per
      se. It seems that the shock prod bury test is most suitable to distinguish
      between exploration and coping style.

PMID- 12429399
TI  - Unilateral destruction of the dorsocentral striatum in rats produces neglect but
      not extinction to bilateral simultaneous stimulation.
AB  - A number of previous studies have indicated that lesions of the medial agranular
      cortex (AGm) in rats induce multimodal neglect and extinction to bilateral
      simultaneous stimulation (extinction), the two major symptoms of the neglect
      syndrome in humans. A recent study demonstrated that lesions of dorsocentral
      striatum (DCS), the site of AGm projections to the striatum, produce multimodal
      neglect qualitatively similar to that found with AGm lesions. In the present
      study, the behavioral effects of unilateral DCS lesions were examined in more
      detail for the major manifestations of neglect: hemineglect, extinction, and
      allesthesia/allokinesia. Subjects were tested for extinction to bilateral
      simultaneous stimulation of the forepaws three times a week for 3 weeks. Neglect
      testing occurred twice weekly and the subjects were tested for the presence of
      neglect by rating the magnitude of orientation to visual, tactile, and auditory
      stimulation. The results indicated that DCS operates, while demonstrating severe
      neglect, failed to demonstrate extinction or allesthesia/allokinesia. These
      findings suggest that the neural mechanisms that underlie neglect and extinction
      are dissociable in this system. A better understanding of the neural mechanisms
      that underlie extinction is particularly important because humans that have
      recovered from neglect often continue to demonstrate the debilitating symptoms of
      extinction.

PMID- 12429400
TI  - Persistence and drug-induced reinstatement of a morphine-induced conditioned
      place preference.
AB  - Morphine induces a conditioned place preference (CPP) for a chamber associated
      with the drug. In the present set of experiments, we explored the persistence,
      extinction, and reinstatement of a morphine-induced CPP using an 'unbiased'
      apparatus with two distinct chambers separated by a smaller neutral zone. Rats
      were given four 45 min pairings of one chamber with morphine (Experiments 1 and
      2: 1.0, 5.0, or 10.0 mg/kg, s.c.; Experiments 3A and 3B: 10.0 mg/kg, s.c.) and
      four pairings of the other chamber with saline on alternate days. Following
      conditioning, rats were given 15 min tests for chamber preference. In Experiment
      1, rats showed a CPP following conditioning with all doses. In Experiment 2, in
      the same animals, the CPP was evident in subsequent tests given either 2 or 6
      weeks following the initial test for preference. Furthermore, in the animals
      tested 2 weeks after the initial CPP test, the CPP was maintained for 12 weeks
      when tests were repeated every 2 weeks. Animals tested at 6 weeks were again
      tested after another 6-week delay and showed a clear preference for the
      previously morphine-paired chamber. In Experiment 3A, rats underwent place
      conditioning as above with 10.0 mg/kg morphine. Following extinction during which
      both chambers were paired with saline for 45 min on four occasions, the CPP was
      no longer evident. The CPP was reinstated by priming injections of 1.0 or 2.5
      mg/kg morphine, but not 0.5 mg/kg in a 30 min test. Similar results were found in
      Experiment 3B, in which the CPP was reinstated following a priming injection of
      morphine (2.5 mg/kg) given immediately or 15 min before a 30 min test; no
      reinstatement was seen after injections of saline. These results show that a
      morphine-induced CPP is persistent over time and can be reinstated by morphine
      after extinction.

PMID- 12429401
TI  - Medial temporal lobe activity during semantic classification using a flexible
      fMRI design.
AB  - In this study, we evaluated the use of a self-paced fMRI design, to allow a
      flexible speed of responding with only four alternating stimulus blocks to
      minimize the influence of task switching on a group of young subjects. This was
      done in view of our intention to use such a design on groups of elderly and
      demented subjects in the near future. In addition, the hypothesis was tested that
      the medial temporal lobe is involved in semantic memory similar to episodic
      memory using a semantic retrieval task. In line with previous imaging studies
      that compared a semantic (living/nonliving) to a perceptual (alphabetically
      ascending/descending) classification condition, activity was seen in lateral
      temporal and inferior frontal regions, indicating the applicability of our
      design. Additional activity was seen in the right, and, at a slightly lower
      threshold, also in the left MTL, providing support for the involvement of the MTL
      in retrieval from semantic memory.

PMID- 12429402
TI  - Lesions of the ventro-medial basal ganglia impair the reinforcement but not the
      recall of memorized color discrimination in domestic chicks.
AB  - Effects of bilateral chemical lesions of the ventro-medial basal ganglia (lobus
      parolfactorius, LPO) were examined in 3-9-day-old domestic chicks. In experiment
      1, chicks were trained to peck at a blue bead that was associated with drops of
      water as a reward. Addition of passive avoidance training using a bitter yellow
      bead resulted in highly selective pecking between blue and yellow. LPO lesion
      (given 3-5 h after training) did not impair the selectivity when chicks were
      tested 24 h afterwards, while the novel reinforcement using a red bead was
      severely impaired. In experiment-2, chicks were trained in a GO/NO-GO color
      discrimination task with food reward. Trained chicks received bilateral LPO
      lesions, and they were tested 48 h afterwards for the number of pecks and latency
      of the first peck in each trial. The LPO lesion did not impair the recall of
      memorized color discrimination in tests, while the chicks were severely deficient
      in post-operative novel training. These results confirm that: (1) bilateral LPO
      ablation does not interfere with selective pecking based on the memorized color
      cues; but (2) it impairs reinforcement in novel training. LPO is thus supposed to
      be involved in acquisition, rather than execution of memorized behaviors.

PMID- 12429403
TI  - Behavioral evidence for working memory of sensory dimension in macaque monkeys.
AB  - For animals, which lack language codes, there might be limitations in the use of
      abstract concepts in guiding their behavior. We trained two macaque monkeys in a
      computerized version of Wisconsin Card Sorting Task (WCST) with two dimensions
      (shape and color) to test their capability for memorizing, updating and using
      representation of sensory dimension. A sample had to be matched with one of three
      test items by either matching in color or shape. The monkeys had to find the
      relevant sensory dimension and its sudden changes by trial and error only based
      on reward and error signals. Both monkeys succeeded in more than ten shifts in
      the rules within a daily session. Several probe tests showed that the monkeys in
      fact used the dimension-based matching rules, because the rule shift was
      generalized from the experience of some samples to all of the others in the
      sample set, and because the rules were immediately applied to newly introduced
      samples. The frequent shifts can be overcome only with representation of the
      sensory dimension in working memory. These results, thus, suggest that nonhuman
      primates can store sensory dimension such as color and shape in working memory,
      dynamically update it based on the behavioral outcomes, and use it to guide
      behavior, despite their lack of apparent language.

PMID- 12429404
TI  - Independent control of the digits predicts an apparent hierarchy of visuomotor
      channels in grasping.
AB  - If an object changes position at the onset of a reach-to-grasp movement, both the
      transport speed and the grip aperture are adjusted. If the object changes in size
      at the onset, only the grip aperture is adjusted. This combination of results has
      been interpreted as being the consequence of a hierarchical relationship between
      visuomotor channels for transport and grip. We argue that our alternative view on
      grasping can account for the observed behaviour without making new assumptions.
      In our view, grasping consists of smooth (minimal jerk) movements of each digit
      to a target position on the object. The digits' target positions change, both
      when object position and when object size change. A model in which the individual
      digits move smoothly to these new positions yields the same behaviour as is
      observed experimentally.

PMID- 12429405
TI  - Multiple injections of thyrotropin releasing hormone fail to reverse learning and
      memory deficits in rats with lesions of the nucleus basalis of meynert.
AB  - The learning and memory enhancing effects of thyrotropin releasing hormone (TRH)
      was examined in an animal model of Alzheimer's disease. Adult rats were prepared
      with either sham surgeries or cholinergic lesions of the nucleus basalis of
      Meynert (nbM). Subjects were injected (ip) with one of three doses of TRH (0, 5,
      10 mg/kg) starting on the day of surgery and continuing once every other day for
      a total of four injections. Performance (four trials/day for 4 days, 30 m inter
      trial interval) in a Morris water maze was assessed one week after the last TRH
      injection (i.e., 2 weeks postoperatively). Latency to find the hidden platform
      served as the dependent variable. Results indicated that damage to the nbM
      impaired task performance in that animals with nbM lesions generally required
      more time to find the platform and showed less trial-to-trial improvement.
      Treatment with TRH failed to reverse this lesion-induced deficit. These results
      suggest that multiple injections of TRH do not provide residual protection
      against the deleterious effects on learning and memory produced by cholinergic
      lesions of the basal forebrain. Other doses and administration parameters,
      however, need to be studied in order to determine the generalizability of these
      findings.

PMID- 12429406
TI  - Effect of chronic inhibition of calpains in the hippocampus on spatial
      discrimination learning and protein kinase C.
AB  - Several behavioral and electrophysiological studies have suggested that a
      sustained activation of protein kinase C would be required to underlie persistent
      changes associated with memory formation. Limited proteolysis of PKCs by
      calpains, calcium-activated proteases, cleaves the catalytic and the regulatory
      domains, generating a free catalytic fragment termed PKM, constitutively active.
      In order to investigate the potential physiological importance of this limited
      proteolysis as a mechanism of PKC activation, we have studied the effect of the
      calpastatin peptide, a specific calpain inhibitor, on the learning of a spatial
      discrimination task in a radial maze. Thus, using osmotic micro-pumps, the
      calpastatin peptide was infused bilaterally into the dorsal hippocampus during
      the six sessions of training and the probe test. The treatment was shown to
      facilitate the performance of the mice on the two last training sessions and on
      the probe test. This behavioral effect was shown to correspond to the reduced
      calpain activity observed in the hippocampus at the very end of the 7-day
      infusion of the calpastatin peptide, suggesting a relation between both events.
      In addition, PKC activity measured immediately after the probe test was notably
      decreased in the membrane fraction of the hippocampus. Although protein levels of
      PKCs and calpains quantified by western blot were not affected by calpastatin
      infusion, we found a noticeable correlation between mu-calpain and PKCgamma
      levels confirming the particular relationship between both proteins. These
      results suggest that calpains influence on PKCs activity may affect cellular
      mechanisms during memory processes.

PMID- 12429407
TI  - Salt appetite of adrenalectomized rats after a lesion of the SFO.
AB  - Circumventricular organs such as the subfornical organ (SFO) may mediate the
      effects of circulating angiotensin (ANG) II on salt appetite under conditions of
      sodium depletion in the rat. We studied the effects of an electrolytic lesion of
      SFO on salt appetite after adrenalectomy (ADX) in Long-Evans rats. The SFO lesion
      had no effect on saline intake, but it did abolish water intake after acute
      peripheral treatments with 2 mg/kg of captopril or a 10 mg/kg of furosemide.
      These findings contrast with other recent data from this laboratory demonstrating
      large reductions in salt appetite in adrenal-intact rats with lesions of either
      SFO or the organum vasculosum laminae terminalis during acute iv infusions of ANG
      II. Thus, the SFO may contribute to the salt appetite response to circulating ANG
      II, but it is not essential for the response to adrenalectomy.

PMID- 12429408
TI  - Locomotor sensitization to cocaine is associated with increased Fos expression in
      the accumbens, but not in the caudate.
AB  - Behavioral sensitization following repeated intermittent cocaine administrations
      is thought to involve alterations in cocaine regulation of neural activity within
      the accumbens and caudate brain regions. Although Fos immunohistochemistry and c
      fos in situ hybridization have frequently been used to assess changes in cocaine
      induced neural activity following prior cocaine exposure, these techniques have
      rarely been used to examine neural activity in the accumbens of behaviorally
      sensitized animals. In the present experiment, we compared the ability of
      increasing doses of cocaine to induce Fos in the accumbens and caudate of rats
      following a treatment procedure (7 once daily injections of 15 mg/kg of cocaine
      or the saline vehicle) shown to produce robust and persistent (1 week) locomotor
      sensitization. In sensitized animals, there was a leftward shift in the dose
      response curve for cocaine induction of Fos in the accumbens, but not in the
      caudate. These results provide the first parametric evidence for sensitization of
      cocaine-induced Fos expression in the accumbens.

PMID- 12429409
TI  - Differential learning abilities of 129T2/Sv and C57BL/6J mice as assessed in
      three water maze protocols.
AB  - Knockout mice are generated by using ES cells from 129 mouse strains and are
      frequently backcrossed with other strains, like C57BL/6. It is important to
      characterise the physiological and, in particular, the behavioural profile of
      each strain in order to correctly analyse the functional contribution of a single
      gene mutation on the 'cognitive' phenotype. The present study compared 129T2/Sv
      (129) and C57BL/6J (C57) mice in three different spatial learning protocols in
      the water maze, using a hidden platform. In the 'standard' reference memory
      protocol, 129 and C57 attained an equivalent level of performance as assessed by
      accuracy in reaching the platform (path length), despite a faster swim speed
      exhibited by C57 mice. In a stepwise learning task, C57 mice showed poorer
      performances over all stages of learning. However they performed better than 129
      in a massed learning protocol which taxes short-term memory, and in which they
      exhibited lower levels of perseveration. The results emphasize the importance of
      using various tasks differing in cognitive demand, but using the same
      experimental environment and motivation, in order to 1) evaluate strain- or
      mutation-dependent learning abilities, and 2) dissociate the roles played by
      cognitive and non-cognitive factors in the behavioural requirements of the tasks.

PMID- 12429410
TI  - Changes in sleep-waking cycle after striatal excitotoxic lesions.
AB  - Huntington's disease (HD) patients show severe diurnal choreic movements, while
      during slow-wave sleep (SWS) abnormal movements subside. Sleep disturbances in
      HD, including irregular delta activity and decreases in SWS, have also been
      reported. Striatal excitotoxic lesions have been shown to induce increased
      nocturnal spontaneous locomotor activity in rodents. In order to characterize the
      changes in circadian activity and sleep patterns and their correlation with motor
      activity after striatal excitotoxic lesions, Sprague-Dawley rats were implanted
      and lesioned; their locomotor and EEG activities were recorded for either 4 or 24
      h during baseline or 7 and 30 days post-lesion. Locomotor activity increased
      significantly at 7 days post-lesion during the dark phase of the light-dark
      cycle. In contrast, total time spent in wakefulness (W) increased at 30 days post
      lesion during the light phase of the cycle. This increase was at the expense of
      SWS duration. No disruption of the circadian curves was observed. Increases in
      the number of W-bouts and decreases in the duration of SWS-bouts were also
      observed. These results suggest the possible participation of the striatum in the
      regulation of the sleep-waking cycle, independent of locomotor activity. The
      increase in W could be due to loss of inhibition of target structures involved in
      regulation of the sleep-waking cycle.

PMID- 12429411
TI  - Chronic administration of fluoxetine impairs inhibitory avoidance in male but not
      female mice.
AB  - The effects of chronic administration of fluoxetine (20 mg/kg/day i.p.) on a one
      trial step-through inhibitory avoidance task were investigated in male and female
      CD1 mice. In Experiment 1, treatment was administered for 21 days before the
      training session, whereas in Experiment 2, other subjects were subjected to the
      same treatment starting 24 h after the training session. The comparison of test
      versus training latencies showed memory deterioration with pre-training
      administration of fluoxetine (Experiment 1), which affected males but not
      females. Sex differences in this task were also observed in Experiment 1, with
      females showing a better performance. Sex differences were evident in controls as
      well as in treated animals. The locomotor activity of the animals was also tested
      in Experiment 1. Due to the absence of sex differences in the drug effects on
      this measure, the sex differences in the effects of fluoxetine on inhibitory
      avoidance were hardly attributable to non specific effects on locomotor activity.
      The lack of effect of post-training administration of fluoxetine (Experiment 2)
      constitutes additional support of the idea that the observed effect on inhibitory
      avoidance in Experiment 1 is specifically related to learning and memory.

PMID- 12429412
TI  - Behavioral and physiological mouse assays for anxiety: a survey in nine mouse
      strains.
AB  - In order to find better and new treatments for anxiety in humans, a variety of
      paradigms are used to study anxiety-related processes in rodents. We studied mice
      in two different anxiety-related assays: the physiological stress-induced
      hyperthermia (SIH) paradigm and the behavioral light-dark exploration (LD) test.
      Eight inbred strains (129S6/SvEvTac, 129S1/SvImJ, A/J, BALB/cByJ, C3H/HeJ,
      C57BL/6J, DBA/2J, and FVB/NJ) and one outbred strain (CD1-ICR) were tested in
      both assays repeatedly. This study describes the first strain survey for the SIH
      paradigm. All strains showed an SIH response, but the magnitude of the response
      varied between lines. The inbred strain distribution pattern for the behavioral
      responses in the LD assay was not correlated with the SIH response. The lack of a
      significant correlation suggests that there is no genetic relation between such
      responses. Mice could be tested repeatedly in both assays without affecting the
      results. A new paradigm, in which both assays were combined, elucidated that
      behavioral responses were not altered by segments of the SIH paradigm. In
      contrast, exposure to the light-dark box instead of the home-cage showed a strain
      dependent effect on the physiological response. We conclude that a combination of
      behavioral and physiological responses might lead to a better understanding in
      anxiety-related processes.

PMID- 12429413
TI  - Behavioral impairment of APP(V717F) mice in fear conditioning: is it only
      cognition?
AB  - Alzheimer's Disease (AD) is a devastating human neurodegenerative disorder
      associated with progressive deterioration of cognitive abilities. The APP(V717F)
      mouse, an animal model of AD showing robust overexpression of the human amyloid
      precursor protein (APP) carrying the mutation 717 V --> F, was also shown to
      exhibit learning and memory performance deficits. However, AD patients suffer
      from other abnormalities including altered emotionality. Emotionality has not
      been analyzed in AD mouse models. Here, motor and posture patterns exhibited by
      APP(V717F) mice are described in a detailed manner in fear conditioning, a
      paradigm that allows one to test both mnemonic and emotional characteristics of
      mice. Our results revealed a complex set of behavioral alterations in APP(V717F)
      mice in measures of exploratory behavior and fear suggesting that the effects of
      APP(V717F) overexpression in this mouse model are not limited to cognition and
      may need to be thoroughly examined in the future in a broad range of behavioral
      tests.

PMID- 12429414
TI  - Effects of 2-mercaptoacetate on ingestive behavior in 18- and 21-day-old rats.
AB  - Previous work has demonstrated that mercaptoacetate (MA), which interferes with
      oxidation of fatty acids, can produce increases in intake in both adult and
      preweanling rats between 12 and 15 days of age. In both pups and adults, the
      increased intake is related to a decrease in the latency to initiate intake, but
      the duration of the effects of MA and the effective doses of MA differ in young
      pups compared to adult rats. Thus, in the present experiments, we examined older
      pups to determine the effects of administration of MA on ingestive behavior and
      energy-related markers (blood glucose, free fatty acids, and beta
      hydroxybutryrate levels and weight loss) during the weaning transition. Pups aged
      18 or 21 days received an i.p. injection of a 0, 22.8, 45.6 or 68.4 mg/kg MA, and
      after 1 h consumed a milk diet from the floor of a test container. Unlike younger
      pups or adult rats, MA did not stimulate intake in 18- or 21-day-old pups in a 30
      or 60 min test, instead, the higher doses significantly suppressed intake. In
      addition, while latency to initiate intake was not reduced, primarily due to the
      very short latencies observed in control pups, the duration of intake was
      decreased by the higher doses of MA. Finally, MA did produce changes in fatty
      acid oxidation in pups at both ages, but baseline levels of free fatty acids and
      beta-hydroxybutryrate differed across the ages, as did the pattern of changes
      produced by MA. The results suggest that in contrast to the effects observed in
      both younger pups and adult rats, during the early weaning period exogenous
      alterations of fatty acid oxidation fail to stimulate intake. In addition,
      similar to effects seen in young pups, high doses of MA can significantly
      suppress intake. These differences in responding to MA during the weaning period
      may reflect heightened sensitivity to similar signals produced endogenously as a
      result of developmental changes in diet and/or metabolism or may result from
      heightened sensitivity to aversive properties of administration of MA.

PMID- 12429415
TI  - In the rat forced swimming test, chronic but not subacute administration of dual
      5-HT/NA antidepressant treatments may produce greater effects than selective
      drugs.
AB  - The rat forced swimming test (FST) distinguishes selective serotonin (5-HT) and
      selective noradrenaline (NA) reuptake-inhibitors, which respectively increase
      swimming and climbing behaviours. However, NA-system-mediated inhibition of 5-HT
      induced swimming prevents dual 5-HT/NA reuptake-inhibition to produce
      concurrently climbing with swimming. Since adaptative neurochemical processes
      occur in the treatment of depression, we examined the influence of long-term
      antidepressant treatment on these interactions. METHODS: (1) Selective
      [fluoxetine: 10 mg/kg; desipramine: 10 mg/kg] and non-selective [milnacipran: 40
      mg/kg; mirtazapine: 20 mg/kg] antidepressants were administered subacutely (3inj)
      and chronically (17inj) over 16 days. (2) A subacute fluoxetine-desipramine
      combination (10-10 mg/kg) was administered in rats that were pre-treated with
      chronic-desipramine (10 mg/kg per day, 14 days). (3) NA-system-mediated
      interactions were further examined by combining the alpha(2)-receptor agonist
      clonidine (5, 10, 20, 200 microg/kg) with 10 mg/kg fluoxetine. RESULTS: (1) Long
      term treatment with either fluoxetine or desipramine does not modify the
      behavioural response produced by their subacute administration. (2) In contrast,
      whereas subacute-milnacipran increases climbing solely, chronic-milnacipran
      produces greater anti-immobility effects and increases both climbing and swimming
      behaviours. Similarly, the fluoxetine-desipramine combination produces climbing
      solely, but increases both climbing and swimming behaviours in animals pre
      treated with chronic-desipramine. Chronic but not subacute-mirtazapine increases
      swimming behaviour. (3) clonidine dose-dependently antagonizes fluoxetine-induced
      anti-immobility effects and swimming behaviour. CONCLUSIONS: Chronic enhancement
      of NA-transmission alters NA-system-mediated inhibition of 5-HT-induced behaviour
      in the FST, which may involve alpha(2)-receptors.

PMID- 12429416
TI  - Hemispheric dissociation of visual-pattern processing and visual rotation.
AB  - We aimed at investigating whether on-line and delayed visual pattern processing
      activated different areas in human prefrontal and parietal cortex. For this
      purpose we measured the regional cerebral blood flow (rCBF) during simultaneous
      and successive visual matrix processing in 10 right-handed subjects. Delayed
      matching to sample activated predominantly left hemispheric ventrolateral
      prefrontal cortex, Broca's area and parts of the parietal cortex. In contrast,
      visuospatial matrix rotation showed activation of the right dorsolateral
      prefrontal cortex and parietal lobe. The present results suggest a hemispheric
      dissociation of fronto-parietal circuits with a left dominance for visual pattern
      processing like storage and a right dominance for visuospatial processing.

PMID- 12429417
TI  - Behavioural pharmacology of octopamine, tyramine and dopamine in honey bees.
AB  - In the honey bee, responsiveness to sucrose correlates with many behavioural
      parameters such as age of first foraging, foraging role and learning. Sucrose
      responsiveness can be measured using the proboscis extension response (PER) by
      applying sucrose solutions of increasing concentrations to the antenna of a bee.
      We tested whether the biogenic amines octopamine, tyramine and dopamine, and the
      dopamine receptor agonist 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene
      (6,7-ADTN) can modulate sucrose responsiveness. The compounds were either
      injected into the thorax or fed in sucrose solution to compare different methods
      of application. Injection and feeding of tyramine or octopamine significantly
      increased sucrose responsiveness. Dopamine decreased sucrose responsiveness when
      injected into the thorax. Feeding of dopamine had no effect. Injection of 6,7
      ADTN into the thorax and feeding of 6,7-ADTN reduced sucrose responsiveness
      significantly. These data demonstrate that sucrose responsiveness in honey bees
      can be modulated by biogenic amines, which has far reaching consequences for
      other types of behaviour in this insect.

PMID- 12429418
TI  - Home cage activity and behavioral performance in inbred and hybrid mice.
AB  - Locomotor activity is a key component in many behavioral tests, suggesting that
      genetic differences in activity levels may be a critical consideration when
      comparing mouse strains. In order to assess the relationship between activity and
      performance, we recorded home cage activity, and locomotion and defecation, a non
      activity-linked behavior, in tests of anxiety in inbred (C57BL/6J (B6), n = 25;
      BALB/cJ (C), n = 24; DBA/2J (D2), n = 28) and hybrid (CB6F1/6J (CB6: B6 x C) n =
      19) mice. Under our test conditions, the strains showed significant differences
      in home cage activity levels: C > B6 > D2. The CB6 mice were similar to the B6
      mice in horizontal activity and were intermediate between the parental strains in
      vertical movement. Based on measures of locomotion and defecation in the open
      field, emergence and novel object tests, and the elevated zero maze, the C mice
      appeared to be the most anxious and the B6 were the least anxious. The D2 mice
      were intermediate on some measures but more similar to B6 mice on others, making
      ranking them more difficult. In addition, the CB6 mice displayed characteristics
      of both parental strains. They had greater similarity to B6 mice in measures of
      horizontal movement in the home cage and locomotion in the open field and
      emergence tests, but exhibited defecation responses similar to those of C mice in
      the novel object test and elevated zero maze. The results suggest that strain
      differences in spontaneous locomotion should be considered when interpreting
      strain differences in behavioral tests, and that home cage activity may be a
      useful interpretive aid.

PMID- 12429419
TI  - The effects of neonatal lesions in the amygdala or ventral hippocampus on social
      behaviour later in life.
AB  - Disruption of normal social behaviour is seen in psychiatric neurodevelopmental
      disorders like schizophrenia or autism. In a rat model of neurodevelopmental
      disorders we investigated the social behavioural changes after damage of limbic
      brain areas, at two early stages of life. The effects of ibotenic acid lesions
      made on day 7 or 21 of life in the amygdala (AM) ((baso)lateral/medical) or
      ventral hippocampal area on social play behaviour, social behaviour unrelated to
      social play behaviour early in life, and social behaviour in adulthood were
      assessed. Lesions of the AM, but not lesions of the ventral hippocampal area,
      resulted in decreased social play behaviour, and no differences were found
      between lesions made on day 7 or 21 of life. Social behaviour unrelated to social
      play behaviour early in life and in adulthood was decreased in animals lesioned
      in the AM on day 7 but not in animals lesioned on day 21 of life. This effect was
      particularly present in animals with an additional lesion in the medial nuclei of
      the AM. Lesions in the ventral hippocampal area did not affect social behaviour.
      It is concluded that the AM is an important structure for social play behaviour.
      The effects on social behaviour that are dependent on the day of lesioning (day 7
      vs. 21) are an indication of a neurodevelopmental deficit of structures connected
      to the (medial part) of the AM.

PMID- 12429420
TI  - The effects of chronic mild stress on male Sprague-Dawley and Long Evans rats: I.
      Biochemical and physiological analyses.
AB  - The chronic unpredictable mild stress (CMS) is a paradigm developed in animals to
      model the relatively minor and unanticipated irritants that lead to a state of
      anhedonia in some individuals. However, the effectiveness of CMS is sometimes
      difficult to establish, for which unique strain sensitivities has been attributed
      as one contributing factor. These considerations led us to design the present
      study, which was an investigation of the corticosterone response to CMS in two
      outbred rat strains--Sprague-Dawley and Long Evans. Animals were exposed to one
      of two conditions--control or CMS--for 3 weeks during which body weight and fecal
      count were regularly monitored. At the end of this period, blood was sampled at a
      variety of time intervals following induction of a brief restraint stressor.
      First, a significant effect of CMS on corticosterone levels was evident at time 0
      (prior to the application of the acute restraint stressor) in both strains.
      Second, the typical quadratic pattern of stressor-elicited fluctuations in this
      measure was similar in both Sprague-Dawley and Long Evans rats, with consistently
      elevated levels for the first hour following exposure to the acute stressor; near
      baseline values were observed at 2 h. However, only in the Long Evans strain were
      CMS related values much less than that observed in the control group after
      restraint stress. Third, both strains showed a reduced weight gain in the CMS
      groups relative to control groups. Fourth, spleen and adrenal weights were
      similar across all groups. Fifth, fecal counts remained stable across weeks of
      treatment in all groups with the exception of the Long Evans rats exposed to CMS;
      in this group, average counts were systematically reduced over the treatment
      period. We conclude that a history of chronic stress significantly blunts
      corticosterone levels in Long Evans but not Sprague-Dawley rats following
      exposure to an acute stressor. Physiological indices however are less influenced
      by this experience, at least when the exposure is limited to 3 weeks.

PMID- 12429421
TI  - The effect of aging on dynamic position sense at the ankle.
AB  - The present study addressed whether dynamic position sense at the ankle--or sense
      of position and velocity during movement--shows a similar decline as a result of
      aging as previously described for static position sense and movement detection
      threshold. Additionally, the involvement of muscle spindle afferents in the
      possible age-related decline was studied. To assess dynamic position sense,
      blindfolded subjects had to open the hand briskly when the right ankle was
      rotating passively through a prescribed target angle. To assess the involvement
      of muscle spindles, the effect of tibialis anterior vibration was studied. The
      results showed that aging lead to a significant increase in deviation from the
      target angle at hand opening as well as in variability of performance. Vibration
      resulted in larger undershoot errors in the elderly compared to the young adults,
      suggesting that the age-related decline in performance on the dynamic position
      sense task is not (solely) due to muscle spindle function changes. Alternatively,
      this degeneration might be due to altered input from other sources of
      proprioceptive input, such as skin receptors. The elderly subjects did show a
      beneficial effect of practice with the task, which may provide solid fundaments
      for rehabilitation.

PMID- 12429422
TI  - 2-Deoxyglucose uptake during vocalization in the squirrel monkey brain.
AB  - In the squirrel monkey (Saimiri sciureus), the cerebral 2-deoxyglucose uptake was
      compared between animals made to vocalize by electrical stimulation of the
      periaqueductal grey and animals stimulated in the same structure, but sub
      threshold for vocalization. A significantly higher 2-deoxyglucose uptake in the
      vocalizers than the non-vocalizers was found in the dorsolateral prefrontal
      cortex, supplementary and pre-supplementary motor area, anterior and posterior
      cingulate cortex, primary motor cortex, claustrum, centrum medianum, perifornical
      hypothalamus, periaqueductal grey, intercollicular region, dorsal mesencephalic
      reticular formation, peripeduncular nucleus, substantia nigra, nucl. ruber,
      paralemniscal area, trigeminal motor, principal and spinal nuclei, solitary tract
      nucleus, nucl. ambiguus, nucl. retroambiguus, nucl. hypoglossus, ventral raphe
      and large parts of the medullary reticular formation. The study makes clear that
      vocalization, even in the case of genetically pre-programmed patterns, depends
      upon an extensive network, beyond the well-known periaqueductal grey, nucl.
      retroambiguus and cranial motor nuclei pathway.

PMID- 12429424
TI  - A competitive enzyme-linked immunosorbent assay for diminazene.
AB  - Diminazene aceturate has remained a very important therapeutic drug for
      trypanosomosis in cattle, sheep and goats since its introduction into the market
      in 1955. Despite its continued use, the methods available for its detection in
      body fluids are lengthy and inefficient for routine monitoring of drug levels in
      treated animals. A competitive enzyme linked immunosorbent assay (ELISA) has now
      been developed and optimized for the detection of diminazene in bovine serum. In
      the assay, diminazene in the test samples and that in a newly developed
      diminazene-horseradish peroxidase conjugate compete for antibodies to diminazene
      raised in rabbits and immobilized on a microtitre plate. Tetramethylbenzidine
      hydrogen peroxide (TMB/H(2)O(2)) is used as chromogen-substrate system. The assay
      has a detection limit of 0.8 ng/ml of serum with a high specificity for
      diminazene. Cross-reactivity with either homidium bromide and quinapyramine
      sulphate/chloride of 0.0004% is negligible while that with isometamidium chloride
      is 0.71%. The assay was able to detect diminazene levels in normal Boran steers
      for at least two weeks after intramuscular injection with the drug at a dose of
      3.5 mg/kg bw. The assay will be useful in monitoring diminazene use, and
      development of resistance in trypanosomosis endemic areas.

PMID- 12429425
TI  - Diversity of Plasmodium falciparum clones infecting children living in a
      holoendemic area in north-eastern Tanzania.
AB  - The diversity of Plasmodium falciparum clones and their role in progression from
      asymptomatic to symptomatic condition in children have been investigated.
      Attempts to identify whether particular parasite genotypes were associated with
      the development of clinical symptoms have been made. A cohort of 34 initially
      asymptomatic parasitaemic children aged 1-5 years were followed daily for 31
      days. Clinical examinations were made each day for signs and symptoms of clinical
      malaria, followed by parasitological investigation. Nineteen children developed
      symptoms suggestive of clinical malaria during this period. Daily blood parasite
      samples from 13 children who developed clinical malaria symptoms and 7 who
      remained asymptomatic were genotyped by PCR-amplification of the polymorphic
      regions of the merozoite surface proteins 1 and 2 (MSP1 and MSP2) and the
      glutamate rich protein (GLURP) genes. Infections were found to be highly complex
      in both groups of children. Every isolate examined from both groups had a mixture
      of parasite clones. Daily changes were observed in both parasite density and
      genotypic pattern. The mean number of genotypes per individual was estimated at
      4.9 and 2.7 for asymptomatic and symptomatic groups of children, respectively.
      Analysis of allele frequency distributions showed that these differed
      significantly for the MSP1 locus only.

PMID- 12429426
TI  - Strategic use of moxidectin or closantel in combination with levamisole in the
      control of nematodes of sheep in the highlands of central Kenya.
AB  - The strategic use of moxidectin or closantel in combination with levamisole (LEV)
      to control gastrointestinal nematodes of sheep in the highlands of central Kenya
      was examined. Thirty Corriedale female lambs aged between 6 and 8 months were
      assigned to three treatment groups of ten lambs each. The three groups of lambs
      were set stocked on separate paddocks for the entire study period of 12 months.
      Lambs in Group 1 were dewormed strategically with moxidectin at 0.2 mg/kg body
      weight and those in Group 2 with closantel at 10 mg/kg body weight together with
      LEV at 7.5 mg/kg body weight. These strategic treatments were given 3 weeks after
      the onset of both the short and long rains and at the end of the long rainy
      season. The third group of lambs remained untreated (control group). Nematode
      infections in the treated groups of lambs and larval infectivity for the pastures
      on which the lambs were grazing were well controlled compared with the untreated
      control group. This resulted in higher weight gains and packed cell volume (PCV)
      in the treated lambs compared with the untreated lambs. These parameters were
      comparable between the lambs treated with moxidectin and those treated with
      closantel plus LEV. The estimated monitory benefit per animal from the control of
      gastrointestinal nematodes using moxidectin or closantel in combination with LEV
      when compared with animals in the control group were US dollars 26 and 25,
      respectively. It was concluded that worm control strategies for sheep in the
      study area, which are based on anthelmintic treatments during the rainy seasons,
      are effective. Due to the extended period during which pastures remain infective
      in the high rainfall central highlands of Kenya, anthelmintics with sustained
      action such as moxidectin or closantel may be most effective. On farms where
      resistance to the commonly used benzimidazoles or LEV groups of anthelmintics has
      developed, moxidectin or closantel may be used in helminth control programs for
      sheep.

PMID- 12429427
TI  - Effects of partial housing improvement and insecticide spraying on the
      reinfestation dynamics of Triatoma infestans in rural northwestern Argentina.
AB  - The long-term effects on domiciliary reinfestation by Triatoma infestans of
      smoothing the plaster of indoor walls prior to insecticide application (in Amama
      village) relative to only insecticide application (in Trinidad-Mercedes villages)
      were evaluated in rural northwestern Argentina from 1992 to 1997. All domestic
      and peridomestic areas of each house were sprayed with 2.5% suspension
      concentrate deltamethrin at 25 mg/m(2) in October 1992, and infestations were
      assessed by various methods every 6 months. Domiciliary infestation decreased
      from 72-88% in 1992 to 6-17% in late 1995, to increase moderately thereafter
      without returning to baseline rates. Peridomestic sites were the first in
      becoming reinfested, and reached more abundant T. infestans populations than
      domiciliary areas. Domiciliary infestation rates and bug abundances were not
      significantly different between communities during surveillance. Domiciliary
      infestation rates in well-plastered houses were very low (5-9%) and approximately
      stable until 1996, but in houses with regular or bad plaster they consistently
      increased from 5 to 19-21% in both communities. Logistic multiple regression
      analysis showed that the likelihood of domestic infestation assessed through
      householders' collections was significantly and positively associated with the
      occurrence of an infested peridomestic site in the respective house, the
      occurrence of high-density domestic infestations before interventions, and well
      plastered walls in 1996. Combining insecticide spraying and partial improvement
      of walls controlled domestic infestations and transmission of Trypanosoma cruzi
      effectively, but was not sufficient to eliminate T. infestans from the study area
      or increase the effectiveness of careful chemical control.

PMID- 12429428
TI  - Serum hyaluronic acid as a comprehensive marker to assess severity of liver
      disease in schistosomiasis.
AB  - Schistosomiasis mansoni is a non-cirrhotic fibrogenic disease model. The mild
      form shows normal liver function with slight or no liver fibrosis whereas in the
      periportal fibrosis form the manifestations of portal hypertension prevail over
      hepatocellular failure. We assessed serum hyaluronic acid as a marker of the
      course of the disease. We studied 24 patients presenting with pure chronic forms
      of schistosomiasis and seven with cirrhosis. In order to measure serum hyaluronic
      acid we developed a sandwich fluorescent ELISA-like assay. alpha2-Macroglobulin,
      prothrombin index, gamma-glutamyltransferase, platelets and ultrasound parameters
      were also assessed. The 20 micro g/l (ROC plot) hyaluronic acid level
      differentiated patients with the mild form (with no portal hypertension) from
      those with the severe form of schistosomiasis with 78% diagnostic efficacy. The
      80 micro g/l cut-off value differentiated patients with the severe form of
      schistosomiasis from the cirrhotic group with similar diagnostic efficacy. alpha2
      Macroglobulin provided no distinction between the groups studied. The hyaluronic
      acid serum concentration correlated positively with the splenic vein diameter
      (P=0.004) and marginally with alpha2-macroglobulin (P=0.059). Serum hyaluronic
      acid is a good marker for the initial phase of hepatic fibrosis and it was able
      to assess severity of liver disease in schistosomiasis.

PMID- 12429429
TI  - Immune correlate study on human Schistosoma japonicum in a well-defined
      population in Leyte, Philippines: I. Assessment of 'resistance' versus
      'susceptibility' to S. japonicum infection.
AB  - This study describes the categorical classification of 155 individuals living in
      an endemic village in Macanip, Leyte, Philippines as 'resistant' or 'susceptible'
      to Schistosoma japonicum infection using available exposure, infection and
      reinfection data collected from a 3-year water contact (WC) study.
      Epidemiological parameters including age, sex, and infection intensities in
      relation to observed reinfection patterns are also described. This classification
      was used in subsequent immunological studies described in two accompanying papers
      to identify protective immune mechanisms among resistant individuals induced by
      defined candidate vaccine molecules for S. japonicum. The study suggests that
      individuals who were most vulnerable to rapid reinfection were children belonging
      to the 5-14 age group. A drop in incidence at age group 15-19 and decreased
      intensity of infection starting at this age group and older (15+) suggests
      development of immunity. Controlling for the effect of the other variables, a
      multivariate analysis showed significant association for sex, in that females
      were more likely to be resistant. This implies that other than acquired immunity
      to infection, some age-dependent host factors may also play an important role in
      the overall changes of reinfection patterns seen in schistosomiasis japonica in
      this population.

PMID- 12429430
TI  - Immune correlate study on human Schistosoma japonicum in a well-defined
      population in Leyte, Philippines: II. Cellular immune responses to S. japonicum
      recombinant and native antigens.
AB  - Cellular immune responses to specific Schistosoma japonicum recombinant and
      native antigens were investigated in a defined study population of 155
      individuals in the Philippines, where data collected from a 3-year observation of
      exposure, infection and reinfection pattern were used to categorically classify
      putative 'resistant' and 'susceptible' individuals. Using peripheral blood
      mononuclear cells (PBMC) of individuals enrolled in the study, in vitro
      lymphocyte proliferation and cytokine (IFN-gamma, IL-5 and IL-10) production in
      response to defined recombinant antigens (97 kDa paramyosin, 22 kDa tegumental
      antigen, 37 kDa glyceraldehyde-3-phosphate dehydrogenase, 14 kDa fatty acid
      binding protein and 28 kDa gluthathione-S-tranferase) and native antigen soluble
      worm antigen preparation (SWAP) were measured. Cellular responses to the
      recombinant and SWAP antigens suggest that Th1 type of response appear to be
      important in predicting resistance in this population. Of the five recombinant
      antigens tested, rPMY induced significant levels of IFN-gamma. The production of
      IL-10, a Th2-type cytokine was strongly implicated in immune regulation. Of
      importance was the evidence found for SWAP and rPMY induced IFN-gamma responses
      in predicting 'resistance'. It was noted that these associations were significant
      even after the effect of age and sex were accounted for in a multivariate
      analysis.

PMID- 12429431
TI  - Use of the Plasmodium vivax merozoite surface protein 1 gene sequence analysis in
      the investigation of an introduced malaria case in Italy.
AB  - Malaria due to Plasmodium vivax is globally widespread and is associated with
      substantial morbidity. The parasite was previously prevalent in temperate areas
      from which it has been eradicated, however there is a risk of re-introduction
      because of increased international travel and migration. Following the occurrence
      of an autochthonous case of P. vivax malaria in Italy after decades of malaria
      eradication, we applied a molecular approach to compare parasites involved in the
      introduced case and to determine whether a highly polymorphic gene marker could
      be useful to tag a P. vivax isolate geographically. To this end, the sequence
      encompassing the interspecies conserved blocks 5 and 6 of the gene encoding for
      merozoite surface protein 1 (msp-1) was determined in 16 P. vivax isolates from
      different regions, and analysed along with 24 pvmsp-1 sequences downloaded from
      published data. Results have shown that: (i). parasites from the introduced case
      and the putative source of infection identified following epidemiological
      investigation, although very similar, differed in three nucleotide substitutions,
      of which one non synonymous; ii). some geographical isolates looked tightly
      clustered (e.g. Korean and Punjab isolates), but others were less so.

PMID- 12429432
TI  - International conference on 'the role of health professionals in addressing
      violence against women': an overview.

PMID- 12429433
TI  - A global overview of gender-based violence.
AB  - This paper provides an overview of the extent and nature of gender-based violence
      and its health consequences, particularly on sexual and reproductive health.

PMID- 12429434
TI  - Overview of international human rights standards and other agreements and
      responses of the judicial system to violence against women.
AB  - This paper describes how violence against women has become part of the United
      Nations agenda. It focuses on violence as a human rights issue, analyzing the
      mechanisms and agreements relevant to addressing it. It also looks at
      implementation at a national level, focusing on national legislation and
      responses of the judicial system.

PMID- 12429435
TI  - Violence against women and Brazilian health care policies: a proposal for
      integrated care in primary care services.
AB  - Describes a counseling and support intervention in primary health care which is
      being piloted in a health center in Sao Paulo, Brazil. This proposal integrates
      sexual and domestic violence assistance and hospital and primary care, providing
      comprehensive care and intersectorial response for women.

PMID- 12429436
TI  - Establishing a one-stop crisis center for women suffering violence in Khonkaen
      hospital, Thailand.
AB  - This paper discusses the experiences of the Khonkaen provincial hospital, which
      has been selected as an intervention case site for a one-stop crisis service for
      women who have been physically or sexually assaulted. It will be compared with
      another provincial hospital where no intervention has taken place.

PMID- 12429437
TI  - Treatment guidelines for healthcare providers' interventions with domestic
      violence victims: experience from the USA.
AB  - In this article, the author shares her own personal experience with the health
      sector and the recommendations made in the United States for universal screening
      for violence of women in the health sector. Healthcare providers can greatly
      assist patients impacted by domestic violence by implementing the interventions
      recommended.

PMID- 12429438
TI  - The Woman Friendly Hospital Initiative in Bangladesh setting: standards for the
      care of women subject to violence.
AB  - The Woman Friendly Hospital Initiative is part of the overall strategy aimed at
      overcoming a situation of high maternal mortality in Bangladesh. It has evolved
      from the reality of 14% of maternal deaths being associated with violence. A key
      of the initiative is the management of violence against women. Training courses
      for doctors developed through a process of multi-sectoral consultation. The focus
      is on effecting a change in the perceptions, emotions, attitude, knowledge and
      skills of providers and nurturing leadership.

PMID- 12429439
TI  - Vezimfilho: a model for health sector response to gender violence in South
      Africa.
AB  - Vezimfilho, a model program for the training of health care workers was
      developed, implemented and evaluated in close collaboration with government and
      non-government partners in South Africa. It was implemented and evaluated in two
      districts in the Eastern Cape and Western Cape provinces, respectively. This
      initiative represents one of the first attempts to build capacity in the health
      sector to address gender-based violence and has been a leading example of how to
      address within the South African context. Outputs have been the development of a
      model for the health sector response to gender violence, a training package
      Vezimfilho! and a partnership with the Department of Health to address the
      sustained integration of capacity building in this area.

PMID- 12429440
TI  - Integrating systematic screening for gender-based violence into sexual and
      reproductive health services: results of a baseline study by the International
      Planned Parenthood Federation, Western Hemisphere Region.
AB  - Three Latin American affiliates of the International Planned Parenthood
      Federation, Western Hemisphere Region, Inc. (IPPF/WHR) have begun to integrate
      gender-based violence screening and services into sexual and reproductive health
      programs. This paper presents results of a baseline study conducted in the
      affiliates. Although most staff support integration and many had already begun to
      address violence in their work, additional sensitization and training, as well as
      institution-wide changes are needed to provide services effectively and to
      address needs of women experiencing violence.

PMID- 12429441
TI  - Women's crisis centers and shelters in Italy: working with battered women and
      with health care providers.
AB  - Results of working with battered women stress the necessity to develop practical
      innovations and create a supportive non-judgmental environment for female victims
      of violence.

PMID- 12429442
TI  - Sexual violence against women. The role of gynecology and obstetrics societies in
      Brazil.
AB  - Sexual violence is highly prevalent although barely visible in most countries.
      While its prevention is a task of the whole society, the care of the women who
      suffer sexual violence, from immediate assistance to treatment of its
      consequences, is a responsibility of obstetricians-gynecologists. One of the most
      severe consequences of rape is unwanted pregnancy, which frequently ends in
      abortion. Currently, even in countries where abortion following rape is accepted
      by the law, raped women do not have access to legal abortion. The role of
      obstetricians-gynecologists in solving this problem is described, giving as an
      example the work of the Brazilian Federation of Gynecology and Obstetrics
      Societies (FEBRASGO). After 5 years of work of a special FEBRASGO Committee,
      services for the comprehensive care of women victims of sexual violence exist in
      all mayor cities in Brazil and are rapidly expanding.

PMID- 12429443
TI  - The American College of Obstetricians and Gynecologists: responding to violence
      against women.
AB  - Domestic violence is a significant social and public health problem that
      disproportionately affects women and girls and often results in injury, chronic
      health problems, and death. Obstetrician-gynecologists are in a unique position
      to identify such patients and to provide intervention. The American College of
      Obstetricians and Gynecologists (ACOG) has responded to this problem and
      encouraged its members to act. ACOG activities reflect the mission of the
      organization and can serve as a template for like societies.

PMID- 12429444
TI  - The American College of Nurse-Midwives Domestic Violence Education Project
      (DVEP).
AB  - OBJECTIVE: The American College of Nurse-Midwives implemented a 4-year Domestic
      Violence Education Project (DVEP) with the goal of educating all midwives in the
      USA to respond appropriately to abuse experienced by the women they serve.
      METHOD: A four-pronged set of objectives was used that included policy, basic
      preservice education, continuing education and activism/advocacy. RESULT: The
      success of this project is the sustainable impact on education of student
      midwives and a continued commitment to this issue. CONCLUSION: The full impact of
      the DVEP on practicing midwives may not be measurable for some time.

PMID- 12429445
TI  - Consequences and outcomes of disclosure for abused women.
AB  - Over the past 30 years feminists and women's organizations, in Ireland and
      globally, have drawn increased attention to the reality of violence against women
      through the provision of services, lobbying, training and research. Intervention
      from untransformed institutions even with the best will of committed individuals,
      must be controlled by the woman herself at every stage of the process.

PMID- 12429446
TI  - Collecting evidence for sexual assault: the role of the sexual assault nurse
      examiner (SANE).
AB  - The development of SANE programs stemmed from healthcare providers and others
      working with rape victims noting that there were inadequate services for rape
      victims. Often the standard of care was lower for rape victims than for other
      patients in the emergency department. In order to better meet the complex needs
      of rape victims healthcare professionals, advocates and others realized the need
      to establish a system that would provide complete, comprehensive, and appropriate
      care.

PMID- 12429447
TI  - Forensic medical expertise in the event of sexual and physical violence in
      Russia.
AB  - Scientific investigation has made it possible to gather new evidence of sexual
      violence in a form acceptable in forensic practice, thereby helping prosecuting
      crimes of violence. Among the new techniques we can include: colposcopy, which
      allows a detailed view of a ruptured hymen as well as an evaluation of the degree
      of hyperemia of the vaginal vestibule as consequence of recent penetration by the
      penis or other objects; the morphology and dynamics of spermatozoa collected from
      the vagina, as well as from the cervical canal, which allows a careful
      determination of their viability and mobility.

PMID- 12429448
TI  - Collecting evidence for domestic and sexual assault: highlighting violence
      against women in health care system interventions.
AB  - Understanding the social and cultural context in which violence against women
      (VAW) happens is essential to develop the social responses to tackle this problem
      and to understand how society can diminish the effects and incidence of these
      crimes. Medical intervention is but one part of the solution.

PMID- 12429449
TI  - Forensic evidence collection for sexual assault: a South African perspective.
AB  - The incidence of rape in South Africa is approximately 300 per 100,000 women,
      with a conviction rate of approximately 10% of cases. Poor medical evidence is
      responsible in part for the low conviction rate. The district surgeon system that
      was responsible for medico-legal procedures and examinations is being phased out
      which has left the examination of sexual offences to all state employed medical
      practitioners. Lack of training and expertise make the present system untenable.
      There are several proposals being considered and implemented in the Western Cape
      Province to address this deficiency, which include the formation of 'one-stop
      centers', training, and complete evidence collection kits.

PMID- 12429450
TI  - 'A practical approach to gender-based violence: a programme guide for health care
      providers and managers' developed by the UN Population Fund.
AB  - Gender-based violence (GBV) is a worldwide problem that can have serious physical
      and psychological consequences. Women need to be assessed for GBV and a logical
      place to do so would be where women go for health care, reproductive health
      facilities. The United Nations Population Fund (UNFPA) has developed 'A Practical
      Approach to Gender-Based Violence: A Program Guide for Health Care Providers and
      Managers' to assist reproductive health facilities in integrating GBV into their
      programs. This article briefly describes the project options and the steps that
      need to be taken in order to implement such projects.

PMID- 12429451
TI  - Violence against women: what is the World Health Organization doing?
AB  - The paper summarizes the activities of the WHO in response to violence against
      women. These focus on research and development of norms and standards.

PMID- 12429452
TI  - Violence against women--what are ICM and its member associations doing about it?
AB  - Midwives are in a key position to address issues surrounding violence against
      women (VAW). The International Confederation of Midwives is committed to keeping
      VAW on the world's health agenda and make sure all the issues receive the
      necessary attention.

PMID- 12429453
TI  - The role of FIGO in addressing violence against women.
AB  - FIGO's priority is to address the barriers of clinicians to respond to violence
      against women through the use of advocacy, training and services.

PMID- 12429454
TI  - Recommendations and conclusions from the International Conference on the Role of
      Health Professionals in Addressing Violence against Women. Naples, October 2000.

PMID- 12429455
TI  - Acetazolamide: future perspective in topical glaucoma therapeutics.
AB  - Through this review it is contemplated that acetazolamide (ACZ), an age-old
      treatment for glaucoma with a myriad of side effects and inadequate topical
      effectiveness, may be formulated into a topically effective agent by utilizing
      various newer formulation approaches of ocular drug delivery. Even though it has
      a poor solubility and penetration power, various studies mentioned in the review
      indicate that it is possible to successfully formulate topically effective ACZ by
      using: (i) high concentration of the drug, (ii) surfactant gel preparations of
      ACZ, (iii) ACZ loaded into liposomes, (iv) cyclodextrins to increase the
      solubility and hence bioavailability of ACZ, and (v) viscolyzers and other
      polymers either alone or in combination with cyclodextrins. With the advent of
      newer topical carbonic anhydrase inhibitors (CAIs) like dorzolamide and
      brinzolamide, a localized effect with fewer side effects is expected. But
      whenever absorbed systemically, a similar range of adverse effects (attributable
      to sulphonamides) may occur upon use. Furthermore, oral ACZ is reported to be
      more physiologically effective than 2% dorzolamide hydrochloride administered
      topically, even though in isolated tissues dorzolamide appears to be the most
      active as it shows the lowest IC(50) values for CA-II and CA-IV [M.F. Surgue, J.
      Ocular Pharmacol. Ther. 12 (1996) 363-376]. Hence, there exists considerable
      scope for the development of more/equally effective and inexpensive topically
      effective formulations of ACZ. The use of various formulation technologies
      discussed in this review can provide a fresh impetus to research in this area.

PMID- 12429456
TI  - Recent advances in the brain-to-blood efflux transport across the blood-brain
      barrier.
AB  - Elucidating the details of the blood-brain barrier (BBB) transport mechanism is a
      very important step towards successful drug targeting to the brain and
      understanding what happens in the brain. Although several brain uptake methods
      have been developed to characterize transport at the BBB, these are mainly useful
      for investigating influx transport across the BBB. In 1992, P-glycoprotein was
      found to act as an efflux pump for anti-cancer drugs at the BBB using primary
      cultured bovine brain endothelial cells. In order to determine the direct efflux
      transport from the brain to the circulating blood of exogenous compounds in vivo,
      the Brain Efflux Index method was developed to characterize several BBB efflux
      transport systems. Recently, we have established conditionally immortalized rat
      (TR-BBB) and mouse (TM-BBB) brain capillary endothelial cell lines from
      transgenic rats and mice harboring temperature-sensitive simian virus 40 large T
      antigen gene to characterize the transport mechanisms at the BBB in vitro. TR-BBB
      and TM-BBB cells possess certain in vivo transport functions and express mRNAs
      for the BBB. Using a combination of newly developed in vivo and in vitro methods,
      we have elucidated the efflux transport mechanism at the BBB for neurosteroids,
      excitatory neurotransmitters, suppressive neurotransmitters, amino acids, and
      other organic anions to understand the physiological role played by the BBB as a
      detoxifying organ for the brain.

PMID- 12429457
TI  - Controlled delivery of metoclopramide using an injectable semi-solid poly(ortho
      ester) for veterinary application.
AB  - In animal health care, current therapeutic regimens for gastrointestinal
      disorders require repeated oral or parenteral dosage forms of anti-emetic agents.
      However, fluctuations of plasma concentrations produce severe side effects. The
      aim of this work is to develop a subcutaneous and biodegradable controlled
      release system containing metoclopramide (MTC). Semi-solid poly(ortho ester)s
      (POE) prepared by a transesterification reaction between trimethyl orthoacetate
      and 1,2,6,-hexanetriol were investigated as injectable bioerodible polymers for
      the controlled release of MTC. MTC is present in the polymeric matrix as a
      solubilised form and it is released rapidly from the POE by erosion and diffusion
      because of its acidic character and its high hydrosolubility. If a manual
      injection is desired, only low molecular weight can be used. However, low
      molecular weight POEs release the drug rapidly. In order to extend polymer
      lifetime and decrease drug release rate, a sparingly water-soluble base Mg(OH)(2)
      was incorporated to the formulation. It was possible to produce low molecular
      weight POE that can be manually injected and releasing MTC over a period of
      several days.

PMID- 12429458
TI  - Deagglomeration of dry powder pharmaceutical aerosols.
AB  - The effect of turbulence and mechanical impaction on dry powder aerosol
      deaggregation was tested using a novel powder deagglomeration rig, with fine
      particle fraction (FPF(ED<5.6 microm)), defined here as particles sized smaller
      than 5.6 microm, measured using an Anderson inertial impactor. Powder from
      GlaxoSmithKline Ventodisks was deaggregated either using turbulence generated
      with a ring of impinging jets, or by impacting the powder on bars of a wire mesh.
      This deaggregation was compared with deaggregation achieved with the
      GlaxoSmithKline Diskhaler. The turbulence levels in the test rig and at the exit
      of the Diskhaler were quantified using laser Doppler velocimetry (LDV). In
      addition, the Ventodisk powder's auto-adhesion properties were altered by
      introducing the powder into a high humidity environment (25 degrees C and 25%
      R.H.) and then deagglomerated by both the rig (using turbulence as the primary
      deagglomeration mechanism) and the Diskhaler. Fine particle fractions were found
      to increase from 13 to 24% as the level of turbulence in the rig was increased.
      However, fine particle fractions found with the Diskhaler were 35%. Turbulence
      levels found in the rig at the highest jet flow rate were significantly higher
      than that at the outlet of the Diskhaler, leading to the conclusion that
      turbulence is not the only method of deaggregation in this inhaler. The
      humidified powders were significantly more difficult to deaggregate, giving a
      FPF(ED<5.6 microm) of 9% when using the rig and 15% when using the Diskhaler.
      Fine particle fractions produced when deagglomerating the powder with the wire
      meshes were similar to those produced without a mesh, showing that mechanical
      impaction had little effect. The results underline the utility of having a rig
      that can explore the ability of a powder to deagglomerate with controlled
      variations in the deaggregation forces.

PMID- 12429459
TI  - Evaluation and simultaneous optimization of some pellets characteristics using a
      3(3) factorial design and the desirability function.
AB  - A 3(3) full factorial design study has been employed in order to investigate the
      effect of three variables on size, size distribution and three shape parameters,
      namely roundness, elongation and e(R), of pellets prepared in a fluid bed rotor
      granulator with the wet granulation technique. The first variable was a
      formulation variable, the % w/w content of microcrystalline cellulose (MCC) and
      the other two variables were processing variables, the temperature of inlet air
      and the spray rate of the granulation liquid. The analysis of variance showed
      that the three variables had a significant effect (P<0.05) on pellet size and the
      shape factors, while only the spray rate influenced the particle size
      distribution. Significant interactions between the factors, for the size and the
      shape, were also found. The multiple regression analysis of the results led to
      equations that adequately describe the influence of the independent variables on
      the selected responses. Furthermore, the desirability function was employed in
      order to optimize the process under study. It was found that the optimum values
      of the responses could be obtained at the low levels of the % w/w content of MCC
      and temperature of inlet air and at the high level of the spray rate.

PMID- 12429460
TI  - The effect of ileal brake activators on the oral bioavailability of atenolol in
      man.
AB  - A study was carried out in human volunteers to investigate whether ileal brake
      activators could alter the bioavailability of atenolol from the small intestine
      by slowing intestinal transit and thereby increasing the time available for
      absorption. Oleic acid and a monoglyceride were formulated into modified release
      capsules that were targeted to the small intestine. Atenolol was either dosed
      separately or incorporated into one of the capsules. Radiolabelled non
      disintegrating tablets were dosed at the same time in order to determine the
      small intestinal transit time (SITT). Plasma concentrations of atenolol were
      determined by HPLC. The results showed that in some volunteers an increase in
      SITT did lead to an increase in the quantity of drug absorbed. However, drug
      absorption was related not only to the total time spent by the drug in the small
      intestine but other factors such as the proportion of such time spent at the
      ileocaecal junction. The study highlights the complexities of exploiting natural
      gastrointestinal processes to enhance the oral bioavailability of drugs.

PMID- 12429461
TI  - Physical property of troglitazone, an equal mixture of four stereoisomers.
AB  - Troglitazone, an oral antidiabetic agent, is an equal mixture of four
      stereoisomers involving two chiral centers. In the present study, the physical
      property of troglitazone were investigated. The solid state of troglitazone drug
      substance is characterized as a simple physical mixture of two diastereomers, as
      shown by the two endothermic peaks caused by the melting of the RR/SS and the
      RS/SR forms by differential scanning calorimetry (DSC). In addition, the powder X
      ray diffraction pattern includes peaks resulting from both the RR/SS and the
      RS/SR forms. The water adsorption of troglitazone drug substance is due to the
      presence of the RR/SS diastereomer, which adsorbs water as a monohydrate. The
      solubility of troglitazone and the diastereomers were increased and the
      solubility ratios of the stereoisomers were changed by quenching. Troglitazone
      was proved to be stable against heat and humidity by the ratio of the
      stereoisomers and from the solid state form indicated by the DSC results.

PMID- 12429462
TI  - Faster determination of membrane permeabilities without using the lag time
      method.
AB  - A new method of data analysis is presented that allows the determination of
      membrane permeabilities. The method is applicable to data obtained from a common
      experimental setup, in which drug dissolved in an inert donor gel diffuses
      through a membrane, initially void of drug, into a receiver for which sink
      conditions are maintained. The equations developed can also be used to predict
      the release of drug from these systems. Fick's Laws are solved, and the early
      time behavior of the mathematical solution is used to develop the analysis
      methods. Limitations of the model and their relations to experimental design are
      determined, and the method of application to experimental data is presented. The
      method is tested numerically using simulated data generated by a 1-d finite
      difference program that was used to numerically solve Fick's Laws, and also
      applied to in vitro human cadaver skin transdermal data for the drugs doxepin,
      imipramine and amitriptyline. It is concluded that this method can be applied to
      determine membrane permeabilities and diffusion coefficients with accuracy
      comparable to other experimental setups, such as lag time experiments and steady
      state experiments, but requiring experiments that can be significantly shorter.

PMID- 12429463
TI  - Preparation of novel double liposomes using the glass-filter method.
AB  - The glass-filter method, a newly developed preparative method for liposomes, was
      applied for preparation of novel double liposomes. Double liposomes were prepared
      by filtering a suspension of liposomes prepared using a G4 filter (pore size: 10
      16 microm) into a G3 filter (pore size: 40-100 microm) coated with a similar
      lipid layer. The morphological structure of the double liposomes was confirmed
      using scanning electron microscopy by the freeze-fracture method to be
      multivesicular vesicles consisting of small liposomes enveloped in larger
      liposomes. The diameter of liposomes prepared using the G4 filter was 0.8-2
      microm and that of liposomes prepared using the G3 filter or double liposomes was
      5-10 microm. These results suggested that the particle size of liposomes is
      dependent on the pore size of the glass-filter. The encapsulation efficiencies of
      double liposomes for brilliant blue FCF (BB) and erythrosine (ER) were higher
      than those of liposomes prepared by the standard Bangham method. Double liposomes
      showed suppressed release of BB or ER compared with normal liposomes. In
      particular, no release of BB was observed from the double liposomes prepared with
      stearylamine. These findings implied that the outer lipid layer protects the
      inner liposomes. The glass-filter method is the only method that we can get the
      double liposomes in a short period, and double liposomes prepared by this novel
      method had adequate size and good stability in vitro.

PMID- 12429464
TI  - Tabletting of pellet-matrix systems: ability of parameters from dynamic and
      kinetic models to elucidate the densification of matrix formers and of pellets.
AB  - Two different types of pellets, i.e. drug-free sugar spheres, and pellets, spray
      layered with crystalline theophylline and coated with Eudragit RS/RL, were
      tabletted each in combination with matrix-forming powder mixtures of Avicel PH200
      and PEG 4000. The die fills from pellets and powder mixtures were regarded as two
      compartment systems with a volume fraction of the pellets being limited to 0.52
      corresponding to a cubic lattice, and the maximum degrees of densifications were
      adjusted related to the matrix. To data measured during single compression cycles
      on an instrumented eccentric tabletting machine and transformed appropriately,
      the Kawakita equation, the Heckel function, and a modified Weibull function were
      fitted, and the total work of compression was calculated. The Kawakita model
      fitted well systems with both types of pellets. Its parameters reflected the
      additional densification of the theophylline pellets separately from that of the
      matrix formers. The Heckel function could only be applied to systems containing
      non-porous sugar spheres, since the theophylline pellets underwent considerable
      densification and deformation. Only, when the Heckel porosity function was
      related to the volume fraction of the matrix, excluding the sugar spheres, the
      approximately linear regions for mixtures with increasing volume proportions of
      sugar spheres occured in comparable regions of densification. Parameters of the
      modified Weibull function demonstrated an increasing resistance against
      densification with increasing amounts of pellets. The total work of compression
      increased steeply with increasing volume fractions for pellets from 0.42 to 0.46
      indicating, that the resistance against densification already rose when the
      pellets were still isolated. In conclusion, the combination of dynamic and
      kinetic models provides a comprehensible insight into the process of tabletting
      powder mixtures with pellets. Particularly, the Kawakita model was a suitable
      tool to differentiate the actual changes in porosity during compression from the
      compressibility of such complex systems.

PMID- 12429465
TI  - Effect of chitosan on in vitro release and ocular delivery of ofloxacin from
      erodible inserts based on poly(ethylene oxide).
AB  - The effects of chitosan hydrochloride (CH-HCl) on in vitro release of ofloxacin
      (OFX) from mucoadhesive erodible ocular inserts and on the relevant ocular
      pharmacokinetics have been studied both to contribute evidence of the ability of
      CH-HCl to enhance transcorneal penetration of drugs and to increase the
      therapeutic efficacy of topically applied OFX. Circular inserts of 6 mm in
      diameter, 0.8-0.9 mm in thickness and 20 mg in weight, medicated with 0.3 mg
      drug, were prepared by powder compression. The addition of 10, 20 or 30%
      medicated CH-HCl microparticles, obtained by spray-drying, to formulations based
      on poly(ethylene oxide) of MW 900 kDa (PEO 900) or 2000 kDa (PEO 2000) produced
      changes in the insert microstructure which accelerated both insert erosion and
      OFX release from inserts. The effect was stronger with higher CH-HCl fractions.
      Of the CH-HCl-containing formulations based on either PEO 900 or PEO 2000, PEO
      900-CH-HCl (9:1 w/w) was more suitable for a prolonged OFX release. Following
      insertion in the lower conjunctival sac of the rabbit's eye, such an insert
      produced no substantial increase of AUC(eff) (AUC in the aqueous humour for
      concentrations >MIC(90%)) with respect to inserts based on plain PEO; however, it
      produced a concentration peak in the aqueous significantly higher than that
      produced by any of the CH-HCl-free PEO inserts, and well higher than the MIC(90%)
      for the more resistant ocular pathogens (7 microg/ml vs. 4 microg/ml). It has
      been argued that the increase was due to the ability of CH-HCl to enhance the
      transcorneal permeability of the drug.

PMID- 12429466
TI  - Prediction of apparent equilibrium solubility of indomethacin compounded with
      silica by 13C solid state NMR.
AB  - The apparent equilibrium solubility (AES) of indomethacin increased by co
      grinding with silica. Change in the long- and short range disorder of
      indomethacin by co-grinding was examined by X-ray powder diffraction and 13C
      solid state NMR, respectively, to elucidate the increased AES. Since the increase
      in AES was particularly marked after complete disappearance of X-ray diffraction
      peaks, we attributed the enhanced AES primarily to the short range disorder on
      the molecular basis. This was confirmed by a high correlation between the
      standardized full width at half maximum (SFWHM) of the specific peaks observed by
      13C solid state NMR and log (AES). The correlation enables the prediction of AES
      as well.

PMID- 12429467
TI  - Influence of food and diabetes on pharmacokinetics of sodium tungstate in rat.
AB  - In this paper, the influence of food and diabetes on the pharmacokinetics of
      sodium tungstate in rat was investigated. The compound was administered
      intravenously (9 mg/kg) and orally in the form of solution (36 mg/kg). An
      empirical Bayes methodology was used to compute individual pharmacokinetic
      parameters. Sodium tungstate followed first-order kinetics, and plasma
      concentration versus time data were described by a two-compartment model. A
      significant relationship was found between the bioavailability and the status of
      the animals. Total plasma clearance and elimination half-life averaged 3.1
      ml/min/kg and 1.6 h, respectively. Food had some effects on the extent of sodium
      tungstate absorption. After oral administration, the bioavailability (0.67 versus
      0.85), C(max) (6.10 versus 15.2 microg/ml) and AUC (70.7 versus 105 mgh/l) were
      20, 60 and 32% lower in fed than in fasted rats, respectively. The presence of
      cellulose and sulphate anions in rat chow could partially explain the fed state
      associated reduction of tungstate bioavailability. In streptozotocin-induced
      diabetic fed rats, a 25% decrease occurred in AUC and F, and a 14% increase
      occurred in the elimination rate constant compared with healthy fed rats. These
      changes could be explain on the one hand, by the increase of liquid consumption
      and food intake, and on the other hand, by a gastroparesis in the early diabetic
      rats.

PMID- 12429468
TI  - Crystal growth and structure of a new hormonal derived compound.
AB  - The 17alpha-acetoxy-6-hydroxymethyl-3,20-dioxo-19-nor-pregna-4,6-diene
      (C(23)H(30)O(5)), a new hormonal derived compound presenting a potential
      therapeutic interest for a pharmaceutical formulation, raises a problem as it
      precipitates spontaneously when in contact with an aqueous solution. The
      solubilization of this potential pharmaceutical drug was investigated to control
      and/or prevent crystal formation in the presence of water. The solubility limit
      of this potential drug, either in Cremophor(R) EL or RH40, was determined to be
      2.6% (w/w). In addition, crystal growth of this compound solubilized in
      Cremophor(R) and in contact with aqueous environment was undertaken to improve
      crystal quality and size and subsequently to determine its three dimensional
      structure. We used a system that allows slow single crystal growth at room
      temperature. The crystallization system that we set-up comprised an interface
      between two solutions: one containing the compound solubilized either in
      Cremophor(R) RH40 or EL and the other containing water and glycine. The crystal
      structure was established by single crystal X-ray diffraction analysis. The
      structure refinement study revealed the presence of one water molecule with
      strong intermolecular hydrogen bonding leading to an atomic arrangement
      corresponding to an infinite chain in the [001] direction.

PMID- 12429469
TI  - Potential applications of PLGA film-implants in modulating in vitro drugs
      release.
AB  - In this work we evaluate poly(lactic/glycolic) acid (PLGA) film-implants as
      potential biodegradable devices for controlled release of two different drugs: 5
      Fluorouridine (5-FUR), a conventional low molecular weight water-soluble compound
      and SPf66 malaria vaccine, a therapeutic synthetic polypeptide. Three types of
      devices were prepared by solvent-casting techniques alone or combined with
      compression method: simple monolithic discs (SMD), multilayer discs with a
      central monolithic layer (MLDM), and multilayer discs with a central drug
      reservoir (MLDR). For the highly water-soluble drug, 5-FUR, in vitro release from
      SMD showed an initial burst (24% in 2 h) followed by prolonged release over 20
      days. In contrast, from a MLDM (two drug-free PLGA discs were added to the SMD)
      showed an initial lag-time of 12 days followed by a very fast second release
      phase. Finally, when the load of this system was increased from 3 to 9%, an
      extended release over 20 days with a low burst effect was obtained. For SPf66,
      the central reservoir containing the synthetic polypeptide MLDR reduces the
      possibility of degradation due to peptide contact with polymer solution. When
      four layers were added, 10 days sustained-release was obtained without any burst
      effect. With six layers a moderate pulse was obtained, 18-22 days from the
      beginning of the release. The results show the suitability of the proposed
      devices to control release and avoid the burst effect with highly water-soluble
      drugs; as well as modulate in vitro peptide release.

PMID- 12429470
TI  - The influence of carbohydrate nature and drying methods on the compaction
      properties and pore structure of new methyl methacrylate copolymers.
AB  - Methyl methacrylate (MMA) copolymers have recently been proposed as an
      alternative in controlled-release matrix tablets. The aims of this study were to
      assess the potential value of these copolymers as direct compression excipients
      and to investigate relationships between the physical and structural properties
      of the polymers and the compression behaviour of the powders and the
      microstructural properties of the tablets. Copolymers were synthesised by free
      radical copolymerisation of MMA with starch or cellulose derivatives and were
      alternatively dried by oven or freeze-drying techniques. Thus, the present study
      focuses on the influence of the carbohydrate nature and the drying process on the
      mechanical and compaction properties of MMA copolymers. Particle size, shape and
      surface texture of the copolymers have been studied in detail and Heckel
      treatment has been chosen for discriminating the densification behaviour of
      powdered materials. Total pore volume and pore size distribution of MMA copolymer
      tablets were investigated with mercury porosimetry. Oven drying gave less porous
      particles with more homogenous surfaces than those freeze-dried. Differences in
      morphology between the MMA copolymers were demonstrated by increasing apparent
      particle densities, smaller flow rates and higher binding capacities for freeze
      dried products. The porousness and mean pore radius of the tablets obtained from
      freeze-dried copolymers were higher than those of tablets obtained from oven
      dried ones.

PMID- 12429471
TI  - Optimization of antibody labeling with rhenium-188 using a prelabeled MAG3
      chelate.
AB  - We report the optimization of polyclonal IgG labeling by 188Re using S-benzoyl
      MAG(3) as a model for labeling monoclonal antibodies (MoAb). We examined the in
      vitro stability of the labeled protein and its localization and excretion in mice
      with induced focal inflammation. Stability in serum was greater than 85.5% after
      24 h. Biodistribution and imaging studies following administration to mice showed
      mainly renal and hepatic excretion and high IT/NT ratios (4.5 and 4.6) at 24 and
      48 h, respectively. This indirect method of labeling antibodies using a 188Re
      labeled active ester of MAG(3) produced 188Re-MAG(3)-IgG of high in vitro
      stability and favorable uptake at sites of focal inflammation.

PMID- 12429472
TI  - Minimization of initial burst in poly(vinyl alcohol) hydrogels by surface
      extraction and surface-preferential crosslinking.
AB  - Surface extraction and surface-preferential crosslinking were investigated as
      effective methods to reduce the burst effect for proxyphylline release from
      poly(vinyl alcohol) hydrogels. Both these techniques involved changing the
      surface characteristics to reduce drug diffusion during the early stages of
      release, with the goal of subtracting the burst effect from the release profile
      without altering the long-term release rate. The extraction process was carried
      out on both relaxed and dry gels. Proxyphylline was extracted from both freshly
      made and dried hydrogel samples, with the extraction from dried samples providing
      better control of the burst effect with smaller amounts of drug removed from the
      gels. The success of extracting from the dried samples was attributed to the lack
      of drug diffusivity and redistribution after extraction when the majority of the
      device remained dry. Surface-preferential crosslinking, by dipping preformed
      proxyphylline-loaded samples in a concentrated crosslinking solution, effectively
      diminished the burst effect by slowing macromolecular relaxation near the
      surface. Notably, this technique maintained the same long-term drug release rate
      as the untreated gels and less than 0.2% of the loaded proxyphylline was removed
      during the crosslinking step.

PMID- 12429473
TI  - Preservation of lysozyme structure and function upon encapsulation and release
      from poly(lactic-co-glycolic) acid microspheres prepared by the water-in-oil-in
      water method.
AB  - When proteins are encapsulated in bioerodible polymers by water-in-oil-in-water
      (w/o/w) encapsulation techniques, inactivation and aggregation are serious
      drawbacks hampering their sustained delivery. Hen egg-white lysozyme was employed
      to investigate whether stabilizing it towards the major stress factors in the
      w/o/w encapsulation procedure would allow for the encapsulation and release of
      structurally unperturbed, non-aggregated, and active protein. When it was
      encapsulated in poly(lactic-co-glycolic) acid (PLGA) microspheres without
      stabilizing additives, lysozyme showed substantial loss in activity and
      aggregation. It has been shown that by co-dissolving various sugars and
      polyhydric alcohols with lysozyme in the first aqueous buffer, interface-induced
      lysozyme aggregation and inactivation can be minimized in the first
      emulsification step [J. Pharm. Pharmacol. 53 (2001) 1217]. Herein, it was found
      that those excipients, which were efficient in preventing interface-induced
      structural perturbations, were also efficient in minimizing lyophilization
      induced structural perturbations (e.g. lactulose). The efficient excipients
      identified also reduced structural perturbations upon lysozyme encapsulation in
      PLGA microspheres and this led to reduced lysozyme inactivation and aggregation.
      However, the data obtained also show that later steps in the encapsulation
      procedure are detrimental to lysozyme activity. Lysozyme inactivation was
      completely prevented only by employing the efficient excipients in the second
      aqueous phase also. In summary, protein aggregation and inactivation were
      minimized by rationally selecting excipients efficient in stabilizing lysozyme
      against the major stress factors of w/o/w encapsulation.

PMID- 12429474
TI  - Prediction of the bitterness of single, binary- and multiple-component amino acid
      solutions using a taste sensor.
AB  - The purpose of this study was to develop a quick, quantitative, prediction method
      for the determination of the bitterness of solutions containing one or more of
      five amino acids (L-isoleucine, L-leucine, L-valine, L-phenylalanine, and L
      tryptophan), using an artificial taste sensor. The bitterness of various
      solutions containing different concentrations (1, 3, 10, 30, and 100 mM) of five
      amino acids, singly and in combination, was estimated using a multichannel taste
      sensor and compared with the results of human gustatory sensation tests with nine
      volunteers. The relative response electric potential patterns were similar for
      all five amino acids. Large sensor outputs were observed in channels 1-4 (which
      are negatively charged) while there were no responses in channels 5-8 (positively
      charged). The sensor output for channel 1, which was the largest output value,
      was used for prediction of bitterness. The change of membrane potential caused by
      adsorption (CPA), which corresponds to aftertaste, could not be used as an
      explanatory variable since the adsorption of the amino acids to the sensor
      membrane was weak and CPA values were small. The bitterness intensity scores for
      single, binary, and multi-component amino acid solutions, could be easily
      predicted on the basis of the sensor output value of channel 1 using regression
      analysis. Principal component analysis of the sensor output data suggested that
      the sourness, astringency and/or smell of the solutions also played a role in the
      perception of bitterness.

PMID- 12429475
TI  - Skin permeation enhancement effect and skin irritation of saturated fatty
      alcohols.
AB  - Though the skin permeation enhancement effect of chemical penetration enhancers
      has been studied extensively, their skin irritation potential has not been
      adequately investigated. The objective of this study was to evaluate the skin
      permeation enhancement effect and skin irritation of saturated fatty alcohols
      using melatonin as a model compound. A saturated solution of melatonin in a
      mixture of water and ethanol (40:60) containing 5% w/v of saturated fatty alcohol
      was used in the skin permeation studies using Franz diffusion cells. For skin
      irritation studies, 230 microl of fatty alcohol solution was applied on the
      dorsal surface of the hairless rats using Hill top chamber. The skin irritation
      was evaluated by visual scoring method and bioengineering methods such as
      measurement of transepidermal water loss (TEWL) and skin blood flow. The flux of
      melatonin across hairless rat skin was found to be dependent on the carbon chain
      length of the fatty alcohols, with decanol showing the maximum permeation of
      melatonin. All fatty alcohols increased the TEWL and skin blood flow
      significantly compared with the vehicle. The fatty alcohols (decanol, undecanol
      and lauryl alcohol), which showed greater permeation of melatonin, also produced
      greater TEWL, skin blood flow and erythema. Tridecanol and myristyl alcohol
      showed lower permeation enhancement effect but caused greater skin irritation.
      Octanol and nonanol may be the most useful enhancers for the transdermal delivery
      of melatonin considering their lower skin irritation and a reasonably good
      permeation enhancement effect. However, further studies are needed to ascertain
      their safety as skin penetration enhancers. Skin permeation and skin irritation
      in experimental animals such as rats are generally higher compared with human
      skin. Further studies in human volunteers using fatty alcohols at the
      concentrations of 5% or lower may provide useful information on the utility of
      these fatty alcohols as permeation enhancers.

PMID- 12429476
TI  - Stability aspects of salmon calcitonin entrapped in poly(ether-ester) sustained
      release systems.
AB  - Poly(ether-ester)s composed of hydrophilic poly(ethylene glycol)-terephthalate
      (PEGT) blocks and hydrophobic poly(butylene terephthalate) (PBT) blocks were
      studied as matrix for the controlled release of calcitonin. Salmon calcitonin
      loaded PEGT/PBT films were prepared from water-in-oil emulsions. The initial
      calcitonin release rate could be tailored by the copolymer composition, but
      incomplete release of calcitonin was observed. FTIR measurements indicated
      aggregation of calcitonin in the matrix, which was not due to the preparation
      method of the matrices, but due to the instability of calcitonin in an aqueous
      environment. Release experiments showed the susceptibility of calcitonin towards
      the composition of the release medium, in particular to the presence of metal
      ions. With increasing amount of sodium ions, a decrease in the total amount of
      released calcitonin was observed due to enhanced aggregation. The calcitonin had
      to be stabilized in the matrix to prevent aggregation. Incorporation of sodium
      dodecyl sulphate (SDS) as a stabilizer in PEGT/PBT matrices increased the
      percentage of calcitonin released, but could not avoid aggregation on a longer
      term.

PMID- 12429477
TI  - A kinetic study of the chemical stability of the antimetastatic ruthenium complex
      NAMI-A.
AB  - NAMI-A is a novel ruthenium complex with selective activity against cancer
      metastases currently in Phase I clinical trials in The Netherlands. The chemical
      stability of this new agent was investigated utilizing a stability-indicating
      reversed-phase high performance liquid chromatographic assay with ultraviolet
      detection and ultraviolet/visible light spectrophotometry. The degradation
      kinetics of NAMI-A were studied as a function of pH, buffer composition, and
      temperature. Degradation of NAMI-A follows first-order kinetics at pH<6 and zero
      order kinetics at pH > or =6. A pH-rate profile, employing rate constants
      extrapolated to zero buffer concentration, was constructed, demonstrating that
      NAMI-A is most stable in pH region 3-4. The degradation rate is not significantly
      affected by specific buffer components. Storage temperature strongly influences
      the degradation rate.

PMID- 12429478
TI  - Pharmaceutical development of a parenteral lyophilized formulation of the
      antimetastatic ruthenium complex NAMI-A.
AB  - This paper describes the development of a stable pharmaceutical dosage form for
      NAMI-A, a novel antimetastatic ruthenium complex, for Phase I testing. NAMI-A
      drug substance was characterized using several spectrometric and chromatographic
      techniques. In preformulation studies, it was found that NAMI-A in aqueous
      solution was not stable enough to allow sterilization by moist heat. The effect
      of several excipients on the stability of the formulation solution was
      investigated. None of them provided sufficient stability to allow long-term
      storage of an aqueous solution of NAMI-A. Therefore, a lyophilized product was
      developed. Five different formulations were prepared and subjected to
      thermogravimetric (TG) analysis and stability studies at various conditions for 1
      year. Minimal degradation during the production process is achieved with a
      formulation solution of pH 3-4. Of the acids tested, only hydrochloric acid (HCl
      0.1 mM) both stabilized the formulation solution and was compatible with the
      lyophilized product. This product was stable for at least 1 year when stored at 
      20 degrees C, 25 degrees C/60% relative humidity (RH) and 40 degrees C/75% RH,
      and was also photostable.

PMID- 12429480
TI  - Application of slurry bridging experiments at controlled water activities to
      predict the solid-state conversion between anhydrous and hydrated forms using
      theophylline as a model drug.
AB  - The role of water activity (a(w)), relative humidity (RH) and temperature on the
      hydration state of theophylline has been investigated. Slurry bridging
      experiments at controlled water activities, using powder X-ray diffraction (PXRD)
      and thermogravimetric analysis (TGA) to characterise the solid phase, established
      that the hydrate is the thermodynamically stable form of theophylline at a(w) >
      or = 0.5 at 4 degrees C, a(w) > or = 0.64 at 30 degrees C, and a(w) > or = 0.76
      at 40 degrees C. These data were used to produce a phase stability diagram for
      anhydrous/hydrate theophylline versus temperature. Anhydrous theophylline was
      spray dried in an attempt to reduce crystallinity. The spray dried theophylline
      was stored at a range of temperatures (4-40 degrees C) and humidities (22-89%
      RH). Samples were analysed at 3, 6, 9, 26 and 52 weeks using TGA and at the 26
      and 52 weeks by PXRD. The solid state stability of the spray dried theophylline
      closely correlated to the phase stability diagram produced using the slurry
      bridging experiments. The data suggest that the slurry bridging technique at
      controlled water activities provides an accurate method of rapidly predicting the
      physically stable form in anhydrous/hydrate systems.

PMID- 12429481
TI  - Ultrasound-compacted and spray-congealed indomethacin/polyethyleneglycol systems.
AB  - The product obtained by ultrasound (US)-assisted compaction was compared with a
      solid dispersion for systems containing polyethyleneglycols (PEGs) of different
      molecular weights and indomethacin (IMC), at the weight ratio 9:1, obtained by
      traditional melting and followed by a new US-assisted spray-congealing technique.
      US-discharge during compaction affects crystallinity of both IMC and PEG: pure
      IMC changes to an amorphous form and, when in mixture with PEG, partially
      dissolves in the excipient: this causes an increase of the dissolution rate of
      the drug. Differential scanning calorimetry (DSC) thermograms do not reveal any
      endothermic peak associated with the melting of the drug, while X-ray
      diffractograms show a loss of crystallinity of both IMC and PEG in the US
      compacted granules. The extent of a back-crystallisation, which reduces the
      dissolution rate, as a function of the ageing of the material, depends on the
      type of the selected PEG. When a molten IMC/PEG mixture was transformed into
      microspheres by an US-assisted spray-congealing technique, the behaviour at
      dissolution almost recalls that of US-compacted granulates and some differences
      are briefly discussed.

PMID- 12429482
TI  - Polymer particle erosion controlling drug release. II. Swelling investigations to
      clarify the release mechanism.
AB  - The aim of the study was a comprehensive swelling investigation of hydrocolloid
      tablets with drug release by diffusion, erosion and polymer particle erosion,
      respectively, in order to reveal differences in the swelling behaviour
      responsible for the diverging drug release mechanisms. Four different methods
      were applied to study swelling of the tablets: determination of the expansion
      factor, texture analysis, visual swelling observation of dye containing tablets
      sandwiched between plexiglas discs and photomicroscopy. Altogether they allowed
      the investigation of dimensional changes, swelling velocity, thickness,
      appearance and strength of the gel layer and front movements. However, none of
      the methods included a determination of all these factors. A combination of the
      different techniques proved to be helpful to provide information necessary for a
      broad understanding of the complex phenomenon of swelling. Intensive swelling was
      observed for matrices with diffusion controlled release (e.g. MHPC 100000), while
      erosion controlled systems (e.g. Pharmacoat 606) were characterized by limited
      swelling and fast polymer erosion. In the case of tablets exhibiting polymer
      particle erosion (e.g. MHEC 10000 B) the importance of the amount of insoluble
      fibres was confirmed. Insoluble fibres were clearly visible in the swelling zone
      of these tablets. They impeded the swelling, weakened the gel layer and caused
      attrition of polymer material, thus only a thin gel layer was formed.
      Synchronization of the movement of swelling and erosion fronts occurred during
      the swelling of tablets with a high content of insoluble fibres. The freely
      soluble drug proxyphylline was found to promote swelling while the poorly soluble
      acetophenetidin hindered the hydration of the tablet. Furthermore, the swelling
      study confirmed the low robustness to hydrodynamic stress of tablets with erosion
      control compared to tables with polymer particle erosion.

PMID- 12429483
TI  - Two spin labeled triazenes: relationship between biochemical and biological
      activities.
AB  - Biochemical and biological activities of two recently synthesized spin labeled
      triazenes, containing the nitroxyl free radical moiety at different places of the
      triazene structure have been studied and compared with those of the antitumor
      drug Dacarbazine (DTIC). Tissue distribution of the triazenes was investigated in
      vitro in organ homogenates, tumor (B16 melanoma) and blood of C57BL mice using
      the electron paramagnetic resonance (EPR) method. The spin labeled triazenes were
      mainly localized in the tumor and in the brain. Normal leucocites, YAC-1 mNK
      target Moloney lymphoma cells and B16 melanoma cells were treated with spin
      labeled triazenes in vitro and the effects on cell viability were compared. Spin
      labeled 3,3-dimethyl triazene with nitroxyl radical as a substituent in the
      benzen ring was more cytotoxic to B16 melanoma cells than to YAC-1 Moloney
      lymphoma cells and normal leucocites in comparison to the spin labeled monomethyl
      triazene. The spin labeled derivatives were assessed with low toxicity for BDF1
      mice hybrids in vivo. These results could be interpreted in terms of a possible
      correlation between tissue distribution and the selective antimelanoma activity
      of the spin labeled triazenes.

PMID- 12429484
TI  - Intestinal absorption of human insulin in pigs using delivery systems based on
      superporous hydrogel polymers.
AB  - In this in vivo study, novel delivery systems based on superporous hydrogel (SPH)
      and SPH composite (SPHC) polymers were used to improve the intestinal absorption
      of insulin in healthy pigs. Six female pigs of approximately 35 kg body weight
      were used. A cannula was inserted into the jugular vein for blood sampling and a
      silicone fistula in the duodenum for administration of gelatin capsules
      containing the delivery systems or insulin solutions. The delivery systems
      consisted of two components, (1) conveyor system made of SPH and SPHC; (2) core
      containing insulin. The core was inserted either into the conveyor system (core
      inside, c.i.) or attached to the surface of conveyor system (core outside, c.o.).
      The following intestinal formulations were investigated: c.i., c.o. and
      intraduodenal (i.d.) administration of insulin solutions. Subcutaneous (s.c.)
      injection of insulin was also investigated for reasons of comparison. Blood
      samples were taken and analyzed for insulin and glucose concentrations. Relative
      bioavalibility values of 1.3+/-0.4 and 1.9+/-0.7% were achieved for c.o. and c.i.
      administrations, respectively. The bioavalibility for i.d. administration of
      insulin solution was 0.5+/-0.2%. These results indicate that the absorption of
      insulin was slightly increased using SPH/SPHC-based delivery systems.
      Furthermore, a large variability was observed, probably due to physiological and
      metabolic changes during the experiments. Blood glucose levels were slightly
      decreased after the c.o. and c.i administrations, whereas these levels did not
      decrease after i.d. administration of insulin solutions. In conclusion, SPH/SPHC
      based delivery systems are able to enhance the intestinal absorption of insulin
      and are, therefore, considered as promising systems for peroral peptide drug
      delivery. However, insulin delivery from these delivery systems under in vivo
      have to be improved.

PMID- 12429485
TI  - Effects of blender rotational speed and discharge on the homogeneity of cohesive
      and free-flowing mixtures.
AB  - The roles of blender rotational speed and blender discharge on the homogeneity of
      free-flowing art sand and of a cohesive placebo formulation were investigated in
      the tote blender. For three practical operating speeds, 6, 10, and 14 RPM,
      spanning the entire range of commercial equipment, the homogeneity of the free
      flowing mixture was independent of rotational speed and blender size. On the
      other hand, the homogeneity of the cohesive pharmaceutical powder mixture was
      dependent on vessel rotational speed in a complex fashion, with 10 RPM producing
      a better final mixture than either 5 or 15 RPM. The homogeneity of the free
      flowing sand mixture was preserved when discharged into a vertical bin, while the
      homogeneity of the fine pharmaceutical powder mixture significantly improved
      after discharge from the tote blender.

PMID- 12429486
TI  - Moisture induced polymorphic transition of mannitol and its morphological
      transformation.
AB  - The effects of moisture on the polymorphic transition of crystalline mannitol
      were investigated. Mannitol has three polymorphic forms, and was classified as
      alpha, beta, and delta form, respectively, by Walter-Levy (C.R. Acad. Sc. Paris
      Ser. C (1968) 267, 1779). The water uptake of delta form crystalline was greater
      than that of the beta form when each crystalline form was stored at 97%RH (25
      degrees C). The different powder X-ray diffraction patterns obtained before and
      after humidification confirmed that a moisture induced polymorphic transition
      from the delta to beta form had occurred. Morphological changes were also
      observed with an increase in the specific surface area of the delta sample from
      0.4 to 2.3 m(2)/g being found on exposure to humidity. Thus it was suggested that
      the observed higher hygroscopicity of the newly formed beta form arose from the
      gradual increase in the surface area with the polymorphic transition from the
      delta to beta form. When considering the mechanism of this polymorphic
      transition, the results from molecular modelling, cross-polarisation/magic angle
      spinning (CP/MAS) solid-state NMR spectra and scanning electron-micrographs
      suggest that water molecules act as a molecular loosener to facilitate conversion
      from delta to the beta form as a result of multi-nucleation.

PMID- 12429487
TI  - Integrity of crystalline lysozyme exceeds that of a spray-dried form.
AB  - The development of proteins as therapeutic agents is challenging partly due to
      their inherent instabilities. Consequently, crystallisation and spray drying
      techniques were assessed to determine their effects on protein integrity using
      lysozyme as a model protein. Unprocessed, crystallised and spray-dried lysozyme
      were characterised by: thermal analysis using hot stage microscopy (HSM),
      differential scanning calorimetry (DSC), high sensitivity differential scanning
      calorimetry (HSDSC) and thermogravimetry (TGA); and spectroscopic analysis
      employing Fourier transform Raman (FT-Raman). Moisture contents were determined
      by TGA and Karl Fisher titration (KFT). Enzymatic assay measured biological
      activity. HSM showed no changes in crystals until complete melting. TGA and KFT
      indicated that spray-dried lysozyme contained a lower moisture content than
      crystals, hence the higher apparent thermal stability was shown by DSC. HSDSC
      revealed that crystallisation and spray drying did not affect the denaturation
      temperature of lysozyme in solution when compared with unprocessed material.
      However, in the solid state, FT-Raman spectra showed perturbation of the
      conformational structure of spray-dried sample, whereas crystal conformation
      remained intact. Enzymatic assay revealed increased activity retention of
      crystals compared with spray-dried powder. Hence, crystals maintained the
      conformational integrity and activity of lysozyme in solution.

PMID- 12429488
TI  - Influence of limonene on the bioavailability of nicardipine hydrochloride from
      membrane-moderated transdermal therapeutic systems in human volunteers.
AB  - The aim of the present study was to develop a membrane-moderated transdermal
      therapeutic system (TTS) of nicardipine hydrochloride using 2%w/w hydroxy propyl
      cellulose (HPC) gel as a reservoir system containing 4%w/w of limonene as a
      penetration enhancer. The permeability flux of nicardipine hydrochloride through
      ethylene vinyl acetate (EVA) copolymer membrane was found to increase with an
      increase in vinyl acetate (VA) content in the copolymer. The effect of various
      pressure-sensitive adhesives (MA-31, MA-38 or TACKWHITE A 4MED) on the
      permeability of nicardipine hydrochloride through EVA membrane 2825 (28% w/w VA)
      or membrane/skin composite was also studied. The results showed that nicardipine
      hydrochloride permeability through EVA 2825 membrane coated with TACKWHITE 4A
      MED/skin composite was higher than that coated with MA-31or MA-38. Thus a new TTS
      for nicardipine hydrochloride was formulated using EVA 2825 membrane coated with
      a pressure-sensitive adhesive TACKWHITE 4A MED and 2%w/w HPC gel as reservoir
      containing 4%w/w of limonene as a penetration enhancer. The bioavailability
      studies in healthy human volunteers indicated that the TTS of nicardipine
      hydrochloride, designed in the present study, provided steady state plasma
      concentration of the drug with minimal fluctuations for 20 h with improved
      bioavailability in comparison with the immediate release capsule dosage form.

PMID- 12429489
TI  - Rheological properties of three component creams containing sorbitan monoesters
      as surfactants.
AB  - Creams from three components, surfactant, purified water and oil, were prepared.
      Comparable molar fractions of components were used in order to better understand
      the structural properties of the components used. The surfactants were sorbitan
      monoesters, sorbitan monolaurate, monopalmitate, monostearate and monooleate,
      which differed from each other in the length or structure of the hydrocarbon
      chain. The oils used were isopropylpalmitate and myristate, and they differed
      from each other in the length of the fatty acid chain. Rheological properties,
      droplet size distributions and types (either o/w or w/o) of the creams were
      studied. The rheological tests used were oscillation stress sweep test, creep
      recovery test and viscosity test. The modelling of the creep phase was based on
      the creep recovery test. Sorbitan monolaurate and monostearate formed w/o creams,
      sorbitan monopalmitate and monooleate o/w creams. It appeared that the double
      bonded structure of the surfactant made the cream less elastic. Elasticity was
      increased due to lengthening of the alkyl chain of the surfactant and increased
      amount of surfactant. Also the lengthening of the fatty acid chain of the oil
      made the creams more elastic. The results of the rheological tests and droplet
      size distributions correlated well each other. According to the modelling of the
      creep phase, creams could be represented either with the Burger model or with the
      Maxwell model.

PMID- 12429490
TI  - Carrier mediated uptake of L-tyrosine and its competitive inhibition by model
      tyrosine linked compounds in a rabbit corneal cell line (SIRC)--strategy for the
      design of transporter/receptor targeted prodrugs.
AB  - The objective of this study was to investigate the presence of amino acid
      transporters on the corneal epithelium and to enhance corneal drug absorption
      through prodrug modification targeted to the amino acid transporters. SIRC was
      used as a model cell line representing the corneal epithelium. Uptake studies
      were carried out using [3H] L-tyrosine at 37 degrees C. Temperature, energy and
      pH dependence studies were carried out. The uptake seems to be composed of a
      major saturable and minor non-saturable component (V(max) =2.9+/-0.62
      nmoles/min/mg protein, K(m) =71+/-21 microM, K(d) =2.6+/-0.6 nl/min/mg protein).
      No significant inhibition of uptake was observed in the presence of metabolic
      inhibitors or in the absence of sodium. Competitive inhibition studies were
      performed in the presence of various amino acids and model tyrosine conjugates (p
      nitro and p-chloro benzyl ether conjugate of L-tyrosine). Uptake was inhibited by
      neutral aromatic and large neutral aliphatic amino acids. L-Tyrosine uptake was
      inhibited by its ether conjugates in a concentration dependent manner suggesting
      that these compounds may be sharing the same transport mechanism. This study
      provides biochemical evidence of the presence of a large neutral amino acid
      transport system on the corneal epithelium, which may be utilized to enhance the
      corneal drug transport.

PMID- 12429491
TI  - Affinity scale between a carrier and a drug in DPI studied by atomic force
      microscopy.
AB  - The dry powder inhalers (DPIs) consist, in the most cases, of ordered mixture
      where the particles adhesion results of interactions between the drug and the
      carrier. Generally, one step of production process is the micronization of the
      drug particles in order to reduce the size for ordered mixing optimization. But
      this operation is known to partially create an amorphous surface. In this case,
      surrounding storage conditions, like relative humidity (RH), are able to modify
      the percentage of amorphous drug surface. The aim of this study was to
      investigate surface reactivity, surface energy and direct force measurements by
      atomic force microscopy (AFM) between lactose (carrier) and zanamivir (drug)
      crystals references in various conditions of RH. Secondly, an amorphization of
      the drug surface was induced by humidity relative treatment in order to evaluate
      the consequences of the transition from crystal to amorphous phase. The study
      demonstrated that the amorphization of drug surface induces an increase of drug
      affinity with the carrier surface. Ex situ and in situ amorphization of zanamivir
      tend to reach the affinity measured between raw materials: carrier and micronized
      drug particles. AFM allowed adhesion force discrimination between the different
      forms of the drug particles and demonstrated the potential for investigating
      adhesion properties in DPI formulation.

PMID- 12429492
TI  - Measurement of pH near dissolving enteric coatings.
AB  - Previous authors have predicted the pH at the surface of enteric coatings using
      mathematical models. The purpose of our work is to experimentally determine the
      pH. A modified laser spectrometer was constructed to excite fluorescein in the
      medium above a dissolving enteric coating--hydroxypropylmethylcellulose phthalate
      (HP) in buffer (pH 6.5 and 7.0) in the absence and presence of forced convection.
      As predicted by mathematical models, the pH near dissolving enteric coatings is
      reduced relative to bulk pH. The reduction in pH is 0.2 to 0.4 depending upon the
      pH of the buffer relative to the pK(a) of the polymer. The pH near (i.e. about
      250 microm from the surface) HP-50 is lower than that near HP-55 under the same
      conditions. The experimental data agree to a first approximation with data from
      mathematical models.

PMID- 12429493
TI  - Physical stability and solubility of the thermotropic mesophase of fenoprofen
      calcium as pure drug and in a tablet formulation.
AB  - The aim of this study was to investigate and compare the physical stability and
      solubility of the liquid crystalline form of fenoprofen calcium as pure drug and
      in a proprietary tablet formulation (Nalfon), and to investigate if a simple heat
      treatment of a proprietary tablet containing fenoprofen calcium may lead to a
      physically stable formulation with enhanced dissolution rate and apparent
      solubility. The liquid crystalline form of fenoprofen calcium (thermotropic
      mesophase) was prepared by heating the crystalline drug to 125 degrees C to
      remove the water of crystallisation. Differential scanning calorimetry
      investigation revealed an endothermic peak at 89 degrees C upon heating (liquid
      crystal formation) attributable to water loss from the crystalline dihydrate. The
      liquid crystalline order was maintained upon cooling. No interference of tablet
      excipients with the thermal behaviour of the drug in the tablet formulation was
      observed. The crystalline dihydrate and liquid crystalline forms of fenoprofen
      calcium could be differentiated by diffuse reflectance infra-red spectroscopy and
      X-ray powder diffraction, both as pure drug and in tablet formulation. The
      supercooled liquid crystal (thermotropic reversed hexagonal phase) alone and in
      preheated and ground tablets was physically stable when stored in a dry
      environment or at 33% relative humidities (RH) at both 20 and 40 degrees C for 2
      months. At 40 degrees C and 75% RH the supercooled mesophase extensively
      converted to the crystalline dihydrate within 6 days. Liquid crystalline
      fenoprofen calcium stored at 20 degrees C and 75% RH showed only partial
      dihydrate conversion after 2 months of storage. The solubility of the crystalline
      dihydrate alone and from the tablet formulation was 2.8+/-0.2 mg/ml and 3.0+/-0.2
      mg/ml (mean+/-s.d.), respectively, (not significantly different), whereas the
      maximum solubility of the liquid crystal was 5.0+/-0.3 mg/ml (mean+/-s.d.) and
      6.9+/-0.6 mg/ml (mean+/-s.d.), respectively (significantly different). The
      difference in maximum solubility between the crystalline dihydrate form of
      fenoprofen calcium and the fenoprofen calcium mesophase was highly significant,
      for both the pure drugs and the tablet formulations. The dissolution rate of the
      liquid crystalline fenoprofen calcium in preheated, intact tablets was
      significantly lower than that of the crystalline form in non-preheated tablets.
      Gross visual changes and scanning electron microscopy indicated that the
      disintegration properties of the tablet may be detrimentally effected by heating
      the tablet to 125 degrees C, diminishing the beneficial effect of improved
      solubility of the liquid crystal. The study has shown that conversion of the
      crystalline form of fenoprofen calcium to the liquid crystal can enhance the
      apparent solubility of the pure drug and the drug in presence of tablet
      excipients, but that the conversion should be performed before tablet formulation
      in order to increase dissolution of this poorly water-soluble drug.

PMID- 12429494
TI  - Developing a study method for producing 400 microm spheroids.
AB  - The aim of this work was to obtain 400 microm spheroids that can be sprinkled on
      food to improve patient compliance particularly in the case of children and old
      people. A methodology to select wet masses for extrusion-spheronization through a
      400 microm orifice was developed. The first step was to define the parameters
      that make it possible to assess the qualities required by the wet mass and the
      extrudates and evaluation norms: plasticity, cohesiveness, brittleness of the
      mass and the extrudates, and appearance of extrudates. A feasibility assay was
      then performed on the cylinder extruder, showing that extrusion of the
      lactose/Avicel PH 101/water (50/50/60) mass is not feasible through the 400
      microm orifice. Precirol ato 5 and Gelucire 50/02 wetted with a sodium lauryl
      sulfate solution at 0.5% show plastic flow through the 400 microm diameter
      orifice. The presence of Avicel PH 101 does not improve plasticity for this
      orifice. Micropellets of 400 microm have been proved feasible as long as
      excipients with suitable pharmaceutical technological properties are used. After
      proving the feasibility of 400 microm spheroids of Gelucire 50/02, we considered
      the association of a drug with it.

PMID- 12429495
TI  - Relationship between inhomogeneity phenomena and granule growth mechanisms in a
      high-shear mixer.
AB  - A poorly understood phenomenon observed during high-shear granulation is the poor
      distribution of a drug in the granulate. To investigate the causes of this
      inhomogeneity, lactose of three different particle sizes was granulated with 0.1%
      micronized estradiol (5 microm) in a 10 l high-shear mixer. An aqueous solution
      of HPC was used as binder. Granulation with the largest lactose particles (141
      microm) yielded a homogeneous granulate. However, at a prolonged process time
      demixing was observed. Contrary to the largest particles, granulation with the
      smaller lactose particles (50 and 23 microm) already leads to demixing in the
      first minute, although to a lesser extent. It was concluded that granulation with
      the largest particles resulted in breakage behavior of the granulate, thereby
      preventing demixing. However, once granules are strong enough (smaller particle
      size and prolonged process time) to survive the shear forces demixing is
      observed. Theoretical calculations of dynamic and static granule strength were
      used to explain the influence of lactose particle size and process time on
      breakage behavior. It was argued that once granules survive, preferential growth
      of the small estradiol particles in favor of the larger lactose particles causes
      the demixing. The extent of demixing depends on the particle size difference.

PMID- 12429496
TI  - Spectroscopic characterisation of the monoclinic and orthorhombic forms of
      paracetamol.
AB  - The metastable orthorhombic form of paracetamol was prepared from the melt of the
      commercially available monoclinic form. Distinct differences were observed in the
      infrared spectra of both forms, especially in the region 1260-1225 cm(-1), in
      which is observed three strong absorptions of approximately equal intensity in
      spectra of the monoclinic form, and two absorptions, one strong and one medium,
      in spectra of the orthorhombic form. No diagnostically useful differences were
      observed in the Raman spectra of the two forms. A 13C CP/MAS solid-state NMR
      spectrum of the monoclinic form and a spectrum of a mixture of forms prepared
      from a melt were obtained. A spectrum of the orthorhombic form was obtained from
      these spectra by difference spectroscopy. The spectra show that the carbons in
      the paracetamol molecules are all in unique chemical environments in both
      crystalline forms, and that clear well-resolved differences in the chemical
      shifts of particular carbons in both forms can be observed.

PMID- 12429497
TI  - A ferredoxin from the thermohalophilic bacterium Rhodothermus marinus.
AB  - A [3Fe-4S](1+/0) ferredoxin was isolated from the thermohalophilic and strict
      aerobic bacterium Rhodothermus marinus. It is a small protein, with an apparent
      molecular mass of 9 kDa. Its N-terminal amino acid sequence reveals the
      capability of binding two tetranuclear clusters. However, upon purification, it
      contains a single [3Fe-4S](1+/0), with an unusually low reduction potential of 
      650 mV, determined by cyclic voltammetry at pH 7.6. [1H]NMR spectroscopy shows
      that the protein contains a single, homogeneous, trinuclear centre. When purified
      under anaerobic conditions, the EPR [3Fe-4S](1+/0) centre signal is also
      observed. However, it can now be reduced by dithionite and a new signal
      attributed to a [4Fe-4S](2+/1+) cluster develops. This can also be observed upon
      reconstitution of the prosthetic groups. The function of this ferredoxin in R.
      marinus is still unknown but it is very sensitive to oxygen, an unexpected
      characteristic for a protein from an aerobic organism. The thermodynamic
      stability of the R. marinus ferredoxin was also investigated and was shown to be
      high. Thermal and chemical unfolding reactions appear as single, cooperative
      transitions. The midpoint (T(m)) for thermally induced unfolding is 102+/-2
      degrees C (pH 7). Unfolding induced by the chemical denaturant guanidine
      hydrochloride (GuHCl) shows a transition midpoint at 5.0 M GuHCl (pH 7.0, 20
      degrees C). The iron-sulfur cluster degrades upon polypeptide unfolding,
      resulting in an irreversible denaturation process.

PMID- 12429498
TI  - Modelling of the human papillomavirus type 16 E5 protein.
AB  - The product of the E5 oncogene in human papillomaviruses (HPVs) participates in
      cellular transformation. The sequences of E5 from high-risk HPV types are closely
      related, and the ability to transform is thought to be associated with their
      structure. Structural determination by standard biophysical methods has proved
      impossible due to the extreme hydrophobicity of the gene product. We have
      achieved limited solubility by dividing the sequence into three, structurally
      distinct domains. Synthetic peptides corresponding to these domains have been
      examined using circular dichroism (CD) spectroscopy, a method that can detect
      secondary structure elements in highly dilute protein solutions. Using data on
      the secondary structure content of these domains under different conditions and
      in systematic combination to detect constructive domain interactions, a model of
      HPV E5 structure and position in the membrane is proposed that is consistent with
      what is known of the larger family of leucine-rich repeat (LRR) proteins to which
      it belongs.

PMID- 12429499
TI  - Novel caged fluorescein diphosphates as photoactivatable substrates for protein
      tyrosine phosphatases.
AB  - We have characterized some novel caged fluorescein diphosphates as
      photoactivatable, cell-permeable substrates for protein tyrosine phosphatases and
      explored their usefulness in identifying inhibitors of tyrosine phosphatases. 1
      (2-Nitrophenyl)ethyl protected fluorescein diphosphate (NPE-FDP) undergoes rapid
      photolysis to release FDP upon irradiation with a 450-W UV immersion lamp and its
      by-product does not inactivate protein tyrosine phosphatase 1B (PTP1B) or alters
      the viability of cells. The generated FDP from photolysis of NPE-FDP was shown to
      have exactly the same properties as FDP, which can be used as a PTP substrate in
      pure enzyme assays. We have also demonstrated that the PTP activity can be
      measured using NPE-FDP in small droplets. Its advantage as an inert substrate
      before photolysis allows the possibility of applying nanospray technology in
      screening and optimizing PTP inhibitors through a large chemical library. Like
      other caged bioeffectors such as nucleotide and inositol trisphosphate, NPE-FDP
      is cell-permeable. The NPE-FDP can be photolyzed to generate FDP inside cells,
      and then can be hydrolyzed by phosphatases to produce fluorescein monophosphate
      and subsequently to fluorescein. Although Jurkat cells contain high
      concentrations of CD45, it has not been possible to use FDP as a substrate to
      measure CD45 activity in the intact cell. This is due to the hydrolysis of FDP by
      several other cellular phosphatases. However, NPE-FDP can be useful as a cell
      permeable substrate for overexpressed phosphatases such as alkaline phosphatase.

PMID- 12429500
TI  - Amino acid substitution of arginine 80 in 17beta-hydroxysteroid dehydrogenase
      type 3 and its effect on NADPH cofactor binding and oxidation/reduction kinetics.
AB  - 17beta-Hydroxysteroid dehydrogenase type 3 (17beta-HSD-3) is a member of the
      short-chain dehydrogenase/reductase (SDR) family and is essential for the
      reductive conversion of inactive C(19)-steroid, androstenedione, to the
      biologically active androgen, testosterone, which plays a central role in the
      development of the male phenotype. Mutations that inactivate this enzyme give
      rise to a rare form of male pseudohermaphroditism, referred to as 17beta-HSD-3
      deficiency. One such mutation is the replacement of arginine at position 80 with
      glutamine, compromising enzyme activity by increasing the cofactor binding
      constant 60-fold. In the absence of a 17beta-HSD-3 crystal structure, we have
      grafted its amino acid sequence for the NADPH binding site on the X-ray crystal
      structures of glutathione reductase (Protein Data Bank code 1gra) and 17beta-HSD
      type 1 (Protein Data Bank codes 1fdv and 1fdu) where we find the trunk of the
      arginine 80 side chain forms part of the hydrophobic pocket for the purine ring
      of adenosine while its guanidinium moiety interacts with the 2'-phosphate to both
      stabilize cofactor binding and neutralize its intrinsic negative charge through
      two hydrogen bonds. To qualitatively assess the role arginine 80 plays in both
      selecting and stabilizing NADPH binding, it was replaced with each amino acid and
      the mutant enzymes subjected to enzymatic analysis. There are only seven enzymes
      exhibiting any measurable enzymatic activity with arginine approximately
      lysine>leucine>glutamine>methionine>tyrosine>isoleucine. With an aspartic acid at
      position 58 in 17beta-HSD-3 occupying the equivalent space in the cofactor
      binding pocket as arginine 224 in glutathione reductase or serine 12 in 17beta
      HSD-1, there was an expectation that some of the mutants might use NADH as a
      cofactor. In no case was NADH found to substitute for NADPH.

PMID- 12429501
TI  - The essential role of C-terminal residues in regulating the activity of hepatitis
      C virus RNA-dependent RNA polymerase.
AB  - We have previously determined the crystal structure of a non-structural 5B (NS5B)
      protein, an RNA-dependent RNA polymerase (RdRp) of hepatitis C virus (HCV). NS5B
      protein with the hydrophobic C-terminal 21 amino acid residues truncated,
      designated NS5B(570), shows a typical nucleotide polymerase structure resembling
      a right-hand shape. In the crystal structure, a C-terminal region between Leu545
      and His562 occupies a putative RNA-binding cleft of this polymerase and seems to
      inhibit the polymerase activity. Varieties of recombinant NS5B proteins
      (NS5B(552), NS5B(544), NS5B(536) or NS5B(531), with C-terminal 39, 47, 55 or 60
      amino acid residues truncated, respectively) were systematically constructed to
      elucidate effects of the region on the polymerase activity. NS5B(544), NS5B(536)
      and NS5B(531) showed markedly higher RdRp activities compared to the activities
      of NS5B(570) or NS5B(552). Furthermore, when the hydrophobic amino acid residues
      Leu547, Trp550 and Phe551 (LWF) in NS5B(570) and NS5B(552) were changed to
      alanine, their activities were higher than that of the original NS5B(570). The
      crystal structures of the various recombinant NS5B proteins were also determined.
      Structural comparison of the NS5B proteins indicates that the activation was
      caused by elimination of a unique hydrophobic interaction between the three C
      terminal residues and a shallowly concave pocket consisting of thumb and palm
      domains.

PMID- 12429502
TI  - Contribution of hydrophobic residues to ice binding by fish type III antifreeze
      protein.
AB  - Type III antifreeze protein (AFP) is a 7-kDa globular protein with a flat ice
      binding face centered on Ala 16. Neighboring hydrophilic residues Gln 9, Asn 14,
      Thr 15, Thr 18 and Gln 44 have been implicated by site-directed mutagenesis in
      binding to ice. These residues have the potential to form hydrogen bonds with
      ice, but the tight packing of side chains on the ice-binding face limits the
      number and strength of possible hydrogen bond interactions. Recent work with
      alpha-helical AFPs has emphasized the hydrophobicity of their ice-binding sites
      and suggests that hydrophobic interactions are important for antifreeze activity.
      To investigate the contribution of hydrophobic interactions between type III AFP
      and ice, Leu, Ile and Val residues on the rim of the ice-binding face were
      changed to alanine. Mutant AFPs with single alanine substitutions, L19A, V20A,
      and V41A, showed a 20% loss in activity. Doubly substituted mutants, L19A/V41A
      and L10A/I13A, had less than 50% of the activity of the wild type. Thus, side
      chain substitutions that leave a cavity or undercut the contact surface are
      almost as deleterious to antifreeze activity as those that lengthen the side
      chain. These mutations emphasize the importance of maintaining a specific surface
      contour on the ice-binding face for docking to ice.

PMID- 12429503
TI  - Antimicrobial peptides and protease inhibitors in the skin secretions of the
      crawfish frog, Rana areolata.
AB  - The dorsal skin of the crawfish frog, Rana areolata, is associated with numerous
      prominent granular glands. Proteomic analysis of electrically stimulated skin
      secretions from these glands enabled the identification and characterization of
      eight peptides with antimicrobial and hemolytic activity belonging to the
      previously identified brevinin-1, temporin-1, palustrin-2, palustrin-3,
      esculentin-1 (two peptides), and ranatuerin-2 (two peptides) families. The
      primary structures of the peptides were consistent with a close phylogenetic
      relationship between R. areolata and the pickerel frog, Rana palustris. Three
      structurally related cationic, cysteine-containing peptides were identified that
      show sequence similarity to peptide Leucine-Arginine, a peptide with
      immunomodulatory and histamine-releasing properties from the skin of the northern
      leopard frog, Rana pipiens. The skin secretions contained a 61-amino-acid-residue
      peptide that inhibited porcine trypsin and possessed a 10-cysteine-residue motif
      that is characteristic of a protease inhibitor previously isolated from the
      parasitic nematode, Ascaris suum. A 48-amino-acid-residue protein containing
      eight cysteine residues in the whey acidic protein (WAP) motif, characteristic of
      elafin (skin-derived antileukoproteinase) and secretory leukocyte protease
      inhibitor, was also isolated. The data suggest that protease inhibitors in skin
      secretions may play a role complementary to cationic, amphipathic alpha-helical
      peptides in protecting anurans from invasions by microorganisms.

PMID- 12429504
TI  - Structure and properties of avian small heat shock protein with molecular weight
      25 kDa.
AB  - The primary structure of chicken small heat shock protein (sHsp) with apparent
      molecular weight 25 kDa was refined and it was shown that this protein has
      conservative primary structure 74RALSRQLSSG(83) at Ser77 and Ser81, which are
      potential sites of phosphorylation. Recombinant wild-type chicken Hsp25, its
      three mutants, 1D (S15D), 2D (S77D+S81D) and 3D (S15D+S77D+S81D), as well as delR
      mutant with the primary structure 74RALS-ELSSG(82) at potential sites of
      phosphorylation were expressed and purified. It has been shown that the avian
      tissues contain three forms of Hsp25 having pI values similar to that of the wild
      type protein, 1D and 2D mutants that presumably correspond to nonphosphorylated,
      mono- and di-phosphorylated forms of Hsp25. Recombinant wild-type protein, its 1D
      mutant and Hsp25, isolated from chicken gizzard, form stable high molecular
      weight oligomeric complexes. The delR, 2D and 3D mutants tend to dissociate and
      exist in the form of a mixture of high and low molecular weight oligomers. Point
      mutations mimicking phoshorylation decrease chaperone activity of Hsp25 measured
      by reduction of dithiothreitol induced aggregation of alpha-lactalbumin, but
      increase the chaperone activity of Hsp25 measured by heat induced aggregation of
      alcohol dehydrogenase. It is concluded that avian Hsp25 has a more stable
      quaternary structure than its mammalian counterparts and mutations mimicking
      phosphorylation differently affect chaperone activity of avian Hsp25, depending
      on the nature of target protein and the way of denaturing.

PMID- 12429505
TI  - Structural characterization of non-native states of sperm whale myoglobin in
      aqueous ethanol or 2,2,2-trifluoroethanol media.
AB  - The effects of aqueous ethanol or 2,2,2-trifluoroethanol media on the structure
      of sperm whale myoglobin have been investigated by absorption, CD, and NMR
      spectra. The structural properties of myoglobin such as heme environments, helix
      contents, protein folding, and interactions between heme and the protein moiety
      have been sharply manifested in these spectra. The characterization demonstrated
      that alcohol-induced conformational change of myoglobin depends on the nature of
      alcohol and its concentration. It was shown for the first time that, upon the
      alcohol-induced denaturation of myoglobin, heme is released from partially
      denatured protein of which helix contents is altered by only about 20% relative
      to that of native state. Myoglobin has shown to unfold and refold reversibly by
      controlling the alcohol concentration. Novel methods for the preparation of
      apomyoglobin and in situ reconstitution of apomyoglobin with heme, based on the
      alcohol-induced denaturation of the protein, were presented.

PMID- 12429506
TI  - GRID/tetrahedral intermediate computational approach to the study of selectivity
      of penicillin G acylase in amide bond synthesis.
AB  - Molecular modelling was used to investigate the catalytic site of penicillin G
      acylase (PGA) by building up a simple enzyme-ligand model able to describe and
      predict the enzyme selectivity. The investigation was based on a double
      computational approach: first, the GRID computational procedure was applied to
      gain a qualitative description of the chemical features of the PGA active site;
      second, a classical "transition state approach" was used to simulate the
      tetrahedral intermediates and to evaluate their energies. GRID calculations
      employed different probes which gave a complete description of the chemical
      interactions occurring upon binding of different ligands, thus indicating those
      structures having good affinity with the active site of the enzyme. Tetrahedral
      intermediates were constructed on the basis of GRID results and provided both
      geometrical features and energies of enzyme-substrate interaction. Such energies
      were compared to experimental kinetic data obtained in the enzymatic acylation of
      L-phenylglycine methyl ester using various methyl phenylacetate derivatives. The
      good agreement of computational results with experimental evidence demonstrates
      the validity of the model as a rapid and flexible tool to describe and predict
      the enzyme selectivity.

PMID- 12429507
TI  - Nonribosomal peptide synthetases-evidence for a second ATP-binding site.
AB  - delta-(L-alpha-Aminoadipyl)-L-cysteinyl-D-valine synthetase (ACVS) catalyses, via
      the protein thiotemplate mechanism, the nonribosomal biosynthesis of the
      penicillin and cephalosporin precursor tripeptide delta-(L-alpha-aminoadipyl)-L
      cysteinyl-D-valine (ACV). The complete and fully saturated biosynthetic system
      approaches maximum rate of product generation with increasing ATP concentration.
      Nonproductive adenylation of ACVS, monitored utilising the ATP-[32P]PP(i)
      exchange reaction, has revealed substrate inhibition with ATP. The kinetic
      inhibition pattern provides evidence for the existence of a second nucleotide
      binding site with possible implication in the regulatory mechanism. Under
      suboptimal reaction conditions, in the presence of MgATP(2-), L-Cys and inorganic
      pyrophosphatase, ACVS forms adenosine(5')tetraphospho(5')adenosine (Ap(4)A) from
      the reverse reaction of adenylate formation involving a second ATP molecule. The
      potential location of the second ATP binding site was deduced from sequence
      comparisons and molecular visualisation in conjunction to data obtained from
      biochemical analysis.

PMID- 12429508
TI  - Calcium-induced decrease of the thermal stability and chaperone activity of alpha
      crystallin.
AB  - Alpha-crystallin, one of the major proteins in the vertebrate eye lens, acts as a
      molecular chaperone, like the small heat-shock proteins, by protecting other
      proteins from denaturing under stress or high temperature conditions. alpha
      Crystallin aggregation is involved in lens opacification, and high [Ca(2+)] has
      been associated with cataract formation, suggesting a role for this cation in the
      pathological process. We have investigated the effect of Ca(2+) on the thermal
      stability of alpha-crystallin by UV and Fourier-transform infrared (FTIR)
      spectroscopies. In both cases, a Ca(2+)-induced decrease in the midpoint of the
      thermal transition is detected. The presence of high [Ca(2+)] results also in a
      marked decrease of its chaperone activity in an insulin-aggregation assay.
      Furthermore, high Ca(2+) concentration decreases Cys reactivity towards a
      sulfhydryl reagent. The results obtained from the spectroscopic analysis, and
      confirmed by circular dichroism (CD) measurements, indicate that Ca(2+) decreases
      both secondary and tertiary-quaternary structure stability of alpha-crystallin.
      This process is accompanied by partial unfolding of the protein and a clear
      decrease in its chaperone activity. It is concluded that Ca(2+) alters the
      structural stability of alpha-crystallin, resulting in impaired chaperone
      function and a lower protective ability towards other lens proteins. Thus, alpha
      crystallin aggregation facilitated by Ca(2+) would play a role in the progressive
      loss of transparency of the eye lens in the cataractogenic process.

PMID- 12429509
TI  - Establishment of a first-order kinetic model of light chain-associated amyloid
      fibril extension in vitro.
AB  - Light chain-associated (AL) amyloidosis is a common and fatal systemic
      amyloidosis. AL amyloid fibrils (fAL) are composed of intact or fragmental
      monoclonal light chains (AL proteins). To elucidate the molecular mechanisms of
      fAL formation from AL proteins, we purified fAL and AL proteins from the amyloid
      deposited organs of five AL amyloidosis patients. By electron microscopy and
      fluorometric thioflavin T method, we observed optimal fibril extension at pH 2.0
      3.5 for the fibrils obtained from four patients, while at pH 7.5-8.0 for those
      obtained from one patient. Fragmental AL proteins were more efficient in the
      extension reaction than intact AL proteins. The fibrils obtained from all five
      patients showed clear fibril extension electron microscopically at pH 7.5. The
      extension of the fibrils obtained from all five patients could be explained by a
      first-order kinetic model, i.e., fibril extension proceeds via the consecutive
      association of AL proteins onto the ends of existing fibrils. Fibril extension
      was accelerated by dermatan sulfate proteoglycan, and inhibited by apolipoprotein
      E, alpha1-microglobulin, fibronectin, and an antioxidant nordihydroguaiaretic
      acid. These findings contribute to our understanding of the molecular mechanism
      underlying the pathogenesis of AL amyloidosis, and will be useful for developing
      a therapeutic strategy against the disease.

PMID- 12429510
TI  - Purification and crystallization of coconut globulin cocosin from Cocos nucifera.
AB  - Cocosin is a legume class reserve protein found in coconut endosperm. Using
      coconut endosperm, two methods of purification were done. Crystallization was
      achieved by vapor diffusion (hanging drop) method using MPD, PEG 3350 and PEG
      4000 as precipitants. X-ray diffraction data to 3.5-A resolution were collected
      using Mar345 image plate detector system. Crystals of cocosin grown under 20%
      MPD, are rhombohedral with space group R3 and cell dimensions a=92.829 A,
      b=92.829 A, c=215.290 A.

PMID- 12429512
TI  - Passive transfer of virus-specific antibodies confers protection against
      reproductive failure induced by a virulent strain of porcine reproductive and
      respiratory syndrome virus and establishes sterilizing immunity.
AB  - Immune mechanisms mediating protective immunity against porcine reproductive and
      respiratory syndrome virus (PRRSV) are not well understood. The PRRSV-specific
      humoral immune response has been dismissed as being ineffective and perhaps
      deleterious for the host. The function of PRRSV antibodies in protective immunity
      against infection with a highly abortifacient strain of this virus was examined
      by passive transfer experiments in pregnant swine. All of a group of pregnant
      gilts (n = 6) that received PRRSV immunoglobulin (Ig) from PRRSV-convalescent,
      hyperimmune animals were fully protected from reproductive failure as judged by
      95% viability of offspring at weaning (15 days of age). On the other hand, the
      totality of animals in a matched control group (n = 6) receiving anti
      pseudorabies virus (PRV) Ig exhibited marked reproductive failure with 4%
      survival at weaning. Besides protecting the pregnant females from clinical
      reproductive disease, the passive transfer of PRRSV Ig prevented the challenge
      virus from infecting the dams and precluded its vertical transmission, as
      evidenced by the complete absence of infectious PRRSV from the tissues of the
      dams and lack of infection in their offspring. In summary, these results indicate
      that PRRSV-Igs are capable of conferring protective immunity against PRRSV and
      furthermore that these Igs can provide sterilizing immunity in vivo.

PMID- 12429511
TI  - Production of hybrid double- or triple-layered virus-like particles of group A
      and C rotaviruses using a baculovirus expression system.
AB  - Dual infections by group A and group C rotaviruses have been reported, but no
      reassortants between group A and group C rotaviruses have been described. The VP6
      major inner capsid protein of group A and C rotaviruses shares common antigens
      detected by monoclonal antibodies and also shares 40-43% amino acid identity.
      Coinfection of Spodoptera frugiperda (Sf9) insect cells with different
      combinations of the recombinant baculoviruses encoding either group A [RF VP2 (A
      VP2), IND VP6 (A-VP6), and VP7 (A-VP7[IND]), 2292B VP7 (A-VP7[2292B])] or C
      [Shintoku VP6 (C-VP6) and VP7 (C-VP7)] bovine rotavirus proteins produced hybrid
      group A/C triple-layered VP2/6/7 virus-like particles (TLPs) composed of A-VP2/C
      VP6/C-VP7, A-VP2/C-VP6/A-VP7(IND), A-VP2/C-VP6/A-VP7(2292B), and A-VP2/A-VP6/C
      VP7. To our knowledge, this is the first report that the inner capsid VP6 of
      group A or group C rotavirus can support attachment of the heterologous,
      antigenically distinct group A (G6, IND or G10, 2292B) or group C rotavirus outer
      capsid VP7 to produce hybrid TLPs in vitro.

PMID- 12429513
TI  - Transcription analysis of Streptococcus thermophilus phages in the lysogenic
      state.
AB  - The transcription of prophage genes was studied in two lysogenic Streptococcus
      thermophilus cells by Northern blot and primer-extension experiments. In the
      lysogen containing the cos-site phage Sfi21 only two gene regions of the prophage
      were transcribed. Within the lysogeny module an 1.6-kb-long mRNA started at the
      promoter of the phage repressor gene and covered also the next two genes,
      including a superinfection exclusion (sie) gene. A second, quantitatively more
      prominent 1-kb-long transcript was initiated at the promoter of the sie gene.
      Another prophage transcript of 1.6-kb length covered a group of genes without
      database matches that were located between the lysin gene and the right
      attachment site. The rest of the prophage genome was transcriptionally silent. A
      very similar transcription pattern was observed for a S. thermophilus lysogen
      containing the pac-site phage O1205 as a prophage. Prophages from pathogenic
      streptococci encode virulence genes downstream of the lysin gene. We speculate
      that temperate phages from lactic streptococci also encode nonessential phage
      genes ("lysogenic conversion genes") in this region that increase the ecological
      fitness of the lysogen to further their own evolutionary success. A comparative
      genome analysis revealed that many temperate phages from low GC content Gram
      positive bacteria encode a variable number of genes in that region and none was
      linked to known phage-related function. Prophages from pathogenic streptococci
      encode toxin genes in this region. In accordance with theoretical predictions on
      prophage-host genome interactions a prophage remnant was detected in S.
      thermophilus that had lost most of the prophage DNA while transcribed prophage
      genes were spared from the deletion process.

PMID- 12429514
TI  - Adenovirus type 37 binds to cell surface sialic acid through a charge-dependent
      interaction.
AB  - Most adenoviruses use the coxsackie-adenovirus receptor (CAR) as a major cellular
      receptor. We have shown recently that adenovirus types 8, 19a, and 37, which are
      the major causes of epidemic keratoconjunctivitis, use sialic acid rather than
      CAR as a major cellular receptor. The predicted isoelectric point of the receptor
      interacting knob domain in the adenovirus fiber protein is unusually high (9.0
      9.1) in type 8, 19a, and 37. The pKa of sialic acid is low, 2.6, implying a
      possible involvement of charge in fiber knob-sialic acid interactions. Here we
      show that (i) positively charged adenovirus knobs require sialic acid for
      efficient cell membrane interactions; (ii) viral and knob interactions with
      immobilized sialic acid or cell-surface sialic acid are sensitive to increased
      ionic strength; (iii) negatively charged molecules such as sulfated
      glycosaminoglycans inhibit the binding of virions to target cells in a
      nonspecific, charge-dependent manner; and that (iv) the ability of adenovirus
      knobs to interact with sialic acid correlates with the overall charge on the top
      surface of the respective knobs as predicted by homology modeling. Taken
      together, the results presented provide strong evidence for a charge mechanism
      during the interaction between the Ad37 fiber knob and sialic acid.

PMID- 12429515
TI  - Enhanced immune responses after DNA vaccination with combined envelope genes from
      different HIV-1 subtypes.
AB  - In a multisubtype approach to HIV-1 vaccination, mice were immunized with HIV-1
      envelope gp160 genes from subtypes A, B, and C. Subsequently the mice were
      challenged with syngeneic primary splenocytes infected with a HIV-1/MuLV
      pseudovirus carrying a subtype B genome. HIV-specific immune responses and
      protection were strongest in the group of animals immunized with a combination of
      subtype A, B, and C specific gp160 genes as compared to subtype B only.
      Immunization with the combination of the cross-reactive subtypes A and C envelope
      genes induced HIV-specific immune responses but did not result in significant
      protection to challenge with subtype B infected cells. From this we conclude that
      immunization with the envelope genes from several HIV-1 subtypes may indeed
      enhance immune responses. This study shows that by using a mix of subtype
      envelope genes, an enhanced protective immunity can be obtained experimentally,
      potentially also in humans.

PMID- 12429516
TI  - Patterns of polymorphism in wheat streak mosaic virus: sequence space explored by
      a clade of closely related viral genotypes rivals that between the most divergent
      strains.
AB  - Nucleotide (nt) sequence polymorphism within a collection of Wheat streak mosaic
      virus (WSMV) isolates was examined. An approximately 1267-nt region encompassing
      the coat protein (CP) cistron and flanking sequences was amplified by reverse
      transcription-polymerase chain reaction (RT-PCR) for each of 49 isolates not
      previously sequenced. Consensus sequences were compiled for each isolate based on
      sequences derived from three clones per RT-PCR product. Among 59 consensus
      sequences examined, only two were identical. Clades A-C contained divergent
      isolates from Mexico (Clade A); the Czech Republic, Hungary, and Russia (Clade
      B); and Iran (Clade C). Fifty-four closely related consensus sequences of
      isolates from the U.S. (51 sequences), Canada (1 sequence), and Turkey (2
      sequences) comprised Clade D. Pair-wise nt divergence between two of the most
      distantly related sequences (Sidney 81 of Clade D and El Batan 3 of Clade A) was
      20%, representing over half of the variable sites (34.1%) in the entire WSMV data
      set. Maximum pairwise nt divergence within Clade D was 3.6%, yet the proportion
      of all variable sites within Clade D (21.4%) was similar to that of the Sidney 81
      El Batan 3 pair. Patterns of polymorphism within Clade D and the Sidney 81-El
      Batan 3 pair were remarkably similar with respect to synonymous, nonsynonymous,
      and noncoding substitutions, as were the proportions of substitutions as a
      function of nt position within codons. The majority of substitutions within Clade
      D were synonymous and randomly distributed throughout the coding region examined,
      whereas nonsynonymous substitutions exhibited a clumped distribution and mostly
      occurred within the 5'-proximal portion of the CP cistron. Because over half of
      the polymorphic sites within Clade D were of allele size class 1, the isolates
      appear to be evolving independently and in a nondeterministic manner, within the
      constraints of selection. These results indicate that Clade D has undergone
      substantial and, most likely, recent divergence with the majority of consensus
      sequence substitutions potentially neutral with respect to fitness. An estimate
      of evolution rate suggests that the present diversity within the U.S. population
      arose in about a century, a timeframe corresponding to the establishment of wheat
      monoculture in the Great Plains.

PMID- 12429517
TI  - Physical and functional interaction between the varicella zoster virus IE63 and
      IE62 proteins.
AB  - The varicella zoster virus (VZV) IE63 protein is required for growth of the virus
      in cell culture and is expressed during both lytic and latent phases of VZV
      infection. We have investigated the physical and functional interaction of this
      protein with the major VZV transactivating protein IE62. The region of the IE63
      protein required for interaction with the IE62 protein has been identified and
      encompasses the N-terminal 142 amino acids. We have found that the interaction is
      stable at physiological ionic strength. We have also shown that a portion of the
      IE63 and IE62 proteins colocalize in VZV-infected cells at both 15 and 48 h
      postinfection. IE63 was found to have no transcriptional activating or repressing
      activity within the context of a minimal VZV glycoprotein promoter. The presence
      of the IE63, however, upmodulated the IE62 transactivation of this promoter.
      Finally, we show that the IE63 protein can be coimmunoprecipitated with the
      cellular RNA polymerase II from infected cell extracts, indicating that it is
      present in a complex with that enzyme.

PMID- 12429518
TI  - Interaction of geminivirus Rep protein with replication factor C and its
      potential role during geminivirus DNA replication.
AB  - Geminivirus DNA replication during the rolling-circle stage depends on the use of
      a DNA primer, a strategy poorly understood as compared with other eukaryotic
      viral systems that rely on RNA or protein as primers. Here we have used wheat
      dwarf virus (WDV) with the aim of elucidating the events leading to recruitment
      of cell factors at the replication origin. We have identified a novel interaction
      of WDV Rep, the replication initiation protein, with the large subunit of the
      wheat replication factor C complex (TmRFC-1). In other systems, the
      heteropentameric RFC clamp loader complex stimulates loading of DNA polymerase
      delta to the primer-template. Expression of TmRFC-1 is subjected to cell-cycle
      regulation, with a peak in early S-phase. We show that WDV Rep stimulates binding
      of recombinant TmRFC-1 to a model substrate containing a 3'-OH terminus and a WDV
      Rep-binding site. This was confirmed using cellular fractions enriched for wheat
      RFC complex, supporting the idea that, in addition to generating a 3'-OH terminus
      during initiation of DNA replication, WDV Rep could participate in the
      recruitment of RFC to the newly formed primer. We propose that this pathway may
      represent an initial event to facilitate the assembly of other replication
      factors, e.g., PCNA and/or DNA polymerase delta, a model that could also apply to
      other eukaryotic replicons, such as nanoviruses, circoviruses, and parvoviruses
      with a similar DNA replication strategy.

PMID- 12429519
TI  - HIV-1 Vpr displays natural protein-transducing properties: implications for viral
      pathogenesis.
AB  - The 14-kDa Vpr protein of human immunodeficiency virus type 1 (HIV-1) serves
      multiple functions in the retroviral life cycle, including the enhancement of
      viral replication in nondividing macrophages, the induction of G2 cell-cycle
      arrest in proliferating T lymphocytes, and the modulation of HIV-1-induced
      apoptosis. Extracellular Vpr has been detected in the sera and cerebral spinal
      fluid of HIV-infected patients. However, it is not known whether such forms of
      Vpr are biologically active. Vpr contains a carboxy-terminal basic amino acid
      rich segment stretch that is homologous to domains that mediate the energy- and
      receptor-independent cellular uptake of polypeptides by a process termed protein
      transduction. Similar functional protein-transducing domains are present in HIV-1
      Tat, herpes simplex virus-1 DNA-binding protein VP22, and the Drosophila
      antennapedia homeotic transcription factor. We now demonstrate effective
      transduction of biologically active, synthetic Vpr (sVpr) as well as the Vpr-beta
      galactosidase fusion protein. However, in contrast to other transducing proteins,
      Vpr transduction is not enhanced by protein denaturation, and Vpr's carboxy
      terminal basic domain alone is not sufficient for its transduction across
      biological membranes. In contrast, the full-length Vpr protein effectively
      transduces a broad array of cells, leading to dose-dependent G2 cell-cycle arrest
      and apoptosis. Addition of Vpr into the extracellular medium also rescues the
      replication of Vpr-deficient strains of HIV-1 in human macrophage cultures.
      Native Vpr may thus be optimized for protein transduction, a feature that might
      enhance and extend the pathological effects of HIV infection.

PMID- 12429520
TI  - The conserved process of TCR/CD3 complex down-modulation by SIV Nef is mediated
      by the central core, not endocytic motifs.
AB  - The Nef protein of Simian immunodeficiency virus (SIV) associates with multiple T
      lymphocyte signaling proteins, including the T cell receptor (TCR) zeta chain. We
      demonstrate here that these interactions are conserved and highly specific. Nefs
      derived from genetically diverse strains of SIV (SIV(mac)239, SIV(smm)PBj, and
      SIV(smm)DeltaB670) all interacted with TCR zeta on two separate domains, referred
      to as SIV Nef interaction domains (SNIDs), as examined in both yeast two-hybrid
      and glutathione-S-transferase (GST) fusion protein pull-down assays. Multiple HIV
      1 Nefs were examined and none interacted with TCR zeta. In contrast, HIV-2(UC1)
      Nef, similar to SIV Nef, interacted with TCR zeta on two domains, although only
      the SIV Nefs potently reduced cell-surface expression of the TCR/CD3 complex in T
      cells. In addition, we examined the abilities of SIV, HIV-2, and HIV-1 Nefs to
      interact with the cytoplasmic domains of other signaling molecules including
      CD3epsilon, CD3gamma, and FcepsilonRIgamma, which also contain YxxL motifs, and
      determined that SIV and HIV-2 Nefs interacted only with TCR zeta, whereas HIV-1
      Nef did not interact with any signal-transducing cytoplasmic domain examined.
      Last, to gain further insight into the mechanism by which Nef down-modulates the
      TCR/CD3 complex, we mutated or deleted regions on Nef involved in endocytosis,
      localization of Nef to the plasma membrane, interaction with cellular kinases, or
      that were conserved among multiple strains of SIV. Mutation of the myristoylation
      site and a conserved region surrounding a putative PKC phosphorylation site were
      the only mutations that abrogated Nef-mediated down-modulation of the TCR/CD3
      complex. These findings demonstrate there is a spectrum of associations between
      SIV, HIV-2, and HIV-1 Nefs, and the TCR/CD3 complex, and suggest that down
      modulation of the TCR/CD3 complex occurs via association with subsets of cellular
      proteins that are different from those involved in CD4 and CD28 down-modulation.

PMID- 12429521
TI  - Chitin synthesis in chlorovirus CVK2-infected chlorella cells.
AB  - Hyaluronan synthesis in chlorovirus PBCV-1-infected Chlorella cells was
      previously reported (DeAngelis et al., 1997). In contrast, we report here on the
      detection, characterization, and expression of a gene for chitin synthase (chs)
      encoded by chlorovirus CVK2 isolated in Kyoto, Japan. The CVK2 chs gene encoding
      an open reading frame of 516 aa was expressed as early as 10 min postinfection
      (p.i.), peaked at 20-40 min p.i., and disappeared at 120-180 min p.i. The chitin
      polysaccharide began to accumulate as chitinase-sensitive, hair-like fibers on
      the outside of the virus-infected Chlorella cell wall by 30 min p.i. All
      chloroviruses without the gene for hyaluronan synthase (has) alternatively
      contained the chs gene, suggesting the importance of polysaccharide production in
      the course of virus infection. A few chloroviruses possessed both the chs and has
      genes and produced chitin and hyaluronan simultaneously. Polysaccharide
      accumulation on the algal surface may protect virus-infected algae from uptake by
      other organisms, such as protozoa. Since CVK2 was reported to encode two
      chitinases and one chitosanase, CVK2 is a very peculiar virus that encodes
      enzymes required for both the synthesis and the degradation of chitin materials.

PMID- 12429522
TI  - Homotypic cell-cell adhesion induced by human T cell leukemia virus type 1 tax
      protein in T cell lines.
AB  - Cell-cell adhesion is involved in the processes of cell growth, activation and
      migration, and inflammation. T cells infected with human T cell leukemia virus
      type 1 (HTLV-1) exhibit a high degree of homotypic cell-cell adhesion in vitro.
      In this study, we investigated the involvement of the viral protein Tax in such
      process. Expression of Tax in an interleukin (IL)-2-dependent mouse T cell line
      (CTLL-2) increased homotypic cell-cell adhesion; however, less cell adhesion was
      induced by Tax than that observed in HTLV-1-infected T cell lines. Moreover, Tax
      induced cell-cell adhesion in a human T cell line, in which the expression of Tax
      is inducible. Microscopic examination also revealed Tax-induced morphologic
      changes, including rounding of CTLL-2 cells, increased cell volume, and increased
      nucleus size. Taken together, our results suggest that Tax induces cell-cell
      adhesion and morphologic changes in HTLV-1-infected cells. Tax may thus play a
      role in persistent HTLV-1 infection and the pathogenesis of associated disease.

PMID- 12429523
TI  - Infection of BALB/c mice with a herpes simplex virus type 1 recombinant virus
      expressing IFN-gamma driven by the LAT promoter.
AB  - A recombinant herpes simplex virus type 1 expressing murine interferon-gamma (IFN
      gamma) was constructed (HSV-IFN-gamma) to study the effect of IFN-gamma
      expression on HSV-1 infection of mice. HSV-IFN-gamma was created by inserting the
      gene for murine IFN-gamma under the control of the latency-associated transcript
      (LAT) promoter in a LAT-negative recombinant virus. ELISA analysis confirmed that
      the recombinant virus expressed high levels of IFN-gamma in tissue culture. The
      recombinant HSV-IFN-gamma had reduced virulence compared with the wild-type and
      LAT(-) parental strains as judged by death following ocular and ip infections in
      BALB/c mice. Replication of HSV-IFN-gamma was wild type in tissue culture and
      mouse eyes. In addition, peak HSV-IFN-gamma titers in mouse trigeminal ganglia
      (TG) and brain were similar for all viruses, although HSV-IFN-gamma appeared in
      the TG and brains of ocularly infected mice earlier than either parental virus.
      Following stimulation with UV-inactivated virus, lymphocytes from HSV-IFN-gamma
      infected mice appeared to produce a steady level of interleukin-2 (IL-2) and IFN
      gamma throughout the first week of infection, while the IL-2 and IFN-gamma levels
      in lymphocytes from wild-type and the LAT-negative parental virus, dLAT2903,
      varied over time. Also in contrast to lymphocytes from wild-type and dLAT2903
      infected mice, lymphocytes from HSV-IFN-gamma-infected mice produced no
      detectable IL-4. Following stimulation with recombinant IFN-gamma (rIFN-gamma),
      lymphocytes from HSV-IFN-gamma-infected mice produced higher levels of IFN-gamma,
      as compared to lymphocytes from control virus-infected mice. Finally, CTL and
      cell proliferation induced by HSV-IFN-gamma were similar to those of both
      parental viruses. Thus, this report demonstrates that (i) HSV-IFN-gamma had
      reduced neurovirulence, despite having enhanced replication in the TG of infected
      mice; (ii) HSV-IFN-gamma did not enhance CTL activity above that seen in wild
      type infected mice; and (iii) HSV-IFN-gamma induced a T(H)1 pattern of cytokine
      response.

PMID- 12429524
TI  - Generation of a consensus sequence from prevalent and incident HIV-1 infections
      in West Africa to guide AIDS vaccine development.
AB  - We considered several key issues regarding the development of a DNA-based human
      immunodeficiency virus type 1 (HIV-1) vaccine: (1) should the candidate vaccine
      construct be derived from incident or prevalent HIV-1 strains; and (2) should
      circulating plasma virus, archived HIV-1 provirus recovered from peripheral blood
      mononuclear cells, or both be included? To address these questions, we collected
      circulating HIV-1 strains from infected individuals residing in Abidjan, Cote
      d'Ivoire. From a panel of 23 strains, 22 were HIV-1 subtype A in gag, 19 of which
      phylogenetically clustered with the recombinant HIV-1, CRF02-AG strains from West
      Africa. The mosaic genome of CRF02-AG was confirmed by sequencing the protease
      gene. A consensus gag p24 protein sequence was generated and 147 of 148 codons
      were identical to CRF02-AG (IbNG). Regardless of the sequence origin (RNA,
      provirus, incident, or prevalent), the gag p24 consensus sequences were highly
      representative of these distinct virologic compartments. These data suggest that
      the consensus sequence generated from incident and prevalent infections may
      provide an appropriate sequence for a DNA vaccine and is largely representative
      of the major circulating viral strain.

PMID- 12429525
TI  - Interaction of HIV-1 gag and membranes in a cell-free system.
AB  - A coupled transcription-translation (TNT) reticulocyte lysate system was used to
      examine posttranslational alterations in HIV-1 Gag upon addition of Jurkat T cell
      membranes. Incubation of the Gag precursor protein, Pr55gag, with membranes
      resulted in a time-dependent alteration in Gag resulting in partial resistance to
      trypsin treatment. Treatment of membranes and TNT extract with apyrase or
      pretreatment of membranes with trypsin prevented this posttranslational
      alteration of Gag. In contrast, this activity was not disrupted by pretreatment
      of membranes with Triton X-100 at 4 degrees C, under conditions which do not
      solubilize raft-associated proteins. Flotation studies revealed that acquisition
      of trypsin-resistance was accompanied by Gag binding to membranes. The
      myristylation signal and nucleocapsid domain were found to mediate Gag binding to
      membranes. The posttranslational alteration of Gag accompanying membrane
      interaction may represent a conformational change, oligomerization, and/or
      association with or envelopment by membranes. These findings provide new clues to
      the stepwise process of HIV-1 assembly.

PMID- 12429526
TI  - The mechanism of inhibition of HIV-1 env-mediated cell-cell fusion by recombinant
      cores of gp41 ectodomain.
AB  - N36(L6)C34 is a recombinant protein that forms a six-helix bundle with high
      thermal stability. It consists of the N-terminal heptad-repeat region (N36
      peptide) and the C-terminal heptad-repeat region (C34) of HIV-1 gp41, connected
      by six polar amino acids. The protein inhibits HIV-1 envelope-induced membrane
      fusion. Whether inhibition occurs while N36(L6)C34 is in its six-helix bundle
      configuration was investigated. Mutating a critical residue within the N36 region
      to promote dissociation of C34 from the grooves of the N36 coiled coil reduced
      bundle stability and increased the inhibition of fusion. In contrast, mutating a
      key residue within the C34 region to reduce bundle stability decreased inhibitory
      potency. The data provide strong evidence that the proteins inhibit fusion while
      they expose their C34 segments, rather than as six-helix bundles. Thus, despite
      high thermal stability of the bundle, the recombinants' less folded structures
      are present in sufficient concentration to inhibit fusion at physiological
      temperatures.

PMID- 12429527
TI  - Initiation site binding protein and the initiator-like promoter element of mouse
      mammary tumor virus.
AB  - The mouse mammary tumor virus (MMTV) promoter contains an element near its
      transcription initiation site that is recognized by a protein termed initiation
      site binding protein (ISBP). Spacing between the TATA box and the ISBP site is
      important for MMTV promoter function, as altered spacing results in heterogeneity
      in start site selection in vitro and in vivo. The sequence of the ISBP site is
      related to initiator elements common in many RNA polymerase II promoters.
      However, binding of partially purified ISBP to several promoters that contain
      well-characterized initiator elements was not detected; these promoters included
      binding sites for a number of previously identified initiator-binding proteins.
      Partially purified ISBP did, however, bind with high affinity to sequences near
      the initiation sites of the SV40 major late and adenovirus 2 E1B promoters.

PMID- 12429528
TI  - B-oligomer of pertussis toxin inhibits HIV-1 LTR-driven transcription through
      suppression of NF-kappaB p65 subunit activity.
AB  - The binding subunit of pertussis toxin (PTX-B) has been shown recently to inhibit
      the entry and postentry events in HIV-1 replication in primary T lymphocytes and
      monocyte-derived macrophages. While the effect of PTX-B on HIV-1 entry was shown
      to involve CCR5 desensitization, the mechanism of postentry inhibition remained
      unclear. In T lymphocytes, PTX-B affected transcription or stability of Tat
      stimulated HIV-1 mRNAs. In this study, we sought to identify the mechanism of
      postentry inhibition of HIV-1 replication by PTX-B in U-937 promonocytic cells.
      We demonstrate that in these cells PTX-B inhibits expression of luciferase
      reporter gene controlled by the HIV-1 LTR promoter. This effect is Tat
      independent and is not restricted to the HIV-1 LTR promoter. Instead, PTX-B
      activity is mediated through suppression of the cellular transcription factor, NF
      kappaB. PTX-B inhibits phosphorylation and nuclear translocation of the p65
      subunit of NF-kappaB. This effect is independent of the cytoplasmic NF-kappaB
      inhibitor, IkappaBalpha, as PTX-B stimulates phosphorylation and subsequent
      degradation of this protein. The suppressive activity of PTX-B on NF-kappaB p65
      phosphorylation and nuclear translocation is delayed, suggesting that PTX-B
      signaling might initiate synthesis and cytoplasmic accumulation of a p65
      phosphorylation inhibitor.

PMID- 12429529
TI  - Clustered charge-to-alanine mutagenesis of human respiratory syncytial virus L
      polymerase generates temperature-sensitive viruses.
AB  - Clustered charge-to-alanine mutagenesis was performed on the large (L) polymerase
      protein of human respiratory syncytial virus to identify charged residues in the
      L protein that are important for viral RNA synthesis and to generate temperature
      sensitive viruses. Clusters of three, four, and five charged residues throughout
      the entire L protein were substituted with alanines. A minigenome replicon assay
      was used to determine the functions of the mutant L proteins and to identify
      mutations that caused temperature sensitivity by comparing the level of reporter
      gene expression at 39 and 33 degrees C. Charge-to-alanine mutations were
      introduced into an antigenomic cDNA derived from RSV A2 strain to recover
      infectious viruses. Of the 27 charge-to-alanine mutations, 17 recombinant viruses
      (63%) were obtained. Seven mutants (41%) exhibited small plaque morphologies
      and/or temperature-sensitive growth in tissue culture. To generate mutant viruses
      with more temperature-sensitive and attenuated phenotypes, several clusters of
      charge-to-alanine substitutions were combined. Five combination mutants were
      recovered that exhibited shut-off temperatures ranging from 36 to 39 degrees C in
      tissue culture and restricted replication in the respiratory tracts of cotton
      rats.

PMID- 12429530
TI  - Enhanced overexpression of an HIF-1/hypoxia-related protein in cancer cells.
AB  - Cap43 is a protein whose RNA is induced under conditions of severe hypoxia or
      prolonged elevations of intracellular calcium. Additionally, Ni and Co also
      induce Cap43 because they produce a state of hypoxia in cells. Cap43 protein is
      expressed at low levels in normal tissues; however, in a variety of cancers,
      including lung, brain, melanoma, liver, prostate, breast, and renal cancers,
      Cap43 protein is overexpressed in cancer cells. The low level of expression of
      Cap43 in some normal tissues compared with their cancerous counterparts, combined
      with the high stability of Cap43 protein and mRNA, makes the Cap43 gene a new,
      important cancer marker. We hypothesize that the mechanism of Cap43
      overexpression in cancer cells involves a state of hypoxia characteristic of
      cancer cells where the Cap43 protein becomes a signature for this hypoxic state.

PMID- 12429531
TI  - Microchimerism in Sjogren's syndrome.

PMID- 12429532
TI  - Detection of maternal-fetal microchimerism in the inflammatory lesions of
      patients with Sjogren's syndrome.
AB  - BACKGROUND: A possible relation between maternal-fetal microchimerism and
      autoimmune diseases with some similarities to chronic graft versus host disease
      (cGVHD) has been reported. OBJECTIVE: To investigate whether cells with male DNA
      exist in female patients with Sjogren's syndrome (SS) as SS has clinical features
      similar to those of cGVHD. METHODS: DNA was extracted from 27 samples of
      peripheral blood mononuclear cells (PBMC), 42 biopsy samples of labial salivary
      glands (LSG), and nine samples of bronchoalveolar lavage fluid (BALF) cells from
      56 female patients with SS. The presence of male DNA was determined by nested
      polymerase chain reaction (PCR) and by fluorescence in situ hybridisation (FISH).
      RESULTS: Among 56 female patients with SS, 42 patients had at least one male
      child. Among those 42 patients, none of the 22 PBMC but 10/28 (36%) LSG samples
      tested positive by PCR for the Y chromosome-specific sequence (p=0.0013). The Y
      chromosome-specific sequence was not detected in the samples of LSG in 10
      patients without SS. In the BALF samples 2/9 (22%) patients with SS tested
      positive by PCR. Cells containing the Y chromosome were shown to exist in all the
      LSG specimens from three female patients with SS by FISH. CONCLUSIONS: Maternal
      fetal microchimerism was shown for the first time to exist in the salivary glands
      and lungs of female patients with SS in this study. The presence of non-host
      cells in the inflammatory lesions but not in the peripheral blood suggests a
      possible role for maternal-fetal microchimerism in the pathogenesis of SS.

PMID- 12429533
TI  - Receptor activator NF-kappaB ligand (RANKL) expression in synovial tissue from
      patients with rheumatoid arthritis, spondyloarthropathy, osteoarthritis, and from
      normal patients: semiquantitative and quantitative analysis.
AB  - OBJECTIVES: To compare receptor activator of NF-kappaB ligand (RANKL) production
      in the synovial tissue from patients with active rheumatoid arthritis (RA),
      inactive RA, spondyloarthropathies (SpA), osteoarthritis, and from normal
      subjects. In addition, to establish the cell lineages expressing RANKL in these
      tissues. METHODS: Immunohistological analysis of frozen synovial tissue biopsy
      specimens was performed using a monoclonal antibody (mAb) to detect RANKL.
      Sections were evaluated by computer assisted image analysis and semiquantitative
      analysis to compare RANKL expression between groups. Dual and sequential
      labelling with mAb RANKL and cell lineage specific monoclonal antibodies were
      used to determine the types of cells expressing RANKL. RESULTS: Higher levels of
      RANKL were expressed in tissues from patients with active RA and SpA than in
      tissues from patients with inactive RA, osteoarthritis, and from normal subjects.
      RANKL protein was associated with CD3 antigen-positive lymphocytes and some
      macrophages. RANKL was predominantly associated with activated, memory T cells
      (CD45Ro positive cells) in patients with active RA and spondyloarthropathy (SpA).
      CONCLUSIONS: The highest levels of RANKL were detected in patients with RA with
      active synovitis and in some patients with SpA. An increase in RANKL in the
      inflamed joint of patients with RA, produced by infiltrating activated T cells
      and macrophages, is likely to be an important cause of joint erosions in RA.

PMID- 12429534
TI  - Ten year outcome in a cohort of patients with early rheumatoid arthritis: health
      status, disease process, and damage.
AB  - OBJECTIVE: To investigate outcome as measured by health status, disease process,
      and damage in an unselected group of patients with early rheumatoid arthritis
      (RA) monitored prospectively for 10 years and to search for prognostic factors.
      PATIENTS AND METHODS: 183 patients with RA with disease duration <2 years were
      assessed annually at a team care unit. Health status was measured by the Health
      Assessment Questionnaire (HAQ) and functional class. Disease process was assessed
      by clinical and laboratory measures of disease activity and evaluation of disease
      course. Damage was quantified as occurrence of major extra-articular
      manifestations and need for large joint replacements. Possible predictive factors
      were evaluated by logistic regression analyses. RESULTS: 168/183 patients
      completed the entire follow up period. Of all 183 patients, 137 (75%) had been
      treated with disease modifying antirheumatic drugs and 84 (46%) with low dose
      oral glucocorticoids. After 10 years 158 patients (94%) managed daily life
      activities independently (functional class I-II). As measured by the HAQ 20% had
      almost no disability, 28% were mildly disabled, and 10% were seriously disabled.
      Median HAQ score had increased from 0.8 to 1.1 (p<0.001). Disease activity was
      significantly reduced. 133 patients (79%) had a relapsing remitting disease
      course and 30 patients (18%) were in remission as defined by the American College
      of Rheumatology criteria. Thirty patients (17%) had undergone large joint
      replacements. Fifteen patients (8%) had developed major extra-articular
      complications. The HAQ score during the first three months predicted disability
      at 10 years with an odds ratio of 13.4. CONCLUSIONS: Prospective studies such as
      this give important knowledge of the variable long term prognosis of RA and
      provide necessary background information for clinical trials of new treatment
      modalities.

PMID- 12429535
TI  - Purine enzymes in patients with rheumatoid arthritis treated with methotrexate.
AB  - OBJECTIVES: To study (a) purine metabolism during treatment with methotrexate
      (MTX) in patients with rheumatoid arthritis (RA) and (b) the relation of purine
      metabolism with efficacy and toxicity of MTX treatment. METHODS: One hundred and
      three patients with active RA who started treatment with MTX were included. The
      initial MTX dosage was 7.5 mg/week and raised to a maximum of 25 mg weekly if
      necessary. The purine enzymes 5'-nucleotidase (5'NT), purine-nucleoside
      phosphorylase (PNP), hypoxanthine-guanine-phosphoribosyltransferase (HGPRT), and
      adenosine-deaminase (ADA) were measured before the start, after six weeks, and
      after 48 weeks or at study withdrawal. The laboratory results were related to
      measures of efficacy and toxicity of MTX treatment. RESULTS: Baseline values of
      5'NT and PNP (16.9 and 206.8 nmol/10(6) mononuclear cells/h, respectively) were
      similar to those in former studies. Activities of HGPRT and ADA were relatively
      low at the start (8.7 and 80.3 nmol/10(6) mononuclear cells/h, respectively).
      After six weeks purine enzyme activities showed no important changes from
      baseline. After 48 weeks of MTX treatment a decrease of the enzyme activities of
      ADA (-21.6 nmol/10(6) mononuclear cells/h; 95% CI -28.6 to -14.7), PNP (-78.9
      nmol/10(6) mononuclear cells/h; 95% CI -109.0 to -48.7), and HGPRT (-2.0
      nmol/10(6) mononuclear cells/h; 95% CI -3.1 to -0.9) was found. No association
      was shown between the enzyme activities of ADA, PNP, and HGPRT, and the efficacy
      or toxicity of MTX treatment. In contrast, enzyme activity of 5'NT showed a
      decrease in the subgroup of patients discontinuing MTX treatment because of
      hepatotoxicity. CONCLUSION: MTX treatment in patients with RA leads to a
      significant decrease of the purine enzyme activities of ADA, PNP, and HGPRT that
      is not related to the anti-inflammatory efficacy or toxicity of MTX.
      Hepatotoxicity was related to a decrease in the enzyme activity of 5'NT. These
      changes may be explained by direct or indirect (via purine de novo and salvage
      metabolism and the homocysteine pathway) effects of MTX.

PMID- 12429536
TI  - Definition of risk factors for death, end stage renal disease, and thromboembolic
      events in a monocentric cohort of 338 patients with systemic lupus erythematosus.
AB  - BACKGROUND: The survival rate in patients with systemic lupus erythematosus (SLE)
      has improved dramatically during the past four decades to 96.6% (five year) in
      the Erlangen cohort, but it is nearly three times as high as in an age and sex
      matched control population. Reasons for death are mainly cardiovascular diseases
      (37%) and infections (29%). OBJECTIVE: To find risk factors existing at disease
      onset for a severe outcome in the Erlangen cohort. PATIENTS AND METHODS: By using
      a database of 338 patients with SLE from a single centre, documented at least one
      to 15 years and including Systemic Lupus International Collaborating
      Clinics/American College of Rheumatology (SLICC/ACR) damage score data and index
      (SDI) and an activity score (European Consensus Lupus Activity Measurement
      (ECLAM)), a retrospective search was made for risk factors for a severe outcome
      like death, end stage renal disease (ESRD), and thromboembolic events (TE) in
      SLE. For this purpose, multivariable Cox regression models were analysed using
      the statistical package SPSS 10.0 for Windows. RESULTS: The following were
      defined as risk factors for death at disease onset: male sex (p<0.001, relative
      risk (RR)=3.5), age >40 at disease onset (p<0.0001, RR=19.9), nephritis (p<0.05,
      RR=1.6), a reduction of creatinine clearance (p<0.001, RR=1.8), heart disease
      (p=0.05, RR=1.5), and central nervous system (CNS) disease (p=0.06, RR=1.6). An
      increase in the SDI of two or more points from the first to the third year of
      disease was the worst prognostic factor (p<0.0001, RR=7.7). The existence of Ro
      or nRNP antibodies, or both, was protective (p<0.05, RR =0.1). A low C3 (p<0.01
      RR=3.0) and splenomegaly (p<0.01 RR=2.7) at disease onset turned out to be risk
      factors for ESRD besides a nephritis. In patients with hypertension (p<0.05)
      and/or high titres of dsDNA antibodies (>70 U/l) (p<0.01) and/or a mean ECLAM
      score of 4 (p<0.01) in the course of disease, a prevalence of ESRD was recorded
      in 9% (p<0.05) and 10% (p<0.01), and 8% (p<0.01) v 4% in the whole group.
      Analysis of risk factors at disease onset for TE identified positive lupus
      anticoagulant (p=0.17, RR=1.6), cryoglobulins (p<0.05, RR=1.8), and nephritis
      (p=0.05, RR=1.4), in addition to an age >40 at disease onset. CONCLUSIONS: A
      subgroup of patients in the Erlangen cohort with a typical clinical and
      serological phenotype at disease onset that is at high risk for a worse outcome
      was identified. Identification of these white patients at risk at disease onset
      will enable treatment to be intensified and thereby possibly prevent or better
      control late stage manifestations.

PMID- 12429537
TI  - Chronic widespread pain in the population: a seven year follow up study.
AB  - OBJECTIVES: To document the natural course of chronic widespread pain (CWP) in a
      general population sample over a seven year period and to identify comorbidities
      which predict persistence. METHODS: A mailed survey questionnaire returned by
      2334 adults registered with two general practices was used to obtain information
      on pain status (no pain, regional pain, or CWP) and other health and pain
      symptoms. Seven years later a second questionnaire was sent to responders who
      were still registered with the same general practice, asking about their current
      pain status. RESULTS: Information was obtained for 1386 adults (an adjusted
      response of 93%). The prevalence of CWP was similar for both surveys at 11% and
      10% respectively. Of those with CWP initially, a third recorded CWP on the second
      survey and 15% were pain free. Only 2% of subjects with no initial pain had
      developed CWP at follow up. Of subjects with CWP on the initial survey who were
      aged over 50 years and reported dry eyes or mouth and daytime tiredness, 77%
      reported CWP seven years later. This contrasts with a persistence of only 9% for
      those aged under 50 and with neither symptom recorded at initial survey.
      CONCLUSION: The proportion of subjects from a general population sample changing
      from CWP to no pain, or vice versa, over a seven year period was very low. This
      suggests that pain, once established, is likely to persist (or recur) especially
      if accompanied by other somatic symptoms and older age.

PMID- 12429538
TI  - Rhythmic variations in pain, stiffness, and manual dexterity in hand
      osteoarthritis.
AB  - OBJECTIVE: To explore circadian variation in pain, stiffness, and manual
      dexterity in patients with hand osteoarthritis (OA). METHODS: Twenty one patients
      with hand OA, as defined by ACR criteria (17 women, four men, mean age 62.2
      years, range 52-74 years) self rated pain and stiffness on separate 10 cm
      horizontal visual analogue scales and performed bead intubation coordinometry
      (BIC) six times each day (on waking up, at bedtime, and every four hours in
      between) for 10 consecutive days. Each series (using data with the trend removed
      if there was a significant trend) was analysed for circadian rhythmicity by a
      cosine vector technique (single cosinor). With individual data expressed as the
      percentage of the mean, group rhythm characteristics at period 24 hours were
      summarised for each variable by population mean cosinor analysis. RESULTS:
      Individual analyses identified significant circadian rhythms at p<or=0.05 for
      pain (n=15/21), stiffness (n=16/20), and dexterity (n=18/21), and a significant
      circadian rhythm on a group basis was identified for pain (p=0.013), stiffness
      (p<0.001), and dexterity (p<0.001). Pain was least at 1610 and stiffness at 1618.
      Peak dexterity occurred in mid-afternoon at 1548 and occurred within the 95%
      confidence interval of least pain (1312-1800) and stiffness (1520-1732).
      CONCLUSIONS: Dexterity was influenced by the patient's level of pain or
      stiffness, which changed systematically throughout the day. Similar results have
      been previously reported in 14 patients with rheumatoid arthritis where peak
      dexterity occurred at 1544 and at 1528 in 14 age and sex matched healthy
      controls. The predictability of rhythmic variation in pain, stiffness, and
      dexterity has implications for scheduling activities of daily living and for
      timing antirheumatic drug treatment.

PMID- 12429539
TI  - Investigation of chromosome 2q in osteoarthritis of the hand: no significant
      linkage in a Tasmanian population.
AB  - BACKGROUND: Previous studies have suggested a strong genetic component to
      osteoarthritis (OA), especially that of the hand, and three linkage studies have
      suggested the existence of susceptibility loci in disparate regions of chromosome
      2q. OBJECTIVE: To examine for linkage to 2q in a Tasmanian population of women
      and men with familial hand OA. METHODS: Hand OA (distal interphalangeal,
      carpometacarpal, and Heberden's nodes) was assessed by a combination of hand
      photographs and radiographs. A non-parametric linkage (NPL) analysis was
      performed on chromosome 2q of 69 members in 22 families with severe distal
      interphalangeal joint OA using Genehunter. A quantitative trait linkage analysis
      of a larger group of 456 members in 68 families was also performed using SOLAR.
      RESULTS: The maximum non-parametric linkage score was 1.05 (p=0.15) at marker
      IL1R1, close to the centromere. All components of hand OA scores had significant
      heritability in this dataset (28%-35%, all p<0.001). Despite this, the
      quantitative trait analysis (after adjustment for age and, where appropriate,
      sex) yielded maximum LOD scores of 0.90 for Heberden's nodes (both sexes
      combined), and 1.19 for carpometacarpal OA score (women only). CONCLUSIONS: These
      results do not provide confirmation of linkage on chromosome 2q in the larger
      white population with hand OA. They suggest that there are regional variations in
      the genetic cause of hand OA and that other loci not on 2q may be important in
      this disease.

PMID- 12429541
TI  - Diagnostic associations in a large and consecutively identified population
      positive for anti-SSA and/or anti-SSB: the range of associated diseases differs
      according to the detailed serotype.
AB  - OBJECTIVE: To determine the diagnostic distribution in a consecutive anti-SSA
      and/or anti-SSB positive population. METHODS: A total of 15 937 serum samples
      from 10 550 consecutive patients were analysed for antinuclear antibodies (ANAs)
      on HEp-2 cells. Serum samples positive for ANAs were analysed by immunodiffusion
      and line immunoassay with recombinant SSA-Ro52, natural SSA-Ro60, and recombinant
      SSB. RESULTS: Among ANA positive patients in whom clinical information was
      available, 181 consecutive patients with anti-SSA and/or anti-SSB antibodies were
      identified, Disease associations were systemic lupus erythematosus (SLE) (45.3%),
      primary Sjogren's syndrome (pSS) (14.4%), scleroderma (8.8%), RA (7.7%),
      cutaneous lupus (7.7%), and dermatomyositis (2.2%). The ratio of diagnoses
      differed according to the anti-SSA/anti-SSB serotype. Scleroderma and
      dermatomyositis were enriched among mono-Ro52 reactive serum samples (34.2% and
      10.5% respectively). Single reactivity towards Ro60 or anti-Ro60 with anti-Ro52
      predisposed for SLE (80.0% and 52.2% respectively). Triple reactivity towards
      Ro52, Ro60, and SSB was primarily linked with SLE (55.8%) followed by pSS
      (20.9%). Anti-SSA on immunodiffusion increased the chance for SLE (62.8%),
      whereas isolated anti-SSB reactivity on immunodiffusion was less indicative for
      SLE (14.3%) and predisposed more for cutaneous lupus (23.8%) and pSS (33.3%).
      CONCLUSION: The diagnostic range associated with anti-SSA or anti-SSB reactivity
      differs significantly according to the detailed serotype defined by line
      immunoassay and immunodiffusion.

PMID- 12429540
TI  - Clinical decision rules in rheumatoid arthritis: do they identify patients at
      high risk for osteoporosis? Testing clinical criteria in a population based
      cohort of patients with rheumatoid arthritis recruited from the Oslo Rheumatoid
      Arthritis Register.
AB  - BACKGROUND: Preliminary clinical criteria based on age, inflammation, and
      immobility have been proposed to identify which patients with rheumatoid
      arthritis (RA) should be examined by dual energy x ray absorptiometry (DXA) to
      diagnose osteoporosis. The three item criteria have not been evaluated in male
      patients with RA or in the entire female RA population. OBJECTIVES: (1) To test
      the proposed criteria in a cohort of men and women thought to be representative
      of the entire underlying RA population. (2) To develop clinical decision rules,
      which could be applied to all patients with RA irrespective of corticosteroid
      use. METHODS: Clinical and demographic data were collected from a total of 287
      representative patients with RA (235 (82%) women, 52 (18%) men, age range 25.3
      73.1 years) from the Oslo RA register (completeness 85%). Bone mineral density
      (BMD) was measured in spine L2-4 (anterior-posterior view) and femoral neck by
      DXA. The criteria were applied and sensitivity, specificity, positive predictive
      value (PPV), and negative predictive value (NPV) were calculated. RESULTS: Mean
      age (SD) for the women and men with RA was 56.8 (11.0) years and 61.5 (10.2)
      years; disease duration was 15.5 (9.5) years and 14.7 (8.6) years. Of the women
      163 (69%) were postmenopausal. One hundred and seventeen (50%) women and 28 (54%)
      men fulfilled the three item criteria. For the diagnosis of osteoporosis (T score
      <or=-2.5) using the original three item criteria sensitivity in women and men was
      74% and 67%, specificity 57% and 50%, PPV 32% and 29% and NPV 89% and 83%, and
      including weight and ever use of corticosteroids in a five item criteria
      sensitivity increased to 82% and 83%, specificity decreased to 45% and 45%, PPV
      was 29% and 31%, and NPV was 90% and 90% respectively. CONCLUSION: The novel five
      item criteria (age, weight, inflammation, immobility, and ever use of
      corticosteroids) are a more accurate tool to identify patients with RA and
      osteoporosis than the original three item criteria (age, inflammation, and
      immobility). The clinical decision rules have an acceptable sensitivity and
      provide a practical tool for the doctor to identify patients with RA who should
      have a DXA measurement performed.

PMID- 12429542
TI  - Loss of transforming growth factor counteraction on interleukin 1 mediated
      effects in cartilage of old mice.
AB  - OBJECTIVE: To investigate if a difference exists between young and old mice in
      the response of articular cartilage to interleukin 1 (IL1) and transforming
      growth factor beta (TGFbeta) alone or in combination. METHODS: The interaction of
      IL1 and TGFbeta was studied in cartilage of young (three months) and old mice (18
      months) both in vivo and in vitro. Therefore, IL1, TGFbeta, or IL1 together with
      TGFbeta was injected into the knee joints of mice on days 1, 3, and 5 before
      harvest of the patellae on day 6. Alternatively, isolated patellae were
      stimulated with IL1, TGFbeta, or IL1 together with TGFbeta in culture for 48
      hours. Proteoglycan (PG) synthesis and nitric oxide (NO) production were
      measured. RESULTS: IL1 inhibited PG synthesis and increased NO production in
      cartilage of both young and old mice. On the other hand, TGFbeta stimulated PG
      synthesis and reduced NO production in both age groups. Importantly, TGFbeta was
      able to counteract IL1 mediated effects on PG synthesis and NO production in
      young but not in old mice. CONCLUSIONS: Contrary to the findings in young mice,
      the cartilage of old animals does not antagonise IL1 effects via TGFbeta. This
      loss of responsiveness to the pivotal cytokine TGFbeta on effects of IL1 can be
      important in the initiation and progression of osteoarthritis (OA).

PMID- 12429543
TI  - A comparison between the Farr radioimmunoassay and a new automated fluorescence
      immunoassay for the detection of antibodies against double stranded DNA in serum.
AB  - OBJECTIVE: To compare test characteristics of the Farr radioimmunoassay and an
      automated fluorescence immunoassay (ELIA dsDNA test) for the diagnosis of
      systemic lupus erythematosus (SLE). METHODS: A cross sectional study comprising
      440 samples from 440 patients, sent to the laboratory over a three month period
      for anti-dsDNA testing. Chart review was performed, blinded for test results, to
      count for each patient the number of American College of Rheumatology criteria
      for the classification of SLE that were fulfilled. At least four criteria were
      met by 248 (56%) patients (SLE), one to three criteria by 77 (18%) (lupus-like
      disease, LLD), and no criterion by 115 (26%) (non-SLE/non-LLD). Results from
      serum samples from the non-SLE/non-LLD and SLE groups were used to calculate
      receiver operating characteristic curves. RESULTS: For the Farr assay,
      specificities of 95% and 99% corresponded to sensitivities of 72% and 56%
      respectively. For the ELIA dsDNA test these levels of specificity corresponded to
      sensitivities of 44% and 17% respectively. CONCLUSIONS: The Farr radioimmunoassay
      is superior to the ELIA dsDNA test for identifying patients with SLE.

PMID- 12429544
TI  - Reliability of the Southampton examination schedule for the diagnosis of upper
      limb disorders in the general population.
AB  - BACKGROUND: Epidemiological research in the field of soft tissue neck and upper
      limb disorders has been hampered by the lack of an agreed system of diagnostic
      classification. In 1997, a United Kingdom workshop agreed consensus definitions
      for nine of these conditions. From these criteria, an examination schedule was
      developed and validated in a hospital setting. OBJECTIVE: To investigate the
      reliability of this schedule in the general population. METHODS: Ninety seven
      adults of working age reporting recent neck or upper limb symptoms were invited
      to attend for clinical examination consisting of inspection and palpation of the
      upper limbs, measurement of active and passive ranges of motion, and clinical
      provocation tests. A doctor and a trained research nurse examined each patient
      separately, in random order and blinded to each other's findings. RESULTS:
      Between observer repeatability of the schedule was generally good, with a median
      kappa coefficient of 0.66 (range 0.21 to 0.93) for each of the specific diagnoses
      considered. CONCLUSION: As expected, the repeatability of tests is poorer in the
      general population than in the hospital clinic, but the Southampton examination
      schedule is sufficiently reproducible for epidemiological research in the general
      population.

PMID- 12429545
TI  - Magnetic resonance imaging of skeletal muscle involvement in limb restricted
      vasculitis.
AB  - BACKGROUND: Limb restricted polyarteritis nodosa (PAN) and PAN-type diseases such
      as isolated vasculitis of skeletal muscle are localised vasculitides affecting
      the skin, muscles, or peripheral nerves, usually of the lower limbs. These
      diseases often present with non-specific clinical symptoms and normal laboratory
      values and electromyograms. The usefulness of magnetic resonance imaging (MRI) of
      skeletal muscle has been poorly investigated to date. OBJECTIVE: To describe the
      MRI findings in the legs of three patients with limb restricted vasculitides (two
      PAN, one isolated vasculitis of the skeletal muscle) with histologically
      established muscle involvement. METHODS: MRI was carried out on calf muscles and
      T(2) weighted images, unenhanced T(1) weighted images, and STIR sequences were
      obtained. RESULTS: Muscle damage resulted in oedema-like changes on MRI
      characterised by hyperintense signals in T(2) weighted and slow tau inversion
      recovery (STIR) sequences and normal unenhanced T(1) weighted sequences of one or
      several leg muscles. CONCLUSIONS: MRI should be considered a useful complementary
      examination that might facilitate the recognition of limb restricted
      vasculitides, and possibly indicate the site for muscle biopsy. It could also be
      useful in monitoring the course of the disease. Future studies should also
      evaluate MRI for systemic PAN or other systemic vasculitides with muscle
      involvement.

PMID- 12429546
TI  - Polymyositis with cardiac manifestations and unexpected immunology.

PMID- 12429547
TI  - Eosinophilic fasciitis with multiple myeloma: a new haematological association.

PMID- 12429548
TI  - Dust exposure: a missed environmental factor of Wegener's granulomatosis.

PMID- 12429549
TI  - Spinal cord stimulation in Buerger's disease.

PMID- 12429550
TI  - Standing committee on epidemiology and health services research.

PMID- 12429551
TI  - Health professionals standing committee.

PMID- 12429552
TI  - Probable adverse effects of long term use of somatostatin analogues in patients
      with RA.

PMID- 12429553
TI  - Role of macula densa cyclooxygenase-2 in renovascular hypertension.
AB  - Upregulation of the inducible cyclooxygenase (COX-2) in the macula densa
      accompanies the activation of the juxtaglomerular apparatus in many high-renin
      conditions. The functional role of COX-2 in these disease states is poorly
      understood. We tested whether COX-2 is required to increase renin in renovascular
      hypertension. Rats with established two-kidney, one-clip (2K1C) hypertension were
      treated for 2 wk with two different inhibitors of COX-2, NS-398 and rofecoxib,
      respectively. Hypertension in 2K1C rats was not affected or slightly enhanced by
      COX-2 inhibition, as measured intra-arterially in conscious animals. The increase
      in plasma renin activity was also unchanged by both rofecoxib and NS-398. The
      number of glomeruli with a renin-positive juxtaglomerular apparatus was elevated
      in clipped kidneys and decreased in contralateral kidneys of 2K1C rats. This
      pattern was unaltered by COX-2 inhibition. To test the effects of COX-2 blockade
      on a primarily macula densa-mediated stimulus, we studied salt depletion for
      comparison. A low-salt diet induced a significant increase in plasma renin
      activity, which was partially inhibited by treatment with NS-398. We conclude
      that inhibition of COX-2 in established renovascular hypertension does not affect
      renin synthesis or release. Thus either COX-2 is not necessary for the macula
      densa mechanism or the macula densa is not important for maintaining high renin
      in renovascular hypertension.

PMID- 12429554
TI  - Transport of cimetidine by flounder and human renal organic anion transporter 1.
AB  - The H(2)-receptor antagonist cimetidine is efficiently excreted by the kidneys.
      In vivo studies indicated an interaction of cimetidine not only with transporters
      for basolateral uptake of organic cations but also with those involved in
      excretion of organic anions. We therefore tested cimetidine as a possible
      substrate of the organic anion transporters cloned from winter flounder (fROAT)
      and from human kidney (hOAT1). Uptake of [(3)H]cimetidine into fROAT-expressing
      Xenopus laevis oocytes exceeded uptake into control oocytes. At -60-mV clamp
      potential, 1 mM cimetidine induced an inward current, which was smaller than that
      elicited by 0.1 mM PAH. Cimetidine concentrations exceeding 0.1 mM decreased PAH
      induced inward currents, indicating interaction with the same transporter. At pH
      6.6, no current was seen with 0.1 mM cimetidine, whereas at pH 8.6 a current was
      readily detectable, suggesting preferential translocation of uncharged cimetidine
      by fROAT. Oocytes expressing hOAT1 also showed [(3)H]cimetidine uptake. These
      data reveal cimetidine as a substrate for fROAT/hOAT1 and suggest that organic
      anion transporters contribute to cimetidine excretion in proximal tubules.

PMID- 12429555
TI  - Hormone-regulated transepithelial Na+ transport in mammalian CCD cells requires
      SGK1 expression.
AB  - To study the role of serum and glucocorticoid-inducible kinase-1 (SGK1) in
      mammalian cells, we compared Na(+) transport rates in wild-type (WT) M1 cortical
      collecting duct cells with M1 populations stably expressing human full-length
      SGK1, NH(2)-terminal truncated (DeltaN-60) SGK1, "kinase-dead" (K127M) SGK1, and
      cells that have downregulated levels of SGK1 mRNA (antisense SGK1). Basal rates
      of transepithelial Na(+) transport were highest in full-length SGK1 populations,
      compared among the above populations. Dexamethasone treatment increased Na(+)
      transport in WT and full-length SGK1 cells 2.7- and 2-fold, respectively. Modest
      stimulation of Na(+) absorption was detected after dexamethasone treatment in
      DeltaN-60 SGK1 populations. However, DeltaN-60 SGK1 transport rates remained
      substantially lower than WT values. Importantly, a combination of high insulin,
      dexamethasone, and serum failed to significantly stimulate Na(+) transport in
      antisense or K127M SGK1 cells. Additionally, expression of antisense SGK1
      significantly decreased transepithelial resistance values. Overall, we concluded
      that SGK1 is a critical component in corticosteroid-regulated Na(+) transport in
      mammalian cortical collecting duct cells. Furthermore, our data suggest that the
      NH(2) terminus of SGK1 may contain a Phox homology-like domain that may be
      necessary for effective Na(+) transport.

PMID- 12429556
TI  - Renal segmental microvascular responses to ANG II in AT1A receptor null mice.
AB  - The relative contributions of AT(1A) and AT(1B) receptors to afferent arteriolar
      autoregulatory capability and afferent and efferent arteriolar responses to ANG
      II are not known. Experiments were conducted in kidneys from wild-type (WT) and
      AT(1A)-/- mice utilizing the in vitro blood-perfused juxtamedullary nephron
      technique. Direct measurements of afferent (AAD) and efferent arteriolar
      diameters (EAD) were assessed at a renal arterial pressure of 100 mmHg. AAD
      averaged 14.8 +/- 0.8 microm for WT and 14.9 +/- 0.8 microm for AT(1A)-/- mice.
      AAD significantly decreased by 7 +/- 1, 16 +/- 1, and 26 +/- 2% for WT mice and
      by 11 +/- 1, 20 +/- 2, and 30 +/- 3% for AT(1A)-/- mice (120, 140, 160 mmHg). AAD
      autoregulatory capability was not affected by the absence of AT(1A) receptors.
      AAD responses to 10 nM ANG II were significantly blunted for AT(1A)-/- mice
      compared with WT (-22 +/- 2 vs. -37 +/- 5%). ANG II (0.1-10 nM) failed to elicit
      any change in EAD for AT(1A)-/- mice. AAD and EAD reductions in ANG II were
      blocked by 1 microM candesartan. We conclude that afferent arteriole
      vasoconstrictor responses to ANG II are mediated by AT(1A) and AT(1B) receptors,
      whereas efferent arteriolar vasoconstrictor responses to ANG II are mediated by
      only AT(1A) receptors in the mouse kidney.

PMID- 12429557
TI  - Maternal and fetal adaptations during pregnancy: lessons in regulatory and
      integrative physiology.

PMID- 12429558
TI  - Intraventricular insulin potentiates the anorexic effect of corticotropin
      releasing hormone in rats.
AB  - Intraventricular corticotropin releasing hormone (CRH) suppresses food intake and
      body weight as a stress response. Insulin, acting within the brain, also
      suppresses food intake and body weight, and this suppression is related to
      caloric homeostasis. We determined if increased insulin within the brain
      potentiates the anorexic effects of intraventricular CRH. Rats were food deprived
      for 17 h each day and then given 30-min access to Ensure. One-half received
      continuous third ventricular infusion of synthetic cerebrospinal fluid via
      osmotic minipumps, and one-half received insulin (0.6 mU/day). During the
      infusion, rats also received 0, 0.1, 1.0, or 5.0 microg of CRH into the lateral
      ventricle just before access to Ensure. Insulin alone had no effect on Ensure
      intake or body weight. CRH dose dependently reduced Ensure intake in both groups,
      and the reduction was greater in the insulin group. Hence, central insulin
      potentiated the ability of centrally administered CRH to suppress food intake.
      These findings suggest that stress-related influences over food intake,
      particularly those mediated via CRH, interact with relative adiposity as signaled
      to the brain by central insulin.

PMID- 12429559
TI  - Effects of hypothermia on neuronal-vascular function after cerebral ischemia in
      piglets.
AB  - We determined whether cerebral arteriolar dilation to N-methyl-d-aspartate
      (NMDA), a response dependent on stimulation of cortical neurons and inhibited by
      anoxic stress, would be preserved by hypothermia during and following ischemia.
      Pial arteriolar diameters in anesthetized piglets were determined via intravital
      microscopy. Arteriolar responses to NMDA (10, 50, and 100 micromol/l) were
      measured before and 1 h after 10 min of global ischemia. Piglets were exposed to
      either total body or selective brain cooling (33-34 degrees C). Arteriolar
      dilation to lower doses or to 100 micromol/l NMDA was not affected by hypothermia
      alone (51 +/- 3 vs. 46 +/- 7%, normothermia vs. hypothermia; n = 7) in
      nonischemic animals. However, arteriolar responses to 100 micromol/l NMDA were
      clearly attenuated after ischemia despite body cooling during ischemia (53 +/- 3
      vs. 32 +/- 6%; n = 8), hypothermia during ischemia and early reperfusion (49 +/-
      10 vs. 20 +/- 3%; n = 8), or selective brain cooling (48 +/- 5 vs. 20 +/- 5%; n =
      10). In contrast, pretreatment with indomethacin resulted in complete
      preservation of NMDA-induced vasodilation after ischemia. Thus, hypothermia fails
      to protect against neuronal dysfunction during ischemia.

PMID- 12429560
TI  - Enhanced mental performance at higher body temperature?

PMID- 12429561
TI  - Estradiol treatment increases CCK-induced c-Fos expression in the brains of
      ovariectomized rats.
AB  - The ovarian hormone estradiol reduces meal size and food intake in female rats,
      at least in part by increasing the satiating potency of CCK. Here we used c-Fos
      immunohistochemistry to determine whether estradiol increases CCK-induced
      neuronal activation in several brain regions implicated in the control of
      feeding. Because the adiposity signals leptin and insulin appear to control
      feeding in part by increasing the satiating potency of CCK, we also examined
      whether increased adiposity after ovariectomy influences estradiol's effects on
      CCK-induced c-Fos expression. Ovariectomized rats were injected subcutaneously
      with 10 microg 17beta-estradiol benzoate (estradiol) or vehicle once each on
      Monday and Tuesday for 1 wk (experiment 1) or for 5 wk (experiment 2). Two days
      after the final injection of estradiol or vehicle, rats were injected
      intraperitoneally with 4 microg/kg CCK in 1 ml/kg 0.9 M NaCl or with vehicle
      alone. Rats were perfused 60 min later, and brain tissue was collected and
      processed for c-Fos immunoreactivity. CCK induced c-Fos expression in the nucleus
      of the solitary tract (NTS), area postrema (AP), paraventricular nucleus of the
      hypothalamus (PVN), and central nucleus of the amygdala (CeA) in vehicle- and
      estradiol-treated ovariectomized rats. Estradiol treatment further increased this
      response in the caudal, subpostremal, and intermediate NTS, the PVN, and the CeA,
      but not in the rostral NTS or AP. This action of estradiol was very similar in
      rats tested before (experiment 1) and after (experiment 2) significant body
      weight gain, suggesting that adiposity does not modulate CCK-induced c-Fos
      expression or interact with estradiol's ability to modulate CCK-induced c-Fos
      expression. These findings suggest that estradiol inhibits meal size and food
      intake by increasing the central processing of the vagal CCK satiation signal.

PMID- 12429562
TI  - GABA-mediated neurotransmission in the ventrolateral NTS plays a role in
      respiratory regulation in the rat.
AB  - Our purpose was to determine whether endogenously released GABA in the
      ventrolateral nucleus of the solitary tract (vlNTS) of the rat influences
      respiration. Experiments were carried out in anesthetized, vagotomized and
      spontaneously breathing rats, and diaphragm electromyogram activity was measured
      while drugs affecting GABAergic neurotransmission were microinjected into the
      vlNTS and medial NTS (mNTS). Bilateral microinjection of nipecotic acid, 5 or 25
      nmol, into the vlNTS (but not in the mNTS) produced dose-dependent increases in
      inspiratory duration (Ti) frequently culminating in apneustic breathing. Neither
      unilateral microinjection of bicuculline nor CGP-35348 (GABA(B) receptor
      antagonist) reversed this response; however, a combination of both GABA receptor
      antagonists effectively reversed apneustic breathing. Bilateral microinjection of
      either muscimol or baclofen into the vlNTS mimicked the effect of nipecotic acid.
      Microinjection of the bicuculline produced apnea, whereas microinjection of CGP
      35348 produced a decrease in Ti and an increase in expiratory duration.
      Immunohistochemical analysis of the vlNTS region revealed GABA(A) receptors
      densely localized to processes, whereas GABA(B) immunoreactivity was localized to
      cell bodies. Our data indicate that GABA activity in the vlNTS is important for
      respiratory function.

PMID- 12429563
TI  - The role of mitochondrial K(ATP) channels in the antiarrhythmic effects of
      ischaemic preconditioning in dogs.

PMID- 12429564
TI  - Unravelling mechanisms underlying ischaemic arrhythmias - the importance of
      models.
AB  - A new model of regional ischaemia using blood-perfused isolated rat hearts is
      reported in this issue. This model has potential value in pharmacology to test
      the actions of drugs against the arrhythmias that arise early period (0-30 min)
      after induction of ischaemia. Unfortunately, the severity of arrhythmias in this
      new model is reduced, when compared to other models, in both the early and the
      late period (1-4 h) of coronary artery occlusion. This commentary compares the
      new model with previous models, and comments on the possible mechanisms of
      arrhythmias induced by ischaemia.

PMID- 12429565
TI  - An assay to evaluate the long term effects of inflammatory mediators on airway
      smooth muscle: evidence that TNF(alpha)up-regulates 5-HT(2A) mediated
      contraction.

PMID- 12429566
TI  - Inhibitory effect of diazepam on muscarinic receptor-stimulated inositol 1,4,5
      trisphosphate production in rat parotid acinar cells.
AB  - 1. This study examined the effect of diazepam (DZP) on phosphoinositide turnover,
      which plays an important role in the regulation of salivary secretion, in rat
      parotid acinar cells. 2. DZP (10(-9) M to 10(-5) M), a potent agonist of both
      central- and peripheral-type benzodiazepine receptors, dose-dependently decreased
      inositol 1,4,5-trisphosphate IP3 production stimulated by carbachol, a muscarinic
      receptor agonist, in the cells. 3. DZP produced a maximum inhibitory response at
      a concentration of 10(-5) M, with IP3 production decreased to 63% of maximal
      levels. The concentration inducing half maximal inhibition of IP3 production was
      approximately 3.5 x 10 (-8) M. 4. An inhibitory response to DZP was produced by a
      short-term pretreatment (<3 min) of the cells and prevented by antagonist and
      competing ligand for the central- and peripheral-type benzodiazepine receptors,
      flumazenil and PK 11195, respectively. 5. DZP showed a non-competitive inhibition
      of carbachol-stimulated IP3 production. It did not directly inhibit the
      activities of GTP-binding regulatory proteins and phosphatidylinositol 4,5
      bisphosphate-specific phospholipase C (PLC) in the parotid gland membranes,
      though choline chloride inhibited PLC activity. 6. DZP (10(-5) M) attenuated the
      increase in the intracellular Ca2+ concentration ([Ca(2+)](i)) in the cells
      following stimulation of the muscarinic and alpha(1)-adrenoceptors. 7. These
      results suggest that in the parotid acinar cells, DZP inhibits muscarinic
      receptor-stimulated IP3 production through benzodiazepine receptors and that PLC
      activity which produces IP3 is inhibited by chloride. The decreases in IP3 and
      [Ca(2+)](i) in the cells may be connected with the suppression of salivary
      secretion induced by DZP.

PMID- 12429567
TI  - T cell selective apoptosis by a novel immunosuppressant, FTY720, is closely
      regulated with Bcl-2.
AB  - 1. A novel immunosuppressant FTY720 caused a significant decrease in peripheral T
      lymphocytes, but not in B lymphocytes upon oral administration. This decrease was
      mainly a result of FTY720-induced apoptosis. In this study, we confirmed FTY720
      induced T cell selective apoptosis using lymphoma cell lines in vitro. 2.
      Viability loss, DNA fragmentation, Annexin V binding, and caspases activation
      (caspase-3, -8, and -9) were observed in Jurkat cells (T lymphoma cells), but not
      significantly in BALL-1 cells (B lymphoma cells). These results indicated that
      FTY720 selectively induced apoptosis in T cell lymphoma to a greater extent than
      in B cell lymphoma, a finding that is similar to the result observed when FTY720
      was treated with T lymphocytes and B lymphocytes in vitro. 3. FTY720 released
      cytochrome c from mitochondria in Jurkat intact cells as well as from isolated
      Jurkat mitochondria directly, but not from mitochondria in BALL-1 cells nor from
      isolated BALL-1 mitochondria. 4. BALL-1 cells and B cells had more abundant
      mitochondria-localized anti-apoptotic protein Bcl-2 than did Jurkat cells and T
      cells. 5. FTY720-induced apoptosis is inhibited by the overexpression of Bcl-2,
      suggesting that the cellular Bcl-2 level regulates the sensitivity to FTY720.

PMID- 12429568
TI  - Functional consequences of perinatal exposure to 3,4
      methylenedioxymethamphetamine in rat brain.
AB  - 1. In this study we have examined methylenedioxymethamphetamine (MDMA)-induced
      toxicity in perinatal rat brain, related this to normal development of serotonin
      transporter sites (SERT), and determined whether early exposure to MDMA
      subsequently alters cerebral function in adults. 2. Perinatal development of SERT
      was visualized and quantified using [(3)H]-paroxetine binding autoradiography in
      embryonic and neonatal rat brain from embryonic day 15 (E15) to postnatal day p30
      (p30). Cerebral glucose utilization (lCMR(glu)) was measured by 2-deoxyglucose
      autoradiography in adult rats. 3. [(3)H]-Paroxetine binding was observed in
      forebrain from E18. From birth (p0), binding was organized into neocortical
      columns (75% higher at p10 than in adult) which declined toward adult levels
      between p20 and p25. 4. MDMA treatment (20 mg x kg(-1) s.c. twice daily for four
      days) commencing at developmental stages from E15 (treatment given to dams) to
      p20, had no effect upon [(3)H]-paroxetine binding measured at p40. Treatments
      started on p25 or later resulted in significant decreases in [(3)H]-paroxetine
      binding (>or=46%). This was coincident with the development of adult patterns of
      binding in forebrain. 5. Despite the lack of MDMA-induced neurotoxicity, rats
      treated in utero (E15) showed increased lCMR(glu) in locus coeruleus (+37%), and
      in areas receiving ascending noradrenergic innervation, such as anterior thalamus
      (+44%) and septal nucleus (+24%). 6 These studies confirm that the susceptibility
      of serotonergic terminals to the neurotoxic properties of MDMA is absent in the
      immediate perinatal period, but also suggests that in utero MDMA exposure
      produces significant long-term effects on cerebral function by a mechanism as yet
      unknown.

PMID- 12429569
TI  - An assay to evaluate the long-term effects of inflammatory mediators on murine
      airway smooth muscle: evidence that TNFalpha up-regulates 5-HT(2A)-mediated
      contraction.
AB  - 1. Asthma research is arguably limited by an absence of appropriate animal models
      to study the pharmacology of inflammatory mediators that affect airway
      hyperresponsiveness and remodelling. Here we assessed an assay based on mouse
      tracheal segments cultured for 1-32 days, and investigated contractile responses
      mediated by muscarinic and 5-hydroxytryptamine (5-HT) receptors following long
      term exposure to tumour necrosis factor-alpha (TNFalpha). 2. Following culture,
      in the absence of TNFalpha, maximum contractile responses to KCl and carbachol
      were similar, with an increase in response up to day two and a decrease to a
      stable level after 8 days. Maximal relaxations to isoprenaline were not affected
      by the culture procedure. The potency of KCl and isoprenaline increased
      throughout the study. DNA microarray data revealed that global gene expression
      changes were greater when tissues were introduced to culture than when they were
      maintained in culture. The morphology of smooth muscle cells was maintained
      throughout the culture period. 3. 5-HT induced a weak contraction in both fresh
      and cultured (up to 8 days) segments. Culture with TNFalpha produced a time- and
      concentration-dependent increase in the maximal contraction to 5-HT, evidently
      mediated by 5-HT(2A) receptors, whereas, the potency for carbachol was reduced.
      4. In conclusion, the phenotype of airway smooth muscle remained largely intact
      during the culture period, even though minor changes were obtained during the
      first days of culture. The time-dependent effect of TNFalpha indicates the
      importance of studying the long-term effect of cytokines on the smooth muscle
      cells in relation to airway hyperresponsiveness and remodelling.

PMID- 12429570
TI  - RhoA kinase and protein kinase C participate in regulation of rabbit stomach
      fundus smooth muscle contraction.
AB  - 1. The degree to which the RhoA kinase (ROK) blockers, Y-27632 (1 micro M) and HA
      1077 (10 micro M), and the PKC blocker, GF-109203X (1 micro M), reduced force
      produced by carbachol, a muscarinic receptor agonist, and phenylephrine, an alpha
      adrenoceptor agonist, was examined in rabbit stomach fundus smooth muscle. 2.
      When examining the effect on cumulative carbachol concentration-response curves
      (CRCs), ROK and PKC blockers shifted the potency EC50 to the right but did not
      reduce the maximum response. 3. In a single-dose carbachol protocol using
      moderate ( approximately EC50 and maximum carbachol concentrations, Y-27632 and
      HA-1077 reduced peak force, but GF-109203X had no effect. By contrast, all three
      agents inhibited the carbachol contractions of rabbit bladder (detrusor) smooth
      muscle. 4. Compared to carbachol, phenylephrine produced a weaker maximum
      response that was not inhibited by phentolamine, atropine nor capsaicin but was
      inhibited by Y-27632, HA-1077 and GF-109203X. 5. In detrusor, classical down
      regulation occurred, but in fundus, up-regulation of responsiveness occurred.
      This up-regulation in fundus may have been a post-receptor event, because a KCl
      induced contraction produced after a carbachol CRC was stronger than one produced
      before the carbachol stimulus. 6. In conclusion, these data suggest that ROK
      plays a critical role in the regulation of rabbit fundus smooth muscle
      contraction, which is distinct from chicken gizzard smooth muscle, where ROK is
      reported to exist but to not play a role in muscarinic receptor-induced
      contraction. Additional unique findings are that PKC participates in
      phenylephrine- but not carbachol-induced contraction in fundus, that carbachol
      does not activate identical subcellular signalling systems in fundus and
      detrusor, and that fundus, unlike detrusor, responds to carbachol stimulation
      with post-receptor up-regulation of contraction.

PMID- 12429571
TI  - Superoxide anions mediate veratridine-induced cytochrome c release and caspase
      activity in bovine chromaffin cells.
AB  - 1. Mitochondrial mechanisms involved in veratridine-induced chromaffin cell death
      have been explored. 2. Exposure to veratridine (30 micro M, 1 h) produces
      cytochrome c release to the cytoplasm that seems to be mediated by superoxide
      anions and that is blocked by cyclosporin A (10 micro M), MnTBAP (10 nM),
      catalase (100 IU ml(-1)) and vitamin E (50 micro M). 3. Following veratridine
      treatment, there is an increase in caspase-like activity, blocked by vitamin E
      (50 micro M) and the mitochondrial permeability transition pore blocker
      cyclosporin A (10 micro M). 4. Superoxide anions open the mitochondrial
      permeability transition pore in isolated mitochondria, an effect that is blocked
      by vitamin E (50 micro M) and cyclosporin A (10 micro M), but not by the Ca2+
      uniporter blocker ruthenium red (5 micro M). 5. These results strongly suggest
      that under the stress situation caused by veratridine, superoxide anions become
      important regulators of mitochondrial function in chromaffin cells. 6. Exposure
      of isolated bovine chromaffin mitochondria to Ca2+ results in mitochondrial
      swelling. This effect was prevented by ruthenium red (5 micro M) and cyclosporin
      A (10 micro M), while it was not modified by vitamin E (50 micro M). 7.
      Veratridine (30 micro M, 1 h) markedly decreased total glutathione and GSH
      content in bovine chromaffin cells. 8. In conclusion, superoxide anions seem to
      mediate veratridine-induced cytochrome c release, decrease in total glutathione,
      caspase activation and cell death in bovine chromaffin cells.

PMID- 12429572
TI  - The intracellular pathway of the acetylcholine-induced contraction in cat
      detrusor muscle cells.
AB  - 1. The present study was aimed to investigate intracellular pathways involved in
      acetylcholine (ACh)-induced contraction in cat detrusor muscle cells 2.
      Contraction was expressed as per cent shortening of length of individually
      isolated smooth muscle cells obtained by enzymatic digestion. Dispersed intact
      and permeabilized cells were prepared for the treatment of drugs and antibody to
      enzymes, respectively. Using Western blot, we confirmed the presence of related
      proteins. 3. The maximal contraction to ACh was generated at 10(-11) M. This
      response was preferentially antagonized by M3 muscarinic receptor antagonist rho
      fluoro-hexahydrosiladifenidol (rhoF-HSD) but not by the M1 antagonist pirenzepine
      and the M2 muscarinic receptor antagonist methoctramine. We identified G-proteins
      (Gq/11), (Gs), (G0), (Gi1), (Gi2) and (Gi3) in the bladder detrusor muscle. ACh
      induced contraction was selectively inhibited by (Gq/11) antibody but not to
      other G subunit. 4. The phosphatidylinositol-specific phospholipase C (PI-PLC)
      inhibitor neomycin reduced ACh-induced contraction. However, the inhibitors of
      the phospholipase D, the phospholipase A2 and protein kinase C did not attenuate
      the ACh-induced contraction. ACh-induced contraction was inhibited by antibody to
      PLC-beta1 but not PLC-beta3 and PLC-gamma. Thapsigargin or strontium, which
      depletes or blocks intracellular calcium release, inhibited ACh-induced
      contraction. Inositol 1,4,5-triphosphate IP3 receptor inhibitor heparin reduced
      ACh-induced contraction. 5. These results suggest that in cat detrusor muscle
      contraction induced by ACh is mediated via M3 muscarinic receptor-dependent
      activation of Gq/11 and PLC-beta1 and IP3-dependent Ca(2+) release.

PMID- 12429573
TI  - Inhibition of cytokine-induced JAK-STAT signalling pathways by an endonuclease
      inhibitor aurintricarboxylic acid.
AB  - 1. Inducible nitric oxide (iNOS) is thought to involve in host defence and tissue
      damage in inflammatory loci. In previous study, we have found that the
      endonuclease inhibitor aurintricarboxylic acid (ATA) can protect macrophages from
      cell death induced by bacterial lipopolysaccharide. This action is through the
      interruption with signalling pathways for NF-kappa B and AP-1 activation, and
      thus iNOS expression. In this study we have addressed the effects of ATA on JAK
      STAT signalling pathways. 2. In murine RAW 264.7 macrophages, IFN-gamma-mediated
      NO production and iNOS expression were concentration-dependently reduced by the
      presence of 3-100 micro M ATA. 3. IFN-gamma-induced STAT1 activation, as assessed
      from its tyrosine phosphorylation, nuclear translocation, binding to specific DNA
      response element and evoked IRF-1 reporter gene assay, were concomitantly
      inhibited by ATA. However, ATA did not alter IFN-gamma binding to RAW 264.7
      cells. 4. The activities of JAK1 and JAK2, the upstream kinases essential for
      STAT1 signalling in response to IFN-gamma, were also reduced by ATA. 5. Moreover,
      IL-4, IL-10, GM-CSF and M-CSF elicited tyrosine phosphorylation of STAT3, STAT5
      and/or STAT6 in macrophages were diminished by the presence of ATA. 6. Taken
      together, we conclude that ATA can interfere JAK-STAT signalling pathways in
      response to cytokines. This action contributes to the inhibition of IFN-gamma
      induced iNOS expression.

PMID- 12429575
TI  - Effects of non-steroidal anti-inflammatory drugs on cyclo-oxygenase and
      lipoxygenase activity in whole blood from aspirin-sensitive asthmatics vs healthy
      donors.
AB  - 1. Cyclo-oxygenase (COX) and lipoxygenase (LO) share a common substrate,
      arachidonic acid. Aspirin and related drugs inhibit COX activity. In a subset of
      patients with asthma aspirin induces clinical symptoms associated with increased
      levels of certain LO products, a phenomenon known as aspirin-sensitive asthma.
      The pharmacological pathways regulating such responses are not known. 2. Here COX
      1 and LO activity were measured respectively by the formation of thromboxane B(2)
      (TXB(2)) or leukotrienes (LT) C(4), D(4) and E(4) in whole blood stimulated with
      A23187. COX-2 activity was measured by the formation of prostaglandin E(2)
      (PGE(2)) in blood stimulated with lipopolysaccharide (LPS) for 18 h. 3. No
      differences in the levels of COX-1, COX-2 or LO products or the potency of drugs
      were found in blood from aspirin sensitive vs aspirin tolerant patients. Aspirin,
      indomethacin and nimesulide inhibited COX-1 activity, without altering LO
      activity. Indomethacin, nimesulide and the COX-2 selective inhibitor DFP [5,5
      dimethyl-3-(2-isopropoxy)-4-(4-methanesulfonylphenyl)-2(5H)-furanone] inhibited
      COX-2 activity. NO-aspirin, like aspirin inhibited COX-1 activity in blood from
      both groups. However, NO-aspirin also reduced LO activity in the blood from both
      patient groups. Sodium salicylate was an ineffective inhibitor of COX-1, COX-2 or
      LO activity in blood from both aspirin-sensitive and tolerant patients. 4. Thus,
      when COX activity in the blood of aspirin-sensitive asthmatics is blocked there
      is no associated increase in LO products. Moreover, NO-aspirin, unlike other
      NSAIDs tested, inhibited LO activity in the blood from both aspirin sensitive and
      aspirin tolerant individuals. This suggests that NO-aspirin may be better
      tolerated than aspirin by aspirin-sensitive asthmatics.

PMID- 12429574
TI  - Immediate and delayed VEGF-mediated NO synthesis in endothelial cells: role of
      PI3K, PKC and PLC pathways.
AB  - 1. The mechanism(s) by which vascular endothelial growth factor (VEGF) induces
      endothelial nitric oxide synthase (eNOS) activation remain(s) unclear up to a
      certain extent. Therefore, we sought to evaluate the contribution of numerous
      pathways in VEGF-induced nitric oxide (NO) synthesis by measuring cGMP
      production. In addition, as VEGF induces the synthesis of NO and platelet
      activating factor (PAF), we wanted to assess if the induction of PAF and NO is
      contributing to the synthesis of each other. 2. Herein, we show that a treatment
      of endothelial cells with a phospholipase C (PLC) inhibitor (U73122), a
      calmodulin antagonist (W-7) or with intracellular calcium chelators (EGTA/AM,
      BAPTA/AM) prevented VEGF-mediated eNOS Ser(1177)-phosphorylation and NO synthesis
      measured by cGMP production. 3. Pretreatment with phosphatidylinositol 3-kinase
      (PI3K) (Wortmannin, LY294002) or protein kinase C (PKC) (GF109203X, Ro318220)
      inhibitors attenuated eNOS Ser(1177)-phosphorylation mediated by VEGF, but did
      not alter immediate (0-10 min) cGMP synthesis induced by VEGF, but abrogated by
      up to 84% the delayed (10-30 min) cGMP synthesis. 4. Pretreatment with PAF
      synthesis inhibitors or with PAF receptor antagonists did not abrogate neither
      eNOS Ser(1177)-phosphorylation nor cGMP synthesis mediated by VEGF. 5. In
      conclusion, VEGF induces an immediate cGMP synthesis through the PLC-Ca2+/CaM
      pathway, and that the induction of delayed cGMP synthesis implies Akt and PKC
      activity.

PMID- 12429576
TI  - Down-regulation of hepatic cytochrome p450 in chronic renal failure: role of
      uremic mediators.
AB  - 1. Chronic renal failure (CRF) is associated with a decrease in liver cytochrome
      p450 (p450). The mechanism remains poorly understood. The present study aimed to
      investigate the effects of the serum of rats with CRF on liver p450. 2. Normal
      rat hepatocytes were incubated for 24 h with serum (concentration of 10%) from
      rats with CRF and from control animals in order to measure (1). total p450 level,
      (2). protein expression and mRNA levels of major p450 isoforms, and (3). some of
      their specific metabolic activities (N-demethylation of erythromycin). Time
      course experiments (incubation time from 12 to 48 h) and dose-response curves
      (concentration of serum ranging from 1 to 30%) have been conducted. 3. In normal
      hepatocytes incubated for 24 h with serum (concentration of 10%) from rats with
      CRF, total p450 level, protein expression and mRNA levels of several p450
      isoforms (CYP2C6, 2C11, 3A1 and 3A2) were decreased by more than 35% (P<0.001)
      compared to serum from control animals. The protein expression as well as the
      mRNA levels of CYP2D were similar in hepatocytes incubated with serum from either
      control or CRF rats. The N-demethylation of erythromycin was decreased by more
      than 35% (P<0.001) in hepatocytes incubated with serum from rats with CRF. The
      inhibitory effect of serum from rats with CRF tended to peak at 48 h of
      incubation and was maximum at a concentration of 20%. 4. In conclusion, uremic
      serum contains mediator(s) that down-regulate the cytochrome p450 of normal
      hepatocytes secondary to reduced gene expression.

PMID- 12429577
TI  - Differential peristaltic motor effects of prostanoid (DP, EP, IP, TP) and
      leukotriene receptor agonists in the guinea-pig isolated small intestine.
AB  - 1. Since the role of prostanoid receptors in intestinal peristalsis is largely
      unknown, the peristaltic motor effects of some prostaglandin (DP, EP, IP),
      thromboxane (TP) and leukotriene (LT) receptor agonists and antagonists were
      investigated. 2. Propulsive peristalsis in fluid-perfused segments from the
      guinea-pig small intestine was triggered by a rise of the intraluminal pressure
      and recorded via the intraluminal pressure changes associated with the
      peristaltic waves. Alterations of distension sensitivity were deduced from
      alterations of the peristaltic pressure threshold and modifications of
      peristaltic performance were reflected by modifications of the amplitude, maximal
      acceleration and residual baseline pressure of the peristaltic waves. 3. Four
      categories of peristaltic motor effects became apparent: a decrease in distension
      sensitivity and peristaltic performance as induced by the EP1/EP3 receptor
      agonist sulprostone and the TP receptor agonist U-46619 (1-1000 nM); a decrease
      in distension sensitivity without a major change in peristaltic performance as
      induced by PGD(2) (3-300 nM) and LTD(4) (10-100 nM); a decrease in peristaltic
      performance without a major change in distension sensitivity as induced by
      PGE(1), PGE(2) (1-1000 nM) and the EP1/IP receptor agonist iloprost (1-100 nM);
      and a decrease in peristaltic performance associated with an increase in
      distension sensitivity as induced by the EP2 receptor agonist butaprost (1-1000
      nM). The DP receptor agonist BW-245 C (1-1000 nM) was without effect. 4. The
      peristaltic motor action of sulprostone remained unchanged by the EP1 receptor
      antagonist SC-51089 (1 micro M) and the DP/EP1/EP2 receptor antagonist AH-6809
      (30 micro M), whereas that of U-46619 and LTD(4) was prevented by the TP receptor
      antagonist SQ-29548 (10 micro M) and the cysteinyl-leukotriene(1) (cysLT(1))
      receptor antagonist tomelukast (10 micro M), respectively. 5. These observations
      and their pharmacological analysis indicate that activation of EP2, EP3, IP, TP
      and cysLT(1) receptors, but not DP receptors, modulate intestinal peristalsis in
      a receptor-selective manner, whereas activation of EP1 seems to be without
      influence on propulsive peristalsis. In a wider perspective it appears as if the
      effect of prostanoid receptor agonists to induce diarrhoea is due to their
      prosecretory but not peristaltic motor action.

PMID- 12429578
TI  - Pacific ciguatoxin-1b effect over Na+ and K+ currents, inositol 1,4,5
      triphosphate content and intracellular Ca2+ signals in cultured rat myotubes.
AB  - 1. The action of the main ciguatoxin involved in ciguatera fish poisoning in the
      Pacific region (P-CTX-1b) was studied in myotubes originated from rat skeletal
      muscle cells kept in primary culture. 2. The effect of P-CTX-1b on sodium
      currents at short times of exposure (up to 1 min) showed a moderate increase in
      peak Na+ current. During prolonged exposures, P-CTX-1b decreased the peak Na+
      current. This action was always accompanied by an increase of leakage currents,
      tail currents and outward Na+ currents, resulting in an intracellular Na+
      accumulation. This effect is blocked by prior exposure to tetrodotoxin (TTX) and
      becomes evident only after washout of TTX. 3. Low to moderate concentrations of P
      CTX-1b (2-5 nM) partially blocked potassium currents in a manner that was
      dependent on the membrane potential. 4. P-CTX-1b (2-12 nM) caused a small
      membrane depolarization (3-5 mV) and an increase in the frequency of spontaneous
      action potential discharges that reached in general low frequencies (0.1-0.5 Hz).
      5. P-CTX-1b (10 nM) caused a transient increase of intracellular inositol 1,4,5
      trisphosphate (IP(3)) mass levels, which was blocked by TTX. 6. In the presence
      of P-CTX-1b (10 nM) and in the absence of external Ca2+, the intracellular Ca2+
      levels show a transient increase in the cytoplasm as well as in the nuclei. The
      time course of this effect may reflect the action of IP(3) over internal stores
      activated by P-CTX-1b-induced membrane depolarization.

PMID- 12429579
TI  - Mechanism of nicotine-evoked release of 3H-noradrenaline in human cerebral cortex
      slices.
AB  - 1. The mechanism of stimulation of noradrenaline (NA) release by nicotine (NIC)
      was investigated in human cerebral cortex slices preloaded with 3H-noradrenaline.
      2 NIC (10-1000 micro M) increased 3H-NA release in a concentration-dependent
      manner. 3. NIC (100 micro M)-evoked 3H-NA release was largely dependent on
      external Ca2+, and was attenuated by omega-conotoxin GVIA (0.1 micro M) but not
      by nitrendipine (1 micro M). 4. Tetrodotoxin (1 micro M) and nisoxetine (0.1
      micro M) attenuated the NIC (100 micro M)-evoked release of 3H-NA. 5.
      Mecamylamine (10 micro M), dihydro-beta-erythroidine (10 micro M) and d
      tubocurarine (30 micro M), but not alpha-bungarotoxin (alpha-BTX, 0.1 micro M),
      attenuated the NIC (100 micro M)-evoked release of 3H-NA. 6. NIC (100 micro M)
      evoked release of 3H-NA was not affected by 6-cyano-7-nitroquinoxaline-2,3-dione
      (CNQX, 30 micro M) and D(-)-2-amino-5-phosphonopentanoic acid (D-AP5, 100 micro
      M), but attenuated by MK-801 (10 micro M). MK-801 (0.1-1000 micro M) displaced
      the specific binding of 3H-nisoxetine with K(i) values of 91.2 micro M. NIC (100,
      300 and 1000 micro M) did not induce 3H-D-aspartate release in human cerebral
      cortex slices. 7. NIC (100 micro M)-evoked release of 3H-NA was attenuated by 7
      nitroindazole (10 micro M), N(G)-nitro-L-arginine methyl ester HCl (L-NAME, 30
      micro M), N(G)-monomethyl-L-arginine acetate (L-NMMA, 300 micro M). [(3)H]-NA
      release induced by NIC (100 micro M) was attenuated by methylene blue (3 micro M)
      and 1H-[1,2,4]oxadiazole[4,3-alpha]quinoxalin-1-one (ODQ, 10 micro M), and
      enhanced by zaprinast (30 micro M). 8. In conclusion, NIC stimulates the release
      of 3H-NA through activation of alpha-BTX-insensitive nicotinic acetylcholine
      receptors in the human cerebral cortex slices and this action of NIC is
      associated with modulation of the NO/cGMP pathway.

PMID- 12429581
TI  - Effects of the selective inhibition of platelet thromboxane synthesis on the
      platelet-subendothelium interaction.
AB  - 1. Drugs that inhibit TxA(2) synthesis are used to reduce platelet aggregation.
      The aim of this study was to compare the effects of a cyclo-oxygenase (COX)
      inhibitor (acetylsalicylic acid, ASA), a thromboxane synthetase (TxS) inhibitor
      (dazoxiben) and a dual TxS inhibitor and TxA(2) receptor blocker (DT-TX 30) on
      platelet aggregation and the platelet-subendothelium interaction in flow
      conditions. 2. The techniques used in this in vitro study were platelet
      aggregometry in whole blood, and measurement of platelet thromboxane B(2) and
      prostaglandin E(2) production and leucocyte production of 6-keto-PGF(1alpha). The
      platelet-subendothelium interaction was evaluated in rabbit aorta subendothelium
      preparations exposed to flowing blood at a shear stress of 800 s(-1).
      Morphometric methods were used to calculate the percentage of subendothelium
      occupied by platelets. 3. The 50% inhibitory concentration (IC(50)) of DT-TX 30
      in whole blood was in the range of 10(-7) micro M (induced with collagen or
      arachidonic acid) to 10(-5) micro M (induced with thrombin) or 10(-4) (induced
      with ADP). IC(50) values under all experimental conditions were lower with DT-TX
      30 than with ASA. For thromboxane B(2) the IC(50) were: ASA 0.84+/-0.05 micro M,
      dazoxiben 765+/-54 micro M, DT-TX 30 8.54+/-0.60 micro M. Prostaglandin E(2) was
      inhibited only by ASA (IC(50) 1.21+/-0.08 micro M). Leucocyte 6-keto-PGF(1alpha)
      was inhibited by ASA (IC(50) 6.58+/-0.76 micro M) and increased by dazoxiben and
      DT-TX 30. The greatest reduction in percentage subendothelial surface occupied by
      platelets after blood perfusion was seen after treatment with DT-TX 30 in the
      range of concentrations that inhibited collagen-induced platelet aggregation
      (control group: 31.20+/-3.8%, DT-TX 30 at 0.1 micro M: 10.71+/-0.55%, at 1.0
      micro M: 6.53+/-0.44%, at 5.0 micro M; 1.48+/-0.07%). All three drugs reduced
      thrombus formation, although ASA (unlike dazoxiben or DT-TX 30) increased the
      percentage surface occupied by adhesions. 4. In conclusion, the effect of
      specific blockage of TxS together with blockage of membrane receptors for TxA(2)
      can surpass the effect of ASA in inhibiting the platelet-subendothelium
      interaction in flow conditions.

PMID- 12429580
TI  - Inhibition of rat platelet aggregation by the diazeniumdiolate nitric oxide donor
      MAHMA NONOate.
AB  - 1. Inhibition of rat platelet aggregation by the nitric oxide (NO) donor MAHMA
      NONOate (Z-1-N-methyl-N-[6-(N-methylammoniohexyl)amino]diazen-1-ium-1,2-diolate)
      was investigated. The aims were to compare its anti-aggregatory effect with
      vasorelaxation, to determine the effects of the soluble guanylate cyclase
      inhibitor, ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one), and to investigate
      the possible role of activation of sarco-endoplasmic reticulum calcium-ATPase
      (SERCA), independent of soluble guanylate cyclase, using thapsigargin. 2 MAHMA
      NONOate concentration-dependently inhibited sub-maximal aggregation responses to
      collagen (2-10 micro g ml(-1)) and adenosine diphosphate (ADP; 2 micro M) in
      platelet rich plasma. It was (i). more effective at inhibiting aggregation
      induced by collagen than by ADP, and (ii). less potent at inhibiting platelet
      aggregation than relaxing rat pulmonary artery. 3. ODQ (10 micro M) caused only a
      small shift (approximately half a log unit) in the concentration-response curve
      to MAHMA NONOate irrespective of the aggregating agent. 4. The NO-independent
      activator of soluble guanylate cyclase, YC-1 (3-(5'-hydroxymethyl-2'-furyl)-1
      benzyl indazole; 1-100 micro M), did not inhibit aggregation. The cGMP analogue,
      8-pCPT-cGMP (8-(4-chlorophenylthio)guanosine 3'5' cyclic monophosphate; 0.1-1
      mM), caused minimal inhibition. 5. On collagen-aggregated platelets responses to
      MAHMA NONOate (ODQ 10 micro M present) were abolished by thapsigargin (200 nM).
      On ADP-aggregated platelets thapsigargin caused partial inhibition. 6. Results
      with S-nitrosoglutathione (GSNO) resembled those with MAHMA NONOate. Glyceryl
      trinitrate and sodium nitroprusside were poor inhibitors of aggregation. 7. Thus
      inhibition of rat platelet aggregation by MAHMA NONOate (like GSNO) is largely
      ODQ-resistant and, by implication, independent of soluble guanylate cyclase. A
      likely mechanism of inhibition is activation of SERCA.

PMID- 12429582
TI  - The isolated blood-perfused rat heart: an inappropriate model for the study of
      ischaemia- and infarction-related ventricular fibrillation.
AB  - 1. Well-characterized in vivo and in vitro models exist for the study of
      ischaemia- and infarction-related ventricular fibrillation (VF). In rats in vivo,
      VF appears to occur in distinct acute ischaemia- (early) and infarction-related
      (late) phases. Interestingly, isolated buffer-perfused rat hearts do not develop
      late VF. This raises the possibility that unidentified components of the blood
      may be responsible for late VF. We thus sought to characterize an isolated blood
      perfused rat heart in order to investigate the possible influence of blood
      components on arrhythmias arising from ischaemia and infarction. 2. Hearts,
      excised from male Wistar rats, were perfused in the Langendorff mode with blood
      from support rats (male Wistar, 350-430 g) via an extracorporeal circuit.
      Perfused hearts underwent left coronary artery occlusion for 240 min or a sham
      procedure (n=10 group(-1)). 3. Only 10% of ischaemic hearts developed late VF (90
      240 min). Tissue myeloperoxidase activity (an index of neutrophil accumulation)
      increased during ischaemia from 0.017+/-0.004 (six fresh hearts) to 0.056+/-0.005
      units mg protein(-1) (P<0.05) at 240 min, but values were similar in sham hearts
      (0.083+/-0.013). Likewise, the decline (-1 vs 240 min of ischaemia shown) in
      circulating total white blood cells from 6.8+/-0.5 to 1.9+/-0.2 x 10(3) micro l(
      1) and in platelets from 441+/-32 to 274+/-16 x 10(3) micro l(-1) (both P<0.05)
      was similar in time-matched sham hearts (data not shown). 4 Surprisingly, only
      10% of ischaemic hearts developed early VF (0-90 min), although the incidence of
      early ventricular tachycardia was 100% in these hearts (P<0.05 vs sham hearts).
      Blood K+ values were normal (hyperkalaemia suppresses VF). 5 Although late VF was
      absent in blood-perfused hearts, it would be premature to conclude from this that
      late VF is not mediated by blood components. This is because the similar
      neutrophil accumulation in ischaemic and sham hearts, the decline in numbers of
      circulating blood components, and the unexpected paucity of early VF all question
      the validity of the model.

PMID- 12429584
TI  - The role of mitochondrial K(ATP) channels in antiarrhythmic effects of ischaemic
      preconditioning in dogs.
AB  - 1. In the canine a single brief (5 min) coronary artery occlusion protects the
      myocardium against the severe ventricular arrhythmias and reduces the ischaemic
      changes that result from a subsequent, more prolonged (25 min) occlusion. The
      main purpose of the present study was to examine whether mitochondrial K(ATP)
      channels are involved in this protection. 2. In chloralose-urethane anaesthetized
      dogs, preconditioning (PC) was induced by a single 5 min period occlusion of the
      left anterior descending (LAD) coronary artery, 20 min prior to a 25 min
      occlusion of the same artery. In some of these PC dogs 5-hydroxydecanoate (5-HD;
      150 micro g kg(-1) min(-1) by intracoronary infusion) was given over a period of
      30 min either before, or after PC. In other dogs the mitochondrial K(ATP) channel
      opener diazoxide (1 mg kg(-1); i.c.) was given, either alone or in the presence
      of 5-HD. Control dogs (infused with saline) were simply subjected to a 25 min
      occlusion and reperfusion. 3. Compared to controls, both PC and diazoxide
      significantly reduced the number of ventricular premature beats (VPBs; 295+/-67
      to 89+/-28 and 19+/-11, respectively; P<0.05), the number of episodes of
      ventricular tachycardia (VT; 8.3+/-4.2 to 1.6+/-0.9 and 0.2+/-0.1; P<0.05) and
      the incidences of VT (100 to 43 and 33%; P<0.05) and ventricular fibrilation (VF;
      60 to 0 and 17%; P<0.05) during the 25 min occlusion of the LAD. Further, 43% of
      the PC dogs and 58% of the diazoxide treated dogs survived the combined ischaemia
      reperfusion insult (cp. 0% in the controls; P<0.05). The protection afforded by
      PC and diazoxide was abolished by 5-HD, especially when it was given prior to the
      PC occlusion. In the presence of 5-HD, three out of 10 dogs fibrillated during
      the PC occlusion and another three dogs died following reperfusion. Furthermore,
      there were no survivors in this group from the prolonged ischaemia/reperfusion
      insult. 5-HD given after PC only attenuated the antiarrhythmic protection. 4.
      Opening of mitoK(ATP) channels prior to ischaemia by preconditioning and
      diazoxide protects the myocardium against ischaemia and reperfusion-induced
      arrhythmias. This protection is abolished if the opening of these channels is
      prevented by the prior administration of 5-HD but only attenuated if 5-HD is
      given after preconditioning. The results indicate that opening of mitoK(ATP)
      channels prior to ischaemia is mandatory for protection against ischaemia and
      reperfusion-induced arrhythmias.

PMID- 12429583
TI  - Overexpression of glutathione S-transferase A1-1 in ECV 304 cells protects
      against busulfan mediated G2-arrest and induces tissue factor expression.
AB  - 1. The antineoplastic drug busulfan is frequently used in preconditioning
      regimens for bone marrow transplantation. Pharmacokinetics vary tremendously
      between patients due to extensive metabolism in the liver via conjugation to
      glutathione catalysed by glutathione S-transferase (GST) A1-1. Since elevated
      busulfan plasma levels have been reported to be a risk factor for developing veno
      occlusive disease (VOD), metabolism of busulfan may play a pivotal role in the
      induction of VOD. 2. Therefore, we developed a cell model to investigate the
      influence of busulfan metabolism on its biological effects. GSTA1-1 cDNA was
      transfected into the cell line ECV 304 and protein expression was demonstrated by
      Western blotting. Enzymatic activity could be detected by formation of
      tetrahydrothiophene. Additionally, effects of busulfan treatment on cell cycle
      and expression of tissue factor have been investigated. 3. A busulfan-induced G2
      arrest was reduced in GSTA1-1-transfected cells, which consequently displayed a
      significantly higher activity of cdc2 kinase (24.1+/-1.5 AU mg(-1) protein) after
      busulfan treatment compared to controls (14.7+/-2.3 AU mg(-1) protein; P<0.01).
      Elevated basal expression of tissue factor in GSTA1-1-transfected ECV 304 cells
      could be 4 fold increased by busulfan treatment. 4. These data demonstrate that
      ECV 304 cells transfected with GSTA1-1 provide a valuable tool to assess busulfan
      metabolism in vitro. Furthermore, overexpression of GSTA1-1 leads to a partial
      protection against cell cycle effects of busulfan and affects tissue factor
      expression.

PMID- 12429585
TI  - Protein kinase C (PKC) dependent induction of tissue factor (TF) by mesangial
      cells in response to inflammatory mediators and release during apoptosis.
AB  - 1. In inflammatory kidney diseases procoagulatory activity (PCA) becomes evident.
      Glomerular fibrin deposits and capillary microthrombi are histopathological
      hallmarks in most forms of glomerulonephritis. 2. Therefore in this study the
      expression of tissue factor (TF) as the main inducer of thrombogenesis was
      examined in cultured human mesangial cells (MC) in response to proinflammatory
      stimuli such as interleukin-1 (IL-1 beta), tumour necrosis factor alpha (TNF
      alpha) and lipopolysaccharide (LPS). Also main signalling pathways were
      investigated. 3. IL-1 beta, TNF-alpha and LPS induced TF in MC in a time and dose
      dependent manner on mRNA and protein levels. Highest activity was found after 12
      h of stimulation. Induction of TF was completely blockable by BAPTA-AM, a
      chelator of intracellular [Ca(2+)](i) as well as calphostin, a protein kinase C
      (PKC) inhibitor. Activation of the protein kinase A (PKA) pathway had no
      influence on basal TF expression, but down-regulated cytokine-induced TF. The PKA
      blocker, KT5720, increased TF formation significantly. Since TF exerts its
      activity primarily on the surface of cells and after release of encrypted
      receptors we further tested TF activity in MC supernatants. IL-1 beta did not
      significantly increase TF activity in supernatants of intact cells. However, when
      MC were rendered apoptotic by oxidative metabolites, IL-1 beta treated MC
      released highly stimulated TF activity into the supernatants, suggesting that a
      paracrine activation of the coagulatory cascade can take place under such
      conditions. 4. Inflammatory mediators up-regulate TF expression in MC by a PKC
      dependent pathway whereas PKA can serve as a negative feed-back link. Apoptosis
      of inflammatory MC may trigger to spread PCA.

PMID- 12429586
TI  - The novel antagonist 3-CBW discriminates between kainate receptors expressed on
      neonatal rat motoneurones and those on dorsal root C-fibres.
AB  - 1. The natural product willardiine is a selective AMPA receptor agonist. We
      report that an N(3)-substituted analogue of willardiine, (S)-3-(4
      carboxybenzyl)willardiine 3-CBW, antagonizes AMPA and kainate receptors expressed
      on motoneurones and dorsal root C-fibres, respectively. 2. Reduction of the fast
      component of the dorsal root-evoked ventral root potential (fDR-VRP) has been
      used as a novel method to compare AMPA receptor antagonists. 3-CBW, NBQX and
      GYKI53655 depressed the fDR-VRP with IC(50) values of 10.3+/-2.4, 0.214+/-0.043
      and 4.03+/-0.31 micro M, respectively. That 3-CBW depressed the fDR-VRP by acting
      at AMPA and not metabotropic glutamate receptors was demonstrated by the lack of
      effect of LY341495 (100 micro M). 3. The Schild plot for antagonism of responses
      to (S)-5-fluorowillardiine on motoneurones by 3-CBW had a slope of 1.11+/-0.13
      giving a pA(2) value of 4.48. The Schild plot for antagonism of kainate responses
      on the dorsal root by 3-CBW had a slope of 1.05+/-0.05 giving a pA(2) value of
      4.96. 4. On neonatal rat motoneurones 3-CBW (200 micro M) almost completely
      abolished responses to AMPA while responses to NMDA, kainate and DHPG were
      101.6+/-11.6%, 39.4+/-5.8% and 110.5+/-9.0% of control, respectively. 3-CBW can
      therefore be used to isolate kainate receptor responses from those mediated by
      AMPA receptors. 5 3-CBW antagonized kainate-induced responses on dorsal root C
      fibres with a pA(2) value of 4.96 whereas kainate receptor mediated responses
      (isolated by including GYKI53655 in the medium) on motoneurones were not
      completely blocked by 200 micro M 3-CBW, substantiating evidence that kainate
      receptors on neonatal rat motoneurones differ from those on dorsal root C-fibres.

PMID- 12429588
TI  - Human gait as a step in evolution.

PMID- 12429589
TI  - Peripheral neuropathies and anti-glycolipid antibodies.
AB  - This review charts the progress of anti-glycolipid antibodies in neuropathy, from
      their original discovery 20 years ago in immunoglobulin M paraproteinaemic
      neuropathy through to current discoveries mapping their relationship to subtypes
      of Guillain-Barre syndrome. Antibodies to >20 different glycolipids have now been
      associated with a wide range of clinically identifiable acute and chronic
      neuropathy syndromes. Particular progress has been achieved in understanding the
      link between acute motor axonal neuropathy and antibodies to GM1, GD1a, GM1b and
      GalNAc-GD1a, and between the cranial, bulbar and sensory variants of GBS and
      antibodies to the disialylated gangliosides GQ1b, GT1a, GD1b and GD3. In addition
      to clinical and serological studies, the origins and measurement of anti
      glycolipid antibodies and their relationships to similar carbohydrate structures
      on infectious organisms, particularly Campylobacter jejuni, are discussed in the
      context of a molecular mimicry hypothesis. The structure and nomenclature of
      relevant glycolipids are outlined, along with information on their localization
      in nerve, and the influence this has on clinical phenotypes. Major advances have
      been made in animal modelling of anti-glycolipid antibody-associated diseases,
      both in vitro and in vivo. This has advanced our understanding of the role of
      anti-GQ1b antibodies in Miller Fisher syndrome with particular respect to the
      motor nerve terminal as a potential site of injury, and led to the creation of
      rabbit models of anti-GD1b and anti-GM1 antibody-mediated sensory and motor
      neuropathy, respectively. With such information in place, it will now be possible
      to determine the precise mechanisms by which antibodies injure the different
      compartments of peripheral nerve and establish how a range of immunomodulating
      therapies, including current treatments, exert their therapeutic effects. Despite
      these very significant advances, considerable gaps in our knowledge persist, and
      it is likely that other pathogenic pathways operate in inflammatory neuropathy
      that are unrelated to glycolipid antibodies, although these are outside the scope
      of this review.

PMID- 12429590
TI  - Locomotor activity in spinal man: significance of afferent input from joint and
      load receptors.
AB  - The aim of this study was to differentiate the effects of body load and joint
      movements on the leg muscle activation pattern during assisted locomotion in
      spinal man. Stepping movements were induced by a driven gait orthosis (DGO) on a
      treadmill in patients with complete para-/tetraplegia and, for comparison, in
      healthy subjects. All subjects were unloaded by 70% of their body weight. EMG of
      upper and lower leg muscles and joint movements of the DGO of both legs were
      recorded. In the patients, normal stepping movements and those mainly restricted
      to the hips (blocked knees) were associated with a pattern of leg muscle EMG
      activity that corresponded to that of the healthy subjects, but the amplitude was
      smaller. Locomotor movements restricted to imposed ankle joint movements were
      followed by no, or only focal EMG responses in the stretched muscles. Unilateral
      locomotion in the patients was associated with a normal pattern of leg muscle EMG
      activity restricted to the moving side, while in the healthy subjects a bilateral
      activation occurred. This indicates that interlimb coordination depends on a
      supraspinal input. During locomotion with 100% body unloading in healthy subjects
      and patients, no EMG activity was present. Thus, it can be concluded that
      afferent input from hip joints, in combination with that from load receptors,
      plays a crucial role in the generation of locomotor activity in the isolated
      human spinal cord. This is in line with observations from infant stepping
      experiments and experiments in cats. Afferent feedback from knee and ankle joints
      may be involved largely in the control of focal movements.

PMID- 12429587
TI  - The colon-selective spasmolytic otilonium bromide inhibits muscarinic M(3)
      receptor-coupled calcium signals in isolated human colonic crypts.
AB  - 1. Otilonium bromide (OB) is a smooth muscle relaxant used in the treatment of
      irritable bowel syndrome. Otilonium bromide has been shown to interfere with the
      mobilization of calcium in intestinal smooth muscle, but the effects on other
      intestinal tissues have not been investigated. We identified the muscarinic
      receptor subtype coupled to calcium signals in colonic crypt derived from the
      human colonic epithelium and evaluated the inhibitory effects of OB. 2. Calcium
      signals were monitored by fluorescence imaging of isolated human colonic crypts
      and Chinese hamster ovary cells stably expressing the cloned human muscarinic
      M(3) receptor subtype (CHO-M(3)). Colonic crypt receptor expression was
      investigated by pharmacological and immunohistochemical techniques. 3. The
      secretagogue acetylcholine (ACh) stimulated calcium mobilization from
      intracellular calcium stores at the base of human colonic crypts with an EC(50)
      of 14 micro M. The muscarinic receptor antagonists 4-DAMP, AF-DX 384, pirenzepine
      and methroctamine inhibited the ACh-induced calcium signal with the following
      respective IC(50) (pK(b)) values: 0.78 nM (9.1), 69 nM (7.2), 128 nM (7.1), and
      2510 nM (5.8). 4. Immunohistochemical analyses of muscarinic receptor expression
      demonstrated the presence of M(3) receptor subtype expression at the crypt-base.
      5. Otilonium bromide inhibited the generation of ACh-induced calcium signals in a
      dose dependent manner (IC(50)=880 nM). 6. In CHO-M(3) cells, OB inhibited calcium
      signals induced by ACh, but not ATP. In addition, OB did not inhibit histamine
      induced colonic crypt calcium signals. 7. The present studies have demonstrated
      that OB inhibited M(3) receptor-coupled calcium signals in human colonic crypts
      and CHO-M(3) cells, but not those induced by stimulation of other endogenous
      receptor types. We propose that the M(3) receptor-coupled calcium signalling
      pathway is directly targeted by OB at the level of the colonic epithelium,
      suggestive of an anti-secretory action in IBS patients suffering with diarrhoea.

PMID- 12429591
TI  - Striatal metabotropic glutamate receptor function following experimental
      parkinsonism and chronic levodopa treatment.
AB  - Excessive activation of ionotropic glutamate receptors in the striatum
      contributes to the pathophysiology of motor symptoms in Parkinson's disease.
      Metabotropic glutamate (mGlu) receptors regulate striatal excitatory synaptic
      transmission, and adaptive changes in their function might occur following
      dopaminergic denervation and chronic levodopa-treatment (L-DOPA). Corticostriatal
      glutamatergic transmission was examined in striatal slices obtained from rats
      unilaterally denervated with the dopaminergic neurotoxin, 6-hydroxy dopamine (6
      OHDA), and from denervated rats chronically treated with L-DOPA plus benserazide
      (25 + 6.25 mg/kg, intraperitoneally, twice daily for 21 days). Selective agonists
      of mGlu2 and -3 receptor subtypes [compounds LY379268 and (2S,2'R,3'R)-2-(2',3'
      [(3)H]-dicarboxycyclopropyl)glycine ([(3)H]DCG-IV)] exhibited a much greater
      potency in depressing excitatory transmission and corticostriatal synapses in
      slices prepared from 6-OHDA-lesioned animals. Dopaminergic denervation affected
      neither the ability of L-(+)-2-amino-4-phosphonobutyric acid (L-AP4; a selective
      agonist of mGlu4, -6, -7 and -8 receptors) to inhibit corticostriatal
      transmission, nor the ability of (S)-3,5-dihydroxyphenylglycine (3,5-DHPG; a
      selective agonist of mGlu1 and -5 receptors) to potentiate responses mediated by
      N-methyl-D-aspartate (NMDA) receptor activation in striatal neurones. The
      increased responsiveness to mGlu2/3 receptor agonists was no longer detected in
      slices from 6-OHDA-lesioned animals chronically treated with L-DOPA. 6-OHDA
      induced denervation also led to an increased expression of striatal mGlu2/3
      receptor proteins and to a >2-fold increase in the maximal density (B(max)) of
      [(3)H]DCG-IV binding sites. These increases were again reversed by chronic
      treatment with L-DOPA. No changes in the expression of mGlu4 receptors or the
      alpha(i1) and alpha(i2) subunits of the G(i) proteins were induced by any of the
      treatments. We suggest that an enhanced sensitivity of pre-synaptic inhibitory
      mGlu2/3 receptors might represent an adaptive change triggered by dopaminergic
      denervation, which can be reversed by L-DOPA treatment.

PMID- 12429592
TI  - Functional brain reorganization for hand movement in patients with multiple
      sclerosis: defining distinct effects of injury and disability.
AB  - Previous work has demonstrated potentially adaptive cortical plasticity that
      increases with brain injury in patients with multiple sclerosis. However, animal
      studies showing use-dependent changes in motor cortex organization suggest that
      functional changes also may occur in response to disability. We therefore wished
      to test whether brain injury and disability lead to distinguishable patterns of
      activation with hand movement in patients with multiple sclerosis. By employing a
      passive as well as an active movement task, we also wished to test whether these
      changes were independent of voluntary recruitment and thus more likely to reflect
      true functional reorganization. Fourteen patients [Extended Disability Status
      Score (EDSS) 0-7.5] with relapsing-remitting multiple sclerosis were selected on
      the basis of pathology load and hand functional impairment for three study
      groups: group 1, low diffuse central brain injury (DCBI) as assessed from
      relative N-acetylaspartate concentration (a marker of axonal integrity) and
      normal hand function (n = 6); group 2, greater DCBI and normal hand function (n =
      4); and group 3, greater DCBI and impaired hand function (n = 4). Functional MRI
      (fMRI) was used to map brain activation with a four-finger and both one-finger
      passive and active flexion-extension movement tasks for the three groups.
      Considering all the patients, we found increased activity in ipsilateral premotor
      and ipsilateral motor cortex (IMC) and in the ipsilateral inferior parietal
      lobule with increasing global disability (as assessed from the EDSS score). These
      changes appear to define true functional reorganization, as fMRI activations in
      IMC (r = 0.87, P < 0.001) and in the contralateral motor cortex (r = 0.67, P <
      0.007) were highly correlated between active and passive single finger movements.
      We attempted to disambiguate any distinct effects of disability and brain injury
      by direct contrasts between patients differing predominantly in one or the other.
      To make these contrasts as powerful as possible, we used impairment of finger
      tapping as a measure of disability specific to the hand tested. A direct contrast
      of patients matched for DCBI, but differing in hand disability (group 3 - group
      2) showed greater bilateral primary and secondary somatosensory cortex activation
      with greater disability alone. A contrast matched for hand disability, but
      differing in DCBI (group 2 - group 1) showed a different pattern of changes with
      relative ipsilateral premotor cortex and bilateral supplementary motor area
      activity. We conclude that the pattern of brain activity with finger movements
      changes both with increasing DCBI and with hand disability in patients with
      multiple sclerosis, and that these changes are distinct. Those related directly
      to disability may reflect responses to altered patterns of use. As injury- and
      disability-related activation changes are found even with passive finger
      movements, they may reflect true brain reorganization.

PMID- 12429594
TI  - A locus for simple pure febrile seizures maps to chromosome 6q22-q24.
AB  - Febrile seizures (FS) syndromes exhibit major clinical and genetic heterogeneity.
      We report a clinical and genetic study of three families with simple FS
      segregating as an autosomal dominant (AD) trait with high penetrance. All
      affected members presented a homogeneous phenotype of simple FS. The FS ceased
      before the age of 5 years. Among the 29 affected family members, only one patient
      presented two afebrile seizures, and none of the others developed concomitant or
      subsequent epilepsy. The phenotype differs from that previously reported in
      families presenting FS or generalized epilepsy with febrile seizures plus
      (GEFS+). After exclusion of already known loci for FS and GEFS+, we performed a
      genome-wide scan in the largest family. It led to the identification of a new
      locus on chromosome 6q22-q24 spanning 6.4 cM between D6S1620 and D6S975. For one
      of the other two families, the trait also segregated with this locus, but linkage
      studies could not restrict the candidate region further. The absence of linkage
      in the third family supports genetic heterogeneity of the AD form of pure simple
      FS. Sequence analysis excluded the implication of five candidate genes [A kinase
      anchoring protein 18 (AKAP18), syntaxin 7, putative neurotransmitter receptor
      (PNR), G protein receptor 57 (GPR57) and G protein receptor 58 (GPR58)] in the
      interval based on function. The locus mapping to 6q22-q24 seems to be the first
      identified locus responsible for pure simple FS, the most frequent form of FS.
      Studies are ongoing to identify the gene.

PMID- 12429593
TI  - The proteasome is a major autoantigen in multiple sclerosis.
AB  - Multiple sclerosis seems to be an autoimmune disease of unknown aetiology
      affecting the white matter of the CNS. It is generally accepted that the
      autoimmune response is directed against specific components of myelin. We show
      here that proteasome, a ubiquitous protease complex composed of 14 different
      subunits, is a target for autoantibodies (IgG and IgM classes) present in the
      serum (66%, 73 out of 110) and in the CSF (61%, 16 out of 26) of patients with
      multiple sclerosis. Using recombinant proteasomal subunits we demonstrate the
      presence of specific autoantibodies against subunits C2, C8, C9 and C5 in
      multiple sclerosis patients. Recombinant C2 constructs allow us to localize an
      immunodominant autoepitope recognized by the sera of multiple sclerosis patients
      within the C-terminal of C2 proteasomal subunit (251-DEPAEKADEPMEH-263). In
      addition, two constructs of the recombinant proteasomal subunits C2 and C8 were
      also used to study the proliferation of peripheral blood mononuclear cells from
      multiple sclerosis patients; 12 out of 30 (40%) multiple sclerosis patients show
      positive proliferation with one or both of these recombinant subunits. The high
      prevalence of anti-proteasome autoantibodies in multiple sclerosis sera compared
      with sera from patients with other chronic inflammatory conditions: systemic
      lupus erythematosus (35%, 35 out of 100), primary Sjogren's syndrome (16%, 5 out
      of 31), vasculitis (0 out of 20), sarcoidosis (7%, 1 out of 13) and Behcet's
      disease (19%, 4 out of 21) suggest that humoral autoreactivity to proteasome
      could be a useful test in multiple sclerosis patients that may be of help in the
      diagnosis and/or progression of this chronic inflammatory disease. Finally, these
      results suggest that some global abnormality in B and/or T cell function is also
      involved in the chronic inflammatory response observed in multiple sclerosis
      patients, as it is frequently observed in other human organ-specific autoimmune
      diseases.

PMID- 12429595
TI  - Clinical and genetic characterization of families with triple A (Allgrove)
      syndrome.
AB  - Triple A (Allgrove) syndrome is characterized by achalasia, alacrima, adrenal
      abnormalities and a progressive neurological syndrome. Affected individuals have
      between two and four of these relatively common clinical problems; hence the
      diagnosis is often difficult in all but the classical presentation. The
      inheritance is autosomal recessive, and most cases of triple A have no family
      history. Using genetic linkage analysis in a small number of families, a locus on
      chromosome 12q13 was identified. The triple A gene was identified recently at
      this locus and called ALADIN (alacrima, achalasia, adrenal insufficiency
      neurologic disorder). Mutations in this gene were reported in families from North
      Africa and Europe. The majority of mutations were homozygous. We have identified
      20 families with between two and four of the clinical features associated with
      the triple A syndrome. Sequencing of the triple A gene revealed five families
      that had a total of nine compound heterozygous mutations, and one Portuguese
      family (previously published) had two homozygous mutations; these changes were
      spread throughout the triple A gene in exons 1, 2, 7, 8, 10, 11, 12, 13 and 16,
      and the poly(A) tract. Those bearing mutations had the classical triple A
      syndrome of achalasia, alacrima, adrenal abnormalities and a progressive
      neurological syndrome. We identified a spectrum of associated neurological
      abnormalities in these cases, including pupil and cranial nerve abnormalities,
      frequent optic atrophy, autonomic neuropathy and upper and lower motor neurone
      signs including distal motor neuropathy and amyotrophy with severe selective
      ulnar nerve involvement. In these families, we have made genotype-phenotype
      correlations. Mutations in the triple A gene are thus an important cause of this
      clinically heterogeneous syndrome, and sequencing represents an important
      diagnostic investigation. Identifying further mutations and defining their
      phenotype along with functional protein analysis will help to characterize this
      neuroendocrine gene.

PMID- 12429596
TI  - The localizing value of ictal consciousness and its constituent functions: a
      video-EEG study in patients with focal epilepsy.
AB  - Using ictal neuropsychological testing in pre-surgical patients with focal
      epilepsies, we examined the localizing value of the constituent functions of
      consciousness as opposed to 'conscious behaviour' as a unitary variable.
      'Conscious behaviour' was defined in terms of awareness and responsiveness. The
      constituent functions of consciousness examined included the orientation to the
      examiner, intentional behaviour demonstrated by expressive or receptive speech,
      and postictal memory. Frequency and patterns of impairment of constituent
      functions and 'conscious behaviour' were assessed. To achieve this, pre-surgical
      video-EEG (n = 40) or video-electrocorticography recordings (n = 76) of ictal
      neuropsychological assessments were reviewed retrospectively. Patients were
      divided into groups with frontal (n = 29), right temporal (n = 21), left temporal
      (n = 38) and bitemporal (n = 28) seizure activity. Consciousness was most
      commonly impaired in patients with bitemporal and left temporal seizure activity.
      There were different patterns of impairment of the assessed constituent functions
      in the four groups: patients with frontal seizure activity showed loss of
      orientation behaviour and expressive speech whereas patients with left temporal
      seizure activity had impairments of memory, expressive and receptive speech.
      Patients with seizure activity limited to the right temporal lobe rarely
      exhibited ictal impairment of any of the assessed functions. In contrast,
      patients with bitemporal seizure activity showed impairment of all examined
      functions. Hence, normal functioning of the left temporal lobe or both temporal
      lobes is necessary for the preservation of all constituent aspects of
      consciousness. The localizing value of patterns of impairment of constituent
      functions is superior to that of 'consciousness' as a whole.

PMID- 12429597
TI  - Repeated mild injury causes cumulative damage to hippocampal cells.
AB  - An interesting hypothesis in the study of neurotrauma is that repeated traumatic
      brain injury may result in cumulative damage to cells of the brain. However, post
      injury sequelae are difficult to address at the cellular level in vivo.
      Therefore, it is necessary to complement these studies with experiments conducted
      in vitro. In this report, the effects of single and repeated traumatic injury in
      vitro were investigated in cultured mouse hippocampal cells using a well
      characterized model of stretch-induced injury. Cell damage was assessed by the
      level of propidium iodide (PrI) uptake and retention of fluorescein diacetate
      (FDA). Uninjured control wells displayed minimal PrI uptake and high levels of
      FDA retention. Mild, moderate and severe levels of stretch caused increasing
      amounts of PrI uptake, respectively, when measured at 15 min and 24 h post
      injury, indicating increased cellular damage with increasing amounts of stretch.
      For repeated injury studies, cultures received a second injury 1 h after the
      initial insult. Repeated mild injury caused a slight increase in PrI uptake
      compared with single injury at 15 min and 24 h post-injury, which was evident
      primarily in glial cells. However, the neurites of neurones in cultures that
      received repeated insults showed signs of damage that were not evident after a
      single mild injury. The release of neurone-specific enolase (NSE) and S-100beta
      protein, two common clinical markers of CNS damage, was also measured following
      the repeated injuries paradigm. When measured at 6 h post-injury, both NSE and S
      100beta were found to be elevated after repeated mild injuries when compared with
      the single injury group. These results suggest that cells of the hippocampus may
      be susceptible to cumulative damage following repeated mild traumatic insults.
      Both glial cells and neurones appear to exhibit increased signs of damage after
      repetitive injury. To our knowledge, this study represents the first report on
      the effects of repeated mechanical insults on specific cells of the brain using
      an in vitro model system. The biochemical pathways of cellular degradation
      following repeated mild injuries may differ considerably from those that are
      activated by a single mild insult. Therefore, we hope to use this model in order
      to investigate secondary pathways of cellular damage after repeated mild
      traumatic injury, and as a rapid and economical means of screening possibilities
      for treatment strategies, including pharmaceutical intervention.

PMID- 12429598
TI  - Language lateralization in monozygotic twin pairs concordant and discordant for
      handedness.
AB  - An unexpectedly high percentage of monozygotic twin pairs is discordant for
      handedness. Some of these twins show mirror-imaging of several ectodermally
      derived features. Both features of discordant left-right asymmetry may be caused
      by relatively late monozygotic twinning, when the original embryo has already
      lost its bilateral symmetry. Language lateralization is related to handedness and
      may therefore also be altered during the development of embryological asymmetry
      in some monozygotic twins. Language lateralization was measured with functional
      MRI in 12 monozygotic twin pairs who were concordant for handedness and in 13
      monozygotic twin pairs discordant for handedness. Lateralization indices were
      calculated from individual language activation patterns. Correlations were
      calculated to test intra-pair resemblance for language lateralization. The intra
      pair correlation for language lateralization was significant in the handedness
      concordant group, but not in the handedness-discordant group. In the handedness
      discordant group, five twin pairs were also discordant for cerebral dominance;
      the other twin pairs of discordant handedness exhibited remarkable similarity in
      language lateralization. The high intra-pair correlation for language
      lateralization in the handedness-concordant twins suggests a genetic basis for
      language lateralization. However, in monozygotic twin pairs of discordant
      handedness, discordance for language dominance occurs in a significant number of
      twins. Discordant language dominance may be caused by a relatively late time of
      splitting of the original embryo, which disrupts the normal development of left
      right asymmetry.

PMID- 12429599
TI  - Abnormal somatotopic arrangement of sensorimotor interactions in dystonic
      patients.
AB  - The aim of the study was to detect abnormalities of sensorimotor interactions and
      their topographic distribution in the hand muscles of dystonic patients. We
      investigated the effect of electrical stimulation of the second (D2) and fifth
      (D5) fingers on the amplitude of motor evoked potentials (MEPs) in response to
      transcranial magnetic stimulation (TMS) and transcranial electrical stimulation
      (TES) in the relaxed first dorsal interosseous (FDI) and abductor digiti minimi
      (ADM) muscles on both sides of eight patients with unilateral hand dystonia (HD)
      and in four patients with cervical dystonia (CD). Six Parkinson's disease
      patients were used as the disease control group and 10 healthy subjects served as
      normal controls. For each muscle, the digital stimulation was applied to a
      contiguous finger (CF) and to a non-contiguous finger (NCF). The digital
      stimulation was set at three times the sensory threshold and preceded TMS or TES
      at intervals ranging from 10 to 100 ms. In normal subjects, a somatotopic
      inhibitory effect was detected, since the CF stimulation was significantly more
      powerful in determining the reduction of MEPs in response to TMS at intervals
      ranging from 20 to 50 ms. In dystonic patients, on the contrary, the somatopic
      effect was not present, because both CF and NCF stimulation evoked a consistent
      MEP inhibition and no significant difference was detected between the
      conditioning effect of CF and NCF stimulation. These abnormalities were present
      in the muscles of both the affected and unaffected hands of HD patients, as well
      as in CD patients. TES conditioning provoked MEP inhibition only at interstimulus
      intervals (ISIs) <40 ms. Significant MEP potentiation was found at ISIs of 20-40
      ms to CF stimulation in Parkinson's disease patients, while there was no effect
      after NCF stimulation. These data suggest that MEP suppression in response to
      digital stimulation is preserved in dystonia, but the somatotopically distributed
      input-output organization of the sensorimotor interactions is lost in dystonic
      patients' hands. The comparison between TMS and TES experiments indicates that
      abnormalities may be present at both the spinal and the cortical level, at least
      in some patients. These findings suggest that a mechanism that normally operates
      in order to focus the effect of somatosensory afferences on the motor system may
      be impaired in dystonia. This abnormality seems specific to dystonia.

PMID- 12429600
TI  - Correlation between motor improvements and altered fMRI activity after
      rehabilitative therapy.
AB  - Motor rehabilitation therapy is commonly employed after strokes, but outcomes are
      variable and there is little specific information about the changes in brain
      activity that are associated with improved function. We performed serial
      functional MRI (fMRI) on a group of seven patients receiving a form of
      rehabilitation therapy after stroke in order to characterize functional changes
      in the brain that correlate with behavioural improvements. Patients were scanned
      while performing a hand flexion-extension movement twice before and twice after a
      two-week home-based therapy programme combining restraint of the unaffected limb
      with progressive exercises for the affected limb. As expected, the extent of
      improvement in hand function after therapy varied between patients. Therapy
      related improvements in hand function correlated with increases in fMRI activity
      in the premotor cortex and secondary somatosensory cortex contralateral to the
      affected hand, and in superior posterior regions of the cerebellar hemispheres
      bilaterally (Crus I and lobule VI). fMRI offers a promising, objective approach
      for specifically identifying changes in brain activity potentially responsible
      for rehabilitation-mediated recovery of function after stroke. Our results
      suggest that activity changes in sensorimotor regions are associated with
      successful motor rehabilitation.

PMID- 12429601
TI  - Magnetic resonance spectroscopy and cognitive function in healthy elderly men.
AB  - Subtle cognitive decrements in older people are important in terms of the
      associated morbidity and as a risk factor for dementia. However, their
      pathophysiological basis is poorly understood. Proton magnetic resonance
      spectroscopy ((1)H-MRS) may provide the means to investigate early changes in
      brain metabolite concentrations. We examined the relationships between N
      acetylaspartate (NAA), choline (Cho) and creatine (Cr) metabolite ratios in a
      voxel in the parietal cortex and cognitive function in 88 healthy, non-demented,
      unmedicated men aged 65-70 years. We also used linear regression to give a value
      for each metabolite adjusted for the levels of the other two metabolites. Both
      NAA/Cr and Cho/Cr ratios correlated positively with tests of verbal memory and a
      verbal memory factor (e.g. NAA/Cr and Logical Memory: r = 0.24, P < 0.05). Cho/Cr
      ratios also correlated positively with tests of visual memory (e.g. visual
      reproduction: r = 0.21, P < 0.05). Adjusted Cr levels correlated negatively and
      significantly with tests of verbal memory and the Verbal Memory Factor. The
      regression analysis suggested that Cr levels better explained the correlations
      between NAA/Cr and Cho/Cr ratios and cognitive variables than NAA or Cho levels.
      These results suggest that in healthy men aged 65-70 years, metabolite levels
      relate to cognitive performance. Rising Cr levels may be an early marker of
      cognitive decline.

PMID- 12429602
TI  - Suppression of false recognition in Alzheimer's disease and in patients with
      frontal lobe lesions.
AB  - Previous research has shown that patients with Alzheimer's disease show
      increasing levels of false recognition across five repeated study-test trials of
      semantic associates. The present study tested the hypotheses that (i) the
      increasing false recognition was partly due to the frontal lobe dysfunction of
      patients with Alzheimer's disease, and (ii) a failure of source monitoring was
      the central mechanism by which frontal lobe dysfunction led to increasing false
      recognition across trials. In Experiment 1, patients with frontal lobe lesions
      and controls were examined in the same repeated trials paradigm as that used
      previously in patients with Alzheimer's disease. Although controls were able to
      reduce their false recognition across trials, the patients with frontal lobe
      lesions were not, and instead showed a constant level of elevated false
      recognition across the study-test trials. In Experiment 2, two groups of patients
      with Alzheimer's disease and healthy older adult controls were studied: the first
      group was given a single study session followed by a recognition test, the second
      group was given five study sessions followed by a single recognition test. Older
      adults who were exposed to five study lists demonstrated lower levels of false
      relative to true recognition, whereas patients with Alzheimer's disease in this
      condition exhibited levels of false recognition elevated to that of their true
      recognition, even with the source memory confusion of intervening tests
      eliminated. The authors suggest that impairment in aspects of frontal lobe
      function, such as verification-inhibition mechanisms, probably contributes to the
      inability of patients with Alzheimer's disease to suppress their false
      recognition across repeated trials. Lastly, it is speculated that one way in
      which the frontal lobes enable normal episodic memory function is by facilitating
      the suppression of false recognition and other distortions of memory.

PMID- 12429603
TI  - Laser-evoked potential abnormalities in central pain patients: the influence of
      spontaneous and provoked pain.
AB  - We recorded laser-evoked cortical potentials (LEPs) in 54 consecutive patients
      presenting with unilateral neuropathic central pain (n = 42) or with lateralized
      pain of non-organic origin (n = 12). A number of cases in each group had
      superimposed hyperalgesia or allodynia. In patients with central pain, LEPs were
      significantly attenuated after stimulation over the painful territory, relative
      to stimulation of the homologous normal territory. LEP attenuation concerned not
      only patients with decreased pain/heat sensation, but also those with allodynia
      or hyperalgesia to laser pulses. In contrast, LEPs were never attenuated in
      patients with non-organic forms of pain, in whom LEPs could even be enhanced to
      stimulation of the painful territory. Increased responses in non-organic pain
      were a reminder of the cognitive modulation observed in normal subjects who
      direct attention to a laser stimulus. Enhanced LEPs never accompanied truly
      neuropathic hyperalgesia or allodynia. In central pain patients with exclusively
      spontaneous pain, LEP attenuation was more pronounced than that observed in those
      with allodynia and hyperalgesia. Patients with allodynia also presented
      occasionally ultra-late responses (>700 ms) to stimulation of the painful side.
      The hypothesis that such responses may reflect activation of a slow conducting
      'medial' pain system is discussed. We conclude that, as currently recorded, LEPs
      essentially reflect the activity of a 'lateral' pain system subserved at the
      periphery by rapidly conducting A-delta fibres. They are useful to document the
      sensorial deficits (deafferentation) leading to neuropathic pain syndromes.
      Conversely, in the case of deafferentation, they fail to index adequately the
      affective aspects of pain sensation. On practical grounds, chronic pain coupled
      with reduced LEPs substantiates the diagnosis of neuropathic pain, whereas the
      finding of normal or enhanced LEPs to stimulation of a painful territory suggests
      the integrity of pain pathways, and does not support a neuropathic
      pathophysiology. In neuropathic cases, partial LEP preservation might increase
      the probability of developing provoked pain (allodynia/hyperalgesia). The
      possible predictive value of this phenomenon, when observed before the
      development of pain, remains to be demonstrated. In selected contexts (pain sine
      materia, non-organic anaesthesia), normal or enhanced LEPs may support a
      psychogenic participation in the syndrome.

PMID- 12429604
TI  - The foot soldiers of science.

PMID- 12429605
TI  - Commentary on Gaspar Jekely's article in EMBO reports, July 2002.

PMID- 12429606
TI  - Training scientists to be journalists. Clear and accessible writing is not good
      enough for the public. Above all, it has to have sparkle.

PMID- 12429607
TI  - Immunology at the crossroads. As decades of research have resulted in few
      clinical applications, it is time to think about new research strategies to
      understand the workings of the immune system.

PMID- 12429608
TI  - How much is a scientist worth? Pay and benefits for postdoctoral researchers.

PMID- 12429609
TI  - When will the bear move on? The current problems of the biotechnology industry
      are not solely a reflection of the whole market but are also caused by some
      specific problems.

PMID- 12429610
TI  - What you don't learn at the bench...conclusions from the EMBO/ELSF-organised
      meeting on career prospects in the life sciences.

PMID- 12429611
TI  - Walking pathways at Heidelberg. Conference on oncogenes and growth control.

PMID- 12429612
TI  - From neurotrophins to immunotrophins. NGF 2002: The 7th international conference
      on NGF and related molecules.

PMID- 12429613
TI  - Arf, Arl, Arp and Sar proteins: a family of GTP-binding proteins with a
      structural device for 'front-back' communication.
AB  - Arf proteins are important regulators of cellular traffic and the founding
      members of an expanding family of homologous proteins and genomic sequences. They
      depart from other small GTP-binding proteins by a unique structural device, which
      we call the 'interswitch toggle', that implements front-back communication from
      the N-terminus to the nucleotide binding site. Here we define the sequence and
      structural determinants that propagate information across the protein and
      identify them in all of the Arf family proteins other than Arl6 and Arl4/Arl7.
      The positions of these determinants lead us to propose that Arf family members
      with the interswitch toggle device are activated by a bipartite mechanism acting
      on opposite sides of the protein. The presence of this communication device might
      provide a more useful basis for unifying Arf homologs as a family than do the
      cellular functions of these proteins, which are mostly unrelated. We review
      available genomic sequences and functional data from this perspective, and
      identify a novel subfamily that we call Arl8.

PMID- 12429615
TI  - Targeting multiple biological pathways as a strategy to improve the treatment of
      cancer.

PMID- 12429614
TI  - Phytochrome-mediated photoperception and signal transduction in higher plants.
AB  - Light provides a major source of information from the environment during plant
      growth and development. Light perception is mediated through the action of
      several photoreceptors, including the phytochromes. Recent results demonstrate
      that light responses involve the regulation of several thousand genes. Some of
      the key events controlling this gene expression are the translocation of the
      phytochrome photoreceptors into the nucleus followed by their binding to
      transcription factors. Coupled with these events, the degradation of positively
      acting intermediates appears to be an important process whereby
      photomorphogenesis is repressed in darkness. This review summarizes our current
      knowledge of these processes.

PMID- 12429616
TI  - To arrest or not to G(2)-M Cell-cycle arrest : commentary re: A. K. Tyagi et al.,
      Silibinin strongly synergizes human prostate carcinoma DU145 cells to doxorubicin
      induced growth inhibition, G(2)-M arrest, and apoptosis. Clin. cancer res., 8:
      3512-3519, 2002.

PMID- 12429617
TI  - In vivo validation of 3'deoxy-3'-[(18)F]fluorothymidine ([(18)F]FLT) as a
      proliferation imaging tracer in humans: correlation of [(18)F]FLT uptake by
      positron emission tomography with Ki-67 immunohistochemistry and flow cytometry
      in human lung tumors.
AB  - PURPOSE: Tumor proliferation has prognostic value in resected early stage non
      small cell lung cancer (NSCLC) and can, therefore, predict which NSCLCs are at
      high risk for recurrence after resection and would benefit from additional
      therapy. It may also predict which tumor will respond to cell cycle-targeted
      chemotherapy and help assess the tumor response, besides helping to differentiate
      benign from malignant lung lesions. We evaluated whether the uptake of the new
      positron emission tomography (PET) tracer 3'deoxy-3'-[18F]fluorothymidine (FLT)
      in a series of suspected NSCLCs correlated with tumor proliferation assessed by
      Ki-67 immunohistochemistry and flow cytometry. EXPERIMENTAL DESIGN: Ten patients
      with 11 biopsy-proven or clinically suspected NSCLC underwent 2-h dynamic PET
      imaging after i.v. injection of 0.07 mCi/kg FLT. Tumor FLT uptake was quantitated
      with the maximum pixel standardized uptake value (maxSUV), the partial volume
      corrected maxSUV (PV-corr-maxSUV), the average SUV over a small region-of
      interest (aveSUV) and with Patlak analysis of FLT flux (aveFLTflux). The lesion
      diameter from computed tomography was used to correct the maxSUV for PV effects
      using recovery coefficients determined for the General Electric Advance PET
      scanner. Two of the 11 lesions were benign inflammatory lesions and 9 were
      NSCLCs. Immunohistochemistry for Ki-67 (proliferation index marker) was performed
      on all 11 tissue specimens (10 resections, 1 NSCLC percutaneous biopsy), and the
      S-phase fraction (SPF) from flow cytometry could be determined for 10. The
      specimens were reviewed for histology and cellular differentiation (poor,
      moderate, well). Lesions ranged from 1.6 to 7.7 cm. RESULTS: Excellent
      correlations were found between SUV measures of FLT uptake and Ki-67 scores
      [percentage of positive cells; maxSUV versus Ki-67: Rho = 0.78, P = 0.0043 (n =
      11); PV-corr-maxSUV versus Ki-67: Rho = 0.83, P = 0.0028 (n = 10); aveSUV versus
      Ki-67: Rho = 0.84, P = 0.0011 (n = 11)]. Correlation between Ki-67 proliferation
      scores and Patlak measures of FLT uptake were also strong: aveFLTflux versus Ki
      67: Rho = 0.94, P < 0.0001 (n = 11). The correlation between the SPF and all
      indices of FLT uptake was weaker and reached statistical significance for only
      two uptake indices [maxSUV versus SPF: Rho = 0.69, P = 0.03 (n = 10); PV-corr
      maxSUV versus SPF: Rho = 0.36, P = 0.35 (n = 9); aveSUV versus SPF: Rho = 0.67, P
      = 0.03 (n = 10); aveFLTflux versus SPF: Rho = 0.46, P = 0.18 (n = 10)].
      CONCLUSION: FLT PET may be used to noninvasively assess proliferation rates of
      lung masses in vivo. Therefore, FLT PET may play a significant role in the
      evaluation of indeterminate pulmonary lesions, in the prognostic assessment of
      resectable NSCLC, and possibly in the evaluation of NSCLC response to
      chemotherapy.

PMID- 12429618
TI  - Methylation profiles of sporadic ovarian tumors and nonmalignant ovaries from
      high-risk women.
AB  - PURPOSE: The purpose of this research was to examine the DNA methylation profiles
      of primary sporadic ovarian cancers and ovarian tissues from high-risk women.
      EXPERIMENTAL DESIGN: We analyzed the DNA methylation status of nine cancer
      related genes in 49 primary ovarian tumors, 39 nonmalignant ovarian tissues
      obtained from 16 women with no known risk and from 23 high-risk women with a
      strong family history of breast and/or ovarian cancer or BRCA1 germ-line
      mutations, and 11 ovarian cancer cell lines, by methylation-specific PCR.
      RESULTS: Our findings are as follows: (a) methylation rates of four of nine
      genes, RASSF1A (41%), HIC1 (35%), E-cadherin (29%), and APC (18%) were
      significantly higher in tumors compared with controls. At least one of the four
      genes was methylated in 76% of the tumors; (b) a low frequency of methylation was
      present in nonmalignant tissues; (c) no significant differences in methylation
      frequencies were seen between the nonmalignant ovarian tissues from women at high
      risk and those with no known risk of developing ovarian cancer; (d) methylation
      of the BRCA1 gene was found in 10% of sporadic tumors but in none of the samples
      from women with a germ-line BRCA1 mutation; and (e) ovarian cancer cell lines
      showed a similar frequency of methylation to ovarian tumors except for the HIC1
      gene. CONCLUSIONS: Our results suggest that aberrant methylation of specific
      genes, including two not described previously, may be important in ovarian cancer
      pathogenesis but not in ovaries at risk for cancer development.

PMID- 12429619
TI  - Detection of JC polyomavirus DNA sequences and cellular localization of T-antigen
      and agnoprotein in oligodendrogliomas.
AB  - PURPOSE: Productive infection of the human neurotropic polyomavirus JCPyV in
      oligodendrocytes leads to the development of progressive multifocal
      leukoencephalopathy, a fatal demyelinating disorder of the central nervous
      system. In addition to its role in viral infection, JCPyV T-antigen can transform
      cells in vitro and induce tumors in experimental animals in the absence of viral
      DNA replication and late gene expression. The goal of this study is to examine
      the presence of JCPyV DNA sequences and viral antigens in a series of human
      oligodendrogliomas. EXPERIMENTAL DESIGN: A total of 20 well-characterized
      oligodendrogliomas were examined for detection of the JCPyV genome by PCR and
      immunohistochemistry for expression of viral proteins. RESULTS: Gene
      amplification has revealed the presence of JCPyV DNA sequences corresponding to
      the NH2-terminal of T-antigen in 15 of 20 samples. DNA sequences corresponding to
      late regions, which are responsible for production of the capsid protein, VP1,
      were detected in 14 of 20 samples. Sequencing of the viral control region
      determined the presence of JCPyV Mad-4 or JCPyV(CY) in these tumors. By
      immunohistochemistry, T-antigen expression was detected in the nuclei of tumor
      cells from 10 samples that also contained corresponding DNA sequences by PCR.
      Eleven of 20 tumors exhibited immunoreactivity for the late auxiliary gene
      product, agnoprotein. None of the samples showed immunoreactivity for the capsid
      proteins, ruling out productive infection of neoplastic cells by JCPyV.
      CONCLUSIONS: Collectively, these observations provide new evidence in support of
      the association of the oncogenic human neurotropic JCPyV and oligodendrogliomas.

PMID- 12429620
TI  - Inhibition of human telomerase enhances the effect of the tyrosine kinase
      inhibitor, imatinib, in BCR-ABL-positive leukemia cells.
AB  - PURPOSE: Telomerase is a ribonucleoprotein enzyme that maintains protective
      structures at the ends of eukaryotic chromosomes. Earlier findings have supported
      an association between progressive telomere shortening in the chronic phase of
      chronic myelogenous leukemia and the up-regulation of telomerase activity
      occurring late in the evolution of the disease. We examined the impact of
      telomerase inhibition by dominant negative-human telomerase reverse transcriptase
      (DN-hTERT) on the biological features of BCR-ABL-transformed cells. EXPERIMENTAL
      DESIGN: We introduced vectors encoding DN-hTERT, wild-type (WT)-hTERT, or a
      control vector expressing only a drug-resistant marker into Philadelphia
      chromosome-positive K562 cells and OM9;22 cells and assessed the biological
      effect of telomerase inhibition on cellular immortality. RESULTS: Ectopic
      expression of DN-hTERT resulted in complete inhibition of telomerase activity and
      reduction of telomere length. The entire population of telomerase-inhibited K562
      cells exhibited cytoplasmic blebbling and chromatin condensation, features of
      apoptosis. In contrast, K562 cells expressing WT-hTERT, which differ from the
      mutants by only two amino acids, exhibited normal morphology. The evidence of
      apoptosis in the telomerase-inhibited cells was determined by flow cytometric
      analysis with APO2.7 monoclonal antibody. We also observed enhanced induction of
      apoptosis by imatinib seen in DN-hTERT-expressing K562 cells, as compared with WT
      hTERT-expressing cells. CONCLUSIONS: These results demonstrate that disruption of
      telomere maintenance limits the cellular life span of leukemia cells and show
      that the combined use of imatinib and telomere maintenance inhibition may be
      effective in the treatment of BCR-ABL-positive leukemia.

PMID- 12429621
TI  - The presence of the adenovirus E3 region improves the oncolytic potency of
      conditionally replicative adenoviruses.
AB  - PURPOSE: The initial development of conditionally replicative adenoviruses
      (CRAds) for cancer treatment has aimed at achieving selective replication in and
      killing of malignant cells. Other aspects such as the potentiation of the
      cytolytic capacity have also been investigated but still require new endeavors.
      As an extension of our prior work, we analyzed the effect of the E3 region, which
      includes the adenovirus death protein, in the context of CRAd oncolytic potency.
      EXPERIMENTAL DESIGN: We constructed E3-positive (E3+) and E3-negative (E3-)
      variants of the previously characterized CRAd, Ad5-Delta 24, and its infectivity
      enhanced version, Ad5-Delta 24RGD, and compared their oncolytic effect in human
      cancer cell lines infected with 0.01 viral particle/cell and in s.c. xenografts
      of A549 human lung cancer cells injected intratumorally with a single dose of
      10(7) adenoviral particles in immunodeficient mice. RESULTS: The in vitro
      experiments showed that the E3+ viruses kill tumor cells 1.6-20 times more
      effectively in different cell lines. As well, the in vivo study demonstrated that
      the administration of E3+ CRAds resulted in a more potent oncolytic effect
      compared with the same dose of their E3- counterparts 35 days after virus
      administration. Moreover, a time course study of virus replication within the
      tumor xenografts established a correlation between higher in situ propagation of
      E3+ CRAds and tumor growth inhibition compared with E3- viruses. CONCLUSIONS:
      These results indicate that the presence of E3 can enhance the antitumor potency
      of CRAds over and above the levels conferred by the enhancement of infectivity
      via Arg-Gly-Asp (RGD).

PMID- 12429622
TI  - A detailed evaluation of cardiac toxicity: a phase II study of doxorubicin and
      one- or three-hour-infusion paclitaxel in patients with metastatic breast cancer.
AB  - PURPOSE: This Phase II study was designed to determine the efficacy and toxicity
      of combination doxorubicin and paclitaxel as front-line treatment for metastatic
      breast cancer. EXPERIMENTAL DESIGN: Eligible patients had no prior anthracycline
      or taxane therapy and normal cardiac function. They were treated with bolus
      doxorubicin 60 mg/m2, followed by paclitaxel 200 mg/m2, as either 1- or 3-h
      infusions for six to seven cycles. Single-agent paclitaxel was continued
      thereafter. Serial multiple gated acquisition scans were performed, and
      endomyocardial biopsies were performed for consenting patients. RESULTS: Eighty
      two patients were enrolled with a median age of 53 years (range, 32-78 years). Of
      79 evaluable patients, 58.2% had an objective response (3.8% complete response +
      54.4% partial response), 34.2% had stable disease, and 7.6% had progressive
      disease. With median follow-up of 37.5 months, median time to progression was 7
      months; median survival was 31 months. Multiple gated acquisition scans were
      performed in 82 of 82 patients at baseline, 75 of 82 patients at a total
      doxorubicin dose of 60-180 mg/m2, 62 of 68 patients at 200-300 mg/m2, 18 of 52
      patients at 310-360 mg/m2, and 4 of 8 patients at 420 mg/m2. Median ejection
      fractions were 62.5, 60, 57.5, 52.5, and 32%, respectively. Fifteen of 82 (18.3%)
      patients had a decrease in ejection fraction > or = 15% to an absolute ejection
      fraction < or = 50%. Eight of these 15 patients (53%) developed clinical
      congestive heart failure: 4 of 8 (50%) who received a total doxorubicin dose of
      420 mg/m2 versus 4 of 74 (5.4%) who received a dose < or = 360 mg/m2 (P = 0.002).
      CONCLUSIONS: When the doxorubicin dose exceeds 360 mg/m2, the combination of
      bolus doxorubicin and paclitaxel presents unacceptable cardiac risk.

PMID- 12429623
TI  - Immunotherapy of metastatic renal cell carcinoma with tumor lysate-pulsed
      autologous dendritic cells.
AB  - PURPOSE: We wanted to evaluate feasibility and safety of dendritic cell-based
      immunotherapy in patients with metastatic renal cell carcinoma (RCC).
      EXPERIMENTAL DESIGN: Patients with metastatic RCC (n = 35) received vaccinations
      (i.v. or i.d.) of CD83+ autologous monocyte-derived dendritic cells (moDCs).
      MoDCs were loaded with lysate of cultured autologous or allogeneic permanent
      tumor cells (A-498) as well as keyhole limpet hemocyanin as control and helper
      antigen. Maturation of moDCs was induced by a combination of tumor necrosis
      factor alpha, interleukin 1 beta, interleukin 6, and prostaglandin E2. RESULTS:
      Treatment was associated with transient flu-like symptoms. In 2 of 27 evaluable
      patients, any evidence of disease disappeared (complete response). In both cases,
      metastatic tissue had been the source of tumor antigen. One patient had an
      objective partial response. Seven patients had stable disease, the remaining 17
      patients had progressive disease. In 11 of 11 patients evaluated, moDCs induced
      strong immune responses against keyhole limpet hemocyanin. In 5 of 6 patients
      tested, enhanced immune responses against oncofetal antigen (immature laminin
      receptor; OFA/LRP) could also be detected. The strongest responses against
      OFA/LRP were detectable in 2 patients with complete response and partial
      response, respectively. At the time of submission, mean follow up is 32 months
      and 8 patients are currently alive. CONCLUSIONS: Our data indicate that moDC
      based vaccination is well tolerated and has immunological as well as clinical
      effects in patients with metastatic RCC. OFA/LRP might be an attractive candidate
      antigen for DC-based immunotherapy of RCC.

PMID- 12429624
TI  - Dose-dependent effect of thalidomide on overall survival in relapsed multiple
      myeloma.
AB  - PURPOSE: Although thalidomide (Thal) was introduced successfully in the treatment
      of multiple myeloma (MM), the optimal Thal dosage and schedule are still
      controversial. The aim of this study was to analyze whether the effect of Thal in
      MM is dose dependent and whether the outcome might be improved when the Thal
      dosage is adjusted to parameters reflecting body size. EXPERIMENTAL DESIGN: From
      December 1998 to March 2001, 83 patients with relapsed MM were enrolled in a
      clinical Phase II trial and treated with a maximum Thal dosage of 400 mg daily.
      We performed a retrospective analysis and studied the effect of the cumulative 3
      month Thal dosage on progression-free survival and overall survival (OS) together
      with age and the pretreatment levels of beta2-microglobulin, C-reactive protein,
      albumin, and hemoglobin in a Cox regression model. RESULTS: After a median follow
      up time of 17 months (range, 1-30 months), the estimated 12-month progression
      free survival and OS were 45% (SE = 6%) and 86% (SE = 4%) for the whole patient
      group. After backward selection, hemoglobin (P = 0.002) and the cumulative 3
      month Thal dosage (P = 0.002) were the remaining factors for OS. The effect on OS
      could not be improved when the cumulative 3-month Thal dosage was adjusted to
      parameters reflecting body size such as height, weight, body surface area, or
      body mass index in comparison with Thal alone. CONCLUSIONS: Our retrospective
      analysis demonstrates that the cumulative 3-month Thal dosage is one of the major
      prognostic factors for OS, supporting the hypothesis of a dose-dependent effect
      of Thal in relapsed MM.

PMID- 12429625
TI  - Interleukin 12 immunotherapy after autologous stem cell transplantation for
      hematological malignancies.
AB  - PURPOSE: To determine the safety, maximum tolerated dose,and biological effects
      of recombinant human IL-12 after autologous stem cell transplantation for cancer.
      EXPERIMENTAL DESIGN: Twelve patients with hematological malignancies (8 non
      Hodgkin's lymphoma, 2 Hodgkin's disease, and 2 plasma cell myeloma) began
      interleukin (IL)-12 therapy at a median of 66 days after transplantation.
      Recombinant human IL-12 was given by bolus i.v. injection in doses of 30, 100, or
      250 ng/kg once as an inpatient and then, after a 2-week hiatus, once daily for 5
      consecutive days every 3 weeks on an outpatient basis. RESULTS: Common side
      effects included fever, chills, fatigue, nausea or vomiting, and asymptomatic
      elevation in serum liver function tests. Transient neutropenia and
      thrombocytopenia were also common, but no patient required platelet transfusion
      or had a neutropenic fever. Dose-limiting toxicities (diarrhea and elevated liver
      function tests) occurred in 2 of 3 patients treated in the 250 ng/kg cohort.
      Biological effects, including increases in serum IFN-gamma levels and transient
      lymphopenia involving CD4 T cells, CD8 T cells, B cells, and NK cells, were seen
      at all three dose levels. CONCLUSIONS: Biologically active doses of IL-12 can be
      given safely to patients after autologous stem cell transplantation for high-risk
      hematological malignancies. Further studies are indicated to assess the efficacy
      of IL-12 in this setting.

PMID- 12429626
TI  - Dendritic cells pulsed with HER-2/neu-derived peptides can induce specific T-cell
      responses in patients with gastric cancer.
AB  - PURPOSE: We have previously reported (K. Kono et al., Int. J. Cancer, 78: 202
      208, 1998) that HER-2/neu-derived peptides are naturally processed as tumor
      associated antigens recognized by tumor-specific, human leukocyte antigen (HLA)
      A2-restricted CTLs in gastric cancer. In the present study, we described a Phase
      1 vaccination trial in gastric cancer patients using dendritic cells (DCs) pulsed
      with the immunodominant HER-2/neu(p369) peptides. EXPERIMENTAL DESIGN: Nine
      enrolled patients, who had HER-2/neu-overexpressing tumors and who were HLA-A2
      positive, received four vaccinations by DCs pulsed with HER-2(p369) peptide at 2
      week intervals intradermally. RESULTS: There were no serious adverse effects
      noted in the immunized patients. Peripheral blood mononuclear cells,
      preimmunization and after the fourth immunization, were cultured with autologous,
      HER-2(p369)-pulsed antigen-presenting cells for 12 days. Thereafter, peptide
      specificity was evaluated by IFN-gamma secretion assay from cultured T cells
      against T2 cells pulsed with HER-2(p369) peptide. HER-2/neu peptide-specific
      recognition could be demonstrated in six of nine patients after immunization,
      whereas there was no HER-2/neu peptide-specific recognition before immunization.
      The peptide-specific CTL lines isolated from two of the patients could also lyse
      a HER2/neu-transfected cell line. Furthermore, a peptide-specific delayed-type
      hypersensitivity response occurred in three of nine patients. One of the patients
      underwent a partial clinical response concurrent with a decrease of tumor marker.
      Another patient demonstrated a stabilization of disease status for a period of 3
      months. CONCLUSIONS: Taken together, tumor vaccination therapy with DCs pulsed
      with HER-2/neu-peptides may be a potential candidate for the novel treatment of
      gastric cancer patients.

PMID- 12429627
TI  - Reinfusion of unprocessed, granulocyte colony-stimulating factor-stimulated whole
      blood allows dose escalation of 186Relabeled chimeric monoclonal antibody U36
      radioimmunotherapy in a phase I dose escalation study.
AB  - PURPOSE: In an earlier Phase I radioimmunotherapy (RIT) study with rhenium-186
      labeled chimeric monoclonal antibody (cMAb) U36 in patients with refractory head
      and neck squamous cell carcinoma, the maximum tolerated activity was established
      at 1.0 GBq/m2, at which bone marrow doses ranged from 0.7 to 1.1 Gy. In the
      present study, further dose escalation in RIT was evaluated using a facile method
      of reinfusion of granulocyte colony-stimulating factor (G-CSF)-stimulated
      unprocessed whole blood. EXPERIMENTAL DESIGN: Nine patients with recurrent or
      metastatic head and neck squamous cell carcinoma were treated at radiation dose
      levels of 1.0, 1.5, and 2.0 GBq/m2. Before RIT, G-CSF (10 microg/kg/day) was
      administered s.c. at home during 5 days. On day 6, just before administration of
      186Relabeled cMAb U36, 1 liter of whole blood was harvested and kept unprocessed
      at 4 degrees C until reinfusion after 72 h. Blood samples were taken for analysis
      of pharmacokinetics and bone marrow dosimetry. Patients were evaluated for
      myelotoxicity and tumor response. RESULTS: Blood harvesting, RIT, and reinfusion
      of whole blood were well tolerated by all patients. G-CSF stimulation resulted in
      a mean of 0.41 x 10(6) CD34+ cells/kg (range, 0.15-0.83 x 10(6) CD34+cells/kg)
      and a mean committed colony-forming units granulocyte macrophage count of 5.62 x
      10(4)/kg (range, 0.62-13.37 x 10(4)/kg). The mean biological half-life of
      186Relabeled cMAb U36 in blood was 72.6 +/- 16.0 h, and bone marrow doses ranged
      from 2.1 to 2.8 Gy at the highest dose level. Myelotoxicity exceeding grade 3 was
      not observed. Stable disease was observed in five of nine patients, ranging from
      3 to 5 months, and was still ongoing in one of these patients. CONCLUSIONS: This
      study indicates that a doubling of the maximum tolerated activity and bone marrow
      dose of 186Relabeled cMAb U36 can be achieved using reinfusion of G-CSF
      stimulated unprocessed whole blood.

PMID- 12429628
TI  - Toxicity, immunogenicity, and induction of E75-specific tumor-lytic CTLs by HER-2
      peptide E75 (369-377) combined with granulocyte macrophage colony-stimulating
      factor in HLA-A2+ patients with metastatic breast and ovarian cancer.
AB  - To determine the toxicity and immunogenicity of the HER-2/neu, HLA-A2-restricted
      peptide E75 in patients with metastatic breast and ovarian cancer, 14 patients
      were vaccinated with escalating amounts of E75 (100, 500, and 1000 microg) mixed
      with 250 microg granulocyte macrophage colony-stimulating factor as adjuvant.
      Each vaccine dose was administered in a total volume of 1.5 ml divided into four
      intradermal injections and administered weekly for 4 weeks, followed by monthly
      boosts for a total of 10 injections. Vaccinations were well tolerated without
      significant toxicity. Blood was drawn before, at 8 weeks, and up to 13-16 months
      after vaccination for measurement of cellular immunity. Seven of 8 patients
      tested had significant delayed type hypersensitivity to E75 defined as >5 mm
      induration. Peripheral blood mononuclear cells from 5 of 9 patients tested
      proliferated to E75 with a stimulation index of > or = 2.0. Of 8 vaccinated
      patients tested for induction of a CTL response, 4 responded to stimulation by
      autologous dendritic cells plus cytokines by eliciting E75-specific lytic
      activity consistent with the presence of activated/memory cells, 2 others after
      in vitro stimulation with E75 + interleukin-12 +/- anti-CD152(33KD), whereas 2
      others did not respond. Four patients with E75-specific CTLs present specifically
      recognized E75 on indicator tumors as demonstrated by cold-target inhibition of
      tumor lysis. These 4 patients showed E75-specific IFN-gamma production.
      peripheral blood mononuclear cell from 3 of these patients proliferated to E75,
      but stimulation indices were higher in the prevaccine samples. All 4 of the
      patients showed DTH responses to E75. These results demonstrate that vaccination
      with E75+ granulocyte macrophage colony-stimulating factor can induce both
      peptide-specific IFN-gamma and epitope specific CTLs, which lyse HER-2/neu+
      tumors in stage IV patients.

PMID- 12429629
TI  - Elevated Skp2 protein expression in human prostate cancer: association with loss
      of the cyclin-dependent kinase inhibitor p27 and PTEN and with reduced recurrence
      free survival.
AB  - The F-box protein Skp2 (Fbl1) is a positive regulator of G1-S transition and
      promotes ubiquitin-mediated proteolysis of the cyclin-dependent kinase inhibitor
      p27. Its overexpression has been implicated in cell transformation and
      oncogenesis in both in vitro and in vivo models. In this study, we investigated
      its role in human prostate cancer progression. Immunohistochemical analysis was
      performed on formalin-fixed paraffin sections of 622 radical prostatectomy
      specimens, 74 prostatic intraepithelial neoplasm specimens, as well as in 4
      normal prostate organ donors assembled into tissue microarrays. We found that
      both luminal and basal epithelial cells in normal prostate had very low Skp2
      levels, but Skp2 levels and labeling frequency increased dramatically in both
      premalignant lesions of prostatic intraepithelial neoplasm (P = 0.0252) and in
      prostate cancer (P = 0.0037). The Skp2 labeling frequency in cancer was
      positively correlated with preoperative serum prostate-specific antigen level (P
      = 0.0499) and Gleason score (P = 0.0002), whereas the Skp2 index was positively
      correlated with extraprostatic extension (P = 0.0454), clinical stage (P =
      0.0170), as well as Gleason score (P = 0.0002). Kaplan-Meier analysis revealed
      that a higher Skp2 labeling index (>10) was a significant predictor of shorter
      biochemical recurrence-free survival time after radical prostatectomy (P <
      0.0363, log-rank test). An inverse correlation of Skp2 was observed with both its
      biochemical target p27 expression in prostate cancer (P = 0.0003) and with its
      putative negative regulator, the PTEN tumor suppressor protein (P = 0.0444).
      These data suggest that induction of Skp2 may be causally linked with decreased
      levels of p27 in prostate cancer and implicate PTEN in the regulation of Skp2
      expression in vivo, as previous tissue culture experiments have suggested.

PMID- 12429630
TI  - Pattern of hormone receptor status of secondary contralateral breast cancers in
      patients receiving adjuvant tamoxifen.
AB  - In breast cancer patients receiving adjuvant tamoxifen after unilateral
      treatment, contralateral breast cancer (CBC) is extremely rare. As a result, only
      limited data are available on the hormone receptor status of CBCs evolving in
      tamoxifen-treated patients. The aim of our investigation was to evaluate the
      pattern of hormone receptor status of CBCs in patients treated with adjuvant
      tamoxifen at our institution. Material was collected from 35 patients. We have
      found that 27 of the 35 patients included into our investigation developed an
      estrogen receptor (ER)-positive CBC despite adjuvant tamoxifen. Seven ER-positive
      CBCs occurred after tamoxifen had been discontinued, and 20 patients developed an
      ER-positive CBC while receiving tamoxifen. Notably, 80% of these CBCs displayed
      moderate-to-strong levels of ER. In our opinion, the selection of ER-negative
      CBCs, which has previously been implicated to be the pivotal mechanism of tumor
      escape of CBCs evolving in tamoxifen-treated patients, is only one mechanism of
      tumor escape in patients receiving antiestrogen treatment. The emergence of ER
      positive CBCs in the majority of tamoxifen-treated patients suggests that
      alternative escape mechanisms may be equally relevant. These include the
      emergence of ER-positive CBCs that display tamoxifen-dependent growth properties,
      the selection of CBCs that are tamoxifen resistant because of ER mutations with
      altered ER function, and, finally, the selection of ER-positive CBCs that
      overexpress c-erbB2.

PMID- 12429631
TI  - Outcome in prostate cancer: association with endothelial nitric oxide synthase
      Glu-Asp298 polymorphism at exon 7.
AB  - PURPOSE: The endothelial cell-specific form of nitric oxide synthases (ecNOS) was
      mapped at 7q35-q36 and plays an important role in vascular development and tumor
      growth in human prostate cancer. Bone metastasis, clinical T-stage, tumor grade,
      and serum prostate-specific antigen (PSA) have been shown to have prognostic
      importance in the outcome of prostate cancer. The purpose of this study was to
      evaluate ecNOS polymorphism as a genetic indicator of the outcome of the disease.
      EXPERIMENTAL DESIGN: In this study, we characterized the Glu-Asp298 ecNOS
      polymorphism in a series of 161 prostate cancer cases. Logistic regression models
      were used to assess the contribution of these genotypes to prostate cancer
      progression. RESULTS: For Glu-Asp298 polymorphism, we found that GG genotype was
      associated to advanced disease [P = 0.020; odds ratio (OR), 2.12; 95% confidence
      interval (CI), 1.12-4.03] and bone metastasis (P = 0.038; OR, 2.23; 95% CI, 1.03
      4.84). Furthermore, after logistic regression analysis with step-wise routine to
      identify predictive parameters of metastasis, which included age at diagnosis,
      advanced stage, GG genotype, high grade, and high serum PSA, we observed that Glu
      Asp298-GG genotype (P = 0.004; OR, 7.4; 95% CI, 1.87-29.26), high grade tumor (P
      = 0.009; OR, 6.15; 95% CI, 1.56-24.17), and high serum PSA (P < 0.001; OR,
      245.12; 95% CI, 19.93-3013.90) were significantly associated with bone
      metastasis. CONCLUSIONS: This study demonstrates a strong association between Glu
      Asp298-GG genotype as a nitric oxide-related genetic factor and advanced disease
      and bone metastasization. The establishment of a genetic profile for each patient
      may be useful in the prediction of the outcome of prostate cancer patients.

PMID- 12429632
TI  - Expression of epidermal growth factor receptor correlates with disease relapse
      and progression to androgen-independence in human prostate cancer.
AB  - PURPOSE: The transforming growth factor alpha-epidermal growth factor receptor
      (EGFR) autocrine pathway has been implicated in prostate cancer cell growth.
      Amplification and/or overexpression of c-erbB-2, a receptor closely related to
      the EGFR, has been recently involved in prostate cancer progression. We
      investigated EGFR and c-erbB-2 expression in primary androgen-dependent and in
      advanced androgen-independent prostate cancer and their potential role as markers
      of disease progression. EXPERIMENTAL DESIGN: EGFR and c-erbB-2 expression were
      evaluated by immunohistochemistry in a consecutive series of 74 prostate cancer
      patients with the following characteristics: 29 patients (group 1) treated with
      radical prostatectomy; 29 patients (group 2) treated with luteinizing hormone
      releasing hormone analogues and antiandrogen therapy followed by radical
      prostatectomy; and 16 patients with hormone-refractory metastatic disease. In all
      patients we evaluated: association between EGFR and/or c-erbB-2 expression and
      clinicopathological parameters; and disease-free survival according to EGFR and c
      erbB-2 expression in univariate analysis (Kaplan-Meier product-limit method) and
      in multivariate analysis (Cox proportional hazards regression model). RESULTS:
      EGFR expression was found in 12 of 29 (41.4%) group 1 patients, in 22 of 29
      (75.9%) group 2 patients (P < 0.0005), and in 16 of 16 (100%) metastatic patients
      (P < 0.005), whereas c-erbB-2 expression was found in 11 of 29 (37.9%) group 1,
      in 10 of 29 (34.5%) group 2 patients, and in 9 of 16 (56.3%) metastatic patients.
      A significant association was found between EGFR expression and a high Gleason
      score (P < 0.01) and between EGFR expression and higher serum prostate-specific
      antigen values (P < 0.02) in all groups of patients. Among the 58 patients
      treated with radical prostatectomy, 23 of 34 EGFR-positive patients (67.6%)
      relapsed, whereas only 2 of 24 EGFR-negative patients (8.3%) relapsed (P <
      0.00004). c-erbB-2 expression did not significantly correlate with disease
      relapse (P = 0.07). In a Cox multivariate analysis, the only parameter with an
      independent prognostic effect on disease-free survival was EGFR expression
      (relative hazard, 11.23; P = 0.0014). CONCLUSIONS: EGFR expression increases
      during the natural history of prostate cancer. Correlation with disease
      progression and hormone-refractory disease suggests that EGFR-targeted drugs
      could be of therapeutic relevance in prostate cancer.

PMID- 12429633
TI  - p16 and p53 Protein expression as prognostic indicators of survival and disease
      recurrence from head and neck cancer.
AB  - PURPOSE: Markers of somatic mutation such as p16 and p53 remain controversial
      prognostic indicators for patients with squamous cell carcinoma of the head and
      neck (SCCHN). The relationship between p53 protein expression and radiation
      therapy is also unclear. EXPERIMENTAL DESIGN: We made a prospective cohort study
      (n = 171) of incident cases receiving standardized therapy for SCCHN. RESULTS:
      Patients whose tumors showed increased p53 protein expression had over twice the
      risk of all-cause mortality after 550 days [hazard ratio (HR), 2.7; 95%
      confidence interval (CI), 1.07-6.66] and three times the risk of dying from
      cancer-specific causes after 550 days (HR, 3.09; 95% CI, 1.15-8.30) after
      adjustment for age, therapy, and stage. Tumors demonstrating alteration of both
      p16 and p53 did not confer any additional diagnostic information over p53 alone.
      Patients whose tumors expressed increased levels of p53 protein and received
      radiation were almost three times more likely to die as compared with those who
      received radiation but whose tumors did not express increased p53 protein after
      adjustment for age and stage (HR, 2.6; 95% CI, 1.03-6.50). CONCLUSIONS: p53
      protein expression was found to violate the proportional hazards assumption for
      our cohort, which may explain the controversial prognostic ability of this
      protein in the literature. p53 protein expression, but not p16 protein
      expression, was related to poor survival in general for men and women. In
      addition, an interaction between p53 expression and radiation therapy was
      demonstrated. Additional studies are needed to confirm and extend our results.

PMID- 12429634
TI  - Prognostic and predictive value of epidermal growth factor receptor in recurrent
      breast cancer.
AB  - PURPOSE: The prognostic and predictive value of epidermal growth factor receptor
      (EGFR) expression was evaluated in patients with recurrent breast cancer.
      EXPERIMENTAL DESIGN: The immunohistochemical expression of EGFR was analyzed in
      241 patients with recurrent breast cancer. RESULTS: EGFR expression was positive
      in 87 of 241 (36%) patients with recurrent breast cancer, whereas the EGFR
      expression inversely correlated with the estrogen receptor (ER) status. The
      patients with positive EGFR expression had a significantly worse postrelapse
      survival than those with a negative EGFR expression, whereas EGFR expression also
      had a postrelapse prognostic significance in patients with a positive ER status.
      A multivariate analysis indicated EGFR expression to be an independently
      significant factor for postrelapse survival, whereas a multivariate analysis in
      which the ER status was added to variables indicated that ER status but not EGFR
      expression to be an independently significant factor. There was a significant
      difference between positive and negative EGFR expression in the treatment
      response of 82 patients who received hormonal therapies and 374 patients who
      received chemotherapies, whereas a multivariate analysis indicated the responses
      to the first-line treatment and EGFR expression to be independently significant
      factors for postrelapse survival. CONCLUSIONS: EGFR expression had prognostic
      significance in recurrent breast cancer, whereas its prognostic value was not
      independent of the ER status. In addition, the EGFR expression was suggested to
      be related to the responses to hormonal therapy and chemotherapy, whereas the
      EGFR expression had an additional prognostic value that was independent of the
      treatment response.

PMID- 12429635
TI  - Alterations of the hSNF5/INI1 gene in central nervous system atypical
      teratoid/rhabdoid tumors and renal and extrarenal rhabdoid tumors.
AB  - Germ-line and acquired mutations of the hSNF5/INI1 tumor suppressor gene have
      been reported in central nervous system (CNS), renal, and soft-tissue rhabdoid
      tumors. The present study was designed to compare the types of INI1 alterations
      among tumors from diverse anatomical sites and identify mutation hot spots.
      Fluorescence in situ hybridization and PCR-based microsatellite, heteroduplex,
      and sequence analysis were used to characterize chromosome 22 deletions and INI1
      mutations among 100 primary rhabdoid tumors. Deletions and/or mutations of INI1
      were detected in 75 patients, including 42 children with atypical
      teratoid/rhabdoid tumors of the brain or spinal cord and 6 children with a brain
      and a renal or soft-tissue tumor. Nineteen tumors arose in the kidney (in one
      child, bilaterally) and eight tumors were extra-renal. Homozygous deletions
      detected by fluorescence in situ hybridization were most often seen in CNS and
      extra-renal rhabdoid tumors, whereas truncating mutations were detected in a high
      percentage of CNS and kidney tumors. The highest frequencies of INI1 mutations
      for kidney tumors were seen in exons 2, 6, and 7, compared with exons 5 and 9 for
      CNS tumors. Two potential hot-spot mutations for CNS atypical teratoid/rhabdoid
      tumors were noted, including a C-to-T transition in codon 201 in exon 5 and a
      cytosine deletion in exon 9. Germ-line mutations were noted in 10 children,
      including 4 patients with two primary tumors. The majority of rhabdoid tumors
      from all sites contained deletions and/or mutations of the INI1 gene. Specific
      mutations were nonrandomly associated with anatomical site.

PMID- 12429636
TI  - Screening of N-ras codon 61 mutations in paired primary and metastatic cutaneous
      melanomas: mutations occur early and persist throughout tumor progression.
AB  - PURPOSE: Mutations in the ras genes often occur during tumorigenesis. In
      malignant melanoma, the most common ras alterations are N-ras codon 61 mutations.
      This study was aimed to measure the frequency of such mutations in a large series
      of paired primary and metastatic melanomas to determine their role in melanoma
      initiation and progression. EXPERIMENTAL DESIGN: Seventy-four primary melanomas
      and 88 metastases originating from 54 of the primary tumors were screened for N
      ras codon 61 mutations using single-strand conformation polymorphism and
      nucleotide sequence analyses. RESULTS: Twenty-one of the 74 primary tumors (28%)
      had activating N-ras codon 61 mutations. From 20 of the mutated primary tumors, a
      total of 34 metastases were analyzed, and all but one showed the same mutation as
      the primary tumor from which they originated. The remaining 53 primary tumors and
      corresponding metastases (n = 54) were wild-type for N-ras codon 61. Analysis of
      the different growth phases of the mutated primary tumors showed that the
      mutations were already present in the radial growth phase. Mutations were also
      detected in tumor-associated nevi. N-ras codon 61 mutations were associated with
      a higher Clark level of invasion (P = 0.012) and a lower age at diagnosis (P =
      0.042) but did not affect survival (P = 0.671). CONCLUSIONS: This study shows
      that N-ras codon 61 mutations occur early in primary melanomas rather than in the
      metastatic stage and that once the mutations have occurred, they persist
      throughout tumor progression. This suggests that activated N-ras may be an
      attractive target for therapy in the subset of melanoma patients carrying such
      mutations.

PMID- 12429637
TI  - Prognostic score of gastric cancer determined by cDNA microarray.
AB  - PURPOSE: To estimate gastric cancer patients' prognosis more comprehensively,we
      tried to develop a prognostic scoring system using a cDNA microarray.
      EXPERIMENTAL DESIGN: RNA was extracted from tumor/normal paired samples of 43
      patients with gastric cancer, and cDNA microarray hybridization was performed.
      RESULTS: We selected 78 genes that were differentially expressed between
      aggressive and nonaggressive groups with respect to five conventional
      pathological factors. Next, we determined a coefficient for each gene. Thereafter
      a prognostic score was calculated by summing-up the value for each gene. It
      ranged from -47 to 201 with a median of 114. There were two peaks in its
      distribution. Ten of 11 patients who were alive with no evidence of recurrence >5
      years after the operation showed a score of <100 points, whereas all 19 patients
      who died of disease showed >100 points. In 13 patients who were alive but the
      follow-up time was <5 years, 2 of the 3 patients with >100 points revealed
      recurrent disease during the follow-up. CONCLUSIONS: These findings demonstrate
      that such a system with cDNA microarray can contribute to the comprehensive
      analysis of malignant behavior of the tumor and may provide accurate information
      on prognosis.

PMID- 12429638
TI  - The influence of dendritic cell infiltration and vascular endothelial growth
      factor expression on the prognosis of non-small cell lung cancer.
AB  - Vascular endothelial growth factor (VEGF) is well known to be produced by many
      human tumors, and it also plays an important role in tumor neovasculature
      formation. In addition to angiogenesis promotion, recent basic research has shown
      that VEGF has another function that allows it to inhibit dendritic cell (DC)
      maturation. However, very little is known about VEGF-dependent DC inhibition in a
      clinical setting. In this study, we analyzed the immunohistochemical expression
      of VEGF, microvessel density (MVD), and intratumoral DC infiltration in 132
      surgically resected lung cancer specimens. We also evaluated the influence of
      these factors on their survival by a multivariate statistical analysis. VEGF
      expression was positively related to MVD (P = 0.0003) and negatively related to
      the degree of DC infiltration (P = 0.0232). A multivariate analysis also showed
      the VEGF expression, MVD, and DC infiltration to be independent prognostic
      factors. Moreover, we also accurately analyzed patient prognoses using the double
      stratification method for determining VEGF expression and DC infiltration. The
      patient group with a high VEGF expression/low DC infiltration showed a worse
      prognosis (P < 0.0001), whereas the group with a low VEGF expression/high DC
      infiltration had a better prognosis (P = 0.0001).

PMID- 12429639
TI  - Reduced nuclear expression of transcription factor AP-2 associates with
      aggressive breast cancer.
AB  - PURPOSE: We proposed to investigate the expression and prognostic significance of
      activator protein 2 (AP-2) in breast cancer. EXPERIMENTAL DESIGN: AP-2 was
      immunohistochemically analyzed in a prospective, consecutive series of 420 breast
      cancer patients diagnosed and treated between 1990 and 1995 at Kuopio University
      Hospital, Kuopio, Finland. AP-2 expression was further compared with
      clinicopathological parameters and patients' survival. RESULTS: Nuclear AP-2
      expression was lower in carcinomas compared with normal ductal breast epithelium
      (P < 0.001). Nuclear expression was more often seen in lobular than in ductal or
      other carcinomas (P = 0.048). Cytoplasmic staining was present in 47% of the
      carcinomas. Low nuclear AP-2 expression level in carcinomas was associated with
      advanced stage (P = 0.002), axillary lymph node positivity (P = 0.012), poor
      differentiation (P = 0.001), and recurrences (P = 0.003). In univariate survival
      analyses, low nuclear AP-2 expression (P = 0.0028), advanced stage (P < 0.0001),
      lymph node metastases (P < 0.0001), and poor differentiation (P = 0.0498)
      predicted shorter recurrence-free survival (RFS). Low nuclear AP-2 staining
      and/or shift to cytoplasmic expression predicted shorter RFS (P = 0.0050) and
      breast cancer-related survival (BCRS; P = 0.0314) in univariate analyses.
      Cytoplasmic expression alone did not have prognostic value. In multivariate
      analysis, low nuclear AP-2 expression (P = 0.0292) and advanced stage (P =
      0.0001) were independent predictors of shorter RFS; and stage (P < 0.0001) and ER
      status (P = 0.0321) independently predicted BCRS. In the lymph-node positive
      patients, RFS was independently predicted by stage (P = 0.0110) and nuclear AP-2
      status (P = 0.0151). CONCLUSIONS: AP-2 seems to have a protective role in breast
      cancer. Low nuclear AP-2 expression was associated with disease progression and
      increased metastatic capability of the tumor. In addition, reduced nuclear AP-2
      expression independently predicted elevated risk of recurrent disease in breast
      cancer.

PMID- 12429640
TI  - Brain tumors in mice are susceptible to blockade of epidermal growth factor
      receptor (EGFR) with the oral, specific, EGFR-tyrosine kinase inhibitor ZD1839
      (iressa).
AB  - Iressa (ZD1839) is a p.o.-active, selective, epidermal growth factor receptor
      tyrosine kinase inhibitor (EGFR-TKI) that blocks signal transduction pathways
      implicated in cancer cell proliferation, survival, and host-dependent processes
      promoting cancer growth. EGFR is up-regulated in primary malignant tumors of the
      central nervous system (CNS) and in many systemic tumors that metastasize to the
      CNS. The purpose of our study was to evaluate the efficacy and toxicity of p.o.
      administered ZD1839 for the treatment of established intracerebral (i.c.) tumors
      expressing EGFR or the tumorigenic mutated variant EGFRvIII, which is
      constitutively phosphorylated. Oral administration of ZD1839 at 50 or 100
      mg/kg/day for 3 weeks in athymic mice with established i.c. A431 human epidermoid
      carcinoma expressing EGFR increased median survival by 88% (P = 0.009) and 105%
      (P < 0.001), respectively. Additionally, there was no evidence of systemic or CNS
      toxicity. However, ZD1839 failed to inhibit either s.c. or i.c. in vivo tumor
      growth when tumorigenicity was conferred by EGFRvIII. Western blotting revealed
      that treatment with ZD1839 virtually ablated phosphorylation of EGFR Tyr-1173 in
      A431 tumors. However, treatment of NR6M tumors with ZD1839 only partially
      decreased phosphorylation of EGFRvIII Tyr-1173 while up-regulating overall
      expression, suggesting that EGFRvIII may not be susceptible to the same molecular
      mechanisms of tyrosine kinase inhibition as EGFR. In conclusion, ZD1839 is active
      in a brain tumor model expressing EGFR, but not EGFRvIII, as EGFR mutations may
      lead to relative therapeutic resistance. On the basis of these observations, we
      believe that clinical trials of ZD1839 against brain tumors expressing EGFR are
      warranted, but that special consideration should be given to tumors that
      coexpress EGFRvIII.

PMID- 12429641
TI  - Interleukin 4 receptor on human lung cancer: a molecular target for cytotoxin
      therapy.
AB  - Previous studies have demonstrated that human lung tumor cell lines express
      interleukin 4 (IL-4) receptors, and IL-4 can mediate modest to moderate
      antiproliferative activity in vitro and in vivo in animal models of human lung
      tumors. On the basis of these studies, IL-4 was tested in clinical trials;
      however, it showed little antitumor activity in lung cancer patients. In the
      present study, we examined the expression of IL-4 receptors (IL-4Rs) in lung
      tumor samples and normal lung tissues and tested whether an IL-4R targeted agent
      will have better antitumor activity in vitro and in vivo compared with IL-4. IL
      4R expression was tested by immunohistochemistry in 54 lung tumor samples and
      normal lung tissues in a tissue array, by reverse-transcription PCR and Northern
      blot analyses in lung tumor cell lines. Cytotoxic activity of IL-4 cytotoxin [IL
      4(38-37)-PE38KDEL], composed of a circular permuted IL-4 and a mutated form of
      Pseudomonas exotoxin (PE38KDEL) was tested by protein synthesis inhibition and
      clonogenic assays in seven lung tumor cell lines. Antitumor activity of IL-4
      cytotoxin was tested in vitro and in immunodeficient animal models of human lung
      tumors. We observed that IL-4Rs are expressed at higher levels in situ in lung
      tumor samples compared with normal lung tissues and IL-4 cytotoxin is highly and
      specifically cytotoxic to lung tumor cell lines in vitro. Intratumoral and i.p.
      administration of IL-4 cytotoxin to immunodeficient mice with s.c. established
      human lung H358 non-small cell lung cancer tumors mediated considerable antitumor
      activity in a dose-dependent manner with the higher dose producing durable
      complete responses. On the other hand, H460 non-small cell lung cancer tumors
      expressing low levels of IL-4R did not respond to IL-4 cytotoxin therapy. Because
      IL-4 cytotoxin mediates its antitumor activity through IL-4R, and a variety of
      lung tumors expressed high levels of IL-4R, we propose testing the safety of this
      agent in patients with lung cancer.

PMID- 12429642
TI  - Silibinin strongly synergizes human prostate carcinoma DU145 cells to doxorubicin
      induced growth Inhibition, G2-M arrest, and apoptosis.
AB  - PURPOSE: We recently demonstrated the strong anticancer efficacy of silibinin,an
      active constituent of a widely consumed dietary supplement milk thistle extract,
      against human prostate cancer cells in culture and nude mice xenografts. We also
      observed that pharmacologically achievable concentrations of silibinin in animal
      studies were in the range of 25-100 microM, depending on the dose regimen, which
      did not show any apparent toxicity to the animals. In this study, we assessed
      whether silibinin synergizes the therapeutic potential of the chemotherapeutic
      drug doxorubicin against prostate cancer, the effectiveness of which is limited
      because of high systemic toxicity. EXPERIMENTAL DESIGN: Prostate cancer cells
      were treated with silibinin and doxorubicin, either alone or in combination, and
      cell growth was determined by manual cell counting. Cell cycle progression was
      assessed by saponin/propidium iodide staining and fluorescence-activated cell
      sorter analysis. Protein levels of cell cycle regulators were determined by
      Western blotting, and cdc2/p34 kinase activity was analyzed by in-beads kinase
      assay. Apoptosis was quantified by annexin V/propidium iodide staining and
      fluorescence-activated cell sorter analysis. RESULTS: Silibinin strongly
      synergized the growth-inhibitory effect of doxorubicin in prostate carcinoma
      DU145 cells (combination index, 0.235-0.587), which was associated with a strong
      G(2)-M arrest in cell cycle progression, showing 88% cells in G2-M phase by this
      combination compared with 19 and 41% of cells in silibinin and doxorubicin
      treatment alone, respectively. The underlying mechanism of G2-M arrest showed a
      strong inhibitory effect of combination on cdc25C, cdc2/p34, and cyclin B1
      protein expression and cdc2/p34 kinase activity. More importantly, this
      combination caused 41% apoptotic cell death compared with 15% by either agent
      alone. Silibinin and doxorubicin alone as well as in combination were also
      effective in inhibiting the growth of androgen-dependent prostate carcinoma LNCaP
      cells. CONCLUSION: These findings suggest a need for in vivo studies with this
      combination in preclinical prostate cancer models. Positive outcomes might be
      relevant for a clinical application in prostate cancer patients.

PMID- 12429643
TI  - Antitumor activity of SS(dsFv)PE38 and SS1(dsFv)PE38, recombinant antimesothelin
      immunotoxins against human gynecologic cancers grown in organotypic culture in
      vitro.
AB  - PURPOSE: Mesothelin, a cell surface glycoprotein overexpressed in ovarian cancer,
      mesotheliomas, and some squamous cell carcinomas, is an attractive candidate for
      targeted therapy because it is not shed in significant amounts into the
      bloodstream and is not present in significant amounts on normal human tissues
      except for mesothelial cells. The objective of this study was to determine the
      antitumor activity of SS1(dsFv)PE38, a recombinant antimesothelin immunotoxin,
      against human gynecologic tumors grown in short-term culture in vitro.
      EXPERIMENTAL DESIGN: Tumor cells obtained from primary cultures of five ovarian
      and one cervical tumor were mixed with an equal proportion of NIH-3T3 fibroblasts
      and plated inside collagen gels in tissue culture plates. After 4-7 days of
      growth, these organotypic cultures were treated with media alone, SS1(dsFv)PE38,
      and a control immunotoxin RFB4(dsFv)PE38, which targets the CD22 antigen not
      present on gynecologic tumors, every other day x 3. The organotypic culture gels
      were then formalin fixed, paraffin embedded, and evaluated for immunotoxin
      sensitivity using light microscopic examination of H&E-stained slides and also
      evaluated for apoptosis using the terminal deoxynucleotidyl transferase-mediated
      nick end labeling assay. RESULTS: Tumors expressing mesothelin showed a
      significant dose-dependent sensitivity to SS1(dsFv)PE38 even at concentrations as
      low as 1 ng/ml, whereas no antitumor activity was seen at 100 ng/ml in tumors
      that did not express mesothelin. This activity was specifically attributable to
      mesothelin targeting because RFB4 (dsFv)-PE38 had no activity against mesothelin
      expressing tumors. CONCLUSIONS: These results demonstrate that ovarian and
      cervical tumor cells obtained from patients can be grown in short-term culture
      using an organotypic culture model. Our results also show low concentrations of
      an immunotoxin targeting mesothelin is cytotoxic to mesothelin-expressing human
      tumors by inducing apoptosis.

PMID- 12429644
TI  - The cyclin-dependent kinase inhibitor flavopiridol induces apoptosis in multiple
      myeloma cells through transcriptional repression and down-regulation of Mcl-1.
AB  - Multiple myeloma (MM) is a B-cell malignancy characterized by the accumulation of
      malignant plasma cells with slow proliferative rate but enhanced survival. MM
      cells express multiple Bcl-2 family members, including Bcl-2, Bcl-XL, and Mcl-1,
      which are thought to play a key role in the survival and drug resistance of
      myeloma. The cyclin-dependent kinase inhibitor flavopiridol has antitumor
      activity against hematopoietic malignancies, including CLL, in which induction of
      apoptosis was associated with reduced expression of antiapoptotic proteins.
      Therefore, we sought to characterize the effect of flavopiridol on the
      proliferation and survival of myeloma cells and to define its mechanisms of
      action. Treatment of MM cell lines (8226, ANBL-6, ARP1, and OPM-2) with
      clinically achievable concentrations of flavopiridol resulted in rapid induction
      of apoptotic cell death that correlated temporally with the decline in Mcl-1
      protein and mRNA levels. Levels of other antiapoptotic proteins did not change.
      Overexpression of Mcl-1 protected MM cells from flavopiridol-induced apoptosis.
      Additional analysis demonstrated that flavopiridol treatment resulted in a dose
      dependent inhibition of phosphorylation of the RNA polymerase II COOH-terminal
      domain, thus blocking transcription elongation. These data indicate that Mcl-1 is
      an important target for flavopiridol-induced apoptosis of MM that occurs through
      inhibition of Mcl-1 mRNA transcription coupled with rapid protein degradation via
      the ubiquitin-proteasome pathway.

PMID- 12429645
TI  - Suppression of malignant glioma recurrence in a newly developed animal model by
      endogenous inhibitors.
AB  - Glioma recurrences develop at the borders of the surgical cavity and are the main
      cause of their poor prognosis. There are no therapeutic advances to reduce the
      incidence of recurrence or animal models that closely mimic the clinical scenario
      to evaluate novel therapeutics. This work investigates the efficacy of endogenous
      inhibitors, in preventing the recurrence of human malignant gliomas, in a newly
      developed animal model of glioma surgical resection. We developed a nude mice
      model in which human glioma xenografts were microsurgically removed. After
      surgery, small islets of tumor cells persisted in the normal brain parenchyma,
      grew, and formed a recurrence. As inhibitors we used PEX and a fragment of
      platelet factor 4 (PF-4/CTF), which were administered systemically on a daily
      basis or in metronomic combination with chemotherapy for 120 days. Treatment was
      started 1 or 15 days after tumor removal. PEX or PF-4/CTF produced a significant
      improvement in survival, and delayed the appearance of glioma recurrence.
      Survival of animals that received daily PEX or PF-4/CTF was similar to that of
      animals that received metronomic PEX or PF-4/CTF and chemotherapy, respectively.
      The effect of treatment was dependent on the time at which the treatment was
      initiated. The highest level of inhibition was observed when the treatment was
      administered 1 day after surgical resection and when PEX was used as the
      inhibitor (120 days versus 35 days of the control). Tumors treated with PEX or PF
      4/CTF were small and well delineated, with few vessels. Postsurgical
      administration of PEX or PF-4/CTF significantly reduces the incidence human
      malignant glioma recurrences for a long period of time.

PMID- 12429646
TI  - Antitumor activity of UCN-01 in carcinomas of the head and neck is associated
      with altered expression of cyclin D3 and p27(KIP1).
AB  - Altered and deregulated cyclin-dependent kinase (cdk) activity is now believed to
      play a major role in the pathogenesis of head and neck squamous cell carcinomas
      (HNSCC), thus providing a suitable cellular target for therapeutic intervention.
      UCN-01 (7-hydroxy-staurosporine), a known protein kinase C and cdk modulator,
      demonstrates antiproliferative and antitumor properties in many experimental
      tumor models and may represent a potential candidate to test in HNSCC. In this
      study, UCN-01 displayed potent antiproliferative properties (IC50 of
      approximately 17-80 nM) in HNSCC cells. Cell cycle analysis revealed that UCN-01
      treatment of HNSCC cells for 24 h leads to a G1 block with a concomitant loss of
      cells in S and G2-M and the emerging sub-G1 cell population, confirmed to be
      apoptotic by terminal deoxynucleotidyl transferase-mediated nick end labeling
      analysis. Additional in vitro studies demonstrated a G1 arrest that was preceded
      by depletion in cyclin D3, elevation of p21(WAF1) and p27(KIP1) leading to a loss
      in activity of G1 cdks (cdk2, cdk4), and reduction in pRb phosphorylation.
      Antitumor properties of UCN-01 were also assessed in vivo by treating HN12
      xenografts (7.5 mg/kg/i.p./daily) with UCN-01 for 5 consecutive days. Total
      sustained abolition of tumor growth (P < 0.00001) was obtained with only one
      cycle of UCN-01 treatment. Terminal deoxynucleotidyl transferase-mediated nick
      end labeling staining of xenograft samples revealed a higher incidence of
      apoptosis in treated tissues when compared with control. Additional tissue
      analysis demonstrated that elevated p27(KIP1) with minimal increase in p21(WAF1)
      and reduced cyclin D3 levels were readily detected in those animals treated with
      UCN-01, similar to those observed in HNSCC cells. Thus, UCN-01 exhibits both in
      vitro and in vivo antitumor properties in HNSCC models, and these effects are
      associated with a decrease in cyclin D3 and an increase in p27(KIP1) protein
      levels, thus providing appropriate surrogate markers to follow treatment efficacy
      in vivo and, therefore, a suitable drug candidate for treating HNSCC patients.

PMID- 12429647
TI  - Adenovirus vector-mediated overexpression of a truncated form of the p65 nuclear
      factor kappa B cDNA in dendritic cells enhances their function resulting in
      immune-mediated suppression of preexisting murine tumors.
AB  - PURPOSE: The purpose of this study was to evaluate the effect of the Rel homology
      domain (RHD) of the transcription factor, nuclear factor kappa B (NF kappa B), on
      proinflammatory gene expression in bone marrow-derived dendritic cells (BMDCs).
      EXPERIMENTAL DESIGN: We used an adenovirus vector encoding only the RHD of the NF
      kappa B (p65 family member) cDNA (AdRHD) to transduce murine BMDCs ex vivo.
      Endpoints measured included BMDC expression of activation markers, cytokine
      secretion, peptide antigen presentation, and the ability of these transduced
      cells to induce antitumor immunity in vivo. RESULTS: AdRHD-transduced BMDCs
      secreted higher levels of the cytokines interleukin (IL) 1 beta, IL-6, and IL-12
      (p40) compared with sham-transduced BMDCs or those transduced with an empty
      vector. AdRHD induced heightened surface expression of the activation markers
      CD40, B7.1, B7.2, and MHC class II on BMDCs, and these cells were able to present
      a peptide antigen to a T-lymphocyte hybridoma more efficiently than controls in
      vitro. Growth of syngeneic, established tumors (CT26 and B16.F10) was inhibited,
      and survival was prolonged in the mice that received intratumoral AdRHD-modified
      BMDCs compared with controls. Splenocytes from CT26 tumor-bearing animals that
      received intratumoral AdRHD-modified BMDCs were able to lyse CT26 target cells
      more efficiently than controls. Similar experiments using host mice harboring
      targeted mutations in CD4 and CD8, as well as BMDCs from mice lacking MHC class
      I, MHC class II, or IL-12 revealed that this tumor immunity was dependent on the
      presence of CD4+ and CD8+ cells in the tumor-bearing host, as well as MHC class
      I, MHC class II, and IL-12 expression by the administered BMDCs. Furthermore,
      induction of IL-12 (p40) expression by AdRHD was completely abrogated in BMDCs
      lacking the c-Rel NF kappa B family member. CONCLUSIONS: We made the following
      conclusions: (a) gene transfer-mediated overexpression of the RHD of NF kappa B
      activates BMDCs; (b) AdRHD-transduced BMDCs induce antitumor immunity when
      administered intratumorally, an effect mediated by both the CD4+ T cell/MHC class
      II and the CD8+ T cell/MHC class I pathways, as well as IL-12; and (c) IL-12
      (p40) up-regulation by the RHD transgene in BMDCs is dependent on the presence of
      the c-Rel NF kappa B family member.

PMID- 12429648
TI  - Enhanced antiangiogenic therapy of squamous cell carcinoma by combined endostatin
      and epidermal growth factor receptor-antisense therapy.
AB  - PURPOSE: We tested the combined effects of antiangiogenic endostatin and
      epidermal growth factor receptor (EGFR) antisense gene therapy on squamous cell
      carcinoma (SCC). EXPERIMENTAL DESIGN AND RESULTS: The 1483 cell line of human
      head and neck SCC (HNSCC) and SCC-VII/SF murine SCC cells was used to establish
      tumors in nude mice and immunocompetent C3H mice, respectively. Tumor-bearing
      mice were treated with endostatin (20 mg/kg/day, s.c.), liposomal EGFR-antisense
      expression plasmid (25 microg/mouse, three times/week, intratumoral), a
      combination of both agents, or liposomal EGFR-sense plasmid as a control.
      Endostatin or EGFR-antisense alone significantly, yet partially, inhibited the
      growth of 1483 and SCC-VII/SF tumors, and a combination of both treatments
      completely blocked tumor growth. Immunohistochemistry analysis demonstrated that
      a complete suppression of tumor angiogenesis was achieved by the combination
      treatment. Down-regulation of vascular endothelial growth factor was shown in
      EGFR-antisense-treated tumors. These results suggest that the EGFR-antisense
      treatment, in addition to its inhibitory activity on tumor cell proliferation,
      might have a synergistic effect with endostatin on SCC-induced angiogenesis. In
      vitro studies demonstrated that EGFR inhibition by antisense oligonucleotides or
      EGFR-specific tyrosine kinase inhibitor down-regulated the production of VEGF in
      HNSCC cells. Additional experiments demonstrated that these EGFR inhibition
      approaches also directly suppressed the growth of endothelial cells. CONCLUSION:
      A combination of endostatin and EGFR targeting strategies profoundly inhibited
      the angiogenesis and growth of SCC in vivo. EGFR-antisense therapy might have
      multiple inhibitory effects against both tumor cells and endothelial cells,
      leading to enhanced antitumor efficacy. Such a combination strategy might
      represent a novel and promising approach for HNSCC therapy.

PMID- 12429649
TI  - Zinc inhibits nuclear factor-kappa B activation and sensitizes prostate cancer
      cells to cytotoxic agents.
AB  - Prostate carcinogenesis involves transformation of zinc-accumulating normal
      epithelial cells to malignant cells, which do not accumulate zinc. In this study,
      we demonstrate by immunoblotting and immunohistochemistry that physiological
      levels of zinc inhibit activation of nuclear factor (NF)-kappa B transcription
      factor in PC-3 and DU-145 human prostate cancer cells, reduce expression of NF
      kappa B-controlled antiapoptotic protein c-IAP2, and activate c-Jun NH(2)
      terminal kinases. Preincubation of PC-3 cells with physiological concentrations
      of zinc sensitized tumor cells to tumor necrosis factor (TNF)-alpha, and
      paclitaxel mediated cell death as defined by terminal deoxynucleotidyl
      transferase-mediated nick end labeling assay. These results suggest one possible
      mechanism for the inhibitory effect of zinc on the development and progression of
      prostate malignancy and might have important consequences for the prevention and
      treatment of prostate cancer.

PMID- 12429650
TI  - Inhibition of platelet-derived growth factor-mediated proliferation of
      osteosarcoma cells by the novel tyrosine kinase inhibitor STI571.
AB  - PURPOSE: Osteosarcoma is an aggressive primary bone cancer characterized by
      expression of platelet-derived growth factor (PDGF) and its cognate receptor.
      Coexpression of the growth factor and receptor suggests their role in autocrine
      or paracrine growth mechanisms. It has been reported previously that STI571 has
      specific activity in inhibiting select tyrosine kinase receptors, including PDGF
      and c-Kit. Osteosarcomas express low levels of c-Kit but abundant levels of PDGF
      receptor (PDGFR). EXPERIMENTAL DESIGN: To investigate the potential of STI571 as
      therapy for osteosarcoma, we studied its effects on PDGF-mediated cell growth in
      vitro and in an in vivo mouse model. RESULTS: PDGF acted as a potent mitogen in a
      dose-dependent manner in two osteosarcoma cell lines. STI571 (1.0 micro M)
      inhibited both PDGFR-alpha and PDGFR-beta phosphorylation and the downstream
      phosphorylation targets extracellular signal-regulated kinase and Akt. STI571
      also inhibited PDGF-mediated growth and induced apoptosis in vitro as determined
      by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and
      terminal deoxynucleotidyl transferase-mediated nick end labeling staining. To
      study the effect of STI571 alone or in combination with Taxol in an in vivo
      model, an osteosarcoma cell line (KRIB) was transplanted into the tibia of
      athymic nude mice. Mice were treated with STI571 (50 mg/kg p.o. q M-F), Taxol (8
      mg/kg i.p. weekly), or STI571 plus Taxol for 6 weeks. There was no significant
      difference in tumor size between treatment and control mice. Aberrant signaling
      pathways downstream of the PDGFR in the v-Ki-ras oncogene-transformed KRIB cell
      line may in part explain this finding. CONCLUSIONS: Our data demonstrate that
      STI571 inhibits PDGF-mediated growth and leads to apoptosis of osteosarcoma cells
      in vitro by selective inhibition of the PDGFR tyrosine kinase. The effectiveness
      of STI571 in our studies suggests targeting of PDGFRs as a novel treatment for
      osteosarcoma.

PMID- 12429651
TI  - Blockade of the epidermal growth factor receptor signaling inhibits angiogenesis
      leading to regression of human renal cell carcinoma growing orthotopically in
      nude mice.
AB  - We determined whether blockade of the epidermal growth factor-receptor (EGF-R)
      signaling pathway by oral administration of the EGF-R tyrosine kinase inhibitor
      PKI166 can inhibit angiogenesis and growth of SN12PM6 human renal cell carcinoma
      (HRCC) in the kidney of nude mice and whether gemcitabine can potentiate these
      effects. In vitro treatment of HRCC cells with PKI166 inhibited EGF-R
      autophosphorylation, which correlated with a decrease in expression of Bcl-xl
      protein and phosphorylation of signal transducers and activators of
      transcription, particularly signal transducers and activators of transcription 3.
      PKI166 also decreased expression of vascular endothelial growth factor and basic
      fibroblast growth factor in a dose-dependent manner. Oral administration of
      PKI166 or PKI166 and injected gemcitabine or gemcitabine alone beginning 7 days
      after implantation of SN12PM6 cells into the kidney of athymic nude mice reduced
      the volume of tumors by 26, 61, and 23%, respectively. In another experiment 28
      days after the orthotopic implantation of SN12PM6 cells, nephrectomy was
      performed followed by 4 weeks of treatment. Treatment with PKI166 and, more so,
      PKI166 plus gemcitabine significantly inhibited lung metastasis, corresponding to
      a significant increase in overall length of survival. EGF-R activation was
      significantly blocked by therapy with PKI166 and was associated with a
      significant reduction in expression of vascular endothelial growth factor and
      interleukin-8, decreased microvessel density, decreased staining of proliferating
      cell nuclear antigen, and increased tumor cell apoptosis. Collectively, the data
      indicate that targeting activation of EGF-R on HRCC produces significant
      therapeutic benefits.

PMID- 12429652
TI  - Dietary modulation of pregnancy estrogen levels and breast cancer risk among
      female rat offspring.
AB  - PURPOSE: Against the hypothesis that high estrogen levels in utero increase the
      risk of developing breast cancer in later life are data showing that pregnancy
      estrogen levels are significantly higher in Asian women who have low breast
      cancer risk than in Caucasian women. We investigated whether maternal dietary
      intake of genistein or n-3 polyunsaturated fatty acids (PUFAs), which are typical
      to Asian but not Caucasian diet, affect pregnancy estrogen levels and
      susceptibility to mammary tumorigenesis among offspring. EXPERIMENTAL DESIGN: For
      that purpose, pregnant female Sprague Dawley rats were fed isocaloric AIN-93
      based diets containing either at 15 mg (low), 150 mg (medium), or 300 mg
      (high)/kg genistein/diet or low- or high-fat (16 versus 39% energy from fat) diet
      composed either of n-3 PUFA menhaden oil or n-6 PUFA corn oil. All diets were
      switched to regular AIN-93 diet when pups were born. RESULTS: Maternal intake of
      n-3 PUFA diets significantly increased pregnancy 17 beta-estradiol (E2) levels
      (48% increase when compared with high n-6 PUFA diet; P < 0.0045). High genistein
      exposure also increased pregnancy estrogen levels, but the increase did not reach
      statistical significance (P < 0.14). The offspring of high-fat n-3 PUFA-consuming
      dams were significantly less likely to develop 7,12-dimethylbenz-[a]anthracene
      induced mammary tumors (38% of these rats developed tumors during week 17 versus
      64% of high n-6 PUFA offspring; P < 0.003). Maternal genistein intake did not
      affect offspring's tumor incidence. The mammary glands of high fat n-3 PUFA
      offspring contained more lobules (P < 0.07) and were thus more differentiated,
      whereas the glands of high genistein offspring contained more terminal end buds
      (P < 0.0015), which are the sites of malignant transformation. CONCLUSIONS: Our
      findings indicate that the elevated estrogen levels in the n-3 PUFA mothers were
      linked to reduced rather than increased breast cancer risk among their offspring,
      suggesting that other effects of n-3 PUFA may counteract the effects of high
      fetal estrogenicity on the mammary gland. High maternal genistein intake did not
      reduce offspring's breast cancer risk, and therefore high maternal soy intake in
      Asian women may not be associated with daughters' low breast cancer risk.

PMID- 12429653
TI  - Pharmacokinetics, toxicity, and efficacy of ends-modified raf antisense
      oligodeoxyribonucleotide encapsulated in a novel cationic liposome.
AB  - Raf-1 protein serine threonine kinase plays an important role in cell survival
      and proliferation. Antisense inhibition of Raf-1 expression has been shown to
      enhance the cytotoxic effects of radiation and anticancer drugs. Here we have
      evaluated the toxicity, pharmacokinetics, and antitumor efficacy of a novel
      formulation of liposome-entrapped raf antisense oligodeoxyribonucleotide
      (LErafAON). The LErafAON preparation showed high liposome entrapment efficiency
      of rafAON (>85%) and stability at room temperature. In CD2F1 mice, administration
      of LErafAON produced no morbidity/mortality (5-35 mg/kg/dose, i.v., x12). Dose
      related elevations in liver enzymes (alanine aminotransferase and aspartate
      aminotransferase) and histopathological changes in liver were noted in LErafAON
      and blank liposome groups. No morbidity/mortality and changes in clinical
      chemistry or histopathology were observed in New Zealand white rabbits (3.75
      mg/kg/dose, i.v., x8; 6.5 mg/kg/dose, i.v., x6) or in cynomolgous monkeys (3.75
      or 6.25 mg/kg/dose, i.v., x9). Transient decrease in total hemolytic complement
      activity (approximately 62-74%) and increases in C3a (approximately 3-fold) and
      Bb levels (approximately 5-12-fold) were observed in LErafAON and blank liposome
      groups of monkeys. A 30 mg/kg i.v. dose of LErafAON in human prostate tumor (PC
      3)-bearing BALB/c athymic mice gave a terminal plasma half-life of 27 h, and
      intact rafAON could be detected in plasma and in normal and tumor tissues for up
      to at least 48 h. In monkeys, the terminal plasma half-life of 30.36 +/- 23.87 h
      was observed at an i.v. dose of 6.25 mg/kg. LErafAON (25 mg/kg/dose, i.v., x10)
      or ionizing radiation (3.8 Gy/day, x5) treatment of PC-3 tumor-bearing athymic
      mice led to tumor growth arrest, whereas a combination of LErafAON and ionizing
      radiation treatments resulted in tumor regression. LErafAON treatment caused
      inhibition of Raf-1 protein expression in normal and tumor tissues in these mice
      (>50%, versus controls). These data have formed a basis of the clinical Phase I
      studies of LErafAON for cancer treatment.

PMID- 12429654
TI  - Vasculogenesis Plays a Role in the Growth of Ewing's Sarcoma in Vivo.
AB  - Vasculogenesis, the process by which endothelial cell precursors are recruited
      and organized to form a vasculature, has traditionally been thought to play a
      role only in embryonic development. However, several studies have now been
      published suggesting that vasculogenesis may have a role in the formation of new
      vascular networks during postnatal life. Recent studies suggest the existence of
      circulating endothelial precursor cells that arise from outside the place of
      vascularization. Using a mouse bone marrow (BM) transplantation model that takes
      advantage of MHC haplotype differences between donor and recipient mice, we
      examined the contribution of donor BM-derived cells to neovascularization in
      recipient nude mice with developing Ewing's sarcoma tumors. We found that the
      donor BM cells gave rise to endothelial cells in vitro and colocalized with
      neovessels in Ewing's sarcomas in vivo. We also found that donor BM-derived cells
      were involved in the formation of the tumor vasculature. Our findings indicate
      that not only angiogenesis but also vasculogenesis was involved in the
      development of Ewing's sarcoma in our mouse model.

PMID- 12429657
TI  - Primary care oncology: essential if high quality cancer care is to be achieved
      for all.

PMID- 12429655
TI  - Suppression of tumorigenesis and induction of p15(ink4b) by Smad4/DPC4 in human
      pancreatic cancer cells.
AB  - PURPOSE: The tumor suppressor gene Smad4/DPC4, a key transcription factorin
      transforming growth factor beta (TGF-beta) signaling cascades,is inactivated in
      50% of pancreatic adenocarcinomas. We seek to determine the role of Smad4/DPC4 in
      the suppression of tumor cell growth and in the regulation of TGF-beta-mediated
      expression of cell-cycle regulatory genes p15(ink4b) and p21(waf1). EXPERIMENTAL
      DESIGN: Smad4/DPC4 is overexpressed by adenoviral infection in CFPac-1 pancreatic
      cancer cells, in which the Smad4/DPC4 is homozygously deleted, and in Capan-1
      pancreatic cancer cells, in which Smad4/DPC4 is not expressed. Expression of the
      TGF-beta downstream target gene p21(waf1), regulation of the p15(ink4b) promoter,
      anchorage-independent growth, and tumorigenesis were examined. RESULTS: We
      demonstrate that expression of Smad4/DPC4 in Capan-1 cells reduced anchorage
      independent growth by more than 50%, and inhibited xenograft tumor growth.
      However, overexpression of Smad4/DPC4 did not inhibit CFPac-1 cell growth.
      Interestingly, Smad4/DPC4 induced expression of p15(ink4b), p21(waf1), and TGF
      beta-responsive reporter gene in Capan-1 but not in CFPac-1 cells. Furthermore,
      we found a previously unidentified Smad4 binding element (SBE) located in the
      region between -356 and -329 bp of the p15(ink4b) promoter. The p15(ink4b)
      promoter reporter gene assays revealed that Smad4-dependent transcriptional
      activation is mediated by this SBE, which indicates that p15(ink4b) is one of the
      downstream target genes regulated by Smad/DPC4. CONCLUSION: These results explain
      the role of Smad4/DPC4 in TGF-beta-mediated inhibition of cell proliferation in
      vitro and in vivo. Moreover, these results suggest that Smad4/DPC4-mediated tumor
      suppression and induction of TGF-beta-regulated cell-cycle-inhibitory genes may
      depend on additional factors that are absent in CFPac-1 cells.

PMID- 12429658
TI  - Patients' understanding of risk: a qualitative study of decision-making about the
      menopause and hormone replacement therapy in general practice.
AB  - OBJECTIVE: To explore women's understanding of the risks associated with the
      menopause and hormone replacement therapy (HRT). METHODS: Two general practices
      in Cambridge participated in this qualitative study using focus groups and semi
      structured interviews. Forty women aged between 50 and 55 years, known to be
      current users, ex-users, or never-users of HRT were included in the study.
      RESULTS: Participants viewed risk as a danger: coping with risk required an
      assessment to facilitate an informed decision. To understand risk and make a
      personal interpretation, patients used their own knowledge, the presentation and
      context of that risk, together with their individual belief system particularly
      relating to representations of womanhood, lay beliefs and fatalism, control and
      choice. Experience, age and emotions often modified the salience of risk, and
      participants then used this meaning to weigh up the risks and benefits of a
      particular threat. CONCLUSION: Participants gained understanding of risk by an
      active risk assessment process involving individual and complex interplay between
      knowledge and core beliefs, allowing the assessment of risks and benefits to
      facilitate an informed decision about the menopause and HRT.

PMID- 12429659
TI  - Internet-based risk assessment and decision support for the management of
      familial cancer in primary care: a survey of GPs' attitudes and intentions.
AB  - BACKGROUND: Computer decision support systems have been proposed as a suitable
      method to enable primary care practitioners to manage familial cancer and advise
      about other developments in clinical genetics. OBJECTIVE: To investigate GPs'
      preferences, attitudes and intentions regarding the use of Genetic Risk
      Assessment on the Internet and Decision Support (GRAIDS) in clinical practice.
      METHODS: GPs were recruited through a physician Internet portal for UK GPs
      (www.ukpractice.net). Electronic questionnaires assessed the respondents' current
      practice regarding family history taking and risk assessment, preferences about
      particular attributes of GRAIDS, intentions to use GRAIDS for familial cancer
      management and factors associated with these intentions. RESULTS: Two hundred and
      sixty-eight GPs completed the electronic survey (adjusted response rate = 51.2%).
      Seventy-two GPs participated in a telephone survey of non-respondents (adjusted
      response rate = 63%). Ninety-two per cent of respondents in the electronic survey
      and 68% in the telephone survey stated that they would be either extremely or
      fairly likely to use GRAIDS. Intentions were associated with positive attitudes
      toward GRAIDS, beliefs that colleagues and patients would find the tool
      acceptable, perceived control and perceived confidence about conducting risk
      assessment and making appropriate decisions about patient management. Key
      attributes for the implementation of GRAIDS in practice were the
      authoritativeness of the guideline, easy user interface, the validity and
      reliability of risk estimation and specific advice about patient management.
      CONCLUSION: GP users of the physician portal www.ukpractice.net value GRAIDS as
      an aid for the management of familial cancer in primary care. These Internet
      literate GPs are likely to be early adopters of GRAIDS in clinical practice and
      could be important in promoting the use of such technology to support high
      quality advice about genetic issues in primary care.

PMID- 12429660
TI  - Understanding risk: women's perceived risk of menopause-related disease and the
      value they place on preventive hormone replacement therapy.
AB  - OBJECTIVES: The aims of this study were to determine women's perceived risk of
      menopause-related disease and to understand how this shapes their decisions about
      taking hormone replacement therapy (HRT) for disease prevention. METHODS: A
      qualitative study based on analysis of audio-taped semi-structured interviews.
      The study was carried out in a community setting in Surrey. The participants were
      32 women aged 51 to 57 years, registered with GPs in the West Surrey Health
      Authority. RESULTS: Women's ideas about the risk of menopause-related disease
      exist on two levels; a collective and an individual level. At a collective level,
      women acknowledge an increased risk of osteoporosis, and to a lesser degree, a
      risk of heart disease, associated with the menopause. At an individual level,
      however, based mainly on their family history and lifestyle, women do not
      generally consider themselves to be at personal risk of disease. Decisions to
      take HRT for the prevention of menopause-related disease are largely based on
      individual assessments of risk and, therefore, most women see a limited value in
      taking HRT primarily for disease prevention. CONCLUSIONS: Whilst women tend to
      associate the menopause with an increased risk of disease, they do not generally
      consider themselves to be at personal risk, and in turn, choose not to take HRT
      primarily for prevention.

PMID- 12429661
TI  - Acceptance of guideline recommendations and perceived implementation of coronary
      heart disease prevention among primary care physicians in five European
      countries: the Reassessing European Attitudes about Cardiovascular Treatment
      (REACT) survey.
AB  - BACKGROUND: Although primary care is the major target of coronary heart disease
      (CHD) clinical recommendations, little is known of how community physicians view
      guidelines and their implementation. The REACT survey was designed to assess the
      views, and perceived implementation, of CHD and lipid treatment guidelines among
      primary care physicians. METHODS: Semi-structured validated telephone interviews
      were conducted, in the relevant native tongue, with 754 randomly selected primary
      care physicians (GPs and family doctors) in five European countries (France,
      Germany, Italy, Sweden and the UK). RESULTS: Most physicians (89%) agreed with
      the content of current guidelines and reported use of them (81%). However, only
      18% of physicians believed that guidelines were being implemented to a major
      extent. Key barriers to greater implementation of guidelines were seen as lack of
      time (38% of all physicians), prescription costs (30%), and patient compliance
      (17%). Suggestions for ways to improve implementation centred on more education,
      both for physicians themselves (29%) and patients (25%); promoting, publicizing
      or increasing guideline availability (23%); simplifying the guidelines (17%); and
      making them clearer (12%). Physicians perceived diabetes to be the most important
      risk factor for CHD, followed by hypertension and raised LDL-C. Most physicians
      (92%) believe their patients do associate high cholesterol levels with CHD. After
      establishing that a patient is 'at risk' of CHD, physicians reported spending an
      average of 16.5 minutes discussing risk factors and lifestyle changes or
      treatment that is required. Factors preventing this included insufficient time
      (42%), having too many other patients to see (27%) and feeling that patients did
      not listen or understand anyway (21%). CONCLUSIONS: Primary care physicians need
      more information and support on the implementation of CHD and cholesterol
      guideline recommendations. This need is recognized by clinicians.

PMID- 12429662
TI  - 'I saw the panic rise in her eyes, and evidence-based medicine went out of the
      door.' An exploratory qualitative study of the barriers to secondary prevention
      in the management of coronary heart disease.
AB  - Background. Coronary heart disease (CHD) is the leading cause of death in the UK,
      yet only 50% of CHD patients receive appropriate secondary prevention.
      Objectives. To explore GP attitudes to evidence about CHD, and to identify
      factors influencing the implementation of secondary prevention in GP
      consultations. METHODS: Semi-structured interviews and focus groups exploring
      consultations with patients previously diagnosed as having CHD. RESULTS: Use of
      evidence is influenced by credibility. Lack of time was the greatest barrier to
      accessing evidence and to implementing secondary prevention. Patients were more
      likely to receive secondary prevention in a dedicated clinic. Patient
      characteristics including physical and mental co-morbidity mitigate against
      secondary prevention. GPs experienced difficulty balancing implementation of
      evidence with the demands of the doctor-patient relationship. CONCLUSIONS: The
      doctor-patient relationship may act as a barrier to the delivery of secondary
      prevention in primary care. It may be time to re-evaluate models of these
      relationships and reconsider the strategies for implementing evidence.

PMID- 12429663
TI  - 'Heads you win, tails I lose': a critical incident study of GPs' decisions about
      emergency admission referrals.
AB  - BACKGROUND: Acute hospital Trusts' inability to cope with the numbers of
      emergency admissions has led to the production of guidelines by the Department of
      Health aimed at reducing inappropriate admissions by GPs. There is a paucity of
      research describing GPs' decisions to (not) admit patients and it is unclear how
      effective these guidelines are in changing these practices. OBJECTIVE: To
      describe GPs' decision-making about referrals for emergency hospital admissions.
      METHODS: Observational design using the critical incident technique to elicit
      data. Eight GPs in West Yorkshire recorded details of memorable emergency
      admission decisions, both prospective and retrospective consultations. The
      transcript data were classified by theme using NUD*IST. RESULTS: Forty
      prospective and 8 retrospective consultations were analysed. Factors affecting
      GPs' decisions were:Identification of all consequences for all stakeholders in
      the decision. Emotional impact on the GP of managing these conflicting needs.
      'Peer review' of the GP's professionalism about the decision. Contextual
      pressures limiting effectiveness of GPs' decision-making. CONCLUSIONS: Referral
      decisions require the evaluation of several conflicting consequences for many
      stakeholders in time-pressured and peer-reviewed situations. These factors
      encourage the use of heuristics, i.e. GPs' judgements will be influenced more by
      the social context of the choice than information about the patient's condition.
      Emergency referral guidelines provide more information to evaluate from another
      stakeholder; introducing guidelines is likely to increase GPs' use of heuristics
      and the making of less optimal decisions.

PMID- 12429664
TI  - Asking for 'rules of thumb': a way to discover tacit knowledge in general
      practice.
AB  - BACKGROUND: Research in decision-making has identified heuristics (rules of
      thumb) as shortcuts to simplify search and choice. OBJECTIVE: To find out if GPs
      recognize the use of rules of thumb and if they could describe what they looked
      like. METHODS: An explorative and descriptive study was set up using focus group
      interviews. The interview guide contained the questions: Do you recognize the use
      of rules of thumb? Are you able to give some examples? What are the benefits and
      dangers in using rules of thumb? Where do they come from? The interviews were
      transcribed and analysed using the templates in the interview guide, and the
      examples of rules were classified by editing analysis. RESULTS: Four groups with
      23 GPs were interviewed. GPs recognized using rules of thumb, producing examples
      covering different aspects of the consultation. The rules for somatic problems
      were formulated as axiomatic simplified medical knowledge and taken for granted,
      while rules for psychosocial problems were formulated as expressions of
      individual experience and were followed by an explanation. The rules seemed
      unaffected by the sparse objections given. A GP's clinical experience was judged
      a prerequisite for applying the rules. The origin of many rules was via word-of
      mouth from a colleague. The GPs acknowledged the benefits of using the rules,
      thereby simplifying work. CONCLUSION: GPs recognize the use of rules of thumb as
      an immediate and semiconscious kind of knowledge that could be called tacit
      knowledge. Using rules of thumb might explain why practice remains unchanged
      although educational activities result in more elaborate knowledge.

PMID- 12429665
TI  - What shapes GPs' work with depressed patients? A qualitative interview study.
AB  - BACKGROUND: The ways that GPs treat depressed patients have been criticized in a
      number of studies. OBJECTIVE: To explore factors that shape how GPs work with
      depressed patients. METHODS: Seventeen GPs from the county of Orebro, Sweden
      participated in a qualitative semi-structured interview study. GPs' conceptions
      of factors shaping their way of working with depressed patients, especially
      continuing medical education (CME), commercial information, inter-collegial
      support, collaboration with psychiatrists and GPs' gender were recorded. RESULTS:
      Private life experiences as well as professional experiences from family medicine
      were more often stressed as formative factors than university education and
      training in psychiatry. Groups of GPs discussisng the doctor-patient relationship
      set out from real cases (Balint groups) and CME groups were regarded as good
      forms of education. Most GPs considered company-sponsored lectures valuable.
      Commercial drug information was seen as more powerful than non-commercial
      information and GPs wished for more non-commercial information. Collaboration
      with psychiatry consultants was perceived as insufficient, and GPs felt a need
      for more inter-collegial support. Traditional female qualities were generally
      seen as advantageous in the work with depressed patients. CONCLUSIONS: Many GPs
      consider personal qualities and experiences, including those of gender, to be
      more influential than academic education and professional literature. This
      reflects a preference for individual 'tacit knowledge'. Although tacit knowledge
      is indispensable in consultations, the low priority given to theoretical CME may
      make GPs less inclined to make optimal use of different therapeutic alternatives
      and also less critical of commercial marketing. CME on depression should start
      with GPs' individual tacit knowledge and assume a more independent stance from
      the drug industry.

PMID- 12429666
TI  - Managing depression in primary care: another example of the inverse care law?
AB  - BACKGROUND: Depression is a common problem, often being recurrent or becoming
      chronic. The National Service Framework for Mental Health (published by the
      Department of Health, 1999) states that people with depression should continue to
      be predominantly managed in primary care. There is much evidence that the
      detection and management of depression by GPs could be improved, but little work
      has focused on GPs' views of their work with depressed patients. OBJECTIVES: This
      was a qualitative study exploring GP attitudes to the management of patients with
      depression. Views of GPs in socio-economically deprived areas are compared with
      those serving more affluent populations. METHODS: Semi-structured interviews were
      conducted with two groups of GPs in north-west England. One group of GPs (22)
      were practising in inner-city areas, and a second group (13) in suburban and semi
      rural practices. All were Principals in practices that participated in
      undergraduate teaching. The interviews were audio-taped and subsequently
      transcribed verbatim. Analysis was by constant comparison until category
      saturation of each theme was achieved. RESULTS: Subjects conceptualized
      depression as an everyday problem of practice, rather than as an objective
      diagnostic category. Thematic coding of their accounts suggests a tension between
      three kinds of views of depressed people: (i) That depression is a common and
      normal response to life events or change and that it reflects the medicalization
      of these conditions; (ii) That the label or diagnosis of depression offers a
      degree of secondary gain to both patients and doctors, particularly to those GPs
      practising in inner-city areas and (iii) That inner-city GPs experienced on-going
      management of depressed people as an interactional problem, in contrast to those
      GPs serving a less deprived population who saw depression as a treatable illness
      and as rewarding work for the GP. CONCLUSION: Depression is commonly presented to
      GPs who feel that the diagnosis often involves the separation of a normal
      reaction to environment and true illness. For those patients living in socio
      economically deprived environments, the problems, and therefore the depression,
      are seen to be insoluble. This has an important implication for the construction
      of educational interventions around improving the recognition and treatment of
      depression in primary care: some doctors may be reluctant to recognize and
      respond to such patients in depth because of the much wider structural and social
      factors that we have suggested in this paper. That it is the doctors working with
      deprived populations who express these views, means that the 'Inverse care law'
      [Tudor Hart J. The inverse care Law. Lancet 1971; 1(7696): 405-412] operates in
      the management of depression.

PMID- 12429668
TI  - Barriers to developing the nurse practitioner role in primary care-the GP
      perspective.
AB  - BACKGROUND: Opportunities exist to develop an advanced nursing role in general
      practice and there is growing evidence that appropriately trained nurses can
      reduce cost and GP workload without compromising quality of care or patient
      satisfaction. Despite the shortfall of doctors entering British general practice
      and the difficulties doctors report in managing an increasing workload in primary
      care, few British practices have chosen to adopt this potential solution. An
      exploration of the barriers to the development of a nurse practitioner role is
      therefore timely. OBJECTIVE: To explore the views of British GPs regarding their
      attitudes towards developing an advanced nursing role in general practice.
      METHODS: A focus group study of GPs from four general practices in Yorkshire
      selected purposefully to represent a spectrum of experience in working with
      different nursing roles in general practice. Each focus group consisted of
      between 6 and 8 participants. A structured framework was used to elicit views,
      the group meetings were recorded and subjected to content analysis by two
      independent assessors. Inter-rater reliability was high (K = 0.921; 95%
      confidence limits 0.86-0.98). RESULTS: The study highlighted significant concerns
      by GPs with regard to the nurse practitioner role in general practice. Four
      themes were identified that may be impeding the development of advanced nursing
      roles in general practice. These are concerned with threats to GP status,
      including job and financial security, nursing capabilities, including training
      and scope of responsibility, and structural and organizational barriers.
      CONCLUSIONS: There is a need to acknowledge GP concerns and encourage a more
      widespread debate about the appropriate mix of skills required in primary care.
      Joint educational events and the development of GP preceptorship may help to
      develop a greater understanding of the potential value of advanced nursing roles
      in general practice.

PMID- 12429667
TI  - The more time spent on listening, the less time spent on prescribing antibiotics
      in general practice.
AB  - OBJECTIVE: To analyse the variation between primary care centres (PCCs) with
      regard to prescribing antibiotics and to investigate whether the variation can be
      explained by factors related to patient satisfaction and to socio-demographic
      characteristics of the populations in the catchment areas of the PCCs. METHODS:
      The frequency of prescription of antibiotics by GPs at the PCCs was used as the
      dependent variable in a multivariate regression analysis. Questionnaire data for
      patient satisfaction and register data for socio-demographic characteristics were
      used as explanatory variables. The study was set in a county in south-east
      Sweden, and 6734 patients consulting GPs at 39 out of the 41 PCCs in the county
      participated. Variables correlating with the frequency of antibiotics
      prescription at PCC level and with patient satisfaction were the main outcome
      measures. RESULTS: A seven-fold variation in the extent of the prescription of
      antibiotics between the PCCs was observed. In the multivariate analysis, a high
      antibiotic prescription rate relates to high overall patient satisfaction with GP
      consultation as well as to the share of males in the listed population but to low
      satisfaction with the time spent by the GP on listening to the patient.
      CONCLUSION: A high frequency of prescription of antibiotics at a PCC may reflect
      a general disposition among GPs to give priority to maintaining good relations
      with the patients. However, a low level of prescription may be consistent with
      patient satisfaction if more time is spent on listening to and informing the
      patients. Thus more time spent on listening to the patients may reduce the
      prescription of antibiotics without reducing patient satisfaction.

PMID- 12429669
TI  - Comparing the characteristics and attitudes of physicians in different primary
      care settings: The Ontario Walk-in Clinic Study.
AB  - BACKGROUND: In Canada, walk-in clinics (WICs) are a focus for debate about access
      to and the costs and quality of primary care. While WICs may offer patients
      easier access through longer hours and shorter waits, it has been argued that
      they may also lead to unnecessary utilization, duplication of services, lack of
      continuity of care, decreased quality and increased costs. OBJECTIVES: The main
      objectives were to analyse the characteristics and attitudes of physicians
      working in different family practice types including WICs. METHODS: We analysed
      the results of a 1998 survey of 728 primary care physicians in Ontario to compare
      physicians working in WICs with those working in solo and group family practices.
      RESULTS: Our survey found that few physicians worked most or all of their hours
      in WICs; most worked in WICs and other family practice types. Compared to family
      physicians in solo and group practices, physicians working in WICs saw more
      patients who were not their regular patients, patients without appointments and
      children. They reported slightly higher frequencies of problems such as backlogs
      (patient queues) and patients who had sought care from other doctors for the same
      problem. WIC physicians were less satisfied than other physicians with their
      relations with patients. They were, however, more satisfied with the availability
      of consultation, support staff, hours, income, and vacation coverage. Further,
      WIC physicians assessed the quality of care in WICs to be neither better nor
      worse than that in other family practices. CONCLUSIONS: We conclude that there
      are important similarities as well as differences, between physicians in WICs and
      those in more conventional family practices. The assessments of primary care
      physicians do not support the generally negative reputation of WICs. Instead,
      greater consideration should be given to the system-level issues which produce
      demand for WICs.

PMID- 12429670
TI  - How do GPs diagnose and manage acute infective conjunctivitis? A GP survey.
AB  - OBJECTIVE: To determine GPs' diagnosis and management of acute infective
      conjunctivitis (AIC)-one of the commonest but least researched acute infections
      seen in primary care. METHODS: A postal questionnaire survey of 300 GPs from two
      Health Authorities in Southern England. RESULTS: 236 (78%) GPs returned the
      questionnaire. 92% of those responding felt confident or very confident in the
      diagnosis of AIC. 95% usually prescribe topical antibiotics for AIC despite 58%
      stating that they thought at least half of the cases they see are viral in origin
      and only 36% believing that they could discriminate between bacterial and viral
      infection. There was considerable variability in GPs' use of individual signs to
      make the diagnosis of AIC (from 99% using eye discharge to 31% using conjunctival
      oedema) and in the features used to discriminate viral from bacterial infection
      (from 87% using type of discharge to 47% using amount of discharge). GPs rarely
      perform eye swabs or give patient information leaflets to patients with AIC.
      CONCLUSION: Most GPs still prescribe topical antibiotics for most cases of AIC-a
      condition where only half of the cases are likely to be due to a bacterial
      infection, and even bacterial infections are self-limiting. Further research is
      needed to explore the potential benefits and disadvantages of topical
      antibiotics, and to develop clinical or microbiological methods to help GPs to
      target antibiotic prescription.

PMID- 12429671
TI  - Mammography uptake predictors in older women.
AB  - BACKGROUND: In women aged under 65 years, socio-economic factors and general
      health behaviours are important predictors of mammography uptake. Little is known
      about whether these factors are important in older women. OBJECTIVE: To examine a
      broad range of mammography uptake predictors in women aged 65 and older
      registered with a London (UK) practice. METHODS: A survey of all female patients
      aged 65 and over (n = 613) in a south London practice included questions on
      mammography and cervical screening, general health and functional ability, socio
      economic factors, mental health, health behaviours, and attitudes to health.
      Associations between mammography uptake and other factors were examined using
      logistic regression. RESULTS: The response rate was 70% (432/613). Increased age
      was strongly associated with decreased mammography uptake. Additionally, socio
      economic factors and general health behaviours (previous cervical smear, drinking
      alcohol and being a non-smoker) were independently predictive of mammography
      uptake. Measures of physical and mental health and health attitudes were not
      independent predictors. Restricting analyses to the oldest women, outside the
      national screening programme, gave very similar results. CONCLUSIONS: In this
      sample of older women, socio-economic factors and general health behaviours were
      more predictive of mammography uptake than measures of physical and mental health
      or attitudes to health. Knowledge of these predictors is of increasing importance
      as the screening programme in the UK is extended up to age 70.

PMID- 12429672
TI  - A randomized controlled trial of group aerobic exercise in primary care patients
      with persistent, unexplained physical symptoms.
AB  - BACKGROUND: The management of persistent, unexplained physical symptoms is
      challenging and often unsatisfactory for patients and doctors. Aerobic exercise
      training has benefited patients referred to secondary care with symptoms of
      chronic fatigue and fibromyalgia. It is not known if this approach is either
      possible or beneficial for patients with the broader range of persistent,
      unexplained symptoms found in primary care. OBJECTIVES: To examine the
      feasibility and effects of aerobic exercise training in primary care patients
      with unexplained physical symptoms persisting more than 12 months. METHODS:
      Randomized comparison (n = 228) of aerobic exercise with stretching as control
      among patients recruited from primary care. Training comprised 20, one-hour,
      sessions led by NHS physiotherapists. Adherence to training was recorded along
      with two groups of outcome measures: (i) documented symptoms and health care use,
      monitored from six months before to six months after training; and (ii) self
      reported measures including emotional state and perceived disability, assessed
      before, during and six months after training. RESULTS: Exercise training proved
      feasible: more than 70% of referred patients attended for assessment and were
      randomized to aerobic or control exercise; 78% of eligible patients attended the
      first session; and median attendance was 11 sessions for both programmes. Primary
      care consultations and prescriptions were significantly reduced in the 6 months
      after training; extent of reduction was related to attendance at training
      sessions, irrespective of type. Whilst self-reported measures improved similarly
      during both training programmes, improvements were unrelated to level of
      attendance. CONCLUSION: For primary care patients with persistent, unexplained
      physical symptoms willing to be involved in exercise training, aerobic exercise
      offers no benefits over non-aerobic exercise. Whilst the observed reduction in
      primary health care use following exercise training is potentially of practical
      importance in a group of patients characterized by high consultation rates,
      improvement in patients' subjective state was not clearly attributable to
      exercise training.

PMID- 12429673
TI  - Breaking bones, breaking budgets: a clinical and economic evaluation of a
      prospective, randomized, practice controlled, intervention study in the
      prevention of accidents in primary care.
AB  - OBJECTIVE: This longitudinal study was designed to assess the effect of an
      educational training package for primary health care teams in accident prevention
      for older people, with reference to the incidence of accidents and their
      associated economic consequence. METHODS: Nineteen general practices in the West
      Midlands serving a population of 138 397 were allocated randomly at the practice
      level either to receive training or continue normal practice. Study data was
      collated from the initial telephone call, reporting an accident, to the surgery,
      advice/treatment given at the practice and/or the community, casualty, inpatient
      care, written correspondence to the patient's GP and any subsequent follow-up
      visits for accidents to people aged 65 years or older. RESULTS: One thousand, six
      hundred and sixty-six (8.2%) patients aged 65 years or older registered with the
      participating practices experienced one accident or more, costing the NHS pound
      1.4 million. Extrapolated nationally, annual costs to the NHS for accidents to
      older people amount to pound 568 million. The educational package had no
      significant impact on the incidence of accidents. A paucity of general safety
      advice was given [48 (1.8%) occasions]. CONCLUSIONS: Budgets are being eroded and
      patients are suffering unnecessarily due to lack of accident prevention advice.
      This should be considered a priority within the primary health care team.
      Educational packages alone do not appear to be a cost-effective approach to
      accident prevention in primary care.

PMID- 12429674
TI  - Survey of HIV/AIDS knowledge and attitudes of Kuwaiti family physicians.
AB  - OBJECTIVES: This study aimed to explore Kuwaiti family physicians' attitudes and
      knowledge about HIV/AIDS. METHODS: One hundred and sixty-two Kuwaiti family
      physicians (95 females and 67 males) from all four health catchment areas have
      completed a 30-item self-administered questionnaire to measure HIV/AIDS-related
      attitudes and knowledge. RESULTS: Knowledge was lacking in areas dealing with HIV
      related neuropsychiatric complications and other issues concerning HIV/AIDS,
      special populations and range of normal sexuality. The majority of physicians
      expressed negative attitudes toward homosexuality and about AIDS patients in
      general. Eighty-three per cent of Kuwaiti family physicians would opt out of
      treating AIDS patients. More than half of the physicians would avoid coming into
      social contact with HIV-seropositive persons. No significant difference was found
      for the total knowledge and attitude scores for gender. CONCLUSION: The results
      of this survey revealed that even in the second decade of the AIDS epidemic, some
      Kuwaiti family physicians continue to have a lack of proper knowledge about HIV
      and harbour negative attitudes toward AIDS patients. There is a need to promote
      an AIDS education early in the medical internship training years which addresses
      many underlying socio-cultural factors.

PMID- 12429675
TI  - Whole-system evaluation research of a scheme to support inner city recruitment
      and retention of GPs.
AB  - BACKGROUND: The GP Assistant/Research Associate scheme developed in the Guy's,
      King's and St Thomas' School of Medicine, London, aims to attract and recruit
      young GPs (GP Assistants) and develop their commitment to work in local inner
      city practices. Continuing professional development for both young and
      established GPs is a key feature of the scheme. OBJECTIVES: The objectives of the
      whole-system evaluation research were to explore the perspectives of 34
      stakeholders in the academic department, the practices and the PCGs, and to
      investigate the experiences of 19 GP Assistants who have participated in the
      scheme. METHODS: Qualitative methods included semi-structured interviews, non
      participant observations in the practices, audio-taped meetings and personal
      journals. Data collection also included reviewing documentation of the scheme,
      i.e. the previous quantitative evaluation report, publications and e-mails. The
      multi-method approach enabled individual, group and team perspectives of the
      scheme and triangulation of the data through comparing dialogue with observations
      and documentary evidence. Thematic analysis was undertaken to elicit the complex
      experiences of the GP Assistants. RESULTS: Wide-ranging findings included
      enthusiastic support for the continuation of the scheme. The GP Assistants'
      personal and professional development was clearly evident from the themes 'eye
      opener', new knowledge, managing multiple roles, feeling vulnerable, time
      constraints and empowering processes. Seven of the GP Assistants have become
      partners and ten chose to remain working in local practices. Significant
      challenges for managing and leading the scheme were apparent. Greater co
      operation and collaborative working between the academic department and the
      practices is required. CONCLUSION: The scheme provides a highly valued visible
      means of support for GPs and could act as a model for a career pathway aimed at
      enhancing recruitment and retention of GPs. The scheme is also at the forefront
      of national initiatives aimed at supporting single-handed practices and helping
      GPs with their continuing professional development. An integrated approach to
      change, education, research and development is advocated to enable recruitment
      and retention of GPs, their academic development, and to underpin the evolution
      of PCTs as learning organizations.

PMID- 12429676
TI  - A Research Information Sheet for Practices (RISP): a tool to facilitate research
      participation.
AB  - BACKGROUND: Practice teams may receive many requests to become involved in
      research studies. The information they receive may not necessarily provide the
      information they need to make a quick and informed decision about participation.
      Facilitating good decisions about research involvement has potential value for
      researchers, practitioners and research/development managers. OBJECTIVE: To
      develop and pilot a template (RISP) for communicating information about research
      studies to practice teams. METHODS: A participatory approach was used to develop
      the template involving primary care practitioners, researchers and
      research/development managers. The process of developing and piloting the
      template was recorded using an action research approach. Data were derived from
      documentation about policy, notes from participant observation and evaluation
      questionnaires. RESULTS: The RISP template was used as a source of reference
      about practical implications of research and as a means to communicate
      information about research studies to practice teams. Practice respondents valued
      its use in enabling members of the practice team to quickly assimilate
      information about the proposed research study and in providing the basis for a
      well-informed decision about participation. Its value to record keeping (and to
      research governance) was anticipated at the planning stage but was not as yet
      strongly evident in responses from practice. CONCLUSION: The RISP template has
      been designed to reflect the concerns of researchers, primary care practitioners
      and research/development managers. It can contribute to the documentation
      required in support of research governance.

PMID- 12429677
TI  - Selections from current literature. Attitudes and practices regarding the
      introduction of solid foods to infants.

PMID- 12429678
TI  - Electrotherapy of isolated human cells in tissue culture.

PMID- 12429679
TI  - Risk maps and three dimensional models: a rejoinder to Misselbrook and Armstrong.

PMID- 12429680
TI  - A chain is as strong as its weakest link but that link could be the subject
      matter of the questionnaire!

PMID- 12429681
TI  - Effectiveness of tonsillectomy? A reply to Howel et al.

PMID- 12429682
TI  - Testicular cancer awareness.

PMID- 12429683
TI  - Interactions of the oral contraceptive pill with antibiotics and St John's work:
      knowledge of female college students.

PMID- 12429684
TI  - Directions in evolutionary biology.
AB  - In order to understand both the past and future directions of research in
      evolutionary biology we need to begin by understanding in what way these programs
      of research differ from the model of most scientific work. The study of
      evolutionary processes and, in particular, the genetics of the evolutionary
      process must confront special difficulties in both the conceptual and the
      methodological aspects of research. On the conceptual side, unlike for molecular,
      cellular, and developmental biology, there is no basic mechanism that
      evolutionists are attempting to elucidate. There is no single cause of the
      evolutionary change in the properties of members of a species. Natural selection
      may be involved but so are random events, patterns of migration and
      interbreeding, mutational events, and horizontal transfer of genes across species
      boundaries. The change in each character of each species is a consequence of a
      particular mixture of these causal pathways.

PMID- 12429685
TI  - Genetic mating systems and reproductive natural histories of fishes: lessons for
      ecology and evolution.
AB  - Fish species have diverse breeding behaviors that make them valuable for testing
      theories on genetic mating systems and reproductive tactics. Here we review
      genetic appraisals of paternity and maternity in wild fish populations.
      Behavioral phenomena quantified by genetic markers in various species include
      patterns of multiple mating by both sexes; frequent cuckoldry by males and rare
      cuckoldry by females in nest-tending species; additional routes to surrogate
      parentage via nest piracy and egg-thievery; egg mimicry by nest-tending males;
      brood parasitism by helper males in cooperative breeders; clutch mixing in oral
      brooders; kinship in schooling fry of broadcast spawners; sperm storage by dams
      in female-pregnant species; and sex-role reversal, polyandry, and strong sexual
      selection on females in some male-pregnant species. Additional phenomena
      addressed by genetic parentage analyses in fishes include clustered mutations,
      filial cannibalism, and local population size. All results are discussed in the
      context of relevant behavioral and evolutionary theory.

PMID- 12429686
TI  - Genetics of motility and chemotaxis of a fascinating group of bacteria: the
      spirochetes.
AB  - Spirochetes are a medically important and ecologically significant group of
      motile bacteria with a distinct morphology. Outermost is a membrane sheath, and
      within this sheath is the protoplasmic cell cylinder and subterminally attached
      periplasmic flagella. Here we address specific and unique aspects of their
      motility and chemotaxis. For spirochetes, translational motility requires
      asymmetrical rotation of the two internally located flagellar bundles.
      Consequently, they have swimming modalities that are more complex than the well
      studied paradigms. In addition, coordinated flagellar rotation likely involves an
      efficient and novel signaling mechanism. This signal would be transmitted over
      the length of the cell, which in some cases is over 100-fold greater than the
      cell diameter. Finally, many spirochetes, including Treponema, Borrelia, and
      Leptospira, are highly invasive pathogens. Motility is likely to play a major
      role in the disease process. This review summarizes the progress in the genetics
      of motility and chemotaxis of spirochetes, and points to new directions for
      future experimentation.

PMID- 12429687
TI  - Recombination in evolutionary genomics.
AB  - Recombination can be a dominant force in shaping genomes and associated
      phenotypes. To better understand the impact of recombination on genomic
      evolution, we need to be able to identify recombination in aligned sequences. We
      review bioinformatic approaches for detecting recombination and measuring
      recombination rates. We also examine the impact of recombination on the
      reconstruction of evolutionary histories and the estimation of population genetic
      parameters. Finally, we review the role of recombination in the evolutionary
      history of bacteria, viruses, and human mitochondria. We conclude by highlighting
      a number of areas for future development of tools to help quantify the role of
      recombination in genomic evolution.

PMID- 12429688
TI  - Development and function of the angiosperm female gametophyte.
AB  - The plant life cycle alternates between a diploid sporophyte generation and a
      haploid gametophyte generation. The angiosperm female gametophyte is critical to
      the reproductive process. It is the structure within which egg cell production
      and fertilization take place. In addition, the female gametophyte plays a role in
      pollen tube guidance, the induction of seed development, and the maternal control
      of seed development. Genetic analysis in Arabidopsis has uncovered mutations that
      affect female gametophyte development and function. Mutants defective in almost
      all stages of development have been identified, and analysis of these mutants is
      beginning to reveal features of the female gametophyte developmental program.
      Other mutations that affect female gametophyte function have uncovered regulatory
      genes required for the induction of endosperm development. From these studies, we
      are beginning to understand the regulatory networks involved in female
      gametophyte development and function. Further investigation of the female
      gametophyte will require complementary approaches including expression-based
      approaches to obtain a complete profile of the genes functioning within this
      critical structure.

PMID- 12429689
TI  - Primordial genetics: phenotype of the ribocyte.
AB  - The idea that the ancestors of modern cells were RNA cells (ribocytes) can be
      investigated by asking whether all essential cellular functions might be
      performed by RNAs. This requires isolating suitable molecules by selection
      amplification when the predicted molecules are presently extinct. In fact, RNAs
      with many properties required during a period in which RNA was the major
      macromolecular agent in cells (an RNA world) have been selected in modern
      experiments. There is, accordingly, reason to inquire how such a ribocyte might
      appear, based on the properties of the RNAs that composed it. Combining the
      intrinsic qualities of RNA with the fundamental characteristics of selection from
      randomized sequence pools, one predicts ribocytes with a cell cycle measured
      (roughly) in weeks. Such cells likely had a rapidly varying genome, composed of
      many small genetic and catalytic elements made of tens of ribonucleotides. There
      are substantial arguments that, at the mid-RNA era, a subset of these nucleotides
      are reproducibly available and resemble the modern four. Such cells are predicted
      to evolve rapidly. Instead of modifying preexisting genes, ribocytes frequently
      draw new functions from an internal pool containing zeptomoles (<1 attomole) of
      predominantly inactive random sequences.

PMID- 12429690
TI  - Studying gene function in eukaryotes by conditional gene inactivation.
AB  - The prospect of specifically controlling gene activities in vivo has become a
      defining hallmark of many model organisms of biological research. Where once the
      aim was to gain control over gene activities using endogenous control elements,
      new technologies have emerged that owe their remarkable specificity to
      heterologous components derived from evolutionarily distant species. This review
      highlights inducible transcriptional systems and site-specific recombination.
      Their quantitative and qualitative characteristics are discussed, with examples
      of how recent developments have expanded the spectrum of cells and organisms that
      are now accessible to genetic dissection of unprecedented precision. Transgenesis
      has already converted the mouse into a prime model for mammalian genetics.
      Combined with the new approaches of conditional activation or inactivation of
      genes, this model has opened up new horizons for the analysis of gene function in
      mammals.

PMID- 12429691
TI  - DNA topology-mediated control of global gene expression in Escherichia coli.
AB  - Because the level of DNA superhelicity varies with the cellular energy charge, it
      can change rapidly in response to a wide variety of altered nutritional and
      environmental conditions. This is a global alteration, affecting the entire
      chromosome and the expression levels of all operons whose promoters are sensitive
      to superhelicity. In this way, the global pattern of gene expression may be
      dynamically tuned to changing needs of the cell under a wide variety of
      circumstances. In this article, we propose a model in which chromosomal
      superhelicity serves as a global regulator of gene expression in Escherichia
      coli, tuning expression patterns across multiple operons, regulons, and stimulons
      to suit the growth state of the cell. This model is illustrated by the DNA
      supercoiling-dependent mechanisms that coordinate basal expression levels of
      operons of the ilv regulon both with one another and with cellular growth
      conditions.

PMID- 12429692
TI  - Meiotic recombination and chromosome segregation in Drosophila females.
AB  - In this review, we describe the pathway for generating meiotic crossovers in
      Drosophila melanogaster females and how these events ensure the segregation of
      homologous chromosomes. As appears to be common to meiosis in most organisms,
      recombination is initiated with a double-strand break (DSB). The interesting
      differences between organisms appear to be associated with what chromosomal
      events are required for DSBs to form. In Drosophila females, the synaptonemal
      complex is required for most DSB formation. The repair of these breaks requires
      several DSB repair genes, some of which are meiosis-specific, and defects at this
      stage can have effects downstream on oocyte development. This has been suggested
      to result from a checkpoint-like signaling between the oocyte nucleus and gene
      products regulating oogenesis. Crossovers result from genetically controlled
      modifications to the DSB repair pathway. Finally, segregation of chromosomes
      joined by a chiasma requires a bipolar spindle. At least two kinesin motor
      proteins are required for the assembly of this bipolar spindle, and while the
      meiotic spindle lacks traditional centrosomes, some centrosome components are
      found at the spindle poles.

PMID- 12429694
TI  - Origins of spontaneous mutations: specificity and directionality of base
      substitution, frameshift, and sequence-substitution mutageneses.
AB  - Spontaneous mutations are derived from various sources, including errors made
      during replication of undamaged template DNA, mutagenic nucleotide substrates,
      and endogenous DNA lesions. These sources vary in their frequencies and resultant
      mutations, and are differently affected by the DNA sequence, DNA transactions,
      and cellular metabolism. Organisms possess a variety of cellular functions to
      suppress spontaneous mutagenesis, and the specificity and effectiveness of each
      function strongly affect the pattern of spontaneous mutations. Base substitutions
      and single-base frameshifts, two major classes of spontaneous mutations, occur
      non-randomly throughout the genome. Within target DNA sequences there are
      hotspots for particular types of spontaneous mutations; outside of the hotspots,
      spontaneous mutations occur more randomly and much less frequently. Hotspot
      mutations are attributable more to endogenous DNA lesions than to replication
      errors. Recently, a novel class of mutagenic pathway that depends on short
      inverted repeats was identified as another important source of hotspot
      mutagenesis.

PMID- 12429693
TI  - Xist RNA and the mechanism of X chromosome inactivation.
AB  - Dosage compensation in mammals is achieved by the transcriptional inactivation of
      one X chromosome in female cells. From the time X chromosome inactivation was
      initially described, it was clear that several mechanisms must be precisely
      integrated to achieve correct regulation of this complex process. X-inactivation
      appears to be triggered upon differentiation, suggesting its regulation by
      developmental cues. Whereas any number of X chromosomes greater than one is
      silenced, only one X chromosome remains active. Silencing on the inactive X
      chromosome coincides with the acquisition of a multitude of chromatin
      modifications, resulting in the formation of extraordinarily stable facultative
      heterochromatin that is faithfully propagated through subsequent cell divisions.
      The integration of all these processes requires a region of the X chromosome
      known as the X-inactivation center, which contains the Xist gene and its cis
      regulatory elements. Xist encodes an RNA molecule that plays critical roles in
      the choice of which X chromosome remains active, and in the initial spread and
      establishment of silencing on the inactive X chromosome. We are now on the
      threshold of discovering the factors that regulate and interact with Xist to
      control X-inactivation, and closer to an understanding of the molecular
      mechanisms that underlie this complex process.

PMID- 12429695
TI  - Genetics of influenza viruses.
AB  - Influenza A viruses contain genomes composed of eight separate segments of
      negative-sense RNA. Circulating human strains are notorious for their tendency to
      accumulate mutations from one year to the next and cause recurrent epidemics.
      However, the segmented nature of the genome also allows for the exchange of
      entire genes between different viral strains. The ability to manipulate influenza
      gene segments in various combinations in the laboratory has contributed to its
      being one of the best characterized viruses, and studies on influenza have
      provided key contributions toward the understanding of various aspects of
      virology in general. However, the genetic plasticity of influenza viruses also
      has serious potential implications regarding vaccine design, pathogenicity, and
      the capacity for novel viruses to emerge from natural reservoirs and cause global
      pandemics.

PMID- 12429696
TI  - Allosteric cascade of spliceosome activation.
AB  - Introns are removed from precursor messenger RNAs in the cell nucleus by a large
      ribonucleoprotein complex called the spliceosome. The spliceosome contains five
      subcomplexes called snRNPs, each with one RNA and several protein components.
      Interactions of the snRNPs with each other and the intron are highly dynamic,
      changing in an ordered progression throughout the splicing process. This
      allosteric cascade of interactions is programmed into the RNA and protein
      components of the spliceosome, and is driven by a family of DExD/H-box RNA
      dependent ATPases. The dependence of cascade progression on multiple intron
      recognition events likely serves to enforce the accuracy of splicing. Here, the
      progression of the allosteric cascade from the first recognition event to the
      first catalytic step of splicing is reviewed.

PMID- 12429697
TI  - Genetic engineering using homologous recombination.
AB  - In the past few years, in vivo technologies have emerged that, due to their
      efficiency and simplicity, may one day replace standard genetic engineering
      techniques. Constructs can be made on plasmids or directly on the Escherichia
      coli chromosome from PCR products or synthetic oligonucleotides by homologous
      recombination. This is possible because bacteriophage-encoded recombination
      functions efficiently recombine sequences with homologies as short as 35 to 50
      base pairs. This technology, termed recombineering, is providing new ways to
      modify genes and segments of the chromosome. This review describes not only
      recombineering and its applications, but also summarizes homologous recombination
      in E. coli and early uses of homologous recombination to modify the bacterial
      chromosome. Finally, based on the premise that phage-mediated recombination
      functions act at replication forks, specific molecular models are proposed.

PMID- 12429698
TI  - Chromosome rearrangements and transposable elements.
AB  - There has been limited corroboration to date for McClintock's vision of gene
      regulation by transposable elements (TEs), although her proposition on the origin
      of species by TE-induced complex chromosome reorganizations in combination with
      gene mutations, i.e., the involvement of both factors in relatively sudden
      formations of species in many plant and animal genera, has been more promising.
      Moreover, resolution is in sight for several seemingly contradictory phenomena
      such as the endless reshuffling of chromosome structures and gene sequences
      versus synteny and the constancy of living fossils (or stasis in general). Recent
      wide-ranging investigations have confirmed and enlarged the number of earlier
      cases of TE target site selection (hot spots for TE integration), implying
      preestablished rather than accidental chromosome rearrangements for nonhomologous
      recombination of host DNA. The possibility of a partly predetermined generation
      of biodiversity and new species is discussed. The views of several leading
      transposon experts on the rather abrupt origin of new species have not been
      synthesized into the macroevolutionary theory of the punctuated equilibrium
      school of paleontology inferred from thoroughly consistent features of the fossil
      record.

PMID- 12429699
TI  - Genetics of sensory mechanotransduction.
AB  - The molecular mechanisms for the transduction of light and chemical signals in
      animals are fairly well understood. In contrast, the processes by which the
      senses of touch, balance, hearing, and proprioception are transduced are still
      largely unknown. Biochemical approaches to identify transduction components are
      difficult to use with mechanosensory systems, but genetic approaches are proving
      more successful. Genetic research in several organisms has demonstrated the
      importance of cytoskeletal, extracellular, and membrane components for sensory
      mechanotransduction. In particular, researchers have identified channel proteins
      in the DEG/ENaC and TRP families that are necessary for signaling in a variety of
      mechanosensory cells. Proof that these proteins are components of the
      transduction channel, however, is incomplete.

PMID- 12429700
TI  - Understanding the function of actin-binding proteins through genetic analysis of
      Drosophila oogenesis.
AB  - Much of our knowledge of the actin cytoskeleton has been derived from biochemical
      and cell biological approaches, through which actin-binding proteins have been
      identified and their in vitro interactions with actin have been characterized.
      The study of actin-binding proteins (ABPs) in genetic model systems has become
      increasingly important for validating and extending our understanding of how
      these proteins function. New ABPs have been identified through genetic screens,
      and genetic results have informed the interpretation of in vitro experiments. In
      this review, we describe the molecular and ultrastructural characteristics of the
      actin cytoskeleton in the Drosophila ovary, and discuss recent genetic analyses
      of actin-binding proteins that are required for oogenesis.

PMID- 12429701
TI  - The genetics of RNA silencing.
AB  - Although initially recognized as a handy tool to reduce gene expression, RNA
      silencing, triggered by double-stranded RNA molecules, is now recognized as a
      mechanism for cellular protection and cleansing: It defends the genome against
      molecular parasites such as viruses and transposons, while removing abundant but
      aberrant nonfunctional messenger RNAs. The underlying mechanisms in distinct gene
      silencing phenomena in different genetic systems, such as cosuppression in plants
      and RNAi in animals, are very similar. There are common RNA intermediates, and
      similar genes are required in RNA silencing pathways in protozoa, plants, fungi,
      and animals, thus indicating an ancient pathway. This chapter gives an overview
      of both biochemical and genetic approaches leading to the current understanding
      of the molecular mechanism of RNA silencing and its probable biological function.

PMID- 12429702
TI  - Transvection effects in Drosophila.
AB  - An unusual feature of the Diptera is that homologous chromosomes are intimately
      synapsed in somatic cells. At a number of loci in Drosophila, this pairing can
      significantly influence gene expression. Such influences were first detected
      within the bithorax complex (BX-C) by E.B. Lewis, who coined the term
      transvection to describe them. Most cases of transvection involve the action of
      enhancers in trans. At several loci deletion of the promoter greatly increases
      this action in trans, suggesting that enhancers are normally tethered in cis by
      the promoter region. Transvection can also occur by the action of silencers in
      trans or by the spreading of position effect variegation from rearrangements
      having heterochromatic breakpoints to paired unrearranged chromosomes. Although
      not demonstrated, other cases of transvection may involve the production of joint
      RNAs by trans-splicing. Several cases of transvection require Zeste, a DNA
      binding protein that is thought to facilitate homolog interactions by self
      aggregation. Genes showing transvection can differ greatly in their response to
      pairing disruption. In several cases, transvection appears to require intimate
      synapsis of homologs. However, in at least one case (transvection of the iab
      5,6,7 region of the BX-C), transvection is independent of synapsis within and
      surrounding the interacting gene. The latter example suggests that transvection
      could well occur in organisms that lack somatic pairing. In support of this,
      transvection-like phenomena have been described in a number of different
      organisms, including plants, fungi, and mammals.

PMID- 12429704
TI  - Toward maintaining the genome: DNA damage and replication checkpoints.
AB  - DNA checkpoints play a significant role in cancer pathology, perhaps most notably
      in maintaining genome stability. This review summarizes the genetic and molecular
      mechanisms of checkpoint activation in response to DNA damage. The major
      checkpoint proteins common to all eukaryotes are identified and discussed,
      together with how the checkpoint proteins interact to induce arrest within each
      cell cycle phase. Also discussed are the molecular signals that activate
      checkpoint responses, including single-strand DNA, double-strand breaks, and
      aberrant replication forks. We address the connection between checkpoint proteins
      and damage repair mechanisms, how cells recover from an arrest response, and
      additional roles that checkpoint proteins play in DNA metabolism. Finally, the
      connection between checkpoint gene mutation and genomic instability is
      considered.

PMID- 12429703
TI  - Genetics of Cryptococcus neoformans.
AB  - Cryptococcus neoformans is a pathogenic fungus that primarily afflicts
      immunocompromised patients, infecting the central nervous system to cause
      meningoencephalitis that is uniformly fatal if untreated. C. neoformans is a
      basidiomycetous fungus with a defined sexual cycle that has been linked to
      differentiation and virulence. Recent advances in classical and molecular genetic
      approaches have allowed molecular descriptions of the pathways that control cell
      type and virulence. An ongoing genome sequencing project promises to reveal much
      about the evolution of this human fungal pathogen into three distinct varieties
      or species. C. neoformans shares features with both model ascomycetous yeasts
      (Saccharomyces cerevisiae, Schizosaccharomyces pombe) and basidiomycetous
      pathogens and mushrooms (Ustilago maydis, Coprinus cinereus, Schizophyllum
      commune), yet ongoing studies reveal unique features associated with virulence
      and the arrangement of the mating type locus. These advances have catapulted C.
      neoformans to center stage as a model of both fungal pathogenesis and the
      interesting approaches to life that the kingdom of fungi has adopted.

PMID- 12429705
TI  - Genetic approaches to molecular and cellular cognition: a focus on LTP and
      learning and memory.
AB  - Long-term potentiation (LTP) is the predominant experimental model for the
      synaptic plasticity mechanisms thought to underlie learning and memory. This
      review is focused on the contributions of genetics to the understanding of the
      role of LTP in learning and memory. These studies have used a combination of
      genetics, molecular biology, neurophysiology, and psychology to demonstrate that
      molecular mechanisms of synaptic plasticity are critical for learning and memory.
      Because of the large scope of this literature, we focus primarily on genetic
      studies of hippocampal-dependent learning. Altogether, these findings not only
      demonstrate a role for plasticity in learning, they also lay down the foundations
      for the new field of molecular and cellular cognition.

PMID- 12429706
TI  - Multiple control of interleukin-8 gene expression.
AB  - Interleukin (IL)-8, a prototypic human chemokine, was detected more than a decade
      ago as the founding member of the chemokine superfamily. One of the most
      remarkable properties of IL-8 is the variation of its expression levels. In
      healthy tissues, IL-8 is barely detectable, but it is rapidly induced by ten- to
      100-fold in response to proinflammatory cytokines such as tumor necrosis factor
      or IL-1, bacterial or viral products, and cellular stress. Recently, significant
      advances in the understanding of signaling pathways, which coordinately regulate
      IL-8 transcription as well as mRNA stabilization in response to external stimuli,
      have been made. Maximal IL-8 amounts are generated by a combination of three
      different mechanisms: first, derepression of the gene promoter; second,
      transcriptional activation of the gene by nuclear factor-kappaB and JUN-N
      terminal protein kinase pathways; and third, stabilization of the mRNA by the p38
      mitogen-activated protein kinase pathway. In that way, cells are able to rapidly
      increase and at the same time, to fine-tune the amount of IL-8 secreted and
      thereby control the extent of leukocytes attracted to sites of tissue injury.

PMID- 12429707
TI  - Interleukin-21 and the IL-21 receptor: novel effectors of NK and T cell
      responses.
AB  - Interleukin (IL)-21 was recently discovered using a functional cloning approach
      based on expression of its receptor. It is similar in domain organization and
      primary sequence to IL-2 and IL-15. Like these cytokines, IL-21 uses the common
      gamma chain of the IL-2/15 receptor, which forms a heterodimeric receptor complex
      with IL-21R. IL-21 is produced by activated T cells, and it influences
      proliferation of T and B cells and cytolytic activity of natural killer cells.
      The elucidation of the unique biological effects of IL-21 represents an intense
      area of interest in current cytokine biology.

PMID- 12429708
TI  - A role for endogenous IL-12 in tumor immunity: IL-12 is required for the
      acquisition of tumor-migratory capacity by T cells and the development of T cell
      accepting capacity in tumor masses.
AB  - Interleukin (IL)-12 plays a central role in the initiation and regulation of T
      cell-mediated immune responses. The present study investigated how IL-12,
      endogenously produced during tumor vaccination, functions for anti-tumor immune
      responses. Mice were given anti-IL-12 monoclonal antibody during immunization
      with attenuated syngeneic tumor cells. Splenic T cells from anti-IL-12-treated
      immunized mice exhibited comparable levels of tumor-neutralizing activity with
      those from tumor-immunized mice without anti-IL-12 treatment. When these two
      groups of mice were directly challenged with viable tumor cells, tumor rejection
      was induced only in anti-IL-12-untreated mice. T cell infiltration was observed
      at the site of tumor challenge in these mice, whereas such a T cell infiltration
      did not occur in anti-IL-12-treated mice. The tumor-migratory capacity was
      directly assessed by transferring spleen cells from tumor-immunized mice into
      syngeneic, tumor-bearing recipient mice and by quantitating donor cells migrating
      into recipients' tumor masses. T cells from anti-IL-12-treated tumor-immunized
      mice were found to exhibit a markedly reduced tumor-migratory capacity when
      compared with that of anti-IL-12-untreated mice. Moreover, the migration of T
      cells from anti-IL-12-untreated mice to tumor masses prepared in anti-IL-12
      treated mice was severely reduced. These results indicate that endogenously
      produced IL-12 has dual roles in anti-tumor-immune resistance: One is to confer T
      cells with a tumor-migratory capacity, and the other is to allow tumor masses to
      develop the capacity to accept tumor-migrating T cells.

PMID- 12429709
TI  - Monocytes are progressively activated in the circulation of pregnant women.
AB  - Pregnancy is characterized by the presence of generalized leukocyte activation.
      We used flow cytometry to investigate changes in phenotype and intracellular
      cytokines of circulating granulocytes, monocytes, and T lymphocytes of pregnant
      women during gestation. We report that peripheral circulation of pregnancy is
      characterized by an increased percentage of granulocytes and a decrease in
      lymphocytes. The proportion of monocytes remains stable throughout gestation;
      however, a progressive up-regulation of surface markers CD11a, CD54, and CD64 was
      detected. Monocytes also showed higher production of interleukin (IL)-12 and IL
      1beta compared with the nonpregnant state, and granulocytes had greater potential
      to synthesize IL-8. All these changes were particularly marked in late gestation.
      T lymphocytes did not have any characteristics of the activated state and showed
      a decreased IL-6 production. These findings demonstrate that activation of
      maternal monocytes and granulocytes increases during pregnancy and support the
      idea that pregnancy results in an elevation of the innate immune system and
      suppression of the adaptive immune system.

PMID- 12429711
TI  - Donor T cell and host NK depletion improve the therapeutic efficacy of allogeneic
      bone marrow cell reconstitution in the nonmyeloablatively conditioned tumor
      bearing host.
AB  - Allogeneic bone marrow cell reconstitution of the nonmyeloablatively conditioned
      host has the advantage that it can be tolerated in suboptimal health conditions.
      However, the problem of graft versus host disease (GvHD) remains. Also, graft
      acceptance may become delicate, and HvGD may arise. We report here on
      advantages/disadvantages of host natural killer (NK) depletion and graft T cell
      depletion in fully allogeneic, healthy and solid tumor-bearing mice. NK depletion
      of the "healthy" host improved the survival rate, whereas graft T cell depletion
      was disadvantageous. In the tumor-bearing host, graft T cell depletion was
      beneficial when the host was NK-depleted. Host NK depletion facilitated B
      lymphopoiesis, repopulation of the thymus, expansion of donor cells, and
      tolerance induction. The disadvantage of graft T cell depletion in the "healthy"
      host was a result of delayed engraftment. Because in tumor-bearing mice, host but
      not graft hematopoiesis was strongly impaired, donor hematopoiesis dominated.
      Graft T cell depletion reduced GvHD but hardly interfered with engraftment.
      Importantly, graft-mediated tumor reactivity appeared late and was unimpaired
      when the graft was T cell-depleted. Thus, concomitant depletion of host NK and
      donor T cells is advantageous when approaching therapeutic treatment of solid
      tumors by allogeneic reconstitution of the nonmyeloablatively conditioned host.

PMID- 12429710
TI  - Disruption of the Nramp1 (also known as Slc11a1) gene in Kupffer cells attenuates
      early-phase, warm ischemia-reperfusion injury in the mouse liver.
AB  - As the natural resistance-associated macrophage protein 1 Nramp1 (also known as
      Slc11a1) modulates Kupffer cell (KC) activation, and KC are responsible for the
      early phase of warm ischemia/reperfusion (I/R) to the liver, we hypothesized that
      livers of Nramp1(-/-) mice will be protected from early-phase I/R injury compared
      with livers of Nramp1(+/+) mice. To test our hypothesis, we induced partial warm
      ischemia to the livers of Nramp1(+/+) and Nramp1(-/-) mice for 45 min of by
      clamping the hilum of the median and left lateral lobes, followed by 30 or 60 min
      of reperfusion. Plasma glutamate oxaloacetate transaminase (pGOT) activity and
      tumor necrosis factor alpha (TNF-alpha) levels were measured, and liver sections
      were stained for polymorphonuclear leukocyte (PMN) accumulation. After 45 min of
      ischemia and 30/60 min of reperfusion of Nramp1(+/+) and Nramp1(-/-) mice livers,
      we found significant increases in plasma pGOT activity and TNF-alpha levels in
      Nramp1(+/+) mice at 30 and 60 min of reperfusion, respectively, compared with
      sham controls and all Nramp1(-/-) mice. A significant accumulation of PMNs was
      also found in livers of Nramp1(+/+) mice at 60 min of reperfusion compared with
      all other groups. We have shown that disruption of the Nramp1 gene attenuates I/R
      injury to the mouse liver during the early phase of warm I/R injury. An increased
      understanding of the role played by Nramp1 is particularly important in the
      liver, as this organ is subjected to a wide variety of injuries during
      hemorrhagic shock, partial resections, and transplantation.

PMID- 12429712
TI  - Restricted replication of primary HIV-1 isolates using both CCR5 and CXCR4 in Th2
      but not in Th1 CD4(+) T cells.
AB  - We have previously reported that CCR5-dependent human immunodeficiency virus type
      1 (HIV-1; R5), but not CXCR4-restricted (X4) virus, efficiently replicates in T
      helper cell type 1 (Th1), Th2, or Th0 polyclonal T cells obtained from human
      umbilical cord blood (CB lines). The X4 virus restriction was env-dependent but
      did not occur at the level of viral entry. Here, we describe that in contrast to
      these monotropic HIVs, primary HIV-1 isolates capable of using CCR5 or CXCR4
      indifferently for entry (i.e., R5X4 viruses) efficiently replicated in Th2 but
      not in Th1 CB lines. Although Th1 cells secreted significantly higher amounts of
      the three CCR5-binding chemokines in comparison with Th2 cells, this restriction
      was not explained by a defective infection of Th1 cells. Interferon-gamma (IFN
      gamma) down-regulated CCR5 in Th1 cells and inhibited, whereas interleukin-4 (IL
      4) up-regulated CXCR4 and enhanced the spreading of R5 and R5X4 viruses in
      polarized CB lines. However, both cytokines did not rescue the replication of X4
      and dualtropic viruses in both types of CB lines or in Th1 cells, respectively,
      whereas addition of anti-IL-4- or anti-IFN-gamma-neutralizing antibodies did not
      activate virus expression. These findings together suggest the existence of post
      entry restriction pathways influenced by gp120 Env/chemokine coreceptor
      interaction that may significantly contribute to the superior capacity of R5 and
      R5X4 HIV-1 strains to spread in vivo in comparison to X4 monotropic viruses.

PMID- 12429713
TI  - Role of CD80, CD86, and CTLA4 on mouse CD4(+) T lymphocytes in enhancing cell
      cycle progression and survival after activation with PMA and ionomycin.
AB  - Cell surface interactions between the T cell costimulatory receptors, CD28 and
      cytotoxic T-lymphocyte antigen-4 (CTLA4), with their cognate ligands, CD80 and
      CD86, on antigen-presenting cells play an important role in T cell activation.
      Although CD80 and CD86 are induced on T cells after activation, not much is known
      about their role in modulating T cell function. We show that CD80, CD86, and
      CTLA4 are induced on purified CD4(+) T cells after in vitro activation with
      phorbol 12-myristate 13-acetate (PMA) and ionomycin, and they play an essential
      role for proliferation and survival. Blockade of CTLA4-CD80/CD86 interactions
      greatly reduces PMA and ionomycin-mediated mouse CD4(+) T cell activation. The
      three key features of this inhibition of activation are: First, late events in T
      cell activation (after 18 h) are affected; second, these cells do not undergo
      anergy; and third, CD4(+)CD25(+) regulatory T cells are not responsible.
      Activation of T cells with PMA and ionomycin together with CTLA4-CD80/CD86
      blockade results in decreased induction of CD25 and Bcl-X(L), reduced interleukin
      (IL)-2, and enhanced transforming growth factor-beta (TGF-beta) production.
      Furthermore, extended CTLA4-CD80/CD86 blockade results in decreased cell-cycle
      progression and enhanced apoptosis in a large proportion of cells. This
      inhibition of T cell proliferation can be rescued completely with anti-CD28 or IL
      2 and partially with TGF-beta antagonists. This study reveals a functional role
      for CD80, CD86, and CTLA4 on CD4(+) T lymphocytes and sheds light on the
      mechanisms by which these molecules enhance activation and survival with PMA and
      ionomycin.

PMID- 12429714
TI  - Dendritic cell maturation and IL-12 synthesis induced by the synthetic immune
      response modifier S-28463.
AB  - Dendritic cells (DC) play a prominent role in the development of T cell-immune
      responses to antigens and have a key influence over the differentiation of naive
      T cells into T helper cell type 1 (Th1) or Th2 effector cells. Consequently,
      there is considerable interest in pharmacological agents that might alter DC
      function and thereby modulate allergic inflammation. We examined the effects of
      the imidazoquinoline S-28463 on human monocyte-derived DC (Mo-DC) cultured in
      granulocyte macrophage-colony stimulating factor and interleukin (IL)-4 to
      determine whether this agent might be useful in augmenting Th1 immunity. We
      determined that S-28463 acts directly on Mo-DC, inducing their maturation and
      enhancing their capacity to present antigen. Importantly, S-28463 strongly
      induces synthesis of bioactive IL-12 p70, a key Th1-polarizing cytokine. We also
      examined the ability of S-28463 to modulate DC function in the context of
      transforming growth factor-beta (TGF-beta), a negative, immunoregulatory cytokine
      released from the epithelium of nonlymphoid organs. S-28463 was able to induce IL
      12 synthesis even in the presence of TGF-beta, whereas lipopolysaccharide (LPS) +
      interferon-gamma-stimulated DC did not produce IL-12 in the presence of TGF-beta.
      Taken together, our findings suggest that S-28463 and LPS are exerting their
      effects via distinctly different pathways and indicate that S-28463 may be
      beneficial in polarizing immune responses toward a Th1 response.

PMID- 12429715
TI  - Differential regulation of dendritic cell function by the immunomodulatory drug
      thalidomide.
AB  - Thalidomide (Thal) was shown to be a potent immunomodulating agent. Because of
      their central role in controlling immunity, we investigated the effects of Thal
      on monocyte-derived dendritic cells (Mo-DC). The addition of 10 micro g/ml or 20
      micro g/ml Thal from the beginning of monocyte culture with granulocyte
      macrophage-colony stimulating factor and interleukin (IL)-4 did not block Mo-DC
      differentiation. Moreover, Thal alone could not induce Mo-DC maturation. However,
      Thal exerted a modulation of Mo-DC functional properties. At 10 micro g/ml, Thal
      modified the allostimulatory capacity of DC little, whereas a dose of 20 micro
      g/ml up-regulated this capacity (P=.05) and increased IL-12p70 production in a
      dose-dependent manner between 10 and 20 micro g/ml (P=.001). Mo-DC generated with
      10 micro g/ml Thal were poor stimulators of T helper cell type 1 (Th1) responses
      (P=.01), but 20 micro g/ml was able to strengthen Th1 responses (P=.03). Also,
      Thal induced a significant reduction of IL-10 production in response to the
      maturation-inducing stimulus CD40L. Similarly, tumor necrosis factor alpha
      production was significantly decreased when Mo-DC were exposed to 10 micro g/ml
      Thal, and a dose of 20 micro g/ml did not induce any significant changes. The
      effects of Thal in vitro on the secretion of IL-12p70 and strengthening of Th1
      responses might contribute to the antitumor effects of Thal. Thus, DC appear to
      be potential targets for the immunomodulatory capacity of Thal, defining a new
      mechanism of action of this drug.

PMID- 12429716
TI  - Induction of regulatory T cells by the immunomodulating cytokines alpha
      melanocyte-stimulating hormone and transforming growth factor-beta2.
AB  - Recently, we have reported that the cytokines alpha-melanocyte-stimulating
      hormone (alpha-MSH) and transforming growth factor-beta2 (TGF-beta2) work in
      synergy to induce the activation of regulatory T (Treg) cells. When we used alpha
      MSH and TGF-beta2 to generate ocular autoantigen-specific Treg cells and
      adoptively transferred them into mice susceptible to experimental autoimmune
      uveoretinitis (EAU), there was suppression in the incidence and severity of EAU.
      Specificity to a retinal autoantigen was required for the Treg cells to suppress
      EAU. When stimulated, these Treg cells produced TGF-beta1, and their production
      of interferon-gamma, interleukin (IL)-10, and IL-4 was suppressed. Also, the Treg
      cells are suppressed in their proliferative response. Our results demonstrate
      that alpha-MSH with TGF-beta2 induce Treg cells that can subdue a tissue-specific
      autoimmune response. This also promotes the possibility of using these
      immunomodulating cytokines to purposely induce antigen-specific Treg cells to
      prevent and suppress autoimmune disease.

PMID- 12429717
TI  - Cyclosporin A inhibits dendritic cell maturation promoted by TNF-alpha or LPS but
      not by double-stranded RNA or CD40L.
AB  - Here, we investigated the influence of cyclosporin A (CsA) on dendritic cell (DC)
      generation. With this aim, human DC were propagated from monocytes in serum-free
      medium with granulocyte macrophage-colony stimulating factor and interleukin-4.
      DC were then exposed to tumor necrosis factor alpha (TNF-alpha) for maturation.
      Our results show that CsA does not impair commitment of monocytes into DC, as
      assessed by loss of CD14 and increase of CD40 and CD1a. However, TNF-alpha
      induced DC maturation was affected, as CsA-treated DC expressed lower levels of
      human leukocyte antigen and costimulatory molecules but sustained levels of CD1a,
      and less DC expressed DC-lysosomal-associated-membrane-protein (LAMP) and CD83.
      Accordingly, CsA inhibited the allostimulatory and accessory cell functions of
      DC. Surprisingly, when other maturation stimuli were used, we observed that CsA
      significantly inhibited maturation induced by lipopolysaccharides but not by
      polyribocytidylic acid or CD40 ligand, as assessed by DC phenotype and functions.
      Therefore, our results indicate that CsA may differentially affect DC maturation.

PMID- 12429718
TI  - Pertussis toxin and the adenylate cyclase toxin from Bordetella pertussis
      activate human monocyte-derived dendritic cells and dominantly inhibit cytokine
      production through a cAMP-dependent pathway.
AB  - Pertussis toxin (PT) and adenylate cyclase toxin (AT) are AB enterotoxins
      produced by Bordetella pertussis. PT is a powerful mucosal adjuvant whose
      cellular target and mechanism of action are unknown; however, emerging evidence
      suggests that dendritic cells (DC) may be a principal adjuvant target of PT.
      Here, we investigate the mechanism underlying the effects of these toxins on
      human monocyte-derived DC (MDDC) in vitro. We found that the effects of PT and AT
      on MDDC, including maturation, are mediated by cyclic adenosine monophosphate
      (cAMP). In this regard, adenosine 5'-diphosphate-ribosylation-defective
      derivatives of PT failed to induce maturation of MDDC, whereas dibutyryl-cAMP (d
      cAMP) and Forskolin mimic the maturation of MDDC and dominant inhibition of
      cytokine production induced by these toxins. Also, cAMP-dependent kinase
      inhibitors blocked the ability of PT, AT, d-cAMP, and Forskolin to activate MDDC.
      Taken together, these results show that the effects of PT and AT on MDDC are
      mediated strictly by cAMP.

PMID- 12429719
TI  - The presence of stomatin in detergent-insoluble domains of neutrophil granule
      membranes.
AB  - Neutrophil azurophil granules, traditionally regarded as the neutrophil
      counterpart to lysosomes, lack the lysosomal marker lysosome-associated membrane
      glycoprotein and have recently been suggested to be nonlysosomal secretory
      organelles. The membrane of the azurophil granules is poorly characterized-CD63
      and CD68 are the only membrane proteins identified so far. Here, azurophil
      granule membranes were isolated by Percoll gradient subcellular fractionation.
      Using matrix-assisted laser desorption ionization time of flight mass
      spectrometry of tryptic peptides from an isolated protein, stomatin was
      identified in these membranes. Using immunoelectron microscopy and immunoblot
      analysis of isolated organelles, stomatin was found to be subcellularly
      localized, not only to the azurophil granules but also by a major part to the
      specific granules and by a minor part to the secretory vesicles/plasma membrane.
      We also show the presence of detergent-insoluble, low-density membrane domains in
      the plasma membrane and the granule membranes and found stomatin to be localized
      to these domains.

PMID- 12429720
TI  - Secretion of interleukin-10 or interleukin-12 by LPS-activated dendritic cells is
      critically dependent on time of stimulus relative to initiation of purified DC
      culture.
AB  - Dendritic cells (DC) are key regulators of adaptive immunity with the potential
      to induce T cell activation/immunity or T cell suppression/tolerance. DC are
      themselves induced by "maturation" signals such as bacterial lipopolysaccharide
      (LPS). We demonstrate here that LPS can stimulate DC to display similar
      maturation phenotypes but to differentiate toward an interleukin (IL)-10(high)-
      or IL-12(high)-secretor profile depending on the timing of maturation signal
      induction. Immediate/early administration of LPS induced purified bone marrow
      derived DC (BMDC) to differentiate as IL-10(high)IL-12(low)-secreting cells,
      termed early DC (eDC). Conversely, delayed administration of LPS altered the DC
      cytokine profile to IL-10(low)IL-12(high), termed later DC (lDC). The presence of
      IL-4 enhanced the yield and maturation of BMDC but inhibited LPS-induced IL-10
      production by eDC. In contrast, interferon-gamma reduced the yield of DC but
      promoted the level of LPS-induced IL-10 production by lDC. Our data provide new
      evidence that ex vivo manipulation and the cytokine environment regulate DC
      maturation status and cytokine-secretor phenotype with implications for the
      control of T cell differentiation and function via DC-based immunotherapeutic
      strategies.

PMID- 12429721
TI  - TNF-related apoptosis-inducing ligand (TRAIL) up-regulates cyclooxygenase (COX)-1
      activity and PGE(2) production in cells of the myeloid lineage.
AB  - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) up-regulated the
      expression of constitutive cyclooxygenase (COX)-1 protein in HL-60 cells without
      affecting COX-2. The TRAIL-mediated COX-1 up-regulation was accompanied by a
      significant increase of the PGE(2) synthesis and release, which was suppressed by
      the COX-1 inhibitor valeryl salicylate but not by the COX-2 inhibitor NS-398.
      Experiments carried out by adding exogenous PGE(2) to HL-60 cells indicated that
      PGE(2) was not involved in TRAIL cytotoxicity and rather showed a dose-dependent
      protection against TRAIL-induced apoptosis. Importantly, the ability of TRAIL to
      increase PGE(2) production was also observed in normal, human CD34-derived
      myeloid cells and in freshly isolated peripheral blood CD14(+) monocytes.
      Moreover, in contrast to HL-60 cells, primary, normal cells were not susceptible
      to TRAIL cytotoxicity. These data indicate that the ability of TRAIL to up
      regulate eicosanoid production and release is not confined to malignant leukemic
      cells, but it may also play a role in normal hematopoiesis.

PMID- 12429722
TI  - IL-12-dependent nuclear factor-kappaB activation leads to de novo synthesis and
      release of IL-8 and TNF-alpha in human neutrophils.
AB  - The cytokine interleukin (IL)-12 plays a bridging role between innate and
      adaptive immunity. Here, we demonstrate that treatment of neutrophils with IL-12
      leads to a transient increase in intracellular-free calcium [Ca(+)(+)](i) levels,
      which is necessary for the production of reactive oxygen metabolites (ROM). This
      production is associated with the activation and nuclear translocation of the
      transcription factor nuclear factor (NF)-kappaB and is inhibited in the presence
      of the intracellular calcium chelator 1,2-bis(O-amminophenoxy) ethane-N,N-N',N'
      tetraacetic acid-acetoxymethyl ester and the ROM production inhibitor diphenyl
      iodonium. We show that IL-12 causes a significant increase in total mRNA levels,
      which appear dependent on the generated ROM. In addition IL-12 induces the de
      novo synthesis and production of IL-8 and tumor necrosis factor alpha (TNF-alpha)
      in a calcium- and ROM-dependent manner. Our data demonstrate a direct role for IL
      12 in the activation of human neutrophils and suggest a ROM-dependent interplay
      between IL-12-induced [Ca(+)(+)](i) transient and the release of IL-8 and TNF
      alpha through NF-kappaB activation.

PMID- 12429723
TI  - Inducible expression of an antimicrobial peptide of the innate immunity in
      polymorphonuclear leukocytes.
AB  - Epithelia- and leukocyte-associated antimicrobial peptides provide immediate
      protection against microbial infections by rapidly inactivating potential
      pathogens. Bac5 is a member of the cathelicidin family of antimicrobial peptides
      and is stored in the cytoplasmic granules of bovine neutrophils. We investigated
      the expression of this gene in airway and intestine, and although the gene was
      not found to be locally expressed in these tissues, a strong Bac5 induction
      signal was detected by in situ hybridization in neutrophils infiltrating infected
      lung, consistent with expression of this gene in activated neutrophils. The Bac5
      gene was also induced in bovine peripheral neutrophils stimulated with
      Escherichia coli or purified lipopolysaccharide (LPS) but not in other blood
      cells and in resting neutrophils. The levels of Bac5 mRNA increased at 12-24 h
      post-stimulation, and a dose-dependent increase in Bac5 expression was determined
      in the presence of increasing amounts of LPS. A metabolically labeled product
      with a molecular weight compatible with that of proBac5 was immunoprecipitated
      from cell-free media of stimulated neutrophils, suggesting that the newly
      synthesized polypeptide is released extracellularly. Collectively, these results
      provide the first evidence that fully differentiated neutrophils are capable of
      de novo synthesis and secretion of a granule-associated antimicrobial peptide.

PMID- 12429724
TI  - CpG-DNA-induced IFN-alpha production involves p38 MAPK-dependent STAT1
      phosphorylation in human plasmacytoid dendritic cell precursors.
AB  - Human plasmacytoid or CD4(+)CD11c(-) type 2 dendritic cell precursors (PDC) were
      identified as natural type I interferon (IFN)-producing cells in response to
      viral and bacterial infection. They represent effector cells of innate immunity
      and link it to the distinct adaptive immunity by differentiating into mature DC.
      It has been reported that oligodeoxyribonucleotides containing unmethylated CpG
      motifs (CpG DNA) stimulate PDC to produce IFN-alpha, but the molecular mechanisms
      involved remain unknown. We found that CpG-DNA-induced IFN-alpha production in
      PDC was completely impaired by the inhibitor of the p38 mitogen-activated protein
      kinase (MAPK) pathway. Expression of IFN regulatory factor (IRF)-7 was enhanced
      by CpG-DNA treatment, which was preceded by the phosphorylation of signal
      transducer and activator of transcription (STAT)1 on Tyr-701, as well as its
      enhanced phosphorylation on Ser-727. All of these events were also suppressed by
      the p38 MAPK inhibitor. STAT1, STAT2, and IRF-9, components of IFN-stimulated
      gene factor 3 (ISGF3), were recognized in the nuclear fraction of CpG-DNA-treated
      cells. Neither anti-IFN-alpha/beta antibodies (Ab) nor anti-IFNAR Ab suppressed
      STAT1 phosphorylation, enhancement of IRF-7 expression, or IFN-alpha production
      in the early phase of the culture. These results suggest that CpG DNA induces p38
      MAPK-dependent phosphorylation of STAT1 in a manner independent of IFN
      alpha/beta, which may cause ISGF3 formation to increase the transcription of the
      IRF-7 gene, thereby leading to IFN-alpha production in human PDC.

PMID- 12429725
TI  - Granulocyte macrophage-colony stimulating factor delays neutrophil apoptosis and
      primes its function through Ia-type phosphoinositide 3-kinase.
AB  - Phosphoinositide 3-kinases (PI3Ks) constitute a family of lipid kinases that
      regulate an array of fundamental cellular responses by neutrophils
      [polymorphonuclear leukocytes (PMN)]. p85alpha Gene-disrupted mice were used to
      help accurately identify the physiological role of the PI3K isoform in PMN
      activation in the presence of granulocyte macrophage-colony stimulating factor
      (GM-CSF). PMN from the p85alpha-/- mice showed normal cellular motility, and the
      quantity of superoxide anion (O(2(-))) produced by PMN upon stimulation with
      formyl-Met-Leu-Phe did not significantly differ between p85alpha-/- and wild-type
      mice under controlled conditions. In p85alpha-/- mice, the O(2(-)) production by
      PMN was enhanced (primed) by GM-CSF when stimulated with the chemotactic peptide
      but to a significantly lesser extent than in wild-type mice. In addition, no
      major GM-CSF-dependent delay in apoptosis or activation of Akt protein
      phosphorylation by GM-CSF was observed in the p85alpha-/- mice. In terms of
      targeting strategy, however, the mutation actually expressed a small amount of Ia
      type (p85alpha-regulated) PI3K activity (partially abrogated) in the mice. These
      results demonstrate that Ia-type PI3K plays a critical role in the enhancement of
      the GM-CSF-modulated function of PMN and in the PI3K/Akt pathway-dependent delay
      of PMN apoptosis.

PMID- 12429726
TI  - The A2A receptor mediates an endogenous regulatory pathway of cytokine expression
      in THP-1 cells.
AB  - Adenosine is an endogenous nucleoside that regulates numerous cellular functions
      including inflammation. Adenosine acts via cell-surface receptors subtyped as A1,
      A2A, A2B, and A3. The A2A receptor (A2AR) has been linked to anti-inflammatory
      effects of adenosine. Furthermore, microarray analysis revealed increased A2AR
      mRNA in lipopolysaccharide (LPS)-stimulated monocytes. We hypothesized that
      endogenous adenosine inhibited LPS-mediated tumor necrosis factor (TNF)
      production via A2AR stimulation. Using THP-1 cells, our results demonstrated that
      LPS increased expression of cellular A2AR and adenosine. A2AR agonism with 2-p-(2
      carboxyethyl)phenethylamino-5'-N-ethylcarboxamido adenosine (CGS 21680) after LPS
      decreased TNF production in a dose- and time-dependent manner, whereas A2AR
      antagonism significantly increased TNF and blocked the inhibitory effect of CGS
      21680. This inhibitory pathway involved A2AR stimulation of cyclic adenosine
      monophosphate (cAMP) to activate protein kinase A, resulting in phosphorylation
      of cAMP response element-binding protein (CREB). Phospho-CREB had been shown to
      inhibit nuclear factor-kappaB transcriptional activity, as was observed with CGS
      21680 treatment. Thus, following immune activation with LPS, endogenous adenosine
      mediates a negative feedback pathway to modulate cytokine expression in THP-1
      cells.

PMID- 12429727
TI  - Increased function and survival of IL-15-transduced human dendritic cells are
      mediated by up-regulation of IL-15Ralpha and Bcl-2.
AB  - It has been recently demonstrated that dendritic cells (DC) coincubated with
      interleukin (IL)-15 express high levels of the Bcl-2 family of proteins and
      display an increased resistance to tumor-induced apoptotic death. Here, the
      phenotype, functions, and survival of human DC transduced with adenoviral vector
      encoding the human IL-15 gene were studied. The transduction of DC with the IL-15
      gene resulted in a significant elevation of expression of CD83, CD86, and CD40
      molecules, which was blocked by anti-IL-15 monoclonal antibodies. This effect was
      also accompanied by an increased production of IL-12 and stimulated ability of DC
      to induce T cell proliferation. Furthermore, transduction of DC with the IL-15
      gene significantly increased their resistance to prostate cancer-induced
      apoptosis: Overexpression of IL-15 on DC blocked tumor-induced inhibition of Bcl
      2 expression and prolonged DC survival after coincubation with tumor cells.
      Finally, overexpression of IL-15 in DC was associated with a higher level of
      expression of IL-15 receptor alpha chain mRNA. In summary, these results suggest
      that transduction of DC with the IL-15 gene markedly stimulates DC function and
      protects them from tumor-induced apoptosis.

PMID- 12429728
TI  - IL-5-induced integrin adhesion of human eosinophils caused by ERK1/2-mediated
      activation of cPLA2.
AB  - We examined the mechanism by which interleukin (IL)-5 causes beta(2)-integrin
      adhesion of human eosinophils. IL-5 caused time-dependent activation of
      extracellular signal-regulated kinases 1 and 2 (ERK1/2) and p38alpha in
      eosinophils as detected by their phosphorylation. Preincubation of eosinophils
      with U0126, a mitogen-activated protein kinase/ERK kinase inhibitor, suppressed
      IL-5-induced activation of cytosolic phospholipase A(2) (cPLA(2)) and eosinophil
      adhesion, and p38 inhibition by SB203580 had neither effect. ERK1/2
      phosphorylation and eosinophil adhesion were blocked by inhibition of the src
      family tyrosine kinase, Janus tyrosine kinase (JAK)2, or phosphoinositide-3
      kinase (PI3K). Coimmunoprecipitation assay demonstrated that Lyn, a src-family
      tyrosine kinase, was constitutively associated with PI3K. Inhibition of src
      tyrosine kinase but not JAK2 suppressed PI3K activation. Our data suggest that IL
      5 induces beta(2)-integrin adhesion of human eosinophils by regulation of cPLA(2)
      activation caused by ERK1/2 phosphorylation. This phosphorylation results from
      activation of PI3K and protein tyrosine kinases. We also find that src-family
      tyrosine kinase, possibly Lyn, is the upstream kinase causing PI3K activation.

PMID- 12429729
TI  - Molecular profiling of the role of the NF-kappaB family of transcription factors
      during alloimmunity.
AB  - Allograft rejection involves a complex network of multiple immune regulators and
      effector mechanisms. In the current study, we focused on the role of nuclear
      factor (NF)-kappaB/Rel. Previous studies had established that deficiency of the
      p50 NF-kappaB family member prolonged allograft survival only modestly. However,
      because of its crucial role in signal transduction in inflammatory and immune
      responses, we hypothesized that other NF-kappaB/Rel family members may produce
      more profound effects on alloimmunity. Therefore, in addition to p50, we analyzed
      the role of c-Rel, which is expressed predominantly in lymphocytes. Also, to
      investigate NF-kappaB activation in T cells, we examined transgenic mice that
      express a transdominant inhibitor of NF-kappaB [IkappaB(DeltaN)] regulated by a T
      cell-restricted promoter. Allograft survival was prolonged indefinitely in the c
      Rel-deficient and IkappaB(DeltaN)-transgenic recipients. To determine the
      molecular basis of NF-kappaB modulation of rejection, we analyzed a panel of 58
      parameters including effector molecules, chemokines, cytokines, receptors, and
      cellular markers using hierarchical clustering algorithms and self-organizing
      maps in p50(-/-), c-Rel(-/-), and IkappaB(DeltaN)-transgenic, experimental groups
      plus allogeneic-, syngeneic-, and lymphocyte-deficient (alymphoid) control
      groups. Surprisingly, profiles of gene expression in the c-Rel recipients (which
      have indefinite graft survival) were similar to the p50(-/-) and allogeneic
      recipients (which rapidly reject grafts). As expected, gene expression in the
      IkappaB(DeltaN) recipients (which also have indefinite graft survival) was
      similar to profiles of nonrejecting syngeneic and alymphoid recipients.
      Importantly, self-organizing maps identified a small subset of genes including
      several chemokine receptors and cytokines with expression profiles that correlate
      with graft survival. Thus, our results demonstrate a crucial role for NF-kappaB
      in acute allograft rejection, identify different molecular mechanisms of
      rejection by distinct NF-kappaB family members, and identify a small subset of
      inducible genes whose inhibition is linked to graft acceptance.

PMID- 12429730
TI  - Multiple determinants are involved in HIV coreceptor use as demonstrated by
      CCR4/CCL22 interaction in peripheral blood mononuclear cells (PBMCs).
AB  - Although a number of chemokine receptors display coreceptor activities in vitro,
      chemokine receptor 5 (CCR5) and CXC chemokine receptor 4 (CXCR4) remain the major
      coreceptors used by the human immunodeficiency virus type 1 (HIV-1). In this
      study, we used an envelope-mediated fusion assay to demonstrate low CCR4
      coreceptor activity with some primary HIV-1 and simian immunodeficiency virus-1
      (mac316) isolates in vitro. The coreceptor activity was sensitive to CCR4
      specific antibodies and to the CCR4-specific chemokine ligand macrophage-derived
      chemokine (MDC)/chemokine ligand 22 (CCL22). Treatment of peripheral blood
      mononuclear cells (PBMCs; which express high levels of CCR4) with CCL22 caused
      down-modulation of endogenous CCR4 but had no significant effect on HIV-1 entry,
      suggesting that CCR4 may not be used as an entry coreceptor. Despite expression
      of other minor coreceptors on PBMCs, CCR5 and CXCR4 are preferentially used by
      HIV-1 isolates, as shown by chemokine-inhibition data. To determine the factors
      involved in this selective use, we analyzed CCR4 coreceptor activity and compared
      it with CCR5 use in PBMCs. We used a quantitative fluorescence-activated cell
      sorting assay to estimate the numbers of CCR4 and CCR5 antibody-binding sites
      (ABS) on PBMCs. Although CCR4 was found on a higher percentage of CD4(+) cells,
      CCR5 ABS was twofold greater than CCR4 ABS on CD4(+) cells. Confocal microscopy
      revealed strong cell-surface CD4/CCR5 but weak CD4/CCR4 colocalization in PBMCs.
      Binding studies demonstrated that soluble gp120 had greater affinity to CCR5 than
      CCR4. The results suggested that coreceptor density, colocalization with CD4, and
      affinity of the viral gp120 to the coreceptor may determine preferential
      coreceptor use by HIV-1.

PMID- 12429731
TI  - Identification of the N-linked glycosylation sites on the high density
      lipoprotein (HDL) receptor SR-BI and assessment of their effects on HDL binding
      and selective lipid uptake.
AB  - The murine class B, type I scavenger receptor mSR-BI, a high density lipoprotein
      (HDL) receptor that mediates selective uptake of HDL lipids, contains 11
      potential N-linked glycosylation sites and unknown numbers of both
      endoglycosidase H-sensitive and -resistant oligosaccharides. We have examined the
      consequences of mutating each of these sites (Asn --> Gln or Thr --> Ala) on post
      translational processing of mSR-BI, cell surface expression, and HDL binding and
      lipid transport activities. All 11 sites were glycosylated; however, disruption
      of only two (Asn-108 and Asn-173) substantially altered expression and function.
      There was very little detectable post-translational processing of these two
      mutants to endoglycosidase H resistance and very low cell surface expression,
      suggesting that oligosaccharide modification at these sites apparently plays an
      important role in endoplasmic reticulum folding and/or intracellular transport.
      Strikingly, although the low levels of the 108 and 173 mutants that were
      expressed on the cell surface exhibited a marked reduction in their ability to
      transfer lipids from HDL to cells, they nevertheless bound nearly normal amounts
      of HDL. Indeed, the affinity of (125)I-HDL binding to the 173 mutant was similar
      to that of the wild-type receptor. Thus, N-linked glycosylation can influence
      both the intracellular transport and lipid-transporter activity of SR-BI. The
      ability to uncouple the HDL binding and lipid transport activities of mSR-BI by
      in vitro mutagenesis should provide a powerful tool for further analysis of the
      mechanism of SR-BI-mediated selective lipid uptake.

PMID- 12429732
TI  - TAB1beta (transforming growth factor-beta-activated protein kinase 1-binding
      protein 1beta ), a novel splicing variant of TAB1 that interacts with p38alpha
      but not TAK1.
AB  - The mitogen-activated protein kinases (MAPKs) play an important role in a variety
      of biological processes. Activation of MAPKs is mediated by phosphorylation on
      specific regulatory tyrosine and threonine sites. We have recently found that
      activation of p38alpha MAPK can be carried out not only by its upstream MAPK
      kinases (MKKs) but also by p38alpha autophosphorylation. p38alpha autoactivation
      requires an interaction of p38alpha with TAB1 (transforming growth factor-beta
      activated protein kinase 1-binding protein 1). The autoactivation mechanism of
      p38alpha has been found to be important in cellular responses to a number of
      physiologically relevant stimuli. Here, we report the characterization of a
      splicing variant of TAB1, TAB1beta. TAB1 and TAB1beta share the first 10 exons.
      The 11th and 12th exons of TAB1 were spliced out in TAB1beta, and an extra exon,
      termed exon beta, downstream of exons 11 and 12 in the genome was used as the
      last exon in TAB1beta. The mRNA of TAB1beta was expressed in all cell lines
      examined. The TAB1beta mRNA encodes a protein with an identical sequence to TAB1
      except the C-terminal 69 amino acids were replaced with an unrelated 27-amino
      acid sequence. Similar to TAB1, TAB1beta interacts with p38alpha but not other
      MAPKs and stimulates p38alpha autoactivation. Different from TAB1, TAB1beta does
      not bind or activate TAK1. Inhibition of TAB1beta expression with RNA
      interference in MDA231 breast cancer cells resulted in the reduction of basal
      activity of p38alpha and invasiveness of MDA231 cells, suggesting that
      TauAlphaBeta1beta is involved in regulating p38alpha activity in physiological
      conditions.

PMID- 12429733
TI  - Structure of the active N-terminal domain of Ezrin. Conformational and mobility
      changes identify keystone interactions.
AB  - Ezrin is a member of the ERM (ezrin, radixin, moesin) family of proteins that
      cross-link the actin cytoskeleton to the plasma membrane and also may function in
      signaling cascades that regulate the assembly of actin stress fibers. Here, we
      report a crystal structure for the free (activated) FERM domain (residues 2-297)
      of recombinant human ezrin at 2.3 A resolution. Structural comparison among the
      dormant moesin FERM domain structure and the three known active FERM domain
      structures (radixin, moesin, and now ezrin) allows the clear definition of
      regions that undergo structural changes during activation. The key regions
      affected are residues 135-150 and 155-180 in lobe F2 and residues 210-214 and 235
      267 in lobe F3. Furthermore, we show that a large increase in the mobilities of
      lobes F2 and F3 accompanies activation, suggesting that their integrity is
      compromised. This leads us to propose a new concept that we refer to as keystone
      interactions. Keystone interactions occur when one protein (or protein part)
      contributes residues that allow another protein to complete folding, meaning that
      it becomes an integral part of the structure and would rarely dissociate. Such
      interactions are well suited for long-lived cytoskeletal protein interactions.
      The keystone interactions concept leads us to predict two specific docking sites
      within lobes F2 and F3 that are likely to bind target proteins.

PMID- 12429734
TI  - Cisplatin sensitivity in Hmbg1-/- and Hmbg1+/+ mouse cells.
AB  - The study presented here investigates the effect of HMGB1 knockout on the
      sensitivity of mouse embryonic fibroblasts treated with the anticancer drug
      cisplatin. We evaluated both the growth inhibition by cisplatin and cisplatin
      induced cell death in the Hmgb1(-/-) cells and its wild-type counterpart. No
      significant differences were observed in the responses of these cells to
      cisplatin, indicating that HMGB1 does not play a significant role in modulating
      the cellular responses to cisplatin in this context. Since HMGB1 significantly
      enhances the cytotoxicity of cisplatin in other cells, these results illustrate
      the importance of cell type in determining the ability of this and probably other
      cisplatin-DNA-binding proteins to influence the efficacy of the drug.

PMID- 12429735
TI  - Syntrophin gamma 2 regulates SCN5A gating by a PDZ domain-mediated interaction.
AB  - SCN5A encodes the alpha subunit of the cardiac muscle and intestinal smooth
      muscle mechanosensitive Na(+) channel. Mechanosensitivity in the intestine
      requires an intact cytoskeleton. We report, using laser capture microdissection,
      single cell PCR, and immunohistochemistry, that syntrophins, scaffolding
      proteins, were expressed in human intestinal smooth muscle cells. The
      distribution of syntrophin gamma 2 was similar to that of SCN5A. Yeast two-hybrid
      and glutathione S-transferase pull-down experiments show that SCN5A and
      syntrophin gamma 2 co-express and that the PDZ domain of syntrophin gamma 2
      directly interacts with the C terminus of SCN5A. In native cells, disruption of
      the C terminus-syntrophin gamma 2 PDZ domain interaction using peptides directed
      against either region result in loss of mechanosensitivity. Co-transfection of
      syntrophin gamma 2 with SCN5A in HEK293 cells markedly shifts the activation
      kinetics of SCN5A and reduces the availability of Na(+) current. We propose that
      syntrophin gamma 2 is an essential Na(+) channel-interacting protein required for
      the full expression of the Na(+) current and that the SCN5A-syntrophin gamma 2
      interaction determines mechanosensitivity and current availability.

PMID- 12429736
TI  - Embryonic expression of the luteinizing hormone beta gene appears to be coupled
      to the transient appearance of p8, a high mobility group-related transcription
      factor.
AB  - A comparison between two pituitary-derived cell lines (alpha T3-1 and L beta T2)
      that represent gonadotropes at early and late stages of development,
      respectively, was performed to further elucidate the genomic repertoire required
      for gonadotrope specification and luteinizing hormone beta (LH beta) gene
      expression. One isolated clone that displayed higher expression levels in L beta
      T2 cells encodes p8, a high mobility group-like protein with mitogenic potential
      that is up-regulated in response to proapoptotic stimuli and in some developing
      tissues. To test the functional significance of this factor in developing
      gonadotropes, a knockdown of p8 in L beta T2 cells was generated. The loss of p8
      mRNA correlated with loss of endogenous LH beta mRNA and the loss of activity of
      a transfected LH beta promoter-driven reporter, even upon treatment with
      gonadotropin-releasing hormone. In addition, expression of p8 mRNA in developing
      mouse pituitary glands mirrored its expression in the gonadotrope-derived cell
      lines and coincided with the first detectable appearance of LH beta mRNA. In
      contrast, p8 mRNA was undetectable in the pituitary glands of normal adults.
      Taken together, our data indicate that p8 is a stage-specific component of the
      gonadotrope transcriptome that may play a functional role in the initiation of LH
      beta gene expression during embryonic cellular differentiation.

PMID- 12429737
TI  - Complex formation of the interferon (IFN) consensus sequence-binding protein with
      IRF-1 is essential for murine macrophage IFN-gamma-induced iNOS gene expression.
AB  - This study describes the role of the interferon (IFN) consensus sequence-binding
      protein (ICSBP or IRF-8) in iNOS gene expression by murine macrophages. An ICSBP
      binding site in the iNOS promoter region (-923 to -913) was identified using an
      electrophoretic mobility shift assay and chromatin co-immunoprecipitation.
      Overexpression of ICSBP greatly enhanced IFN-gamma-induced iNOS promoter
      activation in RAW264.7 cells, and IFN-gamma-induced iNOS promoter activation was
      abolished in ICSBP-/- macrophages. Furthermore, transduction of retrovirus-ICSBP
      in ICSBP-/- macrophages rescued IFN-gamma-induced iNOS gene expression. However,
      transduction of retrovirus-ICSBP in the absence of IFN-gamma activation did not
      induce iNOS expression in either RAW264.7 cells or ICSBP-/- macrophages.
      Interestingly, ICSBP alone transduced into ICSBP-/- macrophages did not bind to
      IFN-stimulated response element site (-923 to -913) of the iNOS promoter region,
      although following activation with IFN-gamma, a DNA.protein complex was formed
      that contains ICSBP and IRF-1. Co-transduction of ICSBP with IRF-1 clearly
      induces nitric oxide production. In addition, interleukin-4 inhibits IFN-gamma
      induced iNOS gene expression by attenuating the physical interaction of ICSBP
      with IRF-1. Complex formation of ICSBP with IRF-1 is essential for iNOS
      expression, and interleukin-4 attenuates the physical interaction of ICSBP with
      IRF-1 resulting in the inhibition of INOS gene expression.

PMID- 12429738
TI  - Latent transforming growth factor beta-binding protein 1 interacts with fibrillin
      and is a microfibril-associated protein.
AB  - Latent transforming growth factor beta-binding protein 1 (LTBP-1) targets latent
      complexes of transforming growth factor beta to the extracellular matrix, where
      the latent cytokine is subsequently activated by several different mechanisms.
      Fibrillins are extracellular matrix macromolecules whose primary function is
      architectural: fibrillins assemble into ultrastructurally distinct microfibrils
      that are ubiquitous in the connective tissue space. LTBPs and fibrillins are
      highly homologous molecules, and colocalization in the matrix of cultured cells
      has been reported. To address whether LTBP-1 functions architecturally like
      fibrillins, microfibrils were extracted from tissues and analyzed
      immunochemically. In addition, binding studies were conducted to determine
      whether LTBP-1 interacts with fibrillins. LTBP-1 was not detected in extracted
      beaded-string microfibrils, suggesting that LTBP-1 is not an integral structural
      component of microfibrils. However, binding studies demonstrated interactions
      between LTBP-1 and fibrillins. The binding site was within three domains of the
      LTBP-1 C terminus, and in fibrillin-1 the site was defined within four domains
      near the N terminus. Immunolocalization data were consistent with the hypothesis
      that LTBP-1 is a fibrillin-associated protein present in certain tissues but not
      in others. In tissues where LTBP-1 is not expressed, LTBP-4 may substitute for
      LTBP-1, because the C-terminal end of LTBP-4 binds equally well to fibrillin. A
      model depicting the relationship between LTBP-1 and fibrillin microfibrils is
      proposed.

PMID- 12429739
TI  - Fibrillins can co-assemble in fibrils, but fibrillin fibril composition displays
      cell-specific differences.
AB  - Fibrillins are microfibril-forming extracellular matrix macromolecules that
      modulate skeletal development. In humans, mutations in fibrillins result in long
      bone overgrowth as well as other distinct phenotypes. Whether fibrillins form
      independent microfibrillar networks or can co-polymerize, forming a single
      microfibril, is not known. However, this knowledge is required to determine
      whether phenotypes arise because of loss of singular or composite functions of
      fibrillins. Immunolocalization experiments using tissues and de novo matrices
      elaborated by cultured cells demonstrated that both fibrillins can be present in
      the same individual microfibril in certain tissues and that both fibrillins can
      co-polymerize in fibroblast cultures. These studies suggest that the molecular
      information directing fibrillin fibril formation may be similar in both
      fibrillins. Furthermore, these studies provide a molecular basis for compensation
      of one fibrillin by the other during fetal life. In postnatal tissues, fibrillin
      2 antibodies demonstrated exuberant staining in only one location: peripheral
      nerves. This surprising finding implicates distinct functions for fibrillin-2 in
      peripheral nerves, because a unique feature in humans and in mice mutant for
      fibrillin-2 is joint contractures that resolve over time.

PMID- 12429740
TI  - Oncogenic Ras leads to Rho activation by activating the mitogen-activated protein
      kinase pathway and decreasing Rho-GTPase-activating protein activity.
AB  - Transformation by oncogenic Ras requires signaling through Rho family proteins
      including RhoA, but the mechanism(s) whereby oncogenic Ras regulates the activity
      of RhoA is (are) unknown. We examined the effect of Ras on RhoA activity in NIH
      3T3 cells either stably transfected with H-Ras(V12) under control of an inducible
      promoter or transiently expressing the activated H-Ras. Using a novel method to
      quantitate enzymatically the GTP bound to Rho, we found that expression of the
      oncogenic Ras increased Rho activity approximately 2-fold. Increased Rho activity
      was associated with increased plasma membrane binding of RhoA and decreased
      activity of the Rho/Ras-regulated p21(WAF1/CIP1) promoter. RhoA activation by
      oncogenic Ras could be explained by a decrease in cytosolic p190 Rho-GAP activity
      and translocation of p190 Rho-GAP from the cytosol to a detergent-insoluble
      cytoskeletal fraction. Pharmacologic inhibition of the Ras/Raf/MEK/ERK pathway
      prevented Ras-induced activation of RhoA and translocation of p190 Rho-GAP;
      expression of constitutively active Raf-1 kinase or MEK was sufficient to induce
      p190 Rho-GAP translocation. We conclude that in NIH 3T3 cells oncogenic Ras
      activates RhoA through the Raf/MEK/ERK pathway by decreasing the cytosolic
      activity and changing the subcellular localization of p190 Rho-GAP.

PMID- 12429741
TI  - Casein kinase 2 interacts with cyclin-dependent kinase 11 (CDK11) in vivo and
      phosphorylates both the RNA polymerase II carboxyl-terminal domain and CDK11 in
      vitro.
AB  - The PITSLRE protein kinases, hereafter referred to as cyclin-dependent kinase 11
      (CDK11) due to their association with cyclin L, are part of large molecular
      weight protein complexes that contain RNA polymerase II (RNAP II) as well as
      numerous transcription and RNA processing factors. Data presented here
      demonstrate that the influence of CDK11(p110) on transcription and splicing does
      not involve phosphorylation of the RNAP II carboxyl-terminal domain by
      CDK11(p110). We have isolated a DRB- and heparin-sensitive protein kinase
      activity that co-purifies with CDK11(p110) after ion exchange and affinity
      purification chromatography. This protein kinase was identified as casein kinase
      2 (CK2) by immunoblot and mass spectrometry analyses. In addition to the RNAP II
      carboxyl-terminal domain, CK2 phosphorylates the CDK11(p110) amino-terminal
      domain. These data suggest that CDK11(p110) isoforms participate in signaling
      pathways that include CK2 and that its function may help to coordinate the
      regulation of RNA transcription and processing events. Future experiments will
      determine how phosphorylation of CDK11(p110) by CK2 specifically affects RNA
      transcription and/or processing events.

PMID- 12429742
TI  - STAT5b, a Mediator of Synergism between c-Src and the Epidermal Growth Factor
      Receptor.
AB  - Overexpression of the epidermal growth factor receptor (EGFR) and its association
      with the tyrosine kinase, c-Src, is correlated with increased cellular
      proliferation and tumorigenesis. Previous studies have shown that EGFR and c-Src
      co-overexpression and association leads to the c-Src-mediated phosphorylation of
      tyrosine 845 of the EGFR and that mutation of Tyr(845) ablates epidermal growth
      factor (EGF)-induced DNA synthesis. Here, we investigate the contribution of the
      signal transducers and activators of transcription (STAT5b) in the signaling
      pathways regulated by EGFR and c-Src overexpression in human breast tumor cell
      lines as well as in a mouse fibroblast model (C3H10T1/2). We demonstrate that 1)
      activation of STAT5b by EGF requires overexpression of the EGFR, 2) co
      overexpression of c-Src alone does not result in EGF-induced activation of STAT5b
      but enhances that seen in EGFR-overexpressing cells, and 3) EGF-induced tyrosine
      phosphorylation of STAT5b requires Tyr(845) of the EGFR. Furthermore, the stable
      overexpression of a kinase-defective c-Src in the context of EGFR overexpression
      results in a decrease in the tyrosine phosphorylation of STAT5b in response to
      EGF and a more dramatic decrease in EGF-induced transcriptional activation of
      STAT5b, suggesting an integral role for c-Src in the physiological actions of
      STAT5b. Using a dominant negative STAT5b, we provide evidence that one such
      physiological action is to mediate EGF-induced DNA-synthesis. Finally, the use of
      site-specific tyrosine mutants demonstrates that EGF-induced phosphorylation of
      STAT5b involves not only tyrosine 699 of STAT5b, which is required for its
      transcriptional activation, but also three previously identified tyrosines in the
      C terminus of STAT5b (Tyr(725)/Tyr(740)/Tyr(743)).

PMID- 12429743
TI  - Tyrosine phosphorylation of I kappa B alpha activates NF kappa B through a redox
      regulated and c-Src-dependent mechanism following hypoxia/reoxygenation.
AB  - NF kappa B is a critical transcription factor involved in modulating cellular
      responses to environmental injuries. Tyrosine 42 phosphorylation of I kappa B
      alpha has been shown to mediate NF kappa B activation following
      hypoxia/reoxygenation (H/R) or pervanadate treatment. This pathway differs from
      the canonical proinflammatory pathways, which mediate NF kappa B activation
      through serine phosphorylation of I kappa B alpha by the IKK complex. In the
      present study, we investigated the involvement of c-Src in the redox activation
      of NFkappaB following H/R or pervanadate treatment. Our results demonstrate that
      pervanadate or H/R treatment leads to tyrosine phosphorylation of I kappa B alpha
      and NF kappa B transcriptional activation independent of the IKK pathway. In
      contrast, inhibition of c-Src by pp2 treatment or in c-Src (-/-) knockout cell
      lines, demonstrated a significant reduction in I kappa B alpha tyrosine
      phosphorylation and NF kappa B activation following pervanadate or H/R treatment.
      Overexpression of glutathione peroxidase-1 or catalase, but not Mn-SOD or Cu,Zn
      SOD, significantly reduced both NF kappa B activation and tyrosine
      phosphorylation of I kappa B alpha. In vitro kinase assays further demonstrated
      that immunoprecipitated c-Src has the capacity to directly phosphorylate GST-I
      kappa B alpha and that this I kappa B alpha kinase activity is significantly
      reduced by Gpx-1 overexpression. These results suggest that c-Src-dependent
      tyrosine phosphorylation of I kappa B alpha and subsequent activation of NF kappa
      B is controlled by intracellular H(2)O(2) and defines an important redox
      regulated pathway for NF kappa B activation following H/R injury that is
      independent of the IKK complex.

PMID- 12429744
TI  - PAC1 receptor activation by PACAP-38 mediates Ca2+ release from a cAMP-dependent
      pool in human fetal adrenal gland chromaffin cells.
AB  - Previous studies have shown that human fetal adrenal gland from 17- to 20-week
      old fetuses expressed pituitary adenylate cyclase-activating polypeptide (PACAP)
      receptors, which were localized on chromaffin cells. The aim of the present study
      was to identify PACAP receptor isoforms and to determine whether PACAP can affect
      intracellular calcium concentration ([Ca(2+)](i)) and catecholamine secretion.
      Using primary cultures and specific stimulation of chromaffin cells, we
      demonstrate that PACAP-38 induced an increase in [Ca(2+)](i) that was blocked by
      PACAP (6-38), was independent of external Ca(2+), and originated from
      thapsigargin-insensitive internal stores. The PACAP-triggered Ca(2+) increase was
      not affected by inhibition of PLC beta (preincubation with U-73122) or by
      pretreatment of cells with Xestospongin C, indicating that the inositol 1,4,5
      triphosphate-sensitive stores were not mobilized. However, forskolin (FSK), which
      raises cytosolic cAMP, induced an increase in Ca(2+) similar to that recorded
      with PACAP-38. Blockage of PKA by H-89 or (R(p))-cAMPS suppressed both PACAP-38
      and FSK calcium responses. The effect of PACAP-38 was also abolished by emptying
      the caffeine/ryanodine-sensitive Ca(2+) stores. Furthermore, treatment of cells
      with orthovanadate (100 microm) impaired Ca(2+) reloading of PACAP-sensitive
      stores indicating that PACAP-38 can mobilize Ca(2+) from secretory vesicles.
      Moreover, PACAP induced catecholamine secretion by chromaffin cells. It is
      concluded that PACAP-38, through the PAC(1) receptor, acts as a neurotransmitter
      in human fetal chromaffin cells inducing catecholamine secretion, through
      nonclassical, recently described, ryanodine/caffeine-sensitive pools, involving a
      cAMP- and PKA-dependent phosphorylation mechanism.

PMID- 12429745
TI  - Receptor-ligand interaction between vitellogenin receptor (VtgR) and vitellogenin
      (Vtg), implications on low density lipoprotein receptor and apolipoprotein B/E.
      The first three ligand-binding repeats of VtgR interact with the amino-terminal
      region of Vtg.
AB  - The vitellogenin receptor (VtgR) belongs to the low density lipoprotein receptor
      (LDLR) gene family. It mediates the uptake of vitellogenin (Vtg) in oocyte
      development of oviparous animals. In this study, we cloned and characterized two
      forms of Oreochromis aureus VtgR. Northern analysis showed that VtgR was
      specifically expressed in ovarian tissues. However, reverse transcription-PCR
      indicates that either there are trace levels of expression of VtgR or a homolog
      of LDLR exists in nonovarian tissues. The VtgR is highly homologous to the very
      low density lipoprotein receptor. To better understand the mechanism by which
      similar structural modules in the ligand-binding domain bind different ligands,
      we used the yeast two-hybrid system to screen for the minimal interaction motifs
      in Vtg and VtgR. The amino-terminal region of the lipovitellin I domain of Vtg
      interacts with the ligand-binding domain of VtgR. The first three ligand-binding
      repeats of the receptor were found to be essential for ligand binding.
      Computational analysis of the binding sequence indicates that Vtg has a similar
      receptor-binding region to apolipoprotein (apo) E and apoB. Site-directed
      mutagenesis of this region indicates electrostatic interaction between Vtg and
      its receptor. Sequence analysis suggests the coevolution of receptor-ligand pairs
      for the LDLR/apo superfamily and suggests that the mode of binding of LDLR/very
      low density lipoprotein receptor to apoB and apoE is inherited from the
      electrostatic attraction of VtgR and Vtg.

PMID- 12429746
TI  - Oligomerization and trafficking of the human dopamine transporter. Mutational
      analysis identifies critical domains important for the functional expression of
      the transporter.
AB  - The dopamine transporter (DAT) is a presynaptic plasma membrane protein
      responsible for the termination of dopaminergic neurotransmission in the central
      nervous system. While most studies have focused on structure/function analysis,
      much less information is available regarding the assembly and the trafficking of
      this protein. To address this problem, we performed a mutational analysis of the
      DAT protein, combined with biochemical, immunological, and functional approaches.
      In mammalian cells co-expressing differentially tagged DAT molecules, HA-tagged
      DAT co-purified with 6His-tagged DAT demonstrating a physical interaction between
      transporter proteins. Evidence for the functional oligomerization of DAT was
      obtained using dominant-negative mutants of DAT. Two loss-of-function mutant
      transporters (Y335A and D79G) that were targeted to the cell surface inhibited
      wild-type DAT uptake activity without affecting the membrane targeting of the
      wild-type transporter. Moreover, non-functional amino and carboxyl termini
      truncated mutants of DAT inhibited wild-type DAT function by interfering with the
      normal processing of the wild-type transporter to the cell membrane. Mutations in
      the leucine repeat of the second transmembrane domain of the transporter could
      eliminate the dominant-negative effect of all these mutants. In addition, a small
      fragment comprising the first two transmembrane domains of DAT inhibited wild
      type transporter function but not when the leucine repeat motif was mutated.
      Taken together, our results suggest that the assembly of DAT monomers plays a
      critical role in the expression and function of the transporter.

PMID- 12429747
TI  - Whole genome expression profiles of yeast RNA polymerase II core subunit, Rpb4,
      in stress and nonstress conditions.
AB  - Organisms respond to environmental stress by adopting changes in gene expression
      at the transcriptional level. Rpb4, a nonessential subunit of the core RNA
      polymerase II has been proposed to play a role in non-stress-specific
      transcription and in the regulation of stress response in yeast. We find that in
      addition to the temperature sensitivity of the null mutant of Rpb4, diploid null
      mutants are also compromised in sporulation and show morphological changes
      associated with nitrogen starvation. Using whole genome expression analysis, we
      report here the effects of Rpb4 on expression of genes during normal growth and
      following heat shock and nutritional starvation. Our analysis shows that Rpb4
      affects expression of a small yet significant fraction of the genome in both
      stress and normal conditions. We found that genes involved in galactose
      metabolism were dependent on the presence of Rpb4 irrespective of the
      environmental condition. Rpb4 was also found to affect the expression of several
      other genes specifically in conditions of nutritional starvation. The general
      defect in the absence of Rpb4 is in the expression of metabolic genes, especially
      those involved in carbon metabolism and energy generation. We report that various
      stresses are affected by RPB4 and that on overexpression the stress-specific
      activators can partially rescue the corresponding defects.

PMID- 12429748
TI  - Expression and activation of the BMP-signaling components in human fracture
      nonunions.
AB  - BACKGROUND: The potential use of bone morphogenetic proteins (BMPs) to promote
      bone-healing is of great interest to orthopaedic surgeons. Although the complex
      mechanism leading from the local presence of BMP (whether endogenous or
      exogenous) to bone formation is increasingly understood, limited information is
      available as to whether endogenous BMPs, their receptors, or other molecules
      involved in their signal transduction, such as Smad1, are present or disappear
      during the development of fracture nonunions. The purpose of the present study
      was to determine, by immunohistochemical analysis, whether BMPs, BMP receptors,
      or Smad1 disappear from tissues during the development of a fracture nonunion.
      METHODS: Twenty-one patients (average age, sixty-one years; range, thirty to
      eighty-five years) with a delayed union (four patients) or a nonunion (seventeen
      patients) were included. The average duration of the delayed union or nonunion
      was twenty-two months (range, 3.5 to 120 months). With use of immunohistochemical
      analysis, we studied the localization of BMP-2, BMP-4, and BMP-7 and their
      receptors BMPR-IA, BMPR-IB, and BMPR-II as well as pSmad1. With use of a pSmad1
      antibody, we also studied whether the BMP receptors that were expressed were
      activated. RESULTS: The immunohistochemical localization of all seven BMP
      signaling components was demonstrated in seventeen (81%) of the twenty-one
      patients. The remaining four patients lacked one or more of the components. Areas
      of newly formed bone had the highest percentage of positively staining cells,
      with the staining generally decreasing in areas remote from bone formation.
      However, even in areas of dense fibrous tissue and in specimens that lacked newly
      formed bone, immunostaining was still present. The staining patterns showed co
      localization of the BMP-2, BMP-4, and BMP-7 proteins with the BMP receptors. The
      presence of pSmad1 signified the activated state of the BMP receptors, which
      implies that the BMP signal is transduced inside the cell.

PMID- 12429749
TI  - Open reduction and internal fixation of three and four-part fractures of the
      proximal part of the humerus.
AB  - BACKGROUND: Controversy persists concerning the preferred treatment of displaced
      fractures of the proximal part of the humerus. The present study was undertaken
      to evaluate the results of open reduction and internal fixation of three and four
      part fractures of the proximal part of the humerus and the functional limitations
      of patients in whom avascular necrosis of the humeral head develops as a
      complication of this fracture. METHODS: We assessed the intermediate and long
      term results for sixty patients with a three or four-part fracture of the
      proximal part of the humerus who had undergone open reduction and internal
      fixation with cerclage wires or a T-plate. The Constant score and a visual analog
      score for pain were calculated, and radiographs of the proximal part of the
      humerus were evaluated. RESULTS: After an average of ten years of follow-up,
      fifty-two patients (87%) had a good or excellent result on the basis of the
      Constant score whereas eight patients (13%) had a poor result. Fifty-one patients
      (85%) were satisfied with the result at the time of the most recent examination.
      Twenty-two patients (37%) had development of avascular necrosis of the humeral
      head, and seventeen (77%) of these twenty-two patients had a good or excellent
      Constant score. CONCLUSIONS: Open reduction and internal fixation with cerclage
      wires or a T-plate yields good functional results in most patients. This option
      should be considered even for patients with fracture-dislocation patterns that
      are associated with a high risk for avascular necrosis of the humeral head, as
      this complication did not preclude a good result.

PMID- 12429750
TI  - Utilization of orthopaedic services in a capitated population.
AB  - BACKGROUND: The utilization rate for orthopaedic services (office visits and
      surgery) is not well known. The purpose of this study was to determine the
      utilization rates for orthopaedic office visits and surgical procedures in a
      large population of captured lives. METHODS: The study population comprised an
      average of 134,902 persons per month who were enrolled under a capitated
      insurance plan between January 1999 and December 1999. This plan was serviced by
      an independent physician association of sixty-two orthopaedic surgeons who were
      responsible for all orthopaedic care. Data were collected prospectively and
      stored in a centralized database. All analyses were conducted with use of monthly
      averages. Poisson regression was used to compare utilization rates and to
      calculate odds ratios in order to determine whether the utilization rates varied
      by age and gender. RESULTS: The highest proportions of office visits were due to
      fractures (21%), osteoarthritis (4%), meniscal tears (4%), and low-back pain or
      sciatica (4%). Knee arthroscopy (30%), foot and ankle procedures (10%), and spine
      procedures (9%) accounted for the highest proportions of surgical procedures. The
      overall utilization rates were 6.96 office visits and 1.99 surgical procedures
      per 1000 covered lives per month. Across all age groups, males and females did
      not differ with respect to the utilization rate for office visits (p = 0.42) or
      surgery (p = 0.09). Increased age was significantly related to increased
      utilization rates for office visits (p < or =0.0002) and surgery (p < or =
      0.002). CONCLUSIONS: These data may be used to determine the size of a capitated
      population that an orthopaedic practice can accommodate, to determine the number
      of orthopaedic providers that is needed to provide services for a capitated
      population, and to estimate the expenses associated with providing orthopaedic
      services for a capitated population in an orthopaedic practice.

PMID- 12429751
TI  - The anatomy of tibial eminence fractures: arthroscopic observations following
      failed closed reduction.
AB  - BACKGROUND: Failed manipulative reduction of avulsion fractures of the tibial
      insertion of the anterior cruciate ligament has been attributed to interposition
      of soft tissues, particularly the anterior horn of the medial meniscus. The
      objectives of the present report were (1) to show that the failure to reduce
      Meyers and McKeever type-III tibial eminence fractures was not due to
      interposition of soft tissues and (2) to discuss the relevance of the finding
      that the anterior third of the lateral meniscus was attached to the avulsed
      anterior cruciate ligament insertion site in all patients studied. METHODS:
      Twelve patients who had had a failed manipulative reduction of a type-III tibial
      eminence fracture underwent arthroscopic reduction and fixation of the avulsed
      fragment. RESULTS: A number of consistent findings were noted. The avulsed
      intercondylar eminence was displaced superiorly into the intercondylar notch.
      Attached to this fragment was not only the anterior cruciate ligament, but also,
      in all cases, the anterior horn of the lateral meniscus. The anterior third of
      the lateral meniscus had been torn from its tibial attachment and displaced
      together with the osseous fragment into the intercondylar notch. No interposition
      of bone or soft tissue was observed. Reduction of the osseous fragment was
      facilitated by traction on, or sutures passed around, the anterior horn of the
      lateral meniscus. Standard fixation methods were utilized. CONCLUSIONS: The
      concept that avulsion fractures of the tibial insertion of the anterior cruciate
      ligament cannot be reduced by manipulation because of soft-tissue interposition
      was not supported by the findings of the present study. The attachment of the
      anterior horn of the lateral meniscus to the avulsed tibial insertion of the
      anterior cruciate ligament may not be an irrelevant incidental finding. The
      observation that the displaced osseous fragment was attached simultaneously to
      the anterior cruciate ligament and to the anterior horn of the lateral meniscus,
      both pulling in different directions, may explain why type-III tibial eminence
      fractures are irreducible by manipulation.

PMID- 12429752
TI  - Pulmonary embolism following shoulder arthroplasty.
AB  - BACKGROUND: While there have been numerous reports concerning the risk of
      pulmonary embolism after knee and hip arthroplasty, no such information is
      available for shoulder arthroplasty, as far as we know. The purpose of this study
      was to determine the prevalence of pulmonary embolism following shoulder
      arthroplasty. METHODS: A review of 2885 consecutive patients who underwent
      primary shoulder arthroplasty at our institution between June 30, 1981, and June
      30, 2001, was performed to identify all patients who sustained a pulmonary
      embolism. RESULTS: During this time-period, five patients sustained a pulmonary
      embolism following shoulder arthroplasty. Three of the five presented with
      symptoms that were originally attributed to causes other than pulmonary embolism.
      None of the patients sustained a fatal pulmonary embolism. CONCLUSIONS: The data
      from this study demonstrate that pulmonary embolism is an uncommon complication
      of shoulder arthroplasty and that surgeons should have a high degree of suspicion
      if patients have respiratory difficulty following shoulder arthroplasty.

PMID- 12429753
TI  - Effect of baseline functional status and pain on outcomes of total hip
      arthroplasty.
AB  - BACKGROUND: It is unknown whether there is an optimal time for surgery-that is,
      whether waiting until a patient has greater disability results in a worse
      outcome. We examined the effect of baseline status on the outcome of total hip
      arthroplasty to determine if such a relationship existed. METHODS: All Medicare
      patients undergoing total hip arthroplasty for osteoarthritis in twelve states
      were identified by the fiscal intermediary beginning in October 1994 and
      continuing for approximately eight months; 1640 eligible patients were
      identified. Consenting patients were surveyed within two months after the
      procedure and again at twelve months after the procedure, and their medical
      records were reviewed. The baseline survey, completed by 1120 patients, included
      items regarding the level of activity, the presence and severity of pain with
      walking, the need for assistance for walking, the distance that the patient could
      walk, and whether the patient could perform Instrumental Activities of Daily
      Living (IADLs). Data on comorbid diagnoses were collected from the medical
      records. RESULTS: Patients with pain during walking at baseline were more likely
      to have pain at one year than those without pain at baseline (21% compared with
      9%; p < 0.05). Patients who needed assistance with walking at baseline were more
      likely to need assistance at one year than those who did not need assistance at
      baseline (38% compared with 15%; p < 0.01). Similar results were seen with regard
      to the need for assistance with housework (39% compared with 18%; p < 0.01) and
      grocery shopping (37% compared with 14%; p < 0.01) and, to a lesser extent, for
      overall participation in moderate activity (17% compared with 10%; p < 0.01).
      These results persisted after controlling for comorbidities in a multiple
      regression equation. However, the worse a patient's preoperative status, the more
      he or she gained in all four measures (p < 0.01). CONCLUSIONS: The findings of
      the present study suggest that the worse a patient's preoperative status, the
      more he or she may benefit from total hip arthroplasty. However, our findings
      also suggest that patients who have a worse preoperative status may not have as
      good an outcome as those who have a better preoperative status. Patients and
      physicians should consider these findings when discussing the timing of total hip
      arthroplasty.

PMID- 12429754
TI  - Late dislocation after total hip arthroplasty.
AB  - BACKGROUND: Some patients have a dislocation for the first time many years after
      a total hip arthroplasty, but little is known about the risk factors and outcomes
      associated with late dislocation. The purposes of this study were (1) to
      determine the prevalence of late dislocation after total hip arthroplasty, (2) to
      characterize demographic and other factors associated with such late
      dislocations, and (3) to report the outcomes of such late dislocations. METHODS:
      Between 1969 and 1995, 19,680 primary total hip arthroplasties were performed in
      15,964 patients at our institution. According to a prospective surveillance
      protocol, the patients were followed routinely at regular intervals and were
      specifically queried at each time-point about whether (and, if so, when) the hip
      had dislocated. First dislocations that occurred five years or more after the
      operation were defined as late dislocations. RESULTS: Five hundred and thirteen
      (2.6%) of the 19,680 hips dislocated. Of the 513 hips, 165 (0.8% of the entire
      cohort; 32% of the dislocated hips) first dislocated five or more years after the
      primary arthroplasty. The median time until the occurrence of these late
      dislocations was 11.3 years (range, five to 24.9 years) after the operation. Late
      dislocation was more frequent than early dislocation in women (p = 0.03), and
      late dislocation was associated with a younger age at the time of the primary
      total hip arthroplasty (median, sixty-three years) than was early dislocation
      (median, sixty-seven years) (p = 0.02). Clinical factors associated with late
      dislocation included previous subluxations without dislocation in twenty
      patients, a substantial episode of trauma in eleven patients, and onset of marked
      cognitive or motor neurologic impairment in eleven patients. Radiographically,
      the late dislocation occurred in association with polyethylene wear of >2 mm in
      eighteen hips, with implant loosening with migration or a change in position in
      eight, and with initial malposition of the acetabular implant (anteversion of <0
      degrees or >30 degrees or abduction of >55 degrees) in thirty. Late dislocation
      recurred in ninety (55%) of the 165 hips and was treated with a reoperation in
      fifty-five hips (33% of the hips with late dislocation; 61% of the hips with
      recurrent dislocation). CONCLUSIONS: Late dislocation is more common than was
      previously thought. Several separate processes, some distinct from those
      associated with early dislocation, can lead to late dislocation. Late dislocation
      can occur in association with a long-standing problem with the prosthesis that
      manifests late (such as malposition of the implant or recurrent subluxation), it
      can occur in association with a new problem (such as neurologic decline, an
      episode of trauma, or polyethylene wear), or it can occur in association with any
      combination of these factors. The likelihood of the first late dislocation
      recurring is high.

PMID- 12429755
TI  - A comprehensive study of patients with surgically treated lumbar spinal stenosis
      with neurogenic claudication.
AB  - BACKGROUND: The relationship between objective measurements and subjective
      symptoms of patients with spinal stenosis and the degree of narrowing of the
      spinal canal is not clear. The purpose of this study was to evaluate patients
      undergoing surgery for lumbar spinal stenosis and intermittent neurogenic
      claudication with functional testing, quantitative imaging, and patient self
      assessment. METHODS: Sixty-two patients with lumbar spinal stenosis and
      neurogenic claudication were prospectively enrolled in the study. All underwent
      preoperative magnetic resonance imaging and/or computed tomography myelography,
      and all were treated with decompressive surgery and were followed for a minimum
      of two years. The evaluation included treadmill and bicycle exercise tests as
      well as patient self-assessment with use of the Oswestry Disability Index and a
      visual analog pain scale preoperatively and postoperatively. RESULTS:
      Preoperatively fifty-eight (94%) of the patients had a positive result
      (provocation of symptoms) on the treadmill test and twenty-seven (44%) had a
      positive result on the bicycle test, whereas postoperatively six and twelve,
      respectively, had positive results. The mean preoperative scores on the Oswestry
      Disability Index and visual analog pain scale were 58.4 and 7.1, respectively.
      Postoperatively, these scores decreased to 21.1 and 2.3, respectively, and both
      decreases were significant (p < 0.05). Forty-seven (76%) of the patients were
      seen to have central stenosis on the preoperative imaging studies; forty-one of
      them had a cross-sectional area of the dural tube of <100 mm (2) at at least one
      level and twelve had a cross-sectional area of <100 mm (2) at at least two
      levels. CONCLUSIONS: A positive treadmill test was consistent with a diagnosis of
      spinal stenosis and neurogenic claudication in >90% of the patients
      preoperatively. Following surgical decompression of the lumbar spinal stenosis,
      more functional improvement was demonstrated by the treadmill test than by the
      bicycle test. The scores on the Oswestry Disability Index and visual analog pain
      scale also improved postoperatively. The severity of central canal narrowing at a
      single level does not appear to limit the postoperative improvement in either
      functional ability or patient self-assessment. Patients with multilevel central
      stenosis were, on the average, older and walked a shorter distance preoperatively
      and postoperatively, although the improvement in their postoperative self
      assessment scores was similar to that of patients with single-level stenosis.

PMID- 12429756
TI  - Anconeus arthroplasty: a new technique for reconstruction of the radiocapitellar
      and/or proximal radioulnar joint.
AB  - BACKGROUND: Management of posttraumatic radiocapitellar and/or proximal
      radioulnar joint dysfunction and pain is a challenging problem, often with more
      than one pathological feature, and to date there are no consistently reliable
      solutions. The unreliability of prosthetic replacement prompted us to develop an
      anconeus arthroplasty wherein the anconeus muscle is rotated into the
      radiocapitellar and/or proximal radioulnar joint. METHODS: Three interposition
      options were assessed in our laboratory and were employed clinically:
      interposition at the radiocapitellar joint (Type I), interposition at the
      radiocapitellar and proximal radioulnar joints (Type II), and proximal radioulnar
      interposition (wrap) (Type III). The clinical outcomes in fourteen patients who
      had been treated with one of the three types of anconeus interposition
      arthroplasty were reviewed at least two years (mean, 6.1 years) postoperatively.
      RESULTS: Anatomic dissection of twenty-five specimens revealed that all three
      applications were possible. Of the fourteen patients, twelve (all six with a Type
      I interposition, three of the five with a Type-II interposition, and all three
      with a Type-III interposition) had a satisfactory overall subjective result. The
      Mayo Elbow Performance Score averaged 63 points before the surgery and 89 points
      after it. CONCLUSIONS: Anconeus interpositional arthroplasty offers a reasonable
      likelihood of improved subjective and objective function in patients with the
      challenging problem of radiocapitellar and/or proximal radioulnar joint
      dysfunction and pain after trauma, even when there is Essex-Lopresti axial
      instability.

PMID- 12429757
TI  - Radius pull test: predictor of longitudinal forearm instability.
AB  - BACKGROUND: Longitudinal instability of the forearm (the Essex-Lopresti lesion)
      following radial head excision may be difficult to detect. This cadaveric study
      examines a stress test that can be performed in the operating room to identify
      injury to the ligamentous structures of the forearm. METHODS: Twelve cadaveric
      upper extremities were randomized into two groups and underwent radial head
      resection. Group 1 underwent sequential transection of the triangular
      fibrocartilage complex and the interosseous membrane. Group 2 underwent
      sequential transection of the interosseous membrane and the triangular
      fibrocartilage complex. Ulnar variance and radial migration were examined with
      use of fluoroscopy of the wrist before, during, and after the application of a
      9.1-kg load via longitudinal traction on the proximal part of the radius.
      RESULTS: Group 1 demonstrated no significant changes in proximal radial migration
      with load (compared with the findings after radial head resection alone) after
      transection of the triangular fibrocartilage complex. However, Group 2
      demonstrated significant changes in proximal radial migration with load after
      transection of the interosseous membrane (p = 0.03; median, 3.5 mm). In both
      groups, transection of both the triangular fibrocartilage complex and the
      interosseous membrane resulted in significant changes in proximal radial
      migration with load (p = 0.001; median, 9.5 mm). When the load was removed,
      specimens were ulnar positive (median, 3.0 mm), with no specimen returning to the
      preload position of ulnar variance (p = 0.001). CONCLUSION: After radial head
      resection, 3 mm of proximal radial migration with longitudinal traction indicated
      disruption of the interosseous membrane. In all specimens, proximal radial
      migration of > or =6 mm with load indicated gross longitudinal instability with
      disruption of all ligamentous structures of the forearm.

PMID- 12429758
TI  - Total knee arthroplasty for patellofemoral arthritis.
AB  - BACKGROUND: Multiple treatment methods have been advocated for patellofemoral
      arthritis. The purpose of the present study was to report on our experience with
      the use of total joint replacement for the treatment of primarily severe
      patellofemoral arthritis of the knee in patients more than fifty-five years of
      age. METHODS: Between January 1980 and December 1994, thirty knee replacements
      were performed in twenty-seven patients for the treatment of arthritis that
      primarily involved the patellofemoral joint. The Ahlbuck radiographic evaluation
      scale was used to grade the severity of arthritis; the mean score was 4.83 points
      (range, 4 to 5 points) for the patellofemoral compartment and 0.6 point (range, 0
      to 1 point) for both the medial and lateral compartments. The patients included
      eighteen women and nine men who had a mean age of seventy-three years (range,
      fifty-nine to eighty-eight years). None of the patients had had any prior
      procedures on the knee, but all had been treated for a minimum of six months with
      nonoperative measures. The mean preoperative Knee Society score was 50 points
      (range, 20 to 64 points). RESULTS: At a mean duration of follow-up of eighty-one
      months (range, forty-eight to 133 months), there were twenty-eight excellent, one
      good, and one poor result. The mean Knee Society objective score was 93 points
      (range, 67 to 100 points). The poor result was in a patient who sustained a
      rupture of the patellar tendon postoperatively as the result of a fall, which
      necessitated a tendon reconstruction. CONCLUSION: Total knee arthroplasty was
      found to be a viable treatment option in patients more than fifty-five years of
      age with primarily severe patellofemoral disease.

PMID- 12429759
TI  - Extracorporeal shock wave therapy in the treatment of lateral epicondylitis : a
      randomized multicenter trial.
AB  - BACKGROUND: On the basis of observational trials, numerous investigators have
      recommended extracorporeal shock wave therapy as an alternative treatment for
      chronic lateral epicondylitis of the elbow. However, there has been no evidence
      of its efficacy from well-designed randomized clinical trials. The objective of
      this study was to find out whether extracorporeal shock wave therapy in
      combination with local anesthesia was superior to placebo therapy in combination
      with local anesthesia. METHODS: A randomized multicenter trial with a parallel
      group design was conducted. Following administration of local anesthesia, either
      extracorporeal shock wave therapy with three treatments of 2000 pulses each and a
      positive energy flux density (ED+) of 0.07 to 0.09 mJ/mm (2) or placebo therapy
      was applied on an outpatient basis. Treatment allocation was blinded for patients
      and for observers. The primary end point was based on the rate of success, as
      determined with the Roles and Maudsley score and whether additional treatment was
      required, twelve weeks after the intervention. Crossover was possible after
      assessment of the primary end point. Secondary end points were the Roles and
      Maudsley score, subjective pain rating, and grip strength after six and twelve
      weeks and after twelve months. The planned number of 272 patients was included in
      the study. RESULTS: The primary end point could be assessed for 90.8% of the
      patients. The success rate was 25.8% in the group treated with extracorporeal
      shock wave therapy and 25.4% in the placebo group, a difference of 0.4% with a
      95% confidence interval of -10.5% to 11.3%. Similarly, there was no relevant
      difference between groups with regard to the secondary end points. Improvement
      was observed in two-thirds of the patients from both groups twelve months after
      the intervention. Few side effects were reported. CONCLUSIONS: Extracorporeal
      shock wave therapy as applied in the present study was ineffective in the
      treatment of lateral epicondylitis. The previously reported success of this
      therapy appears to be attributable to inappropriate study designs. Different
      application protocols might improve clinical outcome. We recommend that
      extracorporeal shock wave therapy be applied only in high-quality clinical trials
      until it is proved to be effective.

PMID- 12429761
TI  - Effect of mechanical compression on the prevalence of proximal deep venous
      thrombosis as assessed by magnetic resonance venography.
AB  - BACKGROUND: Patients have been shown to be at greater risk for deep venous
      thrombosis, particularly proximal thrombosis, after total hip arthroplasty.
      Proximal thrombi are more likely to develop into pulmonary emboli than are distal
      thrombi. The purpose of this randomized, prospective study was to compare the
      prevalence of pelvic and proximal lower-extremity deep venous thrombosis after
      primary total hip arthroplasty between patients treated with an impulse
      mechanical compression device for prophylaxis and those treated with prophylactic
      stockings. METHODS: One hundred patients were evaluated, with use of magnetic
      resonance venography, for proximal deep venous thrombosis after total hip
      arthroplasty. Fifty patients were treated with a mechanical compression device on
      both lower extremities, and the other fifty patients received only prophylactic
      stockings. Both groups of patients received hypotensive epidural anesthesia and
      325 mg of aspirin twice a day. RESULTS: Overall, proximal deep venous thrombi
      were found in 15% of the 100 patients. Of the fifty patients treated with
      mechanical compression, 8% (four) had a positive venogram. Of the fifty control
      patients, 22% (eleven) had a positive venogram (p < 0.05). However, overall the
      rate of occlusive thrombi was 6% (six) compared with an overall rate of
      nonocclusive thrombi of 9% (nine). The rate of occlusive thrombi was 2% (one of
      fifty) in the study group and 10% (five of fifty) in the control group (p =
      0.04). CONCLUSIONS: On the basis of this study, we concluded that patients
      managed with total hip arthroplasty benefit from a reduction in the rates of
      femoral and pelvic deep vein thrombosis when they are treated with hypotensive
      epidural anesthesia, mechanical compression, and aspirin and are subsequently
      assessed with magnetic resonance venography.

PMID- 12429760
TI  - Comparison of a nomogram and physician-adjusted dosage of warfarin for
      prophylaxis against deep-vein thrombosis after arthroplasty.
AB  - BACKGROUND: Warfarin is an effective agent for prophylaxis against deep-vein
      thrombosis following total hip or knee arthroplasty. However, management with
      warfarin in the postoperative setting is problematic because of the need for
      anticoagulant monitoring. We developed a nomogram for the dosing of warfarin that
      was specific for joint arthroplasty. The objective of this study was to compare
      the performance of this nomogram with that of physician-adjusted dosing of
      warfarin for patients undergoing total hip or knee arthroplasty. METHODS: The
      study involved two cohort trials. The historical control group consisted of 1024
      patients who underwent total hip or knee arthroplasty during the course of a
      clinical trial (the Post-Arthroplasty Screening Study [PASS]) in which all
      warfarin dose adjustments were made by two hematologists. The first dose of
      warfarin was given on the evening of the surgery, and the warfarin dose was
      adjusted daily on the basis of the international normalized ratio and was
      discontinued at the time of discharge from the hospital. In the PASS study, the
      dosage of warfarin was designed to prolong the international normalized ratio to
      1.7 by postoperative day 4 and to maintain it between 1.8 and 2.5 until discharge
      from the hospital. Subsequently, a warfarin nomogram was developed on the basis
      of the dose adjustments used in the PASS study, and it was used prospectively to
      manage a cohort of 729 patients undergoing total hip or knee arthroplasty. In the
      nomogram cohort, the initial dose of warfarin was given on the evening of the
      surgery. Both cohorts were followed for twelve weeks after the surgery to
      determine if any venous thromboembolic complications had developed. RESULTS: The
      nomogram cohort and the control cohort had similar daily doses of warfarin (mean,
      3.2 versus 3.3 mg) and levels of international normalized ratio on postoperative
      day 4 (mean, 1.9 versus 1.9) (p > 0.2). The average number of days to achieve an
      international normalized ratio of >1.7 was 4.0 for the nomogram cohort compared
      with 4.3 for the control cohort (p = 0.01). The percentage of days that the
      international normalized ratio was between 1.8 and 2.5 was 61% for the nomogram
      cohort and 58% for the control cohort (p < 0.01), and the percentage of days that
      the international normalized ratio was >3.0 was only 6.5% for the nomogram cohort
      and 6.0% for the control cohort (p > 0.2). Eighty-two percent of the patients
      managed with the nomogram achieved an international normalized ratio of >1.7 by
      the time of discharge from the hospital compared with 92% in the control cohort
      (p = 0.01). In the three-month follow-up period, a deep-vein thrombosis or a
      nonfatal pulmonary embolism developed in nineteen patients (2.6%; 95% confidence
      interval, 1.6% to 4.0%) in the nomogram cohort compared with fourteen patients
      (1.4%; 95% confidence interval, 0.7% to 2.3%) in the control cohort. No major
      bleeding event or fatal pulmonary embolism was observed in the patients managed
      with use of the nomogram. CONCLUSION: This study demonstrated that the
      administration of warfarin during hospitalization with use of a nomogram designed
      for the prevention of deep-vein thrombosis following total hip or knee
      arthroplasty provided effective and safe prophylaxis that was comparable with
      that provided by physician-adjusted dosing of warfarin.

PMID- 12429762
TI  - Talocalcaneal and subfibular impingement in symptomatic flatfoot in adults.
AB  - BACKGROUND: Patients with symptomatic flatfoot deformity often present with pain
      in the lateral part of the hindfoot. The cause of this pain has not been clearly
      established. Impingement between the talus and the calcaneus or between the
      calcaneus and the fibula has been suggested as a cause but has not been
      documented. METHODS: We examined the computed tomographic scans, performed with
      simulated weight-bearing, of nineteen adult patients with symptomatic flatfoot to
      determine the potential causes of pain in the lateral aspect of the foot. The
      scans were performed with use of a custom loading frame designed to simulate
      weight-bearing with the foot in a neutral position while a 75-N axial compressive
      load was applied. Four examiners independently examined the coronal images as
      well as sagittal plane reconstructions for direct (bone-on-bone contact) and
      indirect (subchondral sclerosis or cysts) evidence of (1) extra-articular contact
      between the talus and the calcaneus in the sinus tarsi and (2) contact between
      the calcaneus and the fibula. The data were compared with those from five scans
      of normal feet in neutral alignment. RESULTS: Overall, the prevalence of sinus
      tarsi impingement was 92% and the prevalence of calcaneofibular impingement was
      66% in the flatfoot group versus 0% and 5%, respectively, in the control group.
      The study patients who had calcaneofibular impingement also had sinus tarsi
      impingement. There was substantial agreement among the examiners as to whether
      impingement was present. CONCLUSIONS: There appear to be two frequently occurring
      extra-articular sources of bone impingement in the lateral aspect of the hindfoot
      in adults with symptomatic severe flatfoot deformity. The impingement in the
      lateral aspect of the hindfoot may first occur within the sinus tarsi and then
      involve the calcaneofibular region. Cyst formation and/or sclerosis in this
      region that is visible on plain radiographs or on computed tomographic scans
      performed without weight-bearing should create suspicion of impingement.

PMID- 12429763
TI  - Treatment of displaced intracapsular hip fractures with total hip arthroplasty:
      comparison of primary arthroplasty with early salvage arthroplasty after failed
      internal fixation.
AB  - BACKGROUND: Closed reduction and internal fixation is the preferred initial
      treatment for young active patients who sustain a displaced intracapsular hip
      fracture. However, there is a paucity of information on the outcome in patients
      in whom this procedure fails and who subsequently require revision to a total hip
      arthroplasty. The purpose of this study was to compare a group of patients with a
      displaced intracapsular fracture who required early salvage total hip
      arthroplasty following failure of internal fixation within the first year after
      fracture with a group treated with primary total joint replacement for treatment
      of the same type of fracture. METHODS: With use of a matched-pairs case-control
      design, a group of 107 patients, between the ages of sixty and eighty years, who
      required an early salvage total hip arthroplasty with cement following failed
      reduction and internal fixation of a displaced intracapsular hip fracture (Group
      I) was compared with an age and gender-matched group of patients who had
      undergone total hip arthroplasty with cement as the primary procedure for the
      treatment of such a fracture (Group II). RESULTS: During the first year after the
      arthroplasty, there were fifty-two early complications in thirty-nine patients in
      Group I and twenty-two complications in fourteen patients in Group II (p < 0.05).
      There were significantly more superficial infections and dislocations in Group I
      (p < 0.05). The rate of revision beyond one year was greater and the overall
      prosthetic survival rate at both five and ten years postoperatively was
      significantly worse in Group I (log-rank test, p < 0.05). The functional outcomes
      at one year and at the time of final follow-up were also significantly worse in
      Group I. CONCLUSIONS: Reduction and internal fixation will continue to be used as
      the primary treatment of displaced intracapsular fractures in many younger
      patients because of the benefits of preservation of the normal hip joint.
      However, patients should be counseled that if this method of treatment is
      unsuccessful and requires revision to a total hip arthroplasty with cement, the
      risk of early complications is higher and hip function may be poorer than if the
      arthroplasty had been performed as a primary procedure.

PMID- 12429764
TI  - Rerupture and deep infection following treatment of total Achilles tendon
      rupture.
AB  - BACKGROUND: The incidence of total Achilles tendon rupture has increased, but we
      are not aware of any reports on the incidence of reruptures or deep infections
      following treatment. The outcome after successful treatment is good, but that
      after complications has not been well documented. METHODS: A group of 409
      patients with a complete Achilles tendon rupture was treated at a university
      hospital orthopaedic unit between 1979 and 2000. Twenty-three reruptures
      (prevalence, 5.6%) and nine deep infections (prevalence, 2.2%) occurred in twenty
      nine patients. We retrospectively reviewed the records of these patients to
      determine the overall incidence of ruptures, reruptures, and deep infections and
      to record the known risk factors for these major complications. We analyzed the
      final clinical outcome for twelve patients with a rerupture and seven patients
      with a deep infection at a mean of 4.1 years after the initial treatment.
      RESULTS: The annual incidence of reruptures (per 100,000 inhabitants) increased
      from 0.25 in 1979-1990 to 1.0 in 1991-2000, and that of deep infections increased
      from 0 in the 1980s to 0.63 in the 1990s. The ratio of complications to primary
      ruptures did not change. The patients with deep infections were significantly
      older, received corticosteroid medication more often, had sustained the tendon
      injury during everyday activities more often, and had a longer delay before
      treatment than the patients with simple reruptures. At 4.1 years after the
      primary treatment, eight of twelve patients in the rerupture group had a
      satisfactory clinical outcome and the overall average isokinetic plantar flexion
      strength deficit in that group was only 10%. In contrast, two of the patients in
      the infection group had a fair clinical outcome and five had a poor outcome, and
      the average isokinetic plantar flexion strength deficit in that group was 35%.
      CONCLUSIONS: The incidence of Achilles tendon reruptures and deep infections has
      increased. The outcome is satisfactory after a simple rerupture without
      infection, but the results after a deep infection are often devastating.

PMID- 12429765
TI  - The association of lumbar disc disease with vitamin-D receptor gene polymorphism.
AB  - BACKGROUND: Although the etiology of lumbar disc disease is unknown, it has been
      suggested that a genetic factor contributes to its development. Recently, some
      genetic polymorphisms have been found to be related to clinical disorders. We
      investigated the association between vitamin-D receptor gene and estrogen
      receptor gene polymorphisms and lumbar disc disease in young adults. METHODS: The
      participants included 205 young adults (166 women and thirty-nine men) with or
      without low-back problems. A magnetic resonance imaging scan of the lumbar spine
      was performed for all subjects, and the grade of disc degeneration was
      determined, according to the four-grade classification system of Schneiderman et
      al. The presence or absence of disc herniation was also evaluated. Genomic DNA
      was extracted from peripheral blood samples. The polymorphisms of the vitamin-D
      receptor and estrogen receptor genes were detected with use of a polymerase-chain
      reaction assay. The restriction fragment length polymorphisms (RFLPs) for the
      vitamin-D receptor gene were analyzed by TaqI and ApaI restriction enzymes. XbaI
      and PvuII restriction enzymes were used for the estrogen receptor gene analysis.
      The distribution of polymorphism in subjects with disc degeneration and/or disc
      herniation was compared with that in the normal subjects. RESULTS: The allelic
      frequencies of both vitamin-D receptor gene and estrogen receptor gene
      polymorphisms were similar to those in previous analyses of Japanese subjects.
      The allelic variation in the vitamin-D receptor gene was associated with
      multilevel and severe disc degeneration and disc herniation. The Tt allele was
      found to be more frequently associated with multilevel disc disease, severe disc
      degeneration, and disc herniation than was the TT allele. No additional
      associations were found. CONCLUSIONS: This study revealed that the Tt allele of
      the vitamin-D receptor gene was more frequently associated with multilevel and
      severe disc degeneration and disc herniation than was the TT allele, pointing to
      an increased risk of disc disease at an early age in subjects with the Tt allele
      in the vitamin-D receptor gene.

PMID- 12429766
TI  - Kinematic behavior of the ankle following malleolar fracture repair in a high
      fidelity cadaver model.
AB  - BACKGROUND: Previous studies involving axially loaded ankle cadaver specimens
      undergoing a passive range of motion after fracture have demonstrated rotatory
      instability patterns consisting of excessive external rotation during plantar
      flexion. The present study was designed to expand these studies by using a model
      in which ankle motion is controlled by physiologically accurate motor forces
      generated through phasic force-couples attached to the muscle-tendon units.
      METHODS: Eight right unembalmed cadaver feet were tested in a dynamic gait
      simulator that reproduces the sagittal kinematics of the tibia while applying
      physiological muscle forces to the tendons of the major extrinsic muscles of the
      foot. Six-degrees-of-freedom kinematics of the tibia and talus were measured with
      use of a VICON motion-analysis system. The experimental conditions included all
      combinations of lateral and medial injury to reproduce the clinical
      classifications of ankle fracture. Statistical analysis was performed with
      repeated-measures analyses of variance. RESULTS: The talus of the intact ankles
      demonstrated coupled external rotation and inversion relative to the tibia as the
      ankle plantar flexed. Osteotomy of the fibula, simulating a lateral ankle
      fracture, slightly but significantly increased external rotation and inversion of
      the talus (p < 0.001), whereas disruption of either the superficial or the deep
      deltoid ligament increased talar eversion (p < 0.003) and disruption of the deep
      deltoid ligament increased internal rotation (p < 0.0001). The aberrant motions
      were corrected by repair of the injured structure. CONCLUSIONS: The predominant
      coupled rotation of the talus is external rotation associated with plantar
      flexion. Following progressive ankle destabilization, talar external rotation and
      inversion increased. CLINICAL RELEVANCE: The clinical decision-making process
      regarding the treatment of ankle fractures centers on determination of whether
      the injury is expected to result in abnormal motion, which is thought to
      predispose to the development of arthritis. The present study demonstrated a
      remarkable degree of ankle stability during stance phase even when there was
      severe disruption of medial and lateral structures. This finding suggests that a
      main determinant of clinical outcome after ankle fracture may be ankle motion
      during swing phase, when ankle stability is not augmented by the combination of
      axial loading and active motor control of motion. If swing-phase motion is
      abnormal, then the ankle may be in a vulnerable position at the point of heel
      strike.

PMID- 12429768
TI  - Compartment syndrome in a patient with familial rhabdomyolysis: a case report.

PMID- 12429767
TI  - Pulley plasty versus resection of one slip of the flexor digitorum superficialis
      after repair of both flexor tendons in zone II: a biomechanical study.
AB  - BACKGROUND: The outcome of repair of zone-II lacerations of the flexor digitorum
      superficialis and flexor digitorum profundus tendons remains suboptimal. We
      investigated the effects of two strategies to improve postoperative gliding in a
      human cadaveric hand. METHODS: The second, third, and fourth digits were
      harvested from ten fresh-frozen human cadaveric hands. Complete lacerations and
      repairs were made to the profundus and superficialis tendons at a location where
      both repair sites would pass beneath the A2 pulley with the proximal
      interphalangeal joint in 45 degrees of flexion. The gliding resistance of the
      flexor digitorum profundus tendon was measured following pulley plasty and
      following excision of one slip of the flexor digitorum superficialis. The
      breaking strength of the remaining slip of the flexor digitorum superficialis
      tendon was then measured. RESULTS: Pulley plasty and resection of one slip of the
      flexor digitorum superficialis tendon both significantly decreased gliding
      resistance compared with repair of both slips (p < 0.001). There was no
      difference in the mean gliding resistance between the pulley plasty and one-slip
      resection groups. The flexor digitorum superficialis slip was stronger after
      repair with a Becker suture (28.8 +/- 9.0 N) than after repair with a modified
      Kessler (16.4 +/- 4.5 N) or a zigzag suture (15.0 +/- 5.7 N). CONCLUSION: Both
      pulley plasty and resection of one slip of the flexor digitorum superficialis
      reduce gliding resistance after tendon repair in zone II of the hand.

PMID- 12429769
TI  - Ribbing disease: a case report, a review of the literature, and a description of
      novel treatment.

PMID- 12429770
TI  - Transfer of Paget's disease from one part of the skeleton to another as a result
      of autogenous bone-grafting: a case report.

PMID- 12429771
TI  - Achilles tendinopathy.

PMID- 12429773
TI  - Orthopaedic resident-selection criteria.

PMID- 12429774
TI  - An AOA critical issue. Medical errors in orthopaedics: practical pointers for
      prevention.

PMID- 12429775
TI  - A conservative operation for bunions. 1928.

PMID- 12429776
TI  - Orthopaedic training in the United Kingdom.

PMID- 12429777
TI  - The importance of rotational seating of radial head prostheses in achieving
      valgus stability of the elbow.

PMID- 12429778
TI  - Open reduction and internal fixation versus total hip arthroplasty for the
      treatment of acute displaced acetabular fractures.

PMID- 12429779
TI  - Patient autonomy and decisional capacity.

PMID- 12429781
TI  - Two types of therapeutic shoes were no better than usual footwear for preventing
      foot reulceration.

PMID- 12429783
TI  - Arthroplasty led to fewer failures and more complications than did internal
      fixation for displaced fractures of the femoral neck.

PMID- 12429785
TI  - The addition of a Kirschner wire to an above-the-elbow cast prevented loss of
      position in displaced fractures of the distal radius in children.

PMID- 12429786
TI  - Glossary of terms for evidence-based orthopaedics.

PMID- 12429787
TI  - What's new in orthopaedic trauma.

PMID- 12429788
TI  - Leukemic phase of B-cell lymphomas mimicking chronic lymphocytic leukemia and
      variants at presentation.
AB  - Six cases of non-Hodgkin B-cell lymphoma that mimicked either chronic lymphocytic
      leukemia (CLL) or a CLL variant at presentation are reported. The patients ranged
      from 54 to 89 years and included three females and three males. All six patients
      had prominent peripheral blood lymphocytosis at presentation; the initial
      morphologic impression was CLL in three cases, CLL/prolymphocytic leukemia (PLL)
      in two cases, and PLL in one. Five patients had bone marrow biopsies; each showed
      a lymphoid infiltrate in a focally random, interstitial, and/or diffuse pattern.
      Flow cytometric immunophenotyping showed CD20-positive B cells with surface
      immunoglobulin (Ig) light chain restriction in all six patients. The five cases
      resembling CLL or CLL/PLL had at least a subset of CD5-positive B cells, whereas
      CD5 was absent in the one case that resembled PLL. CD23 was positive in three of
      the four cases studied that resembled CLL or CLL/PLL; CD79b was positive in
      three, FMC7 was positive in two, and surface Ig and CD20 were brightly positive
      in three. A t(11;14) (q13;q32) was found in four cases that resembled CLL or
      CLL/PLL; they were subsequently diagnosed as mantle cell lymphoma. The remaining
      two cases mimicking CLL or PLL were diagnosed as lymphomas of follicle center
      origin with leukemic phase based on the presence of t(14;18) (q32;q21). Thus
      although the morphology of these six cases resembled CLL or variants, and
      immunophenotyping by flow cytometry showed overlapping features, genetic studies
      enabled distinction of these leukemic non-Hodgkin lymphoma from chronic
      lymphocytic leukemia or variants.

PMID- 12429789
TI  - Immunohistochemical comparison of p16 expression in actinic keratoses and
      squamous cell carcinomas of the skin.
AB  - There are approximately 200,000 new cases of cutaneous squamous cell carcinoma
      diagnosed each year in the United States, with between 1300 and 2300 deaths per
      year from metastatic disease. The tumor suppressor p16, encoded by the
      CDKN2/INK4a locus, has been reported mutated in >or=24% of squamous cell
      carcinomas. Mutations of the p16 gene have also been found in actinic keratoses,
      the first identifiable lesion in the continuum from normal skin to squamous cell
      carcinoma. We hypothesized that there may be an appreciable difference in
      expression of p16 between normal skin, actinic keratoses, squamous cell carcinoma
      in situ, and invasive squamous cell carcinoma. Ten actinic keratoses, 10 in situ
      squamous cell carcinomas, and 10 invasive squamous cell carcinomas were examined
      using the immunoperoxidase method with antigen retrieval for anti-p16(INK4a)
      antibody. All 10 actinic keratoses were positive for weak to moderate p16
      staining in the lower third to lower half of the epidermis (especially the basal
      keratinocytes). This staining was significant when compared with the lack of
      staining seen in normal skin controls. Twenty percent of in situ squamous cell
      carcinomas had moderate to strong staining in only the lower half to lower two
      thirds of the epidermis, whereas 70% of the in situ squamous cell carcinomas
      exhibited full-thickness p16 staining, with no staining in the dermis. Thirty
      percent of invasive squamous cell carcinomas had full-thickness staining of the
      in situ component of the lesion, and 100% of invasive squamous cell carcinomas
      exhibited moderate to strong staining of the invasive component of the lesion.
      These findings indicate correlation between the increased expression of p16
      during the progression of skin from actinic keratosis to in situ squamous cell
      carcinoma to invasive squamous cell carcinoma. These data may lend further
      support to the view of the actinic keratosis as a precursor lesion to squamous
      cell carcinoma.

PMID- 12429790
TI  - Morphologic subtyping of papillary renal cell carcinoma: correlation with
      prognosis and differential expression of MUC1 between the two subtypes.
AB  - Papillary renal cell carcinoma is now a well-established entity with distinct
      histological and cytogenetic features. A subdivision has been proposed in
      correlation with prognosis. Type 1 is the most frequent subtype and appears to
      have a better prognosis than Type 2. The subdivision is based on microscopic
      criteria. To investigate these 2 types of papillary renal cell carcinoma, we have
      compared the clinical features, ancillary factors (TNM stage, Fuhrman grade),
      survival and MUC1 expression in 25 Type 1 and 12 Type 2 papillary renal cell
      carcinomas. Type 2 tumors were significantly associated with a higher Fuhrman
      grade (Grade III frequent; P <.001). Type 2 tumors were also associated with a
      poorer prognosis than Type 1 (P <.005). Fuhrman grade was significantly
      associated with prognosis (P <.005). The type and the prognosis were not
      correlated with the TNM stage. We have shown a differential expression of MUC1
      between Type 1 and Type 2 with a polarized expression in Type 1 and a rare
      expression in Type 2. In conclusion we confirm that the morphologic sub-typing
      and Fuhrman grade are valuable factors of outcome of papillary renal cell
      carcinomas and that MUC1 immunostaining is useful in differentiating Type 1 and
      Type 2 tumors.

PMID- 12429791
TI  - Nodal CD8 positive cytotoxic T-cell lymphoma: a distinct clinicopathological
      entity.
AB  - We studied 11 cases of nodal cytotoxic T-cell lymphoma, which express the CD8+
      phenotype and cytotoxic molecules (T-cell intracellular antigen-1, granzyme B and
      perforin), to characterize the clinicopathologic spectrum of these neoplasms. The
      11 cases consisted of four men and seven women, aged 5 to 82 years (mean, 53
      years). All cases were nodal, and eight of 11 had extranodal involvement, the
      most common being in bone marrow (eight cases) and liver (six cases). The
      expression of these cytotoxic molecules has been reported in some T/natural
      killer cell lymphomas mostly involved in extranodal sites of skin, nasopharyngeal
      region, or gastrointestinal tracts, but these types of extranodal involvement
      were rare in our cases. Morphologically these lymphomas could be divided into two
      groups. One group (n = 6) showed a diffuse large cell type and massive necrosis
      or apoptosis that was accompanied by disseminated intravascular coagulation (DIC)
      or hemophagocytic syndrome (HPS) on the initial. The prognosis of this group was
      generally poor (survival = 1-19 months, median = 5 mo), and four of these six
      cases were fulminant. The other group (n = 5) showed a diffuse medium or mixed
      cell type, and the prognosis was not so poor (median survival = 17 mo). Our
      results suggest that these nodal cytotoxic T-cell lymphomas originated from
      activated cytotoxic T-cells and were highly accompanied with DIC or HPS.

PMID- 12429792
TI  - Intraoperative evaluation of sentinel lymph nodes for metastatic breast carcinoma
      by imprint cytology.
AB  - BACKGROUND: The increasing utilization of lymphatic mapping techniques for breast
      carcinoma has made intraoperative evaluation of sentinel lymph nodes attractive.
      Axillary lymph node dissection can be performed during the initial surgery if the
      sentinel lymph node is positive, potentially avoiding a second operative
      procedure. At present the optimal technique for rapid sentinel lymph node
      assessment has not been determined. Both frozen sectioning and intraoperative
      imprint cytology are used for rapid intraoperative sentinel lymph node evaluation
      at many institutions. The purpose of this study is to evaluate experience with
      imprint cytology for intraoperative evaluation of sentinel lymph nodes in
      patients with breast cancer. METHODS: A retrospective review of the
      intraoperative imprint cytology results of 678 sentinel lymph node mappings for
      breast carcinoma was performed. Sentinel nodes were evaluated intraoperatively by
      either bisecting or slicing the sentinel node into 4 mm sections. Imprints were
      made of each cut surface and stained with H&E and/or Diff-Quik. Permanent
      sections were evaluated with up to four H&E stained levels and cytokeratin
      immunohistochemistry. Intraoperative imprint cytology results were compared with
      final histologic results. RESULTS: The sensitivity of imprint cytology was 53%,
      specificity was 98%, positive predictive value was 94%, negative predictive value
      was 82% and accuracy was 84%. The sensitivity for detecting macrometastases (more
      than 2mm) was significantly better than for detecting micrometastases (<or=2 mm),
      81 versus 21%, respectively (P < 00001). CONCLUSIONS: The sensitivity and
      specificity of imprint cytology are similar to that of intraoperative frozen
      section evaluation. Imprint cytology is therefore a viable alternative to frozen
      sectioning when intraoperative evaluation is required. If sentinel lymph node
      micrometastasis is used to determine the need for further lymphadenectomy, more
      sensitive intraoperative methods will be needed to avoid a second operation.

PMID- 12429793
TI  - Idiopathic bronchiolocentric interstitial pneumonia.
AB  - The authors report 10 patients with a distinctive idiopathic bronchiolocentric
      interstitial pneumonia having some histologic similarities to hypersensitivity
      pneumonitis. Bronchiolocentric interstitial pneumonia has a marked predilection
      for women (80%) and occurs in middle age (40-50 years). Chest radiographs and
      pulmonary function tests show interstitial and restrictive lung disease, while
      the histologic appearance is that of a centrilobular inflammatory process with
      small airway fibrosis and inflammation that radiates into the interstitium of the
      distal acinus in a patchy fashion. Granulomas are not identified. At a mean
      followup of approximately 4 years in nine patients, 33% of patients were dead of
      disease and 56% had persistent or progressive disease suggesting a more
      aggressive course than hypersensitivity pneumonitis and nonspecific interstitial
      pneumonia, the two major disease processes in the differential diagnosis. Whether
      Bronchiolocentric interstitial pneumonia is a unique entity or not, the pattern
      of bronchiocentric injury to the lung in the absence of known causes and its
      clinical presentation as interstitial lung disease, warrants further
      investigation of this unusual interstitial process.

PMID- 12429794
TI  - Stromelysin-3 protein expression in invasive breast cancer: relation to
      proliferation, cell survival and patients' outcome.
AB  - Matrix metalloproteinases constitute one of the major extracellular matrix
      degrading enzymic families implicated in cancer development. Stromelysin-3 in
      particular, a member of the matrix metalloproteinases belonging to the
      stromelysins' subgroup, seems to be closely related to invasiveness and tumor
      progression. In this study, we proceeded to the evaluation of stromelysin-3
      protein's expression in paraffin sections of 133 cases of invasive breast
      carcinomas and statistically estimated its relations with known
      clinicopathological prognostic parameters and patients' survival, proliferation
      markers Ki-67 and TopoIIalpha and the antiapoptotic protein bcl-2. Presence of
      stromelysin-3 was immunodetected, in the 73% of our cases, in stromal cells (65%)
      and in epithelial tumor cells (26.26%). Stromelysin-3 epithelial positivity
      presented statistically significant correlations with TopoIIalpha and Ki-67
      proliferation indices (P =.042 and P =.031, respectively) and worse disease
      outcome through multivariate statistics (P =.014). Stromelysin-3 fibroblastic
      expression was significantly associated with nuclear grade (P =.024), ductal
      histological type (P =.037), TopoIIalpha (P =.001) and Ki-67 (P =.019), inversely
      with bcl-2 protein (P =.027) and with adverse overall survival through univariate
      analysis (P =.017). The subgroup of patients with stromelysin-3 co-expression in
      stromal and malignant epithelial cells showed statistically significant
      associations with Ki-67 and TopoIIalpha (P =.019, P <.0001, respectively), an
      inverse one with bcl-2 protein (P =.027) and furthermore with impaired survival
      (P =.002) through multivariate analysis. In conclusion, stromelysin-3 protein
      expression correlated with proliferation indices TopoIIalpha and Ki-67 and the
      anti-apoptotic protein bcl-2, data confirming stromelysin-3's contribution to
      breast cancer progression. Moreover its expression was shown to have a direct
      negative effect on patients' survival, especially in the subgroup of patients
      with simultaneous epithelial and stromal expression.

PMID- 12429795
TI  - Low-grade tubular-mucinous renal neoplasms: morphologic, immunohistochemical, and
      genetic features.
AB  - The current classification system of renal tumors is based on morphologic
      criteria, as supported by genetic findings. We present a group of previously
      unclassified tumors with similar morphologic and genetic features, suggesting a
      new entity within renal neoplasms. Seven renal tumors from five patients (ages 31
      67 years) were analyzed. All cases were stained with periodic acid-Schiff, Hale's
      colloidal iron (HCI), and Alcian blue (AB) at pH 2.5/1.0 with and without
      hyaluronidase (HA) digestion. Immunohistochemical (IHC) stains were performed for
      CK8, CK18, CK19, vimentin, villin, Tamm-Horsfall protein (THP), renal cell
      carcinoma marker (RCC), epithelial membrane antigen (EMA), ulex europaeus
      agglutinin (UEA-1), soy bean agglutinin (SBA), peanut agglutinin (PNA), and MIB
      1. Comparative genomic hybridization (CGH) and loss of heterozygosity (LOH)
      studies were performed on all cases. All tumors showed circumscribed growth, a
      tubular growth pattern with focal solid areas, no significant nuclear atypia and
      absence of necrosis, desmoplasia, or inflammation. Abundant extracellular mucin
      was present. Immunohistochemistry stains support collecting duct origin (EMA+,
      PNA+, SBA+/-, CK 8/18/19+, vimentin+/-, UEA-1-, RCC-, villin-, THP-). The
      proliferative rate was low (<1%). CGH showed multiple consistent chromosomal
      losses (-1,-4, -6, -8, -9, -13, -14, -15, -22). Clinical outcome was favorable,
      with recurrences but no known distant metastases or death of disease. These
      findings are distinct from all previously classified renal neoplasms. Our data
      suggest the presence of a unique tumor entity within tumors of probable
      collecting duct origin: tubular-mucinous renal tumors of low malignant potential.

PMID- 12429796
TI  - MAL expression in lymphoid cells: further evidence for MAL as a distinct
      molecular marker of primary mediastinal large B-cell lymphomas.
AB  - The MAL mRNA was initially identified during T-cell development and was later
      found in myelin-forming cells and certain polarized epithelial cell lines. It
      encodes a proteolipid believed to participate in membrane microdomains
      stabilization, transport machinery and signal transduction. Using a differential
      display reverse-transcription approach, we identified MAL as a distinct molecular
      marker of primary mediastinal large B-cell lymphoma compared with nonmediastinal
      diffuse large B-cell lymphomas. In the present study, we used
      immunohistochemistry to extend MAL expression analysis to normal lymphoid
      tissues; to 185 lymphomas representing most B, T, and Hodgkin lymphoma entities;
      and to the primary mediastinal large B-cell lymphoma derived B-cell line MedB-1.
      In addition, B and T cells from peripheral blood, tonsil, and spleen were
      analyzed by flow cytometry. Our results show that MAL is highly expressed in
      thymocytes, in a large percentage of peripheral CD4 T cells, and in a lower
      proportion of CD8 peripheral T cells. In the normal B-cell compartment, MAL
      expression appears to be restricted to a minor subpopulation of thymic medullary
      B cells and to occasional mature plasma cells located in the interfollicular
      areas of tonsil and lymph nodes. Among B-cell lymphomas (n = 110), MAL expression
      in tumor cells was observed in 21/33 primary mediastinal large B-cell lymphomas
      (70%) and in 3/5 plasmacytoma/myeloma, but not in all other B-cell lymphomas with
      the exception of 1/33 nonmediastinal diffuse large B-cell lymphomas. The MedB-1 B
      cell line was also MAL positive. Among T-cell neoplasms, MAL was highly expressed
      in lymphoblastic tumors (5/6), whereas mature T-cell lymphomas were essentially
      MAL negative (27/28). Among 41 Hodgkin lymphomas, 3 nodular-sclerosing cases with
      mediastinal involvement showed MAL-positive Reed Sternberg cells. In conclusion,
      this study further supports thymic B cells as the putative normal counterpart of
      primary mediastinal large B-cell lymphomas and supports MAL as a distinct
      molecular marker of this lymphoma subtype among diffuse large B-cell lymphomas.

PMID- 12429797
TI  - The utility of keratin 903 as a new prognostic marker in mass-forming-type
      intrahepatic cholangiocarcinoma.
AB  - The cytokeratins phenotype is largely preserved during neoplastic transformation
      and tumor development. We evaluated the immunoreactivity of biliary epithelial
      markers keratin 903 and cytokeratin 7 and 19 for intrahepatic cholangiocarcinoma,
      and compared the results with those for biliary dysplasia and hepatocellular
      carcinoma. Reactivity with keratin 903 was weakly expressed and increased after
      the expression of cytokeratin 7 and 19 during human intrahepatic bile duct
      development. More than 80% of cases of biliary dysplasia showed positive
      reactivity with keratin 903. Of the 30 cases of hepatocellular carcinoma, 3
      (10%), 6 (20%), and 1 (3%) showed positive reactivity with Keratin 903 and
      cytokeratin 7 and 19, respectively. Among the 73 cases of intrahepatic
      cholangiocarcinoma, 54 (74%), 66 (90%), and 61 (84%) showed positive reactivity
      with keratin 903 and cytokeratin 7 and 19, respectively. On clinicopathologic
      examination of intrahepatic cholangiocarcinomas, reduced keratin 903 reactivity
      was significantly higher in tumors with an expansive growth pattern (P <.0001),
      in those with medullary-type stromal reaction (P =.0327), in those without
      perineural invasion (P =.0001), and in those without lymph node metastasis (P
      =.0015). In addition, the reactivity with Keratin 903 was directly correlated
      with expression of cytokeratin 7 and 19 (P =.0153 and P <.0001, respectively).
      Cases showing reduced keratin 903 reactivity were characterized by a distinctive
      morphology indicating an hepatocellular carcinoma-like pattern. Multivariate
      analysis of overall survival revealed that keratin 903 reactivity was a
      significantly independent prognostic factor. In conclusion, patients with
      intrahepatic cholangiocarcinoma showing reduced keratin 903 reactivity had a
      favorable prognosis. Remarkably, the cytokeratin phenotype of intrahepatic
      cholangiocarcinoma was correlated with the morphologic appearance of intrahepatic
      cholangiocarcinoma.

PMID- 12429798
TI  - Circadian variation of topoisomerase II-alpha in human rectal crypt epithelium:
      implications for reduction of toxicity of chemotherapy.
AB  - Topoisomerase II-alpha is a target of common chemotherapeutic agents such as
      doxorubicin and etoposide, which induce DNA damage by altering the activity of
      this enzyme. We took rectal biopsies at 4-hour intervals over a 24-hour period
      (seven total) from each of 10 healthy volunteers and examined immunoperoxidase
      stained coded anti-topoisomerase II-alpha-stained sections. A significant
      circadian periodicity was seen in the number of rectal crypt epithelial cell
      nuclei that were stained (P =.01). Mean peak staining was at 7:23 a.m. +/- 45
      minutes, and the mean rate of change (difference between peak and trough
      expression) was 40%. Topoisomerase II-alpha expression in rectal epithelium has a
      significant circadian variation similar to that of tritiated thymidine
      incorporation. Although direct confirmation is needed, giving topoisomerase II
      targeted chemotherapeutic agents at the proper time of day might reduce their
      mucositis side effects.

PMID- 12429799
TI  - Use of robotic telepathology for frozen-section diagnosis: a retrospective trial
      of a telepathology system for intraoperative consultation.
AB  - Telepathology is the practice of digitizing histological or macroscopic images
      for transmission along telecommunication pathways for diagnosis, consultation, or
      continuing medical education. Previous studies have addressed static versus
      dynamic imaging in several specimen types with a wide variety of systems and
      communication pathways. The goal of this paper was to assess the validity of a
      Web-based telepathology system for frozen section consultation within the Army
      Medical Department. The system provides real-time, dynamic remote control of a
      robotic microscope over standard Internet connections. Oftentimes, a solo
      pathologist is called on to provide diagnostic services without the support of
      immediate second or expert consultation during an intraoperative consultation.
      The use of telepathology is attractive because it provides an opportunity for
      pathologists to obtain immediate consultation. For purposes of the study, 120
      consecutive frozen section cases were diagnosed at a distance using the system.
      Intraobserver agreement between the telepathology diagnosis and glass slide
      diagnosis was observed. Diagnostic agreement was 100% for a wide variety of
      specimens. This study suggests that such a system will help support pathologists
      located at distant sites.

PMID- 12429800
TI  - Topoisomerase IIalpha expression in pituitary adenomas and carcinomas:
      relationship to tumor behavior.
AB  - DNA topoisomerase IIalpha (Topo IIalpha) is a molecular and immunohistochemical
      marker that indicates proliferation rate and is the target for several
      antineoplastic agents. The present immunohistochemical study of a large series of
      surgically removed pituitary tumors was designed to assess the prognostic
      significance of Topo IIalpha expression relative to patient age, gender, tumor
      type and size, invasiveness, metastasis, MIB-1-labeling index and angiogenesis.
      Changes of Topo IIalpha expression in the tumors treated with bromocriptine and
      octreotide, a long-acting somatostatin analogue were also investigated. Topo
      IIalpha immunopositivity was detected only in the nuclei of tumor cells.
      Gonadotroph adenomas, null cell adenomas, and ACTH-producing adenomas had the
      lowest Topo IIalpha indices, whereas primary pituitary carcinomas and silent type
      3 adenomas presented the highest counts. The statistical study demonstrated no
      significant correlation between Topo IIalpha expression, patient gender, and
      vascularity. In contrast, significant negative correlation was found between Topo
      IIalpha expression and patient age. Topo IIalpha expression was significantly
      higher in invasive than noninvasive tumors. A tendency to have higher counts was
      also observed in microadenomas compared with in macroadenomas. Although Topo
      IIalpha and MIB-1 indices were similar in most tumor types, no significant
      correlation between Topo IIalpha and MIB-1-labeling indices (r =.16, P =.09) was
      found. Only non-functioning adenomas showed positive correlation (r =.41, P
      =.006) between both proliferation markers. Our results demonstrated a significant
      decrease in Topo IIalpha index in octreotide-treated, GH-producing adenomas,
      compared with untreated tumors, but no significant changes were observed in
      bromocriptine-treated, PRL-producing adenomas. The present study showed no
      significant advantage of Topo IIalpha over MIB-1 as a prognostic marker; however,
      Topo IIalpha may provide crucial information regarding selection of
      adenohypophyseal tumors responsive to antineoplastic therapy, such as invasive
      pituitary adenomas and pituitary carcinomas, which exhibit a high Topo IIalpha
      index.

PMID- 12429801
TI  - Identification of four distinct regions of allelic imbalances on chromosome 1 by
      the combined comparative genomic hybridization and microsatellite analysis on
      hepatocellular carcinoma.
AB  - Frequent chromosome 1 abnormalities detected in human hepatocellular carcinoma
      have been implicated in early genetic events of liver carcinogenesis. Recurrent
      loss of 1p with a common deleted region 1p36-p34 has been reported from
      microsatellite analysis, whereas common gain of the whole chromosome q-arm was
      described from several comparative genomic hybridization studies. The
      relationships between copy number changes and allelic status however remains
      unclear. In this study, we have conducted a simultaneous comparative genomic
      hybridization and microsatellite analysis study on chromosome 1 in 31
      hepatocellular carcinoma cases. Microsatellite analysis revealed frequent loss of
      heterozygosity on 1p at loci D1S468 (74%), D1S450 (67%), D1S2667 (65%), D1S2697
      (75%), D1S199 (52%), and D1S234 (67%) corresponded to the distal 1p36 region and
      coincided with 12 cases (86%) that presented losses on 1p by comparative genomic
      hybridization analysis. Although comparative genomic hybridization indicated a
      common deleted region of 1p36-p35 in the current series, microsatellite analysis
      has refined the smallest overlapping region (SOR) to 1p36.13-p36.22. Gain of 1q
      as revealed by comparative genomic hybridization suggested low and high-level
      gains, and cases that displayed an amplicon below the heterochromatic region 1q21
      q25. Common allelic imbalances of polymorphic markers D1S2635 (64%), D1S484
      (67%), D1S2878 (65%), D1S196 (70%), D1S249 (64%) D1S2785 (75%), D1S2842 (73%) and
      D1S2836 (74%) that corresponded to the regions 1q23.1-q24.2, 1q32.1 and 1q43-q44
      were detected. Three distinct regions of allelic imbalances were thus suggested
      on recurring 1q gain found in hepatocellular carcinoma. Furthermore,
      microsatellite analysis has enabled a mapping of common overrepresented regions
      and suggested SOR on 1q23.1-q23.3 (D1S2635-D1S2878), 1q25.1-q31.1 (D1S452
      D1S238), and 1q43 (D1S2785-D1S2842). Our current study has refined chromosome 1
      aberrations in hepatocellular carcinoma to four regions of allelic imbalances.
      The SORs delineated should provide basis for further molecular investigation in
      hepatocarcinogenesis on genes residing on these chromosomal regions.

PMID- 12429802
TI  - Clusterin expression in malignant lymphomas: a survey of 266 cases.
AB  - Clusterin expression has been reported to be characteristic of systemic
      anaplastic large cell lymphoma and usually negative in cutaneous anaplastic large
      cell lymphoma as well as other lymphoma types. We surveyed clusterin expression
      using immunohistochemical methods in 266 cases of non-Hodgkin's lymphoma and
      Hodgkin's disease to further assess the diagnostic utility of this marker.
      Clusterin immunostaining was observed in 40 of 49 (82%) systemic anaplastic large
      cell lymphomas and 12 of 29 (41%) cutaneous anaplastic large cell lymphomas.
      Clusterin also was expressed in 5 of 43 (12%) diffuse large B-cell lymphomas (4
      of 5 CD30+), 1 of 14 (7%) peripheral T-cell lymphomas, 1 of 32 (3%) cases of
      nodular sclerosis Hodgkin's disease, and 1 case of mycosis fungoides in large
      cell transformation. Clusterin was negative in all other neoplasms assessed
      including follicular lymphoma of all grades (n = 24), mantle cell lymphoma (n =
      13), marginal zone B-cell lymphoma (n = 12), precursor T-cell or B-cell
      lymphoblastic leukemia/lymphoma (n = 10), mixed cellularity Hodgkin's disease (n
      = 8), chronic lymphocytic leukemia/small lymphocytic lymphoma (n = 7), Burkitt
      lymphoma (n = 7), mycosis fungoides (n = 4), nodular lymphocyte predominant
      Hodgkin's disease (n = 3), lymphoplasmacytic lymphoma/Waldenstrom
      macroglobulinemia (n = 2), and plasmacytoma (n = 2). We conclude that clusterin
      is a marker of anaplastic large cell lymphoma and that addition of clusterin to
      antibody panels designed to distinguish systemic anaplastic large cell lymphoma
      from classical Hodgkin's disease is useful. However, clusterin is also positive
      in a substantial subset of cutaneous anaplastic large cell lymphomas, a smaller
      subset of diffuse large B-cell lymphomas, and rarely in cases of peripheral T
      cell lymphoma and nodular sclerosis Hodgkin's disease.

PMID- 12429803
TI  - Over-expression of p45(SKP2) in Kaposi's sarcoma correlates with higher tumor
      stage and extracutaneous involvement but is not directly related to p27(KIP1)
      down-regulation.
AB  - F-Box protein p45(SKP2) is the substrate-specific receptor of ubiquitin-protein
      ligase SCF/p45(SKP2) and is involved in the degradation of p27(Kip1) through the
      ubiquitin/proteasome pathway. In addition, p45(SKP2) facilitates proteolysis of
      other molecules related to the cell cycle, is frequently over-expressed in
      transformed cells, and induces S phase in quiescent cells. The aim of this study
      was to determine whether p45(SKP2) expression is altered in aggressive lesions of
      Kaposi's sarcoma and its relation to p27(KIP1)down-regulation. We performed
      immunohistochemistry using antibodies directed to p45(SKP2), p27(KIP1), and Ki67
      on paraffin blocks corresponding to 47 cases of Kaposi's sarcoma (8 macules, 10
      plaques, 12 tumors, and 15 extracutaneous lesions). p45(SKP2) nuclear over
      expression was present in all Kaposi's sarcoma stages, being significantly
      increased in skin tumors (mean +/- 95% confidence interval: 39.2 +/- 18.8) and
      extracutaneous lesions (25.8 +/- 17.3) as compared with macules (18.9 +/- 8.2)
      and plaques (29.2 +/- 12.0; P =.0199). On the other hand, Kaposi's sarcoma
      progression was associated with a decrease in p27(KIP1) expression and Ki67
      immunoreactivity was independent of disease stage. No statistically significant
      differences were found in regard to patients' sex and human immunodeficiency
      virus status and regression analysis failed to show a correlation among
      p45(SKP2), p27(KIP1) and Ki67 immunostaining scores. These findings suggest that
      p45(SKP2) is involved in Kaposi's sarcoma progression, not only by promoting the
      degradation of p27(KIP1) but also through other mechanisms still unknown.

PMID- 12429804
TI  - Correspondence re: Gal AA, Velasquez A. Antineutrophil cytoplasmic autoantibody
      in the absence of Wegener's granulomatosis or microscopic polyangiitis:
      implications for the surgical pathologist. Mod Pathol 2002;15:197-204.

PMID- 12429806
TI  - Assessment of epidermal barrier function by photoacoustic spectrometry in
      relation to its importance in the pathogenesis of atopic dermatitis.
AB  - With the use of the photoacoustic spectrometry system, in which a mixture of
      lipid- and water-soluble dyes is applied to the skin and then irradiated with
      light from a xenon lamp (425 nm and 550 nm), we measured photoacoustic signals of
      both dyes within the stratum corneum and their disappearance rate through the
      stratum corneum. The signal intensity was higher and dyes penetrated faster in
      clinically normal skin of patients with atopic dermatitis (AD) compared with
      healthy subjects, indicating an impairment of the in vivo cutaneous permeability
      barrier function against both lipophilic and hydrophilic chemicals. Furthermore,
      penetration rates of the hydrophilic dyes tended to increase in proportion to the
      severity of AD and significantly correlated with serum IgE levels in the severe
      AD group. Thus, abnormal barrier functions of clinically normal skin in AD may
      predispose inflammatory processes evoked by irritants and allergens, especially
      their water-soluble elements.

PMID- 12429807
TI  - Gene array identification of Epstein Barr virus-regulated cellular genes in EBV
      converted Burkitt lymphoma cell lines.
AB  - Epstein Barr virus (EBV) is associated with various B-cell neoplasms such as post
      transplant lymphoproliferative disease or Burkitt lymphoma. B-lymphocyte
      reprogramming by EBV involves the control of numerous cellular genes. To identify
      such EBV-deregulated genes, we have compared the gene expression profile of EBV
      negative Burkitt lymphoma cell lines (BL) (BL2, BL30, BL70) with their EBV
      converted counterpart (BL2-B95, BL30-B95, BL70-B95) by cDNA array. Statistical
      analysis of the results was made using Ward's cluster analysis method. Results
      showed that the expression of up to 26% of the 1176 cellular genes analyzed may
      be modified in EBV-converted BL cells. Within this set of genes, a subset of
      genes markedly regulated in EBV-converted BL cells was defined as those for which
      expression in EBV+ cells was increased or decreased more than 2-fold. Expression
      of various genes was modulated in agreement with their previously reported
      regulation by EBV or by transcription factors activated by EBV. Numerous genes
      were newly identified as modulated in EBV-converted BL cells. Some of these
      results were verified by both semiquantitative RT-PCR and Western blotting, and
      were consistent with functional studies. Functional classification of EBV
      regulated genes gave a comprehensive picture of cellular reprogramming by EBV in
      BL, by pointing out cellular modules such as cell cycle, apoptosis, and signal
      transduction pathways, including BCR and TNF receptor family and interferon
      pathways. Furthermore, and perhaps most importantly, cDNA array results point to
      three families of transcription factors, Rel/NF-kappaB, STAT1, and Ets-related
      proteins Spi-B, Elf-1, and Ets-1 as putative cellular targets of EBV.

PMID- 12429808
TI  - The stem cell factor-c-kit system and mast cells in human pancreatic cancer.
AB  - Stem cell factor (SCF) and its receptor c-kit take part in the regulation of
      developmental processes of mast cells, hematopoietic stem cells, and melanocytes,
      as well as in the growth control of human malignancies. To explore the possible
      role of the SCF-c-kit system and of mast cells in pancreatic cancer, the
      concomitant expression and distribution of the two molecules were examined in 17
      normal and 26 cancerous human pancreatic tissues and in 6 cultured pancreatic
      cancer cell lines. Mast cell distribution was also evaluated in the same tissue
      samples. In addition, the effects of SCF and of the c-kit tyrosine-kinase
      inhibitor STI571 on the growth of the cancer cell lines and of the normal
      pancreatic ductal cell line TAKA-1 were assessed. SCF immunoreactivity was absent
      in acinar, ductal, and islet cells of the normal pancreas and faint in pancreatic
      cancer tissues and cell lines. In contrast, c-kit was clearly present in some
      normal and hyperplastic ducts of the normal pancreas, in the cancer cells of 73%
      of the tumor samples, and in all the cell lines tested. Mast cells, identified by
      tryptase and chymase immunostaining on consecutive tissue sections, showed
      immunoreactivity for SCF and c-kit in both normal and cancerous specimens and
      their number was significantly increased (p = 0.03) in pancreatic cancer compared
      with the normal pancreas. SCF showed a dose-dependent growth inhibitory effect on
      TAKA-1 cells (p < 0.001), whereas pancreatic cancer cells were resistant to the
      SCF-induced growth inhibition. Nonetheless, the growth of TAKA-1 cells and
      pancreatic cancer cells was inhibited by the c-kit tyrosine kinase inhibitor
      STI571. In conclusion, the SCF-c-kit system, possibly with the contribution of
      mast cells, may have a growth-regulating role in the normal pancreas, which is
      altered during malignant transformation.

PMID- 12429809
TI  - Vascular cell adhesion molecule-1 is a key adhesion molecule in melanoma cell
      adhesion to the leptomeninges.
AB  - Leptomeningeal metastases occur in up to 8% of patients with systemic
      malignancies and have a poor prognosis. A better understanding of the
      pathophysiologic processes underlying leptomeningeal metastases is needed for
      more effective treatment strategies. We hypothesized that tumor cells will have
      to adhere to the well-vascularized leptomeninges, because the cerebrospinal fluid
      lacks nutrients and growth factors for efficient tumor cell proliferation.
      Specific receptor-ligand interactions, which are unknown until now, will mediate
      this adhesion process. We determined the growth characteristics of B16F-10
      melanoma cells in cerebrospinal fluid. The expression levels of specific adhesion
      molecules on both mouse leptomeningeal cells (MLMC) and murine B16F-10 melanoma
      cells were measured by immunofluorescence flow cytometry. We used mAbs to
      determine the function of these specific adhesion molecules on B16F-10 melanoma
      cell adhesion to a leptomeningeal cell layer under static and (cerebrospinal
      fluid-like) flow conditions. B16F-10 melanoma cells did not proliferate in
      cerebrospinal fluid because of a lack of nutrients and growth factors. MLMC
      expressed low levels of vascular cell adhesion molecule-1 (VCAM-1), intercellular
      adhesion molecule-1 (ICAM-1), beta1- and beta3-integrin subunits, and CD44. VCAM
      1 expression on MLMC was shown to be up-regulated by TNF-alpha. Blocking VCAM-1
      on the MLMC with a mAb resulted in a 60% inhibition of melanoma cell adhesion to
      a leptomeningeal cell layer under flow but not under static conditions. No
      additive inhibitory effect on melanoma cell adhesion was found by concomitant
      blocking of the beta1- and beta3-integrin subunits and CD44 with mAbs. Our
      experiments indicate that cerebrospinal fluid does not support B16F-10 melanoma
      cell proliferation, suggesting the need for melanoma cell adhesion to the well
      vascularized leptomeninges. VCAM-1, expressed on MLMC, is an important mediator
      of in vitro melanoma cell adhesion under (cerebrospinal fluid-like) flow
      conditions.

PMID- 12429810
TI  - Wound healing involves induction of cyclooxygenase-2 expression in rat skin.
AB  - Cyclooxygenase (COX), an enzyme essential for prostaglandin biosynthesis, has two
      isoforms, COX-1 and -2. We investigated temporal and spatial changes in
      localization of these two COX proteins and mRNAs after excisional injury in rat
      skin. We also quantified the expression of these proteins and studied the effects
      of a specific COX-2 inhibitor on healing. Immunohistochemistry and in situ
      hybridization respectively indicated that the COX-2 protein and mRNA were
      expressed mainly within the basal layer of the epidermis, peripheral cells in the
      outer root sheath of hair follicles, and fibroblast-like cells and capillaries
      near epidermal wound edges. Much less intense expression was observed in normal
      skin than in injured skin. Western analysis demonstrated marked induction of COX
      2 protein beginning within 12 hours and peaking 3 days after injury. In contrast,
      localization of COX-1 protein and mRNA, as well as the amount of protein
      expression, showed no significant change during wound healing. Administration of
      the COX-2 inhibitor delayed re-epithelialization in the early phase of wound
      healing and also inhibited angiogenesis. Thus, COX-2 induction may be important
      in cutaneous wound healing.

PMID- 12429811
TI  - Differential expression of beta-galactoside alpha2,6 sialyltransferase and
      sialoglycans in normal and cirrhotic liver and hepatocellular carcinoma.
AB  - SUMMARY: Sialyltransferases sialylate plasma glycoproteins in hepatocytes and may
      (as hepatic key enzymes) constitute markers for liver diseases. We examined
      expression of the prevalent alpha2,6 sialyltransferase (ST6Gal I) and
      sialoglycans in normal liver, cirrhotic liver, and hepatocellular carcinoma (HCC)
      using a new ST6Gal I-specific mAb and recombinant fusion proteins of CD22 and
      sialoadhesin recognizing alpha2,6- or alpha2,3-sialylated glycans in
      immunohistology and flow cytometry. In normal and cirrhotic liver, ST6Gal I and
      sialoglycans were localized in the Golgi region of hepatocytes surrounding the
      bile canaliculi and along the bile canaliculi, respectively. Sialoglycans were
      additionally recognized in Kupffer cells, bile ducts, endothelial cells, and oval
      cells. Well-differentiated and moderately differentiated HCC showed Golgi and
      diffuse cytoplasmic staining of ST6Gal I and sialoglycans, whereas the
      cytoplasmic staining for ST6Gal I and sialoglycans was decreased or even absent
      in poorly differentiated HCC. Detection of sialoglycans by the recombinant fusion
      proteins in Western blots of cell lysates derived from cell lines revealed two
      major double bands of sialoglycoproteins at 65 and 120 kDa for hepatocytes, three
      major bands at 54, 49, and 44 kDa for colonic epithelial cells, and one band at
      60 kDa for endothelial cells. Our results describe the expression patterns of
      ST6Gal I and sialoglycans in various liver tissues and demonstrate an altered
      expression of these structures between benign and malignant hepatocellular
      lesions.

PMID- 12429812
TI  - Cytogenetic alterations and cytokeratin expression patterns in breast cancer:
      integrating a new model of breast differentiation into cytogenetic pathways of
      breast carcinogenesis.
AB  - The introduction of a concept proposing multiple cellular subgroups in the normal
      female breast, including cytokeratin 5/6 (Ck 5/6)-positive progenitor cells,
      offers a new explanation for the existence of highly aggressive breast cancers
      with and without Ck 5/6 expression. Using the tissue microarray technique, 166
      breast cancer cases, all characterized by comparative genomic hybridization, were
      evaluated by immunohistochemistry, using 15 different antibodies (estrogen
      receptor, progesterone receptor, p53, Ki-67, c-erbB2, epidermal growth factor
      receptor, cyclins A, D1, and E, bcl-2, p21, p27, Ck 5/6, Ck 8/18, and smooth
      muscle actin) and chromogenic in situ hybridization for c-erbB2. Biomathematical
      cluster analysis was applied to confirm the conventional interpretation of the
      results by an independent approach. Ck 5/6-positive breast carcinomas were in
      general negative for estrogen receptor and progesterone receptor, were highly
      proliferating (as reflected by Ki67 and cyclin A), and were associated with
      specific protein expression patterns, such as expression of p53 and epithelial
      growth factor receptor (all related to more aggressive tumor behavior), which
      could further be demonstrated by biomathematical cluster analysis. In contrast Ck
      5/6-negative breast carcinomas revealed a lower tumor proliferation rate, an
      increased expression of p21, p27, c-erbB2, and bcl-2, and a significantly lower
      number of genetic alterations, with losses of chromosomal material of 16q as the
      most common genetic alteration. Our data give the first hints to the hypothesis
      that different cellular subgroups in the female breast give rise to subgroups of
      breast carcinomas with differing protein expression and cytogenetic alteration
      patterns that may be related to clinical behavior.

PMID- 12429813
TI  - Airway obstruction correlates with collagenase-2 (MMP-8) expression and
      activation in bronchial asthma.
AB  - Matrix metalloproteinases (MMPs) contribute to extracellular matrix and basement
      membrane degradation in asthma. The present study analyzed molecular forms and
      degree of activation and expression of MMP-8 in bronchoalveolar lavage fluid
      (BALF), BALF cells, and bronchial tissue specimens from 14 steroid-naive asthma
      patients, 13 uncontrolled severe asthma patients, 13 controlled asthma patients,
      and 14 healthy subjects by Western immunoblotting, immunohistochemistry, and in
      situ hybridization. Immunohistochemistry and in situ hybridization revealed a
      prominent MMP-8 immunoreactivity in submucosal inflammatory, glandular, and shed,
      but not in intact bronchial epithelial cells of asthma patients. In BALF
      cytospins, both MMP-8 protein and mRNA expression were observed in epithelial
      cells, macrophages, and polymorphonuclear leukocytes (PMNs). MMP-8 was present in
      BALFs asthma patients in complex, pro- and active PMN-type, and pro- and active
      non-PMN-type forms. BALF MMP-8 was significantly converted to active form only in
      BALFs from steroid-naive and uncontrolled severe asthma patients, but not in
      BALFs from well-controlled asthma patients or healthy controls. A significant
      inverse correlation between BALF MMP-8 levels and FEV1 (r = -0.283, p = 0.04),
      and BALF activated MMP-8 forms and FEV1 (r = -0.427, p = 0.001) was detected.
      Overall, these data suggest that MMP-8 and its activation has an important role
      in the airway destruction, healing, remodeling, and treatment response in asthma.

PMID- 12429814
TI  - Selective down-regulation of aquaporin-1 in salivary glands in primary Sjogren's
      syndrome.
AB  - Salivary and lacrimal gland secretions are reduced in primary Sjogren's syndrome
      (pSS). Aquaporins (AQPs) are involved in transmembrane water transport, and
      different isoforms show specific cellular and subcellular distributions in
      salivary and lacrimal glands. Changes in expression of AQP molecules have
      therefore been suggested to contribute to the glandular dysfunction in pSS. AQP-5
      is present in the apical membrane of acinar cells, where it mediates fluid
      outflow; however, we have recently shown that its expression is not altered in
      pSS. We therefore studied whether expression of other isoforms of AQP would be
      altered in pSS. Using high-resolution confocal microscopy, we determined the
      distribution of AQP-1 and AQP-3 in labial salivary gland biopsies from 11
      patients with pSS and 9 healthy controls. AQP-1 is present in myoepithelial cells
      surrounding acini, and its expression in these cells was decreased by 38% in pSS
      glands. By contrast, expression of AQP-1 in endothelial cells of nonfenestrated
      capillaries was not altered in pSS. AQP-3 was expressed in the basolateral
      membrane of acinar epithelial cells, and its expression was not altered in
      disease. We therefore conclude that AQP-1 expression in myoepithelial cells is
      selectively down-regulated in pSS and that myoepithelial cell dysfunction may
      play a crucial role in the pathology of this disease.

PMID- 12429815
TI  - Histologic-genetic mapping by allele-specific PCR reveals intraurothelial spread
      of p53 mutant tumor clones.
AB  - Common and clinically important features of urothelial carcinomas are
      multifocality and a high rate of recurrence. Molecular studies demonstrated that
      multifocal tumors are frequently composed of one tumor clone spreading throughout
      the urothelial tract. A combination of histologic and genetic mapping of
      cystectomy specimens from bladder cancer patients is a valuable tool to study
      bladder carcinogenesis and tumor cell spread by correlating urothelial
      morphologic features and defined genetic alterations. In the present study, the
      primary tumors of 14 cystectomy specimens were investigated for p53 protein
      overexpression by immunohistochemistry and p53 gene mutation by genomic
      sequencing. Seven tumors showed a strong nuclear staining for the p53 protein. In
      six of seven tumors, a p53 gene mutation was detected. Allele-specific PCR of
      defined p53 mutations was established in five of six cases with a p53 mutation.
      Subsequent screening of the entire urothelial lining of each cystectomy specimen
      by allele-specific PCR revealed p53-mutant cell clones in urothelial patches with
      carcinoma in situ and dysplasia, but also frequently in histomorphologically
      normal urothelium adjacent to the tumor. The pattern of tumor cell spread
      indicated a continuous intraurothelial growth of the p53-mutant clone. P53
      immunohistochemistry visually confirmed the presence of mutant cells in most of
      these samples. We conclude that allele-specific PCR is a highly sensitive and
      reliable method for tracking specific p53 mutant clones in the urothelium.
      Moreover, the detection of p53-mutant cells in histologically normal or
      preneoplastic urothelial areas in four patients with invasive bladder cancer
      indicates an extensive intraurothelial tumor cell spread. The excellent
      correlation of immunohistochemically positive urothelial patches with the
      presence of a specific mutation highlights the biologic significance of p53
      positive cells in the urothelium of tumor patients.

PMID- 12429816
TI  - Combined noninvasive imaging and luminometric quantification of luciferase
      labeled human prostate tumors and metastases.
AB  - Noninvasive imaging should facilitate the analysis of changes in experimental
      tumors and metastases-expressing photoproteins and result in improved data
      consistency and experimental animal welfare. We analyzed quantitative aspects of
      noninvasive imaging of luciferase-labeled tumors by comparing the efficiency of
      noninvasive light detection with in vitro quantification of luciferase activity.
      An intensified charge coupled device video camera was used to noninvasively image
      luciferase-expressing human prostate tumors and metastases in nude mice, after ip
      inoculation of luciferin. Repeated imaging of anesthetized animals after
      intervening growth periods allowed monitoring of tumor and metastases
      development. Comparison of photon events recorded in tumor images with the number
      of relative light units from luminometric quantification of homogenates from the
      same tumors, revealed that the efficiency with which light escapes tumors is
      inversely related to tumor size and that intensified charge coupled device images
      alone are not sufficient for quantitative evaluation of tumor growth. However, a
      combined videometric and luminometric approach did allow quantification and was
      used to show the cytostatic effects of paclitaxel in three different human
      prostate tumors growing in nude mice.

PMID- 12429817
TI  - Cloning and characterization of a novel six-transmembrane protein STEAP2,
      expressed in normal and malignant prostate.
AB  - By using subtraction and cDNA array hybridizations, we recently identified an
      anonymous transcript that was differentially expressed in benign prostate
      hyperplasia and prostate cancer cell line PC-3. Here, we report the cloning of
      the full-length cDNA of the gene, designated STEAP2 (six-transmembrane epithelial
      antigen of the prostate 2). The gene is located at the chromosomal region 7q21
      and encodes for a 490-amino acid protein with six predicted transmembrane domains
      and is predominantly expressed in prostate epithelial cells. Green fluorescent
      protein fusion construct indicated that the STEAP2 protein is localized mainly in
      the plasma membrane. Real-time quantitative RT-PCR showed that the gene is
      expressed at levels more than 10 times higher in normal prostate than in other
      tissues studied. Of the prostate cancer cell lines, STEAP2 was expressed in
      significant levels only in androgen-responsive LNCaP. The expression of STEAP2
      was significantly higher (p = 0.002) in both untreated primary and hormone
      refractory prostate carcinomas than in benign prostate hyperplasias, suggesting
      that it may be involved in the development of prostate cancer. As a cell-surface
      antigen, STEAP2 is a potential diagnostic or therapeutic target in prostate
      cancer.

PMID- 12429818
TI  - Gelatin zymography and substrate cleavage assays of matrix metalloproteinase-2 in
      breast carcinoma cells overexpressing membrane type-1 matrix metalloproteinase.
AB  - Gelatin zymography is the common method for examining matrix metalloproteinase-2
      (MMP-2) in cells and media samples. Activation of the latent MMP-2 zymogen
      involves its binding to the cell surface MT1-MMP*TIMP-2 (membrane type-1 matrix
      metalloproteinase/tissue inhibitor of matrix metalloproteinase-2) complex with
      subsequent cleavage of proMMP-2 by TIMP-2-free adjacent MT1-MMP. This is followed
      by autolytic maturation of the activation intermediate and the release of the
      mature MMP-2 species from cell surfaces into the extracellular milieu. To observe
      the MMP-2 activation pathway in more detail, proMMP-2-deficient MCF7 breast
      carcinoma cells expressing MT1-MMP were incubated with excess proMMP-2 to
      saturate the available MT1-MMP*TIMP-2 surface receptors. After removal of the
      unbound material, the kinetics of proMMP-2 activation and MMP-2 release from
      cells into media was monitored by gelatin zymography and substrate cleavage. Our
      observations demonstrate that gelatin zymography is insufficient for providing
      meaningful information about the status of MMP-2. The proteolytically competent
      mature MMP-2 moiety alone, but not in its complex with TIMP-2, was released from
      the cells. In tissue culture conditions, the enzyme's proteolytic activity was
      suppressed in the next 30 to 60 minutes by tissue inhibitors of MMPs, especially
      by TIMP-1. The picture emerges that there is a likely temporal regulation of MMP
      2 activity by TIMPs in tumor cells. These relatively rapid changes of the MMP-2
      status cannot be detected by gelatin zymography. Additional studies are needed to
      examine the significance of this phenomenon in vivo.

PMID- 12429819
TI  - Pattern of somatic androgen receptor gene mutations in patients with hormone
      refractory prostate cancer.
AB  - Progression to hormone-refractory growth of prostate cancer has been suggested to
      be mediated by androgen receptor (AR) gene alterations. We analyzed AR for
      mutations and amplifications in 21 locally recurrent prostate carcinomas treated
      with orchiectomy, estrogens, or a combination of orchiectomy and estramustine
      phosphate using fluorescence in situ hybridization, single-strand conformation
      polymorphism, and DNA sequence analyses. Amplification was observed in 4 of 16
      (25%) and amino acid changing mutations was observed in 7 of 21 (33%) of the
      tumors, respectively. Two (50%) tumors with AR amplification also had missense
      mutation of the gene. Four of five (80%) cancers that were treated with a
      combination of orchiectomy and estramustine phosphate had a mutation clustered at
      codons 514 to 533 in the N-terminal domain of AR. In functional studies, these
      mutations did not render AR more sensitive to testosterone, dihydrotestosterone,
      androstenedione, or beta-estradiol. Tumors treated by orchiectomy had mutations
      predominantly in the ligand-binding domain. In summary, we found molecular
      alterations of AR in more than half of the prostate carcinomas that recurred
      locally. Some tumors developed both aberrations, possibly enhancing the cancer
      cell to respond efficiently to low levels of androgens. Furthermore, localization
      of point mutations in AR seems to be influenced by the type of treatment.

PMID- 12429820
TI  - Expression of SHP-1 phosphatase indicates post-germinal center cell derivation of
      B-cell posttransplant lymphoproliferative disorders.
AB  - SHP-1 tyrosine phosphatase acts as a negative regulator of signaling by receptors
      for growth factors, cytokines, and chemokines and by receptors involved in immune
      response. Our recent study showed that SHP-1 is tightly regulated at various
      stages of B-cell differentiation and is expressed in the mantle and marginal
      zones, interfollicular B cells, and plasma cells, whereas it is nondetectable in
      germinal center cells. In this study we evaluated expression of SHP-1 in vitro
      and in vivo in nine cell lines representing three different types of EBV+ B-cell
      populations closely resembling or derived from posttransplant lymphoproliferative
      disorders (PTLDs). Furthermore, we examined tissue samples from 58 patients with
      B-cell PTLDs, both EBV+ (85% of the cases analyzed) and EBV- (15%). SHP-1 protein
      was strongly expressed in all cell lines and PTLD cases. In addition, the PTLD
      cases were essentially negative for germinal center B-cell markers: none
      expressed CD10 and only one expressed BCL-6. More than 40% expressed a late post
      germinal B-cell marker, CD138. The universal expression of SHP-1, lack of
      expression of CD10 and BCL-6, and frequent expression of CD138 suggest that PTLDs
      are derived from post-germinal center B cells regardless of the EBV cell
      infection status. Based on the immunophenotype, B-cell PTLDs could be divided
      into two broad categories corresponding to the early (CD10-/BCL-6-/SHP-1+/CD138-)
      and late (CD10-/BCL-6-/SHP-1+/CD138+) post-germinal center cells. By being
      expressed earlier, SHP-1 is a more sensitive marker of post-germinal center B
      cells than CD138, which is seen on the terminally differentiated immunoblasts and
      plasma cells.

PMID- 12429821
TI  - Analysis of gelatinases in complex biological fluids and tissue extracts.

PMID- 12429822
TI  - CASP, the alternatively spliced product of the gene encoding the CCAAT
      displacement protein transcription factor, is a Golgi membrane protein related to
      giantin.
AB  - Large coiled-coil proteins are being found in increasing numbers on the membranes
      of the Golgi apparatus and have been proposed to function in tethering of
      transport vesicles and in the organization of the Golgi stack. Members of one
      class of Golgi coiled-coil protein, comprising giantin and golgin-84, are
      anchored to the bilayer by a single C-terminal transmembrane domain (TMD). In
      this article, we report the characterization of another mammalian coiled-coil
      protein, CASP, that was originally identified as an alternatively spliced product
      of the CUTL1 gene that encodes CCAAT-displacement protein (CDP), the human
      homologue of the Drosophila homeodomain protein Cut. We find that the
      Caenorhabditis elegans homologues of CDP and CASP are also generated from a
      single gene. CASP lacks the DNA binding motifs of CDP and was previously reported
      to be a nuclear protein. Herein, we show that it is in fact a Golgi protein with
      a C-terminal TMD and shares with giantin and golgin-84 a conserved histidine in
      its TMD. However, unlike these proteins, CASP has a homologue in Saccharomyces
      cerevisiae, which we call COY1. Deletion of COY1 does not affect viability, but
      strikingly restores normal growth to cells lacking the Golgi soluble N
      ethylmaleimide-sensitive factor attachment protein receptor Gos1p. The conserved
      histidine is necessary for Coy1p's activity in cells lacking Gos1p, suggesting
      that the TMD of these transmembrane Golgi coiled-coil proteins is directly
      involved in their function.

PMID- 12429823
TI  - Cotranslational partitioning of nascent prion protein into multiple populations
      at the translocation channel.
AB  - The decisive events that direct a single polypeptide such as the prion protein
      (PrP) to be synthesized at the endoplasmic reticulum in both fully translocated
      and transmembrane forms are poorly understood. In this study, we demonstrate that
      the topological heterogeneity of PrP is determined cotranslationally, while at
      the translocation channel. By evaluating sequential intermediates during PrP
      topogenesis, we find that signal sequence-mediated initiation of translocation
      results in an interaction between nascent PrP and endoplasmic reticulum
      chaperones, committing the N terminus to the lumen. Synthesis of the
      transmembrane domain before completion of this step allows it to direct the
      generation of (Ctm)PrP, a transmembrane form with its N terminus in the cytosol.
      Thus, segregation of nascent PrP into different topological configurations is
      critically dependent on the precise timing of signal-mediated initiation of N
      terminus translocation. Consequently, this step could be experimentally tuned to
      modify PrP topogenesis, including complete reversal of the elevated (Ctm)PrP
      caused by disease-associated mutations in the transmembrane domain. These results
      delineate the sequence of events involved in PrP biogenesis, explain the
      mechanism of action of (Ctm)PrP-favoring mutations associated with
      neurodegenerative disease, and more generally, reveal that translocation
      substrates can be cotranslationally partitioned into multiple populations at the
      translocon.

PMID- 12429824
TI  - Stage-specific requirement of a mitogen-activated protein kinase by Trypanosoma
      brucei.
AB  - In cycling between the mammalian host and the tsetse fly vector, African
      trypanosomes undergo adaptive differentiation steps that are coupled to growth
      control. The signaling pathways underlying these cellular processes are largely
      unknown. Mitogen-activated protein kinases (MAPKs) are known mediators of growth
      and differentiation in other eukaryotic organisms. To establish the function of a
      MAPK homologue, TbMAPK2, in T. brucei, a null mutant was constructed. Bloodstream
      forms of a deltamapk2/deltamapk2 clone were able to grow normally and exhibited
      no detectable phenotype. When these cells were triggered to differentiate in
      vitro, however, they developed to the procyclic (fly midgut) form with delayed
      kinetics and subsequently underwent cell cycle arrest. Introduction of an ectopic
      copy of the TbMAPK2 gene into the null mutant restored its ability to
      differentiate and to divide. In contrast, a TbMAPK2 mutant, in which the T190 and
      Y192 residues of the activating phosphorylation site were replaced by A and F,
      was unable to restore the growth and differentiation phenotypes. Analysis of the
      DNA content and the nucleus/kinetoplast configuration of individual cells showed
      that the null mutant was arrested in all phases of the cell cycle and that 25-30%
      of the cells had failed to segregate their nucleus and kinetoplast correctly.
      This implies that cell cycle progression by the procyclic form depends on a
      constitutive stimulus exerted by the signaling cascade operating through TbMAPK2.

PMID- 12429825
TI  - The intracellular pH-regulatory HCO3-/Cl- exchanger in the mouse oocyte is
      inactivated during first meiotic metaphase and reactivated after egg activation
      via the MAP kinase pathway.
AB  - The HCO(3)(-)/Cl(-) exchanger is quiescent in the unfertilized mouse egg but is
      highly active in regulating intracellular pH in the early embryo and required for
      normal development. We show here that the HCO(3)(-)/Cl(-) exchanger is active in
      first meiotic prophase (GV) oocyte but inactivated during meiotic metaphase
      before the MI to MII transition. Reactivation does not occur until the activated
      egg enters interphase. A quiescent HCO(3)(-)/Cl(-) exchanger is not simply a
      general feature of metaphase, because activity did not decrease during first
      mitotic metaphase. Inactivation of the HCO(3)(-)/Cl(-) exchanger during MI
      coincided with the activation of MAP kinase (MAPK), whereas its reactivation
      coincided with the loss of MAPK activity after egg activation. Maintaining high
      MAPK activity after egg activation prevented the normal reactivation of the
      HCO(3)(-)/Cl(-) exchanger. Inactivating MAPK in unfertilized MII eggs resulted in
      HCO(3)(-)/Cl(-) exchanger activation. Preventing MAPK activation during first
      meiotic metaphase prevented the inactivation of HCO(3)(-)/Cl(-) exchange.
      Conversely, activating MAPK in the GV oocyte resulted in inactivation of HCO(3)(
      )/Cl(-) exchange. These results imply that the HCO(3)(-)/Cl(-) exchanger in mouse
      oocytes is negatively regulated by MAPK. Thus, suppression of pH-regulatory
      mechanisms during meiosis is a novel function of MAPK and cytostatic factor
      activity in the oocyte.

PMID- 12429826
TI  - The two ADF-H domains of twinfilin play functionally distinct roles in
      interactions with actin monomers.
AB  - Twinfilin is a ubiquitous and abundant actin monomer-binding protein that is
      composed of two ADF-H domains. To elucidate the role of twinfilin in actin
      dynamics, we examined the interactions of mouse twinfilin and its isolated ADF-H
      domains with G-actin. Wild-type twinfilin binds ADP-G-actin with higher affinity
      (K(D) = 0.05 microM) than ATP-G-actin (K(D) = 0.47 microM) under physiological
      ionic conditions and forms a relatively stable (k(off) = 1.8 s(-1)) complex with
      ADP-G-actin. Data from native PAGE and size exclusion chromatography coupled with
      light scattering suggest that twinfilin competes with ADF/cofilin for the high
      affinity binding site on actin monomers, although at higher concentrations,
      twinfilin, cofilin, and actin may also form a ternary complex. By systematic
      deletion analysis, we show that the actin-binding activity is located entirely in
      the two ADF-H domains of twinfilin. Individually, these domains compete for the
      same binding site on actin, but the C-terminal ADF-H domain, which has >10-fold
      higher affinity for ADP-G-actin, is almost entirely responsible for the ability
      of twinfilin to increase the amount of monomeric actin in cosedimentation assays.
      Isolated ADF-H domains associate with ADP-G-actin with rapid second-order
      kinetics, whereas the association of wild-type twinfilin with G-actin exhibits
      kinetics consistent with a two-step binding process. These data suggest that the
      association with an actin monomer induces a first-order conformational change
      within the twinfilin molecule. On the basis of these results, we propose a
      kinetic model for the role of twinfilin in actin dynamics and its possible
      function in cells.

PMID- 12429827
TI  - Nucleocytoplasmic distribution of human RNA-editing enzyme ADAR1 is modulated by
      double-stranded RNA-binding domains, a leucine-rich export signal, and a putative
      dimerization domain.
AB  - The human RNA-editing enzyme adenosine deaminase that acts on RNA (ADAR1) is
      expressed in two versions. A longer 150-kDa protein is interferon inducible and
      can be found both in the nucleus and cytoplasm. An amino-terminally truncated 110
      kDa version, in contrast, is constitutively expressed and predominantly nuclear.
      In the absence of transcription, however, the shorter protein is also cytoplasmic
      and thus displays the hallmarks of a shuttling protein. The nuclear localization
      signal (NLS) of human hsADAR1 is atypical and overlaps with its third double
      stranded RNA-binding domain (dsRBD). Herein, we identify regions in hsADAR1 that
      interfere with nuclear localization and mediate cytoplasmic accumulation. We show
      that interferon-inducible hsADAR1 contains a Crm1-dependent nuclear export signal
      in its amino terminus. Most importantly, we demonstrate that the first dsRBD of
      hsADAR1 interferes with nuclear localization of a reporter construct containing
      dsRBD3 as an active NLS. The same effect can be triggered by several other, but
      not all dsRBDs. Active RNA binding of either the inhibitory dsRBD1 or the NLS
      bearing dsRBD3 is required for cytoplasmic accumulation. Furthermore, hsADAR1's
      dsRBD1 has no effect on other NLSs, suggesting RNA-mediated cross talk between
      dsRBDs, possibly leading to masking of the NLS. A model, incorporating these
      findings is presented. Finally, we identify a third region located in the C
      terminus of hsADAR1 that also interferes with nuclear accumulation of this
      protein.

PMID- 12429828
TI  - An algal nucleus-encoded subunit of mitochondrial ATP synthase rescues a defect
      in the analogous human mitochondrial-encoded subunit.
AB  - Unlike most organisms, the mitochondrial DNA (mtDNA) of Chlamydomonas
      reinhardtii, a green alga, does not encode subunit 6 of F(0)F(1)-ATP synthase. We
      hypothesized that C. reinhardtii ATPase 6 is nucleus encoded and identified cDNAs
      and a single-copy nuclear gene specifying this subunit (CrATP6, with eight exons,
      four of which encode a mitochondrial targeting signal). Although the algal and
      human ATP6 genes are in different subcellular compartments and the encoded
      polypeptides are highly diverged, their secondary structures are remarkably
      similar. When CrATP6 was expressed in human cells, a significant amount of the
      precursor polypeptide was targeted to mitochondria, the mitochondrial targeting
      signal was cleaved within the organelle, and the mature polypeptide was assembled
      into human ATP synthase. In spite of the evolutionary distance between algae and
      mammals, C. reinhardtii ATPase 6 functioned in human cells, because deficiencies
      in both cell viability and ATP synthesis in transmitochondrial cell lines
      harboring a pathogenic mutation in the human mtDNA-encoded ATP6 gene were
      overcome by expression of CrATP6. The ability to express a nucleus-encoded
      version of a mammalian mtDNA-encoded protein may provide a way to import other
      highly hydrophobic proteins into mitochondria and could serve as the basis for a
      gene therapy approach to treat human mitochondrial diseases.

PMID- 12429829
TI  - Dynamics of the alpha6beta4 integrin in keratinocytes.
AB  - The integrin alpha6beta4 has been implicated in two apparently contrasting
      processes, i.e., the formation of stable adhesions, and cell migration and
      invasion. To study the dynamic properties of alpha6beta4 in live cells two
      different beta4-chimeras were stably expressed in beta4-deficient PA-JEB
      keratinocytes. One chimera consisted of full-length beta4 fused to EGFP at its
      carboxy terminus (beta4-EGFP). In a second chimera the extracellular part of
      beta4 was replaced by EGFP (EGFP-beta4), thereby rendering it incapable of
      associating with alpha6 and thus of binding to laminin-5. Both chimeras induce
      the formation of hemidesmosome-like structures, which contain plectin and often
      also BP180 and BP230. During cell migration and division, the beta4-EGFP and EGFP
      beta4 hemidesmosomes disappear, and a proportion of the beta4-EGFP, but not of
      the EGFP-beta4 molecules, become part of retraction fibers, which are
      occasionally ripped from the cell membrane, thereby leaving "footprints" of the
      migrating cell. PA-JEB cells expressing beta4-EGFP migrate considerably more
      slowly than those that express EGFP-beta4. Studies with a beta4-EGFP mutant that
      is unable to interact with plectin and thus with the cytoskeleton (beta4(R1281W)
      EGFP) suggest that the stabilization of the interaction between alpha6beta4 and
      LN-5, rather than the increased adhesion to LN-5, is responsible for the
      inhibition of migration. Consistent with this, photobleaching and recovery
      experiments revealed that the interaction of beta4 with plectin renders the bond
      between alpha6beta4 and laminin-5 more stable, i.e., beta4-EGFP is less dynamic
      than beta4(R1281W)-EGFP. On the other hand, when alpha6beta4 is bound to laminin
      5, the binding dynamics of beta4 to plectin are increased, i.e., beta4-EGFP is
      more dynamic than EGFP-beta4. We suggest that the stability of the interaction
      between alpha6beta4 and laminin-5 is influenced by the clustering of alpha6beta4
      through the deposition of laminin-5 underneath the cells. This clustering
      ultimately determines whether alpha6beta4 will inhibit cell migration or not.

PMID- 12429830
TI  - Epsilon-tubulin is an essential component of the centriole.
AB  - Centrioles and basal bodies are cylinders composed of nine triplet microtubule
      blades that play essential roles in the centrosome and in flagellar assembly.
      Chlamydomonas cells with the bld2-1 mutation fail to assemble doublet and triplet
      microtubules and have defects in cleavage furrow placement and meiosis. Using
      positional cloning, we have walked 720 kb and identified a 13.2-kb fragment that
      contains epsilon-tubulin and rescues the Bld2 defects. The bld2-1 allele has a
      premature stop codon and intragenic revertants replace the stop codon with
      glutamine, glutamate, or lysine. Polyclonal antibodies to epsilon-tubulin show
      peripheral labeling of full-length basal bodies and centrioles. Thus, epsilon
      tubulin is encoded by the BLD2 allele and epsilon-tubulin plays a role in basal
      body/centriole morphogenesis.

PMID- 12429831
TI  - Identification of a novel type of cGMP phosphodiesterase that is defective in the
      chemotactic stmF mutants.
AB  - StmF mutants are chemotactic mutants that are defective in a cGMP
      phosphodiesterase (PDE) activity. We identified a novel gene, PdeD, that harbors
      two cyclic nucleotide-binding domains and a metallo-beta-lactamase homology
      domain. Similar to stmF mutants, pdeD-null mutants displayed extensively
      streaming aggregates, prolonged elevation of cGMP levels after chemotactic
      stimulation, and reduced cGMP-PDE activity. PdeD transcripts were lacking in stmF
      mutant NP377, indicating that this mutant carries a PdeD lesion. Expression of a
      PdeD-YFP fusion protein in pdeD-null cells restored the normal cGMP response and
      showed that PdeD resides in the cytosol. When purified by immunoprecipitation,
      the PdeD-YFP fusion protein displayed cGMP-PDE activity, which was retained in a
      truncated construct that contained only the metallo-beta-lactamase domain.

PMID- 12429832
TI  - Identification and characterization of two unusual cGMP-stimulated
      phoshodiesterases in dictyostelium.
AB  - Recently, we recognized two genes, gbpA and gbpB, encoding putative cGMP-binding
      proteins with a Zn(2+)-hydrolase domain and two cyclic nucleotide binding
      domains. The Zn(2+)-hydrolase domains belong to the superfamily of beta
      lactamases, also harboring a small family of class II phosphodiesterases from
      bacteria and lower eukaryotes. Gene inactivation and overexpression studies
      demonstrate that gbpA encodes the cGMP-stimulated cGMP-phosphodiesterase that was
      characterized biochemically previously and was shown to be involved in
      chemotaxis. cAMP neither activates nor is a substrate of GbpA. The gbpB gene is
      expressed mainly in the multicellular stage and seems to encode a dual
      specificity phosphodiesterase with preference for cAMP. The enzyme hydrolyses
      cAMP approximately 9-fold faster than cGMP and is activated by cAMP and cGMP with
      a K(A) value of approximately 0.7 and 2.3 microM, respectively. Cells with a
      deletion of the gbpB gene have increased basal and receptor stimulated cAMP
      levels and are sporogeneous. We propose that GbpA and GbpB hydrolyze the
      substrate in the Zn(2+)-hydrolase domain, whereas the cyclic nucleotide binding
      domains mediate activation. The human cGMP-stimulated cAMP/cGMP phosphodiesterase
      has similar biochemical properties, but a completely different topology:
      hydrolysis takes place by a class I catalytic domain and GAF domains mediate cGMP
      activation.

PMID- 12429833
TI  - Meiotic cohesion requires accumulation of ORD on chromosomes before condensation.
AB  - Cohesion between sister chromatids is a prerequisite for accurate chromosome
      segregation during mitosis and meiosis. To allow chromosome condensation during
      prophase, the connections that hold sister chromatids together must be maintained
      but still permit extensive chromatin compaction. In Drosophila, null mutations in
      the orientation disruptor (ord) gene lead to meiotic nondisjunction in males and
      females because cohesion is absent by the time that sister kinetochores make
      stable microtubule attachments. We provide evidence that ORD is concentrated
      within the extrachromosomal domains of the nuclei of Drosophila primary
      spermatocytes during early G2, but accumulates on the meiotic chromosomes by mid
      to late G2. Moreover, using fluorescence in situ hybridization to monitor
      cohesion directly, we show that cohesion defects first become detectable in
      ord(null) spermatocytes shortly after the time when wild-type ORD associates with
      the chromosomes. After condensation, ORD remains bound at the centromeres of wild
      type spermatocytes and persists there until centromeric cohesion is released
      during anaphase II. Our results suggest that association of ORD with meiotic
      chromosomes during mid to late G2 is required to maintain sister-chromatid
      cohesion during prophase condensation and that retention of ORD at the
      centromeres after condensation ensures the maintenance of centromeric cohesion
      until anaphase II.

PMID- 12429834
TI  - Ammonia pulses and metabolic oscillations guide yeast colony development.
AB  - On solid substrate, growing yeast colonies alternately acidify and alkalinize the
      medium. Using morphological, cytochemical, genetic, and DNA microarray
      approaches, we characterized six temporal steps in the "acid-to-alkali" colony
      transition. This transition is connected with the production of volatile ammonia
      acting as starvation signal between colonies. We present evidence that the three
      membrane proteins Ato1p, Ato2p, and Ato3p, members of the YaaH family, are
      involved in ammonia production in Saccharomyces cerevisiae colonies. The acid-to
      alkali transition is connected with decrease of mitochondrial oxidative
      catabolism and by peroxisome activation, which in parallel with activation of
      biosynthetic pathways contribute to decrease the general stress level in
      colonies. These metabolic features characterize a novel survival strategy used by
      yeast under starvation conditions prevalent in nature.

PMID- 12429835
TI  - Modulation of fibroblast morphology and adhesion during collagen matrix
      remodeling.
AB  - When fibroblasts are placed within a three-dimensional collagen matrix, cell
      locomotion results in translocation of the flexible collagen fibrils of the
      matrix, a remodeling process that has been implicated in matrix morphogenesis
      during development and wound repair. In the current experiments, we studied
      formation and maturation of cell-matrix interactions under conditions in which we
      could distinguish local from global matrix remodeling. Local remodeling was
      measured by the movement of collagen-embedded beads towards the cells. Global
      remodeling was measured by matrix contraction. Our observations show that no
      direct relationship occurs between protrusion and retraction of cell extensions
      and collagen matrix remodeling. As fibroblasts globally remodel the collagen
      matrix, however, their overall morphology changes from dendritic to
      stellate/bipolar, and cell-matrix interactions mature from punctate to focal
      adhesion organization. The less well organized sites of cell-matrix interaction
      are sufficient for translocating collagen fibrils, and focal adhesions only form
      after a high degree of global remodeling occurs in the presence of growth
      factors. Rho kinase activity is required for maturation of fibroblast morphology
      and formation of focal adhesions but not for translocation of collagen fibrils.

PMID- 12429836
TI  - Phospholipase D2 is localized to the rims of the Golgi apparatus in mammalian
      cells.
AB  - Phospholipase D (PLD) hydrolyzes phosphatidylcholine to generate phosphatidic
      acid, a molecule known to have multiple physiological roles, including release of
      nascent secretory vesicles from the trans-Golgi network. In mammalian cells two
      forms of the enzyme, PLD1 and PLD2, have been described. We recently demonstrated
      that PLD1 is localized to the Golgi apparatus, nuclei, and to a lesser extent,
      plasma membrane. Due to its low abundance, the intracellular localization of PLD2
      has been characterized only indirectly through overexpression of chimeric
      proteins. Using antibodies specific to PLD2, together with immunofluorescence
      microscopy, herein we demonstrate that a significant fraction of endogenous PLD2
      localized to the perinuclear Golgi region and was also distributed throughout
      cells in dense cytoplasmic puncta; a fraction of which colocalized with caveolin
      1 and the plasma membrane. On treatment with brefeldin A, PLD2 translocated into
      the nucleus in a manner similar to PLD1, suggesting a potential role in nuclear
      signaling. Most significantly, cryoimmunogold electron microscopy demonstrated
      that in pituitary GH(3) cells >90% of PLD2 present in the Golgi apparatus was
      localized to cisternal rims and peri-Golgi vesicles exclusively. The data are
      consistent with a model whereby PLD2 plays a role in Golgi vesicular transport.

PMID- 12429837
TI  - pp60Src mediates insulin-stimulated sequestration of the beta(2)-adrenergic
      receptor: insulin stimulates pp60Src phosphorylation and activation.
AB  - Insulin stimulates a rapid phosphorylation and sequestration of the beta(2)
      adrenergic receptor. Analysis of the signaling downstream of the insulin receptor
      with enzyme inhibitors revealed roles for both phosphatidylinositol 3-kinase and
      pp60Src. Inhibition of Src with PP2, like the inhibition of phosphatidylinositol
      3-kinase with LY294002 [2-(4-morpholynyl)-8-phenyl-4H-1-benzopyran-4-one],
      blocked the activation of Src as well as insulin-stimulated sequestration of the
      beta(2)-adrenergic receptor. Depletion of Src with antisense morpholinos also
      suppressed insulin-stimulated receptor sequestration. Src is shown to be
      phosphorylated/activated in response to insulin in human epidermoid carcinoma
      A431 cells as well as in mouse 3T3-L1 adipocytes and their derivative 3T3-F422A
      cells, well-known models of insulin signaling. Inhibition of Src with PP2 blocks
      the ability of insulin to sequester beta(2)-adrenergic receptors and the
      translocation of the GLUT4 glucose transporters. Insulin stimulates Src to
      associate with the beta(2)-adrenergic receptor/AKAP250/protein kinase A/protein
      kinase C signaling complex. We report a novel positioning of Src, mediating
      signals from insulin to phosphatidylinositol 3-kinase and to beta(2)-adrenergic
      receptor trafficking.

PMID- 12429838
TI  - Two distinctly localized p-type ATPases collaborate to maintain organelle
      homeostasis required for glycoprotein processing and quality control.
AB  - Membrane transporter proteins are essential for the maintenance of cellular ion
      homeostasis. In the secretory pathway, the P-type ATPase family of transporters
      is found in every compartment and the plasma membrane. Here, we report the
      identification of COD1/SPF1 (control of HMG-CoA reductase degradation/SPF1)
      through genetic strategies intended to uncover genes involved in protein
      maturation and endoplasmic reticulum (ER)-associated degradation (ERAD), a
      quality control pathway that rids misfolded proteins. Cod1p is a putative ER P
      type ATPase whose expression is regulated by the unfolded protein response, a
      stress-inducible pathway used to monitor and maintain ER homeostasis. COD1
      mutants activate the unfolded protein response and are defective in a variety of
      functions apart from ERAD, which further support a homeostatic role. COD1 mutants
      display phenotypes similar to strains lacking Pmr1p, a Ca(2+)/Mn(2+) pump that
      resides in the medial-Golgi. Because of its localization, the previously reported
      role of PMR1 in ERAD was somewhat enigmatic. A clue to their respective roles
      came from observations that the two genes are not generally required for ERAD. We
      show that the specificity is rooted in a requirement for both genes in protein
      linked oligosaccharide trimming, a requisite ER modification in the degradation
      of some misfolded glycoproteins. Furthermore, Cod1p, like Pmr1p, is also needed
      for the outer chain modification of carbohydrates in the Golgi apparatus despite
      its ER localization. In strains deleted of both genes, these activities are
      nearly abolished. The presence of either protein alone, however, can support
      partial function for both compartments. Taken together, our results reveal an
      interdependent relationship between two P-type ATPases to maintain homeostasis of
      the organelles where they reside.

PMID- 12429839
TI  - Microtubule flux and sliding in mitotic spindles of Drosophila embryos.
AB  - We proposed that spindle morphogenesis in Drosophila embryos involves progression
      through four transient isometric structures in which a constant spacing of the
      spindle poles is maintained by a balance of forces generated by multiple
      microtubule (MT) motors and that tipping this balance drives pole-pole
      separation. Here we used fluorescent speckle microscopy to evaluate the influence
      of MT dynamics on the isometric state that persists through metaphase and
      anaphase A and on pole-pole separation in anaphase B. During metaphase and
      anaphase A, fluorescent punctae on kinetochore and interpolar MTs flux toward the
      poles at 0.03 microm/s, too slow to drive chromatid-to-pole motion at 0.11
      microm/s, and during anaphase B, fluorescent punctae on interpolar MTs move away
      from the spindle equator at the same rate as the poles, consistent with MT-MT
      sliding. Loss of Ncd, a candidate flux motor or brake, did not affect flux in the
      metaphase/anaphase A isometric state or MT sliding in anaphase B but decreased
      the duration of the isometric state. Our results suggest that, throughout this
      isometric state, an outward force exerted on the spindle poles by MT sliding
      motors is balanced by flux, and that suppression of flux could tip the balance of
      forces at the onset of anaphase B, allowing MT sliding and polymerization to push
      the poles apart.

PMID- 12429840
TI  - Localization of phospholipase D1 to caveolin-enriched membrane via
      palmitoylation: implications for epidermal growth factor signaling.
AB  - Phospholipase D (PLD) has been suggested to mediate epidermal growth factor (EGF)
      signaling. However, the molecular mechanism of EGF-induced PLD activation has not
      yet been elucidated. We investigated the importance of the phosphorylation and
      compartmentalization of PLD1 in EGF signaling. EGF treatment of COS-7 cells
      transiently expressing PLD1 stimulated PLD1 activity and induced PLD1
      phosphorylation. The EGF-induced phosphorylation of threonine147 was completely
      blocked and the activity of PLD1 attenuated by point mutations (S2A/T147A/S561A)
      of PLD1 phosphorylation sites. The expression of a dominant negative PKCalpha
      mutant by adenovirus-mediated gene transfer greatly inhibited the phosphorylation
      and activation of PLD1 induced by EGF in PLD1-transfected COS-7 cells. EGF
      induced PLD1 phosphorylation occurred primarily in the caveolin-enriched membrane
      (CEM) fraction, and the kinetics of PLD1 phosphorylation in the CEM were strongly
      correlated with PLD1 phosphorylation in the total membrane. Interestingly, EGF
      induced PLD1 phosphorylation and activation and the coimmunoprecipitation of PLD1
      with caveolin-1 and the EGF receptor in the CEM were significantly attenuated in
      the palmitoylation-deficient C240S/C241S mutant, which did not localize to the
      CEM. Immunocytochemical analysis revealed that wild-type PLD1 colocalized with
      caveolin-1 and the EGF receptor and that phosphorylated PLD1 was localized
      exclusively in the plasma membrane, although some PLD1 was also detected in
      vesicular structures. Transfection of wild-type PLD1 but not of C240S/C241S
      mutant increased EGF-induced raf-1 translocation to the CEM and ERK
      phosphorylation. This study shows, for the first time, that EGF-induced PLD1
      phosphorylation and activation occur in the CEM and that the correct localization
      of PLD1 to the CEM via palmitoylation is critical for EGF signaling.

PMID- 12429841
TI  - Regulation of CDC6, geminin, and CDT1 in human cells that undergo
      polyploidization.
AB  - Endomitosis is the process by which mammalian megakaryocytes become polyploid
      during terminal differentiation. As in other endoreplicating cells, cyclin-cdk
      complexes are distinctly regulated, probably to overcome the strict mechanisms
      that prevent rereplication in most somatic cells. We have asked whether key
      factors involved in the assembly and licensing of replication origins are equally
      regulated during endomitosis. Cdc6, cdt1, and geminin expression was analyzed
      during differentiation of two human megakaryoblastic cell lines, HEL and K562,
      which respectively do and do not establish endoreplication cycles. Geminin was
      downregulated, whereas cdt1 levels were maintained upon differentiation of both
      cell lines, independently of whether cells entered extra S-phases. In contrast,
      cdc6 was present and remained nuclear only in differentiated endoreplicating
      cells. Interestingly, cdc6 protein expression was reestablished in K562 cells
      that underwent endomitosis after transient or stable cyclin E overexpression. The
      high levels of cyclin E reached in these cells appeared to influence the
      stabilization of cdc6 protein rather than its RNA transcription rate. Finally,
      cdc6 overexpression drove HEL cells into endoreplication cycles in the absence of
      differentiation stimuli. Our results show that both cdt1 and cdc6 are
      differentially regulated during megakaryocytic differentiation and suggest an
      active role of cdc6 in endomitosis.

PMID- 12429842
TI  - Transforming growth factor-beta receptors interact with AP2 by direct binding to
      beta2 subunit.
AB  - Transforming growth factor-beta (TGF-beta) superfamily members regulate a wide
      range of biological processes by binding to two transmembrane serine/threonine
      kinase receptors, type I and type II. We have previously shown that the
      internalization of these receptors is inhibited by K(+) depletion, cytosol
      acidification, or hypertonic medium, suggesting the involvement of clathrin
      coated pits. However, the involvement of the clathrin-associated adaptor complex
      AP2 and the identity of the AP2 subunit that binds the receptors were not known.
      Herein, we have studied these issues by combining studies on intact cells with in
      vitro assays. Using fluorescence photobleaching recovery to measure the lateral
      mobility of the receptors on live cells (untreated or treated to alter their
      coated pit structure), we demonstrated that their mobility is restricted by
      interactions with coated pits. These interactions were transient and mediated
      through the receptors' cytoplasmic tails. To measure direct binding of the
      receptors to specific AP2 subunits, we used yeast two-hybrid screens and in vitro
      biochemical assays. In contrast to most other plasma membrane receptors that bind
      to AP2 via the mu2 subunit, AP2/TGF-beta receptor binding was mediated by a
      direct interaction between the beta2-adaptin N-terminal trunk domain and the
      cytoplasmic tails of the receptors; no binding was observed to the mu2, alpha, or
      sigma2 subunits of AP2 or to mu1 of AP1. The data uniquely demonstrate both in
      vivo and in vitro the ability of beta2-adaptin to directly couple TGF-beta
      receptors to AP2 and to clathrin-coated pits, providing the first in vivo
      evidence for interactions of a transmembrane receptor with beta2-adaptin.

PMID- 12429843
TI  - Protein kinase MARK/PAR-1 is required for neurite outgrowth and establishment of
      neuronal polarity.
AB  - Protein kinases of the microtubule affinity-regulating kinase (MARK) family were
      originally discovered because of their ability to phosphorylate certain sites in
      tau protein (KXGS motifs in the repeat domain). This type of phosphorylation is
      enhanced in abnormal tau from Alzheimer brain tissue and causes the detachment of
      tau from microtubules. MARK-related kinases (PAR-1 and KIN1) occur in various
      organisms and are involved in establishing and maintaining cell polarity. Herein,
      we report the ability of MARK2 to affect the differentiation and outgrowth of
      cell processes from neuroblastoma and other cell models. MARK2 phosphorylates tau
      protein at the KXGS motifs; this results in the detachment of tau from
      microtubules and their destabilization. The formation of neurites in N2a cells is
      blocked if MARK2 is inactivated, either by transfecting a dominant negative
      mutant, or by MARK2 inhibitors such as hymenialdisine. Alternatively, neurites
      are blocked if the target KXGS motifs on tau are rendered nonphosphorylatable by
      point mutations. The results suggest that MARK2 contributes to the plasticity of
      microtubules needed for neuronal polarity and the growth of neurites.

PMID- 12429844
TI  - Differential regulation of tumor angiogenesis by distinct ErbB homo- and
      heterodimers.
AB  - Interactions between cancer cells and their microenvironment are critical for the
      development and progression of solid tumors. This study is the first to examine
      the role of all members of the ErbB tyrosine kinase receptors (epidermal growth
      factor receptor [EGFR], ErbB-2, ErbB-3, or ErbB-4), expressed singly or as paired
      receptor combinations, in the regulation of angiogenesis both in vitro and in
      vivo. Comparison of all receptor combinations reveals that EGFR/ErbB-2 and ErbB
      2/ErbB-3 heterodimers are the most potent inducers of vascular endothelial growth
      factor (VEGF) mRNA expression compared with EGFR/ErbB-3, EGFR/ErbB-4, ErbB-2/ErbB
      4, and ErbB-3/ErbB-4. Immunohistochemistry of tumor xenografts overexpressing
      these heterodimers shows increased VEGF expression and remarkably enhanced
      vascularity. Enhanced VEGF expression is associated with increased VEGF
      transcription. Deletional analysis reveals that ErbB-mediated transcriptional up
      regulation of VEGF involves a hypoxia-inducible factor 1-independent responsive
      region located between nucleotides -88 to -66 of the VEGF promoter. Mutational
      analysis reveals that the Sp-1 and AP-2 transcription factor binding elements
      within this region are required for up-regulation of VEGF by heregulin beta1 and
      that this up-regulation is dependent on the activity of extracellular signal
      related protein kinases. These results emphasize the biological implications of
      cell signaling diversity among members of the ErbB receptor family in regulation
      of the tumor microenvironment.

PMID- 12429846
TI  - Clint: a novel clathrin-binding ENTH-domain protein at the Golgi.
AB  - We have characterized a novel clathrin-binding 68-kDa epsin N-terminal homology
      domain (ENTH-domain) protein that we name clathrin interacting protein localized
      in the trans-Golgi region (Clint). It localizes predominantly to the Golgi region
      of epithelial cells as well as to more peripheral vesicular structures. Clint
      colocalizes with AP-1 and clathrin only in the perinuclear area. Recombinantly
      expressed Clint interacts directly with the gamma-appendage domain of AP-1, with
      the clathrin N-terminal domain through the peptide motif (423)LFDLM, with the
      gamma-adaptin ear homology domain of Golgi-localizing, gamma-adaptin ear homology
      domain 2, with the appendage domain of beta2-adaptin and to a lesser extent with
      the appendage domain of alpha-adaptin. Moreover, the Clint ENTH-domain
      asssociates with phosphoinositide-containing liposomes. A significant amount of
      Clint copurifies with rat liver clathrin-coated vesicles. In rat kidney it is
      preferentially expressed in the apical region of epithelial cells that line the
      collecting duct. Clathrin and Clint also colocalize in the apical region of
      enterocytes along the villi of the small intestine. Apart from the ENTH-domain
      Clint has no similarities with the epsins AP180/CALM or Hip1/1R. A notable
      feature of Clint is a carboxyl-terminal methionine-rich domain (Met(427)
      Met(605)), which contains >17% methionine. Our results suggest that Clint might
      participate in the formation of clathrin-coated vesicles at the level of the
      trans-Golgi network and remains associated with the vesicles longer than clathrin
      and adaptors.

PMID- 12429845
TI  - Motility determinants in WASP family proteins.
AB  - In response to upstream signals, proteins in the Wiskott-Aldrich Syndrome protein
      (WASP) family regulate actin nucleation via the Arp2/3 complex. Despite intensive
      study of the function of WASP family proteins in nucleation, it is not yet
      understood how their distinct structural organization contributes to actin-based
      motility. Herein, we analyzed the activities of WASP and Scar1 truncation
      derivatives by using a bead-based motility assay. The minimal region of WASP
      sufficient to direct movement was the C-terminal WCA fragment, whereas the
      corresponding region of Scar1 was insufficient. In addition, the proline-rich
      regions of WASP and Scar1 and the Ena/VASP homology 1 (EVH1) domain of WASP
      independently enhanced motility rates. The contributions of these regions to
      motility could not be accounted for by their direct effects on actin nucleation
      with the Arp2/3 complex, suggesting that they stimulate motility by recruiting
      additional factors. We have identified profilin as one such factor. WASP- and
      Scar1-coated bead motility rates were significantly reduced by depletion of
      profilin and VASP and could be more efficiently rescued by a combination of VASP
      and wild-type profilin than by VASP and a mutant profilin that cannot bind
      proline-rich sequences. Moreover, motility of WASP WCA beads was not affected by
      the depletion or addback of VASP and profilin. Our results suggest that
      recruitment of factors, including profilin, by the proline-rich regions of WASP
      and Scar1 and the EVH1 domain of WASP stimulates cellular actin-based motility.

PMID- 12429847
TI  - Cofilin, but not profilin, is required for myosin-I-induced actin polymerization
      and the endocytic uptake in yeast.
AB  - Mutations in the budding yeast myosins-I (MYO3 and MYO5) cause defects in the
      actin cytoskeleton and in the endocytic uptake. Robust evidence also indicates
      that these proteins induce Arp2/3-dependent actin polymerization. Consistently,
      we have recently demonstrated, using fluorescence microscopy, that Myo5p is able
      to induce cytosol-dependent actin polymerization on the surface of Sepharose
      beads. Strikingly, we now observed that, at short incubation times, Myo5p induced
      the formation of actin foci that resembled the yeast cortical actin patches, a
      plasma membrane-associated structure that might be involved in the endocytic
      uptake. Analysis of the machinery required for the formation of the Myo5p-induced
      actin patches in vitro demonstrated that the Arp2/3 complex was necessary but not
      sufficient in the assay. In addition, we found that cofilin was directly involved
      in the process. Strikingly though, the cofilin requirement seemed to be
      independent of its ability to disassemble actin filaments and profilin, a protein
      that closely cooperates with cofilin to maintain a rapid actin filament turnover,
      was not needed in the assay. In agreement with these observations, we found that
      like the Arp2/3 complex and the myosins-I, cofilin was essential for the
      endocytic uptake in vivo, whereas profilin was dispensable.

PMID- 12429848
TI  - The diaphanous-related formin mDia1 controls serum response factor activity
      through its effects on actin polymerization.
AB  - SRF-dependent transcription is regulated by the small GTPase RhoA via its effects
      on actin dynamics. The diaphanous-related formin (DRF) proteins have been
      identified as candidate RhoA effectors mediating signaling to SRF. Here we
      investigate the relationship between SRF activation and actin polymerization by
      the DRF mDia1. We show that the ability of mDia1 to potentiate SRF activity is
      strictly correlated with its ability to promote F-actin assembly. Both processes
      can occur independently of the mDia1 FH1 domain but require sequences in an
      extended C-terminal region encompassing the conserved FH2 domain. mDia-mediated
      SRF activation, but not F-actin assembly, can be blocked by a nonpolymerizable
      actin mutant, placing actin downstream of mDia in the signal pathway. The SRF
      activation assay was used to identify inactive mDia1 derivatives that inhibit
      serum- and LPA-induced signaling to SRF. We show that these interfering mutants
      also block F-actin assembly, whether induced by mDia proteins or extracellular
      signals. These results identify novel functional elements of mDia1 and show that
      it regulates SRF activity by inducing depletion of the cellular pool of G-actin.

PMID- 12429850
TI  - The hemochromatosis protein HFE inhibits iron export from macrophages.
AB  - Hereditary hemochromatosis (HH) is a disorder of iron metabolism caused by common
      mutations in the gene HFE. The HFE protein binds to transferrin receptor-1 (TfR1)
      in competition with transferrin, and in vitro, reduces cellular iron by reducing
      iron uptake. However, in vivo, HFE is strongly expressed by liver macrophages and
      intestinal crypt cells, which behave as though they are relatively iron-deficient
      in HH. These latter observations suggest, paradoxically, that expression of wild
      type HFE may lead to iron accumulation in these specialized cell types. Here we
      show that wild-type HFE protein raises cellular iron by inhibiting iron efflux
      from the monocytemacrophage cell line THP-1, and extend these results to
      macrophages derived from healthy individuals and HH patients. In addition, we
      find that the HH-associated mutant H41D has lost the ability to inhibit iron
      release despite binding to TfR1 as well as wild-type HFE. Finally, we show that
      the ability of HFE to block iron release is not competitively inhibited by
      transferrin. We conclude that HFE has two mutually exclusive functions, binding
      to TfR1 in competition with Tf, or inhibition of iron release.

PMID- 12429849
TI  - Functional proteomic analysis of human nucleolus.
AB  - The notion of a "plurifunctional" nucleolus is now well established. However,
      molecular mechanisms underlying the biological processes occurring within this
      nuclear domain remain only partially understood. As a first step in elucidating
      these mechanisms we have carried out a proteomic analysis to draw up a list of
      proteins present within nucleoli of HeLa cells. This analysis allowed the
      identification of 213 different nucleolar proteins. This catalog complements that
      of the 271 proteins obtained recently by others, giving a total of approximately
      350 different nucleolar proteins. Functional classification of these proteins
      allowed outlining several biological processes taking place within nucleoli.
      Bioinformatic analyses permitted the assignment of hypothetical functions for 43
      proteins for which no functional information is available. Notably, a role in
      ribosome biogenesis was proposed for 31 proteins. More generally, this functional
      classification reinforces the plurifunctional nature of nucleoli and provides
      convincing evidence that nucleoli may play a central role in the control of gene
      expression. Finally, this analysis supports the recent demonstration of a
      coupling of transcription and translation in higher eukaryotes.

PMID- 12429851
TI  - Early stages of energy transduction by myosin: roles of Arg in switch I, of Glu
      in switch II, and of the salt-bridge between them.
AB  - On the basis of the crystallographic snapshots of Rayment and his collaborators
      [Fisher, A. J., Smith, C. A., Thoden, J. B., Smith, R., Sutoh, K., Holden, H. M.,
      & Rayment, I. (1995) Biochemistry 34, 8960-8972], we have understood some basic
      principles about the early stages of myosin catalysis, namely, ATP is drawn into
      the active site, over which the cleft closes. Catalyzed hydrolysis occurs, and
      the first product (orthophosphate) is released from the backdoor of the cleft. In
      the cleft-closing process, the active site incidentally signals its movement to a
      particular remote tryptophan residue, Trp-512. In this work, we expand on some of
      these ideas to rationalize the behavior of a mutated system in action. From the
      behavior of recombinant myosin systems in which Arg-247 and Glu-470 were
      substituted in several ways, we draw the conclusions that (i) the force between
      Arg-247 and gamma-phosphate of ATP may assist in closing the cleft, and
      incidentally in signaling to the remote Trp, and (ii) in catalysis, Glu-470 is
      involved in holding the lytic H(2)O (w(1)). We also propose that w(1) and also a
      second water, w(2), enter into a structure that bridges Glu-470 and the gamma
      phosphate of bound ATP, and at the same time positions w(1) for its in-line
      hydrolytic attack.

PMID- 12429852
TI  - Microarray-based detection and genotyping of viral pathogens.
AB  - The detection of viral pathogens is of critical importance in biology, medicine,
      and agriculture. Unfortunately, existing techniques to screen for a broad
      spectrum of viruses suffer from severe limitations. To facilitate the
      comprehensive and unbiased analysis of viral prevalence in a given biological
      setting, we have developed a genomic strategy for highly parallel viral
      screening. The cornerstone of this approach is a long oligonucleotide (70-mer)
      DNA microarray capable of simultaneously detecting hundreds of viruses. Using
      virally infected cell cultures, we were able to efficiently detect and identify
      many diverse viruses. Related viral serotypes could be distinguished by the
      unique pattern of hybridization generated by each virus. Furthermore, by
      selecting microarray elements derived from highly conserved regions within viral
      families, individual viruses that were not explicitly represented on the
      microarray were still detected, raising the possibility that this approach could
      be used for virus discovery. Finally, by using a random PCR amplification
      strategy in conjunction with the microarray, we were able to detect multiple
      viruses in human respiratory specimens without the use of sequence-specific or
      degenerate primers. This method is versatile and greatly expands the spectrum of
      detectable viruses in a single assay while simultaneously providing the
      capability to discriminate among viral subtypes.

PMID- 12429853
TI  - Bombyxin is a growth factor for wing imaginal disks in Lepidoptera.
AB  - The mechanisms that control the growth rate of internal tissues during
      postembryonic development are poorly understood. In insects, the growth rate of
      imaginal disks varies with nutrition and keeps pace with variation in somatic
      growth. We describe here a mechanism by which the growth of wing imaginal disks
      is controlled. When wing imaginal disks of the butterfly Precis coenia are
      removed from the larva and placed in a standard nutrient-rich tissue culture
      medium they stop growing, suggesting that nutrients alone are not sufficient to
      support normal growth. Such disks can be made to grow at a normal rate by
      supplementing the culture medium with an optimal concentration of the steroid
      hormone 20-hydroxyecdysone and with hemolymph taken from growing larvae. The
      growth-promoting activity of the hemolymph is caused by a heat-stable factor that
      can be extracted from the CNS and appears to be identical to the neurohormone
      bombyxin, a member of the insulin family of proteins. Synthetic bombyxin
      stimulates growth at concentrations as low as 30 ngml, and specific antibodies to
      bombyxin completely remove growth-promoting activity from the hemolymph. Bombyxin
      evidently acts together with 20-hydroxyecdysone to stimulate cell division and
      growth of wing imaginal disks. It appears that the level of bombyxin in the
      hemolymph is modulated by the brain in response to variation in nutrition and is
      part of the mechanism that coordinates the growth of internal organs with overall
      somatic growth.

PMID- 12429854
TI  - Are helionitronium trications stable?
AB  - In a recent article [Olah, G. A., Prakash, G. K. S. & Rasul, G. (1999) Proc.
      Natl. Acad. Sci. USA 96, 3494-3495] the authors found that the helionitronium
      trication, HeNO(2)(3+), is an unusually stable helium-containing polyatomic ion.
      This result was based on second-order many-body perturbation (MP2) calculations
      that showed that strong binding should occur between the oxygen and helium atoms
      in the assumed singlet ground state. The dissociation energy with respect to
      NO(+) and HeO(2+) was predicted to be 7.95 eV. We show here by thorough
      multireference configuration interaction (MRCI) studies that the ground state for
      the helionitronium trication is a triplet (3)B(1) state with He binding to the N
      atom (C(2v)). The HeO bound structure of C(s) symmetry is not stable.
      Dissociation of the helionitronium trication occurs toward NO(2)(2+) and He(+),
      and the trication is bound by at most 0.25 eV. These results indicate that the
      helionitronium trication is unstable under ambient conditions. The discrepancies
      between our results and the previous study are explained by the strong
      multireference character of the wave function of the trication.

PMID- 12429855
TI  - Auditory looming perception in rhesus monkeys.
AB  - The detection of approaching objects can be crucial to the survival of an
      organism. The perception of looming has been studied extensively in the visual
      system, but remains largely unexplored in audition. Here we show a behavioral
      bias in rhesus monkeys orienting to "looming" sounds. As in humans, the bias
      occurred for harmonic tones (which can reliably indicate single sources), but not
      for broadband noise. These response biases to looming sounds are consistent with
      an evolved neural mechanism that processes approaching objects with priority.

PMID- 12429856
TI  - Inflammatory mediators are induced by dietary glycotoxins, a major risk factor
      for diabetic angiopathy.
AB  - Diet is a major environmental source of proinflammatory AGEs (heat-generated
      advanced glycation end products); its impact in humans remains unclear. We
      explored the effects of two equivalent diets, one regular (high AGE, H-AGE) and
      the other with 5-fold lower AGE (L-AGE) content on inflammatory mediators of 24
      diabetic subjects: 11 in a 2-week crossover and 13 in a 6-week study. After 2
      weeks on H-AGE, serum AGEs increased by 64.5% (P = 0.02) and on L-AGE decreased
      by 30% (P = 0.02). The mononuclear cell tumor necrosis factor-alphabeta-actin
      mRNA ratio was 1.4 +/- 0.5 on H-AGE and 0.9 +/- 0.5 on L-AGE (P = 0.05), whereas
      serum vascular adhesion molecule-1 was 1,108 +/- 429 and 698 +/- 347 ngml (P =
      0.01) on L- and H-AGE, respectively. After 6 weeks, peripheral blood mononuclear
      cell tumor necrosis factor-alpha rose by 86.3% (P = 0.006) and declined by 20%
      (P, not significant) on H- or L-AGE diet, respectively; C-reactive protein
      increased by 35% on H-AGE and decreased by 20% on L-AGE (P = 0.014), and vascular
      adhesion molecule-1 declined by 20% on L-AGE (P < 0.01) and increased by 4% on H
      AGE. Serum AGEs were increased by 28.2% on H-AGE (P = 0.06) and reduced by 40% on
      L-AGE (P = 0.02), whereas AGE low density lipoprotein was increased by 32% on H
      AGE and reduced by 33% on L-AGE diet (P < 0.05). Thus in diabetes, environmental
      (dietary) AGEs promote inflammatory mediators, leading to tissue injury.
      Restriction of dietary AGEs suppresses these effects.

PMID- 12429857
TI  - Neuroprotective autoimmunity: naturally occurring CD4+CD25+ regulatory T cells
      suppress the ability to withstand injury to the central nervous system.
AB  - The ability of rats or mice to withstand the consequences of injury to myelinated
      axons in the CNS was previously shown to depend on the ability to manifest a T
      cell-mediated protective immune response, which is amenable to boosting by myelin
      specific T cells. Here we show that this ability, assessed by retinal ganglion
      cell survival after optic nerve injury or locomotor activity after spinal cord
      contusion, is decreased if the animals were immunized as neonates with myelin
      proteins (resulting in their nonresponsiveness as adults to myelin proteins) or
      injected with naturally occurring regulatory CD4(+)CD25(+) T cells immediately
      after the injury, and is improved by elimination of these regulatory T cells. In
      nude BALBc mice replenished with a splenocyte population lacking CD4(+)CD25(+)
      regulatory T cells, significantly more neurons survived after optic nerve injury
      than in nude mice replenished with a complete splenocyte population or in matched
      wild-type controls. In contrast, neuronal survival in wild-type BALBc mice
      injected with CD4(+)CD25(+) regulatory T cells immediately after injury was
      significantly worse than in noninjected controls. These findings suggest that the
      ability to cope with the sequelae of a CNS insult is affected unfavorably by
      nonresponsiveness to myelin self-antigens and favorably by conditions allowing
      rapid expression of an autoimmune response. The regulatory T cells might
      represent an evolutionary compromise between the need to avoid autoimmune
      diseases and the need for autoimmunity on alert for the purpose of tissue
      maintenance.

PMID- 12429858
TI  - Statistical learning of new visual feature combinations by infants.
AB  - The ability of humans to recognize a nearly unlimited number of unique visual
      objects must be based on a robust and efficient learning mechanism that extracts
      complex visual features from the environment. To determine whether statistically
      optimal representations of scenes are formed during early development, we used a
      habituation paradigm with 9-month-old infants and found that, by mere observation
      of multielement scenes, they become sensitive to the underlying statistical
      structure of those scenes. After exposure to a large number of scenes, infants
      paid more attention not only to element pairs that cooccurred more often as
      embedded elements in the scenes than other pairs, but also to pairs that had
      higher predictability (conditional probability) between the elements of the pair.
      These findings suggest that, similar to lower-level visual representations,
      infants learn higher-order visual features based on the statistical coherence of
      elements within the scenes, thereby allowing them to develop an efficient
      representation for further associative learning.

PMID- 12429859
TI  - Conformational-relaxation models of single-enzyme kinetics.
AB  - Fluorescent spectroscopy experiments with single-enzyme molecules yield a large
      volume of statistical data that can be analyzed and interpreted using stochastic
      models of enzyme action. Here, we present two models, each based on the mechanism
      that an enzyme molecule must pass through a sequence of conformational
      transformations to complete its catalytic turnover cycle. In the simplest model,
      only one path leading to the release of product is present. In contrast to this,
      two different catalytic paths are possible in the second considered model. If a
      cycle is started from an active state, immediately after the previous product
      release, it follows a different conformational route and is much shorter. Our
      numerical investigations show that both models generate non-Markovian molecular
      statistics. However, their memory landscapes and distributions of cycle times are
      significantly different. The memory landscape of the double-path model bears
      strong similarity to the recent experimental data for horseradish peroxidase.

PMID- 12429860
TI  - High incidence of epithelial cancers in mice deficient for DNA polymerase delta
      proofreading.
AB  - Mutations are a hallmark of cancer. Normal cells minimize spontaneous mutations
      through the combined actions of polymerase base selectivity, 3' --> 5'
      exonucleolytic proofreading, mismatch correction, and DNA damage repair. To
      determine the consequences of defective proofreading in mammals, we created mice
      with a point mutation (D400A) in the proofreading domain of DNA polymerase delta
      (poldelta, encoded by the Pold1 gene). We show that this mutation inactivates the
      3' --> 5' exonuclease of poldelta and causes a mutator and cancer phenotype in a
      recessive manner. By 18 months of age, 94% of homozygous Pold1(D400A/D400A) mice
      developed cancer and died (median survival = 10 months). In contrast, only 3-4%
      of Pold1(+/D400A) and Pold1(+/+) mice developed cancer in this time frame. Of the
      66 tumors arising in 49 Pold1(D400A/D400A) mice, 40 were epithelial in origin
      (carcinomas), 24 were mesenchymal (lymphomas and sarcomas), and two were
      composite (teratomas); one-third of these animals developed tumors in more than
      one tissue. Skin squamous cell carcinoma was the most common tumor type,
      occurring in 60% of all Pold1(D400A/D400A) mice and in 90% of those surviving
      beyond 8 months of age. These data show that poldelta proofreading suppresses
      spontaneous tumor development and strongly suggest that unrepaired DNA polymerase
      errors contribute to carcinogenesis. Mice deficient in poldelta proofreading
      provide a tractable model to study mechanisms of epithelial tumorigenesis
      initiated by a mutator phenotype.

PMID- 12429861
TI  - A computational method for resequencing long DNA targets by universal
      oligonucleotide arrays.
AB  - Universal arrays contain all possible oligonucleotides of a certain length,
      typically 6-10 bases. They can determine in a single experiment all substrings of
      that length that occur along a target sequence. That information, also called the
      spectrum of the sequence, is not sufficient to uniquely reconstruct a sequence
      longer than a few hundred bases. We have devised a polynomial algorithm that
      reconstructs the sequence, given the spectrum and an additional reference
      sequence, homologous to the target sequence. Such a reference is available, for
      example, in the identification of single-nucleotide polymorphisms. The algorithm
      can handle errors in the spectrum as well as substitutions, insertions, and
      deletions in the target sequence. We present extensive simulation results, which
      show that the algorithm correctly reconstructs target sequences of >2,000
      nucleotides from error-prone 8-mer spectra when realistic levels of single
      nucleotide polymorphisms are present.

PMID- 12429862
TI  - The breast cancer resistance protein protects against a major chlorophyll-derived
      dietary phototoxin and protoporphyria.
AB  - The breast cancer resistance protein (BCRPABCG2) is a member of the ATP-binding
      cassette family of drug transporters and confers resistance to various anticancer
      drugs. We show here that mice lacking Bcrp1Abcg2 become extremely sensitive to
      the dietary chlorophyll-breakdown product pheophorbide a, resulting in severe,
      sometimes lethal phototoxic lesions on light-exposed skin. Pheophorbide a occurs
      in various plant-derived foods and food supplements. Bcrp1 transports
      pheophorbide a and is highly efficient in limiting its uptake from ingested food.
      Bcrp1(-/-) mice also displayed a previously unknown type of protoporphyria.
      Erythrocyte levels of the heme precursor and phototoxin protoporphyrin IX, which
      is structurally related to pheophorbide a, were increased 10-fold.
      Transplantation with wild-type bone marrow cured the protoporphyria and reduced
      the phototoxin sensitivity of Bcrp1(-/-) mice. These results indicate that humans
      or animals with low or absent BCRP activity may be at increased risk for
      developing protoporphyria and diet-dependent phototoxicity and provide a striking
      illustration of the importance of drug transporters in protection from toxicity
      of normal food constituents.

PMID- 12429863
TI  - Quantifying predictability in a model with statistical features of the
      atmosphere.
AB  - The Galerkin truncated inviscid Burgers equation has recently been shown by the
      authors to be a simple model with many degrees of freedom, with many statistical
      properties similar to those occurring in dynamical systems relevant to the
      atmosphere. These properties include long time-correlated, large-scale modes of
      low frequency variability and short time-correlated "weather modes" at smaller
      scales. The correlation scaling in the model extends over several decades and may
      be explained by a simple theory. Here a thorough analysis of the nature of
      predictability in the idealized system is developed by using a theoretical
      framework developed by R.K. This analysis is based on a relative entropy
      functional that has been shown elsewhere by one of the authors to measure the
      utility of statistical predictions precisely. The analysis is facilitated by the
      fact that most relevant probability distributions are approximately Gaussian if
      the initial conditions are assumed to be so. Rather surprisingly this holds for
      both the equilibrium (climatological) and nonequilibrium (prediction)
      distributions. We find that in most cases the absolute difference in the first
      moments of these two distributions (the "signal" component) is the main
      determinant of predictive utility variations. Contrary to conventional belief in
      the ensemble prediction area, the dispersion of prediction ensembles is generally
      of secondary importance in accounting for variations in utility associated with
      different initial conditions. This conclusion has potentially important
      implications for practical weather prediction, where traditionally most attention
      has focused on dispersion and its variability.

PMID- 12429865
TI  - IDEG6: a web tool for detection of differentially expressed genes in multiple tag
      sampling experiments.
AB  - Here we present a novel web tool for the statistical analysis of gene expression
      data in multiple tag sampling experiments. Differentially expressed genes are
      detected by using six different test statistics. Result tables, linked to the
      GenBank, UniGene, or LocusLink database, can be browsed or searched in different
      ways. Software is freely available at the site:
      http://telethon.bio.unipd.it/bioinfo/IDEG6_form/, together with additional
      information on statistical methodologies.

PMID- 12429864
TI  - Lifelong voluntary exercise in the mouse prevents age-related alterations in gene
      expression in the heart.
AB  - We present the first quantitative gene expression analysis of cardiac aging under
      conditions of sedentary and active lifestyles using high-density oligonucleotide
      arrays representing 11,904 cDNAs and expressed sequence tags (ESTs). With these
      data, we test the hypothesis that exercise attenuates the gene expression changes
      that normally occur in the aging heart. Male mice (Mus domesticus) were sampled
      from the 16th generation of selective breeding for high voluntary exercise. For
      the selective breeding protocol, breeders were chosen based on the maximum number
      of wheel revolutions run on days 5 and 6 of a test at 8 wk of age. For the colony
      sampled herein, mice were housed individually over their entire lifetimes (from
      weaning) either with or without access to running wheels. The hearts of these two
      treatment groups (active and sedentary) were assayed at middle age (20 mo) and
      old age (33 mo). Genes significantly affected by age in the hearts of the
      sedentary population by at least a 50% expression change (n = 137) were
      distributed across several major categories, including inflammatory response,
      stress response, signal transduction, and energy metabolism. Genes significantly
      affected by age in the active population were fewer (n = 62). Of the 42 changes
      in gene expression that were common to both treatment groups, 32 (72%) displayed
      smaller fold changes as a result of exercise. Thus exercise offset many age
      related gene expression changes observed in the hearts of the sedentary animals.
      These results suggest that adaptive physiological mechanisms that are induced by
      exercise can retard many effects of aging on heart muscle at the transcriptional
      level.

PMID- 12429866
TI  - Rosiglitazone fails to improve hypertriglyceridemia and glucose tolerance in CD36
      deficient BN.SHR4 congenic rat strain.
AB  - The favorable metabolic effects of thiazolidinediones are supposedly related to
      the peroxisome proliferator-activated receptor-gamma (PPARgamma)-driven changes
      in lipid metabolism, particularly in free fatty acid (FFA) trafficking. The fatty
      acid translocase CD36 is one of the proposed PPARgamma targets to mediate this
      action. We assessed the effect of rosiglitazone (RSG, Avandia) administration in
      two inbred rat strains, BN/Cub and BN.SHR4 congenic strain, differing in 10 cM
      proximal segment of chromosome 4. Rats were fed high-sucrose diet with or without
      RSG for 1 wk. In BN.SHR4, which carries defective Cd36 allele of SHR origin, RSG
      failed to improve glucose tolerance (assessed by the oral glucose tolerance
      test), did not lower triglyceridemia, nor induced increases in epididymal and
      retroperitoneal adipose tissue weights and adipose tissue glucose utilization,
      effects observed in BN/Cub. On the other hand, the RSG-treated BN.SHR4 showed
      lower concentrations of FFA and substantial increase in glycogen synthesis and
      glucose oxidation in skeletal muscle. Altogether, these results support
      involvement of CD36 in RSG action, suggesting this pharmacogenetic interaction
      may be of particular importance in CD36-deficient humans.

PMID- 12429867
TI  - Transcriptomal analysis of failing and nonfailing human hearts.
AB  - Heart failure is a multifactorial disease that may result from different
      initiating events. To contribute to an improved comprehension of normal cardiac
      function and the molecular events leading to heart failure, we performed large
      scale gene expression analysis of failing and nonfailing human ventricle. Our aim
      was to define and compare expression profiles of 4 specific pathophysiological
      cardiac situations: 1) left ventricle (LV) from nonfailing heart; 2) LV from
      failing hearts affected by dilated cardiomyopathy (DCM); 3) LV from failing
      hearts affected by ischemic CM (ICM); 4) right ventricle (RV) from failing hearts
      affected by DCM or ICM. We used oligonucleotide arrays representing approximately
      12,000 human genes. After stringent numerical analyses using several statistical
      tests, we identified 1,306 genes with a similar expression profile in all 4
      cardiac situations, therefore representative of part of the human cardiac
      expression profile. A total of 95 genes displayed differential expression between
      failing and nonfailing heart samples, reflecting a reversal to developmental gene
      expression, dedifferentiation of failing cardiomyocytes, and involvement of
      apoptosis. Twenty genes were differentially expressed between failing LV and
      failing RV, identifying possible candidates for different functioning of both
      ventricles. Finally, no genes were found to be significantly differentially
      expressed between failing DCM and failing ICM LV, emphasizing that transcriptomal
      analysis of explanted hearts results mainly in identification of expression
      profiles of end-stage heart failure and less in determination of expression
      profiles of the underlying etiology. Taken together, our data resulted in
      identification of putative transcriptomal landmarks for normal and disturbed
      cardiac function.

PMID- 12429868
TI  - Targeted drug delivery via the transferrin receptor-mediated endocytosis pathway.
AB  - The membrane transferrin receptor-mediated endocytosis or internalization of the
      complex of transferrin bound iron and the transferrin receptor is the major route
      of cellular iron uptake. This efficient cellular uptake pathway has been
      exploited for the site-specific delivery not only of anticancer drugs and
      proteins, but also of therapeutic genes into proliferating malignant cells that
      overexpress the transferrin receptors. This is achieved either chemically by
      conjugation of transferrin with therapeutic drugs, proteins, or genetically by
      infusion of therapeutic peptides or proteins into the structure of transferrin.
      The resulting conjugates significantly improve the cytotoxicity and selectivity
      of the drugs. The coupling of DNA to transferrin via a polycation or liposome
      serves as a potential alternative to viral vector for gene therapy. Moreover, the
      OX26 monoclonal antibody against the rat transferrin receptor offers great
      promise in the delivery of therapeutic agents across the blood-brain barrier to
      the brain.

PMID- 12429869
TI  - Pivalate-generating prodrugs and carnitine homeostasis in man.
AB  - Prodrugs that liberate pivalate (trimethylacetic acid) after hydrolysis have been
      developed to improve the bioavailability of therapeutic candidates. Catabolism of
      pivalate released by activation of a prodrug is limited in mammalian tissues.
      Pivalate can be activated to a coenzyme A thioester in cells. In humans,
      formation and urinary excretion of pivaloylcarnitine generated from pivaloyl-CoA
      is the major route of pivalate elimination. Because the total body carnitine pool
      is limited and can only slowly be replenished through normal diet or
      biosynthesis, treatment with large doses of pivalate prodrugs may deplete tissue
      carnitine content. Animal models and long-term treatment of patients with
      pivalate prodrugs have resulted in toxicity consistent with carnitine depletion.
      However, low plasma carnitine concentrations after pivalate prodrug exposure may
      not reflect tissue carnitine content and, thus, cannot be used as a surrogate for
      potential toxicity. The extent of tissue carnitine depletion will be dependent on
      the dose of pivalate, because carnitine losses may approximate the pivalate
      exposure on a stoichiometric basis. These concepts, combined with estimates of
      carnitine dietary intake and biosynthetic rates, can be used to estimate the
      impact of pivalate exposure on carnitine homeostasis. Thus, even in populations
      with altered carnitine homeostasis due to underlying conditions, the use of
      pivalate prodrugs for short periods of time is unlikely to result in clinically
      significant carnitine depletion. In contrast, long-term treatment with
      substantial doses of pivalate prodrugs may require administration of carnitine
      supplementation to avoid carnitine depletion.

PMID- 12429870
TI  - Homocysteine determinants and the evidence to what extent homocysteine determines
      the risk of coronary heart disease.
AB  - Cardiovascular diseases (CVD), especially coronary heart disease (CHD), are the
      most important causes of death in industrialized countries. Increased
      concentrations of total plasma homocysteine (tHcy) have been associated with an
      increased risk of CHD. Assuming that this relation is causal, a lower tHcy
      concentration will reduce the occurrence and recurrence of CHD. Therefore, it is
      important to know which factors determine the tHcy concentration. In the general
      population, the most important modifiable determinants of tHcy are folate intake
      and coffee consumption. Smoking and alcohol consumption are also associated with
      the tHcy concentration, but more research is necessary to elucidate whether these
      relations are not originating from residual confounding due to other lifestyle
      factors. The most important nonmodifiable determinant is the 677 C>T polymorphism
      in the gene that encodes methylenetetrahydrofolate reductase (MTHFR), a
      regulating enzyme in homocysteine metabolism. Especially subjects with the
      homozygous form of this polymorphism (i.e., 677TT genotype) and a low folate
      status have elevated tHcy concentrations. Specific clinical conditions like the
      use of antiepileptic drugs or methotrexate, renal failure, cancer, rheumatoid
      arthritis, and hypothyroidism may lead to elevated tHcy concentrations. The
      available epidemiological evidence indicates that an increased tHcy concentration
      is not an important risk factor for CHD in healthy subjects. However, prospective
      studies, which included subjects at high risk of CHD, and secondary prevention
      trials with intermediary endpoints consistently show that elevations in the tHcy
      concentration may be an important risk factor in these subjects for a (recurrent)
      CHD event. The induction of vascular endothelial dysfunction by homocysteine may
      underlie this increased risk. Ongoing intervention trials will indicate whether
      homocysteine-lowering through vitamin supplementation, prevents CHD in the
      treatment groups.

PMID- 12429871
TI  - Protein nitration in cardiovascular diseases.
AB  - There is growing evidence that cardiovascular disease is associated with
      progressive changes in the production of free radicals and radical-derived
      reactive species. These intermediates react with all major cellular constituents
      and may serve several physiological and pathophysiological functions. The
      nitration of protein tyrosine residues has been used as a footprint for in vivo
      production of radical and nonradical reactive species. Tyrosine nitration may
      alter protein function and metabolism and therefore, provides for further
      dysfunctional changes. This review focuses on an appearance of tyrosine nitrated
      proteins in cardiovascular tissues under different settings of cardiovascular
      disease. Sources of reactive species, putative mechanisms of protein nitration in
      vivo, as well as protein nitration under normal physiological conditions, are
      also described. The goal of this review is to attract more attention to
      identification of specific proteins, which undergo tyrosine nitration and to
      study a correlation between their altered function and pathology. Understanding
      how protein nitration affects disease progression may offer a unique option for
      design of antioxidant therapy for the treatment of cardiovascular complications.
      At the same time, protein nitration can be a biological marker of efficiency of
      antioxidant therapy.

PMID- 12429872
TI  - Resistin and adiponectin expression in visceral fat of obese rats: effect of
      weight loss.
AB  - OBJECTIVE: Obesity-related insulin resistance is closely associated with visceral
      fat accumulation. Several adipocyte-secreted molecules have been implicated in
      the development of type 2 diabetes, among them, the recently discovered
      adiponectin and resistin proteins. Some of these adipocytokines are also present
      in the immune system, thus suggesting an intriguing functional connection.
      RESEARCH METHODS AND PROCEDURES: We determined adiponectin and resistin
      expressions in visceral (VAT) and subcutaneous adipose tissue of lean and obese
      Zucker (fa/fa) rats using reverse-transcription polymerase chain reaction.
      Moreover, we analyzed the variations after body-weight reduction in food
      restricted obese rats. RESULTS: Resistin and adiponectin expression was
      significantly lower in VAT of genetically obese in comparison with lean rats; no
      differences were observed when subcutaneous adipose tissues of the same animals
      were compared. Weight loss resulted in an increase of adiponectin expression in
      VAT, whereas a further significant decrease in resistin mRNA level was observed.
      Resistin is also present and equally expressed in splenocytes of lean and obese
      rats. DISCUSSION: Adiponectin and resistin are down-regulated in VAT of obese
      rats. Adiponectin expression is restored to normal levels after body-weight
      reduction, supporting its link with obesity-related insulin resistance. On the
      contrary, the further decrease of resistin mRNA after weight loss does not
      support the hypothesis that resistin may play a causative role in insulin
      resistance in obese rats. Moreover, we demonstrated the presence of resistin in
      immunocompetent cells in both humans and rats, thus adding another factor to the
      list of molecules that adipose tissue shares with the immune system.

PMID- 12429873
TI  - Plasma adiponectin levels in overweight and obese Asians.
AB  - OBJECTIVE: Hypoadiponectin has been documented in subjects with obesity, diabetes
      mellitus, or coronary heart disease, suggesting a potential use of plasma
      adiponectin in following the clinical progress in subjects with metabolic
      syndrome (MS). In this study, we investigated the plasma adiponectin levels in
      relation to the variables of MS among overweight/obese Asian subjects. RESEARCH
      METHODS AND PROCEDURES: The plasma adiponectin, anthropometric and biochemical
      measurements, oral glucose tolerance tests (OGTT), and modified insulin
      suppression tests were performed on 180 overweight/obese Asian subjects [body
      mass index (BMI) >or= 23 kg/m(2)], including 47 subjects with morbid obesity (BMI
      >or= 40 kg/m(2)). RESULTS: The plasma adiponectin levels negatively correlated
      with BMI, waist-to-hip ratio, fasting plasma glucose, insulin, triglyceride, uric
      acid levels, hyperinsulinemia, and glucose intolerance in OGTT, but positively
      with high-density lipoprotein-cholesterol. In contrast, they were not related to
      blood pressure and total cholesterol. Moreover, insulin sensitivity, measured by
      quantitative insulin sensitivity check index (QUICKI) or in insulin suppression
      tests, significantly correlated with the plasma adiponectin levels. Among
      morbidly obese subjects, only the waist-to-hip ratio correlated with the plasma
      adiponectin levels. Using multivariate linear regression models, the area under
      curve of plasma glucose in OGTT and high-density lipoprotein-cholesterol among
      the overweight/obese subjects and WHR among the morbidly obese subjects were
      significantly related to the plasma adiponectin levels after adjustment for other
      variables. DISCUSSION: In overweight/obese Asians, the plasma adiponectin levels
      significantly correlated with various indices of MS except hypertension. Whether
      the plasma adiponectin level could be a suitable biomarker for following the
      clinical progress of MS warrants further investigation.

PMID- 12429874
TI  - Reduction of plasma leptin concentrations by arginine but not lipid infusion in
      humans.
AB  - OBJECTIVE: We examined short-term effects of arginine infusion on plasma leptin
      in diabetic and healthy subjects. RESEARCH METHODS AND PROCEDURES: Arginine
      stimulation tests were performed in C-peptide negative type 1 [DM1; hemoglobin
      A(1c); 7.3 +/- 0.3%], hyperinsulinemic type 2 diabetic (DM2; 7.6 +/- 0.7%), and
      nondiabetic subjects (CON; 5.4 +/- 0.1%). RESULTS: Fasting plasma leptin
      correlated linearly with body mass index among all groups (r = 0.61, p = 0.001).
      During arginine infusion, peak plasma insulin was lower in DM1 than in DM2 (p <
      0.05) and CON (p < 0.01). Plasma leptin decreased within 30 minutes by
      approximately 11% in DM1 (p < 0.001), DM2 (p < 0.01), and CON (p < 0.005), slowly
      returning to baseline thereafter. Plasma free fatty acids (FFAs) were higher in
      DM1 (0.6 +/- 0.1 mM) and DM2 (0.6 +/- 0.1 mM) than in CON (0.4 +/- 0.1 mM, p <
      0.05) and transiently declined by approximately 50% (p < 0.05) at 45 minutes in
      all groups before rebounding toward baseline. To examine the direct effects of
      FFAs on plasma leptin, we infused healthy subjects with lipid/heparin and
      glycerol during fasting, and somatostatin-insulin ( approximately 35 pM) 
      glucagon ( approximately 90 ng/mL) clamps were performed. In both protocols,
      plasma leptin continuously declined by approximately 25% (p < 0.05) during 540
      minutes without any difference between the high and low FFA conditions.
      DISCUSSION: Arginine infusion transiently decreased plasma leptin concentrations
      both in insulin-deficient and hyperinsulinemic diabetic patients, indicating a
      direct inhibitory effect of the amino acid but not of insulin or FFAs.

PMID- 12429875
TI  - Dietary restraint and stress-induced snacking in youth.
AB  - OBJECTIVE: To determine whether dietary restraint modifies stress-induced eating
      in youth. RESEARCH METHODS AND PROCEDURES: Snacking was measured in boys (9.5 +/-
      0.3 years) and girls (9.0 +/- 0.3 years), with and without dietary restraint,
      across a control day after reading children's magazines and/or coloring, and on a
      stress day after giving a videotaped speech, with order of conditions
      counterbalanced. Children were divided into four groups based on dietary
      restraint and changes in perceived stress: low-restraint/low-reactive (n = 9),
      low-restraint/high-reactive (n = 13), high-restraint/low-reactive (n = 10), and
      high-restraint/high-reactive (n = 8). Body composition was estimated by
      skinfolds. RESULTS: Energy intake of snack foods was influenced differently by
      dietary restraint and stress reactivity in the stress and control conditions (p <
      0.01). After being stressed, low-restraint/low-reactive children ate fewer snacks
      and high-restraint/high-reactive children ate more snacks compared with the
      control condition. After covarying for percentage of body fat, the interactions
      remained (p < 0.01). Girls ate less than boys (p < 0.001), but sex did not
      influence eating in control and stress conditions. DISCUSSION: Dietary restraint
      occurs in children and may influence the effect of stress on eating.
      Interpersonal stress decreases snacking in low dietary restrained youth but
      increases snacking in high dietary restrained children, perhaps because of stress
      induced disinhibition.

PMID- 12429876
TI  - Binge-eating disorder in Brazilian women on a weight-loss program.
AB  - OBJECTIVE: To examine binge-eating disorder (BED) and its association with
      obesity, weight patterns, and psychopathology in a Brazilian sample of female
      participants of a weight-loss program in Sao Paulo, Brazil. RESEARCH METHODS AND
      PROCEDURES: Two hundred and seventeen overweight (body mass index >/= 25 kg/m(2))
      women, ages 15 to 59 years, enrolled in the Weight Watchers Program were
      recruited for the study at a program branch meeting after completing the
      Questionnaire on Eating and Weight Patterns-Revised, Beck Depression Inventory,
      and the Toronto Alexithymia Scale-20. Participants were categorized into four
      groups: those who met questionnaire criteria for BED, those who met questionnaire
      criteria for bulimia nervosa (BN), those that reported binge eating but did not
      meet all the criteria for any eating disorder (BE), and those with no eating
      disorder symptoms (No ED). Groups were compared on measures of weight, depressive
      symptoms, and alexithymia. RESULTS: Binge eating was frequently reported by women
      in this study (BED, 16.1%; BN, 4.6%; BE, 22.6%). BED women had significantly
      higher body mass index, greater highest weight ever, and more frequent weight
      cycling than the No ED group. BED women also reported more depressive symptoms
      than BE and No ED women, and were more alexithymic than the No ED group. BE women
      presented more frequent weigh cycling and were also more depressed and
      alexithymic than the No ED group. DISCUSSION: BED is not uncommon in overweight
      Brazilian women, and similar to North American and European samples, it is
      associated with overweight and higher levels of psychopathology in this
      population.

PMID- 12429877
TI  - Quality of life after gastric bypass surgery: a cross-sectional study.
AB  - OBJECTIVE: Numerous reports document significant weight loss after gastric
      bypass; however, there is little objective data on postsurgical changes in health
      related quality of life (HRQL). RESEARCH METHODS AND PROCEDURES: This study
      examined HRQL in four groups of patients: presurgery (T1), several weeks
      postsurgery (T2), 6 months postsurgery (T3), and 1 year postsurgery (T4).
      Subjects were given three HRQL measures: the short form 36 (SF-36), the Impact of
      Weight on Quality of Life-Lite Questionnaire (IWQOL-Lite), and the Bariatric
      Analysis and Reporting Outcome System (BAROS). Subjects also completed the Beck
      Depression Inventory (BDI) and the Rosenberg Self-Esteem Scale (RSE). RESULTS:
      There were no significant differences among the groups on demographics or
      presurgical body mass index. Results showed significant differences between T1
      and T2 on several SF-36 and IWQOL-Lite subscales, as well as the RSE and BDI.
      Significant differences were found on all measures between T2 and T3. Significant
      differences were found on all subscales of the IWQOL-Lite, but no subscales of
      the SF-36, the RSE, or the BDI between T3 and T4. DISCUSSION: This study is the
      first to objectively document these differences in several objective measures of
      HRQL, depression, and self-esteem after gastric bypass in a large sample. It is
      notable that many differences are apparent within several weeks after surgery.
      Furthermore, results indicate that the IWQOL-Lite may be more sensitive than the
      SF-36 to the changes of quality of life that gastric bypass patients report.

PMID- 12429878
TI  - Two measures of health-related quality of life in morbid obesity.
AB  - OBJECTIVE: To compare health-related quality of life (HRQOL) measures in obese
      presurgery patients with and without binge-eating disorder (BED) and to
      investigate the relationship between a generic [short form-36 (SF-36)] and a
      disease-specific HRQOL measure [Impact of Weight on Quality of Life Questionnaire
      (IWQOL)] and measures of eating-related and general psychopathology. RESEARCH
      METHODS AND PROCEDURES: One hundred ten patients ages 19 to 62 years with a mean
      body mass index of 48.4 +/- 8.3 kg/m(2) who were evaluated for gastric bypass
      surgery were asked to fill out questionnaires assessing eating-related and
      general psychopathology (depression, self-esteem), as well as the two HRQOL
      questionnaires. BED was assessed by self-report. RESULTS: Nineteen (17.3%)
      patients met criteria for BED. Significant differences between patients with and
      without BED were found for four of the eight subscales of the SF-36-with effect
      sizes ranging from 0.44 to 0.75-and for the total score and three of the five
      subscales of the IWQOL-Lite-with effect sizes from 0.57 to 0.74. The mental
      composite score of the SF-36 as well as the IWQOL total score correlated
      significantly with the measures of psychopathology. DISCUSSION: This is the first
      study comparing the results of HRQOL measures in morbidly obese presurgery
      patients with and without BED. The results indicate that BED has a profound
      negative impact on HRQOL that exceeds the influence of obesity. Both HRQOL
      measures were able to reliably discriminate between patients with and without
      BED. Depression and self-esteem influenced HRQOL in a similar way as binge
      eating.

PMID- 12429879
TI  - Are obese adolescents and young adults at higher risk for mental disorders? A
      community survey.
AB  - OBJECTIVE: Associations between body mass index (BMI) and mental disorders
      meeting Axis-I diagnoses according to the Diagnostic and Statistical Manual for
      Mental Disorders IV (DSM-IV) were investigated in The Early Developmental Stages
      of Psychopathology Study in a large population-based sample, which included
      adolescents and young adults of both genders for the first time. RESEARCH METHODS
      AND PROCEDURES: A total of 3021 German subjects ranging from 14 to 24 years of
      age were assessed for specific DSM-IV diagnoses derived from a modified version
      of the standardized Composite International Diagnostic Interview, and general
      psychological disturbances, using the Symptom Checklist-90-Revised. BMI
      percentiles for age and gender were calculated to avoid systematic bias in the
      BMI distribution resulting from the young age range represented in the sample.
      Additionally, subjects with a lifetime diagnosis of any eating disorder were
      excluded from statistical analysis to control the confounding effect of body
      weight-related eating disorders on associations between BMI and psychopathology.
      RESULTS: The results based on logistic regression analyses and MANOVAs
      demonstrate that the BMI is not associated with mental disorders or general
      psychopathologies. There were no significant associations between BMI and mood,
      anxiety, substance, and somatoform disorders, a result that contrasts with almost
      all previous clinical studies. Additionally, in contrast to clinical
      investigations and most epidemiological studies, neither obesity nor underweight
      was significantly associated with any kind of general psychopathology.
      DISCUSSION: The overall finding that obesity is not significantly related to
      marked psychopathology in the general German population of adolescents and young
      adults has important clinical implications.

PMID- 12429880
TI  - Ghrelin and the hyposomatotropism of obesity.
AB  - OBJECTIVE: Human obesity is characterized by growth hormone (GH) deficiency,
      which appears primarily related to a central pattern of obesity and is reverted
      on weight loss. As yet, the metabolic basis of the GH deficiency remains to be
      elucidated. The recently discovered endogenous ligand for the GH secretagogue
      receptor, ghrelin, stimulates GH secretion when administered to rodents or
      healthy humans. It may thus be hypothesized that low ghrelin levels underlie the
      hyposomatropism in obesity. RESEARCH METHODS AND PROCEDURES: We have tested this
      hypothesis in individuals with widely varying body mass and fat distribution and
      evaluated whether the improved GH concentrations on weight loss are associated
      with enhanced ghrelin levels. RESULTS: Both plasma GH and ghrelin levels were
      reciprocally related with body mass index (r = -0.67, p < 0.001). However,
      whereas 24-hour GH secretion was negatively related to the visceral fat area (r =
      -0.72, p < 0.01), ghrelin levels showed a positive relationship with the visceral
      fat area (r = 0.49, p < 0.02). Weight loss resulted in increased GH secretion
      (median 24-hour GH area under the curve: 1983 vs. 4024 mU/day before and after
      weight loss, respectively; p < 0.01) but did not affect ghrelin levels. No
      relationship could be found between GH and ghrelin plasma levels in obese
      subjects when comparing diurnal concentration profiles. DISCUSSION: We showed
      that plasma ghrelin and GH levels are both reciprocally related with body mass
      index, but no causative relationship could be demonstrated between low ghrelin
      levels and the hyposomatropism in human obesity.

PMID- 12429881
TI  - Relationship between waist circumference, body mass index, and medical care
      costs.
AB  - OBJECTIVE: Excessive visceral adiposity as measured by anthropomorphic measures
      may be more closely associated with adverse health consequences than body weight
      or body mass index (BMI), the more commonly obtained clinical measures. Waist
      circumference (WC) provides information about regional adiposity and may
      correlate with health care costs better than body weight or BMI. RESEARCH METHODS
      AND PROCEDURES: A total of 424 men (37%) and women (63%) were identified as they
      were seen in outpatient medical clinics at Denver Health, an integrated health
      care system serving a largely indigent population. Height, weight, and WC were
      measured by one examiner. Information on outpatient, laboratory, pharmacy,
      inpatient, and total charges attributable to each subject for the preceding year
      were obtained from computerized databases. Data on health care charges were
      divided into quartiles based on WC and BMI. RESULTS: Total annual health care
      charges were significantly greater in the highest WC quartile (WC < 83.3 cm:
      $6062 +/- $784; 83.3 to 93.5 cm: $5968 +/- $812; 93.7 to 103.5 cm: $6369 +/-
      $1015; >103.5 cm: $8699 +/- $1092; p = 0.047). Those with a WC >103.5 cm
      generated 85% more inpatient charges than the group with a WC <83.3 cm. Although
      there was a positive trend, BMI was not found to significantly correlate with
      total health care charges in this population sample. DISCUSSION: These results
      suggest that abdominal adiposity as assessed by WC is associated with increased
      total health care charges and may be a better predictor of health care charges
      than the more widely used BMI.

PMID- 12429882
TI  - The food amount rating scale: development, reliability, and validity.
AB  - OBJECTIVE: Implied in measures of binge eating is the assumption that individuals
      agree on what comprises a large amount of food. However, whether individuals
      estimate food amounts similarly or whether estimation of food amounts varies as a
      function of personal characteristics is unknown. The Food Amount Rating Scale
      (FARS) is a standardized set of stimuli for assessing individuals' judgment of
      food amounts. RESEARCH METHODS AND PROCEDURES: Two versions of the FARS were
      developed, and their psychometric properties were assessed. These versions are
      the same in all respects except that the rater is instructed to rate various food
      amounts for the average woman on Form W and for the average man on Form M.
      RESULTS: Content validity was confirmed by 14 researchers and research assistants
      in the field of eating disorders. The FARS is a 24-item inventory with adequate
      test-retest reliability (Form W = 0.85; Form M = 0.87) and split-half reliability
      (Form W = 0.90; Form M = 0.89). Convergent validity is suggested by the finding
      that ratings for the average woman (Form W) were significantly higher than
      ratings for the average man (Form M). DISCUSSION: The FARS is a psychometrically
      sound tool for use in basic research focused on identifying whether the
      subjective judgment of food amounts varies as a function of personal
      characteristics and in clinical research where it may be important to know how
      individuals judge food amounts.

PMID- 12429883
TI  - Body composition in a seasonal model of obesity: longitudinal measures and
      validation of DXA.
AB  - OBJECTIVE: Collared lemmings, Dicrostonyx groenlandicus, show rapid changes in
      body mass on a seasonal basis. The objective of this study was to measure
      longitudinal changes in body composition in animals undergoing photoperiod
      induced weight gain and loss using DXA. RESEARCH METHODS AND PROCEDURES: Adult,
      female collared lemmings exposed to either long (LD; 22 hours light/2 hours dark)
      or short (SD; 8 hours light/16 hours dark) photoperiods were anesthetized, and
      DXA was used to determine fat mass, lean tissue mass (LTM), total-body bone
      mineral content, and total-bone mineral density. After a baseline scan, one-half
      of the animals were transferred to the alternate photoperiod (SD-LD, weight loss;
      LD-SD, weight gain) and one-half remained on the same photoperiod (controls; SD
      SD, LD-LD). Body composition was determined by DXA after 4 and 8 weeks. Animals
      were killed, and body composition was determined by carcass analysis. DXA-derived
      data were validated by comparing with carcass analysis. RESULTS: Body composition
      by DXA was highly related to body composition measured by chemical analysis,
      thereby justifying the use of DXA. Lemmings in the SD-LD group lost weight, and
      this was reflected in measurable losses of fat and LTM. Lemmings in the LD-SD
      group gained weight, which was shown by measurable increases in fat, LTM and
      total-body bone mineral content. DISCUSSION: Comparison of body composition
      determined by DXA to that by chemical extraction revealed that DXA is useful for
      measuring body composition. The longitudinal analysis revealed that collared
      lemmings undergo rapid changes in body composition when exposed to changes in
      photoperiod.

PMID- 12429884
TI  - Effects of a high-fat diet and strain on hypothalamic gene expression in rats.
AB  - OBJECTIVE: This study was designed to investigate whether dietary fat and genetic
      background might differentially alter the expression of hypothalamic genes
      involved in food intake. RESEARCH METHODS AND PROCEDURES: Three-month-old Osborne
      Mendel (OM) and S5B/Pl rats were fed either a high-fat or a low-fat diet for 14
      days. mRNA for neuropeptide Y (NPY), corticotrophin-releasing hormone, NPY Y-1
      receptor and Y-5 receptor, and serotonin 2c (5-HT2c) receptors were measured
      using Northern blotting or ribonuclease protection assays. RESULTS: OM rats
      showed an increased expression of NPY and corticotrophin-releasing hormone
      compared with S5B/Pl rats. The expression of NPY-Y1 and -Y5 receptor mRNA was
      significantly higher in the hypothalamus of OM rats compared with S5B/Pl rats.
      The expression of 5HT-2c receptor mRNA was significantly reduced in both strains
      of rats eating a high-fat diet when compared with the animals eating the low-fat
      diet. DISCUSSION: These data suggest that over activity of the NPY system may
      contribute to the development of obesity in OM rats and that expression of the
      5HT-2c receptor gene may be modulated by dietary fat.

PMID- 12429885
TI  - Resistin and adiponectin--of mice and men.

PMID- 12429886
TI  - Cripto, a multifunctional partner in signaling: molecular forms and activities.
AB  - Within a multicellular organism, communication between cells is essential during
      development to ensure proper execution of cell migration, cell fate decisions,
      and differentiation events. It is also essential in the adult for the
      coordination of many physiological functions. Cell-to-cell communications often
      rely on the interaction of cell surface receptors with soluble or membrane-bound
      ligands. Receptors or ligands may interact with additional partners to trigger
      specific signaling cascades inside the cell. In most cases, partners act in a
      specific configuration, either as a diffusible "co-ligand" or a membrane-bound co
      receptor. Here, we examine the case of Cripto, a signaling molecule that has
      prominent functions during vertebrate development. Conflicting results have
      suggested that Cripto has the unusual capacity to act both as a secreted ligand
      and as a cell surface component to control a single signaling pathway. Here, we
      review the recent experiments that attempt to reconcile those results.
      Furthermore, three reports have described the fact that Cripto is modified by the
      addition of sugar residues, including a rare case of fucosylation. These
      modifications are essential for Cripto function, suggesting that, as is the case
      for other key developmental or physiological regulators such as Notch or
      selectins, the activity of Cripto may be controlled by the extent of its
      glycosylation or fucosylation (or both).

PMID- 12429887
TI  - Wachholder and Altenberger 1927: foundational experiments for current hypotheses
      on equilibrium-point control in voluntary movements.

PMID- 12429888
TI  - rTMS to the supplementary motor area disrupts bimanual coordination.
AB  - Bimanual coordination tasks form an essential part of our behaviour. One brain
      region thought to be involved in bimanual coordination is the supplementary motor
      area (SMA). We used repetitive transcranial magnetic stimulation (rTMS) at 1 Hz
      for 5 min to create a temporary virtual lesion of the rostral portion of the
      human SMA immediately prior to performance of a goal-directed bimanual
      coordination task. In two control conditions, participants underwent sham
      stimulation or stimulation over the primary motor cortex (MI). The experimental
      task was to open a drawer with the left hand, catch a ball with the right hand,
      and reinsert the ball into the drawer through an aperture just big enough for the
      ball to pass through, again with the right hand. Hence, the actions of one hand
      depend upon the actions of the other. We calculated time intervals between the
      successive component actions of one hand (unimanual intervals) and actions of
      both hands (bimanual intervals) and analyzed these intervals separately.
      Interestingly, none of the unimanual intervals were affected by the rTMS, but the
      variability of a critical bimanual interval--the time between the left hand
      opening the drawer and the right hand starting to move to catch the ball--was
      increased by rTMS over the rostral parts of the SMA. No such effect was seen
      following rTMS over MI or after sham rTMS. Our results suggest that the rostral
      parts of the SMA play an important role in aspects of functional bimanual tasks,
      which involve tight temporal coordination between different motor actions of the
      two hands.

PMID- 12429889
TI  - Development of force control and timing in a finger-tapping sequence with an
      attenuated-force tap.
AB  - We conducted an experiment to examine age-related differences in the control of
      force and timing in a finger-tapping sequence with an attenuated-force tap.
      Participants between 7 and 20 years old tapped on a load cell with feedback on
      practice trials. They were required to recall the force pattern (300 g, 300 g,
      300 g, 100 g) and the intertap interval (400 ms) without feedback on test trials.
      Analysis indicated that the last attenuated tap affected the first three taps of
      the tapping sequence in adults and adolescents but not in children. Adults and
      adolescents appeared to respond with four taps as a chunk, resulting in a
      contextual effect on the timing of force control, but younger children had
      difficulty with such chunking. Further, adults and adolescents were able to more
      accurately produce individual force magnitudes to match target magnitudes than
      younger children. For the ratio of force in serial positions 1:4, 2:4, and 3:4,
      consequently, 7- to 8-year-old children had lower ratios than the other age
      groups. Although there was no difference among age groups for timing control of
      peak force to press duration as a control strategy of force, 7- to 8-year-old
      children spent more time to produce force than the other age groups. Peak force
      with a decreased force was more variable in the attenuated force serial position
      (4) than in the other serial positions in all five age groups. Peak force
      variability was particularly robust in younger children. These findings suggest
      that younger children have difficulty with both temporal and spatial (i.e.,
      magnitude) components of force control.

PMID- 12429890
TI  - Scaling the components of prehension.
AB  - The experiment reported examined: (a) the role of the geometrical body scaled
      informational invariant for the transition of human grip configurations; (b)
      whether the same invariant can be scaled considering also the force applied
      during the grasp phase; and (c) how the temporal duration of the grasp and
      displacement phases of prehension are scaled to the object properties of size and
      mass. Adult subjects performed a series of trials in reaching, grasping, and
      displacing spheres that varied in size and mass. The grip transitions were
      described by the body scaled relation: [formula: see text] where L(s) and M(s)
      are, respectively, the diameter and the mass of the spheres grasped and L(h) and
      M(h) are the length and the mass of the hand. The impulse during the grasp phase
      was linearly related with the mass of the spheres within each density. The
      temporal durations of the grasp and displacement components were scaled
      coherently to the object properties. These findings provide support to the
      hypothesis that the grasp and displacement components of prehension are organized
      coherently within a single action.

PMID- 12429891
TI  - Influence of biomechanical constraints on horizontal arm movements.
AB  - Influence of mechanical interactions between the shoulder and elbow on production
      of different coordination patterns during horizontal arm movements is
      investigated in the present study. Subjects performed cyclical movements along a
      circle and along lines of 4 different orientations. Cycling frequency was
      manipulated to highlight control features responsible for interactive torque
      regulation. When the shoulder was involved in motion, torque analysis revealed
      that this joint was controlled similarly during all movement types. At the elbow,
      however, each movement type required a specific pattern of regulation of
      interactive torque with muscle torque. When interactive torque acted in the
      direction of the required elbow rotation, the demands for active control were
      lower than when the interactive torque resisted elbow motion and had to be
      actively suppressed. Kinematic analysis demonstrated that increases in cycling
      frequency systematically deformed the fingertip path. The amount of these
      deformations differed across movement types, being more pronounced for movements
      where the interactive torque resisted joint motion. It appears that interactive
      torque can assist or resist movement at the joints, making control of some
      movement types more difficult than others.

PMID- 12429892
TI  - Bimanual coordination dynamics in adults with Down syndrome.
AB  - Previous experiments involving discrete unimanual tasks have shown that
      individuals with Down syndrome (DS) have auditory/verbal-motor deficits. The
      present study investigated unimanual and bimanual continuous perceptual-motor
      actions in adults with DS. Ten adults with DS, 10 typical adults, and 10 children
      drew continuous circles at increasing periods bimanually and unimanually with
      each hand. Movement was paced by either a visual or an auditory metronome. The
      results revealed that for circle shape and coordination measures, children and
      adults were more accurate with the visual metronome, whereas adults with DS were
      more accurate with the auditory metronome. In the unimanual tasks, adults with DS
      displayed hand asymmetries on spatial measures. In the bimanual task, however,
      adults with DS adopted an in-phase coordination pattern and stability more
      similar to adults than children. These results suggest that bimanual coordination
      in adults with DS is functioning effectively despite hand asymmetries evident in
      unimanual performance.

PMID- 12429893
TI  - Physical activity, aerobic fitness, and seven-year changes in adiposity in the
      Canadian population.
AB  - Associations among baseline physical activity, aerobic fitness, changes in
      physical activity, and 7-y changes in adiposity were determined. The sample
      consisted of 602 males and 644 females, aged 20-69 y, from the 1981 Canada
      Fitness Survey and the 1988 Campbell's Survey. Questionnaire-derived measures of
      physical activity level consisted of activity energy expenditure (AEE) and time
      spent on physical activity. Participants were grouped into physical activity
      level categories by AEE and physical activity intensity (based on MET values),
      and physical activity level changes were determined from movement between
      tertiles of AEE from baseline to follow-up. Aerobic fitness levels at baseline
      were determined using the Canadian Aerobic Fitness Test. Changes in body mass,
      the sum of five skinfolds (SF5), and waist circumference (WC) were used as
      indicators of adiposity change. ANCOVA and multiple regression analyses indicated
      that neither baseline physical activity levels, intensity, physical activity
      change categories, nor aerobic fitness levels were significant predictors of
      changes in adiposity. In conclusion, physical activity was not predictive of 7-y
      changes in indicators of adiposity in this sample.

PMID- 12429894
TI  - Maximal accumulated O2 deficit in running and cycling.
AB  - The purpose of this study was to compare values for maximal accumulated O2
      deficit measured in running and cycling. Nine university students performed five
      fatiguing constant-velocity treadmill tests and five fatiguing constant-power
      cycle ergometer tests at intensities within the severe domain. O2 deficit was
      determined making the traditional assumptions that (1) the O2 demand increases
      linearly with the exercise intensity and (2) the O2 demand is constant from the
      onset of exercise if the intensity is kept constant (Medbo, 1996). VO2max was 11%
      higher in running than in cycling. In contrast, O2 deficit was approximately 50%
      higher in cycling than treadmill running. Inspection of the data suggested that
      the O2 demand may have been underestimated, especially in the treadmill tests. It
      was concluded that assumptions associated with measuring maximal accumulated O2
      deficit in running must be revisited.

PMID- 12429895
TI  - Ankle plantar flexion strength in resistance and endurance trained middle-aged
      adults.
AB  - Maximum concentric (CONC) and eccentric (ECC) strength of the ankle plantar
      flexor muscles were compared between middle-aged adults who regularly
      participated in resistance exercise training versus those who participated in
      weight-bearing endurance exercise. A total of 40 men and women with a mean age of
      48.9 years (SD = 5.3) were tested for CONC and ECC plantar flexor (PF) strength,
      using an isokinetic device at 3 velocities: 30, 90 and 180 degrees/s. Mean
      strength values for the groups of men and women involved in resistance exercise
      were consistently higher than those involved in the endurance training for the
      CONC tests, where values ranged from 35% to 46% (avg. 41%, p < .01), but less
      between-group difference was observed for the ECC loading condition: 4% to 30%
      (avg. 18%). Thus ECC/CONC ratios, which rose with increasing velocity, were
      consistently higher for the endurance group vs. resistance-trained. Finally,
      since concentric PF torque values were found to be quite low for the middle-aged
      women who did only endurance training, this movement may require preventive
      strengthening exercises.

PMID- 12429896
TI  - Molecular control of capillary growth in skeletal muscle.
AB  - Angiogenesis, the growth of new capillaries, enhances the oxygen delivery
      capacity of an existing vascular network. This adaptation is a well-documented
      occurrence in exercising skeletal muscle. The purpose of this review is to
      summarize our current understanding of the various stimuli that are involved in
      the initiation of capillary growth in skeletal muscle. The roles of humoral and
      mechanical signals in the cellular regulation of several key angiogenic players,
      vascular endothelial cell growth factor and matrix metalloproteinases, will be
      discussed. Evidence will be presented supporting the existence of angiogenesis
      processes that are distinct from the "classically" defined process. Determining
      how specific angiogenic stimuli can initiate unique patterns of capillary growth
      will provide insight into the complex task of developing effective pro-angiogenic
      therapies.

PMID- 12429897
TI  - Variability in estimating eccentric contraction-induced muscle damage and
      inflammation in humans.
AB  - We studied five young healthy volunteers who performed a "damage protocol"
      consisting of 240 (24 sets x 10 repetitions/set) maximal isokinetic eccentric
      muscle contractions (30 degrees/s) on each leg one week apart. Biopsies were
      taken from the vastus lateralis on two occasions. Two biopsies were taken from
      within the same muscle 24h following the damage protocol. On a second occasion a
      single biopsy was taken from the contralateral leg at 24h following the same
      damage protocol. Biopsies at all three sites showed Z-band disruption, much
      greater (i.e., approximately 14-fold) than is typically observed in resting
      biopsies, with no significant differences (ANOVA) according to site location
      (within legs or between legs). The within-leg coefficient of variation (CV) was,
      however, 41 +/- 30%, and the between-leg CVs were 57 +/- 36% and 68 +/- 36%.
      Macrophage cells were also detected within the muscle, and cell numbers were not
      statistically different between biopsy sites. However, the within-biopsy CV = 52
      +/- 19% and the between-biopsy CVs of 34 +/- 24% and 48 +/- 27%. We conclude that
      eccentric contraction-induced Z-band streaming and inflammatory cell response, as
      detected in muscle biopsy samples from humans, is highly variable with a CV of 40
      70%.

PMID- 12429898
TI  - Ultra-sound imaging for precision implantation of a multi sensor temperature
      probe in skeletal muscle tissue.
AB  - A technique for implanting multi sensor temperature probes in muscle tissue was
      developed to optimize the accuracy of the tissue temperature measurements and the
      internal localization of the probe. Real time ultra-sound imaging was used to (a)
      determine the best perpendicular insertion tract, (b) guide the insertion of the
      probe in order to avoid major blood vessels, and (c) verify the insertion point
      relative to discernable anatomic reference structures such as arteries and bone.

PMID- 12429900
TI  - Basic cell cycle and cancer research: is harmony impossible?

PMID- 12429901
TI  - Heroes for a heroic age.

PMID- 12429902
TI  - No fear of flying.

PMID- 12429903
TI  - Anthrax, MEK and cancer.
AB  - The MEK family of protein kinases plays key roles in regulating cellular
      responses to mitogens as well as environmental stress. Inappropriate activation
      of these kinases contributes to tumorigenesis. In contrast, anthrax lethal
      factor, the principal virulence factor of anthrax toxin, has been demonstrated to
      selectively inactivate MEKs. In this article we will discuss recent advances in
      our understanding of molecular aspects of the pathogenesis of anthrax,
      emphasizing the potential role of MEK signalling in this disease, and outline
      novel strategies to use anthrax lethal toxin in the treatment of cancer.

PMID- 12429904
TI  - DNA-damage-independent checkpoints: yeast and higher eukaryotes.

PMID- 12429905
TI  - Checkpoints that count.

PMID- 12429906
TI  - D1 in G2.

PMID- 12429907
TI  - Not just a CDK inhibitor: regulation of transcription by p21(WAF1/CIP1/SDI1).

PMID- 12429908
TI  - Phosphorylation of the septin cdc3 in g1 by the cdc28 kinase is essential for
      efficient septin ring disassembly.
AB  - The septins constitute a family of filament-forming proteins ubiquitous in
      eukaryotic species. We demonstrate here that the Saccharomyces cerevisiae septin,
      Cdc3, is a substrate of the cell cycle regulatory cyclin-dependent kinase (Cdk),
      Cdc28. Two serines near the C-terminus of Cdc3 are phosphorylated in a Cdc28
      dependent manner. Analysis of a mutant allele that cannot be phosphorylated at
      these sites revealed an effect of Cdc28 phosphorylation of Cdc3 at the time of
      budding. Immunofluorescence analysis of wild-type and mutant Cdc3 indicated that
      prevention of phosphorylation at Cdc28-dependent sites impairs the disassembly of
      the old septin ring, which is inherited at mitosis but which usually disappears
      immediately prior to assembly of a new ring. Furthermore, immuno-fluorescence
      analysis of septin ring dynamics in a G1 cyclin (Cln) mutant suggests that G1
      cyclin function is required for efficient ring disassembly. Thus, phosphorylation
      of Cdc3 by the Cdc28 kinase at the end of G1 may facilitate initiation of a new
      cell cycle by promoting disassembly of the obsolete septin ring from the previous
      cell cycle.

PMID- 12429909
TI  - Ras is active throughout the cell cycle, but is able to induce cyclin D1 only
      during G2 phase.
AB  - The control of cell cycle progression has been studied in asynchronous cultures
      using image analysis and time lapse techniques. This approach allows
      determination of the cycle phase and signaling properties of individual cells,
      and avoids the need for synchronization. In past studies this approach
      demonstrated that continuous cell cycle progression requires the induction of
      cyclin D1 levels by Ras, and that this induction takes place during G2 phase.
      These studies were designed to understand how Ras could induce cyclin D1 levels
      only during G2 phase. First, in studies with a Ras-specific promoter and cellular
      migration we find that endogenous Ras is active in all cell cycle phases of
      actively cycling NIH3T3 cells. This suggests that cyclin D1 induction during G2
      phase is not the result of Ras activation specifically during this cell cycle
      period. To confirm this suggestion oncogenic Ras, which is expected to be active
      in all cell cycle phases, was microinjected into asynchronous cells. The injected
      protein induced cyclin D1 levels rapidly, but only in G2 phase cells. We conclude
      that in the continuously cycling cell the targets of Ras activity are controlled
      by cell cycle phase, and that this phenomenon is vital to cell cycle progression.

PMID- 12429910
TI  - Identification of promoter elements responsible for transcriptional inhibition of
      polo-like kinase 1 and topoisomerase IIalpha genes by p21(WAF1/CIP1/SDI1).
AB  - Induction of p21 (WAF1/CIP1/SDI1), a physiological mediator of cell cycle arrest,
      inhibits multiple genes involved in cell division. We have investigated the
      determinants of p21- mediated inhibition of two of these genes, polo-like kinase
      1 (PLK1) and topoisomerase IIalpha (TOPO IIalpha) p21 expression from an
      inducible promoter in human HT1080 cells rapidly decreases cellular levels of
      PLK1 and TOPO IIalpha promoters in transient and stable transfection assays.
      Promoter mutagenesis studies show that inhibition of the PLK1 promoter by p21 is
      mediated in part by tandem sequences CDE (cell cycle-dependent element) and CHR
      (cell cycle genes homology region). p21 response of the TOPO IIalpha promoter
      inhibition and the effects of promoter mutations differ under the conditions of
      growth arrest produced by p21 induction or by mimosine, a cell cycle inhibitor
      that increases p21 RNA but not protein expression in HT1080 cells. These results
      indicate that inhibition of cell division-associated genes by p21 is mediated by
      different but overlapping mechanisms, which are not a general con-sequence of
      cell cycle arrest.

PMID- 12429911
TI  - Inhibition of transcription results in accumulation of Wt p53 followed by delayed
      outburst of p53-inducible proteins: p53 as a sensor of transcriptional integrity.
AB  - Here we investigate activation of the p53 pathway by inhibition of transcription.
      Comparison of cells with either mutant p53 or wt p53 indicated that inhibition of
      p53- dependent transcription is necessary and sufficient for wt p53 accumulation.
      In addition to Mdm-2, p21 is required for effective p53 degradation. Transient
      inhibition of transcription resulted in initial downregulation of p21 and Mdm-2
      leading to accumulation of wt p53. This was followed by induction of p21 and Mdm
      2, normalization of p53 levels, and p21-dependent growth arrest. Although
      simultaneous induction of p53 and p21 could be detected by immunoblot, levels of
      p53 and p21 were discordant in individual cells. By inducing p21 and Mdm-2, p53
      discriminates between transient and sustained inhibition of transcription.
      Transient inhibition results in p21-dependent growth, while sustained inhibition
      of transcription leads to p53-facilitated cell death. One can envision p53 as a
      physiological sensor of transcriptional integrity. Transient inhibition of p53-
      stimulated transcription by numerous stimuli including nucleotide depletion,
      hypoxia, UV light may be an prevalent mechanism of activation of wt p53 and its
      downstream pathways.

PMID- 12429912
TI  - A mammalian in vitro centriole duplication system: evidence for involvement of
      CDK2/cyclin E and nucleophosmin/B23 in centrosome duplication.
AB  - Centrosome duplication in mammalian cells is a highly regulated process, occurs
      in coordination of other cell cycle events. However, molecular exploration of
      this important cellular process had been difficult due to unavailability of a
      simple assay system. Here, using centrosomes loosely associated with nuclei
      isolated from cultured cells, we developed a cell-free centriole (duplication
      unit of the centrosome) duplication system: unduplicated centrosomes bound to the
      nuclei are able to undergo duplication in the presence of G1/S extracts. We show
      that the ability of G1/S extracts to induce centriole duplication in vitro
      depends on the presence of active CDK2/cyclin E. It has been shown that
      dissociation of centro-somal nucleophosmin (NPM)/B23 triggered by CDK2/cyclin E
      mediated phosphorylation is required for initiation of centrosome duplication. We
      show that centriole duplication is blocked when nuclei were preincubated with the
      anti-NPM/B23 antibody that prevents phosphorylation of NPM/B23 by CDK2/cyclin E.
      These studies provide not only direct evidence for the requirement of CDK2/cyclin
      E and phosphorylation of NPM/B23 for centrosomes to initiate duplication, but a
      valuable experimental system for further exploration of the molecular regulation
      of centrosome duplication in somatic cells of higher animals.

PMID- 12429913
TI  - Enhanced sensitivity of G1 arrested human cancer cells suggests a novel
      therapeutic strategy using a combination of simvastatin and TRAIL.
AB  - Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)
      preferentially induces apoptosis in tumor cells over normal cells. To study the
      relationship between cell cycle progression and TRAIL-induced apoptosis, SW480
      colon cancer and H460 lung cancer cell lines were examined for their sensitivity
      to TRAIL after arrest in different cell cycle phases. Cells were synchronized in
      G0/G1, S, and G2/M phase by serum starvation, aphidicolin, or nocodazole
      treatment, respectively. We found that arrest of cells in G0/G1 phase confers
      significantly higher susceptibility to TRAIL-induced apoptosis as compared to
      cells in late G1, S, or G2/M phase. To determine if cell cycle phase could be
      harnessed for therapeutic gain in the presence of TRAIL, we used the HMG-CoA
      reductase inhibitor, Simvastatin and lovastatin, to enrich a cancer cell
      population in G0/G1. Both simvastatin and lovastatin significantly augmented
      TRAIL-induced apoptosis in tumor cells, but not in normal keratinocytes. The
      results indicate that TRAIL, in combination with a HMG-CoA reductase inhibitor,
      may have therapeutic potential in the treatment of human cancer.

PMID- 12429914
TI  - The cyclin-dependent kinase inhibitor butyrolactone is a potent inhibitor of p21
      (WAF1/CIP1 expression).
AB  - Butyrolactone I (BL) is a competitive inhibitor of ATP for binding and activation
      of cyclin-dependent kinases and is a potent inhibitor of cell cycle progression.
      Treatment of H460 human lung and SW480 human colon cancer cells with doses of BL
      that exceed the Ki for CDK inhibition but which are much lower than doses
      required to inhibit MAPK, PKA, PKC, or EGFR lead to a rapid significant reduction
      of endogenous p21 protein expression. BL-dependent inhibition of p21 expression
      appears to be p53-independent. BL-dependent p21 degradation was blocked by
      lactacystin, consistent with the hypothesis that there is accelerated p21
      proteasomal degradation in the presence of BL. BL also inhibited the p53
      dependent increase of p21 protein expression in cells exposed to the DNA damag
      ing agent etoposide, and favored a greater G2/M arrest as compared to the non-BL
      exposed cells. BL accelerated the degradation of exogenously expressed p21 that
      was not observed with a C-terminal truncated form of p21. Degradation of
      exogenous p21 led to a shift to G2 accumulation in the cells exposed to BL. We
      conclude that BL has effects on the cell cycle beyond its role as a CDK inhibitor
      and can be used as a novel tool to study the mechanism of p21 degradation and the
      consequences towards p21- dependent checkpoints.

PMID- 12429915
TI  - No restriction points in life and science.

PMID- 12429916
TI  - The restriction point of the cell cycle.
AB  - As formulated in 1974, the concept of the restriction point of the cell cycle was
      based on cell biological experiments, yet allowing accurate molecular predictions
      and spurring a search for the restriction factor. Although cyclin D meets the
      criteria of the R-factor, the picture as outlined here is more interesting and
      far more complex. We discuss the relationship between the restriction knot and
      DNA damage-checkpoints. Finally, we discuss how loss of the restriction point in
      cancer leads to loss of checkpoint control and to insensitivity to antimitogens
      including some mechanism-based anticancer therapeutics.

PMID- 12429917
TI  - p53: an internal investigation.

PMID- 12429918
TI  - Butyrolactone: more than a kinase inhibitor?

PMID- 12429919
TI  - New methodology is a key to progress.

PMID- 12429920
TI  - CDK inhibitors: cell cycle arrest versus apoptosis.

PMID- 12429922
TI  - Improved flow cytometric analysis of the budding yeast cell cycle.
AB  - The budding yeast, Saccharomyces cerevisiae has been a remarkably useful model
      system for the study of eukaryotic cell cycle regulation. Flow cytometric
      analysis of DNA content in budding yeast has become a standard tool for the
      analysis of cell cycle progression. However, popular protocols utilizing the DNA
      binding dye, propidium iodide, suffer from a number of drawbacks that confound
      accurate analysis by flow cytometry. Here we show the utility of the DNA binding
      dye, SYTOX Green, in the cell cycle analysis of yeast. Samples analyzed using
      SYTOX Green exhibited better coefficients of variation, improved linearity
      between DNA content and fluorescence, and decreased peak drift associated with
      changes in dye concentration, growth conditions or cell size.

PMID- 12429921
TI  - Sequential activation of caspases and serine proteases (serpases) during
      apoptosis.
AB  - Analogous to caspases, serine (Ser) proteases are involved in protein degradation
      during apoptosis. It is unknown, however, whether Ser proteases are activated
      concurrently, sequentially, or as an alternative to the activation of caspases.
      Using fluorescent inhibitors of caspases (FLICA) and Ser proteases (FLISP), novel
      methods to detect activation of these enzymes in apoptotic cells, we demonstrate
      that two types of Ser protease sites become accessible to these inhibitors during
      apoptosis of HL-60 cells. The prior exposure to caspases inhibitor Z-VAD-FMK
      markedly diminished activation of both Ser protease sites. However, the unlabeled
      inhibitor of Ser-proteases TPCK had modest suppressive effect- while TICK had no
      effect- on the activation of caspases. Activation of caspases, thus, appears to
      be an upstream event and likely a prerequisite for activation of FLISP-reactive
      sites. Differential labeling with the red fluorescing sulforhodamine-tagged VAD
      FMK and the green fluorescing FLISP allowed us to discriminate, within the same
      cell, between activation of caspases and Ser protease sites. Despite a certain
      degree of co-localization, the pattern of intracellular caspase- vs FLISP-
      reactive sites, was different. Also different were relative proportions of
      activated caspases vs Ser protease sites in individual cells. The observed
      induction of FLISP-binding sites we interpret as revealing activation of at least
      two different apoptotic Ser proteases; by analogy to caspases we denote them
      serpases. Their apparent molecular weight (62-65 kD) suggests that they are novel
      enzymes.

PMID- 12429923
TI  - The cancer preventive flavonoid silibinin causes hypophosphorylation of Rb/p107
      and Rb2/p130 via modulation of cell cycle regulators in human prostate carcinoma
      DU145 cells.
AB  - Phosphorylation status of retinoblastoma (Rb) and related proteins is important
      to drive cell cycle progression. In hyperphosphorylated state, they are growth
      stimulatory, but their hypophosphorylation is growth inhibitory. Here we assessed
      whether silibinin causes hypophosphorylation of Rb-related proteins as its growth
      inhibitory response in human prostate cancer (PCA) DU145 cells. Silibinin
      treatment of cells resulted in a strong increase (up to 2.3-and 5.4-fold) in the
      levels of hypophosphorylated Rb/p107 and Rb2/p130, respectively, but a strong
      decrease (91, 78 and 45%) in protein levels of transcription factors E2F3, E2F4
      and E2F5, respectively. In the studies analyzing whether this effect of silibinin
      is via modulation of cell cycle regulators, silibinin-treated cells showed a
      strong increase (up to 13- and 6-fold) in Cip1/p21 and Kip1/p27 levels,
      respectively. Silibinin treatment also resulted in 90 and 70% decrease in CDK4
      and CDK2 levels, respectively, but did not alter the protein levels of cyclin D1
      and cyclin E. Consistent with its effect on G1 cell cycle regulators, silibinin
      treated cells exhibited a strong G1 arrest, almost complete growth inhibition,
      and morphological changes suggestive of differentiation. Together, these results
      suggest that silibinin caused hypophosphorylation of Rb-related proteins may in
      part be responsible for its cancer preventive and anti-carcinogenic efficacy in
      different cancer models including PCA.

PMID- 12429924
TI  - Induction of apoptosis in human leukemia cells by the CDK1 inhibitor CGP74514A.
AB  - We have examined the effects of the CDK1 inhibitor CGP74514A on cell cycle- and
      apoptosis-related events in human leukemia cells. An 18-hr exposure to 5 microM
      CGP74514A induced mitochondrial damage (i.e., loss of Delta psi(m)) and apoptosis
      in multiple human leukemia cell lines (e.g., U937, HL-60, KG-1, CCRF-CEM, Raji,
      and THP; range 30-95%). In U937 cells, CGP74514A- induced apoptosis (5 microM)
      became apparent within 4 hr and approached 100% by 24 hr. The pan- caspase
      inhibitor Boc-fmk and the caspase-8 inhibitor lETD-fmk opposed CGP74514A-induced
      caspase-9 activation and PARP degradation, but not cytochrome c or Smac/DIABLO
      release. CGP74514A-mediated apoptosis was substantially blocked by ectopic
      expression of full-length Bel- 2, a loop-deleted mutant Bcl-2, and Bcl-x(L).
      CGP74514A treatment (5 microM; 18 hr) resulted in increased p21(CIP1) expression,
      p27(KIP1) degradation, diminished E2F1 expression, and dephosphorylation of
      p34(CDC2). It also induced early (i.e., within 2 hr) inhibition of CDK1 activity
      and dephosphorylation of pRb, followed by pRb degradation, but did not block pRb
      phosphorylation at CDK2- and CDK4- specific sites. These findings indicate that
      the selective CDK1 inhibitor, CGP74514A, induces complex changes in cell cycle
      related proteins in human leukemia cells accompanied by extensive mitochondrial
      damage, caspase activation, and apoptosis.

PMID- 12429925
TI  - Phytochemicals as cell cycle modulators--a less toxic approach in halting human
      cancers.
AB  - The multistep nature of cancer development provides a rationale for cancer
      prevention. Activation of oncogenes, inactivation of tumor suppressor genes and
      modulation of mitogenic signal transduction pathways are critical in cancer
      progression and present attractive targets for cancer prevention/intervention. In
      this respect, cell cycle regulation and its modulation by various natural (plant
      derived) and synthetic agents are gaining widespread attention in recent years. A
      number of phytochemicals inhibit cell cycle progression in cancer cells, yet
      their clinical applications are still in infancy. The present review is focused
      on the modulatory effects of phytochemicals on critical cell cycle molecules, and
      discusses how they inhibit proliferation and/or induce apoptotic death in cancer
      cells.

PMID- 12429926
TI  - Linking DNA damage to cell cycle checkpoints.
AB  - Cell cycle checkpoints constitute a network of signal transduction mechanisms to
      monitor DNA damage and replication and thereby regulate progression through the
      cell cycle. A series of events is triggered in cells upon DNA damage. Here we
      describe a framework for the understanding of the functions of the core
      components involved in the cell cycle response to DNA damage and the relevance to
      the origin of cancer.

PMID- 12429927
TI  - Cold-shock and the Mammalian cell cycle.
AB  - Progression through the cell cycle is temperature sensitive, but the relationship
      is not straightforward. In culture, many types of mammalian cells fail to undergo
      the G(2)/M transition after cooling from 37 degrees C to 16-20 degrees C
      (moderate hypothermia). However, progression through G(1) and S is not blocked at
      these temperatures, nor is progression through mitosis in cells cooled after they
      have become committed to the division process. Thus, at least one pathway is
      present during G(2)-but not during G(1), S or mitosis-that is selectively
      disrupted at or below a critical temperature. As a result, a prolonged (24-48 hr)
      exposure to moderate hypothermia can be used to enrich cultures for G(2) cells. A
      brief (1 hr) exposure to severe hypothermia (4-10 degrees C) is also reported to
      induce a high degree of mitotic synchrony (up to 80%) in some mammalian cultures.
      Although the mechanism behind this synchronization remains vague, it may involve
      a cell cycle checkpoint, triggered in response to the cold shock, that
      transiently inhibits the G(1)/S transition.

PMID- 12429928
TI  - Cell cycle in plants: decatenation checkpoint is conserved across the two
      metazoan kingdoms.

PMID- 12429929
TI  - BRCA1 and Chk1 in G2/M checkpoint: a new order of regulation.

PMID- 12429930
TI  - When Duplicated Centrosomes Won't Split.

PMID- 12429931
TI  - Arsenic trioxide (As(2)O(3)): still a mystery.

PMID- 12429932
TI  - A topoisomerase II-dependent checkpoint in G2-phase plant cells can be bypassed
      by ectopic expression of mitotic cyclin B2.
AB  - DNA topoisomerase II is required for mitotic chromosome condensation and
      segregation. Here we characterize the effects of inhibiting DNA topoisomerase II
      activity in plant cells using the non-DNA damaging topoisomerase II inhibitor
      ICRF-193. We report that ICRF-193 abrogated chromosome condensation in cultured
      alfalfa (Medicago sativa L.) and tobacco (Nicotiana tabaccum L.) mitoses and led
      to bridged chromosomes at anaphase. Moreover, ICRF-193 treatment delayed entry
      into mitosis, increasing the frequency of cells having a pre-prophase band of
      microtubules, a marker of late G2 and prophase, and delaying the activation of
      cyclin-dependent kinase. These data suggest the existence of a late G2 checkpoint
      in plant cells that is activated in the absence of topoisomerase II activity. To
      determine whether the checkpoint-induced delay was a result of reduced
      cyclindependent kinase activity, mitotic cyclin B2 was ectopically expressed.
      Cyclin B2 bypassed the ICRF-193-induced delay before mitosis, and
      correspondingly, reduced the frequency of interphase cells with a pre-prophase
      band. These data provide evidence that plant cells possess a topoisomerase II
      dependent G2 cell cycle checkpoint that transiently inhibits mitotic CDK
      activation and entry into mitosis, and that is overridden by raising the level of
      CDK activity through the ectopic expression of a plant mitotic cyclin.

PMID- 12429934
TI  - Arsenic trioxide arrests cells early in mitosis leading to apoptosis.
AB  - Arsenic trioxide (As(2)O(3)) is highly effective in the treatment of acute
      promyelocytic leukemias that express the promyelocytic leukemia-retinoic acid
      receptor-alpha (PML-RARalpha) fusion protein. However, evidence has accumulated
      that As(2)O(3) induces apoptosis regardless of PML-RARalpha status. Here we show
      that, at clinically relevant concentrations, As(2)O(3) causes S and G(2)M phase
      arrest of both PML-RARalpha-positive and -negative leukemia cell lines, thus
      inhibiting their growth. Apoptotic cells are generated predominately from the
      G(2)M fraction. Using several independent methods, we demonstrate that the cells
      accumulated in the G(2)M peak consist primarily of cells arrested in the early
      stages of mitosis, prophase, prometaphase and metaphase. In mitotic cells, there
      was significant activation of caspases, PARP cleavage, and morphological changes
      characteristic of apoptosis. Unlike microtubule-active drugs that arrest cells in
      metaphase, arsenic trioxide did not affect the architecture of microtubules. Our
      data suggest that the antileukemic activities of arsenic may be a result of
      mitotic arrest which culminates in apoptosis.

PMID- 12429933
TI  - Radiation dose-dependent maintenance of G(2) arrest requires retinoblastoma
      protein.
AB  - In response to ionizing radiation (IR), cell cycle checkpoints are activated to
      provide time for DNA repair. Several different checkpoint mechanisms have been
      elucidated. However, mechanisms that regulate the duration of cell cycle arrest
      are not understood. Previous studies have shown that the retinoblastoma tumor
      suppressor protein (RB) is required for radiation-induced G1 arrest. Working with
      primary fibroblasts derived from Rb+/+ and Rb-/- mouse embryos, we show that RB
      also regulates the duration of G2 arrest. The initial G2 checkpoint response is
      enhanced in Rb-/- cells due to a defect in G1 arrest. However, the permanent
      arrest in G2 induced by higher doses of IR does not occur in Rb-/- cells. Rb-/-
      cells either resumed proliferation or underwent apoptosis at IR doses that caused
      the majority of Rb+/+ cells to arrest permanently in G2. The prolongation of G2
      arrest in Rb+/+ cells correlated with a gradual accumulation of
      hypophosphorylated RB. Thus, regulation of the RB function may be an important
      aspect in the maintenance of cell cycle checkpoints in DNA damage response.

PMID- 12429935
TI  - Degradation of ATM-independent decatenation checkpoint function in human cells is
      secondary to inactivation of p53 and correlated with chromosomal destabilization.
AB  - DNA topoisomerase II is required in the cell cycle to decatenate intertwined
      daughter chromatids prior to mitosis. To study the mechanisms that cells use to
      accomplish timely chromatid decatenation, the activity of a catenation-responsive
      checkpoint was monitored in human skin fibroblasts with inherited or acquired
      defects in the DNA damage G2 checkpoint. G2 delay was quantified shortly after a
      brief incubation with ICRF-193, which blocks the ability of topoisomerase II to
      decatenate chromatids, or treatment with ionizing radiation (IR), which damages
      DNA. Both treatments induced G2 delay in normal human fibroblasts. Ataxia
      telangiectasia fibroblasts with defective G2 checkpoint response to IR displayed
      normal G2 delay after treatment with ICRF-193, demonstrating that ATM kinase was
      not required for signaling when chromatid decatenation was blocked. The G2 delay
      induced by ICRF-193 was reversed by caffeine, indicating that active checkpoint
      signaling was involved. ICRF-193-induced G2 delay also was independent of p53
      function, being evident in cells expressing HPV16E6 to inactivate p53. However,
      as fibroblasts expressing HPV16E6 aged in culture, they lost the ability to delay
      entry to mitosis, both after DNA damage and when decatenation was blocked. This
      age-related loss of G2 delay in response to ICRF-193 and IR in E6-expressing
      cells was blocked by induction of telomerase. Expression of telomerase also
      prevented chromosomal destabilization in aging E6-expressing cells. These
      observations lead to a new model of genetic instability, in which attenuation of
      G2 decatenatory checkpoint function permits cells to enter mitosis with
      insufficiently decatenated chromatids, leading to aneuploidy and polyploidy.

PMID- 12429938
TI  - Proteolysis and the cell cycle.
AB  - Without doubt, one of the more dramatic breakthroughs in recent cell cycle
      history has been the discovery that growth regulators are controlled by
      proteolysis. This concept blossomed within the last six or seven years, but the
      story really began when cyclins were discovered, soon followed by the suggestion
      that proteolysis events might control cell cycle transitions. Proteolytic targets
      that are now known include most of the cyclins, cyclin dependent kinase
      inhibitors, DNA replication factors, the securin class of proteins that inhibit
      loss of sister chromatid cohesion following DNA replication and, of course, the
      cohesion factor itself. Protein degradation is controlled in various ways
      including ubiquitin-dependent targeting to proteasomes, activation of ubiquitin
      ligases by ubiquitin-like molecule conjugation, phosphorylation of proteolytic
      targets, and activation of the separin class of proteases.

PMID- 12429936
TI  - Raf-induced cell cycle progression in human TF-1 hematopoietic cells.
AB  - Ras/Raf/MEK/ERK is a crucial pathway regulating cell cycle progression,
      apoptosis, and drug resistance. The Ras oncogene is frequently mutated in human
      cancer, which can result in the activation of the downstream Raf/MEK/ERK cascade
      leading to cell cycle progression in the absence of a growth stimulus. Raf
      induced proliferation has been observed in hematopoietic cells. However, the
      mechanisms by which Raf affects cell cycle progression are not well described. To
      investigate the importance of Raf/MEK/ERK signaling in human hematopoietic cell
      growth, the effects of three different Raf genes, A-Raf, B-Raf and Raf-1, on cell
      cycle progression and regulatory gene expression were examined in TF-1 cells
      transformed to grow in response to beta-estradiol-regulated DeltaRaf:ER genes.
      Raf activation increased the expression of cyclin A, cyclin D, cyclin E, and
      p21(Cip1), which are associated with G(1) progression. Activated DeltaRaf-1:ER
      and DeltaA-Raf:ER but not DeltaB-Raf:ER increased Cdk2 and Cdk4 kinase activity.
      The regulatory role of p16(Ink4a), a potent Cdk4 kinase inhibitor, on the kinase
      activity of Cdk2 and Cdk4 was also examined. Raf induced p16(Ink4a) suppressor
      but this did not eliminate Cdk4 kinase activity. These results indicate that
      human hematopoietic cells transformed to grow in response to activated Raf can be
      used to elucidate the mechanisms by which various cell cycle regulatory molecules
      effect cell cycle progression. Furthermore, the differences that the various Raf
      isoforms have on Cdk4 activity and other cell cycle regulatory molecules can be
      determined in these cells.

PMID- 12429939
TI  - The ubiquitin-associated (UBA) domain: on the path from prudence to prurience.

PMID- 12429940
TI  - SUMO-1 and p53.
AB  - Abundance and activity of the tumor suppressor p53 are regulated by many
      different posttranslational modifications. These include phosphorylation,
      acetylation, ribosylation, O-glycosylation or ubiquitination. Three years ago,
      covalent modification with the ubiquitin- related protein SUMO-1 has been added
      to this list. SUMO-1 resembles ubiquitin both in structure and in the mechanism
      of attachment, and is reversibly attached to a large number of proteins.
      Molecular consequences of this dynamic modification vary between targets and
      include alterations in protein/protein or protein/DNA interactions, changes in
      localization, enzymatic activity, or stability. A role of SUMOylation in
      modulating p53 transcriptional activity has been reported, but is still an issue
      of controversy. Here we will briefly summarize the pathway of SUMOylation and
      discuss possible implications for p53 function.

PMID- 12429941
TI  - Seek and destroy: SCF ubiquitin ligases in mammalian cell cycle control.
AB  - The eukaryotic cell cycle consists of a series of sequential phases, the order of
      which is highly regulated to ensure the faithful transmission of intact genome
      equivalents to daughter cells. Progression through the cell cycle depends on the
      activity of cyclin-dependent kinases (Cdks), which drive the transitions between
      phases by targeting numerous, but largely unknown, substrates for
      phosphorylation. The activity of Cdks is subject to both positive and negative
      regulation by their temporal association with cyclins and Cdk inhibitors,
      respectively. Whereas Cdks are constitutively expressed throughout the cell
      cycle, the levels of cyclins and Cdk inhibitors are regulated by both
      transcriptional and post-transcriptional processes. The discovery that many
      cyclins and Cdk inhibitors are unstable proteins has implicated regulated protein
      degradation as a critical mechanism in cell cycle control. Proteolysis allows for
      the rapid removal of cell cycle regulators promoting irreversible transitions
      between cell cycle phases. The rapid removal of positive regulators prevents them
      from interfering with regulation of subsequent cell cycle events. In this review,
      we highlight the recent advances of our understanding of how a recently
      discovered ubiquitin ligase, designated SCF, contributes to mammalian cell cycle
      control.

PMID- 12429942
TI  - Mitotic regulation: the fine tuning of separase activity.
AB  - Mitotic progression requires the dissolution of cohesion between sister
      chromatids. Cohesion is dissolved by an essential protease known as separase.
      Separase is highly conserved throughout evolution and is subjected to multiple
      levels of regulation. Here we discuss recent studies that unravel several key
      mechanisms for regulating separase activity.

PMID- 12429943
TI  - Combining phorbol ester (PMA) with UCN-01: fueling fire with water.

PMID- 12429944
TI  - The complexity of APC/C regulation: location, location, location.

PMID- 12429945
TI  - Cleavage of BLM and sensitivity of Bloom's syndrome cells to hydroxurea and UV-C
      radiation.
AB  - Patients with Bloom's syndrome (BS) show a strong genetic instability and a
      predisposition to all types of cancer. Here, we report that the Bloom's syndrome
      protein (BLM) is cleaved in response to hydroxyurea (HU)- or UVC-induced
      apoptosis. The appearance and solubility of BLM proteolytic products differed
      according to whether proteolysis occurred in response to HU or UVC. One BS cell
      line homozygous for a null mutation in BLM was resistant to both UVC- and HU
      induced apoptosis, while another one expressing a mutated BLM protein was
      resistant to HU-induced apoptosis but displayed normal sensitivity to UVC. Thus,
      UVC and HU appear to induce apoptosis through distinct pathways.

PMID- 12429947
TI  - UCN-01 (7-hydroxystauorsporine) blocks PMA-induced maturation and reciprocally
      promotes apoptosis in human myelomonocytic leukemia cells (U937).
AB  - Interactions between the protein kinase inhibitor UCN-01 and the PKC activator
      phorbol ester (PMA) have been examined in relation to differentiation and
      apoptosis in human myelomonocytic leukemia cells (U937). Coadministratation of
      100 nM UCN-01 with a low concentration of PMA e.g., 2 nM, inhibited rather than
      promoted differentiation, reflected by reduced surface expression of the
      monocytic maturation marker CD11b and diminished cell adherence. Instead,
      administration of UCN-01 with PMA led to a marked increase in mitochondrial
      injury (e.g, cytochrome c release), activation of caspases-3 and -8, Bid
      cleavage, PARP degradation, and apoptosis, accompanied by a substantial reduction
      in viability and clonogenic survival. These phenomena were associated with
      multiple perturbations in cell cycle regulatory events, including abrogation of
      p21(CIP1) induction, p27(KIP1) cleavage, down-regulation of cyclin D1,
      dephosphorylation (activation) of p34cdc2, and degradation of underphosphorylated
      pRb. Potentiation of PMA-mediated apoptosis was partially mimicked by caffeine
      suggesting the involvement of Chk1 in the potentiation of apoptosis. Induction of
      cell death by UCN-01 and PMA was increased in cells stably expressing a p21(CIP1)
      mRNA antisense construct, suggesting that p21(CIP1) expression may protect cells
      from the lethal effects of this drug combination. Finally, ectopic expression of
      a Bcl-2 but not dominant-negative caspase-8 protected cells from UCN-01/PMA
      mediated apoptosis, suggesting the lethal effects of this combination primarily
      involves the mitochondrial rather than the TNF-related extrinsic apoptotic
      pathway. Taken together, these findings suggest that UCN-01 disrupts a variety of
      cell cycle events in leukemic cells exposed to the maturation-inducing agent PMA,
      causing cells to engage an apoptotic rather than a differentiation-related
      program.

PMID- 12429946
TI  - CHK1-regulated S-phase checkpoint response reduces camptothecin cytotoxicity.
AB  - The cytotoxicity of camptothecin (CPT) is S phase specific and is associated with
      an inhibition of DNA replication. The relationship between CPT-induced inhibition
      of DNA replication and CPT cytotoxicity remains unclear. We previously reported
      that the CPT-induced inhibition reflects an activated S-phase (S) checkpoint
      response and that this response is mainly regulated by ATR/CHK1 pathway. In this
      study, by comparing A1-5 and B4, the two transformed rat embryo fibroblasts cell
      lines, we showed that with higher CHK1 expression, A1-5 cells had a stronger S
      checkpoint response and were more resistant to CPT-treatment. The data suggested
      that over-activated CHK1 in CPT-treated A1-5 cells regulated the strong S
      checkpoint response through the CDC25A/CDK2 pathway. When the CHK-1 regulated
      strong S checkpoint response was abolished, A1-5 cells became much more sensitive
      to CPT-induced killing. These data indicated that CHK1 regulated S checkpoint
      response protected cells from CPT-induced killing.

PMID- 12429949
TI  - Biological terrorism: understanding the threat, preparation, and medical
      response.
AB  - The thought of an outbreak of disease caused by the intentional release of a
      pathogen or toxin in an American city was alien just 10 years ago. Many people
      believed that biological warfare was only in the military's imagination, perhaps
      to be faced by soldiers on a far-away battlefield, if at all. The "anthrax
      letters" and the resulting deaths from inhalation anthrax have changed that
      perception. The national, state, and local governments in the United States are
      preparing for what is now called "not if, but when and how extensive" biological
      terrorism. In contrast to the acute onset and first-responder focus with a
      chemical attack, in a bioterrorist attack, the physician and the hospital will be
      at the center of the fray. Whether the attack is a hoax, a small food-borne
      outbreak, a lethal aerosol cloud moving silently through a city at night, or the
      introduction of contagious disease, the physician who understands threat agent
      characteristics and diagnostic and treatment options and who thinks like an
      epidemiologist will have the greatest success in limiting the impact of the
      attack. As individual health care providers, we must add the exotic agents to our
      diagnostic differentials. Hospital administrators must consider augmenting
      diagnostic capabilities and surveillance programs and even making infrastructure
      modifications in preparation for the treatment of victims of bioterrorism. Above
      all, we must all educate ourselves. If done correctly, preparation for a
      biological attack will be as "dual use" as the facility that produced the weapon.
      A sound public health infrastructure, which includes all of us and our resources,
      will serve this nation well for the control of the disease, no matter what the
      cause of the disease.

PMID- 12429948
TI  - The dephosphorylated form of the anaphase-promoting complex protein Cdc27/Apc3
      concentrates on kinetochores and chromosome arms in mitosis.
AB  - Cell cycle regulated protein ubiquitination and degradation within subcellular
      domains may be essential for the normal progression of mitosis. Cdc27 is a
      conserved component of an essential M-phase ubiquitin-protein ligase called the
      anaphase-promoting complex/cyclosome. We examined the subcellular distribution of
      Cdc27 in greater detail in mammalian cells and found Cdc27 concentrated at
      spindle poles and on spindle microtubules as previously described, but also found
      Cdc27 at kinetochores and along chromosome arms. This localization was not
      dependent on intact microtubules. While the great majority of Cdc27 protein in M
      phase cells is highly phosphorylated, only the dephosphorylated form of Cdc27 was
      found associated with isolated chromosomes. Kinases that also associate with
      isolated chromosomes catalyzed the in vitro phosphorylation of the chromosome
      associated Cdc27. Microinjection of anti-Cdc27 antibody into cells causes arrest
      at metaphase. Microinjection of cells with anti-Mad2 antibody normally induces
      premature anaphase onset resulting in catastrophic nondisjunction of the
      chromosomes. However, coinjection of anti-Cdc27 antibody with anti-Mad2 antibody
      resulted in metaphase arrest. The association of dephosphorylated APC/C
      components with mitotic chromosomes suggests mechanisms by which the spindle
      checkpoint may regulate APC/C activity at mitosis.

PMID- 12429950
TI  - NF-kappaB and breast cancer.

PMID- 12429951
TI  - Issues in medical ethics. Understanding professionalism and its implications for
      medical education. Proceedings of a conference. New York City, New York, USA.
      November 3, 2000.

PMID- 12429953
TI  - Themes in the history of medical professionalism.
AB  - Professionalism in medicine is an ambiguous term. Discussions are hampered by
      understandings of the past that are counterproductive to today s debates. Three
      decades of criticism of physicians as self-interested and arrogant, and of
      professional organizations as unfairly monopolistic have shaken the confidence of
      professional leaders and their constituents in their ability to act as a positive
      social force, and left the concept of professional autonomy without a useful
      meaning. Inherited assumptions about conflict between the profession, government
      and the market have encouraged organizational policies to fight familiar enemies
      for short-term gains, rather than reinvent professionalism as a social force or
      seek new strategic alliances. This article stresses the importance of distancing
      the present from the past in re-inventing professionalism for the future, and
      lists eight fundamental goals.

PMID- 12429954
TI  - Medical professionalism: a Parsonian view.
AB  - This paper argues for a normative conception of medical professionalism based on
      the work of sociologist Talcott Parsons. Such a conception grounds medical
      professionalism on the expert authority of the physician; the concept of 
      authority  is therefore discussed at length. Parsons  view also lays much stress
      on the fact that the proper exercise of medical authority nearly always involves
      aligning the interests of individual patients with those of society at large.
      Parsonian professionalism looks to professional institutions such as medical
      schools, societies and journals to secure the competence and ethical behavior of
      professionals, and to help ensure that professionals  exercise of authority is
      never biased by private financial interests or by public political power.
      Professional institutions should encourage professionals to develop a set of
      preferences and desires (e.g., for respect of their peers, and not for power or
      financial gain) that will tend to make them trustworthy authorities.

PMID- 12429955
TI  - Professionalism and clinical autonomy in the practice of medicine.
AB  - Professionalism in medicine requires a reasonable measure of freedom for
      physicians to determine patients  needs based on their own judgment. However,
      because virtually every medical decision is also a spending decision, third-party
      payers concerned about rising health care costs have introduced cost-containment
      tactics that significantly limit physicians  accustomed autonomy. In response,
      groups of physicians have filed class-action lawsuits against managed care plans,
      alleging causes of action such as fraud, breach of contract, extortion, and
      violations of federal RICO (Racketeer-Influenced and Corrupt Organizations) law.
      Such litigation may have merits, but it also faces significant obstacles, in part
      because the contracts involved may not actually have promised the broad measure
      of clinical autonomy that the physicians allege was promised, then denied. As
      physicians seek to restore and retain their professional autonomy, it will be
      important for them to be increasingly proactive in structuring or modifying the
      contracts under whose terms they practice   as some physicians have successfully
      done.

PMID- 12429956
TI  - Professionalism, profession and the virtues of the good physician.
AB  - The putative loss of  professionalism  in medicine has of late become of serious
      concern to practitioners, educators, ethicists and the public. Impassioned pleas
      for its restitution abound. Serious ethical obligations are linked to the idea of
      a profession. Yet, most of the definitions have been socio-historical, political
      or legal. Important as these aspects may be, there is need for a firmly grounded
      ethical derivation of the moral dimensions of professionalism. This essay
      undertakes to provide a philosophical grounding for ethically responsible
      professionalism in the phenomena of clinical medicine, in the character of the
      professional, and in virtue theory.

PMID- 12429957
TI  - What medical students know about professionalism.
AB  - Three different sources of data are used to explore how medical students think
      about the physician as a professional. The data include exercises employed by the
      University of Minnesota-School of Medicine to foster professionalism among its
      medical students, such as the skills of peer review and self reflection, a 20
      hour course for first-year medical students in which approximately two-thirds of
      the course focuses directly (e.g., topic-specific readings and class exercises)
      and indirectly (e.g., medical training and socialization) on the topic of
      professionalism, and a set of questions asked during admissions interviews which
      highlight issues of professionalism. Although the data are neither definitive nor
      generalizable, they do suggest that medical school applicants approach the
      admissions process well versed in academic and related (e.g., service activities)
      requirements, but without having given much thought to what it means to be a
      physician, particularly in terms of professional values. Once in medical school,
      students express great enthusiasm for  being service oriented  and  doing good 
      but are not necessarily receptive to the notion that they are obliged in these
      respects. Instead, students express a variety of utilitarian views on things like
      codes of ethics and medical oaths to support their stance on nonobligation
      (sometimes directly and sometimes indirectly). Furthermore, students do not draw
      distinctions among the values commonly associated with professionalism. In
      particular, they foresee numerous problems associated with integrating the values
      of altruism and dutifulness into their future practice of medicine.

PMID- 12429958
TI  - Professionalism in the practice of medicine.
AB  - Although medicine is universally recognized as the archetype of the professions,
      it can only be understood as part of the modern medical center, a dynamic social
      system consisting of the university, the hospital, the medical center and, most
      recently, corporate managed care. Such a view results in a portrait of medicine
      as a profession transformed, driven by huge and growing health care markets, its
      fate tied not only to state bureaucracies, but also to the dynamics of both
      health and non-health care businesses. The question asked here is how does such a
      radical change in medical practice affect medical education. Using methods of
      historical analysis, it appears that medical educators operate as though the
      educational process itself determines the values, and therefore the present and
      future behavior of their students. In other words, at the end of their formal
      education, doctors are fully formed professionals. However, from the analysis of
      this paper it can be concluded that the physician as an individual cannot
      function independently of the structure of the society and its general conception
      of the world. In the structure of medicine s present situation, the ethical
      standards of professionalism, as they are classically defined, cannot survive.
      Instead, modern medical graduates, much like their teachers and professional
      mentors, will be forced to adapt to a situation that is contradictory to the best
      traditions of medicine. How to stop this process is the urgent question. Three
      answers are presented.

PMID- 12429959
TI  - Training doctors for professionalism: some lessons from teaching clinical medical
      ethics.
AB  - Medical professionalism encourages physicians to place their patients  interests
      above self-interest. In recent years, many medical organizations, including the
      American Board of Internal Medicine (ABIM), Association of American Medical
      Colleges (AAMC), and the American Medical Association (AMA), have developed
      initiatives to strengthen medical professionalism. By emphasizing
      professionalism, supporters of these initiatives hope that medicine and
      physicians may recapture professional autonomy, decrease public criticism of
      medicine and physicians, and help physicians regain the moral high ground in the
      unending struggle with payers, both public and private. One crucial question
      facing medical educators is whether the concepts of professionalism can be taught
      to medical students and residents. This paper draws upon the author s thirty
      years of experience in teaching clinical medical ethics to provide guidance on
      how to teach the concepts of professionalism to students and residents.

PMID- 12429960
TI  - Professionalism and the teaching of clinical medicine: perspectives of teachers
      and students.
AB  - Principles of medical professionalism include humanistic values, altruism,
      ethical and moral behavior, and a lifelong commitment to scholarship and
      learning. These principles can provide behavioral guidelines to residents,
      fellows and their teacher-physicians during the formative years of postgraduate
      training. This short paper presents some of the challenging professional
      questions raised during these years of training, where medical professionalism
      may help to guide us.

PMID- 12429961
TI  - Teaching professionalism: a student's perspective.
AB  - As a fourth-year medical student, I was asked to speak about the role of the
      medical school in teaching and promoting professionalism in its students, and
      specifically to describe and critique the efficacy of Mount Sinai School of
      Medicine in this endeavor. I concluded that the concept and framework of
      professionalism can, in fact, be effectively taught in medical school, but that
      role modeling and mentoring are also crucial to the development of the
      professional. Finally, I make suggestions for furthering the promotion of
      professionalism through medical education at Mount Sinai.

PMID- 12429962
TI  - Summary remarks: the implications of professionalism for medical education.
AB  - Can professionalism be taught and measured? In the medical school environment,
      particularly with clinical encounters occurring in the first year, a focus on
      professionalism should begin right away. Attitudes and behavior of the students
      are strongly influenced during these encounters between physician-mentors, and
      patients and their families at the bedside or in the clinic. Careful listening
      and the demonstration of communication skills during these encounters are
      paramount. Asking questions may be better than telling students what to do. The
      faculty must provide thoughtful and constructive critiques and must have a
      mechanism for follow-up. By paying attention to how students really function, we
      might better teach the precepts of professionalism without adversely affecting
      their own well being.

PMID- 12429963
TI  - The cardiac gap junction: a potential therapeutic target in the treatment of
      heart disease.
AB  - Cardiac gap junctions have been implicated in maintaining cardiac conduction and
      function. In cardiac disease, expression of connexin 43, the most abundant
      ventricular gap junction protein, is markedly abnormal, a process termed gap
      junction remodeling. To date, however, the gap junction has not been directly
      targeted therapeutically in cardiac disease states. Therefore, we have developed
      novel and complementary experimental models to investigate whether loss of
      connexin 43 expression in the heart can be directly linked to the arrhythmic and
      functional complications of heart disease. In this article, we discuss how data
      from connexin 43 conditional and chimeric knock-out mice support the hypothesis
      that gap junction remodeling is a key molecular feature underlying the high
      incidence of sudden arrhythmic death and exacerbating the ventricular dysfunction
      associated with acquired heart disease.

PMID- 12429964
TI  - Adenoviral gene therapy for cancer: from vectors to targeted and replication
      competent agents (review).
AB  - Gene therapy is an exciting novel approach for treating cancers resistant to
      currently available modalities. Treatment approaches are based on taking
      advantage of molecular differences between normal and tumor cells. Various
      strategies are currently in clinical development, with some promising early
      results reported with mutation compensation, molecular chemotherapy and
      replication competent viruses. Adenoviruses are among the most popular vehicles
      and there is a wealth of clinical data suggesting excellent safety for treatment
      of cancer patients. Current developments include improving targeting strategies
      for gene delivery to tumor cells with tumor specific promoters. Another rapidly
      developing field is replication competent agents, which allow improved tumor
      penetration and local amplification of the anti-tumor effect. Further,
      infectivity enhancement strategies can overcome variable expression of the
      primary adenovirus receptor on tumor cells, which may have reduced the clinical
      efficacy of previous strategies. Adenoviral cancer gene therapy approaches lack
      cross-resistance with other treatment options and frequently synergistic effects
      can be observed. Therefore, the first routine clinical applications are likely to
      be combination treatments.

PMID- 12429966
TI  - Clinicopathologic study of neovascularization and VEGF expression in superficial
      esophageal carcinoma.
AB  - Among superficial esophageal carcinomas (SECs), mucosal carcinoma (m) and
      submucosal carcinoma (sm) markedly differ regarding the presence or absence of
      lymph node metastases and long-term survival. To clarify differences in the
      growth pattern of these two superficial carcinomas, we investigated
      neovascularization around the site of tumor growth and expression of vascular
      endothelial growth factor (VEGF) in tumor cells, in patients undergoing radical
      esophagectomy or endoscopic mucosal resection (EMR). Moreover, we investigated
      whether these factors were related to the prognosis in patients undergoing
      treatment of SEC. This study included 90 SEC patients undergoing radical
      esophagectomy (surgery group) and 35 patients undergoing EMR (EMR group). For
      immunohistochemical staining antibodies against factor VIII-related antigen and
      against VEGF were used. The microvessels around the tumor were counted to
      calculate the vascular index (VI). VI and VEGF expression in the tumor were
      compared in relation to clinicopathologic findings. In the surgery group, the VI
      and the percent of VEGF-positive cells were significantly higher in the case of
      sm carcinomas. Furthermore, tumors with a high VI showed a significantly worse
      prognosis. In the EMR group, the VI and percent of VEGF-positive cells increased
      with the depth of the tumor. The VI and VEGF expression were significantly higher
      in sm carcinomas. This may in part explain the difference in cancer progression
      between m and sm carcinomas. In patients undergoing resection or EMR, examination
      of neovascularization using VI may be potentially useful in evaluating the
      prognosis of SEC.

PMID- 12429967
TI  - Thrombospondin-1 expression as a prognostic predictor of pancreatic ductal
      carcinoma.
AB  - Pancreatic cancer is a malignant tumor with an extremely poor prognosis.
      Thrombospondin-1 (TSP-1) was suggested to be a potential regulator of tumor
      growth and metastasis. We examined TSP-1 expression in 77 cases of invasive
      ductal adenocarcinoma of the pancreas, and analyzed the correlation between the
      TSP-1 expression pattern and clinicopathological features in pancreatic cancer.
      TSP-1 immunoreactivity was detected in the cancer stroma. The diffusely positive
      and focally positive patterns of TSP-1 were found in 33 (42.9%) and 40 (51.9%) of
      77 cases, respectively. The TSP-1 diffuse expression was significantly correlated
      with lymph node metastasis (p<0.01), neural invasion (p<0.05) and TNM stage
      (p<0.01). The prognostic significance of clinicopathological parameters were
      analyzed by univariate and multivariate analysis using the log-rank test and the
      Cox proportional hazards model. Based on the univariate analysis, histological
      differentiation (p<0.01), lymphatic invasion (p<0.01), venous invasion (p<0.05),
      neural invasion (p<0.01), TNM stage (p<0.01) and TSP-1 expression (p<0.01) were
      significant parameters. These observations suggested that TSP-1 plays important
      roles in cancer cell growth and metastasis of human pancreatic cancer, and that
      stromal TSP-1 immunoreactivity is a good prognostic predictor of patients with
      pancreatic cancer.

PMID- 12429965
TI  - Expression of peroxisome proliferator-activated receptor alpha, and PPARalpha
      regulated genes in spontaneously developed hepatocellular carcinomas in fatty
      acyl-CoA oxidase null mice.
AB  - Fatty acyl-CoA oxidase null mice (AOX-/-) develop hepatocellular carcinomas in
      100% of animals between 10 and 15 months. We evaluated spontaneously developed
      HCC in AOX-/- mice for PPARalpha, PPARalpha regulated genes and peroxisome volume
      density and compared with adjacent non-neoplastic liver and liver in wild-type
      (AOX+/+) and heterozygous (AOX+/-) mice. The level of PPARalpha mRNA was 2.5-fold
      higher in HCC compared to the adjacent liver. mRNAs of PPARalpha regulated genes
      such as peroxisomal bifunctional enzyme, thiolase, cytochrome P450 CYP4A1 and
      CYP4A3 were similar in HCC and adjacent liver and increased by 7- to 22-fold
      compared with wild-type and heterozygous mice. Immunoblot analysis of HCC showed
      high amounts of PPARalpha, peroxisomal bifunctional enzyme and thiolase. Electron
      microscopic examination revealed 3.8 and 8.3-fold increase in the volume density
      of peroxisomes in HCC and adjacent liver, respectively, compared to the volume
      density in wild-type mice. These results demonstrate that spontaneously developed
      HCC in AOX-/- mice display a similar type of pleiotropic responses to high levels
      of PPARalpha ligands as the non-neoplastic liver. The changes observed in HCC and
      adjacent liver in AOX-/- mice were identical to those observed in rats and mice
      exposed to peroxisome proliferators.

PMID- 12429968
TI  - Identifying cancer-related genes in nasopharyngeal carcinoma cell lines using DNA
      and mRNA expression profiling analyses.
AB  - The goals of this study were to evaluate the potential of detecting cryptic
      amplification and deletion of cancer-related genes using array-based comparative
      genomic hybridization (CGH), and to identify candidate cancer genes by combined
      parallel analyses of copy number and gene expression profiles in nasopharyngeal
      carcinoma (NPC) cell lines. We established global DNA copy number and mRNA
      expression profiles on human NPC cell lines using a high-density cDNA microarray.
      The DNA copy number alterations detected by array CGH were compared to the DNA
      copy number variations identified by metaphase CGH. A cryptic amplification at
      3q26 was detected by array CGH, which was not found by metaphase CGH. By amplicon
      mapping and parallel analyses of DNA copy number and mRNA expression levels, we
      identified several candidates which could be important mediators in tumor
      formation or progression. Taken together, the combination of copy number and gene
      expression profiling using cDNA microarrays provides an improved strategy for
      gene discovery in human cancer.

PMID- 12429969
TI  - Centromere numerical abnormality in the papillary, papillotubular type of early
      gastric cancer, a further characterization of a subset of gastric cancer.
AB  - Papillary adenocarcinoma of the stomach is a relatively uncommon histological
      type, and it is often detected in the early stage. We recently characterized the
      papillary type of gastric cancer and found frequent microsatellite instability
      and associated mutations. In this study we analyzed the centromere numerical
      abnormality (CNA) of 18 chromosomes (chromosomes 1-4, 6-12, 15-18, 20, X, and Y)
      in the papillary and papillotubular types of gastric cancer by a modified
      fluorescence in situ hybridization technique with microwave treatment. All 3
      cases (100%) of papillary adenocarcinoma had high microsatellite instability (MSI
      H), and low CNA, and 41% (7 cases) of the 17 cases of papillotubular
      adenocarcinoma exhibited MSI-H and all 7 cases had low CNA. Further 8 cases (47%)
      had extensive CNA. In these 15 cases, all the MSI-H cases had lower CNA, and low
      microsatellite instability (MSI-L) and MSS cases had higher CNA. The remaining
      two cases showed low CNA and MSI-L and MSS. These profiles were different from
      those of tubular type gastric cancer, which always had extensive CNA and no MSI.
      Although the numbers of the cases in this series are limited, our data may
      suggest that a modest CNA may be another characteristic of gastric cancer with
      papillary structure.

PMID- 12429971
TI  - Prognostic values of radiation-induced p53 in adjacent normal mucosa and
      p21WAF1/CIP1 expression in rectal cancer patients.
AB  - DNA damage induces p53-mediated cell cycle arrest in which p21WAF1/CIP1, a cyclin
      dependent kinase inhibitor, may play a critical role by being regulated via wild
      type p53. Although adjuvant preoperative radiotherapy in rectal carcinoma is
      generally believed to improve the prognosis, it remains unclear which factors
      control the response. We investigated the interactions between the underlying
      mechanisms of cell cycle perturbation in response to radiotherapy, and local
      recurrence and distant metastasis in patients undergoing radical surgery for
      rectal carcinoma. A retrospective review was carried out in which 63 cases of
      Dukes' B or C, well or moderately differentiated rectal carcinomas in the lower
      two-thirds of the rectum, with or without preoperative radiotherapy, were
      immunohistochemically analyzed using antibodies to p53 and p21WAF1/CIP1. Induced
      p53 expression in adjacent normal mucosa, as seen in seven of 35 cases with
      radiotherapy, and mutually exclusive p21WAF1/CIP1 immunoreactivity, was strongly
      associated with local recurrence (P=0.0001). Furthermore, high p21WAF1/CIP1
      expression was associated with a lack of distant metastasis (P=0.032). Our data
      suggest that there are some cases in which p53 overexpression in adjacent normal
      mucosa induced by radiotherapeutic treatment might heighten the risk of local
      recurrence, and that p21WAF1/CIP1 induction independent of the status of the p53
      gene showing radiosensitivity might lead to a less distant metastasis.

PMID- 12429970
TI  - Treatment of silymarin, a plant flavonoid, prevents ultraviolet light-induced
      immune suppression and oxidative stress in mouse skin.
AB  - It is well documented that ultraviolet (UV) light-induced immune suppression and
      oxidative stress play an important role in the induction of skin cancers.
      Earlier, we have shown that topical treatment of silymarin, a plant flavonoid
      from milk thistle (Silybum marianum L. Gaertn.), to mouse skin prevents
      photocarcinogenesis, but the preventive mechanism of photocarcinogenesis in vivo
      animal system by silymarin is not well defined and understood. To define the
      mechanism of prevention, we employed immunostaining, analytical assays and ELISA
      which revealed that topical treatment of silymarin (1 mg/cm2 skin area) to
      C3H/HeN mice inhibits UVB (90 mJ/cm2)-induced suppression of contact
      hypersensitivity (CHS) response to contact sensitizer dinitrofluorobenzene.
      Prevention of UVB-induced suppression of CHS by silymarin was found to be
      associated with the inhibition of infiltrating leukocytes, particularly CD11b+
      cell type, and myeloperoxidase activity (50-71%). Silymarin treatment also
      resulted in significant reduction of UVB-induced immunosuppressive cytokine
      interleukin-10 producing cells and its production (58-72%, p<0.001). Topical
      treatment of silymarin also resulted in significant reduction of the number of
      UVB-induced H2O2 producing cells and inducible nitric oxide synthase expressing
      cells concomitant with decrease in H2O2 (58-65%, p<0.001) and nitric oxide (65
      68%, p<0.001) production. Together, these data suggest that prevention of UVB
      induced immuno-suppression and oxidative stress by silymarin may be associated
      with the prevention of photocarcinogenesis in mice. The data obtained from this
      study also suggest: i) phase-I clinical trial of silymarin in high skin cancer
      risk human population and ii) development of sunscreen containing silymarin as an
      antioxidant (chemopreventive agent) or silymarin can be supplemented in skin care
      products.

PMID- 12429972
TI  - Efficacy of hypocrellin pharmacokinetics in phototherapy.
AB  - Hypocrellins A and B are pigments which are isolated from the parasitic fungi
      Hypocrella bambuase sacc and Shiraia bambusicola P. Heen found in the People's
      Republic of China and other parts of Asia including Sri Lanka. These agents,
      which belong to the general class of perylene quinonoid pigments, have a long
      history of traditional medicinal agents especially in Asia. Hypocrellins are
      under extensive investigation as photosensitizing agents for photodynamic therapy
      (PDT). Hypocrellin compounds were selected as potential photosensitizers for PDT
      owing to their high quantum yields of singlet oxygen (1O2), and facility for site
      directed chemical modification to enhance phototoxicity, pharmacokinetics,
      solubility, and light absorption in the red spectral region, among other
      properties. The cellular uptake, evaluated by spectrofluorimetry and confocal
      laser scanning microscopy (CLSM) demonstrated that both HA and HB exhibited high
      and fast uptake and rapid internalization as revealed by their bio-distribution
      pattern. In addition, the present study employed both immunocytochemical and
      Western blot techniques to explore the photo-induced expression of apoptosis
      related proteins in NPC as well as other human carcinoma cells. Using
      spectrofluorimetry and CLSM we have determined the cellular fluorescence as a
      marker for the uptake of HA and HB. Co-staining with either HA or HB and
      fluorescent dyes specific for cell organelles revealed an intracellular
      localization of HA and HB in lysosomes other than mitochondria.

PMID- 12429973
TI  - Tetrandrine-induced cell cycle arrest and apoptosis in A549 human lung carcinoma
      cells.
AB  - Tetrandrine, isolated from the root of Stephania tetrandra, has been used in
      Chinese medicine for the treatment of silicosis and arthritis, and it also has
      anti-tumor/growth activities. However, the signaling pathways of tetrandrine
      induced growth arrest and apoptosis in cancer cells remain unclear. We
      investigated the molecular mechanisms of tetrandrine-induced apoptosis and growth
      arrest in human lung carcinoma cells. Upon treatment with tetrandrine, a time
      dependent inhibition of cell growth was observed and cells developed many of the
      hallmark features of apoptosis. Flow cytometry analysis confirmed that
      tetrandrine increased populations of both apoptotic sub-G1 and G1 phase.
      Tetrandrine-induced growth inhibition was associated with induction of Cdk
      inhibitor p21, inhibition of cyclin D1 and activation of caspase-3. Tetrandrine
      also affected the expression patterns of cytoskeletons including distribution of
      F-actin and expression level of microtubule. These results suggest that
      tetrandrine merits further investigation as a cell cycle blocker as well as a
      cancer chemopreventive agent.

PMID- 12429974
TI  - Enhancement of activation-induced apoptosis of lymphocytes by the cytotoxic
      ribonuclease onconase (Ranpirnase).
AB  - Onconase (Onc) is an amphibian ribonuclease of the pancreatic RNase family that
      is cytostatic and cytotoxic to several tumor lines. It also shows anti-tumor
      activity in mouse tumor models and is currently in phase III clinical trials. In
      animal tests and clinical trials Onc shows lesser toxicity and fewer side effects
      compared to most chemotherapeutic drugs. Intriguingly, repeated infusions of this
      protein do not cause apparent immunological reactions in patients. The aim of the
      present study was to investigate sensitivity to Onc of human lymphocytes during
      their mitogenic stimulation in response to the polyvalent mitogen
      phytohemagglutinin (PHA), and in mixed allogeneic lymphocyte cultures.
      Unexpectedly, we observed that frequency of cells undergoing activation-induced
      apoptosis was markedly increased in all cultures containing Onc. Apoptosis was
      measured by flow cytometry using markers that detect activation of caspases, the
      in situ presence of DNA strand breaks, and loss of fragmented DNA ('sub-G1' cell
      subpopulation). The enhancement of frequency of activation-induced apoptosis (up
      to 244%) was observed at 4.2-83 nM Onc concentration, which is at least an order
      magnitude lower than its minimal concentration reported to affect proliferation
      or induce apoptosis of leukemic and solid tumor cell lines. The cell cycle
      progression of lymphocytes that responded to PHA mitogenically was not affected
      at 8.3 or 83 nM Onc concentration. Because activation-induced apoptosis is the
      key mechanism regulating several in vivo immunological functions including
      induction of tolerance, the observed effects of Onc may explain the apparent lack
      of immune reactions to this protein in treated patients. The propensity of Onc to
      potentiate the activation-induced apoptosis suggests that this drug may have
      clinical utility as immunomodulating agent, e.g., to suppress transplant
      rejection or treat autoimmune diseases.

PMID- 12429975
TI  - Unique properties of 189 amino acid isoform of vascular endothelial growth factor
      in tumorigenesis.
AB  - The 189 amino acid isoform of vascular endothelial growth factor (VEGF189) has
      been shown to be more strongly associated with the cell membrane than other
      isoforms of human VEGF (VEGF121, VEGF165). To analyze the biological activities
      of these VEGF isoforms on tumor growth, we transfected human VEGF121, VEGF165 or
      VEGF189 cDNA into the human colon cancer cell line SW-480, and established
      several clones overexpressing these VEGF isoforms. The total amounts of VEGF
      protein in the culture supernatants of the VEGF189-transfectants were less than
      those of VEGF121 and VEGF165-transfectants. These transfectants showed no
      significant differences in growth in culture. Nevertheless, the rate of in vivo
      tumor growth of VEGF189-transfectants was faster than or equivalent to that of
      VEGF121-transfectants, while the VEGF165-transfectant showed the greatest
      enhancement of tumor growth. The protein levels of VEGF were markedly increased
      only in the VEGF189-transfectants cultured in the presence of heparin. The
      enhanced in vivo tumor growth of VEGF189-transfectants can be partly explained by
      the cell-associated features of VEGF189 molecules. The VEGF189 molecule, which is
      strongly bound to the cell surface, has unique properties and high potential in
      local angiogenesis and tumor growth in the cancer inductive microenvironment.

PMID- 12429976
TI  - Mifepristone-induced secretion of transforming growth factor beta1-induced
      apoptosis in prostate cancer cells.
AB  - Successful therapy should induce apoptosis in prostate cancer cells irrespective
      of their androgen response. We have investigated the possibility of utilizing
      Mifepristone and Tamoxifen as treatment options for prostate cancer cells.
      Because preliminary results demonstrated induction of apoptosis by these drugs,
      the mechanism of induction of apoptosis was investigated. LNCaP-C4 prostate
      cancer cells were treated with Mifepristone and/or Tamoxifen. To confirm
      cytotoxic effects, nude mice with LNCaP-C4 xenografts were treated with
      Mifepristone and Tamoxifen. Cell viability was assayed using Sulforhodamine B
      (SRB) assay and DNA fragmentation was measured by ELISA. Culture media from
      vehicle- and drug-treated cells were collected and secretion of transforming
      growth factor beta1 (TGFbeta1) was estimated by ELISA. Role of TGFbeta1 was
      confirmed by inhibiting its function using TGFbeta1 antibody or M6P, which
      blocked activation of TGFbeta1. Apoptotic effects were determined by immunoblots
      of cytochrome c levels in cytosol and by in vitro colorimetric assay of caspase-3
      activity. Results showed that although both drugs induced apoptosis in LNCaP-C4
      cells, Mifepristone was more effective. The effects of these drugs on xenografts
      confirmed in vitro results. It was hypothesized that drug-induced secretion of
      TGFbeta1 may be responsible for induction of apoptosis. Neutralization of
      TGFbeta1 with an antibody or blocking the activation of TGFbeta1 by M6P abrogated
      the effects of Mifepristone and Tamoxifen confirming our hypothesis. Furthermore,
      treatment with Mifepristone and/or Tamoxifen released cytochrome c into the
      cytoplasm and induced activity of caspase-3, providing evidence that the drug
      stimulated secretion of TGFbeta1 was responsible for induction of apoptosis in
      these cells. In conclusion, both Mifepristone and Tamoxifen induced apoptosis
      mediated through TGFbeta1. However, no critical advantage was noted by the
      addition of Tamoxifen to Mifepristone treatment.

PMID- 12429977
TI  - WNT and FGF gene clusters (review).
AB  - Mouse mammary tumor virus (MMTV) is a retrovirus, activating Wnt genes (Wnt1/int
      1, Wnt3/int-4, Wnt10b), Fgf genes (Fgf3/int-2, Fgf4, Fgf8) and other genes
      (Notch4/int-3, Eif3s6/int-6) due to proviral integration. Among 19 WNT genes,
      WNT3 and WNT14B genes are clustered in human chromosome 17q21, WNT3A and WNT14 in
      human chromosome 1q42, WNT10A and WNT6 in human chromosome 2q35, and WNT10B and
      WNT1 in human chromosome 12q13. Among 22 FGF genes, FGF19, FGF4 and FGF3 genes
      are clustered in human chromosome 11q13, while FGF23 and FGF6 in human chromosome
      12p13. WNT and FGF gene clusters are conserved between the human genome and the
      mouse genome. Activation of mouse Wnt or Fgf genes due to proviral integration of
      MMTV occurs in 5 out of 13 clustered genes, and in 1 out of 28 solitary genes
      (p=0.0033), which clearly indicates that mouse Wnt or Fgf gene clusters are
      recombination hot spots associated with carcinogenesis. Recombination results in
      retroviral integration as well as in chromosomal translocation, gene
      amplification and deletion during carcinogenesis. The CCND1-FGF19-FGF4-FGF3 gene
      cluster in human chromosome 11q13 is amplified in breast cancer, squamous cell
      carcinoma of head and neck, and bladder tumors, and is also translocated in
      parathyroid tumors and B-cell lymphoma. WNT gene clusters on human chromosome
      1q42, 2q35, 12q13, and 17q21 as well as FGF gene cluster on human chromosome
      12p13 might be amplified or translocated in human cancer just like FGF gene
      cluster on human chromosome 11q13.

PMID- 12429978
TI  - Inhibitory effects of epigallocatechin-3-gallate on N-nitrosomethylbenzylamine
      induced esophageal tumorigenesis in F344 rats.
AB  - The present study was conducted to assess the inhibitory effects of EGCG
      (epigallocatechin-3-gallate) on NMBA-induced rat esophageal tumorigenesis and to
      seek the potential mechanisms. In experiment I, 81 F344 rats were randomly
      divided into seven experimental groups according to the different regiments of
      NMBA 1 mg/kg subcutaneously (s.c.) and EGCG 4 mg/kg or 10 mg/kg orally or
      intraperitoneally (i.p.). The experiment was terminated at 24 weeks. In
      experiment II, 48 rats were allocated into two groups, each group contained 24
      rats, in which the rats were injected with NMBA 1 mg/kg only or a combination of
      NMBA 1 mg/kg and EGCG 4 mg/kg i.p. Six rats from each group were sacrificed at
      the 12th, 16th, 20th and 24th week, respectively. The expression of cyclin D1 and
      cyclooxygenases (COX-2 and COX-1) was detected using semi-quantitative RT-PCR,
      and the production of prostaglandin E2 (PGE2) was measured by ELISA. In the
      groups which were treated with EGCG at a dose of 4 mg/kg i.p., or 10 mg/kg both
      orally and i.p., the mean number of tumors per rat was significantly reduced to
      48, 56 and 61%, respectively (p<0.05). The incidence rate of esophageal
      carcinomas in the rats that were treated with EGCG 4 mg/kg i.p., was
      significantly lower than that in the rats which only received NMBA 1 mg/kg
      (p<0.05). The expression of cyclin D1 and COX-2, and the levels of PGE2 were also
      decreased by EGCG treatment. These results indicated that EGCG significantly
      inhibits the NMBA-induced rat esophageal carcinogenesis and it inhibitory effects
      may partly target cyclin D1 and COX-2 expression, and PGE2 production.

PMID- 12429979
TI  - Adverse effects of obesity on breast cancer prognosis, and the biological actions
      of leptin (review).
AB  - Leptin is a hormone with multiple biological actions which is produced
      predominantly by adipose tissue; in humans, plasma levels correlate with total
      body fat, and particularly high concentrations occur in obese women. Several
      actions of leptin, including the stimulation of normal and tumor cell growth,
      migration and invasion, and enhancement of angiogenesis, suggest that this
      hormone can promote an aggressive breast cancer phenotype which can be estrogen
      independent. This effect may involve activation of the transcription factor
      NFkappaB. Leptin can also induce aromatase activity, with the potential for the
      promotion of estrogen production from androstenedione in adipose tissue, and
      hence the stimulation of estrogen-dependent breast cancer progression. On this
      basis, we hypothesize that leptin, perhaps in association with insulin, the
      plasma concentrations of which correlate with those of leptin, has an important
      role in the known adverse effect of obesity on breast cancer.

PMID- 12429981
TI  - Analysis of cell growth inhibitory effects of catechin through MAPK in human
      breast cancer cell line T47D.
AB  - We have investigated the cell growth inhibitory effects of crude catechin
      (catechin) containing approximately 53% of epigallocatechin-3-gallate (EGCG) on
      the human breast cancer cell line T47D, and the mechanism of its action, with
      emphasis on the cell cycle and mitogen-activated protein kinases (MAPK). A
      significant dose-dependent growth inhibition was observed after treatment with
      catechin. At 48 h after the addition of catechin, cells at the G2/M phase were
      increased by 8.3%, compared with the control. Analysis of the expression of cell
      cycle-related proteins after the addition of catechin showed that the cyclin
      dependent kinase (cdk) 2 and the cdk4 proteins were decreased after
      administration, the expression of cyclin A protein was increased at 24 h after
      administration, however, the expression of the cyclin D1 and cyclin E proteins
      was unchanged. At 24 h after the administration of catechin, the phosphorylation
      of cell division cycle 2 (cdc2) was inhibited, and the expression of cyclin B1
      protein was also decreased. Furthermore, the analysis of the MAPK expression
      showed that the phosphorylated JNK/SAPK protein began to increase at 3 h after
      catechin administration, and the expression persisted until 24 h after
      administration, then decreased. The phosphorylation of p38 protein was increased
      at 12 h, and began to decrease at 36 h after catechin administration. Based on
      these results, we speculate that, in the breast cancer cell line T47D, catechin
      phosphorylated JNK/SAPK and p38, and that the phosphorylated JNK/SAPK and p38
      inhibited the phosphorylation of cdc2, and regulated the expression of cyclin A,
      cyclin B1, and cdk proteins, thereby causing G2 arrest. The results suggested
      that catechin (EGCG) may be an effective adjuvant therapy after breast cancer
      surgery.

PMID- 12429980
TI  - Phosphorylation of p53, induction of Bax and activation of caspases during beta
      lapachone-mediated apoptosis in human prostate epithelial cells.
AB  - The DNA topoisomerase I inhibitor beta-lapachone, the product of a tree from
      South America, is known to exhibit various biological properties, the mechanisms
      of which are poorly understood. We investigated the effects of beta-lapachone on
      the growth of human prostate epithelial cells. Upon treatment with beta
      lapachone, a concentration-dependent inhibition of cell viability was observed
      and cells developed many of the hallmark features of apoptosis, including
      condensation of chromatin and DNA fragmentation. The apoptotic effects of beta
      lapachone were associated with marked induction of p53 phosphorylation and Bax
      protein without altering the expression of p53 and Bcl-2 protein. In addition,
      the proteolytic cleavage of specific target proteins such as poly(ADP-ribose)
      polymerase, beta-catenin and Rad51, which are hallmarks of apoptosis, were
      observed, and Western blotting demonstrated that processing/activation of
      caspases release cytochrome c from the mitochondria into the cytosol and
      accompany the generation of beta-lapachone-mediating apoptotic cell death.
      However, beta-lapachone did not affect the levels of c-IAP family proteins. The
      present results suggest that apoptotic signals evoked by beta-lapachone in human
      prostate epithelial cells may converge caspases activation through up-regulation
      of phosphorylation of p53 and Bax rather than down-regulation of c-IAPs family.

PMID- 12429982
TI  - Bioactivity of well-defined green tea extracts in multicellular tumor spheroids.
AB  - The effect of green tea extracts (GTE) of a reproducible, well-defined
      composition on cellular viability, proliferation, and antioxidant defense was
      investigated in multicellular spheroids derived from WiDr human colon
      adenocarcinoma cells. The maximum GTE concentration investigated, i.e. 100 micro
      g GTE/ml, was equivalent to the plasma concentration commonly measured in humans
      drinking 6-10 cups of green tea per day. This GTE concentration lead to a
      substantial retardation of spheroid volume growth with diameters reaching only
      half the size of untreated aggregates. Flow cytometric analysis and
      immunocytochemistry showed an enhanced accumulation of cells in G2/M and in the
      non-proliferating compartment, respectively. The emergence of central necrosis
      occurred at larger spheroid diameters compared to control conditions leading to a
      significant increase (p<0.05) in the thickness of the viable cell rim (mean +/-
      SD) from 240+/-49.9 micro m to 294+/-69.5 micro m. This was associated with an
      elevation of the intracellular GSH concentration and, thus, of cellular
      antioxidant defense, as shown by HPLC analysis. A considerable toxicity, however,
      was found at these GTE levels in single cells. Cells did not adhere to culture
      dishes nor did they aggregate to form spheroids when plated as a suspension with
      GTE already in the culture medium. The findings show that green tea constituents
      interfere with early phases of tumorigenesis at a cellular level, e.g., by
      reducing cell-substratum and cell-cell interaction, enhancing G2/M arrest, and
      retarding spheroid volume growth. The differences in GTE effects between single
      cells and cell spheroids underline the importance of inclusion of spheroids in
      pharmaco-/toxicological testing.

PMID- 12429983
TI  - Microvessel density, mast cell density and thymidine phosphorylase expression in
      oral squamous carcinoma.
AB  - To elucidate the role of angiogenesis in the carcinogenesis and progression of
      oral cancer, we investigated microvessel density (mVd), mast cell density (mCd)
      and thymidine phosphorylase (TP) expression in a series of 50 patients with T1-3
      N0-1 M0 oral squamous carcinoma (OSC) and 21 patients with non-dysplastic oral
      leukoplakia (NDOLP). Paraffin-embedded pathological tissue was utilised for the
      immunohistochemical analysis of mVd and TP expression. Toluidine blue
      histochemical method was employed for mast cell identification. OSC and NDOLP
      were not significantly different with respect to mVd (mVd mean value +/- SD: 30+/
      17 and 27+/-18, respectively) and mCd characteristics (mCd mean value +/- SD: 8+/
      6 and 7+/-6 units, respectively). Conversely, tumour epithelia showed some degree
      of TP immunostaining in 100% of cases compared with 76% in NDOLP samples (p< or
      =0.001 by Fisher's test). A good correlation was found between mVd and mCd in
      both NDOLP (c.c. 0.632; p=0.002) and OSC (c.c. 0.496; p=0.000) tissue, whereas no
      association between TP expression and mVd or between mCd and TP status was
      evident. At a median follow-up of 18 months, patients with high mVd tumours
      showed a greater probability of survival than those with low mVd (75 and 40%,
      respectively; p=0.04 log-rank test). Our results suggest that the development of
      oral cancer epithelia is associated with a significant increase in TP expression.
      Conversely, the clinical outcome of OSC seems inversely related specifically to
      mVd.

PMID- 12429985
TI  - Ruthenium-based NAMI-A type complexes with in vivo selective metastasis reduction
      and in vitro invasion inhibition unrelated to cell cytotoxicity.
AB  - A series of analogues of NAMI-A, a reference compound active on solid tumor
      metastases, were synthesized (NAMI-A type complexes). They share the same
      chemical structure of NAMI-A, and differ from it in the nature of the coordinated
      nitrogen ligand, such as pyrazole, thiazole and pyrazine, which are less basic
      than imidazole. This modification confers to the new NAMI-A type complexes a
      better stability in aqueous solution compared to the parent compound, a very
      important characteristic for a class of compounds that, with NAMI-A, is currently
      completing a phase I clinical trial at the Netherlands Cancer Institute of
      Amsterdam. Cytotoxicity and the effects on cell cycle and invasion were
      investigated on TS/A, B16-F10 and MCF-7 tumor cell lines, while the inhibition of
      lung metastases was determined on the mouse experimental tumors Lewis lung
      carcinoma and MCa mammary carcinoma. The new complexes show a pharmacological
      activity very similar to that of the parental compound NAMI-A: in vitro they are
      devoid of meaningful cytotoxicity against tumor cells, and in vivo they inhibit
      metastasis formation and growth approximately to the same extent as NAMI-A. Thus
      the new NAMI-A type complexes retain the same potent characteristic of NAMI-A to
      selectively interact with solid tumor metastases. However, compared to NAMI-A
      they do not stop cell cycle progression at G2-M level and are more active in
      preventing the spontaneous invasion of Matrigel by tumor cells exposed for 1 h to
      10(-4) M concentration. Globally, these complexes take advantage of the knowledge
      on NAMI-A and appear particularly interesting for future clinical handling and
      applications.

PMID- 12429984
TI  - Bombesin and epidermal growth factor potentiate the effect of cytotoxic LH-RH
      analog AN-152 in vitro.
AB  - The conjugation of doxorubicin with [D-Lys6] Luteinizing Hormone-Releasing
      Hormone (LH-RH), yields AN-152, a cytotoxic analog that can be targeted to tumor
      cells expressing LH-RH receptors. This conjugate is more potent against LH-RH
      receptor positive cancer cells and has less peripheral toxicity than free
      doxorubicin. The proliferation of MCF-7 human breast cancer cells in vitro is
      inhibited by AN-152 and this effect can be augmented by the up-regulation of LH
      RH receptor expression through stimulation of tyrosine phosphorylation with
      epidermal growth factor (EGF). Bombesin and gastrin releasing peptide increase
      tyrosine phosphorylation and can act synergistically with EGF, as well as
      independently. The aim of this study was to demonstrate that bombesin enhances
      cytotoxic sensitivity of MCF-7 cells to AN-152 and that a significantly higher
      efficacy of the drug can be achieved in cells exposed to both bombesin and EGF.
      The cells were pretreated with bombesin and/or EGF, and then exposed to 0-10
      micro M AN-152 for 96 h for determination of cytotoxicity. In addition, cells
      pretreated with bombesin and/or EGF were exposed for 1 h to 0.6 micro M AN-152
      labeled with a two-photon fluorophore (AN-152:C625) for fluorescent imaging of
      drug entry. Bombesin as well as EGF increased the uptake and cytotoxicity of AN
      152 in MCF-7 cells. The exposure of the cells to both EGF and bombesin produces a
      synergistic effect and results in increased cellular entry and cytotoxicity of AN
      152. These results suggest that the activation of LH-RH receptors by compounds
      that increase tyrosine phosphorylation could further improve the response to
      targeted chemotherapy with AN-152.

PMID- 12429986
TI  - Vincristine induced apoptosis in acute lymphoblastic leukaemia cells: a
      mitochondrial controlled pathway regulated by reactive oxygen species?
AB  - Vincristine (VCR), a microtubule interfering anti-cancer agent, plays a key role
      in the treatment of childhood acute lymphoblastic leukaemia (ALL). The route of
      VCR induced apoptosis in ALL cells is not well defined. In this study we
      demonstrated caspase-9 and -3 activation in vivo in bone marrow leukaemic cells
      of a child with newly diagnosed ALL, after treatment with a single dose of VCR.
      We hypothesized that VCR induced apoptosis in ALL cells proceeds by a
      mitochondrial controlled pathway. We further studied the route of VCR induced
      apoptosis in Jurkat acute lymphoblastic leukaemia cells. First we showed that VCR
      induces activation of caspase-9 and -3 in Jurkat cells. With the caspase-9
      inhibitor Z-LEHD-FMK we proved that caspase-9 was activated prior to caspase-3.
      Loss of mitochondrial transmembrane potential was independent of caspase-9
      activation. To confirm the mitochondrial role in VCR induced apoptosis, the
      effect of blocking the mitochondrial route upstream of caspase-9 activation was
      investigated at two different levels: reactive oxygen species (ROS) scavenging
      and Bcl-2 overexpression. Generation of ROS was detected early in Jurkat cells
      during VCR exposure. Ascorbic acid, a ROS scavenger, inhibited ROS generation as
      well as caspase-9 and -3 activation and cell death induced by VCR. Furthermore,
      in Bcl-2 overexpressing Jurkat cells mitochondrial membrane potential changes,
      caspase-9 and -3 activation and cell death upon VCR exposure were decreased, in
      comparison to parental Jurkat cells. However, generation of ROS was not decreased
      in Jurkat cells with Bcl-2 overexpression. We concluded that ROS play a
      regulatory role in the initial phase of a mitochondrial controlled pathway of VCR
      induced apoptosis in Jurkat cells.

PMID- 12429987
TI  - Overexpression of the Csk homologous kinase facilitates phosphorylation of
      Akt/PKB in MCF-7 cells.
AB  - The serine/threonine kinase Akt has recently been the focus of intense research.
      Akt activation requires the phosphorylation of both Thr-308 and Ser-473. Src
      kinase was shown to induce activation of Akt, while Lyn kinase seems to inhibit
      this activation. In the present study, we investigated the effect of
      overexpressing the Csk homologous kinase (CHK), an inhibitor of Src-family
      kinases, on the phosphorylation of Akt induced by two different factors:
      heregulin or cisplatin. We used MCF-7 cells stably overexpressing the wild-type
      CHK [CHK(wt)] or dead-kinase CHK [CHK(dk)]. We observed that in MCF-7 CHK(wt)
      cells Lyn kinase activity was more profoundly inhibited than Src kinase activity.
      When the cells were stimulated with heregulin or cisplatin, Akt phosphorylation
      occurred more rapidly in MCF-7 CHK(wt) cells in comparison to the other clones
      used. Interestingly, MCF-7 CHK(wt) cells in vitro were markedly more resistant to
      cisplatin than the other clones used in the experiments, and surprisingly
      chemical inhibition of Akt phosphorylation did not influence this resistance. In
      summary, our results show facilitation of Akt phosphorylation by the
      overexpression of CHK, and provide new insight into the putative role of CHK in
      human cancer.

PMID- 12429988
TI  - Gene expression pattern following photodynamic treatment of the carcinoma cell
      line A-431 analysed by cDNA arrays.
AB  - The photosensitizer protoporphyrin IX, endogenously accumulated from the
      precursor aminolevulinic acid, is a successful agent in photodynamic tumor
      therapy. In spite of encouraging clinical results, the basic mechanisms leading
      to cell death are not fully understood. We therefore set out to analyse the
      alteration of the gene expression pattern in the squamous cell carcinoma cell
      line A-431 after photodynamic treatment with endogenous protoporphyrin IX.
      Radioactively labelled cDNAs from untreated and treated cells were hybridized
      onto UniGene cDNA array filters containing lysed bacterial colonies with inserts
      representing approximately 32000 different human transcripts. Differentially
      expressed genes were identified and verified on sub-arrays containing only the
      candidate genes. We found increased expression of heat shock protein 70 and of
      the immediate early genes p55-c-fos and c-jun, may be due to oxidative stress and
      increased levels of intracellular calcium after photoactivation of protoporphyrin
      IX. Increased expression of heme oxygenase-1 following dark incubation was not
      further increased by irradiation and therefore probably caused by the need for
      heme degradation. Presumably heat shock protein 70 and heme oxygenase-1 serve for
      cell protection. Though similar results have been found for photodynamic
      treatment with external porphyrin-based photosensitizers, this is the first
      report about induction of the genes described above by (photoactivated)
      endogenous protoporphyrin IX.

PMID- 12429989
TI  - The tumour suppressor p33ING1 does not regulate migration and angiogenesis in
      melanoma cells.
AB  - The tumour suppressor ING1 shares many biological functions with p53, such as
      cell cycle arrest, DNA repair, apoptosis, and chemosensitivity. Since p53
      inhibits invasion and angiogenesis of melanoma cells, we sought to investigate if
      p33ING1 (one of ING1 isoforms) is also involved in these biological processes. We
      first overexpressed p33ING1 in melanoma cells and assessed the protein levels in
      MMP-1, MMP-2, and MMP-9. Results from Western blot analysis showed no significant
      difference in these matrix metalloproteinase levels between cells transfected
      with vector, p33ING1, and antisense p33ING1. Wound healing assay was performed to
      examine if p33ING1 plays a role in migration and invasion. Results showed that
      there was no difference between vector, p33ING1, and antisense p33ING1 groups in
      melanoma cell migration across the wound. Western blot analysis also indicated
      that there is no difference in the levels of proteins which are directly involved
      in angiogenesis, such as VEGF, Flt-1, and Flk-1, between cells transfected with
      vector, p33ING1, and antisense p33ING1. Furthermore, functional studies indicated
      that cultured medium derived from p33ING1-transfected melanoma cells did not
      stimulate the growth of HUVEC cells, compared to controls, providing support to
      the lack of functional role of p33ING1 in angiogenesis. In conclusion, we
      demonstrate in vitro that p33ING1, unlike p53, does not play a role in
      angiogenesis and migration in melanoma cells.

PMID- 12429990
TI  - Calcium signalling and control of cell proliferation by tyrosine kinase receptors
      (review).
AB  - Most peptidic growth factors (GFs) that act as mitogens for different cell types
      bind to tyrosine kinase receptors (RTKs) and trigger complex intracellular signal
      transduction pathways finally leading to cell proliferation. Among the early
      events induced by GFs, cytosolic calcium increase plays a key role, and in
      particular calcium entry from extracellular medium appears to be a widespread
      signal. Even if a great amount of data has been provided during the last decades,
      several issues remain to be fully clarified: the nature of the calcium-permeable
      channels involved, their regulation by intracellular messengers, and the
      mechanisms underlying calcium-dependent cell proliferation. This review focuses
      on the relationship between calcium signals and angiogenesis, a process in which
      endothelial cell proliferation, mainly triggered by basic fibroblast growth
      factor (bFGF) and vascular endothelial growth factor (VEGF), is a critical step.

PMID- 12429991
TI  - Paradigm shift in gene-finding method: From bench-top approach to desk-top
      approach (review).
AB  - Gene-finding methods are classified into homology-based bench-top approach
      (degenerate cDNA-PCR and cDNA selection), ab initio bench-top approach (cDNA
      subtraction, two-hybrid system, and exon trapping), homology-based desk-top
      approach (BLAST search), ab initio desk-top approach (Fgenesh and GENSCAN
      programs), and hybrid desk-top approach (GenomeScan program). cDNA-library
      screening, cDNA-PCR, and RACE are used to isolate cDNAs for complete coding
      sequences. Because WNT signaling molecules are potent targets for oncology,
      regenerative medicine, and other fields of medical science, we have cloned and
      characterized many human genes encoding WNT signaling molecules, including 13 out
      of 19 human WNT genes, and 9 out of 10 human FZD genes. We used degenerate cDNA
      PCR and cDNA-library screening in the 20th century, while we use BLAST program
      and cDNA-PCR in the 21st century. The interval between gene-finding and
      manuscript-publication in my laboratory was 17.2+/-7.5 (mean +/- SD) months in
      the 20th century (n=13), 11.5+/-7.8 months in 2001 (n=19), and 5.5+/-1.6 months
      in 2002 (n=13). The interval using desk-top gene-finding approach (7.2+/-2.6
      months, n=30) was significantly shorter than that using bench-top approach
      (19.8+/-8.0 months, n=15) (p=0.003). Gene-finding has been significantly
      accelerated due to paradigm shift from bench-top approach to desk-top approach.
      Dramatic increase of information about human genome, transcriptome and proteome
      accompanied by improvements of genomics, proteonics and bioinformatics
      technologies will accelerate paradigm shift from bench-top science to desk-top
      science.

PMID- 12429992
TI  - Regulation of WNT signaling molecules by retinoic acid during neuronal
      differentiation in NT2 cells: threshold model of WNT action (review).
AB  - NT2/NTera2 cells, derived from human embryonal tumor, differentiate into neuronal
      cells after treatment with all-trans-retinoic acid (ATRA). We have cloned and
      characterized 13 out of 19 human WNT genes, and also 9 out of 10 human Frizzled
      (FZD) genes encoding seven-transmembrane-type WNT receptors, which are potent
      targets for pharmacogenomics in the post-genomic era, especially in the field of
      regenerative medicine and clinical oncology. Because WNT signals are implicated
      in morphogenesis of neural tissues, regulation of 19 WNT genes and 10 FZD genes
      during the early phase of neuronal differentiation in NT2 cells is reviewed.
      Multiple WNTs and FZDs are expressed in NT2 cells. WNT2B/WNT13 gene encode 2
      isoforms due to alternative splicing of alternative promoter type, and WNT2B
      isoform 2 (WNT2B2) rather than WNT2B isoform 1 (WNT2B1) is expressed in NT2
      cells. WNT3A, WNT8A, WNT8B, WNT10B and WNT11 are down-regulated in NT2 cells
      after ATRA treatment, while WNT2, WNT7B and WNT14B are up-regulated. FZD4 and
      FZD10 are up-regulated in NT2 cells after ATRA treatment. Expression of multiple
      WNT signaling molecules are dramatically changed during the early phase of
      neuronal differentiation in NT2 cells. Each WNT activates the beta-catenin - TCF
      pathway, the JNK pathway or the Ca2+-releasing pathway in NT2 cells, and summed
      effects of multiple WNTs might determine the fate of NT2 cells (self-renewal or
      differentiation) through switching intracellular WNT signaling pathways. The
      author proposes the threshold model of WNT action.

PMID- 12429993
TI  - Characterization of the CCK-C (cancer) receptor in human pancreatic cancer.
AB  - The gastrointestinal peptides gastrin and cholecystokinin (CCK) stimulate growth
      of human pancreatic cancer by a receptor-mediated process. The purpose of this
      study was to investigate the molecular and functional characteristics of the
      receptor associated with peptide-induced pancreatic cancer proliferation.
      Utilizing total RNA from human pancreatic cancer cells a cDNA was cloned and
      sequenced by RT-PCR and rapid amplification of cDNA ends methodology. The
      molecular characteristics of the receptor cDNA were studied by Northern analysis
      and protein structure by Western analysis. An antibody raised against the novel
      receptor was utilized to investigate the role of the CCK-C receptor on pancreatic
      cancer cellular growth using in vitro technology. A spliced variant of the CCK-B
      receptor was identified which differed from the CCK-B receptor by the presence of
      intron 4. Northern analysis showed a transcript size of 3.2 Kb for the receptor
      mRNA in the human pancreatic cancer specimens, and Western blotting revealed
      binding to a 49 kDa protein in pancreatic tumors. Immunoreactivity was found in
      pancreatic cancer cells and tumors with localization in the cytoplasm. Treatment
      of BxPC-3 human cancer cells with the antibody resulted in growth inhibition.
      These data reveal the presence of a unique CCK receptor in human pancreatic
      cancer that functions in growth and is not present in normal human pancreas. The
      term CCK-C or 'cancer' receptor has been proposed to signify the relationship of
      this receptor to neoplasia.

PMID- 12429994
TI  - Differential pathomechanisms of epidermal necrolytic blistering diseases.
AB  - Staphylococcal scalded skin syndrome (SSSS) results from the effect of
      exfoliative-toxins produced by staphylococcal strains. The disease affects
      predominantly children, and is rare in adults. We report two cases of the adult
      type of SSSS. Corticotherapy, chronic alcohol abuse and epilepsy-related immune
      changes might have been predisposing factors in these patients. The
      immunopathological characteristics of the inflammatory cell infiltrate in adults
      SSSS have not been thoroughly explored so far in the literature. Biopsies from 2
      patients with bullous SSSS skin were studied by means of immunochemistry using a
      panel of 10 antibodies directed to FXIIIa, CD15, CD31, CD45R0, CD50, CD54, CD62E,
      CD95, CD106, and L1-protein, respectively. Cutaneous biopsies from related
      blistering diseases were compared. They included drug-induced toxic epidermal
      necrolysis (TEN), bullous impetigo and superficial pemphigus. A dense cell
      infiltrate composed of granulocytes (CD15+), macrophages (L1 protein+) and memory
      T cells (CD45R0+) and a strong expression of ICAM-3 (CD50) were present in the
      epidermis. CD95+ keratinocytes were lining the intraepidermal blisters. Type I
      dermal dendrocytes (Factor XIIIa+) were numerous and plump in the dermis. Bullous
      impetigo exhibited the same pattern of inflammatory cells, but with a lower
      density in type I dermal dendrocytes. TEN differed from SSSS by both the absence
      of CD15+ granulocytes and a stronger expression of the pro-apoptotic CD95 antigen
      in the epidermis. In superficial pemphigus, CD95 antigen was not expressed, and
      CD15+ granulocytes, CD45R0+ lymphocytes and L1 protein+ monocytes were much less
      numerous. It is concluded that the specific binding of SSSS-induced exotoxins to
      the desmosomes alters the keratinocyte metabolism leading to an inflammatory
      reaction followed by focal apoptosis. Our findings are in line with the concept
      that SSSS exotoxins might be superantigens. A common pathomechanism leading to
      epidermal destruction is likely operative in SSSS and bullous impetigo. The
      inflammatory cell composition in TEN and superficial pemphigus markedly differs
      from that in SSSS.

PMID- 12429995
TI  - Inhibition of lung metastasis of B16 melanoma cells exposed to blue light in
      mice.
AB  - The effects of blue light on B16 melanoma cells and on the metastasis of these
      cells to the lungs were investigated in mice. The exposure of B16 melanoma cells
      to blue light in two 20-min sessions resulted in marked suppression of cell
      growth measured at 7 days after exposure. When these cells were harvested, re
      inoculated into medium and incubated for a further 7 days, their growth activity
      returned to almost the same level as that of cultured cells from the non-exposure
      control group. The melanoma cells harvested after 7 days of incubation were
      injected intravenously into mice. In the non-exposure group, black nodules
      developed on the lung surface and the nodules increased in size over time. In the
      blue-light-exposure group, the development of such black nodules on the lung
      surface was delayed, and the nodules were smaller. Histopathological examination
      revealed that blue light suppressed the growth of metastatic tumor cells, and no
      increase in the number of melanin-containing cells or atypical cells was induced
      in the metastatic lesions. These results suggest that blue light suppresses the
      metastasis of B16 melanoma cells.

PMID- 12429997
TI  - Breast cancer, consanguinity, and lethal tumor genes: simulation of BRCA1/2
      prevalence over 40 generations.
AB  - Marriage between biological relatives is a social custom with a long history in
      many parts of the world. Today, hundreds of millions of individuals live in
      consanguineous families. The offspring of consanguineous parents are more likely
      to have the same two alleles (homozygosity) by descent. In consanguineous family
      with BRCA1/2 gene mutations, an offspring is more likely to be BRCA1/2
      homozygous. The consequences of BRCA1/2 mutation homozygosity in humans are
      unknown. In knockout mice, BRCA1 or BRCA2 homozygotes die as embryos. Because
      tumor suppressor genes are conserved and less species-specific than other genes,
      human BRCA1/2 homozygotes are likely to be biologically non-viable and are
      unknown to exist. Among the conceptuses of consanguineous couples, there are
      excess deaths (abortions, stillbirths, perinatal and early-childhood deaths) as
      well as a decreased risk of breast cancer, especially in younger females. It has
      been suggested that, in part, the excess deaths are due to BRCA1/2 and other
      still undiscovered tumor gene homozygotes. To examine the consequences of the
      long-term practice of consanguineous marriage on the prevalence of lethal cancer
      genes, we simulated, by computer, the mating of non-consanguineous and
      consanguineous populations over 40 generations. The program was developed in
      Basic for a Macintosh computer. The input comprised the rates of consanguineous
      marriage types and the output parameter was the rate of heterozygotes (carriers)
      in each generation. The combined prevalence of BRCA1/2 mutation of 1% was used as
      a starting reference point. Absence of spontaneous mutations and gene flow were
      assumed. In a randomly mating population, the BRCA1/2 carrier rate decreases on
      average 0.0035% every 25 years. In a highly consanguineous population, the
      carrier rate decreases on average 0.022% every 25 years, or six times faster than
      in a non-consanguineous population. There is a worldwide trend of decreasing
      breast cancer incidence with an increasing consanguinity rate. In conclusion, the
      BRCA1/2 and possibly other undiscovered tumor gene carrier rates are
      significantly lower in consanguineous than in non-consanguineous populations.
      Gene frequency in a population depends on the rate of inbreeding and length of
      consanguineous practices. A drift phenomenon may exert a major effect on the
      carrier rate. Consanguinity may explain part of the worldwide variation of breast
      cancer incidence.

PMID- 12429996
TI  - Comparative study of p63 and p53 expression in tissue microarrays of malignant
      melanomas.
AB  - p63 is a known homologue of p53. In contrast to p53, however, p63 mutations are
      rarely seen in tumours. There have been several reports that p63 plays a
      regulatory role in the normal differentiation of cells, whereas its role in
      tumour biology must still be elucidated. The main aim of this study was to
      compare p63 and p53 expression in tissue microarrays of malignant melanomas and
      to establish any prognostic significance. p63 expression was found in 2 out of 59
      tumours, both pT4. The p63 index did not exceed 30%. p53 expression was found in
      27 out of 59 melanomas, with maximal expression in up to 80% of tumour cells.
      There were no correlations observed between the two markers. Multivariate
      analysis confirmed the prognostically independent role of p53. This study also
      confirmed that tissue microarrays can be used effectively for evaluation of the
      expression of certain tumour markers.

PMID- 12429998
TI  - Expression of the myeloid-specific leukocyte integrin gene CD11d during
      macrophage foam cell differentiation and exposure to lipoproteins.
AB  - The leukocyte integrin gene CD11d is expressed predominantely on subsets of the
      myelomonocytic lineage (myeloid cells), particularly on macrophage foam cells and
      splenic red pulp macrophages. Its expression pattern clearly differs from myeloid
      specific leukocyte integrins CD11b and CD11c and the leukocyte-specific integrin
      CD11a. Although the functions of CD11d have not been determined in any detail,
      its expression in these cell types suggests that it may play a role in the
      atherosclerotic process. To better understand how this gene is regulated, the
      steady-state level of CD11d mRNA in differentiating bone marrow CD34+CD38- cells,
      peripheral blood monocytes, and monocytic cell lines was assessed by Northern
      blot analysis and RT-PCR and compared with those of CD11a, CD11b, and CD11c.
      Expression of CD11d occurs early in CD34+CD38- cells, rises, and then decreases,
      in contrast to the expression of the other leukocyte integrins. Expression of
      CD11d reappears in peripheral blood monocytes differentiating to macrophage foam
      cells. Oxidized lipoproteins (OxLDL) and acetylated lipoproteins (AcLDL) failed
      to upregulate CD11d following differentiation of peripheral blood monocytes or
      the monocytic cell line HL60. However, when both OxLDL and AcLDL were present
      during differentiation, CD11d was further upregulated. This suggests that
      expression of CD11d is coordinately regulated with expression of LDL receptors
      and the development of the foam cell. Site-directed mutagenesis of the -100 to 
      20 region of the CD11d promoter revealed transcription factor binding sites
      essential for expression of this gene. Decoy oligonucleotides to the -100 to -20
      region taken up by CD34+CD38- cells block their differentiation into myeloid
      colonies. This suggests that one or more transcription factors that regulate
      CD11d also are essential for myeloid differentiation, and that the CD11d promoter
      may be used as a model gene to identify transcription factors essential for
      myeloid cell differentiation.

PMID- 12429999
TI  - Stimulatory effect of menaquinone-7 on bone formation in elderly female rat
      femoral tissues in vitro: prevention of bone deterioration with aging.
AB  - Menaquinone-7 (MK-7) is vitamin K2 which is a series of vitamins with
      multiisoprene units at the 3-position of the naphthoquinone. MK-7 has been shown
      to prevent bone loss in ovariectomized rats, an animal model for osteoporosis.
      This study was undertaken to determine whether MK-7 has a stimulatory effect on
      bone components of elderly female rats in vitro. The femoral-diaphyseal and 
      metaphyseal tissues obtained from young (4 weeks old) or elderly (50 weeks old)
      female rats were cultured for 48 h in a Dullbecco's modified Eagle's medium (high
      glucose, 4.5%) supplemented with antibiotics and bovine serum albumin. Calcium
      content, alkaline phosphatase activity and deoxyribonucleic acid (DNA) in the
      diaphyseal and metaphyseal tissues obtained from elderly rats were significantly
      decreased as compared with those of young rats, indicating that aging causes a
      deterioration of bone formation. The presence of MK-7 (10(-6) or 10(-5) M) caused
      a significant increase in biochemical components in the femoral-diaphyseal and 
      metaphyseal tissues obtained from elderly rat in vitro. The anabolic effect of MK
      7 (10(-6) or 10(-5) M) on the femoral calcium content was significantly enhanced
      in the presence of phytoestrogen genistein (10(-6) or 10(-5) M), suggesting that
      the mode of action of MK-7 differ from that of genistein. The effect of MK-7 (10(
      5) M) in increasing calcium content, alkaline phosphatase activity and DNA
      content in the diaphyseal and metaphyseal tissues was completely abolished in the
      presence of cycloheximide (10(-6) M), an inhibitor of protein synthesis in vitro.
      These findings demonstrate that MK-7 has a stimulatory effect on bone formation
      in the femoral tissues of elderly female rats in vitro. MK-7 may have a
      preventive role for bone deterioration with aging.

PMID- 12430000
TI  - Differential expression of genes during TPA-induced differentiation of human
      prostatic cancer TSU-Pr1 cells.
AB  - We are interested in the possibility of a new prostate cancer therapy that would
      control tumor malignancy via induction of terminal cell differentiation. We
      previously reported that 12-O-tetra-decanoylphorbol-13-acetate (TPA) induces
      differentiation into cells with characteristics of microglia and decreases the
      malignant characteristics of human prostatic cancer TSU-Pr1 cells. To investigate
      the mechanism underlying differentiation of TSU-Pr1 cells, we attempted to
      identify genes expressed during differentiation using differential display. We
      identified four genes expressed differentially after TPA treatment. Levels of
      expression of two genes, human flavoprotein subunit of complex II and JKTBP, were
      downregulated by TPA, and expression of two genes, human golgin p245 and bcl-xL,
      was upregulated. Moreover, we found that the changes in expression of flavo
      protein, JKTBP and bcl-xL induced by TPA were blocked by treatment with protein
      kinase C (PKC) or mitogen-activated protein (MAP) kinase inhibitors that prevent
      TPA-induced differentiation of TSU-Pr1 cells. These results suggest that the
      differential expression of these genes is associated with TPA-induced
      differentiation of TSU-Pr1 cells. We expect that understanding the roles of these
      genes during differentiation will provide for new approaches and therapeutic
      targets for treatment of prostate cancer.

PMID- 12430001
TI  - Interleukin-12-mediated induction of systemic immunity in the periphery and
      recruitment of activated T cells into the brain produce limited antitumor effects
      compared with interleukin-2.
AB  - Interleukin-12 (IL-12) stimulates the type 1 helper T (Th1) cell responses and
      augments antitumor immunity. We examined possible antitumor effects of IL-12
      secreted intracerebrally (i.c.) and/or subcutaneously (s.c.) in an experimental
      glioblastoma model and compared the effects with those of IL-2. Rat 9L
      gliosarcoma cells retrovirally transduced with the IL-12 or IL-2 gene (9L/IL-12
      and 9L/IL-2, respectively) were completely rejected when they were s.c.
      inoculated. The transduced cells, implanted i.c., developed progressive brain
      tumors at reduced rates compared with 9L brain tumors and the growth retardation
      of 9L/IL-2 tumors was greater than that of 9L/IL-12 tumors. When rats were s.c.
      immunized with either 9L/IL-12 or 9L/IL-2 cells, the growth of 9L brain tumors
      developed in the rats was suppressed compared with that of 9L tumors in naive
      rats. Among various combinations of simultaneous inoculations of cytokine
      producers s.c. and i.c., 9L/IL-2 but not 9L/IL-12 cells inoculated i.c. were
      rejected when the rats were s.c. immunized with either 9L/IL-12 or 9L/IL-2 cells.
      The synergistic antitumor effects induced were correlated with the infiltration
      levels of CD8+ and CD4+ T cells into brain tumors. Tumor-specific cytotoxic
      activity was induced in the rats immunized s.c. with 9L/IL-2 but not fully in the
      rats with 9L/IL-12 cells. These results collectively suggest that the antitumor
      activity with IL-2 was superior to IL-12 both in the induction of cytotoxic T
      cells and in the recruitment of activated T cells into brain tumors.

PMID- 12430002
TI  - Posthepatectomy hepatitis shortens tumor-free intervals in hepatitis C virus
      associated hepatocellular carcinoma patients.
AB  - In hepatitis C virus (HCV)-associated hepatocellular carcinoma (HCC), serum
      alanine aminotransferase (ALT) is frequently sustained on a high level after
      hepatectomy, with the formation of recurrent HCC tumors during follow-up periods.
      We investigated whether or not postoperative serum ALT level affects the interval
      before recurrence in hepatitis C virus-associated HCC. The subjects studied were
      50 hepatectomized HCC patients who were HCV-Ab(+), and underwent a curable
      surgery in our Hospital from June 1990 to December 1999. We assessed the
      significance of the postoperative serum ALT level affecting tumor-free survival
      rates, as compared with other clinicopathological parameters, using univariate
      and multivariate Cox proportional hazard analysis. Thereafter, tumor-free and
      overall survival rates after hepatectomy were compared between high and low ALT
      groups, using Kaplan-Meier plotting and a log-rank test. The factor of ALT levels
      (a high or low ALT group) was most strongly associated with a tumor-free survival
      rate. Both tumor-free and overall survival rates were significantly poorer in the
      high ALT group than in the low ALT group among HCV-associated HCC cases (p<0.05).
      The results in this study suggest that postoperative hepatitis, which is
      indicated by sustained high ALT levels, may shorten the interval before
      recurrence in HCV-associated HCC. We should take care to control postoperative
      hepatitis to improve the prognoses of HCV-associated HCC cases.

PMID- 12430003
TI  - Molecular analysis on the chemopreventive properties of resveratrol, a plant
      polyphenol microcomponent.
AB  - As a plant microcomponent, resveratrol is a polyphenolic compound produced by
      several species and found especially in Polygonum roots, peanuts seeds, berries
      and also grape and therefore can be present in human diet or beverages (red wine,
      for instance). Traditional chinese medicine and more recent epidemiological
      studies strongly suggested that resveratrol may act as a cancer chemopreventive
      compound. The biochemical mechanism by which resveratrol inhibits cell
      proliferation was provided by studies in numerous human cell lines including our
      work in hepatoblastoma HepG2 and colorectal tumor SW480 cells. The results show
      that resveratrol strongly inhibits cell proliferation at the micromolar range in
      a time- and dose-dependent manner. Resveratrol appears to block the cell cycle at
      the transition S to G2/M since there is no inhibition of [3H]-thymidine
      incorporation observed, while there is an increase of the cell number in S phase.
      On the other hand, in order to evaluate if the amount of resveratrol taken up
      during food or drink consumption is sufficient to ensure in the whole body the in
      vitro described beneficial effects, we evaluated the ratio between plasmatic
      level of resveratrol and its cell bioabsorption. Our study reports a higher
      uptake of resveratrol in the human hepatic derived HepG2 cells than in colorectal
      derived SW480 cells. In contrast, resveratrol is conjugated in these cells and
      derivatives are released in large amounts in the cell medium. Based on present
      knowledge, resveratrol appears to be a promising bioactive natural molecule with
      potential applications in phytotherapy, pharmacology or in nutriprotection
      (nutraceutic food) area.

PMID- 12430004
TI  - Suppressive role of endogenous regucalcin in the regulation of nitric oxide
      synthase activity in heart muscle cytosol of normal and regucalcin transgenic
      rats.
AB  - The role of regucalcin, a regulatory protein of Ca2+ signaling, in the regulation
      of nitric oxide (NO) synthase activity in the cytosol of rat heart muscle was
      investigated. The addition of calcium chloride (5-20 microM) into the enzyme
      reaction mixture containing the heart cytosolic protein caused a significant
      increase in NO synthase activity. The Ca2+ effect was significantly inhibited by
      trifluoperazine (TFP; 20 or 50 microM), an antagonist of calmodulin, indicating
      the existence of Ca2+/calmodulin-dependent NO synthase activity in rat heart
      muscle cytosol. NO synthase activity was significantly decreased by the addition
      of regucalcin (10(-9) or 10(-8) M). This effect was also seen in the presence of
      calcium chloride (10 microM), TFP (50 microM) or EGTA (1 mM), a chelator of Ca2+.
      Meanwhile, the effect of regucalcin (10(-8) M) in decreasing NO synthase activity
      was not seen in the presence of Nw-nitro-L-arginine methylester (NAME; 10(-6) or
      10(-5) M), an inhibitor of the enzyme. The presence of anti-regucalcin monoclonal
      antibody (25 or 50 ng/ml) in the enzyme reaction mixture caused a significant
      increase in NO synthase activity. This effect was completely abolished by the
      addition of regucalcin (10(-7) M). NO synthase activity was not significantly
      changed in the heart muscle cytosol of transgenic rats overexpressing endogenous
      regucalcin as compared with that of wild-type rats. However, the effect of
      calcium (10 micro M) addition in increasing NO synthase activity was
      significantly weakened in the heart muscle cytosol of regucalcin transgenic rats.
      The present study demonstrates that endogenous regucalcin has a suppressive
      effect on NO synthase activity in the heart muscle cytosol of rats.

PMID- 12430005
TI  - Differential expression of adrenomedullin and its receptors in newborn and adult
      rat thymus.
AB  - Adrenomedullin (ADM) is a hypotensive peptide, which derives from the proteolytic
      cleavage of pro(p)ADM and acts via two main subtypes of receptors, referred to as
      L1-receptor (L1-R) and calcitonin-receptor-like receptor (CRLR). While L1-R is
      selective for ADM, CRLR may bind either calcitonin gene-related peptide (CGRP) or
      ADM depending on the expression of the subtype 1 or the subtypes 2 and 3 of a
      family of chaperones, named receptor-activity-modifying proteins (RAMPs). There
      is evidence that ADM, in addition to regulating blood pressure and water and
      electrolyte balance, may be also involved during embryogenesis in the growth and
      differentiation of organs and tissues, especially of those where strong
      mesenchymal-epithelial interactions take place. Thymus is a linfo-epithelial
      organ, which undergoes a very rapid prenatal and postnatal growth, playing a
      pivotal role in the development of immunological defense. Hence, it appeared
      worthwhile to investigate the expression of ADM system in the newborn (3-day-old)
      rat thymus as compared to adult (3-month-old) animals. Reverse transcription (RT)
      polymerase chain reaction (PCR) allowed the detection of the specific mRNAs of
      pADM and peptidyl-glycine alpha-amidating monooxigenase (PAM), the enzyme which
      converts immature ADM to the mature peptide, in both newborn and adult rat
      thymuses. PAM expression was markedly higher in newborn animals, which accords
      well with the more elevated concentrations of ADM measured by RIA in newborn than
      adult rat thymuses. L1-R, CRLR, RAMP1 and RAMP2 mRNA were detected in both groups
      of rats, and with the exception of RAMP1, the expression was markedly higher in
      newborn than adult rat thymus. RAMP3 mRNA was present only in the thymus of
      newborn animals. Collectively, the present findings indicate that ADM system is
      up-regulated in newborn rat thymus, thereby making it likely that ADM may be
      involved in the thymus growth and in the development of immunological defense
      mechanisms.

PMID- 12430006
TI  - Transplacental effects of high fat diets on functional activity of the spleen and
      lymph nodes, cell kinetics and apoptosis in mammary gland tumors in female rat
      offspring.
AB  - We studied whether feeding pregnant female rats different high fat diets affects
      structural zones in the spleen and lymph nodes, involved in production of T and B
      cells, as well as cell kinetics and apoptosis in some offspring with mammary
      glands tumors. Rat mothers were fed either a 7% or 15% corn-oil or a 7% or 15%
      olive-oil diet. At four weeks of age, female offspring (n=10-15 per group) were
      transferred to 7% corn oil diet. Five-week old offspring were exposed twice to
      the carcinogen, dimethylbenz(a)antracene (10 mg/rat/week). Three months later,
      tumors were counted and sized, and samples from the spleen, axillary lymph nodes
      and tumors collected for immunohistochemical analyses. Feeding the mothers with
      both the 7% and 15% olive-oil diets significantly increased the number of tumor
      free rats in offspring. Tumors were characterized with active mitosis, intensive
      lymphoid infiltration inside a knot and high rates of apoptosis, particularly in
      tumors obtained from rats whose mothers were fed the 15% olive-oil diet. In the
      spleen, the 15% olive-oil diet significantly increased the areas of the follicles
      and germinal centers but only in tumor-free rats. In tumor-bearing rats, areas of
      germinal centers increased compared to the 7% olive-oil diet. The 15% olive-oil
      diet increased all areas of the lymph nodes in tumor-free rats, while in tumor
      bearing rats, this diet increased the areas of the cortex and mantle layer. We
      conclude that exposure to various diets in utero and during lactation affects the
      immune system. In addition, the promotion of apoptosis may play a key role in the
      mechanisms involved in the transplacental effects on mammary tumor development as
      seen using a 15% olive-oil diet, similar to the high fat diets of Mediterranean
      countries.

PMID- 12430007
TI  - Response of HT29 cells to butyrate depends on time of exposure and glucose
      deprivation.
AB  - The high level of alkaline phosphatase activity in HT29 cells induced after 2 or
      5 days of butyrate treatment was decreased during their prolonged exposure (about
      30 days) to this agent together with a decrease of sensitivity to apoptosis.
      However, an enormous additive effect on alkaline phosphatase activity was found
      after butyrate treatment of glucose-starved cells. In concert with this finding,
      the substructural analysis revealed a dense brush border, tendency to
      polarization and morphologically normal mitochondria. It can be concluded that
      prolonged butyrate treatment of HT29 cells attenuated their response to this
      agent. On the other hand, glucose deprivation, as another inductor of
      differentiation, was found to increase the sensitivity of HT29 cells to butyrate.

PMID- 12430008
TI  - Effects of perillyl alcohol in glial C6 cell line in vitro and anti-metastatic
      activity in chorioallantoic membrane model.
AB  - The search for new chemotherapeutic drugs has increased, especially for those
      that have a natural origin. The monoterpene perillyl alcohol (POH) has been shown
      to exert chemopreventive activity in mammary, liver, and lung tumor models. It
      has also been used to treat a variety of rodent cancers, including pancreatic and
      breast carcinomas. In vitro data suggest that it may be effective against
      neuroblastomas and leukemias. This work evaluates the effects of the treatment of
      murine glial C6 cells with perillyl alcohol. In vitro, our studies have indicated
      that POH inhibits proliferation of the C6 glial cell line. POH was
      logarithmically diluted in concentrations of 30% through 0.0003% and showed
      inhibition cell proliferation of 78.36% in concentration of 30%; 69.87% in
      concentration of 3%; and 67.04% in concentration of 0.03%. In addition, the anti
      metastatic activity of POH against these cells was evaluated using chick embryos
      as an in vivo model. The experiments have shown anti-metastatic activity of POH
      when the C6 murine glial cells were exposed to a concentration of 0.3 to 0.003%
      POH for 2 h, prior to its inoculation in chick embryo chorioallantoic membrane
      model. This phenomenon shows the possible role of POH as an in vivo anti
      metastatic drug.

PMID- 12430009
TI  - Photoreceptors in Arabidopsis thaliana: light perception, signal transduction and
      entrainment of the endogenous clock.
AB  - To keep track of fluctuations in spectral composition and intensity of incoming
      sunlight, plants engage a plethora of photosensory pigments. Absorption of light
      by these photoreceptors sets in motion signaling cascades that ultimately
      influence the plant's physiology. Many light-controlled processes are based on
      modulation of gene activity in response to changes in irradiation. The molecular
      basis of this regulation and the downstream components transducing signals from
      the photoreceptors are not fully understood yet, but recent evidence suggests
      that some of those routes are rather short. The phytochrome photoreceptors have
      been found to influence light-responsive promoters by direct contact with
      transcription factors. Additionally, the cryptochrome blue-light receptors
      directly interact with a key repressor of photomorphogenesis, suggesting that
      light activation of photoreceptors could initiate photomorphogenesis through
      posttranslational regulation. This review focuses on recent insights into
      photosensory transduction mechanisms as well as on our current understanding of
      light entrainment of the endogenous clock.

PMID- 12430010
TI  - The mechanism of leaf morphogenesis.
AB  - Whether cell division is a driving force in plant morphogenesis has long been
      debated. In this review, the evidence for the existence of cell division
      dependent and cell division-independent mechanisms of plant morphogenesis is
      discussed. The potential mechanisms themselves are then analysed, as is our
      understanding of the regulation of these mechanisms and how they are integrated
      into development, with particular emphasis on data arising from the investigation
      of leaf morphogenesis. The analysis indicates the existence of both cell division
      dependent and cell division-independent mechanisms in leaf morphogenesis and
      highlights the importance of future investigations to unravel the co-ordination
      of these mechanisms.

PMID- 12430011
TI  - Molecular mechanisms of phosphate transport in plants.
AB  - Membrane-spanning transport proteins are responsible for the selective passage of
      most mineral nutrients and metabolites across cellular and intracellular
      membranes. This review's focus is on summarising the current state of research
      covering the molecular regulation and biochemical mechanisms involved in the
      transport of phosphorus, an often growth-limiting nutrient, in vascular plants.
      Physiological data illustrating the tight control of Pi homeostasis on the
      cellular as well as on the organism's level are discussed together with the
      recent results on molecular transport mechanisms.

PMID- 12430012
TI  - Oxygen toxicity from plants to people.
AB  - Over the past 30 years, acute oxygen toxicity in plants, mammals and enteric
      bacteria has been defined in terms of specific interactions of oxygen with a
      limited number of molecular targets. At least in the case of plants and mammals,
      response at the level of the whole organism is a consequence of oxygen's
      interaction with enzymes that should not exhibit oxygen sensitivity, ribulose-1,5
      bisphosphate carboxylase/oxygenase (rubisco) and glutamate decarboxylase (GAD).
      In enteric bacteria, inhibition of acetolactate synthase (ALS), or the production
      of peracetic acid by this enzyme, may be a contributing factor in the
      inactivation of dihydroxyacid dehydratase and loss of the ability to synthesize
      branched-chain amino acids under conditions of hyperbaric oxygen. The facile
      interaction of these enzymes with oxygen has questioned our fundamental
      understanding of their reaction mechanisms. Could these enzymes have radical
      mechanisms?

PMID- 12430014
TI  - Immunocytological localization of two enzymes involved in berberine biosynthesis.
AB  - Using post-embedding immunogold techniques the cytological localization of the
      two branchpoint enzymes of isoquinoline biosynthesis, berberine bridge enzyme
      (BBE) and (S)-tetrahydroprotoberberine oxidase (STOX), was demonstrated. Electron
      microscopic examination revealed their exclusive compartmentation within
      vesicles. After these vesicles have fused with the central vacuole, they release
      their contents, resulting in a characteristic electron-dense precipitate at the
      tonoplast. Vesicles of similar structure could be identified in young
      meristematic tissues of roots or shoots from different Berberis species and
      Papaver somniferum L. The appearance of electron-dense osmiophilic material is
      strictly correlated with the alkaloid content of the tissue. Immunocytological
      staining of P. somniferum tissue with antibodies directed against BBE led to a
      characteristic labeling of electron-dense aggregates in idioblasts that are not
      connected to the laticifer system. This localization demonstrates the strictly
      cytological separation of benzophenanthridine and morphine biosyntheses within
      this plant.

PMID- 12430013
TI  - A multiplex GC-MS/MS technique for the sensitive and quantitative single-run
      analysis of acidic phytohormones and related compounds, and its application to
      Arabidopsis thaliana.
AB  - A highly sensitive and accurate multiplex gas chromatography-tandem mass
      spectrometry (GC-MS/MS) technique is reported for indole-3-acetic acid, abscisic
      acid, jasmonic acid, 12-oxo-phytodienoic acid and salicylic acid. The optimized
      setup allows the routine processing and analysis of up to 60 plant samples of
      between 20 and 200 mg of fresh weight per day. The protocol was designed and the
      equipment used was chosen to facilitate implementation of the method into other
      laboratories and to provide access to state-of-the-art analytical tools for the
      acidic phytohormones and related signalling molecules. Whole-plant organ
      distribution maps for indole-3-acetic acid, abscisic acid, jasmonic acid, 12-oxo
      phytodienoic acid and salicylic acid were generated for Arabidopsis thaliana (L.)
      Heynh. For leaves of A. thaliana, a spatial resolution of hormone quantitation
      down to approximately 2 mm(2) was achieved.

PMID- 12430015
TI  - Molecular characterization of root-specific chalcone synthases from Cassia alata.
AB  - Three cDNAs encoding very similar but unique isoforms of chalcone synthase (EC
      2.3.1.74) were isolated from a cDNA library prepared from RNA from root tissue of
      the Thai medicinal plant Cassia alata L. (ringworm bush, Leguminosae). Gene
      transcript for these three type-III polyketide synthases was found to accumulate
      predominantly in roots. The heterologously expressed enzymes accepted acetyl-, n
      butyryl-, isovaleryl-, n-hexanoyl-, benzoyl-, cinnamoyl-, and p-coumaroyl-CoA as
      starter molecules and together with the co-substrate malonyl-CoA, formed multiple
      products. With the exception of the assay in which acetyl-CoA was used as the
      starter molecule, all substrates yielded a phloroglucinol derivative resulting
      from three sequential condensations of acetate units derived from three malonyl
      CoA decarboxylations. Every substrate tested also produced two pyrone
      derivatives, one resulting from two acetate unit condensations (a bis-noryangonin
      type pyrone derailment product) and one resulting from three acetate unit
      condensations (a 4-coumaroyltriacetic acid lactone-type pyrone derailment). C.
      alata accumulates the flavonoids quercetin, naringenin and kaempferol in roots,
      suggesting that the in planta function of these enzymes is the biosynthesis of
      root flavonoids.

PMID- 12430016
TI  - Cellular machinery of wood production: differentiation of secondary xylem in
      Pinus contorta var. latifolia.
AB  - The objectives of this study were to define cell structure during pine secondary
      xylem development and to integrate this information with current knowledge of the
      biochemistry and physiology of secondary cell wall biosynthesis in gymnosperms.
      Lodgepole pine (Pinus contorta var. latifolia Englem.) cambium and secondary
      xylem were cryofixed using high pressure freezing and freeze-substitution which
      allowed excellent preservation of the cell structure of developing secondary
      xylem and enabled high-resolution transmission electron microscopic viewing of
      these cells for the first time. In contrast to their precursors in the adjacent
      cambial zone, developing tracheids were active in secondary wall deposition, with
      abundant cortical microtubules and developing bordered pits. These cells were
      also characterized by unusual Golgi structures: the trans-Golgi network was
      highly developed and the associated vesicles were large and darkly stained. These
      unusual Golgi structures persisted throughout the period of xylem maturation
      until programmed cell death occurred. Immuno-cytochemistry and enzyme-gold probes
      were used to investigate the distribution of key secretory products (mannans) and
      a lignification-associated enzyme (coniferin beta-glucosidase) during
      xylogenesis. Mannans were localized to the secondary cell wall, the trans-Golgi
      cisternae and trans-Golgi network vesicles of developing xylem. Coniferin beta
      glucosidase was found only in the secondary cell wall. The cell wall localization
      of coniferin beta-glucosidase, the enzyme responsible for cleaving glucose from
      coniferin to generate free coniferyl alcohol, provides a mechanism to de
      glucosylate monolignols in muro. A two-step model of lignification of conifer
      tracheids is proposed. First, Golgi-mediated secretion deposits monolignols into
      the cell wall, where they polymerize in cell corners and middle lamella.
      Secondly, cell lysis releases stored, vacuolar monolignol glucosides into the
      wall where they are deglucosylated and their polymerization is influenced by the
      wall environment including the lignin deposited earlier.

PMID- 12430017
TI  - cDNA microarray analysis of fusicoccin-induced changes in gene expression in
      tomato plants.
AB  - The effects of the fungal toxin fusicoccin (FC) on the tomato (Lycopersicon
      esculentum Mill.) transcriptome were analyzed in the context of defense-related
      genes using a spotted microarray of 235 cDNAs. Pronounced changes in transcript
      abundance were observed for 64 (27%) of the represented genes. FC appears to have
      an antagonistic effect on wound and pathogen defense responses, in that it causes
      the induction of pathogenesis-related and the down-regulation of wound response
      genes. The transcripts for many proteins involved in photosynthesis and
      carbohydrate metabolism were strongly repressed. Genes related to the
      biosynthesis of jasmonic acid and aromatic amino acids, on the other hand, were
      found to be up-regulated. In addition to these expression changes, which occurred
      rather late after FC treatment, rapid and transient induction kinetics were
      observed for a small group of genes encoding a calcium-dependent protein kinase,
      two mitogen-activated protein kinases, a matrix metalloproteinase and a homologue
      of the respiratory burst oxidase. These genes have not been described previously
      in tomato, nor has their regulation by FC been reported. Salicylic acid was shown
      not to be required for the induction of these transcripts and a function for the
      respective proteins in the FC-induced, salicylic acid-independent activation of
      pathogenesis-related genes is discussed.

PMID- 12430018
TI  - The plant PDR family of ABC transporters.
AB  - The plant pleiotropic drug resistance (PDR) family of ATP-binding cassette (ABC)
      transporters has been implicated in the transport of antifungal agents. In this
      paper, we provide an analysis of the entire family of PDR genes present in the
      Arabidopsis thaliana (L.) Heynh. genome. This analysis both resolves
      discrepancies in published inventories of plant ABC proteins and provides an
      expression analysis of all the annotated Arabidopsis PDR genes. The results
      indicate that the Arabidopsis genome contains 15 genes encoding PDR proteins and
      that these genes show a spectrum of specific expression patterns, both at the
      organ level and in response to various hormonal, environmental and chemical
      factors. These data provide a scaffold for the future molecular genetic analysis
      of this important family of ABC transporters. In addition, we demonstrate the
      usefulness of such data by using them to identify an Arabidopsis PDR protein that
      may play a role in the extrusion of the antifungal diterpene sclareol. Electronic
      Supplementary Material is available if you access this article at
      http://dx.doi.org/10.1007/s00425-002-0889-z. On that page (frame on the left
      side), a link takes you directly to the supplementary material.

PMID- 12430019
TI  - Family business: the multidrug-resistance related protein (MRP) ABC transporter
      genes in Arabidopsis thaliana.
AB  - Despite the completion of the sequencing of the entire genome of Arabidopsis
      thaliana (L.) Heynh., the exact determination of each single gene and its
      function remains an open question. This is especially true for multigene
      families. An approach that combines analysis of genomic structure, expression
      data and functional genomics to ascertain the role of the members of the
      multidrug-resistance-related protein ( MRP) gene family, a subfamily of the ATP
      binding cassette (ABC) transporters from Arabidopsis is presented. We used cDNA
      sequencing and alignment-based re-annotation of genomic sequences to define the
      exact genic structure of all known AtMRP genes. Analysis of promoter regions
      suggested different induction conditions even for closely related genes.
      Expression analysis for the entire gene family confirmed these assumptions.
      Phylogenetic analysis and determination of segmental duplication in the regions
      of AtMRP genes revealed that the evolution of the extraordinarily high number of
      ABC transporter genes in plants cannot solely be explained by polyploidisation
      during the evolution of the Arabidopsis genome. Interestingly MRP genes from
      Oryza sativa L. (rice; OsMRP) show very similar genomic structures to those from
      Arabidopsis. Screening of large populations of T-DNA-mutagenised lines of A.
      thaliana resulted in the isolation of AtMRP insertion mutants. This work opens
      the way for the defined analysis of a multigene family of important membrane
      transporters whose broad variety of functions expands their traditional role as
      cellular detoxifiers.

PMID- 12430020
TI  - Cell death and salicylate- and jasmonate-dependent stress responses in
      Arabidopsis are controlled by single cet genes.
AB  - The jasmonic acid (JA)-dependent regulation of the Thi2.1 gene had previously
      been exploited for setting up a genetic screen for the isolation of signal
      transduction mutants of Arabidopsis thaliana (L.) Heynh. that constitutively
      express the thionin gene. Several cet mutants had been isolated which showed a
      Constitutive Expression of the Thionin gene. These cet mutants, except for one,
      also showed spontaneous leaf cell necrosis and were up-regulated in the
      expression of the PR1 gene, reactions often associated with the systemic acquired
      resistance (SAR) pathway. Four of these cet mutants, cet1, cet2, cet3 and cet4.1
      were crossed with the fad triple and coi1 mutants that are blocked at two steps
      within the JA-dependent signaling pathway, and with transgenic NahG plants that
      are deficient in salicylic acid (SA) and are unable to activate SAR. Analysis of
      the various double-mutant lines revealed that the four cet genes act within a
      signaling cascade at or prior to branch points from which not only JA-dependent
      signals but also SA-dependent signaling and cell death pathways diverge.

PMID- 12430021
TI  - How the mutation glycine96 to alanine confers glyphosate insensitivity to 5
      enolpyruvyl shikimate-3-phosphate synthase from Escherichia coli.
AB  - The enzyme 5-enolpyruvyl shikimate-3-phosphate (EPSP) synthase (EC 2.5.1.19) is
      essential for the biosynthesis of aromatic compounds in plants and microbes and
      is the unique target of the herbicide glyphosate. One of the first glyphosate
      insensitive enzymes reported was a Gly96Ala mutant of EPSP synthase from
      Klebsiella pneumoniae. We have introduced this single-site mutation into the
      highly homologous EPSP synthase from Escherichia coli. The mutant enzyme is
      insensitive to glyphosate with unaltered affinity for its first substrate,
      shikimate-3-phosphate (S3P), but displays a 30-fold lower affinity for its second
      substrate, phosphoenolpyruvate (PEP). Using X-ray crystallography, we solved the
      structure of Gly96Ala-EPSP synthase liganded with S3P to 0.17 nm resolution. The
      crystal structure shows that the additional methyl group from Ala96 protrudes
      into the active site of the enzyme. While the interactions between enzyme and S3P
      remain unaffected, the accessible volume for glyphosate binding is substantially
      reduced. Exploiting the crystallographic results for molecular modeling, we
      demonstrate that PEP but not glyphosate can be docked in the Gly96Ala-modified
      binding site. The predicted PEP binding site satisfies the earlier proposed
      interaction pattern for PEP with EPSP synthase and corroborates the assumption
      that glyphosate and PEP target the same binding site.

PMID- 12430022
TI  - Regulatory 14-3-3 proteins bind the atypical motif within the C terminus of the
      plant plasma membrane H(+)-ATPase via their typical amphipathic groove.
AB  - The plant plasma membrane H(+)-ATPase contains a C-terminal autoinhibitory domain
      whose displacement from the catalytic site is caused by binding of regulatory 14
      3-3 proteins. Members of the highly conserved 14-3-3 family bind their individual
      target proteins in a sequence-specific and phosphorylation-dependent manner
      within a central groove, the latter characterized by the presence of highly
      invariant residues. However, an atypical binding site for 14-3-3s within the H(+)
      ATPase has been identified that does not resemble any other 14-3-3 binding motif.
      Combination of site-directed mutagenesis with glutathione S-transferase pull-down
      assays points to the importance of the central 14-3-3 groove for the interaction
      with the apparently unique site of the H(+)-ATPase. Furthermore, a 14-3-3 dimer
      is essential for binding such unusual motif.

PMID- 12430023
TI  - Comparison of peptides in the phloem sap of flowering and non-flowering Perilla
      and lupine plants using microbore HPLC followed by matrix-assisted laser
      desorption/ionization time-of-flight mass spectrometry.
AB  - Physiological evidence indicates that flower formation is hormonally controlled.
      The floral stimulus, or florigen, is formed in the leaves as a response to an
      inductive photoperiod and translocated through the phloem to the apical meristem.
      However, because of difficulties in obtaining and analyzing phloem sap and the
      lack of a bioassay, the chemical nature of this stimulus is one of the major
      unsolved problems in plant biology. A combination of microbore high-performance
      liquid chromatography (HPLC) and matrix-assisted laser desorption/ionization time
      of-flight mass spectrometry (MALDI-TOF-MS) was used to compare the contents of
      the phloem sap from flowering and non-flowering plants. Instead of using one- or
      two-dimensional gel electrophoresis, microbore HPLC separations allowed us to
      detect proteins/peptides that were very small and present at very low levels. We
      detected more than 100 components in the phloem sap of Perilla ocymoides L. and
      Lupinus albusL. Sequences for 16 peptides in a mass range from 1 to 9 kDa were
      obtained. Two of these could be identified, 11 showed similarity to known or
      deduced protein sequences, and three showed no similarity to any known protein or
      translated gene sequence. Four of these peptides were specific to, modified, or
      increased in plants that were flowering, indicating their possible role in flower
      induction. The sequences of these peptides showed similarities to two purine
      permeases, a protein with similarity to protein kinases, and a protein with no
      similarities to any known protein.

PMID- 12430024
TI  - Stimulation of carotenoid metabolism in arbuscular mycorrhizal roots.
AB  - Development of arbuscular mycorrhizal roots is correlated with accumulation of
      various isoprenoids, i.e. acyclic C(14) polyene 'mycorradicin' and C(13)
      cyclohexenone derivatives. We present data indicating a strong stimulation of
      carotenoid metabolism in such roots. Carotenoid profiling revealed mycorrhiza
      specific accumulation of zeta-carotene in Zea mays and Medicago truncatula.
      Precursor accumulation after inhibition of phytoene desaturase (Pds) activity by
      norflurazon indicated an increased phytoene biosynthetic capacity in mycorrhizal
      roots of all species analyzed. Nicotiana tabacum plants transformed with a PDS
      promoter- GUS construct showed a cell-specific induction of PDS promoter activity
      in root cells containing arbuscules. Mycorradicin biosynthesis and, partially,
      mycorrhization were impaired in maize mutants deficient in carotenoid
      biosynthesis. These data indicate that (1) mycorradicin is probably synthesized
      via a C(40) precursor carotenoid, (2) carotenoid biosynthesis is induced in
      mycorrhizal roots, (3) induction occurs, at least partially, at the
      transcriptional level, and (4) that this may play a functional role during
      mycorrhization.

PMID- 12430025
TI  - Occurrence and formation of indole-3-acetamide in Arabidopsis thaliana.
AB  - An HPLC/GC-MS/MS technique (high-pressure liquid chromatography in combination
      with gas chromatography-tandem mass spectrometry) has been worked out to analyze
      indole-3-acetamide (IAM) with very high sensitivity, using isotopically labelled
      IAM as an internal standard. Using this technique, the occurrence of IAM in
      sterile-grown Arabidopsis thaliana (L.) Heynh. was demonstrated unequivocally. In
      comparison, plants grown under non-sterile conditions in soil in a greenhouse
      showed approximately 50% higher average levels of IAM, but the differences were
      not statistically significant. Thus, microbial contributions to the IAM extracted
      from the tissue are likely to be minor. Levels of IAM in sterile-grown seedlings
      were highest in imbibed seeds and then sharply declined during the first 24 h of
      germination and further during early seedling development to remain below 20-30
      pmol g(-1) fresh weight throughout the rosette stage. The decline in indole-3
      aetic acid (IAA) levels during germination was paralleled by a similar decline in
      IAM levels. Recombinant nitrilase isoforms 1, 2 and 3, known to synthesize IAA
      from indole-3-acetonitrile, were shown to produce significant amounts of IAM in
      vitro as a second end product of the reaction besides IAA. NIT2 was earlier shown
      to be highly expressed in developing and in mature A. thaliana embryos, and NIT3
      is the dominantly active gene in the hypocotyl and the cotyledons of young,
      germinating seedlings. Collectively, these data suggest that the elevated levels
      of IAM in seeds and germinating seedlings result from nitrilase action on indole
      3-acetonitrile, a metabolite produced in the plants presumably from
      glucobrassicin turnover.

PMID- 12430026
TI  - New and bioactive compounds from Streptomyces strains residing in the wood of
      Celastraceae.
AB  - Wood from three different plants of the Celastraceae growing in their natural
      habitats in Brazil (Maytenus aquifolia Mart.) and South Africa [Putterlickia
      retrospinosa van Wyk and Mostert, P. verrucosa (E. Meyer ex Sonder) Szyszyl.] was
      established as a source of endophytic bacteria using a medium selective for
      actinomycetes. Two isolates were identified as Streptomyces setonii and S.
      sampsonii whereas two others were not assignable to any of the known Streptomyces
      species. They were preliminarily named Streptomyces Q21 and Streptomyces MaB-QuH
      8. The latter strain produces a new chloropyrrol and chlorinated anthracyclinone.
      The chloropyrrol showed high activity against a series of multiresistent bacteria
      and mycobacteria.

PMID- 12430027
TI  - Gallotannin biosynthesis: two new galloyltransferases from Rhus typhina leaves
      preferentially acylating hexa- and heptagalloylglucoses.
AB  - Current enzyme studies on the biosynthesis of gallotannins with cell-free
      extracts from leaves of staghorn sumac (Rhus typhina L.) revealed the existence
      of two new beta-glucogallin-dependent galloyltransferases (EC 2.3.1.-) that
      preferentially catalyzed the acylation of hexa- and heptagalloylglucoses. One
      enzyme was most active with the hexagalloylglucose, 3-O-digalloyl-1,2,4,6-tetra-O
      galloylglucose, to form the corresponding heptagalloylglucose, 3-O-trigalloyl
      1,2,4,6-tetra-O-galloylglucose. This polyester, in turn, was the preferred
      substrate for a second enzyme that catalyzed its conversion to higher substituted
      derivatives. This latter enzyme also displayed considerable affinity towards 2-O
      digalloyl-1,3,4,6-tetra-O-galloylglucose which was acylated to various hepta- and
      octagalloylglucoses. These recent findings, together with data from earlier
      reported related enzymes, allowed the presentation of a scheme that summarizes
      the major transitions in the biogenetic routes from 1,2,3,4,6-pentagalloylglucose
      to complex gallotannins.

PMID- 12430028
TI  - Jasmonate is involved in the induction of tyrosine aminotransferase and
      tocopherol biosynthesis in Arabidopsis thaliana.
AB  - Coronatine-inducible tyrosine aminotransferase (TAT), which catalyses the
      transamination from tyrosine to p-hydroxyphenylpyruvate, is the first enzyme of a
      pathway leading via homogentisic acid to plastoquinone and tocopherols, the
      latter of which are known to be radical scavengers in plants. TAT can be also
      induced by the octadecanoids methyl jasmonate (MeJA) and methyl-12
      oxophytodienoic acid (MeOPDA), as well as by wounding, high light, UV light and
      the herbicide oxyfluorfen. In order to elucidate the role of octadecanoids in the
      process of TAT induction in Arabidopsis thaliana (L.) Heynh., the jasmonate
      deficient mutant delayed dehiscence (dde1) was used, in which the gene for 12
      oxophytodienoic acid reductase 3 is disrupted. The amount of immunodetectable TAT
      was low. The enzyme was still fully induced by coronatine as well as by MeJA
      although induction by the latter was to a lesser extent and later than in the
      wild type. Treatment with MeOPDA, wounding and UV light, however, had hardly any
      effects. Tocopherol levels that showed considerable increases in the wild type
      after some treatments were much less affected in the mutant. However, starting
      levels of tocopherol were higher in non-induced dde1 than in the wild type. We
      conclude that jasmonate plays an important role in the signal transduction
      pathway regulating TAT activity and the biosynthesis of its product tocopherol.

PMID- 12430029
TI  - Translocation of 3-deoxy-D-arabino-heptulosonate 7-phosphate synthase precursor
      into isolated chloroplasts.
AB  - A cDNA encoding 3-deoxy-D-arabino-heptulosonate 7-phosphate (DAHP) synthase (EC
      4.1.2.15) from potato (Solanum tuberosum L.) presumably specifies a chloroplast
      transit sequence near its 5'-end. In order to show the function of this transit
      sequence, we constructed a plasmid that contains the entire coding region of the
      cDNA downstream from a T7 promoter. Using this plasmid as template, DAHP synthase
      mRNA was synthesized in vitro with T7 RNA polymerase. The resulting mRNA served
      as template for the in vitro synthesis of a 59-kDa polypeptide. This translation
      product was identified as the DAHP synthase precursor by immunoprecipitation with
      a monospecific polyclonal antibody raised against pure tuber DAHP synthase and by
      radiosequencing of the [(3)H]leucine-labeled translation product. Incubation of
      the 59-kDa polypeptide with isolated spinach (Spinacia oleracea L.) chloroplasts
      resulted in a 53-kDa polypeptide that was resistant to protease treatment.
      Fractionation of chloroplasts, reisolated after import, showed the mature DAHP
      synthase in the stroma fraction. Incubation of the 59-kDa polypeptide with a
      chloroplast precursor-processing enzyme cleaved the precursor between Ser49 and
      Ala50, generating a mature DAHP synthase of 489 residues. The uptake of the DAHP
      synthase precursor into isolated chloroplasts was inhibited by anti-DAHP
      synthase, and the precursor was not processed cotranslationally by canine
      microsomal membranes. We conclude that the transit sequence is able to direct
      DAHP synthase into chloroplasts.

PMID- 12430030
TI  - The Arabidopsis male-sterile mutant dde2-2 is defective in the ALLENE OXIDE
      SYNTHASE gene encoding one of the key enzymes of the jasmonic acid biosynthesis
      pathway.
AB  - The Arabidopsis thaliana (L.) Heynh. mutant delayed-dehiscence2-2 (dde2-2) was
      identified in an En1/Spm1 transposon-induced mutant population screened for
      plants showing defects in fertility. The dde2-2 mutant allele is defective in the
      anther dehiscence process and filament elongation and thus exhibits a male
      sterile phenotype. The dde2-2 phenotype can be rescued by application of methyl
      jasmonate, indicating that the mutant is affected in jasmonic acid biosynthesis.
      The combination of genetic mapping and a candidate-gene approach identified a
      frameshift mutation in the ALLENE OXIDE SYNTHASE (AOS) gene, encoding one of the
      key enzymes of jasmonic acid biosynthesis. Expression analysis and genetic
      complementation of the dde2-2 phenotype by overexpression of the AOS coding
      sequence confirmed that the male-sterile phenotype is indeed caused by the
      mutation in the AOS gene.

PMID- 12430031
TI  - [Miyake-Apple video analysis of movement patterns of an accommodative intraocular
      lens implant].
AB  - BACKGROUND: The potentially accommodative intraocular lens (IOL) is a new
      development in IOL design METHODS: We evaluated the new Humanoptics 1CU
      accommodative IOL in a laboratory study with human post mortem autopsy eyes.
      Using the Miyake-Apple posterior view video technique, the movement pattern of
      the IOL was tested and observed from the posterior perspective. RESULTS. A
      circular bend at the level of the ciliary body applied slight circular force onto
      the sclera allowing the relaxation of the zonules. The shift of focus was
      demonstrated by using a reading target. In addition, viscoelastic was injected
      into the vitreous resulting in the same anterior movement of the IOL optic.
      CONCLUSIONS: The 1CU Humanoptics accommodative IOL showed potential accommodative
      behaviour in the laboratory. The accommodative (respectively pseudoaccommodative)
      effect was based on the anterior shift principle with anterior movement of the
      IOL-optic in the state of relaxing zonules. Whether this reflects the clinical
      situation, especially to this extent, must be further evaluated.

PMID- 12430032
TI  - [Validity of anterior chamber depth measurements for the evaluation of
      accommodation after implantation of an accommodative Humanoptics 1CU intraocular
      lens].
AB  - BACKGROUND: Changes in the anterior chamber depth (ACD) after pilocarpin
      application are generally regarded as reflecting an accommodative effect of
      accommodative intraocular lenses (IOLs) METHODS: We implanted Humanoptics 1CU
      accommodative IOLs into 25 eyes of 20 patients aged 53.2+/-14.7 years (range: 30
      83 years). In seven of these patients, we were able to measure anterior chamber
      depth changes after the application of pilocarpine (2%) eye drops 3 months
      postoperatively using a Zeiss IOLMaster, an Orbscan II topography system, as well
      as by ultrasound biomicroscopy (20 MHz-US-head). RESULTS: Uncorrected near acuity
      was on average 0.4+/-0.23 (0.1-0.8) and uncorrected distance acuity was 0.76+/
      0.23 (0.3-1). Before pilocarpine, ACD was 3.19+/-2.11 mm (IOL-Master), 3.35+/
      2.22 mm (Orbscan II) and 3.35+/-2.21 mm (US-biomicroscopy) ( P=0.96). After
      pilocarpine, ACD was 2.61+/-1.71 mm (IOL-Master), 2.63+/-1.78 mm (Orbscan II) and
      3.15+/-2.08 mm (US-biomicroscopy) ( P=0.002). The average individual ACD change
      before/after pilocarpine was 0.83+/-0.25 mm with the IOL-Master, 1.04+/-0.39 mm
      with the Orbscan II System and 0.28+/-0.14 with US-biomicroscopy ( P=0.0004).
      DISCUSSION: The 1CU Humanoptics accommodative IOL presented with potential
      accommodative capabilities in clinical evaluation. Drug induced accommodation by
      pilocarpine does not reflect real accommodative effects. The differences in ACD
      measurements between three different methods were statistically significant.
      Evaluation methods for accommodative IOLs should be carefully analysed and
      further development of objective means for evaluation is needed.

PMID- 12430033
TI  - [Two years experience with the new accommodative 1 CU intraocular lens].
AB  - After marked improvement of optical rehabilitation of cataract patients during
      the last decades due to small incision surgery and foldable intraocular lenses
      (IOL), presbyopia is now one of the great unsolved questions in ophthalmology.
      During recent years a new accommodative IOL, the 1CU lens, has been developed
      based on the concepts of K.D. Hanna and on finite element computer simulation
      models. The 1CU IOL is designed to transform contracting forces of the ciliary
      muscle into anterior movement of the IOL optic (optic-shift concept). After the
      first implantation of a 1CU IOL in Erlangen in June 2000, we have now
      successfully implanted the 1CU IOL in over 90 patients. Our experiences and the
      results of several clinical studies indicate good and safe implantability, good
      centration, no IOL-specific complications, and good distance visual acuity. In
      comparison to control groups with conventional IOL, patients with the 1CU enjoyed
      significantly better distance-corrected near visual acuity, a larger
      accommodative range, and increased anterior and posterior axial movement of the
      lens optic after medical stimulation or inhibition of the ciliary muscle. We
      interpret our results as confirmation of the optic-shift concept of the 1CU IOL.
      Overall, the concept of accommodative IOL appears attractive and may have a great
      potential in the future. Additional studies including randomized blind
      multicenter evaluation of the 1CU IOL are necessary to further evaluate long-term
      and accommodative results.

PMID- 12430034
TI  - [Dynamic aberrometry during accommodation of phakic eyes and eyes with
      potentially accommodative intraocular lenses].
AB  - Since the introduction of potentially accommodative intraocular lenses (IOLs), it
      was hard to perform an objective evaluation of the accommodative amplitude in
      pseudophakic eyes. Laser interferometric measurements were performed to evaluate
      anterior chamber depth changes, which provides information on the functionality
      of potentially accommodative IOLs. By means of wavefront analysis, the dynamic
      behaviour of potentially accommodative IOLs can be determined. All measurements
      in this study were performed using a Hartmann-Shack aberrometer at a frequency of
      7 Hz. Six to 8 weeks after implantation of potentially accommodative IOLs
      (CrystaLens AT-45, C&C Vision, 1CU, Humanoptics), 43 eyes were investigated using
      this dynamic wavefront analysis. Patients focussed at a distance target for 10 s,
      followed by focussing at a near target for 10 s and then again at a distance
      target for a further 10 s. During these 30 s, a total of 200 single measurements
      were performed. The same measurements were also conducted in healthy eyes of
      young persons as well as in eyes after implantation of standard IOLs for
      comparative purposes. The dynamic course of changes in low-order aberrations
      (defocus, astigmatism) as well as high-order (e.g., fourth-order spherical
      aberration) were analysed. Dynamic wavefront analysis allowed objective and
      observer-independent measurement of changes in accommodation in phakic and
      pseudophakic eyes. Dynamic aberrometry is capable of objectively quantifying the
      effect of any surgical option for the treatment of presbyopia. We recommend use
      of this technology in addition to the common psychophysical examinations to
      attain objective information on the efficacy of the treatment modality used.

PMID- 12430035
TI  - [Ocular blood flow in patients with asymmetric glaucoma].
AB  - BACKGROUND: Hemodynamic factors are gaining increasing importance in the
      pathogenesis of glaucoma. This study was designed to investigate ocular blood
      flow in patients with asymmetric glaucoma. METHODS: The more affected and the
      contra-lateral eyes of 15 glaucoma patients with asymmetric scotomas (difference
      in mean deviation >/=8 dB) despite equal IOP were compared with reference to IOP,
      optic nerve head excavation, mean deviation in scotomas and ocular blood flow
      (OBF). Exclusion criteria were defined as follows: operated eyes, secondary
      glaucomas, differences in IOP and in antiglaucoma therapy, differences in visual
      acuity >2 steps and other ophthalmological diseases. For statistical analysis the
      Wilcoxon test for paired samples was used. RESULTS: A comparison of IOP's of the
      more affected eyes with the contralateral eyes showed no differences. Vertical
      and horizontal excavation differed significantly ( p=0.027 and p=0.01,
      respectively) and also the mean deviation in scotomas showed a statistically
      significant difference ( p=0.001). The pulse amplitude and the pulse volume
      showed only a slight tendency, but the pulsatile ocular blood flow was
      significantly lower in the more affected eyes ( p=0.047). CONCLUSION: The lower
      pulsatile ocular blood flow in the more affected eye in patients with asymmetric
      glaucoma could be the lateralizing factor in these patients, and suggests an
      influence of hemodynamic factors in the pathogenesis of glaucoma.

PMID- 12430036
TI  - [Amniotic membrane transplantation with limbal stem cell transplantation as a
      combined procedure for corneal surface reconstruction after severe thermal or
      chemical burns].
AB  - BACKGROUND: Severe thermal and chemical burns may result in limbal deficiency
      leading to persistent epithelial defects, complete conjunctival epithelial
      ingrowth and vascularisation of the cornea. If sufficiently severe, these burns
      may lead to very significant visual impairment. Amniotic membrane transplantation
      with limbal transplantation has recently been proposed as a new method for
      corneal surface reconstruction. PATIENTS AND METHODS: A total of 14 patients (age
      18-62 years, mean age 42 years) with limbal deficiency resulting from thermal (
      n=1) or chemical burns ( n=13) underwent surgery. The corneal pannus was
      completely removed and the amniotic membrane was grafted onto the cornea. Limbal
      transplantation using autografts obtained from contralateral eyes was performed
      simultaneously in seven cases. Allografts from a donor were transplanted in seven
      cases with bilateral involvement. These patients received oral cyclosporin A
      postoperatively. The mean follow-up time was 18 months. RESULTS: In all cases of
      limbal autografts the corneal surface showed a complete and stable
      epithelialisation within a few weeks. Out of seven patients with limbal
      allografts three displayed recurrent epithelial defects in the long term. The
      initially semitransparent amniotic membrane became more translucent and
      biomicroscopically invisible within several months after surgery. There was an
      increase in visual acuity in most cases, limited mostly by irregular astigmatism
      due to the initial stromal loss. CONCLUSIONS: Amniotic membrane transplantation
      with limbal transplantation allows reconstruction ocular surfaces severely
      damaged by chemical or thermal burns. In most cases, however, additional surgical
      procedures such as lamellar or penetrating keratoplasty are required for adequate
      visual rehabilitation.

PMID- 12430037
TI  - [Diffuse lamellar keratitis. Postoperative prophylactic treatment with
      corticosteroids in an experimental animal study].
AB  - PURPOSE: The aim of this experimental ani-mal study was to induce diffuse
      lamellar keratitis (DLK), and investigate a prophylactic treatment with
      corticosteroids. MATERIALS AND METHODS: A corneal flap was cut in 40 eyes from 20
      Dutch-belted rabbits and the interface inoculated with either Pseudomonas
      aeruginosa lipopolysaccharide (LPS) endotoxin ( n=21) or Palmolive Ultra soap (
      n=19). Half of the eyes were treated with topical corticosteroids and the other
      half remained untreated. Slitlamp examinations were performed 1, 3, 5 and 7 days
      postoperatively and DLK was graded from I-IV. RESULTS: At the end of the study 33
      eyes were available for evaluation and 94% of the non-treated eyes developed DLK.
      Out of those eyes treated with steroids 19% developed DLK during the 1 week
      follow-up period. This was statistically significantly lower ( P=0.018) when
      compared to the untreated group. CONCLUSION: Pseudomonas aeruginosa LPS endotoxin
      as well as Palmolive((R)) Ultra caused a very high rate of DLK in rabbit eyes.
      The postoperative prophylactic treatment with corticosteroids showed a
      statistically significant lower DLK rate in this rabbit eye model.

PMID- 12430038
TI  - [Fundus autofluorescence after selective RPE laser treatment].
AB  - BACKGROUND: The selective RPE laser treatment is a new technique which
      selectively damages the RPE and avoids adverse effects to the neural retina. A
      problem is the ophthalmoscopically non-visibility of the laser lesions. The aim
      of the study was to investigate whether fundus autofluorescence (AF), which is
      derived from the lipofuscin contained by the RPE cells, is changed due to the RPE
      damage, and thus may be used for non-invasive treatment control. METHODS: A total
      of 26 patients with macular diseases, i.e. diabetic maculopathy (DMP), soft
      drusen maculopathy (AMD) and central serous retinopathy (CSR), were treated with
      repetitive short laser pulses (800 ns) from a green Nd:YAG laser (parameters: 532
      nm, 100 and 50 pulses at 500 and 125 Hz, retinal spot diameter 200 micrometer,
      pulse energies 70-175 microJ). AF was excited by 488 nm and detected by a barrier
      filter at 500 nm (HRA, Heidelberg engineering). Patients were examined by
      ophthalmoscopy, fluorescein angiography and autofluorescence measurements at
      various times after treatment (i.e. 1 h, 1 and 6 weeks, 3, 6 and 12 months).
      RESULTS: None of the laser lesions was ophthalmoscopically visible during
      treatment although fluorescein angiography showed leakage of the irradiated
      areas. Identification of the lesions was possible by AF imaging showing an
      intensity decay in the irradiated area in 22 out of 26 patients, predominantly in
      patients with CSR and AMD. Lesions could be identified as hypoautofluorescent
      spots 1 h after treatment. During follow-up the laser spots became
      hyperautofluorescent. In patients with DMP some AF images were less helpful due
      to diffuse edema and larger retinal thickness. CONCLUSION: Imaging of non-visible
      selective RPE laser effects can be achieved by AF measurements predominantly in
      patients without retinal edema. Thus AF may replace invasive fluorescein
      angiography in many cases to verify therapeutic laser success.

PMID- 12430039
TI  - [Detergent-like effects of the lipofuscin retinoid component A2-E in retinal
      pigment epithelial cells].
AB  - PURPOSE: Several lines of evidence suggest that excessive accumulation of
      lipofuscin in postmitotic retinal pigment epithelial (RPE) cells with age and in
      various hereditary retinal diseases, plays a pathogenetic role. The lipofuscin
      retinoid component A2-E (N-retinylidene-N-retinylethanolamine) inhibits lysosomal
      degradation. Here we sought to evaluate additional toxic mechanisms of A2-E,
      whereby possible detergent-like effects on various membranes in human RPE cells
      were investigated by latency measurements. METHODS: A postnuclear supernatant
      prepared from cultured human RPE cells was used to isolate intact lysosomes by
      fractionation of cellular organelles in two sequential gradients. Destabilization
      of the lysosomal membrane was tested by incubating the purified lysosomal
      fraction in the presence of A2-E and subsequent measurement of the latency of the
      lysosomal luminal marker beta-hexosaminidase. In order to compare the effect of
      A2-E on other cellular membranes, latencies of the specific markers succinate
      dehydrogenase and UDP-galactosyltransferase were assessed using partially
      purified mitochondria and microsomes. Intactness of the plasma membrane was
      tested by including A2-E in the culture medium before leakage of lactate
      dehydrogenase into the medium was determined. RESULTS: A more than 100-fold
      purification of the lysosomal fraction was achieved. Except for a minor activity
      of the mitochondrial marker, no contamination with other cell fractions was
      observed. Intactness of the purified lysosomes was well preserved during
      incubation in isotonic media and provided the basis for investigations on a
      possible detergent-like action of A2-E on lysosomal integrity. At concentrations
      above 2 microM A2-E, progressive leakage of the lysosomal marker was observed. In
      comparison leakage of the mitochondrial marker was induced at significantly lower
      concentrations (1 microM), whereas ER/Golgi membranes and the plasma membrane
      were relatively insensitive to a detergent effect of the retinoid. CONCLUSIONS:
      The described practical and fast methodology to obtain highly purified and intact
      lysosomes from RPE cells, provides a very suitable tool for investigations on
      compounds affecting the lysosomal structure. The results suggest that A2-E causes
      disintegration of the lysosomal membrane at relatively low concentrations which
      may implicate an involvement of such a mechanism in triggering lipofuscin-induced
      dysfunction of aged RPE in vivo. Secondary to disintegration of the lysosomal
      membrane, damage to mitochondria might be an additional pathogenic mechanism. Our
      data provide evidence for surfactant-like properties of A2-E on biomembranes
      which might be operative in retinal diseases associated with excessive lipofuscin
      accumulation including age-related macular degeneration.

PMID- 12430040
TI  - [Options and limits of visual function tests available on the internet].
AB  - BACKGROUND: The quantitative capability of the visual system can be tested using
      graphic presentations with defined size, form and colour. For presentations a
      chart projector or personal computer (PC) can be used. In the meantime the number
      of visual function tests on the internet is continually increasing. These tests
      are potentially available for over 400 million internet users with different hard
      and software requirements. METHODS: From 38 on-line visual acuity tests and 19
      on-line colour vision tests found by means of search engines on german language
      web pages, the offerer of the test, the type of chart used and the data for the
      test conditions, as well as hard- and software adjustment were registered.
      RESULTS. Various visual function tests, such as visual acuity tests, the Amsler
      grid, stereo and colour vision tests, can already be planned via internet. The
      variability of the tests ranges from a simple presentation of graphic elements to
      a laboriously programmed interactive input by the user to specify the test
      result. Most of the tests are presented by opticians and the optical industry.
      DISCUSSION: The analysed tests allow for a considerable variability of the test
      conditions, for example by missing data concerning the room lighting and lacking
      monitor calibration. Furthermore, problems of the web-based colour presentation
      were not considered or not considered sufficiently in most of the on-line colour
      tests. CONCLUSIONS: Because of the test deficits determined, the results of
      visual function tests on the internet are to be classified as doubtful. At
      present, most data of test offerers are not sufficient with respect to the test
      conditions. Standards should be defined for internet-based visual function tests
      and further studies should be followed to check the effectiveness of these tests
      for screening examinations.

PMID- 12430041
TI  - [A clinico-pathological case report of necrotizing ulcerating keratopathy due to
      topical anaesthetic abuse].
AB  - BACKGROUND: Topical anesthetic abuse is rare, but difficult to diagnose since
      most patients deny its use and the clinical changes are very similar to other
      corneal diseases. CASE REPORT: A 45-year-old medical doctor with a 30-year
      history of soft contact lens wear and recurrent corneal erosion was admitted to
      our clinic with a ring-shaped keratitis and intense ocular pain. A corneal smear
      was negative for bacterial infections and acanthamoeba but the contact lens box
      contained a few dead acanthamoeba and many cocci. Due to the clinical findings
      and the acanthamoeba found in the contact lens box acanthamoeba keratitis was
      diagnosed and treatment with gentamycin, pentamidine isethionat (Brolene((R)))
      and hexamidine (Desomedine((R))) was started. The clinical appearance did not
      change for 6 weeks after onset of treatment and a perforating corneal
      transplantation was performed for pain relief and visual rehabilitation. An iris
      ectropion lacking iris motility and dense cataract developed within 5 weeks and
      the patient admitted on direct questioning to having taken topical anesthetic
      (oxybuprocain) by self-medication. The histological investigation revealed few
      inflammatory cells. The epithelium was largely missing and few vital cells could
      be found in the stroma and the endothelial cell layer. Acanthamoeba could not be
      detected in the tissue. CONCLUSION: Topical anesthetic abuse can mimic different
      corneal diseases and be difficult to diagnose if the patient denies its use. In
      cases of keratitis with no response to treatment and strong ocular pain, topical
      anesthetic abuse should be considered.

PMID- 12430042
TI  - [A case report of unusual retinal findings in a patient with Zieve syndrome].
AB  - BACKGROUND: The Zieve syndrome is characterized by hemolytic anemia in
      conjunction with secondary hyperlipidemia in patients suffering from alcohol
      related toxic liver damage. So far no retinal changes have been reported due to
      the Zieve syndrome. CASE REPORT: A 44-year-old diabetic attended a routine
      control by an ophthalmologist. It was known that he had steatohepatitis due to an
      abuse of ethanol for years and 1 month previously he had suffered from nausea and
      vomiting. The visual acuity was found to be good on both sides (1.0/0.8). In the
      fundus white-colored retinal vessels and peripapillary cotton wool exsudates with
      isolated hemorrhages were found. An extremely lipemic serum and a severe anemia
      were present. The patient was referred to the internal department for further
      investigation and because of the anemia the patient received two blood
      transfusions. The elevated cholesterol and triglyceride levels in the serum could
      be substantially reduced by treatment with a cholesterin synthetase inhibitor and
      a fibrate. The follow-up examination 3 weeks later revealed a regular blood flow
      and a regression of cotton wool exsudates and 1 month later no pathological
      retinal findings were detected. CONCLUSIONS: The retinal changes were caused by
      the combination of severe anemia and hyperlipidemia and these findings played a
      leading role for deciding further diagnostic procedures. After treatment of the
      metabolic disorder the retinal changes were completely reversible without
      functional restrictions.

PMID- 12430043
TI  - [Mentalities and sterilization laws in Europe during the 1930s. Eugenics,
      genetics, and politics in a historic context].
AB  - The laws and related practice of sterilisation in Germany during the Nazi period
      (1933-1945) were not isolated phenomena. Rather, they have to be understood in
      the broader context of the eugenic and racial hygiene movement developing
      internationally during the first decades of the twentieth century. Central
      conditions allowing its emergence were scientific, sociopolitical, and cultural
      factors. Fears of biological degeneration, economic considerations, and trust in
      the future potential of biology and in particular genetics played a crucial role
      in many western societies. Eugenics and the practice of sterilisation are
      constitutively linked to scientific justifications, just as - complementarily -
      the development of genetics, in particular psychiatric genetics, is inextricably
      associated with eugenics and its funding by philanthropic or state institutions.
      Parallels and a multiplicity of mutual relations existed on various levels, in
      particular between Germany, the US, and Scandinavian countries.

PMID- 12430044
TI  - [Informed consent and patient competence in the psychically ill. A review of
      empirical studies].
AB  - In clinical practice, patients' self-determination has become more and more
      important. However, in psychiatry, the practice of informed consent encompasses
      several problems. In many cases the psychiatrist is faced with the issue of
      determining patients' competence. This paper gives an overview of empirical
      studies on competence assessment in psychiatry. In the course of some of these
      studies, test instruments were developed which allow objective and reliable
      assessment of different standards of competence. The applicability of these tests
      is discussed. We present empirical data on the relationship between competence
      and psychopathologic symptoms and cognitive factors. In recent empirical
      research, a shift from an initial skepticism of the applicability of informed
      consent in psychiatry towards a more differentiated approach and an interest in
      multidisciplinary research can be observed.

PMID- 12430045
TI  - [The standard textbook on racial hygiene by Erwin Baur, Eugen Fischer, and Fritz
      Lenz as viewed by the psychiatric and neurological communities from 1921 to
      1940].
AB  - The textbook "Human heredity and Racial Hygiene" by Erwin Baur, Eugen Fischer,
      and Fritz Lenz went through five editions between 1921 and 1940. In contemporary
      journals, it received almost only positive review articles and was considered to
      be the standard textbook on racial hygiene in the Weimar Republic. After Hitler's
      takeover in 1933, it became the "scientific" basis for eugenic sterilization
      programs. In that year, the Nazis enacted a law allowing the involuntary
      sterilization of persons with diseases thought to be hereditary, mostly
      neurological and psychiatric disorders. Using review articles on the book, the
      position of neurologists and psychiatrists towards racial hygiene is analyzed. We
      describe how they prepared and maintained the acceptance of eugenic politics in
      the medical profession by praising the standard work on racial hygiene.

PMID- 12430046
TI  - [Hermann Simon--reformer of psychiatry, social Darwinist, and National
      Socialist?].
AB  - Hermann Simon (1867-1947) was shaped in his psychiatric thinking and views of
      society by the German empire. He showed a strongly conservative attitude and
      thought in ethnic-nationalistic terms. Beginning in 1905 and drawing on practical
      experience, he developed the concept of a "more active therapy." Simon perceived
      patients in a holistic way, regarding them not so much as sick people but as
      fellow men. He believed in the ability of a healthy personality to practice
      responsible and "well ordered self determination." Thus he defined the role of
      the doctor in a new way. Within Germany as well as internationally, active
      therapy was well-received, especially because of its positive effect on the
      atmosphere within asylums. In the context of reform of so-called open care during
      the Weimar epoch, Simon's approach was perceived in a new way because it allowed
      individual views of each patient, enabling assessment of the ability to work and
      chances for release. Simon himself set his concept in a "biological" and
      psychological context, based on his own biologistic and social Darwinistic world
      view. This view was open for eugenic, racial hygienic concepts, and fundamental
      criticism of welfare policy. It was only a short step from this conservative
      tenor, understanding of the state, and biologistic thinking to his open acclaim
      of Hitler and National Socialist (Nazi) racist policy.

PMID- 12430047
TI  - [How did youths deal with their forced sterilisation during the Third Reich?
      Report of a physician involved].
AB  - In 1933, one of the first laws passed by the Nazis in Germany was that to prevent
      the birth of children with hereditary diseases, which legalised forced
      sterilisation in Germany and also applied to minors. On Social Welfare Education
      Day in 1934, the leading physician at the "Anstalt Bethel" (Bethel Institution),
      Werner Villinger, gave a speech on the experience of sterilisation. A main part
      of his speech was the description of the reaction, fears, and resistance of the
      boys involved, and the accuracy of his observations stands in sharp contrast to
      the ruthlessness of the performance of the sterilisation, which was rooted in
      unshakeable faith in the necessity of this measure.

PMID- 12430049
TI  - [Victims of Nazi euthanasia, the so-called T4 action. First results of a project
      at the German Federal Archives to disclose records of killed patients].
AB  - In 1990, previously unknown documents dated from the Nazi era were found in
      Berlin. They had been preserved in the central archives of the Ministry for State
      Security (MfS), the secret service of the now former German Democratic Republic
      (GDR). Nearly 30,000 psychiatric patient files turned out to comprise the smaller
      part of the records of patients who had been murdered in the 1940/41 "T4 action".
      More than 70,000 patients of psychiatric asylums were killed by gas in this first
      campaign of extermination during Nazism, and their files were believed to have
      been lost. Based on a project to be funded by the German Research Association,
      this paper offers a brief survey of the developments in historical research about
      Nazi "euthanasia" and the theories interpreting historical information. The paper
      will also present a research project dedicated to the memory of the victims of
      the "T4 action" and to the rediscovered files now conserved in the German Federal
      Archives in Berlin. The aim is to offer a systematic analysis of 3,000 records in
      an effort to contribute to the perception of the victims as individuals. The
      analysis will also include an examination of the selection criteria stipulated by
      the Nazi psychiatrists (hereditary illness, incurability, and incapacity to work
      productively) to select patients for extermination. In this way, the decision
      making process, criteria, and motives that led to the killing should become more
      clear. This empirical analysis will help to answer questions concerning the
      proportion of eugenic and economic motivations and the Nazi rationale behind the
      extermination campaigns. The project will build upon an earlier preliminary study
      of a nonrepresentative sample of 185 files. As a preliminary result, it can be
      said that most of the victims had been hospitalised over long terms and
      classified as schizophrenic or feeble-minded. A third of the patients killed were
      considered invalid and not working, and almost 50% were described as working
      "mechanically". Five per cent of the victims were working "productively".

PMID- 12430048
TI  - [Werner Villinger and National Socialist medical crimes].
AB  - The biography of the psychiatrist and neurologist Werner Villinger reflects the
      ambivalence of the history of German psychiatry during the first half of the
      twentieth century. Politically committed to the national conservatives, he was
      attracted by many elements of National Socialist (Nazi) ideology. Still, he
      joined the party rather late and reluctantly. Villinger was a eugenist by firm
      conviction. While he still argued against hasty legal regulation of eugenic
      sterilisations in the Weimar Republic, he strongly moved for translating the law
      on preventing hereditarily ill progeny into reality in the institution of von
      Bodelschwingh in Bethel. Since 1941, Villinger, who had become a professor for
      psychiatry and neurology in Breslau in the meantime, acted as an expert in the
      framework of the National Socialist "euthanasia" programme. At the same time,
      however, he supported the quiet diplomacy of Rev. von Bodelschwingh in his
      attempt to terminate the mass murder. Villinger was also involved in criminal
      experiments with human beings. After 1945, he successfully continued his career
      in the Federal Republic of Germany. He never confronted his past during the Third
      Reich.

PMID- 12430050
TI  - [Psychotherapy in a psychiatric hospital].
AB  - This study was aimed to evaluate the role of psychotherapy in psychiatric in
      patient care at the example of the Bezirksklinikum Regensburg (BKR) (Community
      Clinic in Regensburg, Germany). Based on a sample of 6,719 patients suffering
      from F2-F6 ICD-10 diagnoses, the data of the psychiatric basic documentation
      (BADO) from January 1995 until April 1999 was retrospectively analysed regarding
      type and frequency of psychotherapy, influencing factors on indication, and
      effects of psychotherapy on treatment success. In 33% of cases, specific
      psychotherapy was in use. A client-centered therapy was carried out in 20% of
      patients. Other techniques of psychotherapy such as behaviour therapy, cognitive
      therapy, IPT for schizophrenics, or psychodynamic psychotherapy were applied to 2
      6% of patients. Inpatients with eating disorders, personality disorders, neurotic
      disorders, somatization disorders, and depression were more likely to receive a
      specific psychotherapy. A significantly positive effect on treatment success was
      only documented in affective disorders, whereas a significantly negative
      influence was found in personality disorders.

PMID- 12430051
TI  - [Specific behaviour therapy day clinic].
AB  - Psychiatric day care has a long tradition. However, psychotherapeutic day care
      institutions specialising in particular disorders or certain therapeutic
      approaches are still the exception. A day care unit for behaviour therapy was
      established at the Clinic for Psychiatry and Psychotherapy, University Hospital
      Hamburg-Eppendorf in 1998 as part of a complex inpatient, day care, and
      outpatient behaviour therapy unit. The immediate and high acceptance by patients
      and their doctors indicates a strong need of such a treatment setting. We present
      how this day care unit works and how it differs from the traditional psychiatric
      day care.

PMID- 12430052
TI  - [An acute psychiatric ward moves into the community. An empirical test of the
      satellite model].
AB  - A satellite ward is a psychiatric ward at a general hospital settled within a
      catchment area that is administered by a distant psychiatric hospital. The
      objective of the satellite model is to close the gap between patients and their
      community on the one hand and between psychiatry and general medicine on the
      other. The essential size of the satellite ward that enables it to take care for
      the patients in its catchment area is discussed controversially. This study
      investigated admission rates and number of beds needed in two catchment areas
      distant to the psychiatric hospital from 6 months before opening until 12 months
      after the opening of a satellite ward with 21 beds in one of the two catchment
      areas. We registered an 81% increase of admission rates in this catchment area
      (from 130 admissions in the half-year before the opening of the satellite ward to
      235 admissions in the 2nd half-year after it) and a 41% increase in beds needed
      (from 28.8 beds in the half-year before opening to 40.7 beds in the 2nd half-year
      following). This increase was significant in comparison to the increase in the
      controlled catchment area. Thus, only 168 (71%) patients of the catchment area
      (but 82% of the patients with schizophrenia) were treated in the satellite ward.
      The remaining patients were treated in the parent house. A selective admission of
      severely ill patients into the parent house was not observed.

PMID- 12430053
TI  - [Continuous mental disorder as a prerequisite for the loss of legal capacity].
AB  - German civil law differentiates between continuous and temporary mental disorder.
      Loss of legal capacity can only be ascertained if a continuous mental disorder is
      evident. Considering the far-reaching consequences of the loss of legal capacity,
      careful distinction between these two groups of disorders is necessary, but clear
      legal guidelines and unequivocal psychiatric statements are still lacking. The
      solution given here can assure the quality of expert testimony by taking into
      account the current diagnostic conventions of ICD-10 research criteria as well as
      relevant knowledge about clinical course and therapy of psychiatric disorders.

PMID- 12430054
TI  - [A remarkable case of folie a deux].
AB  - This article reports the noteworthy case of a couple who developed three clearly
      separate delusions after marriage. An elaborated delusion of descent was shared
      by the two people, while two further delusions remained private convictions.
      Probable biographical connections of the shared delusions and diagnostic problems
      are discussed, especially the monocausal etiologic hypotheses behind the
      respective categories for shared psychotic disorders of ICD and DSM.

PMID- 12430055
TI  - [The history of the Kaiser Wilhelm Society during the Third Reich. Interim
      reports of the president's commission of the Max Planck Society].
AB  - In 1997 the Max Planck Society set up a presidential commission to do research on
      the historical development of its precursor organization, the Kaiser Wilhelm
      Society (KWG), during the Third Reich. This paper presents some of the important
      results given in the interim reports of this commission that are relevant to
      psychiatry. It focuses on brain research, anthropology, psychiatric genetics, and
      the role of the well-known biochemist Adolf Butenandt. In general, the interim
      reports reflect the numerous links between the biomedical research of the KWG and
      the institutions of the National Socialist (Nazi) state. However, they do not yet
      allow a final historical assessment as to the complex situation of this field of
      research during National Socialism.

PMID- 12430056
TI  - [Stalking--from psychoterror to murder].
AB  - Stalking is a widespread phenomenon describing a pattern of intrusive and
      threatening behavior that leads to the victim's perception of being harrassed and
      rendered afraid. This paper summarizes relevant aspects of the current stalking
      concept and reviews its historical development. Furthermore, different typologies
      of stalking behavior, associated psychiatric diagnoses, frequency and demographic
      data, therapeutic approaches, and the psychomedical effect on victims are
      described and discussed. Stalking is not restricted to celebrities but can affect
      everybody. Members of the medical profession and other socially exposed people
      are especially potential victims of stalkers. Therefore, information on this
      topic is necessary in order to deal with it in a professional manner.

PMID- 12430057
TI  - ["Cause of death: euthanasia". Exhibit of the Prinzhorn Collection at the
      Heidelberg University Clinic March 10 2002-February 3 2003].

PMID- 12430058
TI  - [Anti-inflammatory treatment in sepsis].
AB  - A systemic inflammation with the release of multiple cytokines plays an important
      role in the pathophysiology of sepsis. During the last years, several anti
      inflammatory substances have been investigated with respect to their effects on
      mortality in patients with sepsis. However, only the antibody fragment of the
      TNFalpha binding antibody afelimomab and the recombinant human activated protein
      C (drotrecogin alpha [activated]) were capable of improving the outcome in
      controlled studies with large sample sizes. The possible administration of these
      substances should be restricted to patients who meet the inclusion criteria of
      these studies. In particular, the tight time window, which usually ends 24 h
      after the onset of sepsis, should be taken into consideration before starting an
      anti-inflammatory medication. In addition to the anti-inflammatory treatment, the
      control of the infectious focus and an aggressive hemodynamic stabilization must
      not be neglected. Ibuprofen, interleukin-1 receptor antagonists and soluble
      TNFalpha-receptors as well as high dosages of corticosteroids and antithrombin
      III do not have a place in the anti-inflammatory treatment of sepsis.

PMID- 12430059
TI  - [Anticoagulation in the treatment of sepsis. Correction of microcirculation: a
      new approach manipulating endothelial cell function].
AB  - The correction of coagulation disorders is only one aspect in the treatment of
      severe sepsis. The metabolic changes caused by sepsis are complex. They include
      the interactions of hundreds of plasma proteins. The system works in balanced
      patterns of agonists and antagonists, not allowing a preference for single
      substances. The endothelial cell plays a key role in multiple defence functions
      in sepsis. Thus, future research in sepsis has to focus on the manipulation of
      endothelial cell function.

PMID- 12430060
TI  - [Immunomodulation in sepsis].
AB  - INTRODUCTION: The systemic inflammatory response syndrome is induced by a strong
      inflammatory reaction which is called sepsis when it is caused by an infection.
      However, anti-inflammatory therapeutic strategies in septic patients were not
      successful, indicating a more complex system. It is now clear that systemic hyper
      inflammation induces systemic anti- or hypo-inflammation which can lead to total
      paralysis of the immune system ("immunoparalysis"). METHODS: Several studies were
      performed to evaluate parameters for describing the patient's immunocompetence.
      Based on these parameters, pilot trials were initiated to test immunomodulating
      therapies depending on the patient's immunocompetence. RESULTS: The measurement
      of monocytic HLA-DR expression, as well as the measurement of ex vivo LPS-induced
      TNF-a secretion, are suitable to describe the patient's immunocompetence. In
      addition to classical inflammation markers, the characterization of the
      inflammatory and infection status is completed by measurement of the plasma
      cytokines, LBP and PCT. IFN-g or GM-CSF application as well as the removal of
      inhibitory plasma mediators by hemofiltration/plasmapheresis can reconstitute the
      immune function in patients with "immunoparalysis". CONCLUSIONS: Immunomodulating
      therapeutic strategies in septic patients have to orientate on the patient's
      immunocompetence and inflammatory as well as infectious status: a patient in a
      hyper-inflammatory phase may need anti-inflammatory therapy whereas a patient in
      "immunoparalysis" needs immunoreconstitution/immunostimulating therapy.

PMID- 12430061
TI  - [Trusses in the current management of hernia].
AB  - To assess the frequency and reasons for truss prescription, we surveyed 437
      general practitioners collaborating with the surgical department of the
      Kantonsspital Winterthur and all members of the Swiss Association of Orthotists.
      59% of the general practitioners answered. For 85% of them trusses are obsolete.
      Based on the data of the orthotists, an estimated 1740 trusses are issued in
      Switzerland annually (250 per million population). In Switzerland approximately
      16,000 hernia operations are performed annually. Therefore, 11% of hernia
      patients are supplied with a truss rather than referred for a consultant surgical
      opinion. Patients can be divided into groups, one that wears the truss only for a
      short time in order to delay surgery for medical or occupational reasons and
      another group, especially elderly patients, that wears the truss permanently.
      Poor hernia control and pain, hernia incarceration, or dissatisfaction with the
      uncomfortable truss are reasons for referral to a surgeon. In our personal
      experience with 14 patients, all judged their situation after the operation
      better than with the truss. Our study confirms that despite advances in hernia
      surgery and in the use of regional and local anesthesia trusses are often
      prescribed.

PMID- 12430062
TI  - [Perioperative pain therapy. Deficiencies in children and adolescents].
AB  - Present studies reveal that postoperative pain management for children is still
      insufficient in Germany. This situation is not only caused by a lack of
      knowledge, but, mainly, by a deficiency of standardized protocols in the
      hospitals and the lack of administrative responsibility. This article describes a
      specific concept for postoperative pain management in children. It basically
      focuses on three main topics: prevention of pain, the algorithm for analgesic
      treatment and the evaluation of the efficiency of the treatment. The surgeon
      plays a central role in pain prevention. By intraoperative blocking of the
      peripheral nerves, he can achieve effective analgesia. Postoperatively, he
      prescribes a basic medication according to the procedure used and the surgical
      trauma. Its effectiveness must be measured routinely thereafter and, depending on
      the score, an individual pain medication should be added. Pain measurement in
      children requires the application of specific scales for each age group. The
      evaluation of this concept has revealed therapeutic success, broad acceptance and
      efficiency in ward use. However a long-term benefit can only be achieved when
      postoperative pain management is one of the essential duties of the surgeon and
      it is constantly monitored within a department.

PMID- 12430063
TI  - [Bronchoplastic procedures for the resection of malignant bronchial neoplasms].
AB  - INTRODUCTION: Bronchoplastic procedures have become established in the treatment
      of bronchial malignancies. We report our results on 108 operations performed
      between 1994 and 2001. PATIENTS AND METHODS: Bronchial reconstruction techniques
      (wedge resection, end-to-end-anastomosis, y-sleeve), comorbidity (cardiovascular,
      respiratory, pulmonary, neoadjuvant chemotherapy, alcoholism), postoperative
      complications (septic/aseptic, light/severe), histology, tnm-stage and
      postoperative follow up (days) were recorded prospectively. RESULTS: The
      bronchial tree was reconstructed with an end to end anastomosis in 75 cases
      (69.4%), a y-sleeve in 17 (15.7%) and a wedge resection in 16 (14.8%). In 11
      patients (10.2%), an additional angioplasty of the pulmonary artery was
      performed. The comorbidity rate was 89.8%. A total of 52 patients (49.1%)
      presented with one or more cardiovascular risk factors and 84 patients (77.8%)
      with one or more respiratory risk factors. The overall postoperative morbidity
      was 26.8% and the mortality 5.5%. Aseptic complications were observed in 12 cases
      (11.1%) with a mortality of 25% while septic complications occurred in 17
      patients (15.7%) with a mortality of 17%. Anastomotic fistulas occurred in three
      patients (2.8%) and pneumonia in 11 (10.2%). Stage I was found in 46 patients
      (42.6%), 29 (26.8%) had stage II, 21 (19.5%) stage IIIA, five (4.6%) stage IIIB
      and two had stage IV (1.8%). The follow up period ranged from 64 to 2,654 days
      (mean 756.42+/-643.46, median 575.0). Seven patients (6.5%) died with no evidence
      of disease. After 2 years, 65% of all patients were alive, after five years this
      had dropped to 50%. CONCLUSION: Bronchoplastic procedures are a safe method for
      the treatment of bronchial malignancies, even in cases with high comorbidity, and
      should be performed whenever possible.

PMID- 12430064
TI  - [Tailgut cyst. Rare differential diagnosis of retrorectal tumors].
AB  - Tumors of the retrorectal space are rare entities. The case report of a
      retrorectal tailgut cyst serves to illustrate the clinical and diagnostic
      findings, differential diagnosis, and therapy of retrorectal tumors. Tumors in
      this area can be identified by palpation. The subsequent investigations include
      ultrasound, endosonography, endoscopy, and by choice computed tomography or
      magnetic resonance imaging. Usually tailgut cysts are characterized as cystic
      tumors, well delineated with multicystic formation. The diagnosis has to
      differentiate between carcinomas of the colorectum, hamartomas, lymphomas,
      teratomas, chordomas, abscess formation, dermoid cysts, epidermoid cysts, and
      enteral cysts. An elevated level of CEA may point to malignancy. Complete
      surgical resection is the therapy of choice.

PMID- 12430065
TI  - [Myelosarcoma of the proximal jejunum. A rare primary condition of acute
      myelogenous leukemia].
AB  - Myelosarcoma (chloroma) is a rare primary condition in patients with either a
      myelodysplastic syndrome, or an acute or chronic leukemia. It is an
      extramedullary neoplasm which does not commonly present with changes in
      peripheral blood or bone marrow. The rarity and histomorphological similarity to
      malignant non-Hodgkin lymphoma renders the diagnosis notoriously difficult. Due
      to its coincidental or secondary manifestation followed by myelogenous leukemia,
      this tumor needs to be seen as a primary systemic disease. We present a 40 year
      old man with myelosarcoma of the jejunum and discuss this entity and its
      therapeutic options.

PMID- 12430066
TI  - [Primary operative gastrostomy or percutaneous endoscopic gastrostomy (PEG) in
      progressive oesophageal carcinomas? A case report on abdominal wall metastases
      following PEG].
AB  - INTRODUCTION: Percutaneous endoscopic gastrostomy (PEG) is a safe and easy
      procedure used to provide enteric nourishment in patients with non-operable,
      constricting, malignant tumors of the oropharynx or esophagus. However, as a late
      complication, the development of abdominal wall metastases have been described,
      the mechanism of which is controversially. PATIENTS AND METHODS: We describe two
      cases in which abdominal wall metastases developed 9 and 14 months, respectively,
      following PEG. Both patients suffered from an advanced esophageal carcinoma. One
      patient had to undergo surgery because of the size of the metastasis. This was
      followed by several weeks of hospital treatment. The second patient was already
      in a prefinal condition so that no surgical procedure was performed. Reviewing
      the current literature, we discuss the question of whether, in certain cases, an
      operative gastrostomy should be preferred to a PEG. RESULTS: As in our opinion
      the reason for abdominal wall metastases is direct tumor seeding, we suggest that
      in certain cases, in order to avoid a possible metastasis resection, an operative
      gastrostomy should be discussed. This is particularly relevant if the tumor is
      constricting with a high risk of losing tumor cells. If possible, a minimal
      invasive method is to be preferred.

PMID- 12430067
TI  - [Crohn's disease surgery].

PMID- 12430068
TI  - Reflux disease and Barrett's esophagus.

PMID- 12430069
TI  - Endoscopic tumor diagnosis and treatment.

PMID- 12430070
TI  - Esophagogastric varices and nonvariceal bleeding.

PMID- 12430071
TI  - Colon tumors and colonoscopy.

PMID- 12430072
TI  - Endoscopic retrograde cholangiopancreatography.

PMID- 12430073
TI  - Endoscopic ultrasonography.

PMID- 12430074
TI  - Small-bowel endoscopy.

PMID- 12430075
TI  - Magnetic endoscope imaging: a new technique for localizing colonic lesions.
AB  - BACKGROUND AND STUDY AIMS: The precise localization of advanced colorectal
      lesions preoperatively directs the appropriate surgical management. The use of
      internal landmarks at colonoscopy can be inaccurate, and other methods are
      therefore necessary to localize lesions precisely. Magnetic endoscope imaging
      (MEI), a real-time, nonradiographic technique for imaging of the colonoscope, may
      assist in determining the location of lesions found at colonoscopy. PATIENTS AND
      METHODS: A prospective study was carried out to determine the accuracy of MEI for
      localizing the colonoscope tip anatomically. The MEI system was used to identify
      one of four predetermined locations within the colon. Once identified, two
      endoscopic marking clips were attached to the colonic mucosa, and 400 - 500 ml of
      Urografin radiographic contrast medium was injected to produce an air-contrast
      "enema." The clips were subsequently localized using plain abdominal radiography,
      assessed by a single experienced radiologist who was blinded to the colonoscopic
      findings. RESULTS: Twenty-nine consecutive patients were enrolled in the study.
      The overall accuracy of MEI in comparison with the air-contrast "enema" was 90 %
      (26 of 29 cases). There were three slight errors of localization - clips
      localized to the descending rather than the sigmoid-descending colon junction (n
      = 1), or to either side of the mid-transverse (n = 1) and hepatic flexure (n = 1)
      - but these were not considered to be of surgical or clinical importance.
      CONCLUSIONS: MEI is a reliable and accurate method for determining the anatomical
      position of the endoscope tip during colonoscopy. When it becomes commercially
      available, we believe the use of MEI will avoid the need for unnecessary barium
      enemas for localization of lesions prior to definitive surgery.

PMID- 12430076
TI  - Evaluation of a new three-dimensional magnetic imaging system for use during
      colonoscopy.
AB  - BACKGROUND AND STUDY AIMS: A prototype magnetic imaging system (Scope Guide,
      Olympus Optical Co., Ltd.) provides a new facility for continuous viewing on a
      monitor of the position of the colonoscope during examination, without exposing
      patients or medical staff to radiation. The aim of this prospective study was to
      compare this magnetic imaging system with routine colonoscopy, including
      fluoroscopy. The study parameters were the detection of loops, the location of
      the endoscope tip at defined positions, the insertion time, and the premedication
      rate. MATERIALS AND METHODS: In the first part of the study, 133 consecutive
      patients were examined - 64 using an integrated three-dimensional colonoscope and
      69 with the three-dimensional probe inserted into the biopsy channel of a routine
      video colonoscope. Fluoroscopy was used in all investigations for comparison at
      defined anatomical points and loops, and pathological findings and defined
      anatomic structures were documented using a laser printer both for three
      dimensional colonoscopy and fluoroscopy. In the second part of the study, 25
      further patients underwent colonoscopy with a modified prototype, now exclusively
      using the integrated three-dimensional colonoscope. RESULTS: The total time for
      insertion and the premedication rate did not differ from those of routine
      colonoscopies with fluoroscopy available. Precise detection of loops was observed
      in the first study in 79 - 100 % of cases in comparison with fluoroscopy. Precise
      localization of the endoscopic tip improved from 30 % in the first part of the
      study to 80 % in part 2. CONCLUSION: Using magnetic three-dimensional imaging
      systems, the position of the colonoscope, the detection and observation of loops
      during straightening, and localization of pathological findings can be accurately
      achieved. Modification of the prototype led to satisfactory improvement in all
      parameters tested.

PMID- 12430077
TI  - Diagnosis of biliary strictures in conjunction with endoscopic retrograde
      cholangiopancreaticography, with special reference to patients with primary
      sclerosing cholangitis.
AB  - BACKGROUND AND STUDY AIMS: Strictures of the bile ducts due to malignant changes
      are difficult to distinguish from benign changes, particularly in patients with
      primary sclerosing cholangitis (PSC). The aim of this study was to evaluate
      diagnostic methods for malignancy in biliary strictures in conjunction with
      endoscopic retrograde cholangiopancreaticography (ERCP). PATIENTS AND METHODS:
      Bile duct strictures were identified during ERCP in 57 patients, who were thus
      included in the present study. Brush samples from the strictures were taken for
      cytology and for evaluation of DNA content by flow cytometry. The tumor markers
      CA 19-9 and CEA were determined both in serum and bile fluid. Two independent
      radiologists evaluated all cholangiograms. The diagnostic sensitivity,
      specificity, and accuracy of each diagnostic method were evaluated separately and
      in combination. RESULTS: 32 patients were found to have malignant strictures and
      when the four methods: brush cytology, DNA analysis, serum CA 19-9 and serum CEA
      were combined, a diagnostic sensitivity of 88 % and specificity of 80 % were
      reached. Seven of the 20 patients with PSC were found also to suffer from
      cholangiocarcinoma, yielding a sensitivity and specificity of 100 % and 85 %,
      respectively. Analyses of CA 19-9 and CEA in bile fluid had no diagnostic
      significance. CONCLUSION: An ERCP procedure with brush cytology, a DNA analysis,
      combined with serum analysis of CA 19-9 and CEA, can increase the possibility of
      distinguishing between malignant and benign biliary strictures, especially in PSC
      patients.

PMID- 12430078
TI  - "Floppy" Nissen vs. Toupet laparoscopic fundoplication: quality of life
      assessment in a 5-year follow-up (part 2).
AB  - BACKGROUND AND STUDY AIMS: Quality of life as an outcome variable has become an
      important measure in clinical research. This study is the second part of a
      prospective assessment of the quality of life outcome, in a 5-year follow-up of
      patients who underwent laparoscopic Nissen fundoplication or Toupet
      fundoplication. Data from a 1-year follow-up have been previously published (part
      I). PATIENTS AND METHODS: Using the Gastrointestinal Quality of Life Index
      (GIQLI), the quality of life data of 169 consecutive patients who had undergone a
      laparoscopic Nissen fundoplication (LNF; n = 104) or a laparoscopic Toupet
      fundoplication (LTF; n = 65), were evaluated 3 years and 5 years postoperatively.
      Six patients out of the initial study group (n = 175), including three from each
      group, were excluded from the main analysis because they had undergone
      laparoscopic re-fundoplication during the 1-year follow-up. Data from patients
      with repeat surgery have been analysed separately. In addition to administering
      the GIQLI, we evaluated patient satisfaction with surgery, possible surgical side
      effects or recurrent disease-related symptoms, the use of antireflux medication,
      and also surgical interventions in relation to initial antireflux surgery. In
      those patients, who were willing (n = 111) we also performed esophageal manometry
      and 24-hour pH monitoring 5 years postoperatively. RESULTS: At 3 years and 5
      years postoperatively, the analysis of quality of life data showed that the GIQLI
      score remained stable in comparison with the 1-year follow-up data, with mean
      scores of 121 +/- 8.7 points in the LNF-group and 119.8 +/- 9 points in the LTF
      group, at 5 years after surgery. Laparoscopic re-fundoplication was necessary in
      four patients due to a "slipping" Nissen (LNF group n = 1) or recurrent symptoms
      (LTF group, n = 3). In two patients in the LTF group herniation of a trocar
      incision was found. No patient suffered from severe surgical side effects.
      Patient satisfaction with surgery was rated as "excellent" or "good" in 97.9 % of
      patients. There were no significant differences between the groups concerning
      these data. The results of esophageal manometry and 24-hour pH monitoring also
      remained stable and showed normal values in all but two patients (in the LTF
      group), who suffered from mild and infrequent symptoms of recurrent heartburn
      without endoscopic signs of esophagitis. The outcome in patients who underwent
      laparoscopic re-fundoplication is comparable to the outcomes for those with a
      successful primary intervention. CONCLUSIONS: Both Nissen and Toupet laparoscopic
      fundoplication can significantly improve patients' quality of life during the 5
      years following surgical intervention. Quality of life scores for both surgical
      groups were almost equal and postoperative outcomes were comparable to values in
      healthy controls. Patient satisfaction with surgical treatment was very high,
      even though repeat laparoscopic surgery was necessary in some cases. Patients who
      had a repeat procedure experienced nearly identical outcomes.

PMID- 12430079
TI  - A global positioning system for the colon?

PMID- 12430080
TI  - Cyanoacrylate glue in gastric variceal bleeding.

PMID- 12430081
TI  - New biopsy forceps for gastrointestinal endoscopy.

PMID- 12430082
TI  - Perforation of a nonobstructing gastro-oesophageal carcinoma by oblique-viewing
      endoscopic ultrasound videoscope: a need for a safe technique.

PMID- 12430083
TI  - Endoscopic spraying of sucralfate using the outer sheath of a clipping device.

PMID- 12430084
TI  - Modified rendezvous technique for biliary cannulation.

PMID- 12430085
TI  - Ultrasound catheter probe detection of appendiceal mucocele.

PMID- 12430086
TI  - Wireless capsule video endoscopy: a new diagnostic method for aortoduodenal
      fissure.

PMID- 12430088
TI  - Chronic kidney disease in the United States: an underrecognized problem.
AB  - The continued growth of the population with end-stage renal disease (ESRD) is
      partially related to the underrecognition of earlier stages of chronic kidney
      disease (CKD) and risk factors for the development of CKD. There are several
      published estimates of the prevalence of CKD in the United States. From Third
      National Health and Nutrition Examination Survey data it has been estimated that
      there are 6.2 million individuals with serum creatinine levels at or above 1.5
      mg/dL, or 8.3 million individuals with decreased glomerular filtration rate (<60
      mL/min/1.73 m (2)). Estimates of prevalence from a health maintenance
      organization study suggest that there are 4.2 million Americans with persistently
      elevated serum creatinine levels. In addition to the high prevalence, several
      studies have shown that CKD is associated with increased risk for cardiovascular
      disease, hospitalizations, and mortality. To promote earlier detection of CKD,
      The National Kidney Foundation Guidelines for CKD: Evaluation, Classification and
      Stratification, recommended screening individuals at increased risk for CKD, such
      as patients with diabetes, high blood pressure, and family history of kidney
      disease. Therapeutic interventions to delay progression and reduce comorbidity,
      such as cardiovascular disease, are more likely to be effective if they are
      implemented early in the course of CKD.

PMID- 12430089
TI  - New clinical practice guidelines for chronic kidney disease: a framework for
      K/DOQI.
AB  - Chronic kidney disease affects millions of individuals in the United States, and
      millions more are at risk for the development of kidney disease. The National
      Kidney Foundation (NKF) has recently published 15 clinical practice guidelines
      (CPGs) for chronic kidney disease under the Kidney/Disease Outcomes Quality
      Initiative (K/DOQI). This initial set of guidelines creates a framework for
      additional interventional CPGs currently in development. Importantly, these
      guidelines define and classify CKD. In addition, recommendations for the clinical
      assessment of kidney disease are elaborated. In reviewing the guidelines, we find
      that they follow the basic principles of CPG development and incorporate the
      essential aspects of CPGs. The validity of the CPGs is limited in some areas
      because of the paucity of data. Despite their limitations, the current CPGs allow
      for the development of clinical performance measures and continuous quality
      improvement in the hopes of improving public health and reducing progression to
      end-stage renal disease (ESRD).

PMID- 12430090
TI  - Cardiovascular disease in patients with chronic kidney disease.
AB  - Cardiovascular disease (CVD) is the major cause of morbidity and mortality in
      patients with renal failure. Patients with chronic kidney disease have
      significant CVD, and carry a high cardiovascular burden by the time they commence
      renal replacement therapy (RRT). The severity of CVD that has been observed in
      dialysis patients lead to a growing body of research examining the pathogenesis
      and progression of CVD during the progression of chronic kidney disease (CKD) to
      end-stage renal disease (ESRD) (ie, predialysis phase). Multiple factors are
      involved in the development of CVD in CKD. More importantly, critical and key
      factors seem to develop early in the course of CKD, and result in preventable
      worsening of CVD in this patient population. Anemia is common in patients with
      CKD, and has been shown to have an independent role in the genesis of left
      ventricular hypertrophy (LVH) and subsequent CVD. Unfortunately, it is
      underdiagnosed and undertreated in patients with CKD. Early intervention, and
      better correction of anemia, seems to gain a great momentum in the prevention and
      management of CVD in CKD. Hypertension is another risk factor that has been
      targeted by the National Kidney Foundation Task Force on CVD in chronic kidney
      disease. This article reviews the different factors involved in the pathogenesis
      of CVD in CKD and the evidence supporting early and aggressive intervention.

PMID- 12430091
TI  - Anemia treatment in chronic renal insufficiency.
AB  - Anemia is a common complication of chronic renal insufficiency, one that leads to
      a reduced quality of life and an increased burden on the heart. In recent years,
      it has been shown that anemia is underrecognized and undertreated in these
      patients. The benefits of recombinant human erythropoietin treatment in this
      patient population have been well shown. The major side effect, hypertension, is
      particularly important in chronic renal insufficiency, requiring careful
      monitoring. In this review, the benefits of anemia therapy are weighed against
      the risks and costs. On balance, it is concluded that anemia treatment meets a
      basic and important health need in these patients.

PMID- 12430092
TI  - Issues related to iron replacement in chronic kidney disease.
AB  - Recent epidemiologic studies show that iron deficiency occurs in the vast
      majority of patients with chronic kidney disease (CKD). In patients with CKD,
      increased iron losses and, to a lesser extent, poor oral absorption, can lead to
      iron-deficiency anemia. Correction of iron-deficiency anemia is preferable by the
      oral route, however, data on oral iron use are limited in this population. In CKD
      patients, parenteral iron administered with recombinant human erythropoietin
      (rHuEpo), is the best potential option for the correction of anemia. Nondextran
      iron preparations are preferable because of a reduced incidence of serious
      adverse events. Parenteral iron in CKD patients may not be entirely innocuous
      and, although commonly used, have not received Food and Drug Administration
      approval for use in this patient population. Exposure to intravenous (IV) iron
      may lead to oxidative stress, renal injury, infection, cardiovascular disease,
      and osteomalacia. Studies are needed to confirm the existence and magnitude of
      these complications. The current data suggest that the overall risk-benefit ratio
      favors use of IV iron when compared with untreated or partially treated iron
      deficiency anemia.

PMID- 12430093
TI  - Renal osteodystrophy in chronic renal failure.
AB  - Bone disease develops relatively early in the development of chronic renal
      failure. Much of what is known about the evaluation and management of renal
      osteodystrophy in chronic renal failure is based on knowledge obtained in the
      dialysis population. The classic bone lesion found in the dialysis population is
      osteitis fibrosa, the high turnover lesion of secondary hyperparathyroidism.
      Clearly, hypocalcemia, hyperphosphatemia, and calcitriol deficiency play major
      roles in the development and maintenance of the high turnover disease.
      Interestingly, in both the dialysis and nondialysis patients, the incidence of
      adynamic bone disease, a low turnover lesion, is increasing. It is postulated
      that the aggressive use of calcium-containing phosphate binders and the use of
      calcitriol and other vitamin D analogs to treat secondary hyperparathyroidism may
      contribute to this shift in bone lesions. Treatment in the nondialysis kidney
      disease patient remains aggressive correction of hypocalcemia and
      hyperphosphatemia. The use of calcitriol and other agents to maintain serum
      calcium and to suppress elevated parathyroid hormone remains well supported.
      However, the increase in extraskeletal calcifications and incidence of adynamic
      bone disease in these patients raises concern about current management
      techniques.

PMID- 12430094
TI  - Comorbidity and cardiovascular risk factors in patients with chronic kidney
      disease.
AB  - The mortality rate among dialysis patients is high. Although guidelines have been
      in place to improve outcomes in dialysis patients, new emphasis is being placed
      on better management of patients who are pre-end-stage renal disease (pre-ESRD)
      patients with chronic kidney disease (CKD). Spearheaded by the National Kidney
      Foundation, the National Institute of Health, and the nephrology community at
      large, an effort is underway to improve the care of patients with kidney disease.
      We hope that improvement in health and outcomes of patients with kidney disease
      will be optimized through attention to care before the development of advanced
      renal disease. Cardiovascular disease (CVD) is an important comorbidity of
      chronic kidney disease, and reducing cardiovascular events in this population is
      an important goal for the people who care for chronic kidney disease patients. In
      this article, we review the available literature regarding certain risk factors
      for cardiovascular disease: proteinuria, hyperglycemia, hypertension,
      homocysteine, hyperlipidemia, and inflammation. When possible, recommendations
      for treatment are provided based on the information reviewed.

PMID- 12430095
TI  - Improving dialysis access management.
AB  - Renal replacement therapy requires either placement of a functional hemodialysis
      vascular access or peritoneal dialysis catheter. Early provision of a dialysis
      access improves patient care with reduction in morbidity and reduces the economic
      burden incurred as a result of delayed access placement. Vascular access
      dysfunctions (thrombosis and infection) pose the greatest burden on the end-stage
      renal disease population. This article reviews the current literature on the
      planning of dialysis access, with particular emphasis on issues pertaining to
      vascular access. Current concepts to maximize access patency and efficiently
      manage vascular access complications are highlighted.

PMID- 12430096
TI  - Pretransplant evaluation of renal transplant candidates.
AB  - Kidney transplantation should be strongly considered for all medically suitable
      patients with chronic and end-stage renal disease (ESRD). Improvements in
      outcomes after renal transplantation have resulted in a more liberal selection of
      patients. High-risk category patients including human immunodeficiency virus
      (HIV)-positive, highly sensitized patients, T-cell positive cross-match, and ABO
      blood group-incompatible patients are now considered potential renal transplant
      candidates. Unfortunately, the demand for kidney transplants far exceeds the
      supply of available organs, causing a persistent increase in the number of
      patients on the waiting list with a parallel increase in the waiting time for a
      cadaveric kidney transplant. This has 2 major consequences. First, patients on
      the waiting list are getting sicker and older. Second, living donors have assumed
      increasing importance in renal transplantation. Pre-existing morbidities
      including malignancies, cardiovascular disease, infections, and coagulopathies
      should be extensively evaluated before proceeding to transplantation. Special
      attention should be given to cardiovascular risk factors because the leading
      cause of death after renal transplant is cardiovascular disease. A full
      immunologic evaluation with ABO blood group determination, human leukocyte
      antigen (HLA) typing, screening for antibody to HLA phenotypes, and cross
      matching need to be gathered before transplantation to avoid antibody-mediated
      hyperacute rejection or to proceed with specific protocols in highly sensitized
      or in positive T-cell cross-match patients. With the increased rate of donation
      from living donors, regular follow-up evaluation of kidney donors is recommended
      to detect hypertension or proteinuria in those who may develop it.

PMID- 12430097
TI  - The role of comprehensive renal clinic in chronic kidney disease stabilization
      and management: The Northwestern experience.
AB  - In this article, we maintain that the management of patients with chronic kidney
      disease (CKD) is best provided in a clinic setting that integrates nephrologic
      expertise, patient education, and comprehensive supportive services. Our
      experience with a CKD clinic in an urban academic setting is described. As a way
      to assess and quantify the impact of our clinic on clinical outcomes, we have
      analyzed our results in terms of 2 variables: presence of permanent access at the
      time of dialysis initiation and impact on renal function as assessed by
      calculated glomerular filtration rate (GFR). The number of clinic visits was
      taken as an index of comprehensive renal care before dialysis initiation.
      Individuals who started dialysis with a functioning permanent access had been
      seen in our clinic more frequently than those seen less frequently (20 +/- 3.5
      and 4.4 +/- 2.1 visits, respectively, P <.005). The impact on renal function was
      analyzed in a group of 80 unselected patients stratified into 3 stages based on
      the recently published National Kidney Foundation Disease Outcomes Quality
      Initiative (K/DOQI) guidelines: stage III (mean GFR 39 +/- 1.5 mL/min, n = 21),
      stage IV (mean GFR 21 +/- 0.6 mL/min, n = 46), and stage V (mean GFR 12 +/-.76
      mL/min, n = 13). Provision of comprehensive renal care in conjunction with anemia
      management using weekly injections of erythropoietin subcutaneously resulted in
      stabilization of GFR in patients with stages IV and V over a period of 15 months
      of follow-up evaluation. In patients with stage III CKD, GFR decreased over the
      initial period of follow-up evaluation (first few months), and to a lesser extent
      by the end of follow-up evaluation (15 mo). Further studies are underway to
      discern the factor(s) underlying the overall clinic effect versus a beneficial
      effect of anemia correction on GFR. Our data suggests that stabilization of GFR
      is a goal that can be accomplished with comprehensive renal care provided in an
      organized clinic setting.

PMID- 12430098
TI  - Person-centered approach to care, teaching, and research in fibromyalgia
      syndrome: justification from biopsychosocial perspectives in populations.
AB  - OBJECTIVES: To describe complex interactions of multiple factors believed to
      contribute to fibromyalgia syndrome (FMS) at a person-centered level to enhance
      approaches to care, teaching, and research. The main factors addressed were
      central nervous system sensory sensitization, autonomic nervous system (ANS)
      activation, neurohumoral perturbations, and psychosocial and environmental
      stressors. A person-centered approach is defined as attention to major
      biopsychosocial issues of affected individuals. METHODS: Literature on
      classification, mechanistic pathways, course and outcomes, and management of FMS
      was reviewed to assess applications of person-centered approaches to care,
      teaching, and research. Various biopsychosocial influences were considered in
      relation to the heterogeneous subjective manifestations of this illness,
      including central hyperalgesia, ANS and other neurohumoral perturbations,
      functional hyperexcitability, nonrestorative sleep, and psychologic distress.
      RESULTS: A person-centered approach to FMS can expand on and strengthen
      traditional biomedical concepts. Adding such a focus can help to untangle current
      controversies in the course, outcomes, and treatment of FMS. A person-centered
      approach can also help in the subgrouping of affected patients for greater
      specificity in care programs and in improved clinical investigations. In the
      biomedical model, diverse symptoms of FMS are often addressed separately and
      apart from their interconnectedness and linkages to the patient's individualized
      biopsychosocial factors. However, the causes of FMS symptomatology are not likely
      to be caused by uniform biologic abnormalities across populations. Rather, the
      syndrome likely results from personal reactivities to varied multifactorial
      biopsychosocial influences. Common denominators among individuals may include
      varying degrees of ANS activation (or personal susceptibility to ANS activation),
      nonrestorative sleep, negative affectivity, and other central pain sensitization
      mechanisms, among the pathways reviewed. CONCLUSIONS: Innovative analytical
      methodologies will need to be developed to more effectively investigate complex
      interacting biopsychosocial dynamics at a person-centered level, including
      qualitative research, and multifactorial and multilevel techniques. Adding person
      centered approaches to biopsychosocial concepts of FMS promises to show new
      physiopathogenetic insights and more effective treatment than current biomedical
      models alone. Person-centered approaches enhance patient-physician relationships
      and help prioritize patients' goals in mutually derived treatment plans.

PMID- 12430099
TI  - Pathogenesis and natural history of osteonecrosis.
AB  - BACKGROUND AND OBJECTIVES: Osteonecrosis (avascular necrosis) is a relatively
      common disorder seen by both rheumatologists and orthopedic surgeons. The vast
      majority of cases are secondary to trauma. However, for non-traumatic cases,
      there often remains a diagnostic challenge in defining the cause of bone death.
      The goal of this article is to review data extensively in the medical literature
      with respect to the pathogenesis of osteonecrosis, its natural history, and
      treatment. METHODS: A review of 524 studies on osteonecrosis was performed, of
      which 213 were selected and cited. RESULTS: Non-traumatic osteonecrosis has been
      associated with corticosteroid usage, alcoholism, infections, hyperbaric events,
      storage disorders, marrow infiltrating diseases, coagulation defects, and some
      autoimmune diseases. However, a large number of idiopathic cases of osteonecrosis
      have been described without an obvious etiologic factor. Although corticosteroids
      can produce osteonecrosis, careful history is always warranted to identify other
      risk factors. The pathogenesis of non-traumatic osteonecrosis appears to involve
      vascular compromise, bone and cell death, or defective bone repair as the primary
      event. Our understanding of the pathogenesis of osteonecrosis is now much better
      defined and skeletal scintigraphy and magnetic resonance imaging have enhanced
      diagnosis greatly. Early detection is important because the prognosis depends on
      the stage and location of the lesion, although the treatment of femoral head
      osteonecrosis remains primarily a surgical one. CONCLUSIONS: Osteonecrosis has
      been associated with a wide range of conditions. Many theories have been proposed
      to decipher the mechanism behind the development of osteonecrosis but none have
      been proven. Because osteonecrosis may affect patients with a variety of risk
      factors, it is important that caregivers have a heightened index of suspicion.
      Early detection may affect prognosis because prognosis is dependent on the stage
      and location of the disease. In particular, the disease should be suspected in
      patients with a history of steroid usage, especially in conjunction with other
      illnesses that predispose the patient to osteonecrosis. RELEVANCE: A better
      understanding of the pathophysiology, diagnosis and treatment of osteonecrosis
      will help the physician determine which patients are at risk for osteonecrosis,
      facilitating early diagnosis and better treatment options.

PMID- 12430100
TI  - Tubulointerstitial nephritis and uveitis syndrome in Southern Spain.
AB  - OBJECTIVE: To examine immunogenetic and clinical features in a series of patients
      with the idiopathic tubulointerstitial nephritis and uveitis (TINU) syndrome
      diagnosed at the single referral hospital for a defined population in Southern
      Spain. PATIENTS AND METHODS: Retrospective study of the case records of all
      patients diagnosed with the TINU syndrome in the Departments of Ophthalmology and
      Medicine of the Valme University Hospital (Seville, Spain) from January 1996
      through October 2000. Patients were included in this study if they had a renal
      biopsy showing interstitial edema and infiltration by lymphocytes, plasma cells,
      macrophages, eosinophils, and neutrophils. In these cases fibrosis was
      occasionally seen, but no glomerular changes were found. In addition, a diagnosis
      of uveitis by expert ophthalmologists was always required. Underlying diseases,
      which might be responsible for the renal or ocular manifestations, were excluded.
      Patients were HLA-DRB1 genotyped from DNA by using molecular-based methods.
      RESULTS: Six patients (4 females) fulfilled the definitions described above. Four
      were younger than 18 years. In addition to tubulointerstitial nephritis, non
      granulomatous uveitis (anterior or panuveitis) associated with low visual acuity
      was present at the time of diagnosis. Leukocytosis and increase of acute phase
      reactants were also commonly observed at the time of diagnosis. Topical and oral
      corticosteroids were prescribed to all the patients. Cyclosporine A therapy was
      required in 2 cases. After a 2.5-year median follow-up, visual acuity had
      improved in all cases. Of note, 4 of 6 patients carried the HLA-DRB1*01 allele.
      CONCLUSION: The TINU syndrome should be considered in the differential diagnosis
      of patients presenting with visual and renal manifestations. The presence of
      renal dysfunction in patients with uveitis may be of some help, as a warning
      sign, for the recognition of patients who require a rapid diagnosis and therapy.
      In Southern Spain, the TINU syndrome appears to be associated with HLA-DRB1*01
      allele.

PMID- 12430102
TI  - One hundred years later, I can still make your heart stop and your legs weak: the
      relationship between regional anesthesia and local anesthetic toxicity.

PMID- 12430101
TI  - Clinical manifestations of diffuse idiopathic skeletal hyperostosis of the
      cervical spine.
AB  - OBJECTIVES: To describe the clinical manifestations and the complications of
      cervical spine (C-spine) involvement in diffuse idiopathic skeletal hyperostosis
      (DISH). METHODS: Two patients, who presented with dysphagia resulting from large
      anterior osteophytes of the C-spine, were diagnosed as having DISH. A Medline
      search from 1964 to present, using the terms "diffuse idiopathic skeletal
      hyperostosis" and "cervical spine," identified several clinical manifestations
      associated with DISH. RESULTS: Two groups of conditions associated with DISH were
      found. 1. Spontaneous complications such as: dysphagia, being the commonest,
      dyspnea, stridor, myelopathy associated with ossification of the posterior
      longitudinal ligament (OPLL) or with atlanto-axial pseudoarthrosis or
      subluxation. Other rare events were aspiration pneumonia, sleep apnea and
      thoracic outlet syndrome. 2. Provoked complications such as endoscopic and
      intubation difficulties and fractures of the C-spine with frequent transverse
      shift of the fractured segment and resultant myelopathy. CONCLUSIONS: C-spine
      involvement in DISH is a recognized cause of various clinical manifestations
      involving the pharynx, larynx and the esophagus. Prior knowledge of the existence
      of cervical DISH should alert the clinicians for possible complications, at times
      severe, during invasive procedures in the neck region and as a consequence of
      trauma.

PMID- 12430103
TI  - Cardiac toxicity of local anesthetics in the intact isolated heart model: a
      review.
AB  - An editorial in 1979 by George Albright about sudden cardiac arrest after
      regional anesthesia spawned an era of intense research focusing on what local
      anesthetics do to the heart and how they do it. The ultimate goal of the research
      was to bring to the clinician long-acting local anesthetics that are less
      cardiotoxic than ones available before 1979, bupivacaine and etidocaine, in
      particular. In this article, I will review results of studies of local anesthetic
      cardiotoxicity using the intact mammalian heart in vitro published after the
      Albright editorial through 2001.

PMID- 12430104
TI  - Systemic toxicity and cardiotoxicity from local anesthetics: incidence and
      preventive measures.

PMID- 12430105
TI  - Local anesthetic toxicity--does product labeling reflect actual risk?

PMID- 12430106
TI  - Current concepts in resuscitation of patients with local anesthetic cardiac
      toxicity.

PMID- 12430107
TI  - Local anesthetic neurotoxicity: clinical injury and strategies that may minimize
      risk.

PMID- 12430109
TI  - Hernia surgery, anesthetic technique, and urinary retention-apples, oranges, and
      kumquats?

PMID- 12430108
TI  - Transient neurologic symptoms: etiology, risk factors, and management.

PMID- 12430110
TI  - Infraclavicular plexus block: multiple injection versus single injection.
AB  - BACKGROUND AND OBJECTIVES: This prospective, randomized, and multicentered study
      was undertaken to evaluate the success rate of coracoid infraclavicular nerve
      block performed with a nerve stimulator when either 1 or 3 motor responses were
      sought. METHODS: Eighty patients who presented for elbow, forearm, or wrist
      surgery were randomly allocated to one of the following groups: in group 1
      (single stimulation), 30 mL local anesthetic (LA) was injected after locating
      only 1 of the median, ulnar, or radial motor responses. In group 2
      (multistimulation), 3 responses were located: musculocutaneous, median or ulnar,
      and radial response, corresponding, respectively, to the lateral, medial, and
      posterior cords. A total of 10 mL LA was injected on each response. Bupivacaine
      0.5% and lidocaine 2% with epinephrine 1:200000 (1:1 vol) were used as the LA
      mixture. Sensory and motor blocks were tested by a blinded observer. RESULTS:
      Block duration was slightly increased in the multistimulation group (P =.004).
      The onset time of sensory and motor block was faster in each nerve distribution,
      particularly in the radial, musculocutaneous, and antebrachial nerves. The
      success of anesthesia increased in the multistimulation group. The success rate
      of the block, without any additional block, sedation, or general anesthesia,
      increased from 40% in the single stimulation group to 72.5% in the
      multistimulation group (P <.0001). If the brachial and antebrachial cutaneous
      nerves were not included in the evaluation, success rate reached 87.5%.
      CONCLUSIONS: We conclude that by performing an infraclavicular block with
      stimulation of all 3 cords of the brachial plexus, the success rate is higher
      than when only a single stimulation is used.

PMID- 12430111
TI  - Comparison of anesthetic effect between 0.375% ropivacaine versus 0.5% lidocaine
      in forearm intravenous regional anesthesia.
AB  - BACKGROUND AND OBJECTIVES: Ropivacaine was shown to provide superior postblock
      analgesia to lidocaine in intravenous regional anesthesia (IVRA) in voluntary
      studies. The objective of this study was to compare the anesthesia efficacy,
      postblock analgesia, and local anesthetic-related side effects between
      ropivacaine and lidocaine when forearm IVRA was used. METHODS: Fifty-one patients
      undergoing outpatient hand surgery were randomized to receive forearm IVRA with
      either ropivacaine 0.375% or lidocaine 0.5%. The volume was 0.4 mL/kg up to 25
      mL. Sensation to pinching by forceps and motor function was assessed at 5-minute
      intervals up to 15 minutes. After tourniquet deflation, verbal pain rating score
      (VRPS) at 15-minute intervals for the first 2 hours and time for first analgesic
      in the first 24 hours were evaluated. RESULTS: Eleven patients were excluded from
      the study with 20 patients remaining in each group. Onset time of anesthesia (6.5
      +/- 2.9 minutes v 8.0 +/- 4.1 minutes for lidocaine and ropivacaine groups,
      respectively) and motor block were similar. In the postoperative period, VPRS was
      significantly lower in the ropivacaine group in the first 60 minutes (median, 0;
      P <.05) with significantly more patients in the ropivacaine group pain free
      (VPRS, 0) up to the first 90 minutes (P >.05). More patients in lidocaine group
      requested analgesic in the first 2 hours postblock, and only patients in the
      lidocaine group required supplemental IV morphine in the recovery room. Twenty
      four hour analgesic consumption was the same. No local anesthetic-related side
      effects were observed. CONCLUSIONS: We conclude that 0.375% ropivacaine provides
      effective anesthesia and superior postoperative analgesia compared with 0.5%
      lidocaine when forearm IVRA is used.

PMID- 12430112
TI  - Intrathecal fentanyl added to hyperbaric ropivacaine for cesarean delivery.
AB  - BACKGROUND AND OBJECTIVES: Hyperbaric ropivacaine produces adequate spinal
      anesthesia for cesarean delivery. Addition of opioid to local anesthetics
      improves spinal anesthesia. We assessed the effect of fentanyl added to
      hyperbaric ropivacaine for spinal anesthesia for cesarean delivery. METHODS:
      Fifty-nine healthy, full-term parturients scheduled for elective cesarean
      delivery under spinal anesthesia were randomly assigned in a double-blind fashion
      to receive either fentanyl 10 micro g or normal saline 0.2 mL added to 0.5%
      hyperbaric ropivacaine 18 mg. Characteristics of spinal block, intraoperative
      quality of spinal anesthesia, side effects, complete analgesia (time to first
      feeling of pain), and effective analgesia (time to first request of analgesics)
      were assessed. RESULTS: Duration of sensory block was prolonged in the fentanyl
      group (P <.05). Duration of motor block was similar in both groups. The quality
      of intraoperative analgesia was better in the fentanyl group (P <.05). Incidence
      of side effects did not differ between groups. Duration of complete analgesia
      (143.2 +/- 34.2 minutes v 101.4 +/- 21.4 minutes; P <.001) and effective
      analgesia (207.2 +/- 32.2 minutes v 136.3 +/- 14.1 minutes; P <.001) were
      prolonged in the fentanyl group. CONCLUSIONS: Adding fentanyl 10 micro g to
      hyperbaric ropivacaine 18 mg for spinal anesthesia for cesarean delivery improves
      intraoperative anesthesia and increases the analgesia in the early postoperative
      period.

PMID- 12430113
TI  - Postoperative analgesia by femoral nerve block with ropivacaine 0.2% after major
      knee surgery: continuous versus patient-controlled techniques.
AB  - BACKGROUND AND OBJECTIVES: This prospective study compared the efficacy and
      adverse effects after knee surgery of ropivacaine 0.2% administered as patient
      controlled femoral analgesia (PCFA), as a continuous femoral infusion (Inf), or
      as both (PCFA+Inf). METHODS: Before general anesthesia, 140 adults scheduled to
      undergo major knee surgery received a sciatic/fascia iliaca nerve block with
      0.75% ropivacaine (40 mL). After surgery, they were randomly assigned to receive,
      through the femoral catheter, an infusion of 0.2% ropivacaine administered as
      PCFA (boluses of 10 mL with a lockout time of 60 minutes), Inf (10 mL/h), or PCFA
      + Inf (5 mL/h plus boluses of 5 mL with a lockout time of 60 minutes). Pain was
      assessed at rest, on mobilization, and during physiotherapy using a visual analog
      scale (VAS). Additional use of intravenous (IV) analgesics was noted. RESULTS:
      Patients in all 3 groups experienced similar pain relief at rest, on
      mobilization, and after physiotherapy (P >.05). Additional use of analgesics and
      overall patient satisfaction (excellent or good in 80% of cases) were also
      similar in all groups. However, total postoperative ropivacaine consumption was
      lower in the PCFA group, 150 mL/48 h (90.5 to 210); than in the Inf group, 480
      mL/48 h (478 to 480); and the PCFA + Inf group, 310 mL/48 h (280 to 340) (P
      <.05). Adverse events were similar in all 3 groups (hypotension, vomiting,
      insomnia). No paresthesia or motor block were observed. CONCLUSION: All 3
      strategies provided effective pain relief. PCFA resulted in a lower consumption
      of ropivacaine (toxic and financial impact). PCFA + Inf does not improve
      postoperative analgesia.

PMID- 12430114
TI  - Postherniorrhaphy urinary retention--effect of local, regional, and general
      anesthesia: a review.
AB  - BACKGROUND AND OBJECTIVES: Postherniorrhaphy urinary retention (UR) may depend on
      the anesthetic technique. We therefore reviewed available published studies of UR
      in relation to anesthetic technique. METHODS: A Medline-based search (1966
      November 2001) revealed 70 nonrandomized and 2 randomized studies. RESULTS: The
      incidence of UR was lower with local anesthesia (LA) (33 in 8991 patients, 0.37%,
      95% confidence interval [CI] 0.24%-0.49%) compared with regional anesthesia (RA)
      (150 in 6191 patients, 2.42%, 95% CI 2.04%-2.81%) and general anesthesia (GA)
      (344 in 11471 patients, 3.00%, 95% CI 2.69%-3.31%). CONCLUSION: The low incidence
      of UR with LA is in accordance with the inhibitory effects of RA and GA on
      bladder function. Data from newer short-acting techniques of GA and RA are
      required to define the optimal anesthetic for inguinal herniorrhaphy.

PMID- 12430115
TI  - Assessment of lower extremity nerve block: reprise of the Four P's acronym.
AB  - BACKGROUND AND OBJECTIVES: Successful performance of lower-extremity regional
      anesthesia includes sensory and/or motor block assessment of up to 4 major
      peripheral nerves. This brief report describes a methodology for the rapid
      evaluation of lower-extremity anesthesia before surgical incision. METHODS:
      Illustrations highlight the techniques for evaluation of sciatic, obturator,
      lateral femoral cutaneous, and femoral nerve anesthesia. This methodology is
      based on a Four P's acronym: push, pull, pinch, punt. CONCLUSIONS: Accurate
      assessment of lower-extremity regional anesthesia can be achieved rapidly using
      The Four Ps evaluation tool.

PMID- 12430116
TI  - Safety of spinal endoscopy is contingent on basic image interpretation.

PMID- 12430118
TI  - Cauda equina syndrome after intradiscal electrothermal therapy.

PMID- 12430119
TI  - Clinical hypnosis instead of drug-based sedation for procedures under regional
      anesthesia.

PMID- 12430120
TI  - An anesthetic "bug" at PubMed.

PMID- 12430122
TI  - CT assessment of bone marrow transplant patients with rhinocerebral
      aspergillosis.
AB  - PURPOSE: Invasive rhinocerebral aspergillosis is a hazardous complication of bone
      marrow transplantation. A study was conducted to describe the computed tomography
      (CT) features of this disease. MATERIALS AND METHODS: Charts and CT scans of bone
      marrow transplant patients with invasive rhinocerebral aspergillosis were
      reviewed. The diagnosis was confirmed by otolaryngologic examination and biopsy
      of suspected lesions. Sinus CT scans were conducted without contrast material.
      They were repeated with contrast if intracranial or intraorbital extension was
      suspected. CT scans were correlated with physical examination, history of
      disease, and histology. RESULTS: Of 1,013 bone marrow transplantations carried
      out over a 10-year period, 21 patients (2.07%) developed invasive rhinocerebral
      aspergillosis. In most cases the infection was unilateral. Air-fluid levels and
      calcifications were rarely encountered. Mucosal thickening, soft tissue
      hyperdense masses in the nasal cavity and/or sinuses, and clear (uninvolved)
      ethmoid cells amid diseased cells, were significant CT features that
      characterized invasive fungal infection. Opacification of the sinus represented
      extensive disease with tissue necrosis. When bone destruction was encountered,
      fulminant infection was already present, usually with significant orbital and/or
      brain invasion. CONCLUSIONS: When correlated with clinical findings and
      histologic results, the above CT features can help identify early infection so
      that appropriate medical and surgical treatment can be instituted.

PMID- 12430123
TI  - Effect of submucosal diathermy in chronic nasal obstruction due to turbinate
      enlargement.
AB  - Nasal obstruction is one of the most common chronic presenting symptoms
      encountered by otolaryngologists. In most patients, the cause of nasal
      obstruction is either nasal septal deviation or turbinate hypertrophy owing to
      vasomotor or perennial allergic rhinitis. Most cases of hypertrophic turbinate
      are usually mild and respond to antihistamine therapy, local decongestions, or
      allergy desensitization; however, surgery is required in some cases. Surgical
      treatment is controversial, and many surgical methods of treatment have been
      proposed. We have recently evaluated the results of our experience with
      submucosal diathermy (SMD) on 51 patients suffering from chronic nasal
      obstruction. We have found that diathermy demonstrated good results in 78% of the
      cases at 2 weeks postoperatively and in 76% of the cases 2 months following the
      procedure. Patients who had no complaints and had good nasal airflow were not
      followed-up after 2 months. In the present study, we have carried out a long-term
      follow-up of another group of patients who had undergone SMD diathermy because of
      hypertrophy of the inferior turbinates. Patients were examined at 2 months
      postoperatively and after 1 year, with both subjective and objective assessments
      of nasal breathing. Two months postoperatively 64 of 91 patients (70.3%)
      experienced subjective improvement in nasal breathing, where as 73 patients
      (80.2%) had good nasal breathing as indicated with the Gertner-Podoshin plate.
      During the follow-up year, secondary operations were deemed necessary for 16
      patients because of unsatisfactory results of the original procedure. Of these
      secondary procedures 4 were revision SMD, 9 patients underwent a septoplasty, in
      2 patients functional endoscopic sinus surgery was conducted, and 1 patient had a
      submucosal turbinectomy. This group of patients was excluded from the 1 year
      follow-up evaluation. At the 1-year follow-up visit, 65 patients (of the 75) were
      symptom-free with respect to nasal breathing (86.7%), and 67 patients (89.3%) had
      good nasal breathing as examined with the Gertner-Podoshin plate. No means were
      apparent for predicting preoperatively which patients would benefit most from
      submucosal diathermy. Submucosal diathermy is carried out under local anesthesia
      and can be implemented as an office procedure. It does not require expensive
      instrumentation and is a safe, effective procedure for improving nasal breathing
      in patients with chronic obstructive inferior turbinates, both on a short-term
      and long-term basis.

PMID- 12430124
TI  - Tracheotomy tube placement in children following cardiothoracic surgery:
      indications and outcomes.
AB  - PURPOSE: To review the indications for and outcomes of children requiring
      tracheotomy tube placement following cardiothoracic surgery, charts were reviewed
      retrospectively at a tertiary care center for fifteen children who had undergone
      tracheotomy tube placement following cardiothoracic surgery between 1994 and
      2000. Outcomes Measure: Morbidity and/or mortality associated with tracheotomy
      tube placement in this patient population, duration of tracheotomy tube, and rate
      of decannulation. RESULTS: Fifteen out of approximately 3000 children undergoing
      cardiothoracic surgery required tracheotomy tube placement over a 6-year period.
      Indications included diaphragmatic paresis (DP) (7 patients), vocal cord paresis
      (VP) alone (3 patients), DP and VP (2 patients), subglottic stenosis (SS) and DP
      (1 patient), VP and SS (2 patients), and cerebrovascular infarct (1 patient). The
      mean age at the time of tracheotomy tube placement was 36.5 months (range, 0.75
      108 months). The mean duration of intubation between cardiothoracic procedure and
      tracheotomy was 31.6 days (range, 0-72 days). Six patients were successfully
      decannulated following a mean of 7.4 months of tracheotomy tube dependence. All 6
      decannulated patients had DP necessitating tracheotomy and ventilatory support.
      Eight patients continue to be tracheotomy tube-dependent, and one patient died of
      unrelated causes. There was no short-term or long-term morbidity or mortality
      associated with tracheotomy tube placement. CONCLUSION: Tracheotomy tube
      placement is rarely indicated following cardiothoracic surgery in children. The
      most common indication is DP, which is usually transient. Most children will
      eventually be candidates for decannulation.

PMID- 12430125
TI  - Office-based videoendoscopy for the hypopharynx and cervical esophagus.
AB  - We have manufactured a trial videoendoscope for the hypopharynx and cervical
      esophagus in cooperation with Asahi Optical Co, Ltd, Tokyo, Japan. In this paper
      we report on the clinical trial of this new and useful videoendoscope. The
      videoendoscope has small charge-coupled device (CCD) chip built into the tip of
      this endoscope and is equipped with a transparent hood at the tip, which allows
      observation and treatment of the hypopharynx and cervical esophagus. The outer
      diameters of the hood (7.5 mm) and the insertion tube (5.1 mm) of the
      videoendoscope are relatively small, and the diameter of the instrument channel
      is 2 mm. The videoendoscope system is compact. Compared with conventional
      flexible fiberscopy and rigid endoscopy, this videoendoscope has several clear
      advantages. It presents a clear dynamic color image on a color video monitor and
      provides excellent resolution and recording, thus yielding a high diagnostic
      accuracy. The diameter of the videoendoscope is relatively small and results in
      less discomfort for patients. Patients can be examined in a sitting position on a
      procedure chair at an ENT outpatient clinic, which obviates general anesthesia.
      The endoscope can be used not only for observation but also for examination and
      treatment, including biopsy and foreign body extraction. This new endoscope thus
      widens the indications for office-based endoscopy of the hypopharynx and cervical
      esophagus.

PMID- 12430126
TI  - Autologous fat injection to treat leakage around tracheoesophageal puncture.
AB  - PURPOSE: To evaluate prospectively autologous fat injection as a treatment for
      leakage around tracheoesophageal puncture. PATIENTS AND METHODS: For ten patients
      who exhibited leakage of saliva or liquid around their tracheoesophageal
      puncture, autologous fat injection was carried out into the tracheoesophageal
      wall around the maintained prosthesis. Short-term success was evaluated at one
      month, and long-term follow-up was continued as long as the patients remained
      alive. The effectiveness of the procedure was evaluated based on the presence or
      absence of leakage around the puncture as the patient swallowed methylene blue
      liquid. Patients were adjudged completely improved when no leakage of blue liquid
      was observed, partially improved when a slight stasis was evident, or unimproved
      when a marked leakage of blue liquid was noted. RESULTS: Short-term success was
      achieved for 6 patients, 2 patients partially improved, and the procedure failed
      for 2 others. Long-term success (from 10 to 65 months) was achieved in all 4 of
      the completely improved patients who were free of disease, including 1 patient
      who required an additional injection. Removal of the puncture was later carried
      out in the 2 others for cervical node metastases or tracheal tumor. Definitive or
      transitional puncture closure or removal of the prosthesis was required in 3
      partially or unimproved patients, whereas 1 partially improved patient died of
      lung metastasis 3 months later. CONCLUSIONS: Fat injection around a voice
      prosthesis is a procedure that may be conducted as an alternative to other
      conservative techniques to decrease the size of the puncture. Close endoscopic
      observation is required however to eliminate secondary tumor that might expand
      the size of the puncture.

PMID- 12430127
TI  - The role of gastroesophageal reflux in the pathogenesis of laryngeal carcinoma.
AB  - Gastroesophageal reflux (GER) has been strongly associated with carcinogenesis of
      the lower esophagus and development of several otolaryngologic disorders.
      Epidemiologic studies support concept that the malignant transformation of
      laryngeal mucosal surfaces is due to GER-initiated chronic laryngeal
      inflammation. However, large clinical studies with matched control groups and
      further experimental investigations are necessary to ascertain the relationship
      between reflux and laryngeal carcinoma. This review stresses that early diagnosis
      of GER disease, based on clinical suspicion, ambulatory 24-hour double-probe pH
      monitoring, and endoscopic examination, as well as effective treatment of reflux,
      are considered the keys for relief of symptomatology and preventing the chronic
      irritation of the laryngeal mucosa that may contribute to the development of
      laryngeal carcinoma.

PMID- 12430128
TI  - Amiodarone-induced thyrotoxicosis: a case for surgical management.
AB  - OBJECTIVE: Amiodarone can cause the development of thyroid dysfunction in
      patients with or without previous thyroid disease. Although most cases of
      amiodarone-induced thyrotoxicosis (AIT) are mild, a significant number become
      life threatening. Because of its pharmacokinetics, simply discontinuing
      amiodarone provides no relief and can worsen the patient's condition. Medical
      management frequently fails, and many patients cannot discontinue amiodarone
      because of its effect against resistant arrhythmias. METHODS: This retrospective
      chart review of a case at a tertiary care institution presents the case of a
      fifty-five-year-old male with dilated cardiomyopathy and no previous thyroid
      disease. The patient was in normal sinus rhythm on amiodarone for control of
      atrial fibrillation. He experienced the acute onset of symptoms with return to
      atrial fibrillation resistant to cardioversion. Physical examination, laboratory
      tests, and imaging findings were all consistent with a diagnosis of AIT. An
      attempt to withdraw amiodarone resulted in severe ventricular tachyarrhythmias.
      RESULTS: Despite medical treatment, the patient's condition continued to
      deteriorate. Because amiodarone was the only effective drug, surgical treatment
      was elected. The patient underwent a total thyroidectomy and experienced no
      difficulties or complications. Postoperatively, the patient's condition improved,
      and he was successfully cardioverted. CONCLUSIONS: Although an uncommon clinical
      entity, life-threatening AIT has been reported. Thyrotoxicosis can develop in any
      patient during or after amiodarone therapy. Medical management of this entity is
      extremely difficult because of the lack of a proven, consistent therapeutic
      armamentarium. Surgical management should be considered for patients whose
      conditions necessitate the continuation of amiodarone or those with severe
      symptoms resistant to medical therapy.

PMID- 12430129
TI  - Inflammatory myofibroblastic tumor presenting with tracheal obstruction in a
      pregnant woman.
AB  - Inflammatory myofibroblastic tumor (IMT), also known as inflammatory pseudotumor,
      is a benign lesion predominantly found in the lung and abdomen. Sporadic cases
      have been reported in the trunk, genitourinary tract, and extremities as well as
      in the head and neck. Of critical importance is this entity's correct
      histopathologic diagnosis that differentiate it from malignant neoplasms such as
      spindle cell carcinoma and fibrosarcoma, benign tumors such as neurofibroma, and
      other pseudoneoplastic lesions such as nodular fasciitis. Correct diagnosis is
      followed by wide local excision to prevent recurrence; however, treatment must be
      tailored to the location of tumor and the condition of the patient. We present a
      unique case of IMT of the trachea presenting with acute upper airway obstruction
      in a pregnant woman. Diagnostic considerations as well as the anesthetic and
      surgical approach are discussed.

PMID- 12430130
TI  - Fibrin glue-reinforced closure of postlaryngectomy pharyngocutaneous fistula.
AB  - Pharyngocutaneous fistulization is a dreaded and devastating complication of
      laryngectomy. Although the specific risk factors are controversial, a history of
      prior radiation therapy has generally been accepted to be a major risk factor for
      developing this complication. We present a case of a postlaryngectomy
      pharyngocutaneous fistula developing in a previously irradiated patient that was
      successfully managed by incorporating fibrin glue into the surgical closure. We
      also discuss the underlying theoretical basis for this approach by reviewing the
      relevant literature.

PMID- 12430131
TI  - Dialysis-related amyloidosis of the external auditory canals.
AB  - We present a patient with dialysis-related amyloidosis of the external auditory
      canals. This diagnosis was supported by histological and immunohistochemical
      studies. This is to the best of our knowledge the first reported case of
      amyloidosis of the external auditory canals that relate to the chronic
      hemodialysis.

PMID- 12430132
TI  - Laryngomalacia causing sleep apnea in an osteogenesis imperfecta patient.
AB  - Obstructive sleep apnea is rarely caused by laryngomalacia in adult patients. To
      our knowledge, laryngomalacia secondary to osteogenesis imperfecta inducing
      obstructive sleep apnea has not been reported. We present an adult osteogenesis
      imperfecta patient with obstructive sleep apnea. Oral examination demonstrated an
      extremely long epiglottis in the oral cavity. Fiberoptic nasopharyngoscopy
      revealed that the epiglottis and redundant mucosa of the arytenoids were drawn
      into the laryngeal inlet during inspiration. Supraglottoplasty with intraoral and
      laryngoscopic approach was carried out and resulted in marked decreases in
      snoring, sleep apnea, and daytime sleepiness. In this report, we describe a
      unique laryngeal manifestation inducing obstructive sleep apnea in an adult with
      brittle bone disease. The anomaly of laryngeal structure can be corrected by
      surgical intervention with good response in the sleep-disordered breathing.

PMID- 12430133
TI  - Synchronous parathyroid and papillary thyroid carcinoma: a case report.
AB  - An extremely rare case of synchronous parathyroid and papillary thyroid carcinoma
      is reported for a patient presenting with hyperparathyroidism. This case is the
      first reported in the English literature of hyperfunctioning parathyroid
      carcinoma and concomitant thyroid carcinoma without a previous history of neck
      irradiation.

PMID- 12430134
TI  - Adult laryngomalacia: an uncommon clinical entity.
AB  - A 27-year-old female presented with a several-day history of acute onset
      inspiratory stridor and shortness of breath that worsened with phonation and
      minimal exertion. Flexible fiberoptic direct laryngoscopy revealed prolapse of
      the mucosa overlying the arytenoid cartilages bilaterally, consistent with type 1
      laryngomalacia. These symptoms persisted with only minimal improvement despite
      administration of short-term corticosteroids, several weeks of antireflux
      medications, and other conservative measures. The patient underwent a
      supraglottoplasty and exhibited a marked improvement in her symptoms. The
      literature describes several cases of exercise-induced laryngomalacia in both
      pediatric and adult populations in which symptoms of inspiratory stridor and
      shortness of breath are induced by exercise but resolve upon its discontinuation.
      Adult laryngomalacia appears to be a clinical entity distinct from exercise
      induced laryngomalacia because symptoms fail to resolve after several weeks of
      medical therapy and discontinuation of exertional activity. This case suggests
      that adult laryngomalacia, unlike pediatric and exercise-induced laryngomalacia,
      is less likely to resolve over time with conservative management and may require
      surgical intervention with supraglottoplasty necessary to alleviate symptoms.

PMID- 12430135
TI  - Ganglion cyst of the spinal anterior longitudinal ligament presenting as a
      retropharyngeal mass.
AB  - Cervical spinal synovial and/or ganglion cysts can occur at various periarticular
      sites and should be considered in the differential diagnosis of intraspinal
      extradural or paraspinal masses of the cervical spine. The first report of a
      ganglion cyst of the cervical anterior longitudinal ligament presenting as a
      retropharyngeal mass, is presented. The histopathology, etiology, and clinical
      aspects of synovial and ganglion cysts of the cervical spine are briefly
      reviewed.

PMID- 12430136
TI  - Kuttner tumor (chronic sclerosing sialadenitis).
AB  - Kuttner tumor (KT), known descriptively as chronic sclerosing sialadenitis, is a
      chronic inflammatory disease of the salivary gland. Clinically, it produces a
      firm swelling of the glands and may be difficult to distinguish from neoplasia.
      The diagnosis can only be made histologically and should not be difficult if the
      pathologist is aware of the condition's existence. Errors in diagnosis arise
      because KT is underrecognized and few cases have been reported in the English
      literature. We present a case of KT initially diagnosed as a primary salivary
      gland neoplasm that intraoperative frozen section revealed to be chronic
      sclerosing sialadenitis. Excision of the mass, usually carried out
      diagnostically, is adequate treatment.

PMID- 12430138
TI  - Detection of human polyomaviruses and papillomaviruses in prostatic tissue
      reveals the prostate as a habitat for multiple viral infections.
AB  - BACKGROUND: To determine whether human polyomavirus (hPy) genomes are present in
      prostate tissues, we have carried out a polymerase chain reaction (PCR) screening
      in two sets of prostate samples, archival and fresh frozen, as well as performing
      in situ hybridization (ISH). The frozen prostate samples as well as the urine
      from the same patients were also screened for human papillomavirus (HPV)
      sequences. METHODS: Highly sensitive nested-PCR assays were used. The detection
      of subpopulations of JC virus (JCV) -transcriptional control regions (TCRs) was
      also evaluated by Southern analysis and by direct DNA sequencing. An in situ
      hybridization technique was also used to detect JCV DNA in prostatic tissue.
      RESULTS: The paraffin-embedded archival samples gave variable, unsatisfactory
      results. Results from the fresh frozen samples, however, were consistent and were
      frequently positive for JCV and less frequent for BK virus DNA. ISH confirmed the
      presence of JCV DNA in prostatic glandular epithelium. The TCR region of JCV from
      prostate tissue and urine from prostate cancer patients showed the presence of
      both archetypal and rearranged TCRs, including several new sequence variants. HPV
      DNA was also frequently detected and in some cases also mixed with hPy DNA from
      frozen tissue and urine. CONCLUSION: The use of fresh frozen samples proved to be
      essential for consistent and reproducible detection of HPV and hPy viral DNAs.
      The presence of JCV DNA by ISH and the occurrence of a subpopulation of JCV TCR
      regions suggests that the prostate is a site for virus replication. The prostate
      is a complex habitat where mixed infections with oncogenic DNA viruses frequently
      occur and opens the discussion to the potential role of these viruses in the
      cancer of the prostate.

PMID- 12430137
TI  - Maspin is up-regulated in premalignant prostate epithelia.
AB  - BACKGROUND: Maspin, a novel serine protease inhibitor, has been shown to inhibit
      prostate tumor cell motility and invasion in vitro and to inhibit prostate tumor
      growth and metastasis in vivo. Maspin expression in high-grade prostate carcinoma
      (PC) is reduced compared with that in low-grade PC. Interestingly, however,
      compared with low-grade PC, benign secretory prostate epithelial cells express
      significantly less maspin. This observation appears paradoxical to a putative
      tumor suppressive role of maspin in prostate carcinogenesis, and this finding
      issue needs to be clarified. METHODS: We examined maspin expression
      simultaneously in benign basal cells, benign secretory cells, high-grade prostate
      intraepithelial neoplasia (HGPIN), low-grade PC, and high-grade PC in 46 radical
      prostatectomy specimens plus 51 autopsy prostate glands by a combination of
      immunohistochemistry and in situ hybridization. RESULTS: Benign basal cells
      consistently expressed maspin at a high level. In PC, the loss of basolateral
      maspin expression coincides with loss of the basal cell layer. Maspin expression
      in secretory cells, on the other hand, appears to undergo a biphasic differential
      regulation, i.e., essentially absent in benign secretory cells, dramatically up
      regulated in HGPIN, then progressively down-regulated through low-grade PC to
      high-grade PC. Maspin expression in PC is inversely correlated with tumor grade.
      Furthermore, maspin expression in HGPIN is inversely correlated with the
      Gleason's grade of the adjacent PC. CONCLUSIONS: An up-regulation of maspin
      expression precedes, rather than occurs at, the critical transition from
      premalignant prostate lesion of HGPIN to PC. Our data suggest maspin may mark an
      important transitional phase and play an important role in the premalignancy of
      the prostate gland.

PMID- 12430139
TI  - Response to a lethal dose of heat shock by a transient up-regulation of clusterin
      expression followed by down-regulation and apoptosis in prostate and bladder
      cancer cells.
AB  - BACKGROUND: Clusterin is a ubiquitous, secretory glycoprotein with a wide array
      of functions. Recent studies have implicated that clusterin functioned as heat
      shock response proteins. The objective of the present study was to determine the
      fate of clusterin expression in cancer cells, which were subjected to a lethal
      dose of heat shock, in an attempt to shed light on mechanisms of action of
      clusterin. METHODS: A prostate cancer line, PC-3, and a bladder cancer line, TSU
      Pr1, were selected owing to their aggressive growth behaviors. Apoptosis was
      assessed by enzymatic activities of terminal deoxynucleotidyl transferase as well
      as by activities of caspase-3. Cells were exposed to 45 degrees C for a period of
      60 min. RESULTS: Both cell lines underwent a transient up-regulation of clusterin
      expression followed by down-regulation and apoptosis. TSU-Prl cells produced
      higher levels of clusterin and displayed a greater resistance to apoptosis than
      did PC-3 cells. The addition of exogenous clusterin to the cultures of PC-3 cells
      protected apoptosis. Treatment of oligonucleotide antisense to clusterin to the
      cultures of TSU-Pr1 cells enhanced apoptosis mediated by heat shock. CONCLUSION:
      Clusterin offers a protection to PC-3 and TSU-Prl cells against heat shock and
      plays an important role in the cascade of events initiated by heat shock.
      Prostate 53: 277-285, 2002.

PMID- 12430140
TI  - Synergy is achieved by complementation with Apo2L/TRAIL and actinomycin D in
      Apo2L/TRAIL-mediated apoptosis of prostate cancer cells: role of XIAP in
      resistance.
AB  - BACKGROUND: Tumors have an inherent immunogenicity that can be exploited by
      immunotherapy. However, often tumors develop mechanisms that render them
      resistant to most immunologic cytotoxic effector mechanisms. This study examines
      the underlying mechanism of resistance to Apo2L/TRAIL (tumor necrosis factor
      related apoptosis-inducing ligand)-mediated apoptosis. METHODS: We studied
      prostate tumor cell lines for their sensitivity to Apo2L/TRAIL-mediated apoptosis
      in the presence and absence of the sensitizing agent actinomycin D (Act D).
      Apoptosis was determined by flow cytometry and signaling for apoptosis by Western
      blot. RESULTS: Treatment with subtoxic concentrations of Act D significantly
      sensitizes the tumor cells (CL-1, DU-145, and PC-3 prostate tumor cells) to
      Apo2L/TRAIL-mediated apoptosis. The cytotoxicity of Act D-sensitized prostate
      tumor cells was a result of synergistic activation of caspases (caspase-3, -9,
      and -8), detectable after 6 hr of treatment. Treatment with Apo2L/TRAIL alone,
      although it was insufficient to induce apoptosis, resulted in the loss of
      mitochondrial membrane potential and release of cytochrome c from the
      mitochondria into the cytoplasm in the absence of significant caspases
      activation. These findings suggested that a major apoptosis resistance factor
      blocking the Apo2L/TRAIL apoptotic signaling events is present downstream of the
      mitochondrial activation. The expression of receptors and anti-apoptotic proteins
      were examined in Act D-sensitized CL-1 cells. The earliest and the most
      pronounced change induced by Act D was down-regulation of X-linked inhibitor of
      apoptosis (XIAP) and up-regulation of Bcl-xL/-xS proteins. The role of XIAP in
      resistance was demonstrated by overexpression of Smac/DIABLO, which inhibited
      inhibitors of apoptosis (IAPs) and sensitized the cells to Apo2L/TRAIL.
      Apo2L/TRAIL receptors (DR4, DR5, DcR1, and DcR2), c-FLIP, Bcl-2, and other IAP
      members (c-IAP1 and c-IAP2) were marginally affected at later times in the cells
      sensitized by Act D. CONCLUSION: This study suggests that the combination of Act
      D-induced down-regulation of XIAP (Signal I) and Apo2L/TRAIL-induced release of
      cytochrome c (Signal II) leads to the reversal of resistance to Apo2L/TRAIL
      mediated apoptosis in the tumor cells. The sensitization of tumor cells to
      Apo2L/TRAIL by Act D is of potential clinical application in the immunotherapy of
      drug/Apo2L/TRAIL refractory tumors.

PMID- 12430141
TI  - Androgen-mediated resistance to apoptosis.
AB  - BACKGROUND: Previous studies demonstrate that androgen is capable of exerting a
      protective effect in the androgen-sensitive human prostate cancer cell line
      LNCaP. Limited studies, however, have addressed the underlying mechanisms
      involved, in particular the effects of androgen on both pro- and anti-apoptotic
      gene expression. METHODS: We investigated the effects of androgen on apoptotic
      sensitivity and the expression of the caspases and specific members of the Bcl-2
      family in the LNCaP cell line. The effects of androgen on NF-kappaB activation
      were also investigated by using a gel mobility shift assay. RESULTS: 5alpha
      Dihydrotestosterone (5-alphaDHT) conferred resistance to radiation (5 Gy) and
      etoposide-induced apoptosis in the LNCaP cell line. This finding was associated
      with a time-dependent decrease in the expression of the caspases and pro
      apoptotic Bcl-2 family members. 5-alphaDHT did not confer protection against
      apoptosis in the LNCaP line transfected with the IkappaB super repressor of NF
      kappaB, nor in the androgen insensitive PC-3 and DU-145 cell lines. CONCLUSION:
      The ability of 5-alphaDHT to raise the apoptotic threshold in the LNCaP cell line
      by altering specific pro-apoptotic gene expression suggests that androgen may
      serve as a general survival signal against diverse pathways that ultimately
      signal for apoptosis. We hypothesize that NF-kappaB serves as an important
      mediator in androgen survival signaling.

PMID- 12430142
TI  - Androgen receptor expression induces FGF2, FGF-binding protein production, and
      FGF2 release in prostate carcinoma cells: role of FGF2 in growth, survival, and
      androgen receptor down-modulation.
AB  - BACKGROUND: Alterations in fibroblast growth factors (FGFs) production and/or FGF
      receptors expression have been described to play key roles in prostate tumor
      progression, particularly in androgen-independent tumors. However, the role of
      androgen receptor (AR) in altering FGF-mediated growth and survival of prostatic
      neoplastic cells has not been completely defined. In this study, we investigated
      the alterations in FGF2 production and utilization by the PC3 cell line, after
      transfection with a full-length AR. METHODS: FGF1,2,7, FGF-binding protein (FGF
      BP) production and FGF receptor (FGFR) 1-4 expression were investigated by
      polymerase chain reaction (PCR) and Western blot analysis. RESULTS: De novo AR
      expression by PC3 cells restores FGFR2 IIIb isoform expression and sensitivity to
      FGF7 and FGF2. Androgen stimulation induces AR+ PC3 clones to secrete FGF-BP,
      likely responsible for activation and mobilization from the extracellular matrix
      of the high amounts of FGF2 produced by the same cells. In addition to the
      effects on cell proliferation, FGF2 maintains the survival of AR+ PC3 clones
      through a positive modulation of the Bcl-2 protein and down-modulates AR protein
      expression, allowing the escape of selected clones from androgen regulation.
      CONCLUSION: In the presence of an active AR, the combined production of FGF2 and
      FGF-BP may play an important role in the progression of prostate cancer through
      the selection of AR- clones expressing high levels of Bcl-2.

PMID- 12430143
TI  - Relationship of serum sex-steroid hormones and prostate volume in African
      American men.
AB  - BACKGROUND: Previous epidemiologic investigations of the associations of sex
      steroid hormones and benign prostatic hyperplasia (BPH) have focused on
      predominately white populations. The objective of this study was to evaluate
      potential associations of body mass index (BMI), cigarette smoking, use of
      alcohol, and endogenous sex-steroid hormones with prostate volume in a population
      based sample of African American (AA) men, ages 40-79 yr. METHODS: A total of 369
      AA men without clinical evidence of prostate cancer were identified in the Flint
      Men's Health Study by using a population-based sampling procedure. All subjects
      underwent a complete urologic evaluation that included prostate volume
      determination by transrectal ultrasonography and serum assays for androgens and
      estrogens. RESULTS: After age adjustment, BMI (weight (kg)/height (m)2) was
      positively correlated with increasing levels of androstanediol glucuronide (AG),
      estradiol (E2), estrone sulfate (E1S), and the ratios of E2:total testosterone
      (TT) and E2:free testosterone (FT); however, increasing BMI was negatively
      correlated with androstenedione (AD), FT, TT, and sex hormone-binding globulin
      (SHBG). Multivariable regression models demonstrated that prostate volume
      increased with age (P < 0.001) and BMI (P = 0.02) and decreased with increasing
      levels of SHBG (P = 0.01). Larger prostatic volumes were also marginally
      associated with increasing levels of TT (P = 0.058). CONCLUSION: Circulating
      serum levels of SHBG and endogenous sex-steroid hormones are correlated with
      prostate volume and potentially impact the natural history of BPH. However,
      longitudinal studies are needed to demonstrate the temporal relationships of
      hormones and growth factors in the pathogenesis of BPH in AA men.

PMID- 12430145
TI  - Holmium laser for management of ureterocele calculi.
AB  - BACKGROUND AND OBJECTIVES: Although most ureteral calculi will pass
      spontaneously, those in a ureterocele will usually not pass beyond the stenotic
      orifice. We address both the stone and the underlying anatomic abnormality of a
      ureterocele using the holmium:YAG laser. STUDY DESIGN/MATERIALS AND METHODS: We
      report the first use of the holmium laser to treat ureteral calculi and the
      ureteroceles responsible for their retention. RESULTS: Two patients have been
      successfully treated using the described procedure. CONCLUSIONS: The flexibility
      to treat both the underlying anatomic abnormality and the resultant stone with a
      single minimally invasive device makes the holmium laser ideal in this situation.

PMID- 12430146
TI  - In situ light dosimetry during photodynamic therapy of Barrett's esophagus with 5
      aminolevulinic acid.
AB  - BACKGROUND AND OBJECTIVES: Previous studies with PhotoDynamic Therapy (PDT) in
      bladder and bronchi have shown that due to scattering and reflection, the
      actually delivered fluence rate on the surface in a hollow organ can be
      significantly higher than expected. In this pilot study, we investigated the
      differences between the primary calculated and the actual measured fluence rate
      during PDT of Barrett's Esophagus (BE) using 23 independent clinical measurements
      in 15 patients. STUDY DESIGN/MATERIALS AND METHODS: A KTP-dye module laser at 630
      nm was used as light source. Light delivery was performed using a cylindrical
      light diffuser inserted in the center of an inflatable transparent balloon with a
      length corresponding to the length of the Barrett's epithelium. The total light
      output power of the cylindrical diffuser was calibrated using an integrating
      sphere to deliver a primary fluence rate of 100 mW cm(-2). Two fiber-optic pseudo
      sphere isotropic detectors were placed on the balloon and were used to measure
      fluence rate at the surface of the esophageal wall during PDT. RESULTS AND
      CONCLUSIONS: The actual fluence rate measured was 1.5-3.9 times higher than the
      primary fluence rate for 630 nm. In general, the fluence rate amplification
      factor decreased with increasing redness of the tissue and was less for shorter
      diffusers. Fluence rate variations in time were observed which coincided with
      patients coughing, movement, and esophageal spasms. These factors combined with
      inter patient variability of the fluence rate measured appears to justify the
      routine application of this technique in PDT of BE.

PMID- 12430147
TI  - In vivo light dosimetry for motexafin lutetium-mediated PDT of recurrent breast
      cancer.
AB  - BACKGROUND AND OBJECTIVES: To measure the fluence at tissue surface for patients
      in our Phase II clinical trial of motexafin lutetium (MLu)-mediated chest wall
      photodynamic therapy for recurrent breast carcinoma and to compare it to the
      calculated irradiance. STUDY DESIGN/MATERIALS AND METHODS: The spatial and time
      dependence of light fluence (rate) was monitored in vivo on the chest wall
      surface using isotropic detectors in five patients. Patients were given MLu
      either 4 mg/kg with light at 18 hours or 5 mg/kg with light at 24 hours using an
      irradiance of 150 J/cm(2) at 730 nm, with an incident fluence rate of 75
      mW/cm(2). The ratio of fluence rate to the incident fluence rate was determined
      at the center of the treatment field. This ratio was used to estimate the
      effective attenuation coefficient, mu (eff). RESULTS: The mean and standard
      deviation of the ratio for all patients was 1.6 +/- 0.2. The corresponding range
      of mu (eff) was between 0.87 and 2.1 cm(-1), assuming reduced scattering
      coefficient, mu (s) = 4 cm(-1). CONCLUSIONS: A conversion factor was determined
      to convert the irradiance to fluence rate on the tissue surface. However, the
      fluence (or the ratio) on patient surface varied by 70% due to the heterogeneity
      of optical properties. This supports the use of real-time in vivo dosimetry
      during photodynamic therapy.

PMID- 12430148
TI  - Kinetic thermal response and damage in laser coagulation of tissue.
AB  - BACKGROUND AND OBJECTIVES: Laser induced interstitial coagulation has become a
      method of treating different types of tumors. Theoretical modeling and analysis
      may be used to better understand the complex process involved in the laser
      coagulation and optimized the dosimetry of laser thermotherapy. STUDY
      DESIGN/MATERIALS AND METHODS: A full dynamic theoretical model was developed to
      simulate the dynamic evolution of coagulation in tissue, which accounted for the
      dynamics of the temperature and damage dependence of optical properties, thermal
      properties, and blood-perfusion rate. The simulation of the temperature
      distribution, coagulation depth and its hysteresis during laser thermotherapy for
      full-dynamic model are compared with the calculations from other models. RESULTS:
      Increased scattering in the near surface of applicator prevents light penetration
      into deeper region. Moreover, rise in temperature increases both blood flow at
      the periphery of coagulation region and thermal properties, which reduces the
      damage depth and its hysteresis. It results in a considerable overestimation of
      the temperature distribution and damage depth ignoring the dynamic of optical
      properties. The coagulation would be limited in a smaller region and there is no
      hysteresis if blood perfusion is regarded as a constant. In contrast, the
      hysteresis is overestimated if blood perfusion is ignored. Ignoring the dynamics
      of thermal parameters, there is also overestimation of the rise in temperature
      and damage depth. CONCLUSIONS: Mathematical modeling techniques that simulate
      laser coagulation may not provide reliable information unless they take into
      account these dynamic parameters.

PMID- 12430150
TI  - Sintering mechanism of the CaF2 on hydroxyapatite by a 10.6-l microm CO2 laser.
AB  - BACKGROUND AND OBJECTIVES: Laser has been reported as a heat source for melting
      and re-crystallization. Occurring at about 1100 degrees C, the melting of surface
      dental enamel along with re-crystallization might have an assistant role in the
      therapy of hypersensitive tooth, apical sealing of endodontic surgery in
      dentistry, preventive dentistry for pit and fissure sealing, and fluoridation.
      For laser to be accepted in clinical applications, it is desired that, studies
      must show the incorporation of CaF(2) into hydroxyapatite could reduce the
      sintering temperature for the sake of safety. STUDY DESIGN/MATERIALS AND METHODS:
      In this study, the Sharplan 20XJ CO(2) laser with 10.6- microm wavelength was set
      under the following parameters: power, 5 W; repetitive mode, 0.1 second; beam,
      focused. Fluorite was added to hydroxyapatite as a synthetic compound to lower
      the sintering temperature. Human dental enamel without caries was used for in
      vitro sintering test. Scanning electron microscopy (SEM), X-ray diffractometer
      (XRD), Fourier transforming infrared spectroscopy (FTIR), and differential
      thermal analysis/thermogravimetric analysis (DAT/TGA) were used for the
      investigation of sintering mechanism of CaF(2). RESULTS: Fusion between hexagonal
      shape crystals and cubic shape crystals (CaF(2)) were observed under SEM study.
      Hexagonal shape crystals indicated the formation of fluorapatite under XRD
      analysis. Under FTIR study, we examined reductions of water (3445 cm(-1)) and
      hydroxyl bands (3567 and 627 cm(-1)) in irradiated compounds. From the DTA
      pattern of synthetic compound, it showed the endothermic reaction reaching its
      peak point around 1180 +/- 20 degrees C. It was attributed to the phase
      transformation and/or initial melting. CONCLUSIONS: In this study, we proposed
      the interrelationship of the eutectics between initiator (CaF(2)) and the
      reaction product (calcium hydroxide) that reduced the sintering temperature. It
      appeared that the co-eutectics interacted to reduce the sintering temperature of
      hydroxyapatite below 800 degrees C and that the key eutectic was calcium
      hydroxide. The clinical feasibility of the melting and re-crystallization of
      hydroxyapatite under 10.6-microm CO(2) laser would be therefore enhanced.

PMID- 12430149
TI  - Ultrastructural analysis of bone tissue irradiated by Er:YAG Laser.
AB  - BACKGROUND AND OBJECTIVES: The use of erbium:yttrium aluminum garnet (Er:YAG)
      laser has been suggested for bone ablation, however, little is known about the
      nature of the tissue after irradiation. This study was aimed to analyze the
      ultrastructure of bone tissue treated with Er:YAG laser, as compared to those
      treated with CO(2) laser and bur drilling. STUDY DESIGN/MATERIALS AND METHODS:
      Parietal bones of Wistar rats were treated and analyzed by light microscopy,
      transmission electron microscopy (TEM), electron diffraction analysis and energy
      dispersive X-ray spectroscopy (SEM-EDX). RESULTS: This study demonstrated that
      Er:YAG laser irradiation resulted in a very thin changed layer of approximately
      30 microm thickness, which consisted of two distinct sub-layers: a superficial,
      greatly altered layer and a deep, less affected layer. CONCLUSIONS: The major
      changes found on bone surface after Er:YAG laser irradiation consisted of micro
      cracking, disorganization, and slight recrystallization of the original apatites
      and reduction of surrounding organic matrix.

PMID- 12430151
TI  - Tissue welding with biodegradable polymer films-demonstration of acute strength
      reinforcement in vivo.
AB  - BACKGROUND AND OBJECTIVES: To demonstrate, in vivo, acute strength reinforcement
      benefits of polymer film patches. STUDY DESIGN/MATERIALS AND METHODS: Full
      thickness incisions created in a dorsal skin flap of Sprague-Dawley rats were
      closed by laser-tissue welding: albumin solder was topically applied to the
      incision on the dermal surface, and a poly(lactic-co-glycolic acid) (PLGA)
      polymer film placed on the solder as a patch (controls had no film). Breaking
      strength was tested acutely (15-20 minutes after sacrifice). RESULTS: The patched
      incisions were statistically stronger than the controls (ANOVA, P < 0.05).
      CONCLUSIONS: Polymer film patches may be a viable method to increase acute
      breaking strengths of welds using topically applied solder.

PMID- 12430152
TI  - Effects of 810 nm laser irradiation on in vitro growth of bacteria: comparison of
      continuous wave and frequency modulated light.
AB  - BACKGROUND AND OBJECTIVES: Low intensity laser therapy may modify growth of wound
      bacteria, which could affect wound healing. This study compares the effects on
      bacteria of 810 nm laser using various delivery modes (continuous wave or
      frequency modulated light at 26, 292, 1000, or 3800 Hz). STUDY DESIGN/MATERIALS
      AND METHODS: Staphylococcus (S.) aureus, Escherichia (E.) coli, and Pseudomonas
      (P.) aeruginosa were plated on agar and then irradiated (0.015 W/cm(2); 1-50
      J/cm(2)) or used as controls (sham irradiated); growth was examined after 20
      hours of incubation post exposure. RESULTS: There were interactions of species
      and modulation frequency in the overall effects of irradiation (P = 0.0001), and
      in the radiant exposure mediated effects (P = 0.0001); thus individual
      frequencies and each bacterium were analysed separately. Bacteria increased
      following 3800 Hz (P = 0.0001) and 1000 Hz (P = 0.0001) pulsed irradiation; at
      particular radiant exposures P. aeruginosa proliferated significantly more than
      other bacteria. Pulsed laser at 292 and 26 Hz also produced species-dependent
      effects (P = 0.0001; P = 0.0005); however, the effects for different radiant
      exposures were not significant. Bacterial growth increased overall, independent
      of species, using continuous mode laser, significantly so at 1 J/cm(2) (P =
      0.02). Analysis of individual species demonstrated that laser-mediated growth of
      S. aureus and E. coli was dependent on pulse frequency; for S. aureus, however,
      there was no effect for different radiant exposures. Further tests to examine the
      radiant exposure effects on E. coli showed that growth increased at a frequency
      of 1000 Hz (2 J/cm(2); P = 0.03). P. aeruginosa growth increased up to 192% using
      pulsed irradiation at 1000-3800 Hz; whereas 26-292 Hz laser produced only a
      growth trend. CONCLUSIONS: The findings of this study point to the need for wound
      cultures prior to laser irradiation of infected wounds. Similar investigations
      using other common therapeutic wavelengths are recommended.

PMID- 12430153
TI  - Comparing the effectiveness of 585-nm vs 595-nm wavelength pulsed dye laser
      treatment of port wine stains in conjunction with cryogen spray cooling.
AB  - BACKGROUND AND OBJECTIVES: The objective of this study was to compare the
      efficacy and safety of cryogen spray cooled laser treatment (CSC-LT) at
      wavelengths of 585 nm vs. 595 nm for port wine stain (PWS) birthmarks in a large
      series of patients. STUDY DESIGN/MATERIALS AND METHODS: A retrospective review
      was conducted of 64 patients with PWS treated with the ScleroPLUS [Candela
      (Wayland, MA)] pulsed dye laser (lambda = 585 or 595 nm wavelength; spot size 7
      mm, tau(p) = 1,500 microseconds) over a 3-year period. Subjects' ages ranged
      between 3 months and 64 years; there were 42 females and 22 males, all of whom
      were Asian. Number of treatments ranged from 1 to 6. Duration of treatment ranged
      from 6 months to 2 years 11 months, with a mean of 12 months. Patients (n = 32)
      received CSC-LT (585 nm) using radiant exposures of 7-10 J/cm(2). A second group
      of patients (n = 32) received CSC-LT (595 nm) using radiant exposures of 7-10
      J/cm(2). The primary efficacy measurement was the quantitative assessment of
      blanching response scores for CSC-LT (585 nm) versus CSC-LT (595 nm). Patients
      were monitored for adverse effects. RESULTS: Based on chi-squared analysis, there
      were clinical, and statistically significant, differences in blanching response
      scores favoring PWS receiving CSC-LT (585 nm) as compared to CSC-LT (595 nm) (P
      <.001). Transient hyperpigmentation was noted in 43.7% (n = 14) and 37.5% (n =
      12) of patients in the CSC-LT (585 nm) and CSC-LT (595 nm) groups, respectively.
      In both groups, transient hyperpigmentation resolved in all patients within 1
      year. Permanent hypopigmentation or scarring was not observed in either group.
      CONCLUSIONS: CSC-LT (585 nm) resulted in superior blanching as compared to CSC-LT
      (595 nm). Further study is required to optimize wavelength selection on an
      individual patient basis during PWS therapy in order to improve treatment
      results.

PMID- 12430154
TI  - Evaluation of the long pulsed high fluence alexandrite laser therapy of leg
      telangiectasia.
AB  - BACKGROUND AND OBJECTIVES: The treatment of larger leg veins with laser or
      intense pulsed light often shows varying degrees of success and inconsistent
      clinical response rates. Aim of this study was to evaluate the effectiveness and
      safety of the 755 nm long pulsed high fluence alexandrite laser in the treatment
      of larger leg veins. STUDY DESIGN/MATERIALS AND METHODS: Twenty female volunteers
      aged 25-51 years (mean 39) with 0.3-1.3 mm leg telangiectasias received laser
      treatment, 10 of them with an additional pass done right after the first pass.
      Their skin type ranged from 1 to 3 (five type 1, seven type 2, eight type 3).
      After test spots with increasing fluences (40-90 J/cm(2)) to determine the
      individual safe fluence, the maximum fluence of 90 J/cm(2) could be used in all
      20 subjects. The spot size was 3 x 10 mm, a spray cooling system was used with 80
      milliseconds spray and delay time, respectively. The number of pulses
      administered ranged from 30 to 467 per subject (mean 139). The treated area was
      controlled 1 day, 1 month, and 3 months post-treatment and the side effects were
      quantified. At each visit, the treatment area was photographed. The percent
      clearance in the treated areas was scored by two observers. Subject satisfaction
      was evaluated at the 3 months post-treatment visit. RESULTS: After 3 months, in
      all 20 test subjects some clearance was visible. It ranged from low-grade to
      complete clearance. Most subjects (15 of 20) had a clearance between 26 and 75%.
      Hyperpigmentation was observed in 15 subjects. Hypopigmentation was seen in two
      subjects. No edema, no purpura, no erythema, no scarring, no blistering, and no
      crusts were observed. Mean subject satisfaction score was assessed and all
      volunteers reported to be "satisfied." CONCLUSIONS: The long pulsed high fluence
      alexandrite laser is effective and safe in the treatment of leg veins 0.3-1.3 mm
      in diameter.

PMID- 12430155
TI  - Evaluation of pulse-duration on purpuric threshold using extended pulse pulsed
      dye laser (cynosure V-star).
AB  - BACKGROUND AND OBJECTIVES: Pulsed dye lasers (PDL) with extended pulse-durations
      create new opportunities in the treatment of vascular lesions. Development of
      extended pulse methods requires understanding of tissue effects of extended pulse
      durations. We evaluated tissue effects of extended pulse-duration PDL (EPDL) with
      cooling. Effects of increasing pulse-duration, fluence, and multiple passes were
      evaluated to determine purpuric threshold and delayed purpuric response. STUDY
      DESIGN/PATIENTS AND METHODS: Ten patients were treated with EPDL and air-cooling
      on normal buttocks skin. Exposure pulse-durations of 0.5, 2, 20, and 40
      milliseconds and increasing fluences 3-20 J/cm(2), pulse-duration dependent.
      Exposures were evaluated 0.5, 1, and 24 or 48 hours determining purpuric
      threshold and side effects. RESULTS: Immediate purpuric threshold increased from
      6.2 to 8, 10.4, and 13.8 J/cm(2) at pulse-durations of 0.5, 2, 20, and 40
      milliseconds, respectively. Purpuric threshold dropped after 24 hours to 5.2,
      7.1, 9.3, and 11.9 J/cm(2), respectively. Multi-pass treatment lowered purpuric
      threshold by 1 J/cm(2). EPDL purpura resolved in less time than traditional PDL.
      No side effects were noted. CONCLUSIONS: EPDL exhibits increasing purpuric
      threshold with increasing pulse-durations, and risk of delayed onset of purpura.

PMID- 12430156
TI  - Laser-induced fluorescence spectroscopy for in vivo diagnosis of non-melanoma
      skin cancers.
AB  - BACKGROUND AND OBJECTIVES: Laser-induced fluorescence spectroscopy is a non
      invasive technique previously used for detection of cancer in a variety of organ
      systems. The objective of this study was to determine whether in vivo laser
      induced fluorescence spectroscopy alone at the visible excitation wavelength of
      410 nm could be used to detect non-melanoma skin cancers. STUDY DESIGN/MATERIALS
      AND METHODS: The system consisted of a nitrogen/dye laser tuned at 410 nm, an
      optical multichannel analyzer, and a fiber optic probe for excitation of tissue
      and collection of fluorescence emission. Two hundred and seventy nine
      measurements were performed from normal and abnormal tissues in 49 patients.
      Patients were classified as having either skin types I, II, or III. Biopsy of the
      abnormal tissues were then performed. Each measurement was assigned as either
      normal, basal cell carcinoma (BCC), squamous cell carcinoma (SCC), pre-cancerous,
      or benign. Total emission photon count was used as the discriminating index. A
      threshold value was calculated to separate normal tissue indices from indices of
      cancer tissues. The classification accuracy of each data point was determined
      using the threshold value. RESULTS: Cancers were classified 93, 89, and 78%
      correctly in patients with skin types I, II, and III, respectively. Normal
      tissues were classified 93, 88, and 50% correctly in patients with skin types I,
      II, and III, respectively. Using the same threshold, pre-cancerous spectra were
      classified 78 and 100% correctly in skin types I and III, respectively. Benign
      lesions were classified 100, 46, and 27% correctly in patient with skin types I,
      II, and III, respectively. CONCLUSIONS: In vivo laser induced fluorescence
      spectroscopy at 410 nm excitation and using the intensity of emission signal is
      effective for detection of BCC, SCC, and actinic keratosis, specially in patients
      with light colored skin.

PMID- 12430157
TI  - Effect of delay interval on classical eyeblink conditioning in 5-month-old human
      infants.
AB  - Associative learning was evaluated in human infants with simple delay classical
      eyeblink conditioning. A tone conditioned stimulus (CS) was paired with an
      airpuff unconditioned stimulus (US) at three different delay intervals (250, 650,
      and 1,250 ms). Independent groups of healthy, full-term 5-month-old human infants
      were assigned to these three paired conditions and received two identical
      training sessions 1 week apart. The two longer delays resulted in associative
      conditioning, as confirmed by comparison with unpaired control groups. However,
      only at the 650-ms delay were associative eyeblinks adaptively timed to avoid the
      airpuff. The delay function at 5 months of age appears much sharper than is
      observed in adults. Together with the findings of A. H. Little, L. P. Lipsitt,
      and C. Rovee-Collier (1984), the present study suggests a downward shift in the
      optimal delay interval for associative eyeblink conditioning between 1 and 6
      months of age. However, this delay remains longer than what is typically reported
      in adults.

PMID- 12430158
TI  - Ultrasonic vocalizations and maternal-infant interactions in a rat model of fetal
      alcohol syndrome.
AB  - When isolated from their dams and littermates, rat pups emit ultrasonic
      vocalizations to elicit attention and retrieval from their dams. This study
      examined the effects of perinatal alcohol exposure on ultrasonic vocalizations
      and maternal-infant interactions. Alcohol was administered throughout gestation
      to the dams and during the early postnatal period to the pups. Control groups
      consisted of a nontreated control and an intubated, pair-fed control. Ultrasonic
      vocalizations were measured on postnatal day (PD) 5 under varying conditions of
      isolation. Maternal behaviors were examined on PD2, 4, 6, 8, and 10. Maternal
      behaviors were not significantly affected by prior alcohol administration to
      either the dams or the pups. However, ethanol-exposed rat pups vocalized more on
      PD5 than controls regardless of condition. The heightened vocalization response
      of the ethanol-exposed pups might be an underlying factor in the persistent
      effects of perinatal ethanol exposure on social behavior.

PMID- 12430159
TI  - Intersensory redundancy facilitates discrimination of tempo in 3-month-old
      infants.
AB  - L. Bahrick and R. Lickliter (2000) proposed an intersensory redundancy hypothesis
      that states that information presented redundantly and in temporal synchrony
      across two or more sensory modalities selectively recruits infant attention and
      facilitates perceptual learning more effectively than does the same information
      presented unimodally. In support of this view, they found that 5-month-old
      infants were able to differentiate between two complex rhythms when they were
      presented bimodally, but not unimodally. The present study extended our test of
      the intersensory redundancy hypothesis to younger infants and to a different
      amodal property. Three-month-olds' sensitivity to the amodal property of tempo
      was investigated. Results replicated and extended those of Bahrick and Lickliter,
      demonstrating that infants could discriminate a change in tempo following
      bimodal, but not unimodal, habituation. It appears that when infants are first
      learning to differentiate an amodal stimulus property, discrimination is
      facilitated by intersensory redundancy and attenuated under conditions of
      unimodal stimulation.

PMID- 12430160
TI  - Effects of maternal style on infant behavior in Japanese macaques (Macaca
      fuscata).
AB  - We assessed the association of maternal style and infant behavior of group-living
      Japanese macaques during the first year of infant development. We tested the
      hypothesis that different mothering styles were correlated with the behavioral
      repertoire of infants at three different developmental stages. We expected that
      infants of rejecting mothers would show a higher level of enterprise and that
      infants of protective mothers would be less interested in the external
      environment. We found evidence that maternal style affects infant behavior during
      the early developmental phase, but this influence becomes smaller as the infant
      grows older and approaches complete independence. Maternal protectiveness appears
      to have long-lasting effects on infant exploration as infants of protective
      mothers tended to be less attracted by the external environment. On the other
      hand, mater- nal rejection appears to have long-lasting effects on infant
      interaction with other group members as more rejected infants tended to initiate
      a significantly higher number of contacts with other juveniles and adults. These
      results suggest that both maternal rejection and maternal protectiveness play an
      important role in the independence of the offspring, in opposite directions. That
      is, rejection promotes independence whereas protectiveness delays it.

PMID- 12430161
TI  - Effects of pre- and postnatal stimulation on developmental, emotional, and
      cognitive aspects in rodents: a review.
AB  - Interactions between the organism and its environment, during pregnancy as well
      as during the postnatal period, can lead to important neurobehavioral changes. We
      briefly review the literature, and successively present the main results from our
      laboratory concerning the behavioral effects of prenatal stress, differential
      rearing conditions, and postnatal handling. We show that submitting primiparous
      DA/HAN rats to an acute emotional stress (exposure to a cat) at gestational
      day10, 14, or 19 leads to greatly increased mortality of pups and to decreased
      body weight of surviving animals. The effects of such a stressor on emotional
      reactivity are less obvious. Cognitive processes are impaired depending on the
      learning task. Enriched environments restore abnormal behaviors (emotional
      reactivity, motor skills, motor and spatial learning) due to brain trauma or
      genetic deficiencies. In any case, environmental enrichment does prevent or slow
      down aging effects. The effects of postnatal handling noted when using classical
      tests of emotional reactivity also are clear when defensive reaction paradigms
      are used. Furthermore, pregnant females that are early handled are less anxious
      than nonhandled females. We hypothesize that, when subjected to a stressor, the
      offspring of early-handled females would be protected from the deleterious
      effects of this stress compared to pups of nonhandled females.

PMID- 12430162
TI  - Sweet and sour preferences during childhood: role of early experiences.
AB  - We investigated the effects of early experience on sweet and sour preferences in
      children. Eighty-three children were divided into four groups based on the type
      of formula fed during infancy and age. By using a forced-choice, sip-and-swallow
      procedure, we determined the level of sweetness and sourness preferred in juice.
      Children who were fed protein hydrolysate formulas, which have a distinctive sour
      and bitter taste and unpleasant odor, preferred higher levels of citric acid in
      juice when compared to older children who were fed similar formulas. No such
      difference was observed between the groups for sweet preference. However, the
      level of sweetness preferred in juice was related to the sugar content of the
      child's favorite cereal and whether the mother routinely added sugar to their
      foods. These data illustrate the wide variety of experiential factors that can
      influence flavor preferences during childhood.

PMID- 12430163
TI  - Fetal activity following stimulation of the mother's abdomen, feet, and hands.
AB  - Fetal activity during midgestation (M age=19.8 weeks) was studied in response to
      vibratory stimulation of the mother's abdomen (at the height of the fetal head),
      foot massage, hand massage, or control condition (no stimulation). Consistent
      with previous research conducted during midgestation, the fetuses of mothers who
      received two trials of 3-sec, 60-Hz vibratory stimulation did not show changes in
      movement. In contrast, the fetuses of mothers who received a 3-min foot massage
      showed greater movement than the control fetuses. However, stimulating the
      mother's hand (another highly innervated area) did not increase fetal activity.
      By late gestation (M age=35.4 weeks), vibratory stimulation resulted in increased
      fetal activity. These findings replicate previous research indicating that
      vibratory stimulation to the mother's abdomen does not elicit fetal activity
      until later in gestation. Furthermore, our findings indicate that stimulating the
      mothers' feet, but not the hands, can evoke fetal activity in midgestation.

PMID- 12430165
TI  - Mineral-related proteins of sea urchin teeth: Lytechinus variegatus.
AB  - Sea urchins have a set of five continuously growing teeth, each of which has a
      very complex structure. The mineral phase is calcite of varying Mg content,
      depending on the location within a tooth. The calcium carbonate is present in
      amorphous, plate-like and rod-like forms. It has been hypothesized that the
      mineral deposition is a matrix-mediated process, similar to that in vertebrate
      bone and tooth, wherein certain macromolecules within the organic matrix of the
      mineralized tissue play an important role in nucleating and controlling the
      growth habit of the mineral crystals. It has also been hypothesized that the
      mineral-related macromolecules involved in urchin teeth might bear a direct
      evolutionary relationship to those of the vertebrate tooth. These hypotheses are
      explored here by examining the pattern and nature of the mineral distribution,
      using microCT of intact teeth, and the nature of the mineral-related matrix
      proteins. The mineral-related proteins were extracted and fractionated by anion
      exchange chromatography. The relationship of certain fractions to vertebrate
      matrix proteins was established by immunoblots using antibodies to vertebrate
      tooth proteins. The antibodies were then used to localize the proteins within the
      teeth, by immunocytochemistry and histology with specific staining. The microCT
      data on mineral density has been correlated with the patterns of cellular
      migration and mineral deposition within the tooth as it grows. It appears that
      the mineralization within the different tooth compartments might take place under
      the influence of different matrix proteins. Further studies are in progress to
      more completely describe the vertebrate-invertebrate immunologically cross
      reactive proteins of the urchin teeth.

PMID- 12430166
TI  - Origin and early evolution of vertebrate skeletonization.
AB  - Data from living and extinct faunas of primitive vertebrates imply very different
      scenarios for the origin and evolution of the dermal and oral skeletal
      developmental system. A direct reading of the evolutionary relationships of
      living primitive vertebrates implies that the dermal scales, teeth, and jaws
      arose synchronously with a cohort of other characters that could be considered
      unique to jawed vertebrates: the dermoskeleton is primitively composed of
      numerous scales, each derived from an individual dental papilla; teeth are
      primitively patterned such that they are replaced in a classical conveyor-belt
      system. The paleontological record provides a unique but complementary
      perspective in that: 1) the organisms in which the skeletal system evolved are
      extinct and we have no recourse but to fossils if we aim to address this problem;
      2) extinct organisms can be classified among, and in the same way as, living
      relatives; 3) a holistic approach to the incorporation of all data provides a
      more complete perspective on early vertebrate evolution. This combined approach
      is of no greater significance than in dealing with the origin of the skeleton
      and, combined with recent discoveries and new phylogenetic analyses, we have been
      able to test and reject existing hypotheses for the origin of the skeleton and
      erect a new model in their place.

PMID- 12430167
TI  - Membranes, minerals, and proteins of developing vertebrate enamel.
AB  - Developing tooth enamel is formed as organized mineral in a specialized protein
      matrix. In order to analyze patterns of enamel mineralization and enamel protein
      expression in species representative of the main extant vertebrate lineages, we
      investigated developing teeth in a chondrichthyan, the horn shark, a teleost, the
      guppy, a urodele amphibian, the Mexican axolotl, an anuran amphibian, the leopard
      frog, two lepidosauria, a gecko and an iguana, and two mammals, a marsupial, the
      South American short-tailed gray opossum, and the house mouse. Electron
      microscopic analysis documented the presence of a distinct basal lamina in all
      species investigated. Subsequent stages of enamel biomineralization featured
      highly organized long and parallel enamel crystals in mammals, lepidosaurians,
      the frog, and the shark, while amorphous mineral deposits and/or randomly
      oriented crystals were observed in the guppy and the axolotl. In situ
      hybridization using a full-length mouse probe for amelogenin mRNA resulted in
      amelogenin specific signals in mouse, opossum, gecko, frog, axolotl, and shark.
      Using immunohistochemistry, amelogenin and tuftelin enamel proteins were detected
      in the enamel organ of many species investigated, but tuftelin epitopes were also
      found in other tissues. The anti-M179 antibody, however, did not react with the
      guppy and axolotl enameloid matrix. We conclude that basic features of vertebrate
      enamel/enameloid formation such as the presence of enamel proteins or the mineral
      deposition along the dentin-enamel junction were highly conserved in vertebrates.
      There were also differences in terms of enamel protein distribution and mineral
      organization between the vertebrates lineages. Our findings indicated a
      correlation between the presence of amelogenins and the presence of long and
      parallel hydroxyapatite crystals in tetrapods and shark.

PMID- 12430168
TI  - Mineralization patterns in elasmobranch fish.
AB  - This article reviews current findings on the organic matrix and the
      mineralization patterns in elasmobranchs, including an analysis of the role of
      the dental epithelial cells and the odontoblasts during odontogenesis. Our
      electron micrographs demonstrated that tubular vesicles limited by a unit
      membrane occupied the bulk of the elasmobranch enameloid matrix during the stage
      of enameloid matrix formation. It is likely that the tubular vesicles originated
      from the odontoblast processes. Two types of electron-dense fibrils, with cross
      striations at intervals of approximately either 17 nm or 55 nm, respectively,
      were detected in the enameloid matrix. These data suggest that odontoblasts were
      strongly involved in enameloid matrix formation and in initial enameloid
      mineralization. Two types of odontoblasts, dark and light cells, were recognized
      during the stage of dentinogenesis. The light cells contained numerous
      mitochondria, intermediate filaments, and microtubules that extended their
      processes into the dentin. The dark cells possessed a well-developed Golgi
      apparatus and many cisternae in the rough endoplasmic reticulum, which suggests
      that the dark cells are involved in the formation of dentin. The inner dental
      epithelial (IDE) cells exhibited a well-developed Golgi apparatus, many
      mitochondria, cisternae of smooth endoplasmic reticulum, vesicles, vacuoles, and
      granules during the mineralization and maturation stages. During the stages of
      mineralization and early maturation, ACPase-positive granules were visible in the
      IDE cells and ALPase and Ca-ATPase activities were found at the lateral and
      proximal cell membrane of the IDE cells, suggesting that the IDE cells are
      involved in the removal of enameloid organic matrix and in the process of
      mineralization during later stages of enameloid formation. Our data indicate that
      elasmobranch enameloid is distinct from teleost enameloid, based on its organic
      content, on the mechanisms of its mineralization, and on the role of IDE cells
      concerning enameloid formation.

PMID- 12430169
TI  - First-generation teeth in nonmammalian lineages: evidence for a conserved
      ancestral character?
AB  - The present study focuses on the main characteristics of first-generation teeth
      (i.e., the first teeth of the dentition to develop in a given position and to
      become functional) in representatives of the major lineages of nonmammalian
      vertebrates (chondrichthyans, actinopterygians, and sarcopterygians: dipnoans,
      urodeles, squamates, and crocodiles). Comparative investigations on the LM and
      TEM level reveal the existence of two major types of first-generation teeth. One
      type (generalized Type 1) is characterized by its small size, conical shape,
      atubular dentine, and small pulp cavity without capillaries and blood vessels.
      This type is found in actinopterygians, dipnoans, and urodeles and coincides with
      the occurrence of short embryonic periods in these species. The other type
      assembles a variety of first-generation teeth, which have in common that they
      represent miniature versions of adult teeth. They are generally larger than the
      first type, have more complex shapes, tubular dentine, and a large pulp cavity
      containing blood vessels. These teeth are found in chondrichtyans, squamates, and
      crocodiles, taxa which all share an extended embryonic period. The presence in
      certain taxa of a particular type of first-generation teeth is neither linked to
      their phylogenetic relationships nor to adult body size or tooth structure, but
      relates to the duration of embryonic development. Given that the plesiomorphic
      state in vertebrates is a short embryonic development, we consider the
      generalized Type 1 first-generation tooth to represent an ancestral character for
      gnathostomes. We hypothesize that an extended embryonic development leads to the
      suppression of tooth generations in the development of dentition. These may still
      be present in the form of rudimentary germs in the embryonic period. In our view,
      this generalized Type 1 first-generation teeth has been conserved through
      evolution because it represents a very economic and efficient way of building
      small and simple teeth adapted to larval life. The highly adapted adult dentition
      characteristic for each lineage has been possible only through polyphyodonty.

PMID- 12430170
TI  - Unique dentition of lungfish.
AB  - Lungfish are a group of ancient fish, represented almost continuously in the
      fossil record from their first appearance in the Devonian to the present time.
      They have numerous unique characters in the dentition, found only among lungfish,
      as well as some that are shared with other groups of fish and with higher
      vertebrates, such as a thin layer of true enamel, instead of the enameloid found
      in the dentition of most fish. Unique characters include the diversity of forms
      of dentine in the tooth plates, as well as the organisation of the dentines and
      the unusual mode of continuous growth of the dentition. Their enamel is based on
      amelogenin formed by the ameloblasts of the dental lamina, and is mineralised by
      long crystals of calcium hydroxyapatite deposited in layers over the developing
      tooth. The different forms of dentine, which show progressive evolutionary change
      within the group, are based on an extracellular matrix of collagen, mineralised
      with calcium hydroxapatite of variable crystalline form. Cells that line the oral
      cavity produce the ameloblasts that are endodermal in origin, and cells that form
      the dental papillae are, like the other cells that secrete skeletal tissues,
      derived from head mesoderm, as in other vertebrates. Unique to all dipnoans is
      the fusion of the dental tissues to the underlying bone and the way in which
      bone, included within the tooth plate, remodels to permit growth in the whole
      dentition.

PMID- 12430171
TI  - Caiman periodontium as an intermediate between basal vertebrate ankylosis-type
      attachment and mammalian "true" periodontium.
AB  - The teeth of many fish, amphibia, and reptiles are attached to the alveolar bone
      via ankylosis. In contrast, mammalian periodontia are characterized by a
      gomphosis, an attachment of the tooth root in the alveolar bone socket via
      periodontal ligament fibers. Among the reptiles, the crocodilians are the only
      group featuring a gomphosis-type connection between tooth root and alveolar bone,
      while in other reptiles tooth-root and jawbone are connected via ankylosis. The
      purpose of the present study was to compare several key features of the
      crocodilian periodontium with those of the mammalian and noncrocodilian reptile
      periodontium. As experimental models for our study we chose the periodontium of
      newborn geckos (Hemidacylus turcicus), juvenile caimans (Caiman crocodilus
      crocodilus), and 10-day-postnatal Swiss-Webster mice (Mus musculus) as
      representative models for noncrocodilian reptiles, crocodilian reptiles, and
      mammals. The caiman periodontium emerged as an intermediary between the mineral
      free mouse ligament and the mineralized gecko ankylosis-type attachment. Caiman
      ligament fibers were less organized than mouse ligament fibers but featured
      distinct fasciae surrounding ligament fiber bundles. Caiman Hertwig's epithelial
      root sheath (HERS) was similarly perforated as mouse HERS and distinctly
      different from the continuous gecko HERS. Both caiman and mouse HERS covered the
      entire tooth root length, while in the gecko HERS was limited to the coronal
      portion of the root, allowing for cementoid-mediated ankylosis at the apical tip
      of the root. We interpret our data to indicate distinct differences in mineral
      distribution, periodontal ligament fiber organization, and HERS distribution
      between noncrocodilian reptiles, crocodilian reptiles, and mammals. Mineral
      deposits in the caiman ligament may reflect an evolutionary position of the
      caiman periodontium between ankylosis and gomphosis.

PMID- 12430172
TI  - Abstracts of the Dutch Society for Clinical Pharmacology and Biopharmacy. 8
      October 2001.

PMID- 12430173
TI  - Rel/NF-kappa B/I kappa B signal transduction in the generation and treatment of
      human cancer.
AB  - The Rel/NF-kappa B family is a group of structurally-related, tightly-regulated
      transcription factors that control the expression of a multitude of genes
      involved in key cellular and organismal processes. The Rel/NF-kappa B signal
      transduction pathway is misregulated in a variety of human cancers, especially
      ones of lymphoid cell origin, due either to genetic changes (such as chromosomal
      rearrangements, amplifications, and mutations) or to chronic activation of the
      pathway by epigenetic mechanisms. Constitutive activation of the Rel/NF-kappa B
      pathway can contribute to the oncogenic state in several ways, for example, by
      driving proliferation, by enhancing cell survival, or by promoting angiogenesis
      or metastasis. In many cases, inhibition of Rel/NF-kappa B activity reverses all
      or part of the malignant state. Thus, the Rel/NF-kappa B pathway has received
      much attention as a focal point for clinical intervention.

PMID- 12430174
TI  - Down-regulation of human papillomavirus E6/E7 oncogene by arsenic trioxide in
      cervical carcinoma cells.
AB  - Arsenic trioxide (As2O3) has been implicated as a promising anticancer agent for
      treatment of many cancers including acute promylocytic leukemia. However, the
      molecular mechanisms are not yet fully defined in solid tumor cells, especially
      cervical cancer cells carrying human papillomavirus (HPV) genome. To analyze
      detailed mechanisms in vitro, we treated As2O3 to transformed HeLa cells, a well
      studied cervical cancer cell line carrying HPV-18 sequence, and investigated its
      antiproliferative, antiviral and antimetastatic effects. As2O3 reduced survival
      and growth of HeLa cells in a dose- and time-dependent manner. Several
      indicatives of apoptosis were demonstrated by DNA fragmentation assay, DAPI
      nuclear staining and FACS analysis, respectively. Protein levels of p53 and
      cleavage of poly(ADP)-ribose polymerase were increased in a dose-dependent manner
      following treatment of As2O3. In parallel, semi-quantitative reverse
      transcription-polymerase chain reaction showed that the treatment inhibited HPV
      18 E6/E7 viral gene expression in HeLa cells. Using transient transfection and
      CAT ELISA, we also found that AP-1 sites, located proximal to HPV-18 upstream
      regulatory region (URR) promoter, could be the major target sites for As2O3.
      Furthermore, As2O3-treated HeLa cells showed lesser capacity of invasion than
      those of untreated cells by in vitro invasion assay. Taken together, we proposed
      that antiviral effect, i.e. down-regulation of HPV E6/E7 oncogenes through
      targeting for AP-1 sites located in HPV URR might be associated with
      antiproliferative effect, i.e. induction of apoptosis as be resulted from the
      accumulation of p53, and that antimetastatic effect could be due to the targeted
      inactivation of AP-1, a transcription factor required for the expression of MMP-1
      and -3. Therefore, our finding may provide a logical basis for the development of
      a new agent treating HPV-associated cervical neoplasia.

PMID- 12430175
TI  - Antigen levels of the urokinase-type plasminogen activator and its gene
      polymorphisms in colorectal cancer.
AB  - We analysed the distribution of genotypes of two polymorphisms in the urokinase
      type plasminogen activator (uPA) gene: C-->T substitution in exon 6 and T-->C
      substitution in intron 7 in 52 subjects with colorectal cancer. Genotypes were
      determined in tumour tissue and distant mucosa samples by allele-specific
      polymerase chain reaction. The antigen levels of uPA in cancer tissue were higher
      than in distant mucosa as measured by enzyme-linked immunosorbent assay. The
      level of uPA antigens in cancer samples with the C/C genotype of C-->T
      polymorphism in exon 6 was higher than in samples with C/T and T/T genotypes. No
      differences in the level of uPA antigens between the alleles of the intron 7 T-
      >C polymorphism were found. As uPA can be involved in cancer invasion and
      metastasis, C/C genotype in exon 6 of uPA gene can be further considered as being
      related to colorectal cancer progression.

PMID- 12430176
TI  - Cytotoxicity and cellular differentiation activity of methylenebis(phosphonate)
      analogs of tiazofurin and mycophenolic acid adenine dinucleotide in human cancer
      cell lines.
AB  - Mycophenolic acid (MPA) is a fungally-derived inhibitor of inosine 5'
      monophosphate dehydrogenase (IMPDH). MPA binds IMPDH at the nicotinamide sub-site
      of the NAD cofactor binding domain leaving the adenosine sub-site empty. In order
      to improve the binding affinity we synthesized MPA analogs by linking adenosine
      5'-methylenebis(phosphonate) with mycophenolic alcohols containing 2-, 4-, and 6
      carbon atoms in their aliphatic side chain. Adenine dinucleotide analogs of
      tiazofurin, selenazofurin and benzamide riboside were synthesized as P1, P2
      disubstituted pyrophosphates. Cytotoxicity of each analog was examined in human
      colon adenocarcinoma HT-29 and erythroleukemia K562 cells, and induction of
      differentiation in K562 cells by these agents was determined. Mycophenolic acid
      is currently used as an immunosuppressant but its anticancer action is limited by
      inactivation due to rapid glucuronidation. The new analogs show resistance to
      metabolism to inactive species and exhibit enhanced cytotoxicity in tumor cell
      lines, and therefore could be useful as anticancer agents.

PMID- 12430177
TI  - Effects of FK317, a novel anti-cancer agent, on survival of mice bearing B16BL6
      melanoma and Lewis lung carcinoma.
AB  - The effects of FK317 (11-acetyl-8-carbamoyloxymethyl-4-formyl-6-methoxy-14- oxa
      1,11-diazatraacylo[7.4.1.0(2.7).0(10.2)]-tetradeca-2,4,6-trien-9-yl acetate), a
      novel anti-cancer agent, and mitomycin C (MMC) on survival time of mice bearing
      B16BL6 melanoma and Lewis lung carcinoma (LLC), induced by intravenous
      inoculation of the tumor, were investigated. Treatment with FK317 resulted in a
      significant prolongation of survival time in both tumor models. Four of ten mice
      bearing B16BL6 were disease-free following FK317 treatment. In contrast, MMC was
      not effective in prolonging survival time. Overall, this study demonstrated that
      FK317 shows more potent survival extension in mice bearing B16BL6 and LLC than
      MMC, suggesting that FK317 may have therapeutic utility for cancer chemotherapy.

PMID- 12430178
TI  - Inhibition of progesterone-induced VEGF production in human breast cancer cells
      by the pure antiestrogen ICI 182,780.
AB  - The 'pure' antiestrogen ICI 182,780 (Faslodex) is in clinical trials for
      treatment of human breast cancer. Recently, we showed that ICI 182,780 exhibits a
      novel antiprogestin activity in transient transfection assays in the total
      absence of estrogen receptors. In this work, we determined if ICI 182,780
      displays antiprogestin activity for an endogenous progesterone responsive gene.
      For this purpose, we examined the effect of ICI 182,780 on progestin induction of
      a potent angiogenic growth factor, vascular endothelial growth factor (VEGF), in
      T47-D human breast cancer cells. ICI 182,780 blocks the progestin induction of
      VEGF at both the mRNA and protein levels in T47-D cells. The antihormone does not
      block progestin binding to the progesterone receptor (PR), nor does it enhance
      the down regulation of the endogenous PR in cells that occurs upon progestin
      exposure. These results establish that ICI 182,780, generally considered to be a
      highly selective antiestrogen, displays antiprogestin activity for an endogenous
      progestin-regulated gene. These observations raise the possibility that an
      antiprogestin activity of ICI 182,780 may contribute to the antitumor activity in
      a subset of human breast cancers similar to T47-D cells, by inhibiting
      angiogenesis secondary to blockade of VEGF induction.

PMID- 12430179
TI  - Synthesis and characterization of novel ceramide analogs for induction of
      apoptosis in human cancer cells.
AB  - A variety of anti-cancer drugs elevate endogenous ceramide, thereby inducing
      apoptosis in tumor cells. Recently, we have introduced novel ceramide analogs of
      the beta-hydroxy alkyl amide type, which trigger pro-apoptotic signaling pathways
      without prior elevation of endogenous ceramide. They induce apoptosis
      specifically in rapidly dividing neuroblastoma cells, but not in resting or
      differentiated cells. We characterize new ceramide mimics that have been derived
      from N-acylation of serinol (S), diethanolamine (B), propanolamine (P), and
      tris(hydroxy-methyl)methylamine (T) with myristic (14), palmitic (16), or oleic
      (18) acid. The water solubility of these compounds exceeds that of ceramide by
      more than 100-fold (up to 5 mM). Apoptosis of human neuroblastoma, glioma,
      medulloblastoma, and adenocarcinoma cells is induced by N-(2-hydroxy-1
      (hydroxymethyl)ethyl)-palmitoylamide, C16-serinol (S16), N-(2-hydroxy-1
      (hydroxymethyl)ethyl)-oleoylamide, C18-serinol (S18), N-bis(2-hydroxyethyl)
      myristoyl-amide (B16), and N-tris(hydroxymethyl)methyl-oleoylamide (T18) within
      60 min of incubation, and is completed even after removal of the compound from
      the medium. This is most likely due to a rapid uptake of the analogs followed by
      their slow release from the cells. Alteration of the acyl chain length to less
      than 14 methylene units, removal of the amino group, or reducing the number of
      hydroxyalkyl residues to less than two significantly lowers or eliminates the pro
      apoptotic potential of these compounds. The target specificity of novel ceramide
      analogs for tumor cells, their water solubility, and fast pro-apoptotic mechanism
      indicates a high therapeutic potential for cancer treatment.

PMID- 12430180
TI  - Folate and breast cancer: the role of polymorphisms in methylenetetrahydrofolate
      reductase (MTHFR).
AB  - Evidence is growing that low folate status may be a factor in the aetiology of
      several cancers, including breast cancer. The methylenetetrahydrofolate reductase
      gene (MTHFR), which has a key role in folate metabolism, is polymorphic. We
      report a case-control study of two functional polymorphisms in MTHFR, dietary
      folate intake and breast cancer. Sixty-two cases with invasive breast cancer and
      sixty-six general practice controls participated. Women reporting the highest
      dietary folate intake had non-significantly reduced breast cancer risk (odds
      ratio (OR) = 0.49, 95% confidence interval (CI) 0.20-1.20). Risk was
      significantly lower for the 1298CC genotype compared to AA (OR = 0.24, 95% CI
      0.06-0.97). Relative to compound wild-type subjects, compound heterozygotes had
      moderately reduced risk (OR = 0.47, 95% CI 0.11-1.92) and homozygote variants
      (677TT and/or 1298CC) greater reduced risk (OR = 0.26, 95% CI 0.07-0.96); the
      trend was statistically significant. Patterns in risk with regard to genotype and
      folate combinations are broadly similar those reported for colorectal neoplasia.
      The roles of MTHFR and folate in breast cancer aetiology are likely to be
      complex.

PMID- 12430181
TI  - GSTT1 null genotype increases risk of premenopausal breast cancer.
AB  - The NAT2, GSTM1 and GSTT1 genes are known candidate cancer susceptibility markers
      and have been investigated in breast cancer susceptibility with conflicting
      results. We conducted a case-control study to investigate the role of NAT2, GSTM1
      and GSTT1 in premenopausal breast cancer. Women with the GSTT1 null genotype were
      found to have a significant 3.15-fold increased risk of breast cancer (95% CI =
      1.7-5.8), while GSTM1 and NAT2 genotypes were not associated with breast cancer
      risk. Our results suggest that the GSTT1 null genotype may play a role in early
      onset breast cancer.

PMID- 12430182
TI  - No associations of p73 G4C14-to-A4T14 at exon 2 and p53 Arg72Pro polymorphisms
      with the risk of digestive tract cancers in Japanese.
AB  - A case-control study was conducted to examine the possible association between
      digestive tract cancers and p73 G4C14-to-A4T14 at exon 2 and p53 Arg72Pro
      polymorphisms in Japanese. Cases were 102 esophageal cancer patients, 144 stomach
      cancer patients, and 147 colorectal cancer patients, and controls were 241 non
      cancer outpatients. The genotype frequencies among controls were 55.3% for p73 GG
      at position 4, 40.4% for GA, and 4.3% for AA, and 37.7% for p53 ArgArg, 44.4% for
      ArgPro, and 18.0% for ProPro. No significant differences in the genotype
      frequencies were observed between the controls and each case group or cases as a
      whole.

PMID- 12430184
TI  - Proteomics reveals protein profile changes in doxorubicin--treated MCF-7 human
      breast cancer cells.
AB  - MCF-7 cells are extensively used as a cell model to investigate human breast
      tumors and the cellular mechanism of antitumor drugs such as doxorubicin (DOX),
      an anthracycline antitumor drug widely used in clinical chemotherapy. To
      understand the effects of DOX on the protein expression, we perform a
      comprehensive proteomics to survey global changes in proteins after DOX treatment
      in MCF-7 cells. Exposure of MCF-7 cells to 0.1 microM DOX for 2 days induced a
      differentiation-like phenotype with prominent perinuclear autocatalytic vacuoles,
      abundant filamentous material, and irregular microvilli at the cell surface. In
      this study, we also present a proteome reference map of MCF-7 cells with 21
      identified protein spots via analysis of N-terminal sequencing, mass
      spectrometry, immunoblot and/or computer matching with protein database. Based on
      the proteome map, we found that DOX causes a markedly decrease in the levels of
      three isoforms of heat shock protein 27 (HSP27) whereas the levels of other
      stress associated proteins including HSP60, calreticulin, and protein disulfide
      isomerase were not significantly altered in DOX-treated MCF-7 cells. Taken
      together, we suggest that that action of DOX on breast tumor cells may be partly
      related to dysregulation of HSP27 expression. Modulation of HSP27 levels may be a
      clinically useful potential target for design of antitumor drugs and controlling
      breast tumor growth.

PMID- 12430183
TI  - Phosphorylation of O6-alkylguanine-DNA alkyltransferase: experience with a GST
      fusion protein and a new pull-down assay.
AB  - We showed recently that human O6-alkylguanine-DNA alkyltransferase (AGT), a key
      target for enhancing the efficacy of anticancer alkylating agents, is regulated
      by phosphorylation in brain tumor cells. This report describes the problems we
      encountered in using a glutathione S-transferase (GST)-tagged AGT as the
      substrate in our search for cellular AGT kinases, validation of a new pull-down
      assay for AGT phosphorylation, and its wide applicability for quantitating
      protein kinases in crude extracts and purified fractions. The GST-tag present in
      the fusion protein, by itself, was found to undergo significant phosphorylation
      by tumor cell extracts and contribute to spurious results. Instead, we used a
      histidine-tagged AGT protein, and its micro-scale purification with Talon resin
      as the basis for a quantitative pull-down assay, and applied it for measuring AGT
      phosphorylation by protein kinase C (PKC) and other cellular kinases. The pull
      down procedure can be easily adopted for quantitating protein kinases in a
      variety of settings, as it overcomes the need for substrate immunoprecipitation
      when whole cell extracts are used, and eliminates the autophosphorylated kinase
      proteins, when purified kinases are used. Our observations call for caution in
      interpreting the results with GST-fusion proteins in phosphorylation studies.

PMID- 12430185
TI  - Substitution of arginine for cysteine 643 of the glucocorticoid receptor reduces
      its steroid-binding affinity and transcriptional activity.
AB  - To investigate the mechanism for glucocorticoid resistance in leukemic cells, we
      sequenced the coding region of glucocorticoid receptor (GR) gene in ten Japanese
      leukemic cells. We identified a novel heterozygous mutation (C643R) in the ligand
      binding domain in P30/OHK cells. Western blot analysis for COS-7 cells
      transfected with the wild-type or C643R mutant GR plasmid revealed similar
      protein expression levels. In the ligand-binding assay, the dissociation constant
      of the C643R GR was six-fold higher than that of the wild-type GR. Moreover, the
      C643R GR showed no transcriptional activity in the luciferase reporter assay.

PMID- 12430186
TI  - Frameshift mutations in the MBD4/MED1 gene in primary gastric cancer with high
      frequency microsatellite instability.
AB  - MBD4/MED1 is a newly identified mismatch repair gene, which is mutated in colon,
      endometrial, and pancreatic high-frequency microsatellite instability (MSI-H)
      tumors. To assess its role in gastric cancers, we investigated MBD4/MED1
      mutations in sporadic gastric cancers, compared with colon cancers. Frameshift
      mutations were found in 29% of gastric and 20% of colon MSI-H cancers, but not in
      any low-frequency microsatellite instability/microsatellite stable cancers.
      MBD4/MED1 is mutated in gastric cancers as frequently as in colon cancers; these
      mutations reduce the accuracy of DNA repair, and may lead to cancer progression.

PMID- 12430187
TI  - Compassion, prejudice and mental health nursing.

PMID- 12430188
TI  - What happens when people disclose sexual or physical abuse to staff at a
      community mental health centre?
AB  - The files of 200 users of a community mental health centre revealed that 46% of
      the files contained documentation of sexual or physical abuse as children or
      adults. Only 36% of summary formulations and 33% of treatment plans for the
      abused clients mentioned the abuse. Only 22% of the abused clients received abuse
      focused therapy. Response rates were lower for clients who were male or had a
      schizophrenia spectrum diagnosis, and if the clinician was male or a
      psychiatrist. None of the alleged crimes, past, recent or ongoing, was reported
      to legal authorities. Development of unit policies and training programmes to
      ensure appropriate response to abuse histories is recommended.

PMID- 12430189
TI  - The influence of evil on forensic clinical practice.
AB  - As the medicalization of criminal behaviour expands through forensic psychiatric
      practice it is reliant upon a therapeutic ideology based on clinical assessment
      and effective application of treatment strategies. When such criminal offenses
      are particularly heinous the perpetrators are often referred to as evil by non
      professional accounts. However, the extent to which the concept of evil affects
      the perceptions of mental health professionals working with such offenders is
      little understood. This paper reports on research conducted in a high-security
      psychiatric hospital in the North-west of England and examines the construction
      of care plans in relation to a number of mentally disordered offenders who are
      considered by a group of mental health professionals as evil. Thematic analysis
      of mental health professionals' discourse pertaining to the care plans revealed a
      complex motivational and rational structuring of evil that dictated the switch
      from medical ideological discourse to lay notions of badness. From this, an
      Airaksinen model was constructed to display the types of evil manifestations.

PMID- 12430190
TI  - The impact of ward design on the behaviour, occupational satisfaction and well
      being of psychiatric nurses.
AB  - Studies have shown that modifications to the physical environment of psychiatric
      institutions are associated with positive changes in patients' behaviour,
      attitudes and perceptions. However, little attention has been paid to the impact
      such modifications to the physical environment have on the nursing staff. The
      building of two completely new wards at a rural psychiatric hospital provided an
      opportunity to examine this issue. Measures of the nursing staffs' observed
      behaviour and self-ratings of burnout and job satisfaction were obtained in both
      the old and the new wards. The results showed that the new wards were associated
      with largely positive changes in behaviour and increased burnout, but there was
      no change in job satisfaction. However, it was clear that a vital component in
      the success of any environmental manipulation is an appropriate, corresponding
      change in the organizational climate.

PMID- 12430191
TI  - Quality of life in schizophrenia: a review of the literature from 1995 to 2000.
AB  - The measurement of the quality of life of patients diagnosed with psychiatric
      disorders has become central to evaluating the effectiveness of treatments
      offered by Australian mental health services. The importance of quality of life
      as an indicator of the outcomes of interventions has been reflected by a large
      body of research seeking to measure the impact of variables such as gender,
      ethnicity and duration of illness on the measurable quality of life of an
      individual diagnosed with schizophrenia. This study aims to review and synthesize
      the recent literature in which quality of life has been measured by the use of at
      least one quality of life instrument. It is concludes that while the measurement
      of quality of life is valuable as a measure of outcomes, it should be treated as
      only one means of doing so.

PMID- 12430192
TI  - Survey of aggressive incidents experienced by community mental health staff.
AB  - The phenomenon of aggression experienced by community mental health staff is
      explored in the present study. Qualitative and quantitative data were elicited in
      a self-report questionnaire completed by 92 community mental health workers from
      a metropolitan Area Health Service. Findings indicate that 96% of community
      mental health workers experienced some form of aggression in the course of their
      work, 25% felt that their life had been threatened and 7% sustained physical
      injuries. Issues in need of attention are the normalization of aggression and
      subsequent lack of incident reporting, and the appropriateness of staff safety
      training for community mental health settings.

PMID- 12430193
TI  - Quality improvement projects: finding a pathway through policies.
AB  - It is increasingly common for mental health nurses to develop and implement
      quality improvement and/or research projects. The requirement that these
      activities be conducted in accordance with local, state and national policy;
      organizational accreditation frameworks; and within ethical frameworks is
      daunting. This paper aims to define relevant terms, relate some of the competing
      demands to each other and outline a pathway for developing nurse-based quality
      related projects. When a specific exemplar is required, protocols from Central
      Sydney Area Mental Health Service will be drawn upon as it is likely that policy
      developed in this health area will not be significantly different to that of
      other health areas in New South Wales and other Australian States.

PMID- 12430194
TI  - Fear and learning in mental health settings.
AB  - Health-care students are frequently concerned and anxious about entering the
      mental health setting for their clinical placement. There are many situations in
      mental health clinical settings in which the student will witness or become
      involved in incidents that may challenge existing values, attitudes, ethics and
      provoke strong emotions in the student. This paper examines clinical critical
      incidents that have been identified and reflected on by a cohort of second-year
      student nurses while undertaking their mental health clinical practicum. Data
      were gathered from 260 critical incident reports and was sorted into three broad
      categories: (i) student description of incident; (ii) immediate emotional
      response of the student to the incident; and (iii) student thoughts and feelings'
      about the incident after the opportunity for structured reflection. The findings
      demonstrate a wide range of positive, but predominantly, negative experiences.
      Witnessing psychotic behaviour and incidents involving both actual and threatened
      violence and verbal abuse dominated the critical incidents with 52% describing
      one or both of these issues. To illustrate the range of student-identified
      critical incidents, verbatim examples of student work are included.

PMID- 12430195
TI  - Sources of information when rating the Health of the Nation Outcome Scales.
AB  - Mental health nurses will play an important role in the administration of the
      routine outcome measures currently being implemented across Australia, including
      the Health of the Nation Outcome Scales (HoNOS). Prior research has implied that
      sources of information may be responsible in part for the mixed reliability and
      validity of the HoNOS. This study examines which sources of information
      clinicians use when making a HoNOS rating. Twenty-one mental health clinicians
      that had been using the HoNOS routinely for 2 years were surveyed to determine
      the sources of information they used when making a rating. In addition, 12
      specific HoNOS ratings were reviewed to obtain data about 'actual' sources
      utilized. More than half of all information used when completing a HoNOS rating
      was obtained from interviewing the client or from direct observation of the
      client. The main secondary sources used included medical records and consulting
      with family and carers and other staff. Collateral information from general
      practitioners and police was used in only a small percentage of cases. There was
      high variability amongst clinicians with regard to how much each source was used.
      Training mental health workers in routine use of the HoNOS should encourage
      clinicians to use a range of sources of information when making a rating.

PMID- 12430196
TI  - Behavioural psychotherapy training for nurses in Australia: a trainee's view.
AB  - The training and outcomes for a mental health nurse, who completed a 6-month
      nurse behavioural psychotherapy course at Flinders Medical Centre (Bedford Park,
      South Australia) is described. Completion of this course enabled the nurse to
      work mainly with pathological gamblers as a trainee nurse behaviour therapist.
      Her experience demonstrates that with appropriate training and supervision,
      mental health nurses are able to increase their knowledge base in specialist
      areas and gain skills in therapies that will allow them to work autonomously with
      clients. A brief description of the training, outcome of patient case management
      and skills acquisition achieved through training is presented.

PMID- 12430197
TI  - Health disparities research: from concept to practice.

PMID- 12430198
TI  - Lessons from the past--solutions for the future the millennium nursing shortage.

PMID- 12430199
TI  - Rural nursing research: riddle, rhyme, reality.

PMID- 12430200
TI  - Beyond the patient: caring for families.

PMID- 12430202
TI  - [Development and prospects of clinical diabetology].

PMID- 12430201
TI  - The medication-taking questionnaire for measuring patterned behavior adherence.

PMID- 12430203
TI  - [Diabetic complications: definition, classification and epidemiology].

PMID- 12430204
TI  - [Multinational comparison of vascular complications in diabetes].

PMID- 12430205
TI  - [Long-term intervention trials about diabetic complications in the west].

PMID- 12430206
TI  - [Large-scale randomized intervention trial on diabetes in Japan].

PMID- 12430207
TI  - [Risk factors for diabetic complications: Oxidative stress].

PMID- 12430208
TI  - [Risk factors for diabetic complications: Abnormality of polyol metabolism].

PMID- 12430209
TI  - [Role of PKC in the pathogenesis of diabetic vascular complications].

PMID- 12430210
TI  - [Risk factors for diabetic complications: Angiogenesis factor].

PMID- 12430211
TI  - [Risk factors for diabetic complications: Adhesion molecules].

PMID- 12430212
TI  - [Molecular mechanisms of diabetic atherosclerosis].

PMID- 12430213
TI  - [Genetic risk factor for the onset and progression of diabetic complication].

PMID- 12430214
TI  - [Environmental factors as the risk factors for diabetic complications].

PMID- 12430215
TI  - [Diabetic vascular complications and circulating prorenin].

PMID- 12430216
TI  - [Acute complications due to diabetes mellitus: Diabetic ketoacidotic coma].

PMID- 12430217
TI  - [Acute complications due to diabetes mellitus: Hyperosmolar nonketotic coma].

PMID- 12430218
TI  - [Acute complications due to diabetes mellitus: Lactic acidosis].

PMID- 12430220
TI  - [Clinical features of acute infections in patients with diabetes mellitus].

PMID- 12430219
TI  - [Acute complications due to diabetes mellitus: Hypoglycemic coma].

PMID- 12430221
TI  - [Chronic complications due to diabetes mellitus: Diabetic retinopathy-
      classification, diagnosis, treatment].

PMID- 12430222
TI  - [Chronic complications due to diabetes mellitus: Pathology of diabetic
      retinopathy].

PMID- 12430223
TI  - [Molecular biology in development and progression of diabetic retinopathy].

PMID- 12430224
TI  - [Prevention of diabetic retinopathy in type 2 diabetic patients].

PMID- 12430225
TI  - [Current progress in the treatment for diabetic retinopathy in internal
      medicine].

PMID- 12430226
TI  - [Ophthalmic therapy for diabetic retinopathies--special reference to
      photocoagulation and vitrectomy].

PMID- 12430227
TI  - [Diabetic retinopathy and leukocytes--feasibility of anti-leukostasis therapy for
      diabetic retinopathy].

PMID- 12430229
TI  - [Diagnosis of diabetic polyneuropathy].

PMID- 12430228
TI  - [Diabetic neuropathy--concept, staging, diagnosis, treatment].

PMID- 12430230
TI  - [Pathology of diabetic neuropathy; a review from the updated literature of the
      last 10 years].

PMID- 12430231
TI  - [Risk factors and onset mechanisms of diabetic neuropathy].

PMID- 12430232
TI  - [Early detection of diabetic neuropathy].

PMID- 12430233
TI  - [Electrophysiology in diabetic neurological complications].

PMID- 12430234
TI  - [Variability and assessment of subjective symptoms in painful neuropathy].

PMID- 12430235
TI  - [Sensory disorder and clinical care in painful diabetic neuropathy].

PMID- 12430236
TI  - [Diabetic autonomic neuropathy].

PMID- 12430237
TI  - [Diabetic neuropathic arthropathy (Charcot's joint)].

PMID- 12430238
TI  - [Prevention and treatment of diabetic neuropathy].

PMID- 12430240
TI  - [Pathology of diabetic nephropathy].

PMID- 12430239
TI  - [Diabetic nephropathy].

PMID- 12430241
TI  - [Expression mechanisms and incident factors of diabetic nephropathy].

PMID- 12430242
TI  - [Genetics of diabetic nephropathy].

PMID- 12430243
TI  - [Diabetic nephropathy--predictive methods].

PMID- 12430244
TI  - [Evidence based treatment of diabetic nephropathy].

PMID- 12430245
TI  - [Nutrition support for diabetic patients with chronic renal failure].

PMID- 12430246
TI  - [Dialysis therapy and problem for renal failure of diabetic nephropathy].

PMID- 12430247
TI  - [Primary glomerulonephritis complicating diabetes mellitus--comparison with
      diabetic nephropathy].

PMID- 12430248
TI  - [Evidence for the benefits of ACE inhibitors and AII antagonists in slowing
      progressive renal failure in diabetes].

PMID- 12430249
TI  - [Arteriosclerosis obliterans in diabetes mellitus--concept and management].

PMID- 12430250
TI  - [Diabetes mellitus and cerebrovascular disorders].

PMID- 12430251
TI  - [Ischemic heart disease in diabetes].

PMID- 12430253
TI  - [Treatment and prevention of diabetic foot and ulcer].

PMID- 12430252
TI  - [Diabetic cardiomyopathy].

PMID- 12430254
TI  - [Diabetic orthostatic hypotension].

PMID- 12430255
TI  - [Diabetic erectile dysfunction].

PMID- 12430256
TI  - [Vesico urethral dysfunction due to diabetes mellitus].

PMID- 12430257
TI  - [Diabetic amyotrophy].

PMID- 12430258
TI  - [Dermatologic complications due to diabetes mellitus].

PMID- 12430259
TI  - [Pupillary dysfunction in diabetes mellitus].

PMID- 12430260
TI  - [Diabetes mellitus and osteoporosis].

PMID- 12430261
TI  - [Diabetes mellitus and periodontal disease].

PMID- 12430262
TI  - [Hypertension in diabetics].

PMID- 12430263
TI  - [Obesity in patients with diabetes].

PMID- 12430265
TI  - [Management of diabetic nephropathy with nephrotic syndrome].

PMID- 12430264
TI  - [Diabetes mellitus complicated with hyperlipidemia].

PMID- 12430266
TI  - [Diabetes mellitus and sleep apnea syndrome].

PMID- 12430267
TI  - [Rhabdomyolysis in the diabetic state].

PMID- 12430269
TI  - [Self-control of patients with diabetes--an outline].

PMID- 12430268
TI  - [Gene therapy for peripheral arterial diseases in diabetes mellitus].

PMID- 12430270
TI  - [Self-monitoring of blood glucose].

PMID- 12430271
TI  - [Insulin injection--method and precaution].

PMID- 12430272
TI  - [Home self-monitoring of blood ketone bodies in diabetes mellitus].

PMID- 12430273
TI  - [Exercise, foods and bathing during insulin therapy].

PMID- 12430274
TI  - [Education and care for diabetic patients in Saiseikai Central Hospital Tokyo].

PMID- 12430275
TI  - [Sick day rule and management of hypoglycemia].

PMID- 12430276
TI  - [The importance of medical team care in diabetic treatment and the organizing
      member].

PMID- 12430277
TI  - [The role of certified expert nurse in diabetes nursing].

PMID- 12430278
TI  - [The role of diabetes educator].

PMID- 12430279
TI  - [Part of dietician in diabetic medical treatment].

PMID- 12430280
TI  - [The role of the pharmacist in diabetes mellitus medical care].

PMID- 12430281
TI  - [The Institute for Diabetes Care and Research, Asahi Life Foundation].

PMID- 12430282
TI  - [System of diabetes outpatient clinic at Kurume University Medical School].

PMID- 12430283
TI  - [The system of diabetes outpatient clinic at Tenri Hospital].

PMID- 12430284
TI  - [OKADA Medical Clinic--application of basic diabetes education (OKADA) as a
      model].

PMID- 12430285
TI  - [Portable glucose measuring device].

PMID- 12430286
TI  - [A new method of communication and education for diabetics by glucose monitoring
      via Internet].

PMID- 12430287
TI  - [Patient-centered healthcare service infrastructure on the Internet].

PMID- 12430288
TI  - [The present condition of electronic records, and its future view--states
      centering on cooperation between a hospital and a clinic].

PMID- 12430289
TI  - [Internet for diabetes practice].

PMID- 12430290
TI  - [Administrative measures for diabetes mellitus control by Ministry of Health,
      Labour and Welfare--national health promotion in the 21st century 'Health Japan
      21'].

PMID- 12430291
TI  - [The policy for diabetes of local government].

PMID- 12430292
TI  - [Diabetes prevention program of healthy Japan 21].

PMID- 12430293
TI  - [An economic review of the management of diabetes mellitus].

PMID- 12430294
TI  - [Hepatitis C and diabetes mellitus].

PMID- 12430295
TI  - [PHHI (persistent hyperinsulinemic hypoglycemia of infancy)].

PMID- 12430296
TI  - [Association between intraabdominal disease and type 1 diabetes].

PMID- 12430297
TI  - [Regulation of insulin secretion by incretins].

PMID- 12430298
TI  - [Mitochondrial gene mutations in diabetes mellitus].

PMID- 12430299
TI  - [Mitochondria as the signal generator in the metabolism-secretion coupling in
      pancreatic beta cells].

PMID- 12430300
TI  - [Sulfonylurea receptors].

PMID- 12430301
TI  - [Thyroid hormone and glucose metabolism].

PMID- 12430302
TI  - [Glucose metabolism in adipose tissue].

PMID- 12430303
TI  - [Importance of animal models by gene targeting in diabetes research].

PMID- 12430304
TI  - [Time course of the onset of type 2 diabetes mellitus observed by the follow-up
      studies using oral glucose tolerance test: from the mechanism of its onset to
      prediction and prevention].

PMID- 12430305
TI  - [Guidelines for dining out for diabetics].

PMID- 12430306
TI  - [Syndrome X].

PMID- 12430307
TI  - [Beta 3 adrenergic receptor agonist].

PMID- 12430308
TI  - [Primary and secondary failure of sulphonylureas].

PMID- 12430309
TI  - [Combination therapy with biguanides].

PMID- 12430311
TI  - [Food exchange list, 5th ed].

PMID- 12430310
TI  - [Perspective for personalized medicine for diabetes].

PMID- 12430312
TI  - [Revision points of the sixth edition of food exchange book].

PMID- 12430313
TI  - [Food exchange lists for meal planning in the patients with diabetic
      nephropathy].

PMID- 12430314
TI  - [Recommended dietary allowances for Japanese--6th revision--dietary reference
      intakes].

PMID- 12430315
TI  - [Standard (ideal) body weight].

PMID- 12430316
TI  - Midwifery in crisis or just being challenged.

PMID- 12430317
TI  - Addressing the barriers to midwifery--Australian midwives speaking out.
AB  - This research gives a voice to midwives in identifying the barriers and current
      problems in the organisation of maternity care in Australia. Using a critical
      feminist research approach, data was collected from a cross section of midwives
      nationally. Through standard qualitative research methods, themes were identified
      that enabled analysis of significant issues affecting the current status of
      midwifery. The system of maternity care was identified as being dominated by
      medicine, not evidence based and restricting of women's choices, with midwifery
      autonomy not recognised or supported. The invisibility of midwifery within the
      community was identified as a significant barrier which, in conjunction with the
      occupational imperialism of obstetrics, ensures ongoing strategic control of
      maternity services and a denial of the rights of consumers to access midwifery
      care.

PMID- 12430318
TI  - Identifying the midwifery practice component of Australian Midwifery Education
      Programs. Results of the Australian Midwifery Action Project (AMAP) Education
      Survey.
AB  - This paper is the first in a series of papers reporting on the findings of the
      AMAP Education Survey of the 27 universities providing a program for initial
      authorization to practise midwifery. It concentrates on issues related to the
      practice component of courses. Subsequent papers will present findings related to
      workforce issues and the barriers to effective midwifery education as identified
      by the midwifery course coordinators. Serious concerns are raised about the
      standards of Australian midwifery education, particularly when international
      comparisons are made, in terms of the length of courses, clinical practice
      requirements and the opportunities for students to engage with contemporary
      midwifery practice across community and acute settings.

PMID- 12430319
TI  - Congratulations you're a mother: a strategy for enhancing postnatal education for
      first-time mothers investigated through an action research cycle.
AB  - The transition to motherhood is a time of great change and an experience for
      which many women do not feel adequately prepared. This study sought to benefit
      women in the transition to motherhood by enhancing the postnatal teaching offered
      to first-time mothers in hospital following childbirth. The study followed an
      action research cycle to design, implement and evaluate an educational resource
      for first-time mothers during the immediate postnatal period. Methods for
      collecting data included focus groups and an anonymous self-completed
      questionnaire. The research was undertaken at a suburban public hospital in
      Adelaide. The findings showed that both midwives and first-time mothers
      considered lack of time as a significant factor in giving and receiving postnatal
      education. It was also found that the provision of relevant information was
      important. The study identified that specific information relating to baby-care
      and self-care are primary educational needs for first-time mothers. The resource,
      "Congratulations You're a Mother" was developed in response to these findings and
      was found to be beneficial in providing postnatal education. The study provides a
      platform for further investigation of postnatal education using larger samples in
      the broader context of Australian society.

PMID- 12430320
TI  - Hidden gender.

PMID- 12430321
TI  - Don't blame the box.

PMID- 12430322
TI  - Fever pitch.

PMID- 12430323
TI  - Open house detox.

PMID- 12430324
TI  - Better luck next time.

PMID- 12430325
TI  - More winners than losers?

PMID- 12430326
TI  - Every breath you take.

PMID- 12430327
TI  - Paper trail leads nowhere.

PMID- 12430329
TI  - Fall prevention and the National Service Framework.
AB  - AIM: The aim of this study was to examine the prevalence and nature of fall
      prevention activities carried out by London primary and secondary care NHS
      services and targeted at adults aged 65 years or older, as well as the rationale
      for those activities where they existed. METHOD: A quantitative approach was
      adopted--a non-experimental, descriptive, fixed study design combining a review
      of the literature with the results of a purposive survey of all 143 London NHS
      services. RESULTS: Despite high levels of fall-related mortality and morbidity,
      almost two thirds of London NHS organisations lack fall prevention strategies.
      Where they do exist, none meet the demands of the National Service Framework for
      Older People (DoH 2001). Most initiatives are small scale, lack significant
      multidisciplinary input and focus on extrinsic fall causation factors.
      CONCLUSION: Compliance with the National Service Framework for Older People will
      challenge the NHS in London. Resources must be made available for training,
      equipment and environmental modification. Addressing intrinsic fall causation
      factors demands the involvement of medical and paramedical personnel to a greater
      degree than presently occurs.

PMID- 12430330
TI  - Clinical supervision models for nursing: structure, research and limitations.
AB  - This article highlights the diversity of supervision models currently described
      in the nursing literature, clarifies their structure, discusses research
      conducted on specific supervision models and outlines their limitations. It
      offers insight into some of the common models that have received coverage in the
      nursing literature.

PMID- 12430331
TI  - Wound repair: advanced dressing materials.
AB  - Georgina Casey examines the process of wound healing and describes the roles of
      the main cells and biologically active molecules found in the wound bed.

PMID- 12430332
TI  - Giving children a 'voice'.

PMID- 12430333
TI  - Managing your paperwork.
AB  - The possibilities for better handling of the career's necessary paperwork are
      endless. The important first step is a commitment to improve, one habit or aspect
      at a time. Change is not easy, but your time is worth it.

PMID- 12430334
TI  - Substances of low toxicity by ingestion.

PMID- 12430335
TI  - Vicarious traumatisation.

PMID- 12430336
TI  - Paediatric pain assessment.

PMID- 12430337
TI  - Taking part in the MRC crash trial.

PMID- 12430338
TI  - Termination--an important concept for nursing in long-term care.
AB  - The impending loss a staff has at the termination of a one-to-one relationship
      with a resident in long-term care may provoke deep feelings of grief and sadness
      in both the staff members involved and the resident in the case of a resident who
      leaves for other agency or unit. In some cases termination may result in use of
      defense mechanism including anger and openly hostile comment which may be
      displaced toward other staff or resident. Nurses need to prepare staff,
      particularly, novice staff, to handle these feelings in residents as well as
      understanding their own personal reactions at the loss of a resident.

PMID- 12430339
TI  - "Trading bickering for teamwork".
AB  - Bickering is an unpleasant phenomena found wherever groups of people congregate.
      Bickering on a health care team such as that found in the nurse department can
      create a negative environment and poor morale. The nurse manager should take
      responsibility for action which can deter this type of behavior and should
      visibly lead the staff to more productive interactions.

PMID- 12430340
TI  - Euthanasia: the 21st century nursing dilemma.

PMID- 12430341
TI  - Knowledge regarding preventive care for breast cancer in African American women
      in west Kentucky.

PMID- 12430342
TI  - Kentucky Bioterrorism Advisory Committee--update.

PMID- 12430344
TI  - Impact of a 5-minute scrub on the microbial flora found on artificial, polished,
      or natural fingernails of operating room personnel.
AB  - Edel et al.'s (1998) study gave support to the idea that fingernail treatments
      may put patients at increased risk due to the bacteria carried by nurses or other
      health care providers. The results of this study could be used to support a
      research utilization project to educate nurses of the increased risk of infecting
      patients due to fingernail treatments. Feasibility issues include the cost and
      time to revise hospital policies concerning fingernail treatments and to educate
      nurses in the workplace. Future research is needed with larger sample sizes and
      to investigate possible transmission of infectious bacteria to patients.

PMID- 12430343
TI  - Infection control in today's healthcare environment.

PMID- 12430345
TI  - Pet therapy and increased socialization among elderly clients.
AB  - Churchill et al.'s (1999) study supported the idea that pet therapy increased
      socialization and decreased agitation among persons with AD. This study could be
      used to support the group research utilization project on the use of pet therapy
      to increase socialization. Future research might concentrate on participants with
      varied ethnic backgrounds and varied clinical diagnoses. Some feasibility issues
      would be finding dogs or pets properly trained for therapy and finding nurses
      properly trained on the use of pet therapy.

PMID- 12430346
TI  - Job satisfaction and dissatisfaction as described by staff nurses.
AB  - McNeese-Smith's (1999) study created a clear picture of the factors influencing
      nurse job satisfaction and dissatisfaction. Excess job dissatisfaction results in
      nurses resigning their positions, contributing to the nursing shortage. The
      results of this study could be used to support a research utilization project to
      educate nursing administration of these factors. Attending to these factors could
      enhance nurse retention and recruitment, helping to lessen the nursing shortage.
      Feasibility issues would include the cost and time to educate the nursing
      administration. Future research should be done to identify the factors of job
      satisfaction and dissatisfaction in other areas of nursing besides hospital
      nursing.

PMID- 12430347
TI  - Here we go again. Beware!! Be vigilant!! Be prepared!!

PMID- 12430348
TI  - [Comparison of surgical and nonsurgical techniques in periodontology].
AB  - Actually, there's an evolution of the periodontal treatment. Non surgical therapy
      is the main way of treatment today. Surgery takes place generally after non
      surgical therapy and reevaluation. The aim of this work is to compare these two
      treatments in relation with clinical parameters, to indicate the best therapy for
      the patient.

PMID- 12430349
TI  - [Essential facial neuralgia with bilateral involvement: apropos of a case seen at
      the Cite Verte Hospital in Yaounde].
AB  - Despite the fact that essential facial neuralgia is a well known clinical entity
      as relates to its evolution and treatment, its physiopathology is still a
      controversial issue. The form with bilateral evolution that we observed and that
      we are reporting here is extremely rare and its physiopathology is even more
      controversial. The case of our patient is all the more complicated in that, the
      pain topography is limited to the right to a sensitive region of the trigeminal
      nerve (superior maxillary) and to the left to the region of the mandible
      (inferior maxillary) A similar disease evolution is not described so far in the
      present literature of the disease. We have therefore seized this opportunity to
      out line the possible causes of faulty diagnosis in order that essential facial
      neuralgia should not be labelled as facial pain of tumoral, vascular or other
      origin.

PMID- 12430350
TI  - Salivary gland tumours in Congo (Zaire).
AB  - From the files of the Department of Pathology of Kinshasa University Hospital, a
      retrospective study on salivary gland tumours in Congo (Zaire) had been carried
      out in order to determine their histological and epidemiological profile.
      Salivary gland tumours are rare in Congo, with a relative frequency of 1.8%.
      Pleomorphic adenoma (55.1%) and adenoid cystic carcinoma (15.9%) are the most
      common tumours. Parotid gland (36.6%) is the most frequent location of salivary
      gland tumours in this country. People aged between 30 and 39 years (19.9%) (Mean:
      37.4 +/- 16.2 years) and females (M/F = 0.8/1) are most affected. No case of
      adenolymphoma is recorded in this series.

PMID- 12430351
TI  - [Evaluation of student participation in the management of the activities of the
      medical service of the Centre des Oeuvres Universitaires of Dakar (COUD].
AB  - The students of Centre des Oeuvres Universitaires de Dakar (COUD) do not seem to
      participate to the management of their own health status in spite of their
      financial participation in some services. The aim of this study is to evaluate
      the students's participation in their own health status. The results obtained
      from documents and archives, COUD'S responsible and student's opinion have shown
      a financial participation of 8% from the COUD medical service budget. The
      students wish to participation actively to the management of the medical service
      while COUD's responsible have opposite opinion. For an efficiency management of
      their own health status, students must necessary participate.

PMID- 12430352
TI  - [Noma: apropos of a case in a 9-year-old child at the Centre Hospitalier de
      Libreville (Gabon)].
AB  - The authors report the observation of a disease in fact the noma which one
      believed disappeared, it of it is nothing. This disease, summation of several
      factors, with frightening forecasts immediate and remote, must have before a
      whole preventive treatment by the improvement of the standard of living of the
      populations because its repair is so long, if difficult and so expensive that
      access will have well little there.

PMID- 12430353
TI  - Primary health care approach. Its relevance to oral health in Nigeria.
AB  - This article discusses the concept of Primary Health Care--an idea which started
      with the World Health Assembly agreement in 1977 to work resolutely towards the
      goal of Health for All. This decision was followed by the historic international
      conference on Primary Health Care at Alma Ata in 1978. Many countries including
      Nigeria, adopted the primary health care strategy to achieve health for all by
      the year 2000 (now 2000 and beyond). Since health needs to be seen and dealt with
      in a holistic manner, oral health is an integral part of health. Strategies for
      achieving health for all implicitly and must of necessity involve oral health.
      This article has tried to show the relevance of the strategy of primary health
      care to oral health. It concludes that primary health care approach is very
      relevant to oral health in Nigeria.

PMID- 12430354
TI  - [Limits of nonsurgical techniques in periodontology].
AB  - In the periodontal treatment plane, non surgical therapy takes place a very
      important part. This treatment is easy to do and results are the same like
      surgery with less postoperative trauma and aesthetic damage. Although, non
      surgical therapy presents some limits as: depth of the pockets, radicular
      anatomy, instrumentation With these different clinical parameters, right
      indication and rational treatment plane can be used.

PMID- 12430355
TI  - [Epidemiologic study of the oral health of the nursing staff of the Hopital
      Militaire de Yaounde].
AB  - The aim of this study is to know the impact of odonto-stomatology teaching
      distributed in nurse schools, on nurses mouth-dental health. It is composed of a
      questionnaire and a clinical exam and it was about 127 nurses at Yaounde military
      hospital, from February to march 2001. The results are the following: 53% of
      nurses never benefit from a dental consultation. Prosthesis needs (25%) and
      periodontal cure needs 85.4%) are too high. The general prevalence rate of dental
      caries is high (56%). The middle C.A:O. remains weak (2.94); the number of
      decayed tooth around 2 per person is twice and a half more important among women
      than among men. O. indication (0.025) and therapeutic indication (2.25%) are too
      weak; in fact 97.5% of decayed teeth are not filled. After all, in spite of their
      privileged entry in dental cares in the hospital setting, mouth-dental nurse
      state of health is not better than general population ones. The weak frequent
      visits of dental offices, corroborated by therapeutic indications which are
      especially low; demonstrate the necessity to improve odontostomatology training
      distributed on nurse schools. It appears desirable to stress especially on
      prevention, mouth-dental hygiene and the necessity, of one consultation at least
      per year to the dental surgeon.

PMID- 12430356
TI  - Non-syndrome multiple supernumerary teeth in Nigerians.
AB  - The present study was carried out to ascertain frequency of multiple
      supernumerary teeth not associated with syndrome in Nigerians. A total of 13
      patients comprising of 10 males (76.92%) and 3 female (23.07%) representing
      0.098% of the study population had multiple supernumerary teeth. Multiple
      supernumerary teeth without any associated systemic diseases or syndrome are rare
      as reported by BLUMENTHAL (3) RUHLMAN and NEELY (17), KANTOR et al. (10) is not
      the case in this study. The maxillary region has the highest frequency of
      occurrence with 12 times (66.67%) followed by the mandibular premolar region with
      4 times (22.22%) while maxillary premolar and mandibular anterior region shared
      (5.55%) respectively. The conical and tuberculate types of supernumerary teeth
      were found in the midline region, while the supplemental supernumerary teeth were
      more in the mandibular premolar region with 12 (70.58%) follow by maxillary
      midline 4 (23.52%) and the lower incisor region 1 (5.88%) which is in consonant
      with WINTER and BROOK (2), STAFNE (19) NAZIF, FUTALO ZULLO (15). The role of
      genetics in the aetiology of multiple supernumerary teeth as found in this study,
      the occurrence of supernumerary teeth on two brothers and a daughter to one of
      the affected brothers, tends, to suggest an autosomal dominant mode of
      inheritance and the challenges to management by the orthodontists are discussed.

PMID- 12430357
TI  - Crossing the quality chasm: autonomous physician extenders will necessitate a
      shift to enterprise liability coverage for health care delivery.

PMID- 12430358
TI  - The borders of solidarity: how countries determine the public/private mix in
      spending and the impact on health care.

PMID- 12430359
TI  - The role of the private sector in biotechnology: research and development.

PMID- 12430360
TI  - The Human Genome Project: a public good.

PMID- 12430361
TI  - Conflict of interest in biomedical research.

PMID- 12430362
TI  - The emergence of the Healthcare Information Trust.

PMID- 12430363
TI  - An Rx for reform: a Medicare prescription drug benefit.

PMID- 12430364
TI  - Are we killing the weak to heal the sick?: federally funded embryonic stem cell
      research.

PMID- 12430365
TI  - Forensic nursing: RN practice in prison populations.

PMID- 12430366
TI  - Interface pressure measurement: testing and selecting sensors.

PMID- 12430367
TI  - Meeting the complex care needs of a patient with Darier's disease.

PMID- 12430368
TI  - The healing properties of Promogran in venous leg ulcers.
AB  - OBJECTIVE: To evaluate the healing rate of venous leg ulcers treated with
      Promogran. METHOD: Patients with stagnating venous leg ulcers were recruited.
      Target wounds were > or = 2 cm but < or = 10 cm in any one dimension. Subjects
      were randomly allocated to receive either Promogran or a non-adherent dressing
      (Adaptic) with a secondary dressing of gauze followed by short-stress compression
      (Biflex). Weekly wound assessments occurred over 12 weeks and dressings were
      changed twice weekly by the investigator and/or nurse team. Planimetry tracings
      and photographs were blindly reviewed and assessed by two independent
      investigators. An intent-to-treat analysis was performed. RESULTS: Seventy-three
      patients were included. Thirty-seven were randomly allocated Promogran and 36
      Adaptic. Twenty-nine patients completed the 12-week follow-up visit, 25 healed
      before week 12 and 19 stopped follow-up before week 12 for reasons unrelated to
      healing. Significantly more patients in the Adaptic group than in the Promogran
      group switched to another dressing (22.2% versus 5.4%; p = 0.035). Eleven venous
      leg ulcers healed in the control group (31%) and 15 in the Promogran group (41%)
      (p = 0.373). Overall, 15 venous leg ulcers healed or improved in the control
      group (42%) and 23 in the Promogran group (62%) (p = 0.079). Surface area
      decreased, on average, by 36.5 +/- 11.4% (median decrease: 44.6%) in the Adaptic
      group and by 54.4 +/- 10.9% (median decrease: 82.4%) in the Promogran group (p <
      0.001). A < or = 20% surface area reduction was observed in 15 patients in the
      Adaptic group and in seven in the Promogran group (42% versus 19%; p = 0.034). No
      severe local adverse events were noted in either group, although poor
      tolerability caused a dressing switch in five patients in the control group and
      three in the Promogran group. Dressing acceptability was good or excellent in
      more than 60% of subjects in both groups. CONCLUSION: The results suggest that
      Promogran may accelerate healing in venous leg ulcers and was well tolerated
      compared with the current standard of care.

PMID- 12430369
TI  - Post-surgery vaginal packs.

PMID- 12430370
TI  - The use of oxidised cellulose as a topical haemostatic dressing on a bleeding
      stomal wound.

PMID- 12430371
TI  - A survey of tissue viability nurses' role and background in one region.

PMID- 12430373
TI  - Making multimedia work for you: a wound management CD-ROM.

PMID- 12430372
TI  - Advanced wound care materials: developing an alginate fibre containing branan
      ferulate.
AB  - OBJECTIVE: This laboratory-based study set out to establish whether branan
      ferulate--a polysaccharide compound available in gels such as as Sterigel (SSL
      International, UK)--could be successfully added to the fibre of an alginate
      dressing to provide a superior wound-care dressing. METHOD: A wet extruder
      (Howden Engineering Services, UK) was used to produce the fibres. Researchers
      examined the effect of spinning-bath calcium chloride concentration (used as the
      coagulant in the fibre-spinning process) on the tensile and absorption properties
      of alginate fibres containing 25% w/w branan ferulate. Sodium alginate and branan
      ferulate were separately dissolved in de-ionised water and then stirred together
      to make up a 5% dope solution. The dope was then forced through a spinneret and
      into the calcium chloride bath, where fibres were precipitated and then carried
      over the first set of rollers. The fibres were washed in the next bath and drawn
      at different rates to enhance their tensile properties. At the 'winding-up' stage
      the filaments were either passed over a contact heater and into a furnace (dry
      pick-up) or transferred into acetone baths of increasing concentrations of 50, 80
      and 100% aqueous acetate to remove the water (wet pick-up). The moisture content
      of standard alginate fibres and those with branan ferulate were measured and
      compared. Breaking load, tenacity and breaking extension, and the quantity of
      branan ferulate in the fibres were also measured. The process was repeated four
      times, using different strengths of calcium chloride. Using various draw ratios,
      the effects of liquid uptake were measured using water, saline and a solution
      called A (to mimic human blood and exudate-type fluids). RESULTS: Out of the four
      calcium chloride concentrations used, 1% concentration appeared to give the
      highest and most conclusive results for fibre-breaking load, tenacity and
      breaking extension. CONCLUSION: A 1% w/v concentration of calcium chloride
      provides the optimum conditions for achieving suitably strong fibres with
      adequate absorption capacity, while allowing the least branan ferulate loss
      during wash and post-production treatments. In a laboratory setting the product
      showed promise. Research is now needed in a clinical setting and for comparison
      with existing wound-care products.

PMID- 12430374
TI  - Don't rely on staffing ratios alone: here are cutting-edge strategies to use.
AB  - You need to address acuity, length of stay, and staff skill mix when staffing
      your emergency department (ED). The Emergency Nurses Association has developed
      new staffing guidelines. Track changes in acuity and time spent on nursing tasks
      to obtain additional nursing hours. Use different ratios for specific patient
      groups. Admission holds in the ED must have the same staffing as inpatients.

PMID- 12430375
TI  - ED staff will be first to receive smallpox vaccine.
AB  - According to current plans, emergency department (ED) staff will be offered the
      smallpox vaccination, but important staffing, logistic, and liability issues
      still are unclear. The need for staff to take off work is a major worry for ED
      managers. It is unclear who will assume responsibility for disability and
      liability. There is a concern about immunocompromised individuals being exposed
      to vaccinated staff.

PMID- 12430376
TI  - Toyota's tips drive dramatic ED improvements.
AB  - The Toyota Motor Corp.'s key concepts of allowing workers to make changes,
      putting the customer first, and reducing waste can have a dramatic impact when
      implemented in emergency departments. Staff should be empowered to make changes
      to improve quality. A chain of events should be set in motion for each customer
      request. Identify and eliminate roadblocks that cause delays.

PMID- 12430377
TI  - Try these novel ways to use ancillary staff.
AB  - Ancillary staff can be used to offload nursing tasks and provide improved care to
      patients. A health unit coordinator role can handle such tasks as registration,
      notification of physicians, and patient transport. Physical therapists can
      evaluate orthopedic patients, assist patients in obtaining needed devices, and
      provide follow-up care. Phlebotomists can follow up on orders in addition to
      drawing blood.

PMID- 12430378
TI  - Comply with new standard for disaster volunteers.
AB  - The Joint Commission on Accreditation of Healthcare Organizations has announced a
      new standard for giving emergency privileges to volunteer clinicians during a
      disaster. Emergency privileges can be granted when your facility's emergency
      management plan has been activated. Volunteers must present a current license,
      current hospital identification with license number, or have their identity
      verified by a staff member. Establish mutual aid agreements with other local
      hospitals so you know which clinicians are willing to volunteer.

PMID- 12430379
TI  - Are you meeting the needs of your staff? Here are cutting-edge strategies to use.

PMID- 12430380
TI  - Taking a closer look at the managed care class actions: impact litigation as an
      assist to the market.
AB  - Professor Cerminara examines the use of class action lawsuits to empower
      individuals to challenge health care decision-making. The article begins by
      noting the benefits of class actions which provide strength in numbers and a far
      ranging impact by challenging policy decisions and encouraging corporate
      responsiveness. Professor Cerminara concludes that class actions are but one step
      in the process of empowering individuals and decreasing their resentment of the
      lack of process currently within the health care system.

PMID- 12430382
TI  - Competition law's role in health care quality.
AB  - Professor Jacobi's essay analyzes the various regulatory responses that are
      available to the government when crises in quality of care occur. These responses
      range from complete government involvement, i.e. "command and control"
      regulation, to a limited caretaker role in maximizing market forces. In
      responding to the recent IOM Report on human error in medical care, Professor
      Jacobi looks back to the 1986 IOM Report that revealed the crisis of care going
      on in nursing homes as well as the more recent controversy involving managed
      care. Following his analysis of the varied governmental approaches to these
      issues, Professor Jacobi concludes that both the unfettered use of command and
      control regulation and the more limited remedies of market maintenance are
      inadequate in the face of medical error. He argues instead that limited but
      forceful governmental regulation should be predicated on understanding the
      limitations of professionalism and market forces, in order to fully protect
      patients who are at risk.

PMID- 12430381
TI  - Information is the key to patient empowerment.
AB  - Mr. Kane's paper examines the role of patients to ensure that they have both the
      knowledge and power to direct their health care choices. The evolving health care
      market place is discussed to emphasize the increased importance of individual
      involvement in health decision making. A checklist sets forth questions which a
      patient should ask of herself and of her provider before entering into health
      care decisions.

PMID- 12430383
TI  - The government's role in health care delivery.
AB  - As Secretary of Illinois' largest agency, the Department of Human Services,
      Secretary Baker provides a thorough overview of the role her agency plays in the
      ongoing health and welfare of the citizens of Illinois. Her contention that
      government should play a critical role in health care delivery is buttressed by
      the DHS' role as a funding agent, its contributions of staff and systems, and the
      direct role it plays in the pursuit of truly public health care. Secretary Baker
      effectively demonstrates the complexities and disparities that still exist in
      health care by discussing an inter-generational study of one poor family
      documented in Chicago. She concludes, however, that while such disparities and
      injustices in health care delivery do exist, they can be overcome by the
      effective use and cooperation of state governmental agencies that are committed
      to that goal.

PMID- 12430384
TI  - When self-regulation, market forces, and private legal actions fail: appropriate
      government regulation and oversight is necessary to ensure minimum standards of
      quality in long-term health care.
AB  - Mr. Eremia's paper discusses market forces, professional self-regulation, and
      private litigation individually and collectively as methods of maintaining and
      improving quality of care. He determines that whether separately or in
      conjunction, these three paradigms have not been successful agents in this
      regard. By analyzing the regulatory framework and oversight provided by the
      federal government in the long-term care industry, Mr. Eremia argues persuasively
      that despite its occasional inadequacies, regular and consistent oversight and
      regulation by the government is imperative in order to effect meaningful and
      systemic improvements in the provision of quality care.

PMID- 12430385
TI  - The legal liability regime: how well is it doing in assuring quality, accounting
      for costs, and coping with an evolving reality in the health care marketplace?
AB  - Professor Blumstein's timely article deals with two competing paradigms that
      provide the poles in the spectrum of legal liability regimes. The "professional"
      or "scientific" model of liability assumes a rigidly normative approach to
      medical practice while the second more recent paradigm reflects the principles of
      marketplace economics in considering cost and resource availability to determine
      quality of care standards. Professor Blumstein concludes that the traditional
      approach to determining legal liability is being eroded by both the economics of
      managed care and the recent emphasis on systemic management of health care to
      promote patient safety, and that the traditional regime will have to "bend" in
      order to remain legally viable.

PMID- 12430386
TI  - Health care quality information liability & privilege.
AB  - As the General Counsel for the National Committee for Quality Assurance, which
      accredits health plans and measures outcome performance, Ms. Donohue is in a
      unique position to comment on the use of such data in litigation against health
      plans and providers. After reviewing the growing tide of class-action lawsuits in
      this area, she argues that such information should be protected under the common
      law privilege of self-critical analysis, extended to third parties, because such
      privilege would protect and encourage quality assessment. Ms. Donohue further
      argues that the sharing and reporting of this information on a system-wide level
      will allow plans and providers to make visible headway in improving the care
      provided to patients, and that this benefit to all consumers clearly justifies
      the creation of a federal privilege to combat the abundance of state-level
      lawsuits against plans and providers that attempt to base liability on third
      party accreditation and outcome performance data.

PMID- 12430387
TI  - The business associate brain teaser: a look at problems involving the business
      associate regulations under the Health Insurance Portability and Accountability
      Act of 1996.
AB  - Ms. Heitzman addresses in her article the impact of the Administration
      Simplification statute of the Health Insurance Portability and Accountability Act
      of 1996 on the protection of health information by third parties to health care
      transactions. These regulations were enacted, in part, to increase consumers'
      trust in the health care system. However, their impact on business associates
      that come into contact with the health care entities has been a source of
      contention and confusion since they were drafted. This article concludes that the
      current regulations are too ambiguous and complex to achieve the goals of
      protection of privacy and Congress' goal of simplifying administration.

PMID- 12430388
TI  - Paradigms revised: intersex children, bioethics & the law.
AB  - Ms. Hermer explores the controversy surrounding the management of intersex
      infants and children in America. Her focus on the areas of medical malpractice
      and informed consent leads her to the conclusion that contrary to some
      recommendations, a moratorium on cosmetic genital and sex assignment surgeries
      for infants and children is not warranted. Rather, providers should focus on
      offering parents with complete information, referrals to support groups and
      forthright discussions on the dearth of information available.

PMID- 12430389
TI  - Nurses, it's time to dust off your caps.

PMID- 12430390
TI  - The transition from classroom to online teaching.
AB  - TOPIC: Online teaching. PURPOSE: To describe the pedagogical transition that
      needs to be considered before putting a class online. SOURCES: Published
      literature. CONCLUSIONS: Advances in technology will continue to alter teaching
      strategies. The changing paradigm of online education needs further research to
      advance the science of nursing education.

PMID- 12430392
TI  - Concept analysis of decision making.
AB  - TOPIC: Client decision making in relation to health care. PURPOSE: To develop a
      conceptual analysis of client decision making regarding health care that
      represents the current state of the science in order to better understand how
      clients make decisions. SOURCES: Published literature. CONCLUSIONS: A model of
      client decision making is presented with implications for nursing. Defining
      attributes, antecedents, consequences, and empirical referents of decision making
      are developed and illustrated by case presentations.

PMID- 12430391
TI  - Nurse coach: healthcare resource for this millennium.
AB  - TOPIC: Nurse coach, a new role for nurses. PURPOSE: To describe the components,
      tasks, and interaction of a nurse coach model that is client directed as opposed
      to illness directed. SOURCES: Published literature and authors' experience.
      CONCLUSIONS: A nurse coach can provide a structure and approach to custom fit
      attainable behavior change.

PMID- 12430393
TI  - The why and wherefore of empowerment: the key to job satisfaction and
      professional advancement.

PMID- 12430394
TI  - Can we really afford to spend NHS cash on genetic testing for cancer?

PMID- 12430395
TI  - Nurse-led clinics lose funds.

PMID- 12430396
TI  - On a fast track from Oz.

PMID- 12430397
TI  - Childhood obesity. A walk on the healthy side.

PMID- 12430398
TI  - Relative dangers.

PMID- 12430399
TI  - Knocking out pneumonia.

PMID- 12430400
TI  - Evaluating the merits of interdisciplinary education.
AB  - This article describes interdisciplinary education initiatives developed at
      Columbia University in the USA and cites the difficulties encountered in
      implementing such a programme. The author also discusses problems in evaluating
      such initiatives, and some of the administrative, educational and professional
      factors involved. She argues that while there may be some resistance among
      educators to formal interdisciplinary collaboration, students appear more open to
      the idea. The author concludes that the changing health care environment makes it
      increasingly important to find successful methods of delivering such programmes.

PMID- 12430401
TI  - Inpatient group work for patients with psychosis.
AB  - Nurses working on acute inpatient wards usually think in terms of individualised
      patient care. Indeed, this ethos is at the heart of modern nursing. This article
      suggests that a different perspective is needed if we are to recognise the place
      of the individual in the context of the ward and wider society. Therapy groups
      allow nurses and other members of the mental health team to explore the
      relationships between patient and patient, patient and staff, and patient and
      institution. Although such work is demanding, and requires training and quality
      supervision for the facilitators, it is also creative and fruitful. It offers
      patients the opportunity to make sense of what is happening around them by
      interacting and sharing with others, and by exploring the conflicts and anxieties
      that arise in interpersonal relationships. This article illustrates a way to help
      nurses create that most elusive goal in contemporary mental health care--a safe
      and containing environment on an acute inpatient ward.

PMID- 12430402
TI  - Palliative care nursing. Part 1. Building the foundations for primary nursing.
AB  - Primary nursing offers a structure that can facilitate the development of patient
      centred care and promote the role and status of the nurse. Successful
      introduction of primary nursing depends on a careful analysis of the current
      situation, a shared vision for the future, and a consensus on strengths,
      weaknesses, opportunities and threats. This article explores the experience of
      four senior nurses who set out to introduce primary nursing to a palliative care
      setting.

PMID- 12430403
TI  - Introducing a career development pathway.
AB  - To respond to the career needs of nurses and midwives working in the fields of
      clinical practice, education, research and management in North Bristol NHS Trust,
      a professional development pathway was established. The pathway, which is similar
      to that followed by medical staff, allows nurses and midwives to identify their
      chosen career path and work towards it using a flexible scheme of planned
      clinical rotations supported by academic input. This article discusses the
      pathway, shows how it meets the needs of staff and service delivery, and closes
      the gap between education and practice.

PMID- 12430404
TI  - Nurse prescribing. Week 1. Assessing the data.

PMID- 12430405
TI  - Day in the life.

PMID- 12430406
TI  - Ever thought of playing a major role in the theatre?

PMID- 12430407
TI  - From molecular chemistry to supramolecular chemistry to superdupermolecular
      chemistry. Controlling covalent bond formation through non-covalent and magnetic
      interactions.
AB  - The reactions of carbon centered radical pairs often involve diffusion controlled
      combination and/or disproportionation reactions which are non-selective. A
      triplet geminate pair of radicals is produced by the photolysis of suitable
      ketones. The reactions of such geminate pairs can be controlled though the
      application of supramolecular concepts which emphasize non-covalent interaction
      to "steer" the geminate pair toward a selected pathway. In addition,
      "superdupermolecular" concepts, which emphasize the control of radical pair
      reactions through the orientation of electron spins, can be employed to further
      control the course of geminate pair reactions. Examples of control of a range of
      the selectivity of geminate radical combinations, which form strong covalent
      bonds, through supramolecular and superdupermolecular effects will be presented
      for the photolysis of ketones adsorbed in the supercages of zeolites.

PMID- 12430408
TI  - Thioalkylated tetraethylene glycol: a new ligand for water soluble monolayer
      protected gold clusters.
AB  - Ligand-stabilised, water-soluble gold nanoparticles of two different size ranges
      (2-4 and 5-8 nm) are readily prepared using monohydroxy (1-mercaptoundec-11-yl)
      tetraethylene glycol as a novel capping agent. These nanoparticles are as stable
      as alkylthiol-capped monolayer protected clusters (MPCs) and do not aggregate
      from aqueous solution under a wide range of stringent conditions. It is expected
      that this new material will be useful for a number of bio-analytical
      applications.

PMID- 12430409
TI  - Supramolecular gas-solid reaction between formic acid vapours and solid
      [CoIII(eta 5-C5H4COOH)(eta 5-C5H4COO)].
AB  - Exposure of the solid zwitterion [CoIII(eta 5-C5H4COOH)(eta 5-C5H4COO)] to
      vapours of formic acid quantitatively produces the co-crystal [CoIII(eta 5
      C5H4COOH)(eta 5-C5H4COO)] [HCOOH] without proton transfer from formic acid to the
      deprotonated -COO- group on the zwitterion; formic acid can be quantitatively
      removed by mild thermal treatment, regenerating the starting material.

PMID- 12430410
TI  - Structural control in self-standing mesostructured silica oriented membranes and
      xerogels.
AB  - Large pore (a = 150-200 A) wormlike and highly oriented cubic (IM3m space group)
      and 2D-hexagonal (P6m) mesostructured xerogels have been reproducibly synthesised
      by Evaporation-Induced Self Assembly (EISA). Mesostructure control was attained
      by changing the template (nonionic block copolymer) and water (h = [H2O]/[Si])
      ratio.

PMID- 12430411
TI  - Practical solid oxide fuel cells with anodes derived from self-assembled
      mesoporous-NiO-YSZ.
AB  - Solid oxide fuel cells comprised of an anode made from sintered and reduced
      mesoporous-NiO-YSZ are shown to provide stable current and power densities at the
      operating temperature of 800 degrees C and show better performance than cells
      with anode cermets made from mechanical mixtures of NiO and YSZ, attributable to
      the unique anode microstructure.

PMID- 12430412
TI  - Unexpected solid-solid reaction upon preparation of KBr pellets and its
      exploitation in supramolecular cation complexation.
AB  - Pressing solid [CoIII(eta 5-C5H4COOH)(eta 5-C5H4COO)] with KBr to prepare samples
      for IR spectroscopy leads to a profound solid state rearrangement with formation
      of the supramolecular complex [CoIII(eta 5-C5H4COOH)(eta 5-C5H4COO)]2.K+Br-,
      which can also be obtained from solution crystallization. Similar solid-solid
      supramolecular complexation has been observed with K[PF6] and [NH4][PF6].

PMID- 12430413
TI  - Hammett analysis of a C-C hydrolase-catalysed reaction using synthetic 6-aryl-2
      hydroxy-6-ketohexa-2,4-dienoic acid substrates.
AB  - A Hammett plot (rho = -0.71) has been measured for C-C hydrolase enzyme BphD from
      Pseudomonas LB400, using six 6-aryl-2-hydroxy-6-ketohexa-2,4-dienoic acids
      synthesised by a Heck coupling strategy.

PMID- 12430414
TI  - An expedient synthesis of homophthalimides.
AB  - The six-membered heterocyclic subunit of homophthalimides can be obtained by a
      direct, hitherto unprecedented, radical cyclisation onto an aromatic ring
      starting from a xanthate precursor.

PMID- 12430415
TI  - Microwave-assisted purification of HIPCO carbon nanotubes.
AB  - A very easy way for improving the purity of carbon nanotubes using a domestic
      multimode microwave oven is reported, in which selective burning of metal
      particles helps remove most of the iron content.

PMID- 12430416
TI  - A novel catalytic one-pot synthesis of carbazoles via consecutive amination and C
      H activation.
AB  - Sequential palladium catalysed amination and C-H activation reactions occur
      between 2-chloro-N-alkylated anilines and aryl bromides to give carbazoles in one
      pot.

PMID- 12430418
TI  - DNA minor groove hydration probed with 4'-alkylated thymidines.
AB  - Employing modified oligonucleotides that are 4'-alkylated site-specifically we
      investigated the involvement of DNA minor groove hydration on DNA duplex
      stability and helix conformation.

PMID- 12430417
TI  - A flexible strategy for the divergent modification of pleuromutilin.
AB  - The complex antibacterial natural product, pleuromutilin, can be directly
      modified by the radical addition reaction of various xanthates to the unactivated
      terminal olefin present on C-12.

PMID- 12430419
TI  - Bis(imino)pyridine cobalt alkyl complexes and their reactivity towards ethylene:
      a model system for beta-hydrogen chain transfer.
AB  - Bis(imino)pyridine cobalt(I) n-alkyl complexes react with ethylene by beta
      hydrogen transfer, allowing direct study of a termination step commonly
      encountered in polymerisation and oligomerisation catalysis.

PMID- 12430420
TI  - Pi-electron conjugation effects in antiaromatic dehydro[12]- and aromatic
      dehydro[18]-annulenes.
AB  - N,N-Dimethylanilino-substituted perethynylated dehydro[12]- and dehydro[18]
      annulenes were prepared by oxidative acetylenic coupling of cis-bisdeprotected
      tetraethynylethene derivatives obtained by a new photochemical route; they
      display strongly bathochromically shifted longest-wavelength absorption bands
      compared to their silyl-substituted counterparts resulting from efficient
      intramolecular charge-transfer between the peripheral pi-electron donors and the
      electron-accepting central acetylenic core.

PMID- 12430421
TI  - Small reorganisation energy and unique stabilisation of zwitterionic C60-acceptor
      moieties.
AB  - Fulleropyrrolidine- and fulleropyrrolidinium-based donor-acceptor ensembles, C60
      Fc, were tested in view of intrinsic reorganisation energies for light-induced
      electron transfer events; overall, the zwitterionic character of the reduced
      fulleropyrrolidinium acceptor plays a central role in accelerating charge
      separation and decelerating charge recombination.

PMID- 12430422
TI  - Organic/inorganic supramolecular channel frameworks containing a photosensitive
      azobenzene molecule as an included guest.
AB  - Two independent channel frameworks are occupied by photoactive E-azobenzene in an
      unprecedented one-dimensional zigzag motif and thus form virtual three
      dimensional supramolecular host-guest networks.

PMID- 12430423
TI  - Controlled deposition of nanoparticles at the liquid-liquid interface.
AB  - We report a novel method for the preparation of well-defined metallic
      nanoparticles, which is illustrated with the technologically important example of
      palladium nanoparticles dispersed in gamma-alumina.

PMID- 12430424
TI  - The inner solvation of a cylindrical capsule.
AB  - Solvents inside a cylindrical capsule exchange positions slowly on the NMR
      timescale.

PMID- 12430425
TI  - Photoinduced ground-state singlet biradical--novel insight into the photochromic
      compounds of biindenylidenediones.
AB  - The biindenylidenedione derivative (A) developed a biradical accompanied by the
      simultaneous photocolor development on UV or sunlight irradiation; the former of
      which showed antiferromagnetic behavior on account of the singlet ground state
      and a thermally accessible triplet state.

PMID- 12430426
TI  - Synthesis of long Poly(dA).Poly(dT) DNA without structural defects using
      enzymatic reaction; tailored ligated Poly(dA).Poly(dT).
AB  - Poly(dA).Poly(dT) molecules up to 1000 base pairs (bp) have been synthesized
      using enzymatic reaction, and characterization by STM observation shows that the
      DNA has no defects in the duplex structure.

PMID- 12430427
TI  - Unique 2D metalloporphyrin networks constructed from iron(II) and meso-tetra(4
      pyridyl)porphyrin.
AB  - A one-pot solvothermal reaction of iron(II) with meso-tetra(4-pyridyl)porphyrin
      (TPyP) leads to two novel layered structures with an unprecedented two
      dimensional paddle-wheel-like pattern; the two structures have the same
      composition Fe(TPyP) but a different packing sequence, namely ...ABAB... and
      ...ABCDABCD....

PMID- 12430428
TI  - Non-amine-based furan-containing oligoaryls as efficient hole transporting
      materials.
AB  - A new class of highly stable furan-based hole transporting oligomeric materials,
      synthesized from the corresponding propargylic dithioacetals, serve as efficient
      hole transporting materials in electroluminescent devices. The performance of the
      devices using these furan materials is comparable with or somewhat better than
      those employing the conventional triarylamines (e.g. alpha-NPD).

PMID- 12430429
TI  - 5-azahexenoyl radicals cyclize via nucleophilic addition to the acyl carbon
      rather than 5-exo homolytic addition at the imine.
AB  - Molecular orbital calculations predict that the 5-azahexenoyl radical ring closes
      via nucleophilic addition to the acyl carbon to afford the 5-exo product;
      CCSD(T)/cc-pVDZ/ /BHLYP/cc-pVDZ calculations predict energy barriers of 36.1 and
      46.9 kJ mol-1 for the exo and endo cyclization modes of the 5-azahexenoyl
      radical, respectively.

PMID- 12430430
TI  - A new material for selective removal of nitrogen compounds from gasoils towards
      more efficient HDS processes.
AB  - A selective removal of nitrogen compounds from gasoils is proposed, using a
      recyclable sorbent capable of forming charge-transfer complexes; the selective
      elimination of nitrogen compounds strongly improves the hydrodesulfurization
      (HDS) of denitrogenated feed.

PMID- 12430431
TI  - Spontaneous resolution and absolute configuration of a coordination polymer
      formed by MnII and a ferrocene-based bisnitronyl nitroxide radical.
AB  - Crystallisation of a ferrocenyl bis(nitronyl nitroxide) with manganese(II)
      bis(hexafluoroacetylacetonate) gives rise to spontaneous resolution of a
      coordination polymer formed by the two units creating seven sources of chirality.

PMID- 12430432
TI  - Preferential solvation of an ILCT excited state in bis(terpyridine-phenylene
      vinylene) Zn(II) complexes.
AB  - The excited state of terpyridine derivatives of phenylene-vinylene fragments
      chelating Zn(II) show a strong solvatochromism (up to 56 nm) upon preferential
      solvation by polar solvents of an intraligand charge transfer state.

PMID- 12430433
TI  - Peculiar magnetic behavior in ion-pair complex [1-(4'
      fluorobenzyl)pyridinium][Ni(mnt)2] (mnt2- = maleonitriledithiolate).
AB  - An ion-pair complex [FBzPy][Ni(mnt)2], where [FBzPy]+ = 1-(4'
      fluorobenzyl)pyridinium and mnt2- = maleonitriledithiolate, forms a discrete
      stacking column and shows a peculiar magnetic transition from paramagnetic to
      diamagnetic around 90 K.

PMID- 12430434
TI  - The first asymmetrically beta-polysubstituted porphyrin-based hexagonal columnar
      liquid crystal.
AB  - The preparation of a new beta-tetrasubstituted porphyrin through a short
      synthesis with liquid crystalline properties in a wide range of temperatures
      including room temperature is described.

PMID- 12430435
TI  - A dansylated peptide for the selective detection of copper ions.
AB  - A new peptidyl fluorescent chemosensor for the selective detection of copper ions
      was studied.

PMID- 12430436
TI  - Towards a synthetic model of the photosynthetic water oxidizing complex:
      [Mn3O4(O2CMe)4(bpy)2] containing the [MnIV3(mu-O)4]4+ core.
AB  - The 3 MnIV title compound has been prepared and characterized by X-ray
      crystallography and magnetochemistry; the complex contains a [Mn(mu-O)2Mn(mu
      O)2Mn]4+ core and possesses an S = 3/2 ground state.

PMID- 12430437
TI  - The gas phase proton affinity of uracil: measuring multiple basic sites and
      implications for the enzyme mechanism of orotidine 5'-monophosphate
      decarboxylase.
AB  - We have shown for the first time experimentally that the O2 and O4 sites of
      uracil have different proton affinities, and as implied in previous computational
      studies, the O4 is more basic and would be energetically preferred in an orotate
      ribose 5'-monophosphate decarboxylase catalysis mechanism involving proton
      transfer to oxygen.

PMID- 12430438
TI  - Tris(1-4-eta 4-anthracene)niobate(1-), the first polyaromatic hydrocarbon complex
      of niobium.
AB  - The first tris(arene)niobium complex, [Nb(1-4-eta 4-anthracene)3]-, has been
      obtained by the sodium or potassium anthracene reduction of NbCl4(THF)2,
      structurally characterized by X-ray analysis and shown to undergo facile
      anthracene displacement reactions in the presence of excess CO, PF3, 1,3,5,7
      cyclooctatetraene and P(OMe)3.

PMID- 12430439
TI  - The first 3-D ferrimagnetic nickel fumarate with an open framework: [Ni3(OH)2(O2C
      C2H2-CO2)(H2O)4].2H2O.
AB  - A three-dimensional nickel fumarate has been isolated by hydrothermal reaction
      and its structure solved from powder X-ray diffraction; its organisation reveals
      an unusual topology not previously seen in nickel chemistry and provided a scarce
      ferrimagnetic behaviour below 20 K.

PMID- 12430440
TI  - Asymmetric epoxidation via phase-transfer catalysis: direct conversion of allylic
      alcohols into alpha,beta-epoxyketones.
AB  - Studies into the use of a chiral phase-transfer catalyst in conjunction with
      sodium hypochlorite to effect the enantio-selective formation of alpha,beta
      epoxyketones from allylic alcohols are described.

PMID- 12430441
TI  - Novel method for the synthesis of enamines by palladium catalyzed amination of
      alkenyl bromides.
AB  - The intermolecular palladium catalyzed cross-coupling reaction between secondary
      amines and alkenyl bromides is described for the first time, giving rise to
      enamines with very high yields and regioselectivity.

PMID- 12430442
TI  - Synthesis, structure and magnetism of a new dicubane-like ferromagnetic
      tetranuclear nickel cluster containing versatile azido-only bridges and a
      bis(bidentate) Schiff base blocker.
AB  - A new tetranuclear double-open dicubane complex [Ni4(mu 2-N3)4(mu 3
      N3)2(N3)2(enbzpy)2].2H2O (enbzpy = [N,N-bis(pyridin-2-yl)benzylidene]ethane-1,2
      diamine) has been characterised structurally and magnetostructurally.

PMID- 12430443
TI  - EuII-cryptate with optimal water exchange and electronic relaxation: a synthon
      for potential pO2 responsive macromolecular MRI contrast agents.
AB  - The cryptate [EuII(2.2.2)(H2O)2]2+ displays several interesting features with
      respect to pO2 responsive MRI contrast agent applications: it is relatively
      stable against oxidation, it has two inner sphere water molecules, and the water
      exchange and electron spin relaxation rates are in the optimal range to attain
      high proton relaxivities, provided the rotation is also optimized.

PMID- 12430444
TI  - A modular electrochemical sensor for saccharides.
AB  - A modular electrochemical saccharide sensor using ferrocene has been prepared
      which contains two boronic acid receptor groups and hexamethylene linker.

PMID- 12430445
TI  - C60F36: there is a third isomer and it has C1 symmetry.
AB  - From fluorination of [60]fullerene with MnF3/K2NiF6 at 480 degrees C we have
      isolated and characterized by both 19F NMR spectrum and single crystal X-ray
      analysis, a C1 isomer of C60F36; it has three planar delocalized aromatic rings,
      three short C=C bonds (due to compression from the adjacent fluorines), the
      longest FC-CF bond (1.684 A) yet found in a fluorofullerene, and its stability is
      predicted by calculations.

PMID- 12430446
TI  - Mechanochemistry and co-crystal formation: effect of solvent on reaction
      kinetics.
AB  - We demonstrate that significant improvements in kinetics of co-crystal formation
      by grinding can be achieved by the addition of minor amounts of appropriate
      solvent.

PMID- 12430447
TI  - Dibenzoeilatin: a novel ligand exhibiting remarkable complementary pi-pi stacking
      interactions.
AB  - The complex [Ru(bpy)2(dbneil)][PF6]2 forms discrete dimers in solution held by
      strong pi-pi stacking interactions via its distorted dibenzoeilatin ligand,
      indicating that planarity is not an obligatory requirement for achieving strong
      pi-stacking, as long as complementarity between the stacking moieties can be
      achieved.

PMID- 12430448
TI  - High yield conversion of methane to methyl bisulfate catalyzed by iodine cations.
AB  - Iodine in 2% oleum is an efficient catalyst for the selective, high yield
      oxidation of methane to methyl bisulfate.

PMID- 12430449
TI  - Formation of extraordinarily large nanosheets from K4Nb6O17 crystals.
AB  - Exfoliated K4Nb6O17 bilayer nanosheets in extraordinarily large size (ca. 100
      microns) were prepared by the direct reaction of K4Nb6O17.3H2O crystals with an
      aqueous solution of propylamine; the size was extremely larger than that of
      exfoliated nanosheets (several microns) reported previously.

PMID- 12430450
TI  - Synthesis of (+)-puraquinonic acid.
AB  - (+)-Puraquinonic acid (1a) was synthesized, using a route based on ring-closing
      metathesis and radical cyclization, the chirality of the quaternary carbon being
      controlled by a temporary adjacent asymmetric center.

PMID- 12430451
TI  - High temperature peroxidase activities of HRP and hemoglobin in the galleries of
      layered Zr(IV)phosphate.
AB  - Horseradish peroxidase, and met hemoglobin, when intercalated in the galleries of
      alpha-Zr(IV) phosphate, show peroxidase activities at elevated temperatures (86
      90 degrees C) and the rates increased to 2-3.6 times the rates observed at room
      temperature.

PMID- 12430452
TI  - Tyrosine 92 of aristolochene synthase directs cyclisation of farnesyl
      pyrophosphate.
AB  - A mutant of Aristolochene Synthase (AS), in which Tyr 92 was replaced by Val,
      produced the alicyclic beta-(E)-farnesene as the major product, indicating that
      cyclisation of FPP is controlled by Tyr 92 in AS.

PMID- 12430453
TI  - The role of post-translational modification in the photoregulation of Fe-type
      nitrile hydratase.
AB  - The inactive, nitrosyl bound form of Fe-type nitrile hydratase (NHase) contains
      two active site cysteine residues that are post-translationally modified to
      sulfenate (SO-) and sulfinate (SO2-) ligands. DFT and INDO/S calculations support
      the hypothesis that these unusual modifications play a key role in modulating the
      electronic absorption spectra and photoreactivity of the Fe(III) centre in the
      enzyme.

PMID- 12430454
TI  - Catalytic hydrogenation of arenes with rhodium nanoparticles in a water-in
      supercritical CO2 microemulsion.
AB  - Rhodium nanoparticles dispersed by a CO2 microemulsion are effective catalysts
      for rapid hydrogenation of arenes in supercritical CO2.

PMID- 12430455
TI  - Chemical modification of a viral cage for multivalent presentation.
AB  - Here we present generalized methods for chemically modifying the surface of a
      viral protein cage; this exploits the chemistry of native and engineered surface
      exposed functional groups for multivalent presentation of ligands.

PMID- 12430456
TI  - Oxodiperoxo molybdenum modified mesoporous MCM-41 materials for the catalytic
      epoxidation of cyclooctene.
AB  - A hybrid heterogeneous catalyst system, which has been synthesized by covalently
      anchoring oxodiperoxo molybdenum chelate complexes onto the surface of mesoporous
      MCM-41, is highly active and truly heterogeneous for the liquid-phase epoxidation
      of cyclooctene with tBuOOH as the oxygen source.

PMID- 12430457
TI  - Thioepoxide formation by ring closure of allylthiyl radicals--a novel
      rearrangement of allylic thionitrites.
AB  - Tertiary allylic thionitrites undergo thermal rearrangement to alpha,beta
      episulfide nitroso dimers via ring closure of allylthiyl radicals.

PMID- 12430458
TI  - Characterisation of pillared clays by contrast-matching small-angle neutron
      scattering.
AB  - The contrast-matching SANS technique has been utilised to determine inter-pillar
      distances (and surface texture) in montmorillonite and beidellite pillared
      smectite clays; they lie in the range 1.40-1.80 nm, reflecting different inter
      pillar orderings.

PMID- 12430459
TI  - Synthesis of a new open framework cerium silicate and its structure determination
      by single crystal X-ray diffraction.
AB  - Hydrothermal synthesis of a new open framework cerium silicate and its structure
      determination by single crystal X-ray diffraction are reported.

PMID- 12430461
TI  - Structure of low concentrations of vanadium on TiO2 determined by XANES and ab
      initio calculations.
AB  - The major local structure of low concentrations (1-3 wt% V) of vanadium on TiO2
      was determined to have two terminal oxo groups and in total five oxygen
      coordination by means of vanadium K-edge XANES and ab initio calculations of
      XANES spectra.

PMID- 12430460
TI  - Two-photon induced blue fluorescent emission of heterocycle-based organic
      molecule.
AB  - An organic molecule based on a heterocycle acceptor has been found to exhibit an
      intensive two-photon induced blue emission and a large two-photon absorption
      cross section, which implies that the molecule is a promising candidate for an
      application such as multi-channel two-photon microscopy.

PMID- 12430462
TI  - Heteropolyacids aided rapid and convenient syntheses of highly ordered MCM-41 and
      MCM-48: exploring the accelerated process by 29Si MAS NMR and powder X-ray
      diffraction studies.
AB  - A rapid and convenient route is described for the synthesis of mesoporous MCM-41
      and MCM-48 materials using heteropolyacids as novel promoters, and a probable
      mechanism for the rapid nucleation is proposed based on HSAB theory.

PMID- 12430463
TI  - Uniform formation of uranium oxide nanocrystals inside ordered mesoporous hosts
      and their potential applications as oxidative catalysts.
AB  - Highly dispersed uranium oxide nanocrystals supported on ordered mesoporous
      silica matrixes with large surface areas and porosities have been synthesized via
      a co-assembly methodology; the preliminary catalysis tests showed that these
      materials have a high catalytic activity for the thermal oxidation of volatile
      organic compounds (VOCs).

PMID- 12430465
TI  - Synthesis of large-pore phenylene-bridged mesoporous organosilica using triblock
      copolymer surfactant.
AB  - Periodic mesoporous benzene-silicas with large pores of 6.0 to 7.4 nm in diameter
      are synthesized using triblock copolymer as a template. These mesoporous
      materials have a well-defined hexagonal rod morphology and high thermal stability
      up to 823 K in air.

PMID- 12430464
TI  - A new family of conjugated metallopolymers from electropolymerised
      bis[(terthiophene)dithiolene] complexes.
AB  - Bis(dithiolene) metal complexes incorporating fused terthiophene units have been
      prepared; the nickel analogue undergoes electropolymerisation to afford a low
      bandgap material with very broad absorption characteristics.

PMID- 12430466
TI  - The Baylis-Hillman condensation of alpha,beta-conjugate cycloketones with
      aldehydes using diethylaluminum iodide alone as the promoter.
AB  - The Baylis-Hillman condensation of three types of alpha,beta-conjugate
      cycloketones with aldehydes was successfully performed by using diethylaluminum
      iodide as the Lewis acid promoter alone without the direct use of a Lewis base.
      The reaction proceeded to completion at 0 degree C in CH2Cl2 within 24 h to give
      modest to good yields (53-72%).

PMID- 12430467
TI  - One-pot synthesis of hydrogen phosphonate derivatives of d4T and AZT.
AB  - A simple and one-pot route for the synthesis of d4T or AZT hydrogen phosphonate
      derivatives via reaction of d4T or AZT with phosphorus trichloride, then
      alcoholysis and dealkylation in the presence of the corresponding alcohol is
      described.

PMID- 12430468
TI  - Linear alignment of four sulfur atoms in bis[(8-phenylthio)naphthyl] disulfide:
      contribution of linear S4 hypervalent four-centre six-electron bond to the
      structure.
AB  - The four sulfur atoms in bis[8-(phenylthio)naphthyl]-1,1'-disulfide are
      demonstrated to align linearly by the X-ray crystallographic analysis, where the
      linear S4 alignment is stabilized by the four-centre six-electron interaction.

PMID- 12430469
TI  - Beta zeolite supported on a macroscopic pre-shaped SiC as a high performance
      catalyst for liquid-phase benzoylation.
AB  - Preparation and characterisation of a highly active and stable beta zeolite
      supported on a pre-shaped silicon carbide catalyst for the benzoylation reaction
      in liquid phase.

PMID- 12430470
TI  - Hydrofluorocarbon 245fa: a versatile new synthon in alkyne chemistry.
AB  - The CFC replacement 1,1,1,3,3-pentafluoropropane (HFC 245 fa) has been
      established as a convenient source of trifluoropropynyllithium under mild
      conditions; a range of novel and known trifluoropropynyl-containing systems has
      been prepared in a one-pot procedure.

PMID- 12430471
TI  - Catalytic enantioselective intermolecular [2 + 2 + 2] cycloaddition of an alkene
      and two alkynes.
AB  - A catalytic enantioselective intermolecular [2 + 2 + 2] cycloaddition of one
      molecule of alkene (enone) and two molecules of alkyne was developed in the
      presence of a nickel complex modified by chiral monodentate oxazoline ligands,
      which have not previously been used as chiral ligands for transition metals in
      asymmetric catalysts, and an aluminium phenoxide.

PMID- 12430472
TI  - Improved synthesis of dithieno[3,2-b:2',3'-d]thiophene (DTT) and derivatives for
      cross coupling.
AB  - An improved synthesis of dithieno[3,2-b:2',3'-d]thiophene (DTT) and its 2,6- and
      3,5-dibromo derivatives has been devised; Stille cross coupling of 2,5
      (bistrimethylstannyl)-DTT afforded the oligomer 12.

PMID- 12430473
TI  - Synthesis, spectroscopy and metallation of mixed carbaporphyrinoid systems.
AB  - Modified tripyrranes incorporating furan and thiophene rings were found to
      condense with benzene, pyridine and indene dialdehydes to give a series of novel
      porphyrin analogues, including thia- and oxa-carbaporphyrins; the latter readily
      forms nickel(II) and palladium(II) organometallic complexes.

PMID- 12430474
TI  - A second generation dendrimer incorporating nine S2N2-donor macrocycles and its
      palladium(II) complex.
AB  - A new second generation dendrimer incorporating nine S2N2-donor macrocyclic units
      that bind nine Pd(II) cations is reported.

PMID- 12430475
TI  - Ferrocenoyl glycylcystamine: organization into a supramolecular helicate
      structure.
AB  - Extensive intermolecular hydrogen bonding in ferrocenoyl glycylcystamine gives
      rise to a novel ordered double helical arrangement with a helical pitch height of
      14 A.

PMID- 12430476
TI  - Triple C-H activation of 1,5-bis(di-tert-butylphosphino)-2-(S)
      dimethylaminopentane on ruthenium gives a chiral carbene complex.
AB  - This communication reports the preparation of a novel trans-chelating
      diphosphine, 1,5-bis(di-tert-butylphosphino)-2-(S)-dimethylaminopentane, that
      undergoes triple C-H activation in reaction with [RuCl2(p-cymene)]2 to give a
      chiral square-pyramidal 16-electron carbene complex of ruthenium.

PMID- 12430477
TI  - Synthesis of stable hollow silica microspheres with mesoporous shell in nonionic
      W/O emulsion.
AB  - Stable hollow silica microspheres were synthesized by a solgel method in nonionic
      W/O emulsion; the mesoporous shell wall of the spheres could have potential
      applications as controlled release capsules for drugs, dyes, cosmetics and inks,
      artificial cells, catalysts, and fillers.

PMID- 12430478
TI  - Enantioselective total synthesis of (-)-xialenon A.
AB  - The first total synthesis of (-)-xialenon A (1) via conjugate allylation of a 1,5
      cyclooctadiene-derived bicyclo[3.3.0]octenone 3 and an alpha'-hydroxylation on
      the more hinderd face of enone 9 using hypervalent iodine chemistry, is
      described.

PMID- 12430479
TI  - Chiral discrimination of 2,3-butanediols by laser spectroscopy.
AB  - The resonance enhanced two-photon ionization time-of-flight (R2PI-TOF) excitation
      spectra of supersonically expanded complexes of isomeric 2,3-butanediols with a
      suitable chromophore, i.e. R-(+)-1-phenyl-1-propanol, represent powerful means
      for structurally discriminating the diol moiety and for investigating the nature
      of the intra- and intermolecular interactions involved in the complexes.

PMID- 12430480
TI  - Synthesis of alpha-amino acid derivatives and amines via activation of simple
      alkyl halides by zinc in water.
AB  - A method for the synthesis of alpha-amino acid derivatives and amines is
      developed via a zinc-mediated conjugate addition reaction of alkyl halides to
      alpha-phthalimidoacrylate derivatives and nucleophilic addition to imines in the
      presence of NH4Cl in water. No reaction was observed in the absence of water.

PMID- 12430481
TI  - Direct imaging of o-carborane molecules within single walled carbon nanotubes.
AB  - Ortho-carborane molecules have been inserted into single walled carbon nanotubes
      (SWNTs) and imaged directly by high resolution transmission electron microscopy
      (HRTEM); both discrete molecules and 'zig-zag' 1D chains of o-carborane 'petit
      pois' were observed to pack into the tubule capillaries.

PMID- 12430482
TI  - Light-controlled gas permeability of mesoporous silica glass bearing photochromic
      spironaphthoxazine on its surface.
AB  - N2 and CO2 gas permeability of mesoporous silica glass bearing photochromic
      indolinospironaphth[2,1-b][1,4]oxazine through a covalent linkage was controlled
      by photo-irradiation: the photo-isomerization of the spironaphthoxazine to the
      photomerocyanine form suppressed the gas permeation of the glass.

PMID- 12430484
TI  - Rapid access to tetracyclic ring system of lennoxamine type natural product by
      combined use of a novel three-component reaction and Pummerer cyclization.
AB  - From readily available allylamine, aldehyde and isocyanoacetamide, a three
      component reaction followed by a Pummerer cyclization provided tetracyclic ring
      systems (6-7-5-6 and 6-6-5-6) in excellent overall yields.

PMID- 12430483
TI  - Grafting of synthetic mannose receptor-ligands onto onion vectors for human
      dendritic cells targeting.
AB  - A practical preparation of onion vesicles targeted to dendritic cells involves
      the grafting of mannose-mimetic clusters, bearing a hydrazino group, onto the
      surface of onion vesicles containing an aldehyde functionalized lipid.

PMID- 12430485
TI  - A selective colorimetric anion sensor based on an amide group containing
      macrocycle.
AB  - A new colorimetric anion sensor 4 allows for selective 'naked-eye'
      differentiation of F-, AcO- and H2PO4- with similar basicity.

PMID- 12430486
TI  - 'On-off-on' fluorescent indicators of pH windows based on three separated
      components.
AB  - 'On-off-on' fluorescent indicators for pH windows are obtained with ternary
      systems in which the three separated components are Cu2+, a tetraaza ligand and
      the fluorophore Coumarin 343: protonation of Coumarin 343, its coordination to
      Cu2+ and its displacement from Cu2+ by OH- give an inverse bell-shaped variation
      of emission with pH.

PMID- 12430487
TI  - A right handed peptide helix containing a central double D-amino acid segment.
AB  - The crystal structure of the 13 residue peptide Boc-Leu-Aib-Val-Ala-Leu-Aib-Val
      DAla-DLeu-Aib-Leu-Aib-Val-OMe reveals a continuous helical conformation providing
      an unambiguous characterization of contiguous D-residues in a right handed
      peptide helix.

PMID- 12430488
TI  - Epoxidation of alkenes with hydrogen peroxide catalyzed by iron(III) porphyrins
      in ionic liquids.
AB  - An efficient procedure is described for catalyst recycling and easy product
      isolation in alkene epoxidation with hydrogen peroxide catalyzed by water-soluble
      iron(III) porphyrins in environmentally benign and ambient temperature ionic
      liquids.

PMID- 12430489
TI  - Are metal alkoxides linear owing to electrostatic repulsion?
AB  - Density functional theory calculations on [LnCp2APh] (Ln = La, Lu; Cp = eta 5
      C5H5; A = O, S; Ph = C6H5) suggest that the linearity of the Ln-O-C vectors
      arises largely as a result of electrostatic repulsion between the alpha carbon
      and the trivalent metal centre.

PMID- 12430490
TI  - Children's efforts to make sense of intravenous cannulation.

PMID- 12430491
TI  - The pill crushers' dilemma.

PMID- 12430493
TI  - It is what you know.

PMID- 12430494
TI  - Improving airway care.

PMID- 12430495
TI  - Discharge planning.
AB  - BACKGROUND: Two audits were conducted by a small team of nurses to measure the
      effectiveness of discharge management and planning in a four-ward orthopaedic and
      trauma unit. Co-ordinating this process is an important part of the nurse's role,
      as discharge planning is a vital component of effective bed management. This work
      focused on changing practice and measuring change, rather than on the effects of
      length of stay in hospital. CONCLUSION: The findings showed that some wards were
      proactive: planning started on admission and patients were given realistic
      planned discharge dates and a list of probable capabilities. However, discharge
      planning varied from ward to ward, and there was no shared common practice. Both
      audits reflect the need to raise the profile of discharge planning and audit, to
      increase staff co-operation with the planning process.

PMID- 12430496
TI  - International collaboration in genetic nursing.
AB  - Collaboration across national borders presents unique challenges and
      opportunities. A desire to expand your understanding of healthcare issues, and a
      willingness to share time and intellectual resources generously, contribute to
      successful collaboration. This is especially useful in small but rapidly
      developing healthcare specialities, such as genetic nursing. By outlining the
      benefits of work between two nurses in the UK and the US, this article argues
      that specialist nurses can benefit from international collaboration where the
      partners share problem solving and mentoring on common professional issues.

PMID- 12430497
TI  - The management of breathlessness in palliative care.
AB  - Breathlessness poses a significant problem in cancer care. Tanya Andrewes
      provides an overview of this symptom and discusses strategies for management.

PMID- 12430499
TI  - Excerpts from Mosby's Tour Guide to Nursing School a student's road survival kit.

PMID- 12430500
TI  - Defend yourself against stress.

PMID- 12430501
TI  - Get organized for clinicals 10 tips to use now!

PMID- 12430502
TI  - A study examining the health perceptions and parenting stressors of parenting
      African-American grandparents.
AB  - The objectives of this study of African-American, parenting grandparents were to
      examine the antecedents to grandparent parenting, the grandparents' perception of
      their health status, and their assessment of parenting stress. Thirty-one
      subjects completed a demographic questionnaire, two questions from the Short form
      36-Health Survey, and the Parenting Stress Index (PSI). Results indicated that
      the grandparents parented minor grandchildren because of biological parent
      neglect/abuse, abandonment, mental illness, substance abuse, teen mother, or
      death of a parent. While most grandparents considered their health to be
      satisfactory, the grandparents, ages thirty to sixty reported a greater number of
      health concerns. The PSI identified life stress greater than parenting stress. In
      conclusion, additional research is needed to identify life stresses that add to
      the parenting burden, and grandparents' needs to continue parenting.

PMID- 12430503
TI  - Psychosocial and functional outcomes in African Americans with diabetes mellitus.
AB  - The overall goal of this study was to examine factors in African Americans that
      account for the variance in diabetes self-care, a proxy measure for functional
      status. A descriptive correlational design was used to study a sample of 133
      adult African Americans with diabetes. The protocol included measures of
      psychosocial adjustment, self-efficacy, and functional status. Data were analyzed
      using descriptive statistics, stepwise multiple regression and T-tests. The
      analysis revealed positive attitudes and adjustment to having diabetes, a high
      level of self-confidence, and low functional status. Women compared to men scored
      higher on "negative attitude," and had greater problems with components
      comprising psychosocial adjustment to their diabetes and its related care. A
      description of socio-demographic data enhanced data collection. Level of formal
      education, which consistently correlated with various components of functional
      status was concluded to be the most significant variable associated with a good
      functional status outcome for African Americans with diabetes.

PMID- 12430504
TI  - External examiners: international collaboration in nursing education.
AB  - With the advent of mass communication, air travel, and most recently the World
      Wide Web, the need for global considerations in nursing and nursing education has
      emerged as a strong force. Nurses who serve as external examiners in
      international sites are participating in international collaboration in nursing
      education. The external examiner is defined as a visiting assessor of high
      academic standing with objectivity and integrity, who ensures that examination
      procedures are conducted according to regulations governing the academic degree.
      A long-standing British tradition in higher education, external examiners share
      in the intellectual effort of evaluating student courses and assessment
      strategies. The external examining experience consists of six steps: (1)
      appointment; (2) contract; (3) review of curriculum and examination materials;
      (4) on-site visit; (5) consolidating external and internal assessments; and (6)
      preliminary and final reports. The process is a complex one requiring the
      external examiner to function in multifaceted and complex roles. The authors,
      external examiners in Botswana, southern Africa, over a five-year period ending
      in 1997, present basic information about the process, the experience, and
      potential sources of difficulty when fulfilling the role.

PMID- 12430505
TI  - Great black nurses series: Estelle Massey Riddle Osborne.

PMID- 12430506
TI  - The changing mosaic of mentoring.

PMID- 12430507
TI  - Mentoring: a professional obligation. Interview by Mae McWeeny.

PMID- 12430508
TI  - Mentoring at the edge of chaos.

PMID- 12430509
TI  - Mentoring connections: learning relationships.

PMID- 12430510
TI  - Mentoring. Validating, yet challenging, support.

PMID- 12430511
TI  - Mentoring and its potential nursing role.

PMID- 12430512
TI  - Brigham and Women's balanced scorecard goes hi-tech.

PMID- 12430513
TI  - Use claims data to spotlight weaknesses in delivery of care.

PMID- 12430514
TI  - Access to data warehouse boosts St. Louis physicians' use of generic
      prescriptions.

PMID- 12430515
TI  - Improving patient satisfaction can be data-driven process.

PMID- 12430516
TI  - Hold a hand in need.

PMID- 12430517
TI  - Are you aware? Are you prepared?

PMID- 12430518
TI  - Eczema herpeticum: a dermatologic emergency.
AB  - Eczema herpeticum is a potentially life-threatening herpetic superinfection of a
      pre-existing skin disease. Despite the availability of antiviral therapies,
      eczema herpeticum remains a dermatologic emergency today. Two representative
      cases of eczema herpeticum along with discussion of the etiology, means of
      diagnosis, treatments, and complications of eczema herpeticum are presented.

PMID- 12430519
TI  - College tattoos: more than skin deep.
AB  - Nontattooed (n = 423, 81%) and tattooed (n = 97, 19%) college students report
      their cues, purpose, reason, risks, barriers, and customer criteria for
      tattooing; some psychosocial risks were documented. Challenges are posed and
      suggestions made for developing applicable health education.

PMID- 12430520
TI  - Necrotizing fasciitis: pathophysiology and treatment.
AB  - Necrotizing fasciitis (NF) is a life-threatening bacterial infection causing
      necrosis of the fascia, underlying skin, and vasculature. NF spreads rapidly,
      making immediate diagnosis important for survival. Treatment may involve the
      administration of several broad-spectrum antibiotics, surgical debridement, and
      skin grafting. In the following two articles, the pathophysiology, medical
      management, and nursing care of patients are discussed. An in-depth model care
      plan illustrates the complexity of the disease and its treatment.

PMID- 12430521
TI  - Necrotizing fasciitis: a model nursing care plan.
AB  - Accurate assessment and timely interventions are critical in caring for patients
      diagnosed with necrotizing fasciitis. A case example helps nurses assess and
      intervene the numerous problems commonly experienced by patients with necrotic
      fasciitis.

PMID- 12430522
TI  - What's your assessment? Tinea corporis.

PMID- 12430523
TI  - Ulcerated hemangiomas.

PMID- 12430524
TI  - Musculoskeletal injuries, stress and absenteeism.

PMID- 12430525
TI  - A wellness approach to bereavement support.

PMID- 12430526
TI  - A shared mental health care model.

PMID- 12430527
TI  - Managing legal risks in preceptorships.

PMID- 12430528
TI  - Fighting for others' rights.

PMID- 12430529
TI  - [The nursing profession in Italy in the year 2000].

PMID- 12430530
TI  - Dangerous Darwinism.
AB  - We are concerned with a particular rhetorical narrative that appeared in the
      early stages of the Darwin debate but that has been fiercely resurgent in the
      past two decades. Freud wrote of Darwin's theory as one of three major blows to
      which human vanity had been submitted at the hands of science. Assertions that
      "Darwin's dangerous idea" came as a horrible shock to the Victorians and that it
      is still a profound psychological threat, and therefore widely resisted, remain
      current. When such assertions are offered as the premise on which Darwin is to be
      approached by the general reader they call for some detailed scrutiny, with
      regard both to the bases on which they are made, and the effect they have on the
      terms of public debate. This paper offers a critique of the culture-shock myth
      based on a re-examination of Victorian reactions to Darwin's work, and on an
      analysis of the ways in which the myth functions as a rhetorical strategy in our
      own time.

PMID- 12430531
TI  - Respiratory societies and the medical community.

PMID- 12430532
TI  - "It just goes against the grain." Public understandings of genetically modified
      (GM) food in the UK.
AB  - This paper reports on one aspect of qualitative research on public understandings
      of food risks, focusing on lay understandings of genetically modified (GM) food
      in the UK context. A range of theoretical, conceptual, and empirical literature
      on food, risk, and the public understanding of science are reviewed. The
      fieldwork methods are outlined and empirical data from a range of lay groups are
      presented. Major themes include: varying "technical" knowledge of science, the
      relationship between knowledge and acceptance of genetic modification, the
      uncertainty of scientific knowledge, genetic modification as inappropriate
      scientific intervention in "nature", the acceptability of animal and human
      applications of genetic modification, the appropriate boundaries of scientific
      innovation, the necessity for GM foods, the uncertainty of risks in GM food,
      fatalism about avoiding risks, and trust in "experts" to manage potential risks
      in GM food. Key discussion points relating to a sociological understanding of
      public attitudes to GM food are raised and some policy implications are
      highlighted.

PMID- 12430533
TI  - Increasing public understanding of transgenic crops through the World Wide Web.
AB  - Transgenic crops among the most controversial "science and society" issues of
      recent years. Because of the complex techniques involved in creating these crops
      and the polarized debate over their risks and beliefs, a critical need has arisen
      for accessible and balanced information on this technology. World Wide Web sites
      offer several advantages for disseminating information on a fast-changing
      technical topic, including their global accessibility; and their ability to
      update information frequently, incorporate multimedia formats, and link to
      networks of other sites. An alliance between two complementary web sites at
      Colorado State University and the University of Nebraska-Lincoln takes advantage
      of the web environment to help fill the need for public information on crop
      genetic engineering. This article describes the objectives and features of each
      site. Viewership data and other feedback have shown these web sites to be
      effective means of reaching public audiences on a complex scientific topic.

PMID- 12430534
TI  - [Star figure in medical monitoring during lower body negative pressure test].
AB  - Objective. To find a real-time, quick and audio-visual method to evaluate the
      subject's physiological function condition and possible development. Method. Star
      figure technique was adopted to analyse multiple physiological indices during
      lower body negative pressure test (LBNP). Based on the character and stability of
      the stars figure, the steadiness of the subjects physiological function can be
      judged. Result. Physiological function can be accurately assessed only when the
      model of stress response of an individual is formed. Conclusion. The changes of
      star figure can indicate the possible development of the physiological function
      stage.

PMID- 12430535
TI  - [Comparison of sensitivity of mental load assessment indexes].
AB  - Objective. To compare the sensitivities of indexes used in the assessment of
      mental load. Method. Twenty five indexes belonging to primary task performance,
      additional task performance, subjective rate and psychophysiological measure were
      recorded during performance of 11 different difficult tasks. Result. It showed
      that tracking error (ER), reaction time (RT), correct rate (CR), category scale
      (CS), multistage evaluation scale (MES), multi-dimensional scale (MDS), latency
      of P3 (LAT), inter beat interval (IBI), inter respiration interval (IRI) and
      blink rate (BR) were significantly different among the various tasks. CS, MES and
      MDS were more sensitive to the total load; ER, LAT, IBI and IRI were more
      sensitive to the load of primary task, while RT and CR to that of additional task
      and BR to the visual load. Conclusion. It demonstrated that the sensitivities of
      the various indexes are different and the information are limited. Multi-indexes
      may be preferred for mental load assessment.

PMID- 12430536
TI  - [HRV analysis system based on Windows 95 and its preliminary application].
AB  - Objective. To provide a real useful application system for the HRV research.
      Method. The acquisition, detection and analysis system of HRV signal was set up
      based on Windows 95. The system analyzes the HRV signal with statistic method in
      time domain and power spectrum in frequency domain. And the power spectrum array
      was also introduced into the analysis. HRV signals of some healthy persons and
      some patients were detected and analyzed. Result. The HRV characteristic is much
      more obvious in the diabetics patients. Conclusion. The system is useful in HRV
      signal analysis and cardiovascular research.

PMID- 12430537
TI  - [Biographies of 20th century Polish medical scientists].

PMID- 12430538
TI  - [A reliability growth assessment method and its application in the development of
      equipment in space cabin].
AB  - Objective. To assess and predict reliability of an equipment dynamically by
      making full use of various test informations in the development of products.
      Method. A new reliability growth assessment method based on army material system
      analysis activity (AMSAA) model was developed. The method is composed of the
      AMSAA model and test data conversion technology. Result. The assessment and
      prediction results of a space-borne equipment conform to its expectations.
      Conclusion. It is suggested that this method should be further researched and
      popularized.

PMID- 12430539
TI  - [An experimental study of the Sabatier CO2 reduction subsytem for space station].
AB  - Objective. To develop and fabricate a prototype Sabatier CO2 reduction subsystem
      for long duration manned space missions. Method. The rationale, equipment and
      function of the Sabatier CO2 reduction subsystem were introduced. Groundbased
      experiments with CO2 flows equivalent to a crewsize of 3 persons were conducted
      to verify the operation performance of the prototype. Result. The start-up
      temperature is less than 165 degrees C when the start-up time is 14 min; the lean
      component H2/CO2 conversion efficiency is over 95 percent when H2/CO2 molar
      ratios is 1.9-5.0; The water produced is nearly colorless and neutral.
      Conclusion. The prototype Sabatier CO2 reduction subsystem is simple in operation
      and the test results showed that design goals were achieved.

PMID- 12430540
TI  - 'I never even gave it a second thought': PGCE students' attitudes towards the
      inclusion of children with speech and language impairments.
AB  - Approximately 7% of young school-aged children have specific language
      impairments. Many such children are now being educated in mainstream settings.
      However, there is a dearth of up-to-date and valid research that considers UK
      (student) teachers' attitudes towards such children. This study aimed to
      investigate trainee teachers' attitudes towards teaching children with speech and
      language impairments, to investigate the reported effects of those attitudes on
      participants' acceptance of teaching such children, and to consider any
      implications for speech and language therapy (SLT) services and inclusive
      education. Nineteen trainee teachers (PGCE students) from a university in the
      North West of England took part in semistructured group interviews. The data were
      transcribed and analysed qualitatively, and recurrent themes identified. A range
      of attitudes was expressed, and six major themes were identified from the data.
      Participants discussed concerns about the resources and knowledge they considered
      necessary to support fully children with specific language impairments. There was
      some differentiation of attitudes related to the types of disability that a child
      may have and the subject being taught. Much of the discussion was about
      disabilities in general rather than specific to speech and language impairments.
      Many of the participants reflected on their own previous experiences to inform
      their opinions. Although many of the participants expressed positive attitudes,
      some had concerns about workload and at least one was openly hostile to the idea
      of teaching children with disabilities within mainstream settings. The
      implications of these findings are discussed in relation to previous research,
      the quantitative data obtained in this project, SLT services and the increases in
      the inclusion of children with specific language impairments into mainstream
      educational settings.

PMID- 12430541
TI  - [Effects of 7 d head down tilt on cardiopulmonary circulation during
      orthostasis].
AB  - Objective. To accumulate data for further studies on the mechanisms of the
      decrease of cardiovascular function after weightlessness. Method. Cardiopulmonary
      circulatory function under supine position and head up tilting (HUT) for 20 min
      before and after exposure to 7 d 6 degrees head down tilt (HDT) in 6 healthy
      adults who aged 19-21 were measured with a XXH-2000 lesser (pulmonary)
      circulation and cardiac function instrument. Result. The 7 d HDT resulted in
      orthostatic intolerance of the subjects; the reduction of RVET (j-z) and the
      elevation of RPEP [RVET(Q-j)/(j - z)] indicated a decrease of the right heart
      function. An obvious decrease of the right heart reserves was also observed under
      HUT after HDT. Conclusion. hc and hc/hz were demonstrated to be useful parameters
      to evaluate orthostatic tolerance or to forecast orthostatic syncope. The lesser
      (pulmonary) circulation and cardiac function testing methods are valuable in
      evaluating the cardiopulmonary circulatory function during HUT.

PMID- 12430542
TI  - [Effects of motion sickness evoked by parallel swing stimulation on posture
      equilibrium].
AB  - Objective. To study the effects of motion sickness on posture equilibrium.
      Method. Dynamic posture was tested pre- and following motion sickness evoked by
      parallel swing. 17 healthy men were divided into motion sickness sensitive group
      (12) and motion sickness insensitive groups (5) according to their endurance
      times and the severeness of symptom. Result. The composite equilibrium score
      significantly decreased post-swing in all subjects. The composite equilibrium
      score, certain other equilibrium scores (SOT4, SOT5 and SOT6), the strategy
      scores (STRAT4 and STRAT6) and the sensory score (SEN3 and SEN5) significantly
      decreased in the sensitive group, but unchanged in the insensitive group post
      swing. The equilibrium score (SOT2), and the sensory score (SEN1) pre-swing, the
      strategy score (STRAT3) of insensitive group is significantly higher than the
      sensitive group. Conclusion. Motion sickness can influence postural equilibrium.
      Postural instability and instability of strategy are related to the sensitiveness
      to motion sickness.

PMID- 12430544
TI  - [Variations of EGG in subjects under vestibular stimulation].
AB  - Objective. To investigate the patterns of electrogastrogram [correction of
      electrogastrogragm] (EGG) before, during and after vestibular stimulation.
      Method. 25 subjects were stimulated by Coriolis acceleration and 28 by Coriolis
      [correction of corolis] stimulation. Result. Dysrythmia of EGG and increase of
      tachygastria were recorded in all subjects during the stimulation. The period
      dominant frequency (PDF) of EGG shifted from 2.40-3.70 cpm to 3.70-10.00 cpm
      during Coriolis stimulus in subjects with nausea. Conclusion. It suggests that
      PDF could be a parameter in reflecting the level of motion sickness.

PMID- 12430543
TI  - Reassessing the clinical affinity between Melanie Klein and D.W. Winnicott (1935
      51): Klein's unpublished "Notes on baby" in historical context.
AB  - The author investigates the clinical affinity between Klein and Winnicott (1935
      46) asa way to historically situate Winnicott 's later criticism of Klein's
      'temperamental' inability to understand the impact of the environment on the
      infant's development. By setting out Klein s theories at the time when Winnicott
      began supervision with her in 1935, a context is established for the analysis of
      an unpublished 1937 manuscript by Klein ('Notes on baby'). The author argues that
      this direct and extensive infant observation demonstrates Klein's sensitivity to
      the familial environment. While Winnicott as a paediatrician showed enthusiasm
      for Klein s ideas, he also demonstrated a difference of opinion in emphasising
      the maternal environment of provision after his wartime evacuation experiences
      with London children. The factors leading to their mutual distancing are outlined
      as follows: (1) the post-Controversial Discussion atmosphere of the British
      Psycho-Analytical Society in 1944. The new non-aligned psychoanalytic 'middle
      group' allowed Winnicott to take a pick and choose attitude towards available
      analytic theories; (2) Winnicott us new clinical practices and theory differed
      from Klein 's, leading to a widening gap between 1946 and 1951. Winnicott's new
      theory and practice simultaneously represented his technical marginalisation of
      Klein s emphasis on the direct analysis of the patient s destructiveness by the
      time he delivered the 'Transitional objects' paper in 1951.

PMID- 12430545
TI  - On Marianne Leuzinger-Bohleber & Rolf Pfeifer 'Remembering a depressive primary
      object'.

PMID- 12430546
TI  - [Comparison between two anti-motion sickness drugs].
AB  - Objective. To test the validity of an animal model in selecting anti-motion
      sickness drugs, and compare the effects of two drugs. Method. Anti-motion
      sickness effects of two drugs (Cyclizine and Scopolamin-d-amphetamin compound)
      were observed in rats with motion sickness (MS) induced by rotatory stimulation
      and the amount of Kaolin ate by rats was taken as an evaluation criterion.
      Result. The consumption of Kaolin by the rats decreased significantly after
      administration of both drugs, and the effect of Scopolamin-d-amphetamin compound
      was better than those of Cyclizine under the same condition. Conclusion. It
      suggests that the rat model of motion sickness is practical and useful in
      studying anti-motion sickness drugs.

PMID- 12430547
TI  - It's about time and gender: spousal employment and health.
AB  - This article considers the effect of husbands' and wives' hours of work on each
      others' health. Theoretical analysis focuses on gendering of health-related
      behavior, the needed to promote a spouse's salubrious behavior, and the effects
      of work hours on the availability of time for nonwork activities. Empirical
      analyses are based on 1986 and 1989 longitudinal U.S. data. Fewer than 40 hours
      of work per week by wives has no effect on husbands' health, but more than 40
      hours has substantial negative effect. Long work hours by husbands are not
      detrimental to wives' health. Wives' work hours shows no effect on their own
      health, but husbands' work hours show strong positive effect on their own health.
      Methodological issues are considered.

PMID- 12430548
TI  - On 'The analyst at work'.

PMID- 12430549
TI  - [A method of detecting respiratory rate with a high-sensitivity capacitance
      transducer].
AB  - Objective. To introduce a simple and low cost respiratory rate detection method.
      Method. A high-sensitivity capacitance transducer and corresponding detecting
      system were used in the system. Result. Satisfactory signals were obtained at the
      upper portion of the right thorax with the method. Conclusion. It could be used
      widely. It can be used to comprise the respiratory module in multi-parameter
      patient monitoring, or be used alone to detect respiratory rate.

PMID- 12430550
TI  - The control of H5 or H7 mildly pathogenic avian influenza: a role for inactivated
      vaccine.
AB  - Biosecurity is the first line of defence in the prevention and control of mildly
      pathogenic avian influenza (MPAI). Its use has been highly successful in keeping
      avian influenza (AI) out of commercial poultry worldwide. However, sometimes AI
      becomes introduced into poultry populations and, when that occurs, biosecurity
      again is the primary means of controlling the disease. There is agreement that
      routine serological monitoring, disease reporting, isolation or quarantine of
      affected flocks, application of strict measures to prevent the contamination of
      and movement of people and equipment, and changing flock schedules are
      necessities for controlling AI. There is disagreement as to the disposition of
      MPAI-infected flocks: some advocate their destruction and others advocate
      controlled marketing. Sometimes biosecurity is not enough to stop the spread of
      MPAI. In general, influenza virus requires a dense population of susceptible
      hosts to maintain itself. When there is a large population of susceptible poultry
      in an area, use of an inactivated AI vaccine can contribute to AI control by
      reducing the susceptibility of the population. Does use of inactivated vaccine
      assist, complicate or interfere with AI control and eradication? Yes, it assists
      MPAI control (which may reduce the risk of highly pathogenic AI (HPAI)) but,
      unless steps are taken to prevent it, vaccination may interfere with sero
      epidemiology in the case of an HPAI outbreak. Does lack of vaccine assist,
      complicate or interfere with AI control and eradication? Yes, it assists in
      identification of sero-positive (convalescent) flocks in a HPAI eradication
      program, but it interferes with MPAI control (which in turn may increase the risk
      of emergence of HPAI).A number of hypothetical concerns have been raised about
      the use of inactivated AI vaccines. Infection of vaccinated flocks, serology
      complications and spreading of virus by vaccine crews are some of the
      hypothetical concerns. The discussion of these concerns should take place in a
      scientific framework and should recognize that control of MPAI reduces the risk
      of HPAI. That inactivated vaccines have reduced a flock's susceptibility to AI
      infection, have reduced the quantity of virus shed post-challenge, have reduced
      transmission and have markedly reduced disease losses, are scientific facts. The
      current regulations preventing vaccination against H5 or H7 MPAI have had the
      effect of promoting circulation of MPAI virus in commercial poultry and live
      poultry markets. In the absence of highly pathogenic avian influenza, there is no
      justification for forbidding the use of inactivated vaccine.

PMID- 12430551
TI  - [Psychological issues in manned spaceflight].
AB  - As the duration of manned spaceflight becomes longer and as crews become more
      heterogeneous, psychological and interpersonal factors will be more important in
      affecting the safety of crew and flight mission. In space environment there are
      four types of stressors: physical, physiological, psychological and
      interpersonal. Psychological issues include "Asthenia", alteration in time sense,
      transcendent experiences, sleep problem, career motivation, psychosomatic
      symptoms and psychiatric issues. Interpersonal issues include interpersonal
      tension, interpersonal relationships decreased cohesiveness and deprivation,
      displacement [correction of dispiacement] of anger to outside personnel over
      time.

PMID- 12430552
TI  - Of harvests and health care.

PMID- 12430553
TI  - On 'The analyst at work'.

PMID- 12430554
TI  - [The present status and development of thermal control system of spacesuits for
      extravehicular activity].
AB  - With the extension of extravehicular activity (EVA) duration, the need for more
      effective thermal control of EVA spacesuits is required. The specific schemes
      investigated in heat sink system for EVA are discussed, including radiator, ice
      storage, metal hydride heat pump, phase-change storage/radiator and sublimator.
      The importance and requirements of automatic thermal control for EVA are also
      discussed. Existed automatic thermal control for EVA are reviewed. Prospects of
      further developments of thermal control of spacesuits for EVA are proposed.

PMID- 12430555
TI  - [The effect of weightlessness and simulated weightlessness on the expression of
      genes].
AB  - The research results of the relationship between gene expression and
      weightlessness or simulated weightlessness were studied. The influence of weight
      on the expression of genes in central nervous system were summarized in three
      aspects. It can be concluded that the expression of genes in central nervous
      system were precisely regulated by weight. It was important to study the effects
      of microweight on central nervous system in the molecular level.

PMID- 12430556
TI  - Health and society in early Arkansas, 1810-1860.

PMID- 12430557
TI  - Birth control in Arkansas during the 1930s: the perspective of the physician.

PMID- 12430558
TI  - In war's wake: health care and Arkansas Freedmen, 1863-1868.

PMID- 12430559
TI  - Arkansas' nurse-midwife Mamie O. Hale: "making do with the midwife situation".

PMID- 12430560
TI  - [Otorhinolaryngology Seminar of the Serbian Medical Society. Belgrade. 5-7
      November 2001].

PMID- 12430561
TI  - Medical malpractice in Arkansas in the twentieth century.

PMID- 12430563
TI  - COPD and body weight in a Mediterranean population.

PMID- 12430562
TI  - Mean fluorescence intensity (MFI) of CD11b on CD34-positive (CD34+) cells derived
      from granulocyte colony-stimulating factor (G-CSF) mobilized peripheral blood
      (PB) correlate conversely with the total amount of harvested CD34+ cells.

PMID- 12430564
TI  - Pregnancy in a patient with chronic intestinal failure on long-term parenteral
      nutrition.

PMID- 12430565
TI  - Is the English National Health Service meeting the needs of mentally distressed
      Chinese women?
AB  - OBJECTIVES: To identify barriers to communication between health care workers and
      Chinese women living in England, a group who are known to use the National Health
      Service (NHS) less than other ethnic groups; to consider whether such barriers
      lead to inequitable access to NHS mental health treatment; and to determine the
      extent to which this results from institutional racism. METHOD: A purposive
      sample of 42 Chinese women living in South-East England aged 29-60 years derived
      from a primary care group, two secondary mental health service providers and
      three Chinese associations. Subjects had all consulted a general practitioner and
      had either experienced mental distress (n= 24) and/or had used traditional
      Chinese medicine (n = 25). RESULTS: Communication with health care professionals
      was hindered by a lack of common language and an absence of shared concepts
      concerning the causes and manifestations of health and illness, particularly
      mental health. This lack of communication resulted in delayed diagnoses,
      misunderstood treatment regimens and deterred women from (re-)presenting to the
      NHS. Among our informants, these types of problem were more acute for those women
      who were most marginalised from English-language culture. CONCLUSIONS: Linguistic
      and conceptual problems explain Chinese women's relatively poor access to mental
      health services. The continuing failure to tackle systematically these
      communication problems through the routine provision of interpretation and
      advocacy services lays the health care system open to the charge of
      "institutional racism".

PMID- 12430567
TI  - Marketing gone awry.

PMID- 12430566
TI  - Cloning and molecular characterization of the Schistosoma mansoni genes RbAp48
      and histone H4.
AB  - The human nuclear protein RbAp48 is a member of the tryptophan/aspartate (WD)
      repeat family, which binds to the retinoblastoma (Rb) protein. It also
      corresponds to the smallest subunit of the chromatin assembly factor and is able
      to bind to the helix 1 of histone H4, taking it to the DNA in replication. A cDNA
      homologous to the human gene RbAp48 was isolated from a Schistosoma mansoni adult
      worm library and named SmRbAp48. The full length sequence of SmRbAp48 cDNA is
      1036 bp long, encoding a protein of 308 amino acids. The transcript of SmRbAp48
      was detected in egg, cercariae and schistosomulum stages. The protein shows 84%
      similarity with the human RbAp48, possessing four WD repeats on its C-terminus. A
      hypothetical tridimensional structure for the SmRbAp48 C-terminal domain was
      constructed by computational molecular modeling using the b-subunit of the G
      protein as a model. To further verify a possible interaction between SmRbAp48 and
      S. mansoni histone H4, the histone H4 gene was amplified from adult worm genomic
      DNA using degenerated primers. The gene fragment of SmH4 is 294 bp long, encoding
      a protein of 98 amino acids which is 100% identical to histone H4 from Drosophila
      melanogaster.

PMID- 12430568
TI  - [Imatinib combination therapies--the new CML Study 4].

PMID- 12430569
TI  - [Physiopathology and treatment of laryngeal stenosis in children].

PMID- 12430570
TI  - [Life devoted to science. 100th anniversary of Barbara McClintock's birth].

PMID- 12430571
TI  - The definition of autoimmune disease: are Koch's postulates applicable?

PMID- 12430572
TI  - Autoimmunity in Addison's disease.
AB  - Addison's disease has a low incidence and is most frequently the result of an
      autoimmune disease in developed countries. Addison's disease can present as an
      isolated entity or in combination with other autoimmune diseases: Addison's
      disease can be part of the distinct polyglandular autoimmune syndromes APS I and
      II. Autoantibodies in patients with isolated Addison's disease are directed
      against the enzymes involved in steroid synthesis, P45oc21, P45oscc and P45oc17.
      Addison's disease, both isolated and in the context of APS II, has been
      associated with the haplotype HLA-A1, -B8 and DR3. The value of the increased
      expression of these molecules on adrenocortical cells could point towards an
      infectious pathogenesis. Given the prevalence, up to 80 %, of autoantibodies in
      Addison's disease as well as the high predictive value for developing the disease
      when antibodies are present (41% in three years), we advise screening high-risk
      populations, such as patients with other autoimmune endocrinopathies or their
      relatives for the presence of these antibodies. The adrenocortical function of
      patients positive for antibodies should be followed yearly.

PMID- 12430574
TI  - Contact tracing using DNA fingerprinting in an asylum seeker with pulmonary
      tuberculosis.
AB  - BACKGROUND: The diagnosis of tuberculosis in asylum seekers is followed by
      contact tracing, which is routinely performed by the Municipal Health Service
      (MHS). We investigated cases of tuberculosis whose symptoms became apparent after
      closure of regular contact tracing. METHODS: Analysis of data from the DNA
      Fingerprinting Surveillance Project on all Mycobacterium tuberculosis isolates
      and contact tracing instances. RESULTS: Four additional cases of tuberculosis
      were detected, caused by bacteria of identical DNA fingerprints. No further
      contacts with a bacteriologically confirmed form of tuberculosis were found
      around these four new patients. CONCLUSION: DNA fingerprinting contributed to
      tracing instances of late manifestations of tuberculosis transmission.

PMID- 12430573
TI  - Diuresis pattern, plasma vasopressin and blood pressure in healthy elderly
      persons with nocturia and nocturnal polyuria.
AB  - BACKGROUND: Nocturia, a common symptom in the elderly, is often caused by
      increased urine production at night. METHODS: The present study comprised 17 men
      and six women aged 68.1 +/- 4.7 (mean +/- SD) years with nocturia (> or = 2
      nocturnal voids) and nocturnal polyuria (nocturnal urinary output of > or = 0.9
      mL min(-1)). A physical examination, measurements of recumbent blood pressure
      after a 15-minute rest, plasma AVP assay at noon and midnight, and urine
      collection performed during a 24-hour period. RESULTS: The daytime urine output
      was 1358 +/- 664 mL, and the nocturnal urine output 796 +/- 312 mL. The AVP level
      was lower at midnight than at noon in 17 persons, and higher at midnight in six
      persons. Blood pressure was 142.0 +/- 15.7/87.4 +/- 9.1 mmHg. Systolic (but not
      diastolic) blood pressure increased with decreasing nocturnal plasma AVP.
      Increasing nocturnal diuresis rate (r2= 0.26; p < 0.01) but not plasma AVP was
      associated with increasing systolic blood pressure. CONCLUSION: In elderly
      persons with nocturia and nocturnal polyuria, the plasma AVP is low and does not
      rise nocturnally. The systolic blood pressure is increased with increasing
      diuresis but unaffected by plasma AVP.

PMID- 12430575
TI  - Regular alcohol intake and fibrinolysis.
AB  - BACKGROUND: Light to moderate alcohol consumption is associated with a reduced
      risk of coronary heart disease. Stimulation of fibrinolysis has been suggested as
      one of the mechanisms involved. The present study analyses the effect of regular
      alcohol consumption on various parameters of fibrinolysis. The question whether
      the alcohol-induced plasma increase of plasminogen activator inhibitor (PAI-1)
      may originate from thrombocytes was also addressed. METHODS: Six healthy male
      volunteers consumed three glasses of red wine daily during two periods of a week,
      with a week of abstinence from alcohol in between. PAI-1 antigen and activity
      levels, t-PA antigen and activity levels and plasmin antiplasmin (PAP) complexes
      were measured on days 1, 3, 8, 15, 17 and 22 of the experiment period. On the
      first day, PAI-1 antigen and activity before and after alcohol consumption was
      also measured in platelet-rich plasma (prp). RESULTS: Although some slight shifts
      in the various parameters could be noticed during the drinking periods, all
      favouring impairment rather than stimulation, no significant effect of regular
      moderate alcohol use could be observed on fibrinolysis. Alcohol did not trigger a
      release of PAI-1 from platelets. CONCLUSIONS: Regular moderate alcohol
      consumption has no significant effect on fibrinolysis. The alcohol-induced
      increase of plasma PAI-1 does not originate from thrombocytes. The
      cardioprotective effect of moderate alcohol consumption cannot be explained by a
      beneficial influence on fibrinolysis.

PMID- 12430576
TI  - Severe neutropenia due to naproxen therapy in rheumatoid arthritis: a case report
      and review of literature.
AB  - Rheumatoid arthritis is a chronic inflammatory disease that primarily affects the
      joints and is often treated with non-steroidal anti-inflammatory drugs (NSAIDs)
      on demand and disease-modifying antirheumatic drugs (DMARDs), with a relatively
      low risk of side effects. Although an infrequent side effect, neutropenia has
      been described as a sequel of NSAIDs. We report a case of neutropenia proven (by
      rechallenge) to be due to naproxen therapy. The literature on neutropenia during
      treatment with NSAIDs and DMARDs is briefly reviewed.

PMID- 12430577
TI  - A patient with thymoma and four different organ-specific autoimmune diseases.
AB  - This is the first report of a patient with four organ-specific autoimmune
      diseases; myasthenia gravis, type 1 diabetes mellitus, autoimmune hepatitis and
      Hashimoto's thyroiditis. The clinical history suggests a relationship with a non
      removed thymoma. Not only the thymoma seems to have triggered these four
      diseases, the dramatic progressive course with an active autoimmune hepatitis and
      high concentrations of multiple autoantibodies was probably also associated with
      non-removal of the thymoma. Thymectomy should be performed in myasthenia gravis
      patients with thymoma and associated autoimmune diseases.

PMID- 12430578
TI  - Type 1 diabetes: how to resist a fatal attraction.

PMID- 12430579
TI  - CRP and cardiovascular disease: linked by complement?

PMID- 12430580
TI  - Treatment of autoimmune diseases and vasculitides with immunosuppressive drugs.

PMID- 12430581
TI  - Gene therapy of severe combined immunodeficiencies: from mice to humans.

PMID- 12430583
TI  - Intestinal transplantation.

PMID- 12430582
TI  - Autoimmune hepatitis: clinical and immunological features.

PMID- 12430584
TI  - Celiac disease: the role of (auto)antibody detection in diagnosis and follow-up.

PMID- 12430585
TI  - Immunotherapy of celiac disease: fact or fallacy?

PMID- 12430586
TI  - The persistence of CTL memory.
AB  - A very important question in immunology is to determine which factors decide
      whether an immune response can efficiently clear or control a viral infection,
      and under what circumstances we observe persistent viral replication and
      pathology. This paper summarises how mathematical models help us gain new
      insights into these questions, and explores the relationship between anti-viral
      therapy and long-term immunological control in HIV infection. Particular focus is
      given to the phenomenon of CTL memory, which I define as long-term antigen
      independent persistence of CTLp. Contrary to traditional thinking, theory
      suggests that antigen-independent persistence of memory CTL is required to clear
      the primary infection, because this ensures stable and sustained immunological
      pressure while virus load declines. In the presence of a sustained memory
      response theory suggests that the CTL population is broad, directed against
      multiple epitopes. On the other hand, if memory CTL are not sustained in the
      absence of or at low levels of antigen, then the virus can establish a persistent
      infection. In this case, the model suggests that the CTL response is narrow,
      characterised by only one or a few immunodominant CTL clones. Mathematical models
      and experimental data suggest that HIV persistence and pathology is caused by the
      absence of a sustained CTL memory response, caused by the impairment of CD4 T
      cell help. We show how mathematical models can help us devise therapy regimes
      that can restore CTL memory in HIV-infected patients and result in long-term
      immunological control of the virus in the absence of lifelong treatment.

PMID- 12430587
TI  - Mathematical models of human CD4+ T-cell population kinetics.
AB  - We review how mathematical models help the interpretation of data measuring CD4+
      T-cell kinetics by two recently-developed techniques. Mathematical models are
      developed for the average content of T-cell receptor excision circles (TRECs) and
      the average telomeric restriction fragment (TRF) in T-cells in the peripheral
      blood. Changes in the TRECs were supposed to indicate changes in thymic
      production. The rate at which naive and memory CD4+ T-cells erode their telomeres
      was supposed to reflect their respective division rates. Analysing the
      mathematical models, we show that rapid changes in the TRECs per naive T-cell are
      most likely due to changes in the division rates, and that the rates of telomere
      erosion fail to reflect naive and memory division rates. The model is applied to
      explain data showing that rheumatoid arthritis (RA) patients have abnormal TRECs
      and telomeres.

PMID- 12430588
TI  - Markers and residual time to AIDS.
AB  - The value of immunological and virological markers as predictors of progression
      to AIDS, or death by AIDS, is a topic of much current interest. Mostly, the
      influence of markers is investigated in a time-dependent or a baseline
      proportional hazard model, relating time-varying or baseline marker values to the
      instantaneous AIDS risk. Low CD4 numbers have been shown to increase the AIDS
      risk. Based on this finding, the decision to start treatment has mainly been
      based on a person's CD4 count. Over the last couple of years, high viral load has
      been added as a criterion to start treatment. Relative hazards do not directly
      reveal information on time to AIDS. A better approach is to base the decision to
      start treatment on an estimate of a person's residual time to AIDS or death by
      AIDS. Discrimination and calibration are introduced as criteria to compare
      prediction models. Two models to predict residual time to AIDS are discussed. One
      is a proportional hazards model based on baseline marker values; the other one is
      a combined model of a time-dependent proportional hazards model and a
      longitudinal model for marker development.

PMID- 12430589
TI  - Mathematical epidemiology of Chlamydia trachomatis infections.
AB  - In this paper I discuss the specific problems that one faces when developing a
      model for a sexually-transmitted disease (STD) such as infection with Chlamydia
      trachomatis. I introduce some modelling approaches that take into account the
      heterogeneity within a population in sexual behaviour, the influence of
      partnership duration on the dynamics of a STD, and the impact of contact tracing
      on the effectiveness of STD prevention. Some results are shown that were obtained
      with a network simulation model specifically designed to describe the
      transmission dynamics of Chlamydia trachomatis. The model was used to investigate
      the effects of various screening strategies on the prevalence of asymptomatic
      Chlamydia infections in women.

PMID- 12430590
TI  - Validation of parasite transmission models: the example of onchocerciasis.
AB  - Most parasites have complex life cycles; and mathematical models can help in
      targeting interventions and predicting disease-control efforts. For actual
      applications, quantification and validation of models is a key issue. We
      illustrate the process of validation by presenting a (re)analysis of fly-feeding
      experiments carried out by the Onchocerciasis (river blindness) Control Programme
      (OCP/WHO) in West Africa, with the objective to validate ONCHOSIM, an
      onchocerciasis transmission model. In these experiments flies were fed on human
      patients and dissected to count the number of microfilariae they had ingested. To
      assess microfilarial skin densities, skin snips (biopsies) were taken and
      examined. Originally, the resulting curve was interpreted as showing saturation
      and considered the main regulating (density-dependent) mechanism of
      onchocerciasis transmission in the model. Taking into account measurement errors
      in the skin microfilarial density of human subjects (on whom the flies were fed)
      we now conclude that the relationship is essentially linear. This prompts us to
      requantify ONCHOSIM. Possible alternative density-dependent mechanisms are
      discussed.

PMID- 12430591
TI  - Transmission of nosocomial pathogens.
AB  - Prevention of the spread of antibiotic-resistant micro-organisms is one of the
      challenges for mankind in the new millennium, according to a recent report from
      the World Health Organization. In our Western world resistance problems occur
      mainly in intensive care units (ICUs). However, the observed numbers of
      infections are only the tip of the iceberg of patients colonised with multiple
      resistant pathogens. Remarkably, manifestation of problems with antibiotic
      resistant pathogens within ICUs has specific characteristics. Initially there are
      a few, presumably sporadic, infections, and sometimes an outbreak is feared. Such
      an initial outbreak may be caused by an environmental source within the ward or
      by the admission of a patient colonised or infected with the resistant pathogen.
      After some time, the incidence of infections increases and a considerable part of
      the patient population appears to be colonised. A situation of endemicity has
      developed and the eradication of the resistant micro-organisms from the ward is
      very difficult and may even be impossible. Classical measures of infection
      prevention such as hand disinfection after patient contact remain the cornerstone
      of infection prevention, but little is known about their quantitative effects.
      Compliance with this rule is not 100%, usually not even 50%, but what percentage
      would be sufficient, and can other measures be more effective? Modelling the
      dynamic processes that determine the epidemiology of colonisation may help to
      quantitatively predict what effects will influence this process. Moreover, these
      methods may help to identify new measures for infection control.

PMID- 12430592
TI  - Models for the spread of resistant pathogens.
AB  - I consider three mathematical models of the epidemiology of antibiotic treatment
      and the evolution of resistance. All of these models explore the relationship
      between the volume of antibiotic use and the frequency and rate of ascent (or
      descent) of resistance. The first model is in the population genetics tradition
      and assumes that in the absence of treatment the frequency of resistance wanes at
      a rate proportional to the fitness costs associated with resistance, but
      precipitously ascends to high frequencies in treated patients. The second two
      models are in the compartment, or SIR, model tradition of infectious disease
      epidemiology. The first of these considers the relationship between resistance
      and rates of antibiotic treatment in open communities. The second explores the
      factors contributing to the frequency of resistance in the closed settings of
      hospitals and nursing homes. While I give some consideration to the
      epidemiological and medical implications of the results of the analysis of the
      properties of these models, for the most part the models are the message. I end
      with a harangue about the utility of simple mathematics for these considerations
      and a plea to obtain realistic estimates of the parameters of these models and
      test the validity of the predictions generated from the analysis of these models.

PMID- 12430593
TI  - Modelling the impact of vaccination strategies.
AB  - Many questions in planning for vaccination strategies are not easily answered. In
      order to assess the expected impact of vaccination on incidence of infection and
      disease we have to account explicitly for the transmission process of infectious
      agents, and the interference of vaccination with transmission of infection or
      disease. This requires, in one way or another, a mathematical description and
      analysis of the transmission of infection. We shall briefly discuss the basic
      structure of epidemic models that are used for evaluating vaccination strategies.
      We shall confront the findings with observations, and we shall review some
      practical cases where modelling vaccination strategies has provided crucial
      insights into how vaccination affects patterns of disease incidence.

PMID- 12430594
TI  - Pharmacoepidemiological modelling: Markov models of antibiotic use in patients
      with diabetes.
AB  - The importance of time patterns in drug exposure is increasingly recognised in
      the evaluation of determinants and outcomes of pharmacotherapy. Data on patterns
      of drug exposure over time in individual patients and populations have been found
      to provide important 'fingerprint' information on temporal relations between
      disease course and severity, drug effects, and prognosis. However, data on
      prescriptions of medicines always need to be interpreted in the light of
      complementary data on clinical status, diagnosis, co-morbidity and the like.

PMID- 12430595
TI  - Dual enzyme electrochemical coding for detecting DNA hybridization.
AB  - Enzyme-based hybridization assays for the simultaneous electrochemical
      measurements of two DNA targets are described. Two encoding enzymes, alkaline
      phosphatase and beta-galactosidase, are used to differentiate the signals of two
      DNA targets in connection to chronopotentiometric measurements of their
      electroactive phenol and alpha-naphthol products. These products yield well
      defined and resolved peaks at +0.31 V (alpha-naphthol) and +0.63 V (phenol) at
      the graphite working electrode (vs. Ag/AgCl reference). The position and size of
      these peaks reflect the identity and level of the corresponding target. The dual
      target detection capability is coupled to the amplification feature of enzyme
      tags (to yield fmol detection limits) and with an efficient magnetic removal of
      non-hybridized nucleic acids. Proper attention is given to the choice of the
      substrates (for attaining well resolved peaks), to the activity of the enzymes
      (for obtaining similar sensitivities), and to the selection of the enzymes (for
      minimizing cross interferences). The new bioassay is illustrated for the
      simultaneous detection of two DNA sequences related to the BCRA1 breast-cancer
      gene in a single sample in connection to magnetic beads bearing the corresponding
      oligonucleotide probes. Prospects for electrochemical coding of multiple DNA
      targets are discussed.

PMID- 12430596
TI  - Application of orthogonal signal correction to minimise the effects of physical
      and biological variation in high resolution 1H NMR spectra of biofluids.
AB  - 1H nuclear magnetic resonance (NMR)-based metabonomics is a well-established
      technique used to analyse and interpret complex multiparametric metabolic data,
      and has a wide number of applications in the development of pharmaceuticals.
      However, interpretation of biological data can be confounded by extraneous
      variation in the data such as fluctuations in either experimental conditions or
      in physiological status. Here we have shown the novel application of a data
      filtering method, orthogonal signal correction (OSC), to biofluid NMR data to
      minimise the influence of inter- and intra-spectrometer variation during data
      acquisition, and also to minimise innate physiological variation. The removal of
      orthogonal variation exposed features of interest in the NMR data and facilitated
      interpretation of the derived multivariate models. Furthermore, analysis of the
      orthogonal variation provided an explanation of the systematic
      analytical/biological changes responsible for confounding the original NMR data.

PMID- 12430597
TI  - Surface modification and characterization of microfabricated poly(carbonate)
      devices: manipulation of electroosmotic flow.
AB  - Poly(carbonate), PC, surfaces are chemically modified by treatment with sulfur
      trioxide gas. Sulfur trioxide gas sulfonates the aromatic rings of the
      poly(carbonate) surfaces, making the surfaces more hydrophilic. Sulfonation of
      the poly(carbonate) surface is confirmed by infrared spectroscopy. The modified
      polymer surfaces are found to be smoother in comparison to their unmodified
      counterparts, as noted by scanning force microscopy. The effects of the surface
      modification on electroosmotic flow are studied at a pH range of 4-10. The
      electroosmotic flow in sulfonated poly(carbonate) microchannels was found to be
      significantly higher than that in unmodified poly(carbonate) microchannels at pH
      values below 8.

PMID- 12430598
TI  - Real-time determination of glucose consumption by live cells using a lab-on-valve
      system with an integrated microbioreactor.
AB  - This paper describes a microquantitative method for glucose determination in situ
      of living cells in real-time. In this novel technique adherent cells are cultured
      onto microcarrier beads and packed into a renewable microcolumn within a
      microsequential injection lab-on-valve system (microSI-LOV). Glucose sensing is
      performed through the use of a two-step, NAD-linked enzymatic process. The course
      of the assay is monitored in real-time, by absorbance of NADH at 340 nm. The
      microsequential assay based on plug/nozzle design has a linear dynamic range for
      glucose of 0.1 to 5.6 mM. The design of the (microSI-LOV) system allows the assay
      to be carried out using only 40 microL of the enzyme reagent and 3 microL of
      sample. The technique was tested on a murine hepatocyte cell line (TABX2S)
      adhered to Cytopore beads. Rapid cellular glucose consumption, in this technique,
      is facilitated by a high cell density, which allows a large number of cells
      (10(4)-10(5)) to be retained in a very small volume (3 microL). In turn, this
      cell density results in the rapid depletion of glucose from the cell medium over
      short time periods (< 2 min). In conjunction with the assay development, the
      plug/nozzle design and its ramifications on mixing in general are presented and
      discussed.

PMID- 12430599
TI  - Occurrence and analysis of estrogens and progestogens in river sediments by
      liquid chromatography-electrospray-mass spectrometry.
AB  - In this study, an analytical procedure for the determination in sediment of the
      most abundant and/or physiological active estrogens (estradiol, estriol, estrone,
      ethynyl estradiol, and diethylstilbestrol) and progestogens (progesterone,
      norethindrone. and levonorgestrel) is described. The procedure includes
      ultrasonic extraction of the lyophilized sediment, clean-up with octadecylsilica
      cartridges, and analysis by liquid chromatography-diode array detection-mass
      spectrometry (LC-DAD-MS). MS detection is performed with an electrospray
      interface in the positive ion mode for determination of the progestogens and in
      the negative ion mode for determination of the estrogens. The method was applied
      to the determination of the target compounds in river sediments from the area of
      Catalonia. Estrogens and progestogens were found at concentrations usually in the
      low ng g(-1) range. Estriol and norethindrone were the compounds most frequently
      found whereas maximum concentrations in all sediment samples were obtained for
      ethynyl estradiol (22.8 ng g(-1)) and estrone (11.9 ng g(-1)). Detection limits
      were in the range of 0.04-1.00 ng g(-1). Preliminary conjectures with regards to
      the environmental behavior and impact of estrogens and progestogens in rivers are
      made. To the authors' knowledge, this is the first work reporting a detailed
      method for the analysis of estrogens and progestogens in river sediments and data
      on the environmental occurrence of both groups of compounds.

PMID- 12430600
TI  - Quantitative trace-level speciation of arsenite and arsenate in drinking water by
      ion chromatography.
AB  - We describe an improved method for the determination of inorganic arsenic in
      drinking water. The method is based on comprehensive optimization of the anion
      exchange ion chromatographic (IC) separation of arsenite and arsenate with post
      column generation and detection of the arsenate-molybdate heteropoly acid (AMHPA)
      complex ion. The arsenite capacity factor was improved from 0.081 to 0.13 by
      using a mobile phase (2.0 mL min(-1)) composed of 2.5 mM Na2CO3 and 0.91 mM
      NaHCO3 (pH 10.5). A post-column photo-oxidation reactor (2.5 m x 0.7 mm) was
      optimized (0.37 microM potassium persulfate at 0.50 mL min(-1)) such that
      arsenite was converted to arsenate with 99.8 +/- 4.2% efficiency. Multi-variate
      optimization of the complexation reaction conditions yielded the following
      levels: 1.3 mM ammonium molybdate, 7.7 mM ascorbic acid, 0.48 M nitric acid, 0.17
      mM potassium antimony tartrate, and 1.0% (v/v) glycerol. A long-path length flow
      cell (Teflon AF, 100-cm) was used to measure the absorption of the AMHPA complex
      (818 +/- 2 nm). Figures of merit for arsenite/arsenate include: limit of
      detection (1.6/0.40 microg L(-1)): standard error in absorbance (5.1 x 10(-3)/3.5
      x 10(-3)); and sensitivity (2.9 x 10(-3)/2.2 x 10(-3) absorbance units per ppb).
      Successful application of the method to fortified surface and ground waters (100
      microL samples) is also described.

PMID- 12430601
TI  - Separation and characterisation of caprolactam-formaldehyde reaction products.
AB  - Methylolation and condensation products formed in caprolactam-formaldehyde
      reaction mixtures have been identified using nuclear magnetic resonance (NMR) and
      mass spectrometry (MS). Previously unreported side-products were also detected.
      All of the reaction products were separated by micellar electrokinetic
      chromatography (MEKC) and high performance liquid chromatography (HPLC), and the
      separation parameters, such as efficiency and distribution constants, obtained in
      the two techniques were compared. For quantification, the response factors for
      the monomers were determined using standard calibration and hydrolysis, whilst
      those for the condensation products were deduced from the values of the monomers.
      The accurate determination of the response factors was confirmed by checking the
      mass balance of a known mixture.

PMID- 12430602
TI  - Improved gas chromatography methods for micro-volume analysis of haloacetic acids
      in water and biological matrices.
AB  - A fast headspace solid-phase microextraction gas chromatography method for micro
      volume (0.1 mL) samples was optimized for the analysis of haloacetic acids (HAAs)
      in aqueous and biological samples. It includes liquid-liquid microextraction
      (LLME), derivatization of the acids to their methyl esters using sulfuric acid
      and methanol after evaporation, followed by headspace solid-phase microextraction
      with gas chromatography and electron capture detection (SPME-GC-ECD). The
      derivatization procedure was optimized to achieve maximum sensitivity using the
      following conditions: esterification for 20 min at 80 degrees C in 10 microL
      methanol, 10 microL sulfuric acid and 0.1 g anhydrous sodium sulfate. Multi-point
      standard addition method was used to determine the effect of the sample matrix by
      comparing with internal standard method. It was shown that the effect of the
      matrix for urine and blood samples in this method is insignificant. The method
      detection limits are in the range of 1 microg L(-1) for most of the HAAs, except
      for monobromoacetic acid (MBAA) (3 microg L(-1)) and for monochloroacetic acid
      (MCAA) (16 microg L(-1)). The optimized procedure was applied to the analysis of
      HAAs in water, urine and blood samples. All nine HAAs can be separated in < 13
      min for biological samples and < 7 min for drinking water samples, with total
      sample preparation and analysis time < 50 min. Analytical uncertainty can
      increase dramatically as the sample volume decreases; however, similar precision
      was observed with our method using 0.1 mL samples as with a standard method using
      40 mL samples.

PMID- 12430603
TI  - Determination of monophosphate nucleotides by capillary electrophoresis
      inductively coupled plasma mass spectrometry.
AB  - A preliminary study of a modified microconcentric nebulizer (CEI-100, CETAC) as
      the sample introduction device of capillary electrophoresis inductively coupled
      plasma mass spectrometry (CE-ICP-MS) for the determination of monophosphate
      nucleotides is described. The monophosphate nucleotides studied include adenosine
      5'-monophosphate (AMP), guanosine 5'-monophosphate (GMP), uridine 5'
      monophosphate (UMP) and inosine 5'-monophosphate (IMP). The species studied were
      well separated using a 70 cm length x 75 microm id fused silica capillary while
      the applied voltage was set at -22 kV and a 20 mmol l(-1) ammonium citrate/citric
      acid buffer (pH 4.0) containing 0.1% m/v cationic polymer (hexadimethrine
      bromide, Polybrene) was used as the electrophoretic buffer. The electroosmotic
      flow was reversed by flushing the fused silica capillary with 0.2% m/v Polybrene
      to accelerate separation. The detection limit of various species studied was in
      the range of 0.036-0.054 microg P ml(-1), which corresponded to the absolute
      detection limit of 1.1-1.6 pg P based on the injection volume of 30 nl. We
      determined the concentrations of nucleotides in two IG-enriched monosodium
      glutamates purchased from the local market. The recovery was in the range of 100
      112% for various species, and the concentrations of IMP and GMP in these samples
      were in the range of 0.15-0.18% m/m.

PMID- 12430604
TI  - Determination of aculeatisides based on immunoassay using a polyclonal antibody
      against aculeatiside A.
AB  - An enzyme-linked immunosorbent assay (ELISA) was developed for determination of
      aculeatisides. Aculeatiside A was conjugated with bovine serum albumin (BSA) for
      immunization. The ratio of hapten in an antigen conjugate was determined by
      matrix-assisted laser desorption/ionization TOF mass spectrometry. Polyclonal
      antibody was developed in rabbits against an aculeatiside A-BSA conjugate. The
      antibody was specific for aculeatiside A and aculeatiside B. The range of the
      immunoassay extended from 100 ng ml(-1) to 5 pg ml(-1) of aculeatisides. Good
      correlation between ELISA and HPLC methods was obtained when crude extracts of
      plant samples were analyzed. The optimized ELISA was found to be applicable to
      the determination of total aculeatisides in various plant samples.

PMID- 12430605
TI  - An electrochemical ELISA procedure for the screening of 17beta-estradiol in urban
      waste waters.
AB  - A sensitive electrochemical enzyme-linked immunosorbent assay (ELISA) has been
      used for the detection of 17beta-estradiol in waste waters. The activity of the
      label enzyme (horseradish peroxidase) was measured electrochemically using
      3,3',5,5'-tetramethylbenzidine as electrochemical substrate. The detection limit
      was estimated to be 5 pg mL(-1), interday and intraday precision (RSD), ranged
      from 1 to 3% and from 3 to 6%, respectively. Analysis of waste waters from three
      different treatment plants demonstrated no matrix effect both for samples diluted
      1:1 in buffer and diethyl ether extracted. Data on 36 samples analysed by an LC
      ESI-MS-MS procedure and by the electrochemical ELISA assay were compared. Results
      correlated well. The electrochemical enzyme immunoassay appears suitable as a
      screening tool for analysis of estradiol in waste waters.

PMID- 12430606
TI  - Monitoring of headspace total volatile basic nitrogen from selected fish species
      using reflectance spectroscopic measurements of pH sensitive films.
AB  - The release of amines from decomposing fish such as trimethylamine (TMA),
      dimethylamine (DMA) and ammonia, collectively known as total volatile basic
      nitrogen (TVB-N), are in high enough concentrations in headspace to be monitored
      by a colour change in a pH-sensitive sensor. A method developed here uses a pH
      indicator dye physically trapped in a cellulose polymer film to respond to the
      headspace TVB-N released from selected fish species during spoilage. Two species
      were selected for analysis on the basis of economic importance and the levels of
      volatile amines released were followed with time using uv/vis reflectance
      spectroscopic measurements. The results show that there is a significant increase
      in the TVB-N content in the headspace of fish samples after an incubation period
      of 8-12 h for cod and 12-15 h for orange roughy.

PMID- 12430607
TI  - O2 plasma treated polyimide-based humidity sensors.
AB  - The effect of non-plasma and plasma treated polyimide-based humidity sensors is
      presented. Pure oxygen was used to etch polyimide in a plasma etcher. The sensor
      treated in a plasma exhibited higher sensitivity and faster response speed
      against moisture. The plasma treated sensor had 3.4 times the sensitivity and
      responded almost twice as fast as the non-plasma treated sensor. A further
      comparison of sensor outputs, sensitivity and response speed are presented.
      Chemical analysis of the polyimide surface was carried out by X-ray photoelectron
      spectroscopy (XPS) and Fourier transform infrared spectroscopy (ATR-FTIR). XPS
      and ATR-FTIR showed the increase in carbonyl carbon bonds, C=O, after the plasma
      treatment. Geometrical modification was observed by atomic force microscopy
      (AFM). It showed considerable surface roughness after the plasma treatment. O2
      plasma treatment improved the sensitivity, and reduced the hysteresis of the
      sensor due to the increase in C=O bonds in the polyimide.

PMID- 12430608
TI  - Viscoelasticity in the diffuse electric double layer.
AB  - The electroacoustical impedance of the quartz crystal microbalance (QCM) in
      contact with aqueous electrolyte solutions was measured using the transfer
      function method in a flow injection system . Measurements of both components of
      the impedance of the QCM, the resistance R and the inductive reactance XL, have
      been performed for modified and bare gold and silver surfaces and for different
      concentrations of several aqueous electrolyte solutions. For the experimental
      concentration range of 0-50 mM, unexpectedly the QCM impedance does not follow
      the Kanazawa equation, as is usual for bulk newtonian liquids. This behavior
      indicates the presence of a nanometric sized viscoelastic layer between the
      piezoelectric crystal and the bulk electrolyte solution. This layer can only be
      identified as the Gouy-Chapman diffuse double layer (DDL). Its elasticity and
      viscosity have been estimated by the measurement of R and XL. The viscoelasticity
      of the DDL appears to be independent of the chemical nature of the surface and of
      the solution viscosity but strongly dependent on the surface charge, the bulk
      electrolyte concentration and the dielectric constant of the solvent.

PMID- 12430609
TI  - A selective voltammetric method for uric acid detection at beta-cyclodextrin
      modified electrode incorporating carbon nanotubes.
AB  - A beta-cyclodextrin-coated electrode incorporating carbon nanotubes was
      constructed and applied to the detection of uric acid in the presence of high
      concentration of ascorbic acid. The major obstacle of the overlapped oxidation
      potential of ascorbic acid was overcome owing to the distinct ability of the
      carbon nanotubes-modified electrode to yield a large anodic peak difference ca.
      400 mV. The sensitive detection of uric acid has been further improved by the
      formation of a supramolecular complex between beta-cyclodextrin and uric acid. A
      linear calibration curve was obtained for 5 x 10(-7) to 5 x 10(-5) M in 0.2 M HAc
      NaAc buffer (pH 4.5) with correlation coefficient of 0.998 and detection limit of
      0.2 microM. The practical analytical application was illustrated by a selective
      measurement of uric acid in human urine without any preliminary treatment.

PMID- 12430610
TI  - Bump-hunting for the proficiency tester--searching for multimodality.
AB  - Kernel density estimation is a method for producing a smooth density
      approximation to a dataset and avoiding some of the problems associated with
      histograms. If it is used with a degree of smoothing determined by a fitness for
      purpose criterion, it can be applied to proficiency test data in order to test
      for multimodality in the z-scores. The bootstrap is an essential additional
      technique to determine how rugged the initially estimated kernel density is: the
      random resampling of the data in the bootstrap simulates a complete blind repeat
      of the proficiency test. In addition, useful estimates of the standard error of a
      mode can be thus obtained. It is suggested that a mode and its standard error can
      be used as an assigned value and its standard uncertainty.

PMID- 12430611
TI  - Bead injection for surface enhanced Raman spectroscopy: automated on-line
      monitoring of substrate generation and application in quantitative analysis.
AB  - The technique of bead injection has been adapted for surface enhanced Raman
      scattering (SERS) to substantially improve precision, long term stability and
      sensitivity of SERS detection in analytical chemistry. For this purpose a fully
      automated flow system comprising a dedicated flow-cell has been developed and
      tested. With the developed flow-cell, which contains two inlet and two outlet
      channels, it is possible to retain, perfuse and discharge minute amounts of
      polymer beads while monitoring all steps by Raman spectroscopy. First, beads
      carrying cation exchanger moieties were retained in the flow-cell and
      subsequently perfused with a silver nitrate and a hydroxylamine solution using
      one inlet of the flow cell. By this sequence homogeneous SERS active silver
      layers were formed on the beads. The uniformity of the achieved silver layer was
      studied by secondary electron microscopy. For measurement, the analyte was then
      introduced from the second inlet channel such that the interaction between the
      activated SERS beads and analyte occurred in close proximity and within the focus
      of the laser excitation beam. Due to the complete computer control of all
      experimental steps, including bead entrapment, SERS layer generation, sample
      introduction and final bead removal, highly reproducible conditions for SERS were
      achieved. The method was developed using 9-aminoacridine as a test molecule.
      Quantitative studies were carried out for 9-aminoacridine and acridine showing
      linear calibrations from 1-100 nmol l(-1) and 50-1,000 nmol l(-1), respectively,
      using a sample volume of 200 microl each. Typical relative standard deviations
      were 4.7% for 9-aminoacrine and 5.8% for acridine.

PMID- 12430612
TI  - Near UV quantum yields for rotenone and piperonyl butoxide.
AB  - Rotenone and piperonyl butoxide (PBO) mixtures, so-called "synergized" rotenone,
      are invaluable in fisheries management where they are used to protect the habitat
      of endangered, native species and promote desirable gamefish populations.
      Continued use of synergized rotenone is threatened by inadequate control of
      persistence in surface water, especially where drinking water supplies are
      impacted. The photochemical kinetics of these chemicals were studied in the
      laboratory with a goal to better understand their fate in natural water.
      Disappearance quantum yields (phi) were determined in polychromatic light from
      fluorescent lamps emitting maximally at 350 nm. Rotenone, PBO and trifluralin, an
      actinometer, were irradiated as aqueous solutions at 25 or 50 microg L(-1) and
      the piscicides were determined by electrospray-liquid chromatography-mass
      spectrometry (ESI-LC-MS). In the photoreactor rotenone and PBO photodegraded with
      first-order half-lives of 500 and 220 min, respectively, and corresponding
      quantum yields of 0.00015 and 0.034. Rotenone absorbs sunlight strongly, while
      PRO does not. Differences in spectal overlap tended to counteract the disparities
      in phi and, in general, mathematical modeling indicates moderately rapid direct
      photolysis rates for both substances in surface water.

PMID- 12430613
TI  - Flow-injection electrogenerated chemiluminescence detection of hydrazine based on
      its in-situ electrochemical modification at a pre-anodized platinum electrode.
AB  - In this paper. it was found that the enhancing effect of hydrazine on the weak
      electrogenerated chemiluminescence (ECL) signal of the electrooxidation of
      luminol at a pre-anodized platinum electrode was stronger than that of hydrazine
      at a bare platinum electrode. Based on this finding and the combination of this
      finding with a flow-injection technique, a novel, sensitive and selective ECL
      method for hydrazine was developed. Under the optimum experimental conditions,
      the relative ECL intensity was linear with hydrazine concentration over the range
      2.0 x 10(-8) - 5.0 x 10(-5) mol L(-1), with a detection limit of 6.0 x 10(-9) mol
      L(-1).

PMID- 12430614
TI  - Antimony speciation by inductively coupled plasma mass spectrometry using solid
      phase extraction cartridges.
AB  - A novel and simple method for inorganic antimony speciation is described based on
      selective solid phase extraction (SPE) separation of antimony(III) and highly
      sensitive inductively coupled plasma mass spectrometric (ICP-MS) detection of
      total antimony and antimony(V) in the aqueous phase of the sample. Non-polar SPE
      cartridges, such as the Isolute silica-based octyl (C8) sorbent-containing
      cartridge, selectively retained the Sb(III) complex with ammonium pyrrolidine
      dithiocarbamate (APDC), while the uncomplexed Sb(V) remained as a free species in
      the solution and passed through the cartridge. The Sb(III) concentration was
      calculated as the difference between total antimony and Sb(V) concentrations. The
      detection limit was 1 ng L(-1) antimony. Factors affecting the separation and
      detection of antimony species were investigated. Acidification of samples led to
      partial or complete retention of Sb(V) on C8 cartridge. Foreign ions tending to
      complex with Sb(III) or APDC did not interfere with the retention behavior of the
      Sb(III)-APDC complex. This method has been successfully applied to antimony
      speciation of various types of water samples.

PMID- 12430615
TI  - Chemical vapor generation for sample introduction into inductively coupled plasma
      atomic emission spectroscopy: vaporization of antimony(III) with bromide.
AB  - A new method for antimony determination in soils is proposed. It is based on the
      chemical vapor generation of Sb(III) with bromide, after a reaction in sulfuric
      acid media and transport of the gaseous phase into an inductively coupled plasma
      for atomic emission spectrometry. The experimental variables influencing the
      method were delimited by experimental design and the most important were finally
      optimized by the modified Simplex method. In optimized conditions the method
      involves the reaction of 579 microl concentrated sulfuric acid with 120 microl 5%
      w/v KBr and 250 microl antimony solution. Measurement of antimony emission
      intensity at 217.581 nm provides a method with an absolute detection limit of 3.5
      ng and a precision (RSD) of 5.8% for the injection of five replicates of 175 ng
      Sb(III) (250 microl of 0.7 microg ml(-1) solution). The interference of common
      anions and cations on the antimony signal was evaluated. A 21% Sb(III)
      volatilization efficiency was calculated from the mean of six experiments at
      optimum conditions. The accuracy of the methodology was checked by the analysis
      of one standard reference soil after acid decomposition heating in a microwave
      oven.

PMID- 12430616
TI  - A sensitive and selective assay of nucleic acids by measuring enhanced total
      internal reflected resonance light scattering signals deriving from the
      evanescent field at the water/tetrachloromethane interfacet.
AB  - A total internal reflected resonance light scattering (TIR-RLS) technique, the
      coupling of resonance light scattering (RLS) technique with total internal
      reflected light at the interface of two immiscible liquids, where the steep
      change of the refractive indexes occurs to result in an evanescent field, is
      proposed with the characteristics of separation and enrichment properties of
      analytes and direct use of oil-soluble reagents free from surfactants. At pH 8.69
      and ion strength 0.008, ternary amphiphilic species formed by the interaction of
      nucleic acids, including calf thymus DNA (ctDNA), fish sperm DNA (fsDNA), and
      yeast RNA (yRNA), with Eu(III) in the presence of oil-soluble trioctylphosphine
      oxide (TOPO), are adsorbed to the water/tetrachloromethane (H20/CCl4) interface,
      giving rise to significantly enhanced TIR-RLS signals. It has been found that the
      enhanced TIR-RLS intensity at 348.0 nm is proportional to the concentration of
      thermally denatured ctDNA, fsDNA and yRNA in the range 0.002-2.5 microg ml(-1),
      0.002-2.5 microg ml(-1) and 0.003-2.0 microg ml(-1), respectively and their
      limits of determination (3sigma) are 0.16 ng ml(-1), 0.19 ng ml(-1) and 0.28 ng
      ml(-1), correspondingly. Complicated artificial samples with highly interfering
      backgrounds were determined satisfactorily.

PMID- 12430617
TI  - A practical approach to the evaluation of the anemic child.
AB  - Anemia is a sign of disease and not a final diagnosis. The clinician's goal is to
      define the underlying cause. The anemia may be due to decreased production or
      Increased destruction or loss of red blood cells. Integration of the results of
      the initial CBC. particularly the RBC indices, the peripheral blood smear, the
      history and the physical examination can help organize the focus of further
      evaluations and, ultimately, minimize the number of tests needed to make a firm
      diagnosis.

PMID- 12430618
TI  - Diseases of iron metabolism.
AB  - Diseases of iron metabolism are likely to be both more frequent than expected,
      and exhibit a wider range of clinic severity and effects. Some present without
      evidence of anemia. Unexplained diseases of end organs that are affected by iron
      (liver, heart, pancreas, kidney, adrenals, and cerebellum) should have an iron
      metabolism disorder considered. Review of the blood indices and serum iron and
      ferritin markers may alert the clinician to most disorders. Further research is
      likely to define the scope and approach to clinical diagnosis of the diseases of
      iron metabolism.

PMID- 12430619
TI  - Immune thrombocytopenic purpura.
AB  - Although many advances have been achieved in the understanding of ITP, critical
      issues regarding the pathophysiology and biology of the disease remain to be
      elucidated. The recent characterization of the human genome along with new
      sophisticated molecular biology techniques will allow basic researchers to study
      genes that may affect the presentation and clinical course of the disease.
      Different patterns of gene expression in this population can be studied, leading
      to the identification of subsets of patients with ITP at higher risk of bleeding.
      The multigene patterns of expression might also provide clues about regulatory
      mechanisms and broader cellular functions. In order to answer essential clinical
      questions, like the incidence of ICH in relation to drug treatment or observation
      alone, clinical trials should be appropriately designed. More studies are
      necessary to better define the optimal treatment approach for each child with
      ITP. Even though the incidence of intracranial hemorrhage cannot be used as the
      primary outcome measure because of its rarity, numerous other outcomes, such as
      rate of rise in platelet count, cost and side effects of therapy, health related
      quality of life of the patient and family, and severity of hemorrhage can be
      measured and compared between treatment groups. Future investigators should find
      it attractive to conduct trials in children with this common hematological
      disease so that decision making can be based more on scientific evidence than on
      anecdote and opinion.

PMID- 12430620
TI  - A practical approach to neutrophil disorders.
AB  - This review discusses disorders of altered neutrophil number and function and
      provide a basic framework for patient evaluation and management. The sections
      begin with neutropenia, neutrophilia and neutrophil dysfunction with a general
      screening approach to differentiate common, more benign syndromes from rare,
      often more serious disorders. Also included is a detailed discussion of some
      specific primary neutrophil syndromes at the end of each section. Focus is placed
      on specific disorders that are clinically common or particularly instructive.

PMID- 12430621
TI  - Bone marrow failure syndromes in children.
AB  - There are several common themes that are emerging from our expanding knowledge
      about the inherited bone marrow failure syndromes. Patients have a spectrum of
      birth defects, which are relatively characteristic for each syndrome. but overlap
      in features such as poor growth. radial ray anomalies, and involvement of skin,
      eyes, renal, cardiac, skeletal, and other organs. Within each syndrome the
      composition and severity of the physical phenotype varies widely, and it may
      require the astute observer to make the correct diagnoses in the milder cases.
      There is also a wide spectrum to the hematologic picture. These range from single
      cytopenias such as DBA, SCN, and TAR, which do not develop pancytopenia, to SD
      and Amega patients who begin with deficiency of a specific single lineage, but
      evolve to aplastic anemia, to patients with FA or DC, who may present with a
      deficiency of any one of the cell lines, but almost inevitably end up with full
      blown aplastic anemia. Acute myeloid leukemia has been observed in FA, DBA, DC,
      SD, SCN, and Amega, although not yet in TAR patients. MDS has also been reported
      in all of the same disorders as AML, although whether it is a preleukemic
      condition or an independent bone marrow dyspoiesis is not yet clear. Solid tumors
      are also now appearing in patients whose underlying disease involves
      hematopoiesis and physical development. These tumors occur at much younger ages
      than in the general population, in patients who do not appear to have the usual
      risk factors, and have patterns that are characteristic to the syndrome, such as
      head and neck and gynecologic cancers in FA and DC, and osteogenic sarcomas in
      DBA. The other syndromes have not yet been reported to have a propensity for
      solid tumors. Several genes have been identified that are mutant in some of the
      syndromes, although the pathophysiology is still not entirely clear. The
      inheritance patterns include X-linked recessive, autosomal dominant, autosomal
      recessive, and even mitochondrial. The FA gene products appear to cooperate, and
      are important in the pathways involved in response to DNA damage. However, the
      role of this pathway in developmental defects, hematopoietic failure, and the
      specific malignancies in FA is not fully elucidated. The DC gene products are
      important for maintenance of telomere length, which may have relevance to
      development of aplastic anemia and malignancies, but the relation to the physical
      phenotype is less apparent. The role of mutations in c-mpl in Amega is more
      straightforward. since the gene codes for the receptor for thrombopoietin. which
      is the hormone required for megakaryocyte and platelet development; patients with
      mutant c-mpl do not have birth defects. The role of mutations in RPS19 in
      erythropoiesis or developmental defects in DBA patients is not obvious, and the
      increased frequency of osteogenic sarcomas suggests that at least that subset of
      patients may have a mutant tumor suppressor gene (such as p53, the mutant gene in
      Li-Fraumeni syndrome) [68]. Although patients with SCN have mutations in
      neutrophil elastase, patients with similar mutations may have relatively benign
      cyclic neutropenia, or may even have normal neutrophil levels [69,70]. The
      mitochondrial gene deletions in Pearson's Syndrome result in variable degrees of
      acidosis, and varied organ involvement due to heteroplasmy. Thus, the disorders
      included under the rubric "inherited bone marrow failure syndromes" have
      clinical. hematologic, oncologic, and genetic diversity.

PMID- 12430622
TI  - New approaches to hematopoietic cell transplantation for hematological diseases
      in children.
AB  - Hematopoietic cell transplantation (HCT) has been used for more 30 years for the
      treatment of selected malignant and nonmalignant diseases. Traditionally, HCT for
      hematological disorders has relied on myeloablative conditioning before HLA
      identical sibling bone marrow transplantation to correct the underlying
      hematological defect. Most children with hematological diseases who are referred
      to HCT have features that portend significant morbidity and early mortality.
      Among SAA patients who have HLA-identical sibling donors, younger patients with
      profound pancytopenia might be considered early for HCT. For others who lack
      sibling donors, patients who receive HCT from alternate sources have generally
      failed one or more courses of intensive immunosuppressive therapy and remain
      transfusion-dependent, some with hemosiderosis, red cell alloimmunization, and
      platelet transfusion refractoriness [44,46,48]. Currently, HCT for SCD is
      generally restricted to those who have experienced a significant sickle-related
      complication such as stroke, recurrent acute chest syndrome, or recurrent painful
      episodes [7,13]. In contrast, most reserve HCT in thalassemia for younger,
      Lucarelli class I, good-risk patients who have HLA-identical sibling donors, and
      veer away from older, high-risk thalassemics for whom transplantation is a
      riskier clinical intervention. For groups such as young adults with thalassemia
      major, HCT might become more widely applicable if its toxicity was reduced.
      Several approaches undergoing development include reduced-intensity conditioning
      and attempts to prevent GVHD. New methods to reduce the intensity and toxicity of
      conditioning as well as to use highly purified stem cells with the reduction in
      graft versus host disease may allow for the use of matched unrelated donors or
      haploidentical donors. This would serve to provide potentially more children who
      could benefit from stem cell transplantation with donors. These advances will
      hopefully lead to benefits for the majority of children who lack HLA-identical
      donors.

PMID- 12430623
TI  - Assessment of lymphadenopathy in children.
AB  - The assessment of lymphadenopathy in children is a common diagnostic problem in
      pediatrics. An understanding of the wide variety of diseases and conditions that
      may present as lymphadenopathy is essential to determining the most appropriate
      work up for an individual patient. Although the majority of these children will
      prove to have a benign disorder, it is important that the pediatrician also have
      an appreciation for the malignant diseases that may present with lymphadenopathy,
      so that in such cases the diagnosis of a serious or life-threatening disease can
      be made in a timely manner.

PMID- 12430624
TI  - Older adolescents with cancer in North America deficits in outcome and research.
AB  - In the two decades from the mid 1970s to the mid 1990s, the proportion of 5-year
      survivors among children in North America with cancer has increased nearly 40%.
      Advances in otherwise fatal leukemias, lymphomas, sarcomas, brain tumors, germ
      cell neoplasms and cancer of the kidney account for much of the improvement.
      Unfortunately, older adolescents have not fared as well. Their epidemiological,
      medical, physical, psychological and social needs remain largely unmet despite
      their age juxtaposition with younger patients whose outcomes have so much
      improved. In the United States and Canada, cancer in adolescents 15 to 19 years
      of age occurs at nearly twice the rate observed in 5 to 14 year-olds. Many of the
      types of cancer that occur in older adolescents are unique to this age group, and
      the pattern of distribution occurs at no other age interval. Overall, the cancers
      in older adolescents are more similar to the spectrum of cancer in children than
      to the common types of cancer in adults, but they are also distinctly different
      and require an age-specific approach. There is evidence of a lower degree in
      reduction in cancer mortality in the United States and Canada in this age range
      than in younger or older persons. Moreover, the disparity appears to be
      increasing. The improvement in 5-year survival from diagnosis of cancer from the
      mid 1970s to the early 1990s was lower than the rate of improvement in the
      younger age groups. Survival rates of older adolescents with cancer in the
      general population have not improved as much, especially in comparison with
      results of the national pediatric cooperative cancer groups. In the United States
      and Canada, only about 5% of 15 to 25 year-olds with cancer are entered onto
      clinical trials, in contrast to 60% to 65% of younger patients. Thus, cancer
      during adolescence and early adulthood has been relatively neglected and merits
      enhanced national research programs and resources.

PMID- 12430625
TI  - Caring for children with advanced cancer integrating palliative care.
AB  - The care of children with advanced cancer is multifaceted. Treatment should focus
      on continued efforts to control the underlying illness whenever possible. At the
      same time, children and their families should have access to interdisciplinary
      care aimed at promoting optimal physical, psychological and spiritual wellbeing.
      Open and compassionate communication can best facilitate meeting the goals of
      these children and families. However, there remain significant barriers to
      achieving optimal care related to lack of formal education, reimbursement issues
      and the emotional impact of caring for a dying child. Future research efforts
      should focus on ways to enhance communication, symptom management and quality of
      life for children with advanced cancer and their families. As efforts to break
      down barriers and create the evidence base continue, we conclude as follows: this
      is a most rewarding part of the practice of medicine. A kind word and caring
      attitude are remembered for decades.

PMID- 12430626
TI  - The psychological effect of childhood cancer on families.
AB  - The diagnosis of childhood cancer has a devastating effect on the family because
      of its life threatening nature requiring major shifts in lifestyle and
      psychological reality. An awareness of the developmental and cognitive levels of
      the child at the time of diagnosis, and the psychological and situational status
      of the family is crucial to providing appropriate interventions. The pre
      diagnostic and diagnostic stages of the illness provide an opportunity to assist
      the child and family in developing healthy adjustment strategies for both acute
      and long-term issues. The child and the family need to develop new coping skills,
      make use of outside support and resources, and receive specific interventions in
      order to maximize their adjustment. Continuing improvements in outcomes of cancer
      therapy and in psychotherapeutic treatment will reduce the psychological impact
      and assist in the child and family's adjustment to childhood cancer.

PMID- 12430627
TI  - Late effects of childhood cancer therapy.
AB  - This study reviews the common long-term sequalae of childhood cancer and its
      therapy. It discusses the clinical and research challenges posed by such late
      effects. The authors address related topics of late effects research and clinical
      care, methodological issues, barriers and directions for the future.

PMID- 12430628
TI  - Novel techniques in the delivery of radiation in pediatric oncology.
AB  - The field of radiation oncology continues to develop at a rapid pace, due to
      concurrent progress in high speed computing, improved sensitivity in diagnostic
      imaging (both anatomic and physiologic), and the introduction of rational new
      therapeutics built on solid radiobiologic principles. These innovations will
      become critically important in the field of pediatric oncology, as they will
      allow for an increased therapeutic ratio in the developing child. Maximizing the
      benefit of lower dose radiation through the use of radiation modifiers (hypoxic
      cell sensitizers, signal transduction pathway inhibitors, concurrent
      chemotherapy), increasing the tolerance of normal tissues (radioprotectors) and
      tailoring the target area more closely to the desired critical tissues (IMRT,
      functional simulation with PET and MRS, radiolabeled monoclonal antibodies) will
      lessen the short and long term toxicity of radiation and increase its
      effectiveness.

PMID- 12430629
TI  - Genomics and proteomics: application of novel technology to early detection and
      prevention of cancer.
AB  - Advances in molecular biology over the past decade have helped to enhance our
      understanding of the complex interplay between genetic, transcriptional and
      translational alterations in human cancers. These molecular changes are the basis
      for an evolving field of high-throughput cancer discovery techniques using
      microscopic amounts of patient-based materials. Laser capture microdissection
      allows pure populations of cells to be isolated from both the tumor and stroma in
      order to identify subtle differences in RNA and protein expression. Comparative
      analysis of these alterations between normal, pre-invasive, and invasive tissue
      using powerful bioinformatics programs has allowed us to identify novel tumor
      markers, profile complex protein pathways, and develop new molecular-based
      therapies. Continued refinement of such high-throughput microtechnologies will
      enable us to rapidly query patient specimens to identify novel methods for early
      detection, treatment, and follow-up of a wide array of human cancers.

PMID- 12430630
TI  - Effects of native and cleaved forms of alpha1-antitrypsin on ME 1477 tumor cell
      functional activity.
AB  - Tumor cells synthesize and release a variety of substances, including proteases
      and protease inhibitors involved in cell growth and proliferation. alpha1
      Antitrypsin (AAT) is a serine proteinase inhibitor synthesized primarily in the
      liver, but also in extra-hepatic tissues and cells, including tumor cells. AAT
      exists not only in a native, active inhibitory form, but also in several, non
      inhibitory forms, such as cleaved and/or degraded. This study was designed to
      investigate the synthesis of AAT by melanoma cells, ME 1477, and the effects of
      native, cleaved and C-terminal fragment of AAT (C-36) on cell functional
      activity. We found that ME 1477 cells synthesize and secrete AAT with the same
      apparent molecular mass as described for AAT purified from plasma, but with no
      measurable inhibitory activity. As determined by Western blot after
      immunoprecipitation of [32S]-labeled AAT, exogenous native or modified forms of
      AAT added to the cells at a concentration of 10 microM did not change AAT
      synthesis. Moreover, cells exposed to native AAT show decreased [3H]-thymidine
      incorporation by 53% and tissue inhibitor of metalloproteinases (TIMP)-1 levels
      by 36%. In contrast, cells treated with C-36 peptide significantly increased
      metalloproteinase activity, and [3H]-thymidine incorporation by 35%.
      Specifically, pro-collagenase-1 levels were found to be increased by 1.4-fold and
      decreased by 1.5-fold in cells treated with C-36 peptide and native AAT,
      respectively. Cleaved form of AAT had no significant effects on parameters
      measured. Data obtained from this study suggest that specific forms of AAT have
      multiple effects on tumor cell viability and play diverse roles in tumorogenesis.

PMID- 12430631
TI  - An integrative model on the role of DMBT1 in epithelial cancer.
AB  - The gene, deleted in malignant brain tumors 1 (DMBT1), has been proposed to play
      a role in brain and epithelial cancer, but shows unusual features for a classical
      tumor suppressor gene. We have proposed that its presumptive dual function in
      protection and differentiation is of importance to understand its role in cancer.
      To gain insights into its role in tumorigenesis, we conducted a comprehensive
      study on DMBT1 mutations, expression and location. Twenty-one out of 44 tumors
      showed variable numbers of tandem repeats (VNTRs) due to genetic polymorphism of
      DMBT1, whereas 11 out of 44 tumors displayed presumable mutations. However, none
      of the alterations would be predicted to lead to a complete inactivation of the
      gene. DMBT1 is mucin-like and shows tissue-specific expression and secretion,
      pointing to a function in the protection of monolayered epithelia and to an
      additional function in the differentiation of multilayered epithelia. The
      expression patterns in carcinomas arising from the respective structures support
      this view. Accepting this functional dualism gives rise to an initial model on
      the role of DMBT1 in epithelial cancer.

PMID- 12430632
TI  - Vector-based delivery of tumor-associated antigens and T-cell co-stimulatory
      molecules in the induction of immune responses and anti-tumor immunity.
AB  - It has now been demonstrated in both experimental models and recent clinical
      trials that certain "self" antigens, which are functionally non-immunogenic in
      the host, can become immunogenic if presented to the immune system in a certain
      way. Here, we describe recombinant vaccines and vaccine strategies that have been
      developed to induce and potentiate T-cell responses of the host to such self
      antigens. These strategies include: (a) the use of recombinant poxvirus vectors
      in which the tumor-associated antigen (TAA) is inserted as a transgene.
      Recombinant vaccinia vaccines and recombinant avipox (replication-defective)
      vaccines have been employed to break tolerance to a self-antigen; (b) the use of
      diversified prime and boost strategies using different vaccines; and (c) the
      insertion of multiple T-cell co-stimulatory molecules into recombinant poxvirus
      vectors, along with the TAA gene, to enhance T-cell immune responses to the TAA
      and induce anti-tumor immunity.

PMID- 12430633
TI  - Cytokine network in autoimmune haemolytic anaemia: new probable targets for
      therapy.
AB  - AIMS: Several immunological mechanisms seems to be similar in cancer and
      autoimmune disease. Studying interleukins production and proliferative response
      in autoimmune haemolytic anaemia (AIHA), it is possible to observe that
      manipulation of IL-10/IL-12 balance can have profound effect on the incidence of
      autoimmune diseases and this might be useful for the control of AIHA. METHODS:
      Respective role of IL-2, IL-4, IFN-gamma, IL-10 and IL-12 in non-cancer
      associated AIHA were investigated by examining the spontaneous and mitogen
      induced (OKT3 or LPS) synthesis of these cytokines in PBMC cultures by ELISA
      methods. RESULTS: Our results affirmed that AIHA is a disease which exhibited an
      increased basal synthesis of IL-4 and decreased levels of IFN-gamma by AIHA PBMC
      compared with controls and then there is a basal increase of Th2 cytokines. Th1
      type cytokine decrease in basal state occurred in parallel with an increase of
      constitutive IL-10 production and a IL-12 decrease. CONCLUSIONS: Decreased
      production of Th1-type cytokines and the production of autoantibodies in AIHA may
      be secondary to the imbalance between IL-10 and IL-12 and then the neutralisation
      of IL-10 may be efficacious in diminishing the clinical pathology associated with
      Th2 subset prevalence. In the same way, the treatment with IL-12 could offer a
      second and independent level of blockade against the consequences of the over B
      cell activation associated with AIHA and sometimes with cancer.

PMID- 12430634
TI  - Efficient intracellular delivery of 5-fluorodeoxyuridine into colon cancer cells
      by targeted immunoliposomes.
AB  - Immunoliposomes, liposomes with monoclonal antibodies attached, are being
      developed for targeting the anti-cancer drug 5-fluoro-2'-deoxyuridine (FUdR) to
      colon cancer cells. A monoclonal antibody against the rat colon carcinoma CC531
      was covalently coupled to liposomes containing a dipalmitoylated derivative of
      the anti-cancer drug FUdR (FUdR-dP) as a prodrug in their bilayers. We studied
      the association with the tumor cells of different types of immunoliposomes
      varying in the position and orientation of the antibody at the liposome surface.
      We also assessed the in vitro anti-tumor activity of these liposomes and the
      mechanism by which the active drug FUdR is delivered intracellularly. Specific
      binding of the immunoliposomes to the tumor cells was observed. Immunoliposomes
      containing FUdR-dP caused a much stronger inhibition of CC531 cell growth in
      vitro than FUdR-dP in non-targeted liposomes. After binding to the cell surface
      only limited amounts of the immunoliposomes were internalized. By contrast,
      already within 24 h immunoliposome-incorporated FUdR-dP was hydrolyzed virtually
      completely to the parent drug FUdR, intracellularly. The mechanism of
      intracellular delivery of the drug most likely involves a selective transfer of
      the lipophilic prodrug from the liposomes to the cell membrane and subsequent
      intracellular processing. In conclusion, we developed a targeted liposomal
      formulation, which is able to deliver FUdR to colon carcinoma cells
      intracellularly with high efficiency, without the need for the cells to
      internalize the liposomes as such. This approach may be attractive for other
      lipophilic anti-cancer (pro)drugs. In this sense our system also serves as a
      model for the development of new lipid-based drug delivery systems for anti
      cancer therapy.

PMID- 12430635
TI  - Potential role of lipid peroxidation derived DNA damage in human colon
      carcinogenesis: studies on exocyclic base adducts as stable oxidative stress
      markers.
AB  - Molecular pathways to colorectal cancer involve multiple genetic changes that may
      be caused by overproduction of reactive oxygen species in cancer-related genes.
      Our aim was to investigate, whether besides direct oxidative DNA damage, reactive
      oxygen and nitrogen species induce lipid peroxidation (LPO) that could yield
      etheno-DNA adducts via trans-4-hydroxy-2-nonenal, a major aldehyde generated by
      LPO, in colon tissue. We analyzed the etheno-DNA adducts by a highly specific,
      ultrasensitive method involving immunoaffinity chromatography coupled with 32P
      postlabelling [Carcinogenesis 16 (1995) 613] in affected colon epithelium from
      ulcerative colitis, Crohn's disease and familial adenomatous polyposis (FAP) and
      compared them with asymptomatic colon tissue. In all these cancer prone colon
      tissues, the formation of markedly enhanced etheno adduct levels was demonstrated
      for the first time. Etheno-DNA adducts are promutagenic and cause genomic
      instability that could drive the inflamed colonic epithelia to malignancy. Etheno
      DNA adducts appear promising biomarkers for (i) quantifying increased DNA damage
      in early stages of colon carcinogenesis and for (ii) verifying the efficacy of
      new antioxidants (e.g. [Lancet Oncol. 1 (2000) 107]) and chemopreventive agents
      in lowering oxidative stress and related cancer risk.

PMID- 12430636
TI  - DNA analysis of cholangiocarcinoma cells: prognostic and clinical importance.
AB  - INTRODUCTION: The clinical value of established prognostic factors seems to be
      limited since they fail to predict reliably survival of patients after resection
      of cholangiocarcinoma. DNA ploidy reflecting irregularities of chromosome number
      and content might be an alternative predictor. In this study, we evaluated the
      DNA ploidy as a prognostic factor for survival of patients after resection of
      cholangiocarcinoma. METHODS: This prospective study included 34 patients with
      cholangiocarcinoma which were surgically resected and followed up to death or
      more than 3 years. Tissue specimens were taken from the liver tissue immediately
      after resection and DNA ploidy determined. Survival was related to the type of
      DNA ploidy as well as to five established prognostic factors. RESULTS:
      Multivariate analysis revealed that in this study only DNA ploidy (P = 0.012) was
      significantly associated with prediction of survival. In contrast, neither tumor
      stage pT (P = 0.073) nor tumor grade pG (P = 0.154), resection margins R (P =
      0.322), metastasis M (P = 0.060), lymph node stage pN (P = 0.209), age (P = 0.13)
      nor sex (P = 0.849) could significantly predict survival. Three-year survival was
      best for patients with diploid tumors (n = 6) of whom 75% survived more than 3
      years. Poor prognostic signs associated with short term survival of less than 18
      months were tumors classified as aneuploid (n = 17), large tumors pT4 (n = 8),
      metastasis pM1 (n = 11), undifferentiated tumors pG3 (n = 9) and non-tumor-free
      resection margins R2 (n = 14). The best predictor for poor prognosis was
      aneuploidy since it could identify more patients with a fatal outcome than other
      prognostic factors. DNA ploidy turned out to discriminate highly significant
      between diploid, polyploid and aneuploid tumors. DISCUSSION: The most accurate
      prognostic factor for survival of patients after resection of cholangiocarcinoma
      was DNA ploidy. Most patients suffering from a diploid tumor turned out to be
      long term survivors whereas aneuploid tumors indicated a poor prognosis with a
      rather short survival time of less than 18 months. We conclude that DNA ploidy is
      a valuable diagnostic tool for identifying subgroups of patients that are at
      higher risk for tumor progression.

PMID- 12430637
TI  - Evaluation of an outreach intervention to promote cervical cancer screening among
      Cambodian American women.
AB  - INTRODUCTION: Southeast Asian women have low levels of Papanicolaou (Pap) testing
      participation. We conducted a group-randomized controlled trial to evaluate a
      cervical cancer screening intervention program targeting Seattle's Cambodian
      refugee community. METHODS: Women who completed a baseline, community-based
      survey were eligible for the trial. Neighborhoods were the unit of randomization.
      Three hundred and seventy survey participants living in 17 neighborhoods were
      randomized to intervention or control status. Intervention group women received
      home visits by outreach workers and were invited to group meetings in
      neighborhood settings. The primary outcome measure was self-reported Pap testing
      in the year prior to completing a follow-up survey. RESULTS: The proportion of
      women in the intervention group reporting recent cervical cancer screening
      increased from 44% at baseline to 61% at follow-up (+17%). The corresponding
      proportions among the control group were 51 and 62% (+11%). These temporal
      increases were statistically significant in both the intervention (P < 0.001) and
      control (P = 0.027) groups. DISCUSSION: This study was unable to document an
      increase in Pap testing use specifically in the neighborhood-based outreach
      intervention group; rather, we found an increase in both intervention and control
      groups. A general awareness of the project among women and their health care
      providers as well as other ongoing cervical cancer screening promotional efforts
      may all have contributed to increases in Pap testing rates.

PMID- 12430638
TI  - Soot-water distribution coefficients for polychlorinated dibenzo-p-dioxins,
      polychlorinated dibenzofurans and polybrominated diphenylethers determined with
      the soot cosolvency-column method.
AB  - For many types of hydrophobic compounds, sorption non-linearity and solid-water
      distributions in the field well above expectations from organic matter
      partitioning models have lead to the proposition that strong adsorption to soot
      surfaces may not be limited to polycyclic aromatic hydrocarbons but may extend as
      a significant process for many aromatic compound classes. Here, the soot-water
      distribution coefficients (Ksc) were determined with the soot cosolvency-column
      method for homolog series of five polychlorinated dibenzo-p-dioxins (PCDDs), five
      polychlorinated dibenzofurans (PCDFs) and for two polybrominated diphenylethers
      (PBDEs). All compounds exhibited significantly stronger association with soot
      carbon than expected from estimates of their bulk organic-carbon normalized
      partition coefficients (Koc). The Ksc/Koc ratios (at aqueous concentrations of
      around 0.1-1 microg/l) were for PCDDs (up to tetrachlorination) 19-130 (median
      25), for PCDFs (also up to tetrachlorination) 150-490 (median 300), and for both
      the tetra- and pentabrominated PBDEs a factor of 60. The particularly strong soot
      sorption for the PCDFs is of similar enhancement factors as previously elucidated
      for polycyclic aromatic hydrocarbons. Compound-class specific correlations
      between log Ksc and octanol-water partition coefficients (log Kow) were
      significant for both PCDDs and PCDFs (and with R2 > 98%). These may prove useful
      for anticipating variable fractions of dissolved exposures between different
      environmental regimes and putative remediation objects.

PMID- 12430639
TI  - Fe(III)-solar light induced degradation of diethyl phthalate (DEP) in aqueous
      solutions.
AB  - The degradation of diethyl phthalate (DEP) photoinduced by Fe(III) in aqueous
      solutions has been investigated under solar irradiation in the compound parabolic
      collector reactor at Plataforma Solar de Almeria. Hydroxyl radicals *OH,
      responsible of the degradation, are formed via an intramolecular photoredox
      process in the excited state of Fe(III) aquacomplexes. The primary step of the
      reaction is mainly due to the attack of *OH radicals on the aromatic ring. For
      prolonged irradiations DEP and its photoproducts are completely mineralized due
      to the regeneration of the absorbing species and the continuous formation of *OH
      radicals that confers a catalytic aspect to the process. Consequently, the
      degradation photoinduced by Fe(III) could be an efficient method of DEP removal
      from water.

PMID- 12430640
TI  - Binding of cadmium on raw paper pulp. Relationship between temperature and
      sorption kinetics.
AB  - Several assays have been carried out in order to study in detail the cadmium
      mobility from water to virgin pulp as previous step of cadmium mobility
      description from paper into food. Virgin pulp has been immersed in different
      concentration aqueous solutions at several temperatures and during short and long
      time. The absorbed cadmium amounts have been measured by atomic absorption
      spectroscopy. For a long time, the temperature of storage is not an important
      factor except during the first 3 h. In general, percentage of migrated cadmium
      into pulp is between 30% and 90% of initial charge. Kinetic equation of cadmium
      mobility has been described employing statistics methods with a very good
      correlation.

PMID- 12430641
TI  - Identification and significance of phenazone drugs and their metabolites in
      ground- and drinking water.
AB  - Residues of three phenazone-type pharmaceuticals have been identified in routine
      analyses of groundwater samples from selected areas in the north-western
      districts of Berlin, Germany. Phenazone, propiphenazone, and
      dimethylaminophenazone have been detected in some wells at concentrations up to
      the low microg/l-level. Additionally, three phenazone-type metabolites namely 1
      acetyl-1-methyl-2-dimethyl-oxamoyl-2-phenylhydrazide (AMDOPH), 1-acetyl-1-methyl
      2-phenylhydrazide, and dimethyloxalamide acid-(N'-methyl-N-phenyl)-hydrazide have
      also been identified in these groundwater samples. The residues are suspected to
      originate from former production spills of a pharmaceutical plant located in a
      city north of Berlin. It was observed that with the exception of AMDOPH all other
      residues were efficiently removed during conventional drinking water treatment.
      The drug metabolite AMDOPH deriving from dimethylaminophenazone residues was
      found at concentrations of 0.9 microg/l in finished drinking water. However, a
      following study on the toxicological relevance of the AMDOPH residues has shown
      that there is no toxicological harm for humans at the low concentrations of
      AMDOPH observed in Berlin drinking water.

PMID- 12430642
TI  - Heavy metals in agricultural soils from Piedmont, Italy. Distribution, speciation
      and chemometric data treatment.
AB  - The distribution and speciation of heavy metals in five agricultural soils of
      Piedmont Region (north-western Italy) were investigated. Ten metals, namely Al,
      Cd, Cr, Cu, Fe, Mn, Ni, Pb, Ti and Zn were considered. Analytical determinations
      were performed by atomic emission or atomic absorption spectroscopy after
      microwave sample dissolution in acid solution. Total metal concentrations fit in
      the typical concentration ranges for unpolluted soils, with the exception of
      cadmium and lead content in some horizons. The effect of sampling depth on
      concentrations was discussed. Speciation studies were carried out by applying
      Tessier's procedure, which allows to subdivide the total metal content into five
      fractions, representing portions bound to different components of the soil.
      Moreover, the element labilities in two soils were evaluated by extraction with
      EDTA. Correlations among the variables and/or similarities among the sampling
      points were identified by principal component analysis and hierarchical cluster
      analysis.

PMID- 12430643
TI  - Influence of heavy metals on the microbial degradation of diesel fuel.
AB  - The degradation of diesel fuel by a microbial community from a soil polluted by
      heavy metals (h.m.) in the presence of Cu, Ni, Zn, Pb, Cd, Hg and Cr (as
      chromate) was investigated. Experiments were conducted with soil slurries and the
      extracted community in liquid cultivation. The concentrations applied were in the
      sub-mM and mM range. Whereas the slurries displayed no significant effect,
      degradation in liquid culture was increasingly inhibited by higher metal
      concentrations. The course of degradation in suspension was demonstrated by the
      oxygen consumption. The order of toxicity was found to be: Hg > Cr(VI) > Cu > Cd
      > Ni > Pb > Zn. The absence of any effect for slurries was due to the non
      availability of the metals in the soil, and to precipitation or adsorption to the
      soil in the case of amendment. The paper also includes results on the
      availability of h.m. and changes to the community after exposure.

PMID- 12430644
TI  - Retention behavior of hydrophobic organic chemicals as a function of temperature
      in soil leaching column chromatography.
AB  - To study the transport mechanism of hydrophobic organic chemicals (HOCs) and the
      energy change in soil/solvent system, a soil leaching column chromatographic
      (SLCC) experiment at an environmental temperature range of 20-40 degrees C was
      carried out, which utilized a reference soil (SP 14696) packed column and a
      methanol-water (1:4 by volume ratio) eluent. The transport process quickens with
      the increase of column temperature. The ratio of retention factors at 30 and 40
      degrees C (k'30/k'40) ranged from 1.08 to 1.36. The lower enthalpy change of the
      solute transfer in SLCC (from eluent to soil) than in conventional reversed-phase
      liquid chromatography (e.g., from eluent to C18) is consistent with the
      hypothesis that HOCs were dominantly and physically partitioned between solvent
      and soil. The results were also verified by the linear solvation energy
      relationships analysis. The chief factor controlling the retention was found to
      be the solute solvophobic partition, and the second important factor was the
      solute hydrogen-bond basicity, while the least important factors were the solute
      polarizability-dipolarity and hydrogen-bond acidity. With the increase of
      temperature, the contributions of the solute solvophobic partition and hydrogen
      bond basicity gradually decrease, and the latter decreases faster than the
      former.

PMID- 12430645
TI  - Trace element concentration in tree-rings biomonitoring centuries of
      environmental change.
AB  - Inductively coupled plasma mass spectrometry (ICP-MS) was used to examine trace
      element concentration in tree-rings over three and half centuries to assess macro
      trends of environmental change. Tree-rings of a 350+ year old mammoth ponderosa
      pine (Pinus ponderosa) were analyzed for element concentration and evaluated
      versus local and global historical events. The ponderosa pine was located 100
      miles south of the Canada/USA border and 180 miles east of the Pacific Ocean, and
      grew near apple orchards, a public road, and Swakane Creek in western Washington,
      USA. The elements tested did not all display the same time versus concentration
      patterns. Copper and chromium displayed cyclic concentration patterns over the
      last 350+ years, which appear to be associated with local events. Strontium,
      barium, zinc and cadmium were found to be relatively constant between the mid
      1600s and the early 1800s. Strontium, barium, zinc, and cadmium then increased
      beginning in the early 1800s for approximately 50 years then decreased to present
      day 2000. Significantly, similar changes seen in Ca, Mg, and Zn in other studies
      have been attributed to acid rain, whereas, in our study area there is no history
      of anthropogenic acid rain. Most importantly, our data goes back to the mid-1600s
      several hundred years further back than most other studies of this nature. This
      additional time data provides for a better context of trend data not previously
      available.

PMID- 12430646
TI  - Isotopic fractionation during reductive dechlorination of trichloroethene by zero
      valent iron: influence of surface treatment.
AB  - During reductive dechlorination of trichloroethene (TCE) by zero-valent iron,
      stable carbon isotopic values of residual TCE fractionate significantly and can
      be described by a Rayleigh model. This study investigated the effect of observed
      reaction rate, surface oxidation and iron type on isotopic fractionation of TCE
      during reductive dechlorination. Variation of observed reaction rate did not
      produce significant differences in isotopic fractionation in degradation
      experiments. However, a small influence on isotopic fractionation was observed
      for experiments using acid-cleaned electrolytic iron versus experiments using
      autoclaved electrolytic iron, acid-cleaned Peerless cast iron or autoclaved
      Peerless cast iron. A consistent isotopic enrichment factor of epsilon = 
      16.7/1000 was determined for all experiments using cast iron, and for the
      experiments with autoclaved electrolytic iron. Column experiments using 100% cast
      iron and a 28% cast iron/72% aquifer matrix mixture also resulted in an
      enrichment factor of -16.9/1000. The consistency in enrichment factors between
      batch and column systems suggests that isotopic trends observed in batch systems
      may be extrapolated to flowing systems such as field sites. The fact that
      significant isotopic fractionation was observed in all experiments implies that
      isotopic analysis can provide a direct qualitative indication of whether or not
      reductive dechlorination of TCE by Fe0 is occurring. This evidence may be useful
      in answering questions which arise at field sites, such as determining whether
      TCE observed down-gradient of an iron wall remediation scheme is the result of
      incomplete degradation within the wall, or of the dissolved TCE plume by passing
      the wall.

PMID- 12430647
TI  - Investigations on the binding mechanism of the herbicide simazine to dissolved
      organic matter in leachates of compost.
AB  - 14C-labelled simazine was composted together with biowaste on a pilot (m3) scale.
      The herbicide was quickly bound to the compost matrix. By aqueous extraction of
      29 and 200 days old compost (equivalent to thermophilic and mesophilic phase of
      composting) only 4.2% and 3.1% respectively of the radioactivity in the compost
      samples could be extracted with water. Analysis of the extracts using high
      performance size exclusion chromatography (HPSEC) revealed that the dissolved
      organic matter (DOM) had molecular weights ranging between 2 and 28 kDa. The
      amount of DOM-associated radioactivity increased from 53% (day 29) to 65% (day
      200) of total extractable radioactivity. The type of binding of the 14C-labelled
      residues and the DOM was elucidated by silylation of humic matter and subsequent
      HPSEC. The data demonstrated that besides polar metabolites also intact simazine
      was bound to the DOM. A distinct shift from rather weak interactions to strong
      covalent linkages of simazine and its metabolites with increasing age of the
      compost was observed. The results showed that only low amounts of free simazine
      and its degradates can be extracted with water. We concluded that the shift
      towards stable covalent linkages is equivalent to a detoxification of the
      contaminant in aged compost. Consequently, the use of the analysed compost in its
      mature stage should not pose an environmental risk to the groundwater or the
      subsoil.

PMID- 12430648
TI  - Arsenic and other heavy metals in soils from an arsenic-affected area of West
      Bengal, India.
AB  - Domkal is one of the 19, out of 26 blocks in Murshidabad district where
      groundwater contains arsenic above 0.05 mg/l. Many millions of cubic meters of
      groundwater along with arsenic and other heavy metals are coming out from both
      the hand tubewells, used by the villagers for their daily needs and shallow big
      diameter tubewells, installed for agricultural irrigation and depositing on soil
      throughout the year. So there is a possibility of soil contamination which can
      moreover affect the food chain, cultivated in this area. A somewhat detailed
      study was carried out, in both micro- and macrolevel, to get an idea about the
      magnitude of soil contamination in this area. The mean concentrations (mg/kg) of
      As (5.31), Fe (6740), Cu (18.3), Pb (10.4), Ni (18.8), Mn (342), Zn (44.3), Se
      (0.53), Mg (534), V (44.6), Cr (33.1), Cd (0.37), Sb (0.29) and Hg (0.54) in
      fallow land soils are within the normal range. The mean As (10.7), Fe (7860) and
      Mg (733) concentrations (mg/kg) are only in higher side whereas Hg (0.17 mg/kg)
      is in lower side in agricultural land soils, compared to the fallow land soils.
      Arsenic concentrations (11.5 and 28.0 mg/kg respectively) are high in those
      agricultural land soils where irrigated groundwater contains high arsenic (0.082
      and 0.17 mg/l respectively). The total arsenic withdrawn and mean arsenic
      deposition per land by the 19 shallow tubewells per year are 43.9 kg (mean: 2.31
      kg, range: 0.53-5.88 kg) and 8.04 kg ha(-1) (range: 1.66-16.8 kg ha(-1))
      respectively. For the macrolevel study, soil arsenic concentration decreases with
      increase of distance from the source and higher the water arsenic concentration,
      higher the soil arsenic at any distance. A proper watershed management is
      urgently required to save the contamination.

PMID- 12430649
TI  - Effects of surface coatings on electrochemical properties and contaminant
      sorption of clay minerals.
AB  - Surface charges play a major role in determining the interactions of contaminants
      with soils. The most important sources of soil charges are clay mineral colloids,
      whose electrochemical properties are usually modified by metal-oxides and organic
      matter in natural environments. In this study, effects of coatings of organic
      matter and Fe- and Al-oxides on a series of electrochemical properties and heavy
      metal sorption of three clay minerals (kaolinite, montmorillonite and illite)
      predominant in natural soils were investigated using batch techniques. The
      results indicate that the coatings increased the specific surface area of the
      clay minerals, except for the Al-oxide coated montmorillonite and organic matter
      coated 2:1 clay minerals. The sesquioxide coatings increased amount of positive
      charges but decreased negative charges. This causes great reduction of the
      negative potential on the clay surfaces, shift of the zero point of charge to a
      higher pH, and promotion of fluoride sorption due to presence of more OH- and OH2
      on the oxide surfaces than on the clay surfaces. In contrast, the organic coating
      significantly increased the negativity of surface charges, and thus the zero
      point of charge and zeta-potential of the clays dropped down. The organic coating
      also induced a reduction of fluoride sorption on the clays. With respect to the
      sorption of lead and cadmium, the sesquioxide coatings produced insignificant
      effects. The experiments of lead/cadmium competitive sorption show that on both
      the oxide-coated surface and the original clay surface there exist different
      types of sites, each of which preferentially binds with a heavy metal.

PMID- 12430650
TI  - Studies of metal-binding sites in natural organic matter and their role in the
      generation of disinfection by-products using lanthanide ion probes.
AB  - In this study, the complexation of Tb3+ with natural organic matter (NOM) was
      studied by the method of time-resolved fluorescence spectroscopy. In the presence
      of NOM, the excitation of Tb3+ was observed in a wide range of wavelengths, for
      which virtually no excitation of free Tb3+ took place. The pseudo-quantum yield
      spectra (excitation intensity normalized by corresponding light absorbance
      values) had a maximum at 282 nm. This indicated that the excitation of NOM-bound
      Tb3+ proceeds through energy transfer from aromatic groups in NOM. The
      concentration of the metal-binding sites (C(L)) was determined by titration with
      Tb3+ and was found to range from 0.21% to 0.83% of total moles of organic carbon.
      The actual number of the carbon atoms that comprise these functionalities was
      hypothesized to be at least seven times higher. The C(L) values were well
      correlated with the reactivity of NOM with chlorine quantified by total organic
      halogen formation potential and with the contribution of polyhydroxyaromatic
      moieties determined by pyrolysis-GC/MS method. The correlation of C(L) with the
      contributions of aromatic and carboxylic moieties in NOM determined by 13C NMR
      was poor. Based on the data, it was concluded that the metal binding
      functionalities in NOM are closely associated with halogen attack sites.

PMID- 12430651
TI  - Comparison of the combined monitoring-based and modelling-based priority setting
      scheme with partial order theory and random linear extensions for ranking of
      chemical substances.
AB  - The combined monitoring-based and modelling-based priority setting scheme
      (COMMPS) used to establish a priority setting list within the EU Water Framework
      Directive plays a major role in the European environmental policy on chemical
      substances. The COMMPS procedure can be classified as a so-called scoring method.
      The applied functional relationship and weight factors are established based on
      expert judgement, which unfortunately appears to be vulnerable to subjective
      inputs. In this study an alternative priority setting methods based on partial
      order theory (POT) and random linear extensions (RLE) is suggested and compared
      to the COMMPS procedure. The POT/RLE is characterised as being based on fewer
      assumptions concerning functional relationships and does not apply weighting
      factors. Using the POT/RLE methodology a different ranking result occur than when
      using the COMMPS procedure. Eight of the top 20 substances from the COMMPS
      procedure are not ranked within the top 20 when using POT/RLE. From the viewpoint
      of environmental protection, especially the substances that have been given low
      priority in the COMMPS procedure, but a high rank in POT/RLE, are of interest in
      a regulatory context. These substances are naphthalene, trichloromethane,
      isoproturon, metolachlor, endosulfan, acenaphthene, alachlor and dichloromethane.
      An analysis of the ability of the descriptors to separate the single substance
      discloses that the most significant descriptor is the concentrations detected in
      the environment. Further, the frequency of detection is not applied as a
      descriptor in the COMMPS procedure. However, if this descriptor was to be applied
      the analysis revealed that it would have been the third most significant
      descriptor.

PMID- 12430652
TI  - Phosphine and methane generation by the addition of organic compounds containing
      carbon-phosphorus bonds into incubated soil.
AB  - Formation of phosphine and methane in anaerobic incubation systems was
      investigated under stirred and unstirred conditions. The PH3 and CH4 levels in
      the headspace, as well as the matrix-bound PH3 content in the stirred soil,
      significantly increased upon the addition of phosphonoacetic acid
      (P(O)(OH)2CH2COOH). Both the levels of matrix-bound PH3 and CH4 are positively
      correlated to the buffered dithionite fraction of reactive phosphorus in the soil
      samples, while a negative correlation was observed between matrix-bound PH3/CH4
      levels and the reactive phosphorus fraction.

PMID- 12430653
TI  - Sorptive behavior of the phenylamide fungicides, mefenoxam and metalaxyl, and
      their acid metabolite in typical Cameroonian and German soils.
AB  - Laboratory soil sorption experiments were conducted on mefenoxam, formulated
      metalaxyl (F-metalaxyl), pure metalaxyl (P-metalaxyl) and metalaxyl acid
      metabolite to elucidate differences in their sorptive behaviour on typical
      Cameroonian forest soil (sand clay loam, pH 4.8 and 3.01% OC) and German soil
      (sandy loam, pH 7.2, 1.69% OC) using a batch equilibrium method. The data
      obtained on all test chemicals conformed to linear and Freundlich adsorption
      isotherms. The Langmuir equation failed to describe the sorption of the
      substances tested. All substances were adsorbed to a greater extent by the
      Cameroonian soil. The average percentage adsorptions for mefenoxam, F-metalaxyl,
      P-metalaxyl and the acid metabolite on the Cameroonian soil were 27.8%, 28.3%,
      31.8% and 46.8% respectively while for the German soil they were 21.7%, 21.5%,
      24.7% and 9.8% respectively. The KD and KF parameters and the Freundlich
      exponential term (1/n) were low, indicating that the interactions between soil
      particles and the fungicides were weak. The sorption parameters were lower in the
      German soil. P-metalaxyl exhibited a higher adsorption capacity than F-metalaxyl
      in both soils. Mefenoxam and F-metalaxyl exhibited similar sorption parameters in
      soils, whereas those of P-metalaxyl and acid metabolite differed. Differences
      observed in the adsorption between the two soils could be attributed to their
      properties. Desorption studies revealed that the adsorbed fungicides were not
      firmly retained by soil particles and their adsorption was reversible. Desorption
      of adsorbed mefenoxam, P-metalaxyl and of the acid metabolite from German soil
      was almost completely reversible with percentage desorption rates of more than
      91.0%, whereas the rate for F-metalaxyl was 74.1%. All compounds exhibited some
      resistance to desorption from the Cameroonian soil, with percentage desorption
      rates less than 77.0%. Therefore if degradation in the soil is slow the
      fungicides described have a potential to leach to lower soil horizons.

PMID- 12430654
TI  - Movement of bromacil and hexazinone in soils of Hawaiian pineapple fields.
AB  - Bromacil and hexazinone have been heavily used to control weeds in the pineapple
      fields in central Oahu, Hawaii, USA, since 1970s and 1980s, respectively. The
      last application prior to this study was at a rate of 0.6 kg active ingredient
      (a.i.) ha(-1) for hexazinone and 1.8 or 3.4 kg (a.i.) ha(-1) for bromacil in the
      six study fields during June-October 1998. Soils were collected from 0 to 1860 cm
      below the surface in January-May 1999 to survey the residue profiles of the two
      herbicides. Stratoprobe sampling showed to be an efficient and convenient method
      for deep soil cores. Bromacil was detected in all the soil samples above 60 cm
      (105-1338 ng g(-1) dry weight) and in 74% of the samples above 400 cm (26-473 ng
      g(-1)). Trace amounts of bromacil (90-113 ng g(-1)) were detected in some of the
      samples collected from as deep as 1540 cm. Hexazinone was detected in three of
      the six fields at 0-60 cm only (86-107 ng g(-1) dry weight). The more frequent
      detection of bromacil at higher concentrations than hexazinone is related to the
      prolonged higher application rates of bromacil in the fields and its higher
      persistence and mobility in soil.

PMID- 12430655
TI  - Atmospheric conversion of sulfur dioxide to particulate sulfate and nitrogen
      dioxide to particulate nitrate and gaseous nitric acid in an urban area.
AB  - Sulfur dioxide, nitrogen dioxide, particulate sulfate and nitrate, gaseous nitric
      acid, ozone and meteorological parameters (temperature and relative humidity)
      were measured during the winter season (1999-2000) and summer season (2000) in an
      urban area (Dokki, Giza, Egypt). The average particulate nitrate concentrations
      were 6.20 and 9.80 microg m(-3), while the average gaseous nitric acid
      concentrations were 1.14 and 6.70 microg m(-3) in the winter and summer seasons,
      respectively. The average sulfate concentrations were 15.32 microg m(-3) during
      the winter and 25.10 microg m(-3) during the summer season. The highest average
      concentration ratio of gaseous nitric acid to total nitrate was found during the
      summer season. Particulate sulfate and nitrate and gaseous nitric acid
      concentrations were relatively higher in the daytime than those in the nighttime.
      Sulfur conversion ratio (Fs) and nitrogen conversion ratio (Fn) defined in the
      text were calculated from the field measurement data. Sulfur conversion ratio
      (Fs) and nitrogen conversion ratio (Fn) in the summer were about 2.22 and 2.97
      times higher than those in the winter season, respectively. Moreover, sulfur
      conversion ratio (Fs) and nitrogen conversion ratio (Fn) were higher in the
      daytime than those in the nighttime during the both seasons. The sulfur
      conversion ratio (Fs) increases with increasing ozone concentration and relative
      humidity. This indicates that the droplet phase reactions and gas phase reactions
      are important for the oxidation of SO2 to sulfate. Moreover, the nitrogen
      conversion ratio (Fn) increases with increasing ozone concentration, and the gas
      phase reactions are important and predominant for the oxidation of NO2 to
      nitrate.

PMID- 12430656
TI  - Decarboxylation and alkaline colour fading reactions in presence of humic
      substances.
AB  - Humic substances (HSs) can substantially influence velocity of reactions in the
      environment as shown on example of decarboxylation and alkaline colour (e.g.,
      malachite green and crystal violet) fading reactions. In colour fading and
      decarboxylation reactions of 6-nitrobenzisoxazole-3-carboxylic acid HS act as
      inhibitors, but additions of surfactants change the pattern of reaction. The
      inhibitory activity of HSs much depends on their origin. The velocity of studied
      reactions depends also on pH, temperature and concentration of HS used. Possible
      micellar catalysis mechanism has been suggested.

PMID- 12430657
TI  - Geologic emissions of methane to the atmosphere.
AB  - The atmospheric methane budget is commonly defined assuming that major sources
      derive from the biosphere (wetlands, rice paddies, animals, termites) and that
      fossil, radiocarbon-free CH4 emission is due to and mediated by anthropogenic
      activity (natural gas production and distribution, and coal mining). However, the
      amount of radiocarbon-free CH4 in the atmosphere, estimated at approximately 20%
      of atmospheric CH4, is higher than the estimates from statistical data of CH4
      emission from fossil fuel related anthropogenic sources. This work documents that
      significant amounts of "old" methane, produced within the Earth crust, can be
      released naturally into the atmosphere through gas permeable faults and fractured
      rocks. Major geologic emissions of methane are related to hydrocarbon production
      in sedimentary basins (biogenic and thermogenic methane) and, subordinately, to
      inorganic reactions (Fischer-Tropsch type) in geothermal systems. Geologic CH4
      emissions include diffuse fluxes over wide areas, or microseepage, on the order
      of 10(0)-10(2) mg m(-2) day(-1), and localised flows and gas vents, on the order
      of 10(2) t y(-1), both on land and on the seafloor. Mud volcanoes producing flows
      of up to 10(3) t y(-1) represent the largest visible expression of geologic
      methane emission. Several studies have indicated that methanotrophic consumption
      in soil may be insufficient to consume all leaking geologic CH4 and positive
      fluxes into the atmosphere can take place in dry or seasonally cold environments.
      Unsaturated soils have generally been considered a major sink for atmospheric
      methane, and never a continuous, intermittent, or localised source to the
      atmosphere. Although geologic CH4 sources need to be quantified more accurately,
      a preliminary global estimate indicates that there are likely more than enough
      sources to provide the amount of methane required to account for the suspected
      missing source of fossil CH4.

PMID- 12430658
TI  - Uncertainties and novel prospects in the study of the soil carbon dynamics.
AB  - Establishment of the Kyoto Protocol has resulted in an effort to look towards
      living biomass and soils for carbon sequestration. In order for carbon credits to
      be meaningful, sustained carbon sequestration for decades or longer is required.
      It has been speculated that improved land management could result in
      sequestration of a substantial amount of carbon in soils within several decades
      and therefore can be an important option in reducing atmospheric CO2
      concentration. However, evaluation of soil carbon sources and sinks is difficult
      because the dynamics of soil carbon storage and release is complex and still not
      well understood. There has been rapid development of quantitative techniques over
      the past two decades for measuring the component fluxes of the global carbon
      cycle and for studying the soil carbon cycle. Most significant development in the
      soil carbon cycle study is the application of accelerator mass spectrometry (AMS)
      in radiocarbon measurements. This has made it possible to unravel rates of carbon
      cycling in soils, by studying natural levels of radiocarbon in soil organic
      matter and soil CO2. Despite the advances in the study of the soil carbon cycle
      in the recent decades, tremendous uncertainties exist in the sizes and turnover
      times of soil carbon pools. The uncertainties result from lack of standard
      methods and incomplete understanding of soil organic carbon dynamics, compounded
      by natural variability in soil carbon and carbon isotopic content even within the
      same ecosystem. Many fundamental questions concerning the dynamics of the soil
      carbon cycle have yet to be answered. This paper reviews and synthesizes the
      isotopic approaches to the study of the soil carbon cycle. We will focus on
      uncertainties and limitations associated with these approaches and point out
      areas where more research is needed to improve our understanding of this
      important component of the global carbon cycle.

PMID- 12430659
TI  - Uncertainties in the role of land vegetation in the carbon cycle.
AB  - Since the late 1950s the CO2 concentration of the atmosphere has been increasing
      by around 0.5-3 ppm per year. Understanding of carbon sinks is vital to
      understanding this trend and its future behaviour. Here we examine some of the
      factors which may affect the proportion of anthropogenic CO2 ending up in the
      atmosphere in the present and in the future, and variability in the CO2 increase
      from one year to another. We also examine the evidence for the potential of
      terrestrial ecosystem carbon sinks to take up or release CO2. In some cases, a
      careful re-examination of the research methods used to deduce present and future
      feedbacks may be necessary. The most advanced technology and the most complex
      models do not necessarily produce reliable results. They should be carefully
      checked against a general background knowledge of ecological processes before
      their results are accepted.

PMID- 12430660
TI  - Carbon storage in Amazonia during the last glacial maximum: secondary data and
      uncertainties.
AB  - The Amazonian forest is, due to its great size, carbon storage capacity and
      present-day variability in carbon uptake and release, an important component of
      the global carbon cycle. Paleo-environmental reconstruction is difficult for
      Amazonia due to the scarcity of primary palynological data and the mis
      interpretation of some secondary data. Studies of lacustrine sediment records
      have shown that Amazonia has known periods in which the climate was drier than it
      is today. However, not all geomorphological features such as dunes, and slope
      erosion, which are thought to indicate rainforest regression, date from the time
      of the Late Glacial Maximum (LGM) and these features do not necessarily
      correspond to episodes of forest regression. There is also uncertainty concerning
      LGM carbon storage due to rainforest soils and biomass estimates. Soil carbon
      content may decrease moderately during the LGM, whereas rainforest biomass may
      change considerably in response to changes in the global environment. Biomass per
      unit area in Amazonia has probably been reduced by the cumulative effects of low
      CO2 concentration, a drier climate and lower temperatures. As few paleo
      vegetation data are available, there is considerable uncertainty concerning the
      amount of carbon stored in Amazonia during the LGM, which may have corresponded
      to 44-94% of the carbon currently stored in biomass and soils.

PMID- 12430661
TI  - The contribution of reactive carbon emissions from vegetation to the carbon
      balance of terrestrial ecosystems.
AB  - About 2.4 Pg (1 Pg = 10(15) g) of carbon is emitted annually into the atmosphere
      as reactive compounds and most of it is eventually oxidized to CO2. Isoprene,
      alpha-pinene, methanol, carbon monoxide and other compounds emitted by
      terrestrial vegetation contribute about half of the total flux and are estimated
      to produce about 1 Pg C as CO2 per year. The global average for vegetated
      surfaces is about 7 g C m(-2) per year but could exceed 100 g m(-2) per year at
      some tropical locations. The magnitude of these fluxes on both the landscape and
      global scales are small relative to the total carbon emission or deposition but
      are significant relative to the net fluxes. Reactive carbon fluxes are very
      sensitive to landcover and climate change and may vary significantly due to
      future perturbations. This paper summarizes what is known about reactive carbon
      emissions from vegetation including the magnitude of local, landscape, and global
      scale fluxes and their contribution to atmospheric CO2. Reasons for including
      this term in carbon flux models are presented as well as the potential importance
      on various spatial scales. Past, present and future reactive carbon emissions are
      expected to differ significantly and the implications of this are discussed.

PMID- 12430662
TI  - Holocene biomass burning and global dynamics of the carbon cycle.
AB  - Fire regimes have changed during the Holocene due to changes in climate,
      vegetation, and in human practices. Here, we hypothesise that changes in fire
      regime may have affected the global CO2 concentration in the atmosphere through
      the Holocene. Our data are based on quantitative reconstructions of biomass
      burning deduced from stratified charcoal records from Europe, and South-, Central
      and North America, and Oceania to test the fire-carbon release hypothesis. In
      Europe the significant increase of fire activity is dated approximately 6000 cal.
      yr ago. In north-eastern North America burning activity was greatest before 7500
      years ago, very low between 7500-3000 years, and has been increasing since 3000
      years ago. In tropical America, the pattern is more complex and apparently
      latitudinally zonal. Maximum burning occurred in the southern Amazon basin and in
      Central America during the middle Holocene, and during the last 2000 years in the
      northern Amazon basin. In Oceania, biomass burning has decreased since a maximum
      5000 years ago. Biomass burning has broadly increased in the Northern and
      Southern hemispheres throughout the second half of the Holocene associated with
      changes in climate and human practices. Global fire indices parallel the increase
      of atmospheric CO2 concentration recorded in Antarctic ice cores. Future issues
      on carbon dynamics relatively to biomass burning are discussed to improve the
      quantitative reconstructions.

PMID- 12430663
TI  - Mitral-valve-induced microangiopathic hemolytic anemia.

PMID- 12430664
TI  - Evidence-based clinical reporting: a need for improvement.

PMID- 12430665
TI  - Xenogeneic blood transfusion: a chimeric thought or a potential strategy for use
      in patients with xenogeneic chimerism?

PMID- 12430666
TI  - A prospective, randomized clinical trial of universal WBC reduction.
AB  - BACKGROUND: Recipient exposure to allogeneic donor WBCs results in transfusion
      complications for selected populations of recipients. Whether or not WBC
      reduction should be universally applied is highly controversial. STUDY DESIGN AND
      METHODS: In a general hospital, a randomized, controlled clinical trial of
      conversion to universal WBC reduction was conducted. Patients (11%) with
      established medical indications for WBC-reduced blood were not eligible. All
      other patients who required transfusion were assigned at random to receive either
      unmodified blood components or stored WBC-reduced RBCs and platelets. Analysis
      for each patient was restricted to the first hospitalization. RESULTS: All
      eligible patients (n = 2780) were enrolled. Three specified primary outcome
      measures were not different between the two groups: 1) in-hospital mortality
      (8.5% control; 9.0% WBC-reduced; OR, 0.94 [95% CI, 0.72-1.22]; p = 0.64); 2)
      hospital length of stay (LOS) after transfusion (median number of days, 6.4 for
      control and 6.3 for WBC-reduced; p = 0.21); and 3) total hospital costs (median,
      $19,500 for control and $19,200 for WBC-reduced, p = 0.24). Secondary outcomes
      (intensive care LOS, postoperative LOS, antibiotic usage, and readmission rate)
      were not different between the two groups. Subgroup analysis based on patient
      age, sex, amount of blood transfused, or category of surgical procedure showed no
      effect of WBC reduction. Patients who received WBC-reduced blood had a lower
      incidence of febrile reactions (p = 0.06). CONCLUSION: A beneficial effect of
      conversion from selective to universal WBC reduction was not demonstrated.

PMID- 12430667
TI  - A case-control study of the impact of WBC reduction on the cost of hospital care
      for patients undergoing coronary artery bypass graft surgery.
AB  - BACKGROUND: WBC reduction of blood components may reduce the incidence of
      transfusion reactions. The cost of this intervention might be offset by a
      reduction in the incidence of postoperative infection, thereby reducing the
      length of hospital stay and thus the cost of care for patients receiving
      transfusion. Cedars-Sinai Medical Center provided WBC-reduced blood components to
      all patients for a period of 2 years, creating an opportunity to compare the
      incidence of postoperative infection, length of hospital stay, and total hospital
      costs for patients undergoing coronary artery bypass graft surgery, before,
      during, and after WBC reduction. STUDY DESIGN AND METHODS: Data were obtained by
      examining hospital records of patients who received transfusion and control
      patients who did not receive transfusion for the years 1991 (before WBC
      reduction), 1992 to 1993 (during WBC reduction), and 1994 (following
      discontinuation of WBC reduction). Comparisons were made by use of ANOVA
      following log or square root transformation of the data. RESULTS: Length of
      hospital stay for patients who received transfusion decreased over time. Mean
      hospital stays were 15.9, 14.1, and 12.1 days before, during, and after WBC
      reduction, respectively. A similar trend was seen in the patients who did not
      receive transfusion. There was no indication that WBC reduction functioned as an
      independent variable that was responsible for the observed decrease. The rate of
      postoperative infection stayed constant during WBC reduction and only dropped
      when WBC reduction was stopped. Mean hospital cost showed no significant change
      over time for either the transfusion group or the nontransfusion group.
      CONCLUSION: The cost of providing a totally WBC-reduced blood supply may not be
      offset by immediate savings related to decreased postoperative infections,
      reduced length of hospital stay, and cost of hospital care.

PMID- 12430668
TI  - Effect of WBC reduction of transfused RBCs on postoperative infection rates in
      cardiac surgery.
AB  - BACKGROUND: WBC-replete blood transfusion has been suggested as an independent
      cause of increased postoperative infection. STUDY DESIGN AND METHODS: A total of
      597 patients undergoing elective coronary artery or heart valve surgery were
      randomly assigned to receive plasma-reduced (PR), buffy coat-depleted (BCD), or
      WBC-filtered (WCF) RBCs in the event of requiring blood transfusion. Details of
      postoperative course were recorded. Further information was collected from the
      patient's general practitioner 3 months after discharge. RESULTS: No significant
      difference in inpatient infection rates was observed among patients randomly
      assigned to receive PR, BCD, or WCF RBCs. When only those receiving transfusion
      were analyzed (n = 509), use of PR RBCs was associated with more events coded as
      infections (p < or = 0.05) compared with BCD or WCF RBCs. However, when events
      coded as urinary tract infections were excluded, there was no significant
      difference among the three groups. Follow-up performed after discharge showed no
      difference in readmission rates, but a higher reported rate of infection in those
      randomly assigned to receive WCF RBCs (p < 0.02). CONCLUSION: No evidence has
      been found, analyzed by intention to treat, that use of WBC-reduced, BCD, or WCF
      RBCs reduces postoperative inpatient infection in patients undergoing cardiac
      bypass surgery.

PMID- 12430669
TI  - A historical cohort study of the effect of lowering body iron through blood
      donation on incident cardiac events.
AB  - BACKGROUND: Low body iron may protect against atherosclerotic cardiovascular
      disease through limiting oxidation of low-density lipoprotein cholesterol.
      Observational studies suggest that donation of whole blood might be associated
      with reduced risk of cardiovascular events. STUDY DESIGN AND METHODS: In this
      retrospective cohort study, a total of 1508 adults who donated more than 1 unit
      of whole blood each year between 1988 and 1990 (frequent donors) and 1508 age-
      and sex-matched adults who donated only a single unit in that 3-year period
      (casual donors) were studied. A standardized questionnaire ascertained
      participant characteristics and occurrence of incident acute myocardial
      infarction, coronary angioplasty, coronary bypass surgery, and deaths between
      1990 and 2000. Hospital records confirmed events. Cause of death was determined
      from death certificates. RESULTS: A total of 643 subjects were lost, 113
      declined, 156 were deceased but were included in the analysis, and 2104 were
      surveyed a median of 10 years after the index donation. Frequent donors weighed
      less and were less likely to be currently taking antihypertensive and lipid
      modifying drugs. Events occurred in 6.3 percent of frequent and 10.5 percent of
      casual donors. After adjustment for group differences, the OR was D.60 (85% CIs
      0.43, 0.83; p < 0.001). Events were less frequent in female donors than in male
      donors and less frequent in subjects who had donated before 1988 than in those
      who had not donated before 1988. CONCLUSION: Frequent and long-term whole blood
      donation is associated with a lower risk of cardiovascular events.

PMID- 12430670
TI  - Probability of receiving testing in a national lookback program: the English HCV
      experience.
AB  - BACKGROUND: The HCV lookback program was designed to trace and offer testing to
      recipients who received transfusion of blood components from donors subsequently
      found to be anti-HCV positive. Only approximately 20 percent of transfusable
      components entering lookback did result in a recipient obtaining testing through
      this program. STUDY DESIGN AND METHODS: Data from English blood centers were
      collated to describe the outcomes of the HCV lookback program. The data were used
      to assess factors affecting the likelihood that recipients of lookback components
      received testing by the program. RESULTS: In total, 4424 recipients of 6687 blood
      components that had been issued for transfusion were identified. The lookback
      resulted in a tested recipient for 1067 components. Factors positively associated
      with receiving testing in identified recipients were younger age at transfusion,
      more recent year of transfusion, certain component types, and transfusion under
      the care of certain medical specialties; these effects were largely explained by
      the association of these factors with survival after transfusion. CONCLUSIONS:
      Not accepting testing through this program was largely due to death before the
      lookback and partly due to inability to access information from records and to
      decisions that testing was not in recipients' best interests. The probability of
      obtaining testing through this lookback was associated with several factors that
      could be used to focus the efforts of similar lookbacks in the future.

PMID- 12430671
TI  - Transfusion transmission of HCV infection before anti-HCV testing of blood
      donations in England: results of the national HCV lookback program.
AB  - BACKGROUND: An HCV lookback program started in England in 1995. STUDY DESIGN AND
      METHODS: Data from all English blood centers were collated to describe the
      outcomes of the HCV lookback program in England and to create a retrospective
      cohort for study. Numbers of recipients identified, numbers that were tested, and
      numbers that were found to be HCV infected were summarized. The data set created
      was used to describe the outcomes of the lookback and the HCV infections
      detected. RESULTS: A total of 4424 recipients of 9222 blood components made
      before donation testing for anti-HCV from the donations of 1286 donors found, on
      subsequent testing, to be anti-HCV positive or indeterminate were identified. Of
      these, 1351 blood recipients were reported as having been traced for testing.
      Fifty percent of tested recipients were found to be HCV infected. Factors
      positively associated with HCV infection in tested recipients were more recent
      year of transfusion and PCR positivity of the donor at the time of their testing.
      CONCLUSIONS: The majority of components entering lookback did not result in a
      tested recipient. However, this lookback has identified a large group of HCV
      infected individuals. Follow-up of this group for disease progression will inform
      the natural history of HCV infection.

PMID- 12430672
TI  - Transmission of Babesia microti in Minnesota through four blood donations from
      the same donor over a 6-month period.
AB  - BACKGROUND: Babesiosis is a tick-borne zoonosis caused by intraerythrocytic
      protozoa. More than 40 US cases of Babesia microti infection acquired by blood
      transfusion have been reported. This report describes the identification of a
      transfusion-associated case of babesiosis and the subsequent identification of
      the infected blood donor and three other infected recipients of cellular blood
      components from three other donations by this donor. STUDY DESIGN AND METHODS:
      Serum specimens from the donors of blood that had been made into cellular
      components received by the index recipient and from other recipients of such
      components from the implicated donor were tested by the indirect fluorescent
      antibody (IFA) assay for antibodies to B. microti. Whole blood from IFA-positive
      persons was tested by PCR for B. microti DNA. RESULTS: IFA testing of serum from
      31 of 36 donors implicated a 45-year-old man (titer, 1 in 256), whose donation
      had been used for RBCs. He likely became infected when bitten by ticks while
      camping in Minnesota in June 1999 and had donated blood four times thereafter. As
      demonstrated by PCR, he remained parasitemic for at least 10 months. Of the five
      other surviving recipients of cellular blood components from the implicated
      donor, three recipients (one for each of the three other donations) had become
      infected through either RBC or platelet transfusions. CONCLUSIONS: Babesiosis
      should be included in the differential diagnosis of posttransfusion febrile
      illness, and effective means for preventing transmission by blood transfusion are
      needed.

PMID- 12430673
TI  - The composition of leukapheresis products impacts on the hematopoietic recovery
      after autologous transplantation independently of the mobilization regimen.
AB  - BACKGROUND: Effects of mobilization regimen on the composition of leukapheresis
      products (LPs) and on hematopoietic reconstitution after autologous peripheral
      blood progenitor cell transplantation (PBPCT) are not well known. STUDY DESIGN
      AND METHODS: The effects of three different mobilization regimens--stem cell
      factor (SCF) plus granulocyte colony stimulating factor (G-CSF) plus
      cyclophosphamide (CCP), G-CSF alone, and G-CSF plus CCP--on the composition of
      LPs from patients with nonhematologic PBPC malignancies compared to LPs from G
      CSF-mobilized healthy donors and normal marrow (BM) samples were analyzed. The
      impact of LP composition on both short- and long-term engraftment after
      autologous PBPCT was also evaluated. RESULTS: The most effective regimen for
      mobilization of CD34+ hematopoietic progenitor cells (HPCs) into peripheral blood
      was SCF, G-CSF, and CCP, providing the highest numbers of all CD34+ HPCs subsets
      analyzed. Patients mobilized with SCF plus G-CSF plus CCP showed the highest
      numbers of neutrophils and monocytes, whereas the highest numbers of lymphocytes
      and NK cells were observed in LPs from G-CSF-mobilized patients. The overall
      number of CD34+ HPCs was the strongest factor for predicting recovery of
      platelets, whereas the number of myelomonocytic-committed CD34+ precursors was
      the most powerful independent prognostic factor for WBC and neutrophil recovery.
      The overall number of CD4+ T cells returned showed an independent prognostic
      value for predicting the occurrence of infections, during the first year after
      transplant. CONCLUSIONS: The use of different mobilization regimens modifies the
      overall number of CD34+ HPCs obtained during leukapheresis procedures, and also
      affects both the absolute and the relative composition of the LPs in different
      CD34+ and CD34- cell subsets.

PMID- 12430674
TI  - Isoimmunization against CD36 (glycoprotein IV): description of four cases of
      neonatal isoimmune thrombocytopenia and brief review of the literature.
AB  - BACKGROUND: Platelet CD36 (glycoprotein [GP] IV) deficiency occurs in 3 to 5
      percent of persons of Asian or African ancestry. A subset of these individuals is
      at risk for immunization against CD36, but the magnitude of this problem and its
      significance in transfusion medicine have not yet been clarified. STUDY DESIGN
      AND METHODS: Clinical and laboratory aspects of neonatal thrombocytopenia
      involving five infants born to four CD36- mothers were characterized. The CD36
      gene was sequenced in three mothers. The literature concerning isoimmunization
      against CD36 was reviewed and summarized. RESULTS: Isoantibodies reactive with
      CD36 on normal platelets and platelets from the fathers were identified in each
      of the four mothers. Two African-American mothers were homozygous for a 1264TG
      mutation in the CD36 gene. A mother of Italian ancestry was homozygous for a
      previously unidentified deletion of exons 1 through 3. Previously reported cases
      of isoimmunization against CD36 were reviewed and summarized. CONCLUSION:
      Isoimmunization against CD36 can cause neonatal isoimmune thrombocytopenia
      (NITP), refractoriness to platelet transfusions, and post-transfusion purpura.
      Immunization against this glycoprotein (GP) should be considered in patients with
      apparent alloimmune platelet disorders not explained by immunization against
      recognized platelet-specific alloantigens, especially in persons of African,
      Asian, and, possibly, Mediterranean ancestry.

PMID- 12430675
TI  - Anti-Vel reactivity diminished by adsorption with rabbit RBC stroma.
AB  - BACKGROUND: An anti-Vel, nearly missed in antibody identification studies, and
      the effect of a commercially available rabbit RBC stroma (RESt, Immucor)
      adsorptions on eight anti-Vel sera are reported. Anti-Vel is an antibody to an
      antigen of high prevalence. CASE REPORT: A 48-year-old woman with chronic vaginal
      bleeding presented with a Hct of 14.7 percent. The transfusion service was not
      informed of her history of anti-Vel when she was transferred from another
      institution. Studies performed on an emergency request for transfusion were
      interpreted as a cold autoantibody as adsorption with a commercial source of RESt
      eliminated the reactivity. Stored anti-Vel sera were tested by titration studies
      before and after adsorption with commercial RESt. RESULTS: Serum from the index
      case did not react after adsorption with RESt at the transfusion service. Studies
      with the stored anti-Vel indicated antibody adsorption with four of four samples
      at immediate spin (IS) and room temperature (RT) phases, four of eight samples at
      37 degrees C in albumin (ALB) phase, and four of eight samples at ALB-IgG-AGT
      phase. Variations in antibody reactivity were observed in the samples tested, but
      RESt adsorption diminished antibody reactivity in most samples. All eight stored
      sera demonstrated some reactivity in at least one phase after adsorption with
      RESt. CONCLUSION: Anti-Vel was completely or partially adsorbed by RESt. Caution
      should be used when interpreting cold agglutinins with this method. The
      manufacturer warns that uncommon alloantibodies may be adsorbed.

PMID- 12430676
TI  - Evaluating porcine RBC and platelet alpha-galactosyl expression.
AB  - BACKGROUND: Naturally occurring human xenoreactive antibodies bind and
      agglutinate porcine RBCs. STUDY DESIGN AND METHODS: To determine if xenoantigen
      expression on RBCs of individual pigs of different breeds and blood groups is
      variable, and if it correlates with platelet (PLT) expression, we measured
      adsorption of affinity-purified antibodies to alpha-galactosyl (alphaGal) by RBCs
      or PLTs from 22 pigs representing four breeds. Hemagglutination of RBCs from
      these pigs was also performed with pools of human group OAB, A, B, and AB sera,
      as well as with anti-alphaGal-depleted pooled OAB human serum. RESULTS: There was
      significant variation in alphaGal expression on RBCs and PLTs among pigs. PLT
      alphaGal expression did not correlate with RBC alphaGal. RBCs from all pigs were
      agglutinated by pooled group O, AB, A, or B sera, whereas titers were reduced by
      87 percent with anti-alphaGal-depleted serum and by 82 percent with AB sera from
      two volunteers. Agglutination titers were higher against RBCs from the five
      highest RBC alphaGal expressers compared with those from the five lowest RBC
      alphaGal expressers (92 +/- 12 vs. >160, p < 0.05, where 160 was the maximum
      dilution tested). CONCLUSION: Hemagglutination is a feasible alternative for
      rapid identification of pigs with RBCs carrying less alphaGal.

PMID- 12430678
TI  - Elastic properties of irradiated RBCs measured by optical tweezers.
AB  - BACKGROUND: Gamma irradiation of RBCs results in the production of reactive
      oxygen capable of initiating the process of membrane lipid peroxidation and
      accelerates the leakage of potassium ions from RBCs, resulting in an increase of
      internal viscosity. STUDY DESIGN AND METHODS: The elastic properties of
      irradiated and stored RBC units were studied using laser optical tweezers. The
      laser trapped the cell and the membrane elasticity was analyzed, measuring the
      cell deformation in six different drag velocities. Five RBC units were split into
      two portions. One portion received a gamma irradiation dose of 25 Gy, and the
      second one was used as a control and was not irradiated. All units were stored (4
      degrees C), and the elasticity was examined on Days 1, 14, 21, and 28. RESULTS:
      Elastic properties (mu) from irradiated RBCs stored for 21 and 28 days were
      significantly affected compared with control cells (21 days: control, 0.3 +/-
      0.03 x 10(-3); irradiated, 3.5 +/- 1.3 x 10(-3) dyn/cm; p < 0.001; and 28 days:
      control, 0.5 +/- 0.09 x 10(-3); irradiated, 14 +/- 3.2 x 10(-3) dyn/cm; p <
      0.001). CONCLUSION: The sensitivity of the laser optical tweezers method showed
      that there is no significant change in elasticity over time for up to 14 days of
      storage, regardless of whether the unit was irradiated or not. However, beyond 21
      days of storage, irradiated units demonstrate decreased elasticity.

PMID- 12430677
TI  - Positive (1-->3)-beta-D-glucan in blood components and release of (1-->3)-beta-D
      glucan from depth-type membrane filters for blood processing.
AB  - BACKGROUND: The false-positive elevation of plasma (1-->3)-beta-D-glucan level, a
      serodiagnostic test for deep-seated mycosis, is suspected in patients
      administered with blood components. STUDY DESIGN AND METHODS: (1-->3)-beta-D
      Glucan and endotoxin levels in blood components consisting of 12 albumins, 8
      immunoglobulins, and 3 blood coagulation factors were measured by fungal
      infection tests (Fungitec G-test, Seikagaku Co.; the Wako WB003 test, Wako Pure
      Chemical Industries; and the Endospec ES test, Seikagaku Co.). In vitro release
      of (1-->3)-beta-D-glucan from the depth-type filters made by cellulose membrane
      to process blood components was analyzed through an in vitro filtration process
      as a source of (1-->3)-beta-D-glucan in blood components. RESULTS: The amounts of
      (1-->3)-beta-D-glucan in blood components ranged from 0 to 7510 pg per mL in the
      Fungitec G-test, with wide variations among brands. The positive rates over 20 pg
      per mL were 75 percent in albumin solutions, 40 percent in blood coagulation
      factors, and 63 percent in immunoglobulin solutions. (1-->3)-beta-D-Glucan levels
      released from the five depth filters ranged from 5 to 2516 pg per mL. The (1-->3)
      beta-D-glucan level in filtration fluid was decreased by rinsing with distilled
      water, but rebounded again during the albumin filtration process. CONCLUSION:
      Depth filters are considered the source of (1-->3)-beta-D-glucan content in some
      blood components.

PMID- 12430679
TI  - Use of a flow-cell system to investigate virucidal dimethylmethylene blue
      phototreatment in two RBC additive solutions.
AB  - BACKGROUND: Limited photoinactivation kinetics, use of low-volume 30 percent Hct
      RBCs, and hemolysis have restricted the practicality of the use of
      dimethylmethylene blue (DMMB) and light for RBC decontamination. A flow-cell
      system was developed to rapidly treat larger volumes of oxygenated 45 percent Hct
      RBCs with high-intensity red light. MATERIALS AND METHODS: CPD-whole blood was
      WBC reduced, RBCs were diluted in additive solutions (either Adsol or
      Erythrosol), and suspensions were subsequently oxygenated by gas overlay.
      Intracellular or extracellular VSV and DMMB were sequentially added. VSV-infected
      RBC suspensions (45% Hct) were passed through 1-mm-thick flow cells and
      illuminated. Samples were titered for VSV, stored for up to 42 days, and assayed
      for Hb, supernatant potassium, ATP, and MCV. RESULTS: The use of oxygenated RBCs
      resulted in rapid and reproducible photoinactivaton of > or = 6.6 log
      extracellular and approximately 4.0 log intracellular VSV independent of additive
      solution. Phototreated Adsol RBCs exhibited more than 10 times greater hemolysis
      and 30 percent greater MCV during storage than identically treated Erythrosol
      RBCs. Phototreatment caused RBC potassium leakage from RBCs in both additive
      solutions. ATP levels were better preserved in Erythrosol than Adsol RBCs.
      CONCLUSION: A rapid, reproducible, and robust method for photoinactivating model
      virus in RBC suspensions was developed. Despite improved hemolysis and ATP levels
      in Erythrosol-phototreated RBCs, storage properties were not maintained for 42
      days.

PMID- 12430680
TI  - Circulation and hemostatic function of autologous fresh, liquid-preserved, and
      cryopreserved baboon platelets transfused to correct an aspirin-induced
      thrombocytopathy.
AB  - BACKGROUND: The survival of fresh and preserved platelets has been used primarily
      to determine their therapeutic effectiveness. The function of the fresh and
      preserved platelets has been difficult to assess. In stable thrombocytopenic
      patients, platelet function of fresh and preserved allogeneic platelets is
      evaluated by the reduction in bleeding time. In this study of healthy male
      baboons, both the survival and function of autologous fresh, liquid-preserved,
      and cryopreserved platelets in the correction of an aspirin-induced
      thrombocytopathy was evaluated. STUDY DESIGN AND METHODS: Five healthy male
      baboons were studied on eight occasions over a 4-year period. To produce a
      prolonged bleeding time, the baboon was administered 325 mg of aspirin 18 hours
      before receiving autologous transfusion. The fresh, liquid-preserved, and
      previously frozen washed platelets were labeled with (111)In-oxine before
      autologous transfusion. The autologous, nonaspirinated platelets' ability to
      reduce the aspirin-induced prolonged bleeding time and increase the shed blood
      thromboxane B2 level at the template bleeding time site was studied. RESULTS:
      Platelets stored at 22 degrees C for 48 hours had in vivo recovery values similar
      to those platelets stored for 18 hours, and they significantly reduced the
      bleeding time and increased the shed blood thromboxane level after transfusion.
      Platelets stored at 22 degrees C for 72 hours had in vivo recovery values similar
      to those platelets stored for 18 hours, but the bleeding time was not corrected
      after transfusion, although there was a significant increase in the shed blood
      thromboxane B2 level. The cryopreserved platelets significantly reduced the
      bleeding time and significantly increased the shed blood thromboxane level after
      transfusion. Cryopreserved platelets had better in vivo survival and function
      than the 5-day liquid-stored platelets. CONCLUSIONS: The survival of autologous
      fresh, liquid-preserved, or cryopreserved platelets did not correlate with their
      function to reduce an increased bleeding time in baboons treated with aspirin.

PMID- 12430681
TI  - Durable response to combination therapy including staphylococcal protein A
      immunoadsorption in life-threatening refractory autoimmune hemolysis.
AB  - BACKGROUND: Few therapeutic options are available for severe, life-threatening,
      refractory autoimmune hemolytic anemia. CASE REPORT: A 53-year-old 110-kg man was
      seen with acute onset of symptomatic severe anemia with syncope, unstable angina,
      and jaundice. His nadir Hct was 8.3 percent with a peak total bilirubin of 44 mg
      per dL. The DAT was positive but the IAT was negative. Elution studies
      demonstrated an IgG pan-agglutinin antibody reactive at 37 degrees C. Treatment
      with high-dose corticosteroids and IVIG was instituted. An accessory spleen
      measuring 2 cm was identified and surgically removed, but the patient continued
      to have intense hemolysis. Cyclophosphamide at 200 mg per day was started.
      Apheresis with a staphylococcal protein A immunoadsorption column (Prosorba,
      Cypress Bioscience, Inc.) was initiated on Day 18 and was performed twice weekly
      for a total of six treatments. Cyclophosphamide was continued for a total of 14
      days. His transfusion requirement ceased by the third immunoadsorption treatment.
      Forty units of RBCs were required over 23 days in an attempt to maintain a Hct
      greater than or equal to 15 percent. CONCLUSION: Refractory autoimmune hemolysis
      can be a life-threatening event. The patient did not achieve a response until
      after several different therapeutic modalities were instituted, including
      plasmapheresis with a staphylococcal protein A column (Prosorba). A complete
      response continues to be durable for more than 1 year after therapy.

PMID- 12430682
TI  - Apoptosis, transforming growth factor-beta, and the immunosuppressive effect of
      transfusion.

PMID- 12430683
TI  - The effectiveness of interventions to reduce physician's levels of inappropriate
      transfusion: what can be learned from a systematic review of the literature.

PMID- 12430684
TI  - NAT screening of blood and plasma donations: evolution of technology and
      regulatory policy.

PMID- 12430685
TI  - The risk of transfusion to the wrong patient in Germany.

PMID- 12430686
TI  - Viral marker rates among blood donors before and after the terrorist attacks on
      the United States on September 11, 2001.

PMID- 12430688
TI  - Serotyping and antibiotic resistance profiling of Salmonella in feedlot and
      nonfeedlot beef cattle.
AB  - As part of a larger study to assess risk factors associated with hide and carcass
      contamination of beef cattle during transport to slaughter, a total of 281
      salmonellae were isolated from 1,050 rectal, hide, carcass, and environmental
      samples. For feedlot cattle, salmonellae were recovered from 4.0% of rectal
      samples, 37.5% of hide samples, 19.0% of carcass samples, and 47.4% of
      environmental samples. For nonfeedlot cattle, salmonellae were recovered from
      10.9% of rectal samples, 37.5% of hide samples, 54.2% of carcass samples, and
      50.0% of environmental samples. Overall, the five serotypes most commonly
      associated with feedlot cattle and their environment were Salmonella Anatum
      (18.3% of the isolates), Salmonella Kentucky (17.5%), Salmonella Montevideo
      (9.2%), Salmonella Senftenberg (8.3%), and Salmonella Mbandaka (7.5%). The five
      serotypes most commonly associated with nonfeedlot cattle and their environment
      were Salmonella Kentucky (35.4%), Salmonella Montevideo (21.7%). Salmonella Cerro
      (7.5%), Salmonella Anatum (6.8%), and Salmonella Mbandaka (5.0%). Antimicrobial
      susceptibility testing of all of the isolates associated with feedlot cattle
      revealed that 21.7% were resistant to tetracycline, compared with 11.2% of the
      isolates associated with nonfeedlot cattle. None of the other isolates from
      feedlot cattle were resistant to any of other antimicrobial agents tested,
      whereas 6.2% of nonfeedlot cattle isolates were resistant to more than four of
      the antimicrobial agents tested.

PMID- 12430687
TI  - Prevalence of Salmonella and Campylobacter in beef cattle from transport to
      slaughter.
AB  - The objective of this study was to evaluate the effect of typical production
      practices during the transport of cattle on the resulting incidence of Salmonella
      and Campylobacter in the feces, on the hides, and on the carcasses of these
      cattle and in the environment (trucks, holding pens, and knock boxes). Various
      factors were evaluated, including the type of animal (feedlot cattle vs. adult
      pasture cattle), the breed of cattle, the body condition of the animal, the age
      of the animal, the time of feed and water withdrawal, the contamination level of
      the transport vehicle at the feedlot or farm, the transport time, the time cattle
      were held in the holding pen at the plant, and the contamination level of the
      holding pen. Four groups of each type of animal were sampled on different days.
      Samples were collected from cattle prior to transport and after transport (rectal
      and hide swabs) as well as from the carcasses of these cattle. Pre- and
      posttransit samples were also taken from the transport vehicle and from the
      holding pen and knock box at the slaughter facility. For feedlot cattle, fecal
      shedding stayed fairly constant for both organisms before and after transport (3
      to 5% for Salmonella and 64 to 68% for Campylobacter). However, the shedding rate
      for adult cattle increased from 1 to 21% for Salmonella but stayed constant for
      Campylobacter (6 to 7%). Contamination of hides with Salmonella increased for
      both animal types from a level of 18 to 20% to a level 50 to 56%. For
      Campylobacter, the contamination level decreased from 25 to 13% for feedlot
      cattle but remained unchanged for adult animals (1 to 2%). Nineteen percent of
      feedlot cattle carcasses and 54% of adult cattle carcasses tested positive for
      Salmonella, while only2% of feedlot cattle carcasses and none of the adult cattle
      carcasses tested positive for Campylobacter. Thus, for feedlot cattle, the
      factors considered in this study did not affect the shedding of either organism
      but did affect the contamination of hides with both. For adult animals, the
      factors increased both shedding of and hide contamination with Salmonella only,
      not Campylobacter.

PMID- 12430689
TI  - Prevalence of Arcobacter spp. in raw ground pork from several geographical
      regions according to various isolation methods.
AB  - Studies show that the pathogen Arcobacter is present in beef, poultry, and pork.
      Several methods have been reported for the isolation of this organism, but none
      has been adopted as the standard. This has limited the significance of field
      comparison studies. In the present study, we compared the efficiencies of four
      Arcobacter isolation methods using raw ground pork collected from slaughter
      facilities across the United States. We also evaluated the effect of meat fat
      level and age of animals on the prevalence of Arcobacter in ground pork. The
      methods chosen for comparison of isolation efficiency were those of Collins, a
      modified version of the Collins method (Direct Collins), deBoer, and Johnson
      Murano (JM). These were chosen based on published reports in which they were used
      to detect Arcobacter in pork products. The JM method was found to be the most
      successful in consistently detecting Arcobacter, isolating it in 64 of 200 pork
      samples compared with the Direct Collins method, which isolated Arcobacter in 52
      of 200 of those same samples. The Collins method and the deBoer method found
      Arcobacter present in only a fraction of the samples. The level of contamination
      was found to vary among the plants, ranging from 0% to 68% prevalence, with 32%
      overall for all four plants tested. Additionally, ground pork low in fat had a
      higher contamination frequency (20%) when compared with high-fat pork (4%).
      Results also showed that meat from younger animals was more frequently
      contaminated than that from older animals.

PMID- 12430690
TI  - Calcinated calcium killing of Escherichia coli O157:H7, Salmonella, and Listeria
      monocytogenes on the surface of tomatoes.
AB  - This study was conducted to evaluate the efficacy of calcinated calcium, 200 ppm
      chlorine water (1% active chlorine), and sterile distilled water in killing
      Escherichia coli O157:H7, Salmonella, and Listeria monocytogenes on the surfaces
      of spot-inoculated tomatoes. Inoculated tomatoes were sprayed with calcinated
      calcium, chlorinated water, or sterile distilled water (control) and hand rubbed
      for 30 s. Populations of E coli O157:H7, Salmonella, and L. monocytogenes in the
      rinse water and in the residual (0.1% peptone) wash solution were determined.
      Treatment with 200 ppm chlorine and calcinated calcium resulted in 3.40- and 7.85
      log10 reductions of E. coli O157:H7, respectively, and 2.07- and 7.36-log10
      reductions of Salmonella, respectively. Treatment with 200 ppm chlorine and
      calcinated calcium reduced L monocytogenes numbers by 2.27 and 7.59 log10 CFU per
      tomato, respectively. The findings of this study suggest that calcinated calcium
      could be useful in controlling pathogenic microorganisms in fresh produce.

PMID- 12430691
TI  - Identification of Campylobacter jejuni isolates from cloacal and carcass swabs of
      chickens in Thailand by a 5' nuclease fluorogenic polymerase chain reaction
      assay.
AB  - A rapid 5' nuclease fluorogenic polymerase chain reaction (PCR) assay for
      identifying Campylobacter jejuni was applied to Campylobacter isolates from
      chicken cloacal and carcass swabs collected from three chicken farms and a
      slaughterhouse in Thailand. The primers and the probe were based on the sequence
      of the gyrA gene in C jejuni. C. jejuni isolates were identified by fluorogenic
      PCR assay of bacterial cells directly from Campylobacter-selective agar medium.
      This assay allowed the identification of C. jejuni within 1 day after colonies
      appeared on selective media. The fluorogenic PCR assay yielded results comparable
      to those of the conventional test kit (kappa = 0.76) but required less time. When
      the two methods disagreed with regard to species identification, results were
      confirmed by PCR restriction fragment length polymorphism of 23S rRNA genes. In
      these instances, the fluorogenic PCR assay correctly identified more isolates of
      C. jejuni than did the conventional test kit (six of seven isolates were
      unidentifiable by the conventional test kit). The fluorogenic PCR assay is a
      rapid and specific method that outperforms the conventional test kit in the
      identification of C. jejuni from environmental samples.

PMID- 12430692
TI  - Biofilm formation by acid-adapted and nonadapted Listeria monocytogenes in fresh
      beef decontamination washings and its subsequent inactivation with sanitizers.
AB  - The antimicrobial effects of sodium hypochlorite (SH, 200 ppm, at an adjusted pH
      of 6.80 +/- 0.20 and at an unadjusted pH of 10.35 +/- 0.25), quaternary ammonium
      compound (pH 10.20 +/- 0.12, 200 ppm), and peroxyacetic acid (PAA, pH 3.45 +/-
      0.20, 150 ppm) on previously acid-adapted or nonadapted Listeria monocytogenes
      inoculated (10(5) CFU/ml) into beef decontamination water washings were
      evaluated. The effects of the sanitizers on suspended cells (planktonic or
      deattached) and on cells attached to stainless steel coupons obtained from
      inoculated washings stored at 15 degrees C for up to 14 days were studied. Cells
      were exposed to sanitizers on days 2, 7, and 14. The pathogen had formed a
      biofilm of 5.3 log CFU/cm2 by day 2 of storage (which was reduced to 4.6 log
      CFU/cm2 by day 14), while the total microbial populations showed more extensive
      attachment (6.1 to 6.6 log CFU/cm2). The sanitizers were more effective in
      reducing populations of cells in suspension than in reducing populations of
      attached cells. Overall, there were no differences between previously acid
      adapted and nonadapted L monocytogenes with regard to sensitivity to sanitizers.
      The total microbial biofilms were the most sensitive to all of the sanitizers on
      day 2, but their resistance increased during storage, and they were at their most
      resistant on day 14. Listeria monocytogenes displayed stronger resistance to the
      effects of the sanitizers on day 7 than on day 2 but had become sensitized to all
      sanitizers by day 14. SH at the adjusted pH (6.80) (ASH) was generally more
      effective in reducing bacterial populations than was SH at the unadjusted pH. PAA
      generally killed attached cells faster at 30 to 300 s of exposure than did the
      other sanitizers, except for ASH on day 2. PAA was more effective in killing
      attached cells than in killing cells treated in suspension, in contrast to the
      other sanitizers.

PMID- 12430693
TI  - Prevalence of Listeria monocytogenes during production and postharvest processing
      of cabbage.
AB  - From November 1999 to May 2000, analyses of 425 cabbage, 205 water, and 225
      environmental sponge samples from four cabbage farms with packing sheds and from
      two packing sheds in the Rio Grande Valley and Uvalde, Tex., were conducted to
      determine whether Listeria monocytogenes was present. Samples were tested by the
      Food and Drug Administration method for the isolation of Listeria spp., and
      confirmed isolates were DNA fingerprinted by repetitive-element sequence-based
      polymerase chain reaction (rep-PCR). L monocytogenes was isolated from 3% (26 of
      855) of the samples. Twenty of these isolates were obtained from cabbage (7
      isolates from farms and 13 from packing sheds). Three isolates were from water
      samples(two from farms and one from a packing shed), and three were from
      environmental sponge samples of packing shed surfaces. Rep-PCR-generated
      fingerprints of 21 of the isolates revealed 18 distinctive banding patterns. Four
      isolates from environmental sponge samples of conveyor belts and from cabbage
      samples shared identical banding patterns, suggesting common sources of
      contamination. These identical environmental isolates suggest that contact with
      packing shed surfaces may be a source of contamination of cabbage. However, the
      cabbage samples could have arrived contaminated, since they were not washed.

PMID- 12430694
TI  - Detection of Listeria in crawfish processing plants and in raw, whole crawfish
      and processed crawfish (Procambarus spp.).
AB  - The foodborne pathogen Listeria monocytogenes represents a major concern to the
      food industry and particularly to producers of ready-to-eat (RTE) foods because
      of the severity of human listeriosis infections and because of the ubiquitous
      nature of this organism. Although several studies on the prevalence and sources
      of L monocytogenes in various RTE seafoods have been conducted, limited
      information is available on the presence and potential sources of this organism
      in RTE crawfish products. We thus monitored the presence of L monocytogenes and
      other Listeria spp. in the processing environment, in raw, whole crawfish, and in
      cooked crawfish meat from two processing plants. Samples were collected from the
      two plants throughout one crawfish season (April to June 2001) at 5 and 8
      separate visits, respectively. At each visit, 6 raw, whole crawfish, 6 finished
      product samples (crawfish meat), and 14 mid- or end-of-processing environmental
      sponge samples were collected and tested for L. monocytogenes and Listeria spp.
      Of the 337 samples tested, 31 contained Listeria spp. Although Listeria innocua
      was the predominant Listeria spp. found (20 samples), four samples were positive
      for L monocytogenes. L. monocytogenes was detected in three raw material samples
      and in one environmental sample. Listeria spp. were found in 29.5% of raw, whole
      crawfish (n = 78) and in 4.4% of environmental samples (n = 181) but in none of
      the finished product samples. Among the environmental samples, Listeria spp. were
      found in 15.4% of the drains (n = 39) and in 5.1% of the employee contact
      surfaces (gloves and aprons) (n = 39) but in none of the samples from food
      contact surfaces. Even though a high prevalence of Listeria spp. was detected on
      raw materials, it appears that the heat treatment during the processing of
      crawfish and the practices preventing postprocessing recontamination can
      significantly reduce Listeria contamination of RTE crawfish meat.

PMID- 12430695
TI  - Effect of gamma irradiation on Listeria monocytogenes in frozen, artificially
      contaminated sandwiches.
AB  - Gamma irradiation has been shown to effectively control L monocytogenes in
      uncooked meats but has not been extensively studied in ready-to-eat foods. The
      presence of Listeria in ready-to-eat foods is often due to postprocess
      contamination by organisms in the food-manufacturing environment. Because gamma
      irradiation is applied after products are packaged, the treated foods are
      protected from environmental recontamination. Currently, a petition to allow
      gamma irradiation of ready-to-eat foods is under review by the Food and Drug
      Administration. This study was conducted to determine if gamma irradiation could
      be used to control L. monocytogenes in ready-to-eat sandwiches. Ham and cheese
      sandwiches were contaminated with L. monocytogenes, frozen at -40 degrees C, and
      exposed to gamma irradiation. Following irradiation, sandwiches were assayed for
      L. monocytogenes. A triangle test was performed to determine if irradiated and
      nonirradiated sandwiches differed in sensory quality. We found that the D10
      values ranged from 0.71 to 0.81 kGy and that a 5-log reduction would require
      irradiation with 3.5 to 4.0 kGy. The results of a 39-day storage study of
      sandwiches inoculated with 10(7) CFU of L monocytogenes per g indicated that
      counts for nonirradiated sandwiches remained fairly constant. Counts for
      sandwiches treated with 3.9 kGy decreased by 5 log units initially and then
      decreased further during storage at 4 degrees C. Sensory panelists could
      distinguish between irradiated and nonirradiated sandwiches but were divided on
      whether irradiation adversely affected sandwich quality. Our results suggest that
      manufacturers of ready-to-eat foods could use gamma irradiation to control L.
      monocytogenes and improve the safety of their products.

PMID- 12430696
TI  - Behavior of Listeria monocytogenes in avocado pulp and processed guacamole.
AB  - The potential ability of Listeria monocytogenes to grow or survive in avocado
      pulp (AP) and processed guacamole (PG) stored at 22, 4 to 7, and -18 degrees C
      was studied. Both products were obtained from a factory in Michoacan, Mexico. PG
      consisted of AP mixed with dehydrated vegetables, antioxidants, and
      preservatives. Populations of L monocytogenes in AP stored at 22 degrees C
      increased from 2 to 6 and 9 log CFU/g after 24 and 48 h, respectively. At 4 to 7
      degrees C, the growth rate of L monocytogenes in AP was greatly decreased;
      generation time was 8.2 h, in contrast with 1.35 h observed at 22 degrees C. L.
      monocytogenes populations did not increase in PG either at 22 degrees C for 48 h
      or at 4 to 7 degrees C for 15 days. The bacteriostatic effect in PG may have
      resulted from the presence of added substances, especially citric acid and
      disodium dihydrogen pyrophosphate. Aerobic plate counts and coliforms increased
      in AP and PG stored at ambient temperature and under refrigeration. However,
      these increments did not affect the growth of the pathogen. L. monocytogenes
      (50,000 most probable number [MPN]/g) survived at least 58 weeks in both products
      stored frozen at -18 degrees C; the final population was 335 MPN/g in AP and 23
      MPN/g in PG. Although the composition of avocado fruit differs significantly
      (high content of lipids and scarcity of simple carbohydrates) from that typical
      of most fruits, these results underline AP as a potential vehicle of human
      listeriosis and indicate that freezing should not be used as the sole mechanism
      to control this pathogen.

PMID- 12430697
TI  - Antioxidant power, lipid oxidation, color, and viability of Listeria
      monocytogenes in beef bologna treated with gamma radiation and containing various
      levels of glucose.
AB  - Ionizing radiation can be used to pasteurize ready-to-eat (RTE) meat products.
      Thermal processing of RTE meats that contain dextrose results in the production
      of antioxidants that may interfere with ionizing radiation pasteurization of RTE
      meat products. Beef bologna was manufactured with dextrose concentrations of 0,
      2, 4, 6, and 8%. Antioxidant activity, as measured by the Ferric Reducing
      Antioxidant Power assay, increased with dextrose concentration but was unaffected
      by ionizing radiation. Lipid oxidation increased significantly in irradiated
      bologna (4 kGy) that contained dextrose. Hunter color analysis indicated that the
      addition of dextrose reduced the ionizing radiation-induced loss of redness (a
      value) but promoted the loss of brightness (L-value). The radiation resistance,
      D10-value, of Listeria monocytogenes that was surface-inoculated onto bologna
      slices was not affected by dextrose concentration. L. monocytogenes strains
      isolated from RTE meats after listeriosis outbreaks were utilized. Increased
      antioxidant activity generated by thermal processing of dextrose in fine emulsion
      sausages does not present a barrier to radiation pasteurization of RTE meats.
      However, a high dextrose concentration in combination with gamma irradiation
      increases lipid oxidation significantly.

PMID- 12430698
TI  - Effectiveness of thermal treatments and biocides in the inactivation of
      Argentinian Lactococcus lactis phages.
AB  - The thermal and chemical resistance levels of four autochthonal bacteriophages of
      Lactococcus lactis subsp. lactis, isolated from cheese processes, was
      investigated. The times required to obtain 99% inactivation of phages (T99) at 63
      and 72 degrees C in three suspension media (M17 broth, reconstituted commercial
      nonfat skim milk, and Tris magnesium gelatin buffer) were determined. Thermal
      resistance was dependent on the phage studied, and the results of this study
      demonstrate that pasteurization treatments used in dairy industries may leave
      viable viral particles in milk. It was possible to determine that M17 broth was
      generally the least protective medium, while phosphate buffer was the most
      protective one. Peracetic acid (0.15%, vol/vol) was the most effective viricidal
      agent, with exposures of 5 min being sufficient to inactivate high-titer phage
      suspensions (>10(6) PFU/ml). To achieve total inactivation (<10 PFU/ml) of viral
      suspensions, sodium hypochlorite was effective at 100 ppm for only two phages,
      while the other two phages needed concentrations of 200 and 300 ppm. Ethanol at
      concentrations of 100 and 75% proved to be very efficient in inactivating phages,
      but isopropanol was not effective against them.

PMID- 12430699
TI  - Sensorial and chemical quality of gamma-irradiated fresh-cut iceberg lettuce in
      modified atmosphere packages.
AB  - A study was conducted to investigate the effects of various doses of irradiation
      on the quality of fresh-cut iceberg lettuce and to determine a suitable maximum
      dose. Fresh-cut iceberg lettuce packaged in film bags was exposed to 0, 1, 2, 3,
      and 4 kGy of gamma radiation and stored at 3 degrees C for 14 days. CO2 levels
      were higher and O2 levels were lower in packages containing irradiated lettuce
      than in those containing nonirradiated lettuce for most of the storage period.
      Comparison with nonirradiated lettuce indicated that total ascorbic acid
      (ascorbic acid plus dehydroascorbic acid) content and firmness were not
      significantly influenced by irradiation at 1 or 2 kGy. The overall visual
      appearance was best for lettuce irradiated at 1 or 2 kGy. This improved quality
      may be related to the high CO2 and low O2 levels observed for the irradiated
      samples. Electrolyte leakage for lettuce increased with higher radiation doses
      and was correlated (R2 = 0.99) with a soggy appearance. The leakage for lettuce
      irradiated at > or = 2 kGy was significantly more extensive than that for
      nonirradiated lettuce. The irradiation of fresh-cut lettuce in modified
      atmosphere packages at doses of 1 kGy and perhaps 2 kGy for safety enhancement
      and quality improvement is feasible.

PMID- 12430700
TI  - Inhibition of heterocyclic aromatic amine formation in fried ground beef patties
      by garlic and selected garlic-related sulfur compounds.
AB  - The effects of garlic and selected organosulfur compounds (diallyl disulfide,
      dipropyl disulfide, diallyl sulfide, allyl methyl sulfide, allyl mercaptan,
      cysteine, and cystine) on the formation of heterocyclic aromatic amines (HAAs) in
      fried ground beef patties were evaluated. Minced garlic cloves (ca. 4.8 to 16.7%,
      wt/wt) or organosulfur compounds (0.67 mmol) were added directly to ground beef.
      Patties (100 g) were fried at 225 degrees C (surface temperature) for 10 min per
      side. Two patties were fried for each replication, and five replicates were
      analyzed for each treatment. For each replicate, four subsamples were analyzed
      (two unspiked subsamples for concentration and two spiked subsamples for the
      recovery of HAA standards). The volatile sulfur compounds significantly (P <
      0.05) reduced concentrations of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine
      by reductions of 46 to 81%, while average reductions of 35, 22, and 71%, were
      achieved with cystine, cysteine, and whole garlic, respectively. The volatile
      sulfur compounds reduced concentrations of 2-amino-3,8-dimethylimidazo[4,5
      f]quinoxaline by 34 to 67%, while reductions of 25, 19, and 63% (P < 0.05) were
      achieved with cystine, cysteine, and whole garlic, respectively. These studies
      confirm that garlic and some organosulfur compounds have the potential to reduce
      HAA formation incooked beef patties.

PMID- 12430701
TI  - High-pressure liquid chromatographic determination of ascorbic acid in cooked
      sausages.
AB  - The purpose of this paper was to study and optimize both extraction and high
      pressure liquid chromatography (HPLC)-UV detection procedures to develop a proper
      method for the determination of ascorbic acid content in cooked sausages. A
      simple and sensitive reversed-phase HPLC method for the NH2-bonded phase has been
      described for the determination of ascorbic acid content in cooked sausages.
      Various extracting agents were tested to solubilize the vitamin, with 5% (wt/vol)
      metaphosphoric acid giving the best results. Samples were chromatographed with UV
      detection at 248 nm on a 25-cm Spherisorb NH2 cartridge with a 0.4-cm inside
      diameter with a mixture of 0.02 M potassium phosphate buffer solution (pH 3.6)
      and acetonitrile (40:60, vol/vol) for the mobile phase. The method's precision
      within a day was 1.2%, and its precision between days was 3.8%. The detection
      limit was 1.6 mg/100 g. Recovery ranged from 91.4 to 96.2% for ascorbic acid
      added to meat samples. Twenty samples of six different products were analyzed in
      duplicate. For the samples analyzed, the mean value for ascorbic acid ranged
      between 21.555 and 24.899 mg/100 g of fresh weight.

PMID- 12430702
TI  - Influence of growth in a food medium on the detection of Escherichia coli O157:H7
      by polymerase chain reaction.
AB  - The effects of storage time and growth in broth culture and in a food medium on
      the efficiency of Escherichia coli O157: H7 DNA extraction and on the sensitivity
      of polymerase chain reaction (PCR) detection of E. coli O157:H7 were
      investigated. Detection limits were evaluated with dilution series PCR targeting
      the slt-II gene. The relationship between cell density and DNA yield was
      generally log-linear for pure cultures of E coli O157:H7. When the bacteria were
      suspended in skim milk at a density of 10(6) CFU/ml. held at 4 degrees C, and
      sampled at 24-h intervals, cell density, total DNA yield, and PCR detection
      limits remained stable throughout the 96-h storage period. However, when E coli
      O157:H7 was grown in skim milk to a final cell density of 10(6) CFU/ml, PCR
      amplification efficiency was drastically reduced, although overall DNA yields
      from these samples were consistent with those for the samples in which E. coli
      O157:H7 growth was static over 96 h of storage at 4 degrees C. This result is
      most likely due to poor DNA purity, which was consistently observed when DNA was
      extracted from food matrices in which the pathogen was grown rather than stored.
      The results of this investigation underscore the likelihood that multiple
      components may drastically affect DNA extraction and PCR amplification efficiency
      in the detection of pathogens in the food matrix. It is clear that before nucleic
      acid amplification technologies are widely applied to food systems, it would be
      prudent to test their efficacy in multiple food matrices and under conditions in
      which the bacterial population is both static and actively growing.

PMID- 12430703
TI  - Combined effects of lactic acid and nisin solution in reducing levels of
      microbiological contamination in red meat carcasses.
AB  - Changes in bacterial counts on beef carcasses at specific points during slaughter
      and fabrication were determined, and the effectiveness of nisin, lactic acid, and
      a combination of the lactic acid and nisin in reducing levels of microbiological
      contamination was assessed. Swab samples were obtained from the surfaces of
      randomly selected beef carcasses. Carcasses were swabbed from the neck, brisket,
      and renal site after skinning, splitting, and washing. Treatments involving
      lactic acid (1.5%), nisin (500 IU/ml), or a mixture of nisin and lactic acid were
      applied after the neck area was washed. A control group was not sprayed. Results
      indicated that the highest prevalence of aerobic plate counts (APCs), total
      coliforms, and Escherichia coli was found in the neck site after splitting, and
      the lowest level of microbial contamination was found after skinning. Washing
      with water did not significantly reduce the bacterial load. The largest reduction
      in APCs, total coliforms, and E. coli occurred on carcasses treated with a
      mixture of nisin and lactic acid. A mixture of nisin and lactic acid can be
      applied to beef carcasses through spray washing and can reduce bacterial
      populations by 2 log units.

PMID- 12430704
TI  - Sensitivity of three methods used in the isolation of Arcobacter spp. in raw
      ground pork.
AB  - Arcobacter, an aerotolerant Campylobacter-like organism, has been designated an
      emerging pathogen because of its newly recognized ability to cause diarrheal
      illness in both humans and animals and its presence in the human food supply.
      Because there is no standard isolation method for its detection, the true
      occurrence of this pathogen is largely unknown. In addition, the lack of a
      standardized isolation protocol limits the ability of investigators to compare
      field data. Arcobacter has been detected in whole muscle and ground pork at
      various levels by two different isolation methods (those of deBoer and Collins).
      In this study, these methods were tested along with the Johnson-Murano (JM)
      method, developed in our laboratory. The sensitivity of each method was tested
      for ground pork inoculated with Arcobacter butzleri and Arcobacter cryaerophilus
      IA at levels of 10(4), 10(3), 10(2), and 10(1) CFU/g. Controls included tubes
      with uninoculated pork and broth tubes without pork. All samples that were
      morphologically similar to Arcobacter were analyzed by Gram staining and by
      catalase and oxidasereactions. Presumptive positive samples were confirmed by the
      polymerase chain reaction. The JM method was determined to be the most sensitive,
      detecting A. butzleri down to a level of 10(1) CFU/g in 100% of the samples and
      detecting A. cryaerophilus IA at a level of 10(1) CFU/g in 75% of samples. In a
      pure buffer system, the Collins method was as effective as the JM method in
      isolating both organisms to levels of 10(1) cells per g.

PMID- 12430705
TI  - Lack of a cytolethal distending toxin among Arcobacter isolates from various
      sources.
AB  - Arcobacter has been shown to be present in numerous different sources, including
      poultry, water, and humans exhibiting gastroenteritis. The production of a
      cytolethal distending toxin (CDT) has been documented in Campylobacter,
      Helicobacter, and other species. The polymerase chain reaction was used to screen
      Arcobacter isolates from poultry, cattle, irrigation water, and human diarrhea
      for the presence of CDT genes. Cell filtrates and sonic extracts were also tested
      for CDT-like activity on Chinese Hamster Ovary, HeLa, and Intestinal 407 (INT407)
      cells in culture. No CDT amplimers were observed in any of the Arcobacter
      isolates investigated. However, toxicity to HeLa and INT407 cells was observed
      and was subsequently analyzed for cell cycle arrest in the presence of the
      Arcobacter extracts with flow cytometry. Cells treated with Arcobacter sonic
      extracts and filtrates exhibited normal cell cycles, suggesting that CDT is not
      expressed by Arcobacter. Thus, Arcobacter was shown to produce an entity that was
      toxic to some cells in culture, but this entity was toxic in a manner different
      from that of Campylobacter CDT.

PMID- 12430706
TI  - Antimicrobial resistance of Listeria monocytogenes isolated from various cabbage
      farms and packing sheds in Texas.
AB  - Twenty-one isolates of Listeria monocytogenes from cabbage, environmental, and
      water samples were evaluated for antimicrobial resistance by the disk diffusion
      method. Ninety-five percent (20 of 21) of the isolates tested were resistant to
      two or more antimicrobial agents. This finding is significant, since
      multiresistant strains of Listeria spp. are not commonly found in nature. Eighty
      five percent (17 of 20) of the multiresistant strains were resistant to
      penicillin, and the remaining multiresistant isolates were somewhat sensitive to
      penicillin. A multiresistant strain showing intermediate sensitivity to
      penicillin was resistant to gentamicin. One isolate was susceptible to all
      antimicrobial agents except penicillin. Penicillin- and gentamicin-resistant L.
      monocytogenes have not previously been reported from human, food, or
      environmental samples. This study provides evidence of the emergence of
      multiresistant L. monocytogenes strains, pointing to an increase in the potential
      threat to human health posed by this pathogen.

PMID- 12430707
TI  - Effect of low-dose gamma irradiation on Staphylococcus aureus and product
      packaging in ready-to-eat ham and cheese sandwiches.
AB  - Staphylococcus aureus is a common pathogen that causes foodborne illness.
      Traditional methods for controlling S. aureus do not address postprocess
      contamination. Low-dose gamma irradiation is effective in reducing pathogens in a
      variety of foods and may be effective in reducing S. aureus in ready-to-eat
      foods. The effects of gamma irradiation on product packaging should also be
      considered. The objective of this study was to determine the effects of gamna
      irradiation on product packaging and on S. aureus in ready-to-eat ham and cheese
      sandwiches. The effects of refrigerated storage on irradiated and nonirradiated
      sandwiches were also investigated. Ham and cheese sandwiches were inoculated with
      10(6) or 10(7) CFU of S. aureus per g, frozen, irradiated, and analyzed by a
      standard plate count method. D10-values, the amount of irradiation needed to
      elicit a 1-log10 reduction of bacteria, were calculated. In addition, irradiated
      sandwiches were analyzed after 1, 13, 27, and 39 days of storage at 4 degrees C.
      The integrity of postirradiated packaging material was analyzed using Fourier
      transform infrared (FTIR) spectroscopy. Two experiments yielded D10-values of
      0.62 and 0.63. During refrigerated storage, sandwiches irradiated with 5.9 kGy
      showed no S. aureus growth at any time; sandwiches irradiated with 3.85 kGy
      showed a 6.18-log reduction in S. aureus after 13 days; and nonirradiated
      sandwiches showed a 0.53-log increase in S. aureus after 39 days. FTIR
      spectroscopy showed that the label side and the bulge side were composed of
      polyethylene terephthalate and nylon 6, respectively. No significant change in
      the packaging due to irradiation was detected. In this study, low-dose gamma
      irradiation was shown to be an effective method for reducing S. aureus in ready
      to-eat ham and cheese sandwiches and proved to be more efficacious than
      refrigeration alone. Additionally, package integrity was not adversely affected
      by gamma irradiation.

PMID- 12430708
TI  - Magnetized carbonyl iron and insoluble zirconium hydroxide mixture facilitates
      bacterial concentration and separation from nonfat dry milk.
AB  - A mixture of magnetized carbonyl iron and insoluble zirconium hydroxide was
      investigated for its ability to concentrate various foodborne pathogens from 25
      ml samples of reconstituted nonfat dry milk. Each sample was artificially
      contaminated with 10(3) to 10(6) CFU/25 ml of representative foodborne pathogens
      (Salmonella enterica serovar Enteritidis, Listeria monocytogenes, and Bacillus
      cereus spores) and processed for bacterial concentration with high-speed
      centrifugation for the primary concentration followed by a secondary
      concentration step involving the carbonyl iron-zirconium hydroxide mixture.
      Bacterial recoveries, as evaluated on the basis of loss to discarded
      supernatants, exceeded 75% for all organisms at all inoculum levels and were
      usually >90%. Recovery was confirmed by direct plating of the immobilized pellet,
      for which the valueswere similar albeit more varied. Additional experiments
      confirmed that the magnetized carbonyl iron-insoluble zirconium hydroxide mixture
      was relatively nontoxic to both Salmonella Enteritidis and L monocytogenes
      Overall, the entire concentration scheme resulted in a 25-fold reduction in
      sample volume with the recovery of viable bacterial cells. This novel compound
      shows promise for facilitating inexpensive, rapid, and effective bacterial
      concentration in food systems.

PMID- 12430709
TI  - Listeria monocytogenes virulence and pathogenicity, a food safety perspective.
AB  - Several virulence factors of Listeria monocytogenes have been identified and
      extensively characterized at the molecular and cell biologic levels, including
      the hemolysin (listeriolysin O), two distinct phospholipases, a protein (ActA),
      several internalins, and others. Their study has yielded an impressive amount of
      information on the mechanisms employed by this facultative intracellular pathogen
      to interact with mammalian host cells, escape the host cell's killing mechanisms,
      and spread from one infected cell to others. In addition, several molecular
      subtyping tools have been developed to facilitate the detection of different
      strain types and lineages of the pathogen, including those implicated in common
      source outbreaks of the disease. Despite these spectacular gains in knowledge,
      the virulence of L. monocytogenes as a foodborne pathogen remains poorly
      understood. The available pathogenesis and subtyping data generally fail to
      provide adequate insight about the virulence of field isolates and the likelihood
      that a given strain will cause illness. Possible mechanisms for the apparent
      prevalence of three serotypes (1/2a, 1/2b, and 4b) in human foodborne illness
      remain unidentified. The propensity of certain strain lineages (epidemic clones)
      to be implicated in common-source outbreaks and the prevalence of serotype 4b
      among epidemic-associated stains also remain poorly understood. This review first
      discusses current progress in understanding the general features of virulence and
      pathogenesis of L. monocytogenes. Emphasis is then placed on areas of special
      relevance to the organism's involvement in human foodborne illness, including (i)
      the relative prevalence of different serotypes and serotype-specific features and
      genetic markers; (ii) the ability of the organism to respond to environmental
      stresses of relevance to the food industry (cold, salt, iron depletion, and
      acid); (iii) the specific features of the major known epidemic-associated
      lineages; and (iv) the possible reservoirs of the organism in animals and the
      environment and the pronounced impact of environmental contamination in the food
      processing facilities. Finally, a discussion is provided on the perceived areas
      of special need for future research of relevance to food safety, including (i)
      theoretical modeling studies of niche complexity and contamination in the food
      processing facilities; (ii) strain databases for comprehensive molecular typing;
      and (iii) contributions from genomic and proteomic tools, including DNA
      microarrays for genotyping and expression signatures. Virulence-related genomic
      and proteomic signatures are expected to emerge from analysis of the genomes at
      the global level, with the support of adequate epidemiologic data and access to
      relevant strains.

PMID- 12430710
TI  - Office of Rare Diseases neuropathologic criteria for corticobasal degeneration.
AB  - A working group supported by the Office of Rare Diseases of the National
      Institutes of Health formulated neuropathologic criteria for corticobasal
      degeneration (CBD) that were subsequently validated by an independent group of
      neuropathologists. The criteria do not require a specific clinical phenotype,
      since CBD can have diverse clinical presentations, such as progressive
      asymmetrical rigidity and apraxia, progressive aphasia, or frontal lobe dementia.
      Cortical atrophy, ballooned neurons, and degeneration of the substantia nigra
      have been emphasized in previous descriptions and are present in CBD, but the
      present criteria emphasize tau-immunoreactive lesions in neurons, glia, and cell
      processes in the neuropathologic diagnosis of CBD. The minimal pathologic
      features for CBD are cortical and striatal tau-positive neuronal and glial
      lesions, especially astrocytic plaques and thread-like lesions in both white
      matter and gray matter, along with neuronal loss in focal cortical regions and in
      the substantia nigra. The methods required to make this diagnosis include
      histologic stains to assess neuronal loss, spongiosis and ballooned neurons, and
      a method to detect tau-positive neuronal and glial lesions. Use of either the
      Gallyas silver staining method or immunostains with sensitive tau antibodies is
      acceptable. In cases where ballooned neurons are sparse or difficult to detect,
      immunostaining for phospho-neurofilament or alpha-B-crystallin may prove helpful.
      Methods to assess Alzheimer-type pathology and Lewy body pathology are necessary
      to rule out other causes of dementia and Parkinsonism. Using these criteria
      provides good differentiation of CBD from other tauopathies, except
      frontotemporal dementia and Parkinsonism linked to chromosome 17, where
      additional clinical or molecular genetic information is required to make an
      accurate diagnosis.

PMID- 12430711
TI  - Oligodendrogliomas with neurocytic differentiation. A report of 4 cases with
      diagnostic and histogenetic implications.
AB  - Oligodendroglioma represents a distinct type of diffuse glioma with a relatively
      favorable prognosis. Although an O2A-like glial progenitor cell of origin has
      been suggested, a neuronal-oligodendroglial progenitor cell is also of interest,
      particularly because variable degrees of neuronal marker expression have been
      reported in typical oligodendrogliomas. We present 2 female and 2 male patients
      (ages 34-54) with frontal lobe oligodendrogliomas containing a) morphologically
      distinct collections of small round cells with hyperchromatic nuclei, b) well
      formed Homer Wright-like and perivascular rosettes, and c) demonstrable neuronal
      differentiation by immunohistochemistry and/or electron microscopy in the rosette
      associated regions. Unlike extraventricular neurocytomas, these cases featured an
      infiltrative growth pattern and a classic oligodendroglioma immunophenotype in
      non-rosette bearing portions of each tumor. FISH analysis demonstrated chromosome
      1p and 19q codeletions in 3 (75%) cases, both in regions with and without
      rosettes. Recurrences were common, although all patients are currently alive 4
      months to 13 yr from initial diagnosis. Based on clinicopathologic and genetic
      features, we diagnosed these tumors as oligodendrogliomas with neurocytic
      differentiation. However, it is unclear whether they represent a) gliomas with
      divergent neuronal differentiation, b) a distinctive form of glioneuronal
      neoplasm, or c) a reflection of glioneuronal histogenesis in oligodendrogliomas
      in general. In any case, their occurrence suggests a histogenetic overlap between
      oligodendroglioma and extraventricular neurocytoma not previously recognized.

PMID- 12430712
TI  - Neurotoxic damage of granule cells in the dentate gyrus and the cerebellum and
      cognitive deficit following neonatal administration of phenytoin in mice.
AB  - The use of antiepileptic drugs during human gestation probably increases the risk
      of causing CNS disorders in later life. In brain, granule cells in the dentate
      gyrus (DG) and cerebellum are still developing in the last trimester of human
      gestation and a similar development is taking place during the mouse perinatal
      period. We treated newborn C57BL/6 mice orally with 35 mg/kg phenytoin (PHT)
      daily during postnatal days (PD) 5 to 14. Histopathological investigation
      revealed that the layer of mature granule cells in the DG that was immunoreactive
      to anti-calbindin D28k was thinner in PHT-treated mice. Purkinje cells in the
      treated group also had poor, immature arbors with an irregular arrangement. A
      number of TUNEL-positive cells were observed in the DG and cerebellum during the
      treatment. PHT-treated mice were impaired in the acquisition of a hidden platform
      task in the water maze and committed significantly more errors during the
      learning process in theradial arm maze. These findings demonstrate that neonatal
      administration of PHT interferes with the development of granule cells in the
      hippocampus and the cerebellum and causes spatial leaning deficits in later life.
      Cautious clinical use of this drug for pregnant patients is warranted, especially
      in the last trimester.

PMID- 12430713
TI  - Upregulation of HSP27 in a transgenic model of ALS.
AB  - Mutations of the SOD1 gene underlie 1 form of familial amyotrophic lateral
      sclerosis (ALS). Their pathogenic mechanism remains uncertain, but is thought to
      involve oxidative stress and abnormal protein aggregation, 2 processes known to
      induce heat shock proteins (HSPs). We studied the expression of 3 HSPs (alphaB
      crystallin, HSP27, and HSP70) in transgenic mice overexpressing human mutant
      (G93A and G37R) SOD1, using a combination of immunohistochemistry and
      immunoblotting. Quantitative Western blot analysis demonstrated alphaB-crystallin
      and HSP27 to be upregulated in the spinal cord of mutant SOD1 mice compared to
      mice overexpressing wild-type SOD1. HSP70 levels were normal. Immunocytochemical
      studies of the ventral horn of the spinal cord demonstrated HSP27 to be localized
      in the nucleus of neurons and glial cells in presymptomatic and early symptomatic
      animals, where it often was punctate in pattern. In the later stages of the
      disease, HSP27 was predominantly present in the cytoplasm of reactive glial
      cells. The early nuclear localization was confirmed by Western blot analysis of
      spinal cord nuclear and cytoplasmic fractions. In contrast to HSP27, alphaB
      crystallin was localized exclusively in the cytoplasm of reactive glial cells.

PMID- 12430714
TI  - Autocrine signaling through Ras regulates cell survival activity in human glioma
      cells: potential cross-talk between Ras and the phosphatidylinositol 3-kinase-Akt
      pathway.
AB  - Autocrine fibroblast growth factor (FGF) signaling mediates an uncontrollable
      growth of human gliomas. We investigated the intracellular signaling of FGF on
      cell survival activity. U251MG human glioma cells were infected with adenovirus
      vectors expressing dominant negative type I FGF receptor (DNFR), constitutive
      active Ras (RasL61), or dominant negative Ras (RasN17). DNFR reduced glioma cell
      accumulation with apoptosis and this reduction was alleviated with exogenous
      epidermal growth factor (EGF), which can activate Ras independent of FGFR but not
      with bFGF. RasL61 prevented but RasN17-enhanced DNFR-induced apoptosis.
      Reportedly, cell survival signaling through Akt was constitutively active in
      U251MG cells and this effect may be dependent on autocrine signaling and
      dysfunction of PTEN, a tumor suppressor gene limiting phosphatidylinositol 3
      kinase (PI3K) activity. DNFR dose-dependently inhibited Akt activity and this
      inhibition was recovered by RasL61, whereas RasN17 inhibited Akt activity.
      Wortmannin (a PI3K inhibitor) inhibited Akt activity and mildly promoted
      apoptosis. RasL61 prevented the down-regulation of Akt activity and apoptosis
      induced by wortmannin, but RasN17 plus wortmannin strongly inhibited Akt activity
      and promoted marked apoptosis. Our data suggested that the cell survival activity
      of human gliomas is largely dependent on cross-talk between Ras and the PI3K-Akt
      pathway, and this cross-talk could be a potential target for molecular-based
      therapeutics.

PMID- 12430715
TI  - Promyelocytic leukemia protein is redistributed during the formation of
      intranuclear inclusions independent of polyglutamine expansion: an
      immunohistochemical study on Marinesco bodies.
AB  - Marinesco bodies (MBs) are ubiquitinated intranuclear inclusions observed in
      nigral pigmented neurons. They increase in number during aging, and their
      formation is considered to represent a cellular reaction to stress, but is not
      always associated with neuronal degeneration. We conducted immunohistochemical
      studies on MBs abundant in myotonic dystrophy brains and compared their nature
      with that of neuronal intranuclear inclusions (NIIs) in polyglutamine diseases.
      First, we examined the relationship between MBs and polyglutamine proteins and
      demonstrated that one of the polyglutamine proteins, ataxin-3, as well as a 19S
      proteasomal protein, was preferentially recruited into MBs even in the absence of
      expanded polyglutamine. This indicates that an alternative mechanism during the
      formation of MBs that is not related to polyglutamine expansion or neuronal
      degeneration may recruit ataxin-3 into nuclear inclusions in a protein-specific
      manner. Secondly, we investigated the relationship between MBs and promyelocytic
      leukemia protein (PML), a nuclear matrix-associated protein that is normally
      localized to intranuclear punctate structures (PML nuclear bodies) and is known
      to reorganize itself in association with polyglutamine aggregation. In nigral
      pigmented neurons in myotonic dystrophy, spherical, hemispherical or rod-like PML
      immunoreactive structures, in addition to punctate structures, were observed in
      their nuclei. Similar PML redistribution was also observed in nigral pigmented
      neurons in aged controls and cases of hepatic encephalopathy, 2 other conditions
      in which abundant MBs are formed. Double immunofluorescence study revealed that
      these PML-positive structures undergo morphological changes in association with
      ubiquitin accumulation during MB formation. It is therefore indicated that PML
      reorganization does not represent a specific nuclear event involved in the
      pathogenesis of polyglutamine diseases, but may commonly occur during the
      formation of intranuclear inclusions as a reaction against various stresses that
      involve the ubiquitin-proteasome pathway.

PMID- 12430716
TI  - HIV-1 gp120 proteins and gp160 peptides are toxic to brain endothelial cells and
      neurons: possible pathway for HIV entry into the brain and HIV-associated
      dementia.
AB  - Breakdown of the blood-brain barrier is commonly seen in patients with human
      immunodeficiency virus (HIV)-associated dementia, despite the lack of productive
      HIV-infection of the brain endothelium. Through this damaged blood-brain barrier,
      HIV and HIV-infected monocytes/macrophages infiltrate the brain and further
      infect microglia and brain macrophages. Neuronal cell death and dysfunction are
      the underlying cause of HIV-associated dementia, but no productive HIV-infection
      of neurons has been documented. It is likely that secreted viral products play a
      major role in blood-brain barrier damage and neuronal cell death. The aim of the
      present study was to examine the effect of HIV-1 gp160 peptides and gp120
      proteins on brain microvascular endothelial cells and neurons from both human and
      rats. Four of the 7 gp160 peptides tested evoked significant neurotoxicity. Two
      different full-length recombinant HIV gp120 proteins (HIV-1CM235 gp120 and HIV
      1MN gp120) also induced neuronal and brain endothelial cell death, and
      concentrations as little as 1 ng/ml evoked pronounced morphological changes in
      these cells and marked cytotoxicity. This study suggests that HIV proteins and
      peptides that are shed in vivo may be directly involved in blood-brain barrier
      damage and neuronal cell death in HIV-associated dementia.

PMID- 12430717
TI  - Analysis of the expression of endogenous murine leukemia viruses in the brains of
      senescence-accelerated mice (SAMP8) and the relationship between expression and
      brain histopathology.
AB  - Many studies have explored the premature aging of accelerated senescence-prone
      (SAMP8) mice. However, the cause of premature aging in this strain remains
      unknown. We analyzed the expression of ecotropic, xenotropic, and polytropic
      murine leukemia viruses (MuLVs) in the brains of accelerated senescence-resistant
      (SAMR1) and SAMP8 mice. No ecotropic mRNA was detected in SAMR1 mice, and only
      Akv-type ecotropic MuLV mRNA was detected in SAMP8 mice. Restriction mapping of
      the full-length infectious E-MuLV genome from SAMP8 confirmed its identity as
      Akv. mRNAs corresponding to a prototypical polytropic MuLV and to an unusual
      xenotropic MuLV were detected at equal levels in SAMP8 and SAMR1 mice, but no
      infectious virus of either host range type was detected. In order to determine
      the cellular localization of Akv expression in SAMP8 mice, we used
      immunohistochemistry and electron microscopy to detect expression of the E-MuLV
      capsid gag (CAgag) gene in striatum, brainstem, hippocampus, and cerebellum of 12
      month-old SAMR1 and SAMP8 mice. The CAgag antigen was seen in the neurons,
      oligodendroglia, and vascular endothelium of these brain regions of SAMP8 mice,
      but not in SAMR1 mice. To evaluate the correlation between activation of
      astrocytes and expression of Akv, we performed double-immunohistochemical
      staining for both glial fibrillary acidic protein (GFAP) and CAgag in SAMR1 and
      SAMP8 mice. Strong astrocytic activation and extensive vacuolation were observed
      around CAgag-positive neurons in SAMP8 mice, whereas in SAMR1 mice neither
      astrocytosis nor vacuolation were present. CAgag antigen was also localized in
      astrocytes of the hippocampus region of SAMP8 mice. Electron micrography showed
      that a number of vacuoles were found in the cytoplasm of MuLV-positive neurons
      and the extracellular space surrounding these neurons showed lytic changes. These
      results suggest that endogenous Akv provirus is expressed in neurons, astrocytes,
      vascular endothelium, and oligodendroglia in the brains of SAMP8 and that this
      virus could play an important role in the brain aging processes in this mouse
      strain.

PMID- 12430718
TI  - Broad expression of Toll-like receptors in the human central nervous system.
AB  - The family of Toll-like receptors (TLRs) plays a key role in controlling innate
      immune responses to a wide variety of pathogen-associated molecules. In this
      study we investigated expression of TLRs in vitro by purified human microglia,
      astrocytes, and oligodendrocytes, and in vivo by immunohistochemical examination
      of brain and spinal cord sections. Cultured primary microglia were found to
      express mRNA encoding a wide range of different TLR family members while
      astrocytes and oligodendrocytes primarily express TLR2 and TLR3. Comparisons
      between microglia derived from a series of control subjects and neurodegenerative
      cases indicate distinct differences in levels of mRNA encoding the different TLRs
      indifferent microglia samples. Interestingly, expression of TLR proteins in
      cultured microglia as revealed by immunocytochemistry was restricted to
      intracellular vesicles, whereas in astrocytes they were exclusively localized on
      the cell surface. Finally, in vivo expression of TLR3 and TLR4 was examined by
      immunohistochemical analysis of brain and spinal cord sections from both control
      and multiple sclerosis brains, revealing enhanced expression of either TLR in
      inflamed CNS tissues. Together, our data reveal broad and regulated expression of
      TLRs both in vitro and in vivo by human glia cells.

PMID- 12430719
TI  - AANP award for meritorious contributions to neuropathology presented to Fusahiro
      Ikuta, MD. American Association of Neuropathologists.

PMID- 12430720
TI  - AANP award for meritorious contributions to neuropathology presented to Kurt
      Jellinger, MD. American Association of Neuropathologists.

PMID- 12430721
TI  - AANP award for meritorious contributions to neuropathology presented to Dikran S.
      Horoupian, MD. American Association of Neuropathologists.

PMID- 12430722
TI  - Oligomeric proanthocyanidins: naturally occurring O-heterocycles.
AB  - This review covers the flavan-3-ols (catechins), flavan-4-ols/flavan-3,4-diols
      (leucoanthocyanidins), A-type proanthocyanidins, B-type proanthocyanidins
      including the procyanidins, prodelphinidins, propelargonidins, proteracacinidins,
      promelacacinidins, procassinidins, probutinidins, and non-proanthocyanidins with
      flavan-3-ol constituent units. Newly isolated proanthocyanidins, structure
      elucidation, syntheses, HPLC/MS analysis, NMR/ conformational analysis, and the
      effects of proanthocyanidins on human nutrition and health are reported. The
      literature from January 1999 to December 2001 is reviewed, and 130 references are
      cited.

PMID- 12430723
TI  - Modification of post-PKS tailoring steps through combinatorial biosynthesis.
AB  - This review covers the highlights of combinatorial biosynthesis applied on post
      polyketide synthase modifying enzymes, such as oxygenases. ketoreductases,
      glycosyl- and methyltransferases, acyltransferases, halogenases, cyclases and
      aminotransferases Since this is the first review on this topic, it covers
      literature from 1985 to 2002, and 248 references are given.

PMID- 12430724
TI  - The Claisen condensation in biology.
AB  - The mechanism for carbon-carbon bond formation used in the biosynthesis of
      natural products such as fatty acids and polyketides is a decarboxylating Claisen
      condensation. The enzymes that catalyze this reaction in various bacterial
      systems, collectively referred to as condensing enzymes, have been intensively
      studied in the past several decades, and members of the family have been
      crystallized. The condensing enzymes share a common 3-dimensional fold, first
      described for the biosynthetic thiolase I that catalyzes a non-decarboxylating
      Claisen condensation, although they share little similarity at the amino acid
      level. Their active sites, however, possess significant similarities. The
      initiation condensing enzymes use CoA primers and possess a catalytic triad of
      Cys, His, Asn; and the elongating condensing enzymes that exclusively use ACP
      thioesters have a triad of Cys, His, His. These active site differences affect
      the sensitivity of the respective enzymes to the antibiotics thiolactomycin and
      cerulenin. Different reaction mechanisms have been proposed for the condensing
      enzymes. This review covers the recent structural and mechanistic data to see if
      a unifying hypothesis for the reaction mechanism catalyzed by this important
      family of enzymes can be established.

PMID- 12430725
TI  - Excitatory amino acids.
AB  - Recent developments in the understanding of the molecular function of memory and
      other CNS-mediated processes have arisen from the multidisciplinary interplay of
      excitatory amino acid synthesis and medicinal chemistry, X-ray crystallographic
      structural protein analysis, molecular biology, pharmacology and physiology. This
      review seeks to place recent synthetic developments of EAA analogues in the wider
      pharmacological setting, illustrating the need for and importance of these
      compounds.

PMID- 12430726
TI  - Natural guanidine derivatives.
AB  - The chemistry (isolation, biosynthesis and synthesis) and biological activities
      of natural products bearing a guanidine function are reviewed, including
      macrocyclic derivatives from terrestrial microbes, peptides from cyanobacteria
      and guanidine alkaloids from marine invertebrates. The review contains 258
      references.

PMID- 12430727
TI  - Natural sesquiterpenoids.
AB  - This review covers the isolation, structural determination, synthesis and
      chemical and microbiological transformations of natural sesquiterpenoids. The
      literature from January to December 2001 is reviewed, and 404 references are
      cited.

PMID- 12430728
TI  - Hydration and plasticity following long-term use of a moisturizer: a single-blind
      study.
AB  - Skin hydration is thought to have an influence on skin plasticity, and
      moisturizers have therefore gained widespread use. However, the effects of long
      term moisturizer use on the mechanical properties and the long-term correlation
      between plasticity and hydration of human skin in vivo remain unknown. Nineteen
      healthy volunteers applied a moisturizer to the volar surface of their forearms
      for 3 weeks, once daily on one arm and twice daily on the other. The skin
      capacitance, distensibility, hysteresis and elasticity were measured in both
      treated areas and in an untreated regional control area. Measurements were
      carried out at baseline, at one-week intervals during the trial and one week
      after the termination. Data were assessed in a single-blind fashion. No change
      was found in any of the mechanical parameters in the moisturizer-treated skin
      compared to the control. The capacitance of skin was found to increase
      independently of dose. One week after termination of the treatment, the skin
      capacitance remained increased. No dose-response effect was seen, however. Long
      term use of moisturizers increases skin capacitance significantly, but does not
      change the mechanical properties. In vivo skin hydration is a poor predictor of
      skin mechanics.

PMID- 12430729
TI  - Relevance of reactive oxygen species in the induction of 8-oxo-2'-deoxyguanosine
      in HaCaT keratinocytes.
AB  - There is growing evidence that solar radiation-induced oxidative DNA damage may
      play an important role in carcinogenesis of the skin. One substantial
      modification in this context is the oxidation of the guanine base to 8-oxo-2'
      deoxyguanosine. Using HaCaT keratinocytes, measurement of the 8-oxo-2'
      deoxyguanosine content in this study was performed by flow cytometry on whole
      cells. Hydrogen peroxide and hydroxyl radicals seem not to be involved in the
      process of this DNA alteration. However, our results demonstrate that ultraviolet
      A can cause DNA damage at guanine sites primarily via photosensitized reactions.
      Although singlet oxygen can also lead to 8-oxo-2'-deoxyguanosine, the major
      mechanism seems to be based on formation of the guanylcation radical through
      excited riboflavin and can therefore proceed without the involvement of reactive
      oxygen species.

PMID- 12430730
TI  - Loss of hyaluronan in the basement membrane zone of the skin correlates to the
      degree of stiff hands in diabetic patients.
AB  - Glycosaminoglycans are important components of all extracellular matrices. One of
      the glycosaminoglycans is hyaluronan, which is ubiquitously distributed
      throughout the connective tissue. Hyaluronan is especially abundant in the skin,
      in which it is of both structural and functional importance. This study describes
      the localization and distribution of hyaluronan in the skin of healthy
      individuals and of 23 patients with insulin-dependent diabetes mellitus and
      various degrees of limited joint mobility. In normal skin, hyaluronan staining
      was seen in all layers but most prominently in the papillary dermis and the
      basement membrane zone. In the skin from diabetic patients with normal or only
      moderately restricted mobility of the hands (limited joint mobility grades 0 and
      1), the distribution of hyaluronan was similar to that of normal skin. In the
      skin of patients with severe restriction in joint mobility (limited joint
      mobility grade 2) the staining pattern was significantly different with weak
      hyaluronan staining in the papillary dermis and the basement membrane zone almost
      devoid of hyaluronan. Moreover, an increased epidermal thickness in the latter
      patients was evident as well as a pronounced hyaluronan staining compared with
      normal epidermis.

PMID- 12430731
TI  - IgE-mediated hypersensitivity against human sweat antigen in patients with atopic
      dermatitis.
AB  - Sweating aggravates itch in atopic dermatitis, but the mechanism is unclear. In
      this study, we examined the involvement of type I hypersensitivity in the
      aggravation of atopic dermatitis by sweating. Skin tests with autologous sweat
      were positive in 56 of 66 patients (84.4%) with atopic dermatitis, but only in 3
      of 27 healthy volunteers (11.1%). Sweat samples from both patients and healthy
      volunteers induced varying degrees of histamine release from basophils of
      patients with atopic dermatitis. However, the histamine release was impaired by
      removal of IgE on the basophils. Incubation of basophils with myeloma IgE before
      sensitization with serum of patients blocked the ability to release histamine
      induced sweat. IgE antibody against antigen(s) in sweat may be present in serum
      of patients with atopic dermatitis. Key words:

PMID- 12430732
TI  - Palmoplantar pustulosis: an autoimmune disease precipitated by smoking?
AB  - Ninety-five percent of patients with palmoplantar pustulosis are smokers at onset
      of the disease. The aim of this study was to determine whether these patients
      have serum antibodies to nicotinic acetylcholine receptors (nAChR ab) and if
      their sera induce a specific immunofluorescence in normal palmar skin. Sera from
      45 patients with palmoplantar pustulosis and 23 patients with chronic hand eczema
      were analysed for muscle nAChR ab, and immunofluorescence was performed on
      healthy palmar skin. Forty-two percent of the patients with palmoplantar
      pustulosis but none of the eczema patients had raised levels of nAChR ab.
      Immunofluorescence showed staining on endothelial cells in the papillary dermis
      in 47% of all sera from patients with palmoplantar pustulosis and in those with
      nAChR ab in 68%. On palmar skin from smokers there was also a staining of the
      sweat duct. Sera from patients with chronic hand eczema were negative. Our
      findings indicate that palmoplantar pustulosis is an autoimmune disease, possibly
      induced by smoking.

PMID- 12430733
TI  - The Norwegian version of the dermatology life quality index: a study of validity
      and reliability in psoriatics.
AB  - The aim of this study was to test the Norwegian version of the Dermatology Life
      Quality Index (DLQI-N) for validity and reliability in psoriatic patients. The
      DLQI-N was administered to 230 patients with psoriasis who underwent climate
      therapy on Gran Canaria, with a dermatologist assessing their psoriasis severity
      using the Psoriasis Area and Severity Index. Factor analyses resulted in a
      unidimensional pattern, which supports the use of a total DLQI-N score. The
      internal consistency coefficient of this unidimensional measure was 0.90
      (Cronbach's alpha) and the paired inter-item correlations ranged from 0.20 to
      0.76 (p < 0.01). Questions related to work, sport and sex were the issues most
      often ticked off as not relevant, and the item related to working/studying was
      often misunderstood. DLQI-N scores were significantly associated with disease
      severity, age and sex. We assess DLQI-N as a valid, reliable and clinically
      useful outcome measure for quality of life in Norwegian patients with psoriasis.

PMID- 12430734
TI  - Contact allergy and allergic contact dermatitis in adolescents: prevalence
      measures and associations. The Odense Adolescence Cohort Study on Atopic Diseases
      and Dermatitis (TOACS).
AB  - The aims of this cross-sectional study were to establish the prevalence measures
      of contact allergy and allergic contact dermatitis in 8th grade schoolchildren
      (aged 12-16 years) in Odense, Denmark, and to examine the associations with
      atopic dermatitis, inhalant allergy and hand eczema. Contact allergy to a
      standard series allergen was found in 15.2% of schoolchildren. The point
      prevalence of allergic contact dermatitis was 0.7% and the lifetime prevalence
      7.2%, predominantly in girls. The most common contact allergens were nickel
      (8.6%) and fragrance mix (1.8%). Nickel allergy was clinically relevant in 69%
      and fragrance allergy in 29% of cases. A significant association was found
      between contact allergy and hand eczema while no association was found between
      contact allergy and atopic dermatitis or inhalant allergy. In the future this
      cohort of schoolchildren will be followed with regard to the course and
      development of atopic diseases, hand eczema and contact dermatitis. Key words:
      school-

PMID- 12430735
TI  - Nickel sensitization in adolescents and association with ear piercing, use of
      dental braces and hand eczema. The Odense Adolescence Cohort Study on Atopic
      Diseases and Dermatitis (TOACS).
AB  - The prevalence of nickel allergy (sensitization) and the associations with ear
      piercing, use of dental braces and hand eczema were assessed in a cohort of 1,501
      8th grade schoolchildren (aged 12-16 years) in Odense, Denmark. Nickel allergy
      was found in 8.6% and was clinically relevant in 69% of cases. Nickel allergy was
      found most frequently in girls and the association with ear piercing was
      confirmed. Application of dental braces (oral nickel exposure) prior to ear
      piercing (cutaneous nickel exposure) was associated with a significantly reduced
      prevalence of nickel allergy. In adolescents a significant association was found
      between hand eczema and nickel allergy. A follow-up study of this population is
      planned in order to assess the course and development of contact dermatitis, hand
      eczema and atopic diseases in adulthood and after choice of occupation.

PMID- 12430736
TI  - Gonorrhoea in Denmark: high incidence among HIV-infected men who have sex with
      men.
AB  - Diagnosis of gonorrhoea indicates that relatively recent unprotected sex has been
      practised and thus there is possibly a risk of HIV transmission. A retrospective
      analysis of gonorrhoea cases reported to the Danish national surveillance system
      was carried out for the period 1994-1999. The analysis included demographic
      pattern and mode of transmission of gonorrhoea in Denmark with the focus on
      trends and factors related to infection in men who have sex with men (MSM). We
      found that 646 (82.7%) reported cases of gonorrhoea were men, among whom 41.2%
      cases were due to sex with men, 52.9% were transmitted by heterosexual contact
      and 5.9% were due to unknown causes. The estimated mean annual reported incidence
      of gonorrhoea was more than 30 times greater among MSM than among heterosexual
      men and 6 times greater in MSM known to be HIV-positive, when gonorrhoea was
      diagnosed, than among other MSM (p < 0.001). No difference was found between the
      sites of infection among HIV-positive and HIV-negative MSM. A trend towards
      increase in the annual incidence of gonorrhoea has been seen since 1997, with an
      increase of 35% from 1997 to 1998 and a further increase of 41% from 1998 to
      1999. The increase was mainly due to an increasing number and proportion of cases
      among MSM. The notified cases comprised 49% of patients with laboratory-confirmed
      gonorrhoea, which indicates a similar increasing trend. In conclusion, the rising
      trend of incident gonorrhoea, especially in MSM, may indicate a relapse to more
      unsafe sexual practices, which could lead to the spread of HIV infection. The
      higher incidence among HIV-positive MSM compared with other men underlines this
      concern.

PMID- 12430737
TI  - Treatment of vitiligo vulgaris with narrow band UVB (311 nm) for one year and the
      effect of addition of folic acid and vitamin B12.
AB  - Narrow band UVB is succeeding psoralen and UVA irradiation as the main treatment
      of vitiligo vulgaris in several European countries. Vitamin B12 and folic acid
      deficiency in some vitiligo patients has prompted researchers to investigate the
      efficacy of these vitamins in the treatment of vitiligo. In the present
      controlled study we investigated the value of narrow band UVB phototherapy in the
      treatment of vitiligo and the possible additive effect of vitamin B12 and folic
      acid. Twenty-seven patients with long-term stable vitiligo were included and
      randomized in a "UVB only" (UVB) or "UVB combined with vitamin B12 and folic
      acid" (UVB+) group. Patients were irradiated thrice weekly for one year, whilst
      repigmentation was carefully monitored. In 92% (25/27) of the patients up to 100%
      repigmentation was seen. Repigmentation was notable in lesions on the face, neck
      and throat, lower arm, chest, back and lower legs, whilst repigmentation on the
      hands, wrists, feet and ankles proved to be minimal. Maximum repigmentation rates
      did not differ significantly between the UVB group and the UVB+ group. Our study
      reconfirms that narrow band UVB phototherapy is an effective treatment for
      vitiligo and shows that co-treatment with vitamin B12 and folic acid does not
      improve the outcome of treatment of vitiligo with narrow band UVB phototherapy.

PMID- 12430738
TI  - Serum concentrations of vascular endothelial growth factor in angiosarcomas with
      and without p53 gene mutation.

PMID- 12430739
TI  - Generalized pustulosis and severe tubulointerstitial nephropathy as
      manifestations of carbamazepine hypersensitivity syndrome.

PMID- 12430740
TI  - A four-year history of pruriginous erythroderma leading to the diagnosis of
      idiopathic hypereosinophilic syndrome.

PMID- 12430741
TI  - Two cases of coma-associated bulla with eccrine gland necrosis in patients
      without drug intoxication.

PMID- 12430742
TI  - Management of generalized pruritus in dominant dystrophic epidermolysis bullosa
      using low-dose oral cyclosporin.

PMID- 12430743
TI  - A patient with immunological features of paraneoplastic pemphigus in the absence
      of a detectable malignancy.

PMID- 12430744
TI  - Mixed response to thalidomide therapy in adults: two cases of multisystem
      Langerhans' cell histiocytosis.

PMID- 12430745
TI  - Bilateral chalazia of the lower eyelids associated with pulmonary tuberculosis.

PMID- 12430746
TI  - Topical tacrolimus (FK506): treatment failure in four cases of alopecia
      universalis.

PMID- 12430747
TI  - Azoospermia in a patient receiving interferon alpha for a stage III melanoma.

PMID- 12430748
TI  - Annular erythema associated with essential thrombocythemia.

PMID- 12430749
TI  - Primary cervicofacial nocardiosis due to nocardia asteroides in an adult
      immunocompetent patient.

PMID- 12430750
TI  - Successful treatment of acquired reactive perforating collagenosis with
      doxycycline.

PMID- 12430751
TI  - Erythema multiforme-like rash in a patient sensitive to ofloxacin.

PMID- 12430752
TI  - Gabapentin-induced bullous pemphigoid.

PMID- 12430753
TI  - Beau's lines associated with itraconazole.

PMID- 12430754
TI  - Arsenic and contamination of drinking-water in Bangladesh: a public-health
      perspective.

PMID- 12430755
TI  - Arsenic-related health problems among hospital patients in southern Bangladesh.
AB  - To assess the health effects of arsenic poisoning and to determine the
      relationship among duration and severity of skin lesions, exposure dose of
      arsenic, and nutritional status of people, 150 patients attending the Dermatology
      Outpatients Department of Sher-e-Bangla Medical College Hospital, Barisal,
      Bangladesh, were included in this cross-sectional study. The study was conducted
      during January-December 2000. Records of patients were collected prospectively
      using a pre-tested questionnaire, which included information on demography,
      sources of water for drinking and cooking, duration and amount of drinking-water
      obtained from shallow tubewells, clinical presentations, complications, and
      physical and laboratory findings. Water samples from tubewells currently being
      used by individual patients were examined. Nine percent of the patients were
      unaware that arsenic-contaminated water causes diseases. Due to lack of
      alternative water supplies, 25% of the subjects were still drinking water from
      contaminated tubewells. About 18% did not complain of any clinical symptoms,
      except that their skin lesions were ugly-looking, and 82% had moderate or severe
      skin lesions. Thirty-one percent of the water samples had arsenic concentrations
      10-fold higher than the permissible limit of 0.05 mg/L in Bangladesh and 50-fold
      higher than the WHO guideline value of 0.01 mg/L. The mean arsenic concentration
      in water was significantly associated with the severity of disease. Body mass
      index correlated inversely (r = -0.298, p = 0.013) with the duration of disease
      after controlling for age. The findings suggest the need to enhance public
      awareness on negative health effects of arsenic poisoning in rural Bangladesh.
      From a public-health perspective, effective intervention strategies need to be
      developed to curb the exposure, strengthen rapid diagnostic facilities, establish
      effective treatment facilities in rural areas, and improve the nutritional status
      of people.

PMID- 12430756
TI  - Relationship between carotenoids and anaemia during acute uncomplicated
      Plasmodium falciparum malaria in children.
AB  - A clinic-based cohort study in Kampala, Uganda, was conducted to examine the
      relationship between severe malarial anaemia and plasma micronutrients. Plasma
      carotenoids, retinol, vitamin E, and four trace metal concentrations were
      measured at enrollment and seven days later in 273 children, aged 1-10 year(s),
      with acute, uncomplicated Plasmodium falciparum malaria. Concentrations of plasma
      provitamin A carotenoids (p < 0.0001), non-provitamin A carotenoids (p < 0.0001),
      retinol (p < 0.0001), all four trace elements (all p < 0.001), and vitamin E (p <
      0.0001) rose significantly by day 7 among children without severe anaemia
      (haemoglobin 70 g/L). There was no change in provitamin A carotenoids (p = 0.24)
      among children with severe anaemia (haemoglobin <70 g/L), whereas non
      provitaminAcarotenoids (p < 0.0001), retinol (p < 0.0001), and vitamin E (p =
      0.011) increased. These observations also support the hypothesis that the use of
      provitamin A carotenoids increases during malaria infection.

PMID- 12430757
TI  - Characterization of entamoeba histolytica antigens in circulating immune
      complexes in sera of patients with amoebiasis.
AB  - Isolated circulating immune complexes (CICs) from sera of patients with
      amoebiasis were characterized to determine Entamoeba histolytica antigens that
      participate in the disease process. In total, 116 serum samples were collected
      before starting anti-amoebic therapy, and their CICs were isolated by
      differential polyethylene glycol precipitation. The presence of amoeba-specific
      antigens in CICs was detected by antigen capture enzyme-linked immunosorbent
      assay (ELISA) and by immunoblot assay. Antigen capture ELISA showed significantly
      higher optical density (p < 0.001) in all patients with amoebiasis than in the
      normal healthy controls and patients of non-amoebic hepatic disorder. Immunoblot
      assay detected amoeba-specific CICs in all 18 patients (100%) with confirmed
      amoebic liver abscess, 28 (80%) of 35 patients with clinically-suspected amoebic
      liver abscess, and 18 (78.26%) of 23 patients with amoebic colitis. No patients
      with non-amoebic hepatic disorders and healthy control subjects had any
      detectable level of amoebic antigens in CICs. Immunoblot assay revealed E.
      histolytica antigens of relative molecular masses of 35, 56, 70, and 90 kDa
      present in CICs of 64 of 76 patients with amoebiasis. The 35-kDa polypeptide was
      observed in 52 patients (81.25%). The results of the study suggest that the 35
      kDa polypeptide antigen can be a diagnostic marker in active amoebiasis.

PMID- 12430758
TI  - Predictors of bacteraemia among febrile infants in Ibadan, Nigeria.
AB  - Fever is a common complaint in infancy, and bacteraemia is one of the more
      serious causes of such fever. However, there exists scanty data on risk of
      bacteraemia among febrile infants of developing countries and what clinical
      predictors, if any, could identify those febrile infants with bacteraemia. To
      address this issue, 102 infants aged 1-12 month(s) attending the Children's
      Emergency Ward of University College Hospital, Ibadan, Nigeria, with rectal
      temperatures of > or = 38 degrees C and with a negative history of antimicrobial
      use for at least one week prior to presentation, were studied to identify
      clinical predictors of bacteraemia. Infants, meeting the eligibility criteria of
      the study, underwent a full clinical evaluation and had blood cultures done for
      aerobic organisms by standard methods. Over 38% of the infants had bacteraemia.
      Escherichia coli (35.9%), Staphylococcus aureus (33.3%), and Klebsiella spp.
      (10.3%) of positive cultures were commonly isolated. Three variables, age of < or
      = 6 months, restlessness, and a white cell count of >15,000/mm3, were significant
      independent predictors of bacteraemia. Each of these variables was associated
      with a 3-6-fold increase in risk of bacteraemia (age of < or = 6 months: odds
      ratio 3.2, p = 0.017; restlessness: odds ratio 6.3, p = 0.019; and white cell
      count of >15,000/mm3: odds ratio 5.4, p = 0.024). The variables, in combination,
      correctly classified 70% of the infants into 'bacteraemia' or 'no bacteraemia'.
      It is concluded that; in the setting of the study, about 4 in 10 febrile infants
      would have a positive blood culture for aerobic organisms and that age of < or =
      6 months, restlessness, and a white cell count of > or = 15,000/mm3 are
      associated with a significantly increased risk of bacteraemia. Clinicians
      practising in such a setting need to be aware of the increased risk of
      bacteraemia in infants with these clinical features.

PMID- 12430759
TI  - Diarrhoeagenic bacterial pathogens in HIV-positive patients with diarrhoea in
      rural communities of Limpopo Province, South Africa.
AB  - Potential enteric bacterial pathogens in 60 HIV-positive patients with chronic
      diarrhoea in rural communities of the Limpopo Province, South Africa, were
      identified using standard microbiological methods. The Kirby-Bauer disk-diffusion
      method was employed to determine antibiograms of isolated bacteria. Results
      revealed that diarrhoeagenic bacterial agents were isolated from 48 (80%) of the
      60 HIV-positive patients with diarrhoea. Forty-four (73.3%) and 16 (26.7%) of the
      60 patients were female and male respectively in the age range of 17-55 years
      with a mean of 34 years. Bacterial pathogens isolated comprised Campylobacter
      species (20.0%), Plesiomonas shigelloides (16.6%), Aeromonas species (13.3%), and
      Escherichia coli, Shigella and Salmonella species (10.0% each). No attempts were
      made to isolate parasites, fungi, or viruses. Antibiotic susceptibility profiles
      revealed resistance of the isolates to ampicillin, cephalothin, chloramphenicol,
      erythromycin, and streptomycin. However, all (100%) of P. shigelloides and
      Salmonella species were sensitive to nalidixic acid and ciprofloxacin. Most
      isolates were susceptible to nalidixic acid, ciprofloxacin, and gentamicin,
      indicating the usefulness of these drugs, although antibiograms may not always
      correlate with clinical usefulness.

PMID- 12430760
TI  - HBsAg carriers among healthy Nepalese men: a serological survey.
AB  - The prevalence of hepatitis B surface antigen (HBsAg) was studied among 2,585
      healthy Nepalese men, aged 16-50 years, who required medical check-ups for
      employment abroad. Serum samples, collected during July-September 1999, were
      tested for HBsAg using a third-generation ELISA kit. Of the 2,585 men, 24 (0.93%)
      were positive for HBsAg, indicating that hepatitis B infection in the target
      group was below the intermediate endemicity. The prevalence of HBsAg was minimum
      (0.36%) in the central development region, followed by western, eastern and mid
      western development regions (0.82%,1.16%, and 2.08% respectively, chi2 = 4.76, p
      < 0.2). The positivity of HBsAg was slightly higher in the hilly region (1.11%)
      than in the terai (0.84%) and mountainous regions (0%), which was not significant
      (chi2 = 2.1, p < 0.5). The prevalence was highest in the 46-50-year age group.
      Alanine aminotransferase was tested in all 24 positive and 150 negative subjects
      to indicate the stage of infection. Seven (29.16%) of the 24 positive cases had
      elevated alanine aminotransferase, indicating associated liver damage (chi2 =
      4.16, p < 0.05) and it was significantly associated with positivity of HBsAg
      (chi2 = 32.6, p < 0.001). All 9 positive subjects from the terai region had
      normal alanine aminotransferase, whereas 7 of the 15 subjects from the hilly
      region had it elevated (chi2 = 1.76, p < 0.001). Seven (29%) of the positive
      subjects were chronic carriers with its sequel in the liver, and the remaining 17
      subjects (70.84%) may be in the incubation period or convalescent stage or may be
      chronic carriers. The results suggest that the population should be educated
      about the sequel of the infection.

PMID- 12430761
TI  - Prevalence of malnutrition in rural Karnataka, South India: a comparison of
      anthropometric indicators.
AB  - Malnutrition is a problem at varying proportions in developing countries, and
      anthropometry is a simple tool to assess its magnitude in children. This study
      was aimed at identifying the prevalence of malnutrition among 256 children of
      rural areas of Karnataka in South India, who attended the aanganwadis. The value
      of using various field-based formulae and of various anthropometric indicators
      used for classification of malnutrition was also studied. The children, aged 12
      60 months, came from villages located at the outskirts of Bangalore city. The
      prevalence of wasting, stunting, and wasting and stunting was 31.2%, 9.4%, and
      29.2% respectively. Wasting was more predominant among the younger age groups
      (p<0.01). To detect wasting (acute malnutrition), the best indicator was a
      comparison with the reference weight calculated using Weech's formula. However,
      the age of child had to be rounded off to the nearest quarter of a year. Results
      of the study showed that indicators, such as mid-upper arm circumference (MUAC),
      needed to be used with caution since they are not sensitive enough to detect all
      cases of malnutrition. However, the MUAC-for-height (quac stick) method could be
      used since it was more sensitive. For detection of stunting, if reference tables
      are not available, Weech's formula can be used for calculation of expected height
      taking care to account for age to the nearest quarter, although the sensitivity
      of this indicator is not very high.

PMID- 12430762
TI  - Home management of childhood diarrhoea in a poor periurban community in Dominican
      Republic.
AB  - The purpose of this study was to identify local knowledge and practices of, and
      barriers to, the home management of childhood diarrhoea in a poor periurban
      district of the Dominican Republic. In total, 582 caregivers of children aged
      five years and younger were interviewed using a structured questionnaire. Forty
      six percent of the caregivers reported that one of their children had experienced
      diarrhoea within the last month. There was high reported use of ORS and knowledge
      of its preparation and principal function. However, there were many obstacles to
      its use. Other concerns included high rates of dietary restrictions during
      diarrhoea, positive view of the use of antibiotics, poor knowledge of preparation
      of sugar-salt solutions, and low attention given to clinical indicators as
      reasons for seeking professional treatment. Health-promotion efforts should
      target these areas of concerns to further improve the management of childhood
      diarrhoea in this district.

PMID- 12430763
TI  - Food habits and nutrient density of diets of Pakistani children living in
      different urban and rural settings.
AB  - Food habits and nutrient density of diets of six groups of rural and urban school
      children aged 10-12 years were compared. Data were collected from three-day food
      records. In the UK, data were collected during October-November 1994 and in
      Pakistan during April-May 1995. Based on the apparent level of urbanism, the six
      groups were arbitrarily assigned urbanization rank 1-6. Patterns of their food
      and intake of nutrients were different from each other in various aspects and
      were not always associated with the apparent level of urbanism of the group. With
      urbanization, the intake of fat and sugar increased steadily. The intake of
      carbohydrate, fibre, riboflavin, and vitamin E decreased with urbanization. The
      intake of vitamin C, vitamin B12, and folates was higher among group 4, 5, and 6
      than other groups. Due to various factors, in terms of micronutrient density,
      diets of various urban groups could have more differences than similarities.
      While these differences point toward the need for comprehensive nutrition
      education and community nutrition surveys, they also indicate the possibility of
      having healthy diets in urban settings.

PMID- 12430764
TI  - Perceptions of mothers and use of breastmilk substitutes in Dhaka, Bangladesh.
AB  - To explore the actual practices and perceptions of giving breastmilk and
      breastmilk substitutes (BMS), this cross-sectional study was conducted among 326
      mothers of low (income/month < Tk 4,000, n = 163) and middle (income/month > Tk
      4,000, n = 163) socioeconomic status (SES) with infants aged 6-12 months in Dhaka
      city during February-April 2001. Qualitative data on perceptions of mothers on
      appropriate breast-feeding practices were also documented through focus-group
      discussions (FGDs). The prevalence of exclusive breast-feeding was low in both
      the socioeconomic groups but was comparatively higher among the mothers of middle
      SES (3.1% vs 12.3%, p < 0.001), although predominant breast-feeding was high
      among the mothers of low SES. In addition, the use of BMS was higher among the
      mothers of middle SES than among the mothers of low SES (55.8% vs. 43.5%, p <
      0.001). The majority (62.3%) of the mothers mentioned insufficiency of breastmilk
      as the main reason for introducing BMS. Perception on appropriate feeding
      practices was also significantly different between the two groups. Approximately,
      90% of the mothers of low SES could not differentiate between infant formula and
      milk powder compared to 70% of the mothers of middle SES (p < 0.001). The
      findings of FGDs revealed that some middle-class mothers thought that infant
      formula was the best food for their infants. Programmes to impart proper
      knowledge on breast-feeding practices should be strengthened.

PMID- 12430766
TI  - Prevalence of methicillin-resistant Staphylococcus aureus colonization among
      healthcare workers and healthy community residents.

PMID- 12430765
TI  - Knowledge on, and attitude toward, HIV/AIDS among staff of an international
      organization in Bangladesh.
AB  - Two hundred and ninety-three randomly-selected members of the staff of ICDDR,B:
      Centre for Health and Population Research were surveyed anonymously in June 1998,
      using a pre-tested and self-administered questionnaire, to assess their knowledge
      on, and attitude toward, human immunodeficiency virus (HIV)/acquired
      immunodeficiency syndrome (AIDS). All except 4 (1.4%) heard of AIDS. Main sources
      of information were radio and television (93%), newspapers and magazines (84.8%),
      posters and leaflets (70.2%), and friends (59.2%). About 94% of the respondents
      believed that HIV might spread in Bangladesh. Only 61.6% knew about the causative
      agent for AIDS. More than 96% had knowledge that HIV could be detected through
      blood test. The respondents were aware that unprotected sexual intercourse (92%),
      transfusion of blood and blood components (93.8%), sharing unsterile needles for
      injections (94.1%), and delivery of babies by infected mothers (82.7%) could
      transmit HIV. Similarly, the respondents had the knowledge that HIV infection
      could be prevented by using condom during sexual intercourse (85.5%), having sex
      only with an HIV-negative faithful partner (87.2%), avoiding transfusion of blood
      not screened for HIV (88.9%), and taking injections with sterile needles (86.5%).
      However, only 33.0% had the knowledge that HIV-infected persons can look healthy,
      and 56.4% were unaware of transmission through breastmilk. Most members of the
      staff, particularly at lower level, had misconceptions about transmission and
      prevention of HIV/AIDS. More than 40% of the respondents had the attitude that
      HIV-infected persons should not be allowed to work, while another 10% did not
      have any idea about it. The findings of the study suggest that the members of the
      Centre's staff have a satisfactory level of essential knowledge on HIV/AIDS,
      although half of them have poor attitudes toward persons with HIV/AIDS.
      Therefore, preventive strategy for the staff should be directed toward behaviour
      change communication.

PMID- 12430767
TI  - Estimation of low bacterial concentration: Listeria monocytogenes in raw milk.
AB  - A time-series bacteriological analysis has been carried out on milk collected on
      farms from 1997 to 2001 by a plant producing raw milk soft cheese, with the
      purpose of assessing the time course of the presence/absence of Listeria
      monocytogenes. A standard data collection procedure was used, in which farms were
      tested on a monthly or biweekly basis and 2-3 days after the detection of milk
      tanker contamination. This procedure yielded low figures for contamination
      frequencies. The average value and the median of the monthly prevalence of farms
      detected positive for L. monocytogenes were 2.4 and 0%, respectively. A seasonal
      effect (with peaks in winter) was observed. Between 1997 and 2001, there was no
      significant decrease of contamination rates, in spite of the efforts on the
      contaminated farms. Over the last year of the study (from March 2000 to February
      2001), a new data collection procedure was implemented that allowed much better
      detection of sporadic occurrences. Milk samples were collected from the bulk tank
      of each participating farm just before pick-up, then stored and subsequently
      analysed whenever the milk tanker was found contaminated. The average value and
      the median of the monthly prevalence of positive farms were found equal to 7.7
      and 0%, respectively (for a mean prevalence of L. monocytogenes in the milk
      tanker of 3.2%). These results confirm that farm milk contamination is, most
      often, a sporadic event In addition to this prevalence study, contamination
      levels were quantified by enumerating L. monocytogenes using direct plating of
      small volumes of farm milk previously tested positive. Most often, these levels
      were extremely low. A simple simulation model shows that, when milk tankers were
      found positive, contamination levels in the corresponding bulk-tank milk are
      themselves very low (typically, below 3 L. monocytogenes per millilitre with most
      probable concentration 0.1 Colony Forming Unit (CFU)/ml and median ranging from
      5.10(-2) to 0.1 CFU/ml). Such low levels are very likely to be due to
      environmental contamination.

PMID- 12430768
TI  - Quantitative risk assessment of human salmonellosis from the consumption of a
      turkey product in collective catering establishments.
AB  - The quantitative risk assessment (QRA) approach recommended by the Codex
      Alimentarius Commission was used to assess the risk of human salmonellosis from
      the consumption of 'cordon bleu', a specific turkey product, in collective
      catering establishments (CCEs) of a French department. The complete process was
      modeled and simulated, from the initial storage in the CCE freezer to the
      consumption, using a Monte Carlo simulation software. Data concerning the
      prevalence of contaminated 'cordon bleu', the level of contamination of
      Salmonella, the cooking and storage process were collected from 21 CCEs and 8
      retailers of 'cordon bleu' in the selected department. Thermal inactivation
      kinetics for Salmonella were established to estimate the effect of heat treatment
      on the concentration in the product and to calculate the dose that could be
      ingested by the consumer. The Beta-Poisson dose-response model of Rose and Gerba
      [Water Science and Technology 24 (1991) 29] with the specific parameters for
      Salmonella was used to estimate the probability of infection related to the
      ingestion of a particular dose and a factor was applied to estimate the
      probability of illness from ingestion. The individual risk of salmonellosis, the
      risk of outbreak and the number of cases were calculated using Monte Carlo
      simulation method. The risk of salmonellosis was close to zero when the 'cordons
      bleus' were cooked in the oven. Therefore, the risk was calculated for the fryer
      cooking since the insufficient cooking time observed was, sometimes, at the
      origin of low temperatures (37-89 degrees C). The influence of both the initial
      concentration of Salmonella in the product and the heat storage before
      consumption on the final risk was studied. For a high initial concentration of
      Salmonella in the product, when the 'cordons bleus' are fryer cooked, the average
      risk of salmonellosis was equal to 3.95 x 10(-3) without storage before
      consumption and 2.8 x 10(-4) if the product is consumed after storage. This paper
      presents the results of the QRA and discusses risk management options to minimize
      the risk of salmonellosis.

PMID- 12430769
TI  - Contribution of reutericyclin production to the stable persistence of
      Lactobacillus reuteri in an industrial sourdough fermentation.
AB  - Reutericyclin is a small molecular weight antibiotic produced by the sourdough
      isolate Lactobacillus reuteri LTH2584. This strain was isolated from an
      industrial sourdough, SER, in 1988. To determine whether reutericyclin formation
      contributes to the stable persistence of L. reuteri in sourdough, evaluations
      were made on whether reutericyclin-producing strains were among L. reuteri
      isolates from the SER sourdough obtained in 1994 and 1998. These strains were
      characterised on species and strain level by physiological tests and randomly
      amplified polymorphic DNA (RAPD) and restriction fragment length polymorphism
      (RFLP) patterns. Reutericyclin production in dough was evaluated by two methods,
      a bioassay and HPLC. Throughout 10 years of continuous propagation, reutericyclin
      producing L. reuteri strains were present in SER sourdough. All isolates
      exhibited similar physiological properties and molecular typing revealed closely
      related patterns. Two isolates obtained in 1994 and 1998 were identical.
      Reutericyclin produced in situ by L. reuteri was active in dough against
      reutericyclin-sensitive L. sanfranciscensis. The reutericyclin concentration in
      dough fermented with L. reuteri was 5 mg kg(-1). The results indicate that
      reutericyclin production contributed to the stable persistence of L. reuteri in
      sourdough. Because reutericyclin is produced in active concentrations during
      sourdough fermentations, it is a suitable candidate for use as natural
      preservative.

PMID- 12430770
TI  - Effects of fermentation temperature on the strain population of Saccharomyces
      cerevisiae.
AB  - The influence of fermentation temperature (from 15 to 35 degrees C) on a mixed
      strain population was studied. Mitochondrial DNA analysis was used to
      differentiate Saccharomyces cerevisiae strains and the frequency of each strain
      during the alcoholic fermentation was determined. The chemical analyses of
      resulting wines were carried out. The temperature determined how Saccharomyces
      strains developed and how effectively they fermented. Some strains performed
      better at high temperatures and others at low temperatures. The maximal
      population size was similar at all temperatures. At low temperatures, however, it
      was reached later though it remained constant throughout the alcoholic
      fermentation. On the other hand, viable cells decreased at high temperatures,
      especially at 35 degrees C. Obviously, the composition of the wines changed as
      the temperature of fermentation changed. At low temperatures, alcohol yield was
      higher. Secondary metabolites to alcoholic fermentation increased as the
      temperature increased. Glycerol levels were directly affected by temperature.

PMID- 12430771
TI  - Candida humilis--dominant species in sourdoughs for the production of durum wheat
      bran flour bread.
AB  - Yeasts present in the sourdough that is generally used for the production of
      durum wheat bran flour bread wereisolated and identified. Samples were taken
      during the rebuilding phase and at different intervals of time in order to
      monitor the population dynamics. The results obtained from the phenotypic studies
      were further confirmed by the molecular studies and enabled us to affirm that
      most of the strains, more than 95%, belong to the species Candida humilis. The
      dominance of C. humilis was steady in time. The isolations were carried out at
      sufficiently long intervals so that it was possible to ascertain that the
      conditions in which the sourdough is kept are fundamental to the microbiological
      stability of the dough.

PMID- 12430772
TI  - Solid-state fermentation of cornmeal with the basidiomycete Hericium erinaceum
      for degrading starch and upgrading nutritional value.
AB  - The ability of the basidiomycete Hericium erinaceum to degrade starch and upgrade
      nutritional value of cornmeal during solid-state fermentation was studied. On the
      basal medium which consisted of cornmeal and salt solution, H. erinaceum produced
      a strong alpha-amylase on the 15th day after inoculation, which resulted in a 52%
      degradation of the starch. By supplementation with 5-15 g soybean meal per 100 g
      cornmeal the alpha-amylase activity and degradation rate of starch was raised
      significantly (P < 0.01). Prolongation of fermentation time from 15 to 30 days
      did not increase significantly the degradation rate of starch, though the alpha
      amylase activity reached its maximum value of 179 U/g on the 20th day after
      inoculation. Under conditions close to the theoretical optimum fermentation
      conditions, that was after 25 days at 25 degrees C in the medium with added 15 g
      soybean meal per 100 g cornmeal, the starch content in the product decreased from
      63% to 22% (P < 0.001) and protein content increased from 12% to 17% (P < 0.01).
      In the protein in the product, the lysine content was increased from 36 to 56 mg/
      g and tryptophan from 9 to 13 mg/g. Using egg protein as a standard, an
      evaluation on the protein quality of the fermented product showed that it was
      superior to that of the nonfermented control and to other cereals, was close to
      that of soybean and chicken, but was inferior to that of milk and red meats.

PMID- 12430773
TI  - An improved 16S rRNA based PCR method for the specific detection of Salmonella
      enterica.
AB  - A molecular method for the detection of Salmonella enterica strains based on 16S
      rRNA sequence analysis was developed by a modification of the previously
      described PCR primer 16SFI [J. Appl. Bacteriol. 80 (1996) 659], which was
      combined with a newly developed primer annealing at the position 66-82. Only
      approximately two thirds of now determined Salmonella 16S rRNA sequences
      contained a region identical to the 16SFI primer sequence and the reverse primer
      16SIII was also not specific. Combined, these two primers have been claimed to
      allow the specific detection of all Salmonella; however, in this study, they did
      not recognize S. bongori and 3 out of 78 tested S. enterica strains. They also
      identified some of the tested Enterobacter cloacae strains as Salmonella. On the
      contrary, the new primer pair, MINf and MINr, made it possible to recognize
      correctly all of the 78 tested S. enterica strains, representing 31 different
      Salmonella serovars. None of the 23 non-Salmonella strains from the related gamma
      proteobacterial genera was incorrectly recognized as belonging to S. enterica.

PMID- 12430774
TI  - Study of starch fermentation at low pH by Lactobacillus fermentum Ogi E1 reveals
      uncoupling between growth and alpha-amylase production at pH 4.0.
AB  - Lactobacillus fermentum Ogi E1 is an amylolytic heterofermentative lactic acid
      bacterium previously isolated from ogi, a Benin maize sourdough. In the present
      study, the effect of different pH between 3.5 and 6.0 on starch fermentation
      products and alpha-amylase production was investigated. Whereas a pH of 5.0 was
      optimum for specific growth rate and lactic acid production, growth was only
      slightly affected at suboptimal pH of 4.0 and 6.0. Over a pH range of 6.0 to 3.5,
      yields of product formation from substrate and of biomass relative to ATP were
      constant. These results showed that L. fermentum Ogi E1 was particularly acid
      tolerant, and well adapted to the acid conditions that develop during natural
      fermentation of cereal doughs. This acid tolerance may partly explain the
      dominance of L. fermentum in various traditional African sourdoughs.
      Surprisingly, alpha-amylase production, unlike growth, dropped dramatically when
      the strain was cultivated at pH 4.0 with starch. With maltose as substrate, the
      yield of alpha-amylase relative to biomass remained unchanged at pH 4.0 and 5.0,
      unlike that observed with starch. Based on the distribution of enzyme activity
      between extra- and intracellular fractions and fermentation kinetics, it appears
      that starch was first hydrolyzed into dextrins by alpha-amylase activity, and
      maltose was produced from dextrins by extracellular enzyme activity, transferred
      into the cell and then hydrolyzed into glucose by intracellular alpha
      glucosidase.

PMID- 12430775
TI  - Leuconostoc gasicomitatum is the dominating lactic acid bacterium in retail
      modified-atmosphere-packaged marinated broiler meat strips on sell-by-day.
AB  - Lactic acid bacteria (LAB) in retail, modified-atmosphere-packaged (MAP),
      marinated broiler meat strips on sell-by-day were mainly identified as
      Leuconostoc gasicomitatum. A total of 32 packages, three to five packages of
      seven differently marinated broiler meat products, were studied at the end of the
      producer-defined shelf life (at 6 degrees C, 7-9 days depending on the
      manufacturer). Prior to the microbiological analyses, appearance and smell of the
      product was checked and pH measured. Bacteria were cultured on MRS and Tomato
      Juice Agar (TJA), Rogosa SL agar (SLA), Plate Count Agar (PCA) and Streptomycin
      Thallium Acetate Agar (STAA) for the enumeration of LAB, lactobacilli, total
      bacterial count and Brochothrix thermosphacta, respectively. The average CFU/g of
      the 32 packages was 2.3 x 10(8) on PCA. The highest bacterial average, 3.1 x
      10(8), was recovered on TJA, the corresponding CFU/g averages on MRS and SLA
      being 2.3 x 10(8) and 1.3 x 10(8), respectively. Despite the high LAB numbers
      detected, radical spoilage changes such as unpleasant odor, slime production and
      formation of gas were not seen. B. thermosphacta did not form a significant part
      of the bacterial population since none of the levels exceeded the spoilage
      threshold level of 10(5) CFU/g reported in previous studies for this organism. In
      order to characterize the dominating LAB population, as many as 85, 85 and 88
      colonies from MRS, TJA and SLA, respectively, were randomly picked and cultured
      pure. LAB were identified to species level using a 16 and 23S rDNA HindIiI RFLP
      (ribotyping) database. Fifty-six of the 170 isolates picked from the non
      selective LAB media (MRS and TJA) were identified as L. gasicomitatum, followed
      by Carnobacterium divergens (41 isolates), Lactobacillus sakei and Lactobacillus
      curvatus subsp. melibiosus (31 isolates) and L. curvatus subsp. curvatus (20
      isolates) species. SLA proved not to be completely selective for lactobacilli
      because the growth of Leuconostoc spp. was not inhibited, Carnobacterium spp.
      were the only species not detected on SLA.

PMID- 12430776
TI  - Is "optimal" blood pressure an attainable goal?

PMID- 12430777
TI  - Is "optimal" blood pressure an attainable goal.

PMID- 12430778
TI  - Cardiovascular continuing medical education: what education do you want?
AB  - In summary, continuing medical education is not generic--it is highly specific.
      In my view, it does not matter how physicians obtain knowledge in their areas of
      expertise, only that they obtain the knowledge. Cardiovascular medicine textbooks
      and scientific journals form the core of our knowledge, but many other modes of
      education are available, including audio CDs and tapes and CD ROMs. Now,
      extensive information is available on the internet almost as soon as it is
      discussed at national meetings. One must be careful with these so-called "up to
      date" sources of education, since much of this early information has not been
      peer reviewed. Nonetheless, most of that information turns out to be useful.

PMID- 12430780
TI  - Prognostic value of C-reactive protein, fibrinogen, interleukin-6, and macrophage
      colony stimulating factor in severe unstable angina.
AB  - BACKGROUND: Inflammatory process plays an important role in the pathogenesis of
      acute coronary syndromes. HYPOTHESIS: The study was undertaken to evaluate
      whether admission levels of C-reactive protein (CRP), fibrinogen, interleukin-6
      (IL-6). and macrophage colony stimulating factor (MCSF) can predict short-term
      prognosis in patients with unstable angina. METHODS: C-reactive protein,
      fibrinogen, IL-6, and MCSF were measured on admission in 141 consecutive
      patients, aged 59 +/- 10 years, with unstable angina (Braunwald class IIIb).
      Patients were divided into two groups according to their in-hospital outcome:
      Group 1 comprised 77 patients with a complicated course (2 died, 15 developed
      nonfatal myocardial infarction, and 60 had recurrence of angina), and Group 2
      comprised 64 patients with an uneventful course. RESULTS: Admission median levels
      of CRP (8.8 vs. 3.1 mg/l, p = 0.0002). fibrinogen (392 vs. 340 mg/dl, p = 0.008),
      IL-6 (8.8 vs. 4.5 pg/ml, p = 0.03), and MCSF (434 vs. 307 pg/ml, p = 0.0001) were
      higher in Group I than in Group 2. The MCSF levels were an independent risk
      factor for in-hospital events, with an adjusted odds ratio for eventful in
      hospital outcome of 3.3 (95% confidence interval 1-10.9, p = 0.04), and
      correlated with levels of IL-6 (r(s) = 0.52, p = 0.0001), CRP (r(s) = 0.43, p =
      0.0001), and fibrinogen (r(s) = 0.25, p = 0.004). CONCLUSIONS: These findings
      suggest that among the studied inflammatory indices only increased admission
      levels of MCSF are strongly and independently related with adverse short-term
      prognosis in patients with severe unstable angina.

PMID- 12430779
TI  - Hyperhomocysteinemia and endothelial function in young subjects: effects of
      vitamin supplementation.
AB  - BACKGROUND: The relationship between hyperhomocysteinemia and cardiovascular
      disease has not been totally elucidated. HYPOTHESIS: The study aimed to verify
      the association between hyperhomocysteinemia and endothelial dysfunction before
      and after modification of total homocysteine (tHcy) serum levels with vitamin
      supplementation in young male subjects devoid of any other cardiovascular risk
      factor. METHODS: Twenty hyperhomocysteinemic (tHcy > 15 [micromol/l) male
      volunteers (< or = 40 years) and 20 age-matched subjects with normal tHcy levels
      (tHcy < 13 micromol/l) were included. Exclusion criteria were smoking,
      hypertension, diabetes, vitamin ingestion, obesity, hypercholesterolemia, renal
      failure, and positive antiphospholipid antibodies. Serum tHcy, folate, vitamin
      B12 levels, activated protein C and S, protein C resistance, fibrinogen,
      prothrombin, thrombin, antithrombin III, and in vitro oxidation of low-density
      lipoprotein (LDL) particles were measured. Noninvasive ultrasound measurements of
      endothelium-dependent (EDD) and -independent dilatation (EID) of the brachial
      artery were performed. Each pair was then randomly assigned to receive a vitamin
      capsule (0.6 mg folic acid, 0.8 mg B12. and 2.0 mg B6) oran identical placebo
      during 8 weeks, in a double-blind study design. After the treatment phase, blood
      samples and vascular reactivity were repeated. RESULTS: Nine pairs of volunteers
      received vitamins and 11 received placebo. Hyperhomocysteinemic subjects had
      lower baseline serum levels of vitamin B12. Serum folate levels, antithrombotic
      function, in vitro LDL oxidation, and EDD were similar in all groups. After the
      vitamin supplementation, serum folic acid levels increased significantly both in
      normo- and hyperhomocysteinemic subjects, unlike vitamin B12, which increased
      only in the hyperhomocysteinemic individuals. Plasma tHcy decreased significantly
      in the supplemented groups. Treatment with vitamins was not associated with
      improvement in EDD or antithrombotic function. CONCLUSIONS: Mild
      hyperhomocysteinemia is not associated with endothelial dysfunction in young male
      subjects with no additional cardiovascular risk factors, and reduction of tHcy by
      vitamin supplementation does not modify EDD in this age group. In this sample,
      tHcy was more related to vitamin B12 than to folic acid status.

PMID- 12430781
TI  - Assessment of left internal mammary artery graft patency by transthoracic Doppler
      echocardiography.
AB  - BACKGROUND: The successful application of noninvasive Doppler spectrum analysis
      has been reported for the hemodynamic assessment of LIMA graft after myocardial
      revascularization. HYPOTHESIS: The objective of this study was to assess the
      utility of transthoracic Doppler echocardiography (TTE) in providing information
      on LIMA flow in patients after coronary artery bypass graft surgery. METHODS: In
      all, 22 patients (aged 62 +/- 8 years) with LIMA graft to the left anterior
      descending (LAD) coronary artery who underwent coronary angiography were assessed
      using high-frequency (5 MHz) transthoracic Doppler echocardiography. They were
      compared with 25 patients with angina (control group A, aged 59 +/- 12 years), in
      whom an ungrafted LIMA was assessed, and with 17 patients (control group B, aged
      59 +/- 9 years) with angiographically normal coronary arteries, in whom the LAD
      was assessed. RESULTS: A biphasic pattern (systolic and diastolic) was recorded
      in all cases. In 14 patients with a normal graft or < 70% stenosis (Group 1) and
      in control group B, blood flow was maximal during diastole. In eight patients
      with severe graft stenosis > 70% (Group 2) and control group B, blood flow was
      maximal during systole, with low diastolic flow. The diastolic fraction of the
      velocity time integrals was 0.81 +/- 0.11 for Group 1 and 0.25 +/-0.06 for Group
      2 (p < 0.05). A diastolic velocity time integral fraction < 0.5 predicted > 70%
      stenosis with a sensitivity and specificity of 100%. The ratio of
      systolic/diastolic peak velocities was 0.61 +/- 0.31 for Group 1 and 3.21 +/-
      0.49 for Group 2 (p < 0.05). A systolic/diastolic peak velocity > 1 predicted
      stenosis > 70% with a sensitivity and specificity of 100 and 90%, respectively.
      CONCLUSIONS: High-frequency TTE is a useful noninvasive method for detecting LIMA
      graft blood flow. Severe graft stenoses exhibited Doppler velocity patterns,
      which were different from those of patent grafts, or grafts with moderate
      stenoses.

PMID- 12430782
TI  - Quantification of mitral regurgitation by the proximal flow convergence method-
      comparison of transthoracic and transesophageal echocardiography.
AB  - BACKGROUND: No dataexist to indicate whether transthoracic (TTE) and
      transesophageal echocardiography (TEE) are of comparable value for the detection
      and quantification of mitral regurgitation using the proximal flow convergence
      method. HYPOTHESIS: The study was performed to compare the value of TTE and TEE
      for the detection and quantification of mitral regurgitation using this method.
      METHODS: The study included 57 patients with and 11 patients without mitral
      regurgitation. In all patients, the proximal flow convergence region was imaged
      by transthoracic and transesophageal color Doppler echocardiography, and proximal
      isovelocity surface area radii were determined. In 19 patients, monoplane TEE and
      in 49 patients multiplane TEE was performed. Thirty-one patients with mitral
      regurgitation underwent cardiac catheterization. RESULTS: Both methods had a
      comparable sensitivity for the detection of mitral regurgitation. Proximal
      isovelocity surface area radii derived from TTE and TEE agreed moderately (mean
      difference -0.5 +/- 1.3 mm). TTE and TEE correlated significantly with the
      angiographic grade (rank correlation coefficients 0.83 and 0.81), and both
      differentiated mild to moderate from severe mitral regurgitation with an accuracy
      of 90%. Regurgitant volumes derived from both echocardiographic techniques and
      cardiac catheterization correlated moderately (correlation coefficients between
      0.67 and 0.81). CONCLUSIONS: TTE and TEE were of comparable value for the
      detection and quantification of mitral regurgitation using the proximal flow
      convergence method.

PMID- 12430783
TI  - Signal-averaged P-wave analysis of normal controls and patients with paroxysmal
      atrial fibrillation: a study in gender differences, age dependence, and
      reproducibility.
AB  - BACKGROUND: Atrial fibrillation is often first recognized after a complication
      such as embolic stroke has occurred. Limited data are available for the
      prospective identification of patients at risk for developing atrial
      fibrillation. HYPOTHESIS: Demonstration of areas of slow conduction in the atrium
      by means of P-wave signal averaging may identify individuals at risk for atrial
      fibrillation. METHODS: P-wave signal averaging from the surface electrocardiogram
      was performed in 199 normal controls and 81 patients with paroxysmal atrial
      fibrillation using an automated, P-triggered, high-resolution signal for
      analysis. RESULTS: Of the variables measured, the filtered P-wave duration and P
      wave integral were significantly different between controls and patients
      (filtered P-wave duration 120 +/- 9 vs. 145 +/- 21 and P-wave integral 666 +/-
      208 vs. 868 +/- 352), whereas the terminal root-mean-square (RMS) voltages (RMS
      20, RMS 30, RMS 40) showed no significant differences between the two groups.
      Regression analysis of the first and second measurement of the filtered P-wave
      duration obtained during consecutive tests showed excellent reproducibility (r
      and r2 of 0.96 and 0.92). The duration of the filtered P wave showed no age
      dependence but was shorter in women. CONCLUSION: Utilizing the 90th percentile
      value of the filtered P-wave duration of 133 ms in men and 130 ms in women, the
      sensitivity was 80 and 81%, the specificity 92 and 90%, the positive predictive
      value 84 and 73%, and the negative predictive value 90 and 93%, respectively.

PMID- 12430785
TI  - Profiles in cardiology. Alessandro Volta.

PMID- 12430786
TI  - Images in cardiology: spontaneous coronary artery dissection.

PMID- 12430784
TI  - Possible relationship between insulin resistance and remnant-like lipoprotein
      particles in coronary endothelial dysfunction.
AB  - BACKGROUND: High insulin resistance and elevated remnant lipoprotein levels both
      correlate with impaired coronary vascular endothelial function. Hyperinsulinemia
      induces abnormalities of lipid metabolism. However, the correlation among insulin
      resistance, remnant lipoproteins, and endothelial function has not been
      clinically elucidated. HYPOTHESIS: This study was designed to elucidate the
      correlation among insulin resistance, remnant lipoproteins, and acetylcholine
      (ACh)-induced coronary artery response. METHODS: Forty-nine patients suspected of
      having ischemic heart disease, but without angiographically significant
      atherosclerotic coronary artery disease, underwent an ACh provocation test.
      Fasting venous blood was taken early in the morning on the day coronary
      angiography was performed. The insulin resistance index (IR) was determined from
      fasting plasma glucose and insulin concentrations, using the homeostasis model
      assessment (HOMA). Serum levels of remnant-like lipoprotein particle cholesterol
      (RLP-C) were measured. RESULTS: Homeostasis model assessment IR was significantly
      higher (3.65 +/- 1.38 vs. 0.75 +/- 0.14, p < 0.05) and log-transformed HOMA (Log
      HOMA) was even more significantly higher (0.20 +/- 0.12 vs. -0.29 +/- 0.08, p <
      0.001) in the ACh-positive group (n = 23) than in the ACh-negative group (n =
      26). The serum RLP-C level was also higher in the ACh-positive group than in the
      ACh-negative group (4.37 +/- 0.63 vs. 2.52 +/- 0.18 mg/dl, p < 0.01). Log HOMA
      and RLP-C levels correlated with each other (R = 0.54, p < 0.001). Multiple
      regression analysis indicated that only the RLP-C level was a dependent predictor
      of Log HOMA in various lipid profiles. CONCLUSIONS: Both high insulin resistance
      and elevated remnant lipoprotein levels correlated and might have a crucial role
      in the impairment of coronary vascular endothelial function, even in patients
      without angiographically significant coronary artery disease.

PMID- 12430787
TI  - Comment on "On the complex conjugate roots of the Rayleigh equation: the leaky
      surface wave".

PMID- 12430788
TI  - Sound-wave propagation in a membrane-duct.

PMID- 12430789
TI  - Object localization from acoustic emissions produced by other sonars.

PMID- 12430790
TI  - On the existence of flexural edge waves on thin orthotropic plates.
AB  - This paper is concerned with an investigation into the existence of waves
      propagating along a free edge of an orthotropic plate, where the edge is inclined
      at arbitrary angle to a principal direction of the material. After deriving the
      governing equation and edge conditions, an edge wave ansatz is substituted into
      this system to reduce it to a set of algebraic equations for the edge wave wave
      number and wave vector. These are solved numerically for several typical
      composite materials although analytic expressions can be obtained in the case of
      special values of the material parameters and inclination angle. It is found that
      a unique edge wave solution, which generally exhibits oscillation as well as
      decay away from the free edge, exists in all cases, and its wave speed is
      independent of its direction of propagation along the plate.

PMID- 12430791
TI  - Elastic guided waves in a layered plate with rectangular cross section.
AB  - Guided waves in a layered elastic plate of rectangular cross section (finite
      width and thickness) has been studied in this paper. A semianalytical finite
      element method in which the deformation of the cross section is modeled by two
      dimensional finite elements and analytical representation of propagating waves
      along the length of the plate has been used. The method is applicable to
      arbitrary number of layers and general anisotropic material properties of each
      layer, and is similar to the stiffness method used earlier to study guided waves
      in a laminated composite plate of infinite width. Numerical results showing the
      effect of varying the width of the plate on the dispersion of guided waves are
      presented and are compared with those for an infinite plate. In addition, effect
      of thin anisotropic coating or interface layers on the guided waves is
      investigated.

PMID- 12430792
TI  - The photoacoustic effect generated by an incompressible sphere.
AB  - An incompressible sphere with a vanishing thermal expansivity suspended in a
      fluid can generate a photoacoustic effect when the heat deposited in the sphere
      by a light beam diffuses into the surrounding liquid causing it to expand and
      launch a sound wave. The properties of the photoacoustic effect for the sphere
      are found using a Green's function solution to the wave equation for pressure
      with Neumann boundary conditions. The results of the calculation show that the
      acoustic wave for fast heat liberation is an outgoing compressive pulse followed
      by a reflected pulse whose time profile is modified as a result of frequency
      dependent reflection from the sphere. For slow heat release by the sphere, the
      photoacoustic effect is shown to be proportional to the first time derivative of
      the heat flux at the particle-fluid interface.

PMID- 12430793
TI  - Rectified heat transfer into translating and pulsating vapor bubbles.
AB  - It is well known that, when a stationary vapor bubble is subject to a
      sufficiently intense acoustic field, it will grow by rectified heat transfer even
      in a subcooled liquid. The object of this paper is to study how translation, and
      the ensuing convective effects, influence this process. It is shown that,
      depending on the initial temperature distribution and other factors, convection
      can cause a destabilization of the bubble or its faster growth. Significant
      effects occur in parameter ranges readily encountered in practice. The phenomena
      described can therefore be exploited for bubble management, e.g., by increasing
      the condensation rate or promoting faster bubble growth and coalescence. In a
      saturated or a superheated liquid, heat rectification and convection reinforce
      each other and the bubble growth is accelerated by a translatory motion.

PMID- 12430794
TI  - Validity of the sonar equation and Babinet's principle for scattering in a
      stratified medium.
AB  - The sonar equation rests on the assumption that received sound pressure level
      after scattering can be written in decibels as a sum of four terms: source level,
      transmission loss from the source to the target, target strength, and
      transmission loss from the target to the receiver. This assumption is generally
      not valid for scattering in a shallow water waveguide and can lead to large
      errors and inconsistencies in estimating a target's scattering properties as well
      as its limiting range of detection. By application of coherent waveguide
      scattering theory, the sonar equation is found to become approximately valid in a
      shallow water waveguide when the object's complex scatter function is roughly
      constant over the equivalent horizontal grazing angles +/- delta psi spanned by
      the dominant waveguide modes. This is approximately true (1) for all objects of
      spatial extent L and wavelength lambda when 2delta psi<lambda/2L and (2) for
      spheres and certain other rounded objects in nonforward scatter azimuths, even
      when (1) does not hold. The sonar equation may be made valid by lowering the
      active frequency of operation in a waveguide. This is often desirable because it
      greatly simplifies the analysis necessary for target classification and
      localization. Similarly, conditions are given for when Babinet's principle
      becomes approximately valid in a shallow water waveguide.

PMID- 12430795
TI  - Measurements and modeling of acoustic scattering from partially and completely
      buried spherical shells.
AB  - The use of low-frequency sonars (2-15 kHz) is explored to better exploit
      scattering features of buried targets that can contribute to their detection and
      classification. Compared to conventional mine countermeasure sonars, sound
      penetrates better into the sediment at these frequencies, and the excitation of
      structural waves in the targets is enhanced. The main contributions to target
      echo are the specular reflection, geometric diffraction effects, and the
      structural response, with the latter being particularly important for man-made
      elastic objects possessing particular symmetries such as bodies of revolution.
      The resonance response derives from elastic periodic phenomena such as surface
      circumferential waves revolving around the target. The GOATS'98 experiment,
      conducted jointly by SACLANTCEN and MIT off the island of Elba, involved
      controlled monostatic measurements of scattering by spherical shells which were
      partially and completely buried in sand, and suspended in the water column. The
      analysis mainly addresses a study of the effect of burial on the dynamics of
      backscattered elastic waves, which can be clearly identified in the target
      responses, and is based on the comparison of measurements with appropriate
      scattering models. Data interpretation results are in good agreement with theory.
      This positive result demonstrates the applicability of low-frequency
      methodologies based on resonance analysis to the classification of buried
      objects.

PMID- 12430796
TI  - Normal incidence reflection loss from a sandy sediment.
AB  - Acoustic reflection loss at normal incidence from a sandy sediment, in the
      Biodola Gulf on the north side of the island of Elba, Italy, was measured in the
      frequency band 8-17 kHz, using a self-calibrating method. The water depth was
      approximately 11 m. The mean and standard deviation of the sand grain diameter
      were 2.25 (0.21 mm) and 0.6 phi, respectively. The reflection loss was measured
      using an acoustic intensity integral method, which is insensitive to roughness
      effects within the selected frequency band. The measured value of reflection loss
      was 11 dB, +/- 2 dB. The result is consistent with previous measurements in the
      published literature. The computed reflection loss for a flat interface between
      water and a uniform fluid or visco-elastic medium with the same properties is 8
      dB, +/- 1 dB. The theoretical and experimental values do not significantly
      overlap, which leads to the conclusion that the visco-elastic model is
      inappropriate. The Biot model is suggested as a better alternative but more work
      is needed to ascertain the appropriate parameter values.

PMID- 12430797
TI  - Orientation effects on linear time-reversing array retrofocusing in shallow
      water.
AB  - A time-reversing array (TRA) can retrofocus acoustic energy, in both time and
      space, to the original sound-source location without any environmental
      information. This paper presents results from an analytical and computational
      investigation into the effects that array orientation has on linear TRA
      retrofocusing in shallow water environments. A linear TRA has three limiting
      orthogonal orientations with respect to a distant sound source in a shallow water
      waveguide: vertical, endfire, and broadside. Here, TRA retrofocus characteristics
      are predicted for monochromatic sound propagation in a Pekeris waveguide using a
      modal sum Green's function and in a more realistic sound channel having vertical
      sound speed variation using a computed Green's function. Both analytical and
      computational results are compared for the three orthogonal array orientations
      with vertical arrays performing best. Differences in TRA retrofocusing
      performance in the three orientations are primarily determined by geometrical
      considerations and the extra mode-shape weighting inherent in the back-propagated
      field of horizontal TRAs.

PMID- 12430798
TI  - An inversion for Biot parameters in water-saturated sand.
AB  - The discrepancy between acoustic measurements and the theoretical predictions was
      investigated in the case of water-saturated sand. Two theoretical models were
      considered: visco-elastic and poro-elastic solid models. The visco-elastic solid
      model could not be reconciled with reflection loss measurements and was rejected.
      The poro-elastic solid model using Biot's theory [J. Acoust. Soc. Am. 103, 2723
      2729 (1998)] as formulated by Stoll [J. Acoust. Soc. Am. 70, 149-156 (1981)] was
      an improvement. It was investigated using an inversion process. Operative values
      of grain bulk modulus and the frame bulk and shear moduli of water-saturated sand
      were inverted from simple measurements--reflection loss, compressional and shear
      wave speeds and attenuations. Although the inversion process is nonlinear, in
      practice, it is well behaved and converges quite rapidly to a unique solution.
      The issue of imprecisely known parameter values was handled in a probabilistic
      manner. The inversion results, using published laboratory and in situ
      measurements, showed that further improvement was needed. In an attempt to find a
      solution, two possible hypotheses are put forward. (1) Composite materials: The
      possibility that the frame may contain fluid and that the pore fluid may contain
      loose grains. (2) Independent coefficient of fluid content: The possibility that
      porosity may change with pore fluid pressure. Inversion results were encouraging
      for both hypotheses. It is difficult to say which of the two hypotheses is
      superior, and the two hypotheses are not mutually exclusive. The new hypotheses
      represent a significant advance because they have the potential to resolve the
      remaining discrepancies. At this stage, alternative interpretations of the data
      are possible.

PMID- 12430799
TI  - Performance of an underwater acoustic volume array using time-reversal focusing.
AB  - Time reversal permits acoustic focusing and beam forming in inhomogeneous and/or
      high-scattering environments. A volumetric array geometry can suppress back lobes
      and can fit a large, powerful array of elements into small spaces, like the free
      water spaces on submarines. This research investigates applying the time-reversal
      method to an underwater acoustic volume array. The experiments evaluate the
      focusing performance of a 27-element volume array when different scattering
      structures are present within the volume of the array. The array is arranged in a
      3x3x3 cubic matrix configuration with 18.75-cm vertical and horizontal element
      spacing. The system utilizes second-derivative Gaussian pulses to focus on a
      point 30 cm from the array. Results include a comparison between time-reversal
      focusing and standard focusing, an evaluation of the volume array's ability to
      suppress back lobes, and an analysis of how different scattering environments
      affect focal region size. Potential underwater applications for a volume array
      using time reversal include acoustic imaging, naval mine hunting, sonar, and
      underwater communications.

PMID- 12430800
TI  - Source localization in a time-varying ocean waveguide.
AB  - One of the most stringent impairments in matched-field processing is the impact
      of missing or erroneous environmental information on the final source location
      estimate. This problem is known in the literature as model mismatch and is
      strongly frequency dependent. Another unavoidable factor that contributes to
      model mismatch is the natural time and spatial variability of the ocean
      waveguide. As a consequence, most of the experimental results obtained to date
      focus on short source-receiver ranges (usually <5 km), stationary sources,
      reduced time windows and frequencies generally below 600 Hz. This paper shows
      that MFP source localization can be made robust to time-space environmental
      mismatch if the parameters responsible for the mismatch are clearly identified,
      properly modeled and (time-)adaptively estimated by a focalization procedure
      prior to MFP source localization. The data acquired during the ADVENT'99 sea
      trial at 2, 5, and 10 km source-receiver ranges and in two frequency bands, below
      and above 600 Hz, provided an excellent opportunity to test the proposed
      techniques. The results indicate that an adequate parametrization of the
      waveguide is effective up to 10 km range in both frequency bands achieving a
      precise localization during the whole recording of the 5 km track, and most of
      the 10 km track. It is shown that the increasing MFP dependence on erroneous
      environmental information in the higher frequency and at longer ranges can only
      be accounted for by including a time dependent modeling of the water column sound
      speed profile.

PMID- 12430801
TI  - Necessary conditions for a maximum likelihood estimate to become asymptotically
      unbiased and attain the Cramer-Rao lower bound. II. Range and depth localization
      of a sound source in an ocean waveguide.
AB  - Analytic expressions for the first order bias and second order covariance of a
      maximum-likelihood estimate (MLE) are applied to the problem of localizing an
      acoustic source in range and depth in a shallow water waveguide with a vertical
      hydrophone array. These expressions are then used to determine necessary
      conditions on sample size, or equivalently signal-to-noise ratio (SNR), for the
      localization MLE to become asymptotically unbiased and attain minimum variance as
      expressed by the Cramer-Rao lower bound (CRLB). These analytic expressions can be
      applied in a similar fashion to any ocean-acoustic inverse problem involving
      random data. Both deterministic and completely randomized signals embedded in
      independent and additive waveguide noise are investigated. As the energy ratio of
      received signal to additive noise (SANR) descends to the lower operational range
      of a typical passive localization system, source range and depth estimates
      exhibit significant biases and have variances that can exceed the CRLB by orders
      of magnitude. The spatial structure of the bias suggests that acoustic range and
      depth estimates tend to converge around particular range and depth cells for
      moderate SANR values.

PMID- 12430802
TI  - Sound propagation in concentrated emulsions: comparison of coupled phase model
      and core-shell model.
AB  - The predictions of two models of sound propagation in concentrated emulsions are
      compared with experimental measurements of ultrasonic velocity and attenuation in
      emulsions with volume fractions up to 0.7. The core-shell model includes
      irreversible heat transfer, viscoinertial forces, and multiple scattering
      [McClements et al., J. Acoust. Soc. Am. 105, 915-918 (1999)]. This model accounts
      for the effect of thermal interactions between neighboring particles by
      introducing an effective medium, and is valid for all volume fractions. The
      coupled phase model includes irreversible heat transfer and viscoinertial forces,
      and also is valid for all volume fractions, since it is derived from volume
      averaged balance equations [J. M. Evans and K. Attenborough, J. Acoust. Soc. Am.
      102, 278-282 (1997)]. This model has a significantly simpler formulation than the
      core-shell model and does not require the assumption of an effective medium. The
      coupled phase model is shown to be a good approximation to the core-shell model
      when the acoustic radius is small. Despite the fact that it does not include
      thermal interactions, the coupled phase model is shown to give at least as good
      agreement as the core-shell model with the experimental data, for all volume
      fractions, as long as the acoustic radius is less than 0.01.

PMID- 12430803
TI  - Two-frequency driven single-bubble sonoluminescence.
AB  - Sonoluminescing single bubbles driven simultaneously by two harmonic frequencies
      were recently reported to increase the maximum light output up to a factor of 3
      with respect to single mode excitation. In this paper, experimental and numerical
      results on single-bubble sonoluminescence (SBSL) in an air/water system using the
      fundamental mode of 25 kHz and the second harmonic at 50 kHz are presented. The
      region of light emission is mapped in the three-dimensional parameter space
      spanned by the two driving pressure amplitudes and their relative phase. Good
      agreement was seen between measured light output, maximum bubble radius, and
      stability boundaries and the numerical model which is based on spherical bubble
      oscillations regarding diffusive and shape stability. The maximum brightness was
      enhanced by a factor up to 2.5 with respect to single mode SBSL. However, long
      term measurements reveal great variation of the emission at fundamental mode
      driven SBSL and of the boost factor reached with two frequencies. The overall
      brightness maxima of both excitation methods within a period of several hours
      turn out to show little difference.

PMID- 12430804
TI  - The time-dependent magneto-visco-elastic behavior of a magnetostrictive fiber
      actuated viscoelastic polymer matrix composite.
AB  - The paper develops a one-dimensional magneto-elastic model of a magnetostrictive
      fiber actuated polymer matrix composite material which accounts for a strong
      viscoelastic response in the polymer matrix. The viscoelastic behavior of the
      composite polymer matrix is modeled with a three parallel Maxwell element
      viscoelastic model, the magnetoelastic behavior of the composite fibers is
      modeled with an anhysteric directional potential based domain occupation theory.
      Example calculations are performed to identify and explain the dynamical behavior
      of the composite. These calculations assume that a constant stress and the
      oscillating magnetic field are applied in the fiber longitudinal direction. The
      inclusion of matrix viscosity results in an apparent hysteresis loop in the
      magnetization and magnetostriction curves even though the model does not include
      magnetoelastic hysteresis in the fibers. The apparent hysteresis is a consequence
      of the interaction of the time varying fiber stress caused by matrix viscosity
      with a multidomain state in the fiber. The small increase in fiber longitudinal
      compressive stress due to matrix viscosity under increasing field inhibits the
      occupation of domains with magnetization orientations near the fiber longitudinal
      [112] direction. As a consequence, the summed longitudinal magnetization and
      magnetostriction is reduced as compared to the decreasing field limb.

PMID- 12430805
TI  - Micromechanical modeling of viscoelastic voided composites in the low-frequency
      approximation.
AB  - The self-consistent model of Cherkaoui et al. [J. Eng. Mater. Technol. 116, 274
      278 (1994)] is used to compute the effective material moduli of a viscoelastic
      material containing coated spherical inclusions. Losses are taken into account by
      introducing the frequency-dependent, complex shear modulus of the viscoelastic
      matrix. Mode conversion appears through the localization tensors that govern the
      micromechanical behavior near the inclusions. The results are compared with the
      scattering model and the data of Baird et al. [J. Acoust. Soc. Am. 105, 1527-1538
      (1999)]. The two models are in good agreement. The advantage of the self
      consistent model is that it is applicable to the case of nonspherical inclusions
      embedded in anisotropic materials.

PMID- 12430806
TI  - Optimal design of panel speaker array with omnidirectional characteristics.
AB  - A panel speaker system intended for a projection screen is developed. Like other
      sound sources with large dimension, the panel speaker has a beaming problem in
      high frequencies. To alleviate the problem, panel speakers are integrated into an
      array, with optimal electronic compensation for omnidirectional response and
      array efficiency. The heart of the design procedure is a three-stage optimization
      scheme involving two nonlinear and nonconvex objectives. The process is
      interactive, allowing the array coefficients to be tailored so that the
      specifications of directional response can be met. The optimal design of panel
      speaker array is then implemented by using a multichannel digital signal
      processor. In addition, a Hilbert transformer is required to produce the
      quadrature components of the array coefficients. A small array and a large matrix
      were constructed to validate the implemented array signal processing system. The
      experimental results indicate that, without degradation of efficiency, the
      proposed optimization technique in conjunction with electronic compensation is
      effective in attaining omnidirectional radiation property.

PMID- 12430807
TI  - Analysis of axially polarized piezoelectric ceramic cylindrical shells of finite
      length with internal losses.
AB  - A thin shell analytical model of axially polarized piezoelectric ceramic
      cylinders with internal losses is presented. The Flugge assumptions for strain
      displacement relations, Hamilton's principle extended to piezoelectric shells,
      and the assumption that electric potential has a quadratic variation between the
      curved surfaces, are used to derive displacement-potential relations that are
      similar to equations of motion of elastic shells. A solution, with 12
      coefficients, to these relations is then derived. The coefficients are complex
      when the shell has internal losses and are determined by using three mechanical
      and three electrical boundary conditions at each end--on the flat surfaces.
      Computed values of input electrical admittance are presented for shells with and
      without internal losses, and for thin shells as well as shells with wall
      thickness comparable to the length. They are also compared with results obtained
      using the finite element program--ATILA. It is shown that the analytical values
      of resonance frequencies, the maximum value of input electrical conductance, and
      the maximum and minimum values of input electrical susceptance of thin shells are
      in excellent agreement with finite element results. The dependence of the maxima
      and minima in the complex input electrical admittance on the dimensions of the
      shell is inferred from the numerical results.

PMID- 12430808
TI  - Compressional and torsional wave amplitudes in rods with periodic structures.
AB  - To measure and detect elastic waves in metallic rods a low-frequency
      electromagnetic-acoustic transducer has been developed. Frequencies range from a
      few hertz up to hundreds of kilohertz. With appropriate configuration of the
      transducer, compressional or torsional waves can be selectively excited or
      detected. Although the transducer can be used in many different situations, it
      has been tested and applied to a locally periodic rod, which consists of a finite
      number of unit cells. The measured wave amplitudes are compared with theoretical
      ones, obtained with the one-dimensional transfer matrix method, and excellent
      agreement is obtained.

PMID- 12430809
TI  - Topology optimization of the kerf fillings in linear phased arrays for therapy.
AB  - Cross talk in ultrasonic arrays is an important problem that affects the array
      performance. For therapy arrays, cross talk decreases the acoustic power
      efficiency and array steering capabilities. Since arrays used for therapy are
      generally air-backed, structure-borne cross talk from the kerf fillings that
      connect the elements is predominant. In this paper, design strategies are
      developed to reduce the cross talk in linear phased arrays by optimizing the
      topology of kerf fillings. Two topology optimization schemes, an element-by
      element design and layer-by-layer design, are developed. Sequential linear
      programming is used to solve the nonlinear optimization problem. Using an array
      subset technique as the basis for the design, an objective function based on
      maximizing the normal velocity response of the wet surface of an electrically
      driven element is shown to improve both the power output and steering of the
      array.

PMID- 12430810
TI  - Microphone array measurement system for analysis of directional and spatial
      variations of sound fields.
AB  - A measurement system has been developed that is capable of analyzing the
      directional and spatial variations in a reverberant sound field. A spherical, 32
      element array of microphones is used to generate a narrow beam that is steered in
      60 directions. Using an omnidirectional loudspeaker as excitation, the sound
      pressure arriving from each steering direction is measured as a function of time,
      in the form of pressure impulse responses. By subsequent analysis of these
      responses, the variation of arriving energy with direction is studied. The
      directional diffusion and directivity index of the arriving sound can be
      computed, as can the energy decay rate in each direction. An analysis of the 32
      microphone responses themselves allows computation of the point-to-point
      variation of reverberation time and of sound pressure level, as well as the
      spatial cross-correlation coefficient, over the extent of the array. The system
      has been validated in simple sound fields in an anechoic chamber and in a
      reverberation chamber. The system characterizes these sound fields as expected,
      both quantitatively from the measures and qualitatively from plots of the
      arriving energy versus direction. It is anticipated that the system will be of
      value in evaluating the directional distribution of arriving energy and the
      degree and diffuseness of sound fields in rooms.

PMID- 12430811
TI  - Sweet spot size of virtual acoustic imaging systems at asymmetric listener
      locations.
AB  - Virtual acoustic imaging systems are effective when the listener's head location
      is close to the head location assumed when the system was designed. The "sweet
      spot" refers to the spatial bubble of head location in which the system is still
      effective. Some of the previous work investigating the "stereo dipole" acoustic
      imaging system shows that for the traditional on-axis listener location the
      "sweet spot" is about +/-5 cm for lateral head translations. Larger head
      movements than this require an update of the virtual acoustic imaging filters.
      The interest here is the "sweet spot" size at off-axis asymmetric listener
      locations or an understanding of how often one needs to update the filters to
      ensure the listener perceives a stable virtual image as they move. The
      examination of the off-axis "sweet spot" size comprises a theoretical acoustic
      analysis, computer simulations, and a subjective study. The simulations and
      subjective evaluation both demonstrate that the width of tolerable lateral head
      translations is comparable for the symmetric on-axis listener location and
      asymmetric listener locations that are as far as 25 cm off-axis.

PMID- 12430812
TI  - Fundamental frequency degeneracy of standing surface acoustic waves under
      metallic gratings on piezoelectric substrates.
AB  - The paper studies specific features of surface acoustic waves on piezoelectric
      substrates under infinite periodic grating arrays. The grating is made up of
      identical metallic electrodes of finite thickness and has one electrode per cell.
      It has been shown via the analysis of numerical algorithms and the coupling-of
      modes equations that one of the fundamental frequencies of the standing wave
      under short-circuited grating necessarily coincides with one of the fundamental
      frequencies corresponding to the open-circuited grating if the substrate assumes
      particular orientations connected with its crystallographic symmetry. The
      existence of degeneracy does not depend on the material constants of the
      substrate and the electrode, the thickness of the electrode, and the specific
      electrode shape provided that the electrode is uniform along the wave normal and
      shaped symmetrically in the same direction. The proof applies both to ordinary
      and leaky surface waves.

PMID- 12430813
TI  - Modal analysis of a drumlike silencer.
AB  - Low-frequency duct noise is difficult to deal with by passive methods such as
      porous duct lining. Reactive methods like expansion chamber are rather bulky,
      while compact resonators are too narrow banded. This study shows that a suitably
      stretched thin membrane backed by a slender cavity can achieve a satisfactory
      performance from low to medium frequencies over an octave band. The present paper
      focuses on the details of the modal behavior of the fully coupled membrane-cavity
      system, and examples are given with parameters set in a practical range.
      Typically, the membrane has a structure to air mass ratio of unity, and is
      stretched towards the elastic stress limit for a material like aluminum. The
      backing cavity has a depth equal to the duct height and a length five times the
      duct height. Three resonant peaks are found in the low to medium frequency range
      while the transmission loss between adjacent peaks remain above 10 dB. For the
      first peak, almost complete sound reflection occurs as a result of an out-of
      phase combination of the first and second in vacuo modes of simply supported
      membranes. The second peak is solely contributed to by the first mode, while the
      third peak features mainly the second mode vibration.

PMID- 12430814
TI  - Experimental studies of a drumlike silencer.
AB  - The theoretical finding of the broadband performance of a reactive silencer is
      validated experimentally. The silencer consists of two highly stretched membranes
      lining part of the duct and backed by two long and shallow cavities. The test rig
      was built with a small square duct of 5 cm in dimension, and each cavity is 5 cm
      deep and 25 cm long. Two types of metal foils, stainless steel and copper, were
      used, and the lowest membrane-to-air mass ratio was 1.3. A transmission loss in
      excess of 10 dB was achieved over more than one octave band. For one
      configuration close to the optimal parameters, the predicted ratio of the
      frequency band limits is 2.47, while the experiment gave 2.35. Three spectral
      peaks were found in the stopband, as predicted, but the peaks were broader than
      prediction, indicating the presence of significant sound energy dissipation
      mechanisms. Comparison with theoretical simulation shows that the cavity damping
      dominates over membrane friction. Tests using heavier membranes and membrane with
      different levels of tension also agree with predictions. Issues of practical
      implementation of the concept as a flow-through silencer are also addressed.

PMID- 12430815
TI  - A jet engine noise measurement and prediction tool.
AB  - In this paper, the authors describe an innovative jet engine noise measurement
      and prediction tool. The tool measures sound-pressure levels and frequency
      spectra in the far field. In addition, the tool provides predicted results while
      the measurements are being made. The predictions are based on an existing
      computational fluid dynamics database coupled to an empirical acoustic radiation
      model based on the far-field approximation to the Lighthill acoustic analogy.
      Preliminary tests of this acoustic measurement and prediction tool produced very
      encouraging results.

PMID- 12430816
TI  - Sweep-spread carrier for underwater communication over acoustic channels with
      strong multipath propagation.
AB  - Multipath propagation causes the transmitted signal to take numerous, time
      varying different-length paths to the receiver. Exploitation of conventional
      frequency-constant carrier signals for communication over underwater acoustic
      channels typically shows that intricate mutual time variations of multipath
      arrivals create an extremely hard problem for equalizers to compensate for
      nonstable intersymbol interactions. Communication over such channels can be,
      however, substantially improved by using a new method based on the implementation
      of a sweep-spread carrier (S2C). Such a carrier consists of a succession of
      sweeps, which cause permanent rapid fluctuation of signal frequency. Apart from
      some additional useful effects such as providing multiuser access and reducing
      influence of narrow-band noise, the method provides significant processing
      improvement enabling clear separation of multipath arrivals by converting their
      time delays into their frequency reallocations--the steeper the sweeps, the
      better the multipath resolution that can be achieved. When converting the signal
      into constant intermediate frequencies, the best suitable multipath arrival can
      be separated not as traditionally in time domains, applying complex equalizers,
      but in frequency domains by means of usual band-pass filters. High transmission
      stability of this approach was confirmed in both computer simulations as well as
      in validation experiments carried out since summer 1999.

PMID- 12430817
TI  - Approximating the head-related transfer function using simple geometric models of
      the head and torso.
AB  - The head-related transfer function (HRTF) for distant sources is a complicated
      function of azimuth, elevation and frequency. This paper presents simple
      geometric models of the head and torso that provide insight into its low
      frequency behavior, especially at low elevations. The head-and-torso models are
      obtained by adding both spherical and ellipsoidal models of the torso to a
      classical spherical-head model. Two different numerical techniques--multipole
      reexpansion and boundary element methods--are used to compute the HRTF of the
      models in both the frequency domain and the time domain. These computed HRTFs
      quantify the characteristics of elevation-dependent torso reflections for sources
      above the torso-shadow cone, and reveal the qualitatively different effects of
      torso shadow for sources within the torso-shadow cone. These effects include a
      torso bright spot that is prominent for the spherical torso, and significant
      attenuation of frequencies above 1 kHz in a range of elevations. Both torso
      reflections and torso shadow provide potentially significant elevation cues.
      Comparisons of the model HRTF with acoustic measurements in the horizontal,
      median, and frontal planes confirm the basic validity of the computational
      methods and establish that the geometric models provide good approximations of
      the HRTF for the KEMAR mannequin with its pinnae removed.

PMID- 12430818
TI  - Optimizing the acquisition time of the middle latency response using maximum
      length sequences and chirps.
AB  - The middle latency response (MLR) may be used as an indicator of anesthetic depth
      but has been criticized due to its long acquisition time. This study explores
      methods for optimizing recording of the MLR to maximize signal-to-noise ratio
      (SNR) and hence reduce acquisition time. The first experiment investigates the
      effects of increasing stimulation rate beyond conventional values and also using
      higher rates by means of maximum length sequences (MLS). The second experiment
      compares the use of click and chirp stimuli to elicit the MLR, both at
      conventional and MLS stimulation rates. For all conditions total recording
      duration is fixed at 185 s and stimulation level is fixed at 60 dB SL. It was
      found that SNR increases progressively with rate using conventional click
      stimulation until the theoretical rate limit is reached at the reciprocal of the
      response duration. The SNR improvement is equivalent to increasing test speed by
      a factor of 3. Using MLS stimulation, the SNR increases further until a maximum
      is reached at a rate of 167 clicks/s, equivalent to a fivefold test speed
      improvement relative to a conventional recording at 5 clicks/s. The use of chirp
      stimuli designed to compensate for the frequency dependent cochlear traveling
      wave delay produces an increase in wave V-Na amplitude at all recording rates.
      For the later latency waves of the response an increase in amplitude is seen for
      MLS, but not for conventional chirp trains. The optimum SNR was obtained using
      chirp stimuli at a MLS rate of 167 opportunities/s. It is concluded that the
      combination of chirps and MLS can reduce acquisition time to less than one-tenth
      of that required for conventional stimulation at 5 clicks/s for the same SNR.
      This would confer material benefits for estimating anesthetic depth using MLR.

PMID- 12430819
TI  - Primitive stream segregation of tone sequences without differences in fundamental
      frequency or passband.
AB  - Peripheral-channeling theorists argue that differences in excitation pattern
      between successive sounds are necessary for stream segregation to occur. The
      component phases of complex tones comprising unresolved harmonics (F0=100 Hz)
      were manipulated to change pitch and timbre without changing the power spectrum.
      In experiment 1, listeners compared two alternating sequences of tones, A and B.
      One sequence was isochronous (tone duration=60 ms, intertone interval=40 ms). The
      other began isochronously, but the progressive delay of tone B made the rhythm
      irregular. Subjects had to identify the sequence with irregular rhythm. Stream
      segregation makes this task more difficult. A and B could differ in passband
      (1250-2500 Hz, 1768-3536 Hz, 2500-5000 Hz), component phase (cosine, alternating,
      random), or both. Stimuli were presented at 70 dB SPL in pink noise.
      Dissimilarity in either passband or phase increased discrimination thresholds.
      Moreover, phase differences raised threshold even when there was no passband
      difference. In experiment 2, listeners judged moment-by-moment the grouping of
      long ABA-ABA-... sequences. The measure was the proportion of time a sequence was
      heard as segregated. The factors that increased segregation were very similar to
      those that increased threshold in experiment 1. Overall, the findings indicate
      that substantial stream segregation can occur without differences in power
      spectrum. It is concluded that differences in peripheral channeling are not a
      requirement for stream segregation.

PMID- 12430820
TI  - The effect of spatial separation on informational and energetic masking of
      speech.
AB  - The effect of spatial separation of sources on the masking of a speech signal was
      investigated for three types of maskers, ranging from energetic to informational.
      Normal-hearing listeners performed a closed-set speech identification task in the
      presence of a masker at various signal-to-noise ratios. Stimuli were presented in
      a quiet sound field. The signal was played from 0 degrees azimuth and a masker
      was played either from the same location or from 90 degrees to the right. Signals
      and maskers were derived from sentences that were preprocessed by a modified
      cochlear-implant simulation program that filtered each sentence into 15 frequency
      bands, extracted the envelopes from each band, and used these envelopes to
      modulate pure tones at the center frequencies of the bands. In each trial, the
      signal was generated by summing together eight randomly selected frequency bands
      from the preprocessed signal sentence. Three maskers were derived from the
      preprocessed masker sentences: (1) different-band sentence, which was generated
      by summing together six randomly selected frequency bands out of the seven bands
      not present in the signal (resulting in primarily informational masking); (2)
      different-band noise, which was generated by convolving the different-band
      sentence with Gaussian noise; and (3) same-band noise, which was generated by
      summing the same eight bands from the preprocessed masker sentence that were used
      in the signal sentence and convolving the result with Gaussian noise (resulting
      in primarily energetic masking). Results revealed that in the different-band
      sentence masker, the effect of spatial separation averaged 18 dB (at 51%
      correct), while in the different-band and same-band noise maskers the effect was
      less than 10 dB. These results suggest that, in these conditions, the advantage
      due to spatial separation of sources is greater for informational masking than
      for energetic masking.

PMID- 12430821
TI  - Tests of a within-channel account of comodulation detection differences.
AB  - The threshold for detecting a narrow-band noise signal in one or more masking
      noise bands is higher when the signal and masker bands have the same envelope
      (correlated condition) than when they have independent envelopes (uncorrelated
      condition). This comodulation detection difference (CDD) might be caused by
      perceptual grouping of the signal and masker bands when they are correlated.
      Alternatively, CDD may occur because, in the uncorrelated condition, the signal
      can be detected in the dips of the masker. A previous paper [S. J. Borrill and B.
      C. J. Moore, J. Acoust. Soc. Am. 111, 309-319 (2002)] described results and a
      model supporting a dip-listening explanation. The model predicted steeper
      psychometric functions for the correlated than for the uncorrelated condition, a
      prediction confirmed by experiment 1. In experiment 2, the width of the signal
      and masker bands was varied. The dip-listening model predicts a small decrease in
      CDD with increasing bandwidth, while an account based on perceptual grouping
      predicts a substantial decrease, as across-channel sensitivity to envelope
      disparity decreases with increasing envelope modulation rate. The CDD was
      independent of bandwidth. Experiment 3 showed no effect of masker-signal onset
      asynchrony on CDD, even though asynchrony should reduce perceptual grouping. An
      explanation of CDD is proposed based on the suppression that has been observed in
      cochlear mechanics and in the auditory nerve.

PMID- 12430822
TI  - Direct-to-reverberant energy ratio sensitivity.
AB  - Although the ratio of direct-to-reverberant sound energy is known to be an
      important acoustic cue to sound source distance, human sensitivity to changes in
      this cue is largely unknown. Here, direct-to-reverberant energy discrimination
      thresholds were measured for six listeners using virtual sound source techniques
      that allow for convenient and precise control of this stimulus parameter. Four
      different types of source stimuli were tested: a 50 ms noise burst with abrupt
      onset/offset, a 300 ms duration noise burst with gradual onset/offset, a speech
      syllable, and an impulse. Over a range of direct-to-reverberant ratios from 0 to
      20 dB, an adaptive 2AFC procedure (3-down, 1-up) was used to measure
      discrimination thresholds. For all stimuli, these thresholds ranged from 5 to 6
      dB. A post hoc fitting procedure confirmed that slopes of the psychometric
      functions were homogeneous across stimulus conditions and listeners. These
      threshold results suggest that direct-to-reverberant energy ratio by itself
      provides only a course coding of sound source distance, because threshold values
      correspond to greater than 2-fold changes in physical distance for the acoustic
      environment under examination.

PMID- 12430823
TI  - A broadband tactile array on the fingertip.
AB  - A stimulator array is described which can deliver a wide range of displacement
      waveforms from each contactor, allowing vibratory stimuli to be targeted towards
      different populations of mechanoreceptors in the skin. The array has a working
      bandwidth of 20-400 Hz and 100 moving contactors covering an area of 1 cm2 on the
      fingertip. The array was validated with two experiments on the perception of
      moving vibratory targets within a uniform background vibration. In the first
      experiment, with target and background at the same frequency, equivalent
      discrimination of target movement was obtained at higher values of
      target/background amplitude ratio for 40-Hz stimuli than for 320-Hz stimuli. In
      the second experiment, discrimination of target movement within a different
      frequency background (320-Hz target and 40-Hz background, or vice versa) was
      found to be much easier than within a same-frequency background. These results
      suggest that tactile spatial acuity is better at 320 Hz than 40 Hz and that it is
      possible to target different receptor populations in the skin by using these
      frequencies. However, there are problems with this interpretation: on the basis
      of characterization of touch receptors in previous studies, spatial acuity is
      expected to be worse at 320 Hz than at 40 Hz.

PMID- 12430824
TI  - Chaotic vibration induced by turbulent noise in a two-mass model of vocal folds.
AB  - The contribution of turbulent noise was modeled in symmetric vocal folds. A two
      mass model was used to simulate irregular vocal fold vibrations. The threshold
      values of system parameters to produce irregular vibrations were decreased as a
      result of turbulent airflow. Periodic vibrations were then driven into the
      regions of irregular vibrations. Using nonlinear dynamics including Poincare map
      and Lyapunov exponents, irregular vibrations were demonstrated as chaos. For the
      deterministic vocal-fold model with noise free and steady airflow, a fine period
      doubling bifurcation cascade was shown in a bifurcation diagram. However,
      turbulent noise added to the vocal-fold model would induce chaotic vibrations,
      broaden the regions of irregular vocal fold vibrations, and inhibit the fine
      period-doubling bifurcations in the bifurcation diagrams. The perturbations from
      neurological and biomechanical effects were simulated as a random variation of
      the vocal fold stiffness. Turbulent noise as an external random source, as well
      as random stiffness perturbation as an internal random source, played important
      roles in the presence of irregular vocal fold vibrations.

PMID- 12430825
TI  - Computational aeroacoustics of phonation, part I: Computational methods and sound
      generation mechanisms.
AB  - The aerodynamic generation of sound during phonation was studied using direct
      numerical simulations of the airflow and the sound field in a rigid pipe with a
      modulated orifice. Forced oscillations with an imposed wall motion were
      considered, neglecting fluid-structure interactions. The compressible, two
      dimensional, axisymmetric form of the Navier-Stokes equations were numerically
      integrated using highly accurate finite difference methods. A moving grid was
      used to model the effects of the moving walls. The geometry and flow conditions
      were selected to approximate the flow within an idealized human glottis and vocal
      tract during phonation. Direct simulations of the flow and farfield sound were
      performed for several wall motion programs, and flow conditions. An acoustic
      analogy based on the Ffowcs Williams-Hawkings equation was then used to decompose
      the acoustic source into its monopole, dipole, and quadrupole contributions for
      analysis. The predictions of the farfield acoustic pressure using the acoustic
      analogy were in excellent agreement with results from the direct numerical
      simulations. It was found that the dominant sound production mechanism was a
      dipole induced by the net force exerted by the surfaces of the glottis walls on
      the fluid along the direction of sound wave propagation. A monopole mechanism,
      specifically sound from the volume of fluid displaced by the wall motion, was
      found to be comparatively weak at the frequency considered (125 Hz). The orifice
      geometry was found to have only a weak influence on the amplitude of the radiated
      sound.

PMID- 12430826
TI  - Computational aeroacoustics of phonation, part II: Effects of flow parameters and
      ventricular folds.
AB  - The results are described of the second part of an ongoing study aimed at
      performing direct numerical simulations of translaryngeal flows during phonation.
      The use of accurate numerical schemes allows the radiated sound to be calculated
      directly, without the need for acoustic analogy models. The goal is to develop a
      better understanding of this class of flow, and of the basic sound generation
      mechanisms involved in phonation. In the present study, the effects of subglottal
      pressure and of glottal oscillation frequency on the near-field flow and farfield
      sound were investigated. The effects of the presence of the ventricular folds
      downstream of the oscillating glottal region were also examined. The results
      highlighted the effects of subglottal pressure and oscillation frequency on the
      jet vortical structure, wall pressure and shear stress, and sound radiation. Jet
      impingement on the ventricular folds introduced additional dipole sources similar
      to those observed in problems involving grazing flows over cavities.

PMID- 12430827
TI  - Spectral and temporal cues to pitch in noise-excited vocoder simulations of
      continuous-interleaved-sampling cochlear implants.
AB  - Four-band and single-band noise-excited vocoders were used in acoustic
      simulations to investigate spectral and temporal cues to melodic pitch in the
      output of a cochlear implant speech processor. Noise carriers were modulated by
      amplitude envelopes extracted by half-wave rectification and low-pass filtering
      at 32 or 400 Hz. The four-band, but not the single-band processors, may preserve
      spectral correlates of fundamental frequency (F0). Envelope smoothing at 400 Hz
      preserves temporal correlates of F0, which are eliminated with 32-Hz smoothing.
      Inputs to the processors were sawtooth frequency glides, in which spectral
      variation is completely determined by F0, or synthetic diphthongal vowel glides,
      whose spectral shape is dominated by varying formant resonances. Normal listeners
      labeled the direction of pitch movement of the processed stimuli. For processed
      sawtooth waves, purely temporal cues led to decreasing performance with
      increasing F0. With purely spectral cues, performance was above chance despite
      the limited spectral resolution of the processors. For processed diphthongs,
      performance with purely spectral cues was at chance, showing that spectral
      envelope changes due to formant movement obscured spectral cues to F0.
      Performance with temporal cues was poorer for diphthongs than for sawtooths, with
      very limited discrimination at higher F0. These data suggest that, for speech
      signals through a typical cochlear implant processor, spectral cues to pitch are
      likely to have limited utility, while temporal envelope cues may be useful only
      at low F0.

PMID- 12430828
TI  - Investigating alternative forms of clear speech: the effects of speaking rate and
      speaking mode on intelligibility.
AB  - Sentences spoken "clearly" (and slowly) are significantly more intelligible than
      those spoken "conversationally" for hearing-impaired listeners in a variety of
      backgrounds [Picheny, Durlach, and Braida, J. Speech Hear. Res. 28, 96-103
      (1985); Uchanski et al., J. Speech Hear. Res. 39, 494-509 (1996); Payton,
      Uchanski, and Braida, J. Acoust. Soc. Am. 95, 1581-1592 (1994)]. However, it is
      unknown whether slower speaking rates are necessary for highly intelligible
      speech or whether an alternative form of clear speech exists at faster (i.e.,
      normal) rates. To investigate this question, talkers with significant public
      speaking experience were asked to produce clear and conversational speech at
      slow, normal, and quick rates. A method for eliciting clear speech was introduced
      that ensured the clearest possible speech was obtained at each of these speaking
      rates. To probe for other highly intelligible speaking modes, talkers also
      recorded sentences in two other speaking modes: soft and loud. Intelligibility
      tests indicated that clear speech was the only speaking mode that provided a
      consistent intelligibility advantage over conversational speech. Moreover, the
      advantage of clear speech was extended to faster speaking rates than previously
      reported. These results suggest that clear speech has some inherent acoustic
      properties that contribute to its high intelligibility without altering rate.
      Identifying these acoustic properties could lead to improved signal-processing
      schemes for hearing aids.

PMID- 12430829
TI  - Underwater audiogram of a Pacific walrus (Odobenus rosmarus divergens) measured
      with narrow-band frequency-modulated signals.
AB  - The underwater hearing sensitivity of an 18-year-old male Pacific walrus was
      measured in a pool by using a go/no-go response paradigm and the up-down
      staircase method. Auditory sensitivity was measured using narrow-band, frequency
      modulated signals (1500 ms duration) with center frequencies ranging from 0.125
      to 15 kHz. The resulting underwater audiogram (50% detection thresholds) for this
      individual walrus shows the typical mammalian U-shape. Maximum sensitivity (67 dB
      re 1 microPa) occurred at 12 kHz. The range of best hearing (10 dB from the
      maximum sensitivity) was from 1 to 12 kHz. Sensitivity fell gradually below 1 kHz
      and dropped off sharply above 12 kHz. The animal showed a peculiar insensitivity
      for 2 kHz signals. His much higher sensitivity for 1.5- and 3-kHz signals
      indicated that this is a narrow-band phenomenon. Walrus hearing is relatively
      sensitive to low frequency sound, thus the species is likely to be susceptible to
      anthropogenic noise. The thresholds found during a small test with four
      frequencies with signal durations of 300 ms did not differ significantly from
      those obtained with signal durations of 1500 ms.

PMID- 12430830
TI  - The magnitude of radiation force on ultrasound contrast agents.
AB  - High-speed photography of insonified bubbles with a time resolution of 10 ns
      allows observations of translation due to radiation force, in addition to the
      visualization of radial oscillations. A modified version of the Rayleigh-Plesset
      equation is used to estimate the radius-time behavior of insonified microbubbles,
      and the accuracy of this model is verified experimentally. The translation of
      insonified microbubbles is calculated using a differential equation relating the
      acceleration of the bubble to the forces due to acoustic radiation and the drag
      imposed by the fluid. Simulations and experiments indicate that microbubbles
      translate significant distances with clinically relevant parameters. A 1.5 micron
      radius contrast agent can translate over 5 microns during a single 20-cycle, 2.25
      MHz, 380 kPa acoustic pulse, achieving velocities over 0.5 m/s. Therefore,
      radiation force should be considered during an ultrasonic examination because of
      the possibility of influencing the position and flow velocity of the contrast
      agents with the interrogating acoustic beam.

PMID- 12430831
TI  - Causal capture: contextual effects on the perception of collision events.
AB  - In addition to perceiving the colors, shapes, and motions of objects, observers
      can perceive higher-level properties of visual events. One such property is
      causation, as when an observer sees one object cause another object to move by
      colliding with it. We report a striking new type of contextual effect on the
      perception of such collision events. Consider an object (A) that moves toward a
      stationary object (B) until they are adjacent, at which point A stops and B
      starts moving along the same path. Such "launches" are perceived in terms beyond
      these kinematics: As noted in Michotte's classic studies, observers perceive A as
      being the cause of B's motion. When A and B fully overlap before B's motion,
      however observers often see this test event as a completely noncausal "pass": One
      object remains stationary while another passes over it. When a distinct launch
      event occurs nearby, however, the test event is "captured": It too is now
      irresistibly seen as causal. For this causal capture to occur, the context event
      need be present for only 50 ms surrounding the "impact," but capture is destroyed
      by only 200 ms of temporal asynchrony between the two events. We report a study
      of such cases, and others, that help define the rules that the visual system uses
      to construct percepts of seemingly high-level properties like causation.

PMID- 12430832
TI  - Evidence for attentional capture by a surprising color singleton in visual
      search.
AB  - Three experiments were conducted to investigate whether surprising color
      singletons capture attention. Participants performed a visual search task in
      which a target letter had to be detected among distractor letters. Experiments 1
      and 2 assessed accuracy as the dependent variable. In Experiment 1, the
      unannounced presentation of a color singleton 500 ms prior to the letters (and in
      the same position as the target letter) resulted in better performance than in
      the preceding conjunction search segment, in which no singleton was presented,
      and performance was as good in this surprise-singleton trial as in the following
      feature search segment, in which the singleton always coincided with the target.
      In contrast, no improvement was observed when the color singleton was presented
      simultaneously with the letters in Experiment 2, indicating that attentional
      capture occurred later in the surprise trial than in the feature search segment.
      In Experiment 3, set size was varied, and reaction time was the dependent
      variable. Reaction time depended on set size in the conjunction search segment,
      but not in the surprise trial nor in the feature search segment. The results of
      the three experiments support the view that surprising color singletons capture
      attention independently of a corresponding attentional set.

PMID- 12430833
TI  - Color naming and the phototoxic effects of sunlight on the eye.
AB  - Many languages have no basic color term for "blue." Instead, they call short
      wavelength stimuli "green" or "dark". We show that this cultural, linguistic
      phenomenon could result from accelerated aging of the eye because of high,
      chronic exposure to ultraviolet-B (UV-B) in sunlight (e.g., phototoxic lens
      brunescence). Reviewing 203 world languages, we found a significant relationship
      between UV dosage and color naming: In low-UV localities, languages generally
      have the word "blue"; in high-UV areas, languages without "blue" prevail.
      Furthermore, speakers of these non-"blue" languages often show blue-yellow color
      vision deficiency. We tested our phototoxicity hypothesis in a color-naming
      experiment, using computerized, colorimetric simulations of Munsell colors as
      viewed through clear and brunescent lenses. As predicted, our young subjects used
      "blue" as in English when the simulated lens was clear, but named colors as in
      tropical languages when the lens was dense. Our within-subjects design precludes
      a cultural explanation for this result.

PMID- 12430834
TI  - The automatic evaluation of novel stimuli.
AB  - From classic theory and research in psychology, we distill a broad theoretical
      statement that evaluative responding can be immediate, unintentional, implicit,
      stimulus based, and linked directly to approach and avoidance motives. This
      statement suggests that evaluative responses should be elicited by novel,
      nonrepresentational stimuli (e.g., abstract art, "foreign" words). We tested this
      hypothesis through combining the best features of relevant automatic-affect
      research paradigms. We first obtained explicit evaluative ratings of novel
      stimuli. From these, we selected normatively positive and negative stimuli to use
      as primes in a sequential priming paradigm. Two experiments using this paradigm
      demonstrated that briefly presented novel prime stimuli were evaluated
      automatically, as they facilitated responses to subsequently presented target
      stimuli of the same valence just as much as did pictures or names of real
      objects. A final experiment revealed that exposure to novel stimuli produces
      muscular predispositions to approach or avoid them.

PMID- 12430835
TI  - Probability cuing of target location facilitates visual search implicitly in
      normal participants and patients with hemispatial neglect.
AB  - We explored how variability in the probability of target locations affects visual
      search in normal individuals and in patients with hemispatial neglect, a deficit
      in attending to the contralesional side of space. Young and elderly normal
      participants responded faster when targets appeared in the more probable region
      than when targets appeared in the less probable region. Similarly, patients were
      sensitive to the distribution of targets, even in the neglected field. Although
      the attentional gradient that characterizes neglect was not eliminated, the
      response facilitation due to the probability distribution was proportionate to
      that of control participants and equal in magnitude across the neglected field.
      All participants exploited the uneven distribution of targets to enhance task
      performance without explicit instructions to do so or awareness of biases in
      their behavior. These results suggest that attentional orientation and
      sensitivity to external probabilities are possibly dissociable. An early sensory
      and a late motor mechanism are postulated as possibly being involved in the
      observed probability-matching behavior of participants.

PMID- 12430836
TI  - Thinking of critical words during study is unnecessary for false memory in the
      Deese, Roediger, and McDermott procedure.
AB  - Do participants in the Deese, Roediger, and McDermott (DRM) procedure demonstrate
      false memory because they think of nonpresented critical words during study and
      confuse them with words that were actually presented? In two experiments, 160
      participants studied eight visually presented DRM lists at a rate of 2 s or 5 s
      per word. Half of the participants rehearsed silently: the other half rehearsed
      overtly. Following study, the participants' memory for the lists was tested by
      recall or recognition. Typical false memory results were obtained for both memory
      measures. More important, two new results were observed. First, a large majority
      of the overt-rehearsal participants spontaneously rehearsed approximately half of
      the critical words during study. Second, critical-word rehearsal at study
      enhanced subsequent false recall, but it had no effect on false recognition or
      remember judgments for falsely recognized critical words. Thinking of critical
      words during study was unnecessary for producing false memory.

PMID- 12430837
TI  - Person perception across the menstrual cycle: hormonal influences on social
      cognitive functioning.
AB  - Women's reactions to men shift during the menstrual cycle. For example, during
      the phase of high conception risk, women prefer men with masculinized facial
      features. A favored explanation for this effect is that women display an enhanced
      sensitivity to stimuli that have significant reproductive relevance during the
      phase of the menstrual cycle in which conception risk is high. Consistent with
      this viewpoint, the present research demonstrated that women's cycle-dependent
      attentiveness to "maleness" also extends to basic aspects of the person
      perception process. Specifically, during the phase of high conception risk, women
      displayed an enhanced ability both to categorize men and to access associated
      category-related (i.e., stereotypic) material from semantic memory. The
      implications of these findings for contemporary treatments of person perception
      are considered.

PMID- 12430838
TI  - Late maturation of visual hyperacuity.
AB  - We used a visual evoked-potential measure to study the development of two
      components of pattern vision, vernier acuity and grating acuity, in humans from
      early infancy through adolescence. These two visual functions develop at similar
      rates and have nearly the same absolute values between 1 month and 6 years of
      age. After age 6, grating acuity is constant at the adult level, but vernier
      acuity continues to improve, becoming a hyperacuity. Vernier acuity reaches
      asymptotic levels around age 14 years. These results suggest that adultlike
      vernier hyperacuity is not limited by spatial resolution or sensitivity of small
      receptive fields, but rather that the limitation is imposed by higher-level
      processing. Sensitivity, connections in visual cortical areas, or both therefore
      retain plasticity throughout childhood and into adolescence.

PMID- 12430839
TI  - "Markov at the bat": a model of cognitive processing in baseball batters.
AB  - Anecdotal evidence from players and coaches indicates that cognitive processing
      (e.g., expectations about the upcoming pitch) plays an important role in
      successful baseball batting, yet this aspect of hitting has not been investigated
      in detail. The present study provides experimental evidence that prior
      expectations significantly influence the timing of a baseball swing. A two-state
      Markov model was used to predict the effects of pitch sequence and pitch count on
      batting performance. The model is a hitting strategy of switching between
      expectancy states using a simple set of transition rules. In a simulated batting
      experiment, the model provided a good fit to the hitting performance of 6
      experienced college baseball players, and the estimated model parameters were
      highly correlated with playing level.

PMID- 12430840
TI  - Synesthetic color experiences influence memory.
AB  - We describe the extraordinary memory of C, a 21-year-old student who experiences
      synesthetic colors (i.e., photisms) when she sees, hears, or thinks of digits.
      Using three matrices of 50 digits, we tested C and 7 nonsynesthetes to evaluate
      whether C's synesthetic photisms influence her memory for digits. One matrix
      consisted of black digits, whereas the other two matrices consisted of digits
      that were either incongruent or congruent with the colors of C's photisms. C's
      recall of the incongruently colored digits was considerably poorer than her
      recall of either the black or the congruently colored digits. The 7
      nonsynesthetes did not show such differences in their recall of the matrices. In
      addition, when immediate recall of the black digits was compared with delayed
      recall of those digits (48 hr), C showed no decrease in performance, whereas each
      of the nonsynesthetes showed a significant decrease. These findings both
      demonstrate C's extraordinary memory and show that her synesthetic photisms can
      influence her memory for digits.

PMID- 12430841
TI  - Trunk orientation induces neglect-like lateral biases in covert attention.
AB  - The purpose of this study was to resolve a paradox in the literature on the
      effects of body orientation on spatial attention. Neuropsychological studies have
      found that real or simulated trunk rotation relieves contralesional inattention
      in patients with unilateral neglect, suggesting that trunk orientation affects
      how attention is allocated to space. However in two previous studies, trunk
      orientation did not affect spatial attention in other populations. In this study
      we investigated the effects of trunk orientation on the performance of a covert
      attention task by neurologically intact adults. The covert attention task allowed
      the evaluation of the effects of trunk orientation on both the allocation of
      attention to space and the ability to shift that attention to new locations. As
      in previous research, trunk orientation did not affect participants' response
      times (RTs) to validly cued targets. However rotating participants' trunks to the
      left increased their RTs to invalidly cued targets on the right and decreased
      their RTs to invalidly cued targets on the left. These results indicate that
      trunk orientation induces directional biases in the ability to shift attention.
      Thus, for intact participants, trunk rotation created lateral biases in the
      covert attention task similar to those seen in neglect patients.

PMID- 12430842
TI  - Perceived discrimination in the context of multiple group memberships.
AB  - This study examined the joint impact of gender and ethnicity on expectations of
      general discrimination against oneself and one's group. According to the double
      jeopardy hypothesis, women of color will expect to experience more general
      discrimination than men of color, White women, and White men because they belong
      to both a low-status ethnic group and a low-status gender group. Alternatively,
      the ethnic-prominence hypothesis predicts that ethnic-minority women will not
      differ from ethnic-minority men in their expectations of general discrimination
      because these expectations will be influenced more by perceptions of ethnic
      discrimination, which they share with men of color, than by perceptions of gender
      discrimination. All results were consistent with the ethnic-prominence hypothesis
      rather than the double-jeopardy hypothesis.

PMID- 12430843
TI  - A quantitative trait locus not associated with cognitive ability in children: a
      failure to replicate.

PMID- 12430844
TI  - Stem cell repair in ischemic heart disease: an experimental model.
AB  - Bone marrow stem cells (BMSC) from adult mice are now believed to generate non
      hematopoietic cell types. This newly defined property is referred to as stem cell
      plasticity. We tested the potential of lineage negative c-kit positive (Lin- c
      kit+), GFP+ BMSC to differentiate into cardiac myocytes in myocardial infarcts
      produced by ligation of the left coronary artery. At 9 days post-transplant the
      hearts showed a band of developing GFP+ myocytes within the damaged myocardium.
      These GFP+ myocytes were positive for cardiac specific myosin and early expressed
      transcription factors. Endothelial cells and smooth muscle cells also developed
      from the donor bone marrow cells. Left ventricular end diastolic pressure (LVEDP)
      and left ventricular developed pressure (LVDP) were improved. Lin-c- kit- cells
      did not regenerate myocardium. We next tested the ability of cytokine-mobilized
      BMSC to regenerate myocardium. Nuclei in regenerating cardiomyocytes were
      positive for Csx/Nkx 2.5, GATA-4 and MEF2. Cytoplasmic proteins included desmin,
      nestin and connexin 43. Regenerating arterioles consisted of endothelial cells
      and smooth muscle cells positive for Ki67, and flkl. These regenerating vessels
      contained circulating TER119 positive red blood cells. Repair of infarcted
      myocardium resulted in improved heart function and survival. At day 27 after
      cytokine treatment and surgery, 11 of 15 mice survived compared with 9 of 52 non
      treated mice. Left ventricular ejection fraction in infarcted hearts in cytokine
      treated mice was 48%, 62% and 114% higher than the ejection fraction in non
      treated mice at 9, 16 and 26 days following coronary artery occlusion. These
      findings demonstrate that circulating autologous stem cells traffic to the
      ischemic, infarcted myocardium and undergo differentiation into cardiomyocytes
      and vascular structures. We conclude that adult BMSC have the potential for
      repair in acute, ischemic heart disease.

PMID- 12430845
TI  - Stem cell engineering: the new generation of cellular therapeutics.
AB  - Hematopoietic stem cells (HSCs) supply all blood cells throughout life by making
      use of their self-renewal and multilineage differentiation capabilities. Over the
      last few years, transplantation of hematopoietic stem and progenitor cells from
      mobilized blood stem cells, umbilical cord blood and selected CD34+ cells has
      been used for treatment of patients with hematologic and non-hematologic
      malignances. The techniques have become available that allow the extensive
      proliferation, orderly differentiation, functional activation and gene transfer
      of hematopoietic stem/progenitor cells in ex vivo culture systems. These
      techniques have now developed to the point at which clinical trials are now
      underway in a variety of settings for the applications of hematopoietic stem cell
      transplantation, hematopoietic support after high-dose chemotherapy,
      immunotherapy of cancers, and gene therapy. The article will discuss the
      characteristics, detecting assays, surface markers, expansion, orderly
      differentiation, cell therapy and gene therapy of hematopoietic stem/progenitor
      cells. Except that, it will also discuss some advanced achievements of stem cell
      research, such as the multilineage differentiation of marrow-derived mesenchymal
      stem cells. Some results of different gene expression between stem cells and
      induced cells by gene chip analysis will be reported.

PMID- 12430846
TI  - New strategies for BMT and organ transplantation.
AB  - Bone marrow transplantation (BMT) is now one of the most powerful strategies for
      the treatment of hematologic disorders (leukemia, aplastic anemia, etc),
      congenital immunodeficiencies, metabolic disorders, and also autoimmune diseases.
      Using various autoimmune-prone mice, we have previously shown that conventional
      allogeneic (allo) BMT can be used to treat a range of autoimmune diseases. We
      have very recently established new strategies for BMT and organ grafts. For BMT,
      to minimize the contamination of BMCs with T cells from the peripheral blood, we
      developed, using cynomolgus monkeys, a "Perfusion Method" to replace the
      conventional aspiration method for collecting bone marrow cells (BMCs). We
      injected the BMCs collected this way directly into the bone marrow cavity of
      recipients that had received fractionated irradiation (intra-bone marrow [IBM]
      injection). This "IBM-BMT" was found to be effective in treating autoimmune
      diseases in radiation-sensitive and chimeric-resistant MRL/lpr mice. in addition,
      this strategy was found to be applicable for the transplantation of organs, such
      as the skin and pancreas islets in mice and rats. We believe that these
      strategies for BMT and organ transplantation herald a new era in transplantation.

PMID- 12430848
TI  - Bone marrow transplantation for non-malignant disease.

PMID- 12430847
TI  - Haploidentical stem cell transplantation for acute leukemia.
AB  - PREMISE: Since March 1993, 133 patients with high-risk acute leukemia (66 AML, 67
      ALL) have received a megadose of T-cell depleted hematopoietic stem cells. The
      1993-95 conditioning protocol included TBI, thiotepa, ATG and CY for 36 patients
      who received an inoculum made up of lectin-separated bone marrow and PBPCs. After
      1995, to minimise the extra-hematological toxicity of the conditioning and
      eliminate GvHD, we substituted fludarabine for CY in the conditioning and PBPCs
      were depleted of T-cells by a positive selection of the CD34+ cells using CellPro
      (n=44 patients) or, since January 1999, CliniMacs (n = 53 patients). A later
      modification to the protocol in January 1999 was the suspension of post
      transplant G-CSF. WORK IN PROGRESS: We report here the results in the last 53
      acute leukemia patients all of whom were transplanted under our modified
      protocol. Ages ranged from 9 to 62 years with a median of 38 years for the 33
      patients with AML and 23 for the 20 with ALL. All were at high risk because 25
      were actually in relapse at transplant, 16 were in second or later CR and even
      the 12 patients in CR1 were at high risk because of the unfavourable prognostic
      features. Overall 52/53 patients (98%) engrafted. The TBI-Fludarabine-based
      conditioning was well tolerated even in the 14 patients between 45 and 62 years
      of age. There was no veno-occlusive disease of the liver and the incidence of
      severe mucositis was low. Even though no post-transplant immunosuppressive
      therapy was given, acute GvHD grade > or = II occurred in only 4 cases and only
      one progressed to chronic GvHD. Overall, 16 patients (30%) have died of non
      leukemic causes. Relapses occurred mainly in patients who were already in relapse
      at transplant (12/25). Only 3 of the 28 who were in any CR at transplant have so
      far relapsed. As our group has already shown, donor-vs-recipient NK cell
      alloreactivity exerts a specific graft-vs-AML effect in the absence of GvHD. In
      fact, leukemia relapse was largely controlled in AML recipients whose donor was
      NK alloreactive, with only 2 out of 16 relapsing. To date, 13 of 18 AML (72%) and
      5 of 10 ALL (50%) who were in any CR at transplant, survive disease-free while 4
      of the 15 patients (16%) in relapse at transplant survive. The probability of
      event-free survival for patients transplanted in CR is 60% in the 18 AML patients
      and 38% in the 10 ALL. The probability of EFS was significantly better in the 16
      AML patients whose transplant included donor vs recipient NK cell alloreactivity
      than in those whose transplant did not (70% vs 7%). In conclusion, given our
      current results, the most suitable candidate for the full haplotype mismatched
      transplant should be in early stage disease and selection of an NK alloreactive
      donor is recommended.

PMID- 12430849
TI  - Maternal-fetal relationship, natural chimerism and bilateral transplantation
      tolerance as the basis for non-myeloablative stem cell transplantation.
AB  - Bone marrow transplantation (BMT) which represents an important clinical tool for
      treatment of patients with a wide variety of malignant and non-malignant
      diseases, however, the procedure is associated with procedure-related toxicity
      and mortality as well as unavoidable late complications. Many of the undesirable
      consequences of BMT are caused directly or indirectly by the intensive
      conditioning administered during the pre-transplant period. However, if the main
      goal of the BMT procedure is to enable immunotherapy by alloreactive donor
      lymphocytes, the conditioning prior to BMT needs to be reconsidered, because
      transplantation tolerance across major histocompatibility complex (MHC) occurs
      spontaneously in nature, as evidenced by the fact that pregnant females do not
      reject their conceptus. In fact, as shown by Owens in the 1940s, placental
      parabiosis in utero leads to permanent mixed chimerism and bilateral
      transplantation tolerance. These observations followed by experiments carried out
      in the 1950s by Billingham et al. suggested that infusion of parental stem cells
      into neonates with no exogenous immunosuppressive treatment resulted in mixed
      chimerism and permanent transplantation tolerance to donor alloantigens. Thus, a
      window of opportunity provided shortly after delivery, was sufficient for
      induction of tolerance without the need for heavy conditioning. Tolerant
      recipients were shown to be chimeras with only a small proportion of donor cells.
      However, without corroborating evidence that transplantation tolerance could be
      intentionally induced, the approach could not be applied in clinical practice for
      immunocompetent recipients. Starting in 70s, we documented the feasibility of
      establishing bilateral transplantation tolerance by mixed chimerism following non
      myeloablative conditioning in immu. nologically mature recipients across MHC in
      mice, rats and dogs. Several studies have shown that reduced intensity
      conditioning can be very useful for immunoregulation whereas more intensive the
      pre-grafting immunosuppression resulted in more aggressive the GVHD. These and
      other findings suggested that lower intensity conditioning may be sufficient for
      engraftment of donor stem cells, thus suggesting that immunosuppression without
      myeloablation may be sufficient for prevention of allograft rejection. Following
      engraftment of donor stem cells, donor lymphocytes infused with bone marrow or
      mobilized blood stem cells can eradicate residual hematopoietic cells of host
      origin, occasionally non-hematopoietic tumor cells of host origin as well.
      Whenever indicated, donor lymphocytes infusion (DLI) can be used at a later stage
      post BMT to eradicate residual malignant cells of host origin or for the
      treatment of residual or recurrent disease. Taken together, ongoing clinical
      studies suggest that high-dose, myeloablative chemoradiotherapy, could be safely
      replaced with non-myeloablative conditioning (NST).

PMID- 12430850
TI  - Update on non-myeloablative stem cell transplantation for hematologic
      malignancies.
AB  - Allogeneic stem cell transplantation is an established treatment modality for a
      variety of hematologic malignancies. Unfortunately it carries a high risk of
      complications and toxicities related to the intensive preparative regimen which
      is traditionally used for pre-transplant myeloablation and the graft versus host
      disease, which may be life threatening. Thus allogeneic stem cell transplantation
      has been used only for younger patients with a good performance status, excluding
      many other potential candidates due to advanced age or comorbid conditions. Non
      ablative or reduced intensity preparative regimens for allogeneic stem cell
      transplantation (NST) have been proposed as a strategy that would allow
      exploiting the graft versus tumor effect of allogeneic transplantation without
      the toxicity of myeloablative therapy. After more than five years of cumulative
      clinical experience, it is now well established that NST is a feasible treatment
      option for patients with suboptimal performance status and is mostly effective in
      slow proliferating malignancies, which gives time for a graft versus malignancy
      effect to take place. Additionally achievement of stable donor cell engraftment
      with NSTs provides a platform for adoptive immune cell treatments and may allow
      to extend indications of stem cell transplantation in the future.

PMID- 12430851
TI  - Related and unrelated nonmyeloablative hematopoietic stem cell transplantation
      for malignant diseases.
AB  - Patients with advanced hematological malignancies ineligible for conventional
      myeloablative allogeneic hematopoietic stem cell transplantation (HSCT) due to
      advanced age or medical contraindications were enrolled in multi-center study to
      investigate the safety and efficacy of nonmyeloablative HSCT using a 2 Gy total
      body irradi ation (TBI)-based regimen. A total of 192 patients (median age 55)
      were treated with HLA-matched sibling peripheral blood stem cell (PBSC) grafts,
      and 63 patients (median age 53) received a 10 of 10 HLA-antigen matched unrelated
      donor (URD) HSCT (PBSC graft, n = 48; marrow graft, n = 15). Diagnoses included
      multiple myeloma (n = 61), myelodysplastic syndrome (n = 55), chronic myeloid
      leukemia (n = 31), non-Hodgkin lymphoma (n = 31), acute myeloid leukemia (n =
      28), chronic lymphocytic leukemia (n = 24), Hodgkin Disease (n = 14). The
      conditioning regimen was fludarabine 30 mg/m2/d x 3 days and 2 Gy TBI. Ninety
      five related HSCT patients received 2 Gy TBI without fludarabine. Postgrafting
      immunosuppression was combined mycophenolate mofetil an cyclosporine. Transplants
      were well tolerated with a median of 0 days of hospitalization in the first 60
      days for eligible patients. For related HSCT recipients, median follow-up was 289
      (100-1,188) days. Nonfatal graft rejection occurred in 6.8%. Of those with
      sustained engraftment, graft-versus-host disease (GVHD) occurred in 49% (33%
      grade II, 11% grade III, 5% grade IV). Day-100 non-relapse mortality was 6%.
      Overall, 59% (114/192) of patients were alive. The relapse/disease progression
      mortality was 18%, and non-relapse mortality was 22%. The projecte 2-year
      survival and progression-free survival were 50% and 40%. For the URD HSCT
      recipients, median follow-up was 190 (100-468) days. Graft rejection occurred in
      27% (17/63) of patients, mostly in recipients of marrow grafts (9/15). Acute GVHD
      occurred in 63% (50% grade II, 13% grade III) of 46 engrafted patients. Chronic
      GVHD requiring therapy occurred in 50% of patients. Of the 63 URD HSCT patients,
      54% were alive, 37% in CR, 3% PR, and 14% with disease progression or relapse.
      Related and unrelated nonmyeloablative HSCT is feasible and potentially curative
      in patients with advanced hematological malignancies who have no other treatment
      options.

PMID- 12430852
TI  - Immunological reconstitution and immunoregulatory cells in hematopoietic stem
      cell transplantation.
AB  - Analysis of cytokine gene expression in peripheral blood mononuclear cells from
      patients received allogeneic hematopoietic stem cells transplantation (allo-SCT)
      showed that type 1 helper T cells (Th1)-derived cytokines increased in severe
      graft-versus-host disease (GVHD) while Th2-derived cytokines such as IL-4, IL-10,
      and IL-13 increased in mild GVHD. These results indicate that Th2 cells suppress
      GVHD although Thl cells augment GVHD. Chimerism analysis showed that mixed
      chimerism was often observed in younger (<30 years old) patients. Mixed chimerism
      in older (> or = 30 years old) patients were related to rejection and relapse
      while this situation is not the case in younger patients, thus indicating that
      mixed chimerism is an important prognostic factor in older patients. Among the
      chimerism of various cell populations, donor-derived CD56-positive cells are
      important in early engraftment when determined in allogeneic nonmyeloablative
      stem cell transplantation (allo-NST), regardless of the proportion of donor
      derived CD3-positive cells. This result suggests that donor-derived CD56-positive
      cells are a more useful indicator for engraftment and rejection in early time
      period. Complementary-determining region 3 (CDR3) size spectratyping in T-cell
      receptor (TCR) chain subfamilies (V beta) showed that high level of diversity in
      TCR V beta repertoire is important for a late rejection and skewed TCR V
      repertoire is well correlated to occurrence of GVHD. Expression of inhibitory
      natural killer (NK) cell receptors such as CD158b and CD94/NKG2A on peripheral
      CD3-negative and positive cells were increased in parallel with GVHD.
      Interestingly, these molecules appeared to regulate GVHD while preserving graft
      versus-leukemia (GVL) effect.

PMID- 12430853
TI  - Cellular and cytokine effectors of acute graft versus host disease.
AB  - Graft-versus-host-disease (GVHD) is the major complication of allogeneic Bone
      Marrow Transplant (BMT) and Older BMT recipients are at greater risk for acute
      graft-versus-host-disease. Using well-characterized murine BMT models we have
      explored the mechanisms of increased GVHD in older recipients. GVHD mortality and
      morbidity, as well as pathologic and biochemical indices were all worse in old
      recipients. Donor T cell responses were significantly increased in old recipients
      both in vivo and in vitro when stimulated by antigen-presenting cells (APCs) from
      old mice. In a haploidential GVHD model, CD4+ donor T cells mediated more severe
      GVHD in old mice. We confirmed the role of aged APCs in GVHD using B6D2FI BM
      chimeras created with either old or young BM. APCs from these mice also
      stimulated greater responses from allogeneic cells in vitro. We also evaluated
      whether alloantigen expression on host target epithelium is essential for tissue
      damage induced by GVHD in mouse models. In bone marrow chimeras recipients in
      which either MHC II or MHC I alloantigen was expressed only on APCs, we found
      that acute GVHD does not require alloantigen expression on host target epithelium
      and that neutralization of tumor necrosis factor-alpha and interleukin-1 prevents
      acute GVHD. These results suggest new strategies for the prevention and treatment
      of this toxic complication of BMT.

PMID- 12430854
TI  - Post-transplant immune recovery and the implication for infection risk.

PMID- 12430856
TI  - The use of high dose immunoablative therapy with hematopoietic stem cell support
      therapy in the treatment of severe autoimmune diseases.

PMID- 12430855
TI  - Immune pathophysiology of aplastic anemia.
AB  - Aplastic anemia (AA) remains an elusive disease. Its pathophysiology is not only
      fascinating by the seemingly simple findings of cytopenia and marrow hypoplasia,
      but may also contain key information to the understanding of other fundamental
      processes such as stem cell regeneration, evolution, and immune control of clonal
      diseases. Although measurements of blood counts provide an objective tool to
      assess the disease activity and response to the therapy, immune pathophysiology
      of AA, as inferred from the successes of immunosuppression, provides only few
      other clinical clues. Similarly, the current laboratory evidence remains mostly
      indirect. In spite of the recognition of immune pathways of hematopoietic
      inhibition and apoptosis in AA, the fundamental question about the nature of the
      antigen(s) inciting or maintaining the pathologic immune response that ultimately
      leads to bone marrow failure, remains open. However, recognition of the immune
      targets may aid in understanding not only the pathogenesis but also many of
      clinical associations and the late squelae of AA. For example, abnormal cells in
      AA and myelodysplastic syndrome (MDS) MDS may harbor inciting antigens but the
      immune response lacks selectivity. Clonal selection pressure may be a result of
      this process or alternatively, emergence of tolerance could lead to the
      establishment of abnormal hematopoiesis. Clonal proliferation of large granular
      lymphocytosis could represent an example of an exaggerated response to an
      immunodominant hematopoietic antigen. In addition to the traditional functional
      or phenotypic analysis, pathologic immune response in AA can be studied on
      molecular level by identifying and quantitating T cell clones based on the
      presence of unique variable B-chain CDR3 sequences. Detection of clonal expansion
      is based on the observation that in infections and autoimmune conditions, the
      presence of antigenic drive will lead to the expansion and overrepresentation of
      T cell clones recognizing this antigen. However, simple analysis of clonal
      representation is not sufficient to resolve the complex nature of the immune
      repertoire in the context of genetic and clinical heterogeneity. Therefore, we
      analyzed VB and CDR3 repertoire in CD4 and CD8 cells, activated or effector cell
      subsets. To distinguish truly expanded and likely immunodominant clones, we first
      studied VB distribution and cloned CDR3 sequences from expanded VB families.
      Identified clonotypic sequences can be used to design molecular tests to
      quantitate the strength of pathologic immune response. Clonotype sharing has been
      confirmed in patients with similar clinical features indicating presence of
      common antigens. In addition, quantitative analysis showed correlation with the
      therapy response. Persistence and patterns of clonotypes may be helpful in the
      classification of immune-mediated marrow failure based on the immune
      characteristics and will allow inferences into the inciting pathways.

PMID- 12430857
TI  - Autologous stem cell transplants in treatment of multiple sclerosis: where we
      stand and future prospects.
AB  - Based on experimental and clinical observations, high-dose immunosuppression
      followed by autologous transplantation may induce remissions in severe,
      refractory, autoimmune disorders including multiple sclerosis, a disease which,
      in its progressive form, does not respond to treatment. Phase I/II studies of
      transplantation in MS published by individual centers as well as a comprehensive
      analysis of the reports to the EBMT registry have shown that transplantation may
      positively affect MS by stabilizing the clinical condition of the patients, by
      improving their disability status, and by completely abrogating the inflammatory
      process in the brain as evidenced in magnetic resonance imaging. Other available
      therapies do not appear to be so efficacious as transplantation. However, the
      procedure is associated with a transplant-related mortality risk of about 3 to
      8%. Therefore, it cannot be recommended for the treatment of a chronic, non
      lethal, disease like MS unless it proves superior to standard therapies in terms
      of efficacy. This can be demonstrated only in a randomized trial, which is being
      launched by the EBMT under the name ASTIMS. It compares the BEAM regimen plus
      autotransplantation to mitoxantrone, which is currently regarded as one of the
      best available treatments, in patients with secondary progressive or rapidly
      evolving relapsing/remitting multiple sclerosis.

PMID- 12430858
TI  - Induction of tolerance in autoimmune diseases by hematopoietic stem cell
      transplantation: getting closer to a cure?
AB  - Hematopoietic stem cells (HSCs) are the earliest cells of the immune system,
      giving rise to B and T lymphocytes, monocytes, tissue macrophages, and dendritic
      cells. In animal models, adoptive transfer of HSCs, depending on circumstances,
      may cause, prevent, or cure autoimmune diseases. Clinical trials have reported
      early remission of otherwise refractory autoimmune disorders after either
      autologous or allogeneic hematopoietic stem cell transplantation (HSCT). By
      percentage of transplantations performed, autoimmune diseases are the most
      rapidly expanding indication for stem cell transplantation. Although numerous
      editorials or commentaries have been previously published, no prior review has
      focused on the immunology of transplantation tolerance or development of phase 3
      autoimmune HSCT trials. Results from current trials suggest that mobilization of
      HSCs, conditioning regimen, eligibility and exclusion criteria, toxicity,
      outcome, source of stem cells, and posttransplantation follow-up need to be
      disease specific. HSCT-induced remission of an autoimmune disease allows for a
      prospective analysis of events involved in immune tolerance not available in
      cross-sectional studies.

PMID- 12430859
TI  - A novel therapeutic approach for hematological malignancies based on cellular
      differentiation and apoptosis.
AB  - Hematological malignancies including acute leukemia, and multiple myeloma are
      disorders characterized by the accumulation of neoplastic hematopoietic cells,
      resulting in aggressive clinical manifestations with poor prognosis. The
      therapeutic approach to these disorders is basically chemotherapy for achieving
      complete remission based on the concept of total cell kill. However, severe side
      effects and complications such as serious infection and bleeding due to anti
      cancer drugs are major problems in the clinical setting. In addition, repeated
      episodes of relapse of the disease may lead to refractory or chemotherapy
      resistant disorders. These problems are occurred because anti-cancer agents have
      effects on both cancer cells and normal hematopoietic cells. The clinical
      evidences thus suggest the limitations of the chemotherapy for hematological
      malignancies: novel effective therapeutic approaches with less toxicity are
      therefore actively being sought. Differentiation-inducing therapy employing a
      physiologically active derivative of vitamin A, all-trans retinoic acid (ATRA),
      brought remarkably advances in the therapeutic outcome of APL at the end of last
      century. More recently, the clinical success of imatinib mesylate (STI571),
      potent competitive inhibitor of the Bcr/Abl protein tyrosine kinase, in the
      treatment of CML has focused enthusiasm toward molecular targeted therapy for the
      hematological malignancies. The therapeutic activity of these agents can be
      explained by their abilities to modify cellular growth, differentiation, and
      apoptosis in cells by activating unknown gene programs that molecular cellular
      proliferation. We have actively sought out new agents among natural products and
      cytokines with the ability to induce cellular differentiation and apoptosis. In
      this symposium, I will present our recent data of these novel compounds and their
      molecular mechanisms for inducing differentiation and apoptosis of hematological
      malignant cells.

PMID- 12430860
TI  - Progress in the treatment of acute myeloid leukaemia in adults.
AB  - There has been important progress in the treatment of Acute Myeloid Leukaemia
      (AML) in patients under 60 years. A remission rate of 80% can be achieved by
      several schedules, and 40-45% of patients diagnosed will survive. It may still be
      possible to improve remission induction treatment eg by intensifying the Ara-C
      dose although may this only be detectable in an improved disease free survival.
      The is to reduce relapse. The risk main challenge is pre-determined by a number
      of powerful risk factors. In the experience of the MRC age, cytogenetics and
      clearance of blasts from the bone marrow after course 1. Using the later two in
      combination good risk patients (FAB M3, t(8;21) t(15;17) inv(16)) have a relapse
      risk of 32%. Poor risk (blasts >15% after course 1 or abnormalities of Chs 5 or
      7, 3q- and complex changes have a relapse risk of 82%. All other cases are
      standard risk and ve a relapse risk of 56%. FLT3 mutations have been detected in
      about 25% of cases and provide additional negative predictive value overall and
      within each risk group. The assessment of the most effective consolidation
      treatment must be made taking into account the heterogeneity of the relapse risk.
      The MRC investigated the role of allo and autoBMT in addition to intensive
      chemotherapy. The data was analysis on an intent-to-treat or donor vs no donor
      basis. Although both types of transplant were able to reduce relapse overall and
      in all risk groups, there was an overall survival advantage only in standard risk
      patients. Since chemotherapy has improved since this study, there remains
      uncertainty about the benefit of transplant in all risk groups. Overall this
      experience has demonstrated that relapse can be reduced with more therapy. It is
      probable that the limits of conventional chemotherapy have been reached. The new
      AML15 trial will assess the value of adding the immunoconjugate (Mylotarg) to
      induction and/or chemotherapy. Improvements in older patients have been less
      detectable. MRC trials over the last 20 years show an improvement in remission
      rate (now 65%) but persistent poor survival (12% at 5 years). In the MRC AML11
      Trial three induction schedules were compared (DAT vs ADE vs MAC) with DAT being
      superior. A comparison of a total of 3 vs 6 courses of treatment or the addition
      of interferon maintenance did not improve results. Newer approaches currently
      being assessed include resistance modulation; addition of immunoconjugate and
      minigrafts. New targets for treatment are emerging of which the most interesting
      is FLT3 inhibitors.

PMID- 12430861
TI  - High efficiency gene transfer to human CD34+ cells.
AB  - We have previously reported the development of improved MLV-based retroviral
      vectors whose prototype is entitled MT (Kim et al, J. Virol. 72:994-1044; Yu et
      al, Gene Therapy 7:797-804). The MT vector does not contain any viral coding
      sequences, and thus the possibility of homologous recombination between the
      vector and the packaging genome is virtually nil. Indeed, in a shotgun RCR
      detection assay, an MT-based vector did not produce any RCR. On the contrary, the
      MFG vector, containing parts of all three viral coding sequences (gag, pol, and
      env), generated a significant number of RCR. In addition to being safe, MT-based
      vectors produce levels of gene expression and viral titer comparable to or higher
      than other vectors currently available within the community. Based on this
      vector, we have constructed a number of retroviral vectors that can be used for
      the treatment of a variety of human diseases. Our major target diseases are those
      that can be treated with or the status of which can be significantly improved
      with bone marrow transplantation. To obtain the most significant therapeutic
      effects, it is necessary to achieve the highest possible gene delivery
      efficiency, drive the highest level of gene expression, and prevent expression of
      the inserted therapeutic gene from being negatively influenced by the genome
      environment. To these ends, we compared various LTRs for their effects on the
      level of gene expression, tested the effect of cis-acting elements that may
      influence chromatin structure or position effect of the inserted gene, and
      studied different transduction conditions for their gene delivery efficiency.
      Data recently obtained from these experiments will be presented.

PMID- 12430862
TI  - Immune and cell therapy of hematologic malignancies.
AB  - Advances in molecular biology and immunology have identified means to activate
      the immune response against leukemia-associated antigens. Recent studies indicate
      that the stealth-like phenotype of leukemia cells can be reversed through
      transfer of genes encoding recombinant membrane-stabilized proteins of the tumor
      necrosis factor (TNF) imily, such as the one encoding CD154, the ligand for CD40.
      A phase I clinical trial using autologous CD154-transduced leukemia cells as a
      cellular vaccine has provided encouraging results. Treatment not only appears
      capable of inducing a cellular anti-leukemia immunity, but also may have a direct
      effect on leukemia cells by inducing latent sensitivity to Fas (CD95)-dependent
      leukemia-cell apoptosis. Phase II studies currently are underway using multiple
      injections of autologous leukemia cells made to express recombinant CD154 via
      gene transfer. Conceivably, we may be entering an era of effective gene therapy
      for hematologic malignancies.

PMID- 12430863
TI  - Identification of novel minor histocompatibility antigens responsible for graft
      versus-leukemia (GVL) effect on chronic myeloid leukemia: usefulness of
      determining the clonotype of T cells associated with GVL effect after donor
      leukocyte infusion.
AB  - In an attempt to identify novel mHas that induce GVL effect on chronic myeloid
      leukemia (CML), we analyzed peripheral blood T cells of 4 CML patients who
      relapsed after allogeneic stem cell transplantation and received donor leukocyte
      infusion (DLI), for the presence of antigen-specific T-cell proliferation. When
      peripheral blood lymphocyte collected from patients every 2-4 weeks after DLI
      were subjected to complementarity determining region (CDR) 3 size distribution
      analysis of T-cell receptor beta chain, clonal proliferation of a limited number
      of CD4+ T cells was detected in all patients 2-4 months after DLI in association
      with the occurrence of GVL effect. To identify an epitope of the T-cell clone
      that probably mediates GVL effect, we determined nucleotide sequence of CDR3 of
      the T cells and screened the database for the presence of T cells with a CDR3
      sequence similar to that of the GVL-mediating T cells. In one of 4 patients who
      showed clonal proliferation of a BV16+ T cell, a CDR3 motif QDR was shared by a T
      cell clone that recognized an 85-99 peptide of myelin basic protein presented by
      HLA-DRB1*1501. When the I domain of CD49b, a candidate peptides that could bind
      to this CDR3 motif in the context of DRB1*1501, was studied, codon 256 in the I
      domain of the recipient was ATT (Ile) while that of the donor was GTT (Val). The
      BV16+ T cells showed proliferative response to DRB1*1501 L-cell transfectant
      pulsed with the recipient type CD49b. Thus, identification of a clonotype of T
      cells that mediate GVL effect in patients receiving DLI and a search for T-cell
      clones with a similar clonotype to the GVL-mediating T cells followed by
      screening of polymorphic peptides that could stimulate the T cells appears to be
      useful in identifying novel mHas serving a target antigens of GVL effect.

PMID- 12430864
TI  - Role of NKT cells and alpha-galactosyl ceramide.
AB  - Alfa-Galactosyl Ceramide was isolated from Ocean sponge which has antitumor
      effect against several tumors in in vivo animal model with no cytotoxicity.
      KRN7000(KRN) is the most potent alpha-Galactosyl Ceramide modified from the one
      isolated from Ocean sponge. KRN is also active against metastatic tumors through
      the activation ofanimal immune system. Research efforts in learning the mechanism
      of action, we found the important role of dendritic cells(DC) and NKT cells. NKT
      cells was first characterized in 1988 which is overlap some part with NK cells
      and T-Cells and majority is different from NK and T. KRN is active through the
      activation of DC and NKT in giving antigen specific immune stimulation in animal.
      This antigen specific stimulation is memorized by immune system and can reject
      second tumor challenge. KRN is not active in nude mice and NKT deficient animal.
      NKT cells level in blood is lower in patients with autoimmune disease, cancer,
      HIV positive or aplastic anemia. NKT rapidly releases IL-4 and IFN-gamma at high
      level when activated. NKT is CD1d and TCR restricted. NKT plays important role in
      autoimmune disease such as Type 1 Diabetes, Scleroderma and Systemic Lupus
      Erythematosus, infections such as Mycobacteria, Listeria and Malaria, GVHD
      control and tumor rejection. NKT acts as double edge sword, aggressive and
      suppressive ways. KRN can prevent the onset of Type 1 Diabetes, inhibit
      replication of hepatitis virus B in liver and suppress malaria replication in
      activating NKT cells. KRN can activate NKT through DC and activated NKT activates
      NK, T and macrophage. KRN also expands NKT cells and expanded NKT has full
      function. Although the exact role of DC and NKT is not clear, KRN clinical study
      results in conjunction with DC and NKT cell activation are expected.

PMID- 12430865
TI  - Restructuring of international council for standardization in haematology (ICSH)
      in Asia.
AB  - Standardization and harmonization in Laboratory testing are a key issue in the
      midst of globalization era, because most of laboratory testing has been currently
      achieved with various kinds of automated systems. In the developed countries,
      automated systems with highly-regulated principles are commonly used in the
      routine laboratory. However, there are so many undeveloped and developing
      countries in Asia that diversity of testing levels can be observed in the area.
      Some laboratories use glass chamber method for blood cell counting, while other
      laboratory use semi-automated or fully automated analyzers for complete blood
      count. International standardization on Hematology is focused on the developed
      system but not for the developing system. Established standardized documents
      therefore whould not be unsuitable for Asian societies. In the context,
      International Council for Standardization in Hematology (ICSH) changed its rules
      to adjust our Asian Societies and ICSH started to restructure the body.
      International ICSH society is divided into 5 region sub-groups. Asian area is
      able to possess one new sub-society, ICSH-Asia. Its reconstruction work has been
      just started with Asain colleagues, and we are now extending the new societies to
      discuss Asian problems on the quality of hematology testing.

PMID- 12430866
TI  - Some hematological problems in Indonesia.
AB  - Indonesia consist of many island inhabited by many ethnic groups with different
      social economic condition. As in other parts of the world, anemia is still one of
      the major health problem in Indonesia. The reported anemia prevalence differs in
      each area and age groups, ranging from 5.4% in well nourished preschool children
      to 56.3% in primary school children; and 19% to 62.5% in pregnant women. The
      causes of anemia mostly reported were nutritional like iron deficiency, abnormal
      hemoglobin besides other conditions. In Cipto Mangunkusumo Hospital as the
      national referral hospital in Indonesia, in the adults groups, the cause of
      anemia reported were 14% with iron deficiency, 54% aplastic, 16% hemolytic and
      16% other causes. Whereas in the child health department the cause were 29%
      nutritional deficiency, 31% thalassemia, 10% aplastic, 4% hemolytic and 26% other
      causes. Thalassemia is quite often reported in Indonesia. In 1955 Lie-Injo first
      reported the HbE as the most frequently found abnormality among many ethnic
      groups in Indonesia, ranging from 2.5% to 13.2%. In later studies the prevalence
      reported varies very much. It was reported as 9.5% in newborns, 22% in pregnant
      women, and 15.95% to 60% in athletes. The carrier frequency in some areas was
      between 6-10%, while the pattern of mutation varied widely within each region.
      Hemophilia cases in Indonesia is still not diagnosed adequately, only 530 cases
      were reported. The problems were lack of diagnostic laboratories and awareness.
      As many as 56.9% of the hemophilia patients who received cryoprecipitate were
      reported positive with HCV antibody. Hematological malignancy is now also became
      an increasing problem in Indonesia, in child health department the prevalence of
      leukemia was 57%, and lymphoma 13% among other malignancies. In National Cancer
      hospital, the prevalence leukemia as diagnosed using morphology and
      flowcytometry, were 51.4% AML, 19.7% B-ALL, 14.6% T-ALL, 4.5% preB-ALL, with 9.8%
      cases with co expression, and 30% other malignancies. Due to geographical
      situation, economic condition and lack of diagnostic laboratory facility many
      abnormalities were unable to be diagnosed properly.

PMID- 12430867
TI  - New strategies for the diagnosis and screening of malaria.
AB  - Thin and thick blood film microscopy are the "gold standard" for malaria
      diagnosis. In recent years, there have been important developments in malaria
      diagnostic tests including fluorescence microscopy of malaria parasites stained
      with acridine orange, dipstick immunoassays that detect species-specific parasite
      antigens, and more recently, detection of parasite nucleic acids after
      amplification by PCR. With some of these methods, sensitivities and specificities
      approaching and even exceeding those of the thin and thick film can be attained.
      In particular, PCR-based tests for plasmodium DNA or RNA are more sensitive and
      specific than other tests for malarial parasites. A specific application for PCR
      diagnosis of malaria could be blood donor screening. Clinical trials of blood
      donor sreening for malarial parasites by PCR are being conducted, in which pooled
      donor samples are screened to increase efficiency and reduce costs. Some of the
      new diagnostic methods may have specific applications in particular settings,
      depending on the purpose and location of testing, and other factors such as cost,
      desired sensitivity and specificity, speed and ease of use.

PMID- 12430868
TI  - Laboratory practice at the periphery in developing countries.
AB  - An effective national health service structure requires a comprehensive programme
      for primary health care in peripheral and rural areas. This is especially
      important in under-resourced countries where facilities are sparse, the
      population is widely dispersed and transport is limited. Haematology has a key
      role in diagnosis and patient management by selecting tests for their clinical
      relevance and utility for the specific circumstances, and ensuring their
      technical reliability when used in health clinics and point-of-care testing. WHO
      has proposed a basic menu of tests in three categories: (a) tests such as
      haemoglobin screen which can be performed by nurses, midwives, health-aides or
      community doctors, (b) tests such as haemoglobinometry, microhaematocrit and
      microscopic examination of stained preparations which can be performed by a
      technician or laboratory assistant in a health centre, (c) tests requiring
      greater technical expertise of a laboratory technician or trained doctor. The
      peripheral health clinics and district laboratories must be familiar with the
      guidelines on standardized methods for collecting and storing specimens and
      transporting them to a regional laboratory or a reference centre. A training
      syllabus should be provided at the health centres and district laboratories, and
      this should include on-site instruction from supervisors and access to training
      manuals and distance-learning material. A co-ordinated programme of quality
      assurance and standardization of test methods should be established by a
      reference centre or national health authority with a network which encompasses
      all laboratories and health clinics undertaking any tests. Each regional
      laboratory should foster lower level laboratories or clinics within its
      neighbourhood. Of particular concern is the reliable diagnosis and management of
      anaemia. WHO reports indicate that 40% of the world population suffer from
      anaemia, especially affecting pregnant women, and a high proportion of infants
      and children in developing countries. The Haemoglobin Colour Scale (HCS) was
      recently developed for WHO as a simple, cheap and portable device which reads
      haemoglobin within 1 g/dl of the true value. It has been validated in a number of
      studies and is now manufactured commercially in accordance with WHO
      specifications under control of a WHO Collaborating Centre. It has an important
      potential role in the resource-limited environment where anaemia screening
      presently usually depends on unreliable clinical examination.

PMID- 12430869
TI  - Stem cell transplantation for thalassemia.
AB  - Thalassemia, one of the most common genetic disorders, is considered to be a
      global problem. Several millions of the patients suffer from severe thalassemic
      diseases. Stem cell transplantation is currently the only curative therapy. Bone
      marrow transplantation offers a high probability of cure when performed in young
      children. There is a higher risk as the patient becomes older, especially the
      high incidence of graft rejection. Modified conditioning regimens live been
      developed to overcome graft rejection in patients with class III or full blown
      manifestations. The alternative use of stem cell from cord blood makes possible
      earlier transplant with better chance of cure, although the engraftment is slower
      compared to bone marrow transplantation. More experiences with regard to stem
      cell transplantation in adult patients, the use of stem cell transplantation from
      related donors as well as matched unrelated donors are necessary.

PMID- 12430870
TI  - Current status of Japan marrow donor program (JMDP) and its roles in
      international cooperation.
AB  - Transplants for patients lacking an HLA identical sibling donor have become
      possible, and thank to the establishment of large registries of HLA typed
      volunteers. Japan Marrow Donor Program (JMDP) now stands at about 152,339
      volunteer donors, and have provided 4,013 marrows nationally and internationally.
      Advancements in HLA typing technology and greater precision in donor recipient
      matching have greatly increased the safety of unrelated donor transplants. In the
      JMDP retrospective study the strongest risk factor for acute GVHD and mortality
      was found to be mismatching for the BLA-A locus. Better matching criteria using
      molecular typing, however, will reduce the likelihood of identification of
      donors, especially in minorities. The chance of finding a matched unrelated donor
      is likely to be higher in the registries which share the same ethnic background
      of a recipient. There are five marrow donor registries have been established in
      Asia and are actively functioning. The expansion of volunteer donor pool of those
      registries and their efficient collaboration is very important to increase the
      probability of finding a match. The identification of permissive antigens may
      increase flexibility in donor-recipient pair matching may also be achieved
      through integration of international efforts and the creation of larger HLA data
      base.

PMID- 12430871
TI  - Marrow donor registry and cord blood bank in Taiwan.
AB  - Unrelated Bone marrow transplant was initiated thirty years ago. Though there are
      over millions of donors registered with the bone marrow registries worldwide,
      Asian patients rarely find a match with all these donors. Tzu Chi Marrow Donor
      Registry was established to meet this need. It has become the largest Asian
      marrow donor registry in the world. With the introduction of high technology to
      test the HLA of the donors and recipients, the success rate of bone marrow
      transplant is greatly improved among Asian countries. 50% of blood disease Asian
      patients who cannot find a bone marrow matched donor will be complemented by the
      establishment of cord blood banks in Taiwan.

PMID- 12430872
TI  - Current study of APL treatment in China.
AB  - Natural As4S4 and As2S3 are major components in realgar and orpiment, which also
      contain small amount of As2O3 and other toxic materials. Liu YF showed with us
      that NB4 cell line and its mice model were more sensitive to As4S4 than to As2O3
      and As2S3. That was in agreement with the clinical data available from China.
      Wang FR and we proved in mice and in clinical pharmaceutical study that ground
      Seman platycladi as an excipient can appreciably increase the blood level of
      arsenic when taken P.O. together with As4S4. Our clinical study with 130 patients
      with t(15;17) APL showed both As4S4 and As2S3 alone were very effective in CR
      induction, including cytogenetic remission and PML-RAR reversion, yet the relapse
      rate was higher in the group treated by As4S4 alone than in the group treated
      together with other autileukemic agents, either together or in sequence. In the
      later group, LFS for 1 and 6 years was 96.7% and 87.4%, and the over-all survival
      for 1 and 6 years was 98.9% and 93.9%. High dose chemotherapy was proven to be
      not only unsafe but also unnecessary. In newly diagnosed APL patients with
      neutropenia, CR could be safely achieved by As4S4 P.O. and/with ATRA.
      Chemotherapy was then followed. In patients with leukocytosis, chemotherapeutic
      agents such as hydroxyurea or harringtonine was added at the beginning and then
      followed by anthracycline and asparaginase. The reasons of APL relapse after
      patients receiving As4S4 P.O. were: 1: emergence of a resistant cell clone
      showing additional chromosomal abnormalities other than t(15;17); 2: decrease of
      blood As level. The resistant APL case could respond favorably to combination of
      As4S4 P.O. together with ATRA. The blood level of As could be raised by
      modification of the preparation under investigation. Allogeneic stem cell
      transplantation (allo-SCT) is the last option in relapsed patients, became
      autologous stem cell transplantation (ASCT) has a significantly better outcome.
      In a few hospitals ASCT was performed early in the CR1. In rare cares, patients
      were referred with intra-cranial hemorrhage. CT or EMR scan was done urgently at
      this instance. Cranial surgery carried out without a minute of delay resulted in
      the rescue and long survival of patient, while delay of surgery had resulted in
      irreversible damage of Pons/Medulla oblongata and ended in death. As2O3 IV had
      been used with success in mentally unclear patients not suffering from intra
      cranial hemorrhage. Although no parallel clinical trial has been done to compare
      the efficacy of As2O3 and As4S4, yet the fact was it was easier for doctors and
      patients to carry out and receive maintenance treatment with oral As4S4 rather
      than with As2O3. According to the data and principles above, most of the t(15;17)
      APL patients can be cured.

PMID- 12430873
TI  - Translational development of active immunotherapy for hematologic malignancies.
AB  - The B-cell tumor-derived Ig receptor may be considered a model tumor antigen for
      cancer vaccine development. However, as a non-immunogenic, self-antigen, it also
      must be first rendered immunogenic by chemical or genetic fusion to carriers
      which enable the induction of protective antitumor immunity in experimental tumor
      models. Our group has demonstrated that active immunization of human patients
      with idiotypic protein vaccines containing soluble GM-CSF elicited antigen
      specific CD8+ T cell responses and antitumor effects. An alternative strategy to
      develop vaccines is the genetic fusion of tumor idiotype-derived single chain
      antigen with a chemokine moiety. Administration of these vaccines as fusion
      proteins or naked DNA vaccines may allow more efficient targeting of antigen
      presenting cells in vivo. Potent antitumor immunity was elicited in mice which
      was dependent on the generation of specific antibodies and both CD4+ and CD8+
      effector T-cells. We propose that chemokine fusion may represent a novel, general
      strategy for formulating existing or newly identified tumor and HIV antigens into
      vaccines for cancer and AIDS, respectively, which elicit potent CD8+ T-cell
      immunity.

PMID- 12430874
TI  - Molecular mechanisms of lymphomagenesis through transcriptional disregulation by
      chromosome translocation.
AB  - Chromosome translation plays an important role for lymphomagenesis.
      Transcriptional disregulation type of chromosome translocation involves a
      majority of B-cell lymphoma. These include BCL1/cyclin D1 translocation in mantle
      cell lymphoma, BCL2 in follicular lymphoma and BCL6 in diffuse large B-cell
      lymphoma. It is known that the transcriptional disregulation type causes aberrant
      gene expression at the stages where those genes are down-regulated in normal
      counterpart cells. Normal B-cells at mantle zone stage down-regulate the
      expression of BCL1 gene and become resting in cell cycle. However, BCL1
      expression from translocated allele with immunoglobulin gene is not down
      regulated at the mantle zone stage, preventing cells from entering in resting
      state, and puts cells in cell cycle, leading to development of mantle cell
      lymphoma. BCL2 expression from altered allele also keeps its expression at the
      germinal center stage where normal counterpart cells down-regulate BCL2
      expression, and makes cells to resist apoptosis, leading to development of
      follicular lymphoma. The same scenario can apply to diffuse large B-cell lymphoma
      with BCL6 translocation; i.e. aberrant BCL6 expression at the post germinal
      center stage takes place where normal counterpart cells down-regulate BCL6
      expression. Although a strong association of specific translocations with
      specific disease types is found, these translocations by themselves are not
      sufficient for malignant transformation. The factors other than chromosome
      translocations will be discussed.

PMID- 12430875
TI  - Growth mechanism of human myeloma cells by interleukin-6.
AB  - Human myeloma cells are heterogenous morphologically and phenotypically. Myeloma
      cells can be classified into at least 5 subpopulations; MPC-1-CD45+CD49e-, MPC-1
      CD45-CD49e- immature myeloma cells, MPC-1+CD45-CD49e-, MPC-1+CD45+CD49e-
      intermediate myeloma cells and MPC-1+CD45+CD49e+ mature myeloma cells.
      Interleukin-6(IL-6) is a major growth factor for human myeloma cells, but only
      MPC-1-CD45+CD49e- immature myeloma cells can response directly to IL-6 to
      proliferate. In the U-266 cell lines, IL-6 can lead to the induction of CD45
      expression and CD45+ U-266 cells can proliferate in response to IL-6. In primary
      myeloma cells, MPC-1-CD45-CD49e- immature myeloma cells sorted from bone marrow
      samples can be changed to CD45+ cells by addition of IL-6 in vitro. In both CD45-
      and CD45+ U-266 cells, STAT3 and MAPK(ERK1/2) can be activated in response to IL
      6 equally between them, but src family kinases such as Lyn, Fyn can be activated
      only in CD45+ U-266 cells. Thus, the activation of the src family kinases
      associated with CD45 expression is a prerequisite for the proliferation of
      myeloma cells. In the bone marrow of myeloma patients, most myeloma cells do not
      express CD45, and CD45+ immature myeloma cells are only 1 approximately 2%. In
      order to clarify the difference of cellular context between CD45- and CD45+
      myeloma cells, PCR-based cDNA subtraction was performed from CD45+ U-266 cells to
      CD45-U-266 cells. The series of this subtraction selected several genes.
      Furthermore, sensitivity to stress stimuli between CD45+ and CD45- U-266 cells
      was also compared. CD45-U-266 cells were markedly more resistant to stress
      conditions such as serum-free condition. Therefore, we can speculate that in the
      bone marrow of human myelomas IL-6 can induce proliferation of CD45+ immature
      cells, but the amount of IL-6 is too low to support CD45+ myeloma cells and loss
      of CD45 results in no direct response to IL-6 to proliferate but confers
      resistance to stress condition leading to the longer survival at the limited
      amount of IL-6.

PMID- 12430876
TI  - New insights into role of microenvironment in multiple myeloma.
AB  - Multiple Myeloma (MM) is a malignant disease of terminally differentiated B
      cells. It most likely originates in a B cell which has traversed the germinal
      center and has been exposed there extensively to antigens based on the high
      number of somatic mutations in the complementarity determining regions. The cell
      of origin is either a plasmablast, or more likely, a memory B-cell. Typically MM
      goes through different phases from indolent (MGUS, smoldering myeloma) to overt
      myeloma and then to a fulminant phase, characterized by extramedullary
      manifestations, high LDH, immature morphology and increased proliferation rate.
      In the indolent phase, the disease already has acquired major cytogenetic
      abnormalities as demonstrated by FISH and DNA flow cytometry. It has a gene
      pattern very similar to myeloma cells on gene array analysis. In the early stages
      of overt MM, the myeloma cells are completely dependent upon the micro
      environment for their growth and survival. The interaction between myeloma cells
      and micro-environment causes bone disease, genetic instability and more
      importantly, drug-resistance, which is caused by upregulation of anti-apoptotic
      factors, resistance to apoptosis induced by FAS and TRAIL activation, and by cell
      adhesion-induced growth arrest. In this phase of the disease, MM is susceptible
      to chemotherapy, if delivered with adequate intensity. In the fulminant phase of
      MM, myeloma cells have acquired sufficient genetic alternations to become
      completely independent of the micro-environment which allows them to grow at
      extramedullary sites. Because of the many DNA breaks necessary for immature B
      cells to become mature plasma cells, B cells already have inherent genetic
      instability. DNA breaks are necessary for VDJ recombinations, somatic mutations
      and isotype switching and it is therefore not surprising that genetic
      alternations frequently occur at the Ig heavy chain site at 14q32, which is
      abnormal in three quarters of myeloma patients. Some of the translocations with
      14q32 involve terminal fragments of chromosomes and can not be diagnosed with
      standard cytogenetics. Cytogenetic abnormalities are found in 30-35% of newly
      diagnosed patients and require sufficient proliferation of MM cells to find
      enough analyzable mitoses. The cytogenetic abnormalities are typically complex,
      involving > or = 3 chromosomes in 80% of patients. Almost all chromosomes can be
      involved in deletions, additions or translocations of genetic material. Our group
      has repeatedly stressed the prognostic significance of chromosome 13 deletion by
      conventional cytogenetics. The role of chromosome 13 deletion by FISH. is less
      clear. In addition to chromosome 13 deletion, the presence of a hypodiploid or
      hypotetraploid karyotye also carries a poor prognosis. Frequently, deletions of
      chromosome 13 and hypodiploidy go hand in hand. It remains unclear what specific
      gene confers the poor prognosis to patients with deletion 13. The issues of bone
      disease, drug resistance and cytogenetics will be addressed in detail during this
      presentation.

PMID- 12430877
TI  - Early results of total therapy II in multiple myeloma: implications of
      cytogenetics and FISH.
AB  - Long-term follow-up on Total Therapy I revealed, with a median follow-up of about
      10 years, median durations of event-free survival (EFS) and overall survival (OS)
      of 37 and 80 mos in the 88% of patients lacking cytogenetic abnormalities (CA) of
      chromosome 13 compared to only 28 and 34 mos in those with CA 13. Total Therapy
      II (TT II) was developed to test whether more intensive remission induction and
      post-tandem transplant consolidation chemotherapy prior to interferon maintenance
      could further improve clinical outcome. All patients were also randomized to +/-
      thalidomide at a starting dose of 400 mg. Results obtained in the first 231
      patients enrolled in TT II are presented for the two study arms combined (data
      for effect of thalidomide still blinded). Three-year projection of EFS and OS are
      71% and 77%. On an intent-to-treat basis, 66% achieved complete remission (CR) or
      near-CR. Major independent adverse features associated with shortened survival
      included CA and chromosome 13 deletion using interphase FISH. CA identified 29
      among 102 patients with FISH 13 deletion who had a very grave prognosis (3 yr
      EFS, 32%; OS 49%) compared to all remaining patients who enjoyed 3 yr EFS of 79%
      and OS of 83%. Thus, both cytogenetics and FISH are recommended in the initial
      evaluation of patients with MM.

PMID- 12430878
TI  - Novel biologically based therapies for multiple myeloma.

PMID- 12430879
TI  - Thrombopoietin: from theory to reality.
AB  - Much is now known about the physiology of platelets and their role in primary
      hemostasis; however, until recently far less was understood about their immediate
      precursors, marrow megakaryocytes (MKs). With the cloning and characterization of
      thrombopoietin (TPO), the principle regulator of the growth and development of
      MKs, research has been rapid and broad-based. In several laboratories TPO was
      cloned based on it's binding to the product of the proto-oncogene c-mpl, at the
      time an orphan cytokine receptor, and was subsequently found to affect nearly all
      aspects of thrombopoiesis. Many of the molecular pathways that mediate TPO action
      have been explored. Like all other members of the hematopoietic cytokine receptor
      family upon hormone binding members of the JAK family of kinases are activated,
      which, in turn, phosphorylate the TPO receptor, generating docking sites for
      second messengers that affect multiple signaling pathways. Ultimately, cellular
      proliferative and anti-apoptotic mechanisms are initiated, increasing MK numbers,
      and a process termed endomitosis (EnM) begins, generating large, highly polyploid
      cells. The net result is the expansion of cells that give rise to mature
      platelets, a process that can be accentuated by the therapeutic administration of
      the hormone to thrombocytopenic patients.

PMID- 12430880
TI  - Heparin-induced thrombocytopenia: molecular pathogenesis.
AB  - Heparin-induced thrombocytopenia (HIT) is a common and often serious complication
      of heparin therapy [1,2]. Although the reduction in platelet levels associated
      with HIT is usually not severe, about 10% of patients experience arterial and/or
      venous thromboses (HITT), which can be incapacitating or fatal [3]. Recent work
      done in our laboratory [4] and by others [5-7] has shown that patients with
      HIT/T* almost invariably have antibodies specific for complexes consisting of
      heparin and platelet factor 4 (PF4), a heparin-binding protein found normally in
      platelet alpha granules. We [4] and others [8] have developed hypotheses to
      explain how these antibodies cause HIT/T in patients given heparin, but knowledge
      of the disease process is far from complete. An unusual feature of HIT/T is that
      antibodies important in pathogenesis are specific for complexes made up of two
      normal body constituents: PF4 and heparin. These antibodies are produced by a
      high percentage of certain patient populations treated with heparin, but only a
      minority of antibody formers are adversely affected. We postulate that a fuller
      understanding of the molecular basis for this immune response could lead to
      improved diagnosis, treatment and prevention of HIT/T and to the identification
      of risk factors that predispose to this complication.

PMID- 12430881
TI  - Structure and function of human fibrinogen inferred from dysfibrinogens.
AB  - Fibrinogen is a 340-kDa plasma protein that is composed of two identical
      molecular halves, each consisting of three non-identical subunit polypeptides
      designated as A alpha, B beta- and gamma-chains held together by multiple
      disulfide bonds. Fibrinogen has a trinodular structure, i.e., one central E
      domain comprizing the amino-terminal regions of paired individual three
      polypeptides, and two identical outer D domains. These three nodules are linked
      by two coiled-coil regions [1,2]. After activation with thrombin, a tripeptide
      segment consisting of Gly-Pro-Arg is exposed at the amino-terminus of each alpha
      chain residing at the center of the E domain and combines with its complementary
      binding site, called the 'a' site, residing in the carboxyl-terminal region of
      the gamma-chain in the outer D domain of another molecule. By crystallographic
      analysis [3], the alpha-amino group of alpha Gly-1 is shown to be juxtaposed
      between the carboxyl group of gamma Asp-364 and the carboxyamide of Gln-329 in
      the 'a' site. Half molecule-staggered, double-stranded fibrin protofibrils are
      thus formed [4,5]. Upon abutment of two adjacent D domains on the same strand, D
      D self association takes place involving Arg-275, Tyr-280 and Ser-300 of the
      gamma-chain on the surface of the abutting two D domains [3]. Thereafter,
      carboxyl-terminal regions of the fibrin a-chains are thought to be untethered and
      interact with those of other protofibrils leading to the formation of thick
      fibrin bundles and interwoven networks after appropriate branching [6-9].
      Although many enigmas still remain regarding the mechanisms of these molecular
      interactions, fibrin assembly proceeds in a highly ordered fashion. In my talk, I
      would like to discuss these molecular interactions of fibrinogen and fibrin based
      on the up-date data provided by analyses of normal as well as hereditary
      dysfibrinogens, particularly in the latter by introducing representative
      molecules at each step of fibrin clot formation.

PMID- 12430882
TI  - Neonatal alloimmune thrombocytonpenia due to HLA antibodies.

PMID- 12430883
TI  - The importance of lowering the costs of stem cell transplantation in developing
      countries.
AB  - The effectiveness and efficiency of health care systems can be assessed by
      economic evaluation, comparing the costs and outcomes of alternative
      interventions. Direct costs include accommodation, nursing, physicians' fees,
      diagnostic tests and treatment. Indirect costs derive from the loss of a persons
      ability to use life in a productive way e.g. employment. In cost-effectiveness
      analyses, cost is the numerator and effectiveness (related to health outcomes) is
      the denominator. The unit of measurement of effectiveness is usually years of
      life saved. Cost utility analyses require a preference-based measurement of
      health-related quality of life (HRQL) to allow the calculation of utility scores
      for health states and so the adjustment of effectiveness for quality. Typically,
      this allows the calculation of quality-adjusted life years (QALYs). A review of
      published reports, to be presented in detail, yields the following summation. The
      greater cost of stem cell harvest from peripheral blood is more than offset by
      the reduced costs associated with a shorter hospital stay. Transplants early in
      first remission cost less than those undertaken at later points in disease
      evolution/treatment experience. Changing the primary locus of care from inpatient
      to outpatient may result in notable cost savings but can produce cost-shifting
      (from inpatient to outpatient). Nevertheless, in selected patient, the use of non
      myeloablative transplants may offer a cost-effective option, especially in the
      developing country context.

PMID- 12430884
TI  - Update on non-myeloablative stem cell transplantation for hematologic
      malignancies.
AB  - Allogeneic stem cell transplantation is an established treatment modality for a
      variety of hematologic malignancies. Unfortunately it carries a high risk of
      complications and toxicities related to the intensive preparative regimen which
      is traditionally used for pre-transplant myeloablation and the graft versus host
      disease, which may be life threatening. Thus allogeneic stem cell transplantation
      has been used only for younger patients with a good performance status, excluding
      many other potential candidates due to advanced age or comorbid conditions. Non
      ablative or reduced intensity preparative regimens for allogeneic stem cell
      transplantation (NST) have been proposed as a strategy that would allow
      exploiting the graft versus tumor effect of allogeneic transplantation without
      the toxicity of myeloablative therapy. After more than five years of cumulative
      clinical experience, it is now well established that NST is a feasible treatment
      option for patients with suboptimal performance status and is mostly effective in
      slow proliferating malignancies, which gives time for a graft versus malignancy
      effect to take place. Additionally achievement of stable donor cell engraftment
      with NSTs provides a platform for adoptive immune cell treatments and may allow
      to extend indications of stem cell transplantation in the future.

PMID- 12430885
TI  - Allogeneic stem cell transplantation using non-myeloablative conditioning
      regimens: results of the Mexican approach.
AB  - We have used a novel method to conduct non-myeloablative stem cell
      transplantation (NST), making the following changes in previous methods: Use of
      the cheapest conditioning drugs, tailored number of apheresis sessions in the
      donors, elimination of ganciclovir and IgG, outpatient conduction when possible,
      diminished number of transfusions of blood products and diminished number of
      donor lymphocyte infusions. With this method, we have prospectively conducted 70
      allografts in patients with different diseases: Chronic myelogenous leukemia,
      acute myelogenous leukemia, acute lymphoblastic leukemia, myelodysplasia,
      thalassemia major, relapsed Hodgkins disease, Blackfan-Diamond syndrome and
      aplastic anemia. In them, the median granulocyte recovery time to 0.5 x 10(9)/L
      was 11 d, whereas the median platelet recovery time to 20 x 10(9)/L was 12 d.
      Twenty patients did not need red blood cell transfusions and 17 did not need
      platelet transfusions. In 55 individuals (78%), the procedure could be completed
      fully on an outpatient basis. Follow-up times range between 30 and 800 d.: Four
      patients failed to engraft and recovered endogenous hemopoiesis; 16 patients
      (23%) developed acute graft versus-host disease (GVHD) whereas 28 (49%) developed
      chronic GVHD. Thirty two patients (47%) have died: 21 with a relapsing disease
      and seven as a result of GVHD; the median post-trasplant survival (SV) was 420
      d., whereas the 12-mo. SV was 42%. The 100-day mortality was 3.8% and the
      transplant-related mortality was 14.2%. The median cost of the allografts was
      18,000.00 US dollars. This method could be particularly adequate in developing
      countries, where very few individuals can afford the cost of a conventional bone
      marrow transplantation procedure.

PMID- 12430886
TI  - The simplification of the SCT procedures in developing countries has resulted in
      cost-lowering and availability to more patients.
AB  - In order to simplify and cutting down expenses of the bone marrow transplantation
      procedures we have made some efforts, trying to provide the best transplantation
      technique for the individual patient with scarce resources. In relation with the
      source of stem cells, we have found very attractive the use of peripheral blood
      stem cells (PBSC) instead of bone marrow cells. This procedure can produce
      substantially more rapid engraftment than observed with bone marrow. The rapid
      hematopoietic reconstitution in the recipient of PBSC lower expenses stemming
      from the use of antibiotics, blood bank products and days at the hospital. In
      Mexico, a country with a large number of cases of severe aplastic anemia we
      decided to use PBSC to transplant 10 patients with this disease, in order to take
      advantage of the large number of stem cells that this procedure can provide. We
      had excellent results in these patients, avoiding the high cost of the
      conventional transplantation and the use of ATG. In relation to autologous
      transplantation we have made efforts to perform autografts without the use of
      freezing devices, keeping the stem cells in liquid form using a conventional
      blood bank refrigerator for up to 96 hr. This modifications have resulted in
      diminishing costs and increasing the availability of the procedure to a large
      number of patients. Finally in Mexico we have had experience with non
      myeloablative transplants, and obtained reasonably good results, with a median
      cost of 18,000 USD per allogeneic transplantation procedure. In some cases this
      is the only affordable therapeutic option. In developing countries where very few
      patients can afford the cost of conventional bone marrow transplants, any
      reasonable effort in the direction of simplification must be welcome.

PMID- 12430887
TI  - Goals and activities of the WMDA. World Marrow Donor Association.
AB  - The World Marrow Donor Association (WMDA) has the goal to facilitate reliable
      transfer of bone marrow and other forms of hematopoietic stem cells from one
      country to another, to promote exchange of information internationally about how
      to identify suitable donors and to protect the welfare and safety of the donor.
      It establishes guidelines on standards, ethics and other issues related to the
      goal of the WMDA. Full voting organisational members are those who deal directly
      with the donors and the logistics of hematopoietic stem cell transfer
      internationally for transplantation. Other members are non-voting organisational
      members and individual corresponding members (general members). They are working
      on, or interested in hematopoietic stem cell transplantation or science in the
      field. In order to execute its task, WMDA has several working groups that make
      proposals to the Board that takes decisions related to WMDA goals.

PMID- 12430888
TI  - The role of the EBMT activity survey in the management of hematopoietic stem cell
      transplantation. European Group for Blood Marrow Treansplantation.
AB  - Disease or treatment oriented registries form an integral part of modern
      medicine. They complement industry driven, corporate group sponsored and
      institutional research and are, together with prospective randomised trials
      cornerstones of modern evidence based medicine. Focus has been on rapid
      collection, analysis and dissemination of information on rare procedures with
      stress on patient outcome. In complex expensive procedures, such as hematopoietic
      stem cell transplants (HSCT), novel structures are required to catch outcome at
      team or national level. The annual activity survey of the European Group for
      Blood and Marrow Transplants EBMT forms such an instrument. Since 1990, EBMT has
      been collecting, on an annual basis, numbers of HSCT from the preceding year
      according to indication, donor type and stem cell source. The survey covers all
      European countries. In 1990, 143 teams reported 4,234 HSCT; in the year 2000, 619
      teams reported 19,136 HSCT (33% allogeneic, 67% autologous). This information,
      which covers over 90% of all HSCT performed in Europe and is based on 132,963
      HSCT (33% allogeneic, 67% autologous), gives a clear overview of current status
      and ongoing trends. It shows the general increase in HSCT from 1990 to 2000 with
      few exceptions, such as autologous HSCT for breast cancer and allogeneic HSCT for
      chronic myeloid leukemia. It illustrates the shift in technology from bone marrow
      as stem cell source in 1990 (100%) to peripheral blood in 2000 (96% of
      autologous, 53% of allogeneic HSCT). Supplemented by population data and economic
      factors (Gross national Product, Health Care Expenditures, Health Care systems)
      of the individual countries it allows comparison of transplant rates (Number of
      transplants per 10 million inhabitants), team densities (Number of transplant
      teams per 10 million inhabitants) and trends between countries. It permits
      quantification of the impact of economics and health care systems and provides a
      basis for quality control and allows assessment of the main factors influencing
      team decisions: evidence, disease prevalence, economics and expectations. As
      such, it is an essential tool for patient counselling and health care planning.

PMID- 12430889
TI  - The international bone marrow transplant registry.
AB  - The first successful transplants of hematopoietic stem cells were done in 1968 in
      three children with congenital immune deficiency diseases. In each instance, stem
      cells were collected from the bone marrow of sibling donors who were
      genotypically HLA identical or closely HLA matched to the recipient. Since then,
      thousands of patients have received hematopoietic stem cell transplants to treat
      malignant and non-malignant diseases. Current estimates of annual numbers of stem
      cell transplants are about 50,000 worldwide, with growth at a rate of 10-15% per
      year. The reasons for increasing use include proven and potential efficacy in
      many diseases, better understanding of the appropriate timing of transplantation
      and patient selection, greater availability of donors and better techniques for
      determining HLA match, greater ease of stem cell collection, and improved
      supportive care resulting in less transplant-related morbidity and mortality.
      About two-thirds of hematopoietic stem cell transplants use autologous cells,
      generally collected from peripheral blood by leukapheresis. The remainder are
      allogeneic transplants, most commonly from HLA-identical sibling donors, and most
      often using cells collected directly from bone marrow.

PMID- 12430891
TI  - The diagnosis from the pathological viewpoint of a blood disease.
AB  - The histopathological viewpoints of a blood diseases are namely following the
      cytological examinations except for the viewpoint of organ pathology and has been
      required only the usefulness in case with the difficulty of cytological
      examination. If it looks at a blood disease as hematopoietic organ disease,
      histopathological diagnostic study might make the new paradigm of blood diseases.
      In this time, I would like to present the hematological diagnosis from the
      pathological viewpoint by using histological bone marrow sections. *How to
      examine the bone marrow histology *Hematopoietic microenvironment disorder
      *Differential diagnosis of hypoplastic marrow lesions *Clinicopathological
      characteristics of Hypoplastic leukemia *Hemophagocytosis in bone marrow *How to
      diagnose MDS by histopathology. Bone marrow histology is the valuable diagnostic
      tool of many kinds of marrow disorders especial cases. By using
      immunohistochemistry and Giemsa staining, further information might obtain than
      smear film cytology. Bone marrow clot section aspirated from sternum is enough
      for histological examination except bone marrow biopsy. Precise cytomorphology
      might demonstrate by smear film than section histology. However surface phenotype
      would define by flow cytometric analysis, immunostaining of sections could
      demonstrate which cells show which markers. Structural and architectural disorder
      could only be represent by histology. The histological examination of bone marrow
      might introduce a new aspects of blood disease.

PMID- 12430890
TI  - Molecular nature of antigens implicated in immune neutropenias.
AB  - Granulocyte (neutrophil) antibodies can cause autoimmune neutropenia, drug
      induced neutropenia, immune neutropenia after bone marrow transplantation,
      neonatal immune neutropenia, refractoriness to granulocyte transfusions as well
      as febrile and pulmonary transfusion reactions. In the last decade, considerable
      progress has been made in the characterization of the implicated antigens. In
      1998, the Granulocyte Antigen Working Party of the ISBT introduced a new
      nomenclature for human neutrophil alloantigens (HNA), which is based on the
      antigens' glycoprotein location. In the HNA nomenclature the immunogenic (glyco-)
      proteins are indicated by arabic numbers followed by a letter of the alphabet
      which identify the (glyco-) proteins' polymorphisms, i.e. the specific antigens.
      Currently, seven HNA antigens are assigned to five systems. The HNA-1a, HNA-lb
      and HNA-1c antigens, the former NA1, NA2, and SH antigens, have been identified
      as polymorphic forms of the neutrophil Fc gamma receptor IIIb (CD16b) encoded by
      three alleles. Recently, we could elucidate the primary structure of the HNA-2a
      antigen, the former NB1. We could identify the HNA-2a-bearing glycoprotein as a
      novel member of the Ly-6/uPAR superfamily which has been clustered meanwhile as
      CD177. The HNA-3a antigen, the former 5b, is located on a 70-95 kDa glycoprotein.
      However, its molecular basis is still unknown. Finally, the HNA-4a and HNA-5a
      antigens, the former MART and OND, were found to be caused by single nucleotide
      mutations in the alphaM (CD11b) and alphaL (CD11a) subunits of the leucocyte
      adhesion molecules (beta2 integrins). The glycoproteins CD11b, CD16b, and CD177
      have been found to be also frequent targets of autoantibodies - approximately 30%
      of neutrophil autoantibodies are directed against CD16b. Characterization of
      granulocyte antigens have expanded our diagnostic tools by the introduction of
      genotyping techniques and immunoassays for antibody identification. In addition,
      it allowed new insights in the pathophysiology of immune neutropenias and
      transfusion reactions. Ongoing studies will further improve the prevention and
      management of granulocyte antibody-mediated diseases.

PMID- 12430892
TI  - The role of morphology, cytochemistry and immunohistochemistry in the diagnosis
      of chronic myeloproliferative diseases.
AB  - Chronic myeloprolifeative diseases (CMPD) are clonal hematopoietic stem cell
      disorders characterized by excessive proliferation and production of one or more
      of the myeloid cells and are subclassified according to the predominant cells,
      such as chronic myelogenous leukemia (CNL), chronic eosinophilic leukemia (CEL),
      polycythemia vera (PV), essential thrombocythemia (ET) and chronic idiopathic
      myelofibrosis (CIMF). This brief review focuses on the characteristic morphology
      of each clinical entity and the useful cytochemical (including leukocyte alkaline
      phosphatase, myeloperoxidase, butyrate esterase, chloroacetate esterase and
      cyanide-resistant peroxidase) and immunohistochemical (including von Willebrand
      factor/CD61, keratin, tryptase, CD117, CD68 (PGM-1), c-Mpl and bFGF) stains for
      differential diagnosis.

PMID- 12430893
TI  - The role of morphology, cytochemistry and immunohistochemistry in the diagnosis
      of lymphoproliferative disorders.
AB  - The bone marrow examination is a valuable procedure in the diagnosis and
      management of patients who have NHL. Posttherapy bone marrow examination is
      useful for assessing a patient's response to chemotherapy and for monitoring
      previously treated patients for evidence of recurrent disease. The bone marrow
      examination should include trephine biosy section, trephine imprints, aspiration
      smears, clot sections and blood smears and all of these preparations should be
      studied by the same pathologist. In addition to the morphologic evaluation, the
      aspirated marrow is the best material for several important supplemental studies
      for characterization of NHLs, including immunophenotyping by flow cytometry,
      cytogenetics, most molecular studies, and microbiologic cultures. Flow cytometric
      immunophenotyping studies to determine lineage, clonality of B-cell processes,
      and approximate stage of neoplastic infiltrates are the most useful adjuvant to
      morphologic assessment for NHLs. This review concentrates on the characteristic
      morphology, cytochemistry, immunohistochemical assessment and immunophenotyping
      of each clinical entity according to WHO classification. For the differential
      diagnosis, reactive lymphoid lesions, including lymphocytic aggregates, reactive
      polymorphous lymphohistiocytic lesions, benign follicles with germinal centers
      and polyclonal immunoblastic proliferations will be discussed.

PMID- 12430894
TI  - Mini-transplantation strategy for solid tumors.
AB  - In our phase I reduced-intensity stem cell transplantation (RIST) study with
      fludarabine (180 mg/m2) or cladribine (0.66 mg/kg) plus busulfan (8 mg/kg), with
      or without anti-thymocyte globulin (ATG), a total of 85 patients who had a
      variety of hematological (n=68) or metastatic solid tumors (n=17) were treated.
      This presentation will further update the results of our RIST program,
      highlighting several burning issues in the treatment of patients with solid
      tumors. Pathological classification of solid tumor in this program included renal
      cell carcinoma (RCC, n=8), rhabdomyosarcoma (n=2), malignant melanoma (n=2),
      neuroblastoma (n=2), osteosarcoma (n=1), alveolar saft-part-tumor (n=1) and
      cholangiocarcinoma (n=1). All received PBSCT from an HLA-identical or one antigen
      mismatched relative. Regimen-related toxicities were mild and >90% donor
      chimerism was achieved before day 30 in a majority of patients. The overall
      survival for hematological and solid malignancies was the same ca. 70% at 1 year.

PMID- 12430895
TI  - Chronic graft-versus-host disease and late effects after hematopoietic stem cell
      transplantation.
AB  - Late effects following HSCT are related to either the transplant process or to
      the transplant preparative regimen. Problems related to the transplant process
      include delayed recovery of the immune system and chronic GVHD. Chronic GVHD
      presents between 3-14 months post-HSCT in approximately 20% of matched sibling
      transplants and 40% of matched unrelated donor recipients. Most commonly involved
      sites are skin, mouth, liver, gastrointestinal tract, and eye. Patients with
      platelet count < 100,000/ml and receiving cortocosteroid therapy at day 80 with
      any clinical manifestations of chronic GVHD require prolonged immune suppressive
      therapy with prednisone, cyclosporine +/- other agents. Treatment should be
      administered until all clinical and pathological signs and symptoms of chronic
      GVHD have resolved which may take one to several years. Problems related to the
      transplant preparative regimen include those involving the endocrine system,
      eyes, lungs, bone, and development of secondary malignancies. Endocrine
      deficiencies include growth failure with growth hormone (GH) deficiency, overt
      hypothyroidism, primary gonadal failure, Type 1 or Type 2 diabetes, and exocrine
      pancreatic insufficiency. These problems develop at any time post-HSCT, but
      usually occur within the first few years and should be treated with appropriate
      hormone supplementation. Eye problems are primarily related to development of
      cateracts secondary to total body irradiation (TBI) or prolonged corticosteroid
      use. Cateracts developing after fractionated frequently do not require removal.
      Pulmonary problems may be due to bronchiolitis obliterans (BO) or to restrictive
      lung disease. BO may be associated with chronic GVHD and may respond to chronic
      GVHD therapy. Restrictive lung disease does not occur for many years after HSCT.
      There is not therapy for this problem. Development of decreased bone mineral
      density (BMD) is related to GH deficiency and/or corticosteroid therapy.
      Treatment includes withdrawal of corticosteroids, administration of GH and
      calcium, Vitamin D and antiresorptive agents. All malignant disease survivors are
      at risk for development of secondary malignancies, including survivors of HSCT.
      Recipients of TBI are at highest risk as are children. All pediatric and adult
      survivors of HSCT should be followed for their life-time for development of
      delayed effects of transplantation.

PMID- 12430897
TI  - Targeted gene disruption of natural anticoagulant proteins in mice.
AB  - The blood coagulation system is a complicated cascade of reactions and feedback
      regulations that executes a rapid response to vascular injury, yet avoids
      occlusion of the vessel. There are several key components of this system in the
      regulation of blood clot propagation, such as antithrombin (AT), tissue factor
      pathway inhibitor (TFPI), thrombomodulin (TM) and protein C (PC), of which defect
      causes thromboembolic diseases. In recent years, targeted gene disruption
      technique by homologous recombination has been introduced to investigate the
      physiological roles of those natural anticoagulant molecules, not only in
      thrombogenesis but also in embyrogenesis. We have studied the natural
      anticoagulantion system in a decade, and recently established AT knockout mice as
      well as ryudocan (syndecan-4) knockout mice. Ryudocan is a cell surface heparan
      sulfate proteoglycan, which bears heparin-like glycosaminoglycan (heparan
      sulfate) cahins, originally cloned from rat microvascular endothelial cells. We
      have demonstrated that ryudocan deficiency impairs the control of coagulation in
      fetal vessels of the placenta in mice. We have also reported that complete
      antithrombin deficiency in mice results in embryonic lethality, with severe
      fibrin deposition in the myocardium and the liver, accompanied with extensive
      subcutaneous hemorrhage. In this presentation, recent advances in understanding
      roles of natural anticoagulant molecules through the researches of targeted gene
      knockout mice, including our experiences in antithrombin deficient mice and
      ryudocan deficient mice, will be discussed.

PMID- 12430896
TI  - Allogeneic hemopoietic stem cell transplantation in patients with myelodysplastic
      syndrome or myelofibrosis.
AB  - Myelodysplastic syndrome (MDS) and myeloproliferative disorders associated with
      myelofibrosis (MF) are stem cell disorders, and hemopoietic stem cell
      transplantation (HSCT) is currently the only therapy with curative potential.
      Among patients with less advanced MDS, 3 year survivals of 65% to 70% are
      achievable with HLA-identical related and HLA-matched unrelated donors. The
      probability of relapse is < 5%. Among patients with advanced disease (> or = 5%
      marrow blasts), about 35 to approximately 45% and 25 to approximately 30%,
      respectively, are surviving in remission after transplantation from related or
      unrelated donors. The incidence of post-transplant relapse is 1035%. Criteria of
      the International Prognostic Scoring System (IPSS), originally developed for
      nontransplanted patients, also predict survival following transplantation.
      Patients with MF, either idiopathic or on the basis of pre-existing disorders,
      are also transplanted successfully with stem cells from related or unrelated
      donors. Transplants early in the disease, before leukemic transformation, are
      successful in 60 to approximately 80% of patients. Success rates are lower in
      patients who have developed MDS or leukemia. New conditioning regimens have
      permitted successful HSCT even in patients in the seventh decade of life. Results
      with a regimen using a combination of busulfan (targeted to predetermined plasma
      levels) and cyclophosphamide are particularly encouraging. Improved survival with
      transplants from unrelated volunteer donors may, in part, reflect selection of
      donors on the basis of high resolution (allele-level) HLA typing. Nevertheless,
      transplant-related morbidity and mortality, including graft- vs. -host disease,
      remain challenges that need to be addressed with innovative approaches.

PMID- 12430898
TI  - Treatment of venous thromboembolism.
AB  - The combination of unfractionated heparin or low molecular weight heparin and
      oral anticoagulants is currently the treatment of choice for most patients with
      venous thromboembolism. Oral anticoagulants are started at the same time and
      heparin is discontinued after at least 5 days when the levels of the
      International Normalized Ratio reach the therapeutic range between 2.0 and 3.0.
      Low molecular weight heparin has potential advantages over heparin and is
      administered in subcutaneous weight-adjusted fixed doses without need for
      monitoring. This has made the home treatment of a large proportion of patients
      possible. Randomized clinical trials and several subsequent reports from clinical
      practice have demonstrated the efficacy and safety of this approach. The results
      of currently ongoing trials aimed to assess the efficacy and safety of newer
      compounds for the initial treatment of venous thromboembolism are expected. Oral
      direct thrombin inhibitors or selective factor-Xa inhibitors have the potential
      to become the treatment of choice in the next decade. The optimal duration of the
      secondary prophylaxis with oral anticoagulants is still a matter of debate. The
      rate of recurrence has been shown to be elevated, particularly in patients with
      idiopathic venous thromboembolism. A 3-month therapy is therefore currently
      recommended when a transient risk factor is identified, life-long treatment is
      recommended for patients with a second episode of venous thromboembolism. The
      presence of active cancer or a thrombophilic state may require long-term
      anticoagulation, although not all the congenital hypercoagulable states seem to
      carry the same level of risk. In all other cases, 6 months are recommended, but a
      long-term monitoring of the patients is advisable. The use of more aggressive
      strategies such as thrombolysis is limited to patients presenting with massive
      pulmonary embolism or signs of right ventricular dysfunction.

PMID- 12430899
TI  - Effects of hormone replacement therapy on coagulation and fibrinolysis in
      postmenopausal women.
AB  - It has been speculated that hormone replacement therapy (HRT) containing
      relatively low dose of estrogen would be different from oral contraceptive pills
      in causing thromboembolism because activation of coagulation depends on the
      amount of estrogen. In contrast to this knowledge, activation of coagulation
      pathways has been detected in postmenopausal women treated with HRT in the
      observational and clinical studies. In this regard, recent studies have reported
      a 2 to approximately 4 fold risk of venous thromboembolism or pulmonary embolism
      in postmenopausal women receiving HRT than in non-users of estrogen. On the other
      hands, HRT has shown to enhance systemic fibrinolysis with decreased plasma
      plasminogen activator inhibitor-1 (PAI-1) levels. In addition, levels of D-dimer
      exhibited a significant inverse correlation with PAI-1 levels, suggesting
      enhanced fibrinolysis potential. However, small doses of estrogen/progestogen
      induce increases in fibrinolytic capacity via a marked reduction of PAI-1. In
      other words, HRT at conventional dosages may affect fibrinolytic activity to a
      greater extent than coagulation activity, whereas the converse trend holds at
      higher estrogen doses. The increase in fibrinolytic potential was independent of
      any effect on coagulation of CEE at conventional dosages. However, in contrast to
      healthy postmenopausal women, we recently reported that HRT did not significantly
      decrease PAI-1 antigen levels and rather, increased tissue factor activity and
      prothrombin fragment F(1+2) levels from baseline in hypertensive and/or
      overweight postmenopausal women. Activation of coagulation following HRT may not
      be balanced by activation of fibrinolysis in some postmenopausal women.
      Thrombogenic events are considered more likely in patients with certain heritable
      conditions, such as platelet antigen-2 (PIA-2) polymorphisms. Further, Factor V
      Leiden mutation increases the risk of primary and recurrent venous thromboembolic
      events by three to sixfold and the risk of myocardial infarction. Indeed, HRT may
      decrease or increase atherothrombosis risk depending on the presence of Factor V
      Leiden mutation. Thus, HRT should not be initiated in women with established
      coronary artery disease or the coexistence of other risk factors for
      hypercoagulability-malignancy, immobility, obesity, diabetes, advanced age, or
      inherited traits. However, HRT at conventional dosages improves fibrinolysis
      potential in healthy postmenopausal women.

PMID- 12430900
TI  - Recent advances in the diagnosis of antiphospholipid syndrome.
AB  - Antiphospholipid antibodies are autoantibodies directed against anionic
      phospholipids or protein-phospholipid complexes measured in solid-phase
      immunoassays such as anticardiolipin (aCL) antibody or detected in phospholipid
      dependent clotting tests as lupus anticoagulant (LA). The term "antiphospholipid
      syndrome (APS)" was first coined to denote the clinical association between
      antiphospholipid antibodies and a syndrome of episodes of thrombosis in arteries
      and/or veins, pregnancy loss, and thrombocytopenia. The diagnosis of APS is based
      on the finding of "moderate-to-high" aCL antibody titer and/or an LA test with
      any one of the characteristic clinical features presented. Recently, the
      diagnostic criteria of APS was revised and several newer assays that use
      phosphatidylserine, a mixture of negatively charged phospholipids or beta2
      glycoprotein 1 (beta2-GP1) have been proposed for more specific measurements of
      antibodies present in APS. In this section, recent progress in the laboratory
      diagnosis of antiphopholipid syndrome will be discussed.

PMID- 12430901
TI  - Monitoring the course of chronic myelogenous leukemia by fluorescence in situ
      hybridization.

PMID- 12430902
TI  - Integrating cytogenetics and gene expression profiling in the molecular analysis
      of multiple myeloma.
AB  - Multiple Myeloma (MM), is a currently incurable malignancy of a terminally
      differentiated antibody secreting plasma cell (PC) that can be controlled with
      high dose therapy and stem cell support. Conventional cytogenetic analysis has
      revealed a genomic instability that sets MM apart from the other blood cell
      cancers. In spite of this "genomic chaos" recurrent structural rearrangements and
      ploidy changes have aided the identification of important molecular mechanisms of
      disease etiology and that have also proved to be useful clinical landmarks. Yet,
      abnormal cytogenetics, present in only 30% of cases, combined with other clinical
      parameters, only account for 20% of the variability in clinical outcome, which
      can range from 2 months to > 10 years. Thus, the genomic chaos may mask a
      unifying chromosome abnormality, e.g. Philadelphia chromosome in CML, or may
      indicate that MM is a broad descriptor of constellation of many distinct clinical
      and molecular entities. The advent of microarray profiling of global gene
      expression patterns is providing evidence that both of these possibilities may be
      true. We will discuss how the integration of conventional and molecular
      cytogenetics with gene expression profiling has confirmed past observations and,
      yet fundamentally changed the way we view the disease.

PMID- 12430903
TI  - Cytogenetic and FISH studies in myelodysplasia, acute myeloid leukemia, chronic
      lymphocytic leukemia and lymphoma.
AB  - Conventional cytogenetic studies are widely used today to diagnose and manage
      patients with hematological malignancies. The application of fluorescence in situ
      hybridization (FISH) with chromosome-specific DNA probes helps to further define
      molecular subclasses and cytogenetic risk categories for patients with these
      disorders. Moreover, FISH permits analysis of proliferating (metaphase cells) and
      non-proliferating (interphase nuclei) cells, and is useful in establishing the
      percentage of neoplastic cells before and after therapy (minimal residual
      disease). For patients with myelodysplasia or acute myeloid leukemia, these
      chromosome techniques are important for accurate diagnosis and classification of
      disease and to help decide treatment and monitor response to therapy.
      Conventional cytogenetic studies have been problematic in chronic lymphocytic
      leukemia because the neoplastic cells divide infrequently. However, interphase
      FISH studies now permit detection of chromosome anomalies with prognostic
      significance in chronic lymphocytic leukemia. The World Health Organization
      recognizes that genetic anomalies are one of the most reliable criteria for
      classification of malignant lymphomas. New methods to extract individual nuclei
      from paraffin-embedded tissue are now available which permit the use of
      interphase FISH to detect important chromosome anomalies in lymphoma.

PMID- 12430905
TI  - Thalassemia and abnormal hemoglobin.
AB  - Thalassemia and abnormal hemoglobins are common genetic disorders in Asia.
      Thalassemia is not only an important public health problem but also a socio
      economic problem of many countries in the region. The approach to deal with the
      thalassemic problem is to prevent and control birth of new cases. This requires
      an accurate identification of the couple at high risk for thalassemia. However,
      the diagnosis of thalassemia carrier states need several tests which are not
      practical for screening the population at large. Recently we have used two simple
      laboratory tests to screen for potential thalassemia carriers and hemoglobin E
      individuals. There is also a new development in using the automatic HPLC to
      diagnose thalassemic diseases and the carriers. This system gives both
      qualitative and quantitative analysis of hemoglobin components in the same run
      with good precision and reproducibility. The system has been applied to study
      thalassemia and abnormal Hb in adult and cord blood. This system has enabled us
      to do both prenatal and postnatal diagnosis of thalassemia within the few
      minutes. However, none of these screening tests can accurately give specific
      diagnosis of the thalassemia genotype. Specific thalassemia mutation can be
      carried out by DNA analysis. Many DNA techniques have been used for point
      mutation detection and small deletion. For the last few years there is a
      development of DNA chip technology that has been applied for thalassemia mutation
      as well. Clinically, thalassemia is very heterogeneous in the manifestation. In
      spite of seemingly identical genotypes, severity of beta thalassemic patients can
      vary greatly. Heterogeneity in the clinical manifestation of beta thalassemic
      diseases may occur from the nature of beta globin gene mutation, alpha
      thalassemia gene interaction and difference in the amount of Hb F production
      which is partly associated with a specific beta globin haplotype. However, there
      is still some beta thalassemia cases that have a mild clinical symptom without
      those known genetic fators interaction suggesting that there are other additional
      factors responsible for the mildness of the disease.

PMID- 12430904
TI  - Granulocyte transfusion in the G-CSF era.
AB  - Granulocyte transfusions have been used since the 1960s with varying degrees of
      clinical success in the treatment of infection in patients with neutropenia or
      inherited granulocyte disorders. A number of studies have indicated that efficacy
      may well be associated with the dose of granulocytes delivered. Collection of
      granulocytes using modern apheresis machines and corticosteroid administration
      yields approximately 20 to approximately 30 x 10(9) neutrophils, unlikely to be
      adequate for treating an established infection. The administration of G-CSF to
      healthy donors has resulted in average granulocyte yields up to 8 x 10(10) cells.
      Normal or near normal blood neutrophil counts are often attained when these
      concentrates are transfused to neutropenic recipients, and these levels are
      sustained for up to 24 h. G-CSF-primed granulocytes appear to be functionally
      normal by both in vitro and in vivo measurements. Adverse effects experienced by
      recipients are similar to those seen with traditional doses of granulocytes. G
      CSF administration to donors is well tolerated. Controlled clinical trials are
      needed to determine the therapeutic efficacy of G-CSF-primed granulocyte
      transfusions.

PMID- 12430906
TI  - Thalassemia mutations and their clinical aspects in Japan.
AB  - Thalassemia (thal) is one of the most prevalent congenital disorders in a world,
      especially in an endemic area of Plasmodium falciparum. The thal is relatively
      rare in northeast Asia including Japan where malaria is uncommon. However, thal
      in Japan has peculiar mutation spectrum and characteristics. Most b-thal patients
      in Japan are heteorozygote and thal minor as a phenotype. They are prone to be
      misdiagnosed as iron deficiency anemia. Thirty-four mutations of b-thal were thus
      far identified, and ten of which comprise 80% of beta-thal carriers. Among them
      60% are unique to Japanese and 40% possibly from abroad. The exception is
      homozygote for -31G-A which leads to thal intermedia by beta(+)-thal phenoytpe.
      More than a half of patients with alpha-thal are of Southeast Asian type, but
      mutations of the remaining patients seem to be unique to Japanese and yet
      undetermined. Thus, Japanese thal's have dual origin. The frequency of beta-thal
      is one in 600 to approximately 1,000 of general population, and that of alpha(+)
      thal (- alpha/) is one in 400. Thus, alpha-thal trait (- alpha/- alpha) is
      extremely rare. Another alpha-thal trait (- -/alpha alpha) would be one fifth of
      beta-thal. Seventeen families of HbH disease (- -/- alpha) were found. Many of
      them are related to Southeast Asian. Cases of non-iron deficient microcytosis and
      positive in the screening for hemoglobinopathies are subjected to gene analysis
      using allele-specific PCR, SSCP, direct sequencing and gap PCR. Precise
      breakpoints with large deletion are being identified by gene dosage and PCR
      instead of conventional Southern blotting and cloning. Most Japanese thal's are
      asymptomatic (or not hemolytic) except for microcytosis. However, dominant-type b
      thal (or Heinz body beta-thal) are found, and their clinical phenotype vary with
      mutations. Some of them become symptomatic transiently. This is also seen in beta
      thal coexisting with alpha-triplication. Acute exacerbation or transient
      appearance of Heinz body is seen in ordinary thal mutations on physical
      conditions such as pregnancy.

PMID- 12430907
TI  - Beta-thalassemia in the Korean population.
AB  - Beta-thalassemia is uncommon in the Korean population, however it must be
      considered in the differential diagnosis of hypochromic anemia. The molecular
      characterization of beta-thalassemia is absolutely necessary for molecular
      diagnosis as well as any genetic epidemiological study in this region. We
      analyzed the molecular basis of beta-thalassemia in 47 Korean families. Using
      direct sequencing of genomic DNA amplified through PCR and haplotype analysis, 44
      beta-thalassemia genes were characterized, all of which were heterozygous.
      Fourteen different mutations were identified. The common mutations noted included
      the initiation codon (CD) ATG-->AGG (23.4%), CD 17 A-->T (21.2%), and IVS-II-1 G-
      >A (12.7%). Interestingly, mutations causing dominantly inherited beta
      thalassemia were common (17.0%). All cases of IVS-II-1 G-->A mutations were
      linked to the silent mutation of CD 91 C-->T of the -globin gene. The initiation
      CD ATG-->AGG and IVS-II-1 G-->A with CD 91 C-->T were found in the Far East only,
      and may be inherited from a common origin for each mutation, at least in Koreans.
      CD17 A-->T and CDs 41/42-TTCT were suggested to be introduced by gene-flow from
      southern China. Otherwise, Hb Korea, CDs 89/90 -GT and a novel beta-thalassemia
      mutation, CD 131 CAG-->TAG, were only identified in Koreans. This mutation
      spectrum is characteristic of the low prevalent area of beta-thalassemia, however
      it is quite different even from the adjacent countries, Japan or China.

PMID- 12430908
TI  - Beta-thalassaemia prototype of a single gene disorder with multiple phenotypes.
AB  - As the defective genes for more and more genetic disorders become unravelled, it
      is clear that patients with the same genotype can have many different clinical
      conditions even in monogenic disorders. The remarkable phenotypic diversity of
      the beta thalassaemias is prototypical of how the wide spectrum in disease
      severity can be generated. The most reliable and predictive factor of disease
      phenotype is the nature of the mutation at the beta-globin locus itself. However,
      relating phenotype to genotype is complicated by the complex interaction of the
      environment and other genetic factors at the secondary and tertiary levels, some
      implicated, and others, as yet unidentified. This article reviews the clinical
      and haematological diversity encountered in beta thalassaemia and their
      relationship with the underlying genotypes.

PMID- 12430910
TI  - PTCL: lessons from adult T-cell leukemia.
AB  - Peripheral T-cell lymphoma (PTCL) is a neoplastc disease of peripheral T
      lymphocytes/NK cells, including PTCL unspecified, anaplastic large T-cell
      lymphoma (ALCL), IBL-like T-cell lymphoma (AILD), intestinal T-cell lymphoma
      (ITCL) and adult T-cell leukemia/lymphoma (ATL). The incidence of PTCL is
      relatively uncommon although its incidence shows significant variations in the
      geographical regions and racial populations. In Asia, its incidence is high due
      to HTLV-I infection in Japan. Molecular mechanisms of oncogenesis of PTCLs remain
      unknown. Therefore, analyses of ATL will give us a clue to clarify the molecular
      mechanism.

PMID- 12430909
TI  - Carrier screening and genetic counselling in beta-thalassemia.
AB  - This paper review the most important aspects of carrier detection procedures,
      genetic counselling, population screening and prenatal diagnosis of beta
      thalassemias. Carrier detection can be made retrospectively, following the birth
      of an affected child or prospectively. Several programmes, with the aim of
      preventing homozygous beta-thalassemia, based on carrier screening and
      counselling of couples at marriage; preconception or early pregnancy, are
      operating in several Mediterranean at-risk populations. These programmes have
      been very effective, as indicated by increasing knowledge on thalassemia and its
      prevention by the target population and by the marked decline of the incidence of
      thalassemia major. Carrier detection is carried out by haematological methods
      followed by mutation detection by DNA analysis. Prenatal diagnosis is
      accomplished by mutation analysis on PCR-amplified DNA from chorionic villi.
      Future prospects include automation of the process of mutation-detection,
      simplification of preconception and preimplantation diagnosis and fetal diagnosis
      by analysis of fetal cells in maternal circulation.

PMID- 12430911
TI  - NK cell lymphoma.
AB  - Natural killer (NK) cells are lymphocytes with large granular lymphocyte
      morphology, CD3-CD56+ phenotype, non-MHC-restricted cytotoxicity, and germ-line
      configuration T-cell receptor genes. Two types of lymphomas originating from NK
      cells have been described; blastic NK-cell lymphoma, and nasal-type NK-cell
      lymphoma. Because recent reports indicate that blastic NK-cell lymphoma
      originates from the precursors of plasmacytoid dendritic cells, I will focus
      mainly on nasal-type NK-cell lymphoma, and discuss its pathogenesis, diagnostic
      problems, treatment strategy, and outcome. Nasal-type NK-cell lymphoma develops
      mostly in the nasal cavity and rarely in other sites, such as the skin and
      intestinal tract. Epstein-Barr virus (EBV) is found in lymphoma cells of almost
      all the patients, and is considered to be the etiologic agent. Indeed, EBV easily
      infects NK cells in the absence of CD21 antigen, or EBV receptor, on the surface
      of NK cells. Further, various types of oncogenes and suppressor oncogenes are
      found to be involved in its pathogenesis. Based on the data obtained from
      paraffin-embedded specimens, it is difficult to determine whether the lymphoma
      cells are of T-cell or NK-cell lineage, because immunohistochemical staining of
      cytoplasmic CD3 is positive both in T and NK cells, and CD56 is positive in a
      part of T cells. The presence of CD5 antigen indicates T-cell lineage. When the
      disease is limited, radiation therapy is effective, but not satisfactory. A new
      trial to use simultaneously both radiation and chemotherapy has started in Japan.
      In advanced stages, a combination chemotherapy including L-asparaginase seems to
      be promising, and high-dose chemotherapy with autologous or allogeneic stem cell
      support is under investigation. A recent report described the expression of short
      length P-glycoprotein (P-gp), but not full-length P-gp in NK cells, and this mini
      P-gp is unable to extrude daunorubicin. These findings may change the treatment
      strategy. Finally, I will present the results on interim analysis of 166 cases of
      nasal-type NK-cell lymphoma collected in Japan between 1994 and 1998.

PMID- 12430912
TI  - Idiopathic thrombocytopenic purpura: pathophysiology and management.
AB  - Our understanding of the pathophysiology of ITP owes to pioneering work of W J
      Harrington in 1951, delineating the immunologic nature of platelet destruction.
      In ITP, antibody-coated platelets are destroyed by macrophages of RES. However,
      other mechanisms are also implicated: C-mediated platelet lysis and newly
      described C-independent peroxide injury. Both induce platelet fragmentation and
      lysis, generating procoagulant platelet microparticles (PMP). A third mechanism
      of platelet consumption in the microvasculature is proposed, based on overlapping
      syndromes of ITP and TTP in some patients. In assessing hemostasis in ITP,
      platelet counts alone is not sufficient. Evaluation of platelet clumping, giant
      platelets, and platelet activation, marked by increased PMP is useful. Patients
      with platelet activation or giant platelets bleed less and detection of clumping
      prevents unwarranted therapy. Thrombotic complications may develop in ITP. A
      syndrome, characterized by recurrent TIA-like symptoms, progressive memory loss
      due to ischemic small vessel disease is described. The management of ITP should
      include the search for and elimination of underlying causes and careful
      evaluation of hemostasis. Therapy is divided into definitive vs symptomatic
      measures. The former including splenectomy, danazol, chemotherapy offers lasting
      remission after therapy was stopped, while the later including glucocorticoids,
      gammaglobuin, antiD antibodies and others increases platelet counts but seldom
      sustains remission upon withdrawal. Danazol therapy is up-dated since it is an
      effective and safe definite measure in ITP.

PMID- 12430913
TI  - Deficiency of ADAMTS13 in thrombotic thrombocytopenic purpura.
AB  - Thrombotic thrombocytopenic purpura, characterized by the presence of systemic
      hyaline thrombi in the arterioles and capillaries, is a potentially fatal disease
      that responds to plasma infusion or exchange. Recent studies have demonstrated
      that a metalloprotease in the normal plasma cleaves endothelial von Willebrand
      factor to a series of multimers. A deficiency of the protease, due to autoimmune
      IgG inhibitors or genetic mutations, is detected in patients with thrombotic
      thrombocytopenic purpura. Positional cloning based on kindreds with a genetic
      deficiency of the protease and amino acid sequencing of the purified protein have
      identified the protease as a novel member of the ADAMTS (a disintegrin and
      metalloprotease with thrombospondin type 1 repeat) zinc metalloprotease family
      located on the long arm of chromosome 9. Mutations of the gene are detected in
      patients with the congenital form of thrombotic thrombocytopenic purpura. In the
      circulation, proteolysis of von Willebrand factor is critical in regulating vWF
      platelet interaction. These advances in knowledge provide the basis for a
      rational approach to improving the diagnosis and treatment of thrombotic
      thrombocytopenic purpura.

PMID- 12430914
TI  - Management of bleeding disorders by prohemostatic therapy.
AB  - Pro-hemostatic therapy aims at an improvement of hemostasis, which may be
      achieved by amelioration of primary hemostasis, stimulation of fibrin formation
      or inhibition of fibrinolysis. These treatment strategies may be applied to
      specifically correct a defect in one of the pathways of coagulation, but have in
      some situations also been shown to be effective in reducing bleeding in patients
      without a primary defect in coagulation. Besides the transfusion of platelets in
      case of thrombocytopenia or severe platelet disorders, a pharmacological
      improvement of primary hemostasis may be achieved by the administration of
      desmopressin. The administration of DDAVP results in a marked increase in the
      plasma concentration of Von Willebrand factor (and associated coagulation factor
      VIII) and (also by yet unexplained additional mechanisms) a remarkable
      potentiation of primary hemostasis as a consequence. DDAVP is used for the
      prevention and treatment of bleeding in patients with von Willebrand disease or
      mild hemophilia A, and further in patients with an impaired function of primary
      hemostasis, such as in patients with uremia, liver cirrhosis or in patients with
      aspirin-associated bleeding. Based on the current insight that activation of
      coagulation in vivo predominantly proceeds by the tissue factor/factor VII(a)
      pathway, recombinant factor VIIa has been developed as a prohemostatic agent and
      has recently become available for clinical use. Indeed, in uncontrolled clinical
      studies this compound has been shown to exert a potent procoagulant activity and
      appeared to be highly effective in the prevention and treatment of bleeding,
      although most experience so far has been obtained in patients with severe and
      complicated coagulation defects. At present, a more general use of this agent for
      bleeding patients without an apparent coagulation defect is the subject of a
      number of ongoing clinical trials. Agents that exert anti-fibrinolytic activity
      are aprotinin and the group of lysine analogues. The pro-hemostatic effect of
      these agents proceeds not only by the inhibition of fibrinolysis (thereby
      shifting the procoagulant/anticoagulant balance towards a more procoagulant
      state), but also due to a protective effect on platelets, as has been
      demonstrated at least for aprotinin. The mechanism of this platelet-protective
      effect has, besides a potential prevention of plasmin-mediated loss of platelet
      receptors not been elucidated. Whether the pro-hemostatic effect of the anti
      fibrinolytic agents will eventually result in a higher incidence of
      thromboembolic complications is still a matter of debate (see further), however,
      this has so far not been shown in straightforward clinical trials.

PMID- 12430915
TI  - Molecular diagosis of von Willebrand disease.
AB  - von Willebrand disease (vWD) is one of the most common inherited human bleeding
      disorders, which is caused by quantitative or qualitative defects of von
      Willebrand factor (vWF). vWF is a highly multimerized glycoprotein that promotes
      platelet adhesion and aggregation at a high shear rate, while also acting as a
      carrier of coagulation factor VIII. vWD has been subdivided into three
      categories, which reflect their pathophysiology. Type 1 and type 3 vWD reflect
      partial or complete deficiency of vWF, whereas type 2 vWD reflects qualitative
      defect of vWF. The ability of vWF to interact with its platelet receptor and
      factor VIII, and the analysis of the multimeric composition of vWF are essential
      to identify patients with different vWD subtypes. The prevalence of different vWD
      subtypes was reported in the literature. In the past years, ninety-one patients
      with vWD were consulted in our institution. Of all the vWD patients, 56 (61.5%)
      belong to type 1, 26 (28.6%) type 2 and 9 (9.89%) type 3. The analysis of vWF
      gene was performed in some type 2 and type 3 vWD by denature gradient gel
      electrophoresis and sequencing. We have found six cases of point mutations of vWF
      gene, Ala737-->Glu, Gly 22-->Glu, Met37 Val and Ser71-->stop codon.
      Substitutions, are first reported in international database. We constructed an
      expression plasmid pSVA737EvWF containing full length of cDNA of vWF which
      included the Ala737 Glu substitution by site-direct mutagenesis. The structure of
      recombinant vWF within transfected COS-7 cells and the secretion of high
      molecular-weight (HMW) multimers were similar to wild-type vWF. HMW forms of vWF
      multimers were absent in plasma but present in platelets. The mutation
      corresponds to the group II type 2A vWD characterized by normal secretion of all
      vWF multimers.

PMID- 12430916
TI  - Current and emerging technology for HLA typing.
AB  - Many techniques based on polymerase chain reaction amplification have replaced
      the traditional serological technique in the Histocompatibility laboratory. In
      some tests the specificity is provided in the PCR amplification whereas in others
      all alleles will be amplified and the specificity is obtained in a second step.
      The choice of method will depend on a number of factors including time needed to
      provide result, resolution required and number of samples being processed. New
      methods or variations of existing methods are continually being developed.
      However the cost of equipment makes it difficult for a laboratory to decide on
      which methods to use.

PMID- 12430917
TI  - HLA diversity: detection and impact on unrelated hematopoietic stem cell donor
      characterization and selection.
AB  - Matching of patient and unrelated donor for HLA molecules significantly decreases
      the probability of graft rejection, graft vs. host disease, and transplant
      related mortality in hematopoietic stem cell transplantation. A significant
      challenge in the identification of matched donors is the diversity of the HLA
      system. Almost 1500 alleles have been identified at 12 HLA loci. Significant
      progress has been made in the application of DNA-based testing to identify this
      diversity in patients and unrelated volunteer donors; however, the resolution of
      registry testing remains limited by the need to test many donors inexpensively.
      Thus, the transplant center must predict which donor might be a match for their
      patient using incomplete typing information. Design of a typing strategy based on
      knowledge of allele and haplotype frequencies is critical to speed donor
      identification. A further challenge is to compare patient HLA assignments to the
      over 7.7 million volunteer donors on registries carrying both DNA and serologic
      assignments. The links between alleles and serologic specificities remain unclear
      in many cases and complicate the design of computer algorithms used to match
      patients and donors. Finally, since few patients will find donors who are allele
      matched for all HLA loci, studies are underway to understand which of the HLA
      loci are most critical to match and to define rules of permissive mismatching to
      achieve an acceptable outcome.

PMID- 12430918
TI  - Minor histocompatibility antigens--targets of graft versus leukemia responses.
AB  - Immune-mediated elimination of tumor cells by donor T cells recognizing recipient
      minor H antigens contributes to the curative potential of allogeneic HCT. The
      importance of the allogeneic response to a successful outcome is clearly
      illustrated by the results of stem cell transplant for malignancy after
      nonmyeloablative conditioning. Remarkably little is understood about the
      molecular nature of minor H antigens and this has impeded efforts to determine
      the role of specific disparities in graft versus tumor reactions or to manipulate
      T cell responses to augment antitumor activity without exacerbating GVHD. The
      isolation of minor H antigen-specific CD8+ and CD4+ T cell clones from recipients
      of allogeneic HCT has provided the reagents to characterize their expression on
      leukemic progenitors and to identify the genes encoding these antigens. Using
      cDNA expression cloning, genetic polymorphisms in the human IFI-75, Uty,
      KIAA0020, and UGT2B17 genes have been identified to encode new minor H antigens
      presented by HLA A3, B8, A2, and A29 respectively. Two of these genes are
      preferentially expressed in hematopoietic cells including leukemic progenitors
      suggesting it may be possible to augment T cell responses to promote a selective
      graft versus leukemia effect. A third gene, UGT2B17 is highly expressed in liver
      and GI tract and may be a target for GVHD in these organs. The studies to
      identify the molecular nature of minor H antigens have provided insights into the
      complexities of the graft versus host response associated with allogeneic HCT,
      but the challenge for the future will be to develop strategies that can
      selectively induce durable graft versus tumor effects without GVHD. A critical
      issue in developing specific immunotherapy to augment GVL responses is to
      determine which minor H antigens are expressed on leukemic stem cells. Studies
      using transplantation of human AML into SCID mice have identified a putative
      leukemic stem cell which is contained in the CD34+ CD38- subset of the blast
      population and is present in very low frequency (<1/200,000) in blood or bone
      marrow from AML patents. We have examined the ability of minor H antigen-specific
      CTL to prevent engraftment of human AML in NOD/SCID mice. These studies show that
      engraftment of leukemias derived from individuals encoding the minor H antigen
      can be specifically prevented demonstrating that AML stem cells express minor H
      antigens and are targets for CTL. One approach to determine directly which minor
      H antigens can be selectively targeted to induce a GVL effect without GVHD is to
      adoptively transfer T cell clones of defined specificity and function to patients
      who relapse after HCT. Studies of this approach are now in progress in acute
      leukemia and have provided important insights into potential obstacles of T cell
      therapy for relapsed leukemia after HCT.

PMID- 12430919
TI  - Views on the pathophysiology of aplastic anaemia.
AB  - Aplastic anaemia seems to be predominantly a defect of the stem cell rather than
      the stroma, though abnormalities of the microenvironment may co-exist. There is
      highly suggestive evidence that the stem cell is the target of an immune attack,
      though the main evidence remains the response to immunosuppression with
      antilymphocyte globulin and cyclosporin. The stem cell defect remains even after
      recovery of the peripheral blood counts and the AA marrow is a fertile
      environment for the emergence of abnormal clones, particularly PNH. However, it
      has recently become apparent that there is an overlap with the myelodysplastic
      syndromes and clones of monosomy 7 and trisomy 8 amongst others are not uncommon
      in aplastic anaemia. Recent work has suggested that the emergence of a clone of
      monosomy 7 cells carries a poor prognosis, whereas trisomy 8 has a good prognosis
      particularly in response to cyclosporin. However, the setting in which monosomy 7
      arises may affect the phenotypic expression. The immune targeting of stem cells
      may be associated with increased apoptosis in aplastic anaemia, in part mediated
      by fas expression, but not exclusively. Understanding the pathophysiology of AA
      should help to improve and perhaps target therapy.

PMID- 12430920
TI  - The relationship of aplastic anemia and PNH.
AB  - Bone marrow failure has been regarded as one of the triad of clinical
      manifestations of paroxysmal noctumal hemoglobinuria (PNH), and PNH in turn has
      been described as a late clonal disease evolving in patients recovering from
      aplastic anemia. Better understanding of the pathophysiology of both diseases and
      improved tests for cell surface glycosylphosphatidylinositol (GPI)-linked
      proteins has radically altered this view. Flow cytometry of granulocytes shows
      evidence of an expanded PNH clone in a large proportion of marrow failure
      patients at the time of presentation: in our large NIH series, about 1/3 of over
      200 aplastic anemia cases and almost 20% of more than 100 myelodysplasia cases.
      Clonal PNH expansion (rather than bone marrow failure) is strongly linked to the
      histocompatability antigen HLA.-DR2 in all clinical varieties of the disease,
      suggesting an immune component to its pathophysiology. An extrinsic mechanism of
      clonal expansion is also more consistent with knock-out mouse models and culture
      experiments with primary cells and cell lines, which have failed to demonstrate
      an intrinsic proliferative advantage for PNH cells. DNA chip analysis of multiple
      paired normal and PIG-A mutant cell lines and lymphoblastoid cells do not show
      any consistent differences in levels of gene expression. In aplastic anemia/PNH
      there is surprisingly limited utilization of the V-beta chain of the T cell
      receptor, and patients' dominant T cell clones, which are functionally inhibitory
      of autologous hematopoiesis, use identical CDR3 regions for antigen binding.
      Phenotypically normal cells from PNH patients proliferate more poorly in culture
      than do the same patient's PNH cells, and the normal cells are damaged as a
      result of apoptosis and overexpress Fas. Differences in protein degradation might
      play a dual role in pathophysiology, as GPI-linked proteins lacking an anchor
      would be predicted to be processed by the proteasome machinery and displayed in a
      class I H.A. context, in contrast to the normal pathway of cell surface membrane
      recycling, lysosomal degradation, and presentation by class II HLA. The strong
      relationship between a chronic, organ-specific immune destructive process and the
      expansion of a single mutant stem cell clone remains frustratingly enigmatic but
      likely to be the result of interesting biologic processes, with mechanisms that
      potentially can be extended to the role of inflammation in producing premalignant
      syndromes.

PMID- 12430921
TI  - Aplastic anemia in the Orient.
AB  - Aplastic anemia (AA) is more common in Asia than in Europe or the United States.
      This may be due in part to the high incidence of hepatitis-associated AA in Asia.
      The management of AA has evolved rapidly in Japan during the last decade.
      Advances in the treatment of AA have largely been the result of prospective
      collaborative studies of immunosuppressive therapy and the large registry of bone
      marrow transplantation data. These studies have revealed several differences in
      clinical outcome between Western and Eastern patients, differences that may
      reflect the effects of genetic background on response to treatment or development
      of adverse effects.

PMID- 12430922
TI  - Clinical importance of genetic findings in adult AML.

PMID- 12430923
TI  - New advances in the treatment of acute promyelocytic leukemia.
AB  - OBJECTIVE: Describe the treatment options of newly diagnosed and relapsed APL.
      INDUCTION: The fusion PML/RAR gene provided the rationale for using all-trans
      retinoic acid (ATRA) as differentiation therapy. The standard approach is
      antracycline + ATRA and no ARA-C. CONSOLIDATION: Anthracycline based
      chemotherapy, no high dose ARA-C and perhaps no ARA-C. Maintenance seems to be
      important. Cure with ATRA + chemotherapy increased to 75% from 35% with
      chemotherapy alone. POOR PROGNOSIS FACTORS: WBC >10,000, age >55, platelets
      <40,000 and CD 56 expression. Achieving and maintaining a molecular remission
      (MCR) i.e. RT-PCR (-) for PML/RAR alpha expression, is the best predictor for
      cure. Conversion to PCR (+) will eventually result in relapse. PCR monitoring in
      the first 2 years and intervention during molecular relapse would be safer than
      treatment in clinical relapse. Molecular relapses have been treated successfully
      by ATRA plus BMT. Arsenic trioxide (ATO) or gentuzumab (mylotarg) are also being
      studied. RELAPSE (INDUCTION): Patients after ATRA in first CR are less likely to
      respond to ATRA reinduction regardless of the time off ATRA and rarely achieve a
      molecular remission. Single-agent ATO induced in 52 relapsed patients CR of 87%
      (75% MCR) with low toxicity and no treatment related deaths (U.S. pivotal trial),
      confirmed in a NCI trial. Induction of relapsing patients with single agent ATO
      is preferable than ATRA + chemotherapy because the high molecular remission and
      lower toxicity. RELAPSE (POST REMISSION): No standard approach and the role of
      chemotherapy is unknown. ATO alone: in the pivotal trial, 9/21 patients had long
      remissions without other therapy. BMT: Not indicated in 1st MCR. In young
      patients auto BMT with PCR (-) harvests could be done in subsequent CR. Allo BMT
      has a higher death rate without overall better results. In the pivotal trial 12
      patients were transplanted in CR after ATO alone (9 allo BMT) and 11 still
      without disease. Possibly allo BMT is safer after a less toxic ATO induction.
      OTHER: ATO plus ATRA +/- AntiCD33 conjugated with toxin (gentuzumab) or 131I;
      Synthetic retinoid (Am80); histone deacetylase inhibitors; oral tetra-arsenic
      tetra-sulfide and various combinations.

PMID- 12430924
TI  - Treatment of chronic myeloid leukaemia: lessons and challenges.
AB  - The choice of primary treatment for patients with chronic myeloid leukaemia
      diagnosed in chronic phase has become exceedingly difficult. There is little
      doubt that allogeneic stem cell transplantation (allo-SCT) can eradicate the
      leukaemia and that a 'graft-versus-leukaemia' effect makes a major contribution
      to this result; conversely only a minority of patients are eligible for
      transplant, which still carries an appreciable risk of mortality or protracted
      morbidity. For the majority of patients interferon-alpha prolongs life to some
      degree in comparison with hydroxyurea but is associated with considerable
      toxicity. The newly introduced tyrosine kinase inhibitor imatinib mesylate
      (imatinib, Glivec) induces complete haematologic remission in almost all cases
      and is associated with a very high incidence of cytogenetic response; its
      capacity to prolong life in comparison with interferon-alpha is not yet
      established. Here we review some factors that predict survival after non
      transplant therapy and after allografting for CML in chronic phase. We consider
      two contrasting options for managing the newly diagnosed patient and conclude
      that for the present allogeneic stem cell transplantation soon after diagnosis
      should continue to be offered as an option for selected patients. Further
      experience with the use of imatinib as a single agent or in combination with
      other anti-leukemic agents may alter the picture in the near future.

PMID- 12430926
TI  - Real-time PCR for monitoring minimal residual disease and chimerism in patients
      after allogeneic transplantation.
AB  - Real-time PCR is a new fluorometric method for cycle-to-cycle quantification of
      PCR product growth rates. The real-time PCR method is fast and associated with a
      high reproducibility rate. It is used more often for monitoring MRD and chimerism
      in patients after allogeneic stem cell transplantation (SCT). There are real-time
      PCR methods for patients with CML, AML and ALL patients with inv(16), t(8;21),
      t(15;17); t(1;19) and other chromosomal aberrations. For patients with AML
      monitoring MRD is useful to identify patients who were at high risk for relapse
      after receiving chemotherapy. In patients with CML monitoring MRD might be
      helpful to assess success of after allogeneic SCT, or response to therapies with
      interferon alfa or STI 571. We found, that it is possible to estimate the relapse
      stage in CML after SCT by the amount of bcr-abl fusion transcript detected using
      a real-time PCR method. The median measured bcr-abl amount differ significantly
      (P<0.001) between the various stages, which has relevant clinical implications
      because it enables early therapeutic decisions in relapsing patients after
      transplant as e.g. the application of DLI to induce graft-versus-leukemia
      effects. Using real-time PCR it is possible to detect differences at alleles
      between recipient and donor at a single nucleotide basis (SNP) for chimerism
      analysis. The real-time PCR method enables to achieve a high a sensitivity of up
      to 1x10(-4), which is much more sensitive than all other chimerism methods
      including VNTR-PCR, STR-PCR. Furthermore, chimerism in male recipients with a
      female donor can be monitored also by detecting y-chromosome specific sequences
      by real-time PCR after transplant, which might be the most sensitive method to
      detect host type gene sequences. All in all, new real-time PCR methods offer a
      fast, reliable and very sensitive method to evaluate MRD and chimerism in
      patients after allogeneic SCT and therefore, to help to identify patients who are
      at high risk for leukemic relapse.

PMID- 12430925
TI  - Clinical and scientific advances in the Philadelphia-chromosome negative chronic
      myeloproliferative disorders.
AB  - The chronic myeloproliferative disorders are clonal hematopoietic stem cell
      disorders and include chronic myeloid leukemia (CML), polycythemia vera (PV),
      essential thrombocythemia (ET), and agnogenic myeloid metaplasia (AMM). These
      diseases are characterized by clonal expansion of the myeloid compartment,
      increased marrow angiogenesis, and varying risks for blastic transformation. A
      clear molecular abnormality exists (t(9;22) leading to the fusion of BCR-Abl)
      only for CML, which led to effective targeted therapy (STI-571). Since no similar
      pathogenetic mechanism has been discovered for the t(9;22) negative chronic
      myeloproliferative disorders, their respective diagnosis is currently based on a
      variety of rather cumbersome diagnostic criteria. Polycythemia vera is
      distinguished from reactive erythrocytosis through erythropoietin independent
      growth of erythroid progenitors in vitro, suppressed levels of endogenous
      erythropoietin, possible overexpression of PRV-1 (polycythemia rubra vera-1),
      decreased c-Mpl expression on megakaryocytes, as well as overexpression of bcl
      xL, and potentially aberrant activity of the Jak-Stat pathway. ET is defined by
      thrombocytosis and is distinguished from reactive states by decreased
      megakaryocyte c-Mpl expression, and a propensity for thrombosis. AMM has been
      associated with a variety of observations including increased concentrations of
      pro-fibrotic cytokines, increased angiogenesis, and myeloid expansion. AMM is
      often indistinguishable clinically and prognostically from the advanced phases of
      other CMPD (specifically post-polycythemic and post-thrombocythemia myeloid
      metaplasia), all of which are subentities of a diagnosis of myelofibrosis with
      myeloid metaplasia (MMM). The management of CMPD patients is quite varied given
      the broad range of disease severity and survival observed. The role of stem cell
      transplantation is limited by the age and comorbidities encountered in CMPD
      patients. Since no broadly applicable therapy effects the mortality of the CMPD,
      management currently focuses on the prevention/palliation of disease morbidity
      (i.e. vascular complications, pruritus, organomegaly, constitutional symptoms).
      Palliative strategies which currently focus on non-specific myelosuppresion, will
      hopefully be soon replaced by targeted therapies as insight into pathogenetic
      mechanisms of these diseases evolves.

PMID- 12430927
TI  - Biology and modulation of multidrug resistance (MDR) in hematological
      malignancies.
AB  - Drug resistance is one of the most significant impediments in the treatment of
      hematological malignancies. There have been a number of studies on the incidence
      of P-GP expression in tumor cells or tissues, where detectable level of P-GP has
      been found in all types of hematological malignancies. P-GP expression and
      significance in the patients varies widely between reported studies on patients
      with different ages and different disease types. Some of this validation can be
      accounted for by the threshold used to consider a sample positive for P-GP.
      However, mdr-1 is likely important in determining therapeutic outcome in patients
      with AML, NHL, and MM, although there is a suggestion of a different "behavior"
      between adult and childhood AML. In contrast, the significant prognostic
      association with expression of MRP and LRP is not consistent with disease types
      and disease stages. Clinical trials of modulation of MDR have been limited by
      following major factors. One is inability of achieving adequate blood levels of
      the modulator to reverse MDR, and the other is presence of other resistance
      mechanisms in addition to P-GP. The fact that P-GP modulators alter the
      pharmacokinetics of anti-cancer drugs can potentially increase toxicities if the
      dose of anticancer drugs is not appropriately reduced. Recently, MDR modulators
      such as valspodar have demonstrated substantial inhibition of P-GP. In this
      presentation, a number of characteristics in VCR-resistant cells are reported. We
      demonstrate that acquisition of MDR or recovery from MDR phenotypes differ in one
      cell type to another, a marked correlation between P-GP and susuceptibility to
      oxygen radicals, and altered gene expression of cell membrane antigen and
      apoptosis cascade genes. The efficacy of immunotherapies depends on the altered
      or unchanged target molecules of MDR cells. Thus, immunotherapies or reversal
      agents that aim at these substances in tumor cells should be useful to overcome
      MDR phenotypes.

PMID- 12430928
TI  - Molecular pathogenesis of MDS.
AB  - Myelodysplastic syndromes (MDS) are considered to be a family of clonal disorders
      of hematopoietic stem cells that are characterized by ineffective hematopoiesis
      and susceptibility to acute myelogenous leukemias, and are shown to be strikingly
      refractory to current therapeutic modalities. A substantial proportion of these
      complex diseases arise in the setting of exposures to environmental or
      occupational toxins, including cytotoxic therapy for a prior malignancy or other
      disorder. The conversion of a normal stem cell into a preleukemic and ultimately
      leukemic state is a multistep process requiring the accumulation of a number of
      genetic lesions. On the genomic level, MDS is typified by losses and
      translocations involving certain key gene segments, with disruption of the normal
      structure and function of genes that control the balance of proliferation and
      differentiation of hematopoietic precursors. More than a half of the chromosomal
      abnormalities in MDS comprise deletions of chromosomes 5, 7, 11, 12, 13 and 20.
      This evidence suggests that as yet unidentified tumor suppressor genes should
      have important roles in the molecular mechanisms of MDS. Further molecular
      approaches to such genetic lesions will identify the relevant tumor suppressor
      genes. Over the past years, major signal transduction molecules were identified
      and their genetic alterations were extensively analyzed in MDS as well as
      leukemias. These include receptors for growth factors, RAS signaling molecules,
      cell cycle regulators, and transcription factors. Among them, notable is
      transcription factors that regulate both proliferation and differentiation of
      hematopoitic stem cells. The disruption of the normal flow of the signal
      transduction pathways involving these molecules translates into ineffective
      multilineage hematopoiesis and bone marrow failure. Therefore, MDS provides a
      fertile testing ground on which we could study the molecular dissection
      implicated in the multistep leukemogenesis.

PMID- 12430929
TI  - Important features of myelodysplastic syndrome.
AB  - Myelodysplastic syndromes (MDS) are characterized by peripheral cytopenias in
      combination with a hyperplastic bone marrow. During the last 15 years, important
      progress has been made in the understanding of the biology and prognosis of
      myelodysplastic syndromes. The classification according to the World Health
      Organization (WHO) includes mainly morphological criteria and is supplemented by
      the International Prognostic Scoring System (IPSS) which takes cytogenetical
      changes into consideration when determining the prognosis of MDS. Also MDS after
      radiotherapy, chemotherapy or chemical exposure must be distinguished from
      primary MDS. The underlying mechanisms in primary MDS have not yet been
      established but it is a multistep alteration to the hematopoietic stem cells that
      include genes involved in cell cycle control, mitotic checkpoints as well as
      growth factor receptors, secondary signal proteins and transcription factors
      which gives the cell a growth advantage over its normal counterpart.

PMID- 12430930
TI  - The myelodysplastic syndromes: morphology, risk assessment, and clinical
      management (2002).
AB  - The Myelodysplastic Syndromes (MDS) represent a group of potentially acute
      myeloid leukemic disorders. There exists a delicate balance between increased
      apoptosis and proliferation of the leukemic hematopoietic stem cell that permits
      many patients to survive for years. When the balance shifts towards proliferation
      AML develops with a poor outcome for most but not all patients. I will review the
      latest proposals from the W.H.O. in classification, including pediatric MDS,
      prognostic factors and response criteria. Then I will present a strategy for the
      management of low risk patients with supportive care or low intensity treatment
      (cytokines, Immune modulation, anti-VEGF agents) and finally chemotherapy and
      intensive therapy with auto and allo BMT.

PMID- 12430931
TI  - Human T lymphotropic virus type-I and adult T-cell leukemia in Japan.
AB  - HTLV-I is the first retrovirus to be associated directly with human malignancy.
      In ATL-endemic areas, the rate of HTLV-I carriers is high. Both HTLV-I and ATL
      have been shown to be endemic in some regions of the world, especially in
      southwest Japan, the Caribbean islands, South Americas, and parts of Central
      Africa. Antibodies against HTLV-I have been found in over one million
      individuals, and more than 700 cases of ATL have been diagnosed each year in
      Japan alone. The cumulative incidence of ATL among HTLV-I carriers in Japan is
      estimated at 2.5% (3-5% in males, 1-2% in females). In endemic areas, HTLV-I Ab
      were found in the sera of 6 to 37 percent of healthy adults over 40 years of age.
      This clustering is thought to be due to the limited transmission of virus between
      socially isolated populations. The diagnostic criteria for HTLV-I associated ATL
      have been defined as follows. 1) Histologically and/or cytologically proven
      lymphoid malignancy with T cell antigens. 2) Abnormal T-lymphocytes present in
      the peripheral blood, except in the lymphoma type. 3) Serum specimens for all
      patients with ATL have HTLV-I Ab. 4) Demonstration of clonality of HTLV-I
      proviral DNA is a definite diagnosis of ATL. ATL shows diverse clinical features
      but can be divided into four subtypes: acute, chronic, smoldering, and lymphoma
      type. The pattern of HTLV-I transmission is through one of three different modes.
      Infected mothers can transmit the virus to newborns mainly via breast milk. The
      virus also can be transmitted from male to female by sexual intercourse, and
      through blood transfusion. Chemotherapy is not effective; the acute and lymphoma
      types have a poor prognosis. ATL is generally treated with curative intent using
      combination chemotherapy, although long-term success has been very limited.
      Unfortunately that advance did not translate into an improvement in the overall
      survival; the median remain 10 months. In contrast, smoldering ATL, or some cases
      of chronic ATL, may have a more protracted natural course, which may be
      compromised by aggressive chemotherapy. Alternative strategies for both acute and
      chronic forms are clearly needed. After infection of HTLV-I, there is a long
      latent period before onset of ATL. Analyses by PCR showed that clearly
      proliferation occurred in intermediate state or even carriers with high virus
      load. Such clonal proliferation might be preleukemic stage, which suggested that
      carriers with high virus load should be risk group to have ATL.

PMID- 12430933
TI  - Pathogen inactivation of blood components: current status and introduction of an
      approach using riboflavin as a photosensitizer.
AB  - Riboflavin is a naturally occurring compound and an essential human nutrient.
      Studies in the 1960s and 70s showed that it could be effective, when exposed to
      visible or UV light, in inactivating viruses and bacteria. This suggested to us
      that it could act as a photosensitizer useful in the inactivation of pathogens
      found in blood products, because of its nucleic acid specificity and its limited
      tendency toward indiscriminate oxidation. The riboflavin molecule is a planar,
      conjugated ring structure with a sugar side chain that confers water solubility.
      The planar portion is capable of intercalating between the bases of DNA or RNA.
      Light activated riboflavin oxidizes guanine in nucleic acids, preventing
      replication of the pathogen's genome. Gambro BCT is developing processes using
      riboflavin and light to inactivate pathogens in plasma, platelet, and red cell
      products. We call these Pathogen Eradication Technology (PET) processes.
      Riboflavin is non-toxic; it must be present in the body for good health. The
      photo-byproducts formed in the PET processes are lumichrome and protein adducts.
      The photodegradation of riboflavin in the body is clearly shown by the decrease
      in its concentration in neonates who are treated with intense visible light to
      break down circulating bilirubin, which their immature livers cannot yet handle.
      A definitive lookback study showed no difference in cancer rates between the
      55,000 children receiving this therapy in Denmark from 1977 through 1989 and
      nonirradiated controls. Gambro BCT is developing specific riboflavin-based PET
      processes for platelet concentrates, fresh frozen plasma, and packed red blood
      cells. In each, the process is being optimized to achieve high levels of
      inactivation of specific pathogens, while maintaining acceptable levels of
      product quality and activity. Extra- and intracellular HIV, BVDV (a model for
      HCV), and pseudorabies virus (a herpes virus) have been used to guide process
      development and validation. We have demonstrated 4 to 7 log10 reductions in the
      titers of these viruses, when they are spiked into blood products and irradiated
      in the presence of riboflavin. Porcine parvovirus, a tight-capsid, nonenveloped
      virus is more resistant, a finding in all experimental inactivation approaches. A
      range of bacteria implicated in platelet and red cell transfusion injuries and
      deaths, including S. aureus, E. coli, K. pneumoniae, and Y. enterocolitica, are
      being used to validate antibacterial efficacy. The PET platelet process involves
      the addition of riboflavin to platelets in plasma, illumination of the product,
      storage of the product and transfusion without further manipulation. The lack of
      toxicity of the treatment byproducts permits this ease of use. Quality of the
      platelets throughout storage has been assessed by pH, PO2, lactate, hypotonic
      shock response, morphology, glucose, and GMP-140 expression. In vitro function is
      well maintained. The levels seen are within the range of those reported in
      commonly transfused products. Radiolabeled transfusion studies of treated
      platelets have been carried out in primates to determine a preliminary measure of
      their in-vivo circulation. The in vivo recoveries and survivals of treated and
      control platelets did not differ. This work suggests that an endogenous
      photosensitizer, riboflavin, which has an extremely good safety profile, can
      inactivate high levels of a broad range of viruses and bacteria in platelet
      concentrates, fresh frozen plasma, and in red blood cells, preserving the
      activity and functionality of the components. Planned animal and clinical studies
      are expected to solidify this suggestion into a well-characterized process which
      can be safely and readily applied to reduce the risks of transfusion transmitted
      disease.

PMID- 12430932
TI  - Human herpesvirus 6 and human herpesvirus 7: emerging pathogens in transplant
      patients.
AB  - Human herpesvirus 6 (HHV-6) and HHV-7 are two recently identified beta
      herpesviruses, genetically related to human cytomegalovirus (CMV). Infection with
      both viruses is common worldwide with rates of seropositivity in adults over 90%.
      Infection with both viruses usually occurs in early childhood. In this age group
      HHV-6 is a cause of febrile illness including exanthem subitum, and likewise,
      primary HHV-7 infection has been associated with febrile illness. Similar to the
      other human herpesviruses, in particular CMV, the viruses have the potential for
      enhanced pathogenicity in the immunocompromised host. Active infection with both
      viruses is common following bone marrow or solid organ transplantation, most
      likely through reactivation of recipient's virus or re-infection considering
      their high prevalence in the population. Both viruses can be detected by PCR in
      the peripheral blood of healthy individuals and although the significance of
      blood-borne transmission is not clear, a preliminary study suggested that it was
      not significant for HHV-6. However, there is growing evidence that these viruses
      may be medically important in the post-transplant period. In bone marrow
      transplant patients HHV-6 has been associated with a range of clinical disease
      including encephalitis, interstitial pneumonitis, early and late graft failure
      and bone marrow suppression. There is also growing evidence for potential
      interactions among the beta-herpesviruses in liver and renal transplant patients.
      HHV-6 infection has been associated with an increased risk of developing CMV
      disease and opportunistic infections and HHV-7 infection has also been linked to
      an increased risk of CMV disease.

PMID- 12430934
TI  - The quest for quality blood banking program in the new millennium the American
      way.
AB  - For an industry to succeed and satisfy its customers, "QUALITY" must be a primary
      goal. Quality has been central to blood banking from its inception, with the
      evolution of a Quality Program since the opening of the first blood bank in U.S.
      at the Cook County Hospital in 1937. Over the ensuing decades, continuous
      scientific progress in blood preservation, filters, viral and blood group
      testing, crossmatching, automation, and computerization including bar coding,
      etc. has contributed to the quality and safety of the blood products and
      transfusion service. However, with the advent of the AIDS era, an increasingly
      sensitized and informed public is continuously demanding that the highest level
      of quality be achieved and maintained in all processes involved in providing all
      blood products. The Food and Drug Administration (FDA) introduced the concept of
      a "zero risk blood supply" as the industry goal. Furthermore, the cost
      containment and resource-constrained environment have changed the complexity of
      the quality practice. Both regulatory agencies such as the FDA, the Health Care
      Financing Administration [HCFA, which was recently renamed as the Centers for
      Medicare and Medicaid Services (CMS) in July, 2001], and the State Department of
      Health, and accrediting agencies, such as the American Association of Blood Banks
      (AABB), the College of American Pathologists (CAP), and the Joint Commission on
      Accreditation of Healthcare Organizations (JCAHO), require blood banks and
      transfusion services to establish and follow a Quality Control and Quality
      Assurance Program for their licensing, certification and accreditation. Every
      laboratory has to comply with the Clinical Laboratory Improvement Amendments of
      1988 (CLIA '88) quality requirements being implemented by the CMS. The FDA
      guidelines assist facilities in compliance with Current Good Manufacturing
      Practices (cGMP). The AABB's Quality System Essentials (QSE) are based on these
      specifications and provide additional guidance in implementing practices that
      assure quality and compliance with cGMP. AABB and CAP are granted "deemed status"
      as accrediting organizations under the CLIA '88 program by CMS, as well as JCAHO
      and some states. The International Standards Organization (ISO) has established
      international standards in most fields. The U.S. is represented in ISO by the
      American National Standards Institute (ANSI), and the National Committee for
      Clinical Laboratory Standards (NCCLS), as a global organization headquartered in
      the U.S., is a member of ANSI. The FDA and the AABB had begun incorporating many
      ISO principles into their own regulations and standards. The AABB's 10 QSEs are
      rooted in the 20 clauses of ISO 9000 series and compatible with their standards.
      In a Maslow-type model quality hierarchy by Tsiakals, so far the bottom three of
      the five progressive levels, Quality Control for method control, Quality
      Assurance for process control, and Quality System for system control have been
      implemented just to meet the regulatory and accrediting requirements. The next
      higher level, Quality Management for financial control, and the ultimate highest
      level, Total Quality Management for strategic control, should be our quest in
      this new millennium, and with the help of the AABB, ISO, FDA and all other
      organizations, we will achieve it. We should change our approach to quality
      issues from detection to prevention. We should improve the quality in transfusion
      practice itself by effective utilization of blood as a therapeutic resource with
      clear indication, maximum surgical blood order schedule, alternative transfusion
      such as autologous transfusion, hemodilution, and intra/post-operative blood
      salvage, surgical hemostasis, pharmacological hemostasis, and synthetic
      erythropoietin. Most importantly, implementation of the Quality Program should be
      something that we want to do rather than simply a burden that we have to do. A
      well-managed Quality Program is an effective and cost-efficient operation for the
      blood banks and transfusion services, and will enable us to better serve the
      patients for whom we exist.

PMID- 12430935
TI  - An approach to the diagnosis and treatment of bleeding disorders in infants.
AB  - The approach to a newborn or infant who is bleeding can be troublesome for the
      physician. This lecture will focus upon utilizing the history and screening
      laboratory to narrow the differential diagnosis in order to provide the most
      appropriate treatment for this potentially challenging patient population. First,
      a new approach to understanding the mechanism of coagulation and fibrin
      deposition will be presented followed by a discussion of the unique aspects of
      the coagulation system in the infant as well the importance of properly
      interpreting these laboratory values within the context of the medical history
      will be reviewed. Next, an overview of possible diagnoses for the bleeding infant
      will be surveyed with focus upon five specific bleeding conditions commonly
      encountered in infancy. Finally, general treatment considerations will be
      explored, followed by a brief offering of case studies when diagnosed based upon
      the screening laboratory.

PMID- 12430936
TI  - Non-myeloablative hematopoietic cell transplant for treatment of nonmalignant
      disorders in children.
AB  - Hematopoietic stem cell transplantation (HCT) may offer the only curative therapy
      for certain life-threatening immune deficiency disorders. Conventional HCT poses
      a risk to patients for severe morbidity, mortality, and late sequelae resulting
      from myeloablative preparative regimens. This review summarizes the development
      of nonmyeloablative regimens that have the potential to reduce both short- and
      long-term risks of HCT. Results of NM-HCT in a small number of patients indicate
      that this procedure may play an important role in treatment of life-threatening
      immune deficiencies.

PMID- 12430937
TI  - Designer drugs: new directed therapies for cancer.
AB  - The last thirty years have witnessed major improvements in the survival of
      pediatric cancer patients. This has been due to improvements in the various
      modalities of cancer therapy as well as improvements in supportive care.
      Historically, cancer treatments have been developed in an empiric fashion and
      amplified to the limits of tolerance. As more is learned about the biology of
      oncogenesis, we hope it will become possible to design therapies to deal with the
      unique mechanisms involved in the development of specific types of cancer. These
      rational approaches to cancer therapy should improve efficacy and diminish the
      risks of toxicity. The era of "designer drugs" is just beginning with the
      introduction of therapeutic monoclonal antibodies against tumor antigens, and new
      small molecules that target specific tumors, such as retinoids and imatinib
      mesylate. This presentation will review these advances and provide a perspective
      on potential future directions in this field.

PMID- 12430938
TI  - Umbilical cord blood for unrelated bone marrow replacement; Asia bank and Japan
      cord blood bank network update.
AB  - Cord blood offers many advantages including a high concentration of hematopoietic
      stem cells, a large number of potential donors, and ease of harvest. Furthermore,
      since there is no risk for either the mother or baby, few people refuse to
      donate. There is thought to be a low risk for virus contamination and also
      probably a low incidence and severity of GVHD. Cord blood can be obtained quickly
      without the assistance of a coordinator and one or 2 locus-mismatched HLA is
      usually acceptable. In Japan, there are 10 cord blood banks supported by the
      government. Between 1996 and June 2002, 9,500 units were registered with the
      Japan cord blood bank network (JCBBN). 630 units were delivered and most of these
      were transplanted. The status of registered cord blood units worldwide is shown.
      59,081 units have been registered by NETCORD. The Japan cord blood bank network
      accounts for 13% of these units. I will discuss the Tokyo cord blood tank (TCBB).
      The bank at Tokyo, to which we belong, is one of the largest banks in Japan. We
      helped to establish Asia CORD in 2000 and have held annual conferences and
      meetings in Tokyo to exchange information. So far, China, Korea, Taiwan,
      Thailand, Viet Nam and Japan have participated. We accepted three trainees from
      the Ho Chi Minh City Blood Transfusion and Hematology Center for training in cord
      blood transplantation in May 2001. In January 2002, a patient with ALL received
      cord blood and was successfully engrafted at Ho Chi Minh City Blood Transfusion
      and Hematology Center. We present here the clinical outcome of these patients
      through Tokyo cord blood bank and Japan cord blood bank network. First, the
      number of CB units stored and registered at JCBBN and TCBB has increased rapidly
      over the past two years. Second, the survival rate of acute leukemia patients in
      release was significantly lower than that in patients in CR. Third, the
      engraftment rate in patients with metabolic disease (50%) was lower than that in
      patients with leukemia. Fourth, there was no significant difference in the
      incidence of acute GVHD greater than grade II between patients with a 1-locus and
      2-locus mismatch. Finally, the incidence of acute GVHD was relatively low, and
      there were no deaths related to acute GVHD.

PMID- 12430939
TI  - Research within the field of blood and marrow transplantation nursing: how can it
      contribute to higher quality of care?
AB  - Nursing Science and research within BMT started in the early 80s and has been
      shown to be a useful contribution to obtain and maintain high standards of care.
      Trial and error are no longer accepted. The first studies were conducted together
      with the clinical developments and focused specifically on symptom control and
      management of the treatment. The term "evidence-based nursing" (EBN) is nowadays
      often used to describe the influence of research on practice. And yet we find
      that in general, care given by nurses is not yet based according to the
      guidelines established by research. There are several reasons why care is not
      (yet) based on results from research, like language barrier, diversity in health
      care and nursing educational systems, financial restrains and different roles and
      perceptions of nurses around the globe. Many nursing or multidisciplinary
      research studies have been conducted worldwide on areas such as the prevention or
      care for patients with mucositis, fatigue or pain, care for the central venous
      access devices, outpatient management of care, care for the donor and aspects of
      quality of life. Results have implications on practice and start to show their
      impact on quality of care. Many questions remain unanswered. Results from basic
      science (e.g. the discussion around fetal liver and embryonic derived stemcells
      and their use in treatment other than hematologic malignancies) and developments
      in medical treatments (e.g. introduction of tyrosin-kinase inhibitor, biotherapy
      and genetherapy) have an impact on nursing and should therefore be investigated
      closely to develop clinical pathways. It is obvious that much more time,
      finances, collaboration and support is needed to conduct powerful studies that
      can influence care for the BMT patient. This presentation will focus on
      developments through nursing research within the field of BMT and discuss gaps
      that will need to be filled in the near future.

PMID- 12430940
TI  - Treatment of polycythemia vera with recombinant interferon.

PMID- 12430941
TI  - The therapy of myelofibrosis: targeting pathogenesis.
AB  - Myelofibrosis with myeloid metaplasia (MMM) encompasses the diagnoses of
      agnogenic myeloid metaplasia (idiopathic myelofibrosis), as well as the advanced
      phases of polycythemia vera and essential thrombocythemia (post polycythemic and
      post thrombocythemia myeloid metaplasia, respectively). MMM is a clonal,
      hematopoietic stem cell disorder in which neither the pathogenesis, nor a broadly
      applicable effective therapy have been described. Clinically, these patients
      experience progressive marrow replacement by fibrotic tissue, ineffective
      hematopoiesis, problematic cytopenia's, significant hepato-splenomegaly,
      extramedullary hematopoiesis, profound constitutional symptoms, and a risk of
      blastic transformation. Historically, therapies have been targeted at palliating
      symptoms (i.e. splenectomy, transfusions, hydroxyurea, erythropoietin, androgens,
      localized radiotherapy). Stem cell transplantation appears promising, but is
      often toxic and not broadly applicable due to co-morbidities and age of MMM
      patients. Non-myeloablative approaches to conditioning may broaden the
      applicability of stem cell transplantation in MMM, yet results to date are
      preliminary. Although a definitive molecular abnormality responsible for the
      pathogenesis of MMM has not been described, much has been learned about the
      aberrant expression of pro-fibrotic cytokines and the presence of increased
      angiogenesis in MMM. These pathogenetic insights have led to a series of pilot
      clinical trials with therapeutic agents targeting aberrantly expressed cytokines
      (and possibly angiogenesis) including Thalidomide (alone or in combination),
      Etanercept, and STI-571. Amongst these later agents Thalidomide has demonstrated
      the most promise (palliating disease associated cytopenia's), whereas the TNF
      alpha inhibitor Etanercept has aided with MMM associated constitutional symptoms.
      Although these later trials have been helpful in a subset of patients, no agent
      to date has led to solid complete responses in MMM across the spectrum of disease
      manifestations. Further insights into the pathogenetic mechanisms responsible for
      myeloproliferation (aberrant cell signaling pathways, apoptotic resistance,
      other) are necessary to guide selection and testing of the expanding number of
      novel anti-neoplastic agents in chronic myeloid disorders and MMM.

PMID- 12430944
TI  - Perceptual pilgrimages.

PMID- 12430942
TI  - Basic sciences of the myeloproliferative diseases: pathogenic mechanisms of ET
      and PV.
AB  - The molecular pathogenesis of ET and PV is unknown, although the relatively
      indolent clinical course observed in most patients suggests that the defect may
      be subtle and difficult to establish. Clonality analysis using X-chromosome
      inactivation patterns in females on purified CD34+ cells have confirmed that a
      defect is present in the hematopoietic stem cell. However, at least in ET, a
      significant proportion of patients have polyclonal hemopoiesis, and this
      presumably reflects the heterogeneous nature of the disorder(s). Attention has
      focussed on the potential disruption of the physiological regulators EPO and TPO
      and their respective receptors. In familial disorders, pathological mutations
      have been identified in some, but by no means all, cases: EPO receptor mutations
      in PFCP, TPO mutations in FT and, conversely, TPO receptor (c-mpl) mutations in
      CAMT. Equivalent ligand or receptor mutations have not been detected in ET or PV
      patients. However, there is evidence to suggest that c-mpl expression may be
      dysregulated, with low or absent c-mpl mRNA or protein reported in ET and/or PV
      patients. At present it is not clear whether this is the cause or consequence of
      the paradoxically normal/increased TPO levels found with both primary and
      secondary thrombocytosis. In vitro culture analysis has demonstrated both
      cytokine independence and hyper-sensitivity as a generalised feature of
      progenitor cells from many patients, but differences exist depending on the
      assays used and there is little understanding of the mechanism(s) underlying
      these responses. Two genes have recently been identified with increased mRNA
      expression in PV granulocytes: PRV-1, a novel cell surface receptor closely
      related to the uPAR/Ly6/CD59/snake toxin family of proteins, and NFI-B, a member
      of the nuclear factor I family which may be associated with TGF-beta resistance.
      Investigation of their regulation and biological effects may assist in
      determining the pathobiology of these elusive disorders.

PMID- 12430943
TI  - What is the standard treatment in essential thrombocythemia.
AB  - The treatment of patients with essential thrombocythemia (ET) should be based
      primarily on the expected risk of major thrombotic complications. Although the
      specific values chosen for separating different risk categories are in part
      arbitrary, the following recomendations can be made. Young asymptomatic subjects
      with platelet counts below 1,500x10(9)/L are at lower risk and can be followed
      untreated. However, it should be emphasized that thrombotic events can also occur
      in a small percentage of these lower-risk cases. Low-dose aspirin (100-300
      mg/day) should be given to patients with symptoms of microvascular occlusion,
      such as erythromelalgia or transient neurological attacks, and avoided in those
      with bleeding manifestations. The risk/benefit of low-dose aspirin in the primary
      prevention of thrombosis in asymptomatic patients remains uncertain. For high
      risk patients (age >60 years, or platelet count >1,500x10(9)/L, or previous
      thrombosis), hydroxyurea, plus aspirin in the case of thrombosis, is the
      treatment of choice because its efficacy in preventing thrombotic complications
      has been proven in a randomized clinical trial. However, the possible long-term
      leukemogenicity of this drug, as well as that of other effective cytoreductive
      agents such as busulphan and pipobroman, remains a major concern. Anagrelide and
      interferon could overcome this worry but their efficacy has been hitherto
      demonstrated only in lowering the platelet count. Controlled clinical studies
      showing a benefit in preventing thrombotic and hemorrhagic complications are
      urgently needed.

PMID- 12430945
TI  - Representing motion in a static image: constraints and parallels in art, science,
      and popular culture.
AB  - Representing motion in a picture is a challenge to artists, scientists, and all
      other imagemakers. Moreover, it presents a problem that will not go away with
      electronic and digital media, because often the pedagogical purpose of the
      representation of motion is more important than the motion itself. All
      satisfactory solutions evoke motion-for example, dynamic balance (or broken
      symmetry), stroboscopic sequences, affine shear (or forward lean), and
      photographic blur-but they also typically sacrifice the accuracy of the motion
      represented, a solution often unsuitable for science. Vector representations
      superimposed on static images allow for accuracy, but are not applicable to all
      situations. Workable solutions are almost certainly case specific and subject to
      continual evolution through exploration by imagemakers.

PMID- 12430946
TI  - Spatial but not temporal cueing influences the mislocalisation of a target
      flashed during smooth pursuit.
AB  - Human subjects misjudge the position of a target that is flashed during a pursuit
      eye movement. Their judgments are biased in the direction in which the eyes are
      moving. We investigated whether this bias can be reduced by making the appearance
      of the flash more predictable. In the normal condition, subjects pursued a moving
      target that flashed somewhere along its trajectory. After the presentation, they
      indicated where they had seen the flash. The mislocalisations in this condition
      were compared to mislocalisations in conditions in which the subjects were given
      information about when or where the flash would come. This information consisted
      of giving two warning flashes spaced at equal intervals before the target flash,
      of giving two warning beeps spaced at equal intervals before the target flash, or
      of showing the same stimulus twice. Showing the same stimulus twice significantly
      reduced the mislocalisation. The other conditions did not. We interpret this as
      indicating that it is not predictability as such that influences the performance,
      but the fact that the target appears at a spatially cued position. This was
      supported by a second experiment, in which we examined whether subjects make
      smaller misjudgments when they have to determine the distance between a target
      flashed during pursuit and a reference seen previously, than when they have to
      determine the distance between the flashed target and a reference seen
      afterwards. This was indeed the case, presumably because the reference provided a
      spatial cue for the flash when it was presented first. We conclude that a spatial
      cue reduces the mislocalisation of targets that are flashed during pursuit eye
      movements. The cue does not have to be exactly at the same position as the flash.

PMID- 12430947
TI  - Flag errors in soccer games: the flash-lag effect brought to real life.
AB  - In soccer games, an attacking player is said to be in an offside position if he
      or she is closer to the opponents' goal line than both the ball and the second-to
      last defender. It is an offence for the attacker to be in an offside position and
      in active play at the moment a fellow team member plays the ball. Assistant
      referees often make mistakes when judging an offside offence, probably because of
      optical errors arising from the viewing angle adopted by them (Oudejans,
      Verheijen, Bakker, Gerrits, Steinbruckner, Beek, 2000 Nature 404 33). Looking
      more closely at Oudejans et al's data, we show evidence that the flash-lag effect
      may contribute significantly to these mistakes. Participation of the flash-lag
      effect in assistant referees' misjudgments would take this perceptual phenomenon
      from laboratory setups to a real-life situation for the first time.

PMID- 12430948
TI  - Blur discrimination and its relation to blur-mediated depth perception.
AB  - Retinal images of three-dimensional scenes often contain regions that are
      spatially blurred by different amounts, owing to depth variation in the scene and
      depth-of-focus limitations in the eye. Variations in blur between regions in the
      retinal image therefore offer a cue to their relative physical depths. In the
      first experiment we investigated apparent depth ordering in images containing two
      regions of random texture separated by a vertical sinusoidal border. The texture
      was sharp on one side of the border, and blurred on the other side. In some
      presentations the border itself was also blurred. Results showed that blur
      variation alone is sufficient to determine the apparent depth ordering. A
      subsequent series of experiments measured blur-discrimination thresholds with
      stimuli similar to those used in the depth-ordering experiment. Weber fractions
      for blur discrimination ranged from 0.28 to 0.56. It is concluded that the
      utility of blur variation as a depth cue is constrained by the relatively
      mediocre ability of observers to discriminate different levels of blur. Blur is
      best viewed as a relatively coarse, qualitative depth cue.

PMID- 12430949
TI  - Effects of geometric distortions on face-recognition performance.
AB  - The importance of 'configural' processing for face recognition is now well
      established, but it remains unclear precisely what it entails. Through four
      experiments we attempted to clarify the nature of configural processing by
      investigating the effects of various affine transformations on the recognition of
      familiar faces. Experiment 1 showed that recognition was markedly impaired by
      inversion of faces, somewhat impaired by shearing or horizontally stretching
      them, but unaffected by vertical stretching of faces to twice their normal
      height. In experiment 2 we investigated vertical and horizontal stretching in
      more detail, and found no effects of either transformation. Two further
      experiments were performed to determine whether participants were recognising
      stretched faces by using configural information. Experiment 3 showed that
      nonglobal vertical stretching of faces (stretching either the top or the bottom
      half while leaving the remainder undistorted) impaired recognition, implying that
      configural information from the stretched part of the face was influencing the
      process of recognition--ie that configural processing involves global facial
      properties. In experiment 4 we examined the effects of Gaussian blurring on
      recognition of undistorted and vertically stretched faces. Faces remained
      recognisable even when they were both stretched and blurred, implying that
      participants were basing their judgments on configural information from these
      stimuli, rather than resorting to some strategy based on local featural details.
      The tolerance of spatial distortions in human face recognition suggests that the
      configural information used as a basis for face recognition is unlikely to
      involve information about the absolute position of facial features relative to
      each other, at least not in any simple way.

PMID- 12430950
TI  - Latency correction explains the classical geometrical illusions.
AB  - There is a significant delay between the time when light hits the retina and the
      time of the consequent percept. It has been hypothesized that the visual system
      attempts to correct for this latency by generating a percept representative of
      the way the world probably is at the time the percept is elicited, rather than a
      percept of the recent past. Here we show that such a 'perceiving the present'
      hypothesis explains a number of classical geometrical illusions: the Hering,
      Orbison, Muller-Lyer, Double Judd, Poggendorff, Corner, and Upside-down-T
      illusions. Each stimulus is perceived as it would project in the next moment were
      the observer moving through the scene the stimulus probably represents. We also
      examine one general class of predictions made by the hypothesis, and report
      psychophysical experiments confirming the predictions.

PMID- 12430951
TI  - The haptic Muller-Lyer illusion in sighted and blind people.
AB  - We examined the effect of visual experience on the haptic Muller-Lyer illusion.
      Subjects made size estimates of raised lines by using a sliding haptic ruler.
      Independent groups of blind-folded-sighted, late-blind, congenitally blind, and
      low-vision subjects judged the sizes of wings-in and wings-out stimuli, plain
      lines, and lines with short vertical ends. An illusion was found, since the wings
      in stimuli were judged as shorter than the wings-out patterns and all of the
      other stimuli. Subjects generally underestimated the lengths of lines. In a
      second experiment we found a nonsignificant difference between length judgments
      of raised lines as opposed to smooth wooden dowels. The strength of the haptic
      illusion depends upon the angles of the wings, with a much stronger illusion for
      more acute angles. The effect of visual status was nonsignificant, suggesting
      that spatial distortion in the haptic Muller-Lyer illusion does not depend upon
      visual imagery or visual experience.

PMID- 12430952
TI  - Optimising the Pinna--Brelstaff illusion.

PMID- 12430953
TI  - Structure, function and evolution of the gas exchangers: comparative
      perspectives.
AB  - Over the evolutionary continuum, animals have faced similar fundamental
      challenges of acquiring molecular oxygen for aerobic metabolism. Under
      limitations and constraints imposed by factors such as phylogeny, behaviour, body
      size and environment, they have responded differently in founding optimal
      respiratory structures. A quintessence of the aphorism that 'necessity is the
      mother of invention', gas exchangers have been inaugurated through stiff cost
      benefit analyses that have evoked transaction of trade-offs and compromises.
      Cogent structural-functional correlations occur in constructions of gas
      exchangers: within and between taxa, morphological complexity and respiratory
      efficiency increase with metabolic capacities and oxygen needs. Highly active,
      small endotherms have relatively better-refined gas exchangers compared with
      large, inactive ectotherms. Respiratory structures have developed from the plain
      cell membrane of the primeval prokaryotic unicells to complex multifunctional
      ones of the modern Metazoa. Regarding the respiratory medium used to extract
      oxygen from, animal life has had only two choices--water or air--within the
      biological range of temperature and pressure the only naturally occurring
      respirable fluids. In rarer cases, certain animals have adapted to using both
      media. Gills (evaginated gas exchangers) are the primordial respiratory organs:
      they are the archetypal water breathing organs. Lungs (invaginated gas
      exchangers) are the model air breathing organs. Bimodal (transitional) breathers
      occupy the water-air interface. Presentation and exposure of external (water/air)
      and internal (haemolymph/blood) respiratory media, features determined by
      geometric arrangement of the conduits, are important features for gas exchange
      efficiency: counter-current, cross-current, uniform pool and infinite pool
      designs have variably developed.

PMID- 12430954
TI  - The diaphragm: two physiological muscles in one.
AB  - To the respiratory physiologist or anatomist the diaphragm muscle is of course
      the prime mover of tidal air. However, gastrointestinal physiologists are
      becoming increasingly aware of the value of this muscle in helping to stop
      gastric contents from refluxing into the oesophagus. The diaphragm should be
      viewed as two distinct muscles, crural and costal, which act in synchrony
      throughout respiration. However, the activities of these two muscular regions can
      diverge during certain events such as swallowing and emesis. In addition,
      transient crural muscle relaxations herald the onset of spontaneous acid reflux
      episodes. Studying the motor control of this muscular barrier may help elucidate
      the mechanism of these episodes. In the rat, the phrenic nerve divides into three
      branches before entering the diaphragm, and it is possible to sample single
      neuronal activity from the crural and costal branches. This review will discuss
      our recent findings with regard to the type of motor axons running in the phrenic
      nerve of the rat. In addition, we will outline our ongoing search for homologous
      structures in basal vertebrate groups. In particular, the pipid frogs (e.g. the
      African clawed frog, Xenopus laevis) possess a muscular band around the
      oesophagus that appears to be homologous to the mammalian crural diaphragm. This
      structure does not appear to interact directly with the respiratory apparatus,
      and could suggest a role for this region of the diaphragm, which was not
      originally respiratory.

PMID- 12430955
TI  - Regulation of the depth and composition of airway surface liquid.
AB  - The airways are lined with a film of liquid about 10 microm deep that is in two
      layers. Around the cilia is the watery periciliary sol. Over this is a mucous
      blanket that traps inhaled particles. The low viscosity of the periciliary sol
      allows the cilia to beat and propel the mucous blanket to the mouth. In large
      airways, mucus comes predominantly from the mucous glands but also from goblet
      cells in the surface epithelium. Water is added to the airway surface by gland
      secretion that is driven by active Cl secretion by serous cells. During
      inflammation elevation of the subepithelial hydrostatic pressure may also add
      significant volumes of water to the airway lumen. Water is removed by active Na
      transport across the surface epithelium. In airway diseases, the balance is
      shifted from water secretion to mucus secretion. In bronchitis and asthma this is
      due mainly to conversion of gland serous to mucous cells. In cystic fibrosis,
      gland serous cells cannot secrete water because they lack functioning CFTR in
      their apical membranes (CFTR is the cystic fibrosis transmembrane conductance
      regulator, a Cl channel that is abundant in serous cells). In all three diseases,
      the result is secretion of excessively concentrated gland secretions that are
      poorly moved by the cilia and accumulate. Altered salt and water transport by the
      surface epithelium may also contribute to the pathology of cystic fibrosis.

PMID- 12430956
TI  - Central control of upper airway resistance regulating respiratory airflow in
      mammals.
AB  - This article reviews recent studies on the importance of glycine receptors for
      both the spontaneous and the reflex respiratory modulation of the laryngeal
      abductors and adductors. Our findings show that strychnine blockade of glycine
      receptors within the brainstem changes the eupneic three-phase respiratory
      pattern into two phases. This has major implications for glottal control: (i) the
      inspiratory glottic abduction and early expiratory adduction were both
      compromised--a finding mimicked by 5% hypoxia; (ii) closure of the glottis during
      defensive upper airway reflexes became intermittent and the reflex apnoea
      reversed to sustained inspiratory discharge. Based on these data, we predict that
      periods of prolonged hypoxia, such as those that occur during sleep apnoeas, will
      constrain inspiratory glottic abduction thereby impeding inhalation.

PMID- 12430957
TI  - Airway and blood vessel interaction during lung development.
AB  - In the adult lung the pulmonary arteries run alongside the airways and the
      pulmonary veins show a similar branching pattern to the arteries, though
      separated from them. During early fetal development the airways act as a template
      for pulmonary blood vessel development in that the vessels form by vasculogenesis
      around the branching airways. In later lung development the capillary bed is
      essential for alveolar formation. This paper reviews evidence for the interaction
      of the airways and blood vessels in both normal and abnormal lung development.

PMID- 12430959
TI  - The ICRP and dosimetry: (glasnost) redux. International Commission on
      Radiological Protection.

PMID- 12430960
TI  - Cytogenic investigations of serious overexposures to an industrial gamma
      radiography source.
AB  - This paper describes the sequence of events, medical aspects and dose estimations
      for two radiographers and their driver who were seriously exposed to an iridium
      192 industrial radiography source that became detached from its wind-out cable.
      The men came to medical attention about 1 month later by which time all three
      were severely leucopenic and one had skin burns on both hands. Doses were
      estimated by (i) physics calculations combined with their accounts of the event.
      (ii) the levels of depression of their blood neutrophils, (iii) electron spin
      resonance on tooth enamel and (iv) blood lymphocyte chromosomal analyses by the
      conventional dicentric and the fluorescence in situ hybridisation methods.
      Intercomparison of these methods for estimating doses showed a good level of
      agreement. In brief, the averaged whole body dose for the most seriously exposed
      man was about 2.5-3.0 Gy and for the others it was 1.0-2.0 Gy.

PMID- 12430958
TI  - The structural basis of pulmonary hypertension in chronic lung disease:
      remodelling, rarefaction or angiogenesis?
AB  - Chronic lung disease in humans is frequently complicated by the development of
      secondary pulmonary hypertension, which is associated with increased morbidity
      and mortality. Hypoxia, inflammation and increased shear stress are the primary
      stimuli although the exact pathways through which these initiating events lead to
      pulmonary hypertension remain to be completely elucidated. The increase in
      pulmonary vascular resistance is attributed, in part, to remodelling of the walls
      of resistance vessels. This consists of intimal, medial and adventitial
      hypertrophy, which can lead to encroachment into and reduction of the vascular
      lumen. In addition, it has been reported that there is a reduction in the number
      of blood vessels in the hypertensive lung, which could also contribute to
      increased vascular resistance. The pulmonary endothelium plays a key role in
      mediating and modulating these changes. These structural alterations in the
      pulmonary vasculature contrast sharply with the responses of the systemic
      vasculature to the same stimuli. In systemic organs, both hypoxia and
      inflammation cause angiogenesis. Furthermore, remodelling of the walls of
      resistance vessels is not observed in these conditions. Thus it has been
      generally stated that, in the adult pulmonary circulation, angiogenesis does not
      occur. Prompted by previous observations that chronic airway inflammation can
      lead to pulmonary vascular remodelling without hypertension, we have recently
      shown, using quantitative stereological techniques, that angiogenesis can occur
      in the adult pulmonary circulation. Pulmonary angiogenesis has also been reported
      in some other conditions including post-pneumonectomy lung growth, metastatic
      disease of the lung and in biliary cirrhosis. Such angiogenesis may serve to
      prevent or attenuate increased vascular resistance in lung disease. In view of
      these more recent data, the role of structural alterations in the pulmonary
      vasculature in the development of pulmonary hypertension should be carefully
      reconsidered.

PMID- 12430961
TI  - Galactic and solar radiation exposure to aircrew during a solar cycle.
AB  - An on-going investigation using a tissue-equivalent proportional counter (TEPC)
      has been carried out to measure the ambient dose equivalent rate of the cosmic
      radiation exposure of aircrew during a solar cycle. A semi-empirical model has
      been derived from these data to allow for the interpolation of the dose rate for
      any global position. The model has been extended to an altitude of up to 32 km
      with further measurements made on board aircraft and several balloon flights. The
      effects of changing solar modulation during the solar cycle are characterised by
      correlating the dose rate data to different solar potential models. Through
      integration of the dose-rate function over a great circle flight path or between
      given waypoints, a Predictive Code for Aircrew Radiation Exposure (PCAIRE) has
      been further developed for estimation of the route dose from galactic cosmic
      radiation exposure. This estimate is provided in units of ambient dose equivalent
      as well as effective dose, based on E/H x (10) scaling functions as determined
      from transport code calculations with LUIN and FLUKA. This experimentally based
      treatment has also been compared with the CARI-6 and EPCARD codes that are
      derived solely from theoretical transport calculations. Using TEPC measurements
      taken aboard the International Space Station, ground based neutron monitoring,
      GOES satellite data and transport code analysis, an empirical model has been
      further proposed for estimation of aircrew exposure during solar particle events.
      This model has been compared to results obtained during recent solar flare
      events.

PMID- 12430962
TI  - Uncertainty analysis of the weighted equivalent lung dose per unit exposure to
      radon progeny in the home.
AB  - A parameter uncertainty analysis has been performed to derive the probability
      distribution of the weighted equivalent dose to lung for an adult (w(lung)
      H(lung)) per unit exposure to radon progeny in the home. The analysis was
      performed using the ICRP Publication 66 human respiratory tract model (HRTM) with
      tissue weighting factor for the lung, w(lung) = 0.12 and the radiation weighting
      factor for alpha particles, wR = 20. It is assumed that the HRTM is a realistic
      representation of the physical and biological processes, and that the parameter
      values are uncertain. The parameter probability distributions used in the
      analysis were based on a combination of experimental results and expert judgement
      from several prominent European scientists. The assignment of the probability
      distributions describing the uncertainty in the values of the assigned fractions
      (ABB, Abb, AAI) of the tissue weighting factor proved difficult in practice due
      to lack of quantitative data. Because of this several distributions were
      considered. The results of the analysis give a mean value of w(lung) H(lung) per
      unit exposure to radon progeny in the home of 15 mSv per working level month
      (WLM) for a population. For a given radon gas concentration, the mean value of
      w(lung) H(lung) per unit exposure is 13 mSv per 200 Bq.m(-3).y of 222Rn.
      Parameters characterising the distributions of w(lung) H(lung) per unit exposure
      are given. If the ICRP weighting factors are fixed at their default values (ABB,
      Abb, AAI = 0.333, 0.333, 0.333; w(lung) = 0.12; and wr = 20) then on the basis of
      this uncertainty analysis it is extremely unlikely (P approximately 0.0007) that
      a value of Hw/Pp for exposure in the home is as low as 4 mSv per WLM, the value
      determined with the epidemiological approach. Even when the uncertainties in the
      ABB, Abb, AAI, values are included then this probability is predicted to be
      between 0.01 to 0.08 depending upon the distribution assumed for describing the
      uncertainties in the ABB, Abb, AAI, values. Thus, it is concluded that the
      uncertainties in the HRTM parameters considered in this study cannot totally
      account for the discrepancy between the dosimetric and epidemiological
      approaches.

PMID- 12430963
TI  - Uranium and thorium series radionuclides in drinking water from drilled bedrock
      wells: correlation to geology and bedrock radioactivity and dose estimation.
AB  - Natural radioactivity in drinking water from 328 drilled wells was studied in
      correlation to source parameters. Poor correlation to both aquifer geology and
      bedrock radioactivity was observed. Concentrations of 238U, 226Ra, 228Ra, 222Rn
      and 210Po in groundwater samples was in the ranges <0.027-5.3, <0.016-4.9, <0.014
      1.24, 5-8105 and <0.05-0.947 Bq.l(-1) respectively. In about 80% of the sites the
      radon concentration exceeds the Nordic recommended exemption level for radon in
      drinking water and 15% of the sites exceed the action limit. The effective doses
      from ingestion were calculated and presented in association with geology. Doses
      due to ingestion ranged between 0.05 and 20.4 mSv.y(-1), where the average
      contribution from 222Rn amounted to 75%. In comparison, the effective doses from
      inhalation of indoor 222Rn ranged between 0.2 and 20 mSv.y(-1). The average
      contribution from inhalation of 222Rn in air to the total effective dose
      (ingestion+inhalation) was 58 +/- 22%, 73 +/- 18% and 77 +/- 16% (1 SD) for the
      age categories 1 y, 10 y and adults respectively.

PMID- 12430964
TI  - Spectral ultraviolet measurements by a multichannel monitor and a brewer
      spectroradiometer: a field study.
AB  - Two different instruments for measuring the spectral UV irradiance were used in a
      field comparison study in July 2000 in Rome, Italy: a Brewer spectrophotometer
      and a moderate-bandwidth filter radiometer (GUV-511C). The Brewer is designed to
      measure the solar spectral irradiances in the region from 290 nm to 325 nm with a
      spectral resolution of 0.5 nm. The GUV-511C measures hand-averaged spectral
      irradiance at four wavelengths: 305, 320, 340 and 380 nm with a bandwidth
      depending on the filter type for each channel (about 10 nm full width half
      maximum, FWHM). Comparisons between the two instruments were made for 5 days for
      the two wavelengths 305 and 320 nm under different meteorological conditions with
      the Brewer taken as the reference.

PMID- 12430965
TI  - Exact and approximate Bayesian estimation of net counting rates.
AB  - The stochastic fluctuations in the number of disintegrations, which had already
      been studied experimentally by Rutherford and other investigators at the
      beginning of the twentieth century, make estimation of net counting rates in the
      presence of background counts a challenging statistical problem. Exact and
      approximate Bayesian estimates of net count rates using Poisson and normal
      distributions for the number of counts detected during varying counting intervals
      are derived. The posterior densities for the net count rate are derived and
      plotted for uniform priors. The graphs for the exact, Poisson based, and for the
      approximate posterior densities of the background and net count rates, resulting
      from the normal approximation to the Poisson distribution, were compared. No
      practical differences were found when the number of observed gross counts is
      large. Small numerical differences in the posterior expectations and standard
      deviations of the counting rates appeared when the number of observed counts was
      small. A table showing some of these numerical differences for different
      background and gross counts is included. A normal approximation to the Poisson is
      satisfactory for the analysis of counting data when the number of observed counts
      is large. Some caution has to be exercised when the number of observed counts is
      small.

PMID- 12430966
TI  - The use of computerised glow curve analysis will optimise personal
      thermoluminescence dosimetry measurements. Favouring the proposition.

PMID- 12430967
TI  - The use of computerised glow curve analysis will optimise personal
      thermoluminescence dosimetry measurements. Opposing the proposition.
AB  - Referring to the proposition for this debate, it is necessary to consider what is
      meant by 'optimise personal thermoluminescence dosimetry measurements'. Much
      research has been performed on the thermoluminescence glow curves that can be
      used to determine absorbed dose, and much of the knowledge gained from this
      research has been put into practice. Thermoluminescence dosemeters are capable of
      measuring an extremely wide range of doses and dose rates. Nearly all types of
      radiation can be measured, and some TL dosemeters have been designed to function
      as elementary spectrometers. More recently, the microdosimetric properties of TL
      dosemeters have been investigated. TL dosemeters are worn by a large proportion
      of radiation workers worldwide. But, can we conclude that thermoluminescence
      dosimetry measurements are at an optimum level? Perhaps that is not a fair
      question because it may be impossible to say when anything is truly optimum.
      Although the techniques pointed out by our debaters may not yet be used by all
      large, personal dosimetry services, as with many recent innovations,
      implementation may be as near as the next computer chip upgrade.

PMID- 12430968
TI  - 'Coach class thrombosis': is the risk real? What do we tell our patients?

PMID- 12430969
TI  - Discussing breast cancer and hormone replacement therapy with women.
AB  - Although the results of the Women's Health Initiative showed an increased risk of
      breast cancer in women taking hormone replacement therapy (HRT), the absolute
      risk is very low. We discuss limitations of the study, questions that remain, and
      how to discuss the study with women at average risk and high risk for breast
      cancer.

PMID- 12430970
TI  - Very-low-carbohydrate weight-loss diets revisited.
AB  - Much scientific and anecdotal data demonstrate favorable metabolic responses to
      very-low-carbohydrate diets. We believe that very-low-carbohydrate diets merit
      further study for weight loss, and that criticisms of these diets lack scientific
      evidence.

PMID- 12430971
TI  - Making good decisions about diet: weight loss is not weight maintenance.

PMID- 12430972
TI  - Hematuria: an algorithmic approach to finding the cause.
AB  - Many conditions can cause hematuria, but the differential diagnosis can be
      simplified with a systematic approach. We discuss the common causes of hematuria
      and how to evaluate it.

PMID- 12430973
TI  - Preventing kidney stones: calcium restriction not warranted.
AB  - The traditional wisdom on preventing calcium stones, the most common form of
      kidney stone, has been to advise patients to limit dietary calcium. Research has
      proved this wrong, however. Normal dietary calcium intake, along with reduced
      salt and protein, is now advised. This paper also summarizes the diagnosis and
      treatment of the less-common forms of kidney stones-struvite, uric acid, and
      cystine.

PMID- 12430974
TI  - Mitral valve prolapse: old beliefs yield to new knowledge.
AB  - Much of the conventional wisdom about the prevalance, causes, diagnosis,
      symptoms, effects, and treament of mitral valve prolapse (MVP) is changing. MVP
      has a benign course and excellent prognosis for most patients, with only a small
      minority developing serious complications.

PMID- 12430975
TI  - Bariatric surgery for morbid obesity: why, who, when, how, where, and then what?
AB  - Bariatric surgery is not a cure, but it can take weight off and keep it off,
      improve most obesity-related conditions, reduce the risk of premature death, and
      improve quality of life. Given the interest in the procedure, primary care
      physicians need to understand the risks and benefits to help patients determine
      if this therapy is a good option, and they need to know the health changes that
      may occur after surgery when following these patients.

PMID- 12430976
TI  - A 47-year-old alcoholic man with progressive abnormal gait.
AB  - Central pontine myelinolysis should be considered in the differential diagnosis
      of a patient with a history of alcoholism and malnutrition presenting with
      ataxia, regardless of serum sodium values. T2-weighted images are the most
      sensitive imaging technique, but changes may not be evident for weeks after the
      insult, and in addition, the insult may not be known. Supportive care is
      important to prevent complications, but no treatment has been found to be
      effective in treating the illness. Patient outcomes vary considerably and are
      difficult to predict.

PMID- 12430977
TI  - Lumbar canal stenosis: start with nonsurgical therapy.
AB  - Although surgery is widely viewed as the definitive therapy for lumbar spinal
      stenosis, no randomized trials have compared surgical vs medical treatment. One
      study found that 60% of surgically treated patients improved, compared with 30%
      of those treated nonsurgically. We believe an initial nonsurgical approach is
      advisable for most patients.

PMID- 12430978
TI  - Facilitating an understanding of integrative physiology: emphasis on the
      composition of body fluid compartments.
AB  - As a teaching exercise, we used deductive reasoning and a quantitative analysis
      to convert a number of facts into a series of concepts to facilitate an
      understanding of integrative physiology and shed light on the composition of the
      different body fluid compartments. The starting point was the central need to
      regenerate ATP to perform biologic work. Because a large quantity of O2 must be
      delivered to cells at a sufficiently high concentration to aid its diffusion into
      mitochondria, approximately one third of the O2 in inspired air was extracted;
      this led to a P(CO2) in arterial blood of 40 mmHg (1 mmHg = 133.322 Pa). Blood
      flow to individual organs must be adjusted precisely to avoid having too low or
      too high a P(O2) in mitochondria--the latter augments the formation of reactive
      O2 species. The extracellular fluid (ECF) bicarbonate concentration (E(HCO3))
      must be high to minimize H+ buffering by proteins. This high E(HCO3) sets the ECF
      concentrations of ionized calcium (Ca2+) and inorganic phosphate (HPO4(2-))
      because of solubility issues. Three features defined the intracellular fluid
      (ICF) volume and composition. First, expelling monovalent anions minimized its
      mass (volume). Second, controlling the tissue P(CO2) ensured a relatively
      constant net valence on intracellular proteins. Third, the range of ICF Ca2+
      concentrations must both induce regulatory signals and avoid Ca3(PO4)2 formation.
      All the above were incorporated into the integrated response that optimized the
      capacity for vigorous exercise.

PMID- 12430979
TI  - Investigations into the systemic production of aldehyde-derived peroxidation
      products in a murine model of acute iron poisoning: a dose response study.
AB  - Acute iron poisoning remains a leading cause of morbidity and mortality in pre
      school aged children in North America. Acute iron poisoning leads to organ
      damage, such as respiratory difficulties, cardiac arrhythmias, and possible
      death. The mechanism of iron toxicity is not fully understood, though it is
      thought that free iron is able to catalyze the production of harmful oxygen free
      radicals, which can damage all biochemical classes including lipid membranes,
      proteins, and DNA. Accordingly, we hypothesized that acute iron loading results
      in dose-dependent increases in oxygen free radical production, as quantified by
      the cytotoxic aldehydes hexanal, 4-hydroxynonenal, and malondialdehyde, in an
      experimental murine model. In support of our hypothesis, significant dose
      dependent increases in all aldehydes investigated were reported in comparison to
      controls (p < 0.001). This murine model will assist in providing a better
      understanding of possible mechanism(s) of injury and organ dysfunction following
      acute iron poisoning, and for the development and evaluation of treatment
      regimes.

PMID- 12430980
TI  - Thermoregulation in the cold after physical training at different ambient air
      temperatures.
AB  - Since human thermoregulation at rest is altered by cold exposure, it was
      hypothesized that physical training under cold conditions would alter
      thermoregulation. Three groups (n = 8) of male subjects (mean age 24.3 +/- 0.9
      years) were evaluated: group T (interval training at 21 degrees C), group CT
      (interval training at 1 degrees C), and group C (no training, equivalent exposure
      to 1 degrees C). Each group was submitted, before and after 4 weeks of interval
      training (5 d/week), to a cold air test at rest (SCAT) (dry bulb temperature
      (Tdb) = 1 degrees C) for a 2-h period for evaluation of the thermoregulatory
      responses. During SCAT, after the training/acclimation period, group T exhibited
      a higher rectal temperature (Tre) (P < 0.05) without significant change in mean
      skin temperature (Tsk) whereas metabolic heat production (M) was higher at the
      beginning of the SCAT (P < 0.05). For group CT, no thermoregulatory change was
      observed. Group C showed a lower Tre (P < 0.05) without significant change in
      either Tsk or in M, suggesting the development of a hypothermic general cold
      adaptation. This study showed, first, that the cold thermoregulatory responses
      induced by an interval training differed following the climatic conditions of the
      training and, second, that this training performed in the cold prevented the
      development of a general cold adaptation.

PMID- 12430981
TI  - Tissue elastance influences airway smooth muscle shortening: comparison of
      mechanical properties among different species.
AB  - We have observed striking differences in the mechanical properties of airway
      smooth muscle preparations among different species. In this study, we provide a
      novel analysis on the influence of tissue elastance on smooth muscle shortening
      using previously published data from our laboratory. We have found that isolated
      human airways exhibit substantial passive tension in contrast to airways from the
      dog and pig, which exhibit little passive tension (<5% of maximal active force
      versus approximately 60% for human bronchi). In the dog and pig, airway
      preparations shorten up to 70% from Lmax (the length at which maximal active
      force occurs), whereas human airways shorten by only approximately 12% from Lmax.
      Isolated airways from the rabbit exhibit relatively low passive tension
      (approximately 22% Fmax) and shorten by 60% from Lmax. Morphologic evaluation of
      airway cross sections revealed that 25-35% of the airway wall is muscle in
      canine, porcine, and rabbit airways in contrast to approximately 9% in human
      airway preparations. We postulate that the large passive tension needed to
      stretch the muscle to Lmax reflects the high connective tissue content
      surrounding the smooth muscle, which limits shortening during smooth muscle
      contraction by imposing an elastic load, as well as by causing radial constraint.

PMID- 12430982
TI  - The effect of epidermal growth factor on the distribution of SGLT-1 in rabbit
      jejunum.
AB  - The effect of epidermal growth factor (EGF) on the cellular and villous
      distribution of the sugar transporter SGLT-1 was examined. New Zealand White
      rabbits (1 kg) were anesthetized, and two jejunal blind loops were isolated and
      exposed to either 0.9% saline or EGF (60 ng/mL saline), for 1 h. In separate
      experiments, tissue was harvested for brush border membrane vesicles (BBMV),
      microsomal membranes, or fixed for immunohistochemistry. SGLT-1 was measured in
      membrane fractions by Western immunoblot or localized along the villus-crypt axis
      by immunofluorescent microscopy. EGF increased BBMV SGLT-1 content compared with
      paired controls. EGF stimulation also induced a corresponding decrease in
      microsomal SGLT-1 levels and induced the expression of additional SGLT-1
      immunoreactivity further down the villus axis. The findings suggest that EGF
      upregulates intestinal glucose transport by stimulating the translocation of SGLT
      1 from an internal microsomal pool into the brush border, thereby recruiting more
      villus enterocytes into the glucose transporting population.

PMID- 12430983
TI  - The influence of acetaldehyde and glycosaminoglycans upon factor Xa- and factor X
      deficient plasma.
AB  - The comparative effects of glycosaminoglycans and acetaldehyde (AcH)-
      glycosaminoglycan (GAG) mixtures upon Factor Xa- (FXa) and Factor X-deficient
      plasma (FXDP) have been studied by activated partial thromboplastin time (APTT)
      studies. Heparin at 0.025, 0.030, 0.04, and 0.05 U statistically prolonged the
      APTT when pre-incubated with FXa at 37 degrees C for 3 min prior to addition to
      FXDP and subsequent addition of Ca2+. Upon addition of 0.25, 0.375, and 0.5
      microg heparin-6000 (H6k) to FXa, significant increases in APTT were observed.
      Similarly, profound increases in APTT were observed when 0.5, 0.75, and 1.0
      microg heparin-3000 (H3k) was added to FXa. The chondroitin sulfates (CSA, CSB,
      CSC) had far less impact upon APTT with the FXa-FXDP system. In examining the
      effects of AcH-GAG mixtures upon the clotting factor, it was observed that 44.3
      and 443 mM AcH synergistically prolonged the APTT in a statistically significant
      manner regardless of the order of premixing the three components. Hence, AcH may
      play a role in prolonging APTT in alcoholics. It synergistically prolonged APTT
      in concert with GAGs and FXa at the AcH levels used in this study. The effect of
      the GAGs upon FXDP is far less than its effect upon FXa.

PMID- 12430984
TI  - Effects of stretch on work from fast and slow muscles of mice: damped and
      undamped energy release.
AB  - Stretching active muscle increases the work performed during subsequent
      shortening. The effects of a preceding stretch on work done by the undamped or
      lightly damped series compliance (SC) and by the contractile component (CC),
      which includes cross bridges and damped elements, were assessed using mouse
      soleus (slow) and extensor digitorum longus (fast) muscles with limited tendon.
      Increasing stretch amplitude (0-10% fibre length) increased work done by the SC
      up to a limit, but did not effect work done by the CC. Increasing stretch
      velocity (10-100% Vmax) had almost no effect on work done by either component.
      Increasing the delay between the end of stretch and onset of shortening (0-60 ms)
      caused a decrease in SC work, with no effect on CC work. Recoil of the SC was
      responsible for 50-70% of the total work done during shortening after stretch.
      Usually only 10-40% of the energy imparted during the stretch was recovered as
      work during subsequent shortening; large stretches and long delays between
      stretch and shortening further reduced this recovery by one third to one fifth.
      Results are interpreted in the context of a loss of energy stored in the SC owing
      to forcible detachment of cross bridges with large stretches and cyclic
      detachment with long delays.

PMID- 12430985
TI  - Inhibitory actions of eugenol on rat isolated ileum.
AB  - The effects of eugenol (1-2000 microM) on rat isolated ileum were studied.
      Eugenol relaxed the basal tonus (IC50 83 microM) and the ileum precontracted with
      60 mM KCl (IC50 162 microM), an action unaltered by 0.5 microM tetrodotoxin, 0.2
      mM N(G)-nitro-L-arginine methyl ester, 0.5 mM hexamethonium, and 1 microM
      indomethacin. Eugenol did not alter the resting transmembrane potential (Em) of
      the longitudinal muscle layer under normal conditions (5.0 mM K+) or in
      depolarised tissues. Eugenol reversibly inhibited contractions induced by
      submaximal concentrations of acetylcholine (ACh) and K+ (40 mM) with IC50 values
      of approximately 228 and 237 microM, respectively. Eugenol blocked the component
      of ACh-induced contraction obtained in Ca(2+)-free solution (0.2 mM EGTA) or in
      the presence of nifedipine (1 microM). Our results suggest that eugenol induces
      relaxation of rat ileum by a direct action on smooth muscle via a mechanism
      largely independent of alterations of Em and extracellular Ca2+ influx.

PMID- 12430986
TI  - Effect of ovariectomy and estrogen supplementation on brain acetylcholinesterase
      activity and passive-avoidance learning in rats.
AB  - The effect of ovariectomy and estrogen treatment on the brain
      acetylcholinesterase activity and cognition in rats was investigated in this
      study. Ovariectomized and nonovariectomized rats were treated subcutaneously with
      estradiol dipropionate for 8 d. In the single-trial, passive-avoidance test all
      the groups showed significant learning and retention of memory as evident by the
      increase in transfer latency time in trial 2 as compared with trial 1. No
      transfer response was significantly increased in the estradiol-dipropionate
      treated ovariectomized (80%) and nonovariectomized (60%) group as compared with
      the ovariectomized (30%) group. Specific activity of acetylcholinesterase was
      assayed spectrophotometrically in salt-soluble and detergent-soluble fractions of
      various brain areas: frontal cortex, cerebral cortex, striatum, hippocampus and
      hypothalamus, thalamus, pons, medulla, and cerebellum. The effect of ovariectomy
      and estradiol dipropionate was varied in both fractions of these brain areas.
      Estradiol dipropionate treatment could restore the acetylcholinesterase activity
      to the control level only in the detergent-soluble fraction of hypothalamus and
      salt-soluble fraction of hypothalamus, thalamus, and medulla in ovariectomized
      rats. The results indicate that ovariectomy alters acetylcholinesterase activity
      in the brain areas but not in a uniform manner and affects only qualitative
      aspects of cognitive function, which could be improved by estrogen
      supplementation.

PMID- 12430987
TI  - Time- and dose-related effects of gonadotropin-releasing hormone on growth
      hormone and gonadotropin subunit gene expression in the goldfish pituitary.
AB  - The goldfish brain contains two molecular forms of gonadotropin-releasing hormone
      (GnRH): salmon GnRH (sGnRH) and chicken GnRH-II (cGnRH-II). In a preliminary
      report, we demonstrated the stimulation of gonadotropin hormone (GtH) subunit and
      growth hormone (GH) mRNA levels by a single dose of GnRH at a single time point
      in the goldfish pituitary. Here we extend the work and demonstrate time- and dose
      related effects of sGnRH and cGnRH-II on GtH subunit and GH gene expression in
      vivo and in vitro. The present study demonstrates important differences between
      the time- and dose-related effects of sGnRH and cGnRH-II on GtH subunit and GH
      mRNA levels. Using primary cultures of dispersed pituitary cells, the minimal
      effective dose of cGnRH-II required to stimulate GtH subunit mRNA levels was
      found to be 10-fold lower than that of sGnRH. In addition, the magnitudes of the
      increases in GtH subunit and GH mRNA levels stimulated by cGnRH-II were found to
      be higher than the sGnRH-induced responses. However, no significant difference
      was observed between sGnRH and cGnRH-II-induced responses in vivo. Time-related
      studies also revealed significant differences between sGnRH- and cGnRH-II-induced
      production of GtH subunit and GH mRNA in the goldfish pituitary. In general, the
      present study provides novel information on time- and dose-related effects of
      sGnRH and cGnRH-II on GtH subunit and GH mRNA levels and provides a framework for
      further investigation of GnRH mechanisms of action in the goldfish pituitary.

PMID- 12430988
TI  - Heart rate variability and electrocardiogram waveform as predictors of morbidity
      during hypothermia and rewarming in rats.
AB  - This study examined electrocardiogram (ECG) waveform, heart rate (HR), mean blood
      pressure (BP), and HR variability as potential autonomic signatures of
      hypothermia and rewarming. Adult male Sprague-Dawley rats had telemetry
      transmitters surgically implanted, and 2 weeks were allowed for recovery prior to
      induction of hypothermia. Rats were lightly anesthetized (sodium pentobarbital,
      35 mg/kg i.p.) and placed in a coil of copper tubing through which temperature
      controlled water was circulated. Animals were cooled to a core temperature (Tc)
      of 20 degrees C, maintained there for 30 min, and then rewarmed. Data (Tc, BP, HR
      from ECG, and 10-s strips of ECG waveforms) were collected every 5 min throughout
      hypothermia and rewarming. Both HR and BP declined after initial increases with
      the drop in HR starting at a higher Tc than the drop in BP (29.6 +/- 2.4 degrees
      C vs. 27.1 +/- 3.3 degrees C, p < 0.05). Animals that were not successfully
      rewarmed exhibited a significant (p < 0.05) increase in the normalized standard
      deviation of interbeat intervals (IBI) throughout cooling compared with animals
      that were successfully rewarmed. The T wave of the ECG increased in amplitude and
      area with decreasing Tc. T-wave amplitude and IBI variability show potential as
      predictors of survival in hypothermic victims.

PMID- 12430989
TI  - Activity profile and physiological demands of top-class soccer assistant
      refereeing in relation to training status.
AB  - To determine the movement patterns and physiological demands of top-class soccer
      assistant referees, we performed computerized time-motion analysis and measured
      heart rate and blood lactate concentration in 15 assistant referees during 22
      competitive matches in the top Danish league. To relate match performance to the
      physical capability of the assistant referees, they performed a 3 x 30 m sprint
      protocol before and after matches and a laboratory treadmill test within 3 weeks
      of the games. The mean total distance covered by the top-class assistant referees
      was 7.28 (range 5.78-8.16) km, of which 1.15 (0.86-1.44) km was high-intensity
      running and 1.16 (0.12-2.34) km was sideways running. The amount of high
      intensity running during a game was correlated with performance of repeated
      sprints (r = 0.80, P < 0.05). Mean heart rate was 137 (117-159) beats x min(-1),
      corresponding to 73% (60-88%) of maximal heart rate and 65% (53-80%) of maximal
      oxygen uptake. Blood lactate concentration was 4.7 (1.6-11.0) and 4.8 (1.1-13.7)
      mmol x 1(-1) after the first and second half, respectively. Sprinting performance
      was poorer (P < 0.05) after than before the games. The peak distance to the
      offside line was greater (P < 0.05) in the second than the first half (7 +/- 1 vs
      5 +/- 0 m). Our results show that: (1) top-class assistant soccer refereeing is
      characterized by brief intense bouts of forward and sideways running interspersed
      with long periods of low activity; (2) top-class soccer assistant referees have
      moderate aerobic energy production during games with episodes of high aerobic and
      anaerobic energy turnover; (3) assistant referees' performance of repeated
      sprints correlates with the amount of high-intensity running performed in a game;
      and (4) sprint performance decreases towards the end of a game, which appears to
      affect assistant referees' ability to keep up with play.

PMID- 12430990
TI  - Criterion-related validity of the Borg ratings of perceived exertion scale in
      healthy individuals: a meta-analysis.
AB  - The literature related to Borg's ratings of perceived exertion (RPE) scale has
      revealed inconsistencies about the strength of the relationship between ratings
      of perceived exertion and various physiological criterion measures, such as heart
      rate, blood lactate concentration, percent maximal oxygen uptake (%VO2max),
      oxygen uptake (VO2), ventilation and respiration rate. Using sex of participants,
      fitness, type of RPE scale used, type of exercise, exercise protocol, RPE mode
      and study quality, we undertook a meta-analysis to determine the strength of the
      relationship between RPE scores and the six aforementioned physiological
      measures. The weighted mean validity coefficients were 0.62 for heart rate, 0.57
      for blood lactate, 0.64 for %VO2max 0.63 for VO2, 0.61 for ventilation and 0.72
      for respiration rate. Analysis of moderator variables revealed that the following
      study features could account for the variation of results across studies: heart
      rate--fitness, type of exercise, protocol and RPE mode; blood lactate
      concentration--sex, RPE scale; VO2--sex, exercise type, RPE mode; ventilation-
      sex, RPE mode; respiration rate--exercise protocol, RPE mode. The highest
      correlations between ratings of perceived exertion and the various physiological
      criterion measures were found in the following conditions: when male participants
      (whose VO2 or ventilation was measured) were required to maximally exert
      themselves (measuring %VO2max or ventilation); when the exercise task was unusual
      [e.g. when participants were swimming, which is less common than walking or
      running (when heart rate, %VO2max and VO2 are measured)]; or when the 15-point
      RPE scale (measuring blood lactate concentration) was used. These findings
      suggest that although Borg's RPE scale has been shown to be a valid measure of
      exercise intensity, its validity may not be as high as previously thought (r =
      0.80-0.90), except under certain conditions.

PMID- 12430991
TI  - The effect of interdian and diurnal variation on oxygen uptake kinetics during
      treadmill running.
AB  - The aim of this study was to examine the variability of the oxygen uptake (VO2)
      kinetic response during moderate- and high-intensity treadmill exercise within
      the same day (at 06:00, 12:00 and 18:00 h) and across days (on five occasions).
      Nine participants (age 25 +/- 8 years, mass 70.2 +/- 4.7 kg, VO2max 4137 +/- 697
      ml x min(-1); mean +/- s) took part in the study. Six of the participants
      performed replicate 'square-wave' rest-to-exercise transitions of 6 min duration
      at running speeds calculated to require 80% VO2 at the ventilatory threshold
      (moderate-intensity exercise) and 50% of the difference between VO2 at the
      ventilatory threshold and VO2max (50% delta; high-intensity exercise) on 5
      different days. Although the amplitudes of the VO2 response were relatively
      constant (coefficient of variation approximately 6%) from day to day, the time
      based parameters were more variable (coefficient of variation approximately 15 to
      30%). All nine participants performed replicate square-waves for each time of
      day. There was no diurnal effect on the time-based parameters of VO2 kinetics
      during either moderate- or high-intensity exercise. However, for high-intensity
      exercise, the amplitude of the primary component was significantly lower during
      the 12:00 h trial (2859 +/- 142 ml x min(-1) vs 2955 +/- 135 ml x min(-1) at
      06:00 h and 2937 +/- 137 ml x min(-1) at 18:00 h; P < 0.05), but this effect was
      eliminated when expressed relative to body mass. The results of this study
      indicate that the amplitudes of the VO2 kinetic responses to moderate- and high
      intensity treadmill exercise are similar within and across test days. The time
      based parameters, however, are more variable from day to day and multiple
      transitions are, therefore, recommended to increase confidence in the data.

PMID- 12430992
TI  - A qualitative investigation of the temporal patterning of the precompetitive
      anxiety response.
AB  - The aim of this study was to examine retrospective perceptions and causal beliefs
      about temporal experiences of competitive anxiety and related symptoms in the
      lead up to competition. Qualitative interviews were conducted with 9 elite
      performers to examine the interaction of intensity, frequency and direction of
      symptoms associated with competitive anxiety before competition. Data analysis
      identified six causal networks that supported theoretical predictions suggesting
      that intensity of cognitive anxiety symptoms remained relatively stable in the
      lead up to competition, whereas somatic anxiety peaked sharply at the onset of
      performance. Frequency of anxiety symptoms increased as the competition
      approached and changes in interpretation of anxiety symptoms were also reported,
      with self-confidence identified as a moderating variable. The findings highlight
      the dynamic properties of the stress response and emphasize the need to consider
      the idiosyncratic nature of the level, frequency and interpretation of
      performers' precompetitive experiences.

PMID- 12430993
TI  - Effects of regular training at the same time of day on diurnal fluctuations in
      muscular performance.
AB  - The aim of this study was to determine whether there is an effect of time of day
      on the adaptation to strength training at maximal effort. Fourteen participants
      took part in this experiment. Their peak anaerobic power (Wingate anaerobic test)
      and peak knee extension torque at six angular velocities (1.05, 2.10, 3.14, 4.19,
      5.24 and 6.29 rad x s(-1)) were recorded in the morning (between 07:00 and 08:00
      h) and in the evening (between 17:00 and 18:00 h) just before and 2 weeks after a
      6 week course of regular training. Seven of them trained only in the morning and
      seven only in the evening. Multivariate analysis of variance revealed a
      significant group x pre-/post-training x time of day interaction effect for peak
      torque and peak anaerobic power. Before training, in both groups, peak torque and
      peak anaerobic power were significantly higher in the evening than in the
      morning. After training, there was no significant difference in peak torque and
      peak anaerobic power between the morning and the evening for the morning training
      group. In contrast, in the evening training group, peak torque and peak anaerobic
      power were higher in the evening than in the morning. As a result of training,
      both peak torque and peak anaerobic power increased from their initial values as
      expected. The morning training group improved their peak anaerobic power
      significantly in the morning and in the evening, the absolute increase being
      larger in the morning than in the evening. The evening training group did not
      improve their peak anaerobic power in the morning, whereas it improved
      significantly in the evening. Although peak torque was significantly improved by
      training in the morning and evening in both groups, the absolute increase was
      greater in the morning than in the evening in the morning training group, whereas
      the opposite was the case for the evening training group. These results suggest
      that training twice a week at a specific hour increases the peak torque and the
      peak anaerobic power specifically at this hour and demonstrates that there is a
      temporal specificity to strength training.

PMID- 12430994
TI  - Work-time profile, blood lactate concentration and rating of perceived exertion
      in the 1998 Greco-Roman Wrestling World Championship.
AB  - The aim of this study was to examine work-time profiles, blood lactate
      concentrations and perceived exertion among Greco-Roman wrestlers in the 1998
      World Championship. Forty-two senior wrestlers from nine nations were studied in
      94 matches. Each match was recorded with a video camera (Panasonic AG 455, film
      rate: 25 Hz) and analysed for duration of work (wrestling) and rest (interrupt)
      periods. Blood lactate concentration was determined with an electrochemical
      device (Analox P-LM5) and a rating of perceived exertion scale (Borg) was used to
      estimate general exertion and exertion in the extremity and trunk muscles. The
      mean duration of the matches was 427 s (range 324-535 s), with mean durations of
      work and rest of 317 and 110 s, respectively. The mean periods of work and rest
      were 37.2 and 13.8 s, respectively. Mean blood lactate concentration was 14.8
      mmol x 1(-1) (range 6.9-20.6). The difference in mean blood lactate concentration
      between the first- and final-round matches was not significant (P > 0.05). Blood
      lactate concentration was significantly higher (P < 0.04) in matches of long
      duration than in those of short duration. The mean general rating of perceived
      exertion for all matches was 13.8 according to the scale used. Most of the
      wrestlers (53.3%) perceived exertion to be highest in the flexors of the forearm,
      followed by the deltoids (17.4%) and the biceps brachii muscles (12.0%). In
      addition to a relatively high rating of perceived exertion in the arm muscles,
      this indicates a high specific load on the flexor muscles of the forearm.

PMID- 12430995
TI  - Animal Welfare Bill: government to go ahead.

PMID- 12430996
TI  - The LVI review: an opportunity to be grasped.

PMID- 12430997
TI  - Kitten mortality in the United Kingdom: a retrospective analysis of 274
      histopathological examinations (1986 to 2000).
AB  - The postmortem findings in 274 kittens were reviewed. The kittens were grouped by
      age at death: perinatal (< one day), neonatal (one to 14 days), preweaning (15 to
      34 days) and postweaning (35 to 112 days); 203 (74 per cent) of the kittens were
      postweaning and 38 (14 per cent) were preweaning. Infectious disease was
      identified in 55 per cent of the kittens, and 71 per cent of the infectious
      disease was viral and detected significantly more frequently in rescue shelter
      kittens than in kittens from private homes. Twenty-five per cent of all kitten
      mortality was due to feline parvovirus (FPV). During the neonatal and preweaning
      periods, the main viral infections were feline herpesvirus and calicivirus.
      Feline infectious peritonitis caused the death of 17 kittens in the postweaning
      period. The rescue shelter kittens were significantly younger than the kittens
      from private homes (median survival 49 and 56 days) and were more likely to have
      FPV. The non-pedigree kittens were significantly younger than the pedigree
      kittens (42 v 56 days), and the pedigree kittens were significantly less likely
      to originate from rescue shelters. There was no significant difference between
      the age distribution of the male and female kittens. No diagnosis could be found
      in 33 per cent of the kittens, and this failure was correlated significantly with
      the submission of tissue samples as opposed to the whole carcase.

PMID- 12430998
TI  - Protection of vaccinated pigs against experimental infections with homologous and
      heterologous Haemophilus parasuis.
AB  - The efficacy of a new Haemophilus parasuis vaccine for pigs was investigated. The
      vaccine contains H parasuis serotype 5 cells and is adjuvanted with Diluvac Forte
      (Intervet). Groups of pigs were vaccinated at five and seven weeks with 2 ml and
      their littermates served as unvaccinated controls. The vaccinated pigs were
      protected against a challenge with another strain of Hparasuis serotype 5 at two,
      eight and 17 weeks after the second vaccination, whereas the controls became very
      ill. The susceptibility of the pigs to the infection decreased with increasing
      age. After a heterologous challenge with H parasuis serotypes 1, 12, 13 and 14,
      two weeks after the second vaccination, the vaccine also gave clear protection.
      The severity of the illness among the control pigs differed with the different
      serotypes.

PMID- 12430999
TI  - Pulmonary coccidioidomycosis in a neonatal foal.
AB  - A 13-day-old foal with profound tachypnoea and respiratory distress was examined.
      Thoracic radiographs revealed a severe, diffuse miliary pattern, and the foal was
      markedly hypoxaemic. It failed to improve with empirical treatment, and was
      euthanased. Lesions associated with Coccidioides immitis infection were
      identified at postmortem examination, and were limited to the lower respiratory
      tract.

PMID- 12431000
TI  - Description of the first cases of BSE in Spain.

PMID- 12431001
TI  - Cutaneous and renal glomerular vasculopathy in a great dane resembling 'Alabama
      rot' of greyhounds.

PMID- 12431002
TI  - Backlog in TB testing.

PMID- 12431003
TI  - Atypical sheep scab.

PMID- 12431004
TI  - Herpesvirus B in macaque monkeys.

PMID- 12431005
TI  - Effect of reaction time on PCDD and PCDF formation by de novo synthetic reactions
      under oxygen deficient and rich atmosphere.
AB  - The effect of reaction time on formation of polychlorinated dibenzo-p-dioxins
      (PCDD) and dibenzofurans (PCDF) was studied under laboratory conditions in the
      system containing municipal waste incineration fly ash, activated carbon and
      copper chloride dihydrate at 300 degrees C in 99.999% N2 and N2 + 10% O2
      atmosphere. The concentrations of tetra- to octa-chlorinated isomers as well as I
      TEQ concentrations of toxic congeners are reported. The mechanism of PCDD and
      PCDF formation from chlorophenols and chlorinated biphenyls is discussed in the
      light of the time changes of PCDD/PCDF ratios.

PMID- 12431006
TI  - Surveillance programme on dioxin levels in ambient air sites in Catalonia
      (Spain).
AB  - As part of a survey programme conducted by the Environment Department of the
      Autonomous Government of Catalonia in collaboration with the Spanish Council for
      Scientific Research (CSIC), dioxin concentrations in ambient air were measured in
      the four provinces of Catalonia (Spain). The study was also performed with the
      intention of providing data as a basis for future monitoring and evaluation of
      temporal trends in ambient air. Thus, 91 samples were collected in 25 different
      sites (rural, urban, suburban and industrial) between 1994 and 2000. The levels
      revealed a variable content of PCDDs/PCDFs depending both on the area and the
      contamination source. In particular, industrial areas presented levels ranging
      from 18 to 954 fg I-TEQ/m3. However, findings in urban and suburban sites varied
      between 13 and 357 fg I-TEQ/m3. As expected, the lowest levels were found in
      rural areas with levels between 5 and 125 fg I-TEQ/m3.

PMID- 12431007
TI  - HPLC-PFD determination of priority pollutant PAHs in water, sediment, and
      semipermeable membrane devices.
AB  - High performance liquid chromatography coupled with programmable fluorescence
      detection was employed for the determination of 15 priority pollutant polycyclic
      aromatic hydrocarbons (PPPAHs) in water, sediment, and semipermeable membrane
      devices (SPMDs). Chromatographic separation using this analytical method
      facilitates selectivity, sensitivity (ppt levels), and can serve as a non
      destructive technique for subsequent analysis by other chromatographic and
      spectroscopic techniques. Extraction and sample cleanup procedures were also
      developed for water, sediment, and SPMDs using various chromatographic and wet
      chemical methods. The focus of this publication is to examine the enrichment
      techniques and the analytical methodologies used in the isolation,
      characterization, and quantitation of 15 PPPAHs in different sample matrices.

PMID- 12431008
TI  - Sequestration of priority pollutant PAHs from sediment pore water employing
      semipermeable membrane devices.
AB  - Semipermeable membrane devices (SPMDs) were employed to sample sediment pore
      water in static exposure studies under controlled laboratory conditions using
      (control pond and formulated) sediments fortified with 15 priority pollutant
      polycyclic aromatic hydrocarbons (PPPAHs). The sediment fortification level of
      750 ng/g was selected on the basis of what might be detected in a sediment sample
      from a contaminated area. The sampling interval consisted of 0, 4, 7, 14, and 28
      days for each study. The analytical methodologies, as well as the extraction and
      sample cleanup procedures used in the isolation, characterization, and
      quantitation of 15 PPPAHs at different fortification levels in SPMDs, water, and
      sediment were reported previously (Williamson, M.S. Thesis, University of
      Missouri-Columbia, USA; Williamson et al., Chemosphere (This issue--PII: S0045
      6535(02)00394-6)) and used for this project. Average (mean) extraction recoveries
      for each PPPAH congener in each matrix are reported and discussed. No procedural
      blank extracts (controls) were found to contain any PPPAH residues above the
      method quantitation limit, therefore, no matrix interferences were detected. The
      focus of this publication is to demonstrate the ability to sequester
      environmental contaminants, specifically PPPAHs, from sediment pore water using
      SPMDs and two different types of fortified sediment.

PMID- 12431009
TI  - Comparisons of PBDE composition and concentration in fish collected from the
      Detroit River, MI and Des Plaines River, IL.
AB  - Polybrominated diphenyl ethers (PBDEs) were identified in fish collected from the
      Detroit River, MI and Des Plaines Rivers, IL. In the Detroit River fish, carp and
      large mouth bass, the congener patterns were dominated by the 2,2',4,4'
      tetrabromo (BDE-47) congener, however, in Des Plaines River carp the dominant
      isomers were the heptabromo congeners BDE-181 and BDE-183 and lesser amounts of
      another heptabromo congener, BDE-190, and two hexabromo congeners, BDE-154 and
      BDE-153. Three possible sources exist for these less-commonly identified PBDE
      congeners: (a) waste discharge from manufacturing or discarded products near the
      river, (b) public owned treatment work (POTW) effluents which constitute more
      than 75% of the flow in the Des Plaines River, (c) or formation of these
      congeners by debromination of in-place deposits of decabromodiphenyl ether.
      Average concentration totals (sum of concentrations for seven of the dominant
      PBDE congeners) were similar on a wet weight bases for the carp (5.39 ng/g wet
      weight) and large mouth bass (5.25 ng/g) in the Detroit River samples; however,
      the bass were significantly higher, p = 0.01, when compared on a lipid basis
      (bass--163 ng/g vs. carp--40.5 ng/g lipid weight). Some of the PBDE congeners
      were positively correlated with increasing lipid levels in both fish species.
      Average total PBDE concentrations in the carp from the Des Plaines River (12.48
      ng/g wet weight) were significantly higher, p = 0.01, than in carp from the
      Detroit River. The residues were isolated using standard organochlorine methods
      for fish and analyzed using gas chromatography/mass spectrometry-negative
      chemical ionization methods.

PMID- 12431011
TI  - Polychlorinated dibenzo-p-dioxins and dibenzofurans in River Po sediments.
AB  - The River Po is the main Italian river draining one of the most populated and
      industrialised regions in Italy. As part of a monitoring project to assess
      environmental quality in the River Po, we measured the concentrations of
      polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs) in bottom
      sediments collected along the whole course of the river, from the spring to the
      delta, downstream from the confluence of its main tributaries. The aim was to
      investigate the level of contamination in the main Italian river and the
      contribution of contaminant loads from the subbasins. Composite sediment samples
      were collected in summer and winter surveys in low-flow water conditions and
      analysed by HRGC-HRMS for PCDD and PCDF homologue groups and for the 2,3,7,8
      substituted congeners. The spatial trend observed in the Po River for PCDD and
      PCDF concentrations varied depending on the load of contaminants received from
      the tributaries and the processes of sedimentation. The sum of PCDD and PCDF
      concentrations, and the toxic equivalent content, ranged from 121 to 814 and from
      1.3 to 13 ng/kg dry weight sediment, respectively. These levels of contamination
      seem lower than in the sediments of rivers draining highly industrialised areas.
      The PCDD and PCDF homologue profiles in all the samples were very similar,
      suggesting a common source of this contamination in the River Po. Principal
      component analysis suggested that widespread sources, such as urban runoff and
      domestic wastewaters, are probably the main cause of these levels of PCDDs and
      PCDFs.

PMID- 12431010
TI  - Decolorization of RBBR by plant cells and correlation with the transformation of
      PCBs.
AB  - An extracellular H2O2-requiring Remazol Brilliant Blue R (RBBR) decolorizing
      enzyme activity was detected after cultivation of cells of various plant species
      both in liquid medium and when growing on agar plates containing RBBR. Level of
      the enzyme activity was compared with the ability to metabolize polychlorinated
      biphenyls (PCBs). The ability to decolorize RBBR was tested in the presence and
      absence of PCBs. The cultures with high PCB-transforming activity proved to
      exhibit RBBR oxidase much more resistant towards the influence of PCBs. In
      addition low activities of lignin peroxidase (LiP) and manganese dependent
      peroxidase (MnP) were detected in medium and in plant cells. No correlation of
      MnP and LiP activities with PCB degradation could be found. The RBBR
      decolorization could be used as a rough screening method for plant cultures able
      to metabolize PCBs.

PMID- 12431012
TI  - Regional measurements of PCDD/PCDF concentrations in Korean atmosphere and
      comparison with gas-particle partitioning models.
AB  - The current investigation was aimed at determining the levels of polychlorinated
      dibenzo-p-dioxins and dibenzofurans (PCDD/PCDFs) in the Korean atmosphere along
      with their estimation using gas-particle partitioning. Samples collected from six
      cites showed that large cities were polluted with a concentration of 0.593 pg
      TEQ/m3. Samples were also collected from residential (nine sites), commercial
      (five sites), and industrial (seven sites) districts in each city. Higher levels
      of PCDDs/PCDFs were observed in industrial area than other areas, since it
      includes many sources. Higher chlorinated 2,3,7,8-substituted congeners were
      predominantly found in the particulate phase. HpCDD/Fs and OCDD/Fs shared 97-99%
      of the particulate phase, whereas TCDD/Fs, which dominated the gaseous phase,
      shared 34.8% and 42.8% in 2,3,7,8-substituted congeners. The regression dataset
      was transformed due to the relationship between log K(P) and log P(L)o. A wide
      variation was observed in the slopes for the residential areas when compared with
      the slopes for the commercial and industrial areas. The Junge-Pankow model and
      K(oa) adsorption model were both found to be helpful in describing the gas
      particle partitioning in the current study.

PMID- 12431013
TI  - Levels of dioxins in fish and fishery products on the German market.
AB  - In 1995-1998 the contents of polychlorinated dibenzodioxins and dibenzofurans of
      184 pooled fish samples were analysed. Sampling focused on fish and fishery
      products with a market share of more than 1% and covered all fishing grounds
      important for the supply of the German market. Investigation included 15
      different fish species, shrimp, mussel and squid samples and various fishery
      products, typically on the German market. Generally lean fish species like cod,
      saithe or Alaska pollock were less contaminated on fresh weight basis than fat
      fish species like herring, Greenland halibut and sardine. In herring the dioxin
      content is related to the fishing ground. Low concentrations were found in North
      Sea herring, high concentrations measured in samples from the Baltic Sea. Dioxin
      contents in fishery products did not differ significantly from the raw fish
      samples. Results allow an estimation of the daily intake of dioxins and furans
      via fish consumption in Germany. Based on a daily fish consumption of 20 g the
      average intake of dioxins via fish is 6.2 pg WHO-PCDD/F-TEQs per person and day.

PMID- 12431014
TI  - The role of caspofungin and the echinocandins in the antifungal armamentarium.
AB  - The echinocandins are a recently-developed class of antifungal agents that
      interfere with fungal cell wall synthesis through the inhibition of glucan
      synthesis. Although several intravenous preparations are in various stages of
      development, caspofungin is the only currently approved agent and no oral
      echinocandin derivatives are presently available. Caspofungin is approved for the
      treatment of invasive aspergillosis in patients who are refractory to, or
      intolerant of, other antifungal therapies. This agent has activity against most
      Candida species, and in a prospective randomized trial, was as effective as, and
      better tolerated than amphotericin B in the treatment of candidal esophagitis.
      Activity against the cyst form of Pneumocystis carinii has also been
      demonstrated. Caspofungin is administered in a daily intravenous dose, and is
      well tolerated. Concomitant use of this agent with cyclosporine is presently not
      recommended. Other echinocandin derivatives presently in phase II/III clinical
      development include micafungin and anidulafungin.

PMID- 12431015
TI  - DNA binding compounds targeting fungal pathogens: an emerging concept in the
      discovery of novel antifungal agents.
AB  - With the urgent need for novel agents to combat emerging fungal resistance to
      existing drugs, activity in the exploration of small molecule DNA binders has
      increased. Recently, selected cationic heterocyclic compounds belonging to a
      broad class of molecules known to bind to the minor groove of DNA were revealed
      to have potent antifungal activity. These molecules are different from the
      conventional DNA-interacting drugs such as topoisomerase inhibitors, DNA
      alkylators or intercalators. Selected compounds are fungicidal towards a variety
      of pathogenic yeasts and molds, and a selected lead compound is efficacious in a
      mouse model of systemic candidosis.

PMID- 12431016
TI  - Sitamaquine (GlaxoSmithKline/Walter Reed Army Institute).
AB  - Sitamaquine (WR-6026) is an orally active 8-aminoquinoline analog in development
      by the Walter Reed Army Institute, in collaboration with GlaxoSmithKline
      (formerly SmithKline Beecham), for the potential treatment of visceral
      leishmaniasis. Phase III trials for the treatment of visceral leishmaniasis had
      been initiated by March 2002, at which time GlaxoSmithKline hoped to file an MAA
      in 2003. By 1999, the compound had also undergone phase I trials in HIV-infected
      individuals for the treatment of Pneumocystis carinii infection. Preclinical
      studies have been conducted in primates and rodents for the potential treatment
      of Babesia microti infection.

PMID- 12431017
TI  - Overview: transplantation tolerance--challenges and opportunities for drug
      development.

PMID- 12431018
TI  - 1,25-Dihydroxyvitamin D3 analogs as potential therapies in transplantation.
AB  - While immunosuppressive drugs now permit good control of acute allograft
      rejection, chronic rejection remains an important medical problem, and the
      induction of stable transplantation tolerance has not yet been achieved in
      patients. 1,25-Dihydroxyvitamin D3 (1,25(OH)2D3), a secosteroid hormone that
      controls cell proliferation and differentiation and exerts immunoregulatory
      activities in addition to regulating calcium and bone metabolism, has the
      potential to contribute to the management of allograft rejection. Recent advances
      in understanding the immunomodulatory properties of 1,25(OH)2D3 and its analogs
      suggest the clinical application of these hormones in transplantation, with the
      aim of facilitating tolerance induction and preventing chronic graft rejection.

PMID- 12431019
TI  - Inolimomab (OPi).
AB  - OPi (formerly Orphan Pharma International) is developing inolimomab, an anti
      interleukin-2 receptor (CD25) monoclonal antibody for the potential treatment of
      acute graft versus host disease. As of April 2001, inolimomab was undergoing
      phase II/III clinical trials.

PMID- 12431020
TI  - The role of aldosterone receptor blockade in the management of cardiovascular
      disease.
AB  - The recent revival of interest in aldosterone receptor antagonists for the
      treatment of cardiovascular disease has been underpinned by fresh insights into
      the pathophysiological role of aldosterone in cardiovascular disease, especially
      with regard to its widespread 'non-epithelial' actions, as well as by key
      findings from dinical studies. The therapeutic efficacy of spironolactone
      (Pharmacia Corp) in severe chronic heart failure is established. Emerging
      evidence from an extensive development program for eplerenone (Pharmacia Corp), a
      novel selective aldosterone receptor antagonist, may further expand the evidence
      base for aldosterone receptor antagonism, including its potential in treating
      hypertension. Importantly, eplerenone does not appear to cause the hormonal side
      effects observed with spironolactone.

PMID- 12431021
TI  - Clevidipine (the Medicines Company).
AB  - The Medicines Company (under license from AstraZeneca) is developing clevidipine,
      a short-acting dihydropyridine calcium antagonist, for the potential treatment of
      peri-operative hypertension. By 1997, the compound was undergoing phase II
      clinical evaluation by the original developer, AstraZeneca. By March 2002, The
      Medicines Company was conducting phase III clinical trials.

PMID- 12431022
TI  - Aliskiren (Speedel).
AB  - Speedel Pharma is developing aliskiren (formerly CGP-60536), a renin inhibitor
      under license from Novartis, for the potential treatment of several
      cardiovascular disorders. By October 2001, a phase IIb study in hypertension had
      been completed, and phase III studies for this indication were anticipated for
      2002; at this time, phase II studies in congestive heart failure and chronic
      renal failure were ongoing.

PMID- 12431023
TI  - Ambrisentan (Myogen).
AB  - Ambrisentan (LU-208075, BSF-208075) and LU-302146 (BSF-302146) are being
      developed by Myogen, under license from Abbott (formerly BASF Pharma), for the
      potential treatment of post-ischemic acute renal failure and cardiovascular
      disease . By August 2001, ambrisentan had entered phase II trials for chronic
      heart failure, hypertension, kidney failure and pulmonary hypertension.

PMID- 12431024
TI  - Female sexual dysfunction.

PMID- 12431025
TI  - Phosphodiesterase inhibitors for the treatment of erectile dysfunction.
AB  - The key event in penile erection is relaxation of the cavernous smooth muscle. As
      phosphodiesterases (PDEs) are key enzymes of the signaling pathway, knowledge
      about cavernous PDEs is of major importance in understanding the effects and side
      effect profile of new and selective pharmacological agents for erectile
      dysfunction. Experimental studies revealed that gene transcripts of 14 different
      PDE isoenzymes are present in human cavernous tissue. Of these, PDE3 and 5 have
      the most prominent functional role. The effects and side effects of clinically
      available PDE5 inhibitors can be explained both by the distribution pattern of
      these two isoenzymes in various tissues, by direct inhibition of PDE5 and
      indirect inhibition of PDE3 in various tissues, and by the putative selectivity
      for a cavernous-specific PDE splice variant.

PMID- 12431026
TI  - Alvimopan (Adolor/GlaxoSmithKline).
AB  - Alvimopan is a potent, peripherally active, mu-opioid receptor antagonist being
      developed by Adolor and GlaxoSmithKline (GSK) as a potential treatment for post
      operative ileus and opioid bowel dysfunction.

PMID- 12431027
TI  - Palonosetron (Helsinn).
AB  - Palonosetron, a selective 5-HT3 receptor antagonist, is being developed by
      Helsinn for the potential treatment of chemotherapy-induced nausea and vomiting.
      By 1999, it was in phase III trials, and as of May 2002, an NDA filing was
      scheduled for the third quarter of 2002.

PMID- 12431028
TI  - (S)-oxybutynin (Sepracor).
AB  - Sepracor is developing (S)-oxybutynin, a single-isomer version of Alza's Ditropan
      (racemic oxybutynin), a muscarinic acetylcholine receptor antagonist, as a
      potential treatment for urinary incontinence.

PMID- 12431029
TI  - DNA topoisomerases in cancer chemotherapy: using enzymes to generate selective
      DNA damage.
AB  - DNA topoisomerase II targeting agents such as etoposide and doxorubicin are well
      established cancer chemotherapeutic agents. Topotecan (Hycamtin) and irinotecan
      (Camptosar) are launched drugs that target topoisomerase I and have significant
      activity against many solid malignancies. These agents have important mechanistic
      similarities, converting their target enzyme(s) to generate DNA damage. Recent
      structural and biochemical studies on targeting of topoisomerases by antitumor
      agents are providing a framework for understanding drug action at the enzyme
      level, and at the level of cellular pathways important for responses to this
      unique type of DNA damage. These investigations into the mechanisms of action of
      topoisomerase-targeting agents should aid in the design of dinical protocols that
      optimize the activity of these agents.

PMID- 12431030
TI  - Irofulven (MGI Pharma).
AB  - MGI Pharma is developing irofulven, a semi-synthetic compound derived from
      illudin S, a toxin from the Omphalotus illudens mushroom, for the potential
      treatment of refractory and relapsed tumors, including ovarian, prostate,
      hepatocellular, breast, lung and colon cancers. Phase II trials of the compound
      as a monotherapy or in combination therapies are ongoing for a number of these
      indications.

PMID- 12431031
TI  - Glufosfamide (Baxter Oncology).
AB  - Glufosfamide is a sugar phosphamide alkylating agent under development by Baxter
      Oncology (formerly ASTA Medica) as a potential treatment for cancer. By April
      2000, glufosfamide had commenced phase II trials, one of which involved
      intrathecal administration to patients with carcinomatous meningioma.

PMID- 12431032
TI  - Troxacitabine (Shire Pharmaceuticals).
AB  - Shire Pharmaceuticals (formerly BioChem Pharma) is developing troxacitabine
      (Troxatyl), a novel dioxolane nucleoside analog, as a potential treatment for
      acute myeloid leukemia (AML), pancreatic cancer and solid tumors. Phase I and II
      clinical studies in patients with pancreatic cancer and AML are in progress.

PMID- 12431033
TI  - Memory for animal tracks: a possible cognitive artifact of human evolution.
AB  - Although many human behaviors are held to have adaptive significance, specific
      examples of behaviors that represent direct holdovers from the ancient world have
      been few, particularly in the cognitive realm. In the present research, the
      authors tested the hypothesis that such cognitive examples might in fact exist
      and be experimentally verifiable. They suggested that human predispositions to
      learn basic aspects of hunting with relative ease might be "left over" from human
      evolution in the pre-agricultural past. This hypothesis was tested in 3
      experiments with reference to the learning and recall of animal tracks, an
      activity of probable high adaptive significance within the area of visual memory.
      Undergraduate students selected at random learned and recalled animal tracks with
      significantly greater ease than they recalled other animate and inanimate items.
      A single exception lay in relatively unfamiliar kitchen implements, which were
      recalled with greater facility than were animal tracks, consistent with current
      theoretical considerations. Results indicate that direct behavioral holdovers
      from the ancient world may exist in the cognitive realm and that these may be
      accessed experimentally and predictably under appropriate conditions.

PMID- 12431034
TI  - Exploring the mental health of Mexican migrant farm workers in the Midwest:
      psychosocial predictors of psychological distress and suggestions for prevention
      and treatment.
AB  - The purposes of the present study were threefold: (a) to assess the prevalence
      levels of anxiety and depression in a sample of Mexican migrant farm workers in
      the midwestern United States; (b) to explore the relationships among
      acculturative stress, anxiety, and depression; and (c) to examine the variables
      that best predict anxiety and depression. The overall sample revealed elevated
      levels of anxiety and depression. Migrant farm workers with heightened levels of
      acculturative stress were more likely to report high levels of anxiety and
      depression. Family dysfunction, ineffective social support, low self-esteem, lack
      of agreement with the decision to migrate, high education levels, high levels of
      acculturative stress, and high levels of anxiety were significantly associated
      with high depression levels. The overall findings suggest that migrant farm
      workers who experience elevated levels of acculturative stress may be at risk for
      experiencing high levels of anxiety and depression. The findings highlight the
      importance of establishing prevention and treatment services for migrant farm
      workers that aim to increase levels of emotional support, self-esteem, and coping
      skills.

PMID- 12431035
TI  - Test-retest reliability of the emotional stroop task: examining the paradox of
      measurement change.
AB  - The Emotional Stroop (ES) task (I. H. Gotlib & C. D. McCann, 1984) has been
      proposed as an experimental measure to assess the processing of emotion or the
      bias in attention of emotion-laden information. However, study results have not
      been consistent. To further examine its reliability for empirical research, the
      authors of this study administered the ES task to 33 participants on 2 separate
      occasions separated by 1 week. Results indicated that retest reliabilities for
      reaction times (RTs) derived from the 3 separate emotion conditions (manic,
      neutral, and depressive) across the 1 week interval were very high. However,
      consistent with previous research, the reliabilities were very low for the
      interference indices (manic and depressive). These low reliabilities reflect the
      very high intercorrelation between the RTs derived from the 3 conditions. The
      authors concluded that a better indicator of the reliability for this task is the
      individual RTs from each emotion condition.

PMID- 12431036
TI  - Perceptions of goal-directed activities of optimists and pessimists: a personal
      projects analysis.
AB  - In this research the authors examined the relationship between optimism and
      personal projects in a community sample. Three hundred twenty-five community
      volunteers completed the Personal Projects Analysis (PPA; B. R. Little, 1983) and
      measures of self-reported optimism and sociodemographic information. Participants
      who reported high levels of optimism rated their idiosyncratic personal goals
      significantly higher on PPA factors reflecting Positive Identity Fulfillment and
      Mastery-Control and significantly lower on the factor reflecting Perceived Strain
      than did participants who reported low levels of optimism. After the impact of
      age and education on optimism were statistically controlled, the Perceived Strain
      and Mastery-Control factors made significant contributions to the prediction of
      self-reported optimism in both initial and cross-validation samples. Findings
      indicate that highly optimistic individuals can be differentiated from their less
      optimistic peers on the basis of their perceptions of idiosyncratic goals. From
      an expectancy valence perspective, such differences have a direct bearing on
      individuals' behavior and may be associated with outcomes such as learned
      helplessness and procrastination.

PMID- 12431037
TI  - Empowerment in the service industry: an empirical study in Taiwan.
AB  - Employee empowerment is an essential managerial means that can be used to obtain
      competitive advantages from human resources in the new millennium. A
      comprehensive understanding of the essence of empowerment is crucial to
      facilitate its effective implementation. In this article, the author proposes a 4
      dimensional empowerment model in an organizational setting and a matrix that
      incorporates the 4 dimensions and the 7S (R. H. Waterman, T. J. Peters, & J. R.
      Phillips, 1980) organizational factors. In addition, this study represents an
      empirical examination of the effects of personal and company characteristics on
      empowerment. The implications of the research results are discussed.

PMID- 12431038
TI  - The Age Universal I-E Scale-12 and orientation toward religion: confirmatory
      factor analysis.
AB  - Confirmatory factor analysis was used to explore the suggested 2-factor and 3
      factor models of the Age Universal I-E Scale-12 among 4,160 respondents. The
      present findings suggested that the 3-factor model provided a better fit of the
      data than the 2-factor model did. The findings with this version of the Age
      Universal I-E Scale were consistent with recent theories that the main
      distinctions in intrinsic and extrinsic religious orientation comprise intrinsic,
      extrinsic-personal, and extrinsic-social religious dimensions.

PMID- 12431039
TI  - Five-factor model (Big Five) personality traits and universal-diverse orientation
      in counselor trainees.
AB  - In this study the authors explored the relationship between five-factor model
      (FFM: Big Five) personality traits (J. M. Digman, 1990; R. R. McCrae & O. P.
      John, 1992; J. S. Wiggins & P. D. Trappnell, 1997) and universal-diverse
      orientation (UDO; M. L. Miville et al., 1999) in counselor trainees. FFM traits
      were measured using the NEO-Personality Inventory-Revised (P. T. Costa & R. R.
      McCrae, 1992). Statistically significant relationships were found between UDO and
      one of the Big Five personality traits (Openness to Experience) in counselor
      trainees. Further regression analysis suggested a relationship between UDO and a
      particular facet of Openness to Experience, Openness to Aesthetics. This finding
      suggests that counselor trainees who are open to the creative expressions of
      others may be comfortable working with a wide variety of clients. These results
      suggest that counselor training that encourages experiences of aesthetic
      diversity in addition to an exploration of values may promote trainees' ability
      to work with diverse clients.

PMID- 12431040
TI  - Love and achievement motives in women's and men's suicide notes.
AB  - It is often assumed that women kill themselves because of love and men because of
      achievement problems. The authors evaluated the suicide notes of 56 U.S. adult
      women and men with regard to love and achievement motives. Love themes were
      significantly more common than achievement themes, independent of sex and age.
      This suggests that, at least for U.S. adults who leave suicide notes,
      relationship concerns may be a dominant component of the motivation for suicide.

PMID- 12431041
TI  - Ocular tolerability and safety of ketotifen fumarate ophthalmic solution.
AB  - Ketotifen fumarate, formulated for the treatment of allergic conjunctivitis, is a
      histamine H1-receptor antagonist, mast cell stabilizer, and eosinophil inhibitor
      (decreases chemotaxis and activation of eosinophils). In this study, healthy
      volunteers 3 years of age or older received ketotifen fumarate .025% ophthalmic
      solution (n = 330) or placebo (n = 165) four times daily for 6 weeks. Ketotifen
      was safe and well tolerated in the adult and pediatric populations, with an
      incidence of ocular adverse events of 18.2%, compared with 15.2% with placebo. No
      ocular rebound vasodilation or itching was observed within 48 hours after
      treatment. Ketotifen has a favorable safety and tolerability profile, which may
      have a positive impact on compliance, an important aspect of effective
      symptomatic control of allergic conjunctivitis.

PMID- 12431042
TI  - Bone graft gel: autologous growth factors used with autograft bone for lumbar
      spine fusions.
AB  - A method to combine autologous growth factors (AGF) with autologous bone graft in
      a bone graft gel for spine fusions is described. The bone graft gel can be
      inserted into cages for interbody fusions or used directly for posterolateral
      intertransverse fusions. Sixty patients have undergone spinal fusion surgery
      under this technique. No equipment problems have been encountered and no adverse
      effects observed that could be attributed to AGF. Early clinical outcomes
      indicated solid or maturing fusions in 58 of 60 patients. AGFs to enhance bone
      healing represent an economical and readily available autologous source of growth
      factors.

PMID- 12431043
TI  - Thyroid abnormalities in lithium-treated patients.
AB  - The purposes of this study were to evaluate possible effects of lithium on
      thyroid function, determine the relationship among thyroid function, antibody
      levels, and demographic/clinical variables, and establish the prevalence of
      lithium-related goiter, clinical hypothyroidism, and thyroid antibodies. Forty
      nine patients who had taken lithium for a minimum of 6 months were enrolled, as
      were 46 age- and sex-matched controls naive to lithium use. Blood was drawn to
      measure levels of total and free T3, T4, thyroid-stimulating hormone (TSH), and
      antimicrosomal and antithyroglobulin antibodies. Thyroid volume was quantified on
      ultrasonography. Twenty-nine patients in the study group (59%) and 7 in the
      control group (15%) had goiter. Free T4 levels were significantly lower in the
      study group, and TSH levels were higher. Among lithium-treated patients, 12% had
      clinical hypothyroidism and 2% had subclinical hypothyroidism. Thyroid antibodies
      were present in 23% of the lithium group and 15% of the control group. No
      significant relationship was apparent among thyroid antibodies, thyroid volume,
      and clinical hypothyroidism. Our findings suggested that along with its
      goitrogenic effects, lithium inhibited thyroid function and led to clinical
      hypothyroidism. Older age, family history of thyroid disorders, and the presence
      of thyroid antibodies significantly influenced thyroid function in the present
      study.

PMID- 12431044
TI  - Single dose of ketotifen fumarate .025% vs 2 weeks of cromolyn sodium 4% for
      allergic conjunctivitis.
AB  - This single-masked, contralateral-eye, active-controlled allergen-challenge study
      compared ketotifen fumarate .025% and cromolyn sodium 4% ophthalmic solutions in
      the prevention of ocular itching, tearing, and redness induced by allergen
      challenge. After a confirmatory conjunctival provocation test (CPT), 56 patients
      randomly received masked study medication (placebo in one eye, cromolyn in the
      other eye) four times daily for 2 weeks. At visit 3, patients received one drop
      of ketotifen in the eye previously treated with placebo and cromolyn in the other
      eye. Ocular comfort was assessed 30 seconds postinstillation, and a CPT was
      conducted 15 minutes and 4 hours postinstillation to evaluate ocular itching,
      tearing, and redness. Forty-seven patients were analyzed for efficacy. At the 15
      minute and 4-hour challenges, ketotifen was superior to cromolyn in preventing
      itching (P < .001) at all assessments and redness (ciliary, conjunctival, and
      episcleral) (P < or = .001) at most assessments. Tearing scores were higher in
      cromolyn-treated eyes than in ketotifen-treated eyes. Patients reported greater
      comfort in the ketotifen-treated than in the cromolyn-treated eye (P = .066). The
      most common adverse event was burning/stinging with cromolyn. A single dose of
      ketotifen was superior to a 2-week four-times-daily regimen of cromolyn in
      alleviating symptoms of allergic conjunctivitis in the conjunctival allergen
      challenge model.

PMID- 12431045
TI  - Effects of methylprednisolone and betamethasone injections on the rotator cuff:
      an experimental study in rats.
AB  - Thirty-one female Sprague-Dawley rats were used to determine the effects of
      subacromial corticosteroid injections on the rotator cuff. The injection
      technique was tested in 6 animals, which were excluded from the study. The
      remaining 25 rats were randomly divided into three groups of 8 animals each; a
      single rat received no injections. Every other week for 8 weeks, one shoulder in
      each rat was injected with methylprednisolone, betamethasone, or saline in a
      dosage equivalent to that used in humans. The supraspinatus and infraspinatus
      tendons were removed 10 days after the last injection and evaluated. There were
      no pathologic changes in the tendons injected with saline. In 43% of the
      methylprednisolone-treated rats and 29% of the betamethasone-treated rats, the
      tendons were abnormally soft and light-colored. In 43% of the methylprednisolone
      group and 71% of the betamethasone group, fragmentation of collagen bundles and
      inflammatory cell infiltration were evident. Subacromial injections of
      methylprednisolone or betamethasone repeated frequently can cause deleterious
      changes in the normal structure of the rat rotator cuff. In light of these
      findings, therapy for subacromial impingement syndrome of the shoulder with
      frequent, repeated steroid injections is potentially harmful.

PMID- 12431046
TI  - Novel soluble cationic trans-diaminedichloroplatinum(II) complexes that are
      active against cisplatin resistant ovarian cancer cell lines.
AB  - Positively charged, water soluble cis/trans-[PtCl(2)(piperazine)(Am1)] (where Am1
      = NH(3), n-butylamine, isopropylamine, 4-picoline, piperidine, and piperazine)
      has significant cytotoxic activity against cisplatin resistant ovarian cancer
      cells. The charged complexes are taken up by cancer cells much more rapidly than
      cisplatin and bind to cellular DNA and to calf thymus DNA much faster than
      cisplatin or transplatin. The platinum-piperazine complexes bind proteins
      (ubiquitin and myoglobin) very slowly as compared to cisplatin and to their
      neutral piperidine analogues. Altogether, the results reported here suggest that
      combination of positively charged ligands with a trans-Pt(II)Cl(2) center may
      lead to the discovery of platinum complexes that are able to circumvent cisplatin
      resistance.

PMID- 12431047
TI  - Novel apoptosis-inducing trans-platinum piperidine derivatives: synthesis and
      biological characterization.
AB  - The synthesis, chemical characterization, and interaction with cells of new
      sterically hindered trans- and cis-diaminedichloroplatinum(II) complexes are
      described. The amine ligands include monofunctional piperidine (pip) and
      piperazine (pz). The poor solubility of trans-diaminedichloroplatinum complexes
      was overcome by introducing the positively charged pz ligand, which allows
      retaining of the classic platinum coordination sphere. In vitro evaluation in OV
      1063 and C-26 tumor cells revealed that replacing one NH3 of the inactive
      transplatin by an aromatic planar ligand (4-picoline, 4-pic) or by an aliphatic
      nonplanar heterocyclic ligand (pip) or replacing both NH3 groups with a 4-pic
      ligand and a pip or pz ligand significantly increases the cytotoxic activity of
      these complexes. The unsymmetric complexes trans-[PtCl2(4-pic)(pip)] and trans
      [PtCl2(4-pic)(pz)]HCl were the most cytotoxic compounds against the cisplatin
      sensitive tumor cell line C-26 (IC50 = 4.5 and 5.5 microM, respectively) and the
      cisplatin-sensitive tumor cell line OV-1063 (IC50 = 6.5 and 7.4 microM,
      respectively). In contrast, replacing one NH3 of the cis isomer by an aromatic
      planar ligand (4-pic) or by an aliphatic amine lowered their cytotoxiciy in
      comparison to cisplatin. Cell penetration and Pt-DNA adduct formation were also
      evaluated, and it was clearly shown that both trans-[PtCl2(4-pic)(pip)] and trans
      [PtCl2(4-pic)(pz)]HCl penetrate efficiently the cellular membrane of the tumor
      cells and platinate the cellular DNA. When comparing cellular DNA platination,
      positively charged trans-[PtCl2(4-pic)(pz)]HCl was 7-fold higher than both
      cisplatin and its neutral analogue trans-[PtCl2(4-pic)(pip)]. Moreover, in
      contrast to cisplatin, in the cell lines used, cell death caused by both
      complexes appeared to be apoptotic according to several criteria including early
      phosphatidylserine exposure, activation of caspases, and characteristic
      morphological changes. Our results suggest that these novel mixed nonclassical
      trans-Pt(II) complexes are biologically and mechanistically distinct from known
      Pt complexes and deserve evaluation of their efficacy in tumor-bearing animals.

PMID- 12431048
TI  - Antitumor agents. 1. Synthesis, biological evaluation, and molecular modeling of
      5H-pyrido[3,2-a]phenoxazin-5-one, a compound with potent antiproliferative
      activity.
AB  - The iminoquinone is an important moiety of a large number of antineoplastic drugs
      and plays a significant role in the nucleus of actinomycins, powerful, highly
      toxic, natural antibiotics that target DNA as intercalating agents. A series of
      polycyclic iminoquinonic compounds, 2-amino-3H-phenoxazin-3-one (1), 2-amino-1,9
      diacetyl-3H-phenoxazin-3-one (2), 2-acetylamino-3H-phenoxazin-3-one (3), 3H
      phenoxazin-3-one (4), 5H-pyrido[3,2-a]phenoxazin-5-one (5), and 5H-pyrido[3,2
      a]phenothiazin-5-one (6), strictly related to the actinomycin chromophore, were
      synthesized for developing new anticancer intercalating drugs. The
      antiproliferative activity of these compounds, evaluated against representative
      human liquid and solid neoplastic cell lines, showed that 5 and its isoster 6
      were the most active compounds inhibiting cell proliferation in a submicromolar
      range. Compound 5 was also evaluated against KB subclones (KBMDR, KB7D, and
      KBV20C), which overexpress the MDR1/P-glycoprotein drug efflux pump responsible
      for drug resistance. All the above KB subclones did not show altered sensitivity
      to the antiproliferative activity of 5. UV-vis and (1)H NMR spectroscopy
      experiments support the phenoxazinone 5/DNA binding. Molecular mechanics methods
      were used to build a three-dimensional model of the 5/[d(GAAGCTTC)]2 complex.
      Electrostatic interactions between the hydrogen of the positively charged
      pyridine nitrogen of 5 and the negatively charged oxygen atoms (O4' and O5') of
      the cytosine C5 residue together with stacking forces contribute to the high
      antiproliferative activity. The metal(II)-assisted synthesis procedure of 5 is
      described, and the formation mechanism is proposed.

PMID- 12431049
TI  - Antitumor agents. 2. Synthesis, structure-activity relationships, and biological
      evaluation of substituted 5H-pyridophenoxazin-5-ones with potent
      antiproliferative activity.
AB  - New antiproliferative compounds, 5H-pyrido[3,2-a]phenoxazin-5-ones (1-10), 5H
      benzophenoxazin-5-one (11), 5H-pyrido[2,3-a]phenoxazin-5-one (12), 5H-pyrido[3,4
      a]phenoxazin-5-one (13), and 5H-pyrido[4,3-a]phenoxazin-5-one (14), were
      synthesized and evaluated against representative human neoplastic cell lines. The
      excellent cytotoxic activity of these polycyclic phenoxazinones, structurally
      related to the actinomycin chromophore, is discussed in terms of structural
      changes made to rings A and D (Chart 1). Electron-withdrawing or electron
      donating substituents were introduced at different positions of ring A to probe
      the electronic and positional effects of the substitution. A nitro group in R(2)
      or in R(1) increases the cytotoxic activity, whereas electron-donating methyl
      groups in any position lead to 10- to 100-fold decreasing of the activity. The
      low antiproliferative activity of benzophenoxazinone 11 and pyridophenoxazinones
      13 and 14 confirms the crucial role of pyridine nitrogen in the W position of
      ring D in DNA binding. The unexpected high activity exhibited by 12, which has
      the nitrogen in the X position, could be ascribed to a different mechanism of
      action, which needs further investigation.

PMID- 12431050
TI  - Synthesis and evaluation of indenopyrazoles as cyclin-dependent kinase
      inhibitors. 2. Probing the indeno ring substituent pattern.
AB  - We disclose a novel series of indenopyrazole-based cyclin-dependent kinase (CDK)
      inhibitors. Kinetic experiments confirmed our initial molecular modeling studies
      that the compounds are competitive with respect to adenosine 5'-triphosphate
      (ATP) and bind in the kinase ATP pocket. A unique combination of active
      pharmacophores led us to a series of semicarbazide-based inhibitors that are
      highly potent against CDK2 and CDK4 while maintaining selectivity against other
      relevant serine/threonine kinases. These compounds were active against a
      transformed human colon cancer cell line (HCT116) while maintaining an acceptable
      margin of activity against a normal fibroblast cell line. The compounds were
      found to be highly protein bound in our cell-based assay with the exception of
      11k, which maintained a reasonable level of activity in the presence of human
      plasma proteins.

PMID- 12431051
TI  - Synthesis and evaluation of indenopyrazoles as cyclin-dependent kinase
      inhibitors. 3. Structure activity relationships at C3(1,2).
AB  - The identification of indeno[1,2-c]pyrazol-4-ones as inhibitors of cyclin
      dependent kinases (CDKs) has led to the discovery of a series of novel and potent
      compounds. Herein, we report the effects of substitutions at C3 of the indeno[1,2
      c]pyrazol-4-one core with alkyls, heterocycles, and substituted phenyls.
      Substitutions at the para position of the phenyl ring at C3 were generally well
      tolerated; however, larger groups were generally inactive. For alkyls directly
      attached to C3, longer chain substituents were not tolerated; however, shorter
      alkyl groups and cyclic alkyls were acceptable. In general, the heterocycles at
      C3 gave the most potent analogues. One such heterocycle, 24j, was examined in
      detail and was determined to have a biological profile consistent with CDK
      inhibition. An X-ray crystal structure of one of the alkyl compounds, 13q,
      complexed with CDK2 was determined and showed the inhibitor residing in the
      adenosine 5'-triphosphate pocket of the enzyme.

PMID- 12431052
TI  - Molecular docking and 3D-QSAR studies on gag peptide analogue inhibitors
      interacting with human cyclophilin A.
AB  - The interaction of a series gag peptide analogues with human cyclophilin A
      (hCypA) have been studied employing molecular docking and 3D-QSAR approaches. The
      Lamarckian Genetic Algorithm (LGA) and divide-and-conquer methods were applied to
      locate the binding orientations and conformations of the inhibitors interacting
      with hCypA. Good correlations between the calculated interaction free energies
      and experimental inhibitory activities suggest that the binding conformations of
      these inhibitors are reasonable. A novel interaction model was identified for
      inhibitors 11, 15, and 17 whose N-termini were modified by addition of the
      deaminovaline (Dav) group and the C-termini of 15 and 17 were modified by
      addition of a benzyl group. Accordingly, two new binding sites (sites A and D in
      Figure 1) were revealed, which show a strong correlation with inhibitor potency
      and thus can be used as a starting point for new inhibitor design. In addition,
      two predictive 3D-QSAR models were obtained by CoMFA and CoMSIA analyses based on
      the binding conformations derived from the molecular docking calculations. The
      reasonable r(cross)(2) (cross-validated) values 0.738 and 0.762 were obtained for
      CoMFA and CoMSIA models, respectively. The predictive ability of these models was
      validated by four peptide analogues test set. The CoMFA and CoMSIA field
      distributions are in general agreement with the structural characteristics of the
      binding groove of hCypA. This indicates the reasonableness of the binding model
      of the inhibitors with hCypA. Considering all these results together with the
      valuable clues of binding from references published recently, reasonable
      pharmacophore elements have been suggested, demonstrating that the 3D-QSAR models
      about peptide analogue inhibitors are expected to be further employed in
      predicting activities of the novel compounds for inhibiting hCypA.

PMID- 12431053
TI  - Novel dual inhibitors of AChE and MAO derived from hydroxy aminoindan and
      phenethylamine as potential treatment for Alzheimer's disease.
AB  - Carbamate derivatives of N-propargylaminoindans (Series I) and N
      propargylphenethylamines (Series II) were synthesized via multistep procedures
      from the corresponding hydroxy precursors. The respective rasagiline- and
      selegiline-related series were designed to combine inhibitory activities of both
      acetylcholine esterase (AChE) and monoamine oxidase (MAO) by virtue of their
      carbamoyl and propargylamine pharmacophores. Each compound was tested for these
      activities in vitro in order to find molecules with similar potencies against
      each enzyme. Compounds with such dual AChE and MAO inhibitory activities are
      expected to have potential for the treatment of Alzheimer's disease. The observed
      SAR also offers insight into the requirements of the active sites on these
      enzymes. A carbamate moiety was found to be essential for AChE inhibition, which
      was absent in the corresponding hydroxy precursors. The propargyl group caused 2
      70-fold decrease in AChE inhibitory activity (depending on the position of the
      carbamoyl group) of Series I, but had little or no effect in Series II. Thus, the
      6- and 7-carbamyloxyphenyls in Series I were either equipotent to, or slightly (2
      to 5-fold) less active as AChE inhibitors than, the corresponding compounds in
      Series II, while the 4-carbamyloxyphenyls were more potent. The presence of the
      carbamate moiety in 6- and 7-carbamyloxyphenyls of Series I, considerably
      decreased MAO-A and -B inhibitory activity, compared to that of the parent
      hydroxy analogues, while the opposite was true for Series II. Thus, the 6- and 7
      carbamyloxyphenyls in Series I were 2-3 orders of magnitude weaker MAO inhibitors
      while the 4- carbamyloxyphenyls were equipotent with the corresponding compounds
      in Series II. In both series, N-methylation of the propargylamine enhanced the
      MAO (A and B equally) inhibitory activities and decreased the AChE inhibitory
      activity. Two candidates belonging to the indan and tetralin ring systems (24c,
      27b) and one phenethylamine (53d) were identified as possible leads for further
      development based on the following criteria: (a) comparable AChE and MAO-B
      inhibitory activities, (b) good to moderate AChE inhibitory activity, and (c)
      lack of strong MAO-A selectivity. However, it is likely that these compounds will
      be metabolized to the corresponding phenols, with inhibitory activities against
      AChE and/or MAO-A or -B, different from those of the parent carbamates. Thus, the
      apparent enzyme inhibition will be a result of the combined inhibition of all of
      these individual metabolites. The results of our ongoing in vivo screening
      programs will be published elsewhere.

PMID- 12431054
TI  - Novel, potent ORL-1 receptor agonist peptides containing alpha-Helix-promoting
      conformational constraints.
AB  - The ORL-1 receptor has recently been cloned and is implicated in a wide variety
      of physiological and pathophysiological processes. Toward the goal of elucidating
      important features of the receptor-bound conformation of the endogenous ligand,
      nociceptin (NC), several conformationally constrained analogues were prepared.
      Either alpha-aminoisobutyric acid (Aib) or N-methylalanine (MeAla) were inserted
      as replacement(s) for Ala7, Ala11, or Ala15 in the native NC sequence
      (FGGFTGARKSARKLANQ). In vitro assays measuring human ORL-1 receptor affinity
      (competition binding against [3H] NC), functional potency ([35S]GTP gamma S), and
      efficacy (as compared to NC) were performed for each new peptide. The receptor
      affinities of the Aib-containing peptides generally matched NC, showing K(i)'s in
      the range of 0.1-0.5 nM. By comparison, the receptor affinities of the MeAla
      containing peptides were significantly diminished. Peptide 14
      (FGGFTG[Aib]RKS[Aib]RKLANQ-NH2), which contains two constrained alanine residues
      (positions 7 and 11) and a C-terminal amide modification, was found to be a very
      potent agonist with K(i) = 0.05 nM and EC50 = 0.08 nM in the human ORL-1 assays.
      The data support a hypothesis that the receptor-bound form of NC might adopt an
      amphipathic helix in the "address" segment of the sequence.

PMID- 12431055
TI  - Structure-activity studies of the melanocortin peptides: discovery of potent and
      selective affinity antagonists for the hMC3 and hMC4 receptors.
AB  - We have designed and synthesized several novel cyclic SHU9119 analogues (Ac-Nle4
      [Asp5-His6-DNal(2')7-Arg8-Trp9-Lys10]-NH2) modified in position 6 with
      nonconventional amino acids. SHU9119 is a high affinity nonselective antagonist
      at hMC3R and hMC4R with potent agonist activity at hMC1R and hMC5R. We measured
      the binding affinity and agonist potency of the novel analogues at cloned hMC3R,
      hMC4R, and hMC5R receptors and identified several selective, high affinity hMC3R
      and hMC4R antagonists. Compound 4 containing Che substitution in position 6 is a
      high affinity hMC4R antagonist (IC50 = 0.48 nM) with 100-fold selectivity over
      hMC3R antagonist. Analogue 7 with a Cpe substitution in position 6 is a high
      affinity hMC4R antagonist (IC50 = 0.51 nM) with a 200-fold selectivity vs the
      hMC3R. Interestingly, analogue 9 with an Acpc residue in position 6 is a high
      affinity hMC3R antagonist (IC50 = 2.5 nM) with 100-fold selectivity vs the hMC4R
      antagonist based on its binding affinities. This compound represents the first
      cyclic lactam antagonist with high selectivity for the hMC3R vs hMC4R. To
      understand the possible structural basis responsible for selectivity of these
      peptides at hMCR3 and hMCR4, we have carried out a molecular modeling study in
      order to examine the conformational properties of the cyclic peptides modified in
      position 6 with conformationally restricted amino acids.

PMID- 12431056
TI  - Sulfamide-based inhibitors for carboxypeptidase A. Novel type transition state
      analogue inhibitors for zinc proteases.
AB  - N-Sulfamoylphenylalanine and its derivatives having varied alkyl groups on the
      terminal amino group were designed rationally as transition state analogue
      inhibitors for carboxypeptidase A (CPA) and synthesized. In CPA inhibitory assays
      the parent compound having the (S)-configuration, i.e., (S)-1a, showed potent
      inhibitory activity with the K(i) value of 0.64 microM. Its enantiomer was shown
      to be much less potent (K(i) = 470 microM). Introduction of an alkyl group such
      as methyl or isopropyl group on the terminal amino group of (S)-1a lowered the
      inhibitory potency drastically. Introduction of a methyl group on the internal
      amino group of (S)-1a also caused a drastic reduction of the inhibitory activity.
      The structure of the CPA x(S)-1a complex determined by single-crystal X-ray
      diffraction reveals that the sulfamoyl moiety interacts with the zinc ion and
      functional groups at the active site of CPA, which is reminiscent of the
      postulated stabilization mode of a tetrahedral transition state in the CPA
      catalyzed hydrolysis of a peptide substrate. On the basis of the design rationale
      and the binding mode of (S)-1a to CPA shown by X-ray crystallographic analysis,
      the present inhibitors are inferred to be a novel type of transition state
      analogue inhibitor for CPA.

PMID- 12431057
TI  - Design, synthesis, and tripeptidyl peptidase II inhibitory activity of a novel
      series of (S)-2,3-dihydro-2-(4-alkyl-1H-imidazol-2-yl)-1H-indoles.
AB  - Butabindide, 1, was previously reported as a potent inhibitor (IC50 = 7 nM) of
      the serine protease enzyme tripeptidyl peptidase II (TPPII), an endogenous
      protease that degrades cholecystokinin-8 (CCK-8). We found that 1 has some
      inherent chemical instability, yielding diketopiperazine 2 fairly readily under
      mimicked physiological conditions. We therefore prepared imidazoles 3, which are
      void of 1's inherent instability, and have found that our novel analogues
      maintained comparable TPPII inhibitory activity (e.g.,for 3c, IC50 = 4 nM) as 1.

PMID- 12431058
TI  - A new approach to finding natural chemical structure classes.
AB  - In modern drug discovery, large compound libraries need to be compared and the
      diversity of compound libraries needs to be analyzed. Classification algorithms
      are important tools for accomplishing these tasks. In this paper, a chemical
      structural scaffold based classification approach is reported. The goals of the
      approach are to find natural structure families from a large (millions of
      entries) compound library within a feasible time period and to view the library
      in two-dimensional data space using chemically meaningful methods.

PMID- 12431059
TI  - Design of noncovalent inhibitors of human cathepsin L. From the 96-residue
      proregion to optimized tripeptides.
AB  - A novel series of noncovalent inhibitors of cathepsin L have been designed to
      mimic the mode of autoinhibition of procathepsin L. Just like the propeptide,
      these peptide-based inhibitors have a reverse-binding mode relative to a
      substrate and span both the S' and S subsites of the enzyme active site. In
      contrast to previous studies in which even moderate truncation of the full-length
      propeptide led to rapid reduction in potency, these blocked tripeptide-sized
      inhibitors maintain nanomolar potency. Moreover, these short peptides show higher
      selectivity (up to 310-fold) for inhibiting cathepsin L over K versus only 2-fold
      selectivity of the 96-residue propeptide of cathepsin L. A 1.9 A X-ray
      crystallographic structure of the complex of cathepsin L with one of the
      inhibitors confirms the designed reverse-binding mode of the inhibitor as well as
      its noncovalent nature. Enzymatic analysis also shows the inhibitors to be
      resistant to hydrolysis at elevated concentrations of the enzyme. The mode of
      inhibition of these molecules provides a general strategy for inhibiting other
      cathepsins as well as other proteases.

PMID- 12431060
TI  - Effects of isoprenoid analogues of SDB-ethylenediamine on multidrug resistant
      tumor cells alone and in combination with chemotherapeutic drugs.
AB  - Multidrug resistance (MDR) mediated by P-glycoprotein (Pgp) remains the major
      obstacle for successful treatment of cancer. Inhibition of Pgp transport is
      important for higher efficacy of anticancer drugs. Lipophilic cationogenic amines
      with at least one tertiary N atom, such as verapamil, are classical PgP-blocking
      agents. In a search for novel accessible compounds potent against MDR tumor
      cells, we synthesized a series of arylalkylamines that contain isoprenoid side
      chains of different length. Two out of seven new analogues of the known N,N'
      bis(3,4-dimethoxybenzyl)-N-solanesylethylenediamine (SDB-ethylenediamine),
      namely, compounds with C10 and C15 side chains, at low micromolar concentrations
      were preferentially toxic for several mammalian tumor cell lines that acquired
      MDR during prolonged drug selection. Moreover, at noncytotoxic concentrations,
      these compounds potently sensitized MDR cells to Pgp substrates vinblastine and
      adriamycin. We conclude that these analogues of SDB-ethylenediamine may have dual
      therapeutic advantage because (i) they are preferentially toxic for MDR cells
      when administered alone and (ii) they potentiate the cytotoxicity of Pgp
      transported anticancer drugs.

PMID- 12431061
TI  - Syntheses and calcium-mobilizing evaluations of N1-glycosyl-substituted stable
      mimics of cyclic ADP-ribose.
AB  - Cyclic ADP-ribose (cADPR) is not only a potent endogenous calcium modulator but
      also a second messenger. However, studies on the mechanism of cADPR action were
      limited due to its instability and lack of available structural modifications in
      the N1-glyosyl unit of cADPR. In the present work, a series of N1-glycosyl mimics
      with different configurational glycosyls or an ether strand were designed and
      synthesized mimicking the furanose ring. S(N)2 substitutions were carried out
      between the protected inosine and glycosyl triflates to form the N1
      glycosylinosine derivatives, accompanied with some O6-glycosyl-substituted as
      side products. The intramolecular cyclization was followed the strategy described
      by Matsuda et al. It was found that the 8-unsubstituted substrate could also be
      used to construct the intramolecular cyclic pyrophosphate. The activities of N1
      glycosyl-substituted cADPR mimics were evaluated by induced Ca2+ release in rat
      brain microsomes and HeLa cells. It was found that the configuration of the N1
      glycosyl moiety in cADPR is not a critical structural factor for retaining the
      activity of mobilizing Ca2+ release. More interestingly, the N1-acyclic analogue
      6 exhibited strong activity by inducing Ca2+ release in both rat brain microsomes
      and HeLa cells. It constitutes a useful tool for further studies.

PMID- 12431062
TI  - Probing opioid receptor interactions with azacycloalkane amino acids. Synthesis
      of a potent and selective ORL1 antagonist.
AB  - Azacycloalkane turn mimics 6-9 were used to explore the relationship between
      conformation and biological activity of peptide ligands to the opioid receptor
      like (ORL1) receptor. Three azabicyclo[x.y.0]alkane amino acids and a 5-tBuPro
      type VI beta-turn mimic were introduced into peptides 10-13 by solid-phase
      synthesis on MBHA resin. Biological examination of peptides 10-13 showed two new
      antagonists (10 and 12) exhibiting increased selectivity for the ORL1 receptor.

PMID- 12431063
TI  - Investigations on estrogen receptor binding. The estrogenic, antiestrogenic, and
      cytotoxic properties of C2-alkyl-substituted 1,1-bis(4-hydroxyphenyl)-2
      phenylethenes.
AB  - C2-Alkyl-substituted 1,1-bis(4-hydroxyphenyl)-2-phenylethenes were synthesized
      and assayed for estrogen receptor binding in a competition experiment with
      radiolabeled estradiol ([3H]-E2) using calf uterine cytosol. The relative binding
      affinity decreased with the length of the side chain R = H (3a: 35.2%) > Me (3b:
      32.1%) > Et (3c: 6.20%) approximately CH2CF3 (3d: 5.95%) > n-Pr (3e: 2.09%) > Bu
      (3f: 0.62%). Agonistic and antagonistic effects were evaluated in the luciferase
      assay with MCF-7-2a cells stably transfected with the plasmid ERE(wtc)luc. All
      compounds showed high antiestrogenic activity without significant agonistic
      potency. The comparison of the IC(50) values for the inhibition of E2 (1 nM)
      documented the dependence of the antagonistic effects on the kind of the side
      chain: 3a (IC50 = 150 nM), 3b (IC50 = 30 nM), and 3f (IC50 = 500 nM) were weak
      antagonists, while 3c (IC50 = 15 nM), 3d (IC50 = 9 nM), and 3e (IC50 = 50 nM)
      were full antiestrogens and antagonized the effect of E2 completely. The most
      active compound 3d possessed the same antagonistic potency as 4-hydroxytamoxifen
      (4OHT: IC50= 7 nM) without bearing a basic side chain. 3d as well as all other
      1,1-bis(4-hydroxyphenyl)-2-phenylalkenes were not able to influence the
      proliferation of hormone dependent MCF-7 cells despite the antagonistic mode of
      action. In this assay tamoxifen (TAM) and 4OHT reduced the cell growth
      concentration dependent up to T/C(corr) = 15% and 25%, respectively.

PMID- 12431064
TI  - Structure-activity relationships of 1-alkyl-5-(3,4-dichlorophenyl)- 5-[2-[(3
      substituted)-1-azetidinyl]ethyl]-2-piperidones. 1. Selective antagonists of the
      neurokinin-2 receptor.
AB  - The design, synthesis, and pharmacological evaluation of a novel class of
      neurokinin-2 (NK2) antagonists 1-alkyl-5-(3,4-dichlorophenyl)-5-[2-[(3
      substituted)-1-azetidinyl]ethyl]-2-piperidones (5-44) are described. These
      compounds are formally derived from 2 by incorporating the metabolically
      vulnerable N-methylamide function into a more stable six-membered ring lactam 4,
      resulting in increased stability in human liver microsome (HLM) preparations
      relative to 2 (T1/2(HLM) of 30 min vs <10 min for 2). This series was further
      optimized by replacing the 4,4-disubstituted piperidine functionality found in 4
      with simple 3-substituted azetidines. This series, exemplified by 1-benzyl-5-(3,4
      dichlorophenyl)-5-[2-[3-(4-morpholinyl)-1-azetidinyl]ethyl]-2-piperidone 5, was
      found to possess excellent functional potency for the NK2 receptor in the Rabbit
      pulmonary artery (RPA) assay (pA2 = 9.3) and increased in vitro metabolic
      stability (T1/2(HLM) = 70 min) relative to 4. Metabolic route identification
      studies revealed that N-benzyl oxidation was a major route in this relatively
      lipophilic lead (log D = 3.2). Further exploration of the N-lactam substituent
      SAR targeting reduced lipophilicity to attenuate P-450 metabolism revealed that
      incorporation of a cyclopropylmethyl group in this region of the molecule gave a
      balance of good potency and high metabolic stability. For example, the
      significantly less lipophilic analogue 29 (log D = 2.3) possessed both good
      functional potency (RPA, pA2 = 8.1) and high in vitro metabolic stability
      (T1/2(HLM) = 120 min). Optimization in this N-cyclopropylmethyllactam series by
      modification of the nature of the azetidine 3-substituent as a strategy to
      further increase potency and moderate log D led to the identification of
      sulfamide analogue 33, which possessed both excellent metabolic stability in
      vitro (T1/2(HLM) >120 min) and high potency in both RPA (pA2 = 8.9) and human
      bladder smooth muscle (pK(b) = 8.9) functional assays. In addition, NK2
      antagonist 33 (IC50 = 4 nM) showed excellent selectivity over both the related
      human neurokinin receptors h-NK1 (IC50 = 7.9 microM) and h-NK3 (IC50 = 1.8
      microM) in radioligand binding studies.

PMID- 12431065
TI  - Synthesis and biological evaluation of 14-alkoxymorphinans. 17. Highly delta
      opioid receptor selective 14-alkoxy-substituted indolo- and benzofuromorphinans.
AB  - 14-Alkoxy analogues of naltrindole and naltriben differently substituted in
      positions 5 and 17 and at the indole nitrogen (compounds 28-44) have been
      synthesized in an effort to enhance the delta potency and/or delta selectivity
      and in order to further elaborate on structure-activity relationships of this
      class of compounds. Introduction of a 14-alkoxy instead of the 14-hydroxy group
      present in naltrindole resulted in somewhat lower delta binding affinity, while
      in many cases (compounds 31, 34, 37, 40, 41, 44, HS 378) the delta receptor
      selectivity was considerably increased. An ethoxy group in position 14 is
      superior to other alkoxy groups concerning delta affinity and selectivity (34,
      41, 42, 44, HS 378). In [35S]GTP gamma S binding, compounds 34, 41, and HS 378
      exhibited about one-tenth the antagonist potency of naltrindole at delta opioid
      receptors while their delta antagonist selectivity was considerably higher. 17
      Methyl-substituted compounds 35 and 44 were found to be pure delta receptor
      agonists in this test.

PMID- 12431066
TI  - Adenosine 5'-O-(1-boranotriphosphate) derivatives as novel P2Y(1) receptor
      agonists.
AB  - P2-receptors (P2-Rs) represent important targets for novel drug development. Most
      ATP analogues proposed as potential drug candidates have shortcomings such as
      limited receptor-selectivity and limited stability that justify the search for
      new P2-R agonists. Therefore, a novel series of nucleotides based on the
      adenosine 5'-O-(1-boranotriphosphate) (ATP-alpha-B) scaffold was developed and
      tested as P2Y(1)-R agonists. An efficient four-step one-pot synthesis of several
      ATP-alpha-B analogues from the corresponding nucleosides was developed, as well
      as a facile method for the separation of the diastereoisomers (A and B isomers)
      of the chiral products. The potency of the new analogues as P2Y(1)-R agonists was
      evaluated by the agonist-induced Ca2+ release of HEK 293 cells stably transfected
      with rat-brain P2Y(1)-R. ATP-alpha-B A isomer was equipotent with ATP (EC50 = 2 x
      10(-7) M). However, 2-MeS- and 2-Cl- substitutions on ATP-alpha-B (A isomer)
      increased the potency of the agonist up to 100-fold, with EC50 values of 4.5 x
      10(-9) and 3.6 x 10(-9) M, compared to that of the ATP-alpha-B (A isomer).
      Diastereoisomers A of all ATP-alpha-B analogues were more potent in inducing Ca2+
      release than the corresponding B counterparts, with a 20-fold difference for 2
      MeS-ATP-alpha-B analogues. The chemical stability of the new P2Y(1)-R agonists
      was evaluated by 31P NMR under physiological and gastric-juice pH values at 37
      degrees C, with rates of hydrolysis of 2-MeS-ATP-alpha-B of 1.38 x 10(-7) s-1
      (t1/2 of 1395 h) and 3.24 x 10(-5) s-1 (t1/2 = 5.9 h), respectively. The
      enzymatic stability of the new analogues toward spleen NTPDase was evaluated.
      Most of the new analogues were poor substrates for the NTPDase, with ATP-alpha-B
      (A isomer) hydrolysis being 5% of the hydrolysis rate of ATP. Diastereoisomers A
      and B exhibited different stability, with A isomers being significantly more
      stable, up to 9-fold. Furthermore, A isomers that are potent P2Y(1)-R agonists
      barely interact with NTPDase, thus exhibiting protein selectivity. Therefore, on
      the basis of our findings, the new, highly water-soluble, P2Y(1)-R agonists may
      be considered as potentially promising drug candidates.

PMID- 12431067
TI  - Synthesis of halogen-substituted pyridyl and pyrimidyl derivatives of [3,2
      c]pyrazolo corticosteroids: strategies for the development of glucocorticoid
      receptor mediated imaging agents.
AB  - Ligands for the glucocorticoid receptor labeled with high-energy isotopes are
      highly desired for their potential applications in nuclear medical studies of the
      brain where the dysregulation of this receptor system is thought to be involved
      in various neurodegenerative disorders. Analogues of the glucocorticoid
      cortivazol have previously been prepared as target compounds for labeling with
      high-energy isotopes. However, the phenyl rings of arylpyrazoles of this type are
      not sufficiently activated for nucleophilic substitution reactions that are
      generally required for the synthesis of radiohalogenated analogues. Since
      suitably substituted aromatic nitrogen heterocyclic groups are amenable to
      nucleophilic substitution, the goal of this study was the synthesis of
      pyridylpyrazolo and pyrimidylpyrazolo analogues similar to cortivazol that could
      be labeled with radiohalogens in the pyridine or pyrimidine rings. We describe
      the synthesis of several [3,2-c]pyrazolo steroids containing pyridyl,
      halopyridyl, and pyrimidyl substituents at the 2' position of the pyrazole ring.
      These compounds were tested for binding to the glucocorticoid receptor and for
      biological activity in glucocorticoid responsive HeLa cells grown in tissue
      culture. Of the pyridyl and pyrimidyl derivatives, 2'-(3-pyridyl)-11 beta,17,21
      trihydroxy-16 alpha-methyl-20-oxopregn-4-eno[3,2-c]pyrazole showed superior
      activity in both assays and it was used as the basis for the synthesis of several
      analogues that were halogenated in the pyridine ring. These halogenated compounds
      were all tested for their binding to the glucocorticoid receptor and for their
      biological activity. One, a fluorinated compound 2'-(2-fluoro-5-pyridyl)-11
      beta,17,21-trihydroxy-16 alpha-methyl-20-oxopregn-4-eno[3,2-c]pyrazole had
      excellent activity, considerably better than the potent glucocorticoid
      dexamethasone. Most importantly, fluorination was achieved using a nucleophilic
      exchange reaction, a method that is adaptable to radiolabeling with the positron
      emitting isotope fluorine-18. Thus, considering its superior biological activity
      and adaptability for facile radiosynthesis, this target compound has the
      potential for imaging of glucocorticoid receptor containing tissues using
      positron emission tomography.

PMID- 12431068
TI  - Nitric oxide releasing morpholine derivatives as hypolipidemic and antioxidant
      agents.
AB  - The synthesis and evaluation of activity of some nitric acid esters of
      substituted morpholines are presented. All compounds inhibit lipid peroxidation
      and reduce cholesterol (20-63%) and triglyceride (37-85%) plasma levels. The more
      potent NO donors 14 and 17 specifically reduce low-density lipoprotein (LDL).
      These data indicate that proper structural modifications to the hypolipidemic and
      antioxidant morpholines enabling NO production, besides preserving or enhancing
      the above activities, offer a remarkable reduction of LDL, considered
      advantageous for antiatheromatic agents.

PMID- 12431071
TI  - Benzyl alcohol and transition metal chlorides as a versatile reaction system for
      the nonaqueous and low-temperature synthesis of crystalline nano-objects with
      controlled dimensionality.
AB  - The reaction of transition metal chlorides with benzyl alcohol leads at low
      temperatures to oxidic nanostructures with low-dimensional particle shapes such
      as nearly spherical titania anatase nanoparticles, vanadium oxide nanorods, and
      tungsten oxide nanoplatelets. The process is simple, allows a scale-up in gram
      quantities, and leads to highly crystalline materials. Ethanol solutions
      containing tungsten oxide nanoparticles exhibit blue luminescence upon UV
      irradiation at room temperature.

PMID- 12431069
TI  - Design, synthesis, structure-activity relationships, and molecular modeling
      studies of 2,3-diaryl-1,3-thiazolidin-4-ones as potent anti-HIV agents.
AB  - Starting from 1H,3H-thiazolo[3,4-a]benzimidazoles (TBZs), we performed the
      design, synthesis, and the structure-activity relationship studies of a series of
      2,3-diaryl-1,3-thiazolidin-4-ones. Some derivatives proved to be highly effective
      in inhibiting HIV-1 replication at nanomolar concentrations with minimal
      cytotoxicity, thereby acting as nonnucleoside HIV-1 RT inhibitors (NNRTIs).
      Computational studies were used to delineate the ligand-RT interactions and to
      probe the binding of the ligands to HIV-1 RT.

PMID- 12431072
TI  - Enantioselective synthesis of 1,5-anti- and 1,5-syn-diols using a highly
      diastereoselective one-pot double allylboration reaction sequence.
AB  - Highly diastereo- and enantioselective syntheses of 1,5-disubstituted (E)-1,5
      anti-pent-2-endiols 1 and (Z)-1,5-syn-pent-2-endiols 2 have been achieved via the
      one-pot coupling of two different aldehydes with either (E)-gamma-(1,3,2
      dioxaborinanyl)-allyl]diisopinocampheylborane (4) or (E)-gamma-(4,4,5,5
      tetraphenyl-1,3,2-dioxaborolanyl)allyl]diisopinocampheylborane (11),
      respectively. The indicated diols 1 and 2 are obtained in 63-95% yield with 89
      96% ee and >/=20:1 diastereoselectivity in all cases. The bifunctional gamma
      boryl-substituted allylborane reagents 4 and 11 were generated in situ by the
      hydroboration of allenes 3 and 10 with diisopinocampheylborane. The keys to the
      success of this method are the excellent stereocontrol in the allylboration step
      leading to 5 and the corresponding substituted methallylboronate derived from 11,
      the stereospecificity of the subsequent allylboration reaction of the substituted
      methallylboronate intermediates, and the ability of the diol auxiliary to induce
      equatorial or axial placement of the substituent alpha to boron in transition
      states 7 and 8.

PMID- 12431073
TI  - Development of a new Lewis acid-catalyzed [3,3]-sigmatropic rearrangement: the
      allenoate-Claisen rearrangement.
AB  - A new Lewis acid-catalyzed Claisen rearrangement has been developed that allows
      the stereoselective construction of beta-amino-alpha,beta,epsilon,zeta
      unsaturated-gamma,delta-disubstituted esters from simple allylic amines and
      allenoate esters. This reaction, which is contingent upon the use of Lewis acid,
      can be conducted with a range of metal salts (Yb(OTf)3, AlCl3, Sn(OTf)2,
      Cu(OTf)2, MgBr2.Et2O, FeCl3, Zn(OTf)2) with catalyst loadings as low as 5 mol %.
      This catalytic process provides access to a diverse range of beta-amino
      alpha,beta,epsilon,zeta-unsaturated-gamma,delta-disubstituted esters in high
      yield and with excellent levels of diastereoselectivity for a series of allyl
      pyrrolidines (R1 = H, Me, i-Pr, Ph, NR2 = pyrrolidine, piperidine, NMe2; >/=81%
      yield, >/=94:6 syn:anti) and allenoate esters (R2 = H, Me, i-Pr, Ph, allyl, NPht,
      Cl; >/=75% yield, >/=91:9 syn:anti). The capacity of this new Claisen
      rearrangement to provide catalytic access to elusive structural motifs has also
      been demonstrated in the stereospecific formation of quaternary carbon bearing
      frameworks arising from geranyl- and neryl pyrrolidine (>/=93% yield, >98:2 dr).

PMID- 12431074
TI  - The practical synthesis of a novel and highly potent analogue of bryostatin.
AB  - Macrocycle 1 is a new highly potent analogue of bryostatin 1, a promising anti
      cancer agent currently in human clinical trials. In vitro, 1 displays picomolar
      affinity for PKC and exhibits over 100-fold greater potency than bryostatin 1
      when tested against various human cancer cell lines. Macrocycle 1 can be
      generated in clinically required amounts by chemical synthesis in only 19 steps
      (LLS) and represents a new clinical lead for the treatment of cancer.

PMID- 12431075
TI  - Rapid-injection NMR study of iodo- and cyano-Gilman reagents with 2
      cyclohexenone: observation of pi-complexes and their rates of formation.
AB  - Rapid-injection is a very useful technique for the preparation of temperature
      sensitive and air-sensitive compounds in the cold, nitrogen-filled probe of an
      NMR spectrometer. We have used this method to prepare solutions of pi-complexes
      from 2-cyclohexenone and prototypical cuprates Me2CuLi.LiI and Me2CuLi.LiCN, and
      we have assigned structures on the basis of 1H and 13C NMR. In each case two pi
      complexes were observed, and in the former, their rates of formation were
      measured by rapid-injection 1H NMR and EXSY spectroscopy. These results provide
      insights into the normal and anomalous conjugate addition reactions of
      organocuprates.

PMID- 12431076
TI  - Rationalization of anomalous nonlinear effects in the alkylation of substituted
      benzaldehydes.
AB  - Anomalous nonlinear effects in the alkylation of substituted benzaldehydes with
      diethylzinc using aminoalcohol catalysts are rationalized in terms of a simple
      extension of the Noyori model to allow for nonthermodynamically controlled
      partitioning of the catalyst between monomeric and dimeric species. This work
      highlights the fact that catalyst composition in such systems may be influenced
      by substrate properties.

PMID- 12431077
TI  - A de novo enantioselective total synthesis of (-)-laulimalide.
AB  - An enantioselective total synthesis of the naturally occurring anticancer agent (
      )-laulimalide is described. The synthesis is characterized by extensive use of
      new reaction methodologies based on catalytic asymmetric acyl halide-aldehyde
      cyclocondensation (AAC) reactions and transformations of the derived
      enantioenriched beta-lactones. The synthesis also incorporates a unique
      allenylstannane glycal acetate alkylation and chemoselective ring-closing
      metathesis reaction.

PMID- 12431078
TI  - Sterically induced shape and crystalline phase control of GaP nanocrystals.
AB  - We demonstrate a novel synthetic scheme that can be used to control the
      crystalline phase and shape of GaP semiconductor nanocrystals. Our study shows
      that steric effects of surfactant ligands can modulate the crystalline phases and
      control the shapes of nanocrystals. The shape of the nanocrystals obtained varies
      from zero-dimensional spheres to one-dimensional rods via controlling the ratio
      between primary and tertiary alkylamines. III-V semiconductors (in our case: GaP)
      under 10 nm in width are first reported, and unique optical properties due to
      shape anisotropy are also observed.

PMID- 12431079
TI  - The reactivity of Mo(PMe3)(6) towards heterocyclic nitrogen compounds:
      transformations relevant to hydrodenitrogenation.
AB  - The reactions of Mo(PMe3)6 towards a variety of five- and six-membered
      heterocyclic nitrogen compounds (namely, pyrrole, indole, carbazole, pyridine,
      quinoline, and acridine) have been studied to provide structural models for the
      coordination of these heterocycles to the molybdenum centers of
      hydrodenitrogenation catalysts. Pyrrole reacts with Mo(PMe3)6 to yield the eta5
      pyrrolyl derivative (eta5-pyr)Mo(PMe3)3H, while indole gives sequentially (eta1
      indolyl)Mo(PMe3)4H, (eta5-indolyl)Mo(PMe3)3H, and (eta6-indolyl)Mo(PMe3)3H, with
      the latter representing the first example of a structurally characterized complex
      with an eta6-indolyl ligand. Likewise, carbazole reacts with Mo(PMe3)6 to give
      (eta6-carbazolyl)Mo(PMe3)3H with an eta6-carbazolyl ligand. The reactions of
      Mo(PMe3)6 with six-membered heterocyclic nitrogen compounds display interesting
      differences in the nature of the products. Thus, Mo(PMe3)6 reacts with pyridine
      to give an eta2-pyridyl derivative [eta2-(C5H4N)]Mo(PMe3)4H as a result of alpha
      C-H bond cleavage, whereas quinoline and acridine give products of the type (eta6
      ArH)Mo(PMe3)3 in which both ligands coordinate in an eta6-manner. For the
      reaction with quinoline, products with both carbocyclic and heterocyclic
      coordination modes are observed, namely [eta6-(C6)-quinoline]Mo(PMe3)3 and [eta6
      (C5N)-quinoline]Mo(PMe3)3, whereas only carbocyclic coordination is observed for
      acridine.

PMID- 12431080
TI  - Au nanowire fabrication from sequenced histidine-rich peptide.
AB  - A new biological approach to fabricate Au nanowires was examined by using
      sequenced histidine-rich peptide nanowires as templates. The sequenced histidine
      rich peptide molecules were assembled as nanowires, and the biological
      recognition of the sequenced peptide toward Au lead to efficient Au coating on
      the nanowires. Monodisperse Au nanocrystals were uniformly coated on the
      histidine peptide nanowires with the high-density coverage, and the crystalline
      phases of the Au nanocrystals were observed as (111) and (220). The uniformity of
      the Au coating on the nanowires without contamination of precipitated Au
      aggregates is advantageous for the fabrication of electronics and sensor devices
      when the nanowires are used as the building blocks. We believe this simple metal
      nanowire fabrication method can be applied to various metals and semiconductors
      with peptides whose sequences are known to mineralize specific ions.

PMID- 12431081
TI  - Boronic acids: new coupling partners in room-temperature Suzuki reactions of
      alkyl bromides. Crystallographic characterization of an oxidative-addition adduct
      generated under remarkably mild conditions.
AB  - The Suzuki reaction is an exceptionally useful cross-coupling process that has
      been widely applied in synthetic chemistry, and boronic acids are, by far, the
      most commonly employed coupling partner. To date, however, no versatile method
      has been developed for cross-coupling boronic acids with unactivated alkyl (as
      opposed to aryl or vinyl) electrophiles. This report describes a catalyst system
      that achieves this objective at room temperature. On the mechanistic side, this
      study demonstrates that Pd(P(t-Bu)2Me)2 undergoes oxidative addition under
      surprisingly mild conditions (0 degrees C). The resulting adduct is sufficiently
      stable toward beta-hydride elimination that it can be structurally characterized,
      and it is a chemically competent intermediate in the cross-coupling process.

PMID- 12431082
TI  - Symmetry-enforced conformational control of photochemical reactivity in 2-vinyl
      1,3-terphenyl.
AB  - The photocyclization of o-vinylbiphenyl to 9,10-dihydrophenanthrene occurs with
      very low quantum yield because of the low ground-state population of the reactive
      syn rotamer. 2-Vinyl-1,3-terphenyl exists as a single rotamer which undergoes
      highly efficient photocyclization. Irradiation at 77 K in a rigid glass permits
      observation of the 8a,9-dihydrophenanthrene which rearranges to the 9,10
      dihydrophenanthrene upon warming of the glass. The barriers for photocyclization
      and the thermal sigmatropic hydrogen shift are both remarkably small.

PMID- 12431083
TI  - Tailored synthesis of structurally defined polymers by organotellurium-mediated
      living radical polymerization (TERP): synthesis of poly(meth)acrylate derivatives
      and their di- and triblock copolymers.
AB  - The organotellurium-mediated living radical polymerization (TERP) method allows
      the synthesis of various polyacrylate and polymethacrylate derivatives with
      precise control of molecular weight and with defined end groups. The method can
      be applied to the synthesis of AB-diblock and ABA- and ABC-triblock copolymers
      composed of different families of monomers.

PMID- 12431084
TI  - First homoleptic complexes of isocyanoferrocene.
AB  - Interaction of aminoferrocene with a 65/35 mol % mixture of phenyl formate/phenol
      followed by subsequent dehydration of the resulting ferrocenylformamide with
      POCl3 produced a high yield of air- and thermally stable, peach-colored
      isocyanoferrocene (CNFc). Combining 6 equiv of CNFc with
      bis(naphthalene)chromium(0) afforded orange-red Cr(CNFc)6, the first homoleptic
      complex of CNFc. Successive one-electron oxidations of the latter with Ag+
      quantitatively produced saddle-brown [Cr(CNFc)6]+ and forest-green [Cr(CNFc)6]2+.
      The compounds [Cr(CNFc)6]0,1+,2+ are air-, light-, and thermally robust and are
      remarkable due to the incorporation of seven potentially electroactive transition
      metal ions within a relatively compact ML6 motif. Their properties demonstrate
      that the pi-accepting potential of the ferrocenyl substituent, customarily
      compared to an alkyl group, may have been underestimated. Indeed, the
      donor/acceptor ratio of the CNFc ligand appears to be similar to those of aryl
      isocyanides but quite different from those of alkyl isocyanides. Spectroscopic
      (including multinuclear paramagnetic NMR), magnetic, structural, and
      electrochemical characteristics of the above substances are discussed. In
      addition, a DFT analysis of the Frontier molecular orbitals of CNFc is presented.

PMID- 12431085
TI  - Synthesis of leucascandrolide A via a spontaneous macrolactolization.
AB  - We have developed a concise, convergent, and stereocontrolled synthesis of (+/-)
      leucascandrolide A (18 steps from commercially available precursors), featuring a
      complete relay of the initial stereochemical information via a series of
      diastereoselective transformations. Spontaneous macrolactolization discovered
      during this synthetic exercise has provided unprecedented access to this
      macrolide and demonstrated the possibility of accessing even large-ring systems
      in a highly controlled and efficient manner.

PMID- 12431086
TI  - A unique and highly efficient method for catalytic olefin aziridination.
AB  - A facile, high yielding, and stereospecific method for olefin aziridination is
      described. This process capitalizes on the unique reactivity of sulfamate esters
      in combination with 1-2 mol % Rh2(tfacam)4 and PhI(OAc)2 as the terminal oxidant
      to promote N-atom transfer reactions. A range of structurally and electronically
      disparate alkenes are found to react under conditions that employ substrate as
      the limiting reagent and only a slight excess of H2NSO3CH2CCl3 as the nitrogen
      source. The product alkoxysulfonyl aziridines are useful intermediates that react
      smoothly with nucleophiles to generate 1,2-amine derivatives. Following aziridine
      ring-opening, the N-trichloroethoxysulfonyl group can be removed under mild
      reductive conditions (Zn(Cu)/AcOH-MeOH) to give the corresponding 1 degrees
      amine. The efficient and convenient performance of this chemistry should
      establish it as a useful tool for synthesis.

PMID- 12431087
TI  - Nonequilibrium capillary electrophoresis of equilibrium mixtures--a single
      experiment reveals equilibrium and kinetic parameters of protein-DNA
      interactions.
AB  - We introduce a novel electrophoretic method, nonequilibrium capillary
      electrophoresis of equilibrium mixtures (NECEEM), and demonstrate its use for
      studying protein-DNA interactions. The equilibrium mixture of protein and DNA
      contains three components: free protein, free DNA, and the protein-DNA complex. A
      short plug of such a mixture is injected into the capillary, and the three
      components are separated under nonequilibrium conditions. The resulting
      electropherograms are composed of characteristic peaks and exponential curves. An
      easy nonnumerical analysis of a single electropherogram reveals two parameters:
      the equilibrium binding constant and the monomolecular rate constant of complex
      decay. The bimolecular rate constant of complex formation can then be calculated
      as the product of the two experimentally determined constants. NECEEM was applied
      to study the interaction between single-stranded DNA binding protein and a
      fluorescently labeled 15-mer oligonucleotide. It allowed us to measure for the
      first time the rate constant of complex decay for this important protein-DNA
      pair, k-1 = 0.03 s-1. The value of the equilibrium binding constant, Kb = 3.6 x
      10-6 M-1, was in good agreement with those measured by other methods. As low as
      10-18 mol of the protein was sufficient for the measurements. Thus, the new
      method is simple, informative, and highly sensitive. Moreover, it can be equally
      applied to other noncovalent protein-ligand complexes. These features of NECEEM
      make this method an indispensable tool in studies of macromolecular interactions.
      They also emphasize the potential role of NECEEM in the development of extremely
      sensitive protein assays using nucleotide aptamers.

PMID- 12431088
TI  - Direct determination of absolute configuration of monoalcohols by bis(magnesium
      porphyrin).
AB  - Ethane bridged bis(Mg porphyrin) has been found to be an effective sensor for the
      direct determination of the absolute configuration of a variety of monoalcohols
      at millimolar concentrations and room temperature based on the CD exciton
      chirality method. Examination of a variety of synthetic and natural monoalcohols,
      including alpha-substituted aliphatic and aromatic alkanols with one chiral
      center, as well as alicyclic alcohols with 2-5 chiral centers, gave consistent
      results. In the case of alcohols with multiple chiral centers, the absolute
      configuration of the carbon alpha to OH is always read out.

PMID- 12431089
TI  - Asymmetric intramolecular [3 + 2] cycloaddition reactions of
      acylhydrazones/olefins using a chiral zirconium catalyst.
AB  - Catalytic asymmetric intramolecular [3 + 2] cycloaddition of hydrazone/olefins
      has been attained. In the presence of a chiral zirconium catalyst prepared from
      zirconium alkoxide and a BINOL derivative, the desired pyrazolidine derivatives
      were obtained in high yields with high selectivities. The products were easily
      converted to 1,3-diamine or beta-aminonitrile derivatives by N-N bond cleavage.

PMID- 12431091
TI  - LNAzymes: incorporation of LNA-type monomers into DNAzymes markedly increases RNA
      cleavage.
AB  - Incorporation of two alpha-L-LNA/LNA nucleotides into each of the two binding
      arms of a "10-23" DNAzyme has been accomplished and the RNA cleavage with these
      novel LNAzymes studied. In comparison with the unmodified DNAzyme, the LNAzymes
      show significantly improved cleavage of the phosphodiester backbone at the target
      nucleotide in a small RNA substrate (58n RNA) under single-turnover conditions.
      The LNAzymes show efficient multiple turnover. With the LNAzymes, efficient
      cleavage was accomplished also of a naturally occurring ribosomal RNA at a target
      site within a highly structured region. The reference DNAzyme was ineffective at
      cleaving the ribosomal RNA target.

PMID- 12431090
TI  - Strong binding in the DNA minor groove by an aromatic diamidine with a shape that
      does not match the curvature of the groove.
AB  - A combination of biophysical techniques has been used to characterize the
      interaction of an antitrypanosomal agent, CGP 40215A, with DNA. The results from
      a broad array of methods (DNase I footprinting, surface plasmon resonance, X-ray
      crystallography, and molecular dynamics) indicate that this compound binds to the
      minor groove of AT DNA sequences. Despite its unusual linear shape that is not
      complementary to that of the DNA groove, a high binding affinity was observed in
      comparison with other similar but more curved diamidine compounds. The amidine
      groups at both ends of the ligand and the -NH groups on the linker are involved
      in extensive and dynamic H-bonds to the DNA bases. Complementary and consistent
      results were obtained from both the X-ray and molecular dynamics studies; both of
      these methods reveal direct and water-mediated H-bonds between the ligand and the
      DNA.

PMID- 12431092
TI  - A novel silver(i)-mediated DNA base pair.
AB  - We have generated a novel silver(I)-mediated unnatural DNA base pair consisting
      of two 2,6-bis(ethylthiomethyl)pyridine nucleobases SPy. This metallo-base pair
      has a remarkably high pairing stability and selectivity which rivals that of the
      natural base pairs dA:dT and dC:dG. UV-melting experiments revealed that the
      dSPy:dSPy self-pair can replace natural base pairs at multiple sites and still
      form stable DNA duplexes.

PMID- 12431093
TI  - The bicyclic n,n'-diacylaminal: a new motif for molecular self-assembly.
AB  - A cage-shaped N,N'-diacylaminal crystallizes from some aromatic solvents as
      "supramolecular chair cyclohexanes", squat cylindrical hexamers with approximate
      D3d symmetry containing two arene molecules, and from other aromatic and
      nonaromatic solvents as infinite tapes. A homologous diacylaminal crystallizes
      only as an infinite tape. The hexamers represent the first examples of cyclic
      hexamers held together by
      %@mt;sys@%%@bold@%R%@rsf@%%@sx@%2%@be@%2%@sxx@%%@fn;(;vis;full;auto@%8%@fnx;);vis
      full@%-type%@mx@% hydrogen bonds in which the hydrogen-bonded atoms are not
      coplanar. The diacylaminal represents a new supramolecular synthon, one perhaps
      more suited to the design of three-dimensional architectures.

PMID- 12431094
TI  - Synthesis of nearly uniform single-walled carbon nanotubes using identical metal
      containing molecular nanoclusters as catalysts.
AB  - Uniform and small-diameter single-walled carbon nanotubes (SWNTs) have been
      produced using identical molecular nanoclusters containing Fe and Mo atoms with a
      defined molecular formula and a specific structure as catalysts in a chemical
      vapor deposition method. The average diameter of the SWNTs produced in these
      experiments is 1.0 nm with a standard deviation for the diameter distribution of
      17%. The diameters of SWNTs were obtained by atomic force microscopy and Raman
      spectroscopy.

PMID- 12431095
TI  - Direct conversion of carbonyl compounds into organic halides: indium(III)
      hydroxide-catalyzed deoxygenative halogenation using chlorodimethylsilane.
AB  - The reaction of carbonyls and chlorodimethylsilane was effectively catalyzed by
      indium(III) hydroxide and afforded the corresponding deoxygenative chlorination
      products, in which the carbonyl carbon accepted two nucleophiles (H and Cl) with
      releasing oxygen. Only In(OH)3 catalyzed the reaction, and typical Lewis acids
      such as TiCl4, AlCl3, and BF3.OEt2 showed no catalytic activity. The reaction
      mechanism of this deoxygenative chlorination includes initial hydrosilylation
      followed by chlorination. Other nucleophiles such as allyl or iodine were
      available for this methodology. The moderate Lewis acidity of indium catalyst
      enabled chemoselective reaction, and therefore ester, nitro, cyano, or halogen
      groups were not affected during the reaction course.

PMID- 12431096
TI  - Enantioselective hydrogenation of 3-alkylidenelactams: high-throughput screening
      provides a surprising solution.
AB  - High-throughput screening of 256 potential catalysts (8 metal precursors x 32
      phosphine ligands) has identified [(BDPP)Ir(COD)]BF4 as a catalyst for the
      enantioselective hydrogenation of 3-alkylidenelactams. This result is surprising
      given the highly flexible backbone of the BDPP ligand and the ineffectiveness of
      this catalyst in other applications. The asymmetric hydrogenation appears fairly
      general for five- and six-membered lactams and in one case has been scaled up to
      a 20 kg level.

PMID- 12431097
TI  - Interconnecting carbon nanotubes with an inorganic metal complex.
AB  - Intermolecular carbon nanotube junctions were formed through amide linkage of
      amino functionalized multiwall carbon nanotubes and [Ru (dcbpy)(bpy)2](PF6)2, an
      inorganic metal complex. Nanotube interconnects were visualized using atomic
      force microscopy. Absorption and emission spectroscopy showed significant changes
      between starting products and the resulting ruthenium nanotube complex,
      indicative of successful chemical modification.

PMID- 12431098
TI  - NO-induced activation mechanism of the heme-regulated eIF2alpha kinase.
AB  - The heme-regulated eukaryotic initiation factor 2alpha (eIF2alpha) kinase (HRI),
      which is found primarily in reticulocytes, contains an N-terminal heme-binding
      domain (NT-HBD). Binding of NO to the heme iron of the NT-HBD of HRI activates
      its eIF2alpha kinase activity, thus inhibiting the initiation of translation in
      reticulocyte lysate. The EPR spectrum of the NO-bound NT-HBD showed several
      derivative-shaped lines around g = 2.00, which is one of the well-documented
      signature patterns of a six-coordinate NO complex with histidine as the axial
      ligand. This is in sharp contrast to that of another prototypical NO-sensor
      protein, soluble guanylate cyclase (sGC), in which the NO binding to the heme
      iron disrupts the iron-histidyl bond forming a five-coordinate NO. The NO
      mediated activation of HRI is, therefore, not triggered by the cleavage of the
      iron-histidyl bond. As evidenced by the resonance Raman spectra, two inactive
      forms of HRI, the ferrous ligand-unbound and the CO-bound states of the NT-HBD,
      contain a six-coordinate complex as found for the NO complex, indicating that the
      replacement of the sixth ligand of the heme iron is not sufficient to trigger the
      activation of HRI. Because the configuration of liganded NO is different from
      that of liganded CO, we propose that specific interactions between liganded NO
      and surrounding amino acid residues, which would not be formed in the CO complex,
      are responsible for the NO-induced activation of HRI.

PMID- 12431099
TI  - Metal-ligand interplay in blue copper proteins studied by 1H NMR spectroscopy:
      Cu(II)-pseudoazurin and Cu(II)-rusticyanin.
AB  - The blue copper proteins (BCPs), pseudoazurin from Achromobacter cycloclastes and
      rusticyanin from Thiobacillus ferrooxidans, have been investigated by (1)H NMR at
      a magnetic field of 18.8 T. Hyperfine shifts of the protons belonging to the
      coordinated ligands have been identified by exchange spectroscopy, including the
      indirect detection for those resonances that cannot be directly observed (the
      beta-CH(2) of the Cys ligand, and the NH amide hydrogen bonded to the
      S(gamma)(Cys) atom). These data reveal that the Cu(II)-Cys interaction in
      pseudoazurin and rusticyanin is weakened compared to that in classic blue sites
      (plastocyanin and azurin). This weakening is not induced by a stronger
      interaction with the axial ligand, as found in stellacyanin, but might be
      determined by the protein folding around the metal site. The average chemical
      shift of the beta-CH(2) Cys ligand in all BCPs can be correlated to geometric
      factors of the metal site (the Cu-S(gamma)(Cys) distance and the angle between
      the CuN(His)N(His) plane and the Cu-S(gamma)(Cys) vector). It is concluded that
      the degree of tetragonal distortion is not necessarily related to the strength of
      the Cu(II)-S(gamma)(Cys) bond. The copper-His interaction is similar in all BCPs,
      even for the solvent-exposed His ligand. It is proposed that the copper xy
      magnetic axes in blue sites are determined by subtle geometrical differences,
      particularly the orientation of the His ligands. Finally, the observed chemical
      shifts for beta-CH(2) Cys and Ser NH protons in rusticyanin suggest that a less
      negative charge at the sulfur atom could contribute to the high redox potential
      (680 mV) of this protein.

PMID- 12431100
TI  - Direct structure determination using residual dipolar couplings: reaction-site
      conformation of methionine sulfoxide reductase in solution.
AB  - Residual dipolar couplings (RDC) from partially aligned molecules provide long
      range structural data and are thus particularly well adapted to rapid structure
      validation or protein fold recognition. Extensive measurements in two alignment
      media can also provide precise de novo structure from RDC alone. We have applied
      a novel combination of these approaches to the study of methionine sulfoxide
      reductase (MsrA) from Erwinia chrysanthemi, a 27 kDa enzyme essential for
      repairing oxidative stress damage. The tertiary fold was initially validated by
      comparing backbone RDC to expected values from the crystal structure of the
      homologous MsrA from Escherichia coli. Good agreement was found throughout the
      chain, verifying the overall topology of the molecule, with the exception of the
      catalytically important peptide P196-L202, where strong and systematic RDC
      violation was observed. No evidence for local differential mobility in this
      region was detected, implying that the structure of the strand differs in the two
      molecules. We have therefore applied the de novo approach meccano to determine
      the conformation of this peptide using only RDC. A single conformation is found
      that is in agreement with all measured data. The aligned peptide can be docked
      onto the expected covalence of the rest of the template molecule while respecting
      its strictly defined relative orientation. In contrast to the structure of MsrA
      from E. coli, the reactive side chain of Cys200 is oriented toward the interior
      of the molecule and therefore closer to the catalytic Cys53, obviating the need
      for previously proposed conformational reorganization prior to formation of this
      disulfide intermediate. This analysis requires only backbone assignment and uses
      unambiguously assigned and readily measurable structural data, thereby greatly
      economizing investigation time compared to established nuclear Overhauser effect-
      (nOe-) based structure calculation methods.

PMID- 12431101
TI  - Crystal structure of a B-form DNA duplex containing (L)-alpha-threofuranosyl (3'-
      >2') nucleosides: a four-carbon sugar is easily accommodated into the backbone of
      DNA.
AB  - (L)-alpha-Threofuranosyl-(3'-->2')-oligonucleotides (TNA) containing vicinally
      connected phosphodiester linkages undergo informational base pairing in an
      antiparallel strand orientation and are capable of cross-pairing with RNA and
      DNA. TNA is derived from a sugar containing only four carbon atoms and is one of
      the simplest potentially natural nucleic acid alternatives investigated thus far
      in the context of a chemical etiology of nucleic acid structure. Compared to DNA
      and RNA that contain six covalent bonds per repeating nucleotide unit, TNA
      contains only five. We have determined the atomic-resolution crystal structure of
      the B-form DNA duplex [d(CGCGAA)Td(TCGCG)](2) containing a single (L)-alpha
      threofuranosyl thymine (T) per strand. In the modified duplex base stacking
      interactions are practically unchanged relative to the reference DNA structure.
      The orientations of the backbone at the TNA incorporation sites are slightly
      altered in order to accommodate fewer atoms and covalent bonds. The conformation
      of the threose is C4'-exo with the 2'- and 3'-substituents assuming quasi-diaxial
      orientation.

PMID- 12431102
TI  - Cross-modulation of physicochemical character of aglycones in dinucleoside (3'-
      >5') monophosphates by the nearest neighbor interaction in the stacked state.
AB  - Each nucleobase in a series of stacked dinucleoside (3'-->5') monophosphates, in
      both acidic and alkaline pH, shows ((1)H NMR) not only its own pK(a) but also the
      pK(a) of the neighboring nucleobase as a result of cross-modulation of two
      coupled pi systems of neighboring aglycones. This means that the electronic
      character of two nearest neighbors are not like the monomeric counterparts
      anymore; they have simultaneously changed, almost quantitatively, to something
      that is a hybrid of the two due to two-way transmission of charge (i.e. 3'-->5'
      as well as 5'-->3'). This change is permanent due to total modulation of each
      others pseudoaromatic character by intramolecular stacking, which can be tuned by
      the nature of the medium across the whole pH range. The small difference observed
      in the pK(a) of the dimer compared to the monomer is a result of the change in
      microenvironment in the former. The charge transfer takes place between two
      stacked nucleobases from the negatively charged end because of the attempt to
      minimize the charge difference between the two neighboring pseudoaromatic
      aglycones. Experimental evidence points that the charge transmission in the
      stacked state takes place by atom-pisigma interaction between nearest neighbor
      nucleobases in 1-6. The net result of this cross-talk between two neighboring
      aglycones is a unique set of aglycones in an oligo- or polynucleotide, whose
      physicochemical property and the pseudoaromatic character are completely
      dependent both upon the sequence makeup, and whether they are stacked or
      unstacked. Thus, the physicochemical property of individual nucleobases in an
      oligonucleotide is determined in a tunable manner, depending upon who the nearest
      neighbors are, which may have considerable implication in the specific ligand
      binding ability of an aptamer, the pK(a) and the hydrogen bonding ability in a
      microenvironment, in the use of codon triplets in the protein biosynthesis or in
      the triplet usage by the anticodon-codon interaction.

PMID- 12431103
TI  - Trinuclear copper(II) complex showing high selectivity for the hydrolysis of 2'
      5' over 3'-5' for UpU and 3'-5' over 2'-5' for ApA ribonucleotides.
AB  - The cooperative action of multiple Cu(II) nuclear centers is shown to be
      effective and selective in the hydrolysis of 2'-5' and 3'-5' ribonucleotides.
      Reported herein is the specific catalysis by two trinuclear Cu(II) complexes of
      L3A and L3B. Pseudo first-order kinetic studies reveal that the L3A trinuclear
      Cu(II) complex effects hydrolysis of Up(2'-5')U with a rate constant of 28 x 10(
      )(4) min(-)(1) and Up(3'-5')U with a rate constant of 0.5 x 10(-)(4) min(-)(1).
      The hydrolyses of Ap(3'-5')A and Ap(2'-5')A proceed with rate constants of 24 x
      10(-)(4) min(-)(1) and 0.5 x 10(-)(4) min(-)(1) respectively. The L3A trinuclear
      Cu(II) complex demonstrates high specificity for Up(2'-5')U and Ap(3'-5')A.
      Similar studies with the more rigid L3B trinuclear Cu(II) complex shows no
      selectivity and yields lower rate constants for hydrolysis. The selectivity
      observed with the L3A ligand is attributed to the geometry of the ligand-bound
      diribonucleotide which ultimately dictates the proximity of the attacking
      hydroxyl and the phosphoester to a Cu(II) center for activation and subsequent
      hydrolysis.

PMID- 12431105
TI  - A novel organic intercalation system with layered polymer crystals as the host
      compounds derived from 1,3-diene carboxylic acids.
AB  - A new type of organic intercalation system using poly(muconic acid) and
      poly(sorbic acid) crystals as the host compounds is described. The layered
      polymer crystals as the host are derived from benzyl-, dodecyl-, or
      naphthylmethylammonium salts of (Z,Z)-muconic or (E,E)-sorbic acids by
      topochemical polymerization. The subsequent solid-state hydrolysis of the
      resulting ammonium polymer crystals provides the corresponding carboxylic acid
      polymer crystals. When alkylamines are reacted with poly(muconic acid) or
      poly(sorbic acid) crystals dispersed in methanol at room temperature for a few
      hours, the intercalation proceeds to give layered ammonium polymer crystals via
      solid-state reactions, in which the polymers maintain a layered structure
      throughout. The interplanar spacing value of the polymer crystals changes
      according to the size of the guest molecules; that is, it exactly depends on the
      carbon number of the alkylamines used for each reaction of poly(muconic acid) or
      poly(sorbic acid) crystals. The stacking structure of alkyl chains with a tilt in
      the intercalated alkylammonium layers exists irrespective of the chemical and
      crystal structures of the host polymers. The intercalation of higher alkylamines
      into poly(muconic acid) crystals proceeds fast and quantitatively, while the
      conversion is dependent on the reaction conditions such as the structure and
      amount of the amine and the reaction time during the intercalation with
      poly(sorbic acid) crystals, due to the difference in the repeating layered
      structures of these polymer crystals. Some functional amines are also used as the
      guest molecules for this organic intercalation system.

PMID- 12431104
TI  - Self-organizing properties of natural and related synthetic glycolipids.
AB  - In this article we report on the syntheses, self-organizing properties, and
      structures of a variety of cerebrosides and related synthetic glycolipids. The
      thermotropic and lyotropic liquid crystalline properties of the materials were
      evaluated in detail. All of the families of materials studied exhibited columnar
      mesophases. In the dry state the aliphatic chains were found to be located on the
      exterior of the columns, whereas in the wet state the reverse was the case with
      the polar headgroups on the exterior. Thus, the aliphatic chains act almost like
      hydrocarbon solvents in the dry state.

PMID- 12431106
TI  - Supramolecular polymer chemistry: self-assembling dendrimers using the DDA.AAD
      (GC-like) hydrogen bonding motif.
AB  - Heterocyclic unit 2 containing complementary donor-donor-acceptor (DDA) and
      acceptor-acceptor-donor (AAD) hydrogen bonding arrays at an angle of about 60
      degrees was designed to self-assemble into a hexamer. To investigate whether this
      unit could self-assemble dendrimers, the 2,8-diamino-2-N-ethylpyrimido-(4,5
      b)(1,8)naphthyridine-3H-4-one subunit was synthesized with a first (2a), second
      (2b), and third generation (2c) Frechet-type dendron attached to the 8-amino
      group. The synthesis of 2a-c was accomplished in 11 steps beginning with 2,6
      diaminopyridine and the corresponding dendron bromide. Studies using (1)H NMR,
      size exclusion chromatography (SEC), and dynamic light scattering (DLS) support
      the cooperative formation of cyclic hexamers in apolar solvents. The stability of
      the self-assembled dendrimers is dependent on the size of the attached dendron,
      and mixing studies with 2a-c indicate their usefulness in constructing dynamic
      combinatorial libraries.

PMID- 12431107
TI  - Cyclooctatetraene computational photo- and thermal chemistry: a reactivity model
      for conjugated hydrocarbons.
AB  - We use ab initio CASSCF and CASPT2 computations to construct the composite
      multistate relaxation path relevant to cycloocta-1,3,5,7-tetraene singlet
      photochemistry. The results show that an efficient population of the dark excited
      state (S(1)) takes place after ultrafast decay from the spectroscopic excited
      state (S(2)). A planar D(8)(h)-symmetric minimum represents the collecting point
      on S(1). Nonadiabatic transitions to S(0) appear to be controlled by two
      different tetraradical-type conical intersections, which are directly accessible
      from the S(1) minimum following specific excited-state reaction paths. The higher
      energy conical intersection belongs to the same type of intersections previously
      documented in linear and cyclic conjugated hydrocarbons and features a triangular
      -(CH)(3)- kink. This point mediates both cis --> trans photoisomerization and
      cyclopropanation reactions. The lowest energy conical intersection has a boat
      shaped structure. This intersection accounts for production of semibullvalene or
      for double-bond shifting. The mapping of both photochemical and thermal reaction
      paths (including also Cope rearrangements, valence isomerizations, ring
      inversions, and double-bond shifting) has allowed us to draw a comprehensive
      reactivity scheme for cyclooctatetraene, which rationalizes the experimental
      observations and documents the complex network of photochemical and thermal
      reaction path interconnections. The factors controlling the selection and
      accessibility of a number of conjugated hydrocarbon prototype conical
      intersections and ground-state relaxation channels are discussed.

PMID- 12431108
TI  - Amination of pyridylketenes: experimental and computational studies of strong
      amide enol stabilization by the 2-pyridyl group.
AB  - Laser flash photolyses of 2-, 3-, and 4-diazoacetylpyridines 8 give the
      corresponding pyridylketenes 7 formed by Wolff rearrangements, as observed by
      time-resolved infrared spectroscopy, with ketenyl absorptions at 2127, 2125, and
      2128 cm(-1), respectively. Photolysis of 2-, 3-, and 4-8 in CH(3)CN containing n
      BuNH(2) results in the formation of two transients in each case, as observed by
      time-resolved IR and UV spectroscopy. The initial transients are assigned as the
      ketenes 7, and this is confirmed by IR measurements of the decay of the ketenyl
      absorbance. The ketenes then form the amide enols 12, whose growth and decay are
      monitored by UV. Similar photolysis of diazoacetophenone leads to phenylketene
      (5), which forms the amide enol 17. For 3- and 4-pyridylketenes and for
      phenylketene, the ratios of rate constants for amination of the ketene and for
      conversion of the amide enol to the amide are 3.1, 7.7, and 22, respectively,
      while for the 2-isomer the same ratio is 1.8 x 10(7). The stability of the amide
      enol from 2-7 is attributed to a strong intramolecular hydrogen bond to the
      pyridyl nitrogen, and this is supported by the DFT calculated structures of the
      intermediates, which indicate this enol amide is stabilized by 12.8 kcal/mol
      relative to the corresponding amide enol from phenylketene. Calculations of the
      transition states indicate a 10.9 kcal/mol higher barrier for conversion of the 2
      pyridyl amide enol to the amide as compared to that from phenylketene.

PMID- 12431109
TI  - Structure-based design of selective agonists for a rickets-associated mutant of
      the vitamin d receptor.
AB  - The nuclear and steroid hormone receptors function as ligand-dependent
      transcriptional regulators of diverse sets of genes associated with development
      and homeostasis. Mutations to the vitamin D receptor (VDR), a member of the
      nuclear and steroid hormone receptor family, have been linked to human vitamin D
      resistant rickets (hVDRR) and result in high serum 1,25(OH)(2)D(3) concentrations
      and severe bone underdevelopment. Several hVDRR-associated mutants have been
      localized to the ligand binding domain of VDR and cause a reduction in or loss of
      ligand binding and ligand-dependent transactivation function. The missense
      mutation Arg274 --> Leu causes a >1000-fold reduction in 1,25(OH)(2)D(3)
      responsiveness and is, therefore, no longer regulated by physiological
      concentrations of the hormone. In this study, computer-aided molecular design was
      used to generate a focused library of nonsteroidal analogues of the VDR agonist
      LG190155 that were uniquely designed to complement the Arg274 --> Leu associated
      with hVDRR. Half of the designed analogues exhibit substantial activity in the
      hVDRR-associated mutant, whereas none of the structurally similar control
      compounds exhibited significant activity. The seven most active designed
      analogues were more than 16 to 526 times more potent than 1,25(OH)(2)D(3) in the
      mutant receptor (EC(50) = 3.3-121 nM). Significantly, the analogues are selective
      for the nuclear VDR and did not stimulate cellular calcium influx, which is
      associated with activation of the membrane-associated vitamin D receptor.

PMID- 12431110
TI  - Unusual frequency dispersion effects of the nonlinear optical response in highly
      conjugated (polypyridyl)metal-(porphinato)zinc(II) chromophores.
AB  - The syntheses and electrooptic properties of a new family of nonlinear optical
      chromophores are reported. These species feature an ethyne-elaborated, highly
      polarizable porphyrinic component and metal polypyridyl complexes that serve as
      integral donor and acceptor elements. Examples of this structural motif include
      ruthenium(II) [5-(4'-ethynyl-(2,2';6',2' '-terpyridinyl))-10,20-bis(2',6'-bis(3,3
      dimethyl-1-butyloxy)phenyl)porphinato]zinc(II)-(2,2';6',2' '-terpyridine)(2+) bis
      hexafluorophosphate (Ru-PZn); osmium(II) [5-(4'-ethynyl-(2,2';6',2''
      terpyridinyl))-10,20-bis(2',6'-bis(3,3-dimethyl-1
      butyloxy)phenyl)porphinato]zinc(II)-(2,2';6',2''-terpyridine)(2+) bis
      hexafluorophosphate (Os-PZn); ruthenium(II) [5-(4'-ethynyl-(2,2';6',2''
      terpyridinyl))-15-(4'-nitrophenyl)ethynyl-10,20-bis(2',6'-bis(3,3-dimethyl-1
      butyloxy)phen-yl)porphinato]zinc(II)-(2,2';6',2' '-terpyridine)(2+) bis
      hexafluorophosphate (Ru-PZn-A); osmium(II) [5-(4'-ethynyl-(2,2';6',2' '
      terpyridinyl))-15-(4'-nitrophenyl)ethynyl-10,20-bis(2',6'-bis(3,3-dimethyl-1
      butyloxy)phenyl)porphinato]zinc(II)-(2,2';6',2' '-terpyridine)(2+) bis
      hexafluorophosphate (Os-PZn-A); and ruthenium(II) [5-(4'-ethynyl-(2,2';6',2' '
      terpyridinyl))osmium(II)-15-(4'-ethynyl-(2,2';6',2''-terpyridinyl))-10,20-bis
      (2',6'-bis(3,3-dimethyl-1-butyloxy)phenyl)porphinato]zinc(II)-bis(2,2';6',2''
      terpyridine)(4+) tetrakis-hexafluorophosphate (Ru-PZn-Os). The frequency
      dependence of the dynamic hyperpolarizability of these compounds was determined
      from hyperRayleigh light scattering (HRS) measurements carried out at fundamental
      incident irradiation wavelengths (lambda(inc)) of 800, 1064, and 1300 nm. These
      data show that (i) coupled oscillator photophysics and metal-mediated cross
      coupling can be exploited to elaborate high beta(0) supermolecules that exhibit
      significant excited-state electronic communication between their respective
      pigment building blocks; (ii) high-stability metal polypyridyl compounds
      constitute an attractive alternative to electron releasing dialkyl- and
      diarylamino groups, the most commonly used donor moieties in a wide range of
      established nonlinear optical dyes; (iii) this design strategy enables ready
      elaboration of chromophores having extraordinarily large dynamic
      hyperpolarizabilities (beta(lambda) values) at telecommunication relevant
      wavelengths; and (iv) porphyrin B- and Q-state-derived static
      hyperpolarizabilities (beta(0) values) can be designed to have the same or
      opposite sign in these species, thus providing a new means to regulate the
      magnitude of lambda(inc)-specific dynamic hyperpolarizabilities.

PMID- 12431111
TI  - Synthesis and explosive decomposition of organometallic dehydro[18]annulenes: an
      access to carbon nanostructures.
AB  - The synthesis of eight new cyclobutadiene or ferrocene-fused organometallic
      dehydroannulenes is reported. Cadiot-type coupling of a 1-bromoethynyl-2
      silylethynylbenzene derivative to an organometallic diyne (1,2-diethynyl-3,4
      bis(trimethylsilyl)cyclobutadiene(cyclopentadienyl )cobalt or 1,2
      diethynylferrocene) is followed by deprotection and Cu(OAc)(2)-promoted ring
      closure. Five of the organometallic dehydroannulenes were structurally
      characterized. Three of the novel cycles explode at temperatures from 196 to 293
      degrees C and form insoluble carbon materials. The soot produced from 13a shows a
      high abundance of onion-like carbon nanostructures. The nanostructures were
      characterized by high-resolution transmission electron microscopy.

PMID- 12431112
TI  - Tetrakis(trimethylsilyl)tetrahedrane.
AB  - Tetrakis(trimethylsilyl)tetrahedrane 3 has been synthesized upon irradiation of
      tetrakis(trimethylsilyl)cyclobutadiene 8, which can be prepared either by thermal
      nitrogen elimination from trimethylsilyl[1,2,3-tris(trimethylsilyl)-2-cycloprop-1
      enyl]diazomethane 7 or by mild oxidation of cyclobutadiene dianion 9 with 1,2
      dibromoethane. The structural characterization of tetrahedrane 3 has been
      achieved by X-ray crystallography. The surprising thermal stability of 3 - which
      is stable up to 300 degrees C - is discussed.

PMID- 12431114
TI  - Nitrosyliron(III) porphyrinates: porphyrin core conformation and FeNO geometry.
      Any correlation?
AB  - The synthesis, structural, and spectroscopic characterization of
      (nitrosyl)iron(III) porphyrinate complexes designed to have strongly nonplanar
      porphyrin core conformations is reported. The species have a nitrogen-donor axial
      ligand trans to the nitrosyl ligand and display planar as well as highly
      nonplanar porphyrin core conformations. The systems were designed to test the
      idea, expressly discussed for the heme protein nitrophorin (Roberts, et al.
      Biochemistry 2001, 40, 11327), that porphyrin core distortions could lead to an
      unexpected, bent geometry for the FeNO group. For [Fe(OETPP)(1
      MeIm)(NO)]ClO(4).C(6)H(5)Cl (H(2)OETPP = octaethyltetraphenylporphyrin), the
      porphyrin core is found to be severely saddled. However, this distortion has
      little or no effect on the geometric parameters of the coordination group: Fe
      N(p) = 1.990(9) A, Fe-N(NO) = 1.650(2) A, Fe-N(L) = 1.983(2) A, and Fe-N-O =
      177.0(3) degrees. For the complex [Fe(OEP)(2-MeHIm)(NO)]ClO(4).0.5CH(2)Cl(2)
      (H(2)OEP = octaethylporphyrin), there are two independent molecules in the
      asymmetric unit. The cation denoted [Fe(OEP)(2-MeHIm)(NO)](+)(pla) has a close-to
      planar porphyrin core. For this cation, Fe-N(p) = 2.014(8) A, Fe-N(NO) = 1.649(2)
      A, Fe-N(L) = 2.053(2) A, and Fe-N-O = 175.6(2) degrees. The second cation,
      [Fe(OEP)(2-MeHIm)(NO)](+)(ruf), has a ruffled core: Fe-N(p) = 2.003(7) A, Fe
      N(NO) = 1.648(2) A, Fe-N(L) = 2.032(2) A, and Fe-N-O = 177.4(2) degrees. Thus,
      there is no effect on the coordination group geometry caused by either type of
      nonplanar core deformation; it is unlikely that a protein engendered core
      deformation would cause FeNO bending either. The solid-state nitrosyl stretching
      frequencies of 1917 cm(-)(1) for [Fe(OEP)(2-MeHIm)(NO)]ClO(4) and 1871 cm(-)(1)
      for [Fe(OETPP)(1-MeIm)(NO)]ClO(4) are well within the range seen for linear Fe-N
      O groups. Mossbauer data for [Fe(OEP)(2-MeHIm)(NO)]ClO(4) confirm that the ground
      state is diamagnetic. In addition, the quadrupole splitting value of 1.88 mm/s
      and isomer shift (0.05 mm/s) at 4.2 K are similar to other (nitrosyl)iron(III)
      porphyrin complexes with linear Fe-N-O groups. Crystal data: [Fe(OETPP)(1
      MeIm)(NO)]ClO(4).C(6)H(5)Cl, monoclinic, space group P2(1)/c, Z = 4, with a =
      12.9829(6) A, b = 36.305(2) A, c = 14.0126(6) A, beta = 108.087(1) degrees;
      [Fe(OEP)(2-MeHIm)(NO)]ClO(4).0.5CH(2)Cl(2), triclinic, space group Ponemacr;, Z =
      4, with a = 14.062(2) A, b = 16.175(3) A, c = 19.948(3) A, alpha = 69.427(3)
      degrees, beta = 71.504(3) degrees, gamma = 89.054(3) degrees.

PMID- 12431113
TI  - Mechanistic studies on the addition of dihydrogen to tantalocene complexes.
AB  - The mechanism of dihydrogen addition to Cp(2)Ta(CH(2))(H) was examined using
      parahydrogen-induced polarization (PHIP), (13)C labeling, and comparison to the
      related complex Cp(2)Ta(CH(2))(CH(3)). The reaction of para-enriched hydrogen
      with Cp(2)Ta(CH(2))(H) leads to polarized resonances for both
      Cp(2)Ta(CH(3))(H)(2) and Cp(2)TaH(3), even at the earliest reaction times. Use of
      the labeled compound Cp(2)Ta((13)CH(2))(H) shows that the polarized resonances of
      Cp(2)Ta(CH(3))(H)(2) correspond to the two hydride ligands. The results thus
      support a mechanistic pathway of H(2) addition to an unsaturated Ta(III)
      intermediate, [Cp(2)Ta(CH(3))], rather than addition directly across the Ta=C
      bond. In a same sample comparison, the rates of initial H(2) addition and
      subsequent C-H reductive elimination for both Cp(2)Ta(CH(2))(H) and
      Cp(2)Ta(C(6)H(4))(H) were examined. The methylene complex exhibits greater
      reactivity than the benzyne complex, with the major difference due to the C-H
      coupling step, in which formation of methane is more facile than that of benzene.
      The reactivity of the related ethylene hydride complex, Cp(2)Ta(C(2)H(4))(H),
      with hydrogen was also examined. The PHIP study of this system leads to unusual
      and unexpected polarization, which is found to be due to a minor impurity in the
      sample.

PMID- 12431115
TI  - Spectroscopic and computational studies on [(PhTt(tBu))2Ni2(mu-O)2]: nature of
      the bis-mu-oxo (Ni3+)2 diamond core.
AB  - Spectroscopic and density functional theory (DFT) electronic structure
      computational studies on a binuclear bis-mu-oxo bridged (Ni(3+))(2) complex,
      [(PhTt(t(Bu))(2)Ni(2)(mu-O)(2)] (1), where (PhTt(t(Bu)) represents phenyl
      tris((tert-butylthio)methyl)borate, are presented and discussed. These studies
      afford a detailed description of the Ni(2)O(2) core electronic structure in bis
      mu-oxo (Ni(3+))(2) dimers and provide insight into the possible role of the
      (PhTt(t(Bu)) thioether ligand in the formation of 1 from a Ni(1+) precursor by
      O(2) activation. From a normal coordinate analysis of resonance Raman data, a
      value of k(Ni)(-)(O) = 2.64 mdyn/A is obtained for the Ni-O stretch force
      constant for 1. This value is smaller than k(Cu)(-)(O) = 2.82-2.90 mdyn/A
      obtained for bis-mu-oxo (Cu(3+))(2) dimers possessing nitrogen donor ligands,
      indicating a reduced metal-oxo bond strength in 1. Electronic absorption and
      magnetic circular dichroism spectroscopic techniques permit identification of
      several O-->Ni and S-->Ni charge transfer (CT) transitions that are assigned on
      the basis of DFT calculations. The dominant O-->Ni CT transition of 1 occurs at
      17 700 cm(-)(1), red-shifted by approximately 7000 cm(-)(1) relative to the
      corresponding transition in bis-mu-oxo (Ni(3+))(2) dimers with nitrogen donor
      ligands. This red-shift along with the relatively low value of k(Ni)(-)(O) are
      due primarily to the presence of the thioether ligands in 1 that greatly affect
      the compositions of the Ni(2)O(2) core MOs. This unique property of the thioether
      ligand likely contributes to the reactivity of the Ni center in the precursor
      [(PhTt(t(Bu))Ni(1+)CO] toward O(2). DFT computations reveal that conversion of a
      hypothetical side-on peroxo (Ni(2+))(2) dimer, [(PhTt(t(Bu))(2)Ni(2)(mu
      eta(2):eta(2)-O(2))], to the bis-mu-oxo (Ni(3+))(2) dimer 1 is energetically
      favorable by 32 kcal/mol and occurs without a significant activation energy
      barrier (DeltaH++) = 2 kcal/mol).

PMID- 12431116
TI  - Iron-catalyzed cross-coupling reactions.
AB  - Simple iron salts such as FeCl(n), Fe(acac)(n) (n = 2,3) or the salen complex 4
      turned out to be highly efficient, cheap, toxicologically benign, and
      environmentally friendly precatalysts for a host of cross-coupling reactions of
      alkyl or aryl Grignard reagents, zincates, or organomanganese species with aryl
      and heteroaryl chlorides, triflates, and even tosylates. An "inorganic Grignard
      reagent" of the formal composition [Fe(MgX)(2)] prepared in situ likely
      constitutes the propagating species responsible for the catalytic turnover, which
      occurs in many cases at an unprecedented rate even at or below room temperature.
      Because of the exceptionally mild reaction conditions, a series of functional
      groups such as esters, ethers, nitriles, sulfonates, sulfonamides, thioethers,
      acetals, alkynes, and -CF(3) groups are compatible. The method also allows for
      consecutive cross-coupling processes in one pot, as exemplified by the efficient
      preparation of compound 12, and has been applied to the first synthesis of the
      cytotoxic marine natural product montipyridine 8. In contrast to the clean
      reaction of (hetero)aryl chlorides, the corresponding bromides and iodides are
      prone to a reduction of their C-X bonds in the presence of the iron catalyst.

PMID- 12431117
TI  - Mesoscopic monodisperse ferromagnetic colloids enable magnetically controlled
      photonic crystals.
AB  - We report here the first synthesis of mesoscopic, monodisperse particles which
      contain nanoscopic inclusions of ferromagnetic cobalt ferrites. These
      monodisperse ferromagnetic composite particles readily self-assemble into
      magnetically responsive photonic crystals that efficiently Bragg diffract
      incident light. Magnetic fields can be used to control the photonic crystal
      orientation and, thus, the diffracted wavelength. We demonstrate the use of these
      ferromagnetic particles to fabricate magneto-optical diffracting fluids and
      magnetically switchable diffracting mirrors.

PMID- 12431118
TI  - Molecular structure of the solvated proton in isolated salts. Short, strong, low
      barrier (SSLB) H-bonds.
AB  - Large, inert, weakly basic carborane anions of the icosahedral type
      CHB(11)R(5)X(6)(-) (R = H, Me; X = Cl, Br) allow ready isolation and structural
      characterization of discrete salts of the solvated proton,
      [H(solvent)(x)][CHB(11)R(5)X(6)], (solvent = common O-atom donor). These oxonium
      ion Bronsted acids are convenient reagents for the tuned delivery of protons to
      organic solvents with a specified number of donor solvent molecules and with
      acidities leveled to those of the chosen donor solvent. They have greater thermal
      stability than the popular [H(OEt(2))(2)][BAr(F)] acids based on fluorinated
      tetraphenylborate counterions because carborane anions can sustain much higher
      levels of acidity. When organic O-atom donors such as diethyl ether,
      tetrahydrofuran, benzophenone, and nitrobenzene are involved, the coordination
      number of the proton (x) in [H(solvent)(x)()](+) is two. A mixed species
      involving the [H(H(2)O)(diethyl ether)](+) ion has also been isolated. These
      solid-state structures provide expectations for the predominant molecular
      structures of solvated protons in solution and take into account that water is an
      inevitable impurity in organic solvents. The O.O distances are all short, lying
      within the range from 2.35 to 2.48 A. They are consistent with strong, linear
      O.H.O hydrogen bonding. Density functional theory calculations indicate that all
      H(solvent)(2)(+) cations have low barriers to movement of the proton within an
      interval along the O.H.O trajectory, i.e., they are examples of so-called SSLB H
      bonds (short, strong, low-barrier). Unusually broadened IR bands, diagnostic of
      SSLB H-bonds, are observed in these H(solvent)(2)(+) cations.

PMID- 12431119
TI  - Novel mixed-valent (V/VI) triple perovskite ruthenates: observation of a complex
      low-temperature structural and magnetic transition.
AB  - Two new mixed-valent triple perovskites, Ba(3)MRu(2)O(9) (M = Li, Na), were grown
      from reactive hydroxide fluxes. They crystallize in the hexagonal space group
      P6(3)/mmc, where Ru(V) and Ru(VI) are disordered on only one crystallographic
      site. Upon cooling, single crystals of Ba(3)NaRu(2)O(9) undergo a complex
      symmetry-breaking structural transition at ca. 225 K from room-temperature
      hexagonal symmetry to a low-temperature orthorhombic symmetry, space group Cmcm.
      Accompanying this structural transition is a rather abrupt decrease in the
      magnetic susceptibility at 210 K followed by a steady decrease in the
      susceptibility with decreasing temperature. Interestingly, the lithium analogue
      does not display any structural transition down to 100 K. The structural
      transition in Ba(3)NaRu(2)O(9) generates three crystallographically unique Ru
      sites in the low-temperature structure as compared to only one distinct site in
      the room-temperature structure. On the basis of an analysis of the Ru-Ru
      distances in the face-sharing bi-octahedra, the structural transition also
      appears to involve charge ordering of Ru(V) and Ru(VI), causing all Ru(V) to
      occupy one set of bi-octahedra and all Ru(VI) to occupy another set.

PMID- 12431120
TI  - Synthesis and properties of 1,3,5-benzene periodic mesoporous organosilica (PMO):
      novel aromatic PMO with three point attachments and unique thermal
      transformations.
AB  - A new aromatic periodic mesoporous organosilica material containing benzene
      functional groups that are symmetrically integrated with three silicon atoms in
      an organosilica mesoporous framework is reported. The material has a high surface
      area, well-ordered mesoporous structure and thermally stable framework aromatic
      groups. The functional aromatic moieties were observed to undergo sequential
      thermal transformation from a three to two and then to a one point attachment
      within the framework upon continuous thermolysis under air before eventually
      being converted to periodic mesoporous silica devoid of aromatic groups at high
      temperatures and longer pyrolysis times. The mesoporosity of the material was
      characterized by powder X-ray diffraction (PXRD), transmission electron
      microscopy (TEM), and nitrogen porosimetry, whereas the presence and
      transformation of the aromatic groups in the walls of the materials were
      characterized by solid-state NMR spectroscopy, mass spectrometry, and
      thermogravimetric analysis. The attachment of a benzene ring symmetrically onto
      three siloxanes of the framework was used advantageously as a cross-linker to
      enhance the thermal stability of the organic group. Some of these properties are
      investigated in comparison with other aromatic PMOs that have only two point
      attachments and an amorphous phenylsilica gel that has only one point attachment.
      The successful synthesis of the first aromatic PMO with its organic group
      attached within the framework through more than two points is an important step
      toward the synthesis of PMOs having organic groups with more complex and multiple
      attachments within the framework.

PMID- 12431121
TI  - Evidence for orbital-specific electron transfer to oriented haloform molecules.
AB  - Beams of hyperthermal K atoms cross beams of the oriented haloforms CF(3)H,
      CCl(3)H, and CBr(3)H, and transfer of an electron mainly produces K(+) and the X(
      ) halide ion which are detected in coincidence. As expected, the steric asymmetry
      of CCl(3)H and CBr(3)H is very small and the halogen end is more reactive.
      However, even though there are three potentially reactive centers on each
      molecule, the F(-) ion yield in CF(3)H is strongly dependent on orientation. At
      energies close to the threshold for ion-pair formation ( approximately 5.5 eV), H
      end attack is more reactive to form F(-). As the energy is increased, the more
      productive end switches, and F-end attack dominates the reactivity. In CF(3)H
      near threshold the electron is apparently transferred to the sigma(CH)
      antibonding orbital, and small signals are observed from electrons and CF(3)(-)
      ions, indicating "activation" of this orbital. In CCl(3)H and CBr(3)H the steric
      asymmetry is very small, and signals from free electrons and CX(3)(-) ions are
      barely detectable, indicating that the sigma(CH) antibonding orbital is not
      activated. The electron is apparently transferred to the sigma(CX) orbital which
      is believed to be the LUMO. At very low energies the proximity of the incipient
      ions probably determines whether salt molecules or ions are formed.

PMID- 12431122
TI  - Vinylphosphirane-phospholene rearrangements: pericyclic [1,3]-sigmatropic shifts
      or not?
AB  - The conversion of "free" and Cr(CO)(5)-complexed 2-vinylphosphiranes into 3
      phospholenes via [1,3]-sigmatropic shifts was studied with density functional
      theory and compared with the corresponding hydrocarbon system, that is, the
      vinylcyclopropane-cyclopentene rearrangement. All three systems behave similarly
      with subtle but important differences. No intermediate was found on any of the
      potential energy surfaces. 2-Vinylphosphiranes have smaller rearrangement
      barriers than vinylcyclopropane, and those carrying the Cr(CO)(5) group have
      still smaller ones. The rearrangement of both anti- and syn-2-vinylphosphiranes
      occurs in a concerted pericyclic manner with inversion of configuration at the
      migrating phosphorus, requiring, respectively, 29.3 and 36.7 kcal/mol, much in
      contrast to the 44.6 kcal/mol demanding diradical-like process for the
      hydrocarbon analogue. Epimerization at the phosphorus center (syn right arrow
      over left arrow anti) requires approximately 32.0 kcal/mol and occurs in a single
      step, reflecting a diradical-like ring opening-ring closure process that can
      occur in both a clockwise and counterclockwise fashion. Complexation of the
      phosphorus center by Cr(CO)(5) results in the substantial stabilization of
      reagents and products and further reduces the barriers for rearrangement. The
      anti isomer has the lowest barrier for the [1,3]-shift (DeltaE = 20.5 kcal/mol),
      which is slightly less than that needed for P-epimerization and for conversion of
      the syn isomer, both of which are nonpericyclic processes. When a P-phenyl group
      is introduced, the diradical-like conversion of the syn isomer is favored over
      the anti isomer, in agreement with experimental reports. The influence of
      torquoselectivity is discussed for the rearrangements of these structures with
      their heavy substituents. The origin of the stabilization rendered by the
      Cr(CO)(5) group and its influence on the [1,3]-conversion are also analyzed. The
      DFT activation energies for the diradical-like [1,3]-sigmatropic shifts were
      verified with a multireference method.

PMID- 12431123
TI  - Nuclear magnetic resonance shifts in paramagnetic metalloporphyrins and
      metalloproteins.
AB  - We report the first detailed investigation of the (1)H, (13)C, (15)N, and (19)F
      nuclear magnetic resonance (NMR) spectroscopic shifts in paramagnetic
      metalloprotein and metalloporphyrin systems. The >3500 ppm range in
      experimentally observed hyperfine shifts can be well predicted by using density
      functional theory (DFT) methods. Using spin-unrestricted methods together with
      large, locally dense basis sets, we obtain very good correlations between
      experimental and theoretical results: R(2) = 0.941 (N = 37, p < 0.0001) when
      using the pure BPW91 functional and R(2) = 0.981 (N = 37, p < 0.0001) when using
      the hybrid functional, B3LYP. The correlations are even better for C(alpha) and
      C(beta) shifts alone: C(alpha), R(2) = 0.996 (N = 8, p < 0.0001, B3LYP); C(beta),
      R(2) = 0.995 (N = 8, p < 0.0001, B3LYP), but are worse for C(meso), in part
      because of the small range in C(meso) shifts. The results of these theoretical
      calculations also lead to a revision of previous heme and proximal histidine
      residue (13)C NMR assignments in deoxymyoglobin which are confirmed by new
      quantitative NMR measurements. Molecular orbital (MO) analyses of the resulting
      wave functions provide a graphical representation of the spin density
      distribution in the [Fe(TPP)(CN)(2)](-) (TPP = 5,10,15,20
      tetraphenylporphyrinato) system (S = (1)/(2)), where the spin density is shown to
      be localized primarily in the d(xz) (or d(yz)) orbital, together with an analysis
      of the frontier MOs in Fe(TPP)Cl (S = (5)/(2)), Mn(TPP)Cl (S = 2), and a
      deoxymyoglobin model (S = 2). The ability to now begin to predict essentially all
      heavy atom NMR hyperfine shifts in paramagnetic metalloporphyrins and
      metalloproteins using quantum chemical methods should open up new areas of
      research aimed at structure prediction and refinement in paramagnetic systems in
      much the same way that DFT methods have been used successfully in the past to
      predict/refine elements of diamagnetic heme protein structures.

PMID- 12431125
TI  - Electron density topological analysis of hydrogen bonding in glucopyranose and
      hydrated glucopyranose.
AB  - Topological analysis of the electron density profiles and the atomic basin
      integration data for the most energetically favorable (4)C(1) and (1)C(4)
      conformers of beta-D-glucopyranose, calculated at the B3LYP/6-31+G(d), MPWlPW91/6
      311+G(2d,p), and MP2/6-31+G(d) levels, demonstrates that intramolecular hydrogen
      bonding between adjacent ring OH groups does not occur in glucopyranose, given
      the need to demonstrate a bond critical point (BCP) of correct (3,-1) topology
      for such an interaction to be termed a hydrogen bond. On the other hand, pyranose
      ring OH groups separated by three, rather than just two, carbon atoms are able to
      form an intramolecular hydrogen bond similar in topological properties and
      geometry to that found for propane-1,3-diol. Vicinal, equatorial OH groups in the
      (4)C(1) conformer of glucopyranose are, however, able to form strong bidentate
      hydrogen bonds with water molecules in a cooperative manner, each water molecule
      acting simultaneously as both hydrogen bond donor and acceptor, and characterized
      by (3,-1) bond critical points with increased values for the electron density and
      the Laplacian of rho(r) compared to an isolated ethane-1,2-diol/water complex.

PMID- 12431124
TI  - Mossbauer quadrupole splittings and electronic structure in heme proteins and
      model systems: a density functional theory investigation.
AB  - We report the results of a series of density functional theory (DFT) calculations
      aimed at predicting the (57)Fe Mossbauer electric field gradient (EFG) tensors
      (quadrupole splittings and asymmetry parameters) and their orientations in S = 0,
      (1)/(2), 1, (3)/(2), 2, and (5)/(2) metalloproteins and/or model systems.
      Excellent results were found by using a Wachter's all electron basis set for
      iron, 6-311G for other heavy atoms, and 6-31G for hydrogen atoms, BPW91 and B3LYP
      exchange-correlation functionals, and spin-unrestricted methods for the
      paramagnetic systems. For the theory versus experiment correlation, we found R(2)
      = 0.975, slope = 0.99, intercept = -0.08 mm sec(-)(1), rmsd = 0.30 mm sec(-)(1)
      (N = 23 points) covering a DeltaE(Q) range of 5.63 mm s(-)(1) when using the
      BPW91 functional and R(2) = 0.978, slope = 1.12, intercept = -0.26 mm sec(-)(1),
      rmsd = 0.31 mm sec(-)(1) when using the B3LYP functional. DeltaE(Q) values in the
      following systems were successfully predicted: (1) ferric low-spin (S = (1)/(2))
      systems, including one iron porphyrin with the usual (d(xy))(2)(d(xz)d(yz))(3)
      electronic configuration and two iron porphyrins with the more unusual
      (d(xz)d(yz))(4)(d(xy))(1) electronic configuration; (2) ferrous NO-heme model
      compounds (S = (1)/(2)); (3) ferrous intermediate spin (S = 1)
      tetraphenylporphinato iron(II); (4) a ferric intermediate spin (S = (3)/(2)) iron
      porphyrin; (5) ferrous high-spin (S = 2) deoxymyoglobin and deoxyhemoglobin; and
      (6) ferric high spin (S = (5)/(2)) metmyoglobin plus two five-coordinate and one
      six-coordinate iron porphyrins. In addition, seven diamagnetic (S = 0, d(6) and
      d(8)) systems studied previously were reinvestigated using the same functionals
      and basis set scheme as used for the paramagnetic systems. All computed asymmetry
      parameters were found to be in good agreement with the available experimental
      data as were the electric field gradient tensor orientations. In addition, we
      investigated the electronic structures of several systems, including the
      (d(xy))(2)(d(xz),d(yz))(3) and (d(xz),d(yz))(4)(d(xy))(1)
      [Fe(III)/porphyrinate](+) cations as well as the NO adduct of
      Fe(II)(octaethylporphinate), where interesting information on the spin density
      distributions can be readily obtained from the computed wave functions.

PMID- 12431126
TI  - Efficient CH-group selection and identification in 13C solid-state NMR by dipolar
      DEPT and 1H chemical-shift filtering.
AB  - A new spectral-editing technique for solid-state nuclear magnetic resonance
      (NMR), based principally on the different dipolar-dephasing properties of CH and
      CH(2) multiple-quantum (MQ) coherence, yields pure C-H spectra with overall
      efficiencies of up to 14%. The selection is based on dephasing of methylene
      heteronuclear MQ coherence by the second proton and can be considered essentially
      as a solid-state, slow-magic-angle-spinning version of the distortionless
      enhancement by polarization transfer (DEPT) experiment. A short dipolar transfer
      and inverse gated decoupling suppress quaternary-carbon resonances, and T(1)
      filtering reduces methyl signals. Applications to amorphous polymers with long,
      flexible sidegroups demonstrate excellent suppression of the signals of partially
      mobile methylene groups, consistent with simulations and superior to existing
      methods. CH selection in various model compounds and a humic acid confirms the
      robust nature and good sensitivity of the technique. Distinction of NCH and CCH
      groups, which have overlapping (13)C chemical-shift ranges, is achieved by
      combining dipolar DEPT with (1)H isotropic-chemical-shift filtering. In the humic
      acid, this permits unequivocal assignment of the methine resonance near 53 ppm to
      NCH groups.

PMID- 12431127
TI  - Photoinduced electron transfer between a carotenoid and TiO2 nanoparticle.
AB  - The dynamics of photoinduced electron injection and recombination between all
      trans-8'-apo-beta-caroten-8'-oic acid (ACOA) and a TiO(2) colloidal nanoparticle
      have been studied by means of transient absorption spectroscopy. We observed an
      ultrafast ( approximately 360 fs) electron injection from the initially excited
      S(2) state of ACOA into the TiO(2) conduction band with a quantum yield of
      approximately 40%. As a result, the ACOA(*)(+) radical cation was formed, as
      demonstrated by its intense absorption band centered at 840 nm. Because of the
      competing S(2)-S(1) internal conversion, approximately 60% of the S(2)-state
      population relaxes to the S(1) state. Although the S(1) state is
      thermodynamically favorable to donate electrons to the TiO(2), no evidence was
      found for electron injection from the ACOA S(1) state, most likely as a result of
      a complicated electronic nature of the S(1) state, which decays with a
      approximately 18 ps time constant to the ground state. The charge recombination
      between the injected electrons and the ACOA(*)(+) was found to be a highly
      nonexponential process extending from picoseconds to microseconds. Besides the
      usual pathway of charge recombination forming the ACOA ground state, about half
      of the ACOA(*)(+) recombines via the ACOA triplet state, which was monitored by
      its absorption band at 530 nm. This second channel of recombination proceeds on
      the nanosecond time scale, and the formed triplet state decays to the ground
      state with a lifetime of approximately 7.3 micros. By examination of the process
      of photoinduced electron transfer in a carotenoid-semiconductor system, the
      results provide an insight into the photophysical properties of carotenoids, as
      well as evidence that the interfacial electron injection occurs from the
      initially populated excited state prior to electronic and nuclear relaxation of
      the carotenoid molecule.

PMID- 12431129
TI  - Should beta-blockers be used for the treatment of pediatric patients with chronic
      heart failure?
AB  - In multiple clinical trials, beta-blockers have been shown to significantly
      improve morbidity and mortality in adults with chronic congestive heart failure,
      but there is little reported experience with their use in children. Heart failure
      involves activation of the adrenergic nervous system and other neurohumoral
      systems in order to maintain cardiovascular homeostasis. These compensatory
      mechanisms have been shown to cause myocardial damage with chronic activation,
      which has been hypothesized to be a major contributing factor to the clinical
      deterioration of adults with heart failure. Studies have demonstrated inhibition
      of this neurohumoral response and concomitant clinical benefits with beta
      blockers. Consequently, beta-blockers have evolved to become an important part of
      comprehensive medical therapy for congestive heart failure in adults. Pediatric
      heart failure represents an entirely different spectrum of disease, caused more
      commonly by congenital heart disease than cardiomyopathy. Surgical palliation and
      correction are important components of pediatric heart failure therapy, and
      residual, postsurgical cardiac lesions can lead to chronic heart failure.
      Although neurohumoral activation in children is similar to that in adults with
      heart failure, there are important differences from adults in physiology and
      developmental changes that are especially observed in infants. Current published
      clinical experience with beta-blocker use in children with heart failure is
      limited to case series with relatively small numbers of patients. Nevertheless,
      these series show consistent symptomatic improvement, and improvement in
      ventricular systolic function in patients with cardiomyopathies and congenital
      heart disease, similar to findings in adults. Adverse effects were common and
      many patients in these studies had adverse outcomes (death and/or need for
      transplantation). One study has noted differences in pharmacokinetics in children
      compared with adults. However, a multicenter, randomized controlled trial to
      evaluate carvedilol in pediatric heart failure from systolic ventricular
      dysfunction is currently ongoing and should help to clarify the efficacy and
      tolerability of carvedilol in children.

PMID- 12431130
TI  - Tinea capitis: epidemiology, diagnosis and management strategies.
AB  - Tinea capitis is a common superficial fungal infection of the scalp in children,
      particularly in those of African descent. Trichophyton tonsuran, an
      anthropophilic dermatophyte, is responsible for the majority of cases in North
      America. The clinical presentations are variable and include: (i) a "seborrheic"
      form that is scaling, often without noticeable hair loss; (ii) a pustular,
      crusted pattern, either localized or more diffuse; (iii) a "black dot" variety
      characterized by small black dots within areas of alopecia; (iv) a kerion, which
      is an inflammatory mass; and (v) a scaly, annular patch. Most experts still
      consider griseofulvin to be the drug of choice, but recommend a higher dosage of
      20-25 mg/kg/day for 8 weeks because of the increase in treatment failures.
      Despite a history of having an excellent tolerability profile, the long treatment
      course and higher doses required for griseofulvin have led to consideration of
      new antifungal agents for this infection. Terbinafine, itraconazole, and
      fluconazole compartmentalize in skin, hair, and nails, thereby allowing shorter
      treatment courses of < or =4 weeks. All have generally been shown to be effective
      in the treatment of tinea capitis and appear relatively well tolerated, with
      gastrointestinal symptoms being the most common adverse effect. Monitoring for
      liver enzyme elevations is generally unnecessary if therapy is limited to </=4
      weeks. As more data regarding efficacy, tolerability, and dose administration
      becomes available, one or more of these new antifungal agents may become first
      line therapy for tinea capitis. For now, we recommend their use in cases of
      treatment failure or recurrent noncompliance. Our personal preference in the
      younger child is fluconazole. It has a favorable tolerability profile and is
      available in liquid form. In the older child who can take a tablet, terbinafine
      is recommended. More data is available on this drug in the treatment of tinea
      capitis than the other two, and it is the least expensive. Although the oral
      antifungal agents are the most important aspect of therapy, adjunctive therapy
      may be beneficial. Sporicidal shampoos, such as selenium sulfide, can aid in
      removing adherent scales and hasten the eradication of viable spores from the
      scalp in the hope of decreasing the spread of this infection. The use of
      corticosteroids for the treatment of kerions is controversial. Many of the
      studies have design flaws or show variable results. We recommend either a short
      burst of oral corticosteroids or topical corticosteroids in patients with the
      most severe disease.

PMID- 12431131
TI  - Diabetes insipidus in children: pathophysiology, diagnosis and management.
AB  - In diabetes insipidus, the amount of water ingested and the quantity and
      concentration of urine produced needs to be carefully regulated if fluid volume
      and osmolality are to be maintained within the normal range. One of the principal
      mechanisms controlling urine output is vasopressin which is released from the
      posterior pituitary gland and enhances water reabsorption from the renal
      collecting duct. In diabetes insipidus, the excessive production of dilute urine,
      and the causes of this clinical picture can be divided into three main groups:
      the first is primary polydipsia where the amount of fluid ingested is
      inappropriately large; the second group is cranial diabetes insipidus where the
      production of vasopressin is abnormally low; and, the third group is nephrogenic
      diabetes insipidus where the kidney response to vasopressin is impaired. The
      history and examination may suggest an underlying explanation for diabetes
      insipidus but a range of baseline and more extensive investigations may be
      required before a diagnosis can be reached. These investigations are not without
      risk, and the results need to be interpreted carefully because children do not
      always segregate neatly into a particular diagnostic category on the basis of one
      test alone. Children with cranial diabetes insipidus typically respond to
      arginine vasopressin or its manufactured analogue, desmopressin, with an increase
      in urine osmolality and an associated reduction in urine output. Such children
      usually require neuroimaging to look for evidence of evolving CNS pathology, such
      as an intracranial tumour. Vasopressin "replacement" with desmopressin is the
      treatment of choice in patients with cranial diabetes insipidus although extreme
      caution is required when treating babies or small children because of the danger
      of fluid overload. Abnormal production of other pituitary hormones in children
      with CNS disease can also influence fluid balance. Nephrogenic diabetes insipidus
      can be due to abnormal electrolyte concentrations, therefore these should be
      measured as part of the initial assessment. In a small number of children the
      defect is a primary abnormality of the vasopressin receptor or one of the water
      channel proteins (aquaporins) involved in water transport. The treatment of these
      patients is difficult and typically involves therapy with a diuretic such as
      chlorothiazide, as well as indomethacin. These agents enhance urine osmolality by
      their effect on circulating volume and renal solute and water handling. The fluid
      intake of most young children with primary polydipsia can be safely reduced to a
      more appropriate level.

PMID- 12431132
TI  - A contemporary approach to dysmenorrhea in adolescents.
AB  - Dysmenorrhea is the most common gynecologic complaint among adolescent girls.
      Despite progress in understanding the physiology of dysmenorrhea and the
      availability of effective treatments, many adolescent girls do not seek medical
      advice or are undertreated. Dysmenorrhea in adolescents is usually primary
      (functional), and is associated with normal ovulatory cycles and no pelvic
      pathology. In approximately 10% of adolescents with severe dysmenorrhea, pelvic
      abnormalities such as endometriosis or uterine anomalies may be found. Potent
      prostaglandins from the second series and potent leukotrienes from the fourth
      series play an important role in generating dysmenorrhea symptoms. Nonsteroidal
      anti-inflammatory drugs (NSAIDs) are the most common pharmacologic treatment for
      dysmenorrhea. A loading dose of NSAIDs (typically twice the regular dose) should
      be used as initial treatment for dysmenorrhea in adolescents followed by a
      regular dose until symptoms abate. Adolescents with symptoms that do not respond
      to treatment with NSAIDs for three menstrual periods should be offered combined
      estrogen/ progestin oral contraceptive pills for three menstrual cycles.
      Adolescents with dysmenorrhea who do not respond to this treatment should be
      evaluated for secondary causes of dysmenorrhea. Adolescent care providers have
      the important roles of educating adolescent girls about menstruation-associated
      symptoms, as well as evaluating and effectively treating patients with
      dysmenorrhea.

PMID- 12431133
TI  - Ulcerative colitis in children: medical management.
AB  - Ulcerative colitis is a chronic relapsing inflammatory disorder of the colonic
      mucosa of unknown etiology. The inflammatory process involves the mucosa and
      submucosa in a continuous segment of bowel with rectal involvement in almost all
      cases. Since its etiology is unknown, therapy is directed at modulating the
      inflammatory response in order to control symptoms and to prevent relapses. 5
      aminosalicylates and corticosteroids have been the most widely used therapeutic
      agents for treatment of ulcerative colitis. Recently, experience has been gained
      with the use of other immunomodulators, such as mercaptopurine, azathioprine,
      methotrexate, cyclosporine, and tacrolimus, in pediatric patients. Colectomy is
      indicated in patients with severe colitis who do not respond to intensive medical
      therapy. The care of children with ulcerative colitis not only involves control
      of symptoms from gastrointestinal and extraintestinal manifestations, but also
      optimizing growth and development. The complications of chronic inflammation and
      long-term medical therapy must be weighed against the risks and benefits of
      surgery for children and adolescents with this condition.

PMID- 12431135
TI  - Carotid artery stenting in older patients: is age a risk factor for poor outcome?
AB  - PURPOSE: To assess the impact of age on technical success and complications of
      carotid stenting in a prospective single-center cohort study. METHODS: One
      hundred eleven consecutive patients (74 men; median age 70 years) with >or=70%
      symptomatic (n=33) or >or=90% asymptomatic (n=78) internal carotid artery (ICA)
      stenosis underwent carotid artery stent implantation. Primary technical success
      and periprocedural complications were compared in patients aged >75 years (n=28)
      to patients <75 years (n=83). RESULTS: Patient groups below and above 75 years
      compared well with respect to baseline demographic and clinical data. Successful
      stenting was achieved in 108 (97%) patients. The combined neurological
      complication rate was 7% (n=8), with 1 (1%) major stroke, 1 (1%) minor stroke,
      and no 30-day mortality. Technical angiographic complications occurred in 8 (7%)
      patients. No significant differences between patients >75 years and those <75
      years were observed for primary success rates (100% [28/28] versus 96% [80/83];
      p=0.8), overall complications (14% [4/28] versus 16% [13/83]; p=1.0),
      neurological complications (7% [2/28] versus 7% [6/83]; p=1.0), or technical
      complications (7% [2/28] versus 4% [3/83]; p=0.6). CONCLUSIONS: Elective carotid
      stenting can be performed safely in older patients with several comorbidities.
      Patient age does not seem to be an independent risk factor for poor outcome after
      endovascular treatment of internal carotid artery stenosis.

PMID- 12431134
TI  - Antibiotics and breast-feeding: a critical review of the literature.
AB  - Continuous breast-feeding, an integral component of the postpartum period, is
      often threatened upon maternal initiation of antibiotics. The real risk of
      antibiotic use while breast-feeding must be carefully analysed with regard to all
      the variables that influence the extent of antibiotic distribution into breast
      milk, including breast milk composition, physicochemical properties of the
      antibiotic (molecular weight, lipid solubility, pH, protein binding), length of
      feeding, and maternal disposition. In addition, infant disposition, including
      ability to absorb, metabolize, eliminate, and tolerate any amounts of antibiotic,
      must also be considered prior to maternal administration of antibiotic. The milk
      to plasma (M/P) ratio is a frequently quoted parameter used to predict drug
      distribution into breast milk. However, its utility is questionable and often
      fraught with misinterpretation. An alternative approach when the amount of
      antibiotic concentration in breast milk is known (through clinical trials) is to
      calculate an estimated or expected infant drug exposure factoring in
      known/expected milk consumption, drug concentration and bioavailability. In this
      review, the following antibiotic classes and current literature regarding their
      distribution into breast milk are critically reviewed: beta-lactam antibiotics,
      fluoroquinolones, sulfonamides, macrolides, aminoglycosides, tetracyclines,
      nitrofurantoin, metronidazole, vancomycin, clindamycin and chloramphenicol. In
      the majority of instances, these antibiotics do not distribute into breast milk
      in sufficient concentrations to be of any clinical consequence in the breast
      feeding infant.

PMID- 12431136
TI  - Early postsurgical carotid restenosis: redo surgery versus angioplasty/stenting.
AB  - PURPOSE: To compare the results of balloon angioplasty/stenting (BA/S) versus
      redo surgery in patients with early carotid restenosis. METHODS: Sixty-one
      patients (35 women; mean age 69 years, range 46-82) with early restenosis (<24
      months from the primary endarterectomy) in 63 carotid arteries were treated
      during a 5-year period; 41 patients (41 arteries) had redo surgery (group A) and
      20 patients (22 arteries) had BA/S (group B). Patients were followed regularly
      with duplex ultrasound to detect >or=50% recurrent restenosis (RRS) after redo
      surgery or BA/S. Kaplan-Meier life-table analysis was used to estimate the stroke
      free survival rates and freedom from >or=50% RRS. RESULTS: The demographic and
      clinical characteristics were comparable for both groups, as were the
      perioperative stroke and death rates (2.4% and 0% for group A, respectively,
      versus 4.5% and 0% for group B, p=0.46). Group A had a 12% incidence of cranial
      nerve injury (all transient) versus 0% for group B (p=0.11); however, group B had
      a higher incidence of >or=50% RRS than group A (32% versus 0%, p=0.0003). The
      stroke-free survival rates for redo surgery at 6, 12, 24, 36, and 48 months were
      100%, 100%, 100%, 100%, and 88% versus 95%, 95%, 84%, 84%, and 63% for BA/S
      (p=0.067). Redo surgery had a 100% freedom from >or=50% RRS at the same time
      intervals, while recurrent restenosis rates for the BA/S patients were 95%, 86%,
      69%, 52%, and 52% (p<0.0001). CONCLUSIONS: BA/S and redo surgery have comparable
      stroke and death rates in the treatment of early RCS; however, redo surgery is
      associated with cranial nerve injuries (transient), while stent patients have a
      higher incidence of recurrent lesions. These considerations should be kept in
      mind when selecting the appropriate treatment for patients with early
      postsurgical restenosis.

PMID- 12431137
TI  - Endovascular repair of traumatic descending aortic transection.
AB  - PURPOSE: To present the results of endovascular repair of acute traumatic
      descending aortic transection. METHODS: Among 66 thoracic stent-graft repairs
      performed between 1995 and 2001, 11 patients (9 men; mean age 34 years, range 12
      73) underwent emergent endovascular repair of acute traumatic descending aortic
      transection following traffic accidents. Immediate treatment of aortic rupture
      was indicated in all patients because of a marked fresh hematoma with hemothorax;
      the spiral computed tomographic (CT) scans showed circular or semicircular
      descending thoracic aortic injuries. The devices used included 11 thoracic
      Excluders and 1 Talent stent-graft. RESULTS: No patient required conversion to an
      open transthoracic operation. No patient developed temporary or permanent
      neurological deficit after endovascular treatment. Two type I endoleaks required
      periprocedural treatment: a second stent-graft was deployed in one and the
      existing stent-graft was balloon dilated in the other. Two patients underwent
      secondary procedures (iliac access complication and revascularization of the left
      subclavian artery). One patient died 22 days postoperatively secondary to
      injuries unrelated to the aortic repair. Over a mean 14-month follow-up (range 1
      26), the surveillance CT scans have shown the stent-graft to be correctly
      positioned in all patients. CONCLUSIONS: The treatment of acute traumatic
      descending aortic transection with an endovascular approach is feasible and safe
      and may offer the best means of therapy. Mortality and the risk of neurological
      deficit are low compared with open operations.

PMID- 12431138
TI  - Endoluminal repair of infrarenal AAA in the presence of aortic dissection.
AB  - PURPOSE: To report a challenging case of infrarenal abdominal aortic aneurysm
      (AAA) treated with a commercial stent-graft in the face of thoracoabdominal
      aortic dissection. CASE REPORT: A 73-year-old patient was admitted because of
      acute descending thoracic and abdominal aortic dissection. He was also found to
      have an 8-cm infrarenal AAA. After initial medical management of the acute aortic
      dissection, the patient underwent endoluminal AAA repair with an AneuRx stent
      graft. The completion angiogram showed that the graft was deployed in the false
      lumen; this complication was treated with fenestration of the intimal flap,
      establishing flow through both lumens. The patient's recovery was uneventful, and
      he was discharged on the fourth postoperative day. Follow-up at 1 year with
      computed tomographic angiography documented a stable descending thoracic aorta
      with a suggestion of a type II endoleak and no change in the aneurysm volume.
      CONCLUSIONS: This case illustrates the feasibility of endograft repair of
      infrarenal AAA with a modular stent-graft in the presence of aortic dissection
      extending below the renal arteries.

PMID- 12431139
TI  - Crossing the limbs: a useful adjunct for successful deployment of the AneuRx
      stent-graft.
AB  - PURPOSE: To describe a technique for deploying an AneuRx stent-graft in an
      abdominal aortic aneurysm (AAA) with an acutely angled aortic neck. TECHNIQUE: In
      routine cases, the AneuRx stent-graft main body is positioned with the nose cone
      notch facing the contralateral side. In severely angulated aortic necks, however,
      the main body of the AneuRx stent-graft can be positioned with the nose cone
      notch and iliac limb gate facing the ipsilateral side; this dramatically reduces
      the acuity of the angle at the aortic neck and the iliac gate. This technique of
      "crossing the limbs" has been successfully used in 7 cases since FDA approval of
      the AneuRx device. CONCLUSIONS: Proximal neck angulation is an important factor
      for successful endovascular AAA repair. Crossing the graft limbs reduces the
      effect of neck angulation on the proximal main body and may decrease the stress
      upon the contralateral limb gate, which may avoid graft gate disconnection and
      endoleak.

PMID- 12431140
TI  - Early rupture of a partially treated abdominal aortic aneurysm: another
      endovascular lesson.
AB  - PURPOSE: To report early rupture of a partially treated abdominal aortic
      aneurysm. CASE REPORT: A 76-year-old man with a 6.4-cm abdominal aortic aneurysm
      had the main body of a bifurcated graft inserted into the aneurysm. However, it
      was not possible to cannulate the short cuff of the graft to deploy the
      contralateral limb, probably due to a proximal aortic stenosis compressing the
      stent-graft. The plan was for the patient to return on another date for a further
      attempt at recannulation; however, shortly after the patient was discharged, the
      aneurysm ruptured, necessitating conventional open repair, which the patient
      survived. CONCLUSIONS: Every effort should be made to complete endovascular
      treatment of abdominal aortic aneurysms at a single session.

PMID- 12431141
TI  - Endovascular exclusion of a ruptured pseudoaneurysm of the infrarenal abdominal
      aorta secondary to pancreatitis.
AB  - PURPOSE: To report the successful repair of a ruptured pseudoaneurysm of the
      infrarenal abdominal aorta secondary to pancreatitis. CASE REPORT: A 47-year-old
      man was admitted with abdominal pain due to an acute exacerbation of chronic
      alcoholic pancreatitis. He was found to have an infrarenal abdominal aortic
      aneurysm, which was confirmed by spiral computed tomography (CT), but there had
      been no evidence of aneurysm formation on a scan performed 1 year previously.
      Persistent symptoms prompted a further CT scan 48 hours later; this revealed
      evidence of a ruptured infrarenal abdominal aortic pseudoaneurysm. The
      pseudoaneurysm was excluded using a Zenith aortomonoiliac endovascular graft.
      Recovery was uneventful, and the patient underwent pancreatic resection 6 months
      later. A duplex scan 10 months after endograft placement could not identify an
      aneurysm sac. CONCLUSIONS: In selected cases, endovascular repair provides a
      useful method of excluding ruptured aortic pseudoaneurysms due to pancreatitis.
      It allows hemorrhage control in a potentially infected operative field and
      permits elective pancreatic resection. Prolonged follow-up is mandatory to ensure
      there is no evidence of graft sepsis and that aneurysm exclusion is maintained.

PMID- 12431142
TI  - Initial clinical results of tenecteplase (TNK) in catheter-directed thrombolytic
      therapy.
AB  - PURPOSE: To investigate the safety and immediate efficacy of 2 different doses of
      tenecteplase (TNK) in peripheral catheter-directed thrombolytic therapy of
      arterial occlusions and deep vein thrombosis (DVT). METHODS: Over a 20-month
      period, 63 nonconsecutive patients underwent catheter-directed thrombolytic
      therapy with either 0.25 mg/h or 0.50 mg/h of TNK in a nonrandomized, open-label
      study. Of these, 55 patients (60 limbs) were treated for DVT (36 limbs in 16 men
      and 15 women; mean age 41 years, range 21-73) or peripheral arterial occlusions
      (24 limbs in 16 men and 8 women; mean age 63 years, range 32-91). The primary
      endpoints were major bleeding complications and angiographic reduction in clot
      burden. RESULTS: The mean duration of infusion was 18 +/- 4 hours in patients
      with arterial occlusions and 30 +/- 13 in those with DVT. Twenty-one (87.5%)
      patients with occlusive disease had marked or complete lysis of clot. Thirty
      (83.3%) limbs with DVT had either marked or complete resolution of thrombus.
      There were 4 (7.3%) episodes of minor bleeding with 1 (1.8%) major hemorrhagic
      event. Fibrinogen levels dropped by an average of 23%. CONCLUSIONS: Preliminary
      evidence suggests that TNK doses of 0.25 mg/h to 0.50 mg/h appear to be safe and
      effective. The potential benefits of TNK therapy warrant further investigation.

PMID- 12431143
TI  - Complex endovascular treatment for critical limb ischemia in poor surgical
      candidates: a pilot study.
AB  - PURPOSE: To evaluate the effectiveness of complex endovascular treatment for limb
      salvage in patients with critical limb ischemia. METHODS: In a prospective study,
      23 patients (13 men; mean age 70 +/- 11 years, range 44-87) with ischemic
      ulceration or gangrene of 25 lower limbs were enrolled at 4 sites to evaluate
      treatment with excimer laser recanalization followed by balloon angioplasty with
      optional stenting in the superficial femoral, popliteal, and/or tibial arteries.
      RESULTS: Multiple lesions (mean 3.1, range 1-8) were treated in most cases.
      Reduction of stenosis/occlusion to <50% was achieved in 22 (88%) limbs.
      Individual cases of vessel perforation, inability to cross the lesion, and
      excessive residual stenosis accounted for the 3 failures. Over a 6-month period,
      4 patients died of cardiac comorbidity and 1 was lost to follow-up. Adverse
      events included 4 minor and 2 below-knee amputations, 4 secondary angioplasties,
      and 4 femorodistal bypasses. The mean wound area reduction was 70% at 3 months,
      increasing to 89% at 6 months. According to life table analysis, the limb salvage
      rate was 90% with bypass and 69% without in the successfully treated patients
      (corresponding intention-to-treat rates were 79% and 61%). CONCLUSIONS: Complex
      endovascular treatment combining laser debulking and angioplasty/stenting offers
      an alternative for patients with critical limb ischemia who lack good surgical
      options.

PMID- 12431144
TI  - Renal atrophy outcome after revascularization in fibromuscular dysplasia disease.
AB  - PURPOSE: To assess clinical, biological, and kidney parameters before and 6
      months after revascularization of renal artery stenosis due to fibromuscular
      dysplasia (FMD). METHODS: Twenty hypertensive patients (18 women; mean age 48.7
      +/- 15.4 years) with unilateral de novo FMD stenosis were studied before and 6
      months after revascularization (balloon angioplasty 19; bypass surgery 1). Blood
      pressure and creatinine clearance were measured, and renal length, cortical
      thickness, cortical area (CA), and medullary length (ML) were evaluated by spiral
      computed tomographic angiography (CTA) in 20 poststenotic and 20 contralateral
      kidneys. RESULTS: Six months after revascularization, the systolic and diastolic
      blood pressures decreased by 19 mmHg and 10 mmHg, respectively (p=0.02), the
      number of antihypertensive drugs decreased by 1 (p=0.01), but the increase in
      creatinine clearance was not significant. At baseline, the poststenotic kidneys
      were significantly more atrophied than the contralateral normal kidney (ML in
      normal kidney 89 +/- 9 mm versus 81 +/- 10 mm in poststenotic kidney, p<0.001; CA
      in normal kidney 824 +/- 149 mm(2) versus 703 +/- 156 mm(2) in poststenotic
      kidney, p<0.01), which persisted at 6 months (ML in normal kidney 89 +/- 10
      versus 80 +/- 11 in poststenotic kidney, p<0.001; CA in normal kidney 807 +/- 145
      mm(2) versus 696 +/- 157 mm(2) in poststenotic kidney, p<0.01). Renal length was
      still within normal range in all kidneys, and the morphological parameters
      remained stable after revascularization. CONCLUSIONS: We demonstrated significant
      cortical/medullary atrophy in poststenotic kidneys compared to contralateral
      normal kidneys. Despite intraparenchymal disease, clinical outcome was favorable
      after revascularization. Cortical/medullary thinning appears to be an early
      marker of renal ischemia that could support revascularization in FMD disease.

PMID- 12431145
TI  - Interventional treatment of traumatic priapism.
AB  - PURPOSE: To describe the effectiveness of transarterial embolization of traumatic
      priapism. METHODS: Six patients ranging in age from 6 to 37 years with traumatic
      high-flow priapism underwent superselective embolization with gelatin sponges
      (n=3) or minicoils (n=3). Embolization was repeated up to 3 times. RESULTS:
      Embolization was successful in all cases. In 2 patients, repeated embolization
      led to a flow reduction in the fistula, which spontaneously occluded a few days
      later. All patients experienced normal erections after intervention, and no side
      effects were observed. CONCLUSIONS: Transarterial superselective embolization is
      an effective and well-tolerated therapy in patients with traumatic priapism.

PMID- 12431146
TI  - Early ambulation after diagnostic angiography using 4-f catheters and sheaths: a
      feasibility study.
AB  - PURPOSE: To assess the feasibility and safety of early ambulation in patients
      undergoing transfemoral diagnostic angiography using 4-F catheters or sheaths.
      METHODS: In this prospective study approved by the institutional review board,
      patients undergoing diagnostic angiography were randomized to ambulate 3 or 6
      hours after catheter or sheath removal. All patients were assessed for hematoma
      formation, pseudoaneurysm development, and other groin complications during the
      in-hospital recovery period and after 30 days. Patient satisfaction and comfort
      level were also assessed by survey. RESULTS: Of 110 patients (66 men; mean age
      64.9 +/- 12.8 years) who participated in this study, 47 were randomized to the 6
      hour (6-H) group and 63 to the 3-hour (3-H) group. In the 3-H and 6-H groups,
      respectively, a 4-F catheter was used in 45 (71%) and 35 (74%) patients and a 4-F
      sheath in 18 (29%) and 12 (26%). No clinically significant groin complications
      were encountered in either group. Moderate to severe discomfort was reported in 9
      (16%) of the 56 patients responding to the discomfort survey in the 3-H group
      compared to 10 (26%) of the 38 in the 6-H survey respondents. CONCLUSIONS: It is
      feasible and safe to ambulate patients 3 hours after diagnostic angiography
      performed with a 4-F catheter with or without a 4-F sheath. Early ambulation of
      patients after angiography has the additional benefits of increasing patient
      satisfaction and resource utilization.

PMID- 12431147
TI  - Management of unexpected balloon rupture during deployment of balloon-expandable
      stents.
AB  - PURPOSE: To describe a method for dealing with balloon rupture during stent
      deployment. TECHNIQUE: A 10-mL Luer-Lock syringe containing contrast material and
      heparinized saline is used to re-expand a balloon ruptured during stent
      deployment, permitting maximum balloon expansion and successful initial stent
      wall apposition. No adjunctive use of probing catheters or a power injector is
      necessary to achieve adequate stent expansion. Analysis of the rupture may
      identify procedural deficiencies that can be rectified. CONCLUSIONS: This
      technique is simple and timesaving, and interventionists should maintain
      vigilance when handling of balloon-expandable stents.

PMID- 12431148
TI  - Gadodiamide as an alternative contrast agent during angioplasty in patients with
      contraindications to iodinated media.
AB  - PURPOSE: To evaluate gadodiamide as an alternative contrast agent for peripheral
      and renal angioplasty in patients with contraindications to iodinated contrast
      media. METHODS: Seventeen patients (10 men; mean age 74 years, range 68-83) with
      contraindication to iodinated contrast media were given gadodiamide as the
      contrast agent during peripheral and renal intra-arterial digital subtraction
      angiography (DSA) and subsequent percutaneous interventions (balloon angioplasty,
      stent placement). RESULTS: The mean volume of gadodiamide used was 136 +/- 46 mL
      (range 60-200). No serious side effects were observed, especially no change in
      renal or thyroid function; no exanthema or other allergic reactions were noted.
      In patients without renal artery intervention, serum creatinine at discharge
      remained unchanged (2.57 +/- 1.43 mg/dL to 2.40 +/- 1.28 mg/dL, p=NS). In
      patients undergoing angioplasty/stenting of renal artery stenoses, serum
      creatinine decreased significantly from 3.53 +/- 1.75 mg/dL to 2.36 +/- 1.15
      mg/dL (p<0.01). All but 1 intervention was successful. Using a simple scoring
      system, 2 judges blinded to the contrast agent graded the quality of the
      peripheral DSAs as "good," whereas renal DSA images were only "sufficient."
      CONCLUSIONS: For patients with contraindications to iodinated materials,
      gadodiamide may be a suitable alternative for renal or peripheral DSA followed by
      angioplasty.

PMID- 12431149
TI  - Trends in endovascular surgery training.
AB  - PURPOSE: To gather vascular surgery fellows' opinions on various issues related
      to endovascular surgery (EVS) over a 2-year period and analyze the responses to
      identify trends in EVS training. METHODS: Vascular surgery fellows in 2
      consecutive years were given a 2-page questionnaire inquiring about training
      protocols and local practice habits. Respondents included 64 vascular fellows
      from the academic year 1998-1999 (F98) and 52 vascular fellows from the academic
      year 1999-2000 (F99) (78% men in the entire population; mean age 34 years),
      representing a significant fraction of trainees in North America. Data from F98
      and F99 were compared and analyzed. RESULTS: The majority (66%) of vascular
      surgery fellows were trained at university hospitals and performed EVS at the
      time of the survey: 83% in the F98 class and 92% in the F99 group (p=0.17).
      Utilization rates among the 9 interventions surveyed ranged from angiography
      (83%) and angioplasty (77%) to intravascular ultrasound (33%) and atherectomy
      (15%). Performance of endovascular grafting significantly increased among
      trainees (50% versus 81%, p<0.005), while atherectomy and angioscopy decreased.
      EVS performed in the operating room with portable imaging equipment decreased
      (67% versus 42%, p=0.02) as access to the radiology and cardiology suites
      increased. In most communities (63%), radiology specialists performed most of the
      EVS procedures, but the portion of communities where vascular surgery performed
      the majority of EVS procedures increased from 20% to 35% (p=0.10) from F98 to
      F99. Responders (90%) believed that EVS would become a major component of
      vascular surgery and comprise 30% of their future practice. The proportion of
      fellows who believed they were sufficiently trained in endovascular techniques
      increased from 30% to 50% (p=0.04), with the remainder willing to devote a short
      period (<3 months) for further training. CONCLUSIONS: The vast majority of
      vascular trainees perform EVS and believe that it will have an increasing role in
      their practice. Trends include increased endovascular grafting and performance of
      EVS by vascular surgeons in interventional suites.

PMID- 12431150
TI  - Endotension distribution and the role of thrombus following endovascular AAA
      exclusion.
AB  - PURPOSE: To determine the pattern of strain and pressure transmitted to an aortic
      aneurysm wall before and after endovascular exclusion and to evaluate the role of
      sac thrombus on the conduction of pressure and wall strain. METHODS: Three canine
      thoracic aortas were used to create abdominal aortic aneurysms (AAA). The
      segments were placed on a pulsatile pump system, and 8 strain transducers were
      positioned in the aneurysm sac. Baseline strain/pressure (S/P) was recorded in 1
      animal, then the AAA was excluded with a stent-graft. Thrombin was injected into
      the sac, and strain/pressure was recorded at 7 systemic pressures (35 to 120
      mmHg) over 6 hours. The thrombus was replaced with fibrin glue, and S/P was
      recorded over 4 hours. Additional trials using whole and 50% diluted unclotted
      blood were performed prior to sac thrombosis. Computed tomography and angiography
      were performed before and after aneurysm exclusion. RESULTS: Pressure transmitted
      to the aneurysm wall decreased following stent-graft placement (p<or=0.001).
      Strain/pressure was not distributed evenly in the sac (p<or=0.05), and varying
      systemic pressures did not affect this distribution. Pressures near the stent
      graft were higher than those laterally (p<or=0.001) in all trials with interposed
      fresh thrombus and fibrin thrombus. The fibrin group had elevated baseline
      measurements, but correction for the elevated values did not influence the
      statistical significance (p<or=0.001). Blood and fibrin thrombus reduced
      transmitted wall pressure to a similar degree. Overall S/P in the fluid-filled
      nonclotted sac was significantly lower (p<or=0.001) than in the thrombus groups.
      CONCLUSIONS: Endovascular AAA exclusion reduced strain and pressure conducted to
      the aneurysm wall, and the distribution of transmitted pressure in the excluded
      sac without endoleak differed regardless of the sac contents. Fresh thrombus
      reduced transmittedS/P in all trials at all systemic pressures, as did fibrin
      thrombus but in a less predictable fashion.

PMID- 12431151
TI  - Stent-graft migration following endovascular repair of aneurysms with large
      proximal necks: anatomical risk factors and long-term sequelae.
AB  - PURPOSE: To evaluate the outcome of aortic endografts deployed in large
      infrarenal necks and to identify any association of preoperative aneurysm
      characteristics and postoperative morphological changes with the incidence of
      neck dilatation and device migration in this patient subset. METHODS: The records
      of 47 patients (41 men; mean age 74, range 55-84) with large aortic neck
      diameters treated with Talent stent-grafts from 1998 to 2001 were reviewed.
      Patients with anatomical criteria that precluded aneurysm exclusion with
      currently available devices were preferentially selected. Mean baseline aneurysm
      morphology included 27.6-mm (range 18-33.4) suprarenal and 28.1-mm (range 24-34)
      infrarenal neck diameters; the infrarenal neck length was 26 +/- 16 mm with
      angulation of 37 degrees +/- 18 degrees. Computed tomographic (CT) angiograms up
      to 3 years were analyzed using specialized interactive software; migration was
      defined as >1-cm change in the distance from the lower renal artery to the top of
      the device. Pre- and postoperative morphological characteristics of the aneurysm
      were compared between patients with and without migration. RESULTS: Of the 45
      patients successfully treated, 40 had complete CT data for analysis. During a
      mean 17-month follow-up, 7 (17.5%) of the 40 devices exhibited distal migration.
      Six patients required secondary procedures; 5 were in the migration cohort. No
      preoperative anatomical characteristic or degree of neck dilatation over time was
      predictive of stent-graft migration. Aneurysm sac regression was significant at 1
      (-0.09 +/- 4.90 mm) and 2 (-1.48 +/- 2.56 mm) years in endografts without
      migration (p<0.001). Distal endograft migration >1 cm predicted the need for
      secondary interventions (p<0.001), with 83% sensitivity and 94% specificity.
      CONCLUSIONS: Endovascular repair is successful in patients with large infrarenal
      necks and complex neck morphology. Changes in aneurysm remodeling over time were
      similar to reported observations in patients with more favorable neck criteria.
      Although no anatomical factor associated with migration could be identified from
      this analysis, distal displacement >1 cm correlated with the need for a secondary
      intervention.

PMID- 12431152
TI  - Aneurysm wall stress and tendency to rupture are features of physical wall
      properties: an experimental study.
AB  - PURPOSE: To use bench top techniques to examine the biophysical phenomena
      affecting the risk of abdominal aortic aneurysm (AAA) rupture relative to the
      physical properties of the aneurysm sac. METHODS: Three latex AAAs with different
      wall elasticities were tested in a validated pulsatile flow model (PFM). Strain
      gauges were wired to each AAA model at the neck, inflection point, and at the
      maximum diameter. In initial studies, the influence of pressurization and the
      mechanical properties of AAA wall stress were evaluated. In subsequent studies,
      the latex AAAs were excluded with a tube graft and retested in the PFM. After
      creation of either a type I or II endoleak of known size and pressure, the
      systemic/intrasac pressure and the AAA wall stress were measured. RESULTS: Each
      model had a complex wall-stress pattern comprising radial, longitudinal, and
      shear components. The peak wall stress at any point, in the presence of systemic
      pressurization or endoleak pressure, only reached 1% of the failure strength. In
      an AAA with a reinforced wall, the peak stress was significantly greater.
      Statistical analysis showed that wall strength contributed more significantly to
      wall stress than increasing pressurization within the AAA sac. CONCLUSIONS: AAA
      wall mechanics contribute more significantly to peak wall stress than pressure
      variations within the system. In particular, increased stiffness (analogous to
      collagen deposition) significantly increased peak wall stress, which was located
      at the inflection point rather than at the maximum diameter. Techniques to
      measure the AAA wall mechanics and the rate of deterioration may predict AAA
      rupture in the untreated state or in the presence of an endoleak following
      endovascular repair.

PMID- 12431153
TI  - Restenting for subclavian in-stent restenosis with symptomatic recurrent coronary
      subclavian steal.
AB  - PURPOSE: To determine whether restenting for recurrent coronary-subclavian
      syndrome is technically feasible, provides durable results, and is a reasonable
      alternative to surgery. CASE REPORT: A 58-year-old woman with a left internal
      mammary artery (LIMA) bypass to the left anterior descending artery underwent
      angioplasty and stent placement for left subclavian stenosis and coronary
      subclavian steal. Twenty-three months later, she returned with progressive angina
      and left arm claudication; heart catheterization demonstrated restenosis of the
      subclavian artery at the stent site with recurrence of the coronary-subclavian
      steal. Successful redo angioplasty and stenting resulted in normal antegrade flow
      through the LIMA graft. The patient has remained asymptomatic for 3 years without
      evidence of recurrent in-stent stenosis on serial noninvasive studies.
      CONCLUSIONS: Restenting is technically feasible and appears to be a durable
      response to subclavian in-stent restenosis in patients with coronary subclavian
      steal.

PMID- 12431154
TI  - Fatal pericardial tamponade after Wallstent implantation for malignant superior
      vena cava syndrome.
AB  - PURPOSE: To report a rare, fatal complication of superior vena cava Wallstent
      implantation. CASE REPORT: A 59-year-old man presenting with superior vena cava
      syndrome caused by small-cell lung cancer underwent stent implantation of 2
      kissing Wallstents >1.5 cm above the right atrium. Despite correct stent
      deployment, vessel perforation occurred in a section not encased by tumor, which
      led to fatal pericardial tamponade shortly after the procedure. Autopsy revealed
      perforation of a stent strut through the caval wall into the pericardial space.
      Anatomical and methodological reasons are discussed. CONCLUSIONS: The
      interventionist should be aware of this rare complication. Alternative stent
      designs avoiding the sharp ends of Wallstents and Palmaz stents should be
      considered.

PMID- 12431155
TI  - Accidental small bowel perforation after antegrade femoral artery access for
      percutaneous thromboembolectomy and angioplasty.
AB  - PURPOSE: To report a rare complication of antegrade femoral access for
      percutaneous aspiration thromboembolectomy and transluminal angioplasty. CASE
      REPORT: A 73-year-old obese woman underwent antegrade femoral aspiration
      thromboembolectomy for lower limb arterial embolism. Fifteen hours later, she
      presented with acute abdomen and decreased hemoglobin. Computed tomography showed
      small bowel obstruction, incarcerated femoral hernia, and free peritoneal air and
      fluid suggesting bowel perforation. Emergent laparotomy revealed an incarcerated,
      perforated femoral bowel loop and 4-quadrant peritonitis. CONCLUSIONS: Femoral
      hernia injury is an exceptional complication of vascular interventions. Knowledge
      of this potential hazard may help to avoid its occurrence.

PMID- 12431156
TI  - Percutaneous stent-graft repair of mycotic common femoral artery aneurysm.
AB  - PURPOSE: To report successful percutaneous repair of a peripheral mycotic
      aneurysm as a bridge to standard surgical therapy. CASE REPORT: An aneurysm of
      the left common femoral artery was diagnosed in a 43-year-old man with subacute
      infective endocarditis. A Jostent stent-graft was percutaneously deployed to
      exclude the mycotic lesion. Computed tomography at 8 months after the procedure
      documented aneurysm regression and stent-graft patency without evidence of
      infection. Arteriography at 18 months has confirmed continued stent-graft patency
      and the patient remains asymptomatic. CONCLUSIONS: The standard management of
      mycotic aneurysms is usually by surgical resection and repair. However, this case
      suggests that percutaneous stent-graft implantation may be an option for the
      treatment of mycotic aneurysms.

PMID- 12431157
TI  - Endovascular aneurysm exclusion along a femorodistal venous bypass in active
      Behcet's disease.
AB  - PURPOSE: To report the endovascular repair of dual aneurysms along a femorodistal
      venous bypass graft in a patient with Behcet's disease. CASE REPORT: A 55-year
      old man of middle European ancestry with Behcet's disease had dual aneurysms
      evolve along the proximal segment of a femorodistal venous bypass that had been
      implanted 2.5 years earlier for recurrent false aneurysm formation. Owing to the
      lack of suitable venous conduits and the active nature of the disease, the
      aneurysms were successfully excluded with overlapping Hemobahn and Jostent
      endografts; the immunosuppressive therapy was intensified. Rupture of the
      aneurysms was successfully prevented, but the stent-grafts thrombosed 6 weeks
      later owing to exacerbation of the underlying disease. CONCLUSIONS: Endovascular
      exclusion of aneurysm in venous bypass grafts in Behcet's disease is feasible.
      Although the stent-grafts thrombosed, they did prevent rupture of the aneurysms.

PMID- 12431158
TI  - Twin pregnancy following endoluminal exclusion of an iliac arteriovenous fistula.
AB  - PURPOSE: To demonstrate the sustained efficacy of stent-graft exclusion of a
      pelvic arteriovenous fistula (AVF) in a woman who became pregnant after
      treatment. CASE REPORT: An iatrogenic iliac arteriovenous fistula caused by redo
      surgery for a herniated disk in a 23-year-old woman was successfully treated with
      percutaneous endoluminal exclusion. Intravascular ultrasound was particularly
      useful for localization of the fistula during the procedure. The patient
      subsequently became pregnant, and serial Doppler studies were used to monitor the
      stent-graft until the uneventful delivery of twins by Caesarian section. At 36
      months after endograft implantation, the patient has no complaints relative to
      the device. CONCLUSIONS: Uncomplicated twin pregnancy following stent-graft
      repair of an AVF in the pelvis appears feasible.

PMID- 12431159
TI  - Hematoma after percutaneous transpopliteal stenting and remote suturing of the
      popliteal artery.
AB  - PURPOSE: To present a case of extensive thigh hematoma that developed after use
      of a percutaneous suturing device for retrograde popliteal artery puncture. CASE
      REPORT: A 55-year-old woman underwent endovascular treatment for a short
      occlusion of the right superficial femoral artery via a retrograde popliteal
      approach, after which the puncture site was closed with a Closer suture-mediated
      device. Several hours later, massive hematoma of the right thigh developed, which
      was noticed only after the patient's leg became markedly swollen and hypotension
      developed. CONCLUSIONS: The use of a suture-mediated closure device for a
      retrograde popliteal artery puncture may not be recommended.

PMID- 12431160
TI  - Type I endoleaks: is aneurysm rupture risk dependent on the presence of type II
      endoleaks?

PMID- 12431161
TI  - Research training in otolaryngology: an impending crisis?

PMID- 12431162
TI  - What have you done for you lately?

PMID- 12431163
TI  - Children with cystic fibrosis: who should visit the otorhinolaryngologist?
AB  - BACKGROUND: Sinonasal complications are common in children with cystic fibrosis
      (CF). Generally, those children with persistent symptoms of sinonasal polyposis
      are referred to an otorhinolaryngologic (ORL) physician for sinus surgery.
      Several studies have reported differences in clinical characteristics between CF
      patients with and without sinonasal polyps. OBJECTIVES: To predict the presence
      of sinonasal polyposis in children with CF on the basis of symptoms and clinical
      characteristics and so to select those children who might benefit from referral
      to an ORL physician. DESIGN, SETTING, AND PATIENTS: Survey of data from a
      database on the results of yearly multidisciplinary examinations of 140 children
      with CF. MAIN OUTCOME MEASURE: Presence of sinonasal polyposis. RESULTS: In the
      total population of 140 children, no combination of ORL symptoms and clinical
      characteristics could accurately predict the presence of sinonasal polyposis. In
      a subgroup of 73 children with a history of nasal symptoms, independent
      predictors for the presence of sinonasal polyposis were male sex, age 10 years or
      older, presence of rhinorrhea, and a forced vital capacity 70% or more of the
      predicted value. The area under the receiver operating characteristic curve of a
      scoring rule including these independent predictors was 0.77. The positive and
      negative predictive values of this rule were 0.86 and 0.71, respectively.
      CONCLUSION: A scoring rule including the independent predictors sex, age,
      symptoms of rhinorrhea, and forced vital capacity values could reasonably
      classify children with CF and nasal symptoms into a category with increased risk
      for sinonasal polyposis, thus facilitating the decision on ORL referral.

PMID- 12431164
TI  - Indications for tracheotomy in the pediatric intensive care unit population: a
      pilot study.
AB  - OBJECTIVE: To define the indications for tracheotomy in patients requiring
      prolonged intubation (>1 week) in the pediatric intensive care unit (PICU).
      DESIGN: Retrospective chart review and follow-up telephone survey. SETTING: A
      tertiary care center PICU. OUTCOME MEASURE: Tracheotomy or extubation. PATIENTS:
      All patients older than 30 days in the PICU intubated for longer than 1 week
      between 1997 and 1999. RESULTS: During the study, 63 total admissions required
      intubation for longer than 1 week. A tracheotomy was necessary in 14% of
      admissions (n = 9). The mean length of intubation before the tracheotomy was 424
      hours, whereas the mean length of intubation without the need for tracheotomy was
      386 hours. Length of intubation, age, and number of intubations did not increase
      the probability of having a tracheotomy. Of those requiring a tracheotomy, 2 had
      tracheomalacia, 1 had subglottic edema, 1 had plastic bronchitis, 1 had Down
      syndrome with apnea resulting in right heart failure, 3 required long-term
      ventilation after cardiopulmonary collapse, and 1 had mitochondrial cytopathy. Of
      these 9 children, 7 were successfully decannulated, 1 patient died of underlying
      disease, and 1 patient remained cannulated secondary to the mitochondrial
      cytopathy. Twenty families of the patients who did not undergo a tracheotomy were
      reached by telephone after discharge. Most of the families reported that their
      children were free of stridor and hoarseness after extubation. CONCLUSIONS:
      Children tolerate prolonged intubation without laryngeal complications. The
      consideration for tracheotomy in the PICU setting must be highly individualized
      for each child.

PMID- 12431165
TI  - The utility of chest radiography following percutaneous dilational tracheotomy.
AB  - OBJECTIVE: To determine the need for routine chest radiography following
      percutaneous dilational tracheotomy (PDT). DESIGN: Retrospective chart review.
      SETTING: Tertiary care academic medical center. PATIENTS: The records of 119
      patients undergoing PDT between 1993 and 2000 for indications of prolonged
      intubation or need for pulmonary toilet. All patients received a portable chest
      radiograph immediately following the procedure. OUTCOME MEASURE: Incidence of
      postoperative pneumothorax or pneumomediastinum. RESULTS: One patient (0.8%)
      undergoing PDT experienced a postoperative pnuemothorax. This patient was noted
      to have respiratory distress within 10 minutes following the procedure,
      suggesting a pneumothorax. A postoperative chest radiograph confirmed the
      clinical impression. No asymptomatic patients were diagnosed as having a
      pnuemothorax or pneumomediastinum using postoperative chest radiography.
      CONCLUSIONS: Chest radiography following PDT is indicated when there are clinical
      findings suggesting pneumothorax or pneumomediastinum. Without clinical signs or
      symptoms, routine use of postoperative chest radiographs are unnecessary and not
      cost-effective.

PMID- 12431166
TI  - A cost-utility scenario analysis of bilateral cochlear implantation.
AB  - CONTEXT: Unilateral cochlear implantation is a cost-effective intervention for
      profound bilateral hearing loss. There is worldwide interest in providing
      implants bilaterally. OBJECTIVE: To use modeling to estimate the cost of gaining
      a quality-adjusted life-year by providing implants to both ears of profoundly
      postlingually deafened adults. DESIGN: Economic scenario analysis relating the
      costs of providing implants to estimates of the gain in health-related quality of
      life (utility) from unilateral and bilateral implantation. SETTING: Fourteen
      hospitals in the United Kingdom National Health Service and 1 Medical Research
      Council research unit. PARTICIPANTS: Normal-hearing adult volunteers with
      knowledge of implantation (n = 70). Adults undergoing unilateral implantation who
      either did not benefit from acoustic hearing aids preoperatively (type 1, n = 87)
      or benefited marginally (type 2, n = 115). MAIN OUTCOME MEASURES: Changes in
      utility from unilateral and bilateral implantation estimated with the time trade
      off technique (volunteers) and from unilateral implantation measured with the
      Mark II Health Utilities Index (patients); costs of providing implants and
      sustaining patients who have undergone implantation (health care perspective).
      RESULTS: Gains in utility from unilateral implantation estimated by volunteers
      did not differ significantly from gains recorded by patients, giving credibility
      to the volunteers' estimate of the gain from bilateral compared with unilateral
      implantation. Cost-utility ratios, in pounds sterling per quality-adjusted life
      year, based on volunteers' estimates, were pound 16,774 (type 1: unilateral
      implantation vs no intervention), pound 27,401 (type 2: unilateral implantation
      vs management with hearing aids), pound 61,734 (simultaneous bilateral
      implantation vs unilateral implantation), and pound 68,916 (provision of an
      additional implant vs no additional intervention). CONCLUSION: More quality of
      life is likely to be gained per unit of expenditure on unilateral implantation
      than bilateral implantation.

PMID- 12431167
TI  - Vagus nerve stimulator implantation in children.
AB  - BACKGROUND: Vagus nerve stimulation was approved in 1997 as an adjunctive
      treatment of partial-onset seizures refractory to medical therapy. Subsequent to
      the initial clinical trials, few studies have been published specifically
      addressing perioperative management issues. OBJECTIVES: To review the operative
      technique and perioperative management of patients undergoing vagus nerve
      stimulator implantation and to analyze complications and their management.
      DESIGN: Retrospective medical record review and survey of patients who underwent
      implantation. SETTING: A tertiary care pediatric hospital in Kansas City, Mo.
      PATIENTS: One hundred two patients aged 21 months to 40 years. INTERVENTION:
      Vagus nerve stimulator implantation and lead placement. MAIN OUTCOME MEASURES:
      The surgical technique of vagus nerve stimulator implantation is presented in
      detail. Perioperative complications are enumerated, and strategies for their
      management are described. A subjective patient survey addresses some quality-of
      life issues and the effect on swallowing and voice. RESULTS: One hundred two
      patients successfully underwent vagus nerve stimulator implantation. Three
      patients experienced infection of the chest wound holding the generator and
      required explantation. These 3 patients underwent reimplantation within 2 months
      after the infection had cleared. Most patients experience some degree of
      hoarseness when the generator is activated, but this symptom usually does not
      significantly affect the ability to communicate. Responses to questions regarding
      quality of life are positive. CONCLUSIONS: Vagus nerve stimulator implantation
      has a low incidence of serious complications. Quality of life seems to be
      improved for most patients. Modifications to the surgical procedure must be
      considered when performing the implantation on a young patient.

PMID- 12431168
TI  - Patient education and informed consent in head and neck surgery.
AB  - OBJECTIVE: To examine the effects of an educational intervention, in the form of
      printed material, on patient knowledge and recall of possible risks from
      parotidectomy or thyroidectomy. DESIGN: Prospective, randomized, controlled study
      conducted during a 9-month period. SETTING: Head and neck surgery clinic of an
      academic tertiary care hospital. PATIENTS: One hundred twenty-five consecutive
      patients older than 16 years who were undergoing thyroidectomy or parotidectomy
      at the head and neck surgery clinic were recruited. Four patients were excluded
      from analysis because their follow-up interview was not within the required
      limits. INTERVENTION: At the preoperative visit during the routine consent
      process, both groups received a verbally delivered checklist of risks specific
      for the surgery to be performed. The intervention group was also given a pamphlet
      with written information accompanied by illustrations. MAIN OUTCOME MEASURES: The
      effectiveness of the educational intervention was determined by comparing the
      average rate of risk recall between the intervention and control groups. The
      effects of age, sex, level of education, and time between the consent and recall
      interviews on recall rate were also assessed. RESULTS: The overall risk recall
      rate for both procedures was 39.1%. The recall rate of the intervention group was
      50.3% compared with 29.5% for the control group (P<.001). CONCLUSIONS: The
      intervention consistently improved risk recall for all patients regardless of
      age, sex, and level of education. Patients' ability to recall potential risks was
      significantly increased by an educational intervention; all patients would
      benefit from this intervention.

PMID- 12431169
TI  - Tumor above the spinal accessory nerve in papillary thyroid cancer that involves
      lateral neck nodes: a common occurrence.
AB  - OBJECTIVE: To describe the nature and extent of lateral neck node metastases from
      papillary thyroid cancer in relation to presenting physical examination and
      staging radiologic studies. DESIGN: Retrospective study. SETTING: Tertiary
      referral cancer center. PATIENTS: Consecutive patients who underwent
      comprehensive neck dissection with or without concurrent thyroidectomy for well
      differentiated thyroid cancer between 1991 and 2001. Excluded were patients with
      well-differentiated thyroid cancer diagnosed incidentally at the time of
      treatment of other primary head and neck cancer, those with previous neck
      dissection for nonthyroid malignancies, and those undergoing surgery for
      medullary thyroid cancer. INTERVENTIONS: All pathology and operative and
      preoperative radiology reports for patients undergoing comprehensive neck
      dissection for well-differentiated thyroid malignancy were reviewed. Data were
      collected on previous procedures, preoperative evaluation, operative details, and
      pathologic findings. MAIN OUTCOME MEASURE: Identification of metastatic thyroid
      cancer in one or more nodes in anatomically defined drainage basins of the
      central and lateral neck. RESULTS: A total of 51 neck dissections were performed.
      All patients had preoperative evidence of metastatic disease. In addition to the
      usual comprehensive node dissection encompassing all lymphatic tissue in levels
      II through V, level I nodes and level II nodes above the spinal accessory nerve
      were labeled as distinct regions in 16 (31%) and 34 (67%) specimens,
      respectively. Disease was confined to a single nodal level in 20 (39%) of 51
      specimens and was present in 4 or more levels in 7 (14%) of 50 neck dissections.
      There was cancer at 2 or 3 levels in 16 (31%) and 15 (29%) cases, respectively.
      Seven (21%) of the 34 patients undergoing separate analysis of nodes from above
      the spinal accessory nerve had cancer there. In 3 of the 34 it was the sole
      disease in level II. CONCLUSIONS: Tumor involvement at multiple nodal levels
      occurs in most cases when patients have lateral cervical node metastases. "Skip"
      metastases and cancer above the spinal accessory nerve are common. Neck
      dissections should include all node stations likely to be involved because
      selective node excision is likely to leave metastatic disease in situ.

PMID- 12431170
TI  - The role of parotid biopsy in the diagnosis of pediatric Sjogren syndrome.
AB  - OBJECTIVES: To describe our experience with primary and secondary Sjogren
      syndrome (SS) in the pediatric population and to evaluate the effectiveness of
      parotid gland biopsy in the diagnosis of pediatric SS. DESIGN: Case series review
      of 6 pediatric patients evaluated during a 4-year period with varied head and
      neck manifestations of SS. SETTING: Tertiary care children's hospital. PATIENTS:
      Six children (4 boys and 2 girls) ranging in age from 6 to 12 years, who were
      diagnosed as having primary or secondary SS. INTERVENTION: Six minor salivary
      gland and 4 parotid gland biopsies for pathologic examination. MAIN OUTCOME
      MEASURES: Pathologic examination of salivary tissue consistent with SS. RESULTS:
      All 6 patients underwent minor salivary gland biopsy, 2 (33%) were consistent
      with SS, while the remaining 4 (67%) were nondiagnostic. The 4 patients with
      nondiagnostic minor salivary gland biopsy results went on to have parotid
      biopsies, of which all 4 had histologic findings consistent with SS. No
      complications were encountered. CONCLUSION: Parotid gland biopsy is an effective
      and safe means of obtaining salivary gland tissue for histologic evaluation of SS
      in the pediatric population.

PMID- 12431171
TI  - Simple predictors of survival in head and neck squamous cell carcinoma.
AB  - OBJECTIVE: To develop a simple prognostic survival rule from easily obtained
      characteristics of patients undergoing potentially curative resection of head and
      neck squamous cell carcinoma using classification and regression trees. DESIGN:
      Inception cohort. SETTING: Tertiary care center. PATIENTS: Consecutive patients
      undergoing resection lasting at least 2 hours, from July 1993 through June 1997.
      MAIN OUTCOME MEASURE: Survival, age, TNM tumor stage, functional class, systolic
      and diastolic blood pressure, body mass index, and serum albumin concentration
      were evaluated as predictors. RESULTS: Four hundred six patients were followed up
      for 5 to 1446 days (median, 391 days), during which time 172 deaths occurred.
      Median survival was 687 days. Patients with TNM stage I, II, or III squamous cell
      carcinoma had a mean survival of 1068 days. Patients with TNM stage IV or
      recurrent disease were further stratified. Those with a serum albumin
      concentration less than 3.85 g/dL had a median survival of 404 days (95%
      confidence interval, 286-532 days), and those with an serum albumin concentration
      of 3.85 g/dL or above had a median survival of 625 days (95% confidence interval,
      536-1032 days). A similar survival was found using age younger than 66.5 years as
      a predictor instead of serum albumin concentration less than 3.85 g/dL.
      CONCLUSIONS: At our institution, patients with stage I, II, or III squamous cell
      carcinoma had a mean survival of approximately 3 years. Those with stage IV or
      recurrent squamous cell carcinoma could be stratified by either serum albumin
      concentration or by age into 2 groups with a median survival of 1 or 2 years.

PMID- 12431172
TI  - The use of sentinel node biopsy to upstage the clinically N0 neck in head and
      neck cancer.
AB  - OBJECTIVE: To investigate the possible role of sentinel node biopsy (SNB) alone
      to upstage the clinically N0 neck in patients with oral and oropharyngeal
      squamous cell carcinoma. DESIGN: Prospective clinical study. SETTING: Head and
      neck referral center. PATIENTS: Patients with primary untreated oral and/or
      oropharyngeal squamous cell carcinoma accessible to injection and with clinically
      N0 necks were enrolled in the study. INTERVENTION: An SNB was performed after
      radiocolloid and blue dye injection. Preoperative lymphoscintigraphy and the
      perioperative use of a gamma probe identified radioactive sentinel nodes and
      visualization of blue-stained lymphatics identified blue sentinel nodes. If the
      sentinel node was found negative, there was no further treatment to the neck. If
      the sentinel node tested positive, a therapeutic neck dissection was performed.
      All patients underwent regular follow-up at the outpatient clinic to identify
      possible recurrence. MAIN OUTCOME MEASURES: Upstaging of the clinically N0 neck
      by SNB and development of subsequent disease in SNB-negative necks. RESULTS: An
      SNB was performed on 57 clinically N0 necks in 48 patients. Sentinel nodes were
      harvested in 43 (90%) of 48 patients. Fifteen (35%) of 43 patients were upstaged
      by SNB and 28 (65%) of 43 were staged SNB negative. There was a mean follow-up of
      18 months. One patient developed subsequent disease after having been staged
      negative with SNB. The overall sensitivity of the procedure using the full
      pathologic protocol was 94% (15/16). CONCLUSIONS: Sentinel node biopsy can be
      used to upstage the N0 neck in patients with early subclinical nodal disease.
      However, before it becomes the standard of care in head and neck squamous cell
      carcinoma, longer follow-up observational trials are needed.

PMID- 12431173
TI  - Correlation of presentation and pathologic condition in primary ciliary
      dyskinesia.
AB  - OBJECTIVES: To better characterize primary ciliary dyskinesia (PCD) and improve
      the diagnosis of this uncommon disorder. STUDY DESIGN AND SETTING: We
      retrospectively reviewed the records of 118 patients with ciliary biopsy or
      brushing specimens examined at Yale University School of Medicine from 1991 to
      2001. RESULTS: Sinonasal, middle ear, and pulmonary infections were more common
      in patients with PCD-positive biopsy results than in those with negative results.
      In addition, PCD caused by random ciliary orientation presented similarly to PCD
      caused by other ultrastructural defects. CONCLUSIONS: Patients who present with
      cough alone are highly unlikely to have PCD (chi(2 ) test, 24.85; P<.001). In
      contrast, patients who present with multiple manifestations are highly likely to
      have PCD (chi(2) test, 22.2; P<.001). This information may assist the clinician
      in the diagnosis of PCD.

PMID- 12431174
TI  - Cytokine profile of chronic sinusitis in patients with cystic fibrosis.
AB  - BACKGROUND: The inflammatory-cell and cytokine profiles of chronic sinusitis (CS)
      are well documented in the literature. In contrast, little is known about the
      pathogenesis of this condition in patients with cystic fibrosis (CF). OBJECTIVE:
      To determine whether patients with CF have inflammatory-cell and cytokine
      profiles that differ from other patients with CS. METHODS: Patients with CF (n =
      7) and adults with CS (n = 7) undergoing functional endoscopic sinus surgery were
      recruited for the study. Patients with no allergies or sinus disease (n = 6) were
      used as controls. Using immunohistochemical analysis, we assessed sinus mucosal
      specimens for the presence of T lymphocytes, eosinophils, macrophages, and
      neutrophils. Using in situ hybridization, we assessed the expression of
      interleukin (IL) 4, IL-5, IL-8, IL-10, and interferon gamma. RESULTS: There was a
      higher number of neutrophils, macrophages, and cells expressing messenger RNA for
      interferon gamma and IL-8 in patients with CF than in patients with CS or in
      controls (P<.01). The number of eosinophils and cells expressing messenger RNA
      for IL-4, IL-5, and IL-10 was higher in patients with CS than in those with CF
      and controls (P<.01). CONCLUSIONS: Sinus disease in patients with CF presents
      different inflammatory-cell and cytokine profiles than that seen in other
      patients with CS. These results may explain the difference in response to
      treatment in the CF group.

PMID- 12431175
TI  - Incidence of occult cerebrospinal fluid fistula during paranasal sinus surgery.
AB  - OBJECTIVE: To determine the incidence of occult cerebrospinal fluid fistulas
      after endoscopic paranasal sinus surgery. DESIGN: Prospective diagnostic test
      study with a 6-month follow-up in case of cerebrospinal fluid detection. SETTING:
      Tertiary care hospital. SUBJECTS: The study population comprised 69 patients
      undergoing routine endoscopic paranasal sinus surgery. Patients with an obvious
      intraoperative or postoperative cerebrospinal fluid fistula were not included.
      INTERVENTION: Analysis of 112 samples from intraoperative applied tamponades and
      of 69 serum samples using a nephelometric research assay for beta-trace protein
      (prostaglandin D synthase). MAIN OUTCOME MEASURES: Incidence of occult
      cerebrospinal fluid fistula during endoscopic paranasal sinus surgery as
      indicated with the help of a test for beta-trace protein; at least a 6-month
      follow-up of patients with an occult cerebrospinal fluid fistula; and relation of
      occult cerebrospinal fluid fistula with surgical experience of the surgeon.
      RESULTS: Beta-trace protein was found in ethmoid roof samples from 2 patients,
      giving an incidence of 2.9% for occult cerebrospinal fluid fistula. Both patients
      were operated on by very experienced surgeons. Signs of a cerebrospinal fluid
      fistula were not found at follow-up at least 6 months after surgery. CONCLUSIONS:
      Nephelometric beta-trace protein assay is a highly sensitive method to detect
      otherwise unobserved cerebrospinal fluid fistulas. The clinical course of the 2
      patients with an occult cerebrospinal fluid fistula indicated the possibility of
      an uneventful follow-up of patients with small fistulas.

PMID- 12431176
TI  - Ocular findings in children with congenital sensorineural hearing loss.
AB  - OBJECTIVE: To examine the yield of ophthalmologic examination in the diagnostic
      workup of unexplained sensorineural hearing loss (SNHL) in children. DESIGN:
      Retrospective analysis of ophthalmologic findings in children with unilateral or
      bilateral SNHL between January 1998 and May 2000. SETTING: Tertiary care
      university hospital. PARTICIPANTS: Children 18 years or younger presenting with
      unilateral or bilateral SNHL. OUTCOME MEASURES: Ophthalmologic findings. RESULTS:
      Of the 49 patients with SNHL for whom ophthalmologic examination results were
      available, 15 (31%) had ocular abnormalities. Hyperopia was the most common
      abnormality, present in 7 patients (46%). Myopia was found in 2 patients (13%)
      and astigmatism in 1 (2%). Two other patients had multiple abnormalities: one
      with hyperopia and astigmatism and the other with myopia and astigmatism. The
      remaining 4 patients had the following abnormalities: Lisch nodules, esotropia,
      ptosis, and allergic conjunctivitis. As a result of ophthalmologic examination, 5
      interventions were performed in 4 children: 2 children received prescription
      lenses; 2 children underwent surgery; and 1 child was treated with eyedrops.
      Ophthalmologic examination in 2 children contributed to the diagnosis of a
      hearing loss syndrome. CONCLUSION: In children with SNHL, ophthalmologic
      examination is useful in evaluating visual acuity and determining or confirming
      the cause of hearing impairment.

PMID- 12431177
TI  - Hearing loss and changes in transient evoked otoacoustic emissions after gamma
      knife radiosurgery for acoustic neurinomas.
AB  - OBJECTIVE: To evaluate the neuro-otological effects of gamma knife radiosurgery
      in patients with acoustic neurinoma. DESIGN: Prospective study. SETTING:
      University hospital in Milan, Italy. PATIENTS: Thirty consecutive patients with
      acoustic neurinoma who underwent gamma knife radiosurgery. INTERVENTION: Gamma
      knife radiosurgery. MAIN OUTCOME MEASURES: Results of neuro-otological tests,
      including pure-tone audiometry, auditory brainstem responses, and transient
      evoked otoacoustic emissions, during a 2-year follow-up. RESULTS: Three patients
      showed slight tumor growth, 1 complained of a transient facial disturbance, and 5
      complained of mild trigeminal disturbances. Seven of the 26 patients with a
      measurable threshold before radiosurgery experienced a 2-year decrease of more
      than 20 dB in at least 1 hearing level, and 2 of these became deaf in the
      affected ear. The analysis of auditory brainstem responses showed no significant
      increase in mean wave V latency after radiosurgery, but intensity of transient
      evoked otoacoustic emissions worsened in 9 of the 12 patients who had them before
      treatment. A statistically significant correlation was found between the 2-year
      decrease in low-tone average, pure-tone average, and high-tone average hearing
      levels and the 2-year decrease in transient evoked oacoustic emissions (P<.001, P
      =.008, and P<.001, respectively), and between the 2-year decrease in high-tone
      average hearing and the maximal cochlear dose (P =.03). CONCLUSIONS: Although
      most patients had only a slight fluctuation of their hearing threshold after
      gamma knife radiosurgery, several experienced a remarkable hearing worsening.
      Hearing impairment was found to be mainly due to cochlear irradiation and maximal
      cochlear dose, which was correlated to hearing loss.

PMID- 12431178
TI  - Idiopathic inflammatory medial meatal fibrotizing otitis.
AB  - BACKGROUND: Idiopathic inflammatory medial meatal fibrotizing otitis (IMFO) is
      rare. Only a few cases with unknown cause have been reported. OBJECTIVE: To
      report 3 cases of IMFO as a specific diagnostic entity. PATIENTS AND METHODS: Two
      adults and 1 child with bilateral IMFO were observed for several years at the
      Department of Otorhinolaryngology of Helsinki University Hospital, Helsinki,
      Finland. RESULTS: Only the osseous part of the external ear canals was affected
      by IMFO. The skin and skin organs over the lateral cartilage of the ear canals
      remained rigorously and constantly uninflamed through the active, relentless
      progression of the disease over several years, resulting in the formation of a
      fibrous plug of the medial meatal canal. The middle ears and mastoid air cells
      were not affected during the active inflammatory phase. CONCLUSION: IMFO has its
      own specific pathophysiologic characteristics, and perhaps also etiopathologic
      characteristics, which are still unknown.

PMID- 12431179
TI  - Laryngeal duplication cyst.
AB  - Benign congenital laryngeal cysts are rare. Infants and children with these
      lesions can present with chronic or intermittent airway obstructive symptoms,
      hoarseness, aspiration, chronic cough, or failure to thrive. The most common
      congenital laryngeal cysts include saccular cysts, laryngoceles, and ductal
      cysts. Other more unusual laryngeal lesions, such as hamartomas, choristomas, and
      teratomas, can also present with these symptoms. We describe a unique congenital
      cyst that arose in continuity with the larynx in a child with hoarseness and
      intermittent stridor. The features of this lesion are similar to those of
      bronchogenic duplication cysts of the trachea, but with histopathological
      features of the larynx.

PMID- 12431180
TI  - Neonatal lingual choristoma with respiratory and gastric epithelium.
AB  - Lingual choristomas are rare entities that typically present as benign cystic
      masses that are lined with a variety of heterotopic epithelia. Lingual
      choristomas that are lined with respiratory and/or gastric or intestinal mucosa
      are believed to derive from pluripotential cells of the embryonic foregut. We
      describe a neonate with a lingual cyst that was lined predominantly by
      respiratory epithelium and focally by gastric foveolar epithelium, and we review
      the terminology, etiology, and management of lingual cysts of presumed foregut
      origin.

PMID- 12431181
TI  - Pathology quiz case 1. Intraparotid facial schwannoma.

PMID- 12431182
TI  - Pathology quiz case 2. Extranodal natural killer (NK)/T-cell lymphoma (Epstein
      Barr virus associated).

PMID- 12431183
TI  - Radiology quiz case 1. Vascular leiomyoma of the larynx.

PMID- 12431184
TI  - Radiology quiz case 2. Nasopharyngeal lipoma.

PMID- 12431185
TI  - Age-related changes in the composition, the molecular stoichiometry and the
      stability of proteoglycan aggregates extracted from human articular cartilage.
AB  - The heterogeneity of the components of proteoglycan aggregates, their
      stoichiometry within the aggregate and the aggregates' stability was investigated
      in normal human articular cartilage specimens (age-range newborn to 63 years).
      Proteoglycans were extracted from tissue by sequentially extracting them with PBS
      alone, PBS containing oligosaccharides of hyaluronan, and PBS containing
      solutions of increasing guanidinium chloride concentration (1 M, 2 M, 3 M and 4
      M). A high proportion of each of the components of the proteoglycan aggregate,
      i.e. uronic acid, sulphated glycosaminoglycan, hyaluronan binding domain of
      aggrecan (G1-domain), link protein (LP) and hyaluronan, was extracted from
      immature cartilage by PBS alone and PBS containing oligosaccharides of
      hyaluronan. This was in marked contrast to adult cartilage, which required high
      concentrations of guanidinium chloride for the efficient extraction of these
      components. The molar ratios of total G1-domain:LP and the G1-domain associated
      with aggrecan:LP also differed markedly between immature and mature cartilage and
      between each of the sequential extracts. The concentration of LP was less than
      that of the G1-domain in all extracts of cartilage from individuals over 13
      years, but this was particularly noticeable in the 1 M guanidinium chloride
      extracts, and it was surmised that a deficiency in LP produces unstable
      aggregates in situ. The fragmentation of LP, which is known to occur with
      advancing age, did not influence the extractability of LP, and fragments were
      present in each of the sequential extracts. Therefore the generally accepted
      model of proteoglycan aggregation presented in the literature, which is mostly
      derived from analysis of immature animal cartilage, cannot be used to describe
      the structure and organization of aggregates in adult human articular cartilage,
      where a heterogeneous population of complexes exist that have varying degrees of
      stability.

PMID- 12431186
TI  - Evidence for involvement of 3'-untranslated region in determining angiotensin II
      receptor coupling specificity to G-protein.
AB  - The mRNA 3'-untranslated region (3'-UTR) of many genes has been identified as an
      important regulator of the mRNA transcript itself as well as the translated
      product. Previously, we demonstrated that Chinese-hamster ovary-K1 cells stably
      expressing angiotensin receptor subtypes (AT(1A)) with and without 3'-UTR
      differed in AT(1A) mRNA content and its coupling with intracellular signalling
      pathways. Moreover, RNA mobility-shift assay and UV cross-linking studies using
      the AT(1A) 3'-UTR probe identified a major mRNA-binding protein complex of 55 kDa
      in Chinese-hamster ovary-K1 cells. In the present study, we have determined the
      functional significance of the native AT(1A) receptor 3'-UTR in rat liver
      epithelial (WB) cell lines by co-expressing the AT(1A) 3'-UTR sequence 'decoy' to
      compete with the native receptor 3'-UTR for its mRNA-binding proteins. PCR
      analysis using specific primers for the AT(1A) receptor and [(125)I]angiotensin
      II (AngII)-binding studies demonstrated the expression of the native AT(1A)
      receptors in WB (B(max)=2.7 pmol/mg of protein, K(d)=0.56 nM). Northern-blot
      analysis showed a significant increase in native receptor mRNA expression in 3'
      UTR decoy-expressing cells, confirming the role of 3'-UTR in mRNA
      destabilization. Compared with vehicle control, AngII induced DNA and protein
      synthesis in wild-type WB as measured by [(3)H]thymidine and [(3)H]leucine
      incorporation respectively. Activation of [(3)H]thymidine and [(3)H]leucine
      correlated with a significant increase in cell number (cellular hyperplasia). In
      these cells, AngII stimulated GTPase activity by AT(1) receptor coupling with G
      protein alpha i. We also delineated that functional coupling of AT(1A) receptor
      with G-protein alpha i is an essential mechanism for AngII-mediated cellular
      hyperplasia in WB by specifically blocking G-protein alpha i activation. In
      contrast with wild-type cells, stable expression of the 3'-UTR 'decoy' produced
      AngII-stimulated protein synthesis and cellular hypertrophy as demonstrated by a
      significant increase in [(3)H]leucine incorporation and no increase in
      [(3)H]thymidine incorporation and cell number. Furthermore, [(125)I]AngII cross
      linking and immunoprecipitation studies using specific G-protein alpha antibodies
      showed that in wild-type cells, the AT(1A) receptor coupled with G-protein alpha
      i, whereas in cells expressing the 3'-UTR 'decoy', the AT(1A) receptor coupled
      with G-protein alpha q. These findings indicate that the 3'-UTR-mediated changes
      in receptor function may be mediated in part by a switch from G-protein alpha i
      to G-protein alpha q coupling of the receptor. Our results suggest that the 3'
      UTR-mediated post-transcriptional modification of the AT(1A) receptor is critical
      for regulating tissue-specific receptor functions.

PMID- 12431188
TI  - Which conference should I attend?

PMID- 12431187
TI  - Identification and characterization of G beta 3s2, a novel splice variant of the
      G-protein beta 3 subunit.
AB  - The T-allele of a polymorphism (C825T) in the gene for the G-protein beta 3
      subunit (GNB3) is associated with cardiovascular and metabolic disorders,
      distinct cellular features and altered drug responses. The molecular mechanisms
      that give rise to this complex phenotype have been linked to the occurrence of G
      beta 3s, a splice variant of GNB3. G beta 3s is predominantly expressed in cells
      with the 825T-allele. In the present study we describe the identification and
      characterization of an additional G beta 3 splice variant referred to as G beta
      3s2. Its mRNA is expressed in heart, blood cells and tumour tissue, and its
      expression is also tightly associated with the GNB3 825T-allele. G beta 3s2 is
      generated by alternative splicing using non-canonical splice sites. G beta
      subunits belong to the family of propeller proteins and consist of seven regular
      propeller blades. Transcripts for G beta 3s2 are lacking 129 bp of the coding
      sequence of the wild-type G beta 3 protein. Thus the predicted structure consists
      of only six propeller blades, which resembles the structure of G beta 3s. Co
      immunoprecipitation analyses indicated that G beta 3s2 dimerizes with different G
      gamma subunits, e.g. G gamma 5, G gamma 8(C) and G gamma 12. In Sf9 insect cells,
      expression of G beta 3s2 together with G gamma 12 enhances receptor-stimulated
      activation of G alpha(i2). Expression of G beta 3s2 in mammalian cells activated
      the mitogen-activated protein kinase cascade. Together, these results suggest
      that G beta 3s2 is a biologically active G beta variant which may play a role in
      the manifestation of the complex phenotype associated with the 825T-allele.

PMID- 12431189
TI  - Functional symptoms confused with allergic disorders in children and adolescents.
AB  - The diagnosis of a functional respiratory disorder is sometimes difficult and
      time-consuming, because the symptoms often resemble those of organic diseases.
      The most common entities are hyperventilation syndrome, psychogenic cough,
      sighing dyspnea, and vocal cord dysfunction. Typical signs are heavy breathing or
      dyspnea, cough or sneezing, various breathing sounds, tightness of the throat or
      chest, pain, and fear. Criteria for differentiation include the lack of nocturnal
      symptoms, the sudden occurrence, no typical trigger factors, the variable
      duration, a quick regression, and that symptoms do not respond to adequate
      pharmacotherapy and finally normal results of diagnostic work-up. Therapeutic
      options comprise psychological intervention (by reassurance, relaxation
      techniques, and behaviour therapy) and physiotherapy (e.g. breathing therapy,
      voice training). Intensive efforts should be made to diagnose functional symptoms
      at an early stage because this will prevent stigmatization and fixation of
      symptoms and disease, and also prevent children from undergoing unnecessary and
      potentially harmful therapies.

PMID- 12431190
TI  - Expression of CD64 as a potential marker of neonatal sepsis.
AB  - The aim of this study was to identify a novel immunological indicator useful for
      the early diagnosis (through a rapid and single determination) of neonatal sepsis
      (NS). Peripheral blood samples were taken from 63 neonates, who were classified
      into four groups: proven NS (n = 17); clinical NS (n = 14); disease without
      infection (n = 17); and healthy newborns (n = 15). Neutrophil expression of CD64,
      CD43, CD44, CD50, CD62L and Mac-1, and plasma levels of interleukin (IL)-1beta,
      IL-6, tumor necrosis factor-alpha (TNF-alpha) and soluble L-selectin (sCD62L),
      were determined. Expression of CD64 was significantly enhanced in the group with
      proven sepsis and clinical NS compared to newborns without infection (p < 0.05).
      Eight newborns with proven or clinical sepsis, but only one with disease without
      infection, showed an increased percentage of CD64+ cells (diagnostic specificity
      = 96.8%). No significant differences were found in the expression of the other
      leucocyte differentiation antigens studied. As previously described, TNF-alpha
      and IL-6 levels were significantly elevated in newborns with proven or clinical
      sepsis compared to neonates without infection (p < 0.05). Our results suggest
      that, through a single determination, the enhanced expression of CD64 is a highly
      specific indicator of NS, although its diagnostic sensitivity is low (25.8%). In
      contrast, we found that plasma levels of IL-1beta and sCD62L, as well as the
      expression of Mac-1, CD43, CD44, CD50, and CD62L, do not appear to be useful for
      the diagnosis of NS.

PMID- 12431191
TI  - Serum immunoglobulin E levels in human immunodeficiency virus-infected children
      with pneumonia.
AB  - Elevated serum immunoglobulin E (IgE) levels have been reported in association
      with human immunodeficiency virus (HIV) infection in adults, but there is little
      information in children. The aim of the present study was to compare serum IgE
      levels in HIV-positive and -negative children hospitalized with pneumonia in
      South Africa and to investigate whether IgE may be useful as a marker of specific
      infections or prognosis in HIV-infected children. History, examination, blood
      tests, and induced sputum or bronchoalveolar lavage were carried out. Of 122
      children [45% female, median age 8 months (3-20 months)], 81 were infected with
      HIV. A history of allergy or asthma was present in three children (two of whom
      were HIV positive). Serum IgE was higher in HIV-infected children [83 (33-147)
      vs. 29 (6-113) IU/l; p = 0.011] as was immunoglobulin G (IgG) [49 (37-63) vs.
      27.5 (23-34) g/l; p < 0.001]. CD4 lymphocytes [600 (330-1,210) vs. 1,900 (1,500
      3,030) cells/ micro l], percentage CD4 cells [13.6 (9.4-20.3) vs. 40.1 (31.1
      44.9)] and CD4 : CD8 ratio [0.3 (0.2-0.4) vs. 2 (1.4-2.8)] were lower in HIV
      positive children (p < 0.001 for all). Bacteremia occurred in 12 (10%) children;
      other specific pathogens identified included Mycobacterium tuberculosis in eight
      (7%) and Pneumocystis carinii in nine (7%). There was no correlation with CD4
      count, CD4 : CD8 ratio, or the presence of specific pathogens, and IgE level. In
      hospital mortality (11%) did not correlate with IgE levels. HIV-infected children
      with pneumonia have higher serum IgE compared with seronegative patients. In HIV
      positive children, IgE levels did not correlate with the degree of
      immunosuppression or with outcome.

PMID- 12431192
TI  - Exposure to pets and allergies in children.
AB  - Currently, there is ongoing discussion regarding potential protective effects of
      exposure to pets during early childhood on the development of atopic disorders in
      children later in life. We used data from three consecutive cross-sectional
      surveys to study the relationship between contact with dogs, cats and other pets,
      and allergic diseases in schoolchildren 5-14 years of age. In three study areas
      of the former East Germany, 7,611 questionnaires were received from 5,360
      different children who were examined between 1992 and 1999 as school entrants, or
      third- or sixth-graders. Allergic sensitization to common aeroallergens (birch,
      grass, mite, cat) was assessed by specific serum immunoglobulin E (IgE)
      concentrations [using radioallergosorbent testing (RAST)] for 85% of the
      children. After adjustment for possible confounders, inverse associations were
      found between contact with dogs in the first year of life and lifetime
      prevalences of asthma [odds ratio (OR) = 0.68; 95% confidence interval (CI): 0.43
      1.08], hay fever (OR = 0.61; 95% CI: 0.39-0.95), eczema (OR = 0.76; 95% CI: 0.61
      0.94), itchy rash (OR = 0.76; 95% CI: 0.61-0.94), and pollen sensitization (RAST
      >/= 4: OR = 0.56; 95% CI: 0.38-0.82). These effects were more pronounced for
      children with atopic parents. Similar associations were observed for current
      contact with dogs. We identified no clear relationships for the other pets (cats,
      rodents, birds), with the exception that children currently exposed to cats were
      more likely to be sensitized against cats. In conclusion, this study supports the
      hypothesis of a potential protective mechanism related to dog exposure in early
      life, especially for children of atopic parents. However, this association was
      found only for dogs and not for cats.

PMID- 12431193
TI  - Epidemiological studies of the very high prevalence of asthma and related
      symptoms among school children in Costa Rica from 1989 to 1998.
AB  - The aim of our study was to determine the prevalence of asthma and related
      respiratory symptoms in school children from Costa Rica during the last 10 years,
      from 1989 to 1998. Using nationally representative samples of school children
      from Costa Rica during the last 10 years we have performed three studies.
      Altogether 9,931 children were investigated. The age groups: study I, 5-17 years
      (n = 2,682), study II, 6-7 years (n = 2,944), 13-14 years (n = 3,200) and study
      III, 10 years (n = 1,105). The diagnostic criteria for asthma used in these
      studies was as follows: study I (1989), diagnosis by a doctor in combination with
      the presence of four kinds of respiratory symptoms; studies II (1995) and III
      (1998), history of wheeze in the past 12 months. The two latter were part of the
      International Study of Asthma and Allergies in Childhood (ISAAC). A very high
      prevalence of a history of wheezing was found in the three studies (46.8%, 42.9%,
      and 45.1%) as well as a diagnosis of asthma (23.4%, 27.7% and 27.1%). The
      physician's diagnosis of asthma reported in the first study (23%) increased from
      23.1 in study II to 27.7% in study III (p = 0.004). This increment could be a
      real increase in asthma prevalence, or be due to a better awareness about asthma.
      In study II the group of 6-7-year-olds had respiratory symptoms significantly
      more often than 13-14-year-olds (p < 0.001). Boys more often had a history of
      wheezing (p = 0.001), wheeze during the previous 12 months (p = 0.01) and an
      asthma diagnosis at the age of 6-7 years (p = 0.002) than girls, but girls had
      more respiratory symptoms than boys at the age of 13-14 years (p < 0.005).
      Wheezing in the past 12 months was more common for those living in urban areas
      aged 6-7 years (p = 0.04), and there was an increase of wheeze after exercise (p
      = 0.01). For the 13-14-year-olds the risk of wheezing was higher during the
      previous 12 months if they lived in temperate areas (<20 degrees C) and at a high
      altitude (>1,000 m). Living in a rural area and in a warm region (>20 degrees C),
      increased the risk of dry cough during the previous 12 months in the group of 13
      14-year-olds. In conclusion, Costa Rica is located in the tropics with a very
      high humidity, an enormous variety of flora and fauna and a very high prevalence
      of mite and cockroach allergens, which provide important risk factors that may
      explain the high prevalence of asthma and asthma-related symptoms. Further
      possible factors, such as the change towards a more Western life style, resulting
      in fewer infections and parasitic diseases in the first years of life and changes
      in bedding material, may also be unresolved. Increased environmental pollution
      may add to the very high prevalence of asthma and related respiratory symptoms.
      The very extensive exposure to mites and cockroaches in bed material and in homes
      with poor ventilation may be an important factor, but many asthmatic children
      behave as non atopic, with a viral respiratory infection as a major precipitating
      factor.

PMID- 12431195
TI  - Clostridium difficile, atopy and wheeze during the first year of life.
AB  - Differences have been suggested to occur in the composition of intestinal
      microflora from allergic and non-allergic children. In this study we used a semi
      quantitative enzyme-linked immunosorbent assay (ELISA) for the measurement of
      Clostridium difficile-specific immunoglobulin G (IgG) (CDIgG). CDIgG was
      excellent in differentiating between adults with or without Cl. difficile colitis
      (absorbance levels, positive vs. negative controls: geometric mean (GM) 0.301,
      95% CI: 0.289-0.314 vs. GM 0.167, 95% CI: 0.155-0.181; mean difference 1.8-fold,
      95% CI: 1.65-1.95; p < 0.0001). We used this technique to investigate whether
      there are any differences between atopic wheezy infants and non-atopic non-wheezy
      controls. In a prospective cohort study (n = 390) 10 patients were identified at
      1 year of age (atopic, history of recurrent wheeze) and matched (gender, month of
      birth, exposure to Der p 1, Fel d 1 and Can f 1) with a control group of infants
      (non-atopic, no history of wheeze). The patients had significantly higher Cl.
      difficile-specific IgG absorbance levels (GM 0.298, 95% CI: 0.249-0.358) compared
      with controls (GM 0.235, 95% CI: 0.201-0.274; mean difference 1.27-fold, 95% CI:
      1.07-1.50; p = 0.01). These results suggest that there may be differences in the
      composition of intestinal microflora between allergic and non-allergic infants at
      1 year of age, with allergic children having higher Cl. difficile IgG antibody
      levels.

PMID- 12431194
TI  - Interleukin-6, interleukin-8, interleukin-11, and interferon-gamma levels in
      nasopharyngeal aspirates from wheezing children with respiratory syncytial virus
      or influenza A virus infection.
AB  - The differences between respiratory syncytial virus (RSV) and influenza A virus
      (IFAV) in the pathogenesis of wheezing in young children have not been clearly
      defined. The aim of this study was to assess the contributions of RSV vs IFAV in
      the pathogenesis of upper airway inflammation in wheezy young children. We
      compared interleukin (IL)-6, IL-8, IL-11, and interferon-gamma (IFN-gamma) levels
      in nasopharyngeal aspirates (NPA) from non-asthmatic children with respiratory
      virus infections (RSV in 17 children and IFAV in 13 children), asthmatic children
      with viral infections (RSV in nine children, IFAV in 10 children), and 22
      unaffected healthy children (controls). Levels of IL-11 in NPA from asthmatic
      children were significantly higher than those from non-asthmatic children with
      RSV infection, and RSV infection enhanced the IL-11 production in NPA
      significantly compared to IFAV infection. Nasopharyngeal epithelium from children
      with RSV infection secreted more IL-6 than that of children with IFAV infection.
      There was little difference in the IL-8 and IFN-gamma levels between asthmatic
      and non-asthmatic children with RSV or IFAV infection. In conclusion, asthma
      enhanced IL-11 production in RSV infection rather than IFAV infection in early
      childhood. There was a trend towards greater IL-6 production in RSV infection
      compared with IFAV infection.

PMID- 12431196
TI  - Hypertonic saline challenge tests in the diagnosis of bronchial
      hyperresponsiveness and asthma in children.
AB  - The hypertonic saline challenge test is the recommended method to assess
      bronchial hyperresponsiveness in the International Study of Asthma and Allergies
      in Childhood (ISAAC). The sensitivity of this procedure to assess asthma
      symptoms, however, has been reported to vary among study centers. The purpose of
      our study was to evaluate the value of this provocation test in an
      epidemiological survey in children, and to relate the degree of bronchial
      hyperresponsiveness to the severity of asthma symptoms. All 11-13-year-old
      children from 16 randomly selected schools in Linkoping, Sweden received a
      questionnaire regarding respiratory symptoms and allergic disease. Skin prick
      tests with eight inhalant allergens were performed. In addition, all children
      with wheeze over the past 12 months (current wheeze) and a random sample of
      children without current wheeze were invited to perform hypertonic saline
      provocation tests. A complete data set was available for 170 children, including
      50 with and 120 without current wheeze. Bronchial hyperresponsiveness (BHR) was
      defined as at least 15% decline in FEV1. The degree of BHR was represented by the
      response/dose ratio, i.e. the fall in FEV1 divided by total dose of inhaled
      saline. The severity of asthma symptoms was classified by the number of wheezing
      episodes over the past 12 months. 'Asthma ever' was defined by a combination of
      symptoms in the questionnaires. Children with 'asthma ever' and current wheeze
      were considered as having current asthma. Current atopic asthma was defined as
      current asthma with at least one positive skin prick test. The sensitivity of the
      procedure to detect 'asthma ever', current asthma and current atopic asthma was
      62, 61 and 83%, and the specificity 83, 81 and 60%, respectively. The positive
      challenge rate was 52, 34, 13 and 7% among current wheezers, previous wheezers,
      non-wheezers with a history of allergy and healthy children. The degree of
      bronchial hyperresponsiveness increased with the number of wheezing episodes.
      Thus, the median and range of the response/dose ratio were 4.8%/ml (2.1-14.8),
      2.6%/ml (0.7-8.6) and 1.3%/ml (0.8-2.7), respectively, for children with >/= 4
      episodes, 1-3 episodes and no wheezing episodes over the past 12 months
      (p<0.001). In conclusion, hypertonic saline provocation test is useful as a tool
      to detect asthma in epidemiological studies in children. The degree of bronchial
      hyperresponsiveness, as represented by the response/dose ratio, reflects the
      severity of asthma symptoms.

PMID- 12431197
TI  - Skin-prick test findings in atopic asthmatic children: a follow-up study from
      childhood to puberty.
AB  - In a prospective cohort study we investigated the course of allergic
      sensitization from childhood to puberty in a group of children with atopic
      asthma. An attempt was made to correlate the findings with the persistence of
      asthma. A total of 150 children with atopic asthma established at 7 years of age
      were evaluated when 8-10 years of age. A battery of skin-prick tests (SPTs) to
      common environmental allergens, a detailed clinical history for asthma severity
      classification, and spirometric analyses, were performed. In 127 of these
      children a re-evaluation was performed at puberty. A variety of statistical
      methods were used to analyze the results regarding changes in skin test
      reactivity to individual aeroallergens and atopic index (degree of atopy), as
      well as to determine any correlation between these changes and the persistence of
      asthma in puberty. A wide spectrum of modification in skin reactivity to common
      environmental allergens was observed, including the complete loss of
      sensitization to some allergens or the development of a new one to others.
      Specifically, 34% of asthmatic children sensitive to Dermatophagoides
      pteronyssinus and 52.7% sensitive to cat lost their sensitivity in puberty, while
      only 7.5% and 11.1%, respectively, became sensitized (p = 0.03 and p = 0.001,
      respectively). In contrast, regarding pollen sensitivity, 30.2% and 24% of
      asthmatic children became sensitive in puberty to olive pollen and grasses mix,
      respectively, and only 11.7% and 12.5%, respectively, lost their sensitivity to
      these allergens (p = 0.04). No correlation was shown between the skin test
      reactivity changes to individual allergens and the persistence of asthma, but a
      significant correlation was found between atopic index to indoor allergens in
      childhood and the persistence of asthma at puberty (p = 0.04). Interestingly,
      multi-sensitivity to allergens (>/= 4 allergens) in childhood was also found to
      correlate with the persistence of asthma at puberty [p = 0.05, odds ratio (OR) =
      2.65, 95% confidence interval (CI) 1.2-7.2]. Our findings indicate that
      significant modification of skin reactivity to common environmental allergens in
      atopic children with asthma in puberty can occur. However, no association between
      these changes and the persistence of asthma could be demonstrated, although
      children with indoor allergic sensitization and multi-reactivity were found to
      have a higher probability of maintaining their asthma in puberty.

PMID- 12431198
TI  - Glucocorticoids enhance interleukin-4 production to neo-antigen (hyaluronidase)
      in children immunocompromised with cytostatic drugs.
AB  - Immunoglobulin E (IgE)-mediated immediate-type allergic reactions to
      hyaluronidase have been observed in children with central nervous system (CNS)
      tumors. Glucocorticoids, used as therapy for brain edema, are discussed
      controversially as T helper 2 (Th2) stimulatory factors. In this study we
      investigated the role of glucocorticoids on a Th2 cytokine-promoting effect in
      children with CNS tumors. Peripheral blood mononuclear cells (PBMCs) from: 29
      children suffering from malignant brain tumors, of whom 23 received short-term
      glucocorticoid treatment (for 3-4 days) during the course of chemotherapy; 18
      children with nephrotic syndrome or renal transplantation receiving long-term
      glucocorticoid treatment; and 13 healthy children, were incubated with
      phytohemagglutinin (PHA) and/or anti-CD28 monoclonal antibody (mAb) and, in a
      second approach, with hyaluronidase. The concentrations of Th cell-mediated
      cytokines - interleukin (IL)-4, IL-10, and interferon-gamma (IFN-gamma) - were
      measured in supernatants. The IL-4 production of PBMCs incubated with PHA/anti
      CD28 mAb from children with repeated co-administration of glucocorticoids,
      hyaluronidase, and cytostatic drugs (median: 249.9 pg/ml; range: 234.4-261.7) was
      significantly higher (p < 0.0001) than IL-4 production of PBMC from children of
      all the other groups (median: 86.18; range: 16.0-212.5). There was no significant
      difference in the levels of IL-10 and IFN-gamma within the groups. PBMCs
      stimulated only with hyaluronidase failed to produce detectable levels of
      cytokines. The results of this study indicate that repeated co-administration of
      glucocorticoids and hyaluronidase (a neo-antigen) enhance IL-4 production in
      vitro and thus may induce the production of specific IgE antibodies in children
      immunocompromised with cytostatic drugs. Hyaluronidase itself does not stimulate
      in vitro IL-4 synthesis in PBMCs of children receiving cytostatic drugs.

PMID- 12431199
TI  - Immunodeficiency with recurrent panlymphocytopenia, impaired maturation of B
      lymphocytes, impaired interaction of T and B lymphocytes, and impaired integrity
      of epithelial tissue: a variant of idiopathic CD4+ T lymphocytopenia?
AB  - Idiopathic CD4+ T lymphocytopenia (ICL) has been defined as a cause of
      immunodeficiency with a variable clinical course and an unknown etiology. Here we
      describe a now 18-year-old boy with ICL, chronic mucocutaneous candidiasis (CMC),
      recurrent abscesses, and relapsing aphthous and ulcerous lesions. In addition to
      ICL the patient frequently showed a panlymphocytopenia. An increased percentage
      of gamma+delta+ T lymphocytes and IgD+ IgM+ B lymphocytes, and a decreased
      percentage of CD21+ B lymphocytes, were observed. In vitro assays showed normal T
      cell responses to candidin and T-cell mitogens, but impaired B-cell responses to
      pokeweed mitogen (PWM). B-cell maturation after stimulation with Staphylococcus
      aureus Cowan I (SAC) and interleukin 2 (IL-2) was nearly normal. The clinical
      course of the patient improved substantially on administration of constant low
      dose therapy with fluconazole.

PMID- 12431200
TI  - Therapy of chronic hepatitis B: current challenges and opportunities.
AB  - Better understanding of hepatitis B virus (HBV) replication, natural history and
      the immunopathogenesis of chronic hepatitis B, together with the introduction of
      effective agents with different mechanisms of action are the basis for better
      therapeutic strategies against chronic hepatitis B. Among currently available
      drugs, interferon-alpha and thymosin-alpha1 have only modest efficacy
      (approximately 40% vs 9-20% in controls). In the past decade, lamivudine has
      dominated in the treatment of chronic HBV infection because it is easy to use,
      safe, and is effective in terms of hepatitis B e antigen and/or HBV-DNA loss, ALT
      normalization, and improvement in histology. The response rate increases with
      increasing pretherapy alanine aminotransferase (ALT) levels, suggesting that
      patients with stronger endogenous immune response against HBV have a better
      response to direct antiviral agents. Lamivudine is also beneficial in
      decompensated cirrhotics with HBV replication. Hepatitic flares may occur after
      stopping lamivudine therapy in nonresponders and also in responders. Therefore,
      prolonged therapy is usually required. However, tyrosine-methionine-aspartate
      aspartate (YMDD) mutations conferring resistance to lamivudine start to emerge
      after 6-9 months of therapy, and hepatitis flare, even decompensation, may
      develop after viral breakthrough. Thus the benefits of long-term lamivudine
      therapy must be balanced against the concern about YMDD mutations and the
      durability of treatment response. Adefovir dipivoxil, entecavir, emtricitabine,
      clevudine and other nucleoside/ nucleotide analogues have shown encouraging
      results and some agents appear effective in patients with YMDD mutants. Further
      development of new drugs and new strategies may help to improve treatment in the
      new century.

PMID- 12431201
TI  - Characterization of the immune response against hepatitis C infection in
      recovered, and chronically infected chimpanzees.
AB  - The immune response to hepatitis C virus (HCV) is believed to be critical in
      determining the outcome of the disease. In this study we have analysed epitope
      recognition, cytokine profile, and anti-HCV antibody responses in chronically HCV
      infected and recovered chimpanzees. Quantitative measurement of anti-HCV antibody
      in HCV-infected chimpanzees revealed that the response in HCV- recovered
      chimpanzees peaked within 4-20 weeks. In contrast, the anti-HCV antibody
      responses in chronically HCV infected chimpanzees did not peak until 100-200
      weeks after infection, and decreased gradually thereafter. T cell proliferation
      assays measuring responses to pooled HCV proteins revealed significant increases
      in the 3H-uptake during the early stages of infection in recovered chimpanzees in
      comparison to the chronically infected ones. Class I-restricted epitopes of the
      core, and NS3 proteins of HCV were analysed using 9-10 mer overlapping peptides
      covering the core and NS3 proteins, and IFN-gamma ELISPOT technique. Our data
      indicated early and broad class-I restricted core, and NS3 protein epitope
      recognitions in HCV-recovered chimpanzees but not in chimpanzees that had been
      chronically infected. Additionally, dominant epitopes recognized early in
      infection (8 weeks) were no longer recognized later in infection (followed up to
      64 weeks). Cytokines profiling revealed a 50-fold increase in TNF-alpha secretion
      in the supernatant of core-specific CD8 memory cells of the chronically infected
      chimpanzees in comparison to the recovered ones. In summary, multiple parameters
      correlate with HCV recovery in chimpanzees.

PMID- 12431202
TI  - Characterization of nuclease-resistant ribozymes directed against hepatitis B
      virus RNA.
AB  - Hepatitis B virus (HBV) is responsible for > 350 million cases of chronic
      hepatitis B worldwide and 1.2 million deaths each year. To explore the use of
      ribozymes as a novel therapy for HBV infection, nuclease-resistant ribozymes that
      target highly conserved regions of HBV RNA were screened in cell culture. These
      synthetic ribozymes have the potential to cleave all four major HBV RNA
      transcripts and to block the HBV lifecycle by cleavage of the pregenomic RNA. A
      number of the screened ribozymes demonstrate activity in cell culture systems, as
      measured by decreased levels of HBV surface antigen, HBV e antigen and HBV DNA.
      In addition, a lead anti-HBV ribozyme maintains activity against a lamivudine
      resistant HBV variant in cell culture. Treatment of HBV transgenic mice with lead
      anti-HBV ribozymes significantly reduced viraemia compared with saline-treated
      animals and was as effective as treatment with lamivudine. In conclusion, the
      therapeutic use of a ribozyme alone or in combination with current therapies
      (lamivudine or interferons) may lead to improved HBV therapy.

PMID- 12431203
TI  - Inducible nitric oxide synthase expression in chronic viral hepatitis and its
      relation with histological severity of disease.
AB  - The role of nitric oxide in the pathogenesis of chronic viral hepatitis is not
      known. Elevated nitric oxide production is assumed to be responsible for the
      pathological changes in many inflammatory conditions, mainly via peroxynitrite, a
      potential oxidant that is produced by the reduction of superoxide anion with
      nitric oxide. The intensity and the distribution of the immunohistochemical
      staining of intrahepatic inducible nitric oxide synthase were studied in the
      biopsy specimens obtained from 63 patients with viral hepatitis and 13 patients
      with elevated transaminase levels of various aetiologies. Hepatic inducible
      nitric oxide synthase staining was significantly more intense in the viral
      hepatitis group (P = 0.000). Inducible nitric oxide synthase staining levels
      correlated well with the severity of the viral hepatitis using the Knodell's
      liver histological activity index (r = 0.393, P = 0.002) Among the viral
      hepatitis group, the pathological distribution of the inducible nitric oxide
      synthase staining favoured the periportal hepatocytes (zone 1) whereas less
      staining was observed in parenchymal hepatocytes zone of 2 and 3 and bile duct
      epithelium. As nitric oxide mediated nitration of hepatocellular proteins is
      elevated in inflamed hepatic tissues and is correlated with the severity of the
      disease, we suggest that inducible nitric oxide synthase can possibly have a
      critical role in the pathogenesis of chronic viral hepatitis.

PMID- 12431204
TI  - The role of lamivudine and predictors of mortality in severe flare-up of chronic
      hepatitis B with jaundice.
AB  - Patients with chronic hepatitis B (CHB) may develop severe disease exacerbations
      (flare) with jaundice, and some may progress to fulminant hepatic failure.
      Whether early administration of lamivudine can prevent liver failure and
      mortality is uncertain. We investigated the role of lamivudine treatment in
      severe hepatitis B virus (HBV) exacerbations. Consecutive patients presented with
      severe flare-up of HBV (new onset of jaundice plus alanine aminotransferase
      greater than five times upper limit of normal) treated with lamivudine and
      historical controls who did not receive lamivudine were studied. All patients had
      no hepatic encephalopathy on admission. Univariate analysis and multivariate
      logistic regression were performed on various clinical and laboratory factors for
      the prediction of mortality. Twenty-eight patients treated with lamivudine and 18
      controls were identified. Overall, nine patients died and two other received
      liver transplants for fulminant hepatic failure. Six of 28 (21.4%) lamivudine
      treated patients vs five of 18 (27.8%) controls died or received a liver
      transplant (P = 0.62). On multivariate analysis, platelet < or = 143 x 10E9/L
      (odds ratio 22.4, 95% CI 1.8-281.6) and bilirubin > 172 micromol/L (odds ratio
      18.4, 95% CI 1.5-228.5) were independent predictors of liver-related mortality.
      The mortality of patients who had thrombocytopenia and high bilirubin,
      thrombocytopenia, high bilirubin, and no risk factor were 69.2%, 11.1%, 12.5% and
      0% respectively. Hence lamivudine confers no survival benefit to conventional
      treatment in severe exacerbations of CHB. Patients with thrombocytopenia and high
      bilirubin should be considered for liver transplantation.

PMID- 12431205
TI  - Virus-specific antibody titres in different phases of hepatitis C virus
      infection.
AB  - This study aimed to examine anti hepatitis C virus (HCV) antibody titres, their
      changes and differences in acute, chronic and past HCV infection and to examine
      them after IFN-alpha-therapy. Ninety five patients were studied in a cross
      sectional investigation and 18 of them were followed long-term. Titres of IgM and
      IgG antibodies against core, NS3, NS4 (A + B), NS5A proteins were determined by
      the third generation enzyme immunoassays. Patients with acute hepatitis C
      developed IgG antibodies against core protein in titres 1/5-1/800 and against
      individual NS proteins at the same titres. During the first to second month of
      acute hepatitis C IgG antibody titres to HCV proteins were very low, but they had
      risen considerably by the fourth to sixth month. Anti-HCV IgM antibodies were
      found in half the acute hepatitis serum samples, titres were 1/5-1/40. Sixty
      individuals with chronic hepatitis C showed IgG antibodies against core in titres
      1/800-1/40,000 and against individual NS proteins in titres 1/5-1/20,000. Eight
      patients with chronic hepatitis C had invariable anti-HCV IgG antibodies over 2-3
      years. About 81.7% of chronically infected patients had anti-HCV IgM antibodies
      in titres 1/5-1/160. Patients with resolution of HCV infection showed only anti
      core IgG antibodies (titres 1/5-1/200) or no virus-specific antibodies.
      Individuals with different response to IFN-alpha-therapy showed two distinct
      patterns of anti-HCV antibody titres. Acute and chronic HCV infection may be
      distinguished by anti-core titres.

PMID- 12431206
TI  - Serological response to infection with different isolates of hepatitis C virus.
AB  - Different isolates of hepatitis C virus (HCV) show nucleotide sequence
      variability throughout the genome. Detection of antibodies to recombinant
      proteins derived from hepatitis C virus genotype 1, the prototype HCV clone HCV
      PT, constitutes the main method for screening HCV infection. The influence of the
      genomic variability on the serological diagnosis of HCV by enzyme immunoassay
      remains poorly defined. The aim of this study was to assess the serological
      reactivity of a panel of well characterized French HCV isolates typed by sequence
      analysis from patients with chronic hepatitis. The 73 sera samples were tested in
      three third generation EIA tests and three confirmatory assays. HCV isolates were
      determined by RT-PCR and sequencing in NS5B region of the genome. The 73 sera
      were positive in the three EIA tests. The three confirmatory tests showed a
      weaker reactivity with NS5 protein whatever the genotype, and a lower reactivity
      in NS4 antigens of non-type 1 sequences, particularly for genotype 3. Even though
      the reactivity of the antigens differed among the HCV isolates, the 73 isolates
      from genotype 1-6 were reactive with the three commercial screening assays. These
      results demonstrate that using a single test is adequate in the routine diagnosis
      of HCV infection in clinical laboratory, as recommended by the last French and
      European consensus conference.

PMID- 12431207
TI  - Interobserver variation in interpretation of serial liver biopsies from patients
      with chronic hepatitis C.
AB  - Reliable and accurate assessment of liver histopathology in patients with chronic
      hepatitis C is important for decision regarding treatment and for evaluation of
      therapy. However, little data on interobserver variation have been published. In
      this study, five specialist histopathologists evaluated 46 liver biopsies from 20
      patients treated with interferon-alpha. Knodell's and Ishak's scoring systems, De
      Groote's classification and a four level general necro-inflammatory activity
      score (GNAS) were applied. Besides kappa statistics, slide by slide analysis was
      performed. We defined an acceptable slide by slide agreement as eight of ten
      observer pairs agreed on 80% of the slides. The best agreement was seen for
      Knodell's and Ishak's fibrosis score, De Groote's classification and GNAS (mean
      weighted kappa (kappa(w)) = 0.49, 0.51, 0.50 and 0.44, respectively). By
      condensing data from Knodell's and Ishak's scores to presence or absence of
      cirrhosis and piecemeal necrosis respectively, concordance was substantial
      concerning cirrhosis (mean kappa = 0.69 and 0.72, respectively) but only moderate
      concerning piecemeal necrosis (mean kappa = 0.40 and 0.39, respectively). Slide
      by slide analysis showed the highest agreement on Knodell's fibrosis score and
      GNAS; only one point of difference in score was to be accepted to obtain 'eight
      of ten' agreement. In contrast, five points of difference were necessary to
      accept in order to reach the same agreement for Knodell's total activity score.
      Moreover, in serial biopsies the GNAS was sufficient to detect changes in disease
      activity following treatment. Thus, a simple scoring system with four category
      scales was reproducible and sufficient for detection of therapy induced changes.

PMID- 12431208
TI  - A phylogenetic-tree analysis elucidating nosocomial transmission of hepatitis C
      virus in a haemodialysis unit.
AB  - Nosocomial transmission of hepatitis C virus (HCV) subtype 1b involving 11
      haemodialysis patients occurred in a haemodialysis unit in Japan in March 2000.
      Sequencing of the HCV-E1 region (411-bp) and phylogenetic-tree analysis showed
      near identity between HCV isolates derived from these patients and a
      haemodialysis patient who was known to be HCV-positive. The mode of transmission
      could not be conclusively established, but retrospective analysis suggested that
      the sharing of contaminated multidose vials of heparin-saline solutions, which
      were prepared in the Haemodialysis Center using accidentally contaminated
      instruments such as needles, may have been responsible for the outbreak. To
      prevent transmission of HCV in a haemodialysis unit, it may be important to
      observe strictly standard precautions and to prepare all medications in the
      Pharmacy. After these measures were taken, no new seroconversions and no new
      nosocomial transmissions of HCV have been observed in our haemodialysis unit.

PMID- 12431209
TI  - Prevalence of SENV-H viraemia among healthy subjects and individuals at risk for
      parenterally transmitted diseases in Germany.
AB  - The prevalence of a newly described DNA virus (SENV-H) was examined in a
      population of 599 individuals by polymerase chain reaction (PCR). All individuals
      were assigned to a nonrisk or a risk group depending on the presence of
      historical or serological factors indicating an increased risk for parenterally
      transmitted diseases. In a group of 226 healthy blood donors, 38 (16.8%) were
      found to be SENV-H viraemic. The highest prevalence of SENV-H viraemia was
      observed among patients infected by HIV (28 of 63; 44.4%). Contrarily, of 78
      individuals on maintenance haemodialysis, only 10 (12.8%) were found positive in
      the SENV-H PCR. Our results demonstrate that SENV-H viraemia is widespread in the
      general population. Therefore, it seems to be questionable if parenteral
      transmission is the main route for spreading SENV-H. The hepatitis-inducing
      capacity of SENV-H is unclear. However, taking our clinical and epidemiological
      data into account it seems unlikely that this virus is responsible for hepatitis.

PMID- 12431210
TI  - Risk of hepatitis A infection following travel.
AB  - Travel to endemic areas is one of the most frequently reported risk factors for
      infection with the hepatitis A virus (HAV). We evaluated the association between
      HAV infection and travel, by area of destination. We conducted a case-control
      study on all cases of HAV infection reported to the Italian National Surveillance
      System for Acute Viral Hepatitis in the period 1996-2000. The study population
      consisted of 9695 persons with HAV infection (cases) and 2590 with HBV infection
      (controls). The risk of acquiring HAV was highest for travel to Asia, Africa and
      Latin America [Odds Ratio = 9.30 (95%CI = 6.71-12.9)]; a three-fold statistically
      significant excess of risk was found for travel to southern Italy (OR = 3.03) and
      to the Mediterranean Area and Eastern Europe (OR = 3.15). Travel was implicated
      in 28% of the cases of HAV infection. When stratifying the analysis by area of
      residence (northern and central Italy vs southern Italy and the Islands), the
      above-mentioned risks were confirmed only for those residing in northern and
      central Italy, with no significant risk for those residing in southern Italy and
      the Islands. Travel to areas endemic for HAV infection constitutes a considerable
      risk. Our results highlight the importance of developing health policies for
      improving environmental and hygienic conditions, as well as the prevention of
      certain eating habits. Vaccination before travelling to a medium or high endemic
      area could be a safe and effective means of preventing travel-related HAV
      infection.

PMID- 12431211
TI  - Authors' reply: first-phase parameters in hepatitis C viral kinetics.

PMID- 12431215
TI  - Upregulation of [3H]methyllycaconitine binding sites following continuous
      infusion of nicotine, without changes of alpha7 or alpha6 subunit mRNA: an
      autoradiography and in situ hybridization study in rat brain.
AB  - It is well established that exposure of experimental animals to nicotine results
      in upregulation of the alpha4beta2-subtype of neuronal nicotinic acetylcholine
      receptors (nAChRs). The aim of this study was to determine the effect of nicotine
      on the levels of alpha7-nAChRs in rat brain, for which only partial information
      is available. Rats were infused with nicotine (3 mg/kg/day) or saline for 2 weeks
      and their brains processed for receptor autoradiography with
      [3H]methyllycaconitine (MLA), a radioligand with nanomolar affinity for alpha7
      nAChRs. In control rats binding was high in hippocampus, intermediate in cerebral
      cortex and hypothalamus, and low in striatum, thalamus and cerebellum. There was
      high correlation between the distribution of [3H]MLA binding sites and alpha7
      subunit mRNA (r = 0.816). With respect to saline-treated controls, nicotine
      treated rats presented higher [3H]nicotine binding in 11 out of 15 brain regions
      analysed (average increase 46 +/- 6%). In contrast, only four regions showed
      greater [3H]MLA binding, among which the ventral tegmental area (VTA) and
      cingulate cortex (mean increase 32 +/- 3%). No changes in alpha7 mRNA levels were
      observed after nicotine treatment. Similarly, there was no variation of alpha6
      subunit transcript in the VTA, a region which may contain MLA-sensitive (non
      alpha7)-alpha6*-nAChRs (Klink et al., 2001). In conclusion, nicotine increased
      [3H]MLA binding, although to a smaller extent and in a more restricted regional
      pattern than [3H]nicotine. The enhancement of binding was not paralleled by a
      significant change of alpha7 and alpha6 subunit transcription. Finally, the
      present results provide the first anatomical description of the distribution of
      [3H]MLA binding sites in rat brain.

PMID- 12431216
TI  - No evidence for calcium electrogenic exchanger in frog semicircular canal hair
      cells.
AB  - We investigated the possibility that, in hair cells mechanically isolated from
      frog semicircular canals, Ca2+ extrusion occurs via a Na+ : Ca2+ (cardiac type)
      or a Na+ : Ca2+,K+ (retinal type) exchanger. Cells concurrently imaged during
      whole-cell patch-clamp recordings using the Ca2+ sensitive fluorescent dye Oregon
      Green 488 BAPTA-1 (100 micro m) showed no voltage dependence of Ca2+ clearance
      dynamics following a Ca2+ load through voltage-gated Ca2+ channels. Reverse
      exchange was probed in hair cells dialyzed with a Ca2+- and K+-free solution,
      containing a Na+ concentration that saturates the exchanger, after zeroing the
      contribution to the whole-cell current from Ca2+ and K+ conductances. In these
      conditions, no reverse exchange current was detected upon switching from a Ca2+
      free external solution to a solution containing concentrations of Ca2+ alone, or
      Ca2+ + K+ that saturated the exchanger. By contrast, the same experimental
      protocol elicited peak exchange currents exceeding 100 pA in gecko rod
      photoreceptors, used as positive controls. In both cell types, we also probed the
      forward mode of the exchanger by rapidly increasing the intracellular Ca2+
      concentration using flash photolysis of two novel caged Ca2+ complexes, calcium
      2,2'-([1-(2-nitrophenyl)ethane-1,2-diyl]bis(oxy))bis(acetate) and calcium 2,2'
      ([1-(4,5-dimethoxy-2-nitrophenyl)ethane-1,2-diyl]bis(oxy)) bis(acetate), in the
      presence of internal K+ and external Na+. No currents were evoked by UV-triggered
      Ca2+ jumps in hair cells, whereas exchanger conformational currents up to 400 pA,
      followed by saturating forward exchange currents up to 40 pA, were recorded in
      rod photoreceptors subjected to the same experimental conditions. We conclude
      that no functional electrogenic exchanger is present in this hair cell
      population, which leaves the abundant plasma membrane Ca2+-ATPases as the primary
      contributors to Ca2+ extrusion.

PMID- 12431217
TI  - Lesion response of long-term and recently immigrated resident endoneurial
      macrophages in peripheral nerve explant cultures from bone marrow chimeric mice.
AB  - Resident macrophages of the peripheral nervous system have recently been shown to
      respond rapidly to Wallerian degeneration before the influx of blood-derived
      macrophages. Because resident endoneurial macrophages are slowly but incompletely
      exchanged from the blood within 3 months, they could potentially comprise a
      heterogenous cell population consisting of long-term resident cells and more
      mobile cells undergoing turnover. We used bone marrow chimeric mice created by
      transplanting bone marrow from green fluorescent protein-transgenic mice into
      irradiated wildtype recipients to selectively analyse the response of these two
      resident macrophage populations to Wallerian degeneration in sciatic nerve
      explant cultures. In such nerves, recently immigrated macrophages exhibit green
      fluorescence whereas long-term resident macrophages do not. Studies in cultures
      from wildtype controls revealed rapid morphological changes of resident
      macrophages towards a bloated phenotype, a proliferative response resulting in a
      3.7-fold increase of macrophage numbers over 2 weeks, and phagocytosis of myelin
      basic protein-immunoreactive myelin debris. When chimeric mice were analysed,
      both populations of resident endoneurial macrophages participated in
      morphological transformation, proliferation and phagocytosis. Quantitative
      studies revealed a stronger proliferative and phagocytic response in long-term
      resident endoneurial macrophages compared with recently immigrated macrophages.
      Our results point towards subtle, but not principal, differences between the two
      macrophage populations, which might indicate different stages of macrophage
      differentiation rather than the existence of entirely distinct endoneurial
      macrophage populations. The results further underline the versatility of resident
      endoneurial macrophages following peripheral nerve injury, which is reminiscent
      of the lesion response of microglial cells within the brain.

PMID- 12431218
TI  - Neuroanatomical distribution of CXCR4 in adult rat brain and its localization in
      cholinergic and dopaminergic neurons.
AB  - Accumulating evidence supports a role of chemokines and their receptors in brain
      function. Up to now scarce evidence has been given of the neuroanatomical
      distribution of chemokine receptors. Although it is widely accepted that
      chemokine receptors are present on glial cells, especially in pathological
      conditions, it remains unclear whether they are constitutively present in normal
      rat brain and whether neurons have the potential to express such chemokine
      receptors. CXCR4, a G protein-coupled receptor for the chemokine stromal cell
      derived factor-1 (SDF-1/CXCL12) was reported to have possible implications in
      brain development and AIDS-related dementia. By dual immunohistochemistry on
      brain sections, we clearly demonstrate that CXCR4 is constitutively expressed in
      adult rat brain, in glial cells (astrocytes, microglia but not oligodendrocytes)
      as well as in neurons. Neuronal expression of CXCR4 is mainly found in cerebral
      cortex, caudate putamen, globus pallidus, substantia innominata, supraoptic and
      paraventricular hypothalamic nuclei, ventromedial thalamic nucleus and substantia
      nigra. Using confocal microscopy, a differential distribution of CXCR4 in
      neuronal perikarya and dendrites can be observed according to the brain
      structure. Furthermore, this work demonstrates for the first time the coexistence
      of a chemokine receptor with classical neurotransmitters. A localization of CXCR4
      is thus observed in neuronal cell bodies expressing choline acetyltransferase
      immunoreactivity in the caudate putamen and substantia innominata, as well as in
      tyrosine hydroxylase-positive neurons in the substantia nigra pars compacta. In
      conclusion, the constitutive neuronal CXCR4 expression suggests that SDF-1/CXCL12
      could be involved in neuronal communication and possibly linked up with
      cholinergic and dopaminergic neurotransmission and related disorders.

PMID- 12431219
TI  - Time of genesis determines projection and neurokinin-3 expression patterns of
      diencephalic neurons containing melanin-concentrating hormone.
AB  - Anatomical and functional evidence suggests that the diencephalic melanin
      concentrating hormone- (MCH-) containing neurons do not form a homogeneous
      population. In this work, the expression of the neurokinin-3 receptor (NK3) has
      been researched in MCH neurons which have been retrogradely labelled following
      fast blue injections into either the spinal cord or the cerebral cortex. The
      birth-date of these cortically and spinally projecting cells has been determined
      using the bromodeoxyuridine method. The results obtained show that neurons
      projecting to the spinal cord are born early (E11) and most of them (78,7%) do
      not express NK3, but neurons that send axons to the cerebral cortex are born
      later (E12-E13) and most of them (84,8%) express NK3. Both neuronal types are
      largely intermingled in the lateral hypothalamic area proper. These results are
      discussed in terms of the functional organization of the MCH neuronal population.

PMID- 12431220
TI  - Long-term survival and cell death of newly generated neurons in the adult rat
      olfactory bulb.
AB  - In the adult rat olfactory bulb, neurons are continually generated from
      progenitors that reside in the lateral ventricle wall. This study investigates
      long-term survival and cell death of newly generated cells within the adult
      olfactory bulb. After injecting rats at 2 months of age with 5-bromodeoxyuridine
      (BrdU), the newly generated cells were quantified over a period of 19 months. A
      peak of BrdU-positive cells was reached in the olfactory bulb 1 month after BrdU
      injection, when all new cells have finished migrating from the ventricle wall.
      Thereafter, a reduction of BrdU-positive cells to about 50% was observed and it
      was confirmed by dUTP-nick end-labelling (TUNEL) that progenitors and young
      neurons undergo programmed cell death. However, cells that survived the first 3
      months after BrdU injection persisted for up to 19 months. The majority of the
      BrdU-positive cells that reach the olfactory bulb differentiate into granule
      cells, but a small fraction migrate further into the glomerular layer. These
      newborn cells differentiate more slowly into periglomerular interneurons, with a
      delay of more than 1 month when compared to the granule cells. The newly
      generated periglomerular neurons, among them a significant fraction of
      dopaminergic cells, showed a similar decline in number compared to the granule
      cell layer and long-term survival for the remaining new neurons of up to 19
      months. Rather than replacing old neurons, this data suggests that adult
      olfactory bulb neurogenesis utilizes the overproduction and turnover of young
      neurons, which is reminiscent of the cellular dynamics observed during brain
      development.

PMID- 12431221
TI  - Modulation of secretion by the endoplasmic reticulum in mouse chromaffin cells.
AB  - The endoplasmic reticulum (ER) has been suggested to modulate secretion either
      behaving as a Ca2+ sink or as a Ca2+ source in neuronal cells. Working as a Ca2+
      sink, through ER-Ca2+ pumping, it may reduce secretion induced by different
      stimuli. Instead, working as a Ca2+ source through the Ca2+ induced Ca2+ release
      (CICR) phenomenon, it may potentiate secretion triggered by activation of plasma
      membrane Ca2+ channels. We have previously demonstrated the presence of CICR in
      bovine chromaffin cells, but we now find that mouse chromaffin cells almost lack
      functional caffeine-sensitive ryanodine receptors in the ER and, consistently, no
      CICR from the ER could be observed. In addition, inhibition of ER Ca2+ pumping
      with ciclopiazonic acid or thapsigargin strongly stimulated high-K+-evoked
      catecholamine secretion and cytosolic [Ca2+] ([Ca2+]c) transients. Surprisingly,
      5 mm caffeine reduced high-K+-induced [Ca2+]c peaks but considerably potentiated
      secretion induced by high-K+ stimulation. However, this potentiation was
      insensitive to ryanodine and additive to that induced by emptying the ER of Ca2+
      with thapsigargin, suggesting that it is unrelated to the activation of ryanodine
      receptors. We conclude that, in mouse chromaffin cells, CICR is not functional
      and the ER strongly inhibits secretion by acting as a damper of the [Ca2+]c
      signal.

PMID- 12431222
TI  - The lemniscal-cuneate recurrent excitation is suppressed by strychnine and
      enhanced by GABAA antagonists in the anaesthetized cat.
AB  - In the somatosensory system, cuneolemniscal (CL) cells fire high frequency
      doublets of spikes facilitating the transmission of sensory information to
      diencephalic target cells. We studied how lemniscal feedback affects ascending
      transmission of cutaneous neurons of the middle cuneate nucleus. Electrical
      stimulation of the contralateral medial lemniscus and of the skin at sites
      evoking responses with minimal threshold induced recurrent activation of CL cells
      at a latency of 1-3.5 ms. The lemniscal feedback activation was suppressed by
      increasing the stimulating intensity at the same sites, suggesting recurrent
      mediated lateral inhibition. The glycine antagonist strychnine blocked the
      recurrent excitatory responses while GABAA antagonists uncovered those obscured
      by stronger stimulation. CL cells sharing a common receptive field (RF)
      potentiate one another by recurrent activation and disinhibition, the
      disinhibition being produced by serial interactions between glycinergic and
      GABAergic interneurons. Conversely, CL cells with different RFs inhibit each
      other through recurrent GABA-mediated inhibition. The lemniscal feedback would
      thus enhance the surround antagonism of a centre response by increasing the
      spatial resolution and the transmission of weak signals.

PMID- 12431223
TI  - Autoradiography of opioid and ORL1 ligands in opioid receptor triple knockout
      mice.
AB  - Three genes for the opioid receptors ( micro, delta and kappa) and a gene coding
      for a related receptor (ORL1) have been cloned but pharmacological studies
      suggest that further subtypes exist that remain poorly understood. To determine
      if there are other classically defined opioid binding sites we have carried out
      homogenate binding and section autoradiography with [3H]naloxone in mice that
      lack all three opioid genes and are hyperalgesic in a thermal nociceptive test.
      We have also examined [3H]bremazocine labelling in triple knockout brain and
      spinal cord as this ligand has been proposed to label novel kappa-receptors. No
      receptor labelling for either ligand was detected in the brains or spinal cord of
      knockout mice demonstrating that all binding is the product of the three known
      receptors and that there is no cross-labelling of the ORL1 receptor. Nociceptin
      (1 micro m) caused marked displacement of [3H]bremazocine in wild-type brains
      indicating that nociceptin at high concentrations can displace classical opioid
      binding. As a number of studies have proposed a close association between the
      classical opioid receptors and the ORL1 system we also hypothesized that loss of
      all of the classical opioid receptors might lead to compensatory changes in ORL1
      receptors. Labelling of the ORL1 receptor with [3H]nociceptin showed region
      dependent quantitative increases in triple knockout brains indicating a close
      relationship between the two systems in specific brain areas.

PMID- 12431224
TI  - Retinofugal projections following early lesions of the visual cortex in the
      ferret.
AB  - Extensive lesions of the occipital cortex comprising the developing occipital
      visual areas and beyond in young ferrets (postnatal day 5) are followed by
      massive, but incomplete, degeneration of the lateral geniculate (LGN) and
      lateralis posterior (LP) nuclei of the thalamus, and minor volumetric reduction
      of the superior colliculus. Retinal projections (revealed by intraocular tracer
      injections), while reduced, remain confined to their territories of normal
      termination, both in the adult and throughout development. Comparisons with other
      mammalian species point to several common features in the developmental
      plasticity of retinofugal pathway.

PMID- 12431225
TI  - Characterization of a novel NCAM ligand with a stimulatory effect on neurite
      outgrowth identified by screening a combinatorial peptide library.
AB  - The neural cell adhesion molecule, NCAM, plays a key role in neural development
      and plasticity mediating cell adhesion and signal transduction. By screening a
      combinatorial library of synthetic peptides with NCAM purified from postnatal day
      10 rat brains, we identified a nonapeptide, termed NCAM binding peptide 10
      (NBP10) and showed by nuclear magnetic resonance analysis that it bound the NCAM
      IgI module of NCAM. NBP10 modulated cell aggregation as well as neurite outgrowth
      induced specifically by homophilic NCAM binding. Moreover, both monomeric and
      multimeric forms of NBP10 stimulated neurite outgrowth from primary hippocampal
      neurons. The neurite outgrowth response to NBP10 was inhibited by a number of
      compounds previously shown to inhibit neurite outgrowth induced by homophilic
      NCAM binding, including voltage-dependent calcium channel antagonists, suggesting
      that NBP10 induced neurite outgrowth by activating a signal transduction pathway
      similar to that activated by NCAM itself. Moreover, an inhibitor of intracellular
      calcium mobilization, TMB-8, prevented NBP10-induced neurite outgrowth suggesting
      that NCAM-dependent neurite outgrowth also requires mobilization of calcium from
      intracellular calcium stores in addition to calcium influx from extracellular
      sources. By single-cell calcium imaging we further demonstrated that NBP10 was
      capable of inducing an increase in intracellular calcium in PC12E2 cells. Thus,
      the NBP10 peptide is a new tool for the study of molecular mechanisms underlying
      NCAM-dependent signal transduction and neurite outgrowth, and could prove to be a
      useful modulator of regenerative processes in the peripheral and central nervous
      system.

PMID- 12431226
TI  - Sexual dimorphism in the spontaneous recovery from spinal cord injury: a gender
      gap in beneficial autoimmunity?
AB  - Immune cells have been shown to contribute to spontaneous recovery from central
      nervous system (CNS) injury. Here we show that adult female rats and mice recover
      significantly better than their male littermates from incomplete spinal cord
      injury (ISCI). This sexual dimorphism is wiped out and recovery is worse in adult
      mice deprived of mature T cells. After spinal cord contusion in adult rats,
      functional recovery (measured by locomotor scores in an open field) was
      significantly worse in females treated with dihydrotestosterone prior to the
      injury than in placebo-treated controls, and significantly better in castrated
      males than in their noncastrated male littermates. Post-traumatic administration
      of the testosterone receptor antagonist flutamide promoted the functional
      recovery in adult male rats. These results, in line with the known inhibitory
      effect of testosterone on cell-mediated immunity, suggest that androgen-mediated
      immunosuppression plays a role in ISCI-related immune dysfunction and can
      therefore partly explain the worse outcome of ISCI in males than in female. We
      suggest that females, which are more prone to develop autoimmune response than
      males, benefit from this response in cases of CNS insults.

PMID- 12431227
TI  - The respective contribution of lumbar segments to the generation of locomotion in
      the isolated spinal cord of newborn rat.
AB  - Various studies on isolated neonatal rat spinal cord have pointed to the
      predominant role played by the rostral lumbar area in the generation of locomotor
      activity. In the present study, the role of the various regions of the lumbar
      spinal cord in locomotor genesis was further examined using compartmentalization
      and transections of the cord. We report that the synaptic drive received by
      caudal motoneurons following N-methyl-d-l-aspartate (NMA)/5-HT superfusion on the
      entire lumbar cord is different from that triggered by the same compounds
      specifically applied on the rostral segments. These differences appear to be due
      to the direct action of NMA/5-HT on motoneuron membrane potential, rather than on
      premotoneuronal input activation. In order to assess the possible participation
      of the caudal lumbar segments in locomotor rhythm generation, the segments were
      over-stimulated with high concentrations of NMA or K+. We find that significant
      variations in motor cycle period occurred during the over-activation of the
      rostral segments. Over-activation of caudal segments only si+gnificantly
      increased the caudal ventral roots burst amplitude. We find that low 5-HT
      concentrations were unable to induce fictive locomotion under our experimental
      conditions. When a hemi-transection of the cord was performed between the L2-L3
      segments, rhythmic bursting in the ipsilateral L5 disappeared while rhythmicity
      persisted on the contralateral side. Sectioning of the remaining L2-L3 side
      totally suppressed rhythmic activity in both L5 ventral roots. These results show
      that the thoracolumbar part of the cord constitutes the key area for locomotor
      pattern generation.

PMID- 12431229
TI  - Reorganization of descending motor tracts in the rat spinal cord.
AB  - Following lesion of the central nervous system (CNS), reinnervation of denervated
      areas may occur via two distinct processes: regeneration of the lesioned fibres
      or/and sprouting from adjacent intact fibres into the deafferented zone. Both
      regeneration and axonal sprouting are very limited in the fully mature CNS of
      higher vertebrates, but can be enhanced by neutralizing the neurite outgrowth
      inhibitory protein Nogo-A. This study takes advantage of the distinct spinal
      projection pattern of two descending tracts, the corticospinal tract (CST) and
      the rubrospinal tract (RST), to investigate if re-innervation of denervated
      targets can occur by sprouting of anatomically separate, undamaged tracts in the
      adult rat spinal cord. The CST was transected bilaterally at its entry into the
      pyramidal decussation. Anatomical studies of the RST in IN-1 antibody-treated
      rats showed a reorganization of the RST projection pattern after neutralization
      of the myelin associated neurite growth inhibitor Nogo-A. The terminal
      arborizations of the rubrospinal fibres, which are normally restricted to the
      intermediate layers of the spinal cord, invaded the ventral horn but not the
      dorsal horn of the cervical spinal cord. Moreover, new close appositions were
      observed, in the ventral horn, onto motoneurons normally receiving CST
      projections. Red nucleus microstimulation experiments confirmed the
      reorganization of the RST system. These observations indicate that mature
      descending motor tracts are capable of significant intraspinal reorganization
      following lesion and suggests the expression of cues guiding and/or stabilizing
      newly formed sprouts in the adult, denervated spinal cord.

PMID- 12431228
TI  - Overexpression of corticotropin-releasing hormone in transgenic mice and chronic
      stress-like autonomic and physiological alterations.
AB  - To gain a greater insight into the relationship between hyperactivity of the
      corticotropin-releasing hormone (CRH) system and autonomic and physiological
      changes associated with chronic stress, we developed a transgenic mouse model of
      central CRH overproduction. The extent of central and peripheral CRH
      overexpression, and the amount of bioactive CRH in the hypothalamus were
      determined in two lines of CRH-overexpressing (CRH-OE) mice. Furthermore, 24 h
      patterns of body temperature, heart rate, and activity were assessed using
      radiotelemetry, as well as cumulative water and food consumption and body weight
      gain over a 7-day period. CRH-OE mice showed increased amounts of CRH peptide and
      mRNA only in the central nervous system. Despite the presence of the same CRH
      transgene in their genome, only in one of the two established lines of CRH-OE
      mice (line 2122, but not 2123) was overexpression of CRH associated with
      increased levels of bioactive CRH in the hypothalamus, increased body temperature
      and heart rate (predominantly during the light (inactive) phase of the diurnal
      cycle), decreased heart rate variability during the dark (active) phase, and
      increased food and water consumption, when compared with littermate wildtype
      mice. Because line 2122 of the CRH transgenic mice showed chronic stress-like
      neuroendocrine and autonomic changes, these mice appear to represent a valid
      animal model for chronic stress and might be valuable in the research on the
      consequences of CRH excess in situations of chronic stress.

PMID- 12431230
TI  - Long-term depression and long-term potentiation in horizontal connections of the
      barrel cortex.
AB  - Synaptic plasticity of horizontally orientated connections between barrels, in
      the barrel cortex of adult mice, was studied in slice preparations cut across
      rows of barrels. Field potentials were evoked in the middle of one barrel column
      (in layer IV or V) and recorded in the neighbouring barrel (in layer IV and V).
      In layer IV, long-term depression (LTD) by 26.5 +/- 5% was first induced by a low
      frequency stimulation (2 Hz) applied for 10 min. After 30 min, theta-burst
      stimulation was delivered to previously depressed connections, resulting in long
      term potentiation (LTP) by 28.8 +/- 11.8%. When theta-burst stimulation was
      delivered without an earlier low-frequency stimulation, no LTP was induced.
      Similar results were obtained in layer V connections (LTD: 40.6 +/- 12.5%; LTP:
      26.9 +/- 12.5%). In layer IV, the application of 100 micro m d,l-2-amino-5
      phosphonovaleric acid (APV), an antagonist of NMDA receptors, blocked the
      induction of both LTD and LTP. These experiments show that a potential for
      synaptic plasticity is retained in granular and infragranular layers of adult
      mice.

PMID- 12431231
TI  - Calcineurin regulates induction of late phase of cerebellar long-term depression
      in rat cultured Purkinje neurons.
AB  - Cerebellar long-term depression (LTD), a candidate cellular mechanism of motor
      learning, is induced by conjunctive activation of parallel fibres and a climbing
      fibre. Previous studies have shown that combinatorial application of high
      potassium and glutamate (K/glu) to cultured cerebellar neurons can mimic this
      conjunctive stimulation of presynaptic fibres and induces the LTD of miniature
      excitatory postsynaptic current (mEPSC) amplitudes lasting for more than 24 h.
      The late phase of this LTD (LLTD, > 3 h) depends on de novo transcription induced
      by prolonged conditioning. Here, the role of Calcineurin in the LLTD induction
      was examined. Application of a Calcineurin inhibitor FK506 mimicked the effect of
      K/glu-treatment by decreasing mEPSC amplitudes for more than 24 h. FK506-induced
      depression, as well as the K/glu-induced LLTD, was blocked by inhibitors of
      either mRNA synthesis or Ca/Calmodulin dependent kinase. In addition, the FK506
      induced depression and K/glu-induced LLTD occluded each other, suggesting that
      they share the same mechanism. On the other hand, misexpression of the
      constitutively active form of Calcineurin in the Purkinje neuron nucleus blocked
      the LLTD induction by the K/glu-treatment. These results suggest that Calcineurin
      is involved in the induction of LLTD as a negative regulator. Furthermore, it was
      found that trapping superoxide, which is increased by neuronal activity and
      inactivates Calcineurin, suppressed the LLTD induction. Taken together, these
      results suggest that the LLTD might be induced by down-regulation of Calcineurin
      activity through superoxide in cultured Purkinje neurons.

PMID- 12431232
TI  - Cellular imaging with zif268 expression in the rat nucleus accumbens and frontal
      cortex further dissociates the neural pathways activated following the retrieval
      of contextual and cued fear memory.
AB  - Quantitative in situ hybridization revealed that the expression of the plasticity
      associated gene zif268 was increased in specific regions of the rat frontal
      cortex and nucleus accumbens following fear memory retrieval. Increased
      expression of zif268 was observed in neurons in the core of the nucleus accumbens
      during the retrieval of contextual and discrete cued fear associations. In
      contrast, zif268 expression was additionally induced in neurons of the nucleus
      accumbens shell and the anterior cingulate cortex during the retrieval of
      contextual but not cued fear memories. No changes in the expression of this gene
      were seen in the ventral medial prefrontal cortex or ventral and lateral regions
      of the orbitofrontal cortex that were correlated specifically with the retrieval
      of fear memory. These experiments demonstrate the specific and dissociable
      activation of limbic cortical-ventral striatal regions that accompanies cued and
      contextual fear. These data, together with those previously published by our
      laboratory (Hall, J., Thomas, K.L. & Everitt, B.J. (2001) J. Neurosci., 21, 2186
      2193), suggest that retrieval of contextual fear memories activates a wider
      limbic cortical-ventral striatal neural circuitry than does retrieval of cued
      fear memories. Moreover, the expression of zif268 may contribute to plasticity
      and reconsolidation of fear memory in these dissociable pathways.

PMID- 12431234
TI  - Visual information process in Williams syndrome: intact motion detection
      accompanied by typical visuospatial dysfunctions.
AB  - It has been suggested that visuospatial cognitive disabilities seen in children
      with Williams syndrome (WMS) are related to a dysfunction of the dorsal stream in
      the visual information analysis system. We investigated whether visual motion
      detection is also impaired in WMS because it is one of the main functions of the
      dorsal stream. Using various psychophysical examinations and
      magnetoencephalography, we studied a child with WMS who had the typical features
      of the syndrome. We found profound impairments in the visuospatial cognitions, as
      previously reported in WMS. In contrast, he had normal ability for the direction
      discrimination of coherent motion on a background of randomly moving dots, and he
      perceived apparent motion as do normal children. Furthermore, the latencies of
      both responses to the coherent and incoherent motions as measured by
      magnetoencephalography were within the mean +/- 2 SD among normal adults and the
      estimated origins were near the human homologue of V5/MT (visual area 5/middle
      temporal area). The results indicate that the visuospatial cognitive deficits in
      WMS can occur without impairment of the visual motion detection. We consider that
      the deficits are caused by a restricted dysfunction of the neural groups for
      position and three-dimensional form perceptions in the dorsal stream of the
      visual system, though other possibilities are not excluded.

PMID- 12431233
TI  - The role of the medial supramammillary nucleus in the control of hippocampal
      theta activity and behaviour in rats.
AB  - The medial supramammillary nucleus (mSUM) controls the frequency of hippocampal
      theta activity, completely in anaethsetized rats and partially in free-moving
      rats. mSUM could therefore influence hippocampal contributions to cognition and
      emotion. Using chemical lesions of mSUM in rats, we tested whether mSUM is
      involved in controlling several hippocampal-dependent functions: (i) defensive
      behaviour (open field, fear conditioning); (ii) behavioural inhibition (fixed
      interval schedule, differential reinforcement of low rates schedule); and (iii)
      spatial learning (water maze). Theta frequency was measured in all these tasks.
      mSUM lesions produced a pattern of changes in motivated/emotional behaviours
      (hyperactivity in defensive and operant tasks) similar to the pattern produced by
      hippocampal lesions, but had no significant effect on spatial learning. mSUM
      lesion decreased theta frequency modestly (by approximately 0.4 Hz) in behaving
      rats if the amount of movement was unchanged. There was not always a parallel
      between changes in theta frequency and behaviour; behaviours changed despite
      unchanged theta in defensive tasks and learning changed little despite a lower
      frequency of theta in the water maze task. This suggests that mSUM function
      impacts on emotional behaviour more than cognition, and can modulate theta and
      behaviour independently.

PMID- 12431235
TI  - Key role for enkephalinergic tone in cortico-striatal-thalamic function.
AB  - Whereas the role of dopaminergic tone in the cortico-striatal-thalamic system is
      well-established, the role of endogenous opioids in the function of this system
      is less understood. We show that Borna disease virus infection of adult rats
      results in an increase in preproenkephalin transcripts in the striatum of Borna
      infected rats, a region important for forming coordinated sequential motor
      actions and in developing programmes of thought and motivation. Stereotypic
      behaviours and dyskinesias, the clinical hallmarks of infection in adult Lewis
      rats (BD rats), are accompanied by a disrupted pattern of immediate early gene c
      fos activation in the motor thalamus, with significance for the breakdown in
      coordinated sequential motor actions. We also find increased preproenkephalin in
      infected cultured neuroblastoma and rat foetal glial cells. The expression
      pattern of enkephalin mRNA in vivo and in vitro suggest that increased enkephalin
      function is one of the neuropharmacological means by which Borna disease virus
      causes motor disease of animals and possibly cognitive and affective disease in
      man, and further suggest that enkephalins play a critical role in the maintenance
      of a balanced tone of activity in the cortico-basal ganglia-thalamo-cortical
      loops.

PMID- 12431236
TI  - Time-dependent hierarchical organization of spatial working memory: a
      transcranial magnetic stimulation study.
AB  - The performance of memory-guided saccades with two different delays (3 and 30 s
      of memorization) was studied in seven healthy subjects. Double-pulse transcranial
      magnetic stimulation (dTMS) with an interstimulus interval of 100 ms was applied
      over the right dorsolateral prefrontal cortex (DLPFC) early (1 s after target
      presentation) and late (28 s after target presentation). Early stimulation
      significantly increased in both delays the percentage of error in amplitude (PEA)
      of contralateral memory-guided saccades compared to the control experiment
      without stimulation. dTMS applied late in the delay had no significant effect on
      PEA. Furthermore, we found a significantly smaller effect of early stimulation in
      the long-delay paradigm. These results suggest a time-dependent hierarchical
      organization of the spatial working memory with a functional dominance of DLPFC
      during the early memorization, independent from the memorization delay. For a
      long memorization delay, however, working memory seems to have an additional,
      DLPFC-independent component.

PMID- 12431238
TI  - Autologous stem-cell transplantation for patients with acute myeloid leukemia
      aged over 60 yr.
AB  - OBJECTIVES: Preliminary reports have suggested that autologous stem-cell
      transplantation (ASCT) is feasible in elderly patients with acute myeloid
      leukemia (AML). The objective of this study was to describe the disease
      characteristics and treatment results from a series of 22 elderly AML patients
      undergoing ASCT. METHODS: The median age was 64 yr (range 61-71). Twenty patients
      were in first complete remission (CR1), two in CR2, and all were in performance
      status 0-1. The median interval between CR achievement and ACST was 3 months
      (range 2-5). In 20 cases peripheral blood stem cells were infused, in two bone
      marrow. RESULTS: All patients had a successful engrafment. One patient (5%) died
      from transplant-related complications. The median number of days to granulocytes
      > 500 mm-3 and platelets > 20 000 mm-3 was 11(range 9-15) and 13 (range 9-20),
      respectively. Non-hematologic toxicity included WHO grade III-IV stomatitis in
      32% patients and grade IV nausea and vomiting in one (4.5%). Seven patients had
      fever of unknown origin, while in 14 a documented infection was diagnosed. Median
      duration of hospitalization was 31 d (range 16-60). CONCLUSIONS: After a median
      follow-up of 12 months from ASCT, nine patients are alive in continuous CR and 13
      died from AML relapse. Median survival from diagnosis and disease-free survival
      (DFS) was 19 and 14 months, respectively. Our data show that ASCT with a standard
      conditioning regimen is feasible in AML patients aged more than 60 yr. Toxicity
      and hemopoietic recovery do not substantially differ from those observed in young
      adults. DFS and overall survival (OS) duration are encouraging, but a longer
      follow up is needed on a larger series of patients.

PMID- 12431237
TI  - Fulminant tumour lysis syndrome in acute myelogenous leukaemia with
      inv(16)(p13;q22).
AB  - Tumour lysis syndrome (TLS) is caused by rapid breakdown of malignant cells
      resulting in electrolyte disturbances and acute renal failure. TLS has rarely
      been described in patients with acute myelogenous leukaemia (AML). Between
      November 1997 and July 2001, 114 consecutive adult AML patients aged <60 yr
      received induction chemotherapy consisting of cytosine arabinoside 1.5 g m(-2) q
      12 h x 12 doses and daunorubicin 45 mg m(-2) d(-1) x 3 doses. During induction
      chemotherapy (CT), seven patients (6.1%, 95% CI 2.5-12.2) developed fulminant
      TLS, resulting in acute renal failure; five of these seven patients had inversion
      of chromosome 16 [inv(16)(p13;q22)], and one patient had a biological equivalent
      [t(16,16)(p13;q22)]. Four of the TLS patients underwent leukapheresis for a
      presenting white blood cell (WBC) count > 100 x 10(9) L(-1) prior to commencing
      chemotherapy, and six patients subsequently required haemodialysis for a median
      of 2 (range 1-8) wk. One TLS patient died of intracerebral hemorrhage on day 10
      and another patient of multiorgan failure on day 17. Of the other five patients,
      all entered a complete remission (CR) and recovered normal renal function. Four
      patients remain in continuous CR [median follow-up 20 (range 12-25) months]. One
      patient relapsed at 12 months and again developed TLS on re-induction. In
      univariate analysis, TLS patients were more likely to have an elevated
      presentation and pre-chemotherapy WBC counts, elevated serum creatinine, and uric
      acid levels at presentation, as well as an inv(16). In multivariate analysis,
      only serum creatinine and inv(16) remained statistically significant (P < 0.001
      for each). Patients with an inv(16) are a unique AML subgroup at high risk for
      fulminant TLS.

PMID- 12431239
TI  - Diverse role of MMP-2 and MMP-9 in the clinicopathological behavior of Hodgkin's
      lymphoma.
AB  - This is the first study to describe the role of MMP-2 and MMP-9 in Hodgkin's
      disease. Strong MMP-2 expression correlated with a favorable prognosis, while MMP
      9 expression showed a tendency toward an adverse outcome. MMP-9 expression
      correlated with B symptoms and decreased new vessel formation. MMP-2 expression
      was associated with the nodular sclerosis subtype, and its expression was most
      pronounced in the vicinity of sclerosis. Neither of the gelatinases nor the
      extent of neovascularization correlated with tumor stage, the occurrence of bulky
      disease, or extranodal infiltrates. Together, these findings imply that the
      adverse role of MMP-9 may be associated with the controlling of immunological
      processes but not the invasion probabilities or neovascularization of the tumor.
      The favorable prognostic value of MMP-2 is surprising in view of the role of MMPs
      in solid tumors. This, however, may be linked to the basic biological differences
      of hematological malignancies vs. other tumors.

PMID- 12431240
TI  - Cost analysis of CHOP (-like) chemotherapy regimens for patients with newly
      diagnosed aggressive non-Hodgkin's lymphoma.
AB  - Many cost analyses of stem-cell transplantations are available, which is in sharp
      contrast to the level of cost analyses on first-line chemotherapy for aggressive
      non-Hodgkin's lymphoma (NHL). Given the scarcity of cost analyses of first-line
      chemotherapy for NHL, it is difficult to assess the economic impact of upcoming
      new treatment modalities. Therefore we performed an analysis on costs of
      diagnosis and treatment of patients with newly diagnosed NHL who were treated
      with standard CHOP (-like) chemotherapy. As many NHL patients are treated in
      trials and the economic effects of the trial participation are unknown, our
      analysis included both patients treated according to trial protocols and patients
      treated according to standard local practice (SLP). The cost analysis was based
      on the total medical consumption of the patients. It was found that costs of the
      trial and SLP groups are within comparable ranges, although costs of diagnostic
      tests were somewhat higher within the trials. In elderly patients, SLP
      chemotherapy was discontinued more frequently in case of leucocytopenia or
      thrombocytopenia. This analysis provides basic information about the costs of
      first-line standard chemotherapy for patients with newly diagnosed aggressive NHL
      and the plausible ranges in which these costs may vary. Given the results, we
      will initiate larger studies to investigate whether trial treatments (showing
      more or less similar costs as SLP treatments) are more cost-effective for
      patients with aggressive NHL.

PMID- 12431241
TI  - The prognostic significance of CA 125 in patients with non-Hodgkin's lymphoma.
AB  - OBJECTIVE: To assess the association of serum CA 125 in patients with non
      Hodgkin's lymphoma (NHL) with prognostic parameters of the disease, response to
      treatment, and survival. PATIENTS AND METHODS: Sixty-eight patients [38 males,
      median age 56 (range 17-82) yr] with NHL were evaluated. CA 125 was measured by
      an enzyme immunoradiometric assay at diagnosis and at the end of first-line
      treatment. RESULTS: Median overall CA 125 was 49 (1-963) U mL-1, whereas 49
      patients had initially abnormal (>35 U mL) CA 125 levels. High CA 125 was found
      to correlate with failure of treatment (P = 0.001) and relapse (P = 0.01), and to
      be independently associated with bulky disease, effusions, LDH, and the
      International Prognostic Index (IPI) score (P<0.01 for each of these four
      variables). An initially abnormal CA 125 value was associated with poorer 5-yr
      survival [median survival of patients with CA 125>35 U mL-1 33 (18-72) months
      compared to 58 (20-77) months for those with CA 125 = 35 U mL-1, P = 0.012].
      Moreover, CA 125>35 U mL-1 (among stage III/IV and LDH>460 mU mL-1) emerged as an
      independent predictor of death within 5 yr from diagnosis (Relative Risk (RR)
      3.1, 95% CI 1.5-12.8, P = 0.02). CONCLUSION: Measurement of serum CA 125 is
      useful for staging, monitoring, and estimating prognosis in patients with NHL.

PMID- 12431242
TI  - Retinoid-induced apoptosis in B-cell chronic lymphocytic leukaemia cells is
      mediated through caspase-3 activation and is independent of p53, the retinoic
      acid receptor, and differentiation.
AB  - The aim of this study was to investigate the effects of all-trans retinoic acid
      (ATRA) on apoptosis induction, Bcl-2 family protein expression, and
      differentiation in B-cell chronic lymphocytic leukaemia (B-CLL) cells. ATRA
      induced apoptosis in all the B-CLL samples tested, and this was accompanied by a
      specific reduction in Bcl-2 and Mcl-1 protein expression in the apoptotic cells.
      In contrast, Bax, p21, and p53 expression was not altered in either the viable or
      apoptotic B-CLL cells, inferring that ATRA utilises a p53-independent cell death
      pathway. Caspase-3 activation was shown to be a prerequisite for ATRA-induced
      apoptosis, which was inhibited by the pan-caspase inhibitor Z-VAD-FMK and the
      caspase-9 inhibitor Z-LEHD-FMK. In addition, the retinoic acid receptor (RAR)
      antagonist AGN194310 failed to abrogate the apoptotic effects of ATRA, indicating
      that RAR binding was not necessary for ATRA-induced apoptosis. Furthermore, there
      was no evidence of ATRA-induced differentiation of the B-CLL cells in this study
      either in terms of altered morphology or immunophenotype. In summary these data
      indicate that ATRA induces apoptosis via the intrinsic apoptotic pathway, and
      this is independent of RAR binding, p53 activation, and cellular differentiation
      in B-CLL cells.

PMID- 12431243
TI  - Possible ameliorative effect of taurine in the treatment of iron-deficiency
      anaemia in female university students of Gaza, Palestine.
AB  - The aim of the study was to evaluate the haematological effects of adding the
      antioxidant taurine to iron sulfate in the treatment of iron-deficiency anaemia
      (IDA). A sample of 730 students from Al-Azhar University, Gaza, in Palestine
      underwent screening with complete blood counts and serum samples. In subjects
      with microcytosis/hypochromasia, Alpha2 delta2 (HbA2) and serum concentrations of
      iron, total iron binding capacity (TIBC), ferritin and taurine were determined.
      Samples from 17 normocytic, normochromic, and non-anaemic subjects were used as
      baseline controls. At base-line, 81 of the 730 subjects (11.1%) had
      microcytosis/hypochromasia, 26 (3.6%) were diagnosed as beta-thalassemia
      carriers, none of which was iron deficient. Four subjects had microcytosis of
      unknown cause. Fifty-one subjects (all females) had iron-deficiency anaemia and
      were included in the therapeutic study, which lasted for 20 wk. They were matched
      for Hb into pairs and were treated with oral iron (325 mg of slow-release iron
      sulfate). In addition, they were, in a double-blind procedure, randomised to
      additional oral taurine (1000 mg d(-1) at a cost comparable to that of adding
      ascorbic acid) or placebo. Mean S-taurine was significantly lower in the IDA
      subjects than in the controls. After 20 wk of iron supplementation, both the
      taurine and placebo group significantly improved their Hb concentrations and
      normalised the markers of iron deficiency. Apart from the expected, albeit in
      this study mild side-effects of oral iron, no significant side-effects were
      noted. In the taurine group, there was a statistically significant additive
      positive change from the baseline values on Hb (2.67 +/- 1.24 g dL(-1)), red
      blood cell (RBC) count [(0.57 +/- 0.25) x 1012 L(-1)] and serum ferritin (30.33
      +/- 17.99 microg L(-1)) as compared to placebo group values, which were 1.80 +/-
      1.10 g dL-1, (0.39 +/- 0.36) x 1012 L(-1), and 20.11 +/- 7.34 microg L(-1),
      respectively. Oral taurine appears to increase the effectiveness of oral iron in
      the treatment of IDA, and has no significant side-effects. This merits further
      cost-benefit and clinical analyses.

PMID- 12431244
TI  - Pseudothrombocytopenia: a report of a new method to count platelets in a patient
      with EDTA- and temperature-independent antibodies of the IgM type.
AB  - Pseudothrombocytopenia is usually associated with blood specimens anticoagulated
      with ethylenediamine tetraacetic acid (EDTA) or other anticoagulants. It may be
      caused by temperature-independent, EDTA-dependent antibodies of the
      immunoglobulin-M (IgM) type. Here a patient with EDTA-independent and temperature
      independent pseudothrombocytopenia mediated by IgM or IgM-containing immune
      complex is reported, and a reliable method is described for a proper counting of
      platelets in such cases.

PMID- 12431245
TI  - Epstein-Barr virus-associated lymphoproliferative disease occurring in a patient
      with sarcoidosis treated by methotrexate and methylprednisolone.
AB  - We describe the case of a 51-yr-old man with systemic sarcoidosis, complicated by
      the occurrence of a lymphoproliferative disease following a 36-month (duration)
      immunosuppressive treatment with methotrexate (MTX) and methylprednisolone. Four
      years after the onset of sarcoidosis, the patient presented a large necrotizing
      anal fistula. Pathological examination of this lesion showed a diffuse
      polymorphic infiltrate containing large Epstein-Barr virus (EBV)-positive
      lymphoid cells associated with areas of necrosis, all features similar to
      classical B-cell lymphoproliferative disorders occurring in immunosuppressed
      solid-organ recipients. MTX has been recently implicated in the development of
      lymphoproliferative disease in connective tissue diseases. This case supports the
      hypothesis that immunosuppression therapy may contribute to an increased risk for
      the development of EBV-associated lymphoproliferative disorders in patients
      suffering from sarcoidosis.

PMID- 12431246
TI  - Imatinib-induced acute generalized exanthematous pustulosis (AGEP) in two
      patients with chronic myeloid leukemia.
AB  - Imatinib mesylate blocks bcr/abl kinase activity effectively, and thus is a
      promising drug in Philadelphia chromosome positive leukemias. While under
      imatinib treatment high hematological and cytogenetic response rates could be
      observed, usually only mild non-hematological side-effects like skin rash, edema,
      and muscular cramps occur. Here we report two severe cases of acute generalized
      exanthematous pustulosis due to imatinib. In both patients the generalized
      pustular eruptions could be observed 12 wk after initiation of imatinib
      treatment. Numerous microbiological investigations excluded an infectious
      etiology, and histopathology of cutaneous lesions was consistent with acute
      generalized exanthematous pustulosis. Accordingly, withdrawal of imatinib led to
      a restitutio at integrum of the integument. Our report confirms another single
      observation of acute generalized exanthematous pustulosis in chronic myeloid
      leukemia under imatinib therapy, and confirms that this is a rare but proven
      adverse effect of imatinib.

PMID- 12431247
TI  - Pathogenesis of hereditary tumors: beyond the "two-hit" hypothesis.
AB  - Knudson's 'two-hit' hypothesis has provided extremely important insights into the
      pathogenesis of tumors in autosomal dominant tumor predisposition syndromes, but
      recent evidence suggests that some such tumors may occur without a 'second hit'
      or require more than two mutations. Inactivation of both RB1 alleles appears to
      be insufficient by itself to cause malignancy in the tumors that develop in
      patients with hereditary retinoblastoma. On the other hand, certain tumors in
      patients with tuberous sclerosis complex appear to develop in haploinsufficient
      tissues that do not have 'second hit' mutations of a tuberous sclerosis gene. The
      molecular pathogenesis of certain other tumors in patients with tuberous
      sclerosis complex or neurofibromatosis 1 may not be fully explained by the 'two
      hit' hypothesis either. Hereditary tumors, like non-hereditary tumors, may arise
      by a variety of molecular mechanisms, with loss of both alleles of a particular
      tumor suppressor gene being a frequent, but not invariably necessary or
      sufficient, event. Four models are presented to explain how various tumors may
      arise in patients with inherited tumor predisposition syndromes such as
      hereditary retinoblastoma, tuberous sclerosis complex or neurofibromatosis 1.
      Even tumors of one particular type may develop by more than one mechanism.

PMID- 12431248
TI  - Diabetic flies? Using Drosophila melanogaster to understand the causes of
      monogenic and genetically complex diseases.
AB  - Approximately three-quarters of human disease loci have counterparts in the fruit
      fly Drosophila melanogaster. This model organism is therefore extremely valuable
      for using to understand the role of these loci in normal development, and for
      unravelling genetic pathways in which these loci take part. Important advantages
      for Drosophila in such studies are its completed genome, the unparalleled
      collection of mutations already in existence, the relative ease in which new
      mutations can be generated, the existence of convenient techniques for
      inactivating or overexpressing genes in dispensable tissues that are easily
      observed and measured, and the ability to readily carry out second-site modifier
      genetics. Recent work in Drosophila on the insulin-signaling pathway, a pathway
      of profound clinical importance, is reviewed as an illustration of how such
      research can provide fundamental insights into the functions of this pathway in
      regulating growth and development. Moreover, Drosophila research is now
      identifying heretofore unknown regulators of insulin signaling, as well as
      indicating novel functions for this pathway in suppressing benign tumor formation
      and regulating life span.

PMID- 12431249
TI  - Modeling classic female Rett Syndrome in male mice.

PMID- 12431250
TI  - Enteroviruses prefer the dystrophin-deficient heart.

PMID- 12431251
TI  - HIP1 as a marker of aggressive prostate cancer.

PMID- 12431252
TI  - Diploid/triploid mosaicism in dysmorphic patients.
AB  - Diploid/triploid mosaicism is a dysmorphology syndrome consisting of mental
      retardation, truncal obesity, body and/or facial asymmetry, growth retardation,
      hypotonia, a small phallus, malformed low-set ears and micrognathia. In 75% of
      the cases, the blood karyotype is normal and the diagnosis can only be
      established after analysis of cultured fibroblasts. This chromosome abnormality
      may therefore be underdiagnosed. This paper focuses on the identification of
      mentally retarded and dysmorphic patients with diploid/triploid mosaicism.
      Detailed clinical description of well-defined patients may help in deciding if a
      skin biopsy for karyotyping of fibroblasts should be taken. Three new cases are
      presented, in which DNA marker analysis showed that the extra set of chromosomes
      in each case was derived from the mother. We present a review of 25 cases
      described in the literature and we discuss the inclusion of a second polar body
      into an early diploid embryo as the most likely mechanism.

PMID- 12431253
TI  - An unstable dicentric Robertsonian translocation in a markedly discordant twin.
AB  - Karyotypes from independent amniocenteses reflected a rare, unstable,
      functionally dicentric Robertsonian translocation chromosome in most cells in
      male Twin B who grew more slowly than the chromosomally normal female sib (Twin
      A). Twin B's balanced de novo Robertsonian translocation dic(13;14)(p11.1;p11.1),
      present in 81% of cells, underwent recurrent centromeric fission in 6 out of 30
      independent colonies that explains a balanced 46,XY,-13,+fis(13)(p11.1),
      14,+fis(14)(p11.1) karyotype. Aneuploidy for chromosomes 13q or 14q was present
      in 5% of cells. Instability of the Robertsonian translocation was evident because
      nine of the 30 colonies (30%) grown from single amniocytes had metaphase cells
      with more than one chromosome complement. Although uniparental disomy was
      excluded and a targeted ultrasound was normal, the couple was advised of the
      uncertain but real risk of abnormalities in Twin B and the risk to Twin A of
      terminating Twin B. The pregnancy proceeded and at 31 weeks gestation Twin A was
      in the 33rd percentile for size and Twin B in the 1st percentile. At 32 weeks,
      chromosome analysis revealed a balanced 45,XY,dic(13;14)(p11.1;p11.1) karyotype
      in all of Twin B's newborn cord blood cells with no evidence of fission or
      aneuploidy. Selection against unbalanced mitotic products of the unstable,
      functionally dicentric chromosome in early fetal development is proposed to
      result in Twin B's highly discordant small birth size.

PMID- 12431254
TI  - The changing survival profile of people with Down's syndrome: implications for
      genetic counselling.
AB  - Cohort studies have indicated that the survival of individuals with Down's
      syndrome has dramatically increased over the past 50 years. Early childhood
      survival in particular has shown major improvement, due largely to advances in
      cardiac surgery and in general health management. The present study was based on
      a continuous cohort of 1332 people with Down's syndrome in Western Australia,
      registered for intellectual disability services between 1953 and 2000. Their life
      expectancy was 58.6 years, 25% lived to 62.9 years, and the oldest living person
      is 73 years of age. Life expectancy for males was greater than females by 3.3
      years. The substantial increase in survival across the study period means that
      the life expectancy of people with Down's syndrome is approaching that of the
      general population, but accompanied by a range of significant mid-life health
      problems. The findings are of relevance to all developed countries and have
      considerable implications in terms of the counselling information provided to
      families at risk of having a child with Down's syndrome.

PMID- 12431255
TI  - Frequency of the thermolabile variant C677T in the MTHFR gene and lack of
      association with neural tube defects in the State of Yucatan, Mexico.
AB  - The C677T variant in the MTHFR gene is considered to be an associated risk factor
      for neural tube defects. However, the association has not been found in some
      ethnic groups. In order to assess the association between neural tube defects and
      the C677T variant, we determined the frequency of this variant in the MTHFR gene
      in the State of Yucatan, Mexico, where neural tube defects are highly prevalent.
      The study was performed on 65 subjects with spine bifida, 60 of their mothers and
      110 control subjects. The presence of the C677T variant was determined by
      amplification and digestion with HinF1 of each subject's DNA. Genotypic and
      allelic frequencies were calculated for all groups. We did not observe any
      statistically significant difference in the genotypic or allelic frequencies
      between cases and controls for any of the groups studied (p > 0.05), suggesting
      that the thermolabile variant C677T is not an associated risk factor neither for
      the development of neural tube defects nor for mothers to have affected offspring
      in the population from Yucatan. Interestingly, the frequency of the C677T variant
      (54%) obtained in the Yucatan population is one of the highest reported (p <
      0.01) and confirmed the high frequency of this allele throughout Mexico.

PMID- 12431256
TI  - Genetic heterogeneity in Malattia Leventinese.
AB  - Malattia Leventinese (ML) is a dominant macular dystrophy characterized by drusen
      at the posterior pole. ML has been associated with a single mutation (R345W) in
      the EGF-containing fibulin-like extracellular matrix protein 1 (EFEMP-1) gene,
      but also the EFEMP-2 gene, known to share genetic homology with EFEMP-1, is
      considered a candidate gene for this genetic disorder. We have characterized
      clinically and genetically seven members of a three-generation family affected by
      ML. Results showed that five family members were clinically affected but the DNA
      sequencing failed to reveal the typical R345W mutation. Furthermore, the linkage
      analysis to EFEMP-1 (using polymorphic markers D2S337 and D2S2368) and to EFEMP-2
      (using D11S987 and D11S1314 markers) gave negative results. Therefore, our
      results suggest EFEMP-1 or EFEMP-2 genes cannot be excluded as being responsible
      for ML but other genes have to be considered in the pathogenesis of the disease.

PMID- 12431257
TI  - SCA8 in the Spanish population including one homozygous patient.
AB  - Controversial data have been reported about SCA8 since its description in 1999.
      The most accepted hypothesis is that CTG expansions within the CTA/CTG combined
      repeat expansion in the SCA8 locus causes SCA8. It is inherited as a dominant
      trait with reduced penetrance. The present study, reports the first data
      regarding SCA8 in the Spanish population and the clinical findings in patients
      carrying expanded alleles, including one homozygous patient. Two hundred and
      forty-six individuals from the Spanish population, including controls (149) and
      ataxic patients (97), were studied. DNA was extracted from blood samples using
      standard methods. Amplification of the CTA/CTG 3'untranslated region was achieved
      by PCR using primers SCA8-F3 and SCA8-R4 and conditions described previously.
      Neurological reevaluation was done in individuals carrying the expanded allele.
      We detected five unrelated expanded alleles corresponding to three affected
      patients (one of them homozygous) and one healthy individual. SCA8 represents 4%
      of the total dominant spinocerebellar ataxias studied in our group (Spanish
      population) (three index patients out of 75 dominant ataxic independent nucleus).
      The patient that resulted homozygous for the expansion is a 25-year-old man with
      a clinical picture of progressive ataxia and dysarthria that began at the age of
      12. On neurological examination, he showed ataxia, slight dysarthria and
      nystagmus to the extreme lateral gaze. A cranial MRI showed global atrophy of
      cerebellum but the brainstem was spared. Family history showed the presence of
      ataxia in his grandfather and father. His mother is healthy at the age of 52 and
      a molecular study of SCA8 reveals one allele that could be considered as
      premutated. She has no ataxia antecedents in her family. Our results provide
      additional information about the SCA8 expansion, within the Spanish population.
      These results are in agreement with the hypothesis of the CTG expansion in the
      SCA8 locus being responsible for the SCA8 ataxia showing reduced penetrance.
      Besides homozygous status, advancing age at onset (as previously described for
      other SCAs) supports this idea.

PMID- 12431258
TI  - Involvement of a palindromic chromosome 22-specific low-copy repeat in a
      constitutional t(X; 22)(q27;q11).
AB  - Segmental duplications or low-copy repeats (LCRs) on chromosome 22q11 have been
      implicated in several chromosomal rearrangements. The presence of AT-rich regions
      in these duplications may lead to the formation of hairpin structures, which
      facilitate chromosomal rearrangement. Here we report the involvement of such a
      low-copy repeat in a t(X;22) associated with a neural tube defect. Molecular
      analysis of the chromosomal breakpoints revealed that the chromosome 22
      breakpoint maps in the palindromic non-AT-rich NF1-like region of low-copy repeat
      B (LCR-B). No palindromic region was encountered near the breakpoint on
      chromosome X. Our findings confirm that there is no single mechanism leading to
      translocations with chromosome 22q11 involvement. Because LCR-B does not contain
      genes involved in neural tube development, we believe that the gene responsible
      for the observed phenotype is most likely localized on chromosome X.

PMID- 12431259
TI  - Ring syndrome caused by ring chromosome 7 without loss of subtelomeric sequences.
AB  - Ring chromosome 7 is an unusual chromosome anomaly. Here we describe a patient
      with ring chromosome 7 and we show that both subtelomeres are still present. The
      diagnosis agrees with 'ring syndrome'. This report helps to further delineate the
      clinical manifestations of 'ring syndrome' and to distinguish the phenotypic
      consequences of the presence of a ring chromosome 7 from the phenotypic
      consequences of terminal chromosome 7 submicroscopic deletions.

PMID- 12431260
TI  - Sleep disturbance in mucopolysaccharidosis type III (Sanfilippo syndrome): a
      survey of managing clinicians.
AB  - Sanfilippo syndrome (mucopolysaccharidosis type III) is the commonest
      mucoploysaccharidosis. It causes neurodegeneration with often profound sleep and
      behavioral disturbance. Management of the sleep disturbance is difficult and
      inconsistent. In this study, we surveyed clinicians with particular expertise in
      the management of individuals with mucopolysaccharidoses. We found that sleep
      problems are almost universal in this patient population and that no one
      treatment is consistently viewed as beneficial. Among the clinicians surveyed,
      melatonin is reported as the medication most likely to be of benefit.
      Benzodiazepines, chloral hydrate, antihistamines and antipsychotic agents are
      overall reported as less efficacious. The major side-effect of the medications as
      a group was reported to be daytime somnolence. Based on this study,
      recommendations are given regarding the approach to sleep disturbance in
      Sanfilippo syndrome.

PMID- 12431262
TI  - To question or not to question?

PMID- 12431263
TI  - Women's views of pregnancy ultrasound: a systematic review.
AB  - BACKGROUND: Ultrasound has become a routine part of care for pregnant women in
      most countries with developed health services. It is one of a range of techniques
      used in screening and diagnosis, but it differs from most others because of the
      direct access that it gives parents to images of the fetus. A review of women's
      views of ultrasound was commissioned as part of a larger study of the clinical
      and economic aspects of routine antenatal ultrasound use. METHODS: Studies of
      women's views about antenatal screening and diagnosis were searched for on
      electronic databases. Studies about pregnancy ultrasound were then identified
      from this material. Further studies were found by contacting researchers, hand
      searches, and following up references. The searches were not intentionally
      limited by date or language. Studies that reported direct data from women about
      pregnancy ultrasound were then included in a structured review. Studies were not
      excluded on the basis of methodological quality unless they were impossible to
      understand. They were read by one author and tabulated. The review then addressed
      a series of questions in a nonquantitative way. RESULTS: The structured review
      included 74 primary studies represented by 98 reports. Studies from 18 countries
      were included, and they employed methods ranging from qualitative interviewing to
      psychometric testing. The review included studies from the very early period of
      ultrasound use up to reports of research on contemporary practice. Ultrasound is
      very attractive to women and families. Women's early concerns about the safety of
      ultrasound were rarely reported in more recent research. Women often lack
      information about the purposes for which an ultrasound scan is being done and the
      technical limitations of the procedure. The strong appeal of diagnostic
      ultrasound use may contribute to the fact that pregnant women are often
      unprepared for adverse findings. CONCLUSIONS: Despite the highly varied study
      designs and contexts for the research included, this review provided useful
      information about women's views of pregnancy ultrasound. One key finding for
      clinicians was the need for all staff, women, and partners to be well informed
      about the specific purposes of ultrasound scans and what they can and cannot
      achieve.

PMID- 12431264
TI  - Racial and ethnic disparities in breastfeeding among United States infants: Third
      National Health and Nutrition Examination Survey, 1988-1994.
AB  - BACKGROUND: The studies suggesting that blacks are less likely to initiate and
      maintain breastfeeding than whites in the United States are limited either by the
      representativeness of the sample or by the ambiguousness of attribution of racial
      and ethnic disparities to generally poor socioeconomic status among blacks. The
      purpose of this study was to examine racial and ethnic disparities in
      breastfeeding rates among U.S. infants using national representative data.
      METHODS: We analyzed breastfeeding data reported by parents of children ages 12
      to 71 months at the time of interview from the Third National Health and
      Nutrition Examination Survey (1988-1994). Breastfeeding data were stratified by
      both race and ethnicity, and by a series of sociodemographic and health-related
      characteristics. RESULTS: The proportion of children ever breastfed was 60
      percent among non-Hispanic whites, 26 percent among non-Hispanic blacks, and 54
      percent among Mexican Americans. By 6 months postpartum, the proportion still
      breastfed decreased to 27, 9, and 23 percent, correspondently. Blacks also had a
      significantly lower rate of exclusive breastfeeding at 4 months than whites
      (14%). In addition, the differentials in breastfeeding rates between high and low
      socioeconomic classes were most substantial among blacks. CONCLUSIONS: Blacks had
      consistent lower breastfeeding rates than whites regardless of their
      sociodemographic status. The large differentials between high and low
      socioeconomic classes among blacks suggest that socioeconomic status has a bigger
      impact on breastfeeding practices among blacks. Therefore, blacks, particularly
      those who are poor or less educated, need to be targeted for promotion,
      protection, and support of breastfeeding.

PMID- 12431265
TI  - Home versus hospital breastfeeding support for newborns: a randomized controlled
      trial.
AB  - BACKGROUND: The advantages of breastfeeding have been well established for both
      mothers and their infants. Existing research reports equivocal effects of early
      discharge and postpartum home care on breastfeeding success. The purpose of this
      study was to compare the effects of breastfeeding support offered in hospital and
      home settings on breastfeeding outcomes and maternal satisfaction for mothers of
      term and near-term newborns who experienced standard or early discharge. METHODS:
      In a randomized controlled trial with prognostic stratification for gestational
      age, 101 term and 37 near-term (35-37 weeks' gestational age) mother-newborn
      pairs were randomized to either a standard care group (standard care and standard
      length of hospitalization) or an experimental group (standard hospital care with
      early discharge and home support from nurses who were certified lactation
      consultants). Data collection occurred before randomization, at discharge from
      hospital, and from 5 to 12 days postpartum. Primary outcomes included
      breastfeeding rates and maternal satisfaction. RESULTS: More mothers of term
      newborns in the experimental group were breastfeeding exclusively at follow-up (p
      = 0.02) compared with the control group. No significant breastfeeding differences
      occurred among mothers with near-term newborns in the experimental and standard
      care groups. CONCLUSIONS: In-home lactation support appears to facilitate
      positive breastfeeding outcomes for mothers of term newborns. This may also be a
      beneficial model of postpartum care for mothers of near-term newborns; however,
      further research is required. The findings suggest implications for health
      caregivers and policy makers with respect to postpartum lactation and health care
      services.

PMID- 12431266
TI  - Immigrant women's views about care during labor and birth: an Australian study of
      Vietnamese, Turkish, and Filipino women.
AB  - BACKGROUND: Few studies of immigrant women's views of maternity care in their new
      homelands have been conducted. In Victoria, Australia, approximately 1 woman in 7
      giving birth was born overseas in a non-English speaking country. This paper
      examines the views of three groups of immigrant women about the care they
      received in hospital for the birth of their babies and compares the findings with
      a population-based statewide survey. METHODS: Mothers in a New Country was a
      study of 318 Vietnamese, Turkish, and Filipino women interviewed about their
      maternity care experiences by bicultural interviewers 6 months after giving birth
      in Melbourne, Australia. The interview schedule was adapted from the 1994
      Victorian Survey of Recent Mothers, a population-based postal survey of 1336
      women. RESULTS: Of the 3 groups, 27 percent of Vietnamese, 48 percent of Turkish,
      and 39 percent of Filipino women reported their care during labor and birth as
      "very good," figures significantly lower than for the statewide survey, in which
      61 percent of women experiencing similar models of care described their care as
      "very good." This significant differential in views about care was also present
      for many individual aspects of care. In the current study of mothers in a new
      country, comments about aspects of care with which women were particularly happy
      and unhappy highlighted their appreciation of care that was safe, kind,
      supportive, and respectful, and conversely, illustrated how distressed women were
      when care failed to meet these basic standards. CONCLUSIONS: What immigrant women
      wanted from their maternity care proved to be extremely similar to what
      Australian-born women--and women the world over--want. Unfortunately, immigrant
      women were much less likely to experience care that gave them what they wanted.

PMID- 12431267
TI  - Barriers to implementing the group B streptococcal prevention guidelines.
AB  - BACKGROUND: Group B streptococcal disease is the leading cause of neonatal sepsis
      in the United States. We assessed predictors of compliance with the consensus
      guidelines for perinatal group B streptococcus disease prevention at two Group
      Health Cooperative hospitals. METHODS: A descriptive and cohort analysis was
      conducted of failure to comply with the screening-based approach to group B
      streptococcus prevention among singleton birth pregnancies in two Group Health
      Cooperative hospitals, September 1, 1996 to December 31, 1997. We studied
      determinants of failure to screen pregnant women for group B streptococcus at 35
      to 37 weeks' gestation and failure to deliver intrapartum antibiotic prophylaxis
      to Group B streptococcus-positive women. RESULTS: Nearly 28 percent of 1969 women
      delivering at two Group Health Cooperative hospitals were not screened
      appropriately for group B streptococcus. Women who were not screened properly
      were more likely to be in their teens. A short length of hospital stay before
      delivery was the strongest predictor of the lack of administration of intrapartum
      antibiotic prophylaxis to infected multiparas at delivery. Group B streptococcus
      positive women without pregnancy complications were less likely to receive
      intrapartum antibiotic prophylaxis than infected women with complications.
      CONCLUSIONS: The findings of this study suggest that to improve group B
      streptococcus disease prevention, screening efforts should focus on teenage
      women, and intrapartum antibiotic prophylaxis delivery efforts should be aimed at
      low-risk women with precipitous labor.

PMID- 12431277
TI  - A multidisciplinary program for achieving lipid goals in chronic hemodialysis
      patients.
AB  - BACKGROUND: There is little information on how target lipid levels can be
      achieved in end stage renal disease (ESRD) patients in a systematic,
      multidisciplinary fashion. METHODS: We retrospectively reviewed a pharmacist
      directed hyperlipidemia management program for chronic hemodialysis (HD)
      patients. All 26 adult patients on chronic HD at a tertiary care medical facility
      were entered into the program. A clinical pharmacist was responsible for
      laboratory monitoring, patient counseling, and the initiation and dosage
      adjustment of an appropriate 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA)
      reductase inhibitor (statin) using a dosing algorithm and monitoring guidelines.
      The low-density lipoprotein (LDL) cholesterol goal was leq; 100 mg/dl. A renal
      dietitian provided nutrition counseling and the nephrologist was notified of
      potential or existing drug interactions or adverse drug reactions (ADRs).
      Patients received a flyer containing lipid panel results to encourage compliance.
      Data was collected at program initiation and for 6 months thereafter. RESULTS: At
      the start of the program, 58% of patients were at target LDL cholesterol. At 6
      months, 88% had achieved target LDL (p = 0.015). Mean LDL cholesterol decreased
      from 96 +/- 5 to 80 +/- 3 mg/dl (p < 0.01), and mean total cholesterol decreased
      from 170 +/- 7 to 151 +/- 4 mg/dl (p < 0.01). Fifteen adjustments in drug therapy
      were made. Eight adverse drug reactions were identified; 2 required drug
      discontinuation or an alternative agent. Physicians were alerted to 8 potential
      drug-drug interactions, and appropriate monitoring was performed. CONCLUSIONS:
      Our findings demonstrate both feasibility and efficacy of a multidisciplinary
      approach in management of hyperlipidemia in HD patients.

PMID- 12431278
TI  - Chromosomal aberrations in patients with head and neck squamous cell carcinoma do
      not vary based on severity of tobacco/alcohol exposure.
AB  - BACKGROUND: Head and neck squamous cell carcinomas (HNSCC) have been causally
      associated with tobacco and alcohol exposure. However, 10-15% of HNSCC develop in
      absence of significant carcinogen exposure. Several lines of evidence suggest
      that the genetic composition of HNSCC varies based on the extent of
      tobacco/alcohol exposure, however, no genome wide measures have been applied to
      address this issue. We used comparative genomic hybridization (CGH) to screen for
      the genetic aberrations in 71 patients with head and neck squamous cell carcinoma
      and stratified the findings by the status of tobacco/alcohol exposure. RESULTS:
      Although the median number of abnormalities (9), gains (6) and losses (2) per
      case and the overall pattern of abnormalities did not vary significantly by the
      extent of tobacco/alcohol exposure, individual abnormalities segregating these
      patients were identified. Gain of 1p (p = 0.03) and 3q amplification (p = 0.05)
      was significantly more common in patients with a history of tobacco/alcohol
      exposure. CONCLUSIONS: This data suggests that the overall accumulated
      chromosomal aberrations in head and neck squamous cell carcinoma are not
      significantly influenced by the severity of tobacco/alcohol exposure with limited
      exceptions.

PMID- 12431279
TI  - FunSpec: a web-based cluster interpreter for yeast.
AB  - BACKGROUND: For effective exposition of biological information, especially with
      regard to analysis of large-scale data types, researchers need immediate access
      to multiple categorical knowledge bases and need summary information presented to
      them on collections of genes, as opposed to the typical one gene at a time.
      RESULTS: We present here a web-based tool (FunSpec) for statistical evaluation of
      groups of genes and proteins (e.g. co-regulated genes, protein complexes, genetic
      interactors) with respect to existing annotations (e.g. functional roles,
      biochemical properties, localization). FunSpec is available online at
      http://funspec.med.utoronto.ca CONCLUSION: FunSpec is helpful for interpretation
      of any data type that generates groups of related genes and proteins, such as
      gene expression clustering and protein complexes, and is useful for predictive
      methods employing "guilt-by-association."

PMID- 12431280
TI  - Guidelines for management of acute cervical spinal injuries. Introduction.

PMID- 12431281
TI  - Cervical spine immobilization before admission to the hospital.
AB  - STANDARDS: There is insufficient evidence to support treatment standards.
      GUIDELINES: There is insufficient evidence to support treatment guidelines.
      OPTIONS: All trauma patients with a cervical spinal column injury or with a
      mechanism of injury having the potential to cause cervical spine injury should be
      immobilized at the scene and during transport by using one of several available
      methods. A combination of a rigid cervical collar and supportive blocks on a
      backboard with straps is effective in limiting motion of the cervical spine and
      is recommended. The long-standing practice of attempted cervical spine
      immobilization using sandbags and tape alone is not recommended.

PMID- 12431282
TI  - Transportation of patients with acute traumatic cervical spine injuries.
AB  - STANDARDS: There is insufficient evidence to support treatment standards.
      GUIDELINES: There is insufficient evidence to support treatment guidelines.
      OPTIONS: Expeditious and careful transport of patients with acute cervical spine
      or spinal cord injuries is recommended, from the site of injury by the most
      appropriate mode of transportation available to the nearest capable definitive
      care medical facility.

PMID- 12431283
TI  - Clinical assessment after acute cervical spinal cord injury.
AB  - NEUROLOGICAL EXAMINATION: STANDARDS: There is insufficient evidence to support
      neurological examination standards. GUIDELINES: There is insufficient evidence to
      support neurological examination guidelines. OPTIONS: The American Spinal Injury
      Association international standards for neurological and functional
      classification of spinal cord injury are recommended as the preferred
      neurological examination tool for clinicians involved in the assessment and care
      of patients with acute spinal cord injuries. FUNCTIONAL OUTCOME ASSESSMENT:
      STANDARDS: There is insufficient evidence to support functional outcome
      assessment standards. GUIDELINES: The Functional Independence Measure is
      recommended as the functional outcome assessment tool for clinicians involved in
      the assessment and care of patients with acute spinal cord injuries. OPTIONS: The
      modified Barthel index is recommended as a functional outcome assessment tool for
      clinicians involved in the assessment and care of patients with acute spinal cord
      injuries.

PMID- 12431284
TI  - Radiographic assessment of the cervical spine in asymptomatic trauma patients.
AB  - STANDARDS: Radiographic assessment of the cervical spine is not recommended in
      trauma patients who are awake, alert, and not intoxicated, who are without neck
      pain or tenderness, and who do not have significant associated injuries that
      detract from their general evaluation.

PMID- 12431285
TI  - Radiographic assessment of the cervical spine in symptomatic trauma patients.
AB  - STANDARDS: A three-view cervical spine series (anteroposterior, lateral, and
      odontoid views) is recommended for radiographic evaluation of the cervical spine
      in patients who are symptomatic after traumatic injury. This should be
      supplemented with computed tomography (CT) to further define areas that are
      suspicious or not well visualized on the plain cervical x-rays. GUIDELINES: There
      is insufficient evidence to support treatment guidelines. OPTIONS: It is
      recommended that cervical spine immobilization in awake patients with neck pain
      or tenderness and normal cervical spine x-rays (including supplemental CT as
      necessary) be discontinued after either a) normal and adequate dynamic
      flexion/extension radiographs, or b) a normal magnetic resonance imaging study is
      obtained within 48 hours of injury. Cervical spine immobilization in obtunded
      patients with normal cervical spine x-rays (including supplemental CT as
      necessary) may be discontinued a) after dynamic flexion/extension studies
      performed under fluoroscopic guidance, or b) after a normal magnetic resonance
      imaging study is obtained within 48 hours of injury, or c) at the discretion of
      the treating physician.

PMID- 12431286
TI  - Initial closed reduction of cervical spine fracture-dislocation injuries.
AB  - STANDARDS: There is insufficient evidence to support treatment standards.
      GUIDELINES: There is insufficient evidence to support treatment guidelines. Early
      closed reduction of cervical spine fracture-dislocation injuries with
      craniocervical traction is recommended to restore anatomic alignment of the
      cervical spine in awake patients. Closed reduction in patients with an additional
      rostral injury is not recommended. Patients with cervical spine fracture
      dislocation injuries who cannot be examined during attempted closed reduction, or
      before open posterior reduction, should undergo magnetic resonance imaging (MRI)
      before attempted reduction. The presence of a significant disc herniation in this
      setting is a relative indication for a ventral decompression before reduction.
      MRI study of patients who fail attempts at closed reduction is recommended.
      Prereduction MRI performed in patients with cervical fracture dislocation injury
      will demonstrate disrupted or herniated intervertebral discs in one-third to one
      half of patients with facet subluxation. These findings do not seem to
      significantly influence outcome after closed reduction in awake patients;
      therefore, the usefulness of prereduction MRI in this circumstance is uncertain.

PMID- 12431287
TI  - Management of acute spinal cord injuries in an intensive care unit or other
      monitored setting.
AB  - STANDARDS: There is insufficient evidence to support treatment standards.
      GUIDELINES: There is insufficient evidence to support treatment guidelines.
      OPTIONS: Management of patients with acute spinal cord injury, particularly
      patients with severe cervical level injuries, in an intensive care unit or
      similar monitored setting is recommended. Use of cardiac, hemodynamic, and
      respiratory monitoring devices to detect cardiovascular dysfunction and
      respiratory insufficiency in patients after acute cervical spinal cord injury is
      recommended.

PMID- 12431288
TI  - Blood pressure management after acute spinal cord injury.
AB  - STANDARDS: There is insufficient evidence to support treatment standards.
      GUIDELINES: There is insufficient evidence to support treatment guidelines.
      OPTIONS: Hypotension (systolic blood pressure <90 mmHg) should be avoided if
      possible or corrected as soon as possible after acute spinal cord injury.
      Maintenance of mean arterial blood pressure at 85 to 90 mmHg for the first 7 days
      after acute spinal cord injury to improve spinal cord perfusion is recommended.

PMID- 12431289
TI  - Pharmacological therapy after acute cervical spinal cord injury.
AB  - CORTICOSTEROIDS:  STANDARDS: There is insufficient evidence to support treatment
      standards. GUIDELINES: There is insufficient evidence to support treatment
      guidelines. OPTIONS: Treatment with methylprednisolone for either 24 or 48 hours
      is recommended as an option in the treatment of patients with acute spinal cord
      injuries that should be undertaken only with the knowledge that the evidence
      suggesting harmful side effects is more consistent than any suggestion of
      clinical benefit. GM-1 GANGLIOSIDE: STANDARDS: There is insufficient evidence to
      support treatment standards. GUIDELINES: There is insufficient evidence to
      support treatment guidelines. OPTIONS: Treatment of patients with acute spinal
      cord injuries with GM-1 ganglioside is recommended as an option without
      demonstrated clinical benefit.

PMID- 12431290
TI  - Deep venous thrombosis and thromboembolism in patients with cervical spinal cord
      injuries.
AB  - STANDARDS: Prophylactic treatment of thromboembolism in patients with severe
      motor deficits due to spinal cord injury is recommended. The use of low-molecular
      weight heparins, rotating beds, adjusted dose heparin, or a combination of
      modalities is recommended as a prophylactic treatment strategy. Low-dose heparin
      in combination with pneumatic compression stockings or electrical stimulation is
      recommended as a prophylactic treatment strategy. GUIDELINES: Low-dose heparin
      therapy alone is not recommended as a prophylactic treatment strategy. Oral
      anticoagulation alone is not recommended as a prophylactic treatment strategy.
      OPTIONS: Duplex Doppler ultrasound, impedance plethysmography, and venography are
      recommended for use as diagnostic tests for deep venous thrombosis in the spinal
      cord-injured patient population. A 3-month duration of prophylactic treatment for
      deep venous thrombosis and pulmonary embolism is recommended. Vena cava filters
      are recommended for patients who do not respond to anticoagulation or who are not
      candidates for anticoagulation therapy and/or mechanical devices.

PMID- 12431291
TI  - Nutritional support after spinal cord injury.
AB  - STANDARDS: There is insufficient evidence to support treatment standards.
      GUIDELINES: There is insufficient evidence to support treatment guidelines.
      OPTIONS: Nutritional support of patients with spinal cord injuries is
      recommended. Energy expenditure is best determined by indirect calorimetry in
      these patients because equation estimates of energy expenditure and subsequent
      caloric need tend to be inaccurate.

PMID- 12431292
TI  - Management of pediatric cervical spine and spinal cord injuries.
AB  - DIAGNOSTIC:  STANDARDS: There is insufficient evidence to support diagnostic
      standards. GUIDELINES: In children who have experienced trauma and are alert,
      conversant, have no neurological deficit, no midline cervical tenderness, and no
      painful distracting injury, and are not intoxicated, cervical spine x-rays are
      not necessary to exclude cervical spine injury and are not recommended. In
      children who have experienced trauma and who are either not alert, nonconversant,
      or have neurological deficit, midline cervical tenderness, or painful distracting
      injury, or are intoxicated, it is recommended that anteroposterior and lateral
      cervical spine x-rays be obtained. OPTIONS: In children younger than age 9 years
      who have experienced trauma, and who are nonconversant or have an altered mental
      status, a neurological deficit, neck pain, or a painful distracting injury, are
      intoxicated, or have unexplained hypotension, it is recommended that
      anteroposterior and lateral cervical spine x-rays be obtained. In children age 9
      years or older who have experienced trauma, and who are nonconversant or have an
      altered mental status, a neurological deficit, neck pain, or a painful
      distracting injury, are intoxicated, or have unexplained hypotension, it is
      recommended that anteroposterior, lateral, and open-mouth cervical spine x-rays
      be obtained. Computed tomographic scanning with attention to the suspected level
      of neurological injury to exclude occult fractures or to evaluate regions not
      seen adequately on plain x-rays is recommended. Flexion/extension cervical x-rays
      or fluoroscopy may be considered to exclude gross ligamentous instability when
      there remains a suspicion of cervical spine instability after static x-rays are
      obtained. Magnetic resonance imaging of the cervical spine may be considered to
      exclude cord or nerve root compression, evaluate ligamentous integrity, or
      provide information regarding neurological prognosis. TREATMENT:  STANDARDS:
      There is insufficient evidence to support treatment standards. GUIDELINES: There
      is insufficient evidence to support treatment guidelines. OPTIONS: Thoracic
      elevation or an occipital recess to prevent flexion of the head and neck when
      restrained supine on an otherwise flat backboard may allow for better neutral
      alignment and immobilization of the cervical spine in children younger than 8
      years because of the relatively large head in these younger children and is
      recommended. Closed reduction and halo immobilization for injuries of the C2
      synchondrosis between the body and odontoid is recommended in children younger
      than 7 years. Consideration of primary operative therapy is recommended for
      isolated ligamentous injuries of the cervical spine with associated deformity.

PMID- 12431293
TI  - Spinal cord injury without radiographic abnormality.
AB  - DIAGNOSIS:  STANDARDS: There is insufficient evidence to support diagnostic
      standards. GUIDELINES: There is insufficient evidence to support diagnostic
      guidelines. OPTIONS: Plain spinal x-rays of the region of injury and computed
      tomographic scanning with attention to the suspected level of neurological injury
      to exclude occult fractures are recommended. Magnetic resonance imaging of the
      region of suspected neurological injury may provide useful diagnostic
      information. Plain x-rays of the entire spinal column may be considered. Neither
      spinal angiography nor myelography is recommended in the evaluation of patients
      with spinal cord injury without radiographic abnormality. TREATMENT:  STANDARDS:
      There is insufficient evidence to support treatment standards. GUIDELINES: There
      is insufficient evidence to support treatment guidelines. OPTIONS: External
      immobilization is recommended until spinal stability is confirmed by
      flexion/extension x-rays. External immobilization of the spinal segment of injury
      for up to 12 weeks may be considered. Avoidance of "high-risk" activities for up
      to 6 months after spinal cord injury without radiographic abnormality may be
      considered. PROGNOSIS:  STANDARDS: There is insufficient evidence to support
      prognostic standards. GUIDELINES: There is insufficient evidence to support
      prognostic guidelines. OPTIONS: Magnetic resonance imaging of the region of
      neurological injury may provide useful prognostic information about neurological
      outcome after spinal cord injury without radiographic abnormality.

PMID- 12431294
TI  - Diagnosis and management of traumatic atlanto-occipital dislocation injuries.
AB  - DIAGNOSTIC:  STANDARDS: There is insufficient evidence to support diagnostic
      standards. GUIDELINES: There is insufficient evidence to support diagnostic
      guidelines. OPTIONS: A lateral cervical x-ray is recommended for the diagnosis of
      atlanto-occipital dislocation. If a radiological method for measurement is used,
      the basion-axial interval-basion-dental interval method is recommended. The
      presence of upper cervical prevertebral soft tissue swelling on an otherwise
      nondiagnostic plain x-ray should prompt additional imaging. If there is clinical
      suspicion of atlanto-occipital dislocation, and plain x-rays are nondiagnostic,
      computed tomography or magnetic resonance imaging is recommended, particularly
      for the diagnosis of non-Type II dislocations. TREATMENT:  STANDARDS: There is
      insufficient evidence to support treatment standards. GUIDELINES: There is
      insufficient evidence to support treatment guidelines. OPTIONS: Treatment with
      internal fixation and arthrodesis using one of a variety of methods is
      recommended. Traction may be used in the management of patients with atlanto
      occipital dislocation, but it is associated with a 10% risk of neurological
      deterioration.

PMID- 12431295
TI  - Occipital condyle fractures.
AB  - DIAGNOSTIC:  STANDARDS: There is insufficient evidence to support diagnostic
      standards. GUIDELINES: Computed tomographic imaging is recommended for
      establishing the diagnosis of occipital condyle fractures. Clinical suspicion
      should be raised by the presence of one or more of the following criteria: blunt
      trauma patients sustaining high-energy craniocervical injuries, altered
      consciousness, occipital pain or tenderness, impaired cervical motion, lower
      cranial nerve paresis, or retropharyngeal soft tissue swelling. OPTIONS: Magnetic
      resonance imaging is recommended to assess the integrity of the craniocervical
      ligaments. TREATMENT:  STANDARDS: There is insufficient evidence to support
      treatment standards. GUIDELINES: There is insufficient evidence to support
      treatment guidelines. OPTIONS: Treatment with external cervical immobilization is
      recommended.

PMID- 12431296
TI  - Isolated fractures of the atlas in adults.
AB  - STANDARDS: There is insufficient evidence to support treatment standards.
      GUIDELINES: There is insufficient evidence to support treatment guidelines.
      OPTIONS: Treatment options in the management of isolated fractures of the atlas
      are based on the specific atlas fracture type. It is recommended that isolated
      fractures of the atlas with an intact transverse atlantal ligament be treated
      with cervical immobilization alone. It is recommended that isolated fractures of
      the atlas with disruption of the transverse atlantal ligament be treated with
      either cervical immobilization alone or surgical fixation and fusion.

PMID- 12431297
TI  - Isolated fractures of the axis in adults.
AB  - FRACTURES OF THE ODONTOID: STANDARDS: There is insufficient evidence to support
      treatment standards. GUIDELINES: Type II odontoid fractures in patients 50 years
      and older should be considered for surgical stabilization and fusion. OPTIONS:
      Type I, Type II, and Type III fractures may be managed initially with external
      cervical immobilization. Type II and Type III odontoid fractures should be
      considered for surgical fixation in cases of dens displacement of 5 mm or more,
      comminution of the odontoid fracture (Type IIA), and/or inability to achieve or
      maintain fracture alignment with external immobilization. TRAUMATIC
      SPONDYLOLISTHESIS OF THE AXIS (HANGMAN'S FRACTURE): STANDARDS: There is
      insufficient evidence to support treatment standards. GUIDELINES: There is
      insufficient evidence to support treatment guidelines. OPTIONS: Traumatic
      spondylolisthesis of the axis may be managed initially with external
      immobilization in most cases. Surgical stabilization should be considered in
      cases of severe angulation of C2 on C3 (Francis Grade II and IV, Effendi Type
      II), disruption of the C2--C3 disc space (Francis Grade V, Effendi Type III), or
      inability to establish or maintain alignment with external immobilization.
      FRACTURES OF THE AXIS BODY (MISCELLANEOUS FRACTURES): STANDARDS: There is
      insufficient evidence to support treatment standards. GUIDELINES: There is
      insufficient evidence to support treatment guidelines. OPTIONS: External
      immobilization is recommended for treatment of isolated fractures of the axis
      body.

PMID- 12431298
TI  - Management of combination fractures of the atlas and axis in adults.
AB  - STANDARDS: There is insufficient evidence to support treatment standards.
      GUIDELINES: There is insufficient evidence to support treatment guidelines.
      OPTIONS: Treatment of atlas-axis combination fractures based primarily on the
      specific characteristics of the axis fracture is recommended. External
      immobilization of most C1--C2 combination fractures is recommended. C1--Type II
      odontoid combination fractures with an atlantodens interval of 5 mm or more and
      C1--hangman's combination fractures with C2--C3 angulation of 11 degrees or more
      should be considered for surgical stabilization and fusion. In some cases, the
      surgical technique must be modified as a result of loss of the integrity of the
      ring of the atlas.

PMID- 12431299
TI  - Os odontoideum.
AB  - DIAGNOSIS:  STANDARDS: There is insufficient evidence to support diagnostic
      standards. GUIDELINES: There is insufficient evidence to support diagnostic
      guidelines. OPTIONS: Plain x-rays of the cervical spine (anteroposterior, open
      mouth odontoid, and lateral) and plain dynamic lateral x-rays performed in
      flexion and extension are recommended. Tomography (computed or plain) and/or
      magnetic resonance imaging of the craniocervical junction may be considered.
      MANAGEMENT:  STANDARDS: There is insufficient evidence to support treatment
      standards. GUIDELINES: There is insufficient evidence to support treatment
      guidelines. OPTIONS: Patients with os odontoideum, either with or without C1--C2
      instability, who have neither symptoms nor neurological signs may be managed with
      clinical and radiographic surveillance. Patients with os odontoideum,
      particularly with neurological symptoms and/or signs, and C1--C2 instability may
      be managed with posterior C1--C2 internal fixation and fusion. Postoperative halo
      immobilization as an adjunct to posterior internal fixation and fusion is
      recommended unless successful C1--C2 transarticular screw fixation and fusion can
      be accomplished. Occipitocervical fusion with or without C1 laminectomy may be
      considered in patients with os odontoideum who have irreducible cervicomedullary
      compression and/or evidence of associated occipitoatlantal instability. Transoral
      decompression may be considered in patients with os odontoideum who have
      irreducible ventral cervicomedullary compression.

PMID- 12431300
TI  - Treatment of subaxial cervical spinal injuries.
AB  - SUBAXIAL CERVICAL FACET DISLOCATION INJURIES: STANDARDS: There is insufficient
      evidence to recommend treatment standards. GUIDELINES: There is insufficient
      evidence to recommend treatment guidelines. OPTIONS: Closed or open reduction of
      subaxial cervical facet dislocation injuries is recommended. Treatment of
      subaxial cervical facet dislocation injuries with rigid external immobilization,
      anterior arthrodesis with plate fixation, or posterior arthrodesis with plate or
      rod or interlaminar clamp fixation is recommended. Treatment of subaxial cervical
      facet dislocation injuries with prolonged bedrest in traction is recommended if
      more contemporary treatment options are not available. SUBAXIAL CERVICAL INJURIES
      EXCLUDING FACET DISLOCATION INJURIES: STANDARDS: There is insufficient evidence
      to recommend treatment standards. GUIDELINES: There is insufficient evidence to
      recommend treatment guidelines. OPTIONS: Closed or open reduction of subluxations
      or displaced subaxial cervical spinal fractures is recommended. Treatment of
      subaxial cervical spinal injuries with external immobilization, anterior
      arthrodesis with plate fixation, or posterior arthrodesis with plate or rod
      fixation is recommended.

PMID- 12431301
TI  - Management of acute central cervical spinal cord injuries.
AB  - STANDARDS: There is insufficient evidence to support treatment standards.
      GUIDELINES: There is insufficient evidence to support treatment guidelines.
      OPTIONS: Intensive care unit (or other monitored setting) management of patients
      with acute central cervical spinal cord injuries, particularly patients with
      severe neurological deficits, is recommended. Medical management, including
      cardiac, hemodynamic, and respiratory monitoring, and maintenance of mean
      arterial blood pressure at 85 to 90 mmHg for the first week after injury to
      improve spinal cord perfusion is recommended. Early reduction of fracture
      dislocation injuries is recommended. Surgical decompression of the compressed
      spinal cord, particularly if the compression is focal and anterior, is
      recommended.

PMID- 12431302
TI  - Management of vertebral artery injuries after nonpenetrating cervical trauma.
AB  - DIAGNOSTIC:  STANDARDS: There is insufficient evidence to support diagnostic
      standards. GUIDELINES: There is insufficient evidence to support diagnostic
      guidelines. OPTIONS: Conventional angiography or magnetic resonance angiography
      is recommended for the diagnosis of vertebral artery injury after nonpenetrating
      cervical trauma in patients who have complete cervical spinal cord injuries,
      fracture through the foramen transversarium, facet dislocation, and/or vertebral
      subluxation. TREATMENT:  STANDARDS: There is insufficient evidence to support
      treatment standards. GUIDELINES: There is insufficient evidence to support
      treatment guidelines. OPTIONS: Anticoagulation with intravenous heparin is
      recommended for patients with vertebral artery injury who have evidence of
      posterior circulation stroke. Either observation or treatment with
      anticoagulation in patients with vertebral artery injuries and evidence of
      posterior circulation ischemia is recommended. Observation in patients with
      vertebral artery injuries and no evidence of posterior circulation ischemia is
      recommended.

PMID- 12431303
TI  - Methodology of guideline development.

PMID- 12431304
TI  - The ECG: predicting cardiac events after myocardial infarction with a brief
      historical perspective.

PMID- 12431305
TI  - Adrenergic nervous system influences on the induction of ventricular tachycardia.
AB  - BACKGROUND: Sudden cardiac death is a major cause of mortality in western
      countries and the ventricular tachyarrhythmias are mainly involved in this
      regard. The adrenergic autonomic nervous system has influences in provoking life
      threatening arrhythmias, and the prevention of such arrhythmias with beta
      blockers supports this viewpoint. To evaluate the effect of the adrenergic
      nervous system and some catecholamine-releasing stimuli on the induction of
      ventricular tachycardia, we decided to explore the occurrence of ventricular
      tachycardia in patients subjected to three consecutive tests, exercise testing,
      isoproterenol infusion, and mental stress. METHODS: Nineteen subjects who
      experienced exercise test-induced ventricular tachycardia were subjected to an
      isoproterenol infusion and mental stress. All but one patient had cardiac
      disease, with 70% due to Chagas' disease. Seventeen of the 19 study subjects had
      normal ventricular function. RESULTS: Exercise test-induced ventricular
      tachycardia was nonsustained in 17 patients and sustained in 2 cases.
      Isoproterenol infusion induced nonsustained ventricular tachycardia in 9 of 19
      patients. Mental stress, on its own, was able to induce nonsustained ventricular
      tachycardia in 2 of 19 patients. CONCLUSIONS: Among patients preselected for
      exercise-induced ventricular tachycardia, almost half could be induced into
      ventricular tachycardia by isoproterenol infusion. Mental stress was a less
      powerful inducer of ventricular arrhythmias in this study group.

PMID- 12431306
TI  - Computer-based analysis of dynamic QT changes: toward high precision and
      individual rate correction.
AB  - BACKGROUND: New strategies are needed to improve the results of automatic
      measurement of the various parts of the ECG signal and their dynamic changes.
      METHODS: The EClysis software processes digitally-recorded ECGs from up to 12
      leads at 500 Hz, using strictly defined algorithms to detect the PQRSTU points
      and to measure ECG intervals and amplitudes. Calculations are made on the
      averaged curve of each sampling period (beat group) or as means +/- SD for beat
      groups, after being analyzed at the individual beat level in each lead. Resulting
      data sets can be exported for further statistical analyses. Using QT and R-R
      measured on beat level, an individual correction for the R-R dependence can be
      performed. RESULTS: EClysis assigns PQRSTU points and intervals in a sensitive
      and highly reproducible manner, with coefficients of variation in ECG intervals
      corresponding to ca. 2 ms in the simulated ECG. In the normal ECG, the CVs are 2%
      for QRS, 0.8% for QT, and almost 6% for PQ intervals. EClysis highlights the
      increase in QT intervals and the decrease of T-wave amplitudes during almokalant
      infusion versus placebo. Using the observed linear or exponential relationships
      to adjust QT for R-R dependence in healthy subjects, one can eliminate this
      dependence almost completely by individualized correction. CONCLUSIONS: The
      EClysis system provides a precise and reproducible method to analyze ECGs.

PMID- 12431307
TI  - Late potential analysis: is a mathematically-derived X,Y,Z lead system comparable
      to a true orthogonal X,Y,Z lead system?
AB  - BACKGROUND: Analysis of ventricular late potentials (LP) with signal-averaged ECG
      (SAECG) using three bipolar, orthogonal X,Y, Z leads is a validated method of
      risk-stratification in patients prone to ventricular tachycardia. The aim of this
      study was to validate a ECG system, which allows LP analysis using X,Y, Z leads
      mathematically derived from the standard 12-lead ECG. METHODS AND RESULTS: In 36
      patients (age 56 +/- 12 years, coronary artery disease 71%, LVEF 46 +/- 14%) with
      known or suspected ventricular tachyarrhythmia, two consecutive SAECGs were
      recorded, one with mathematically derived and another one with true X,Y, Z leads.
      Time domain measurements with these different lead systems were compared using
      linear regression analysis and "Bland-Altman" plots. Correlation was good (r =
      0.92) for the filtered QRS complex duration, but poor for the terminal QRS
      amplitude (RMS) and duration (LAS) criteria (r = 0.66 and 0.61, respectively; P <
      0.0001). Defining LPS as present if at least two of the three time domain
      criteria were abnormal, the result matched in 28 (78%), but differed in 8 (22%)
      patients. CONCLUSION: SAECG using X,Y, Z leads mathematically derived from the
      standard 12-lead ECG compared to true bipolar X,Y, Z leads show a close
      correlation in filtered QRS duration, but can differ considerably in the other
      time domain measurements, resulting in different interpretation of LP analysis in
      22%. Therefore, SAECG registration should currently be performed with true X,Y, Z
      leads, until the accuracy of other approaches is validated.

PMID- 12431308
TI  - Cardiovascular autonomic function in conscious rats: a novel approach to
      facilitate stationary conditions.
AB  - BACKGROUND: An experimental setting and software were developed to evaluate
      cardiovascular autonomic function in conscious rats. A restrained approach was
      used, which, upon proper habituation, induced little or no stress in the rats and
      limited motion artifacts. METHODS: The ECG and arterial blood pressure were
      recorded. Time- and frequency-domain indices of heart rate variability (HRV) and
      blood pressure variability (BPV) were calculated. The spontaneous baroreflex
      sensitivity (spBRS) was estimated using the method of statistical dependence.
      RESULTS: The power spectra clearly concentrated in a frequency band with center
      frequency around 0.4 Hz, the low frequency (LF) component, and one at the
      respiratory frequency at 1.5 Hz, the high frequency (HF) component. In baseline
      conditions, a direct association existed between mean R-R and especially HRV
      parameters denoting vagal modulation such as rMSSD, pNN5, and HF power. Beta
      adrenergic blockade by propranolol diminished basal heart rate. Vagal indices
      increased while there was an exclusive decrease in the low frequency band of HRV.
      Alpha-adrenergic blockade with phentolamine produced a depressor response with
      tachycardia, and a clear decrease in the LF component of BPV. Both the LF and HF
      component in the HRV spectrum were virtually absent. Cholinergic blockade with
      atropine did not significantly alter BP but induced a clear tachycardia with
      decreased vagal indices. The HF component of HRV was completely abolished and the
      LF band was reduced. CONCLUSIONS: Both alpha- and beta-adrenergic blockade left
      spBRS virtually unaltered, while cholinergic blockade profoundly diminished
      spBRS. Spectral fluctuations of beta-sympathetic tone were restricted to the LF
      range of HRV, while the HF respiratory component represented vagal modulation.
      The alpha-sympathetic system played a dominant role in the LF oscillations of
      BPV. A role of the vagus in the HF oscillations of BPV in the rat is questioned.
      The baroreflex depended mainly on changes in vagal activity.

PMID- 12431309
TI  - Beat-to-beat repolarization variability measured by T wave spectral variance
      index in chronic infarcted animals.
AB  - BACKGROUND: Recent experimental and clinical studies have shown that beat-to-beat
      variability of repolarization morphology is associated with an increased risk for
      developing malignant ventricular arrhythmias. However, few data exist on the
      relationship between beat-to-beat repolarization variability and myocardial
      infarction itself. METHODS AND RESULTS: In the present work we tested the
      algorithm of T wave spectral variance (TWSV) using the two dimension fast Fourier
      transform, in an animal model of myocardial infarction to extend the evidences
      that support the existence of beat-to-beat alteration in repolarization during
      the chronic stage of myocardial infarction. Thirty-four New Zealand rabbits were
      included in the study and divided in two groups. Group I (N = 24) exposed to
      surgical ligation of the left anterior descendent coronary artery. Group II (N =
      10) sham operated animals. The TWSV index was calculated before and after 15 and
      45 days of surgery. Both groups showed significant increments in TWSV after 15
      days postsurgery. However, while the sham animals return to its control value,
      the infarcted group exhibited values of the TWSV index that remains significantly
      high after 45 days of surgery, with a mean increment of 28.7% (P < 0.05 against
      sham). Moreover, when the infarcted group was qualitatively divided in three
      subgroups, according to its infarction areas, a trend was found in the
      correlation between the magnitude of the infarcted area and the TWSV index.
      CONCLUSION: This noninvasive measure confirms the presence of temporal
      repolarization variability associated with chronic myocardial infarction and
      further contributes to identify the infarcted animals.

PMID- 12431310
TI  - Influence of atropine on fractal and complexity measures of heart rate
      variability.
AB  - BACKGROUND: Measurement of short-term fractal-like correlation properties of
      heart rate dynamics has been shown to be a useful prognostic indicator of adverse
      events in cardiac patients. Complexity measurements of heart rate variability
      (HRV) have already provided important information in many cardiac conditions.
      However, data on the physiological background of these newer nonlinear measures
      of HRV are limited. METHODS: Nine healthy subjects (aged from 22 to 35 years, 6
      males, 3 females) had an electrocardiographic (ECG) recording during controlled
      breathing in supine position. HRV was analyzed for 5 min periods before and after
      intravenous injection of 0.6 mg of atropine using conventional HRV measures and
      newer nonlinear HRV measures including the short-term scaling exponent (alpha(1))
      and approximate entropy (ApEn). RESULTS: The short-term scaling exponent alpha(1)
      increased significantly after atropine injection (1.01 +/- 0.23 vs 1.43 +/- 0.19,
      P = 0.001). There was no significant difference between ApEn values before and
      after atropine injection (0.87 +/- 0.17 vs 0.70 +/- 0.31, respectively, P =
      0.27). At baseline before atropine administration, alpha(1) had a significant
      negative correlation with SDNN, RMSSD, and HF (r = -0.70, -0.76, -0.67,
      respectively, P < 0.05 for all), and a significant positive correlation with
      heart rate (r = 0.76, P < 0.05). After atropine injection, alpha(1) did not have
      significant correlation with any of the HRV parameters or heart rate. There were
      no significant correlations between ApEn and any of the HRV measures or heart
      rate either before or after atropine administration. CONCLUSIONS: Vagal tone has
      an important influence on the values of the short-term scaling exponent alpha(1).
      However, vagal modulation is not a major determinant of the values of ApEn.

PMID- 12431311
TI  - Effects of sympathetic stimulation on various repolarization indices in the
      congenital long QT syndrome.
AB  - Sympathetic stimulation or catecholamines modulate ventricular repolarization and
      provoke ventricular tachyarrhythmias in a variety of heart diseases and
      conditions. Among those, the congenital form of long QT syndrome (LQTS) has long
      been known to be a Rosetta stone for sympathetic-related ventricular
      tachyarrhythmias. Recent experimental studies employing arterially-perfused
      ventricular wedge preparations as well as some clinical studies have greatly
      advanced our knowledge of the cellular mechanism of the T wave and the various
      repolarization indices in the ECG, as well as the effect of sympathetic
      stimulation on these repolarization indices under normal and long QT conditions.
      Differences in the time course of repolarization of the three predominant cell
      types, the epicardial, midmyocardial (M), and endocardial cells, across the
      ventricular wall give rise to voltage gradients responsible for the inscription
      of normal T waves as well as the manifestation of abnormal T waves in the
      congenital LQTS. The data from the wedge experiments suggest that the
      repolarization time of the longest M cell action potential determines the Q-Tend
      interval, while that of the epicardial action potential determines the Q-Tpeak
      interval. Therefore, Tpeak-end interval in the ECG may provide an index of
      transmural dispersion of repolarization (TDR). In this review article,
      sympathetic stimulation with isoproterenol or epinephrine infusion is
      demonstrated to modulate differentially these repolarization indices in the ECG
      as well as the action potentials of the three cells between the LQT1, LQT2, and
      LQT3 syndromes both experimentally and clinically, explaining the differences in
      the sensitivity of genotypes of congenital LQTS to sympathetic stimulation.

PMID- 12431312
TI  - QT interval in patients with unstable angina and non-Q wave myocardial
      infarction.
AB  - BACKGROUND: Non-Q wave myocardial infarction (NQMI) and unstable angina (UAP)
      have similar clinical presentations and similar ST-T changes on the
      electrocardiogram. The purpose of this study was to assess whether changes in QT
      interval might help differentiating between these entities. METHODS: The QT
      intervals of 52 patients hospitalized with NQMI were compared to those of 52
      patients hospitalized for UAP. All patients had repeated ECG for at least 4 days.
      RESULTS: Maximal QTc in patients with NQMI was significantly longer than in
      patients with UAP (475 vs 439 ms, P < 0.0001). QTc on the admission ECG was 450
      ms in patients with NQMI compared to 417 ms in UAP (P < 0.005). QTc > 460 ms was
      present in 48% patients with NQMI and in 19% of UAP patients. Maximal QT
      prolongation was observed within 36 hours of admission with return to normal
      within 96 hours. QT dispersion was within normal range, being longer in patients
      with NQMI than patients with UAP (55 vs 43 ms, P < 0.003). QT prolongation was
      not associated with increased frequency of arrhythmia. The cause of QT
      prolongation in NQMI may be related to the damage of subendocardial layer
      exposing the M cells layer which markedly prolong action potential duration.
      CONCLUSION: Transient QT prolongation is observed in about half of patients with
      NQMI. These ECG changes may help differentiating between patients with NQMI and
      UAP already on admission.

PMID- 12431313
TI  - Direct epicardial mapping can differentiate hibernating from scarred myocardium:
      a validation study with 18F-FDG-PET.
AB  - AIM: This study investigated the value of epicardial mapping immediately before
      CABG in the differentiation of hibernating from scarred myocardium in correlation
      to the noninvasive gold standard (18)F-FDG PET. METHODS AND RESULTS: In 35
      patients with CAD, myocardial perfusion ((99m)Tc-Tetrofosmin-SPECT), viability
      ((18)F-FDG-PET), and function (LVangiography) were assessed before CABG. 102
      bipolar epicardial electrograms per patient (n = 3570 electrograms) were recorded
      simultaneously with a ventricular jacket array. Based on the scintigraphic and LV
      angiographic data at the site of each electrode with good myocardial contact (n =
      1963), segments (n = 492, 14.1 +/- 5.6 per patient; mean +/- SD) were classified
      into three groups: hibernating (n = 139), scarred (n = 104), and control (n =
      249). Regional mean bipolar voltage values were calculated for Receiver Operating
      Characteristic (ROC) analysis. Mean bipolar voltage was significantly lower in
      scarred when compared to hibernating myocardium. ROC curve analysis (area under
      the curve of 0.92 +/- 0.47, mean +/- SE) for mean bipolar voltage to discriminate
      between hibernating and scarred myocardium revealed a sensitivity of 94% with a
      specificity of 83% at a cut-off value of 8.75 mV. CONCLUSION: Hibernating
      myocardium can be differentiated correctly from scarred myocardium by direct
      epicardial mapping. In the future, hibernating myocardium may be detectable by
      body surface mapping techniques using inverse solutions.

PMID- 12431314
TI  - The immediate and short-term effect of successful percutaneous coronary
      intervention on repolarization in acute myocardial infarction patients.
AB  - OBJECTIVES: The primary objective was to assess the immediate and short-term
      impact of successful percutaneous coronary intervention (PCI) on QT dispersion
      (QT disp) and corrected QT dispersion (QTc disp). Secondarily, the impact of PCI
      on QT and QTc disp within different infarct-related arteries and the impact of
      successful PCI in these different arteries were evaluated. METHODS: Patients (n =
      140, age 61.6 +/- 12.9, 69% male) undergoing direct primary PCI for acute MI were
      evaluated. Twelve-lead ECGs were obtained before (baseline), immediately after (0
      h), 24hours after, and 3 days after PCI. The QT and QTc interval in each of the
      12-leads were measured and the shortest interval was subtracted from the longest
      to derive the QT disp and QTc disp, respectively. RESULTS: Angiography showed
      blockages in the left anterior descending, right coronary artery, and circumflex
      in 37.1, 48.9, and 15.0% of patients, respectively. Overall, 97 patients achieved
      successful reflow. QT and QTc disp were significantly improved in the group with
      successful reflow at each follow-up time after PCI versus baseline and
      corresponding values in the unsuccessful reflow group. QT disp was improved among
      patients with successful reflow irrespective of which infarct artery was
      responsible for the acute myocardial infarction. CONCLUSIONS: Successful reflow
      with PCI is associated with a rapid reduction in QT disp and QTc disp that is
      maintained for at least 3 days after the event. Conversely, unsuccessful reflow
      was not associated with significant reductions in QT or QTc disp.

PMID- 12431315
TI  - P wave dispersion and P wave duration on SAECG in predicting atrial fibrillation
      in patients with acute myocardial infarction.
AB  - BACKGROUND: Atrial fibrillation (AF) is a frequent complication of acute
      myocardial infarction (AMI), with reported incidence of 7% to 18%. The incidence
      of congestive heart failure, in-hospital mortality, and long-term mortality is
      higher in AMI patients with AF than in AMI patients without AF. P wave duration
      on signal-averaged ECG (PWD) and P wave dispersion on standard ECG (Pd) are
      noninvasive markers of intra-atrial conduction disturbances, which are believed
      to be the main electrophysiological cause of AF. METHODS: In the present study we
      investigated prospectively whether P wave duration on SAECG and P wave dispersion
      on standard ECG can predict development of AF in a group of patients with AMI.
      One hundred and thirty patients (100 men and 30 women, aged 56.9 +/- 12) with AMI
      were investigated. PWD, Pd, their clinical and hemodynamic characteristics were
      collected. RESULTS: During the observation up to 14 days, 22 patients (16.9%)
      developed AF. Univariate analysis variables associated with development of AF:
      age > 65 years, Killip class III-IV, PWD > 125 ms, and Pd > 25 ms. Stepwise
      logistic regression analysis showed that age > 65 years, PWD > 125 ms, and Pd >
      25 ms were independently associated with AF. CONCLUSIONS: PWD and Pd both
      measured in a very early period of AMI are useful in predicting AF.

PMID- 12431316
TI  - Predictive value of admission electrocardiogram for multivessel disease in acute
      anterior and anterior-inferior myocardial infarction.
AB  - BACKGROUND: Our aim was to investigate the correlation between admission ECG and
      coronary angiography findings in terms of predicting the culprit vessel
      responsible for the infarct or multivessel disease in acute anterior or anterior
      inferior myocardial infarction (AMI). METHODS: We investigated 101 patients with
      a diagnosis of anterior AMI with or without ST-segment elevation or ST-segment
      depression in at least two leads in DII, III, aVF. The patients were classified
      as those with vessel involvement in the left anterior descending (LAD) coronary
      artery and patients with multivessel disease. Vessel involvement in LAD +
      circumflex artery (Cx) or LAD + right coronary artery (RCA) or LAD + Cx + RCA
      were considered as multivessel disease. Thus, (a) anterior AMI patients with
      reciprocal changes in inferior leads, (b) anterior AMI patients with inferior
      elevations, (c) all anterior AMI patients according to the ST-segment changes in
      the inferior region were analyzed according to the presence of LAD or multivessel
      involvement. RESULTS: Presence of ST-segment depression in aVL and V6 was
      significantly correlated with the presence of multivessel disease in anterior AMI
      patients with reciprocal changes in the inferior leads (P = 0.005 and P = 0.003,
      respectively). No statistically significant difference between the leads were
      detected in terms of ST-segment elevation in predicting vessel involvement in the
      two groups of anterior AMI patients with inferior elevations. When all the
      patients with anterior AMI were analyzed, the presence of ST-segment depression
      in leads aVL, V4, V5 and V6 were significantly associated with the presence of
      multivessel disease (P = 0.035, P = 0.010, P = 0.011, P = 0.001, respectively).
      CONCLUSIONS: The presence of ST-segment depression in anterolateral leads in the
      admission ECG of anterior AMI patients with reciprocal changes in inferior leads
      was associated with multivessel disease.

PMID- 12431317
TI  - Heart rate variability by triangular index in infants exposed prenatally to
      cocaine.
AB  - BACKGROUND: In adults, heart rate variability triangular index (HRVi) is a highly
      reproducible measure of heart rate variability (HRV), which makes it more
      suitable for use in longitudinal studies. Although normative data have been
      published for newborns, studies in infants with pathological conditions are
      lacking. METHODS: From 1997 to 2000, within the first 4 days of life, we
      prospectively evaluated HRVi in cocaine-exposed asymptomatic newborns (N = 97) by
      Holter monitoring. Their data were compared with infants from two control groups
      (one with no in utero drug exposure, N = 102; the other with exposure to alcohol,
      nicotine, or marijuana but no cocaine, N = 111). RESULTS: In assessing
      concordance between and within operators for HRVi, the intraclass correlations
      were 0.983 (95% CI: 0.958, 0.994) and 0.997 (95% CI: 0.984, 0.999), respectively.
      Infants with in utero cocaine exposure had significantly (P < 0.0001) lower HRVi
      than those exposed to other drugs and to no drugs in utero. If abnormal HRVi is
      defined as < fifth percentile for the no drug exposed group (HRVi < 8), 10% of
      the cocaine-exposed newborns, in contrast to 2% in each of the control groups (P
      = 0.003) had abnormal values. CONCLUSION: HRVi is a reliable measure to study
      heart rate variability in newborns. Asymptomatic infants with in utero cocaine
      exposure have lower HRVi. Our study supports the clinical use of an abnormal HRVi
      as a value < 8 for newborn infants.

PMID- 12431318
TI  - Cardiac effects of chronic oral beta-blockade: lack of agreement between heart
      rate and QT interval changes.
AB  - BACKGROUND: Although well established on the sinus node, the effects of beta
      blockade on ventricular repolarization are still conflicting. The aim of the
      study was to investigate the effects of a chronic beta-blockade on sinus node and
      repolarization parameters and their relationship. METHODS: Sixteen healthy
      volunteers (10 males, mean age: 40 +/- 6.7 years) were randomized to placebo or
      atenolol (100 mg). After 7 days, subjects were crossed over. Heart rate (HR) and
      HRV indices were calculated from long-term ECG recordings separately during the
      day and at night, together with ventricular repolarization parameters (QT
      interval duration and QT rate-dependence). RESULTS: Mean R-R intervals were
      significantly and consistently increased after atenolol (Day: 916 +/- 103 ms vs.
      712 +/- 89 ms, and Night: 1149 +/- 93 vs. 996 +/- 125 ms). HRV changes under
      atenolol were also consistent, with a significant decrease in sympathovagal
      ratio. In contrast, atenolol only lowered diurnal QT rate-dependence (0.123 +/-
      0.032 vs. 0.190 +/- 0.065 on placebo, P < 0.001), but not the nocturnal pattern.
      After multivariate analysis QT rate-dependence changes induced by atenolol were
      correlated with pretreatment QT/RR relation (r = 0.65, P < 0.01) but not with any
      HR or HRV parameters. CONCLUSIONS: In healthy subjects, repolarization changes
      following chronic beta-blockade cannot be predicted by HR or HRV changes, but are
      dependent on pretreatment rate-dependence.

PMID- 12431319
TI  - Late QRS activity in signal-averaged magnetocardiography, body surface potential
      mapping, and orthogonal ECG in postinfarction ventricular tachycardia patients.
AB  - BACKGROUND: Delayed electrical activity necessary for re-entrant ventricular
      tachycardia (VT) is detectable noninvasively with high resolution techniques. We
      compared high resolution signal-averaged analysis of magnetocardiography (MCG),
      body surface potential mapping (BSPM), and orthogonal three-lead ECG (SA-ECG) in
      the identification of patients prone to VT after myocardial infarction (MI).
      METHODS: Patients with remote myocardial infarction and cardiac dysfunction were
      studied, 22 with (VT group) and 22 without VT (control group). MCG with seven
      channels and BSPM with 63 and SA-ECG with three orthogonal leads were registered.
      After signal-averaging and highpass filtering, three time domain analysis (TDA)
      parameters describing late electrical activity were computed: QRS duration
      (QRSd), root mean square amplitude (RMS) of the last 40 ms of QRS, and the
      duration of the low-amplitude QRS end (LAS). RESULTS: All parameters by each
      method were significantly different between the patients' groups. For example,
      LAS parameter in MCG was 59 (SD 22) ms in the VT group vs. 37 (SD 13) ms in
      controls (P < 0.001), 77 (SD 22) ms vs. 56 (SD 19) ms in BSPM (P = 0.002), and 60
      (SD 24) ms vs. 39 (SD 22) ms in SA-ECG (P = 0.005). The combination of LAS
      parameter in MCG and SA-ECG resulted in improved performance in comparison to any
      single parameter with 95% sensitivity and 68% specificity. CONCLUSIONS: All three
      high resolution methods identified VT propensity among post-MI patients with
      cardiac dysfunction and between-method differences were small. Information in MCG
      and SA-ECG may be complementary and their combination could be of value in
      postinfarction arrhythmia risk assessment.

PMID- 12431321
TI  - Filological notes in electrocardiography.

PMID- 12431320
TI  - Implementation of MADIT and MUSTT in clinical practice: results of an
      international survey.
AB  - BACKGROUND: The long-awaited dramatically positive outcome of the Multicenter
      Automatic Defibrillator Implantation Trial (MADIT II), just published by Moss et
      al.,(14) has generated cardiologists' interest on the implementation into
      clinical practice of that trial. Important lessons may be learned by examining
      the clinical implementation of two preceding randomized, prospective,
      prophylactic ICD trials: the original MADIT trial, published late 1996, and the
      Multicenter Unsustained Tachycardia Trial (MUSTT), published late 1999. Both
      demonstrated that implantable cardioverter defibrillators reduce all-cause
      mortality by over 50% in high risk patients without previous sustained
      arrhythmias. METHODS: In early 2000, we surveyed 133 active electrophysiology
      centers (47 American, 81 European, 5 Canadian) to determine the extent to which
      these practices have been implemented in clinical practice during 1999, and the
      responses were compared to a similar survey for the year 1998. RESULTS: ICDs
      implanted for MADIT or MUSTT criteria accounted for 18% of new ICD implants in
      1999, 65% greater than in 1998, increasing from 6% to 11% in Europe, and from 15%
      to 24% in America. During 1999, 53% of patients receiving ICDs for these
      indications were inpatients identified during hospitalization, 27% were
      outpatients referred specifically for MADIT/MUSTT indications, and 20% were
      identified by routine screening. Per the survey, in 1999 68% of responders were
      "somewhat (10-20%)" and 14% were "considerably (>20%)" more likely to implant
      ICDs for all indications. CONCLUSIONS: Extrapolating the results of this survey
      to all initial ICD implants for 1999, we estimate that 8500 implants for
      MADIT/MUSTT criteria took place in 1999, with the overall number of such implants
      substantially increased over the previous year, irrespective of geographic
      location, and influenced significantly by the publication of MUSTT. However,
      screening and implant practices between centers continue to vary over a broad
      spectrum. It will be interesting to observe whether similar patterns will follow
      with MADIT II.

PMID- 12431322
TI  - Guidelines and trials.

PMID- 12431323
TI  - Adjuvant chemotherapy for deep muscle-invasive transitional cell bladder
      carcinoma - a practice guideline.
AB  - BACKGROUND AND PURPOSE: To examine the role of adjuvant chemotherapy in the
      treatment of patients with deep muscle-invasive transitional cell carcinoma (TCC)
      of the bladder who have undergone cystectomy. MATERIALS AND METHODS: A systematic
      review of the published literature was combined with a consensus process,
      involving the interpretation of evidence within the context of conventional
      practice, to develop an evidence-based practice guideline for use in Ontario.
      RESULTS: Five randomized controlled trials (RCTs) comparing adjuvant chemotherapy
      with observation were found that reported data on survival. Sample sizes of the
      trials were small, and each of the trials evaluated a cisplatin-based
      chemotherapy regimen; however, none studied less toxic combination chemotherapy
      regimens such as gemcitabine-cisplatin or dose-intensive methotrexate-vinblastine
      doxorubicin-cisplatin (MVAC) with granulocyte-colony stimulating factor (G-CSF).
      One trial was excluded due to inadequate reporting of outcomes. The remaining
      four studies failed to demonstrate an overall survival benefit in favor of
      adjuvant chemotherapy, although three of the four trials showed statistically
      significant benefits for adjuvant chemotherapy with respect to disease-free
      survival. CONCLUSIONS: As randomized trials have not proven a benefit in overall
      survival, adult patients with deep muscle-invasive TCC of the bladder should not
      be routinely offered adjuvant chemotherapy following cystectomy. Disease-free
      survival may be improved by adjuvant chemotherapy, but it is unclear whether this
      improvement compensates for the detrimental effects of chemotherapy. If a patient
      chooses adjuvant chemotherapy to improve disease-free survival they should be
      made aware of the lack of proven overall survival benefit, and a cisplatin-based
      combination chemotherapy regimen such as MVAC or CMV is recommended. RCTs of
      gemcitabine-cisplatin and dose-intensive MVAC plus G-CSF in the setting of
      metastatic TCC of the bladder provide indirect evidence that these regimens could
      offer equivalent benefit to MVAC and CMV but with less toxicity in patients with
      muscle-invasive disease. The use of these regimens in the adjuvant setting after
      cystectomy is currently being evaluated in a randomized trial (EORTC trial
      30994).

PMID- 12431324
TI  - Renal cancer and pregnancy in two different female cohorts.
AB  - PURPOSE: Although human renal cell carcinoma (RCC) is considered refractive to
      hormone therapy, this lesion can be induced in the Syrian hamster by exogenous
      estrogen. Human RCC also has been demonstrated to contain estrogen receptors.
      Since there are significant changes of estrogen levels during pregnancy, we
      wanted to investigate if there were any associations between the hormonal
      variations of pregnancy and renal cancer in women using two distinct cohorts.
      MATERIALS AND METHODS: We reviewed the charts of 57 females who presented for
      treatment of renal cancer. We assessed the size of each tumor radiologically and
      pathologically, the tumor stage, the number of pregnancies and/or
      abortions/miscarriages, age at menarche, and use of oral contraceptives. We
      compared this cohort to a sample of 985 nuns, and then reviewed the literature on
      the association of pregnancy, contraceptives and renal cell carcinoma. We used
      analysis of multiple variables (ANOVA) and the student's t test to determine any
      significance (p<0.05). RESULTS: Our age range was 39 to 67 years, with a mean of
      51. The tumor volumes ranged from 9 cm(3) to 1500 cm(3), and the number of
      pregnancies ranged from 1 to 14. Menarche ranged from 8 to 14. We did not find
      any significant correlation between menarche or the number of pregnancies and the
      size or stage of renal cancers. However, our nun population did not reveal any
      incidence or illness from renal cell carcinoma over a 20 year review.
      CONCLUSIONS: Although our first cohort did not demonstrate any significant
      associations between the number of pregnancies or age at menarche and RCC, our
      second cohort and a review of the literature supports the notion that pregnancy
      is a risk factor for renal cell carcinoma.

PMID- 12431325
TI  - Surveillance in stage I testicular seminoma - risk of late relapse.
AB  - INTRODUCTION: Surveillance is an alternative to adjuvant radiotherapy for stage I
      testicular seminoma. We present the long-term results of seminoma surveillance,
      with emphasis on quantifying the risk of late relapse beyond 5 years. METHODS:
      From 1981 to 1993, of 431 men with stage I testicular seminoma, 203 were managed
      by surveillance following radical orchidectomy. The surveillance protocol
      comprised a combination of clinical examination, CT scans of abdomen and pelvis,
      chest x-rays and serum markers, at defined intervals. RESULTS: At a median follow
      up of 9.2 years, 35 men have relapsed. Five of the relapses occurred more than 5
      years after orchidectomy (at 5.1, 6.9, 7.3, 7.3, and 9.0 years). The actuarial
      risk of relapse at 5 and 10 years was 15% (standard error [SE] 1.1%) and 18% (SE
      1.8%) respectively. One hundred sixty one men were free of relapse at 5 years,
      and have been followed beyond this point for a median of 4.3 years. The actuarial
      risk of relapse between 5 and 10 years was 4% (SE 0.5%). CONCLUSIONS: These
      results demonstrate that there is a small but clinically significant risk of
      relapse more than 5 years after orchidectomy for stage I seminoma. These data
      support the need for long term surveillance.

PMID- 12431326
TI  - The utility of buccal mucosa graft in salvage urethroplasty.
AB  - OBJECTIVE: To evaluate our results with buccal mucosa free grafts in salvage
      urethroplasty. PATIENTS AND METHODS: Retrospective chart review of autologous
      buccal mucosa grafts for urethral reconstruction at Winnipeg Children's Hospital
      and Children's Hospital of Eastern Ontario between November 1992 and March 2000.
      RESULTS: Nine patients (median age 4 years) underwent such reconstruction. Seven
      of the nine patients had experienced failed previous attempts at hypospadias
      repair. Onlay grafts were used in all but one patient who required a tube graft.
      Urethrocutaneous fistula was the most common post-operative complication,
      affecting four of nine patients. Two patients developed urethral strictures and
      one a meatal stenosis. Satisfactory functional results were ultimately achieved
      in all patients. Harvest site complications were minimal. CONCLUSIONS: Buccal
      mucosa is a readily available and useful source for urethral grafting material,
      but should only be used in patients with insufficient penile skin. Grafts may be
      used as onlays or tubes. It is our experience that despite precautionary
      measures, fistulae and strictures are common.

PMID- 12431327
TI  - Pigmented pseudotumor of the testis: a unique testicular and para-testicular
      mass.
AB  - We report on the case of a 24 year old male with a testicular and paratesticular
      melanin-like, pigmented lesion. This is the first report of this type of lesion
      which we have designated a pigmented pseudotumor.

PMID- 12431328
TI  - Management of urethral catheter knot in a neonate.
AB  - To accommodate the small size of the infant urethra, finer, more flexible tubes
      are often used for urinary catheterization in the pediatric intensive care units.
      These tubes have the ability to knot in the bladder, occasionally requiring
      surgical removal. The mechanism of knotting appears to result from excessive
      intravesical catheter coiling, and as the bladder decompresses the catheter tip
      can migrate through a coil thereby creating a knot. Review of the literature from
      1975 to 2000 identified 19 cases of urethral catheter knotting in the pediatric
      bladder with two reports of prostatic urethral involvement. Herein, we describe
      the first reported instance of catheter knotting within the penile urethra and
      describe the surgical technique employed for its removal.

PMID- 12431329
TI  - Retroperitoneoscopic left nephrectomy in a horseshoe kidney with the use of the
      harmonic scalpel.
AB  - Laparoscopy has greatly evolved over the years. More recently,
      retroperitoneoscopy has gained wide acceptance as the preferred approach for
      simple and complicated nephrectomies. We report on a 12 year-old girl who
      underwent a left nephrectomy on a horseshoe kidney through a retroperitoneoscopic
      approach using the harmonic scalpel for dissection and isthmus division. The
      operation was successful, recovery uneventful, and the patient was discharged 24
      hrs post operatively, with excellent cosmesis. Retroperitoneoscopy can be
      considered if ablative surgery is contemplated in a horseshoe kidney, with
      adequate preoperative evaluation and solid retroperitoneoscopic surgical
      experience. The use the harmonic scalpel was greatly beneficial for the overall
      success of this complicated intervention.

PMID- 12431330
TI  - Transperitoneal laparoscopic radical nephrectomy for bulky renal tumors.
AB  - Laparoscopic management of kidney cancer is becoming accepted as an alternative
      to open radical nephrectomy. Technical considerations have limited the
      application of laparoscopic radical nephrectomy to relatively small, clinically
      localized tumors. At the National Cancer Institute, we have broadened the
      indications to include bulky tumors. Herein, we describe the operation with
      attention to the technical caveats that have been gained with experience.

PMID- 12431332
TI  - Editorial.

PMID- 12431333
TI  - Anti-angiogenesis: A new potential strategy to inhibit restenosis.
AB  - Microvessels are an integral component of the neointima developing in response to
      the acute vascular injury resulting from angioplasty. These vessels originate
      from the vasa vasorum of the adventitia, and as such appear similar to the
      microvessels present in atherosclerotic plaques. Several angiogenic factors have
      been found in atherosclerotic plaques and have been associated with increased
      microvascularity. In addition, most of these agents - either directly or
      indirectly - also induce smooth muscle cell (SMC) proliferation, an essential
      component of the developing neointima. We therefore propose: (1) these newly
      formed blood vessels are necessary for the development, maintenance, and
      expansion of the neointimal lesions present in restenosis; (2) the initiation,
      regulation and maintenance of these vessels is, at least in part, due to the
      coordinate sequential expression of hypoxia-inducible factor 1 (HIF-1), vascular
      endothelial growth factor (VEGF), angiopoietin-1 (Ang-1), and/or other angiogenic
      factors such as the fibroblast growth factor (FGF) family of proteins; (3)
      targeted disruption of the signal transduction pathways modulated by these
      molecules may reduce vasa vasorum expansion and SMC proliferation. These effects,
      in turn, may inhibit neointimal expansion and thus the development of restenosis,
      especially following stenting.

PMID- 12431334
TI  - Platelet glycoprotein IIb/IIIa receptor inhibition in primary angioplasty for
      acute myocardial infarction: The new paradigm of direct revascularization.
AB  - Acute myocardial infarction results from thrombotic occlusion superimposed on a
      ruptured athersoclerotic plaque. Immediate restoration of normal flow in the
      infarct-related artery can be achieved either with fibrinolytic or with direct
      mechanical revascularization. Primary PTCA has been shown to be superior to
      fibrinolytic therapy with respect to mortality, reinfarction, non-fatal stroke
      and length of hospitalization. Its results can be further improved by the
      addition of potent platelet inhibitors directed against the final common
      component of all stimuli for platelet aggregation, the glycoprotein (GP) IIb/IIIa
      receptor. In randomized clinical trials, primary angioplasty with adjunctive
      abciximab - a monoclonal antibody against the GP IIb/IIIa - was better than
      conventional primary angioplasty with heparin only. Abciximab use was associated
      with a significant reduction in reinfarction, need for urgent target vessel
      revascularization, microcirculatory dysfunction and regional left ventricular
      dysfunction as well as with a strong trend towards a reduction in mortality, even
      in patients receiving coronary stents.

PMID- 12431335
TI  - Selective use of abciximab in coronary stenting: overall outcomes can still be
      equivalent to those in the EPISTENT treatment group.
AB  - BACKGROUND: The EPISTENT trial reported improved early outcomes with routine use
      of abciximab after coronary stenting. Increasing use of stents means that routine
      abciximab adds significantly to costs of percutaneous coronary intervention
      (PCI). This paper reports the results of a protocol encouraging restriction of
      abciximab therapy to high-risk patients only. METHODS: Data were collected
      prospectively over a 34-month period for patients undergoing PCI with stenting.
      In addition to those who fulfilled criteria for inclusion in the EPISTENT trial,
      patients treated in the setting of acute myocardial infarction (AMI) were
      studied. Demographic data, procedural details and early clinical outcomes were
      recorded. RESULTS: Of 808 patients studied, 601 fulfilled EPISTENT inclusion
      criteria and comprised 367 patients (45%) treated for stable angina and 234 (30%)
      treated for unstable or post-infarct angina. The additional 207 patients (25%)
      were treated during AMI. The 808 patients received a total of 981 stents.
      Abciximab was given in only 88 cases (10.9%). Major adverse clinical events
      occurred in 39 patients (4.8%). CONCLUSION: Selective use of abciximab for
      patients undergoing coronary stenting can be associated with outcomes equivalent
      to those reported for routine use, but with significant cost savings.

PMID- 12431336
TI  - Intravascular ultrasound assessment of culotte stent deployment for the treatment
      of stenoses at major coronary bifurcations.
AB  - BACKGROUND: The mechanism for the disappointing late outcome following stenting
      of bifurcation lesions is unclear. This prospective observational study aims to
      evaluate culotte stent deployment and dimensions with intravascular ultrasound
      (IVUS). PATIENTS AND METHODS: Patients with bifurcation stenoses were treated
      using two stents in a culotte configuration. After optimizing the angiographic
      appearance of both stents, IVUS was used to evaluate both limbs of the culotte.
      The main outcome measures were cross-sectional area (CSA) and minimal lumen
      diameter (MLD) assessed by IVUS. RESULTS: Within the culotte stent, the final
      mean CSA in the main limb was 6.1 mm(2) (97% of reference) and in the side-limb
      was 5.9 mm(2) (97% of reference). However, in each case, the minimum CSA and IVUS
      MLD of both limbs was at the bifurcation point. For all patients, the final mean
      CSA at the bifurcation point of the main limb was 4.3 mm(2) (70% of main stent)
      and of the side-limb was 4.4 mm(2) (75% of side stent). The IVUS MLD at the
      bifurcation point of the main limb was 2.1 mm (78% of main stent) and of the side
      limb was 2.1 mm (84% of the side stent). Importantly, this significant residual
      stenosis was not detectable with quantitative coronary angiography. CONCLUSIONS:
      IVUS evaluation of culotte stents is feasible. The minimum IVUS CSA and MLD of
      both limbs of the culotte stent is at the bifurcation point. Despite an optimal
      angiographic appearance a significant residual stenosis was noted with IVUS at
      each bifurcation point.

PMID- 12431337
TI  - Clinical outcomes of long coronary stents: a single-center experience.
AB  - BACKGROUND: Coronary artery stenting is particularly useful during percutaneous
      coronary intervention for long lesions previously associated with a low
      procedural success rate and a high complication rate of dissection and occlusion.
      Current treatment options include implantation of a single long stent, multiple
      contiguous stents, or 'spot' stenting. However, multiple stent implantation may
      result in sections of overlapping stent or gaps of unstented segments and is an
      independent predictor of restenosis. The early and intermediate clinical outcome
      of single and multiple long stent (>/= 30 mm) implantation is not established.
      METHODS AND RESULTS: The authors retrospectively identified 123 consecutive
      patients who had undergone stenting using one or more long coronary stents.
      Baseline clinical data, procedural outcomes and completed clinical follow-up to
      52 weeks were obtained by case-note review. The majority (69%) required
      intervention for stable coronary disease. Seventy-seven per cent of lesions were
      either type B2 or C and only 2% were in saphenous vein grafts. The procedural
      success rate was 94%. A total of 15 major events occurred in 13 patients (11%).
      Ten acute events occurred and five events were during the follow-up period from
      30 days to 52 weeks. Two patients died, one from uncontrolled bleeding secondary
      to the use of antithrombotic agents and one at four weeks due to sudden death.
      One patient had a postprocedural infarct. Two patients required in-hospital
      repeat revascularization for acute vessel closure and eight required
      revascularization during follow-up (three cases of occlusion/thrombosis and five
      cases of restenosis). CONCLUSIONS: The use of long coronary stents (>/= 30 mm)
      for the treatment of long diffuse native vessel disease, saphenous vein graft
      disease and long coronary dissections is associated with a reasonable procedural
      success rate and acceptable early and intermediate-term clinical outcomes.

PMID- 12431338
TI  - Percutaneous coronary intervention with adjunctive abciximab and clopidogrel in a
      patient with chronic idiopathic thrombocytopaenic purpura.
AB  - The use of the antiplatelet agents abciximab and clopidogrel is now accepted
      therapy in percutaneous coronary intervention. We present a case in which these
      agents were used in a patient with idiopathic thrombocytopaenic purpura and a
      platelet count of 40x10(9)/l undergoing primary multivessel coronary stenting.
      This case shows that unstable coronary syndromes can occur in patients with
      thrombocytopaenia and that antiplatelet agents may be used safely in this
      context.

PMID- 12431339
TI  - Anginal syndrome due to giant unruptured sinus of Valsalva aneurysm.
AB  - This paper presents a rare cause of angina pectoris in a 43-year-old woman. Her
      evaluation revealed a compressed and proximally occluded right coronary artery by
      a giant, unruptured, right sinus of Valsalva aneurysm. The aneurysm was
      surgically resected and the sinus was successfully reconstructed. On follow-up
      the patient is asymptomatic.

PMID- 12431340
TI  - Staged transcatheter closure of chronic postinfarction ventricular septal defects
      with the Amplatzer septal occluder.
AB  - Ventricular septal rupture is a serious complication of myocardial infarction
      with an extremely poor outcome. There are single reports of transcatheter closure
      of postmyocardial septal defects and clinical experience is limited. This paper
      reports on a successful staged transcatheter closure of two chronic
      postmyocardial defects using the Amplatzer septal occluder in a 52-year-old male.

PMID- 12431341
TI  - An awl inflicted chest wound causing acute myocardial infarction.
AB  - Penetrating chest wounds are frequent. When involving the heart, they usually
      cause tamponade. In our case, caused by an awl, laceration of the LAD occured
      without intrapericardial bleeding. The coronary angiography demonstrates the
      damage to the wall of the LAD.

PMID- 12431342
TI  - Conduction disturbances related to percutaneous balloon mitral valvuloplasty.
AB  - During the performance of 280 consecutive percutaneous balloon mitral
      valvuloplasty operations, two cases of conduction disturbances were reported
      (0.7%). These rare complications are transient and due to the mechanical pressure
      of the balloon on the conduction system.

PMID- 12431343
TI  - Editorial.

PMID- 12431344
TI  - Intermediate coronary artery stenosis: evidence-based decisions in interventions
      to avoid the oculostenotic reflex.
AB  - The prevalence of intermediate coronary artery stenosis (defined as a diameter
      stenosis of 40% to 70%) is quite large in patients undergoing PTCA. The coronary
      angiogram is considered the 'gold standard' for the definition of coronary
      anatomy, in spite of various limitations associated with its use. In recent
      years, sensor tipped guidewire based methods of physiologic assessment of
      stenosis severity, like myocardial fractional flow reserve, and poststenotic
      coronary flow reserve had established their role in the decision making in
      catheterization laboratory. The decision making should combine morphologic and
      physiologic assessment as better evidence based approach in guiding therapy to
      avoid the 'oculostenotic reflex'.

PMID- 12431345
TI  - Medical costs of intravascular ultrasound optimization of stent deployment.
      Results of the multicenter randomized 'REStenosis after Intravascular ultrasound
      STenting' (RESIST) study.
AB  - OBJECTIVE: Intravascular ultrasound (IVUS) can be used to optimize the deployment
      of stents. The aim of this study was to assess the acute and long-term medical
      costs of the use of IVUS through the results of the 'REStenosis after
      Intravascular ultrasound STenting' (RESIST) study. METHODS: One hundred and fifty
      five patients were randomized to routine stent deployment with (n = 79) versus
      without (n = 76) IVUS guidance, with clinical follow-up over 18 months. The
      medical costs (hospitalization plus procedural costs) were calculated using a
      cost accounting system at the time of stent implantation and for all repeat
      lesion revascularizations. (At the time of writing the exchange rate was 1 Euro =
      1 US dollar.) RESULTS: Because of the cost of IVUS catheters and the need for
      more balloons, acute procedural costs were 18% higher in the group with IVUS
      guidance (2934 +/- 670 Euros vs 2481 +/- 911 Euros). Clinical events (death,
      myocardial infarction, unstable angina or lesion revascularization) occurred in
      28/76 (37%) in the group without IVUS, versus 20/79 (25%) (OR = 1.7; 95%CI =
      [0.82; 3.63]) in the group with IVUS. There was a higher number of
      revascularization procedures in the control group (31 in the control group vs 20
      in the IVUS group). The cumulative medical costs at 18 months were only slightly
      higher in the IVUS group (4535 +/- 2020 Euros vs 4679 +/- 1471 Euros in the IVUS
      group), as the higher acute costs in the group with IVUS guidance were partially
      offset by the lower cost for revascularization procedures. Sensitivity analysis
      using variations of the unit costs as well as variations in the number of
      revascularization procedures and length of hospital stay showed that the overcost
      remained in a range between 1% and 7.6%. CONCLUSIONS: Over 18 months of followup,
      despite higher acute costs, IVUS optimization of stent deployment did not
      considerably increase the medical costs.

PMID- 12431347
TI  - Technical delivery of myogenic cells through an endocardial injection catheter
      for myocardial cell implantation.
AB  - BACKGROUND: The next clinical frontier in the therapeutics of ischemic heart
      disease may involve the development and delivery of specific molecules and cells
      into the myocardium. The aim of the present study was to evaluate the efficiency
      and safety of the MyoStar injection catheter (Biosense-Webster Inc.) that has
      recently been developed to deliver molecules and cells to the myocardium. The 8
      Fr (110 cm length) catheter comprises a navigation sensor with a 27 gauge needle
      at the distal tip. METHODS: Mouse myogenic cells (C2) were delivered to a tissue
      culture dish through different modalities: a standard laboratory pipette, a
      syringe needle (27 gauge) and the injection catheter. The cells were counted and
      monitored for growth and differentiation in the tissue culture immediately after
      delivery and two, three and six days later. Cells that were injected through a
      regular syringe needle or through the injection catheter demonstrated the same
      capacity to proliferate in tissue culture up to six days. RESULTS: The behavior
      of the cells in culture (fusion) was identical for the cells delivered to the
      tissue culture by a pipette or by the injection catheter. CONCLUSION: The results
      of the present study indicate that delivery of cells through the MyoStar
      injection catheter is a method with no significant loss or adverse effects to the
      cells along the path of the catheter. The catheter, which possesses both
      injection and navigation capabilities, can be used to deliver cell therapy to
      patients with ischemic heart disease.

PMID- 12431346
TI  - Multicenter evaluation of the phosphorylcholine-coated biodivYsio stent in short
      de novo coronary lesions: The SOPHOS study.
AB  - AIMS: The BiodivYsio trade mark stent (Biocompatibles Ltd, Farnham, UK) is coated
      with a phosphorylcholine (PC)-containing copolymer to confer biocompatibility.
      The SOPHOS (Study Of PHosphorylcholine coating On Stents) study was designed to
      assess the safety and efficacy of this novel coronary stent and by indirect
      comparison to indicate equivalence with other formal stent studies. METHODS AND
      RESULTS: Patients with angina and a single short (#x2A7F;12 mm) de novo lesion in
      a native coronary artery of >/=2.75 mm diameter were included. A total of 425
      patients were allocated in 24 centers. Clinical data were collected at one-, six-
      and nine-month follow-up. Angiography was performed before and after the stent
      implantation. In addition, in the first 200 patients (SOPHOS A) angiography was
      routinely performed at six months. The following 225 patients (SOPHOS B) were
      merely followed up clinically. The primary end-point of the study, the six-month
      MACE-rate (MACE = Major Adverse Cardiac Events) was 13.4% (two cardiac death;
      five Q-wave/nine non-Q-wave myocardial infarctions (MI); nine CABG and 32 target
      lesion revascularization (TLR), which is similar to the calculated 15% MACE-rate
      in comparable reference studies. Secondary end-points included among others
      restenosis at six months in the SOPHOS A population. The target vessel diameter
      was 2.98 +/- 0.48 mm. Minimal lumen diameter pre/post procedure and at follow-up
      was 1.00 +/- 0.32, 2.69 +/- 0.37, 1.91 +/- 0.71 mm, respectively. The binary
      restenosis rate (>/=50% diameter stenosis at follow-up) was 17.7%. CONCLUSION:
      The coronary BiodivYsio stent is safe and effective as a primary device for the
      treatment of native coronary artery lesions in patients with stable or unstable
      angina pectoris. Clinical and angiographic results are in the statistical range
      of equivalence with comparable studies with other current stents.

PMID- 12431348
TI  - Subclavian artery stenting: Immediate and mid term clinical follow-up results.
AB  - BACKGROUND: Intravascular stents are increasingly being used to treat subclavian
      artery obstructive disease. This study aimed to assess the immediate and mid-term
      clinical outcome of subclavian artery stenting. METHODS AND RESULTS: Total
      occlusion of the subclavian artery was seen in 7 (28%) out of the 25 consecutive
      patients treated for subclavican artery stenosis. Mean lesion length was 14 +/-
      4.3 mm. The mean preprocedure diameter stenosis was reduced from 83.2 +/- 14.9%
      to 9.6 +/- 5.4% postprocedure. Procedural success was achieved in all patients.
      Clinical follow-up was obtained in all patients. The initial success was
      maintained at follow-up (mean = 12 +/- 4 months) in 24 (96%) patients. Recurrence
      of symptoms occurred in 1 (4%) patient who had an angiographically documented
      restenosis four months after the procedure. It was successfully redilated.
      CONCLUSION: Stenting for subclavian artery obstructive disease is safe,
      technically feasible and has favorable clinical outcomes. It may be considered as
      the therapy of choice for subclavian artery obstructive disease.

PMID- 12431349
TI  - Echocardiographically documented acute aortic insufficiency induced by Amplatz
      left guide catheter.
AB  - This paper examines a case of sudden systolic pressure fall, tachycardia, low
      pulse pressure, and high pulmonary artery wedge pressure due to acute aortic
      insufficiency which was induced by an Amplatz left (AL-1) guide catheter used for
      better guide support during percutaneous transluminal coronary angioplasty of the
      right coronary artery. AL guide catheters can cause acute aortic insufficiency,
      of which practitioners should be aware when sudden hemodynamic collapse occurs.

PMID- 12431350
TI  - Glycoprotein IIb/IIIa receptor antagonists in acute myocardial infarction and
      primary coronary stenting: Not always effective.
AB  - Glycoprotein IIb/IIIa antagonists have been shown to be effective in reducing
      thrombotic complications prior to high-risk coronary interventions. Some studies
      have reported improved coronary flow after abciximab in slow or no-reflow
      phenomenon. We report a case in which abciximab did not clear the thrombotic
      occlusion or restore artery flow. Further studies are needed into the refractory
      no-flow phenomenon.

PMID- 12431351
TI  - Acute left main dissection with complete obliteration of flow followed by
      emergency stenting without predilatation.

PMID- 12431352
TI  - My journey in public health in the Caribbean.
AB  - As part of its 100th-anniversary celebration, the Pan American Health
      Organization has named 12 persons as "Public Health Heroes of the Americas" in
      recognition of their noteworthy contributions to public health in the Region of
      the Americas. Over the course of this year, the Revista Panamericana de Salud
      Publica/Pan American Journal of Public Health will be carrying pieces written by
      or about these heroes. Como parte de la celebracion de su Centenario, la
      Organizacion Panamericana de la Salud (OPS) ha distinguido con el titulo de
      Heroes de la Salud Publica a 12 personalidades que se han destacado por su
      valiosa contribucion a la salud en el continente americano. A lo largo de este
      ano, la Revista Panamericana de Salud Publica/Pan American Journal of Public
      Health publicara una serie de escritos de los mismos galardonados o acerca de
      ellos.

PMID- 12431353
TI  - [WHO world report on health and violence: a working tool].

PMID- 12431354
TI  - [Epidemiology of homicides in Cali, Colombia, 1993-1998: six years of a
      population-based model].
AB  - OBJECTIVES: To demonstrate the usefulness of an effective and timely information
      model, underscore the seriousness of the problem of homicides, and point out the
      need to apply this type of model as well as comprehensive prevention projects,
      such as Desarrollo, Seguridad y Paz (DESESPAZ). From 1993 to 1998, 11 457
      homicides were registered in Cali, Colombia, through an epidemiological
      surveillance model established under DESESPAZ by the mayor's office in Cali.
      METHODS: Beginning in January 1993, a work group organized by DESESPAZ reviewed
      and standardized the variables that different institutions gathered about the
      victims, their assailants, and the facts surrounding each case, and issued a
      weekly summary bulletin for the mayor and other local authorities. RESULTS:
      Between 1983 and 1994, the homicide rate increased from 23 to 124 per 100 000
      inhabitants. Subsequently, rates went down in 1995, 1996, and 1997 to 112, 102,
      and 86,1 per 100 000, respectively, and again rose slightly in 1998 to 88 per 100
      000. Even though people of all ages, including children under 5, have been
      victims of violence, the most affected group is that of men between the ages of
      20 and 34. The ratio of men to women has varied from 14.3:1 to 9.2:1. In terms of
      numbers, percentages, and rates, low-income groups are the most seriously
      affected, although the highest-income groups have had rates as high as 160 per
      100 000. A firearm was used in over 80% of homicides, and the crime was most
      often committed at night and on a weekend. A suspect was identified in only a few
      cases (8% to 21%). The bivariate analysis revealed a positive association with
      alcohol consumption by the victim, as well as with the use of firearms by the
      assailant (OR: 3.1; 95% CI: 2.6 to 3.6). Cases that occurred during a fight
      between individuals or during group fighting showed an association with the use
      of a sharp weapon and with alcohol consumption by the victim (OR: 1.9; 95% CI:
      1.4 to 2.6). CONCLUSIONS: A map shows the homicide distribution by neighborhood,
      and the benefits of a population-based surveillance model are discussed,
      particularly their usefulness for identifying risk factors and the measures that
      can be applied to prevent and control this form of violence.

PMID- 12431355
TI  - An evaluation of the adverse reaction potential of three measles-mumps-rubella
      combination vaccines.
AB  - OBJECTIVE: To compare the incidence of adverse events following the
      administration of three commercially available measles-mumps-rubella (MMR)
      combination vaccines. METHODS: A randomized double-blind clinical trial was
      performed in 1996 that involved a total of 10 142 students 6-12 years of age in
      the state of Rio Grande do Sul, in Brazil. An MMR vaccine containing the
      Edmonston-Zagreb, Leningrad-Zagreb, and RA 27/3 strains ("vaccine A") was
      administered to 2 226 students (21.9% of the total); an MMR vaccine with the
      Moraten, Jeryl Lynn, and Wistar 27/3 strains ("vaccine B") was administered to 2
      216 children (21.8%); and an MMR vaccine containing the Schwartz, Urabe AM-9, and
      Wistar 27/3 strains ("vaccine C") was given to 2 179 students (21.5%). A control
      group of 3 521 students (34.7%) was not vaccinated. Both the vaccinated subjects
      and the control subjects were followed daily for 30 days to detect any clinical
      manifestations. RESULTS: Adverse events were more frequent in the vaccinated
      children than in the control group (P < 0.01). In terms of causing parotitis,
      vaccine A had a relative risk (RR) of 5.72 (95% confidence interval (CI) = 3.11
      10.54) when compared with vaccine B, and an RR of 2.33 (95% CI = 1.52-3.58) when
      compared with vaccine C. Vaccine A was also associated with an increased risk of
      lymphadenopathy when compared with vaccine B (RR = 3.11; 95% CI = 1.78-5.45) and
      with vaccine C (RR = 2.22; 95% CI = 1.35-3.66). Vaccine C was associated with an
      increased risk of parotitis when compared with vaccine B (RR = 2.46; 95% CI =
      1.26-4.80). Three cases of aseptic meningitis were detected among the children in
      the study group, but only one case of vaccine-related aseptic meningitis was
      identified, among the children receiving vaccine A. CONCLUSIONS: The three MMR
      vaccines that we studied are associated with different risks of adverse events.
      We found vaccine A to cause more reactions than the two other vaccines,
      especially vaccine B. In addition, vaccine A presented both a temporal and a
      cause-and-effect association with one case of aseptic meningitis. We hope that
      this study will contribute information that can be used in choosing MMR vaccines
      with safe and effective strains, especially for mass vaccination strategies.

PMID- 12431356
TI  - Primary and booster vaccination with DTPw-HB/Hib pentavalent vaccine in Costa
      Rican children who had received a birth dose of hepatitis B vaccine.
AB  - OBJECTIVE: The DTPw-HB/Hib pentavalent combination vaccine has been developed
      following recommendations of the World Health Organization for the introduction
      of hepatitis B (HB) and Haemophilus influenzae type b (Hib) vaccines into routine
      childhood vaccination programs. The objectives of this study were to: 1) analyze
      the immunogenicity and the reactogenicity of the DTPw-HB/Hib pentavalent
      combination vaccine in comparison to separate injections of DTPw-HB and Hib
      vaccines as primary vaccination in a group of children who had received a dose of
      HB vaccine at birth and 2) in the second year of life to assess the antibody
      persistence as well as the response to a DTPw-HB/Hib or DTPw/Hib booster.
      METHODS: In the first part of the study (primary-vaccination stage), conducted in
      1998-1999, we analyzed the immunogenicity and reactogenicity of the DTPw-HB/Hib
      combination vaccine in comparison to separate injections of DTPw-HB and Hib
      vaccines as primary vaccination at 2, 4, and 6 months of age in 207 Costa Rican
      children who had received a dose of HB vaccine at birth. Later, in the booster
      vaccination stage of the study, in 1999-2000, in a subset of the children (69
      toddlers, now 15-18 months old), antibody persistence was measured, and response
      to a DTPw-HB/Hib or DTPw/Hib booster was also assessed. RESULTS: In both primary
      vaccination groups, at least 97.5% of the infants reached protective levels of
      antibodies (seropositivity) against the antigens employed in the vaccines. The
      DTPw-HB/Hib pentavalent combination vaccine did not result in more local
      reactions than did the DTPw-HB vaccine alone, and, in terms of general reactions,
      there was no clinically significant difference between the combination or
      separate injections, and with the pentavalent vaccine having the benefit of
      needing one less injection. Nine months after the third dose of the primary
      vaccination course, antibody persistence was similar in both groups, with over
      93% of children still having protective/seropositive titers for Hib, HB, and
      tetanus and about 50% for diphtheria and Bordetella pertussis. At 15 months of
      age, virtually all the toddlers responded with a strong boost response to all the
      vaccine antigens, whether they received the DTPw-HB/Hib pentavalent vaccine or
      the DTPw/Hib vaccine as a booster. Both booster regimens were equally well
      tolerated, indicating that up to five doses of the HB vaccine can be given
      without impact on safety. CONCLUSIONS: Our study confirms that the DTPw-HB/Hib
      pentavalent vaccine is highly immunogenic as a primary vaccination in children
      who received an HB vaccine at birth, with the pentavalent combination inducing
      both persisting immunity and boostable memory. The pentavalent vaccine was safe
      both for primary and booster vaccinations. Thus, this study in Costa Rican
      infants supports the routine use of the pentavalent DTPw-HB/Hib vaccine as part
      of childhood vaccination programs in Latin America and the Caribbean.

PMID- 12431357
TI  - [Clinical and laboratory features of aseptic meningitis associated with measles
      mumps-rubella vaccine].
AB  - OBJECTIVE: To describe epidemiological, clinical, and cerebrospinal fluid (CSF)
      findings in cases of aseptic meningitis associated with measles-mumps-rubella
      vaccination following a mass immunization campaign in the Brazilian state of
      Bahia in August 1997 promoted by the country's Ministry of Health, and to compare
      these cases to the cases of aseptic meningitis not associated with the vaccine
      that occurred in the same year. METHODS: Between March 1997 and October 1997, all
      individuals between 1 and 12 years of age admitted to the Couto Maia Hospital
      (the Bahia reference hospital for infectious illnesses) with a clinical and
      laboratory diagnosis of aseptic meningitis were prospectively followed. The study
      population was divided into two groups: one with individuals who had received the
      vaccine, and one with individuals who had not received the vaccine. Demographic,
      clinical, and laboratory information was collected on both groups. RESULTS: In
      September, following the vaccination campaign, 74 cases of aseptic meningitis
      were registered at the Couto Maia Hospital, versus the monthly average of 7.5
      cases. We observed a greater frequency of nuchal rigidity and increased CSF
      cellularity among children whose meningitis was associated with the vaccine.
      However, encephalitic involvement was more frequent in the group of children with
      non-vaccinal meningitis. CONCLUSIONS: Although the course of post-vaccinal
      meningitis is more benign than that of other forms of the disease, its treatment
      generates costs related to ancillary exams and hospitalizations. Mass vaccination
      campaigns should employ less reactogenic vaccine strains.

PMID- 12431358
TI  - [Premature death from infectious diseases in Spain, 1908-1995].
AB  - OBJECTIVES: Infectious diseases have traditionally been one of the leading causes
      of death in developed countries. The objectives of this research were to: 1)
      quantify the importance of infectious diseases as a cause of premature mortality
      in Spain between 1908 and 1995, and 2) determine the frequency and distribution
      of the infectious diseases with the greatest impact on premature death. METHODS:
      The study was carried out based on data on mortality from infectious causes
      published by the National Institute of Statistics in the Movimiento natural de la
      poblacion (Natural Movement of the Population) for the study period. Three
      indicators of premature mortality were used: the potential years of life lost
      (PYLL), the crude rate of PYLL per 1 000 population, and the percentage and the
      average of PYLL. RESULTS: Between 1908 and 1995, the number and the rate of PYLL
      from infectious causes clearly declined. The decrease was more prominent starting
      in the 1950s, and it was seen in all age groups. Tuberculosis was the leading
      cause of premature death from the beginning of the century until the 1970s, but
      after that, the leading causes became pneumonia and AIDS. CONCLUSIONS: The impact
      of infectious diseases as determinants of premature death in Spain declined
      during the 20th century, especially starting in the 1970s.

PMID- 12431362
TI  - Effectively managing public concerns about immunization safety.

PMID- 12431359
TI  - Congenital rubella syndrome in Haiti (Short communication).
AB  - OBJECTIVE: To determine if there is an unrecognized problem of congenital rubella
      syndrome (CRS) in Haiti, a country without a national rubella immunization
      program. METHODS: During March 2001 and June 2001, screening physicals were
      conducted on approximately 80 orphans at three orphanages in Haiti that accept
      disabled children. Children were classified as probable CRS cases based on
      established clinical criteria. Photo documentation of findings was obtained
      whenever possible. RESULTS: Six children met the criteria for probable CRS. Using
      data from surrounding Caribbean countries and from the United States of America
      prior to rubella immunization, we estimated that there are between 163 and 440
      new cases of CRS per year in Haiti. CONCLUSIONS: CRS exists in Haiti, but its
      presence is generally unrecognized. A national rubella immunization policy should
      be considered.

PMID- 12431363
TI  - [Screening for colorectal cancer].
AB  - This piece summarizes new recommendations from the Preventive Services Task Force
      of the United States of America concerning screening for colorectal cancer (CRC).
      These recommendations update and replace ones that were issued in 1996. The Task
      Force strongly recommends that physicians carry out CRC screening tests for both
      men and women who are 50 years of age or older. The Task Force found fair or good
      evidence that: 1) several screening methods are effective in reducing mortality
      from CRC, 2) the benefits of screening outweigh its risks, although the quality
      of the tests, the magnitude of the benefits, and the potential harms vary
      according to the method, and 3) periodic fecal occult blood testing (FOBT)
      reduces mortality from CRC. In addition, there is fair evidence that
      sigmoidoscopy, either alone or in combination with FOBT, reduces CRC mortality.
      There is no direct evidence that screening colonoscopy is effective in reducing
      CRC mortality, nor is it clear if the greater accuracy of colonoscopy in
      comparison to other tests compensates for its additional complications,
      inconvenience, and costs. Double-contrast barium enema is less sensitive than
      colonoscopy, and there is no direct evidence that it is effective in lowering
      mortality rates. There are insufficient data to determine which screening
      strategy is best in terms of the balance of benefits, potential harms, and cost
      effectiveness. Regardless of the strategy chosen, CRC screening is likely to be
      cost-effective (less than US$ 30 000 per year of life gained).

PMID- 12431364
TI  - Spring forward and fall back: dynamics in formation of somite boundaries.
AB  - Oscillating signaling systems mediate the progressive division of mesoderm into
      segmental units, termed somites. A recent study using time-lapse analysis in
      living chick embryos has revealed that the process of somite boundary formation
      relies on a carefully choreographed series of cell movements, which are both
      unexpected and surprisingly intricate.

PMID- 12431365
TI  - Survival signaling goes BAD.
AB  - Work published in this issue of Developmental Cell demonstrates, in vivo, that
      the proapoptotic gene BAD provides a genetic link between the cell death
      machinery and survival signaling. This work has implications for development,
      tissue homeostasis, and tumorigenesis.

PMID- 12431366
TI  - Protein origami for beginners.
AB  - In the October issue of Molecular Cell, Kowarik et al. examine cotranslational
      translocation and folding during the synthesis of secretory and integral membrane
      proteins. Their results suggest that these potentially competing processes are
      regulated in surprising ways and reveal novel insights into the mechanisms by
      which proteins are assembled into membranes.

PMID- 12431367
TI  - Dam1 is the right one: phosphoregulation of kinetochore biorientation.
AB  - Chromosomes have to establish the proper attachment to the spindle before
      segregation-a process that requires Ipl1p Aurora kinase. Recent work has
      identified Dam1p, a member of the DASH complex, as the key Ipl1p substrate
      responsible for kinetochore/microtubule interaction.

PMID- 12431368
TI  - Portrait of a stem cell.
AB  - There is great enthusiasm for the potential use of stem cells in treating tissue
      degenerative disorders, but little is known about the intrinsic molecular
      programs defining self-renewal and differentiation. New data sets produced by
      transcriptional profiling of purified stem cell populations begin to establish
      the nature of "stemness."

PMID- 12431369
TI  - Morphogen transport along epithelia, an integrated trafficking problem.
AB  - Graded signals are an important component of current models of pattern formation.
      Typically, a group of cells produces a signal that decays as it spreads through
      neighboring tissue. By contrast with endocrine signals, which spread
      systemically, patterning signals or morphogens have a restricted zone of
      influence, an area classically known as a field. The widely accepted model is
      that graded distribution of such signals allow cells to measure their position
      relative to the source. Although it provides a framework for understanding
      pattern formation, the concept of the morphogen raises many mechanistic issues.
      For example, how the distribution of a morphogen is established and maintained
      remains an outstanding issue. There is no doubt that signals are transported over
      distances of tens of cell diameters and that stable gradients do form. The
      question of how this is achieved has aroused the interest of many cell
      biologically minded developmental biologists.

PMID- 12431370
TI  - T-box time in England.
AB  - T-box genes encode DNA binding transcription factors known to regulate a wide
      variety of developmental processes during embryogenesis and are present in the
      genomes of all multicellular animals. Indeed, alongside other more familiar
      families of developmental regulators such as Hox, Sox, and Pax, T-box genes
      constitute one of the fundamental components of the universal metazoan "toolkit"
      of developmental genes. A recent meeting in Nottingham, England celebrated the
      first decade of T-box gene research and demonstrated just how much has been
      learned in the relatively short time since their discovery.

PMID- 12431371
TI  - Survival factor-mediated BAD phosphorylation raises the mitochondrial threshold
      for apoptosis.
AB  - Growth factor suppression of apoptosis correlates with the phosphorylation and
      inactivation of multiple proapoptotic proteins, including the BCL-2 family member
      BAD. However, the physiological events required for growth factors to block cell
      death are not well characterized. To assess the contribution of BAD inactivation
      to cell survival, we generated mice with point mutations in the BAD gene that
      abolish BAD phosphorylation at specific sites. We show that BAD phosphorylation
      protects cells from the deleterious effects of apoptotic stimuli and attenuates
      death pathway signaling by raising the threshold at which mitochondria release
      cytochrome c to induce cell death. These findings establish a function for
      endogenous BAD phosphorylation, and elucidate a mechanism by which survival
      kinases block apoptosis in vivo.

PMID- 12431372
TI  - Sustained activation of N-WASP through phosphorylation is essential for neurite
      extension.
AB  - Neurite extension is a key process for constructing neuronal circuits during
      development and remodeling of the nervous system. Here we show that Src family
      tyrosine kinases and proteasome degradation signals synergistically regulate N
      WASP in neurite extension. Src family kinases activate N-WASP through tyrosine
      phosphorylation, which induces Arp2/3 complex-mediated actin polymerization.
      Tyrosine phosphorylation of N-WASP also initiates its degradation through
      ubiquitination. When neurite growth is stimulated in culture, degradation of N
      WASP is markedly inhibited, leading to accumulation of the phosphorylated N-WASP.
      On the other hand, under culture conditions that inhibit neurite extension, but
      favor proliferation, the phosphorylated N-WASP is degraded rapidly. Collectively,
      neurite extension is regulated by the balance of N-WASP phosphorylation
      (activation) and degradation (inactivation), which are induced by tyrosine
      phosphorylation.

PMID- 12431373
TI  - Drosophila 14-3-3/PAR-5 is an essential mediator of PAR-1 function in axis
      formation.
AB  - PAR-1 kinases are required to determine the anterior-posterior (A-P) axis in C.
      elegans and Drosophila, but little is known about their molecular function. We
      identified 14-3-3 proteins as Drosophila PAR-1 interactors and show that PAR-1
      binds a domain of 14-3-3 distinct from the phosphoserine binding pocket. PAR-1
      kinases phosphorylate proteins to generate 14-3-3 binding sites and may therefore
      directly deliver 14-3-3 to these targets. 14-3-3 mutants display identical
      phenotypes to par-1 mutants in oocyte determination and the polarization of the A
      P axis. Together, these results indicate that PAR-1's function is mediated by the
      binding of 14-3-3 to its substrates. The C. elegans 14-3-3 protein, PAR-5, is
      also required for A-P polarization, suggesting that this is a conserved mechanism
      by which PAR-1 establishes cellular asymmetries.

PMID- 12431374
TI  - Centrosome maturation and mitotic spindle assembly in C. elegans require SPD-5, a
      protein with multiple coiled-coil domains.
AB  - The maternally expressed C. elegans gene spd-5 encodes a centrosomal protein with
      multiple coiled-coil domains. During mitosis in mutants with reduced levels of
      SPD-5, microtubules assemble but radiate from condensed chromosomes without
      forming a spindle, and mitosis fails. SPD-5 is required for the centrosomal
      localization of gamma-tubulin, XMAP-215, and Aurora A kinase family members, but
      SPD-5 accumulates at centrosomes in mutants lacking these proteins. Furthermore,
      SPD-5 interacts genetically with a dynein heavy chain. We propose that SPD-5,
      along with dynein, is required for centrosome maturation and mitotic spindle
      assembly.

PMID- 12431375
TI  - Gamma-tubulin37C and gamma-tubulin ring complex protein 75 are essential for
      bicoid RNA localization during drosophila oogenesis.
AB  - bicoid (bcd) RNA localization requires the activity of exuperantia and swallow at
      sequential steps of oogenesis and is microtubule dependent. In a genetic screen,
      we identified two novel genes essential for bcd RNA localization. They encode
      maternal gamma-Tubulin37C (gammaTub37C) and gamma-tubulin ring complex protein 75
      (Dgrip75), both of which are gamma-tubulin ring complex components. Mutations in
      these genes specifically affect bcd RNA localization, whereas other microtubule
      dependent processes during oogenesis are not impaired. This provides direct
      evidence that a subset of microtubules organized by the gamma-tubulin ring
      complex is essential for localization of bcd RNA. At stage 10b, we find
      gammaTub37C and Dgrip75 anteriorly concentrated and propose the formation of a
      microtubule-organizing center at the anterior pole of the oocyte.

PMID- 12431376
TI  - GLD-3, a bicaudal-C homolog that inhibits FBF to control germline sex
      determination in C. elegans.
AB  - The FBF RNA binding proteins control multiple aspects of C. elegans germline
      development, including sex determination. FBF promotes the oocyte fate at the
      expense of spermatogenesis by binding a regulatory element in the fem-3 3'UTR and
      repressing this sex-determining gene. Here we report the discovery of GLD-3, a
      Bicaudal-C homolog and cytoplasmic protein that physically interacts with FBF.
      Using RNAi and a gld-3 deletion mutant, we show that GLD-3 promotes the sperm
      fate, a sex determination effect opposite to that of FBF. By epistasis analysis,
      GLD-3 acts upstream of FBF, and, in a yeast three-hybrid assay, GLD-3 interferes
      specifically with FBF binding to the fem-3 3'UTR. We propose that GLD-3 binds FBF
      and thereby inhibits its repression of target mRNAs.

PMID- 12431377
TI  - Sequential activation of signaling pathways during innate immune responses in
      Drosophila.
AB  - Innate immunity is essential for metazoans to fight microbial infections. Genome
      wide expression profiling was used to analyze the outcome of impairing specific
      signaling pathways after microbial challenge. We found that these transcriptional
      patterns can be dissected into distinct groups. We demonstrate that, in addition
      to signaling through the Toll and Imd pathways, signaling through the JNK and
      JAK/STAT pathways controls distinct subsets of targets induced by microbial
      agents. Each pathway shows a specific temporal pattern of activation and targets
      different functional groups, suggesting that innate immune responses are modular
      and recruit distinct physiological programs. In particular, our results may imply
      a close link between the control of tissue repair and antimicrobial processes.

PMID- 12431378
TI  - Eliminating zebrafish pbx proteins reveals a hindbrain ground state.
AB  - The vertebrate hindbrain is divided into serially homologous segments, the
      rhombomeres (r). Pbx and Hox proteins are hypothesized to form heterodimeric, DNA
      binding transcription complexes which specify rhombomere identities. Here, we
      show that eliminating zebrafish Lzr/Pbx4 and Pbx2 function prevents hindbrain
      segmentation and causes a wholesale anterior homeotic transformation of r2-r6, to
      r1 identity. We demonstrate that Pbx proteins interact with Hox paralog group 1
      proteins to specify segment identities broadly within the hindbrain, and that
      this process involves the Pbx:Hox-1-dependent induction of Fgf signals in r4. We
      propose that in the absence of Pbx function, r2-r6 acquire a homogeneous ground
      state identity, that of r1, and that Pbx proteins, functioning primarily with
      their Hox partners, function to modify this ground state identity during normal
      hindbrain development.

PMID- 12431379
TI  - The hypoblast of the chick embryo positions the primitive streak by antagonizing
      nodal signaling.
AB  - The hypoblast (equivalent to the mouse anterior visceral endoderm) of the chick
      embryo plays a role in regulating embryonic polarity. Surprisingly, hypoblast
      removal causes multiple embryonic axes to form, suggesting that it emits an
      inhibitor of axis formation. We show that Cerberus (a multifunctional antagonist
      of Nodal, Wnt, and BMP signaling) is produced by the hypoblast and inhibits
      primitive streak formation. This activity is mimicked by Cerberus-Short (CerS),
      which only inhibits Nodal. Nodal misexpression can initiate an ectopic primitive
      streak, but only when the hypoblast is removed. We propose that, during normal
      development, the primitive streak forms only when the hypoblast is displaced away
      from the posterior margin by the endoblast, which lacks Cerberus.

PMID- 12431380
TI  - Nodal antagonists in the anterior visceral endoderm prevent the formation of
      multiple primitive streaks.
AB  - The anterior visceral endoderm plays a pivotal role in establishing anterior
      posterior polarity of the mouse embryo, but the molecular nature of the signals
      required remains to be determined. Here, we demonstrate that Cerberus-like(-/
      );Lefty1(-/-) compound mutants can develop a primitive streak ectopically in the
      embryo. This defect is not rescued in chimeras containing wild-type embryonic,
      and Cerberus-like(-/-);Lefty1(-/-) extraembryonic, cells but is rescued in
      Cerberus-like(-/-); Lefty1(-/-) embryos after removal of one copy of the Nodal
      gene. Our findings provide support for a model whereby Cerberus-like and Lefty1
      in the anterior visceral endoderm restrict primitive streak formation to the
      posterior end of mouse embryos by antagonizing Nodal signaling. Both antagonists
      are also required for proper patterning of the primitive streak.

PMID- 12431381
TI  - Reactive oxygen species regulation of immune function.

PMID- 12431382
TI  - VCAM-1 signals during lymphocyte migration: role of reactive oxygen species.
AB  - Vascular cell adhesion molecule-1 (VCAM-1) regulates leukocyte migration from the
      blood into tissues. VCAM-1 expression is induced on endothelial cells during
      inflammatory bowel disease, atherosclerosis, allograft rejection, infection, and
      asthmatic responses. During these responses, VCAM-1 forms a scaffold for
      leukocyte migration. VCAM-1 also activates signals within endothelial cells
      resulting in the opening of an "endothelial cell gate" through which leukocytes
      migrate. Immediately following this migration, the endothelial cell-endothelial
      cell contact is re-established. VCAM-1 outside-in signals are mediated by NADPH
      oxidase production of reactive oxygen species and subsequently activation of
      matrix metalloproteinases. These signals are required for endothelial cell shape
      changes and leukocyte migration. In addition, VCAM-1-activated signals in
      endothelial cells are regulated by cytokines indicating that it is important to
      consider both endothelial cell adhesion molecule expression and function during
      inflammatory processes.

PMID- 12431384
TI  - Negative signaling.

PMID- 12431383
TI  - Reactive oxygen intermediates in TNF signaling.
AB  - Tumor necrosis factor (TNF) is arguably the most potent inducer of several
      intracellular signals, including apoptosis, cell differentiation, and gene
      transcription. It does so through the activation of caspases, specific kinases
      including mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase
      (JNK), transcription factors Activated protein 1 (AP-1), and nuclear factor kappa
      B (NF-kappaB). By activating these signals, TNF mediates pro-apoptotic and pro
      survival mechanisms in the cell. It has also been suggested that TNF mediates its
      intracellular signaling by adjusting the redox potential of the cell,
      specifically through reactive oxygen intermediates (also known as reactive oxygen
      species). Here we review the evidence linking ROI to TNF-induced signaling and
      propose that ROI mediate both pro-apoptotic and pro-survival signals. How these
      antagonistic signals are balanced to maintain homeostasis is still not clear.

PMID- 12431385
TI  - How do inhibitory phosphatases work?
AB  - We present a hypothesis regarding the mode of induction of the inhibitory
      phosphatases SHP-1 and SHIP in hematopoietic cells. One mode is a general one in
      which the phosphatase regulates but does not abort signal transduction and
      biology. Regulator phosphatases are induced by directly or indirectly engaging
      the amino acid motifs present in the activating receptor, and act to control the
      biochemical and biological output. The other mode of induction is a specific one,
      which critically involves paired co-clustering of activating and inhibitory
      receptors. Phosphatases working in this way act only under conditions of paired
      co-clustering of activating and inhibitory receptors, and directly bind amino
      acid motifs present in the inhibitory receptor. However, this mode of induction
      is apparently more efficient, as cellular activation is completely aborted. This
      review presents several examples of each mode of inhibition and speculates on
      their mechanisms.

PMID- 12431386
TI  - The two faces of IL-6 on Th1/Th2 differentiation.
AB  - Interleukin (IL)-6 is a cytokine produced by several cell types including antigen
      presenting cells (APC) such as macrophages, dendritic cells, and B cells. IL-6 is
      involved in the acute phase response, B cell maturation, and macrophage
      differentiation. Here, we discuss a novel function of IL-6: the control of T
      helper (Th) 1/Th2 differentiation. IL-6 promotes Th2 differentiation and
      simultaneously inhibits Th1 polarization through two independent molecular
      mechanisms. IL-6 activates transcription mediated by nuclear factor of activated
      T cells (NFAT) leading to production of IL-4 by nai;ve CD4(+) T cells and their
      differentiation into effector Th2 cells. While the induction of Th2
      differentiation by IL-6 is dependent upon endogenous IL-4, inhibition of Th1
      differentiation by IL-6 is IL-4- and NFAT-independent. IL-6 inhibits Th1
      differentiation by upregulating supressor of cytokine signaling (SOCS)-1
      expression to interfere with IFNgamma signaling and the development of Th1 cells.
      Since IL-6 is abundantly produced by APC, it is a likely source of early Th1/Th2
      control during CD4(+) T cell activation. Thus, by using two independent molecular
      mechanisms, IL-6 plays a dual role in Th1/Th2 differentiation.

PMID- 12431387
TI  - Interleukin-15 and the regulation of lymphoid homeostasis.
AB  - Interleukin-15 (IL-15) is a cytokine that plays unique roles in both innate and
      adaptive immune cell homeostasis. While early studies suggested that IL-15
      resembled IL-2, more recent work suggests that IL-15 may play multiple unique
      roles in immune homeostasis befitting its pleiotropic expression pattern. This
      review will focus on recent studies that highlight some of these functions.

PMID- 12431388
TI  - CCP1-4 of the C4b-binding protein alpha-chain are required for factor I mediated
      cleavage of complement factor C3b.
AB  - C4b-binding protein (C4BP) is a potent regulator of the complement system because
      it strongly inhibits the classical pathway of complement. Furthermore, C4BP
      serves as a cofactor to factor I (FI) in the cleavage of fluid phase C3b and can,
      therefore, influence the alternative pathway of complement. The major form of
      C4BP in plasma consists of seven identical alpha-chains and one beta-chain. Both
      types of subunits are composed of complement control protein (CCP) domains, eight
      such domains make up one alpha-chain. To elucidate the structural requirements
      for the interaction between C3b and the alpha-chain, nineteen recombinant C4BP
      variants were used: six truncated monomeric variants, nine polymeric variants in
      which individual CCPs were deleted, and finally four variants in which double
      alanine residues were introduced between CCPs. We found that C4BP requires all
      four N-terminal CCPs of the alpha-chain, with CCP2 and 3 being the most
      important, to act as a cofactor in the cleavage of C3b. Also, a cluster of
      positively charged amino acids on the interface between CCP1 and 2 is involved in
      the binding. Compared to the interaction with C4b, we conclude that binding of
      C3b to C4BP requires larger molecular surface on C4BP. We found that C4BP was
      able to act as cofactor in degradation of surface bound C3b and to accelerate
      decay of alternative C3-convertase. However, in both cases 1,000-fold molar
      excess of C4BP over factor H (FH), well known inhibitor of the alternative
      pathway, was required to obtain the same effect.

PMID- 12431389
TI  - Compstatin, a peptide inhibitor of complement, exhibits species-specific binding
      to complement component C3.
AB  - Although activation of complement protein C3 is essential for the generation of
      normal inflammatory responses against pathogens, its unregulated activation
      during various pathological conditions leads to host cell damage. Previously we
      have identified a 13-residue cyclic peptide, Compstatin, that inhibits C3
      activation. In this study, we have examined the species-specificity of
      Compstatin. Bimolecular interaction analysis using a real-time surface plasmon
      resonance-based assay showed that Compstatin exhibits exclusive specificity for
      primate C3s and does not bind either to C3s from lower mammalian species or to
      two structural homologs of C3, human C4 and C5. Furthermore, it showed that
      although the kinetics of binding of Compstatin to non-human primate C3s were
      distinctly different from those to human C3, like human C3 its mechanism of
      binding to non-human primate C3 was biphasic and did not follow a simple 1:1
      interaction, suggesting that this binding mechanism could be important for its
      inhibitory activity. Analysis of Ala substitution analogs of Compstatin for their
      inhibitory activities against mouse and rat complement suggested that the lack of
      binding of Compstatin to mouse and rat C3s was not a result of sterically
      hindered access to the binding pocket due to individual bulky side chains or the
      presence of charge on the Compstatin molecule. These results suggest that
      Compstatin's exclusive specificity for primate C3s could be exploited for the
      development of species-specific complement inhibitors.

PMID- 12431390
TI  - Dynamics of measles virus protein expression are reflected in the MHC class I
      epitope display.
AB  - Following measles virus (MV) infection, viral peptides are presented to CTL by
      MHC class I molecules on infected antigen presenting cells at widely different
      epitope densities. Whereas three MV epitopes (MV-M(211-219), MV-F(438-446) and MV
      H(30-38)) derived from different structural proteins occur at regular densities,
      one peptide derived from the non-structural C protein (MV-C(84-92)) fully
      dominates the MV peptide display in HLA class I molecules on end-stage-infected
      human B cells. Here we demonstrate that this hierarchy in MV epitope density is
      not a constant, but varies with progression of infection. While MV-M(211-219), MV
      F(438-446) and MV-H(30-38) epitopes were already presented by HLA class I
      molecules early in infection, expression of MV-C(84-92) was restricted to the
      later phases of infection. These dynamics in epitope densities correlated with
      features of MV protein expression. Synthesis of C protein mainly focused towards
      the final stages of infection, while the other MV proteins were more readily
      synthesised from earlier time points on, in line with the emergence of their
      respective epitopes. Furthermore, the most abundant MV epitope was derived from
      the most unstable viral protein and vice versa, suggesting that the stability of
      viral proteins may be an indicator for the final abundance of their epitopes.
      Thus, even though many other factors may influence the generation of peptide-MHC
      class I complexes, we here report that the regulation of viral protein expression
      seems closely linked to the viral MHC class I epitope display. Finally, the
      observed dynamics in viral epitope hierarchy may have important implications for
      the induction of antiviral T cell immunity.

PMID- 12431391
TI  - The transcription factor Spi-B is not required for somatic hypermutation.
AB  - Mice with a homozygous inactivation of the transcription factor gene Spi-B(-)/(-)
      have abnormal B cell functions and a defect in germinal center (GC) formation. We
      report here that somatic hypermutation (SHM) of VH1 and VH11 genes is not
      diminished in Peyer's patches of Spi-B(-)/(-) mice. However, the mutation pattern
      shows an increase in the ratio of replacement to silent mutations in the
      framework sequences of the variable regions, suggesting that selection of mutated
      B cells based on functionality is affected. In support of this, two of the six
      sequences from Spi-B mutant mice have a point mutation in the framework which
      introduces predicted steric clashes with another amino acid in the variable
      region. This mutation (Leu81Phe) has not been observed in 120 mutated VH1 or VH11
      genes of germinal center B cells from Spi-B wildtype mice. The mutation also does
      not exist in any of 136 published heavy chain proteins of the same VH family. The
      mutations causing the change to Phe are transitions which are favored by the SHM
      process over transversions. Clearly, Phe-81 must arise relatively frequently, but
      is not selected in Spi-B wildtype mice.

PMID- 12431392
TI  - Overexpression of the c-fos gene perturbs functional maturation of M1 cells into
      macrophages.
AB  - Expression of the proto-oncogene c-fos is induced in normal myelopoiesis.
      However, functions of c-Fos in the process of differentiation towards macrophages
      are still controversial. To explore the functions, we used the murine
      myeloblastic leukemia cell line M1. Stimulation of M1 cells with bacterial LPS
      promotes their terminal differentiation into functional macrophages.
      Overexpression of c-fos in M1 cells dramatically increased sensitivity of the
      cells for LPS-induced differentiation and generation of morphologically
      differentiated cells. However, the overexpression did not modulate phagocytotic
      functions, surface expression of macrophage markers such as CD16/CD32 (Fcgamma
      Receptor) and CD54 (ICAM-1), and expression of lysozyme, esterase and c-fms mRNA.
      Surprisingly, induction of the MHC class II expression on M1 cells after
      stimulation was inhibited by the overexpression. Expression of CIITA, as an
      essential transcription factor for the expression, was also reduced in the M1
      cells. These results suggest that overexpression of c-fos in differentiating M1
      cells perturbs their functional maturation.

PMID- 12431393
TI  - The major allergen (parvalbumin) of codfish is encoded by at least two isotypic
      genes: cDNA cloning, expression and antibody binding of the recombinant
      allergens.
AB  - The major allergen (parvalbumin) from cod, designated Allergen M Gad c 1, has
      been intensively studied both from the structural and immunological sides. In the
      present study, transcripts of two isotypic parvalbumin genes in Atlantic cod were
      identified and characterized. Subsequently, subfragments were inserted into the
      expression vector pET-19b, generating plasmids with coding capacity for complete
      parvalbumin polypeptides fused to an N-terminal his(10) tag. Most of the
      recombinant products were found in the soluble fraction of the expression host
      Escherichia coli. The target proteins showed to react with polyclonal antibodies
      raised against Allergen M and demonstrated binding to specific IgE from 12 sera
      of patients allergic to cod in ELISA inhibition experiments. Sera with classes 4
      and 5 CAP FEIA exhibited also strong binding to recombinant parvalbumins in
      immunoblots.

PMID- 12431394
TI  - Vaccination for birch pollen allergy. Induction of affinity-matured or blocking
      IgG antibodies does not account for the reduced binding of IgE to Bet v 1.
AB  - Specific allergy vaccination (SAV) is associated with increased levels of
      allergen specific IgG in serum. It is not clear, however, to what extent
      qualitative changes in allergen binding to IgG may be induced as well. We
      therefore analyzed the binding of the major allergen in pollen of birch (Betula
      verrucosa) (Bet v 1), the major allergen in birch pollen, to serum IgG and IgE,
      separately and in competition. Sera from six birch pollen-allergic patients were
      obtained before and after 5 years of SAV, and binding was assessed with 125I-Bet
      v 1. Before SAV, IgG bound more than eight times the amount of Bet v 1 compared
      with IgE, and together they accounted for more than 85% of the serum binding
      capacity. While SAV induced minimal changes in IgE binding, the IgG binding
      capacities increased 6-32 times. In contrast, the binding avidities (K(d) 28
      40pM) changed less than 20%, pre- and post-SAV IgG provided similar inhibition of
      Bet v 1 binding to IgE at equimolar levels, and cross inhibition studies between
      IgG and IgE showed low inter-individual differences. Following SAV, all sera
      reduced Bet v 1 binding to CD23(+) cells, correlating with reduced binding of Bet
      v 1 to IgE (P<0.001). These results show that high avidity IgG of low inter
      individual difference in Bet v 1 binding quality is the dominant binding factor
      of Bet v 1 in sera of birch pollen-allergic patients, and that SAV-induced
      inhibition of binding of Bet v 1 to IgE can be explained mainly or solely by
      increased amounts of IgG.

PMID- 12431395
TI  - Changes in the fatty acid composition of phospholipids in tissues of farmed sea
      bass (Dicentrarchus labrax) during an annual cycle. Roles of environmental
      temperature and salinity.
AB  - We quantified seasonal effects on fatty acid composition of tissue phospholipids
      in farmed sea bass. Major changes in percent phosphatidylethanolamine and
      phosphatidylcholine were observed in all tissues between February and March, and
      the phosphatidylcholine/phosphatidylethanolamine ratio was drastically reduced at
      this time. Different changes in the fatty acid composition of total phospholipids
      were observed in all tissues examined. Fish fed all year on the same commercial
      diet showed a significant correlation between water salinity and percentage of
      22:6n-3 in muscle, liver and gill phospholipids, but no correlation was found
      between percent 22:6n-3 of phospholipids and water temperature. In each tissue,
      we observed annual variation in the 20:5n-3/20:4n-6 ratio in phospholipids, but
      maximum and minimum values occurred at different times in each organ. From these
      results, we conclude that salinity can play a significant role in modulating the
      activities of enzymes acting on lipid metabolism during their natural circannual
      cycles.

PMID- 12431396
TI  - Dietary amino acid profiles and growth performance in juvenile kuruma prawn
      Marsupenaeus japonicus.
AB  - To assess the reference dietary amino acid profiles for juvenile kuruma prawn
      Marsupenaeus japonicus a feeding trial was conducted using six semi-purified
      diets containing casein-gelatin and pre-coated supplemental crystalline amino
      acids (CAA) and a control diet containing intact protein (casein-gelatin). Pre
      coated CAA were supplemented to the diets to simulate dietary amino acid profiles
      to those of the prawn egg protein (PEP), prawn larvae whole body protein (PLP),
      prawn juvenile whole body protein (PJP), squid meal protein (SMP), short-necked
      clam protein (SNP) and brown fish meal protein (BFP). The result showed that
      kuruma prawn juveniles are capable of utilizing the pre-coated CAA and higher
      growth performances were observed in the groups fed the PJP, SMP and the control
      diets than those fed the PLP, SNP, BFP and PEP diets. The essential amino acid
      proportions (A/E ratios) of the whole body of kuruma prawn differ slightly when
      compared with the other penaeids or freshwater prawn. The results suggest that
      PJP and SMP would be suitable as a reference dietary amino acid profile for
      juvenile prawn.

PMID- 12431397
TI  - Notothenioid fish, krill and phytoplankton from Antarctica contain a vitamin E
      constituent (alpha-tocomonoenol) functionally associated with cold-water
      adaptation.
AB  - The vitamin E (VE) content of tissues from the Antarctic notothenioid fish,
      Chaenocephalus aceratus, Champsocephalus gunnari and Gobionotothen gibberifrons,
      and extracts of Antarctic krill Euphausia superba and phytoplankton collected
      from the Antarctic Peninsula was examined. Included in the VE composition was a
      newly described 'marine-derived' tocopherol (MDT), an unsaturated-isoprenoid
      derivative of alpha-tocopherol, that is attributed to enhancing antioxidant
      protection of cellular lipids at low temperature. MDT was found to co-exist with
      alpha-tocopherol in all Antarctic samples, ranging from 2.8 to 22.3% of the total
      VE composition. The highest level of VE was found in the liver of G. gibberifrons
      (VE=416.7 pmol/mg wet tissue) although this tissue had a low MDT composition
      (7.7%), whereas the greatest MDT composition was measured in the liver of C.
      gunnari (MDT=22.3%). In notothenioids, the pectoral adductor muscle, which has a
      high density of mitochondria, contained higher levels of VE than white myotomal
      muscle, but differences in MDT composition were small. Phytoplankton and krill
      also contained MDT, which supports the contention that MDT is obtained directly
      from the primary food chain. Our finding of MDT in Antarctic organisms is
      consistent with its putatively adaptive function to enhance antioxidant
      protection in coldwater metabolism.

PMID- 12431398
TI  - A cathepsin B-like enzyme from mackerel white muscle is a precursor of cathepsin
      B.
AB  - A cathepsin B-like enzyme from the white muscle of common mackerel Scomber
      japonicus was a cysteine protease that hydrolyzed Z-Arg-Arg-MCA, the substrate
      for cathepsin B. In a partial purified cathepsin B-like enzyme preparation at 4
      degrees C left over time, a converted enzyme that hydrolyzes Z-Arg-Arg-MCA and Z
      Phe-Arg-MCA appeared in the preparation. The converted enzyme was purified from
      the cathepsin B-like enzyme, characterized and was identified as mackerel
      cathepsin B. These results suggested that the mackerel cathepsin B-like enzyme
      was a precursor of cathepsin B. Mackerel cathepsin B formed in the purified
      cathepsin B-like enzyme preparation by adding of a small amount of the purified
      cathepsin B to the preparation. Therefore, mackerel cathepsin B-like enzyme was
      converted to the mature form of cathepsin B by autoactivation. The conversion of
      the cathepsin B-like enzyme (molecular mass 60 kDa) to cathepsin B (molecular
      mass 23 kDa) was detected by immunoblotting by using human anti-(cathepsin B)
      antibody. The intermediate forms of 40 kDa and 38 kDa were also detected during
      the conversion.

PMID- 12431399
TI  - Evidence for cAMP-dependent protein kinase in the dinoflagellate, Amphidinium
      operculatum.
AB  - A cAMP dependent protein kinase (PKA) was identified in the dinoflagellate
      Amphidinium operculum. In vitro kinase activity towards kemptide, a PKA-specific
      substrate, was not detectable in crude lysates. However, fractionation of
      dinoflagellate extracts by gel filtration chromatography showed PKA-like activity
      toward kemptide at approximately 66 kDa. These findings suggest that possible low
      molecular mass inhibitors in crude lysates were removed by the gel filtration
      chromatography. Pre-incubation of extracts with cAMP prior to chromatography
      resulted in an apparent molecular mass shift in the in vitro kinase assay to 40
      kDa. An in-gel kinase assay reflected activity of the free catalytic subunit at
      approximately 40 kDa. Furthermore, western blotting with an antibody to the human
      PKA catalytic subunit confirmed a catalytic subunit with a mass of approximately
      40 kDa. Results from this study indicate that the PKA in A. operculatum has a
      catalytic subunit of similar size to that in higher eukaryotes, but with a
      holoenzyme of a size suggesting a dimeric, rather than tetrameric structure.

PMID- 12431400
TI  - A homologue of human placental protein, PP11, and mouse T cell-specific protein,
      Tcl-30, in exocrine pancreas of a teleost (Paralichthys olivaceus).
AB  - We cloned a 1401-bp cDNA encoding a novel pancreatic protein (PPSB) with two
      cysteine-rich somatomedin B-like domains from Japanese flounder (Paralichthys
      olivaceus). PPSB is predicted to be composed of 385 amino acids, including a
      signal sequence. The peptide sequence shares high homology with human placental
      protein 11 (PP11) and mouse T-cell specific protein (Tcl-30), which both contain
      a single somatomedin B-like domain. PPSB shares 47% and 44% identity with PP11
      and Tcl-30, respectively. The unique point of PPSB is that an additional,
      somatomedin B-like domain is tandemly inserted. Unlike PP11 and Tcl-30, PPSB mRNA
      is specifically expressed by the exocrine pancreatic acinar cells, together with
      trypsinogen. Since PP11 has serine protease activity, it is predicted that its
      teleost homologue, PPSB, may function as a pancreatic digestive enzyme.

PMID- 12431401
TI  - Comparative biochemical studies of carotenoids in catfishes.
AB  - The carotenoids of 12 species of Siluriformes fishes (eight families) were
      investigated from a comparative biochemical point of view. The patterns of
      carotenoids in catfishes belonging to the family Siluridae were quite different
      from those of the other seven families of catfishes (Bagridae, Amblycipitidae,
      Clariidae, Plotosidae, Ictaluridae, Callichthyidae and Malapteruridae). 7, 8
      Dihydro-beta-carotene; 7, 8, 7', 8'- and 7, 8, 9, 10-tetrahydro-beta-carotene;
      (3R)-7', 8'-dihydro-beta-cryptoxanthin; 7, 8-dihydrolutein A; 7, 8-dihydrolutein
      B; parasiloxanthin; 7', 8'-dihydroparasiloxanthin; and 4 or 4'
      hydroxyparasiloxanthin were characteristic carotenoids found in only one family,
      Siluridae, and these carotenoids accounted for 24-60% of total carotenoids. In
      catfishes belonging to the other seven families except Siluridae, the carotenoid
      patterns were very similar and the most predominant carotenoid was zeaxanthins
      (23-56%).

PMID- 12431402
TI  - Cuticular hydrocarbons of the flea beetles, Aphthona lacertosa and Aphthona
      nigriscutis, biocontrol agents for leafy spurge (Euphorbia esula).
AB  - The adult beetles Aphthona lacertosa and Aphthona nigriscutis, used as biocontrol
      agents for leafy spurge, had a complex mixture of hydrocarbons on their cuticular
      surface consisting of alkanes, methylalkanes, alkenes and alkadienes as
      determined by gas chromatography-mass spectrometry. A trace amount of wax esters
      were present. In both species, the hydrocarbons were the major cuticular lipid
      class and the gas chromatographic profiles of the total hydrocarbons were
      similar. However, the profiles for the saturated hydrocarbon fraction were
      distinct for each species. Alkanes (n-alkanes and methyl-branched alkanes),
      alkenes and alkadienes comprised 26, 44 and 30%, respectively, for A. lacertosa,
      and 48, 26 and 26%, respectively, for A. nigriscutis, of the total hydrocarbons.
      The major methyl-branched hydrocarbons were 2-methylalkanes: 2-methyloctacosane
      and 2-methyltriacontane. The major monoene was hentriacontene and the major diene
      was tritriacontadiene. The species were unique in that a number of di- and
      trimethyl-branched alkanes were present in minor quantities in which the first
      methyl branch was on carbon 2 or 3. Examples of structures were 2,10-, 2,12-, 2,6
      , 2,4- and 3,7-dimethylalkanes. 2,10,12-Trimethylalkanes and a 2,10,12,24
      tetramethylalkane with one methylene between adjacent methyl branch points also
      were identified. The adjacent methyl branch points of the 2,4- and 2,10,12- and
      2,10,12,24-methyl-branched alkanes appeared to cause additional fragmentations in
      the mass spectra. Dimethylalkanes with an odd number of carbons in the backbone
      of the molecule were identified as 2,23-dimethylnonacosane and 2,25
      dimethylhentriacontane; their mass spectra also corresponded to mass spectra
      expected for a 2,6 branching sequence. However, a 2,6 branching sequence is not
      biosynthetically feasible because such a structure has a straight-chain tail with
      an odd number of carbon atoms beyond the last methyl branch point. The 2,23 and
      2,25 branching sequences could be synthesized starting with a primer derived from
      the amino acid leucine which would account for both the even number of carbons
      between the branch points and an even number of carbons beyond the last methyl
      branch point.

PMID- 12431403
TI  - Isolation, characterization and inhibition by acarbose of the alpha-amylase from
      Lactobacillus fermentum: comparison with Lb. manihotivorans and Lb. plantarum
      amylases.
AB  - Extracellular alpha-amylase from Lactobacillus fermentum (FERMENTA) was purified
      by glycogen precipitation and ion exchange chromatography. The purification was
      approximately 28-fold with a 27% yield. The FERMENTA molecular mass (106,000 Da)
      is in the same range as the ones determined for L. amylovorus (AMYLOA), L.
      plantarum (PLANTAA) and L. manihotivorans (MANIHOA) alpha-amylases. The amino
      acid composition of FERMENTA differs from the other lactobacilli considered here,
      but however, indicates that the peptidic sequence contains two equal parts: the N
      terminal catalytic part; and the C-terminal repeats. The isoelectric point of
      FERMENTA, PLANTAA, MANIHOA are approximately the same (3.6). The FERMENTA optimum
      pH (5.0) is slightly more acidic and the optimum temperature is lower (40 degrees
      C). Raw starch hydrolysis catalyzed by all three amylases liberates maltotriose
      and maltotretaose. Maltose is also produced by FERMENTA and MANIHOA. Maltohexaose
      FERMENTA catalyzed hydrolysis produces maltose and maltotriose. Finally, kinetics
      of FERMENTA, PLANTAA and MANIHOA using amylose as a substrate and acarbose as an
      inhibitor, were carried out. Statistical analysis of kinetic data, expressed
      using a general velocity equation and assuming rapid equilibrium, showed that:
      (1) in the absence of inhibitor k(cat)/Km are, respectively, 1x10(9), 12.6x10(9)
      and 3.2x10(9) s(-1) M(-1); and (2) the inhibition of FERMENTA is of the mixed non
      competitive type (K(1i)=5.27 microM; L(1i)=1.73 microM) while the inhibition of
      PLANTAA and MANIHOA is of the uncompetitive type (L(1i)=1.93 microM and 1.52
      microM, respectively). Whatever the inhibition type, acarbose is a strong
      inhibitor of these Lactobacillus amylases. These results indicate that, as found
      in porcine and barley amylases, Lactobacillus amylases contain in addition to the
      active site, a soluble carbohydrate (substrate or product) binding site.

PMID- 12431404
TI  - Molecular characterization of vitellin from the ovaries of the white shrimp
      Penaeus (Litopenaeus) vannamei.
AB  - Vitellin (Vt) was purified from ovary extracts of mature females of the white
      shrimp Penaeus vannamei using Sepharose CL-4B and Q-Sepharose columns. Native Vt
      had an apparent molecular weight of 388 kDa as detected in Native-PAGE, bound the
      lipophilic dye Oil Red O and had a total lipid content of approximately 43.8%.
      Under reducing and denaturing conditions (SDS-PAGE), Vt is composed of three
      major subunits of 87, 78 and 46 kDa, although minor bands of 65, 61 and 31 kDa
      are also detected. The 87- and 78-kDa polypeptides were strongly recognized by
      Penaeus semisulcatus anti-Vt polyclonal and Penaeus monodon anti-Vt monoclonal
      antibodies. Furthermore, the N-terminal amino acid sequence of the 78-kDa
      polypeptide is very similar to Penaeus japonicus vitellogenin (Vg) and P.
      semisulcatus Vt, with an identity of 76%. Circular dichroism indicates that the
      beta-helix content of Vt is 25% while beta-sheets correspond to 37 and 14% of
      unordered secondary structure. These values are similar to insect
      microvitellogenin. Vt has an emission fluorescence maximum at 329 nm, comparable
      to the shrimp high-density lipoprotein/beta-glucan binding protein (HDL/BGBP).

PMID- 12431405
TI  - Cloning and characterization of testis-specific tektin in Bombyx mori.
AB  - A testis-specific cDNA library of Bombyx mori was constructed by an mRNA
      subtraction technique. Several clones were randomly selected and determined for
      their nucleotide sequences. One of them, designated as BmTST, contained a 3'-part
      of an open reading frame homologous to tektin, the protein known to form
      filamentous polymers in the walls of ciliary and flagellar microtubules. Also
      isolated was a genomic fragment, which contains the 5'-part of the coding
      sequence of BmTST and its promoter region. As a whole, the complete open reading
      frame was found to encode 508 amino acid residues, whose sequence had 28, 28 and
      30% identities with the Strongylocentrotus purpuratus tektins A1, B1 and C1,
      respectively. Expression analysis by reverse transcription polymerase chain
      reaction with the cDNA and Western blotting with a polyclonal antibody indicated
      that the BmTST gene was expressed specifically in the testis during sperm
      maturation. The protein was immunologically detected exclusively in the fraction
      expected to contain the 9 + 2 flagellar axonemes of sperms. We infer that the
      BmTst protein is possibly involved in the spermatogenesis of B. mori.

PMID- 12431406
TI  - Influence of molting and starvation on the synthesis of proteolytic enzymes in
      the midgut gland of the white shrimp Penaeus vannamei.
AB  - We investigated the effect of starvation as a stimulant of the digestive system
      on digestive proteinase activities in the white shrimp Penaeus vannamei. The
      starved organisms were sampled periodically according to the molting stage and
      compared with a continuously fed group. Molting stage was included as an
      independent variable. Most analyzed variables, except for trypsin, were more
      affected by starvation than by molting, indicating that starvation is a stimulant
      that masks the effect of molting and showing that food or alimentary stress is
      more conspicuous than physiological ones. We found that starvation is a stimulant
      that surpasses the effect of molting, and because it affects the activity of
      digestive proteinases, studies of starving organisms in combination with tools of
      molecular biology, can be a helpful working model in the understanding of
      mechanisms of regulation of digestive enzyme activity. In the starved organisms,
      trypsin and chymotrypsin activities were similar, suggesting dependence of one to
      the other. Changes in proteolytic activities and the number of protein bands in
      electrophoresis showed evidence of synthesis regulation in the midgut gland of
      white shrimp.

PMID- 12431407
TI  - Dietary conjugated linoleic acid reduces body fat mass and affects gene
      expression of proteins regulating energy metabolism in mice.
AB  - ICR and C57BL/6J mice were fed experimental diets containing either a 2% fatty
      acid preparation rich in conjugated linoleic acid (CLA) or a preparation rich in
      linoleic acid and free of CLA for 21 days. CLA greatly decreased weights of white
      adipose tissue and interscapular brown adipose tissue in the two strains. CLA
      reduced mRNA levels of glucose transporter 4 (Glut 4) in white and brown adipose
      tissue of both strains. A CLA-dependent decrease in mRNA levels of peroxisome
      proliferator activated receptor (PPAR) gamma was seen in interscapular brown
      adipose tissue of both strains and in white adipose tissue of C57BL/6J but not
      ICR mice. Dietary CLA was found to cause a decrease in the mRNA levels of
      uncoupling protein (UCP) 1 in brown adipose tissue when the value was corrected
      for the expression of a house-keeping gene (beta-actin) in the two strains.
      Uncorrected values were, however, indistinguishable between the animals fed the
      CLA diet and CLA-free diet. UCP 3 expression in brown adipose tissue was much
      lower in mice fed the CLA diet than in those fed the control diet in both
      strains. In contrast, CLA greatly up-regulated the gene expression of UCP 2 in
      brown adipose tissue. Dietary CLA also increased UCP 2 mRNA level in skeletal
      muscle. It is apparent that dietary CLA decreases white and brown adipose tissue
      mass, accompanying changes in the gene expression of proteins regulating energy
      metabolism in white and brown adipose tissues, and skeletal muscle of mice.

PMID- 12431408
TI  - Minor participation of cAMP on the protein kinase phosphorylation of
      mitochondrial and cytosolic fractions from Ascaris suum: a comparative study with
      porcine heart muscle.
AB  - In contrast to porcine heart muscle in which cAMP effectively activated the
      phosphorylation of cytosolic proteins, cAMP exerted a minor effect on the
      phosphorylation of proteins from the soluble fraction of Ascaris suum muscle.
      Similarly, cAMP did not enhance the kinase activity in the mitochondrial
      membranes from porcine heart and A. suum, although major differences in protein
      phosphorylation were observed between both fractions. However, cAMP-dependent
      protein kinases (PKA) were evidenced in the parasitic soluble mitochondrial
      fraction, since the phosphorylation of histone IIA and kemptide was augmented in
      this fraction, in the presence of cAMP. An increase in the phosphorylation of
      exogenously added A. suum phosphofructokinase was also obtained when cAMP was
      added to the parasite soluble mitochondrial fraction. The phosphorylation of
      phosphofructokinase by this fraction was inhibited when kemptide and cAMP were
      included in the reaction mixture, suggesting substrate competition for the same
      PKA. Although PKI (6-22), a reported inhibitor of the catalytic subunit of
      mammalian cAMP-dependent PKAs, did not affect the endogenous phosphorylation of
      proteins in the various A. suum fractions, an inhibition on the phosphorylation
      of exogenously added kemptide and phosphofructokinase was observed when PKI (6
      22) was incubated with the parasite mitochondrial soluble fraction.

PMID- 12431409
TI  - Molecular analysis of the seasonal expression of genes coding for different
      functional markers of the digestive gland of the bivalve mollusk Pecten maximus
      (L.).
AB  - Digestive gland cells of Pecten maximus accumulate and release lipid storage
      according to a seasonal cycle. For the first time in molluscs, molecular probes
      were developed and applied to monitor the lipid accumulation and consumption
      cycle related to phytoplankton blooms and phenomena of cellular proliferation and
      apoptosis. The molecular probes consisted of glyceraldehyde-3-phosphate
      dehydrogenase (GPD), which is involved in the acetylation of fatty acids;
      aldolase, which favours the formation of pyruvate and dihydroxyacetone; actin, an
      essential element of the cytoskeleton that disappears during adipocyte cell
      transformation; and cycline B, an ubiquitous cell cycle protein. Alpha-amylase,
      provided by IFREMER-Brest (France), was used to relate these different events to
      the animal's food supply. A positive relation between GPD and aldolase gene
      expressions was inversely correlated with that of actin, confirming results in
      mammals. In P. maximus, mRNA transcripts of GPD and aldolase decrease rapidly
      before gamete emissions whereas those of actin increase rapidly. After gamete
      emission, the mRNA levels of aldolase, GPD and alpha-amylase increase, while
      those of actin decrease. Cycline B mRNA transcripts indicate that the period of
      digestive cell proliferation is initiated during winter, prior to the release of
      lipids into the digestive tract and apoptosis.

PMID- 12431410
TI  - Functional and molecular determination of carbonic anhydrase levels in bovine and
      cultured human chondrocytes.
AB  - In this study, bovine articular and human chondrocytes from the C-20/A4 cell line
      were tested for the functional activity and molecular presence of the enzyme
      carbonic anhydrase. This enzyme is classically considered to be important in the
      maintenance of high cellular buffering capacity by catalysing the slow attainment
      of equilibrium between CO(2) and HCO(3)(-). The first functional assay measured
      the rate of pH equilibration after administration of a fixed dose of CO(2)
      solution to cell lysates. Compared to positive controls (human erythrocytes,
      murine M1 cells and purified carbonic anhydrase), chondrocyte lysates attained
      equilibrium at a significantly slower rate, similar to the rate obtained with a
      negative control (Xenopus oocytes). A second functional assay studied CO(2)
      hydration kinetics in intact C-20/A4 cells, using a pH-sensitive fluorescent dye,
      as the CO(2) content of the extracellular solution was changed. It was shown that
      C-20/A4 cells accelerate hydration only to a small degree. Hydration kinetics
      were reduced to the spontaneous rate in the presence of acetazolamide. Western
      immunoblotting with isoform-nonspecific antibodies to carbonic anhydrase
      demonstrated weak staining in both bovine and human chondrocytes.

PMID- 12431411
TI  - Astaxanthin from the red crab langostilla (Pleuroncodes planipes): optical R/S
      isomers and fatty acid moieties of astaxanthin esters.
AB  - The composition of the fatty acids of astaxanthin esters and the distribution of
      astaxanthin optical RS isomers in the esterified and unesterified astaxanthin
      fractions extracted from the meal of the pelagic red crab langostilla
      (Pleuroncodes planipes; Decapoda, Anomura) were determined. Astaxanthin diesters
      comprised approximately 70%, monoesterified astaxanthin approximately 12%, and
      unesterified astaxanthin approximately 10% of total carotenoids, respectively.
      Unidentified carotenes and minor yellow xanthophylls represented approximately 8%
      of the total carotenoids. Three astaxanthin diester fractions (ratio 5:4:1) and
      one monoester fraction were clearly distinguished by thin-layer chromatography,
      and fatty acid moieties were determined in all of them. Saturated fatty acids
      accumulated in astaxanthin diesters, but were reduced in the monoester fraction
      when compared to langostilla crude oil extract (CE). Astaxanthin diesters, but
      not monoesters were enriched in C16:0 and C18:1n-9, when compared to the CE.
      Astaxanthin monoesters were rich in polyunsaturated fatty acids (approximately
      70% of total fatty acids), in particular C20:5n-3 and C22:6n-3. Acylation of
      astaxanthin in langostilla seems to be selective rather than specific. The three
      diesterified astaxanthin fractions of langostilla had a ratio of approximately
      3:1:3 between the (3R,3'R)-, (3R,3'S)-, and (3S,3'S)-astaxanthin isomers, whereas
      in the monoesterified and unesterified fractions the ratio was approximately
      4:1:4. The astaxanthin optical RS isomer composition indicates that langostilla
      is unable to racemize astaxanthin.

PMID- 12431412
TI  - Purification, properties, and partial amino acid sequences of alanine racemase
      from the muscle of the black tiger prawn Penaeus monodon.
AB  - Alanine racemase [EC 5.1.1.1], which catalyzes the interconversion between D- and
      L-alanine, was purified to homogeneity from the muscle of black tiger prawn
      Penaeus monodon. The isolated enzyme had a molecular mass of 44 kDa on sodium
      dodecyl sulfate-polyacrylamide gel electrophoresis, and 90 kDa on gel filtration,
      indicating a dimeric nature of the enzyme. The enzyme was highly specific to D-
      and L-alanine and did not catalyze the racemization of other amino acids. K(m)
      values toward both D- and L-alanine were almost equal and considerably high
      compared with those of bacterial enzymes. The purified enzyme retained its
      activity in the absence of pyridoxal 5'-phosphate as a cofactor but carbonyl
      reagents inhibited the activity, suggesting the tightly binding of the cofactor
      to the enzyme protein. Several partial amino acid sequences of peptide fragments
      of the purified enzyme showed positive homologies from 52 to 76% with bacterial
      counterparts and a catalytic tyrosine residue of the bacterial enzyme was also
      retained in the prawn one, indicating alanine racemase gene is well conserved
      from bacteria to invertebrates.

PMID- 12431413
TI  - Spatial learning and memory is preserved in rats after early development in a
      microgravity environment.
AB  - This study evaluated the cognitive mapping abilities of rats that spent part of
      their early development in a microgravity environment. Litters of male and female
      Sprague-Dawley rat pups were launched into space aboard the National Aeronautics
      and Space Administration space shuttle Columbia on postnatal day 8 or 14 and
      remained in space for 16 days. These animals were designated as FLT groups. Two
      age-matched control groups remained on Earth: those in standard vivarium housing
      (VIV) and those in housing identical to that aboard the shuttle (AGC). On return
      to Earth, animals were tested in three different tasks that measure spatial
      learning ability, the Morris water maze (MWM), and a modified version of the
      radial arm maze (RAM). Animals were also tested in an open field apparatus to
      measure general activity and exploratory activity. Performance and search
      strategies were evaluated in each of these tasks using an automated tracking
      system. Despite the dramatic differences in early experience, there were
      remarkably few differences between the FLT groups and their Earth-bound controls
      in these tasks. FLT animals learned the MWM and RAM as quickly as did controls.
      Evaluation of search patterns suggested subtle differences in patterns of
      exploration and in the strategies used to solve the tasks during the first few
      days of testing, but these differences normalized rapidly. Together, these data
      suggest that development in an environment without gravity has minimal long-term
      impact on spatial learning and memory abilities. Any differences due to
      development in microgravity are quickly reversed after return to earth normal
      gravity.

PMID- 12431414
TI  - The effects of aging and dorsal hippocampal lesions: performance on spatial and
      nonspatial comparable versions of the water maze.
AB  - Aged intact and young hippocampal-lesioned rats show similar deficits on the
      spatial water maze. However, this does not necessitate that the source of these
      deficits in the aged animals is due to hippocampal damage. These water maze
      deficits may arise from other aging factors such as changes in thermoregulation,
      muscle fatigue, swim ability, and response to stress. Consequently, it is
      imperative to examine the performance of aged rats on a comparable nonhippocampal
      version of this task. Past attempts to develop a hippocampus-independent version
      of the water maze were confounded because these tasks were easier (i.e., the rats
      spent much less time swimming in the water) than the spatial versions of the
      task. The current study examined performance on a hippocampus-independent task
      comparable in difficulty to the spatial water one. Middle-aged (16-m) and old (25
      m) male F344 rats were given sham or dorsal hippocampus lesions and tested on
      both a spatial and a nonspatial water maze. The middle-aged rats with hippocampal
      lesions were impaired on the spatial task but not on the nonspatial task.
      Conversely, aged animals showed a similar impairment on both types of water maze
      tasks. Additionally, hippocampal lesions exacerbated the age-related impairment
      on both tasks. These findings indicate that caution must be used when
      interpreting the results of water maze tasks for aged animals.

PMID- 12431415
TI  - Cortical spreading depression and involvement of the motor cortex, auditory
      cortex, and cerebellum in eyeblink classical conditioning of the rabbit.
AB  - The interrelationships of cerebellar and cerebral neural circuits in the eyeblink
      paradigm were explored with the controlled application of cortical spreading
      depression (CSD) and lidocaine in the New Zealand albino rabbit. The initial
      research focus was directed toward the involvement of the motor cortex in the
      conditioned eyeblink response. However, CSD timing and triangulation results
      indicate that other areas in the cerebral cortex, particularly the auditory
      cortex (acoustic conditioned stimulus), appear to be critical for the CSD effect
      on the eyeblink response. In summary: (1) CSD can be elicited, monitored, and
      timed and its side effects controlled in 97% of awake rabbits in the right and/or
      left cerebral hemisphere(s) during eyeblink conditioning. (2) The motor cortex
      appears to play little or no part in classical conditioning of the eyeblink in
      the rabbit in the delay paradigm. (3) Inactivating the auditory cortex with CSD
      or lidocaine temporarily impairs the conditioned response during the first 5 to
      15 days of training, but has little effect past that point.

PMID- 12431416
TI  - The effects of beta-noradrenergic receptor blockade on acquisition of eyeblink
      conditioning in 3-month-old F344 rats.
AB  - There is evidence that blocking beta-noradrenergic receptors will cause deficits
      in some forms of learning. We investigated the effects of systemic injections of
      1, 5, and 10 mg/kg doses of propranolol on acquisition of delay eyeblink
      conditioning in 3-month-old Fischer 344 rats. We presented a 3-kHz, 90-dB tone as
      a conditioning stimulus and a 6 psi airpuff as our unconditioned stimulus to
      freely moving rats. We monitored eyelid activity using EMG signals. The treatment
      subjects were injected with either propranolol or saline 0.5 h prior to daily
      training sessions. Two groups of control subjects, one receiving injections of
      saline and one receiving injections of 5 mg/kg propranolol, received daily
      training sessions with unpaired and randomized presentation of the tone and
      airpuff. Each daily training session for the treatment groups consisted of 27
      paired training trials and 3 conditioned stimulus-alone training trials. Rats
      injected with saline vehicle or with 1 mg/kg propranolol achieved a 60% or better
      learned response rate within two training sessions. Rats injected with 5 or 10
      mg/kg propranolol never achieved a response rate significantly different from
      animals that received unpaired, random presentations of the tone and airpuff
      stimuli. These results agree with prior studies from our lab that have shown a
      dose-dependent effect of beta-noradrenergic receptor blockade on learning in
      rabbit eyeblink conditioning as well as in a runway, motor learning paradigm. We
      believe that the beta-noradrenergic system plays an important role in learning
      and memory in more than one cerebellar-dependent learning paradigm.

PMID- 12431417
TI  - No sex difference in contextual control over the expression of latent inhibition
      and extinction in Pavlovian fear conditioning in rats.
AB  - Three experiments with Wistar rats searched for a sex difference in contextual
      control over the expression of latent inhibition and extinction. Experiment 1
      used a latent inhibition procedure; Experiments 2 and 3 employed an extinction
      preparation. All experiments used a shock as the unconditioned stimulus, a tone
      as the conditioned stimulus, and suppression of food magazine visits as the
      measure of conditioned responding to the tone. Each experiment revealed a
      reliable context effect on conditioned responding to the tone; after conditioning
      in a separate context, conditioned responding in the former latent inhibition or
      extinction context was attenuated relative to conditioned responding in a control
      context. There was no sex difference in the magnitude of this effect. These
      results are discussed in the framework of sex differences in the hippocampus and
      of the putative role of this structure in various instances of contextual
      learning.

PMID- 12431418
TI  - Posttraining prefrontal lesions impair jaw movement conditioning performance, but
      have no effect on accompanying heart rate changes.
AB  - This experiment examined the role of the medial prefrontal cortex (mPFC) in
      regulating learned autonomic and somatomotor responses in rabbits using
      appetitive Pavlovian conditioning. Interstimulus interval (ISI) duration [i.e.,
      the time between the onset of the conditioned stimulus (CS) and unconditioned
      stimulus (US)] was manipulated in order to determine whether ISI duration was
      related to the heart rate (HR) responses obtained during conditioning. Two groups
      received either a 1- or a 4-s ISI, with a tone as the CS and an intraoral pulse
      of water as the US. Another two groups received explicitly unpaired presentations
      of either the 1- or 4-s tone CS and water US. Few conditioned jaw movement (JM)
      or HR conditioned responses (CRs) were observed in the unpaired conditions.
      Significant JM conditioning was, however, elicited by the paired conditions,
      especially to the 4-s ISI. Consistent CS-evoked HR accelerations were observed in
      both ISI conditions. After five sessions of training, the mPFC was lesioned in
      half the animals. A separate group of paired animals received sham lesions. After
      surgical recovery, all animals received 3 days of postoperative training. During
      the first postoperative training session, JM CRs significantly declined in both
      groups with mPFC lesions in comparison to the groups with sham lesions. The mPFC
      lesions, however, did not affect the CS-evoked cardiac accelerations, which again
      occurred during postoperative training.

PMID- 12431419
TI  - Protective effect of practice on cognition during aging: implications for
      predictive characteristics of performance and efficacy of practice.
AB  - In the present study, the effect of previous experience on spatial memory, which
      required the retention of information either over long intervals or within a
      single session, was longitudinally tested in the water maze in male F-344 rats
      that were from 6 to 24 months of age. Performance in these tasks was found to be
      age-dependent (Markowska, 1999). Other behavioral tasks in the straight alley and
      with a visible platform in the water maze controlled the noncognitive components
      of performance. For all tasks, performance was significantly correlated between
      12-month-old and 18-month-old rats, indicating that cognitive performance at the
      early, but not advanced, stage of aging could be predicted from performance at a
      younger age if the novelty of the first exposure to the task was eliminated. The
      protective effect of experience was more robust in the reference memory task as
      compared to the working memory task and was modified by age when training was
      initiated. Behavior during the probe trials was more sensitive to the effect of
      aging and more resistant to the beneficial effect of practice as compared to the
      performance in the platform trials. The speed of swimming of experienced rats
      progressively decreased with age only when tested in the cognitive tasks but not
      in the straight alley. This indicates that speed of swimming during cognitive
      tasks does not exclusively reflect the ability to swim, but might be also
      affected by the cognitive demands of the task. Protective effect of experience on
      cognition was not modified by restriction in diet.

PMID- 12431420
TI  - Carryover effects associated with the single-trial passive avoidance learning
      task in the young chick.
AB  - The single-trial passive avoidance task is a useful procedure for examining
      learning and memory in the young chick. However, it has recently been suggested
      that discrepant results reported by different laboratories are due to differences
      in training procedure. The present study investigated a number of parameters
      surrounding the passive avoidance task, using day-old White Leghorn, Black
      Australorp cockerels. The results suggested that presentation of a water-dipped
      bead immediately after the aversive bead significantly altered retention levels.
      In addition, when the water-dipped bead was presented after the aversive bead,
      chicks failed to discriminate between beads for a period of 10 min following
      exposure to the aversant experience. A novel variant of the passive avoidance
      procedure, involving pretraining with a water-dipped red bead, training with an
      aversant-coated red bead, and testing with a dry red bead, was evaluated. A
      measure of avoidance was calculated using all three trials. It is suggested that
      the use of a single bead, measured both before and after the training experience
      and using both aversant- and water-trained controls, results in the most concise
      characterization of memory-related phenomena in the chick which is not
      contaminated by a carryover effect from the aversive training experience to the
      nonaversive bead.

PMID- 12431421
TI  - Proximal versus distal cue utilization in spatial navigation: the role of visual
      acuity?
AB  - Proximal versus distal cue use in the Morris water maze is a widely accepted
      strategy for the dissociation of various problems affecting spatial navigation in
      rats such as aging, head trauma, lesions, and pharmacological or hormonal agents.
      Of the limited number of ontogenetic rat studies conducted, the majority have
      approached the problem of preweanling spatial navigation through a similar
      proximal-distal dissociation. An implicit assumption among all of these studies
      has been that the animal's visual system is sufficient to permit robust spatial
      navigation. We challenged this assumption and have addressed the role of visual
      acuity in spatial navigation in the preweanling Fischer 344-N rat by training
      animals to locate a visible (proximal) or hidden (distal) platform using double
      or null extramaze cues within the testing environment. All pups demonstrated
      improved performance across training, but animals presented with a visible
      platform, regardless of extramaze cues, simultaneously reached asymptotic
      performance levels; animals presented with a hidden platform, dependent upon
      location of extramaze cues, differentially reached asymptotic performance levels.
      Probe trial performance, defined by quadrant time and platform crossings,
      revealed that distal-double-cue pups demonstrated spatial navigational ability
      superior to that of the remaining groups. These results suggest that a pup's
      ability to spatially navigate a hidden platform is dependent on not only its
      response repertoire and task parameters, but also its visual acuity, as
      determined by the extramaze cue location within the testing environment. The
      standard hidden versus visible platform dissociation may not be a satisfactory
      strategy for the control of potential sensory deficits.

PMID- 12431422
TI  - Site-selective N-methyl-D-aspartate and alpha-amino-3-hydroxy-5-methyl-4
      isoxazolepropionate antagonists produce distinct effects in rats performing
      complex discriminations.
AB  - Glutamate receptor-dependent neural plasticity is thought to be implicated in
      memory processes. Ionotropic N-methyl-D-aspartate- (NMDA) sensitive and alpha
      amino-3-hydroxy-5-methyl-4-isoxazolepropionate- (AMPA) sensitive glutamate
      receptors have been particularly studied for their role in synaptic plasticity.
      Drugs can alter AMPA and NMDA receptor neurotransmission by competing for the
      glutamate site or other sites on these receptor proteins. Variants of the protein
      subunits forming AMPA and NMDA heteromers contribute to the complexity of
      pharmacological activity at these receptors. The NMDA receptor has numerous
      modulatory centers, including the glycine binding site, NR2B protein specific
      binding site, and an intrachannel (PCP) binding site. In this study, the accuracy
      and rate of rats performing under a Fixed Consecutive Number (FCN) operant task
      were measured after administrations of site-selective AMPA and NMDA receptor
      modulators. Test compounds included two glycine site NMDA agonists [(+)HA 966 and
      D-cycloserine], two NR2-B site NMDA antagonists (eliprodil and ifenprodil), an
      NMDA channel blocking antagonist (MK 801), and a competitively acting AMPA
      receptor antagonist (NBQX). The accuracy of FCN performance was not affected by
      response-rate-altering doses of (+) HA 966, D-cycloserine, eliprodil, ifenprodil,
      or NBQX. MK 801, on the other hand, reduced performance accuracy at several
      doses. These results are consistent with earlier studies suggesting that AMPA
      antagonists minimally affect working memory and that glycine and NR2B protein
      specific modulatory sites may have advantages as targets for the development of
      medications intended to alter NMDA receptor-mediated transmission.

PMID- 12431423
TI  - The effects of pretraining and reminder treatments on retrograde amnesia in rats:
      comparison of lesions to the fornix or perirhinal and entorhinal cortices.
AB  - The present experiment examined the effects of pretraining and reminder
      treatments on the retention of a nonrelational odor-guided digging task following
      lesions to the hippocampal formation (i.e., fornix) or parahippocampal region
      (i.e., perirhinal and entorhinal cortices). The results showed that fornix
      lesioned rats and control rats had good retention of the task and did not differ
      from each other; however, perirhinal- and entorhinal-lesioned rats were severely
      impaired and differed from fornix and control rats. The present experiment found
      no attenuation of amnesia following pretraining, which may be due to the lesion
      technique employed and the size of the resulting lesions. However, the experiment
      found a significant difference in performance following a reminder treatment,
      even in the severely impaired perirhinal- and entorhinal-lesioned group.

PMID- 12431424
TI  - Brain interleukin-1 is involved in spatial memory and passive avoidance
      conditioning.
AB  - Within the brain, the inflammatory cytokine interleukin-1 (IL-1) mediates illness
      associated neural, neuroendocrine, and behavioral responses; however, its role in
      normal neurobehavioral processes is not clear. To examine the role of IL-1
      signaling in memory, we infused Long-Evans rats intracerebroventricularly with IL
      1beta (10 ng/rat), IL-1 receptor antagonist (IL-1ra, 100 microg/rat), or saline
      immediately following a learning task and tested memory functioning 1-8 days
      later. In the Morris water maze (MWM), IL-1ra caused memory impairment in the
      hippocampus-dependent, spatial version, whereas IL-1beta had no effect. Neither
      IL-1beta nor IL-1ra influenced the hippocampus-independent, nonspatial version of
      the MWM. In the passive avoidance response, which also depends on hippocampal
      functioning, IL-1ra caused memory impairment, and IL-1beta caused memory
      improvement. These results suggest that IL-1 signaling within the hippocampus
      plays a critical role in learning and memory processes.

PMID- 12431426
TI  - Effects of fimbria lesions on trace two-way active avoidance acquisition and
      retention in rats.
AB  - The fimbria-fornix (FF) is the main subcortical input to the hippocampus. It has
      been shown that FF lesions facilitate performance on a standard-delay two-way
      active avoidance task (AA2), thought to involve implicit memory. The hippocampal
      region is required for explicit or relational memory. It has been proposed that
      the hippocampus and related structures might associate events that are separated
      in space or time and detect elements shared in common by such discontiguous
      episodes. Therefore, FF lesions would be expected to impair performance on a
      trace paradigm, which introduces an interval between the CS (conditioned
      stimulus) and the US (unconditioned stimulus) and is generally considered a model
      of explicit memory. We predicted that FF lesions would impair memory in a trace
      AA2 procedure, while the same lesions would facilitate memory in a standard delay
      version of the task. To test this hypothesis, two experiments were carried out in
      102 male Wistar rats. The first experiment characterized the trace paradigm using
      this kind of conditioning and demonstrated that control rats were able to acquire
      and retrieve (24 h and 11 days postacquisition) the association between the CS
      (tone) and the US (electric foot shock) when a trace interval (5, 10, or 20 s)
      was interposed between both stimuli. In the second experiment, we investigated
      the effects of FF electrolytic lesions on the same task using delay and trace (10
      s trace interval) paradigms. Surprisingly, FF lesions facilitated the acquisition
      and the 24-h retention of the AA2 not only on the standard delay paradigm, but
      also with the trace paradigm. We suggest that facilitative effects could be a
      result of impairment in contextual learning.

PMID- 12431425
TI  - The effects of adenosine receptor agonists and antagonists on morphine state
      dependent memory of passive avoidance.
AB  - Pretraining administration of morphine (5 mg/kg, intraperitonically) in a step
      down passive avoidance task led to state-dependent learning with impaired
      retrieval on the test day that was dose-dependently restored by pretest
      administration of morphine (0.5, 1, 3, and 5 mg/kg). This restoration was
      reversible by pretest naloxone administration. Pretest administration of
      adenosine receptor antagonists theophylline or 8-phenyltheophylline (8-PT) did
      not alter morphine-induced amnesia. However, both the antagonists inhibited the
      restoration of memory by pretest morphine (5 mg/kg). Adenosine A(1) receptor
      agonists N(6)-cyclohexyladenosine (CHA) or N(6)-phenylisopropyladenosine (R-PIA)
      only at the higher doses used, and adenosine A(2) receptor agonist 5'-N
      ethylcarboxaminoadenosine (NECA), at all doses used, decreased morphine-induced
      amnesia in a dose-dependent manner. Pretest administration of low doses of CHA, R
      PIA, or NECA significantly showed additive effects with low dose pretest morphine
      (1 mg/kg) in restoring memory. The promnestic effects of high-dose CHA and R-PIA
      were inhibited by theophylline or 8-PT but not by naloxone. The additive effects
      of low-dose CHA or R-PIA and morphine were inhibited by theophylline, 8-PT, or a
      higher dose of naloxone. The promnestic effect of NECA and its additive effect
      with low-dose morphine were both inhibited by theophylline and naloxone but not
      by 8-PT. It is concluded that activation of the adenosinergic system, through
      both A(1) and A(2) receptors, can reverse morphine-induced amnesia and is
      involved in morphine state of memory.

PMID- 12431427
TI  - Extinction of conditioned odor potentiation of startle.
AB  - Several recent studies with rats (Sprague-Dawley strain) have documented that an
      odor previously paired with shock potentiates the acoustic startle response, a
      phenomenon referred to as conditioned odor potentiation of startle (OPS). A
      surprising finding in these studies was that OPS did not extinguish even though
      the odor was present throughout the 25-min test session. Therefore, the present
      study more fully examined extinction of OPS. The results of Experiment 1, which
      employed both within-subject and between-group comparisons, showed that
      extinction of OPS occurred in adult rats only after several days of testing.
      Experiment 2 used the between-group procedure and found similar results with 23
      day-old rats, the youngest age that exhibits the OPS effect. Experiment 2 also
      showed that giving rats 15 odor-shock pairings at 16 days of age, an age where
      they acquire the odor-shock association but cannot express it via OPS, does not
      increase subsequent resistance to extinction following odor-shock pairings at 23
      days of age. Taken together, the results of this study show that (1) although OPS
      is somewhat resistant to extinction, it does extinguish with repeated tests and
      (2) suggests that there are no age differences in the rate of extinction of OPS.

PMID- 12431428
TI  - Sleep-dependent hippocampal slow activity correlates with waking memory
      performance in humans.
AB  - The positive effect of postlearning sleep on memory consolidation as well as the
      relationship between sleep-related memory processes and the hippocampal formation
      are increasingly clarified topics in neurobiology. However, the possibility of a
      stable relationship between waking mnemonic performance and sleep-dependent
      hippocampal electric activity is unexplored. Here we report a correlative
      analysis between sleep-dependent parahippocampal-hippocampal (pHip-Hip) electric
      activity recorded by foramen ovale (FO) electrodes and different types of memory
      performances in epileptic patients. Psychological testing was performed days or
      weeks before electrophysiological recordings. The relative spectral power of the
      slow activity (below 1.25 Hz) during deep non-REM (NREM) sleep at the right pHip
      Hip region correlated positively with the visual memory performance according to
      Rey-Osterrieth Complex Figure Test (ROCFT). Along the posterior-anterior
      direction of the hippocampal formation a linear increasing of correlations was
      observed. The relative power of the activity below 1.25 Hz at the left pHip-Hip
      during phasic REM sleep correlated positively with verbal learning performance
      and mnemonic retention values according to ROCFT. It is concluded that the pHip
      Hip structures' capacity of producing high amplitude and synchronized slow (< 1
      Hz) oscillation during deep NREM sleep is related to the functional power of
      these structures. We hypothesize that the asymmetric (side-specific) propagation
      of ponto-geniculo-occipital (PGO) activity to the pHip-Hip region is related to
      the memory correlates of phasic REM sleep.

PMID- 12431429
TI  - Posttraining glucocorticoid receptor agonist enhances memory in appetitive and
      aversive Pavlovian discrete-cue conditioning paradigms.
AB  - Glucocorticoid modulation of emotional memory has repeatedly been shown in
      aversive learning paradigms, but has received little attention in appetitive
      tasks. It has also been suggested that it may be selective for contextual cues.
      In order to investigate if glucocorticoids can modulate memory in discrete-cue
      conditioning of both appetitive and aversive tasks, two experiments were carried
      out. Male Lister-Hooded rats received pairings of an auditory cue and either food
      reward (experiment 1) or footshock (experiment 2), followed immediately by
      posttraining injections of the glucocorticoid receptor agonist dexamethasone
      (0.3, 0.6, and 1.2 mg/kg) or vehicle. Dexamethasone (1.2 mg/kg) led to
      significantly enhanced learning. These results give support to the notion that
      glucocorticoids play a role in the modulation of both appetitive and aversive
      emotional memories and show that their role in learning goes beyond the
      construction of context representations. The modulation of appetitive and
      aversive discrete-cue learning may be subserved by a common mechanism.

PMID- 12431430
TI  - Agmatine facilitates memory of an inhibitory avoidance task in adult rats.
AB  - Agmatine is a new putative neurotransmitter; however, the physiological role(s)
      of this endogenous released polyamine is still to be determined. We investigated
      its cognitive effect in an inhibitory avoidance task in adult rats. Agmatine
      (0.1, 1, 10, and 20 mg/kg) or saline was administered ip immediately after
      training or 1 h before testing. Posttraining injection of agmatine facilitated (p
      < 0.05) memory consolidation in this task; however pretest treatment showed no
      effect on retrieval (p > 0.05). We suggest that the facilitatory effect of
      agmatine on memory consolidation in inhibitory avoidance task might be mediated
      through the activation of the locus coeruleus.

PMID- 12431431
TI  - Hippocampal formation lesions impair performance in an odor-odor association task
      independently of spatial context.
AB  - The rodent hippocampal system is known to play an important role in memory.
      Evidence that this role is not limited to spatial memory has come from studies
      using a variety of non-spatial memory tasks. One example is the social
      transmission of food preference paradigm, a task in which rats learn an odor-odor
      association with no explicit spatial memory component. However, because training
      and testing in this task typically take place in the same environment, it is
      possible that memory for the spatial context in which odors are experienced
      during training is critical to subsequent retention performance. If this is the
      case, it might be expected that lesions of the hippocampal system would impair
      memory performance by disrupting the establishment of a representation of the
      training environment. We addressed this issue by training rats in one spatial
      context and then testing them either in the same or a different spatial context.
      Normal control rats performed equally well when tested in an environment that was
      the same or different from that used during training, and the retention
      impairment exhibited by rats with hippocampus plus subiculum lesions was
      equivalent in the two test environments. These results support the view that the
      hippocampal system is necessary for the flexible expression of nonspatial
      memories even when the spatial context in which the memory is acquired is not
      critical to retrieval.

PMID- 12431432
TI  - Retrograde enhancement of kinesthetic memory by alcohol and by glucose.
AB  - Several studies have reported that administration of a low dose of alcohol is
      capable of retrograde enhancement of memory. It has been postulated that the
      neurobiological mechanisms underlying this effect may involve the liberation of
      glucose and/or activation of reward centers. Here the effects of a low dose of
      alcohol were compared to those of glucose on kinesthetic memory. Mood and blood
      glucose levels were also measured. Compared with a placebo, both glucose and
      alcohol significantly enhanced kinesthetic memory performance. Only glucose
      ingestion resulted in significantly elevated blood glucose levels. The three
      groups' mood scores were statistically indistinguishable. Low-dose alcohol
      consumption does not result in the release of glucose nor does it affect any
      aspect of mood, at least as measured here. These results confirm that kinesthetic
      memory can be improved by administration of alcohol and extend the range of tasks
      which are sensitive to enhancement by glucose.

PMID- 12431433
TI  - Nuclease enzymes.

PMID- 12431434
TI  - Visualizing the structure and mechanism of a small nucleolytic ribozyme.
AB  - Time-resolved crystallography has recently evolved into a powerful and invaluable
      technique for observing conformational and chemical intermediate states at or
      near atomic resolution in protein enzymes. The application of monochromatic time
      resolved X-ray crystallographic freeze-trapping experiments to an RNA enzyme, the
      hammerhead ribozyme, is outlined here.

PMID- 12431435
TI  - Analysis of substrate recognition by the ribonucleoprotein endonuclease RNase P.
AB  - Ribonuclease P (RNase P), is a ribonucleoprotein complex that catalyzes the site
      specific cleavage of pre-tRNA and a wide variety of other substrates. Although
      RNase P RNA is the catalytic subunit of the holoenzyme, the protein subunit plays
      a critical role in substrate binding. Thus, RNase P is an excellent model system
      for studying ribonucleoprotein function. In this review we describe methods
      applied to the in vitro study of substrate recognition by bacterial RNase P,
      covering general considerations of reaction conditions, quantitative measurement
      of substrate binding equilibria, enzymatic and chemical protection, cross
      linking, modification interference, and analysis of site-specific substitutions.
      We describe application of these methods to substrate binding by RNase P RNA
      alone and experimental considerations for examining the holoenzyme. The combined
      use of these approaches has shown that the RNA and protein subunits cooperate to
      bind different portions of the substrate structure, with the RNA subunit
      predominantly interacting with the mature domain of tRNA and the protein
      interacting with the 5(') leader sequence. However, important questions
      concerning the interface between the two subunits and the coordination of RNA and
      protein subunits in binding and catalysis remain.

PMID- 12431436
TI  - Group II introns: highly specific endonucleases with modular structures and
      diverse catalytic functions.
AB  - Group II introns are large catalytic RNAs with a remarkable repertoire of
      reactions. Here we present construct designs and protocols that were used to
      develop a set of kinetic frameworks for studying the structure and reaction
      mechanisms of group II introns and ribozymes derived from them. In addition, we
      discuss application of these systems to structure/function analysis of the
      ai5gamma group II intron.

PMID- 12431437
TI  - Capturing splicing complexes to study structure and mechanism.
AB  - At its most basic level, pre-mRNA splicing can be described as two coordinated
      nuclease reactions that cleave an intron at either end and result in ligation of
      the flanking exons. The fact that these reactions are catalyzed by a
      approximately 3-MDa behemoth of protein and RNA (the spliceosome) challenges most
      biochemical and structural approaches currently used to characterize lesser-sized
      enzymes. In addition to this molecular complexity, the highly dynamic nature of
      splicing complexes provides additional hurdles for mechanistic studies or three
      dimensional structure determination. Thus, the methods used to study the
      spliceosome often probe individual properties of the machine, but no complete,
      high-resolution picture of splicing catalysis has yet emerged. To facilitate
      biochemical and structural studies of native splicing complexes, we recently
      described purification of the catalytic form of the spliceosome (known as C
      complex). This native complex is suitable for electron microscopic structure
      determination by single-particle methods. In this paper, we describe the
      purification in detail and discuss additional methods for trapping and analyzing
      other splicing complexes.

PMID- 12431438
TI  - Genetic screen to dissect protein-protein interactions: ribonuclease inhibitor
      ribonuclease A as a model system.
AB  - Protein-protein interactions are critical for the function of biological systems.
      Here, we describe a means to dissect a protein-protein interaction. Our method is
      based on the in vivo interaction between a target protein and the peptide
      epitopes derived from its partner. This interaction is detected by using hybrid
      proteins in which the target protein and peptide epitopes are fused to the DNA
      binding domain of the lambda repressor protein. An interaction prevents the
      transcription of a reporter gene. The efficacy of this approach is demonstrated
      with the ribonuclease inhibitor protein and ribonuclease A, which form a complex
      with an equilibrium dissociation constant in the femtomolar range. Our method can
      enable the identification of residues important in a designated protein-protein
      interaction and the development of antagonists for that interaction.

PMID- 12431439
TI  - Type II restriction endonucleases.
AB  - Type II restriction endonucleases have emerged as important paradigms for the
      study of protein-nucleic acid interactions. This is due to their ability to
      catalyse phosphodiester bond cleavage with very large rate enhancements while
      also maintaining exquisite sequence selectivities. The principles and methods
      developed to analyze site-specific binding and catalysis for restriction
      endonucleases can be applied to other enzymes which also operate on nucleic
      acids. This paper reviews biochemical and structural approaches to
      characterization of these enzymes, with particular attention to the multiple
      crucial roles of divalent metal ions, the possibilities for use of alternative
      substrates in binding and catalytic experiments, the strategies for exploring the
      detailed chemistry of phosphoryl transfer, and the use of X-ray crystallography
      to provide descriptions of conformational pathways at specific, nonspecific, and
      noncognate DNA sites.

PMID- 12431440
TI  - Characterization of homing endonucleases.
AB  - Homing endonucleases are a class of site-specific DNA endonucleases encoded by
      open reading frames within introns and inteins. They initiate the mobility of
      their host element by recognizing intronless or inteinless alleles of their host
      gene and making a double-strand break. The homing endonucleases are notable for
      their long target sites and a tolerance for sequence polymorphisms in their
      substrates. The methods used to study homing endonucleases are similar to those
      used to study protein-DNA interactions in general. However, some variations and
      specialized techniques are useful in characterizing homing endonucleases and
      these methods are discussed.

PMID- 12431441
TI  - Cre-loxP biochemistry.
AB  - Cre recombinase is now widely used to carry out complex manipulations of DNA
      molecules both in vitro and in vivo. For in vitro experiments, there is a clear
      need for highly pure preparations of Cre and of Cre mutants that serve as
      controls or supply an altered activity or specificity. In vivo experiments
      utilizing Cre variants also often require in vitro characterization and some
      applications involve transfection of purified enzyme to achieve transient
      activity in the cell. This review outlines a detailed protocol for purification
      of native Cre and describes straightforward assays that can be used to test for
      recombination activity in vitro. The design of experiments to trap the
      intermediates of Cre-loxP site-specific recombination for biophysical studies is
      also presented. The methods described should be useful to any investigator with a
      need for purified Cre recombinase and should be broadly applicable to related
      site-specific recombination systems.

PMID- 12431442
TI  - Local cardiac renin-angiotensin system: hypertension and cardiac failure.
AB  - In addition to the effect on arterial pressure, angiotensin II, the effector
      peptide of the renin-angiotensin system (RAS), exerts mitogenic and growth
      promoting effects on cardiac myocytes and non-myocytic elements; and both of
      these effects significantly contribute to the development and progression of
      hypertensive heart disease (HHD). The traditional concept of the RAS as a
      systemic, endocrine system has been expanded and the identification of its
      components in many organs and tissue has been amassed. This paper reviews
      evidence that supports the concept that the cardiac RAS participate importantly
      in the development and risk of HHD.

PMID- 12431444
TI  - Role of the local renin-angiotensin system in cardiac damage: a minireview
      focussing on transgenic animal models.
AB  - The local generation of all components of the renin-angiotensin system (RAS) in
      the heart has been the basis for the postulation of a tissue RAS in this organ.
      Since angiotensin II is involved in the induction of cardiac hypertrophy and
      fibrosis the local generation of this peptide may be of highest clinical
      importance. Several transgenic animal models have been generated to evaluate the
      functional importance of the cardiac RAS. We have established a new hypertensive
      mouse model lacking local angiotensinogen expression in the heart. In these
      animals, cardiac weight and collagen synthesis are increased compared to
      normotensive control mice but to a lesser extent than in mice with equally
      enhanced blood pressure but intact cardiac angiotensinogen generation. Thus, we
      have shown that local synthesis of this protein is involved but not essential in
      the development of cardiac hypertrophy and fibrosis.

PMID- 12431443
TI  - Interplay between the cardiac renin angiotensin system and JAK-STAT signaling:
      role in cardiac hypertrophy, ischemia/reperfusion dysfunction, and heart failure.
AB  - Recent studies have shown that the JAK-STAT signaling pathway plays a central
      role in cardiac pathophysiology. JAK-STAT signaling has been implicated in
      pressure overload-induced cardiac hypertrophy and remodeling, ischemic
      preconditioning, and ischemia/reperfusion-induced cardiac dysfunction. The
      different STAT family members expressed in cardiac myocytes appear to be linked
      to different, and at times, opposite responses, such as cell growth/survival and
      apoptosis. Thus, differential activation and/or selective inhibition of the STAT
      proteins by agonists for G-protein coupled receptors, such as angiotensin II, may
      contribute to cardiac dysfunction during ischemia and heart failure. In addition,
      JAK-STAT signaling may represent one limb of an autocrine loop for angiotensin II
      generation, that serves to amplify the actions of angiotensin II on cardiac
      muscle. The purpose of this article is to provide an overview of recent findings
      that have been made for JAK-STAT signaling in cardiac myocytes and to highlight
      some unresolved issues for future investigation. The central focus of this review
      is on recent studies suggesting that modulation or activation of JAK-STAT
      signaling by ANG II has pathological consequences for heart function.

PMID- 12431445
TI  - Prorenin uptake in the heart: a prerequisite for local angiotensin generation?
AB  - Interference with locally generated angiotensin II most likely underlies the
      beneficial effects of renin-angiotensin system blockers in cardiac disorders.
      Since renin is not synthesized in the heart, this enzyme must be sequestered from
      the circulation in order to allow angiotensin generation at cardiac tissue sites.
      This review addresses the various ways through which circulating (i.e., kidney
      derived) renin may reach cardiac tissue sites, considering in particular the
      possibility that prorenin, the inactive precursor of renin, is involved in
      cardiac angiotensin generation, as the plasma concentrations of prorenin are
      tenfold higher than those of renin. Renin and prorenin diffuse into the cardiac
      interstitial space and bind to cardiac (pro)renin receptors/renin-binding
      proteins. One of these receptors is the mannose 6-phosphate/insulin-like growth
      factor II receptor. This receptor not only binds mannose 6-phosphate-containing
      ligands like renin and prorenin, it also internalizes these enzymes, and
      activates prorenin intracellularly. This process possibly represents (pro)renin
      clearance, since intracellular angiotensin generation could not be demonstrated
      following (pro)renin uptake by cardiomyocytes. Angiotensin II-mediated myocyte
      proliferation did occur when incubating cardiomyocytes with prorenin plus
      angiotensionogen. The effects of prorenin plus angiotensinogen were comparable to
      those of 100nmol/l angiotensin II, although the angiotensin II levels in the
      medium during exposure of the cells to prorenin plus angiotensinogen were
      <1nmol/l. This suggests that cardiac angiotensin II generation by circulating
      renin occurs predominantly on the cell surface. The presence of ACE and/or renin
      on the cell membrane, in the microenvironment of angiotensin receptors, would
      allow maximal efficiency of local angiotensin II generation, i.e., immediate
      binding of angiotensin II to its receptors with minimal loss into the
      extracellular space.

PMID- 12431446
TI  - Do defects in the late sodium current in human ventricular cells cause heart
      failure?

PMID- 12431447
TI  - Gating of the late Na+ channel in normal and failing human myocardium.
AB  - We previously reported an ultraslow inactivating late Na+ current (INaL) in left
      ventricular cardiomyocytes (VC) isolated from normal (NVC) and failing (FVC)
      human hearts. This current could play a role in heart failure-induced
      repolarization abnormalities. To identify properties of NaCh contributing to
      INaL, we examined early and late openings in cell-attached patches of HEK293
      cells expressing human cardiac NaCh alpha-subunit (alpha-HEK) and in VC of one
      normal and three failing human hearts. Two types of the late NaCh openings
      underlay INaL in all three preparations: scattered late (SLO) and bursts (BO).
      Amplitude analysis revealed that slope conductance for both SLO and BO was the
      same compared to the main level of early openings (EO) in both VC (21 vs 22.7pS,
      NVC; 22.7 vs 22.6pS, FVC) and alpha-HEK (23.2 vs 23pS), respectively. Analysis of
      SLO latencies revealed voltage-independent ultraslow inactivation in all
      preparations with tendency to be slower in FVC compared to NCV. EO and SLO render
      one open voltage-independent state (tau approximately 0.4ms) for NVC and FVC. One
      open (voltage-dependent) and two closed states (one voltage-dependent and another
      voltage-independent) were found in BO of both specimens. Burst duration tend to
      be longer in FVC ( approximately 50ms) than in NVC ( approximately 30ms). In FVC
      we found both modes SLO and BO at membrane potential of -10mV that is attribute
      for take-off voltages (from -18 to -2mV) for early afterdepolarizations (EAD's)
      in FVC. In conclusions, we found a novel gating mode SLO that manifest slow
      (hundreds of ms), voltage-independent inactivation in both NVC and FVC. We were
      unable to reliably demonstrate any differences in the properties of the late NaCh
      in failing vs a normal human heart. Accordingly, the late current appears to be
      generated by a single population of channels in normal and failing human
      ventricular myocardium. Both SLO and BO could be implicated in EADs in HF.

PMID- 12431448
TI  - Release of preformed Ang II from myocytes mediates angiotensinogen and ET-1 gene
      overexpression in vivo via AT1 receptor.
AB  - The role of angiotensin II in pressure overload is still debated because
      notwithstanding its effects on myocyte contractility angiotensin II is not an
      obligatory factor for the development of hypertrophy. To define the role of
      angiotensin II in acute pressure overload we studied the effects of AT1 blockade
      (valsartan 80mg per day) on myocardial contractility, cardiac growth factor gene
      expression, and myocardial hypertrophy in aortic banded (60mmHg) pigs. Acute
      pressure overload caused an abrupt reduction of myocardial contractility,
      measured by the end-systolic stiffness constant, and a sharp increase in end
      systolic stress which rapidly normalized (within 12h) in the placebo group. In
      AT1-blocked animals end-systolic stiffness constant remained significantly
      depressed up to 24h and end-systolic stress was still elevated up to 48h (both
      P<0.05 vs placebo). In both groups confocal microscopy revealed that granular
      staining of angiotensin II in cardiomyocyte cytoplasm disappeared after 30min of
      pressure overload. AT1 blockade abolished following cardiac overexpression of
      angiotensinogen and endothelin-1 genes as shown in RT-PCR studies and the
      consequent angiotensin II and endothelin-1 release in the coronary circulation.
      Conversely, insulin-like growth factor-I and ACE mRNA overexpression, as well as
      the onset of left ventricular mass increase, were not significantly affected by
      AT1 blockade. IN CONCLUSION: (1) mechanical stress releases preformed angiotensin
      II from myocyte in vivo; (2) the AT1 blockade abolishes cardiac angiotensin II
      and endothelin-1 production with delayed recovery of myocardial contractility;
      whereas (3) the overexpression of insulin-like growth factor-I gene and the
      development of myocardial hypertrophy are not angiotensin II-mediated effects.

PMID- 12431449
TI  - Excitation-dependent intracellular Ca2+ waves at the border zone of the cryo
      injured rat heart revealed by real-time confocal microscopy.
AB  - Intracellular Ca2+ waves, which develop under Ca2+-overloaded conditions of the
      injured myocardium, are regarded as an important substrate for triggered
      arrhythmias. However, little is known about whether Ca2+ waves arise or become
      proarrhythmic in the injured heart in situ. On the hypothesis that injured
      myocardium manifests frequent Ca2+ waves and produce an oscillatory [Ca2+]i rise
      leading to triggered activity, we applied cryo-injury to the epicardial surface
      of fluo 3-AM-loaded perfused rat hearts and analyzed spatiotemporal [Ca2+]i
      changes at border zones of the injured myocardium using real-time confocal
      microscopy. In intact regions Ca2+ waves barely emerged, whereas the border zone
      myocardium exhibited frequent Ca2+ waves, propagating randomly within the
      individual cells. Two different types of Ca2+ waves were identified: highly
      frequent waves (159.6+/-86.5 waves/min/cell, n=266) adjacent to the cryo-ablated
      regions, and less frequent waves (79.0+/-50.1 waves/min/cell, n=160) slightly
      farther (>2 cells) away from the ablated regions (vicinities). The former Ca2+
      waves emerged asynchronously to Ca2+ transients. Contrariwise, the latter
      depended on ventricular excitation: they vanished instantaneously on Ca2+
      transients, but emerged more frequently and propagated more swiftly after
      cessation of higher-frequency pacing. Immediately after 3-Hz pacing, some cryo
      injured hearts exhibited oscillatory [Ca2+]i rises; an instantaneous and
      synchronous elevation of [Ca2+]i followed by burst occurrence of Ca2+ waves with
      a gradual decrease in incidence and propagation velocity in a considerable number
      of cells. These observations indicate that myocardial injury induces Ca2+ waves
      in the heart, and that their synchronous occurrence could become a substrate for
      triggered arrhythmias.

PMID- 12431450
TI  - Quantitation and distribution of beta-tubulin in human cardiac myocytes.
AB  - Increasing evidence suggests that derangements of cytoskeletal proteins
      contribute to alterations in intracellular signaling, myocyte function, and the
      coupling of myocytes to the extracellular matrix during cardiac hypertrophy and
      failure. Data from animal studies have shown an increased density of beta-tubulin
      protein in the right or left ventricle subjected to pressure overload, and have
      demonstrated that interfering with excess polymerization of beta-tubulin improves
      contractility. We tested the hypothesis that beta-tubulin is increased in human
      left ventricular hypertrophy and end-stage heart failure. Confocal microscopy of
      fluorescently labeled beta-tubulin protein revealed an increased density of the
      beta-tubulin network in cardiomyocytes from both hypertrophied and failing human
      hearts as compared to cells from nonfailing hearts. Western blot analysis on
      total heart homogenate showed no change in beta-tubulin when data were normalized
      to either actin or calsequestrin, although there was a significant increase in
      failing human hearts when data were normalized only for a constant amount of
      protein per heart. The mRNA for beta-tubulin was not changed in hypertrophied
      hearts, but was significantly decreased in failing human hearts. Thus, similar to
      animal models, we have shown that the density of the microtubular network within
      the cardiomyocyte is increased in end-stage failing human hearts. We have also
      shown for the first time that beta-tubulin density is increased in cells from
      hypertrophied human hearts. Although the functional implications of this finding
      in the human heart remain to be explored, data from animal studies suggest that
      increased beta-tubulin protein contributes to cardiac dysfunction.

PMID- 12431452
TI  - Upregulation of myocardial Na+/H+ exchanger induced by chronic treatment with a
      selective inhibitor.
AB  - Rats exposed to prolonged administration of the NHE-1 inhibitor cariporide showed
      enhanced activity of the exchanger in cardiac tissue, as assessed by the rise in
      the steady-state pHi value in the absence of bicarbonate (7.15+/-0.01 in control
      vs 7.49+/-0.06 and 7.41+/-0.05 in cariporide-treated for 1 or 2 months,
      respectively, P<0.05). In the presence of bicarbonate, the change in pHi was
      blunted due to a compensatory activation of acid loading pHi regulatory
      mechanisms. The enhancement of NHE activity disappeared after 1 week of the
      inhibitor withdrawal. The kinetic analysis of H+ fluxes after an acid load
      revealed an increased net H+ efflux (JH+) at any given pHi value and an alkaline
      shift of the apparent "set-point" of the exchanger (from 7.11+/-0.02 to 7.38+/
      0.04,P <0.05) in treated rats. In the presence of the PKC inhibitor
      chelerythrine, the "set-point" of the exchanger was normalized in the cariporide
      treated rats while JH+ at acidic pHi values persisted elevated. Cardiac NHE-1
      mRNA levels and protein expression were increased in cariporide-treated rats. In
      addition to the increased protein expression after the treatment, the
      normalization of the augmented "set-point" by chelerythrine suggests an increased
      turnover rate of the units through a PKC dependent pathway. These data
      demonstrate that long-term treatment with the NHE-1 inhibitor cariporide enhances
      the antiporter activity in cardiac tissue through an increase of the number and
      turnover of functional units. This finding deserves further experimental and
      clinical evaluations to consider whether it would be advisable a gradual
      withdrawal of prolonged NHE inhibition to avoid an enhanced response when the
      exchanger is stimulated.

PMID- 12431451
TI  - Intracellular angiotensin II increases the long isoform of PDGF mRNA in rat
      hepatoma cells.
AB  - Our recent published studies suggest that angiotensin II (AII), generated and
      retained intracellularly, enhances growth of H4-II-E-C3 rat hepatoma cells, an
      average of 33%. Proliferation conferred by introduction of a plasmid [ Ang(
      S)Exp/pSVL ] encoding a signal sequence-depleted angiotensinogen [Ang(-S)Exp]
      into these cells (which we have shown possess ACE and renin mRNAs) is mediated,
      at least in part, by enhanced PDGF-A chain mRNA production and protein secretion.
      The mitogenic effect is inhibited by losartan suggesting that it involves AII
      interaction with an AT(1)-like receptor. Introduction of anti-AII antibodies into
      the medium of these transfected cells has no effect upon growth of the cells,
      suggesting that AII is retained by the cells and that intracellular AII is growth
      stimulatory. In the present study, we sought to further characterize the
      intracellular localization and mode of action of Ang(-S)Exp. Consistent with our
      expectations, we now show that a fusion product of Ang(-S)Exp with green
      fluorescent protein [Ang(-S)Exp/EGFP], generated from an expression plasmid, is
      abundant and primarily cytoplasmic. Wild-type angiotensinogen/EGFP, in contrast,
      is only detectable following a cold-block (which acts to enhance folding-kinetics
      and slow secretion) and is largely restricted to the secretory pathway. We
      further show, using semi-quantitative RT/PCR that the long isoform of PDGF mRNA
      is elevated in Ang(-S)Exp transfected cells and in AII-treated naive cells but
      not in losartan-treated Ang(-S)Exp transfected cells. We identify C-terminal
      amidation recognition sites within the long-form protein (that are not present in
      the short-form) and show that these cells possess PAM (amidating enzyme
      precursor) and carboxypeptidase E mRNAs (the corresponding proteins of which are
      sufficient for amidation). Inhibitors of amidation inhibit growth of naive and
      Ang(-S)Cntr/ pSVL -transfected cells (2.6-fold for phenylbutenoic acid and 3.5
      fold for disulfiram treatment) but more profoundly inhibit growth of Ang(
      S)Exp/pSVL -transfected cells (6.7-fold for phenylbutenoic acid and 13-fold for
      disulfiram). In conclusion, these data confirm that signal sequence-depleted Ang(
      S)Exp is retained within cells and is largely cytoplasmic. Because C-terminal
      amidation is absolutely required for full biological potency of a number of
      peptide hormones (including oxytocin, gastrin and calcitonin), we postulate that
      growth effects of both intracellular AII and exogenous AII can be conferred by
      PDGF long-form, possibly through an amidation-dependent mechanism.

PMID- 12431453
TI  - Glyceraldehyde phosphate dehydrogenase oxidation during cardiac ischemia and
      reperfusion.
AB  - OBJECTIVES: Protein S-glutathiolation is a predicted mechanism by which protein
      thiol groups are oxidized during the oxidative stress of ischaemia and
      reperfusion. We measured protein S-thiolation during ischaemia and reperfusion
      and investigated the effect of this oxidative modification on the function of
      GAPDH. METHODS: Glutathione was biotinylated (biotin-GSH) and used to probe for
      protein S-glutathiolation in isolated rat hearts using non-reducing Western blots
      and streptavidin-HRP. Streptavidin-agarose was used to purify S-glutathiolated
      proteins and these were identified using N-terminal sequencing and database
      searching. RESULTS: Little protein S-glutathiolation occurred in control
      preparations, but this increased 15-fold during reperfusion. Protein S
      glutathiolation was attenuated by the antioxidant mercaptopropionylglycine and
      was shown to occur only during the firstminutes of reperfusion. Affinity
      purification of the S-glutathiolated proteins showed 20 dominant S
      glutathiolation substrates. A dominant S-thiolated protein was N-terminally
      sequenced (VKVGVNGFG) and HPLC peptide mapping gave additional sequence nearer
      the site of oxidation (TGVFTTMEKA). The first sequence was the N-terminus of
      GAPDH, and the second a peptide from the same protein starting at residue 96.
      GAPDH was immunopurified from aerobic, ischemic or reperfused hearts.
      Maleimidofluorescein labeling of purified GAPDH provided an index of its reduced
      thiol status. In the absence of DTT, ischemia induced a reduction in the number
      of free thiols on GAPDH that was reversed on reperfusion. When treated with DTT,
      the free thiol status of GAPDH could be increased in ischemic but not reperfused
      samples. Ischemia induced a reduction in GAPDH activity that was partially
      restored by reperfusion. DTT-treatment reactivated ischemic GAPDH, but had little
      effect on the activity from reperfused tissue. Mass spectra acquired from aerobic
      GAPDH preparations were relatively simple whereas spectra from ischemic or
      reperfused preparations were highly complex, possibly indicative of oxidation by
      multiple oxidants. CONCLUSIONS: Many proteins, including GAPDH, are targets for S
      glutathiolation during cardiac oxidative stress. GAPDH oxidation is associated
      with a loss in reduced cysteine status that correlates with the inactivation of
      this enzyme.

PMID- 12431454
TI  - Biomechanical interaction between hyphae of two Pythium species (Oomycota) and
      host tissues.
AB  - Forces exerted by hyphae of the phytopathogen Pythium graminicola and mammalian
      pathogen Pythium insidiosum were compared with the mechanical resistance of their
      hosts' tissues. Hyphal apices of both species exerted a mean force of 2 microN,
      corresponding to mean pressures of 0.19 microN microm(-2) (or MPa) for P.
      graminicola, and 0.14 microN microm(-2) for P. insidiosum. Experiments with glass
      microprobes showed that the epidermis of grass roots resisted penetration until
      the pressure applied at the probe tip reached 1-12 microN microm(-2). Previously
      published data show that mammalian skin offers even greater resistance (10-47
      microN microm(-2)). Clearly, tissue strength exceeds the pressures exerted by
      hyphae of these pathogens, verifying that secreted enzymes must play a critical
      role in reducing the resistance of plant and animal tissues. It is presumed that
      hyphae are sufficiently powerful to bore through any obstacles remaining after
      enzyme action.

PMID- 12431455
TI  - Special issue in honor of Salomon Bartnicki-Garcia.

PMID- 12431456
TI  - Reef coral fluorescent proteins for visualizing fungal pathogens.
AB  - The fluorescent proteins AmCyan, ZsGreen, ZsYellow, and AsRed, modified versions
      of proteins identified recently from several Anthozoa species of reef corals,
      were expressed for the first time in a heterologous system and used for imaging
      two different fungal plant pathogens. When driven by strong constitutive fungal
      promotors, expression of these reef coral fluorescent proteins yielded bright
      cytoplasmic fluorescence in Fusarium verticillioides and Magnaporthe grisea, and
      had no detectable effect on either growth rate or the ability to cause disease.
      Differential intracellular localization of the fluorescent proteins resulted in
      the discrimination of many subcellular organelles by confocal and multi-photon
      microscopy, and facilitated monitoring of such details as organelle dynamics and
      changes in the permeability of the nuclear envelope. AmCyan and ZsGreen were
      sufficiently excited at 855 and 880 nm, respectively, to allow for time-resolved
      in planta imaging by two-photon microscopy.

PMID- 12431457
TI  - Analysis of three separate probes suggests the absence of endocytosis in
      Neurospora crassa hyphae.
AB  - Reports of the existence of endocytosis in filamentous fungi have been
      conflicting and inconclusive. For this reason, we have tested three independent
      markers in Neurospora crassa: the electron opaque marker lanthanum (La) and the
      fluorescent probes Lucifer yellow (LY) and FM4-64. Both La and LY were
      endocytosed by Saccharomyces cerevisiae cells, which were used as positive
      controls for endocytosis, but the probes did not accumulate in N. crassa hyphae.
      Only FM4-64 became internalized into N. crassa hyphae, but it induced abnormal
      changes in membrane systems and its internalization could be explained by
      mechanisms other than endocytosis. Together, our results suggest that endocytosis
      does not occur in N. crassa hyphae and question whether the styryl dyes do in
      fact reliably report normal endocytosis in filamentous fungi.

PMID- 12431458
TI  - Live-cell imaging of endocytosis during conidial germination in the rice blast
      fungus, Magnaporthe grisea.
AB  - Although there is growing evidence that endocytosis is important in hyphal tip
      growth, it has not previously been shown to occur during fungal spore
      germination. We have analysed and characterized endocytosis during the
      germination of living conidia of the rice blast fungus, Magnaporthe grisea.
      Conidia treated with the endocytic markers Lucifer Yellow carbohydrazide, FITC
      dextran, and FM4-64 were imaged by confocal microscopy. Internalization of these
      fluorescent marker dyes by conidia was blocked by chemical and temperature
      treatments that inhibit endocytosis, and the sequential staining of organelles by
      the membrane-selective dye FM4-64 was consistent with dye internalization by
      endocytosis. FM4-64 uptake occurred within 2-3 min of conidial hydration, more
      than 40 min before the emergence of the germ tube. The times at which each of the
      three conidial cells initiated dye internalization were different as were the
      rates of dye uptake by each cell. Using these techniques we have demonstrated for
      the first time that ungerminated and germinated spores of filamentous fungi
      undergo endocytosis. Furthermore, internalization of FITC-dextran and Lucifer
      Yellow carbohydrazide by germinating conidia provides the first direct evidence
      for fluid-phase endocytosis in a filamentous fungus. FM4-64 was internalized by
      both ungerminated conidia and conidial germlings on the rice leaf suggesting that
      endocytosis might play a significant role in spore germination and germ tube
      growth during the pre-penetration phase of infection.

PMID- 12431459
TI  - Ultrastructural morphogenesis of dimorphic arcuate infection (gun) cells of
      Haptoglossa erumpens an obligate parasite of Bunonema nematodes.
AB  - Haptoglossa is a genus of biflagellate organisms that has been placed in the
      oomycetes and is characterised by producing unique infective gun cells, which
      usually infect by physically rupturing the nematode cuticle. Haptoglossa erumpens
      is a parasite of Bunonema nematodes that produces arcuate infection cells and
      aplanospores that are discharged following the swelling and rupture of the
      thallus wall and distended host cuticle. Recent isolations of H. erumpens have
      revealed that the germinating aplanospores develop into two similar-sized but
      morphologically distinct infection cells. The uni-nucleate, convexly arcuate, gun
      cells were observed to fire in response to host nematodes, producing a
      cylindrical sporidium inside the host body. These gun cells had an apical missile
      chamber containing a needle with a unique arrangement of investing cones. Unlike
      previously described gun cells, the tube tail did not wind around the nucleus but
      continued into the basal vacuole where it terminated. The second type of
      infection cell was a concavely arcuate, bi-nucleate, cell that had an unusually
      large and elongate annulus component in the missile chamber. These modified bi
      nucleate gun cells were never observed to fire in response to contact with
      Bunomena nematodes. The patterns of morphological and structural variations in
      these infection structures in this genus are reviewed in the light of these
      findings.

PMID- 12431461
TI  - Force and compliance: rethinking morphogenesis in walled cells.
AB  - In the turgid cells of plants, protists, fungi, and bacteria, walls resist
      swelling; they also confer shape on the cell. These two functions are not
      unrelated: cell physiologists have generally agreed that morphogenesis turns on
      the deformation of existing wall and the deposition of new wall, while turgor
      pressure produces the work of expansion. In 1990, I summed up consensus in a
      phrase: "localized compliance with the global force of turgor pressure." My
      purpose here is to survey the impact of recent discoveries on the traditional
      conceptual framework. Topics include the recognition of a cytoskeleton in
      bacteria; the tide of information and insight about budding in yeast; the role of
      the Spitzenkorper in hyphal extension; calcium ions and actin dynamics in shaping
      a tip; and the interplay of protons, expansins and cellulose fibrils in cells of
      higher plants.

PMID- 12431460
TI  - Aspergillus nidulans polarity mutant swoA is complemented by protein O
      mannosyltransferase pmtA.
AB  - Previously swoA was identified in Aspergillus nidulans as a single locus,
      temperature-sensitive (ts) mutant aberrant in polarity maintenance. swoA was
      complemented by transformation with a plasmid genomic library. The sequence of
      the complementing gene was identical to a previously submitted GenBank sequence
      for pmtA, a protein O-mannosyltransferase. The pmtA/swoA-2 gene hybridized to
      three cosmids that are located on chromosome V and the swoA mutation was
      mitotically mapped to chromosome V. PMTs are endoplasmic reticulum-resident
      proteins responsible for the first step of O-glycosylation. Structural
      predictions suggest that PmtA contains seven membrane spans similar to PMTs from
      Saccharomyces cerevisiae and other organisms. Phylogenetic analysis indicates
      that PmtA is most closely related to the S. cerevisiae sub-family of PMTs
      containing Pmt2, Pmt3 and Pmt6. The mutant pmtA/swoA-2 locus contained a lesion
      that changed Y662 to a stop codon, eliminating the final membrane spanning domain
      and interrupting a domain essential for function in other PMTs.

PMID- 12431462
TI  - Digital knowledge.

PMID- 12431463
TI  - The potential therapeutic effect of sentinel lymphadenectomy.
AB  - Sentinel lymph node (SLN) biopsy in a minimally invasive staging procedure for
      early breast cancer patients that is currently being investigated in many
      institutional and multi-institutional studies. Its main perspectives are the
      omission of axillary dissection in sentinel lymph node-negative patients and an
      improved staging as a result of more intensive histopathological methods for the
      detection of nodal involvement. The hypothesis presented in this article suggests
      that sentinel lymphadenectomy may also serve as a therapeutic intervention in
      some patients. The background for this comes from historical studies before the
      general use of systemic adjuvant treatment, which suggest that some node-positive
      breast cancer patients seem to be curable by locoregional treatment alone. Recent
      studies show that many patients have nodal metastases limited to the SLNs, where
      (considering the sigmoid growth model of solid tumours) small metastases may grow
      faster than larger ones. Large metastases are associated with worse prognosis. It
      is suggested that, in consequence of its expected therapeutic effects, sentinel
      lymphadenectomy, i.e. the removal of the lymph nodes most likely to harbour
      metastases, should be preferred to the omission of axillary dissection, or any
      other surgical staging procedure based on predictive models of nodal involvement
      derived from primary tumour characteristics.

PMID- 12431464
TI  - New diagnostic techniques in staging in the surgical treatment of cutaneous
      malignant melanoma.
AB  - The emphasis of the research on the surgical treatment of melanoma has been on
      the resection margins, the role of elective lymph node dissection in high risk
      patients and the value of adjuvant regional treatment with hyperthermic isolated
      lymph perfusion with melphalan. Parallel to this research, new diagnostic
      techniques, such as Positron Emission Tomography and the introduction of the
      sentinel lymph node biopsy with advanced laboratory methods such as immuno
      histochemical markers, and reverse transcriptase polymerase chain reaction, have
      been developed to facilitate early detection of metastatic melanoma. The role of
      these new techniques on the staging and surgical treatment of melanoma is
      discussed in this paper.

PMID- 12431465
TI  - Subareolar injection for sentinel lymph node location in breast cancer.
AB  - AIM: Several different injection techniques are currently used for sentinel node
      (SN) identification in patients with breast cancer. Some studies suggest that the
      subareolar plexus drains lymph from the whole breast to the same axillary SN. In
      order to test this hypothesis, we ascertained whether subareolar blue dye
      injection and subdermal radioisotope injection close to the tumour identify the
      same axillary nodes. METHODS: One day prior to surgery, 50 patients with breast
      cancer underwent subdermal injection of 30-40MBq of 99m-Tc colloidal albumin
      (Nanocoll) at the site of the cutaneous projection of the tumour. Ten minutes
      before surgery, each patient received a subareolar injection of 2-3cc of patent
      blue. All axillary radioactive nodes and blue-stained nodes were excised and a
      histologic examination was made. RESULTS: Radioisotope marked the SNs in 47/50
      (94%) cases, and the blue dye in 43/50 cases (86%). In three cases, SNs were not
      identified with either method. Of the 43 cases in which both the tracers reached
      the axilla, in 40 (93%) the SN was hot and blue-stained, while in 3 cases the two
      tracers identified different nodes. CONCLUSIONS: Our findings suggest that
      subareolar injection and subdermal injection elsewhere in the breast usually
      identify the same SN. Subareolar injection appears to be particularly valuable in
      patients with multicentric or deep non-palpable breast tumours.

PMID- 12431466
TI  - Shoulder-arm morbidity following axillary dissection and sentinel node only
      biopsy for breast cancer.
AB  - AIMS: The purpose of this study was to examine the outcome of shoulder-arm
      morbidity in patients with breast cancer after various axillary staging
      procedures. We used a new specific summation score to compare conventional
      axillary node dissection (AD) and sentinel node only biopsy for postoperative
      shoulder-arm morbidity. METHODS: Eighty-five patients undergoing conventional AD
      and 66 patients undergoing sentinel node biopsy were evaluated both subjectively
      (questionnaire) and objectively (clinical examination) for reduced muscle
      strength, limited range of motion, lymphedema and pain, dysesthesias and loss of
      sensitivity. The symptoms elicited were rated by their severity with a single
      summation score describing all symptoms reported. RESULTS: Subjective evaluation
      of patients undergoing breast conserving surgery showed a highly significant
      difference in favor of SNB only (P< or =0.002). On clinical examination the
      outcome of patients with SNB only was also significantly or highly significantly
      better (difference in arm volume:P =0.007; difference in arm muscle strength:
      P=0.016; loss of sensitivity: P<0.001). Of a total score of 100 (=no symptoms),
      the mean for AD patients was 80.2 vs 92.8 for SNB patients (P=0.001). In patients
      undergoing total mastectomy the difference was only significant for pain
      sensations and total scores. CONCLUSIONS: SNB appears to reduce morbidity.
      Summation scores are a suitable and practicable tool for describing the symptoms
      associated with axillary surgery.

PMID- 12431467
TI  - Inoperable adenocarcinoma of the oesophagogastric junction: a comparative
      clinical study of laser coagulation versus self-expanding metallic stents with
      special reference to cost analysis.
AB  - AIMS: Neither clinical nor financial comparisons yet exist between self-expanding
      metallic stents (SEMS) and laser therapy, concentrating on the treatment of
      obstructive adenocarcinomas of the oesophagogastric junction. The aim of our
      study was to compare the relative lifetime costs and clinical results of the
      Nd:YAG laser to those of SEMS as alternative forms of primary palliation of
      dysphagia for adenocarcinoma near the oesophagogastric junction. METHODS: Fifty
      two patients with distal oesophageal or oesophagogastric adenocarcinomas
      underwent palliative treatment for dysphagia: 32 treated with laser therapy and
      20 with SEMS in this retrospective study. The clinical outcome and real
      cumulative costs as physical units and in financial terms were analysed for these
      study groups. RESULTS: Although patients palliated with SEMS underwent fewer
      procedures (1.9+/-1.6 vs 3.4+/-4.0, P=0.0048) and spent less time in endoscopic
      theatre (38+/-25min vs 118+/-152min, P=0.0048), they spent as many days in
      hospital (12.9 vs 15.1, P=0.370) and required as high overall costs for therapy
      (5360 EUR vs 5450 EUR, P=0.679) as those treated with laser therapy. In addition,
      they had higher morbidity rates (30 vs 6.3%, P=0.043), hospital mortality (20 vs
      3.1%, P=0.066), and 30-day mortality (40 vs 3.1%, P=0.0011) than did patients
      with laser therapy, with no evidence of SEMS being the more effective treatment
      modality. CONCLUSIONS: In patients with adenocarcinoma at the distal oesophagus
      or at the oesophagogastric junction, laser therapy palliates dysphagia
      effectively with lower morbidity and mortality rates and without increased costs
      or hospital stays than does use of self-expanding metallic stents.

PMID- 12431468
TI  - Late locoregional recurrence in rectal carcinoma.
AB  - AIMS: Locoregional recurrence in rectal carcinoma usually occurs within the first
      five years of treatment. In recent years we have increasingly diagnosed patients
      with late locoregional recurrence more than 5 years after primary treatment.
      METHODS: The data of 978 patients with invasive stage I-III rectal carcinoma who
      underwent curative resection (R0) between 1978 and 1990 were analysed
      retrospectively. The median follow-up time was 10 years. RESULTS: The earliest
      locoregional recurrence was observed at 2 months, the latest at 148 months
      (extramural locoregional recurrence) after primary treatment. Within 1, 2 and 5
      years 34, 64 and 91 per cent of all locoregional recurrences had been diagnosed.
      The 2-, 5- and 10-year locoregional recurrence rates of all patients increased
      from 11.3 to 16.7 to 18.8 per cent. The time lapse to diagnosis of locoregional
      recurrence was significantly influenced by the pN category (pN0: later), grading
      (low grade: later) and tumour cell dissemination (present: earlier). Locoregional
      recurrence was also diagnosed significantly earlier in patients undergoing
      regular follow-up. The curative reoperation rate was 22 per cent (n=37), being
      higher in patients with intramural locoregional recurrence (49 per cent), after
      primary anterior resection (32 per cent) and in the absence of distant metastases
      (29 per cent). CONCLUSION: Long-term follow-up beyond five years demonstrates
      increasing numbers of late locoregional recurrences.

PMID- 12431469
TI  - Indications and results of resection for hepatocellular carcinoma.
AB  - AIM: In this retrospective series we evaluate our experience in surgical
      treatment of HCC and examine early and long-term results of 46 hepatic
      resections. METHODS: Eighty-eight patients with HCC have been observed at our
      Department. Fifty patients (57%) have been operated, but only 46 (92%) could be
      resected; 43 patients (93.5%) carried liver cirrhosis. We performed 28 non
      anatomical resections (60.8%) and 18 anatomical resections (39.2%). Tumour
      clearance at resection margin of at least 1cm was considered for a curative
      resections. RESULTS: Overall mortality and morbidity were 8.7 and 30.4%
      respectively. These rates significantly decreased in the last years: from 1995 to
      2000 no hospital mortality has been recorded. Hospital mortality among non
      anatomical and anatomical resection subgroups was 3.5 and 16.6% respectively
      (P<0.02). After a median f.u. of 41 months, 19 patients (45.2%) had recurrences:
      it was intrahepatic in 16 (84.4%). We observed a 3-, 5- and 10-years actuarial
      survival rate 62, 51.1 and 22.5% respectively. Long term survival significantly
      differed between non-anatomical and anatomical resections, with 5-year and 10
      year values of 61.1 and 34.3% vs 37.7 and 18.8% respectively (P=0.0224).
      CONCLUSIONS: Early results after hepatic resection for HCC can be improved by
      using a limited surgical approach. Long-term results are still unsatisfactory,
      because of the high recurrence rate that is not influenced by different surgical
      approaches.

PMID- 12431470
TI  - The role of cyclooxygenase-2 (COX-2) in breast cancer, and implications of COX-2
      inhibition.
AB  - The cyclooxygenase (COX) enzyme system is composed of two isoenzymes, COX-1 and
      COX-2. Recent sources of experimental and epidemiological evidence suggest a
      significant role for the COX enzymes, particularly COX-2, in the pathogenesis of
      breast cancer. This has important implications for treatment of the disease. This
      article reviews the evidence for a relationship between the COX enzyme system and
      mammary carcinogenesis, and discusses the likely therapeutic roles and potential
      pitfalls of COX inhibition.

PMID- 12431471
TI  - How I do it: D2 gastrectomy.

PMID- 12431472
TI  - Diagnosis of deep vein thrombosis and pulmonary embolism in pregnancy.
AB  - Venous thromboembolism (VTE) is a major cause of maternal morbidity and
      mortality. Because unrecognized and untreated pulmonary embolism (PE) can result
      in maternal mortality, physician vigilance for this disease should remain high.
      The diagnosis of both PE and deep vein thrombosis (DVT) in the pregnant patient,
      as in the nonpregnant patient, requires the use of accurate objective imaging.
      However, unlike the nonpregnant population, there is a paucity of trials
      evaluating the safety and accuracy of objective testing for PE or DVT diagnosis
      in pregnant patients--likely because of concerns surrounding the use of ionizing
      radiation associated with diagnostic tests during pregnancy. Regardless of
      extrapolating results from studies in the nonpregnant population, the use of
      compression leg ultrasound and ventilation-perfusion (VQ) scanning during
      pregnancy is central to the diagnosis of DVT and PE, respectively. Data on the
      utility of structured clinical models or D-dimer testing for the diagnosis of DVT
      or PE during pregnancy is currently unavailable. Future research is urgently
      needed to validate the use of current approaches and perhaps define safer and
      more accurate strategies to reduce maternal morbidity from this disease.

PMID- 12431473
TI  - Pharmacokinetics, pharmacodynamics and clinical effects of the oral direct
      thrombin inhibitor ximelagatran in acute treatment of patients with pulmonary
      embolism and deep vein thrombosis.
AB  - INTRODUCTION: Ximelagatran is a novel, oral direct thrombin inhibitor that is
      currently being investigated for the prophylaxis and treatment of thromboembolic
      events. This study evaluated the pharmacokinetics, pharmacodynamics, and clinical
      effects of melagatran, the active form of ximelagatran, in patients with both
      deep vein thrombosis (DVT) and pulmonary embolism (PE). MATERIALS AND METHODS: In
      this open-label study, 12 patients received a fixed dose of 48 mg oral
      ximelagatran twice daily for 6-9 days. Plasma samples were collected for
      determination of melagatran concentrations and scintigraphic changes and adverse
      events were recorded. RESULTS: Peak plasma concentrations of melagatran were
      attained approximately 2 h after administration of ximelagatran. Melagatran
      plasma concentration profiles were similar on Days 1, 2, and 6-9. Plasma
      activated partial thromboplastin time increased following administration of
      ximelagatran and reached a peak that was approximately twofold higher than the
      predose activated partial thromboplastin time and correlated with melagatran
      plasma concentrations (R(2) = 0.69). All but one patient (with malignancy) showed
      regressed or unchanged lung scintigraphic findings, and six of these demonstrated
      no, or only minor, perfusion defects at central evaluation after 6-9 days of
      ximelagatran treatment. Clinical symptoms, including chest pain, dyspnoea, cough,
      and oedema, and pain in the affected leg, were improved. Ximelagatran was well
      tolerated with no deaths or severe bleeding events reported during treatment.
      CONCLUSION: Treatment with a fixed dose of oral ximelagatran, used without
      routine coagulation monitoring, showed reproducible pharmacokinetics and
      pharmacodynamics with a rapid onset of action and promising clinical results in
      patients with pulmonary embolism.

PMID- 12431474
TI  - Blood rheology in deep venous thrombosis--relation to persistent and transient
      risk factors.
AB  - INTRODUCTION: The risk of recurrence in patients with symptomatic deep venous
      thrombosis (DVT) is higher in patients with persistent risk factors than in
      patients with transient risk factors. The purpose of this prospective study was
      to investigate the course of rheological variables in patients with DVT up to 1
      year after the acute event in relation to risk factors. PATIENTS AND METHODS: In
      37 patients with proven DVT plasma fibrinogen, plasma viscosity, red cell
      aggregation, whole blood viscosity, hematocrit and platelet aggregation were
      studied in the acute phase, at 6 weeks and at 12 months. RESULTS: In the acute
      phase, patients had higher fibrinogen (medians and ranges; 450 [270-611] vs. 247
      [170-340] mg/dl, p < 0.01), plasma viscosity (1.67 [1.48-1.96] vs. 1.60 [1.50
      1.70] mPa s, p < 0.01), red cell aggregation (9.76 [5.87-12.66] vs. 5.66 [3.67
      8.46] arbitrary units; p < 0.01) and whole blood viscosity (5.78 [5.61-5.87] vs.
      5.59 [5.27-5.9] mPa s, p < 0.01), but lower hematocrit (40 [32-46] vs. 45 [38
      50]%, p < 0.01) and platelet aggregation (by epinephrine: 41 [13-85] vs. 79 [29
      91]%, (p < 0.01) than controls. During the 1-year follow-up, fibrinogen, plasma
      viscosity, red cell aggregation and whole blood viscosity constantly decreased,
      whereas hematocrit and platelet aggregation increased in the total of patients
      (all p < 0.01). Subgroup analysis according to risk factors showed that at 12
      months patients with persistent risk factors (N = 21) had higher plasma
      fibrinogen (357 [235-450] vs. 247 [214-335] mg/dl, p < 0.01), plasma viscosity
      (1.65 [1.50-1.80] vs. 1.59 [1.42-1.77] mPa s, p < 0.05) and red cell aggregation
      (7.82 [6.0-11.3] vs. 6.3 [5.2-7.1] arb. units, p < 0.01) than patients with
      transient risk factors (N = 16). Compared with controls, these variables were
      increased in patients with persistent risk factors (all p < 0.01), but not in
      patients with transient risk factors (all n.s.). CONCLUSION: In patients with
      persistent risk factors rheological changes are still present 1 year after acute
      DVT, whereas in patients with transient risk factors blood rheology returns to
      normal. Further studies are needed to clarify whether blood rheology might be
      helpful to identify patients at high risk of recurrence.

PMID- 12431475
TI  - Analysis of the thrombomodulin gene in patients with venous thrombosis.

PMID- 12431476
TI  - The 4G/5G-polymorphism in the PAI-1 gene is not associated with markers of
      atherosclerosis in male smokers.

PMID- 12431477
TI  - The GP IIb/IIIa inhibitor abciximab (c7E3) inhibits the binding of various
      ligands to the leukocyte integrin Mac-1 (CD11b/CD18, alphaMbeta2).
AB  - Cross-reactivity with integrins other than glycoprotein IIb/IIIa (GP IIb/IIIa) is
      discussed as a potential reason for the overall clinical benefits of the GP
      IIb/IIIa-blocking antibody-fragment abciximab. We evaluated whether abciximab
      binds to the leukocyte integrin Mac-1, whether it inhibits binding of the
      distinct ligands and thereby may modulate inflammation, cell proliferation and
      coagulation. Binding of fluorescence-labelled abciximab to phorbolmyristate
      acetate-stimulated monocytes and to a monocytic cell line (THP-1) could be
      detected in flow cytometry. The binding of fibrinogen, the inactivated complement
      factor 3b (iC3b), and the coagulation factor X to Mac-1 could be inhibited by
      abciximab (10 microg/ml) in vitro. As a functional consequence, the conversion of
      factor X to factor Xa mediated by Mac-1, as detected by the chromogenic substrate
      SZ-2222, was impaired by abciximab. Adhesion of THP-1 cells to immobilized
      intercellular adhesion molecule 1 (ICAM-1) and to fibrinogen was reduced
      significantly by abciximab. Fibrinogen-mediated cell aggregation was also
      impaired. In conclusion, we describe binding of abciximab to Mac-1 on stimulated
      monocytes. Thereby, abciximab inhibits binding of the ligands fibrinogen, ICAM-1,
      iC3b and factor X. Furthermore, we demonstrated that Mac-1-dependent conversion
      from factor X to factor Xa is impaired by abciximab, arguing for the direct
      modulation of the coagulation cascade by abciximab. Overall, the inhibition of
      Mac-1 could provide additional clinical benefits of abciximab beyond the well
      described blockade of GP IIb/IIIa.

PMID- 12431478
TI  - Lack of evidence for contribution of Glu298Asp (G894T) polymorphism of
      endothelial nitric oxide synthase gene to plasma nitric oxide levels.
AB  - INTRODUCTION: Both positive and negative associations between a rare allele of 27
      bp repeat polymorphism in intron 4 of endothelial nitric oxide synthase and
      plasma nitric oxide (NO) levels were previously reported, and further, these
      conflicting results were suggested to be partly accounted for smoking status of
      subjects. However, the genetic contribution of Glu298Asp (G894T) polymorphism to
      plasma NO levels with respect to smoking status has not been published. METHODS:
      In a group of 411 healthy Korean subjects aged 19-81 years, the end product of NO
      (NO(x): nitrite plus nitrate) as an index of plasma NO levels was measured by the
      Griess method. The genotypes of G894T polymorphism were determined by the banding
      patterns on gel electrophoresis after restriction enzyme digestion. RESULTS:
      Comparison of plasma NO(x) levels revealed no significant differences across the
      genotypes and alleles of G894T polymorphism, which is independently of smoking
      status. However, significant differences in plasma NO(x) levels between
      nonsmokers and smokers were observed (P = 0.0040). Furthermore, only the common G
      allele was found to be responsible for these differences. Multiple regression
      analysis showed that the most independent contributing factor for plasma NO(x)
      levels was smoking (P = 0.0119) and followed by triglycerides (P = 0.0384).
      CONCLUSIONS: Our results indicate no substantial effect of G894T polymorphism on
      the variance of plasma NO(x) levels in healthy Korean population.

PMID- 12431479
TI  - Serum from patients with chronic idiopathic thrombocytopenic purpura frequently
      affect the platelet function.
AB  - In most, but not all, cases of chronic idiopathic thrombocytopenic purpura (ITP),
      bleeding complications are known to occur when the platelet count is low. The
      present study investigates the effect of ITP sera on the in vitro platelet
      function of donor platelets. Sera from 58 ITP patients were investigated. Using
      an indirect monoclonal antibody specific immobilisation of platelet antigen
      (MAIPA) technique, GPIIb/IIIa and GPIb/IX specific antibodies were found in 23
      and 20 patients, respectively. Twelve of them had antibodies against both
      glycoprotein (GP) complexes. The ITP sera's effect on donor platelets was
      investigated by aggregometry and the results were compared with the ones of 26
      healthy donor sera. Grouped together, the ITP sera significantly impaired the ADP
      induced platelet aggregation of donor platelets compared to the control sera; the
      mean relative aggregation response (T(max)) seen for the ITP and control sera
      were 82 +/- 21% and 92 +/- 7%, respectively (p = 0.0157). However, 6 ITP sera
      gave an enhanced aggregation response, whereas 17 ITP sera resulted in an
      impaired platelet aggregation, when using the mean +/- 2 S.D. recorded for the
      controls as the normal range. There was not any correlation between aggregation
      response, platelet number or the presence of GPIb/IX or GPIIb/IIIa specific
      antibodies, other than the fact that all ITP sera causing an enhanced aggregation
      were from patients with a platelet number less then 100 x 10(9)/l at the time of
      blood sampling. It is concluded that some ITP sera can either enhance or impair
      the platelet aggregation response, but in most cases, a normal response is
      obtained.

PMID- 12431480
TI  - Effect of resveratrol, a natural polyphenolic compound, on platelet activation
      induced by endotoxin or thrombin.
AB  - Resveratrol (3, 4', 5-trihydroxystilbene), a natural polyphenol, is found in some
      plants that are used in human nutrition. Grapes are a major source for
      resveratrol, and a significant amount can also be found in red wine. Several
      experimental studies have demonstrated biological properties of resveratrol,
      especially its anti-inflammatory, antioxidant, anti-platelet and antitumor
      effects. In the present study, we investigated the first step of platelet
      activation-platelet adhesion stimulated by lipopolysaccharide (LPS) from Proteus
      mirabilis (weak stimulator) and thrombin (strong activator) in the presence of
      resveratrol. Our studies show that endotoxin (0.3 microg/10(8) platelets), like
      thrombin (0.2 U/10(8) platelets), induced the adhesion of platelets (expressed as
      absorbance of cell attached proteins) to collagen and fibrinogen. Preincubation
      of washed platelets with resveratrol at physiological plasma concentrations (25
      100 microg/ml, 30 min, 37 degrees C) had an inhibitory effect on adhesion of
      platelets to collagen after activation by LPS alone or LPS with thrombin. The
      strongest effect on this process was caused by resveratrol at the concentration
      of 100 microg/ml. Pretreatment of platelets with resveratrol (25-100 microg/ml,
      30 min, 37 degrees C) had also inhibitory effects on adhesion of platelets to
      fibrinogen after stimulation of these cells by LPS alone or by LPS with thrombin
      at the same concentration. In conclusion, we suggest that resveratrol present in
      human diet may be an important compound responsible for the reduction of platelet
      adhesion and changed reactivity of blood platelets in inflammatory process.

PMID- 12431481
TI  - Thrombapheresis causes a transient impairment of platelet responsiveness to
      epinephrine in healthy donors.

PMID- 12431482
TI  - A neoantigenic determinant in the D-dimer fragment of fibrin.
AB  - Monoclonal antibody (mAb) III-3b binds D-dimer with K(d)=1.4 x 10(-10) M without
      cross-reaction with fibrin(ogen). The epitope for this mAb is in Bbeta134-190,
      presumably in Bbeta155-160. The latter site is buried in the coiled coil
      structure of fibrin(ogen) but it is exposed as a neoantigenic determinant in D
      dimer upon plasmic lysis of fibrin. mAb III-3b may be used as a tool for
      immunodiagnostic quantification of D-dimer in blood plasma.

PMID- 12431483
TI  - Evidence that heterodimers exist in the fibrinogen Matsumoto II (gamma308N-->K)
      proband and participate in fibrin fiber formation.
AB  - INTRODUCTION: In this report, we established the gamma308K/N fibrinogen-secreting
      Chinese hamster ovary (CHO) cell line, which is an artificially heterozygous,
      Matsumoto II (M-II; gamma308K-->N) type of dysfibrinogen, to indirectly
      demonstrate the existence of heterodimeric molecules in propositus plasma and the
      participation of these molecules in fibrin fiber formation. MATERIALS AND
      METHODS: We co-transfected the gamma-chain of gamma308K- and gamma308N-coding
      vectors into CHO cells expressing Aalpha- and Bbeta-chains and selected the
      clones by utilizing the unique electrophoretic mobility of the variant gamma
      chain of gamma308K. Although sodium dodecyl sulfate-polyacrylamide gel
      electrophoresis analysis under reducing conditions showed that the amount of the
      variant gamma-chain was slightly less than the amount of normal gamma-chain in
      recombinant gamma308K/N fibrinogen, we judged that our selected clone was still a
      useful model of the M-II individual. RESULTS AND CONCLUSION: Functional analyses
      demonstrated that thrombin-catalyzed fibrin polymerization decreased in the
      following order: gamma308N, gamma308K/N, an equimolar mixture of gamma308K with
      gamma308N. The difference in the polymerization curves between gamma308N and
      gamma308K/N is highly similar to the difference between plasma fibrinogen from a
      normal control and the M-II proband. In addition, experimental results using the
      equimolar mixture indicated that gamma308K is able to polymerize into fibrin
      fibers and does not inhibit the gamma308N polymerization. In conclusion, our
      results indirectly demonstrated that gamma308K/N fibrinogen is the mixture of
      normal homodimers, heterodimers, and variant homodimers, and all of these can
      participate in the fibrin fiber formation.

PMID- 12431484
TI  - Effects of ximelagatran, the oral form of melagatran, in the treatment of caval
      vein thrombosis in conscious rats.
AB  - The antithrombotic effects of direct (ximelagatran and hirudin) and indirect
      (dalteparin) anticoagulants were compared using a deep venous thrombosis (DVT)
      treatment model in conscious rats. Thrombus formation was induced in the inferior
      caval vein by total stasis plus topically applied ferric chloride. After 1-h
      thrombus maturation, one group of 10 rats were sacrificed and the mean thrombus
      weight in this group was 27.3 +/- 2.7 mg. This thrombus weight was handled as a
      reference to which all other results were compared. In all other groups, the
      total occlusion was removed after 1 h but a partial stasis was retained,
      permitting some blood flow around the thrombus. Groups of animals received
      subcutaneous (s.c.) dalteparin (200 IU/kg), s.c. hirudin (0.75 micromol/kg), one
      of four oral doses of ximelagatran (2.5, 5, 10 or 20 micromol/kg) or s.c. saline
      (control). After the 3-h treatment, mean thrombus weight in the saline group
      (26.5 +/- 3.3 mg) did not differ significantly from that of the reference group
      (27.3 +/- 2.7 mg, see above). Ximelagatran decreased thrombus weight in a dose
      dependent manner, with an estimated ID(50) of 15 micromol/kg. Mean thrombus
      weight with the highest ximelagatran dose (11.1 +/- 1.3 mg) was similar to that
      with hirudin (13.0 +/- 1.5 mg). The effect of dalteparin on thrombus regression
      was much less pronounced (20.2 +/- 1.2 mg), compared with ximelagatran and
      hirudin, even though it was administered at a dose that yielded a similar
      activated partial thromboplastin time (APTT) prolongation. In conclusion, the
      results from this DVT treatment model showed that direct thrombin inhibitors
      ximelagatran and hirudin exhibited superior antithrombotic properties to low
      molecular weight heparin (LMWH).

PMID- 12431485
TI  - Plasminogen activator-plasmin system potentiates the proliferation of hepatocytes
      in primary culture.
AB  - BACKGROUND/AIMS: Liver regeneration after partial hepatectomy is thought to be
      regulated by various molecules including the components of the plasminogen
      activator (PA)-plasmin system. We have examined the role of fibrinolytic factors,
      i.e., tissue-type plasminogen activator (tPA) and urokinase-type plasminogen
      activator (uPA), and their substrate, plasminogen, in the proliferation of
      hepatocytes in primary culture. METHODS: Hepatocyte and nonparenchymal liver
      cells were isolated from Wistar strain rat by a method perfusing the liver with
      collagenase. DNA synthesis was assessed by measuring the incorporation of [3H]
      thymidine into cellular DNA fraction. tPA, uPA and type-1 plasminogen activator
      inhibitor (PAI-1) gene expressions were measured by Northern blotting. PA
      activity was measured by fibrin/agarose plate method. RESULTS: Cellular density
      dependent DNA synthesis was observed in the primary cultured hepatocytes; DNA
      synthesis was lower at high cell density (1.0 x 10(5) cells/cm(2)) than that at
      low cell density (0.2 x 10(5) cells/cm(2)). DNA synthesis in the hepatocytes
      cultured at a low cell density was increased by co-culture with nonparenchymal
      liver cells. Under these growth-stimulated culture conditions, tPA and uPA mRNAs
      were induced and up-regulated. On the contrary, the PAI-1 mRNA level was
      decreased under these conditions, and total PA activity was augmented
      accordingly. The synthetic plasmin inhibitor tranexamic acid, a competitive
      inhibitor for the plasmin molecule, and PASI-535, a plasmin active center
      directed inhibitor, both suppressed hepatocyte proliferation in a dose-dependent
      fashion. Anti-plasmin antibody also suppressed hepatocyte proliferation.
      CONCLUSIONS: The up-regulation of PA activity for ensuring plasmin activity
      should be an important mechanism in the proliferation of hepatocytes.

PMID- 12431486
TI  - The autoantibody expression against different source of oxidized low density
      lipoprotein in patients with acute myocardial infarction.
AB  - The aim of this study was to examine the expression of antibodies against two
      different sources of low density lipoprotein (LDL) that were oxidized by CuSO(4),
      in patients with early stage of acute myocardial infarction (AMI). When LDL
      purified from sera with high level of LDL was used as a modified antigen, the
      results indicated that the titers of antibodies against the oxidized LDL in 30
      patients were increased by 135% compared to those in normal subjects; however,
      the titers of antibody against modified LDL purified from normal-range LDL in the
      same patients were only slightly increased by 52%. Comparing the levels of
      autoantibody expressed in the high LDL sera group, high triglyceride sera group,
      and AMI patients sera group (total of 41; in addition to 30 AMI patients, 11 more
      sera of AMI patients were collected), the amount of autoantibody against the
      oxLDL purified from high LDL sera in AMI patients sera group was significantly
      increased up to 195%. In contrast to AMI patients, the sera titers against the
      same antigen in two subject groups with either high LDL or high triglyceride are
      only 50% higher than normal subjects. Moreover, the ratio of thromboxane B(2)
      over 6-keto-prostaglandin F(1alpha) (6-keto-PG F(1alpha)) in the acute myocardial
      infarction patients was 1.79, which is much lower than the normal subjects, 4.19.
      Concluding from the above observations, we suggest that the expression level of
      anti-oxidized LDL antibody may play a role on the pathogenesis of acute
      myocardial infarction disease, but is independent with the levels of thromboxane
      A(2) and prostacyclin in the examined sera.

PMID- 12431487
TI  - Significant influence of the instrument on the result of the ProC Global assay. A
      multicenter evaluation using lyophilized plasmas and frozen plasma samples from
      carriers and non-carriers of the factor V Leiden mutation.

PMID- 12431490
TI  - Recipient selection in cardiac transplantation: contraindications and risk
      factors for mortality.
AB  - Currently the only acknowledged, definitive treatment for refractory heart
      failure is heart transplantation (HTx). During the past 10 years, selection
      criteria for heart transplant recipients have been developed that use an analysis
      of risk factors associated with mortality, which were identified by consensus
      opinion and by single-center and multi-center database review. A number of other
      studies also have been designed to evaluate specific risk factors for transplant
      such as advanced age, diabetes, and sex. This review identifies variables that
      continue to provoke controversy during the candidate selection process or
      variables that have changed from absolute to relative contraindications for HTx.
      Clinicians may use the data summarized in this review as a guide to making
      decisions about patient candidacy for HTx. One could conclude from this analysis
      that a more formalized and objective scale to select patients and to assess risk
      of death after HTx is necessary. Moreover, as alternative therapies to HTx become
      reality, a better instrument for triaging patients to one form of therapy or
      another may be necessary.

PMID- 12431491
TI  - Vascular endothelial cell apoptosis induced by anti-donor non-MHC antibodies: a
      possible injury pathway contributing to chronic allograft rejection.
AB  - BACKGROUND: Non-major histocompatibility complex (non-MHC) alloantibodies may
      play a pathogenic role in chronic rejection but remain poorly characterized.
      METHODS: The kinetics of alloantibody production and the mechanism by which non
      MHC alloantibodies cause graft injury were investigated in a Lewis-to-Fischer 344
      (LEW-to-F344) rat model of cardiac transplantation. RESULTS: Flow cytometry
      detected that all the F344 recipients of LEW allografts produced anti-donor
      immunoglobulin G (IgG) antibodies reactive with LEW lymphocytes and endothelial
      cells. A sub-group of recipients that rejected their grafts in 30 to 60 days
      exhibited markedly increased levels of anti-donor IgG antibodies (n = 6, mean
      fluorescence intensity [MFI]:23.85 +/- 2.7) than recipients with long-surviving
      allografts (n = 4, MFI:11.23 +/- 0.81; p = 0.00058). Passive transfer of anti
      donor sera induced chronic rejection of LEW heart allografts in an immune non
      responsiveness model of F344 rats induced by intrathymic inoculation of donor
      specific lymphocytes. Immunoglobulin G antibodies purified from the anti-LEW sera
      exhibited complement-dependent cytotoxicity against LEW vascular endothelial
      cells in flow-cytometric cytotoxicity assay. The targeted endothelial cells
      displayed early (annexin V+) and late (TUNEL+) evidence for programmed cell
      death. Western blot analysis of poly (ADP-ribose) polymerase (PARP) demonstrated
      that the 25-kD PARP-cleavage fragment was present at the lysates of the vascular
      endothelial cells treated with anti-donor IgG antibodies, indicating apoptosis
      associated caspase activity in these cells. In situ teminal deoxynucleotidyl
      transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining demonstrated
      that vascular endothelial cell apoptosis was consistently present in all LEW
      heart allografts with chronic rejection. CONCLUSIONS: Non-MHC alloantibodies are
      pathogenic and capable of causing chronic graft injury through an antibody
      induced cell apoptosis mechanism. The results emphasize the importance of non-MHC
      antibodies as a common predisposing factor in the development of chronic
      rejection.

PMID- 12431492
TI  - Localized immunosuppression in the cardiac allograft induced by a new liposome
      mediated IL-10 gene therapy.
AB  - BACKGROUND: Overexpression of interleukin 10 (IL-10) in the donor heart prolongs
      allograft survival in animals. Interleukin-10 has many immunosuppressive effects;
      however, the mechanism(s) of its protective effect on allograft rejection remains
      unknown. METHODS: Recently, we optimized an ex vivo, intracoronary infusion of
      the GAP:DLRIE, liposome-mediated, IL-10 gene method using a rabbit, cervical,
      heterotopic heart transplant model. RESULTS: The efficiency of this new
      generation, liposome-mediated, IL-10 gene transfer to the donor hearts was 15% in
      hypothermic conditions, which represents a 30% increase from the efficiency of
      other liposomes, such as DOSPA/DOPE, DOGS/DOPE, and DMRIE/DOPE. Cardiac allograft
      survival was prolonged from 6.0 +/- 0.7 days to 14.3 +/- 1.8 days. Infiltrating
      lymphocyte sub-populations CD3+, CD4+, and CD8) decreased significantly in the
      gene therapy group compared with the control group. Local IL-10 overexpression
      correlated significantly with decreased CD4+ and CD8+ responsiveness and Type-1
      helper (Th1) cytokine gene (IL-2, interferon-gamma, and tumor necrosis factor
      alpha) expression level and correlated inversely with the allograft rejection
      grade. In the gene therapy group, the cytotoxic activity of infiltrating T cells
      in the allograft decreased greatly, but the time course of this decrease did not
      parallel the rejection process. CONCLUSION: We conclude that GAP:DLRIE is the
      best cationic liposome for ex vivo gene transfection in hypothermic conditions.
      The effects of IL-10 gene therapy on antigen-specific T-lymphocyte proliferation
      and Th1-cytokine expression may play an important role in localized
      immunosuppression and tolerance induction.

PMID- 12431493
TI  - Acitretin for prophylaxis of cutaneous malignancies after cardiac
      transplantation.
AB  - BACKGROUND: Heart transplant recipients have an increased risk of developing
      actinic keratoses and non-melanotic skin cancers when compared with the general
      population. Systemic retinoids have been shown to be beneficial in the treatment
      of such lesions in recipients of other organs, but as of yet the heart transplant
      model has rarely been studied. In this investigation we describe our experience
      with the use of acitretin in a group of heart transplant patients. METHODS: Five
      heart transplant recipients with multiple new skin cancer presentations were
      treated with acitretin at doses of either 10 or 25 mg/day. Inclusion criteria
      were based on progressive actinic keratoses, recurrent skin malignancies or
      continuous lesions despite treatment with appropriate topical therapies. Patients
      were excluded if they were women of child-bearing age, had severe hepatic or
      renal impairment or were taking contraindicated medications. RESULTS: Over the
      treatment period all patients showed a reduction in the number of new non
      melanotic skin cancers excised and histologically confirmed. Three patients had a
      very large reduction and 2 patients had a more moderate reduction in the number
      of new presentations. All patients had an objective decrease in the number of
      actinic keratoses. All patients tolerated the drug well with only 1 patient
      transiently discontinuing the Acitretin due to side effects. No significant
      alterations in the biochemical tests or serum lipids were reported. CONCLUSIONS:
      Over the treatment period, low-dose acitretin proved a valuable addition in the
      long-term strategy of reduction and treatment of non-melanotic skin cancers in
      heart transplant recipients with multiple skin cancers and actinic keratoses.

PMID- 12431494
TI  - Non-immune acute graft injury after lung transplantation and the risk of
      subsequent bronchiolitis obliterans syndrome (BOS).
AB  - BACKGROUND: Primary graft dysfunction remains a major cause of early morbidity
      and mortality after lung transplantation. Evidence from animal models shows acute
      non-immune lung injury increases organ immunogenicity by enhancing MHC Class II
      expression. We hypothesized that acute non-immune injury in the lung allograft
      may impact, not only on early survival, but also on longer term survival by
      increasing the incidence of bronchiolitis obliterans syndrome (BOS). METHODS: A
      single-center, retrospective, observational study in a population of over 320
      lung transplant recipients was undertaken. The histologic diagnosis of diffuse
      alveolar damage (DAD) in an early graft biopsy was used to define those
      recipients at risk. Serial measurements of forced expiratory volume in 1 second
      (FEV(1)) in long-term follow-up defined the incidence of BOS. RESULTS: Early
      graft biopsy was available in 291 of the recipients following transplantation.
      DAD was confirmed in 55 (19%); their 30-day survival (62.5%) was significantly
      worse than in recipients without DAD (87.5%; p < 0.0001, chi-square test). When
      30-day deaths were excluded, however, there was no difference in survival between
      recipients with and without DAD (hazards ratio 0.69 [0.37 to 1.3]; p = 0.25,
      Wilcoxon's survival analysis). The incidence of subsequent BOS over the follow-up
      period was not significantly different in those with and without DAD on early
      biopsy at 46% and 59%, respectively (hazards ratio 0.88 [0.48 to 1.62]; p = 0.22,
      chi-square test). BOS did not occur any earlier in the DAD group (median 953
      days, range 152 to 1,393) days compared with the non-DAD group (median 665 days,
      range 52 to 4,299) (p = 0.48, Fisher's exact test). CONCLUSIONS: The development
      of severe non-immune acute graft injury after lung transplantation has a poor
      early prognosis. However, recipients with non-immune acute graft injury who
      survive >30 days show no significant difference in long-term survival or BOS-free
      time compared with recipients without early injury.

PMID- 12431495
TI  - Efficacy and safety of atorvastatin after pediatric heart transplantation.
AB  - BACKGROUND: Lipid abnormalities are prevalent after pediatric and adult heart
      transplantation. 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase
      inhibitors are efficacious and safe and can lower the incidence of graft coronary
      artery disease after heart transplantation in adults. Given the high prevalence
      of lipid abnormalities and the increased recognition of graft coronary disease in
      children, we retrospectively investigated the efficacy and safety of atorvastatin
      among pediatric heart transplant recipients. METHODS: Thirty-eight patients were
      started on atorvastatin 48.2 +/- 54.4 months after transplantation. Atorvastatin
      dosage was 0.2 +/- 0.1 mg/kg per day. No patient had changes in drug dose unless
      there was evidence for rhabdomyolysis, myositis or an asymptomatic rise in
      creatine kinase above normal. Laboratory studies included total cholesterol,
      triglycerides; high, low and very low-density lipoproteins (HDL, LDL and VLDL,
      respectively); creatine kinase; creatine; and serum alanine transaminase.
      RESULTS: Significant declines in total cholesterol (20%), triglyceride (18%) and
      LDL (26%) were observed after starting atorvastatin therapy. There were no
      significant changes in HDL or VLDL compared with baseline. There were also no
      differences in alanine transaminase pre- vs post-atorvastatin therapy.
      Complications included muscle pain (n = 2) and asymptomatic elevations in
      creatine kinase (n = 2). Two of these 4 patients developed rhabdomyolysis.
      Excluding these 4 patients, creatine kinase did not rise compared with baseline.
      No patient developed alterations in renal function. CONCLUSIONS: Use of
      atorvastatin in pediatric heart transplant recipients is effective in lowering
      total cholesterol, triglyceride and LDL without altering HDL levels.
      Complications included rhabdomyolysis, seen in 5%. Baseline and routine screening
      of creatine kinase should be employed in all pediatric patients undergoing HMG
      CoA reductase inhibitor therapy.

PMID- 12431496
TI  - HLA alloimmunization in patients requiring ventricular assist device support.
AB  - BACKGROUND: Ventricular assist devices (VADs) are often necessary to maintain
      circulation in patients with heart failure prior to cardiac transplantation.
      However, the use of such devices has been reported to be associated with a high
      incidence of development of human leukocyte antigen (HLA) antibodies, due
      perhaps, according to some investigators, to immune-activating properties of the
      VAD itself. We looked at HLA antibody formation in our patients during VAD
      support to determine the rate and potential causes of antibody formation.
      METHODS: Between 1995 and 2000, 54 patients were placed on a VAD at our
      institution. We reviewed clinical and blood transfusion history and HLA antibody
      testing of the 29 patients without HLA antibodies prior to implantation. HLA
      antibody testing was performed by an anti-globulin-augmented cytotoxicity method
      or by a commercial enzyme-linked immunoassay (ELISA) kit. RESULTS: Eight of 29
      patients (28%) developed HLA antibodies. Patients who developed HLA antibodies
      after VAD implantation received significantly more total peri- and post-operative
      transfusions than did those who remained negative (99 transfusions vs 34
      transfusions, p = 0.0014). Within this small study group, gender, age, etiology
      of heart failure, previous cardiac surgery and duration of VAD support showed no
      statistically significant correlation with formation of HLA antibodies.
      CONCLUSIONS: Our data suggest that HLA alloimmunization during VAD support may be
      due to extensive blood transfusion. The rate of HLA alloimmunization does not
      appear to be greater than that reported in other populations of multi-transfused
      patients. Leukoreduction of cellular components, as well as plasma, or other
      initiatives is needed to reduce the rate of alloimmunization and, potentially,
      the wait to transplantation.

PMID- 12431497
TI  - Mycoplasma hominis infection in heart and lung transplantation.
AB  - "Culture-negative" wound infection and mediastinitis secondary to Mycoplasma
      hominis have been reported after cardiothoracic surgery but no case cluster has
      ever been described. We report 4 cases of infection in 3 cardiac and 1 bilateral
      sequential lung transplant recipient over 3 weeks of hospitalization. Successful
      treatment was achieved with early aggressive surgical intervention and
      combination antibiotics of clindamycin, doxycycline and/or ciprofloxacin. This
      cluster raises the question of nosocomial transmission of infection and supports
      a recommendation for single-room isolation and universal precautions for infected
      individuals.

PMID- 12431498
TI  - Activity of disinfectants against Gram-negative bacilli isolated from patients
      undergoing lung transplantation for cystic fibrosis.
AB  - Lung transplant recipients with cystic fibrosis are frequently colonized with
      antibiotic-resistant bacteria. We evaluated the in vitro activity of 5
      disinfectants frequently used in cardiac surgery against strains of Burkholderia
      cepacia and Pseudomonas aeruginosa isolated from patients undergoing sequential
      single lung transplantation. Our results suggest that the activity of Taurolin
      and Noxyflex is superior to conventional disinfectants.

PMID- 12431499
TI  - Primary anti-phospholipid antibody syndrome caused by isolated anti
      phosphatidylethanolamine antibodies presenting as cryptogenic fibrosing
      alveolitis with recurrent pulmonary hemorrhage after single-lung transplantation.
AB  - A 28-year-old man underwent a single-lung transplantation for rapidly progressive
      usual interstitial pneumonitis. Following transplantation, primary anti
      phospholipid antibody syndrome was diagnosed after a thromboembolic event and
      continued dyspnea. Review of his native lung and allograft tissue showed diffuse
      hemorrhage secondary to capillary injury, probably reflecting anti-phospholipid
      antibody effects on endothelia.

PMID- 12431500
TI  - Allergic bronchopulmonary aspergillosis in a lung transplant patient successfully
      treated with nebulized amphotericin.
AB  - A case of allergic bronchopulmonary Aspergillosis (ABPA) complicating lung
      transplantation for cystic fibrosis is described. Control of ABPA was only
      achieved with 20 mg of prednisone and 600 mg of itraconazole per day. However, a
      prompt clinical and physiologic response was observed when nebulized amphotericin
      was introduced, which allowed prednisone to be reduced to 7.5 mg per day and, in
      time, all anti-fungal therapy to be withdrawn.

PMID- 12431501
TI  - Late Aspergillus fumigatus endomyocarditis with brain abscess as a lethal
      complication after heart transplantation.
AB  - We report the case of a 65-year-old male patient who died from lethal Aspergillus
      fumigatus endomyocarditis and multiple cerebral septic emboli 6 months after
      cardiac transplantation. This complication developed 4 weeks after diagnosis of
      bilateral pulmonary aspergillosis, which was immediately treated by surgical
      removal and intravenous amphotericin B. Preceding colonization with Aspergillus
      spp was not identified. Primary cytomegalovirus infection (donor+/recipient-) and
      toxoplasmosis reactivation (donor+/recipient+) occurring at 1 and 2 months post
      transplantation were successfully treated.

PMID- 12431502
TI  - Mechanical circulatory support for myocarditis: how much recovery should occur
      before device removal?
AB  - A 12-year-old girl with presumed myocarditis was supported with right and left
      ventricular assist devices for 68 days before device removal. During this time,
      the patient underwent echocardiography and right heart catheterization for
      evaluation of cardiac recovery. This case report serves as the basis for a
      discussion of criteria for deciding when to terminate mechanical circulatory
      support in a patient with recovery after acute myocarditis.

PMID- 12431503
TI  - Combined heart-single-lung transplantation: a unique operation for unique
      indications.
AB  - Combined heart-lung transplantation has been a proven therapeutic option for
      patients with end-stage cardiopulmonary disease since 1981. Occasional patients
      are not candidates to receive both lungs en bloc. We describe such a case and
      propose indications and a surgical technique and present the limited published
      experience of combined heart-single-lung transplantation.

PMID- 12431505
TI  - Education, a chance to modify organ shortage: a different message to society.

PMID- 12431506
TI  - Family refusal in organ donation: analysis of three patterns.

PMID- 12431507
TI  - Marginal cadaveric kidney donors: an attractive way to expand the donor pool.

PMID- 12431508
TI  - The molecular events underlying ischemia/reperfusion injury.

PMID- 12431509
TI  - Sirolimus and FTY720: new approaches to transplant immunosuppression.

PMID- 12431510
TI  - Mycophenolate mofetil treatment in conditions different from organ
      transplantation.

PMID- 12431511
TI  - Renal transplantation in Venezuela, 2001.

PMID- 12431512
TI  - Almost all patients who are waiting for a regraft of a kidney transplant have
      anti-HLA antibodies.

PMID- 12431513
TI  - Pediatric renal transplantation under tacrolimus or cyclosporine
      immunosuppression and basiliximab induction.

PMID- 12431514
TI  - Experience in a single transplant center with 421 living donors: follow-up of 9
      years.

PMID- 12431515
TI  - Lymphoproliferative disorders following kidney transplantation.

PMID- 12431516
TI  - Kidney transplantation in patients with ventricular ejection fraction less than
      50 percent: features and posttransplant outcome.

PMID- 12431517
TI  - Vesical augmentation and continent ureterostomy in kidney transplant patients.

PMID- 12431518
TI  - Noninvasive acute rejection diagnosis in kidney transplantation.

PMID- 12431520
TI  - Trilogy 2001 symposium: tackling the organ shortage problem.

PMID- 12431521
TI  - How to promote organ donation: a successful experience at the National Taiwan
      University Hospital.

PMID- 12431522
TI  - Donor shortage in organ transplantation: perspective from Hong Kong.

PMID- 12431523
TI  - Organ donation in Sweden.

PMID- 12431524
TI  - Increasing living donations: expanding the National MOTTEP community grassroots
      model. Minority Organ Tissue Transplant Education Program.

PMID- 12431525
TI  - Five-year results of living related renal donation are similar to cadaveric
      transplantation in black South Africans.

PMID- 12431526
TI  - Current strategies for the use of sub-optimal grafts in living donor liver
      transplantation.

PMID- 12431527
TI  - Methanol-intoxicated donors: an acceptable source of organs.

PMID- 12431528
TI  - Effects of exogenous adrenaline on the number of the beta-adrenergic receptors
      after brain death in humans.

PMID- 12431529
TI  - Brain-death diagnosis and organ procurement in misleading conditions.

PMID- 12431530
TI  - Gasless laparoscopy-assisted live donor nephrectomy.

PMID- 12431531
TI  - Kidney transplantation from hepatitis C virus positive donors.

PMID- 12431532
TI  - Early infant kidneys as marginal donor sources: histology and pathophysiology.

PMID- 12431533
TI  - Assessment of brain-dead cadaver donor for lung transplantation in Japan.

PMID- 12431534
TI  - The effect of donor age in graft coronary atherosclerosis after cardiac
      transplantation.

PMID- 12431535
TI  - Five years of experience with non-heart-beating donors coming from the streets.

PMID- 12431536
TI  - Kidney transplantation from non-heart-beating donors: short- and long-term
      results.

PMID- 12431537
TI  - Usefulness of continuous hypothermic perfusion preservation in renal
      transplantation from non-heart-beating donors.

PMID- 12431538
TI  - Long-term renal function after transplantation from non-heart-beating donor
      kidneys.

PMID- 12431539
TI  - Non-heart-beating donors under extracorporeal membrane oxygenation support.

PMID- 12431540
TI  - Total body cooling using cardiopulmonary bypass for procurement from non-heart
      beating donors.

PMID- 12431541
TI  - Cadaveric renal transplantation from non-heart-beating donors with graft survival
      for more than 10 years.

PMID- 12431542
TI  - New strategy for liver transplantation from non-heart-beating donors.

PMID- 12431543
TI  - Machine perfusion preservation for liver transplantation from non-heart-beating
      donors with agonal stage.

PMID- 12431544
TI  - Studies of multiorgan procurement system from non-heart-beating donors.

PMID- 12431545
TI  - Use of streptokinase in a non-heart-beating donor animal model.

PMID- 12431546
TI  - An experimental study of porcine pancreas allotransplantation from non-heart
      beating donors.

PMID- 12431547
TI  - Suppression of graft coronary arteriosclerosis by gene gun-mediated CTLA4-Ig gene
      transfer.

PMID- 12431548
TI  - Gene gun-mediated CTLA4Ig-gene transfer for modification of allogeneic cardiac
      grafts.

PMID- 12431549
TI  - Transfection and transgene expression in a human kidney during ex vivo warm
      perfusion.

PMID- 12431550
TI  - The potential of repairing organs ex vivo.

PMID- 12431551
TI  - Emotional conditions of donor families: a comparison of Japanese and American
      outcomes.

PMID- 12431552
TI  - Posttraumatic stress disorder in the families of cadaveric and living donor
      population: a comparison of Japanese and American outcomes.

PMID- 12431553
TI  - Psychiatric problems in living-related transplantation (III): pretransplant
      psychological assessment in living-related transplantation.

PMID- 12431554
TI  - Psychiatric problems in living-related transplantation (I): incidence rate of
      psychiatric disorders in living-related transplantation.

PMID- 12431555
TI  - Psychiatric problems in living-related transplantation (II): the association
      between paradoxical psychiatric syndrome and guilt feelings in adult recipients
      after living donor liver transplantation.

PMID- 12431556
TI  - New strategy for preventing ischemia/reperfusion-induced organ injury and
      promoting regeneration: a novel trial for improving transplant organ function by
      targeted regulation of cellular signals.

PMID- 12431557
TI  - Overexpression of redox factor-1 protects against postischemic liver injury by
      reducing oxidative stress and NF-kappa B activity.

PMID- 12431558
TI  - Beneficial effects of a Rho-associated coiled-coli forming protein
      serine/threonine kinase inhibitor, Y-27632, on survival of recipients in rat
      liver transplantation following warm ischemia.

PMID- 12431559
TI  - Potential role of mitochondrial permeability transition pore following long-time
      hypothermic heart preservation.

PMID- 12431560
TI  - Overexpression of the heat shock protein 70 confers protection against oxidative
      injury in HEPG2 cells.

PMID- 12431561
TI  - Effect of melatonin on the antioxidant enzymes in the kidneys of cyclosporine
      treated rats.

PMID- 12431562
TI  - Effect of melatonin on antioxidant status in the plasma of cyclosporine-treated
      rats.

PMID- 12431563
TI  - Production of oxygen free radicals and of hemolysis by cyclosporine.

PMID- 12431564
TI  - Reperfusion injury after warm ischemia or cold storage of the liver: role of
      apoptotic cell death.

PMID- 12431565
TI  - Mechanism of hepatic ischemia/reperfusion injury and protection against
      reperfusion injury.

PMID- 12431566
TI  - Effect of lazaroids on NF-kappa B activation of Kupffer cells in liver
      preservation.

PMID- 12431567
TI  - Effect of ethanolamine on liver regeneration after 90% hepatectomy in rats.

PMID- 12431568
TI  - Renal warm ischaemic injury in the rat is potentiated by cyclosporine.

PMID- 12431569
TI  - Mechanisms of preservation and ischemic/reperfusion injury in liver
      transplantation.

PMID- 12431570
TI  - Cytoprotective effect of hepatic cell pretreatment with 15-deoxyspergualin to
      prevent warm ischemic reperfusion injuries in rats.

PMID- 12431571
TI  - Beneficial effects of pentoxifylline and propentofylline on the warm ischemic
      injury of rat livers.

PMID- 12431572
TI  - Protective effect of magnolol on the small intestinal ischemia-reperfusion
      injury.

PMID- 12431573
TI  - The challenges of the use of human biomaterials for research purpose in Japan.

PMID- 12431574
TI  - Establishment of public human tissue resource bank for research purposes with
      surgically removed tonsil tissue: potential scientific value and ethical problem.

PMID- 12431575
TI  - Outcomes in clinical pancreas transplantation with the two-layer cold storage
      method versus simple storage in University of Wisconsin solution.

PMID- 12431576
TI  - Effects of vascular endothelial growth factor on islet isografts.

PMID- 12431577
TI  - In vitro and in vivo studies on the cryopreserved pancreatic islets.

PMID- 12431578
TI  - Effect of gliclazide on islet transplants.

PMID- 12431579
TI  - Effects of multiple site implantation on islet transplantation.

PMID- 12431580
TI  - Effect of pefabloc on islet isolation from cold preserved rat pancreas.

PMID- 12431581
TI  - Hepatic stem cells.

PMID- 12431582
TI  - Experimental study of plasma recycling system by off-line bioartificial liver in
      rats.

PMID- 12431583
TI  - Off-line bioartificial liver: a novel concept of treatment and its potency of
      liver regeneration.

PMID- 12431584
TI  - Porcine liver transplantation as an estimation system for bridge-use of
      bioartificial liver.

PMID- 12431585
TI  - Comparison of cell labeling procedures for bone marrow cell transplantation to
      treat heart failure: long-term quantitative analysis.

PMID- 12431586
TI  - Microchimerism following vascularized bone allotransplantation.

PMID- 12431587
TI  - Designer dendritic cells for transplant tolerance.

PMID- 12431588
TI  - Identification of alterations in gene expression in rat recipients with long-term
      surviving cardiac grafts.

PMID- 12431589
TI  - Improvement of heart allograft acceptability by pretreatment of donors with
      granulocyte colony-stimulating factor.

PMID- 12431591
TI  - Role of xenoreactive natural antibodies in pig-to-human lung xenotransplantation.

PMID- 12431590
TI  - Identification of novel genes associated with immunosuppression in renal
      transplant patients.

PMID- 12431592
TI  - Prolongation of xenograft survival by combining donor-specific intravenous
      presensitization with FK 506.

PMID- 12431593
TI  - Organ perfusion combined with platelet aggregation inhibitor reduce IgM
      deposition and hyperacute xenorejection in a guinea pig-to-rat lung
      transplantation model.

PMID- 12431594
TI  - The effects of cryopreserved aortic xenografts on secondary cardiac xenografts.

PMID- 12431595
TI  - Removal of alpha-galactosyl antigens from vascular endothelial cells in pig
      organs by intravenous infusion of endo-beta-galactosidase.

PMID- 12431596
TI  - Inhibitory effect of gene transfer with endo-beta-galactosidase C on alpha
      galactosyl xenoantigen expression.

PMID- 12431597
TI  - Depletion of natural anti-pig antibodies by the continuous infusion of
      oligosaccharides in a pig-to-baboon model.

PMID- 12431598
TI  - The role of mouse stroma in rat haematopoiesis in xenogeneic rat/mouse bone
      marrow transplantation chimeras.

PMID- 12431599
TI  - Felix Rapaport memorial lecture: moving toward a perfect transplant for pediatric
      kidney recipients.

PMID- 12431600
TI  - Psychiatric problems among recipients of kidney transplants: a 10-year follow-up.

PMID- 12431601
TI  - Maladjustment behaviors in pediatric living-related transplantation.

PMID- 12431602
TI  - Noncompliance as a cause of renal graft loss.

PMID- 12431603
TI  - Beneficial effect of antibody removal and enhanced immuno suppression in flow
      cytometry cross match-positive and ABO-incompatible renal transplantation.

PMID- 12431604
TI  - Short-term results in ABO-incompatible living related kidney transplantation.

PMID- 12431605
TI  - Morphological examinations of donor's bladder wall and the ureter in kidney
      transplantation.

PMID- 12431606
TI  - Are women privileged organ recipients?

PMID- 12431607
TI  - Drug interaction of tacrolimus and proton pump inhibitors in renal transplant
      recipients with CYP2C19 gene mutation.

PMID- 12431608
TI  - Hemolytic-uremic syndrome after kidney transplantation.

PMID- 12431610
TI  - Effect of reduction of portal vein pressure on the outcome of extreme small size
      liver transplants.

PMID- 12431609
TI  - Novel method using near-infrared spectroscopy to assess intrahepatic anastomosis
      between hepatic veins of right lobe graft in living-donor liver transplantation.

PMID- 12431611
TI  - Absorption of cyclosporine (Neoral) from a microemulsion formulation in a living
      donor liver transplant recipient.

PMID- 12431612
TI  - Anticoagulant therapy in living-related liver transplantation.

PMID- 12431613
TI  - Reversal of hypoxemia by inhaled nitric oxide in a child with hepatopulmonary
      syndrome after living-related liver transplantation.

PMID- 12431614
TI  - Prolonged hyperbilirubinemia after living-related liver transplantation: a
      pediatric case report.

PMID- 12431615
TI  - Treatment of low portal flow in a living related liver transplant recipient by
      ligation of the splenic vein.

PMID- 12431616
TI  - Liver transplantation in Seoul National University Hospital.

PMID- 12431617
TI  - The context framing the changes in health-related quality of life and working
      competence before and after lung transplantation: one-year follow-up in Taiwan.

PMID- 12431618
TI  - Minor ABO-incompatible living-related lung transplantation.

PMID- 12431619
TI  - Apoptosis and expression of heme oxygenase-1 in heart transplant recipients
      during acute rejection episode.

PMID- 12431620
TI  - Chronic renal failure after cardiac transplantation: predictive factors and
      influence on mortality-results of a monocenter study in 141 patients.

PMID- 12431621
TI  - Serology and DNA based generic typing for HLA-A;B;DR antigens of cadaver organ
      donors are concordant in 98% of cases in a retrospective study.

PMID- 12431622
TI  - Influence of the type of renal replacement therapy on peritonitis rate after
      simultaneous pancreas kidney transplantation.

PMID- 12431623
TI  - Arterial hypertension in renal transplant recipients treated with tacrolimus or
      cyclosporine-Neoral.

PMID- 12431624
TI  - Lowering immunosuppression is safe and effective to treat altered pattern of CMV
      infection in renal transplant recipients on valaciclovir prophylaxis.

PMID- 12431625
TI  - C2 therapeutic drug monitoring of cyclosporine: sources of variability.

PMID- 12431626
TI  - An orthotopic aortic graft mouse model to study the immunopathology of chronic
      vascular rejection.

PMID- 12431627
TI  - Use of mature dendritic cells for anti-human papillomavirus peptide-based
      vaccination in transplant patients.

PMID- 12431628
TI  - An immunoregulatory role for natural killer cells in transplanted patients.

PMID- 12431629
TI  - Value of lipid peroxidation by-products detected during the renal procurement on
      renal graft function.

PMID- 12431630
TI  - Expression of cyclooxygenase 2 and prostaglandin E synthase after renal ischemia
      reperfusion.

PMID- 12431632
TI  - Acquisition of MHC:peptide complexes by mouse CD4+ T cells may play a role in T
      cell-mediated immunoregulation.

PMID- 12431633
TI  - Dendritic cells prohibited by anergic T cells acquire tolerogenic properties.

PMID- 12431634
TI  - Establishing the optimal method to estimate the frequencies of alloreactive CD4+
      T cells.

PMID- 12431635
TI  - Human CD4+ CD25+ T cells regulate CD8+ T-cell activation.

PMID- 12431636
TI  - Mechanisms of action of mycophenolate mofetil in preventing chronic rejection.

PMID- 12431637
TI  - Fibrogenesis in chronic allograft rejection: underlying mechanisms and
      pharmacological control.

PMID- 12431638
TI  - Effect of rapamycin and prednisolone in differentiated THP-1 and U937 cells.

PMID- 12431639
TI  - Simvastatin effect on NK cells activity in vivo: a double-blind randomized,
      placebo-controlled study.

PMID- 12431640
TI  - Assessment of immunosuppression by lymphocyte functions in human blood.

PMID- 12431641
TI  - Pharmacodynamics of sirolimus and cyclosporine combination therapy.

PMID- 12431642
TI  - Killer T cells: a promising new tool for adoptive immunotherapy.

PMID- 12431643
TI  - Sirolimus attenuates the expression of metalloproteinase-2 and -9 and inhibits
      intimal hyperplasia following balloon angioplasty.

PMID- 12431644
TI  - The change of immunosuppressive effect of X-irradiation after transplant period
      for aortic transplantation in rat.

PMID- 12431645
TI  - The origin of cynomolgus monkey affects the outcome of kidney allografts under
      Neoral immunosuppression.

PMID- 12431646
TI  - Peritransplant donor-specific transfusion combined with anti-CD4 and cyclosporine
      induction therapy prolongs foetal rat pancreas allograft survival.

PMID- 12431647
TI  - Effects of mycophenolate sodium with or without FTY720 in a DA-to-Lewis rat heart
      transplantation model.

PMID- 12431648
TI  - Adoptive transfer of regulatory T cells following chronic allograft rejection
      induces tolerance for secondary allografts.

PMID- 12431649
TI  - Initial organ engraftment with a short-term low-dose CyA treatment induces
      tolerance for consecutive grafts in a model of strong histoincompatibility.

PMID- 12431650
TI  - Donor treatment prolongs survival of rat cardiac allografts in sensitized rat
      recipients.

PMID- 12431651
TI  - TGF-beta 1 gene expression in stable renal transplant recipients: influence of
      TGF-beta 1 gene polymorphism and immunosuppression.

PMID- 12431652
TI  - Role of codon 10 and codon 25 polymorphisms on TGF-beta 1 gene expression and
      protein synthesis in stable renal allograft recipients.

PMID- 12431653
TI  - Preventing acute rejection with basiliximab and triple immunosuppression after
      renal transplantation.

PMID- 12431654
TI  - Side effects of protein A immunoadsorption and plasma exchange in renal allograft
      recipients.

PMID- 12431655
TI  - IL-2 antibody induction and the outcome of pediatric renal transplants.

PMID- 12431656
TI  - Bolus anti-thymocyte globulin induction in renal transplant recipients: a
      comparison with conventional ATG or anti-interleukin-2 receptor antibody
      induction.

PMID- 12431657
TI  - Cyclosporine from twice to single daily dosing: impact on renal function,
      mortality, and graft loss.

PMID- 12431658
TI  - Mycophenolate mofetil for the prophylaxis of acute graft-versus-host disease in
      stem cell transplant recipients.

PMID- 12431659
TI  - Autologous stem cell transplantation for refractory juvenile idiopathic
      artrhitis: current results and perspectives.

PMID- 12431660
TI  - Donor T lymphocyte infusion following ex vivo depletion of donor anti-host
      reactivity by a specific anti-interleukin-2 receptor P55 chain immunotoxin.

PMID- 12431661
TI  - Maintenance treatment of primary plasma cell leukemia with interferon alpha.

PMID- 12431662
TI  - Immunosuppressive treatment of severe acute graft-versus-host disease after
      allogeneic hematopoietic stem cell transplantation.

PMID- 12431663
TI  - Significance of mycophenolate mofetil treatment in patients with HCV reinfection
      after liver transplantation: impact on clinical course and histologic damage.

PMID- 12431664
TI  - Mycophenolate mofetil reduces calcineurin inhibitor-induced side effects after
      liver transplantation.

PMID- 12431665
TI  - Mycophenolate mofetil for treatment of ongoing or chronic rejections after liver
      transplantation.

PMID- 12431666
TI  - Impact of HLA compatibilities after liver transplantation.

PMID- 12431667
TI  - Anti-CD25 therapy impairs donor-specific Th1 and Th2 cytokine-producing
      peripheral blood cells after clinical heart transplantation.

PMID- 12431669
TI  - Systemic lupus erythematosus and microchimerism in autoimmunity.

PMID- 12431668
TI  - Tailored immunosuppression: the way we should follow?

PMID- 12431670
TI  - Splenectomy: the last option of immunosuppressive therapy in patients with
      chronic or relapsing idiopathic thrombotic thrombocytopenic purpura?

PMID- 12431671
TI  - Inhibition of autoimmune diabetes by mycophenolate mofetil is associated with
      down-regulation of TH1 cytokine-induced apoptosis in the target tissue.

PMID- 12431672
TI  - In vitro effects of ginkgolide B combined with cyclosporin A on T-lymphocyte
      activation and IL-5 expression in peripheral blood mononuclear cells from
      asthmatic subjects.

PMID- 12431673
TI  - The immunosuppressant LF 15-0195 prevents experimental autoimmune myasthenia
      gravis in Brown-Norway rats.

PMID- 12431674
TI  - Beneficial effect of the immunosuppressant LF 15-0195 on passively induced rat
      experimental autoimmune encephalomyelitis.

PMID- 12431676
TI  - Pretreatment with indomethacin protects from acute renal failure following
      ischemia-reperfusion injury.

PMID- 12431675
TI  - TNF-alpha-mediated cell death is attenuated by retrovirus delivery of human heme
      oxygenase-1 gene into human microvessel endothelial cells.

PMID- 12431677
TI  - High mycophenolic acid area under-the-curve values in renal transplant recipients
      on long-term mycophenolate mofetil treatment.

PMID- 12431678
TI  - The efficacy of mycophenolate mofetil treatment in the prevention of acute renal
      rejection is related to plasma level of mycophenolic acid.

PMID- 12431679
TI  - Evaluation of the new EMIT enzyme immunoassay for the determination of whole
      blood tacrolimus concentrations in kidney, heart, and liver transplant
      recipients.

PMID- 12431680
TI  - Rituximab and rapamycin for posttransplant lymphoproliferative disease treatment:
      report of three cases.

PMID- 12431681
TI  - Effect of calcineurin inhibitors on QT dispersion in renal transplant recipients.

PMID- 12431682
TI  - Severe fungal infections in kidney graft recipients.

PMID- 12431683
TI  - Infectious complications of immunosuppressive treatment for anti-neutrophil
      cytoplasm antibody-related vasculitis.

PMID- 12431684
TI  - Posttransplant diabetes mellitus: a serious complication of immunosuppression in
      renal allograft recipients.

PMID- 12431685
TI  - Outcome and prognosis of cyclosporine-related hemolytic-uremic syndrome in kidney
      graft recipients: clinical and histopathologic study of 13 cases.

PMID- 12431686
TI  - Ureteric stenosis after renal transplantation: no effect of acute rejection or
      immunosuppression.

PMID- 12431687
TI  - Cosmetic side effects of immunosuppressive therapy in children and adolescents
      with renal grafts.

PMID- 12431692
TI  - Non-cancerous ophthalmic clues to non-ocular cancer.
AB  - This survey reviews selected medical disorders in which the ophthalmologist has a
      unique opportunity of anticipating the existence of asymptomatic, life
      threatening disease simply by recognizing that certain benign conditions
      involving the eye or adnexa represent clues to occult non-ocular cancer and other
      neoplasias. Having knowledge that these clues are associated with specific types
      of neoplasia, the ophthalmologist can then initiate a goal-directed oncologic
      investigation designed to identify the underlying neoplasm with the hope of
      providing potentially life-saving therapy. The survey is organized to feature
      each clue separately. The clinical characteristics of the clue are described and
      illustrated with color photographs when possible. A discussion reviews associated
      malignancies and other important medical features. The survey begins with clues
      expressed anteriorly in the lids, progressively reviewing those clues located
      more posteriorly, concluding with clues involving the retinal pigment epithelium
      and choroid.

PMID- 12431693
TI  - Central serous chorioretinopathy and glucocorticoids.
AB  - Central serous chorioretinopathy is a relatively common retinal disease
      characterized by the accumulation of subretinal fluid at the posterior pole of
      the fundus, creating a circumscribed area of serous retinal detachment. It
      typically affects young and middle-aged men with no previous medical and family
      history, and no systemic symptoms or signs. However, it has been noted that
      central serous chorioretinopathy is associated with different conditions,
      characterized by exposure to increased levels of endogenous or exogenous
      glucocorticoids. In fact, central serous chorioretinopathy has been described in
      patients with endogenous Cushing's syndrome. It is also prevalent in patients
      with type-A behavior, and following stressful events, and pregnancy probably
      represents a risk factor for central serous chorioretinopathy; these conditions
      are characterized by endogenous hypercortisolism. In addition, many cases of
      central serous chorioretinopathy have been described during or following
      treatment with glucocorticoids, administrated by any route, for various systemic
      or ocular conditions. Central serous chorioretinopathy, when related to the
      exposure to exogenous glucocorticoids, has a less prominent male predilection,
      presents more often with a chronic or atypical form, and is frequently bilateral.
      Furthermore, treatment of central serous chorioretinopathy with glucocorticoids
      was found to exacerbate the clinical picture. Based on these observations it
      could be suggested that glucocorticoids may be involved in the development of
      central serous chorioretinopathy, even though the exact pathogenic mechanism
      remains unclear. Glucocorticoids should not be used in the treatment of central
      serous chorioretinopathy and central serous chorioretinopathy should be added to
      the list of ocular complications of glucocorticoids.

PMID- 12431694
TI  - Gene therapy for genetic and acquired retinal diseases.
AB  - We present an overview of the current status of basic science and translational
      research being applied to gene therapy for eye disease, focusing on diseases of
      the retina. We discuss the viral and nonviral methods being used to transfer
      genes to the retina and retinal pigment epithelium, and the advantages and
      disadvantages of each approach. We review the various genetic and somatic
      treatment strategies that are being used for genetically determined and acquired
      diseases of the retina, including gene replacement, gene silencing by ribozymes
      and antisense oligonucleotides, suicide gene therapy, antiapoptosis, and growth
      factor therapies. The rationales for the specific therapeutic approaches to each
      disease are discussed. Schematics of gene transfer methods and therapeutic
      approaches are presented together with a glossary of gene transfer terminology.

PMID- 12431695
TI  - Ocular adnexal lymphomas: five case presentations and a review of the literature.
AB  - The ocular adnexal lymphomas represent the malignant end of the spectrum of
      lymphoproliferative lesions that occur in these locations. The Revised European
      and American Lymphoma (REAL) Classification and the new World Health Organization
      Classification of Tumors of Hemopoietic and Lymphoid Tissues are the most
      suitable for subdividing the ocular adnexal lymphomas, whereby the extranodal
      marginal zone B-cell lymphoma represents the most common lymphoma subtype. This
      review is based on five cases subtyped according to the above classifications
      three "typical" lymphomas (an extranodal marginal zone B-cell lymphoma, a diffuse
      large cell B-cell lymphoma arising from an extranodal marginal zone B-cell
      lymphoma, and a follicular lymphoma) and two "atypical" lymphomas (a non-endemic
      Burkitt lymphoma in an immune competent elderly patient, and a primary Hodgkin
      lymphoma of the eyelid) of the ocular adnexa. Management of patients with ocular
      adnexal lymphomas includes a thorough systemic medical examination to establish
      the clinical stage of the disease. The majority of patients with ocular adnexal
      lymphoma have stage IE disease. Current recommended therapy in stage IE tumors is
      radiotherapy, while disseminated disease is treated with chemotherapy. Despite
      usually demonstrating an indolent course, extranodal marginal zone B-cell
      lymphomas are renowned for recurrence in extranodal sites, including other ocular
      adnexal sites. Long-term follow-up with 6-month examinations are therefore
      recommended. Major prognostic criteria for the ocular adnexal lymphomas include
      anatomic location of the tumor; stage of disease at first presentation; lymphoma
      subtype as determined using the REAL classification; immunohistochemical markers
      determining factors such as tumor growth rate; and the serum lactate
      dehydrogenase level.

PMID- 12431696
TI  - A sticky situation.
AB  - A 19-year-old woman presented with frontal headaches, papilledema, and binocular
      horizontal double vision due to a left VI nerve palsy. MRV demonstrated sagittal
      sinus and bilateral transverse sinus thrombosis. The clinical and neuro
      radiologic signs resolved after anticoagulation.

PMID- 12431697
TI  - The trachoma menace in the United States, 1897-1960.
AB  - Although largely considered a problem of developing countries today, trachoma was
      once extremely common in parts of the United States and accounted for a large
      proportion of blindness. Under an act signed by President Woodrow Wilson in June
      1913, a substantial part of the U.S. Public Health Service budget was earmarked
      to fight trachoma. Numerous trachoma surveys revealed the presence of a "trachoma
      belt" across the mid United States, and the prevalence of trachoma reached as
      high as 50-90% among school children on some Indian reservations. Crowding,
      poverty, and lack of clean water and hygiene were identified as risk factors for
      trachoma. Measures taken to combat trachoma included isolation schools for
      infected children, special government trachoma hospitals and field clinics,
      screening of immigrants to the U.S., improvements in hygiene and sanitation, and
      antibiotic therapy. The Indian Health Service utilized radical eyelid surgery
      with reportedly disastrous consequences. Prevalence surveys show a clear decline
      in trachoma in the U.S. during the twentieth century.

PMID- 12431701
TI  - Treatment of hypertensive retinopathy.

PMID- 12431703
TI  - A novel guinea pig model with cyclic flow reductions following thrombotic
      cerebral ischemia.
AB  - Cyclic flow reductions (CFRs), a phenomenon indicated with repeating rethrombosis
      following thrombolysis in clotted vessel has been observed in coronal, carotid
      and popliteal arteries in various species when they were occluded with vessel
      damage, suggesting the presence of CFRs in the acute phase of stroke in man.
      Although much effort has been directed toward rethrombosis or ischemia
      reperfusion injuries in acute strokes, a therapy for CFRs in strokes has not been
      established because of the lack of ideal animal models. We have established a
      novel guinea pig model with CFRs in the middle cerebral artery (MCA) using a
      photothrombotic technique, in which the MCA was spontaneously recanalized within
      20 min after the first occlusion with subsequent CFRs. We also investigated the
      effects of antiplatelet agents and the anticoagulant heparin using this model.
      All tested antiplatelet agents inhibited CFRs, whereas an anticoagulant did not.
      These results show that this model is unique with respect to its development of
      MCA cyclic flow reductions, and may be suitable for investigating mechanisms and
      therapeutic reagents of CFRs in the MCA.

PMID- 12431704
TI  - An in vitro model of neurotrauma in organotypic spinal cord cultures from adult
      mice.
AB  - Cellular degeneration after spinal cord injury (SCI) involves numerous pathways.
      It is essential to use appropriate experimental models in order to understand the
      complex processes, which evolve after the initial trauma. The purpose of this
      study was to develop and assess an in vitro model of neurotrauma using
      organotypic slice culture of adult mice spinal cord. This model will facilitate
      the investigation of primary and secondary mechanisms of cell death that occurs
      after SCI. We modified previously described methods for generating organotypic
      cultures of murine spinal cord. The viability of organotypic cultures was
      assessed by observing the outgrowth of neurites and by using a mitochondria
      dependent dye for live cells (tetrazolium dye; MTT). The morphological integrity
      of cultures was examined histologically by hematoxylin and eosin (H&E) staining
      for general morphology and with luxol fast blue (LFB) for myelin. Neuronal and
      glial (GFAP; CNPase) markers were used to identify neurons, astrocytes and
      oligodendroglia, respectively. Primary injury was achieved by using a weight drop
      (0.2 g) model of injury. Cell death after primary injury was attenuated by pre
      treatment with two known neuroprotective agents: the AMPA/KA blocker CNQX and
      methylprednisolone. The nuclear markers Propidium iodide and Sytox-green, as well
      as the TUNEL (in situ terminal deoxytransferase-mediated dUTP nick end labeling)
      technique, were used as a quantitative indicators of cell death at 24, 48 and 72
      h post-injury using a confocal microscope and image analysis software. This novel
      in vitro model of SCI is easy to reproduce, will facilitate the examination of
      post-trauma cell death mechanisms and the neuroprotective effects of
      pharmacological agents and aid in the study of transgenic murine models.

PMID- 12431705
TI  - Neonatal prefrontal cortex lesion using CO2 laser technique.
AB  - Prefrontal cortex (PFC) is a large area of the brain and its neonatal lesion with
      ibotenic or kainic acid is used to study the early abnormalities in
      neurodevelopment that lead to behavioral changes linked to schizophrenia.
      However, these exitotoxic drugs produce a large and asymmetric damage in the PFC.
      We produced the bilateral lesions of the dorsal part of the PFC of neonatal
      Sprague-Dawley rats (postnatal day 7, P7) at the anteroposterior +2.5 mm and
      mediolateral +/-0.4 coordinates by the new laser technique that employ the
      confined radiation of the CO(2) laser in the pulsed mode. The laser was used
      because its coherent radiation can be focused in a very small spot and as small
      as of several tens of micrometers in diameters. The CO(2) laser radiation is
      strongly absorbed by water that is present in any soft tissue. Thereafter, the
      configuration of the heated zone and, consequently, that of the lesion does not
      depend on the morphological non-homogeneity of particular structures. We obtained
      the symmetric, conical in shape and small-size bilateral lesions of the PFC. The
      size of the lesion depended on the beam spot-size and could be as small as
      several dozens of micrometers in diameter. Our data suggests that the laser
      technique will be used for the anatomical-functional studies of the PFC in the
      brain.

PMID- 12431706
TI  - Single cell RT-PCR analysis of tyrosine kinase receptor expression in adult rat
      retinal ganglion cells isolated by retinal sandwiching.
AB  - We describe a protocol for analysis of gene expression in single, acutely
      dissociated adult rat retinal ganglion cells using RT-PCR. Retrograde tracing of
      retinal ganglion cells from the superior colliculi was conducted using
      Fluorogold. Retinas were dissected and ganglion cells isolated using retinal
      layer separation (sandwiching). Single, fluorescently labelled retinal ganglion
      cells were aspirated using a micropipette and used for PCR. Two PCR protocols are
      described where single cell cDNA was analysed for TrkB and GAPDH or TrkB, TrkC,
      Ret, Met, ErbB2 and Beta-actin by multiplex-PCR. All five tyrosine kinase
      receptors were amplified from single retinal ganglion cells. The method will
      prove useful for the molecular characterization of adult retinal ganglion cells.

PMID- 12431707
TI  - Jugular vein catheterization for repeated blood sampling in the unrestrained
      conscious rat.
AB  - The ability to obtain repeated, low-stress blood samples from adult rats enables
      the design of complex experiments in which time course information or evaluation
      of repeated treatments is necessary. Furthermore, it reduces the number of
      animals necessary to acquire such information and, thus, facilitates compliance
      with the animal use 3Rs (reduction, refinement and replacement). To this end, a
      microsurgical technique to collect blood samples from the right atrium through a
      catheter (cannula) implanted into the right external jugular vein of adult rats
      is described. Rats tolerate this simple and efficient vascular access technique
      as evidenced by the absence of overt morbidity or abnormal behaviors. Blood is
      easily sampled while the rats reside in their home cages. Because the sample
      volume is replaced, repeated sampling is possible without compromising blood
      volume. Successful adoption of this procedure by other investigators will be
      aided by the photographic illustrations accompanying this detailed description of
      the procedure. Application of this technique to monitor temporal changes in
      plasma stress hormones during stressor paradigms as well as after behavioral and
      pharmacological challenges is discussed.

PMID- 12431708
TI  - Measurement of dorsal root ganglion P2X mRNA by SYBR Green fluorescence.
AB  - The P2X receptor is a receptor-gated cationic channel that responds to ATP. The
      quantification of P2X mRNA expression in dorsal root ganglion (DRG) provides
      important information for neuropathic pain studies. We developed a rapid and
      sensitive external-standard-based real-time quantitative PCR assay for the
      quantification of mRNA of P2X receptors in mouse tissue samples. The assay uses a
      double-stranded DNA fluorescent dye, SYBR Green I, to continuously monitor
      product formation with a GeneAmp 5700 Sequence Detection System (PE Applied
      Biosystems). To establish the quantitative PCR amplification in a wide range of
      target transcripts, optimum parameters of primer sequences, concentrations of
      primers and/or templates, and PCR thermal protocols were experimentally
      determined. We also tested the reliability of this method in established
      experimental murine models, which were made by ligation or cutting down of the
      sciatic nerve. The parameters defined in this assay should be applicable to the
      quantification of other types of pain models and other tissue samples of mouse.

PMID- 12431709
TI  - Microdialysis in trigeminal ganglia.
AB  - Recent evidence demonstrates that neurons in sensory ganglia contribute to
      sensory signaling in both physiological and pathological states. In vivo sampling
      from this site may provide important insights into which substances mediate or
      modulate sensory transmission. To address this possibility, we have applied the
      microdialysis technique to the guinea pig trigeminal ganglia (TG). The large size
      and easy access of the TG in the guinea pig make it an ideal sampling site, while
      the somatotopic organization allows for specific regions of innervation to be
      studied at the ganglionic level. This report describes the use of microdialysis
      probes within the TG and use recovery and analysis of substance P (SP) and
      adenosine triphosphate (ATP) as case in points. Various physiological and
      pharmacological manipulations can be made, for example release of peptides from
      ganglionic neurons can be monitored in the presence or absence of inflammation in
      the orofacial region. Microdialysis performed in the TG thus provides a valuable
      site for recovery and measurement of a variety of extracellular substances that
      may be integral in the processing of trigeminal sensory information.

PMID- 12431710
TI  - A method for characterising cell death in vitro by combining propidium iodide
      staining with immunohistochemistry.
AB  - The fluorescent exclusion dye propidium iodide (PI) is widely used as a vital dye
      in tissue culture systems and labels the nucleus in dying cells which lack an
      intact plasma membrane. We have developed a method, which allows the preservation
      of the PI signal in paraformaldehyde-fixed tissue, enabling subsequent
      immunohistochemical characterisation of labelled cells. We have tested this
      method in a model of ischemia based on oxygen and glucose deprivation in
      organotypic hippocampal slice cultures, in combination with immunocytochemical
      detection of calpain-I mediated spectrin breakdown products (BDPs). Using
      confocal laser microscopy it was possible to correlate at the single cell level
      which cells were PI positive and which cells expressed BDPs. This method can also
      be used with other immunocytochemical markers to determine the phenotype of
      cells, which accumulate PI in vitro. By fixing tissue at different times after
      insults, it is possible to obtain a 'snapshot' of viability at any time during
      the experimental protocol and subsequently characterise those cells which had
      accumulated PI at the time of fixation. The technique may also prove useful in
      characterising cell death in other in vitro and in vivo systems.

PMID- 12431711
TI  - Mapping of the human visual cortex using image-guided transcranial magnetic
      stimulation.
AB  - We describe a protocol using transcranial magnetic stimulation (TMS) to
      systematically map the visual sensations induced by focal and non-invasive
      stimulation of the human occipital cortex. TMS is applied with a figure of eight
      coil to 28 positions arranged in a 2x2-cm grid over the occipital area. A
      digitizing tablet connected to a PC computer running customized software, and
      audio and video recording are used for detailed and accurate data collection and
      analysis of evoked phosphenes. A frameless image-guided neuronavigational device
      is used to describe the position of the actual sites of the stimulation coils
      relative to the cortical surface. Our results show that TMS is able to elicit
      phosphenes in almost all sighted subjects and in a proportion of blind subjects.
      Evoked phosphenes are topographically organized. Despite minor inter-individual
      variations, the mapping results are reproducible and show good congruence among
      different subjects. This procedure has potential to improve our understanding of
      physiologic organization and plastic changes in the human visual system and to
      establish the degree of remaining functional visual cortex in blind subjects.
      Such a non-invasive method is critical for selection of suitable subjects for a
      cortical visual prosthesis.

PMID- 12431712
TI  - Nutrition in specific surgical diseases.

PMID- 12431713
TI  - Global benefits of nutrition intervention of the sick patient over the life
      cycle.

PMID- 12431714
TI  - Nutrition support during acute pancreatitis.
AB  - Studies have shown that protein catabolism increases by 80% and energy
      expenditure by 20% in acute pancreatitis, indicating that nutritional
      requirements are elevated. Other studies have associated the resolution of
      negative nitrogen balance by nutrition support with improved outcome.
      Consequently, the need for effective nutrition is one cornerstone of management
      of acute pancreatitis. Concerns that feeding may exacerbate the disease process
      by stimulating the synthesis of proteolytic enzymes in the acinar cell and
      perpetuating autolysis has led to the widespread use of total parenteral
      nutrition (TPN) and bowel rest. Unfortunately, the use of TPN in clinical
      practice has been associated with major metabolic and infective complications,
      possibly because 1). patients with acute pancreatitis are intolerant of glucose
      due to coexistent pancreatic endocrine dysfunction and 2). the disease causes
      immune suppression. This has led to the search for alternatives. Based on
      physiologic studies, infusion of nutrients into the distal jejunum bypasses the
      stimulatory effect of feeding on pancreatic secretion. Many controlled trials
      have compared TPN with jejunal feeding. No study has shown that jejunal feeding
      exacerbates the disease. Further, jejunal feeding is associated with fewer
      infectious and metabolic complications. These observations and the fact that
      enteral feeding is one-tenth the cost of TPN has resulted in the general
      acceptance of jejunal feeding as the preferred mode for maintaining nutrition in
      patients with acute pancreatitis.

PMID- 12431715
TI  - Early oral feeding after elective abdominal surgery--what are the issues?
AB  - This review analyzes the literature and the historical concerns (restrictions,
      traditions, nasogastric tube) and pathophysiologic factors (postoperative ileus,
      risk of anastomotic dehiscence, nausea and vomiting, loss of appetite) invoked
      for not instituting early oral feeding after major abdominal procedures. It
      appears that several factors may promote postoperative oral feeding such as
      thoracic epidural analgesia, multimodal anti-emetic treatment, opioid-sparing
      analgesia, selective peripheral opioid antagonists, and enforced oral nutrition.
      Recent data from multimodal fast-track rehabilitation surgical programs in
      abdominal surgery provide a rational basis for future studies to investigate and
      facilitate enforced oral feeding after major abdominal procedures.

PMID- 12431716
TI  - Impact of the inflammatory reaction on intermediary metabolism and nutrition
      status.

PMID- 12431717
TI  - Rationale and indications for preoperative feeding of malnourished surgical
      cancer patients.

PMID- 12431718
TI  - Nutrition support of the trauma patient.
AB  - Hypercatabolism after trauma may lead to acute protein malnutrition, ultimately
      resulting in multiple organ failure. Nutrition support may prevent this sequence.
      This review addresses the need for early nutrition support, the preferred route
      of substrate delivery, and the potential advantages of "immune-enhancing" diets.

PMID- 12431719
TI  - Nutrition support of infants with short bowel syndrome.

PMID- 12431720
TI  - Catabolic response to stress and potential benefits of nutrition support.
AB  - The catabolic response to sepsis, severe injury, and burn is characterized by
      whole-body protein loss, mainly reflecting increased breakdown of muscle
      proteins, in particular myofibrillar proteins. Glucocorticoids and various
      proinflammatory cytokines are important regulators of muscle proteolysis in
      stressed patients. There is evidence that breakdown of proteins by the ubiquitin
      proteasome pathway plays an important role in muscle cachexia, although other
      mechanisms may participate, such as calcium- and calpain-dependent release of
      myofilaments from the sarcomere. Three types of treatments have been used to
      reduce or prevent the catabolic response to injury and sepsis: 1). nutritional,
      2). hormonal, and 3). pharmacologic. With regard to nutrition support, it is
      generally believed that enteral feeding is superior to parenteral feeding and
      that early feeding is better than late feeding. Although "immune-enhancing"
      enteral nutrition has been shown in several recent studies to improve outcome in
      critically ill patients, the specific effects of these treatments on the
      catabolic response in muscle are not known. In addition to nutrition support,
      various hormones, including insulin, growth hormone, and insulin-like growth
      factor-1, may blunt the catabolic response in patients with stress. Experimental
      studies have indicated that other treatments may become available in the future,
      including cytokine antibodies, calcium antagonists, and induction of heat shock
      response. Methods to prevent or reduce the catabolic response to stress are
      important considering the significant clinical consequences of muscle cachexia.

PMID- 12431721
TI  - Malnutrition is a risk factor in cirrhotic patients undergoing surgery.
AB  - Cirrhotic patients may become candidates for elective and emergency surgery. This
      may be due to conditions requiring operations such as cholecystectomy,
      herniotomy, or gastrointestinal malignancies, more common in cirrhotics when
      compared with the general population, or to complications of the liver disease
      such as resectable hepatocellular carcinomas or surgical portosystemic shunts to
      treat portal hypertension. It has been estimated that 10% of cirrhotics undergo
      at least one operative procedure during the final 2 y of their lives. Many
      studies have documented a high risk of morbidity and mortality associated with
      surgical procedures in these patients, and several factors influencing the
      postoperative outcome have been identified. Malnutrition, which is frequently
      encountered in cirrhotic patients, has been shown to have an important impact on
      the surgical risk. A poor nutrition status also has been associated with a higher
      risk of complications and mortality in patients undergoing liver transplantation.
      Few data are available concerning the perioperative nutrition support in surgical
      cirrhotic patients. The results of these studies are sometimes encouraging in
      reporting that the nutrition therapy may improve the clinical outcome in
      cirrhotic patients undergoing general surgery and/or liver transplantation. The
      limited number of patients and their heterogeneity, however, do not allow
      definitive conclusions, and more research on this issue is needed.

PMID- 12431722
TI  - Anorexia and malnutrition in patients with obstructive jaundice.

PMID- 12431723
TI  - Intestinal failure in complex gastrointestinal fistulae.

PMID- 12431725
TI  - Characterization of an additional molt inhibiting hormone-like neuropeptide from
      the shrimp Metapenaeus ensis.
AB  - We have identified a second form of the type-II neuropeptide encoding a molt
      inhibiting hormone-like (MeeMIH-B) neuropeptide. MeeMIH-B showed only a 70% amino
      acid identity to the MIH-A (formerly MIH) isolated from the same species,
      suggesting a possible different function of the deduced neuropeptide. Like other
      neuropeptide members of the CHH family, the MIH-B gene consists of three exons
      separated by two introns. The levels of MIH-B mRNA transcript in the eyestalk
      decrease in the initial phase of gonad maturation and increase towards the end of
      maturation. The drop in MIH-B level suggests an inhibitory role for this
      neuropeptide in the initiation of vitellogenesis. MIH-B transcripts can also be
      detected in the brain, thoracic ganglion and ventral nerve cord. Together with
      the CHH-B peptide that we have previously described, this is the second peptide
      of the CHH family that can also be identified in the ventral nerve cord and in
      the XOSG complex. A recombinant MIH-B was produced and a polyclonal antibody
      against rMIH-B was subsequently generated. Specific anti-rMIH-B antiserum
      recognized the presence of MIH-B in the sinus gland, X-organs, as well as a giant
      neuron of the ventral nerve cord. Injection of rMIH-B delayed the molting cycle
      of the maturing female. Taken together, the results of this study suggest that a
      drop in MIH-B level may be required for the delay in the molting of the maturing
      females.

PMID- 12431726
TI  - Occurrence of insect kinins in the flesh fly, stable fly and horn fly-mass
      spectrometric identification from single nerves and diuretic activity.
AB  - MALDI-TOF mass spectrometric analysis of single lateral abdominal nerves (LANs)
      demonstrate the presence of the insect kinin Musdo-K in the housefly Musca
      domestica, and identify heretofore unknown insect kinins in two other Dipteran
      species as Musdo-K in the stable fly Stomoxys calcitrans and horn fly Haematobia
      irritans. The insect kinin native to the flesh fly Neobellieria bullata is
      identified as Drome-K. Musdo-K and Drome-K are identical save for the
      conservative substitution of Ser for Thr in position 2. The sequences of the
      insect kinins are, therefore, remarkably conserved throughout Dipterans. The in
      vitro Malpighian tubule fluid secretion activity of Musdo-K in the stable fly is
      similar to that in the housefly, whereas that of Drome-K is 30-fold more potent
      in the flesh fly than in the fruit fly. Given the structural identities of the
      kinins and CRF-like diuretic hormones of these Dipteran species, the housefly can
      serve as a model insect for the study of diuretic peptides and their functions in
      the stable fly and horn fly, both livestock pests.

PMID- 12431727
TI  - Four novel PYFs: members of NPY/PP peptide superfamily from the eyestalk of the
      giant tiger prawn Penaeus monodon.
AB  - An immunocytochemical method was used for localization of pancreatic polypeptide
      (PP) immunoreactive substances in the eyestalk of Penaeus monodon using anti-C
      terminal hexapeptide of PP (anti-PP6) antiserum. Approximately 200 neuronal cell
      bodies were recognized in the ganglia between the medulla interna (MI) and
      medulla terminalis (MT) and surrounding MT in conjunction with the neuronal
      processes in medulla externa (ME), MI, MT and sinus gland. About half of the PP
      immunoreactive neurons were also recognized by a combination of three monoclonal
      antibodies raised against FMRFamide-like peptides. Isolation of the PP
      immunoreactive substances from the eyestalk was performed using 7500 eyestalks
      extracted in methanol/acetic acid/water (90/1/9) followed by five to six steps of
      RP-HPLC separation. Dot-ELISA with anti-PP6 antiserum was used to monitor PP-like
      substances in various fractions during the purification processes. Four new
      sequences of one hexapeptide; RARPRFamide, and three nonapeptides;
      YSQVSRPRFamide, YAIAGRPRFamide and YSLRARPRFamide were identified, and named as
      Pem-PYF1-4 due to their structural similarity to the PYF found in squid Loligo
      vulgaris. Each of the new peptides shares four to seven common residues with the
      C-terminus of the squid PYF and with the NPFs found in other invertebrates. The
      NPY/PP superfamily as well as the FMRFamide peptide family may be present
      throughout vertebrates and invertebrates.

PMID- 12431728
TI  - Search for peptidic molecular markers in hemolymph of crowd-(gregarious) and
      isolated-reared (solitary) desert locusts, Schistocerca gregaria.
AB  - An HPLC analysis of hemolymph extracts was undertaken to uncover differences
      between desert locusts, Schistocerca gregaria, reared under either crowded or
      isolated conditions. Some differences in the chromatographic pattern could be
      detected. One of the major peaks in the hemolymph of crowd-reared adults was
      found to be a minor one in isolated-reared individuals, whereas other peaks
      increased after solitarization. The differences became even more pronounced after
      several generations of isolated rearing. The dominant chromatographic peak in
      hemolymph extracts of the crowd-reared animals was identified as a novel peptide
      with a molecular mass of 6080Da. Edman degradation in combination with enzymatic
      fragmentation and quadrupole-time of flight (Q-Tof) mass spectrometry revealed
      the full sequence: DNADEDTICVAADNKFYLYANSLKLYTCYNQLPKVYVVKPKSQCRSSLSDCPTS. This
      54 aa-peptide is very abundant in hemolymph of crowd-reared adults. Its
      concentration in hemolymph amounts to 0.1mM. To uncover the function, its effects
      were investigated in several bioassays, so far without positive results. One of
      the other peaks differentially expressed in the individuals of the two phases was
      identified as SGPI-2 (MW=3794Da), which is a serine protease inhibitor in
      locusts.

PMID- 12431729
TI  - Evidence for crustacean cardioactive peptide-like innervation of the gut in
      Locusta migratoria.
AB  - Hindguts from female Vth instar larvae, young adults (1-2 days) and old adults
      (>10 days) are equally sensitive to the crustacean cardioactive peptide (CCAP),
      with changes in contraction occurring at a threshold concentration of 10(-9)M and
      maximal responses observed at concentrations ranging between 10(-7) and 5x10(
      6)M. An immunohistochemical examination of the gut of Locusta migratoria with an
      antiserum raised against CCAP revealed an extensive network of CCAP-like
      immunoreactive processes on the hindgut and posterior midgut via the 11th sternal
      nerve arising from the terminal abdominal ganglion. Anterograde filling of the
      11th sternal nerve with neurobiotin revealed extensive processes and terminals on
      the hindgut. Retrograde filling of the branch of the 11th sternal nerve which
      innervates the hindgut with neurobiotin revealed two bilaterally paired cells in
      the terminal abdominal ganglion which co-localized with CCAP-like
      immunoreactivity. Results suggest that a CCAP-like substance acts as a
      neurotransmitter/neuromodulator at the locust hindgut.

PMID- 12431730
TI  - Central effects of the peptides, SchistoFLRFamide and proctolin, on locust
      oviduct contraction.
AB  - We have developed a semi-intact preparation-consisting of an isolated oviduct
      with abdominal ganglia VII and VIII intact and attached-with which to
      characterize the effects on oviduct contraction, of peptides that are bath
      applied to CNS tissues. The work presented here offers a qualitative analysis of
      the central effects of SchistoFLRFamide and proctolin upon action potentials
      recorded from the oviducal nerves and upon oviduct contraction. In the process of
      this, we hope to demonstrate that a previously characterized putative CNS
      SchistoFLRFamide receptor [Peptides 23 (2002) 765] is a functional
      receptor.SchistoFLRFamide (10(-6)M), bath applied to abdominal ganglion VII,
      caused an increase in action potential frequencies recorded from the oviducal
      nerves, as well as an increase in the frequency of phasic contractions of the
      oviduct. Although the function of this response is not known, these results
      further support the possibility that the putative CNS SchistoFLRFamide receptors
      are functional receptors. Proctolin (10(-6)M), bath applied to abdominal ganglion
      VIII, altered the rhythmic bursting of action potentials recorded from the
      oviducal nerve and changed the appearance and cycle duration of neurogenic
      oviduct contractions.

PMID- 12431731
TI  - Biological activity of Manduca sexta allatotropin-like peptides, predicted
      products of tissue-specific and developmentally regulated alternatively spliced
      mRNAs.
AB  - The insect neuropeptide, allatotropin (Manse-AT), exerts multiple functions
      including the stimulation of juvenile hormone (JH) biosynthesis in adults and the
      inhibition of active ion transport across the midgut epithelium of feeding
      larvae. The Manse-AT gene is expressed in multiple regions of the nervous system
      as three mRNAs that differ by alternative splicing. The specific mRNA isoform
      present differs in a tissue- and developmental-specific manner thus providing a
      mechanism for the regulated production of peptides specific to each isoform.
      These peptides are predicted to include three allatotropin-like (Manse-ATL)
      peptides that exhibit limited structural identity to Manse-AT and overlapping
      biological activities.

PMID- 12431732
TI  - Differential expression of CMG peptide and crustacean hyperglycemic hormones
      (CHHs) in the eyestalk of the giant tiger prawn Penaeus monodon.
AB  - Mouse antiserum against C-terminal amide of Pem-CMG (a peptide in the family of
      CHH/MIH/GIH) penta-deca peptide (RPRQRNQYRAALQRLamide=CMG-15) was generated and
      used for localization of the peptide in tissue and extract of the eyestalk of
      Penaeus monodon by means of immunohistochemistry and dot-ELISA in comparison with
      anti-T+ antiserum (T+=YANAVQTVamide : the putative C-terminal amide of crustacean
      hyperglycemic hormone (CHH) of Macrobrachium rosenbergii). The anti-CMG-15
      antiserum did not show cross-reactivity to T+ peptide by dot-ELISA and vice versa
      for anti-T+ antiserum. In dot-ELISA of eyestalk extract of P. monodon after one
      step separation by RP-HPLC, anti-CMG-15 antiserum recognized different peptide
      fractions (F38-39) from those recognized by anti-T+ antiserum (F19, 40-41 and 47
      51). Most of the T+ immunoreactive fractions (except F19) show higher
      hyperglycemic activity than the CMG immunoreactive fractions. In
      immunohistochemical localization, anti-CMG antiserum recognized only 2-3 neurons
      in medulla terminalis X-organ complex (MTXO) with long processes terminated in
      the sinus gland. The CMG-immunoreactive neurons were clearly distinct from CHH
      containing neurons situated in the same area. This evidence confirms the existing
      of CMG peptide which may play distinct roles from CHHs in hormonal regulation in
      P. monodon.

PMID- 12431733
TI  - The different effects of three Drosophila melanogaster dFMRFamide-containing
      peptides on crop contractions suggest these structurally related peptides do not
      play redundant functions in gut.
AB  - A Drosophila melanogaster dFMRFamide gene product, TPAEDFMRFamide, decreased crop
      contractions. However, DPKQDFMRFamide and SDNFMRFamide, also encoded in
      dFMRFamide, did not affect crop motility, which suggests these peptides are not
      functionally redundant in the crop and their unique N-terminal structures are
      important for activity. TPAEDFMRFamide-specific antisera did not stain the crop,
      which suggests it acts as a hormone. TDVDHVFLRFamide (DMS), encoded in D.
      melanogaster myosuppressin, stops crop contractions. TPAEDFMRFamide and DMS each
      contains a RFamide C-terminus; however, their effects on crop contractions
      differ, which suggests that unique receptors or different ligand:receptor binding
      requirements exist for these structurally related peptides.

PMID- 12431734
TI  - Structural and functional diversities of the Aplysia Mytilus inhibitory peptide
      related peptides.
AB  - Aplysia Mytilus inhibitory peptide-related peptides (AMRPs) are multiple
      hexapeptides coded on a single precursor. By comparing the AMRP precursors of two
      species of Aplysia (Aplysia californica and Aplysia kurodai), we found that there
      are substantial numbers of species-specific AMRPs. We next compared the function
      of AMRPs on the anterior aorta between A. kurodai and Aplysia juliana. In A.
      juliana, AMRPs inhibited the contractile activity of the aorta (EC(50)=10(-9) to
      10(-8)M), whereas the peptides had no obvious action in A. kurodai up to 10(-7)M.
      These results indicate that AMRPs are both structurally and functionally diverse
      neuropeptides even among closely related species.

PMID- 12431735
TI  - Evidence for CRF-like and kinin-like peptides as neurohormones in the blood
      feeding bug, Rhodnius prolixus.
AB  - In Rhodnius prolixus, the rapid post-feeding diuresis is under neurohormonal
      control. While serotonin has been demonstrated to be a diuretic neurohormone [J
      Exp Biol 156 (1991) 557], a peptide is also known to be involved. Previously, we
      have demonstrated the presence of corticotropin releasing factor (CRF)-like and
      kinin-like peptides in the central nervous system (CNS) of 5th instar Rhodnius [J
      Exp Biol 202 (1999) 2017; Peptides 22 (2001) 161]. These peptides are present in
      neurohemal sites of the corpus cardiacum and are co-localized in neurohemal sites
      on abdominal nerves. While various CRF-like peptides have been demonstrated to
      increase Rhodnius Malpighian tubule secretion the kinin-like peptides do not
      [Peptides 23 (2002) 671]. The kinin-like peptides do however, increase hindgut
      contraction which may contribute to the rapid post feeding diuresis by the mixing
      of hemolymph and/or hindgut contents and the removal of wastes. The presence of
      these peptides in neurohemal sites suggests that they could be released into the
      hemolymph and act as neurohormones. We have used immunohistochemical techniques
      and radioimmunoassay (RIA) to demonstrate qualitative and quantitative changes of
      CRF-like and kinin-like peptides in the CNS associated with feeding. As well we
      have examined Malpighian tubule secretion in response to assays of hemolymph from
      unfed and fed insects. Hemolymph was also partially purified by Sep-Pak and HPLC
      and the fractions assayed for kinin-like immunoreactivity and the ability to
      stimulate Malpighian tubule secretion. The results suggest that both kinin-like
      and CRF-like peptides are neurohormones in Rhodnius, released in response to
      feeding.

PMID- 12431736
TI  - Methyl farnesoate and juvenile hormone production in embryos of Diploptera
      punctata in relation to innervation of corpora allata and their sensitivity to
      allatostatin.
AB  - Corpora allata (CA) of embryos of Diploptera punctata have been previously shown
      to produce JH III. We have re-examined sesquiterpenoid biosynthesis throughout
      embryonic development and have found that early embryos produce both methyl
      farnesoate (MF) and JH III; as development proceeds, less MF and more JH is
      produced. The cockroach allatostatin peptide Dippu-allatostatin (AST) 7 inhibits
      sesquiterpenoid production by CA of mid to late embryos whereas it exerts a dose
      dependent stimulatory effect in early embryos. This stimulatory effect is
      particularly apparent on MF biosynthesis. CA become innervated by allatostatin
      containing nerves in early embryos (35% development). Shortly thereafter, the
      allatostatin-containing innervation of the CA appears complete.

PMID- 12431737
TI  - Aplysia cardioactive peptide (NdWFamide) enhances the L-type Ca2+ current of
      Aplysia ventricular myocytes.
AB  - NdWFamide is a D-amino acid containing tripeptide purified from Aplysia heart.
      Although the cardioexcitatory action of NdWFamide is well established, little is
      known about how the excitatory action is induced. To examine the action of the
      peptide on the ion channels expressed in the Aplysia heart muscles, we carried
      out whole cell clamp experiments in the isolated Aplysia ventricular myocytes. We
      found that the high voltage-activated (HVA) Ca(2+) current of Aplysia ventricular
      myocytes is mostly a nifedipine-sensitive L-type current, and that the current
      was enhanced by NdWFamide via the activation of G proteins.

PMID- 12431738
TI  - Functional analysis of synthetic insectatachykinin analogs on recombinant
      neurokinin receptor expressing cell lines.
AB  - The activity of a series of synthetic tachykinin-like peptide analogs was studied
      by means of microscopic calcium imaging on recombinant neurokinin receptor
      expressing cell lines. A C-terminal pentapeptide (FTGMRa) is sufficient for
      activation of the stomoxytachykinin receptor (STKR) expressed in Schneider 2
      cells. Replacement of amino acid residues at the position of the conserved
      phenylalanine (F) or arginine (R) residues by alanine (A) results in inactive
      peptides (when tested at 1microM), whereas A-replacements at other positions do
      not abolish the biological activity of the resulting insectatachykinin-like
      analogs. Calcium imaging was also employed to compare the activity of C
      terminally substituted tachykinin analogs on three different neurokinin
      receptors. The results indicate that the major pharmacological and evolutionary
      difference between tachykinin-related agonists for insect (STKR) and human (NK1
      and NK2) receptors resides in the C-terminal amino acid residues (R versus M). A
      single C-terminal amino acid change can turn an STKR-agonist into an NK-agonist
      and vice versa.

PMID- 12431739
TI  - Extracellular peptidases of imaginal discs of Drosophila melanogaster.
AB  - The imaginal discs of Drosophila melanogaster give rise to the adult epidermis
      during metamorphosis. During this developmental period several peptidase genes
      are expressed in disc cells, but there is a paucity of biochemical information
      regarding substrate specificity. We have used peptides and peptidyl 7-amino-4
      methylcoumarin (AMC) substrates to detect several peptidases either positioned on
      the surface of wing discs or secreted by the imaginal cells. Using
      [Leu(5)]enkephalin as a substrate, a captopril sensitive dipeptidyl
      carboxypeptidase (angiotensin I-converting enzyme) and an amastatin-sensitive
      aminopeptidase were detected as prominent activities associated with intact
      discs. The formation of [Leu(5)]enkephalin-derived Phe was attributed to the
      concerted action of the D. melanogaster angiotensin I-converting enzyme (Ance)
      and a dipeptidase. The disc Ance also showed endopeptidic activity towards locust
      tachykinin-1 (LomTK-I) by cleaving the Gly-Val peptide bond, but this enzyme was
      not the sole endopeptidase activity associated with discs. Complete inhibition of
      the endopeptidic hydrolysis of the LomTK-1 by a disc homogenate required a
      combination of captopril and the neprilysin inhibitor, phosphoramidon, providing
      biochemical evidence for a neprilysin-like peptidase, in addition to Ance, in
      imaginal discs of D. melanogaster. Peptidyl AMC substrates for furin, prohormone
      convertase and tryptase provided evidence for trypsin-like serine endopeptidases
      in addition to the metalloendopeptidases. We conclude that imaginal discs are
      endowed with a variety of peptidases from different families that together are
      capable of hydrolyzing a broad range of peptides and proteins. Some of these
      peptidases might be responsible for the metabolic activation/inactivation of
      signaling peptides, as well as being involved in the production of dipeptides and
      free amino acids required for protein synthesis and osmotic balance during adult
      morphogenesis.

PMID- 12431740
TI  - Degradation of Manduca sexta allatostatin and allatotropin by proteases
      associated with the foregut of Lacanobia oleracea larvae.
AB  - The degradation of synthetic Manduca sexta allatostatin (Manse-AS) and
      allatotropin (Manse-AT), by enzymes of the foregut of larvae of the tomato moth,
      Lacanobia oleracea was investigated using reversed-phase high performance liquid
      chromatography (RP-HPLC) together with matrix-assisted laser desorption
      ionization-time of flight mass spectrometry (MALDI-TOF MS) and Edman sequencing.
      Metabolism of 1nmol Manse-AS by foregut extract (1microg protein) was rapid,
      t(1/2) approximately 5min, with two major products produced. Mass spectrometry of
      HPLC fractions identified cleavage products Manse-AS-(4-15) and Manse-AS-(6-15),
      which indicates enzymatic cleavage at the C-terminal side of arginine residues
      (R(3) and R(5)). This degradation of Manse-AS could be inhibited by up to 80% by
      the serine protease inhibitor aprotinin, but not PMSF, pepstatin, E64, EDTA, or
      1,10-phenanthroline.M. sexta allatotropin was also rapidly degraded when
      incubated with foregut extract, t(1/2) approximately 8min, producing two
      metabolic products, one of which was identified as Manse-AT-(1-11), showing
      enzymatic cleavage at the C-terminal side of arginine (R(11)). The second product
      was identified as Manse-AT-(1-8). Hydrolysis of Manse-AT could only be partially
      inhibited by high doses of aprotinin (30%).

PMID- 12431741
TI  - Peptidyl dipeptidases (Ance and Acer) of Drosophila melanogaster: major
      differences in the substrate specificity of two homologs of human angiotensin I
      converting enzyme.
AB  - Drosophila melanogaster angiotensin converting enzyme (Ance) and angiotensin
      converting enzyme related (Acer) are single domain homologs of mammalian peptidyl
      dipeptidase A (angiotensin I-converting enzyme) whose physiological substrates
      have not as yet been identified. We have investigated the in vitro substrate
      specificities of the two peptidases towards a variety of insect and mammalian
      peptides. Ance was generally much better than Acer at hydrolyzing peptides of 5
      13 amino acids in length. Only two of the peptides, [Leu(5)]enkephalinamide and
      leucokinin-I were cleaved faster by Acer. Increasing NaCl concentration had
      opposite affects on the cleavage of [Leu(5)]enkephalin and
      [Leu(5)]enkephalinamide by Acer, decreasing the activity towards
      [Leu(5)]enkephalin but increasing the activity towards [Leu(5)]enkephalinamide.
      Of the insect peptides tested, the tachykinin-related peptide, Lom TK-1, proved
      to be the best substrate for Ance with a k(cat)/K(m) ratio of 0.122s(-1) microM(
      1). However, in comparison, the D. melanogaster tachykinins, DTK-1, DTK-2, DTK-3
      and DTK-4 were poor Ance substrates. DTK-5 was the best substrate of this family,
      but the apparent high K(m) for hydrolysis by Ance suggested that this peptide
      would not be a natural Ance substrate. This low affinity for DTK-5 is the likely
      reason why the peptide was not rapidly degraded in D. melanogaster hemolymph,
      where Ance was shown to be a major peptide-degrading activity.

PMID- 12431742
TI  - Enhanced oral availability/pheromonotropic activity of peptidase-resistant
      topical amphiphilic analogs of pyrokinin/PBAN insect neuropeptides.
AB  - The peptide bond between active core residues Pro and Arg is the primary site of
      susceptibility for the pyrokinin/PBAN neuropeptides to insect tissue-bound
      peptidases, and incorporation of modified Pro residues can enhance resistance to
      peptidase hydrolysis. An Hyp-containing amphiphilic analog (Hex-FT[Hyp]RLa) is
      shown to operate as a topically active tissue-bound peptidase-resistant analog of
      the pyrokinin/PBAN class of insect neuropeptides in adult Heliothis virescens
      moths. An Oic amphiphilic analog (Hex-FT[Oic]RLa) is ineffective topically, but
      proves to be a superior tissue-bound, peptidase-resistant pyrokinin/PBAN analog
      for oral administration; outperforming both the Hyp analog and the orally
      inactive natural hormone PBAN in the moths. The Oic analog is effective in
      penetrating an isolated, ligated foregut preparation, but less successful in
      transmigrating an isolated midgut preparation; whereas the opposite behavior is
      observed for the Hyp analog. The success of the Oic analog via oral
      administration may be related to its ability to effectively penetrate the
      foregut, thereby bypassing the hostile environment of the midgut region.

PMID- 12431743
TI  - Approaches to radioiodination of insect neuropeptides.
AB  - High quality radioiodinated neuropeptides are essential to radioimmunoassays
      (RIA) and receptor binding assays. Approaches of direct and indirect labeling of
      neuropeptides with 125Iodine (125I) are compared. An HPLC equipped with an in
      line gamma detector and UV absorbance detector was used to evaluate selected
      labeling methods and products. Treatment of [Y(1)]-adipokinetic hormone-I ([Y(1)]
      AKH-I) with chloramine-T caused oxidative damage, whereas enzymatic labeling with
      lactoperoxidase in the presence of H(2)O(2) produced a good yield of intact,
      apparently monoiodinated peptide. Labeling of the FMRFamide-related peptide
      (YGGFMRFa), with chloramine-T apparently formed the methionine sulfoxide, which
      subsequently could be reduced with dithiothreitol. Products of high specific
      activity typically are achievable.

PMID- 12431744
TI  - Neuropeptides in flatworms.
AB  - The use of well-characterized antibodies raised to neuronal signal substances and
      their application through immunocytochemistry and confocal scanning laser
      microscopy has revolutionized studies of the flatworm nervous system (NS). Data
      about flatworm neuropeptides and the spatial relationship between neuropeptides
      and other neuronal signal substances and muscle fibers are presented.
      Neuropeptides form a large part of the flatworm NS. Neuropeptides are especially
      important as myoexcitatory transmitters or modulators, controlling the
      musculature of the attachment organs, the stomatogastric and the reproductive
      systems.

PMID- 12431745
TI  - A review of the involvement of proctolin as a cotransmitter and local
      neurohormone in the oviduct of the locust, Locusta migratoria.
AB  - The pentapeptide proctolin, originally identified in the cockroach, has been
      shown to be widely distributed in many insects and to have a broad range of
      physiological functions. In the oviduct of the locust, Locusta migratoria,
      proctolin's role as a neurotransmitter/neuromodulator has been well documented;
      however, a neurohormonal role in the locust is less certain. This review will
      examine the various roles of proctolin in locust oviduct contraction and will
      present evidence that a substance chromatographically, immunologically and
      physiologically indistinguishable from proctolin is present in the hemolymph of
      the locust, L. migratoria. This material is concentrated in the plasma, rather
      than the hemocytes, and is present at concentrations ranging from 0.1 to 0.2nM.
      This review extends the role of proctolin in insects, and suggests that proctolin
      may play a neurohormonal role in the locust.

PMID- 12431746
TI  - The medial pain system: neural representations of the motivational aspect of
      pain.
AB  - In this article, we propose that the pathways mediating the motivational aspect
      of pain originate in laminae VII and VIII of the spinal cord, and in the deep
      layers of the spinal trigeminal complex, and projections from these areas reach
      three central structures where pain motivation is represented, the ventrolateral
      quadrant of the periaqueductal gray, posterior hypothalamic nucleus, and
      intralaminar thalamic nuclei. A final representation of the motivational aspect
      of pain is located within the anterior cingulate cortex, and this representation
      receives inputs from the intralaminar nuclei. Outputs from these representations
      reach premotor structures located in the medulla, striatum, and cingulate
      premotor cortex. We discuss pathways and structures that provide inputs to these
      representations, including those involved in producing involuntary (innate) and
      instrumental responses which occur in response to the recognition of stimuli
      associated with footshock and other nociceptive stimuli.

PMID- 12431747
TI  - Differential sensitivities of pyrogenic chemokine fevers to cyclooxygenase
      isozymes antibodies.
AB  - It has been proposed that prostaglandin (PG)E(2) production via a process
      catalyzed by the inducible isoform of cyclooxygenase (COX)-2 and activation of
      specific PGE(2) receptor subtypes within the preoptic/anterior hypothalamus
      (AH/POA) is the last step and unique pathway in the induction of a fever.
      However, many data support the existence of a PG-independent pathway. That is,
      other more rapid mechanisms, which involve the constitutive COX-1 isozyme, may be
      more critical for a PG-dependent fever. Thus, we examined the role of both COX
      isoforms in the AH/POA in fevers induced by macrophage inflammatory protein (MIP)
      1beta, a PG-independent pyrogen, and RANTES (regulated on activation, normal T
      cells expressed and secreted), a PG-dependent pyrogen. In freely moving rats, two
      independent polyclonal antibodies were used which neutralize COX-1 and COX-2. The
      microinjection of either MIP-1beta or RANTES into the pyrogen-sensitive region of
      the AH/POA induced an intense fever of rapid onset. Peripheral pretreatment with
      an antipyretic dose of dexamethasone which prevents COX-2 expression, or the
      microinjections into the AH/POA of either anti-COX-1 or anti-COX-2, blocked the
      febrile response induced by RANTES but not that induced by MIP-1beta. These
      results provide strong evidence for the existence of rapid mechanisms in the
      AH/POA which involve both COX isozymes during the fever induced by RANTES, and
      further support the existence of an alternative PG-independent pathway in the
      febrile response.

PMID- 12431748
TI  - Dual 5-HT mechanisms in basolateral and central nuclei of amygdala in the
      regulation of the defensive behavior induced by electrical stimulation of the
      inferior colliculus.
AB  - Regulatory mechanisms in the basolateral nucleus of the amygdala (BLA) serves as
      a filter for unconditioned and conditioned aversive information that ascend to
      higher structures from the brainstem whereas the central nucleus (CeA) is the
      main output for the resultant defense reaction. We have shown that neural
      substrates in the inferior colliculus are activated by threatening stimuli of
      acoustic nature and have important functional links with the amygdala. In this
      work, we examined the influence of lesions with 5,7-dihydroxytryptamine (5,7-DHT)
      of these nuclei of amygdala on the aversive responses induced by electrical
      stimulation of the inferior colliculus. Thus, rats were implanted with an
      electrode in the CeA of the inferior colliculus for the determination of the
      thresholds of alertness, freezing and escape responses. Each rat also bore a
      cannula implanted in the BLA or CeA for injection of 5,7-DHT (8.0 microg/0.8
      microl) or its vehicle. The data obtained show that CeA lesions increase the
      thresholds of aversive responses whereas BLA lesions decrease the thresholds of
      these responses. From this evidence it is suggested that defensive behavior
      induced by activation of the neural substrates of aversion in the inferior
      colliculus seems to depend on the integrity of the amygdala. BLA regulates the
      input and CeA functions as the output for these aversive states generated at
      brainstem level. It is likely that aversive information ascending from the
      inferior colliculus may receive either inhibitory or excitatory influences of 5
      HT mechanisms in the BLA or CeA, respectively.

PMID- 12431749
TI  - Long-Evans rats have a larger cortical topographic representation of movement
      than Fischer-344 rats: a microstimulation study of motor cortex in naive and
      skilled reaching-trained rats.
AB  - Intracortical microstimulation of the frontal cortex evokes movements in the
      contralateral limbs, paws, and digits of placental mammals including the
      laboratory rat. The topographic representation of movement in the rat consists of
      a rostral forelimb area (RFA), a caudal forelimb area (CFA), and a hind limb area
      (HLA). The size of these representations can vary between individual animals and
      the proportional representation of the body parts within regions can also change
      as a function of experience. To date, there have been no investigations of strain
      differences in the cortical map of rats, and this was the objective of the
      present investigation. The effect of cortical stimulation was compared in young
      male Long-Evans rats and Fischer-344 rats. The overall size of the motor cortex
      representation was greater in Long-Evans rats compared to Fischer-344 rats and
      the threshold required to elicit a movement was higher in the Fischer-344 rats.
      An additional set of animals were trained in a skilled reaching task to rule out
      the possibility that experiential differences in the groups could account for the
      result and to examine the relationship between the differences in topography of
      cortical movement representations and motor performance. The Long-Evans rats were
      quantitatively and qualitatively better in skilled reaching than the Fischer-344
      rats. Also, Long-Evans rats exhibited a relatively larger area of the topographic
      representation and lower thresholds for eliciting movement in the contralateral
      forelimb. This is the first study to describe pronounced strain-related
      differences in the microstimulation-topographic map of the motor cortex. The
      results are discussed in relation to using strain differences as a way of
      examining the behavioral, the physiological, and the anatomical organization of
      the motor system.

PMID- 12431750
TI  - Intrathecal transplantation of neuroblastoma cells decreases heat hyperalgesia
      and cold allodynia in a rat model of neuropathic pain.
AB  - Intrathecal grafting of cells as biological pumps to deliver monoamines,
      endorphins, and/or trophic factors, has been shown to be effective in treating
      chronic pain both in experimental animals and in clinical trials. We have tested
      whether intrathecal implantation of neuroblastoma cells reduces heat hyperalgesia
      and cold allodynia in a rat model of neuropathic pain induced by chronic
      constriction injury (CCI) of the sciatic nerve. Behavioral tests and
      cerebrospinal fluid (CSF) collection were performed before CCI, 1 week later
      (after which, vehicle or NB69 cells were intrathecally injected) and at 4, 7, and
      14 days post-injection. Both CSF sampling and injection of the cells were
      performed by direct lumbar puncture. Intrathecal grafting of 4 x 10(6) NB69
      neuroblastoma cells reduced to basal levels the nociceptive response to heat in
      nerve-injured hindpaws, while the response of control limbs remained unchanged.
      Similarly, the allodynic response to cold elicited by acetone evaporation
      decreased in the animals implanted with NB69 cells. An increase in the
      concentrations of dopamine and serotonin metabolites of around 150% was observed
      in the CSF of animals that received grafts of NB69 cells. These data suggest that
      the monoamines released by NB69 cells in the intrathecal space produce analgesia
      to neuropathic pain in rats.

PMID- 12431751
TI  - Biological effects of stannous chloride, a substance that can produce stimulation
      or depression of the central nervous system.
AB  - It was demonstrated that tin, as stannous chloride (SnCl(2)), can facilitate the
      neuromuscular transmission by accelerating the transmitter release from the nerve
      terminals in the mouse. When this salt is injected into laboratory animals, it
      can produce stimulation or depression of the central nervous system. Because
      calcium (Ca(2+)) influx into the cytoplasm is indispensable to release the
      transmitter, it would be possible that SnCl(2) increases the Ca(2+) influx at the
      nerve terminals but not by blocking the K(+) channels. SnCl(2) is known to
      inhibit the immune response in rodents and to induce tumor generation in thyroid
      gland. There is no general agreement regarding its genotoxicity and it was
      discussed that the effects of this salt might depend on the physicochemical
      conditions and the route of its administration. SnCl(2) has been used in many
      sectors of human interest, such as food industry and nuclear medicine. This salt
      is directly administered to human beings endovenously, when it is used as a
      reducing agent to prepare 99mTc-radiopharmaceuticals which are also used for
      cerebral studies. SnCl(2) is capable to promote the generation of reactive oxygen
      species (ROS) that are responsible for the oxidative stress. Oxidative stress has
      been related with aging and other neurological diseases. So, it is relevant to
      evaluate other biological effects of SnCl(2). We decided to study these effects
      using Escherichia coli mutant strains, deficient in DNA repair genes, and
      supercoiled plasmid DNA. We evaluated the influence of medicinal plants, metal
      chelating agents, and ROS scavengers against the SnCl(2) deleterious effects. Our
      results show that SnCl(2) produced lesions in vitro as well as in vivo. This
      inactivation may be due to the production of ROS. We observed that the genotoxic
      effect of SnCl(2) was partly inhibited or disappeared, when the treatments were
      done in the presence of medicinal plants, metal chelating agents, and ROS
      scavengers. In conclusion, these findings suggest that the SnCl(2) biological
      effects may be associated with the generation of ROS. Moreover, we can speculate
      that ROS could be associated with the detrimental effects in the brain due to
      exogenous or endogenous metals.

PMID- 12431752
TI  - Estrous cycle influences on sexual diergism of HPA axis responses to cholinergic
      stimulation in rats.
AB  - Central cholinergic systems differentially modulate hypothalamic-pituitary
      adrenal (HPA) axis activity in female and male animals (sexual diergism). We
      previously reported that male rats had significantly greater HPA axis responses
      to stimulation by physostigmine (PHYSO), an acetylcholinesterase (AChE)
      inhibitor, compared to females. Females in defined estrous cycle stages, however,
      were not studied because of sample size limitations. We, therefore, determined
      HPA axis responses to stimulation by PHYSO in females during all estrous cycle
      stages (n = 78), and in male rats (n = 75). Plasma arginine vasopressin (AVP),
      adrenocorticotropic hormone (ACTH), and corticosterone (CORT) were measured.
      Estrous cycle stage was determined by light microscopy of vaginal smears.
      Proestrous and estrous females had higher ACTH and CORT responses compared to
      metestrous and diestrous females. Males had higher ACTH and AVP responses
      compared to females in all cycle stages. CORT responses followed the ACTH
      responses, except that females started from a higher baseline in all estrous
      stages, compared to males. These results suggest that cholinergic regulation of
      the HPA axis differs among females across stages of the estrous cycle, as well as
      between males and females. These effects are likely due to differences in
      circulating sex steroids and their actions within the brain.

PMID- 12431753
TI  - Effects of hydroxyflutamide in the medial preoptic area or lateral septum on
      reproductive behaviors in male rats.
AB  - We examined whether androgen receptors in the medial preoptic area (MPOA) and
      lateral septum (LS) are required for the expression of copulation and sexual
      motivation. Castrated males received testosterone-filled silastic capsules to
      restore behavior, and were implanted with the antiandrogen hydroxyflutamide (OHF)
      or blank cannulae. One group was implanted in either the anteroventral MPOA or LS
      (ANT group). Another group was implanted in the posterodorsal MPOA or LS (POST
      group). Copulation was tested on days 2, 6, 10, and 14 of OHF exposure; partner
      preference, a measure of sexual motivation, was tested on day 15. The results
      showed that sexual behavior was significantly suppressed by OHF in the MPOA of
      the ANT group, but not the POST group. However, sexual motivation was
      significantly reduced by OHF in the MPOA of the POST group, but not the ANT
      group. In the LS, OHF had no effect on sexual behavior and partner preference
      regardless of implant site. The data suggest site specificity within the MPOA for
      androgen receptor activation of male reproductive behaviors.

PMID- 12431754
TI  - Lateral frontal cortex oxygenation changes during translation and language
      switching revealed by non-invasive near-infrared multi-point measurements.
AB  - The organisation of language in the brain of multilingual people remains
      controversial. Using a high temporal resolution 12-channel near-infrared
      continuous wave spectroscopy system, we have demonstrated that it is possible to
      monitor non-invasively, comfortably and, without the interferences due to
      intrinsic limitations of positron emission tomography (PET) and functional
      magnetic resonance imaging (fMRI), cortical oxygenation changes in the Broca's
      area in response to translation of short sentences and language switching. Eight
      Dutch students proficient in English translated aloud from their native language
      into English or vice versa or alternating (switching) short visually presented
      sentences. These tasks provoked, in the left inferior frontal cortex which
      includes the Broca's area, a consistent and incremental rise in oxyhaemoglobin
      accompanied by a smaller decrease in deoxyhaemoglobin. The investigated cortical
      areas surrounding the Broca's area showed no uniform and consistent oxygenation
      changes upon the three different translation tasks. These results confirm that
      Broca's area is involved in the translation process and its so called activation
      is unaffected by the direction of the translation. In addition, these results
      strengthen the role of near-infrared multi-point measurements as a powerful tool
      for investigating the spatial and temporal features of the cortical oxygenation
      changes during language processing.

PMID- 12431755
TI  - A procedure for direct lumbar puncture in rats.
AB  - We have set out to establish a fast, simple and innocuous method for repeatedly
      obtaining cerebrospinal fluid (CSF) samples from rats that are undergoing
      different experimental procedures or suffering pathological conditions. Here, we
      report a method that has been optimized to repeatedly collect 30-50 microl of CSF
      in rats by direct lumbar puncture using a procedure that generally takes 15-20
      min to perform and presents very little hazard to the animal. The rats are
      anaesthetized with isofluorane and placed on a board in such a way that the spine
      is curved at the level of the L3-L5 vertebrae. After performing a small incision
      in the skin of the back, a neonatal lumbar puncture needle is introduced into the
      intrathecal space and CSF is passively collected in the needle cup (facilitating
      maneuvers are described herein). Moreover, we have further adapted this method to
      permit the intrathecal delivery of pharmacological agents and cell suspensions.
      In such experiments, behavioral tests can be conducted 10-15 min after the
      intrathecal injection and the activity of the implanted cells can be assessed by
      sampling lumbar CSF at later times.

PMID- 12431756
TI  - Will using exogenous insulin earlier in disease progression prevent vascular
      disease in diabetes?

PMID- 12431757
TI  - Beta-cell dysfunction and insulin resistance in type 2 diabetes: role of
      metabolic and genetic abnormalities.
AB  - Defects in insulin action and insulin secretion are both present in type 2
      diabetes, and both are believed to be genetically predetermined. In the absence
      of a defect in beta-cell function, individuals can compensate indefinitely for
      insulin resistance with appropriate hyperinsulinemia, as observed even in obese
      populations such as the Pima Indians of Arizona. However, loss of beta-cell
      function leads eventually to the postprandial and fasting hyperglycemia that
      characterizes type 2 diabetes. This progression occurs despite initially
      effective antidiabetic therapies, a situation clearly demonstrated by the United
      Kingdom Prospective Diabetes Study (UKPDS). External factors (access to high
      calorie foods, lack of exercise, weight gain), the increased insulin requirements
      imposed by insulin resistance, and toxicities from hyperglycemia and elevated
      free fatty acids may all contribute to beta-cell deterioration. Free fatty acids,
      resistin, and tumor necrosis factor (TNF)-alpha potentially worsen the insulin
      resistance. beta-Cell dysfunction resulting from glucose toxicity and
      lipotoxicity is potentially reversible with restoration of metabolic control.
      Therefore, attention to these toxicities may delay the deterioration of beta-cell
      function and suggest new approaches to the management of type 2 diabetes.

PMID- 12431758
TI  - Effects of glycemic control and other determinants on vascular disease in type 2
      diabetes.
AB  - Cardiovascular disease is the leading cause of death in patients with type 2
      diabetes, with more than 77,000 deaths each year. The risk remains high despite
      normalization of well-known cardiovascular risk factors, and the impact of
      glycemic control on risk reduction remains controversial. Deleterious changes in
      fibrinolysis, platelet function, and coagulation secondary to insulin resistance
      and/or the metabolic derangements of type 2 diabetes have emerged as likely
      mechanisms underlying increased cardiovascular risk. Plasminogen activator
      inhibitor-1 (PAI-1) is an inhibitor of the fibrinolytic system. Thus, elevated
      concentrations of PAI-1 promote persistence of clots. Concentrations of PAI-1 are
      elevated in the blood and vessel walls of patients with type 2 diabetes or other
      insulin-resistant states. We have hypothesized that increased PAI-1 can create
      conditions favorable to the evolution of unstable, lipid-laden atherosclerotic
      coronary plaques, thereby rendering patients with diabetes highly susceptible to
      rupture of vulnerable plaques and acute coronary syndromes. Therapeutic
      interventions that may alter this evolution by reducing concentrations of PAI-1
      or correct metabolic derangements that promote it are being studied. Antiplatelet
      therapy has been directed at the increased platelet reactivity characteristic of
      patients with diabetes. Its use has reduced complications after percutaneous
      coronary intervention following the onset of unstable angina. Amelioration of
      diabetic cardiomyopathy by correction of impaired myocardial energy metabolism
      and limiting the accumulation of advanced glycation end products is being
      evaluated as well.

PMID- 12431759
TI  - Evaluation of alternative strategies for optimizing glycemia: progress to date.
AB  - Adequate control of blood sugar has been repeatedly shown to translate into
      reductions in diabetic complications. Although insulin therapy in patients with
      type 2 diabetes can achieve and maintain near-normal glycemic goals associated
      with reductions in microvascular and macrovascular end points, it is often
      reserved for the later stages of management of these patients because of real or
      perceived concerns; these include fear and anxiety about worsening diabetes,
      failure of self-management, loss of quality of life, the pain of self-injection,
      and the possibility of multiple daily injections. Risks of hypoglycemia, weight
      gain, and cardiovascular disease may be concerns of physicians, but these risks
      are either manageable or, in the case of cardiovascular disease, unfounded. Taken
      together, the barriers to insulin therapy frequently compel physicians to
      consider it a treatment of last resort. Some of the more common barriers have
      been addressed through device options such as insulin pens and jet injectors,
      which may improve convenience but do not alleviate pain and discomfort.
      Transdermal delivery options using iontophoresis or ultrasound are in early
      stages of development, but methods based on transmucosal delivery-including
      buccal, nasal, and pulmonary routes-are further advanced. In particular, recent
      evidence shows that pulmonary forms of insulin are as safe and effective as rapid
      acting injected insulin, and are well accepted by patients even over long-term
      periods of use. These innovative delivery systems may help overcome the barriers
      to insulin use.

PMID- 12431760
TI  - Diabetes management in the primary care setting: summary.

PMID- 12431761
TI  - The Brn-3a POU family transcription factor stimulates p53 gene expression in
      human and mouse tumour cells.
AB  - The Brn-3a POU family transcription factor is able to induce the expression of
      genes encoding anti-apoptotic proteins such as Bcl-2 and Bcl-x and protects
      neuronal cells from apoptosis. This effect is opposed by the pro-apoptotic p53
      protein which completely inhibits the ability of Brn-3a to activate the Bcl-2 and
      Bcl-x promoters. Here we demonstrate that Brn-3a is able to stimulate p53
      expression. Thus, in co-transfection experiments, Brn-3a activates the p53
      promoter acting via a region from +22 to +67, located between the most proximal
      (+1) and the most distal (+105) transcriptional start sites. Similarly, reduction
      of Brn-3a expression using anti-sense constructs reduces endogenous p53
      expression in human neuroblastoma or cervical carcinoma cell lines growing in
      vitro and as tumours in nude mice whilst increasing Brn-3a levels enhances p53
      expression. These results suggest the existence of a negative feedback loop in
      which elevated Brn-3a expression induces the expression of p53 which, in turn,
      antagonises the anti-apoptotic activity of Brn-3a.

PMID- 12431762
TI  - The anchoring effect in lightness perception in humans.
AB  - Simultaneous lightness contrast is a classical visual illusion, which has been
      the focus of research for several generations of visual scientists. Still, there
      is no agreement on its mechanisms. There are two main competing accounts. The
      first is descended from ideas of Ewald Hering [Hering, E., Outline of a Theory of
      the Light Sense, (1874), translated from the German by L. Hurvich and D. Jameson,
      Harvard University, Cambridge, MA (1964)]. It is based on low-level retinal
      mechanisms processing the local luminance contrast between the target and the
      background. The second, originally proposed by Herman von Helmholtz [von
      Helmholtz, H., Handbuch der Physiologischen Optik, Leipzig, Voss, (1867).]
      suggests that the illusion is the result of a misjudgement of the illumination.
      We present a new demonstration, which challenges both explanations. It suggests
      that simultaneous lightness contrast is not specifically a lightness illusion,
      being a particular case of a more general phenomenon known as the 'anchoring
      effect'.

PMID- 12431763
TI  - Parallel distributed processing neuroimaging in the Stroop task using spatially
      filtered magnetoencephalography analysis.
AB  - Parallel distributed processing neuroimaging in the Stroop color word
      interference task in five healthy subjects was studied. The total reaction time
      was set at 650 ms with a time window of 200 ms in steps of 50 ms. Spatially
      filtered magnetoencephalography analysis, as used in synthetic aperture
      magnetometry, was used. Neural activation began in the left posterior parietal
      occipital area (150-250 ms post-stimulus), followed by the right prefrontal polar
      area (250-350 ms), the left dorsolateral prefrontal cortex (250-400 ms), and the
      mid- to lower- primary motor area (350-400 ms). Successive and temporally
      overlapping activation of various cortical regions were successfully estimated
      within a short 200 ms time interval, contrary to previous positron emission
      tomography and fMRI studies.

PMID- 12431764
TI  - The visual control of ball interception during human locomotion.
AB  - According to the required velocity model, on-line modulations of movement
      acceleration are performed on the basis of an optically specified difference
      between required and current behavior. Can this model account for observed
      displacement regulations in an interceptive task requiring locomotive
      displacements? In the present study, a virtual reality set-up was coupled to a
      treadmill. Subjects walking on the treadmill were required to intercept a virtual
      ball approaching at eye-level by adjusting their velocity, if necessary. While
      the required velocity model could partially account for displacement regulation
      late in the interception, it was ineffective to explain early regulations. The
      possible use of a bearing angle strategy to control displacement regulation and
      the possible degree of complimentarity of these strategies are discussed.

PMID- 12431765
TI  - Serotonin transporter gene polymorphism influences age at onset in patients with
      bipolar affective disorder.
AB  - Serotonin transporter (SLC6A4) gene polymorphism is associated with several
      behavioral and psychiatric traits. In bipolar affective disorder, two
      polymorphisms of the SLC6A4 gene, a variable number of tandem repeats in the
      second intron and a 44 bp insertion/deletion in the serotonin transporter gene
      linked polymorphic region (5-HTTLPR), have been extensively studied. The findings
      are conflicting possibly because of the heterogeneity of bipolar disorder. Early
      onset bipolar disorder appears to be clinically and genetically more homogeneous
      and was recently suggested to be associated with the 5-HTTLPR polymorphism. We
      tested the association between two polymorphisms of the SLC6A4 gene and age at
      onset (AAO) in a sample of bipolar patients. For both SLC6A4 gene polymorphisms,
      AAO of subjects with different genotypes were compared. SLC6A4 genotype
      distributions of different AAO groups were also compared. The variable number of
      tandem repeats (VNTR) polymorphism significantly influences the AAO but the
      serotonin transporter gene linked polymorphic region (5-HTTLPR) polymorphism did
      not. Patients carrying at least one VNTR STin2.12 allele began their illness
      later whereas patients carrying the 'ss' genotype tended to begin their illness
      earlier. Differential sampling procedures may influence the proportion of AAO
      subgroups in a given association study, and therefore these results may explain
      the conflicting results obtained in studies of the association between the SLC6A4
      gene polymorphism and bipolar affective disorder (BPAD).

PMID- 12431766
TI  - Inhibitor of nuclear factor-Kappa B activation attenuates venular constriction,
      leukocyte rolling-adhesion and microvessel rupture induced by ethanol in intact
      rat brain microcirculation: relation to ethanol-induced brain injury.
AB  - The present study was designed to test the hypothesis that acute, local
      administration of a specific inhibitor of nuclear factor-Kappa B activation
      (which prevents rapid proteolysis of IKB-alpha) will attenuate cerebral
      (cortical) venular constrictions, leukocyte-endothelial wall interactions and
      postcapillary damage induced by medium to high concentrations of ethanol in the
      intact rat brain. Perivascular or i.p. administration of ethanol (100, 250 mg/dl)
      to the intact rat brain resulted in concentration-dependent venular vasospasm,
      rolling and adherence of leukocytes to venular walls and rupture of postcapillary
      venules with focal hemorrhages. Superfusion of the in-situ brain with N(alpha)-L
      tosyl-L-phenylalanine chloromethyl ketone (TPCK), a specific inhibitor of IKB
      alpha proteolysis, attenuated greatly the spasmogenic, leukocyte rolling
      endothelial cell adhesion and postcapillary hemorrhages induced by ethanol. These
      new data suggest that inhibition of alcohol-inducible degradation of IKB-alpha by
      TPKC can prevent much of the adverse microvascular actions of ethanol in the
      intact rat brain. Moreover, these new in-situ results suggest that activation of
      nuclear factor-Kappa B seems to play a major modulatory role in the adverse
      cerebral vascular actions of concentrations of alcohol found in the blood of
      alcohol-intoxicated subjects and human stroke victims.

PMID- 12431767
TI  - Differential blocking effects of the monoclonal anti-GQ1b IgM antibody and alpha
      latrotoxin in the absence of complement at the mouse neuromuscular junction.
AB  - Numerous in vitro electrophysiological studies found different effects of anti
      ganglioside antibodies on neuromuscular transmission. Since a complement
      dependent, latrotoxin-like effect has been described for the mouse monoclonal
      anti-GQ1b IgM antibody (termed CGM3), we here investigated the effect of CGM3 and
      alpha-latrotoxin by means of the perfused macro-patch clamp electrode in mice
      hemidiaphragms in the absence of complement. The CGM3 mab depressed evoked
      quantal release dose-dependently, whereas the rate of spontaneous releases and
      the amplitude of postsynaptic currents was not significantly affected. Alpha
      latrotoxin induced an increase in spontaneous releases followed by a blockade of
      evoked quantal release, this was not altered by CGM3. The complement-independent
      presynaptic block by CGM3 was different from the action of alpha-latrotoxin.

PMID- 12431768
TI  - Response of the infrared receptors of a crotaline snake to ethanol.
AB  - The pit organs of crotaline snakes can sense infrared (IR). The pit membrane has
      a finer, flatter, more convoluted vasculature than other sensory organs. Using
      extracellular recording from IR-sensitive trigeminal ganglion (TG) neurons
      (primary neurons) and tectal (OT) neurons of the crotaline snake Trimeresurus
      flavoviridis, we examined the IR response to ethanol (EtOH) in vivo. The response
      to EtOH was recorded in the TG and OT 20-80 s after 10% EtOH in Ringer's solution
      (100 microl/ 500 g body weight) was injected via the heart. The responses to EtOH
      and those to lower or higher temperature stimulation were additive. At a constant
      temperature (25 degrees C), EtOH significantly potentiated the IR-triggered
      discharges of IR-sensory pathways in this snake. These results suggest that the
      IR response to EtOH is due to either its vasodilatory effect on the abundant
      vasculature of the pit membrane or its chemical effect on temperature-sensitive
      receptors.

PMID- 12431769
TI  - Quantification of axotomized ganglion cell death by explant culture of the rat
      retina.
AB  - We first demonstrated a temporal profile of retinal ganglion cell (RGC) death
      after axotomy in situ using a newly developed retinal explant culture system.
      1,1'- dioctadecyl- 3,3,3',3'-tetramethylindocarbocyanine perchlorate, a
      fluorescent tracer, was administered to the superior colliculi of 2 day old
      Wistar rats to label RGCs retrogradely. Small pieces of retinas were dissected
      and maintained at the interface between a 5% CO(2) atmosphere and culture media,
      and temporally observed by fluorescent microscopy. The number of surviving RGCs,
      identified as fluorescent spots, gradually decreased during the course of
      experiments for up to 10 days in vitro. We identified apoptotic RGCs by terminal
      deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling.
      Administration of cycloheximide, actinomycin D, or a caspase-3 inhibitor to media
      significantly decreased RGC death. This system provides a method of quantifying
      axotomized RGC death in relation to time-dependent changes in an identical
      retinal slip.

PMID- 12431770
TI  - Spatial versus object feature processing in human auditory cortex: a
      magnetoencephalographic study.
AB  - The human visual system is divided into two pathways specialized for the
      processing of either objects or spatial locations. Neuroanatomical studies in
      monkeys have suggested that a similar specialization may also divide auditory
      cortex into two such pathways. We used the identical stimulus material in two
      experimental sessions in which subjects had to either identify auditory objects
      or their location. Magnetoencephalograms were recorded and M100 dipoles were
      fitted into individual brain models. In the right hemisphere, the processing of
      auditory spatial information lead to more lateral activations within the temporal
      plane while object identification lead to more medial activations. These findings
      suggest that the human auditory system processes object features and spatial
      features in distinct areas.

PMID- 12431771
TI  - Role of serotonin1A receptors on the modulation of rat spinal mono-synaptic
      reflexes in vitro.
AB  - The present study aimed at determining the role of the serotonin(1A) (5-HT(1A))
      receptor subtype on the modulation of the mono-synaptic reflex (MSR) elicited by
      dorsal root stimulation and recorded from ventral roots in the hemisected spinal
      cord obtained from rat pups. Serotonin and 5-carboxamidotryptamine (5-CT)
      depressed both the MSR and the cumulative depolarisation (CD) produced by
      repetitive dorsal root stimulation, whereas the specific 5-HT(1A) receptor
      agonist (R)-(+)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) applied at 1
      microM showed a selective depressant effect on the MSR. Superfusion of the 5
      HT(1A) receptor antagonist (+)-N-tert-butyl-3(4(2-methoxyphenyl)-piperazin-1-yl)
      2-phenylprpanamide ((+)WAY 100135) produced a complete blockade of 8-OH-DPAT
      effects. In addition (+)WAY 100135 blocked partially the effects of 5-HT and 5-CT
      on the MSR but not the effects of these compounds on the CD. The results are
      consistent with an intervention of 5-HT(1A) receptors in the modulation of non
      nociceptive reflexes but do not support a prominent role for this receptor in the
      modulation of nociceptive reflexes.

PMID- 12431772
TI  - The extracellular current blocking effect of cesium chloride on the theta wave in
      the rabbit hippocampal CA1 region.
AB  - We studied the extracellular effects of cesium chloride (CsCl), a blocker of the
      hyperpolarization-activated cationic current (I(h)), on the hippocampal theta
      wave in pentobarbital-anesthetized rabbits. We recorded spontaneous field
      potentials at the hippocampal CA1 region before and at three time periods after
      CsCl or saline injections. We found that CsCl injected into the apical dendritic
      layer attenuated the theta wave amplitude. CsCl affected neither the frequency
      nor the phase reversal of the theta wave between the apical and basal dendritic
      layers. Our findings indicate that I(h) in pyramidal neurons contributes to
      current generation of the limbic theta wave in vivo.

PMID- 12431773
TI  - Discovery of a protein sequence in the N-terminal region of the human neuronal
      alpha7 nicotinic acetylcholine receptor involved in homomeric interactions.
AB  - The neuronal nicotinic acetylcholine receptor subunit, alpha7, can form
      homopentameric receptor/ion channel complexes. Potential contributions of its N
      terminal region to homomeric interactions were investigated, in comparison with
      the corresponding region of an analogous heteromeric subunit, alpha3. Recombinant
      chimeras were prepared upon engineering the N-terminal alpha7 (M1-V224) or alpha3
      (M1-S232) sequence into the background of another homomeric mouse 5
      hydroxytryptamine3 (5-HT)(3) receptor. The alpha7/5-HT(3) chimera, when expressed
      heterologously in a human epithelial cell line, SH-EP1, robustly expressed alpha
      bungarotoxin binding sites as homooligomers while the alpha3/5-HT(3) did not
      produce epibatidine (non-selective ligand) binding sites, and did not interfere
      the alpha7/5-HT3 phenotype, upon co-expression. Yeast two hybrid assays with the
      N-terminal regions showed positive responses between alpha7:alpha7, but not
      between alpha7:alpha3 and alpha3:alpha3. Similar assays with the alpha7 N
      terminal region and its five smaller fragments (G23-N46, D47-N90, V91-N133, S134
      M182and Q183-V224) revealed that the G23-N46 sequence is involved in homomeric
      interactions. Replacement of the corresponding region of the alpha3/5-HT(3)
      chimera with the alpha7 G23-N46 sequence conferred a dominant negative role on
      the chimera, by abolishing the alpha7/5-HT(3) phenotype. These results support
      the view that the G23-N46 portion of the alpha7 N-terminal region may contribute
      to receptor homooligomerizations.

PMID- 12431774
TI  - Endomorphin-2 is not released from rat spinal dorsal horn in response to
      intraplantar formalin.
AB  - Antibody coated microprobes, inserted into the spinal cord at the L4-5 level,
      were used to detect whether endomorphin-2 (Endo2) was released from spinal dorsal
      horns in anesthetized rats in response to formalin injected into the hindpaw
      footpads. Saline injections were used as a control and substance P (SP) was
      measured to verify activation of nociceptive afferent fibers. SP but not Endo2
      was released during pre-stimulation periods. Saline injections did not cause the
      release of either Endo2 or SP from the spinal cord. Formalin injections caused an
      increase in Fos expression as well as a release of SP, but not Endo2 from the
      ipsilateral side dorsal horn in L4-5. We conclude that Endo2 does not play a role
      in mediating the in vivo responses to acute inflammatory nociceptive signals at
      the spinal level in the anesthetized rat model.

PMID- 12431775
TI  - Effect of naloxone-precipitated morphine withdrawal on CRH and vasopressin mRNA
      expression in the rat hypothalamic paraventricular nucleus.
AB  - Morphine withdrawal is characterized by an increase in the hypothalamus-pituitary
      adrenocortical (HPA) axis activity. Here, by means of in situ hybridization, the
      changes in CRH and vasopressin (AVP) mRNAs have been analysed within the rat
      hypothalamic paraventricular nucleus (PVN) during morphine dependence and after
      naloxone-precipitated morphine withdrawal. CRH and AVP mRNA expression were
      analysed 30 min following administration of saline or naloxone to control groups
      and to morphine dependent rats. The data for in situ hybridization analysis of
      PVN neurons show that there were no changes in the total size of labelled area
      for CRH or AVP mRNA during morphine withdrawal, indicating that dependence on
      morphine does not involve alterations in the number of neurons expressing CRH or
      AVP mRNA. However, levels of mRNA encoding for CRH were decreased in the PVN
      during morphine dependence and withdrawal. By contrast, injection of saline or
      naloxone to morphine dependent rats did not affect the intensity of AVM mRNA
      expression. All these findings are discussed in term of cellular events that
      couple morphine dependence-increased HPA axis activity with changes in gene
      expression in selective neurons of the PVN.

PMID- 12431776
TI  - Differential activation of caspase-3 at two maturational stages during okadaic
      acid-induced rat neuronal death.
AB  - Okadaic acid (OA), a protein phosphatase inhibitor, is used as a research model
      of Alzheimer's disease to induce tau phosphorylation and neuronal death. We
      reported previously that OA induces neuronal apoptosis of immature neurons (in
      vitro days (IVD) 3-5), which is inhibited by cycloheximide (CHX). In this study,
      we demonstrate that CHX fails to prevent OA-induced neuronal death in mature
      neurons (IVD 14-15). Upon comparison of both types of dying cells, the immature
      neurons displayed characteristic features of apoptosis, such as nuclear
      fragmentation, phosphatidylserine externalization and prominent caspase-3
      activation, while the mature neurons showed few characteristic features of
      apoptosis. Lack of the beneficial effects of CHX and the lesser activation of
      caspase-3 in the mature neurons argue against typical apoptotic neuronal death in
      the OA-induced neurodegeneration model.

PMID- 12431777
TI  - Association analysis between the human interleukin 1beta (-511) gene polymorphism
      and susceptibility to febrile convulsions.
AB  - Recently, an association between a regulatory polymorphism in the gene encoding
      the pro-inflammatory cytokine interleukin (IL)-1beta and febrile convulsions (FC)
      has been reported. In this study we attempted to confirm these findings in a
      sample consisting of 99 FC patients and 126 ethnically matched controls. Since
      about 3% of all FC patients experience unprovoked seizures (epilepsy) later
      during life we furthermore genotyped 43 patients with non-lesional temporal lobe
      epilepsy who reported a history of FC. In both samples we failed to show an
      association between the IL-1beta polymorphism and an increased risk for FC. We
      only found a trend towards an increased frequency and carriage of the putative IL
      1beta susceptibility allele two in a sub-sample of 43 FC patients who reported a
      positive family history for seizures in first and/or second degree relatives.
      However, these trends did not reach statistical significance.

PMID- 12431778
TI  - TGF-beta1 inhibits multiple caspases induced by TNF-alpha in murine osteoblastic
      MC3T3-E1 cells.
AB  - Tumor necrosis factor alpha (TNF-alpha) is a proinflammatory cytokine that
      induces apoptosis in a number of cell systems, including osteoblasts.
      Transforming growth factor beta1 (TGF-beta1) is an abundant growth factor that is
      known to stimulate bone formation. This study was designed to examine the role of
      TGF-beta1 on TNF-alpha-induced apoptosis in murine osteoblastic MC3T3-E1 cells.
      Total RNA was extracted from MC3T3-E1 cells treated with 20 ng/ml of TNF-alpha,
      10 ng/ml of TGF-beta1, or combination, for 6 h. TNF-alpha exerted a variety of
      effects on the apoptotic gene expression in osteoblasts. Ribonuclease protection
      assays (RPA) revealed that TNF-alpha upregulated the mRNA levels of caspase-1, 
      7, -11, -12, and FAS. Western blot analysis showed enhanced processing of caspase
      1, -7, -11, and -12, with the appearance of their activated enzymes 24 h after
      TNF-alpha treatment. In addition, caspase-3-like activity was significantly
      activated following TNF-alpha treatment. Levels of cleaved poly(ADP-ribose)
      polymerase and FAS protein were also elevated by TNF-alpha. Finally, Hoechst
      staining, terminal deoxynucleotidyl-transferase nick-end labeling (TUNEL) assay,
      and oligonucleosome ELISA all indicated that TNF-alpha induced apoptosis. In
      contrast, the addition of TGF-beta1 attenuated all of the aforementioned effects
      of TNF-alpha. Our results demonstrate that TGF-beta1 can decrease TNF-alpha
      induced apoptosis in murine osteoblasts at least in part by attenuating TNF-alpha
      induced caspase gene expression.

PMID- 12431779
TI  - Thimerosal stimulates focal adhesion kinase and cytoskeletal changes by redox
      modulation.
AB  - Thimerosal is one of the most widely used preservatives and has been reported to
      cause chemically mediated side effects. However, the mechanism of the side
      effects is not clearly understood yet. In the present study, we showed that HeLa
      S cells treated by thimerosal generated reactive oxygen species (ROS). Thimerosal
      generated ROS stimulated the tyrosine phosphorylation of focal adhesion kinase
      (FAK) and also induced cytoskeletal changes. Pretreatment with intracellular
      calcium chelator, BAPTA did not block the thimerosal-mediated FAK tyrosine
      phosphorylation. On the other hand, either FAK inhibitor, tyrphostin or ROS
      scavenger, N-acetyl-L-cysteine (NAC) suppressed the tyrosine phosphorylation and
      cytoskeletal changes. These results suggest that thimerosal seems to induce FAK
      tyrosine phosphorylation and cytoskeletal changes by ROS generation but not by
      intracellular calcium mobilization. We think the present finding can be an
      important clue to understanding the mechanism of thimerosal-mediated side
      effects, such as contact dermatitis, and allergy.

PMID- 12431780
TI  - RGD-functionalized spherulites as targeted vectors captured by adherent cultured
      cells.
AB  - Spherulites are multilamellar vesicles consisting of concentric shells that can
      encapsulate small organic molecules or macromolecules. We investigate the
      possibility of targeting neutral spherulites to adherent culture cells by
      functionalizing their surface with RGD-containing ligands. The strength and
      specificity of association of RGD spherulites with several cell lines (EAhy 926
      endothelial cell line, human umbilical vein endothelial cell (HUVEC) and human
      osteoprogenitor (HOP) primary cells) was studied, and the molecular interaction
      of RGD spherulites with the EAhy 926 cell surface was investigated. We show that,
      after binding to cells, spherulites are internalized.

PMID- 12431781
TI  - The flavonoid, quercetin, differentially regulates Th-1 (IFNgamma) and Th-2 (IL4)
      cytokine gene expression by normal peripheral blood mononuclear cells.
AB  - Flavonoids are plant metabolites that are dietary antioxidants and exert
      significant anti-tumor, anti-allergic, anti-inflammatory and anti-viral effects.
      It is generally accepted that Th-1 derived cytokines such as IL-2, IFNgamma and
      IL-12 promote cellular immunity while Th-2 derived cytokines such as IL-4, IL-5,
      IL-6 exert negative immunoregulatory effects on cellular immunity while
      upregulating humoral immunity. The molecular mechanisms underlying the biological
      activities of flavonoids have not been elucidated. We hypothesize that the
      flavonoid, quercetin, exert significant anti-viral and anti-tumor effects
      possibly by modulating the production of Th-1 and Th-2 derived cytokines.
      Peripheral blood mononuclear cells (PBMC, 1 x 10(6) cells/ml) from normal
      subjects were cultured with different concentrations of quercetin (0.5-50 microM)
      for 24-72 h and supernates were quantitated for IFN-gamma and IL-4 by ELISA and
      antiviral activity of IFNgamma by bioassay. FACS analysis was done to determine
      the number of IFN-gamma and IL-4 positive cells and RT-PCR was done to quantitate
      gene expression. Quercetin significantly induces the gene expression as well as
      the production of Th-1 derived IFNgamma and the downregulates Th-2 derived IL-4
      by normal PBMC. Further, quercetin treatment increased the phenotypic expression
      of IFNgamma cells and decreased IL-4 positive cells by FACS analysis, which
      corroborate with protein secretion and gene expression studies. These results
      suggest that the beneficial immuno-stimulatory effects of quercetin may be
      mediated through the induction of Th-1 derived cytokine, IFNgamma, and inhibition
      of Th-2 derived cytokine, IL-4.

PMID- 12431782
TI  - Probing for submandibular gland peptide-T receptors on leukocytes with
      biotinylated-Lys-[Gly](6)-SGP-T.
AB  - Submandibular gland peptide-T (SGP-T) is a potent anti-chemotactic agent for
      human neutrophils possessing anti-inflammatory properties. Biologically active
      analogues of SGP-T have been synthesized and a biotinylated form (KG(6)-SGP-T;
      Bio-KG(6)-SGP-T) was utilized to identify binding sites on isolated human
      neutrophils. Neutrophils incubated with Bio-KG(6)-SGP-T followed by phycoerythrin
      (PE)-avidin secondary reagent were fixed and visualized using histochemistry and
      flow cytometry. At doses of 10(-8) and 10(-9) M, Bio-KG(6)-SGP-T was shown to
      bind to neutrophils. The binding of Bio-KG(6)-SGP-T, at doses of 10(-8) and 10(
      9) M, to neutrophils was abolished by a 100-fold excess of non-biotinylated
      peptide (KG(6)-SGP-T), but not by 100-fold excess of SGP-T. However, all
      peptides, dose-dependently reduced the binding of a CD16b antibody (LNK16 clone)
      to isolated human neutrophils. This discrepancy probably results from different
      preferred conformations for Bio-KG(6)-SGP-T, KG(6)-SGP-T and SGP-T, since
      exhaustive conformational searches revealed a high degree of overlap between
      alpha-Bio-KG(6)-SGP-T and KG(6)-SGP-T that was not seen with SGP-T.

PMID- 12431783
TI  - Phosphorylation of the cell cycle inhibitor p21Cip1/WAF1 by Pim-1 kinase.
AB  - The serine/threonine kinase, Pim-1, appears to be involved in regulating
      proliferation, differentiation and cell survival of lymphoid and myeloid cells.
      In this study, we have found that amino acid residues 140-147 (RKRRQTSM) at the C
      terminal end of p21(Cip1/WAF1), a cyclin-dependent kinase (CDK) inhibitor,
      constitute an ideal phosphorylation consensus sequence for Pim-1. We demonstrate
      that Pim-1 efficiently phosphorylates this peptide sequence as well as the p21
      protein in vitro. We also demonstrate by pull-down assay and by
      immunoprecipitation that Pim-1 associates with p21. During phorbol ester-induced
      differentiation of U937 cells, both Pim-1 and p21 expression levels increase with
      Pim-1 levels increasing in both the nucleus and cytoplasm while p21 remains
      primarily cytoplasmic. Co-transfection of wild type p21 with wild type Pim-1
      results in cytoplasmic localization of p21 while co-transfection of wild type p21
      with kinase dead Pim-1 results in nuclear localization of p21. Consistent with
      the results from the phosphoamino acid assay, Pim-1 phosphorylates transfected
      p21 only on Thr(145) in p21-deficient human fibroblasts and this phosphorylation
      event results in the cytoplasmic localization of p21. These findings demonstrate
      that Pim-1 associates with and phosphorylates p21 in vivo, which influences the
      subcellular localization of p21.

PMID- 12431784
TI  - An inducible Ku86-degrading serine protease in human cells.
AB  - The Ku autoantigen has been implicated in a number of cellular functions
      including growth control, immunoglobulin gene rearrangement and DNA repair. A
      variant truncated form of Ku86, with an apparent molecular weight of 70 kDa, has
      been reported to be present in many human cell types. We have previously shown
      that the amount of variant Ku86 is strongly increased in human peripheral blood
      mononuclear cells (PBMC) by storage of blood prior to isolation of the PBMC. In
      this study we report that formation of variant Ku86 in protein extracts is
      mediated by an inducible trypsin-like serine protease with a higher concentration
      in the nuclear compartment, as compared with the cytoplasm. However, experiments
      with SDS-PAGE assay of whole cells yielded no evidence of truncated Ku86,
      suggesting that the protease is not active in intact cells, but is exerting a
      marked activity during the protein extraction procedure. Interestingly, the
      protease level became markedly reduced upon transfer of the cells to growth
      medium. Protease induction did not correlate with apoptosis, necrotic cell death
      or with signs of general proteolysis or cytotoxicity. Our findings have
      methodological implications for the interpretation of experimental Ku86 data, and
      suggest that this protease may play a role for cellular regulation of Ku
      function.

PMID- 12431786
TI  - Involvement of HMGB1 and HMGB2 proteins in exogenous DNA integration reaction
      into the genome of HeLa S3 cells.
AB  - High mobility group 1 and 2 proteins (HMGB1 and HMGB2) are abundant chromosomal
      proteins in eukaryotic cells. We examined the involvement of HMGB1 and HMGB2 in
      nonhomologous illegitimate recombination. The HMGB1 or HMGB2 expression plasmid,
      carrying the neo(r) gene as a selection marker, was introduced into HeLa S3 cells
      to obtain stably-transfected cells. The number of G418-resistant colonies was
      about 10 times the number of colonies of control cells transfected with plasmids
      not carrying the HMGB genes. The copy number of the stably-integrated neo(r) gene
      was higher in the cells transfected with the HMGB expression plasmids than in
      control cells. The exogenous DNA integration was suggested to have occurred by
      nonhomologous illegitimate recombination. On the contrary, the introduction of
      the HMGB antisense RNA expression plasmid with a reporter plasmid carrying the
      neo(r) gene into HeLa S3 cells decreased the number of G418-resistant colonies.
      These results indicate that HMGB1 and HMGB2 each have a novel function as
      stimulators of stable integration of plasmid DNA into the host genome and that
      they may be important for the process of spontaneous DNA integration in living
      cells.

PMID- 12431785
TI  - Adenosine A1 receptor agonist treatment up-regulates rat brain metabotropic
      glutamate receptors.
AB  - Chronic R-N(6)-phenylisopropiladenosine (R-PIA) subcutaneous injection for 6 days
      significantly increased total glutamate receptor number (180% of control) in rat
      brain synaptic plasma membranes (SPM), without affecting receptor affinity. A
      higher increase in metabotropic glutamate (mGlu) receptor number (258% of
      control) was also detected, indicating that mGlu is the main type of glutamate
      receptor affected by this treatment. On the other hand, the observed increase in
      basal and calcium- and Gpp(NH)p-stimulated phospholipase C (PLC) activity after
      treatment was associated with a significant increase in PLC beta(1) isoform,
      detected in SPM by immunoblotting assays. Moreover, an increase in PLC activity
      stimulation with trans-ACPD, in the absence and in the presence of Gpp(NH)p, was
      detected after R-PIA treatment. These results show that mGlu receptors and its
      effector system, PLC activity, are up-regulated by chronic exposure to an
      adenosine A(1) receptor agonist and suggest the existence of a cross-talk
      mechanism between both signal transduction pathways in rat brain.

PMID- 12431787
TI  - Selenium supplementation acting through the induction of thioredoxin reductase
      and glutathione peroxidase protects the human endothelial cell line EAhy926 from
      damage by lipid hydroperoxides.
AB  - The human endothelial cell line EAhy926 was used to determine the importance of
      selenium in preventing oxidative damage induced by tert-butyl hydroperoxide (tert
      BuOOH) or oxidised low density lipoprotein (LDLox). In cells grown in a low
      selenium medium, tert-BuOOH and LDLox killed cells in a dose-dependent manner. At
      555 mg/l LDLox or 300 microM tert-BuOOH, >80% of cells were killed after 20 h. No
      significant cell kill was achieved by these agents if cells were pre-incubated
      for 48 h with 40 nM sodium selenite, a concentration that maximally induced the
      activities of cytoplasmic glutathione peroxidase (cyGPX; 5.1-fold), phospholipid
      hydroperoxide glutathione peroxidase (PHGPX;1.9-fold) and thioredoxin reductase
      (TR; 3.1-fold). Selenium-deficient cells pre-treated with 1 microM gold
      thioglucose (GTG) (a concentration that inhibited 25% of TR activity but had no
      inhibitory effect on cyGPX or PHGPX activity) were significantly (P<0.05) more
      susceptible to tert-BuOOH toxicity (LC(50) 110 microM) than selenium-deficient
      cells (LC(50) 175 microM). This was also the case for LDLox. In contrast, cells
      pre-treated with 40 nM selenite prior to exposure to GTG were significantly more
      resistant to damage from tert-BuOOH and LDLox than Se-deficient cells. Treatment
      with GTG or selenite had no significant effect on intracellular total glutathione
      concentrations. These results suggest that selenium supplementation, acting
      through induction of TR and GPX, has the potential to protect the human
      endothelium from oxidative damage.

PMID- 12431788
TI  - Taurine modulates induction of cytochrome P450 3A4 mRNA by rifampicin in the
      HepG2 cell line.
AB  - Taurine is not only present in foods, tonics and nutrient drinks but is also used
      as a medicinal agent mainly for treatment of chronic heart failure and liver
      disease. However, little is known about its influence on drug-metabolizing
      enzymes, especially cytochrome P450 (CYP), in human. We examined whether taurine
      could affect the expression of CYP3A4 mRNA in the presence or absence of
      rifampicin (RFP), which is a potent inducer of CYPs, with HepG2 cells. Taurine
      enhanced twice the induction of CYP3A4 mRNA by RFP, but did not affect the
      expression by itself. This effect was both concentration- and time-dependent. On
      the other hand, taurine did not affect the induction by phenobarbital. Taurine
      did not increase intracellular uptake of RFP. Therefore, we conclude that taurine
      is an enhancer for the induction of CYP3A4 by RFP.

PMID- 12431789
TI  - Cholecystokinin-stimulated tyrosine phosphorylation of PKC-delta in pancreatic
      acinar cells is regulated bidirectionally by PKC activation.
AB  - PKC-delta is important in cell growth, apoptosis, and secretion. Recent studies
      show its stability is regulated by tyrosine phosphorylation (TYR-P), which can be
      stimulated by a number of agents. Many of these stimuli also activate
      phospholipase C (PLC) cascades and little is known about the relationship between
      these cascades and PKC-delta TYR-P. Cholecystokinin (CCK) stimulates PKCs but it
      is unknown if it causes PKC-delta TYR-P and if so, the relationship between these
      cascades is unknown. In rat pancreatic acini, CCK-8 stimulated rapid PKC-delta
      TYR-P by activation of the low affinity CCK(A) receptor state. TPA had a similar
      effect. BAPTA did not decrease CCK-stimulated PKC-delta TYR-P but instead,
      increased it. A23187 did not stimulate PKC-delta TYR-P. Wortmannin and LY 294002
      did not alter CCK-stimulated PKC-delta TYR-P. GF 109203X, at low concentrations,
      increased PKC-delta TYR-P stimulated by CCK or TPA and at higher concentrations,
      inhibited it. The cPKC inhibitors, Go 6976 and safingol, caused a similar
      increase in TPA- and CCK-stimulated PKC-delta TYR-P. These results demonstrate
      that CCK(A) receptor activation causes PKC-delta TYR-P through activation of only
      one of its two receptor affinity states. This PKC-delta TYR-P is not directly
      influenced by changes in [Ca(2+)](i); however, the resultant activation of PKC
      alpha has an inhibitory effect. Therefore, CCK activates both stimulatory and
      inhibitory PKC cascades regulating PKC-delta TYR-P and, hence, likely plays an
      important role in regulating PKC-delta degradation and cellular abundance.

PMID- 12431790
TI  - Update on biological actions of 1alpha,25(OH)2-vitamin D3 (rapid effects) and
      24R,25(OH)2-vitamin D3.
AB  - All biologic responses to vitamin D are now known to arise as a consequence of
      the metabolism of this seco-steroid into its two principal biologically active
      metabolites 1alpha,25(OH)(2)-vitamin D(3) (1ALPHA;,25(OH)(2)D(3)) and
      24R,25(OH)(2)-vitamin D(3) (24R,25(OH)(2)D(3)). 1alpha,25(OH)(2)D(3) is the
      dominant metabolite and produces a wide array of biological responses via
      interacting both with the classical vitamin D nuclear receptor (VDR(nuc)) that
      regulates gene transcription in over 30 target organs and with a putative cell
      membrane receptor (VDR(mem1,25)) that mediates rapid (within seconds to minutes)
      biological responses. Ligand occupancy of VDR(mem1,25) is linked to signal
      transduction systems that can mediate the opening of Ca(2+) and chloride voltage
      gated channels as well as activation of MAP-kinase. MAP-kinase activation in some
      cells containing VDR(mem1,25)+VDR(nuc) then results in "cross-talk" from
      VDR(mem1,25) to VDR(nuc) which modulates transactivation of 1alpha,25(OH)(2)D(3)
      responsive gene promoters. The 24R,25(OH)(2)D(3) metabolite has been shown to be
      an essential hormone for the process of bone fracture healing. The activity of
      the enzyme responsible for the production of 24R,25(OH)(2)D(3), the renal 25(OH)D
      24-hydroxylase, becomes elevated within 4-11 days after imposition of a tibial
      fracture, thereby increasing the blood concentrations of 24R,25(OH)(2)D(3) by
      threefold. The 24R,25(OH)(2)D(3) likely initiates its biological responses via
      binding to the ligand binding domain of a second cell membrane receptor, the
      VDR(mem24,25), which is stereospecific for 24R,25(OH)(2)D(3) in comparison with
      24S,25(OH)(2)D(3) and 1alpha,25(OH)(2)D(3). This report summarizes the status of
      several current research frontiers in this arena of the vitamin D endocrine
      system.

PMID- 12431791
TI  - The role of vitamin D receptor gene polymorphisms in bone biology.
AB  - The role of vitamin D and its receptor (VDR) in skeletal metabolism is well known
      but the vitamin D endocrine system seems to play an important role in other
      metabolic pathways as well, such as those involved in osteoarthritis, the immune
      response and cancer. One approach to understand the vitamin D endocrine system is
      to study the influence of variations in the DNA sequence of important proteins of
      this system. For example, deleterious mutations in the VDR gene cause 1,25
      dihydroxyvitamin D-resistant rickets, a rare monogenetic disease. More subtle
      sequence variations (polymorphisms) in the VDR gene occur much more frequently
      but their effects are poorly understood. Their influence on the vitamin D
      endocrine system is currently under scrutiny in relation to a number of so-called
      complex diseases and traits such as osteoporosis. The interpretation of
      polymorphic variations in the VDR gene is severely hindered by the fact that
      several of the polymorphisms used have unknown effects. However, current data
      indicate that dozens of additional polymorphic variations exist in the VDR gene
      that could each have different types of consequences. Therefore, efforts are
      focussed on finding novel sequence variations and to study their interaction in
      molecular- and cell-biological experiments as well as in genomic epidemiological
      studies. The ultimate goal of this approach is to identify the combinations of
      functional sequence variants that modulate the vitamin D endocrine system and
      confer risk of disease.

PMID- 12431792
TI  - Vitamin D3 metabolism in dogs.
AB  - Plasma concentrations of the main vitamin D(3) metabolites (i.e., 25(OH)D(3),
      1,25(OH)(2)D(3), and 24,25(OH)(2)D(3)) were measured in 14 weeks old large- and
      small-breed dogs (adult body weight 60 kg vs. 6 kg), raised under the same
      conditions. Levels of 25(OH)D(3) (approx. 22 microg/l) and 1,25(OH)(2)D(3)
      (approx. 40 ng/l) were similar in both groups, whereas plasma 24,25(OH)(2)D(3)
      concentrations were lower in large-breed dogs (7 microg/l vs. 70 microg/l, large-
      vs. small-breed dogs, respectively). The lower plasma 24,25(OH)(2)D(3)
      concentrations could be explained by the higher plasma GH and IGF-I
      concentrations in the large- vs. small-breed dogs, and these hormones are known
      to suppress 24-hydroxylation. Plasma 24,25(OH)(2)D(3) concentrations increased
      during Ca supplementation in small-breed but not in large-breed dogs (100
      microg/l vs. 7 microg/l, respectively). Hypophosphatemia induced by a high
      dietary Ca content was only seen together with increased plasma 1,25(OH)(2)D(3)
      concentrations in euparathyroid dogs and not in hypoparathyroid dogs.
      Hyperparathyroidism due to Ca deficiency was accompanied by increased plasma
      1,25(OH)(2)D(3) concentrations and decreased plasma 24,25(OH)(2)D(3)
      concentrations in both large- and small-breed dogs, together with generalized
      osteoporosis. Large-breed pups fed on a standard diet supplemented with Ca and P
      had decreased plasma concentrations of both 25(OH)D(3) and 1,25(OH)(2)D(3), which
      may indicate an increased clearance of these metabolites; the low plasma
      concentrations of the di-hydroxylated vitamin D metabolites were considered
      responsible for the disturbance in cartilage maturation (i.e., osteochondrosis)
      in these dogs. Even lower concentrations of all vitamin D(3) metabolites were
      seen in young dogs raised on a vitamin D(3)-deficient diet, and led to disturbed
      osteoid and cartilage mineralization (i.e., rickets). These studies indicate that
      there is a hierarchy of factors regulating vitamin D(3) metabolism in dogs, i.e.,
      GH and IGF-I suppress 24-hydroxylase more than hypercalcemia or hypophosphatemia
      does; 1,25(OH)(2)D(3) and 24,25(OH)(2)D(3) are only reciprocally related in
      hyperparathyroidism; excessive Ca and P intake increases the turnover of vitamin
      D(3) metabolites; and the synergism between parathyroid hormone and 1,25(OH)D(3)
      seems to play a role in skeletal mineralization. The low plasma 24,25(OH)(2)D(3)
      concentrations in large-breed dogs raised on standard dog food may play a role in
      the etiology of disturbances in endochondral ossification during the rapid growth
      phase.

PMID- 12431793
TI  - Glucocorticoids inhibit vascular endothelial growth factor expression in growth
      plate chondrocytes.
AB  - Vascular endothelial growth factor (VEGF) plays an essential role in angiogenesis
      in the growth plate and ultimately in regulating endochondral ossification. Since
      longitudinal bone growth is often disturbed in children who are treated with
      glucocorticoids, we investigated the effects of dexamethasone on VEGF expression
      by epiphyseal chondrocytes. Cells were cultured from tibial growth plates of
      neonatal piglets. Using Northern blotting and RT-PCR techniques, the chondrocyte
      specific markers aggrecan, collagen II and CD-RAP were detected. Also the
      glucocorticoid receptor (GR) was expressed. VEGF protein secreted from these
      cells was examined by ELISA and Western immunoblotting. The VEGF(121) and
      VEGF(165) isoforms were detected in the supernatant. As determined by RT-PCR, all
      three major mRNA splice variants were produced, including the species encoding
      VEGF(189). Dexamethasone (100 nM) inhibited both protein and mRNA expression by
      approximately 45%. Hydrocortisone (cortisol) and prednisolone also inhibited VEGF
      secretion, but they were less active than dexamethasone. The inhibitory actions
      of dexamethasone were almost completely blocked by the GR antagonist Org34116,
      indicating that the GR mediates these actions. Degradation of the VEGF mRNA was
      not accelerated by dexamethasone. Therefore, a transcriptional mechanism seems
      likely. Downregulation of this important growth factor could lead to disruption
      of the normal invasion of blood vessels in the growth plate, which could
      contribute to disturbed endochondral ossification and growth.

PMID- 12431794
TI  - Genes that fashion the pituitary gland.
AB  - The pituitary gland with its distinct populations of hormone-producing cells is
      formed from precursor cells that are created when epithelial cells from the
      prospective diencephalon about the roof of the oral cavity during early
      development of the mammalian embryo. Successive steps of assembly during
      development lead from a rudimentary pouch to a definitive structure called
      Rathke's pouch, and finally to the pituitary gland with its anterior,
      intermediate and posterior lobes. The proliferation and differentiation of highly
      specialized cells from their precursors is directed by signaling cascades and
      transcriptional events that are being dissected by genetic and molecular
      approaches. Our current state of knowledge in this regard allows us to use the
      pituitary as a paradigm to delineate general principles of organogenesis in the
      mammalian organism.

PMID- 12431795
TI  - Current approaches for deciphering the molecular basis of combined anterior
      pituitary hormone deficiency in humans.
AB  - This review focuses on the general strategies currently used to decipher the
      molecular bases of combined pituitary hormone deficiency (CPHD) of genetic
      origin. By summarizing illustrative approaches that turned out to be successful
      for identifying an increasing number of genes involved in CPHD in the human, this
      article consider predictable obstacles specific to the investigation of these
      rare and heterogeneous conditions, while underlining the previously unsuspected
      roles of several of these genes during the development of extrapituitary
      structures.

PMID- 12431796
TI  - Exclusion of the lim homeodomain gene LHX4 as a candidate gene for pituitary
      dwarfism in German shepherd dogs.
AB  - Pituitary dwarfism in the German shepherd dog is an autosomal recessive inherited
      abnormality. We tested the hypothesis that a variant of the LIM homeodomain gene
      LHX4 is responsible for the dwarfism phenotype. To this end, we isolated
      Bacterial Artificial Chromosome clones for the canine LHX4 gene. Southern
      blotting experiments showed that the LHX4 gene is a single copy gene in the
      canine genome. A complex CA-repeat was isolated from the BAC clones and was found
      to be polymorphic in German shepherd dogs. Genotyping 5 litters in which the
      dwarfism was segregating showed disconcordance between the inheritance of the
      dwarfism phenotype and the DNA marker. It is concluded that the LHX4 gene does
      not play a primary role in the pituitary dwarfism in the German shepherd dogs.

PMID- 12431798
TI  - Glucocorticoid receptors and Cushing's disease.
AB  - Corticotrophinomas are characterized by a relative resistance to the negative
      feedback action of cortisol on ACTH secretion. In this respect there is a
      similarity with the clinical syndrome of cortisol resistance (CR). As CR can be
      caused by genetic abnormalities in the glucocorticoid receptor (GR) gene, we
      investigated whether the insensitivity of corticotrophinomas to cortisol is also
      caused by the Novo Mutations in the GR gene. We found that somatic mutations of
      the GR gene are not a frequent cause of relative CR in these cells, but our
      observations indicate that loss of heterozygosity (LOH) at the GR gene locus is a
      relativity frequent phenomenon in pituitary adenomas of patients with Cushing's
      disease.

PMID- 12431797
TI  - Growth factors and human pituitary adenomas.
AB  - In recent years the demonstration that human pituitary adenomas are monoclonal
      provides further evidence of genomic mutations occurring in the progenitor cell
      that subsequently undergoes clonal expansion. Up to now the only mutations
      identified in a significant proportion of pituitary tumors, and particular in GH
      secreting adenomas, occur in the Gsalpha gene and cause constitutive activation
      of the cAMP pathway. Subsequent studies revealed that these mutations are
      associated with several feedback mechanisms that, at least in part, counteract
      the oncogenic potential of mutant Gsalpha. As far as the promoting agents are
      concerned, several lines of evidence indicate that in pituitary tumors growth
      factors or their receptors may be overexpressed at variable levels. The
      contribution of these defects in human pituitary tumorigenesis remains to be
      established.

PMID- 12431799
TI  - The neurosurgical management of Cushing's disease.
AB  - Cushing's disease and its associated clinical syndrome reflect the effects of
      excess cortisol on the individual. The cause of Cushing's disease is ordinarily
      an ACTH-secreting benign pituitary adenoma. The diagnosis of Cushing's disease is
      established by sophisticated endocrine testing and comprehensive imaging studies.
      Because of the devastating effects of excess cortisol, therapy that provides
      prompt and effective normalization of serum cortisol is essential. Currently,
      this goal is best achieved by transsphenoidal microsurgery. This paper reviews
      the clinical presentation, laboratory analysis, surgical management and outcome
      in patients with Cushing's disease.

PMID- 12431800
TI  - Imaging of the pituitary gland in dogs with pituitary-dependent
      hyperadrenocorticism.
AB  - Detailed imaging of the pituitary gland is a prerequisite for a successful
      outcome of transsphenoidal hypophysectomy in dogs because it allows for accurate
      preoperative localization and assessment of the size of the pituitary gland.
      Cisternography allows assessment of even small increases in the height of the
      pituitary gland, but the magnitude of suprasellar expansion of pituitary tumors
      cannot be assessed with this technique. Large pituitary tumors with suprasellar
      expansion can readily be detected with conventional contrast-enhanced computed
      tomography (CT), while pituitary microadenomas can be localized with dynamic
      contrast-enhanced CT. Dynamic examination of the entire pituitary may be possible
      with spiral dynamic CT. Magnetic resonance imaging (MRI) of the canine pituitary
      gland provides a clear differentiation between the pituitary gland and the
      surrounding structures, but it remains to be investigated whether in dogs MRI can
      replace dynamic CT for the detection of microadenomas and whether it allows
      accurate localization of the pituitary gland relative to the surgical landmarks.

PMID- 12431801
TI  - Progress in transsphenoidal hypophysectomy for treatment of pituitary-dependent
      hyperadrenocorticism in dogs and cats.
AB  - Cushing's disease or pituitary-dependent hyperadrenocorticism (PDH) is common in
      dogs and rare in cats. PDH is caused by a pituitary tumor producing
      adrenocorticotropin (ACTH). Pituitary imaging with computed tomography (CT) or
      magnetic resonance imaging (MRI) is required to assess the size and location of
      the pituitary adenoma in relation to the surgical landmarks. In a specialized
      veterinary institution, microsurgical transsphenoidal hypophysectomy has proven
      to be a safe and effective treatment for dogs (n=84) and cats (n=7) with
      Cushing's disease. Pituitary surgery requires a team approach and the
      neurosurgeon performing hypophysectomies must master a learning curve. The
      surgical results compared favorably with those for dogs with PDH treated
      medically with mitotane at the same institution. The recurrence rate after
      initially successful surgery increases with longer follow up-times. Pituitary
      function testing in 39 dogs with PDH treated with hypophysectomy revealed that,
      much more so than the other adenohypophyseal cell types, residual corticotropes
      present in the sella turcica after surgery are functional. Such normal ACTH
      secreting cells may maintain normocorticism whereas residual adenoma cells may
      lead to mild recurrence after relatively long periods of remission. Microsurgical
      transsphenoidal hypophysectomy is an effective treatment for canine and feline
      Cushing's disease.

PMID- 12431802
TI  - Effects of growth hormone-releasing peptides in healthy dogs and in dogs with
      pituitary-dependent hyperadrenocorticism.
AB  - The aim of this study is to investigate the effects of ghrelin and GH-releasing
      peptide-6 (GHRP-6) on the release of growth hormone (GH), adrenocorticotrophic
      hormone (ACTH), and cortisol in dogs with pituitary-dependent
      hyperadrenocorticism (PDH) and in healthy dogs of comparable age. In eight
      healthy dogs, the responses to ghrelin and GHRP-6 were compared to those of GH
      releasing hormone (GHRH) and NaCl 0.9% (control). In seven dogs with PDH, the
      effects of ghrelin and GHRP-6 were compared with their effects in healthy dogs.
      In the healthy dogs, GHRH, GHRP-6, and ghrelin caused a significant rise in
      plasma GH concentrations. GHRH administration elicited significantly higher
      plasma GH concentrations than administration of ghrelin and GHRP-6. In the dogs
      with PDH, the GHRP-6-induced release of GH was significantly lower than in
      healthy dogs. Administration of ghrelin elicited a GH release that did not differ
      significantly between dogs with PDH and healthy dogs. Ghrelin and GHRP-6 did not
      cause a significant rise in plasma ACTH and cortisol concentrations in either the
      healthy dogs or the dogs with PDH. It is concluded that in comparison with GHRH,
      GHRP-6 and ghrelin have a low GH-releasing potency in healthy dogs. In dogs with
      PDH, the GH release in response to GHRP-6 is impaired. Neither GHRP-6 nor ghrelin
      activates the pituitary-adrenocortical axis in healthy elderly dogs and dogs with
      PDH.

PMID- 12431803
TI  - Stress adaptation, cortisol and pubertal development in the male common carp,
      Cyprinus carpio.
AB  - This paper reviews a series of recent studies on the effect of adaptation to
      chronic stress on pubertal development in the common carp. In pre-pubertal male
      common carp adaptation to temperature stress caused a retardation of testicular
      development. Stress-induced delay of the first wave of spermatogenesis could be
      prevented by treatment with a cortisol antagonist, indicating that the stress
      effect is mediated by cortisol. Chronically elevated cortisol levels affected all
      parts of the brain-pituitary-gonad (BPG)-axis. In the hypothalamus lower levels
      of sGnRH were observed, in the pituitary the steady state levels of FSHbeta-m RNA
      were decreased, while the testicular production of especially the 11-oxygenated
      androgens 11-ketoandrostenedione (OA) and 11keto-testosterone (11KT) was strongly
      diminished. OA and 11KT have been shown to promote testicular development in
      fish. The LH-induced androgen synthesis in vitro was strongly inhibited by
      cortisol and its agonist dexamethasone. Although cortisol was shown also to
      interfere with the synthesis of the 11-oxygenated androgens in vivo, the lower
      androgen levels induced by cortisol were mainly due to the reduced testicular
      mass. Restoration of the plasma concentrations of these androgens by implantation
      could not prevent the cortisol-induced retardation of testicular growth and the
      first wave of spermatogenesis. Therefore, it is suggested that cortisol acts
      directly on Sertoli cells and/or on germ cells, which is supported by the
      demonstration of GRs on germ cells. We have little indication that the cortisol
      induced retardation of testicular development is mediated by a decreased
      secretion of LH, but a crucial role for FSH can not be excluded.

PMID- 12431804
TI  - The role of luteinizing hormone in the pathogenesis of hyperadrenocorticism in
      neutered ferrets.
AB  - Four studies were performed to test the hypothesis that gonadotrophic hormones,
      and particularly luteinizing hormone (LH) play a role in the pathogenesis of
      ferrets: (I) adrenal glands of ferrets with hyperadrenocorticism were studied
      immunohistochemically to detect LH-receptors (LH-R); (II) gonadotrophin-releasing
      hormone (GnRH) stimulation tests were performed in 10 neutered ferrets, with
      measurement of androstenedione, 17alpha-hydroxyprogesterone and cortisol as
      endpoints; (III) GnRH stimulation tests were performed in 15 ferrets of which 8
      had hyperadrenocorticism, via puncture of the vena cava under anesthesia; and
      (IV) urinary corticoid/creatinine (C/C) ratios were measured at 2-week intervals
      for 1 year in the same ferrets as used in study II. Clear cells in hyperplastic
      or neoplastic adrenal glands of hyperadrenocorticoid ferrets stained positive
      with the LH-R antibody. Plasma androstenedione and 17alpha-hydroxyprogesterone
      concentrations increased after stimulation with GnRH in 7 out of 8
      hyperadrenocorticoid ferrets but in only 1 out of 7 healthy ferrets.
      Hyperadrenocorticoid ferrets had elevated urinary C/C ratios during the breeding
      season. The observations support the hypothesis that gonadotrophic hormones play
      a role in the pathogenesis of hyperadrenocorticism in ferrets. This condition may
      be defined as a disease resulting from the expression of LH-R on sex steroid
      producing adrenocortical cells.

PMID- 12431805
TI  - The role of prolactin and growth hormone in mammary gland development.
AB  - Development and differentiation of the mammary gland occur primarily during
      pregnancy. Females homozygous (-/-) for the null mutation of the PRL receptor
      (PRLR) gene are sterile due to a complete failure of blastocysts to implant. In
      progesterone-treated mice pregnancy is rescued but the mammary gland is severely
      underdeveloped. Interestingly, females hemizygous for the PRLR (+/-) in their
      first lactation show an almost complete failure to lactate. This phenotype
      disappears in the second and subsequent pregnancies in inbred 129/Sv mice but is
      maintained in inbred C57BL/6 mice. In GH receptor (GHR) KO mice litter size is
      markedly decreased, probably due to an ovarian defect. To assess the relevance of
      the GH and PRLRs in the mammary gland development, GHR and PRLR null epithelia
      were transplanted into cleared fat pads of wild-type mice. Such studies show that
      epithelial GHR is not required for functional mammary development. In contrast,
      epithelial PRLRs are required for mammary development and milk protein gene
      expression during pregnancy. Since ductal development is impaired in GHR -/-
      mice, it appears that GH signals through the stromal compartment. In summary, it
      is now established that GH and PRL activate Stat5 in separate compartments,
      reflecting their specific roles in ductal and alveolar development and
      differentiation.

PMID- 12431806
TI  - Cloning and characterization of the 5'-flanking region of the canine growth
      hormone gene.
AB  - The growth hormone (GH) gene is expressed in a variety of tissues outside the
      pituitary, including the mammary gland. GH expression in the mammary gland is
      stimulated by progestins. The local synthesis of mammary GH may provide a highly
      proliferative environment within the mammary gland that may contribute to the
      development or progression of mammary tumours. To elucidate the mechanism
      regulating mammary GH expression, we cloned the 5'-flanking region of the canine
      GH gene using inverse polymerase chain reaction. Gel-shift experiments showed
      that several sequences in the 5'-flanking region of the GH gene bind mammary
      nuclear proteins and may be involved in basal and progesterone-induced mammary GH
      expression. Sequence analysis and comparison with the GH promoters of human, rat,
      and mouse genes revealed a number of shared binding sites for transcription
      factors such as Pit-1, which is involved in pituitary GH expression, and for
      factors involved in the differentiation of lymphoid cells. Moreover, a putative
      binding site for the progesterone receptor (PR) was identified in all promoters,
      indicating that the progestin-induced expression of GH in mammary tissue is most
      probably a direct effect of activated PRs on the GH gene promoter and that this
      may occur in various species.

PMID- 12431807
TI  - The ubiquitin-proteasome pathway and the regulation of growth hormone receptor
      availability.
AB  - The number of growth hormone receptors (GHR) per cell are regulated and this
      feature plays a major role in the hormone responsiveness of the body. This
      article deals with the regulatory mechanisms underlying the availability of GHR
      for serum growth hormone. The availability of membrane proteins at the cell
      surface can be regulated at different locations within the cell: (1) The amount
      of protein synthesized in the endoplasmic reticulum (ER) is largely controlled by
      gene transcription. In addition, the ER quality control system regulates the
      exiting of properly folded proteins from the ER. (2) In the trans-Golgi network,
      proteins can either be diverted directly to the lysosomes or be transported to
      the cell surface. (3) At the plasma membrane, the endocytic machinery can select
      proteins for endocytosis via clathrin-coated pits or proteins may be subject to
      proteolysis, resulting in shedding of the extracellular domain. (4) In endosomes,
      internalized proteins are either recycled back to the plasma membrane or targeted
      to the lysosome for degradation. At each of these cellular locations the
      ubiquitin-proteasome pathway can specifically regulate protein levels via
      different mechanisms. In transfected Chinese hamster lung cells, GHR availability
      is determined by three factors: endocytosis (75%), shedding (10%), and other
      undetermined mechanisms (15%). As outlined in this article the level of GHR at
      the cell surface, defined as GHR availability, is mainly regulated by the
      ubiquitin-proteasome pathway.

PMID- 12431808
TI  - Morphogenic and tumorigenic potentials of the mammary growth hormone/growth
      hormone receptor system.
AB  - Due to the characteristics of the luteal phase of the ovarian cycle in the dog,
      which spans a prolonged time period, this species is a suitable model to study
      the role of progestins in both normal morphogenic and abnormal tumorigenic
      processes in the mammary gland. It has been convincingly shown that progestins,
      including endogenous progesterone, induce the synthesis of growth hormone (GH) in
      the normal and the tumorous canine mammary gland. The growth hormone receptor
      (GHR) is also expressed in normal and tumorous canine mammary tissues and in this
      concise overview we highlight recent advances in our understanding of the
      significance of the GH/GHR system for mammary gland (patho)biology. In an attempt
      to unravel the cellular and molecular mechanisms associated with the GH/GHR
      system, we were able to show that both GH and GHR are differentially expressed in
      normal canine mammary tissues. Maximum expression of both GH and GHR occurs
      during the proliferation phase of the tissue, which links the progestin-induced
      mammary GH synthesis to the progestin-associated proliferation of epithelial
      cells in the mammary gland. Expression of the GH/GHR system is also present in
      most canine mammary tumors, albeit that GHR expression may be downregulated in
      undifferentiated mammary carcinomas. Upon GH stimulation of the GHR-positive CMT
      U335 canine mammary tumor cell line, the transcription factors STAT5A and STAT5B
      become phosphorylated on their tyrosine residues, which is likely to reflect the
      significance of mammary GH in vivo. Molecular analysis of the canine mammary GHR
      transcripts by RT-PCR provided evidence for normal and alternative processing of
      the GHR primary transcript encoding the full-length plasma membrane GHR and at
      least four putative GH binding proteins (GHBPs), respectively. The translation
      products from the alternatively spliced GHR transcripts indicate an intact N
      terminal ligand binding domain and an unique C-terminal portion, lacking the
      transmembrane domain and cytoplasmic tail. Thus, these proteins are considered to
      be able to bind GH, but have lost their signaling potential. The exact biological
      role of these GHBPs remains to be established, but GHBPs may have a transport
      function in the endocrine route, regulate the level of biologically available GH
      locally, or dominant-negatively influence the full-length plasma membrane GHR. In
      dog mammary cancer specimens strongly reduced levels of alternatively spliced GHR
      transcripts were found compared to the non-malignant mammary tissue. Notably,
      expression of both GH and GHR in mammary cancer cells is not restricted to dogs.
      Recent experiments generated evidence for GH and GHR expression in human breast
      cancer cells, and also in human prostate cancer cells, which represents another
      highly prevalent hormone-sensitive human malignancy. In agreement with our
      findings in the dog, the expression of the hGH-N gene in human mammary cancer
      cells seemed to correlate positively with their progesterone receptor status,
      which warrants, in our opinion, a reconsideration of the role of progestins in
      breast cancer of women. In human prostate cancer cells four different hGH-N
      transcripts were detected, which encode classical 22 kDa GH and GH-related
      proteins. Consistent with the findings on the canine GHR, different GHR
      transcripts in human mammary cancer cells and prostate cancer cells were detected
      encoding the full-length plasma membrane GHR and putative GHBPs.

PMID- 12431809
TI  - Secretion of growth hormone and prolactin during progression of the luteal phase
      in healthy dogs: a review.
AB  - In some dogs the long exposure to high circulating progesterone levels during
      each oestrous cycle may result in a syndrome of growth hormone (GH) excess, i.e.
      acromegaly. The progesterone-induced GH production in dogs with acromegaly
      originates from the mammary gland. Also in healthy cyclic bitches, the pulsatile
      secretion pattern of GH changes during progression of the luteal phase, with
      basal GH secretion being higher and pulsatile GH secretion being lower when
      plasma progesterone concentration is high. This may be explained by partial
      suppression of pituitary GH release by progesterone-induced GH production in the
      mammary gland. Progesterone also modulates the secretion of prolactin in the
      bitch. In pregnant and overtly pseudopregnant bitches, the plasma prolactin
      concentration starts to rise about 1 month after ovulation, which is when the
      plasma progesterone concentration begins to decline. Also in healthy cyclic
      bitches, most prolactin is released during the second half of the luteal phase.
      The changes in GH and prolactin release during the luteal phase may promote the
      physiological proliferation and differentiation of mammary gland tissue in the
      bitch. In the early part of the luteal phase progesterone-induced mammary GH
      initiates proliferation of the mammary epithelium, whereas in the late luteal
      phase, when progesterone concentrations decrease, prolactin release increases and
      promotes lobuloalveolar differentiation.

PMID- 12431810
TI  - Role of growth hormone and growth hormone receptor in oocyte maturation.
AB  - Near the completion of growth, mammalian oocytes acquire the competence to resume
      and complete meiosis. In vivo the preovulatory LH surge triggers the resumption
      of meiosis in the oocyte contained in preovulatory follicles. When immature
      oocytes and the surrounding cumulus cells are released from their follicular
      environment, resumption of meiosis is induced spontaneously. Culture of bovine
      cumulus oocyte complexes (COCs) obtained from antral follicles results in
      blastocyst formation following in vitro maturation, in vitro fertilisation and in
      vitro embryo culture. Addition of growth hormone (GH) to the maturation medium
      accelerates nuclear maturation of cumulus enclosed bovine oocytes, induces
      cumulus expansion and promotes early embryonic development following in vitro
      fertilisation. The effect of GH is exerted through the cumulus cells and not
      mediated by IGF-I. Cumulus cells and the oocyte express mRNA for GH receptor.
      Using specific inhibitors it has been shown that the effect of GH on oocyte
      maturation and cumulus expansion is mediated by the cyclic AMP signal
      transduction pathway. Within COCs both cumulus cells and oocyte show GH
      immunoreactivity while expression of GH mRNA is only found in the oocyte. These
      observations point to a paracrine and/or autocrine action of GH in oocyte
      maturation.

PMID- 12431811
TI  - Growth hormone gene expression in canine normal growth plates and spontaneous
      osteosarcoma.
AB  - The indirect growth-promoting action of pituitary-derived growth hormone (GH) on
      skeletal growth is thought to be mediated by systemically released insulin-like
      growth factor-I (IGF-I) and by locally produced IGF-I. The aim of the present
      study was to document whether GH is expressed locally in canine bone and
      spontaneous osteosarcoma. Using RT-PCR the expression of GH mRNA was demonstrated
      in the metaphyseal, but not in the majority of epiphyseal ends of the canine
      growth plate. GH mRNA was also present in 25% of the canine osteosarcoma
      specimens. The expression of GH mRNA in predominantly active osteoid forming
      areas was associated with the presence of immunoreactive GH in osteoblasts, as
      shown by immunohistochemistry. It is concluded that locally produced GH is
      involved in osteoid formation and may play a role in the growth of neoplastic
      bone lesions in the dog.

PMID- 12431812
TI  - Locally produced growth hormone in canine insulinomas.
AB  - The production and release of GH has been demonstrated in a variety of extra
      pituitary tissues. In this respect insulin-producing pancreatic tumours are also
      of interest because it has been observed that GH may promote islet cell
      proliferation. However, these effects have only been related to GH of pituitary
      origin and the possibility of local production of GH with autocrine-/paracrine
      effects has not been considered. In this study, a reverse transcriptase
      polymerase chain reaction (RT-PCR) was used to demonstrate the presence of GH
      mRNA in pancreatic tissue of five healthy dogs and insulinomas of 14 dogs. After
      Southern blotting of the RT-PCR products, blots were hybridized using a canine
      specific GH-probe and quantified using phosphor imaging. GH gene expression was
      further demonstrated by in situ hybridization using a canine digoxigenin-labelled
      GH-specific cDNA probe. In addition, GH immunohistochemistry was performed. In
      five samples of normal pancreatic tissue a weak hybridization signal was found.
      This signal was significantly higher in nine of 12 primary tumours. In ten of 11
      metastases there was a positive hybridization signal, and this signal was also
      significantly higher than in the primary tumours. In situ hybridization in one
      sample demonstrated that GH mRNA was only produced in the tumour cells. The local
      production of GH was confirmed by positive staining of tumour tissue with anti-GH
      antibodies in ten of 12 samples. It is concluded that canine insulinomas express
      the gene encoding GH mRNA. The locally produced GH may have an
      autocrine/paracrine effect on tumour progression. The relatively high expression
      levels in metastases of these tumours may be related to the low inhibitory
      influence of somatostatin outside the pancreas.

PMID- 12431813
TI  - Early disturbances in insulin secretion in the development of type 2 diabetes
      mellitus.
AB  - After a short description of normal glucose homeostasis, recent findings in
      relation to insulin release in three groups with a high risk of future
      development of type 2 diabetes are described. Hyperglycemic clamps in subjects
      with impaired glucose tolerance (IGT) clearly indicate that pancreatic beta cell
      function is decreased, in addition to the decreased insulin sensitivity. In women
      with former gestational diabetes mellitus (GDM), insulin release is also lower
      than in controls. In Caucasian first-degree relatives (FDRs) with normal glucose
      tolerance, various studies have shown that beta cell function is lower than in
      controls, while on the average insulin sensitivity is normal. This implies that
      beta cell function is disturbed earlier in subjects at risk of developing
      diabetes than is often appreciated. In the near future, the genetic studies
      currently underway will presumably unravel the pathogenesis of disturbances both
      in insulin secretion and in insulin action, in type 2 diabetes mellitus.

PMID- 12431814
TI  - Role of islet amyloid in type 2 diabetes mellitus: consequence or cause?
AB  - Type 2 diabetes mellitus (DM2) is characterized metabolically by defects in both
      insulin secretion and insulin action, resulting in hyperglycemia.
      Histopathologically, DM2 is characterized by depositions of protein in the
      pancreatic islets. This 'islet amyloid' is present in >90% of patients with DM2,
      as well as in monkeys and cats with DM2. The pathogenesis of DM2 is heterogeneous
      and multifactorial, although insulin resistance seems to be the predominant
      initiating factor for development of the disease. In the longer term, an insulin
      secretion defect is also revealed (referred to as 'beta-cell failure'), resulting
      in clinically manifest diabetes. Recent data, particularly from transgenic mouse
      studies, indicate that islet amyloidosis is a diabetogenic factor, which is both
      consequence (of insulin resistance) and cause (of beta-cell failure) of DM2.
      Available transgenic mouse models with islet amyloid formation in vivo will
      provide the opportunity to assess the effectiveness of novel anti-amyloidogenic
      therapies, for which promising results are emerging.

PMID- 12431815
TI  - Pathogenesis of feline diabetes mellitus.
AB  - The common form of spontaneous diabetes mellitus that occurs in domestic cats
      bears close resemblance clinically and pathologically to human type 2 diabetes
      mellitus (T2DM). For example, the typical diabetic cat is obese and middle-aged,
      and has low but detectable circulating insulin levels. However, the most striking
      similarity is the occurrence of islet amyloidosis (IA) in nearly all diabetic
      cats and in over 90% of humans with T2DM. IA in both humans and cats is derived
      from islet amyloid polypeptide (IAPP, or amylin) which is a hormone produced and
      secreted along with insulin by the pancreatic beta cells. Since all cats and
      humans normally produce IAPP, additional factors must be invoked in order to
      explain the development of IA. Several lines of evidence support the concept that
      IA is caused by chronically increased stimulus for beta cells to secrete IAPP
      (and insulin). For example, peripheral insulin resistance such as in chronic
      obesity results in increased IAPP and insulin secretion. A recent study, in which
      diabetes mellitus was induced in cats, demonstrated that IAPP hypersecretion was
      induced by treatment with a sulfonylurea drug and resulted in 4/4 cats in this
      group developing IA. In contrast, cats treated with insulin had low IAPP
      secretion and minimal IA developed in 1/4 cats. Several human-IAPP transgenic
      mouse models, in which there is IAPP overexpression, also support the notion that
      prolonged high expression of IAPP leads to IA. In vitro models of IAPP
      overexpression also support this mechanism for IA formation and by demonstrating
      an association between IA formation and beta cell toxicity, suggest a linkage
      between IA formation and loss of beta cells in T2DM. A recent study has indicated
      that intermediate-sized IAPP-derived amyloid fibrils can disrupt cell membranes
      and therefore, may be involved in the destruction of beta cells. Striking
      parallels between the pathogenesis of IA and beta-amyloid plaque formation in
      Alzheimer's disease suggest possible parallel pathogenetic mechanisms of cell
      death and provide potential avenues for future studies into the pathogenesis of
      IA.

PMID- 12431816
TI  - Comparative aspects of diabetes mellitus in dogs and cats.
AB  - Diabetes mellitus is a common disease in cats and dogs. Its incidence is
      increasing, possibly due to an increase in obesity in both species. Different
      types of diabetes have been identified in pet animals. The classification of
      diabetic dogs and cats is modeled after the human classification but especially
      in the diabetic dogs, many aspects are different. The diabetic cat, however,
      resembles type 2 diabetic human patients more closely. The clinical presentation,
      pathophysiology, and histologic findings are described for both dog and cat and
      possible etiological mechanisms are discussed.

PMID- 12431817
TI  - Interleukin-6 regulates androgen receptor activity and prostate cancer cell
      growth.
AB  - Interleukin-6 (IL-6) is a multifunctional cytokine which is involved in
      regulation of growth of various malignant tumors. IL-6 binds to its receptor,
      which is composed of a ligand-binding and a signal-transducing subunit and
      activates pathways of signal transducers and activators of transcription and
      mitogen-activated protein kinases (MAPKs). In prostate cancer cells, IL-6 induces
      divergent proliferative responses. Serum levels of IL-6 are elevated in patients
      with therapy-resistant carcinoma of the prostate. We have investigated whether IL
      6 interacts with the androgen signaling pathway in prostate cancer cells. In DU
      145 cells, transiently transfected with androgen receptor (AR) cDNA, IL-6 caused
      ligand-independent and synergistic activation of the AR. Nonsteroidal antagonists
      of the AR down-regulated AR activity induced by IL-6. In LNCaP cells, IL-6
      induced expression of the AR-regulated prostate-specific antigen gene. Inhibitors
      of protein kinase A and C and MAPK down-regulated IL-6-induced AR activity. IL-6
      expression in human prostate tissue was studied by immunohistochemistry. In
      benign prostatic tissue, IL-6 immunoreactivity was confined to basal cells. In
      prostate intraepithelial neoplasia and in cancer tissue, atypical intraluminal
      and cancer cells expressed IL-6. The expression of IL-6 receptor was demonstrated
      in benign and malignant tissue in both epithelium and stroma. In the authors'
      laboratory, IL-6-inhibited proliferation of parental LNCaP cells. A new LNCaP
      subline was generated to investigate changes in signal transduction which might
      occur after prolonged treatment with IL-6. In the subline LNCaP-IL-6+, IL-6
      neither reduced a number of cells nor caused G1 growth arrest. IL-6 receptor
      expression declined during long-term IL-6 treatment. However, IL-6-up-regulated
      AR expression and was capable of inducing AR activity in LNCaP-IL-6+ cells.
      Parental LNCaP cells do not express IL-6. In contrast, IL-6 mRNA and protein
      expression were detectable in high passages of LNCaP-IL-6+ cells. Thus changes in
      signal transduction occur in prostate cancer cells after prolonged IL-6 treatment

PMID- 12431818
TI  - Angiogenesis in prostate cancer: its role in disease progression and possible
      therapeutic approaches.
AB  - The interaction between cancer cells and their microenvironment is a promising
      area for the development of novel therapeutic anti-cancer modalities. The
      formation of new blood vessels, angiogenesis, is an important step in cancer
      progression. Angiogenesis is a complex multistep process involving close
      orchestration of endothelial cells, extracellular matrix, and soluble factors.
      Essentially every step has been found to be regulated by inducers and inhibitors.
      Prostate cancer has the ability to produce angiogenic factors such as
      metalloproteinases, vascular endothelial growth factor, fibroblast growth factor
      2, transforming growth factor-beta and cyclooxygenase-2. In several studies in
      prostate cancer an increased microvessel density is associated with poorer
      prognosis. On the other hand several endogenous inhibitors of angiogenesis have
      been described in prostate cancer e.g., angiostatin, endostatin, prostate
      specific antigen (PSA), thrombospondin-1, interleukin 10, interferons and
      retinoids. The expanding insight in the process of angiogenesis has resulted in a
      large number of pharmaceutical agents that have been tested in preclinical
      studies and are currently tested in clinical trials. These agents inhibit
      endothelial cell proliferation or migration and induce apoptosis. This ultimately
      will affect the formation of new vessels thereby inducing tumor dormancy. Because
      antiangiogenic treatment is cytostatic rather than cytotoxic, patients will need
      long-term therapy to prevent regrowth of the tumor. Prostate cancer is an ideal
      tumor for antiangiogenic studies because of the availability of a reliable tumor
      marker, PSA, the indolent clinical course of this cancer and the low rate of
      proliferation even in metastatic sites. Furthermore, clinical studies showed
      limited side effects, which is advantageous in this elderly patient group.
      Whether the ultimate antiangiogenic treatment is effective as a single agent or
      in combination with radiation therapy, chemotherapy or immunotherapy remains to
      be determined.

PMID- 12431819
TI  - Canine prostate carcinoma: epidemiological evidence of an increased risk in
      castrated dogs.
AB  - The present retrospective study investigated the frequency of prostate carcinoma
      (PCA) among prostate abnormalities in dogs and determined whether castration
      influences the incidence of PCA in dogs. During the years 1993-1998, 15,363 male
      dogs were admitted to the Utrecht University Clinic of Companion Animals, and of
      these dogs 225 were diagnosed with prostatic disease. In addition, another 206
      male dogs were diagnosed as having prostatic disease based on cytologic
      examination of aspiration biopsies submitted by referring veterinarians. Benign
      prostatic hyperplasia was diagnosed in 246 dogs (57.1%), prostatitis in 83 dogs
      (19.3%), and PCA in 56 dogs (13%). Dogs with PCA were significantly older (mean
      age=9.9 years) than dogs with other prostatic diseases (mean age=8.4 years). The
      Bouvier des Flandres breed had an increased risk (odds ratio (OR)=8.44; 95% CI
      4.38-16.1) of having PCA. Castration (26/56) increased the risk (OR=4.34; 95% CI
      2.48-7.62) of PCA. The mean age at diagnosis of PCA in castrated dogs and in
      intact male dogs was not significantly different. The interval between castration
      and onset of prostatic problems was highly variable, suggesting that castration
      does not initiate the development of PCA in the dog, but it does favour tumor
      progression.

PMID- 12431820
TI  - New bone formation in nude mouse calvaria induced by canine prostate tissue.
AB  - Osteoblastic metastases are common in patients with advanced prostate cancer. The
      pathophysiology of the new bone formation at metastatic sites is not currently
      known, but it is hypothesized that growth factors secreted by the prostate may be
      involved. Unfortunately, most rodent models of prostate cancer with metastasis to
      bone are osteolytic and not osteoblastic. Significant osteolysis by tumor cells
      at metastatic sites also may lead to fractures or bone instability.
      Misinterpretation of new periosteal bone due to bone instability as tumor-cell
      osteo-induction is another disadvantage of the osteolytic models. To circumvent
      these problems, we have developed a model system of new bone formation in the
      calvaria of nude mice stimulated by normal canine prostate tissue. Collagenase
      digested normal prostate tissue was implanted adjacent to the calvaria of nude
      mice. Calvaria were examined at 2 weeks post-implantation for changes in the bone
      microenvironment by histology, calcein uptake at sites of bone mineralization,
      and tartrate-resistant acid phosphatase staining for osteoclasts. The prostate
      tissue remained viable and induced abundant new woven bone formation on the
      adjacent periosteal surface. In some cases new bone formation also was induced on
      the distant or concave calvarial periosteum. The new bone stained intensely with
      calcein, which demonstrated mineralization of the bone matrix. The new bone
      formation on prostate-implanted calvaria significantly increased (1.7-fold) the
      thickness of the calvaria compared with control calvaria. New bone formation was
      not induced in calvaria of mice implanted with normal canine kidney, urinary
      bladder, spleen, or skeletal muscle tissue, or mice with surgically-induced
      disruption of the periosteum. Osteoclast numbers in the medullary spaces and
      periosteum of calvaria were mildly increased (61%) in mice with implanted
      prostate tissue. In conclusion, this animal model will be useful for
      investigating the roles of prostate-derived growth factors on new bone formation
      in vivo.

PMID- 12431822
TI  - Activity of pemetrexed (alimta), a new antifolate, against non-small cell lung
      cancer.
AB  - Chemotherapy for non-small cell lung cancer (NSCLC) has developed within the past
      decade into an important part of treatment with palliative aims as well as part
      of curative combined-modality treatment. Furthermore, second-line treatment has
      become an accepted part of the palliative approach as well. Pemetrexed (alimta)
      is one of the recently introduced agents that have been evaluated for efficacy
      against NSCLC. In single-agent phase II studies in previously untreated NSCLC,
      pemetrexed resulted in a response rate of around 20%. In combination with
      cisplatin, response rates of 40% were achieved. As a second-line single agent in
      patients with early progression after first-line treatment, the response rate is
      9%. Toxicity is mainly hematologic and can be reduced by supportive measures.
      Overall, pemetrexed is an active agent that further improves the chemotherapeutic
      options of physicians involved in the treatment of NSCLC.

PMID- 12431823
TI  - Gemzar platinum combinations: phase III trials in non-small cell lung cancer.
AB  - Lung cancer accounts for about 28% of all cancer-related deaths. Non-small cell
      lung cancer (NSCLC) constitutes 80% of all lung cancer cases, and in 70% of
      patients, the disease is diagnosed when it is locally advanced or metastatic. In
      these situations, chemotherapy has played only a minor role in modifying the
      natural history according to a 1995 meta-analysis. New drugs such as gemcitabine,
      vinorelbine, and the taxanes have been combined with cisplatin and tested in
      several phase-II and phase-III clinical trials versus cisplatin alone and
      different cisplatin/new drug combinations. Overall, the data seem to confirm
      that, despite a possible increase in response rate, no major difference in long
      term survival has been achieved. Moreover, toxicity and cost may be significant
      with some of the combinations and schedules. While the combination of cisplatin
      and gemcitabine seems to be fairly active and better tolerated, we all look
      forward to the results of ongoing studies on the association of these regimens
      with the new biological drugs.

PMID- 12431824
TI  - Gemcitabine (Gemzar)-based induction chemotherapy in non-small-cell lung cancer.
AB  - The gemcitabine/cisplatin combination is a key regimen in unresectable locally
      advanced and metastatic non-small-cell lung cancer (NSCLC), and, consequently, it
      is a logical step forward to investigate the activity of this new combination in
      less advanced stages of NSCLC. Efficacy data of several phase II studies
      performed in a mixed study population of stage IIIA and IIIB disease
      investigating gemcitabine/cisplatin as induction treatment indicate an average
      response rate > 60%. The treatment is rather well tolerated and toxicity is
      especially mild when a 3-week schedule is used. More recently, five randomized
      studies, one already completed, have been designed to investigate the role of
      induction chemotherapy in early stage (I and II) NSCLC. In Italy, an ongoing
      randomized clinical trial called Chemotherapy for Early Stages Trial (ChEST)
      compares the efficacy of surgery alone or surgery plus induction
      gemcitabine/cisplatin in operable patients (T2-3N0, T1-2N1, T3N1) having
      progression-free survival as a primary end point.

PMID- 12431825
TI  - Healthcare outcomes: gemcitabine cost-effectiveness in the treatment of non-small
      cell lung cancer.
AB  - The introduction of any new chemotherapy agent for non-small cell lung cancer
      (NSCLC) ought to be considered carefully in light of both costs and measurable
      benefits. Decision making is straightforward if a new treatment is relatively
      cheaper and more effective (i.e. introduce new therapy) or more expensive and
      less effective (i.e. reject new treatment) than standard therapies. However, if a
      treatment is more expensive and also more effective, or less expensive but also
      less effective, decision making becomes more complicated. An economic evaluation
      of the cost-effectiveness of gemcitabine in advanced NSCLC was performed as a
      case study. A comprehensive literature search for published economic evaluations
      of gemcitabine was carried out. Economic studies examining treatment for advanced
      NSCLC were limited to cost-minimization analyses and cost-effectiveness analyses.
      The analyses included primary economic studies, e.g. trials that included an
      integral economic evaluation, and secondary research, e.g. analyses based on
      published trial data and modeling. Overall, gemcitabine regimens proved cost
      effective against standard therapies in this analysis. Prospective economic and
      quality-of-life analyses should be incorporated into study designs to help
      identify treatments that will maximize societal health benefits.

PMID- 12431826
TI  - Targeted therapy in non-small cell lung cancer.
AB  - Cytotoxic chemotherapy for advanced non-small cell lung cancer (NSCLC) offers
      only modest benefits over best supportive care alone by modestly prolonging
      survival, reducing symptoms, and improving quality of life. Despite the
      introduction of a number of new agents over the past decade, we have seen no
      convincing improvements in efficacy and safety with platinum-based regimens. It
      appears that a plateau has been reached in the development of traditional
      cytotoxic chemotherapy and a new paradigm is needed. Novel treatment modalities
      have emerged from advances in the understanding of tumor cell biology. These
      sophisticated new agents home in on and neutralize specific targets in the
      biologic pathway of cancer. This "targeted therapy" represents a new generation
      of anticancer treatment and a chance to revitalize the moribund state of NSCLC
      treatment.

PMID- 12431827
TI  - Gemcitabine/carboplatin in advanced non-small cell lung cancer.
AB  - Gemcitabine/cisplatin is among the most widely used regimens in Europe for first
      line treatment of non-small cell lung cancer (NSCLC). Problems with cisplatin use
      in this setting include significant nonhematologic toxicity and difficulty of use
      in outpatients. Carboplatin constitutes a reasonable alternative to cisplatin in
      this combination, since it shows synergy with gemcitabine in vitro, is easier to
      use in ambulatory patients, and has a better nonhematologic toxicity profile.
      Studies of gemcitabine/cisplatin on a 28-day schedule (gemcitabine on days 1, 8,
      15 and carboplatin on day 1) generally indicate excessive thrombocytopenia. Use
      of a 21-day schedule (e.g. gemcitabine on days 1 and 8, carboplatin on day 1) is
      associated with reduced toxicity and comparable efficacy. Results of one
      randomized phase II study suggest reduced toxicity and reduced objective response
      rate with gemcitabine/carboplatin versus gemcitabine/cisplatin. We are currently
      conducting a phase III comparison of gemcitabine 1200 mg/m(2) on days 1 and 8
      plus carboplatin at an area under the curve of 5 mg/ml/min on day 1 versus
      gemcitabine at the same dose plus cisplatin 80 mg/m(2) on day 1 every 21 days in
      chemotherapy-nai;ve patients with stage IIIB/IV NSCLC; interim analysis indicates
      comparable response rates (47 and 48%). A better understanding of the relative
      toxicities of these regimens should be provided by the final results of this
      trial.

PMID- 12431828
TI  - Past, present, and future of gemcitabine and carboplatin regimens in advanced non
      small cell lung cancer.
AB  - Several chemotherapeutic regimens have emerged in the past 5 years with the
      capability to improve survival and quality of life of patients with advanced non
      small cell lung cancer (NSCLC). Among these treatments, the regimen of
      gemcitabine (Gemzar) and carboplatin (Paraplatin) has gained increasing
      acceptance. The combination of these two drugs was initially hampered by
      unacceptable platelet toxicity. However, the use of a 21-day schedule with the
      administration of gemcitabine on days 1 and 15 or the use of a 28-day schedule
      with the omission of day-15 gemcitabine has clearly been well tolerated and
      active. Unlike taxane based regimens, there is no need for steroid premedication,
      and neurotoxicity and alopecia are absent. This regimen is well tolerated and
      easily administered on an outpatient basis. It therefore represents an excellent
      "platform regimen" for the addition of new agents, particularly those associated
      with minimal myelotoxicity. Three-drug regimens consisting of
      gemcitabine/carboplatin and a taxane have been evaluated both with concurrent and
      sequential administration of the drugs. Trials are under way or planned for the
      addition of novel agents such as C225, UCN-01, PKC-alpha antisense, bexarotene,
      COX-2 inhibitors and other agents.

PMID- 12431829
TI  - Does chemotherapy have a role as palliative therapy for unfit or elderly patients
      with non-small-cell lung cancer?
AB  - Elderly patients and younger "unfit" patients with poor Eastern Cooperative
      Oncology Group (ECOG) performance status (PS) (> or = 2) suffering from advanced
      non-small-cell lung cancer (NSCLC) are two different populations--both of which
      require palliative treatments. Elderly patients frequently experience progressive
      decline of organ function and multiple comorbidities, which need to be considered
      when choosing therapy. ECOG 1594 showed that advanced NSCLC patients with an ECOG
      PS of 2 did not tolerate platinum-based chemotherapy (cisplatin/paclitaxel,
      carboplatin/paclitaxel, cisplatin/docetaxel, carboplatin/paclitaxel). These data
      confirm that treatments designed specifically for this patient subset are needed.
      Single-agent chemotherapy seems to be a reasonable approach, and non-platinum
      based combination chemotherapy should also be investigated. The oncology
      community has become increasingly aware of the magnitude of the problem of cancer
      in the elderly. More than 30% of lung cancers arise in patients > or = 70 years
      old. Elderly patients tolerate chemotherapy poorly, according to the few
      published papers, and are not considered eligible for aggressive cisplatin-based
      chemotherapy in clinical practice. A phase III randomized trial (ELVIS [Elderly
      Lung Cancer Vinorelbine Italian Study]) demonstrated survival and quality-of-life
      benefits with single-agent vinorelbine versus best supportive care. Among the
      newer drugs, gemcitabine has demonstrated activity and low toxicity in phase II
      studies. With this background, we performed a randomized, multicenter phase III
      trial (MILES [Multicenter Italian Lung Cancer in the Elderly Study]) in 707
      advanced NSCLC elderly patients. The MILES study compared single-agent
      chemotherapy with vinorelbine or gemcitabine versus polychemotherapy with
      gemcitabine plus vinorelbine. Results showed no benefit in response rate, time to
      progression, survival, and quality of life for the combination. Single-agent
      chemotherapy remains the standard treatment approach for elderly NSCLC patients
      with advanced disease.

PMID- 12431830
TI  - Non-platinum gemcitabine combinations in non-small cell lung cancer.
AB  - Lung cancer remains the most common cause of cancer related death. Although the
      primary goal of therapy is improvement in survival, improvement of symptoms, and
      quality of life are also important. Platinum-based chemotherapy has been shown to
      confer a modest but statistically significant survival benefit. Platinum-based
      therapy, however, has been associated with significant toxicity. Newer agents,
      such as gemcitabine, vinorelbine, paclitaxel, docetaxel, and irinotecan have been
      introduced into clinical practice. These agents have different mechanisms of
      activity and improved toxicity profiles. Combinations of these novel agents have
      been developed in an attempt to improve the toxicity profile and efficacy of the
      treatment of non-small cell lung cancer. This paper evaluates gemcitabine-based
      non-platinum combinations in the treatment of non-small cell lung cancer. Ongoing
      research evaluating the optimal dose, schedule, and combination is important in
      achieving improved outcomes in terms of survival and quality of life.

PMID- 12431831
TI  - Alimta (pemetrexed disodium): a multitargeted antifolate for the treatment of
      mesothelioma.
AB  - Pemetrexed disodium is an antimetabolite with multiple sites of action. It
      inhibits dihydrofolate reductase, thymidylate synthase, and glycinamide
      ribonucleotide formyl transferase (GARFT). As a single agent it is active against
      a variety of solid tumors. One phase II trial demonstrated a 14.5% response rate
      for single-agent pemetrexed disodium in patients with previously untreated
      mesothelioma. The combination of pemetrexed disodium and cisplatin was associated
      with very encouraging regression rates in mesothelioma patients treated as part
      of a phase I trial. A subsequent trial showed similarly encouraging activity (10
      partial responses out of 25 evaluable patients [40%]) in mesothelioma patients
      treated with pemetrexed and carboplatin. A large, prospectively randomized, phase
      III trial of cisplatin alone versus cisplatin and pemetrexed with vitamin support
      has been completed. The findings will be presented at the 38th Annual Meeting of
      the American Society of Clinical Oncology in May 2002.

PMID- 12431832
TI  - GnRH neurons and episodic bursting activity.

PMID- 12431833
TI  - The IGF-II-deficient placenta: aspects of its function.

PMID- 12431834
TI  - Jost's hormone inhibitrice comes of age.
AB  - The First International Workshop on Anti-Mullerian hormone/Mullerian inhibiting
      substance was held in Aix-en-Provence, France, from 7-8 October 2002.

PMID- 12431837
TI  - Applications of novel resonance energy transfer techniques to study dynamic
      hormone receptor interactions in living cells.
AB  - Many aspects of hormone receptor function that are crucial for controlling signal
      transduction of endocrine pathways can be monitored more accurately with the use
      of non-invasive, live cell resonance energy transfer (RET) techniques.
      Fluorescent RET (FRET), and its variation, bioluminescent RET (BRET), can be used
      to assess the real-time responses to specific hormonal stimuli, whilst preserving
      the cellular protein network, compartmentalization and spatial arrangement. Both
      FRET and BRET can be readily adapted to the study of membrane proteins. Here, we
      focus on their applications to the analysis of interactions involving the
      superfamily of hormone G-protein-coupled receptors. RET is also emerging as a
      significant tool for the determination of protein function in general. Such
      techniques will undoubtedly be of value in determining the functional identities
      of the vast array of proteins that are encoded by the human genome.

PMID- 12431839
TI  - Growth hormone-releasing hormone and pituitary adenylate cyclase-activating
      polypeptide in the reproductive system.
AB  - Growth hormone-releasing hormone (GHRH) and pituitary adenylate cyclase
      activating polypeptide (PACAP) are both members of the glucagon superfamily that,
      with gonadotropins, act at central and peripheral levels as paracrine and
      autocrine coregulators of reproductive function. GHRH and PACAP are ancient
      peptides. Their original forms (both 27 amino acids long) were encoded by a
      single ancestral gene, several duplications of which led to the genes that encode
      the neuropeptides of the glucagon superfamily. In the male and female
      reproductive tracts, GHRH and PACAP interact with a subset of G protein-coupled
      receptors that are structurally similar to the PACAP receptor and variants of the
      vasoactive intestinal peptide receptor, and share several biological actions.
      These are related mainly to the modulation of cAMP-dependent and other signal
      transduction pathways in several cells of the pituitary-gonadal axis. The recent
      discovery that antagonists of GHRH and PACAP suppress the growth of human cancer
      cell lines that are derived from reproductive tissues indicates the potential
      importance of these peptides as local regulators of cell division, cell cycle
      arrest, differentiation and cell death.

PMID- 12431838
TI  - Estrogen action and cytoplasmic signaling pathways. Part II: the role of growth
      factors and phosphorylation in estrogen signaling.
AB  - In recent years, distinct signaling pathways involving specific complexes of
      cytoplasmic proteins have been shown to orchestrate estrogen action. These
      pathways might supplement or augment genomic effects of estrogen that are
      attributable to transcriptional activation by liganded receptor. Signals might be
      transduced through phosphorylation of the estrogen receptors (ERs), or indirectly
      through effects upon transcriptional coactivators or cell receptors. Estrogen
      signaling is coupled to growth factor signaling with feedback mechanisms directly
      impacting function of growth factor receptors. These signaling pathways regulate
      important physiological processes, such as cell growth and apoptosis. Here, we
      focus on cytoplasmic signaling pathways leading to activation of ERs.

PMID- 12431840
TI  - Functional characteristics of CRH receptors and potential clinical applications
      of CRH-receptor antagonists.
AB  - Corticotropin-releasing hormone (CRH) plays a major role in coordinating the
      behavioral, endocrine, autonomic and immune responses to stress. CRH and CRH
      related peptides and their receptors are present in the central nervous system
      and in a wide variety of peripheral tissues, including the immune, cardiovascular
      and reproductive systems, and have been associated with the pathophysiology of
      many disease states. These observations have led to the development of several
      CRH receptor type-selective antagonists, which have been used experimentally to
      elucidate the role of CRH and related peptides in physiological and disease
      processes, such as anxiety and depression, sleep disorders, addictive behavior,
      inflammatory and allergic disorders, neurological diseases and pre-term labor.
      Because of the complex network of multiple CRH receptor subtypes and their tissue
      and agonist-specific signaling diversity, antagonists need to be developed that
      can target specific CRH receptor isoform-driven signaling pathways.

PMID- 12431842
TI  - Somatostatin analogs in the diagnosis and treatment of cancer.
AB  - Over the past few years, significant progress has been made in our understanding
      of the biology and functional significance of somatostatin receptors (sst) on
      human tumors. Somatostatin analogs, such as octreotide, bind predominantly to
      sst(2) and successfully control hormone hypersecretion in patients with
      acromegaly, islet cell tumors and carcinoids, and (temporary) control of tumor
      growth is often also seen. Furthermore, sst(2) on tumors can be imaged in vivo
      after the injection of radionuclide-coupled octreotide. Targeted chemo- and
      radiotherapy, in which somatostatin analogs coupled to a chemotherapeutic agent
      or a radionuclide are selectively internalized by sst-positive tumors, are now
      being studied for their effect on tumor growth. Knowledge about the differential
      anti-tumor effects of the sst subtypes on tumor cells might have clinical
      significance after the development of new subtype-specific somatostatin analogs.

PMID- 12431841
TI  - Role of Akt/protein kinase B in metabolism.
AB  - Since its discovery more than a decade ago, the Ser/Thr kinase Akt/PKB (protein
      kinase B) has been recognized as being remarkably well conserved across a broad
      range of species and involved in a diverse array of cellular processes. Among its
      many roles, Akt appears to be common to signaling pathways that mediate the
      metabolic effects of insulin in several physiologically important target tissues.
      Refining our understanding of those pivotal molecular components that normally
      coordinate insulin action throughout the body is essential for a full
      understanding of insulin resistance in diabetes mellitus and ultimately the
      successful treatment of this disease.

PMID- 12431844
TI  - Noradrenaline reuptake inhibition enhances the antipsychotic-like effect of
      raclopride and potentiates D2-blockage-induced dopamine release in the medial
      prefrontal cortex of the rat.
AB  - We have previously observed that addition of an alpha(2)-adrenoceptor antagonist
      to a selective dopamine (DA) D(2) receptor antagonist enhances the antipsychotic
      like effect of the D(2) blocker and also selectively increases DA output in the
      medial prefrontal cortex (mPFC) in rats. These data also correlate well with
      previous clinical trials showing augmentation by an equivalent drug combination
      in schizophrenia. Since the selective noradrenaline reuptake inhibitor reboxetine
      was found to cause similar effects on the mesolimbocortical DA system as alpha(2)
      adrenoceptor antagonists, the present study was undertaken to explore whether
      also reboxetine might augment the effect of the DA D(2) receptor antagonist
      raclopride in the same preclinical model of antipsychotic activity, the
      conditioned avoidance response (CAR) test. We also investigated the effect of
      this combination in the catalepsy test for extrapyramidal side effect liability,
      as well as on DA output in the mPFC and the nucleus accumbens, respectively.
      Reboxetine (6 mg/kg, i.p.) significantly enhanced the suppressant effect of
      raclopride (0.1 mg/kg, s.c.) on CAR without affecting catalepsy. Administration
      of raclopride (0.1 mg/kg, s.c.) to rats pretreated with reboxetine (6 mg/kg,
      i.p.) resulted in a greatly enhanced effect on DA output in the mPFC but not in
      the nucleus accumbens when compared with raclopride alone. Consequently, these
      results suggest that noradrenaline reuptake inhibition may provide means of
      augmenting the efficacy of classical D(2)-antagonists in the treatment of
      schizophrenia, and, in principle, to generate an atypical antipsychotic drug
      profile.

PMID- 12431845
TI  - Atomoxetine increases extracellular levels of norepinephrine and dopamine in
      prefrontal cortex of rat: a potential mechanism for efficacy in attention
      deficit/hyperactivity disorder.
AB  - The selective norepinephrine (NE) transporter inhibitor atomoxetine (formerly
      called tomoxetine or LY139603) has been shown to alleviate symptoms in Attention
      Deficit/Hyperactivity Disorder (ADHD). We investigated the mechanism of action of
      atomoxetine in ADHD by evaluating the interaction of atomoxetine with monoamine
      transporters, the effects on extracellular levels of monoamines, and the
      expression of the neuronal activity marker Fos in brain regions. Atomoxetine
      inhibited binding of radioligands to clonal cell lines transfected with human NE,
      serotonin (5-HT) and dopamine (DA) transporters with dissociation constants
      (K(i)) values of 5, 77 and 1451 nM, respectively, demonstrating selectivity for
      NE transporters. In microdialysis studies, atomoxetine increased extracellular
      (EX) levels of NE in prefrontal cortex (PFC) 3-fold, but did not alter 5-HT(EX)
      levels. Atomoxetine also increased DA(EX) concentrations in PFC 3-fold, but did
      not alter DA(EX) in striatum or nucleus accumbens. In contrast, the
      psychostimulant methylphenidate, which is used in ADHD therapy, increased NE(EX)
      and DA(EX) equally in PFC, but also increased DA(EX) in the striatum and nucleus
      accumbens to the same level. The expression of the neuronal activity marker Fos
      was increased 3.7-fold in PFC by atomoxetine administration, but was not
      increased in the striatum or nucleus accumbens, consistent with the regional
      distribution of increased DA(EX). We hypothesize that the atomoxetine-induced
      increase of catecholamines in PFC, a region involved in attention and memory,
      mediates the therapeutic effects of atomoxetine in ADHD. In contrast to
      methylphenidate, atomoxetine did not increase DA in striatum or nucleus
      accumbens, suggesting it would not have motoric or drug abuse liabilities.

PMID- 12431846
TI  - Nicotine-induced attentional enhancement in rats: effects of chronic exposure to
      nicotine.
AB  - Consistent with human literature, previous studies identified attention-enhancing
      effects of nicotine in rats, using a 5-choice task. The present study addressed
      the influence of repeated exposure to nicotine on these effects. Over six weeks,
      the effects of nicotine (0.0, 0.05 and 0.2 mg/kg) given ten min before sessions
      were tested each week. In addition, rats were injected daily two hours after
      sessions. In the first week, when these post-session injections were of saline
      for all rats, pre-session nicotine had profound rate-disruptive effects at the
      larger dose. In weeks 2-6, when half the rats received post-session injections of
      saline and the other half of nicotine (0.4 mg/kg), the disruptive effects of pre
      session nicotine had disappeared and it enhanced attentional performance on all
      response indices. These effects did not differ significantly between post-session
      treatment groups or weeks, although they appeared less pronounced in the last two
      weeks. When tested under modified task parameters in weeks 9 and 10, nicotine
      (0.1 mg/kg) robustly enhanced performance in both groups despite continuing daily
      post-session administration of nicotine or saline. These studies provide evidence
      that, following tolerance to initial disruptive effects, the nicotine-induced
      attentional enhancement is stable across lengthy periods of chronic exposure.
      This is important for potential therapeutic applications of the drug and
      indicates that these effects can be a continuous motive for smoking behavior.

PMID- 12431847
TI  - Dopamine D2 receptor-mediated inhibition of dopaminergic neurons in mice lacking
      D2L receptors.
AB  - Two isoforms of the dopamine (DA) D2 receptor are generated from the same gene by
      alternative splicing, D2L and D2S. To identify which isoform is involved in the
      autoregulation of midbrain DA neuron activity, intracellular electrophysiological
      recordings were performed from substantia nigra and ventral tegmental area
      neurons of mice lacking either D2L(D2L-/-) or both D2L and D2S receptors (D2-/-).
      In midbrain DA neurons from wild-type mice, DA and quinpirole, a DA D2-like
      receptor agonist, produced a significant somatic membrane hyperpolarization,
      which led to a reversible inhibition of firing activity. Interestingly, this
      effect was fully abolished in D2-/- neurons but still present in D2L-/- DA
      neurons. These data clearly show that D2S receptors are the main somatodendritic
      autoreceptors of central DA neurons. Thus, pharmacological compounds able to
      interfere selectively with presynaptic D2S receptors might constitute effective
      therapeutic strategies in neuropsychiatric disorders, by causing negligible side
      effects.

PMID- 12431848
TI  - Selective blockade of drug-induced place preference conditioning by ACPC, a
      functional NDMA-receptor antagonist.
AB  - ACPC (1-aminocyclopropanecarboxylic acid) is a partial agonist at the strychnine
      insensitive glycine receptor site on the NMDA receptor complex, and a functional
      NMDA antagonist. A series of experiments was conducted to assess the effects of
      ACPC in a biased place conditioning paradigm. As previously reported, ACPC itself
      did not support either appetitive or aversive place conditioning. However, co
      administration of ACPC (200 mg/kg) blocked the acquisition of place preferences
      conditioned using a variety of psychoactive drugs (amphetamine, cocaine,
      nomifensine, diazepam, morphine, nicotine). No tolerance was seen to this effect
      following two weeks of chronic ACPC administration. Overall, ACPC did not affect
      the expression of place conditioning when administered immediately before the
      post-conditioning test. However, these effects appeared somewhat variable between
      drugs, and further analysis showed that ACPC did block the expression of
      preferences conditioned with some drugs (diazepam, morphine, nicotine), but not
      others (amphetamine, cocaine, nomifensine). The effects of ACPC could not be
      accounted for by state dependence, as ACPC blocked morphine and cocaine place
      preferences when administered during both the acquisition and the expression
      phase of conditioning. In contrast to the blockade by ACPC of drug-induced place
      preferences, ACPC had no effect on the acquisition of place preferences
      conditioned using a variety of natural non-drug reinforcers (food, sucrose,
      social interaction, novelty). ACPC also had no effect on the acquisition of drug
      induced place aversions (naloxone, picrotoxin). Thus, ACPC selectively blocked
      appetitive conditioning by drug reinforcers, without affecting either appetitive
      conditioning by natural reinforcers or drug-induced aversions. As place
      preference conditioning has been demonstrated to have high predictive validity
      for detecting compounds with an abuse potential in humans, this selective action
      suggests that ACPC might have some clinical utility in the treatment of
      addiction, without affecting responses to natural rewards.

PMID- 12431849
TI  - Odor-induced variation in anxiety-like behavior in mice is associated with
      discrete and differential effects on mesocorticolimbic cholecystokinin mRNA
      expression.
AB  - The present investigation assessed alterations in mesocorticolimbic
      cholecystokinin (CCK) mRNA following novel predator and non-predator odor
      exposure and light-dark testing in CD-1 mice. In brief, acute exposure of CD-1
      mice to the predator odor, 2,5-dihydro-2, 4,5-trimethylthiazoline (TMT; the major
      component of the anal gland secretions of the red fox), or the control odor,
      butyric acid (BA), suppressed rearing behavior during odor presentation,
      subsequently induced anxiety in the light dark test, and was associated with
      increased mesocorticolimbic CCK mRNA relative to saline treated mice. Only mice
      exposed to TMT displayed elevated freezing behaviors during odor treatment. In
      the light-dark test, mice exposed to either BA or TMT took longer to reenter the
      light section of the apparatus and spent less cumulative time in the light
      relative to mice exposed to saline. The decreased time spent in the light as well
      as light dark transitions were exaggerated among mice exposed to fox odor. Odor
      presentation was associated with increased CCK mRNA in mesocorticolimbic sites.
      Butyric acid was associated with enhanced CCK gene expression in the VTA, while
      both BA and TMT were associated with increased medial prefrontal cortex (mPFC)
      CCK mRNA levels. Increased CCK mRNA within the VTA and mPFC was evident among
      mice despite testing in the light-dark box. In contrast, basolateral nucleus of
      the amygdala (BLA) CCK mRNA was enhanced following odor exposure among mice in
      the light dark test relative only to saline treated mice which demonstrated a
      natural decrease in BLA CCK mRNA following the light dark test. The differential
      pattern of CCK mRNA associated with discrete psychogenic stressor manipulations
      and the provocation of anxiety-like behavior associated with such experiences is
      discussed.

PMID- 12431850
TI  - Early life stress changes concentrations of neuropeptide Y and corticotropin
      releasing hormone in adult rat brain. Lithium treatment modifies these changes.
AB  - Experiences of early life stress are more prevalent among depressed patients than
      healthy controls. Neuropeptide Y (NPY) was suggested to play a role in the
      pathophysiology of depression. Consequently, we investigated in adult rats the
      effects of maternal deprivation for 3 h/day during postnatal days (PND) 2-14 and
      of dietary lithium during PND 50-83 on brain levels of NPY-like immunoreactivity
      (LI). Brain levels of corticotropin-releasing hormone (CRH) and serum
      corticosterone were also measured. Maternal deprivation reduced NPY-LI levels in
      the hippocampus and the striatum but increased NPY-LI and CRH-LI levels in the
      hypothalamus. Lithium treatment counteracted the effect of maternal deprivation
      in the hippocampus and striatum by increasing NPY-LI levels. In the hypothalamus,
      lithium tended to decrease CRH-LI but further increased levels of NPY-LI; it also
      increased serum corticosterone levels. The results suggest that early life stress
      has long-term effects on brain NPY with implications for the development of
      depression/vulnerability to stress, and that one therapeutic mechanism of action
      of lithium is to increase brain NPY.

PMID- 12431851
TI  - Provisional mapping of quantitative trait loci modulating the acoustic startle
      response and prepulse inhibition of acoustic startle.
AB  - Prepulse inhibition (PPI) of the acoustic startle response (ASR) is a form of
      sensorimotor gating, defined as an inhibition of the startle response when a low
      intensity stimulus, the prepulse, precedes the startling stimulus. Deficits in
      PPI have been reported in schizophrenia and other psychiatric/neurological
      disorders, and correlate with symptom severity in schizophrenia, suggesting that
      deficient PPI per se or abnormalities in neural circuits regulating PPI may cause
      some symptoms of schizophrenia. If so, then genes conferring reduced PPI may
      contribute toward genetic vulnerability to schizophrenia. Studies with
      selectively bred rodent strains indicate that PPI is under genetic control;
      however, the identity of the relevant genes is unknown. The current study used
      recombinant congenic mouse strains derived from C57BL/6J and A/J parents to
      assess genetic variability in PPI and in ASR and to identify provisional
      quantitative trait loci (QTLs) modulating these phenotypes. Significant between
      strain differences in ASR and in PPI at each of several prepulse intensities (75,
      80, 85, 90, 95 dB) were found. Correlations between PPI at the various prepulse
      intensities were highly significant, suggesting appreciable overlap in genetic
      regulation of PPI across prepulse intensities. Five QTLs (chromosomes 3, 5, 7,
      16) associated with PPI across all prepulse intensities, but not with ASR, were
      identified. Two additional QTLs (chromosomes 2, 11) associated with both PPI and
      ASR were found. Fifteen QTLs were associated with ASR alone. Data on genotypes of
      informative congenic strains were used to support probable involvement of loci
      modulating PPI and to narrow the probable chromosomal location of QTLs. If
      confirmed, these QTLs may suggest candidate genes directing novel mechanisms for
      regulation of PPI

PMID- 12431852
TI  - Predictors of fluvoxamine response in contamination-related obsessive compulsive
      disorder: a PET symptom provocation study.
AB  - The purpose of this study was to identify neuroimaging predictors of medication
      response in contamination-related obsessive compulsive disorder (OCD). Prior
      studies of OCD had indicated that glucose metabolic rates within orbitofrontal
      cortex (OFC) were inversely correlated with subsequent response to serotonergic
      reuptake inhibitors (SRIs) and that glucose metabolic rates within posterior
      cingulate cortex (PCC) were positively correlated with subsequent response to
      cingulotomy. Nine subjects with contamination-related OCD underwent a 12-week
      open trial of treatment with the SRI fluvoxamine. Percent change in Yale-Brown
      Obsessive Compulsive Scale score, from pre- to post-treatment, served as the
      index of treatment response. Positron emission tomography (PET) measurements of
      regional cerebral blood flow (rCBF) were obtained prior to treatment, in the
      context of a symptom provocation paradigm. Statistical parametric mapping was
      used to identify brain loci where pre-treatment rCBF was significantly correlated
      with subsequent treatment response. Consistent with a priori hypotheses, lower
      rCBF values in OFC and higher rCBF values in PCC predicted better treatment
      response. This same pattern of associations was present regardless of whether the
      imaging data were acquired during a provoked or neutral state. These findings are
      consistent with prior studies of OCD, indicating that PET indices of brain
      activity within OFC are inversely correlated with subsequent response to SRIs. In
      addition, similar to findings regarding cingulotomy for OCD, indices of activity
      within PCC appear to be positively correlated with response to fluvoxamine as
      well. Finally, this pattern is sufficiently robust as to be relatively
      independent of symptomatic state at the time of tracer uptake.

PMID- 12431853
TI  - Anatomical MRI study of subgenual prefrontal cortex in bipolar and unipolar
      subjects.
AB  - This study attempted to replicate previous findings of decreased gray matter
      content in the subgenual prefrontal cortex (SGPFC) in mood disorder patients.
      Eighteen DSM-IV unipolar patients, 27 DSM-IV bipolar patients, and 38 healthy
      controls were studied. A 1.5T GE Signa Imaging System with Signa 5.4.3 software
      was used. The semi-automated software MedX (Sensor Systems, Sterling, VA) was
      utilized for the anatomical measures of SGPFC volumes. There were no significant
      differences in SGPFC volumes in familial and non-familial unipolar and bipolar
      patients compared with healthy controls, nor between drug-free and lithium
      treated bipolar patients (ANOVA, p >.05). In vivo abnormalities in the volumes of
      SGPFC were not identified in mildly depressed or euthymic unipolar or bipolar
      mood disorder outpatients, either familial or non-familial.

PMID- 12431854
TI  - The effects of gender and gonadal steroids on the neuroendocrine and temperature
      response to m-chlorophenylpiperazine in leuprolide-induced hypogonadism in women
      and men.
AB  - Studies of the effects of gender and gonadal steroids on serotonergic activity in
      humans are few in number and often contradictory. We examined the neuroendocrine
      and core temperature response to a serotonergic stimulus, m
      chlorophenylpiperazine (m-CPP) (0.08 mg/kg body weight, IV), in asymptomatic
      female and male volunteers during induced hypogonadism (leuprolide acetate) and
      hormone replacement (estradiol (E2) or progesterone (P4) in women; testosterone
      (T) in men). Compared with the hypogonadal state, basal prolactin (PRL) secretion
      was significantly higher during both P4 and E2 replacement (p <.05) in women and
      during T replacement in men (p <.05). m-CPP stimulated PRL secretion was
      significantly greater only during P4 (p <.05) but not E2 (women) or T (men)
      replacement, compared with hypogonadism. Basal but not stimulated plasma growth
      hormone (GH) levels were significantly higher during P4 in women and T in men (p
      <.05), and no significant differences in basal or m-CPP stimulated plasma levels
      of ACTH or cortisol were observed. Finally, basal core temperatures were
      significantly higher during P4 replacement compared with either E2 replacement or
      the hypogonadal condition (p <.01) in women, with no differences observed in men.
      Comparisons of measures by gender (and matched for baseline plasma T levels)
      revealed that during the hypogonadal state m-CPP-stimulated GH secretion was
      significantly greater (p <.01) and m-CPP-stimulated ACTH (p <.05) and cortisol (p
      <.01) significantly less in women compared with men. Although our data are
      limited to those components of the central serotonergic system influenced by m
      CPP administration, our findings suggest the following: the regulatory effects of
      gonadal steroids on serotonergic function are modest in humans during leuprolide
      induced hypogonadism; menstrual cycle phase effects of serotonergic agents on PRL
      secretion may reflect both the effects of P4 and E2; the effects of P4 in humans
      may occur without E2 priming of the progesterone receptor; and gender differences
      in GH secretion occur independent of the presence of gonadal steroids.

PMID- 12431855
TI  - Acute administration of d-amphetamine decreases impulsivity in healthy
      volunteers.
AB  - This study investigated the acute behavioral effects of d-amphetamine on several
      behavioral indices of impulsivity. Impulsivity has been defined, variously, as
      difficulty in inhibiting inappropriate behaviors, inability to wait,
      insensitivity to delayed consequences or an alteration in the perception of time;
      standardized procedures have been developed to measure these behavioral
      dimensions. However, it is not known how drugs affect these measures, and few
      studies have examined more than one measure in a single study. In this study, 36
      healthy men and women participated in three sessions, in which they received
      placebo, 10 mg, or 20 mg d-amphetamine in randomized order. On each session they
      performed the following five tasks: the Stop Task, which measures behavioral
      inhibition, a delay discounting task, which measures the relative value of
      immediate vs. delayed rewards, a delay of gratification task, a Go/No-Go task,
      and a time estimation task. Subjects also completed mood questionnaires.
      Amphetamine produced its expected subjective, mood-altering effects, including
      increases in POMS Friendliness and Elation scales, and ARCI Euphoria and
      Stimulant scales. On the measures of impulsivity, amphetamine decreased impulsive
      responding on three of the tasks: on the Stop Task it decreased Stop reaction
      times without affecting Go reaction time, on the Go/No-Go task, it decreased the
      number of false alarms, and on the delay discounting measure, amphetamine (20 mg)
      decreased k values indicating less discounting of delayed reward. Other measures
      of impulsive behavior were unaffected. These results suggest that acute doses of
      amphetamine decrease several forms of impulsive behavior. These findings extend
      and confirm previous findings in humans and laboratory animals.

PMID- 12431856
TI  - Selective alterations in ionotropic glutamate receptors in the anterior cingulate
      cortex in schizophrenia.
AB  - The anterior cingulate cortex is a brain area of potential importance to our
      understanding of the pathophysiology of schizophrenia. Previous studies suggest
      abnormalities in the glutamatergic neurotransmission in the anterior cingulate
      cortex in schizophrenia patients. In the present study we used quantitative
      autoradiography to investigate the binding of [3H]MK801, [3H]L-alpha-amino-3
      hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), and [3H]kainate, which
      respectively label the N-methyl-D-aspartate (NMDA), AMPA, and kainate receptors
      of the ionotropic glutamate receptor family, in the left anterior cingulate
      cortex of 10 schizophrenia patients and 10 controls, matched for age, gender, and
      postmortem interval.AMPA receptor densities were higher in cortical layer II,
      whereas NMDA receptor densities were higher in cortical layers II-III in the
      anterior cingulate cortex of both control and schizophrenia group. In contrast,
      kainate receptors displayed the highest density in cortical layer V. [3H]AMPA
      binding was significantly increased by 25% in layer II in the schizophrenia group
      as compared with the control group. Similarly, a significant 17% increase of
      [3H]MK801 binding was observed in layers II-III in the schizophrenia group. No
      statistically significant difference was observed for [3H] kainate binding
      between the schizophrenia and control groups. These results suggest that
      ionotropic glutamate receptors are differentially altered in the anterior
      cingulate region in schizophrenia. The increase in [3H]AMPA and [3H]MK801 binding
      in the superficial layers suggests a postsynaptic compensation for impaired
      glutamatergic neurotransmission in the anterior cingulate cortex in
      schizophrenia. The findings add to a growing body of literature that supports a
      dysfunction of excitatory activity in the anterior cingulate cortex in
      schizophrenia.

PMID- 12431857
TI  - Effects of acute tryptophan depletion on mood and cortisol release in first
      degree relatives of type I and type II bipolar patients and healthy matched
      controls.
AB  - Biological vulnerability for bipolar disorders (BD) in relatives of BD patients
      has not as yet been established. Serotonergic vulnerability was studied, using
      acute tryptophan depletion (ATD), in healthy first-degree relatives of BD
      patients and healthy controls. The effects of ATD on mood and cortisol release in
      30 healthy adult, lifetime symptom free, unaffected first-degree relatives of BD
      patients (Family History; FH) were compared with effects in 15 healthy matched
      controls in a placebo-controlled, double-blind, crossover design. During ATD and
      placebo, salivary cortisol response was also assessed during a stress-inducing
      speech task (SIST). First-degree relatives of type II BD patients (FH II) showed
      an elevation of mood, whereas control subjects and relatives of type I BD
      patients (FH I) showed a lowering of mood after ATD. ATD was followed by a
      decrease in cortisol level in both FH subgroups, but not in the controls. The
      results suggest serotonergic vulnerability that affected mood in FH II subjects
      and cortisol release in both FH I and FH II subjects.

PMID- 12431858
TI  - Mid-morning tryptophan depletion delays REM sleep onset in healthy subjects.
AB  - Because serotonin is involved in the diachronic regulation of sleep, we tested
      the effect of a midmorning rapid deficiency in the serotonin precursor tryptophan
      on the next night's sleep. After a 48-h low-protein diet, 17 healthy volunteers
      received either a tryptophan-free mixture of amino acids or a placebo at 10:30
      A.M., in a randomized double-blind cross-over design, resulting in a 77% decrease
      and 41% decrease of serum tryptophan at 3:30 P.M. and 9:30 P.M., respectively.
      Urinary sulfatoxy-melatonin excretion and mood were unaffected by the rapid
      tryptophan depletion (RTD), but rapid eye movement (REM) sleep latency increased
      by 21 min (from 91.5 +/- 4.5 min to 112.2 +/- 6.9 min), sleep fragmentation 58%,
      and REM density of the first REM sleep period doubled. The results show that
      midmorning RTD delays REM sleep latency during following night-time sleep,
      whereas evening RTD shortens REM sleep latency in previous studies, and suggest
      that the serotonin control of REM sleep latency is upregulated.

PMID- 12431859
TI  - Predictors of mood response to acute tryptophan depletion. A reanalysis.
AB  - Acute tryptophan depletion (ATD) induces depressive symptoms in 50-60% of
      selective serotonin reuptake inhibitor (SSRI) treated, recovered depressed
      patients. However, no reliable predictors of mood response to ATD have been
      established. In the present study, individual subject data of six ATD studies
      were pooled ('mega-analysis') in order to investigate the mediating role of
      clinical, demographic and biochemical characteristics in the mood response to
      ATD. A procedure was developed to make different versions of the Hamilton scale
      comparable. Recurrent depressive episodes, female gender, prior exposure to SSRI
      antidepressant treatment and previous serious suicidal thoughts/attempts all
      appear to be independent predictors of mood response to ATD. Chronicity of
      illness is the most powerful predictor. Residual symptoms of depression were not
      found to predict response to ATD. ATD may be useful to study the mechanism of
      action of SSRI antidepressants and individual biological vulnerability of the
      serotonin system. Whether the effects of ATD represent a reversal of the action
      of SSRI antidepressants or individual vulnerability probably depends upon the
      timing of the procedure in the course of remission of a depressive episode.

PMID- 12431860
TI  - Serotonin modulates early cortical auditory processing in healthy subjects:
      evidence from MEG with acute tryptophan depletion.
AB  - We studied the effects of acute tryptophan depletion (ATD) on early cortical
      auditory processing. Middle-latency auditory evoked fields (MAEF) were
      investigated in 14 healthy subjects after 5 h of ATD or control mixture ingestion
      in a randomized, double-blinded, controlled cross-over design study. MAEFs to
      monaural click stimuli (0.1-ms duration) were recorded with a 122-channel
      neuromagnetometer. Total plasma tryptophan (Trp), free Trp, and large neutral
      amino acid (LNAA) concentrations were determined by using high-performance liquid
      chromatography. ATD lowered the total plasma Trp levels by 75%, free Trp level by
      47%, and the ratio Trp/SigmaLNAA by 92%. The control mixture increased total Trp
      level by 45% and free Trp by 32%, and decreased the ratio Trp/SigmaLNAA by 35%.
      The ratio tyrosine/SigmaLNAA did not differ between ATD and control experiment.
      ATD resulted in a significant main effect on Pam latencies and a near-significant
      main effect on Pam amplitudes. A significant Mixture ingestion X Sex interaction
      on Nbm amplitude and a significant Mixture ingestion X Sex X Hemisphere
      interaction on Pam latency were observed. ATD did not affect the MAEF source
      dipoles. The Pam latencies in both hemispheres had a significant negative
      relationship with the extent of ATD. The results suggest that the
      neurotransmitter serotonin is involved in early auditory cortical processing.
      Further, the serotonin modulation may be different in males and females.

PMID- 12431861
TI  - Sleep and sleep homeostasis in mice lacking the 5-HT2c receptor.
AB  - Studies in humans and rats indicate that serotonin (5-hydroxytryptamine, 5-HT)
      receptors are involved in mammalian sleep expression. We investigated the
      contribution of the 5-HT2c receptor to sleep expression by examining sleep
      patterns in mice bearing a targeted null mutation of this receptor. 5-HT2c
      receptor knock-out mice had more wakefulness, several abnormalities in rapid eye
      movement sleep expression and an enhanced response to sleep deprivation compared
      with wild-type control mice. These findings suggest that 5HT2c receptors may
      mediate several effects on sleep that have been ascribed to serotonin.

PMID- 12431862
TI  - Plasma concentrations of neuroactive steroids before and after repetitive
      transcranial magnetic stimulation (rTMS) in major depression.
AB  - There is evidence for altered levels of neuroactive steroids in major depression
      that normalize after successful antidepressant pharmacotherapy. Currently it is
      not known whether this is a general principle of clinically effective
      antidepressant therapy or a pharmacological effect of antidepressants. Here, we
      investigated whether repetitive transcranial magnetic stimulation (rTMS) may
      affect plasma concentrations of neuroactive steroids in a similar way as
      antidepressant pharmacotherapy. Progesterone, 3alpha,5alpha
      tetrahydroprogesterone (3alpha,5alpha-THP), 3alpha,5beta- tetrahydroprogesterone
      (3alpha,5beta-THP), 3beta,5alpha-tetrahydroprogesterone (3beta, 5alpha-THP) and
      dehydroepiandrosterone (DHEA) were quantified in 37 medication-free patients
      suffering from a major depressive episode before and after 10 sessions of left
      prefrontal rTMS. Plasma samples were analyzed by means of a highly sensitive and
      specific combined gas chromatography/mass spectrometry analysis. There was a
      significant reduction of depressive symptoms after rTMS. However, plasma
      concentrations of neuroactive steroids were not affected by rTMS and not related
      to clinical response. Clinical improvement after extended daily treatment with
      rTMS is not accompanied by changes in neuroactive steroid levels. Changes in
      neuroactive steroid levels after antidepressant pharmacotherapy more likely
      reflect specific pharmacological effects of antidepressant drugs and are not
      necessary for the amelioration of depressive symptoms.

PMID- 12431863
TI  - Where do we go from here? The importance of initial values.

PMID- 12431865
TI  - The place of probiotics in human intestinal infections.
AB  - A number of studies have been carried out on the effect of several probiotic
      species on treatment and prevention of intestinal infections. The most commonly
      used microorganisms are lactic-acid producing bacteria such as lactobacilli and
      bifidobacteria belonging to the human normal microflora. In vitro and animal
      studies have shown that probiotic microorganisms interfere with the colonisation
      of Helicobacter pylori and of enteropathogenic microorganisms. In humans the
      significance is more uncertain. Clinically significant benefits of probiotics
      have been demonstrated in the treatment of rotavirus induced diarrhoea and of
      Saccharomyces boulardii in the prevention of antibiotic-associated diarrhoea
      (AAD). In patients suffering from inflammatory bowel disease, several probiotic
      strains have been shown to be as effective as traditional medication in
      preventing relapses. Standardised and well performed studies are needed to
      elucidate further the mechanisms of action and the clinical significance of
      probiotics.

PMID- 12431866
TI  - The prophylaxis and treatment of anthrax.
AB  - Bacillus anthracis infection can occur in three forms: cutaneous,
      gastrointestinal and inhalation depending on the mode of infection. Anthrax is a
      zoonotic disease but the inhalation form can also be used as a biological warfare
      agent. The recent mail spread outbreak of bioterrorism-related infections in the
      USA prompted the introduction of specific guidelines by the USA Centers for
      Disease Control and Prevention. Postexposure prophylaxis is indicated to prevent
      inhalational anthrax, and therapy with ciprofloxacin or doxycycline is
      recommended for adults and children for 60 days. The same agents are also
      advocated for the treatment of inhalation anthrax. However, therapy with two or
      more antimicrobial agents that are predicted to be effective are recommended.
      Other agents with in vitro activity are also suggested for be use in conjunction
      with ciprofloxacin or doxycycline include rifampciin, vancomycin, imipenem,
      chloramphenicol, penicillin and ampicillin, clindamycin, and clarithromycin.

PMID- 12431867
TI  - TDM coupled with Bayesian forecasting should be considered an invaluable tool for
      optimizing vancomycin daily exposure in unstable critically ill patients.
AB  - A randomized two-arm prospective study was planned to assess the role of
      therapeutic drug monitoring (TDM) coupled with a Bayesian approach in tailoring
      vancomycin dosages in unstable critically ill patients. Group A (n=16) had their
      regimen adjusted day-by-day according to TDM and Bayesian forecasting (D(a));
      group B (n=16) had their regimen adjusted day-by-day according to Moellering's
      nomogram (D(M)). Blood samples were collected every 1-2 days to assess the trough
      and peak plasma concentrations. In group A, the tailored D(a) required for
      optimizing vancomycin exposure were considerably higher than the D(M) in 7/16
      cases, and lower than the D(M) in 1/16 cases. In group B, standard D(M) caused
      under-treatment in 3/16 cases and over-treatment in 4/16 cases. Most of these
      patients concomitantly had some conditions that might have altered vancomycin
      disposition. The TDM-guided Bayesian-based approach should be considered an
      invaluable tool for clinicians to handle appropriately on real-time vancomycin
      therapy in critically ill patients.

PMID- 12431868
TI  - Impact of an antibiotic policy on antibiotic use in a paediatric department.
      Individual based follow-up shows that antibiotics were chosen according to
      diagnoses and bacterial findings.
AB  - Guidelines and clinical Cupertino for rational antibiotic use were implemented in
      a Norwegian paediatric department in 1994. From 1994 to 1998 the use of
      antibiotics and expenditures was reduced by 50%. There was an 80% decrease in the
      use of cloxacillin, a 74% decrease of aminoglycosides and a 59% decrease of
      cephalosporins. The use of penicillin V and G increased by 14% and ampicillins by
      8%. Eight point prevalence studies showed that on average 23% (range 21-38%) of
      the patients were treated with antibiotics. Penicillins were used in 44% of
      courses, aminoglycosides in 35% of courses and cephalosporins in 9% of courses.
      Treatment was mostly adjusted to bacteriological findings. Compliance with
      guidelines was >90%. Guidelines for rational antibiotic policy and
      multidisciplinary co-operation lead to reduction in the use and expenses of
      antibiotics in a paediatric department.

PMID- 12431869
TI  - Distribution and susceptibility of bacterial urinary tract infections in Dakar,
      Senegal.
AB  - To assess the current distribution and antibiotic susceptibility patterns of
      uropathogens isolated from community-acquired urinary tract infections (UTIs) in
      Dakar, a retrospective study was carried out at the biomedical laboratory of
      Institut Pasteur de Dakar between January 1999 and December 2000. The most
      important finding, among Enterobacteriaceae, was the emergence of multidrug
      resistant strains (extended-spectrum beta-lactamase and both chromosomally
      derepressed and plasmid mediated cephalosporinase producing strains) affecting
      2.9% of all Enterobacteriaceae. Of Gram-positive cocci, 15% of Staphylococcus
      aureus were methicillin-resistant. Our data show the original distribution of
      uropathogens from UTIs in ambulant patients and the emergence of multidrug
      resistant strains in Dakar.

PMID- 12431870
TI  - Disposition and intracellular activity of azithromycin in human THP-1 acute
      monocytes.
AB  - Uptake of [14C]-azithromycin into THP-1 human monocytes was determined at pH 7.4,
      6.8 or 5.5 over 4-log antibiotic concentrations for 24 h under a number of
      conditions. Stimulation of cells was with bacteria, latex beads,
      lipopolysaccharide (LPS), or zymogen A. Subcellular organelle disposition was
      determined after isolation by ultracentrifugation or sucrose gradients.
      Hydrolytic enzyme activities and mediators of intracellular inflammation (IL-1,
      IL-6, IL-8, and TNFalpha) were assessed. Azithromycin uptake into human THP-1
      monocytes was initially linear achieving approximately 2% of the extracellular
      concentration. At pH 7.4, uptake was both passive- and carrier-mediated, but as
      the pH became more acidic, the uptake was exclusively passive. The intracellular
      concentration was not pH-dependent over 24 h. Uptake was dependent upon
      temperature but not the presence of foetal calf serum. Intracellular disposition
      in zymogen A-stimulated and unstimulated cells was throughout all compartments of
      the cell, but was higher in the nucleus and cell sap. Phagosomes of stimulated
      cells contained higher level of the antibiotic. Efflux from THP-1 monocytes was
      complete between 3 and 4 h. After 1 h treatment with zymogen A, THP-1 monocytes
      demonstrated an increase in intracellular acidity, protein kinase C, SOD and NAG
      activities, and NO, H(2)O(2), TNFalpha and IL-1 release over the 1st h. After 2-4
      h the pH became alkaline, activities of NADPH reductase, NAG and cathepsin were
      reduced, and the release of NO, H(2)O(2), TNFalpha and IL-6 were suppressed.
      Protein synthesis and killing of the bacteria was evident in bacteria kept in
      monocyte-free medium and those phagocytized by the THP-1 monocytes moderately at
      2 h, but more significantly at 24 h. The early killing of the bacteria appears to
      be a cidal mechanism whereas later, a standard bacteriostatic mechanism was
      evident. Nevertheless, suppression of these chemical mediators and hydrolytic
      enzyme activities would reduce the infection and the spread to adjacent areas.

PMID- 12431871
TI  - Stimulation of microbial autolytic system by tryptic casein hydrolysate.
AB  - Antimicrobial activity of a tryptic casein hydrolysate (TCH), its mode of
      antimicrobial action and its efficacy in treatment using a newborn calf
      colibacillosis model are described. The antimicrobial activity of TCH activated
      the autolytic system of the microbial cell and was expressed mathematically as
      the autolysis activation index. TCH stimulated the autolytic enzyme system of the
      19 bacterial and five fungal strains tested. The autolysis activation index for
      naturally-autolyzing microorganisms was 1.45-22.0. Autolysis in three bacterial
      and one fungal strain that did not lyse in the absence of TCH was increased in
      its presence by 3.9-56.7% showing activation of latent autolysis. The in vivo
      trials on 800 newborn calves revealed 93.0% therapeutic and 93.5% prophylactic
      efficacy for TCH. These levels were similar to the 95.0 and 95.5% attained when
      Fermosorb, an authorized antimicrobial drug, was used.

PMID- 12431873
TI  - Ciclopiroxolamine: in vitro antifungal activity against clinical yeast isolates.
AB  - The in vitro susceptibility of 225 clinical isolates of yeasts to
      ciclopiroxolamine (CPO) was compared with that of clotrimazole, econazole,
      ketoconazole, miconazole, tioconazole, fluconazole, itraconazole and nystatin
      using a standardized agar diffusion method (NeoSensitabs). Two hundred and eight
      strains of yeasts comprising 16 species of Candida and 22 strains belonging to
      other yeast genera were tested. One strain (0.4%) was resistant, four strains
      (1.8%) of intermediate susceptibility and 220 strains (97.3%) susceptible to CPO.
      More strains were susceptible to CPO than to the other antifungals studied.
      Susceptibility patterns of antifungal agents were not linked to species. The in
      vitro antifungal susceptibility profile of CPO was better than topical azole
      derivatives or fluconazole and itraconazole against a wide variety of clinically
      important yeasts.

PMID- 12431872
TI  - Antianaerobic activity of moxifloxacin compared with that of ofloxacin,
      ciprofloxacin, clindamycin, metronidazole and beta-lactams.
AB  - Minimal inhibitory concentrations of moxifloxacin were compared with those of
      ofloxacin, ciprofloxacin, clindamycin, metronidazole and six beta-lactams for 159
      anaerobes isolated from human clinical samples. Unlike other fluoroquinolones,
      moxifloxacin demonstrated high activity against the 76 strains of the Bacteroides
      fragilis group as the minimal inhibitory concentration(50) was 0.5 mg/l.
      Porphyromonas, Prevotella, Fusobacterium and Gram-positive anaerobic cocci were
      inhibited by 1 mg/l or less of moxifloxacin. It inhibited 93.7, 94.9 and 98% of
      the 159 strains investigated at concentrations of 1, 2 and 4 mg/l, respectively.
      Moxifloxacin was more potent than ofloxacin and ciprofloxacin against Gram
      positive rods and anaerobic cocci. Its broad anaerobic spectrum in vitro is
      promising for the treatment of intra-abdominal and respiratory infections.

PMID- 12431874
TI  - Epidemiological typing of imipenem-resistant Pseudomonas aeruginosa.
AB  - The level of genetic heterogeneity of nine isolates of Pseudomonas aeruginosa
      resistant or intermediately susceptible to imipenem was determined by
      epidemiological typing using macrorestriction analysis of chromosomal DNA. The
      strains were isolated between December 2000 and February 2001 from a variety of
      specimens from nine patients hospitalized in five different departments of the
      University Medical Center in Ljubljana and in the nursing home. They belonged to
      seven genotypes or clones (A-G). Six isolates were heterogeneous, with different
      B-G genotypes. Three isolates had an identical A genotype but it is more likely
      that this genotype was more prone to develop imipenem resistance than to spread
      among the patients.

PMID- 12431875
TI  - The comparison of in the vitro effect of imipenem or meropenem combined with
      ciprofloxacin or levofloxacin against multidrug-resistant Pseudomonas aeruginosa
      strains.
AB  - This study evaluated the in vitro effects of the combination of a carbapenem
      (imipenem or meropenem) with a quinolone (ciprofloxacin or levofloxacin) using a
      microbroth dilution chequerboard technique and multidrug-resistant Pseudomonas
      aeruginosa strains. The ciprofloxacin and meropenem combination was only
      synergistic against 2 strains (6.2%) and ciprofloxacin and imipenem against 1
      strain (3.1%). Levofloxacin and imipenem or meropenem were not synergistic for
      against any strain. None of the combinations showed an antagonistic effect.

PMID- 12431876
TI  - Epidemiology of bacterial resistance in gastro-intestinal pathogens in a tropical
      area.
AB  - During 1999-2000 a total of 4131 faecal specimens were collected and analysed at
      the medical centre St. Camille at Ouagadougou. Eight hundred and twenty-six
      (8.0%) grew significant bacteria. Escherichia coli (35%), Salmonella spp. (15%)
      and Shigella spp. (10%) were most frequently isolated. A large number of E. coli
      strains were resistant to aminopenicillins (>90%) and cotrimoxazole (80%); for
      Yersinia spp the resistance was 80 and 25%, respectively. Norfloxacin was the
      most active antibiotic but was rarely used. The study showed that it is necessary
      to create antibiotic-resistance surveillance centres in developing countries so
      that therapy may be appropriate and the spread of antibiotic resistance to other
      developed countries via increased emigration may be reduced.

PMID- 12431877
TI  - In vitro investigation of the susceptibility of Acinetobacter baumannii strains
      isolated from clinical specimens to ampicillin/sulbactam alone and in combination
      with amikacin.
AB  - The sensitivity of 52 strains of Acinetobacter baumannii was determined to 13
      antimicrobial drugs. All strains tested were multiresistant. Compared with MICs
      of amikacin and ampicillin/sulbactam alone, there was a significant decrease in
      MICs for both drugs when the combination was used. The results of the in vitro
      study of this combination showed a synergistic or partial synergistic effect in
      98% of the strains.

PMID- 12431878
TI  - A case of purpuric drug eruption due to cefaclor.

PMID- 12431879
TI  - In vitro bactericidal activity of ABT-773 versus four other agents against
      Streptococcus pneumoniae and Haemophilus influenzae.

PMID- 12431881
TI  - Synthesis of D- and L-myo-inositol 2,4,5-trisphosphate and trisphosphorothioate:
      structural analogues of D-myo-inositol 1,4,5-trisphosphate.
AB  - The preparation of D- and L-myo-inositol 2,4,5-trisphosphate is described,
      together with the phosphorothioate counterparts. The known chiral diols D- and L
      1,4-di-O-benzyl-5,6-bis-O-p-methoxybenzyl-myo-inositol were regioselectively
      protected at the 3-position using a benzyl group via a 2,3-O-stannylene acetal.
      Removal of the p-methoxybenzyl groups of each enantiomer gave D- and L-1,3,6-tri
      O-benzyl-myo-inositol. Phosphitylation with
      bis(benzyloxy)diisoproplyaminophosphine and 1H-tetrazole gave the trisphosphite
      intermediate for each enantiomer. Oxidation with 3-chloroperoxybenzoic acid gave
      the fully protected D- and L-myo-inositol 2,4,5-trisphosphates. Sulphoxidation of
      the D- and L-2,4,5-trisphosphite intermediates gave the fully protected D- and L
      myo-inositol 2,4,5-trisphosphorothioate compounds. The fully protected
      trisphosphates were deblocked using hydrogenolysis and the phosphorothioates were
      deprotected using sodium in liquid ammonia. The individual compounds were then
      purified using ion exchange chromatography to afford pure D- and L-myo-inositol
      2,4,5-trisphosphates together with the corresponding phosphorothioates.

PMID- 12431882
TI  - The use of tri-O-acetyl-D-glucal and -D-galactal in the synthesis of 3-acetamido
      2,3-dideoxyhexopyranoses and -hexopyranosides.
AB  - Addition of hydrazoic acid to alpha,beta-unsaturated aldehydes derived from tri-O
      acetyl-D-glucal and -D-galactal gave 3-azido-2,3-dideoxyhexopyranoses. These were
      converted into 1,4,6-tri-O-acetyl-3-azido-2,3-dideoxyhexopyranoses as well as
      methyl and ethyl glycosides. Hydrogenation of the proamine group in 3-azido-2,3
      dideoxy derivatives provided different 3-amino and 3-acetamido sugars. The
      configuration and conformation of all products were established on the basis of
      the 1H and 13 C NMR, IR and polarimetric data.

PMID- 12431883
TI  - Oligosaccharide synthesis by dextransucrase: new unconventional acceptors.
AB  - The acceptor reactions of dextransucrase offer the potential for a targeted
      synthesis of a wide range of di-, tri- and higher oligosaccharides by the
      transfer of a glucosyl group from sucrose to the acceptor. We here report on
      results which show that the synthetic potential of this enzyme is not restricted
      to 'normal' saccharides. Additionally functionalized saccharides, such as
      alditols, aldosuloses, sugar acids, alkyl saccharides, and glycals, and rather
      unconventional saccharides, such as fructose dianhydride, may also act as
      acceptors. Some of these acceptors even turned out to be relatively efficient:
      alpha-D-glucopyranosyl-(1-->5)-D-arabinonic acid, alpha-D-glucopyranosyl-(1-->4)
      D-glucitol, alpha-D-glucopyranosyl-(1-->6)-D-glucitol, alpha-D-glucopyranosyl-(1-
      >6)-D-mannitol, alpha-D-fructofuranosyl-beta-D-fructofuranosyl-(1,2':2,3')
      dianhydride, 1,5-anhydro-2-deoxy-D-arabino-hex-1-enitol ('D-glucal'), and may
      therefore be of interest for future applications of the dextransucrase acceptor
      reaction.

PMID- 12431884
TI  - Structural elucidation of the EPS of slime producing Brevundimonas vesicularis
      sp. isolated from a paper machine.
AB  - The slime forming bacteria Brevundimonas vesicularis sp. was isolated from a
      paper mill and its EPS was produced on laboratory scale. After production, the
      exopolysaccharide (EPS) was purified and analysed for its purity and homogeneity,
      HPSEC revealed one distinct population with a molecular mass of more than 2,000
      kDa. The protein content was around 9 w/w%. The sample was analysed to determine
      its chemical structure. The EPS was found to consist of rhamnose, glucose,
      galacturonic acid and glucuronic acid. Due to the presence of uronic acids the
      molar ratio between the four sugars found varies from 3:5:2:4 by sugar
      composition analyses after methanolysis to 1:1:1:1 found by NMR. A repeating unit
      with a molecular mass of 678 Da was confirmed by MALDI-TOF mass spectrometry
      after mild acid treatment. 13C and 1H hetero- and homonuclear 2D NMR spectroscopy
      of the native and partial hydrolysed EPS revealed a repeating unit, no non-sugar
      substituents were present.

PMID- 12431885
TI  - Ab initio computational study of beta-cellobiose conformers using B3LYP/6
      311++G**.
AB  - The molecular structure of 27 conformers of beta-cellobiose were studied in vacuo
      through gradient geometry optimization using B3LYP density functionals and the 6
      311++G** basis set. The conformationally dependent geometry changes and energies
      were explored as well as the hydrogen-bonding network. The lowest electronic
      energy structures found were not those suggested from available crystallographic
      and NMR solution data, where the glycosidic dihedral angles fall in the region
      (phi, psi) approximately (40 degrees, -20 degrees ). Rather, 'flipped'
      conformations in which the dihedral angles are in the range (phi, psi)
      approximately (180 degrees, 0 degrees ) are energetically more stable by
      approximately 2.5 kcal/mol over the 'experimentally accepted' structure. Further,
      when the vibrational free energy, deltaG, obtained from the calculated
      frequencies, is compared throughout the series, structures with (phi, psi) in the
      experimentally observed range still have higher free energy ( approximately 2.0
      kcal/mol) than 'flipped' forms. The range of bridging dihedral angles of the
      'normal' conformers, resulting from the variance in the phi dihedral is larger
      than that found in the 'flipped' forms. Due to this large flat energy surface for
      the normal conformations, we surmise that the summation of populations of these
      conformations will favor the 'normal' conformations, although evidence suggests
      that polar solvent effects may play the dominant role in providing stability for
      the 'normal' forms. Even though some empirical studies previously found the
      'flipped' conformations to be lowest in energy, these studies have been generally
      discredited because they were in disagreement with experimental results. Most of
      the DFT/ab initio conformations reported here have not been reported previously
      in the ab initio literature, in part because the use of less rigorous theoretical
      methods, i.e. smaller basis sets, have given results in general agreement with
      experimental data, that is, they energetically favored the 'normal' forms. These
      are the first DFT/ab initio calculations at this level of theory, apparently
      because of the length and difficulty of carrying out optimizations at these high
      levels.

PMID- 12431886
TI  - A DFT/ab initio study of hydrogen bonding and conformational preference in model
      cellobiose analogs using B3LYP/6-311++G**.
AB  - A series of beta-cellobiose analogs were studied at the B3LYP/6-311++G** level of
      theory to isolate and understand how the various electronic components of the
      beta-(1-->4)-linked disaccharide, cellobiose, contribute to the energetic
      stability of the molecule in vacuo. Previous studies on beta-cellobiose (see
      accompanying paper) showed that the most energetically stable conformation was
      that in which the dihedral angle phi (phi(H)) was 'flipped' by approximately 180
      degrees relative to the 'normal' form. From our examination of eight sets of
      structures in which different combinations of functional hydroxyl and
      hydroxymethyl groups were removed, it was determined that only beta-cellobiose
      and one other analog (analog 7, beta-xylobioside), an analog in which both
      hydroxymethyl groups were removed but the exocyclic hydroxyl groups retained, can
      form a 'cooperative' hydrogen-bonding network. Only in these two molecules did we
      find continuous synergistic 'communication' through hydrogen bonding from one
      sugar moiety to the other. This 'cooperative' hydrogen bonding energetically
      stabilizes the 'flipped' conformation of beta-cellobiose and beta-xylobioside,
      while the other analogs studied were unable to form a 'cooperative' grouping of
      hydrogen bonds and thus were more stable in their 'normal' conformational state.

PMID- 12431887
TI  - Disaccharide conformational maps: 3D contours or 2D plots?
AB  - The potential energy surfaces of several alpha-(1-->3)- and beta-(1-->4)-linked
      disaccharides were obtained and plotted in terms of energy versus psi glycosidic
      angle. These plots were compared to those obtained previously in the way of the
      usual 3D contour maps, which relate the energy with the two glycosidic angles
      (phi and psi). Given the usually small variations of the phi angle in the low
      energy regions (at least using MM3), both kinds of graphs lead to similar
      conclusions concerning flexibility measurements by two different methods and
      assessment of the effects of sulfation and/or hydroxyl group orientation. Only
      second-order effects were found with some sulfated disaccharides, not changing
      the general conclusions. The computational efforts required to produce those
      plots are smaller, and the plots are easier to interpret. Besides, the conversion
      of a 3D map into a 2D plot leaves the possibility of constructing 3D maps of
      carbohydrates including a second variable different to phi, e.g., the second psi
      angle of a trisaccharide or the omega angle of a 6-linked disaccharide.

PMID- 12431888
TI  - Effect of sodium orthovanadate on glycosylation of the phosphopeptidomannans
      involved in the cell-cell aggregation of the yeast Kluyveromyces bulgaricus.
AB  - In studies of yeast flocculation it has been found that low concentrations of
      vanadium contained in sodium orthovanadate do not affect the growth and the cell
      cell adhesion of the yeast Kluyveromyces bulgaricus, whereas high concentrations
      delay the growth of the yeasts and strongly inhibit flocculation. Moreover,
      higher sensitivity to Hygromycin B and calcofluor white was taken to imply
      altered cell wall integrity which is supported by compositional analysis of the
      extracted phosphopeptidomannans. Yeasts grown on sodium orthovanadate show a
      decrease in the percentage of phosphopeptidomannans and their compositions. It is
      proposed that the vanadium contained in sodium orthovanadate has a similar
      conformation to phosphorus and competes with phosphorus in phosphorylated
      compounds. The decrease of carbohydrate components and phosphorus linking to
      phosphopeptidomannans detected may alter their structure and modify ligand
      binding properties.

PMID- 12431889
TI  - Achieving organizational change in primary care: simmer gently for two years.

PMID- 12431890
TI  - Improving quality of organizing cardiovascular preventive care in general
      practice by outreach visitors: a randomized controlled trial.
AB  - BACKGROUND: Adequate care for patients with cardiovascular risks requires an
      adequate practice organization. Educational outreach visits are a promising
      approach to modifying professional behavior. We aimed to assess whether the
      quality of cardiovascular preventive care in general practice can be improved
      through a comprehensive intervention implemented by an educational outreach
      visitor. METHODS: After baseline measurements, general practices (n = 124) in the
      southern half of The Netherlands were randomly allocated to either intervention
      or control group. The intervention, based on the educational outreach model,
      comprised 15 practice visits over a period of 21 months and addressed a large
      number of issues around task delegation, availability of instruments and patient
      leaflets, record-keeping, and follow-up routines. Twenty-one months after the
      start of the intervention, postintervention measurements were performed. The
      difference between ideal and actual practice in each aspect of organizing
      preventive care was defined as a deficiency score. Primary outcome measure was
      the difference in deficiency scores before and after the intervention. RESULTS:
      All practices completed both baseline and postintervention measurements. The
      difference in change between intervention and control group adjusted for baseline
      was statistically significant (P < 0.001) for each aspect of organizing
      preventive care. The largest absolute improvement was found for the number of
      preventive tasks performed by the practice assistant. CONCLUSIONS: This study
      showed that a comprehensive intervention implemented by outreach visitors was
      effective in improving organization of cardiovascular preventive care in general
      practice.

PMID- 12431891
TI  - Organizing cardiovascular preventive care in general practice: determinants of a
      successful intervention.
AB  - BACKGROUND: Although outreach visitor interventions have proven to be effective,
      more detailed studies are needed to understand what elements of interventions
      work and why. In this study we investigate the determinants of success of an
      intervention for optimizing cardiovascular preventive care in general practice.
      METHODS: After baseline measurements and randomization, 62 general practices
      received a comprehensive intervention program, by means of outreach visitors,
      lasting 21 months. Data on practice management and preventive activities were
      gathered at baseline and at postintervention measurements. Key characteristics of
      the intervention considered possible determinants of success were gathered by
      questionnaire. The difference between ideal and actual practice in each aspect of
      organizing cardiovascular preventive care was calculated as a deficiency score.
      The difference between deficiency scores before and after the intervention were
      the main outcome measures. RESULTS: The key characteristic, duration of exposure
      to an aspect (in months), was positively related to the change in availability of
      separate clinics and in the amount of teamwork. The improvement in instruments
      and materials was positively related to the general practitioner's opinion about
      the given feedback. No relations were found between the key characteristics and
      changes in record-keeping or follow-up routines. CONCLUSIONS: Although
      implementation of a comprehensive prevention program is effective, we could not
      fully disentangle the "black box" of the intervention. The duration of exposure
      to an aspect of organizing cardiovascular care was the key determinant to
      success.

PMID- 12431892
TI  - Nutrition counseling in the promoting cancer prevention in primary care study.
AB  - BACKGROUND: Little is known about the influence of personal and practice-level
      factors on physicians' dietary counseling practices. METHODS: Primary care
      physicians (n = 130) were surveyed regarding the frequency that they "ask"
      patients about their diet, "assess" patients' reasons for and against dietary
      changes, "advise" patients to eat less fat and more fiber, "assist" patients in
      changing their diet, and "arrange" a follow-up contact to discuss their diet. In
      addition, physicians were asked their personal dietary practices, counseling
      confidence, practice demographics, and medical specialty. RESULTS: Physicians who
      (a) reported consistently avoiding dietary fat, (b) were more confident in their
      diet counseling abilities, and (c) were sole owners of their practice were more
      likely to counsel than physicians who were employees or part owners of the
      practice. For example, physicians who reported consistently avoiding dietary fat
      (50.7% of physicians) were 3.2 (95% CI: 1.3-7.9) times more likely to "ask" their
      patients about their diet and 3.5 (95% CI: 1.5-8.6) times likely to "advise"
      their patients to eat less fat and more fiber. CONCLUSIONS: Given the strong and
      consistent effects of a physician's dietary pattern on their counseling
      practices, future studies should examine the impact of modifying a physician's
      diet on their patients' dietary behavior.

PMID- 12431893
TI  - Primary care physicians' awareness and implementation of screening guidelines for
      colorectal cancer.
AB  - OBJECTIVE: The objective was to determine primary care physicians' (PCPs)
      familiarity and implementation of screening guidelines for colorectal cancer
      (CRC) in central Israel. METHODS: Fifty PCPs were interviewed and 1000 charts of
      their asymptomatic patients ages 50-70 were examined. All CRC patients treated at
      the regional Oncology Institute in 1980-1984 and in 1993-1997 were then compared,
      with emphasis on the event leading to diagnosis and tumor stage. RESULTS: Almost
      all PCPs endorsed screening. Fecal occult blood testing (FOBT) was appropriately
      recommended by 40% (annually), and the use of flexible sigmoidoscopy (FS) was
      appropriately recommended by 12% of physicians (every 3-5 years). Only four (8%)
      were correct in the use of both techniques. Most PCPs estimated that >25% of
      their patients had been screened for CRC. In fact, 92/1,000 had FOBT (9.2%),
      14/1,000 had screening FS (1.4%), and 3 patients only had both tests. Only 1.2%
      of CRC diagnoses in the 1980s (n = 175) and 2.6% in the 1990s (n = 343) were
      established as a result of screening (P > 0.25, NS). Tumor stage distribution at
      diagnosis was similar. CONCLUSIONS: PCPs studied endorse CRC screening but they
      are not familiar with accepted guidelines and do very little about implementing
      them, and this has not changed much over the past decade. CRC screening has a
      potential to markedly decrease mortality, yet the best screening strategy is
      worthless without physician education and compliance.

PMID- 12431894
TI  - Application of the protection motivation theory to genetic testing for breast
      cancer risk.
AB  - BACKGROUND: Many women, even women at low risk, are interested in genetic testing
      for breast cancer risk. However, the test has little to offer for women at low to
      moderate risk. We applied the Protection Motivation Theory (PMT) to investigate
      predictors of women's motivation to obtain such a test. METHODS: Women at low to
      moderate risk (n = 330) were recruited through a physician network. They received
      an informational letter by mail and completed a telephone survey and a written
      baseline questionnaire. RESULTS: Structural equation analyses with motivation to
      test as the outcome variable showed that the full model was not supported by the
      data. However, modifications to the model resulted in good model fit and
      explained 51% of the variance. Women with increased breast cancer worries, which
      were influenced by perceived risk, and women who saw more disadvantages of not
      getting tested showed more motivation to pursue testing. Women who saw more
      advantages of not getting tested showed less motivation. CONCLUSIONS: Applying
      the PMT was helpful in determining factors that play a role in women's intentions
      to obtain genetic testing. Counseling should aim at decreasing perceived risk and
      breast cancer worries and include a discussion of the consequences of not getting
      tested.

PMID- 12431895
TI  - Validation of recall of breast and cervical cancer screening by women in an
      ethnically diverse population.
AB  - BACKGROUND: Screening mammogram and Pap smear rates are lower for women in
      underserved racial and ethnic groups, yet may be overestimated due to reliance on
      patients' self-reports. The purpose of this study was to determine accuracy of
      self-reports of mammograms and Pap smears in a multiethnic, multilingual
      population of African American, Latina, Chinese, Filipina, and White women
      residing in low-income census tracts of Alameda County, California. METHODS:
      Following a baseline telephone survey of 1,464 women regarding receipt of
      mammograms and Pap smears, we examined computerized and written medical records
      to validate the dates and locations of tests reported by women. RESULTS: Of 1,464
      subjects, 94.9% reported having had a Pap smear, and 87% reported having had a
      mammogram. For Pap smears, in a subsample of 448 cases, we validated only 69.4%
      of the women's self-reports, and for mammography, in a subsample of 846 women, we
      validated only 75.4% of the self-reports. Validation rates differed significantly
      by ethnicity and site of care for both Pap smears and mammograms. CONCLUSIONS:
      Population estimates of breast and cervical cancer screening rates based upon
      patient self-reports need to be adjusted downward, by as much as one-quarter to
      one-third, for low-income, ethnic women.

PMID- 12431896
TI  - Evaluations of dieting prevention messages by adolescent girls.
AB  - BACKGROUND: Dieting prevention interventions have been relatively unsuccessful
      and may be more effective if they concentrate on messages known to be relatively
      high on persuasive properties. We aimed to identify anti-dieting messages rated
      most strongly on persuasive dimensions and participant characteristics that
      predicted message evaluations in adolescent girls. METHODS: Grade 7 and 8 girls
      completed questionnaires assessing risk factors for, and early symptoms of,
      eating disorders. Two weeks later, participants viewed on video seven messages
      (each 2-3 minutes long) frequently used to dissuade against dieting in prevention
      interventions and one control message. After viewing each message, participants
      rated it on a scale assessing the persuasive dimensions of Relevance,
      Believability, Emotional Response, and Intention to Diet. RESULTS AND
      CONCLUSIONS: A quarter to a third of participants felt less likely to go on a
      diet after viewing the messages. "Skipping meals makes you feel starved so you
      overeat and feel bad" and "Don't be fooled by the fad diets promoted in the
      media" were rated most strongly. Higher dieting, body dissatisfaction, and
      negative affect were generally associated with lower persuasive ratings,
      suggesting the importance of intervention prior to the establishment of dieting
      behaviors after which there is more message resistance. Age was also a predictor
      of Believability for some messages, supporting the importance of ensuring the age
      appropriateness of messages.

PMID- 12431897
TI  - Anthropometric indices of school children and familiar risk factors.
AB  - BACKGROUND: Overweight in adolescence predicts adverse health effects in
      adulthood. We carried out a primary school health program and assessed children's
      growth and body composition. METHODS: Were screened 869 (448 M, 421 F) primary
      school children: height, weight, four skinfolds, and four circumferences were
      measured. A family-reported questionnaire was used to determine family
      composition, history, and lifestyle. RESULTS: Age was 118 +/- 5 months, BMI 18 +/
      3 kg/m(2). No difference by gender was observed as for BMI or blood pressure.
      Girls had higher skinfold thickness at the biceps (BCF), triceps (TCF),
      subscapular (SSF), and suprailiac (SIF) areas (P < 0.001), hip and thigh
      circumferences (P < 0.01), body fat percentage (P < 0.001). Boys had higher waist
      circumference (P < 0.01), waist/thigh ratio, and conicity index (P < 0.001).
      Offspring BMI was correlated with birth weight (P < 0.05), parental BMI and
      scholarship level (P < 0.001), children blood pressure (P < 0.001), and hours per
      day spent in television viewing (P < 0.01). Family history for diabetes was
      associated with higher BMI, SSF, waist circumference (P < 0.05), and upper thigh
      (P < 0.01). Family history for hypertension was associated with higher SSF/TCF
      ratio (P < 0.05). CONCLUSIONS: Three of 869 children had BMI >30 kg/m(2) (2 boys
      and 1 girl), 33 had BMI >25 kg/m(2) (17 boys and 16 girls). The percentages of
      children who could be considered overweight (BMI >/=95(th) percentile of age- and
      sex-specific NHANES I reference data) were boys, 10.0%, and girls, 9.3%.
      Anthropometric and anamnestic data on child and family yield more accurate
      estimates of risk profile: fat distribution seems relevant for metabolic and
      cardiovascular disorders.

PMID- 12431898
TI  - Physical development and lifestyle of Hong Kong secondary school students.
AB  - BACKGROUND: Objectives of the present investigation were to study the growth and
      development of adolescents in Hong Kong, to analyze the interrelationship between
      their development and lifestyle, and to provide some helpful suggestions for
      lifestyle modification. METHODS: A total of 404 secondary students ages 12-18
      years served as subjects. Morphological measures, blood pressure, blood lipids,
      aerobic fitness, and body composition were tested. A self-report questionnaire
      was administered to assess physical activity and dietary habits. RESULTS AND
      CONCLUSIONS: Systolic blood pressure and diastolic blood pressure increased with
      age, and a gender difference was noted. Body height and body weight increased
      with age. Total cholesterol showed a lowering trend with age, and high-density
      lipoprotein had a slight rise. The percentage body fat for boys decreased with
      age but increased for girls. The higher percentage of overweight and obesity was
      closely associated with physical inactivity and inappropriate food selection such
      as eating snacks or food rich in fat or cholesterol. Tailor-made physical
      activity and nutritional education programs should be designed for adolescents,
      especially girls during puberty.

PMID- 12431899
TI  - Outcome evaluation of a high school smoking reduction intervention based on
      extracurricular activities.
AB  - BACKGROUND: An outcome evaluation of a high school tobacco control intervention
      using extracurricular activities developed by teachers and students is reported.
      METHODS: Eligible subjects (n = 3,028) had participated in a randomized trial of
      an elementary school smoking prevention curriculum. Their high schools were
      matched in pairs; one school in each pair was randomly assigned to the
      intervention condition, the second to a "usual-care" control condition. Data were
      collected at the end of Grades 9 and 10. RESULTS: For Grade 8 never smokers,
      regular smoking rates were significantly lower for males from intervention
      schools (9.8 vs 16.2%, P = 0.02) at the end of Grade 10. There were no
      significant differences among Grade 10 smoking rates for females, or for students
      of either gender with previous smoking experience in Grade 8. CONCLUSIONS: The
      extracurricular activities approach to tobacco control is practical to implement
      and has promise.

PMID- 12431901
TI  - Reporting medical information: effects of press releases and newsworthiness on
      medical journal articles' visibility in the news media.
AB  - BACKGROUND: Characteristics defining newsworthiness of journal articles appearing
      in JAMA and NEJM were examined to determine if they affect visibility in the news
      media. It was also hypothesized that press releases affected the amount of news
      coverage of a journal article due to the fact that the most newsworthy journal
      articles are selected for press releases. METHODS: Journal articles (N = 95) were
      coded for characteristics believed to describe the "newsworthiness" of journal
      articles. Quantity of news coverage of the journal articles was estimated using
      the LEXIS-NEXIS database. Bivariate associations were examined using one-way
      analysis of variance, and multivariate analyses utilized OLS regression. RESULTS:
      Characteristics of the newsworthiness of medical journal articles predicted their
      visibility in newspapers. The issuing of press releases also predicted newspaper
      coverage. However, press releases predicted newspaper coverage largely because
      more newsworthy journal articles had accompanying press releases rather than
      because the press release itself was influential. CONCLUSIONS: Journalists report
      on medical information that is topical, stratifies risk based on demographic and
      lifestyle variables, and has lifestyle rather than medical implications. Medical
      journals issue press releases for articles that possess the characteristics
      journalists are looking for, thereby further highlighting their importance.

PMID- 12431900
TI  - Evidence of the dose effects of an antitobacco counteradvertising campaign.
AB  - OBJECTIVE: The objectives were to assess the cumulative effects of exposure to
      multiple antitobacco advertisements shown over a 22-month period on smoking
      uptake, and determine if there is evidence of a dose effect and how this effect
      operates through response to the campaign's major message theme and antitobacco
      attitudes. METHODS: A follow-up telephone survey of persons ages 12-20 years was
      conducted after 22 months of the Florida "truth" antitobacco media campaign.
      Logistic regression analyses were used to estimate adjusted odds ratios for the
      likelihood that time-one nonsmokers would remain nonsmokers at time two by levels
      of confirmed advertisement awareness, self-reported influence of the campaign's
      message theme, and anti-tobacco industry manipulation attitudes. Separate cohorts
      are analyzed and controls include gender and time-one susceptibility. RESULTS:
      The likelihood of nonsmokers remaining nonsmokers increases as the number of ads
      confirmed, the self-reported influence of the campaign's major message theme, and
      the level of antitobacco attitudes increases. The pattern to these relationships
      holds within cohorts of young and older youth and for a cohort that has aged into
      the early young adult years. Considering all variables simultaneously suggests
      that ad confirmation operates through its effects on the influence of the message
      theme and antitobacco industry manipulation attitudes. CONCLUSIONS: There is
      evidence of a dose effect; however, considering only ad confirmation
      underestimates this. Antitobacco campaigns that target youth can have effects at
      least through the early young adult ages. The uniqueness of the Florida campaign
      may limit the generalization of reported results.

PMID- 12431903
TI  - Exposure to schistosome eggs protects mice from TNBS-induced colitis.
AB  - Crohn's disease results from dysregulated T helper (Th)1-type mucosal
      inflammation. Crohn's disease is rare in tropical countries but prevalent in
      developed countries with temperate climates, in which its incidence rose after
      1940. In contrast, exposure to helminthic parasites is common in tropical
      countries but is rare in developed countries. Helminthic parasites induce
      immunomodulatory T cell responses in the host. We hypothesize that
      immunomodulatory responses due to helminths may attenuate excessive Th1-type
      inflammation. To test that hypothesis, mice were exposed to eggs of the helminth
      Schistosoma mansoni and then challenged rectally with trinitrobenzesulfonic acid
      (TNBS) to induce colitis. Schistosome egg exposure attenuated TNBS colitis and
      protected mice from lethal inflammation. Schistosome egg exposure diminished IFN
      gamma and enhanced IL-4 production from alphaCD3-stimulated spleen and mesenteric
      lymph node cells of TNBS-treated mice. Schistosome egg exposure decreased colonic
      IFN-gamma but increased IL-10 mRNA expression in TNBS-treated mice. Intact signal
      transducer and activator of transcription 6 was required for attenuation of
      colitis. Exposure to helminths can decrease murine colonic inflammation.

PMID- 12431904
TI  - Prosurvival and antiapoptotic effects of PGE2 in radiation injury are mediated by
      EP2 receptor in intestine.
AB  - The biological activities of PGE(2) are mediated through EP receptors (EP(1)
      EP(4)), plasma membrane G protein-coupled receptors that differ in ligand binding
      and signal-transduction pathways. We investigated gastrointestinal EP(2) receptor
      expression in adult mice before and after radiation injury and evaluated
      intestinal stem cell survival and crypt epithelial apoptosis after radiation
      injury in EP(2) null mice. EP(2) was expressed throughout the gut. Intestinal
      EP(2) mRNA increased fivefold after gamma-irradiation. Crypt survival was
      diminished in EP(2)-/- mice (4.06 crypts/cross section) compared with wild-type
      littermates (8.15 crypts/cross section). Radiation-induced apoptosis was
      significantly increased in EP(2)-/- mice compared with wild-type littermates.
      Apoptosis was 1.6-fold higher in EP(2) (-/-) mice (5.9 apoptotic cells/crypt)
      than in wild-type mice (3.5 apoptotic cells/crypt). The EP(2) receptor is
      expressed in mouse gastrointestinal epithelial cells and is upregulated following
      radiation injury. The effects of PGE(2) on both crypt epithelial apoptosis and
      intestinal crypt stem cell survival are mediated through the EP(2) receptor.

PMID- 12431905
TI  - Role of thromboxane A2 in early BDL-induced portal hypertension.
AB  - Although the mechanisms of cirrhosis-induced portal hypertension have been
      studied extensively, the role of thromboxane A(2) (TXA(2)) in the development of
      portal hypertension has never been explicitly explored. In the present study, we
      sought to determine the role of TXA(2) in bile duct ligation (BDL)-induced portal
      hypertension in Sprague-Dawley rats. After 1 wk of BDL or sham operation, the
      liver was isolated and perfused with Krebs-Henseleit bicarbonate buffer at a
      constant flow rate. After 30 min of nonrecirculating perfusion, the buffer was
      recirculated in a total volume of 100 ml. The perfusate was sampled for the
      enzyme immunoassay of thromboxane B(2) (TXB(2)), the stable metabolite of TXA(2).
      Although recirculation of the buffer caused no significant change in sham
      operated rats, it resulted in a marked increase in portal pressure in BDL rats.
      The increase in portal pressure was found concomitantly with a significant
      increase of TXB(2) in the perfusate (sham vs. BDL after 30 min of recirculating
      perfusion: 1,420 +/- 803 vs. 10,210 +/- 2,950 pg/ml; P < 0.05). Perfusion with a
      buffer containing indomethacin or gadolinium chloride for inhibition of
      cyclooxygenase (COX) or Kupffer cells, respectively, substantially blocked the
      recirculation-induced increases in both portal pressure and TXB(2) release in BDL
      group. Hepatic detection of COX gene expression by RT-PCR revealed that COX-2 but
      not COX-1 was upregulated following BDL, and this upregulation was confirmed at
      the protein level by Western blot analysis. In conclusion, these results clearly
      demonstrate that increased hepatic TXA(2) release into the portal circulation
      contributes to the increased portal resistance in BDL-induced liver injury,
      suggesting a role of TXA(2) in liver fibrosis-induced portal hypertension.
      Furthermore, the Kupffer cell is likely the source of increased TXA(2), which is
      associated with upregulation of the COX-2 enzyme.

PMID- 12431906
TI  - ERG K+ channels modulate the electrical and contractile activities of gallbladder
      smooth muscle.
AB  - The current study was undertaken to test the existence and possible role of ether
      a-go-go-related gene 1 (ERG1) protein K(+) channels in gallbladder smooth muscle
      (GBSM). Transcripts encoding ERG1 were detected in human, mouse, and guinea pig
      GBSM, and ERG1 immunoreactivity was observed in GBSM cells. In intracellular
      voltage recordings, addition of E-4031 (100 nM-1 microM) or cisapride (100 nM-2
      microM) caused concentration-dependent excitation of guinea pig GBSM that was not
      affected by 500 nM TTX + 5 microM atropine, and E-4031 also depolarized the
      resting membrane potential. In muscle strip studies, E-4031 either induced phasic
      contractions or significantly increased the amplitude of phasic contractions in
      spontaneously active tissues (P = 0.001). E-4031 also potentiated bethanechol
      induced contractions. In conclusion, ERG1 channels are expressed in the GBSM,
      where they play a role in excitation-contraction coupling probably by
      contributing to repolarization of the plateau phase of the action potential and
      to the resting membrane potential.

PMID- 12431907
TI  - Plasminogen directs the pleiotropic effects of uPA in liver injury and repair.
AB  - The urokinase-type plasminogen activator (uPA) plays a central role in liver
      repair. Nevertheless, the hepatic overexpression of uPA results in panlobular
      injury and neonatal mortality. Here, we define the molecular mechanisms of liver
      injury and explore whether uPA can regulate liver repair independently of
      plasminogen. To address the hypothesis that the liver injury in transgenic mice
      results from the intracellular activation of plasminogen by transgene-derived uPA
      (uPAT), we generated mice that overexpress uPAT and lack functional plasminogen
      (uPAT-Plg(-)). In these mice, loss of plasminogen abolished the hepatocyte
      specific injury and prevented the formation of regenerative nodules displayed by
      uPAT littermates. Despite the increased expression of hepatic uPA, livers of uPAT
      Plg(-) mice were unable to clear necrotic cells and restore normal lobular
      organization after an acute injury. Notably, high levels of circulating uPA in
      uPAT-Plg(-) mice did not prevent the long-term extrahepatic abnormalities
      previously associated with plasminogen deficiency. These data demonstrate that
      plasminogen directs the hepatocyte injury induced by uPAT and mediates the
      reparative properties of uPA in the liver.

PMID- 12431908
TI  - Sensory and biomechanical responses to ramp-controlled distension of the human
      duodenum.
AB  - The aim of this study was to develop a new method for investigation of the
      relationship among the mechanical stimulus, the biomechanical properties, and the
      visceral perception evoked by volume/ramp-controlled distension in the human
      duodenum in vivo. An impedance planimetric probe for balloon distension was
      placed in the third part of the duodenum in seven healthy volunteers. Distension
      of the duodenum was done at infusion rates of 10, 25, and 50 ml/min. The pump was
      reversed when level 7 was reached on a visual analog scale ranging from 0 to 10.
      Distensions were done with and without the administration of the antimuscarinic
      drug butylscopolamine. The total circumferential tension (T(total)) and the
      passive circumferential tension (T(passive)) were determined from the distension
      tests without and with the administration of butylscopolamine, respectively.
      T(total) and T(passive) showed an exponential behavior as a function of strain (a
      measure of deformation). The active circumferential tension (T(active)) was
      computed as T(total)-T(passive) and showed a bell-shaped behavior as a function
      of strain. At low distension intensities, the intensity of sensation at 10 ml/min
      was significantly higher than that obtained at 25 and 50 ml/min. The coefficient
      of variation at the pain threshold for circumferential strain (average 4.34) was
      closer to zero compared with those for volume (8.72), pressure (31.22), and
      circumferential tension (31.55). This suggests that the mechanoreceptors in the
      gastrointestinal wall depend primarily on circumferential strain. The stimulus
      response functions provided evidence for the existence of low- and high-threshold
      mechanoreceptors in the human duodenum. Furthermore, the data suggest that high
      threshold receptors are nonadapting.

PMID- 12431909
TI  - Glu496Ala polymorphism of human P2X7 receptor does not affect its
      electrophysiological phenotype.
AB  - A glutamate to alanine exchange at amino acid position 496 of the human P2X(7)
      receptor was recently shown to be associated with a loss of function in human B
      lymphocytes in terms of ATP-induced ethidium(+) uptake, Ba(2+) influx, and
      induction of apoptosis (Gu BJ, Zhang WY, Worthington RA, Sluyter R, Dao-Ung P,
      Petrou S, Barden JA, and Wiley JS. J Biol Chem 276: 11135-11142, 2001). Here we
      analyzed the effect of the Glu(496) to Ala exchange on the channel properties of
      the human P2X(7) receptor expressed in Xenopus oocytes with the two
      microelectrode voltage-clamp technique. The amplitudes of ATP-induced whole cell
      currents characteristic of functional expression, kinetic properties including
      ATP concentration dependence, and permeation behavior were not altered by this
      amino acid exchange. Also in HEK293 cells, the Ala(496) mutant mediated typical
      P2X(7) receptor-dependent currents like the parent Glu(496) hP2X(7) receptor.
      Because the function of the P2X(7) receptor as an ATP-gated channel for small
      cations including Ba(2+) remained unaffected by this mutation, we conclude that
      Glu(496) plays a critical role in pore formation but does not determine the ion
      channel properties of the human P2X(7) receptor.

PMID- 12431910
TI  - Diacylglycerol and ceramide formation induced by dopamine D2S receptors via Gbeta
      gamma -subunits in Balb/c-3T3 cells.
AB  - Diacylglycerol (DAG) and ceramide are important second messengers affecting cell
      growth, differentiation, and apoptosis. Balb/c-3T3 fibroblast cells expressing
      dopamine-D2S (short) receptors (Balb-D2S cells) provide a model of G protein
      mediated cell growth and transformation. In Balb-D2S cells, apomorphine (EC(50) =
      10 nM) stimulated DAG and ceramide formation by 5.6- and 4.3-fold, respectively,
      maximal at 1 h and persisting over 6 h. These actions were blocked by
      pretreatment with pertussis toxin (PTX), implicating G(i)/G(o) proteins. To
      address which G proteins are involved, Balb-D2S clones expressing individual PTX
      insensitive Galpha(i) proteins were treated with PTX and tested for apomorphine
      induced responses. Neither PTX-insensitive Galpha(i2) nor Galpha(i3) rescued D2S
      induced DAG or ceramide formation. Both D2S-induced DAG and ceramide signals
      required Gbetagamma-subunits and were blocked by inhibitors of phospholipase C [1
      (6-[([17beta]-3-methoxyestra-1,2,3[10]-trien- 17yl)amino]hexyl)-1H-pyrrole-2,5
      dione (U-73122) and partially by D609]. The similar G protein specificity of D2S
      induced calcium mobilization, DAG, and ceramide formation indicates a common
      Gbetagamma-dependent phospholipase C-mediated pathway. Both D2 agonists and
      ceramide specifically induced mitogen-activated protein kinase (ERK1/2),
      suggesting that ceramide mediates a novel pathway of D2S-induced ERK1/2
      activation, leading to cell growth.

PMID- 12431911
TI  - Topographic requirements and dynamics of signaling via L-selectin on neutrophils.
AB  - Cross-linking of L-selectin on leukocytes signals phosphorylation of mitogen
      activated protein kinases (MAPKs) leading to activation of CD18 function and
      enhanced transmigration on inflamed endothelium. We examined how alterations in
      the topography of L-selectin correlate with the dynamics of CD18 activation and
      phosphorylation of MAPK. Simultaneous ligation of humanized antibodies DREG55 and
      DREG200 provided a strategy for regulating the extent of cross-linking.
      Triggering of CD11b/CD18 upregulation and adhesion required clustering of L
      selectin to microvillus-sized patches of approximately 0.2 microm(2).
      Immunofluorescence revealed that L-selectin was colocalized with high-affinity
      CD18. Anti-L-selectin-coated protein A microspheres indicated that a single site
      of contact to a 5.5-microm bead, or multiple contacts to 0.94- or 0.3-microm
      beads, elicited maximum neutrophil activation. Adhesion signaled via L-selectin
      coincided with the kinetics of MAPK phosphorylation and was inhibited by blocking
      p38 or p42/44 activity. These data demonstrate the capacity of L-selectin to
      transduce signals effecting rapid ( approximately 1 s) neutrophil adhesion that
      is regulated by the size and frequency of receptor clustering.

PMID- 12431913
TI  - Research in medical education: what do we know about the link between what
      doctors are taught and what they do?

PMID- 12431912
TI  - Peroxynitrite and nitric oxide differ in their effects on pig coronary artery
      smooth muscle.
AB  - Peroxynitrite generated in arteries from superoxide and nitric oxide (NO) may
      damage their function. Here, we compare the effects of peroxynitrite and
      peroxynitrite/NO-generating agents SIN-1 (3-morpholinosydnonimine hydrochloride),
      SNAP (S-nitroso-N-acetyl-penicillamine), SNP (sodium nitroprusside), and NONOate
      (spermine NONOate) on pig coronary artery. Deendothelialized artery rings were
      pretreated with these agents and then washed before examining their
      contractility. Pretreatment with all agents (200 microM) results in a decrease in
      the force of contraction in response to the sarco(endo)plasmic Ca(2+) (SERCA)
      pump inhibitor cyclopiazonic acid (CPA): SNAP > NONOate > or = peroxynitrite > or
      = SIN-1 > SNP. Pretreatment with SNAP, NONOate, or SIN-1 also inhibits the force
      of contraction produced with 30 mM KCl, with SNAP being the most potent.
      Including catalase plus superoxide dismutase (SOD) during the preincubation has
      no effect. Including an NO scavenger [2-(4-carboxyphenyl)-4,4,5,5
      tetramethylimidazoline-1-oxyl-3-oxide] or a guanylate cyclase inhibitor (1H
      [1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one) partially protects against SNAP.
      Pretreatment of cultured cells with peroxynitrite, but not with SNAP, inhibits
      the Ca(2+) transients produced in response to CPA. Pretreating isolated membrane
      vesicles with peroxynitrite inhibits the Ca(2+) uptake due to the SERCA pump,
      with all the other agents being less effective. Thus peroxynitrite and NO both
      inhibit the CPA-induced contractions in deendothelialized artery rings,
      peroxynitrite by damage to the SERCA pump and NO possibly by a step downstream
      from the increase in cytosolic Ca(2+).

PMID- 12431914
TI  - A new approach to medicare: implications for health care reform and for medical
      education.
AB  - Medicare Parts A and B engender a system of payment and delivery at odds with
      that of health maintenance organizations (HMOs). Most evident in the conflicting
      incentives and requirements levied on primary care physicians participating today
      in both traditional Medicare and HMOs, the dichotomy has vitiated the promise of
      managed care and constitutes a significant factor in both the rising cost
      inflation in health care and the growing dissatisfaction of patients, physicians,
      payers, and insurers. The resulting impact affects the robustness and quality of
      medical education as well as the character and quality of health care delivery.
      An innovative incentive-based system of payment and delivery is proposed as an
      alternative option for Medicare, with expectation that the system, which the
      authors title Medicare-New, or Part N, could trigger a more effective approach to
      health care reform for Medicare, foster more rational support for medical
      education and the care of the indigent, and benefit private insurance programs as
      well. Positive changes in both public and private sectors would strengthen both
      medical education and the access to and quality of health care throughout the
      nation.

PMID- 12431915
TI  - Complexity and uncertainty in financing graduate medical education.
AB  - The current sources and structure of graduate medical education (GME) financing
      policies are being challenged. To foster understanding of these challenges, the
      author explains the current GME financing system and explores the impacts that
      various policy changes and legislation under consideration would have on
      residency programs and the health of already financially stressed teaching
      hospitals. Specifically, the wide variety of revenue sources (mostly third-party
      payers) are discussed, particularly the present Medicare direct graduate medical
      education (DGME) payments and indirect medical education (IME) adjustment
      payments, and their policy implications. The author concludes that a serious
      problem in advocating a new approach to the financing of GME (which would focus
      on changes in Medicare support) is the absence of a common vision, not only among
      policymakers but also within the academic medical community. Too much energy has
      been expended on how GME and the special missions of teaching hospitals should
      not be funded, and not enough attention focused on how to achieve a dependable
      source of revenue to help finance them. The public policy challenge is how to
      sustain Medicare's traditional support for GME in the face of intense pressure to
      "save" Medicare through fundamental reforms.

PMID- 12431916
TI  - Clinical research career development: the individual perspective.
AB  - The process of integrating medical scientific breakthroughs into improved
      clinical practice requires talented and dedicated clinical investigators.
      Unfortunately, substantial impediments deter gifted physicians from clinical
      research. The experience of "Dr. Ross," an aspiring (fictional) clinical
      investigator, is presented in this report. The factors that ultimately contribute
      to Dr. Ross' choice to abandon an academic clinical research career are explored.
      Issues relating to research training, mentoring, funding, and academic promotion
      standards are analyzed from his individual perspective. Special emphasis is given
      to the intense financial pressure trainees face. Finally, potential solutions are
      presented. These include a description of the National Institutes of Health K23,
      K24, and K30 programs and its new extramural Loan Repayment Program for clinical
      researchers. These important advances provide much-needed support, but additional
      work must be done. In the absence of further reform, academic medicine's mission
      to train tomorrow's clinical investigators will erode further.

PMID- 12431917
TI  - Industry, academia, investigator: managing the relationships.
AB  - Financial self-interests in medical research are again the subject of increasing
      public and government concern. Proposed new statutes and regulations would
      prescribe research conduct and oversight, as well as faculty behavior, in ways
      that would represent an unprecedented interposition of federal authority into
      areas of traditional university autonomy. Overly zealous regulation could also
      interdict a fruitful product development pathway of enormous benefit to public
      health. Yet, the universities and their academic medical centers have failed to
      respond sufficiently or credibly to the profound transformation of their research
      culture in the past two decades, which has witnessed a dramatic increase in the
      privatization of historically public biomedical research, and in the financial
      self-interests of investigators and institutions in the research they conduct.
      The author reviews the history of federal regulation of individual conflicts of
      interest in biomedical research, and examines the always-complex relationships
      and expectations of research universities with industry and society. While
      university oversight of individual conflicts of interest demands strengthening,
      the issues are long debated and well understood. In contrast, the financial
      interest of institutions in the medical research they conduct is recent, more
      complicated, poorly understood, and highly sensitive, involving investment
      decisions that lie at the heart of university autonomy. The author argues that
      institutions and professional societies must promulgate and enforce transparent
      standards of conduct, and strengthen oversight and management of financial self
      interests, to avoid burdensome federal intervention and corrosive public
      skepticism. He concludes by reporting three promising responses from academia and
      major medical journals.

PMID- 12431918
TI  - Should medical school faculty see assessments of students made by previous
      teachers?
AB  - Whether medical school faculty should be provided with assessments of students
      made by previous teachers remains controversial. To document which schools have
      implemented policies that address this issue and to characterize the specific
      features of these policies, in 1998 the authors conducted a direct mail survey of
      deans of student affairs and medical education at 144 medical schools in the
      United States, Canada, and Puerto Rico. Replies were received from 129 (90%) of
      the 144 medical schools. Of those schools, 72 (56%) reported having policies that
      address this issue. The policies permit the sharing of information in 38 (53%) of
      the 72 schools that had policies; therefore, at the time of this study, 29% of
      the 129 medical schools that responded to the survey had a policy that permits
      the sharing of assessment information. The policies permit the sharing of
      information related to problems with academic performance (35%), professional
      conduct (35%), physical health (25%), and miscellaneous circumstances, such as
      learning disability (5%). Information may be shared with clerkship coordinators
      (44%), course directors (35%), faculty mentors (11%), clinical faculty
      supervisors (8%), and resident supervisors (3%). The findings show that there is
      considerable diversity in the format and content of policies that address the
      issue of whether medical school faculty should be provided with information about
      students' assessments made by previous teachers. The authors explain why policies
      that require the provision of such information are helpful to medical school
      faculty, and offer recommendations based on the survey findings.

PMID- 12431919
TI  - Four models of medical education about elder mistreatment.
AB  - The authors describe four models of incorporating elder-mistreatment curricular
      content and collaboration with adult protective service (APS) community service
      agencies into geriatrics medical education. Geriatrics education programs at four
      academic health centers-the University of Medicine and Dentistry of New Jersey
      Robert Wood Johnson Medical School; the University of California, Irvine College
      of Medicine; Hennepin County Medical Center, Minneapolis, Minnesota; and Baylor
      College of Medicine Geriatrics Program at the Harris County Hospital District,
      Houston, Texas-were surveyed and information collated. All programs incorporated
      direct interactions between learners and APS workers into their teaching
      programs. Learners were fellows, residents, and medical students. While two
      programs provided direct patient care, two others restricted learners to
      consultant roles, supporting the APS service providers with medical input. In
      addition to directly meeting curricular training needs of elder abuse and
      neglect, clinical cases provided valued learning experiences in applied clinical
      ethics, the role of physicians with community-based programs, the interaction
      between the medical and legal professions in cases of financial exploitation, and
      assessment of elder individuals' decision-making capacity. In two programs APS
      workers also contribute to the assessment of trainees' humanistic competencies.
      The authors conclude that APS community service agencies can successfully be
      incorporated into medical training programs to address a wide range of curricular
      goals.

PMID- 12431920
TI  - Case Western Reserve University School of Medicine.

PMID- 12431921
TI  - The length of our journey: care near the end of life.

PMID- 12431922
TI  - Medicine and the arts. Semmelweis [excerpt] by Jens Bjorneboe. Commentary.

PMID- 12431924
TI  - Third place - the clinical experience that taught me the most.

PMID- 12431925
TI  - Clerkship directors' perceptions of the effects of managed care on medical
      students' education.
AB  - PURPOSE: Little is known about the effect of managed care on medical students'
      education. Because clerkship directors (CDs) are especially well positioned to
      observe any changes, this study surveyed CDs from six medical specialties about
      their perceptions of the effects of managed care on medical students' education.
      METHOD: Anonymous questionnaires were mailed to 808 CDs from departments of six
      medical specialties at 125 U.S. allopathic medical schools between October 1997
      and March 1998. Among other questions, respondents were asked whether they had
      observed changes in 19 different aspects of medical students' education, whether
      these changes were beneficial or detrimental, and whether they believed the
      changes were due to managed care and/or to other factors. Results were analyzed
      to determine perceptions of the overall magnitude and source(s) of changes, the
      perceived positive versus negative effect of managed care, and whether these
      outcomes were statistically associated with the perceived degree of managed
      care's market penetration. RESULTS: Five hundred questionnaires (61.9%) were
      returned. For full-time and voluntary faculty teaching, faculty availability for
      educational administration, directors' clinical responsibilities, and quality of
      professional life, the most common response was that managed care had an adverse
      effect. For faculty's enthusiasm for teaching, directors' administrative and
      educational duties, and clerkship training sites, the second most common response
      after "not changed" was that managed care had a negative effect. The majority of
      respondents held negative opinions of managed care and thought that medical
      students did not understand it. CONCLUSIONS: CDs in six medical specialties
      perceived that managed care has negatively affected medical students' education.
      These perceptions may influence medical students' education. Measures must be
      taken to ensure excellent education through adequate resources and training in
      the context of high-quality medical care.

PMID- 12431926
TI  - Evaluation of a faculty development program in managing care.
AB  - PURPOSE: To evaluate a faculty development program that teaches quality
      improvement and cost-effectiveness. METHOD: From October 2000 to February 2001, a
      two-part faculty development program was offered to 39 physicians from 19 U.S.
      medical schools supported by grants from the Partnerships for Quality Education
      (PQE) and Undergraduate Medical Education in the 21st Century (UME-21). Special
      features of the program included partnerships between academic and community
      physicians from each school, development of an educational innovation of interest
      to the participants, concurrent development of teaching skills and new medical
      knowledge, learning leadership skills (e.g., how to train colleagues to teach),
      and practice periods. The program focused on quality improvement and cost
      effectiveness, but included other "managing care" topics. Prior to and after the
      course, participants assessed their knowledge of and competence to teach these
      topics, as well as other managing care topics. They also assessed their
      competence as medical educators and leaders. After the course, they indicated
      their progress in implementing their proposed educational innovations. RESULTS:
      Thirty-two of the 39 physicians completed evaluations both before and after the
      program. Self-assessed knowledge and competence to teach quality improvement and
      cost-effectiveness were significantly higher at the end of the course, as were
      all self-assessed teaching and leadership skills. The largest change scores
      occurred in assessments of competency to teach the new topics and to teach in new
      ways. Participants who implemented their innovations rated their competencies to
      teach quality improvement and cost-effectiveness higher than did non
      implementers. CONCLUSION: Opportunities for faculty to learn how to teach a topic
      of stated importance to them, to practice what they have learned, and to work
      collaboratively with partners improved teaching skills.

PMID- 12431927
TI  - Managed care education: what medical students are telling us.
AB  - PURPOSE: To examine graduating medical students' perceptions of the adequacy of
      instruction in managed care and in 11 curricular content areas identified by
      experts as a necessary part of managed care education. This study sought to
      determine whether medical students perceived these content areas as relevant to
      managed care and to evaluate the extent to which students' perceptions of the
      adequacy of instruction varied as a function of managed care penetration in the
      locations of their respective medical schools. METHOD: Data from the Association
      of American Medical Colleges' 1999 Medical School Graduation Questionnaire (GQ)
      were analyzed. Students' ratings of adequacy of instruction were summarized.
      Correlations between ratings of instruction in managed care and 11 related
      content areas were calculated, as well as correlations between managed care
      penetration in the locations of the students' schools and the proportion of
      students rating instruction as inadequate. RESULTS: A majority of 1999 medical
      school graduates (60%) rated instruction in managed care as inadequate; other
      content areas to which majorities of graduates gave inadequate ratings were
      practice management (72%), quality assurance (57%), medical care cost control
      (57%), and cost-effective medical practice (56%). Ratings in these four content
      areas were highly correlated with ratings of instruction in managed care. The
      correlation between managed care penetration and rating of instruction in managed
      care was statistically significant (r = -.37); correlations between managed care
      penetration and instruction in the other content areas were not. CONCLUSIONS: On
      the 1999 GQ, a majority of medical students responded that they felt they had not
      received adequate instruction in managed care. Further, the responses suggest
      that these medical students defined managed care in terms of managing costs,
      rather than managing health care, or developing population-based approaches to
      the delivery of health care.

PMID- 12431928
TI  - Self and peer assessment in tutorials: application of a relative-ranking model.
AB  - PURPOSE: While self assessment continues to be touted as being of paramount
      importance for continuing professional competence, problem-based learning
      curricula, and adult learning theory, techniques for ensuring valid judgments
      have proven elusive. This study tested the applicability of an innovative
      relative-ranking procedure to problem-based learning tutorials. METHOD: A total
      of 36 students in the McMaster University Faculty of Health Sciences' MD program
      were provided relative-ranking forms listing seven domains of competence along
      with their definitions. The student, two of the student's peers, and the
      student's tutor were asked to complete the ranking exercise after their second,
      fourth, and sixth tutorials. RESULTS: Combining each level of the time and rater
      variables generated 66 correlation coefficients, none of which was significantly
      different from zero. Re-performing the analysis on only the extreme domains did
      not improve this result. CONCLUSION: The relative-ranking instrument developed
      did not prove to be a reliable measure of tutorial performance. Ratings were
      inconsistent from one week to the next as well as across raters within a week.

PMID- 12431929
TI  - Teaching digital rectal examinations to medical students: an evaluation study of
      teaching methods.
AB  - PURPOSE: The digital rectal examination (DRE) is a necessary part of a complete
      physical examination and evaluation of a patient, yet teaching of this
      examination to medical students is often inadequate. This study was a comparative
      evaluation of the effectiveness of the rectal teaching associate (RTA), lecture,
      role-playing, and simulated models as methods for teaching the DRE procedure to
      undergraduate medical students at Memorial University of Newfoundland Faculty of
      Medicine. METHOD: A total of 65 third-year medical students were randomly
      assigned to either an experimental or control group. Both groups received a
      lecture and practiced the DRE on a simulated model. The experimental group
      received further training from an RTA. Students completed a pre- and post
      intervention knowledge assessment, an objective structured clinical exam (OSCE)
      measuring performance of the DRE, and a satisfaction survey. RESULTS: Mean
      knowledge scores increased significantly for both groups (18.73 to 22.32, p
      <.0001). The control group scored significantly higher on the post-intervention
      assessment than did the experimental group (23.11 versus 21.47, p =.025) The
      experimental group scored higher on the OSCE (27.52 versus 23.80, p =.001) and
      rated the RTA as a more effective method for learning the DRE. CONCLUSIONS: This
      first study using RTAs to teach the DRE as a global skill for evaluating the
      rectum suggests that the RTA method is effective for increasing skills and
      students' confidence in the procedure.

PMID- 12431930
TI  - Use of live animals in the curricula of U.S. medical schools: survey results from
      2001.
AB  - PURPOSE: The use of live animals in U.S. medical education declined progressively
      from 1985 to 1994. This study determined whether this trend continued into 2001.
      METHOD: The authors used postage-paid postcards and follow-up e-mails, faxes, and
      telephone calls to survey department chairs of pharmacology, physiology, and
      surgery in all 125 U.S. medical schools about the use of live animals in their
      undergraduate medical courses. RESULTS: The response rates were 97% for
      physiology and surgery departments and 100% for pharmacology departments.
      Respondents reported that live animals were used in 5% of pharmacology courses
      and 18% of physiology and surgery courses. When live-animal laboratories were
      used in the curricula, attendance was optional in 76% of the courses, and the
      percentages of students opting out of the laboratories varied from none to over
      half. The most commonly used animals were pigs and dogs, followed by rodents,
      rabbits, and cats. CONCLUSIONS: During the last seven years, the use of live
      animals in medical school pharmacology and physiology courses has continued to
      decline, but the use of live animals in surgery courses has remained stable.
      Overall, the majority of U.S. medical schools (68%) do not use live animals in
      any of their pharmacology, physiology, or surgery courses, and when live-animal
      laboratories are used, attendance is usually optional.

PMID- 12431931
TI  - A method for real-time, evidence-based general medical attending rounds.
AB  - PURPOSE: To assess the utility and practicality of an evidence-based format in
      internal medicine attending rounds. METHOD: Two randomly selected teams of
      residents and medical students in the internal medicine program at the Montefiore
      Medical Center participated in "Evidence-Based Medicine Attending Month." The
      process entailed the development of patient-based, searchable questions, a search
      for the evidence, the critical appraisal of the retrieved literature, and the
      application of the evidence to the care of the patient. At the last meeting,
      participants evaluated each case by answering three questions about whether the
      process (1) had changed the medical management of the patient during the
      admission, (2) had changed the way they would manage similar patients in the
      future, and (3) had informed them about the disease process in general. RESULTS:
      A total of 12 of 16 formal EBM questions were developed and assessed (75%
      completion rate) during the four-week period, in addition to the standard
      background literature reviews usually performed. Twenty-two articles were
      retrieved and critically appraised. The evaluation demonstrated that 50% of the
      participants felt the process had changed the active management of patients
      currently treated by the team, 75% reported that the process would affect the
      care of future patients with comparable medical problems, and over 90% believed
      the program had informed them about the disease process. CONCLUSIONS: The formal
      EBM approach was conveniently implemented and enhanced the learning experience of
      the participants. It helped inform students' and residents' patient care at the
      time and their attitudes towards future patients. Hence, it is both practical and
      useful to perform formal EBM attending rounds.

PMID- 12431932
TI  - Implementation of the mini-CEX to evaluate medical students' clinical skills.
AB  - OBJECTIVE: The majority of medicine clerkships use faculty and resident summative
      ratings to assess medical students' clinical skills. Still, many medical students
      complete training without ever being observed performing a clinical skill. The
      mini-CEX is method of clinical skills assessment developed by the American Board
      of Internal Medicine for graduate medical education. The brief, focused
      encounters are feasible and produce scores with adequate reproducibility if
      enough observations are made.(1) The mini-CEX has been used in the medicine core
      clerkship, being performed once to augment feedback by faculty evaluators in the
      inpatient setting.(2) However, additional study is needed to address at least two
      feasibility issues if the mini-CEX is to be used as a measurement tool: (1)
      multiple settings (inpatient and outpatient) and (2) resident-completed
      evaluations. Our objective was to determine the feasibility of having students
      receive multiple mini-CEX's in both the inpatient and outpatient settings from
      resident and faculty evaluators. DESCRIPTION: We introduced the mini-CEX into our
      nine-week medicine clerkship (six weeks inpatient and three weeks outpatient) in
      July 2001. The clerkship uses four inpatient clinical sites and 16 outpatient
      practices. Inpatient faculty rotate on two-week blocks and residents on four-week
      blocks. At our clerkship orientation, each student (n = 39) received a booklet of
      ten adapted mini-CEX forms. In the mini-CEX, students are observed conducting a
      focused history and physical examination and then receive immediate feedback.
      Students are rated in seven competencies (interviewing, physical examination,
      professionalism, clinical judgment, counseling, organization, and overall
      clinical competence) using a nine-point rating scale (1 = unsatisfactory and 9 =
      superior). Our students were instructed to collect nine evaluations: three from
      faculty (one every two weeks), three from residents (one every two weeks), and
      three from their out-patient attendings (one per week). Students and evaluators
      were asked to rate their satisfaction with the exercise using a nine-point scale
      (1 = low and 9 = high). Students were asked to turn in their booklets the day of
      the exam. Prior to implementation, we reviewed the mini-CEX forms and rationale
      for use with residents and inpatient faculty. Similar information was mailed to
      outpatient faculty preceptors. DISCUSSION: Booklets were received from 32
      students. The mean number of evaluations completed per student was 7.3 (range 2
      9), for a total of 232 evaluations. Faculty completed 58% of the evaluations; 68%
      were from the inpatient setting. The observation and feedback took an average of
      21 minutes and 8 minutes, respectively. Satisfaction with the exercise was rated
      by faculty/residents as 7.2 and by students as 6.8. We believe these findings
      support the feasibility of collecting multiple mini-CEX assessments from both
      inpatient and outpatient sites using faculty and resident evaluators. The
      feasibility of collecting multiple assessments is important if the mini-CEX is to
      be a reproducible assessment of clinical skills. Having established feasibility,
      we plan to look at the reproducibility and validity of mini-CEX scores in order
      to determine if it can be used as a formal means of clinical skills assessment.
      We also plan to evaluate the impact on the quality and specificity of end-of
      clerkship summative ratings.

PMID- 12431933
TI  - Early assessment of medical students' clinical skills.
AB  - OBJECTIVE: To provide first-year medical students with a non-threatening,
      standardized, clinical-skills assessment at the end of the first year (M1CSA),
      and provide resources to help them build on their strengths and address any
      weaknesses before starting the second year. DESCRIPTION: Implemented for the
      first time in April 2001, the M1CSA was designed to help first-year students
      identify strengths and weaknesses in their developing repertoire of clinical
      skills. It was composed of five stations (abdominal exam, cardiovascular exam,
      lung exam, informed consent, social history) and a self-assessment. Each station
      involved working with a standardized patient (SP), and all SP encounters were
      videotaped so students could review their work during the self-assessment. The
      M1CSA was truly formative in nature; there was no passing or failing mark. To
      help students prepare for the abdominal, cardiovascular, and lung examinations,
      we distributed via Blackboard(R) an electronic copy of the same exam-skills
      checklists that the SPs would be using in the exam stations. To facilitate
      preparation for the social history and informed consent stations, we used
      Blackboard to provide the scenarios in advance. While students were not allowed
      to bring these checklists or scenario descriptions into the stations, they did
      know exactly what was expected. Immediately after each student encounter, SPs
      completed skills checklists and entered evaluative comments via computer
      workstations. Upon completing all five stations, students were provided with
      printouts of the checklists and comments, and proceeded to review their
      videotapes and write self-assessments indicating specific areas for improvement.
      Faculty members were available on-site to review portions of the videotapes,
      answer questions, and offer suggestions. Students also received a resource sheet,
      which listed faculty members and clinics where they could obtain help developing
      their clinical skills over the summer months. The M1CSA was designed by a
      clinical-skills assessment committee and refined through discussion with
      students. The committee was composed of all four of the first-and second-year
      clinical skills unit directors, as well as the Patient, Physician & Society
      course coordinator, the associate dean for medical informatics and computer
      assisted learning, the two staff members of Northwestern's Clinical Education and
      Evaluation Center, the office of medical education's director of evaluation, and
      the associate dean for education (ex-officio). Students evaluated this first
      iteration of the M1CSA very positively, and provided useful feedback for making
      specific improvements. DISCUSSION: The primary motivation for implementing the
      M1CSA was the fact that, over the past several years, many students reported
      starting the second year with considerable uncertainty about their clinical
      skills. The M1CSA was designed to offer a standardized inventory of students'
      proficiencies, and to encourage continued development in anticipation of working
      with real patients in the second year. The content reflects a broad view of
      clinical skills, encompassing communication and ethics, as well as the physical
      examination. The formative nature of the M1CSA complements the long-standing
      M2CSA, which is summative (i.e., students must demonstrate proficiency before
      beginning clerkships).

PMID- 12431934
TI  - A computer-based OSCE station to measure competence in evidence-based medicine
      skills in medical students.
AB  - OBJECTIVE: To create a feasible, valid, and reliable tool to measure third-year
      medical students' skills in evidence-based medicine (EBM). DESCRIPTION: EBM
      skills-asking clinical questions, finding appropriate medical information
      resources, and appraising and applying them to patients-involve higher-order
      critical thinking abilities and are essential to being a competent physician.
      Students at our institution must pass a required OSCE exam at the end of their
      third year. As part of this exam, we developed a new 20-minute computer-based
      station to assess students' EBM skills. Using a specific case scenario, we asked
      the students to (1) ask a question using the
      population/intervention/comparison/outcome (PICO) framework; (2) generate
      appropriate search terms, given a specific question; and (3) select an
      appropriate abstract to answer a given question and state why two other abstracts
      were not appropriate. Prior to the assessment, we determined grading and passing
      criteria for each of the three components and for the station overall. Of the 140
      students who completed the station, the percentages that passed the components
      were 71%, 81%, and 49% respectively, with only 29% passing all three parts.
      Preliminary analysis of psychometric properties of the station shows very good to
      excellent interrater reliability, with 65%, 67%, and 94% agreement on the scoring
      for the components, and kappas of.64,.82, and.94, respectively. DISCUSSION:
      Although there are many curricula for teaching EBM concepts, there are few tools
      to measure whether students are competent in applying their EBM skills. Our pilot
      station appears to be an innovative and promising tool to measure several EBM
      skills independently. By being computer-based, it is relatively simple to
      administer, grade, and evaluate. While preliminary data show good inter-rater
      reliability with our use of a single case, future work will include further
      testing of reliability and assessment of different types of cases. We will also
      use the results of this assessment to drive continuous improvement in our EBM
      curriculum. The students who completed this pilot station had not received an
      extensive formal EBM curriculum, whereas future groups will. We also will explore
      whether scores on our station correlate with those on other OSCE stations that
      also assess critical thinking skills, or if scores correlate with a student's
      clinical grades or overall class standing. We hope to test these hypotheses: (1)
      skills used in EBM are useful and valid measures of critical thinking abilities
      in learners and (2) tools such as ours will help to measure these essential
      competencies.

PMID- 12431935
TI  - Performance-based assessment of internal medicine interns: evaluation of baseline
      clinical and communication skills.
AB  - OBJECTIVE: To assess baseline clinical and communication skills of entering
      internal medicine interns in performance of the medical interview and in written
      documentation of the clinical encounter. DESCRIPTION: Over three years, entering
      internal medicine interns at the University of New Mexico Health Sciences Center
      have taken an OSCE during their first week of training. Each year the process was
      refined based on feedback from both residents and faculty. This year, the intern
      examination consisted of four standardized cases. Twenty-two interns performed a
      focused interview and physical examination on each actor patient. For three of
      the cases, the intern wrote a chart note following the interview. After the
      fourth case, a trained faculty member who had watched the interview via a
      television monitor gave immediate feedback to the intern about his or her
      communication skills. The standardized patients were trained to complete
      checklists that included history, physical exam, and communication items for each
      intern. The written notes were graded using templates devised for each case that
      covered key historical and physical exam findings, problem identification,
      differential diagnosis, clinical reasoning, and logical diagnostic or treatment
      plans. The interns filled out an anonymous evaluation of the exercise where they
      were asked about whether the cases were appropriate for their level of training,
      and about how prepared they felt for the examination. The results for each set of
      skills were then reported to the interns and their supervising clinic attendings.
      For comparison, they were given the performance standards expected of fourth-year
      medical students at our institution. The videotaped encounters and the written
      notes are available for the faculty and trainees to review either together or
      independently. DISCUSSION: This exercise has given the faculty a detailed view of
      baseline clinical and written documentation skills of our entering interns.
      Overall, the residents demonstrated at least minimal competency in history taking
      and communication skills, but not in performing the expected focused physical
      exam. Their written reports showed adequate documentation of historical items but
      not of pertinent physical findings. The interns did not consistently make a
      problem list, provide a differential diagnosis, or show clinical reasoning
      despite being instructed to do so. There was great variation in performances
      between interns. Analysis of the interns' evaluations of this exercise showed
      that they felt it covered appropriate material, and they felt sufficiently
      prepared. Several interns had never done an OSCE prior to this exam. Written
      comments were positive about getting structured feedback early in their training.
      This format has allowed the identification of specific deficiencies in clinical
      skills for each of our interns, and this information will be used to guide our
      clinic preceptors in their teaching and in future evaluations. It would be ideal
      to design a second OSCE based on cases specific to internal medicine for the
      third-year residents, and compare skills developed over time.

PMID- 12431936
TI  - Intersessions: covering the bases in the clinical year.
AB  - OBJECTIVE: At most medical schools students spend the core clerkship year
      entirely in clinical settings, geographically dispersed, and assigned to separate
      teams. Because of the immediacy of experiential learning in the clinical
      environment, this year is often the highlight of medical school. However, the
      intensity of the experience and the dispersion of students poses serious
      challenges to student well being and professional development, and to meeting
      important educational objectives best taught in the clinical year but difficult
      to implement in competition with direct patient care. To address these challenges
      in a way that does not interfere with the clinical experiences, we developed and
      are implementing three one-week intersessions. These are designated weeks between
      clerkship rotations when all third-year students are "off rotations" and studying
      together in an integrative, collaborative and reflective manner. DESCRIPTION: We
      identified themes for the intersession course from several sources. In response
      to strong documentation by past students of isolation and insufficient
      opportunity to reflect on their experiences during the core clerkships we placed
      a high priority on students gathering together as a class and on professional
      development. Additionally, based on knowledge gaps identified in the AAMC
      Graduation Questionnaire and our commitment to integrating basic science teaching
      into the clinical year, we developed the following five themes: evidence-based
      medicine, ethics, health systems (quality; resource allocation), advances in
      science (recent advances that fundamentally shift clinical practice), and
      professional development. Each intersession week consists of 20 hours of
      structured contact time; 75% is devoted to small-group learning. The weeks rely
      heavily on student directed and collaborative learning to complete required
      readings and assignments. All sessions build on the clinical experiences students
      have had during clerkships and enhance the students' skills for upcoming
      rotations. DISCUSSION: In 1999-2000, we restructured the clinical core year into
      eight-week modules allowing us to gather the entire class, in between clerkships,
      for intersessions. We phased in two intersession weeks in 2000-2001 and are
      implementing three intersession weeks in 2001-2002 (October, February, and June).
      In the evaluations of the first year's intersessions students valued the
      opportunity to gather together, to process their clinical experience, and to
      utilize their clinical experience to drive learning in important, clinically
      relevant areas that are not consistently taught in the clerkships. Evaluations
      from the first intersession of the second cycle further underscore the preference
      for learning experiences that are highly relevant to the clinical year (e.g.,
      practicing efficient search strategies to quickly answer clinical questions,
      utilizing systematic reviews, discussing ethics cases from the students'
      experiences) and the benefits of faculty facilitated small-group discussions over
      lecture time. The advances in science sessions are most effective when they focus
      on advances in diseases that students are likely to have encountered. In our next
      phase, we will use Web-based interfaces to collect cases from students on
      clerkships and to promote discussion of topics in anticipation of the next
      intersession. As we continue to refine intersessions, our experience so far
      provides good evidence to support intersessions as a successful curricular
      innovation.

PMID- 12431937
TI  - Communicating about sexuality: an initiative across the core clerkships.
AB  - OBJECTIVES: Recently there has been a renewed interest in teaching communication
      skills in U.S. medical schools. Yet a large number of physicians and medical
      students may be uncomfortable discussing matters of sexuality with their
      patients. We have developed a comprehensive, cross-clerkship curriculum for third
      year medical students that strives to fill the educational gap concerning a
      variety of topics in sexuality. The objectives of this project are (1) to
      increase awareness among medical students that communication about sexuality is
      central to comprehensive health care; (2) to train faculty to teach students the
      knowledge, skills and attitudes necessary for communicating effectively with
      patients about issues of sexuality; and (3) to improve the level of student
      comfort in discussing sexual issues. DESCRIPTION: With support from the Josiah
      Macy, Jr. Foundation (part of the UMass Macy Initiative in Health Communication),
      and in consultation with clerkship directors, specific topics in sexuality were
      chosen for inclusion in four clerkships: internal medicine, family medicine,
      pediatrics, and psychiatry. The family medicine clerkship incorporated a
      fictional female adolescent into their case-based "standardized family." Faculty
      were trained to lead their small groups in a discussion of the potentially wide
      range of sexual behavior in this case study. Supplemental readings were provided
      and a PDA application is being developed. During the internal medicine clerkship
      a "difficult interview" session was held. Student volunteers interviewed three
      standardized patients with sexual issues: a sexually active young woman desiring
      contraception, a homosexual young man at risk for HIV, and a heterosexual male
      noncompliant with blood pressure medication due to sexual dysfunction. An HIV
      counselor was brought in as a discussant. The pediatric clerkship utilized a
      multimodal format to cover topics pertaining to gay and lesbian youth. Included
      were a didactic presentation, a videotaped panel discussion featuring two youths
      and a parent, and a modeled patient interview. The psychiatry clerkship included
      three relevant interventions: a didactic session around the topic of medication
      related sexual dysfunction; a videotaped modeled interview of a sexually
      traumatized woman; and a session involving a standardized patient-a lesbian whose
      sexual orientation was not part of her psychopathology. Adjunct activities
      included a cross-clerkship faculty development session, evaluation components,
      and a module designed for the staff of a private office. The latter was piloted
      in the office of a community pediatrician. DISCUSSION: Medical students who
      experienced the curriculum found it valuable. Student self-evaluations, done at
      the end of each clerkship, indicate increased comfort in dealing with issues of
      sexuality. During the pediatric clerkships only, half the students received the
      curriculum while the other half served as a comparison group. The intervention
      group showed a slight decrease in homophobic attitudes; the lack of a larger
      effect is likely due to a high level of baseline acceptance and comfort around
      issues of sexual orientation in this particular medical school class. The
      pediatric segment will be modified to take this into account and present more
      advanced topics around sexual orientation and interviewing. The entire curriculum
      is being incorporated into ongoing clerkships using existing resources at the
      medical school.

PMID- 12431938
TI  - Medical students, clinical preventive services, and shared decision-making.
AB  - OBJECTIVE: Improving access to preventive care requires addressing patient,
      provider, and systems barriers. Patients often lack knowledge or are skeptical
      about the importance of prevention. Physicians feel that they have too little
      time, are not trained to deliver preventive services, and are concerned about the
      effectiveness of prevention. We have implemented an educational module in the
      required family practice clerkship (1) to enhance medical student learning about
      common clinical preventive services and (2) to teach students how to inform and
      involve patients in shared decision making about those services. DESCRIPTION:
      Students are asked to examine available evidence-based information for preventive
      screening services. They are encouraged to look at the recommendations of various
      organizations and use such resources as reports from the U.S. Preventive Services
      Task Force to determine recommendations they want to be knowledgeable about in
      talking with their patients. For learning shared decision making, students are
      trained to use a model adapted from Braddock and colleagues(1) to discuss
      specific screening services and to engage patients in the process of making
      informed decisions about what is best for their own health. The shared decision
      making is presented and modeled by faculty, discussed in small groups, and
      students practice using Web-based cases and simulations. The students are
      evaluated using formative and summative performance-based assessments as they
      interact with simulated patients about (1) screening for high blood cholesterol
      and other lipid abnormalities, (2) screening for colorectal cancer, (3) screening
      for prostate cancer, and (4) screening for breast cancer. The final student
      evaluation is a ten-minute, videotaped discussion with a simulated patient about
      screening for colorectal cancer that is graded against a checklist that focuses
      primarily on the elements of shared decision making. DISCUSSION: Our medical
      students appear quite willing to accept shared decision making as a skill that
      they should have in working with patients, and this was the primary focus of the
      newly implemented module. However, we have learned that students need to deepen
      their understanding of screening services in order to help patients understand
      the associated benefits and risks. The final videotaped interaction with a
      simulated patient about colorectal cancer screening has been very helpful in
      making it more obvious to faculty what students believe and know about screening
      for colorectal cancer. As the students are asked to discuss clinical issues with
      patients and discuss the pros and cons of screening tests as part of the shared
      decision-making process, their thinking becomes transparent and it is evident
      where curricular changes and enhancements are required. We have found that an
      explicit model that allows students to demonstrate a process for shared decision
      making is a good introductory tool. We think it would be helpful to provide
      students with more formative feedback. We would like to develop faculty
      development programs around shared decision making so that more of our clinical
      faculty would model such a process with patients. Performance-based assessments
      are resource-intensive, but they appear to be worth the added effort in terms of
      enhanced skills development and a more comprehensive appraisal of student
      learning.

PMID- 12431939
TI  - Student's perceptions of a virtual PBL experience.
AB  - OBJECTIVE: Our purpose is to present findings regarding student attitudes towards
      a virtual PBL program used to standardize their pediatric clinical experience.
      DESCRIPTION: With funding provided by the Fund for the Improvement of Post
      Secondary Education, we developed Project LIVE (Learning through Interactive
      Video Education), a CD-ROM/Web hybrid program that uses digital video cases to
      conduct "virtual" problem-based learning groups with students doing a clinical
      rotation in a remote setting. Cases were progressively disclosed by videos of
      patient/physician encounters on a CD-ROM. Groups of five students and a faculty
      facilitator collaborated, teaching each other within the discussion section of
      the program. We conducted a multifaceted evaluation of Project LIVE to study the
      impact of case modality or distance on student learning and attitudes. We placed
      students in one of three groups (1) a face-to-face group with a paper case (FFT),
      (2) a face-to-face group with a video case (FFV), and (3) a virtual group (VG)
      with the digital video case. We then studied student attitudes about the three
      teaching formats. Over a six-month period three education specialists, who were
      not a part of the development team, conducted eight focus groups lasting one hour
      to assess student attitudes about Project LIVE. No one from the project team was
      present during these groups, and an independent evaluator analyzed the notes
      taken by each focus group leader. DISCUSSION: Trends across the groups included
      the following: (1) Authenticity (video)-Students reported that the authenticity
      of the case was a critical feature and that, "seeing (videos) made learning more
      memorable." Virtual and FFV groups reported more confidence in their ability to
      recognize abnormal findings in their patients. "You can't expect to teach
      clinical exam skills with a piece of paper." (2) Use of time-Students from all
      groups believed the cases were a good use of their time and improved their
      ability to solve clinical problems. They said it gave them an opportunity to "get
      away from just doing and focus on learning." However, the virtual groups
      complained of the lack of "a barometer for how much is too much" time. Some
      students reported spending an average of eight to ten hours per case over the
      period of a week. (In contrast, face-to-face groups met for three hours.) (3)
      Modeling clinical reasoning-Students believed the cases were valuable in
      structuring their knowledge, conceptualizing how to handle difficult situations,
      distinguishing abnormal from normal physical examination findings, and
      collaborating with their peers and their mentor to develop critical thinking. "It
      forced us to be logical" and ". how to think through the process-it mimics the
      real setting." (4) Technical support-The responsiveness of the Project LIVE staff
      was essential in assisting students in troubleshooting problems. (5) Distance
      component-Students preferred to work through the cases in face-to-face groups but
      agreed that the virtual experience is "good if you are in the middle of nowhere."
      This program was enjoyed by students and gave us an approach to standardizing
      experiences across multiple clinical sites.

PMID- 12431940
TI  - Learning by doing: teaching critical appraisal of randomized trials by performing
      an in-class randomized trial.
AB  - OBJECTIVE: Our medical students often encounter difficulty because many have
      trouble appreciating the relative merits and limitations of clinical research
      design. In order to remedy these deficits, we developed a novel in-class
      simulated randomized trial in which students were blinded to their treatment
      assignment. Specifically, our goals for the session were to demonstrate the
      importance of randomization of subject populations, to define and use basic
      terminology such as relative risk reduction along with absolute risk reduction,
      and to demonstrate the strengths and pitfalls of analysis of subsets of subjects.
      DESCRIPTION: We proposed the study of a hypothetical new drug, "Flunkimmune,"
      which was claimed to prevent students from failing tests. Students received a
      random assignment to either the "Flunkimmune" or the placebo group. Students then
      received an opaque plastic egg appropriate for their randomization. We had
      prepared the eggs a-priori to each contain a piece of candy, and some to contain
      a blue dot. The flavor of the candy signified whether a particular student was in
      the treatment or control group. After all students had received their eggs, we
      "unblinded" the study by having the students open their eggs and learn to which
      treatment they had received. We then used an audience response system to
      construct a demographics table commonly known as Table 1 for the randomized trial
      based characteristics of the students' choosing (e.g., "drinks Diet cola," "over
      six feet tall," "birth weight under seven pounds"). We asked the class to
      critique their own Table 1 and to comment on the adequacy of the randomization.
      Students were then informed that the presence of the blue dot signified a
      "failing" grade on a hypothetical exam to test the efficacy of "Flunkimmune." The
      eggs had been loaded so that the treatment group had a relative risk reduction of
      failure rates of 50% compared with the control group and an absolute risk
      reduction of 20%. This result prompted a debate among students about the relative
      merits of absolute or relative risk reduction in reporting the results of the
      study. Students also performed subgroup analyses by determining the failure rates
      for treatment and control students seated in particular aisles of the lecture
      hall. This enhanced discussion about the processes of bias and confounding
      inherent in subgroup analyses. DISCUSSION: This experiential teaching method
      allowed students to participate directly in a simulated randomized controlled
      trial, thereby facilitating understanding of this type of study. Students
      reported that the experience was enjoyable and stimulated active engagement with
      critical appraisal of randomized trials. Students' subsequent homework
      assignments, in which they were asked to critically appraise a randomized trial,
      demonstrated a depth of understanding not previously encountered at this level.
      We plan to develop and rigorously evaluate additional experiential activities
      that expose students to the role of the research investigator.

PMID- 12431941
TI  - Distributed radiology clerkship for the core clinical year of medical school.
AB  - OBJECTIVE: The central role that diagnostic radiology has in the modern practice
      of medicine has not always been reflected in radiology's place in the curriculum.
      We developed a new radiology clerkship for undergraduate medical students during
      their core clinical year that was supported by Web technology. The assumptions
      underlying the design of the clerkship were that radiology is best learned from
      radiologists and that students are most receptive to learning radiology when it
      is related to concurrent patient care experiences. DESCRIPTION: Beginning in May
      2000, a required radiology clerkship experience was incorporated into the core
      clinical year at Wake Forest University School of Medicine. The core clinical
      year was organized into three 16-week blocks of clerkships. Two or four
      independent half-day radiology tutorial sessions were included with each
      clerkship block, and attended by all students in the block (approximately 35
      students), regardless of their specific clerkship assignments. There were ten
      different radiology tutorials, each given three times during the year as students
      rotated through the clerkship blocks. Thus, each student attended a radiology
      tutorial session every four to eight weeks during the year. The topics covered
      during the tutorials were correlated with the content of the clerkship blocks and
      included adult and pediatric chest radiology, adult and pediatric abdominal
      radiology, body CT, neuroradiology, obstetric ultrasound, gynecologic ultrasound,
      osteoporosis, adult and pediatric fractures, mammography, and cervical spine
      trauma. The tutorials included pre- and post-test, lectures, case presentations,
      and sometimes tours of the radiology department. The educational emphasis was on
      pragmatic case-based learning exercises, development of verbal and visual
      vocabulary, and learning when and where to seek more information. To provide
      continuity and organization, Web-based curriculum materials were designed and
      implemented as a component of the clerkship. The home page of the Web site
      provided the schedule, faculty names, attendance and grading policies, course
      overview, and links to individual tutorials. The pages for individual tutorials
      included educational objectives, glossary of radiology terminology relevant to
      the subject, lecture slides and handouts, and teaching cases. All students had
      laptop computers and access to the academic network, but did not use them during
      the actual tutorial sessions. DISCUSSION: Implementation of the radiology
      clerkship required extensive negotiation with directors of other clerkships so
      that students could be released from their other responsibilities in order to
      attend the radiology tutorials. The radiology clerkship format has proven to be
      complex in its administration, with faculty and students on different schedules
      commuting to the radiology lecture hall from various locations. Extensive use of
      e-mail and communication via the Web site have been instrumental in reminding
      faculty and students of upcoming sessions. Preliminary evaluations have indicated
      that students liked the radiology sessions and learned a great deal, but disliked
      the scheduling and the lack of continuity. An evaluation of the curriculum and
      its components is ongoing.

PMID- 12431942
TI  - 360 degrees: planning a new pediatric clerkship.
AB  - OBJECTIVE: Mount Sinai School of Medicine is midway through a major curriculum
      revision. The immediate goal for the core third-year clerkships was to create a
      modular schedule with varied and integrated clinical experiences. Some clerkships
      were lengthened; others, blended. Clerkship directors were asked to find ways to
      ally with those also in their 12-week module. Content material, only presented at
      Mount Sinai, was to be delivered at all affiliate sites. Each clerkship had one
      year to prepare. DESCRIPTION: Core pediatrics faced multiple challenges. Once an
      eight-week clerkship, pediatrics was condensed into a six-week block and paired
      with ob-gyn at the same affiliate sites. Material presented during weekly,
      lecture-based didactic sessions at Mount Sinai was to be delivered at all sites,
      some of which were considerable distances away. To enable students to have both
      content and clinical experiences at the same site, new teaching formats and
      techniques had to be utilized and faculty retrained to implement their new roles.
      Three approaches met both conditions: (1) interactive case-based learning of
      clerkship content objectives, (2) use of Web-based instruction to provide
      resources to all sites, and (3) the identification and training core educators to
      deliver this new content material. Generalist and specialist pediatricians
      prepared clinical cases. Each author was given a case-writing template, so that
      all cases included objectives, references, a case presentation, and guiding
      questions. Cases were written with extended answers to each of eight standard
      questions, including key teaching points, to create a teacher's manual. Three
      faculty members reviewed each case to assure that the content matched the
      objectives for the module and that cases were written at an appropriate level for
      third-year medical students. Weekly seminars are now interactive, small-group,
      and Web-based. Cases use multimedia resources and integrate multiple clinical
      disciplines. The structure of the seminars, modeled on adult learning theory,
      include review of the basic approach to patients, organization of data, and
      generation of a prioritized differential diagnosis. The seminars also review
      basic management principles for a variety of common pediatric conditions. Core
      educators were designated to facilitate the cases at each clinical site. They
      were given instructions for case facilitation, a detailed teacher's manual, and a
      multimedia CD-ROM. The teacher's manual contains the course syllabus as well as
      extended case discussions. The accompanying CD-ROM contains photographic images,
      growth charts, x-rays, microscopy, and sound files. Computers are available at
      each site and are linked to WEB-CT, the program supporting the Mount Sinai
      undergraduate online curriculum. DISCUSSION: We have not yet reached 360 degrees
      in revising our clerkship. Feedback from both students and clinician educators
      has been extremely positive. Future plans include further enhancement of the
      cases to incorporate clinical pathology, genetics, laboratory medicine,
      radiology, and evidence-based medicine. We will also develop and implement a
      faculty development program to equip our faculty with tools for effective, time
      efficient, case facilitation. Starting anew with a few core organizing principles
      and a multidisciplinary approach has enhanced the learning for both faculty and
      students.

PMID- 12431943
TI  - Medical students as health coaches.
AB  - OBJECTIVES: The purpose of this project was to teach students how to work
      effectively with patients in the area of health-behavior change. As part of the
      patient-doctor course, first-year medical students worked with diabetic patients
      who were selected by their primary physicians. In preparation for their patient
      interactions, students were taught basic communication concepts and the role of
      the relationship in improving patient outcomes, and continuity issues were
      addressed as students learned to collaboratively develop behavioral-change plans
      with their patients and then followed their patients' progress over the course of
      the year. DESCRIPTION: An educational research trial was conducted to compare the
      traditional community placement track (shadowing) with the health-coaches track.
      Students were randomly assigned to the two educational tracks. Health coaches
      were assigned in pairs to a family medicine patient with diabetes. Under
      supervision by the patient's medical provider, student pairs worked with the
      patient in an area of health-behavior change (i.e., weight loss, smoking
      cessation, exercise, or adherence to medication regimen). Students were required
      to have at least six patient contacts over the course of a year, consisting of at
      least three face-to-face visits and including one home visit. Didactic sessions
      with health coaches taught by either a behavioral consultant or health educator
      covered the basics of diabetes and behavior-change areas appropriate to
      respective patients. Students were also given reading assignments from
      communication and health-behavior change literature and handouts for patients.
      Behavior-change specialists were available as needed for consultation. In support
      of the health coaching process, students participated in eight small-group
      discussion sessions (eight students each) led by a behavioral change specialist.
      Small-group sessions lasted approximately 90 minutes each and contained didactic
      and experiential elements. Topics were: "Getting Started" (interviewing, the
      patient's story), "Fundamentals of a Home Visit," "Changing Behaviors" (stages of
      change, relapse prevention), "Home Visit Feedback" (report and reflections),
      "Challenging Patients to Change" (difficulties, challenging irrational ideas),
      "Giving Direct Guidance," "Non-verbal Skills," "Ending and Celebrating"
      (terminating the helping relationship). Evaluation methods included a pre- and
      post-physician belief scale completed by students, pre- and post-provider's
      evaluation of patient, and a patient-completed health behavior questionnaire. As
      available, patients' HbA1C levels were compared pre- and post-intervention.
      DISCUSSION: As expected, initially some health coach students complained about
      their perceived increased workloads compared with the workloads of students in
      the shadowing track. Some students also expressed reservations about their
      abilities to be effective with their patients, but these complaints diminished as
      students made contact with patients. For many, this opportunity to establish
      continuity relationships with patients helped students begin to understand
      difficulties inherent in effecting health-behavior change. Some students
      expressed appreciation for the opportunity to discuss their increased self
      awareness about communication as well as relationship difficulties and strengths
      during the small-group sessions. Data analysis is under way. Lessons learned from
      this project influenced a major first-year curriculum revision the following
      year, resulting in increased emphasis on basic communication skills and the use
      of small groups to reach a variety of curricular objectives.

PMID- 12431944
TI  - Teaching communication skills: a skills-based approach.
AB  - OBJECTIVES: The purpose of this project was to design structured training
      activities to emphasize key points about patient-physician communication.
      Effective communication has been shown to enhance patient satisfaction,
      compliance with treatment, and medical decisions and outcomes. Basic
      communication skills and behavioral-change interview skills are taught.
      DESCRIPTION: Communication is a core "building block" of a four-semester, two
      year Essentials of Clinical Medicine Course (ECM), which is in its second year of
      existence. Four interactive lab sessions have been designed, each with structured
      learning exercises. At the beginning of each session, students work in groups of
      30 completing activities based on videos developed by the Bayer Institute for
      HealthCare Communication.(1) Subsequently, two groups of three students each work
      with a behavioral or physician facilitator. A formal training and administration
      manual for all activities has been developed and an evaluation system developed
      and implemented. Session 1, "Initial Interview Skills," teaches opening,
      mirroring, and encouraging non-interrogation activities. Session 2, "Empathic
      Responses," includes activities entitled "Cue Detection," "Accurate Empathy," and
      "Getting the Story Straight." In Session 3, "Obtaining an HPI," students view an
      exemplary medical interview, then role-play computerized cases(2) and practice
      the HPI data collection based on clinical facts taken from the computerized
      cases. During the Session 4, "Putting It All Together," students interview a
      standardized patient (SP) for five to seven minutes and receive and give feedback
      from peers, SPs, and facilitators. Subsequent to the communication lab, students
      conduct six physician-supervised patient interviews practicing their medical
      interviewing skills and write-ups. Two subsequent small-group sessions include
      "group" interviews of SPs in which students assess readiness for behavioral
      change (e.g., quitting smoking, losing weight) and also learn to conduct more
      "difficult' health-promotion conversations (e.g., sexual behavior, alcohol use).
      Evaluation methods include the use of a professional behavior evaluation form
      completed by communication facilitators and small-group leaders. This assessment
      form consists of ratings on: reliability and responsibility, relationships with
      others, self-improvement and adaptability, upholding professional standards, and
      communication skills dimensions. A formal interview-behavior checklist is used
      during the training and in the feedback sessions. Finally, SP OSCEs of
      communication and behavioral-change interviewing occur at the end of the first
      year of training. DISCUSSION: The communication labs have been well received by
      students. Students have reported increased understanding of their upcoming roles
      as physicians, have stated they have gained insights about the importance of
      connecting with patients in order to give them proper medical treatment, and have
      requested additional training in communication. Students have reported increased
      confidence in their interviewing skills prior to interactions with "actual"
      patients, and clinical preceptors have reported increased levels of preparedness
      among students who have participated in the structured learning experience.
      Future plans include adding communication training with problem patients, and
      about end-of-life and other challenging issues.

PMID- 12431945
TI  - An advanced communication skills course for fourth-year, post-clerkship students.
AB  - OBJECTIVE: A novel five-module advanced communication skills course entitled
      "Doctor-Patient Relationships" was planned and implemented in 2000-01 at the
      University of British Columbia (UBC). The course was part of the final four-month
      component of the new MD undergraduate program: Effective Skills for Medical
      Practice. The goals of the communication skills course were to (1) address
      problems experienced by the students so far; (2) address deficiencies in
      achieving the UBC exit competencies; (3) help the students pass the Medical
      Council of Canada examinations, in particular objectives related to the
      Considerations of the Legal, Ethical, and Organizational aspects of the practice
      of medicine (CLEO); and (4) help students prepare for their roles beyond
      undergraduate medicine (residency, independent practice). DESCRIPTION: The course
      was developed by an interdisciplinary team (family practice, pathology,
      pediatrics, psychiatry, surgery) with input from students. The broad strengths
      and weaknesses of their communication skills training were identified by seven
      third-year medical students who kept logs over the course of their clinical
      clerkships to document their learning of communication skills. Analysis of these
      logs plus feedback meetings with the students revealed attitudinal and skills
      issues that needed to be addressed in the new course. The goals and principles of
      the course were in part agreed upon by focus groups with students, attended by
      faculty observers, to ensure their relevance to students. The first module
      "Beyond the Mask: Surviving and Thriving in Residency Training" is designed to
      focus students' attention on the personal relevance of developing excellence in
      communication skills in preparation for residency training. It includes a video
      of residents talking about their experiences of communication problems to trigger
      reflection and discussion. In the remaining four modules the students are
      required to put communication skills together with their medical knowledge. Each
      module includes pre-readings, video demonstrations (in sessions 4 and 5),
      practice with standardized patients (total of 14 scenarios) and structured
      feedback from SPs, students, and tutor. The themes of the sessions are "Dealing
      with Emotionally Challenging Patient Situations (informing about bad news),
      "Compliance and Patient Information," "Informed Consent and Shared Decision
      Making," and "Difficult Physician-Patient Encounters." Each module lasts two
      hours. The course was implemented for 120 students, facilitated by 14 tutors
      (seven to eight students per group). DISCUSSION: Student involvement in many
      different ways provided an important reality check and made us think about how to
      present the new course so that it was relevant and interesting to students.
      Attention to student input was a major contributor to the good evaluations given
      the course. Students rated the course highly: the relevance of the weekly themes
      was rated 4.21 on a five-point scale; the effectiveness of the SP interviews,
      4.10; the effectiveness of the group discussion and feedback, 4.18; and overall
      course effectiveness in enhancing communication skills, 3.91. The tutors also
      rated the course highly, and the students rated the tutors highly. Minor changes
      will be made to the course next year based on the specific suggestions for
      improvement, which were identified.

PMID- 12431946
TI  - Advanced communication skills: conflict management and persuasion.
AB  - OBJECTIVE: There is an increasing need in the medical school curriculum to
      adequately prepare students for professionalism in the workplace. This senior
      seminar is a four-week course designed to develop fluency in handling conflict
      and negotiation as well as understanding the elements of persuasive
      communication. Students used the Meyers-Brigg Personality Inventory as a paradigm
      for understanding different communication styles. DESCRIPTION: The class was
      piloted in October and November 2001 and consisted of four modules. In module
      one, each student was given the Meyers-Brigg Personality Inventory to take.
      Discussions and exercises provided insight into the student's own communication
      style as well as styles the individual student might find more problematic. The
      second module consisted of four sessions focusing on conflict management and
      negotiating skills. Students were given strategies for dealing with conflict as
      well as specific approaches for communicating with "difficult" patients. In the
      subsequent sessions, students had a chance to further incorporate these
      strategies by (1) discussing in a small-group setting a conflict situation that
      they had either witnessed or experienced in order to systematically evaluate how
      to incorporate conflict-management approaches into their particular communication
      style. (2) Role-playing four conflict situations students' were likely to
      encounter in their professional lives. Role-plays were videotaped and individual
      feedback was given immediately after the role-play by the observing students, the
      patient-actor, and the evaluator, who had been trained to give specific feedback
      on the conflict strategies. (3) Watching specific videotaped role-plays as a
      class allowed students to see and give feedback on particularly effective
      strategies that their colleagues used. The third module was devoted to giving bad
      news and ways that different people prefer to receive bad news, using the MBTI
      personality types as examples. The final module outlined the principles used in
      persuasion. Each student had the opportunity to make a five-to-ten-minute
      persuasive speech, the topic to be applicable to the student's specialty, which
      was reviewed by his peers. Feedback was tailored specifically to the different
      principles of persuasion. DISCUSSION: The curriculum was judged to be effective
      in changing confidence and attitudes as evidenced by pre- and post-course
      evaluations that students filled out during the last session of the class. Six
      things contributed to its success: (1) the class was offered as a fourth-year
      seminar; students could see its relevance and therefore were motivated to learn.
      (2) Activities were designed to build on learning in ways that graduated from
      passive to active. In such a way the theoretical was made practical. (3) Feedback
      was immediate and congruent. For example, the evaluators and patient-actors were
      all trained in the conflict management principles taught. (4) Feedback done by
      peer review allowed students to internalize strategies. (5) Concrete steps were
      given for behavioral change. (6) Small-group sessions invited camaraderie and
      allowed for individualized attention. Future activities include integrating this
      curriculum into residency teaching; the course is a continuation of a first-year
      course on interviewing skills taken by every student.

PMID- 12431947
TI  - The role of spirituality in patient care: incorporating spirituality training
      into medical school curriculum.
AB  - OBJECTIVE: To answer the call for the implementation of spirituality into medical
      school curriculum,(1) UMKC-School of Medicine has incorporated experiential
      spirituality instruction into the third year of a six-year combined BA-MD degree
      program. The multifaceted objective of the program is to (1) expand students'
      conceptualization of the patient as person to include dimensions of spiritual
      beliefs and needs, (2) develop an understanding of how patients' spiritual belief
      systems impact their health, (3) recognize how the student's spiritual beliefs
      impact his or her practice of medicine, and (4) highlight the value of the
      chaplain as a member of the health care team. With increased understanding of the
      role spirituality plays in healing as well as the spiritual services available to
      patients, students will be able to serve the needs of their patients.
      DESCRIPTION: To accomplish this objective, students participate in lectures on
      spirituality, small-group activities focusing on skills such as taking/crafting
      spiritual histories, and an on-call experience with a hospital chaplain. During
      the oncall experience, students shadow a chaplain for approximately six hours.
      The experience includes discussing philosophies of spirituality and medicine with
      the chaplain, rounding with the chaplain, visiting and praying with patients when
      requested, comforting family members, and assisting with advance directive
      discussions and paperwork. After completing the experience, the students are
      required to write a reflective essay examining the following components: (1) the
      interaction between the chaplain and other members of the health care team, (2)
      the utilization of alternative interview and history taking methods, (3) the
      connection between spirituality and illness as illustrated through patient
      encounters, and (4) the insights gained from the experience that can be applied
      to the practice of medicine. DISCUSSION: The writing of one's spiritual history
      and the on-call experience were integrated into a new portion of the curriculum.
      The components were initially met with some reticence. In the beginning, students
      had difficulty distinguishing spirituality from religion and were concerned that
      the curriculum would take away from their study of "real medicine." To ease
      concerns regarding the spiritual history, the course director modeled the
      objectives by sharing her own spiritual journey. Participation in the on-call
      experience substantially changed students' negative attitudes toward the
      curriculum. Essays revealed that the on-call experience had greatly impacted
      their view of the chaplain as well as their practice of medicine. Specifically,
      students demonstrated an understanding of the role of spirituality in healing,
      identified key components of the chaplain role in the hospital setting, shared
      ways in which they would utilize chaplains in the future, and discovered personal
      struggles. Crafting one's spiritual history, the on-call experience, and essays
      will continue to be a required part of the third-year curriculum. Modifications
      include adding the option of constructing one's own advance directive and
      striving for increased diversity of spiritual perspectives. The data provided in
      the essays and course evaluations will be utilized in several ways to determine
      the success of the curriculum and to answer critical research questions in the
      areas of spirituality and medical education.

PMID- 12431948
TI  - Mediating the gap between the white coat ceremony and the ethics and
      professionalism curriculum.
AB  - OBJECTIVE: Like many other medical schools, the University of California, Irvine
      annually conducts a White Coat ceremony in which incoming students take a
      professional oath of ethical conduct.(1) We report a new educational activity to
      connect the values expressed in the oath taken to the Ethics and Professionalism
      (EP) curriculum for first-year medical students(2) and its potential impact on
      physician training. DESCRIPTION: Following the White Coat ceremony, students
      participated in the Patient Doctor Society course that integrates diverse
      curricular topics centered on physician-patient communication. During this
      course, the students were introduced to EP content through a collaborative peer
      exercise. With the assistance of background readings on professional values and
      ethics concepts, small groups of students were asked to construct their own codes
      of ethics. The process of working in a group became part of the learning. After
      developing a code of ethics, each group was asked to identify primary values
      embodied in its code; primary obligations to patients and their families, other
      members of the health care team, and the community; key factors influencing code
      development; and likely effects of the code on the conduct of medical students
      and physicians. The goals of the session were to recognize formally both
      individual values and the values to which students commit themselves during the
      White Coat ceremony, to facilitate understanding of those values, and to begin to
      reconcile differences between personal and professional values. The small groups
      convened to report their findings in a three-hour session. Common values
      expressed by the students included patient autonomy, respect, beneficence, and
      professionalism. The delivery of quality health care, communication, education,
      and the equitable distribution of health care were among the most often listed
      obligations. The students reported that culture, societal values, family,
      experience, religion, education, and assigned readings were the key sources of
      the values in their codes. Most of the students enjoyed and learned from the
      exercise, believing that a code of ethics will serve as a helpful educational
      guide while they are students and as an action guide in their future practices.
      Student evaluations, narrative feedback, and faculty observation indicated that
      the students appreciated the opportunity to work in teams and to explore
      professional values. The students' most common suggestion for improvement
      involved incorporating analysis of clinical cases in which questions about
      professional values arise. DISCUSSION: Medical educators suggest that students'
      values and professional behaviors change throughout medical school, but such
      change is difficult to assess. The code-development exercise established a
      baseline of values at entry to medical school. We plan to track this cohort of
      students by reintroducing this exercise in their fourth year and will compare the
      codes developed in their first and fourth years to identify changes in values and
      to suggest what the students have learned about values during medical school. The
      comparison will be used to inform further development of the EP curriculum toward
      the goal of shaping and supporting the positive professional growth of our
      student-physicians.

PMID- 12431949
TI  - The profession of medicine: an integrated approach to basic principles.
AB  - OBJECTIVE: The University of South Florida College of Medicine developed and
      implemented an innovative three-week course entitled, "The Profession of
      Medicine: An Integrated Approach to Basic Principles" to introduce new medical
      students to topics and skills that are important to their successful study of
      medicine. Demonstrating the clinical relevance of the basic sciences, the
      importance of lifelong learning, and ethics and professionalism in medicine were
      emphasized. Basic physical examination techniques, searching the medical
      literature and evidence-based medicine, and study and computer skills were
      introduced in addition to traditional orientation topics. DESCRIPTION: Four
      interdisciplinary "state of the art" presentations demonstrated the importance of
      lifelong learning and the clinical relevance of basic science concepts. Lectures
      on acute myocardial infarction, breast cancer, duodenal ulcer, and pulmonary
      prematurity were presented as if the lectures were being given in 1980. Students
      attended lectures on basic science principles relevant to these topics, and then
      met in small groups with librarians, content experts, and small-group
      facilitators to begin investigating an assigned topic. For example, student
      groups researched the development of EMS and chest pain centers, thrombolysis and
      percutaneous coronary intervention, and the psychological implications of acute
      myocardial infarction for patients and families. Students were introduced to
      effective literature-searching techniques, the tenets of evidence-based medicine,
      and effective computer skills in the context of studying their assigned topics.
      Each group then selected a student presenter to deliver an eight-minute
      PowerPoint presentation of its 2001 "state of the art" findings, making
      particular note of scientific advances and new therapeutic protocols developed
      since 1980, such as the use of artificial surfactant in premature babies, the
      role of H. pylori in duodenal ulcers, and the discovery of the genetics of breast
      cancer. These projects as well as a series of small-group educational programs
      enabled students and faculty to develop a strong sense of team-work and
      cohesiveness. Students had opportunities to practice components of the history
      and physical examination on standardized patients relevant to the four clinical
      topic areas, such as cardiac and abdominal examinations with emphasis on anatomic
      principles. Basic ethical principles and their application to cases that
      pertained to the four clinical topics were introduced, and students participated
      in a small-group ethics case conference. Throughout the course, students and
      faculty were required to wear specially designed nametags. By the time the course
      concluded with the White Coat ceremony, the 75 participating faculty and 104
      students knew one another, making the ceremony particularly meaningful.
      DISCUSSION: The pace at which scientific findings revolutionize the practice of
      medicine continues to accelerate. While it is important for undergraduate medical
      students to master the basic and clinical science foundations of medical
      practice, it may be even more important to teach students how to find and
      interpret medical information, form professional relationships with mentors and
      peers, and make a commitment to lifelong learning and professionalism. It is
      critical that students understand that the curricular program at any college of
      medicine is only the beginning of a life of study.

PMID- 12431950
TI  - Talking medicine: a course in medical humanism--what do third-year medical
      students think?
AB  - OBJECTIVE: The early 1990s sparked an interest in organized medicine to reclaim
      and re-evaluate how it promotes professionalism among physicians. The American
      Board of Internal Medicine (ABIM) launched Project Professionalism as a means to
      define and evaluate professionalism as a component of clinical competence. The
      course "Talking Medicine" was developed to create a series of small-group
      discussions on humanism and professionalism where students can reflect on the
      process of becoming a physician and share personally or ethically difficult and
      rewarding cases with each other. We asked students to define these concepts and
      use these definitions to spark small-group discussion. DESCRIPTION: "Talking
      Medicine" is predicated on the belief that humanism and professionalism come to
      students and others through understanding a number of core concepts and
      relationships complemented by self-reflection. "Talking Medicine" offers a
      consistent (every other week for ten weeks) opportunity to share experiences in
      small groups (six to eight students), facilitated by two preceptors, in a format
      driven by students' experiences. Although the focus is on students' experiences,
      readings are provided on basic topics and contexts in humanism and
      professionalism (e.g., end-of-life care, mistakes, spirituality in medicine, and
      boundaries between patients and doctors). Also, at the beginning of each internal
      medicine clerkship we asked students to define humanism and professionalism
      anonymously on sheets of paper to be handed to the preceptors. DISCUSSION:
      "Talking Medicine" began in summer 2000. We hope to expand it to other
      institutions. We surveyed students and found 94% felt "very" or "somewhat"
      comfortable in the course. Seventy-three percent of students reported that the
      course increased their "connectedness" to classmates, and 61% favored its
      occurring during all rotations. Fifty-nine percent reported that their interest
      in caring for patients improved, and 53% reported their interest in internal
      medicine as a field improved. Answers to open-ended questions highlighted the
      importance of "Talking Medicine" as a forum to connect with others-both students
      and faculty. Despite this course's focus during an internal medicine clerkship,
      students see a broader definition of professionalism than the ABIM; the student's
      definitions were similar in many ways to the Group of Educational Affairs
      definition of professionalism. Third-year medical students focus more on
      tolerance of difference (e.g., race, socioeconomic status, and varying health
      beliefs), and the importance of collegiality and collaboration in the new
      environment of patient care. Their vantage point early in training allows them to
      look critically at the profession they are joining and view its shortcomings and
      strengths. Future work is needed that focuses on how these definitions change as
      students' progress through fourth year, into residency, and finally continuing
      medical education. Nevertheless, we suggest that "Talking Medicine" may be most
      effective in helping classmates connect to and learn from each other, thereby
      setting a foundation for changes in how they interact with patients.

PMID- 12431951
TI  - Using literature as the framework for a new course.
AB  - OBJECTIVE: The award-winning book The Spirit Catches You and You Fall Down,(1) a
      true story of the collision between two cultures (American and Hmong) with
      heartrending consequences for the patient, the patient's family, and the medical
      professionals who care for them, has been favorably reviewed(2) and used to
      stimulate teaching of cultural diversity, ethics, and professionalism to students
      and residents. We used it as a required text for a new Patient Doctor Society
      (PDS) course for 184 first- and second-year medical students. This report
      describes the scope and contexts in which the book was used to meet specific
      course goals. DESCRIPTION: PDS is a required 90-hour introduction to medical
      interviewing, which integrates ethics, communication, clinical reasoning,
      cultural diversity, humanities, spirituality, integrative medicine, nutrition,
      and behavioral science. To provide a common experience among these diverse
      topics, faculty members were asked to use examples from the book to achieve their
      learning objectives. A required faculty development session illustrated
      strategies for effectively using the text. Focusing on chapter 13 ("Code X"),
      dramatic portrayals of differences in beliefs about end-of-life care and
      clinician-family communication, facilitated the introduction of methods including
      point-of-view writing, role-plays, and faculty-facilitated discussions as
      techniques for meeting course objectives. At PDS orientation, we used the same
      chapter, and had faculty members lead small groups of students using the teaching
      techniques they acquired. About 90% of students read the book prior to
      orientation. Students favorably reviewed this three-hour session. For the ethics
      session, unfacilitated small groups of students were asked to identify and
      discuss the ethical issues in chapter 11 ("The Big One"), which describes a major
      turning point in the health care provided to the text's central character, Lia.
      Each group presented its "moral diagnosis" and ethical arguments for resolution.
      Class discussion then focused on the diverse views presented, to emphasize the
      importance of justifying decisions and to practice using tools of ethical
      analysis. In the communication skills workshop, we excerpted dramatic readings
      from the book. Faculty members played the roles of the author, the patient's
      mother, and one of Lia's physicians. The interaction became a dialogue to
      illustrate the points of view of the participants. The dialogue was used to
      stimulate discussion about potential pitfalls in physician-patient communication
      and understanding. In a medical humanities session, excerpts from the book were
      compared with poetry explicating themes of physician arrogance and humility.
      DISCUSSION: The Spirit Catches You and You Fall Down provides a context
      appropriate to teaching students how to listen to, and learn from patient
      stories. The story will be reintroduced in the pediatrics clerkship. Caution will
      be exercised to (1) avoid overexposure to the text, (2) counteract the potential
      to interpret the story too narrowly, and (3) assure that faculty become familiar
      with the text and its uses. We intend to track outcomes in knowledge, skills and
      attitudes for each content area, and observe the degree that the book facilitates
      achievement of objectives. We will follow several cohorts of students to verify
      longitudinally the learning effects observed.

PMID- 12431952
TI  - Mentoring for a new era.
AB  - OBJECTIVE: Over the course of their education, medical students must develop an
      identity that involves a deep understanding of professional principles and the
      skills to apply these ideals. This task is so important that it cannot be left to
      informal means and should be cultivated by a structured system that is focused on
      professionalism. The overall goal of our student-mentoring program is to advance
      the professional development of our students during the first two years of
      medical school through regular group meetings with skilled, trained faculty
      facilitators. DESCRIPTION: We shaped the program to foster meaningful mentoring
      relationships among students and faculty, facilitate personal reflection, and
      encourage exploration of larger questions related to professional development.
      This program has evolved from a model of individual student-faculty pairings that
      resulted in uneven experiences. It is organized through a new "Master Scholars
      Program" (MSP), inaugurated in 2001-2002. The MSP features five theme-based
      societies composed of students and faculty who share interests in the theme
      (e.g., bioethics/human rights, health policy/public health, arts/humanities in
      medicine, biomedical/health sciences, medical informatics/biotechnology).
      Approximately once per month, eight students and two faculty members from each
      society meet over lunch for student-led discussions on topics related to their
      own professional development. In the first session, structured exercises enable
      students to get to know one another and brainstorm a curriculum for the year. In
      subsequent sessions, student pairs lead discussions on topics of interest to the
      group ranging from "the role of medical professionals in the aftermath of the
      World Trade Center attacks" to "balancing careers in medicine with family." A
      list of each group's discussion topics is posted on an electronic bulletin board
      to inform others. Two faculty mentors lead each group to ensure continuity and
      diversity over the two-year course of their meetings. A total of 57 out of 78
      (73%) attended workshops to learn about the program and enhance their
      facilitation skills. Professional behaviors are explicitly emphasized in the
      materials outlining expectations of both students and faculty. Students are
      expected to attend, participate in and lead discussions, be constructive,
      respectful, and supportive, and accept/act on constructive feedback. Mentors are
      to facilitate the group's process, and provide feedback and guidance about the
      students' ideas and passions and the challenges they encounter. The faculty
      mentors will contribute descriptive material for the dean's letter on each
      student. We assessed student understanding of the definition of professionalism
      prior to the mentoring program and will follow up at regular intervals. Formative
      evaluation of the program includes surveys and focus groups with students and
      faculty to assess the effectiveness of the group process in accomplishing the
      stated goals of the program. DISCUSSION: Our medical school has committed
      resources, and our faculty and students have given thought, energy, and
      enthusiasm, to our mentoring program. This innovative new model has the potential
      to deepen and enrich the culture of medicine by providing a forum and skills for
      students to reflect on their own professional development and interact in a
      meaningful way with committed and skilled faculty who share similar interests.

PMID- 12431953
TI  - Translational medicine in the first year: integrative cores.
AB  - OBJECTIVE: The intensity of the first year leaves many students pondering the
      wisdom of their career choice. In creating its new curriculum, Mount Sinai School
      of Medicine faced this issue of burnout by devoting the last three weeks of the
      first year to a course that links basic science concepts introduced at the bench
      to the clinical care of patients. The goal of "Bench to Bedside Selectives" is to
      reenergize students' career choice by allowing them to experience a
      multidisciplinary approach to translational medicine. Students participate in an
      in-depth study of a selected disease entity under the direction of a faculty core
      leader. DESCRIPTION: In 2001, students selected either a research core (n = 57),
      which allowed them to expand their summer research time, or a disease-focused
      core (n = 48). Six diseasefocused cores were offered, each consisting of didactic
      sessions, exposure to basic research, diagnostic laboratory techniques, ethics,
      health policy, pharmacology, and clinical experiences. The cores were as follows:
      (1) Atherosclerotic Heart Disease: Integration of Basic Science and Clinical
      Medicine; (2) Translational Medicine in HIV: A Road to a Cure; (3) Gene Therapy:
      A Journey from Scientific Principles to Clinical Applications; (4) Solid Organ
      Transplantation: Defying Mother Nature; (5) The ABC's of Liver Disease; (6) The
      New Frontiers in Aging. Core leaders were responsible for developing and
      implementing their programs and recruiting faculty from many departments. All
      students completed an independent project tailored to their core. For example,
      the HIV core included modules on AIDS in Africa and needle-exchange programs, and
      the students' final project was a debate on whether "there will or will not be an
      effective HIV vaccine in the next 5 years." Students ranked their top three
      choices among the cores. Most (96%) were enrolled in their first or second
      choices, forming groups of six to eight. On the last day of core, students
      attended a focus group and filled out questionnaires about the strengths and
      weaknesses of their experience. DISCUSSION: There was overwhelming support for
      the core experience at the focus session. Most students commented that the
      program successfully overcame their end-of-first-year blues. All students felt
      that cores should be continued and recommended additional core selections.
      Weaknesses cited were inequality in the time and amount of work required for
      individual cores and an imbalance between excessive didactic material and
      insufficient clinical exposure in one core. Seventy-one percent of participants
      also completed the feedback questionnaires; 97% of them strongly agreed that the
      core successfully integrated material from previous courses; 88% strongly agreed
      that the clinical presentations demonstrated the relevance of content to medical
      practice; and 69% strongly agreed that the proportionate mix of lab, clinical,
      and small-group sessions was appropriate. Faculty were also enthusiastic about
      their experience. This program will be continued and expanded in 2002. We
      recommend this teaching format as an antidote to first-year burnout and a novel
      way to promote the development of physicians with an appreciation of the
      scientific basis of disease and the role ethics and health policy play in
      medicine.

PMID- 12431954
TI  - Mentorship through advisory colleges.
AB  - OBJECTIVE: Medical students face pressures ranging from the need to create a
      social network to learning vast amounts of scientific material. Students often
      feel isolated in this system and lack mentorship. In order to counteract feelings
      of bureaucratic anonymity and isolation, the University of California San
      Francisco has created an advisory college to foster the professional and personal
      growth and well being of students. DESCRIPTION: UCSF has developed a formal
      structure to advise medical students. A selection committee, chaired by the
      associate dean of student affairs, appointed five faculty mentors to head
      advisory colleges. These five colleges serve as the advising and well-being
      infrastructure for the students. Mentors were chosen from a balanced range of
      clinical disciplines, both primary and specialty. The disciplines are obstetrics
      gynecology, otolaryngology/head and neck surgery, medicine, pediatrics, and
      psychiatry. The mentors have demonstrated excellence in advising and counseling
      of students. Mentors meet individually at the beginning of the academic year with
      incoming first-year and second-year students. They then have bimonthly meetings
      with eight to ten students within each college throughout the academic year.
      Curricula for these group sessions include well-being discussions and coping
      techniques, sessions on the hidden and informal curriculum of professionalism,
      and discussions on career choices and strategies. For third-year students,
      advisory college meetings are scheduled during intersessions, which are weeklong
      courses that occur between the eight-week clerkship blocks. Mentors are available
      throughout the year to meet with students on an as-needed basis, and advisory
      colleges may hold group social activities. The dean's office supports each mentor
      with 20% salary and provides administrative support for the group college
      activities. DISCUSSION: Historically, UCSF students feel they receive an
      excellent education and appropriate job opportunities, but they do not feel they
      receive adequate advising and mentoring. This may have as its root cause the
      financial, clinical, and research pressures placed upon a faculty who are also
      responsible for mentoring residents and fellows. The advisory colleges begin by
      providing an infrastructure for developing a relationship for the student with a
      single faculty member. The advisory college system is incorporated into the
      academic schedule rather than relying on ad-hoc activities from well-meaning but
      inconsistently available faculty. In the early part of medical school, the
      advisory college relationship concentrates on assimilation into the new
      environment and provides the student with advice pertaining to mastering academic
      material. The college also serves as a sounding board for problems that can then
      be relayed to course directors to improve the educational experience. For
      students encountering academic difficulty, the college advisor can provide
      discreet advice about tutoring resources and can direct the student to a
      separately staffed Student Well-being Program. As time progresses, the mentors
      can direct students to key people in different fields of interest such as program
      directors and keep the students on track to make career decisions in a timely
      manner. The college system can help transform an anonymous medical school
      experience into a supportive, rich environment.

PMID- 12431955
TI  - A thematic approach to enhance clinical content in a cell and tissue biology
      course.
AB  - OBJECTIVE: (1) To integrate clinical problem solving into freshman cell and
      tissue biology (CTB) and (2) to enhance understanding of diabetes using CTB
      principles to explain the etiology, management, and development of complications
      in terms of cell, tissue, and organ structure and function. DESCRIPTION: First
      year medical students often question the need to learn detailed basic science
      material. Although clinical content has increased throughout basic science
      courses, little attempt has been made to link clinical correlations to one
      another or to enhance use of basic science material in clinical problem solving.
      The CTB course applies pertinent cell biology concepts such as cell
      proliferation, differentiation, migration, adhesion, and morphogenesis to tissue
      and organ function. Diabetes mellitus was chosen as a theme for CTB as diabetes
      has devastating effects on multiple tissues, and the disease has reached epidemic
      proportions in the United States, affecting individuals of every age and
      population group. Type I diabetes, presenting as ketoacidosis in a ten-year-old
      boy, was introduced by generalist physicians using a "grand rounds" approach.
      This format challenged students on the first day of medical school to diagnose a
      patient's problem and to explain the clinical findings in terms of anatomic,
      biochemical, and physiologic changes. The role of the blood/bicarbonate buffering
      system was the main focus of faculty-led discussion. The patient was then
      presented at age 25 with many diabetic complications. This stimulated discussion
      of the etiology of diabetes (type I versus type II), glycation, and the use of
      hemoglobin (Hb) A1c to monitor blood sugar control. Compliance and other aspects
      of diabetes management were added to the discussion. Faculty provided scientific
      information as necessary, and summary materials were distributed after the
      sessions. The interaction of a cell biologist with two generalist physicians
      optimized the integration of basic science with clinical problem solving. During
      the two semesters of CTB, the diabetes case is frequently referenced. Insulin
      synthesis provides the model for protein synthesis. Glycation, advanced glycation
      end products (AGE), and receptors (RAGE) are discussed. Other diabetes-related
      topics include wound healing (epithelium), basement membrane thickening
      (connective tissue), insulin regulation of muscle metabolism, diabetic neuropathy
      (neurohistology), platelet adhesiveness, glycation and HbA1c (blood),
      osteoporosis and Charcot joints (skeletal system), autoimmune mechanisms
      (cellular immunology), atherosclerosis and high blood pressure (blood vessels),
      diabetic nephropathy (renal), altered hepatic and gastrointestinal function,
      impotence (male reproductive system), and a comparison of type I and type II
      diabetes (endocrine system). DISCUSSION: Students have provided very positive
      feedback. The initial case enhanced interest in CTB, established clinical
      relevance, and has motivated learning and integration of materials from different
      parts of CTB and other courses. Other courses are now formally linking to the
      theme. For example, neuroscience will revisit diabetic neuropathy and
      retinopathy, physiology will relate ketoacidosis to acid-base balance, a human
      anatomy clinical correlation is being designed for transplantation surgeons to
      "cure" our diabetic patient with a renal-pancreas transplant. Uses of the case
      for introduction to clinical medicine, aspects of medical ethics, preventive
      medicine, and courses in pharmacology and pathology are contemplated.

PMID- 12431956
TI  - Reaching and teaching new medical students.
AB  - OBJECTIVE: Each year 150 new medical students enter UCLA. During Foundations week
      they are introduced to the resources and services, which will support their
      studies, as well as to the problem-based learning (PBL) approach of instruction.
      The library is responsible for introducing print and digital resources and
      illustrating how these support the PBL approach. This has been a challenge, given
      students' belief that they already know about libraries and the limited time
      frame (roughly 45 minutes) allotted to us. This year we developed a
      collaborative, student-centered, active learning approach. Students were exposed
      to a variety of relevant resources and given the opportunity to critique them for
      appropriateness to their PBL case of the week. DESCRIPTION: Sessions were
      designed for 50 students at once in the instructional microcomputing facility
      (IMF), with two or three students sharing each workstation. Since the IMF is
      equipped with classroom control software, librarians could display resources on
      each workstation while discussing them. Since we wish to encourage students to
      begin at our Web page, we wore t-shirts with the logo "Start@Biomed" and our URL.
      Instruction started with a "Guided Tour of the Biomedical Library Web Page"
      during which we discussed general services, highlighted special features,
      including Web-based tutorials and subject guides, and illustrated how to connect
      to relevant resources such as PubMed, MDConsult, STAT!Ref, and MEDLINEPlus. The
      student groups then critically reviewed one resource identified by a card next to
      their workstation by answering the following questions in writing: Would this
      resource address your specific PBL learning issue? If not, what type of learning
      issue would it address? Describe an outstanding feature or a barrier to use for
      this resource? After ten minutes, students were asked to report to the entire
      group. The use of a hand-held mike, which we passed among the students, added an
      element of fun to the proceedings and simulated a talk show atmosphere.
      DISCUSSION: This emphasis on active learning, critical thinking, and problem
      solving was a successful way to introduce students to the library and its
      resources, and reinforced the library's role in PBL. The friendly, casual talk
      show approach, coupled with our Start@Biomed t-shirts, created a setting in which
      we became real partners in the learning enterprise. Students reported they
      enjoyed the experience, and they are returning to us for additional help. Their
      written feedback, which we collected, summarized, and distributed to the entire
      class, illustrated a clear understanding of the resources and their usefulness.
      Both the medical school faculty and the librarians involved feel we have
      developed a useful, interesting, and appropriate way to reach beginning medical
      students, who often feel that they already know a great deal about using a
      library.

PMID- 12431957
TI  - Improving medical students' comfort with, and skill in handling, gender-related
      inquiries during the residency selection process.
AB  - OBJECTIVE: Previous work has identified that medical students experience
      instances of gender discrimination and sexual harassment during the residency
      selection process (i.e., "audition" elective rotations, residency interviews, and
      career counseling).(1,2) Examples of such instances include male students who
      report being counseled away from obstetrics-gynecology and a female student who
      reported being asked about her sexual orientation because of an expressed
      interest in breast disease. Students also report confusion about what constitutes
      an appropriate question or inappropriate gender-related comments. A common
      example is questioning about plans for child care during residency. We developed
      an education intervention focused on gender- and family-related issues that may
      arise during the residency selection process in an attempt to improve our
      students' ability to (1) recognize appropriate and inappropriate questions and
      situations and (2) handle such situations in a professional manner. DESCRIPTION:
      Our educational intervention is a voluntary, intense, active learning situation
      composed of four parts. First, data outlining the problem-including personal
      stories of students-are presented. Second, a faculty member with dual experience
      as a residency training director and dean for student affairs presents examples
      of appropriate and inappropriate questions (both types of questions can be
      uncomfortable if not contemplated in advance), potential ways to approach these
      questions, and a thoughtful approach for the student to take when integrating his
      or her experiences during the residency selection process with ultimate decisions
      about career and ranked programs. During the third part of the workshop, students
      draw two cases of 15 potential situations from a hat. They work in pairs, first
      to identify whether the case outlines an appropriate or inappropriate situation
      and second to develop and practice their responses. The session concludes with
      open discussion about the various scenarios and responses. DISCUSSION: This
      workshop has been well received by our medical students. In post-workshop
      surveys, students universally reported that the session was useful. Ninety
      percent of attendees felt better able to recognize appropriate and inappropriate
      questions and situations during the residency selection process. Seventy-seven
      percent of students reported that they felt better able to handle inappropriate
      situations during the residency selection process in a professional manner.
      Student comments reflected great satisfaction with the interactive nature of the
      exercise, interest in expanding the amount of time dedicated to the workshop, and
      a desire for clear rules about what can/cannot be said. Faculty offering the
      workshop reported satisfaction doing the workshop and noted that the greatest
      challenge in presenting the material is balancing the discussion about reasonable
      responses to inappropriate behaviors with the students' interest in performing
      well on all interviews in order to maximize their options. Interest in the
      program has resulted in the authors' being invited to share the workshop at an
      upcoming GME retreat for the institution's program directors. Based on these
      results we plan to continue the workshop in an expanded version. In addition, we
      plan to use this format of the workshop as a springboard for similar sessions for
      medical students interested in confronting issues of discrimination and
      harassment in the educational setting.

PMID- 12431958
TI  - Preparing medical students to teach.
AB  - OBJECTIVE: Residents do a significant amount of teaching. Therefore, as medical
      students prepare for the clinical aspects of their residency, it is also
      important for them to prepare for their role of physician as teacher. With the
      goal of offering fourth-year students an opportunity to enhance their teaching
      skills, an elective was designed that presented them with an opportunity to
      expand their knowledge base in education, and then apply and practice this new
      set of knowledge. A week-long elective, Physician as Teacher, was designed to
      encompass core educational information such as needs assessment of learners,
      establishing goals and objectives, teaching methods, and evaluation and feedback.
      This core information was then applied and enriched during an end-of-course
      teaching presentation. Aside from this course, there is no forum during their
      undergraduate medical training for the students to acquire knowledge and skills
      about how to be teachers. DESCRIPTION: The course was developed with the
      appreciation that application of knowledge is a rich source of learning. The
      course began with interactive classroom teaching sessions designed to facilitate
      acquisition of core educational knowledge. Sessions topics included assessment of
      learner needs, methods of teaching, learning styles, microprecepting, and
      feedback. Also incorporated were sessions on facilitating small groups, and
      teaching and learning how to use technology. Those classroom sessions were then
      enhanced by a complement of sessions that asked the students to apply their new
      knowledge to clinical situations. Those more application-based sessions included
      observation and follow-up discussion of clinical teaching and small-group
      teaching sessions with the goal of developing the students' skills with respect
      to the teaching and learning process. An end-of-course teaching presentation by
      each student provided them with a capstone experience of applying the knowledge
      and skills learned throughout the week. The topic of the teaching presentation
      was of their choosing, and could incorporate technology. Each student's teaching
      presentation was videotaped, immediately viewed by the student, and discussed
      using a structured format of facilitated feedback. DISCUSSION: Students reported
      that the end-of-course teaching presentation was a rich source of their learning,
      and an important vehicle for helping them apply and synthesize the new knowledge.
      Fifteen percent of fourth-year students enrolled in and completed the elective.
      Seventy-one percent of those students "strongly agreed" and 29% "agreed" that the
      course provided useful knowledge and skills. Seventy-nine percent "strongly
      agreed" and 21% "agreed" that their teaching would be better because of the
      course. Based on comments, the students appeared to feel that the experience of
      presenting a teaching session at the end of the course was a rich source of their
      learning, and helped them to apply and synthesize the new knowledge. Students
      noted, "the teaching project was an excellent idea to see how much we have
      learned; I never realized what a responsibility we have as residents to teach our
      peers; I have been enlightened this past week and will now consciously make an
      effort to share what little information I currently have; I will be a better
      teacher because I have been given the appropriate tools."

PMID- 12431959
TI  - Clinical skills center attending: an innovative senior medical school elective.
AB  - OBJECTIVE: Although residents are expected to assume teaching responsibilities,
      the traditional medical school curriculum does not formally prepare students for
      the teaching role. In 1999 an elective was developed to provide senior medical
      students with opportunities to acquire instructional and leadership skills by
      participating in clinical education activities as a clinical skills center
      attending. This elective also allowed the senior student to explore academic
      medicine as a potential career choice. DESCRIPTION: During the four-week
      elective, a senior student acted as an attending in the clinical skills center
      (CSC), a state-of-the-art facility that is designed and equipped for teaching and
      testing medical skills. (The CSC has ten fully operational patient examining
      rooms for student-patient interaction, and each room is equipped with dual
      cameras and two-way audio response capability.) The participating student spent
      approximately 40 hours per week teaching clinical skills to freshmen, sophomore,
      and junior medical students and assisting with testing activities for the
      Colleges of Medicine, Pharmacy, and Nursing. A specific requirement for full
      credit was writing an objective standardized clinical examination (OSCE) case.
      The case format required development of a checklist for minimal competencies of
      the examinee and suggested techniques for evaluating those competencies. Another
      specific requirement was that the senior student participate in the training of
      standardized patients to portray one or more OSCE cases. Other activities were
      tailored to meet the needs of the senior student and/or users of the CSC. Two
      course co-directors provided guidance for all students. Evaluation was on a
      "pass/fail" basis. There were no written or oral exams. The purpose of the
      elective was achieved through individual research and completion of the assigned
      activities. DISCUSSION: This elective was first offered to senior medical
      students at during 1999-2000. Each student participated in an average of ten
      teaching sessions or assessments. To date, six senior students, five women and
      one man, have completed the elective. These students entered family medicine,
      pediatrics, internal medicine, psychiatry, and surgery residencies. Participants
      were asked to rate the elective using a five-point Likert-type scale with 5
      signifying "strong agreement." The response rate was 67%. These students felt the
      requirements were adequate (4.75) and said they would recommend it to other
      senior students (4.75). They agreed that the objectives were clear and attainable
      (4.5) and that it better prepared them to teach as resident (4.25). Areas of
      weakness identified were the elective's ability to increase the student's
      understanding of medical education (3.75) and meet the student's expectations
      (4.0). The organization of the elective (4.0) could be improved as well. Most
      participants were interested in academic medicine before (4.25) and after (4.75)
      the experience. We plan to follow these students over time to see what careers
      they eventually pursue. Although our experience is limited and the student
      population is small, we believe the elective is an effective method for
      developing teaching skills and helping the upper-level medical student who is
      interested in education to better understand the nature and function of academic
      clinical medicine.

PMID- 12431960
TI  - A few months to live: different paths to life's end.

PMID- 12431961
TI  - Autologous stem-cell transplantation as a component of initial treatment for poor
      risk patients with aggressive non-Hodgkin's lymphoma: resolved issues versus
      remaining opportunity.

PMID- 12431962
TI  - Randomized study to evaluate the use of high-dose therapy as part of primary
      treatment for "aggressive" lymphoma.
AB  - PURPOSE: This trial of the German High-Grade Non-Hodgkin's Lymphoma Study Group
      compares the use of high-dose therapy (HDT) as part of primary treatment with
      cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus etoposide
      followed by involved-field (IF) radiotherapy in a randomized, multicenter, phase
      III study. PATIENTS AND METHODS: Three hundred twelve patients with "aggressive"
      non-Hodgkin's lymphoma aged <or= 60 years with elevated serum lactate
      dehydrogenase levels were included from 1990 to 1997. Patients with at least a
      minor response after two cycles of CHOEP (CHOP + etoposide 3 x 100 mg/m(2)) were
      to receive three further cycles of CHOEP followed by IF radiotherapy (arm A) or
      one further cycle of CHOEP followed by autologous stem-cell transplantation and
      IF radiotherapy (arm B). RESULTS: Among 158 patients randomized to arm B, 103
      (65%) received HDT. The complete remission rate at the end of treatment was 62.9%
      in arm A and 69.9% in arm B. With a median observation time of 45.5 months,
      overall survival for all 312 patients was 63% after 3 years (63% for arm A, 62%
      for arm B; P =.68). Event-free survival was 49% for arm A versus 59% for arm B (P
      =.22). Relapse in arm B was associated with a significantly worse survival rate
      than relapse in arm A (P <.05). Relapse after HDT occurred early (median
      interval, 3 months). Six patients developed secondary neoplasia, three in arm A
      and three in arm B. CONCLUSION: Results of the randomized trial comparing CHOP
      like chemotherapy with early HDT do not support the use of HDT with carmustine,
      etoposide, cytarabine, and melphalan following shortened standard chemotherapy.

PMID- 12431963
TI  - Phase I trial of the proteasome inhibitor PS-341 in patients with refractory
      hematologic malignancies.
AB  - PURPOSE: To determine the maximum-tolerated dose (MTD), dose-limiting toxicity
      (DLT), and pharmacodynamics (PD) of the proteasome inhibitor bortezomib
      (previously known as PS-341) in patients with refractory hematologic
      malignancies. PATIENTS AND METHODS: Patients received PS-341 twice weekly for 4
      weeks at either 0.40, 1.04, 1.20, or 1.38 mg/m(2), followed by a 2-week rest. The
      PD of PS-341 was evaluated by measurement of whole blood 20S proteasome activity.
      RESULTS: Twenty-seven patients received 293 doses of PS-341, including 24
      complete cycles. DLTs at doses above the 1.04-mg/m(2) MTD attributed to PS-341
      included thrombocytopenia, hyponatremia, hypokalemia, fatigue, and malaise. In
      three of 10 patients receiving additional therapy, serious reversible adverse
      events appeared during cycle 2, including one episode of postural hypotension,
      one systemic hypersensitivity reaction, and grade 4 transaminitis in a patient
      with hepatitis C and a substantial acetaminophen ingestion. PD studies revealed
      PS-341 induced 20S proteasome inhibition in a time-dependent manner, and this
      inhibition was also related to both the dose in milligrams per meter squared, and
      the absolute dose of PS-341. Among nine fully assessable patients with heavily
      pretreated plasma cell dyscrasias completing one cycle of therapy, there was one
      complete response and a reduction in paraprotein levels and/or marrow
      plasmacytosis in eight others. In addition, one patient with mantle cell lymphoma
      and another with follicular lymphoma had shrinkage of nodal disease. CONCLUSION:
      PS-341 was well tolerated at 1.04 mg/m(2) on this dose-intensive schedule,
      although patients need to be monitored for electrolyte abnormalities and late
      toxicities. Additional studies are indicated to determine whether incorporation
      of dose/body surface area yields a superior PD model to dosing without
      normalization. PS-341 showed activity against refractory multiple myeloma and
      possibly non-Hodgkin's lymphoma in this study, and merits further investigation
      in these populations.

PMID- 12431964
TI  - Children from ethnic minorities have benefited equally as other children from
      contemporary therapy for rhabdomyosarcoma: a report from the Intergroup
      Rhabdomyosarcoma Study Group.
AB  - PURPOSE: To define the clinical characteristics of rhabdomyosarcoma (RMS)
      occurring in children from ethnic minorities and determine whether these children
      have benefited equally from advances in therapy. PATIENTS AND METHODS: This was a
      retrospective cohort analysis of children treated on the Intergroup
      Rhabdomyosarcoma Study Group protocols between 1984 and 1997. The clinical
      features and outcomes of 336 African-American children and 286 children from
      other ethnic minorities were compared with those of white children (n = 1,721).
      RESULTS: African-American, other ethnic group, and white children enjoyed similar
      5-year failure-free survivals (FFS) of 61%, 61%, and 66%, respectively, P =.15.
      Compared with white children, nonwhite patients more often had (1) invasive, T2
      tumors (P =.03); (2) stage 2 or 3 tumors (P =.003); (3) large tumors (more than 5
      cm, P <.006); and/or (4) tumors with positive regional nodes (ie, N1, P =.002).
      Using Cox proportional hazards analysis, seven patient risk categories were
      defined with significant differences in outcome. This model was then used to
      search for other factors associated with FFS after adjusting for these risk
      categories. Only T stage and age remained associated with FFS (P =.001 and P
      <.001, respectively). After adjusting for T stage, risk category, and age, we
      explored the relationship of ethnic group to FFS and found that, compared with
      whites, the relative risk of failure was 1.14 for African-American patients and
      1.2 for other ethnic minority patients, values that are not significantly
      different. CONCLUSION: Patients from ethnic minority groups more often have
      larger, invasive tumors with positive lymph nodes. Nevertheless, they have
      benefited as equally as white children from the dramatic progress in therapy of
      RMS.

PMID- 12431965
TI  - Prospective, randomized, double-blind, placebo-controlled trial of marimastat
      after response to first-line chemotherapy in patients with small-cell lung
      cancer: a trial of the National Cancer Institute of Canada-Clinical Trials Group
      and the European Organization for Research and Treatment of Cancer.
AB  - PURPOSE: Increased expression of metalloproteinases is associated with poor
      prognosis in small-cell lung cancer (SCLC). This trial was undertaken to
      determine whether adjuvant treatment with the metalloproteinase inhibitor
      marimastat could prolong survival in responding patients with SCLC after
      chemotherapy. PATIENTS AND METHODS: SCLC patients in complete or partial
      remission were eligible. They were stratified by radiotherapy (early, late, or
      none), stage (extensive or limited), response (complete or partial), and
      cooperative group (National Cancer Institute of Canada-Clinical Trials Group or
      European Organization for Research and Treatment of Cancer). They were randomized
      to receive marimastat 10 mg or placebo orally bid for up to 2 years. RESULTS:
      There were 532 eligible patients (266 marimastat and 266 placebo). Stage was
      limited for 279 patients (52%) and extensive for 253 (48%). Best response to
      induction therapy was complete remission for 176 patients (33%), partial
      remission for 341 (64%), and 15 patients (3%) had undergone surgical resection.
      The median time to progression for marimastat patients was 4.3 months compared
      with 4.4 months for placebo patients (P =.81). Median survivals for marimastat
      and placebo patients were 9.3 months and 9.7 months, respectively (P =.90)
      Toxicity was generally limited to musculoskeletal symptoms (18% grade 3/4 for
      marimastat). Dose modifications for musculoskeletal toxicity were required in 90
      patients (33%) on the marimastat arm, and 87 (32%) permanently stopped marimastat
      because of toxicity. Patients on marimastat had significantly poorer quality of
      life at 3 and 6 months. CONCLUSION: Treatment with marimastat after induction
      therapy for SCLC did not result in improved survival and had a negative impact on
      quality of life.

PMID- 12431966
TI  - Safety and pharmacokinetic effects of TNP-470, an angiogenesis inhibitor,
      combined with paclitaxel in patients with solid tumors: evidence for activity in
      non-small-cell lung cancer.
AB  - PURPOSE: Preclinical studies suggested that the antiangiogenic agent TNP-470 was
      synergistic with cytotoxic therapy. TNP-470 was administered with paclitaxel to
      adults with solid tumors to define the safety and optimal dose of the combination
      regimen and to assess pharmacokinetic interactions. PATIENTS AND METHODS: Thirty
      two patients were enrolled chronologically onto one of two treatment arms. Arm A
      involved a fixed TNP-470 dose with escalating doses of paclitaxel, and Arm B
      involved a fixed paclitaxel dose with escalating doses of TNP-470. Paclitaxel and
      TNP-470 pharmacokinetics were evaluated along with toxicity. RESULTS: The
      combination of TNP-470 administered at 60 mg/m(2) three times per week and
      paclitaxel 225 mg/m(2) administered over 3 hours every 3 weeks was defined as
      both the maximum-tolerated dose and the optimal dose. Myelosuppression was
      similar to that expected with paclitaxel alone. Mild to moderate neurocognitive
      impairment was observed; however, the majority of changes were subclinical and
      reversible as determined by prestudy and poststudy neuropsychiatric test results.
      A clinically insignificant decrease of paclitaxel clearance was observed for the
      combination. Median survival for all patients was 14.1 months. Partial responses
      were reported in eight (25%) of 32 patients and in six (38%) of 16 patients with
      NSCLC, 60% of whom had received prior chemotherapy. CONCLUSION: The combination
      of TNP-470 and paclitaxel, each at full single-agent dose, seems well tolerated,
      with minimal pharmacokinetic interaction between the two agents. Further studies
      of TNP-470 with chemotherapy regimens are warranted in NSCLC and other solid
      tumors.

PMID- 12431967
TI  - Prognostic factors for relapse in stage I seminoma managed by surveillance: a
      pooled analysis.
AB  - PURPOSE: Several management options are available to patients with stage I
      seminoma, including adjuvant radiotherapy, surveillance, and adjuvant
      chemotherapy. We performed a pooled analysis of patients from the four largest
      surveillance studies to better delineate prognostic factors associated with
      disease progression. PATIENTS AND METHODS: Individual patient data were obtained
      from each center (Princess Margaret Hospital, Danish Testicular Cancer Study
      Group, Royal Marsden Hospital, and Royal London Hospital) for 638 patients. Tumor
      characteristics (size, histologic subtype, invasion of rete testis, and tumor
      invasion into small vessels [SVI]) as well as age at diagnosis were analyzed for
      prognostic importance for relapse. RESULTS: With a median follow-up of 7.0 years
      (range, 0.02 to 17.5 years), 121 relapses were observed for an actuarial 5-year
      relapse-free rate (RFR) of 82.3%. On univariate analysis, tumor size (RFR: <or= 4
      cm, 87%; > 4 cm, 76%; P =.003), rete testis invasion (RFR: 86% [absent] v 77%
      [present], P =.003), and the presence of SVI (RFR: 86% [absent] v 77% [present],
      P =.038) were predictive of relapse. On multivariate analysis, tumor size (<or= 4
      cm v > 4 cm, hazard ratio 2.0; 95% confidence interval [CI], 1.3 to 3.2) and
      invasion of the rete testis (hazard ratio 1.7; 95% CI, 1.1 to 2.6) remained as
      important predictors for relapse. CONCLUSION: We have identified size of primary
      tumor and rete testis invasion as important prognostic factors for relapse in
      patients with stage I seminoma managed with surveillance. This information will
      allow patients and clinicians to choose management based on a more accurate
      assessment of an individual patient's risk of relapse. In addition, it will allow
      clinicians to tailor follow-up protocols based on risk of occult disease.

PMID- 12431968
TI  - Efficacy of fluorine-18-deoxyglucose positron emission tomography in detecting
      tumor recurrence after local ablative therapy for liver metastases: a prospective
      study.
AB  - PURPOSE: The aims of this prospective study were to investigate the potential
      role of fluorine-18-deoxyglucose (FDG) positron emission tomography (PET) in
      determining the efficacy of the local tumor ablative process and to determine the
      added value of FDG-PET in the detection of tumor recurrence during follow-up.
      PATIENTS AND METHODS: Twenty-three patients with unresectable colorectal liver
      metastases were followed up after local ablative therapy consisting of a standard
      protocol including FDG-PET scanning, computed tomography (CT) scanning, and
      carcinoembryonic antigen measurements. The mean follow-up period was 16 months
      (range, 10 to 21 months). RESULTS: Ninety-six lesions was treated, 56 by local
      ablative treatment. Within 3 weeks after local ablative treatment, 51 lesions
      became photopenic on FDG-PET, while five lesions (in five patients) showed
      persistent activity on FDG-PET. In four of five FDG-PET-positive lesions, a local
      recurrence developed during follow-up; one FDG-PET-positive lesion turned out to
      be an abscess. None of the FDG-PET-negative lesions developed a local recurrence
      during a mean follow-up period of 16 months. During follow-up, 11 patients showed
      recurrence in the liver outside of the treated area. In all cases, previously
      negative FDG-PET scans became positive. Extrahepatic recurrence was encountered
      in nine patients during follow-up; FDG-PET showed all nine cases of tumor
      recurrence. There was one false-positive FDG-PET caused by an intra-abdominal
      abscess. In all patients, the time point of detection of recurrence by FDG-PET
      was considerably earlier than the detection by CT. CONCLUSION: FDG-PET seems to
      have a significant impact in measuring treatment efficacy directly after local
      ablative therapy. Furthermore, FDG-PET has an added value in patient follow-up
      because it reveals recurrences earlier than conventional diagnostic modalities.

PMID- 12431969
TI  - Therapeutic efficacy of transcatheter arterial chemoembolization as compared with
      hepatic resection in hepatocellular carcinoma patients with compensated liver
      function in a hepatitis B virus-endemic area: a prospective cohort study.
AB  - PURPOSE: Identifying a special subgroup of hepatocellular carcinoma (HCC)
      patients who may benefit from transcatheter arterial chemoembolization (TACE)
      when compared with the standard treatment of hepatic resection (HR) warrants
      research in Asian countries. PATIENTS AND METHODS: From January 1993 to December
      1994, 182 patients with operable HCC (Child-Pugh class A and International Union
      Against Cancer [UICC] stage T1-3N0M0) were enrolled. After initial TACE and
      lipiodol computed tomography, 91 received HR and 91, who refused the operation,
      received repeated sessions of TACE. After stratification according to the tumor
      stage (UICC and Cancer of the Liver Italian Program [CLIP]) and lipiodol
      retention pattern, the survival rates of the two treatment groups were compared.
      The median follow-up period was 83 months. RESULTS: As of December 31, 2000, 48
      patients who underwent HR and 68 patients who underwent TACE had died. In a
      subgroup analysis according to tumor stage, the HR group survival rate was
      significantly higher than the TACE group in both UICC T1-2N0M0 (P =.0058) and
      CLIP 0 (P =.0027) subgroups. However, there was no significant difference in
      either UICC T3N0M0 (P =.7512) or CLIP 1-2 (P =.5366) subgroups. Even in patients
      with UICC T1-2N0M0 HCC, when lipiodol was compactly retained, the survival rate
      of the HR group was comparable to that of the TACE group (P =.0596). CONCLUSION:
      TACE proved to be as effective as HR in the subpopulations with UICC T3N0M0 or
      CLIP 1-2 HCC and adequate liver function, and even with UICC T1-2N0M0 HCC when
      lipiodol was compactly retained in the tumor. In such cases, the choice of
      treatment modality between TACE and HR may be left to the patient's preference.

PMID- 12431970
TI  - Efficacy and safety of carbon ion radiotherapy in bone and soft tissue sarcomas.
AB  - PURPOSE: To evaluate the tolerance for and effectiveness of carbon ion
      radiotherapy in patients with unresectable bone and soft tissue sarcomas.
      PATIENTS AND METHODS: We conducted a phase I/II dose escalation study of carbon
      ion radiotherapy. Fifty-seven patients with 64 sites of bone and soft tissue
      sarcomas not suited for resection received carbon ion radiotherapy. Tumors
      involved the spine or paraspinous soft tissues in 19 patients, pelvis in 32
      patients, and extremities in six patients. The total dose ranged from 52.8 to
      73.6 gray equivalent (GyE) and was administered in 16 fixed fractions over 4
      weeks (3.3 to 4.6 GyE/fraction). The median tumor size was 559 cm(3) (range, 20
      to 2,290 cm(3)). The minimum follow-up was 18 months. RESULTS: Seven of 17
      patients treated with the highest total dose of 73.6 GyE experienced Radiation
      Therapy Oncology Group grade 3 acute skin reactions. Dose escalation was then
      halted at this level. No other severe acute reactions (grade > 3) were observed
      in this series. The overall local control rates were 88% and 73% at 1 year and 3
      years of follow-up, respectively. The median survival time was 31 months (range,
      2 to 60 months), and the 1- and 3-year overall survival rates were 82% and 46%,
      respectively. CONCLUSION: Carbon ion radiotherapy seems to be a safe and
      effective modality in the management of bone and soft tissue sarcomas not
      eligible for surgical resection, providing good local control and offering a
      survival advantage without unacceptable morbidity.

PMID- 12431971
TI  - Function and health status outcomes in a randomized trial comparing preoperative
      and postoperative radiotherapy in extremity soft tissue sarcoma.
AB  - PURPOSE: Morbidity associated with wound complications may translate into
      disability and quality-of-life disadvantages for patients treated with
      radiotherapy (RT) for soft tissue sarcoma (STS) of the extremities. Functional
      outcome and health status of extremity STS patients randomized in a phase III
      trial comparing preoperative versus postoperative RT is described. PATIENTS AND
      METHODS: One hundred ninety patients with extremity STS were randomized after
      stratification by tumor size dichotomized at 10 cm. Function and quality of life
      were measured by the Musculoskeletal Tumor Society Rating Scale (MSTS), the
      Toronto Extremity Salvage Score (TESS), and the Short Form-36 (SF-36) at
      randomization, 6 weeks, and 3, 6, 12, and 24 months after surgery. RESULTS: One
      hundred eighty-five patients had function data. Patients treated with
      postoperative RT had better function with higher MSTS (25.8 v 21.3, P <.01), TESS
      (69.8 v 60.6, P =.01), and SF-36 bodily pain (67.7 v 58.5, P =.03) scores at 6
      weeks after surgery. There were no differences at later time points. Scores on
      the physical function, role-physical, and general health subscales of the SF-36
      were significantly lower than Canadian normative data at all time points. After
      treatment arm was controlled for, MSTS change scores were predicted by a lower
      extremity tumor, a large resection specimen, and motor nerve sacrifice; TESS
      change scores were predicted by lower-extremity tumor and prior incomplete
      excision. When wound complication was included in the model, patients with
      complications had lower MSTS and TESS scores in the first 2 years after
      treatment. CONCLUSION: The timing of RT has minimal impact on the function of STS
      patients in the first year after surgery. Tumor characteristics and wound
      complications have a detrimental effect on patient function.

PMID- 12431972
TI  - Randomized discontinuation design: application to cytostatic antineoplastic
      agents.
AB  - PURPOSE: Propose a phase II study design to evaluate the activity of a putative
      cytostatic agent, acknowledging heterogeneity of tumor growth rates in the
      population of patients. METHODS: In the setting of renal cell carcinoma, some
      patients' tumors will grow slowly naturally. An appropriate design has to
      distinguish antiproliferative activity attributable to the novel agent from
      indolent disease. We propose a randomized discontinuation design that initially
      treats all patients with the study agent (stage 1) and then randomizes in a
      double-blind fashion to continuing therapy or placebo only those patients whose
      disease is stable (stage 2). This design allows the investigators to determine if
      apparent slow tumor growth is attributable to the drug or to selection of
      patients with naturally slow-growing tumors. RESULTS: By selecting a more
      homogeneous population, the randomized portion of the study requires fewer
      patients than would a study randomizing all patients at entry. The design also
      avoids potential confounding because of heterogeneous tumor growth. Because the
      two randomly assigned treatment groups each comprise patients with apparently
      slow growing tumors, any difference between the groups in disease progression
      after randomization is more likely a result of the study drug and less likely a
      result of imbalance with respect to tumor growth rates. Stopping rules during the
      initial open-label stage and the subsequent randomized trial stage allow one to
      reduce the overall sample size. Expected average tumor growth rate is an
      important consideration when deciding the duration of follow-up for the two
      stages. CONCLUSION: The randomized discontinuation design is a feasible
      alternative phase II study design for determining activity of possibly cytostatic
      anticancer agents.

PMID- 12431973
TI  - BRCA1/2 genetic testing in the community setting.
AB  - PURPOSE: BRCA1/2 genetic testing has been commercially available in the United
      States since 1996. Most published reports described BRCA1/2 testing as research
      studies at large academic centers, but less is known about testing in the
      community. This study evaluates the process and early outcomes of BRCA1/2 genetic
      testing as a clinical service in the community setting. METHODS: Surveys were
      mailed to women in the United States whose health care providers ordered BRCA1/2
      genetic testing from Myriad Genetic Laboratories from August 1998 through July
      2000. Women tested at 149 large academic centers were excluded. Main outcome
      measures were demographic characteristics, recall of and satisfaction with the
      genetic testing process, and likelihood of pursuing cancer prevention strategies.
      RESULTS: Among the 646 respondents, 414 (64%) had a personal history of cancer
      and 505 (78%) had at least one first-degree relative with breast and/or ovarian
      cancer. Most subjects (82%) recalled discussions of informed consent before
      testing (median time, 30 minutes). Genetic results were conveyed during an office
      visit (57%), by telephone (39%), or by mail (3%). More than 75% of respondents
      were "very satisfied with the counseling received." Cancer-free subjects with a
      germline mutation were more likely to consider prevention strategies after
      receiving the genetic results. CONCLUSION: Virtually all respondents had a
      personal and/or family history of breast/ovarian cancer. Although pretest and
      posttest communications were not standardized, overall satisfaction with clinical
      breast cancer genetic testing was high. Additional follow-up will provide data on
      future cancer prevention practices and cancer incidence.

PMID- 12431974
TI  - Limb salvage and amputation in survivors of pediatric lower-extremity bone
      tumors: what are the long-term implications?
AB  - The past four decades have seen tremendous progress in the treatment of pediatric
      and adolescent cancers. As a consequence, there are increasing numbers of adult
      childhood cancer survivors. This has prompted investigation into the long-term
      consequences of cancer treatments. One group that merits special study is the
      survivors of lower-extremity bone tumors. Their function and quality of life may
      depend in part on both the surgery and the age at which it was performed.
      Comparisons between studies are difficult because small numbers of patients and
      the use of varying research designs and methods have limited research in this
      area. The purpose of this article is to review the major surgical approaches to
      lower-limb bone tumors and their impact on pediatric patients. The results show
      that survival is equivalent between amputation and limb salvage. Complications
      occur more frequently in limb salvage. The long-term outcomes of those undergoing
      amputation and limb salvage have not been found to be substantially different in
      regard to quality of life. In conclusion, prospective long-term follow-up of
      pediatric patients with lower-limb tumors is needed to (1) determine in a uniform
      manner the long-term complications, quality of life, and functionality of this
      population and describe differences within this patient population based on age
      at diagnosis and surgical procedure, (2) identify areas of concern that are
      amenable to intervention, and (3) provide clinicians and future patients a better
      understanding of the surgical options.

PMID- 12431975
TI  - RNA-guided nucleotide modification of ribosomal and other RNAs.

PMID- 12431976
TI  - Thrombin rapidly induces protein kinase D phosphorylation, and protein kinase C
      delta mediates the activation.
AB  - Thrombin plays a critical role in hemostasis, thrombosis, and inflammation.
      However, the responsible intracellular signaling pathways triggered by thrombin
      are still not well defined. We report here that thrombin rapidly and transiently
      induces activation of protein kinase D (PKD) in aortic smooth muscle cells. Our
      data demonstrate that protein kinase C (PKC) inhibitors completely block thrombin
      induced PKD activation, suggesting that thrombin induces PKD activation via a PKC
      dependent pathway. Furthermore, our results show that thrombin rapidly induces
      PKC delta phosphorylation and that the PKC delta-specific inhibitor rottlerin
      blocks thrombin-induced PKD activation, suggesting that PKC delta mediates the
      thrombin-induced PKD activation. Using dominant negative approaches, we
      demonstrated that expression of a dominant negative PKC delta inhibits the
      phosphorylation and activation of PKD induced by thrombin, whereas neither PKC
      epsilon nor PKC zeta affects thrombin-induced PKD activation. In addition, our
      results of co-immunoprecipitation assays showed that PKD forms a complex with PKC
      delta in smooth muscle cells. Taken together, the findings of the present study
      demonstrate that thrombin induces activation of PKD and reveal a novel role of
      PKC delta in mediating thrombin-induced PKD activation in vascular smooth muscle
      cells.

PMID- 12431977
TI  - Membrane topography of human phosphatidylethanolamine N-methyltransferase.
AB  - In liver, phosphatidylethanolamine is converted to phosphatidylcholine through a
      series of three sequential methylation reactions. Phosphatidylethanolamine N
      methyltransferase (PEMT) catalyzes each transmethylation reaction, and S
      adenosylmethionine is the methyl group donor. Biochemical analysis of human liver
      revealed that the methyltransferase activity is primarily localized to the
      endoplasmic reticulum and mitochondria-associated membranes. Bioinformatic
      analysis of the predicted amino acid sequence suggested that the enzyme adopts a
      polytopic conformation in those membranes. To elucidate the precise membrane
      topography of PEMT and thereby provide the basis for in-depth functional
      characterization of the enzyme, we performed endoproteinase-protection analysis
      of epitope-tagged, recombinant protein. Our data suggest a topographical model of
      PEMT in which four transmembrane regions span the membrane such that both the N
      and C termini of the enzyme are localized external to the ER. Two hydrophilic
      connecting loops protrude into the luminal space of the microsomes whereas a
      corresponding loop on the cytosolic side remains proximate to the membrane.
      Further support for this model was obtained following endoproteinase-protection
      analysis of mutant recombinant PEMT derivatives in which specific protease
      cleavage sites had been genetically engineered or ablated.

PMID- 12431978
TI  - Src kinase mediates phosphatidylinositol 3-kinase/Akt-dependent rapid endothelial
      nitric-oxide synthase activation by estrogen.
AB  - 17beta-Estradiol activates endothelial nitric oxide synthase (eNOS), enhancing
      nitric oxide (NO) release from endothelial cells via the phosphatidylinositol 3
      kinase (PI3-kinase)/Akt pathway. The upstream regulators of this pathway are
      unknown. We now demonstrate that 17beta-estradiol rapidly activates eNOS through
      Src kinase in human endothelial cells. The Src family kinase specific-inhibitor 4
      amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2) abrogates
      17beta-estradiol- but not ionomycin-stimulated NO release. Consistent with these
      results, PP2 blocked 17beta-estradiol-induced Akt phosphorylation but did not
      inhibit NO release from cells transduced with a constitutively active Akt. PP2
      abrogated 17beta-estradiol-induced activation of PI3-kinase, indicating that the
      PP2-inhibitable kinase is upstream of PI3-kinase and Akt. A 17beta-estradiol
      induced estrogen receptor/c-Src association correlated with rapid c-Src
      phosphorylation. Moreover, transfection of kinase-dead c-Src inhibited 17beta
      estradiol-induced Akt phosphorylation, whereas constitutively active c-Src
      increased basal Akt phosphorylation. Estrogen stimulation of murine embryonic
      fibroblasts with homozygous deletions of the c-src, fyn, and yes genes failed to
      induce Akt phosphorylation, whereas cells maintaining c-Src expression
      demonstrated estrogen-induced Akt activation. Estrogen rapidly activated c-Src
      inducing an estrogen receptor, c-Src, and P85 (regulatory subunit of PI3-kinase)
      complex formation. This complex formation results in the successive activation of
      PI3-kinase, Akt, and eNOS with consequent enhanced NO release, implicating c-Src
      as a critical upstream regulator of the estrogen-stimulated PI3-kinase/Akt/eNOS
      pathway.

PMID- 12431979
TI  - Cell cycle-dependent expression of HERG1 and HERG1B isoforms in tumor cells.
AB  - The role of K(+) channel activity during cell cycle progression has become a
      research topic of considerable interest. Blocking of K(+) channels inhibits the
      proliferation of many cell types, although the mechanism of this inhibition is
      unclear. There is speculation that K(+) channels differentially regulate the
      electrical potential of the plasma membrane (V(m)) during proliferation. We have
      demonstrated that in tumor cells the value of V(m) is clamped to rather
      depolarized values by K(+) channels belonging to the HERG family. We report here
      that tumor cell lines preferentially express the herg1 gene and a truncated, N
      deleted form that corresponds to herg1b. This alternative transcript is also
      expressed in human primary acute myeloid leukemias. Both HERG1 and HERG1B
      proteins are expressed on the plasma membrane of tumor cells and can form
      heterotetramers. The expression of HERG protein isoforms is strongly cell cycle
      dependent, accounting for variations in HERG currents along the mitotic cycle.
      Moreover, the blocking of HERG channels dramatically impairs cell growth of HERG
      bearing tumor cells. These results suggest that modulated expression of different
      K(+) channels is the molecular basis of a novel mechanism regulating neoplastic
      cell proliferation.

PMID- 12431980
TI  - Secretion of Annexin II via activation of insulin receptor and insulin-like
      growth factor receptor.
AB  - Annexin II is secreted into the extracellular environment, where, via
      interactions with specific proteases and extracellular matrix proteins, it
      participates in plasminogen activation, cell adhesion, and tumor metastasis and
      invasion. However, mechanisms regulating annexin II transport across the cellular
      membrane are unknown. In this study, we used coimmunoprecipitation to show that
      Annexin-II was bound to insulin and insulin-like growth factor-1 (IGF-1)
      receptors in PC12 cells and NIH-3T3 cells overexpressing insulin (NIH-3T3(IR)) or
      IGF-1 receptor (NIH-3T3(IGF-1R)). Stimulation of insulin and IGF-1 receptors by
      insulin caused a temporary dissociation of annexin II from these receptors, which
      was accompanied by an increased amount of extracellular annexin II detected in
      the media of PC12, NIH-3T3(IR), and NIH-3T3(IGF-1R) cells but not in that of
      untransfected NIH-3T3 cells. Activation of a different growth factor receptor,
      the platelet-derived growth factor receptor, did not produce such results.
      Tyrphostin AG1024, a tyrosine kinase inhibitor of insulin and IGF-1 receptor, was
      shown to inhibit annexin II secretion along with reduced receptor
      phosphorylation. Inhibitors of a few downstream signaling enzymes including
      phosphatidylinositol 3-kinase, pp60c-Src, and protein kinase C had no effect on
      insulin-induced annexin II secretion, suggesting a possible direct link between
      receptor activation and annexin II secretion. Immunocytochemistry revealed that
      insulin also induced transport of the membrane-bound form of annexin II to the
      outside layer of the cell membrane and appeared to promote cell aggregation.
      These results suggest that the insulin receptor and its signaling pathways may
      participate in molecular mechanisms mediating annexin II secretion.

PMID- 12431981
TI  - Repression of 92-kDa type IV collagenase expression by MTA1 is mediated through
      direct interactions with the promoter via a mechanism, which is both dependent on
      and independent of histone deacetylation.
AB  - Although the expression of the metastases-associated gene MTA1 correlates with
      tumor metastases, its role in regulating type IV collagenase expression is
      unknown. Enforced MTA1 expression in HT1080 cells reduced basal and 12-myristate
      13-acetate-induced 92-kDa type IV collagenase (MMP-9) protein/mRNA levels. DNase
      I hypersensitivity and PstI accessibility assays revealed multiple regions of the
      MMP-9 promoter (-650/-450 and -120/+1), showing reduced hypersensitivity in the
      MTA1-expressing cells. Chromatin immunoprecipitation assays demonstrated MTA1
      binding to the distal region, which spans several regulatory cis elements. Co
      immunoprecipitation and chromatin immunoprecipitation assay experiments revealed
      histone deacetylase 2 (HDAC2)-MTA1 protein-protein interactions and the MTA1
      dependent recruitment of HDAC2 to the distal MMP-9 promoter region, yielding
      diminished histone H3/H4 acetylation. However, HDAC2 binding and H3/H4
      acetylation at the proximal MMP-9 region were unaffected by MTA1 expression.
      Furthermore, trichostatin treatment only partially relieved MTA1-repressed MMP-9
      expression, indicating a HDAC-insensitive component possibly involv ing the
      nucleosome-remodeling Mi2 activity, which was recruited to the promoter by MTA1.
      In summary, (a) MMP-9 adds to a short list of MTA1-regulated genes, which so far
      only includes c-myc and pS2, and (b) MTA1 binds to the MMP-9 promoter, thereby
      repressing expression of this type IV collagenase via histone-dependent and
      independent mechanisms.

PMID- 12431982
TI  - Mechanisms of regulation of phospholipase D1 by protein kinase Calpha.
AB  - It has been suggested that protein-protein interaction is important for protein
      kinase C (PKC) alpha to activate phospholipase D1 (PLD1). To determine the one or
      more sites on PKCalpha that are involved in binding to PLD1, fragments containing
      the regulatory domain, catalytic domain, and C1-C3 domain of PKCalpha were
      constructed and shown to be functional, but they all failed to bind and activate
      PLD1 in vivo and in vitro. A C-terminal 23-amino acid (aa) deletion mutant of
      PKCalpha was also found to be inactive. To define the binding/activation site(s)
      in the C terminus of PKCalpha, 1- to 11-aa deletion mutants were made in this
      terminus. Deletion of up to 9 aa did not alter the ability of PKCalpha to bind
      and activate PLDl, whereas a 10-aa deletion was inactive. The residue at position
      10 was Phe(663). Mutations of this residue (F663D and F663A) caused loss of
      binding, activation, and phosphorylation of PLD1, indicating that Phe(663) is
      essential for these activities. Time course experiments showed that the
      activation of PLD1 by PMA was much faster than its phosphorylation, and its
      activity decreased as phosphorylation increased with time. Staurosporine, a PKC
      inhibitor, completely inhibited PLD1 phosphorylation in response to 4beta-phorbol
      12-myristate 13-acetate PMA and blocked the later decrease in PLD activity. The
      same results were found with the D481E mutant of PKCalpha, which is unable to
      phosphorylate PLD1. These results indicate that neither the regulatory nor
      catalytic domains of PKCalpha alone can bind to or activate PLD1 and that a
      residue in the C terminus of PKCalpha (Phe(663)) is required for these effects.
      The initial activation of PLD1 by PMA is highly correlated with the binding of
      PKCalpha. Although PKCalpha can phosphorylate PLD1, this is a relatively slow
      process and is associated with inactivation of the enzyme.

PMID- 12431983
TI  - Encapsulation of an 86-kDa assembly intermediate inside the cavities of GroEL and
      its single-ring variant SR1 by GroES.
AB  - We described previously that during the assembly of the alpha(2)beta(2)
      heterotetramer of human mitochondrial branched-chain alpha-ketoacid dehydrogenase
      (BCKD), chaperonins GroEL/GroES interact with the kinetically trapped
      heterodimeric (alphabeta) intermediate to facilitate conversion of the latter to
      the native BCKD heterotetramer. Here, we show that the 86-kDa heterodimeric
      intermediate possesses a native-like conformation as judged by its binding to a
      fluorescent probe 1-anilino-8-naphthalenesulfonate. This large heterodimeric
      intermediate is accommodated as an entity inside cavities of GroEL and its single
      ring variant SR1 and is encapsulated by GroES as indicated by the resistance of
      the heterodimer to tryptic digestion. The SR1-alphabeta-GroES complex is isolated
      as a stable single species by gel filtration in the presence of Mg-ATP. In
      contrast, an unfolded BCKD fusion protein of similar size, which also resides in
      the GroEL or SR1 cavity, is too large to be capped by GroES. The cis-capping
      mechanism is consistent with the high level of BCKD activity recovered with the
      GroEL-alphabeta complex, GroES, and Mg-ATP. The 86-kDa native-like heterodimeric
      intermediate in the BCKD assembly pathway represents the largest protein
      substrate known to fit inside the GroEL cis cavity underneath GroES, which
      significantly exceeds the current size limit of 57 kDa established for unfolded
      proteins.

PMID- 12431984
TI  - Folding of the voltage-gated K+ channel T1 recognition domain.
AB  - Voltage-gated K(+) channels (Kv) are tetramers whose assembly is coordinated in
      part by a conserved T1 recognition domain. Although T1 achieves its quaternary
      structure in the ER, nothing is known about its acquisition of tertiary
      structure. We developed a new folding assay that relies on intramolecular cross
      linking of pairs of cysteines engineered at the folded T1 monomer interface.
      Using this assay, we show directly that the T1 domain is largely folded while the
      Kv protein is still attached to membrane-bound ribosomes. The ER membrane
      facilitates both folding and oligomerization of Kv proteins. We show that folding
      and oligomerization assays can be used to study coupling between these two
      biogenic events and diagnose defects in assembly of Kv channels.

PMID- 12431985
TI  - The hsp90 Co-chaperone XAP2 alters importin beta recognition of the bipartite
      nuclear localization signal of the Ah receptor and represses transcriptional
      activity.
AB  - The mouse aryl hydrocarbon receptor (mAhR) is a ligand-activated transcription
      factor that exists in a tetrameric, core complex with a dimer of the 90-kDa heat
      shock protein, and the hepatitis B virus X-associated protein 2 (XAP2).
      Transiently expressed mAhR-YFP (yellow fluorescent protein fused with the mAhR)
      localizes throughout cells, with a majority occupying nuclei. Co-expression of
      XAP2 with mAhR-YFP results in a distinct redistribution to the cytoplasm. We have
      utilized several approaches to attempt to identify the mechanism by which XAP2
      modulates the sub-cellular localization of the mAhR. The nuclear export
      inhibitor, leptomycin B, was used to demonstrate that XAP2 inhibits ligand
      independent nucleocytoplasmic shuttling of the receptor. Results from
      cytoskeletal disruption and the addition of an alternate nuclear localization
      sequence (NLS) to mAhR-YFP suggest that XAP2 does not physically tether the
      complex in the cytoplasm. The use of a rabbit polyclonal antibody raised against
      a portion of the bipartite NLS of the mAhR revealed that XAP2 does not appear to
      block access to the NLS. However, XAP2 hinders importin beta binding to the mAhR
      complex, suggesting that XAP2 alters the conformation of the bipartite NLS of
      mAhR. XAP2 also represses the transactivation potential of the AhR, in contrast
      to previously published reports, perhaps by stabilizing the receptor complex
      and/or blocking nucleocytoplasmic shuttling of the AhR complex.

PMID- 12431987
TI  - The 3'-untranslated region of p21WAF1 mRNA is a composite cis-acting sequence
      bound by RNA-binding proteins from breast cancer cells, including HuR and poly(C)
      binding protein.
AB  - Despite promoting growth in many cell types, epidermal growth factor (EGF)
      induces growth inhibition in a variety of cancer cells that overexpress its
      receptor. The cyclin-dependent kinase inhibitor p21(WAF1) is a central component
      of this pathway. We found in human MDA-468 breast cancer cells that EGF up
      regulates p21(WAF1) mRNA and protein, through a combination of increased mRNA
      stability and transcription. The decay rate of a hybrid luciferase reporter full
      length p21(WAF1) 3'-untranslated region (UTR) mRNA was significantly faster than
      that of a control mRNA. Transfections with a variety of p21(WAF1) 3'-UTR
      constructs identified multiple cis-acting elements capable of reducing basal
      reporter activity. Short wavelength ultraviolet light induced reporter activity
      in constructs containing the 5' region of the p21(WAF1) 3'-UTR, whereas EGF
      induced reporter activity in constructs containing sequences 3' of the UVC
      responsive region. These cis-elements bound multiple proteins from MDA-468 cells,
      including HuR and poly(C)-binding protein 1 (CP1). Immunoprecipitation studies
      confirmed that HuR and CP1 associate with p21(WAF1) mRNA in MDA-468 cells. Over-
      and underexpression of HuR in MDA-468 cells did not affect EGF-induced p21(WAF1)
      protein expression or growth inhibition. However, binding of HuR to its target 3'
      UTR cis-element was regulated by UVC but not by EGF, suggesting that these
      stimuli modulate the stability of p21(WAF1) mRNA via different mechanisms. We
      conclude that EGF-induced p21(WAF1) protein expression is mediated largely by
      stabilization of p21(WAF1) mRNA elicited via multiple 3'-UTR cis-elements.
      Although HuR binds at least one of these elements, it does not appear to be a
      major modulator of p21(WAF1) expression or growth inhibition in this system. CP1
      is a novel p21(WAF1) mRNA-binding protein that may function cooperatively with
      other mRNA-binding proteins to regulate p21(WAF1) mRNA stability.

PMID- 12431986
TI  - Globular adiponectin protected ob/ob mice from diabetes and ApoE-deficient mice
      from atherosclerosis.
AB  - The adipocyte-derived hormone adiponectin has been shown to play important roles
      in the regulation of energy homeostasis and insulin sensitivity. In this study,
      we analyzed globular domain adiponectin (gAd) transgenic (Tg) mice crossed with
      leptin-deficient ob/ob or apoE-deficient mice. Interestingly, despite an
      unexpected similar body weight, gAd Tg ob/ob mice showed amelioration of insulin
      resistance and beta-cell degranulation as well as diabetes, indicating that
      globular adiponectin and leptin appeared to have both distinct and overlapping
      functions. Amelioration of diabetes and insulin resistance was associated with
      increased expression of molecules involved in fatty acid oxidation such as acyl
      CoA oxidase, and molecules involved in energy dissipation such as uncoupling
      proteins 2 and 3 and increased fatty acid oxidation in skeletal muscle of gAd Tg
      ob/ob mice. Moreover, despite similar plasma glucose and lipid levels on an apoE
      deficient background, gAd Tg apoE-deficient mice showed amelioration of
      atherosclerosis, which was associated with decreased expression of class A
      scavenger receptor and tumor necrosis factor alpha. This is the first
      demonstration that globular adiponectin can protect against atherosclerosis in
      vivo. In conclusion, replenishment of globular adiponectin may provide a novel
      treatment modality for both type 2 diabetes and atherosclerosis.

PMID- 12431988
TI  - Binding of the anticonvulsant drug lamotrigine and the neurotoxin batrachotoxin
      to voltage-gated sodium channels induces conformational changes associated with
      block and steady-state activation.
AB  - Voltage-gated sodium channels are dynamic membrane proteins characterized by
      rapid conformational changes that switch the molecule between closed resting,
      activated, and inactivated states. Sodium channels are specifically blocked by
      the anticonvulsant drug lamotrigine, which preferentially binds to the channel
      pore in the inactivated open state. Batrachotoxin is a lipid-soluble alkaloid
      that causes steady-state activation and binds in the inner pore of the sodium
      channel with overlapping but distinct molecular determinants from those of
      lamotrigine. Using circular dichroism spectroscopy on purified voltage-gated
      sodium channels from Electrophorus electricus, the secondary structures
      associated with the mixture of states present at equilibrium in the absence of
      these ligands were compared with specific stabilized states in their presence. As
      the channel shifts to open states, there appears to be a significant change in
      secondary structure to a more alpha-helical conformation. The observed changes
      are consistent with increased order involving the S6 segments that form the pore,
      the domain III-IV linker, and the P-loops that form the outer pore and
      selectivity filter. A molecular model has been constructed for the sodium channel
      based on its homology with the pore-forming regions of bacterial potassium
      channels, and automated docking of the crystal structure of lamotrigine with this
      model produces a structure in which the close contacts of the drug are with the
      residues previously identified by mutational studies as forming the binding site
      for this drug.

PMID- 12431989
TI  - Transcriptional regulation of mouse delta-opioid receptor gene. Ikaros-2 and
      upstream stimulatory factor synergize in trans-activating mouse delta-opioid
      receptor gene in T cells.
AB  - Considerable evidence indicates that transcription of the delta-opioid receptor
      (dor) gene is correlated with both the expression of DOR on T cells and the
      capacity of DOR agonists to modulate the immunological functions of the T cell.
      We previously reported that increased Ikaros (Ik) binding activity over an Ik
      binding site at -378 to -374 (with the translation start site designated as +1)
      in the mouse dor promoter was required for the enhanced transcription of dor gene
      in phytohemagglutinin-activated EL-4 cells, a mouse T cell line that
      constitutively expresses DOR. In the present study, we have analyzed further the
      mouse dor promoter in EL-4 cells and have demonstrated that Ik-2 homodimers bind
      to the -378/-374 Ik-binding site and exerts a position-dependent trans-activation
      effect on the dor promoter. Moreover, an E box (-185 to -180) that binds upstream
      stimulatory factor is essential for the dor promoter activity in both resting and
      phytohemagglutinin-activated T cells. Furthermore, we have demonstrated that Ik-2
      and upstream stimulatory factor synergize in trans-activating the dor promoter
      via the putative Ik-binding site and the E box, respectively.

PMID- 12431990
TI  - HIV-1 entry into T-cells is not dependent on CD4 and CCR5 localization to
      sphingolipid-enriched, detergent-resistant, raft membrane domains.
AB  - The contribution of raft domains to human immunodeficiency virus (HIV) 1 entry
      was assessed. In particular, we asked whether the CD4 and CCR5 HIV-1 receptors
      need to associate with sphingolipid-enriched, detergent-resistant membrane
      domains (rafts) to allow viral entry into primary and T-cell lines. Based on
      Triton X-100 solubilization and confocal microscopy, CD4 was shown to distribute
      partially to rafts. In contrast, CCR5 did not associate with rafts and localized
      in nonraft plasma membrane domains. HIV-1-receptor partitioning remained
      unchanged upon viral adsorption, suggesting that viral entry probably takes place
      outside rafts. To directly investigate this possibility, we targeted CD4 to
      nonraft domains of the membrane by preventing CD4 palmitoylation and interaction
      with p56(lck). Directed mutagenesis of both targeting signals significantly
      prevented association of CD4 with rafts, but did not suppress the HIV-1 receptor
      function of CD4. Collectively, these results strongly suggest that the presence
      of HIV-1 receptors in rafts is not required for viral infection. We show,
      however, that depleting plasma membrane cholesterol inhibits HIV-1 entry. We
      therefore propose that cholesterol modulates the HIV-1 entry process
      independently of its ability to promote raft formation.

PMID- 12431991
TI  - Tumor necrosis factor-regulated biphasic activation of NF-kappa B is required for
      cytokine-induced loss of skeletal muscle gene products.
AB  - NF-kappaB activation is classically defined as a transient response initiated by
      the degradation of IkappaB inhibitor proteins leading to nuclear import of NF
      kappaB and culminating with the resynthesis of IkappaBalpha and subsequent
      inactivation of the transcription factor. Although this type of regulation is
      considered the paradigm for NF-kappaB activation, other regulatory profiles are
      known to exist. By far the most common of these is chronic or persistent
      activation of NF-kappaB. In comparison, regulation of NF-kappaB in a biphasic
      manner represents a profile that is scarcely documented and whose biological
      significance remains poorly understood. Here we show using differentiated
      skeletal muscle cells, that tumor necrosis factor (TNF) induces NF-kappaB
      activation in a biphasic manner. Unlike the first transient phase, which is
      terminated within 1 h of cytokine addition, the second phase persists for an
      additional 24-36 h. Biphasic activation is mediated at both the levels of NF
      kappaB DNA binding and transactivation function, and both phases are dependent on
      the IKK/26 S proteasome pathway. We find that regulation of the first transient
      phase is mediated by the degradation and subsequent resynthesis of IkappaBalpha,
      as well as by a TNF-induced expression of A20. Second phase activity correlates
      with persistent down-regulation of both IkappaBalpha and IkappaBbeta proteins,
      derived from a continuous TNF signal. Finally, we demonstrate that inhibition of
      NF-kappaB prior to initiation of the second phase of activity inhibits cytokine
      mediated loss of muscle proteins. We propose that the biphasic activation of NF
      kappaB in response to TNF may play a key regulatory role in skeletal muscle
      wasting associated with cachexia.

PMID- 12431992
TI  - Capacitive calcium entry is directly attenuated by mutant presenilin-1,
      independent of the expression of the amyloid precursor protein.
AB  - Mutant presenilin-1 (PS1) increases amyloid peptide production, attenuates
      capacitative calcium entry (CCE), and augments calcium release from the
      endoplasmatic reticulum (ER). Here we measured the intracellular free Ca(2+)
      concentration in hippocampal neurons from six different combinations of
      transgenic and gene-ablated mice to demonstrate that mutant PS1 attenuated CCE
      directly, independent of the expression of the amyloid precursor protein (APP).
      On the other hand, increased Ca(2+) release from the ER in mutant PS1 neurons, as
      induced by thapsigargin, was clearly dependent on the presence of APP and its
      processing by PS1, i.e. on the generation of the amyloid peptides and the APP C99
      fragments. This observation was corroborated by the thapsigargin-induced increase
      in cytosolic [Ca(2+)](i) in PS1 deficient neurons, which accumulate C99 fragments
      due to deficient gamma-secretase activity. Moreover, co-expression of mutant
      APP[V717I] in PS1-deficient neurons further increased the apparent size of the ER
      calcium stores in parallel with increasing levels of the APP processing products.
      We conclude that mutant PS1 deregulates neuronal calcium homeostasis by two
      different actions: (i) direct attenuation of CCE at the cell-surface independent
      of APP; and (ii) indirect increase of ER-calcium stores via processing of APP and
      generation of amyloid peptides and C99 fragments.

PMID- 12431993
TI  - Transcription dependence of chromosomal gene targeting by triplex-forming
      oligonucleotides.
AB  - Triplex-forming oligonucleotides (TFOs) recognize and bind to specific DNA
      sequences and have been used to modify gene function in cells. To study factors
      that might influence triplex formation at chromosomal sites in mammalian cells,
      we developed a restriction protection assay to detect triplex-directed psoralen
      crosslinks in genomic DNA prepared from TFO-transfected cells. Using this assay,
      we detected binding of a G-rich TFO to a chromosomal site even in the absence of
      transcription when high concentrations of the TFO were used for transfection.
      However, experimental induction of transcription at the target site, via an
      ecdysone-responsive promoter, resulted in substantial increases (3-fold or more)
      in target site crosslinking, especially at low TFO concentrations. When RNA
      polymerase activity was inhibited, even in the ecdysone-induced cells, the level
      of TFO binding was significantly decreased, indicating that transcription through
      the target region, and not just transcription factor binding, is necessary for
      the enhanced chromosomal targeting by TFOs. These findings provide evidence that
      physiologic activity at a chromosomal target site can influence its accessibility
      to TFOs and suggest that gene targeting by small molecules may be most effective
      at highly expressed chromosomal loci.

PMID- 12431994
TI  - Essential role of the prion protein N terminus in subcellular trafficking and
      half-life of cellular prion protein.
AB  - Aberrant metabolism and conformational alterations of the cellular prion protein
      (PrP(c)) are the underlying causes of transmissible spongiform encephalopathies
      in humans and animals. In cells, PrP(c) is modified post-translationally and
      transported along the secretory pathway to the plasma membrane, where it is
      attached to the cell surface by a glycosylphosphatidylinositol anchor. In surface
      biotinylation assays we observed that deletions within the unstructured N
      terminus of murine PrP(c) led to a significant reduction of internalization of
      PrP after transfection of murine neuroblastoma cells. Truncation of the entire N
      terminus most significantly inhibited internalization of PrP(c). The same
      deletions caused a significant prolongation of cellular half-life of PrP(c) and a
      delay in the transport through the secretory pathway to the cell surface. There
      was no difference in the glycosylation kinetics, indicating that all PrP
      constructs equally passed endoplasmic reticulum-based cellular quality control.
      Addition of the N terminus of the Xenopus laevis PrP, which does not encode a
      copper-binding repeat element, to N-terminally truncated mouse PrP restored the
      wild type phenotype. These results provide deeper insight into the life cycle of
      the PrP(c), raising the novel possibility of a targeting function of its N
      proximal part by interacting with the secretory and the endocytic machinery. They
      also indicate the conservation of this targeting property in evolution.

PMID- 12431995
TI  - ZIP3, a new splice variant of the PKC-zeta-interacting protein family, binds to
      GABAC receptors, PKC-zeta, and Kv beta 2.
AB  - The correct targeting of modifying enzymes to ion channels and neurotransmitter
      receptors represents an important biological mechanism to control neuronal
      excitability. The recent cloning of protein kinase C-zeta interacting proteins
      (ZIP1, ZIP2) identified new scaffolds linking the atypical protein kinase PKC
      zeta to target proteins. GABA(C) receptors are composed of three rho subunits
      (rho 1-3) that are highly expressed in the retina, where they are clustered at
      synaptic terminals of bipolar cells. A yeast two-hybrid screen for the GABA(C)
      receptor rho 3 subunit identified ZIP3, a new C-terminal splice variant of the
      ZIP protein family. ZIP3 was ubiquitously expressed in non-neuronal and neuronal
      tissues, including the retina. The rho 3-binding region of ZIP3 contained a ZZ
      zinc finger domain, which interacted with 10 amino acids conserved in rho 1-3 but
      not in GABA(A) receptors. Consistently, only rho 1-3 subunits bound to ZIP3. ZIP3
      formed dimers with ZIP1-3 and interacted with PKC-zeta and the shaker-type
      potassium channel subunit Kv beta 2. Different domains of ZIP3 interacted with
      PKC-zeta and the rho 3 subunit, and simultaneous assembly of ZIP3, PKC-zeta and
      rho 3 was demonstrated in vitro. Subcellular co-expression of ZIP3 binding
      partners in the retina supported the proposed protein interactions. Our results
      indicate the formation of a ternary postsynaptic complex containing PKC-zeta,
      ZIP3, and GABA(C) receptors.

PMID- 12431996
TI  - Enhancement of BRCA1 E3 ubiquitin ligase activity through direct interaction with
      the BARD1 protein.
AB  - The breast and ovarian cancer-specific tumor suppressor RING finger protein BRCA1
      has been identified as an E3 ubiquitin (Ub) ligase through in vitro studies,
      which demonstrated that its RING finger domain can autoubiquitylate and
      monoubiquitylate histone H2A when supplied with Ub, E1, and UBC4 (E2). Here we
      report that the E3 ligase activity of the N-terminal 110 amino acid residues of
      BRCA1, which encodes a stable domain containing the RING finger, as well as that
      of the full-length BRCA1, was significantly enhanced by the BARD1 protein
      (residues 8-142), whose RING finger domain itself lacked Ub ligase activity in
      vitro. The results of mutagenesis studies indicate that the enhancement of BRCA1
      E3 ligase activity by BARD1 depends on direct interaction between the two
      proteins. Using K48A and K63A Ub mutants, we found that BARD1 stimulated the
      formation of both Lys(48)- and Lys(63)-linked poly-Ub chains. However, the
      enhancement of BRCA1 autoubiquitylation by BARD1 mostly resulted in poly-Ub
      chains linked through Lys(63), which could potentially activate biological
      pathways other than BRCA1 degradation. We also found that co-expression of BRCA1
      and BARD1 in living cells increased the abundance and stability of both proteins
      and that this depended on their ability to heterodimerize.

PMID- 12431997
TI  - BCL-2 improves oxidative phosphorylation and modulates adenine nucleotide
      translocation in mitochondria of cells harboring mutant mtDNA.
AB  - Members of the BCL-2-related antiapoptotic family of proteins have been shown
      previously to regulate ATP/ADP exchange across the mitochondrial membranes and to
      prevent the loss of coupled mitochondrial respiration during apoptosis. We have
      found that BCL-2/BCL-x(L) can also improve mitochondrial oxidative
      phosphorylation in cells harboring pathogenic mutations in mitochondrial tRNA
      genes. The effect of BCL-2 overexpression in mutated cells was independent from
      apoptosis and was presumably associated with a modulation of adenine nucleotide
      exchange between mitochondria and cytosol. These results suggest that BCL-2 can
      regulate respiratory functions in response to mitochondrial distress by
      regulating the levels of adenine nucleotides.

PMID- 12431998
TI  - Purification, characterization, and in vitro mineralization studies of a novel
      goose eggshell matrix protein, ansocalcin.
AB  - Biomineralization is an important process in which hard tissues are generated
      through mineral deposition, often assisted by biomacromolecules. Eggshells,
      because of their rapid formation via mineralization, are chosen as a model for
      understanding the fundamentals of biomineralization. This report discusses
      purification and characterization of various proteins and peptides from goose
      eggshell matrix. A novel 15-kDa protein (ansocalcin) was extracted from the
      eggshell matrix, purified, and identified and its role in mineralization
      evaluated using in vitro crystal growth experiments. The complete amino acid
      sequence of ansocalcin showed high homology to ovocleidin-17, a chicken eggshell
      protein, and to C-type lectins from snake venom. The amino acid sequence of
      ansocalcin was characterized by the presence of acidic and basic amino acid
      multiplets. In vitro crystallization experiments showed that ansocalcin induced
      pits on the rhombohedral faces at lower concentrations (<50 microg/ml). At higher
      concentrations, the nucleation of calcite crystal aggregates was observed.
      Molecular weight determinations by size exclusion chromatography and sodium
      dodecyl sulfate -polyacrylamide gel electrophoresis showed reversible
      concentration-dependent aggregation of ansocalcin in solution. We propose that
      such aggregated structures may act as a template for the nucleation of calcite
      crystal aggregates. Similar aggregation of calcite crystals was also observed
      when crystallizations were performed in the presence of whole goose eggshell
      extract. These results show that ansocalcin plays a significant role in goose
      eggshell calcification.

PMID- 12432000
TI  - Stroke frequencies of emperor penguins diving under sea ice.
AB  - During diving, intermittent swim stroke patterns, ranging from burst/coast
      locomotion to prolonged gliding, represent potential energy conservation
      mechanisms that could extend the duration of aerobic metabolism and, hence,
      increase the aerobic dive limit (ADL, dive duration associated with onset of
      lactate accumulation). A 5.6 min ADL for emperor penguins had been previously
      determined with lactate measurements after dives of <50 m depth. In order to
      assess locomotory patterns during such dives, longitudinal acceleration was
      measured with an attached accelerometer in 44 dives of seven adult birds diving
      from an isolated dive hole in the sea ice of McMurdo Sound, Antarctica. Detection
      of wing strokes in processed accelerometer data was verified in selected birds
      with analysis of simultaneous Crittercam underwater video footage. Mean dive
      duration of birds equipped with the accelerometer and a time-depth recorder (TDR)
      was 5.7+/-2.2 min; 48% of these dives were greater than the measured 5.6 min ADL
      (ADL(M)). Highest stroke frequencies (0.92+/-0.31 Hz, N=981) occurred during the
      initial descent to 12 m depth. Swimming effort was reduced to a mean stroke
      frequency <0.70 Hz during other phases of the dive (while traveling below 12 m
      depth, during foraging ascents/descents to and from the sub-ice surface, and
      during final ascents to exit). The longest stroke interval (8.6 s) occurred
      during a feeding excursion to the undersurface of the ice. In dives >ADL(M), mean
      stroke frequency during travel segments was significantly less than that in dives
      <ADL(M) (P<0.05). Mean stroke frequency of the entire dive correlated inversely
      (P<0.05) with diving duration (r=-0.67) and with mean dive depth (r=-0.43).
      Emperor penguins did not exhibit any significant (>10 s) periods of prolonged
      gliding during these shallow (<60 m) foraging dives. However, a stroke/glide
      pattern was evident with more than 50% of strokes associated with a stroke
      interval >1.6 s, and with lower stroke frequency associated with increased dive
      duration.

PMID- 12432001
TI  - The ilio-marsupialis muscle in the dasyurid marsupial Sminthopsis douglasi: form,
      function and fibre-type profiles in females with and without suckling young.
AB  - The form, function and fibre-type profiles of the ilio-marsupialis muscles,
      branches of which insert on to the skin of the nipples and pouch, have been
      investigated in the small dasyurid marsupial Sminthopsis douglasi. Single fibres
      from the branches of muscles associated with unsuckled nipples in non-lactating
      females and with both unsuckled and suckled nipples at four stages during the 70
      day suckling period were typed according to their sensitivity to the activators
      strontium (Sr(2+)) and calcium (Ca(2+)) into fast-twitch, slow-twitch and
      composite types. An unusual finding was the predominance of composite fibres in
      the resting state (unsuckled nipples). Changes in fibre-type composition were
      observed during the suckling period and these changes correlated with events in
      the development of the suckling young. Composite fibres declined during the
      suckling period and, at the stage when the young can no longer be accommodated in
      the pouch but must still be carried by the mother while she is foraging, an
      increase in fast-twitch fibres that are associated with dynamic muscular activity
      was seen. Later in the suckling period, when the mammary tissue is greatly
      enlarged but the mother does not carry the young while out feeding, there was an
      increase in the proportion of slow-twitch (fatigue-resistant) fibres. The high
      proportion of fast-twitch fibres present late in the suckling period may be
      associated with vibratory movements that result in the young relinquishing the
      nipples.

PMID- 12432002
TI  - Rotational lift: something different or more of the same?
AB  - This paper addresses the question, do the rotational forces in the hovering fruit
      fly Drosophila melanogaster reflect something different (the Magnus effect) or
      more of the same (circulatory-and-attached-vortex force)? The results of an
      unsteady blade-element model using empirically derived force coefficients from
      translating (root-oscillating) wings are compared with recent results derived
      from both the measured forces on a dynamically scaled Drosophila wing and the
      computational fluid dynamic (CFD)-modeled forces on a virtual Drosophila wing.
      The behavior of the forces in all three models during wing rotation supports the
      hypothesis that rotational lift is not a novel aerodynamic mechanism but is
      caused by the same fluid-dynamic mechanism that occurs during wing translation. A
      comparison of the unsteady model with a quasi-steady model that employs
      empirically derived rotational coefficients further supports the hypothesis that
      rotational forces are more of the same. Finally, the overall similarity of the
      results between the unsteady model, the physical wing model and the CFD model
      suggests that the unsteady model can be used to explore the performance
      consequences of kinematic variation and to investigate locomotor control in
      freely moving animals.

PMID- 12432003
TI  - Localisation of an acoustic signal in a noisy environment: the display call of
      the king penguin Aptenodytes patagonicus.
AB  - King penguin chicks identify their parents by an acoustic signal, the display
      call. This call consists of a succession of similar syllables. Each syllable has
      two harmonic series, strongly modulated in frequency and amplitude, with added
      beats of varying amplitude generated by a two-voice system. Previous work showed
      that only one syllable of the call is needed for the chick to identify the
      calling adult. Both the frequency modulation pattern of the syllable and the two
      voice system play a role in the call identification. The syllabic organisation of
      the call, the harmonic structure and the amplitude modulations of the syllables
      apparently do not contribute to individual recognition. Are these acoustic
      features useless? To answer to this question, playback experiments were conducted
      using three categories of experimental signals: (i) signal with only the
      fundamental frequencies of the natural call, (ii) signal with the amplitude of
      each syllable kept at a constant level and (iii) signals with only one syllable,
      repeated or not. The responses of chicks to these experimental signals were
      compared to those obtained with the calls of their natural parents. We found that
      these acoustic features, while not directly implicated in the individual
      recognition process, help the chicks to better localise the signal of their
      parents. In addition, the redundant syllabic organisation of the call is a means
      of counteracting the masking effect of the background noise of the colony.

PMID- 12432004
TI  - The Dh gene of Drosophila melanogaster encodes a diuretic peptide that acts
      through cyclic AMP.
AB  - Dh, the gene that encodes a CRF-like peptide in Drosophila melanogaster, is
      described. The product of this gene is a 44-amino-acid peptide (Drome-DH(44))
      with a sequence almost identical to the Musca domestica and Stomoxys calcitrans
      diuretic hormones. There are no other similar peptides encoded within the known
      Drosophila genomic sequence. Functional studies showed that the deduced peptide
      stimulated fluid production, and that this effect was mediated by cyclic AMP in
      principal cells only: there was no effect on the levels of either cyclic GMP or
      intracellular calcium. Stimulation also elevated levels of cyclic AMP (but not
      cyclic GMP) phosphodiesterase, a new mode of action for this class of hormone.
      The transcript was localised by in situ hybridisation, and the peptide by
      immunocytochemistry, to two groups of three neurones in the pars intercerebralis
      within the brain. These cells also express receptors for leucokinin, another
      major diuretic peptide, implying that the cells may be important in homeostatic
      regulation.

PMID- 12432005
TI  - Epithelial interactions in Hydra: apoptosis in interspecies grafts is induced by
      detachment from the extracellular matrix.
AB  - Apoptosis plays an important role in immunity and is widely used to eliminate
      foreign or infected cells. Cnidaria are the most basal eumetazoans and have no
      specialised immune cells, but some colonial cnidarians possess a genetic system
      to discriminate between self and non-self. By grafting epithelia of different
      species we have previously shown that the freshwater polyp Hydra eliminates non
      self cells by phagocytosis. Here we have investigated whether apoptosis is
      involved in the histocompatibility reactions. We studied epithelial interactions
      between Hydra vulgaris and Hydra oligactis and show that a large number of
      apoptotic cells accumulate in the contact region of interspecies grafts.
      Histological analysis of the graft site revealed that displacement of the
      endodermal layer of Hydra vulgaris by endoderm from Hydra oligactis coincided
      with impaired cell-cell and cell-matrix contacts. We therefore suggest that in
      interspecies grafts, apoptosis is induced by the detachment of epithelial cells
      from the extracellular matrix (anoikis) and not by a discriminative
      allorecognition system.

PMID- 12432006
TI  - The notochord of hagfish Myxine glutinosa: visco-elastic properties and
      mechanical functions during steady swimming.
AB  - To determine the possible locomotor functions of the hagfish notochord, we
      measured its flexural stiffness EI (N m(-2)) and flexural damping C (kg m(3) s(
      1)), under in vitro conditions that mimicked the body curvature and bending
      frequency measured during steady undulatory swimming. To assess the notochord's
      contribution to the mechanical behavior of the whole body, we also measured EI
      and C of the whole body, the body with skin removed, and the notochord with the
      outer fibrous sheath removed. When subjected to dynamic bending at angular
      frequencies from pi to 6pi rad s(-1) and midline curvatures from 11 to 40 m(-1),
      1 cm in situ body segments (N=4), located at an axial position of 37% of the body
      length, showed significant changes in EI, C, the Young's modulus or material
      stiffness (E, MPa), the net work to bend the body over a cycle (W, J) and
      resilience (R, % energy return). When skin, muscles and the outer fibrous sheath
      of the notochord were removed sequentially, each structural reduction yielded
      significant changes in mechanical properties: C decreased when the skin was
      removed, E increased when the muscles were removed, and EI and R decreased when
      the outer fibrous sheath was removed. Although occupying only a small portion of
      the cross-sectional area, the notochord provides the body with 75% of its total
      EI and 80% of total C, by virtue of its high E, ranging from 4 to 8 MPa, which is
      an order of magnitude greater than that of the whole body. Thus, as the body's
      primary source of EI and C, the notochord determines the passive (i.e. internal,
      non-muscular) mechanical behavior of the swimming hagfish. EI and C covary
      inversely and non-linearly such that as C increases, EI decreases. However, the
      bending moments M (Nm) produced by each property increase proportionally, and the
      ratio of stiffness to damping moments, also known as the amplification ratio at
      resonance, is nearly invariant (approximately 7) with changes in driving
      frequency. If the body operates in life at or near resonance, the variables EI
      and C interact over a range of swimming speeds to produce passive mechanical
      stability.

PMID- 12432007
TI  - How the viewing of familiar landscapes prior to release allows pigeons to home
      faster: evidence from GPS tracking.
AB  - Providing homing pigeons with a 5 min preview of the landscape at familiar sites
      prior to release reliably improves the birds' subsequent homing speeds. This
      phenomenon has been taken to suggest that the visual panorama is involved in
      familiar-site recognition, yet the exact nature of the improvement has never been
      elucidated. We employed newly developed miniature Global Positioning System (GPS)
      tracking technology to investigate how access to visual cues prior to release
      affects pigeons' flight along the length of the homing route. By applying a
      variety of novel analytical techniques enabled by the high-resolution GPS data
      (track efficiency, virtual vanishing bearings, orientation threshold), we
      localised the preview effect to the first 1000 m of the journey. Birds denied
      preview of a familiar landscape for 5 min before take-off flew an initially more
      tortuous path, including a high incidence of circling, possibly as part of an
      information-gathering strategy to determine their position. Beyond the first 1000
      m, no differences were found in the performance of birds with or without preview.
      That the effect of the visual treatment was evident only in the early part of the
      journey suggests that lack of access to visual cues prior to release does not
      result in a non-specific effect on behaviour that is maintained throughout the
      flight. Instead, it seems that at least some decisions regarding the direction of
      home can be made prior to release and that such decisions are delayed if visual
      access to the landscape is denied. Overall, the variety of approaches applied
      here clearly highlight the potential for future applications of GPS tracking
      technology in navigation studies.

PMID- 12432008
TI  - Magnetic compass orientation in European robins is dependent on both wavelength
      and intensity of light.
AB  - Magnetic compass orientation in birds has been shown to be light dependent.
      Results from behavioural studies indicate that magnetoreception capabilities are
      disrupted under light of peak wavelengths longer than 565 nm, and shifts in
      orientation have been observed at higher light intensities (43-44x10(15) quanta
      s(-1) m(-2)). To investigate further the function of the avian magnetic compass
      with respect to wavelength and intensity of light, we carried out orientation
      cage experiments with juvenile European robins, caught during their first autumn
      migration, exposed to light of 560.5 nm (green), 567.5 nm (green-yellow) and 617
      nm (red) wavelengths at three different intensities (1 mW m(-2), 5 mW m(-2) and
      10 mW m(-2)). We used monochromatic light of a narrow wavelength range (half
      bandwidth of 9-11 nm, compared with half bandwidths ranging between 30 nm and 70
      nm used in other studies) and were thereby able to examine the magnetoreception
      mechanism in the expected transition zone between oriented and disoriented
      behaviour around 565 nm in more detail. We show (1) that European robins show
      seasonally appropriate migratory directions under 560.5 nm light, (2) that they
      are completely disoriented under 567.5 nm light under a broad range of
      intensities, (3) that they are able to orient under 617 nm light of lower
      intensities, although into a direction shifted relative to the expected migratory
      one, and (4) that magnetoreception is intensity dependent, leading to
      disorientation under higher intensities. Our results support the hypothesis that
      birds possess a light-dependent magnetoreception system based on magnetically
      sensitive, antagonistically interacting spectral mechanisms, with at least one
      high-sensitive short-wavelength mechanism and one low-sensitive long-wavelength
      mechanism.

PMID- 12432009
TI  - Effects of waterborne exposure of octylphenol and oestrogen on pregnant
      viviparous eelpout (Zoarces viviparus) and her embryos in ovario.
AB  - Exposure to oestrogenic chemicals (xeno-oestrogens) may have severe effects on
      embryonic development. The present study investigates whether the oestrogenic
      endocrine disruptor 4-tert-octylphenol (4-tOP) or 17beta-oestradiol (E(2)) is
      accumulated in the viviparous fish the eelpout (Zoarces viviparus) and
      transferred to the embryos in ovario and subsequently affects embryonic
      development, including gonadal differentiation. Pregnant eelpouts were exposed to
      nominal concentrations of 25 micro gl(-1) or 100 micro gl(-1) 4-tOP (OP25 or
      OP100, respectively) or 0.5 micro gl(-1) E(2) in water. During 4-tOP exposure,
      the compound accumulated in both plasma and ovarian fluid in a concentration
      dependent manner. In the mother fish, the oestrogenic biomarkers, vitellogenin
      (Vtg) in plasma, Vtg mRNA in liver and oestrogen-binding activity in liver, were
      all induced by 4-tOP (and by E(2)) at an actual concentration of 14 micro gl(-1).
      E(2) and 4-tOP were examined for their potency to disturb the maternal-foetal
      trophic relationship by disturbing the physiology of the ovary and by changing
      the distribution of essential nutrients normally transported to embryos during
      pregnancy. After exposure to E(2) or 4-tOP, calcium was depleted from the ovarian
      fluid and the level of free amino acids available in maternal plasma was
      decreased. A marked overall effect on ovarian components, including the ovarian
      sac, ovarian fluid and embryonic mass, was evident. Embryonic growth was
      significantly decreased, which might in part be attributed to disturbances of the
      maternal-foetal trophic relationship. Marked inductions of Vtg mRNA and Vtg
      protein, determined by RT-PCR and immunohistochemistry, respectively, were found
      in embryos from the OP100 group - the only group to show considerable
      accumulation of an oestrogenic compound in the ovarian fluid. A different pattern
      of gonadal development was found in embryos from the OP100 group compared with
      embryos from the control, OP25 or E(2) groups, in which approximately 50% had
      normal ovaries and 50% had normal presumptive male gonads. In the OP100 group,
      46% had normal ovaries but, in contrast to controls, only 22% had normal
      presumptive male gonads, whereas the remaining 32% had abnormal male gonads with
      structures resembling the endo-ovarian cavity of a female gonad. As oestrogen
      receptor (ER) expression was detected by in situ hybridisation in early
      differentiating gonads, these effects could be mediated by direct interaction of
      the xeno-oestrogens with gonadal ER. In conclusion, this study indicates that the
      xeno-oestrogen 4-tOP can be transferred from the water via the mother fish to the
      ovarian fluid and can subsequently disturb the maternal-foetal trophic
      relationship and cause severe effects on embryonic development, including gonadal
      differentiation in ovario.

PMID- 12432010
TI  - The relationship between maximum jumping performance and hind limb
      morphology/physiology in domestic cats (Felis silvestris catus).
AB  - A critical role of functional morphology is to demonstrate form-function
      relationships that can then be used by evolutionary biologists to infer the
      evolutionary history of the structure in question. Tests of theoretical
      expectations about the effects of many aspects of morphology/physiology on
      locomotor performance have had very mixed results. If systems such as jumping can
      be shown to reliably predict performance from morphology, this would provide a
      foundation upon which hypotheses for the evolutionary origin of certain
      morphologies can be generated. The present study examined whether a relationship
      exists between maximum takeoff velocity (TOV) and several carefully chosen
      morphological and physiological traits in domestic cats (Felis silvestris catus).
      Based on the contributions of extensor muscle work to increasing the kinetic and
      potential energy of the center of mass (CM) during takeoff, we predicted that
      maximum TOV would be dependent upon relative limb length, relative extensor
      muscle mass, body mass and the percentage of fast-twitch muscle fibers. Both
      maximum TOV and this series of traits were measured in 18 cats. We found that
      variation in cat maximum TOV is significantly explained by both hind limb length
      and fat mass relative to lean body mass, but not by extensor muscle mass relative
      to lean mass or fast-twitch fiber content. The effect of body fat mass is
      pervasive because it reduces the proportion of muscle mass/body mass and thus
      increases the muscle work invested in increasing the CM potential energy as
      compared with kinetic energy during takeoff.

PMID- 12432011
TI  - Two sniffing strategies in palinurid lobsters.
AB  - Most studies of lobster chemoreception have focused on the model systems of
      Panulirus argus (Palinuridae) and Homarus americanus (Nephropidae). We compare
      antennule morphology across lobsters and conduct the first kinematic study of
      antennule flicking in a palinurid species other than P. argus. High-speed video
      analysis shows that Palinurus elephas flicks at a rate more than an order of
      magnitude higher than in P. argus. However, both species flick their antennular
      flagella at a Reynolds number (Re) of approximately one, such that an asymmetry
      in the speed of the flick phases causes both species to have a leaky closing
      flick phase and a non-leaky opening phase. The antennular flagella of P. argus
      are nearly seven times longer than those of P. elephas, and, when compared across
      palinurid genera, Panulirus species sample far greater areas of water over
      greater spatial and time scales than do any other palinurid genera. Palinurid
      lobsters appear to have two sniffing strategies: low flick rates over a large
      area of water (e.g. P. argus) or high flick rates over a small area of water
      (e.g. P. elephas). P. argus is a highly informative model system in which to
      study aquatic chemoreception; however, its antennule anatomy and kinematics
      suggest a separate strategy, unique to Panulirus species, for sensing chemical
      plumes in fluid environments.

PMID- 12432012
TI  - 'Fixed-axis' magnetic orientation by an amphibian: non-shoreward-directed compass
      orientation, misdirected homing or positioning a magnetite-based map detector in
      a consistent alignment relative to the magnetic field?
AB  - Experiments were carried out to investigate the earlier prediction that prolonged
      exposure to long-wavelength (>500 nm) light would eliminate homing orientation by
      male Eastern red-spotted newts Notophthalmus viridescens. As in previous
      experiments, controls held in outdoor tanks under natural lighting conditions and
      tested in a visually uniform indoor arena under full-spectrum light were homeward
      oriented. As predicted, however, newts held under long-wavelength light and
      tested under either full-spectrum or long-wavelength light (>500 nm) failed to
      show consistent homeward orientation. The newts also did not orient with respect
      to the shore directions in the outdoor tanks in which they were held prior to
      testing. Unexpectedly, however, the newts exhibited bimodal orientation along a
      more-or-less 'fixed' north-northeast-south-southwest magnetic axis. The
      orientation exhibited by newts tested under full-spectrum light was
      indistinguishable from that of newts tested under long-wavelength light, although
      these two wavelength conditions have previously been shown to differentially
      affect both shoreward compass orientation and homing orientation. To investigate
      the possibility that the 'fixed-axis' response of the newts was mediated by a
      magnetoreception mechanism involving single-domain particles of magnetite,
      natural remanent magnetism (NRM) was measured from a subset of the newts. The
      distribution of NRM alignments with respect to the head-body axis of the newts
      was indistinguishable from random. Furthermore, there was no consistent
      relationship between the NRM of individual newts and their directional response
      in the overall sample. However, under full-spectrum, but not long-wavelength,
      light, the alignment of the NRM when the newts reached the 20 cm radius criterion
      circle in the indoor testing arena (estimated by adding the NRM alignment
      measured from each newt to its magnetic bearing) was non-randomly distributed.
      These findings are consistent with the earlier suggestion that homing newts use
      the light-dependent magnetic compass to align a magnetite-based 'map detector'
      when obtaining the precise measurements necessary to derive map information from
      the magnetic field. However, aligning the putative map detector does not explain
      the fixed-axis response of newts tested under long-wavelength light. Preliminary
      evidence suggests that, in the absence of reliable directional information from
      the magnetic compass (caused by the 90 degrees rotation of the response of the
      magnetic compass under long-wavelength light), newts may resort to a systematic
      sampling strategy to identify alignment(s) of the map detector that yields
      reliable magnetic field measurements.

PMID- 12432013
TI  - Landmark use and development of navigation behaviour in the weakly electric fish
      Gnathonemus petersii (Mormyridae; Teleostei).
AB  - African mormyrids, such as Gnathonemus petersii, migrate: nocturnally, from
      daytime shelters to find food and return by morning, and seasonally, spawning in
      swamps flooded during the rainy season. The present study examined whether the
      fish use landmarks detected via electrolocation to locate an aperture, whether
      they detect changes in landmark size and respond appropriately, whether landmarks
      or hydrostatic pressure are the primary cues for navigation and whether fish of
      different developmental stages behave differently with respect to landmarks and
      navigation. The fish's task was to locate and swim through a circular aperture in
      a wall dividing an aquarium into two compartments. Two groups of fish were
      trained to find the aperture with a landmark present, while a control group had
      no such landmark. The water level remained constant throughout training. At the
      end of training, the fish's task was to locate the aperture after the landmark
      size had changed or the water level had increased. The results show that G.
      petersii use landmarks to orient and navigate. They can detect changes in
      landmark size and will modify their locomotor behaviour to integrate the change
      into an internal representation. If the water level changes, increasing
      hydrostatic pressure, the fish orient to a landmark, if present. If no landmark
      is present, the fish rely on an internal representation oriented to hydrostatic
      pressure. Larger, early-adult G. petersii located the aperture faster than
      smaller, sub-adult fish.

PMID- 12432014
TI  - Vision in the peafowl (Aves: Pavo cristatus).
AB  - The visual sense of the Indian blue-shouldered peafowl Pavo cristatus was
      investigated with respect to the spectral absorption characteristics of the
      retinal photoreceptors, the spectral transmittance of the ocular media and the
      topographic distribution of cells in the retinal ganglion cell layer.
      Microspectrophotometry revealed a single class of rod, four spectrally distinct
      types of single cone and a single class of double cone. In the case of the single
      cone types, which contained visual pigments with wavelengths of maximum
      absorbance (lambda(max)) at 424, 458, 505 and 567 nm, spectral filtering by the
      ocular media and the different cone oil droplets with which each visual pigment
      is associated gives predicted peak spectral sensitivities of 432, 477, 537 and
      605 nm, respectively. Topographic analysis of retinal ganglion cell distribution
      revealed a large central area of increased cell density (at peak, 35,609 cells
      mm(-2)) with a poorly defined visual streak extending nasally. The peafowl has a
      calculated maximum spatial resolution (visual acuity) in the lateral visual field
      of 20.6 cycles degrees(-1). These properties of the peafowl eye are discussed
      with respect to its visual ecology and are compared with those of other closely
      related species.

PMID- 12432015
TI  - Hyperpnea training attenuates peripheral chemosensitivity and improves cycling
      endurance.
AB  - Well-trained endurance athletes frequently have a lower peripheral chemoreceptor
      (pR(c)) sensitivity and a lower minute ventilation (E) during exercise compared
      to untrained individuals. We speculated that the decreased pR(c) response may be
      specifically associated with repeated exposure to the high rates of ventilation
      occurring during exercise training. We therefore examined the effect of
      respiratory muscle training (RMT; 20x 30 min sessions of voluntary normocapnic
      hyperpnea) on the pR(c) sensitivity during exercise and on cycling performance.
      RMT was chosen to achieve a high E, similar to that of heavy exercise, while
      avoiding the other accompanying effects of whole body exercise. 20 trained male
      cyclists were randomized into RMT (N=10) or control (N=10) groups. Subjects'
      pR(c) response was assessed by a modified Dejours O(2) test (10-12 breaths of
      100% O(2), repeated 4-6 times) during cycling exercise at 40% of the maximal work
      capacity ((max)). Cycling performance was measured during a cycling test to
      exhaustion (85% (max)). The RMT group exhibited a significantly reduced pR(c)
      sensitivity (mean +/- S.D.) compared to the control group (-5.8+/-6.0% versus
      0.1+/-4.6%, P<0.5). Cycling endurance improved significantly after RMT in
      comparison to the control group (+3.26+/-4.98 versus -1.46+/-3.67 min, P<0.05).
      However, these changes in pR(c) response were not significantly correlated with
      exercise ventilation or cycling endurance time. We conclude that the high levels
      of ventilation achieved during exercise, as simulated by RMT in this study,
      appear to be accompanied by a reduction in pR(c) sensitivity; however, the role
      of the pR(c) in the control of ventilation during exercise seems to be minor.

PMID- 12432016
TI  - Oxygen uptake during post dive recovery in a diving bird Aythya fuligula:
      implications for optimal foraging models.
AB  - The rate of oxygen uptake at the surface between dives was measured for four
      tufted ducks, Aythya fuligula, during bouts of foraging dives to a depth of 1.8
      m. The ducks surfaced into a respirometer box after each dive so that the rate of
      oxygen uptake ((O(2))) could be measured. (O(2)) decreased over time at the
      surface and there was a particularly rapid phase of oxygen uptake for
      approximately the first 3s. The specific shape of the oxygen uptake curve is
      dependent upon the duration of the preceding dive. The uptake curve after longer
      dives was significantly steeper during the first 3s at the surface than after
      shorter dives, although (O(2)) after the first 3s was not significantly different
      between these two dive duration bins. Thus, the mean total oxygen uptake
      (V(O(2))) was higher after surface periods following longer dives. Due to the
      high (O(2)) during the initial part of the surface period, the curve associated
      with longer dives was statistically biphasic, with the point of inflection at
      3.3s. The curve for shorter dives was not statistically biphasic. The birds may
      increase their respiratory frequency during the first 3s after longer dives,
      producing the increased (O(2)), which would enable the birds to resaturate their
      oxygen stores more rapidly in response to the increased oxygen depletion of the
      longer submergence time.

PMID- 12432017
TI  - Effects of intestinal nematodes during lactation: consequences for host
      morphology, physiology and offspring mass.
AB  - Sublethal parasites are often assumed to have no detrimental effects on their
      host. However, the sublethal intestinal nematode Heligmosomoides polygyrus
      affects both the morphology and the physiology of its laboratory mouse (Mus
      musculus) host and therefore has the potential to affect host life history. The
      objectives of the present study were to determine (1) whether lactating and non
      lactating mice responded similarly to experimental infection with H. polygyrus
      and (2) whether the changes in morphology and physiology that occurred with
      parasite infection affected host reproductive performance. Parasitized mice had
      greater whole body mass as a result of greater lean mass compared with
      unparasitized mice. Parasitized mice had larger organs (spleen, stomach, cecum
      and small intestine) and a diminished rate of glucose transport by the small
      intestine compared with unparasitized mice. Lactating mice had larger organs
      (liver, kidney, spleen, heart, stomach, large intestine, cecum and small
      intestine), lean mass and whole body mass, but a similar rate of glucose
      transport compared with virgin mice. Resting metabolism increased with lactation
      but not with parasitism. Lactating and non-lactating mice responded similarly to
      parasite infection for most measured variables. Production of large litters was
      followed by production of small litters for parasitized but not unparasitized
      females. After adjusting for parity and litter size, parasitized mothers produced
      female pups that were 6% smaller at weaning than female pups from unparasitized
      mothers, but there was no effect of maternal parasite infection on mass at
      weaning for male pups. Other measures of reproductive output were not affected by
      parasite infection.

PMID- 12432018
TI  - Maternal and direct effects of the intestinal nematode Heligmosomoides polygyrus
      on offspring growth and susceptibility to infection.
AB  - The laboratory mouse (Mus musculus) has a naturally occurring intestinal nematode
      (Heligmosomoides polygyrus) that induces an immune response, causes phenotypic
      plasticity in metabolism and in organ structure and function, and results in
      changes in host reproductive output. The objectives of the present study were to
      determine (1) whether pups infected with parasites at weaning grew differently
      and had a different body composition at adulthood compared with uninfected pups,
      (2) whether offspring from parasitized mothers grew differently and had a
      different body composition at adulthood compared with offspring from
      unparasitized mothers, (3) whether parasite effects on body composition of pups
      varied under different infection intensities and (4) whether maternal parasite
      infection affected susceptibility, duration and intensity of offspring parasite
      infection. H. polygyrus had direct and maternal effects on offspring growth, but
      final adult mass was not affected by parasites. Parasite infection in offspring
      had no effect on overall fat mass, but mass changes for some organs were greater
      for mice that had a high infection intensity compared with mice that had a low
      infection intensity. Only offspring from parasitized mothers cleared their
      parasite infection; however, if the infection was not cleared, the final
      infection intensity was greater for offspring born to parasitized mothers than to
      unparasitized mothers. This study shows that chronic, sublethal parasite
      infection with H. polygyrus has both maternal and direct effects that induce
      physiological changes in growing mice sufficient to alter host growth
      trajectories, morphology and susceptibility to parasite infection.

PMID- 12432019
TI  - Levamisole receptor phosphorylation: effects of kinase antagonists on membrane
      potential responses in Ascaris suum suggest that CaM kinase and tyrosine kinase
      regulate sensitivity to levamisole.
AB  - A two-micropipette current-clamp technique was used to record
      electrophysiological responses from the somatic muscle of Ascaris suum.
      Levamisole and acetylcholine were applied to the bag region of the muscle using a
      microperfusion system. Depolarizations produced by 10 s applications of 10 micro
      mol l(-1) levamisole or 20 s applications of 10 micro mol l(-1) acetylcholine
      were recorded. The effect on the peak membrane potential change of the kinase
      antagonists H-7, staurosporine, KN-93 and genistein was observed. H-7 (30 micro
      mol l(-1)), a non-selective antagonist of protein kinases A, C and G but which
      has little effect on Ca(2+)/calmodulin-dependent kinase II (CaM kinase II), did
      not produce a significant effect on the peak response to levamisole or
      acetylcholine. Staurosporine (1 micro mol l(-1)), a non-selective kinase
      antagonist that has effects on protein kinases A, C and G, CaM kinase and
      tyrosine kinase, reduced the mean peak membrane potential response to levamisole
      from 6.8 mV to 3.9 mV (P<0.0001) and the mean response to acetylcholine from 5.5
      mV to 2.8 mV (P=0.0016). The difference between the effects of H-7 and
      staurosporine suggested the involvement of CaM kinase II and/or tyrosine kinase.
      KN-93, a selective CaM kinase II antagonist, reduced the mean peak response to
      levamisole from 6.2 mV to 2.7 mV (P=0.035) and the mean peak response of
      acetylcholine from 4.7 mV to 2.0 mV (P=0.0004). The effects indicated the
      involvement of CaM kinase II in the phosphorylation of levamisole and
      acetylcholine receptors. The effect of extracellular Ca(2+) on the response to
      levamisole was assessed by comparing responses to levamisole in normal and in low
      Ca(2+) bathing solutions. The response to levamisole was greater in the presence
      of Ca(2+), an effect that may be explained by stimulation of CaM kinase II.
      Genistein (90 micro mol l(-1)), a selective tyrosine kinase antagonist, reduced
      peak membrane potential responses to levamisole from a mean of 6.4 mV to 3.3 mV
      (P=0.001). This effect indicated the involvement of tyrosine kinase in
      maintaining the receptor.

PMID- 12432021
TI  - Plant culture: thirteen seasonal pieces. Introduction--plenty has made us poor.

PMID- 12432020
TI  - Electrospray ionisation mass spectrometric analysis of lipid restructuring in the
      carp (Cyprinus carpio L.) during cold acclimation.
AB  - Cold acclimation of carp from 30 degrees C to 10 degrees C causes a restructuring
      of liver microsomal phospholipids characterised by increased proportions of
      monounsaturated fatty acid in phosphatidylcholine (PC) and
      phosphatidylethanolamine (PE). Here, we have used electrospray ionisation mass
      spectrometry (ESI-MS) to determine the patterns of alteration to individual
      molecular species compositions of PC, PE and phosphatidylinositol (PI) in
      response to gradually decreasing temperature. The results demonstrate that cold
      induces precise changes to a limited number of phospholipid species, and that
      these changes are distinct and different for each phospholipid class. The major
      change for PC was increased 16:1/22:6, but for PE the species that increased was
      18:1/22:6. By contrast, the PI species that increased during cold acclimation
      were characterised by an sn-1 monounsaturated fatty acid in combination with
      arachidonoyl or eicosapentaenoyl fatty acid at the sn-2 position. Analysis of
      acyl distribution indicates that cold only caused the accumulation of
      monounsaturated fatty acids at the sn-1 and not at the sn-2 position of
      phospholipids. These results highlight the tight and restricted range of
      modifications that membranes make to their phospholipid composition in response
      to thermal stress.

PMID- 12432022
TI  - Generation and possible roles of NO in plant roots and their apoplastic space.
AB  - In recent years, three different enzymatic pathways and a few non-enzymatic
      reactions have been proposed for the generation of NO in plant roots. Two of the
      enzymatic pathways are located in the cytosol of the plant cells, whereas the
      third is exclusively located in the root plasma membrane facing the apoplast from
      where it seems to interact with nitrate metabolism by producing signals. A
      response of the NO pathways to external nitrate concentrations by preventing
      excess nitrate nutrition, particularly in the apoplast, as well as a regulatory
      role in root morphogenesis of NO in interaction with plant hormones is suggested.
      Other functions of NO, those in stimulating plant defence reactions against
      pathogens and against abiotic stress are reported. In addition to enzymatic NO
      formation by the plant, sources of NO in the soil, and hence in the rhizosphere
      from bacterial nitrification and denitrification, are discussed in view of their
      possible interaction with the plant roots. A synoptical perspective is given on
      the assumed roles of apoplastic NO in plant roots, based upon known facts and
      with some assumptions about the gaps in current knowledge.

PMID- 12432023
TI  - Utilization of glycine and serine as nitrogen sources in the roots of Zea mays
      and Chamaegigas intrepidus.
AB  - Glycine and serine are potential sources of nitrogen for the aquatic resurrection
      plant Chamaegigas intrepidus Dinter in the rock pools that provide its natural
      habitat. The pathways by which these amino acids might be utilized were
      investigated by incubating C. intrepidus roots and maize (Zea mays) root tips
      with [(15)N]glycine, [(15)N]serine and [2-(13)C]glycine. The metabolic fate of
      the label was followed using in vivo NMR spectroscopy, and the results were
      consistent with the involvement of the glycine decarboxylase complex (GDC) and
      serine hydroxymethyltransferase (SHMT) in the utilization of glycine. In
      contrast, the labelling patterns provided no evidence for the involvement of
      serine:glyoxylate aminotransferase in the metabolism of glycine by the root
      tissues. The key observations were: (i) the release of [(15)N]ammonium during
      [(15)N]-labelling experiments; and (ii) the detection of a characteristic set of
      serine isotopomers in the [2-(13)C]glycine experiments. The effects of
      aminoacetonitrile, amino-oxyacetate, and isonicotinic acid hydrazide, all of
      which inhibit GDC and SHMT to some extent, and of methionine sulphoximine, which
      inhibited the reassimilation of the ammonium, supported the conclusion that GDC
      and SHMT were essential for the metabolism of glycine. C. intrepidus was observed
      to metabolize serine more readily than the maize root tips and this may be an
      adaptation to its nitrogen-deficient habitat. Overall, the results support the
      emerging view that GDC is an essential component of glycine catabolism in non
      photosynthetic tissues.

PMID- 12432024
TI  - Using array hybridization to monitor gene expression at the single cell level.
AB  - Advances in high-throughput genome sequencing demand the development of more
      efficient ways of examining gene expression at a cellular level. During recent
      years, polymerase chain reaction (PCR)-based methods have been developed that
      allow the amplification of mRNA from small amounts of material, even from single
      animal cells. In parallel, several analytical tools permit a global monitoring of
      gene expression. To date, high throughput analysis methods have not been
      accessible for single plant cell samples. In the protocol described here, cDNA
      array hybridization (expression profiling) and an amplification strategy using
      reverse transcriptase PCR are merged with high spatial resolution sampling from
      undamaged plant tissue. This protocol gives us a new tool to examine tissue
      specific gene expression patterns on a comprehensive scale. To demonstrate the
      usefulness of this tool, gene expression patterns in samples from Arabidopsis
      thaliana L. cv. C24 leaf epidermal and mesophyll cells were measured; several
      differentially expressed genes were identified when single cell samples were
      compared. The protocol described has the potential of increasing the efficiency
      of tissue-specific expression analysis by combining high-throughput profiling
      with straightforward sampling and amplification procedures.

PMID- 12432025
TI  - The novel ethylene-regulated gene OsUsp1 from rice encodes a member of a plant
      protein family related to prokaryotic universal stress proteins.
AB  - Using subtractive hybridization a submergence-induced gene was identified from
      deepwater rice, OsUsp1, that encodes a homologue of the bacterial universal
      stress protein family. Sequence analysis revealed that OsUSP1 is most closely
      related to the bacterial MJ0577-type of ATP-binding USP proteins which have been
      suggested to act as a molecular switch. USP protein homologues appear to be
      ubiquitous in plants and are encoded by gene families, but are absent in animal
      species. In the youngest internode of deepwater rice plants, OsUsp1 expression
      was very strongly induced within 1 h of submergence. Elevated transcript levels
      were observed in dividing cells, in expanding cells and in differentiated tissue
      indicating that USP1 mediates a general process. Gene induction was shown to be
      regulated by ethylene with a highly similar expression pattern to that observed
      with submergence treatment. Based on sequence information and on expression data
      it is hypothesized that OsUSP1 plays a role in ethylene-mediated stress
      adaptation in rice.

PMID- 12432026
TI  - Characterization of two putative ethylene receptor genes expressed during peach
      fruit development and abscission.
AB  - Two peach genes homologous to the Arabidopsis ethylene receptor genes ETR1 and
      ERS1, named Pp-ETR1 and Pp-ERS1 respectively, have been isolated and
      characterized. Pp-ETR1 and Pp-ERS1 are conserved in terms of exon numbers and
      intron positions, although the first and fifth introns of Pp-ETR1 have an unusual
      length. In addition, two putative polyadenylation sites, that may cause an
      incomplete splicing at the 3' terminus, are present in the fifth intron. A motif
      of 28 nt, which shows high homology with ethylene responsive elements found in
      promoters of genes up-regulated by ethylene, is present in the promoter region of
      Pp-ERS1. Expression analysis, carried out by quantitative RT-PCR, was performed
      during fruit development and ripening, and leaf and fruitlet abscission. The
      level of Pp-ETR1 transcripts remained unchanged in all the tissues and
      developmental stages examined, whereas Pp-ERS1 mRNA abundance increased in
      ripening mesocarp, in leaf and fruitlet activated abscission zones, and following
      propylene application. 1-methylcyclopropene (1-MCP), an inhibitor of ethylene
      action, did not affect Pp-ETR1 transcription, while it down-regulated Pp-ERS1. A
      rise in ethylene evolution, accompanied by an increase of Pp-ERS1 transcript
      accumulation occurred within 24 h from the end of 1-MCP treatment. These results
      indicate that Pp-ERS1 might play a role in abscission and ripening.

PMID- 12432027
TI  - Plastid genes transcribed by the nucleus-encoded plastid RNA polymerase show
      increased transcript accumulation in transgenic plants expressing a chloroplast
      localized phage T7 RNA polymerase.
AB  - A gene fusion encoding a plastid-targeted bacteriophage T7 RNA polymerase
      (T7RNAP) under the transcriptional control of the light-regulated promoter and
      the plastid-targeting signals of a ribulose-bisphosphate carboxylase/oxygenase
      (Rubisco) small-subunit (SSU) gene was introduced into the nuclear genome of
      Nicotiana tabacum (tobacco). Immunoblot analysis, in vitro transcription assays
      and protease treatment of isolated chloroplasts revealed that T7RNAP activity was
      localized within chloroplasts. RNA gel blot analyses showed a substantial
      increase in transcript abundance for several plastid genes that are normally
      transcribed by the nucleus-encoded plastid RNA polymerase (NEP) including rpoC1,
      rpl33, rps18, rps12, and clpP. By contrast, no significant changes were observed
      in the levels of psbD, 16SrDNA, and ndhA transcripts. These results suggest a
      possible direct or indirect T7RNAP-mediated enhancement of transcription of a
      subset of plastid genes that contain NEP promoters. Despite these alterations in
      plastid transcript levels, the plants showed no visible abberant phenotype.

PMID- 12432028
TI  - Elevated pCO(2 )favours nitrate reduction in the roots of wild-type tobacco
      (Nicotiana tabacum cv. Gat.) and significantly alters N-metabolism in
      transformants lacking functional nitrate reductase in the roots.
AB  - The impact of elevated pCO(2 )on N-metabolism of hydroponically grown wild-type
      and transformed tobacco plants lacking root nitrate reduction was studied in
      order to elucidate the effects on (i) nitrate uptake, (ii) long-distance
      transport of N, (iii) nitrate reduction with emphasis on root-NR, and (iv) the
      allocation of N between the root and shoot. The findings were related to
      alterations of growth rates. At elevated pCO(2 )the wild type exhibited higher
      growth rates, which were accompanied by an increase of NO(3)(-)-uptake per plant,
      due to a higher root:shoot ratio. Furthermore, elevated pCO(2 )enhanced nitrate
      reduction in the roots of the wild type, resulting in enhanced xylem-loading of
      organic N (amino-N) to supply the shoot with sufficient nitrogen, and decreased
      phloem-transport of organic N in a basipetal direction. Transformed tobacco
      plants lacking root nitrate reduction were smaller than the wild type and
      exhibited lower growth rates. Nitrate uptake per plant was decreased in
      transformed plants as a consequence of an impeded root growth and, thus, a
      significantly decreased root:shoot ratio. Surprisingly, transformed plants showed
      an altered allocation of amino-N between the root and the shoot, with an increase
      of amino-N in the root and a substantial decrease of amino-N in the shoot. In
      transformed plants, xylem-loading of nitrate was increased and the roots were
      supplied with organic N via phloem transport. Elevated pCO(2 )increased shoot-NR,
      but only slightly affected the growth rates of transformed plants, whereas
      carbohydrates accumulated at elevated pCO(2 )as indicated by a significant
      increase of the C/N ratio in the leaves of transformed plants. Unexpectedly, the
      C/N balance and the functional equilibrium between root and shoot growth was
      disturbed dramatically by the loss of nitrate reduction in the root.

PMID- 12432029
TI  - How do water transport and water storage differ in coniferous earlywood and
      latewood?
AB  - The goal of this research project was to determine the water transport behaviour
      of earlywood versus latewood in the trunk of 21-year-old Douglas-fir [Pseudostuga
      menziesii (Mirb.) Franco] trees. Specific conductivity (k(s)) and the
      vulnerability of xylem to embolism were measured on a single growth ring and in a
      subset of earlywood and latewood samples within the same ring. Earlywood/latewood
      ratio, trunk water potential (Psi) and relative water content (RWC) were used to
      predict differences in conductivities and vulnerability to embolism. Earlywood
      has about 11 times the k(s) of latewood, and up to 90% of the total flow occurred
      through the earlywood. Earlywood's vulnerability to embolism followed the same
      trend as that of the whole wood, with 50% loss of conductivity at -2.2 MPa
      (P(50)). Latewood was more vulnerable to embolism than earlywood at high Psi, but
      as Psi decreased, the latewood showed very little further embolism, with a P(50)
      <-5.0 MPa. The lowest trunk Psi estimated in the field was about -1.4 MPa,
      indicating that latewood and earlywood in the field experienced about 42% and 16%
      loss of k(s), respectively. The higher vulnerability to embolism in latewood than
      in earlywood at field Psi was associated with higher water storage capacity
      (21.8% RWC MPa(-1) versus 4.1% RWC MPa(-1), latewood and earlywood,
      respectively). The shape of the vulnerability curve suggests that air seeding
      through latewood may occur directly through pores in the margo and seal off at
      lower pressure than earlywood pores.

PMID- 12432030
TI  - The role of phytochelatins in constitutive and adaptive heavy metal tolerances in
      hyperaccumulator and non-hyperaccumulator metallophytes.
AB  - Using the gamma-glutamylcysteine synthetase inhibitor, L-buthionine-[S,R]
      sulphoximine (BSO), the role for phytochelatins (PCs) was evaluated in Cu, Cd,
      Zn, As, Ni, and Co tolerance in non-metallicolous and metallicolous,
      hypertolerant populations of Silene vulgaris (Moench) Garcke, Thlaspi
      caerulescens J.&C. Presl., Holcus lanatus L., and Agrostis castellana Boiss. et
      Reuter. Based on plant-internal PC-thiol to metal molar ratios, the metals'
      tendency to induce PC accumulation decreased in the order As/Cd/Cu > Zn > Ni/Co,
      and was consistently higher in non-metallicolous plants than in hypertolerant
      ones, except for the case of As. The sensitivities to Cu, Zn, Ni, and Co were
      consistently unaffected by BSO treatment, both in non-metallicolous and
      hypertolerant plants, suggesting that PC-based sequestration is not essential for
      constitutive tolerance or hypertolerance to these metals. Cd sensitivity was
      considerably increased by BSO, though exclusively in plants lacking Cd
      hypertolerance, suggesting that adaptive cadmium hypertolerance is not dependent
      on PC-mediated sequestration. BSO dramatically increased As sensitivity, both in
      non-adapted and As-hypertolerant plants, showing that PC-based sequestration is
      essential for both normal constitutive tolerance and adaptive hypertolerance to
      this metalloid. The primary function of PC synthase in plants and algae remains
      elusive.

PMID- 12432031
TI  - Partial purification of tomato fruit peroxidase and its effect on the mechanical
      properties of tomato fruit skin.
AB  - Peroxidase (EC 1.11.1.7)-mediated stiffening of cell walls within the fruit skin
      of tomato is hypothesized to regulate fruit growth. However, to date, there is no
      experimental evidence demonstrating that peroxidase affects the mechanical
      properties of skin tissue. Here, the mechanical properties of skin strips excised
      from a range of fruits at different ages were determined using an 'Instron'
      universal material testing instrument. The stiffness of tomato fruit skin strips
      increases 3-fold with increasing fruit age. Application of partially-purified
      peroxidase from the cell walls of mature tomato fruit skin significantly
      increased the stiffness of fruit skin irrespective of the age of fruit.
      Furthermore, the application of hydrogen peroxide significantly increased the
      stiffness of skin strips excised from fruit of an age when endogenous peroxidase
      isozymes associated with the termination of growth are first detected. The
      results support the hypothesis that the tomato fruit skin plays an integral role
      in the regulation of tomato fruit growth, and that changes in its mechanical
      properties may be mediated by peroxidase. As far as is known, this is the first
      demonstration that peroxidases alter the mechanical properties of the plant cell
      wall.

PMID- 12432032
TI  - Water stress-induced abscisic acid accumulation triggers the increased generation
      of reactive oxygen species and up-regulates the activities of antioxidant enzymes
      in maize leaves.
AB  - The interrelationship among water-stress-induced abscisic acid (ABA)
      accumulation, the generation of reactive oxygen species (ROS), and the activities
      of several antioxidant enzymes such as superoxide dismutase (SOD), catalase
      (CAT), ascorbate peroxidase (APX), and glutathione reductase (GR) was
      investigated in leaves of detached maize (Zea mays L.) plants exposed to -0.7 MPa
      water stress induced by polyethylene glycol (PEG 6000). Time-course analyses of
      ABA content, the production of ROS, and the activities of antioxidant enzymes in
      water-stressed leaves showed that a significant increase in the content of ABA
      preceded that of ROS, which was followed by a marked increase in the activities
      of these antioxidant enzymes. Pretreatment with an ABA biosynthesis inhibitor,
      tungstate, significantly suppressed the accumulation of ABA, and also reduced the
      increased generation of ROS and the up-regulation of these antioxidant enzymes in
      water-stressed leaves. A mild oxidative stress induced by paraquat, which
      generates O(2)(-) and then H(2)O(2), resulted in a significant enhancement in the
      activities of antioxidant enzymes in non-water-stressed leaves. Pretreatment with
      some ROS scavengers, such as Tiron and dimethylthiourea (DMTU), and an inhibitor
      of NAD(P)H oxidase, diphenyleneiodonium (DPI), almost completely arrested the
      increase in ROS and the activities of these antioxidant enzymes induced by water
      stress or ABA treatment. These data suggest that water stress-induced ABA
      accumulation triggers the increased generation of ROS, which, in turn, leads to
      the up-regulation of the antioxidant defence system.

PMID- 12432033
TI  - Effects of solar UV-B radiation on canopy structure of Ulva communities from
      southern Spain.
AB  - Within the sheltered creeks of Cadiz bay, Ulva thalli form extended mat-like
      canopies. The effect of solar ultraviolet radiation on photosynthetic activity,
      the composition of photosynthetic and xanthophyll cycle pigments, and the amount
      of RubisCO, chaperonin 60 (CPN 60), and the induction of DNA damage in Ulva aff.
      rotundata Bliding from southern Spain was assessed in the field. Samples
      collected from the natural community were covered by screening filters,
      generating different radiation conditions. During daily cycles, individual thalli
      showed photoinhibitory effects of the natural solar radiation. This inhibition
      was even more pronounced in samples only exposed to photosynthetically active
      radiation (PAR). Strongly increased heat dissipation in these samples indicated
      the activity of regulatory mechanisms involved in dynamic photoinhibition.
      Adverse effects of UV-B radiation on photosynthesis were only observed in
      combination with high levels of PAR, indicating the synergistic effects of the
      two wavelength ranges. In samples exposed either to PAR+UV-A or to UV-B+UV-A
      without PAR, no inhibition of photosynthetic quantum yield was found in the
      course of the day. At the natural site, the top layer of the mat-like canopies is
      generally completely bleached. Artificially designed Ulva canopies exhibited fast
      bleaching of the top layer under the natural solar radiation conditions, while
      this was not observed in canopies either shielded from UV or from PAR. The
      bleached first layer of the canopies acts as a selective UV-B filter, and thus
      prevents subcanopy thalli from exposure to harmful radiation. This was confirmed
      by the differences in photosynthetic activity, pigment composition, and the
      concentration of RubisCO in thalli with different positions within the canopy. In
      addition, the induction of the stress protein CPN 60 under UV exposure and the
      low accumulation of DNA damage indicate the presence of physiological protection
      mechanisms against harmful UV-B. A mechanism of UV-B-induced inhibition of
      photosynthesis under field conditions is proposed.

PMID- 12432034
TI  - Effect of local irradiance on CO(2) transfer conductance of mesophyll in walnut.
AB  - The acclimation responses of walnut leaf photosynthesis to the irradiance
      microclimate were investigated by characterizing the photosynthetic properties of
      the leaves sampled on young trees (Juglans nigraxregia) grown in simulated sun
      and shade environments, and within a mature walnut tree crown (Juglans regia) in
      the field. In the young trees, the CO(2) compensation point in the absence of
      mitochondrial respiration (Gamma*), which probes the CO(2) versus O(2)
      specificity of Rubisco, was not significantly different in sun and shade leaves.
      The maximal net assimilation rates and stomatal and mesophyll conductances to
      CO(2) transfer were markedly lower in shade than in sun leaves. Dark respiration
      rates were also lower in shade leaves. However, the percentage inhibition of
      respiration by light during photosynthesis was similar in both sun and shade
      leaves. The extent of the changes in photosynthetic capacity and mesophyll
      conductance between sun and shade leaves under simulated conditions was similar
      to that observed between sun and shade leaves collected within the mature tree
      crown. Moreover, mesophyll conductance was strongly correlated with maximal net
      assimilation and the relationships were not significantly different between the
      two experiments, despite marked differences in leaf anatomy. These results
      suggest that photosynthetic capacity is a valuable parameter for modelling within
      canopies variations of mesophyll conductance due to leaf acclimation to light.

PMID- 12432035
TI  - Contribution of vegetative storage proteins to seasonal nitrogen variations in
      the young shoots of peach trees (Prunus persica L. Batsch).
AB  - Qualitative and quantitative variations in the level of two low molecular weight
      vegetative storage proteins (VSP 19 kDa and 16.5 kDa) in peach shoots were
      compared with annual variations in total nitrogen and total soluble proteins.
      Protein patterns were obtained by SDS-PAGE and silver staining on each of the 12
      kinetic samples collected between October 1995 and November 1996. VSP 16.5 kDa
      and 19 kDa exhibited typical annual VSP variations in both parenchyma and phloem.
      In wood, VSP 16.5 kDa was only present in November. All N compounds tested were
      stored in the autumn and their levels fell in the spring. Parenchyma was the
      principal stem storage tissue for all N compounds tested, even if proteins were
      more often highly concentrated in phloem and even if wood was the major shoot
      constituent. In winter, the two VSP accounted for 13% of bark proteins and 11% of
      wood proteins. Their storage yield, given by the winter/summer (W/S) ratio was
      higher (18.5) than that of total proteins (4). Between August to March, i.e.
      during the storage phase, N fractions obtained from VSP (N3) and total soluble
      proteins minus VSP (N2) accounted, respectively, for only 3% and 21% of total N
      accumulation in the bark, the remainder being due to the fraction not extracted
      (N1). A marked drop in all N compound levels characterized the mobilization phase
      (March to April), particularly for N3 (-84% between March and April) which were
      mobilized slightly before other N compounds. Although N3 exhibited the best
      mobilization yield, it represented only 5% of the total N mobilized. So, in spite
      of a similarity between VSP and N annual variation patterns, there was no tight
      correlation between their contents in bark. N2 supplied a high proportion of the
      N used for spring regrowth (40%), but the larger share (55%) came from N1 which
      was probably made up of free amino acids. Very tight positive correlations have
      been observed between these two N fractions and the N status. The lower bark
      total N content measured in August (6.4 mg N g(-1 )DW) during the assimilation
      phase (April to August) was equal to the unavailable N fraction, and the bark N
      mobilization potential (between March and August) was estimated at 6.35 mg N g(
      1) DW. VSP did not quantitatively represent the main stored N pool. But, because
      of their high W/S ratio and their early remobilization, they seemed to play an
      important role in spring regrowth initiation.

PMID- 12432036
TI  - Root-zone acidity and nitrogen source affects Typha latifolia L. growth and
      uptake kinetics of ammonium and nitrate.
AB  - The NH(4)(+) and NO(3)(-) uptake kinetics by Typha latifolia L. were studied
      after prolonged hydroponics growth at constant pH 3.5, 5.0, 6.5 or 7.0 and with
      NH(4)(+) or NO(3)(-) as the sole N-source. In addition, the effects of pH and N
      source on H(+) extrusion and adenine nucleotide content were examined. Typha
      latifolia was able to grow with both N sources at near neutral pH levels, but the
      plants had higher relative growth rates, higher tissue concentrations of the
      major nutrients, higher contents of adenine nucleotides, and higher affinity for
      uptake of inorganic nitrogen when grown on NH(4)(+). Growth almost completely
      stopped at pH 3.5, irrespective of N source, probably as a consequence of pH
      effects on plasma membrane integrity and H(+) influx into the root cells. Tissue
      concentrations of the major nutrients and adenine nucleotides were severely
      reduced at low pH, and the uptake capacity for inorganic nitrogen was low, and
      more so for NO(3)(-)-fed than for NH(4)(+)-fed plants. The maximum uptake rate,
      V(max), was highest for NH(4)(+) at pH 6.5 (30.9 micro mol h(-1) g(-1) root dry
      weight) and for NO(3)(-) at pH 5.0 (31.7 micro mol h(-1) g(-1) root dry weight),
      and less than 10% of these values at pH 3.5. The affinity for uptake as estimated
      by the half saturation constant, K((1/2)), was lowest at low pH for NH(4)(+) and
      at high pH for NO(3)(-). The changes in V(max) and K((1/2)) were thus consistent
      with the theory of increasing competition between cations and H(+) at low pH and
      between anions and OH(-) at high pH. C(min) was independent of pH, but slightly
      higher for NO(3)(-) than for NH(4)(+) (C(min)(NH(4)(+)) approximately 0.8 mmol m(
      3); C(min)(NO(3)(-)) approximately 2.8 mmol m(-3)). The growth inhibition at low
      pH was probably due to a reduced nutrient uptake and a consequential limitation
      of growth by nutrient stress. Typha latifolia seems to be well adapted to growth
      in wetland soils where NH(4)(+) is the prevailing nitrogen compound, but very low
      pH levels around the roots are very stressful for the plant. The common
      occurrence of T. latifolia in very acidic areas is probably only possible because
      of the plant's ability to modify pH-conditions in the rhizosphere.

PMID- 12432037
TI  - Isolation and expression of a novel starch-storing cell-specific gene containing
      the KH RNA binding domain from tobacco-cultured cells BY-2.
AB  - In cultured Bright Yellow-2 tobacco (Nicotiana tabacum) cells, the depletion of
      2,4-dichlorophenoxyacetic acid (2,4-D) in the culture medium induces amyloplast
      development. This differentiation also includes a decrease in cell
      multiplication, and an increase in cell size. These changes were primarily
      triggered by the depletion of 2,4-D, and accelerated by the addition of
      benzyladenine (BA). Three cDNAs were identified whose transcript levels are
      specifically increased during differentiation of starch-storing cells using the
      differential display method, and designated as starch-storing cell induced genes
      (SCI genes). One of these cDNAs, SCI2 encodes a 285 amino acids long protein with
      a KH RNA-binding domain. A database search revealed that this protein showed
      similarity to respective domains of mammalian quaking proteins. 2,4-D addition,
      which can convert starch-storing cells into dividing cells, to starch-storing BY
      2 cells, immediately decreases the SCI2 transcript level, suggesting that SCI2
      may have some role in starch-storing cell differentiation in BY-2 cells.

PMID- 12432038
TI  - Isolation and expression analysis of the isopropylmalate synthase gene family of
      Arabidopsis thaliana.
AB  - Isopropylmalate synthase (IPMS) is the first enzyme in the leucine biosynthetic
      pathway. It is the branch point in the biosynthesis of leucine and the other
      branched-chain amino acids. IPMS is also regulated by negative feedback
      inhibition by the end-product leucine. There are four highly homologous loci
      within the Arabidopsis thaliana genome, which contain sequences that code for
      IPMS. Through library screening and RT-PCR the expression patterns of three of
      these loci namely IMS1, IMS2, and IMS3 have been isolated and then characterized.
      cDNAs of IMS2 and IMS3 lacking the 5' chloroplast leader sequence were able to
      complement a leucine auxotroph of E. coli.

PMID- 12432039
TI  - Isolation and characterization of a potato cDNA corresponding to a 1
      aminocyclopropane-1-carboxylate (ACC) oxidase gene differentially activated by
      stress.
AB  - 1-Aminocyclopropane-1-carboxylate (ACC) oxidase enzyme catalyses the final step
      in ethylene biosynthesis, converting 1-aminocyclopropane-1-carboxylic acid to
      ethylene. A cDNA clone encoding an ACC oxidase, ST-ACO3, was isolated from potato
      (Solanum tuberosum L.) by differential screening of a Fusarium eumartii infected
      tuber cDNA library. The deduced amino acid sequence exhibited similarity to other
      ACC oxidase proteins from several plants species. Northern blot analysis revealed
      that the ST-ACO3 mRNA level increased in potato tubers upon inoculation with F.
      eumartii, as well as after treatment with salicylic acid and indole-3-acetic
      acid, suggesting a cross-talk between different signalling pathways involved in
      the defence response of potato tubers against F. eumartii attack.

PMID- 12432040
TI  - Cyclin E and prognosis in patients with breast cancer.

PMID- 12432041
TI  - Dexamethasone in adults with bacterial meningitis.
AB  - BACKGROUND: Mortality and morbidity rates are high among adults with acute
      bacterial meningitis, especially those with pneumococcal meningitis. In studies
      of bacterial meningitis in animals, adjuvant treatment with corticosteroids has
      beneficial effects. METHODS: We conducted a prospective, randomized, double
      blind, multicenter trial of adjuvant treatment with dexamethasone, as compared
      with placebo, in adults with acute bacterial meningitis. Dexamethasone (10 mg) or
      placebo was administered 15 to 20 minutes before or with the first dose of
      antibiotic and was given every 6 hours for four days. The primary outcome measure
      was the score on the Glasgow Outcome Scale at eight weeks (a score of 5,
      indicating a favorable outcome, vs. a score of 1 to 4, indicating an unfavorable
      outcome). A subgroup analysis according to the causative organism was performed.
      Analyses were performed on an intention-to-treat basis. RESULTS: A total of 301
      patients were randomly assigned to a treatment group: 157 to the dexamethasone
      group and 144 to the placebo group. The base-line characteristics of the two
      groups were similar. Treatment with dexamethasone was associated with a reduction
      in the risk of an unfavorable outcome (relative risk, 0.59; 95 percent confidence
      interval, 0.37 to 0.94; P=0.03). Treatment with dexamethasone was also associated
      with a reduction in mortality (relative risk of death, 0.48; 95 percent
      confidence interval, 0.24 to 0.96; P=0.04). Among the patients with pneumococcal
      meningitis, there were unfavorable outcomes in 26 percent of the dexamethasone
      group, as compared with 52 percent of the placebo group (relative risk, 0.50; 95
      percent confidence interval, 0.30 to 0.83; P=0.006). Gastrointestinal bleeding
      occurred in two patients in the dexamethasone group and in five patients in the
      placebo group. CONCLUSIONS: Early treatment with dexamethasone improves the
      outcome in adults with acute bacterial meningitis and does not increase the risk
      of gastrointestinal bleeding.

PMID- 12432042
TI  - Comparison of C-reactive protein and low-density lipoprotein cholesterol levels
      in the prediction of first cardiovascular events.
AB  - BACKGROUND: Both C-reactive protein and low-density lipoprotein (LDL) cholesterol
      levels are elevated in persons at risk for cardiovascular events. However,
      population-based data directly comparing these two biologic markers are not
      available. METHODS: C-reactive protein and LDL cholesterol were measured at base
      line in 27,939 apparently healthy American women, who were then followed for a
      mean of eight years for the occurrence of myocardial infarction, ischemic stroke,
      coronary revascularization, or death from cardiovascular causes. We assessed the
      value of these two measurements in predicting the risk of cardiovascular events
      in the study population. RESULTS: Although C-reactive protein and LDL cholesterol
      were minimally correlated (r=0.08), base-line levels of each had a strong linear
      relation with the incidence of cardiovascular events. After adjustment for age,
      smoking status, the presence or absence of diabetes mellitus, categorical levels
      of blood pressure, and use or nonuse of hormone-replacement therapy, the relative
      risks of first cardiovascular events according to increasing quintiles of C
      reactive protein, as compared with the women in the lowest quintile, were 1.4,
      1.6, 2.0, and 2.3 (P<0.001), whereas the corresponding relative risks in
      increasing quintiles of LDL cholesterol, as compared with the lowest, were 0.9,
      1.1, 1.3, and 1.5 (P<0.001). Similar effects were observed in separate analyses
      of each component of the composite end point and among users and nonusers of
      hormone-replacement therapy. Overall, 77 percent of all events occurred among
      women with LDL cholesterol levels below 160 mg per deciliter (4.14 mmol per
      liter), and 46 percent occurred among those with LDL cholesterol levels below 130
      mg per deciliter (3.36 mmol per liter). By contrast, because C-reactive protein
      and LDL cholesterol measurements tended to identify different high-risk groups,
      screening for both biologic markers provided better prognostic information than
      screening for either alone. Independent effects were also observed for C-reactive
      protein in analyses adjusted for all components of the Framingham risk score.
      CONCLUSIONS: These data suggest that the C-reactive protein level is a stronger
      predictor of cardiovascular events than the LDL cholesterol level and that it
      adds prognostic information to that conveyed by the Framingham risk score.

PMID- 12432043
TI  - Cyclin E and survival in patients with breast cancer.
AB  - BACKGROUND: Cyclin E, a regulator of the cell cycle, affects the behavior of
      breast-cancer cells. We investigated whether levels of cyclin E in the tumor
      correlated with survival among patients with breast cancer. METHODS: Tumor tissue
      from 395 patients with breast cancer was assayed for cyclin E, cyclin D1, cyclin
      D3, and the HER-2/neu oncogene with the use of Western blot analysis. Full
      length, low-molecular-weight, and total cyclin E were measured.
      Immunohistochemical assessments of cyclin E were also made of 256 tumors. We
      sought correlations between levels of these molecular markers and disease
      specific and overall survival. RESULTS: The median follow-up was 6.4 years. A
      high level of the low-molecular-weight isoforms of cyclin E, as detected by
      Western blotting, correlated strongly with disease-specific survival whether
      axillary lymph nodes were negative or positive for metastases (P<0.001). Among
      114 patients with stage I breast cancer, none of the 102 patients with low levels
      of cyclin E in the tumor had died of breast cancer by five years after diagnosis,
      whereas all 12 patients with a high level of low-molecular-weight cyclin E had
      died of breast cancer within that period. In multivariate analysis, a high total
      cyclin E level or high levels of the low-molecular-weight forms of cyclin E were
      significantly correlated with poor outcome. The hazard ratio for death from
      breast cancer for patients with high total cyclin E levels as compared with those
      with low total cyclin E levels was 13.3--about eight times as high as the hazard
      ratios associated with other independent clinical and pathological risk factors.
      CONCLUSIONS: Levels of total cyclin E and low-molecular-weight cyclin E in tumor
      tissue, as measured by Western blot assay, correlate strongly with survival in
      patients with breast cancer.

PMID- 12432044
TI  - Antimicrobial treatment in diabetic women with asymptomatic bacteriuria.
AB  - BACKGROUND: Asymptomatic bacteriuria is common among women with diabetes, and the
      treatment of such infections has been recommended to prevent complications
      related to symptomatic urinary tract infection. METHODS: We enrolled women (>16
      years of age) with diabetes, bacteriuria (> or =105 colony-forming units of an
      organism per milliliter in cultures of two consecutive urine specimens), and no
      urinary symptoms; 50 were randomly assigned to receive placebo and 55 to receive
      antimicrobial therapy. For the first six weeks, which included the initial course
      of treatment, the study was placebo-controlled and double-blind. Subsequently,
      the women were screened for bacteriuria every three months for up to three years;
      antimicrobial therapy was provided to women in the antimicrobial-therapy group
      who had asymptomatic bacteriuria. RESULTS: Four weeks after the end of the
      initial course of therapy, 78 percent of placebo recipients had bacteriuria, as
      compared with 20 percent of women who received antimicrobial agents (P<0.001).
      During a mean follow-up of 27 months, 20 of 50 women in the placebo group (40
      percent) and 23 of 55 women in the antimicrobial-therapy group (42 percent) had
      at least one episode of symptomatic urinary tract infection. The time to a first
      symptomatic episode was similar in the placebo group and the antimicrobial
      therapy group (P=0.67 by the log-rank test), as were the (+/-SD) rates of any
      symptomatic urinary tract infection (1.10+/-0.17 and 0.93+/-0.14 per 1000 days of
      follow-up, respectively; relative risk, 1.19; 95 percent confidence interval,
      0.28 to 1.81), pyelonephritis (0.28+/-0.08 and 0.13+/-0.05 per 1000 days of
      follow-up; relative risk, 2.13; 95 percent confidence interval, 0.81 to 5.62),
      and hospitalization for urinary tract infection (0.10+/-0.36 and 0.06+/-0.22 per
      1000 days of follow-up; relative risk, 1.93; 95 percent confidence interval, 0.47
      to 7.89). The women in the antimicrobial-therapy group had almost five times as
      many days of antibiotic use for urinary tract infection as did the women in the
      placebo group (158.2+/-1.7 vs. 33.7+/-0.91 per 1000 days of follow-up; relative
      risk, 0.21; 95 percent confidence interval, 0.20 to 0.22). CONCLUSIONS: Treatment
      of asymptomatic bacteriuria in women with diabetes does not appear to reduce
      complications. Diabetes itself should not be an indication for screening for or
      treatment of asymptomatic bacteriuria.

PMID- 12432045
TI  - Images in clinical medicine. Coronary-artery calcification.

PMID- 12432046
TI  - Contribution of major diseases to disparities in mortality.
AB  - BACKGROUND: Mortality from all causes is higher for persons with fewer years of
      education and for blacks, but it is unknown which diseases contribute most to
      these disparities. METHODS: We estimated cause-specific risks of death from data
      from the National Health Interview Survey conducted from 1986 through 1994 and
      from linked vital statistics. Using these risk estimates, we calculated potential
      years of life lost and potential gains in life expectancy related to specific
      causes, with stratification according to education level and race. RESULTS:
      Persons without a high-school education lost 12.8 potential life-years per person
      in the population, as compared with 3.6 for persons who graduated from high
      school (ratio, 3.5; P<0.001). Ischemic heart disease contributed most (11.7
      percent) to the difference according to education in potential life-years lost
      (with all cardiovascular diseases accounting for 35.3 percent). All cancers
      accounted for 26.5 percent, including 7.7 percent due to lung cancer; other lung
      diseases and pneumonia contributed 10.1 percent of the total, whereas human
      immunodeficiency virus (HIV) disease accounted for none of the difference
      according to education. The pattern of disparities according to level of income
      was similar to that according to level of education. Blacks and whites lost 7.0
      and 5.2 potential life-years per person, respectively, as a result of deaths from
      any cause (ratio, 1.35; P<0.001). Cardiovascular diseases accounted for one third
      of this disparity, in large part because of hypertension (15.0 percent); HIV
      disease (11.2 percent) contributed almost as much as ischemic heart disease (5.5
      percent), stroke (2.8 percent), and cancer (3.4 percent) combined; trauma and
      diabetes mellitus accounted for 10.7 percent and 8.5 percent, respectively.
      CONCLUSIONS: Although many conditions contribute to socioeconomic and racial
      disparities in potential life-years lost, a few conditions account for most of
      these disparities - smoking-related diseases in the case of mortality among
      persons with fewer years of education, and hypertension, HIV, diabetes mellitus,
      and trauma in the case of mortality among black persons. These findings have
      important implications for targeting efforts to reduce existing disparities in
      mortality rates.

PMID- 12432047
TI  - Rules for making human tumor cells.

PMID- 12432048
TI  - Case record of the Massachusetts General Hospital. Weekly clinicopathological
      exercises. Case 35-2002. A nine-year-old girl with cold intolerance, visual-field
      defects, and a suprasellar tumor.

PMID- 12432049
TI  - Corticosteroids for everyone with meningitis?

PMID- 12432050
TI  - C-reactive protein--to screen or not to screen?

PMID- 12432051
TI  - Asymptomatic bacteriuria in patients with diabetes--enemy or innocent visitor?

PMID- 12432052
TI  - Therapeutic cloning.

PMID- 12432053
TI  - Osteoprotegerin deficiency and juvenile Paget's disease.

PMID- 12432054
TI  - Lansoprazole for the prevention of recurrences of ulcer complications from long
      term low-dose aspirin.

PMID- 12432055
TI  - Varicella vaccine in recipients of hematopoietic-cell transplants.

PMID- 12432056
TI  - Long-term care after hematopoietic-cell transplantation in adults.

PMID- 12432057
TI  - Nipple piercing and hyperprolactinemia.

PMID- 12432058
TI  - Anxiety and genetically engineered mice.

PMID- 12432059
TI  - Reporting of adverse events.

PMID- 12432060
TI  - The Ena/VASP enigma.
AB  - Ena/VASP proteins are actin-binding proteins that localize to actin stress
      fibres, the tips of filopodia and the lamellipodial leading edge. In the past few
      years, a number of seemingly conflicting studies have confused the Ena/VASP
      field, pointing to roles for these proteins in both promotion and inhibition of
      actin-dependent processes. Recent discoveries resolve these contradictions and
      suggest a novel mechanism of Ena/VASP function, in which the proteins function as
      'anti-capping' proteins that antagonize capping proteins at the barbed end of
      actin filaments.

PMID- 12432061
TI  - Apoptosis-inducing factor (AIF): key to the conserved caspase-independent
      pathways of cell death?
AB  - Numerous pro-apoptotic signal transducing molecules act on mitochondria and
      provoke the permeabilization of the outer mitochondrial membrane, thereby
      triggering the release of potentially toxic mitochondrial proteins. One of these
      proteins, apoptosis-inducing factor (AIF), is a phylogenetically old flavoprotein
      which, in healthy cells, is confined to the mitochondrial intermembrane space.
      Upon lethal signaling, AIF translocates, via the cytosol, to the nucleus where it
      binds to DNA and provokes caspase-independent chromatin condensation. The crystal
      structures of both human and mouse AIF have been determined, and the fine
      mechanisms accounting for its oxidoreductase activity and its electrostatic
      interaction with double-stranded DNA have been elucidated. Importantly, the
      apoptogenic and oxidoreductase functions of AIF can be dissociated. Thus,
      mutations that abolish the AIF-DNA interaction suppress AIF-induced chromatin
      condensation, yet have no effect on the NADH oxidase activity. Recent studies
      suggest AIF to be a major factor determining caspase-independent neuronal death,
      emphasizing the central role of mitochondria in the control of physiological and
      pathological cell demise.

PMID- 12432062
TI  - Absence of retinoids can induce motoneuron disease in the adult rat and a
      retinoid defect is present in motoneuron disease patients.
AB  - We generated retinoid-deficient adult rats by the removal of retinoids from their
      diet. We show that their motoneurons undergo neurodegeneration and that there is
      an accumulation of neurofilaments and an increase in astrocytosis, which is
      associated with motoneuron disease. These effects are mediated through the
      retinoic acid receptor alpha. The same receptor deficit is found in motoneurons
      from patients suffering from spontaneous amyotrophic lateral sclerosis.
      Furthermore, we show that there is a loss of expression of the retinaldehyde
      dehydrogenase enzyme II in motoneurons. Therefore, we propose that a defect in
      the retinoid signalling pathway is in part be responsible for some types of
      motoneuron disease.

PMID- 12432063
TI  - Protein kinase CKII regulates the interaction of beta-catenin with alpha-catenin
      and its protein stability.
AB  - beta-Catenin is a multi-functional cellular component and a substrate for several
      protein kinases. Here we investigated the interaction of protein kinase CKII
      (casein kinase II) and beta-catenin. We show that CKII phosphorylates the N
      terminal region of beta-catenin and we identified Ser29, Thr102, and Thr112 as
      substrates for the enzyme. We provide evidence that CKII regulates the
      cytoplasmic stability of beta-catenin and acts synergistically with GSK-3beta in
      the multi-protein complex that controls the degradation of beta-catenin. In
      comparing wild-type and Ser/Thr-mutant beta-catenin, a decreased affinity of the
      mutant protein to alpha-catenin was observed. Moreover, kinase assays in vitro
      demonstrate a CKII-dependent increase in the binding of wild-type beta-catenin
      with alpha-catenin. In line with that, cells expressing Ser/Thr-mutant beta
      catenin exhibit an increased migratory potential, which correlates with an
      enhanced cytosolic localization and a reduced association with the cytoskeleton
      of the mutant protein. From these results we conclude that CKII regulates the
      function of beta-catenin in the cadherin adhesion complex as well as its
      cytoplasmic stability.

PMID- 12432065
TI  - Differential acetylation of histones H3 and H4 in paternal and maternal germline
      chromosomes during development of sciarid flies.
AB  - A classic example of chromosome elimination and genomic imprinting is found in
      sciarid flies (Diptera. Sciaridae), where whole chromosomes of exclusively
      paternal origin are discarded from the genome at different developmental stages.
      Two types of chromosome elimination event occur in the germline. In embryos of
      both sexes, the extrusion of a single paternal X chromosome occurs in early germ
      nuclei and in male meiotic cells the whole paternal complement is discarded. In
      sciarids, early germ nuclei remain undivided for a long time and exhibit a high
      degree of chromatin compaction, so that chromosomes are cytologically
      individualized. We investigated chromatin differences between parental
      chromosomes in Sciara ocellaris and S. coprophila by analyzing histone
      acetylation modifications in early germ nuclei. We examined germ nuclei from
      early embryonic stages to premeiotic larval stages, male meiotic cell and early
      somatic nuclei following fertilization. In early germ cells, only half of the
      regular chromosome complement is highly acetylated for histones H4 and H3. The
      chromosomes that are highly acetylated are paternally derived. An exception is
      the paternal X chromosome that is eliminated from germ nuclei. At later stages
      preceding the initiation of mitotic gonial divisions, all chromosomes of the
      germline complement show similar high levels of histone H4/H3 acetylation. In
      male meiosis, maternal chromosomes are highly acetylated for histones H4 and H3,
      whereas the entire paternal chromosome set undergoing elimination appears under
      acetylated. The results suggest that histone acetylation contributes towards
      specifying the imprinted behavior of germline chromosomes in sciarids.

PMID- 12432064
TI  - SARA, a FYVE domain protein, affects Rab5-mediated endocytosis.
AB  - Rab5, a member of the small GTPase family of proteins, is primarily localized on
      early endosomes and has been proposed to participate in the regulation of early
      endosome trafficking. It has been reported that phosphatidylinositol 3-kinases
      and FYVE domain proteins, such as EEA1, can be recruited onto early endosomes and
      act as Rab5 effectors. SARA (Smad anchor for receptor activation), also a FYVE
      domain protein, was initially isolated as a participant in signal transduction
      from the transforming growth factor beta receptor. Overexpressed SARA has been
      found on EEA1-positive early endosomes. In this report, we show that endogenous
      SARA is present on early endosomes and overexpression of SARA causes endosomal
      enlargement. Functionally, SARA overexpression significantly delays the recycling
      of transferrin. The transferrin receptor distributed on the cell surfaces was
      also greatly reduced in cells overexpressing SARA. However, the internalization
      rate of transferrin is not affected by SARA overexpression. The morphological and
      functional alterations caused by SARA overexpression resemble those caused by
      overexpression of Rab5:GTP mutant Rab5Q79L. Finally, all SARA-mediated phenotypic
      changes can be counteracted by overexpression Rab5:GDP mutant Rab5S34N. These
      results collectively suggested that SARA plays an important functional role
      downstream of Rab5-regulated endosomal trafficking.

PMID- 12432066
TI  - Assembly of the PINCH-ILK-CH-ILKBP complex precedes and is essential for
      localization of each component to cell-matrix adhesion sites.
AB  - PINCH, integrin-linked kinase (ILK) and calponin homology-containing ILK-binding
      protein (CH-ILKBP) form a ternary complex that plays crucial roles at cell
      extracellular matrix adhesion sites. To understand the mechanism underlying the
      complex formation and recruitment to cell-adhesion sites we have undertaken a
      combined structural, mutational and cell biological analysis. Three-dimensional
      structure-based point mutations identified specific PINCH and ILK sites that
      mediate the complex formation. Analyses of the binding defective point mutants
      revealed that the assembly of the PINCH-ILK-CH-ILKBP complex is essential for
      their localization to cell-extracellular matrix adhesion sites. The formation of
      the PINCH-ILK-CH-ILKBP complex precedes integrin-mediated cell adhesion and
      spreading. Furthermore, inhibition of protein kinase C, but not that of actin
      polymerization, inhibited the PINCH-ILK-CH-ILKBP complex formation, suggesting
      that the PINCH-ILK-CH-ILKBP complex likely serves as a downstream effector of
      protein kinase C in the cellular control of focal adhesion assembly. Finally, we
      provide evidence that the formation of the PINCH-ILK-CH-ILKBP complex, while
      necessary, is not sufficient for ILK localization to cell-extracellular matrix
      adhesion sites. These results provide new insights into the molecular mechanism
      underlying the assembly and regulation of cell-matrix adhesion structures.

PMID- 12432067
TI  - Lasp-1 binds to non-muscle F-actin in vitro and is localized within multiple
      sites of dynamic actin assembly in vivo.
AB  - Lasp-1 has been identified as a signaling molecule that is phosphorylated upon
      elevation of [cAMP]i in pancreas, intestine and gastric mucosa and is selectively
      expressed in cells within epithelial tissues. In the gastric parietal cell, cAMP
      dependent phosphorylation induces the partial translocation of lasp-1 to the
      apically directed F-actin-rich canalicular membrane, which is the site of active
      HCl secretion. Lasp-1 is an unusual modular protein that contains an N-terminal
      LIM domain, a C-terminal SH3 domain and two internal nebulin repeats. Domain
      based analyses have recently categorized this protein as an epithelial
      representative of the nebulin family, which also includes the actin binding,
      muscle-specific proteins, nebulin, nebulette and N-RAP. In this study, we show
      that lasp-1 binds to non-muscle filamentous (F) actin in vitro in a
      phosphorylation-dependent manner. In addition, we provide evidence that lasp-1 is
      concentrated within focal complexes as well as in the leading edges of
      lamellipodia and the tips of filopodia in non-transformed gastric fibroblasts. In
      actin pull-down assays, the apparent K(d) of bacterially expressed his-tagged
      lasp-1 binding to F-actin was 2 micro M with a saturation stoichiometry of
      approximately 1:7. Phosphorylation of recombinant lasp-1 with recombinant PKA
      increased the K(d) and decreased the B(max) for lasp-1 binding to F-actin.
      Microsequencing and site-directed mutagenesis localized the major in vivo and in
      vitro PKA-dependent phosphorylation sites in rabbit lasp-1 to S(99) and S(146).
      BLAST searches confirmed that both sites are conserved in human and chicken
      homologues. Transfection of lasp-1 cDNA encoding for alanine substitutions at
      S(99) and S(146), into parietal cells appeared to suppress the cAMP-dependent
      translocation of lasp-1 to the intracellular canalicular region. In gastric
      fibroblasts, exposure to the protein kinase C activator, PMA, was correlated with
      the translocation of lasp-1 into newly formed F-actin-rich lamellipodial
      extensions and nascent focal complexes. Since lasp-1 does not appear to be
      phosphorylated by PKC, these data suggest that other mechanisms in addition to
      cAMP-dependent phosphorylation can mediate the translocation of lasp-1 to regions
      of dynamic actin turnover. The localization of lasp-1 to these subcellular
      regions under a range of experimental conditions and the phosphorylation
      dependent regulation of this protein in F-actin rich epithelial cells suggests an
      integral and possibly cell-specific role in modulating cytoskeletal/membrane
      based cellular activities.

PMID- 12432068
TI  - Molecular structure of cytoplasmic dynein 2 and its distribution in neuronal and
      ciliated cells.
AB  - Cytoplasmic dynein is involved in a wide variety of cellular functions. In
      addition to the initially characterized form (MAP 1C/dynein 1), a second form of
      cytoplasmic dynein (dynein 2) has been identified and implicated in
      intraflagellar transport (IFT) in lower eukaryotes and in Golgi organization in
      vertebrates. In the current study, the primary structure of the full-length
      dynein 2 heavy chain (HC) was determined from cDNA sequence. The dynein 1 and
      dynein 2 sequences were similar within the motor region, and around the light
      intermediate chain (LIC)-binding site within the N-terminal stem region. The
      dynein 2 HC co-immunoprecipitated with LIC3, a homologue of dynein 1 LICs. Dynein
      2 mRNA was abundant in the ependymal layer of the neural tube and in the
      olfactory epithelium. Antibodies to dynein 2 HC, LIC3 and a component of IFT
      particles strongly stained the ependymal layer lining the lateral ventricles.
      Both dynein 2 HC and LIC3 staining was also observed associated with connecting
      cilia in the retina and within primary cilia of non-neuronal cultured cells.
      These data support a specific role for dynein 2 in the generation and maintenance
      of cilia.

PMID- 12432069
TI  - Wnt regulation of chondrocyte differentiation.
AB  - The Wnt family of growth factors are important regulators of several
      developmental processes including skeletogenesis. To further investigate the role
      of Wnts we analysed their expression in the developing chick limb and performed
      functional analyses in vivo and in vitro. We found that Wnt5b and Wnt11 are
      restricted within the prehypertrophic chondrocytes of the cartilage elements,
      Wnt5a is found in the joints and perichondrium, while Wnt4 is expressed in the
      developing joints and, in some bones, a subset of the hypertrophic chondrocytes.
      These Wnts mediate distinct effects on the initiation of chondrogenesis and
      differentiation of chondrocytes in vitro and in vivo. Wnt4 blocks the initiation
      of chondrogenesis and accelerates terminal chondrocyte differentiation in vitro.
      In contrast, Wnt5a and Wnt5b promote early chondrogenesis in vitro while
      inhibiting terminal differentiation in vivo. As Wnt5b and Wnt11 expression
      overlaps with and appears after Indian hedgehog (Ihh), we also compared their
      effects with Ihh to see if they mediate aspects of Ihh signalling. This showed
      that Ihh and Wnt5b and Wnt11 control chondrogenesis in parallel pathways.

PMID- 12432070
TI  - Essential role of citron kinase in cytokinesis of spermatogenic precursors.
AB  - During spermatogenesis, the first morphological indication of spermatogonia
      differentiation is incomplete cytokinesis, followed by the assembly of stable
      intercellular cytoplasmic communications. This distinctive feature of
      differentiating male germ cells has been highly conserved during evolution,
      suggesting that regulation of the cytokinesis endgame is a crucial aspect of
      spermatogenesis. However, the molecular mechanisms underlying testis-specific
      regulation of cytokinesis are still largely unknown. Citron kinase is a myotonin
      related protein acting downstream of the GTPase Rho in cytokinesis control. We
      previously reported that Citron kinase knockout mice are affected by a complex
      neurological syndrome caused by cytokinesis block and apoptosis of specific
      neuronal precursors. In this report we show that, in addition, these mice display
      a dramatic testicular impairment, with embryonic and postnatal loss of
      undifferentiated germ cells and complete absence of mature spermatocytes. By
      contrast, the ovaries of mutant females appear essentially normal. Developmental
      analysis revealed that the cellular depletion observed in mutant testes is caused
      by increased apoptosis of undifferentiated and differentiating precursors. The
      same cells display a severe cytokinesis defect, resulting in the production of
      multinucleated cells and apoptosis. Our data indicate that Citron kinase is
      specifically required for cytokinesis of the male germ line.

PMID- 12432071
TI  - Identification of a novel sorting determinant for the regulated pathway in the
      secretory protein chromogranin A.
AB  - Chromogranin A (CgA) is the index member of the chromogranin/secretogranin (or
      'granin') family of regulated secretory proteins that are ubiquitously
      distributed in amine- and peptide-containing secretory granules of endocrine,
      neuroendocrine and neuronal cells. Because of their abundance and such widespread
      occurrence, granins have often been used as prototype proteins to elucidate
      mechanisms of protein targeting into dense-core secretory granules. In this
      study, we used a series of full-length, point mutant or truncated CgA-green
      fluorescent protein (GFP) chimeras to explore routing of CgA in neuroendocrine
      PC12 cells. Using sucrose gradient fractionation and 3D deconvolution microscopy
      to determine the subcellular localization of the GFP chimeras, as well as
      secretagogue-stimulated release, the present study establishes that a CgA-GFP
      fusion protein expressed in neuroendocrine PC12 cells is trafficked to the dense
      core secretory granule and thereby sorted to the regulated pathway for
      exocytosis. We show that information necessary for such trafficking is contained
      within the N-terminal but not the C-terminal region of CgA. We find that CgA's
      conserved N-terminal hydrophobic Cys(17)-Cys(38) loop structure may not be
      sufficient for sorting of CgA into dense-core secretory granules, nor is its
      stabilization by a disulfide bond necessary for such sorting. Moreover, our data
      reveal for the first time that the CgA(77-115) domain of the mature protein may
      be necessary (though perhaps not sufficient) for trafficking CgA into the
      regulated pathway of secretion.

PMID- 12432072
TI  - Temporal pattern of NFkappaB activation influences apoptotic cell fate in a
      stimuli-dependent fashion.
AB  - The transcription factor NFkappaB is a critical immediate early response gene
      involved in modulating cellular responses and apoptosis following diverse
      environmental injuries. The activation of NFkappaB is widely accepted to play an
      anti-apoptotic role in cellular responses to injury. Hence, enhancing NFkappaB
      activation in the setting of injury has been proposed as one potential
      therapeutic approach to environmental injuries. To this end, we constructed a
      recombinant adenoviral vector (Ad.IkappaBalphaAS) expressing antisense
      IkappaBalpha mRNA that is capable of augmenting NFkappaB activation prior to and
      following four types of cellular injury [TNF-alpha, UV, hypoxia/reoxygenation
      (H/R) or pervanadate treatment]. Biochemical and functional analyses of NFkappaB
      activation pathways for these injuries demonstrated two categories involving
      either serine (S32/36) phosphorylation (TNF-alpha, UV) or tyrosine (Y42)
      phosphorylation (H/R or PV) of IkappaBalpha. We hypothesized that activation of
      NFkappaB prior to injury using antisense IkappaBalpha mRNA would reduce
      apoptosis. As anticipated, recombinant adenoviral IkappaBalpha phosphorylation
      mutants (Ad.IkappaBalphaS32/36A or Ad.IkappaBalphaY42F) preferentially reduced
      NFkappaB activation and enhanced apoptosis following injuries associated with
      either serine or tyrosine phosphorylation of IkappaBalpha, respectively. These
      studies demonstrate for the first time that an IkappaBalphaY42F mutant can
      effectively modulate NFkappaB-mediated apoptosis in an injury-context-dependent
      manner. Interestingly, constitutive activation of NFkappaB following
      Ad.IkappaBalphaAS infection reduced apoptosis only following injuries associated
      with IkappaBalpha Y42, but not S32/36, phosphorylation. These findings
      demonstrate that the temporal regulation of NFkappaB and the apoptotic
      consequences of this activation are differentially influenced by the pathway
      mediating NFkappaB activation. They also provide new insight into the therapeutic
      potential and limitations of modulating NFkappaB for environmental injuries such
      as ischemia/reperfusion and pro-inflammatory diseases.

PMID- 12432073
TI  - A role for myosin VI in actin dynamics at sites of membrane remodeling during
      Drosophila spermatogenesis.
AB  - Myosin VI has been implicated in membrane dynamics in several organisms. The
      mechanism of its participation in membrane events is not clear. We have used
      spermatogenesis in Drosophila to investigate myosin VI's in vivo role. We
      demonstrate that myosin VI colocalizes with and is required for the accumulation
      of the actin polymerization regulatory proteins, cortactin and arp2/3 complex, on
      actin structures that mediate membrane remodeling during spermatogenesis. In
      addition, we show that dynamin localizes to these actin structures and that when
      dynamin and myosin VI function are both impaired, major defects in actin
      structures are observed. We conclude that during spermatogenesis myosin VI and
      dynamin function in parallel pathways that regulate actin dynamics and that
      cortactin and arp2/3 complex may be important for these functions. Regions of
      myosin VI accumulation are proposed as sites where actin assembly is coupled to
      membrane dynamics.

PMID- 12432074
TI  - Structure of laminin substrate modulates cellular signaling for neuritogenesis.
AB  - Laminin, a major component of basement membranes, can self-assemble in vitro into
      a typical mesh-like structure, according to a mass-action-driven process.
      Previously, we showed that pH acidification dramatically increased the efficiency
      of laminin self-assembly, practically abolishing the necessity for a minimal
      protein concentration. Here we have characterized the morphologies of laminin
      matrices produced in either neutral or acidic conditions and compared their
      capacities to induce neuritogenesis of rat embryonic cortical neurons. Although
      laminin matrices formed in neutral buffer presented aggregates of heterogeneous
      morphology, the acidic matrix consisted of a homogeneous hexagonal sheet-like
      structure. The latter was comparable to the matrix assembled in vivo at the inner
      limiting membrane of the retina in newborn rats, shown here, and to matrices
      secreted by cultivated cells, shown elsewhere. The average neurite length of
      cortical neurons plated on acidic matrices was 244.9 micro m, whereas on neutral
      matrices this value dropped to 104.1 micro m. Increased neuritogenesis on the
      acidic matrix seemed to be associated with a higher degree of neuronal
      differentiation, since cell proliferation was immediately arrested upon plating,
      whereas on neutral matrices, the cell number increased six-fold within 24 hours.
      Investigation of the mechanisms mediating neurite outgrowth on each condition
      revealed that the extensive neuritogenesis observed on the acidic matrix involved
      activation of protein kinase A, whereas moderate neuritogenesis on neutral
      laminin was mediated by activation of protein kinase C and/or myosin light-chain
      kinase. Explants of cerebral cortex from P2 rats did not grow on the neutral
      laminin substrate but presented extensive cell migration and neurite outgrowth on
      the acidic laminin matrix. We propose that laminin can self-assemble
      independently of cell contact and that the assembling mode differentially
      modulates neuritogenesis and neuroplasticity.

PMID- 12432075
TI  - Trafficking of lysosomal cathepsin B-green fluorescent protein to the surface of
      thyroid epithelial cells involves the endosomal/lysosomal compartment.
AB  - Cathepsin B, a lysosomal cysteine proteinase, is involved in limited proteolysis
      of thyroglobulin with thyroxine liberation at the apical surface of thyroid
      epithelial cells. To analyze the trafficking of lysosomal enzymes to
      extracellular locations of thyroid epithelial cells, we have expressed a chimeric
      protein consisting of rat cathepsin B and green fluorescent protein. Heterologous
      expression in CHO cells validated the integrity of the structural motifs of the
      chimeric protein for targeting to endocytic compartments. Homologous expression,
      colocalization and transport experiments with rat thyroid epithelial cell lines
      FRT or FRTL-5 demonstrated the correct sorting of the chimeric protein into the
      lumen of the endoplasmic reticulum, and its subsequent transport via the Golgi
      apparatus and the trans-Golgi network to endosomes and lysosomes. In addition,
      the chimeras were secreted as active enzymes from FRTL-5 cells in a thyroid
      stimulating-hormone-dependent manner. Immunoprecipitation experiments after pulse
      chase radiolabeling showed that secreted chimeras lacked the propeptide of
      cathepsin B. Thus, the results suggest that cathepsin B is first transported to
      endosomes/lysosomes from where its matured form is retrieved before being
      secreted, supporting the view that endosome/lysosome-derived cathepsin B
      contributes to the potential of extracellular proteolysis in the thyroid.

PMID- 12432076
TI  - Genome-wide gene expression profiling in Arabidopsis thaliana reveals new targets
      of abscisic acid and largely impaired gene regulation in the abi1-1 mutant.
AB  - The phytohormone abscisic acid (ABA) plays important regulatory roles in many
      plant developmental processes including seed dormancy, germination, growth, and
      stomatal movements. These physiological responses to ABA are in large part
      brought about by changes in gene expression. To study genome-wide ABA-responsive
      gene expression we applied massively parallel signature sequencing (MPSS) to
      samples from Arabidopsis thaliana wildtype (WT) and abi1-1 mutant seedlings. We
      identified 1354 genes that are either up- or downregulated following ABA
      treatment of WT seedlings. Among these ABA-responsive genes, many encode signal
      transduction components. In addition, we identified novel ABA-responsive gene
      families including those encoding ribosomal proteins and proteins involved in
      regulated proteolysis. In the ABA-insensitive mutant abi1-1, ABA regulation of
      about 84.5% and 6.9% of the identified genes was impaired or strongly diminished,
      respectively; however, 8.6% of the genes remained appropriately regulated.
      Compared to other methods of gene expression analysis, the high sensitivity and
      specificity of MPSS allowed us to identify a large number of ABA-responsive genes
      in WT Arabidopsis thaliana. The database given in our supplementary material
      (http://jcs.biologists.org/supplemental) provides researchers with the
      opportunity to rapidly assess whether genes of interest may be regulated by ABA.
      Regulation of the majority of the genes by ABA was impaired in the ABA
      insensitive mutant abi1-1. However, a subset of genes continued to be
      appropriately regulated by ABA, which suggests the presence of at least two ABA
      signaling pathways, only one of which is blocked in abi1-1.

PMID- 12432077
TI  - Identification of an evolutionarily conserved superfamily of DOCK180-related
      proteins with guanine nucleotide exchange activity.
AB  - Mammalian DOCK180 protein and its orthologues Myoblast City (MBC) and CED-5 in
      Drosophila and Caenorhabditis elegans, respectively, function as critical
      regulators of the small GTPase Rac during several fundamentally important
      biological processes, such as cell motility and phagocytosis. The mechanism by
      which DOCK180 and its orthologues regulate Rac has remained elusive. We report
      here the identification of a domain within DOCK180 named DHR-2 (Dock Homology
      Region-2) that specifically binds to nucleotide-free Rac and activates Rac in
      vitro. Our studies further demonstrate that the DHR-2 domain is both necessary
      and sufficient for DOCK180-mediated Rac activation in vivo. Importantly, we have
      identified several novel homologues of DOCK180 that possess this domain and found
      that many of them directly bind to and exchange GDP for GTP both in vitro and in
      vivo on either Rac or another Rho-family member, Cdc42. Our studies therefore
      identify a novel protein domain that interacts with and activates GTPases and
      suggest the presence of an evolutionarily conserved DOCK180-related superfamily
      of exchange factors.

PMID- 12432078
TI  - Novel function of Chat in controlling cell adhesion via Cas-Crk-C3G-pathway
      mediated Rap1 activation.
AB  - Chat (Cas/HEF1-associated signal transducer) is a novel signaling molecule with
      an N-terminal SH2 domain and C-terminal Cas/HEF1 association domain that is
      implicated in the regulation of cell adhesion. The Cas/HEF1 association domain
      also shows sequence similarity with guanine nucleotide exchange factors for Ras
      family small GTPases. In this study, we found significant activation of Rap1 in
      Chat-overexpressing cells. Myr-Chat, a membrane-targeted form of Chat, activated
      Rap1 more efficiently. Interestingly, Chat and Cas synergistically activated
      Rap1. Certain Cas, Crk or C3G mutants suppressed Rap1 activation by Chat. We also
      confirmed the ternary complex formation consisting of Chat, Cas and Crk. Thus, it
      is likely that Chat-induced Rap1 activation was mediated by upregulation of the
      Cas-Crk-C3G signaling pathway rather than direct guanine nucleotide exchange
      factor activity of Chat. We further demonstrated that Myr-Chat expression induced
      cell periphery spreading and cell shape branching and that this activity also
      depended on the Cas-Crk-C3G pathway and Rap1 activity. Moreover, expression of
      Myr-Chat enhanced integrin-mediated cell adhesion. Taken together we propose a
      novel role for the Chat-Cas complex in controlling cell adhesion via the
      activation of Rap1.

PMID- 12432079
TI  - Subcellular targeting of metabolic enzymes to titin in heart muscle may be
      mediated by DRAL/FHL-2.
AB  - During sarcomere contraction skeletal and cardiac muscle cells consume large
      amounts of energy. To satisfy this demand, metabolic enzymes are associated with
      distinct regions of the sarcomeres in the I-band and in the M-band, where they
      help to maintain high local concentrations of ATP. To date, the mechanism by
      which metabolic enzymes are coupled to the sarcomere has not been elucidated.
      Here, we show that the four and a half LIM-only protein DRAL/FHL-2 mediates
      targeting of the metabolic enzymes creatine kinase, adenylate kinase and
      phosphofructokinase by interaction with the elastic filament protein titin in
      cardiomyocytes. Using yeast two-hybrid assays, colocalisation experiments, co
      immunoprecipitation and protein pull-down assays, we show that DRAL/FHL-2 is
      bound to two distinct sites on titin. One binding site is situated in the N2B
      region, a cardiac-specific insertion in the I-band part of titin, and the other
      is located in the is2 region of M-band titin. We also show that DRAL/FHL-2 binds
      to the metabolic enzymes creatine kinase, adenylate kinase and
      phosphofructokinase and might target these enzymes to the N2B and is2 regions in
      titin. We propose that DRAL/FHL-2 acts as a specific adaptor protein to couple
      metabolic enzymes to sites of high energy consumption in the cardiac sarcomere.

PMID- 12432080
TI  - Effects of Charcot-Marie-Tooth-linked mutations of the neurofilament light
      subunit on intermediate filament formation.
AB  - Neurofilaments (NFs) are the major intermediate filaments (IFs) of mature
      neurons. They play important roles in the structure and function of axons.
      Recently, two mutations in the neurofilament light (NFL) subunit have been
      identified in families affected by Charcot-Marie-Tooth (CMT) neuropathy type 2.
      We have characterized the effects of these NFL mutations on the formation of IF
      networks using a transient transfection system. Both mutations disrupted the self
      assembly of human NFL. The Q333P mutant in the rod domain of NFL also disrupted
      the formation of rat and human NFL/NFM heteropolymers. The phenotypes produced by
      the P8R mutation in the head domain of NFL were less severe. The P8R mutant NFL
      co-polymerized with NFM to form bundled filaments and, less often, aggregates.
      Our results suggest that alterations in the formation of a normal IF network in
      neurons elicited by these NFL mutations may contribute to the development of
      Charcot-Marie-Tooth neuropathy.

PMID- 12432081
TI  - Sbh1p, a subunit of the Sec61 translocon, interacts with the chaperone calnexin
      in the yeast Yarrowia lipolytica.
AB  - The core component of the translocation apparatus, Sec61p or alpha, was
      previously cloned in Yarrowia lipolytica. Using anti-Sec61p antibodies, we showed
      that most of the translocation sites are devoted to co-translational
      translocation in this yeast, which is similar to the situation in mammalian cells
      but in contrast to the situation in Saccharomyces cerevisiae, where post
      translational translocation is predominant. In order to characterize further the
      minimal translocation apparatus in Y. lipolytica, the beta Sec61 complex subunit,
      Sbh1p, was cloned by functional complementation of a Deltasbh1, Deltasbh2 S.
      cerevisiae mutant. The secretion of the reporter protein is not impaired in the
      Y. lipolytica sbh1 inactivated strain. We screened the Y. lipolytica two-hybrid
      library to look for partners of this translocon component. The ER-membrane
      chaperone protein, calnexin, was identified as an interacting protein. By a co
      immunoprecipitation approach, we confirmed this association in Yarrowia and then
      showed that the S. cerevisiae Sbh2p protein was a functional homologue of
      YlSbh1p. The interaction of Sbh1p with calnexin was shown to occur between the
      lumenal domain of both proteins. These results suggest that the beta subunit of
      the Sec61 translocon may relay folding of nascent proteins to their
      translocation.

PMID- 12432082
TI  - Plasma membrane localization of the Yck2p yeast casein kinase 1 isoform requires
      the C-terminal extension and secretory pathway function.
AB  - The S. cerevisiae Yck2 protein is a plasma membrane-associated member of the
      casein kinase 1 protein kinase family that, with its homolog Yck1p, is required
      for bud morphogenesis, cytokinesis, endocytosis and other cellular processes.
      Membrane localization of Yckp is critical for its function, since soluble mutants
      do not provide sufficient biological activity to sustain normal growth. Yck2p has
      neither a predicted signal sequence nor obvious transmembrane domain to achieve
      its plasma membrane localization, but has a C-terminal -Cys-Cys sequence that is
      likely to be palmitoylated. We demonstrate here that Yck2p is targeted through
      association with vesicular intermediates of the classical secretory pathway.
      Yck2p lacking C-terminal Cys residues fails to associate with any membrane,
      whereas substitution of these residues with a farnesyl transferase signal
      sequence allows sec-dependent plasma membrane targeting and biological function,
      suggesting that modification is required for interaction with early secretory
      membranes but that targeting does not require a particular modification. Deletion
      analysis within the 185 residue C-terminus indicates that the final 28 residues
      are critical for membrane association, and additional sequences just upstream are
      required for proper plasma membrane targeting.

PMID- 12432083
TI  - Claudin-2 expression induces cation-selective channels in tight junctions of
      epithelial cells.
AB  - Tight junctions seal the paracellular pathway of epithelia but, in leaky tissues,
      also exhibit specific permeability. In order to characterize the contribution of
      claudin-2 to barrier and permeability properties of the tight junction in detail,
      we studied two strains of Madin-Darby canine kidney cells (MDCK-C7 and MDCK-C11)
      with different tight junctional permeabilities. Monolayers of C7 cells exhibited
      a high transepithelial resistance (>1 kOhms cm(2)), compared with C11 cells (<100
      Ohms cm(2)). Genuine expression of claudin-1 and claudin-2, but not of occludin
      or claudin-3, was reciprocal to transepithelial resistance. However, confocal
      microscopy revealed a marked subjunctional localization of claudin-1 in C11
      cells, indicating that claudin-1 is not functionally related to the low tight
      junctional resistance of C11 cells. Strain MDCK-C7, which endogenously does not
      express junctional claudin-2, was transfected with claudin-2 cDNA. In transfected
      cells, but not in vector controls, the protein was detected in colocalization
      with junctional occludin by means of immunohistochemical analyses. Overexpression
      of claudin-2 in the originally tight epithelium with claudin-2 cDNA resulted in a
      5.6-fold higher paracellular conductivity and relative ion permeabilities of
      Na(+) identical with 1, K(+)=1.02, NMDG(+)=0.79, choline(+)=0.71, Cl(-)=0.12, Br(
      )=0.10 (vector control, 1:1.04:0.95:0.94:0.85:0.83). By contrast, fluxes of
      (radioactively labeled) mannitol and lactulose and (fluorescence labeled) 4 kDa
      dextran were not changed. Hence, with regular Ringer's, Na(+) conductivity was
      0.2 mS cm(-2) in vector controls and 1.7 mS cm(-2) in claudin-2-transfected
      cells, while Cl(-) conductivity was 0.2 mS cm(-2) in both cells. Thus, presence
      of junctional claudin-2 causes the formation of cation-selective channels
      sufficient to transform a 'tight' tight junction into a leaky one.

PMID- 12432084
TI  - Spatial regulation of the guanine nucleotide exchange factor Lte1 in
      Saccharomyces cerevisiae.
AB  - In budding yeast, activation of the small Ras-like GTPase Tem1 triggers exit from
      mitosis and cytokinesis. Tem1 is regulated by Bub2/Bfa1, a two-component GTPase
      activating protein (GAP), and by Lte1, a putative guanine nucleotide exchange
      factor. Lte1 is confined to the bud cortex, and its spatial separation from Tem1
      at the spindle pole body (SPB) is important to prevent untimely exit from
      mitosis. The pathways contributing to Lte1 asymmetry have not been elucidated.
      Here we show that establishment of Lte1 at the cortex occurs by an actin
      independent mechanism, which requires activation of Cdc28/Cln kinase at START and
      Cdc42, a key regulator of cell polarity and cytoskeletal organisation. This
      defines a novel role for Cdc42 in late mitotic events. In turn, dissociation of
      Lte1 from the cortex in telophase depends on activation of the Cdc14 phosphatase.
      Ectopic expression of Cdc14 at metaphase results in premature dephosphorylation
      of Lte1 coincident with its release from the cortex. In vitro phosphatase assays
      confirm that Lte1 is a direct substrate for Cdc14. Our results suggest that the
      asymmetry in Lte1 localisation is imposed by Cdc28-dependent phosphorylation.
      Finally, we report a mutational analysis undertaken to investigate intrinsic Lte1
      determinants for localisation. Our data suggest that an intrameric interaction
      between the N-and C-terminal regions of Lte1 is important for cortex association.

PMID- 12432085
TI  - Intracellular localization and dynamics of myosin-II and myosin-IC in live
      Acanthamoeba by transient transfection of EGFP fusion proteins.
AB  - We developed a reliable method for transient transfection of Acanthamoeba using
      Superfect (Qiagen) and a vector with the Acanthamoeba ubiquitin promoter and
      enhanced green fluorescent protein (EGFP) as the reporter gene. The transfection
      efficiency was 3% for profilin-I-EGFP and EGFP-myosin-II tail, and less than 0.5%
      for larger constructs such as full length myosin-II or myosin-IC. Profilin-I-EGFP
      was distributed throughout the cytoplasm as observed previously with rhodamine
      labeled profilin, while EGFP alone accumulated in the nucleus. EGFP fused to full
      length myosin-II or to the C-terminal 256 residues of the myosin-II tail
      concentrated in fluorescent spots similar to thick filaments and minifilaments
      identified previously in fixed cells with fluorescent antibodies. Thick filaments
      were located in the dorsal cytoplasm and along the lateral margins of the back
      half of the cell. Thick filaments formed behind the leading edge and moved
      continuously towards the rear of the cell, where they disassembled. If
      phosphorylation of the myosin-II heavy chain was prevented by mutation of all
      three phosphorylated serines to alanine, thick filaments of unphosphorylated
      myosin-II accumulated around vesicles of various sizes. EGFP-myosin-IC was spread
      throughout the cytoplasm but concentrated transiently around contractile vacuoles
      and macropinocytosis cups providing that the construct included both the head and
      a tail with the SH3 domain.

PMID- 12432086
TI  - Identification of CfNek, a novel member of the NIMA family of cell cycle
      regulators, as a polypeptide copurifying with tubulin polyglutamylation activity
      in Crithidia.
AB  - Post-translational glutamylation of tubulin plays an important role in regulating
      the interaction between microtubules and associated proteins, but so far the
      enzymes involved in this process have not been cloned from any cellular source.
      Using a modified purification scheme that employs a hydroxyapaptite
      chromatography as the final step we identified a 54 kDa band as the major
      polypeptide copurifying with tubulin polyglutamylation activity from the
      trypanosomatid Crithidia fasciculata. Based on peptide sequence information we
      have cloned the corresponding cDNA and identify Crithidia p54 as a novel member
      (termed CfNek) of the NIMA family of putative cell cycle regulators. CfNek is a
      protein of 479 amino acids that contains an unusual protein kinase domain that
      lacks the glycine-rich loop in subdomain I. The protein also harbours a PEST
      sequence and a pleckstrin homology domain. The tubulin polyglutamylase
      preparation displays the beta-casein phosphorylation activity typical for NIMA
      related kinases. Recombinant His-tagged CfNek expressed in Crithidia localises to
      the flagellar attachment zone/basal body of the parasite. After purification on a
      Ni(2+)-column the recombinant enzyme preparation displays ATP-dependent tubulin
      polyglutamylation activity as well as casein-phosphorylation activity.

PMID- 12432087
TI  - An IP3-activated Ca2+ channel regulates fungal tip growth.
AB  - Hyphal extension in fungi requires a tip-high Ca(2+) gradient, which is generated
      and maintained internally by inositol (1,4,5)-trisphosphate (IP(3))-induced
      Ca(2+) release from tip-localized vesicles and subapical Ca(2+) sequestration.
      Using the planar bilayer method we demonstrated the presence of two types of
      IP(3)-activated Ca(2+) channels in Neurospora crassa membranes with different
      conductances: one low (13 picosiemens), the other high (77 picosiemens). On
      sucrose density gradients the low conductance channel co-localized with
      endoplasmic reticulum and plasma membrane, and the high conductance channel co
      localized with vacuolar membranes. We correlated the effect of inhibitors on
      channel activity with their effect on hyphal growth and Ca(2+) gradients. The
      inhibitor of IP(3)-induced Ca(2+) release, 2-aminoethoxidiphenylborate (2-APB),
      inhibits both channels, while heparin, 8-(N,N-diethylamino)-octyl-3,4,5
      trimethoxybenzoate, hydrochloride (TMB-8) and dantrolene inhibit only the large
      conductance channel. Because 2-APB inhibits hyphal growth and dissipates the tip
      high cytosolic [Ca(2+)] gradient, whereas heparin microinjection, TMB-8 and
      dantrolene treatments do not affect growth, we suggest that the small conductance
      channel generates the obligatory tip-high Ca(2+) gradient during hyphal growth.
      Since IP(3) production must be catalyzed by tip-localized phospholipase C, we
      show that a number of phospholipase C inhibitors [neomycin, 1-[6-((17beta-3
      methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl]- 1H-pyrrole-2,5-dione (U-73122)
      (but not the inactive pyrrolidine U-73343), 3-nitrocoumarin] inhibit hyphal
      growth and affect, similarly to 2-APB, the location of vesicular Ca(2+) imaged by
      chlortetracycline staining.

PMID- 12432088
TI  - Interaction of periplakin and envoplakin with intermediate filaments.
AB  - Periplakin is a component of desmosomes and the epidermal cornified envelope. Its
      N-terminal domain interacts with the plasma membrane; it heterodimerises with
      envoplakin via its rod domain; and its C-terminus interacts with intermediate
      filaments. Periplakin has the shortest C-terminus of the plakin family,
      comprising only the linker domain found in all conventional plakins. By transient
      transfection of COS7 cells and primary human epidermal keratinocytes with
      deletion mutants of the periplakin C-terminus we mapped sequences required for
      intermediate filament interaction to two regions of the linker motif that are
      most highly conserved amongst the plakins. The results were confirmed by overlay
      assays of the binding of in vitro translated periplakin constructs to keratins
      and vimentin. We found that envoplakin and periplakin could still associate with
      each other when parts of their rod domains were deleted and, surprisingly, that
      removal of the entire rod domain did not completely inhibit their interaction. Co
      transfection of constructs containing the C-termini of envoplakin and periplakin
      suggested that the periplakin C-terminus may stabilise the interaction of the
      envoplakin C-terminus with intermediate filaments. We conclude that the
      periplakin C-terminus plays an important role in linking periplakin and
      envoplakin to intermediate filaments.

PMID- 12432089
TI  - The signal of ancient introns is obscured by intron density and homolog number.
AB  - In ancient genes whose products have known 3-dimensional structures, an excess of
      phase zero introns (those that lie between the codons) appear in the boundaries
      of modules, compact regions of the polypeptide chain. These excesses are highly
      significant and could support the hypothesis that ancient genes were assembled by
      exon shuffling involving compact modules. (Phase one and two introns, and many
      phase zero introns, appear to arise later.) However, as more genes, with larger
      numbers of homologs and intron positions, were examined, the effects became
      smaller, dropping from a 40% excess to an 8% excess as the number of intron
      positions increased from 570 to 3,328, even though the statistical significance
      remained strong. An interpretation of this behavior is that novel inserted
      positions appearing in homologs washed out the signal from a finite number of
      ancient positions. Here we show that this is likely to be the case. Analyses of
      intron positions restricted to those in genes for which relatively few intron
      positions from homologs are known, or to those in genes with a small number of
      known homologous gene structures, show a significant correlation of phase zero
      intron positions with the module structure, which weakens as the density of
      attributed intron positions or the number of homologs increases. These effects do
      not appear for phase one and phase two introns. This finding matches the
      expectation of the mixed model of intron origin, in which a fraction of phase
      zero introns are left from the assembly of the first genes, while other introns
      have been added in the course of evolution.

PMID- 12432090
TI  - Transcriptional profiling of a mouse model for Rett syndrome reveals subtle
      transcriptional changes in the brain.
AB  - The Mecp2 gene has been shown to be mutated in most cases of human Rett syndrome,
      and mouse models deleted for the ortholog have been generated. Lineage-specific
      deletion of the gene indicated that the Rett-like phenotype is caused by Mecp2
      deficiency in neurons. Biochemical evidence suggests that Mecp2 acts as a global
      transcriptional repressor, predicting that mutant mice should have genome-wide
      transcriptional deregulation. We tested this hypothesis by comparing global gene
      expression in wild-type and Mecp2 mutant mice. The results of numerous microarray
      analyses revealed no dramatic changes in transcription even in mice displaying
      overt disease symptoms, although statistical power analyses of the data indicated
      that even a small number of relatively subtle changes in transcription would have
      been detected if present. However, a classifier consisting of a combined small
      set of genes was able to distinguish between mutant and wild-type samples with
      high accuracy. This result suggests that Mecp2 deficiency leads to subtle gene
      expression changes in mutant brains which may be associated with the phenotypic
      changes observed.

PMID- 12432091
TI  - SWI/SNF-dependent long-range remodeling of yeast HIS3 chromatin.
AB  - Current models for the role of the SWISNF chromatin remodeling complex in gene
      regulation are focused on promoters, where the most obvious changes in chromatin
      structure occur. Here we present evidence that the SWISNF complex is involved in
      the remodeling of the chromatin structure of an entire gene in vivo. We compared
      the native chromatin structures of a small yeast plasmid containing the HIS3 gene
      purified from uninduced and induced cells. Relative to uninduced chromatin,
      induced chromatin displayed a large reduction in negative supercoiling, a large
      reduction in sedimentation rate, and increased accessibility to restriction
      enzymes with sites located both near and far from the HIS3 promoter. These
      observations indicate that the entire plasmid was remodeled as a result of
      induction. Loss of supercoiling required the presence of the SWISNF remodeling
      complex and the activator Gcn4p in vivo. The TATA boxes were not required,
      suggesting that remodeling was not the result of transcription. The induction
      dependent loss of negative supercoiling was not apparent in cells, indicating
      that the supercoils were lost preferentially from induced chromatin during
      purification. Thus, induced HIS3 chromatin has a highly labile structure that is
      revealed as a result of purification. It is concluded that induction of HIS3
      creates a domain of labile chromatin structure that extends far beyond the
      promoter to include the entire gene. We propose that the SWISNF complex is
      recruited to the HIS3 promoter by Gcn4p and then directs remodeling of a
      chromatin domain, with important implications for transcription.

PMID- 12432092
TI  - An allelic series of mutations in Smad2 and Smad4 identified in a genotype-based
      screen of N-ethyl-N- nitrosourea-mutagenized mouse embryonic stem cells.
AB  - Using selectable genes as proof of principle, a new high-throughput genotype
      based mutation screen in mouse embryonic stem (ES) cells was developed [Chen et
      al. (2002) Nat. Genet. 24, 314-317]. If expanded to nonselectable genes, this
      approach would allow one to proceed quickly from sequence to whole-animal
      phenotypes. Here data are presented showing that a screen of a cryopreserved
      library of clonal, germ line competent, N-ethyl-N-nitrosurea (ENU) mutagenized ES
      cells can identify a large series of allelic mutations in Smad2 and Smad4, two
      nonselectable genes of the transforming growth factor beta superfamily of
      signaling molecules. Whole animal phenotypic analyses of some of these alleles
      provided evidence for novel developmental processes mediated by these components
      of transforming growth factor beta signaling, demonstrating the utility of non
      null alleles created by chemical mutagens. The accurately assessed mutation load
      of the ES cell library indicates that it is a valuable resource for developing
      mouse lines for genetic and functional studies. This methodology can conceptually
      be applied for the generation of an allelic series of subtle mutations at any
      locus of interest in the mouse.

PMID- 12432093
TI  - Role of the thyroid-stimulating hormone receptor signaling in development and
      differentiation of the thyroid gland.
AB  - The thyroid-stimulating hormone/thyrotropin (TSH) is the most relevant hormone in
      the control of thyroid gland physiology in adulthood. TSH effects on the thyroid
      gland are mediated by the interaction with a specific TSH receptor (TSHR). We
      studied the role of TSHTSHR signaling on gland morphogenesis and differentiation
      in the mouse embryo using mouse lines deprived either of TSH (pit(dw)pit(dw)) or
      of a functional TSHR (tshr(hyt)tshr(hyt) and TSHR-knockout lines). The results
      reported here show that in the absence of either TSH or a functional TSHR, the
      thyroid gland develops to a normal size, whereas the expression of
      thyroperoxidase and the sodium/iodide symporter are reduced greatly. Conversely,
      no relevant changes are detected in the amounts of thyroglobulin and the thyroid
      enriched transcription factors TTF-1, TTF-2, and Pax8. These data suggest that
      the major role of the TSH/TSHR pathway is in controlling genes involved in iodide
      metabolism such as sodium/iodide symporter and thyroperoxidase. Furthermore, our
      data indicate that in embryonic life TSH does not play an equivalent role in
      controlling gland growth as in the adult thyroid.

PMID- 12432095
TI  - RAG-dependent peripheral T cell receptor diversification in CD8+ T lymphocytes.
AB  - Rearrangement of T cell receptor (TCR) genes is driven by transient expression of
      V(D)J recombination-activating genes (RAGs) during lymphocyte development.
      Immunological dogma holds that T cells irreversibly terminate RAG expression
      before exiting the thymus, and that all of the progeny arising from mature T
      cells express the parental TCRs. When single pancreatic islet-derived, NRP-A7
      peptide-reactive CD8(+) T cells from nonobese diabetic (NOD) mice were repeatedly
      stimulated with peptide-pulsed dendritic cells, daughter T cells reexpressed
      RAGs, lost their ability to bind to NRP-A7K(d) tetramers, ceased to transcribe
      tetramer-specific TCR genes, and, instead, expressed a vast array of other TCR
      rearrangements. Pancreatic lymph node (PLN) CD8(+) T cells from animals
      expressing a transgenic NRP-A7-reactive TCR transcribed and translated RAGs in
      vivo and displayed endogenous TCRs on their surface. RAG reexpression also
      occurred in the PLN CD8(+) T cells of wild-type NOD mice and could be induced in
      the peripheral CD8(+) T cells of nondiabetes-prone TCR-transgenic B10.H2(g7) mice
      by stimulation with peptide-pulsed dendritic cells. In contrast, reexpression of
      RAGs could not be induced in the CD8(+) T cells of B6 mice expressing an
      ovalbumin-specific, K(b)-restricted TCR, or in the CD8(+) T cells of NOD mice
      expressing a lymphocytic choriomeningitis virus-specific, D(b)-restricted TCR.
      Extra-thymic reexpression of the V(D)J recombination machinery in certain CD8(+)
      T cell subpopulations, therefore, enables further diversification of the
      peripheral T cell repertoire.

PMID- 12432094
TI  - Defining thyrotropin-dependent and -independent steps of thyroid hormone
      synthesis by using thyrotropin receptor-null mice.
AB  - The thyrotropin (TSH) receptor (TSHR) is a member of the heterotrimeric G protein
      coupled family of receptors whose main function is to regulate thyroid cell
      proliferation as well as thyroid hormone synthesis and release. In this study, we
      generated a TSHR knockout (TSHR-KO) mouse by homologous recombination for use as
      a model to study TSHR function. TSHR-KO mice presented with developmental and
      growth delays and were profoundly hypothyroid, with no detectable thyroid hormone
      and elevated TSH. Heterozygotes were apparently unaffected. Knockout mice died
      within 1 week of weaning unless fed a diet supplemented with thyroid powder.
      Mature mice were fertile on the thyroid-supplemented diet. Thyroid glands of TSHR
      KO mice produced uniodinated thyroglobulin, but the ability to concentrate and
      organify iodide could be restored to TSHR-KO thyroids when cultured in the
      presence of the adenylate cyclase agonist forskolin. Consistent with this
      observation was the lack of detectable sodium-iodide symporter expression in TSHR
      KO thyroid glands. Hence, by using the TSHR-KO mouse, we provided in vivo
      evidence, demonstrating that TSHR expression was required for expression of
      sodium-iodide symporter but was not required for thyroglobulin expression,
      suggesting that the thyroid hormone synthetic pathway of the mouse could be
      dissociated into TSHR-dependent and -independent steps.

PMID- 12432096
TI  - Bornyl diphosphate synthase: structure and strategy for carbocation manipulation
      by a terpenoid cyclase.
AB  - The x-ray crystal structure of dimeric (+)-bornyl diphosphate synthase, a metal
      requiring monoterpene cyclase from Salvia officinalis, is reported at 2.0-A
      resolution. Each monomer contains two alpha-helical domains: the C-terminal
      domain catalyzes the cyclization of geranyl diphosphate, orienting and
      stabilizing multiple reactive carbocation intermediates; the N-terminal domain
      has no clearly defined function, although its N terminus caps the active site in
      the C-terminal domain during catalysis. Structures of complexes with aza
      analogues of substrate and carbocation intermediates, as well as complexes with
      pyrophosphate and bornyl diphosphate, provide "snapshots" of the terpene
      cyclization cascade.

PMID- 12432097
TI  - Infection of a human hepatoma cell line by hepatitis B virus.
AB  - Among numerous established human hepatoma cell lines, none has been shown
      susceptible to hepatitis B virus (HBV) infection. We describe here a cell line,
      called HepaRG, which exhibits hepatocyte-like morphology, expresses specific
      hepatocyte functions, and supports HBV infection as well as primary cultures of
      normal human hepatocytes. Differentiation and infectability are maintained only
      when these cells are cultured in the presence of corticoids and dimethyl
      sulfoxide. The specificity of this HBV infection model was ascertained by both
      the neutralization capacity of HBV-envelope protein-specific antibodies and the
      competition with an envelope-derived peptide. HepaRG cells therefore represent a
      tool for deciphering the mechanism of HBV entry. Moreover, their close
      resemblance to normal human hepatocytes makes them suitable for many applications
      including drug metabolism studies.

PMID- 12432098
TI  - On the global Cauchy problem for the nonlinear Schrodinger equation.
AB  - We mainly survey recent results on the nonlinear Schrodinger equations with
      special emphasis on the Cauchy problem, local and global in time and for various
      regularity assumptions on the initial data.

PMID- 12432099
TI  - Polkappa protects mammalian cells against the lethal and mutagenic effects of
      benzo[a]pyrene.
AB  - Several low-fidelity DNA polymerases have recently been discovered that are able
      to bypass DNA lesions during DNA synthesis in vitro. The efficiency and accuracy
      of lesion bypass is, however, both polymerase and lesion specific. For example,
      in vitro studies revealed that human DNA polymerase kappa (Polkappa) is unable to
      insert a base opposite a cis-syn thymine-thymine dimer or cisplatin adduct, yet
      can bypass some DNA lesions such as abasic site and acetylaminofluorene-adducted
      guanine in an error-prone manner. More importantly, Polkappa is able to bypass
      benzo[a]pyrene (B[a]P)-adducted guanine accurately and efficiently. To
      investigate the biological function of Polkappa, we have generated mouse
      embryonic stem (ES) cells deficient in the Polk gene encoding the enzyme. Polk
      deficient ES cells grow normally and their sensitivities to UV and x-ray
      radiation are only slightly affected. In contrast, the mutant cells are highly
      sensitive to both killing and mutagenesis induced by B[a]P. Furthermore, the
      spectrum of mutations recovered in the Polk-deficient cells is different from
      that in the wild-type cells. Thus, our results indicate that Polkappa plays an
      important role in suppressing mutations at DNA lesions generated by B[a]P.

PMID- 12432100
TI  - Structure of factor-inhibiting hypoxia-inducible factor 1: An asparaginyl
      hydroxylase involved in the hypoxic response pathway.
AB  - Precise regulation of the evolutionarily conserved hypoxia-inducible
      transcription factor (HIF) ensures proper adaptation to variations in oxygen
      availability throughout development and into adulthood. Oxygen-dependent
      regulation of HIF stability and activity are mediated by hydroxylation of
      conserved proline and asparagine residues, respectively. Because the relevant
      prolyl and asparginyl hydroxylases use O(2) to effect these posttranslational
      modifications, these enzymes are implicated as direct oxygen sensors in the
      mammalian hypoxic response pathway. Here we present the structure of factor
      inhibiting HIF-1 (FIH-1), the pertinent asparaginyl hydroxylase involved in
      hypoxic signaling. Hydroxylation of the C-terminal transactivation domain (CTAD)
      of HIF by FIH-1 prevents CTAD association with transcriptional coactivators under
      normoxic conditions. Consistent with other structurally known hydroxylases, FIH-1
      is comprised of a beta-strand jellyroll core with both Fe(II) and the cosubstrate
      2-oxoglutarate bound in the active site. Details of the molecular contacts at the
      active site of FIH-1 have been elucidated and provide a platform for future drug
      design. Furthermore, the structure reveals the presence of a FIH-1 homodimer that
      forms in solution and is essential for FIH activity.

PMID- 12432101
TI  - Parallel phenotypic analysis of sporulation and postgermination growth in
      Saccharomyces cerevisiae.
AB  - We have quantitatively monitored the sporulation and germination efficiencies of
      approximately 4,200 yeast deletion strains in parallel by using a molecular bar
      coding strategy. In a single study, we doubled the number of genes functionally
      implicated in sporulation to approximately 400, identifying both positive and
      negative regulators. Our set of 261 sporulation-deficient genes illustrates the
      importance of autophagy, carbon utilization, and transcriptional machinery during
      sporulation. These general cellular factors are more likely to exhibit fitness
      defects when deleted and less likely to be transcriptionally regulated than
      sporulation-specific genes. Our postgermination screening assay identified
      recombinationchromosome segregation genes, aneuploid strains, and possible
      germination-specific factors. Finally, our results facilitate a genome-wide
      comparison of expression pattern and mutant phenotype for a developmental process
      and suggest that 16% of genes differentially expressed during sporulation confer
      altered efficiency of spore production or defective postgermination growth when
      disrupted.

PMID- 12432103
TI  - Testing neoclassical competitive market theory in the field.
AB  - This study presents results from a pilot field experiment that tests predictions
      of competitive market theory. A major advantage of this particular field
      experimental design is that my laboratory is the marketplace: subjects are
      engaged in buying, selling, and trading activities whether I run an exchange
      experiment or am a passive observer. In this sense, I am gathering data in a
      natural environment while still maintaining the necessary control to execute a
      clean comparison between treatments. The main results of the study fall into two
      categories. First, the competitive model predicts reasonably well in some market
      treatments: the expected price and quantity levels are approximated in many
      market rounds. Second, the data suggest that market composition is important:
      buyer and seller experience levels impact not only the distribution of rents but
      also the overall level of rents captured. An unexpected result in this regard is
      that average market efficiency is lowest in markets that match experienced buyers
      and experienced sellers and highest when experienced buyers engage in bargaining
      with inexperienced sellers. Together, these results suggest that both market
      experience and market composition play an important role in the equilibrium
      discovery process.

PMID- 12432104
TI  - CT and MR imaging of ovarian tumors with emphasis on differential diagnosis.
AB  - Ovarian tumors are classified on the basis of tumor origin as epithelial tumors
      (serous and mucinous tumors, endometrioid and clear cell carcinomas, Brenner
      tumor), germ cell tumors (mature and immature teratomas, dysgerminoma, endodermal
      sinus tumor, embryonal carcinoma), sex cord-stromal tumors (fibrothecoma;
      granulosa cell, sclerosing stromal, and Sertoli-Leydig cell tumors), and
      metastatic tumors. Epithelial tumors are primarily cystic and, when malignant,
      are associated with varying proportions of a solid component. Papillary
      projections are a distinctive feature of epithelial tumors. Profuse papillary
      projections are highly suggestive of borderline (low-malignant-potential) or
      malignant tumor. Ovarian teratomas demonstrate lipid material at computed
      tomography and magnetic resonance (MR) imaging. Malignant germ cell tumors
      manifest as a large, complex abdominal mass that contains both solid and cystic
      components. Tumor markers are helpful in diagnosis. The radiologic appearance of
      sex cord-stromal tumors varies from small solid masses to large multicystic
      masses. Granulosa cell tumors are usually large multicystic masses with solid
      components. Fibrothecoma, sclerosing stromal tumor, and Sertoli-Leydig cell
      tumors are usually solid masses. Fibromas have very low signal intensity on T2
      weighted MR images. Certain radiologic findings predominate for each type of
      tumor. Knowledge of these key features of ovarian tumors provides the criteria
      for making a specific diagnosis or substantially narrowing the differential
      diagnosis.

PMID- 12432102
TI  - Developmental regulation of intestinal angiogenesis by indigenous microbes via
      Paneth cells.
AB  - The adult mouse intestine contains an intricate vascular network. The factors
      that control development of this network are poorly understood. Quantitative
      three-dimensional imaging studies revealed that a plexus of branched
      interconnected vessels developed in small intestinal villi during the period of
      postnatal development that coincides with assembly of a complex society of
      indigenous gut microorganisms (microbiota). To investigate the impact of this
      environmental transition on vascular development, we compared the capillary
      networks of germ-free mice with those of ex-germ-free animals colonized during or
      after completion of postnatal gut development. Adult germ-free mice had arrested
      capillary network formation. The developmental program can be restarted and
      completed within 10 days after colonization with a complete microbiota harvested
      from conventionally raised mice, or with Bacteroides thetaiotaomicron, a
      prominent inhabitant of the normal mouse/human gut. Paneth cells in the
      intestinal epithelium secrete antibacterial peptides that affect luminal
      microbial ecology. Comparisons of germ-free and B. thetaiotaomicron-colonized
      transgenic mice lacking Paneth cells established that microbial regulation of
      angiogenesis depends on this lineage. These findings reveal a previously
      unappreciated mechanism of postnatal animal development, where microbes
      colonizing a mucosal surface are assigned responsibility for regulating
      elaboration of the underlying microvasculature by signaling through a bacteria
      sensing epithelial cell.

PMID- 12432105
TI  - Spectrum of CT findings in acute pyogenic pelvic inflammatory disease.
AB  - Pelvic inflammatory disease (PID) is a common medical problem, affecting nearly 1
      million women each year. Although the radiology literature is replete with
      discussions of the sonographic manifestations of PID, little has been published
      regarding the computed tomographic (CT) appearances of this entity. CT findings
      in early PID include obscuration of the normal pelvic floor fascial planes,
      thickening of the uterosacral ligaments, cervicitis, oophoritis, salpingitis, and
      accumulation of simple fluid in the endometrial canal, fallopian tubes, and
      pelvis. As the disease progresses, this simple fluid may become complex and the
      inflammatory changes may progress to frank tubo-ovarian or pelvic abscesses.
      Reactive inflammation of adjacent structures is common and can manifest as small
      or large bowel ileus or obstruction, hydroureter and hydronephrosis, right upper
      quadrant inflammation (Fitz-Hugh-Curtis syndrome), or peritonitis. Familiarity
      with the CT appearances of these manifestations is important for timely diagnosis
      and treatment of PID and its complications.

PMID- 12432106
TI  - Differential diagnosis of periampullary carcinomas at MR imaging.
AB  - Periampullary carcinomas arise within 2 cm of the major duodenal papilla and
      comprise carcinomas of the ampulla, distal common bile duct, pancreas, and
      duodenum. Their clinical features and anatomic locations are similar, as are the
      therapeutic approaches; however, their long-term outcomes vary. Magnetic
      resonance (MR) images of 89 pathologically proved periampullary carcinomas (29
      ampullary carcinomas, 27 distal common bile duct carcinomas, 21 pancreatic
      carcinomas, six duodenal carcinomas, and six unclassified carcinomas) were
      reviewed. Ampullary carcinoma manifests as a small mass, periductal thickening,
      or bulging of the duodenal papilla. Pancreatic carcinoma is characterized by a
      discrete parenchymal mass, which enhances poorly on dynamic gadolinium-enhanced
      images. Sometimes, two proximal and two distal pancreatic and biliary ducts
      appear as four separate ducts (the four-segment sign). Dilatation of side
      branches of the pancreatic ducts is frequently seen in pancreatic carcinoma but
      not in other periampullary carcinomas. Distal bile duct carcinoma manifests as
      luminal obliteration and wall thickening or as an intraductal polypoid mass. A
      dilated proximal bile duct, a nondilated distal bile duct, and a dilated or
      nondilated pancreatic duct may form the three-segment sign. MR
      cholangiopancreatography and sectional MR imaging are useful in determining the
      origins of periampullary carcinomas.

PMID- 12432107
TI  - CT-guided transgluteal drainage of deep pelvic abscesses: indications, technique,
      procedure-related complications, and clinical outcome.
AB  - Deep pelvic abscesses may present a unique challenge for percutaneous drainage
      because of numerous overlying structures, which preclude safe percutaneous
      access. These structures include the pelvic bones, intestine, bladder, iliac
      vessels, and gynecologic organs. Use of the transgluteal approach to drain these
      abscesses can circumvent these obstacles and provide a useful surgical
      alternative or a temporizing measure. The transgluteal approach requires a
      thorough understanding of the anatomy of the sciatic foramen region and
      associated anatomic structures. The ideal approach for transgluteal access is to
      insert the catheter as close to the sacrum as possible, at the level of the
      sacrospinous ligament. Transgluteal drainage can be performed with the tandem
      trocar technique or the Seldinger technique. Modifications of the procedure are
      needle aspiration not followed by catheter placement, use of the angled gantry
      technique, bilateral transgluteal drainage, combined anterior and posterior
      drainage, and drainage of necrotic pelvic masses. The transgluteal approach is a
      useful option in pediatric patients. Daily catheter care is essential for
      successful percutaneous catheter therapy. Although pain has been cited as a
      common complication of the technique, this complication can be minimized with
      judicious use of analgesia and a meticulous technique. Other complications are
      hemorrhage and catheter malposition.

PMID- 12432108
TI  - Selections from the buffet of food signs in radiology.
AB  - Certain pathologic conditions have classic radiologic manifestations that
      resemble various types of food. These "food signs" are highly memorable and
      easily recognizable and include findings that resemble various fruits and
      vegetables; meat, fish, and egg dishes; pasta, rice, grains, and bread
      (carbohydrates); desserts, cakes, and candy; and dishes, cutlery, condiments, and
      so on. It is important that radiologists recognize these classic signs, which
      will allow confident diagnosis on the basis of imaging findings alone or
      narrowing of the differential diagnosis.

PMID- 12432109
TI  - Pulmonary activity on labeled leukocyte images: physiologic, pathologic, and
      imaging correlation.
AB  - Accurate interpretation of labeled leukocyte images requires knowledge of
      pulmonary labeled leukocyte uptake: its prevalence and patterns and its
      correlation with technical, physiologic, and pathologic conditions as well as
      with other imaging findings. Images obtained shortly after injection of labeled
      cells are characterized by diffuse pulmonary activity, which decreases over time,
      until about 4 hours after injection when it becomes indistinguishable from
      background activity, remaining constant thereafter. Focal pulmonary uptake that
      is segmental or lobar in appearance is most often associated with bacterial
      pneumonia. Focal pulmonary uptake that is not segmental or lobar results from
      technical problems during labeling or reinfusion and is not usually associated
      with infection. Diffuse pulmonary uptake on images obtained more than 4 hours
      after reinjection of labeled cells is associated with a variety of pathologic
      conditions, some of the more common being opportunistic infection, radiation
      pneumonitis, pulmonary drug toxicity, adult respiratory distress syndrome, and
      sepsis. However, this pattern is almost never seen in bacterial pneumonia. When
      pulmonary uptake patterns are analyzed and correlated with the clinical
      situation, labeled leukocyte scintigraphy can provide useful information about
      pulmonary disease.

PMID- 12432111
TI  - Bronchial and nonbronchial systemic artery embolization for life-threatening
      hemoptysis: a comprehensive review.
AB  - Massive hemoptysis is one of the most dreaded of all respiratory emergencies and
      can have a variety of underlying causes. In 90% of cases, the source of massive
      hemoptysis is the bronchial circulation. Diagnostic studies for massive
      hemoptysis include radiography, bronchoscopy, and computed tomography (CT) of the
      chest. Bronchoscopy and chest radiography have been considered the primary
      methods for the diagnosis and localization of hemoptysis. Many researchers
      currently suggest that CT should be performed prior to bronchoscopy in all cases
      of massive hemoptysis. Bronchial artery embolization (BAE) is a safe and
      effective nonsurgical treatment for patients with massive hemoptysis. However,
      nonbronchial systemic arteries can be a significant source of massive hemoptysis
      and a cause of recurrence after successful BAE. Knowledge of the bronchial artery
      anatomy, together with an understanding of the pathophysiologic features of
      massive hemoptysis, are essential for planning and performing BAE in affected
      patients. In addition, interventional radiologists should be familiar with the
      techniques, results, and possible complications of BAE and with the
      characteristics of the various embolic agents used in the procedure.

PMID- 12432112
TI  - Neuroimaging in pediatric leukemia and lymphoma: differential diagnosis.
AB  - Recent advances in therapy for pediatric hematologic neoplasms have greatly
      improved the prognosis but have resulted in an increased incidence of associated
      complications and toxic effects. The main neuroimaging features in pediatric
      patients with leukemia or lymphoma treated with chemotherapy or radiation therapy
      were retrospectively reviewed. To simplify the approach and facilitate
      differential diagnosis, the neuroimaging features have been classified into three
      main categories: central nervous system manifestations of primary disease, side
      effects of therapeutic procedures (radiation therapy, chemotherapy, bone marrow
      transplantation), and complications due to immunosuppression, particularly
      infections. Manifestations of primary disease include cerebrovascular
      complications (hemorrhage, cerebral infarction) and central nervous system
      involvement (infiltration of the meninges, parenchyma, bone marrow, orbit, and
      spine). Effects of radiation therapy include white matter disease, mineralizing
      microangiopathy, parenchymal brain volume loss, radiation-induced cryptic
      vascular malformations, and second neoplasms. Effects of chemotherapy and bone
      marrow transplantation include hemorrhage, dural venous thrombosis, white matter
      disease, reversible posterior leukoencephalopathy syndrome, and anterior
      lumbosacral radiculopathy. Both the underlying malignancy and antineoplastic
      therapy can cause immunosuppression. Fungi are the most frequent causal
      microorganisms in immunosuppressed patients with infection. Familiarity with the
      imaging findings is essential for proper diagnosis of neurologic symptoms in
      pediatric patients with oncohematologic disease.

PMID- 12432113
TI  - US of renal insufficiency in neonates.
AB  - Congenital and acquired renal diseases that can produce renal insufficiency
      during the neonatal period may be classified according to their ultrasonographic
      (US) characteristics: increased parenchymal echogenicity (renal parenchymal
      diseases, angiotensin-converting enzyme inhibitor fetopathy, cortical necrosis),
      cystic disease (glomerulocystic kidney disease, autosomal recessive polycystic
      renal disease, multicystic dysplastic kidney, cystic renal dysplasia),
      obstructive uropathies (ureteropelvic junction obstruction, posterior urethral
      valves), infections (candidal infections and bezoars), and renal agenesis. High
      resolution sector and linear-array transducers allow characterization of the
      underlying pathologic conditions in many cases. Findings of renal parenchymal
      disease will vary at Doppler US and, during the acute phase, diastolic flow can
      be decreased, absent, or reversed. In patients with glomerulocystic kidney
      disease, US shows bilaterally enlarged kidneys with diffusely increased
      echogenicity and retention of a reniform contour, loss of corticomedullary
      differentiation, and cortical cysts. Obstruction of the ureteropelvic junction,
      the most common cause of hydronephrosis in neonates, can be seen at US as a
      dilated renal pelvis with dilated and communicating calices, lack of dilatation
      in the distal portion of the ureter, changes of renal dysplasia with increased
      echogenicity of the renal parenchyma, and parenchymal cysts, depending on the
      severity and duration of the obstruction. High-resolution US provides improved
      characterization of the renal parenchyma and more precise description of renal
      architecture.

PMID- 12432114
TI  - Abdominal manifestations of situs anomalies in adults.
AB  - A study was made of 19 adults with situs anomalies (situs inversus [n = 10],
      situs ambiguous with polysplenia [n = 8], situs ambiguous with asplenia [n = 1]).
      No patient had congenital heart disease, bowel obstruction related to
      malrotation, or immune deficiency disorders. All 10 patients with situs inversus
      had mirror-image location of the abdominal organs relative to situs solitus; nine
      had dextrocardia, and one had levocardia. The eight adults with situs ambiguous
      with polysplenia demonstrated a spectrum of abnormalities. All had some degree of
      abdominal heterotaxy, including midline livers and gallbladders (n = 5), right
      sided stomachs and spleens (n = 3), and rotational abnormalities of the small
      bowel and colon (n = 7). Other findings included multiple spleens (n = 7),
      interruption of the inferior vena cava (IVC) with azygous or hemiazygous
      continuation (n = 7), truncation of the pancreas (n = 6), and ipsilateral
      location of the aorta and IVC (n = 1). In the one patient with asplenia, a
      midline liver, right-sided stomach, bowel rotation abnormality, IVC interruption,
      and pancreatic truncation were noted. Recognition of the spectrum of situs
      anomalies is important because the altered anatomy associated with these
      anomalies may result in confusing imaging findings when seen in conjunction with
      acquired diseases.

PMID- 12432115
TI  - Soft-tissue and osseous impingement syndromes of the ankle: role of imaging in
      diagnosis and management.
AB  - Soft-tissue and osseous impingement syndromes of the ankle can be an important
      cause of chronic pain, particularly in the professional athlete. The main
      impingement syndromes are anterolateral, anterior, anteromedial, and posterior
      impingement. These conditions arise from initial ankle injuries, which, in the
      subacute or chronic situation, lead to development of abnormal osseous and soft
      tissue thickening within the ankle joint. The relative contributions of the
      osseous and soft-tissue abnormalities are variable, but whatever component is
      dominant there is physical impingement and painful limitation of ankle movement.
      Conventional radiography is usually the first imaging technique performed and
      allows assessment of any potential bone abnormality, particularly in anterior and
      posterior impingement. Computed tomography (CT) and isotope bone scanning have
      been largely superseded by magnetic resonance (MR) imaging, but the accuracy and
      role of MR imaging in assessment of possible ankle impingement have not been
      clearly established. MR imaging can demonstrate osseous and soft-tissue edema in
      anterior or posterior impingement. Studies of conventional MR imaging have
      produced conflicting sensitivities and specificities in assessment of
      anterolateral impingement. CT and MR arthrographic techniques allow the most
      accurate assessment of the capsular recesses, albeit with important limitations
      in diagnosis of clinical impingement syndromes.

PMID- 12432117
TI  - Central neurocytoma.

PMID- 12432118
TI  - From the archives of the AFIP. Cerebral intraventricular neoplasms: radiologic
      pathologic correlation.
AB  - Intraventricular neoplasms are readily seen on cross-sectional images, but the
      myriad possibilities may make a focused differential diagnosis elusive.
      Consideration of the tissue within and composing the ventricular lining and the
      clinical findings provide the means to limit the differential diagnosis when
      analyzing an intraventricular mass on an imaging study. Ependymomas are typically
      calcified, are more common in children, are more common in the fourth ventricle,
      and show intense enhancement on contrast-enhanced images. Subependymomas and
      central neurocytomas have an affinity for the anterior portion of the lateral
      ventricle, and both commonly demonstrate a heterogeneous cystic appearance on
      cross-sectional images. Subependymomas are more common in older adults, whereas
      central neurocytomas are more common before 40 years of age. Subependymal giant
      cell astrocytomas always lie near the foramen of Monro and are characterized by
      frequent calcification, intense enhancement on contrast-enhanced studies, and the
      presence of other stigmata seen in tuberous sclerosis. When a mass is centered on
      the choroid plexus, a highly vascular tumor-either choroid plexus papilloma,
      choroid plexus carcinoma, meningioma, or metastasis-should be suspected. The
      characteristic heavily lobulated appearance of a choroid plexus tumor favors this
      diagnosis over other possibilities, although it is not always possible to
      distinguish between the more common benign form, the choroid plexus papilloma,
      and the less common malignant counterpart, the choroid plexus carcinoma. By using
      clinical, demographic, and imaging findings, one can significantly limit the
      differential diagnosis for many of the most common intraventricular neoplasms.

PMID- 12432119
TI  - Best cases from the AFIP. Invasive pulmonary aspergillosis: radiologic and
      pathologic findings.

PMID- 12432120
TI  - Best cases from the AFIP. Malignant peritoneal mesothelioma.

PMID- 12432122
TI  - 2001 Plenary Session: Friday Imaging Symposium. CT Screening for Cancer.

PMID- 12432123
TI  - Why a CT scan instead of a history and physical examination?

PMID- 12432124
TI  - CT screening for colorectal cancer.

PMID- 12432125
TI  - Screening CT: rationale.

PMID- 12432127
TI  - AAPM/RSNA Physics Tutorial for Residents: Topics in CT. Radiation dose in CT.
AB  - This article describes basic radiation dose concepts as well as those
      specifically developed to describe the radiation dose from computed tomography
      (CT). Basic concepts of radiation dose are reviewed, including exposure, absorbed
      dose, and effective dose. Radiation dose from CT demonstrates variations within
      the scan plane and along the z axis because of its unique geometry and usage.
      Several CT-specific dose descriptors have been developed: the Multiple Scan
      Average Dose descriptor, the Computed Tomography Dose Index (CTDI) and its
      variations (CTDI(100), CTDI(w), CTDI(vol)), and the dose-length product. Factors
      that affect radiation dose from CT include the beam energy, tube current-time
      product, pitch, collimation, patient size, and dose reduction options. Methods of
      reducing the radiation dose to a patient from CT include reducing the milliampere
      seconds value, increasing the pitch, varying the milliampere-seconds value
      according to patient size, and reducing the beam energy. The effective dose from
      CT can be estimated by using Monte Carlo methods to simulate CT of a mathematical
      patient model, by estimating the energy imparted to the body region being
      scanned, or by using conversion factors for general anatomic regions. Issues
      related to radiation dose from CT are being addressed by the Society for
      Pediatric Radiology, the American Association of Physicists in Medicine, the
      American College of Radiology, and the Center for Devices and Radiological Health
      of the Food and Drug Administration.

PMID- 12432128
TI  - Integrating the healthcare enterprise: a primer. Part 6: the fellowship of IHE:
      year 4 additions and extensions.
AB  - Recently, one of my friends, a computer wizard, paid me a visit. As we were
      talking, I mentioned that I had recently installed a picture archiving and
      communication system and a radiology information system. I told him how happy I
      was with the system and showed him a compact disk (CD) from it. To my surprise,
      he threw it into my microwave oven and turned it on. Instantly I got very upset,
      because the System had become precious to me, but he said, "Do not worry, it is
      unharmed." After a few minutes, he took the CD out, gave it to me and said, "Take
      a close look at it." To my surprise, the CD was quite cold to hold and it seemed
      to be heavier than before. At first, I could not see anything, but on the inner
      edge of the central hole, I saw an inscription, an inscription finer than
      anything I had ever seen before. The inscription shone piercingly bright, and yet
      remote, as if out of a great depth:
      12413AEB2ED4FA5E6F7D78E78BEDE8209450920F923A40Eel0E50CC98D444AA08E324. "I cannot
      understand the fiery letters," I said in a timid voice. "No, but I can," he said.
      "The letters are Hex, of an ancient mode, but the language is that of DICOM,
      which I shall not utter here. But in common English, this is what it says: Two
      integration profiles to schedule work flow. Five for radiology with room to grow.
      One for the bacon to bring it home. One for HIPAA all alone. And one for results
      for those who would know. One technical framework in which to find them. One
      technical framework to guide them. One technical framework to bring them all. And
      in the Connect-a-thon bind them. In the Land of Lincoln where no shadows are. We
      continue the saga of the fellowship of the IHE: clinicians, radiologists,
      informaticians, administrators, technologists, imaging system vendors, and non
      imaging system vendors, as they begin their year 4 transactions.

PMID- 12432129
TI  - Improving educational computer exhibits at radiologic meetings by modifying
      computer environment: results of an observational study.
AB  - An observational study of educational computer exhibits (ECEs) at the 86th
      Scientific Assembly and Annual Meeting of the Radiological Society of North
      America in 2000 was performed to determine the frequency with which the ECEs were
      in working order. At any given time, an average of 10% of the 71 exhibits were
      found to be inoperable, and, although some exhibits were functioning 100% of the
      time, others were not functioning up to 55% of the time. These observations
      underscore the importance of careful design when creating a computer-based
      exhibit for a meeting. Downtime of ECEs at meetings is the result of both
      intentional and unintentional user actions. Given that traditional poster
      presentations are "working" 100% of the time, modifications made to the
      environment of an exhibit computer to reduce downtime would be beneficial.
      Several relatively easy computer configuration steps can be taken that will
      likely improve the amount of time that an exhibit is functional. Electronic
      exhibits allow a more interactive experience for users and, with some assistance,
      will continue to be an effective educational tool.

PMID- 12432130
TI  - Integration of a multimedia teaching and reference database in a PACS
      environment.
AB  - In one radiology department, a computerized authoring and editing environment was
      developed and integrated with the picture archiving and communication systems
      (PACS) for creation of image-based electronic teaching files to replace a
      collection of printed film images. This multimedia database and authoring
      environment allows physicians to create reference databases for teaching and
      research directly from clinical cases being reviewed on PACS diagnostic
      workstations. The database engine allows users to generate stand-alone CD-ROMs
      (compact disks, read-only memory) and World Wide Web-based teaching files. The
      system is fully compliant with the Digital Imaging and Communications in Medicine
      (DICOM) standard and supports a large number of standard multimedia image file
      formats. The focus of the development was on convenience and ease of use of a
      generic system adaptable to all users. The software was integrated on the PACS
      workstations to allow users to add new cases to the database at any time and
      anywhere in the department. A pilot system was implemented in clinical operation,
      with a central server and several client units.

PMID- 12432131
TI  - Cardiovascular MR imaging: technique optimization and detection of disease in
      clinical practice.
AB  - Magnetic resonance (MR) imaging has emerged as an important and growing means of
      cardiovascular imaging, with many advantages over other radiologic modalities,
      including excellent spatial and temporal resolution, lack of ionizing radiation,
      and noninvasiveness. In this article, the utility of MR imaging in cardiovascular
      imaging and in the diagnosis of cardiovascular disease will be discussed. MR
      techniques for evaluating the heart and vasculature will be described, and
      troubleshooting techniques will be presented. Imaging findings in congenital
      anomalies such as septal defects, patent ductus arteriosus, transposition of the
      great arteries, and tetralogy of Fallot will be identified. Valvular lesions and
      methods for evaluating valvular function will be discussed. MR imaging findings
      in acquired disorders such as aneurysms and pericardial disease will be
      described.

PMID- 12432132
TI  - Urban sprawl and public health.

PMID- 12432133
TI  - Collaborative HIV Prevention Research in Minority Communities Program: a model
      for developing investigators of color.
AB  - The Collaborative HIV Prevention Research in Minority Communities Program was
      developed to address the simultaneous overrepresentation of communities of color
      among those with HIV and under-representation of researchers of color at the
      National Institutes of Health. The program is designed to help scientists develop
      their programs of research and obtain significant research funding. The 27-month
      program has the following elements: small grant funding, a structured summer
      program, individualized long-term research collaboration, access to behavioral
      science expertise, and internal peer review of all products. To date, the 19
      program participants, eight of whom have not completed the program, have received
      almost $11,000,000 in research funding and have conducted culturally specific
      research with communities of color. In addition, a network of HIV prevention
      investigators of color has been created. Institutes throughout the National
      Institutes of Health (NIH) and other entities could use this model to develop
      investigators of color, improve the quality of research with communities of
      color, and begin to address health disparities.

PMID- 12432135
TI  - Effect of race and/or ethnicity in use of antiretrovirals and prophylaxis for
      opportunistic infection: a review of the literature.
AB  - OBJECTIVE: The authors performed a systematic and critical review of published
      studies investigating potential associations between race and/or ethnicity and
      use of HIV-related medications, including antiretroviral medications and
      medications used for prophylaxis of opportunistic infections. METHODS: The
      authors conducted a Web-based search of the University of California
      MEDLINE/HealthSTAR database for articles published from January 1, 1985, to
      October 31, 2001. References cited in articles were used to identify potential
      additional articles for this review. The authors reviewed articles published in
      peer-reviewed scientific journals that analyzed race/ethnicity as a predictor of
      antiretroviral or HIV-related prophylactic medication use. RESULTS: The authors
      identified 28 reports, including: (a) 26 studies published in 1991-2001 that
      addressed antiretroviral use, spanning data collection periods from 1984 to 1999;
      (b) 11 studies published in 1994-2001 that addressed prophylaxis for Pneumocystis
      carinii pneumonia (PCP), reporting on data collected from 1989 to 1998; and (c)
      three studies published from 1998 to 2001 that addressed prophylaxis for other
      opportunistic infections, reporting on data collected from 1993 to 1998. Among
      the studies that addressed antiretroviral use, 14 found a negative association
      between non-white race and at least one measure of antiretroviral use, three
      studies found a positive association, and 16 studies found no association; seven
      studies found mixed results across several measures of antiretroviral use. Only
      four of 11 studies found a negative association between race/ethnicity and PCP
      prophylaxis; the remainder found no association. Two out of three studies found a
      negative association between race/ethnicity and prophylaxis for other infections.
      CONCLUSIONS: There is evidence of racial/ethnic disparities in utilization of
      antiretrovirals, which are known to be strongly associated with positive HIV
      health outcomes. It is now imperative for researchers and policy makers to better
      understand the causes of these disparities, evaluate programs that affect the
      delivery of HIV medications, and implement program and policy changes necessary
      to address the disparities.

PMID- 12432136
TI  - Access to and use of HIV antiretroviral therapy: variation by race/ethnicity in
      two public insurance programs in the U.S.
AB  - OBJECTIVES: To examine access to and use of HIV highly active antiretroviral
      therapy (HAART) by race/ethnicity in Medicaid and the AIDS Drug Assistance
      Program (ADAP) in 1998 in four states. METHODS: The authors analyzed
      reimbursement claims and AIDS surveillance data in California, Florida, New York,
      and Texas. Study subjects were identified using diagnostic or medication codes
      specific to HIV. The race/ethnicity of program enrollees was compared to
      representation in the HIV epidemic to examine access. Claims for antiretroviral
      (ARV) use were compared to U.S. Public Health Service treatment guidelines to
      assess HAART use. RESULTS: The authors identified 151,000 HIV-infected
      individuals in these two programs in the four states. Evidence of AIDS or
      symptomatic HIV was present in 78%-88% of enrollees in Medicaid, versus 31%-48%
      in ADAP. African Americans participated in Medicaid 10%-53% above and in ADAP 17%
      31% below representation in the epidemic. Non-Latino whites exhibited the
      opposite pattern, being in Medicaid 5%-38% below and in ADAP 9%-65% above
      epidemic representation. Latinos participated more in ADAP (7%-31%), except in
      New York. HAART use over 90 days (July-September) ranged from 38% to 76% by
      program and state. Differences by race/ethnicity were inconsistent and small:
      African Americans had lower HAART use by 6%-14% in California and Florida
      Medicaid, and Latinos had higher HAART use by 2%-11% in ADAP and in Texas
      Medicaid. CONCLUSIONS: African Americans were more likely to access HIV drugs
      through Medicaid than through ADAP, which may reflect differences in program
      eligibility criteria as well as care seeking later in HIV disease. Differences in
      the use of HAART by race/ethnicity within state programs were small.

PMID- 12432137
TI  - Responding to racial and ethnic disparities in use of HIV drugs: analysis of
      state policies.
AB  - OBJECTIVES: The objectives of this study were to assess racial/ethnic trends in
      surveillance data in four states--California, New York, Florida and Texas,
      identify structural barriers to and facilitators of access to HIV pharmaceuticals
      by individuals in Medicaid and the AIDS Drug Assistance Program (ADAP), and
      identify treatment education and outreach efforts responding to the needs of
      ethnic minority HIV patients. METHODS: State surveillance and claims data were
      used to assess trends by race/ethnicity in AIDS cases and mortality as well as
      participation rates in Medicaid and ADAP. Key informant interviews with state
      program administrators and local clinic-based benefit eligibility workers were
      used to identify social and policy barriers to and facilitators of access to HIV
      drugs and state strategies for overcoming racial/ethnic disparities. RESULTS:
      Racial/ethnic disparities in the reduction of AIDS-related mortality were
      identified in three of the four states studied. Policy barriers included Medicaid
      requirements for legal immigration status and residency, limits on Medicaid
      eligibility based on disability requirements, and state-imposed income and
      benefit limits on ADAP. Social barriers to accessing AIDS medications included
      lack of information, distrust of government, and HIV-related stigma. State
      strategies for overcoming disparities included contracting with community-based
      organizations for treatment education and outreach, the use of regional minority
      coordinators, and public information campaigns. CONCLUSIONS: State policies play
      a significant role in determining access to HIV drugs, and state policies can be
      used to reduce racial/ethnic disparities in pharmaceutical access. Overall,
      eliminating racial/ethnic disparities in access to HIV pharmaceuticals appears to
      be an achievable goal.

PMID- 12432138
TI  - A summary measure of health disparity.
AB  - OBJECTIVES: Eliminating health disparities is a goal of Healthy People 2010. In
      order to track progress toward this goal, we need improved methods for measuring
      disparity. The authors present the Index of Disparity (ID) as a summary measure
      of disparity. METHODS: The ID, a modified coefficient of variation, was used to
      measure disparity across populations defined on the basis of race/ethnicity,
      income, education, and gender. Disparity was also assessed for a diverse range of
      health indicators and over time to monitor trends. RESULTS: Disparity in
      cardiovascular disease deaths decreased based on gender from 1989 to 1998 but was
      largely unchanged based on race/ethnicity. The magnitude of disparities in
      cervical cancer and cholesterol screening, smoking, exercise, and health
      insurance ranged from 1.9% to 78.6%. The largest disparities for health
      indicators were not associated with any particular population classification,
      whether defined on the basis of race/ethnicity, education, or income.
      CONCLUSIONS: To eliminate disparities, we need a means to assess disparities
      across many types of health indicators. Furthermore, for a given health
      indicator, disparities may differ for populations defined on the basis of
      race/ethnicity, education, income, and so on. The ID is a simple method for
      summarizing disparities across groups within a population that can be applied
      across health indicators regardless of magnitude, over time to monitor trends,
      and across different populations.

PMID- 12432139
TI  - Smoking cessation and prevention: an urgent public health priority for American
      Indians in the Northern Plains.
AB  - OBJECTIVE: The purpose of this study was to compare the prevalence of cigarette
      smoking and smoking cessation among American Indians living on or near Montana's
      seven reservations to those of non-Indians living in the same geographic region.
      METHODS: Data for Montana Behavioral Risk Factor Surveillance System (BRFSS)
      respondents (n = 1,722) were compared to data from a BRFSS survey of American
      Indians living on or near Montana's seven reservations in 1999 (n = 1,000).
      Respondents were asked about smoking and smoking cessation as well as
      cardiovascular disease (CVD) and selected risk factors. Quit ratios were
      calculated for both groups. RESULTS: American Indians were more likely to report
      current smoking (38%) than non-Indians (19%; p < 0.001). Thirty-seven percent of
      Indian respondents with CVD risk factors reported current smoking, compared with
      17% of non- Indians with CVD risk factors. However, there was no significant
      difference in reported smoking rates between Indians (21%) and non-Indians (27%)
      with a history of CVD. Indian smokers were more likely to report quitting for one
      or more days in the past year (67%), compared with non-Indians (43%). Quit ratios
      were significantly lower among Indians (43%) than among non-Indians (65%).
      CONCLUSIONS: High smoking rates in Indians, particularly among those with other
      CVD risk factors, demonstrate an urgent need for culturally sensitive smoking
      cessation interventions among Northern Plains Indians and highlight the need for
      the Surgeon General's focus on smoking in minority populations.

PMID- 12432140
TI  - Assessing the evidence submitted in the development of a workplace smoking
      regulation: the case of Maryland.
AB  - OBJECTIVE: This study compared the characteristics of the basic science,
      biomedical, and socioeconomic literature submitted in 1993-1994 by supporters and
      opponents of the proposed workplace regulation of tobacco smoke developed by the
      Maryland Occupational Safety and Health (MOSH) Advisory Board. METHODS: The
      authors retrospectively analyzed 544 written publications submitted to the MOSH
      Advisory Board regarding the proposed workplace regulation of tobacco smoke.
      Outcome measures included the type and year of publication and, for journal
      articles, the journal's peer review policy and impact factor. RESULTS: Supporters
      of regulation submitted fewer documents (n = 164) than opponents (n = 380).
      Supporters of regulation submitted a lower proportion of conference proceedings
      and a higher proportion of government reports. The publications submitted to the
      regulators by the supporters of regulation were more recently published than the
      materials submitted by opponents. Journal articles represented more than half of
      the publications submitted; most were peer-reviewed. Supporters of regulation
      submitted articles from journals with higher impact factors (median impact factor
      2.78) than did opponents of regulation (median 1.66; p = 0.0005), and articles
      that were published more recently (median year of publication 1990) than those
      submitted by opponents (median 1989; p = 0.0001). CONCLUSIONS: Public health
      advocates should highlight the scientific evidence base that supports tobacco
      control regulations. Public health advocates should encourage and support
      regulatory officials' use of the criteria of peer review, impact factor, and date
      of publication to prioritize their review of submitted documents in order to base
      policy on the best available evidence.

PMID- 12432141
TI  - IOM study: uninsured don't get needed health care.

PMID- 12432143
TI  - Community-based environmental risk assessment.

PMID- 12432144
TI  - Harm reduction: 25 years later.

PMID- 12432145
TI  - Geoff Bible's class.

PMID- 12432147
TI  - Germany: how did it get like this?

PMID- 12432152
TI  - Pakistan: a hard and lonely struggle for the resistance.

PMID- 12432154
TI  - The ID effect on youth access to cigarettes.
AB  - OBJECTIVE: To estimate the effect on cigarette sales rates when minors present
      identification (ID). DESIGN: Controlled experiment in which minors attempting to
      purchase cigarettes either carried a valid photo ID (documenting they were
      minors) or carried no ID, and were instructed to show the ID or admit having no
      ID if the clerk requested proof of age. SETTING: Census of retail stores in six
      urban and suburban Colorado counties. SUBJECTS: Retail cigarette clerks,
      uninformed of the study. MAIN OUTCOME MEASURES: Relative risk (RR) of cigarette
      sale to a minor when ID was requested and presented versus requested but not
      presented. RESULTS: When clerks requested ID, sales were more than six times as
      frequent if minors presented ID than if they did not (12.2% v 2.0%, RR 6.2, p <
      0.0001). The relative risk remained substantially unchanged under adjustment for
      demographic and circumstantial covariates. CONCLUSIONS: Presentation of photo ID
      in compliance checks increases illegal cigarette sales to minors. The impact may
      vary among states or locales and depends strongly on how often clerks request
      proof of age. Clerk training and responsible cigarette sales practices should
      include age calculations from photo ID. Programmes relying on investigative
      purchase attempts to estimate actual rates of cigarette sales to minors should
      ascertain and replicate local ID presenting behaviours that minors typically use
      during genuine attempts to buy cigarettes.

PMID- 12432155
TI  - Socially cued smoking in bars, nightclubs, and gaming venues: a case for
      introducing smoke-free policies.
AB  - OBJECTIVE: To assess smokers' perceived effects of smoking bans in bars,
      nightclubs, and gaming venues on their smoking behaviour. DESIGN: Cross sectional
      structured interview telephone survey of a random sample of smokers. SETTING:
      Population survey in Victoria, Australia. PARTICIPANTS: The sample comprised 597
      smokers and analyses were conducted on 409 smokers who reported patronising bars,
      nightclubs or gaming venues at least monthly. OUTCOME MEASURES: Two outcomes
      studied were socially cued smoking and readiness to quit as a result of
      restrictions on smoking in social venues. Respondents were identified as socially
      cued smokers if they reported attending bars, nightclubs or gaming venues at
      least monthly and said that they smoke more in these venues. The potential
      influence of bans in social venues on readiness to quit was measured by asking
      respondents if they would be more or less likely to quit smoking if smoking were
      banned in hotels, licensed bars, gaming venues, and nightclubs. RESULTS: Of all
      adult smokers, 69% attended bars, nightclubs or gaming venues at least monthly.
      Of these smokers, 70% reported smoking more in these settings (socially cued
      smokers) and 25% indicated they would be likely to quit if smoking were banned in
      social venues. Compared to smokers not likely to quit if there were bans, smokers
      likely to quit were more likely to be socially cued (odds ratio (OR) 2.64), to be
      contemplating or preparing to quit (OR 2.22), to approve of bans in social venues
      (OR 2.44), and to be aged under 30 years (OR 1.73). Compared with smokers not
      socially cued, socially cued smokers were more likely to be under the age of 30
      years (OR 6.15), more likely to believe that there is a safe level of cigarette
      consumption (OR 2.25), and more likely to have previously made a quit attempt (OR
      2.60). CONCLUSIONS: These findings suggest that bans on smoking in bars,
      nightclubs, and gaming venues could reduce cigarette consumption and increase
      quitting among smokers who frequently patronise these settings. These beneficial
      effects are likely to be strongest among younger smokers.

PMID- 12432156
TI  - Tobacco industry success in preventing regulation of secondhand smoke in Latin
      America: the "Latin Project".
AB  - OBJECTIVE: To examine the tobacco industry's strategy to avoid regulations on
      secondhand smoke exposure in Latin America. METHODS: Systematic search of tobacco
      industry documents available through the internet. All available materials,
      including confidential reports regarding research, lobbying, and internal
      memoranda exchanged between the tobacco industry representatives, tobacco
      industry lawyers, and key players in Latin America. RESULTS: In Latin America,
      Philip Morris International and British American Tobacco, working through the law
      firm Covington & Burling, developed a network of well placed physicians and
      scientists through their "Latin Project" to generate scientific arguments
      minimising secondhand smoke as a health hazard, produce low estimates of
      exposure, and to lobby against smoke-free workplaces and public places. The
      tobacco industry's role was not disclosed. CONCLUSIONS: The strategies used by
      the industry have been successful in hindering development of public health
      programmes on secondhand smoke. Latin American health professionals need to be
      aware of this industry involvement and must take steps to counter it to halt the
      tobacco epidemic in Latin America.

PMID- 12432157
TI  - ASHRAE Standard 62: tobacco industry's influence over national ventilation
      standards.
AB  - OBJECTIVE: To describe the role of the tobacco industry in the development of
      ventilation standards for indoor air quality by influencing the American Society
      of Heating, Refrigeration, and Air Conditioning Engineers (ASHRAE). METHODS:
      Review of tobacco industry documents available on the internet between January
      2001 and March 2002. Search terms included "ASHRAE", "ventilation", "minutes",
      "memo", and the names of key players and organisations as identified in the
      initial searches. Analysis of ASHRAE and other relevant documents publicly
      available and the personal files of a Standard 62 committee member; interviews of
      a selected number of ASHRAE players; observation of an ASHRAE meeting. RESULTS:
      The tobacco industry has been involved in the development of ventilation
      standards for over 20 years. It has successfully influenced the standard and
      continues to attempt to change the standard from a smoke-free framework into an
      "accommodation" framework. The industry acts directly and through consultants and
      allies. The major health groups have been largely absent and the health interests
      have been poorly represented in standard development. While concentrated in the
      USA, ASHRAE standards are adopted worldwide. CONCLUSION: The tobacco industry
      determined that allowing smoking in ventilation standards for indoor air quality
      was a high priority and dedicated significant human and financial resources to
      ensure that its interests were represented. The health groups, until recently,
      have largely ignored the policy implications for tobacco control of standard
      development. This situation is changing, but unless health groups maintain high
      visibility within ASHRAE, the tobacco industry may succeed in creating a standard
      that ignores the dangers of secondhand smoke.

PMID- 12432158
TI  - Dissemination of the AHCPR clinical practice guideline in community health
      centres.
AB  - OBJECTIVE: To evaluate dissemination of the Agency for Health Care Policy and
      Research (AHCPR) Smoking cessation clinical practice guideline in community
      health centres. DESIGN: Pre- and post-trial. SETTING: Fourteen community health
      centres in Rhode Island. SUBJECTS: Provider performance was assessed with 1798
      and 1591 patient contacts, in pre-post cross sectional consecutive samples,
      respectively, and 891 contacts at one year follow up. INTERVENTIONS: Three, one
      hour on-site provider training sessions, on review of effective tobacco
      interventions, use of office systems, and tobacco counselling skill building.
      OUTCOME MEASURES: Chart documentation of four A's (Ask, Advise, Assist, and
      Arrange follow up) at most recent primary care visit. RESULTS: While average
      performance rates increased for Ask and Advise (from 30% to 44%, and 19% to 26%,
      pre-post, respectively), significant increases were found only for some visit
      types, with further differences by patient sex. There were significant increases
      for Ask for all except obstetric/gynaecological (ob/gyn) visit types. Patients at
      yearly physicals and first visits were more likely to be asked at all time
      points, while males were more likely to be asked at acute visits than were
      females. There were no significant increases for Advise, Assist, and Arrange
      across time, although female patients showed a differential increase in Advise
      post-training. Advise was significantly more likely in yearly physicals and first
      visits, and less likely in ob/gyn visits, at all time points. CONCLUSIONS: This
      guideline dissemination effort resulted in quite different provider counselling
      rates across patient sexes, and visit types. Guideline implementation may require
      more sustained efforts, with multiple strategies, which are reinforced at higher
      policy levels, to more fully integrate tobacco interventions into routine primary
      care practice with all patients who smoke.

PMID- 12432159
TI  - African American leadership groups: smoking with the enemy.
AB  - BACKGROUND: Among all racial and ethnic groups in the USA, African Americans bear
      the greatest burden from tobacco related disease. The tobacco industry has been
      highly influential in the African American community for decades, providing
      funding and other resources to community leaders and emphasising publicly its
      support for civil rights causes and groups, while ignoring the negative health
      effects of its products on those it claims to support. However, the industry's
      private business reasons for providing such support were unknown. OBJECTIVE: To
      understand how and for what purposes the tobacco industry sought to establish and
      maintain relationships with African American leaders. METHODS: Review and
      analysis of over 700 previously secret internal tobacco industry documents
      available on the internet. RESULTS: The tobacco industry established
      relationships with virtually every African American leadership organisation and
      built longstanding social connections with the community, for three specific
      business reasons: to increase African American tobacco use, to use African
      Americans as a frontline force to defend industry policy positions, and to defuse
      tobacco control efforts. CONCLUSION: As the tobacco industry expands its global
      reach, public health advocates should anticipate similar industry efforts to
      exploit the vulnerabilities of marginalised groups. The apparent generosity,
      inclusion, and friendship proffered by the industry extract a price from groups
      in the health of their members. Helping groups anticipate such efforts, confront
      industry co-optation, and understand the hidden costs of accepting tobacco
      industry largesse should be part of worldwide tobacco control efforts.

PMID- 12432160
TI  - The case for fire safe cigarettes made through industry documents.
AB  - OBJECTIVES: To examine the extensive research undertaken by the tobacco industry
      over the past 25 years toward development of a fire safe cigarette. METHODS:
      Research was conducted through a web based search of internal tobacco industry
      documents made publicly available through the 1998 Master Settlement Agreement.
      RESULTS: The documents reveal that the tobacco industry produced a fire safe
      cigarette years ago, but failed to put it on the market. These findings
      contradict public industry claims that denied the technical feasibility and
      commercial acceptability of fire safe cigarettes. Internal documents also reveal
      a decades long, coordinated political strategy used to block proposed legislation
      and obfuscate the fire safe issue. CONCLUSIONS: Federal legislation mandating
      fire safe cigarettes is needed.

PMID- 12432161
TI  - Assessment of nicotine dependence symptoms in adolescents: a comparison of five
      indicators.
AB  - OBJECTIVE: To examine the psychometric properties, test-retest reliability, and
      convergent construct validity of five indicators of nicotine dependence (ND)
      symptoms in adolescents. DESIGN: Analysis of baseline data from a prospective
      study on the natural history of ND in 1264 adolescents aged 12-13 years. SETTING:
      Ten Montreal high schools. SUBJECTS: 233 grade 7 students who had smoked
      cigarettes one or more times in the three months preceding the baseline data
      collection. MAIN OUTCOME MEASURES: Five indicators of ND symptoms including two
      that are multi-dimensional (a proxy measure of ICD-10 criteria for tobacco
      dependence; the Hooked on Nicotine Checklist (HONC)) and three new indicators of
      "symptom clusters" that emerged from principal component analysis (ND/cravings,
      withdrawal symptoms, self medication). RESULTS: All five indicators demonstrated
      acceptable internal and test-retest reliability. The correlation between the HONC
      and ND/cravings was 0.910. All other correlations between indicators ranged
      between 0.716-0.824. There was considerable overlap in the independent correlates
      identified for each indicator. CONCLUSIONS: All five indicators performed well
      psychometrically. Until the meaning, relative importance, and usefulness of each
      scale is clarified in longitudinal work, decisions regarding which scale(s) are
      most informative will depend more on the content of the scales, the need for a
      multi- or unidimensional indicator, and whether or not the scale is theory based.

PMID- 12432162
TI  - Evaluation of a culturally appropriate smoking cessation intervention for
      Latinos.
AB  - BACKGROUND: Many believe that smoking cessation programmes for Latinos should be
      tailored to the values and beliefs of the culture. However, randomised studies of
      culturally appropriate smoking cessation interventions with Latinos are rare.
      METHODS: Latino smokers (n = 313) were randomised to an intervention condition or
      a comparison group. The intervention was a three month programme based on social
      cognitive constructs and delivered in the smoker's home by trained lay health
      advisors, or promotores. Comparison group participants were referred to the
      California Smoker's Helpline in Spanish. Predictors of abstinence among all
      participants also were examined. RESULTS: About one week post-intervention,
      validated (carbon monoxide) past week abstinence rates were more than twice as
      high in the intervention group (20.5%) than in the comparison (8.7%) (p < or =
      0.005). The pattern of results held for self reported abstinence, and after
      recoding dropouts to non-abstinence. The primary predictor of abstinence was
      number of cigarettes smoked per day at baseline, a common measure of addiction.
      CONCLUSIONS: The culturally appropriate intervention facilitated abstinence in
      Latino smokers, at least in the short term. Strengths and weaknesses of the study
      are discussed.

PMID- 12432163
TI  - Mentholated cigarettes and smoking habits in whites and blacks.
AB  - OBJECTIVE: To determine if cigarette mentholation is associated with the
      frequency of smoking and with quitting, and whether mentholation explains racial
      differences in these two smoking behaviours. DESIGN: Cross sectional analysis of
      case-control data on smoking and lung cancer. SUBJECTS: Limited to 19 545 current
      and former cigarette smokers. MAIN OUTCOME MEASURES: Smoking > 20 cigarettes per
      day (cpd) versus < or = 20 cpd, and continued smoking versus quit smoking.
      RESULTS: Among blacks, the prevalence odds ratio (POR) of heavy smoking (> or =
      21 cpd) associated with mentholated cigarettes versus non-mentholated cigarettes
      was 0.7 (95% confidence interval (CI) 0.5 to 0.9) in current smokers and 0.6 (95%
      CI 0.4 to 0.9) in former smokers. Among whites, the corresponding POR were 0.9
      (95% CI 0.8 to 1.0) and 0.9 (95% CI 0.8 to 1.0). Blacks were less likely to have
      been heavy smokers than whites, but the difference was unrelated to cigarette
      mentholation. The POR of continued smoking versus quitting, associated with
      mentholated cigarettes was 1.1 (95% CI 1.0 to 1.2) for both blacks and whites.
      CONCLUSION: Smoking > 20 cpd was independently associated with white race. Among
      blacks, smoking < or = 20 cpd was independently associated with mentholated
      cigarettes. The risk of quitting was not associated with cigarette menthol
      flavour.

PMID- 12432164
TI  - Tobacco spending and children in low income households.
AB  - OBJECTIVE: To examine the role of tobacco use in creating financial hardship for
      New Zealand (NZ) low income households with children. DATA: The 1996 NZ census
      (smoking prevalence by household types), Statistics NZ (household spending
      surveys 1988-98), and NZ Customs (tobacco released from bond 1988-98). MAIN
      OUTCOME MEASURES: Proportion of children in households with smokers and < or =
      15,000 NZ dollars gross income per adult. Proportion of spending on tobacco of
      second lowest equivalised household disposable income decile and of solo parent
      households. RESULTS: In < or = 15,000 NZ dollars gross income per adult
      households with both children and smokers, there were over 90,000 children, or
      11% of the total population aged less than 15 years. Enabling second lowest
      income decile households with smokers to be smoker-free would on average allow an
      estimated 14% of the non-housing budgets of those households to be reallocated.
      CONCLUSIONS: The children in low income households with smokers need to be
      protected from the financial hardship caused by tobacco use. This protection
      could take the form of more comprehensive government support for such households
      and stronger tobacco control programmes. A reliance on tobacco price policy alone
      to deter smokers is likely to have mixed outcomes-for example, increased hardship
      among some of these households. The challenge for tobacco control is to move from
      a sole focus on "doing good" towards incorporating the principle of "doing no
      harm".

PMID- 12432165
TI  - Acute effects of Advance: a potential reduced exposure product for smokers.
AB  - OBJECTIVE: To examine the acute effects of Advance, a potential reduced exposure
      product (PREP) for smokers marketed as a means to reduce exposure to toxic gases
      and tobacco specific nitrosamines. DESIGN, SETTING, PARTICIPANTS: Latin square
      ordered, three condition, laboratory based, crossover design with 20 smokers of
      light or ultra-light cigarettes (15 or more cigarettes/day). In each 2.5 hour
      condition, participants completed an 8-puff smoking bout from their own brand,
      Advance, or an unlit cigarette (that is, sham smoking) every 30 minutes for a
      total of four bouts. MAIN OUTCOME MEASURES: Subject rated measures of
      tobacco/nicotine withdrawal; carbon monoxide (CO), and heart rate; plasma
      nicotine concentrations. RESULTS: Relative to own brand, Advance produced similar
      withdrawal suppression and heart rate increase, lower CO boost, and higher plasma
      nicotine concentrations. CONCLUSIONS: PREPs for smokers need to be evaluated
      using a comprehensive strategy that includes empirical examination of acute and
      long term effects. Adequate withdrawal suppression and potentially lower
      concentrations of CO associated with Advance use are positive factors, although
      higher nicotine concentrations do not constitute "reduced exposure". Overall,
      longer exposure periods are necessary to determine carcinogen delivery. PREP
      evaluation is complex and should be completed objectively.

PMID- 12432167
TI  - Be wary of subsidising nicotine replacement therapy.

PMID- 12432168
TI  - Are smoke-free policies good for business?

PMID- 12432169
TI  - Impact of the new EU health warnings on the Dutch quit line.

PMID- 12432170
TI  - Intervention effects on youth tobacco use in the Community Intervention Trial
      (COMMIT).

PMID- 12432171
TI  - Voluntary food intake by elite female cyclists during training and racing:
      influence of daily energy expenditure and body composition.
AB  - We estimated self-reported energy intake (EI) and cycling energy expenditure
      (CEE) during racing and training over 26 days (9 days recovery [REC], 9 days
      training [TRN], and 8 days racing [RACE], which included a 5-day stage race) for
      8 members of the Australian National Training Squad [mean SD; 25.1 4.0 years,
      59.2 4.4 kg, 3.74 0.24 L min-1 VO 2 peak, 13.6 4.5 % Body fat (% B fat)]. After
      70 days of training and racing, average body mass increased by 1.1 kg (95%CI 0.5
      to 1.7 kg; p <.01) and average % B fat decreased by 0.9% (95%CI 1.7 to 0.1%; p
      <.05). These minor changes, however, were not considered clinically significant.
      CEE was different between RACE, TRN, and REC (2.15 0.18 vs. 1.73 0.25 vs. 0.72
      0.15 MJ d-1, p <.05). Reported EI for RACE and TRN were higher than REC (14.87
      3.03, 13.70 4.04 vs. 11.98 3.57 MJ d-1, p <.05). Reported intake of carbohydrate
      for RACE and TRN were also higher than REC (588 122, 536 130 vs. 448 138 g d-1, p
      <.05). Reported intake of fat (59 21 68 21 g d-1) was similar during RACE, TRN,
      and REC, whereas protein intake tended to be higher during TRN (158 49 g d-1)
      compared to RACE and REC (136 33; 130 33 g d-1). There was a relationship between
      average CEE and average EI over the 26 days (r = 0.77, p <.05), but correlations
      between CEE and EI for each of the women varied (r = 0.02 to 0.67). There was a
      strong trend for an inverse relationship between average EI and % Bf at (r = 
      .68, p =.06, n = 8). In this study, increases in reported EI during heavy
      training and racing were the result of an increase in carbohydrate intake. Most
      but not all cyclists modulated EI based on CEE. Research is required to determine
      whether physiological or psychological factors are primarily responsible for the
      observed relationship between CEE and EI and also the inverse correlation between
      % B fat and EI.

PMID- 12432172
TI  - Nutritional intake of French soccer players at the clairefontaine training
      center.
AB  - Young, French male athletes undergoing intensive elite sports training at the
      National Training Centre in Clairefontaine served as the subjects (N = 180; age
      range: 13 to 16 years) in a 3-year dietary survey aimed at characterizing their
      nutritional intake in terms of energy, macronutrients, calcium, and iron. Each
      year, the subjects were grouped by level into 3 promotions so that 9 groups could
      be studied. Dietary intake data were collected each year for each subject in the
      9 groups, using a 5-day food record. The results showed that their total energy
      intake (TEI) was insufficient for athletes (ranging from 2352   454 to 3395   396
      kcal/d as opposed to the recommended range of between 3819 and 5185 kcal/d).
      Furthermore, their diet was unbalanced, with too great an emphasis upon fatty
      foods (29.1   2.8 to 34.1   3.1% TEI vs. the 20% recommended), to the detriment
      of carbohydrates (48.5   4.3 to 56.6   3.1% TEI vs. the 55 to 60% recommended).
      The calcium intake was too low in 5 of the 9 groups while, in contrast, the iron
      intake was satisfactory in all groups. Furthermore, during this 3-year period at
      the Clairefontaine Centre, the subjects significantly (p <.05) improved their
      calcium and iron intakes (1021   197 and 12   2 mg/d in 1996, 1299   155 and 16  
      2 mg/d in 1997, and 1252   184 and 17   2 mg/d in 1998). This rise in
      micronutrient intakes may have been due to a physiological adaptation to growth
      or to the positive effects of courses on nutrition given during their stay at the
      Centre.

PMID- 12432173
TI  - Disorders of the female athlete triad among collegiate athletes.
AB  - This study examined the prevalence of and relationship between the disorders of
      the female athlete triad in collegiate athletes participating in aesthetic,
      endurance, or team/anaerobic sports. Participants were 425 female collegiate
      athletes from 7 universities across the United States. Disordered eating,
      menstrual dysfunction, and musculoskeletal injuries were assessed by a
      health/medical, dieting and menstrual history questionnaire, the Eating Attitudes
      Test (EAT-26), and the Eating Disorder Inventory Body Dissatisfaction Subscale
      (EDI-BD). The percentage of athletes reporting a clinical diagnosis of anorexia
      and bulimia nervosa was 3.3% and 2.3%, respectively; mean ( SD) EAT and EDI-BD
      scores were 10.6 9.6 and 9.8 7.6, respectively. The percentage of athletes with
      scores indicating "at-risk" behavior for an eating disorder were 15.2% using the
      EAT-26 and 32.4% using the EDI-BD. A similar percentage of athletes in aesthetic,
      endurance, and team/anaerobic sports reported a clinical diagnosis of anorexia or
      bulimia. However, athletes in aesthetic sports scored higher on the EAT-26 (13.5
      10.9) than athletes in endurance (10.0 9.3) or team/anaerobic sports (9.9 9.0, p
      <.02); and more athletes in aesthetic versus endurance or team/anaerobic sports
      scored above the EAT-26 cut-off score of 20 (p <.01). Menstrual irregularity was
      reported by 31% of the athletes not using oral contraceptives, and there were no
      group differences in the prevalence of self-reported menstrual irregularity.
      Muscle and bone injuries sustained during the collegiate career were reported by
      65.9% and 34.3% of athletes, respectively, and more athletes in aesthetic versus
      endurance and team/anaerobic sports reported muscle (p =.005) and/or bone
      injuries (p <.001). Athletes "at risk" for eating disorders more frequently
      reported menstrual irregularity (p =.004) and sustained more bone injuries (p
      =.003) during their collegiate career. These data indicate that while the
      prevalence of clinical eating disorders is low in female collegiate athletes,
      many are "at risk" for an eating disorder, which places them at increased risk
      for menstrual irregularity and bone injuries.

PMID- 12432174
TI  - Effect of carbohydrate ingestion during exercise on post-exercise substrate
      oxidation and energy intake.
AB  - Thirteen physically active, eumenorrheic, normal-weight (BMI < 25 kg/m2) females,
      aged 18-30 years, completed 4 experimental conditions, with the order based on a
      Latin Square Design: (a). CHO/Ex: moderate-intensity exercise (65% VO2peak) with
      a net energy cost of approximately 500 kcals, during which time the subject
      consumed a carbohydrate beverage (45 g CHO) at specific time intervals; (b).
      CHO/NoEx: a period of time identical to (a). but with subjects consuming the
      carbohydrate while sitting quietly rather than exercising; (c). NoCHO/Ex: same
      exercise protocol as condition (a.) during which time subjects consumed a non
      caloric placebo beverage; and (d). NoCHO/NoEx: same as the no-exercise condition
      (b). but with subjects consuming a non-caloric placebo beverage. Energy
      expenditure, and fat and carbohydrate oxidation rates for the entire
      exercise/sitting period plus a 90-min recovery period were determined by
      continuous indirect calorimetry. Following recovery, subjects ate ad libitum
      amounts of food from a buffet and were asked to record dietary intake during the
      remainder of the day. Total fat oxidation (exercise plus recovery) was attenuated
      by carbohydrate compared to placebo ingestion by only approximately 4.5 g. There
      was a trend (p =.08) for a carbohydrate effect on buffet energy intake such that
      the CHO/Ex and CHO/NoEx energy intakes were lower than the NoCHO/Ex and
      NoCHO/NoEx energy intakes, respectively (mean for CHO conditions: 683 kcal; NoCHO
      conditions: 777 kcal). Average total energy intake (buffet plus remainder of the
      day) was significantly lower (p <.05) following the conditions when carbohydrate
      was consumed (CHO/Ex = 1470 kcal; CHO/NoEx = 1285 kcal) compared to the
      noncaloric placebo (NoCHO/Ex =1767 kcal; NoCHO/NoEx = 1660 kcal). In conclusion,
      in young women engaging in regular exercise, ingestion of 45 g of carbohydrate
      during exercise only modestly suppresses total fat oxidation during exercise.
      Furthermore, the ingestion of carbohydrate with or without exercise resulted in a
      lower energy intake for the remainder of the day.

PMID- 12432175
TI  - The effects of a pre-exercise feeding with or without fungal carbohydrases
      (Carbogen) on blood parameters and exercise performance in elite cyclists: a
      preliminary study.
AB  - The effect of fungal carbohydrases (Carbogen[C]) consumed with a meal replacement
      bar (MBR) on glucose metabolism and exercise performance was determined in 5 male
      competitive cyclists. After a 12-hour fast, subjects performed two 60-min cycling
      bouts at 80% VO2max followed by a time-to-exhaustion (TE) ride at 100% VO2max.
      One hour prior to each cycling bout, subjects ingested a MRB + 160-mg C or 160-mg
      CaCO3 placebo (PL) in a double-blind, counterbalanced fashion. Blood was drawn
      for determination of glucose, insulin, and lactate at: fasting, 1 hour post
      feeding, minutes 30 and 60 of exercise, and after TE. Two-way ANOVA revealed a
      significant (p <.05) treatment and time effect for glucose, with C being higher
      than PL. Interaction effects were observed for insulin and lactate. An increase
      in TE (min) at 100% VO2max was observed in the C versus PL trial (6.3 3.4 vs. 4.4
      2.9, p <.001). A MRB+C may benefit cyclists due to increased BG and improved
      exercise performance.

PMID- 12432176
TI  - Effect of high-fat, high-carbohydrate, and high-protein meals on metabolism and
      performance during endurance cycling.
AB  - The effect of pre-exercise meal composition on metabolism and performance in
      cycling were investigated in a crossover study. Twelve competitive cyclists
      ingested high-fat, high-carbohydrate, or high-protein meals 90 min before a
      weekly exercise test. The test consisted of a 1-hour pre-load at 55% peak power,
      five 10-min incremental loads from 55 to 82% peak power (to measure the peak fat
      oxidation rate), and a 50-km time trial that included three 1-km and 4-km
      sprints. A carbohydrate supplement was ingested throughout the exercise. Relative
      to the high-protein and high-fat meals, the high-carbohydrate meal halved the
      peak fat-oxidation rate and reduced the fat oxidation across all workloads by a
      factor of 0.20 to 0.58 (p =.002-.0001). Reduced fat availability may have
      accounted for this reduction, as indicated by lower plasma fatty acid, lower
      glycerol, and higher pre-exercise insulin concentrations relative to the other
      meals (p =.04-.0001). In contrast, fat oxidation following the high-protein meal
      was similar to that following the high-fat meal. This similarity was linked to
      evidence suggesting greater lipolysis and plasma fat availability following high
      protein relative to high-carbohydrate meals. Despite these substantial effects on
      metabolism, meal composition had no clear effect on sprint or 50-km performance.

PMID- 12432177
TI  - Effect of creatine supplementation and a lacto-ovo-vegetarian diet on muscle
      creatine concentration.
AB  - The purpose of this investigation was to examine the effects of preceding oral
      creatine monohydrate with a lacto-ovo-vegetarian diet on muscle creatine
      concentration. Thirty-two healthy men, who regularly consumed an omnivorous diet,
      were randomly assigned to consume a weight maintaining, lacto-ovo-vegetarian
      (LOV; n = 16) or omnivorous (Omni; n = 16) diet for 26 days. In addition to their
      assigned diet, on day 22 of the study, subjects were assigned in a double-blind
      manner to receive either creatine monohydrate (CM; 0.3 g   kg   d 1 + 20 g
      Polycose) or an equivalent dose of placebo (PL) for 5 days. There were no
      significant differences between the LOV and Omni groups at baseline with respect
      to age, height, and weight. The results demonstrated that consuming a LOV diet
      for 21 days was an effective procedure to decrease muscle creatine concentration
      (p <.01) in individuals who normally consume meat and fish in their diet.
      However, muscle total creatine (TCr) following creatine supplementation did not
      differ statistically between LOV and Omni diet groups (148.6   4.5 vs. 141.7  
      4.5 mmol kg-1 d.m.).

PMID- 12432178
TI  - Oral bovine colostrum supplementation enhances buffer capacity but not rowing
      performance in elite female rowers.
AB  - A randomized, double-blind, placebo controlled design was used in which 13 elite
      female rowers, all of whom had competed at World Championships, were supplemented
      with 60 g day-1 of either bovine colostrum (BC; n = 6) or concentrated whey
      protein powder (WP; n = 7) during 9 weeks of pre-competition training. All
      subjects undertook the study as a group and completed the same training program.
      Prior to, and after 9 weeks of supplementation and training, subjects completed
      an incremental rowing test (ROW1) on a rowing ergometer consisting of 3 3 4-min
      submaximal workloads and a 4-min maximal effort (4 max), each separated by a 1
      min recovery period. The rowing test was repeated after a 15-min period of
      passive recovery (ROW2). The 4 max for ROW1 provided a measure of performance,
      and the difference between the 4 max efforts of ROW1 and ROW2 provided an index
      of recovery. Blood lactate concentrations and pH measured prior to exercise and
      at the end of each workload were used to estimate blood buffer capacity (beta).
      Food intake was recorded daily for dietary analysis. There were no differences in
      macronutrient intakes (p >.56) or training volumes (p >.99) between BC and WP
      during the study period. Rowing performance (distance rowed and work done) during
      4 max of ROW2 was less than ROW1 at baseline (p <.05) but not different between
      groups (p >.05). Performance increased in both rows by Week 9 (p <.001), with no
      difference between groups (p >.75). However, the increase was greatest in ROW2 (p
      <.05), such that by Week 9 there was no longer a difference in performance
      between the two rows in either group (p >.05). b was not different between groups
      for ROW1 at baseline (BC 38.3 5.0, WP 38.2 7.2 slykes; p >.05) but was higher in
      BC by Week 9 (BC 40.8 5.9, WP 33.4 5.3 slykes; p <.05). b for ROW2 followed the
      same pattern of change as for ROW1. We conclude that supplementation with BC
      improves b, but not performance, in elite female rowers. It was not possible to
      determine whether b had any effect on recovery.

PMID- 12432179
TI  - An interview with Katherine A. Beals. Interview by Louise Burke.

PMID- 12432181
TI  - Unresolved issues about post-ERCP pancreatitis: an overview.
AB  - Pancreatitis represents the most common and feared complication after endoscopic
      retrograde cholangio-pancreatography. Since the introduction of ERCP into
      clinical practice, many attempts have been made to identify the mechanisms and
      conditions that can place patients at risk of developing post-procedure
      pancreatitis, with conflicting and in most cases unsatisfactory results. The
      following questions about post-ERCP pancreatitis still remain unanswered: the
      knowledge of the mechanisms involved in the onset of pancreatitis, procedural
      factors that can induce pancreatic damage, patient conditions that can increase
      the risk of developing pancreatitis in the post-procedure period, criteria for
      predicting the occurrence of pancreatitis, and possible methods of preventing the
      complication. Moreover, the criteria used to define post-ERCP pancreatitis differ
      in various studies and, consequently, there is a wide variation in the literature
      of the incidence of this complication and it is still not clear what its real
      incidence is. In the last six years, a significant advance in knowledge has been
      achieved in most of the above-mentioned fields. Four large prospective
      multicentre trials seemed to definitely identify patient- and technique-related
      risk factors that can place patients at risk of developing post-ERCP
      pancreatitis; clinical conditions, procedure- and patient-related factors, and
      laboratory tests able to predict the occurrence of post-ERCP pancreatitis in the
      early phase have been identified. An attempt to identify criteria for defining
      post-ERCP pancreatitis has also been carried out, although these proposed
      criteria have not been widely adopted by all Authors.

PMID- 12432180
TI  - Muscle blood flow and mitochondrial function: influence of aging.
AB  - Skeletal muscle mitochondrial capacity (mito), tissue blood flow (BF) capacity,
      and oxygen exchange capacity (e.g., DO2) appear to be well matched. The different
      skeletal muscle fiber types and muscle remodeled, due to inactivity (e.g.,
      related to aging or disease) or exercise training, exhibit widely differing
      aerobic capacities (VO2max). Yet, there are remarkably coordinated alterations in
      these 3 parameters in each of these conditions. With such a balance, there is
      likely shared control among these parameters in limiting VO2max of muscle,
      although this is a matter of considerable debate. The reduction in aerobic
      capacity in elderly can be improved by submaximal aerobic exercise training; this
      is related to increases in muscle mitochondria concentration and capillarity, but
      probably not BF capacity, as this is limited by central cardiovascular function.
      Thus, exercise-induced biochemical adaptations and angiogenesis occur in the
      elderly. The increase in muscle capillarity likely contributes to the increased
      oxygen exchange capacity, typical of endurance type training. The increase in
      [mito] appears essential to realize the increased in muscle VO2max with training
      and amplifies the rate-limiting influence of the muscles oxygen exchange
      capacity. Further, vascular remodeling induced by exercise in the elderly could
      be effective at improving flow capacity, if limited by peripheral obstruction.
      Thus, the limits to aerobic function specific to aged muscle appear most
      influenced by inactivity, whereas central cardiovascular changes impact whole
      body performance. Some may consider the aged myocyte as a small, inactive, normal
      myocyte in need of activity!

PMID- 12432182
TI  - Mechanisms involved in the onset of post-ERCP pancreatitis.
AB  - In various prospective studies, the frequency of post-ERCP pancreatitis ranges
      from 1 to 14%. After exposure to trigger events, injury to the gland occurs
      extremely rapidly. In experimental models of acute pancreatitis, it has been
      suggested that digestive enzyme activation might occur within acinar cells and it
      has been shown that in the early stages of acute pancreatitis induced by
      secretagogues or by diet, there is a co-localization of digestive enzymes and
      lysosomal hydrolases within large cytoplasm vacuoles; this co-localization
      mechanism might result in activation of the digestive enzyme. In this article, we
      will review the trigger events which may determine the final effect of acute
      pancreatitis during ERCP and endoscopic sphincterotomy: mechanical, chemical,
      enzymatic and microbiological. Nonetheless, factors related to the patient and
      the physician will be considered. Finally, the hypothesis of activation of
      chemokines by endoscopic maneuvers as a cause of acute pancreatitis will be
      described.

PMID- 12432183
TI  - Post-ERCP pancreatitis: patient and technique-related risk factors.

PMID- 12432184
TI  - Post-ERCP pancreatitis: is the endoscopist's experience the major risk factor?
AB  - The assumption that the endoscopist is an important factor in outcome of ERCP is
      not easy to document. There are plenty of reasons for the difficulties in
      defining experience and skill of an endoscopist, and establishing suitable
      endpoints for their measurement. Suitable proxy variables are ERCP-frequency
      (ongoing volumes) and ERCP-experience (life-time volumes) of the endoscopist, as
      well as individual and institutional conditions. Important confounders are
      difficulty of ERCP, patient-related and procedure-related risk factors and risk
      reducing factors. Endpoints should include success and (specific) complications
      of ERCP. Only few studies are available that analyse the influence of the
      endoscopist's skills on post-ERCP pancreatitis. Studies with a high preponderance
      of dominating patient-related risk factors for post-ERCP pancreatitis, e.g.
      suspect of SOD and unexplained abdominal pain, failed to prove such a dependence.
      On the other hand, evidence increases from studies with patient populations of
      more traditional indications for ERCP that suggests the existence of an
      association between ERCP-frequency of the endoscopist or ERCP-frequency of the
      environment and the incidence of post-ERCP pancreatitis and other complications.
      ERCP-experience measured in overall live-time volumes, however, does not seem to
      influence the risk of pancreatitis due to ERCP, although the data are very
      limited. During the ERCP-training of young endoscopists an impaired success rate
      appears more important than an increased complication rate. Nevertheless, all
      undesired outcomes of ERCP should be applied to the endpoints of quality
      assessment in ERCP-training. Further studies on this topic are needed. Since many
      variables significantly interact with the endpoints post-ERCP pancreatitis and
      complications of ERCP, a special study design appears indispensable to
      conclusively prove a relationship between an endoscopist's expertise and specific
      complications of ERCP.

PMID- 12432186
TI  - Why the incidence of post-ERCP pancreatitis varies considerably? Factors
      affecting the diagnosis and the incidence of this complication.
AB  - The reported incidence of post-ERCP/sphincterotomy pancreatitis ranges between
      1.3 and 24.4% in non-selected series. This varying incidence likely reflects on
      the one hand difference in patient populations, indications and endoscopic
      expertise and, on the other hand, different definitions of pancreatitis and
      methods of data collection. Among a number of patient-related factors recognized
      at risk for post-ERCP pancreatitis in four recent large prospective studies, the
      combination of female gender, normal serum bilirubin levels and recurrent
      abdominal pain suggesting sphincter of Oddi dysfunction and previous post-ERCP
      pancreatitis placed patients at an increasingly higher risk of pancreatitis.
      Among the technique-related risk factors for post-ERCP pancreatitis, biliary
      sphincter balloon dilation, difficult cannulation, sphincter of Oddi manometry
      and pancreatic sphincterotomy have also been recognized as significant risk
      factors. However, since the case mix in non-selected series does not
      significantly differ in the different studies, it is logical to assume that the
      different criteria adopted for defining the post-ERCP pancreatitis play a key
      role in the reported wide variation of incidence reported for this complication.
      The occurrence and duration of pain and the amplitude of serum amylase after ERCP
      are critical points in the definition of post-ERCP pancreatitis. Although a
      consensus conference identified 24-hour persisting pain associated with
      hyperamylasemia greater than 3 times the upper reference limit as an indicator of
      pancreatitis, these two parameters are however considered in a different manner
      in the studies available up to now. In a prospective study where we calculated
      the incidence of post-ERCP pancreatitis by using the most widely used criteria,
      for both occurrence and duration of pancreatic pain and serum amylase amplitude,
      the incidence of post-procedure pancreatitis ranged from 1.9 to 11.7% depending
      on the criteria adopted.

PMID- 12432185
TI  - What are the predictors of post-ERCP pancreatitis, and how useful are they?
AB  - Acute pancreatitis is one of the major complications of ERCP. It is of paramount
      importance that we accurately identify which patients will go on to develop post
      ERCP pancreatitis. As most ERCPs are performed on an outpatient basis, early
      evaluation can allow safe discharge of the majority of patients who will not
      develop post-ERCP pancreatitis or develop only mild symptoms that will be self
      limited. Alternatively, early detection of those patients who will go on to
      develop moderate or severe post-ERCP pancreatitis can guide decisions regarding
      hospital admission and aggressive management and can help direct the use of
      targeted therapies that have the potential to prevent or mitigate pancreatic
      inflammation. Thus, significant efforts have focused on trying to identify
      predictors of post-ERCP pancreatitis. These parameters can be organized into
      three categories of tests: 1) pancreatic enzymes as markers of pancreatic injury:
      serum amylase/urine amylase; 2) markers of proteolytic activation: trypsinogen,
      trypsinogen activation peptide; 3) markers of systemic inflammation: C-reactive
      protein, various interleukins such as IL-6 and IL-10. A serum amylase level
      greater than 4-5 times the upper reference limit in conjunction with clinical
      symptoms has been shown to be an accurate and reliable predictor of post-ERCP
      pancreatitis. However, the exact timing and level of amylase elevation remains
      debatable. Urine testing of amylase and trypsinogen-2 in post-ERCP patients has
      also been shown to be highly sensitive and specific for detecting pancreatitis.
      The main advantage of these urinary markers is that they are available as rapid
      dipstick tests. Serum trypsinogen-2 levels have also been studied in post-ERCP
      pancreatitis patients; high levels seem to correlate with severity of disease.
      Among the markers of systemic inflammation, serum CRP is an accurate and readily
      available laboratory test for predicting severity of post-ERCP pancreatitis, but
      it appears to be helpful at 24-48 hours and, therefore, is not an early marker.
      Several other markers remain investigational and have not yet found wide clinical
      applicability.

PMID- 12432188
TI  - Extent of use of immediate-release formulations of calcium channel blockers as
      antihypertensive monotherapy by primary care physicians: multicentric study from
      Bahrain.
AB  - BACKGROUND: The issue of cardiovascular safety of calcium channel blockers (CCBs)
      has been widely debated in view of reflex increase in sympathetic activity
      induced by immediate release (IR) / short acting formulations. It is generally
      agreed that such CCBs should not be used alone in the management of hypertension.
      AIMS: We have determined the extent to which primary care physicians prescribe
      CCBs as monotherapy, especially the immediate release formulations, in the
      management of uncomplicated hypertension and diabetic hypertension - with an
      emphasis upon the age of the patients. SETTING, DESIGN AND METHODS: A
      retrospective prescription-based study was carried out in seven out of 18 Health
      Centres in Bahrain. The study involved a registered population of 229,300
      representing 46% of registered individuals, and 35 physicians representing 43% of
      all primary care physicians. The data was collected between November 1998 and
      January 1999 using chronic dispensing cards. RESULTS: In all categories CCBs were
      the third commonly prescribed antihypertensive as monotherapy, with a
      prescription rate of 11.1% in uncomplicated hypertension, 18% in diabetic
      hypertension and 20.1% in elderly patients above 65 years of age. Nifedipine
      formulations were the most extensively prescribed CCBs. Almost half of the CCB
      treated patients were on IR-nifedipine, whereas IR-diltiazem and IR-verapamil,
      and amlodipine were infrequently prescribed. CONCLUSION: Prescription of IR
      formulations of CCBs as monotherapy by primary care physicians does not conform
      with recommended guidelines. In view of concerns about the safety of such
      practice, measures to change the prescribing pattern are required.

PMID- 12432189
TI  - Diagnostic value of enzyme linked immuno-sorbent assay for cytomegalovirus
      disease.
AB  - BACKGROUND: Since interpretation of results of enzyme linked immuno-sorbent assay
      (ELISA) for diagnosis of Cytomegalovirus (CMV) infection in India is difficult,
      its diagnostic value required evaluation. AIMS: To evaluate the diagnostic value
      of ELISA against polymerase chain reaction (PCR) in CMV disease. SETTINGS AND
      DESIGN: Results of ELISA test for CMV antibodies in CMV-DNA PCR positive and
      negative patients and normal healthy blood donors were analysed. METHODS AND
      MATERIAL: Anti-CMV antibodies were assayed by ELISA on the sera of 26 CMV PCR
      positive and 21 PCR negative patients and 35 normal healthy blood donors.
      STATISTICAL ANALYSIS: Chi square and Fischer exact test were used for statistical
      analysis. RESULTS: Anti-CMV antibodies (IgG or IgG and IgM) were present in 20
      (76.9%) of 26 PCR positive and 13 (61.9%) of 21 PCR negative patients. ELISA was
      negative in six (23.1%) of 26 PCR positive patients. Of the 28 paediatric
      patients, ELISA was positive in 14 (73.7%) of 19 PCR positive and three (33.3%)
      of nine PCR negative patients showing a statistically significant difference (Chi
      square test, P value 0.038). Among the 19 patients having complications after
      organ transplant, ELISA showed anti-CMV antibodies in six (85.7%) of seven PCR
      positive and 11 (91.7%) of 12 PCR negative patients showing no significant
      difference. CMV-DNA was not detected in the buffy coat of 35 sero-positive blood
      donors. CONCLUSION: ELISA has no diagnostic value in the detection of CMV
      activation although it may help in the differential diagnosis of CMV infection in
      the paediatric age group.

PMID- 12432191
TI  - Abnormal Doppler flow velocimetry in the growth restricted foetus as a predictor
      for necrotising enterocolitis.
AB  - BACKGROUND: Obstetric decision- making for the growth restricted foetus has to
      take into consideration the benefits and risks of waiting for pulmonary maturity
      and continued exposure to hostile intra-uterine environment. Necrotising
      Enterocolitis (NEC) results from continued exposure to hostile environment and is
      an important cause of poor neonatal outcome. AIMS: To evaluate the predictive
      value of abnormal Doppler flow velocimetry of the foetal umbilical artery for NEC
      and neonatal mortality. SETTINGS AND DESIGN: A retrospective study carried out at
      a tertiary care centre for obstetric and neonatal care. MATERIALS AND METHOD:
      Seventy-seven neonates with birth weight less than 2000 gm, born over a period of
      18 months were studied. These pregnancies were identified as having growth
      abnormalities of the foetus. Besides other tests of foetal well-being, they were
      also subjected to Doppler flow velocimetry of the foeto-placental vasculature.
      Obstetric outcome was evaluated with reference to period of gestation and route
      of delivery. The neonatal outcome was reviewed with reference to birth weight,
      Apgar scores and evidence of NEC. STATISTICAL ANALYSIS USED: Chi square test.
      RESULTS: In the group of patients with Absent or Reverse End Diastolic
      Frequencies (A/R EDF) in the umbilical arteries, positive predictive value for
      NEC was 52.6%, (RR 30.2; OR 264). The mortality from NEC was 50%. When umbilical
      artery velocimetry did not show A/REDF, there were no cases of NEC or mortality.
      Abnormal umbilical or uterine artery flow increased the rate of caesarean section
      to 62.5% as compared to 17.6% in cases where umbilical artery flow was normal.
      CONCLUSION: In antenatally identified pregnancies at risk for foetal growth
      restriction, abnormal Doppler velocimetry in the form of A/REDF in the umbilical
      arteries is a useful guide to predict NEC and mortality in the early neonatal
      period.

PMID- 12432190
TI  - Azithromycin as treatment for cryptosporidiosis in human immunodeficiency virus
      disease.
AB  - BACKGROUND: Cryptosporidiosis caused by the protozoa Cryptosporidium, is the
      common cause of diarrhoea in Acquired Immune Deficiency Syndrome (AIDS). AIM: To
      study the efficacy of short-term azithromycin in the management of
      cryptosporidiosis. SETTINGS AND DESIGN: Randomised, controlled trial. MATERIAL
      AND METHODS: All consecutive patients infected with Human Immunodeficiency Virus
      (HIV), who were positive for cryptosporidial oocysts were taken for this
      prospective randomised study. RESULT: Short-term azithromycin treatment for
      cryptosporidial diarrhoea in AIDS patients was associated with good clinical
      improvement but parasitological benefit was doubtful. All 13 patients, who had
      symptoms of cryptosporidiosis, symptomatically improved with 5 days of treatment
      with azithromycin and became asymptomatic after 7 days of antibiotic, but stool
      sample was positive for cryptosporidium even after 7 days of therapy. After 14
      days of treatment with azithromycin in 13 patients, in five patients stool was
      free of cryptosporidial oocyst. The drug was well tolerated in all the patients.
      CONCLUSION: Short-term azithromycin can be used as a safe and effective treatment
      for symptomatic Cryptosporidiosis but not effective in eradicating
      Cryptosporidial infection.

PMID- 12432192
TI  - Lipid peroxidation and antioxidant enzymes in male infertility.
AB  - BACKGROUND AND AIM: Mammalian spermatozoa are rich in polyunsaturated fatty acids
      and are very susceptible to attack by reactive oxygen species (ROS) and membrane
      lipid peroxide ion. Normally a balance is maintained between the amount of ROS
      produced and that scavenged. Cellular damage arises when this equilibrium is
      disturbed. A shift in the levels of ROS towards pro-oxidants in semen and vaginal
      secretions can induce an oxidative stress on spermatozoa. The aim was to study
      lipid peroxidation and antioxidant enzymes such as catalase, glutathione
      peroxidase and superoxide dismutase (SOD) and to correlate the same, with the
      'water test', in male infertility. SETTINGS: Experimental study. SUBJECTS AND
      METHODS: Ejaculates from a total of 83 infertile and fertile healthy individuals
      were obtained. Lipid peroxidation and antioxidant enzyme levels were studied and
      correlated with water test. RESULTS: The results indicate that (i) the
      antioxidant enzyme catalase showed no significant changes in the various
      pathological samples, (ii) antioxidant enzymes SOD and glutathione peroxidase
      correlate positively with asthenozoospermic samples and (iii) the degree of lipid
      peroxidation also correlates positively with the poorly swollen sperm tails. The
      increase in SOD and glutathione peroxidase values, in the pathological cases
      represents an attempt made to overcome the reactive oxygen species. CONCLUSION:
      Water test could be used as a preliminary marker test for sperm tail damage by
      reactive oxygen species, since it correlates very well with lipid peroxidation
      and antioxidant enzymes.

PMID- 12432193
TI  - A 34-year-old renal transplant recipient with high-grade fever and progressive
      shortness of breath.

PMID- 12432194
TI  - Concomitant acral necrosis and haemolytic uraemic syndrome following ingestion of
      quinine.
AB  - Thrombotic microangiopathy, which broadly includes thrombotic thrombocytopaenic
      purpura (TTP) and haemolytic uraemic syndrome (HUS), is a multisystemic disorder
      that is characterised by thrombocytopaenia, microangiopathic haemolytic anemia
      and ischaemic manifestations, resulting from platelet agglutination in the
      arterial microvasculature. Acral necrosis (distal necrosis of fingers and toes)
      occurs usually as a sequel to severe Raynaud's phenomenon, a vasculospastic
      disorder frequently related to endothelial cell dysfunction. We report a case of
      quinine induced TTP-HUS and acral necrosis, two distinct clinical abnormalities
      which have not yet been reported together in association with quinine. Both of
      these conditions in this case resolved promptly to treatment with
      corticosteroids.

PMID- 12432195
TI  - Colonic metastasis from bronchogenic carcinoma presenting as pancolitis.
AB  - The colonic metastases from bronchogenic carcinoma are rare. We present a 73-year
      old man presented with features suggestive of pan colitis after metastasis from
      undifferentiated large cell carcinoma of the lung. The plain radiograph and
      computed tomography scan of the chest had revealed a mass lesion in the right
      lower lobe of lung. He had no evidence of significant lesions elsewhere.
      Considering the advanced stage and poor differentiation of the tumour, no active
      therapy was undertaken and he survived for three months.

PMID- 12432196
TI  - Spontaneous cryptococcal peritonitis in cirrhotic patients.
AB  - Spontaneous bacterial peritonitis is a common complication in patients with
      cirrhosis and ascites. However, spontaneous peritonitis caused by Cryptococcus
      neoformans is uncommon. Delayed diagnosis of cryptococcal peritonitis often
      results in death. We describe three cases of spontaneous cryptococcal peritonitis
      in patients with decompensated cirrhosis. One case had associated symptomatic
      human immunodeficiency virus infection. Clinical awareness of this entity may
      lead to the early diagnosis and proper treatment.

PMID- 12432197
TI  - Spontaneous aortocaval fistula.
AB  - Spontaneous aortocaval fistula is rare, occurring only in 4% of all ruptured
      abdominal aortic aneurysms. The physical signs can be missed but the presence of
      low back pain, palpable abdominal aortic aneurysm, machinery abdominal murmur and
      high-output cardiac failure unresponsive to medical treatment should raise the
      suspicion. Pre-operative diagnosis is crucial, as adequate preparation has to be
      made for the massive bleeding expected at operation. Successful treatment depends
      on management of perioperative haemodynamics, control of bleeding from the
      fistula and prevention of deep vein thrombosis and pulmonary embolism. Surgical
      repair of an aortocaval fistula is now standardised--repair of the fistula from
      within the aneurysm (endoaneurysmorraphy) followed by prosthetic graft
      replacement of the aneurysm. A case report of a 77-year-old woman, initially
      suspected to have unstable angina but subsequently diagnosed to have an
      aortocaval fistula and surgically treated successfully, is presented along with a
      review of literature.

PMID- 12432198
TI  - World Medical Association Declaration of Helsinki: ethical principles for medical
      research involving human subjects.

PMID- 12432199
TI  - Split hand-foot malformation: a congenital central limb ray deficiency.

PMID- 12432200
TI  - Placental site trophoblastic tumour.

PMID- 12432201
TI  - Intradiploic epidermoid cyst.

PMID- 12432202
TI  - Cryptosporidiosis in HIV-infected patients.

PMID- 12432203
TI  - Laboratory diagnosis of cryptosporidiosis.

PMID- 12432204
TI  - Monitoring the injured brain in the intensive care unit.
AB  - The primary aim of managing patients with acute brain injury in the intensive
      care unit is to minimise secondary injury by maintaining cerebral perfusion and
      oxygenation. The mechanisms of secondary injury are frequently triggered by
      secondary insults, which may be subtle and remain undetected by the usual
      systemic physiological monitoring. Continuous monitoring of the central nervous
      system in the intensive care unit can serve two functions. Firstly it will help
      early detection of these secondary cerebral insults so that appropriate
      interventions can be instituted. Secondly, it can help to monitor therapeutic
      interventions and provide online feedback. This review focuses on the monitoring
      of intracranial pressure, blood flow to the brain (Transcranial Doppler),
      cerebral oxygenation using the methods of jugular bulb oximetry, near infrared
      spectroscopy and implantable sensors, and the monitoring of function using
      electrophysiological techniques.

PMID- 12432205
TI  - The role and effectiveness of adjunctive hyperbaric oxygen therapy in the
      management of musculoskeletal disorders.
AB  - The management of musculoskeletal disorders is an increasing challenge to
      clinicians. Successful treatment relies on a wide range of multidisciplinary
      interventions. Adjunctive hyperbaric oxygen (HBO) therapy has been used as an
      orthopaedic treatment for several decades. Positive outcomes have been reported
      by many authors for orthopaedic infections, wound healing, delayed union and non
      union of fractures, acute traumatic ischemia of the extremities, compromised
      grafts, and burn injuries. Severe side effects have also been reported with this
      therapy. To aid in the use of HBO therapy in orthopaedics, we reviewed 43 papers
      published in the past four decades and summarised the mechanisms, effectiveness,
      indications and contraindications, side effects, and cost impact of adjunctive
      hyperbaric oxygen therapy in the management of difficult musculoskeletal
      disorders. Adjunctive HBO therapy is an effective treatment modality for the
      management of some severe and refractory musculoskeletal problems. If appropriate
      candidates are carefully identified, hyperbaric oxygen is a limb- and sometimes
      life-saving therapy. HBO therapy significantly reduces the length of the
      patient's hospital stay, amputation rate, and wound care expenses. Thus, it is a
      cost-effective modality. A clinician must understand the side effects and risks
      of HBO treatment. Close monitoring throughout the treatment is warranted to
      minimise the risk to the patients.

PMID- 12432206
TI  - Bipolar hermaphroditism of somatic cell as the basis of its being and becoming:
      celldom appreciated.

PMID- 12432207
TI  - Congenital heart disease with rheumatic fever and rheumatic heart disease: a
      coincidence or an association?

PMID- 12432208
TI  - Fibromyositis after intramuscular pentazocine abuse.

PMID- 12432209
TI  - Neonatal adrenal haemorrhagic pseudocyst.

PMID- 12432210
TI  - Anaesthetic management of clip ligation of ruptured intracranial aneurysm
      associated with coarctation of aorta.

PMID- 12432211
TI  - Prolapsed fallopian tube with squamous metaplasia.

PMID- 12432212
TI  - History of anatomy in India.

PMID- 12432213
TI  - Repaglinide: a short acting insulin secretagogue for postprandial hyperglycaemia.

PMID- 12432214
TI  - Cytogenetic and molecular genetic aspects of childhood
      myeloproliferative/myelodysplastic disorders.
AB  - Of the myeloproliferative/myelodysplastic disorders (MPD/MDS) that occur in
      childhood most, regarding the cytogenetic and molecular genetic basis, is known
      about the two purely paediatric disorders: juvenile myelomonocytic leukaemia
      (JMML) and transient myeloproliferative disorder (TMD). Although much has been
      published about these two disorders, their aetiology is by no means fully
      established. It would appear, however, that in this paediatric subset of MPDs a
      stage/developmentally specific vulnerability for proliferation and transformation
      exists. The study of the molecular basis of many other MPD-like syndromes that
      also occur in childhood, has been greatly accelerated by the identification of
      rare, but recurring, cytogenetic abnormalities involving 8p11 and 5q31-33. Good
      collaborative studies could result in similar progress being made in the
      understanding of JMML and TMD.

PMID- 12432215
TI  - Cytogenetic and molecular genetic aspects of chronic myeloid leukaemia.
AB  - Chronic myeloid leukaemia (CML) is caused by the product of the BCR-ABL oncogene,
      located on the Philadelphia (Ph) chromosome. BCR-ABL is generated as a result of
      a reciprocal t(9;22) chromosomal translocation. The mechanisms responsible for
      this illegitimate recombination event remain elusive but are presumed to require
      a close spatial association of the translocation partners (chromosomes 9 and 22).
      BCR-ABL fusion transcripts can be detected by a sensitive reverse transcription
      polymerase chain reaction (RT-PCR) in the leucocytes of some healthy individuals
      suggesting that chromosomal translocations may occur frequently in the general
      population. The presence of BCR-ABL fusion transcripts does not imply that the
      individual will inevitably develop CML since other conditions must be favourable
      for expansion of the abnormal clone. Breakpoints in the ABL gene occur within a
      5' segment. BCR-ABL fusion transcripts lack ABL exon a1 and consist of BCR exons
      fused directly to ABL exon a2. The breakpoints in the BCR gene on chromosome 22
      are found within three defined regions. Depending on the position of the BCR
      breakpoint, fusion genes are generated that encode 190-, 210- or 230-kD forms of
      the Bcr-Abl tyrosine kinase. Since the ABL component of the fusion gene is
      largely invariant, it follows that variability in disease phenotype may be due to
      protein sequences encoded by the translocation partner, BCR. Different disease
      phenotypes are associated with each of the three Bcr-Abl oncoproteins, p190(Bcr
      Abl), p210(Bcr-Abl )and p230(Bcr-Abl). Mechanisms associated with malignant
      transformation include altered cellular adhesion, activation of mitogenic
      signalling pathways, inhibition of apoptosis and proteasomal degradation of
      physiologically important cellular proteins. CML is subject to an inexorable
      progression from an 'indolent' chronic phase to a terminal blast crisis. Disease
      progression is presumed to be associated with the phenomenon of genomic
      instability.

PMID- 12432216
TI  - Gene expression and biological significance of hexokinase in erythroid cells.
AB  - Red blood cells (RBCs) express two hexokinase (HK) isoforms, HK-I and HK-R. Both
      isozymes are generated from the HK-I gene by use of an alternate promoter. Gene
      structure and exon-intron organization of the HK-I gene have been elucidated from
      a sequence of three contiguous genomic clones localized at human chromosome 10.
      The sequence spans about 131 kb, and consists of 25 exons, which include 6 testis
      and 1 erythroid-specific exons. HK-R has been shown as an erythroid-specific
      isozyme whose expression is turned on in the early erythroid-progenitors and is
      significantly induced during their differentiation. HK-R unfolds major HK
      activity in immature RBCs and is rapidly degraded during the maturation process.
      HK-I has a porin-binding domain in its N-terminus. Recent studies have shown that
      HK isozymes with a porin-binding domain play a role in mitochondrial integrity,
      suggesting that HK-I-deficient erythroid cells might be eliminated by apoptosis.
      It is most likely that RBCs are most labile as a result of HK-I/R deficiency
      since the HK-I gene but not the other isozyme genes are expressed in fetal and
      adult RBCs.

PMID- 12432217
TI  - Molecular basis of red cell membrane disorders.
AB  - We will consider an array of genetic disorders of the red cell membrane. Some
      affect well-known genes. The mutations of most cases of hereditary spherocytosis
      (HS) are located in the following genes: ANK1, SPTB, SLC4A1, EPB42 and SPTA1,
      which encode ankyrin, spectrin beta-chain, the anion exchanger 1 (band 3),
      protein 4.2 and spectrin alpha-chain, respectively. A dominant form of distal
      renal tubular acidosis also stems from distinct mutations in the SLC4A1 gene. The
      mutations responsible for hereditary elliptocytosis (HE) and its aggravated form,
      poikilocytosis (HP), lie in the SPTA1 and SPTB gene, already mentioned, and in
      the EPB41 gene encoding protein 4.1. Whereas in HS, the SPTA1 and SPTB gene
      mutations tend to abolish the synthesis of the corresponding chains, in HE/HP,
      they hinder spectrin tetramerization. Allele alpha(LELY) is a common polymorphic
      allele which plays the role of an aggravating factor when it occurs in trans of
      an elliptocytogenic allele of the SPTA1 gene. Southeast Asian ovalocytosis
      results from a 27- nucleotide deletion in the SLC4A1 gene. Besides these
      conditions in which the mutations were reached from known alterations in the
      proteins, other conditions required a positional cloning approach. Such are the
      genetic disorders of membrane permeability to monovalent cations. Knowledge is
      the most advanced as regards dehydrated hereditary stomatocytois (DHS). DHS was
      shown to belong to a pleiotropic syndrome: DHS + fetal edema +
      pseudohyperkalemia, which maps to 16q23-24. Concerning DHS and another disease of
      the same class, overhydrated hereditary stomatocytosis, splenectomy almost
      certainly appears to elicit thromboembolic accidents.

PMID- 12432218
TI  - The glycosylphosphatidylinositol anchor and paroxysmal nocturnal
      haemoglobinuria/aplasia model.
AB  - Paroxysmal nocturnal haemoglobinuria (PNH) is unique because it is an acquired
      haemolytic anaemia, resulting from an intrinsic red cell membrane disorder. The
      disease has been shown to be due to a somatic mutation of the
      phosphatidylinositol glycan complementation class A (pig-a) gene at the level of
      the haemopoietic stem cell. The defect in synthesis of the
      glycosylphosphatidylinositol (GPI) anchor results in a deficiency of all proteins
      that are GPI-bound to red cell, leucocyte and platelet membranes. The function of
      these proteins is extremely varied but a critical role is the protection of the
      cell from complement and it is the unopposed action of the complement cascade
      that results in the intravascular haemolysis and venous thrombosis which are
      hallmarks of the disease. The relationship between PNH and aplastic anaemia
      remains intriguing. It appears likely that an insult to a haemopoietic progenitor
      alters it in such a way that it becomes vulnerable to immune-mediated attack by
      cytotoxic T cells and/or cytokines. This attack requires one or more GPI-anchored
      molecules to be effective. Thus a GPI-negative clone would be at a relative
      advantage, and it is the balance between bone marrow impairment and proliferation
      of the GPI-negative clone(s) that determines the clinical picture. Prospects for
      molecular therapy continue to improve. Cell-to-cell transfer of GPI-linked
      proteins has been demonstrated in murine studies and recombinant CD59 has been
      expressed on GPI-deficient lymphocytes in vitro. Gene therapy remains a
      tantalising possibility, although a greater understanding of the pathophysiology
      of PNH is required, as well as advances in gene therapy techniques, before such
      an approach can be seriously considered.

PMID- 12432219
TI  - Evolutionary clues to the molecular function of fanconi anemia genes.
AB  - Fanconi anemia (FA) is an autosomal recessively inherited disease with diverse
      clinical symptoms including developmental anomalies, predisposition to neoplasia,
      and a deficiency of hematopoietic stem cells resulting in progressive aplastic
      anemia. FA is genetically heterogeneous with at least 8 genes being implicated on
      the basis of functional complementation studies. To date, six FA genes are known:
      FANCA, FANCC, FANCD2, FANCE, FANCF and FANCG, all of which encode orphan proteins
      sharing no homology to each other nor to any other known protein. In addition,
      they do not appear to possess any domains with homology to currently known
      protein domains, which makes a prediction about their molecular action difficult.
      Studying the molecular evolution of FA genes and their products using sensitive
      database search methods such as PSI-BLAST may provide novel insight into the
      nature of the FA pathway and its relationship to hematopoiesis, embryonic
      development and the origin of malignancies. Preliminary results of such an
      approach show that at least one FA protein, FANCG, may contain a known domain,
      suggesting that this protein is a member of the family of tetratricopeptide
      repeat-containing proteins.

PMID- 12432220
TI  - Roles of hematopoietic transcription factors GATA-1 and GATA-2 in the development
      of red blood cell lineage.
AB  - The transcription factors GATA-1 and GATA-2 play key roles in gene regulation
      during erythropoiesis. Gene ablation studies in mouse revealed that GATA-2 is
      crucial for the maintenance and proliferation of immature hematopoietic
      progenitors, whereas GATA-1 is essential for the survival of erythroid
      progenitors as well as the terminal differentiation of erythroid cells. Both GATA
      1 and GATA-2 are regulated in a cell-type-specific manner, their expression being
      strictly controlled during the development and differentiation of erythroid
      cells. Closer examination revealed a cross-regulatory mechanism by which GATA-1
      can control the expression of GATA-2 and vice versa, possibly via essential GATA
      binding sites in their cis-acting elements. In addition, recent studies
      identified several human inherited hematopoietic disorders that are caused by
      mutations in cis-acting GATA binding motifs or mutations in GATA-1 itself.

PMID- 12432222
TI  - Melanocyte destruction and repigmentation in vitiligo: a model for nerve cell
      damage and regrowth.
AB  - Melanocytes (MCs) are melanin-producing cells of the skin that are derived from
      neural crest cells. Vitiligo vulgaris is a common depigmentation disorder
      resulting from the destruction of functional MCs in the affected skin. The three
      prevailing pathomechanisms of vitiligo are the immune hypothesis, the neural
      hypothesis and the autocytotoxic hypothesis. None of these mechanisms has been
      conclusively proven. Melanoblasts (MBs) in the outer root sheath of the hair
      follicles are the reservoir cells for repigmentation. Recovery from vitiligo is
      initiated by activation and proliferation of these MBs, followed by upward
      migration to the nearby epidermis that forms perifollicular pigmentation islands.
      Migration, proliferation and differentiation of MCs and MBs are regulated by
      keratinocyte-derived factors and some coat color genes. Any therapy for vitiligo
      must explain not only the repopulation of MCs but also their functional
      development. In patients with vitiligo, MCs are destroyed in the skin, the eyes,
      and possibly the ears. However, the concept of vitiligo as a systemic disease
      will be clearly established only when the mechanisms involved in vitiligo are
      identified. Recent advances in the fields of neural crest cell culture and
      molecular genetics have opened new perspectives in the understanding of vitiligo.
      Not only will this result in better treatments for vitiligo patients, but
      possibly will also provide a key to triggering nerve cell regrowth in other
      nervous diseases.

PMID- 12432223
TI  - Bilateral otolith contribution to spatial coding in the vestibular system.
AB  - Recent work on the coding of spatial information in central otolith neurons has
      significantly advanced our knowledge of signal transformation from head-fixed
      otolith coordinates to space-centered coordinates during motion. In this review,
      emphasis is placed on the neural mechanisms by which signals generated at the
      bilateral labyrinths are recognized as gravity-dependent spatial information and
      in turn as substrate for otolithic reflexes. We first focus on the spatiotemporal
      neuronal response patterns (i.e. one- and two-dimensional neurons) to pure
      otolith stimulation, as assessed by single unit recording from the vestibular
      nucleus in labyrinth-intact animals. These spatiotemporal features are also
      analyzed in association with other electrophysiological properties to evaluate
      their role in the central construction of a spatial frame of reference in the
      otolith system. Data derived from animals with elimination of inputs from one
      labyrinth then provide evidence that during vestibular stimulation signals
      arising from a single utricle are operative at the level of both the ipsilateral
      and contralateral vestibular nuclei. Hemilabyrinthectomy also revealed neural
      asymmetries in spontaneous activity, response dynamics and spatial coding
      behavior between neuronal subpopulations on the two sides and as a result
      suggested a segregation of otolith signals reaching the ipsilateral and
      contralateral vestibular nuclei. Recent studies have confirmed and extended
      previous observations that the recovery of resting activity within the vestibular
      nuclear complex during vestibular compensation is related to changes in both
      intrinsic membrane properties and capacities to respond to extracellular factors.
      The bilateral imbalance provides the basis for deranged spatial coding and motor
      deficits accompanying hemilabyrinthectomy. Taken together, these experimental
      findings indicate that in the normal state converging inputs from bilateral
      vestibular labyrinths are essential to spatiotemporal signal transformation at
      the central otolith neurons during low-frequency head movements.

PMID- 12432224
TI  - Human T cell lymphotropic viruses (HTLV-I/II) in South America: should it be a
      public health concern?
AB  - The presence of the human T cell lymphotropic virus (HTLV-I/II) in South America
      is well established. Its origin and spectrum in the continent still remain a
      matter of debate. There are signs now that HTLV-I/II was already present in the
      Amerindian population coming originally from Asia and that HTLV-I was also
      introduced with African slave trade and with immigration of individuals from
      endemic areas of Japan. South America has approximately 350 million inhabitants
      in its 13 countries. The presence of HTLV-I/II has been reported with impressive
      numbers in most of them and may be considered endemic in this continent. The
      distribution of HTLV I/II among native Amerindian populations has shown a
      geographic clustering of type I in the Andean highlands and Brazilian coast,
      while type II predominates in lowlands of South America. Although comparability
      between studies conducted among blood donors in different countries may be
      difficult, the data indicate that the viruses are also circulating among
      otherwise healthy individuals. Undoubtedly, HTLV-I/II infection and its related
      diseases should be considered a public health concern in South America and
      measures to prevent its spread should be emphasized.

PMID- 12432225
TI  - Differential effects of foods traditionally regarded as 'heating' and 'cooling'
      on prostaglandin E(2) production by a macrophage cell line.
AB  - Some components of natural foods may enhance or inhibit prostaglandin formation
      and potentially affect the inflammation condition. A macrophage cell line,
      RAW264.7, was employed to examine the effects of foods traditionally regarded as
      'heating' or 'cooling' on the production of PGE(2), a well-known proinflammatory
      mediator. Foods traditionally regarded as 'heating' (litchi, longan, and dried
      longan) or 'cooling' (chrysanthemum flower, bitter gourd, and lotus seed plumule)
      were extracted sequentially with water and ethyl acetate. The water extracts (WE)
      and ethyl acetate extracts (EAE) were applied to RAW264.7 macrophages in the
      presence or absence of LPS (lipopolysaccharide). In the absence of LPS, the WEs
      from the 'heating foods', litchi, longan, or dried longan had a dose-dependent
      enhancing effect on PGE(2) production, with respective EC(50)s of 8.4, 16, and 11
      mg/ml. This effect was accompanied by significant induction of COX-2 protein
      expression, as shown by Western blot analysis. In contrast, LPS-induced PGE(2)
      production was inhibited in a dose-dependent manner by the WEs of the 'cooling
      foods', chrysanthemum flower, bitter gourd, and lotus seed plumule, with
      respective IC(50)s of 0.6, 0.13, and 0.08 mg/ml. At the concentrations tested,
      none of the EAEs had any effect on basal PGE(2 )production, while LPS-induced
      PGE(2) production was inhibited or increased by the EAE from bitter gourd and
      longan, respectively. Water-soluble extracts of foods traditionally regarded as
      'heating' enhanced basal PGE(2) production, while those from 'cooling' foods
      significantly inhibited LPS-induced PGE(2) production by the macrophage cell
      line. This subject merits further study to determine whether appropriate food
      selection may help patients suffering from chronic inflammatory conditions.

PMID- 12432226
TI  - Myosin mediates contractile force generation by hepatic stellate cells in
      response to endothelin-1.
AB  - Although endothelin-1-stimulated contractile force generation by stellate cells
      is believed to play an important role in hepatic pathophysiology, the molecular
      signals that mediate this process are incompletely understood. The aim of this
      study was to test the hypothesis that myosin mediates the contractile force
      generated by stellate cells in response to endothelin-1. Contractile force
      generation by primary and immortalized stellate cells was directly and
      quantitatively measured. Myosin phosphorylation and reorganization, and actin
      stress fiber formation were investigated in immortalized stellate cells.
      Endothelin-1 stimulated a rapid and robust generation of contractile force by
      primary and immortalized stellate cells with a similar dose dependence. Myosin
      phosphorylation, actin stress fiber assembly, and reorganization of myosin to
      stress fibers were induced by concentrations of endothelin-1 that also stimulated
      stellate cell contraction. BQ-123, a selective endothelin receptor antagonist,
      inhibited myosin phosphorylation and contractile force generation. Y-27632, which
      selectively inhibits rho-associated kinase, also blocked endothelin-1-stimulated
      myosin phosphorylation and contractile force generation with a similar dose
      dependence. These results suggest that endothelin-1-stimulated contractile force
      generation by stellate cells is mediated by myosin.

PMID- 12432227
TI  - Physiological and chemical indicators for early and late stages of sepsis in
      conscious rats.
AB  - Endotoxin shock is a major cause of death in patients with septicemia. Endotoxin
      induces nitric oxide (NO) production and causes tissue damage. In addition, the
      release of oxygen free radicals has also been observed in endotoxin shock and was
      found to be responsible for the occurrence of multiple organ failure. The purpose
      of the present study was to evaluate suitable indicators for early and late
      stages of endotoxin shock. The experiments were designed to induce endotoxin
      shock in conscious rats by means of an Escherichia coli lipopolysaccharide (LPS)
      injection. Arterial pressure (AP) and heart rate (HR) were continuously monitored
      for 72 h after LPS administration. The maximal decrease in AP and increase in HR
      and nitrate/nitrite level occurred at 9-12 h following LPS administration. The
      white blood cell (WBC) count had decreased at 3 h. Hydroxyl radical (methyl
      guanidine, MG) decreased rapidly after LPS administration. Plasma levels of blood
      urea nitrogen (BUN), creatinine (Cr), lactic dehydrogenase (LDH), creatine
      phosphokinase (CPK), and glutamic oxaloacetic transaminase increased before the
      rise of amylase. Our results suggest that changes in AP, HR, WBC, free radicals,
      and chemical substances (BUN, Cr) can possibly serve as approximate indicators
      for the early stage of endotoxin shock. Severe multiple organ damage may be
      caused by amylase release in the late stage of endotoxin shock.

PMID- 12432228
TI  - Inhibition of Ras-mediated cell proliferation by benzyloxybenzaldehyde.
AB  - Excessive proliferation of vascular smooth muscle cells (VSMC) in the intima is
      an important etiologic factor in vascular proliferative disorders such as
      atherosclerosis and restenosis after balloon angioplasty. Therefore, control of
      VSMC growth may be a suitable therapeutic intervention in vascular proliferative
      disorders. In the present work, we have studied the 2-benzyloxybenzaldehyde
      (CCY1a)-mediated antiproliferative effect and its mechanisms of action. CCY1a
      inhibited serum-induced VSMC proliferation in a concentration-dependent manner,
      as demonstrated using [(3)H]thymidine incorporation and MTT assays; the IC(50)
      values were calculated to be 7.0 x 10(-6) and 1.2 x 10(-5) M, respectively.
      Furthermore, it also significantly suppressed serum-induced progression of the
      cell cycle, as shown by flow cytometric analysis. CCY1a as well as PD98059 almost
      completely abolished serum-induced activation of p42/44 mitogen-activated protein
      kinase (MAPK), the downstream effectors of c-fos and c-jun mRNA expression and
      activator protein-1 (AP-1) DNA binding activity, suggesting the central roles of
      these signaling cascades. Interestingly, CCY1a also effectively blocked serum
      induced Ikappa B-alpha phosphorylation, Ikappa B-alpha degradation and nuclear
      factor-kappa B (NF-kappa B) binding activity. Based on these observations, we
      examined the effect of CCY1a on serum-mediated Ras activity, an upstream
      regulator of the above signaling events. The data demonstrated a marked
      inhibition of Ras activation by CCY1a. We conclude that CCY1a blocks cell
      proliferation via inhibition of the upstream effector of Ras and downstream
      events, including p42/44 MAPK activation and c-fos and c-jun mRNA expression, as
      well as NF-kappa B and AP-1 DNA binding activities.

PMID- 12432230
TI  - Pharmacological doses of Zn2+ induce a muscarinic cholinergic supersensitivity.
AB  - The goal of this study was to evaluate the effect of chronic Zn2+ administration
      (1 mg/kg/day for 1 month) in Sprague-Dawley rats (n = 11) on motility and rearing
      behaviors (number of events/10 min measured in motility cage), on memory
      (percentage of failures using a foot-shock double T maze), on the number of
      muscarinic receptors (using [(3)H]-QNB as a marker) and on the
      cholinacetyltransferase (Chat) activity (determined by Fonnun's method) in
      various brain areas (striatum, hippocampus and frontal cortex), as compared with
      saline-treated rats (n = 10). Our results showed that Zn2+ induced a decrease in
      rearing (control: 24.6 +/- 3; Zn2+: 15.91 +/- 2.19) and in locomotor activity
      (control: 37 +/- 3.79; Zn2+: 25 +/- 4.37), a decrease in failures during memory
      trials (control: 26.12 +/- 5.6; Zn2+: 5.33 +/- 2.71) and an increase in
      muscarinic receptor density (fmol/mg) in the striatum (control: 539 +/- 6.18;
      Zn2+: 720 +/- 14.69), hippocampus (control: 396 +/- 7.41; Zn 2+: 458 +/- 5.05)
      and frontal cortex (control: 506 +/- 10.28; Zn2+: 716 +/- 16.54). Chat activity
      (pmol/mg/min) was decreased only in the striatum (control: 4240 +/- 158; Zn2+:
      2311 +/- 69). We conclude that Zn 2+ induces a cholinergic functional
      supersensitivity which is related to receptor upregulation.

PMID- 12432229
TI  - Establishment of a human somatic hybrid cell line for recombinant protein
      production.
AB  - Cell fusion techniques were used to derive mammalian host cell lines suitable for
      large-scale production of therapeutic proteins. Although the 293S cell line, of
      human embryonic kidney origin, is an excellent host cell for mammalian gene
      expression, these cells have a tendency to form large and tight aggregates in
      suspension cultures and bioreactors. To solve the problem of aggregation, 293S
      cells were fused to a human suspension cell line, 2B8 (a Burkitt's lymphoma
      derivative), using polyethylene glycol (PEG). The PEG-treated 293S and 2B8 cells
      were selected in a medium supplemented with hypoxanthine-aminopterin-thymidine
      and G418 (1 mg/ml) to eliminate nonfused cells. These hybrid clones, designated
      as HKB (hybrid of kidney and B cells), are negative for endogenous immunoglobulin
      expression. Most clones are readily adaptable to serum-free suspension culture
      under shaking conditions without forming large and tight aggregates. One clone,
      HKB11, was shown to support high-level expression of cytokines [interleukin (IL)
      2 and IL-4], ICAM-1 and rFVIII in a side-by-side comparison with 293 and Chinese
      hamster ovary cells. The above-described characteristics of HKB cells indicate
      that HKB11 is a favorable cell host for the production of human therapeutic
      proteins.

PMID- 12432231
TI  - Characterization of enolase allergen from Rhodotorula mucilaginosa.
AB  - Rhodotorula mucilaginosa (also known as R. rubra) is among the most commonly
      found yeast strains in our environment. However, allergens from R. mucilaginosa
      have not yet been characterized at the molecular level. The purpose of this study
      was to characterize the enolase allergen from R. mucilaginosa and examine the
      allergenic/antigenic cross-reactivity among fungal enolases. The full-length cDNA
      encoding the R. mucilaginosa enolase was isolated through the reverse
      transcriptase-polymerase chain reaction in conjunction with the 5'-end and 3'-end
      rapid amplification cDNA end reactions. The corresponding natural enolase from R.
      mucilaginosa was identified using two-dimensional gel electrophoresis and N
      terminal amino acid sequence analysis. The results showed that the enolase from
      R. mucilaginosa is a protein of 439 residues and is encoded by a cDNA of 1497 bp.
      It shares high sequence identity with enolase allergens from Candida albicans
      (85%), Saccharomyces cerevisiae (76%), Penicillium citrinum (76%), Aspergillus
      fumigatus (76%), Cladosporium herbarum (76.5%), and Alternaria alternata (74%). A
      47-kD component in the R. mucilaginosa extracts was found to react with IgE or
      rabbit anti-enolase antiserum and has an N-terminal amino acid sequence identical
      to that deduced from the isolated enolase cDNA. Sera from three (21%) of 14
      allergic patients sensitized to R. mucilaginosa showed IgE binding to this 47-kD
      R. mucilaginosa component and the His-tagged recombinant enolase. A rabbit
      antiserum against the P. citrinum enolase and a monoclonal antibody (MoAb; Afueno
      8) against the A. fumigatus enolase reacted with all 5 fungal enolases tested.
      However, an MoAb (E2a) generated by using the Saccharomyces enolase as antigen
      could only recognize the immunizing enolase. In addition, heterogeneity in
      immunoblot profiles of IgE antibodies in serum samples from 9 allergic patients
      against 5 different fungal enolases tested was also observed. The presence of IgE
      cross-reactivity among enolase allergens from R. mucilaginosa, C. albicans and P.
      citrinum was detected by immunoblot inhibition. In conclusion, a new and cross
      reactive enolase allergen from R. mucilaginosa (Rho m 1) was identified. Although
      enolases are highly conserved allergens among different fungal species, most of
      the allergic patients examined in this study differed in their IgE reactivity to
      the 5 different fungal enolases tested. The results obtained will be of value in
      understanding the role of enolase allergen in clinical mould allergy.

PMID- 12432232
TI  - Antioxidant and antiviral activities of Euphorbia thymifolia L.
AB  - The antioxidant and antiviral activities of Euphorbia thymifolia L.
      (Euphorbiaceae) were investigated in this study. The results showed that all of
      the fractions (MeOH, CHCl(3), EtOAc, n-butanol and water) and pure compounds (3-O
      galloyl-4,6-(S)-HHDP-D-glucose, rugosin B and 1,3,4,6-tetra-O-galloyl-K-beta-D
      glucose)tested possessed antioxidant activities, with the exception of the
      organic aqueous fraction in the anti-lipid and anti-superoxide formation assays.
      The range of IC(50) of anti-lipid formation, anti-superoxide formation and free
      radical scavenging assays for all fractions and pure compounds were 2.81-7.63,
      0.03-2.18 and 0.013-2.878 mg/ml, respectively. Electron spin resonance studies
      showed that water extract and pure compounds of E. thymifolia exhibited
      superoxide radical and hydroxyl radical scavenging activities. Besides
      antioxidant activities, 3-O-galloyl-4,6-(S)-HHDP-D-glucose and EtOAc fraction
      also showed anti-HSV-2 activity. Thus, E. thymifolia was concluded to possess
      antioxidant and anti-HSV-2 activities.

PMID- 12432233
TI  - Autocrine stimulation by insulin-like growth factor I is involved in the growth,
      tumorigenicity and chemoresistance of human esophageal carcinoma cells.
AB  - Insulin-like growth factor I (IGF-I) receptor (IGF-IR)-mediated signals are known
      to be involved in cell growth and transformation and prevention of apoptosis. In
      this study, we demonstrated the coexpression of IGF-I and IGF-IR in human
      esophageal carcinoma tissues. We also demonstrated the IGF-I autocrine system in
      esophageal carcinoma cell lines. Both the CE48T/VGH and CE81T/VGH cell lines
      showed proliferative responses to IGF-I stimulation. Autokinase activity of IGF
      IR in these cells can be triggered by the exogenous addition of IGF-I. In
      addition, an IGF-I peptide antagonist, JB1, specifically inhibited ligand-induced
      receptor autophosphorylation in a dose-dependent manner. Under serum-free
      conditions, JB1 also reduced the degree of IGF-IR phosphorylation and cell
      numbers. Furthermore, the addition of JB1 decreased the number of CE81T/VGH
      colonies formed in methyl cellulose agar and the size and the incidence of tumors
      which grew in mice with severe combined immunodeficiency. These results imply
      that an IGF-I autocrine system in human esophageal carcinoma cells could
      stimulate tumor growth. Finally, we found that IGF-I prevented the apoptosis of
      CE81T/VGH cells induced by chemotherapeutic drugs, such as cisplatin, 5
      fluorouracil and camptothecin. Thus, interruption of IGF-IR function may provide
      a way to retard tumor growth and increase the sensitivity of esophageal carcinoma
      to chemotherapy.

PMID- 12432234
TI  - Repeated DNA vaccinations elicited qualitatively different cytotoxic T
      lymphocytes and improved protective antitumor effects.
AB  - The use of DNA vaccines for generating antigen-specific CD8+ T cell responses has
      been well established. However, little is known about the quantitative and
      qualitative aspects of CD8+ T cell responses and protective immunity generated
      after repeated DNA vaccinations. We used human papillomavirus (HPV) type-16 E7 as
      a model tumor antigen in an E7-expressing tumor model, TC-1, to assess the
      influence of the frequency of DNA vaccinations on E7-specific immunological and
      antitumor responses. Mice were vaccinated with 1-4 inoculations of pcDNA 3-E7
      DNA. Immunological assays and tumor protection experiments were performed to
      assess the effect of repeated E7 DNA vaccination on E7-specific T cells and E7
      expressing tumors. Our results demonstrated that mice receiving an increased
      number of E7 DNA vaccinations exhibited higher E7-specific CTL activity, a rapid
      expansion of E7-specific IFN-gamma-secreting CD8+ T cells upon stimulation with
      E7 antigen, and a stronger antitumor effect against an E7-expressing tumor.
      Furthermore, we found that increasing the number of E7 DNA vaccinations followed
      by vaccinia booster enhanced the functional avidity of E7-specific CD8+ T cells.
      Our data suggest that quantitative and qualitative characteristics of antigen
      specific CD8 + T cell responses and the ensuing protective antitumor effect can
      be influenced by the frequency of DNA vaccinations. These results have important
      clinical implications for the use of naked DNA vaccines in cancer immunotherapy.

PMID- 12432235
TI  - CpG DNA induced IL-12 p40 gene activation is independent of STAT1 activation or
      production of interferon consensus sequence binding protein.
AB  - The host immune system responds to CpG motifs in bacterial DNA by rapidly
      producing proinflammatory cytokines. The host response to CpG DNA resembles, in
      many ways, the response to bacterial lipopolysaccharide (LPS). While both agents
      can induce a powerful inflammatory response, CpG DNA promotes Th1 and suppresses
      Th2 immunity. The regulation of macrophage IL-12 p40 secretion in response to
      stimulation with LPS and interferon-gamma (IFN-gamma) is dependent on the action
      of a nuclear transacting factor, interferon consensus sequence binding protein
      (ICSBP), a STAT1-dependent gene product. We found that CpG DNA induced IL-12 p40
      secretion by macrophages from mice with either disrupted STAT1 or ICSBP genes.
      Additionally, CpG DNA did not induce translocation of transcription factors that
      bind to the gamma-activated sequence in the ICSBP gene nor did CpG DNA induce
      ICSBP transcription. CpG DNA, which activates macrophages by the TLR9 pathway, is
      a strong inducer of IL-12 p40, yet does so independently of IFN-gamma, STAT1 or
      ICSBP. Thus, CpG DNA-induced IL-12 p40 secretion is mediated by one or more
      signaling elements distinct from those induced by either LPS or IFN-gamma.

PMID- 12432236
TI  - Overexpression and incorporation of GagPol precursor does not impede packaging of
      HIV-1 tRNA(Lys3) but promotes intracellular budding of virus-like particles.
AB  - We have recently demonstrated that alteration of the human immunodeficiency virus
      type 1 (HIV-1) Gag/GagPol ratio in virus-producing cells reduces the infectivity
      of progeny viruses and hinders the formation of stable virion RNA dimers without
      impairing virion packaging of the viral genomic RNA. In addition, we have
      previously shown that the expression of GagPol mediates the selective packaging
      of tRNA(Lys3). In this study we report that overexpression of uncleaved GagPol in
      the virus-producing cell did not alter the packaging levels of tRNA(Lys3).
      Similarly, altering the virion-associated Gag/GagPol ratio did not affect the
      virion packaging of the HIV-1 envelope protein nor cyclophilin A. Thin section
      electron microscopy analysis of the cells overexpressing protease-defective [PR(
      )] GagPol revealed immature virions but no mature virions. These immature virions
      were seen both extracellularly and in membrane-bound cytoplasmic vacuoles.
      Furthermore, an accumulation of electron-dense material was occasionally found at
      the plasma membrane and associated with intracytoplasmic membranous vacuoles in
      cells expressing excess PR(-) GagPol. No intracellular HIV was seen in the wild
      type control. Density gradient analysis showed that the overall density of these
      mutant virions with excess PR(-) GagPol was identical to that of the wild-type
      HIV-1. The findings indicate that overexpression of PR(-) GagPol, in the presence
      of Gag synthesis, promotes intracellular budding of the mutant virions and
      inhibits virus maturation.

PMID- 12432237
TI  - Interaction of hepatitis B virus X protein with damaged DNA-binding protein p127:
      structural analysis and identification of antagonists.
AB  - The hepatitis B virus X protein is a multifunctional protein that is essential
      for natural infection and has also been implicated in liver cancer development.
      Previous studies have identified the DDB1 subunit of the damaged-DNA binding
      complex as a critical partner of X protein in the infection process, X-mediated
      cytotoxicity and stability of the viral protein. Here, we investigated the
      structural and functional constraints of X-DDB1 interaction using various
      mutational analyses. Our data show that the interaction interface of X with DDB1
      is confined to a 15-residue epitope. All substitutions responsible for loss of
      binding mapped to this core-binding domain. In contrast, a marked increase in
      affinity for DDB1 resulted from substitutions at clustered positions lying close
      to the DDB1-binding epitope and correlated with loss of apoptotic potential.
      Selection of mutations in DDB1 that partially rescue the binding defect of an X
      mutant gave further insight into the contacts established between the two
      proteins. Importantly, both the core-binding domain of X and the gain-of-affinity
      X mutants inhibited DDB1- mediated stabilization of wild-type X protein. These X
      protein derivatives thus provide the basis for the development of therapeutic
      agents that antagonize X function through competitive inhibition of X-DDB1
      interaction.

PMID- 12432238
TI  - Early loss of deleted in colorectal carcinoma gene transcript detected in a group
      of benign colon adenomas.
AB  - We examined the expression of the putative tumor suppressor gene deleted in
      colorectal carcinoma (DCC) in human colon adenoma tissues and cell lines. One
      allele of DCC is deleted in 70% of human colon carcinomas, and DCC expression is
      undetectable in 90% of colon carcinoma cell lines. One DCC allele is also deleted
      in 50% of human colon adenomas, but results from protein expression studies have
      differed as to whether complete loss of DCC expression could occur in colon
      adenomas, or instead correlates with progression of colon adenoma to carcinoma.
      To further examine the timing of DCC expression loss in colon adenomas, we
      assayed DCC transcript levels in adenoma cell lines and tissues. We measured DCC
      expression by a sensitive assay using Southern blot detection of the RT-PCR
      amplified DCC transcript. DCC expression was negligible or greatly reduced in 4
      of 14 colon adenomas, including 2 of 2 adenoma cell lines and 2 of 12 adenoma
      tissue samples. These data are the first evidence that expression of DCC
      transcript can be silenced in colon adenoma cell lines and tissues. These data
      indicate that loss of DCC expression occurs in some colon adenomas, but is
      insufficient to drive the adenoma to carcinoma progression.

PMID- 12432241
TI  - EWS-FLI1 and Ewing's sarcoma: recent molecular data and new insights.
AB  - The EWS-FLI1 fusion resulting from the specific t(11;22)(q24;q12) of Ewing's
      sarcoma was the first sarcoma gene fusion to be cloned, a decade ago. Moving from
      the cloning of this oncogenic chimeric transcription factor to the further
      elucidation of its pathogenetic mechanisms has revealed new complexities in the
      biology of this tumor which may be relevant to other fusion oncogenes as well.
      The present review highlights recent advances in three avenues of investigation
      that are providing new insights into this particular neoplasm and into the
      biology of EWS-FLI1 and related fusion proteins, namely the identification of
      various mitogenic targets of this aberrant transcription factor, its possible
      role as a deregulator of splicing, and the role of the p53 pathway in modulating
      its oncogenicity.

PMID- 12432239
TI  - A macrophage-tropic HIV-1 that expresses green fluorescent protein and infects
      alveolar and blood monocyte-derived macrophages.
AB  - We describe the construction of a macrophage-tropic HIV-1 molecular clone, pNLAD8
      EGFP, which expresses enhanced green fluorescent protein. We show that NLAD8-EGFP
      can infect monocyte-derived macrophages as well as alveolar macrophages. NLAD8
      EGFP-infected macrophages can be easily and sensitively detected based on the
      visualization of intracellular green fluorescent protein.

PMID- 12432242
TI  - The role of ubiquitin-proteasome pathway in oncogenic signaling.
AB  - Oncogenic activation of genes that regulate cell proliferation and survival plays
      a central role in the development of human cancer. This activation is frequently
      achieved by the aberrant expression of oncogene products due to the gene
      amplification, enhanced transcription or stabilization of their mRNA or protein.
      The ubiquitin-proteasome pathway(UPP) is the key player in the intracellular
      degradation of regulatory proteins in eukaryotes. UPP controls the abundance and
      activity of important protein regulators of cellular signal transduction
      including a variety of cellular proto-oncogenes. Alteration of ubiquitination and
      degradation of these proto-oncogene proteins often occurs during tumorigenesis
      and critically contributes to cell decisions as per proliferation/differentiation
      and survival/death. This article attempts to briefly overview the role of UPP in
      the regulation of several signal transduction pathways that contribute to
      development of cancer.

PMID- 12432243
TI  - CDK9: from basal transcription to cancer and AIDS.
AB  - Cdk9 is a member of the Cdc2-like family of kinases. Its cyclin partners are
      members of the family of cyclin T (T1, T2a and T2b) and cyclin K. The Cdk9/cyclin
      T complexes appear to be involved in regulating several physiological processes.
      Cdk9/cyclin T1 belongs to the P-TEFb complex, and is responsible for the
      phosphorylation of the carboxyl-terminal domain (CTD) of the RNA Polymerase II,
      thus promoting general elongation. Cdk9 has also been described as the kinase of
      the TAK complex, which is homologous to the P-TEFb complex and involved in HIV
      replication. Cdk9 also appears to be involved in the differentiation program of
      several cell types, such as muscle cells, monocytes and neurons, suggesting that
      it may have a function in controlling specific differentiative pathways. In
      addition, Cdk9 seems to have an anti-apoptotic function in monocytes, that may be
      related to its control over differentiation of monocytes. This data suggests the
      involvement of Cdk9 in several physiological processes in the cell, the
      deregulation of which may be related to the genesis of transforming events, that
      may in turn lead to the onset of cancer. In addition, since the complex
      Cdk9/cyclin T1 is able to bind to the HIV-1 product Tat, the study of the
      functions of Cdk9/cyclin T may be of interest in understanding the basal
      mechanisms that regulate HIV replication.

PMID- 12432244
TI  - The role of environmental carcinogens, viruses and genetic predisposition in the
      pathogenesis of mesothelioma.
AB  - Mesothelioma is one of the most aggressive human cancers and kills approximately
      2500 people per year in the US. This cancer was almost unknown until the second
      half of the 20th century, and its rapid increase has been linked to the
      widespread use of asbestos. In spite of an enormous research effort, the
      mechanisms of asbestos carcinogenicity have remained an enigma. Why only a
      fraction of individuals exposed to high levels of asbestos develop mesothelioma
      while individuals with low to no asbestos exposure also develop this cancer
      remains unknown. Recently, simian virus 40, a DNA tumor virus known to
      preferentially cause mesotheliomas in hamsters, and genetic factors have been
      linked to mesothelioma development. Therefore, a new research front has been
      opened in mesothelioma, a cancer that appears to be caused by the environmental
      carcinogens asbestos and erionite, viruses, and genetic predisposition. The
      challenge for future research is to establish how these apparently very different
      factors interact to cause mesotheliomas.

PMID- 12432245
TI  - In situ gene expression analysis of cancer using laser capture microdissection,
      microarrays and real time quantitative PCR.
AB  - The simultaneous development of laser capture microdissection (LCM) and high
      throughput mRNA analysis platforms has provided a significant technological
      advance in the world of cancer biology. The combination of such technologies
      provides a unique and powerful opportunity to directly assess the in situ
      molecular genetic events that are associated with initiation and progression of
      human malignancies. Despite these technological advances, the integration of LCM
      with high-throughput gene expression analysis has been met with various
      challenges. The goal of this review is to highlight some of the obstacles that we
      have faced and continue to face as we try to optimally apply LCM to in situ gene
      expression analysis.

PMID- 12432246
TI  - Four birds with one stone: RAPA as potential anticancer therapy.

PMID- 12432247
TI  - Clinicopathologic implications of hMSH2 gene expression and microsatellite
      instability in prostate cancer.
AB  - Human mismatch repair (MMR) genes encode highly conserved interacting proteins
      that correct replication errors predisposing to hereditary gastrointestinal and
      genitourinary malignancies. We previously investigated expression of the
      prototype MMR gene hMSH2 in normal, benign prostatic hyperplasia and malignant
      prostate tissues (Velasco et al., Cancer 94:690-699, 2002). An association was
      detected between reduced hMSH2 staining and favorable outcome as determined by
      undetectable serum prostate specific antigen (PSA) after radical prostatectomy.
      We now investigate the association between clinicopathological variables and
      hMSH2 expression or microsatellite instability (MSI). A statistically significant
      association was found between tumors exhibiting MSI (MSI+ tumors) and lower
      preoperative serum PSA values, smaller tumor volumes and lower frequency of
      surgical specimens with extracapsular extension of tumor. No statistically
      significant association (P value less than or equal to 0.05) was found between
      hMSH2 staining and these clinicopathologic variables. Based on our analysis, we
      conclude that MMR deficiency has important clinicopathologic implications in
      prostate cancer. Furthermore, specific MMR genes may have different effects on
      prostate cancer biology.

PMID- 12432248
TI  - More watchful (less waiting?) for mismatch repair in prostate cancer.

PMID- 12432249
TI  - Selenomethionine inhibits growth and suppresses cyclooxygenase-2 (COX-2) protein
      expression in human colon cancer cell lines.
AB  - Currently, selenium (in the form of high selenium containing yeast or
      selenomethionine) is being evaluated for anticancer effects against both human
      colon polyp recurrence and human prostate cancer, respectively. Chemical
      speciation analysis of the high selenium containing yeast indicates that
      selenomethionine (SeMet) is a major constituent of selenized yeast. We tested the
      hypothesis that SeMet might affect colon cancer cell growth by mechanisms
      involving cyclooxygenases (COX). The growth of all four-colon cancer cell lines
      tested was inhibited by selenomethionine. Furthermore, selenomethionine decreased
      COX-2 protein and PGE2 levels in HCA-7 cells. Selenomethionine suppressed COX-2
      RNA levels in HCA-7 cells which could account for decreased COX-2 protein levels.
      Finally, the addition of PGE2 protected cells from the antiproliferative effects
      of selenomethionine in a concentration dependent manner. Selenomethionine might
      regulate COX-2 at the transcriptional level. These data suggests that Se-Met
      induced cell growth inhibition may be, in part, mediated by COX-2 dependent
      mechanisms. The results of this study support the use of selenium agents in colon
      cancer chemoprevention trials.

PMID- 12432250
TI  - Absence of SV40 in Austrian tumors correlates with low incidence of
      mesotheliomas.
AB  - Between 1955 and 1963 millions of people were worldwide vaccinated with polio
      vaccines that were contaminated with the simian virus 40 (SV40). This tumor
      inducing virus has subsequently been detected in several human tumors. In
      Austria, polio mass vaccination started in winter 1961/62 with a presumably SV40
      free British vaccine. Thus, we hypothesized that the Austrian population should
      be SV40-free. We used a polymerase chain reaction-based (PCR) method to search
      for SV40 sequences in DNA that was extracted from 14 giant cell tumors, ten
      osteosarcomas and eight mesotheliomas. SV40 was easily detected in two bone tumor
      DNAs from Italy, and one from the USA, and in one SV40 positive cell line. In
      parallel experiments all Austrian samples tested consistently negative. Our
      findings support the notion that: 1) polio vaccination is the main source for
      SV40 in human populations, 2) Austria was not exposed to SV40, and 3) its absence
      correlates with the low incidence of mesotheliomas in Austria.

PMID- 12432251
TI  - A member of the GAGE family of tumor antigens is an anti-apoptotic gene that
      confers resistance to Fas/CD95/APO-1, Interferon-gamma, taxol and gamma
      irradiation.
AB  - Attractive targets for cancer therapy are gene products whose inactivation is not
      detrimental in essential tissues. The GAGE family of Cancer/Testis Antigens is a
      group of appealing candidates for cancer therapy since they are expressed in a
      wide variety of human tumors and are silent in most adult tissues, with the
      exception of testis. Interestingly, expression of GAGE has been associated with
      poor prognosis in some cancers. Nevertheless, no function has been reported for
      any of the GAGE family members. Here we describe for the first time an anti
      apoptotic activity exerted by GAGE. We have cloned GAGE-7C from HeLa cells and
      showed that it renders transfected cells resistant to apoptosis induced by
      Interferon-gamma (IFN-gamma) or by the death receptor Fas/CD95/APO-1. Similarly,
      transfection of GAGE-7/7B also confers resistance to Fas induced apoptosis. In
      the Fas pathway, the anti-apoptotic activity of GAGE-7C maps downstream of
      caspase-8 activation and upstream of poly (ADP-ribose) polymerase (PARP)
      cleavage. Furthermore, GAGE-7C renders the cells resistant to the therapeutic
      agents Taxol and gamma-irradiation. Following the various apoptotic stimuli, the
      surviving GAGE-7C transfectants actively proliferate and exhibit enhanced long
      term survival in colony formation assays. Overall, our data establishes a
      functional link between GAGE-7C and two aspects of human tumor progression;
      namely, resistance to Fas induced apoptosis and to chemo- and radio-therapy.

PMID- 12432252
TI  - To live or not to live: that depends on GAGE?

PMID- 12432253
TI  - Telomerase protects cancer-prone human cells from chromosomal instability and
      spontaneous immortalization.
AB  - Studies were conducted to directly test whether the introduction of telomerase
      protects cancer-prone human mammary epithelial cells from chromosomal instability
      and spontaneous immortalization. Using a model for Li Fraumeni Syndrome (LFS),
      infection of human telomerase resulted in maintenance of telomere lengths,
      extension of in vitro lifespan, and prevention of spontaneous immortalization. In
      stark contrast to the spontaneously immortalized LFS cells, cells expressing
      ectopic telomerase displayed a remarkably stable karyotype and even after >150
      population doublings, did not express endogenous telomerase. Since the hTERT
      infected and spontaneously immortal LFS cells, like the parental cells, exhibit
      loss of p53 function, our data suggests that telomere shortening is the primary
      driving force for the genomic instability characteristic of LFS cells, while p53
      inactivation is necessary for triggering the spontaneous immortalization event.
      Collectively, our data indicate that exogenous telomerase prevents chromosomal
      instability and spontaneous immortalization of LFS cells, suggesting a unique
      protective role for telomerase in the progression to immortalization.

PMID- 12432254
TI  - Senescence, telomere shortening and telomere maintenance.

PMID- 12432255
TI  - Downregulation of c-FLIP sensitizes DU145 prostate cancer cells to Fas-mediated
      apoptosis.
AB  - Although DU145 prostate cancer cells are resistant to exogenously applied Fas
      agonist CH-11 (anti-Fas monoclonal antibody), Fas-resistance can be overcome
      using a FasL expressing adenovirus (AdGFPFasL(TET)) [Hyer et al., Molecular
      Therapy, 2000; 2:348-58 (ref.12)]. The purpose of this study was to try to
      understand why DU145 cells are resistant to CH-11 and determine the signaling
      pathway utilized by AdGFPFasL(TET) to induce apoptosis in these Fas-resistant
      cells. Using immunoblot analysis, we show that AdGFPFasL(TET) is capable of
      initiating the classic Fas-mediated apoptotic pathway in DU145 cells, which
      includes activation of caspases-8, -3, -7, and -9, BID cleavage, cytochrome c
      release from mitochondria, and PARP cleavage. In contrast, CH-11 binds to Fas,
      but is unable to transmit the death signal beyond the plasma membrane suggesting
      a block at the DISC (death inducing signaling complex). The anti-apoptotic
      protein c-FLIP (cellular Flice-like inhibitory protein), which has been shown to
      inhibit Fas-mediated apoptosis at the DISC, was down-regulated following
      AdGFPFasL(TET) treatment prompting us to investigate its role in inhibiting CH-11
      induced cell death. Using c-FLIP anti-sense oligonucleotides to down-regulate c
      FLIP we sensitized DU145 cells to CH-11-induced apoptosis. These data suggest
      that c-FLIP may play a critical role in regulating Fas-mediated apoptosis in
      prostate cancer cells and that modulation of c-FLIP may enhance Fas signaling
      based therapies.

PMID- 12432256
TI  - The FLIP side of cancer cell death.

PMID- 12432257
TI  - Phase I study of prolonged infusion Bryostatin-1 in patients with advanced
      malignancies.
AB  - PURPOSE: Bryostatin-1 is a compound known to inhibit protein kinase C expression.
      Clinical trials have focused on administration schedules ranging from 1 hour to
      72 hour infusions. Preclinical data suggest that the down regulation of the
      target PKC occurs only as long as the drug is being infused. Therefore we
      performed a phase 1 clinical trial to determine the safety and recommended dose
      of prolonged infusion Bryostatin-1. EXPERIMENTAL DESIGN: Patients with advanced
      metastatic cancer were enrolled in this traditional phase 1 clinical trial
      utilizing prolonged infusion Bryostatin-1. The administration of Bryostatin-1 was
      initially begun at 96 hours and extended to 14 days. Doses were escalated using
      the 96 hour infusion time and then duration of infusion was increased. All
      patients underwent extensive sampling for determination of PKC levels as well as
      other key biologic end points. The determination of maximum tolerated dose and
      recommended phase two dose were based on toxicity. RESULTS: 38 patients were
      enrolled in the study. The recommended phase two doses were 24 mcg/m2 over five
      days, 16 mcg/m2 over six days and 8 mcg/m2 over 14 days. At the higher dose
      levels we demonstrated consistent down regulation of PKC-alpha. This was not
      observed at the low dose level. Toxicities were limited to myalgias and fatigue
      and were dose-related. The results of downstream signaling effects were less
      clear. MMP expression was not altered by treatment with Bryostatin-1. Only
      limited evidence for alterations in PKC activity as measured by expression of
      phosphorylated MAPK was observed. No objective responses were observed with five
      patients having prolonged stabilization of disease. CONCLUSIONS: Bryostatin-1 is
      safely administered over prolonged infusion schedules. There appears to be a dose
      response for PKC inhibition. Bryostatin-1 is a complicated compound as is the
      target PKC and its related signaling pathways. There is only limited clinical
      activity with this compound as a single agent; future studies should focus on
      combinations with other cytotoxics or targeted therapies.

PMID- 12432258
TI  - Bryostatin-I: an antineoplastic treasure from the deep?

PMID- 12432259
TI  - Flavopiridol inversely affects p21(WAF1/CIP1) and p53 and protects p21-sensitive
      cells from paclitaxel.
AB  - Resting cells are relatively resistant to microtubule-active drugs including
      paclitaxel (PTX). By causing p53-mediated arrest, pretreatment with low
      concentrations of doxorubicin (DOX) protected HCT116 cells from the cytotoxicity
      caused by PTX. Unlike DOX, flavopiridol (FL) did not protect HCT116 cells. Low
      concentrations of FL (50 nM) induced p21 but not p53. High concentrations of FL
      (500 nM) decreased levels of p21 and Mdm-2 but dramatically induced p53. Thus, FL
      reciprocally affects p21 and p53. In LNCaP, a prostate cancer cell line which is
      highly sensitive to p21-induced growth arrest (p21-sensitive), low concentrations
      of FL (50 nM) induced p21 (without induction of p53) and caused G1 and G2 arrest.
      This precluded mitotic arrest, Bcl-2 and Raf-1 phosphorylation, and diminished
      cell death caused by PTX. In contrast, FL did not protect PC3M, arrest-resitant
      and highly aggressive prostate cancer cells. Like LNCaP, HL60 and SKBr3 cells are
      known to be p21-sensitive. As predicted, low concentrations of FL antagonized PTX
      mediated cytotoxicity in HL60 and SKBr3 cell lines. In summary, only low
      concentrations of FL can induce p21, and, in turn, only p21-sensitive cells are
      protected from PTX.

PMID- 12432260
TI  - Role reversal for anticancer agents.

PMID- 12432261
TI  - The pro-oncoprotein EWS (Ewing's Sarcoma protein) interacts with the Brn-3a POU
      transcription factor and inhibits its ability to activate transcription.
AB  - The Brn-3a POU family transcription factor is able to induce the expression of a
      number of neuronally-expressed genes as well as to enhance neuronal
      differentiation and inhibit apoptosis. Many of these effects are mediated by the
      C-terminal POU domain of Brn-3a which acts both as a DNA binding domain and a
      transcriptional activation domain. To identify the mechanisms by which this
      domain acts, we carried out a yeast two hybrid assay to identify proteins which
      interact with it. We show that both full length Brn-3a and the isolated POU
      domain interact with the EWS transcription factor and its oncogenic derivative
      EWS-Fli1. Moreover, EWS can block Brn-3a-mediated activation of the Bcl-x
      promoter whereas this effect is lost in EWS-Fli1. The significance of this novel
      interaction is discussed in terms of the manner in which Brn-3a regulates its
      target promoters and the mechanism of oncogenic transformation by EWS-Fli1.

PMID- 12432262
TI  - Visual genotyping of a coat color tagged p53 mutant mouse line.
AB  - The p53 knockout mouse has been widely used as a model in cancer research and
      other applications. Because neither homozygous nor heterozygous mutant p53 mice
      exhibit an overt phenotype, each animal requires laborious molecular genotyping.
      Here we describe a new p53 mutant mouse that is tagged with a tyrosinase coat
      color minigene. On an albino background, heterozygous tyrosinase-tagged p53
      mutant mice exhibit a light tan coat color, while homozygous mutants display a
      darker brown coat color. Thus, by 8-10 days of age, mice with two, one, or no
      mutant p53 alleles are immediately distinguishable by their coat color,
      eliminating the time, costs, and errors associated with molecular genotyping.
      Moreover, the homozygous mutant p53-tyrosinase mice display a tumor incidence and
      spectrum virtually identical to previous p53 null mouse lines. Thus, tagging
      targeted mutations with such coat color markers provides a generally applicable
      genotyping method for embryonic stem cell-derived mice.

PMID- 12432263
TI  - Phenomenology and scientific progress.

PMID- 12432267
TI  - Exploring and exploiting instability.
AB  - Genetic instability was postulated to be essential for tumor development almost
      three decades ago, and yet its exact nature in and relationship with cancer
      continue to be ill-understood and hotly debated subjects. In this article, we
      review and discuss current knowledge and thinking about the existence,
      characteristics, reasons for and mechanisms of genetic instability in human
      cancers, as well as how its study can help us better understand and fight cancer.
      Particular emphasis is given to chromosomal instability, the most common and
      least understood of the types of genetic instability found in human tumors.

PMID- 12432268
TI  - Cycling to cancer with cyclin D1.
AB  - Genetic aberrations in the regulatory circuits that govern transit through the
      G(1) phase of the cell cycle occur frequently in human cancer and overexpression
      of the G(1) phase cyclin, cyclin D1, is one of the most commonly observed
      alterations. Cyclin D1 accumulates and activates its cognate CDK (CDK4/6) in
      response to mitogenic growth factors in early to mid G(1) phase. The resulting
      cyclin D1-dependent kinase initiates the phosphorylation-dependent inactivation
      of the retinoblastoma tumor suppressor protein. Mitogen-dependent activation of
      the cyclin D1 kinase occurs through increased transcription, protein
      accumulation, cyclin/CDK assembly, reduced cyclin proteolysis, and decreased
      nuclear export. Perturbations at any step, which result in reduced growth factor
      requirements for cyclin D1/CDK activation, will provide cells with a distinct
      growth advantage over their normal counterparts and thus likely represents an
      early event in neoplasia.

PMID- 12432269
TI  - FHIT as tumor suppressor: mechanisms and therapeutic opportunities.
AB  - Chromosomal abnormalities including homozygous deletions and loss of
      heterozygosity at 3p l4.2 are commonly observed in most human tumors, including
      lung, breast and kidney cancers. This region also contains the most common human
      fragile site FRA3B, a familial kidney cancer-associated translocation breakpoint
      and papilloma virus integration sites. The FHIT gene is a tumor suppressor, which
      is frequently inactivated by mentioned genomic alterations at 3pl4.2. In the last
      few years considerable amount of data describing inactivation of FHIT in a
      variety of human malignancies and demonstrating the tumor suppressor potential of
      Fhit has accumulated. However, these have not yet led to major advances in
      uncovering the precise molecular mechanism of Fhit action. This review focuses on
      the most recent progress in understanding of Fhit function as a tumor suppressor
      and opportunities for gene cancer therapy with Fhit.

PMID- 12432270
TI  - SUMO in cancer--wrestlers wanted.
AB  - SUMO (small ubiquitin-related modifier) represents a class of ubiquitin-like
      proteins that is conjugated, like ubiquitin, by a set of enzymes to cellular
      regulatory proteins, including oncogenes and tumor suppressor genes, that play
      key roles in the control of cell growth, differentiation and apoptosis. SUMO
      conjugation affects substrates' subcellular localization and stability as well as
      transcriptional activities. Given the substrates involved, protein SUMOylation
      would be expected to be important in the course of tumorigenesis and,
      accordingly, altered in human cancer. Although evidence to support this notion is
      still scarce, this review summarizes the current knowledge of protein sumoylation
      and highlights the challenges to be addressed in the context of human cancer.

PMID- 12432272
TI  - CHK and MEK inhibitors team up to trigger cancer cell suicide.

PMID- 12432271
TI  - Inhibitors of MEK1/2 interact with UCN-01 to induce apoptosis and reduce colony
      formation in mammary and prostate carcinoma cells.
AB  - Recent studies have suggested that inhibition of the mitogen activated protein
      kinase (MAPK) pathway as well as abrogation of cell cycle check-point control can
      potentiate the lethal actions of chemotherapeutic drugs and radiation. We
      therefore investigated the impact of combined exposure to the check-point
      abrogator (UCN-01) in conjunction with MEK1/2 inhibitors upon survival of breast
      and prostate carcinoma cells. Treatment of cells with UCN-01 alone resulted in
      prolonged activation of the MAPK pathway. Inhibition of MEK1/2 caused modest
      reductions in basal MAPK activity and transiently suppressed UCN-01-stimulated
      MAPK activity below that of MEK1/2 inhibitor alone. Significantly, combined, but
      not individual, exposure of cells to UCN-01 and MEK1/2 inhibitors enhanced BAX
      association with mitochondria and triggered release of cytochrome c into the
      cytosol, accompanied by activation of effector pro-caspases, resulting in a
      greater than additive potentiation of apoptosis within 1 8-24h. Radiation
      exposure of drug treated cells did not further enhance apoptosis. Treatment of
      cells with both caspase 9 and caspase 8 inhibitors was required to completely
      inhibit apoptosis in carcinoma cells. Overexpression of Bcl-(xL) blocked
      cytochrome c release and cell killing induced by the drug combination. Colony
      forming assays demonstrated that cells exposed to both agents exhibited a
      substantial reduction in clonogenic survival compared to either drug alone;
      moreover, radiation further reduced clonogenic survival despite failing to
      promote additional apoptosis. Collectively, these data demonstrate that combined
      exposure of carcinoma cells to UCN-01 and MEK1/2 inhibitors induces apoptosis and
      interacts with radiation to further reduce clonogenic survival.

PMID- 12432273
TI  - The effects of beta-estradiol on Raf activity, cell cycle progression and growth
      factor synthesis in the MCF-7 breast cancer cell line.
AB  - The aim of this study was to test the hypothesis that some of the proliferative
      effects of steroid hormones on cancer cells are mediated by the Raf proto
      oncogenes. The human breast cancer cell line MCF-7 is estrogen-receptor (ER)
      positive (+). NCI/ADR-RES is a human cell line lacking the estrogen receptor (ER
      ) that was initially named MCF-ADR. Raf-1, A-Raf and B-Raf kinase activities were
      examined in cell lines treated with beta-estradiol for 24 hours. Increases in Raf
      1 and A-Raf activities were observed after treatment with beta-estradiol in the
      ER (+) MCF-7 cells but not in the ER (-) NCI/ADR-RES cells. In contrast, no
      significant changes in B-Raf activity were observed. Thus beta-estradiol can
      induce Raf-1 and A-Raf activities in ER (+) cells. In addition, beta-estradiol
      caused cell cycle progression in MCF-7 cells and an increased proliferative
      response to beta-estradiol was observed in MCF-7, which overexpressed
      constitutively-active Raf-1 (MCF/DeltaRaf-1). Increased mRNA levels of the ligand
      for the c-erb-B2 receptor, amphiregulin (ARG) were observed after beta-estradiol
      treatment of MCF-7 cells whereas constitutively higher levels of ARG and its
      receptor, c-erb-B2 mRNAs were detected in MCF/DeltaRaf-1 cells. These findings
      suggest that targeting Raf may prove efficacious in breast cancer therapies.

PMID- 12432274
TI  - Variable sensitivity of endothelial cells to epirubicin in xenografts of human
      nasopharyngeal carcinoma CNE-2 cells.
AB  - Conventional anticancer drugs show non-specific vascular toxicity, and using
      anticancer drugs as angiogenesis inhibitors was suggested. However, our previous
      study suggested that vascular endothelial growth factor (VEGF) protected
      endothelial cells against chemotherapy drugs in vitro. To further test whether
      the vascular toxicity of anticancer drugs is active in vivo, epirubicin was i.p.
      injected into nude mice with s.c. xenografts of human nasopharyngeal carcinoma
      CNE-2 once (one-day schedule) or once a day from day 1 to day 7 (seven-day
      schedule). At 48 hours after the single injection or the 7th injection tumors
      were removed for detection of apoptosis of vascular endothelial cells vessels and
      the content of VEGF in tumor tissues. The results showed that epirubicin damaged
      tumor microvessels when the drug was given as a single dose, whereas epirubicin
      lost its vascular toxicity when the drug was given continuously for seven days,
      accompanied by higher levels of VEGF in tumor tissues. These results suggest the
      sensitivity of endothelial cells lining tumor vessels is variable during
      chemotherapy, and the protective effect of VEGF on endothelial cells might be
      related to the schedule of administration.

PMID- 12432275
TI  - Poisoning the messengers: could tumor endothelial cells acquire drug resistance?

PMID- 12432276
TI  - The type IV phosphodiesterase inhibitor rolipram induces expression of the cell
      cycle inhibitors p21(Cip1) and p27(Kip1), resulting in growth inhibition,
      increased differentiation, and subsequent apoptosis of malignant A-172 glioma
      cells.
AB  - Upregulation of the cAMP/protein kinase A (PKA) pathway has been shown to result
      in decreased proliferation, increased differentiation, and subsequent apoptosis
      of malignant glioma cells. Conventional cAMP analogs, however, are difficult to
      use in a clinical setting. Therefore, we investigated the effects of rolipram, a
      drug that has undergone clinical trials as an antidepressant and has also been
      proposed as a treatment for multiple sclerosis. Rolipram acts as a specific
      inhibitor of type IV phosphodiesterase (PDE4), leading to increased intracellular
      levels of cAMP. We report that the inhibition of PDE4 by rolipram results in the
      activation of the cAMP/PKA pathway, with potent stimulation of a reporter gene
      containing a cAMP-responsive element in its promoter region. Further, treatment
      of the human glioma cell line A-172 with rolipram results in increased expression
      of the cell cycle inhibitors p21(Cip1) and p27(KiP1), and decreased activity of
      cdk2, a cyclin-dependent kinase essential for cell cycle progression. As a
      result, the proliferation of A-172 cells is inhibited, with induction of a Gl
      block. Eventually, rolipram-treated A-172 cells undergo differentiation, which is
      followed by apoptotic cell death. As we observe this effect with other glioma
      cell cultures as well, our results suggest that rolipram could prove useful as a
      novel differentiating agent with both cytostatic and cytotoxic potential in the
      treatment of malignant gliomas.

PMID- 12432277
TI  - p53 Antiproliferative function is enhanced by aspartate substitution at threonine
      18 and serine 20.
AB  - Previous studies have demonstrated the irradiation-induced phosphorylation of p53
      at Thrl8 and Ser20, residues integral within an a-helical segment of the
      transactivation domain. Importantly, phosphorylation at either site has been
      correlated with decreased binding to the inhibitory partner Mdm-2 and enhanced
      transactivation of p53 target genes. In this study, we investigated the impact of
      Asp substitution at Thrl8 and Ser20 (p53Tl8D/S20D) on the functional regulation
      of p53. Asp substitution is commonly accepted as a means of mimicking
      phosphorylation due to the introduction of negative charge within the functional
      group. p53T18D/S20D was refractory to in vitro digestion by calpain, a protease
      recognizing a-helical structure within the transactivation domain. In addition,
      transfected p53T18D/S20D poorly bound GST-Mdm-2 in vitro, enhanced the endogenous
      expression of the p53 transactivation targets p21(Waf1/Cip1) and fas/APO-1, and
      significantly curtailed cell proliferation relative to wild-type p53 transfected
      cells. Thus, Asp substitution at Thr18 and Ser20 within the a-helical segment of
      the transactivation domain reduced Mdm-2 interaction, upregulating
      transactivation of cell-cycle and apoptotic regulatory targets, curtailing
      cellular proliferation.

PMID- 12432278
TI  - p53 Induction: phosphorylation sites cooperate in regulating.

PMID- 12432279
TI  - Death receptor 5 regulation during selenium-mediated apoptosis in human prostate
      cancer cells.
AB  - Selenium is an essential micronutrient that is currently being tested for
      prostate cancer chemoprevention. In spite of its significant promise as a
      chemopreventive agent, the molecular mechanisms of selenium-mediated effects
      remain to be elucidated. Recent evidence suggests that selenium may mediate its
      chemopreventive effects by inducing apoptosis in human prostate cancer cells.
      Here we report that selenium-mediated apoptosis appears to involve membrane death
      receptor, DR5-dependent pathway in human prostate cancer cells. Selenium
      specifically upregulated DR5 expression but not that of DR4. Selenium
      upregulation of DR5 was coupled with caspase 8 activation and Bid cleavage
      thereby suggesting the existence of a potential cross-talk between the DR5 and
      the mitochondrial pathways. Thus, our results suggest that DR5 is specifically
      regulated by selenium and its activation may play an important role in selenium
      mediated chemoprevention.

PMID- 12432280
TI  - On the chemoprevention TRAIL.

PMID- 12432281
TI  - Aberrant methylation of the 5' CpG island of TSLC1 is common in pancreatic ductal
      adenocarcinoma and is first manifest in high-grade PanlNs.
AB  - The recently identified tumor-suppressor gene TSLC1 on chromosome 11q23.2 is
      frequently inactivated in human non-small cell lung adenocarcinoma by DNA
      methylation-associated silencing. The aim of this study was to determine if TSLC1
      is inactivated in adenocarcinoma of the pancreas. We analyzed 17 pancreatic
      cancer cell lines, 91 primary pancreatic adenocarcinoma, 46 pancreatic
      intraepithelial (PanIN) precursor lesions and 15 microscopically normal pancreata
      for methylation of the 5' CpG island of the TSLC1 gene through methylation
      specific PCR. We observed 5' CpG methylation of TSLC1 in 4 of 17 cell lines
      (24%). In each cell line the aberrant methylation was associated with loss of
      TSLC1 expression by RT-PCR that was reversible after treatment with the DNA
      methyl-transferase inhibitor 5-aza-2'- deoxycytidine. Furthermore, we observed
      that TSLC1 was methylated in 25 of 91 primary pancreatic adenocarcinomas (27%),
      and in 2 of 7 highgrade PanIN-3 lesions (29%), but not in low-grade PanIN (0 of 9
      PanlN-2 and 0 of 30 PanIN-1) lesions or in normal pancreata (n=15). We conclude
      that epigenetic silencing of TSLC1 expression through 5' CpG island associated
      methylation is common in pancreatic adenocarcinoma and is a late event in
      pancreatic neoplastic development.

PMID- 12432282
TI  - Inactivation of tumor suppressor genes by promoter methylation is important in
      the pathogenesis of pancreatic cancer.

PMID- 12432283
TI  - Effect of reproductive hormones on ovarian epithelial tumors: I. Effect on cell
      cycle activity.
AB  - We examined the effects of the 4 major female reproductive hormones, estradiol
      (E2), progesterone (P4), follicle stimulating hormone (FSH), and luteinizing
      hormone (LH) on thymidine incorporation in benign and malignant ovarian
      epithelial tumors cultured in vitro. Treatment of these tumors with E2, FSH and
      LH resulted in increased thymidine incorporation while treatment with P4
      inhibited growth as well as thymidine incorporation. The inhibitory effect of
      progesterone could not be reproduced by treating the cells with ligands for other
      steroid hormone receptors known to interact with P4 such as the mineralocorticoid
      and glucocorticoid receptors. All cells lines expressed at least the PR-A isoform
      of the progesterone receptor. ORG2058, R5020, RU486, and ZK98299 acted as
      progesterone receptor agonists with regard to their effect on thymidine
      incorporation. P4 down-regulated cyclin Bl expression and cdkl activity and up
      regulated the p21 and p27 proteins. Expression of a reporter gene downstream to
      an AP-1 responsive element in a plasmid construct transfected into ovarian
      epithelial tumor cells was induced by P4 and inhibited by RU486. We conclude that
      P4 inhibits cell cycle activity in ovarian epithelial tumors, in part via down
      regulation of the cdkl/cyclin B complex. This inhibitory effect may have
      therapeutic utility against ovarian epithelial tumors.

PMID- 12432284
TI  - Effect of reproductive hormones on ovarian epithelial tumors: II. Effect on
      angiogenic activity.
AB  - Menstrual cycle activity predisposes to ovarian epithelial tumors based on
      numerous epidemiological studies. We showed that the hormones involved in
      menstrual cycle regulation modulate cell cycle activity in these tumors in an
      accompanying paper. We investigated whether such hormones could also influence
      angiogenesis, an important determinant of tumor progression, in the same tumors.
      Treatment with progesterone (P4) stimulated VEGF protein secretion in 4 of 5
      ovarian carcinoma cell lines examined. Northern blot analyses performed in MCV50
      cells showed that this effect was accompanied by increased VEGF mRNA levels. P4
      also stimulated VEGF promoter activity in these cells. Estradiol (E2) showed a
      similar, but substantially smaller effect on VEGF secretion which was additive to
      that of P4. Conditioned medium from P4-treated cells strongly stimulated
      angiogenesis on chicken chorio-allantoic membranes. Incubating the conditioned
      medium with a neutralizing anti-VEGF antibody, but not with non-specific
      immunoglobulins abolished this effect. Angiogenic activity was not altered by
      treatment of the membranes with P4 directly. We conclude that P4 can stimulate
      angiogenic activity via induction of VEGF secretion in some ovarian epithelial
      tumors. Therapeutic use of progestins may be most effective when administered in
      combination with an anti-angiogenic agent, at least against a subset of ovarian
      carcinomas.

PMID- 12432285
TI  - East is East, etc.

PMID- 12432287
TI  - Assessment of quality of life in the treatment of patients with neuropathic fecal
      incontinence.
AB  - INTRODUCTION: Development of quality-of-life measures has been the focus of
      research in colorectal disorders in recent years. The assessment of quality of
      life for fecal incontinence should be more important than quantitative
      measurement of soiling. PURPOSE: This study assesses specific patient quality-of
      life objectives, categorizes objectives, and correlates these objectives with
      continence scores. METHODS: One hundred eighteen patients entered into a
      randomized, controlled trial of biofeedback were assessed using the Direct
      Questioning of Objectives quality-of-life measure. All objectives were
      documented, categorized, and correlated with continence scores and analog scales.
      RESULTS: In patients with neuropathic fecal incontinence, the most frequent
      quality-of-life group concerned the ability to get out of home, to socialize
      outside of home, to go shopping, and not to have to worry about the location of
      the nearest toilet while out of home (34 percent; 123/364). At least one of these
      four objectives was stated by 72 percent of patients (85/118). Only 31 percent of
      patients (37/118) nominated an objective related to the physical act of soiling.
      The ability to travel (29 percent), exercise including walking (25 percent),
      perform home duties (19 percent), family and relationships (22 percent), and job
      (13 percent) were less frequently cited by patients. CONCLUSION: Continence
      scores focus heavily on the physical aspects of incontinence such as soiling and
      hygiene, aspects which seem to be less important to the patients themselves. It
      is important, therefore, that assessments of fecal incontinence should include
      reference to quality of life, and in particular to its impact on activities
      relating to "getting out of the house."

PMID- 12432288
TI  - Objective comparison of stapled anopexy and open hemorrhoidectomy: a randomized,
      controlled trial.
AB  - PURPOSE: This trial compares stapled anopexy with open hemorrhoidectomy in
      patients with prolapsing (Grade 3) hemorrhoids. Particular attention was paid to
      changes in anorectal physiology, nature of tissue resected, quality-of-life
      assessments, and cost implications of the treatments studied. METHODS: An initial
      pilot study was followed by a randomized, controlled trial in a District General
      Hospital in the United Kingdom. All patients had Grade 3 hemorrhoids. Nineteen
      patients were studied in the pilot study, with 99 patients in the randomized,
      controlled trial. All patients in the pilot study and 59 in the randomized,
      controlled trial underwent stapled anopexy. Thirty patients in the randomized,
      controlled trial underwent open hemorrhoidectomy. Of the 59 patients in the
      stapled group, 32 were treated with the Ethicon PPH stapling device, and 27
      received stapling with a reusable Autosuture stapling device. The following
      variables were measured: demographic details, quality of life (Medical Outcomes
      Study Short Form 36 and directed questions), anorectal manometry, and histology.
      RESULTS: There was no difference in the case mix within or between the groups.
      The stapled anopexy groups showed a significant reduction in operative time (P <
      0.001) and blood loss (P < 0.001) compared with open hemorrhoidectomy. Open
      hemorrhoidectomy resulted in significantly greater usage of protective pads
      postoperatively (P < 0.001) and longer rehabilitation (P < 0.006). CONCLUSIONS:
      Stapled anopexy is an effective alternative treatment for prolapsing hemorrhoids
      that allows reduced operative time and shorter rehabilitation. It does not appear
      to affect continence or overall quality of life.

PMID- 12432289
TI  - Fecal incontinence in females with a past history of vaginal delivery:
      significance of anal sphincter defects detected by ultrasound.
AB  - PURPOSE: The aim of this study was to determine the significance of anal
      sphincter defects detected by ultrasonography, in a population of fecal
      incontinent parous females without previous anoperineal surgery. METHODS: From
      100 consecutive incontinent patients, 61 females with at least one previous
      vaginal delivery and no past anoperineal surgery were studied. The severity of
      fecal incontinence was assessed by the Cleveland Clinic questionnaire score.
      Lesions of the internal or external anal sphincters, and the radial size of these
      defects were assessed by ultrasonography. Anal vector manometry was performed to
      measure anal pressures at rest and during voluntary squeeze, and the anal
      asymmetry index. RESULTS: Twenty-three had a normal sphincter (38 percent), and
      38 (62 percent) had a defect detected by ultrasonography: 20 isolated defects of
      the external sphincter and 18 combined defects of the internal and external
      sphincters. Combined defects were significantly larger. The radial size of the
      defects was positively correlated with the severity of clinical symptoms. Anal
      pressure asymmetry index was significantly increased in the group with combined
      defects compared with the two other groups. An index of 25 percent or greater had
      a very high (100 percent) negative predictive value for the presence of a defect
      larger than 90 degrees. CONCLUSIONS: This study confirms the high prevalence of
      anal sphincter defects detected by ultrasonography in a population of incontinent
      parous females without previous proctologic surgery. The clinical symptoms are
      related to the size of these defects. Anal vector manometry may be a useful tool
      to confirm the relation between echographic anal sphincter lesions and fecal
      incontinence.

PMID- 12432291
TI  - Internal sphincterotomy with hemorrhoidectomy does not relieve pain: a
      prospective, randomized study.
AB  - PURPOSE: Pain after hemorrhoidectomy is universal. Several attempts have been
      made to reduce or alleviate the pain after excisional hemorrhoidectomy. The
      origin of pain is undetermined. Current theories propose that the pain is
      mediated through the internal sphincter. This prospective, randomized study was
      performed to assess the degree of discomfort in patients with and without a
      sphincterotomy when performing a closed hemorrhoidectomy. METHODS: Between
      December 1999 and September 2001, 42 patients (22 males), median age 52 (range,
      30-80) years, who underwent excisional hemorrhoidectomy were randomly chosen to
      have an internal sphincterotomy in the base of the left lateral wound. RESULTS:
      Thirty-nine patients were available for the study. Parameters elicited in the
      study were pain, postoperative bleeding, urinary retention, impairment of
      continence by day and by night, and day the patient returned to work. There was
      no statistical difference in the postoperative pain in each of the two categories
      at four hours after surgery, after the first bowel movement, or four days after
      surgery. CONCLUSIONS: Results showed no difference in the perception of pain
      after hemorrhoidectomy in patients who had an internal sphincterotomy compared
      with those who did not. Both groups were equally likely to have difficulty with
      control of gas and soiling.

PMID- 12432292
TI  - Primary closure techniques in chronic pilonidal sinus: a survey of the results of
      different surgical approaches.
AB  - PURPOSE: Pilonidal sinus is a common disease and surgical removal and subsequent
      wound closure is crucial for lasting cure. To evaluate the outcome of different
      primary closure techniques we performed a pooled analysis of data published in
      the past 35 years. METHODS: We identified reports on wound infection, early
      failure, and late recurrence status in relation to treatment modality. Surgical
      techniques were classified into five groups: simple closure technique in the
      midline, asymmetric or oblique closure techniques, and full-thickness flap
      techniques like rhomboid flaps, vy-plasty, and z-plasty. Estimations of the
      incidences resulted from the quotient of number of responses and the number of
      patients for each study, and these quotients were summarized over all studies.
      RESULTS: The MEDLINE search identified 74 publications including 10,090 patients.
      Pooled data analysis revealed an inhomogeneous effect of the surgical techniques
      on the infection rate. In contrast, there was a significantly lower early failure
      rate and late recurrence rate of both the asymmetric-oblique closure techniques
      and the full-thickness flap techniques when compared with the midline repair
      technique. No difference was found between the asymmetric repairs and the full
      thickness flap techniques. CONCLUSION: Beside the various statistical
      considerations when using a pooled data analysis combining results from the
      literature, this overview suggests a significant benefit of asymmetric-oblique
      closure techniques or flap techniques in comparison with simple closure in the
      midline. Thus, we recommend an asymmetric closure technique for primary closure
      of a chronic pilonidal sinus. These asymmetric procedures provide better results
      than the simple closure in the natal midline. Furthermore, they are not as
      sophisticated as the full-thickness plasty techniques.

PMID- 12432293
TI  - Topical nifedipine with lidocaine ointment vs. active control for treatment of
      chronic anal fissure: results of a prospective, randomized, double-blind study.
AB  - PURPOSE: Chronic anal fissure may be treated by chemical or surgical
      sphincterotomy. The aim of this study was to test the efficacy of local
      application of nifedipine and lidocaine ointment in healing chronic anal fissure.
      METHODS: The study was performed according to a prospective, randomized, double
      blind design. One hundred ten patients who gave informed consent were recruited.
      They received a clinical examination, a questionnaire to evaluate symptoms and
      pain, anorectal manometry, and anoscopy. Healing of anal fissure at Day 42 of
      therapy was defined as the primary efficacy variable of the study. Patients
      treated with nifedipine (n = 55) used topical 0.3 percent nifedipine and 1.5
      percent lidocaine ointment every 12 hours for 6 weeks. The control group (n = 55)
      received topical 1.5 percent lidocaine and 1 percent hydrocortisone acetate
      ointment during therapy. Anal pressures were measured by recording resting and
      maximal voluntary contraction pressures at baseline and at Day 21. Long-term
      outcomes were determined after a median follow-up of 18 months. RESULTS: Healing
      of chronic anal fissure was achieved after 6 weeks of therapy in 94.5 percent of
      the nifedipine-treated patients (P < 0.001) as opposed to 16.4 percent of the
      controls. Mean anal resting pressure decreased from a mean value +/- standard
      deviation of 47.2 +/- 14.6 to 42 +/- 12.4 mmHg in the nifedipine group. This
      represents a mean reduction of 11 percent (P = 0.002). Changes of maximal
      voluntary contraction in nifedipine-treated patients were not significant. No
      changes in mean anal resting pressure and maximal voluntary contraction were
      observed in the control group. We did not observe any systemic side effect in
      patients treated with nifedipine. After the blinding was removed, recurrence of
      the fissure was observed in 3 of 52 patients in the nifedipine group within 1
      year of treatment, and 2 of these patients healed with an additional course of
      topical nifedipine and lidocaine ointment. CONCLUSIONS: Our study clearly
      demonstrates that the therapeutic use of topical nifedipine and lidocaine
      ointment should be extended to the conservative treatment of chronic anal
      fissure.

PMID- 12432294
TI  - Sentinel node mapping for colorectal cancer with radioactive tracer.
AB  - PURPOSE: The aim of this study was to test the feasibility and accuracy of
      radioactivity-guided mapping of the first lymph nodes found in draining the
      primary tumor site for colorectal cancer. METHODS: We enrolled 56 consecutive
      patients with preoperative diagnosis of curatively resectable colorectal cancer.
      Endoscopic injection of technetium Tc 99m-labeled tin colloid (15 MBq) was
      performed preoperatively, and radioactive sentinel nodes were identified
      intraoperatively with a gamma probe. Standard radical resection with lymph node
      dissection was performed in all patients, and all resected nodes were evaluated
      by routine histopathologic examination. RESULTS: Radioactivity-guided methods
      were used to detect sentinel nodes in 51 (91 percent) of 56 patients. The number
      of lymph nodes resected was 23.9 +/- 15.2 per case. The number of sentinel nodes
      was 3.5 +/- 2.1 (range, 0-8) per case. In 18 of 22 patients with lymph node
      metastasis, the sentinel node was positive. The incidence of metastasis in the
      sentinel node (22 percent) was significantly higher than that in nonsentinel
      nodes (3 percent, P < 0.01). Diagnostic accuracy according to sentinel node
      status was 92 percent (47/51). Four false-negative cases in this study were
      advanced cases with T3 primary tumors. The detection rate and diagnostic accuracy
      for patients with T1 or T2 primary tumors (29 cases) were 100 percent each.
      CONCLUSION: Intraoperative radioactivity-guided sentinel node mapping was
      accurate for patients with colorectal cancer with T1 or T2 tumors. The results
      suggest that sentinel node mapping and intraoperative biopsy may be a sensitive
      and specific diagnostic method for detecting metastasis in regional lymph nodes
      in patients with colorectal cancer.

PMID- 12432295
TI  - Does laparoscopic abdominoperineal resection of the rectum compromise long-term
      survival?
AB  - PURPOSE: Laparoscopic techniques for bowel resection have not enjoyed widespread
      popularity. Of concern is that long-term follow-up data of cancer specific
      outcomes is not yet available. The aim of our study was to examine the long-term
      outcome of abdominoperineal resection for cancer done laparoscopically compared
      with a similar cohort who underwent open surgery. METHODS: A retrospective review
      was performed of all abdominoperineal resections done in our center between 1992
      and 2000, comparing the cancer-specific outcomes of the laparoscopic cohort with
      the open cohort. The analysis was performed on an intention-to-treat basis and
      survival analysis was calculated by the techniques of Kaplan-Meier. RESULTS:
      Eighty-nine patients were reviewed. Twenty-eight operations were done
      laparoscopically, and 61 were open. The two groups were matched for age and stage
      of disease. There was no difference in mean length of overall survival (open =
      30.3 months; laparoscopic = 40.8 months; P = 0.355 log rank). No difference in
      overall recurrence rate, isolated recurrence rate, or distant recurrence rates
      was seen nor was there any difference in the disease-free period. There was no
      difference in the number of lymph nodes harvested from the resected specimens,
      and the distance to the lateral margins or involvement of tumor in the lateral
      margins between the two groups was the same. The laparoscopic cohort did have a
      significantly shorter length of stay (mean, 13 days) compared with the open
      cohort (mean, 18 days), P = 0.008 Mann-Whitney U test. CONCLUSIONS: Laparoscopic
      abdominoperineal resection of the rectum for cancer does not compromise cancer
      specific survival outcomes. The patients avoid a large abdominal wound, which
      improves cosmesis and presumably is responsible for the significantly shorter
      length of stay.

PMID- 12432296
TI  - Conformal preoperative endorectal brachytherapy treatment for locally advanced
      rectal cancer: early results of a phase I/II study.
AB  - PURPOSE: Downstaging rectal carcinoma by preoperative radiotherapy decreases
      local recurrence, and recent phase II studies suggest that, in the lower one
      third lesions, sphincter-preserving surgery can be considered. The purpose of the
      current study was to assess the efficacy and the toxicity of endorectal high dose
      rate brachytherapy as a preoperative downstaging treatment modality. METHODS:
      Patients with newly diagnosed invasive rectal adenocarcinoma, T2 to very early
      T4, operable tumors were eligible. A dose of 26 Gy was given over four
      consecutive daily treatments of 6.5 Gy prescribed at the tumor radial margin
      using endorectal brachytherapy with high dose-rate delivery system. Surgery as
      planned initially was done four to eight weeks later to allow for tumor
      downstaging. Patients found to have pathologic positive nodes received
      postoperative external beam (45 Gy/25 fractions) to the pelvis and systemic 5
      fluorouracil-leucovorin chemotherapy. RESULTS: Forty-nine patients entered the
      study. Tumors were in the lower one-third in 24 patients, middle one-third in 22,
      and upper one-third in 3. With preoperative endorectal ultrasound and magnetic
      resonance imaging, the clinical staging of the tumors was: 3 T2, 42 T3, 4 T4, and
      16 N1-2. Acute toxicity related to brachytherapy was limited to a moderate
      proctitis (Radiation Therapy Oncology Group acute toxicity scoring system, Grade
      2) in all patients, with two patients with tumors extending into the anal canal
      having Grade 3 dermatitis. Forty-seven patients underwent surgery. Two patients
      refused their operation based on a normal endoscopic rectal ultrasound after
      treatment. A complete clinical response was obtained in 32 of 47 (68 percent)
      patients with 32 percent pathologically pT0N0-1, and 36 percent had only residual
      microfoci of carcinoma. The surgical approaches did not yield more complications
      than expected. CONCLUSION: Preoperative high dose-rate endorectal brachytherapy
      seems to be safe, because acute toxicity was mainly local, with moderate
      proctitis (Grade 2) and occasional dermatitis (Grade 3) for very low tumors.
      Finally, this modality, by providing high rate of tumor downstaging and
      downsizing especially for patients with lesions in the lower one-third of the
      rectum, represents a definite potential for sphincter-preserving surgery for
      investigation in future studies.

PMID- 12432298
TI  - Adenocarcinoma of the small bowel: a study of 37 cases with emphasis on
      histologic prognostic factors.
AB  - PURPOSE: Primary small-bowel adenocarcinoma is uncommon. There are few large
      studies that have evaluated the prognostic impact of clinical and pathologic
      parameters. The purpose of this study was to perform a comprehensive analysis of
      the Cleveland Clinic experience with small-bowel adenocarcinoma, with emphasis on
      histopathologic parameters as prognostic indicators. METHODS: Thirty-seven cases
      of primary small-bowel adenocarcinomas resected at the Cleveland Clinic between
      1978 and 1999 were retrospectively studied. Metastatic tumors and those arising
      from the biliary system were excluded from analysis. Clinical and pathologic data
      were recorded and their impact on prognosis was evaluated by either Kaplan-Meier
      or Cox proportional hazards analysis. RESULTS: The cohort included 25 males, and
      the age range was 24 to 82 (mean, 56) years. Tumor location was duodenum (18),
      jejunum (10), ileum (2), and site not specified (7). Patients most frequently
      presented with abdominal pain (48 percent), anemia (39 percent) and small-bowel
      obstruction (33 percent). Underlying conditions included Crohn's disease (4) and
      familial adenomatous polyposis (2). Overall survival was 52 and 47 percent at 5
      and 10 years, respectively, with a mean follow-up of 50.5 (range, 0.5-184) months
      for all patients. Features found to be negative prognostic factors for survival
      were positive surgical margins (P < 0.001), extramural venous spread (P < 0.001),
      lymph node metastases (P = 0.038), poor tumor differentiation (P = 0.015), depth
      of tumor invasion (P = 0.023), and history of Crohn's disease (P < 0.001). Age,
      gender, tumor size, growth pattern, lymphocytic host response, and adjuvant
      therapy did not affect survival. CONCLUSIONS: Pathologic features, including
      positive surgical margins, extramural venous spread, positive lymph nodes, poor
      tumor differentiation, depth of tumor invasion, and history of Crohn's disease,
      are of major prognostic significance in small-bowel adenocarcinoma. Although many
      of these prognostic features are similar to the ones used for colorectal
      adenocarcinoma, they are easily applicable and reproducible for small-bowel
      adenocarcinomas. This is important considering the often dismal prognosis of
      small-bowel adenocarcinoma.

PMID- 12432299
TI  - Evaluation of aggressively treated patients with unresectable multiple liver
      metastases from colorectal cancer.
AB  - PURPOSE: The aim of this study was to assess the value of aggressively treating
      patients with unresectable liver metastases from colorectal cancer and a poor
      prognosis. METHODS: From 1988 to 1999, 64 patients with unresectable multiple
      liver metastases from colorectal cancer who had received hepatic arterial
      infusion chemotherapy were investigated. All patients did not have synchronous
      extrahepatic metastases at the time of initiating our treatment. When liver
      metastases were suitable for resection after hepatic arterial infusion
      chemotherapy, we excised them and repeated prophylactic hepatic arterial infusion
      chemotherapy as long as possible. We evaluated the efficacy of hepatic arterial
      infusion chemotherapy by computed tomography and divided these patients into
      responders and nonresponders. We performed univariate analysis using the log-rank
      test to calculate predictive factors. In addition, the Cox proportional hazards
      model was used to perform multivariate analysis of factors related to survival.
      RESULTS: The survival rate of all patients was 67.8 percent after 1 year and 10
      percent after 5 years. However, the survival rate for 16 patients who received
      hepatectomy after hepatic arterial infusion chemotherapy was 35.1 percent after
      five years. Multivariate analysis demonstrated that the response after hepatic
      arterial infusion chemotherapy was the most indicative prognostic factor.
      CONCLUSIONS: The prognosis of selected patients who responded to hepatic arterial
      infusion chemotherapy and received hepatectomy was improved. Applying aggressive
      treatment as outlined in our strategy may improve the chances of long-term
      survival.

PMID- 12432300
TI  - Expression of connective tissue growth factor in intra-abdominal adhesions.
AB  - PURPOSE: Connective tissue growth factor stimulates fibroblast proliferation and
      extracellular matrix deposition in many fibrotic disorders. The aim of our study
      was to determine the expression pattern of connective tissue growth factor in
      postoperative intra-abdominal adhesions. METHODS: Adhesions were created in 46
      Sprague-Dawley rats by complete dissection and resuturing of a peritoneal patch 2
      cm in diameter, lateral from the midline incision. Animals were killed at
      postoperative Days 3, 6, 9, 12, 15, 18, and 21 and the adhesions scored on a
      scale of 0 to 5. Tissue samples from adhesion areas and from uninvolved
      peritoneum were evaluated by Northern and Western blotting for temporal
      connective tissue growth factor mRNA and protein expression, respectively.
      Immunohistochemical analysis was performed for connective tissue growth factor
      localization. RESULTS: Adhesions formed in all animals after surgery and were
      confined to the peritoneal patches. Adhesion formation increased across time,
      with significant correlation between adhesion scores and postoperative days (r =
      0.329, P = 0.026). Connective tissue growth factor mRNA concentrations were
      significantly elevated in adhesion tissue throughout the three-week period when
      compared with normal peritoneum (P = 0.012); peak levels occurred between Days 6
      and 15. Western blots demonstrated connective tissue growth factor protein
      expression in adhesions from Days 6 to 21, in contrast to negligible bands in
      normal peritoneum. Fibroblasts within the adhesive tissue, but not in uninjured
      peritoneum, stained positive for connective tissue growth factor by
      immunohistochemistry. CONCLUSIONS: We have demonstrated a specific temporal and
      spatial expression pattern for connective tissue growth factor in intra-abdominal
      adhesions during a three-week postoperative time course. According to what is
      known about the functional role of connective tissue growth factor in
      fibrogenesis, our findings warrant further investigations addressing a causal
      relationship between this growth factor and fibrous adhesion formation.

PMID- 12432301
TI  - Prognostic significance of laminin-5 gamma2 chain expression in colorectal
      carcinoma: immunohistochemical analysis of 103 cases.
AB  - PURPOSE: The laminin-5 gamma2 chain plays an important role in cell migration
      during tumor invasion and tissue remodeling. Although this chain has been
      reported to be expressed in tumor-stroma interface of colorectal carcinoma,
      prognostic significance of its expression has not been elucidated in these
      tumors, so we investigated the clinicopathologic significance of Laminin-5 gamma2
      chain expression in colorectal carcinoma. METHODS: Laminin-5 gamma2 chain
      expression was investigated immunohistochemically in 103 colorectal carcinoma
      patients with Stage II, III, and IV disease. The patients were categorized into
      three groups according to the number of immunopositive tumor cells in the
      sections containing the maximum diameter of the tumor as follows: +, less than 20
      tumor cells were positive; ++, 20 to 500 tumor cells were positive; +++, more
      than 500 tumor cells were positive. RESULTS: Laminin-5 gamma2 chain expression
      was observed in cytoplasm of tumor cells, especially those in the invasive front
      of the tumor penetration. Eighteen (17 percent) of tumors showed +, 60 (58
      percent) showed ++, and 25 (24 percent) showed +++. The increased number of
      immunopositive tumor cells was significantly associated with synchronous liver
      metastasis (P = 0.048). The univariate (P = 0.036) and multivariate (P = 0.001)
      analysis of the patients' survival revealed that the prognosis became
      significantly poorer in patients with the increased number of immunopositive
      tumor cells. CONCLUSIONS: Increased laminin-5 gamma2 chain immunoreactivity,
      suggesting a high invasive potential of tumor cells, was a significant poor
      prognostic indicator for the patients with colorectal carcinoma.

PMID- 12432302
TI  - Indeterminate colitis: the real story.
AB  - PURPOSE: Up to one in five patients undergoing surgery for ulcerative colitis
      will have ambiguous histology, with features of both ulcerative colitis and
      Crohn's disease, and are categorized as having indeterminate colitis. We
      hypothesized that functional outcomes in indeterminate colitis patients
      undergoing ileal pouch-anal anastomosis are comparable with those of ulcerative
      colitis patients undergoing ileal pouch-anal anastomosis. METHODS: Physician
      conducted interviews of 120 consecutive ileal pouch-anal anastomosis patients
      with a preoperative diagnosis of ulcerative colitis were reviewed, with a mean
      follow-up of 54 months. All colectomy specimens were reviewed by a single
      pathologist. Any changes in histologic diagnosis from ulcerative colitis to
      indeterminate colitis or Crohn's disease, frequency of postoperative
      complications, pouch function, and long-term postoperative medication usage were
      recorded. RESULTS: Although postoperative fistulas were more common in
      indeterminate colitis than ulcerative colitis (26 vs. 10 percent; P = 0.02, chi
      squared), no indeterminate colitis patient required a permanent ileostomy as
      compared with six ulcerative colitis patients. Long-term functional results were
      similar. Overall, two-thirds of patients developed pouchitis. Ulcerative colitis
      and Crohn's disease patients were more likely to have had >3 episodes of
      pouchitis (58 and 72 percent) compared with indeterminate colitis patients (29
      percent; P = 0.006, chi-squared). A greater number of Crohn's disease patients
      required maintenance oral antibiotic therapy (64 percent) to achieve satisfactory
      functional results compared with both indeterminate colitis and ulcerative
      colitis patients (20 and 28 percent; P = 0.014, chi-squared). CONCLUSIONS:
      Although ileal pouch-anal anastomosis patients with indeterminate colitis have
      more postoperative fistulas, long-term function is equal to that of ulcerative
      colitis patients and better than Crohn's disease patients. Ileal pouch-anal
      anastomosis should be offered to patients with indeterminate colitis and those
      with severe colitis in whom clear differentiation between indeterminate colitis
      and ulcerative colitis cannot be made.

PMID- 12432303
TI  - Primary squamous-cell carcinoma of the rectum: report of six cases and review of
      the literature.
AB  - PURPOSE: The majority of colorectal carcinomas diagnosed are adenocarcinomas.
      Squamous-cell carcinoma is a rare pathologic curiosity. Since 1943, only 18 cases
      have been described in the medical literature. The aim of this study was to
      report retrospectively six new cases and to review the medical literature.
      PATIENTS: Of the 6 cases, 4 were females, and age ranged from 43 to 93 years.
      Tumors were located 7 to 12 (mean, 8.5) cm from the anal verge. Five patients
      underwent surgical resection. Intraoperative radiotherapy was performed in one
      case. One patient was treated only by external beam radiotherapy. In two cases
      neoadjuvant combination of external beam radiotherapy and chemotherapy and in one
      case neoadjuvant contact x-ray treatment were performed. This treatment was
      followed by external beam radiotherapy in two cases and by chemotherapy in two
      cases, in patients with lymph node involvement. RESULTS: The clinical tumor
      response to radiotherapy was almost complete for the patient who did not undergo
      surgery. One tumor was sterilized by preoperative radiation. Three patients were
      alive without recurrence at 6 months, 2 years, and 16 years. CONCLUSION: The
      etiopathogenicity of squamous-cell carcinoma of the rectum is discussed. The
      prognosis of these tumors seems to be worse than that for adenocarcinoma because
      of a delayed diagnosis. Surgical resection seems to be the most important
      treatment. Chemotherapy and especially radiotherapy may have some indications.

PMID- 12432304
TI  - Contrast-enhanced three-dimensional magnetic resonance angiography for
      visualization of ectopic varices.
AB  - We report the case of a 62-year-old male with portal hypertension and recurrent
      bleeding refractory to surgical intervention from varices in a sigmoid stoma.
      Although stomal varices were detected neither by physical examination, stomal
      endoscopy, nor duplex sonography, contrast-enhanced three-dimensional magnetic
      resonance angiography of the portal vein and its collateral branches demonstrated
      their presence. Surgical revisions of the stoma failed to prevent bleeding, but
      implantation of a transjugular intrahepatic shunt successfully prevented
      recurrent hemorrhage. This case indicates that contrast-enhanced, three
      dimensional magnetic resonance angiography is useful to detect this rare
      complication of portal hypertension and helps to tailor adequate treatment in
      patients with recurrent bleeding from stomal varices.

PMID- 12432305
TI  - Obscure intestinal bleeding from ileo-ovarian vascular malformation: report of a
      case.

PMID- 12432306
TI  - Combined perineal and endorectal repair of rectocele by circular stapler: a novel
      surgical technique.
AB  - PURPOSE: The aim of this study was to present a new technique for treatment of
      disabling rectocele when associated with internal mucosal prolapse or hemorrhoids
      using a 33-mm circular stapler. METHODS: Eight female patients complaining of
      obstructed defecation because of distention rectocele associated with internal
      mucosal prolapse or hemorrhoids and perineal descent entered the study. The
      rectovaginal septum was opened by diathermy up to the end of the rectal wall
      weakness. The perineal wound and the anus were held open by a self-retractor.
      Using a transparent anoscope (PPH 01 system), 2 mucosal pursestrings were
      prepared 5 and 8 to 9 cm distant from the dentate line. Posteriorly, only the
      submucosa was included in the pursestring; anteriorly, it included the rectal
      wall, which was kept separate from the vaginal wall. A transanal 33-mm circular
      stapler was then used to close the rectocele and treat the mucosal prolapse.
      Before closing the perineum a levatorplasty was fashioned. RESULTS: One patient
      had a vaginal tear during dissection of the septum, which healed spontaneously in
      one month. No other complications were recorded. Postoperative defecography
      showed correction of the rectocele and the posterior rectal prolapse in all
      patients. In two of them, a small lateral diverticulum could be seen, although
      this was asymptomatic. After a median follow-up of 12 months, all had
      significantly improved defecation (chronic constipation score dropped from 14.3
      to 5, P < 0.04). CONCLUSION: Combined perineal and endorectal stapler repair of
      rectocele may be a useful new surgical tool for correcting distention rectocele
      associated with mucosal prolapse or hemorrhoids and perineal descent in selected
      patients. A longer follow-up on a larger number of patients is needed to confirm
      these preliminary results.

PMID- 12432307
TI  - Prospective evaluation of anesthetic technique for anorectal surgery.
AB  - PURPOSE: Deep intravenous sedation plus local anesthesia for anorectal surgery in
      the prone position is used frequently at our institution, but is not widely
      accepted because of concerns regarding airway management. The purpose of this
      study was to prospectively evaluate the safety and efficacy of this anesthetic
      technique for anorectal surgery. METHODS: Data were collected prospectively on
      413 consecutive patients (mean age, 47 years; mean weight, 80 kg) undergoing
      anorectal surgical procedures. RESULTS: Of the 389 patients who underwent
      anorectal procedures in the prone position, 260 (67 percent) received intravenous
      sedation plus local anesthesia, 125 (32 percent) received regional anesthesia
      (spinal or epidural), and 4 (1 percent) received general endotracheal anesthesia.
      Of the 24 patients who underwent anorectal procedures in the lithotomy position,
      13 (54 percent) received intravenous sedation plus local anesthesia, 2 (8
      percent) received regional anesthesia, 2 (8 percent) received general
      endotracheal anesthesia, and 7 (29 percent) received mask inhalational
      anesthesia. Forty-two adverse events attributable to the anesthetic occurred in
      18 patients: nausea and vomiting (n = 17), transient hypotension, bradycardia, or
      arrhythmia (n = 8), transient hypoxia or hypoventilation (n = 7), urinary
      retention (n = 6), and severe patient discomfort (n = 2). These complications
      occurred in 4 percent (10/273) of patients receiving intravenous sedation plus
      local anesthesia and in 6 percent (8/127) of patients receiving regional
      anesthesia. Two of 260 patients (0.8 percent) receiving intravenous sedation plus
      local anesthesia in the prone position were rolled supine before completing the
      surgical procedure. Recovery time before discharge for patients treated on an
      ambulatory basis was significantly shorter for those patients undergoing
      intravenous sedation plus local anesthesia (79 +/- 34 minutes, n = 174) than for
      patients undergoing regional anesthesia (161 +/- 63 minutes, n = 45; P < 0.001, t
      test). CONCLUSION: Intravenous sedation plus local anesthesia in the prone
      position is safe and effective for anorectal surgery and offers potential cost
      savings by decreasing recovery room time for outpatient procedures.

PMID- 12432309
TI  - Importance of the anterior plane of rectal mobilization.

PMID- 12432310
TI  - Tailored sphincterotomy or fissurectomy and anoplasty?

PMID- 12432311
TI  - Additional experience of endoscopic T-bar sigmoidopexy.

PMID- 12432312
TI  - National analgesia prescribing patterns in emergency department patients with
      burns.
AB  - Previous studies suggest that many patients with burns receive inadequate
      analgesia. A secondary analysis of the 1992 to 1999 National Hospital Ambulatory
      Medical Care Survey (a national, weighted sample of emergency department [ED]
      encounters) was performed to estimate national analgesia prescribing patterns in
      ED patients with burns. In 1999, there were 21,103 patient encounters sampled
      from 376 EDs, resulting in an estimated 102.8 million ED visits in 1999. One
      hundred thirty-eight patients in the sample (0.7%) had burns for an estimated
      827,000 annual burns. Patient mean age was 28 years. Forty-three percent were
      female, 25% were children under 18 years of age, and 81% were white. Pain
      assessments were performed in about half of the patients, and only half of the
      patients received analgesics. Analgesia administration did not differ by year,
      sex, age, race, ethnicity, geographic location, or insurance payment type, yet it
      was more likely with increased pain. We conclude that many patients with burns do
      not have documentation of pain assessment or analgesia administration while in
      the ED.

PMID- 12432313
TI  - The efficacy of honey in inhibiting strains of Pseudomonas aeruginosa from
      infected burns.
AB  - Because there is no ideal therapy for burns infected with Pseudomonas aeruginosa,
      there is sufficient need to investigate the efficacy of alternative
      antipseudomonal interventions. Honey is an ancient wound remedy for which there
      is modern evidence of efficacy in the treatment of burn wounds, but limited
      evidence for the effectiveness of its antibacterial activity against Pseudomonas.
      We tested the sensitivity of 17 strains of P. aeruginosa isolated from infected
      burns to two honeys with different types of antibacterial activity, a pasture
      honey and a manuka honey, both with median levels of activity. All strains showed
      similar sensitivity to honey with minimum inhibitory concentrations below 10%
      (vol/vol); both honeys maintained bactericidal activity when diluted more than 10
      fold. Honey with proven antibacterial activity has the potential to be an
      effective treatment option for burns infected or at risk of infection with P.
      aeruginosa.

PMID- 12432314
TI  - Cecal perforation in thermal injury: case report and review of the literature.
AB  - Gastrointestinal complications in burn patients include ileus, constipation,
      hemorrhage from ulcerations, ischemic bowel, and rarely, perforations. Patients
      with hypotensive episodes and sepsis are at risk for developing ischemic bowel
      disease. There have been three reports in the literature of cecal perforation in
      burn patients. We present an additional case and review of the literature.

PMID- 12432315
TI  - The 2002 Presidential Address: N.P.D.G.B. and other surgical sayings.

PMID- 12432316
TI  - The 2002 Everett Idris Evans Memorial Lecture. Burn care in Brazil: ideas from
      the past, trends of the present, and hopes for the future.

PMID- 12432317
TI  - The 2002 Clinical Research Award. An evaluation of the safety of early vs delayed
      enteral support and effects on clinical, nutritional, and endocrine outcomes
      after severe burns.
AB  - Early enteral support is believed to improve gastrointestinal, immunological,
      nutritional, and metabolic responses to critical injury; however, this premise is
      in need of further substantiation by definitive data. The purpose of this
      prospective study was to examine the effectiveness and safety of early enteral
      feeding in pediatric patients who had burns in excess of 25% total body surface
      area. Seventy-seven patients with a mean percent total body surface area burn of
      52.5 +/- 2.3 (range 26-91), percent full thickness injury of 44.7 +/- 2.8 (range
      0-90), and age ranging from 3.1 to 18.4 (mean 9.3 +/- 0.5) were randomized to two
      groups: early (feeding within 24 hours of injury) vs control (feeding delayed at
      least 48 hours postburn). Nutrient intake was measured daily, indirect
      calorimetry was performed biweekly, and blood and urine samples were obtained for
      the assay of cortisol, glucagon, insulin, gastrin, epinephrine, norepinephrine,
      dopamine, triiodothyronine, tetraiodothyronine, albumin, transferrin, prealbumin,
      retinol-binding protein, glucose, nitrogen balance, and 3-methylhistidine
      throughout the study period. Three protocol violations occurred, and two patients
      were transferred to another hospital; these patients were excluded from the
      study. No patient in either group experienced tube feeding aspiration. No
      differences were evident in infection, diarrhea, hospital length of stay, or
      mortality outcomes. A higher incidence of reportable adverse events coincided
      with early feeding (22 vs 8%), but this was not statistically significant. The
      delayed feeding group demonstrated a significant caloric deficit during postburn
      week (PBW) 1 (P <.0001) and PBW2 (P =.0022). Serum insulin (P =.0004) and
      triiodothyronine (P =.0162) were higher in the early fed group during PBW1. A
      decrease in 3-methylhistidine output (suggesting a decrease in protein breakdown)
      was also evident during PBW1 (P =.0138). No other significant trends in study
      outcome variables were noted. In conclusion, provision of enteral nutrients
      shortly after burn injury reduces caloric deficits and may stimulate insulin
      secretion and protein retention during the early phase postburn. These data,
      however, do not necessarily reaffirm the safety of early enteral feeding, nor do
      they associate earlier feeding with a direct improvement in endocrine status or a
      reduction in morbidity, mortality, hypermetabolism, or hospital stay. Future
      studies are needed to establish precise feeding implementation times that
      maximize clinical benefit while minimizing morbidity in the critically injured
      burn patient.

PMID- 12432318
TI  - The 2002 Moyer Award. Metabolic effects of vitamin D on serum calcium, magnesium,
      and phosphorus in pediatric burn patients.
AB  - Severe burn injury results in profound metabolic derangements. Recently, we have
      shown that vitamin D metabolism is disturbed after burn injury. Vitamin D is
      essential for calcium and phosphorus homeostasis and skeletal bone integrity. The
      role of vitamin D on magnesium homeostasis is not well understood. The purpose of
      this study was to assess the effects of vitamin D deficiency on serum
      electrolytes. Forty-one pediatric burn patients with a mean (+/- SEM) total body
      surface area burn of 53.1 +/- 2.9% and full-thickness injury of 44.2 +/- 4.1%
      were studied from July 1996 to December 2000. The mean age of the patients was
      6.5 +/- 0.8 years. Patients were studied for 6 weeks after admission to the
      hospital. Blood samples were obtained weekly for serum 25-hydroxycholecalciferol
      (25D), 1,25-dihydroxycholecalciferol (1,25D), and daily for calcium, magnesium,
      and phosphorus. Total intravenous (IV) replacement of calcium, magnesium, and
      phosphorus was also quantitated retrospectively. Bivariate and multivariate
      correlational analysis was used for statistical comparison. For the study
      duration, multivariate analysis demonstrated a positive correlation between 25D
      and serum calcium (r =.47, P <.05) and 1,25D and calcium (r =.27, P <.05).
      Overall, calcium had a positive correlation with phosphorus and a negative
      correlation with IV calcium replacement (ie, patients with lower calcium received
      more IV replacement). During the initial week of hospitalization (week 0),
      decreased 25D (mean 11.6 ng/ml; normal range 15-57 ng/ml) and 1,25D (mean 13.9
      pg/ml; normal range 15-75 pg/ml) did not correlate with any other measured
      variable. In week 1, 1,25D (mean 15.2 ng/ml) had a positive correlation (r =.410,
      P <.05) with calcium (mean 7.70 mg/dl). Hypovitaminosis D observed in burn injury
      correlates with serum calcium and phosphorus abnormalities. Early after injury
      (<1 week) there was no observed correlation between vitamin D and other variables
      possibly because of the effects of burn shock. After 1 week, vitamin D appears to
      significantly effect phosphorus homeostasis. The relationship between vitamin D
      and magnesium is not well established. These results may indicate a role for
      vitamin D replacement therapy during the initial phase of burn resuscitation.

PMID- 12432319
TI  - The 2002 Lindberg Award. PRN vs regularly scheduled opioid analgesics in
      pediatric burn patients.
AB  - Very little has been published on treating acute pain in children younger than
      the age of 3 for burns or any other trauma etiology. This study prospectively
      monitored the pain behavior and opioid analgesic intake of 31 pediatric burn
      patients (mean age = 23.71 months; SD = 15.75). Twelve of those children were
      randomized to conditions in which they either received opioid analgesics pro re
      nata (ie, as needed, pain contingent) or on a regular basis. The two groups did
      not show differences in demonstrable pain but, interestingly, they received
      equivalent does of opioid analgesics. As such, the pro re nata group was likely
      medicated largely on a regularly scheduled basis. For most of the remaining
      (nonrandomized) subjects, physicians ordered regularly scheduled opioid
      analgesics, suggesting that this practice has become largely institutionalized in
      the study setting. Information on pediatric opioid analgesic dosing and pain
      measurement strategies for nonverbal subjects can be derived from the findings.

PMID- 12432320
TI  - Early tracheostomy does not improve outcome in burn patients.
AB  - Early tracheostomy (ET) has been claimed to reduce ventilator support or
      intensive care unit or hospital length of stay in intensive care unit patients.
      This study was performed to assess the potential benefits of ET in burn patients.
      From October 1996 to July 2001, we evaluated all intubated and acutely burned
      adults using a formula to predict the probability of prolonged ventilator
      dependence. We randomized each patient with a probability of prolonged ventilator
      dependence more than 0.5 to ET, performed on the next operative day, or to
      conventional therapy (CON), which consisted of continued endotracheal intubation
      as needed, with tracheostomy (TRACH) performed on postburn day (PBD) 14 if
      necessary. During this period, 44 patients were randomized, 23 to CON and 21 to
      ET. Groups did not differ in age, total burn size, or inhalation injury, although
      ET patients had larger full-thickness burns. ET patients underwent TRACH at a
      mean of PBD 4 vs PBD 14.8 for CON patients (P <.01). ET patients had a
      significant improvement in PaO2 /FiO2 ratios within 24 hours following TRACH (139
      +/- 15 vs 190 +/- 12; P <.01). There were no differences in ventilator support,
      length of stay, incidence of pneumonia, or survival. However, six CON patients
      (26%) were successfully extubated by PBD 14 compared with one ET patient (P
      <.01). Although tracheostomy offers some advantages in terms of patient comfort
      and security, routine performance of ET in burn patients does not improve
      outcomes, nor does it result in earlier extubation. This may be partly caused by
      the comfort and convenience of tracheostomy.

PMID- 12432321
TI  - The utility of D-dimer levels in screening for thromboembolic complications in
      burn patients.
AB  - Recent studies confirm that thromboembolic complications in burn patients are
      higher than previously reported. Swelling, pain, and erythema are not useful
      indicators of deep venous thrombosis (DVT) in burned extremities. We propose that
      D-dimer levels may be useful in determining which patients would benefit from
      further screening for DVT. Thirty adult hospitalized burn patients were screened
      for DVT with duplex ultrasound on admission and then weekly until discharge. D
      dimer levels were measured at the same intervals. Seven patients developed 11
      cases of DVT. The mean time to DVT diagnosis was 6.7 days. D-dimer levels were
      elevated in 86% of DVT patients at week 1, with a negative predictive value of
      94%. The evaluation of elevated D-dimer levels at week 1 may be a useful
      screening tool for detecting DVT in the burn population.

PMID- 12432322
TI  - A prospective, randomized comparison of the Volume Diffusive Respirator vs
      conventional ventilation for ventilation of burned children. 2001 ABA paper.
AB  - The Volume Diffusive Respirator (VDR) is a high-frequency time cycled pressure
      ventilator that can ventilate, oxygenate, and promote secretion removal. The VDR
      provides ventilation at lower airway pressures than those required for
      conventional ventilation in the pressure control mode (PCV). A prospective,
      randomized, institutional review board-approved study was conducted comparing the
      VDR to PCV in burned children with respiratory failure from all causes. METHODS:
      Pediatric burn patients requiring ventilation were stratified by presence of
      inhalation injury and ventilated by VDR or PCV to achieve predefined arterial
      blood gases. RESULTS: Sixty-four patients were prospectively assigned ventilator
      type; 32 to VDR, 32 to PCV. Data are reported as mean + SEM. Patient age was 7.4
      + 0.7 years, TBSA was 56 + 3%, and number of patients with inhalation injuries
      was 55 (86%). Maximum peak inspiratory pressure with the VDR was significantly
      less than with PCV (30.9 + 0.8 cm H2O vs 39.5 + 1.8 cm H2O,P < 0.05) and the best
      PaO2 /FIO2 ratio was significantly higher with the VDR compared with PCV (563 +
      15 vs 507 + 13, P < 0.05). No patient in the VDR group had evidence of barotrauma
      compared with two in the PCV group. Five patients in the PCV group died compared
      with two in the VDR group. CONCLUSION: Patients ventilated with the VDR required
      significantly lower peak inspiratory pressure and achieved a significantly higher
      PaO2 /FIO2 ratio compared with PCV. This demonstrates the VDR is a safe and
      effective method of ventilation for pediatric burn patients and it offers
      advantages when compared with conventional ventilation.

PMID- 12432323
TI  - Evaluation of a peer consultation program for burn inpatients. 2000 ABA paper.
AB  - A burn survivor may provide unique psychological support to patients who have
      been burned more recently and enhance their adjustment to burn injury. The
      purpose of this study was to describe the peer consultation/burn survivor support
      program at a large regional burn center in the Northwest United States. Over the
      course of 17 months, three specially trained peer consultants who had survived
      their own burn injuries in the past made 167 visits to 108 patients, who, in
      turn, completed evaluation forms for each visit. Findings indicated that patients
      reported that the peer consultants approached them in an appropriate manner,
      answered their questions, and provided useful support and information.

PMID- 12432324
TI  - Valacyclovir (valtrex) for herpes labialis.

PMID- 12432325
TI  - Rasburicase (elitek) for hyperuricemia.

PMID- 12432326
TI  - [Menorrhagia and inherited disorders of coagulation].
AB  - Menorrhagia, a common complaint among women, may be a manifestation of an
      underlying inherited disorder of coagulation. In this review, the most frequent
      hereditary bleeding disorders associated with menorrhagia are briefly analyzed.
      Particularly, the epidemiological, clinical and diagnostic characteristics of von
      Willebrand disease, factor VIII, factor IX and factor XI deficiencies are
      examined. The influence of external factors (age, phase of menstrual cycle and
      hormonal therapy) on coagulation factor levels is also analyzed. Finally, the
      main therapeutic options (such as hormonal therapy, tranexamic acid and
      desmopressin), for the treatment of menorrhagia in women with hereditary bleeding
      disorders are reviewed. Since inherited bleeding disorders are frequently
      associated with menorrhagia, the conclusion is drawn that an underlying
      congenital bleeding disorder should be ruled out in any woman with menorrhagia.

PMID- 12432327
TI  - [Options for uterine distension during hysteroscopy].
AB  - BACKGROUND: This comparative study evaluated effectiveness, complications and
      patient satisfaction following the use of carbon dioxide (CO2) compared with
      physiological solution for uterine distension during hysteroscopy. The study was
      motivated by doubts concerning the choice of distension methods and the
      implications of their use. METHODS: The study population included 189 patients
      attending the outpatient services of the Obstetrics/Gynecological Clinic of the
      University of Naples for sterility/infertility disorders. Patients were randomly
      assigned by computer to either of two treatment groups. Both groups underwent
      hysteroscopy. In Group A (92 patients), uterine distension was performed using
      carbon dioxide (CO2), while in Group B (97 patients) physiological solution was
      used. Treatment was assessed for effectiveness, causes of discomfort, patient
      compliance and satisfaction rate. RESULTS: Compared with carbon dioxide (CO2),
      the use of physiological solution as a means of uterine distension was
      demonstrated certain advantages that were statistically significantly for the
      parameters of operating time, onset of vagal reactions, causes of discomfort,
      compliance and satisfaction rate, and cost-effectiveness of equipment.
      CONCLUSIONS: The use of physiological solution for uterine distension was
      observed to enhance patient compliance with hysteroscopy, because the method was
      better tolerated, more rapid and involved fewer failures.

PMID- 12432328
TI  - [Laser conization for cervical intraepithelial neoplasias, grade III. Personal
      experience of 77 cases].
AB  - BACKGROUND: Evalutation of the efficacy of laser conization for cervical high
      grade squamous intraepithelial lesions (Hg-SIL). METHODS: A retrospective
      evaluation. Case collection: A total of 77 women, 47 outpatients and 30
      inpatients with endocervical CIN3 or CIN2, were treated by carbon dioxide (CO2)
      laser between 1993 and 1995. A preoperative diagnosis has been made by means of
      Pap-smear, colposcopy and marked biopsy. In 47 cases a laser conization was
      performed in Day Surgery, without vessel constrictors or local anesthetics. In 30
      cases a narcosis (Diprivan ) was induced. The former were discharged 2-3 hours
      and the latter 24 hours after treatment. RESULTS: The histological examination
      confirmed preoperative diagnosis in 64 (86.5%) cases and negligible one grade
      discrepancy was reported in 7 cases (6 over- and 1 underestimated); missed
      invasion and no free margins were reported in the remaining 4 and 2 patients
      respectively, so these latter 6 patients were submitted to other surgical
      procedures. No serious complications occurred with the exception of mild vaginal
      postoperative bleeding. During the follow-up of 36-82 months, cervical
      alterations were described only in 12 out of 71 cases, flat condilomatosy in 8
      cases, CIN2 in 2 patients and CIN3 in other 2 patients. At present, all the
      patients are free of disease. CONCLUSIONS: The conization with dioxide laser is a
      good therapy for cervical intraepithelial neoplasia, even if expensive; infact
      poor side-effects are observed as well as a very good reliability.

PMID- 12432329
TI  - Seventy-five ectopic pregnancies. Medical and surgical management.
AB  - BACKGROUND: The aim of this study was to evaluate the treatment options of
      ectopic pregnancy. METHODS: Retrospective analysis performed on 75 patients
      diagnosed and hospitalised with ectopic pregnancy from January 1996 to May 2001.
      The medical records of each patient were evaluated. RESULTS: Treatment options:
      immediate surgical treatment (44%), methotrexate (MTX) therapy (43%) and
      expectant management (13%). MTX therapy success rate was 78.1%. Laparotomy was
      performed in 52.5% of surgically treated women. Over time there was an increase
      in the use of laparoscopic surgery: 75% of women underwent laparoscopy in the
      period 2000-2001. The rate of laparotomy still remains higher than the rate
      previously reported in other studies; the reason is that in our hospital no
      equipment for laparoscopy is available for emergency condition. Expectant
      management was effective when there was no pain and serum hCG levels were
      constantly low or were decreasing. CONCLUSIONS: Technological advances allow
      diagnosis of ectopic pregnancy before severe clinical symptoms arise. Although
      early diagnosis may contribute to higher incidence, it has also contributed to a
      decline in morbidity, deaths, and treatment costs. Timely and early diagnosis has
      made this disorder amenable to medical therapy, with success rates similar to
      those of traditional surgical treatment. Surgery is preferred when there are
      tubal ruptures or a high potential for rupture, hypotension, anaemia or ectopic
      pregnancy which is larger than 3 cm in diameter.

PMID- 12432330
TI  - [Myomectomy during cesarean section and outside pregnancy. Different outcomes of
      scars].
AB  - BACKGROUND: The purpose of this study is the comparison between the scar of
      myomectomy performed during cesarean section and out of the pregnancy. METHODS:
      Eighteen pregnant patients were submitted to cesarean section between 37 and 39
      weeks of gestation for previous myomectomy. The previous myomectomy has been
      performed in 8 patients during a cesarean section, in 10 patients out of
      pregnancy; in all patients only one subserous-intramural myoma of uterine fundus
      or body with a maximum diameter of 4-5 cm has been excised. RESULTS: In
      myomectomies performed during cesarean section the scar appeared more linear,
      with good well defined limits, less wide and with modest introflection in
      comparison to surrounding myometrium. The myometrial thickness did not present
      variations and was well contracted. CONCLUSIONS: Our results show substantial
      differences: in fact, according to personal opinion, the different evolution of
      the healing process is due to variations occurring in pregnancy and particularly
      for local immunology system which in pregnancy is hyperactive. The presence and
      increased synthesis of immunological substances support a better healing with an
      optimal functional recovery.

PMID- 12432331
TI  - Evaluation of bone mass in young amenorrheic women with anorexia nervosa.
AB  - BACKGROUND: In the last 10 years an impressive increase in the frequency of food
      disorders (bulimia and anorexia) in teenagers has been recorded. Food disorders,
      present especially in girls, (part of more complex relational-familiar disorders)
      cause progressive repercussions on the general endocrine structure and in
      particular on the reproductive system of the subject. The most visible effect of
      this endocrine perturbation is the block of the ovarian function with secondary
      amenorrhoea and low levels of gonadotropins and estrogens due to the food
      disorder. In fact the qualitative and quantitative food deficit is responsible
      for the interruption of the normal hypothalamic and pituitary pulses regulating
      the correct monthly process of follicular growth. As in the physiological
      postmenopausal period, very low plasma levels of 17-b-estradiol (<30 pg/ml) can
      start the bone resorption with bone loss and/or osteoporosis related to the
      amount and the time of exposure to low levels of estrogens. OBJECTIVES: in our
      study we evaluate the influence of anorexia and amenorrhoea on bone mineral
      density. METHODS: We evaluate bone mineral density (BMD) with computerised bone
      mineralometry (MOC), a dual-energy-X-Ray (DEXA), in 18 women with anorexia
      nervosa and weight loss, 9-12 months amenorrhoea and with low plasma levels of 17
      b-estradiol. The BMD was measured at the lumbar spine (L2-L4) and on total body
      in all subjects enrolled for this study. RESULTS: All the patients showed a
      decrease on the lumbar BMD with bone loss (49%) or osteoporosis (51%). On the
      other side the values of total body BMD were around the normal levels (86%) or
      showed bone loss (14%). CONCLUSIONS: Our data support the hypothesis that lower
      estrogenic levels associated with anorexia nervosa have an impact on BMD,
      especially at lumbar level, with early incidence for quantitative and qualitative
      lower food intake.

PMID- 12432332
TI  - [Postpartum perineal assessment].
AB  - BACKGROUND: To evaluate the incidence of urogenital and anorectal dysfunctions
      during puerperium, verify the correlation between obstetric perineal damage
      observed during labour and puerperal symptoms, test the efficacy of tests to
      evaluate perineal function in pelvic floor dysfunctions consequent to vaginal
      birth. METHODS: A total of 693 consecutive puerperae were recruited two months
      after birth. All completed a clinical and anamnestic questionnaire and underwent
      clinical urogynecological examination, digital test, vaginal manometry and
      uroflowmetric evaluation of the voluntary capacity to interrupt micturition. From
      a statistical point of view, persistent urinary incontinence was identified by
      graphic representation on frequency tables and predictive tests, and statistical
      "kappa" was used to evaluate the correlation between perineal function tests.
      RESULTS: Stress urinary incontinence (15.1%) represents the most widespread
      symptom, a postpartum perineal inspection provides a sufficiently accurate
      estimate of posterior damage, but does not identify those puerperae who will
      develop urinary incontinence. None of the tests used was able to predict
      persistant urinary incontinence. CONCLUSIONS: Postpartum perineal inspection
      seems to be effective in predicting anorectal dysfunctions, but is not so useful
      for urethro-vesical disorders. None of the diagnostic methods examined allowed a
      sufficiently accurate selection of those puerperae at risk.

PMID- 12432333
TI  - [Medical treatment in abnormal uterine bleeding: evaluation of a GnRH therapy
      versus danazol therapy in perimenopausal women].
AB  - BACKGROUND: Dysfunctional uterine bleedings are uterine hemorrhage, frequent in
      the climacteric period and are a usual gynecologic pathology in ambulatorial
      controls (10%). METHODS: 60 premenopausal women, have been enrolled, all affected
      by hyper-polymenorrhea or dysfunctional uterine bleeding; than they were
      subdivided them into 2 groups; Group I: 30 patients with GnRH analogues treatment
      (Decapeptyl da 3.75 mg/month, 6 months of therapy); Group II: 30 patients with
      Danazol treatment (danatrol, 200 mg/daily, 6 months of therapy). Clinical
      controls were performed by visit, a questionnaire compilation (Kuppermann index)
      and biochemical examinations, with this frequency: 0, 3, 6 and 9 months.
      Statistical evaluation was performed by Student "t" test. RESULTS: In both
      groups, either amenorrohea and symptomatic improvement after 3 months of therapy
      were observed, without statistical differences; a statistical difference (p>0.01)
      was assessed in patients compliance, since were observed, without statistical
      differences a major frequency in collateral effects in II Group, with danazol
      therapy was observed. The results of this study show that, the limited occurrence
      of side effects in perimenopausal patients affected by dysfunctional uterine
      bleeding, treated with GnRH analogues, could affect the choice of pharmacological
      therapy in favor of these one.

PMID- 12432334
TI  - [Pelvic actinomycosis and sub-acute abdomen].
AB  - An interesting case of pelvic actinomycosis with paculiar clinical manifestation
      is presented. A 42 years-old patient came to our emergency service for an
      abdominal pelvic pain and fever. Past history showed IUD in situ for over 15
      years. The patient was submitted to a ultrasonographic scan and a complete
      hematological screening was performed. The diagnosis was of subacute abdomen, and
      an exploratory laparotomy was carried out. During laparotomy an atypical reactive
      tissue and a suppurative cavity were found. The histological finding of tissue
      biopsy showed pelvic actinomycosis. On the basis of these findings the conclusion
      is drawn that a better prevention of pelvic actinomycosis is necessary of its
      diffusion in the last years due to sexual habit changes.

PMID- 12432335
TI  - [Congenital hepatic fibrosis in pregnancy].
AB  - The purpose of this study was to analyse the course of pregnancy of a 20-year-old
      woman suffering from congenital hepatic fibrosis (CHF), a genetic disease with
      recessive autosomic transmission, attributed to the group of hepato-nephro
      pancreatic fibropolycystic familial diseases. This was the only time such a case
      had ever been encountered in a pregnancy in the history of Turin University's
      Obstetrics and Gynaecological Clinic. The case of a 20-year-old woman is
      considered. She was admitted to our observation at the Obstetrics and
      Gynaecological Department of Faculty "B" of the University of Turin, suffering
      from CHF, a primigravid in the eighth week of gestation. Haematochemical tests
      carried out on the patient showed a platelet deficiency without evident changes
      in liver and renal function. Objective examination revealed a slight
      hepatosplenomegaly confirmed by abdominal echotomography. The haematochemical
      examinations subsequently carried out confirmed thrombocytopenia due to
      hepatosplenic hyperhaemocataresis. In agreement with the will of the patient and
      her family, and after having heard the opinion of our hospital's anaesthetists
      and internists, a conservative approach was decided on and close monitoring of
      maternal and foetal conditions was planned, with hospitalisations scheduled for
      every fortnight. Together with the internists and anaesthetists, it was decided
      to allow the pregnancy to proceed as far as foetal maturity but not to term, to
      avoid problems relating to the excessive increase in uterine volume which would
      have led to pressure on the portal tree and so favoured haemorrhaging due to
      rupture of the oesophageal varices. Caesarean delivery was planned for the 37th
      week of gestation. The birth went according to plan and the foetus was a live,
      vital male with Apgar index of 9/9. The placenta presented normal characteristics
      and a weight of 590 g. No haemorrhagic complications were observed either in the
      course of surgery or in the postoperative phase, notwithstanding the preoperative
      finding of a platelet count of 64,000 platelets/ mm3. Although in our case
      neither the pregnancy nor the delivery constituted a serious danger for the life
      of the mother, possible obstetric complications are among the most serious
      encountered in obstetric pathology and can lead both to maternal death and to the
      intrauterine death of the foetus. For these reasons we believe it essential to
      provide correct, clear and adequate information about the risks involved for
      patients suffering from congenital hepatic fibrosis, especially if they are
      associated with renal polycystic disease, and who are admitted to our wards with
      the desire to programme a pregnancy.

PMID- 12432336
TI  - Uterine bleeding pattern during low dosage Noretisterone acetate and 17-b
      Estradiol treatment in postmenopausal patients.
AB  - BACKGROUND: Recent years have been characterized by progressive optimization of
      postmenopausal hormonal replacement therapy. More physiological therapeutic
      protocols have been, in fact, proposed to control the possible symptomatology and
      to prevent the associated risks, with estro-progestinic compounds characterized
      by lower effective dosages and suitable for the single patient need. However this
      therapy is not widely accepted by the women from our country for the fears and
      the inconvenience raised around such side effects as abnormal uterine bleeding
      and spotting. AIM: to obtain a good compliance and clinical benefits a continuous
      administration protocol of the hormonal replacement therapy, alternatively to the
      sequential one has been proposed. METHODS: Our research group has been observing
      a sample of 42 patients for 12 months, taking oral 17-b-estradiol 1
      mg/noretisterone 0.5 mg in continuous administration. All of them were aged from
      42 to 63 years and had been in symptomatic menopause for at least 3 months. The
      characteristics, the onset and the trend of vaginal bleeding were registered in
      appropriate monthly diaries. Endometrial thickness was evaluated by transvaginal
      sonography before starting the administration, not exceeding 4 mm in all the
      women considered. RESULTS: The incidence of bleeding (calculated as a percent of
      women who experienced a vaginal bleeding for al least a day during a menstrual
      cycle) was from 26% to 32% in the 1st trimester, reducing during the following
      months. At 6 months of therapy only 5% of women reported evident vaginal
      bleeding; at 12 months 90% of women complained with absence of bleeding or
      spotting. At 12 months no women showed an endometrial thickness over 6 mm.
      CONCLUSIONS: This observational study suggests that the majority of treated
      patients proved to be positively responsive to the treatment and that the 17-b
      estradiol 1 mg/noretisterone 0.5 mg association reduces the incidence of bleeding
      and spotting with a sufficient endometrial protection from hyperplasia.

PMID- 12432337
TI  - Vaginal micronized progesterone in continuous hormone replacement therapy. A
      prospective randomized study.
AB  - BACKGROUND: In the non-hysterectomized post-menopausal woman undergoing estrogen
      replacement therapy, the co-administration of a progestogen is mandatory to
      counteract the estrogenic proliferative effect on the endometrium. Metabolic and
      tissue effects of the various progestins vary with dosage and route of
      administration. This study was performed to evaluate the effects of selected
      progestins on the lipidic profile and endometrial morphology. METHODS: This is a
      prospective randomised study including 60 post-menopausal women undergoing
      hormonal replacement therapy (HRT). All patients received transdermic ethinil
      estradiol in a continuous schedule. The utilized progestogens were:
      medroxyprogesterone acetate (MPA) 10 mg p.o. 12 days/month, transdermic nor
      ethisterone acetate (NETA) 0.25 mg integrated in the ethinil-estradiol patches
      for the last two weeks of each cycle, micronized progesterone (MP) 100 mg
      transvaginally 12 days/month. RESULTS: None of the tested protocols significantly
      altered the lipidic profile of this group of patients. We noticed different
      effects on the estrogen stimulated endometrium elicited by the different
      progestinic regimens. While the cyclic administration of oral MPA or transdermic
      NETA more frequently resulted in endometrial atrophy, the trans-vaginal
      administration of MP more often induced (p<0.005 at six-month and p <0.001 after
      1 year) a functional-like secretive endometrium. CONCLUSIONS: Micronized
      progesterone, cyclically administered in the form of a vaginal cream, offers an
      acceptable and effective alternative for women on continuous HRT wishing to
      maintain their monthly cycle.

PMID- 12432339
TI  - [Ferti-test. A simple method for tubal function diagnosis: feasibility study].
AB  - BACKGROUND: To indicate the simplicity and the feasibility of this new diagnostic
      technique for infertility investigation. Ferti-test is a technique which combines
      dye-test and pelvic post coital test, using inexpensive surgical material. Ferti
      test allows to perform laparoscopy only in very necessary cases, without loosing
      diagnostic quality. METHODS: Up to September 2001, 30 patients aged from 24 to 46
      years, with infertile problems were enrolled. All the patients, in a preovulatory
      period, underwent dye-test combined with pPCT. Before the operation, all the
      patients were investigated for endocrinological assessment; an evaluation of
      sperm liquid in all the partners and a PCT have been carried out. All these data
      were organized in a specific diagram, which allowed to recognize the normality or
      the specific class of pathology of infertile couple. RESULTS: The purpose of this
      study is to remark the simplicity and the feasibility of this new diagnostic
      method. In our study, no patients who underwent dye-test and pelvic PCT had any
      complications. Only 7 patients with negative dye-test and pelvic PCT underwent
      diagnostic laparoscopy. CONCLUSIONS: The results of this study indicate that
      Ferti-test is an effective and reliable technique for the first level evaluation
      in infertile couples. Ferti-test is well tolerated and requires minimal cost.
      With Ferti-test it is possible to screen the patients who actually need
      laparoscopy and to reduce risks and costs.

PMID- 12432338
TI  - Evaluation of the ultrasonographic volume of breast fibroadenomas in women
      treated with tamoxifen.
AB  - BACKGROUND: Fibroadenomas are the most frequent benign breast neoplasias.
      Although they are hormone-dependent, no hormonal treatment of proven
      effectiveness is available for these neoplasias. The objective of the present
      study was to evaluate the ultrasonographic volume of fibroadenomas in
      premenopausal women treated with tamoxifen at the doses of 5, 10, 20 mg/day or
      with placebo for 50 days, starting on the 1st day of the menstrual cycle.
      METHODS: A prospective and randomized study was conducted on 62 eumenorrheic
      women aged 15 to 45 years with no hormonal treatment or pregnancy during the last
      12 months, with a clinical, cytologic and ultrasonographic diagnosis of
      fibroadenoma, later followed by a biopsy diagnosis. The patients were divided at
      random into 4 groups: A (n=15; placebo), B (n= 16; 5 mg/day tamoxifen), C (n=16;
      10 mg/day tamoxifen), and D (n=15; 20 mg/day tamoxifen). Fibroadenoma volume was
      measured by ultrasound at 3 different times: on the 22nd day of the cycle that
      preceded the beginning of tamoxifen treatment, after 1 month of treatment, and on
      the day of the biopsy (50th day). The mean volume obtained for groups A, B, C and
      D was 3, 3.3, 1.9, and 2.3 cm3, respecti-vely. RESULTS: Statistical analysis
      revealed a significant reduction in nodule size only in group D (p=0.0024).
      CONCLUSIONS: We conclude that tamoxifen significantly reduced fibroadenoma volume
      when administered for 50 days at the dose of 20 mg/day. Further clinical studies
      are needed using the drug for a longer period of time, and in order to exclude
      the need for unnecessary treatment in some women.

PMID- 12432340
TI  - P-glycoprotein expression in human retinal pigment epithelium.
AB  - PURPOSE: The retinal pigment epithelium (RPE) is a transporting epithelial
      monolayer that controls hydration and composition of the subretinal space. P
      glycoprotein is an ATP-binding cassette transport protein known to transport a
      wide range of hydrophobic compounds. The expression of P-glycoprotein in barrier
      epithelial cells suggests that it could serve a normal protective function,
      possibly clearing potentially harmful substances from sensitive compartments,
      like the subretinal space. The present study is designed to determine the
      expression and activity of P-glycoprotein in normal human RPE. METHODS: RT-PCR
      and direct sequencing were employed to examine the presence of mdr1 mRNA in
      cultured human RPE. P-glycoprotein-specific antibodies were employed in Western
      blotting to identify P-glycoprotein in cultured human RPE and in an established
      RPE cell line (D407). Anti-P-glycoprotein antibodies were also used to localize
      the protein in frozen, formaldehyde-fixed sections of native human RPE/choroid by
      immunohistochemistry. Finally, rhodamine uptake was performed in cultured human
      RPE monolayers to assess P-glycoprotein activity. The inhibitory antibody 4E3 and
      reversins 121 and 205 were used to block transport activity. RESULTS: P
      glycoprotein is expressed, and is active, in human RPE tissue not exposed to any
      known inducers of P-glycoprotein. RT-PCR yielded a 546 bp product that was 100%
      identical in sequence to published data for the mdr1 isoform of human P
      glycoprotein. Western blotting demonstrated expression at the protein level, with
      specific bands observed at about 220 and 165 kD. In native tissue, P-glycoprotein
      immunoreactivity was predominantly membrane associated, with localization to both
      apical and basolateral cell membranes. Finally, P-glycoprotein expressed in human
      RPE is active. Steady-state rhodamine accumulation was increased in the presence
      of compounds reported to block P-glycoprotein mediated rhodamine efflux.
      CONCLUSIONS: Human RPE, not exposed to inducer treatment, expresses P
      glycoprotein with localization to both apical and basal cell surfaces.
      Basolateral P-glycoprotein could serve a protective function for the neural
      retina helping to clear unwanted substances from subretinal space. The finding
      that P-glycoprotein is also on the apical surface suggests possible additional
      roles for P-glycoprotein in the RPE.

PMID- 12432341
TI  - Quantifying DNA concentrations using fluorometry: a comparison of fluorophores.
AB  - Detection of low concentrations of DNA is important in vision research because
      many animal models only provide scant samples of ocular tissue. Quantitative
      analysis of low concentrations of double stranded DNA is now feasible using
      fluorometry with newer fluorophores. This technique offers a rapid way to
      evaluate the DNA content of samples based on the measurement of fluorescence
      enhancement emitted by fluorophore-bound DNA and is more sensitive than
      absorption spectrometry. The purpose of this study was to compare the sensitivity
      of several different fluorophores for measuring DNA concentrations by
      fluorometry. Based on our studies, we conclude that SYBR Green I and PicoGreen
      are substantially more sensitive for quantifying DNA concentrations than ethidium
      bromide and Hoechst 33258.

PMID- 12432343
TI  - Part-time growth.

PMID- 12432342
TI  - Mimecan/osteoglycin-deficient mice have collagen fibril abnormalities.
AB  - PURPOSE: To study the role of mimecan, a member of the small leucine-rich
      proteoglycans (SLRPs) gene family and one of the major components of the cornea
      and other connective tissues, mice that lack a functional mimecan gene were
      generated and characterized. METHODS: Mimecan-deficient mice were generated by
      gene-targeting using standard techniques. Mice were genotyped by Southern blot
      analysis. The absence of mimecan transcripts was confirmed by Northern blot
      analysis. Corneal clarity was examined by slit lamp biomicroscopy. The strength
      of the skin was evaluated using a biomechanical skin fragility test. Collagen
      morphology in cornea and skin preparations from mimecan-null and control wild
      type mice was analyzed by transmission electron microscopy. The diameter of
      collagen fibrils in these tissues was determined by morphometric analysis.
      RESULTS: Mice lacking mimecan appear to develop normally, are viable and fertile.
      In a controlled laboratory environment they do not display an evident
      pathological phenotype compared to wild type mice. Examination of corneal clarity
      and measurements of corneal thickness show no significant changes in the cornea.
      However, a skin fragility test revealed a moderate reduction in the tensile
      strength of skin from mutant mice. Ultrastructural analyses show, on average,
      thicker collagen fibrils in both corneal and skin preparations from mimecan-null
      mice. Collagen fibrils from the cornea of mutant mice show an average diameter of
      31.84+/-0.322 nm, versus 22.40+/-0.296 nm in their wild type litter-mates. The
      most pronounced increase in collagen fibril diameter was found in the skin of
      mimecan-null mice, who demonstrated an average diameter of 130.33+/-1.769 nm,
      versus 78.82+/-1.157 nm in the wild type mice. In addition, size variability and
      altered collagen morphology was detected in dorsal and tail skin preparations
      from the mutant mice. CONCLUSIONS: The results of the present study demonstrate
      that mimecan, similar to other members of the SLRP gene family, has a role in
      regulating collagen fibrillogenesis in vivo. Further studies, such as functional
      challenges, an evaluation of potential compensation by other proteins (including
      members of the SLRP family), and generation of double-knockouts will be necessary
      to fully uncover physiological functions of mimecan in mice.

PMID- 12432344
TI  - The trials of gene therapy.

PMID- 12432345
TI  - Frameworks can be too rigid.

PMID- 12432346
TI  - Microbe hunt raises doubts over local benefits of bioprospecting.

PMID- 12432347
TI  - Ground-breaking web test gears up.

PMID- 12432348
TI  - Call for more data forms basis of Bush climate strategy.

PMID- 12432349
TI  - Outcry greets US plan to test smallpox vaccine on children.

PMID- 12432351
TI  - Space station set for sky-high profile.

PMID- 12432350
TI  - Tribe blasts 'exploitation' of blood samples.

PMID- 12432352
TI  - Conduct code mooted for bioweapons treaty.

PMID- 12432353
TI  - Academy slams internet arts and sciences lookalike.

PMID- 12432354
TI  - Venus Express cleared for take-off.

PMID- 12432355
TI  - Republican win sparks fears for science funds.

PMID- 12432358
TI  - A lens less ordinary.

PMID- 12432357
TI  - A tragic setback.

PMID- 12432359
TI  - The next challenge is to map the human mind.

PMID- 12432360
TI  - Moving beyond 'industry vs ecologists' stereotype.

PMID- 12432361
TI  - Liberal world of science.

PMID- 12432367
TI  - A physical response to architecture.

PMID- 12432368
TI  - Back to the beginning.

PMID- 12432369
TI  - Metabolic balance sheets.

PMID- 12432370
TI  - Is it all in the crust?

PMID- 12432371
TI  - Terahertz power.

PMID- 12432372
TI  - Single-neuron mnemonics.

PMID- 12432373
TI  - The Sun under a microscope.

PMID- 12432374
TI  - Medicine: lipid signals in pain control.

PMID- 12432375
TI  - Developmental biology: first come, first served.

PMID- 12432377
TI  - Obituary: Peter W. Hochachka (1937-2002).

PMID- 12432378
TI  - Halteres used in ancient Olympic long jump.

PMID- 12432379
TI  - Evolutionary biology: significance of primate sexual swellings.

PMID- 12432381
TI  - Magnetic properties: parasitic ferromagnetism in a hexaboride?

PMID- 12432383
TI  - Serial deletions and duplications suggest a mechanism for the collinearity of
      Hoxd genes in limbs.
AB  - Hox genes, located at one end of the HoxD cluster, are essential for the
      development of the extremities of our limbs; that is, the digits. This
      'collinear' correspondence is accompanied by a gradual decrease in the
      transcriptional efficiency of the genes. To decipher the underlying regulatory
      mechanisms, and thus to understand better how digits develop, we engineered a
      series of deletions and duplications in vivo. We find that HoxD genes compete for
      a remote enhancer that recognizes the locus in a polar fashion, with a preference
      for the 5' extremity. Modifications in either the number or topography of Hoxd
      loci induced regulatory reallocations affecting both the number and morphology of
      digits. These results demonstrate why genes located at the extremity of the
      cluster are expressed at the distal end of the limbs, following a gradual
      reduction in transcriptional efficiency, and thus highlight the mechanistic
      nature of collinearity in limbs.

PMID- 12432384
TI  - Dark cores in sunspot penumbral filaments.
AB  - Sunspot umbrae--the dark central regions of the spots--are surrounded by brighter
      filamentary penumbrae, the existence of which remains largely inexplicable. The
      penumbral filaments contain magnetic fields with varying inclinations and are
      associated with flowing gas, but discriminating between theoretical models has
      been difficult because the structure of the filaments has not hitherto been
      resolved. Here we report observations of penumbral filaments that reveal dark
      cores inside them. We cannot determine the nature of these dark cores, but their
      very existence provides a crucial test for any model of penumbrae. Our images
      also reveal other very small structures, in line with the view that many of the
      fundamental physical processes in the solar photosphere occur on scales smaller
      than 100 km.

PMID- 12432385
TI  - High-power terahertz radiation from relativistic electrons.
AB  - Terahertz (THz) radiation, which lies in the far-infrared region, is at the
      interface of electronics and photonics. Narrow-band THz radiation can be produced
      by free-electron lasers and fast diodes. Broadband THz radiation can be produced
      by thermal sources and, more recently, by table-top laser-driven sources and by
      short electron bunches in accelerators, but so far only with low power. Here we
      report calculations and measurements that confirm the production of high-power
      broadband THz radiation from subpicosecond electron bunches in an accelerator.
      The average power is nearly 20 watts, several orders of magnitude higher than any
      existing source, which could enable various new applications. In particular, many
      materials have distinct absorptive and dispersive properties in this spectral
      range, so that THz imaging could reveal interesting features. For example, it
      would be possible to image the distribution of specific proteins or water in
      tissue, or buried metal layers in semiconductors; the present source would allow
      full-field, real-time capture of such images. High peak and average power THz
      sources are also critical in driving new nonlinear phenomena and for pump-probe
      studies of dynamical properties of materials.

PMID- 12432386
TI  - Ferromagnetism of a graphite nodule from the Canyon Diablo meteorite.
AB  - There are recent reports of weak ferromagnetism in graphite and synthetic carbon
      materials such as rhombohedral C(60) (ref. 4), as well as a theoretical
      prediction of a ferromagnetic instability in graphene sheets. With very small
      ferromagnetic signals, it is difficult to be certain that the origin is
      intrinsic, rather than due to minute concentrations of iron-rich impurities. Here
      we take a different experimental approach to study ferromagnetism in graphitic
      materials, by making use of meteoritic graphite, which is strongly ferromagnetic
      at room temperature. We examined ten samples of extraterrestrial graphite from a
      nodule in the Canyon Diablo meteorite. Graphite is the major phase in every
      sample, but there are minor amounts of magnetite, kamacite, akaganeite, and other
      phases. By analysing the phase composition of a series of samples, we find that
      these iron-rich minerals can only account for about two-thirds of the observed
      magnetization. The remainder is somehow associated with graphite, corresponding
      to an average magnetization of 0.05 Bohr magnetons per carbon atom. The magnetic
      ordering temperature is near 570 K. We suggest that the ferromagnetism is a
      magnetic proximity effect induced at the interface with magnetite or kamacite
      inclusions.

PMID- 12432387
TI  - Tristable nematic liquid-crystal device using micropatterned surface alignment.
AB  - It has long been appreciated that liquid-crystal (LC) devices in which the LC
      molecules adopt multiple stable orientations could drastically reduce the power
      consumption required for high-information-content displays. But for the commonly
      used nematic LCs, which are intrinsically uniaxial in symmetry, no industrially
      feasible multi-stable LC device has been realized. Recently we demonstrated how
      bistability can be robustly engineered into a nematic LC device, by patterning a
      substrate with an orientational chequerboard pattern that enforces orthogonal LC
      alignment in neighbouring square domains. As a result of the four-fold symmetry
      of the pattern, the two diagonal axes of the chequerboard become equally stable
      macroscopic orientations. Here we extend this symmetry approach to obtain a
      tristable surface-aligned nematic LC. A microscopic pattern exhibiting six-fold
      symmetry is inscribed on a polyimide surface using the stylus of an atomic force
      microscope. The hexagonal symmetry of the microscopic orientational domains in
      turn gives rise to three stable macroscopic LC orientations, which are mutually
      switchable by an in-plane electric field. The resulting switching mode is surface
      driven, and hence should be compatible with demanding flexible display
      applications.

PMID- 12432388
TI  - Variability of El Nino/Southern Oscillation activity at millennial timescales
      during the Holocene epoch.
AB  - The variability of El Nino/Southern Oscillation (ENSO) during the Holocene epoch,
      in particular on millennial timescales, is poorly understood. Palaeoclimate
      studies have documented ENSO variability for selected intervals in the Holocene,
      but most records are either too short or insufficiently resolved to investigate
      variability on millennial scales. Here we present a record of sedimentation in
      Laguna Pallcacocha, southern Ecuador, which is strongly influenced by ENSO
      variability, and covers the past 12,000 years continuously. We find that changes
      on a timescale of 2-8 years, which we attribute to warm ENSO events, become more
      frequent over the Holocene until about 1,200 years ago, and then decline towards
      the present. Periods of relatively high and low ENSO activity, alternating at a
      timescale of about 2,000 years, are superimposed on this long-term trend. We
      attribute the long-term trend to orbitally induced changes in insolation, and
      suggest internal ENSO dynamics as a possible cause of the millennial variability.
      However, the millennial oscillation will need to be confirmed in other ENSO proxy
      records.

PMID- 12432389
TI  - First-principles study of illite-smectite and implications for clay mineral
      systems.
AB  - Illite-smectite interstratified clay minerals are ubiquitous in sedimentary
      basins and they have been linked to the maturation, migration and trapping of
      hydrocarbons, rock cementation, evolution of porewater chemistry during
      diagenesis and the development of pore pressure. But, despite the importance of
      these clays, their structures are controversial. Two competing models exist, each
      with profoundly different consequences for the understanding of diagenetic
      processes: model A views such interstratified clays as a stacking of layers
      identical to endmember illite and smectite layers, implying discrete and
      independently formed units (fundamental particles), whereas model B views the
      clays as composed of crystallites with a unique structure that maintains
      coherency over much greater distances, in line with local charge balance about
      interlayers. Here we use first-principles density-functional theory to explore
      the energetics and structures of these two models for an illite-smectite
      interstratified clay mineral with a ratio of 1:1 and a Reichweite parameter of 1.
      We find that the total energy of model B is 2.3 kJ atom(-1) mol(-1) lower than
      that of model A, and that this energy difference can be traced to structural
      distortions in model A due to local charge imbalance. The greater stability of
      model B requires re-evaluation of the evolution of the smectite-to-illite
      sequence of clay minerals, including the nature of coexisting species, stability
      relations, growth mechanisms and the model of fundamental particles.

PMID- 12432390
TI  - Synchronization of animal population dynamics by large-scale climate.
AB  - The hypothesis that animal population dynamics may be synchronized by climate is
      highly relevant in the context of climate change because it suggests that several
      populations might respond simultaneously to climatic trends if their dynamics are
      entrained by environmental correlation. The dynamics of many species throughout
      the Northern Hemisphere are influenced by a single large-scale climate system,
      the North Atlantic Oscillation (NAO), which exerts highly correlated regional
      effects on local weather. But efforts to attribute synchronous fluctuations of
      contiguous populations to large-scale climate are confounded by the synchronizing
      influences of dispersal or trophic interactions. Here we report that the dynamics
      of caribou and musk oxen on opposite coasts of Greenland show spatial synchrony
      among populations of both species that correlates with the NAO index. Our
      analysis shows that the NAO has an influence in the high degree of cross-species
      synchrony between pairs of caribou and musk oxen populations separated by a
      minimum of 1,000 km of inland ice. The vast distances, and complete physical and
      ecological separation of these species, rule out spatial coupling by dispersal or
      interaction. These results indicate that animal populations of different species
      may respond synchronously to global climate change over large regions.

PMID- 12432391
TI  - Selective habituation shapes acoustic predator recognition in harbour seals.
AB  - Predation is a major force in shaping the behaviour of animals, so that precise
      identification of predators will confer substantial selective advantages on
      animals that serve as food to others. Because experience with a predator can be
      lethal, early researchers studying birds suggested that predator recognition does
      not require learning. However, a predator image that can be modified by learning
      and experience will be advantageous in situations where cues associated with the
      predator are highly variable or change over time. In this study, we investigated
      the response of harbour seals (Phoca vitulina) to the underwater calls of
      different populations of killer whales (Orcinus orca). We found that the seals
      responded strongly to the calls of mammal-eating killer whales and unfamiliar
      fish-eating killer whales but not to the familiar calls of the local fish-eating
      population. This demonstrates that wild harbour seals are capable of complex
      acoustic discrimination and that they modify their predator image by selectively
      habituating to the calls of harmless killer whales. Fear in these animals is
      therefore focused on local threats by learning and experience.

PMID- 12432392
TI  - Graded persistent activity in entorhinal cortex neurons.
AB  - Working memory represents the ability of the brain to hold externally or
      internally driven information for relatively short periods of time. Persistent
      neuronal activity is the elementary process underlying working memory but its
      cellular basis remains unknown. The most widely accepted hypothesis is that
      persistent activity is based on synaptic reverberations in recurrent circuits.
      The entorhinal cortex in the parahippocampal region is crucially involved in the
      acquisition, consolidation and retrieval of long-term memory traces for which
      working memory operations are essential. Here we show that individual neurons
      from layer V of the entorhinal cortex-which link the hippocampus to extensive
      cortical regions-respond to consecutive stimuli with graded changes in firing
      frequency that remain stable after each stimulus presentation. In addition, the
      sustained levels of firing frequency can be either increased or decreased in an
      input-specific manner. This firing behaviour displays robustness to distractors;
      it is linked to cholinergic muscarinic receptor activation, and relies on
      activity-dependent changes of a Ca2+-sensitive cationic current. Such an
      intrinsic neuronal ability to generate graded persistent activity constitutes an
      elementary mechanism for working memory.

PMID- 12432393
TI  - The F-box protein slimb controls the levels of clock proteins period and
      timeless.
AB  - The Drosophila circadian clock is driven by daily fluctuations of the proteins
      Period and Timeless, which associate in a complex and negatively regulate the
      transcription of their own genes. Protein phosphorylation has a central role in
      this feedback loop, by controlling Per stability in both cytoplasmic and nuclear
      compartments as well as Per/Tim nuclear transfer. However, the pathways
      regulating degradation of phosphorylated Per and Tim are unknown. Here we show
      that the product of the slimb (slmb) gene--a member of the F-box/WD40 protein
      family of the ubiquitin ligase SCF complex that targets phosphorylated proteins
      for degradation--is an essential component of the Drosophila circadian clock.
      slmb mutants are behaviourally arrhythmic, and can be rescued by targeted
      expression of Slmb in the clock neurons. In constant darkness, highly
      phosphorylated forms of the Per and Tim proteins are constitutively present in
      the mutants, indicating that the control of their cyclic degradation is impaired.
      Because levels of Per and Tim oscillate in slmb mutants maintained in light:dark
      conditions, light- and clock-controlled degradation of Per and Tim do not rely on
      the same mechanisms.

PMID- 12432394
TI  - Non-redundant role of the long pentraxin PTX3 in anti-fungal innate immune
      response.
AB  - Pentraxins are a superfamily of conserved proteins that are characterized by a
      cyclic multimeric structure. The classical short pentraxins, C-reactive protein
      (CRP) and serum amyloid P component (SAP), are acute-phase proteins produced in
      the liver in response to inflammatory mediators. Short pentraxins regulate innate
      resistance to microbes and the scavenging of cellular debris and extracellular
      matrix components. In contrast, long pentraxins have an unrelated, long amino
      terminal domain coupled to the carboxy-terminal pentraxin domain, and differ,
      with respect to short pentraxins, in their gene organization, chromosomal
      localization, cellular source, and in their stimuli-inducing and ligand
      recognition ability. To investigate the in vivo function of the long pentraxin
      PTX3, we generated mice deficient in Ptx3 by homologous recombination. Ptx3-null
      mice were susceptible to invasive pulmonary aspergillosis. Ptx3 binds selected
      microbial agents, including conidia of Aspergillus fumigatus, and we found that
      susceptibility of Ptx3-null mice was associated with defective recognition of
      conidia by alveolar macrophages and dendritic cells, as well as inappropriate
      induction of an adaptive type 2 response. Thus, the long pentraxin Ptx3 is a
      secreted pattern-recognition receptor that has a non-redundant role in resistance
      to selected microbial agents, in particular to the opportunistic fungal pathogen
      Aspergillus fumigatus.

PMID- 12432395
TI  - Escherichia coli K-12 undergoes adaptive evolution to achieve in silico predicted
      optimal growth.
AB  - Annotated genome sequences can be used to reconstruct whole-cell metabolic
      networks. These metabolic networks can be modelled and analysed (computed) to
      study complex biological functions. In particular, constraints-based in silico
      models have been used to calculate optimal growth rates on common carbon
      substrates, and the results were found to be consistent with experimental data
      under many but not all conditions. Optimal biological functions are acquired
      through an evolutionary process. Thus, incorrect predictions of in silico models
      based on optimal performance criteria may be due to incomplete adaptive evolution
      under the conditions examined. Escherichia coli K-12 MG1655 grows sub-optimally
      on glycerol as the sole carbon source. Here we show that when placed under growth
      selection pressure, the growth rate of E. coli on glycerol reproducibly evolved
      over 40 days, or about 700 generations, from a sub-optimal value to the optimal
      growth rate predicted from a whole-cell in silico model. These results open the
      possibility of using adaptive evolution of entire metabolic networks to realize
      metabolic states that have been determined a priori based on in silico analysis.

PMID- 12432396
TI  - Metabolic network structure determines key aspects of functionality and
      regulation.
AB  - The relationship between structure, function and regulation in complex cellular
      networks is a still largely open question. Systems biology aims to explain this
      relationship by combining experimental and theoretical approaches. Current
      theories have various strengths and shortcomings in providing an integrated,
      predictive description of cellular networks. Specifically, dynamic mathematical
      modelling of large-scale networks meets difficulties because the necessary
      mechanistic detail and kinetic parameters are rarely available. In contrast,
      structure-oriented analyses only require network topology, which is well known in
      many cases. Previous approaches of this type focus on network robustness or
      metabolic phenotype, but do not give predictions on cellular regulation. Here, we
      devise a theoretical method for simultaneously predicting key aspects of network
      functionality, robustness and gene regulation from network structure alone. This
      is achieved by determining and analysing the non-decomposable pathways able to
      operate coherently at steady state (elementary flux modes). We use the example of
      Escherichia coli central metabolism to illustrate the method.

PMID- 12432397
TI  - The heteromeric cyclic nucleotide-gated channel adopts a 3A:1B stoichiometry.
AB  - Cyclic nucleotide-gated (CNG) channels are crucial for visual and olfactory
      transductions. These channels are tetramers and in their native forms are
      composed of A and B subunits, with a stoichiometry thought to be 2A:2B (refs 6,
      7). Here we report the identification of a leucine-zipper-homology domain named
      CLZ (for carboxy-terminal leucine zipper). This domain is present in the distal C
      terminus of CNG channel A subunits but is absent from B subunits, and mediates an
      inter-subunit interaction. With cross-linking, non-denaturing gel electrophoresis
      and analytical centrifugation, this CLZ domain was found to mediate a trimeric
      interaction. In addition, a mutant cone CNG channel A subunit with its CLZ domain
      replaced by a generic trimeric leucine zipper produced channels that behaved much
      like the wild type, but less so if replaced by a dimeric or tetrameric leucine
      zipper. This A-subunit-only, trimeric interaction suggests that heteromeric CNG
      channels actually adopt a 3A:1B stoichiometry. Biochemical analysis of the
      purified bovine rod CNG channel confirmed this conclusion. This revised
      stoichiometry provides a new foundation for understanding the structure and
      function of the CNG channel family.

PMID- 12432398
TI  - Establishment of transcriptional competence in early and late S phase.
AB  - In animal cells, the process of DNA replication takes place in a programmed
      manner, with each gene region designated to replicate at a fixed time slot in S
      phase. Housekeeping genes undergo replication in the first half of S phase in all
      cell types, whereas the replication of many tissue specific genes is
      developmentally controlled, being late in most tissues but early in the tissue of
      expression. Here we employ nuclear DNA injection as an experimental system to
      test whether this phenomenon is due to differences in the ability to set up
      transcriptional competence during S phase. Our results show that, regardless of
      sequence, exogenous genes are a better template for transcription when injected
      into nuclei of cells in early as opposed to late S phase, and this expression
      state, once initiated, is preserved after cell division. DNA injected in late S
      phase is apparently repressed because it is packaged into chromatin containing
      deacetylated histones, and the same is true for late replicating chromosomal DNA.
      These findings suggest a mechanistic connection between replication timing and
      gene expression that might help to explain how epigenetic states can be
      maintained in vivo.

PMID- 12432404
TI  - Computational systems biology.
AB  - To understand complex biological systems requires the integration of experimental
      and computational research -- in other words a systems biology approach.
      Computational biology, through pragmatic modelling and theoretical exploration,
      provides a powerful foundation from which to address critical scientific
      questions head-on. The reviews in this Insight cover many different aspects of
      this energetic field, although all, in one way or another, illuminate the
      functioning of modular circuits, including their robustness, design and
      manipulation. Computational systems biology addresses questions fundamental to
      our understanding of life, yet progress here will lead to practical innovations
      in medicine, drug discovery and engineering.

PMID- 12432405
TI  - The language of genes.
AB  - Linguistic metaphors have been woven into the fabric of molecular biology since
      its inception. The determination of the human genome sequence has brought these
      metaphors to the forefront of the popular imagination, with the natural extension
      of the notion of DNA as language to that of the genome as the 'book of life'. But
      do these analogies go deeper and, if so, can the methods developed for analysing
      languages be applied to molecular biology? In fact, many techniques used in
      bioinformatics, even if developed independently, may be seen to be grounded in
      linguistics. Further interweaving of these fields will be instrumental in
      extending our understanding of the language of life.

PMID- 12432406
TI  - The structure of the protein universe and genome evolution.
AB  - Despite the practically unlimited number of possible protein sequences, the
      number of basic shapes in which proteins fold seems not only to be finite, but
      also to be relatively small, with probably no more than 10,000 folds in
      existence. Moreover, the distribution of proteins among these folds is highly non
      homogeneous -- some folds and superfamilies are extremely abundant, but most are
      rare. Protein folds and families encoded in diverse genomes show similar size
      distributions with notable mathematical properties, which also extend to the
      number of connections between domains in multidomain proteins. All these
      distributions follow asymptotic power laws, such as have been identified in a
      wide variety of biological and physical systems, and which are typically
      associated with scale-free networks. These findings suggest that genome evolution
      is driven by extremely general mechanisms based on the preferential attachment
      principle.

PMID- 12432407
TI  - Engineered gene circuits.
AB  - A central focus of postgenomic research will be to understand how cellular
      phenomena arise from the connectivity of genes and proteins. This connectivity
      generates molecular network diagrams that resemble complex electrical circuits,
      and a systematic understanding will require the development of a mathematical
      framework for describing the circuitry. From an engineering perspective, the
      natural path towards such a framework is the construction and analysis of the
      underlying submodules that constitute the network. Recent experimental advances
      in both sequencing and genetic engineering have made this approach feasible
      through the design and implementation of synthetic gene networks amenable to
      mathematical modelling and quantitative analysis. These developments have
      signalled the emergence of a gene circuit discipline, which provides a framework
      for predicting and evaluating the dynamics of cellular processes. Synthetic gene
      networks will also lead to new logical forms of cellular control, which could
      have important applications in functional genomics, nanotechnology, and gene and
      cell therapy.

PMID- 12432408
TI  - Control, exploitation and tolerance of intracellular noise.
AB  - Noise has many roles in biological function, including generation of errors in
      DNA replication leading to mutation and evolution, noise-driven divergence of
      cell fates, noise-induced amplification of signals, and maintenance of the
      quantitative individuality of cells. Yet there is order to the behaviour and
      development of cells. They operate within strict parameters and in many cases
      this behaviour seems robust, implying that noise is largely filtered by the
      system. How can we explain the use, rejection and sensitivity to noise that is
      found in biological systems? An exploration of the sources and consequences of
      noise calls for the use of stochastic models.

PMID- 12432409
TI  - Computational approaches to cellular rhythms.
AB  - Oscillations arise in genetic and metabolic networks as a result of various modes
      of cellular regulation. In view of the large number of variables involved and of
      the complexity of feedback processes that generate oscillations, mathematical
      models and numerical simulations are needed to fully grasp the molecular
      mechanisms and functions of biological rhythms. Models are also necessary to
      comprehend the transition from simple to complex oscillatory behaviour and to
      delineate the conditions under which they arise. Examples ranging from calcium
      oscillations to pulsatile intercellular communication and circadian rhythms
      illustrate how computational biology contributes to clarify the molecular and
      dynamical bases of cellular rhythms.

PMID- 12432410
TI  - The community of the self.
AB  - Good health, which reflects the harmonious integration of molecules, cells,
      tissues and organs, is dynamically stable: when displaced by disease,
      compensation and correction are common, even without medical care. Physiology and
      computational biology now suggest that healthy dynamic stability arises through
      the combination of specific feedback mechanisms and spontaneous properties of
      interconnected networks. Today's physicians are already testing to 'see if the
      network is right'; tomorrow's physicians may well use therapies to 'make the
      network right'.

PMID- 12432412
TI  - A family-based program of care for women with recurrent breast cancer and their
      family members.
AB  - PURPOSE/OBJECTIVES: To evaluate the FOCUS Program (family involvement, optimistic
      attitude, coping effectiveness, uncertainty reduction, and symptom management), a
      family-based program of care for women with recurrent breast cancer and their
      family caregivers. DATA SOURCES: Randomized clinical trial. SETTING: Midwest
      region of the United States. DATA SYNTHESIS: The family-based program of care
      consisted of five components: family involvement, optimistic attitude, coping
      effectiveness, uncertainty reduction, and symptom management. The program was
      delivered in three home visits and two follow-up phone calls over a five-month
      period of time. CONCLUSIONS: Patients with recurrent breast cancer and their
      family members reported high satisfaction with the FOCUS Program. Although the
      FOCUS Program had a number of strengths, limitations of the program also were
      identified that need to be addressed in future family-based interventions.
      IMPLICATIONS FOR NURSING: A need exists for family-based programs of care that
      enable both patients and their family members to manage the multiple demands
      associated with recurrent breast cancer.

PMID- 12432413
TI  - Symptom distress and quality of life in patients with cancer newly admitted to
      hospice home care.
AB  - PURPOSE/OBJECTIVES: To evaluate the relationships between quality of life (QOL)
      and symptom distress, pain intensity, dyspnea intensity, and constipation
      intensity in people with advanced cancer who were newly admitted to hospice home
      care. DESIGN: Descriptive and correlational. SETTING: A large hospice that
      provides primarily home care. SAMPLE: 178 adult hospice homecare patients with
      cancer who were accrued to a clinical trial funded by the National Institutes of
      Health focusing on symptom management and QOL. Patients were excluded if they
      received a score lower than seven on the Short Portable Mental Status
      Questionnaire. METHOD: The patients were invited to participate in the clinical
      trial within 48 hours of admission to hospice home care. Among the questionnaires
      they completed were a QOL index and a distress scale. Scales measuring present
      intensity of pain, dyspnea, and constipation also were administered. MAIN
      RESEARCH VARIABLES: QOL, symptom distress, pain intensity, dyspnea intensity, and
      constipation intensity. FINDINGS: The most frequently reported symptoms among the
      sample were lack of energy, pain, dry mouth, and shortness of breath. Lack of
      energy caused the greatest distress, followed closely by dry mouth and pain. The
      results of the regression analysis indicated that total distress score, pain
      intensity, dyspnea intensity, and constipation intensity were related to QOL at
      the univariate level. When all predictors were considered simultaneously, only
      the total distress score remained a significant predictor of QOL (p< 0.001),
      accounting for about 35% of variance. CONCLUSIONS: QOL was affected by symptom
      distress in people with advanced cancer near the end of life. IMPLICATIONS FOR
      NURSING: The symptoms most commonly reported and those that cause the greatest
      patient distress should be addressed first by hospice nurses. Continued effort is
      needed in the important area of symptom management.

PMID- 12432414
TI  - Feasibilty of a sleep intervention during adjuvant breast cancer chemotherapy.
AB  - PURPOSE/OBJECTIVES: To evaluate the feasibility of an intervention designed to
      promote sleep and modify fatigue during four cycles of adjuvant breast cancer
      chemotherapy. DESIGN: Prospective, repeated measures, quasi-experimental
      feasibility study. SETTING: Midwestern urban oncology clinics. SAMPLE: 25 women
      between the ages of 40-65 (mean = 54.3) with stage I-II breast cancer receiving
      doxorubicin-based chemotherapy. METHODS: Each woman developed, reinforced, and
      revised an individualized sleep promotion plan (ISPP) with four components: sleep
      hygiene, relaxation therapy, stimulus control, and sleep restriction techniques.
      A daily diary, the Pittsburgh Sleep Quality Index, a wrist actigraph, and the
      Piper Fatigue Scale were used to collect data two days before and seven days
      after each treatment. MAIN RESEARCH VARIABLES: Adherence, sleep and wake
      outcomes, and fatigue. FINDINGS: Adherence rates with the components of the ISPP
      varied during treatments one through four: sleep hygiene (68%-78%), relaxation
      therapy (57%-67%), stimulus control (46%-67%), and sleep restriction (76%-80%).
      Mean sleep and wake outcomes at baseline, peak, and rebound times were that (a)
      sleep latency remained brief (less than 30 minutes per night), (b) time awake
      after sleep onset exceeded the desired less than 30 minutes per night, (c) sleep
      efficiency scores remained stable at 85%-90%, (d) total rest time remained stable
      at 8-10 hours per night, (e) subjective ratings of feelings on arising were
      stable, and (f) nighttime awakenings were 8-10 per night. Fatigue outcomes were
      that fatigue was stable two days after each treatment and mean daily fatigue
      intensity was lower at treatment three than at treatment one but rebounded at
      treatment four. CONCLUSIONS: The intervention was feasible, adherence rates
      improved over time, and most sleep and wake patterns were consistent with normal
      values. Revisions will focus on decreasing nighttime awakenings. IMPLICATIONS FOR
      NURSING: Adopting behaviors to promote sleep may assist in maintaining sleep and
      managing fatigue during chemotherapy.

PMID- 12432415
TI  - Frequency of use of complementary and alternative medicine in women with breast
      cancer.
AB  - PURPOSE/OBJECTIVES: To estimate the frequency of use of complementary and
      alternative medicine (CAM) therapies among women diagnosed with breast cancer and
      to identify demographic and clinical factors associated with CAM use in these
      patients. DESIGN: A descriptive, cross-sectional survey. SAMPLE: A convenience
      sample of 105 predominantly Caucasian women (mean age = 59 years) with a
      diagnosis of breast cancer was recruited from the Tampa Bay area and a rural
      midwestern area. METHODS: Utilizing the "Use of Complementary Therapies Survey,"
      frequency of CAM use was calculated for 33 individual therapies listed on the
      survey and among three survey-defined subscales of CAM therapies (i.e., diet and
      nutritional supplements, stress-reducing techniques, and traditional and ethnic
      medicines). MAIN RESEARCH VARIABLES: Use of CAM therapies and types of treatment
      in women with breast cancer. FINDINGS: Among diet and nutritional supplements,
      64% of all participants reported regular use of vitamins and minerals and 33%
      regularly used antioxidants, herbs, and health foods. Among stress-reducing
      techniques, 49% of all participants regularly used prayer and spiritual healing,
      followed by support groups (37%) and humor or laughter therapy (21%). Traditional
      and ethnic medicine therapies rarely were used with the exception of massage,
      which 27% of all participants used at least once after diagnosis. More frequent
      CAM use was observed among study participants who had undergone previous
      chemotherapy treatment and those with more than a high school education. Also,
      being less satisfied with their primary physician was associated with patients'
      more frequent CAM use. CONCLUSIONS: CAM use is increasing among women with breast
      cancer, and frequency of specific use according to type of CAM is higher than
      what has been reported in other studies. Use increased in patients who had
      undergone chemotherapy and in those with a high school education. IMPLICATIONS
      FOR NURSING: Oncology nurses are in a key position to identify what treatments
      patients are using and implement CAM therapies that can be helpful to relieve
      patient symptoms related to treatment and psychological distress.

PMID- 12432416
TI  - A qualitative exploration of the experiences of lesbian and heterosexual patients
      with breast cancer.
AB  - PURPOSE/OBJECTIVES: To explore similarities and differences between lesbian and
      heterosexual survivors of breast cancer regarding cancer experiences, medical
      interactions related to cancer treatment, and quality of life (QOL). DESIGN:
      Qualitative study using focus groups. SETTING: Urban, community-based health
      center. SAMPLE: A convenience sample of lesbians (n = 13) and heterosexual women
      (n = 28) with a diagnosis of breast cancer within the past five years.
      Participants were recruited via posted advertisements. METHODS: Focus groups were
      conducted as part of a larger study exploring coping and adjustment in lesbian
      survivors of breast cancer. Transcribed focus group data were analyzed through
      thematic and representative case study methods. MAIN RESEARCH VARIABLES: Broad
      aspects of medical interactions and the patient-provider relationship that may be
      associated with improved QOL of lesbian and heterosexual patients with cancer.
      FINDINGS: Data suggested similarities between lesbians and heterosexual women in
      their overall QOL. However, differences did emerge between the groups. Lesbians
      reported higher stress associated with diagnosis, lower satisfaction with care
      received from physicians, and a trend toward lower satisfaction with the
      availability of emotional support. CONCLUSIONS: Study findings have important
      implications for future research on adjustment and coping among lesbian patients
      with breast cancer and for the improvement of their mental and physical
      healthcare services. IMPLICATIONS FOR NURSING: Study findings may help improve
      healthcare services for lesbians with cancer.

PMID- 12432417
TI  - Compatibility and stability of 5-HT3 receptor antagonists: a pharmacology review.
AB  - PURPOSE/OBJECTIVES: To compare stability and compatibility among the 5-HT3
      antiemetics in multidrug cytotoxic regimens. DATA SOURCES: Published articles,
      product-prescribing information, and direct communication with manufacturers.
      DATA SYNTHESIS: Stability and compatibility of ondansetron and granisetron with a
      variety of other agents used in the oncology setting generally are similar.
      Granisetron is compatible with all tested Y-site drugs; ondansetron is not
      compatible with amsacrine or fluorouracil. Information for dolasetron is not as
      readily available; therefore, comparisons are difficult to make. CONCLUSION:
      Although 5-HT3 receptor antagonists have made a significant impact in decreasing
      severe emesis, administration of complex regimens can be confusing at best for
      nurses because of the lack of compatibility data. By partnering with pharmacists,
      nurses can develop administration guidelines to minimize complications and
      improve outcomes. IMPLICATIONS FOR NURSING: To maximize patients' outcomes,
      oncology nurses must be knowledgeable about stability and compatibility of
      complex multidrug regimens that include the commonly used 5-HT3 receptor
      antagonist antiemetics.

PMID- 12432418
TI  - Preparing children to be bone marrow donors.
AB  - PURPOSE/OBJECTIVES: To review literature regarding children as bone marrow donors
      and describe the evaluation of an individualized intervention to support children
      who will be donors for parents or siblings. DATA SOURCE: Research studies,
      abstracts, and clinical reports describing interventions or psychosocial issues
      related to child donors, parent interviews, and clinical experiences. DATA
      SYNTHESIS: Child marrow donors and caregivers benefit from interventions that
      illuminate the process and provide psychosocial support. Use of a teaching book
      enhances intervention and provides a tool for parents to use after
      transplantation. CONCLUSIONS: Psychosocial distress in child marrow donors and
      parents can be minimized through education and therapeutic interventions.
      Research is needed to validate the efficacy of interventions and determine
      whether psychosocial complications are decreased. IMPLICATIONS FOR NURSING: Child
      donors, especially those for parents, should receive support and attention for
      their unique psychosocial needs.

PMID- 12432419
TI  - The experience of using decisional support aids by patients with breast cancer.
AB  - PURPOSE/OBJECTIVES: To explore the lived experience of patients with breast
      cancer using decisional support aids during the prediagnosis, diagnosis, and
      treatment phases of their disease. RESEARCH APPROACH: Descriptive,
      phenomenologic. SETTING: Community-based. PARTICIPANTS: 12 women, ages 38-68,
      diagnosed with and treated for breast cancer. METHODOLOGIC APPROACH: Audiotaped
      interviews were transcribed and analyzed according to Colaizzi's method. MAIN
      RESEARCH VARIABLES: Use of decisional support aids. FINDINGS: Six major themes
      were identified: being too stressed and overwhelmed to make a decision, feeling
      an internal sense of urgency to have the breast cancer managed quickly, trusting
      the opinion and advice of physicians about treatment decisions, appreciating the
      importance of support from family and friends in decision making, finding nurses
      were unavailable or uninvolved in decision making initially, and missing out on
      the benefits of a multidisciplinary approach. CONCLUSIONS: Being presented with
      the diagnosis of breast cancer evokes a range of feelings and emotions. By
      identifying, explaining, and expressing their accounts, participants revealed
      their lived experience and its meaning. The description of this phenomena may
      assist other women diagnosed with breast cancer in the decision-making process.
      INTERPRETATION: Oncology nurses need to be aware of and understand the issues
      surrounding the decision-making process of patients with breast cancer. Gaps
      clearly exist in the information and support provided to these participants.
      Nurses must target areas that are insufficient in providing decisional support
      aids and plan for partnerships to ensure a multidisciplinary approach in this
      process.

PMID- 12432420
TI  - The nurse's relationship-based perceptions of patient quality of life.
AB  - PURPOSE/OBJECTIVES: To explore patients' quality of life (QOL) as defined by RNs
      in adult and pediatric oncology settings and to examine, from the perspectives of
      clinical nurses, the knowledge that is needed to apply QOL research outcomes in
      clinical practice. DESIGN: Qualitative research design using a focus group
      technique to explore the research questions. SETTING: Three sites (i.e., a
      pediatric research center in western Tennessee and oncology nurses from a chapter
      of the Oncology Nursing Society [ONS] in Central Florida and another in upstate
      New York). SAMPLE: 24 oncology nurses working with adult or pediatric patients or
      both. METHODS: Oncology nurses were approached at work or through their local ONS
      chapters for a focus group discussion. FINDINGS: 47 unique themes were reported
      by all five focus groups in response to three questions. The most frequently
      reported themes were (a) Using the Patient's Standard, (b) Nursing Strategies,
      (c) Differences Decrease QOL Care, (d) Maintaining Social Interests, (e)
      Insightful Relations With Patient, and (f) Nurse-Patient Communication.
      CONCLUSIONS: Nurses' assessments of QOL primarily are based on their established
      relationships with their patients. From these relationships, nurses derive
      perceptions of patients' QOL and clinical direction for interventions to
      positively influence QOL. Based on these findings, the investigators developed a
      conceptual model of the nurses' relationship-based perceptions of patients' QOL.
      IMPLICATIONS FOR NURSING: The current QOL measures have minimal importance to
      nurse clinicians. Because nurse clinicians rely on their relationships with
      patients to assess QOL, available tools should be made more clinically useful.
      Further research should be conducted using the new conceptual model, specifically
      to learn more about how nurses complete a QOL assessment within the context of
      the nurse-patient relationship.

PMID- 12432421
TI  - Reciprocity for patients with head and neck cancer participating in an instrument
      development project.
AB  - PURPOSE/OBJECTIVES: To examine reciprocity (i.e., a mutual exchange of benefit)
      in study participation via a thematic analysis of field notes on study
      participation from a parent psychometric study. DESIGN: Qualitative. SETTING:
      Head and neck surgery clinic in an urban tertiary hospital. SAMPLE: Seven
      patients with head and neck cancer recruited to participate in an instrument
      development project. METHODS: Symbolic interactionism was employed to frame the
      examination of field notes from observations and interactions with patients, as
      well as participant notes accompanying returned retest questionnaires. Analysis
      relied on the constant comparative technique at the levels of open and axial
      coding. MAIN RESEARCH VARIABLES: Participation in an instrument development
      project. FINDINGS: Four content themes emerged in the analysis: Willingness to
      Help, Reassurance That the Deficits Patients Experience Are Common, Participation
      Provides Social Contact, and Confirmation of Clinically Significant Findings. A
      process theme, Unveiling the Experience, integrated the content themes in
      relation to participation itself. The role of the study nurse appears to be
      pivotal in this process. CONCLUSIONS: A notion of reciprocity in research
      participation is apparent. The role of the study nurse is an important element in
      the process of reciprocity. This role should be explored to enhance study
      participation. IMPLICATIONS FOR NURSING: Implications, particularly for clinical
      trial nurses, include recasting the benefits of participating in research, better
      addressing preparation for patients scheduled to receive treatment for head and
      neck cancer, and exploring and enhancing the role of the study nurse.

PMID- 12432422
TI  - Itraconazole (Sporanox(r)) for vulvovaginal candidiasis.
AB  - Vulvovaginal candidiasis is a common occurrence among women over 25 years of age.
      The likelihood of developing infection increases with pregnancy, the use of oral
      contraceptives or antibiotics, or immune disorders. However, in many cases, the
      etiology of the disorder is unknown. Sobel1 suggests that some cases of
      reinfection may actually be cases of relapse, due to either inadequate testing
      methods, which result in false-negative results after treatment, or to
      ineffective treatments. Misdiagnosis of the causative organism may also result in
      ineffective treatment. The most common causal Candida species is C. albicans.
      However, other, less easily eradicated species may also be involved.

PMID- 12432423
TI  - Itraconazole (Sporanox(r)) for seborrheic dermatitis.
AB  - Seborrheic dermatitis is a common superficial dermatosis, characterized by red,
      flaking areas of the skin, which may in some cases be covered with yellowish
      flakes. The most commonly affected areas are the nasolabial folds, ears,
      eyebrows, scalp and chest. While seborrheic dermatitis may be easy to recognize
      clinically, the variability of the lesions in both appearance and location may
      complicate the diagnosis. Seborrheic dermatitis has been described as resembling
      psoriasis (in which case, the condition may be called "sebopsoriasis") and, when
      affecting the eyes or ears, has also been described as blepharitis and otitis,
      respectively. Seborrheic dermatitis tends to be chronic, though seasonal
      variation is common, with lesions worsening in the dry, winter months.

PMID- 12432424
TI  - The Scoring Clinical Index for Onychomycosis (SCIO index).
AB  - Onychomycosis is a common disease, and there are a number of factors that may
      affect the duration and dosage of treatment including the type of onychomycosis,
      the area and thickness of nail involvement, the age of the patient, and the
      location of the digit that is affected. We report a composite index, the Scoring
      Clinical Index for Onychomycosis (SCIO) that combines these factors to give an
      index of the overall severity of onychomycosis. The use of the SCIO may have
      treatment implications; by matching patients with similar SCIO scores, it may be
      possible to better compare the clinical response to therapy.

PMID- 12432425
TI  - Butenafine: an update of its use in superficial mycoses.
AB  - Butenafine is a synthetic benzylamine antifungal agent that may be fungicidal
      against susceptible organisms, e.g., dermatophytes. Butenafine may be effective
      and safe in the treatment of interdigital tinea pedis (apply twice daily for 1
      week or once daily for 4 weeks), tinea corporis/tinea cruris (apply twice daily
      for 2 weeks), and pityriasis versicolor (apply once daily for 2 weeks). The
      effectiveness of the drug persists for at least 4 weeks following the
      discontinuation of therapy suggesting that there is some retention of the drug in
      the skin following termination of active therapy.

PMID- 12432426
TI  - Prevention of polymorphous light eruption and solar urticaria.
AB  - Polymorphous light eruption (PLE) and solar urticaria (SU) are two
      photodermatoses that are induced by ultraviolet radiation and sometimes by
      visible light. This article will review the various means of preventing PLE and
      SU with an emphasis on the role of sunscreens.

PMID- 12432427
TI  - Lessons in congenital and acquired renal disease from alpha8 integrin mutant
      mice.
AB  - Cell-matrix interactions have been shown to be important during renal development
      and in various forms of kidney diseases. The alpha8 integrin chain is expressed
      during early nephrogenesis. In alpha8 gene mutated mice, lack of alpha8 results
      in unilateral or bilateral renal agenesis in part of the animals. No human
      disease with mutations in the alpha8 integrin gene locus has been described to
      date. However, similar renal defects are displayed in disorders with mutations
      affecting other adhesion molecules. In the kidneys of adult mice, alpha8 is
      expressed in vascular smooth muscle cells and mesangial cells of the glomerulus.
      Although alpha8-deficient mice surviving with reduced renal mass do not show any
      glomerular abnormalities, they have an increased susceptibility to glomerular
      damage upon mechanical or inflammatory stress of glomerular cells. Thus, alpha8
      seems to be important for normal renal development and could help to maintain the
      structural integrity of the glomerulus following injury during various kidney
      diseases.

PMID- 12432428
TI  - Endothelin-1 produces no renal vasoconstriction in conscious newborn lambs.
AB  - Experiments were carried out to investigate the effects of endothelin-1 (ET-1) on
      renal vascular tone during development under physiological conditions in
      conscious lambs. Renal blood flow (RBF), renal vascular resistance (RVR), mean
      arterial pressure (MAP), and heart rate (HR) were measured in conscious,
      chronically instrumented lambs aged approximately 1 week and 6 weeks before and
      after intra-arterial (i.a.) injection of 0, 100, 200, and 400 ng/kg body weight
      of ET-1. In addition, plasma levels of ET-1 were measured in 39 sheep aged 5-85
      days. In 6-week-old lambs, i.a. injection of ET-1 was associated with a rapid
      dose-dependent decrease in RBF that resulted from a dose-dependent increase in
      RVR. In 1-week-old lambs, there was no renal vasoconstriction observed after ET-1
      administration, even at the highest dose tested. In response to i.a. injection of
      ET-1 to 1-week-old and 6-week-old lambs, MAP increased and there was a
      concomitant decrease in HR; these effects were dose dependent but not age
      dependent. Plasma levels of ET-1 were 10.7+/-4.2 pg/ml at 5-10 days, and remained
      constant throughout the first 3 months of life in conscious sheep. We conclude
      that ET-1 is not a renal vasoconstrictor agent in the immediate newborn period,
      and that the effects of ET-1 on renal vascular tone appear to be developmentally
      regulated.

PMID- 12432429
TI  - Genetic analysis--a diagnostic tool for primary hyperoxaluria type I.
AB  - Primary hyperoxaluria type I is an autosomal recessive metabolic disease in which
      excessive oxalates are formed by the liver and excreted by the kidneys, causing a
      wide spectrum of disease, ranging from renal failure in infancy to mere renal
      stones in late adulthood. The diagnosis may be suspected when clinical signs and
      increased urinary oxalate and glycolate excretion present, and is confirmed by
      the measurement of decreased alanine:glyoxylate aminotransferase activity in a
      liver sample. The enzymatic assay is not readily available to pediatric
      nephrologists in many parts of the world. We describe three families from Croatia
      in whom the diagnosis of primary hyperoxaluria was solely based on clinical
      findings that included nephrolithiasis and nephrocalcinosis accompanied by
      increased urinary oxalates and glycolate excretion, as enzymatic assays of liver
      samples could not be performed. Mutation analysis of the AGXT gene encoding the
      defective enzyme confirmed the diagnosis, revealing three alleles carrying the
      C156ins mutation and two the G630A mutation. Screening first-degree relatives for
      the relevant mutation disclosed an asymptomatic affected sibling. Mutation
      analysis of the AGXT gene is a non-invasive and accurate tool for the diagnosis
      of type I primary hyperoxaluria that may replace enzymatic assays of liver
      biopsies.

PMID- 12432430
TI  - Renal tract ultrasonography and calcium homeostasis in Williams-Beuren syndrome.
AB  - Renal ultrasound scan, circulating creatinine and calcium, and the urinary
      calcium excretion rate were investigated in 57 patients with clinically and
      genetically typical Williams-Beuren syndrome (25 female and 32 male subjects,
      aged from 1.0 year to 23 years, median 8.5 years) on regular follow up at our
      institution. Twenty-three unilateral abnormalities were detected in 20 patients:
      pelvic dilatation ( n=6), renal hypoplasia ( n=5), isolated renal cyst ( n=3),
      kidney surface irregularity ( n=3), kidney duplication ( n=2), renal agenesis (
      n=1), megaureter ( n=1), pelvic kidney dystopia ( n=1), and renal stone ( n=1).
      Both infantile hypercalcemia and nephrocalcinosis was absent in the 57 patients.
      Mild hypercalcemia was noted in 1 and mild hypercalciuria in 2 patients after the
      1st year of life. In conclusion, the study indicates the frequent occurrence of
      intrinsic renal tract abnormalities detected by ultrasonography in Williams
      Beuren syndrome. However, the study does not confirm the importance given in the
      past to the occurrence of hypercalcemia and hypercalciuria.

PMID- 12432431
TI  - Estimation of glomerular filtration rate in children.
AB  - The aim of this study was to develop a method to predict the glomerular
      filtration rate (GFR) in children by using the population pharmacokinetic
      approach. This powerful approach is widely used for drug development in order to
      study relationships between patients' characteristics (demographic,
      morphological, biological covariates) and pharmacokinetic parameters. For the
      first time, (51)Cr-EDTA plasma concentrations from 64 children (development data
      set) were analyzed using the Non-linear Mixed Effects Model (NONMEM) program to
      determine the most appropriate equation to relate (51)Cr-EDTA clearance (as a
      measurement of GFR) and patient characteristics. The most predictive equation was
      based on body weight, square height, and plasma creatinine (PCr, determined by
      the Jaffe method). This equation was then validated using the data from a further
      33 patients. This equation produced estimates of GFR that were less biased and
      more precise than those obtained using the widely used Schwartz formula. The
      coefficient of correlation between estimated and actual GFR was 0.83, and the
      10th to 90th percentiles for percentage errors were -20% to +30%. Finally,
      analysis of the whole data set (97 patients) led to an equation (i.e., GFR
      (ml/min)=[56.7 x Body weight (kg)+0.142 x Length(2)(cm)]/PCr ( microM)) very
      similar to that obtained from the development data set. This equation would be
      useful for estimating GFR in children when isotopic determination of the (51)Cr
      EDTA clearance cannot be performed.

PMID- 12432432
TI  - Neuropsychological outcome in children with acquired or congenital renal disease.
AB  - The neuropsychological abilities of children with congenital ( n=13) or acquired
      ( n=11) end-stage renal disease (ESRD) were compared. Patients were being treated
      with or being prepared for dialysis and were awaiting transplantation. None of
      the children had an identifiable syndrome with associated central nervous system
      (CNS) dysfunction or had exposure to drugs with known CNS toxicity. There were no
      group differences in intelligence, academic achievement, behavior, or immediate
      memory. Children with congenital ESRD had poorer fine motor coordination and more
      difficulty on tests of verbal and nonverbal long-term memory than children with
      acquired ESRD. However, the neuropsychological outcome for congenital ESRD is
      more favorable than previously described. Psychological and education treatment
      recommendations should be considered.

PMID- 12432433
TI  - Increased urinary albumin excretion in children from families with Balkan
      nephropathy.
AB  - Balkan nephropathy (BN) has not been described in children. However, some
      previous studies have revealed abnormalities of the urinary tract in children
      from families with BN. In the present study, urinary excretion of albumin was
      studied in 703 healthy children, age 9-13 years, from endemic and non-endemic
      settlements around the South Morava River. Since BN is an environmentally induced
      disease, with possible seasonal variation of toxicant(s), children were studied
      three times a year: spring, autumn, and winter. After a water load of 15 ml/kg
      body weight, a 3-h urine sample was collected, from 7 to 10 a.m. Albumin
      excretion in urine was highest in children from families with BN in all three
      periods investigated. It was significantly different from excretion in children
      from the city, and in autumn it was also different ( P<0.01) from children in non
      endemic families. Correlation analysis of albumin excretion with some urinary
      markers of tubular nephrotoxicity shows the highest correlation with both beta(2)
      microglobulin and N-acetyl-beta-D-glucosaminidase in endemic villages in autumn.
      If the upper limit of albumin excretion is set at 8.5 mg/mmol creatinine, then in
      autumn increased albumin excretion was found in 15 of 229 children from endemic
      settlements and in only 5 of 454 children from non-endemic areas ( P<0.0001).
      Evidence is presented that in autumn children from families with BN excreted
      significantly more albumin than those from non-endemic families but living in the
      same settlements, or from children living outside of the endemic region in the
      city of Nis.

PMID- 12432434
TI  - Ceruloplasmin levels in antineutrophil cytoplasmic antibody-positive patients.
AB  - Anti-myeloperoxidase (MPO) antibodies are associated with the development of anti
      neutrophil cytoplasmic antibody (ANCA)-related vasculitis. The imbalance between
      the protease-antiprotease activity in the neutrophils has been implicated in the
      pathogenesis of ANCA-related vasculitis. Ceruloplasmin is an acute-phase protein
      that has antiproteinase and antioxidant properties and inhibits MPO activity. We
      attempted to study the association between serum ceruloplasmin and ANCA in
      childhood vasculitis. Forty-five ANCA-related diseases were included in the
      study. The age range was 4-16 years. Patients were divided into two groups based
      on indirect immunofluorescence and/or ELISA specificity (MPO). Twenty-six
      patients had p-ANCA- and 19 patients had c-ANCA-positive disease. Nine patients
      with Henoch-Schonlein purpura were studied as an ANCA-negative control group.
      Serum ceruloplasmin levels in p-ANCA-, c-ANCA-positive patients, and controls
      were 125.85+/-93.48 mg/dl, 59.79+/-17.60 mg/dl, and 64.34+/-18.77 mg/dl,
      respectively, and were significantly higher in patients with p-ANCA ( P<0.05).
      Ceruloplasmin levels were significantly decreased in remission ( P<0.05). Median
      MPO level in p-ANCA-positive patients was 15.2 (5-250) and was negative in all c
      ANCA-positive patients. There was a significant positive correlation between MPO
      and ceruloplasmin levels ( r=0.70, P<0.05). Of 26 patients (53.8%) in the p-ANCA
      positive group, 14 had renal involvement. The patients with renal disease had
      significantly higher ceruloplasmin levels than others (151.17+/-92.14 and
      134.64+/-95.16 mg/dl respectively, P<0.05). In conclusion, the increase in
      ceruloplasmin levels during the acute phase suggests that this might be an
      activation criterion or a response to neutrophil-mediated tissue injury.
      Increased ceruloplasmin levels together with p-ANCA positivity may be predictive
      for renal involvement and a serious clinical course. The correlation between
      ceruloplasmin and MPO levels supports their association. Further studies are
      necessary to elucidate whether genetic and/or functional alterations in
      ceruloplasmin are effective in the pathogenesis of vasculitis.

PMID- 12432435
TI  - Endothelin levels in Henoch-Schonlein purpura.
AB  - Henoch-Schonlein purpura (HSP) is one of the most common types of vasculitis
      disorders seen in childhood and is characterized by a rash, arthritis, abdominal
      pain, and renal involvement. Although HSP is an immunoglobulin A (IgA) related
      immune complex disease, the pathogenesis has not been fully elucidated. Cytokines
      have been implicated in the pathogenesis, but endothelins (ET) - vasoconstrictor
      hormones produced by endothelial cells - have not been studied in patients with
      HSP. In a controlled study, we measured ET-1 levels in children with HSP during
      the acute and remission phases. ET-1 levels were significantly higher in the HSP
      patients during the acute phase compared with the control group and the HSP
      patients in the remission phase. There was no correlation between ET-1 levels and
      disease severity, acute phase reactant response, or morbidity. The role of
      endothelins and other cytokines in the pathogenesis of HSP needs to be further
      explored.

PMID- 12432436
TI  - Implications of blood soluble and cell surface tumor necrosis factor receptors in
      childhood nephrotic syndrome.
AB  - We investigated whether leukocyte cell surface TNF receptors (cTNFR) and plasma
      soluble TNF receptors (sTNFR) could serve as predictors of childhood steroid
      resistant nephrotic syndrome (SRNS) during the early stage of diagnosis. We
      recruited 39 nephrotic children for studies correlating plasma sTNFR and
      leukocyte cTNFR with disease activity and therapeutic response. We found that
      patients with idiopathic childhood nephrotic syndrome (NS) had higher pre
      treatment plasma sTNFR1 ( P<0.001) and sTNFR2 levels ( P<0.001) than controls
      without NS. In contrast, cTNFR1 ( P<0.001) and cTNFR2 ( P=0.014) expression on
      granulocytes but not lymphocytes was lower in patients than controls. Patients
      with SRNS, similar to steroid-sensitive nephrotic syndrome (SSNS), had higher
      sTNFR1 and sTNFR2 levels pre treatment. However, patients with SRNS revealed
      higher expression of cTNFR1 ( P<0.001) and cTNFR2 ( P=0.023) than those with
      SSNS. After 4 weeks of steroid treatment, plasma sTNFR1 and sTNFR2 levels
      returned to normal in both patients with SRNS and SSNS. Post treatment, the
      decreased cTNFR1 and cTNFR2 expression on granulocytes in patients with SSNS
      returned to normal, while patients with SRNS revealed no change before and after
      treatment. This study suggests that a higher plasma sTNFR level associated with
      lower cTNFR expression reflects NS disease activity, whereas a higher initial
      granulocyte cTNFR expression tends to predict steroid resistance. TNFR may play a
      pathophysiological role in childhood NS.

PMID- 12432437
TI  - Pharmacokinetics of darbepoetin alfa in pediatric patients with chronic kidney
      disease.
AB  - Darbepoetin alfa is a novel erythropoiesis-stimulating protein with a two- to
      threefold longer half-life than recombinant human erythropoietin (epoetin) in
      adult patients with chronic kidney disease (CKD). This randomized, open-label,
      crossover study was conducted to determine the pharmacokinetic profile of
      darbepoetin alfa in pediatric patients with CKD. Twelve patients 3-16 years of
      age with CKD were randomized and received a single 0.5 micro g/kg dose of
      darbepoetin alfa administered intravenously (IV) or subcutaneously (SC). After a
      14- to 16-day washout period, patients received an identical dose of darbepoetin
      alfa by the alternate route. After IV administration, the mean clearance of
      darbepoetin alfa was 2.3 ml/h per kg, with a mean terminal half-life of 22.1 h.
      After SC administration, absorption was rate limiting, with a mean terminal half
      life of 42.8 h and a mean bioavailability of 54%. Comparison of these results
      with those from a previous study of darbepoetin alfa in adult patients indicated
      that the disposition of darbepoetin alfa administered IV or SC is similar in
      adult and pediatric patients, although absorption may be slightly more rapid in
      pediatric patients after SC dosing. The mean terminal half-life of darbepoetin
      alfa in this study was approximately two- to fourfold longer than that previously
      reported for epoetin in pediatric patients.

PMID- 12432438
TI  - Ambulatory blood pressure monitoring in children with isolated haematuria.
AB  - Ambulatory blood pressure monitoring (ABPM) was performed in 29 children, ages
      8.5-10.5 years (mean 11.6+/-3.0) with isolated haematuria (IH) and in 27 age,
      sex, weight and height matched healthy controls (C). Isolated haematuria was
      defined as >or=5 RBC/HPF on three separate urinalyses over a 3-month period with
      normal renal function, a normal appearing ultrasound examination of the kidneys
      and the absence of hypercalciuria. Haematuria had been documented for at least 3
      years prior to ABPM. Daytime and nighttime periods were 0800-2200 and 2200-0800
      hours, respectively. The total number of successful blood pressure readings was
      21.8 and 20.7 per subject (90.0 and 86.1% of all attempted measurements) in IH
      and C, respectively. Mean 24-h, daytime and nighttime heart rate, mean arterial
      pressure, and systolic and diastolic blood pressure in IH did not differ from
      that of controls. Nocturnal dipping was present in all IH patients and was of
      equal magnitude to C (9.5 vs 8.4 and 13.7 vs 10.3% for average systolic blood
      pressure (SBP) and diastolic blood pressure (DBP) dips, respectively). We
      conclude that normal blood pressure values, as well as the circadian rhythm of
      blood pressure, are maintained in children with IH of at least 3 years' duration.

PMID- 12432439
TI  - The usefulness of renal vein renin studies in hypertensive children: a 25-year
      experience.
AB  - Lateralised renin secretion predicts improvement following surgery/angioplasty of
      the affected kidney in paediatric hypertension. We retrospectively analysed all
      our renal vein renin (RVR) studies undertaken in hypertensive children and their
      subsequent clinical outcomes over a 25-year period. The outcomes were categorised
      as cure, improvement or no change in hypertension. The proportions that benefited
      by 'following' or 'ignoring' the RVR results in relation to the aetiology of
      hypertension and subsequent therapy were compared. A ratio between the RVR value
      of the dominant kidney and that of the contralateral kidney (R/Rc ratio) above
      1.5 was considered to show significant lateralisation. A ratio between RVR value
      of the contralateral kidney and that of the caudal inferior vena cava (Rc/P
      ratio) of less than 1.3 was considered to indicate contralateral renin
      suppression. Of 233 RVR records, 137 were suitable for analysis. Of these, 39 had
      reflux nephropathy (RN), 73 renovascular disease (RVD) and the others
      miscellaneous conditions. Of the 39 hypertensive children with RN, the R/Rc ratio
      was over 1.5 in 20 subjects, of whom 11 underwent surgery. Amongst the 19 with an
      R/Rc less than 1.5, 4 also had surgery. Of the 73 hypertensive children with RVD,
      the R/Rc ratio was over 1.5 in 38 subjects, of whom 20 underwent
      surgery/angioplasty. Amongst the 35 with an R/Rc less than 1.5, 7 also underwent
      surgery/angioplasty. In RN there was no significant difference in the proportion
      that improved with allocated treatment, as suggested by the 'test' when compared
      with those who were 'misallocated'. In RVD, however, the proportion improved
      (35.0%) by 'following the test' (i.e. R/Rc ratio) was significantly greater than
      the proportion improved (12.5%) in the group in whom the test was 'ignored'. This
      was true for both R/Rc and Rc/P ratios. Thus, RVR measurements are useful for
      identifying hypertensive children with RVD that may have a favourable outcome
      after surgery, but this does not apply to children with RN. Measurements,
      however, may have diagnostic value even if surgery or angioplasty is not
      anticipated.

PMID- 12432440
TI  - White coat effect and white coat hypertension in pediatric patients.
AB  - We evaluated the prevalence of white coat (WC) effect in pediatric age patients
      and that of white coat hypertension (WCH) in hypertensive pediatric patients. Two
      hundred and six patients (136 normotensive and 70 hypertensive patients, 107 boys
      and 99 girls, aged 6-25 years, mean 13.4, SD 4.7) were studied. Hypertension was
      diagnosed when systolic and/or diastolic blood pressure (BP) measurements with
      auscultatory technique were >or= the 95th percentile for sex and age. WC effect
      was defined as office BP minus daytime mean ambulatory BP (ABP). WCH was
      diagnosed in the hypertensive patients when daytime ABP values were < the 95th
      percentile for sex and height of reference values. There was a positive
      correlation between office BP and WC effect ( P<0.05). A WC effect of >or= 10
      mmHg was observed more frequently in hypertensive patients (50%) than in
      normotensive patients (25%). Among 70 hypertensive patients, 33 (47%) had WCH.
      There was no significant difference in the prevalence of WCH in relation to age,
      gender, or the presence or absence of causes of hypertension. In conclusion, WC
      effect is frequently seen in pediatric patients, and is more common in subjects
      with higher office BP.

PMID- 12432441
TI  - Spontaneous improvement of hypertension in multicystic dysplastic kidney: a case
      report.
AB  - We report a case of transitory hypertension associated with unilateral
      multicystic dysplastic kidney (MCDK). A newborn girl with MCDK, detected by
      prenatal ultrasonography, was conservatively treated and has been followed for 18
      months at the Pediatric Nephrourology Unit (HC-Belo Horizonte, Brazil). Arterial
      hypertension was observed at about 4 months of age and was associated with high
      levels of plasma renin activity and circulating angiotensin, and also with
      changes in renal Doppler ultrasonography. For these reasons, a nephrectomy was
      initially proposed. However, a spontaneous improvement of blood pressure levels
      was noticed at about 10 months of age. Serial Doppler ultrasonography showed
      involution of the affected renal volume and decreased arterial flow. The
      anatomical improvement was observed simultaneously with normalization of the
      peripheral renin and angiotensin values. The literature is reviewed regarding the
      relationship between hypertension and MCDK.

PMID- 12432442
TI  - Transient hyporeninemic hypoaldosteronism in acute glomerulonephritis.
AB  - While hyporeninemic hypoaldosteronism (HH) has been well described in relation to
      chronic renal diseases, transient HH has rarely been reported. Here we present a
      9-year-old boy with acute glomerulonephritis who developed hyperkalemia, which
      persisted for a period of 3 weeks despite normal values of creatinine clearance
      and an absence of acidosis. He was diagnosed as having HH because of low basal
      plasma renin activity and serum aldosterone level. Renal biopsy showed diffuse
      endocapillary proliferative glomerulonephritis. There were no apparent
      pathological changes in the juxtaglomerular apparatus (JGA). Rapid
      adrenocorticotropic hormone administration increased adequately both serum
      aldosterone and cortisol levels. Responses of both plasma renin activity and
      serum aldosterone level following the furosemide upright provocation were blunted
      in the hyperkalemic acute phase, but recovered in the normokalemic convalescent
      phase. Serum levels of human atrial natriuretic peptide were within normal range,
      both in the hyperkalemic and normokalemic phases. These results suggested that a
      transient dysfunction of the JGA, without volume expansion or structural damage
      of the JGA, caused HH in this patient.

PMID- 12432443
TI  - Bilateral multicystic kidneys--an unusual case.
AB  - Multicystic dysplasia of the kidneys is a condition whose prognosis is good as it
      usually presents unilaterally. Bilateral cases are usually fatal in utero. We
      report a case of bilateral multicystic dysplasia of the kidneys where the lower
      moiety of the right kidney was spared cystic change. The patient had normal renal
      function and, following conservative management, remains alive and well 6 months
      later.

PMID- 12432444
TI  - Peritonitis due to Leuconostoc species in a child receiving peritoneal dialysis.
AB  - Leuconostoc species are rarely pathogenic in humans, but may cause infection in
      patients at risk. A 7-year-old girl with p-ANCA-positive crescentic
      glomerulonephritis, treated with peritoneal dialysis, developed peritonitis due
      to Leuconostoc species. She had a history of treatment with vancomycin and a
      brief course of immunosuppressive therapy. The peritonitis responded well to
      ampicillin therapy. To date, only 47 cases of Leuconostoc infection, including
      our patient, have been reported in the medical literature; 25 of the cases
      occurred in children. Only 1 prior case has been reported in the setting of
      peritoneal dialysis. The risk factors for Leuconostoc infections are not clear,
      but commonly associated conditions include immunocompromised status and
      indwelling medical devices. Leuconostoc species are easily misidentified as
      streptococci in culture, but they possess inherent resistance to vancomycin
      despite sensitivity to most other antibiotics. In patients with gram-positive
      peritonitis, Leuconostoc should be considered as a possible etiological agent,
      particularly if vancomycin resistance is noted in an organism thought to be a
      Streptococcus species.

PMID- 12432445
TI  - Continuous venovenous hemodiafiltration in hypernatremic hyperglycemic nonketotic
      coma.
AB  - Rapid changes in serum sodium concentration can result in adverse neurological
      outcome. The gradual correction of hypernatremia in the setting of acute renal
      failure can be difficult to achieve. We describe an obese female teenager who
      presented with severe hypernatremia, hyperosmolar hyperglycemic nonketotic coma,
      acute renal failure, and rhabdomyolysis. Her hypernatremia and other serum
      chemistries were gradually corrected by repeatedly adjusting the dialysate
      electrolyte composition used during continuous venovenous hemodiafiltration. She
      had a full recovery of her renal function. She does not have clinical
      neurological sequelae from hypernatremia during a 1-year follow-up period.

PMID- 12432446
TI  - Cytosolic and nuclear aggregation of the amyloid beta-peptide following its
      expression in the endoplasmic reticulum.
AB  - Misfolded secretory and membrane proteins are known to be exported from the
      endoplasmic reticulum (ER) to the cytosol where they are degraded by proteasomes.
      When the amount of exported misfolded proteins exceeds the capacity of this
      degradation mechanism the proteins accumulate in the form of pericentriolar
      aggregates called aggresomes. Here, we show that the amyloid beta-peptide (Abeta)
      forms cytosolic aggregates after its export from the ER. These aggregates share
      several constituents with aggresomes. However, Abeta aggregates are distinct from
      aggresomes in that they do not accumulate around the centrosome but are
      distributed randomly around the nucleus. In addition to these cytosolic
      aggregates, Abeta forms intranuclear aggregates which have as yet not been found
      for proteins exported from the ER. These findings show that proteins exported
      from the ER to the cytosol which escape degradation by the proteasome are not
      necessarily incorporated into aggresomes. We conclude that several distinct
      aggregation pathways may exist for proteins exported from the ER to the cytosol.

PMID- 12432447
TI  - Cellular localization of the endothelin receptor subtypes ET(A) and ET(B) in the
      rat heart and their differential expression in coronary arteries, veins, and
      capillaries.
AB  - In the heart, the endothelin (ET)/endothelin-receptor system is markedly involved
      in pathophysiological mechanisms underlying various cardiac diseases. Based upon
      pharmacological studies both ET-receptor subtypes take part in the regulation of
      coronary vascular tone, however, their detailed cellular distribution in the
      coronary vascular bed based upon direct mRNA and protein detection is unknown.
      This issue was addressed in the rat heart by means of non-radioactive in situ
      hybridization, RT-PCR, and immunohistochemistry. Expression of vascular ET(A)
      receptors was detected in arterial smooth muscle and capillary endothelium while
      ET(B)-receptors were present in arterial, venous, and capillary endothelium, and
      in arterial and venous smooth muscle cells. This differential distribution of the
      ET-receptor subtypes supports the concept that ET(A)- as well as ET(B)-receptors
      mediate arterial vasoconstriction, while postcapillary vascular resistance is
      exclusively regulated by ET(B)-receptors. The observed capillary endothelial
      expression of the ET(A)-receptor correlates with the known ability of ET(A)
      receptor antagonists to attenuate increases in cardiac microvascular permeability
      during endotoxin shock and ischemia/reperfusion injury.

PMID- 12432448
TI  - Nitric oxide synthase II in rat skeletal muscles.
AB  - Constitutive expression of nitric oxide synthase (NOS) II was found in rat
      hindlimb muscles by immunohistochemistry and western blotting during development
      from embryonic day 21 to the adult stage of 75 days. The immunohistochemical NOS
      II expression pattern was related to the physiological metabolic fibre types SO
      (slow-oxidative), FOG I, II (fast-oxidative glycolytic; I more glycolytic, II
      more oxidative) and FG (fast-glycolytic) and to the myosin-based fibre types I
      and IIA, IIB (IIX not separated) identified in serial sections by enzyme
      histochemistry and immunohistochemistry. In adult muscles only the small
      population of FOG II fibres, which is a part of both IIA and IIB fibre
      population, showed NOS II immunoreactivity. This is the reason that only weak NOS
      II expression in adult hindlimb muscles has been detected by western blotting.
      Hindlimb muscles of embryonic, neonatal and young rats of 8 days expressed more
      NOS II as compared with adult rat hindlimb muscles. This can be explained by the
      findings that before the age of 21 days fast fibres were metabolically
      undifferentiated, all of them were NOS II positive and contribute to the NOS II
      expression of the muscle. In muscles of diabetic rats the NOS II expression was
      elevated indicating an inhibition of glucose uptake into the muscle fibres of
      diabetic muscles. Our findings suggest that the NOS II may be designated both as
      constitutive and inducible.

PMID- 12432449
TI  - In vivo response of neutrophils and epithelial cells to lipopolysaccharide
      injected into the monkey ileum.
AB  - Since few previous studies have investigated the in vivo response of intestinal
      mucosa to the luminally administered lipopolysaccharide (LPS), we examined the
      cellular localization of exogenously applied LPS in the intestinal mucosa and the
      expression of Toll-like receptor (TLR) and IL-1 receptor-associated kinase (IRAK)
      in the epithelial cells of monkey ileum. FITC-labeled LPS was injected into the
      lumen of monkey ileum. Thirty minutes after the LPS injection, the ileal tissue
      was fixed and localization of FITC fluorescence in the ileal mucosa was examined.
      We applied Factor C immunohistochemistry to demonstrate the bioactivity of LPS
      taken up by the mucosal tissue. The expression of TLR4 and IRAK-1 in the
      epithelial cells was also examined by immunohistochemistry. FITC fluorescence was
      detected in the cells migrated into the epithelium and those in the lamina
      propria. The FITC-labeling cells were completely overlapped with the Factor C
      immunoreactive cells. These FITC-labeling/Factor C-positive cells were identified
      as neutrophils by the immunoelectron microscopic analysis. TLR4 and IRAK-1 were
      expressed at the apical membrane of the epithelial cells in the ileum of both
      control and FITC-LPS injected animals. These results suggest that intraluminal
      injection of LPS stimulates the transmigration of neutrophils into the epithelium
      and these neutrophils may uptake luminally applied LPS and possibly inactivate
      the enterotoxin. Expression of TLR4 and IRAK-1 in the epithelial cells suggests
      that epithelial cells may react to LPS and produce chemoattractant mediator to
      induce the neutrophil chemotaxis.

PMID- 12432450
TI  - Cleared extrachromosomal domain (CED): a nuclear domain enriched in nuclear
      matrix filaments is a common structure in sturgeon podocytes.
AB  - The cell nucleus is divided into chromosome territories and the extrachromosomal
      domain. The latter includes several structural and functional compartments
      involved in RNA processing and transport. Morphological and cytochemical analyses
      of the cell nucleus in sturgeon podocytes revealed the existence of a previously
      uncharacterised nuclear compartment. It appears as a cleared nucleoplasmic area
      of variable size within the extrachromosomal domain. Conventional light and
      electron microscopy revealed that this compartment, here referred to as cleared
      extrachromosomal domain (CED), appears free of chromatin and RNA-containing
      organelles and is closely surrounded by heterochromatin masses. Cytochemical and
      immunogold electron microscope studies indicated that CEDs lack DNA, RNA and
      glycoconjugates. The ultrastructural examination of Lowicryl-embedded sections
      showed that CEDs are formed by a fibrillar network. In resinless preparations,
      this network appears as a dense mesh of crosslinked nuclear matrix filaments. The
      density of nuclear matrix filaments within the CED is remarkably higher than that
      observed in the rest of the nucleus. Our results indicate that the CED is a
      single, distinct extrachromosomal domain of the nuclear matrix of sturgeon
      podocytes. The absence in the CED of detectable DNA and RNA, as well as the lack
      of chromatin and RNA-containing structures, suggests that transcription and RNA
      processing do not occur in this novel nuclear compartment. The volume occupied by
      the CED may preserve the volume-to-cytoplasm ratio in the podocyte and contribute
      to modulate the spatial organisation and the volume occupied by the chromosomal
      territories.

PMID- 12432451
TI  - Expression of NDRG1, a differentiation-related gene, in human tissues.
AB  - NDRG1 is a member of the new N-myc downregulated gene (NDRG) family which belongs
      to the alpha/beta hydrolase superfamily, but without presenting a hydrolytic
      catalytic site. Diverse physiological and pathological conditions (hypoxia,
      cellular differentiation, heavy metal, N-myc, neoplasia) modulate NDRG1
      transcription, mRNA stability, and translation. In this report we present the
      immunohistochemical localization of NDRG1 in a large set of normal human tissues
      at light and electron microscopic levels. The immunoreactivity of NDRG1 is mostly
      found in epithelial cells with different aspects. We observed NDRG1 primarily in
      the cytoplasm, but it is also associated with the cellular membrane and adherens
      junctions. Given the strong upregulation of NDRG1 under hypoxia and its nuclear
      localization, we propose a role for NDRG1 in protection from ischemic cell
      damage. The multiple localizations of this protein also suggest pleiotropic
      functions amongst which a functional involvement in the E-cadherin/catenin
      complex.

PMID- 12432452
TI  - Change in expression of a 90-kDa glycoprotein GP90-MC301 during prenatal and
      postnatal testicular development: a differentiation marker for rat germ cells.
AB  - GP90-MC301, a 90-kDa glycoprotein recognized by the monoclonal antibody MC301, is
      a reliable stage-specific marker for preleptotene to pachytene spermatocytes in
      adult rat testes. In this study we confirmed that the glycoprotein is also useful
      as a marker for germ cells in prenatal and postnatal testes. Immunohistochemical
      analysis showed a dramatic change in GP90-MC301 expression in germ cells during
      testis development. Strong expression was detected in primordial germ cells at
      embryonic day (E) 13 and in gonocytes at E16, and the expression was then
      markedly reduced at around the time (E18) gonocytes undergo G1/G0 arrest, and was
      not restored in gonocytes or spermatogonia afterward. Thereafter, it reappeared
      in primary spermatocytes in the prepubertal period. Testicular somatic cells such
      as Sertoli cells, Leydig cells, and peritubular myoid cells expressed GP90-MC301
      during specific periods which were largely correlated with periods of active
      proliferation of these testicular somatic cells. Western blotting showed that
      GP90-MC301 was expressed during testis development without a change in its
      molecular size. Thus, GP90-MC301 is potentially useful for the analysis of not
      only spermatogenesis but also early testis development.

PMID- 12432453
TI  - The proliferation marker pKi-67 becomes masked to MIB-1 staining after expression
      of its tandem repeats.
AB  - The Ki-67 antigen, pKi-67, is one of the most commonly used markers of
      proliferating cells. The protein can only be detected in dividing cells (G(1)-, S
      , G(2)-, and M-phase) but not in quiescent cells (G(0)). The standard antibody to
      detect pKi-67 is MIB-1, which detects the so-called 'Ki-67 motif' FKELF in 9 of
      the protein's 16 tandem repeats. To investigate the function of these repeats we
      expressed three of them in an inducible gene expression system in HeLa cells.
      Surprisingly, addition of a nuclear localization sequence led to a complete
      absence of signal in the nuclei of MIB-1-stained cells. At the same time
      antibodies directed against different epitopes of pKi-67 did not fail to detect
      the protein. We conclude that the overexpression of the 'Ki-67 motif', which is
      present in the repeats, can lead to inability of MIB-1 to detect its antigen as
      demonstrated in adenocarcinoma tissue samples. Thereafter, in order to prevent
      the underestimation of Ki-67 proliferation indices in MIB-1-labeled preparations,
      additional antibodies (for example, MIB-21) should be used. Additionally, we
      could show in a mammalian two-hybrid assay that recombinant pKi-67 repeats are
      capable of self-associating with endogenous pKi-67. Speculating that the tandem
      repeats are intimately involved in its protein-protein interactions, this offers
      new insights in how access to these repeats is regulated by pKi-67 itself.

PMID- 12432454
TI  - Deformation of lipid droplets in fixed samples.
AB  - Nile red, Sudan III, and oil red O have been used to stain lipid droplets (LDs)
      for fluorescence microscopy. We noticed that LDs labeled by Nile red are
      different in appearance from those stained by the latter two dyes. To understand
      the cause of the difference, we used sequential labeling procedures (first LD
      stain-photography-quenching-second LD stain-photography), and examined the effect
      of several factors. Immunofluorescence labeling for adipose differentiation
      related protein (ADRP), an LD marker, was also observed comparatively with the
      lipid stains. As a result, we found that ethanol and isopropanol used for Sudan
      III and oil red O staining, respectively, and glycerol used for mounting, cause
      fusion of adjacent LDs even in glutaraldehyde-fixed samples. By the same
      treatment, immunofluorescence labeling for ADRP was dislocated to the rim of
      large LDs that were formed as a result of the artifactual fusion. The result
      indicates that the LD structure can be better observed with Nile red than with
      Sudan III or oil red O.

PMID- 12432455
TI  - Characterization of Cr(VI)-resistant bacteria isolated from chromium-contaminated
      soil by tannery activity.
AB  - Bacterial strains, previously isolated from a chromium-polluted soil, were
      identified on the basis of Gram reaction and biochemical characteristics (Biolog
      system). Moreover, chromate MICs, chromate reduction capability, multiple heavy
      metal tolerance, and antibiotic susceptibility were tested for each isolate. All
      strains but one were Gram-positive and resistant to high concentrations of
      chromate. The most Cr(VI)-resistant isolate (22m M) was identified as
      Corynebacterium hoagii. All Cr(VI)-resistant strains except the isolate ChrC20
      were capable of catalyzing the reduction of Cr(VI) to Cr(III), a less toxic and
      less water-soluble form of chromium. The only isolate Cr(VI)-sensitive,
      attributed to the Pseudomonas genus, also exhibited Cr(VI)-reduction. Isolates
      were also screened for the presence of plasmid DNA. The strains ChrC20 and ChrB20
      harbored one and two plasmids of high molecular mass, respectively. This approach
      permitted selection of some bacterial strains, which could be used for
      bioremediation of Cr(VI)-polluted environments.

PMID- 12432456
TI  - Ecophysiological variabilities in ectohydrolytic enzyme activities of some
      Pseudoalteromonas species, P. citrea, P. issachenkonii, and P. nigrifaciens.
AB  - The ecophysiological variabilities in the ectohydrolytic enzyme profiles of the
      three species of Pseudoalteromonas, P. citrea, P. issachenkonii, and P.
      nigrifaciens, have been investigated. Forty-one bacteria isolated from several
      invertebrates, macroalgae, sea grass, and the surrounding water exhibited
      different patterns of hydrolytic enzyme activities measured as the hydrolysis of
      either native biopolymers or fluorogenic substrates. The activities of the
      following enzymes were assayed: proteinase, tyrosinase, lipase, amylase,
      chitinase, agarase, fucoidan hydrolase, laminaranase, alginase, pustulanase,
      cellulase, beta-glucosidase, alpha- and beta-galactosidases, beta-N
      acetylglucosaminidase, beta-glucosaminidase, beta-xylosidase, and alpha
      mannosidase. The occurrence and cell-specific activities of all enzymes varied
      over a broad range (from 0 to 44 micromol EU per hour) and depended not only on
      taxonomic affiliation of the strain, but also on the source/place of its
      isolation. This suggests 'specialization' of different species for different
      types of polymeric substrates as, for example, all strains of P. citrea and P.
      issachenkonii hydrolyzed alginate and laminaran, while strains of P. nigrifaciens
      were lacking the ability to hydrolyze most of the algal polysaccharides. The
      incidence of certain enzymes such as fucoidan hydrolases, alginate lyases,
      agarases, and alpha-galactosidases might be strain specific and reflect its
      particular ecological habitat.

PMID- 12432457
TI  - Herpetomonas samuelpessoai: dimethylsulfoxide-induced differentiation is
      influenced by proteinase expression.
AB  - In this study, we analyzed the influence of proteinase expression on the cellular
      differentiation of Herpetomonas samuelpessoai. Along cellular differentiation,
      which was induced by dimethylsulfoxide (DMSO), the trypanosomatids secreted
      several molecules with variable proteolytic activity. All of them were inhibited
      by 10 m M 1,10-phenanthroline, suggesting that they are zinc-metalloproteinases.
      Analysis of parasite extracts revealed the occurrence of a 63-kDa
      metalloproteinase and a 45-kDa cysteine proteinase. After extraction with Triton
      X-114 followed by water-detergent partition, the 63-kDa component was present in
      both aqueous and detergent phases, which indicated that this enzyme may be
      distributed over different cellular compartments including membrane domains. The
      45-kDa component, however, presented hydrophilic properties and was predominantly
      expressed by DMSO non-treated parasites, suggesting that proteinases may be
      involved in the process of cellular differentiation in H. samuelpessoai. This was
      confirmed by the fact that a cysteine proteinase inhibitor abrogated parasite
      differentiation. The role of proteinases and their relevance in the
      differentiation of H. samuelpessoai are discussed.

PMID- 12432458
TI  - Factors affecting the antibacterial activity of the ruminal bacterium,
      Streptococcus bovis HC5.
AB  - Streptococcus bovis HC5 inhibits a variety of S. bovis strains and other Gram
      positive bacteria, but factors affecting this activity had not been defined.
      Batch culture studies indicated that S. bovis HC5 did not inhibit S. bovis JB1 (a
      non-bacteriocin-producing strain) until glucose was depleted and cells were
      entering stationary phase, but slow-dilution-rate, continuous cultures (0.2 h(
      1)) had as much antibacterial activity as stationary-phase batch cultures.
      Because the activity of continuous cultures (0.2-1.2 h(-1)) was inversely related
      to the glucose consumption rate, it appeared that the antibacterial activity was
      being catabolite repressed by glucose. When the pH of continuous cultures (0.2 h(
      1)) was decreased from 6.7 to 5.4, antibacterial activity doubled, but this
      activity declined at pH values less than 5.0. Continuous cultures (0.2 h(-1))
      that had only ammonia as a nitrogen source had antibacterial activity, and large
      amounts of Trypticase (10 mg ml(-1)) caused only a 2.0-fold decline in the amount
      of HC5 cell-associated protein that was needed to prevent S. bovis JB1 growth.
      Because S. bovis HC5 was able to produce antibacterial activity over a wide range
      of culture conditions, there is an increased likelihood that this activity could
      have commercial application.

PMID- 12432459
TI  - Effects of carboxymethylcellulose and carboxypolymethylene on morphology of
      Aspergillus fumigatus NRRL 2346 and fumagillin production.
AB  - Aspergillus fumigatus NRRL 2346 is the producer of fumagillin, an antitumor
      antibiotic that inhibits angiogenesis. This strain is very difficult to grow
      reproducibly in shake flasks owing to an extreme form of pellet growth and
      extensive wall growth. The effects of carboxymethylcellulose (CMC) and
      carboxypolymethylene (Carbopol) on growth and fumagillin production by A.
      fumigatus were investigated. By adding the polymers to the fermentation medium,
      the growth form of the mold was changed from a single large glob to small
      reproducible pellets, and wall growth was diminished to a minimum. Carbopol, at a
      lower concentration, was more effective than CMC in improving both morphology and
      production. Small pellets were produced which favored fumagillin biosynthesis.
      1.5% (wt/vol) CMC and 0.3% (wt/vol) Carbopol were found to be the optimum
      concentrations; higher levels increased viscosity to an unacceptable level.

PMID- 12432460
TI  - Biofilm formation and biocide susceptibility testing of Mycobacterium fortuitum
      and Mycobacterium marinum.
AB  - The ability of non-tuberculous mycobacteria to form biofilms may allow for their
      increased resistance to currently used biocides in medical and industrial
      settings. This study examines the biofilm growth of Mycobacterium fortuitum and
      Mycobacterium marinum, using the MBEC trade mark assay system, and compares the
      susceptibility of planktonic and biofilm cells to commercially available
      biocides. With scanning electron microscopy, both M. fortuitum and M. marinum
      form biofilms that are morphologically distinct. Biocide susceptibility testing
      suggested that M. fortuitum biofilms displayed increased resistance over their
      planktonic state. This is contrasted with M. marinum biofilms, which were
      generally as or more susceptible over their planktonic state.

PMID- 12432461
TI  - Cloning and characterization of two novel crystal protein genes from a Bacillus
      thuringiensis serovar dakota strain.
AB  - Two genes encoding the 32- and 40-kDa polypeptides of Bacillus thuringiensis
      strain 90-F-45-14 crystals were cloned, expressed in an acrystalliferous B.
      thuringiensis strain, and sequenced. The polypeptides had deduced molecular
      weights of 30,319 and 33,885, respectively. The amino acid sequence of the 32-kDa
      protein was 37.7% identical to the known sequence of a non-insecticidal
      parasporal protein in B. thuringiensis serovar thompsoni crystals. The sequence
      of the cloned 40-kDa protein was 37.0% and 22.3% identical to that of the
      existing Cry protein classes, Cry15Aa1 and Cry23Aa1, respectively. Thus, this
      protein constitutes a novel protein class, Cry33Aa1. The open reading frames of
      the two genes were located on the predominant plasmid of 17,629 bp (=11,752 MDa)
      in the same orientation, and they were separated by the sequence of 32
      nucleotides. The two proteins are likely produced simultaneously from a single
      transcript to form spherical crystals.

PMID- 12432462
TI  - Naphtho[1,2- b]thiophene degradation by Pseudomonas sp. HKT554: involvement of
      naphthalene dioxygenase.
AB  - Pseudomonas sp. strain HKT554 degrades naphtho[1,2- b]thiophene and two other
      isomers, naphtho[2,1- b]thiophene and naphtho[2,3- b]thiophene, by cometabolism,
      in the absence of any specific inducer, at similar degradation rates. A mutant of
      strain HKT554, deficient in dibenzothiophene degradation, was generated by using
      a recently developed transposition system. Sequence analysis of the mutant
      revealed that the knocked out gene was almost identical to naphthalene
      dioxygenase (EC 1.14.12.12). The mutant, HKT554M, degraded neither the
      naphthothiophene isomers nor dibenzothiophene, suggesting that the naphthalene
      dioxygenase is responsible for the initial catabolic reactions onto
      naphthothiophenes and dibenzothiophene.

PMID- 12432463
TI  - Mannose-specific lectin activity of parasporal proteins from a lepidoptera
      specific Bacillus thuringiensis strain.
AB  - Lectin activity, agglutinating sheep erythrocytes, was associated with parasporal
      inclusion proteins from a Lepidoptera-specific isolate of Bacillus thuringiensis
      serovar galleriae (H5ab). The activity was generated when parasporal inclusions
      were solubilized in an alkaline condition. Proteolytic processing was not
      required for generation of the lectin activity; the activity level was not
      affected by the presence/absence of the three proteases (trypsin, chymotrypsin,
      and proteinase K). SDS-PAGE analysis revealed that (1) alkali-solubilized
      parasporal inclusion proteins consisted of two major components of 130 kDa and 65
      kDa, and (2) proteinase K treatment of alkali-solubilized proteins yielded a
      single major protein of 60 kDa. Lectin activity of our isolate was strongly
      inhibited by preincubation with D-mannose, but not with the six other
      monosaccharides: D-galactose, D-glucose, L-fucose, N-acetyl- D-glucosamine, N
      acetyl- D-galactosamine, and N-acetylneuraminic acid. In contrast, D-mannose did
      not inhibit the in vivo larvicidal activity of the proteins against the silkworm,
      Bombyx mori.

PMID- 12432464
TI  - Degradation of cinnamate via beta-oxidation to benzoate by a defined, syntrophic
      consortium of anaerobic bacteria.
AB  - A syntrophic consortium was enriched in a basal medium containing cinnamate as
      the carbon and energy source. It was found to consist of three morphologically
      distinct microbes, viz., a short, rod-shaped, non-motile bacterium with
      distinctly pointed ends, Papillibacter cinnamivorans; a rod-shaped, motile
      bacterium with rounded ends, Syntrophus sp.; and a methanoarchaeon,
      Methanobacterium sp. This methanogen was then replaced by a collection strain of
      Methanobacterium formicicum. A syntrophic interdependency of the three partners
      of the consortium was observed during growth on cinnamate. In the presence of
      bromoethanesulfonic acid (BESA), cinnamate was transformed to benzoate, whereas
      under methanogenic conditions without BESA, cinnamate was first transformed to
      benzoate via beta-oxidation and subsequently completely degraded into acetate,
      CH(4), and CO(2). Papillibacter cinnamivorans was responsible for benzoate
      production from cinnamate, whereas a syntrophic association between Syntrophus
      sp. and the methanogen degraded benzoate to acetate, CH(4), and CO(2). A new
      anaerobic degradation pathway of cinnamate into benzoate via beta-oxidation by a
      pure culture of P. cinnamivorans is proposed.

PMID- 12432465
TI  - Methanogenic activity in human periodontal pocket.
AB  - Samples of subgingival dental tissues were examined for the presence of
      methanogenic activities. Using enrichment cultures, methanogenic activities were
      detected in 9 of 17 individuals. A mesophilic, Gram-positive, irregular coccoid
      methanogen, which showed close resemblance to a Methanosarcina sp., was isolated
      from one sample collected from a patient with type IV periodontal pocket (the
      periodontal pocket is a space bounded by the tooth on one side and by ulcerated
      epithelium lining the soft tissue wall on the other). The isolate used methanol,
      methylamine, acetate, and H(2)-CO(2) as the sole source of carbon. However, the
      isolate was unable to use formate and trimethylamine as growth substrates. The
      organism had an optimum pH of 6.5 and an optimum temperature of 37 degrees C. The
      isolate not only used ammonia, but also used nitrate as a nitrogen source. The
      niche of this methanogen in periodontal pockets may be to carry out terminal
      oxidation of simple organic compounds such as methanol and acetate produced by
      other obligate anaerobes present in periodontal pockets. This methanogen may also
      play a vital role in interspecies hydrogen transfer, as demonstrated by its use
      of H(2)-CO(2) as a substrate. The isolate produced significant amount of methane
      in vitro.

PMID- 12432466
TI  - Regulation of potassium uptake in the sodium-resistant (NaCl(r)) and thalium
      resistant (TlCl(r)) mutant strain of diazotrophic cyanobacterium Anabaena
      variabilis.
AB  - A thalium chloride-resistant (TlCl(r)) mutant strain and a sodium chloride
      resistant (NaCl(r)) mutant strain of the diazotrophic cyanobacterium Anabaena
      variabilis have been isolated by spontaneous and chemical mutagenesis by using
      TlCl, a potassium (K(+)) analog, and nitrosoguanidine (NTG), respectively. The
      TlCl(r) mutant strain was found to be defective in K(+) transport and showed
      resistance against 10 microM TlCl. However, it also showed sensitivity against
      NaCl (LD(50), 50 m M). In contrast, neither wild-type A. variabilis nor its
      NaCl(r) mutant strain could survive in the presence of 10 microM TlCl and died
      even at 1 microM TlCl. The TlCl(r) mutant strain exhibited almost negligible K(+)
      uptake, indicating the lack of a K(+) uptake system. High K(+) uptake was,
      however, observed in the NaCl(r) mutant strain, reflecting the presence of an
      active K(+) uptake system in this strain.DCMU, an inhibitor of PS II, inhibited
      the K(+) uptake in wild-type A. variabilis and its TlCl(r) and NaCl(r) mutant
      strains, suggesting that K(+) uptake in these strains is an energy-dependent
      process and that energy is derived from photophosphorylation. This contention is
      further supported by the inhibition of K(+) uptake under dark conditions.
      Furthermore, the inhibition of K(+) uptake by KCN, DNP, and NaN(3) also suggests
      the involvement of oxidative phosphorylation in the regulation of an active K(+)
      uptake system. The whole-cell protein profile of wild-type A. variabilis and its
      TlCl(r) and NaCl(r) mutant strains growing in the presence of 50 m M KCl was made
      in the presence and absence of NaCl. Lack of transporter proteins in TlCl(r)
      mutant strain suggests that these proteins are essentially required for the
      active transport and accumulation of K(+) and make this strain NaCl sensitive. In
      contrast, strong expression of the transporter proteins in NaCl(r) mutant strain
      and its weak expression in wild-type A. variabilis is responsible for their
      resistance and sensitivity to NaCl, respectively. Therefore, it appears that the
      increased salt tolerance of the NaCl(r) mutant strain was owing to increased K(+)
      uptake and accumulation, whereas the salt sensitivity of the TlCl(r) mutant
      strain was owing to the lack of K(+) uptake and accumulation.

PMID- 12432467
TI  - Metabolism of DDT [1,1,1-Trichloro-2,2-bis(4-chlorophenyl)ethane] by Alcaligenes
      denitrificans ITRC-4 under aerobic and anaerobic conditions.
AB  - An isolated bacterium, Alcaligenes denitrificans ITRC-4, metabolizes 1,1,1
      trichloro-2,2-bis(4-chlorophenyl)ethane (DDT) under both aerobic and anaerobic
      conditions. The aerobic metabolism is inhibited by 38% and 47% in the presence of
      1.0 g L(-1) of sodium acetate and sodium succinate, respectively, but remains
      uninhibited in the presence of 1.0 g L(-1) of glucose. Also, the metabolism is
      inhibited completely in the presence of biphenyl vapors, as well as 0.8 g L(-1)
      of 2,2'-bipyridyl. Under anaerobic conditions, DDT is metabolized into 1,1
      dichloro-2,2-bis(4-chlorophenyl)ethane (DDD), which is further enhanced by 50% in
      the presence of 1.0 g L(-1) of glucose. Besides, the bacterium also metabolizes 4
      chlorobenzoate, which is accompanied by the release of chloride ions.

PMID- 12432468
TI  - Role for the cyanobacterial HtpG in protection from oxidative stress.
AB  - The heat shock protein HtpG, which is a homolog of HSP90, is essential for basal
      and acquired thermotolerances in cyanobacteria. Recently we demonstrated that
      HtpG was involved in the acclimation to low temperatures in cyanobacteria. In
      this study, we elucidated a role of HtpG in the cyanobacterium Synechococcus sp.
      PCC 7942, in the acclimation to oxidative stress that was caused by high
      irradiance and/or methyl viologen. The inactivation of the htpG gene resulted in
      a decrease in the survival rate and an increase in the photoinhibition of
      photosystem II when cells in a liquid medium were incubated under high light
      conditions. The htpG mutant was highly sensitive to methyl viologen when it was
      grown on an agar plate. High irradiance and/or methyl viologen greatly increased
      the expression of the htpG gene as well as the groEL gene in the wild-type
      strain. Taken together, our results suggest that HtpG may play a role by itself
      or with other molecular chaperones in the acclimation to oxidative stress.

PMID- 12432469
TI  - Refinements in rejuvenative facial lipomorphoplasty.
AB  - Facial planes and pilasters are introduced, defined, and classified. Their
      progressive changes in robustness, shape, and direction with age are
      demonstrated. These changes in the pilasters result largely from age-related fat
      atrophy which also leads to a structural volume deficit and chronic muscle
      action. Restoration of the pilasters to a more youthful position, shape,
      direction, and robustness enhances the results of rejuvenative facial
      lipomorphoplasty achieved by correction of the structural volume deficit in the
      early stages of aging.

PMID- 12432470
TI  - Laser lipolysis: flaccidity under control.
AB  - An innovative liposuction technique using a laser device is presented. It is a
      precise method, less traumatic than the conventional one. The interaction between
      the laser and the adipocyte causes lipolysis with reduced bleeding and its effect
      on collagen tone promotes collagen retraction and skin shrinkage. The results of
      the use of laser lipolysis on flaccid areas or in areas with the potential for
      flaccidity are shown. The resulting skin retraction and the pathologic anatomy
      confirm these claims.

PMID- 12432471
TI  - A new, T-shaped adaptor for easy, quick and efficient fat harvesting during
      liposuction.
AB  - Although there is a controversy about success and failure of autologous fat
      tissue transfers, it is a widely accepted method for soft tissue augmentation and
      is performed by many plastic surgeons as well as dermatologists all around the
      world. Its advantages are that it does not cause reactions, its absorption rates
      have been reduced by increased knowledge, experience, and techniques, it can
      yield good, long-term results, and there are now preservation techniques that
      allow reinjections when necessary. However, no single ideal technique has been
      determined. In this paper a new, simple, T-shaped adaptor for easy, quick, and
      efficient fat harvesting during liposuction is described. This study not only
      describes the clinical use of the adaptor, but also histologically examines its
      effects on fat cells under various vacuum pressures (-250 mmHg, -500 mmHg, -700
      mmHg). The study shows that the cell structure of fat tissue harvested under
      medium power (with vacuum pressures of -250 mmHg and -500 mmHg) is not disrupted,
      while that of tissue harvested with a vacuum pressure of -700 mmHg was
      traumatized and occasional cell wall fragmentation occurred. In conclusion, it is
      shown that the T-shaped adaptor allows harvesting of the desired amount of fat
      tissue without causing trauma to fat cells when it is used with medium-power
      suction.

PMID- 12432472
TI  - Soft tissue composition in upper leg lipodystrophy: application of dual energy x
      ray absorptiometry.
AB  - Liposuction is a safe procedure for removal of subcutaneous fat in patients with
      upper leg lipodystrophy. We present a young woman with lipodystrophy of upper leg
      who underwent ultrasound-assisted three-dimensional suction lipectomy. The aim of
      the study was to determine the amount of fat to be removed before liposuction and
      to evaluate soft tissue composition before and after liposuction. At the initial
      meeting and four months later, body composition parameters were examined by dual
      X-ray absorptiometry (DXA), which produced a precise assessment of regional fat
      distribution. The baseline DXA measurements revealed excess of fat tissue for the
      lateral regions of the right and left legs, and for the area from the waist to
      hip. After liposuction of established amount of tissue, the same measurements
      revealed a decrease of fat tissue in all three regions, whereas no significant
      differences were observed for lean mass. We concluded that the suction lipectomy
      produced decrease in the fat mass of legs without musculature damage. The DXA
      technique can be useful in predicting fat removal before suction lipectomy and in
      estimating changes in soft tissue composition after surgical treatment.

PMID- 12432473
TI  - Considerations on anthropometric measurements of the female breast.
AB  - Anthropometric measurements of the breasts and their relevant position taken from
      fixed skeletal points provide a useful tool in the accurate evaluation of
      patients preoperatively and the assessment of surgical results. This paper
      presents the clinical correlation obtained by statistical analysis of the results
      of measurements of 973 women.

PMID- 12432474
TI  - Long-term prospective follow-up of botulinum toxin treatment for facial rhytides.
AB  - Some wrinkles and unsightly facial expressions are due to hyperactivity of the
      underlying facial musculature. Clostridium botulinum type A exotoxin reversibly
      paralyzes selected muscles and is a safe, helpful adjunct to many other
      treatments for facial rejuvenation. Fifty-two patients were treated and all data
      recorded in a prospective fashion. Only areas requested by the patient were
      treated. The dosage and dilution given in each area were carefully noted and all
      patients had pretreatment and posttreatment photographs. The effect of botulinum
      toxin injections on the horizontal brow rhytides was recorded by measuring the
      distance from the frontal hairline to the superior edge of the eyebrow in the mid
      pupillary line. Patients were followed for one to three years (mean 16.3 months).
      One patient was not responsive to botulinum toxin in spite of repeated
      injections. Three further patients required touch-up injections two weeks after
      the initial treatment due to a weak initial response. Repeat injections were
      required every three to six months (mean 4.05) to maintain the desired
      improvement. Asymmetry of the brow was seen in two patients and corrected with
      further administration of botulinum toxin. Twenty-five patients had their
      forehead rhytides injected and the appropriate measurements taken. Brow ptosis
      occurred in 22 of the 25 patients and varied 1-6 mm with a mean value of 2.3 mm.
      This difference was statistically significant (paired t-test p <0.001). Two
      patients reported dryness and flakiness of the frontal area after injections. No
      cases of eyelid ptosis or hypersensitivity were seen. Botulinum toxin injections
      are safe and all undesired effects are reversible. Great care has to be taken not
      to aggravate the degree of brow ptosis. Injection of the forehead depressors
      minimizes the risk of brow ptosis. Careful planning of injection sites and doses
      avoids a mask-like upper face. The use of botulinum toxin provides a useful
      adjunct to laser and surgical procedures for facial rejuvenation.

PMID- 12432475
TI  - Usefulness and limitations of artificial dermis implantation for posttraumatic
      deformity.
AB  - We have previously reported the use of artificial dermis implantation to cover
      exposed major vessels and to correct a depressed region after tissue resection
      and bone deformity with satisfactory results. In this paper, we present cases
      with depressed lesions and adhesive lesions after trauma, treated with artificial
      dermis implantation. Artificial dermis (Terudermis, Terumo Co. Ltd., Tokyo,
      Japan) was implanted in 12 cases of posttraumatic deformity. Eight of the 12
      cases involved a depressed lesion, and the other four involved adhesive lesions.
      There was no postoperative infection or allergic reaction in any of the patients.
      Improvement of the deformity was obtained in all cases, but the degree of volume
      reduction in traumatic cases is likely to be more severe than that in the non
      traumatic cases previously reported. In conclusion, artificial dermis
      implantation is an easy, safe, and useful method to correct a posttraumatic
      deformity, such as a depression or an adhesion, although it is important to note
      that depressions require overcorrection in order to obtain satisfactory results,
      as compared with non-traumatic cases treated with artificial dermis.

PMID- 12432476
TI  - Tranilast as an additional treatment with conservative therapy for concave
      deformity following traumatic hematoma.
AB  - Fibrotic scar tissue resulting from a cheek hematoma sometimes seriously
      contracts to form a concave deformity, despite conservative therapy. We used
      Tranilast as an additional treatment with conservative therapy for four patients
      who were resistant to massage and compression therapy. Four months after oral
      administration of Tranilast, all the deformities were resolved. Tranilast is used
      for the treatment of allergic diseases and keloids. It inhibits the release of
      transforming growth factor b-1, interleukin-1 b, and prostaglandin E2. It also
      suppresses collagen synthesis by fibroblasts.

PMID- 12432477
TI  - Late hematoma after aesthetic breast augmentation with saline-filled, textured
      silicone prosthesis.
AB  - Late, progressive enlargement of the breast after augmentation mammaplasty is an
      extremely rare complication. We present two cases of late capsular hematoma after
      augmentation mammaplasty with saline-filled, textured silicone implants. The MRI
      and C-T scan both clearly showed fluid accumulated within the capsule in one
      case. In this patient, we examined the interior of the fibrous capsule
      endoscopically, finding no persistent bleeding source. However, the inner lining
      had granulated tissue with new capillary ingrowth. After replacement with smooth
      surface prostheses, neither patient had recurrence of the complication. No
      identifiable etiology could be demonstrated, however, the breakdown of an eroded
      capsular artery is suspected, caused by friction between the rough surface of the
      textured prosthesis and the fibrous capsule.

PMID- 12432478
TI  - Unilateral brachial plexus injury occurring after reduction mammaplasty.
AB  - A left neuropraxic brachial plexus injury was seen after reduction mammaplasty.
      The clinical signs of plexopathy were noted in the very early postoperative
      period. The partial axonal damage was heavy in the upper and posterior branches
      and moderate in the medial branch of the plexus. The hyperabduction of the upper
      extremity during the surgery was thought to be the main cause. With a close
      followup and extensive physiotherapy, in addition to B complex vitamins, a full
      recovery was achieved at the end of the tenth week.

PMID- 12432479
TI  - Complications of breast augmentation with injected hydrophilic polyacrylamide
      gel.
AB  - Since 1997, the hydrophilic polyacrylamide gel (PAAG), an injectable alloplastic
      biomaterial, imported from the Ukraine has been used for augmentation mammaplasty
      in China. There were twelve patients with various complications visiting our
      hospitals after breast augmentation with injected hydrophilic polyacrylamide gel
      by other clinics, even though such procedures are not performed in our clinical
      practices. The complications included four cases of PAAG-induced multiple
      induration and lumps, and one with lactation, three cases of hematoma, two cases
      of inflammation (infection), and persistent mastodymia, unsatisfactory contour
      results and abnormal skin sensations in each case. All patients have been treated
      by removing the injected gel and giving antibiotics. Other procedures included
      replacement by silicon breast prostheses, mammotomy, and segmental mastectomy. We
      suggest that the injectable hydrophilic polyacrylamide gel be contraindications
      for breast augmentation in any young female who is not married, or without a
      child, with a tendency to hemorrhage, and with little mammary tissue. Some
      considerations to prevent and manage these complications are discussed.

PMID- 12432480
TI  - Rupture of a silicone gel mammary prosthesis and amyloidosis: a case report.
AB  - There has been a great deal of controversy regarding the safety of silicone
      breast implants. Silicone gel prostheses older than 10 years have the risk of
      either leakage or outright rupture. The role of silicone gel in relation to
      connective tissue disease or amyloidosis has not been proved by current
      serologic, immunologic, or epidemiologic tests. In this paper, we present a case
      with renal amyloidosis and a history of untreated silicone implant rupture for
      five years.

PMID- 12432481
TI  - A new experimental hypertrophic scar model in guinea pigs.
AB  - Many aspects of the biology and effective therapy of proliferative scars remain
      undefined, in part due to a lack of an accurate, practical, reproducible, and
      economical animal model for systematically studying hypertrophic scars. This
      study was designed to investigate whether hypertrophic scar formation could be
      induced in guinea pigs by removal of the panniculus carnosus alone, and by a
      combination of the removal of the panniculus carnosus with application of coal
      tar afterwards. Whole thickness skin excision or deep partial thickness injury
      was used to create the lesions on intact skin. Different anatomic locations were
      tested in different groups. Scars thus developed were examined morphologically by
      light microscopy and electron microscopy (TEM and SEM) and biochemically by
      measuring the activity of glucose-6-phosphate dehydrogenase (G6PD) to check
      whether these scars had morphological and biochemical properties specific to
      hypertrophic scars. The albino guinea pigs used in this study were divided into
      three groups. Removal of the panniculus carnosus was performed from the ventral
      aspect of the torso in animals in groups I and II. On the skin overlying the area
      of panniculectomy, circular skin excision was performed in group I, and deep
      partial thickness burn injury was inflicted in group II, to see whether wounds
      would heal with hypertrophic scars. In group III, dorsal aspect of the torso were
      used and wounds were produced by circular skin excisions followed by
      panniculectomy on both sides but coal tar was applied to only one side. Tissue
      samples were taken from the scars that were hypertrophic in appearance, and from
      normal scars and normal skin for comparison. Light and electron microscopic
      examinations and G6PD activity measurements were performed on these samples.
      While hypertrophic scar development was not seen in group I and group II, scars
      with morphological and biochemical properties specific to hypertrophic scars
      developed in one third of animals in group III after healing of the wounds
      treated with coal tar. In conclusion, it is shown that it is possible to develop
      experimental hypertrophic scars in guinea pigs with morphological and biochemical
      properties similar to those of human proliferative scars. Therefore this model is
      a new, practical, and economical experimental animal model to study proliferative
      scars, although improvements are needed to increase yield.

PMID- 12432482
TI  - Coronary artery disease.
AB  - SUMMARY: Prevention is equivalent to causal treatment of cardiovascular disease.
      Nowadays, guidelines are elaborated on the basis of large-scale long-term
      intervention studies and structured meta-analyses. This review attempts a
      synopsis of guidelines of the American and German Heart Associations. For
      secondary prevention, smoking cessation, blood pressure treatment, dietary lipid
      management, aerobic activity, correct body weight, Mediterranean diet, treatment
      of diabetes to a HbA1c of 7%, ingestion of marine w-3 fatty acids (1 g / day),
      platelet inhibitors, lipid-lowering agents (statins), beta-blockers and ACE
      inhibitors are established. In primary prevention pharmaceutical agents are not
      incorporated, but all non-pharmacological approaches are being recommended. The
      guidelines mentioned are based on unequivocal evidence, risk-benefit and cost
      benefit ratios are good, nevertheless implementation remains a serious problem.
      Primary and secondary prevention are already giving way to risk-adapted
      prevention, based on an individual assessment of a person's cardiovascular risk.

PMID- 12432483
TI  - [Epidemiology of septicaemia pathogens].
AB  - BACKGROUND AND OBJECTIVE: Because of high mortality of septicaemia correct
      initial antimicrobial treatment is essential. Multicentre studies sponsored by
      Paul-Ehrlich-Society provide the necessary epidemiological data. MATERIAL AND
      METHODS: Two institutes from Austria and 20 from Germany participated in this
      third one year study on septicaemia pathogens conducted between September 2000 to
      August 2001. RESULTS: Data on gender, age, hospital, department, ward, pathogen,
      susceptibility pattern, underlying disease and port of entry was collected on
      10,052 pathogens from 9,555 patients and compared with the two studies of 1991/92
      and 1983/85. Spectrum of pathogen has remained constant: E. coli (22.6 %) and S.
      aureus (21.6 %) were most frequent. There was a further reduction in Haemophilus
      (0.3 %) and P. aeruginosa (3.4 %). In comparison to second study the rate of
      pneumococci fell to 3.5 %. There is an increase in resistance to betalactams:
      oxacillin resistance in S. aureus 15 %, coagulase negative staphylococci 68 %;
      resistance to ampicillin, piperacillin, cefazolin in E. coli 77, 43 and 25 %
      respectively. Ciprofloxacin resistance in Enterobacteriaceae is 5 - 15 %. In
      endocarditis 42.8 % of pathogens were non-haemolytic streptococci or enterococci,
      in pulmonary infections 42.5 % were S. aureus or pneumococci, in urosepsis resp.
      abdominal infection 77.2 % resp. 62 % were enterobacteriaceae. In patients with
      diabetes, or intravascular devices, or undergoing haemodialysis S. aureus was
      cultured in 30 - 47 %. CONCLUSION: Demographical parameters are similar. Increase
      is resistance against beta-lactams and ciprofloxacin and rate of MRSA is
      reported.

PMID- 12432484
TI  - [Diabetic ketoacidosis and hyperosmolar hyperglycemia. 24 consecutive cases].
AB  - BACKGROUND: Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemia (HH)
      remain life-threatening complications of diabetes mellitus. Herein, we evaluated
      a standardized protocol for the therapy of acute hyperglycemic crises. PATIENTS
      AND METHODS: Retrospective study of patients treated in a medical intensive care
      unit for acute and severe hyperglycemia. Therapy was standardized according to
      internal guidelines effective for all treating physicians. RESULTS: 24 diabetic
      patients (11 men, 13 women, age 54 +/- 16 years, 11 DKA, 13 HH) were included
      into this study. All except one patient in the DKA-group had diabetes mellitus
      type 1. All patients with HH had diabetes mellitus type 2. Patients with DKA were
      significantly younger and complained more often about nausea and vomiting
      compared to the HH-group. Infections were the major cause for acute hyperglycemia
      followed by non-compliance. The arterial pH-value in the DKA-group was lower than
      in the HH-group (7,07 +/- 0,12 vs. 7,36 +/- 0,05). The length of stay in the
      intensive care unit was 1,8 +/- 1,2 days in patients with DKA and 2,2 +/- 1,2
      days in patients with HH. The length of stay in the hospital was 11,5 +/- 5,9
      days in patients with DKA and 18,3 +/- 10,9 days in patients with HH. No patient
      died during hospitalization. CONCLUSION: This study emphasizes the relevance of
      standardized written guidelines for the therapy of acute hyperglycemic crises in
      diabetic patients.

PMID- 12432485
TI  - [The "needle man": more than 40,000 injections in 40 years].
AB  - HISTORY AND ADMISSION FINDINGS: A now 65-year-old man had undergone a subtotal
      thyroidectomy over 40 years ago, which postoperatively resulted in
      hypoparathyroidism. His doctor began daily intravenous injections of a calcium
      preparation (1880 mg to 3760 mg calcium per day, over 40000 injections during
      this period), a regimen continued subsequently by a total of more than 15 other
      doctors for over 40 years. On admission the patient complained of oral
      paresthesias and paresthesias of the limbs. INVESTIGATIONS: Low calcium and
      parathormone levels confirmed the diagnosis of hypoparathyroidism. TREATMENT AND
      COURSE: Normal levels of calcium were achieved after a short course of 1.25
      dihydroxycalciferol. This was followed by the administration of cholecalciferol
      and calcium. The patient soon became symptom-free and calcium levels returned to
      normal. Late sequelae have been calcification of the basal ganglia, first signs
      of nephrocalcinosis and bilateral cataract. CONCLUSION: This case demonstrates
      that appropriate treatment of hypoparathyroidism [corrected] might not be given
      in every case.

PMID- 12432486
TI  - [Transgenic plants--principle and medical relevance].

PMID- 12432487
TI  - [Sensible disinfection in the hospital].

PMID- 12432488
TI  - [Treatment of chronic heart failure with beta-adrenoceptor antagonists. Guideline
      based optimization with ERICA, a quality register].

PMID- 12432489
TI  - [How should eosinophilic gastroenteropathy be treated?].

PMID- 12432490
TI  - [How is antianginal therapy with pentaerythritol tetranitrate executed?].

PMID- 12432491
TI  - [Acute hepatitis A despite combined vaccination against hepatitis A and B--re the
      article from DMW 30/2002, page 1581-3].

PMID- 12432492
TI  - [Myocarditis caused by enteroviruses in Greece--and in Germany?--re the article
      from DMW 25-26/2002, page 1364].

PMID- 12432493
TI  - [South of the Alps is also an early summer meningoencephalitis endemic area--re
      the article from DMW 10/2002, page 487].

PMID- 12432496
TI  - Thiamin-diphosphate-dependent enzymes: new aspects of asymmetric C-C bond
      formation.
AB  - Starting from a thorough investigation of mechanistic aspects of ThDP-dependent
      (ThDP = thiamin diphosphate) enzymes in combination with mutagenesis studies and
      a detailed substrate screening, new general synthetic methods have been developed
      based on Umpolung reactions by thiamin catalysis. A selective donor-acceptor
      concept was established leading to the first asymmetric cross-benzoin
      condensation, and a kinetic racemic resolution through C-C bond cleavage was
      developed. With these tools and in combination with protein engineering, we
      approached the synthesis of new chiral building blocks on a preparative scale. An
      outlook is given with respect to the potential of other ThDP-dependent enzymes as
      catalysts in asymmetric synthesis.

PMID- 12432495
TI  - Male mouse recombination maps for each autosome identified by chromosome
      painting.
AB  - Linkage maps constructed from genetic analysis of gene order and crossover
      frequency provide few clues to the basis of genomewide distribution of meiotic
      recombination, such as chromosome structure, that influences meiotic
      recombination. To bridge this gap, we have generated the first cytological
      recombination map that identifies individual autosomes in the male mouse. We
      prepared meiotic chromosome (synaptonemal complex [SC]) spreads from 110 mouse
      spermatocytes, identified each autosome by multicolor fluorescence in situ
      hybridization of chromosome-specific DNA libraries, and mapped >2,000 sites of
      recombination along individual autosomes, using immunolocalization of MLH1, a
      mismatch repair protein that marks crossover sites. We show that SC length is
      strongly correlated with crossover frequency and distribution. Although the
      length of most SCs corresponds to that predicted from their mitotic chromosome
      length rank, several SCs are longer or shorter than expected, with corresponding
      increases and decreases in MLH1 frequency. Although all bivalents share certain
      general recombination features, such as few crossovers near the centromeres and a
      high rate of distal recombination, individual bivalents have unique patterns of
      crossover distribution along their length. In addition to SC length, other, as
      yet-unidentified, factors influence crossover distribution leading to hot regions
      on individual chromosomes, with recombination frequencies as much as six times
      higher than average, as well as cold spots with no recombination. By reprobing
      the SC spreads with genetically mapped BACs, we demonstrate a robust strategy for
      integrating genetic linkage and physical contig maps with mitotic and meiotic
      chromosome structure.

PMID- 12432497
TI  - Inorganic nanotubes and fullerene-like materials.
AB  - Following the discovery of fullerenes and carbon nanotubes, it was shown that
      nanoparticles of inorganic layered compounds, like MoS2, are unstable in the
      planar form and they form closed cage structures with polyhedral or nanotubular
      shapes. Various issues on the structure, synthesis, and properties of such
      inorganic fullerene-like structures are reviewed, together with some possible
      applications.

PMID- 12432498
TI  - A rare example of a rearrangement involving four structural isomers: alpha
      phosphinonitrile/C-phosphinoketenimine/1-aza-4- phosphabutadiene/1,2-dihydro-1,2
      azaphosphete.
AB  - The stable compound [bis(dicyclohexylamino)phosphino](trimethylsilyl)-carbene (1)
      reacts with dimethyl cyanamide to afford the original 1,2-dihydro-1,2
      azaphosphete 4a (51% yield). The surprising formation of this heterocycle
      involves the transient formation of a nitrile, a keteneimine, and a 1-aza-4
      lambda 3-phosphabutadiene derivative. By using substituent effects and different
      synthetic routes, all of these structural isomers have been isolated.

PMID- 12432499
TI  - Bicyclo[3.2.1]amide-DNA: a chiral, nonchiroselective base-pairing system.
AB  - The design, synthesis, and base-pairing properties of bicyclo[3.2.1]amide-DNA
      (bca-DNA), a novel phosphodiester-based DNA analogue, are reported. This analogue
      consists of a conformationally constrained backbone entity, which emulates a B
      DNA geometry, to which the nucleo-bases were attached through an extended,
      acyclic amide linker. Homobasic adenine-containing bca decamers form duplexes
      with complementary oligonucleotides containing bca, DNA, RNA, and, surprisingly,
      also L-RNA backbones. UV and CD spectroscopic investigations revealed the
      duplexes with D- or L-complements to be of similar stability and enantiomorphic
      in structure. Bca oligonucleotides that contain all four bases form strictly
      antiparallel, left-handed complementary duplexes with themselves and with
      complementary DNA, but not with RNA. Base-mismatch discrimination is comparable
      to that of DNA, while the overall thermal stabilities of bca-oligonucleotide
      duplexes are inferior to those of DNA or RNA. A detailed molecular modeling study
      of left- and right-handed bca-DNA-containing duplexes showed only minor changes
      in the backbone structure and revealed a structural switch around the base-linker
      unit to be responsible for the generation of enantiomorphic duplex structures.
      The obtained data are discussed with respect to the structural and energetic role
      of the ribofuranose entities in DNA and RNA association.

PMID- 12432500
TI  - A new mechanism of Raman enhancement and its application.
AB  - Strong electronic Raman bands corresponding to the transition between 4I9/2 and
      4I11/2 manifolds of Nd3+, caused by a Raman-enhancement effect, are observed in
      the FT-Raman spectrum of Nd2O3. Neither resonance enhancement (RR) nor surface
      enhancement (SERS) accounts for the Raman enhancement observed here. We propose a
      new mechanism of Raman enhancement called the "feed-back" mechanism. A YAG laser
      excites the final state of the Raman transition (4I11/2 of Nd3+) to the 4F3/2
      state and causes a significant decrease in the population of Nd3+ at the 4I11/2
      state. This causes the population ratio of Nd3+ at 4I9/2 and 4I11/2 to deviate
      from the value required by Boltzmann's law. To restore equilibrium, Raman
      scattering is enhanced so that more Nd3+ ions are brought from the 4I9/2 state to
      the 4I11/2 state. This hypothesis gets support from the temperature-variable FT
      Raman spectroscopic results. Additionally, obvious differences between the Stokes
      and anti-Stokes Raman spectrum of Nd3+ provide further evidence to support the
      feed-back mechanism. The Raman-enhancement effect confers on the electronic Raman
      bands a special ability to reflect the variation of coordinated structure around
      metal ions. The structural variations in polymer-metal ion composites and
      biomineralization systems have been investigated by using the electronic Raman
      bands.

PMID- 12432501
TI  - Preferential transmission of type 1 diabetes from parents to offspring: fact or
      artifact?
AB  - It has been widely reported that men with type 1 diabetes (T1D) tend to be more
      likely to transmit the disease to their offspring than their female counterparts
      in Caucasoid populations. Several theories to explain this preferential
      transmission have been proposed, but so far none of them has been unequivocally
      proven. Whatever the mechanism, confirmation or refutation of this observation is
      nonetheless important and practical to the design of future genetic studies of
      T1D. We carried out some statistical modeling of the preferential transmission.
      The well-established fact that males have higher a prevalence of T1D than
      females, an apparent sex difference in fecundity, and a possible
      misclassification of gestational diabetes mellitus (GDM) as T1D in women have
      been considered. We demonstrated, first, that the ascertainment of study families
      through the affected offspring with T1D would generate a higher proportion of
      fathers than mothers having T1D, even though there was no preferential
      transmission at all. This can be explained by the male preponderance in T1D
      prevalence as compared with females, coupled with a greater likelihood of being
      selected and/or recruited for study in families with T1D fathers due to the
      fecundity difference. Second, when the study population is ascertained through
      affected parents, misclassification of mothers with GDM as T1D, and the existence
      of male/female difference in fecundity in conjunction with a birth order effect,
      can contribute to the observed preferential transmission, even though there was
      none. In light of the plausibility of assumptions employed in the analysis and,
      in particular, an apparent failure to critically examine the effects of these
      causes of bias in earlier studies, it is perhaps prudent to say that the jury for
      the existence of preferential transmission in T1D is still out.

PMID- 12432502
TI  - Univariate and multivariate family-based association analysis of the IL-13
      ARG130GLN polymorphism in the Childhood Asthma Management Program.
AB  - Interleukin 13 (IL-13) has been demonstrated to have a crucial role in animal
      models of allergy and asthma. In human case-control genetic-association studies,
      the Arg130Gln polymorphism has been associated with elevated total serum IgE and
      an asthma diagnosis in atopic and nonatopic individuals (Graves et al. [2000] J.
      Allergy Clin. Immunol. 105:506-513; Heinzmann et al. [2000] Hum. Mol. Genet.
      9:549-559). To apply family-based association methods, we obtained DNA samples
      from 685 asthmatic children from 640 sibships and their parents in the Childhood
      Asthma Management Program (CAMP). Six hundred and sixty-six asthmatic children
      had complete phenotypic information and were used for this analysis. We performed
      quantitative association analysis using the transmission disequilibrium test
      (TDT) on 22 individual phenotypes and 5 grouped phenotypes relating to allergy,
      airway responsiveness, pulmonary function, bronchodilator responsiveness, and
      asthma severity, using genotypes at the Arg130Gln polymorphism of the IL-13 gene.
      A positive association was obtained between Arg130Gln and a grouped phenotype of
      allergy (consisting of the individual phenotypes of eosinophils, IgE, and
      positive skin tests), using FBAT-GEE, a multivariate extension of the family
      based association test (Lange et al. [2002] Biostatistics 1:1-15). The three
      phenotypes were then evaluated individually and revealed a significant
      association between total eosinophil count and the Arg130Gln locus; there was a
      trend for association between total IgE and the Arg130Gln polymorphism. The
      Arg130Gln polymorphism is associated with an elevated eosinophil count as well as
      with a grouped allergy phenotype, in children with mild to moderate asthma. No
      evidence for association was found between Arg130Gln and airway responsiveness,
      asthma diagnosis, or asthma severity.

PMID- 12432503
TI  - Segregation analysis of 389 Icelandic pedigrees with Breast and prostate cancer.
AB  - Breast cancer and prostate cancer are the most commonly occurring cancers in
      females and males, respectively. The objective of this project was to test the
      hypothesis that breast cancer in females and prostate cancer in males represent
      homologous cancers that may be controlled by one or more common unidentified
      genes that may explain some of the observed familial aggregation. We modeled the
      transmission of a breast-prostate cancer phenotype in 389 pedigrees ascertained
      through a breast cancer proband drawn from the Icelandic Cancer Registry.
      Assuming that age at diagnosis of this combined phenotype followed a logistic
      distribution, segregation analyses were performed to evaluate residual parental
      effects, a sibship covariate, and a dichotomous cohort effect. The most
      parsimonious model was a Mendelian codominant model, which could partly explain
      the familial aggregation of both cancers. Inheritance of a putative high-risk
      allele (A) predicted gender-specific mean ages of onset for females as 53.8
      years, 59.7 years, and 65.6 years for the putative AA, AB, and BB genotypes,
      respectively. Similarly, the predicted means were 73.7 years, 75.6 years, and
      78.3 years, respectively, among males. Under this codominant model, the lifetime
      risk of a woman being affected was 19% by age 80 years. This implies that when
      prostate cancer among male relatives of breast cancer probands (unselected for
      family history or early-onset disease) is considered a pleiotrophic effect of the
      same gene that increases the risk for breast cancer, women are predicted to have
      a less than 1 in 5 risk of developing breast cancer when they carry the putative
      high-risk allele. However, this is a higher risk than in the general Icelandic
      population. Our results suggest that BRCA2 mutations alone are inadequate to
      explain all of the excess clustering of prostate cancer cases in families of
      breast cancer probands, and that additional genes conferring excess risk to both
      breast and prostate cancer may exist in this population.

PMID- 12432504
TI  - Evidence that BCL3 plays a role in the etiology of nonsyndromic oral clefts in
      Brazilian families.
AB  - The BCL3 gene has been considered a susceptibility locus for nonsyndromic cleft
      lip with or without cleft palate (NSCL/P), based on association and linkage
      studies in some populations. We evaluated an intragenic marker at the BCL3 gene
      and the microsatellite D19S178 (1.1 cM distant from the BCL3 gene) among 98
      infants born with NSCL/P and their parents, using the transmission disequilibrium
      test (TDT) and a method for haplotype analysis. Our analysis, based on BCL3
      alleles, revealed the existence of a marginal association of allele 135pb of the
      BCL3 gene with NSCL/P (chi(2)=3.60; P=0.058; 1 df), with a major effect in female
      (chi(2)=5.77; P=0.016; 1 df) and in familial cases (chi(2)=3.79; P=0.051; 1 df).
      However, the haplotype analysis detected no significant segregation distortion,
      even if the alleles of the D19S178 were grouped into two classes. These findings
      support previous findings that BCL3 plays a role in the etiology of NSCL/P as an
      allele of low penetrance or as a modifier locus. We hypothesize that there might
      be more than one mutation in this gene associated with NSCL/P, or alternatively,
      that more than one mutation has arisen associated with the 135-bp allele. Genet.
      Epidemiol. 23:364-374, 2002

PMID- 12432505
TI  - Regressive threshold model for familial analysis of complex diseases with
      variable age of onset.
AB  - Few models for segregation (or combined segregation-linkage) analysis have been
      developed to account for variable age of onset. The unified model (UM) can only
      take into account age at examination. In the logistic hazard model (LHM), Abel
      and Bonney ([1990] Genet. Epidemiol. 7:391-407) incorporated survival analysis
      concepts into the regressive logistic model of Bonney ([1986] Am. J. Med. Genet.
      18:731-749), but interpretation of familial dependence parameters is difficult.
      In this article, we extended the regressive threshold model (RTM) proposed by
      Demenais ([1991] Am. J. Hum. Genet. 49:773-785) to account for a variable age of
      onset of complex diseases. This model assumes an underlying liability to disease
      and is more general than the original logistic formulation, since the phenotypes
      of each individual's antecedents can be adjusted for their own genotypes and
      covariate effects. The variation of risk with age can be expressed as a general
      step function, and variants of the model have been proposed by imposing different
      types of constraints among the time-dependent thresholds. The performances of the
      three models (UM, LHM, and RTM) were compared in the context of segregation
      analysis of family data generated with variable age of onset. All analysis models
      were robust with respect to false conclusion of a major gene, and the best
      results were obtained under RTM. The power to detect the major gene was higher
      under LHM than RTM, but the best fit of the estimated cumulative age-dependent
      penetrance with respect to the true value was obtained under RTM. This new model
      may thus prove helpful in contributing to identification of genes underlying
      complex diseases, since it can easily include linked marker loci and linkage
      disequilibrium.

PMID- 12432506
TI  - Score test for mapping quantitative-trait loci with sibships of arbitrary size
      when the dominance effect is not negligible.
AB  - In the linakge analysis of quantitative traits, an additive model that assumes no
      dominance effect is often adopted. Intuitively, when the no-dominance-effect
      assumption does not hold, such a practice does not make efficient use of the
      data, and its power to detect linkage can be improved. Here we introduce a score
      statistic for detecting quantitative trait loci when the dominance effect is not
      neglible or the dominance effect is a concern. This statistic is derived from a
      normal likelihood function for sibships of arbitrary size. In the derivation, the
      inherent genetic constraints on model parameters are fully taken into
      consideration. This score statistic is asymptotically equivalent to the
      corresponding likelihood ratio statistic, but it is much easier to compute. The
      asymptotic distribution of this statistic is derived, which is a mixture of
      chi(0) (2), chi(1) (2), and chi(2) (2). Weights for distribution components are
      functions of the informativeness of the marker data. The type I error rate and
      the power of the proposed statistic in finite sample are evaluated via
      simulations.

PMID- 12432507
TI  - Impact of parental relationships in maximum lod score affected sib-pair method.
AB  - Many studies are done in small isolated populations and populations where
      marriages between relatives are encouraged. In this paper, we point out some
      problems with applying the maximum lod score (MLS) method (Risch, [1990] Am. J.
      Hum. Genet. 46:242-253) in these populations where relationships exist between
      the two parents of the affected sib-pairs. Characterizing the parental
      relationships by the kinship coefficient between the parents (f), the maternal
      inbreeding coefficient (alpha(m), and the paternal inbreeding coefficient
      (alpha(p)), we explored the relationship between the identity by descent (IBD)
      vector expected under the null hypothesis of no linkage and these quantities. We
      find that the expected IBD vector is no longer (0.25, 0.5, 0.25) when f,
      alpha(m), and alpha(p) differ from zero. In addition, the expected IBD vector
      does not always follow the triangle constraints recommended by Holmans ([1993]
      Am. J. Hum. Genet. 52:362-374). So the classically used MLS statistic needs to be
      adapted to the presence of parental relationships. We modified the software
      GENEHUNTER (Kruglyak et al. [1996] Am. J. Hum. Genet. 58: 1347-1363) to do so.
      Indeed, the current version of the software does not compute the likelihood
      properly under the null hypothesis. We studied the adapted statistic by
      simulating data on three different family structures: (1) parents are double
      first cousins (f=0.125, alpha(m)=alpha(p)=0), (2) each parent is the offspring of
      first cousins (f=0, alpha(m)=alpha(p)=0.0625), and (3) parents are related as in
      the pedigree from Goddard et al. ([1996] Am. J. Hum. Genet. 58:1286-1302)
      (f=0.109, alpha(m)=alpha(p)=0.0625). The appropriate threshold needs to be
      derived for each case in order to get the correct type I error. And using the
      classical statistic in the presence of both parental kinship and parental
      inbreeding almost always leads to false conclusions.

PMID- 12432508
TI  - Relative efficiency of ambiguous vs. directly measured haplotype frequencies.
AB  - Haplotypes are useful for both fine-mapping of susceptibility loci and evaluation
      of sequence variation at multiple sites along a chromosome. However, they are
      difficult to directly measure over long stretches of DNA in diploid organisms.
      Consequently, multiple genetic markers are typically measured, without linkage
      phase information, giving rise to a subject's diplotype. From diplotype data,
      haplotypes are often inferred by pedigree information, or treated as partially
      missing data when haplotype frequencies are estimated among unrelated subjects.
      This latter ambiguity can increase the variance of the estimated haplotype
      frequencies. Douglas et al. ([2001] Nat. Genet. 28:361-364) recently quantified
      the relative efficiency of estimating haplotype frequencies from the diplotypes
      of unrelated subjects, relative to directly measured haplotypes via somatic cell
      hybrids (conversion technology), and demonstrated that unknown linkage phase can
      lead to a large loss of efficiency. However, their results were based on linkage
      equilibrium among marker loci, which may not be realistic for closely linked
      markers. We extend their relative efficiency calculations by several aspects: 1)
      allowance for linkage disequilbrium (LD) among marker loci; 2) evaluation of
      different patterns of LD; and 3) evaluation of nuclear families with and without
      parents. We show that although the loss in efficiency of haplotype frequencies
      among unrelated subjects decreases as LD increases to its maximum value, the
      general conclusions of Douglas et al. ([2001] Nat. Genet. 28:361-364) hold true
      for a variety of LD patterns and magnitudes. However, our results also
      demonstrate that trios of parents+one child are highly efficient for haplotype
      frequency estimation, that additional children offer little information, and that
      siblings without parents can be grossly inefficient. Genet. Epidemiol. 23:426
      443, 2002.

PMID- 12432509
TI  - "Mixture models for linkage analysis of affected sibling pairs with covariates".

PMID- 12432512
TI  - "Power comparisons for genotypic vs. allelic TDT methods with >2 alleles".

PMID- 12432517
TI  - Multitrophic interactions of the silverleaf whitefly, host plants, competing
      herbivores, and phytopathogens.
AB  - Our laboratory found that silverleaf whitefly (SLW; Bemisia argentifolii Bellows
      & Perring) feeding alters host plant physiology and chemistry. The SLW induces a
      number of host plant defenses, including pathogenesis-related (PR) protein
      accumulation (e.g., chitinases, beta-1,3-glucanases, peroxidases, chitosanases,
      etc.). Induction of the PR proteins by SLW feeding occurs in various plant
      species and varieties. The extent and type of induction is dependent on a number
      of factors that include host plant growing conditions, the length of time the
      host plant is exposed to SLW feeding, the plant variety, and SLW population
      densities. The appearance of PR proteins correlates well with reduced
      infestations of conspecific insect herbivore competitors. Greenhouse and field
      experiments in which herbivore competitors (cabbage looper, Trichoplusia ni; leaf
      miner, Liromyza trifolii) were placed on plants previously exposed to SLW feeding
      demonstrated behavioral differences (oviposition, feeding preferences) and
      reduced survival rates and development times of these insects. The interaction
      was asymmetrical, i.e., SLW infestations of plants previously exposed to leaf
      miners had little or no effect on SLW behavior (oviposition). Induction of plant
      defensive proteins by SLW feeding was both local (at the feeding site) and
      systemic (uninfested leaves distant to the feeding site). There are interactions
      between diseases such as tomato mottle virus (ToMoV; a geminivirus) and the host
      plant and SLW. PR proteins were induced in tomato plants infected with ToMoV much
      as they were via non-viruliferous SLW feeding. The presence of ToMoV in tomato
      plants significantly increased the number of eggs produced by SLW females.
      Experiments using tomato plants, powdery mildew (PM), and tobacco mosaic virus
      (TMV) show that whitefly infestations can affect plant pathogen relationships but
      the effects vary among pathogen types. Enzyme analyses prior to pathogen
      inoculation showed that whitefly treatment significantly increased the activities
      of foliar chitinase and peroxidase. Evaluation of pathogen growth 3 weeks after
      inoculation showed that whitefly feeding significantly reduced the incidence of
      PM. However, TMV levels evaluated by ELISA were not significantly affected by
      whitefly feeding. Six weeks after inoculation with pathogens, the chitinase and
      peroxidase activities were still elevated in plants initially fed on by
      whiteflies but continuing pathogen infection had no effect on these enzymes. The
      possibility that geminivirus infection and/or SLW infestations isolate the host
      plant for the selected reproduction of the virus and the insect is discussed.
      Multitrophic cascade effects may contribute to the successful eruptive appearance
      of SLW on various crops, ranking them as a major pest. They may explain the
      general observation that when SLW infest a host plant there are few if any
      competing insect herbivores and pathogens found in the host. However, the results
      indicate that certain SLW-virus relationships could be mutualistic.

PMID- 12432518
TI  - Induced responses in clover to an herbaceous mite.
AB  - Halotydeus destructor feeding on subterranean clover cotyledons can cause severe
      damage. The mites live on the soil surface and move up onto plants to feed.
      Foraging behaviour consists of palpating, probing, and feeding with frequent
      transitions between them. Sustained feeding is made up of a series of short (1-2
      min) feeds separated by periods of palpating. The mites tend to feed in
      aggregations, and are attracted to cotyledons damaged by other mites feeding or
      by mechanical damage. Mites can distinguish between resistant and susceptible
      cotyledons within 30 min and resistance is antixenotic due to deterrence. Study
      of the mechanisms shows this to be induced plant resistance. Several green leaf
      volatiles are involved in the plant/mite interaction. After feeding commences, 2
      E-hexenal is released that at low concentrations is attractive to mites, perhaps
      causing the feeding aggregations. The wound-induced C(8) compound, 1-octen-3-one,
      plays a significant role in the deterrence of cotyledons of resistant
      subterranean clover varieties to H. destructor. Damaged cotyledons of resistant
      varieties produce more 1-octen-3-one that those of susceptible varieties.
      Screening for resistance has identified varieties from Italy showing resistance.
      H. destructor does not occur in Europe. Production of damage-induced volatiles by
      the resistant plants may have resulted from invasion by herbivores or pathogens,
      but not from coevolution with these mites. The responses of H. destructor are
      probably an adaptation to these general plant defensive compounds.

PMID- 12432519
TI  - Gene expression profiling of Arabidopsis thaliana in compatible plant-aphid
      interactions.
AB  - Phloem feeding involves unique biological interactions between the herbivore and
      its host plant. The economic importance of aphids, whiteflies, and other phloem
      feeding insects as pests has prompted research to isolate sources of resistance
      to piercing-sucking insects in crops. However, little information exists about
      the molecular nature of plant sensitivity to phloem feeding. Recent discoveries
      involving elicitation by plant pathogens and chewing insects and limited studies
      on phloem feeders suggest that aphids are capable of inducing responses in plants
      broadly similar to those associated with pathogen infection and wounding. Our
      past work showed that compatible aphid feeding on leaves of Arabidopsis thaliana
      induces localized changes in levels of transcripts of genes that are also
      associated with infection, mechanical damage, chewing herbivory, or resource
      allocation shifts. We used microarray and macroarray gene expression analyses of
      infested plants to better define the response profile of A. thaliana to M.
      persicae feeding. The results suggest that genes involved in oxidative stress,
      calcium-dependent signaling, pathogenesis-related responses, and signaling are
      key components of this profile in plants infested for 72 or 96 h. The use of
      plant resistance to aphids in crops will benefit from a better understanding of
      induced responses. The establishment of links between insect elicitation, plant
      signaling associated with phloem feeding, and proximal resistance mechanisms is
      critical to further research progress in this area.

PMID- 12432520
TI  - Interactions between Spinacia oleracea and Bradysia impatiens: a role for
      phytoecdysteroids.
AB  - Plant produced insect molting hormones, termed phytoecdysteroids (PEs), are
      thought to function as plant defenses against insects by acting as either feeding
      deterrents or through developmental disruption. In spinach (Spinacia oleracea),
      20-hydroxyecdysone (20E) concentrations in the roots rapidly increase following
      root damage, root herbivory, or methyl jasmonate (MJ) applications. In this
      inducible system, we investigated the plant defense hypothesis by examining
      interactions of roots, 20E concentrations, and larvae of the dark-winged fungus
      gnat (Bradysia impatiens). Root herbivory by B. impatiens larvae resulted in a
      4.0- to 6.6-fold increase in root 20E concentrations. In paired-choice tests,
      increases in dietary 20E stimulated B. impatiens feeding deterrency. B. impatiens
      larvae preferred control diets, low in 20E, to those constructed from induced
      roots and those amended with 20E (25 to 50 micro g/g wet mass). When confined to
      20E-treated diets, concentrations as low as 5 micro g/g (wet mass) resulted in
      significantly reduced B. impatiens survivorship compared to controls. The
      induction of root 20E levels with MJ resulted in a 2.1-fold increase in 20E
      levels and a 50% reduction in B. impatiens larval establishment. In a paired
      choice arena, untreated control roots were damaged significantly more by B.
      impatiens larvae than MJ-induced roots that contained 3-fold greater 20E levels.
      Based on dietary preference tests, the 20E concentrations present in the MJ
      induced roots (28 micro g/g wet mass) were sufficient to explain this reduction
      in herbivory. Interactions between spinach roots and B. impatiens larvae
      demonstrate that PEs can act as inducible defenses and provide protection against
      insect herbivory.

PMID- 12432521
TI  - Potential for the use of elicitors of plant resistance in arthropod management
      programs.
AB  - Plants protect themselves from arthropod herbivores both directly, by expressing
      biochemical and morphological traits that interfere with herbivore development or
      behavior, and indirectly, by facilitating the action of natural enemies of
      herbivores. These direct and indirect resistance mechanisms are not always
      expressed at maximal levels by plants, but rather can be induced to higher levels
      by a variety of stimuli, most notably prior herbivory. The recent discovery of
      chemical elicitors of induced responses has led to interest in manipulating the
      inducible responses of plants for crop protection. Applications of elicitors of
      induced responses made at appropriate times during the growing season of a crop
      have the potential of activating both direct and indirect mechanisms of plant
      resistance and thereby simultaneously augmenting host-plant resistance and
      biological control. This strategy may serve as an important component of a
      multifaceted, ecologically-based pest management program and is unlikely to
      precipitate the rapid evolution of countermeasures by target pests. However, this
      strategy will not be appropriate in all crops or against all arthropod pests. The
      conditions under which the use of an elicitor is likely to be successful are
      discussed, and examples of the successful use of elicitors are reviewed.

PMID- 12432524
TI  - Editorial: electrophoresis.

PMID- 12432525
TI  - Amperometric and voltammetric detection for capillary electrophoresis.
AB  - The focus of this article is amperometric and voltammetric detection coupled with
      capillary electrophoresis. Fundamental concepts and progress in the field of
      capillary electrophoresis with electrochemical detection (CEEC) that have
      occurred within the past three years, including new methodologies and unique
      applications, are highlighted. This review contains 95 references.

PMID- 12432526
TI  - Conductimetric and potentiometric detection in conventional and microchip
      capillary electrophoresis.
AB  - Potentiometric detection is rarely used in separation methods but is promising
      for certain classes of analytes which can only with difficulty be quantified by
      more standard methods. Conductimetric detection of ions is very versatile and has
      recently received renewed interest spurned by the introduction of the
      capacitively coupled contactless configuration. Both are useful and complementary
      alternatives to the established optical detection methods, and to the more widely
      known electrochemical method of amperometry. The simplicity of the
      electrochemical methods makes them particularly attractive for microfabricated
      devices, but relatively little work has to date been carried out with regard to
      potentiometric and conductimetric detection.

PMID- 12432528
TI  - Deviceless decoupled electrochemical detection of catecholamines in capillary
      electrophoresis using gold microband array electrodes.
AB  - Samples containing microM concentrations of dopamine, (+/-)-isoproterenol, para
      aminophenol and chlorogenic acid have been separated by capillary electrophoresis
      (CE) and detected using end-column amperometric detection based on a novel
      decoupling method. The present decoupling approach involves the use of an
      electrochemical detector chip containing an array of microband electrodes where
      the working and reference electrodes are positioned only 10 microm from each
      other. The short distance between the working and reference electrodes ensures
      that both electrodes are very similarly affected by the presence of the CE
      electric field. With this method, no shift in the detection potential was seen
      when the CE high voltage was applied. This eliminated the need for a
      reoptimization of the detection potential to compensate for the influence of the
      separation voltage on the detection. It is also demonstrated that catecholamines
      can be detected using gold microband electrodes by careful adjustment of the
      detection potential to avoid the formation of gold oxide. Such careful
      adjustments of the detection potential are straightforward using the present
      decoupling method.

PMID- 12432527
TI  - Recent developments in amperometric detection for microchip capillary
      electrophoresis.
AB  - The interest in microfluidic devices has increased considerably over the past
      decade due to the numerous advantages of working within a miniature,
      microfabricated format. This review focuses on recent advances in coupling
      amperometric detection with microchip capillary electrophoresis (CE). Advances in
      electrochemical cell design, isolation of the detector from the separation field,
      and integration of both pre- and postseparation reaction chambers are discussed.
      The use of microchip CE with amperometric detection for enzyme/immunoassays,
      clinical and environmental assays, and the determination of neurotransmitters is
      described.

PMID- 12432529
TI  - New technique for capillary electrophoresis directly coupled with end-column
      electrochemiluminescence detection.
AB  - A new end-column electrochemiluminescence (ECL) detection technique coupling to
      capillary electrophoresis (CE) is characterized. A 300 microm diameter Pt working
      electrode was used to directly couple with a 75 microm inner diameter separation
      capillary without an electric field decoupler. The hydrodynamic cyclic
      voltammogram (CV) of Ru(bpy) 3 2+ showed that electrophoretic current did not
      affect the ECL reaction. The presence of high-voltage (HV) field only resulted in
      the shift of the ECL detection potential. The distance of capillary to electrode
      was an important parameter for optimizing detection performance as it determined
      the characteristics of mass transport toward the electrode and the actual
      concentration of Ru(bpy) 3 2+ in the detection region. The optimum distance of
      capillary to electrode was decided by the inner diameter of the capillary, too.
      For a 75 microm capillary, the working electrode should be placed away from the
      capillary outlet at a distance within the range of 220-260 microm. The effects of
      pH value of ECL solution and molecular structure of analytes on peak height and
      theoretical plate numbers were discussed. Using the 75 microm capillary, under
      the optimum conditions, the method provided a linear range for tripropylamine
      (TPA) between 1 x 10(-10) and 1 x 10(-5) mol/L with correlation coefficient of
      0.998. The detection limit (signal-to-noise ratio S/N = 3) was 5.0 x 10(-11)
      mol/L. The relative standard deviation in peak height for eight consecutive
      injections was 5.6%. By this new technique lidocaine spiked in a urine sample was
      determined. The method exhibited the linear range for lidocaine from 5.0 x 10(-8)
      to 1.0 x 10(-5) mol/L with correlation efficient of 0.998. The limit of detection
      (S/N = 3) was 2.0 x 10(-8) mol/L.

PMID- 12432530
TI  - Capillary electrophoresis with solid-state electrochemiluminescence detector.
AB  - We report capillary electrophoresis coupling to a solid-state
      electrochemiluminescence (ECL) detector for the first time. The solid-state ECL
      detector was fabricated by immobilizing the ECL reagent tris(2,2'
      bipyridyl)ruthenium (TBR) in poly-(p-styrenesulfonate)-silica-poly(vinyl alcohol)
      grafting 4-vinylpyridine copolymer films. The excellent stability of the solid
      state ECL detector in the phosphate solution satisfied application in CE. The CE
      with solid-state ECL detector system was characterized using tripropylamine (TPA)
      and proline. The influences of detection potential, the concentration of TBR in
      the film, and pH value of ECL buffer were investigated. The linear range for TPA
      and proline was 0.005-10 microM and 5-10 mM with correlation coefficients of
      0.997 and 0.998, respectively. The detection limit (signal-to-noise ratio S/N =
      3) was estimated to be 0.002 and 2.0 microM for TPA and proline, respectively.
      The relative standard deviations for 1.0 microM TPA and 1.0 mM proline were 8.7%
      and 7.5% with theoretical plate numbers of 70 000 and 16 000, respectively.
      Compared with the CE-ECL of TBR in aqueous solution, the CE coupling with solid
      state ECL detector system gave the same sensitivity of analysis.

PMID- 12432531
TI  - Evaluation of the inhibition of choline uptake in synaptosomes by capillary
      electrophoresis with electrochemical detection.
AB  - A direct method for evaluating choline uptake by the high-affinity choline
      transport system in synaptosomes was developed using capillary electrophoresis
      (CE) with electrochemical (EC) detection. On-column EC detection of choline and
      the internal standard, butyrylcholine, was accomplished with a 25 microm platinum
      electrode modified with the enzymes, choline oxidase and acetylcholinesterase.
      Choline uptake was evaluated as a function of choline concentration and a KM
      value of 1.7 microM was determined. The method was also used to evaluate a new
      class of redox affinity inhibitors of choline transport. In particular, the
      effectiveness of 3-[(trimethylammonio)methyl]catechol (TMC) as an inhibitor of
      choline uptake was examined independently and relative to the inhibition of the
      well-known inhibitor of choline transport, hemicholinium-3. The IC50 and KI for
      TMC were determined to be 30 microM and 14 microM, respectively. The combination
      of the selectivity and sensitivity afforded by CEEC provides a relatively
      straightforward approach for monitoring choline transport in synaptosomes.

PMID- 12432532
TI  - Determination of uric acid in human serum by capillary electrophoresis with
      polarity reversal and electrochemical detection.
AB  - Capillary zone electrophoresis (CE) under conditions of reversed polarity is used
      in conjunction with electrochemical detection (EC) at carbon fiber microcylinder
      electrodes for the selective and sensitive determination of uric acid in human
      blood serum. Comigration of anions with the electroosmotic flow is accomplished
      with reversed polarity and the buffer additive cetyltrimethylammonium bromide
      (CTAB) in a 2-(N-morpholino)ethanesulfonic acid (MES) buffer system, giving rise
      to rapid and sensitive analyses. Optimal buffer conditions (pH 7.0), detection
      potential (0.80 V vs. Ag/AgCl), and electrokinetic injection are employed to
      allow for maximal resolution and signal intensity. Amperometric end-column
      detection with a carbon fiber microcylinder electrode results in lower limits of
      detection for uric acid of about 25 nM (ca. 140 amol injected) without the need
      for decoupling. Linear calibration plots using uric acid standards in water and
      serum are obtained over a linear range from 5.00 x 10(-4) M to 2.50 x 10(-7) M.
      Uric acid concentrations obtained for human sera using the CE-EC approach
      described here are shown to compare favorably to the accepted laboratory values.

PMID- 12432533
TI  - Nonaqueous capillary electrophoresis with indirect electrochemical detection.
AB  - Nonaqueous capillary electrophoresis (NACE) which makes use of organic solvents
      in place of conventional aqueous electrophoresis buffers is gaining increasing
      importance among modern separation techniques. Recently, it has been shown that
      amperometric detection in conjunction with acetonitrile-based NACE offers an
      extended accessible potential range and an enhanced long-term stability of the
      amperometric responses generated at solid electrodes. The present contribution
      takes advantage of the latter aspect to develop reliable systems for NACE with
      indirect electrochemical detection (IED). In this context, several compounds such
      as (ferrocenylmethyl)trimethylammonium perchlorate, tris(1,10
      phenanthroline)cobalt(III) perchlorate and bis(1,4,7-triazacyclononane)nickel(II)
      perchlorate were studied regarding their suitability to act as electroactive
      buffer additives for IED in NACE. The performance characteristics for the
      respective buffer systems were evaluated. Tetraalkylammonium perchlorates served
      as model compounds for the optimization of the NACE-IED system. Target analytes
      choline and acetylcholine could easily be separated and determined by means of
      NACE-IED. In the case of a buffer system containing 10(-4) M tris(1,10
      phenanthroline)cobalt(III) perchlorate the limits of detection were 2.5 x 10(-7)
      M and 4.6 x 10(-7) M for choline and acetylcholine, respectively. With the
      elaborated analytical procedure choline could be determined in pharmaceutical
      preparations.

PMID- 12432534
TI  - A contactless conductivity detector for capillary electrophoresis: effects of the
      detection cell geometry on the detector performance.
AB  - The effect of the gap between the electrodes and of their width on the behavior
      of a capacitively wired contactless conductivity detector was studied. The
      results obtained have indicated that the detector response can be qualitatively
      described by a model based on the concept of the effective electrode width which
      is a complex parameter determined by the gap between the electrodes, the
      frequency of the input signal and the conductivity of the test solution. The
      detector sensitivity and the effect on the separation efficiency depend on the
      difference between the effective and geometric electrode widths. Higher detection
      sensitivities have been attained for detectors with wide electrodes operating at
      lower frequencies, however, better separation efficiencies have been achieved
      using detectors with narrow electrodes and higher operational frequencies. The
      noise increases with decreasing gap between the electrodes and increasing
      frequency, especially with detectors employing narrow electrodes.

PMID- 12432535
TI  - Simultaneous determination of inorganic and organic anions, alkali, alkaline
      earth and transition metal cations by capillary electrophoresis with contactless
      conductometric detection.
AB  - Simultaneous separation of up to 22 inorganic and organic anions, alkali,
      alkaline earth and transition metal cations was achieved in less than 3 min in
      the capillary electrophoresis system with contactless conductometric detector.
      The sample was injected from both capillary ends (dual opposite end injection)
      and anionic and cationic species were detected in the center of the separation
      capillary. The parameters of the separation electrolyte, such as pH,
      concentration of the electrolyte, concentration of complexing agents and
      concentration of 18-crown-6 were studied. Best results were achieved with
      electrolytes consisting of 8 mM L-histidine, 2.8 mM 2-hydroxyisobutyric acid,
      0.32 mM 18-crown-6 at pH 4.25 or 9 mM L-histidine, 4.6 mM lactic acid, 0.38 mM 18
      crown-6 at pH 4.25. Other electrolytes containing complexing agents such as malic
      or tartaric acid at various concentrations could also be used. The detection
      limits achieved for most cations and anions were 7.5 - 62 micro gL(-1) except for
      Ba2+ (90 micro gL(-1)), Cd 2+, Cr 3+ and F- (125 micro gL(-1)), and fumarate (250
      micro gL(-1)). The repeatability of migration times and peak areas was better
      than 0.4% and 5.9%, respectively. The developed method was applied for analysis
      of real samples, such as tap, rain, drainage and surface water samples, plant
      exudates, plant extracts and ore leachates.

PMID- 12432536
TI  - Prototyping disposable electrophoresis microchips with electrochemical detection
      using rapid marker masking and laminar flow etching.
AB  - Two novel methods are described for the fabrication of components for microchip
      capillary electrophoresis with electrochemical detection (microchip CEEC) on
      glass substrates. First, rapid marker masking is introduced as a completely
      nonphotolithographic method of patterning and fabricating integrated thin-film
      metal electrodes onto a glass substrate. The process involves applying the
      pattern directly onto the metal layer with a permanent marker that masks the
      ensuing chemical etch. The method is characterized, and the performance of the
      resulting electrode is evaluated using catecholamines. The response compares well
      with photolithographically defined electrodes and exhibits detection limits of
      648 nM and 1.02 microM for dopamine and catechol, respectively. Second, laminar
      flow etching is introduced as a partially nonphotolithographic method of
      replicating channel networks onto glass substrates. The replication process
      involves applying a poly(dimethylsiloxane) (PDMS) mold of the channel network
      onto a slide coated with a sacrificial metal layer and then pulling solutions of
      metal etchants through the channels to transfer the pattern onto the sacrificial
      layer. The method is tested, and prototype channel networks are shown. These
      methods serve to overcome the time and cost involved in fabricating glass-based
      microchips, thereby making the goal of a disposable high performance lab-on-a
      chip more attainable.

PMID- 12432537
TI  - Microchip-based amperometric immunoassays using redox tracers.
AB  - A new chip-based electrochemical immunoassay protocol, based on the use of a
      ferrocene redox label, is described. Two reaction formats, based on direct
      (noncompetitive) and competitive modes of operation, were employed for
      illustrating the use of redox tracers in chip-based electrochemical immunoassays.
      The direct assay consisted of mixing the ferrocene-tagged antibody and the
      antigen analyte, a rapid electrophoretic separation of labeled free antibody and
      the labeled antigen/antibody complex, and a downstream anodic detection of the
      ferrocene tracer at gold-plated carbon screen-printed electrode detector. The
      competitive assay integrates precolumn reactions of the labeled antigen and the
      target antigen with the antibody with electrophoretic separation of the free and
      bound labeled antigens, along with amperometric detection of the redox tag. An
      internal standard has been used to normalize the peak area for the construction
      of calibration plots. Fundamental operating variables are examined and optimized.
      The use of a redox tracer offers the advantages of simplified protocol, wider
      linear range, higher stability, and higher separation efficiency compared to an
      analogous use of enzyme tags. The direct mouse-immunoglobulin G (IgG) assay and
      the competitive 3,3',5-triiodo-L-thyronine (T(3)) one were accomplished within
      less than 150 and 130 s (with field strengths of 256 and 192 V/cm), and offer
      minimum detectable concentrations of 2.5 x 10(-12) and 1 x1 0(-6) g/mL,
      respectively. Such use of redox labels for chip-based amperometric immunoassay
      protocols offers considerable promise for decentralized clinical or environmental
      testing.

PMID- 12432538
TI  - Microchip capillary electrophoresis coupled to sinusoidal voltammetry for the
      detection of native carbohydrates.
AB  - The development of a microchip electrophoresis system involving integrated
      frequency based electrochemical detection is described. The use of
      poly(dimethylsiloxane) (PDMS) as the channel substrate greatly simplifies the
      fabrication process while decreasing cost and time consumption. Characterization
      of this system is accomplished through the detection of native carbohydrates at
      planar copper electrodes. Various photolithographic techniques are explored in
      the optimization of electrode area. Separation efficiency of 1 x 10(5)
      theoretical plates per meter is demonstrated. Sinusoidal voltammetry utilizes
      information in the frequency domain to achieve sensitive detection through either
      of two approaches, maximization of signal or minimization of noise. Mass
      detection limits (S/N = 3) of less than 200 amol have been accomplished for
      glucose and sucrose. Sinusoidal voltammetry also facilitated the selective
      isolation of an analyte signal from a pair of chromatographically unresolved
      species through the use of phase discrimination.

PMID- 12432539
TI  - Contact conductivity detection of polymerase chain reaction products analyzed by
      reverse-phase ion pair microcapillary electrochromatography.
AB  - We describe the development of an integrated microelectrophoretic system
      consisting of a contact conductivity detector mounted on-chip for monitoring the
      separation of double-stranded (ds) DNA fragments produced via the polymerase
      chain reaction (PCR) using microcapillary electrochromatography as the separation
      mode. The separation was carried out in a polymer-based microfluidic device, hot
      embossed into poly(methylmethacrylate) (PMMA), whose walls were functionalized to
      produce a C(18)-terminated surface to act as the stationary phase (open channel
      format). The carrier electrolyte contained the ion-pairing agent,
      triethylammonium acetate (TEAA) to allow the separation to be carried out using
      reverse-phase ion-pair capillary electrochromatography (RP-IPCEC). The
      microelectrophoretic separations were investigated utilizing various solvent
      strengths (acetonitrile/water) with 25 mM TEAA to observe the effects on the
      separation efficiency as well as the chromatographic development time and
      detector performance. The field strength significantly affected the quality of
      the separation, with no separation observed at 333 V/cm for a low mass dsDNA
      sizing ladder, but baseline separation achieved using a field strength of 67
      V/cm. It was observed that the solvent strength affected the retention behavior
      of the polyanionic molecules as well as the electroosmotic mobility. Higher
      acetonitrile compositions in the run buffer resulted in reduced plate numbers,
      which produced lower chromatographic resolution. The use of conductivity
      detection allowed mass detection sensitivities in the range of 10(-21) mol with a
      separation efficiency of 10(4) plates and the performance of the detector
      independent of the acetonitrile content used in the carrier electrolyte.

PMID- 12432540
TI  - A microchip electrophoresis system with integrated in-plane electrodes for
      contactless conductivity detection.
AB  - We present a new approach for contactless conductivity detection for microchip
      based capillary electrophoresis (CE). The detector integrates easily with well
      known microfabrication techniques for glass-based microfluidic devices. Platinum
      electrodes are structured in recesses in-plane with the microchannel network
      after glass etching, which allows precise positioning and batch fabrication of
      the electrodes. A thin glass wall of 10-15 microm separates the electrodes and
      the buffer electrolyte in the separation channel to achieve the electrical
      insulation necessary for contactless operation. The effective separation length
      is 34 mm, with a channel width of 50 microm and depth of 12 microm. Microchip CE
      devices with conductivity detection were characterized in terms of sensitivity
      and linearity of response, and were tested using samples containing up to three
      small cations. The limit of detection for K+ (18 microM) is good, though an order
      of magnitude higher than for comparable capillary-based systems and one recently
      reported example of contactless conductivity on chip. However, an integrated
      field-amplified stacking step could be employed prior to CE to preconcentrate the
      sample ions by a factor of four.

PMID- 12432541
TI  - High-voltage contactless conductivity detection of metal ions in capillary
      electrophoresis.
AB  - The detection of alkali, alkaline earth and heavy metal ions with a high-voltage
      capacitively coupled contactless conductivity detector (HV-C(4)D) was
      investigated. Eight alkali, alkaline earth metal ions and ammonium could be
      separated in less than 4 min with detection limits in the order of 5 x 10(-8) M.
      The heavy metals Mn2+, Pb2+, Cd2+ Fe2+, Zn2+, Co2+, Cu2+ and Ni2+ could also be
      successfully resolved with a 10 mM 2-(N-morpholino)ethanesulfonic acid/DL
      histidine (MES/His)-buffer. Zn2+, Co2+, Cu2+ and Ni2+ showed an indirect
      response. The detection limits for the heavy metals were determined to range from
      about 1 to 5 microM.

PMID- 12432544
TI  - The green tea polyphenol, epigallocatechin-3-gallate, protects against the
      oxidative cellular and genotoxic damage of UVA radiation.
AB  - A number of biological activities have been ascribed to the major green tea
      polyphenol epigallocatechin-3-gallate (EGCG) to explain its chemopreventive
      properties. Its antioxidant properties emerge as a potentially important mode of
      action. We have examined the effect of EGCG treatment on the damaging oxidative
      effects of UVA radiation in a human keratinocyte line (HaCaT). Using the ROS
      sensitive probes dihydrorhodamine 123 (DHR) and 2',7'-dichlorodihydrofluorescein
      diacetate (DCFH-DA), we detected a reduction in fluorescence in UVA-irradiated
      (100 kJ/m(2)) cells in the case of the former but not the latter probe after a 24
      hr treatment with EGCG (e.g., 14%, [p < 0.05] after 10 microM EGCG). In the
      absence of UVA, however, both DHR and DCFH detected a pro-oxidant effect of EGCG
      at the highest concentration used of 50 microM. Measurements of DNA damage in UVA
      exposed cells using the single cell gel electrophoresis assay (comet assay) also
      showed the protective effects of EGCG. A concentration of 10 microM EGCG
      decreased the level of DNA single strand breaks and alkali-labile sites to 62% of
      the level observed in non-EGCG, irradiated cells (p < 0.001) with a 5-fold higher
      concentration producing little further effect. Correspondingly, EGCG ablated the
      mutagenic effects of UVA (500 kJ/m(2)) reducing an induced hypoxanthine-guanine
      phosphoribosyl transferase (HPRT) mutant frequency of (3.39 +/- 0.73) x 10(-6) to
      spontaneous levels (1.09 +/- 0.19) x 10(-6). Despite having an antiproliferative
      effect in the absence of UVA, EGCG also served to protect against the cytotoxic
      effects of UVA radiation. Our data demonstrate the ability of EGCG to modify
      endpoints directly relevant to the carcinogenic process in skin.

PMID- 12432545
TI  - The copper chelator trientine has an antiangiogenic effect against hepatocellular
      carcinoma, possibly through inhibition of interleukin-8 production.
AB  - Recent studies have revealed that copper is an important cofactor for several
      angiogenic agents. We examined the antiangiogenic effect against hepatocellular
      carcinoma (HCC) of the copper chelator trientine, especially focusing on the
      relationship between copper and interleukin-8 (IL-8), a potent angiogenic factor
      produced by hepatoma cells. HuH-7 hepatoma cells were transplanted into nude mice
      and the growth of xenograft tumors was compared to and without administration of
      trientine. Using the resected tumor, microvessel density, apoptotic potential and
      proliferative activity were analyzed histologically and IL-8 mRNA was
      semiquantified by RT-PCR. In addition, HuH-7 cells were cultured in control
      medium, medium supplemented with copper, medium supplemented with trientine and
      medium supplemented with both copper and trientine. Human IL-8 levels were
      measured in the supernatants by ELISA. Using the extracts from cultured cells, IL
      8 mRNA was semiquantified by RT-PCR. Trientine suppressed the growth of xenograft
      tumors significantly. Histologically, apoptotic potential was increased
      significantly and microvessel density, decreased. The production of IL-8 from the
      tumor was suppressed by trientine. In vitro, IL-8 production by HuH-7 cells in
      copper-containing medium was significantly greater than that in copper-free
      medium, and this effect was weakened when trientine was added. However, no
      significant change was apparent when trientine was added to the medium alone. In
      conclusion, the chelating effect of trientine prevented copper from functioning
      as a cofactor in angiogenesis, which resulted in reduced IL-8 production from HuH
      7 cells.

PMID- 12432546
TI  - Interference with TGF-beta1 and -beta3 in tumor stroma lowers tumor interstitial
      fluid pressure independently of growth in experimental carcinoma.
AB  - A high tumor interstitial fluid pressure (TIFP) is a pathologic characteristic
      distinguishing the stroma of carcinomas from normal interstitial loose connective
      tissues. The role of TGF-beta1 and -beta3 in generating a high TIFP was
      investigated in xenografted experimental anaplastic thyroid carcinoma (ATC)
      derived from the human ATC cell line KAT-4. A single intravenous injection of a
      soluble recombinant TGF-beta receptor type II-murine Fc:IgG(2A) chimeric protein
      that specifically inhibits TGF-beta1 and -beta3, significantly lowered TIFP in a
      time and concentration dependent manner but did not change total tissue water
      content in the tumors. Tumor growth rate was higher in tumors treated with the
      TGF-beta1 and -beta3 inhibitor compared to control tumors during the first 10
      days after administration of the inhibitor. The apoptotic index of carcinoma
      cells, and expression of the cell cycle inhibitor p27(Kip1), were, however,
      increased in TGF-beta1 and -beta3 inhibitor-treated tumors. Prolonged treatment
      periods and administration of a second dose of the inhibitor decreased tumor
      growth rate. The TGF-beta1 and -beta3 inhibitor did not affect proliferation or
      expression of phosphorylated Smad2 protein in KAT-4 cells cultured in vitro. Our
      results indicate that members of the TGF-beta family are potential targets for
      novel anti-cancer treatment directed to the stroma. First by controlling TIFP and
      by that potentially the uptake of anticancer drugs into tumors and second by
      their suggested role in maintaining a supportive tumor stroma.

PMID- 12432547
TI  - In vitro and in vivo antitumor properties of the cyclin dependent kinase
      inhibitor CYC202 (R-roscovitine).
AB  - CDK2 inhibitors have been proposed as effective anti-cancer therapeutics. We show
      here that CYC202 (R-roscovitine) is a potent inhibitor of recombinant CDK2/cyclin
      E kinase activity (IC(50) = 0.10 microM) with an average cytotoxic IC(50) of 15.2
      microM in a panel of 19 human tumour cell lines, and we also demonstrate
      selectivity for rapidly proliferating cells over non-proliferating cells. A study
      of the cell cycle effects of CYC202 in Lovo colorectal carcinoma cells showed
      that the major effect was not the predicted arrest in one part of the cycle, but
      rather an induction of cell death from all compartments of the cell cycle. The
      maximum tolerated dose given intravenously to mice was in excess of 20 mg/kg.
      Doses up to 2,000 mg/kg were tolerated when administered orally in mice.
      Following repeated intraperitoneal administration (3 times daily for 5 days) of
      100 mg/kg to nude mice bearing the Lovo human colorectal tumour, CYC202 induced a
      significant antitumour effect with a 45% reduction in tumour growth compared to
      controls. A second experiment using the human uterine xenograft MESSA-DX5 treated
      with orally administered CYC202 (500 mg/kg 3 times daily for 4 days) also
      exhibited a significant reduction in the rate of growth of the tumour (62%).
      These data, showing enzyme and cellular potency together with antitumour
      activity, confirm the potential of CDK2 inhibitors such as CYC202 as anticancer
      drugs.

PMID- 12432548
TI  - Targeting of RGD-modified proteins to tumor vasculature: a pharmacokinetic and
      cellular distribution study.
AB  - Angiogenesis-associated integrin alpha(v)beta(3) represents an attractive target
      for therapeutic intervention because it becomes highly upregulated on angiogenic
      endothelium and plays an important role in the survival of endothelial cells.
      Cyclic RGD peptides were prior shown to have a high affinity for alpha(v)beta(3)
      and can induce apoptosis of endothelial cells. In our laboratory, monocyclic RGD
      peptides (cRGDfK) were chemically coupled to a protein backbone. Previous results
      demonstrated that the resulting RGDpep-HuMab conjugate bound with increased
      avidity to alpha(v)beta(3)/alpha(v)beta(5) on endothelial cells. In our present
      study, RGDpep-HuMab was injected intravenously and intraperitoneally in B16.F10
      tumor-bearing mice to determine its pharmacokinetics and organ distribution. In
      the tumor, the RGDpep-HuMab conjugate specifically localized at the endothelium
      as was demonstrated by immunohistochemistry. The control RADpep-HuMab conjugate
      was not detected in the tumor. Besides tumor localization RGDpep-HuMab was found
      in liver and spleen associated with macrophages. This uptake by macrophages is
      probably responsible for the more rapid clearance of RGDpep-HuMab from the
      circulation than HuMab and RADpep-HuMab. The half-life of RGDpep-HuMab (90 min)
      was still considerably longer than that of free RGD peptides (<10 min). This
      prolonged circulation time may be favorable for drug targeting strategies because
      the target cells are exposed to the conjugate for a longer time period. Taken
      together these results indicate that RGD-modified proteins are suitable carriers
      to deliver therapeutic agents into tumor or inflammation induced angiogenic
      endothelial cells.

PMID- 12432549
TI  - Nuclear factor-kappaB, induced in human carcinoma cell line A2780 by the new
      anthracycline men 10755, is devoid of transcriptional activity.
AB  - The new disaccharide anthracycline MEN 10755 induces activation of both NF-kappaB
      and p53 transcription factors in A2780 cells. Nevertheless, pharmacologic
      inhibition of NF-kappaB activation does not modify the sensitivity of A2780 cells
      to MEN 10755 treatment. To better characterize the role of NF-kappaB in MEN 10755
      induced cytotoxicity, we analyzed the expression of a number of genes that are
      known to be regulated by NF-kappaB. None of these genes is modified by MEN 10755
      treatment. On the contrary, our results suggest that the p53 DNA damage
      responsive pathway is fully activated in A2780 cells, several genes controlled by
      p53 being up- or downregulated according to the described action of p53 on their
      promoters. Thus, in the A2780 cell line, the role of p53 in transducing the DNA
      damage signal appears to be relevant, whereas NF-kappaB, although activated,
      appears to be nonfunctional. Other human carcinoma cell lines besides A2780
      activate NF-kappaB DNA binding in response to MEN 10755 treatment, but again,
      this binding does not always lead to target gene activation. These results
      suggest that other factors, tumor type-specific and different from mere
      activation, could influence NF-kappaB transcriptional activity. Therefore, care
      should be taken when considering the pharmacologic inhibition of NF-kappaB as a
      means to improve anticancer therapy efficacy.

PMID- 12432550
TI  - Cell-free 27 kDa heat shock protein (hsp27) and hsp27-cytochrome c complexes in
      the cervix of women with ovarian or endometrial cancer.
AB  - Antibodies to the 27 kDa heat shock protein (hsp27) are present in some women
      with ovarian and endometrial cancers but not in women with nonmalignant
      conditions or healthy women. The appearance of these antibodies suggests that the
      corresponding protein (hsp27) may be present in an extracellular form in
      gynecologic cancer patients. Synthesis of hsp27 is upregulated in gynecologic
      cancers and inhibits induction of apoptosis. We now report the detection of hsp27
      as well as hsp27-cytochrome c complexes in cell-free endocervical or posterior
      vaginal specimens from women with endometrial or ovarian cancer. Specimens were
      obtained with a cotton swab from 209 consecutive patients seen by a gynecologic
      oncologist. After removal of cellular components, aliquots of supernatants were
      assayed by ELISA for hsp27, using cytochrome c bound to microtiter plate wells,
      and for hsp27-cytochrome c complexes, using antibodies to cytochrome c and hsp27.
      Among 47 women with ovarian cancer, 38.3% were positive for hsp27 and 27.7% had
      hsp27-cytochrome c complexes. Similarly, among 52 women with endometrial cancer,
      34.6% were hsp27-positive and 30.8% had hsp27-cytochrome c complexes. In contrast
      to the women with ovarian or endometrial cancer, of the 86 women with benign
      diagnoses only, 10.5% had cervical hsp27 (p < 0.002) and 8.1% had hsp27
      cytochrome c complexes (p < 0.004). Among ovarian cancer patients, hsp27 was
      identified in 44.0% of the 25 women with active disease as opposed to 17.6% of
      the 17 patients in remission (p < 0.05). In women with stage 1-2 active ovarian
      cancer, 8 of 10 (80.0%) were hsp27-positive as opposed to 3 of 14 (21.4%) stage 3
      4 patients (p < 0.01). For hsp27-cytochrome c complexes, 50% of ovarian cancer
      patients with active stage 1-2 disease as opposed to 21.4% with stage 3-4 disease
      were positive. Among women with endometrial cancer, only 10 of the 52 patients
      had active disease and 44 were in stage 1-2. For this malignancy, there was no
      relation between detection of hsp27 or hsp27-cytochrome c and active disease or
      cancer stage. Our results suggest that cell-free hsp27 and hsp27-cytochrome c
      complexes can be detected in the lower genital tract of women with ovarian and
      endometrial cancers. Identification of these biomarkers may be beneficial in the
      early diagnosis of these malignancies.

PMID- 12432551
TI  - Replication efficiency and sequence analysis of full-length hepatitis B virus
      isolates from hepatocellular carcinoma tissues.
AB  - Prolonged replication of hepatitis B virus (HBV) in liver tissues of hepatitis B
      patients has been considered as an important risk factor for the development of
      malignancy. Few studies on full-length HBV sequencing in association with the
      replication efficiency of isolates from HCC tissues have been reported. To study
      the structural and functional genomics of HBV isolates from Chinese
      hepatocellular carcinoma (HCC) patients, full-length HBV genomes were amplified
      from 6 HBV-marker positive HCC tissues and used to transfect HepG2 cells. Five of
      6 isolates showed high replicative efficiency. All isolates were of genotype C
      and "hot-spots" mutations were detected in the B cell and T helper (Th) cell
      epitopes of the envelope and the core region. In addition, the X region of 2
      isolates contained a stop-codon mutation that was predicted to result in a
      truncated X protein. High replicative HBV immune escape mutants that persist in
      infected hepatocytes could be 1 of the important factors to initiate pathological
      processes for the development of HCC in Chinese patients.

PMID- 12432552
TI  - Generation of monoclonal antibodies against Hong Kong nasopharyngeal carcinoma
      associated Epstein-Barr virus latent membrane protein 1 (LMP1).
AB  - A panel of monoclonal antibodies specific to Hong Kong Chinese nasopharyngeal
      carcinoma (NPC)-associated Epstein-Barr virus (EBV) latent membrane protein 1
      (LMP1) variants has been generated. These monoclonal antibodies not only
      differentiate the Hong Kong Chinese NPC-associated LMP1 variants from the
      prototype B95-8 LMP1, derived from Caucasian infectious mononucleosis, but also
      differentiate the 2 highly homologous LMP1 deletion variants commonly found in
      Hong Kong primary NPC. The predominant deletion type variant, DV-Asp335, is
      characterized by an aspartic acid at residue 335 located in the cytoplasmic C
      terminal region, whereas the other minor deletion variant, DV-Gly335, has a
      glycine in the same residue position. 335D is hitherto found predominantly in
      LMP1 of the China 1 strain in association with NPC in the Chinese populations
      located in southern China and Malaysia. These antibodies, which are applicable in
      ELISA, immunofluorescence, immunoprecipitation, immunoblotting and
      immunohistochemistry on paraffin sections, are the first variant-specific anti
      LMP1 monoclonal antibodies produced, and will be useful in investigating the
      functional significance of 335D in NPC.

PMID- 12432553
TI  - Identification of HLA-A3-restricted CD8+ T cell epitopes derived from mammaglobin
      A, a tumor-associated antigen of human breast cancer.
AB  - Mammaglobin-A is highly overexpressed in breast cancer cell lines and primary
      breast tumors. This pattern of expression is restricted to mammary epithelium and
      metastatic breast tumors. Thus, mammaglobin-A-specific T cell immune responses
      may provide an important approach for the design of breast cancer-specific
      immunotherapy. The purpose of our study was to define the T cell-mediated immune
      response to mammaglobin-A. We determined that the frequency of mammaglobin-A
      reactive CD8+ and CD4+ T cells in breast cancer patients is significantly higher
      than that observed in healthy female controls using limiting dilution analyses (p
      = 0.026 and p = 0.02, respectively). We identified 8 mammaglobin-A-derived 9-mer
      peptides with the highest binding affinity for the HLA-A3 molecule (Mam-A3.1-8)
      using a computer-assisted analysis of the mammaglobin-A protein sequence.
      Subsequently, we determined that CD8+ T cells from breast cancer patients reacted
      to peptides Mam-A3.1 (23-31, PLLENVISK), Mam-A3.3 (2-10, KLLMVLMLA), Mam-A3.4 (55
      63, TTNAIDELK) and Mam-A3.8 (58-66, AIDELKECF) using an IFN-gamma enzyme-linked
      immunospot assay. A CD8+ T cell line generated in vitro against HLA-A*0301
      transfected TAP-deficient T2 cells loaded with these peptides showed significant
      cytotoxic activity against the Mam-A3.1 peptide. This CD8+ T cell line showed a
      significant HLA-A3-restricted cytotoxic activity against mammaglobin-A-positive
      but not mammaglobin-A-negative breast cancer cells. In summary, our study
      identified four HLA-A3-restricted mammaglobin-A-derived epitopes naturally
      expressed by breast cancer cells, indicating the immunotherapeutic potential of
      this novel antigen for the treatment and prevention of breast cancer.

PMID- 12432555
TI  - HER2 overexpression in muscle-invasive urothelial carcinoma of the bladder:
      prognostic implications.
AB  - The HER2 (c-erbB-2) receptor is overexpressed in a variety of human malignant
      tumors and, in breast carcinoma, has been identified as a target for anti-HER2
      directed therapy with the monoclonal antibody (MAb) trastuzumab. The aim of this
      retrospective study was to evaluate immunohistochemic HER2 expression in a large
      cohort of muscle-invasive urothelial cell carcinomas of the urinary bladder and
      to compare the results to pathologic characteristics and survival. Paraffin
      embedded tumor specimens from 138 patients undergoing radical cystectomy for
      muscle-invasive bladder carcinoma were studied immunohistochemically with the
      Food and Drug Administration (FDA)-approved HercepTest (Dako, Glostrup, Denmark).
      HER2 overexpression was observed in 57 of 138 tumors (41%) and occurred more
      frequently in high-grade carcinomas than in low-grade carcinomas (p = 0.036). No
      significant relationship with HER2 overexpression was registered for tumor
      staging and lymph node status. Kaplan-Meier curves showed a significantly worse
      disease-related survival (p = 0.034) in patients with HER2-overexpressing tumors
      compared to those without HER2 overexpression. In addition to lymph node status
      (p = 0.0001; relative risk [RR] = 2.93), HER2 status (p = 0.020; RR = 2.22) was
      identified as an independent predictor for disease-related survival in a
      multivariate analysis. These results suggest that HER2 expression might provide
      additional prognostic information in patients with muscle-invasive bladder
      carcinomas. Because many of these patients harbor HER2-overexpressing tumors,
      clinical trials evaluating the efficacy of trastuzumab in bladder carcinoma are
      warranted.

PMID- 12432554
TI  - Expression of mitogen-activated protein kinase phosphatase-1 (MKP-1) in primary
      human ovarian carcinoma.
AB  - The mitogen-activated protein kinase phosphatase-1, MKP-1 (CL100) is involved in
      inactivation of MAP-kinase pathways, regulation of stress-responses and
      suppression of apoptosis. We investigated expression of MKP-1 in 90 cases of
      primary ovarian tumors, 11 normal ovaries as well as 4 ovarian carcinoma cell
      lines. Immunohistochemical expression of MKP-1 protein was reduced in tissue from
      LMP tumors and invasive ovarian carcinomas compared to normal ovaries and
      cystadenomas. A moderate to strong expression of MKP-1 was detected in 57.6% of
      invasive ovarian carcinomas. In a descriptive univariate survival analysis, MKP-1
      expression was a prognostic marker for shorter progression-free survival of
      patients with invasive ovarian carcinomas. Patients with carcinomas positive for
      MKP-1 had a median progression-free survival of only 18.3 months compared to 40.6
      months for patients with carcinomas negative for MKP-1 (log-rank test, p =
      0.019). Other prognostic parameters for progression-free survival were FIGO
      stage, grade and pT stage. In an exploratory multivariate analysis, we found that
      MKP-1 expression as well as FIGO stage and grade were independent prognostic
      factors for progression-free survival. In contrast to progression-free survival,
      we did not find any influence of MKP-1 expression on patient overall survival. We
      investigated expression and regulation of MKP-1 mRNA by Northern Blot in vitro
      using 4 ovarian carcinoma cell lines (SKOV-3, OVCAR-3, CAOV-3, OAW-42). MKP-1
      mRNA was inducible by interleukin-1beta and tumor necrosis factor-alpha in SKOV-3
      and OVCAR-3 cells, whereas CAOV-3 and OAW-42 expressed MKP-1 mRNA constitutively.
      In OVCAR-3 cells MKP-1 mRNA levels were strongly inducible upon treatment of
      cells with cisplatin. Our data indicate that MKP-1 is expressed in a subset of
      ovarian carcinomas and regulated by inflammatory mediators. Expression of MKP-1
      may be associated with shorter progression-free survival times. Further studies
      are needed to determine whether MKP-1 expression is a clinically useful marker to
      estimate patient prognosis as well as the response to chemotherapy.

PMID- 12432556
TI  - Recurrent human papillomavirus infection detected with the hybrid capture II
      assay selects women with normal cervical smears at risk for developing high grade
      cervical lesions: a longitudinal study of 3,091 women.
AB  - To test the reliability of the Hybrid Capture II (HC-II) assay detecting 13 high
      risk human papillomavirus (HR-HPV) types for the screening of cervical lesions,
      we monitored by cytology, HR-HPV testing, colposcopy and biopsy, 3,091 women with
      normal smears at the first entry. Our primary endpoint was clinical progression
      defined as the presence of a high-grade lesion (HGSIL) at the biopsy. In our
      population of 659 HR-HPV-infected women, 241 (36.6%) had a positive HR-HPV test
      at 2 to 4 examinations with a final histological diagnosis of HGSIL in 51 cases
      (21.2%) within 4 to 36 months, while women with regressive HPV infection did not
      develop any lesion during the same period. In the cohort of 2,432 women testing
      negative for HR-HPV infection, only 2 women (0.08%) developed a HGSIL. Both were
      HR-HPV positive 18 and 24 months after the first entry, at the time of diagnosis
      of disease. The RR of incident HGSIL when a HR-HPV was detected at enrollment in
      women with normal smears was 96.7 (95% CI, 95.8-97.7). The RR increased to 237.3
      (95% CI, 222.8-251.8) when the HR-HPV test remained positive at 2 controls, and
      to 314.3 (95% CI, 260.7-367.9) when the HR-HPV test was positive at 3 controls.
      The evaluation of the viral load of HR-HPV by the HC-II did not represent a
      sensitive approach to predict the recurrence of HR-HPV infection and/or the
      apparition of HGSIL. Nevertheless, a recurrent HR-HPV infection detected with HC
      II represents a reliable tool to select populations at risk for the development
      of HGSIL.

PMID- 12432557
TI  - Association of functional polymorphisms of matrix metalloproteinase (MMP)-1 and
      MMP-3 genes with colorectal cancer.
AB  - Matrix metalloproteinase (MMP)-1 and MMP-3 genes are associated with tumor cell
      invasion and metastasis with their promoter polymorphisms influencing the level
      of transcription. Our study explored the association of these polymorphisms with
      colorectal cancer risk in a Japanese population. DNA was extracted from
      peripheral blood of 101 patients with colorectal cancer and 127 age- and gender
      matched healthy volunteers. Genotyping was carried out using PCR-RFLP and direct
      sequencing. In the MMP-1 gene polymorphism, the frequency of the 2G/2G genotype
      that is associated with higher enzyme activity was significantly increased in
      colorectal cancer patients when compared to controls (p = 0.0067; OR = 2.077; 95%
      CI = 1.221-3.534). With regard to the MMP-3 polymorphism, unexpectedly, the
      frequency of the 6A/6A genotype causing lower enzyme activity was significantly
      increased in patients (p = 0.0129; OR = 2.110; 95% CI = 1.165-3.822). Because the
      loci for the 2 MMP genes are closely linked, we examined linkage disequilibrium
      between the 2 loci using expectation-maximization algorithm. We found that the 2
      loci were in linkage disequilibrium and that 2G-6A haplotype was significantly
      increased in patients compared to controls (p = 0.0010; OR = 1.949; 95% CI =
      1.305-2.911). Our present data suggest that the MMP-1 and MMP-3 promoter
      polymorphisms may be associated with a colorectal cancer susceptibility in
      Japanese.

PMID- 12432558
TI  - Myeloperoxidase (MPO) genotype and lung cancer histologic types: the MPO -463 A
      allele is associated with reduced risk for small cell lung cancer in smokers.
AB  - MPO participates in the metabolic activation of tobacco carcinogens such as PAHs.
      A frequent MPO -463 G-->A polymorphism in the promoter region reduces MPO
      transcription and has been correlated with >4-fold lower benzo[a]pyrene-DNA
      adduct levels in the skin of coal tar-treated patients. Four of 7 case-control
      studies found significantly reduced lung cancer risk associated with the A
      allele. Due to their different etiologies, we examined whether the MPO genotype
      affects histologic lung cancer types differentially. A case-control study was
      conducted in 625 ever-smoking lung cancer patients, including 228
      adenocarcinomas, 224 SCCs, 135 SCLCs and 340 ever-smoking hospital controls. MPO
      genotyping was performed by capillary PCR followed by fluorescence-based melting
      curve analysis. Combining the MPO -463 (G/A+A/A) genotypes, a protective effect
      approaching significance (OR = 0.75, 95% CI 0.55-1.01) was observed when
      comparing all lung cancer cases to controls. Among histologic types of lung
      cancer, a weak protective effect was found for both adenocarcinoma (OR = 0.81, CI
      0.55-1.19) and SCC (OR = 0.82, CI 0.56-1.21); a stronger and significant effect
      was found for SCLC (OR = 0.58, CI 0.36-0.95; p = 0.029). Our results also suggest
      that the MPO genotype varies among inflammatory nonmalignant lung diseases. In
      conclusion, our results emphasize the need for a separate analysis of lung cancer
      histologic types and an adjustment for inflammatory nonmalignant lung diseases in
      future MPO-related studies. We confirm that the MPO -463 A variant affords a
      protective effect against lung cancer risk in smokers, which was strongest for
      SCLC patients.

PMID- 12432559
TI  - A case-control analysis of lymphocytic chromosome 9 aberrations in lung cancer.
AB  - Cytogenetic aberrations on chromosome 9 have been reported to be one of the most
      frequent genetic changes in lung tumorigenesis. Although many of these changes
      have been detected in lung carcinoma specimens, there is growing evidence showing
      the concordance between chromosomal alterations in primary lung tumors and
      peripheral blood lymphocytes (PBLs). We investigated whether spontaneous
      aberrations on chromosome 9 in PBLs are associated with the presence of lung
      cancer and with a family history of cancer. A personal interview, to construct a
      detailed epidemiologic profile including family history of cancer, was conducted
      on 174 lung cancer cases and 162 matched controls. One hundred metaphases from
      PBLs of each subject were analyzed for chromosome 9 aberrations using the whole
      chromosome painting technique. Overall, the mean proportion of individuals with
      chromosome 9 abnormalities in their PBLs was significantly higher in cases
      (96.0%) than in controls (60.5%) (p < 0.05). After adjustment by age, gender,
      ethnicity, family size, and pack-years, there was a 16.63-fold significantly
      elevated odds ratio (OR) for lung cancer associated with chromosome 9
      aberrations. When subjects were categorized by frequencies of the chromosome 9
      lesions, we observed significantly increased odds ratios of 11.13 (4.66, 26.58)
      and 27.45 (11.15, 67.54) for individuals with 1 chromosome 9 aberration and >/=2
      chromosome 9 aberrations, respectively. By performing family history analyses, we
      further observed that control individuals with chromosome 9 aberrations were more
      likely to report a family history of any cancer (OR = 1.67 [0.84, 3.32]) and lung
      cancer (OR = 2.49 [0.81, 7.67]). Our findings suggest that chromosome 9
      aberrations in PBLs might be considered a marker of lung cancer predisposition
      and may be associated with familial aggregation of cancer.

PMID- 12432560
TI  - Evidence of benefit from centralised treatment of ovarian cancer: a nationwide
      population-based survival analysis in Finland.
AB  - To assess the effect of different hospital types or surgical volume on the
      survival of ovarian cancer patients, a nationwide and population-based analysis
      was carried out in Finland. The study included all 3,851 ovarian cancer patients
      operated from 1983-94. The patients were classified according to the hospital of
      the first surgery. The hospitals were categorized by type (university, central or
      other hospital) and, separately, into quartiles by the number of operated
      patients (surgical volume). The patients operated at university hospitals had
      better survival than those operated in central hospitals, the 5-year relative
      survival rates (RSR) being 45% (95% CI = 42-48%) and 37% (34-40%), respectively.
      RSR in the 'other hospital' category was 45% (42-48%). The RSR for the patients
      operated in the highest volume hospitals was 47% (43-50%), and by decreasing
      volume (quartile) the RSR was 40% (36-43%), 40% (36-43%) and 42% (38-45%),
      respectively. After controlling for potential confounding by stage and age using
      regression models, the results remained practically the same. The results
      indicate that further centralizing of operative treatment of ovarian cancer may
      still improve survival rates on a population level in Finland.

PMID- 12432561
TI  - Dietary folate and colorectal cancer.
AB  - Folate may be inversely related to colorectal cancer risk, possibly in
      combination with low methionine and high alcohol consumption. We considered,
      therefore, the relation between folate and colorectal cancer in a multicentric
      case-control study of 1,953 cases and 4,154 controls from Italy, i.e., a
      population with frequent regular alcohol drinking. In the overall data set, the
      odds ratio (OR) was 0.72 for the highest quintile of folate, and the continuous
      OR per 100 microg was 0.86. The inverse relation was similar in men and women and
      somewhat stronger for the rectum (OR = 0.59 for the highest quintile) compared to
      the colon (OR = 0.81). It was also somewhat stronger in the highest tertile of
      alcohol drinking (OR = 0.65), though trends were not heterogeneous across strata
      of alcohol, whereas no appreciable difference was observed across strata of
      methionine intake. Compared to subjects reporting low alcohol, high methionine
      and high folate intake, the OR was 1.83 for those reporting high alcohol, low
      methionine and low folate intake. The present findings support a favorable role
      of folate in colorectal carcinogenesis.

PMID- 12432562
TI  - Attributable risk for familial breast cancer.

PMID- 12432564
TI  - Differential recognition of structural details of bacterial lipopeptides by toll
      like receptors.
AB  - The question which detailed structures of bacterial modulins determine their
      relative biological activity and respective host cell receptors was examined with
      synthetic variants of mycoplasmal lipopeptides as model compounds, as well as
      recombinant outer surface protein A (OspA) of Borrelia burgdorferi and
      lipoteichoic acid. Mouse fibroblasts bearing genetic deletions of various toll
      like receptors (TLR) were the indicator cells to study receptor requirements,
      primary macrophages served to measure dose response. The following results were
      obtained: (i) the TLR system discriminates between modulins with three and those
      with two long-chain fatty acids in their lipid moiety, in that lipopeptides with
      three fatty acids were recognized by TLR2, whereas those with two long-chain
      fatty acids and lipoteichoic acid required the additional cooperation with TLR6;
      (ii) substitution of the free N terminus of mycoplasmal lipopeptides with an
      acetyl or palmitoyl group decreased the specific activity; (iii) removal of one
      or both ester-bound fatty acids lowered the specific activity by five orders of
      magnitude or deleted biological activity; (iv) oxidation of the thioether group
      lowered the specific activity by at least four orders of magnitude. The
      implications of these findings for physiological inactivation of lipopeptides and
      host-bacteria interactions in general are discussed.

PMID- 12432565
TI  - Inflammatory stimuli recruit cathepsin activity to late endosomal compartments in
      human dendritic cells.
AB  - Proteolysis by endocytic cysteine proteases is a central element of the antigen
      presentation machinery in dendritic cells (DC). It controls the generation of
      immunogenic peptides, guides the transit of both MHC class II and MHC-like
      molecules through the endocytic compartment and converts class II into a peptide
      receptive state - features closely linked to DC maturation. Differential activity
      of endocytic proteases, in particular cathepsins, in subcellular compartments has
      been implicated as a key regulatory element in controlling this machinery in
      murine DC. We analyzed the expression and subcellular distribution of the major
      endocytic cysteine proteases (cathepsins S, B, L and H) along with their major
      endogenous inhibitor, Cystatin C, in resting and stimulated human DC. Although
      the majority of cathepsin activity was restricted to lysosomes in resting DC,
      cathepsins selectively accumulated in late endosomes after LPS-induced
      stimulation. Surprisingly, expression and distribution of Cystatin C was
      unaffected by DC maturation. Thus, late endosomes represent a specialized
      compartment where proteolytic activity is developmentally regulated in DC. This
      could facilitate the conversion of exogenous protein into MHC class II-peptide
      complexes.

PMID- 12432566
TI  - Role of CREB transcription factor in c-fos activation in natural killer cells.
AB  - In natural killer (NK) cells, interleukin-2 (IL-2) differentially regulates the
      expression of several transcription factors, including JunB and c-fos. The cAMP
      response element binding protein, CREB, is a key transcriptional regulator of a
      large number of genes containing the octanucleotide CRE consensus sequence in
      their upstream regulatory regions. We studied here the functional role of CREB in
      the IL-2-mediated transcriptional regulation of c-fos in human NK cells. Our
      results show that IL-2 activates CREB in human NK cells and that CREB activation
      hasa prominent regulatory role on the IL-2-induced expression of functional c-fos
      and AP-1 in NK cells. We identify two domains of the c-fos promoter, containing
      three CRE sites, which are critical for the transcriptional activity induced by
      IL-2. The first domain is located within the first 220 nucleotides of the c-fos
      promoter, while the second encompasses the nucleotides - 440 and - 220. Our
      results show that CREB has a relevant role in the cytokine-mediated activation of
      NK cells, and are particularly remarkable in the light of the several genes that
      are positively regulated by c-fos and AP-1, such as IFN-gamma, IL-2 and GM-CSF
      genes.

PMID- 12432567
TI  - Optimization of peptide linker length in production of MHC class II/peptide
      tetrameric complexes increases yield and stability, and allows identification of
      antigen-specific CD4+T cells in peripheral blood mononuclear cells.
AB  - Reliable, efficient systems for producing soluble HLA-DR molecules, suitable for
      multimerization and use as staining reagents, have proved elusive. We found that
      the addition of a flexible linker between peptide and N terminus of the DRB1*0101
      chain (Crawford, F., Kozono, H., White, J., Marrack, P. and Kappler, J., Immunity
      1998. 8: 675-682.), results in greater in vitro folding efficiency of Escherichia
      coli-expressed alpha- and beta-chains, and increases both the yield and stability
      of the DRA1*0101/DRB1*0101/peptide complexes. Although a 10-amino acid linker
      functioned efficiently for a 20mer epitope from HIV p24, a longer linker was
      required to produce a DR1 MHC class II tetramer with the influenza hemagglutinin
      epitope (HA(306-318)). The DR1-HA tetramer was able to stain positively over 98%
      of a specific clone (HA 1.7) with only a brief 30-min incubation. The tetrameric
      complexes detected clone cells diluted into PBMC, with high sensitivity, coupled
      with low background staining in CD4(+) cells. It was possible to detect antigen
      specific CD4(+) T cells within a population of PBMC stimulated with the HA
      peptide. This demonstrates the potential to monitor CD4(+) T cell responses in
      peripheral blood in a number of clinical scenarios.

PMID- 12432568
TI  - Role of ICOS versus CD28 in antiviral immunity.
AB  - The costimulatory protein ICOS is inducibly expressed on activated T cells.
      Previous results have shown that ICOS(-/-) mice are defective in germinal center
      formation, antibody (Ab) production and class switch as well as Th1 and Th2
      cytokine production in response to protein or parasite antigens. However, ICOS-Ig
      failed to block antiviral Ab responses. To date the immune response to viruses
      has not been examined in ICOS(-/-) mice. In this report we compared antiviral Ab
      responses to LCMV, VSV and influenza virus in ICOS(-/-) versus wild-type mice.
      Our results show that ICOS is important in the Ab response to all three viruses,
      with greater effects on primary as compared to secondary responses. Although
      ICOS(-/-) mice are impaired in some immune responses following influenza
      infection, the effects were less severe than for CD28(-/-) mice. There was no
      defect in initial influenza-specific CD8 T cell expansion in ICOS(-/-) mice or in
      cytotoxic effector function. However, ICOS was important in maintaining CD4
      cytokine production and CD8 T cell numbers late in the primary response. Upon
      secondary infection, ICOS(-/-) mice show wild-type levels of influenza-specific
      CD8 T cells, whereas CD28(-/-) mice show greatly impaired secondary CD8 T cell
      expansion. Overall, our results show that ICOS plays a clear role in the primary
      response to viruses at the level of Ab production, germinal center formation and
      Th cytokine production, but has diminished effects following secondary viral
      challenge.

PMID- 12432569
TI  - Inefficient clustering of tyrosine-phosphorylated proteins at the immunological
      synapse in response to an antagonist peptide.
AB  - Interactions of T cells with MHC plus peptide in the peripheral lymphoid system
      are important for their survival. In this study we investigated further the
      molecular consequences of such interactions using F5 TCR transgenic mice and
      peptides previously shown to induce either negative or positive selection in the
      thymus. Following TCR ligation with the negatively selecting agonist peptide,
      mature CD8(+) cells proliferated and up-regulated the activation marker CD69.
      Interestingly, ligation of this TCR with MHC molecules loaded with high
      concentrations of the positively selecting peptide also resulted in the
      aforementioned changes, but with slower kinetics. Analysis of the biochemical
      changes that occur following stimulation with these peptides showed that
      phosphorylation of key signaling molecules, such as ZAP-70, CD3zeta, Vav, SLP-76,
      LAT, and ERK-1 and 2, could be detected after exposure to agonist but not
      antagonist peptide. Confocal microscopy, however, revealed infrequent
      phosphorylation 'patches' at the site of contact between T cells and APC
      presenting the antagonist peptide. Our data suggest that peptides capable of
      inducing positive selection in the thymus can be recognized by mature T cells and
      cause proliferation, up-regulation of CD69 and accumulation of phosphorylated
      proteins at the immunological synapse with low efficiency; however no
      phosphorylation of signaling molecules can be detected using conventional
      biochemical assays.

PMID- 12432570
TI  - 1alpha,25-dihydroxyvitamin D3 inhibits anti-CD40 plus IL-4-mediated IgE
      production in vitro.
AB  - In the present study, we examined whether anti-CD40+IL-4-mediated B cell
      proliferation and immunoglobulin synthesis is affected by vitamin D (VD) and its
      low-hypercalcemic analogue EB1089 in Bcells from healthy donors. Analysis of
      vitamin D receptor (VDR) expression showed that only anti-CD40+IL-4-stimulated,
      but not resting B cells express VDR. Studies on B cell proliferation revealed
      that anti-CD40+IL-4-mediated proliferation of B cells was not affected by VD or
      EB1089. By contrast, IgE synthesis was markedly inhibited by both, VD and EB1089,
      starting at concentrations from 10(-10) M for VD and 10(-12) M for EB1089, with
      maximal inhibition at 10(-6) M (VD 85.5+/-9.7%; EB1089 77.3+/-10.8%). The
      production of the other Ig (IgA and IgG) was not significantly inhibited by VD
      after anti-CD40+IL-4 stimulation, and IgM production was only slightly reduced
      (18.7+/-7.9%). These observations were confirmed by intracellular staining of the
      different isotypes in B cells after anti-CD40+IL-4 stimulation, which showed a
      strong reduction of IgE(+) cells in the presence of VD. Analyses of molecules
      that are known to affect IgE production (CD23 and IL-6) revealed that these are
      not involved in VD-dependent inhibition of IgE production. By contrast, epsilon
      germ-line transcription was inhibited by VD (41.2+/-26.1%; n=5), as was NF-kappaB
      (p50 and p65) protein expression in stimulated cells. These data show that VD and
      its analogue EB1089 inhibit IgE production of anti-CD40+IL-4-stimulated B cells
      in vitro. The involved mechanism includes epsilon germ-line transcription, NF
      kappaB activation and switch recombination suggesting that complex mechanisms of
      VD action in anti-CD40+IL-4-stimulated B cells are responsible.

PMID- 12432571
TI  - Feto-maternal microchimerism in connective tissue diseases.
AB  - Fetal progenitor cells traffic to the mother during pregnancy and can persist in
      the maternal circulation for many years. Feto-maternal microchimerism has been
      reported in women with scleroderma, but its contribution to the disease
      pathogenesis remains unclear. Furthermore, the involvement of microchimerism in
      other connective tissue diseases is controversial. We studied 243 females, 122 of
      whom had previously carried a male fetus (50 healthy controls, 23 patients with
      scleroderma, and 49 with other connective tissue diseases). The presence of the
      male-specific SRY sequence was analyzed using a kinetic quantitative ELISA PCR
      assay that allows detection of one to three male cells in one million female
      cells. The percentage of SRY-positive samples was not different among women
      having borne son(s): 16% (95% confidence interval 0.07-0.29) in healthy controls,
      21.7% (0.07-0.44) in patients with scleroderma and 25.5% (0.14-0.40) in patients
      with connective tissue diseases (p=0.25). The mean number of fetal cells was
      similar in the three groups. Among the 121 females who never carried a male
      fetus, no healthy woman was SRY positive. However, 33% of patients with
      scleroderma and 22.9% of women with connective tissue diseases were chimeric, a
      phenomenon which might be related to early miscarriage(s). Therefore, feto
      maternal microchimerism is a common event in both healthy controls and patients
      with connective tissue diseases, and is unlikely to represent per se a risk
      factor for these diseases.

PMID- 12432572
TI  - Induction of oral tolerance in experimental antiphospholipid syndrome by feeding
      with polyclonal immunoglobulins.
AB  - Intravenous immunoglobulins (IVIG) contain a wide spectrum of anti-idiotypes
      associated with autoimmune diseases. Since part of these anti-idiotypes may bear
      an internal image of the eliciting antigen, IVIG might be suitable for induction
      of oral tolerance. In the current study we attempted to induce tolerance in an
      experimental model of anti-phospholipid syndrome (APS) by oral administration of
      IVIG. Naive mice were fed with IVIG, or anti-beta 2GPI-specific anti-idiotypic
      IVIG(alpha Id). Significantly diminished humoral response was noted in mice IVIG/
      IVIG-F(ab')(2)or IVIG(alpha Id)-tolerized mice, accompanied by a significant
      attenuation of clinical manifestations. The maximal effect was achieved in the
      mice tolerized before disease induction. Abrogation of T lymphocyte proliferation
      to beta 2GPI was detected in the mice fed with IVIG prior to beta 2GPI
      immunization, mediated by TGFbeta and IL-10 secretion. The tolerance induced by
      IVIG-feeding was nonspecific and could be adoptively transferred to syngeneic
      mice by CD8alpha (+) cells. These CD8alpha (+) T cells, were found to secrete
      high levels of TGFbeta and IL-10. In summary, IVIG-induced oral tolerance has a
      nonspecific immunomodulatory effect in experimental APS, mediated by TGFbeta and
      IL-10-secreting CD8alpha (+) cells. Our results point to a possible application
      of IVIG in the induction of oral tolerance against various autoimmune diseases.

PMID- 12432573
TI  - Mouse MHC class I tetramers that are unable to bind to CD8 reveal the need for
      CD8 engagement in order to activate naive CD8 T cells.
AB  - Although the role of CD8 as a supplier of lck is unchallenged, its role in
      contributing to the formation of a stable complex between class I molecules and
      the TCR, as well as its role as an adhesion molecule, is less clear. To address
      the role of CD8/MHC-I interactions, we generated tetramers composed of H2-K(b)
      molecules with mutations in the alpha 3 domain of H2-K(b) that abolish CD8
      binding. We show that the ability of tetramers to stain and activate CD8 T cells
      is strongly dependent on binding of CD8 to the same class I molecule engaged by
      the TCR. We characterize a mutation in the alpha 3 domain that results in H2-K(b)
      molecules capable of staining specific CD8 T cells with little ensuing
      activation. Although CD8 to some extent serves an adhesive function, this
      contribution is modest and does not substitute for lack of binding of CD8 to the
      class I molecule engaged by the TCR. We show that CD8 and the TCR associate in a
      process independent of binding of CD8 to class I. Our data support the notion
      that CD8 is required to form a stable complex between class I and the TCR.

PMID- 12432574
TI  - Chemokines modulate experimental autoimmune thyroiditis through attraction of
      autoreactive or regulatory T cells.
AB  - A critical event in the pathogenesis of experimental autoimmune thyroiditis (EAT)
      is the entry of thyroid-specific T lymphocytes into the thyroid gland. To
      investigate the role of soluble mediators in that infiltration, we have assayed
      the expression of various chemokines in diseased thyroid glands and in cytokine
      treated cultures of normal thyroid epithelial cells. MCP-1 (monocyte chemotactic
      protein-1) and RANTES are produced during EAT and induced in vitro by IFN-gamma,
      IL-10, TNF-alpha, and IL-1beta. In vitro chemotaxis experiments using immune
      lymph node (LN) cells showed that RANTES attracted mTg-specific responder LN
      cells, whereas MCP-1 attracted mTg-specific CD4(+), CD25(+) regulator cells that
      secreted IL-10. The in vivo transfer of LN T cells attracted in vitro either by
      RANTES or by MCP-1 confirmed their opposite effects on the course of EAT.

PMID- 12432575
TI  - Novel CNBP- and La-based translation control systems for mammalian cells.
AB  - Throughout the development of Xenopus, production of ribosomal proteins (rp) is
      regulated at the translational level. Translation control is mediated by a
      terminal oligopyrimidine element (TOP) present in the 5' untranslated region
      (UTR) of rp-encoding mRNAs. TOP elements adopt a specific secondary structure
      that prevents ribosome-binding and translation-initiation of rp-encoding mRNAs.
      However, binding of CNBP (cellular nucleic acid binding protein) or La proteins
      to the TOP hairpin structure abolishes the TOP-mediated transcription block and
      induces rp production. Based on the specific CNBP-TOP/La-TOP interactions we have
      designed a translation control system (TCS) for conditional as well as adjustable
      translation of desired transgene mRNAs in mammalian cells. The generic TCS
      configuration consists of a plasmid encoding CNBP or La under control of the
      tetracycline-responsive expression system (TET(OFF)) and a target expression
      vector containing a TOP module between a constitutive P(SV40) promoter and the
      human model product gene SEAP (human secreted alkaline phosphatase) (P(SV40)-TOP
      SEAP-pA). The TCS technology showed excellent SEAP regulation profiles in
      transgenic Chinese hamster ovary (CHO) cells. Alternatively to CNBP and La, TOP
      mediated translation control can also be adjusted by artificial phosphorothioate
      anti-TOP oligodeoxynucleotides. Confocal laser-scanning microscopy demonstrated
      cellular uptake of FITC-labeled oligodeoxynucleotides and their localization in
      perinuclear organelles within 24 hours. Besides their TOP-based translation
      controlling capacity, CNBP and La were also shown to increase cap-independent
      translation from polioviral internal ribosomal entry sites (IRES) and La alone to
      boost cap-dependent translation initiation. CNBP and La exemplify for the first
      time the potential of RNA-binding proteins to exert translation control of
      desired transgenes and to increase heterologous protein production in mammalian
      cells. We expect both of these assets to advance current gene therapy and
      biopharmaceutical manufacturing strategies.

PMID- 12432576
TI  - Expression of a plant-derived peptide harboring water-cleaning and antimicrobial
      activities.
AB  - Drinking water is currently a scarce world resource, the preparation of which
      requires complex treatments that include clarification of suspended particles and
      disinfection. Seed extracts of Moringa oleifera Lam., a tropical tree, have been
      proposed as an environment-friendly alternative, due to their traditional use for
      the clarification of drinking water. However, the precise nature of the active
      components of the extract and whether they may be produced in recombinant form
      are unknown. Here we show that recombinant or synthetic forms of a cationic seed
      polypeptide mediate efficient sedimentation of suspended mineral particles and
      bacteria. Unexpectedly, the polypeptide was also found to possesses a
      bactericidal activity capable of disinfecting heavily contaminated water.
      Furthermore, the polypeptide has been shown to efficiently kill several
      pathogenic bacteria, including antibiotic-resistant isolates of Staphylococcus,
      Streptococcus, and Legionella species. Thus, this polypeptide displays the
      unprecedented feature of combining water purification and disinfectant
      properties. Identification of an active principle derived from the seed extracts
      points to a range of potential for drinking water treatment or skin and mucosal
      disinfection in clinical settings.

PMID- 12432577
TI  - Stability of expanded beds during the application of crude feedstock.
AB  - Expanded bed adsorption is an integrated technology that allows the introduction
      of a particle containing feedstock without the risk of blocking the bed. Provided
      a perfectly classified fluidized bed (termed expanded bed) is formed in the crude
      feed, a sorption performance comparable to packed beds is found. During the
      application of biomass containing samples to stable expanded beds an increase in
      bed expansion due to the higher density and viscosity of the feed is encountered.
      In this article it is investigated whether the expanded bed condition is also
      fulfilled during the transition in bed expansion from lower to higher density
      (i.e., from an equilibration buffer to a biomass containing feedstock). Residence
      time distribution analyses were performed by using model systems and a yeast
      suspension during this transition phase. It is shown that in systems in which the
      biomass does not interact with the fluidized stationary phase, the perfectly
      classified fluidization is maintained also during this transition phase
      regardless of the type of feedstock. Additional bed expansion takes place in an
      "ordered" manner without compromising bed stability. In case of biomass/adsorbent
      interactions, a deterioration in bed stability is found directly when the crude
      feed is loaded.

PMID- 12432578
TI  - Biooxidation of n-hexanol by alcohol oxidase and catalase in biphasic and
      micellar systems without solvent.
AB  - Alcohol oxidase from Pichia pastoris together with catalase from bovine liver was
      used to oxidize n-hexanol to hexanal. For this purpose, an aqueous buffer
      solution was mixed with large amounts of hexanol by simple agitation, yielding a
      biphasic system, or by adding the nonionic surfactant Brij 35. Initial velocities
      and reaction yields after 24 h were measured as a function of various parameters
      such as the amounts of enzymes, hexanol, or surfactant. High enzymatic activity
      was determined for hexanol concentrations of between 20 mass% and 80 mass%
      without using any additional organic solvent. The homogenization of the biphasic
      systems with the help of Brij 35 did not yield a significant improvement of the
      bioconversion, which would justify the use of surfactants.

PMID- 12432579
TI  - Metabolic flux analysis of cultured hepatocytes exposed to plasma.
AB  - Hepatic metabolism can be investigated using metabolic flux analysis (MFA), which
      provides a comprehensive overview of the intracellular metabolic flux
      distribution. The characterization of intermediary metabolism in hepatocytes is
      important for all biotechnological applications involving liver cells, including
      the development of bioartificial liver (BAL) devices. During BAL operation,
      hepatocytes are exposed to plasma or blood from the patient, at which time they
      are prone to accumulate intracellular lipids and exhibit poor liver-specific
      functions. In a prior study, we found that preconditioning the primary rat
      hepatocytes in culture medium containing physiological levels of insulin, as
      opposed to the typical supraphysiological levels found in standard hepatocyte
      culture media, reduced lipid accumulation during subsequent plasma exposure.
      Furthermore, supplementing the plasma with amino acids restored hepatospecific
      functions. In the current study, we used MFA to quantify the changes in
      intracellular pathway fluxes of primary rat hepatocytes in response to low
      insulin preconditioning and amino acid supplementation. We found that culturing
      hepatocytes in medium containing lower physiological levels of insulin decreased
      the clearance of glucose and glycerol with a concomitant decrease in glycolysis.
      These findings are consistent with the general notion that low insulin,
      especially in the presence of high glucagon levels, downregulates glycolysis in
      favor of gluconeogenesis in hepatocytes. The MFA model shows that, during
      subsequent plasma exposure, low-insulin preconditioning upregulated
      gluconeogenesis, with lactate as the primary precursor in unsupplemented plasma,
      with a greater contribution from deaminated amino acids in amino acid
      supplemented plasma. Concomitantly, low-insulin preconditioning increased fatty
      acid oxidation, an effect that was further enhanced by amino acid supplementation
      to the plasma. The increase in fatty acid oxidation reduced intracellular
      triglyceride accumulation. Overall, these findings are consistent with the notion
      that the insulin level in medium culture presets the metabolic machinery of
      hepatocytes such that it directly impacts on their metabolic behavior during
      subsequent plasma culture.

PMID- 12432580
TI  - Increase of the yields of eicosapentaenoic and docosahexaenoic acids by the
      microalga Pavlova lutheri following random mutagenesis.
AB  - The high commercial values of eicosapentaenoic (EPA) and docosahexaenoic (DHA)
      acids have driven a strain-improvement program, aimed at increasing the content
      of those fatty acids in the microalga Pavlova lutheri (SMBA 60) as parent strain.
      After a round of mutation using UV-light as mutagenic agent, an isolate strain
      (tentatively called II#2) was obtained, the EPA and DHA contents of which (in %
      dry biomass) were 32.8% and 32.9% higher than those of the control, native
      strain. The final EPA yields, when the cultures were maintained under appropriate
      conditions, were 17.4 and 23.1 mg. g(-1) dry biomass, for the wild-type and the
      II#2 strain, respectively, whereas the final DHA yields were 8.0 and 10.6 mg. g(
      1) dry biomass, respectively. These results suggest that random mutagenesis can
      successfully be applied to increase the yield of n-3 fatty acids by microalgae.

PMID- 12432581
TI  - Endoplasmic reticulum signaling as a determinant of recombinant protein
      expression.
AB  - Generation of functional recombinant proteins requires efficient and undisturbed
      functioning of the ER-Golgi secretory pathway in host cells. In large-scale
      production, where target proteins are highly overexpressed, this pathway can be
      easily congested with unfolded or misfolded proteins. Accumulating evidence
      suggests that, in addition to responsibility for protein processing, ER is also
      an important signaling compartment and a sensor of cellular stress. Two ER
      responses have been described to arise from the overaccumulation of proteins:
      unfolded protein response (UPR) and ER overload response (EOR). UPR and EOR
      employ various mechanisms at the transcriptional and the translational levels to
      deal efficiently and appropriately with encountered stress. This review will
      outline the molecular bases of ER functioning and stress response, highlight the
      relevance of ER signaling to the large-scale cell culture productivity and
      discuss possible approaches to the improvement of the secretion capacities of
      recombinant cells.

PMID- 12432582
TI  - Distributed model of solid waste anaerobic digestion: effects of leachate
      recirculation and pH adjustment.
AB  - A distributed model of solid waste digestion in a 1-D bioreactor with leachate
      recirculation and pH adjustment was developed to analyze the balance between the
      rates of polymer hydrolysis/acidogenesis and methanogenesis during the anaerobic
      digestion of municipal solid waste (MSW). The model was calibrated on previously
      published experimental data generated in 2-L reactors filled with shredded refuse
      and operated with leachate recirculation and neutralization. Based on model
      simulations, both waste degradation and methane production were stimulated when
      inhibition was prevented rapidly from the start, throughout the reactor volume,
      by leachate recirculation and neutralization. An optimal strategy to reduce the
      time needed for solid waste digestion is discussed.

PMID- 12432583
TI  - Thermally triggered purification and immobilization of elastin-OPH fusions.
AB  - A bifunctional fusion protein consisting of organophosphorus hydrolase (OPH) and
      elastin-like polypeptide (ELP) was synthesized for the detoxification of
      organophosphorus compounds. ELPs undergo a reversible phase transition upon an
      increase in temperature, forming hydrophobic aggregates. This thermally triggered
      property of phase transition allows for a simple and rapid means of purifying the
      fusion protein. Over 1,300-fold purification was achieved after only 2 cycles of
      inverse phase transition. The purified fusion protein showed identical kinetic
      properties as the native OPH with only a modest 10% increase in K(m) and a 5%
      decrease of K(cat). The ability of the ELP domain to form collapsed aggregates
      also improved long-term stability of the fusion enzyme. Aggregated ELP-OPH
      retained nearly 100% activity over a span of three weeks. In addition to
      facilitating purification and stability, the ELP moiety served as a hydrophobic
      tag for one-step immobilization of the fusion protein onto hydrophobic surfaces.
      The ELP-OPH was capable of rapidly degrading paraoxon while immobilized. The
      protein also retained ELP functionality of reversible phase transition thereby
      allowing for the regeneration of the treated surface. This technology offers a
      swift and convenient means for purification, immobilization, and regeneration of
      OPH onto a variety of hydrophobic surfaces by simple environmental triggers.

PMID- 12432584
TI  - Unveiling steady-state multiplicity in hybridoma cultures: the cybernetic
      approach.
AB  - Mammalian cells grown in suspension produce waste metabolites such as lactate,
      alanine, and ammonia, which reduce the yield of cell mass and the desired product
      on the nutrients supplied. Previous studies (Cruz et al., 1999; Europa et al.,
      2000; Follstad et al., 1999) have shown that the cells can be made to alter their
      metabolism by starving them on their nutrients in continuous cultures at low
      dilution rates or starting the culture as a fed-batch. This leads to multiple
      steady states in continuous reactors, with some states being more favorable than
      others. Mathematical models that take into account the metabolic regulation that
      leads to these multiple steady states are invaluable tools for bioreactor
      control. In this article we present a cybernetic modeling strategy in which
      Metabolic Flux Analysis (MFA) is used to guide the cybernetic formulation. The
      hybridoma model presented as a result of this strategy considers the partially
      substitutable, partially complementary nature of glucose and glutamine. The
      choice of competitions within the network is guided by MFA and the model is
      successful in explaining the three multiple steady states observed. The
      cybernetic model though identified for the hybridoma experiments of Hu and others
      (Europa et al., 2000) seem generally applicable to mammalian systems as it
      captures the pathways that are common to mammalian cells grown in suspension. The
      model presented here could be used for start-up strategies for continuous
      reactors and model-based feedback control for maintaining high productivity of
      the reactor.

PMID- 12432585
TI  - Metabolic model for glycogen-accumulating organisms in anaerobic/aerobic
      activated sludge systems.
AB  - Glycogen-accumulating organisms (GAO) have the potential to directly compete with
      polyphosphate-accumulating organisms (PAO) in EBPR systems as both are able to
      take up VFA anaerobically and grow on the intracellular storage products
      aerobically. Under anaerobic conditions GAO hydrolyse glycogen to gain energy and
      reducing equivalents to take up VFA and to synthesise polyhydroxyalkanoate (PHA).
      In the subsequent aerobic stage, PHA is being oxidised to gain energy for
      glycogen replenishment (from PHA) and for cell growth. This article describes a
      complete anaerobic and aerobic model for GAO based on the understanding of their
      metabolic pathways. The anaerobic model has been developed and reported
      previously, while the aerobic metabolic model was developed in this study. It is
      based on the assumption that acetyl-CoA and propionyl-CoA go through the
      catabolic and anabolic processes independently. Experimental validation shows
      that the integrated model can predict the anaerobic and aerobic results very
      well. It was found in this study that at pH 7 the maximum acetate uptake rate of
      GAO was slower than that reported for PAO in the anaerobic stage. On the other
      hand, the net biomass production per C-mol acetate added is about 9% higher for
      GAO than for PAO. This would indicate that PAO and GAO each have certain
      competitive advantages during different parts of the anaerobic/aerobic process
      cycle.

PMID- 12432586
TI  - The response of virally infected insect cells to dissolved oxygen concentration:
      recombinant protein production and oxidative damage.
AB  - The effects of dissolved oxygen (DO) concentration on virally infected insect
      cells were investigated in 3-L bioreactor culture. Specifically, cultures of
      Spodoptera frugiperda Sf-9 (Sf-9) and Trichoplusia ni BTI-Tn-5B1-4 (Tn-5B1-4)
      were infected with Autographa californica multiple nucleopolyhedrovirus
      expressing secreted alkaline phosphatase (SEAP). Following infection at a DO
      concentration of 50% air saturation, the DO concentration was adjusted to a final
      value of either 190%, 50%, or 10% air saturation. Recombinant SEAP production,
      cell viability, protein carbonyl content, and thiobarbituric acid reactive
      substances (TBARS) content were monitored. The increases in protein carbonyl and
      TBARS contents are taken to be indicators of protein oxidation and lipid
      oxidation, respectively. DO concentration was found to have no noticeable effect
      on SEAP production or cell viability decline in the Sf-9 cell line. In the Tn-5B1
      4 cell line, cells displayed an increased peak SEAP production rate for 190% air
      saturation and displayed an increased rate of viability decline at increased DO
      concentration. Protein carbonyl content showed no significant increase in the Sf
      9 cell line by 72 h postinfection (pi) at any DO concentration but showed a
      twofold increase at 10% and 50% DO concentration and a threefold increase at 190%
      DO concentration by 72 h pi in Tn-5B1-4 cells. TBARS content was found to
      increase by approximately 50% in Sf-9 cells and by approximately twofold in Tn
      5B1-4 cells by 72 h pi with no clear relationship to DO concentration. It is
      hypothesized that oxygen uptake changes due to the viral infection process may
      bear a relation to the observed increases in protein and lipid oxidation and that
      lipid oxidation may play an important role in the death of virally infected
      insect cells.

PMID- 12432587
TI  - A mutant of the green alga Dunaliella salina constitutively accumulates
      zeaxanthin under all growth conditions.
AB  - A novel mutant (zea1) of the halotolerant unicellular green alga Dunaliella
      salina is impaired in the zeaxanthin epoxidation reaction, thereby lacking a
      number of the beta-branch xanthophylls. HPLC analysis revealed that the zea1
      mutant lacks neoxanthin (N), violaxanthin (V) and antheraxanthin (A) but
      constitutively accumulates zeaxanthin (Z). Under low-light physiological growth
      conditions, the zea1 (6 mg Z per g dry weight or 8 x 10(-16) mol Z/cell) had a
      substantially higher Z content than the wild type (0.2 mg Z per g dry weight or
      0.5 x 10(-16) mol Z/cell). Lack of N, V, and A did not affect photosynthesis or
      growth of the zea1 strain. Biochemical analyses suggested that Z constitutively
      and quantitatively substitutes for N, V, and A in the zea1 strain. This mutant is
      discussed in terms of its commercial value and potential utilization by the algal
      biotechnology industry for the production of zeaxanthin, a high-value bioproduct.

PMID- 12432588
TI  - Doing the right thing and doing it correctly.

PMID- 12432589
TI  - Total quality management in laparoscopic cholecystectomy. Quality of care and
      quality perception in ambulatory laparoscopic cholecystectomy.
AB  - OBJECTIVE: Analysis of acceptance and perception of quality in patients
      undergoing ambulatory laparoscopic cholecystectomy. PATIENTS: 84 consecutive
      patients undergoing elective laparoscopic cholecystectomy within SVS (Servei
      Valencia de Salut) through a special plan for waiting lists. METHODS: A
      prospective analysis of related variables with quality perception evaluated by a
      specialized nurse with no interaction with the surgical team. RESULTS: Ambulatory
      acceptance, 80 percent; return to work or daily activities at 72 hours after
      surgery, 40 percent. Extra need of medical attention was as follows: emergency
      general practitioner 2.7 percent, emergency room attention in 1.3 percent, extra
      telephone interview with the surgeon 6.0 percent. Global estimation of the
      procedure was very good or good by 94.7 percent. CONCLUSIONS: High acceptance
      rate, high quality perception. Up to 20 percent of patients would change from
      ambulatory to traditional surgery, possibly due to cultural factors.

PMID- 12432591
TI  - Success rate of complete extraction of common bile duct stones at first endoscopy
      attempt.
AB  - BACKGROUND AND AIM: ERCP with biliary sphincterotomy is the usual method to
      extract common bile duct stones. However, after sphincterotomy and by means of
      balloons and Dormia baskets not all stones may be extracted during the first
      endoscopy session. We present our experience regarding success rate after first
      ERCP. PATIENTS AND METHODS: 100 consecutive patients were included. All were
      diagnosed with choledocholitiasis by using ERCP. After biliary sphincterotomy,
      attempts to extract stones by means of balloons and Dormia baskets only were
      made. Billroth II gastrectomies and bile duct strictures of any origin were
      excluded. RESULTS: During the first attempt at ERCP, complete stone clearance was
      achieved in 73 patients. Of the remaining 27 patients: 3 underwent surgery for
      choledocholithiasis, 20 had a plastic stent inserted, and 4 needed another ERCP
      for stones having been left in place. Mean extracted stone size was 9.4 mm (+/-
      3.8), and mean non-extracted stone size was 17 mm (+/- 7.3): p < 0.001.
      Male/female ratio was 35/38 in the extracted group and 6/21 in the non-extracted
      group (p < 0.05). There were 11 complications (one patient underwent surgery
      because of duodenal perforation not related to sphincterotomy). There was no
      mortality. CONCLUSIONS: In our experience, after endoscopic biliary
      sphincterotomy and by means of balloons and Dormia baskets a complete stone
      clearance has been achieved in 73% of patients at first endoscopy attempt. Failed
      extraction seems to be related to stone size and was more frequently found in
      women.

PMID- 12432590
TI  - Impact of the recommendations made by Spanish Club for the Study of Helicobacter
      pylori on eradication indications.
AB  - AIM: A Spanish Consensus Conference had been arranged by the Spanish Club for the
      Study of Helicobacter pylori to encourage the use of eradication regimens in
      appropriate indications. The aim of our study was to assess whether the
      publication of these recommendations in November 1999 induced a change on the
      indications of eradication in the referring primary care district. METHOD:
      Patients who had undergone Helicobacter pylori eradication therapy indicated by a
      gastroenterologist and referred to perform the 13C-labelled marked urea breath
      test were evaluated. Indications of eradication therapy were analysed and divided
      in: a) use of Conference recommended procedures (duodenal or gastric ulcer,
      erosive duodenitis, gastric MALT lymphoma and after resection of gastric
      adenocarcinoma); and b) other procedures not included in the recommendations (the
      rest). Indications established during former and latter years of publication of
      the Club's recommendations were compared. RESULTS: A total of 659 established
      eradications in 1999 against 537 in 2000, were studied. Regarding established
      eradications in 1999, 418 out of 659 (63%) followed the recommendations made by
      the Spanish Club, while 241 (37%) did not. In 2000, the proportion of eradication
      therapy administered using the recommendations made by the Spanish Club was
      similar to previous year: 338 (63%) followed the recommendations, against 199
      (37%) that did not (p = not significant). In both years, considering those
      indications not recommended, patients either with superficial chronic gastritis
      with or without dyspepsia or with gastrooesophageal reflux disease were the main
      disorders to indicate eradication therapy. CONCLUSIONS: The recommendations of
      the Spanish Helicobacter pylori Study Club have not triggered a significant
      change after their publication on the indications for Helicobacter pylori
      eradication therapy in the setting studied.

PMID- 12432592
TI  - Genetic susceptibility and regulation of inflammation in Crohn's disease.
      Relationship with the innate immune system.

PMID- 12432594
TI  - [Experimental model of colorectal cancer].

PMID- 12432593
TI  - Clostridium septicum infection associated with perforation of colon diverticulum.
AB  - Non-traumatic or spontaneous gas gangrene by Clostridium septicum is a rare
      infection in humans, characterised by extensive destruction of muscle tissue, a
      mortality rate of 100% if left untreated (1), and often associated with
      haematological or colorectal diseases. An associated malignancy was found in 80%
      of patients with Clostridium septicum infection: 34% had a colorectal carcinoma
      and 40% had a haematological malignancy (2); the infection usually lies in an
      often-ulcerated intestinal lesion (3). We report here a case of spontaneous gas
      gangrene by Clostridium septicum in the right thigh due to perforation of a
      diverticulum in the sigmoid colon.

PMID- 12432595
TI  - [Abdominal actinomycosis].

PMID- 12432596
TI  - [Report of 2 cases of rhabdoid tumor originating in the small intestine].

PMID- 12432597
TI  - [Submucosal lipoma of the colon].

PMID- 12432598
TI  - [Systemic sclerosis and intestinal inflammatory disease].

PMID- 12432599
TI  - [Consequences of the premenstrual stress syndrome in women's life].
AB  - This study has as objective to identify the possible consequences of the Syndrome
      of the Pre-menstrual Tension in the woman's life. Through the questionnaire, we
      identified disturb related to physical and emotional discomfort and as
      consequences the alterations in the relationships involving son,
      husband/boyfriend and family, as well as in the work atmosphere.

PMID- 12432600
TI  - [Review of nursing literature on arterial hypertension in pregnancy].
AB  - Nursing literature review, related to pregnancy induced hypertension, from 1980
      to 1999, with the objective of identifying the tendencies of those publications.
      58 publications were found in the English, Portuguese and Spanish languages,
      being 52 articles from periodicals and 6 monographs, dissertations and thesis.
      Most of the articles was published in nursing periodicals (84.6%), prevailing the
      English ones (73.1%), written by academicians, with sole writing. The focuses
      nursing care (25.9%) and pharmacological treatment predominated (25.9%). An
      increment was observed in the publications starting from 1985. The national
      publications concerning the pregnancy induced hypertension are still incipient.

PMID- 12432601
TI  - [Problem solving training: intervention for depressed women].
AB  - This is an exploratory and descriptive study which has aimed from the Problem
      Solving Training accomplished in 12 group sessions with women admitted to
      hospital suffering from depression, to evaluate the effect of this intervention.
      BECK Depression Scale, SPILBERGER Anxiety State Scale, MCKAY Problem List, a
      Written Simulation Exercises about coping in five situations and an interview
      about the perception of group participation were used for the assessment of the
      patients. It was concluded that the training had positive effects about the women
      as for the technique used as for the communication established and for group
      therapeutic factors which appeared in this scenery.

PMID- 12432602
TI  - [Care of women victims of spouse violence from the Heidegger's perspective of the
      technology world].
AB  - This is concerned with a reflexive text that approaches the subject of the care
      to women that suffer conjugal violence in an analytic perspective of the world of
      the technique, developed from conceptions and concepts of Martin Heidegger,
      contemporary philosopher of phenomenology. The care of women that suffer conjugal
      violence appears as one that considers values, decision, trust to care, knowledge
      and care actions and its consequences.

PMID- 12432603
TI  - [Oral history of life: in search of the meaning of hemodialysis in chronic renal
      patients].
AB  - This article has the objective to show the use of life oral history as
      methodological framework for qualitative data collection and analysis, aimed to
      understand the meaning of hemodialysis and the impact of this therapeutic
      modality of treatment in the patient's life in the Hemodialysis Unity at the
      University Hospital at the University of Sao Paulo.

PMID- 12432604
TI  - [Body experience workshop: movement, reflection, and self-appropriation].
AB  - The present study approaches an innovative activity in the Nursing teaching area.
      This activity, theoretical-experiential, known as the "Corporal Experience
      Workshop" is intended to promote body awareness, understand the fundamentals
      related to corporality, and improve the reflections about the own self and the
      "other's" body when undergoing nursing care. The investigation was carried out
      with first grade undergraduation Nursing students of the Universidade Federal de
      Sao Paulo--UNIFESP/EPM, and presents a descriptive study where the phenomenon is
      described and explained, and at the same time, it seeks to investigate some
      aspects concerning experiences the participating 202 students were submitted to
      during the activities developed in the workshops, during in the years 1997, 1998
      and 1999.

PMID- 12432605
TI  - [Ergonomics in the transfer of patients: a study carried out with workers of a
      transportation center at a university hospital].
AB  - The purpose of this study was to evaluate ergonomic aspects involved in using a
      stretcher and a wheel chair to transfer patients. 249 transfers carried out by
      the workers of a university hospital lifting sector were observed. The
      observations showed that the idea of having a team to transfer patients has to be
      stimulated but the members of the team require specific training in handling and
      transferring patients. Mechanical equipment and other devices should also be
      available.

PMID- 12432606
TI  - [Home care for the elderly: profile of the formal caregiver -- Part I].
AB  - The frail elderly, maintained in its home, request specific cares, which are
      accomplished many times by people contracted, denominated formal caregivers, With
      the increase of offer of these people's work and the shortage on its profile, we
      developed a study with 41 advertisers that offered its services in two newspapers
      of larger circulation in the city of Campinas, Sao Paulo, with the following
      objectives: 1. to characterize these caregivers and 2. to verify the activities
      proposals for care to the elderly. In the present work the referring data are
      presented the caregivers' characteristics as: to the sex, the age, the formation
      and previous experience, schedule readiness and demanded remuneration.

PMID- 12432607
TI  - [Overview of nursing sciences: analytical sources of care practices].
AB  - This essay goals to present a reflection about issues of research and nursing
      practice in Brazil, in the context of the end of Second Millnnium. It criticizes
      current and traditional framework adopted in researches and practices. Finally it
      suggests the adoption of new paradigm in the researches and practices of nursing.

PMID- 12432608
TI  - [Nursing: idealism and realism. Perspectives of nursing students on the nursing
      profession].
AB  - Exploratory and descriptive study with the following objectives: to identify the
      nursing students' feelings related to the undergraduate course and their
      perception towards the nursing profession. After the four-year course, 57.4% of
      students perceived nursing in a positive way as a profession for the future,
      valued, recognised, compensating even with some limitations. However, 25% of
      students still perceived nursing as a mechanical, manual and sacrificed
      profession, with a limited scientific vision and with a gap between theory and
      practice and as a consequence a lower recognition by the society. If current
      trends are maintained, the nurse's value would be much greater in the next
      decades within the Brazilian society according to 61% of respondents.

PMID- 12432609
TI  - [Organizational culture according to the perception of nursing service directors
      in hospitals of different ethnic groups].
AB  - The Nursing Service Managers from five Hospitals, all created and maintained by
      immigration communities, in Sao Paulo city, express in this study the influence
      of the culture of the organization on their job performance. The verbal report of
      each of them in na interview, starting from a template, has evidenced the
      identify the professional life, the remaining on the institution as well the
      relationship with other managers and with the individuals of the ethnic group.

PMID- 12432610
TI  - [Iatrogenic occurrences in health care: difficulties involved in the subject
      study].
AB  - The author examines the main difficulties involved in the study of iatrogenic
      occurrences in health care. Conceptual problems and difficulties related to
      research methodologies issues are discussed.

PMID- 12432611
TI  - [The process of socialization of nurses at an intensive care center].
AB  - The objective of this study was to understand the process of socialization of the
      new professionals that are part of the subculture of an intensive care unit
      (ICU). Considering that the ICU is a subculture of the hospital, and that the
      professionals share symbols and meanings that were developed through social
      interactions in the context of Intensive Care the symbolic interacionism and the
      ethnographic description were used as a theoretical and methodological basis for
      this study. The participant observation, the ethnographic interview and the
      documented analysis were used to understand the process of internalization of the
      symbolic universe of the ICU. The results showed that in the socialization
      process quality values, discipline, commitment, sense of unit, rules and
      organizational values were reproduced. This process is permeated with feelings of
      insecurity, anxiety, distress, incompetence and fear. The causes for these
      feelings have a strong component in the previous nonexistence and in the gap of
      professional career. This process occurs in a formal and informal way but is
      always referred as difficult, lonely and sometimes shared.

PMID- 12432612
TI  - Administration of chemotherapy: evaluating a framework for developing practice.

PMID- 12432614
TI  - Supporting the parents of adolescents with conduct disorder.

PMID- 12432613
TI  - Diabetic children and foot care: are we heading in the right direction?
AB  - This study investigated parents' knowledge and understanding of foot care for
      their child with diabetes mellitus (Type I). Thirty parents of diabetic children
      in four out-patient clinics within the same trust (not the author's place of
      work) were asked to complete a questionnaire. There was a clear lack of parental
      knowledge concerning the children's foot care. Only 40 per cent of the children
      had had their feet examined by a healthcare professional since diagnosis; a
      recommendation in the Diabetes UK guidelines (2000). Only sixty-three per cent of
      families had ever received any foot care advice, which is consistent with the
      results of a study by Barnett et al in 1995. Parents wanted more verbal and
      written foot care advice. More emphasis needs to be placed on foot care education
      and regular foot examinations are essential if foot ulcers and limb amputations
      are to be prevented in later life.

PMID- 12432615
TI  - Play preparation for children with special needs.

PMID- 12432616
TI  - Introducing a protocol for procedural pain.
AB  - Children endure painful experiences while in hospital, often without
      understanding why. This study aimed to assess whether the use of a protocol for
      assessing, preparing and distracting children during procedures such as
      cannulation would decrease levels of pain and distress reported by children,
      parents and nurses. Pain thermometers and 'scary faces' were used as tools to
      assess pain and anxiety levels of 82 children. The results were ambiguous and
      inconsistent. However, nurses have a responsibility to reduce children's pain and
      anxiety as much as possible and distraction is one way of doing this.

PMID- 12432617
TI  - 'I want to be a nurse, but...': a student's experience of clinical placements.

PMID- 12432618
TI  - Paediatric pharmacological principles: an update. Part 1: Drug development and
      pharmacodynamics.

PMID- 12432619
TI  - [Perinatal health in danger].

PMID- 12432620
TI  - [Nicotine, major risk factor in sudden infant death].

PMID- 12432621
TI  - [Young people's alarming ignorance about AIDS].

PMID- 12432622
TI  - [Ethical and deontological limits of genetics].

PMID- 12432623
TI  - [Genetic tests in pediatrics].

PMID- 12432625
TI  - [Prenatal diagnosis of triplet expansion disease. Example of Huntington chorea].

PMID- 12432624
TI  - [Prenatal diagnosis].

PMID- 12432626
TI  - [Genetics. A child at what price?].

PMID- 12432627
TI  - [That which genetics cannot do...].

PMID- 12432628
TI  - [Incarceration in juvenile detention of Alexander, an adolescent insulin
      dependent diabetic].

PMID- 12432629
TI  - [Filiation and recognition, what are the child's rights?].

PMID- 12432630
TI  - [Critical emergencies. 3/7 Duodenal atresia].

PMID- 12432632
TI  - [HIV/AIDS: "sharing" the management of patients].

PMID- 12432633
TI  - [Nurse's aides, a profession of the future].

PMID- 12432634
TI  - [The contrary adolescent: examples from school].

PMID- 12432635
TI  - [Development of a care unit in a school].

PMID- 12432636
TI  - [Piercing: how to unite beauty and safety? Interview by Corinne Taeron].

PMID- 12432637
TI  - [Preadolescent addictive behavior].

PMID- 12432638
TI  - [Eating disorders in adolescence].

PMID- 12432639
TI  - [Tobacco: quitting without superfluous weight gain].

PMID- 12432640
TI  - [Nursing students take flight].

PMID- 12432641
TI  - [Peritoneal dialysis].

PMID- 12432642
TI  - [Phase 3, a spring-board in the life of the convalescent cardiac patient].

PMID- 12432643
TI  - [Resolution on paramedical professions (art. L. 4391-1 et s)].

PMID- 12432644
TI  - [Omeprazole. Antiulcer and gastric anti-secretory agent: one of the most
      prescribed drugs in France].

PMID- 12432645
TI  - [What future for long term care facilities?].

PMID- 12432646
TI  - [Abuse, towards better protection for the elderly?].

PMID- 12432647
TI  - [Autonomic 2002, professionalization of home care and development of temporary
      alternatives].

PMID- 12432648
TI  - [Pain and aging: normal, inevitable or nursing challenge?].

PMID- 12432649
TI  - [Clinical and therapeutic aspects of pain].

PMID- 12432650
TI  - [Pain protocol].

PMID- 12432652
TI  - [Touch-massage, a good thing for elderly patients].

PMID- 12432651
TI  - [Expression and rehabilitation in geriatrics].

PMID- 12432653
TI  - [From the need to eat to the pleasure of nourishment].

PMID- 12432654
TI  - [Risk factors in burned elderly patients].

PMID- 12432655
TI  - [Pleasure and knowledge in the caring relationship with demented elderly
      patients].

PMID- 12432656
TI  - [First results of the Credes study on home care services].

PMID- 12432657
TI  - Workforce planning. Grow your own nurses.

PMID- 12432658
TI  - Security at work. Sign of the times.

PMID- 12432659
TI  - Do RAEs accurately measure the quality of nursing research?

PMID- 12432660
TI  - Meeting of minds.

PMID- 12432661
TI  - The voice of reason.

PMID- 12432662
TI  - The value of research in clinical decision-making.
AB  - This article examines the application of research-based information in clinical
      decision-making. In doing so it draws on the findings (and work in progress) of
      two research projects that seek to contribute to establishing the potential for
      evidence-based approaches in nursing. The authors conclude that understanding the
      types of decisions nurses make, their clinical uncertainties and unanswered
      questions is of value to both researchers, policy makers and practitioners.

PMID- 12432663
TI  - Organising UK cancer nursing services: a review.
AB  - This article describes an NTResearch survey which outlines how UK cancer nursing
      services have evolved over the past seven years in response to changes in
      government policy.

PMID- 12432664
TI  - Palliative care nursing. Part 2. Addressing bereavement issues through education.
AB  - Nurses working in acute care often have to support people who have experienced a
      bereavement. It is important that nurses understand the issues that arise during
      this delicate time so that they can confidently administer the appropriate care
      and support. This article describes how Salford Royal Hospitals NHS Trust
      developed a programme to enhance the quality of nursing care given to dying
      patients and their relatives. It focused particularly on instances of sudden and
      unexpected death and aimed to develop nurses' reflective specialist knowledge,
      skills and attitudes. Evaluation has shown that the programme has increased
      nurses' confidence in providing support to the bereaved and in this way the
      project has improved the services offered by the trust.

PMID- 12432665
TI  - How patients and staff view the use of seclusion.
AB  - Some patients have found seclusion helpful and it is regarded as an assertive
      treatment by its advocates. Others see it as a highly invasive and abusive
      experience. This study, which was carried out on a unit for people with
      challenging behaviours, explored this contentious issue from the perspective of
      both staff and patients. Areas of agreement and disagreement were identified with
      a view to exploring the impact of seclusion on nurse-patient relationships. A key
      conclusion was that the quality of the relationship was maintained and not
      damaged by the act of secluding a patient, which may merit a wider study.

PMID- 12432666
TI  - Nurse prescribing.
AB  - This article and that overleaf continue this series on a range of topics aimed at
      helping you to update your knowledge and assist you with your continuing
      professional development (PREP Requirements).  The number of hours you spend
      studying the material in this article should be recorded in your professional
      portfolio (see Study Hours panel below).

PMID- 12432667
TI  - Who's teaching whom? A study of family education in brain injury.
AB  - Acquired brain injury affects every aspect of life-cognition, emotional response,
      physical ability, and behavior. Although the changes affect the person with the
      brain injury most directly, people who provide care also experience changes.
      Family members play a critical role in the long-term rehabilitation of a person
      with a brain injury. The demands involved can deplete the most resourceful of
      families. Therefore, they must have multiple resources available to them to
      ensure the best possible outcome for the brain-injured member. A formalized
      family education program is an important resource in helping family members
      understand the brain injury and their ability to cope with and assist in the
      rehabilitation process (Maitz & Sachs, 1995). This article reports a qualitative
      study that measured the perceptions of 15 families that received an educational
      program about the care of a person with a brain injury.

PMID- 12432668
TI  - The meaning of communication: experiences with augmentative communication
      devices.
AB  - This study is a secondary analysis of data collected from end-users of
      Augmentative and Alternative Communication (AAC) devices as part of a project of
      the Rehabilitation Engineering Research Center on Technology Transfer (T2RERC).
      The original data, obtained from a Web-based focus group, were used to identify
      unmet consumer needs in existing AAC devices. The purpose of the secondary
      analysis was to give context to the original study through phenomenological
      interpretation of the narratives, thereby gaining an understanding of the common
      meanings and shared experiences and practices of people who use AAC technology.
      Underlying this study is the interpretive approach of Heideggerian hermeneutics;
      through reflective thinking, understanding of the human situation of AAC users in
      everyday life is uncovered or extended. Six themes and one constitutive pattern
      emerged to explain the participants' experiences with AAC devices: (a)
      maintaining effective communication, (b) interacting in various situations, (c)
      AAC device-imposing limitations, (d) wading through prepackaged technology, (e)
      AAC device giving more than a voice, (f) accepting the AAC device. The
      constitutive pattern was communication technology enables humanness. This
      information will make rehabilitation nurses aware of the value of the AAC device
      for the users and the limitations that the technology may impose on the users, as
      well as the need for others to accept the device. Nurses gaining this
      understanding may facilitate integration of AAC systems and the development of
      patient/nurse communication partnerships.

PMID- 12432669
TI  - Individualized music--a different approach to the restraint issue.
AB  - Rehabilitation nurses who work with geriatric patients are concerned about
      reliance on physical restraints, as are all nurses. Controversy exists as to the
      benefits and risks, as well as the ethical and legal consequences, of their use.
      Nurses are ambivalent about using restraints, believing that they affect
      patients' freedom, self-respect, and self-reliance; they also often believe that
      there are no appropriate alternatives. This pilot study explored the use of music
      as a potential alternative to using physical restraints with hospitalized
      patients. The research question was: Will patients have more positive behaviors,
      as measured by the Restraint Music Response Instrument (RMRI), while out of
      restraints and listening to preferred music compared with the patients not
      listening to music who are out of restraints while being observed? Forty medical
      surgical patients participated in the study and were randomized into either the
      experimental group (music) or the control group (no music). The mean age of the
      21 males and 19 females was 76.6 years (range 56-94). A t test for equality of
      means was used to determine if there were differences in the number of positive
      and negative behaviors in the preintervention, intervention, and postintervention
      phases between the two groups. There was a significant difference (p < .01) in
      behaviors during the intervention phase. Patients who listened to preferred music
      had more positive behaviors while out of restraints than patients who were out of
      restraints but not exposed to music.

PMID- 12432670
TI  - The effects of music on the rate of perceived exertion and general mood among
      coronary artery bypass graft patients enrolled in cardiac rehabilitation phase
      II.
AB  - The purpose of the study was to identify the effect of music on perceived
      exertion and mood in 30 coronary artery bypass graft patients during cardiac
      rehabilitation. The modified Borg Scale of Perceived Exertion (RPE) and the
      Rejeski Feeling Scale (FS) were the dependent variables. Group A subjects
      exercised with music and Group B subjects exercised without music as they rated
      their perceived exertion and mood. The use of music to reduce perceived exertion
      was not supported (p = 0.16). However, Group A members reported significantly
      enhanced mood while exercising to music and Group B members reported a
      significantly decreased mood without music (p = 0.0006). Enhancement of mood
      might lead to increased compliance with a regular exercise routine.

PMID- 12432671
TI  - Beliefs, perceptions, and practices related to osteoporosis risk reduction among
      women with multiple sclerosis.
AB  - Women with multiple sclerosis (MS) are at increased risk for osteoporosis and
      fracture; in turn, osteoporosis has the potential to exacerbate the physical
      limitations imposed by MS. This qualitative study explored the understanding of
      osteoporosis risk and risk reduction, strategies being used to reduce risk, and
      related beliefs among 27 women with MS. Participants were recruited at a regional
      MS Society meeting. The women completed personal data forms, and responded to
      open-ended questions during taped interviews, which were transcribed and
      subjected to comparative content analysis. Five themes emerged from the data:
      knowledge about osteoporosis, sense of vulnerability, interactions with
      healthcare providers, preventive actions, and sense of control. All of the women
      had some knowledge about osteoporosis risk reduction, and most of the women were
      actively attempting to reduce their risk. However, few of the women had full
      knowledge, or were doing all that they might do, to minimize their risk. Few of
      their healthcare providers had discussed the issue or responded to their
      concerns, even when women had histories of multiple fractures. The women did
      comprehened their increased risk and most attempted to manage it, although input
      was lacking from healthcare providers about osteoporosis risk reduction.

PMID- 12432672
TI  - [Nursing competence, the reverse countdown has started].

PMID- 12432673
TI  - [Nursing, a profession with still a future?].

PMID- 12432674
TI  - [Palliative care, how to be helpful?].

PMID- 12432675
TI  - [Shortage of nurses increases in Ile-de-France].

PMID- 12432676
TI  - [Intimacy and nursing function].

PMID- 12432677
TI  - [Reunion Island, between modern care and Creole tradition].

PMID- 12432678
TI  - [The necessity to coordinate in home care services].

PMID- 12432679
TI  - [Classification and management of severely burned patients].

PMID- 12432680
TI  - [Nursing care of burned patients].

PMID- 12432681
TI  - [Daily care of the burned patient, an act of faith].

PMID- 12432682
TI  - [Psychological approach in the severely burned patient].

PMID- 12432683
TI  - [Methods of covering severe burns].

PMID- 12432684
TI  - [Nursing care. The quality of life in question].

PMID- 12432685
TI  - [Recognition of the burn centers in the French health system].

PMID- 12432686
TI  - [A. Classification of antibiotics. 4/12--The quinolones].

PMID- 12432687
TI  - [Identification and coping strategies in professional burnout].